PMID- 24947666 TI - Identification of the in vivo function of the high-efficiency D-mannonate dehydratase in Caulobacter crescentus NA1000 from the enolase superfamily. AB - The d-mannonate dehydratase (ManD) subgroup of the enolase superfamily contains members with varying catalytic activities (high-efficiency, low-efficiency, or no activity) that dehydrate d-mannonate and/or d-gluconate to 2-keto-3-deoxy-d gluconate [Wichelecki, D. J., et al. (2014) Biochemistry 53, 2722-2731]. Despite extensive in vitro characterization, the in vivo physiological role of a ManD has yet to be established. In this study, we report the in vivo functional characterization of a high-efficiency ManD from Caulobacter crescentus NA1000 (UniProt entry B8GZZ7) by in vivo discovery of its essential role in d glucuronate metabolism. This in vivo functional annotation may be extended to ~50 additional proteins. PMID- 24947667 TI - Control of reaction pathways in the photochemical reaction of a quinone with tetramethylethylene by metal binding. AB - The present study reports a novel supramolecular photochemical reaction that focuses on the direct electronic interactions between a host reaction substrate and guest metal salts. The reaction pathways in the photochemical reactions of quinone derivatives bearing a methoxy group and a long oligoether sidearm QEn (n = 0 and 3) with tetramethylethylene (TME) are changed upon noncovalent complexations of the host reactant with alkali and alkaline earth metal ions and a transition metal salt. The photochemical reaction of QEn with TME provides a mixture of [2 + 2] cycloadducts 1aEn and 1bEn, hydroquinone H2QEn, and monoallyl ether adducts of hydroquinones 2aEn and 2bEn. The photochemical reaction proceeds by the photoinduced electron transfer mechanism, where photoirradiation brings about formation of a radical ion pair [QEn(-), TME(+)] as the primary intermediate. We found that the yields and selectivity of these photoproducts are changed upon electronic interactions of QEn(-) with the metal salts. The photochemical reaction in the absence of metal salts provides H2QEn as its major product, whereas QE3, having the long sidearm, dominantly produces 2aE3 at the expense of 1aE3, 1bE3, and H2QE3 when it forms a size-favorable host-guest complex with divalent Ca(2+). In contrast, QEn selectively provides oxetanes 1aEn and 1bEn in the presence of Pd(OAc)2, which can form complexes with the quinone through metal-olefin and coordination interactions in the ground and photoexcited states of the quinone. PMID- 24947668 TI - Tyrosinase-catalyzed site-specific immobilization of engineered C-phycocyanin to surface. AB - Enzymatic crosslinking of proteins is often limited by the steric availability of the target residues, as of tyrosyl side chains in the case of tyrosinase. Carrying an N-terminal peptide-tag containing two tyrosine residues, the fluorescent protein C-phycocyanin HisCPC from Synechocystis sp. PCC6803 was crosslinked to fluorescent high-molecular weight forms with tyrosinase. Crosslinking with tyrosinase in the presence of L-tyrosine produced non fluorescent high-molecular weight products. Incubated in the presence of tyrosinase, HisCPC could also be immobilized to amino-modified polystyrene beads thus conferring a blue fluorescence. Crosslinking and immobilization were site specific as both processes required the presence of the N-terminal peptide in HisCPC. PMID- 24947670 TI - Variations and inter-relationship in outcome from emergency admissions in England: a retrospective analysis of Hospital Episode Statistics from 2005-2010. AB - BACKGROUND: The quality of care delivered and clinical outcomes of care are of paramount importance. Wide variations in the outcome of emergency care have been suggested, but the scale of variation, and the way in which outcomes are inter related are poorly defined and are critical to understand how best to improve services. This study quantifies the scale of variation in three outcomes for a contemporary cohort of patients undergoing emergency medical and surgical admissions. The way in which the outcomes of different diagnoses relate to each other is investigated. METHODS: A retrospective study using the English Hospital Episode Statistics 2005-2010 with one-year follow-up for all patients with one of 20 of the commonest and highest-risk emergency medical or surgical conditions. The primary outcome was in-hospital all-cause risk-standardised mortality rate (in-RSMR). Secondary outcomes were 1-year all-cause risk-standardised mortality rate (1 yr-RSMR) and 28-day all-cause emergency readmission rate (RSRR). RESULTS: 2,406,709 adult patients underwent emergency medical or surgical admissions in the groups of interest. Clinically and statistically significant variations in outcome were observed between providers for all three outcomes (p < 0.001). For some diagnoses including heart failure, acute myocardial infarction, stroke and fractured neck of femur, more than 20% of hospitals lay above the upper 95% control limit and were statistical outliers. The risk-standardised outcomes within a given hospital for an individual diagnostic group were significantly associated with the aggregated outcome of the other clinical groups. CONCLUSIONS: Hospital-level risk-standardised outcomes for emergency admissions across a range of specialties vary considerably and cross traditional speciality boundaries. This suggests that global institutional infra-structure and processes of care influence outcomes. The implications are far reaching, both in terms of investigating performance at individual hospitals and in understanding how hospitals can learn from the best performers to improve outcomes. PMID- 24947669 TI - Phosphorylation dependence and stoichiometry of the complex formed by tyrosine hydroxylase and 14-3-3gamma. AB - Phosphorylated tyrosine hydroxylase (TH) can form complexes with 14-3-3 proteins, resulting in enzyme activation and stabilization. Although TH was among the first binding partners identified for these ubiquitous regulatory proteins, the binding stoichiometry and the activation mechanism remain unknown. To address this, we performed native mass spectrometry analyses of human TH (nonphosphorylated or phosphorylated on Ser19 (TH-pS19), Ser40 (TH-pS40), or Ser19 and Ser40 (TH pS19pS40)) alone and together with 14-3-3gamma. Tetrameric TH-pS19 (224 kDa) bound 14-3-3gamma (58.3 kDa) with high affinity (Kd = 3.2 nM), generating complexes containing either one (282.4 kDa) or two (340.8 kDa) dimers of 14-3-3. Electron microscopy also revealed one major population of an asymmetric complex, consistent with one TH tetramer and one 14-3-3 dimer, and a minor population of a symmetric complex of one TH tetramer with two 14-3-3 dimers. Lower phosphorylation stoichiometries (0.15-0.54 phosphate/monomer) produced moderate changes in binding kinetics, but native MS detected much less of the symmetric TH:14-3-3gamma complex. Interestingly, dephosphorylation of [(32)P]-TH-pS19 was mono-exponential for low phosphorylation stoichiometries (0.18-0.52), and addition of phosphatase accelerated the dissociation of the TH-pS19:14-3-3gamma complex 3- to 4-fold. All together this is consistent with a model in which the pS19 residues in the TH tetramer contribute differently in the association to 14 3-3gamma. Complex formation between TH-pS40 and 14-3-3gamma was not detected via native MS, and surface plasmon resonance showed that the interaction was very weak. Furthermore, TH-pS19pS40 behaved similarly to TH-pS19 in terms of binding stoichiometry and affinity (Kd = 2.1 nM). However, we found that 14-3-3gamma inhibited the phosphorylation rate of TH-pS19 by PKA (3.5-fold) on Ser40. We therefore conclude that Ser40 does not significantly contribute to the binding of 14-3-3gamma, and rather has reduced accessibility in the TH:14-3-3gamma complex. This adds to our understanding of the fine-tuned physiological regulation of TH, including hierarchical phosphorylation at multiple sites. PMID- 24947665 TI - Life at the border: adaptation of proteins to anisotropic membrane environment. AB - This review discusses main features of transmembrane (TM) proteins which distinguish them from water-soluble proteins and allow their adaptation to the anisotropic membrane environment. We overview the structural limitations on membrane protein architecture, spatial arrangement of proteins in membranes and their intrinsic hydrophobic thickness, co-translational and post-translational folding and insertion into lipid bilayers, topogenesis, high propensity to form oligomers, and large-scale conformational transitions during membrane insertion and transport function. Special attention is paid to the polarity of TM protein surfaces described by profiles of dipolarity/polarizability and hydrogen-bonding capacity parameters that match polarity of the lipid environment. Analysis of distributions of Trp resides on surfaces of TM proteins from different biological membranes indicates that interfacial membrane regions with preferential accumulation of Trp indole rings correspond to the outer part of the lipid acyl chain region-between double bonds and carbonyl groups of lipids. These "midpolar" regions are not always symmetric in proteins from natural membranes. We also examined the hydrophobic effect that drives insertion of proteins into lipid bilayer and different free energy contributions to TM protein stability, including attractive van der Waals forces and hydrogen bonds, side-chain conformational entropy, the hydrophobic mismatch, membrane deformations, and specific protein-lipid binding. PMID- 24947671 TI - [Sequelae after harvesting latissimus dorsi flap and derivates--review]. AB - INTRODUCTION: The latissimus dorsi (LD) appears as a therapeutic option in many cases of reconstruction. Its large surface and reliability make it an ideal therapeutic choice. Since its initial description in 1896 by Tansini, many publications have been reported on its clinical application and the low donor site morbidity. However, harvesting of LD can be a source of functionnal and aesthetic sequelae. The purpose of this study is to provide a state of the science regarding the potential functional, aesthetic and pain sequelae related to harvesting of LD flap in its original description, but also in its modifications (muscle-sparing LD flap [MSLD-flap] and thoracodorsal artery perforator flap [TAP-flap]). MATERIAL AND METHODS: A review of the literature was realized, the database PubMed was chosen. Keywords used for the research were: LD flap; LD flap morbidity; donor site sequelae of LD flap; TAP-flap AND donor site morbidity; MSLD-flap AND donor site morbidity. RESULTS: Literature report suggests that harvesting of the whole LD muscle flap can provoke pain and functional deficit which diminish and even tend to disappear over time due to functional replacement by the other muscle groups. The partial (MSLD) or total (TAP-flap) preservation of the muscle leads to less pain, functional and aesthetic sequelae. These results are supported by objective, reliable and reproducible studies. CONCLUSION: Well-targeted and well-designed studies could allow for better evaluation of the advantages and disadvantages of each technique. This would lead to better selection of candidates for each technique. PMID- 24947672 TI - ATG5 defines a phagophore domain connected to the endoplasmic reticulum during autophagosome formation in plants. AB - Autophagosomes are the organelles responsible for macroautophagy and arise, in yeast and animals, from the sealing of a cup-shaped double-membrane precursor, the phagophore. How the phagophore is generated and grows into a sealed autophagosome is still not clear in detail, and unknown in plants. This is due, in part, to the scarcity of structurally informative, real-time imaging data of the required protein machinery at the phagophore formation site. Here we find that in intact living Arabidopsis tissue, autophagy-related protein ATG5, which is essential for autophagosome formation, is present at the phagophore site from early, sub-resolution stages and later defines a torus-shaped structure on a flat cisternal early phagophore. Movement and expansion of this structure are accompanied by the underlying endoplasmic reticulum, suggesting tight connections between the two compartments. Detailed real-time and 3D imaging of the growing phagophore are leveraged to propose a model for autophagosome formation in plants. PMID- 24947673 TI - Minireview: Central Sirt1 regulates energy balance via the melanocortin system and alternate pathways. AB - In developed nations, the prevalence of obesity and its associated comorbidities continue to prevail despite the availability of numerous treatment strategies. Accumulating evidence suggests that multiple inputs from the periphery and within the brain act in concert to maintain energy metabolism at a constant rate. At the central level, the hypothalamus is the primary component of the nervous system that interprets adiposity or nutrient-related inputs; it delivers hormonal and behavioral responses with the ultimate purpose of regulating energy intake and energy consumption. At the molecular level, enzymes called nutrient energy sensors mediate metabolic responses of those tissues involved in energy balance ( 1 ). Two key energy/nutrient sensors, mammalian target of rapamycin and AMP activated kinase, are involved in the control of food intake in the hypothalamus as well as in peripheral tissues ( 2 , 3 ). The third more recently discovered nutrient sensor, Sirtuin1 (Sirt1), a nicotinamide adenine dinucleotide-dependent deacetylase, functions to maintain whole-body energy homeostasis. Several studies have highlighted a role for both peripheral and central Sirt1 in regulating body metabolism, but its central role is still heavily debated. Owing to the opaqueness of central Sirt1's role in energy balance are its cell-specific functions. Because of its robust central expression, targeting cell-specific downstream mediators of Sirt1 signaling may help to combat obesity. However, when placed in the context of a physiologically relevant model, there is compelling evidence that central Sirt1 inhibition in itself is sufficient to promote negative energy balance in both the lean and diet-induced obese state. PMID- 24947674 TI - Research resource: comparison of gene profiles from wild-type ERalpha and ERalpha hinge region mutants. AB - We showed previously that the hinge region of estrogen receptor (ER) alpha is involved in mediating its actions. The hinge 1 (H1) ERalpha mutant has disrupted nuclear localization and has lost interaction with c-JUN, but retains estrogen response element (ERE)-mediated functions. The hinge 2 + nuclear export sequence (H2NES) ERalpha mutant does not maintain nuclear translocation with hormone and no longer activates ERE target genes but does retain a nongenomic, nonnuclear, rapid-action response. Herein, we used the human endometrial cancer Ishikawa stable cell lines (Ishikawa/vector, Ishikawa/wild-type [WT] ERalpha, Ishikawa/H1 ERalpha, or Ishikawa/H2NES ERalpha) to characterize the biological activities of these 2 ERalpha hinge region mutants. We confirmed by confocal microscopy increased cytoplasmic ERalpha in the H1 ERalpha cell line and full cytoplasmic ERalpha localization in the H2NES ERalpha cell line. Luciferase assays using the 3xERE reporter showed activation of H1 ERalpha and H2NES ERalpha by estradiol (E2) treatment, but using the endogenous pS2 reporter, luciferase activity was only seen with the H1 ERalpha cell line. Examining cell proliferation revealed that only the WT ERalpha and H1 ERalpha cell lines increased proliferation after treatment. Using microarrays, we found that WT ERalpha and H1 ERalpha cluster together, whereas vector and H2NES ERalpha are most similar and cluster independently of E2 treatment. These studies revealed that the nongenomic activities of ERalpha are unable to mediate proliferative changes or the transcriptional profile after treatment and demonstrate the importance of genomic action for ERalpha/E2-mediated responses with the nongenomic actions of ERalpha being complementary to elicit the full biological actions of ERalpha. PMID- 24947675 TI - A randomized controlled trial and novel mathematical analysis of the analgesic effect of oxycodone versus paracetamol orodispersible tablets. AB - BACKGROUND: For effective treatment of acute pain, a rapid onset of action is important. Here we quantify the antinociceptive profile of an orodispersible oxycodone tablet (OOT) in a randomized, double-blind, active comparator (paracetamol orodispersible tablet, POT), crossover study design in a population of healthy volunteers. METHODS: Twelve female volunteers were randomized to receive 20 mg OOT and 500 mg POT sublingually on two occasions. The electrical pain threshold (EPTh), electrical pain tolerance (EPTol) and pressure pain threshold (PPT) were obtained at regular intervals for 5 h. Time-response data were analysed with a longitudinal pharmacodynamic model characterized by rate constants for analgesia onset (kON ), offset (kOFF ), potency parameter (EFF) and validated with a bootstrap analysis. Values are the median (95% CI) as derived from the bootstrap analysis. RESULTS: OOT produced a rapid increase in response values. For electrical pain analgesia onset, t1/2kON , 44 (25-67) versus analgesia offset, t1/2kOFF , 156 (63-552) min, p < 0.01. For pressure pain, t1/2kON equalled t1/2kOFF : 30 (16-48) min. OOT was most potent on EPTol: EFF 0.95 (0.39-1.71), p < 0.01, with similar potencies on EPTh, 0.43 (0.19-0.87) and PPT, 0.40 (0.21-0.67). Paracetamol displayed 14% of the analgesic efficacy of oxycodone. CONCLUSIONS: The analgesic effect of orodispersible oxycodone was successfully quantified using a mathematical model of analgesia evolution. This method allows quantification of a variety of responses times from sparse data sets. Response times as defined by a 30% increase in response thresholds varied significantly among end points: EPTol 15 min, PPTh 18 min and EPTh 41 min. PMID- 24947677 TI - A manufactu(RED) ethics: labor, HIV, and the body in Lesotho's "sweat-free" garment industry. AB - Employing mostly women and producing for major U.S. labels, Lesotho's primarily foreign-owned garment industry undertook efforts to become "sweat-free" in 2006; simultaneously, it also began producing for the Product(RED) campaign. This article explores the parameters and ethical challenges of an industry-wide, public-private partnership providing HIV prevention and treatment services in this industry. Here, HIV services are intimately bound up in emerging patterns of humanitarian consumption and the production of an ethical industry. Within this ethical production zone, all is not what it seems: Labor violations persist, workers confront occupational hazards, and an elaborate theatrics of ethical practice plays out on the factory floor during routine inspections. This article explores the place and purpose of HIV treatment in the context of such humanitarian fetishism, highlighting the uses to which worker bodies are put and the conceptions of bodily well-being that prevail in these new "moral" economies. PMID- 24947676 TI - Characterizing a collective and dynamic component of chromatin immunoprecipitation enrichment profiles in yeast. AB - BACKGROUND: Recent chromatin immunoprecipitation (ChIP) experiments in fly, mouse, and human have revealed the existence of high-occupancy target (HOT) regions or "hotspots" that show enrichment across many assayed DNA-binding proteins. Similar co-enrichment observed in yeast so far has been treated as artifactual, and has not been fully characterized. RESULTS: Here we reanalyze ChIP data from both array-based and sequencing-based experiments to show that in the yeast S. cerevisiae, the collective enrichment phenomenon is strongly associated with proximity to noncoding RNA genes and with nucleosome depletion. DNA sequence motifs that confer binding affinity for the proteins are largely absent from these hotspots, suggesting that protein-protein interactions play a prominent role. The hotspots are condition-specific, suggesting that they reflect a chromatin state or protein state, and are not a static feature of underlying sequence. Additionally, only a subset of all assayed factors is associated with these loci, suggesting that the co-enrichment cannot be simply explained by a chromatin state that is universally more prone to immunoprecipitation. CONCLUSIONS: Together our results suggest that the co-enrichment patterns observed in yeast represent transcription factor co-occupancy. More generally, they make clear that great caution must be used when interpreting ChIP enrichment profiles for individual factors in isolation, as they will include factor specific as well as collective contributions. PMID- 24947678 TI - Development and pilot of Case Manager: a virtual-patient experience for veterinary students. AB - There is an increasing demand in veterinary education to engage students, teach and reinforce clinical reasoning, and provide access anytime/anywhere to quality learning opportunities. In addition, accrediting bodies are asking for more concrete documentation of essential clinical-skills outcomes. Unfortunately, during the clinical year in a referral hospital setting, students are at the mercy of chance regarding the types of cases they will encounter and the opportunities they will have to participate. Patient- and case-simulation technology is becoming more popular as a way to achieve these objectives in human and veterinary medical education. Many of the current options available to the veterinary medical education community to develop virtual-patient cases are too time-consuming, cost prohibitive, or difficult for the instructor or learner to use. In response, we developed a learning tool, Case Manager, which is low-cost and user-friendly. Case Manager was designed to meet the demands of veterinary education by providing students with an opportunity to cultivate clinical reasoning skills and allowing for real-time student feedback. We launched a pilot test with 37 senior veterinary medical students as part of their Small Animal Internal Medicine clinical rotation. Students reported that Case Manager increased their engagement with the material, improved diagnostic and problem solving skills, and broadened their exposure to a variety of cases. In addition, students felt that Case Manager was superior to a more traditional, less interactive case presentation format. PMID- 24947679 TI - Validation of a realistic simulator for veterinary gastrointestinal endoscopy training. AB - This article reports on the face, content, and construct validity of a new realistic composite simulator (Simuldog) used to provide training in canine gastrointestinal flexible endoscopy. The basic endoscopic procedures performed on the simulator were esophagogastroduodenoscopy (EGD), gastric biopsy (GB), and gastric foreign body removal (FBR). Construct validity was assessed by comparing the performance of novices (final-year veterinary students and recent graduates without endoscopic experience, n=30) versus experienced subjects (doctors in veterinary medicine who had performed more than 50 clinical upper gastrointestinal endoscopic procedures as a surgeon, n=15). Tasks were scored based on completion time, and specific rating scales were developed to assess performance. Internal consistency and inter-rater agreement were assessed. Face and content validity were determined using a 5-point Likert-type scale questionnaire. The novices needed considerably more time than the experts to perform EGD, GB, and FBR, and their performance scores were significantly lower (p<.010). Inter-rater agreement and the internal validity of the rating scales were good. Face validity was excellent, and both groups agreed that the endoscopy scenarios were very realistic. The experts highly valued the usefulness of Simuldog for veterinary training and as a tool for assessing endoscopic skills. Simuldog is the first validated model specifically developed to be used as a training tool for endoscopy techniques in small animals. PMID- 24947680 TI - Hypoxia-inducible factor-1alpha mediates up-regulation of neprilysin by histone deacetylase-1 under hypoxia condition in neuroblastoma cells. AB - Hypoxia-inducible factor (HIF)-1 is the key transcriptional activator mediating both adaptive and pathological responses to hypoxia. The purpose of this study was to find the role of HIF-1 in regulating neprilysin (NEP) at the early stage of hypoxia and explore the underlying mechanism. In this study, we demonstrated that both NEP mRNA and protein levels in neuroblastoma cells were elevated in early stages of hypoxia. Over-expression of HIF-1alpha gene increased NEP mRNA/protein levels, as well as enzyme activity while knockdown of HIF-1alpha decreased them. Meanwhile, HIF-1alpha was shown to bind to histone deacetylase (HDAC)-1 and reduced the association of HDAC-1 with NEP promoter, thus activating NEP gene transcription in a de-repression way. In summary, our results indicated that hypoxia in the early stages would up-regulate NEP expression, in which interaction of HIF-1alpha and HDAC-1 may play a role. This study suggested that NEP up-regulation might be an adaptive response to hypoxia, which was mediated by HIF-1alpha binding to HDAC-1 at the early stage of hypoxia. PMID- 24947682 TI - Reply to "role of Western diet in inflammatory autoimmune diseases" by Manzel et al. In current allergy and asthma reports (volume 14, issue 1, January 2014). PMID- 24947681 TI - Anaphylaxis as a clinical manifestation of clonal mast cell disorders. AB - Clonal mast cell disorders comprise a heterogeneous group of disorders characterized by the presence of gain of function KIT mutations and a constitutively altered activation-associated mast cell immunophenotype frequently associated with clinical manifestations related to the release of mast cells mediators. These disorders do not always fulfil the World Health Organization (WHO)-proposed criteria for mastocytosis, particularly when low-sensitive diagnostic approaches are performed. Anaphylaxis is a frequent presentation of clonal mast cell disorders, particularly in mastocytosis patients without typical skin lesions. The presence of cardiovascular symptoms, e.g., hypotension, occurring after a hymenoptera sting or spontaneously in the absence of cutaneous manifestations such as urticaria is characteristic and differs from the presentation of anaphylaxis in the general population without mastocytosis. PMID- 24947683 TI - Familial pseudohyperkalemia in blood donors: a novel mutation with implications for transfusion practice. AB - BACKGROUND: Familial pseudohyperkalemia (FP) is a dominantly inherited condition in which red blood cells (RBCs) have an increased cold-induced permeability to monovalent cations. Potassium leaks into the supernatant of all stored blood with time, but FP RBCs leak potassium more rapidly. We investigated two unrelated blood donors whose RBC donations demonstrated unexpectedly high potassium after 5 and 6 days' storage. We matched the observed pattern of RBC cation leak to a previously recognized family with FP (FP-Cardiff) and investigated the likely cause with targeted DNA analysis. STUDY DESIGN AND METHODS: Cation leakage from the donor RBCs and from standard donor units was measured. DNA analysis of donors and family members with FP-Cardiff was performed. Allele frequencies were obtained from human variation databases. RESULTS: Both implicated donors were found to have increased cold-induced potassium leak identical in pattern to affected members of the family with FP-Cardiff. We found a heterozygous substitution Arg723Gln in the ATP-binding cassette, Subfamily B, Member 6 protein that segregated with FP in the Cardiff family and was also present in both blood donors. Arg723Gln is listed in human variation databases with an allele frequency of approximately 1:1000. CONCLUSIONS: We describe a novel FP mutation that may affect 1:500 European blood donors and causes rapid loss of potassium from stored RBCs. This finding has implications for neonates and infants receiving large volume RBC transfusions. Genomic screening of donors could be used to identify donors with this mutation and potentially improve the quality and safety of donor units. PMID- 24947684 TI - The prevalence and associated factors of colorectal neoplasms in acromegaly: a single center based study. AB - PURPOSE: Colorectal neoplasms are well known to be a complication in cases of acromegaly; however, data on the prevalence of colorectal neoplasms in Asian patients with acromegaly are limited. Further, the factors associated with colorectal neoplasms in cases of acromegaly are controversial. Therefore, we aimed to clarify the prevalence of and factors associated with colorectal neoplasms in Japanese patients with acromegaly in a single center. METHODS: We analyzed consecutive 57 patients who had undergone full-length colonoscopy at the time of diagnosis at Kobe University Hospital between 1986 and 2012. RESULTS: Of the 57 patients, 22 (38.6%), 18 (31.6%) and 3 (5.3%) patients were diagnosed with hyperplastic polyps, adenomas, and adenocarcinomas, respectively and the prevalence was significantly higher than in a historical control group, Chinese patients with irritable bowel syndrome (The odds ratio was 4.0, 8.7, and 17.5, respectively). The prevalence of adenocarcinomas was also significantly higher in these patients than in the general Japanese population (odds ratio 14.5). Patients with acromegaly who had colorectal neoplasms had longer disease duration than those without colorectal neoplasms. Of note, the area under the growth hormone (GH) concentration-time curve (GH AUC) during the oral glucose tolerance test was significantly higher in patients with adenocarcinomas than in those with no colonic lesion or those with hyperplastic polyps. CONCLUSION: Japanese patients with acromegaly exhibited an increased risk of colorectal neoplasms, especially colorectal adenocarcinomas. An increased GH AUC was associated with an increased risk for colon adenocarcinomas in patients with acromegaly. PMID- 24947685 TI - Pharmacological effects of vitamin D and its analogs: recent developments. AB - Calcitriol, the hormonally active form of vitamin D, is well known for its diverse pharmacological activities, including modulation of cell growth, neuromuscular and immune function and reduction of inflammation. Calcitriol and its analogs exert potent effects on cellular differentiation and proliferation, regulate apoptosis and produce immunomodulatory effects. The purpose of this review is to provide information on various physiological and pharmacological activities of calcitriol and its newly discovered analogs. Special emphasis is given to skin diseases, cancer, diabetes and multiple sclerosis. A discussion is raised on the mechanisms of action of calcitriol and its analogs in various diseases, as well as on possible methods of delivery and targeting. PMID- 24947686 TI - Competitive reaction pathway for site-selective conjugation of Raman dyes to hotspots on gold nanorods for greatly enhanced SERS performance. AB - Common methods to prepare SERS (surface-enhanced Raman scattering) probes rely on random conjugation of Raman dyes onto metal nanostructures, but most of the Raman dyes are not located at Raman-intense electromagnetic hotspots thus not contributing to SERS enhancement substantially. Herein, a competitive reaction between transverse gold overgrowth and dye conjugation is described to achieve site selective conjugation of Raman dyes to the hotspots (ends) on gold nanorods (GNRs). The preferential overgrowth on the nanorod side surface creates a barrier to prevent the Raman dyes from binding to the side surface except the ends of the GNRs, where the highest SERS enhancement factors are expected. The SERS enhancement observed from this special structure is dozens of times larger than that from conjugates synthesized by conventional methods. This simple and powerful strategy to prepare SERS probes can be extended to different anisotropic metal nanostructures with electromagnetic hotspots and has immense potential in in-depth SERS-based biological imaging and single-molecule detection. PMID- 24947687 TI - Lower serum fibroblast growth factor-23 levels may suggest malnutrition in maintenance haemodialysis patients. AB - AIM: It is reported that high serum fibroblast growth factor-23 (FGF-23) levels are associated with increased mortality in haemodialysis patients, and can be caused by hyperphosphataemia and loss of residual renal function. However, hypophosphataemia is also associated with increased mortality in maintenance haemodialysis (MHD) patients. We studied the determinants of the serum FGF-23 levels in MHD patients, focusing on nutritional status and residual renal function. METHODS: A total of 332 Japanese MHD patients with a median age of 69 years, and median dialysis vintage of 66 months, were studied. The serum levels of intact FGF-23, albumin, phosphate, and intact parathyroid hormone (iPTH), corrected serum calcium (Ca) levels, urine volume, (creatinine clearance+urea clearance)/2, phosphate clearance, Kt/Vurea, body mass index (BMI), normalized protein catabolic rate (nPCR), normalized protein equivalent of nitrogen appearance (nPNA), geriatric nutritional risk index (GNRI), and the prescribed dosages of active vitamin D and phosphate binders were assessed. RESULTS: The significant independent factors for InFGF-23 by multivariate analysis were age, GNRI, serum phosphate, Ca, iPTH levels and dosage of active vitamin D in patients without residual renal function (P<0.05). Among all MHD patients, the lowest BMI, nPNA, nPCR, GNRI, serum albumin, creatinine, phosphate, Ca, Ca x P product and iPTH values were seen in the lowest serum FGF-23 quartile (FGF-23<311 pg/mL). CONCLUSIONS: The determinants of the serum FGF-23 level in MHD patients without residual renal function were age, serum phosphate, Ca, iPTH levels, the active vitamin D dose and the GNRI. The lower serum FGF-23 levels may suggest malnutrition in MHD patients. PMID- 24947689 TI - Recurrent episodes of neuro-Sweet syndrome in a Caucasian patient. PMID- 24947688 TI - Cannabis smoking and lung cancer risk: Pooled analysis in the International Lung Cancer Consortium. AB - To investigate the association between cannabis smoking and lung cancer risk, data on 2,159 lung cancer cases and 2,985 controls were pooled from 6 case control studies in the US, Canada, UK, and New Zealand within the International Lung Cancer Consortium. Study-specific associations between cannabis smoking and lung cancer were estimated using unconditional logistic regression adjusting for sociodemographic factors, tobacco smoking status and pack-years; odds-ratio estimates were pooled using random effects models. Subgroup analyses were done for sex, histology and tobacco smoking status. The shapes of dose-response associations were examined using restricted cubic spline regression. The overall pooled OR for habitual versus nonhabitual or never users was 0.96 (95% CI: 0.66 1.38). Compared to nonhabitual or never users, the summary OR was 0.88 (95%CI: 0.63-1.24) for individuals who smoked 1 or more joint-equivalents of cannabis per day and 0.94 (95%CI: 0.67-1.32) for those consumed at least 10 joint-years. For adenocarcinoma cases the ORs were 1.73 (95%CI: 0.75-4.00) and 1.74 (95%CI: 0.85 3.55), respectively. However, no association was found for the squamous cell carcinoma based on small numbers. Weak associations between cannabis smoking and lung cancer were observed in never tobacco smokers. Spline modeling indicated a weak positive monotonic association between cumulative cannabis use and lung cancer, but precision was low at high exposure levels. Results from our pooled analyses provide little evidence for an increased risk of lung cancer among habitual or long-term cannabis smokers, although the possibility of potential adverse effect for heavy consumption cannot be excluded. PMID- 24947690 TI - Let's put an expiration date on the current approach to drug expiration dates. PMID- 24947691 TI - Comments on "Bullous pemphigoid associated with chronic renal allograft rejection". PMID- 24947692 TI - Toxic epidermal necrolysis and early transfer to a regional burn unit: is it time to reevaluate what we teach? PMID- 24947693 TI - Goeckerman regimen for psoriatic patients refractory to biologic therapy. PMID- 24947694 TI - Reply to "Transitory contractile dermatosis--a new entity?". PMID- 24947695 TI - Transitory contractile dermatosis--a new entity? PMID- 24947696 TI - Evidence of human herpesvirus-6 and -7 reactivation in miscarrying women with pityriasis rosea. PMID- 24947697 TI - Buying indoor tanning with university debit cards. PMID- 24947698 TI - Proactive infectious disease approach to dermatologic patients who are taking tumor necrosis factor-alfa antagonists: Part I. Risks associated with tumor necrosis factor-alfa antagonists. AB - Tumor necrosis factor-alfa levels are linked to disease severity in patients with inflammatory conditions, such as psoriasis. Inhibitors of this cytokine are commonly used with significant success in the treatment of such inflammatory disorders. Their use, however, can be plagued by infectious complications. An awareness of potential infections associated with these therapies is critical in order to maximize preventive efforts both before and during therapy. This review provides a guide for dermatologists caring for patients in need of this type of biologic therapy to preemptively address the infectious risks. Part I of this continuing medical education article reviews background information on the various infectious risks associated with tumor necrosis factor inhibitor therapy and appropriate historical data to obtain in the context of pretherapy evaluations. PMID- 24947701 TI - Dermoscopy of satellite metastasis of balloon cell melanoma. PMID- 24947699 TI - Proactive infectious disease approach to dermatologic patients who are taking tumor necrosis factor-alfa antagonists: Part II. Screening for patients on tumor necrosis factor-alfa antagonists. AB - Tumor necrosis factor-alfa levels are linked to disease severity in patients with inflammatory conditions, such as psoriasis. Inhibitors of this cytokine are commonly used with significant success in the treatment of such inflammatory disorders. Their use, however, can be plagued by infectious complications. An awareness of potential infections associated with these therapies is critical in order to maximize preventive efforts both before and during therapy. This review provides a guide for dermatologists caring for patients in need of this type of biologic therapy to preemptively address the infectious risks. Part II of this continuing medical education article reviews recommended screening methods for patients undergoing evaluations for tumor necrosis factor inhibitor therapy for psoriasis or other dermatologic diseases, and discusses possible prophylactic strategies to use, including the appropriate use of immunizations. PMID- 24947702 TI - Second-degree burns on skin marked for photoepilation: the need for white pencil use in cutaneous marking. PMID- 24947703 TI - Successful treatment of discoid lupus erythematosus with fumaric acid esters. PMID- 24947704 TI - Miliarial gout: a rare clinical presentation. PMID- 24947705 TI - A case of dermatitis herpetiformis after a mini-gastric bypass surgery. PMID- 24947706 TI - Subcutaneous Sweet syndrome associated with disseminated nontuberculous mycobacterial infection leading to the diagnosis of adult-onset immunodeficiency. PMID- 24947708 TI - Reticulated hyperpigmentation following chemotherapy for radiation-induced osteosarcoma. PMID- 24947707 TI - Collodion-like membrane in a newborn exposed to infliximab. PMID- 24947709 TI - Occurrence of psoriatic plaques on previous adalimumab injection sites during disease relapse in a patient with pustular psoriasis. PMID- 24947710 TI - Frontal fibrosing alopecia and lichen planus pigmentosus. PMID- 24947711 TI - Remission of metastatic primary mucinous carcinoma of the skin with anastrozole. PMID- 24947713 TI - A worrisome sudden change: targetoid hemosiderotic nevus. PMID- 24947714 TI - Basal cell carcinoma with spontaneous regression: added value of reflectance confocal microscopy when the dermoscopic diagnosis is uncertain. PMID- 24947715 TI - Equine lamellar energy metabolism studied using tissue microdialysis. AB - Failure of lamellar energy metabolism may contribute to the pathophysiology of equine laminitis. Tissue microdialysis has the potential to dynamically monitor lamellar energy balance over time. The objectives of this study were to develop a minimally invasive lamellar microdialysis technique and use it to measure normal lamellar energy metabolite concentrations over 24 h. Microdialysis probes were placed (through the white line) into either the lamellar dermis (LAM) (n = 6) or the sublamellar dermis (SUBLAM) (n = 6) and perfused continuously over a 24 h study period. Probes were placed in the skin dermis (SKIN) for simultaneous comparison to LAM (n = 6). Samples were collected every 2 h and analysed for glucose, lactate, pyruvate, urea and glycerol concentrations. LAM was further compared with SUBLAM by simultaneous placement and sampling in four feet from two horses over 4 h. Horses were monitored for lameness, and either clinically evaluated for 1 month after probe removal (n = 4) or subjected to histological evaluation of the probe site (n = 10). There were no deleterious clinical effects of probe placement and the histological response was mild. Sample fluid recovery and metabolite concentrations were stable for 24 h. Glucose was lower (and lactate:glucose ratio higher) in LAM compared with SUBLAM and SKIN (P < 0.05). Pyruvate was lower in SUBLAM than SKIN and urea was lower in LAM than SKIN (P < 0.05). These differences suggest lower perfusion and increased glucose consumption in LAM compared with SUBLAM and SKIN. In conclusion, lamellar tissue microdialysis was well tolerated and may be useful for determining the contribution of energy failure in laminitis pathogenesis. PMID- 24947716 TI - Electrical stimulation influences satellite cell differentiation after sciatic nerve crush injury in rats. AB - INTRODUCTION: Electrical stimulation is often used to prevent muscle atrophy and preserve contractile function, but its effects on the satellite cell population after nerve injury are not well understood. In this study we aimed to determine whether satellite cell differentiation is affected by electrical stimulation after nerve crush. METHODS: The sciatic nerves of Sprague-Dawley (SD) rats were crushed. Half of the injured rats received daily electrical stimulation of the gastrocnemius muscle, and the others did not. Tests for detecting paired box protein 7 (Pax7), myogenic differentiation antigen (MyoD), embryonic myosin heavy chain (eMyHC), and force production were performed 2, 4, and 6 weeks after injury. RESULTS: More Pax7+/MyoD+ nuclei in stimulated muscles were observed than in non-stimulated muscles. eMyHC expression was elevated in stimulated muscles and correlated positively with enhanced force production. CONCLUSIONS: Increased satellite cell differentiation is correlated with preserved muscle function in response to electrical stimulation after nerve injury. PMID- 24947717 TI - Association of beta-blocker therapy at discharge with clinical outcomes in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - OBJECTIVES: This study sought to investigate the association of beta-blocker therapy at discharge with clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PCI). BACKGROUND: Limited data are available on the efficacy of beta-blocker therapy for secondary prevention in STEMI patients. METHODS: Between November 1, 2005 and September 30, 2010, 20,344 patients were enrolled in nationwide, prospective, multicenter registries. Among these, we studied STEMI patients undergoing primary PCI who were discharged alive (n = 8,510). We classified patients into the beta-blocker group (n = 6,873) and no-beta-blocker group (n = 1,637) according to the use of beta-blockers at discharge. Propensity-score matching analysis was also performed in 1,325 patient triplets. The primary outcome was all-cause death. RESULTS: The median follow-up duration was 367 days (interquartile range: 157 to 440 days). All-cause death occurred in 146 patients (2.1%) of the beta-blocker group versus 59 patients (3.6%) of the no-beta-blocker group (p < 0.001). After 2:1 propensity-score matching, beta-blocker therapy was associated with a lower incidence of all-cause death (2.8% vs. 4.1%, adjusted hazard ratio: 0.46, 95% confidence interval: 0.27 to 0.78, p = 0.004). The association with better outcome of beta-blocker therapy in terms of all-cause death was consistent across various subgroups, including patients with relatively low-risk profiles such as ejection fraction >40% or single-vessel disease. CONCLUSIONS: Beta-blocker therapy at discharge was associated with improved survival in STEMI patients treated with primary PCI. Our results support the current American College of Cardiology/American Heart Association guidelines, which recommend long-term beta-blocker therapy in all patients with STEMI regardless of reperfusion therapy or risk profile. PMID- 24947718 TI - Assessing oral beta-blocker therapy after percutaneous coronary intervention for ST-segment elevation myocardial infarction: the role of observational data. PMID- 24947719 TI - Prasugrel versus clopidogrel in patients with ST-segment elevation myocardial infarction according to timing of percutaneous coronary intervention: a TRITON TIMI 38 subgroup analysis (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38). AB - OBJECTIVES: This study sought to evaluate the efficacy of prasugrel versus clopidogrel in ST-segment elevation myocardial infarction (STEMI) by the timing of percutaneous coronary intervention (PCI). BACKGROUND: Treatment strategies and outcomes for patients with STEMI may differ when treated with primary compared with secondary PCI. METHODS: STEMI patients in the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38) were randomized to prasugrel or clopidogrel on presentation if primary PCI was intended or later during secondary PCI. Primary PCI was defined as within 12 h of symptom onset. The primary endpoint was cardiovascular death, myocardial infarction (MI), or stroke. Because periprocedural MI is difficult to assess in the setting of STEMI, we performed analyses excluding these events. RESULTS: Reductions in the primary endpoint with prasugrel versus clopidogrel (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.65 to 0.97; p = 0.022) were consistent between primary and secondary PCI patients at 15 months (HR: 0.89; 95% CI: 0.69 to 1.13 vs. HR: 0.65; 95% CI: 0.46 to 0.93; p interaction = 0.15). However, a tendency toward a difference in treatment effect at 30 days (HR: 0.68; 95% CI: 0.54 to 0.87; p = 0.002) was observed between primary and secondary PCI patients (HR: 0.81; 95% CI: 0.60 to 1.09 vs. HR: 0.51; 95% CI: 0.34 to 0.76; p interaction = 0.06). When periprocedural MI was excluded, the efficacy of prasugrel remained consistent among primary and secondary PCI patients at 30 days (HR: 0.53; 95% CI: 0.34 to 0.81 vs. HR: 0.44; 95% CI: 0.22 to 0.88; p interaction = 0.68) and 15 months (HR: 0.76; 95% CI: 0.56 to 1.03 vs. HR: 0.75; 95% CI: 0.46 to 1.21; p interaction = 0.96). CONCLUSIONS: The efficacy of prasugrel versus clopidogrel was consistent irrespective of the timing of PCI, particularly in preventing nonprocedural events. (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38; NCT00097591). PMID- 24947720 TI - Uncovering the shroud on antiplatelet therapy for patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. PMID- 24947721 TI - Erroneous measurement of the aortic annular diameter using 2-dimensional echocardiography resulting in inappropriate CoreValve size selection: a retrospective comparison with multislice computed tomography. AB - OBJECTIVES: This study sought to assess the differential adherence to transcatheter heart valve (THV)-oversizing principles between transesophageal echocardiography (TEE) and multislice computed tomography (CT) and its impact on the incidence of paravalvular leak (PVL). BACKGROUND: CT has emerged as an alternative to 2-dimensional TEE for THV sizing. METHODS: In our early experience, TEE-derived aortic annular diameters determined THV size selection. CT datasets originally obtained for vascular screening were retrospectively interrogated to determine CT-derived annular diameters. Annular dimensions and expected THV oversizing were compared between TEE and CT. The incidence of PVL was correlated to TEE- and CT-based oversizing calculations. RESULTS: Using TEE derived annulus measurements, 157 patients underwent CoreValve implantation (23 mm: n = 66; 29 mm: n = 91). The estimated THV oversizing on the basis of TEE was 20.1 +/- 8.2%. Retrospective CT analysis yielded larger annular diameters than TEE (p < 0.0001). When these CT diameters were used to recalculate the percentage of oversizing achieved with the TEE-selected CoreValve, the actual THV oversizing was only 10.4 +/- 7.8%. Consequently, CT analysis suggested that up to 50% of patients received an inappropriate CoreValve size. When CT-based sizing criteria were satisfied, the incidence of PVL was 21% lower than that with echocardiography (14% vs. 35%; p = 0.003). Adherence to CT-based oversizing was independently associated with a reduced incidence of PVL (odds ratio 0.36; 95% confidence interval: 0.14 to 0.90; p = 0.029); adherence to TEE-based sizing was not. CONCLUSIONS: Retrospective CT-based annular analysis revealed that CoreValve size selection by TEE was incorrect in 50% of patients. The percentage of oversizing with CT was one-half of that calculated with TEE resulting in the majority of patients receiving a THV that was too small. PMID- 24947722 TI - Early regression of severe left ventricular hypertrophy after transcatheter aortic valve replacement is associated with decreased hospitalizations. AB - OBJECTIVES: This study sought to examine the relationship between left ventricular mass (LVM) regression and clinical outcomes after transcatheter aortic valve replacement (TAVR). BACKGROUND: LVM regression after valve replacement for aortic stenosis is assumed to be a favorable effect of LV unloading, but its relationship to improved clinical outcomes is unclear. METHODS: Of 2,115 patients with symptomatic aortic stenosis at high surgical risk receiving TAVR in the PARTNER (Placement of Aortic Transcatheter Valves) randomized trial or continued access registry, 690 had both severe LV hypertrophy (left ventricular mass index [LVMi] >= 149 g/m(2) men, >= 122 g/m(2) women) at baseline and an LVMi measurement at 30-day post-TAVR follow-up. Clinical outcomes were compared for patients with greater than versus lesser than median percentage change in LVMi between baseline and 30 days using Cox proportional hazard models to evaluate event rates from 30 to 365 days. RESULTS: Compared with patients with lesser regression, patients with greater LVMi regression had a similar rate of all-cause mortality (14.1% vs. 14.3%, p = 0.99), but a lower rate of rehospitalization (9.5% vs. 18.5%, hazard ratio [HR]: 0.50, 95% confidence interval [CI]: 0.32 to 0.78; p = 0.002) and a lower rate of rehospitalization specifically for heart failure (7.3% vs. 13.6%, p = 0.01). The association with a lower rate of rehospitalization was consistent across subgroups and remained significant after multivariable adjustment (HR: 0.53, 95% CI: 0.34 to 0.84; p = 0.007). Patients with greater LVMi regression had lower B-type natriuretic peptide (p = 0.002) and a trend toward better quality of life (p = 0.06) at 1 year follow-up than did those with lesser regression. CONCLUSIONS: In high-risk patients with severe aortic stenosis and severe LV hypertrophy undergoing TAVR, those with greater early LVM regression had one-half the rate of rehospitalization over the subsequent year compared to those with lesser regression. PMID- 24947724 TI - A journey into the carotid artery microenvironment in high resolution: challenging the stenosis-symptoms paradigm. PMID- 24947723 TI - Intravascular frequency-domain optical coherence tomography assessment of carotid artery disease in symptomatic and asymptomatic patients. AB - OBJECTIVES: The goal of this study was to investigate carotid plaque characteristics in symptomatic versus asymptomatic patients with the use of nonocclusive optical coherence tomography (OCT). BACKGROUND: The identification of asymptomatic patients with carotid disease who are at risk of stroke remains a challenge. There is an increasing awareness that plaque characteristics may best risk-stratify this population. We hypothesized that OCT, a new high-resolution (~ 10 MUm) imaging modality, might be useful for the identification of low-risk versus high-risk carotid plaque features and help us to understand the relationship between carotid diameter stenosis and plaque morphology to ischemic stroke. METHODS: Fifty-three patients undergoing diagnostic carotid angiography were studied with OCT. Data analysis was carried out by imaging experts who were unaware of the clinical characteristics of the study population. RESULTS: Plaque with American Heart Association type VI complicated features was more common in symptomatic than asymptomatic patients (74.1% vs. 36.4%, p = 0.02). This was largely driven by differences in the incidence of thin-cap fibroatheroma with rupture (40.7% vs. 13.6%, p = 0.056) and thrombus (67.7% vs. 36.4%, p = 0.034). Conversely, non-type VI plaques were more common in asymptomatic than symptomatic patients (63.6% vs. 25.9%, p = 0.02). No association between the degree of stenosis and plaque morphology was identified. CONCLUSIONS: This retrospective analysis of carotid OCT data supports the hypothesis that the evaluation of carotid plaque characteristics with this high-resolution imaging technique has the potential to alter the understanding and treatment of carotid artery disease. PMID- 24947726 TI - Detection of angioscopic yellow plaque by intracoronary near-infrared spectroscopy. PMID- 24947727 TI - Annulus remodeling and double orifice repair using a multiple clip approach in complex mitral valve anatomy. PMID- 24947728 TI - Three-dimensional intravascular optical coherence tomography rendering assessment of spontaneous coronary artery dissection concomitant with left main ostial critical stenosis. PMID- 24947729 TI - Plaque erosion: in vivo diagnosis and treatment guided by optical coherence tomography. PMID- 24947730 TI - Identification of fragmented balloon materials in coronary arteries by optical coherence tomography. PMID- 24947731 TI - Rescue percutaneous coronary intervention revealing impending left ventricle rupture. PMID- 24947732 TI - Rupture of equine pericardial aortic-root patch after aortic valve replacement with aortic annulus enlargement: a case report. AB - There are no previous reports of rupture of a heterologous pericardial patch after aortic annulus enlargement. Our patient, a 72-year-old Japanese female, presented with congestive heart failure resulting from heart compression from pseudoaneurysm formation in the aortic root. At 57 years of age the patient had undergone replacement of the ascending aorta for Stanford type A acute aortic dissection. At 66 years of age she had undergone aortic valve replacement with a mechanical valve, accompanied by enlargement of the aortic annulus using an equine pericardial patch, for severe aortic valve stenosis with a narrow aortic annulus. Equine pericardial patch was used in the aortic annulus enlargement to form the aortic root from the ascending aortic vascular prosthesis to the non coronary cusp of the aortic valve. We performed repeat median sternotomy under cardiopulmonary bypass with moderate hypothermia. The ascending aorta was balloon occluded because of dense adhesions around the superior vena cava and ascending aorta due to the pseudoaneurysm. A tear in the equine pericardial patch was noted at the aortic root. The patient underwent pseudoaneurysm excision and repair of the aortic root using a double-layered, Hemashield-reinforced bovine pericardial patch. Routine follow-up with computed tomography should be performed for early detection of complications from a heterologous pericardial patch. PMID- 24947734 TI - Classifying glaucoma surgical techniques. PMID- 24947733 TI - Leptin and leptin receptor gene polymorphisms and their association with plasma leptin levels and obesity in a multi-ethnic Malaysian suburban population. AB - BACKGROUND: This study was to investigate the prevalence of single nucleotide polymorphisms (SNPs) in leptin gene LEP (A19G and G2548A) and leptin receptor gene LEPR (K109R and Q223R) and their association with fasting plasma leptin level (PLL) and obesity in a Malaysian suburban population in Kampar, Perak. METHODS: Convenience sampling was performed with informed consents, and the study sample was drawn from patients who were patrons of the Kampar Health Clinic. A total of 408 subjects (mean age, 52.4 +/- 13.7 years; 169 men, 239 women; 190 obese, 218 non-obese; 148 Malays, 177 ethnic Chinese, 83 ethnic Indians) participated. Socio-demographic data and anthropometric measurements were taken, and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The LEP A19G, G2548A and LEPR K109R, Q223R variant allele frequencies were 0.74, 0.67 and 0.61, 0.79, respectively. The genotype and allele distributions of these gene variants were significantly different among ethnic groups, but not among body mass index (BMI) classes. Subjects with LEPR K109 and Q223 allele had significantly higher systolic blood pressure and adiposity indices after adjustment for ethnicity (higher BMI, total body and subcutaneous fat; lower skeletal muscle percentage). Subjects with LEPR 109R allele had lower PLL than their wild-type allele counterparts. The influence of LEP A19G and G2548A SNPs on blood pressures, anthropometrics, and PLL was not evident. Interestingly, synergistic effect of the LEP and LEPR SNPs was observed as subjects homozygous for all four SNPs studied exhibited significantly higher subcutaneous fat and PLL than those with other genotype combinations. CONCLUSIONS: The LEP and LEPR SNPs in this study may not be an obesity marker among Malaysians in this population, but were associated with ethnicity. Our findings suggest that each of these SNPs contributes to minor but significant variation in obesity-related traits and in combination they display synergistic effects on subcutaneous fat and PLL. PMID- 24947735 TI - A copper(II) perchlorate-promoted tandem reaction of internal alkynol and salicyl N-tosylhydrazone: direct access to isochromeno[3,4-b]chromene. AB - A copper(ii) perchlorate-promoted tandem reaction of internal alkynol and salicyl N-tosylhydrazone provides a novel, concise method for constructing isochromeno[3,4-b]chromene in 35-94% yields. The tandem reaction involves cycloisomerization, formal [4+2] cycloaddition and an elimination process. PMID- 24947737 TI - Connections for health, ecosystems and society leading to action and change. PMID- 24947736 TI - Haemophilus influenzae type b as an important cause of culture-positive acute otitis media in young children in Thailand: a tympanocentesis-based, multi center, cross-sectional study. AB - BACKGROUND: Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae (H. influenzae) are considered major causes of bacterial acute otitis media (AOM) worldwide, but data from Asia on primary causes of AOM are limited. This tympanocentesis-based, multi-center, cross-sectional study assessed bacterial etiology and antimicrobial susceptibility of AOM in Thailand. METHODS: Children 3 to 59 months presenting with AOM (< 72 hours of onset) who had not received prescribed antibiotics, or subjects who received prescribed antibiotics but remained symptomatic after 48-72 hours (treatment failures), were eligible. Study visits were conducted from April 2008 to August 2009. Bacteria were identified from middle ear fluid collected by tympanocentesis or spontaneous otorrhea swab sampling (< 20% of cases). S. pneumoniae and H. influenzae serotypes were determined and antimicrobial resistance was also assessed. RESULTS: Of the 123 enrolled children, 112 were included in analysis and 48% of the 118 samples were positive for S. pneumoniae (23% (27/118)), H. influenzae (18% (21/118)), Moraxella catarrhalis (6% (7/118)) or Streptococcus pyogenes (3% (4/118)). The most common pneumococcal serotypes were 19F (26%) and 14 (22%). The majority of H. influenzae isolates were encapsulated (18/21), with 13 type b (Hib) representing 62% of all H. influenzae isolate or 11% of all samples (13/118), and there were only 3 non-typeable isolates. Despite high antibiotic resistance, amoxicillin/clavulanate susceptibility was high. No pneumococcal vaccine use was reported. CONCLUSIONS: S. pneumoniae and H. influenzae, both frequently antibiotic resistant, were leading causes of bacterial AOM and there was an unexpectedly high burden of Hib in this population unvaccinated by any Hib conjugate vaccine. Conjugate vaccines effective against pneumococcus and H. influenzae could potentially reduce the burden of AOM in this population. PMID- 24947738 TI - Chlamydiosis in British Garden Birds (2005-2011): retrospective diagnosis and Chlamydia psittaci genotype determination. AB - The significance of chlamydiosis as a cause of mortality in wild passerines (Order Passeriformes), and the role of these birds as a potential source of zoonotic Chlamydia psittaci infection, is unknown. We reviewed wild bird mortality incidents (2005-2011). Where species composition or post-mortem findings were indicative of chlamydiosis, we examined archived tissues for C. psittaci infection using PCR and ArrayTube Microarray assays. Twenty-one of 40 birds tested positive: 8 dunnocks (Prunella modularis), 7 great tits (Parus major), 3 blue tits (Cyanistes caeruleus), 2 collared doves (Streptopelia decaocto, Order Columbiformes), and 1 robin (Erithacus rubecula). Chlamydia psittaci genotype A was identified in all positive passerines and in a further three dunnocks and three robins diagnosed with chlamydiosis from a previous study. Two collared doves had genotype E. Ten of the 21 C. psittaci-positive birds identified in the current study had histological lesions consistent with chlamydiosis and co-localizing Chlamydia spp. antigens on immunohistochemistry. Our results indicate that chlamydiosis may be a more common disease of British passerines than was previously recognized. Wild passerines may be a source of C. psittaci zoonotic infection, and people should be advised to take appropriate hygiene precautions when handling bird feeders or wild birds. PMID- 24947739 TI - Beyond proximity: the importance of green space useability to self-reported health. AB - Access to parks and green spaces within residential neighbourhoods has been shown to be an important pathway to generating better physical and mental health for individuals and communities. Early research in this area often failed to identify specific attributes that contributed to reported health outcomes, with more recent research focused on exploring relationships between health outcomes and aspects of access and design. A mixed methods research project conducted in Perth, Western Australia examined the role that neighbourhood green space played in influencing residents' self-reported health status, and this paper identifies significant relationships found between perceptions of green space quality and self-reported health. It focuses on the factors that were found to be most positively associated with better health outcomes: proximity, retention, useability and visitation of neighbourhood green space. PMID- 24947740 TI - Isolation and characterization of rat intestinal bacteria involved in biotransformation of (-)-epigallocatechin. AB - Two intestinal bacterial strains MT4s-5 and MT42 involved in the degradation of ( )-epigallocatechin (EGC) were isolated from rat feces. Strain MT4s-5 was tentatively identified as Adlercreutzia equolifaciens. This strain converted EGC into not only 1-(3, 4, 5-trihydroxyphenyl)-3-(2, 4, 6-trihydroxyphenyl)propan-2 ol (1), but also 1-(3, 5-dihydroxyphenyl)-3-(2, 4, 6-trihydroxyphenyl)propan-2-ol (2), and 4'-dehydroxylated EGC (7). Type strain (JCM 9979) of Eggerthella lenta was also found to convert EGC into 1. Strain MT42 was identified as Flavonifractor plautii and converted 1 into 4-hydroxy-5-(3, 4, 5 trihydroxyphenyl)valeric acid (3) and 5-(3, 4, 5-trihydroxyphenyl)-gamma valerolactone (4) simultaneously. Strain MT42 also converted 2 into 4-hydroxy-5 (3, 5-dihydroxyphenyl)valeric acid (5), and 5-(3, 5-dihydroxyphenyl)-gamma valerolactone (6). Furthermore, F. plautii strains ATCC 29863 and ATCC 49531 were found to catalyze the same reactions as strain MT42. Interestingly, formation of 2 from EGC by strain MT4s-5 occurred rapidly in the presence of hydrogen supplied by syntrophic bacteria. Strain JCM 9979 also formed 2 in the presence of the hydrogen or formate. Strain MT4s-5 converted 1, 3, and 4 to 2, 5, and 6, respectively, and the conversion was stimulated by hydrogen, whereas strain JCM 9979 could catalyze the conversion only in the presence of hydrogen or formate. On the basis of the above results together with previous reports, the principal metabolic pathway of EGC and EGCg by catechin-degrading bacteria in gut tract is proposed. PMID- 24947741 TI - Increasing access to renal transplantation in India through our single-center kidney paired donation program: a model for the developing world to prevent commercial transplantation. AB - Because access to transplantation with HLA-desensitization protocols and ABO incompatible transplantation is very limited due to high costs and increased risk of infections from more intense immunosuppression, kidney paired donation (KPD) promises hope to a growing number of end-stage renal disease (ESRD) patient in India. We present a government and institutional ethical review board approved study of 56 ESRD patients [25 two-way and 2 three-way pairs] who consented to participate in KPD transplantation at our center in 2013, performed to avoid blood group incompatibility (n = 52) or positive cross-match (n = 4). All patients had anatomic, functional, and immunologically comparable donors. The waiting time in KPD was short as compared to deceased donor transplantation. Laparoscopic donor nephrectomy was performed in 54 donors. Donor relationships were spousal (n = 40), parental (n = 13), others (n = 3), with median HLA match of 1. Graft survival was 97.5%. Three patients died with functioning graft. 16% had biopsy-proven acute rejection. Mean serum creatinine was 1.2 mg/dl at 0.73 +/ 0.32 months follow-up. KPD is a viable, legal, and rapidly growing modality for facilitating LDRT for patients who are incompatible with their healthy, willing living donor. To our knowledge, this is the largest single-center report from India. PMID- 24947742 TI - Daniel Molliere (1848-1890): major surgeon, anatomist, great teacher, and an innovative scientist of supreme operating action. PMID- 24947743 TI - The winds of change. PMID- 24947744 TI - Patient education. Filipino "kulinarya" cuisine and chronic kidney disease. PMID- 24947745 TI - Oropharyngeal teratomas in newborns: management and outcome. AB - OBJECTIVES: Congenital teratomas of the oropharyngeal cavity are extremely rare and are associated with a high neonatal mortality rate due to severe airway obstruction. Management has been improved with progress in antenatal diagnosis. The authors describe this progress in the light of a series of 4 cases and a review of the literature. METHODS: The medical charts of four neonates treated in the department since 1995 were reviewed. The following criteria were studied: age at diagnosis, clinical and radiological features of the tumour, management at birth and outcome. RESULTS: All four cases occurred in female neonates with an antenatal diagnosis in two cases, allowing preparation for endoscopy in the delivery room in one case and an EXIT procedure in the other case. Three neonates had to be intubated in the delivery room. Imaging showed invasion of the infratemporal fossa in 3 of the 4 cases. Surgical resection via various approaches to the infratemporal fossa was complete in every case. Adjuvant chemotherapy was administered in one case. CONCLUSION: Surgery for these mostly benign tumours is very challenging and requires a multidisciplinary team. Perinatal planning allows appropriate management at birth, decreasing the risk of airway obstruction. Surgery is the mainstay of treatment of teratomas. PMID- 24947747 TI - Epilepsy following neonatal hypoglycaemia--a spectrum of severity. PMID- 24947746 TI - Use of neuromuscular monitoring to detect prolonged effect of succinylcholine or mivacurium: three case reports. AB - Mutations in the butyrylcholinesterase gene can lead to a prolonged effect of the neuromuscular blocking agents, succinylcholine and mivacurium. If the anaesthesiologist is not aware of this condition, it may result in insufficient respiration after tracheal extubation. However, this can be avoided with the use of objective neuromuscular monitoring if used adequately. Three case reports of prolonged effect of succinylcholine or mivacurium were presented to illustrate the importance of neuromuscular monitoring during anaesthesia. In the first case, continuous intraoperative neuromuscular monitoring allowed a prolonged neuromuscular blockade to be discovered prior to tracheal extubation of the patient. The patient was extubated after successful reversal of the neuromuscular blockade. On the contrary, neuromuscular monitoring was not used during anaesthesia in the second patient; hence, the prolonged effect of the neuromuscular blocking agent was not discovered until after extubation. In the third patient, the lack of response to nerve stimulation was interpreted as a technical failure and the prolonged effect of succinylcholine was discovered when general anaesthesia was terminated. Both patients had insufficient respiration. They were therefore re-sedated, transferred to the intensive care unit and the tracheas were extubated after full recovery from neuromuscular blockade. We recommend the use of monitoring every time these agents are used, even with short acting drugs like succinylcholine and mivacurium. PMID- 24947748 TI - Maintenance of undifferentiated state of human induced pluripotent stem cells through cytoskeleton-driven force acting to secreted fibronectin on a dendrimer immobilized surface. AB - Understanding of the fundamental mechanisms that govern adhesive properties of human induced pluripotent stem cells (hiPSCs) to culture environments provides surface design strategies for maintaining their undifferentiated state during cell expansion. Polyamidoamine dendrimer surface with first-generation (G1) with dendron structure was used for co-cultures of hiPSCs and SNL feeder cells that formed tightly packed compact hiPSC colonies, similar to those on a conventional gelatin-coated surface. hiPSCs passaged up to 10 times on the G1 surface maintained their undifferentiated state. Immunostaining and reverse transcriptase PCR analysis of fibronectin showed that the secreted fibronectin matrix from feeder cells on the G1 surface contributed to hiPSC attachment. Compared with cells on the gelatin-coated surface, F-actin and paxillin immunostaining revealed a well-organized network of actin stress fibers and focal adhesion formation at cell-substrate sites in hiPSC colonies on the G1 surface. E-cadherin expression levels on these surfaces were almost same, but paxillin and Rac1 expression levels on the G1 surface were significantly higher than those on the gelatin coated surface. Zyxin showed prominent expression on the G1 surface at sites of focal adhesion and cell-cell contact in colonies, whereas zyxin expression on the gelatin-coated surface was not observed in regions of cell-cell contact. These findings indicate that transduction of mechanical stimuli through actin polymerization at sites of focal adhesion and cell-cell contact results in maintenance of undifferentiated hiPSC colonies on G1 surface. The G1 surface enables a substrate design based on the mechanical cues in the microenvironment from feeder cells to expand undifferentiated hiPSCs in long-term culture. PMID- 24947749 TI - The volatile emission of Eurosta solidaginis primes herbivore-induced volatile production in Solidago altissima and does not directly deter insect feeding. AB - BACKGROUND: The induction of plant defenses in response to herbivory is well documented. In addition, many plants prime their anti-herbivore defenses following exposure to environmental cues associated with increased risk of subsequent attack, including induced volatile emissions from herbivore-damaged plant tissues. Recently, we showed in both field and laboratory settings that tall goldenrod plants (Solidago altissima) exposed to the putative sex attractant of a specialist gall-inducing fly (Eurosta solidaginis) experienced less herbivory than unexposed plants. Furthermore, we observed stronger induction of the defense phytohormone jasmonic acid in exposed plants compared to controls. These findings document a novel class of plant-insect interactions mediated by the direct perception, by plants, of insect-derived olfactory cues. However, our previous study did not exclude the possibility that the fly emission (or its residue) might also deter insect feeding via direct effects on the herbivores. RESULTS: Here we show that the E. solidaginis emission does not (directly) deter herbivore feeding on Cucurbita pepo or Symphyotrichum lateriflorum plants--which have no co-evolutionary relationship with E. solidaginis and thus are not expected to exhibit priming responses to the fly emission. We also document stronger induction of herbivore-induced plant volatiles (HIPV) in S. altissima plants given previous exposure to the fly emission relative to unexposed controls. No similar effect was observed in maize plants (Zea mays), which have no co-evolutionary relationship with E. solidaginis. CONCLUSIONS: Together with our previous findings, these results provide compelling evidence that reduced herbivory on S. altissima plants exposed to the emission of male E. solidaginis reflects an evolved plant response to olfactory cues associated with its specialist herbivore and does not involve direct effects of the fly emission on herbivore feeding behavior. We further discuss mechanisms by which the priming of HIPV responses documented here might contribute to enhanced S. altissima defense against galling. PMID- 24947750 TI - Omega: an overlap-graph de novo assembler for metagenomics. AB - MOTIVATION: Metagenomic sequencing allows reconstruction of microbial genomes directly from environmental samples. Omega (overlap-graph metagenome assembler) was developed for assembling and scaffolding Illumina sequencing data of microbial communities. RESULTS: Omega found overlaps between reads using a prefix/suffix hash table. The overlap graph of reads was simplified by removing transitive edges and trimming short branches. Unitigs were generated based on minimum cost flow analysis of the overlap graph and then merged to contigs and scaffolds using mate-pair information. In comparison with three de Bruijn graph assemblers (SOAPdenovo, IDBA-UD and MetaVelvet), Omega provided comparable overall performance on a HiSeq 100-bp dataset and superior performance on a MiSeq 300-bp dataset. In comparison with Celera on the MiSeq dataset, Omega provided more continuous assemblies overall using a fraction of the computing time of existing overlap-layout-consensus assemblers. This indicates Omega can more efficiently assemble longer Illumina reads, and at deeper coverage, for metagenomic datasets. AVAILABILITY AND IMPLEMENTATION: Implemented in C++ with source code and binaries freely available at http://omega.omicsbio.org. PMID- 24947751 TI - Correcting for link loss in causal network inference caused by regulator interference. AB - MOTIVATION: There are a number of algorithms to infer causal regulatory networks from time series (gene expression) data. Here we analyse the phenomena of regulator interference, where regulators with similar dynamics mutually suppress both the probability of regulating a target and the associated link strength; for instance, interference between two identical strong regulators reduces link probabilities by ~50%. RESULTS: We construct a robust method to define an interference-corrected causal network based on an analysis of the conditional link probabilities that recovers links lost through interference. On a large real network (Streptomyces coelicolor, phosphate depletion), we demonstrate that significant interference can occur between regulators with a correlation as low as 0.865, losing an estimated 34% of links by interference. However, levels of interference cannot be predicted from the correlation between regulators alone and are data specific. Validating against known networks, we show that high numbers of functional links are lost by regulator interference. Performance against other methods on DREAM4 data is excellent. AVAILABILITY AND IMPLEMENTATION: The method is implemented in R and is publicly available as the NIACS package at http://www2.warwick.ac.uk/fac/sci/systemsbiology/research/software. PMID- 24947753 TI - Extended endoscopic endonasal approach for recurrent or residual adult craniopharyngiomas. AB - BACKGROUND: The aim of this study was to evaluate the effectiveness of the extended endoscopic endonasal transsphenoidal approach (TSA) for recurrent or residual craniopharyngiomas, focusing on the extent of tumor resection and complications resulting from surgery at a single institution. METHODS: Twelve adult patients (six men and six women) underwent extended endoscopic endonasal TSA for a recurrent or residual craniopharyngioma after a previous surgical intervention at a single institution by a single surgeon. The mean number of surgeries patients had undergone before TSA was 1.3 (range, 1-3). The mean period between patients' most recent surgery and extended TSA was 55.9 months (range, 1 184). The mean preoperative (that is, pre-extended TSA) tumor volume was 2.87 cm3. The mean follow-up period was 15.8 months (range, 4-32). We reviewed clinical and radiological features in each case, focusing on the degree of tumor resection as well as endocrinological and ophthalmological outcomes. RESULTS: Gross total resection was achieved in ten patients (83.3 %), and the mean resection rate was 87 % in the other two cases. There were no significant differences between pre- and postoperative endocrine function, except in one patient who suffered postoperative panhypopituitarism resulting in pituitary stalk resection, which was necessary because of obvious tumor involvement. Three patients suffered transient diabetic insipidus (DI). With respect to ophthalmological outcomes, three patients showed improvement, two others showed decline, and the remainder showed no significant changes. CONCLUSION: The extended endoscopic endonasal transsphenoidal approach is an effective and safe surgical approach for treating recurrent or residual craniopharyngioma. PMID- 24947752 TI - PGS: a tool for association study of high-dimensional microRNA expression data with repeated measures. AB - MOTIVATION: MicroRNAs (miRNAs) are short single-stranded non-coding molecules that usually function as negative regulators to silence or suppress gene expression. Owning to the dynamic nature of miRNA and reduced microarray and sequencing costs, a growing number of researchers are now measuring high dimensional miRNA expression data using repeated or multiple measures in which each individual has more than one sample collected and measured over time. However, the commonly used univariate association testing or the site-by-site (SBS) testing may underutilize the longitudinal feature of the data, leading to underpowered results and less biologically meaningful results. RESULTS: We propose a penalized regression model incorporating grid search method (PGS), for analyzing associations of high-dimensional miRNA expression data with repeated measures. The development of this analytical framework was motivated by a real world miRNA dataset. Comparisons between PGS and the SBS testing revealed that PGS provided smaller phenotype prediction errors and higher enrichment of phenotype-related biological pathways than the SBS testing. Our extensive simulations showed that PGS provided more accurate estimates and higher sensitivity than the SBS testing with comparable specificities. AVAILABILITY AND IMPLEMENTATION: R source code for PGS algorithm, implementation example and simulation study are available for download at https://github.com/feizhe/PGS. PMID- 24947754 TI - Psychological consequences of aggression in pre-hospital emergency care: cross sectional survey. AB - BACKGROUND: Pre-hospital emergency care is a particularly vulnerable setting for workplace violence. However, there is no literature available to date on the psychological consequences of violence in pre-hospital emergency care. OBJECTIVES: To evaluate the psychological consequences of exposure to workplace violence from patients and those accompanying them in pre-hospital emergency care. DESIGN: A retrospective cross-sectional study. SETTING: 70 pre-hospital emergency care services located in Madrid region. PARTICIPANTS: A randomized sample of 441 health care workers (135 physicians, 127 nurses and 179 emergency care assistants). METHODS: Data were collected from February to May 2012. The survey was divided into four sections: demographic/professional information, level of burnout determined by Maslach Burnout Inventory (MBI), mental health status using General Health Questionnaire (GHQ-28) and frequency and type of violent behaviour experienced by staff members. RESULTS: The health care professionals who had been exposed to physical and verbal violence presented a significantly higher percentage of anxiety, emotional exhaustion, depersonalization and burnout syndrome compared with those who had not been subjected to any aggression. Frequency of verbal violence (more than five times) was related to emotional exhaustion and depersonalization. CONCLUSION: Type of violence (i.e. physical aggression) is especially related to high anxiety levels and frequency of verbal aggression is associated with burnout (emotional exhaustion and depersonalization). Psychological counselling should be made available to professional staff who have been subjected to physical aggression or frequent verbal violence. PMID- 24947755 TI - The relationship between individualized care and the practice environment: an international study. AB - BACKGROUND: Previous research studies have found that the better the quality of practice environments in hospitals, the better the outcomes for nurses and patients. Practice environment may influence nurses' ability to individualize care but the detailed relationship between individualized care and the professional practice environment has not been investigated widely. Some evidence exists about the association of practice environments with the level of individualization of nursing care, but this evidence is based on single national studies. OBJECTIVES: The aim of this study was to determine whether nurses' views of their professional practice environment associate with their views of the level of care individualization in seven countries. DESIGN: This study had an international, multisite, prospective, cross-sectional, exploratory survey design. SETTINGS: The study involved acute orthopedic and trauma surgical inpatient wards (n=91) in acute care hospitals (n=34) in seven countries, Cyprus, Finland, Greece, the State of Kansas, USA, Portugal, Sweden, and Turkey. PARTICIPANTS: Nurses (n=1163), registered or licensed practical, working in direct patient care, in orthopedic and trauma inpatient units in acute care hospitals in seven countries participated in the study. METHODS: Self administered questionnaires, including two instruments, the Revised Professional Practice Environment and the Individualized Care Scale-Nurse (Individualized Care Scale-Nurse A and B) were used for data collection. Data were analyzed statistically using descriptive statistics, simultaneous multiple regression analysis, and generalized linear model. RESULTS: Two regression models were applied to assess the predictive validity of the Revised Professional Practice Environment on the Individualized Care Scale-Nurse-A and B. The results showed that elements of the professional practice environment were associated with care individualization. Internal work motivation, cultural sensitivity, control over practice, teamwork, and staff relationship with physicians were predictors of support (Individualized Care Scale-A) for and the delivery (Individualized Care Scale-B) of individualized care. CONCLUSIONS: The results of this study provide evidence that environment aspect could explain variations in care individualization. These findings support the assertion that individualized care needs to be understood in a broader context than the immediate nurse-patient relationship and that careful development of the care environment may be an effective way to improve care quality and outcomes. PMID- 24947756 TI - Human rhinovirus infection causes different DNA methylation changes in nasal epithelial cells from healthy and asthmatic subjects. AB - BACKGROUND: Mechanisms underlying the development of virus-induced asthma exacerbations remain unclear. To investigate if epigenetic mechanisms could be involved in virus-induced asthma exacerbations, we undertook DNA methylation profiling in asthmatic and healthy nasal epithelial cells (NECs) during Human Rhinovirus (HRV) infection in vitro. METHODS: Global and loci-specific methylation profiles were determined via Alu element and Infinium Human Methylation 450 K microarray, respectively. Principal components analysis identified the genomic loci influenced the most by disease-status and infection. Real-time PCR and pyrosequencing were used to confirm gene expression and DNA methylation, respectively. RESULTS: HRV infection significantly increased global DNA methylation in cells from asthmatic subjects only (43.6% to 44.1%, p = 0.04). Microarray analysis revealed 389 differentially methylated loci either based on disease status, or caused by virus infection. There were disease-associated DNA methylation patterns that were not affected by HRV infection as well as HRV induced DNA methylation changes that were unique to each group. A common methylation locus stood out in response to HRV infection in both groups, where the small nucleolar RNA, H/ACA box 12 (SNORA12) is located. Further analysis indicated that a relationship existed between SNORA12 DNA methylation and gene expression in response to HRV infection. CONCLUSIONS: We describe for the first time that Human rhinovirus infection causes DNA methylation changes in airway epithelial cells that differ between asthmatic and healthy subjects. These epigenetic differences may possibly explain the mechanism by which respiratory viruses cause asthma exacerbations. PMID- 24947757 TI - No differences in dual-task costs between forced- and free-choice tasks. AB - Humans appear to act in response to environmental demands or to pursue self chosen goals. In the laboratory, these situations are often investigated with forced- and free-choice tasks: in forced-choice tasks, a stimulus determines the one correct response, while in free-choice tasks the participants choose between response alternatives. We compared these two tasks regarding their susceptibility to dual-task interference when the concurrent task was always forced-choice. If, as was suggested in the literature, both tasks require different "action control systems," larger dual-task costs for free-choice tasks than for forced-choice tasks should emerge in our experiments, due to a time-costly switch between the systems. In addition, forced-choice tasks have been conceived as "prepared reflexes" for which all intentional processing is said to take place already prior to stimulus onset giving rise to automatic response initiation upon stimulus onset. We report three experiments with different implementations of the forced- vs. free-choice manipulation. In all experiments we replicated slower responses in the free- than in the forced-choice task and the typical dual-task costs. These latter costs, however, were equivalent for forced- and free-choice tasks. These results are easier to reconcile with the assumption of one unitary "action control system." PMID- 24947758 TI - Competitor rule priming: evidence for priming of task rules in task switching. AB - In task-switching experiments, participants switch between task rules, and each task rule describes how responses are mapped to stimulus information. Importantly, task rules do not pertain to any specific response but to all possible responses. This work examined the hypothesis that task rules, as wholes, rather than (just) specific responses are primed by their execution, such that, in the following trial, response conflicts are exacerbated when the competing responses are generated by these recently primed rules, and performance becomes relatively poor. This hypothesis was supported in two task-switching experiments and re-analyses of additional three published experiments, thus indicating Competitor Rule Priming. Importantly, the Competitor Rule-Priming effect was independent of response repetition vs. switch, suggesting that it reflects the priming of the entire task rule rather than the priming (or suppression) of specific responses. Moreover, this effect was obtained regardless of Backward Inhibition, suggesting these effects are unrelated. PMID- 24947759 TI - Motor contagion: the contribution of trajectory and end-points. AB - Increased involuntary arm movement deviation when observing an incongruent human arm movement has been interpreted as a strong indicator of motor contagion. Here, we examined the contribution of trajectory and end-point information on motor contagion by altering congruence between the stimulus and arm movement. Participants performed cyclical horizontal arm movements whilst simultaneously observing a stimulus representing human arm movement. The stimuli comprised congruent horizontal movements or vertical movements featuring incongruent trajectory and end-points. A novel, third, stimulus comprised curvilinear movements featuring congruent end-points, but an incongruent trajectory. In Experiment 1, our dependent variables indicated increased motor contagion when observing the vertical compared to horizontal movement stimulus. There was even greater motor contagion in the curvilinear stimulus condition indicating an additive effect of an incongruent trajectory comprising congruent end-points. In Experiment 2, this additive effect was also present when facing perpendicular to the display, and thus with end-points represented as a product of the movement rather than an external spatial reference. Together, these findings support the theory of event coding (Hommel et al., Behav Brain Sci 24:849-878, 2001), and the prediction that increased motor contagion takes place when observed and executed actions share common features (i.e., movement end-points). PMID- 24947760 TI - Maintenance of a physically active lifestyle after pulmonary rehabilitation in patients with COPD: a qualitative study toward motivational factors. AB - OBJECTIVES: To explore determinants of behavior change maintenance of a physically active lifestyle in patients with chronic obstructive pulmonary disease (COPD) 8-11 months after completion of a 4-month outpatient pulmonary rehabilitation program. DESIGN: A qualitative descriptive study of semistructured interviews. SETTING: Pulmonary rehabilitation assessment center. PARTICIPANTS: Patients with COPD. MEASUREMENTS: Semistructured interviews until data saturation, coded by 2 independent researchers. Patients were classified as responder (maintenance or improvement) or nonresponder (relapse or decrease), based on 3 quantitative variables reflecting exercise capacity (Constant Work Rate Test), health-related quality of life (Short-Form health survey [SF-36]), and self-management abilities (Self-Management Ability Scale [SMAS-30/Version 2]). RESULTS: Mean (SD) forced expiratory volume in the first second (FEV1) among interviewees was 52.5% (14.4%) predicted and the mean age was 63.5 years (range: 45-78). The group consisted of 15 responders and 7 nonresponders. Physical limitations reduced competence to engage in an active lifestyle and responders appeared to experience higher levels of perceived competence. Social support was found important and the experienced understanding from fellow patients made exercising together enjoyable. Particularly, responders expressed autonomous motivation and said they exercised because of the benefits they gain from it. Unexpectedly, only responders also experienced controlled motivation. CONCLUSION: Perceived competence and autonomous motivation are important determinants for maintenance of an active lifestyle in patients with COPD. In contrast to common theoretical assumptions, a certain threshold level of controlled motivation may remain important in maintaining a physically active lifestyle after a pulmonary rehabilitation program. PMID- 24947761 TI - Clarion call for a dedicated clinical and research approach to post-acute care. PMID- 24947762 TI - Validating the SARC-F: a suitable community screening tool for sarcopenia? AB - OBJECTIVES: Using data from the Hong Kong Mr and Ms Os study, we validated the SARC-F against 3 consensus definitions of sarcopenia from Europe, Asia, and an international group, and compared the ability of all 4 measures to predict 4-year physical limitation, walking speed, and repeated chair stands. DESIGN: Prospective cohort study. SETTING: Hong Kong community. PARTICIPANTS: Four thousand men and women living in the community. MEASUREMENTS: A questionnaire regarding ability to carry a heavy load, walking, rising from a chair, climbing stairs, and falls frequency was administered. These questions were used to calculate the SARC-F score. Measurements, including appendicular muscle mass, were taken using dual-energy X-ray, grip strength using a dynamometer, 6-m gait speed, and time taken for repeated chair stand. Classification using the SARC-F score was compared using consensus panel criteria from international, European, and Asian sarcopenia working groups. The performance of all 4 methods was compared by examining the predictive ability for 4-year outcomes using ROC curve. RESULTS: The SARC-F has excellent specificity but poor sensitivity for sarcopenia classification; however, all 4 methods have comparable but modest predictive power for 4-year physical limitation. CONCLUSION: The SARC-F may be considered a suitable tool for community screening for sarcopenia. PMID- 24947764 TI - Oedema-based model for diffuse low-grade gliomas: application to clinical cases under radiotherapy. AB - OBJECTIVES: Diffuse low-grade gliomas are characterized by slow growth. Despite appropriate treatment, they change inexorably into more aggressive forms, jeopardizing the patient's life. Optimizing treatments, for example with the use of mathematical modelling, could help to prevent tumour regrowth and anaplastic transformation. Here, we present a model of the effect of radiotherapy on such tumours. Our objective is to explain observed delay of tumour regrowth following radiotherapy and to predict its duration. MATERIALS AND METHODS: We have used a migration-proliferation model complemented by an equation describing appearance and draining of oedema. The model has been applied to clinical data of tumour radius over time, for a population of 28 patients. RESULTS: We were able to show that draining of oedema accounts for regrowth delay after radiotherapy and have been able to fit the clinical data in a robust way. The model predicts strong correlation between high proliferation coefficient and low progression-free gain of lifetime, due to radiotherapy among the patients, in agreement with clinical studies. We argue that, with reasonable assumptions, it is possible to predict (precision ~20%) regrowth delay after radiotherapy and the gain of lifetime due to radiotherapy. CONCLUSIONS: Our oedema-based model provides an early estimation of individual duration of tumour response to radiotherapy and thus, opens the door to the possibility of personalized medicine. PMID- 24947763 TI - Feasibility study of electrocardiographic and respiratory gated, gadolinium enhanced magnetic resonance angiography of pulmonary veins and the impact of heart rate and rhythm on study quality. AB - BACKGROUND: We aimed to assess the feasibility of 3 dimensional (3D) respiratory and ECG gated, gadolinium enhanced magnetic resonance angiography (MRA) on a 3 Tesla (3 T) scanner for imaging pulmonary veins (PV) and left atrium (LA). The impact of heart rate (HR) and rhythm irregularity associated with atrial fibrillation (AF) on image and segmentation qualities were also assessed. METHODS: 101 consecutive patients underwent respiratory and ECG gated (ventricular end systolic window) MRA for pre AF ablation imaging. Image quality (assessed by PV delineation) was scored as 1 = not visualized, 2 = poor, 3 = good and 4 = excellent. Segmentation quality was scored on a similar 4 point scale. Signal to noise ratios (SNRs) were calculated for the LA, LA appendage (LAA), and PV. Contrast to noise ratios (CNRs) were calculated between myocardium and LA, LAA and PV, respectively. Associations between HR/rhythm and quality metrics were assessed. RESULTS: 35 of 101 (34.7%) patients were in AF at time of MRA. 100 (99%) patients had diagnostic studies, and 91 (90.1%) were of good or excellent quality. Overall, mean +/- standard deviation (SD) image quality score was 3.40 +/- 0.69. Inter observer agreement for image quality scores was substantial, (kappa = 0.68; 95% confidence interval (CI): 0.46, 0.90). Neither HR adjusting for rhythm [odds ratio (OR) = 1.03, 95% CI = 0.98,1.09; p = 0.22] nor rhythm adjusting for HR [OR = 1.25, 95% CI = 0.20, 7.69; p = 0.81] demonstrated association with image quality. Similarly, SNRs and CNRs were largely independent of HR after adjusting for rhythm. Segmentation quality scores were good or excellent for 77.3% of patients: mean +/- SD score = 2.91 +/- 0.63, and scores did not significantly differ by baseline rhythm (p = 0.78). CONCLUSIONS: 3D respiratory and ECG gated, gadolinium enhanced MRA of the PVs and LA on a 3 T system is feasible during ventricular end systole, achieving high image quality and high quality image segmentation when imported into electroanatomic mapping systems. Quality is independent of HR and heart rhythm for this free breathing, radiation free, alternative strategy to current MRA or CT based approaches, for pre AF ablation imaging of PVs and LA. PMID- 24947765 TI - Unusual presentation of adult Marfan syndrome as a complex diaphragmatic hiatus hernia. AB - Marfan syndrome is multisystem connective tissue disorder that primarily involves the skeletal, cardiovascular, and ocular systems. The gastrointestinal complications in Marfan syndrome are rare, with only a few case reports described in the literature. We present a 25-year-old woman who presented with acute abdominal pain for 1 day. The imaging features revealed complex diaphragmatic hiatus hernia with organoaxial gastric volvulus. This is a unique case report about an adult patient with Marfan syndrome who presented with symptomatic paraesophageal hernia and organoaxial gastric volvulus. PMID- 24947766 TI - Laparoscopic management of symptomatic urachal remnants in adulthood. AB - BACKGROUND: The traditional surgical approach to the excision of persistent urachal remnants is a lower midline laparotomy or semicircular infraumbilical incision. The aim of this study is to report our experience with laparoscopic urachus excision as a minimally invasive diagnostic and surgical technique. METHODS: This study was a prospective study involving patients who were diagnosed with persistent urachus and underwent laparoscopic excision. The morbidity, recovery, and outcomes of surgery were reviewed. RESULTS: Fourteen patients (8 men) with a mean age of 22.8 +/- 6.42 years underwent laparoscopic excision. All patients presented with discharge from the umbilicus. Although four patients had no sonographic evidence of a patent urachus, a diagnostic laparoscopy detected a patent urachus that was excised laparoscopically. One patient required laparoscopic reoperation for persistent discharge, and one patient presented with bladder injury, which was repaired via a small Pfannenstiel incision without any morbidity. The mean operative time was 71.1 +/- 0.28 minutes, and the mean duration of hospital stay was 1.3 +/- 1.38 days. Pathological examination confirmed a benign urachal remnant in all cases. CONCLUSION: Laparoscopy is a useful alternative for the management of persistent or infected urachus, especially when its presence is clinically suspected despite the lack of sonographic evidence. The procedure is associated with low morbidity, although a small risk of bladder injury exists, particularly in cases of severe active inflammation. Recurrence is uncommon and was caused by inadequate excision of inflammatory tissue in our series that was easily managed laparoscopically. PMID- 24947767 TI - Cryptococcus neoformans meningoencephalitis in a patient with polyarteritis nodosa. AB - Case of 59-year-old male with chronic obstructive pulmonary disease and a number of comorbidities, who has developed meningoencephalitis caused by Cryptococcus neoformans var. grubii with polyarteritis nodosa diagnosed during hospitalization, was presented. Before evidence of meningoencephalitis, the patient was being treated with ketoconazole and low doses of fluconazole (200 mg/day) for alleged candidiasis. The dosage was increased (800 mg/day) following laboratory diagnosis of C. neoformans based on positive latex agglutination test and biochemical identification of encapsulated yeast isolated from the blood and CSF. Later, the yeast identification was confirmed by sequencing analysis. Owing to inadequate clinical response, fluconazole therapy was switched to voriconazole (400 mg/day) and later to intravenous amphotericin B (1.0 mg/kg per day). Despite of a temporary stabilization and improvement, which correlated with decline of cryptococcal antigen titers (from 1:1024 to 1:8), after 6 weeks, the patient's underlying condition deteriorated due to severe pancolitis and serious nosocomial bacterial infections. The patient died of multiorgan failure several days later. Our case demonstrates a possible connection between the development of life threatening cryptococcosis and an autoimmune vasculitis disease and emphasizes that the outcome of the management of cryptococcal meningoencephalitis is highly dependent on early diagnosis, adequate treatment, including dosage, and last but not least control of underlying disease and risk factors. PMID- 24947768 TI - Tourniquet modification of the associating liver partition and portal ligation for staged hepatectomy procedure. AB - BACKGROUND: In staged liver resections, associating liver partition and portal ligation for staged hepatectomy (ALPPS) achieves sufficient hypertrophy of the future liver remnant (FLR) in 7 days. This is based on portal vein ligation and transection, and on occlusion of intrahepatic collaterals. This article presents a new surgical technique for achieving rapid hypertrophy of the FLR, which also involves adding intrahepatic collateral occlusion to portal vein transection. METHODS: Patients scheduled for two-stage liver resection for primary or secondary liver tumours, in whom the FLR was considered too small, were enrolled prospectively. In the first stage, a tourniquet was placed around the parenchymal transection line, and the right portal vein was ligated and cut (associating liver tourniquet and portal ligation for staged hepatectomy, ALTPS). The tourniquet was placed on the umbilical ligament if a staged right trisectionectomy was planned, and on Cantlie's line for staged right hepatectomy. RESULTS: From September 2011, 22 ALTPS procedures were carried out (right trisectionectomy in 15, right hepatectomy in 7). Median FLR at 7 days increased from 410 to 700 ml (median increase 61 (range 33-189) per cent). The median duration of the first stage was 125 min and no patient received a blood transfusion. The median duration of the second stage was 150 min and five patients required a blood transfusion. Fourteen patients had complications, most frequently infected collections, and five patients developed postoperative liver failure. Two patients died. CONCLUSION: The ALTPS technique achieved adequate hypertrophy of the FLR after 7 days. It may provide a less aggressive modification of the ALPPS procedure. PMID- 24947769 TI - Bilirubin oxidase-like proteins from Podospora anserina: promising thermostable enzymes for application in transformation of plant biomass. AB - Plant biomass degradation by fungi is a critical step for production of biofuels, and laccases are common ligninolytic enzymes envisioned for ligninolysis. Bilirubin oxidases (BODs)-like are related to laccases, but their roles during lignocellulose degradation have not yet been fully investigated. The two BODs of the ascomycete fungus Podospora anserina were characterized by targeted gene deletions. Enzymatic assay revealed that the bod1(Delta) and bod2(Delta) mutants lost partly a thermostable laccase activity. A triple mutant inactivated for bod1, bod2 and mco, a previously investigated multicopper oxidase gene distantly related to laccases, had no thermostable laccase activity. The pattern of fruiting body production in the bod1(Delta) bod2(Delta) double mutant was changed. The bod1(Delta) and bod2(Delta) mutants were reduced in their ability to grow on ligneous and cellulosic materials. Furthermore, bod1(Delta) and bod2(Delta) mutants were defective towards resistance to phenolic substrates and H2 O2 , which may also impact lignocellulose breakdown. Double and triple mutants were more affected than single mutants, evidencing redundancy of function among BODs and mco. Overall, the data show that bod1, bod2 and mco code for non canonical thermostable laccases that participate in the degradation of lignocellulose. Thanks to their thermal stability, these enzymes may be more promising candidate for biotechnological application than canonical laccases. PMID- 24947770 TI - Non-alcoholic fatty liver disease, metabolic syndrome and patatin-like phospholipase domain-containing protein3 gene variants. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease was traditionally interpreted as a condition which may progress to liver-related complications. However, the increased mortality is primarily a result of cardiovascular diseases. It has been suggested that fatty liver can be considered as the hepatic consequence of the metabolic syndrome. The aim was to describe the different clinical presentations of non-alcoholic fatty liver disease on the basis of the patatin-like phospholipase domain-containing protein3 (PNPLA3) rs738409 gene variant. METHODS: Fatty liver was defined by ultrasonographic Hamaguchi's criteria in 211 consecutive subjects with non-alcoholic fatty liver disease. The rs738409 polymorphism was determined by TaqMan assays. Metabolic syndrome was defined according to ATPIII modified criteria. RESULTS: Prevalence of PNPLA3 148II, PNPLA3-148IM, and PNPLA3-148MM genotypes was 45.0%, 40.7%, and 14.3% respectively. Prevalence of metabolic syndrome progressively increased with the severity of liver steatosis (from 52.5% to 65.2%, and 82.3% respectively, p<0.01). The PNPLA3-148MM group had significantly lower mean serum triglycerides (p<0.001), Framingham cardiovascular risk score (p<0.01) and lower prevalence of metabolic syndrome (p<0.05) and its components. Age and HOMA-IR were positive independent predictors of metabolic syndrome, while a negative independent association was found between metabolic syndrome and the homozygotes PNPLA3 I148M variant. CONCLUSIONS: We suggest a lower prevalence of MetS and reduced cardiovascular risk in NAFLD patients with PNPLA3MM genotype. PMID- 24947771 TI - Debated waters. PMID- 24947777 TI - Nanoscale friction: Sliding charges. PMID- 24947778 TI - Material witness: The clean air act. PMID- 24947779 TI - Crystal nucleation: Zeroing in on ice. PMID- 24947780 TI - Supercooled water: Continuous trends. PMID- 24947781 TI - Supercooled water: Two phases? PMID- 24947784 TI - Lapatinib induces autophagic cell death and inhibits growth of human hepatocellular carcinoma. AB - Lapatinib, an orally administered small-molecule tyrosine kinase inhibitor targeting epidermal growth factor receptors (EGFR) and Her2/Neu, has been widely accepted in the treatment of breast cancer. In this study, we found that lapatinib induced cytotoxicity in human hepatoma Huh7, HepG2 and HA22T cells. For the mode of cell death, we found lapatinib induced a higher percent of dead cells and a lower percent of hypodiploid cells, suggesting non-apoptotic cell death in lapatinib-treated hepatoma cells. Moreover, lapatinib-induced autophagy in hepatoma cells was confirmed by the detection of autophagic LC3-II conversion, the up-regulation of autophagy-related proteins, and the down-regulation of p62 by immunoblotting. Autophagic cell death was demonstrated by images of punctuated LC3 patterns, a higher percent of acridine orange positive cells, as well as a partial rescue of cell death by autophagy inhibitor 3-methyladenine or chloroquine. We also found massive vacuoles in lapatinib-treated hepatoma cells by electronic microscopy. In addition, the shRNA of knocked-down autophagy related proteins rescued the hepatoma cells from lapatinib-induced growth inhibition. We also demonstrated a reduction of tumorigenesis by lapatinib in vivo. In conclusion, lapatinib induced autophagic cell death and the growth of human hepatoma cells. Our study provides potential cancer therapies by using lapatinib as a treatment for hepatoma. PMID- 24947785 TI - Joint modeling of longitudinal and survival data with missing and left-censored time-varying covariates. AB - We propose a joint model for longitudinal and survival data with time-varying covariates subject to detection limits and intermittent missingness at random. The model is motivated by data from the Multicenter AIDS Cohort Study (MACS), in which HIV+ subjects have viral load and CD4 cell count measured at repeated visits along with survival data. We model the longitudinal component using a normal linear mixed model, modeling the trajectory of CD4 cell count by regressing on viral load, and other covariates. The viral load data are subject to both left censoring because of detection limits (17%) and intermittent missingness (27%). The survival component of the joint model is a Cox model with time-dependent covariates for death because of AIDS. The longitudinal and survival models are linked using the trajectory function of the linear mixed model. A Bayesian analysis is conducted on the MACS data using the proposed joint model. The proposed method is shown to improve the precision of estimates when compared with alternative methods. PMID- 24947786 TI - Changes in BMI before and during economic development and subsequent risk of cardiovascular disease and total mortality: a 35-year follow-up study in China. AB - OBJECTIVE: It is unclear whether changes in BMI during rapid economic development influence subsequent mortality. RESEARCH DESIGN AND METHODS: We analyzed whether BMI in 1976 and 1994 and changes in BMI during 1976-1994 predict cardiovascular disease (CVD) and all-cause mortality in a 35-year follow-up cohort of 1,696 Chinese (1,124 men and 572 women, aged 35-65 years) in Xi'an, China. Participants were categorized as underweight (<18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), and overweight (>=25.0 kg/m(2)). RESULTS: During 51,611 person-years of follow-up, we identified 655 deaths from all causes and 234 from CVD. From 1976 to 1994, the prevalence of overweight rose from 9.2 to 27.8%. With each unit increment in 1976 BMI, multivariate hazard ratios (HRs) (95% CI) were 0.78 (0.72 0.84) for CVD and 0.91 (0.87-0.95) for all-cause mortality. In contrast, corresponding HRs were 1.14 (1.08-1.19) and 1.05 (1.01-1.08) in 1994 BMI. The HRs for each unit increment in BMI change from 1976 to 1994 were 1.35 (1.25-1.41) for CVD and 1.09 (1.05-1.13) for all-cause mortality. Compared with participants with stable normal weight in 1976 and 1994, HRs of all-cause mortality for those who had normal weight in 1976 but became overweight in 1994 and for those who were persistently overweight during 1976-1994 were 1.42 (1.12-1.80) and 1.80 (1.04 3.14), respectively. CONCLUSIONS: Gaining weight with increased BMI at middle age in Chinese during economic development was associated with elevated risks of all cause and CVD mortality. Higher BMI measured before economic development was associated with lower mortality risk, whereas BMI measured afterward was associated with increased mortality. PMID- 24947787 TI - Mortality trends among people with type 1 and type 2 diabetes in Australia: 1997 2010. AB - OBJECTIVE: With improvements in cardiovascular disease (CVD) rates among people with diabetes, mortality rates may also be changing. However, these trends may be influenced by coding practices of CVD-related deaths on death certificates. We analyzed trends of mortality over 13 years in people with diabetes and quantified the potential misclassification of CVD mortality according to current coding methods. RESEARCH DESIGN AND METHODS: A total of 1,136,617 Australians with diabetes registered on the National Diabetes Services Scheme between 1997 and 2010 were linked to the National Death Index. Excess mortality relative to the Australian population was reported as standardized mortality ratios (SMRs). Potential misclassification of CVD mortality was determined by coding CVD according to underlying cause of death (COD) and then after consideration of both the underlying and other causes listed in part I of the death certificate. RESULTS: For type 1 diabetes, the SMR decreased in males from 4.20 in 1997 to 3.08 in 2010 (Ptrend < 0.001) and from 3.92 to 3.46 in females (Ptrend < 0.01). For type 2 diabetes, the SMR decreased in males from 1.40 to 1.21 (Ptrend < 0.001) and from 1.56 to 1.22 in females (Ptrend < 0.001). CVD deaths decreased from 35.6 to 31.2% and from 31.5 to 27.2% in males and females with type 1 diabetes, respectively (Ptrend < 0.001 for both sexes). For type 2 diabetes, CVD decreased from 44.5 to 29.2% in males and from 45.5 to 31.6% in females (Ptrend < 0.001 for both sexes). Using traditional coding methods, ~38 and 26% of CVD deaths are underestimated in type 1 diabetes and type 2 diabetes, respectively. CONCLUSIONS: All-cause and CVD mortality has decreased in diabetes. However, the total CVD mortality burden is underestimated when only underlying COD is considered. This has important ramifications for understanding mortality patterns in diabetes. PMID- 24947788 TI - Metabolic syndrome, prediabetes, and brain abnormalities on mri in patients with manifest arterial disease: the SMART-MR study. AB - OBJECTIVE: Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors leading to atherosclerosis and diabetes. Diabetes is associated with both structural and functional abnormalities of the brain. MetS, even before diabetes is diagnosed, may also predispose to cerebral changes, probably through shared mechanisms. We examined the association of MetS with cerebral changes in patients with manifest arterial disease. RESEARCH DESIGN AND METHODS: Cross-sectional data on MetS and brain MRI were available in 1,232 participants with manifest arterial disease (age 58.6 +/- 10.1 years; 37% MetS). Volumes of brain tissue, ventricles, and white matter hyperintensities (WMH) were obtained by automated segmentation and expressed relative to intracranial volume. Infarcts were distinguished into lacunar and nonlacunar infarcts. RESULTS: The presence of MetS (n = 451) was associated with smaller brain tissue volume (B -0.72% [95% CI -0.97, -0.47]), even in the subgroup of patients without diabetes (B -0.42% [95% CI -0.71, 0.13]). MetS was not associated with an increased occurrence of WMH or cerebral infarcts. Impaired glucose metabolism, abdominal obesity, and elevated triglycerides were individual components associated with smaller brain volume. Obesity and hypertriglyceridemia remained associated with smaller brain volume when patients with diabetes were excluded. Hypertension was associated with an increased occurrence of WMH and infarcts. CONCLUSIONS: In patients with manifest arterial disease, presence of MetS is associated with smaller brain volume, even in patients without diabetes. Screening for MetS and treatment of its individual components, in particular, hyperglycemia, hypertriglyceridemia, and obesity, may prevent progression of cognitive aging in patients with MetS, even in a prediabetic stage. PMID- 24947789 TI - Do experiences consistent with a medical-home model improve diabetes care measures reported by adult Medicaid patients? AB - OBJECTIVE: The patient-centered medical home has gained much traction. Little is known about the relationship between the model and specific health care processes for chronic diseases such as diabetes. This study assesses the impact of features of a medical home on diabetes care. RESEARCH DESIGN AND METHODS: A cross sectional survey of 540 patients with Medicaid (Medi-Cal) health insurance and type 2 diabetes in Los Angeles County was performed. The Primary Care Assessment Tools was used to measure seven features of medical-home performance. RESULTS: The response rate of the patient survey was 68.9%. Patient-reported medical-home performance averaged a score of 2.85 +/- 0.29 (on a 1-4 scale, with 4 equaling the best care). Patients who received more timely and thorough diabetes care reported higher medical-home performance in every feature except for the comprehensiveness-services available. For example, the first-contact access feature score was higher among patients who had an HbA1c test in the past 6 months versus those who did not (2.38 vs. 2.25; P < 0.05). Before and after adjusting for sociodemographics and health status, total medical-home performance was positively associated with each diabetes care measure. A 1-point increase in total medical-home score was associated with 4.53 higher odds of an HbA1c test in the past 6 months and 1.88 higher odds of an eye exam in the past year. CONCLUSIONS: Features consistent with higher medical-home performance are associated with improvements in patient-reported diabetes care process measures, even in this low socioeconomic status setting. The patient-centered medical-home model may help in caring for people with type 2 diabetes. PMID- 24947790 TI - Metabolite traits and genetic risk provide complementary information for the prediction of future type 2 diabetes. AB - OBJECTIVE: A genetic risk score (GRS) comprised of single nucleotide polymorphisms (SNPs) and metabolite biomarkers have each been shown, separately, to predict incident type 2 diabetes. We tested whether genetic and metabolite markers provide complementary information for type 2 diabetes prediction and, together, improve the accuracy of prediction models containing clinical traits. RESEARCH DESIGN AND METHODS: Diabetes risk was modeled with a 62-SNP GRS, nine metabolites, and clinical traits. We fit age- and sex-adjusted logistic regression models to test the association of these sources of information, separately and jointly, with incident type 2 diabetes among 1,622 initially nondiabetic participants from the Framingham Offspring Study. The predictive capacity of each model was assessed by area under the curve (AUC). RESULTS: Two hundred and six new diabetes cases were observed during 13.5 years of follow-up. The AUC was greater for the model containing the GRS and metabolite measurements together versus GRS or metabolites alone (0.820 vs. 0.641, P < 0.0001, or 0.820 vs. 0.803, P = 0.01, respectively). Odds ratios for association of GRS or metabolites with type 2 diabetes were not attenuated in the combined model. The AUC was greater for the model containing the GRS, metabolites, and clinical traits versus clinical traits only (0.880 vs. 0.856, P = 0.002). CONCLUSIONS: Metabolite and genetic traits provide complementary information to each other for the prediction of future type 2 diabetes. These novel markers of diabetes risk modestly improve the predictive accuracy of incident type 2 diabetes based only on traditional clinical risk factors. PMID- 24947791 TI - Basal insulin peglispro demonstrates preferential hepatic versus peripheral action relative to insulin glargine in healthy subjects. AB - OBJECTIVE: We evaluated the endogenous glucose production (EGP) and glucose disposal rate (GDR) over a range of doses of basal insulin peglispro (BIL) and insulin glargine in healthy subjects. RESEARCH DESIGN AND METHODS: This was a single-center, randomized, open-label, four-period, incomplete-block, crossover study conducted in eight healthy male subjects. Subjects had 8-h euglycemic clamps performed with primed, continuous infusions of BIL (5.1 to 74.1 mU/min) in three dosing periods and insulin glargine (20 or 30 mU/m(2)/min) in a fourth period, targeted to achieve 50-100% suppression of EGP. D-[3-(3)H] glucose was infused to assess rates of glucose appearance and disappearance. RESULTS: Mean BIL and insulin glargine concentrations (targeted to reflect the differences in intrinsic affinities of the two basal insulins) ranged from 824 to 11,400 and 212 to 290 pmol/L, respectively, and increased accordingly with increases in dose. Suppression of EGP and stimulation of GDR were observed with increasing concentrations of both insulins. At insulin concentrations where EGP was significantly suppressed, insulin glargine resulted in increased GDR. In contrast, at comparable suppression of EGP, BIL had minimal effect on GDR at lower doses and had substantially less effect on GDR than insulin glargine at higher doses. CONCLUSIONS: The novel basal insulin analog BIL has relative hepatopreferential action and decreased peripheral action, compared with insulin glargine, in healthy subjects. PMID- 24947792 TI - No effect of high-dose vitamin D supplementation on glycemic status or cardiovascular risk factors in subjects with prediabetes. AB - OBJECTIVE: In observational studies, low serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with insulin resistance and other risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS: We present 1 year data from an ongoing 5-year trial in 511 individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) randomly assigned to 20,000 IU/week vitamin D3 or placebo. An oral glucose tolerance test was performed at baseline and after 1 year. RESULTS: Mean baseline serum 25(OH)D was 59.9 nmol/L and 61.1 nmol/L in the vitamin D and placebo groups, respectively, and increased by 45.8 nmol/L and 3.4 nmol/L, respectively. With adjustment for baseline concentrations, no differences in measures of glucose metabolism, insulin secretion or sensitivity, blood pressure, or hs-CRP were found after 1 year. There was a slight, but significant decrease in total and LDL cholesterol in the vitamin D group compared with the placebo group, but as there was also a decrease in HDL cholesterol, the change in the total/HDL cholesterol ratio did not differ significantly. Only analyzing subjects with 25(OH)D <50 nmol/L did not change the results. CONCLUSIONS: This study shows that vitamin D supplementation does not improve glycemic indices, blood pressure, or lipid status in subjects with IFG and/or IGT. PMID- 24947793 TI - Introduction of IADPSG criteria for the screening and diagnosis of gestational diabetes mellitus results in improved pregnancy outcomes at a lower cost in a large cohort of pregnant women: the St. Carlos Gestational Diabetes Study. AB - OBJECTIVE: The use of the new International Association of the Diabetes and Pregnancy Study Groups criteria (IADPSGC) for the diagnosis of gestational diabetes mellitus (GDM) results in an increased prevalence of GDM. Whether their introduction improves pregnancy outcomes has yet to be established. We sought to evaluate the cost-effectiveness of one-step IADPSGC for screening and diagnosis of GDM compared with traditional two-step Carpenter-Coustan (CC) criteria. RESEARCH DESIGN AND METHODS: GDM risk factors and pregnancy and newborn outcomes were prospectively assessed in 1,750 pregnant women from April 2011 to March 2012 using CC and in 1,526 pregnant women from April 2012 to March 2013 using IADPSGC between 24 and 28 weeks of gestation. Both groups received the same treatment and follow-up regimes. RESULTS: The use of IADPSGC resulted in an important increase in GDM rate (35.5% vs. 10.6%) and an improvement in pregnancy outcomes, with a decrease in the rate of gestational hypertension (4.1 to 3.5%: -14.6%, P < 0.021), prematurity (6.4 to 5.7%: -10.9%, P < 0.039), cesarean section (25.4 to 19.7%: -23.9%, P < 0.002), small for gestational age (7.7 to 7.1%: -6.5%, P < 0.042), large for gestational age (4.6 to 3.7%: -20%, P < 0.004), Apgar 1-min score <7 (3.8 to 3.5%: -9%, P < 0.015), and admission to neonatal intensive care unit (8.2 to 6.2%: -24.4%, P < 0.001). Estimated cost savings was of ?14,358.06 per 100 women evaluated using IADPSGC versus the group diagnosed using CC. CONCLUSIONS: The application of the new IADPSGC was associated with a 3.5-fold increase in GDM prevalence in our study population, as well as significant improvements in pregnancy outcomes, and was cost-effective. Our results support their adoption. PMID- 24947794 TI - Health-related quality of life in Korean lymphoma survivors compared with the general population. AB - The objective of this study was to evaluate the health-related quality of life (HRQOL) of lymphoma survivors, to compare it with that of the general population, and to identify its predictors in lymphoma survivors. We enrolled 837 participants (mean age, 54.6 years; mean time since diagnosis, 6.3 years) with a history of Hodgkin's lymphoma (HL) (n = 58) or non-Hodgkin's lymphoma (NHL) (n = 779) who had been treated at any of three Korean hospitals from 1989 through 2010. For controls, we selected 1,000 subjects randomly from a representative Korean population. We administered the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the Hospital Anxiety and Depression Scale. Overall, the HRQOL in both groups of survivors and the general population were comparable, but we observed clinically meaningful worse social functioning in NHL survivors (p < 0.001) and more severe fatigue in HL survivors (p < 0.001) than in the general population. Analysis of covariance revealed no clinically meaningful difference in HRQOL associated with age or sex. Survivors who received peripheral blood stem cell transplants showed clinically meaningful worse role (p = 0.001) and social (p < 0.001) functioning than those who were treated with first-line chemotherapy alone. In multivariate analyses, fatigue, depression, and financial difficulties emerged as the strongest predictors for almost all subscales of functioning and global quality of life. Interventions for alleviating fatigue, depression, and financial difficulties are needed to enhance the HRQOL of Korean lymphoma survivors. PMID- 24947795 TI - Do UGT1A1 and HMOX1 gene promoter polymorphisms increase the risk of hyperbilirubinemia and gallstones in patients with hereditary spherocytosis? PMID- 24947796 TI - Salvage therapy with single agent L-asparaginase followed by local irradiation in an elderly patient with CD56-positve primary isolated extramedullary T-cell lymphoblastic lymphoma of the sinus. PMID- 24947797 TI - Monoclonal and polyclonal gammopathy measured by serum free light chain and immunofixation subdivide the clinical outcomes of diffuse large B-cell lymphoma according to molecular classification. AB - Elevated serum free light chain (FLC) is known to be an adverse prognostic factor for diffuse large B-cell lymphoma (DLBCL). We hypothesized that monoclonal gammopathy (MG; elevated kappa [kappa] or lambda [lambda] FLC with an abnormal kappa/lambda ratio or a positive IF [immunofixation]) and polyclonal gammopathy (PG; elevated kappa and/or lambda FLC with a normal kappa/lambda ratio and a negative IF) would have different clinical outcome according to the molecular classification of DLBCL. In addition, MG would be a poor prognostic factor in patients with activated B-cell like type of DLBCL. Molecular classification of DLBCL, such as germinal center B-cell (GCB) type and non-GCB type, was performed according to the Hans algorithm. Among 175 newly diagnosed DLBCL patients, 96 (54.9 %) patients had an elevated FLC. MG and PG were observed in 34 and 68 patients, respectively. The 2-year overall survival (OS) and event-free survival (EFS) rates were 79.0 % and 71.6 %, respectively. In multivariate analysis, high intermediate/high International Prognostic Index score and elevated FLC were significant for the OS (P = 0.002, P = 0.005, respectively) and EFS (P < 0.002, P = 0.010, respectively). MG and PG were also associated with inferior OS (P = 0.002, P = 0.011, respectively) and EFS (P = 0.002, P = 0.013, respectively). Ninety-six patients from a total 133 evaluable patients were classified to the non-GCB type. Patients with PG showed inferior clinical outcome for OS and EFS in patients with the GCB type (P = 0.006, P = 0.035, respectively). MG was a significant poor prognostic factor for OS and EFS in patients with the non-GCB type (P = 0.017, P = 0.004, respectively). MG was a poor prognostic maker in patients with the non-GCB type and PG was a poor prognostic indicator for the GCB type of DLBCL who were treated with R-CHOP. PMID- 24947798 TI - Concurrent chemoradiotherapy followed by L-asparaginase-containing chemotherapy, VIDL, for localized nasal extranodal NK/T cell lymphoma: CISL08-01 phase II study. AB - We conducted a phase II trial of concurrent chemoradiotherapy (CCRT) followed by 2 cycles of L-asparaginase-containing chemotherapy for patients who were newly diagnosed with stages IE and IIE nasal extranodal NK/T cell lymphoma (ENKTL). CCRT consisted of 40-44 Gy of radiotherapy with weekly administration of 30 mg/m(2) of cisplatin for 4 weeks. Two cycles of VIDL (etoposide (100 mg/m(2)), ifosfamide (1,200 mg/m(2)), and dexamethasone (40 mg) from days 1 to 3, and L asparaginase (4,000 IU/m(2)) every other day from days 8 to 20) were administered sequentially. CCRT yielded a 90 % overall response rate without significant side effects in 30 patients, including 20 patients with complete response (CR); however, two patients showed distant disease progression. After CCRT, VIDL chemotherapy showed an 87 % final CR rate (26/30). Although grade III or IV hematologic toxicity was frequent during VIDL chemotherapy, no treatment-related mortality was observed, and L-asparaginase-associated toxicity was manageable. With a median follow-up of 44 months, 11 patients showed local (n = 4) and distant (n = 7) relapse or progression. The estimated 5-year progression-free and overall survival rates were 73 and 60 %, respectively. In conclusion, CCRT followed by L-asparaginase-containing chemotherapy is a feasible treatment for newly diagnosed stages IE/IIE nasal ENKTL. PMID- 24947799 TI - Sleep problems and psychological distress in family members of patients with hematological malignancies in the Japanese population. AB - Patients with cancer frequently suffer from insomnia symptoms, and additionally, their family members also often experience these symptoms. The aim of this study was to investigate the prevalence of insomnia symptoms in both family members and patients with hematological malignancies. We conducted an observational cross sectional study using a clinical self-reported questionnaire for sleep conditions, depressive symptoms (two-question method), and worries (five items that originated from the Brief Cancer Worry Inventory). One hundred twelve family members and 153 patients were investigated. A t test and Chi-square test were used to compare the prevalence of insomnia and depressive symptoms between family members and patients. Logistic regression was used to determine whether insomnia symptoms or worries related to patients' disease had an impact on depressive symptoms. The presence of insomnia symptoms in family members (87 %) was significantly higher than that in patients (60 %, p < 0.001). The prevalence of depressive mood and anhedonia in family members were 55 and 34 %, respectively, and these values were higher than those in patients (43 and 28 %, respectively). Insomnia symptoms and worries about present/prospective disease conditions were significantly associated with depressive mood (insomnia symptoms, odds ratios (OR) 4.3, confidence intervals (CI) 1.2-15.2, p = 0.025; worries, OR 4.4, CI 1.0 19.3, p = 0.048). Taken together, our results demonstrated that insomnia symptoms and depressive symptoms are highly prevalent in family members as well as in patients with hematological malignancies. PMID- 24947800 TI - Spermiophagic activity in the female genital system of some species of terrestrial isopods (Crustacea, Halophilosciidae). AB - The females of some species of the family Halophilosciidae receive in the course of mating a quantity of sperm considerably redundant with respect to the number of eggs that can be fertilized; this is possible thanks to the peculiar morpho functional organization that characterizes their genital system and that allows them to store the sperm not only in the great seminal receptacle but also within the ovary. While most of the sperm stay free in the lumen of the seminal receptacle, a part of those present in the ovary undergoes a process of capture by the follicular cells with consequent internalization within endocellular cavities. This process concerns exclusively the immotile tail, that characterizes the peculiar spermatozoon of the isopods and which is essentially of proteic nature. After their capture the sperm tails undergo a gradual process of digestion, which seems to be apparently realized without the intervention of lysosomes. The possible role of this spermiophagic activity might be to represent a significant trophic paternal investment aimed at improving the fitness of the female and of the offsprings. PMID- 24947801 TI - Decisive influence of substitution positions in molecular self-assembly. AB - Molecular self-assembly provides a versatile tool for creating functional molecular structures at surfaces. A rational design of molecular structure formation requires not only an in-depth understanding of the subtle balance between intermolecular and molecule-surface interactions, but might also involve considering chemical changes of the molecules, such as deprotonation. Here, we present a systematic investigation of a comparatively simple class of molecules, namely dihydroxybenzoic acid, which, nevertheless, enables creating a rich variety of structures when deposited onto calcite (10.4) held at room temperature. Based on non-contact atomic force microscopy measurements in ultra high vacuum, our study demonstrates the decisive impact of the positions of the hydroxyl groups on the structure formation. Six isomers of dihydroxybenzoic acid exist which form six different molecular structures on the calcite surface. Surprisingly, only two isomers arrange into stable, ordered structures at sub monolayer coverage: 2,5-dihydroxybenzoic acid forms a commensurate (1 * 5) structure, composed of deprotonated molecules. A double-row structure consisting of protonated molecules is observed for 3,5-dihydroxybenzoic acid. The positions of the functional groups steer the molecular self-assembly of dihydroxybenzoic acids in three distinct ways, namely by (a) affecting the deprotonation tendency of the acid group, (b) influencing the intermolecular interaction as already indicated by greatly different bulk structures and (c) altering the molecule substrate matching. Our results, thus, shed light on the impact of rather small changes in the molecular structure on the structural variety in molecular self assembly on surfaces. PMID- 24947802 TI - Uncovering allosteric pathways in caspase-1 using Markov transient analysis and multiscale community detection. AB - Allosteric regulation at distant sites is central to many cellular processes. In particular, allosteric sites in proteins are major targets to increase the range and selectivity of new drugs, and there is a need for methods capable of identifying intra-molecular signalling pathways leading to allosteric effects. Here, we use an atomistic graph-theoretical approach that exploits Markov transients to extract such pathways and exemplify our results in an important allosteric protein, caspase-1. Firstly, we use Markov stability community detection to perform a multiscale analysis of the structure of caspase-1 which reveals that the active conformation has a weaker, less compartmentalised large scale structure compared to the inactive conformation, resulting in greater intra protein coherence and signal propagation. We also carry out a full computational point mutagenesis and identify that only a few residues are critical to such structural coherence. Secondly, we characterise explicitly the transients of random walks originating at the active site and predict the location of a known allosteric site in this protein quantifying the contribution of individual bonds to the communication pathway between the active and allosteric sites. Several of the bonds we identify have been shown experimentally to be functionally critical, but we also predict a number of as yet unidentified bonds which may contribute to the pathway. Our approach offers a computationally inexpensive method for the identification of allosteric sites and communication pathways in proteins using a fully atomistic description. PMID- 24947803 TI - Association of genetic variants with non-alcoholic fatty liver disease in an urban Sri Lankan community. PMID- 24947804 TI - Is enough attention given to climate change in health service planning? An Australian perspective. AB - BACKGROUND: Within an Australian context, the medium to long-term health impacts of climate change are likely to be wide, varied and amplify many existing disorders and health inequities. How the health system responds to these challenges will be best considered in the context of existing health facilities and services. This paper provides a snapshot of the understanding that Australian health planners have of the potential health impacts of climate change. METHODS: The first author interviewed (n=16) health service planners from five Australian states and territories using an interpretivist paradigm. All interviews were digitally recorded, key components transcribed and thematically analysed. RESULTS: Results indicate that the majority of participants were aware of climate change but not of its potential health impacts. Despite this, most planners were of the opinion that they would need to plan for the health impacts of climate change on the community. CONCLUSION: With the best available evidence pointing towards there being significant health impacts as a result of climate change, now is the time to undertake proactive service planning that address market failures within the health system. If considered planning is not undertaken then Australian health system can only deal with climate change in an expensive ad hoc, crisis management manner. Without meeting the challenges of climate change to the health system head on, Australia will remain unprepared for the health impacts of climate change with negative consequences for the health of the Australian population. PMID- 24947805 TI - The serum- & glucocorticoid-inducible kinase in the regulation of platelet function. AB - The serum- and glucocorticoid-inducible kinase 1 (SGK1) is expressed in megakaryocytes and circulating platelets. In megakaryocytes, SGK1 activates transcription factor nuclear factor kappa-B (NF-kappaB), which in turn stimulates expression of Orai1, a Ca(2+) channel protein accomplishing store-operated Ca(2+) enrty (SOCE). SGK1 enhances SOCE and several Ca(2+) -sensitive platelet functions, including degranulation, integrin alphaII b beta3 activation, phosphatidylserine exposure, aggregation and thrombus formation. As shown in other cell types, stimulators of SGK1 expression include ischaemia, oxidative stress, hyperglycaemia, advanced glycation end products (AGEs) and a variety of hormones such as glucocorticoids, mineralocorticoids, transforming growth factor beta (TGFbeta), interleukin 6 (IL-6), platelet-derived growth factor (PDGF), thrombin and endothelin. Thus, SGK1-sensitive Ca(2+) signalling may contribute to altered platelet function in several clinical conditions including inflammation, metabolic syndrome, diabetes mellitus and chronic renal failure. Nevertheless, further studies are needed defining the contribution of altered SGK1 expression and activity to physiology and pathophysiology of platelets. PMID- 24947806 TI - Improvement of a dry formulation of Pseudomonas fluorescens EPS62e for fire blight disease biocontrol by combination of culture osmoadaptation with a freeze drying lyoprotectant. AB - AIMS: To study the effect of lyoprotectants and osmoadaptation on viability of Pseudomonas fluorescens EPS62e during freeze-drying and storage and to evaluate the formulation in terms of efficacy in biocontrol and fitness on pear flowers. METHODS AND RESULTS: A wettable powder formulation of a biocontrol agent of fire blight was optimized by means of lyoprotectants and culture osmoadaptation. Freeze-drying was used to obtain dehydrated cells, and the best viability (70% of survival) was obtained using lactose as lyoprotectant. Survival during lyophilization was additionally improved using physiological adaptation of cells during cultivation under salt-amended medium (osmoadaptation). The procedure increased the survival of cells after freeze-drying attaining viability values close to a 100% in the lactose-formulated product (3 * 10(11) CFU g(-1) ), and through the storage period of 1 year at 4 degrees C. The dry formulation showed also an improved biocontrol efficacy and survival of EPS62e on pear flowers under low relative humidity conditions. CONCLUSIONS: Cell viability after freeze-drying was improved using lactose as lyoprotectant combined with a procedure of osmoadaptation during cultivation. The powder-formulated product remained active for 12 months and retained biocontrol levels similar to that of fresh cells. The formulation showed an improved survival of EPS62e on flowers and an increase of the efficacy of biocontrol of fire blight at low relative humidity. SIGNIFICANCE AND IMPACT OF THE STUDY: The results have a potential value for commercial application in biocontrol agents not only of fire blight but also of other plant diseases. PMID- 24947807 TI - Comparison of different types of outlet frits in slurry-packed capillary columns. AB - Fused-silica capillary columns for high-performance liquid chromatography with 320 and 250 MUm inner diameter were prepared by slurry packing with 5 and 3 MUm Nucleosil C18 stationary phase. Different types of mechanical and monolithic outlet frits were used and their influence on the resulting column performance was evaluated. Columns with quartz wool exhibited symmetrical peaks and low theoretical plate height, and the preparation time was short. The performance of monolithic frits varied based on type of monolith, length of the frit, and silanization procedure. The best frit performed similarly to the quartz wool ones, but the preparation took several hours. Their main advantage lies in the possibility of on-column detection, because the detection window can be burnt immediately behind the frit. PMID- 24947809 TI - Muscle oxygenation of superficial and deep regions in knee extensor and plantar flexor muscles during repeated isometric contractions. AB - AIM: The purpose of this study was to investigate changes in muscle oxygenation of knee extensor and plantar flexor muscles during repeated muscle contractions under the same condition. In addition, we compared changes in muscle oxygenation between superficial and deep regions of both muscles. METHODS: Eleven healthy males participated in this study. During repeated knee extensions and plantar flexions (50 repetitions at 50% of the isometric maximum voluntary contraction for 3 s with 3 s relaxations), blood volume and oxygen saturation (StO2) of the vastus lateralis and medial gastrocnemius muscles (superficial and deep region of each muscle) were measured using near infrared spectroscopy. RESULTS: The decrement of StO2at the end of exercises was greater in plantar flexor muscle than in knee extensor muscle (P<0.001). For both muscles, the decrement of StO2at the end of exercises was greater in the deep region than in the superficial one (both P<0.001). CONCLUSION: These results suggested that the oxygen utilization of plantar flexor muscle and deep regions of each muscle were higher than that of knee extensor muscle and superficial regions of each muscle. PMID- 24947808 TI - Effect of a long-term regular physical activity on hypertension and body mass index in type 2 diabetes patients. AB - AIM: Hypertension and overweight are prevalent problems in type 2 diabetic patients. The purpose of this study was to assess the effects of long term regular aerobic exercise training on blood pressure (BP) as well as body mass index (BMI) in type 2 diabetes mellitus (T2DM). METHODS: In a randomized, controlled trial, 60 patients with T2DM aged 40-65 years were randomly divided in two groups (30 subjects in exercise group and 30 subjects in control group). Supervised exercise program was performed three times per week for 3 years. Finally, 28 patients who completed the optimal sessions, entered in statistical analysis. RESULTS: Systolic and diastolic blood pressure (SBP, DBP) had no significant changes in control group (respectively 127.48+/-12.79 to 129.28+/ 8.52 and 78.90+/-8.06 to 77.55+/-5.95). These changes were statistically significant in the exercise group (respectively 132.57+/-14.82 to 118.00+/-12.48 and 82.89+/-9.19 to 74.00+/-6.57; P<0.001). Furthermore, the BMI of exercise group reduced significantly (28+/-5.26 to 26.42+/-4.36; P<0.001) in comparison with control group that showed a significant increase in terms of this variable (30.02+/-4.79 to 31.05+/-4.84; P<0.05). CONCLUSION: The present study suggests that long term aerobic exercise has positive effects on systolic and diastolic blood pressure as well as heart rate of T2DM patients. We observed significant differences in levels of BMI in two groups after intervention. PMID- 24947810 TI - Relationships between oxygen uptake, dynamic body acceleration and heart rate in humans. AB - AIM: Accurate estimation of energy expenditure (EE) is important in human and animal behavior analysis. Rate of oxygen consumption (VO2) reflects EE during aerobic metabolism but is not always convenient. Alternative methods include heart rate (HR) and overall dynamic body acceleration (ODBA). A favorable ODBA VO2 relationship was recently reported but the strength of association between VO2, ODBA, HR and its variability (HRV) is less clear. METHOD: Fifteen young (23+/-4 years) healthy males of similar aerobic fitness (maximal oxygen uptake, VO2max=49.7+/-8.5 mL.kg(-1).min(-1)) carried out progressive maximal exercise. ODBA, HRV and VO2 were recorded continuously. Relationships between ODBA, HRV and VO2 were explored using regression methods. RESULTS: VO2 was strongly related to ODBA and RR during walking (R=0.45,0.30; P<5x10(-5)) and running (R=0.60,0.38; P<5x10(-5)). HRV was related to VO2 during walking only (R=0.11-0.26; 0.005=4% from baseline) was measured indirectly using an ear-lobe pulse oximeter included in the K4 (Cosmed) used for measured cardiorespiratory responses. RESULTS: During the R test, 9 athletes developed EIH whereas only 7 in SR test. Tests duration was the same furthermore at the end of tests, fall of SpO2 was significantly higher in R compared to RS (-9.11+/-1.51 vs. -5.89+/-1.09; P<0.01). SpO2 was significantly lower in R compared to RS from 75% of VO2max to VO2max (P<0.05). VO2max was significantly higher in R than in RS (61.33+/-6.36 vs. 57+/-6.60 mL.min-1.kg-1; P<0.001). No difference of maximal heart rate, global ventilation, tidal volume or respiratory frequency was present during and at the end of tests. CONCLUSION: We concluded that prevalence and severity of EIH was more important during R than RS exercises and that EIH differences may be due to a greater gas exchange abnormality in R. PMID- 24947812 TI - Combined isometric and vibration training does not enhance strength beyond that of isometric training alone. AB - AIM: Research considering combined vibration and strength training is extensive yet results are equivocal. However, to date there appears no research which has considered the combination of both direct vibration and whole-body vibration when used in an isometric deadlift position. The aim of this study was to compare groups performing isometric training with and without direct and whole-body vibration. METHODS: Twenty four participants (19-24 years) were randomly divided into: isometric training with vibration (ST+VT: N.=8), isometric training without vibration (ST: N.=8), and control (CON: N.=8). Within the training groups participants trained twice per week, for 6 weeks, performing 6-sets of maximal isometric deadlift contractions, increasing in duration from 30 seconds to 40 seconds (weeks 1-6). Hip and knee angle was maintained at 60 degrees and 110 degrees , respectively for both testing and training. Training sessions for ST+VT were identical to ST with the addition of a direct vibratory stimulus through hand-held straps and whole-body vibration via standing on vibration a platform. The amplitude remained constant (2 mm) throughout the intervention whilst the frequency increased from 35Hz to 50Hz. Pre- and post-test isometric strength was measured using an isometric deadlift dynamometer. RESULTS: Results revealed significant increases in isometric strength for both ST+VT (P<0.001, 23.8%) and ST (P<0.001, 32.5%) compared to CON, with no significant differences between ST+VT and ST training groups. CONCLUSION: The present study provides evidence to suggest that there are no greater gains to be incurred by the addition of a vibratory stimulus to traditional strength training. PMID- 24947813 TI - Physical demands in elite team handball: comparisons between male and female players. AB - AIM: The aim of the present study was to examine potential differences in the physical demands imposed on male vs. female adult elite team handball players during match-play. METHODS: Male and female elite team handball players were monitored over a six and five season time span, respectively. Each player was evaluated during match-play by use of video recording and subsequent computerized locomotive and technical match analysis. Furthermore, physiological measurements during match-play, physical testing and anthropometric measurements were performed. RESULTS: Female players (FP, N.=82) covered a longer mean total distance per match (4693+/-333 m, group means+/-SD) compared to male players (MP, N.=83, 3945+/-538 m) when playing full time (P<0.01). FP exercised at a greater relative workload (79.4% of VO2-max) than MP (70.9% of VO2-max, P<0.05), but performed less high-intense running per match (2.5% of total distance covered) than MP (7.9%, P<0.01). FP also spent less time standing still (10.8% of total effective playing time) compared to MP (36.9%, P<0.001) and showed fewer activity changes (663.8+/-99.7) compared to MP (1482.4+/-312.6, P<0.001). MP received more tackles in total in offence (34.5+/-21.3) and performed more tackles in total in defence (29.9+/-12.3) compared to FP (14.6+/-9.2, 20.7+/-9.7, P<0.05). Furthermore, MP performed more high-intense technical playing actions per match (36.9+/-13.1) than FP (28.3+/-11.0, P<0.05). The mean body height and body mass differed between MP (189.6+/-5.8 cm, 91.7+/-7.5 kg) and FP (175.4+/-6.1 cm, 69.5+/-6.5 kg, P<0.001). CONCLUSIONS: Substantial gender-specific differences in the physical demands in elite team handball were observed, with MP performing more high-intense, strength-related playing actions and high-intensity running than FP. Conversely, FP covered a greater total distance and demonstrated a higher relative workload than MP. The physical training of male and female elite team handball players should be designed to reflect these contrasting needs. PMID- 24947814 TI - One injection of platelet-rich plasma associated to a submaximal eccentric protocol to treat chronic jumper's knee. AB - AIM: Jumper's knee is a frequent chronic overuse syndrome of the proximal part of the patellar tendon. Platelets contain lots of growth factors which could enhance the healing process of tendons. The aim of this study was to clarify the possible efficacy of one injection of Platelet-rich plasma (PRP) in cases of rebel jumper's knees. METHODS: Twenty patients with chronic proximal patellar tendinopathy were enrolled. Assessments were made before infiltration of PRP, and 6 weeks and 3 months after the infiltration, using a 10-point visual analogic scale of pain, clinical examinations with a pressure algometer, algofunctional scores (IKDC and VISA-P), functional assessments (isokinetic and optojump evaluations) and imagery (ultrasounds and MRI). The PRP was obtained with an apheresis system (COMTEC(r), Fresenius-Kabi, Bad Homburg, Germany). Six millilitres of PRP were injected without local anesthetic. One week after infiltration, patients started a standardized sub-maximal eccentric reeducation. RESULTS: During daily activities pain significantly decreased with time. At functional evaluation, it decreased as well, but without significant functional improvement. No improvements in the imagery measurements were observed. Younger patients seemed to be more susceptible to have an improvement of pain by the PRP infiltration. CONCLUSION: This study demonstrates that a local infiltration of PRP associated with a submaximal eccentric protocol can improve symptoms of chronic jumper's knee in patients non-responsive to classical conservative treatments. PMID- 24947815 TI - Intracellular selection of peptide inhibitors that target disulphide-bridged Abeta42 oligomers. AB - The beta-amyloid (Abeta) peptide aggregates into a number of soluble and insoluble forms, with soluble oligomers thought to be the primary factor implicated in Alzheimer's disease pathology. As a result, a wide range of potential aggregation inhibitors have been developed. However, in addition to problems with solubility and protease susceptibility, many have inadvertently raised the concentration of these soluble neurotoxic species. Sandberg et al. previously reported a beta-hairpin stabilized variant of Abeta42 that results from an intramolecular disulphide bridge (A21C/A31C; Abeta42cc), which generates highly toxic oligomeric species incapable of converting into mature fibrils. Using an intracellular protein-fragment complementation (PCA) approach, we have screened peptide libraries using E. coli that harbor an oxidizing environment to permit cytoplasmic disulphide bond formation. Peptides designed to target either the first or second beta-strand have been demonstrated to bind to Abeta42cc, lower amyloid cytotoxicity, and confer bacterial cell survival. Peptides have consequently been tested using wild-type Abeta42 via ThT binding assays, circular dichroism, MTT cytotoxicity assays, fluorescence microscopy, and atomic force microscopy. Results demonstrate that amyloid-PCA selected peptides function by both removing amyloid oligomers as well as inhibiting their formation. These data further support the use of semirational design combined with intracellular PCA methodology to develop Abeta antagonists as candidates for modification into drugs capable of slowing or even preventing the onset of AD. PMID- 24947816 TI - Why are the truncated cyclin Es more effective CDK2 activators than the full length isoforms? AB - Cell cycle regulating enzymes, CDKs, become activated upon association with their regulatory proteins, cyclins. The G1 cyclin, cyclin E, is overexpressed and present in low molecular weight (LMW) isoforms in breast cancer cells and tumor tissues. In vivo and in vitro studies have shown that these LMW isoforms of cyclin E hyperactivate CDK2 and accelerate the G1-S phase of cell division. The molecular basis of CDK2 hyperactivation due to LMW cyclin E isoforms in cancer cells is, however, unknown. Here, we employ a computational approach, combining homology modeling, bioinformatics analyses, molecular dynamics (MD) simulations, and principal component analyses to unravel the key structural features of CDK2 bound full-length and LMW isoforms of cyclin E1 and correlate those features to their differential activity. Results suggest that the missing N- and C-terminal regions of the cyclin E LMW isoforms constitute the Nuclear Localization Sequence (NLS) and PEST domains and are intrinsically disordered. These regions, when present in the full-length cyclin E/CDK2 complex, weaken the cyclin-CDK interface packing due to the loss of a large number of key interface interactions. Such weakening is manifested in the decreased contact area and increased solvent accessibility at the interface and also by the absence of concerted motions between the two partner proteins in the full-length complex. More effective packing and interactions between CDK2 and LMW cyclin E isoforms, however, produce more efficient protein-protein complexes that accelerate the cell division processes in cancer cells, where these cyclin E isoforms are overexpressed. PMID- 24947818 TI - Synthesis, antibacterial activities, and theoretical studies of dicoumarols. AB - Four dicoumarols (DC, 2-PyDC, 3-PyDC and 4-PyDC) were synthesized and characterized via IR, (1)H NMR, HRMS, and single crystal X-ray crystallography. Two classical intramolecular O-H...O hydrogen bonds (HBs) stabilized their structures. The total HB energies in DC, 2-PyDC, 3-PyDC and 4-PyDC were calculated with the density functional theory (DFT) [B3LYP/6-31G*] method. The in vitro antibacterial activity of DC, 2-PyDC, 3-PyDC and 4-PyDC against Staphylococcus aureus (S. aureus ATCC 29213), methicillin-resistant S. aureus (MRSA XJ 75302), vancomycin-intermediate S. aureus (Mu50 ATCC 700699), and USA 300 (Los Angeles County clone, LAC) was evaluated by observing the minimum inhibitory concentration and time-kill curves. The results showed that among all the compounds, 2-PyDC exhibited the most potent antibacterial activity. PMID- 24947817 TI - Use of drug therapy in the management of symptomatic ureteric stones in hospitalized adults (SUSPEND), a multicentre, placebo-controlled, randomized trial of a calcium-channel blocker (nifedipine) and an alpha-blocker (tamsulosin): study protocol for a randomized controlled trial. AB - BACKGROUND: Urinary stone disease is common, with an estimated prevalence among the general population of 2% to 3%. Ureteric stones can cause severe pain and have a significant impact on quality of life, accounting for over 15,000 hospital admissions in England annually. Uncomplicated cases of smaller stones in the lower ureter are traditionally treated expectantly. Those who fail standard care or develop complications undergo active treatment, such as extracorporeal shock wave lithotripsy or ureteroscopy with stone retrieval. Such interventions are expensive, require urological expertise and carry a risk of complications.Growing understanding of ureteric function and pathophysiology has led to the hypothesis that drugs causing relaxation of ureteric smooth muscle, such as the selective alpha-blocker tamsulosin and the calcium-channel blocker nifedipine, can enhance the spontaneous passage of ureteric stones. The use of drugs in augmenting stone passage, reducing the morbidity and costs associated with ureteric stone disease, is promising. However, the majority of clinical trials conducted to date have been small, poor to moderate quality and lacking in comprehensive economic evaluation.This trial aims to determine the clinical and cost-effectiveness of tamsulosin and nifedipine in the management of symptomatic urinary stones. METHODS/DESIGN: The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial is a multicentre, double-blind, randomized controlled trial evaluating two medical expulsive therapy strategies (nifedipine or tamsulosin) versus placebo.Patients aged 18 to 65 with a ureteric stone confirmed by non-contrast computed tomography of the kidney, ureter and bladder will be randomized to receive nifedipine, tamsulosin or placebo (400 participants per arm) for a maximum of 28 days. The primary clinical outcome is spontaneous passage of ureteric stones at 4 weeks (defined as no further intervention required to facilitate stone passage). The primary economic outcome is a reduction in the incremental cost per quality-adjusted life years, determined at 12 weeks. The analysis will be based on all participants as randomized (intention to treat). The trial has 90% power with a type I error rate of 5% to detect a 10% increase in primary outcome between the tamsulosin and nifedipine treatment groups. TRIAL REGISTRATION: ISRCTN69423238; EudraCT number: 2010-019469-26. PMID- 24947819 TI - Epigenetic regulation by chromatin activation mark H3K4me3 in primate progenitor cells within adult neurogenic niche. AB - Histone 3 lysine 4 trimethylation (H3K4me3) is known to be associated with transcriptionally active or poised genes and required for postnatal neurogenesis within the subventricular zone (SVZ) in the rodent model. Previous comparisons have shown significant correlation between baboon (Papio anubis) and human brain. In this study, we demonstrate that chromatin activation mark H3K4me3 is present in undifferentiated progenitor cells within the SVZ of adult baboon brain. To identify the targets and regulatory role of H3K4me3 within the baboon SVZ, we developed a technique to purify undifferentiated SVZ cells while preserving the endogenous nature without introducing culture artifact to maintain the in vivo chromatin state for genome-wide studies (ChIP-Seq and RNA-Seq). Overall, H3K4me3 is significantly enriched for genes involved in cell cycle, metabolism, protein synthesis, signaling pathways, and cancer mechanisms. Additionally, we found elevated levels of H3K4me3 in the MRI-classified SVZ-associated Glioblastoma Multiforme (GBM), which has a transcriptional profile that reflects the H3K4me3 modifications in the undifferentiated progenitor cells of the baboon SVZ. Our findings highlight the importance of H3K4me3 in coordinating distinct networks and pathways for life-long neurogenesis, and suggest that subtypes of GBM could occur, at least in part, due to aberrant H3K4me3 epigenetic regulation. PMID- 24947820 TI - ScFv-decorated PEG-PLA-based nanoparticles for enhanced siRNA delivery to Her2+ breast cancer. AB - Patients with Her2-overexpressing (Her2(+)) breast cancers generally have a poorer prognosis due to the high aggressiveness and chemoresistance of the disease. Small interfering RNA (siRNA) targeting the gene encoding polo-like kinase 1 (Plk1; siPlk1) has emerged as an efficient therapeutic agent for Her2(+) breast cancers. Poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PLA)-based nanoparticles for siRNA delivery were previously developed and optimized. In this study, for targeted delivery of siPlk1 to Her2(+) breast cancer, anti-Her2 single chain variable fragment antibody (ScFv(Her2))-decorated PEG-PLA-based nanoparticles with si Plk1 encapsulation (ScFv(Her2)-NP(si) Plk1) are developed. With the rationally designed conjugation site, ScFv(Her2)-NP(siRNA) can specifically bind to the Her2 antigen overexpressed on the surface of Her2(+) breast cancer cells. Therefore, ScFv(Her2)-NP(si) Plk1 exhibits improved cellular uptake, promoted Plk1 silencing efficiency, and induced enhanced tumor cell apoptosis in Her2(+) breast cancer cells, when compared with nontargeted NP(si) Plk1. More importantly, ScFv(Her2)-NP(siRNA) markedly enhances the accumulation of siRNA in Her2(+) breast tumor tissue, and remarkably improves the efficacy of tumor suppression. Dose-dependent anti-tumor efficacy further demonstrates that ScFvHer2 -decorated PEG-PLA-based nanoparticles with siPlk1 encapsulation can significantly enhance the inhibition of Her2(+) breast tumor growth and reduce the dose of injected siRNA. These results suggest that ScFvHer2 -decorated PEG PLA-based nanoparticles show great potential for targeted RNA interference therapy of Her2(+) breast tumor. PMID- 24947822 TI - Scoping review of patient-centered care approaches in healthcare. AB - BACKGROUND: The purpose of this scoping review was to describe how three tenants of patient-centered care provision: communication, partnership, and health promotion are addressed in patient-centered care models/frameworks across the literature. METHODS: A scoping review of literature published in English since 1990 was conducted using Medline, CINAHL, and EMBASE. A key term search strategy was employed using "patient-centered care", "client-centered care", "framework" and "model" to identify relevant studies. RESULTS: Application of the search strategy resulted in a hit total of 101 articles. Nineteen articles met inclusion criteria, of which 12 were review articles; 5 were qualitative research papers; one was a randomized control trial; and one was a prospective study. From these articles, 25 different patient-centered care frameworks/models were identified. CONCLUSIONS: The fact that all identified approaches to patient-centered care incorporated strategies to achieve effective communication, partnership, and health promotion indicates that clinicians can select a patient-centered approach from the literature that best suits their patient's needs, and be confident that it will satisfy the three core elements of patient-centered care provision. While empirical literature on specific patient-centric frameworks and models was limited, much empiric evidence was sourced for the most consistently defined component of patient-centered care, communication. PMID- 24947824 TI - Changes of plasma concentration of osteoprotegerin and its association with endothelial dysfunction before and after hypouricemic therapy in patients with hyperuricemia. AB - OBJECTIVE: Osteoprotegerin (OPG) is a secreted glycoprotein in the regulation of bone turnover. Recently, many studies showed that OPG acts as an important regulatory molecule in the vascular systems. Our objective was to examine the plasma OPG levels alteration and its association with endothelial function before and after hypouricemic therapy in patients with hyperuricemia. METHODS: Thirty patients (28 males and 2 females, serum uric acid > 7.0 mg/dl) with hyperuricemia were selected. Thirty healthy individuals (28 males and 2 females) with normal serum uric acid were also selected as control. Patients were administered with hypouricemic therapy for 6 months. Plasma OPG concentration was measured in duplicate using a sandwich ELISA and high-resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperemia and after sublingual glyceryltrinitrate. RESULTS: Plasma OPG levels in patients with hyperuricemia before hypouricemic therapy was significantly higher than those in controls (3.39 +/- 0.25 vs. 2.05 +/- 0.74 ng/L, p < 0.01). After hypouricemic therapy, OPG levels decreased markedly (2.54 +/- 0.38 ng/L, p < 0.01). Flow mediated dilation (FMD) in patients with hyperuricemia was 3.07 +/- 1. 23%, which was significantly lower than that in control subjects (4.62 +/- 0.69%, p < 0.01), and it improved significantly after hypouricemic therapy (3.91 +/- 1.37%, p < 0.01). The absolute changes in OPG showed a significant positive correlation with the changes in serum uric acid (p < 0.05) and negative correlation with the changes in FMD (p < 0.01) in patients with hyperuricemia during the course of hypouricemic therapy. CONCLUSION: The current study demonstrates that plasma OPG levels increased significantly in patients with hyperuricemia and decreased significantly after hypouricemic therapy, and are correlated with FMD. These findings support the growing concept that elevated plasma OPG levels may be involved with the development of endothelial dysfunction in patients with hyperuricemia. PMID- 24947823 TI - Three functionally distinct classes of C-fibre nociceptors in primates. AB - In primates, C-fibre polymodal nociceptors are broadly classified into two groups based on mechanosensitivity. Here we demonstrate that mechanically sensitive polymodal nociceptors that respond either quickly (QC) or slowly (SC) to a heat stimulus differ in responses to a mild burn, heat sensitization, conductive properties and chemosensitivity. Superficially applied capsaicin and intradermal injection of beta-alanine, an MrgprD agonist, excite vigorously all QCs. Only 40% of SCs respond to beta-alanine, and their response is only half that of QCs. Mechanically insensitive C-fibres (C-MIAs) are beta-alanine insensitive but vigorously respond to capsaicin and histamine with distinct discharge patterns. Calcium imaging reveals that beta-alanine and histamine activate distinct populations of capsaicin-responsive neurons in primate dorsal root ganglion. We suggest that histamine itch and capsaicin pain are peripherally encoded in C MIAs, and that primate polymodal nociceptive afferents form three functionally distinct subpopulations with beta-alanine responsive QC fibres likely corresponding to murine MrgprD-expressing, non-peptidergic nociceptive afferents. PMID- 24947825 TI - Pseudothrombocytosis caused by cryoglobulin crystals in a patient with primary Sjogren's syndrome. PMID- 24947826 TI - Clinical characteristics of Japanese patients with reactive arthritis following intravesical BCG therapy for bladder cancer. PMID- 24947827 TI - Sustained expression of coagulation factor IX by modified cord blood-derived mesenchymal stromal cells. AB - BACKGROUND: Hemophilia B patients are subject to frequent and spontaneous bleeding caused by a deficiency of clotting factor IX (FIX). Mesenchymal stromal cells (MSCs) have been used in cellular therapies as a result of their immunomodulatory properties, the ability to home to sites of injury and their amenability to various ex vivo modifications, including lentiviral-mediated gene transfer. METHODS: MSCs were isolated from human umbilical cord blood and differentiated into adipogenic, chondrogenic and osteogenic lineages. A lentiviral DNA vector containing the human FIX gene was generated using traditional restriction enzyme digest and ligation techniques to generate viable replication-incompetent lentiviral particles that were used to transduce MSCs. Quantitative measurement of FIX expression was conducted using an enzyme-linked immunosorbent assay. RESULTS: The over-expression of FIX was sustained in vitro at levels > 4 ug/10(6) cells/24 h and FIX coagulant activity was > 2.5 mIU/10(6) cells/24 h for the 6-week duration of study. Lentiviral modification of cells with a multiplicity of infection of 10 did not adversely affect the potential of cord blood (CB) MSCs to differentiate to adipocytes, chondrocytes and osteoblastic cells, and the expression of functional FIX was sustained after differentiation and was similar to that in nondifferentiated cells. CONCLUSIONS: Modification of human CB MSCs with a lentiviral vector resulted in sustained high FIX expression in vitro after differentiation to adipogenic, chondrogenic and osteoblastic cells. These modified MSCs could have applications in cellular therapies for hemophilia B. PMID- 24947829 TI - Deaf capital: an exploration of the relationship between stigma and value in deaf multilevel marketing participation in Urban India. AB - This article ethnographically examines how some deaf people in urban India have begun to orient themselves toward the future by participating in multilevel marketing businesses. In the absence of other structural possibilities for deaf future-making, deaf Indians have turned to such businesses in search of social, economic, and moral livelihood. This article analyzes participation in one particular business and asks how participating within the business both enables and disables the cultivation of specific ideas of development. Particular attention is devoted to exploring the multiple registers of the concept of "deaf development" and how such development may be cultivated through multilevel marketing businesses. This article aims to make a critical intervention in medical anthropology studies of disability by arguing that disability (or in this case deafness) can function as a source of value, therefore highlighting tensions between stigma and value. PMID- 24947830 TI - The Bard's birthday, immunization, and public health. PMID- 24947828 TI - A genetic approach of wine yeast fermentation capacity in nitrogen-starvation reveals the key role of nitrogen signaling. AB - BACKGROUND: In conditions of nitrogen limitation, Saccharomyces cerevisiae strains differ in their fermentation capacities, due to differences in their nitrogen requirements. The mechanisms ensuring the maintenance of glycolytic flux in these conditions are unknown. We investigated the genetic basis of these differences, by studying quantitative trait loci (QTL) in a population of 133 individuals from the F2 segregant population generated from a cross between two strains with different nitrogen requirements for efficient fermentation. RESULTS: By comparing two bulks of segregants with low and high nitrogen requirements, we detected four regions making a quantitative contribution to these traits. We identified four polymorphic genes, in three of these four regions, for which involvement in the phenotype was validated by hemizygote comparison. The functions of the four validated genes, GCN1, MDS3, ARG81 and BIO3, relate to key roles in nitrogen metabolism and signaling, helping to maintain fermentation performance. CONCLUSIONS: This study reveals that differences in nitrogen requirement between yeast strains results from a complex allelic combination. The identification of three genes involved in sensing and signaling nitrogen and specially one from the TOR pathway as affecting nitrogen requirements suggests a role for this pathway in regulating the fermentation rate in starvation through unknown mechanisms linking nitrogen signaling to glycolytic flux. PMID- 24947831 TI - Anticoagulation control and cost of monitoring of older patients on chronic warfarin therapy in three settings in North East England. AB - BACKGROUND: novel oral anticoagulants may be particularly cost-effective when INR control (TTR) with warfarin is poor or monitoring difficult. SETTING: the Newcastle upon Tyne monitoring service, set in hospital or general practice and a domiciliary-based service for housebound patients. OBJECTIVES: to examine anticoagulation stability and costs of monitoring. SUBJECTS: three hundred and twenty-six atrial fibrillation patients, 75 years and over, with target INR of two to three, accessing hospital (n = 100), general practice (n = 122) and domiciliary (n = 104) service. METHODS: age, co-morbidities, length of warfarin treatment, medications, INR values and dose changes from January to December 2011 were recorded, and costs analysed. RESULTS: home-monitored patients had taken warfarin for longer, mean 5.2 years, than hospital (3.7) or general practice (3.1) patients. Age and total number of drugs prescribed chronically were negatively related to TTR. INR measurements and dose changes were negatively associated with the duration of treatment, positively correlated with co morbidities. The mean TTR was 78% in hospital, 71% in general practice and 68% in domiciliary monitored patients. INR was monitored more often in hospital and domiciliary groups than in general practice and more dose changes occurred in the domiciliary group than in others. Costs of warfarin and monitoring were L128 per patient per year for hospital, L126 for general practice and L222 for domiciliary patients. CONCLUSIONS: further exploration of the clinical effectiveness of novel anticoagulants in dependent patients is warranted to determine to what extent trial outcomes so far achieved in a fitter elderly population are influenced by the chronic co-morbidities of old age. PMID- 24947833 TI - Social media: opportunities for quality improvement and lessons for providers-a networked model for patient-centered care through digital engagement. AB - Social media brings a new dimension to health care for patients, providers, and their support networks. Increasing evidence demonstrates that patients who are more actively involved in their healthcare experience have better health outcomes and incur lower costs. In the field of cardiology, social media are proposed as innovative tools for the education and update of clinicians, physicians, nurses, and medical students. This article reviews the use of social media by healthcare providers and patients and proposes a model of "networked care" that integrates the use of digital social networks and platforms by both patients and providers and offers recommendations for providers to optimize their use and understanding of social media for quality improvement. PMID- 24947834 TI - Roles of obstetricians in quality management of cord blood collection and informing potential donors: a survey on obstetricians' understanding of cord blood in Korea. AB - BACKGROUND: The obstetrician's role in vitalizing cord blood (CB) banking is important in both informing donors and beginning CB processing. The aim of the study was to investigate obstetricians' understanding of CB and their roles in informing donors and collection management. STUDY DESIGN AND METHODS: Questionnaires examining the management and awareness of CB were distributed to collection centers, and we analyzed 57 respondents who had collection experience. RESULTS: All respondents were experienced, and 82.5% had CB collection experience of at least 4 years. If patients asked for information, one-third provided information about CB themselves, and two-thirds provided CB banks' (CBBs') contact information. Less than half of the respondents knew the legal regulations and had a collection manual. Regarding the awareness of transportation and storage of CB, 58% rated their knowledge as minimal, and respondents who knew the legal regulations rated their knowledge at a higher level. One-fifth of the participants felt that CB collection distracted the labor process, and 16% were concerned about delayed bleeding control. The probability of autologous CB transplantation was overestimated, and the matching probability in public CBBs was underestimated. Approximately 82.7% of the respondents correctly rated the therapeutic use of CB, and 54% rated their knowledge level about CB usefulness as average. CONCLUSION: Obstetricians' understanding of CB was lower than expected, considering that they are associated with CB collection centers. Obstetricians who provide information and recognize regulations seem to collect CB in compliance with the regulations better. These results will be helpful in CB collection management and education planning for obstetricians. PMID- 24947832 TI - Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways. AB - Genetic studies show that LRRK2, and not its closest paralogue LRRK1, is linked to Parkinson's disease. To gain insight into the molecular and cellular basis of this discrepancy, we searched for LRRK1- and LRRK2-specific cellular processes by identifying their distinct interacting proteins. A protein microarray-based interaction screen was performed with recombinant 3xFlag-LRRK1 and 3xFlag-LRRK2 and, in parallel, co-immunoprecipitation followed by mass spectrometry was performed from SH-SY5Y neuroblastoma cell lines stably expressing 3xFlag-LRRK1 or 3xFlag-LRRK2. We identified a set of LRRK1- and LRRK2-specific as well as common interactors. One of our most prominent findings was that both screens pointed to epidermal growth factor receptor (EGF-R) as a LRRK1-specific interactor, while 14 3-3 proteins were LRRK2-specific. This is consistent with phosphosite mapping of LRRK1, revealing phosphosites outside of 14-3-3 consensus binding motifs. To assess the functional relevance of these interactions, SH-SY5Y-LRRK1 and -LRRK2 cell lines were treated with LRRK2 kinase inhibitors that disrupt 14-3-3 binding, or with EGF, an EGF-R agonist. Redistribution of LRRK2, not LRRK1, from diffuse cytoplasmic to filamentous aggregates was observed after inhibitor treatment. Similarly, EGF induced translocation of LRRK1, but not of LRRK2, to endosomes. Our study confirms that LRRK1 and LRRK2 can carry out distinct functions by interacting with different cellular proteins. LRRK1 and LRRK2 (leucine-rich repeat kinase) interaction partners were identified by two different protein protein interaction screens. These confirmed epidermal growth factor receptor (EGR-R) as a LRRK1-specific interactor, while 14-3-3 proteins were LRRK2 specific. Functional analysis of these interactions and the pathways they mediate shows that LRRK1 and LRRK2 signaling do not intersect, reflective of the differential role of both LRRKs in Parkinson's disease. PMID- 24947837 TI - Treatment of hepatic failure after hepatectomy by the MARS hepatic dialysis system. PMID- 24947835 TI - OsJAR1 is required for JA-regulated floret opening and anther dehiscence in rice. AB - Jasmonates are important phytohormones regulating reproductive development. We used two recessive rice Tos17 alleles of OsJAR1, osjar1-2 and osjar1-3, to study the biological function of jasmonates in rice anthesis. The florets of both osjar1 alleles stayed open during anthesis because the lodicules, which control flower opening in rice, were not withering on time. Furthermore, dehiscence of the anthers filled with viable pollen, was impaired, resulting in lower fertility. In situ hybridization and promoter GUS transgenic analysis confirmed OsJAR1 expression in these floral tissues. Flower opening induced by exogenous applied methyl jasmonate was impaired in osjar1 plants and was restored in a complementation experiment with transgenics expressing a wild type copy of OsJAR1 controlled by a rice actin promoter. Biochemical analysis showed that OsJAR1 encoded an enzyme conjugating jasmonic acid (JA) to at least Ile, Leu, Met, Phe, Trp and Val and both osjar1 alleles had substantial reduction in content of JA Ile, JA-Leu and JA-Val in florets. We conclude that OsJAR1 is a JA-amino acid synthetase that is required for optimal flower opening and closing and anther dehiscence in rice. PMID- 24947836 TI - The role of the MCM2-7 helicase complex during Arabidopsis seed development. AB - The MINICHROMOSOME MAINTENANCE 2-7 (MCM2-7) complex, a ring-shaped heterohexamer, unwinds the DNA double helix ahead of the other replication machinery. Although there is evidence that individual components might have other roles, the essential nature of the MCM2-7 complex in DNA replication has made it difficult to uncover these. Here, we present a detailed analysis of Arabidopsis thaliana mcm2-7 mutants and reveal phenotypic differences. The MCM2-7 genes are coordinately expressed during development, although MCM7 is expressed at a higher level in the egg cell. Consistent with a role in the egg cell, heterozygous mcm7 mutants resulted in frequent ovule abortion, a phenotype that does not occur in other mcm mutants. All mutants showed a maternal effect, whereby seeds inheriting a maternal mutant allele occasionally aborted later in seed development with defects in embryo patterning, endosperm nuclear size, and cellularization, a phenotype that is variable between subunit mutants. We provide evidence that this maternal effect is due to the necessity of a maternal store of MCM protein in the central cell that is sufficient for maintaining seed viability and size in the absence of de novo MCM transcription. Reducing MCM levels using endosperm specific RNAi constructs resulted in the up-regulation of DNA repair transcripts, consistent with the current hypothesis that excess MCM2-7 complexes are loaded during G1 phase, and are required during S phase to overcome replicative stress or DNA damage. Overall, this study demonstrates the importance of the MCM2-7 subunits during seed development and suggests that there are functional differences between the subunits. PMID- 24947838 TI - Delayed diagnosis of a traumatic intrapericardial diaphragmatic hernia. PMID- 24947839 TI - The importance of the discharge summary reports. PMID- 24947840 TI - On the analysis of the results of a survey on trauma systems in Spain. PMID- 24947841 TI - A decade of laparoscopic hepatic surgery: from cyst fenestration to right hepatectomy for living donor liver transplant. PMID- 24947842 TI - Activated carbon peritonitis. PMID- 24947843 TI - Combined magnetic nanoparticle-based microRNA and hyperthermia therapy to enhance apoptosis in brain cancer cells. AB - A novel therapy is demonstrated utilizing magnetic nanoparticles for the dual purpose of delivering microRNA and inducing magnetic hyperthermia. In particular, the combination of lethal-7a microRNA (let-7a), which targets a number of the survival pathways that typically limit the effectiveness of hyperthermia, with magnetic hyperthermia greatly enhances apoptosis in brain cancer cells. PMID- 24947844 TI - IgG1 anti-epidermal growth factor receptor antibodies induce CD8-dependent antitumor activity. AB - Anti-EGFR monoclonal antibodies (mAb) like Cetuximab are commonly used for treatment of EGFR+ solid tumors mainly by exerting their therapeutic effect through inhibition of signal transduction. Additionally, IgG1 is a potent mediator of antibody-dependent cytotoxicity (ADCC). In case of the IgG1, Cetuximab induction of ADCC in vivo is controversially discussed. In our study, we investigated the efficiency of Cetuximab-mediated ADCC in a humanized mouse tumor model in vivo and analyzed the contribution of immunologic processes toward antitumor activity. Therefore, we used immunodeficient NOD/Scid mice transgenic for human MHC class I molecule HLA-A2 and adoptively transferred human HLA-A2+ PBMC after engraftment of human epidermoid cell carcinoma A431. Here, we show that high doses of anti-EGFR mAb induced strong tumor regression independent of the immune system. However, tumor regression by low doses of anti-EGFR mAb treatment was ADCC dependent and mediated by tumor infiltrating CD8+ T effector cells. This novel mechanism of ADCC conducted by CD8+ T effector cells was restricted to IgG1 anti-EGFR mAb, dependent of binding to CD16 on T cells and could be inhibited after EGFR blockade on tumor cells. Furthermore, CD8+ T effector cell-mediated ADCC was enhanced in the presence of IL-15 and strongly improved after glycosylation of anti-EGFR mAb indicating the potential of glycoengineered therapeutic mAb as efficient biologicals in cancer therapy. PMID- 24947845 TI - [Invisibility of care that make women]. PMID- 24947846 TI - [The breast cancer screening. do you need to change?]. PMID- 24947847 TI - Depressive symptoms and compromised parenting in low-income mothers of infants and toddlers: distal and proximal risks. AB - Low-income mothers develop depressive symptoms at higher rates than the general population, adding to the existing risk that economic hardship places on their infants and toddlers. Emphasizing a few key intervention targets, an approach that is especially relevant to mothers when depressive symptoms compromise their energy and concentration, can improve interventions with populations facing adversity. The goal of this study was to identify contextual risk factors that significantly contributed to depressive symptoms and that, in combination with depressive symptoms, were associated with compromised parenting. Using baseline data from 251 ethnically diverse mothers from six Early Head Start programs in the Northeastern and Southeastern US, who were recruited for a clinical trial of an in-home intervention, Belsky's ecological framework of distal to proximal levels of influence was used to organize risk factors for depressive symptoms in hierarchical regression models. Under stress, mothers of toddlers reported more severe depressive symptoms than mothers of infants, supporting the need for depressive symptom screening and monitoring past the immediate postpartum period. Multivariate models revealed intervention targets that can focus depression prevention and intervention efforts, including helping mothers reduce chronic day to-day stressors and conflicts with significant others, and to effectively handle challenging toddler behaviors, especially in the face of regional disciplinary norms. Presence of a live-in partner was linked to more effective parenting, regardless of participants' depressive symptom severity. PMID- 24947849 TI - Selective Kumada biaryl cross-coupling reaction enabled by an iron(III) alkoxide N-heterocyclic carbene catalyst system. AB - A catalyst system comprising Fe2(O(t)Bu)6 and an N-heterocyclic carbene ligand enables efficient syntheses of (hetero)biaryls from the reactions of aryl Grignard reagents with a diverse spectrum of (hetero)aryl chlorides. Amongst the alkoxide and amide counterions investigated, tert-butoxide was the most effective in inhibiting the homocoupling of arylmagnesiums. PMID- 24947848 TI - Video-assisted thoracoscopic surgery using mobile computed tomography: new method for locating of small lung nodules. AB - BACKGROUND: The O-arm is an intraoperative imaging device that can provide computed tomography images. Surgery for small lung tumors was performed based on intraoperative computed tomography images obtained using the O-arm. This study evaluated the usefulness of the O-arm in thoracic surgery. METHODS: From July 2013 to November 2013, 10 patients with small lung nodules or ground glass nodules underwent video-assisted thoracoscopic surgery using the O-arm. A needle was placed on the visceral pleura near the nodules. After the lung was re expanded, intraoperative computed tomography was performed using the O-arm. Then, the positional relationship between the needle marking and the tumor was recognized based on the intraoperative computed tomography images, and lung resection was performed. RESULTS: In 9 patients, the tumor could be seen on intraoperative computed tomography images using the O-arm. In 1 patient with a ground glass nodule, the lesion could not be seen, but its location could be inferred by comparison between preoperative and intraoperative computed tomography images. In only 1 patient with a ground glass nodule, a pathological complete resection was not performed. There were no complications related to the use of the O-arm. CONCLUSIONS: The O-arm may be an additional tool to facilitate intraoperative localization and surgical resection of non-palpable lung lesions. PMID- 24947850 TI - [HIV and pregnancy: 2013 guidelines from the French expert working group]. AB - With effective antiretroviral therapy, the risk of mother to child transmission (MTCT) is now under 1%. The 2013 French guidelines emphasize early antiretroviral lifelong antiretroviral therapy. Thus, the current trend for women living with HIV is to take antiretroviral therapy before, during and after their pregnancies. A major issue today is the choice of antiretroviral drugs, to maximize the benefits and minimize the risks of fetal exposure. This requires interdisciplinary care. The use of effective therapies permits gradual but profound changes in obstetric practice. When maternal plasma viral load is controlled (<50 copies/ml), obstetrical care can be more similar to standards in HIV-negative women. Prophylactic cesarean section is recommended when the viral load in late pregnancy is above 400 copies/mL. Intravenous zidovudine during labor is recommended only if the last maternal viral load is>400 copies/mL or in case of complications such as preterm delivery, bleeding or chorio-amnionitis during labor. In case of premature rupture of membranes before 34 weeks, a multidisciplinary decision should be made, based on gestational age and control of maternal viral load; if the woman is under antiretroviral therapy and especially if her viral load is undetectable, steroids and antibiotics should be offered and pregnancy can be continued except in case of signs or symptoms of chorio-amnionitis. Breastfeeding is not recommended in women living with HIV in France, as in industrialized countries. Prophylaxis in the newborn is usually zidovudine for 1 month. In case of significant exposure to HIV perinatally, in particular when, maternal viral load is>1000 copies/mL, prophylactic combination therapy is recommended. Monitoring of the child is necessary to determine whether or not it is free of HIV infection and to monitor possible adverse effects of perinatal exposure to antiretroviral drugs. PMID- 24947852 TI - What should the ideal HIV self-test look like? A usability study of test prototypes in unsupervised HIV self-testing in Kenya, Malawi, and South Africa. AB - HIV self-testing (HIVST) is increasingly being sought and offered globally, yet there is limited information about the test features that will be required for an HIV self-test to be easy to use, acceptable to users, and feasible for manufacturers to produce. We conducted formative usability research with participants who were naive to HIVST using five prototypes in Kenya, Malawi, and South Africa. The tests selected ranged from early-stage prototypes to commercially ready products and had a diverse set of features. A total of 150 lay users were video-recorded conducting unsupervised self-testing and interviewed to understand their opinions of the test. Participants did not receive a test result, but interpreted standardized result panels. This study demonstrated that users will refer to the instructions included with the test, but these can be confusing or difficult to follow. Errors were common, with less than 25% of participants conducting all steps correctly and 47.3% of participants performing multiple errors, particularly in sample collection and transfer. Participants also had difficulty interpreting results. To overcome these issues, the ideal HIV self-test requires pictorial instructions that are easy to understand, simple sample collection with integrated test components, fewer steps, and results that are easy to interpret. PMID- 24947851 TI - The association between internet addiction and psychiatric co-morbidity: a meta analysis. AB - BACKGROUND: This study evaluates the association between Internal Addiction (IA) and psychiatric co-morbidity in the literature. METHODS: Meta-analyses were conducted on cross-sectional, case-control and cohort studies which examined the relationship between IA and psychiatric co-morbidity. Selected studies were extracted from major online databases. The inclusion criteria are as follows: 1) studies conducted on human subjects; 2) IA and psychiatric co-morbidity were assessed by standardised questionnaires; and 3) availability of adequate information to calculate the effect size. Random-effects models were used to calculate the aggregate prevalence and the pooled odds ratios (OR). RESULTS: Eight studies comprising 1641 patients suffering from IA and 11210 controls were included. Our analyses demonstrated a significant and positive association between IA and alcohol abuse (OR = 3.05, 95% CI = 2.14-4.37, z = 6.12, P < 0.001), attention deficit and hyperactivity (OR = 2.85, 95% CI = 2.15-3.77, z = 7.27, P < 0.001), depression (OR = 2.77, 95% CI = 2.04-3.75, z = 6.55, P < 0.001) and anxiety (OR = 2.70, 95% CI = 1.46-4.97, z = 3.18, P = 0.001). CONCLUSIONS: IA is significantly associated with alcohol abuse, attention deficit and hyperactivity, depression and anxiety. PMID- 24947854 TI - Current knowledge on the transport and fate of spermatozoa in the reproductive tract of the bitch. AB - Canine sperm transport, distribution, storage and detachment is a complex, dynamic and highly regulated process. Transport of sperm within the bitch's reproductive tract is rapid and is influenced by the method of semen deposition (natural mating or artificial insemination) and by the timing of breeding in relation to the day of ovulation. The fertile lifespan of spermatozoa in the reproductive tract of the bitch is considerably longer than in most other domestic species, and the main sperm reservoirs appear to be the uterine crypts and the distal part of the uterotubal junction, where spermatozoa attach by their heads to uterine epithelium. While several in vitro studies demonstrated prolonged motility and viability of canine spermatozoa after coincubation with uterine tube explants, spermatozoal storage has not been documented in the canine uterine tube isthmus or ampulla in vivo. Several factors, including exposure to progesterone, solubilized zona pellucida proteins and post-ovulation uterine tube fluid, appear to trigger membrane events resulting in capacitation-like changes with subsequent motility pattern changes (transitional and hyperactivated) that are associated with sperm detachment. After mating or insemination, a normal low magnitude post-mating uterine inflammatory response occurs, evidenced by an influx of polymorphonuclear neutrophils (PMNs), increased uterine contractions and an increased uterine artery blood flow. Recently, it was also shown that normal dogs with cystic endometrial hyperplasia develop a more significant endometritis, show fewer mating-induced uterine contractions, a decreased ability of spermatozoa to bind to uterine explants in vitro and a slower uterine clearance after mating. PMID- 24947855 TI - Pharmacological treatment for common prostatic conditions in dogs - benign prostatic hyperplasia and prostatitis: an update. AB - The two most frequent prostatic diseases in dogs are benign prostatic hyperplasia (BPH) and prostatitis. Prostatitis requires prolonged antibiotic treatment. In acute prostatitis, the blood-prostate barrier is broken, thus facilitating the penetration of antibiotics, whereas in chronic prostatitis, the barrier prevents the penetration of many drugs into the gland. The selection of antibiotic agents is based on the sensitivity test and the drug's ability to penetrate into the gland. Many protocols for the treatment of BPH are available. In non-breeding dogs, surgical and optionally pharmacological castration by means of GnRH agonists may be performed. In breeding dogs, drugs retaining fertility are used. Recently, androgen receptor antagonistic treatment with osaterone acetate has been applied. Other drugs used for BPH treatment include progestagens, oestrogens, antioestrogens and 5alpha-reductase inhibitors. Some of these compounds may provoke severe side effects. The efficiency of GnRH antagonists used for the treatment of prostatic diseases, such as neoplasia and BPH, in humans has been recently investigated in dogs. This androgen deprivation therapy (ADT) is devoid of an initial exacerbation of androgen-dependent symptoms, which is typical for GnRH agonistic treatment. In many cases, BPH and prostatitis must be treated simultaneously as these conditions may develop in combination. PMID- 24947856 TI - Diagnostic and prognostic markers for uterine diseases in dogs. AB - Common uterine diseases in female dogs include cystic endometrial hyperplasia (CEH), mucometra, hydrometra and pyometra. It is important in clinical practice to recognize pyometra because it is potentially life-threatening due to the systemic illness induced by bacterial infection of the uterus. In contrast, the uterine content is sterile in CEH and mucometra/hydrometra, and clinical signs are mostly mild or absent. Optimal treatment depends on the type of uterine disease and its severity, but diagnosis and prognosis determination may be challenging and the diseases difficult to separate clinically. Diagnostic findings or biomarkers that may aid in the differentiation of the diseases are valuable, especially when several bitches are admitted with a fluid-filled uterus during night-time, and it has to be decided which patient to operate on first. Additionally, some variables may indicate outcome as measured by mortality or morbidity. If the uterus is not enlarged or fluid-filled, detection of uterine disease can be even more difficult. In this study, clinically useful variables with possible diagnostic or prognostic value for uterine diseases in dogs are discussed. PMID- 24947857 TI - Suppression of fertility in pre-pubertal dogs and cats. AB - Pre-pubertal gonadectomy in dogs and cats is still controversially discussed because some consequences cause health problems. Nevertheless, postponement of puberty, that is, prevention of an increase in sexual hormones and thereby prevention of their manifold effects, is of major importance, not only in controlling overpopulation but also to preserve the genetic base for future breeding stock and pets. Therefore, alternatives for surgical suppression of fertility in pre-pubertal animals were critically reviewed. As a promising alternative, the slow-release GnRH agonist deslorelin and other GnRH analogues have been investigated. In female dogs and cats, puberty could be significantly postponed without initial flare-up effect and without disturbance of body development. First trials to delay puberty in female and male cats by application of a 4.7-mg deslorelin implant 24 h after birth so far are promising. In female dogs, a previous investigation showed that when the implant was inserted at the age of 4 months, the initial flare-up effect was prevented. Body development was normal in the studies reviewed here, and with the 9.4-mg implant, puberty was significantly delayed until the age of 21 months or older. In one study, bitches either received a 4.7- or a 9.4-mg implant at the age of 4 months and the epiphyses were mostly closed before the time of first oestrus. Using a 4.7-mg deslorelin implant in pre-pubertal male dogs significantly postponed puberty, and age at puberty was >2 years when a 9.4-mg implant was used. However, further investigations are required, especially concerning the effect of different GnRH agonist dosages and resorption rates on the duration of postponement of puberty as well as long-term effects in both dogs and cats. PMID- 24947858 TI - Medical treatment for pyometra in dogs. AB - Pyometra is a reproductive disorder very common in bitches over 8 years of age in which physiological effects of progesterone on the uterus play a major role. The traditional therapy for pyometra is ovariohysterectomy. The main advantage of ovariohysterectomy over medical management is that it is both curative and preventive for recurrence of pyometra. However, surgery is associated with the risk of anaesthesia and renders the bitch sterile. During the last 10 years, numerous medical treatments have been proposed to treat both open and closed cervix pyometra. The most effective medical treatment with minor side effects seems to be the repeated administration of aglepristone with or without the additional treatment with low doses of prostaglandins. PMID- 24947859 TI - Suppression of fertility in adult cats. AB - Cats are animals with highly efficient reproduction, clearly pointing to a need for suppression of fertility. Although surgical contraception is highly effective, it is not always the method of choice. This is predominantly because it is cost-intensive, time-consuming and irreversible, with the latter being of major importance for cat breeders. This article reviews the use of progestins, scleroting agents, immunocontraception, melatonin, GnRH antagonists and finally, GnRH agonists, in adult male and female cats in detail, according to the present state of the art. By now, various scientific and clinical options are available for the suppression of fertility in adult cats and the decision as to which should be chosen - independent of the legal registration of any state - depends on different facts: (i) feral or privately owned animal? (ii) temporary or permanent suppression of fertility wanted/needed? (iii) sex of the animal? New effective and available methods for hormonal contraception include melatonin implants for short-term post ponement of oestrus in adult queens and slow-release GnRH-agonist implants containing deslorelin (Suprelorin((r)) ) for short- and long-term contraception in male and female companion and breeding cats. PMID- 24947860 TI - Uterine and placental expression of canine oxytocin receptor during pregnancy and normal and induced parturition. AB - Oxytocin (OT) plays an important role as an inducer of uterine contractility, acting together with its receptor (OTR) to increase synthesis of prostaglandins. Although OT is commonly used in the treatment for dystocia and uterine inertia in the bitch, little attention has been paid to the role of OT in mechanisms regulating parturition in the dog, so that knowledge about the expression of OTR in the canine uterus and placenta is sparse. Consequently, the expression and cellular localization of OTR were investigated in canine utero/placental compartments and interplacental sites throughout pregnancy and at normal and antigestagen-induced parturition, by real-time PCR, immunohistochemistry, western blot and in situ hybridization. The utero/placental and interplacental expression of OTR was constant from pre-implantation until mid-gestation, with a significant increase observed at prepartum luteolysis. In antigestagen-treated mid-pregnant dogs, OTR was upregulated in both interplacental and utero/placental samples. Besides clear myometrial signals, cellular localization of OTR was evident in the endometrial surface epithelial, stromal and vascular endothelial cells. Weaker signals were observed in superficial and deep uterine glandular epithelial cells. Placental OTR was localized in maternal decidual cells and capillary pericytes. Finally, OTR was colocalized with the progesterone receptor (PGR) in maternal decidual cells, coinciding with previously reported increased availability of prostaglandins in the foetal part of the placenta during normal and induced parturition. These findings suggest involvement of OTR in the signalling cascade leading to the prepartum release of prostaglandins from the pregnant canine uterus. PMID- 24947861 TI - Diagnosis of common prostatic conditions in dogs: an update. AB - Prostatic diseases account for 3-10% of intact male dogs presented to veterinary surgeons. Conditions vary according to severity and frequency ranging from the most common, such as prostatic hyperplasia and cysts to the rarer conditions such as prostatic abcesses and neoplasia. Different causes of prostatic disease can often not be distinguished by evaluation of clinical signs, as these are not very distinctive and may be similar for many prostatic conditions. Understanding which additional diagnostic tools to use for each of the possible conditions is essential in making a correct diagnosis leading to the proper treatment. This article will discuss the different etiologies, age groups of dogs and the decision-making process which will help the practitioner to choose the right investigative tools, treatments and prognosis when dealing with prostatic disease. PMID- 24947862 TI - Suppression of fertility in adult dogs. AB - Unfortunately, the overpopulation of dogs is still a problem in the majority of countries and even though surgical methods of sterilization, the most traditional and commonly used technique, have been intensively performed, the impact on the dog population is negligible. The neutering of companion animals as ovariohysterectomy (spaying) or orchidectomy (castration) has its limitations because of the cost, the need of a surgical environment and the risk of surgical and/or anaesthetical complications (ACCD 2009). In fact, surgical castration has been banished in some northern European countries and has limited acceptance in other countries. In a survey performed in Sao Paulo, Brazil, 56.5% of the owners of adopted shelter dogs were against the surgical procedure for different reasons (Soto et al. 2005). Currently, the options for contraception, defined as suppression of fertility are based on hormonal treatment. The treatments can be divided into analogues of gonadotropin releasing hormone (GnRH), progestins and androgens. Other possibilities of contraception are via the immunological system with vaccinations against GnRH, the luteinizing hormone (LH) receptor and the zona pellucida proteins. Finally, there is also the intra-epididymal or intratesticular injection of sclerosing substances in dogs. Mechanical devices to disrupt fertility are not used anymore due to the side effects. Suppression of fertility in adult dogs will be reviewed in order of use and possible impact on the dog population. PMID- 24947863 TI - Causes, diagnosis and therapy of common diseases in neonatal puppies in the first days of life: cornerstones of practical approach. AB - Neonatal diseases and losses are a common and often unavoidable problem within breeding kennels. Altogether, morbidity and mortality ranges, according to the literature, from 5 to 35%. Among non-infectious causes besides hypoxia during birth, hypothermia, hypoglycaemia and dehydration are mostly responsible for puppy diseases and losses. Approximately 90% of all deaths in hypoxaemic pups occur during the first 2 days. Of 183 pups with hypoxia, 63 died, 92.7% of them within 48 h after birth. Among infectious causes, bacterial infection is the most common cause of neonatal mortality. Escherichia coli, streptococci, staphylococci, Pseudomonas sp., Klebsiella sp., Enterobacter sp. and some other micro-organisms are regularly involved in neonatal infections. Post-mortem findings especially document E. coli, Staphylococcus sp. and Streptococcus sp. as responsible bacteria. The dam and the environment are suspected as sources of neonatal infections as it was shown by genetic relatedness of responsible bacterial strains isolated in both puppies and their dams. From a total of 517 puppies with bacterial infections, the treatment results documented that parenteral administration of amoxicillin/clavulanic acid in 308 neonates showed the best result. Diagnosis of diseases is often made difficult by the absence of variability in clinical signs contrary to adult dogs. Findings during a physical examination in pups differ from those in adults. Furthermore, treatment recommendations have to meet the special conditions in neonates concerning drug metabolism and excretion. PMID- 24947864 TI - Urinary incontinence in the bitch: an update. AB - Urinary incontinence (UI), defined as the involuntary loss of urine during the filling phase of the bladder (Abrams et al. 2002), is a commonly seen problem in veterinary practice. Urinary sphincter mechanism incompetence (USMI) after spaying is the most common micturition disorder, and its medical treatment is normally successful, even though the underlying pathophysiological mechanism is not fully understood. Hormonal changes inducing structural and functional alterations in the bladder, as well as in the urethra composition, are discussed. To manage incontinent patients successfully, possible underlying abnormalities besides USMI should be ruled out. In the majority of cases, history, physical examination and simple tests including urinalysis and urine bacterial culture lead to a presumed aetiology. If USMI is the most likely cause, then the advantage of further diagnostic tests should be discussed with the owner before starting a trial therapy with alpha-adrenergic drugs. Potential side effects of this therapy have to be mentioned even though they rarely occur. It is important to thoroughly evaluate the success of the initial treatment. Its failure should lead to further diagnostic testing. Specialized clinical assessments may provide an aetiological diagnosis, and this could serve as a basis for discussing further treatment options. Surgical procedures, which may in rare cases cause irreversible side effects, may be instituted. If incontinence reoccurs after initial treatment was successfully performed, the diagnostic work-up including urinalysis should always be repeated. As results of urinalysis did not correlate well with results of bacterial culture, a urine culture is recommended (Comer and Ling 1981). Cystocentesis is the preferred method of urine collection (Bartges 2004). Equivocal results of quantitative cultures of urine samples obtained during midstream voiding or by catheterization require repeat collection by cystocentesis (Comer and Ling 1981). PMID- 24947865 TI - Control of reproduction in ferrets, rabbits and rodents. AB - Reproduction control of small mammals is challenging. The purposes are the control of fertility and the reduction of sexual behaviour, aggressiveness and odour. Moreover, some species like ferret females need to be neutered to prevent bone marrow suppression caused by hyperoestrogenism. Many methods of sterilization have been reported, including surgical and chemical techniques. This article describes the reproductive physiology of ferrets and the techniques used to control their reproduction. Some aspects of the use of long-acting deslorelin implants in rabbits and rodents are also described. PMID- 24947866 TI - Cats and dogs: two neglected species in this era of embryo production in vitro? AB - During the last decades, in vitro fertilization (IVF) has become a routine technique in most domestic animals. However, in the dog the technique has lagged behind, with to date not a single pup born after IVF. In cats, healthy kittens have been born, but in fewer numbers than in cattle and horses. In pet animals, research in reproduction has mainly been focused on contraception, although recently, the introduction of new drugs especially marketed for cats and dogs will probably expand fertility research in carnivores towards the previously neglected area of assisted reproduction. In particular, the dog remains a real challenge for the reproductive biologist, due to the low meiotic capacity of canine follicular oocytes. In cats, oocyte maturation is less of a problem and embryo production rates comparable to those of cattle can be achieved. The domestic cat is a valuable model for endangered felids and it can even be used as a recipient for wild felid embryos. In this short review, we list some of the problems associated with the implementation of IVF in dogs and cats in relation to their reproductive characteristics, and we discuss the state-of-the-art of IVF in several other domestic species such as cattle, horses and pigs. PMID- 24947867 TI - Organic anion transporting polypeptides and organic cation transporter 1 contribute to the cellular uptake of the flavonoid quercetin. AB - Flavonoids such as quercetin and kaempferol mediate several health protective effects, e.g., anticancer effects. They are inhibitors of organic anion transporting polypeptides (OATP) and organic cation transporters (e.g., OCT2). However, little is known whether such transporters contribute to the cellular uptake of flavonoids. Therefore, we investigated the cellular uptake of kaempferol and quercetin using HEK293 cell lines stably expressing different human OATPs or OCT1. Kaempferol was not a substrate of any of the investigated transporters (OATP1A2, OATP1B1, OATP1B3, OATP2A1, OATP2B1, OATP3A1, OATP4A1, OATP5A1, and OCT1). Quercetin showed a significantly higher uptake into the HEK293-OATP1A2, HEK293-OATP2A1, HEK293-OATP2B1, and HEK293-OCT1 cells compared to control cells. The OATP1A2-, OATP2B1-, and OCT1-mediated quercetin uptake was inhibited by known inhibitors such as naringin, cyclosporin A, and quinidine, respectively. The cellular accumulation of quercetin into HEK293-OATP2A1 cells was not inhibited by prostaglandin E2 and diclofenac. The ionophore carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) reduced the net uptake of quercetin by increasing the uptake in the HEK293-control cells and causing no significant change in the HEK293-OATP2B1 cells indicating that quercetin follows the FCCP-driven proton flux through the plasma membrane. In addition to passive diffusion, the SLC transporters OATP1A2, OATP2B1, and OCT1 contribute to cellular accumulation of quercetin. PMID- 24947868 TI - Amide-type local anesthetics action on the sarcoplasmic reticulum Ca-ATPase from fast-twitch skeletal muscle. AB - Myotoxic effects related to intracellular Ca(2+) disturbances have been reported for local anesthetics. Such effects might derive from Ca-ATPase dysfunction. The aim of this work was to describe the effect of lidocaine and bupivacaine on the sarcoplasmic reticulum (SR) Ca-ATPase from fast-twitch skeletal muscle and to identify the affected steps of the enzyme's cycle. SR sealed vesicles were isolated from rabbit fast-twitch muscles by ultracentrifugation. The effect of the anesthetics on Ca-ATPase activity was assessed with a colorimetric method and Ca(2+) binding, uptake, phosphorylation of the enzyme by ATP, Ca(2+) dissociation kinetics and phosphoenzyme formation and decomposition levels were tested with radioisotopic methods. Lidocaine and bupivacaine inhibited Ca-ATPase activity with half-maximal inhibitory concentrations (Ki) of 25.3 and 31.4 mM, respectively, and the steady-state Ca(2+) transport ability with Ki values of 33.6 and 46.5 mM, decreasing the maximal transport rate without modification of the Ca(2+) or ATP affinity for the enzyme. This is consistent with an absence of competition for the transport and catalytic sites. The anesthetics did not inhibit Ca(2+) binding but inhibited the phosphorylation partial reactions. Ca(2+) dissociation kinetics was not affected, but the phosphoenzyme levels were decreased, and the decomposition rate of the phosphoenzyme became faster in the presence of the anesthetics. It is concluded that lidocaine and bupivacaine at concentrations available in pharmaceutical formulations for clinical medical and dental uses inhibit the SR Ca-ATPase through inhibition of key phosphorylation steps of the enzymatic cycle. PMID- 24947869 TI - Protective effect of vitexin compound B-1 against hypoxia/reoxygenation-induced injury in differentiated PC12 cells via NADPH oxidase inhibition. AB - Vitexin compound B-1 (VB-1) is a novel member of the vitexins family isolated from the seeds of the Chinese herb Vitex negundo. This study aims to investigate whether VB-1 is able to protect nerve cells against oxidative injury and whether the antioxidative effects of VB-1 occur through a mechanism involving the inhibition of NADPH oxidase (NOX) in a manner of hypoxia-inducible factor 1alpha (HIF-1alpha)-dependent. To establish a neuronal in vitro model of oxidative stress, the differentiated PC12 cells were subjected to 5 h of hypoxia followed by 20 h of reoxygenation (H/R). Three dosages of VB-1 (10(-8), 10(-7), and 10(-6) M) were chosen to evaluate the effect of VB-1 on H/R-induced injury and the underlying mechanisms. At the end of the experiments, culture mediums and cells were collected for analysis of cellular apoptosis, lactate dehydrogenase (LDH) and caspase 3/7-like activities, reactive oxygen species (ROS) levels, 4 hydroxynonenal (4-HNE) and malondialdehye (MDA) contents, and HIF-1alpha and NOX expression, respectively. Our results showed that cell injury (indicated by apoptosis ratio, caspase 3/7-like activity, and LDH release), oxidative stress (indicated by ROS production, 4-HNE, and MDA contents), NOX activity, and NOX expression (NOX2 and NOX4 isoforms) were dramatically increased in PC12 cells following H/R, which were attenuated in the presence of VB-1 at dosage of 10(-7) or 10(-6) M. There was no significant change in HIF-1alpha expression in all experimental groups. These results provide evidence that VB-1 is able to protect the PC12 cells against H/R-induced injury through a mechanism involving the suppression of NOX expression and subsequent reduction of ROS production. The effect of VB-1 on H/R-induced NOX expression is independent on HIF-1alpha inhibition. PMID- 24947870 TI - Quercetin mitigates Adriamycin-induced anxiety- and depression-like behaviors, immune dysfunction, and brain oxidative stress in rats. AB - This study was designed to evaluate the effect of quercetin, a natural flavonoid, on behavioral alterations, brain oxidative stress, and immune dysregulation caused by a chemotherapeutic agent, Adriamycin (ADR; 7 mg/kg of body weight). Different subsets of male Wistar rats were used to determine the benefit of quercetin on ADR-related depression-like and anxiety-like behaviors in the forced swim test, open field, and elevated plus maze, respectively. Quercetin (60 mg/kg of body weight) was administered 24, 5, and 1 h before the test session of forced swim test (FST) or at the same time points before the elevated plus maze/open field (EPM/OF) tests. Other subsets of rats were sacrificed after quercetin injections to assess the plasma corticosterone level, the brain oxidative status, and the immune cell count. Our results indicate that quercetin alleviated the anxio-depressive-like behavior, attenuated the brain oxidative stress, and suppressed the corticosterone excess that appeared following ADR treatment. The ADR-induced immune disturbance was slightly diminished after quercetin administration, especially for the lymphocyte count. This study suggests that quercetin can mitigate the neurobehavioral and immunological impairments that manifest in ADR-treated rats. Therefore, the combination of quercetin treatment with the chemotherapeutic regimen seems to be beneficial against chemotherapy related complications. PMID- 24947872 TI - Intense imagery movements: a common and distinct paediatric subgroup of motor stereotypies. AB - AIM: The aim of this article is to describe a subgroup of children who presented with stereotyped movements in the context of episodes of intense imagery. This is of relevance to current discussions regarding the clinical usefulness of diagnosing motor stereotypies during development. METHOD: The sample consisted of 10 children (nine males, one female; mean age 8y 6mo [SD 2y 5mo], range 6-15y). Referrals were from acute paediatricians, neurologists, and tertiary epilepsy services. Children were assessed by multidisciplinary teams with expertise in paediatric movement disorders. RESULTS: Stereotypies presented as paroxysmal complex movements involving upper and lower limbs. Imagery themes typically included computer games (60%), cartoons/films (40%), and fantasy scenes (30%). Comorbid developmental difficulties were reported for 80% of children. Brain imaging and electrophysiological investigations had been conducted for 50% of the children before referral to the clinic. INTERPRETATION: The descriptive term 'intense imagery movements' (IIM) was applied if (after interview) the children reported engaging in acts of imagery while performing stereotyped movements. We believe these children may form a common and discrete stereotypy subgroup, with the concept of IIM being clinically useful to ensure the accurate diagnosis and clinical management of this paediatric movement disorder. PMID- 24947873 TI - Hepatic neoplasms in children: a focus on differential diagnosis. AB - Paediatric hepatic neoplasias are rare, accounting for 1-4% of all solid childhood tumors. Liver tumors in children can be classified into benign or malignant; some of the benign lesions can have the potential of malignant transformation. Two-thirds of liver tumors in children are malignant. Hepatoblastoma accounts for two-thirds of malignant liver tumors in children. Other liver malignancies in children include sarcomas, germ cell and rhabdoid tumours, and hepatocellular carcinoma. Benign tumors of the liver in children include vascular tumours, hamartomas, adenomas, and focal nodular hyperplasia. The histology and anatomy of a paediatric liver tumour guides the treatment and prognosis. Although benign and malignant liver masses share some clinical manifestations, treatment and prognosis differ. PMID- 24947871 TI - Update on health literacy and diabetes. AB - PURPOSE: Inadequate literacy is common among patients with diabetes and may lead to adverse outcomes. The authors reviewed the relationship between literacy and health outcomes in patients with diabetes and potential interventions to improve outcomes. METHODS: We reviewed 79 articles covering 3 key domains: (1) evaluation of screening tools to identify inadequate literacy and numeracy, (2) the relationships of a range of diabetes-related health outcomes with literacy and numeracy, and (3) interventions to reduce literacy-related differences in health outcomes. RESULTS: Several screening tools are available to assess patients' print literacy and numeracy skills, some specifically addressing diabetes. Literacy and numeracy are consistently associated with diabetes-related knowledge. Some studies suggest literacy and numeracy are associated with intermediate outcomes, including self-efficacy, communication, and self-care (including adherence), but the relationship between literacy and glycemic control is mixed. Few studies have assessed more distal health outcomes, including diabetes-related complications, health care utilization, safety, or quality of life, but available studies suggest low literacy may be associated with increased risk of complications, including hypoglycemia. Several interventions appear to be effective in improving diabetes-related outcomes regardless of literacy status, but it is unclear if these interventions can reduce literacy-related differences in outcomes. CONCLUSIONS: Low literacy is associated with less diabetes-related knowledge and may be related to other important health outcomes. Further studies are needed to better elucidate pathways by which literacy skills affect health outcomes. Promising interventions are available to improve diabetes outcomes for patients with low literacy; more research is needed to determine their effectiveness outside of research settings. PMID- 24947874 TI - A new C19-diterpenoid alkaloid from the roots of Aconitum duclouxii. AB - A new C19-diterpenoid alkaloid, ducloudine F (1), was obtained from the roots of Aconitum duclouxii, along with eight known alkaloids (2-9) isolated from this species for the first time. Their structures were established on the basis of extensive spectroscopic analyses. The antimicrobial activities of these compounds were investigated. PMID- 24947875 TI - Depression diagnosis and treatment amongst multimorbid patients: a thematic analysis. AB - BACKGROUND: We explored experiences of depression diagnosis and treatment amongst multimorbid patients referred to a metropolitan multidisciplinary outpatient clinic to identify commonalities across this patient group. METHODS: Patients with two or more chronic conditions and a diagnosis of depression participated in semi-structured interviews that were digitally recorded and transcribed. Thematic analysis was performed on the transcriptions. RESULTS: Multimorbid patients attributed depressive symptoms to the loss of 'normal' roles and functionality and struggled to reconcile the depression diagnosis with their sense of identity. Beliefs about themselves and depression affected their receptivity to diagnosis and intervention strategies. These included prescribed interventions, such as psychotherapy or pharmacotherapy, and patient-developed strategies. CONCLUSIONS: Functional and social role losses present a clear context in which GPs should raise the subject of mood, with the situational attribution of depression suggesting that psychotherapy, which is rarely offered, should be prioritised in these circumstances. PMID- 24947876 TI - CLU rs2279590 polymorphism contributes to Alzheimer's disease susceptibility in Caucasian and Asian populations. AB - It is reported that CLU rs2279590 polymorphism is significantly associated with Alzheimer's disease (AD) in European ancestry. Recent studies investigated rs2279590 polymorphism in Asian population (Chinese, Japanese and Korean). Four studies showed negative association and two studies showed weak association between rs2279590 and AD. We believe that the weak association or no association may be caused by the relatively small sample size in Asian population. Here, we reinvestigated the association in Asian population. Meanwhile, to investigate the genetic heterogeneity of the rs2279590 polymorphism in Asian and Caucasian populations, we searched the PubMed and AlzGene databases and selected 11 independent studies (6 studies in Asian population and 5 studies in Caucasian population) including 20,655 individuals (8,605 cases and 12,050 controls) for meta-analysis. Our results showed significant association between rs2279590 polymorphism and AD in Asian population with P = 2.00E-04 and P = 2.00E-04 using additive and recessive models, respectively. We observed no significant heterogeneity between Asian and Caucasian populations. We believe that our results may be helpful to understand the mechanisms of CLU in AD pathogenesis and will be useful for future genetic studies in AD. PMID- 24947878 TI - A comprehensive rehabilitation program improves disease severity in patients with obstructive sleep apnea syndrome: a pilot randomized controlled study. AB - BACKGROUND: Exercise training may improve components of metabolic syndrome and obstructive sleep apnea syndrome (OSAS). The objective of our pilot randomized controlled study was to determine the benefits of a short intensive inpatient individualized exercise training (IET) program in sedentary untreated OSAS patients. METHODS: Twenty-two sedentary patients with moderate to severe OSAS were randomly assigned either to one-month education activity sessions (n=11; control group) or to inpatient rehabilitation program (n=11), including IET, education activities sessions, and dietary management. Full polysomnography (PSG), OSLER (Oxford Sleep Resistance test), body composition, anthropometric measurements, metabolic syndrome components, and questionnaires were performed at baseline and at study end point. RESULTS: No changes occurred in the control group in all variables. Compared to controls, participants randomized to the IET group presented a significant decrease in apnea-hypopnea index (AHI) (40.6+/-19.4 vs. 28.0+/-19.3; P<0.001), oxygen desaturation index (ODI), and arousal index, which occurred in conjunction with significant decrease in body mass index (BMI), neck circumference, fat mass, fasting glucose, and diastolic blood pressure. Increased sleep latency was found in participants in the IET group with altered values at baseline. CONCLUSIONS: IET reduced OSAS severity with improvement of metabolic syndrome components with concomitant loss in body fat in sedentary adults. If confirmed on a larger scale, a comprehensive rehabilitation program could constitute an additional or alternative treatment for moderate to severe OSAS patients. PMID- 24947879 TI - From CPAP to trilevel adaptive servo ventilation in chronic heart failure--have we got the magic bullet? PMID- 24947877 TI - Patients with mild cognitive impairment have an abnormal upper-alpha event related desynchronization/synchronization (ERD/ERS) during a task of temporal attention. AB - There are several evidences indicating that an impairment in attention-executive functions is present in prodromal Alzheimer's disease and predict future global cognitive decline. In particular, the issue of temporal orienting of attention in patients with mild cognitive impairment (MCI) due to Alzheimer's disease has been overlooked. The present research aimed to explore whether subtle deficits of cortical activation are present in these patients early in the course of the disease. We studied the upper-alpha event-related synchronization/desynchronization phenomenon during a paradigm of temporal orientation of attention. MCI patients (n = 27) and healthy elderly controls (n = 15) performed a task in which periodically omitted tones had to be predicted and their virtual onset time had to be marked by pressing a button. Single-trial responses were measured, respectively, before and after the motor response. Then, upper-alpha responses were compared to upper-alpha power during eyes-closed resting state. The time course of the task was characterized by two different behavioral conditions: (1) a pre-event epoch, in which the subject awaited the virtual onset of the omitted tone, (2) a post-event epoch (after button pressing), in which the subject was in a post-motor response condition. The principal findings are: (1) during the waiting epoch, only healthy elderly had an upper-alpha ERD at the level of both temporal and posterior brain regions; (2) during the post-motor epoch, the aMCI patients had a weaker upper-alpha ERS on prefrontal regions; (3) only healthy elderly showed a laterality effect: (a) during the waiting epoch, the upper-alpha ERD was greater at the level of the right posterior-temporal lead; during the post-motor epoch, the upper alpha ERS was greater on the left prefrontal lead. The relevance of these findings is that the weaker upper-alpha response observed in aMCI patients is evident even if the accuracy of the behavioral performance (i.e., button pressing) is still spared. This abnormal upper-alpha response might represent an early biomarker of the attention-executive network impairment in MCI due to Alzheimer's disease. PMID- 24947880 TI - Construct validity of the parent-child sleep interactions scale (PSIS): associations with parenting, family stress, and maternal and child psychopathology. AB - STUDY OBJECTIVES: Using a multi-method design, this study examined the construct validity of the Parent-Child Sleep Interactions Scale (PSIS; Alfano et al., 2013), which measures sleep-related parenting behaviors and interactions that contribute to preschoolers' sleep problems. METHODS: Participants included a community sample of 155 preschoolers (ages 3-5years; 51.6% female). Primary caregivers completed the PSIS. Parenting styles and behaviors were assessed with laboratory observations and parent reports. Parent and child psychopathology and family life stress were assessed with clinical interviews and parent reports. RESULTS: Bivariate correlations revealed significant associations between the PSIS and a number of variables, including lower observed parental support and quality of instruction; higher observed parental intrusiveness; authoritative, authoritarian, and permissive parenting styles; current maternal depressive and/or anxiety disorders and depressive symptomatology; increased stressful life events; lower marital satisfaction; and higher child depressive, anxiety, attention-deficit/hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD) symptoms. The patterns of association varied based on the specific PSIS scale. CONCLUSIONS: The PSIS demonstrates meaningful associations with parenting, maternal psychopathology, family stress, and child psychopathology and functioning. Findings suggest that the PSIS is a valid measure for assessing sleep-related parent/child behaviors and interactions among preschoolers, suited to real-world settings. PMID- 24947881 TI - Antititin antibody in early- and late-onset myasthenia gravis. AB - OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against neuromuscular junction proteins, 85% of patients have antibodies against acetylcholine receptor (AChR-MG). Antititin antibodies are present in a subset of patients with MG. We aimed to determine the value of antititin antibodies as severity markers and thymoma predictors in early- and late-onset MG. MATERIALS & METHODS: Two-hundred and ninety-five consecutive MG patients (188 F and 107 M) aged 12-89 years (mean 50y) were included. 164 patients had early-onset (EOMG, <=50 years of age), 131 had late-onset MG (LOMG). Twenty-six patients had thymoma. symptoms, severity graded with MGFA scale, thymus histology, medications, and treatment results were analyzed. RESULTS: Antititin antibodies were present in 81 (27%) of all patients: 54% of thymoma MG, 0.6% of non thymomatous EOMG, and 55% of LOMG, with proportion of titin-positive patients increasing linearly from 40% in the 6th to 88% in the 9th decade of life. Titin positive patients had more bulbar symptoms (P = 0.003). Severity of MG, need for immunosuppression, myasthenic crisis risk or treatment results were not related to its presence. Antititin antibodies had 56% sensitivity, 99% specificity, 90% positive predictive value (PPV), and 95% negative predictive value (NPV) for thymoma diagnosis in EOMG, and 50% sensitivity, 75% specificity, 71% PPV and 55% NPV in LOMG. CONCLUSIONS: Antititin antibodies have high PPV and NPV for thymoma in EOMG. In MG without thymoma, antititin antibodies can be considered as markers of LOMG, but not of a severe course in our MG cohort. PMID- 24947883 TI - Benzo[a]pyrene-specific online high-performance liquid chromatography fractionation of air particulate extracts - a tool for evaluating biological interactions. AB - Benzo[a]pyrene (B[a]P) is a known human carcinogen and is commonly used as a surrogate for assessing the carcinogenic risk posed by complex mixtures of polycyclic aromatic hydrocarbons (PAHs) present in air particulate matter (PM). However, studies have shown that using B[a]P as a surrogate may underestimate the carcinogenic potential of PAH mixtures, as the risk assessment approach does not consider interaction effects. Thus, toxicological studies using B[a]P to assess its carcinogenic potential in environmentally derived complex mixtures, as opposed to single compound experiments, could improve risk assessment. The intention of the present study was to develop an online HPLC fractionation system for the selective removal of B[a]P from air PM extracts. Two serial pyrenylethyl (PYE) columns enabled selective separation of B[a]P from its isomers and other PAHs as well as a short fractionation cycle of 30min. One run consisted of three collection steps: the first fraction contained PAHs eluting earlier than B[a]P, the second contained B[a]P and the last contained later-eluting PAHs. The selectivity and recovery of the system was investigated using extracts of Stockholm air PM samples. The overall recovery for all PAHs was approximately 80%, and the system proved to be selective, as it removed 94% of B[a]P and less than 3% of benzo[b]fluoranthene from the complex PAH mixture. Exposing human cells to blanks generated by the fractionation system did not induce cytotoxicity or DNA damage signalling. In conclusion, the online HPLC system was selective for B[a]P fractionation whilst minimising run-to-run variation and allowing repeated fractionations for larger samples due to its relatively short run time. PMID- 24947884 TI - Cyclodextrins in capillary electrophoresis: recent developments and new trends. AB - Despite the fact that extensive research in the field of separations by capillary electrophoresis (CE) has been carried out and many reviews have been published in the last years, a specific review on the use and future potential of cyclodextrins (CDs) in CE is not available. This review focuses the attention in the CD-CE topic over the January 2013-February 2014 period (not covered by previous more general CE-reviews). Recent contributions (reviews and research articles) including practical uses (e.g. solute-CD binding constant estimation and further potentials; 19% of publications), developments and applications (mainly chiral and achiral analysis; 38 and 24% of publications, respectively) are summarized in nine comprehensive tables and are commented. Statistics and predictions related to the CD-CE publications are highlighted in order to infer the current and expected research interests. Finally, trends and initiatives on CD-CE attending to real needs or practical criteria are outlined. PMID- 24947882 TI - Volume of the hippocampal subfields in healthy adults: differential associations with age and a pro-inflammatory genetic variant. AB - The hippocampus is one of the most age-sensitive brain regions, yet the mechanisms of hippocampal shrinkage remain unclear. Recent studies suggest that hippocampal subfields are differentially vulnerable to aging and differentially sensitive to vascular risk. Promoters of inflammation are frequently proposed as major contributors to brain aging and vascular disease but their effects on hippocampal subfields are unknown. We examined the associations of hippocampal subfield volumes with age, a vascular risk factor (hypertension), and genetic polymorphisms associated with variation in pro-inflammatory cytokines levels (IL 1beta C-511T and IL-6 C-174G) and risk for Alzheimer's disease (APOEepsilon4) in healthy adult volunteers (N = 80; age = 22-82 years). Volumes of three hippocampal subfields, cornu ammonis (CA) 1-2, CA3-dentate gyrus, and the subiculum were manually measured on high-resolution magnetic resonance images. Advanced age was differentially associated with smaller volume of CA1-2, whereas carriers of the T allele of IL-1beta C-511T polymorphism had smaller volume of all hippocampal subfields than CC homozygotes did. Neither of the other genetic variants, nor diagnosis of hypertension, was associated with any of the measured volumes. The results support the notion that volumes of age-sensitive brain regions may be affected by pro-inflammatory factors that may be targeted by therapeutic interventions. PMID- 24947885 TI - High-capacity thermo-responsive magnetic molecularly imprinted polymers for selective extraction of curcuminoids. AB - Thermo-responsive magnetic molecularly imprinted polymers (TMMIPs) for selective recognition of curcuminoids with high capacity and selectivity have firstly been developed. The resulting TMMIPs were characterized by TEM, FT-IR, TGA, VSM and UV, which indicated that TMMIPs showed thermo-responsiveness [lower critical solution temperature (LCST) at 33.71 degrees C] and rapid magnetic separation (5s). The polymerization, adsorption and release conditions were optimized in detail to obtain the highest binding capacity, selectivity and release ratio. We found that the adopted thermo-responsive monomer [N-isopropylacrylamide (NIPAm)] could be considered not only as inert polymer backbone for thermo-responsiveness but also as functional co-monomers combination with basic monomer (4-VP) for more specific binding sites when ethanol was added in binding solution. The maximum adsorption capacity with highest selectivity of curcumin was 440.3MUg/g (1.93 times that on MMIPs with no thermosensitivity) at 45 degrees C (above LCST) in 20% (v/v) ethanol solution on shrunk TMMIPs, and the maximum release proportion was about 98% at 20 degrees C (below LCST) in methanol-acetic acid (9/1, v/v) solution on swelled TMMIPs. The adsorption process between curcumin and TMMIPs followed Langumuir adsorption isotherm and pseudo-first-order reaction kinetics. The prepared TMMIPs also showed high reproducibility (RSD<6% for batch-to-batch evaluation) and stability (only 7% decrease after five cycles). Subsequently, the TMMIPs were successfully applied for selective extraction of curcuminoids from complex natural product, Curcuma longa. PMID- 24947886 TI - Impact of biomolecule solute size on the transport and performance characteristics of analytical porous polymer monoliths. AB - Porous monolithic poly(styrene-co-divinylbenzene) stationary phases in 4.6mm ID analytical format have been investigated with respect to their transport properties probed by solutes of biological origin varying vastly in size. Elucidation of several properties of these benchmark and robust materials gave complementary insight. These are: (i) the porous polymers' apparent dry-state microscopic appearance, (ii) the columns porosity probed by the biomolecules and modulated by mobile phase solvent composition, (iii) the impact of probe solute size on apparent retention at varying mobile phase solvent compositions, and (iv) the elution performance under both nonretained and retained elution conditions. By varying the volume percentage of acetonitrile in the mobile phase, it is demonstrated that the monolithic scaffold shows a variable porosity experienced in particular by the larger sized solutes, while the smaller solutes are gradually less affected. The nanoscale swelling and solvation of porous monolithic adsorbents resulting in gel porosity varied with mobile phase solvent composition was, therefore, indicated. The plate height curves for the solutes under nonretained conditions show a moderate increase at increased flow velocity while approaching plateau values. These plateau values were in conjunction with a trend of a decreased performance at an increased molecular weight of the solute. The systematic shape of the plate height curves at increased flow velocity indicates pre-asymptotic dispersion. This is because the column bed aspect ratio of length-to-diameter is equal or smaller than 10. Imposing retention on the solutes at a constant flow velocity deteriorates isocratic elution performance, more pronouncedly for the larger sized solutes at even weak retention. This is explained with slow pore fluid-gel interface diffusion. Additionally, the apparent retention factor for elution of the probe solutes becomes a function of flow rate, consequently a function of imposed pressure experienced by the scaffold. PMID- 24947887 TI - Phenylboronic acid as a multi-modal ligand for the capture of monoclonal antibodies: development and optimization of a washing step. AB - In this work, phenylboronic acid (PBA) was thoroughly investigated as a synthetic ligand for the purification of an immunoglobulin G (IgG) from a clarified cell supernatant from Chinese Hamster Ovary (CHO) cell cultures. In particular, the study was focused on the development of a washing step and in the optimization of the elution step using a serum containing supernatant. From the different conditions tested, best recoveries - 99% - and purifications - protein purity of 81% and a purification factor of 16 out of a maximum of 20 - were achieved using 100mM d-sorbitol in 10mM Tris-HCl as washing buffer and 0.5M d-sorbitol with 150mM NaCl in 10mM Tris-HCl as elution buffer. The purification outcome was also compared with protein A chromatography that revealed a recovery of 99%, 87% protein purity and 29 out of a maximum of 33 purification factor. Following the main purification, purified IgG was characterized in terms of isoelectric point, size and activity. In the end, a proof of concept was performed using two different mAbs from serum-free CHO cell cultures. PMID- 24947888 TI - Are analysts doing method validation in liquid chromatography? AB - Method validation is being applied in the reported analytical methods for decades. Even before this protocol was defined, authors already somehow validated their methods without full awareness. They wished to assure the quality of their work. Validation is an applied approach to verify that a method is suitable and rugged enough to function as a quality control tool in different locations and times. The performance parameters and statistical protocols followed throughout a validation study vary with the source of guidelines. Before single laboratory validation, an analytical method should be fully developed and optimized. The purpose of the validation is to confirm performance parameters that are determined during method development, and it should provide information on how the method will perform under routine use. An unstable method may require re validation. Further method development and optimization will be needed if validation results do not meet the accepted performance standards. When possible, the validation protocol should also be conducted as a collaborative study by multiple laboratories, on different instruments, reagents, and standards. At this point, it would be interesting to know how people are validating their methods. Are they evaluating all defined validation parameters? Are they indicating the followed guidelines? Is re-validation really currently used? Is validation performed by a single laboratory, or is it a collaborative work by several laboratories? Is it an evolving discipline? In this survey, we will try to answer these questions focused to the field of liquid chromatography. PMID- 24947889 TI - FYWHCLDE-based affinity chromatography of IgG: effect of ligand density and purifications of human IgG and monoclonal antibody. AB - This work reports the development of an octapeptide-based affinity adsorbent for the purification of human IgG (hIgG) and monoclonal antibody (mAb). The octapeptide was FYWHCLDE selected earlier by the biomimetic design of affinity peptide ligands for hIgG. The ligand was coupled to Sepharose gel at four densities from 10.4 to 31.0MUmol/mL, and the effect of peptide density on the adsorption of hIgG and bovine serum albumin (BSA) was first investigated. The binding capacity of hIgG increased from 104.2 to 176.4mg/mL within the ligand density range, and the binding affinity (dissociation constant) kept at 2.4 3.7MUM. Batch adsorption revealed that the selectivity of FYWHCLDE-Sepharose for IgG was 30-40 times over BSA. The effective pore diffusivity of IgG decreased somewhat with increasing ligand density, but the dynamic binding capacity at 10% breakthrough, measured by using 10-fold diluted human serum as feedstock, doubled with increasing ligand density from 10.4 to 31.0MUmol/mL due to the remarkable increase of static binding capacity. By using the affinity column with a ligand density of 23.9MUmol/mL, hIgG and humanized mAb purifications from human serum and cell culture supernatant, respectively, were achieved at high purities and recovery yields. Finally, the robustness of the peptide gel was demonstrated by recycled use of the affinity column in 20 breakthrough cycles. PMID- 24947890 TI - Chromatographic separation of arsenic species with pentafluorophenyl column and application to rice. AB - Arsenic species, including arsenous acid, arsenic acid, methylarsonic acid, and dimethylarsinic acid, were determined using HPLC-ICPMS. The species were separated with a Discovery HS F5 column and a simple, volatile, and isocratic mobile phase of 0.1% (v/v) formic acid and 1% (v/v) methanol. The Discovery HS F5 column with a pentafluorophenyl (PFP) stationary phase gave sharp peaks and full separation of the arsenic species in 5min, and other PFP columns showed lower performance. This separation method was applied to arsenic species analysis in rice. The extraction of arsenic from rice samples was performed using 0.15M nitric acid. The methodology was validated by use of certified reference materials, NMIJ CRM 7503-a and NIST SRM 1568a, and extremely low arsenic rice samples as blank samples. PMID- 24947891 TI - Histamine monolith versatility to purify supercoiled plasmid deoxyribonucleic acid from Escherichia coli lysate. AB - Preparation of high quantities of supercoiled plasmid DNA of pharmaceutical grade purity is a research area where intensive investigation is being performed. From this standpoint, several downstream methods have been proposed, among them the monolithic chromatographic strategies owing to excellent mass transfer properties of monolithic supports and their high binding capacity for large biomolecules. The present study explores the physicochemical properties of histamine ligand in a supercoiled plasmid DNA purification process from an Escherichia coli clarified lysate, where the emphasis is given to the elution strategy that allows higher selectivity and efficient removal of other impurities besides the open circular isoform. The combination of high NaCl concentration and acidic pH allowed the elimination of 89% of RNA during the preparative loading of the lysate sample. The results of the purification strategy with ascending sodium chloride gradient revealed that 97% of supercoiled plasmid DNA was recovered with a purity degree of 99%. In addition, using a combined purification strategy with ascending sodium chloride (capture step) and then descending ammonium sulfate (polishing step) gradient, it was achieved a lower supercoiled plasmid DNA recovery yield of 79% with a purity degree of 92%, although the dynamic binding capacity under these conditions was higher than in the previous strategy. A significant reduction of host contents, such as proteins, RNA and genomic DNA, was obtained in both purification strategies. Accordingly, histamine is a useful and versatile ligand that allows the desirable supercoiled plasmid purification with high yield and purity level. PMID- 24947892 TI - Favorable control of rapidly progressive retroperitoneal pleomorphic leiomyosarcoma with multimodality therapy: a case report. AB - BACKGROUND: Retroperitoneal sarcomas (RPS), such as pleomorphic leiomyosarcoma, often invade or displace vital organs in the abdominal cavity and exhibit an aggressive clinical course. Complete surgical resection of the tumor and preoperative radiotherapy and chemotherapies can be used for non-metastatic RPS. However, in case of huge retroperitoneal sarcoma fully occupying the abdominal cavity, surgical resection tends to be insufficient, resulting in poor outcomes. This report describes a case of rapidly progressive retroperitoneal pleomorphic leiomyosarcoma that was favorably controlled by debulking surgery followed by combination chemotherapy and radiotherapy. CASE PRESENTATION: A 65-year-old Japanese woman developed abdominal discomfort due to a huge retroperitoneal tumor fully occupying the abdominal cavity. The immunohistochemical diagnosis was pleomorphic leiomyosarcoma with high-grade malignancy and aggressive proliferative features. Debulking surgery could be performed, but the small residual tumor had rapidly grown to an approximately 22 cm in length on the major axis within 38 days after the operation. The patient's general condition progressively declined. Combination chemotherapy, consisting of doxorubicin and ifosfamide, was successfully administered for six cycles while maintaining dose intensity. The best objective response was a partial response, and the chemotherapy was well tolerated. Approximately 50 Gy of radiotherapy was delivered to the remaining tumor. This multimodal strategy resulted in progression-free survival for more than 17 months and achieved sustained symptomatic relief. CONCLUSIONS: Multimodal therapy with debulking surgery, combination chemotherapy and radiotherapy controlled a rapidly progressive retroperitoneal pleomorphic leiomyosarcoma. Maintaining dose intensity of the chemotherapy and radiotherapy might contribute to overall tumor control. PMID- 24947893 TI - Incorporation of apical lymph node status into the seventh edition of the TNM classification improves prediction of prognosis in stage III colonic cancer. AB - BACKGROUND: The node classification outlined in the seventh edition of the TNM classification is based solely on the number of metastasized lymph nodes. This study examined the prognostic value of apical lymph node (ALN) metastasis and the additional value of incorporating ALN status into a risk model based on the seventh edition. METHODS: This was a cohort study of patients with stage III colonic cancer who underwent tumour resection with dissection of regional (including apical) lymph nodes at 71 hospitals across Japan between 2000 and 2002. The main exposure was pathologically confirmed ALN metastasis, and the primary endpoint was cancer-specific death. RESULTS: ALN metastasis was present in 113 (8.3 per cent) of 1355 patients. During 5356 patient-years of follow-up (median 5.0 years), 221 instances (16.3 per cent) of cancer-specific death were observed. After adjustment for tumour and node classification (as described in the seventh edition of the TNM classification) and other prognostic factors, ALN metastasis was found to be independently associated with cancer-specific death (hazard ratio 2.29, 95 per cent confidence interval (c.i.) 1.49 to 3.52). Incorporation of ALN metastasis into the prognostic model based on the seventh edition of the TNM classification significantly improved discriminative performance for cancer-specific death (difference in concordance index 0.0146, 95 per cent c.i. 0.0030 to 0.0262) and risk reclassification for cancer-specific death at 5 years (category-free net reclassification improvement 19.4 (95 per cent c.i. 5.0 to 33.4) per cent). CONCLUSION: Assessment of ALN metastasis provided independent prognostic information beyond that achievable with the seventh edition of the TNM classification in patients with stage III colonic cancer. PMID- 24947894 TI - The expression of dendritic cell subsets in severe chronic rhinosinusitis with nasal polyps is altered. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized as a Th2-driven disease. Activated dendritic cells (DCs) are the main T-cell activators; their role in the chronic inflammatory process of nasal polyposis is still unclear. METHODS: The regulation of DC subsets was analyzed in nasal polyp tissue from CRSwNP patients and compared to inferior turbinate tissue from healthy subjects. Tissue localization and expression of both plasmacytoid and myeloid DCs were assayed by means of immunohistochemistry and flow cytometry. Plasmacytoid DCs were also assayed by PCR, and tissue homogenates were assayed for various inflammatory markers. RESULTS: The number of plasmacytoid (pDCs) and myeloid (mDCs) dendritic cells was significantly increased in nasal polyp tissue when compared to non-inflamed nasal mucosa. The number of pDCs, but not mDCs, was down-regulated in more severe cases (nasal polyps with asthma) and varied with the cytokine milieu. The amount of pDCs was significantly decreased in IL5+IFNgamma - nasal polyp tissue compared to tissues with high IFNgamma levels (IL5+IFNgamma+). Furthermore, levels of indoleamine 2,3-dioxygenase were increased in nasal polyp compared to inferior turbinate tissue and correlated negatively with the number of pDCs. CONCLUSIONS: There is an altered balance of pDC and mDC numbers in nasal polyp tissue. pDCs seem to be more susceptible to an inflammatory cytokine milieu and may play a crucial role in disease severity. PMID- 24947895 TI - Comparison of conventional autopsy and magnetic resonance imaging in determining the cause of sudden death in the young. AB - BACKGROUND: Sudden death in the young is a tragic complication of a number of medical diseases. There is limited data regarding the utility of post-mortem Magnetic Resonance (MR) imaging and Computer Tomography (CT) scanning in determining the cause of sudden death. This study sought to compare the accuracy of post-mortem cross-sectional imaging (MR and CT) with the conventional autopsy in determining the cause of sudden death in the young. METHODS: Consecutive patients from 2010 to 2012 (aged 1-35 years) who had sudden death were included. Patients were scanned by CT and 1.5 T MR imaging prior to the conventional autopsy being performed. The primary outcome was diagnostic congruence between imaging and conventional autopsy. RESULTS: In 17 patients studied, the mean age at death was 23 +/- 11 years, with a male predominance (n = 12; 71%). The most common cause of death was a primary cardiac pathology (n = 8; 47%), including ARVC (24%) and ischemic heart disease (12%). Non-cardiac causes identified included pulmonary embolism (6%), and aortic dissection (6%). MR imaging correctly identified the diagnosis in 12 patients who subsequently had positive findings at conventional autopsy, while the diagnosis in the remaining 5 cases remained unexplained. MR imaging was found to be highly sensitive (100%) with a high negative (100%) and positive (80%) predictive value. CONCLUSIONS: Dedicated post-mortem MR imaging of the heart and brain is a useful modality in determining the cause of sudden death in children and young adults, particularly in situations where a conventional autopsy cannot be performed for logistic, cultural or personal reasons. PMID- 24947896 TI - Adverse outcomes of critical illness from a dyadic perspective. PMID- 24947897 TI - piRNA pathway gene expression in the malaria vector mosquito Anopheles stephensi. AB - The ability of transposons to mobilize to new places in a genome enables them to introgress rapidly into populations. The piRNA pathway has been characterized recently in the germ line of the fruit fly, Drosophila melanogaster, and is responsible for downregulating transposon mobility. Transposons have been used as tools in mosquitoes to genetically transform a number of species including Anopheles stephensi, a vector of human malaria. These mobile genetic elements also have been proposed as tools to drive antipathogen effector genes into wild mosquito populations to replace pathogen-susceptible insects with those engineered genetically to be resistant to or unable to transmit a pathogen. The piRNA pathway may affect the performance of such proposed genetic engineering strategies. In the present study, we identify and describe the An. stephensi orthologues of the major genes in the piRNA pathway, Ago3, Aubergine (Aub) and Piwi. Consistent with a role in protection from transposon movement, these three genes are expressed constitutively in the germ-line cells of ovaries and induced further after a blood meal. PMID- 24947898 TI - Dashboard systems: implementing pharmacometrics from bench to bedside. AB - In recent years, there has been increasing interest in the development of medical decision-support tools, including dashboard systems. Dashboard systems are software packages that integrate information and calculations about therapeutics from multiple components into a single interface for use in the clinical environment. Given the high cost of medical care, and the increasing need to demonstrate positive clinical outcomes for reimbursement, dashboard systems may become an important tool for improving patient outcome, improving clinical efficiency and containing healthcare costs. Similarly the costs associated with drug development are also rising. The use of model-based drug development (MBDD) has been proposed as a tool to streamline this process, facilitating the selection of appropriate doses and making informed go/no-go decisions. However, complete implementation of MBDD has not always been successful owing to a variety of factors, including the resources required to provide timely modeling and simulation updates. The application of dashboard systems in drug development reduces the resource requirement and may expedite updating models as new data are collected, allowing modeling results to be available in a timely fashion. In this paper, we present some background information on dashboard systems and propose the use of these systems both in the clinic and during drug development. PMID- 24947899 TI - Global Burden of Severe Tooth Loss: A Systematic Review and Meta-analysis. AB - The goal of the Global Burden of Disease 2010 Study has been to systematically produce comparable estimates of the burden of 291 diseases and injuries and their associated 1,160 sequelae from 1990 to 2010. We aimed to report here internally consistent prevalence and incidence estimates of severe tooth loss for all countries, 20 age groups, and both sexes for 1990 and 2010. The systematic search of the literature yielded 5,618 unique citations. After titles and abstracts were screened, 5,285 citations were excluded as clearly not relevant to this systematic review, leaving 333 for full-text review; 265 publications were further excluded following the validity assessment. A total of 68 studies including 285,746 individuals aged 12 yr or older in 26 countries-were included in the meta-analysis using modeling resources of the Global Burden of Disease 2010 Study. Between 1990 and 2010, the global age-standardized prevalence of edentate people decreased from 4.4% (95% uncertainty interval: 4.1%, 4.8%) to 2.4% (95% UI: 2.2%, 2.7%), and incidence rate decreased from 374 cases per 100,000 person-years (95% UI: 347, 406) to 205 cases (95% UI: 187, 226). No differences were found by sex in 2010. Prevalence increased gradually with age, showing a steep increase around the seventh decade of life that was associated with a peak in incidence at 65 years. Geographic differences in prevalence, incidence, and rate of improvement from 1990 to 2010 were stark. Our review of available quality literature on the epidemiology of tooth loss shows a significant decline in the prevalence and incidence of severe tooth loss between 1990 and 2010 at the global, regional, and country levels. PMID- 24947901 TI - Exaggerated waiting impulsivity associated with human binge drinking, and high alcohol consumption in mice. AB - There are well-established links between impulsivity and alcohol use in humans and animal models; however, whether exaggerated impulsivity is a premorbid risk factor or a consequence of alcohol intake remains unclear. In a first approach, human young (18-25 years) social binge and non-binge drinkers were tested for motor impulsivity and attentional abilities in a human version of the Five-Choice Serial Reaction Time Task (Sx-5CSRTT), modeled on the rodent 5CSRTT. Participants completed four variants of the Sx-5CSRT, in addition to being screened for impulsive traits (BIS-11 questionnaire) and impulsive behavior (by means of the Delay Discounting Questionnaire, Two-Choice Impulsivity Paradigm (TCIP), Stop Signal Reaction Time, and Time Estimation Task). Using a second approach, we compared one of these impulsivity measures, 5CSRTT performance, in two inbred strains of mice known to differ in alcohol intake. Compared with non-bingers (NBD; n=22), binge drinkers (BD, n=22) showed robust impairments in attention and premature responding when evaluated under increased attentional load, in addition to presenting deficits in decision making using the TCIP. The best predictors for high binge drinking score were premature responding in the Sx-5CSRTT, trait impulsivity in the BIS-11, and decision making in the TCIP. Alcohol-naive C57BL/6J (B6) mice (alcohol preferring) were more impulsive in the 5CSRTT than DBA2/J (D2) mice (alcohol averse); the degree of impulsivity correlated with subsequent alcohol consumption. Homologous measures in animal and human studies indicate increased premature responding in young social BD and in the ethanol preferring B6 strain of mice. PMID- 24947903 TI - Therapeutic application of endothelial progenitor cells for treatment of cardiovascular diseases. AB - Cardiovascular disease is the leading cause of death worldwide. Despite significant progress in understanding of the disease mechanisms, most therapies remain at best palliative. Few therapeutic approaches offer direct tissue repair and regeneration. Cell-based therapy offers a promising approach that involves transplantation of healthy and functional cells to replenish damaged cells and repair injured tissue. Endothelial dysfunction is one of the most important mechanisms of cardiovascular disease, thus endothelial progenitor cells (EPC) and their derivatives have been investigated as a potential source for cell therapy. In pre-clinical and pilot clinical studies, treatment with EPCs or their derivatives as well as their co-transplantation with other cell types has shown some initial promising results. In this review, we will first describe the importance of endothelial cells and EPC homeostasis in the pathophysiology of cardiovascular disease. The potential sources of EPCs, including their isolation and purification, differentiation from pluripotent stem cells and adult stem cells, and trans-differentiation from somatic cells will then be summarized. Lastly, the application of target genome editing tools, such as Zinc Finger Nuclease (ZFN), Transcription Activator Like Effector Nucleases (TALEN) and RNA Guided Endo Nuclease (RGEN) to modify EPCs and their derivatives will be described. These technologies promise to further improve the therapeutic potential of EPCs and their derivatives to treat cardiovascular disease. PMID- 24947902 TI - Afatinib and its encapsulated polymeric micelles inhibits HER2-overexpressed colorectal tumor cell growth in vitro and in vivo. AB - Colorectal cancer (CRC) is known as a common malignant neoplasm worldwide. The role of EGFR/HER2 in CRC is unclear. Afatinib is an irreversible EGFR/HER2 inhibitor. There were few studies of afatinib on CRC. Here, we investigated the protein levels/expressions of HER2 in sera and tumors from CRC patients and the therapeutic effect of afatinib on HER2-overexpressed CRC in vitro and in vivo. The increased HER2 levels were detected in the collected sera and tumors of patients with CRC. The serological HER2 levels were correlated with the tumor HER2 expressions in patients. Afatinib also inhibited the HER2-positive tumor cell growth and caused apoptosis in HER2-overexpressed human colorectal cancer HCT-15 cells but not in low HER2 expressed human gastric cancer MKN45 cells. In vivo study showed that afatinib reduced tumor growth in HER2-overexpressed xenografts. Moreover, afatinib-encapsulated micelles displayed higher cytotoxic activity in HCT-15 cells and were more effective for tumor growth suppression in HCT-15-induced tumor xenografts than afatinib performance alone. Taken together, these findings suggest that higher serum HER2 levels reflect the higher HER2 contents in tumors of CRC patients, and the improved afatinib-encapsulated micelles possess high therapeutic efficacy in HER2-overexpressed CRC in vitro and in vivo. PMID- 24947900 TI - Obesity and symptoms of depression contribute independently to the poor asthma control of obesity. AB - Obesity is a major risk factor for poorly controlled asthma, but the reasons for poor asthma control in this patient population are unclear. Symptoms of depression have been associated with poor asthma control, and increase with higher body mass index (BMI). The purpose of this study was to assess whether depressive symptoms underlie poor asthma control in obesity. METHODS: We determined the relationship between BMI, psychological morbidity and asthma control at baseline in a well-characterized patient population participating in a clinical trial conducted by the American Lung Association-Asthma Clinical Research Centers. RESULTS: Obese asthmatic participants had increased symptoms of depression (Center for Epidemiologic Studies Depression Scale score in lean 10.1 +/- 8.1, overweight 10.0 +/- 8.1, obese 12.4 +/- 9.9; p = 0.03), worse asthma control (Juniper Asthma Control Questionnaire score in lean 1.43 +/- 0.68, overweight 1.52 +/- 0.71, obese 1.76 +/- 0.75; p < 0.0001), and worse asthma quality of life (scores in lean 5.21 +/- 1.08, overweight 5.08 +/- 1.05, obese 4.64 +/- 1.09; p < 0.0001). Asthmatics with obesity and those with symptoms of depression both had a higher risk of having poorly controlled asthma (adjusted odds ratio of 1.83 CI 1.23-3.52 for obesity, and 2.08 CI 1.23-3.52 for depression), but there was no interaction between the two. CONCLUSION: Obesity and symptoms of depression are independently associated with poor asthma control. As depression is increased in obese asthmatics it may be an important co morbidity contributing to poor asthma control in this population, but factors other than depression also contribute to poor asthma control in obesity. PMID- 24947904 TI - A characterization of missingness at random in a generalized shared-parameter joint modeling framework for longitudinal and time-to-event data, and sensitivity analysis. AB - We consider a conceptual correspondence between the missing data setting, and joint modeling of longitudinal and time-to-event outcomes. Based on this, we formulate an extended shared random effects joint model. Based on this, we provide a characterization of missing at random, which is in line with that in the missing data setting. The ideas are illustrated using data from a study on liver cirrhosis, contrasting the new framework with conventional joint models. PMID- 24947905 TI - Postoperative endophthalmitis due to Burkholderia cepacia complex from contaminated anaesthetic eye drops. AB - OBJECTIVE: To report the clinical presentation and outcomes of cluster postcataract Burkholderia cepacia complex endophthalmitis, the source of infection and clonal relatedness of the isolates. METHODS: This was a retrospective study on 13 patients who developed acute postoperative endophthalmitis, along with an infiltrate at the corneal section, after an uneventful cataract surgery with intraocular lens implantation. Aqueous aspirates, vitreous aspirates and environmental surveillance specimens were sampled. Genotypic diversity was determined by PCR using BOX-PCR for each strain, and the clonal relationship was established between clinical and eye drops isolates. RESULTS: Vitreous samples showed B. cepacia in cultures in all 13 eyes. Among the samples from various surveillance specimens cultured, topical anaesthetic eye drops grew B. cepacia. The isolates from the patients and the eye drops solution revealed matching banding patterns in BOX-PCR. Isolates from the patients and eye drops were susceptible to cefotaxime and piperacillin/tazobactam only. 9 (69%) patients out of 13 had a final visual acuity of 6/60 or better. Among the remaining four patients, three had a vision of perception of light and one had final vision of 1/60. CONCLUSIONS: Microbiology culture and BOX-PCR results revealed contamination of local anaesthetic eye drops and the same organism was cultured from a group of patients with acute-onset postoperative endophthalmitis after an uneventful cataract surgery. Outbreaks may occur in the most vigilant settings, and any sterile consumable may be a common link. PMID- 24947906 TI - Assessment of regional climatic changes in the Eastern Himalayan region: a study using multi-satellite remote sensing data sets. AB - In this study, an attempt has been made to capture the sensitivity of a mountainous region to elevation-dependent warming and the response of a glacier laden surface to increasing greenhouse gases (GHGs) and aerosol concentration. Some of the changes Sikkim has undergone due to urban sprawl are as follows: an increase of ~0.7 +/- 0.46 degrees C temperature in the past 40 years at an altitude of 5.5 km; a 2.21 km(2)/year rate of loss of glacierised area in the past 33 years; an increase in absorbed longwave radiation (6 +/- 2.41 W/m(2)); an increase in heat fluxes (2 +/- 0.97 W/m(2)); a decrease in albedo during the last 30 years; an increase in the concentrations of carbon dioxide (4.42%), methane (0.61%), ozone (0.67%) and black carbon column optical depth (7.19%); a decrease in carbon monoxide (2.61%) and an increase in aerosol optical depth (19.16%) during the last decade; a decrease in precipitation, water yield, discharge and groundwater; and an increase in evapotranspiration during 1971-2005. Detection of three climate signals (1976, 1997 and 2005) in the entire analysis is the quantification of the fact that the climate of Sikkim is moving away from its inter-annual variability. An increase in temperature (0.23 degrees C/decade) at higher altitude (~5.5 km), suppression of precipitation, decreasing water availability and rapid loss of glacierised area are the evidences of the fact that air pollution is playing a significant role in bringing about regional climatic changes in Sikkim. In this study, change detection method has been used for the first time for the estimation of change in a glacierised area of the region. PMID- 24947907 TI - Dip in the gene pool: metagenomic survey of natural coccolithovirus communities. AB - Despite the global oceanic distribution and recognised biogeochemical impact of coccolithoviruses (EhV), their diversity remains poorly understood. Here we employed a metagenomic approach to study the occurrence and progression of natural EhV community genomic variability. Analysis of EhV metagenomes from the early and late stages of an induced bloom led to three main discoveries. First, we observed resilient and specific genomic signatures in the EhV community associated with the Norwegian coast, which reinforce the existence of limitations to the capacity of dispersal and genomic exchange among EhV populations. Second, we identified a hyper-variable region (approximately 21kbp long) in the coccolithovirus genome. Third, we observed a clear trend for EhV relative amino acid diversity to reduce from early to late stages of the bloom. This study validated two new methodological combinations, and proved very useful in the discovery of new genomic features associated with coccolithovirus natural communities. PMID- 24947908 TI - Role of salivary and candidal proteins in denture stomatitis: an exploratory proteomic analysis. AB - Denture stomatitis, inflammation and redness beneath a denture, affects nearly half of all denture wearers. Candidal organisms, the presence of a denture, saliva, and host immunity are the key etiological factors for the condition. The role of salivary proteins in denture stomatitis is not clear. In this study 30 edentulous subjects wearing a maxillary complete denture were recruited. Unstimulated whole saliva from each subject was collected and pooled into two groups (n = 15 each), healthy and stomatitis (Newton classification II and III). Label-free multidimensional liquid chromatography/tandem mass spectrometry (2D-LC MS/MS) proteomics on two mass spectrometry platforms were used to determine peptide mass differences between control and stomatitis groups. Cluster analysis and principal component analysis were used to determine the differential expression among the groups. The two proteomic platforms identified 97 and 176 proteins (ANOVA; p < 0.01) differentially expressed among the healthy, type 2 and 3 stomatitis groups. Three proteins including carbonic anhydrase 6, cystatin C, and cystatin SN were found to be the same as previous study. Salivary proteomic profiles of patients with denture stomatitis were found to be uniquely different from controls. Analysis of protein components suggests that certain salivary proteins may predispose some patients to denture stomatitis while others are believed to be involved in the reaction to fungal infection. Analysis of candidal proteins suggests that multiple species of candidal organisms play a role in denture stomatitis. PMID- 24947910 TI - High valence 3p and transition metal based MOFs. AB - This article focuses on high valence 3p and transition metal based metal organic frameworks. In the first part we will discuss the complex solution chemistry of these metals which makes this sub-class of MOFs more of a challenge than the traditional low valence metal based MOFs. This is followed by a short review of the different classes of solids based on phosphonates, carboxylates and other linkers. Finally, we report some of the most relevant properties of these solids such as their chemical or thermal stability as well as their catalytic, redox- and photo-activities. PMID- 24947909 TI - Phase II trial of gemcitabine plus UFT as salvage treatment in oxaliplatin, irinotecan and fluoropyrimidine-refractory metastatic colorectal cancer. AB - PURPOSE: To investigate the efficacy of gemcitabine plus uracil-tegafur (UFT) combination chemotherapy as a salvage treatment in patients with metastatic colorectal cancer (MCRC). METHODS: This single-arm phase II study was conducted at three institutions in Korea. Patients with MCRC refractory to fluoropyrimidine, oxaliplatin and irinotecan were enrolled. Gemcitabine 800 mg/m(2) was administered intravenously on days 1, 8 and 15. UFT 200 mg/m(2)/day was taken orally in three divided doses on days 1-21. Cycles were repeated every 4 weeks, and tumor evaluation was carried out every 8 weeks. The primary endpoint of this study was 8-week progression-free survival (PFS) rate. RESULTS: Forty-one patients were enrolled. Fourteen patients received gemcitabine/UFT as a third line treatment and 37 patients as a fourth-line or later-line therapy. Toxicities were easily manageable, and non-hematologic toxicities of >=grade 3 were rare. The most common toxicity of >=grade 3 was neutropenia (20.0 %). One patient showed partial response (response rate, 2.4 %) and 14 (34.1 %) showed stable disease. The 8-week PFS rate was 42.3 %. The median PFS was 1.7 months [95 % confidence interval (CI) 1.6-1.8 months], and the median overall survival was 9.2 months (95 % CI 5.8-12.6 months). CONCLUSIONS: Overall efficacy of gemcitabine/UFT in refractory MCRC was unsatisfactory. However, we could find a minor proportion of patients who showed prolonged tumor stabilization to gemcitabine/UFT. Further studies are warranted to identify a patient subgroup that might have benefits from gemcitabine/UFT therapy. PMID- 24947911 TI - Pyogenic liver abscess in end-stage renal disease patients: a nationwide longitudinal study. AB - End-stage renal disease (ESRD) patients are more prone to infectious disease because of their immunocompromised status. However, the association between pyogenic liver abscess (PLA) and ESRD remains not clear. The aim of our study is to evaluate the incidence, risk factors, and outcomes of PLA in ESRD patients. We recruited all incident ESRD patients from the Taiwan National Health Insurance database from 1998 to 2006. The incidence rate of PLA in ESRD patients was compared with that of a randomly selected non-ESRD control group matched for age, sex gender, Charlson comorbidity score, diabetes mellitus, and cirrhosis. Among the 57,761 incident dialysis patients, there were 538 cases of PLA. The incidence rate of PLA was 18.20 per 10,000 person-years in the ESRD cohort and 6.34 per 10,000 person-years in matched control cohort. The rate of PLA was significantly higher in the ESRD cohort (hazard ratio 3.63, 95% confidence interval 2.83-4.65, P < 0.001). The mortality rates of PLA were higher in the ESRD cohort than those in matched control cohort. Diabetes mellitus was an independent risk factor for mortality of PLA. Compared with non-ESRD patients, ESRD patients have a higher risk of PLA and poorer outcomes. PMID- 24947912 TI - Global hypoperfusion: a new explanation of border zone strokes in hypereosinophilia. PMID- 24947913 TI - A simple, rapid, cost-effective and sensitive method for detection of Salmonella in environmental and pecan samples. AB - AIMS: PCR is widely used in the routine detection of foodborne human pathogens; however, challenges remain in overcoming PCR inhibitors present in some sample matrices. The objective of this study was to develop a simple, sensitive, cost effective and rapid method for processing large numbers of environmental and pecan samples for Salmonella detection. This study was also aimed at validation of a new protocol for the detection of Salmonella from in-shell pecans. METHODS AND RESULTS: Different DNA template preparation methods, including direct boiling, prespin, multiple washing and commercial DNA extraction kits, were evaluated with pure cultures of Salmonella Typhimurium and with enriched soil, cattle feces and in-shell pecan each spiked individually with Salmonella Typhimurium. PCR detection of Salmonella was conducted using invA and 16S rRNA gene (internal amplification control) specific primers. The effect of amplification facilitators, including bovine serum albumin (BSA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) and gelatin on PCR sensitivity, was also evaluated. Conducting a prespin of sample matrices in combination with the addition of 0.4% (w/v) BSA and 1% (w/v) PVP in PCR mix was the simplest, most rapid, cost-effective and sensitive method for PCR detection of Salmonella, with up to 40 CFU Salmonella per reaction detectable in the presence of over 10(9 ) CFU ml(-1) of background micro-organisms from enriched feces soil or pecan samples. CONCLUSIONS: The developed method is rapid, cost effective and sensitive for detection of Salmonella from different matrices. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides a method with broad applicability for PCR detection of Salmonella in complex sample matrices. This method has a potential for its application in different research arenas and diagnostic laboratories. PMID- 24947914 TI - Predictors of the risk factors for suicide identified by the interpersonal psychological theory of suicidal behaviour. AB - The Interpersonal-Psychological Theory of Suicide (IPTS) has been supported by recent research. However, the nature of the models' three major constructs- perceived burdensomeness, thwarted belongingness and acquired capability - requires further investigation. In this paper, we test a number of hypotheses about the predictors and correlates of the IPTS constructs. Participants aged 32 38 from an Australian population-based longitudinal cohort study (n=1167) were assessed. IPTS constructs were measured by items from the Interpersonal Needs Questionnaire (INQ) and Acquired Capability for Suicide Scale (ACSS), alongside demographic and additional measures, measured concurrently or approximately 8 years earlier. Cross-sectional analyses evaluating the IPTS supported earlier work. Mental health was significantly related to all three IPTS constructs, but depression and anxiety caseness were associated only with perceived burdensomeness. Various social support measures were differentially associated with the three constructs. Stressful events and lifetime traumas had robust independent associations with acquired capability for suicide only. The IPTS model provides a useful framework for conceptualising suicide risk. The findings highlight the importance of perceived social support in suicide risk, identify the importance of personality and other factors as new avenues of research, and provide some validation for the independence of the constructs. PMID- 24947915 TI - Functions, lifetime frequency, and variety of methods of non-suicidal self-injury among college students. AB - Borderline Personality Disorder (BPD) and intrapersonal functions of non-suicidal self-injury (NSSI) have both been found to have strong relationships with NSSI. The present study examines their role in the lifetime frequency and variety of NSSI methods, taken as indicators of severity of NSSI. We hypothesized that intrapersonal functions would explain frequency and variety of NSSI beyond the effects of interpersonal functions. Further we hypothesized that intrapersonal functions would moderate the effect of BPD characteristics on frequency of NSSI. College students (n=52) who endorsed at least one lifetime act of NSSI completed self-report measures and semi-structured interviews about NSSI behaviors, frequency, variety and functions, and BPD symptoms. Results supported the hypotheses that intrapersonal functions play a role in the lifetime frequency and variety of NSSI behaviors in addition to that of interpersonal functions, but did not support the role of intrapersonal functions as a moderator. Findings are discussed in terms of relative importance of all factors involved in explaining severity of NSSI, measured as lifetime frequency and variety. PMID- 24947916 TI - Always on guard: test of high vs. low control conditions in obsessive-compulsive disorder patients. AB - Obsessive-compulsive disorder (OCD) is a relatively common psychiatric disorder characterized by recurrent obsessive thoughts and/or compulsive behaviors. It has been shown that OCD patients suffer from deficits in executive control. During Stroop task performance, it was found that cognitive control in healthy participants adjusts adaptively - control is reduced when conflict is less likely. Twenty-four individuals meeting criteria for OCD and 27 controls carried out two blocks of a Stroop task; one with high control (a third of the trials were neutral) and one with low control (75% of the trials were neutral). In the healthy control group, results replicated previous findings showing increased interference and decreased facilitation in the low control condition compared to the high control condition. OCD participants, on the other hand, showed no difference in results between the two blocks. Moreover, in the high control condition, interference was larger and facilitation was smaller compared to healthy controls, indicating less efficient executive control for both the informational and task conflict. We concluded that healthy controls adjust the level of control to changing circumstances whereas OCD patients have difficulties to adaptively make such adjustments. Implications for this novel evidence of deficient executive control of flexibility in OCD patients are discussed. PMID- 24947917 TI - Theory of mind in first degree relatives of individuals with bipolar disorder. AB - We assessed theory of mind (ToM) performance in unaffected first-degree relatives of individuals with bipolar disorder compared to healthy controls across several well recognised tasks. Results indicated that the former group were significantly impaired on the verbal but not visual or higher-order ToM tasks, suggesting that a verbal ToM deficit might be a useful endophenotypic marker for bipolar disorder. PMID- 24947918 TI - The role of social relationships in bipolar disorder: a review. AB - Social relationships and attachment are core developmental elements of human existence and survival that evolve over the lifetime of an individual. The internal and external factors that influence them include the presence of illness in the individual or in their immediate environment. The developmental aspects of attachment and social relationships have become increasingly of interest and relevance in light of early developmental epigenetic modification of gene expression patterns that may influence subsequent behavioral patterns and outcomes. This review examines extant literature on attachment and social relationships in bipolar cohorts. Despite many methodological challenges, the findings indicate that social relationships and capacity for attachment are significantly compromised in individuals with bipolar disorder compared to other mood disorders and normal controls. Though extant research is limited, research clearly points toward the importance of social relationships on the etiology, course, and consequences of bipolar disorder. We highlight a number of key considerations for future research. PMID- 24947919 TI - Impaired oxygen uptake kinetics in the first high-level athlete with Hb Hope: a case study. AB - Hemoglobin (Hb) Hope is a beta-globin chain variant with reduced oxygen (O2) affinity, known to induce anemia. This usually leads to limitations in O2uptake (VO2) and exercise tolerance. We studied the case of a high-level female athlete with Hb Hope. She had been selected for cross-country races from 13 yrs onward, then was a national junior champion in 400-m race, and finally failed to win any cross-country races as an adult. Hematological analysis revealed normal red blood cell indices and Hb level (12.3 g.dL-1). Incremental exercise showed peak work rate (WR), VO(2max) and gas exchange threshold (GET) within normal ranges for healthy females. Constant WR testing at 90% of GET showed that kinetics of pulmonary VO2included the presence of a slow component. This was in disagreement with the data on VO2kinetics response to exercise intensities below GET. Phase 2 parameters, time constant (tau2, 31 s), time delay (TD2, 39 s), amplitude (A2, 780 ml.min-1), and gain in VO2(DeltaVO2 .DeltaWR-1, 9.2 ml.min-1.W-1) were within normal ranges. Phase 3 showed a slow component similar to that reported in severe exercise. The absence of anemia and the normality of phase 2 suggested normal O2delivery and oxidative metabolism in exercising muscles. In contrast, phase 3 suggested poor aerobic capacity and limited exercise tolerance. However, the lack of symptoms during testing also suggested that the slow component was due to the specific recruitment of fast-twitch fibers in this former champion athlete with Hb Hope in races requiring mainly anaerobic metabolism. PMID- 24947920 TI - Analysis of anterior, middle and posterior deltoid activation during single and multijoint exercises. AB - AIM: Although comparison between multi and single joint exercises has been conducted, there is insufficient evidence that these exercises could lead to different muscle activations. The aim of this study was to compare deltoid muscle activation during multi and single joint exercises. METHODS: Twelve male participants (23.4+/-1.6 years) with at least one year of strength training experience were assessed performing inclined lat pull-down, reverse peck deck and seated row exercises. Surface electromyography was used to measure activation of anterior, middle and posterior portions of deltoid muscle during each exercise. Deltoid activation was recorded during maximum voluntary isometric contraction (MVIC) and during dynamic isoinertial exercises of ten maximum repetitions for inclined lateral pull-down, reverse peck deck and seated row. RESULTS: There was no difference in activation of the anterior portion of deltoid muscle for any of the three exercises (P=0.08). The middle portion presented greater activation during the reverse peck deck (P=0.03) and during the seated row (P=0.03) compared to the inclined lat pull-down. For the posterior portion of deltoid muscle there was greater activation during the reverse peck deck (P=0.001) compared to the seated row and to the inclined lat pull-down. CONCLUSION: Results indicate that reverse peck deck and seated row should be more appropriate for recruitment of the middle portion of the deltoid muscle than the inclined lat pull-down. Differently, the reverse peck deck should be primarily used rather than the seated row and the lat pull-down for recruitment of the posterior portion of the deltoid muscle. PMID- 24947921 TI - Physical impairment in HIV infections and AIDS: responses to resistance and aerobic training. AB - AIM: The aim of this paper was to examine impairments in muscle strength and aerobic power associated with HIV and AIDS, to define optimal regimes of resistance and aerobic training, and to explore possible influences of HAART treatment upon responses. METHODS: Data from HealthStar/Ovid (1985 to 2013) were supplemented by references in identified articles and material in the author's personal files, yielding 133 citations. Detailed analysis was restricted to controlled trials (16 studies of resistance training, 17 of aerobic training). RESULTS: HIV infection and AIDS are often marked by substantial muscle wasting of multi-factorial origin. Impairment of aerobic function is more variable, with possible effects from physical inactivity, HAART therapy and muscular weakness. Most patients respond well to moderate resistance and aerobic training, showing substantial gains of strength, smaller improvements of aerobic power, and no adverse changes in CD4+ count or viral load. Moreover, these responses do not seem adversely affected by HAART therapy. CONCLUSION: Patients with HIV and AIDS should participate in moderate combined resistance and aerobic training programs. Such training elicits substantial gains in strength and cardiac function, and improves mood state and quality of life without adverse effects upon disease progression. Moreover, responses are not adversely affected by HAART therapy. The main challenge in the western world is to maintain compliance, since adherence to rehabilitation programs is often poor. There is also a need to develop exercise programs appropriate to regions where the disease is most prevalent, and to monitor possible interactions between rehabilitation and newly emerging forms of treatment. PMID- 24947922 TI - Medical professionalism: an experimental look at physicians' Facebook profiles. AB - BACKGROUND: Use of social networking services (SNS) is on the rise. While many users sign in for personal purposes, it is not uncommon for professionals to connect over SNSs with clients, students, and patients. METHODS: The present study used an experimental approach to examine how medical doctors' SNS profiles impacted potential patients' impressions of professionalism. Participants (N=250 students) were randomly assigned to view one of six Facebook profiles. Profiles were populated with 1) solely professional material, 2) personal material that was strictly healthy, or 3) personal material that included unhealthy behavior. Profiles portrayed a male or female physician resulting in a total of six experimental conditions. Medical professionalism was measured with the First Impressions of Medical Professionalism (FIMP) scale, specifically developed for this study. RESULTS: There was a large and statistically significant main effect for profile type, F(2, 250)=54.77, p<0.001, etap(2)=0.31. Post hoc tests indicated that personal profiles that contained healthy behavior were rated as most professional followed by profiles with strictly professional content. Personal unhealthy profiles were rated as least professional. Additionally, female profiles consistently received higher professionalism ratings across all three profile types [F(1, 250)=5.04, p=0.026, etap(2)=0.02]. CONCLUSION: Our results suggest that a physician's SNS profile affects a patient's perception of that physician's medical professionalism. A personal, healthy profile may augment a patient's perception of that physician's character virtues if the profile content upholds the decorum of the medical field. PMID- 24947923 TI - Complex disease-, gene-, and drug-drug interactions: impacts of renal function, CYP2D6 phenotype, and OCT2 activity on veliparib pharmacokinetics. AB - PURPOSE: Veliparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, undergoes renal excretion and liver metabolism. This study quantitatively assessed the interactions of veliparib with metabolizing enzyme (CYP2D6) and transporter (OCT2) in disease settings (renal impairment). EXPERIMENTAL DESIGN: Veliparib in vitro metabolism was examined in human liver microsomes and recombinant enzymes carrying wild-type CYP2D6 or functional defect variants (CYP2D6*10 and *4). Plasma pharmacokinetics were evaluated in 27 patients with cancer. A parent metabolite joint population model was developed to characterize veliparib and metabolite (M8) pharmacokinetics and to identify patient factors influencing veliparib disposition. A physiologically based pharmacokinetic model integrated with a mechanistic kidney module was developed to quantitatively predict the individual and combined effects of renal function, CYP2D6 phenotype, and OCT2 activity on veliparib pharmacokinetics. RESULTS: In vitro intrinsic clearance of CYP2D6.1 and CYP2D6.10 for veliparib metabolism were 0.055 and 0.017 MUL/min/pmol CYP, respectively. Population mean values for veliparib oral clearance and M8 clearance were 13.3 and 8.6 L/h, respectively. Creatinine clearance was identified as the significant covariate on veliparib oral clearance. Moderate renal impairment, CYP2D6 poor metabolizer, and co-administration of OCT2 inhibitor (cimetidine) increased veliparib steady-state exposure by 80%, 20%, and 30%, respectively. These factors collectively led to >2-fold increase in veliparib exposure. CONCLUSIONS: Renal function (creatinine clearance) is a significant predictor for veliparib exposure in patients with cancer. Although a single factor (i.e., renal impairment, CYP2D6 deficiency, and reduced OCT2 activity) shows a moderate impact, they collectively could result in a significant and potentially clinically relevant increase in veliparib exposure. PMID- 24947924 TI - The combination of circulating Ang1 and Tie2 levels predicts progression-free survival advantage in bevacizumab-treated patients with ovarian cancer. AB - PURPOSE: Randomized ovarian cancer trials, including ICON7, have reported improved progression-free survival (PFS) when bevacizumab was added to conventional cytotoxic therapy. The improvement was modest prompting the search for predictive biomarkers for bevacizumab. EXPERIMENTAL DESIGN: Pretreatment training (n=91) and validation (n=114) blood samples were provided by ICON7 patients. Plasma concentrations of 15 angio-associated factors were determined using validated multiplex ELISAs. Our statistical approach adopted PFS as the primary outcome measure and involved (i) searching for biomarkers with prognostic relevance or which related to between-individual variation in bevacizumab effect; (ii) unbiased determination of cutoffs for putative biomarker values; (iii) investigation of biologically meaningfully predictive combinations of putative biomarkers; and (iv) replicating the analysis on candidate biomarkers in the validation dataset. RESULTS: The combined values of circulating Ang1 (angiopoietin 1) and Tie2 (Tunica internal endothelial cell kinase 2) concentrations predicted improved PFS in bevacizumab-treated patients in the training set. Using median concentrations as cutoffs, high Ang1/low Tie2 values were associated with significantly improved PFS for bevacizumab-treated patients in both datasets (median, 23.0 months vs. 16.2; P=0.003) for the interaction of Ang1-Tie2 treatment in Cox regression analysis. The prognostic indices derived from the training set also distinguished high and low probability for progression in the validation set (P=0.008), generating similar values for HR (0.21 vs. 0.27) between treatment and control arms for patients with high Ang1 and low Tie2 values. CONCLUSIONS: The combined values of Ang1 and Tie2 are predictive biomarkers for improved PFS in bevacizumab-treated patients with ovarian cancer. These findings need to be validated in larger trials due to the limitation of sample size in this study. PMID- 24947925 TI - A novel KLF4/LDHA signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer. AB - PURPOSE: Kruppel-like factor 4 (KLF4) is a transcription factor and putative tumor suppressor. However, little is known about its effect on aerobic glycolysis in pancreatic tumors. Therefore, we investigated the clinical significance, biologic effects, and mechanisms of dysregulated KLF4 signaling in aerobic glycolysis in pancreatic cancer cells. EXPERIMENTAL DESIGN: Expression of KLF4 and lactate dehydrogenase A (LDHA) in 70 primary pancreatic tumors and 10 normal pancreatic tissue specimens was measured. Also, the underlying mechanisms of altered KLF4 expression and its impact on aerobic glycolysis in pancreatic cancer cells were investigated. RESULTS: We found a negative correlation between KLF4 and LDHA expression in pancreatic cancer cells and tissues and that their expression was associated with clinicopathologic features of pancreatic cancer. KLF4 underexpression and LDHA overexpression were correlated with disease stage and tumor differentiation. Experimentally, KLF4 overexpression significantly attenuated the aerobic glycolysis in and growth of pancreatic cancer cells both in vitro and in orthotopic mouse models, whereas knockdown of KLF4 expression had the opposite effect. Enforced KLF4 expression decreased LDHA expression, whereas small interfering RNA-mediated knockdown of KLF4 expression had the opposite effect. Mechanistically, KLF4 bound directly to the promoter regions of the LDHA gene and negatively regulated its transcription activity. CONCLUSIONS: Dysregulated signaling in this novel KLF4/LDHA pathway significantly impacts aerobic glycolysis in and development and progression of pancreatic cancer. PMID- 24947926 TI - CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance. AB - PURPOSE: Gastric cancers may harbor a subset of cells with cancer stem cell (CSC) properties, including chemotherapy resistance, and CD44 is a gastric CSC marker. The Hedgehog (HH) pathway is a key developmental pathway that can be subverted by CSCs during tumorigenesis. Here, we examine the role of HH signaling in CD44(+) gastric cancer cells. EXPERIMENTAL DESIGN: Gastric cancer cell lines, tumor xenografts, and patient tumors were examined. RESULTS: Gastric cancer cell lines AGS, MKN-45, and NCI-N87 grown as spheroids or sorted for CD44(+) were found to have upregulation of HH pathway proteins. HH inhibition using Smoothened (Smo) shRNA or vismodegib (VIS) decreased spheroid formation and colony formation. CD44(+) cells, compared with unselected cells, were also resistant to 5 fluorouracil and cisplatin chemotherapy, and this resistance was reversed in vitro and in xenografts with Smo shRNA or VIS. CD44(+) cells also had significantly more migration, invasion, and anchorage-independent growth, and these properties could all be blocked with HH inhibition. Clinical tumor samples from a phase II trial of chemotherapy with or without VIS for advanced gastric cancer were analyzed for CD44 expression. In the chemotherapy alone group, high CD44 expression was associated with decreased survival, whereas in the chemotherapy plus VIS group, high CD44 expression was associated with improved survival. CONCLUSIONS: HH signaling maintains CSC phenotypes and malignant transformation phenotypes in CD44(+) gastric cancer cells, and HH inhibition can reverse chemotherapy resistance in CD44(+) cells. Gastric cancer is a heterogeneous disease, and the strategy of combining chemotherapy with HH inhibition may only be effective in tumors with high CD44 levels. PMID- 24947928 TI - Association of EGFR expression level and cetuximab activity in patient-derived xenograft models of human non-small cell lung cancer. AB - PURPOSE: To explore in a panel of patient-derived xenograft models of human non small cell lung cancer (NSCLC) whether high EGFR expression, was associated with cetuximab activity. EXPERIMENTAL DESIGN: NSCLC patient-derived xenograft models (n=45) were implanted subcutaneously into panels of nude mice and randomization cohorts were treated with either cetuximab, cisplatin, cisplatin plus cetuximab, vehicle control, or else were left untreated. Responses according to treatment were assessed at week 3 by analyzing the relative change in tumor volume and an experimental analogue of the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. An EGFR IHC score was calculated for each patient-derived xenograft model and response was assessed according to EGFR expression level. RESULTS: When tumors were stratified into high and low EGFR expression groups (IHC score threshold 200; scale 0-300), a stronger antitumor activity was seen in the high EGFR expression group compared with the low EGFR expression group in both the cetuximab monotherapy and cisplatin plus cetuximab combination therapy settings. For tumors treated with cisplatin plus cetuximab, the objective response rate was significantly higher in the high EGFR expression group compared with the low EGFR expression group (68% vs. 29%). Objective response rates were similar in high and low expression groups for tumors treated with cisplatin alone (27% vs. 24%, respectively). CONCLUSION: Cetuximab activity in NSCLC patient derived xenograft models was demonstrated clearly only in tumors that expressed high levels of EGFR, as defined by an IHC score of >=200. PMID- 24947927 TI - Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations. AB - PURPOSE: This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor. EXPERIMENTAL DESIGN: We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added. RESULTS: Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications. CONCLUSIONS: Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. Clin Cancer Res; 20(16); 4251-61. (c)2014 AACR. PMID- 24947929 TI - PBX1 is a favorable prognostic biomarker as it modulates 13-cis retinoic acid mediated differentiation in neuroblastoma. AB - PURPOSE: Neuroblastoma is an embryonic childhood cancer with high mortality. 13 cis retinoic acid (13-cisRA) improves survival for some patients, but many recur, suggesting clinical resistance. The mechanism of resistance and the normal differentiation pathway are poorly understood. Three-amino-acid loop extension (TALE) family genes are master regulators of differentiation. Because retinoids promote differentiation in neuroblastoma, we evaluated TALE family gene expression in neuroblastoma. EXPERIMENTAL DESIGN: We evaluated expression of TALE family genes in RA-sensitive and -resistant neuroblastoma cell lines, with and without 13-cisRA treatment, identifying genes whose expression correlates with retinoid sensitivity. We evaluated the roles of one gene, PBX1, in neuroblastoma cell lines, including proliferation and differentiation. We evaluated PBX1 expression in primary human neuroblastoma samples by qRT-PCR, and three independent clinical cohort microarray datasets. RESULTS: We confirmed that induction of PBX1 expression, and no other TALE family genes, was associated with 13-cisRA responsiveness in neuroblastoma cell lines. Exogenous PBX1 expression in neuroblastoma cell lines, mimicking induced PBX1 expression, significantly impaired proliferation and anchorage-independent growth, and promoted RA dependent and -independent differentiation. Reduced PBX1 protein levels produced an aggressive growth phenotype and RA resistance. PBX1 expression correlated with histologic neuroblastoma subtypes, with highest expression in benign ganglioneuromas and lowest in high-risk neuroblastomas. High PBX1 expression is prognostic of survival, including in multivariate analysis, in the three clinical cohorts. CONCLUSIONS: PBX1 is an essential regulator of differentiation in neuroblastoma and potentiates retinoid-induced differentiation. Neuroblastoma cells and tumors with low PBX1 expression have an immature phenotype with poorer prognosis, independent of other risk factors. PMID- 24947930 TI - Acquired resistance to endocrine treatments is associated with tumor-specific molecular changes in patient-derived luminal breast cancer xenografts. AB - PURPOSE: Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC. EXPERIMENTAL DESIGN: Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays. RESULTS: HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival. CONCLUSIONS: PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314-25. (c)2014 AACR. PMID- 24947931 TI - Screening for cardiac dysfunction in anthracycline-exposed childhood cancer survivors. AB - PURPOSE: To examine the utility and reliability of obtaining early echocardiographic measurements of left ventricular (LV) remodeling as well as blood biomarkers of cardiac injury in asymptomatic childhood cancer survivors at risk for LV dysfunction and congestive heart failure due to past exposure to anthracycline chemotherapy. EXPERIMENTAL DESIGN: Using a cross-sectional design, anthracycline-exposed childhood cancer survivors with preserved ejection fraction (EF; >=50%) were evaluated using early echocardiographic indices and blood biomarkers of LV dysfunction. Survivors treated with >=300 mg/m(2) anthracyclines [high risk (HR): n = 100] were compared with those treated with <300 mg/m(2) anthracyclines [low risk (LR): n = 50] and matched healthy controls (HC: n = 50). All echocardiograms were interpreted by an institutional cardiologist and a study cardiologist blinded to risk status. RESULTS: Time from diagnosis was comparable for HR (12.0 years) and LR (13.2 years, P = 0.8) survivors. Echocardiograms: HR had lower LV thickness-dimension ratio (Z-score: HR: -0.62, LR: -0.03, HC: -0.02; P < 0.001), increased LV wall stress (HR: 66.7 g/cm(2), LR: 56.6 g/cm(2), HC: 54.2 g/cm(2); P < 0.01), and higher myocardial performance index (HR: 0.51, LR: 0.46, HC: 0.46; P < 0.01). Interobserver correlation (clinical/blinded reading) for all echocardiographic indices was excellent (range: R = 0.76-0.97, P < 0.001). Blood biomarkers: With the exception of NT-proBNP (r = 0.28, P < 0.01), there was no correlation between blood biomarkers (B-type natriuretic peptide, Troponin-T, ST-2, Galectin-3) and LV dysfunction. CONCLUSION: Childhood cancer survivors with preserved EF 10+ years from anthracycline exposure had dose dependent changes in echocardiographic markers of LV dysfunction. PMID- 24947932 TI - Noninvasive detection of glutamate predicts survival in pediatric medulloblastoma. AB - PURPOSE: Medulloblastoma is the most common malignant brain tumor occurring in childhood and is a significant cause of morbidity and mortality in pediatric oncology. More intense treatment strategies are recommended for patients displaying high-risk factors; however, considerable variation in outcome remains, indicating a need for improved predictive markers. In this study, 1H magnetic resonance spectroscopy (MRS) was used to investigate noninvasive molecular biomarkers of survival in medulloblastoma. EXPERIMENTAL DESIGN: MRS was performed on a series of 35 biopsy-confirmed medulloblastoma cases. One case was excluded because of poor quality MRS. The prognostic value of MRS detectable biomarkers was investigated using Cox regression, retrospectively (N=15). A subsequent validation analysis (N=19) was also performed to reduce the chance of type I errors. Where available, high-resolution ex vivo MRS of biopsy tissue was used to confirm biomarker assignments. RESULTS: The retrospective analysis revealed that creatine, glutamate, and glycine were markers of survival (P<0.01). The validation analysis showed that glutamate was a robust marker, with a hazard ration (HR) of 8.0 for the full dataset (P=0.0003, N=34). A good correlation between in vivo and ex vivo MRS glutamate/total-choline was found (P=0.001), validating the in vivo assignment. Ex vivo glutamate/total-choline was also associated with survival (P<0.01). CONCLUSION: The identification of glutamate as a predictive biomarker of survival in pediatric medulloblastoma provides a clinically viable risk factor and highlights the importance of more detailed studies into the metabolism of this disease. Noninvasive biomarker detection using MRS may offer improved disease monitoring and potential for widespread use following multicenter validation. PMID- 24947933 TI - Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. AB - PURPOSE: Pancreatic cancer is characterized by stromal desmoplasia and perineural invasion (PNI). We sought to explore the contribution of pancreatic stellate cells (PSC) activated by paracrine Sonic Hedgehog (SHH) in pancreatic cancer PNI and progression. EXPERIMENTAL DESIGN: In this study, the expression dynamics of SHH were examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of carcinomatous and nonneoplastic pancreatic tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of PSCs activated by paracrine SHH signaling in pancreatic cancer PNI and progression. RESULTS: We show that SHH overexpression in tumor cells is involved in PNI in pancreatic cancer and is an important marker of biologic activity of pancreatic cancer. Moreover, the overexpression of SHH in tumor cells activates the hedgehog pathway in PSCs in the stroma instead of activating tumor cells. These activated PSCs are essential for the promotion of pancreatic cancer cell migration along nerve axons and nerve outgrowth to pancreatic cancer cell colonies in an in vitro three-dimensional model of nerve invasion in cancer. Furthermore, the coimplantation of PSCs activated by paracrine SHH induced tumor cell invasion of the trunk and nerve dysfunction along sciatic nerves and also promoted orthotropic xenograft tumor growth, metastasis, and PNI in in vivo models. CONCLUSIONS: These results establish that stromal PSCs activated by SHH paracrine signaling in pancreatic cancer cells secrete high levels of PNI associated molecules to promote PNI in pancreatic cancer. PMID- 24947934 TI - Mechanical performance of macrofibers of cellulose and chitin nanofibrils aligned by wet-stretching: a critical comparison. AB - Renewable nanofibrillated cellulose (NFC) and nanofibrillated chitin (NFCh) are attractive fibrillar bionanoparticles due to their remarkable properties such as outstanding mechanical stiffness and strength, thermostability, barrier properties, and also for their global availability from renewable resources and food waste. One major bottleneck to maximize the mechanical properties of materials based on these bionanoparticles (e.g., nanopapers and macroscale fibers) is to find pathways to control their direction of alignment and understand how preferred alignment correlates with macroscale properties. Herein, we will demonstrate how strain-rate controlled wet-stretching of rehydrated macroscale fibers composed of nanofibrillated chitin and cellulose (NFCh, NFC) induces a high degree of orientation and how the degree of alignment scales with macroscale mechanical stiffness. We find similar degrees of alignment in both types of nanofibril-based macrofibers, yet substantially different macroscale stiffness, with the NFC-based fibers (E(NFC) = 33 GPa) outperforming the NFCh based ones (E(NFCh) = 12 GPa) considerably. These differences can be correlated to the mechanical properties of the underlying cellulose I and alpha-chitin crystals and the degree of crystallinity of the nanofibrils, which both govern the stiffness of an individual nanofibril. Our study likely demonstrates the maximum performance in terms of stiffness of materials prepared by NFC and NFCh and reveals a critical difference in the performance of both classes of bionanoparticles. PMID- 24947935 TI - Analysis of touch used by occupational therapy practitioners in skilled nursing facilities. AB - Instrumental touch is identified as having purposeful physical contact in order to complete a task. Expressive touch is identified as warm, friendly physical contact and is not solely for performing a task. Expressive touch has been associated with improved client status, increased rapport and greater gains made during therapy. The purpose of the study was to observe the frequency of expressive and instrumental touch utilized by an occupational therapist during an occupational therapy session. Thirty-three occupational therapy professionals, including occupational therapists and occupational therapy assistants, employed at skilled nursing facilities in southwest Florida were observed. Data were collected on the Occupational Therapy Interaction Assessment. The results of the data analysis showed a positive relationship between the gender of the therapist and the frequency of expressive touch. The data also showed that a large majority of touches were instrumental touch and pertained to functional mobility. The results of the study can contribute to a better understanding of the holistic aspects of occupational therapy. By the use of more expressive touch, occupational therapy practitioners may have a positive, beneficial effect on both the client and the therapy process as a whole. Further research is needed to determine the effect an occupational therapy setting has on the frequency of instrumental and expressive touch. A larger sample size and a distinction between evaluation and treatment sessions would benefit future studies. PMID- 24947936 TI - XPC Lys939Gln polymorphism contributes to colorectal cancer susceptibility: evidence from a meta-analysis. AB - BACKGROUND: Published studies investigating the association between XPC Lys939Gln polymorphism and colorectal cancer (CRC) risk reported inconclusive results. We performed a meta-analysis to derive a precise estimation of the relationship. METHODS: A comprehensive literature search was done in databases PubMed, EMBASE, and Cochrane library up to December 2013. The association between XPC Lys939Gln polymorphism and CRC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). RESULTS: Eight studies with 3,301 cases and 4,177 controls were included in the meta-analysis. We observed that the XPC Lys939Gln polymorphism was correlated with an increased CRC risk when all studies were pooled into the meta-analysis (Gln/lys vs. Lys/Lys: OR = 1.293, 95% CI 1.169 1.430, P = 0.000; Gln/Gln + Gln/lys vs. Lys/Lys: OR = 1.260, 95% CI 1.145-1.388, P = 0.000). In stratified analyses by ethnicity, smoking, and study quality, significant increased CRC risk was found in Asians (Gln/lys vs. Lys/Lys: OR = 1.345, 95% CI 1.187-1.523, P = 0.000; Gln/Gln + Gln/lys vs. Lys/Lys: OR = 1.317, 95% CI 1.170-1.484, P = 0.000), nonsmokers (Gln/Gln + Gln/lys vs. Lys/Lys: OR = 1.286, 95% CI 1.020-1.622, P = 0.033), and high quality studies. In subgroup analysis by source of control, significant increased CRC risk was found in both hospital-based studies and population-based studies. However, in subgroup analysis according to cancer location, no any significant association was detected. CONCLUSIONS: This meta-analysis suggests that the XPC is a candidate gene for CRC susceptibility. The XPC Lys939Gln polymorphism may play an important role in CRC development among Asians and nonsmokers. Further large and well designed studies are needed to confirm this association. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1665902729125948. PMID- 24947937 TI - Nazarov-like cyclization reactions. AB - The Nazarov cyclization, a well-known method for the formation of cyclopentenones, mechanistically involves the 4pi electrocyclization of a 1,4 pentadienyl cation, generated from cross-conjugated divinyl ketones. Recently, advances related to this cyclization, such as the incorporation of heteroatoms as well as the use of cyclopropanes as double bond equivalents have extended the scope of the original reaction. The modifications discussed in this review, which covers the years 2009-2013, have allowed the realization of both heteroatom- and homo-Nazarov cyclizations. PMID- 24947939 TI - The construction of tissue-engineered blood vessels crosslinked with adenosine loaded chitosan/beta-cyclodextrin nanoparticles using a layer-by-layer assembly method. PMID- 24947938 TI - Rational design and validation of a Tip60 histone acetyltransferase inhibitor. AB - Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer. PMID- 24947940 TI - Glycosphingolipid-functionalized nanoparticles recapitulate CD169-dependent HIV-1 uptake and trafficking in dendritic cells. AB - Ganglioside GM3, a host-derived glycosphingolipid incorporated in the membrane of human immunodeficiency virus-1 (HIV-1) viral particles, mediates interactions between HIV-1 and Siglec1/CD169, a protein expressed on dendritic cells (DCs). Such interactions, which seem to be independent of viral envelope glycoprotein gp120, are poorly understood. Here we develop a model system consisting of self assembled artificial virus nanoparticles (AVNs) that are free of viral glycoproteins or other host-derived glycolipids and glycoproteins. These plasmonic AVNs contain a membrane of defined composition wrapped around a solid metal core. GM3-containing AVNs are captured by CD169-expressing HeLa cells or mature DCs, and are sequestered within non-lysosomal tetraspanin-positive compartments. This distribution is reminiscent of CD169-dependent HIV-1 sequestration in mature DCs. Our results highlight GM3-CD169 binding as a gp120 independent signal for sequestration and preservation of HIV-1 infectivity. They also indicate that plasmonic AVNs offer improved features over liposome-based systems and represent a versatile tool for probing specific virus-cell interactions. PMID- 24947941 TI - Palliative care professional education via video conference builds confidence to deliver palliative care in rural and remote locations. AB - BACKGROUND: People living in rural and remote locations are disadvantaged in accessing palliative care. This can be attributed to several factors including the role diversity and the low numbers of patients with specific conditions, as well as the difficulties rural health practitioners have in accessing opportunities for professional education. A program of multidisciplinary palliative care video conferences was presented to health practitioners across part of northern Australia in an effort to address this problem. METHOD: The educational content of the video conferences was developed from participant responses to an educational needs assessment. Following cycles of four consecutive video conferences, 101 participants completed evaluative on-line surveys. The quantitative data were analysed using frequencies and analysis of variance tests with post-hoc analyses where appropriate, and an accessibility and remoteness index was used to classify their practice location. RESULTS: All participants found the content useful regardless of their remoteness from the tertiary centre, their years of experience caring for palliative care patients or the number of patients cared for each year. However, change in confidence to provide palliative care as a result of attending the video conferences was significant across all disciplines, regardless of location. Doctors, medical students and allied health professionals indicated the greatest change in confidence. CONCLUSIONS: The provision of professional education about palliative care issues via multidisciplinary video conferencing increased confidence among rural health practitioners, by meeting their identified need for topic and context specific education. This technology also enhanced the networking opportunities between practitioners, providing an avenue of ongoing professional support necessary for maintaining the health workforce in rural and remote areas. However, more attention should be directed to the diverse educational needs of allied health professionals. PMID- 24947942 TI - Climate change enhances the negative effects of predation risk on an intermediate consumer. AB - Predators are a major source of stress in natural systems because their prey must balance the benefits of feeding with the risk of being eaten. Although this 'fear' of being eaten often drives the organization and dynamics of many natural systems, we know little about how such risk effects will be altered by climate change. Here, we examined the interactive consequences of predator avoidance and projected climate warming in a three-level rocky intertidal food chain. We found that both predation risk and increased air and sea temperatures suppressed the foraging of prey in the middle trophic level, suggesting that warming may further enhance the top-down control of predators on communities. Prey growth efficiency, which measures the efficiency of energy transfer between trophic levels, became negative when prey were subjected to predation risk and warming. Thus, the combined effects of these stressors may represent an important tipping point for individual fitness and the efficiency of energy transfer in natural food chains. In contrast, we detected no adverse effects of warming on the top predator and the basal resources. Hence, the consequences of projected warming may be particularly challenging for intermediate consumers residing in food chains where risk dominates predator-prey interactions. PMID- 24947943 TI - "I swear to God, I only want people here who are losers!" cultural dissonance and the (problematic) allure of Azeroth. AB - We use ethnographically informed survey and interview data to explore therapeutic and problematic play in the online World of Warcraft (WoW). We focus on how game play in WoW is driven by shared and socially transmitted models of success that we conceptualize as cultural ideals. Our research reveals associations between having higher online compared to offline success, on the one hand, and gamers' reports about how their play both adds to and subtracts from their mental wellness, on the other. Fusing William Dressler's notion of "cultural consonance" (an individual's relative consistency with his or her culture) with Leon Festinger's "cognitive dissonance" (the tendency of individuals to suffer distress when they cannot eliminate incompatibilities in conflicting beliefs and attitudes), we develop the notion of "cultural dissonance," which in this context refers to how conflicts between online and offline lives, and also subsequent attempts to minimize the conflicts through psychological negotiations, impact gamers' mental health. PMID- 24947945 TI - A functional variant in the 5'-flanking region of the chicken serotonin transporter gene is associated with increased body weight and locomotor activity. AB - In this study, we identified a polymorphism in the 5'-flanking region of the chicken serotonin transporter (5-HTT) gene. Sequencing analysis revealed that in comparison with the wild-type variant (W), a deleted variant (D) is generated by deletion of four nucleotides (5'-AATT-3') and a single nucleotide change (A->T). Using a polyacrylamide gel electrophoresis system, we found that the 360-bp DNA fragment containing the W variant with the wild-type sequence 5'-AATTAATT-3' shows intrinsic DNA curvature while the 356-bp fragment containing the D variant lacking the four base pairs AATT is not curved. Quantitative real-time RT-PCR and ELISA demonstrated that the expression of 5-HTT in D/D chickens was higher than that in W/W and W/D chickens. In addition, transient transfection experiments with chloramphenicol acetyltransferase reporter gene constructs revealed increased 5-HTT promoter activity mediated by the D variant and a silencer activity of the W variant. Interestingly, females and males with D/D genotype showed significant greater increase in body weight from 6 weeks and 16 weeks of age, respectively, and higher body mass index. Moreover, we found that D/D chickens of both genders were physically more active than W/W and W/D chickens. PMID- 24947944 TI - Quantitative proteomics and transcriptomics of potato in response to Phytophthora infestans in compatible and incompatible interactions. AB - BACKGROUND: In order to get global molecular understanding of one of the most important crop diseases worldwide, we investigated compatible and incompatible interactions between Phytophthora infestans and potato (Solanum tuberosum). We used the two most field-resistant potato clones under Swedish growing conditions, which have the greatest known local diversity of P. infestans populations, and a reference compatible cultivar. RESULTS: Quantitative label-free proteomics of 51 apoplastic secretome samples (PXD000435) in combination with genome-wide transcript analysis by 42 microarrays (E-MTAB-1515) were used to capture changes in protein abundance and gene expression at 6, 24 and 72 hours after inoculation with P. infestans. To aid mass spectrometry analysis we generated cultivar specific RNA-seq data (E-MTAB-1712), which increased peptide identifications by 17%. Components induced only during incompatible interactions, which are candidates for hypersensitive response initiation, include a Kunitz-like protease inhibitor, transcription factors and an RCR3-like protein. More secreted proteins had lower abundance in the compatible interaction compared to the incompatible interactions. Based on this observation and because the well-characterized effector-target C14 protease follows this pattern, we suggest 40 putative effector targets. CONCLUSIONS: In summary, over 17000 transcripts and 1000 secreted proteins changed in abundance in at least one time point, illustrating the dynamics of plant responses to a hemibiotroph. Half of the differentially abundant proteins showed a corresponding change at the transcript level. Many putative hypersensitive and effector-target proteins were single representatives of large gene families. PMID- 24947946 TI - Is emergent laparoscopic cholecystectomy for acute cholecystitis safe in a low volume resource poor setting? AB - BACKGROUND: The outcomes of emergent laparoscopic cholecystectomy (LC) for acute cholecystitis have not been documented in the low-volume, resource-poor Caribbean setting. SETTINGS AND DESIGN: This study was carried out in a low-resource setting across three islands in the Anglophone Caribbean. METHODS AND MATERIALS: The records of all consecutive patients who had emergency LC for acute cholecystitis over 82 months were examined. The data were extracted and analysed using SPSS version 14. RESULTS: There were 74 patients with acute cholecystitis at a mean age of 45 (SD 11.8) years. The mean duration of operation was 99 (SD 45) min. There were 3 (4.1%) conversions and 6 (8.1%) complications. No bile duct injuries or deaths were recorded. There was more morbidity in patients with complicated disease, longer mean operation times and longer mean intervals between admission and operation. CONCLUSIONS: Emergent LC for acute cholecystitis is effective and safe in a low-volume setting in the Caribbean. However, the operations are technically demanding and should be performed by trained laparoscopic surgeons. PMID- 24947947 TI - Regarding "optimal level of sympathectomy for primary palmar hyperhidrosis: T3 versus T4 in a retrospective cohort study". PMID- 24947948 TI - Short-term results for laparoscopic repair of large paraesophageal hiatal hernias with Gore Bio A(r) mesh. AB - BACKGROUND: The application of mesh-reinforced hiatal closure has resulted in a significant reduction in recurrence rates in comparison with primary suture repair. One of the most debated issues is the risk of complications related to the use of the prosthesis, such as esophageal erosion and postoperative dysphagia. The aim of this study is to present our short-terms results in the treatment of laparoscopic paraesophageal hiatal hernia (LPHH) with a synthetic polyglycolic acid:trimethylene carbonate mesh (Gore Bio A((r))). METHODS: From January 2011 to December 2012, 10 patients with large paraesophageal hiatal hernias and hiatal defect over 5 cm were included. Primary simple suture of the crura and additional reinforcement with a Gore Bio A((r)) mesh was performed. Hiatal hernia or gastroesophageal reflux disease (GERD) symptoms recurrence, dysphagia and mesh-related complications were investigated. RESULTS: Of the 10 patients undergoing mesh repair, there were 7 women and 3 men with a mean age of 65.5 years. All operations were completed laparoscopically. Median postoperative stay was 3 days. After a median follow-up of 20.3 months, one patient developed a recurrent hiatal hernia (10%). There were no mesh-related complications. CONCLUSIONS: The use of Gore Bio A((r)) mesh for the laparoscopic repair of large paraesophageal hiatal hernias is safe and with a reasonably low recurrence rate in this short-term study. Additional long-term studies with ample numbers carried out for years will be necessary to see if this synthetic mesh is not only safe but also successful in the prevention of recurrences. PMID- 24947949 TI - Comparison of outcomes in ideal donor and extended criteria donor in deceased donor liver transplant: a prospective study. AB - INTRODUCTION: The number of patients who could benefit from liver transplantation markedly exceeds the number of available donors. This increasing gap has fuelled efforts to maximize existing donor pool and identify new avenues. AIMS AND OBJECTIVES: To compare the outcome in deceased donor liver transplant (DDLT) based on extended donor selection criteria. MATERIALS AND METHODS: Donor and recipients' data were analyzed following DDLT from Mar 2007 to Feb 2013. Donors were grouped into either ideal donor (ID) or extended criteria donor (ECD) based on donor and graft related characteristics. Primary nonfunction (PNF) and patient survival were the primary endpoints while early graft dysfunction (EGD) and incidence of major postoperative complications were the secondary endpoints of the study. RESULTS: We had a total of 6 mortalities (13%) at the end of 1 year. The Kaplan Meier survival analysis at 7 days, 3, 6 and 12 months were not statistically different (p > 0.05). PNF occurred in three (6.5%) patients and was not significantly different nor influenced by cumulative number of risk factors in the subgroup analysis (p < 0.3). However, the incidence of EGD was significantly influenced by the cumulative number of risk factors (p < 0.005). A total of 12 (26.1%) patients were graded with 3 or more complications according to the 'Clavien Dindo Grade' for major post operative complications, although it did not reach a statistical significance in the various subgroups. Univariate analysis of the donor risk factors showed that none of these factors were predictive for PNF and mortality in deceased donor liver transplant recipients. CONCLUSION: Although the incidence of early graft dysfunction is statistically more with increase in number of donor risk factors, the overall survival and outcome in extended criteria liver donors are similar to that of an ideal donor. With the supply demand gap widening, extended criteria for selection of deceased donors will definitely expand the donor pool without adversely affecting the outcome of liver transplantation. PMID- 24947950 TI - Role of prophylactic antibiotics in Milligan Morgan hemorrhoidectomy - a randomized control trial. AB - OBJECTIVE: Role of prophylactic antibiotics in Milligan Morgan hemorrhoidectomy - A prospective, randomized control trial. DESIGN: Randomized control trial. PLACE AND DURATION OF STUDY: Combined Military Hospital Malir, Bannu and HIT hospital Taxilla, September 2008 to February 2011. PATIENTS AND METHODS: Patients undergoing Milligan Morgan hemorrhoidectomy for grade III and IV hemorrhoids were randomized in 2 groups by using computer generated table. Group A did not receive any prophylactic antibiotic whereas group B received 500 mg I/V metronidazole and 1 g Ceftriaxone I/V before induction of anesthesia. All the patients had standardized post operative care. Pain scores on 100 mm Visual Analogue Scale and consumption of oral analgesics were noted from 1st to 7th post operative day. Time required for complete healing was also noted. Data was entered on SPSS 16.0 and p value was calculated. RESULTS: Out of 100 patients, 96 patients (47 in group A and 49 in group B) completed the study. Demographical data was comparable in both the groups. There was no difference in the pain scores, analgesic consumption and rate of healing between both the groups. CONCLUSION: Prophylactic antibiotics have got no role in cases of Milligan Morgan hemorrhoidectomy. PMID- 24947951 TI - Changes in the degree of mineralization with osteoporosis and its treatment. AB - The diagnosis of osteoporosis is based on low bone mineral density (BMD) and/or the occurrence of fragility fractures. The majority of patients, however, have also abnormally low bone matrix mineralization. The latter is indicative of alterations in bone turnover rates and/or in kinetics of mineral accumulation within the newly formed bone matrix. Osteoporosis therapies can alter the bone matrix mineralization according to their action on bone turnover and/or mineralization kinetics. Antiresorptives, including the most widely used bisphosphonates, reduce the bone turnover rate resulting in a decrease in heterogeneity and an increase in the degree of mineralization toward to or even beyond normal values. Anabolic agents increase the bone volume and the amount of newly formed bone resulting in a likely transient decrease in mean degree and homogeneity of mineralization. Hence, the measurement of bone matrix mineralization is a sensitive tool to evaluate the response to therapy. PMID- 24947952 TI - Sclerosing bone dysplasias: leads toward novel osteoporosis treatments. AB - Sclerosing bone dysplasias are a group of rare, monogenic disorders characterized by increased bone density resulting from the disturbance in the fragile equilibrium between bone formation and resorption. Over the last decade, major contributions have been made toward better understanding of the pathogenesis of these conditions. These studies provided us with important insights into the bone biology and yielded the identification of numerous drug targets for the prevention and treatment of osteoporosis. Here, we review this heterogeneous group of disorders focusing on their utility in the development of novel osteoporosis therapies. PMID- 24947953 TI - Targeting the IL-17/IFN-gamma axis as a potential new clinical therapy for type 1 diabetes. AB - Type 1 diabetes (T1D) results from the autoimmune destruction of insulin producing pancreatic beta cells. There is now mounting evidence that pro inflammatory pathways, which are mediated by T cells that secrete IL-17 and IFN gamma, play a critical role in the loss of beta cells. These data suggest that blockade of T cells that secrete IL-17 and IFN-gamma may halt or reverse disease in subjects with recent-onset T1D. Agents to facilitate this approach are currently in clinical use. Ustekinumab, a humanized monoclonal antibody that targets the shared p40 subunit of IL-12 and IL-23, has been used for the treatment of psoriasis, an indication for which it has proven to be safe and effective. In this review, we summarize the evidence that supports a combined pathogenic role of IL-17 and IFN-gamma in the development of T1D, with the aim of providing a rationale for testing agents such as ustekinumab for the treatment of T1D. PMID- 24947954 TI - Similar dynamics of intraapheresis autologous CD34+ recruitment and collection efficiency in patients undergoing mobilization with or without plerixafor. AB - BACKGROUND: Compared with growth factor (G) alone, the combination of G with plerixafor (G + P) increases peripheral blood CD34+ count (PB-CD34+) and improves CD34+ collection yield (yCD34+) in multiple myeloma and lymphoma patients undergoing autologous hematopoietic progenitor cell (AHPC) mobilization. It is unknown whether the improved yCD34+ with G + P results entirely from expansion of PB-CD34+ or also from increased intraapheresis CD34+ recruitment and collection efficiency. STUDY DESIGN AND METHODS: We retrospectively studied 192 patients who underwent AHPC mobilization and collection with G (n = 73) or G + P (n = 119) to compare the adjusted relative efficiency (aRE), the proportion of the circulating CD34+ pool that is captured for each blood volume processed. Additionally, in a prospective cohort of nine patients mobilizing with G and 11 with G + P, PB-CD34+ after leukapheresis allowed calculation of the recruitment coefficient (RC), proportion of the initial CD34+ pool recruited from the marrow into peripheral blood for each blood volume processed. RESULTS: There was no difference in aRE between G and G + P (0.50 vs. 0.46; p = 0.37) and no substantial decline in aRE with higher blood volumes processed in either group. RC was also not different between G and G + P (median, 0.39 and 0.38, respectively; p = 0.7). Prediction of yCD34+ was determined essentially by PB-CD34+ and not affected independently by plerixafor. CONCLUSION: Kinetics of intraapheresis CD34+ recruitment and collection is proportional to PB-CD34+ but not influenced further by plerixafor. PMID- 24947955 TI - Interventional therapies for malignant pleural effusions: the present and the future. AB - The approach to management of malignant pleural effusions (MPE) has changed over the past few decades. The key goals of MPE management are to relieve patient symptoms using the least invasive means and in the most cost-effective manner. There is now a realization that patient-reported outcome measures should be the primary goal of MPE treatment, and this now is the focus in most clinical trials. Efforts to minimize patient morbidity are complemented by development of less invasive treatments that have mostly replaced the more aggressive surgical approaches of the past. Therapeutic thoracentesis is simple, effective and generally safe, although its benefits may only be temporary. Pleurodesis is the conventional and for a long time the only definitive therapy available. However, the efficacy and safety of talc pleurodesis has been challenged. Indwelling pleural catheter (IPC) drainage is increasingly accepted worldwide and represents a new concept to improve symptoms without necessarily generating pleural symphysis. Recent studies support the effectiveness of IPC treatment and provide reassurance regarding its safety. An unprecedented number of clinical trials are now underway to improve various aspects of MPE care. However, choosing an optimal intervention for MPE in an individual patient remains a challenge due to our limited understanding of the underlying pathophysiology of breathlessness in MPE and a lack of predictors of survival and pleurodesis outcome. This review provides an overview of common pleural interventional procedures used for MPE management, controversies and limitations of current practice, and areas of research most needed to improve practice in future. PMID- 24947956 TI - Effect of surfactants on apparent oxygen consumption of photosystem I isolated from Arthrospira platensis. AB - Surfactants play a significant role in solubilization of photosystem I (PSI) in vitro. Triton X-100 (TX), n-Dodecyl-beta-D-maltoside (DDM), and sodium dodecyl sulfate (SDS) were employed to solubilize PSI particles in MES buffer to compare the effect of surfactant and its dosage on the apparent oxygen consumption rate of PSI. Through a combined assessment of sucrose density gradient centrifugation, Native PAGE and 77 K fluorescence with the apparent oxygen consumption, the nature of the enhancement of the apparent oxygen consumption activity of PSI by surfactants has been analyzed. Aggregated PSI particles can be dispersed by surfactant molecules into micelles, and the apparent oxygen consumption rate is higher for surfactant-solubilized PSI than for integral PSI particles. For DDM, PSI particles are solubilized mostly as the integral trimeric form. For TX, PSI particles are solubilized as incomplete trimeric and some monomeric forms. For the much harsher surfactant, SDS, PSI particles are completely solubilized as monomeric and its subunit forms. The enhancement of the oxygen consumption rate cannot be explained only by the effects of surfactant on the equilibrium between monomeric and trimeric forms of solubililized PSI. Care must be taken when the electron transfer activity of PSI is evaluated by methods based on oxygen consumption because the apparent oxygen consumption rate is influenced by uncoupled chlorophyll (Chl) from PSI, i.e., the larger the amount of uncoupled Chl, the higher the rate of apparent oxygen consumption. 77 K fluorescence spectra can be used to ensure that there is no uncoupled Chl present in the system. In order to eliminate the effect of trace uncoupled Chl, an efficient physical quencher of (1)O2, such as 1 mM NaN3, may be added into the mixture. PMID- 24947957 TI - Selecting a donor polymer for realizing favorable morphology in efficient non fullerene acceptor-based solar cells. PMID- 24947958 TI - Self-organization of a recurrent network under ongoing synaptic plasticity. AB - We investigated the organization of a recurrent network under ongoing synaptic plasticity using a model of neural oscillators coupled by dynamic synapses. In this model, the coupling weights changed dynamically, depending on the timing between the oscillators. We determined the phase coupling function of the oscillator model, Gamma(phi), using conductance-based neuron models. Furthermore, we examined the effects of the Fourier zero mode of Gamma(phi), which has a critical role in the case of spike-time-dependent plasticity-organized recurrent networks. Heterogeneous layered clusters with different frequencies emerged from homogeneous populations as the Fourier zero mode increased. Our findings may provide new insights into the self-assembly mechanisms of neural networks related to synaptic plasticity. PMID- 24947959 TI - Inhibition of tumor growth by U0126 is associated with induction of interferon gamma production. AB - Several MEK1/2 inhibitors have been in clinical trial evaluation for cancer treatment. Interferon-gamma (IFN-gamma) is a cytokine with multiple biological functions including antitumor activity. Expression of IFN-gamma can be induced by liver X receptor (LXR), a ligand-activated transcription factor. However, it remains unknown if the anti-cancer action of MEK1/2 inhibitors is completed, at least in part, by activating IFN-gamma expression. In this study, we determined that U0126, a MEK1/2 inhibitor, increased tumor-free and survival rates and decreased growth of inoculated Lewis lung carcinomas in wild type mice. However, the protective effects were substantially attenuated in IFN-gamma deficient (IFN gamma-/-) mice. At cellular and molecular levels, MEK1/2 inhibitors increased IFN gamma protein and mRNA expression and activated natural IFN-gamma promoter but not the IFN-gamma promoters with mutations of the LXR responsive elements (LXREs). MEK1/2 inhibitors also enhanced formation of the LXRE-nuclear protein complexes by inducing LXR expression and nuclear translocation. Similarly, MEK1/2 siRNA inhibited phosphorylation of ERK1/2 by MEK1/2 while activated IFN-gamma expression. In contrast, inhibition of LXR expression by siRNA blocked MEK1/2 inhibitors-induced IFN-gamma expression. U0126 also inhibited chemicals-induced pulmonary carcinomas, which was associated with increased IFN-gamma expression in the lung. Taken together, our study suggests that MEK1/2 inhibitors induce IFN gamma production in an LXR-dependent manner and the induction of IFN-gamma expression can partially contribute to the anti-tumorigenic properties of U0126. PMID- 24947960 TI - Chiral separation of 12 cathinone analogs by cyclodextrin-assisted capillary electrophoresis with UV and mass spectrometry detection. AB - In this study, a rapid chiral separation of 12 cathinones analogs has been developed and validated using cyclodextrin-assisted CE with UV and TOF-MS detection. Optimum separation was obtained on a 57.5 cm * 50 MUm capillary using a buffer system consisting of 10 mM beta-cyclodextrin (beta-CD) in a 100 mM phosphate buffer for CE-UV, and 0.6% v/v highly sulfated-gamma-cyclodextrin (HS gamma-CD) in a 50 mM phosphate buffer for CE-MS. In the CE-MS experiment, a partial filling technique was employed to ensure that a minimum amount of cyclodextrin entered the mass spectrometer. All analytes were separated within 18 min in the CE-UV separation and identified by TOF-MS. Ten compounds were enantiomerically separated using beta-CD in the UV mode and an additional two more were enantiomerically separated using HS-gamma-CD in the MS mode. Detection limits down to 1.0 ng/mL were obtained. The method was then applied to examine seized drugs. PMID- 24947961 TI - The importance of being Walter. PMID- 24947962 TI - Decompression as a treatment for odontogenic cystic lesions of the jaw. PMID- 24947963 TI - Letters to the editor. PMID- 24947964 TI - Anterior sinus grafts for angled implant placement for severe maxillary atrophy as an alternative to zygomatic implants for full arch fixed restoration: technique and report of 5 cases. AB - We report on 5 cases, 4 to demonstrate the anterior sinus graft technique for angled implant placement and 1 comparison zygomatic case, all for immediate function implant restoration despite severe maxillary atrophy. The sinus graft was low volume, with less than 5 mL of bone morphogenetic protein-2/absorbable collagen sponge allograft in a 50% mixture placed against the lateral nasal wall, often in conjunction with implant placement. The importance of the technique is to simplify treatment of severe maxillary atrophy for immediate function to avoid the need for zygomatic implant placement in the vast majority of severely atrophic maxillas. PMID- 24947965 TI - Comprehensive surgical management of cocaine-induced midline destructive lesions. AB - PURPOSE: This article presents a review of the literature and proposes a protocol for managing acute and chronic midfacial cocaine-induced injuries. MATERIALS AND METHODS: This report describes a series of 4 patients affected by cocaine-induced midline destructive lesions. Three patients came to the authors' attention after 18 months of drug withdrawal and underwent surgical treatments to restore nasal and palatal morphology and function, and the fourth patient was referred because of acute cocaine-induced destructive lesions and was treated by aggressive debridement. An 18-month drug-free period is planned before beginning any reconstructive procedures in this latter patient. RESULTS: Long-term follow-up showed stable results without relapse of palatal fistulas and good esthetic nasal appearance in all 3 patients undergoing reconstruction. The fourth patient did not show any disease progression and will be monitored for drug withdrawal. CONCLUSION: Chronic cocaine consumption may cause multiple types of damage to the soft and hard tissues of the midface. Acute lesions must be addressed with aggressive debridement. As a result of chronic injury, the palate and nose are deformed in a very complex way and the vascularity of the remaining local tissues may be compromised or inadequate for flap harvesting. Palatal and nasal reconstructions are very delicate operations and should be addressed separately to maximize the predictability of the result. PMID- 24947966 TI - Maxillary distraction osteogenesis for treatment of cleft lip and palate in a patient with X-linked agammaglobulinemia. AB - X-linked agammaglobulinemia (XLA) is a congenital immune deficiency disorder caused by abnormal antibody production. It is a rare disease with an estimated frequency of 1 in 379,000 that has X-linked recessive heredity and develops only in males. The clinical problems include bacterial infection such as otitis media, sinusitis, and bronchitis. In recent years it has become possible to diagnose XLA in the early stage and intravenous immunoglobulin replacement therapy has permitted survival to adulthood. However, there have been no reports of oral surgery in patients with XLA. Here, we describe a case in which immunoglobulin replacement therapy given pre- and postoperatively was used to control infection in oral surgery and maxillary distraction osteogenesis performed for improving occlusion and appearance of a cleft lip and palate in a patient with XLA. PMID- 24947967 TI - Monte Carlo photon beam modeling and commissioning for radiotherapy dose calculation algorithm. AB - The aim of the present work was a Monte Carlo verification of the Multi-grid superposition (MGS) dose calculation algorithm implemented in the CMS XiO (Elekta) treatment planning system and used to calculate the dose distribution produced by photon beams generated by the linear accelerator (linac) Siemens Primus. The BEAMnrc/DOSXYZnrc (EGSnrc package) Monte Carlo model of the linac head was used as a benchmark. In the first part of the work, the BEAMnrc was used for the commissioning of a 6 MV photon beam and to optimize the linac description to fit the experimental data. In the second part, the MGS dose distributions were compared with DOSXYZnrc using relative dose error comparison and gamma-index analysis (2%/2 mm, 3%/3 mm), in different dosimetric test cases. Results show good agreement between simulated and calculated dose in homogeneous media for square and rectangular symmetric fields. The gamma-index analysis confirmed that for most cases the MGS model and EGSnrc doses are within 3% or 3 mm. PMID- 24947968 TI - Factors related to the use of reperfusion strategies in elderly patients with acute myocardial infarction. AB - BACKGROUND: About eighty percent of acute myocardial infarction (AMI) cases occur in the elderly, we aim to examine the use of reperfusion strategies in elderly patients (>=65 years) with AMI and to investigate the factors affecting the use of these strategies. METHODS: A total of 352 consecutive elderly patients (>=65 years) with ST-elevated AMI (STAMI) were admitted, they were divided into 2 groups based on reperfusion treatment (thrombolysis or percutaneous coronary intervention, PCI): reperfusion therapy group (n = 268) and non-reperfusion therapy group (n = 84). Demographic and medical data were collected for comparison. Odds ratios (OR) and 95% confidence interval (C.I.) were calculated directly from the estimated regression coefficients. RESULTS: About 76.1% of the elderly patients with AMI received reperfusion treatment (62.5% received PCI, and 13.6% received thrombolysis). Stepwise Logistic regression analysis revealed that a patient age >=75 years (95% CI: 0.194 ~ 0.590, OR = 0.338, P = 0.000) and medical history of angina (95% CI: 0.281 ~ 0.928, OR = 0.501, P = 0.014) were determining factors for receiving less reperfusion therapy. Complications including right ventricular myocardial infarction (MI) (95% CI: 1.618 ~ 12.907, OR = 4.472, P = 0.003), unbearable symptoms (95% CI: 1.132 ~ 3.928, OR = 1.839, P = 0.021) and medical insurance (95% CI: 1.313 ~ 4.524, OR = 2.429, P = 0.004) were independent predictors of reperfusion therapy. The reperfusion therapy subset analysis revealed that intracranial hemorrhage (2.7% vs. 8.3%, P = 0.000), left ventricular ejection fraction (LVEF) <45% (13.2% vs. 29.2%, P = 0.019) and mortality rate within 1 year (2.7% vs. 6.3%, P = 0.045) were significantly decreased in the PCI group as compared with thrombolysis. CONCLUSION: Elderly patients with a medical history of angina, right ventricular MI, unbearable symptoms and medical insurance are likely be recipients of reperfusion strategies. PMID- 24947969 TI - Antiangiogenic therapy in metastatic renal cell carcinoma: more promises and more challenges for imaging. PMID- 24947970 TI - Clinical image in gastroenterology. The sign of Leser-Trelat associated with rectal carcinoma. PMID- 24947971 TI - Biotransformation and in vivo stability of protein biotherapeutics: impact on candidate selection and pharmacokinetic profiling. AB - Historically, since the metabolism of administered peptide/protein drugs ("biotherapeutics") has been expected to undergo predictable pathways similar to endogenous proteins, comprehensive biotherapeutic metabolism studies have not been widely reported in the literature. However, since biotherapeutics have rapidly evolved into an impressive array of eclectic modalities, there has been a shift toward understanding the impact of metabolism on biotherapeutic development. For biotherapeutics containing non-native chemical linkers and other moieties besides natural amino acids, metabolism studies are critical as these moieties may impart undesired toxicology. For biotherapeutics that are composed solely of natural amino acids, where end-stage peptide and amino acid catabolites do not generally pose toxicity concerns, the understanding of biotherapeutic biotransformation, defined as in vivo modifications such as peripherally generated intermediate circulating catabolites prior to end-stage degradation or elimination, may impact in vivo stability and potency/clearance. As of yet, there are no harmonized methodologies for understanding biotherapeutic biotransformation and its impact on drug development, nor is there clear guidance from regulatory agencies on how and when these studies should be conducted. This review provides an update on biotherapeutic biotransformation studies and an overview of lessons learned, tools that have been developed, and suggestions of approaches to address issues. Biotherapeutic biotransformation studies, especially for certain modalities, should be implemented at an early stage of development to 1) understand the impact on potency/clearance, 2) select the most stable candidates or direct protein re-engineering efforts, and 3) select the best bioanalytical technique(s) for proper drug quantification and subsequent pharmacokinetic profiling and exposure/response assessment. PMID- 24947972 TI - Gut microbiota-mediated drug interactions between lovastatin and antibiotics. AB - Orally administered drugs may be metabolized by intestinal microbial enzymes before absorption into the blood. Accordingly, coadministration of drugs affecting the metabolic activities of gut microbes (e.g., antibiotics) may lead to drug-drug interactions (DDI). In this study, gut microbiota-mediated DDI were investigated by studying the pharmacokinetics of lovastatin in antibiotic-treated rats. Incubation of lovastatin with human and rat fecalase preparations produced four metabolites, M1 (demethylbutyryl metabolite), M4 (hydroxylated metabolite), M8 (the active hydroxy acid metabolite), and M9 (hydroxylated M8), indicating involvement of the gut microbiota in lovastatin metabolism. The plasma concentration-time profiles of M8 were compared after oral administration of lovastatin to control rats or those treated with either ampicillin (100 mg/kg) or an antibiotic mixture consisting of cefadroxil (150 mg/kg), oxytetracycline (300 mg/kg), and erythromycin (300 mg/kg). Pharmacokinetic analyses indicated that systemic exposure to M8 was significantly lower in antibiotic-treated rats compared with controls. In addition, fecal M8 formation decreased by 58.3 and 59.9% in the ampicillin- and antibiotic mixture-treated rats, respectively. These results suggested that antibiotic intake may reduce the biotransformation of orally administered drugs by gut microbiota and that the subsequent impact on microbiota metabolism could result in altered systemic concentrations of either the intact drug and/or its metabolite(s). PMID- 24947973 TI - Portable pH-inspired electrochemical detection of DNA amplification. AB - A portable and label-free pH-mediated electrochemical method for the detection of DNA amplification is described. With protons released as readouts, DNA amplifications were detected in real-time or at the end-point. PMID- 24947974 TI - Dietary patterns are associated with obesity in Japanese patients with schizophrenia. AB - BACKGROUND: Obesity among patients with schizophrenia is a growing concern because being overweight is widely regarded as a major risk factor for cardiovascular disease and premature death. Dietary patterns have been suggested as one modifiable factor that may play a role in development of obesity. The objective of this study was to examine the association between dietary patterns and obesity among patients with schizophrenia in Japan. METHODS: We recruited patients (n = 338) aged 44.0 +/- 13.2 (mean +/- SD) years with a DSM-IV diagnosis of schizophrenia who were admitted to four psychiatric hospitals using a cross sectional design. Diet was assessed with a validated brief-type self-administered diet history questionnaire (BDHQ). Dietary patterns from 52 predefined food groups were extracted by principal component analysis. RESULTS: A total of 61 subjects (18.0%) were classified as obese. Three dietary patterns were identified: the healthy dietary pattern, the processed food dietary pattern, and the alcohol and accompanying dietary patterns. After adjusting for age and gender, patients within the high tertile of each healthy dietary pattern (OR = 0.29, 95% CI = 0.13 to 0.62) and processed food dietary pattern (OR = 0.44, 95% CI = 0.22 to 0.89) had a significantly lower risk for obesity compared with low tertile of dietary pattern. CONCLUSIONS: Our findings suggest that dietary patterns, including higher intake of protein, fat, n-3 polyunsaturated fatty acids, n-6 polyunsaturated fatty acids, and vitamins, may be related to a decreased prevalence of obesity within patients with schizophrenia. Future longitudinal research exploring dietary patterns and obesity among patients with schizophrenia is warranted. PMID- 24947975 TI - Reconstruction of fibrous skeleton: technique, pitfalls and results. AB - Destruction of the mitral-aortic (or mitroaortic) intervalvular fibrosa (IVF) by infective endocarditis is a marker of advanced pathology. Patients are at high risk, as they are sicker, have more comorbidities and have more advanced pathology, requiring a difficult operation that includes debriding and reconstructing the IVF. The anatomy and surgical techniques for that reconstruction are presented and discussed. Operative risk is high and remains high for the first year, before becoming equivalent to that of conventional operations for endocarditis. Current outcomes are better than in the past, but there is room for further improvement. PMID- 24947978 TI - Neonatal hypoxic-ischaemic encephalopathy: what lies ahead? PMID- 24947977 TI - 3.0 Tesla MRI in the early evaluation of inferior alveolar nerve neurological complications after mandibular third molar extraction: a prospective study. AB - OBJECTIVES: To evaluate the use of 3.0 T MRI in the prognosis of inferior alveolar nerve (IAN) sensory disorders after mandibular third molar extraction, in the early post-operative period. METHODS: 343 IANs were examined before and 3 days after surgery. Two radiologists evaluated the course of the nerve and the relative signal intensity (RSI). Cohen's kappa coefficient (kappa) and intraclass correlation coefficient (ICC) were used to evaluate the interobserver (k = 0.891) and intra-observer variability (ICC = 0.927; 0.914, respectively). The IANs were divided into four groups on the basis of neurosensory disorders recovery time. ANOVA was used to evaluate the differences among the RSIs of the four groups, and multiple comparisons were performed with Tukey's range test. RESULTS: No differences in the course of IANs were found before and after surgery. In 280 IANs, no iatrogenic paraesthesia was found (Group A). 63 IANs showed a neurosensory impairment. 38 IANs showed recovery of post-operative paraesthesia at 3-month follow-up (Group B). 16 IANs showed a full recovery of iatrogenic paraesthesia at 6-month follow-up (Group C). Seven IANs displayed a full recovery at 12-month follow-up and two IANs showed persistence of neurosensory disorders at 18-month follow-up (Group D). The one-way ANOVA results indicated statistically significant difference among all groups (p < 0.05), except between Groups C and D (p = 0.504). CONCLUSIONS: The early evaluation of RSI values represents a valid tool to determine the prognosis of IAN sensory disorders after mandibular third molar extraction. PMID- 24947976 TI - The role of ghrelin in addiction: a review. AB - RATIONALE: Ghrelin is a fast-acting hormone that is produced primarily by the stomach and by the brain although in smaller quantities. The regulation and the secretion of ghrelin are complex and not limited to aspects of feeding. Ghrelin exerts powerful effects on multiple processes, and it has been demonstrated that it mediates the rewarding properties of food as well as of drugs of abuse. OBJECTIVES: The purpose of this review is to summarize the findings of preclinical and clinical studies related to ghrelin's possible role in addiction for each specific class of substances. Questions related to ghrelin's involvement in addiction are highlighted. Recurrent methodological issues that render the interpretation of the findings challenging are discussed. Also, the potential of targeting ghrelin as a pharmacologic treatment strategy for addiction is explored. RESULTS: Ghrelin signaling is implicated in the mediation of behavioral and biochemical effects of drugs of abuse that are cardinal for the development of addiction, especially for alcohol, nicotine, and stimulants. The available literature implicating ghrelin in opioid or cannabis use disorders is currently limited and inconclusive. CONCLUSIONS: There is intriguing, although not always consistent, evidence for the involvement of ghrelin signaling in aspects of addiction, especially in the cases of alcohol, nicotine, and stimulants. Further research, particularly in humans, is recommended to replicate and expand on the findings of the current literature. Improved and novel methodologies that take into account the volatile and complex nature of ghrelin are required to clarify the inconsistencies of the findings. PMID- 24947979 TI - Yield improvement strategies for the production of secondary metabolites in plant tissue culture: silymarin from Silybum marianum tissue culture. AB - Plant cell culture can be a potential source for the production of important secondary metabolites. This technology bears many advantages over conventional agricultural methods. The main problem to arrive at a cost-effective process is the low productivity. This is mainly due to lack of differentiation in the cultured cells. Many approaches have been used to maximise the yield of secondary metabolites produced by cultured plant cells. Among these approaches: choosing a plant with a high biosynthetic capacity, obtaining efficient cell line for growth and production of metabolite of interest, manipulating culture conditions, elicitation, metabolic engineering and organ culture. This article gives an overview of the various approaches used to maximise the production of pharmaceutically important secondary metabolites in plant cell cultures. Examples of using these different approaches are shown for the production of silymarin from Silybum marianum tissue culture. PMID- 24947982 TI - Impacts of terminal (4R)-fluoroproline and (4S)-fluoroproline residues on polyproline conformation. AB - Many interests have been focused on prolyl cis-trans isomerization which is related to protein folding and isomer-specific biochemical recognition. Since polyproline can adopt either type I (PPI) helices with all cis amide bonds or type II (PPII) helices with all trans amide bonds, it has been a valuable model to study the prolyl isomerization. Recent studies have shown that stereoelectronic effects govern the stability of PPII structure and the rate of PPII -> PPI conversion. To further explore the terminal stereoelectronic effects on polyproline conformation, herein we synthesized a series of host-guest peptides in which (2S,4S)-4-fluoroproline (flp) or (2S,4R)-4-fluoroproline (Flp) residues are incorporated into the C- or N-terminal end of a peptide and studied the thermodynamic and kinetic consequences on polyproline conformation. Circular dichroism measurements revealed that inserting 4-fluoroproline residues into the C terminus of a polyproline peptide induces a great stereoelectronic effect on PPII stability and PPII -> PPI conversion rates. From the C terminus, a (Flp)3 triplet stabilizes PPII structure and increases the transition barrier of PPII -> PPI conversion by 1.53 kJ mol-1 while a (flp)3 triplet destabilizes PPII conformation and reduce the PPII -> PPI transition barrier by 4.61 kJ mol-1. In contrast, the 4-fluoroproline substitutions at the N terminus do not exhibit distinct stereoelectronic effects on PPII stability and PPII -> PPI conversion rates. Our data demonstrate that the C-terminal stereoelectronic effects have a more dramatic impact on PPII stability and PPII -> PPI conversion kinetics. PMID- 24947981 TI - Russian gonococcal antimicrobial susceptibility programme (RU-GASP)--resistance in Neisseria gonorrhoeae during 2009-2012 and NG-MAST genotypes in 2011 and 2012. AB - BACKGROUND: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major concern worldwide and gonococcal AMR surveillance globally is imperative for public health purposes. In Eastern Europe, gonococcal AMR surveillance is exceedingly rare. However, in 2004 the Russian gonococcal antimicrobial susceptibility programme (RU-GASP) was initiated. The aims of this study were to describe the prevalence and trends of gonococcal AMR from 2009 to 2012, and molecular epidemiological genotypes in 2011 and 2012 in Russia. METHODS: Gonococcal isolates from 12-46 surveillance sites distributed across Russia, obtained in 2009 (n = 1200), 2010 (n = 407), 2011 (n = 423), and 2012 (n = 106), were examined for antimicrobial susceptibility using agar dilution method. Gonococcal isolates from 2011 and 2012 were investigated with N. gonorrhoeae multi-antigen sequence typing (NG-MAST). RESULTS: During 2009-2012, the proportions of gonococcal isolates resistant to ciprofloxacin, penicillin G, azithromycin and spectinomycin ranged from 25.5% to 44.4%, 9.6% to 13.2%, 2.3% to 17.0% and 0.9% to 11.6%, respectively. Overall, the resistance level to penicillin G was stable, the resistance level to ciprofloxacin was decreasing, however, the level of resistance to azithromycin increased. All isolates were susceptible to ceftriaxone using the US CLSI breakpoints. However, using the European breakpoints 58 (2.7%) of the isolates were resistant to ceftriaxone. Interestingly, this proportion was decreasing, i.e. from 4.8% in 2009 to 0% in 2012. CONCLUSIONS: In Russia, the diversified gonococcal population showed a high resistance to ciprofloxacin, penicillin G and azithromycin. In general, the MICs of ceftriaxone were relatively high, however, they were decreasing from 2009 to 2012. Ceftriaxone should be the first-line for empiric antimicrobial monotherapy of gonorrhoea in Russia. It is essential to further strengthen the surveillance of gonococcal AMR (ideally also gonorrhoea treatment failures) in Russia. PMID- 24947980 TI - Increased copy number of the DLX4 homeobox gene in breast axillary lymph node metastasis. AB - DLX4 is a homeobox gene strongly implicated in breast tumor progression and invasion. Our main objective was to determine the DLX4 copy number status in sentinel lymph node (SLN) metastasis to assess its involvement in the initial stages of the axillary metastatic process. A total of 37 paired samples of SLN metastasis and primary breast tumors (PBT) were evaluated by fluorescence in situ hybridization, quantitative polymerase chain reaction and array comparative genomic hybridization assays. DLX4 increased copy number was observed in 21.6% of the PBT and 24.3% of the SLN metastasis; regression analysis demonstrated that the DLX4 alterations observed in the SLN metastasis were dependent on the ones in the PBT, indicating that they occur in the primary tumor cell populations and are maintained in the early axillary metastatic site. In addition, regression analysis demonstrated that DLX4 alterations (and other DLX and HOXB family members) occurred independently of the ones in the HER2/NEU gene, the main amplification driver on the 17q region. Additional studies evaluating DLX4 copy number in non-SLN axillary lymph nodes and/or distant breast cancer metastasis are necessary to determine if these alterations are carried on and maintained during more advanced stages of tumor progression and if could be used as a predictive marker for axillary involvement. PMID- 24947983 TI - Measuring suicidality using the personality assessment inventory: a convergent validity study with federal inmates. AB - Although numerous studies have examined the psychometric properties and clinical utility of the Personality Assessment Inventory in correctional contexts, only two studies to date have specifically focused on suicide ideation. This article examines the convergent validity of the Suicide Ideation Scale and the Suicide Potential Index on the Personality Assessment Inventory in a large, nontreatment sample of male and female federal inmates (N = 1,120). The data indicated robust validity support for both the Suicide Ideation Scale and Suicide Potential Index, which were each correlated with a broad group of validity indices representing multiple assessment modalities. Recommendations for future research to build upon these findings through replication and extension are made. PMID- 24947984 TI - Predicting performance on the Columbia Card Task: effects of personality characteristics, mood, and executive functions. AB - Behavioral measures of risky decision making are frequently used by researchers and clinicians; however, most of these measures are strongly associated with personality characteristics and state mood. The present study sought to examine personality, mood, and executive function predictors of performance on a newer measure of decision making, the Columbia Card Task (CCT). Participants were 489 undergraduate students who completed either the hot or cold version of the CCT as well as measures of state mood, impulsive sensation seeking, behavioral inhibition and activation systems, and executive functions (Wisconsin Card Sort Task; Digit Span). Results indicated that performance on the CCT-cold was predicted by Wisconsin Card Sort Task errors, and Digit Span predicted the CCT hot. In addition, significant correlations were found between the CCT information use variables and the predictor variables. Implications for the utility of the CCT as a clinical instrument and its relationship with other measures of decision making are discussed. PMID- 24947985 TI - Evaluation of coding-independent functions of the transcribed bovine aromatase pseudogene CYP19P1. AB - BACKGROUND: CYP19A1 encodes the aromatase which catalyzes the final reaction of estrogen biosynthesis. The bovine genome also contains a non-coding copy of CYP19A1, the transcribed pseudogene CYP19P1. Whereas CYP19A1 is transcribed in all estrogen-producing tissues, mainly in the placenta and gonads, the CYP19P1 transcript so far was detected in the placenta. Strikingly, one sequence segment of both transcripts exhibits an exceptional high identity of 98%, which implies selective pressure and suggests some kind of function. Only recently, indeed, coding-independent functions of several transcribed pseudogenes were reported. Therefore, we analyzed CYP19P1 and CYP19A1 transcripts with the aim to detect clues for gene-pseudogene interference. FINDINGS: The CYP19P1 transcript was first examined in silico for the presence of microRNA coding sequences and microRNA targets. Further, to identify tissues where CYP19P1 and CYP19A1 transcripts are co-expressed, as a pre-requisite for transcript interference, expression profiling was performed in a variety of bovine tissues. Our in silico analyses did neither reveal potential microRNA coding sequences, nor microRNA targets. Co-expression of the CYP19 loci was demonstrated in placental cotyledons and granulosa cells of dominant follicles. However, in granulosa cells of dominant follicles the concentration of CYP19P1 mRNA was very low compared to CYP19A1 mRNA. CONCLUSIONS: CYP19P1 and CYP19A1 transcripts might interfere in placental cotyledons. However, in granulosa cells of dominant follicles relevant interference between gene and pseudogene transcripts is unlikely to occur because of the very low CYP19P1/CYP19A1 transcript ratio. PMID- 24947987 TI - PET/CT imaging in cancer: current applications and future directions. AB - Positron emission tomography (PET) is a radiotracer imaging method that yields quantitative images of regional in vivo biology and biochemistry. PET, now used in conjunction with computed tomography (CT) in PET/CT devices, has had its greatest impact to date on cancer and is now an important part of oncologic clinical practice and translational cancer research. In this review of current applications and future directions for PET/CT in cancer, the authors first highlight the basic principles of PET followed by a discussion of the biochemistry and current clinical applications of the most commonly used PET imaging agent, (18) F-fluorodeoxyglucose (FDG). Then, emerging methods for PET imaging of other biologic processes relevant to cancer are reviewed, including cellular proliferation, tumor hypoxia, apoptosis, amino acid and cell membrane metabolism, and imaging of tumor receptors and other tumor-specific gene products. The focus of the review is on methods in current clinical practice as well as those that have been translated to patients and are currently in clinical trials. PMID- 24947986 TI - Communicative participation restrictions in multiple sclerosis: associated variables and correlation with social functioning. AB - Individuals with multiple sclerosis (MS) are at risk for communication problems that may restrict their ability to take participation in important life roles such as maintenance of relationships, work, or household management. The aim of this project is to examine selected demographic and symptom-related variables that may contribute to participation restrictions. This examination is intended to aid clinicians in predicting who might be at risk for such restrictions and what variables may be targeted in interventions. Community-dwelling adults with MS (n=216) completed a survey either online or using paper forms. The survey included the 46-item version of the Communicative Participation Item Bank, demographics (age, sex, living situation, employment status, education, and time since onset of diagnosis of MS), and self-reported symptom-related variables (physical activity, emotional problems, fatigue, pain, speech severity, and cognitive/communication skills). In order to identify predictors of restrictions in communicative participation, these variables were entered into a backwards stepwise multiple linear regression analysis. Five variables (cognitive/communication skills, speech severity, speech usage, physical activity, and education) were statistically significant predictors of communication participation. In order to examine the relationship of communicative participation and social role variables, bivariate Spearman correlations were conducted. Results suggest only a fair to moderate relationship between communicative participation and measures of social roles. Communicative participation is a complex construct associated with a number of self-reported variables. Clinicians should be alert to risk factors for reduced communicative participation including reduced cognitive and speech skills, lower levels of speech usage, limitations in physical activities and higher levels of education. LEARNING OUTCOMES: The reader will be able to: (a) describe the factors that may restrict participation in individuals with multiple sclerosis; (b) list measures of social functioning that may be pertinent in adults with multiple sclerosis; (c) discuss factors that can be used to predict communicative participation in multiple sclerosis. PMID- 24947989 TI - Neuroanatomy-based matrix-guided trimming protocol for the rat brain. AB - Brain trimming through defined neuroanatomical landmarks is recommended to obtain consistent sections in rat toxicity studies. In this article, we describe a matrix-guided trimming protocol that uses channels to reproduce coronal levels of anatomical landmarks. Both setup phase and validation study were performed on Han Wistar male rats (Crl:WI(Han)), 10-week-old, with bodyweight of 298 +/- 29 (SD) g, using a matrix (ASI-Instruments((r)), Houston, TX) fitted for brains of rats with 200 to 400 g bodyweight. In the setup phase, we identified eight channels, that is, 6, 8, 10, 12, 14, 16, 19, and 21, matching the recommended landmarks midway to the optic chiasm, frontal pole, optic chiasm, infundibulum, mamillary bodies, midbrain, middle cerebellum, and posterior cerebellum, respectively. In the validation study, we trimmed the immersion-fixed brains of 60 rats using the selected channels to determine how consistently the channels reproduced anatomical landmarks. Percentage of success (i.e., presence of expected targets for each level) ranged from 89 to 100%. Where 100% success was not achieved, it was noted that the shift in brain trimming was toward the caudal pole. In conclusion, we developed and validated a trimming protocol for the rat brain that allow comparable extensiveness, homology, and relevance of coronal sections as the landmark-guided trimming with the advantage of being quickly learned by technicians. PMID- 24947988 TI - Inner gray halo, a novel dermoscopic feature for the diagnosis of pigmented actinic keratosis: clues for the differential diagnosis with lentigo maligna. AB - BACKGROUND: Pigmented actinic keratosis (PAK) is a frequent simulator of lentigo maligna (LM) on the face upon clinical and dermoscopic examination, leading to misdiagnosis and unnecessary excisions. LM and PAK share dermoscopic features, making it difficult to have a confident diagnosis of PAK only with current dermoscopic knowledge. OBJECTIVE: We sought to evaluate sensitivity, specificity, and interobserver reproducibility of a novel dermoscopic feature, inner gray halo (IGH), and establish its histopathological and confocal correlations. METHODS: Dermoscopists blinded to histopathological diagnosis evaluated 58 PAK and 21 LM for the presence of IGH and dermoscopy parameters. Areas exhibiting IGH were marked and imaged with reflectance confocal microscopy before sampling for histopathologic correlation. Reflectance confocal microscopy and transverse histologic sectioning were performed in 14 of 79 cases. RESULTS: IGH was present in 53 of 58 (94.1%) PAK and in 5 of 21 (23.8%) LM in our series (sensitivity 91.4%; specificity 71.4%; positive predictive value 89.8%). Interobserver agreement was excellent (Kappa 0.846). Through transverse and perpendicular histologic sections, a dermoscopic-histologic-confocal correlation of IGH was established. LIMITATIONS: A larger test set is needed to further validate the use of IGH in the differential diagnosis of PAK and facial pigmented lesions. CONCLUSION: IGH is a novel dermoscopic parameter useful for the differentiation of PAK from LM on the face. PMID- 24947990 TI - Comparative dose-responses of recombinant human IL-2 and IL-7 on STAT5 phosphorylation in CD4+FOXP3- cells versus regulatory T cells: a whole blood perspective. AB - Interleukin(IL)-2 and IL-7 are cytokines with important functions related to CD4(+) lymphocyte proliferation, differentiation and survival. Depending on doses, they theoretically activate regulatory (Treg) and/or effector T cells (Teff) and thus may be indicated with different therapeutic objectives. In this study we assessed ex vivo the differential dose-responses of CD4(+) T cell subsets (Treg versus CD4(+)FOXP3(-) cells) to recombinant human (rh) IL-2 and rhIL-7. Fresh whole blood from healthy donors was stimulated with increasing doses of cytokines. By using a novel flow cytometry procedure of intracellular signaling pathway staining (e.g., detection of STAT5 phosphorylation; a pivotal marker of cytokine-induced activation; in combination with intracellular FOXP3 staining), we were able to specifically measure Treg and CD4(+)FOXP3(-) cell responses in the same tube. Half maximal effective concentrations (EC50) were calculated. We observed a dose-response effect on Treg and CD4(+)FOXP3(-) cells for both cytokines. Interestingly, low doses of hIL-2 preferentially activated Treg (EC50 Treg = 0.15 pg/ml versus CD4(+)FOXP3(-) cells = 750 pg/ml - p < 0.0001) whereas low doses of rhIL-7 preferentially induced CD4(+)FOXP3(-) cell activation (EC50 Treg = 25 pg/ml and CD4(+)FOXP3(-) cells = 2.5 pg/ml - p < 0.0001). To our knowledge, this work is the first to show differential dose response effects on CD4(+)FOXP3(-) cells versus Treg of rhIL-7 and rhIL-2 in one ex vivo whole blood single tube assay including two intracellular stainings (i.e., pSTAT5 and FOXP3). Beyond the confirmation of the dose-dependent differential effects of IL-2 versus IL-7 on CD4(+)FOXP3(-) cells/Treg, our results illustrate the value of this approach for monitoring drugs' activities by flow cytometry in daily clinical practice. PMID- 24947991 TI - Medical, psychological and social features in a large cohort of adults with Prader-Willi syndrome: experience from a dedicated centre in France. AB - BACKGROUND: Prader-Willi syndrome (PWS) is a developmental genetic disorder characterised by a variable expression of medical, cognitive and behavioural symptoms. In adulthood, the prevalence and severity of these symptoms determine the quality of life of the affected persons. Because of their rare disease condition, data on health and social problems in adults with PWS are scarce. In this research, we present medical, psychological and social features of a large cohort of adults admitted to a specialised PWS centre in France and analyse the differences according to genotype, gender and age. METHODS: Data from 154 patients (68 men/86 women), with a median age of 27 years (range 16-54), were collected during their stay in our centre. Clinical histories were completed using information from parents or main caregivers, and the same medical team performed the diagnosis of different clinical conditions. Statistical analyses were performed to determine the influence of factors such as genotype, age or gender. RESULTS: Paternal deletion genotype was the most frequent (65%) at all ages. Most patients had mild or moderate intellectual disability (87%). Only 30% had studied beyond primary school and 70% were in some special educational or working programme. Most of them lived in the family home (57%). The most prevalent somatic comorbidities were scoliosis (78%), respiratory problems (75%), dermatological lesions (50%), hyperlipidaemia (35%), hypothyroidism (26%), Type 2 diabetes mellitus (25%) and lymph oedema (22%). Some form of psychotropic treatment was prescribed in 58% of subjects, and sex hormones in 43%. Patients with deletion had a higher body mass index (44 vs. 38.9 kg/m(2)) and displayed higher frequency of sleep apnoeas. Non-deletion patients received insulin treatment (19% vs. 4%) and antipsychotic treatment (54.8% vs. 32.7%) more frequently. No difference was observed in the prevalence of Type 2 diabetes between the two genotype groups. Patients >27 years of age had a higher rate of comorbidities (Type 2 diabetes, hypertension, respiratory problems and lymph oedema). Gender differences were minor. CONCLUSIONS: Adult patients with PWS showed high prevalence of comorbid health problems that need to be monitored for early treatment. Some of them are influenced by genotype and age. Another salient problem concerns the lack of adapted structures for better social integration. Further data about the real life and health conditions of adults with PWS are necessary to further our knowledge of the natural history of the disease and to design appropriate care strategies. PMID- 24947992 TI - [Avoidable visual impairment among residents in care institutions: lessons from an intervention project in the Den Bosch region]. AB - INTRODUCTION: Many elderly in care institutions in The Netherlands are visually impaired (visual acuity < 0.3). They fall more frequently, are more depressed and require more care. In this project visually impaired residents were identified and referred for adequate eye care. The aim of this study is to evaluate the intervention, including validation of the screening, assessment of the prevalence and causes of visual impairment as well as the outcome of the treatment. The effectiveness of the care chain is also evaluated. MATERIALS AND METHODS: 640 residents were offered a basic eye examination and 210 of them were referred, via their general practitioner, to an optometrist (10), ophthalmologist (98), or centre for visually impaired persons (1). RESULTS: Compliance in this study was poor. The prevalence of visual impairment (24%) was lower than in comparable studies. Cataract was the main cause in 51%. Overall 17 (8.1%) residents were treated by ophthalmologists and nine (4.3%) were referred to optical shops. Constraints in the care chain are identified. DISCUSSION: Vision screening in care institutions for elderly is feasible and useful. The care chain should be shorter and simpler. That will increase the effectiveness of this intervention, and thereby the quality of life for many residents. PMID- 24947993 TI - Barriers to access for Canadians who use cannabis for therapeutic purposes. AB - BACKGROUND: There is increased interest in the therapeutic potential of cannabis in recent decades. Canada, the Netherlands, Israel and some states in the United States have developed programs to allow access to cannabis for therapeutic purposes (CTP). In Canada, enrollment in the federal CTP program represents fewer than 5% of the estimated users of CTP. The discrepancy between the number of Canadians who report using CTP and the rate of utilization of the federal CTP program suggests the existence of barriers to access to this program. METHODS: In the present study we employ a health services analytical framework to examine barriers to access to CTP among 628 current CTP users. We define barriers to access as areas of poor fit between clients and services. We use five dimensions of accommodation, accessibility, availability, affordability, and acceptability to examine access to CTP. RESULTS: Our findings reveal that it is difficult for Canadians to find a physician to support their application to access CTP. Accessing CTP from unauthorized sources was common; only 7% of respondents accessed CTP exclusively from authorized sources. Access to CTP was positively associated with the presence of medical cannabis dispensaries, which were not included in the regulatory regime. Access to CTP varied by medical condition and general quality of health. Affordability of CTP was a substantial barrier to access. CONCLUSIONS: Strategies need to be developed to encourage scientific inquiry into CTP and address the barriers to access to CTP and the stigma and controversy that surround CTP and strain patient-physician relationships. PMID- 24947994 TI - Increased drug seizures in Hatay, Turkey related to civil war in Syria. PMID- 24947995 TI - Are we there yet? Assessing achievement of vaccine-preventable disease goals in WHO's Western Pacific Region. AB - Accelerated disease control goals have long been appreciated for their role in galvanizing commitment and bringing a sense of urgency for disease prevention. WHO's Western Pacific Region has 14 on-going communicable disease reduction goals including 1 targeting eradication, 10 targeting elimination, and 3 control initiatives. These goals cover mother-to-child transmission of HIV, congenital syphilis, tuberculosis, leprosy, five parasitic diseases and four vaccine preventable diseases (VPD). The initiatives have distinct objectives, approaches, and means in which to measure achievement of the goals. Given the long history and experience with VPD initiatives in the Western Pacific Region, this manuscript focuses on the Region's following initiatives: (1) smallpox eradication, (2) polio eradication, (3) measles elimination, (4) maternal and neonatal tetanus elimination (MNTE), and (5) hepatitis B control. There is good consistency across the Region's VPD initiatives yet a pattern of more robust and representative data requirements, stricter evaluation criteria, and more formal evaluation bodies are linked to the intensity of the goal - with eradication being the peak. On the other end of this spectrum, the Regional hepatitis B control initiative has established efficient and low-cost approaches for measuring impact and evaluating if the goals have been met. Even within the confines of VPD initiatives there are some deviations in use of terminology and comparisons across other disease control initiatives in the Region are provided. PMID- 24947996 TI - Targeting the K-Ras--JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation. AB - Cancer cells with self-renewal and tumor-initiating capacity, either quiescent (cancer stem cells, CSCs) or proliferating (cancer stem-like cells, CSLCs), are now deemed responsible for the pervasive therapy resistance of pancreatic cancer, one of the deadliest human cancers characterized by high prevalence of K-Ras mutation. However, to date, much remains unknown how pancreatic CSCs/CSLCs are regulated. Here we show that the K-Ras - JNK axis plays a pivotal role in the maintenance of pancreatic CSCs/CSLCs. In vitro inhibition of JNK, either pharmacological or genetic, caused loss of the self-renewal and tumor-initiating capacity of pancreatic CSLCs. Importantly, JNK inhibition in vivo via systemic JNK inhibitor administration, which had no discernible effect on the general health status of mice, efficiently depleted the CSC/CSLC population within pre established pancreatic tumor xenografts. Furthermore, knockdown of K-Ras in pancreatic CSLCs with K-Ras mutation led to downregulation of the JNK pathway as well as in loss of self-renewal and tumor-initiating capacity. Together, our findings suggest that pancreatic CSCs/CSLCs are dependent on K-Ras activation of JNK and also suggest that the K-Ras - JNK axis could be a potential target in CSC/CSLC-directed therapies against pancreatic cancer. PMID- 24947997 TI - Symptomatic presentation of carotid sinus hypersensitivity is associated with impaired cerebral autoregulation. AB - BACKGROUND: Carotid sinus hypersensitivity (CSH) is associated with syncope, unexplained falls, and drop attacks in older people but occurs asymptomatically in 35% of community-dwelling elders. We hypothesized that impaired cerebral autoregulation is associated with the conversion of asymptomatic CSH to symptomatic CSH. We therefore conducted a case-control study evaluating individuals with CSH with and without the symptoms of syncope or unexplained falls, as well as non-CSH controls, to determine whether the blood pressure and heart rate changes associated with CSH are associated with symptoms only when cerebral autoregulation is altered. METHODS AND RESULTS: Bilateral middle cerebral artery blood flow velocities (BFV) were measured in consecutive patients with symptomatic CSH (n=22) and asymptomatic controls with (n=18) and without CSH (n=14) using transcranial Doppler ultrasonography during lower body negative pressure-induced systemic hypotension. Within-group comparisons revealed significantly lower cerebrovascular resistance index (CVRi) at nadir for the asymptomatic CSH group (right, mean [95% CI]: 2.2 [1.8, 2.8] versus 2.6 [2.2, 3.0]; P=0.005; left: 2.8 [2.4, 3.3] versus 3.1 [2.7, 3.8]; P=0.016). Between group comparisons showed higher mean BFV (right: estimated mean difference, B=5.49 [1.98, 8.80], P=0.003; left: 4.82 [1.52, 8.11], P=0.005) and lower CVRi (right: B=0.08 [0.03, 0.12], P=0.003, left: B=0.07 [0.02, 0.12], P=0.006) in asymptomatic CSH versus symptomatic CSH groups. There were no significant differences in bilateral mean BFV or right CVRi between the non-CSH and symptomatic CSH groups but differences were present for left CVRi (B=0.07 [0.02, 0.013], P=0.015). CONCLUSION: Cerebral autoregulation is altered in symptomatic CSH and therefore appears to be associated with the development of hypotension related symptoms in individuals with CSH. PMID- 24947999 TI - Reducing readmissions: what might it take? PMID- 24948000 TI - Multi-well fungal co-culture for de novo metabolite-induction in time-series studies based on untargeted metabolomics. AB - The induction of fungal metabolites by fungal co-cultures grown on solid media was explored using multi-well co-cultures in 2 cm diameter Petri dishes. Fungi were grown in 12-well plates to easily and rapidly obtain the large number of replicates necessary for employing metabolomic approaches. Fungal culture using such a format accelerated the production of metabolites by several weeks compared with using the large-format 9 cm Petri dishes. This strategy was applied to a co culture of a Fusarium and an Aspergillus strain. The metabolite composition of the cultures was assessed using ultra-high pressure liquid chromatography coupled to electrospray ionisation and time-of-flight mass spectrometry, followed by automated data mining. The de novo production of metabolites was dramatically increased by nutriment reduction. A time-series study of the induction of the fungal metabolites of interest over nine days revealed that they exhibited various induction patterns. The concentrations of most of the de novo induced metabolites increased over time. However, interesting patterns were observed, such as with the presence of some compounds only at certain time points. This result indicates the complexity and dynamic nature of fungal metabolism. The large-scale production of the compounds of interest was verified by co-culture in 15 cm Petri dishes; most of the induced metabolites of interest (16/18) were found to be produced as effectively as on a small scale, although not in the same time frames. Large-scale production is a practical solution for the future production, identification and biological evaluation of these metabolites. PMID- 24948001 TI - Fathers of Children With Type 1 Diabetes: Perceptions of a Father's Involvement From a Health Promotion Perspective. AB - This study describes how fathers of children diagnosed with type 1 diabetes understand their involvement in their child's daily life from a health promotion perspective. Sixteen Swedish fathers of children living with type 1 diabetes were interviewed. Manifest and latent content analysis was used to identify two themes: the inner core of the father's general parental involvement and the additional involvement based on the child's diabetes. The former was underpinned by the fathers' prioritization of family life and the fathers being consciously involved in raising the child, and the latter by the fathers promoting and controlling the child's health and promoting and enabling the child's autonomy. The results highlight that the quality of the fathers' involvement is essential in the management of a child's chronic illness. It is important for pediatric diabetes health care professionals to assess the quality of fathers' involvement to promote the child's health. PMID- 24947998 TI - DNA methylation is developmentally regulated for genes essential for cardiogenesis. AB - BACKGROUND: DNA methylation is a major epigenetic mechanism altering gene expression in development and disease. However, its role in the regulation of gene expression during heart development is incompletely understood. The aim of this study is to reveal DNA methylation in mouse embryonic hearts and its role in regulating gene expression during heart development. METHODS AND RESULTS: We performed the genome-wide DNA methylation profiling of mouse embryonic hearts using methyl-sensitive, tiny fragment enrichment/massively parallel sequencing to determine methylation levels at ACGT sites. The results showed that while global methylation of 1.64 million ACGT sites in developing hearts remains stable between embryonic day (E) 11.5 and E14.5, a small fraction (2901) of them exhibit differential methylation. Gene Ontology analysis revealed that these sites are enriched at genes involved in heart development. Quantitative real-time PCR analysis of 350 genes with differential DNA methylation showed that the expression of 181 genes is developmentally regulated, and 79 genes have correlative changes between methylation and expression, including hyaluronan synthase 2 (Has2). Required for heart valve formation, Has2 expression in the developing heart valves is downregulated at E14.5, accompanied with increased DNA methylation in its enhancer. Genetic knockout further showed that the downregulation of Has2 expression is dependent on DNA methyltransferase 3b, which is co-expressed with Has2 in the forming heart valve region, indicating that the DNA methylation change may contribute to the Has2 enhancer's regulating function. CONCLUSIONS: DNA methylation is developmentally regulated for genes essential to heart development, and abnormal DNA methylation may contribute to congenital heart disease. PMID- 24948002 TI - Upregulation of Gem relates to retinal ganglion cells apoptosis after optic nerve crush in adult rats. AB - GTP-binding protein Gem, a member protein of the Ras superfamily, can regulate actin cytoskeleton reorganization mediated by Rho-associated coiled-coil containing protein kinase (ROCK). One attractive activity of the ROCK is playing a potential role in physiological and pathological process in retinal ganglion cells (RGCs) apoptosis. However, the function of Gem in retina is still with limited understanding. To investigate whether Gem is involved in optic nerve injury, we performed an optic nerve crush (ONC) model in adult rats. Western blot analysis indicated that Gem was significantly increased in the retina at the 3rd day after ONC. Meanwhile, double-immunofluorescent staining showed that Gem expression was mainly up-regulated in ganglion cell layer and co-localized with NeuN (a marker of RGCs). Additionally, the co-localizations of Gem/active-caspase 3 and Gem/TUNEL-positive cells were detected in RGCs. Furthermore, the expression of active-caspase-3 and TUNEL-positive cells was parallel with that of Gem. Finally, expression pattern of ROCK family (only ROCK2 but not ROCK1) was increased in the differentiated process, which was collected with the expression of GEM and active-caspase-3. Based on the present results, it is suggested that Gem might play a crucial role in RGCs apoptosis after ONC, which might be involved in ROCK pathway. PMID- 24948004 TI - Smart chemistry in polymeric nanomedicine. AB - This review provides an overview of smart chemistry developed and utilized in the last 5-10 years in polymer-based drug delivery nanomedicine. Smart chemistry not only facilitates the controlled drug loading in a highly specific manner, but also potentially controls the drug release kinetics at the targeted tissues. This review highlights the emergence of new chemistry or unique utilization of conventional chemistry in drug delivery, which is believed to play an important role in developing next generation nanomedicine. PMID- 24948003 TI - Differential expression of the Kv1 voltage-gated potassium channel family in the rat nephron. AB - Several potassium (K(+)) channels contribute to maintaining the resting membrane potential of renal epithelial cells. Apart from buffering the cell membrane potential and cell volume, K(+) channels allow sodium reabsorption in the proximal tubule (PT), K(+) recycling and K(+) reabsorption in the thick ascending limb (TAL) and K(+) secretion and K(+) reabsorption in the distal convoluted tubule (DCT), connecting tubule (CNT) and collecting duct. Previously, we identified Kv.1.1, Kv1.3 and Kv1.6 channels in collecting ducts of the rat inner medulla. We also detected intracellular Kv1.3 channel in the acid secretory intercalated cells, which is trafficked to the apical membrane in response to dietary K(+) to function as a secretory K(+) channel. In this work we sought to characterize the expression of all members of the Kv1 family in the rat nephron. mRNA and protein expression were detected for all Kv1 channels. Immunoblots identified differential expression of each Kv1 in the cortex, outer and inner medulla. Immunofluorescence labeling detected Kv1.5 in Bowman's capsule and endothelial cells and Kv1.7 in podocytes, endothelial cells and macula densa in glomeruli; Kv1.4, Kv1.5 and Kv1.7 in PT; Kv1.2, Kv1.4 and Kv1.6 in TAL; Kv1.1, Kv1.4 and Kv1.6 in DCT and CNT and Kv1.3 in DCT, and all the Kv1 family in the cortical and medullary collecting ducts. Recently, some hereditary renal syndromes have been attributed to mutations in K(+) channels. Our results expand the repertoire of K(+) channels that contribute to K(+) homeostasis to include the Kv1 family. PMID- 24948006 TI - (R)-alpha-methylhistamine suppresses inhibitory neurotransmission in hippocampal CA1 pyramidal neurons counteracting propofol-induced amnesia in rats. AB - BACKGROUND: Propofol is a short-acting, intravenous general anesthetic that is widely used in clinical practice for short procedures; however, it causes depressed cognitive function for several hours thereafter. (R)-alpha methylhistamine (RAMH), a selective histamine H3 receptor agonist, can enhance memory retention and attenuates memory impairment in rats. In this study, we investigated whether RAMH could rescue propofol-induced memory deficits and the underlying mechanisms partaking in this process. METHODS: In the modified Morris water maze (MWM) test, rats were randomized into the following groups: control, propofol (25 mg/kg, i.p., 30 min before training), RAMH (10 mg/kg, i.p., 60 min before training), and propofol plus RAMH. All randomized rats were subjected to 2 days of training, and a probe test was conducted on day 3. Field excitatory postsynaptic potentials were recorded from CA1 neurons in rat hippocampal slices, and long-term potentiation (LTP) was induced by either theta-burst stimulation (TBS) or high-frequency tetanic stimulation (HFS). Spontaneous and miniature inhibitory (sIPSCs, mIPSCs) or excitatory (sEPSCs, mEPSCs) postsynaptic currents were recorded from CA1 pyramidal neurons by whole-cell patch clamp. RESULTS: In the MWM task, propofol injection significantly impaired spatial memory retention. Pretreatment with RAMH reversed propofol-induced memory retention. In hippocampal CA1 slices, propofol perfusion markedly inhibited TBS- but not HFS-induced LTP. Co-perfusion of RAMH reversed the inhibitory effect of propofol on TBS-induced LTP reduction. Furthermore, in hippocampal CA1 pyramidal neurons, RAMH significantly suppressed the frequency but not the amplitude of sIPSCs and mIPSCs and had little effects on both the frequency and amplitude of sEPSCs and mEPSCs. CONCLUSIONS: Our results suggest that RAMH, by inhibiting presynaptic GABAergic neurotransmission, suppresses inhibitory neurotransmission in hippocampal CA1 pyramidal neurons, which in turn reverses inhibition of CA1 LTP and the spatial memory deficits induced by propofol in rats. PMID- 24948005 TI - Update on crescentic glomerulonephritis. AB - The recent years have seen a number of major progresses in the field of extracapillary glomerulonephritis. This entity is the final damage caused by unrelated immunological disorders such as immune complexes glomerular deposits or microvascular injury caused by proinflammatory cytokines, neutrophil extracellular traps (NET), and cell adhesion molecules in the context of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This review provides a summary of recent advances in the understanding of crescentic glomerulonephritis, focusing on interplays of local immune cells and on local mediators participating to crescent formation especially in anti-glomerular basement membrane (anti-GBM) antibody disease. The recent advances about AAV and lupus nephritis are covered by other chapters of this issue. Nevertheless, these considerations may apply to the general case of crescentic glomerulonephritis of all causes. PMID- 24948007 TI - Allele-dependent association of chicken MHC class I molecules with the invariant chain. AB - Invariant chain (Ii) associates with MHC class I molecules in cross-presentation pathway in mouse, but the association of Ii with MHC class I molecules in chicken was not clear. In this study we selected five typical alleles from about 100 B-FA and some B-FB sequences and tested. Confocal microscopy revealed that only two alleles of alpha chain (CD type) rather than beta chain showed incomplete co localization with Ii own, or as a combined cytosolic and transmembrane domains in the co-transfected 293T cells, while other allele types, CK and CL, had no this ability. Co-immunoprecipitation (IP) indicated that one of both alleles bound only full-length Ii. Interestingly, further analysis of five sequences showed that the types CK had a tail and the most variable sites (39/44) localize within MHC I alpha1 and alpha2 regions, this suggests that the tail and multi-sites are crucial to the association with Ii. Additionally, qRT-PCR revealed that Ii transcription levels in different organs were positively correlated with those of B-FA or B-FB gene. These results suggest that the allele-dependent association of chicken MHC class I molecules with its Ii with bases on a multi-site determinative spatial structure and that Ii as carrier potentially perform similar roles in MHC II as well as in MHC I antigen peptide presentation. PMID- 24948008 TI - 'All illness is personal to that individual': a qualitative study of patients' perspectives on treatment adherence in bronchiectasis. AB - BACKGROUND: Adherence to treatment is low in bronchiectasis and is associated with poorer health outcomes. Factors affecting adherence decisions have not been explored in patients with bronchiectasis. OBJECTIVE: We aimed to explore patients' perspectives on adherence, factors affecting adherence decision making and to develop a conceptual model explaining this decision-making process in adults with bronchiectasis. METHODS: Adults with bronchiectasis participated in one-to-one semi-structured interviews. Interviews were audio-recorded, transcribed verbatim and analysed independently by two researchers using thematic analysis. Data from core themes were extracted, categorized into factors affecting adherence decision making and used to develop the conceptual model. RESULTS: Participants' beliefs about treatment, the practical aspects of managing treatment, their trust in health-care professionals and acceptance of disease and treatment were important aspects of treatment adherence. The conceptual model demonstrated that adherence decisions were influenced by participants' individual balance of barriers and motivating factors (treatment-related, disease-related, health-care-related, personal and social factors). CONCLUSION: Adherence decision making in bronchiectasis is complex, but there is the potential to enhance adherence by understanding patients' specific barriers and motivators to adherence and using this to tailor adherence strategies to individual patients and treatments. PMID- 24948010 TI - DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo. AB - Human mutations and in vitro studies indicate that DLX3 has a crucial function in bone development, however, the in vivo role of DLX3 in endochondral ossification has not been established. Here, we identify DLX3 as a central attenuator of adult bone mass in the appendicular skeleton. Dynamic bone formation, histologic and micro-computed tomography analyses demonstrate that in vivo DLX3 conditional loss of function in mesenchymal cells (Prx1-Cre) and osteoblasts (OCN-Cre) results in increased bone mass accrual observed as early as 2 weeks that remains elevated throughout the lifespan owing to increased osteoblast activity and increased expression of bone matrix genes. Dlx3OCN-conditional knockout mice have more trabeculae that extend deeper in the medullary cavity and thicker cortical bone with an increased mineral apposition rate, decreased bone mineral density and increased cortical porosity. Trabecular TRAP staining and site-specific Q-PCR demonstrated that osteoclastic resorption remained normal on trabecular bone, whereas cortical bone exhibited altered osteoclast patterning on the periosteal surface associated with high Opg/Rankl ratios. Using RNA sequencing and chromatin immunoprecipitation-Seq analyses, we demonstrate that DLX3 regulates transcription factors crucial for bone formation such as Dlx5, Dlx6, Runx2 and Sp7 as well as genes important to mineral deposition (Ibsp, Enpp1, Mepe) and bone turnover (Opg). Furthermore, with the removal of DLX3, we observe increased occupancy of DLX5, as well as increased and earlier occupancy of RUNX2 on the bone-specific osteocalcin promoter. Together, these findings provide novel insight into mechanisms by which DLX3 attenuates bone mass accrual to support bone homeostasis by osteogenic gene pathway regulation. PMID- 24948009 TI - Getting TRAIL back on track for cancer therapy. AB - Unlike other members of the TNF superfamily, the TNF-related apoptosis-inducing ligand (TRAIL, also known as Apo2L) possesses the unique capacity to induce apoptosis selectively in cancer cells in vitro and in vivo. This exciting discovery provided the basis for the development of TRAIL-receptor agonists (TRAs), which have demonstrated robust anticancer activity in a number of preclinical studies. Subsequently initiated clinical trials testing TRAs demonstrated, on the one hand, broad tolerability but revealed, on the other, that therapeutic benefit was rather limited. Several factors that are likely to account for TRAs' sobering clinical performance have since been identified. First, because of initial concerns over potential hepatotoxicity, TRAs with relatively weak agonistic activity were selected to enter clinical trials. Second, although TRAIL can induce apoptosis in several cancer cell lines, it has now emerged that many others, and importantly, most primary cancer cells are resistant to TRAIL monotherapy. Third, so far patients enrolled in TRA-employing clinical trials were not selected for likelihood of benefitting from a TRA comprising therapy on the basis of a valid(ated) biomarker. This review summarizes and discusses the results achieved so far in TRA-employing clinical trials in the light of these three shortcomings. By integrating recent insight on apoptotic and non-apoptotic TRAIL signaling in cancer cells, we propose approaches to introduce novel, revised TRAIL-based therapeutic concepts into the cancer clinic. These include (i) the use of recently developed highly active TRAs, (ii) the addition of efficient, but cancer-cell-selective TRAIL-sensitizing agents to overcome TRAIL resistance and (iii) employing proteomic profiling to uncover resistance mechanisms. We envisage that this shall enable the design of effective TRA-comprising therapeutic concepts for individual cancer patients in the future. PMID- 24948011 TI - Mitochondrial Ca(2+) influx targets cardiolipin to disintegrate respiratory chain complex II for cell death induction. AB - Massive Ca(2+) influx into mitochondria is critically involved in cell death induction but it is unknown how this activates the organelle for cell destruction. Using multiple approaches including subcellular fractionation, FRET in intact cells, and in vitro reconstitutions, we show that mitochondrial Ca(2+) influx prompts complex II of the respiratory chain to disintegrate, thereby releasing an enzymatically competent sub-complex that generates excessive reactive oxygen species (ROS) for cell death induction. This Ca(2+)-dependent dissociation of complex II is also observed in model membrane systems, but not when cardiolipin is replaced with a lipid devoid of Ca(2+) binding. Cardiolipin is known to associate with complex II and upon Ca(2+) binding coalesces into separate homotypic clusters. When complex II is deprived of this lipid, it disintegrates for ROS formation and cell death. Our results reveal Ca(2+) binding to cardiolipin for complex II disintegration as a pivotal step for oxidative stress and cell death induction. PMID- 24948013 TI - [Introduction to the Claude Bernard Meeting--What is pain?]. PMID- 24948012 TI - A novel PPARgamma2 modulator sLZIP controls the balance between adipogenesis and osteogenesis during mesenchymal stem cell differentiation. AB - Mesenchymal stem cells (MSCs), also known as multipotent stromal cells, are used in clinical trials. However, the use of MSCs for medical treatment of patients poses a potential problem due to the possibility of transdifferentiation into unwanted tissues. Disruption of the balance during MSC differentiation leads to obesity, skeletal fragility, and osteoporosis. Differentiation of MSCs into either adipocytes or osteoblasts is transcriptionally regulated by the two key transcription factors PPARgamma2 and Runx2. PPARgamma2 is highly expressed during adipocyte differentiation and regulates expression of genes involved in adipogenesis. Runx2 induces osteogenic gene expression and, thereby, increases osteoblast differentiation. Although transcriptional modulation of PPARgamma2 has been investigated in adipogenesis, the underlying molecular mechanisms to control the balance between adipogenesis and osteogenesis in MSCs remain unclear. In this study, the role of sLZIP in regulation of PPARgamma2 transcriptional activation was investigated along with sLZIP's involvement in differentiation of MSCs into adipocytes and osteoblasts. sLZIP interacts with PPARgamma2 and functions as a corepressor of PPARgamma2. sLZIP enhances formation of the PPARgamma2 corepressor complex through specific interaction with HDAC3, resulting in suppression of PPARgamma2 transcriptional activity. We found that sLZIP prevents expression of PPARgamma2 target genes and adipocyte differentiation both in vitro and in vivo. sLZIP also upregulates Runx2 transcriptional activity via inhibition of PPARgamma2 activity, and promotes osteoblast differentiation. sLZIP transgenic mice exhibited enhanced bone mass and density, compared with wild-type mice. These results indicate that sLZIP has a critical role in the regulation of osteogenesis and bone development. However, sLZIP does not affect chondrogenesis and osteoclastogenesis. We propose that sLZIP is a novel PPARgamma2 modulator for control of the balance between adipogenesis and osteogenesis during MSC differentiation, and that sLZIP can be used as a therapeutic target molecule for treatment of obesity, osteodystrophy, and osteoporosis. PMID- 24948014 TI - [Functional imaging of pain]. AB - In this review, we summarize the contribution of functional imaging to the question of nociception in humans. In the beginning of the 90's, brain areas supposed to be involved in physiological pain processes essentially concerned the primary somatosensory area (SI), thalamus, and anterior cingulate cortex. In spite of these a priori hypotheses, the first imaging studies revealed that the main brain areas and those providing the most consistent activations in pain conditions were the insular and the SII cortices, bilaterally. This has been checked with other techniques such as intracerebral recordings of evoked potentials after nociceptive stimulations with laser showing a consistent response in the operculo-insular area whose amplitude correlates with pain intensity. In spite of electrode implantations in other areas of the brain, only rare and inconsistent responses have been found outside the operculo-insular cortices. With electrical stimulation delivered directly in the brain, it has also been shown that stimulation in this area only - and not in other brain areas - was able to elicit a painful sensation. Thus, over the last 15 years, the operculo-insular cortex has been re-discovered as a main area of pain integration, mainly in its sensory and intensity aspects. In neuropathic pain also, these areas have been demonstrated as being abnormally recruited, bilaterally, in response to innocuous stimuli. These results suggest that plastic changes may occur in brain areas that were pre-defined for generating pain sensations. Conversely, when the brain activations concomitant to pain relief were taken in account, a large number of studies pointed out medial prefrontal and rostral cingulate areas as being associated with pain controls. Interestingly, these activations may correlate with the magnitude of pain relief, with the activation of the peri-acqueductal grey (PAG) and, at least in some instances, with the involvement of endogenous opioids. PMID- 24948015 TI - [Acid-Sensing Ion Channels (ASICs) in pain]. AB - The discovery of new drug targets represents a real opportunity for developing fresh strategies against pain. Ion channels are interesting targets because they are directly involved in the detection and the transmission of noxious stimuli by sensory fibres of the peripheral nervous system and by neurons of the spinal cord. Acid-Sensing Ion Channels (ASICs) have emerged as important players in the pain pathway. They are neuronal, voltage-independent depolarizing sodium channels activated by extracellular protons. The ASIC family comprises several subunits that need to associate into homo- or hetero-trimers to form a functional channel. The ASIC1 and ASIC3 isoforms are particularly important in sensory neurons, whereas ASIC1a, alone or in association with ASIC2, is essential in the central nervous system. The potent analgesic effects associated with their inhibition in animals (which can be comparable to those of morphine) and data suggesting a role in human pain illustrate the therapeutic potential of these channels. PMID- 24948016 TI - [Neurotrophins and pain]. AB - Neurotrophins are a family of trophic factors well known for their effects on neuronal survival, growth and neuronal differentiation. During the last decade, a large literature has shown in humans and in animal models that nerve growth factor (NGF) is a peripheral mediator of pain, especially in the states of inflammatory pain. NGF synthesis is indeed increased in a wide variety of inflammatory diseases and NGF neutralizing molecules are effective analgesic agents in these models of persistent pain. Therapeutical strategies targeting the sequestering of NGF did yield very encouraging results in clinical trials (stages II and III) but have been on hold since 2010 due to potential harmful effects in combination with non-steroid anti-inflammatory drug. NGF regulates the expression of a second neurotrophin, Brain Derived Neurotrophic Factor (BDNF), in nociceptors. BDNF is released where nociceptors are activated, and it acts as a modulator of pain in the central nervous system and is involved in central sensitization. PMID- 24948017 TI - [Chemokines and attraction of myeloid cells in peripheral neuropathic pains]. AB - Chronic neuropathic pain has become a real social issue, due to the difficulty of its treatment and by the major impairment to quality of life that it causes in every day behavior. Understanding neurobiological basis and pathophysiological causes of diverse painful syndromes constantly evolves and reports the complexity of its mechanisms. Unfortunately this complexity makes it difficult to discover effective treatments against chronic pain syndromes, in particular as regards peripheral neuropathic pains. Recent studies reveal that, during chronic peripheral neuropathy, inflammatory mediators (in particular chemokines), besides their implications in the modulation of nociceptive messages and central neuroinflammatory mechanisms, play a critical role in the orchestration of the immune response induced by a peripheral nerve lesion. In this review, after a brief introduction about chemokines and their role in neuromodulation of the nociceptive message, we will attempt to define their functions and implications in the immune response associated to peripheral neuropathies. Thus, perfectly understanding the molecular and cellular communications between the nervous system and the immune system will be useful for the future development of novel and innovative therapeutic strategies against these highly disabling pathologies. PMID- 24948018 TI - [Classical actions of vitamin D: insights from human genetics and from mouse models on calcium and phosphate homeostasis]. AB - At the beginning of the 20th century, the discovery of vitamin D by Sir EV McCollum allowed a better comprehension of its origin and its role, and made it possible to cure rickets, a largely prevalent disease at that time. The main role of vitamin D3 is to maintain calcium and phosphate homeostasis through the action of 1,25-dihydroxyvitamin D3, its active form. This underlies physiological functions related to calcium and phosphate, such as bone mineralization or muscle function. Progress in basic research for the last 40 years led to the discovery of the main hydroxylation steps that produce and catabolize the active form of vitamin D. It also uncovered the molecular aspects of vitamin D action, from its nuclear receptor, VDR, to the various target genes of this hormone. Recent progress in human genetics pointed out mutations in genes involved in vitamin D metabolism and 1,25-dihydroxyvitamin D3 actions. It also helped to understand the role of the major actors that control vitamin D production and effects, through 1,25-dihydroxyvitamin D3 actions on phosphate and calcium homeostasis, and on bone biology. Genetical engineering targeting the whole animal or defined tissues or cell types have yielded many mouse models in the past decades. When targeted to tissues important for vitamin D metabolism and activity, these models allowed a more detailed comprehension of vitamin effects on calcium and phosphorus homeostasis. PMID- 24948019 TI - [Metabolism and effects of vitamin D. Definition of vitamin D deficiency]. AB - There is a growing interest for vitamin D in the medical and scientific community as well as in the public media as illustrated by a huge number of publications. Most experts claim that vitamin D deficiency/insufficiency is widespread with potential important public health consequences. It may seem surprising for many persons that a deficiency in a vitamin may be so frequent in countries where food is so diversified and easily available. In fact, vitamin D is not a vitamin stricto sensu as it is mainly synthesized in the skin under the action of UVB rays, while its food sources are scarce. Furthermore, UVB rays are absent during a marked part of the year at latitudes greater than 35-40 degrees , while pollution, cloud cover reduce the number of UVB reaching the earth, and many factors such as age, skin pigmentation, covering clothes, sun creams reduce the capacity of the skin to synthesize vitamin D3. Vitamin D must be hydroxylated to form 1,25-dihydroxyvitamin D (1,25OH2D), the active metabolite. As 1,25OH2D is released into the bloodstream and binds to a receptor present in several distant tissues, it may be considered as a hormone, vitamin D being thus a pre prohormone. In the present article, we review briefly the metabolism and various effects of vitamin D as well as vitamin D treatments. We define vitamin D deficiency/insufficiency considering separately the population and the patient level and propose our opinion according to which patients may beneficiate from vitamin D testing. PMID- 24948020 TI - [Repairing the spinal cord with vitamin D: a promising strategy]. AB - In 2014, a phase II randomised, double blind clinical trial assessing the efficacy of cholecalciferol (vitamin D3) in patients with a cervical trauma will be set up. This trial stems from previous studies showing that vitamin D supplementation improves functional recovery in rat models of peripheral or central nerve injury. In a first series of experiments, we used a rat model of peripheral nerve trauma to demonstrate the therapeutic efficiency of vitamin D. We first demonstrated that ergocalciferol (vitamin D2) increases the number and the diameter of newly formed axons and improves the response of metabosensitive fibers from tibialis muscle, in a model of transected peroneal nerve. Then, we compared vitamin D2 and vitamin D3 and observed that the latter is more efficient. At the dose of 500 IU/kg/day, vitamin D3 induces a dramatic functional recovery. We also demonstrated that vitamin D3 increases the number of preserved or newly formed axons in the proximal end, the mean axon diameter in the distal end, neurite myelination in both the distal and proximal ends as well as the expression of genes involved in axogenesis and myelination. In parallel, we assessed the therapeutic role of vitamin D on the central nervous system. In a first study, using a rat model of spinal cord compression at the T10 thoracic level, we delivered vitamin D3 (cholecalciferol) orally at the dose of 50 IU/kg/day or 200 IU/kg/day. When compared to control animals, vitamin D-treated rats displayed, three months after injury, a significant improvement of ventilatory frequency and a reduction of H reflex indicating functional improvements at three months post-injury. In a second study, we used a rat model of cervical hemisection (C2) with a higher dose of oral vitamin D3 (500 IU/kg/day) delivered weekly, during 12 weeks. We observed an improved locomotor recovery, a reduced spasticity and a significantly higher rate of axons crossing the lesion site in treated animals. However, it must be pointed out that the functional improvement is reduced when vitamin D is provided one week after the trauma. PMID- 24948021 TI - [Role of vitamin D in the physiopathology of neurodegenerative diseases]. AB - The involvement of vitamin D in brain function has been discovered in the past 25 years by epidemiological and fundamental studies. Research on neurodegenerative diseases and their animal or cellular models unveiled converging lines of evidence indicating that hypovitaminosis D is not just an effect of the progression of neurodegenerative diseases, but truly an aggravating co-factor, sometimes very closely related to their physiopathology. Vitamin D is a steroid hormone capable of regulating the expression of hundreds of genes through both genetic and epigenetic mechanisms. This reflects the highly pleiotropic nature of its action in its conventional bone and phosphocalcic metabolism targets. Its role in the central nervous system and neurodegenerative diseases makes no exception to this rule. Here we focus on the identified role and mechanisms of vitamin D in multiple sclerosis, Alzheimer's disease and Parkinson's disease. The important prevalence of hypovitaminosis D under our latitudes in general and in at-risk groups in particular, its easy evaluation and correction, and the results of early clinical studies, suggest that vitamin D supplementation could usefully complement our therapeutic armory to fight these diseases. PMID- 24948022 TI - [Vitamin D and Alzheimer's disease: from an intriguing idea to a therapeutic option]. AB - Beyond the classically described regulation of calcium and bone metabolism, vitamin D is a neurosteroid hormone essential to neurophysiological function (regulation of neurotransmitters and neurotrophins) with anti-inflammatory and antioxidant neuroprotective action. In contrast, hypovitaminosis D, which is extremely frequent in the elderly, may result in neurological dysfunction and may explain part of the cognitive disorders in this population. Epidemiology is consistent with this notion and has repeatedly shown an association between hypovitaminosis D and cognitive decline, either in the general population or in Alzheimer's patients. Preliminary intervention trials confirm the causal relationship and quantify the cognitive effect of vitamin D supplementation in the elderly. This raises prospects for primary/secondary prevention of cognitive decline by exogenous supplies of vitamin D. In particular, although current anti dementia drugs are only symptomatic, future treatment options could rely on drug combinations preventing several neurodegenerative mechanisms at once. As such, vitamin D enhances the efficacy of memantine in terms of neuronal protection and prevention of cognitive decline in Alzheimer's disease. PMID- 24948023 TI - Hydrophobic polyalanine modified hyperbranched polyethylenimine as high efficient pDNA and siRNA carrier. AB - Successful gene therapy for cancer treatment and various human genetic diseases relies on high efficient gene carriers, and many carriers can efficiently deliver plasmid DNA to cells, while most of them are unefficient in siRNA delivery. In this study, a series of amphiphilic copolymers are synthesized for pDNA and siRNA delivery by grafting hydrophobic polyalanine to polyethylenimine (named PPAs). There are 12.5, 7.2, 12.3 and 11.3 times of gene expression more than PEI in HeLa, 293T, A549 and CHO cell lines for the optimal PPAs, and the highest luciferase knockdown efficiency in Huh7 and CT26 cells are investigated to be 90.4% and 89.0%, respectively. This meant the PPAs have the potential as efficient transfection reagents for pDNA and siRNA delivery in future gene therapy. PMID- 24948024 TI - Immunomodulatory properties of green propolis. AB - Propolis is a resinous material collected by honeybees from numerous plants and serves as a defense against intruders. Because of its relevant curative properties, it is now gaining popularity in health foods and in cosmetic products. Understanding the underlying molecular mechanisms of phytochemicals has become a good strategy in bioprospection for new anti-inflammatory compounds. The biological activity of propolis derives from its high levels of phenolic acids, while flavonoids are thought to account for the activity of propolis extracts. The comprehension of the relationship between propolis and the immune system has progressed in the last years, recent articles have provided important contributions to this investigation field. Studies have shown that propolis suppressed the "IL-6-induced phosphorylation of signal transducer and STAT3", an essential cytokine-activated transcription factor in Th17 development. Therefore, action mechanisms of "propolis on Th17 differentiation could be instrumental in controlling disturbed cytokine networks in inflammation, autoimmune diseases, and infections." The use of propolis has been proposed in some patents as: WO201363714; CN102885854, WO2013142936, US20130266521, and US20130129808, which are related to the treatment of dental diseases; adjuvant in anti-cancer treatment; in cosmetic products; as an anti-inflammatory agent and natural antibiotic. Although there are many publications regarding the propolis efficacy, its applicability to human health and mechanisms of action are not completely understood, creating opportunities for new studies. PMID- 24948026 TI - Dicyanobenzene and dicyanopyrazine derived X-shaped charge-transfer chromophores: comparative and structure-property relationship study. AB - A series of novel X-shaped push-pull compounds based on benzene-1,2 dicarbonitrile has been designed, synthesized and further investigated by X-ray analysis, electrochemistry, absorption and emission spectra, SHG experiment and quantum-chemical calculations. The obtained data were compared with those for isolobal 5,6-disubstituted pyrazine-2,3-dicarbonitriles. Structure-property relationships were elucidated. The extension, composition and planarization of the pi-linker used as well as the electron-withdrawing ability of both dicyano substituted acceptor units affect the linear and nonlinear properties of the target charge-transfer chromophores most significantly. PMID- 24948025 TI - Postnatal growth velocity and overweight in early adolescents: a comparison of rural and urban African boys and girls. AB - OBJECTIVES: To compare growth velocity of two African child cohorts and examine the relationship between postnatal growth velocity in infancy/early childhood and the risk of overweight/stunting in early adolescence. METHODS: The study used data from two child cohorts from urban (Birth to Twenty Cohort, South Africa) and rural (Lungwena Child Survival Study, Malawi) African settings. Mixed effect modelling was used to derive growth and peak growth velocities. T-tests were used to compare growth parameters and velocities between the two cohorts. Linear and logistic regression models were used to determine the relationship between growth velocity and early adolescent (ages 9-11 years) body mass index and odds of being overweight. RESULTS: Children in the BH cohort were significantly taller and heavier than those in the Lungwena cohort, and exhibited faster weight and height growth velocity especially in the first year of life (P < 0.05). No significant association was shown between baseline weight (alphaw ) and overweight in early adolescence (OR = 1.25, CI = 0.67, 2.34). The weight growth velocity parameter betaw was highly associated with odds of being overweight. Association between overweight in adolescence and weight velocity was stronger in infancy than in early childhood (OR at 3 months = 4.80, CI = 2.49, 9.26; OR at 5 years = 2.39, CI = 1.65, 3.47). CONCLUSION: High weight and height growth velocity in infancy, independent of size at birth, is highly associated with overweight in early adolescence. However, the long term effects of rapid growth in infancy may be dependent on a particular population's socio-economic status and level of urbanization. PMID- 24948028 TI - New vanadium compounds in Venezuela heavy crude oil detected by positive-ion electrospray ionization fourier transform ion cyclotron resonance mass spectrometry. AB - Metalloporphyrins are ubiquitous in nature, particularly iron porphyrins (hemes) and magnesium dihydroporphyrins or chlorophylls. Oxovanadium (IV) complexes of alkyl porphyrins are widely distributed in petroleum, oil shales and maturing sedimentary bitumen. Here we identify new vanadium compounds in Venezuela Orinoco heavy crude oil detected by Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS). These compounds likely have the main structure of porphyrin, with the addition of more aromatic rings, thiophene and amino functional groups, corresponding to molecular series of C(n)H(2n-40)N(4)V(1)O(1) (36 <= n <= 58),C(n)H(2n-42)N(4)V(1)O(1) (37 <= n <= 57),C(n)H(2n-44)N(4)V(1)O(1) (38 <= n <= 59),C(n)H(2n-46)N(4)V(1)O(1) (43 <= n <= 54),C(n)H(2n-48)N(4)V(1)O(1) (45 <= n <= 55),C(n)H(2n-38)N(4)V(1)S(1)O(1) (36 <= n <= 41),C(n)H(2n 40)N(4)V(1)S(1)O(1) (35 <= n <= 51),C(n)H(2n-42)N(4)V(1)S(1)O(1) (36 <= n <= 54),C(n)H(2n-44)N(4)V(1)S(1)O(1) (41 <= n <= 55),C(n)H(2n-46)N(4)V(1)S(1)O(1) (39 <= n <= 55),C(n)H(2n-27)N(5)V(1)O(1) (29 <= n <= 40),C(n)H(2n-29)N(5)V(1)O(1) (34 <= n <= 42),C(n)H(2n-33)N(5)V(1)O(1) (31 <= n <= 38),C(n)H(2n-35)N(5)V(1)O(1) (32 <= n <= 41),C(n)H(2n-27)N(5)V(1)O(2) (32 <= n <= 41) and C(n)H(2n-29)N(5)V(1)O(2) (33 <= n <= 42). These findings are significant for the understanding of the existing form of vanadium species in nature, and are helpful for enhancing the amount of information on palaeoenvironments and improving the level of applied basic theory for the processing technologies of heavy oils. PMID- 24948027 TI - Inter-observer variability between general pathologists and a specialist in breast pathology in the diagnosis of lobular neoplasia, columnar cell lesions, atypical ductal hyperplasia and ductal carcinoma in situ of the breast. AB - BACKGROUND: This study aimed to assess inter-observer variability between the original diagnostic reports and later review by a specialist in breast pathology considering lobular neoplasias (LN), columnar cell lesions (CCL), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) of the breast. METHODS: A retrospective, observational, cross-sectional study was conducted. A total of 610 breast specimens that had been formally sent for consultation and/or second opinions to the Breast Pathology Laboratory of Federal University of Minas Gerais were analysed between January 2005 and December 2010. The inter-observer variability between the original report and later review was compared regarding the diagnoses of LN, CCL, ADH, and DCIS. Statistical analyses were conducted using the Kappa index. RESULTS: Weak correlations were observed for the diagnoses of columnar cell change (CCC; Kappa=0.38), columnar cell hyperplasia (CCH; Kappa=0.32), while a moderate agreement (Kappa=0.47) was observed for the diagnoses of flat epithelial atypia (FEA). Good agreement was observed in the diagnoses of atypical lobular hyperplasia (ALH; Kappa=0.62) and lobular carcinoma in situ (LCIS; Kappa=0.66). However, poor agreement was observed for the diagnoses of pleomorphic LCIS (Kappa=0.22). Moderate agreement was observed for the diagnoses of ADH (Kappa=0.44), low-grade DCIS (Kappa=0.47), intermediate grade DCIS (Kappa=0.45), and DCIS with microinvasion (Kappa=0.56). Good agreement was observed between the diagnoses of high-grade DCIS (Kappa=0.68). CONCLUSIONS: According to our data, the best diagnostic agreements were observed for high grade DCIS, ALH, and LCIS. CCL without atypia and pleomorphic LCIS had the worst agreement indices. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1640072350119725. PMID- 24948029 TI - Inclusion of disability-related content in nurse practitioner curricula. AB - PURPOSE: To examine the integration of disability-content in a national sample of nurse practitioner curricula. DATA SOURCES: Responses of National Organization of Nurse Practitioner Faculties (NONPF) members to an online 34-item survey designed to assess disability-related content included in nurse practitioner (NP) curricula; populations of people with disabilities addressed; models of disability; and resources used to teach about disability, facilitators and barriers to inclusion of disability, and respondents' assessment of the adequacy of coverage of disability in their programs. A survey used previously to assess integration of disability content in undergraduate nursing programs was modified to make it relevant to NP curricula. Nursing faculty and people with disability validated the survey to ensure its completeness and sensitivity to the disability community. Participating programs represent 111 (33.6%) NP programs. CONCLUSIONS: Lack of disability-related content reported by NP faculty in the majority of programs suggests that there is considerable room for improvement in efforts to address this often vulnerable population. Because people with disabilities can be found in any setting where health care is provided, all NPs need to be prepared to care for people with disabilities across the life span. IMPLICATIONS FOR PRACTICE: Strategies need to be developed and implemented to increase the awareness of NP faculty about the health issues of people with disabilities and integration of disability-related content without disrupting existing overloaded NP curricula. PMID- 24948030 TI - Fully-printed high-performance organic thin-film transistors and circuitry on one micron-thick polymer films. AB - Thin, ultra-flexible devices that can be manufactured in a process that covers a large area will be essential to realizing low-cost, wearable electronic applications including foldable displays and medical sensors. The printing technology will be instrumental in fabricating these novel electronic devices and circuits; however, attaining fully printed devices on ultra-flexible films in large areas has typically been a challenge. Here we report on fully printed organic thin-film transistor devices and circuits fabricated on 1-MUm-thick parylene-C films with high field-effect mobility (1.0 cm(2) V(-1) s(-1)) and fast operating speeds (about 1 ms) at low operating voltages. The devices were extremely light (2 g m(-2)) and exhibited excellent mechanical stability. The devices remained operational even under 50% compressive strain without significant changes in their performance. These results represent significant progress in the fabrication of fully printed organic thin-film transistor devices and circuits for use in unobtrusive electronic applications such as wearable sensors. PMID- 24948031 TI - Production of medium chain length polyhydroxyalkanoate in metabolic flux optimized Pseudomonas putida. AB - BACKGROUND: Pseudomnas putida is a natural producer of medium chain length polyhydroxyalkanoates (mcl-PHA), a polymeric precursor of bioplastics. A two-fold increase of mcl-PHA production via inactivation of the glucose dehydrogenase gene gcd, limiting the metabolic flux towards side products like gluconate was achieved before. Here, we investigated the overproduction of enzymes catalyzing limiting steps of mcl-PHA precursor formation. RESULTS: A genome-based in silico model for P. putida KT2440 metabolism was employed to identify potential genetic targets to be engineered for the improvement of mcl-PHA production using glucose as sole carbon source. Here, overproduction of pyruvate dehydrogenase subunit AcoA in the P. putida KT2440 wild type and the Deltagcd mutant strains led to an increase of PHA production. In controlled bioreactor batch fermentations PHA production was increased by 33% in the acoA overexpressing wild type and 121% in the acoA overexpressing Deltagcd strain in comparison to P. putida KT2440. Overexpression of pgl-encoding 6-phosphoglucolactonase did not influence PHA production. Transcriptome analyses of engineered PHA producing P. putida in comparison to its parental strains revealed the induction of genes encoding glucose 6-phosphate dehydrogenase and pyruvate dehydrogenase. In addition, NADPH seems to be quantitatively consumed for efficient PHA synthesis, since a direct relationship between low levels of NADPH and high concentrations of the biopolymer were observed. In contrast, intracellular levels of NADH were found increased in PHA producing organisms. CONCLUSION: Production of mcl-PHAs was enhanced in P. putida when grown on glucose via overproduction of a pyruvate dehydrogenase subunit (AcoA) in combination with a deletion of the glucose dehydrogenase (gcd) gene as predicted by in silico elementary flux mode analysis. PMID- 24948032 TI - Homoeologous duplicated regions are involved in quantitative resistance of Brassica napus to stem canker. AB - BACKGROUND: Several major crop species are current or ancient polyploids. To better describe the genetic factors controlling traits of agronomic interest (QTL), it is necessary to understand the structural and functional organisation of these QTL regions in relation to genome duplication. We investigated quantitative resistance to the fungal disease stem canker in Brassica napus, a highly duplicated amphidiploid species, to assess the proportion of resistance QTL located at duplicated positions. RESULTS: Genome-wide association analysis on a panel of 116 oilseed rape varieties genotyped with 3228 SNP indicated that 321 markers, corresponding to 64 genomic regions, are associated with resistance to stem canker. These genomic regions are relatively equally distributed on the A (53%) and C (47%) genomes of B. napus. Overall, 44% of these regions (28/64) are duplicated homoeologous regions. They are located in duplications of six (E, J, R, T, U and W) of the 24 ancestral blocks that constitute the B. napus genome. Overall, these six ancestral blocks have 34 duplicated copies in the B.napus genome. Almost all of the duplicated copies (82% of the 34 regions) harboured resistance associated markers for stem canker resistance, which suggests structural and functional conservation of genetic factors involved in this trait in B. napus. CONCLUSIONS: Our study provides information on the involvement of duplicated loci in the control of stem canker resistance in B. napus. Further investigation of the similarity/divergence in sequence and gene content of these duplicated regions will provide insight into the conservation and allelic diversity of the underlying genes. PMID- 24948033 TI - Carotid artery stenting and patient outcomes: the CABANA surveillance study. AB - OBJECTIVES: The purpose of the prospective, multicenter, nonrandomized CABANA study was to evaluate periprocedural clinical outcomes in high surgical risk patients with carotid artery stenosis treated with the Carotid WALLSTENT plus FilterWire EZ Embolic Protection System by a diverse group of clinicians. BACKGROUND: There is a need for additional evidence evaluating carotid artery stenting (CAS) performed by operators with various experience and training levels. METHODS: The study enrolled symptomatic (>=50% carotid artery stenosis) and asymptomatic (>=80% carotid stenosis) patients at high risk for carotid endarterectomy. Study centers were grouped into three tiers based on previous CAS experience while individual operators were grouped by their CAS training. The primary endpoint was the 30-day composite of major adverse events [MAEs; including stroke, death, and myocardial infarction (MI)]. Individual event rates were evaluated across the overall study, and by center experience and physician training tier. RESULTS: Of 1,097 enrolled patients, 1,025 were evaluable for 30 day MAE rate. The stroke rate (3.3%) was a major contributing factor in the overall MAE rate (4.6%). Mortality was 1.3% and the MI rate was 0.5%. There was no statistically significant association between MAE rates among the center experience tiers (P = 0.61) nor among the operator training categories (P = 0.26). CONCLUSIONS: CAS with the Carotid WALLSTENT and FilterWire EZ yielded a low 30-day MAE rate that did not differ significantly across operator experience and training levels. Clinicaltrials.gov identifier: NCT00741091. PMID- 24948035 TI - Localization of RANK, RANKL and osteoprotegerin during healing of surgically created periodontal defects in sheep. AB - BACKGROUND AND OBJECTIVE: Modeling of periodontal bone regeneration in a large animal enables better examination of the spatial and temporal regulation of osteogenesis and the remodeling of the healing defect. RANK, RANKL and osteoprotegerin (OPG) are known to be important regulators of bone healing. The aim of this study was to create periodontal defects surgically in a large animal model and to examine bone regeneration and the expression of RANK, RANKL and OPG proteins in the defect site during bone regeneration. MATERIAL AND METHODS: Periodontal defects were made in the furcation of the second mandibular premolar of sheep. Wound healing was examined 6 h, and 1, 4 and 6 wk after surgery and in control tissue. The teeth and defect region were decalcified and paraffin embedded. Immunohistochemistry for RANK, RANKL and OPG was conducted. Osteoclasts were identified using TRAP staining. RESULTS: The defects were examined at different time points after surgery and by 6 wk the defect region had fully regenerated with new bone, albeit less dense than that in the unwounded controls. RANK-positive osteoclasts were present at the edge of the wound from week 1 and were found within the defect at week 6, corresponding to osteoclast activation and bone remodeling. RANKL staining increased from week 1 compared with unwounded tissue, and peaked at 4 and 6 wk, as the osteoblast numbers increased. At the same time, OPG immunostaining was high in controls and at week 6, suggesting that it may act to block RANKL and control the bone remodeling within the defect. CONCLUSION: Distinctive temporal and spatial expression patterns for RANK, RANKL and OPG proteins were observed during healing of surgically created periodontal wounds in a sheep model. The research identifies possible therapeutic approaches to periodontal bone repair via modulation of these members of the tumor necrosis factor family. PMID- 24948034 TI - Differential prefrontal and subcortical circuitry engagement during encoding of semantically related words in patients with late-life depression. AB - OBJECTIVE: Verbal memory difficulties are common among individuals with late-life depression (LLD), though there is limited knowledge about disruptions to underlying cerebral circuitry. The purpose of this study is to examine aberrations to cerebral networks implicated in encoding novel verbal semantic material among older adults with LLD. METHODS: Twenty-four older adults with early-onset LLD and 23 non-depressed comparisons participated in the study. Participants completed a word list-learning task while undergoing functional magnetic resonance imaging. RESULTS: In the context of equivalent recall and recognition of words following scanning and similar hippocampal volumes, patients with LLD exhibited less activation in structures known to be relevant for new learning and memory, including hippocampus, parahippocampal gyrus, insula, and cingulate, relative to non-ill comparisons. An important region in which the LLD group displayed greater activation than the non-depressed comparison group was in left inferior frontal gyrus, an area involved in cognitive control and controlled semantic/phonological retrieval and analysis; this region may be critical for LLD patients to consolidate encoded words into memory. CONCLUSIONS: Functional irregularities found in LLD patients may reflect different modes of processing to be-remembered information and/or early changes predictive of incipient cognitive decline. Future studies might consider mechanisms that could contribute to these functional differences, including hypothalamic-pituitary-adrenal axis functioning and vascular integrity, and utilize longitudinal designs in order to understand whether functional changes are predictive of incipient cognitive decline. PMID- 24948036 TI - The use of autologous buccal mucosa grafts in vaginal reconstruction. AB - Vaginal reconstruction can be challenging when there is a paucity of tissue, as the ideal donor source has yet to be determined. Many of the existing and commonly used techniques, such as vaginal replacement with skin grafts or bowel segments, have both advantages and disadvantages. A novel technique for vaginal replacement and reconstruction is with autologous buccal mucosa, an epithelium which is an excellent tissue match to the vagina. As urologists often have extensive experience with the use of oral mucosa for urethral reconstruction, it is fitting to apply these techniques to procedures where native vaginal tissue is lacking. This review presents the existing literature as well as the author's own experience with the use of autologous buccal mucosa for a variety of vaginal reconstructive procedures. PMID- 24948037 TI - Quantification of dynamic changes to blood volume and vascular flow in the primate corpus luteum during the menstrual cycle. AB - BACKGROUND: The objective of the current study was to determine changes to vascular parameters of nonhuman primate dominant ovarian structures by dynamic contrast-enhanced ultrasound (DCE-US). MATERIALS AND METHODS: Dynamic contrast enhanced ultrasound with intravenous microbubble infusion was performed on the rhesus macaque ovary bearing the pre-ovulatory follicle and corpus luteum (CL) sequentially during the natural luteal phase (n = 8) and GnRH antagonist (antide) induced luteal regression (n = 6). RESULTS: Changes in luteal blood volume (BV) and vascular flow (VF) were observed between stages of the luteal phase Luteal BV was highest in early stage CL, before decreasing 2.5-fold in late stage CL (P < 0.06); in contrast, luteal VF peaked at mid luteal stage (P < 0.01). Two females identified with luteal insufficiency trended toward lower peak BV, compared to typical CLs. Another female was identified with a luteal cyst on the contralateral ovary, and a CL that regressed before P levels declined. After 72 hours of antide exposure, BV was reduced 2.3-fold (P = 0.03). CONCLUSIONS: DCE-US provides a sensitive, non-invasive measurement of the dynamics of blood volume and flow in dominant ovarian structures. PMID- 24948038 TI - Relationship between leptin and adiponectin concentrations in plasma and femoral and spinal bone mineral density in spinal cord-injured individuals. AB - BACKGROUND CONTEXT: Previously, the associations between leptin and adiponectin levels with bone mineral density (BMD) have been reported in different populations, and occasionally, controversial results have been demonstrated. Until now, these relationships in spinal cord-injured individuals have not yet been described. PURPOSE: We tried to investigate the correlation between leptin and adiponectin concentrations in plasma and BMD in Iranian patients with spinal cord injury (SCI). STUDY DESIGN/SETTING: Cross-sectional investigation. PATIENT SAMPLE: Referred patients with SCI who did not meet our exclusion criteria such as pregnancy, lactation, amputation, history of diabetes, cancer, endocrinology disease, and use of special medications entered the study. OUTCOME MEASURES: Bone mineral density of femoral neck, trochanter, intertrochanteric zone, total hip, and lumbar vertebrae assessed by dual-energy X-ray absorptiometry and serum leptin and adiponectin levels measured by blood sample analysis using immunoassay techniques. METHODS: Patient demographic characteristics were measured during face-to-face visits. Injury level and Spinal cord Injury Association (ASIA) score were assessed by clinical examination and were confirmed by imaging aids. Measured levels of leptin and adiponectin and dual-energy X-ray absorptiometry results were analyzed with partial correlation analysis method after adjustment for weight, body mass index (BMI), and age. RESULTS: Total of 104 patients (19 females and 85 males) entered this investigation. Higher leptin concentration was significantly associated with higher BMD in femoral neck (p=.006, r=0.73), femoral intertrochanteric zone (p=.001, r=0.83), and hip (p=.001, r=0.81) only in female patients, whereas no such association was detected in male participants after adjusting for BMI and age. Leptin and adiponectin levels were not associated with lumbar spine BMD in both genders. Neither injury level nor ASIA score and plegia type (paraplegia or tetraplegia) influenced on leptin and adiponectin concentrations. CONCLUSIONS: We found no association between leptin concentration and BMD in male individuals, whereas a positive correlation between leptin and BMD of femoral neck, intertrochanter, and hip was observed in female patients that shows a sexual polymorphism in this relationship. However, by considering the low number of female participants, these results should be interpreted cautiously. Lumbar spine BMD was associated with neither leptin nor adiponectin level in both genders. PMID- 24948039 TI - Biomechanical analysis of an interbody cage with three integrated cancellous lag screws in a two-level cervical spine fusion construct: an in vitro study. AB - BACKGROUND CONTEXT: Despite an increase in the clinical use of no-profile anchored interbody cages (AIC) for anterior cervical discectomy and fusion (ACDF) procedures, there is little published biomechanical data describing its stabilizing effect relative to the traditional anterior plating technique over two contiguous levels. PURPOSE: To biomechanically compare the acute stability conferred by a stand-alone interbody fusion device with three integrated fixation screws ("anchored cage") with a traditional six-hole rigid anterior plate in a two contiguous levels (C4-C5+C5-C6) fusion construct. We hypothesized that the anchored cage would confer comparable segmental rigidity to the cage and anterior plate construct. STUDY DESIGN: A biomechanical laboratory study using cadaveric human cervical spines. METHODS: Seven (n=7) cadaveric human cervical spines (C3 C7) were subjected to quasistatic, pure-moment loading (+/-1.5 Nm) in flexion extension (flex/ext), right/left lateral bending (RB/LB), and right/left axial rotation (RR/LR) for the following test conditions: intact; after discectomy and insertion of the AIC at C4-C5 and C5-C6 with anchoring screws engaged; after the removal of the integrated anchoring screws and instrumentation of an anterior locking plate (ALP) over both levels; and cage-only (CO) configuration with screws and anterior plate removed. Intervertebral range of motion (ROM) at the instrumented levels was the primary biomechanical outcome. RESULTS: Flex/ext, RB/LB, and RR/LR ROMs were significantly reduced (p<.001) over both levels by AIC and ALP constructs relative to the CO construct. Significant reduction in flex/ext motion was achieved with the ALP (6.8+/-3.7) relative to the AIC (10.2 degrees +/-4.6 degrees ) (p=.041) construct. No significant differences were seen in ROM reductions over the two levels between the AIC and APL groups in lateral bending or axial rotation (p>.826). CONCLUSIONS: The anchored cage fusion construct conferred similar acute biomechanical stability in lateral bending and axial rotation ROMs relative to rigid anterior plating. We identified a statistically significant reduction (Delta=3.4 degrees , combined over two levels) in sagittal plane ROM conferred by the ALP relative to the AIC construct. Our biomechanical findings may support the clinical use of no-profile integrated interbody devices over two contiguous levels in ACDF. PMID- 24948040 TI - Interpretation of lung function in infants and young children with cystic fibrosis. AB - The last decade has seen a significant advance in understanding about early lung disease in cystic fibrosis (CF). As studies that have measured lung function in preschool years are conducted in association with surveillance of infection, inflammation and early structural changes, and emerging longitudinal data become available, a better insight into the very early onset and nature of such lung disease is emerging. Interventions during the preschool years are increasingly viewed as being crucial to delaying and minimizing disease progression as this is the most important period of postnatal life in terms of lung development and airway remodelling. Lung function measurement in CF is potentially an important assessment tool and is used in routine clinical practice in several centres already. Results of studies from lung function tests that, on the basis of their underpinning physiology, are viewed as being best suited currently for the early detection of lung disease in CF are reviewed. PMID- 24948041 TI - Conceptualizing disability in US national surveys: application of the World Health Organization's (WHO) International Classification of Functioning, Disability, and Health (ICF) framework. AB - PURPOSE: Disability data inform resource allocation and utilization, characterize functioning and changes over time, and provide a mechanism to monitor progress toward promoting and protecting the rights of individuals with disability. Data collection efforts, however, define and measure disability in varied ways. Our objective was to see how the content of disability measures differed in five US national surveys and over time. METHODS: Using the WHO ICF as a conceptual framework for measuring disability, we assessed the National Health Interview Survey (NHIS), Current Population Survey (CPS), Survey of Income and Program Participation (SIPP), National Survey of SSI Children and Families (NSCF), and American Community Survey (ACS) for their content coverage of disability relative to each of the four ICF components (i.e., body functions, body structures, activities and participation, and environment). We used second-level ICF three digit codes to classify question content into categories within each ICF component and computed the proportion of categories within each ICF component that was represented in the questions selected from these five surveys. RESULTS: The disability measures varied across surveys and years. The NHIS captured a greater proportion of the ICF body functions and body structures components than did other surveys. The SIPP captured the most content of the ICF activities and participation component, and the NSCF contained the most content of the ICF environmental factors component. CONCLUSIONS: This research successfully illustrated demonstrated the utility of the ICF in examining the content of disability measures in five national surveys and over time. PMID- 24948042 TI - Restructuring and remodeling of NaREF4 nanocrystals by electron irradiation. AB - NaREF4 nanocrystals are found to be highly manipulable by electron beam irradiation. With 200 kV electron beam irradiation, both 14.6 nm spherical NaGdF4 :Yb,Er nanoparticles and 44.7 nm * 34.1 nm ellipsoidal NaYF4 :Yb,Er nanorods form hollow structures and eventually convert to the corresponding REF3 upon prolonged irradiation. Furthermore, the NaYF4 nanorods fractured with irradiation with a 100 kV electron source are found to be subsequently self-healed when irradiated with a 200 kV source. The detailed experimental results, in combination with theoretical analysis, suggest that knock-on effects, specific lattice energy, and the inherently low surface energy of NaREF4 collectively contribute to the formation of the hollow structures. These mechanisms allow controlled engineering and manipulation of RE nanomaterials on the nanometer scale. PMID- 24948043 TI - Factor structure for the frailty syndrome was consistent across Europe. AB - OBJECTIVES: We explored the measurement properties of frailty with the goal of optimizing frailty assessment according to phenotype definition of Fried and comparing measurement properties across countries. STUDY DESIGN AND SETTING: Data are from the Survey of Health, Ageing and Retirement in Europe (n = 27,938), a population-based study of community-dwelling adults aged >=50 years. Frailty was specified as a unidimensional construct, and measurement invariance across the 12 countries was tested. To assess our measurement model, we used confirmatory factor analysis (CFA) and multigroup CFA to assess measurement invariance. RESULTS: The unidimensional model fit the data well (adjusted chi(2)(48) = 82.74, P = 0.001), and the same structure was satisfactory for all countries. Inclusion of equality constraints led to significant model deterioration (adjusted chi(2)diff(88) = 995.05, P < 0.001), suggesting differences in parameters across countries. Spain was removed from further analyses, and equality constraints for Greece, Sweden, Israel, Italy, and France were not tenable. Accounting for these led to satisfactory model fit (adjusted chi(2)(113) = 414.33, P < 0.001). Significant mean frailty differences were identified. CONCLUSION: The relationships between the construct of frailty and indicators, although broadly constant, do vary across some countries. Furthermore, there was evidence of differing levels of frailty for the middle-aged and older populations across European countries. PMID- 24948044 TI - The novel colorectal cancer biomarkers CDO1, ZSCAN18 and ZNF331 are frequently methylated across gastrointestinal cancers. AB - We have previously shown that gastrointestinal cancers display similar epigenetic aberrations. In a recent study, we identified frequently methylated genes for cholangiocarcinoma (CDO1, DCLK1, SFRP1 and ZSCAN18), where one of these genes, DCLK1, was also confirmed to be highly methylated in colorectal cancer. The aim of the present study was to determine whether these four genes, in addition to one gene found to be methylated in colon cancer cell lines (ZNF331), are commonly methylated across gastrointestinal malignancies, as well as explore their role as potential biomarkers. Quantitative methylation specific PCR (qMSP) of colorectal cancer (n=164) and normal colorectal mucosa (n=106) samples showed that all genes were frequently methylated in colorectal cancer (71-92%) with little or no methylation in normal mucosa (0-3%). Methylation of minimum two of these five genes identified 95% of the tumors with a specificity of 98%, and an area under the receiver operating characteristics curve (AUC) of 0.98. For gastric (n=25) and pancreatic (n=20) cancer, the same panel detected 92% and 90% of the tumors, respectively. Seventy-four cancer cell lines were further analyzed by qMSP and real time RT-PCR. In addition to the previously reported DCLK1, a high negative correlation between promoter DNA methylation and gene expression was observed for CDO1, ZNF331 and ZSCAN18. In conclusion, the high methylation frequency of these genes in colorectal- as well as in gastric-, pancreatic- and bile duct cancer confirmed an epigenetic similarity between gastrointestinal cancer types, and simultaneously demonstrated their potential as biomarkers, particularly for colorectal cancer detection. PMID- 24948045 TI - [The 2013 Sixto Obrador Award. A triple-axis topographical model for surgical planning of craniopharyngiomas. Part II: Anatomical and neuroradiological evidence to define triple-axis topography and its usefulness in predicting individual surgical risk]. AB - INTRODUCTION AND OBJECTIVES: This study evaluates the pathological and magnetic resonance imaging evidence to define the precise topographical relationships of craniopharyngiomas and to classify these lesions according to the risks of hypothalamic injury associated with their removal. MATERIAL AND METHODS: An extensive, systematic analysis of the topographical classification models used in the surgical series of craniopharyngiomas reported in the literature (n=145 series, 4,588 craniopharyngiomas) was performed. Topographical relationships of well-described operated craniopharyngiomas (n=224 cases) and of non-operated cases reported in autopsies (n=201 cases) were also analysed. Finally, preoperative and postoperative magnetic resonance imaging studies displayed in craniopharyngiomas reports (n=130) were compared to develop a triple-axis model for the topographical classification of these lesions with qualitative information regarding the associated risk of hypothalamic injury. RESULTS: The 2 major variables with prognostic value to define the topography of a craniopharyngioma are its position relative to the sellar diaphragm and its degree of invasion of the third ventricle floor. A multivariate diagnostic model including 5 variables -patient age, presence of hydrocephalus and/or psychiatric symptoms, the relative position of the hypothalamus and the mammillary body angle makes it possible to differentiate suprasellar craniopharyngiomas displacing the third ventricle upwards (pseudointraventricular craniopharyngiomas) from either strictly intraventricular craniopharyngiomas or lesions developing primarily within the third ventricle floor (infundibulo-tuberal or not strictly intraventricular craniopharyngiomas). CONCLUSIONS: A triple-axis topographical model for craniopharyngiomas that includes the degree of hypothalamus invasion is useful in planning the surgical approach and degree of resection. Infundibulo tuberal craniopharyngiomas represent 42% of all cases. These lesions typically show tight, circumferential adhesion to the third ventricle floor, with their removal being associated with a 50% risk of hypothalamic injury. The endoscopically-assisted extended transsphenoidal approach provides a proper view to assess the degree and extension of craniopharyngioma adherence to the hypothalamus. PMID- 24948046 TI - Objective Structured Assessment of Technical Skills (OSATS) evaluation of hysteroscopy training: a prospective study. AB - OBJECTIVES: To describe the performance curve of hysteroscopy-naive probands repeatedly working through a surgery algorithm on a hysteroscopy trainer. STUDY DESIGN: We prospectively recruited medical students to a 30min demonstration session teaching a standardized surgery algorithm. Subjects subsequently performed three training courses immediately after training (T1) and after 24h (T2) and 48h (T3). Skills were recorded with a 20-item Objective Structured Assessment of Technical Skills (OSATS) at T1, T2, and T3. The presence of a sustained OSATS score improvement from T1 to T3 was the primary outcome. Performance time (PT) and self assessment (SA) were secondary outcomes. Statistics were performed using paired T-test and multiple linear regression analysis. RESULTS: 92 subjects were included. OSATS scores significantly improved over time from T1 to T2 (15.21+/-1.95 vs. 16.02+/-2.06, respectively; p<0.0001) and from T2 to T3 (16.02+/-2.06 vs. 16.95+/-1.61, respectively; p<0.0001). The secondary outcomes PT (414+/-119s vs. 357+/-88s vs. 304+/-91s; p<0.0001) and SA (3.02+/-0.85 vs. 3.80+/-0.76 vs. 4.41+/-0.67; p<0.0001) also showed an improvement over time with quicker performance and higher confidence. SA, but not PT demonstrated construct validity. In a multiple linear regression analysis, gender (odds ratio (OR) 0.96; 95% confidence interval (CI) 0.35-2.71; p=0.9) did not independently influence the likelihood of OSATS score improvement. CONCLUSIONS: In a hysteroscopy-naive population, there is a continuous and sustained improvement of surgical proficiency and confidence after multiple training courses on a hysteroscopy trainer. Serial hysteroscopy trainings may be helpful for teaching hysteroscopy skills. PMID- 24948047 TI - Endocannabinoid signaling in mammalian ovary. AB - The role of the endocannabinoid system (ECS) in mammalian reproduction is a rather active field of research, due to its potential exploitation to combat human infertility. Available data shows that the aberrant endocannabinoid signaling negatively affects embryo development, implantation and pregnancy. Although many efforts have been devoted to a better understanding of the ECS in these steps of female reproduction, very little is known about its role in regulating ovarian follicle development and production of mature oocytes. This is the subject of the present review where we discuss current knowledge about the impact and potential exploitation of the ECS and endocannabinoid signaling in mammalian ovary and folliculogenesis. PMID- 24948048 TI - Effectiveness of mifepristone in combination with ethacridine lactate for second trimester pregnancy termination. AB - OBJECTIVE: To compare the efficacy of mifepristone and ethacridine lactate with ethacridine lactate alone for second trimester pregnancy termination. STUDY DESIGN: Two hundred and seventy-six healthy women between 16 and 27 weeks of gestation, desiring a termination, were assigned at random into two groups. The study group consisted of 140 women who received an intra-amniotic injection of 100mg ethacridine lactate, followed by oral administration of 50mg mifepristone at 0, 12 and 24h (total dose of mifepristone 150mg). The control group consisted of 136 women who received an intra-amniotic injection of 100mg ethacridine lactate alone. The primary outcome measure was the induction-to-abortion interval. Secondary outcomes included blood loss in 24h, successful abortion rate, retained placental tissue rate, rate of uterine evacuation and cervical laceration. RESULTS: Induction-to-abortion interval, blood loss in 24h, rate of retained placental tissue and uterine evacuation were significantly less in the study group compared with the control group (p<0.001). Termination was successful in 140 of 140 women (100%) in the study group and 133 of 136 women (97.8%) in the control group. All women in the study group delivered within 72h, and three nulliparous women in the control group did not deliver within 72h. The cervical laceration rate was 0 and 1.47% (2/136) in the study group and the control group, respectively. No significant difference in the successful abortion rate (p=0.235) or the cervical laceration rate (p=0.242) was found between the two groups. CONCLUSION: Mifepristone in combination with ethacridine lactate may significantly improve the outcomes of second trimester pregnancy termination compared with ethacridine lactate alone, without increasing complications and side effects apart from nausea. PMID- 24948049 TI - Effect of necrostatin on mouse ovarian cryopreservation and transplantation. AB - OBJECTIVE: To investigate the effects of necrostatin-1 (Nec-1) supplementation on vitrification, warming and transplantation of ovarian tissue. STUDY DESIGN: Ovaries from 4-week-old ICR mice were vitrified using a two-step procedure; ovaries were suspended in equilibration solution for 10min, and then mixed with vitrification solution for 5min. Ovaries were divided at random into three groups and 0 (control), 25 or 100MUM Nec-1 was added to the vitrification solution. After warming, follicular morphology and apoptosis were assessed. For each group, a sample of vitrified, warmed ovaries was autotransplanted. The same dose of Nec 1 that was added to the vitrification solution was added to each warming solution and injected intraperitoneally. Follicular morphology and apoptosis of transplanted ovaries were assessed after 2 weeks. RESULTS: After vitrification and warming, morphological analysis revealed that the intact follicle ratio was significantly higher in the Nec-1-treated groups compared with the control group (control, 45.1%; 25MUM Nec-1, 51.7%; 100MUM Nec-1, 57.9%). The rate of apoptosis was lower in the Nec-1 treated groups compared with the control group (control, 11.2%; 25MUM Nec-1, 8.5%; 100MUM Nec-1, 7.2%). After transplantation of the vitrified, warmed ovaries, morphological analysis revealed that the intact follicle ratio was significantly higher in the Nec-1 treated groups compared with the control group (control, 43.1%; 25MUM Nec-1, 60.6%; 100MUM Nec-1, 70.7%). The rate of apoptosis was lower in the Nec-1 treated groups compared with the control group (control, 5.3%; 25MUM Nec-1, 2.5%; 100MUM Nec-1, 2.0%). CONCLUSIONS: Nec-1 supplementation during vitrification, warming and transplantation has beneficial effects on the survival of ovarian tissue. These results can help to improve ovarian tissue vitrification and transplantation protocols for fertility preservation. PMID- 24948050 TI - Statins - are they anticonvulsant? AB - Statins are the most popular and effective lipid-lowering medications beneficial in hypercholesterolemias and prevention of cardiovascular diseases. Growing evidence supports theory that statins exhibit neuroprotective action in acute stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis or epilepsy. Hereby, we present available experimental data regarding action of this group of drugs on seizure activity and neuronal cell death. The most commonly examined statins, such as atorvastatin and simvastatin, display anticonvulsant action with only inconsiderable exceptions. However, the mechanism of this effect remains unexplained. Simvastatin, as a lipophilic statin, which can pass blood-brain barrier easily, was recommended as the best candidate for an anticonvulsant agent. Nevertheless, it is still indistinct, whether the protective activity of statins depends on cholesterol lowering properties or its pleiotropic characteristics. One of the most interesting of 3-hydroxy-3-methylglutaryl coenzyme A inhibitor's actions involves influence on nitric oxide metabolism. PMID- 24948051 TI - Vitamin C: a new auxiliary treatment of epilepsy? AB - Although many approaches to the therapy of epilepsy exist, most of antiepileptic drugs, beside certain and unquestioned benefits, have convinced disadvantages. That is the reason for looking for new methods of treatment. Ascorbic acid, as an antioxidant and electron donor accumulated in central nervous system, seems to take part in diminishing reactions of oxidative stress in brain and cooperate with other antioxidants like alpha-tocoferol. Vitamin C, easily transported through the blood-brain barrier, is proved to reduce injury in the hippocampus during seizures. Depending on type of seizures, it has mostly inhibitory activity and even decreases mortality. Moreover, vitamin C acts as a neuroprotective factor by consolidating cell membranes and decreasing lipid peroxidation. A possible adjunctive role of vitamin C in epileptic patients needs to be considered. PMID- 24948052 TI - Essential elements in depression and anxiety. Part I. AB - Essential elements are very important for the proper functioning of the human body. They are required for fundamental life processes such as cell division and differentiation and protein synthesis. Thus a deficiency of these essential elements is associated with an enormous health risk that can ultimately lead to death. In recent years, studies have provided valuable information on the involvement of essential elements in psychiatric disorders, in particular depression and anxiety. There is strong evidence indicating that deficiency of essential elements can lead to the development of depressive and/or anxiogenic behaviour and supplementation can enhance therapeutic effect of antidepressants and anxiolytics. This review presents the most important results from preclinical and clinical studies showing involvement of essential elements such as zinc, magnesium, lithium, iron, calcium and chromium in depression and anxiety. From these studies it is evident that different types of depression and anxiety respond to treatment at different receptors indicating that the underlying mechanisms are slightly different. Furthermore, administration of low dose antidepressants supplemented with an element is effective and can reduce unwanted side effects in different types of depression/anxiety. PMID- 24948053 TI - Antiarrhythmic drugs and epilepsy. AB - For a long time it has been suspected that epilepsy and cardiac arrhythmia may have common molecular background. Furthermore, seizures can affect function of the central autonomic control centers leading to short- and long-term alterations of cardiac rhythm. Sudden unexpected death in epilepsy (SUDEP) has most likely a cardiac mechanism. Common elements of pathogenesis create a basis for the assumption that antiarrhythmic drugs (AADs) may affect seizure phenomena and interact with antiepileptic drugs (AEDs). Numerous studies have demonstrated anticonvulsant effects of AADs. Among class I AADs (sodium channel blockers), phenytoin is an established antiepileptic drug. Propafenone exerted low anti electroshock activity in rats. Lidocaine and mexiletine showed the anticonvulsant activity not only in animal models, but also in patients with partial seizures. Among beta-blockers (class II AADs), propranolol was anticonvulsant in models for generalized tonic-clonic and complex partial seizures, but not for myoclonic convulsions. Metoprolol and pindolol antagonized tonic-clonic seizures in DBA/2 mice. Timolol reversed the epileptiform activity of pentylenetetrazol (PTZ) in the brain. Furthermore, amiodarone, the representative of class III AADs, inhibited PTZ- and caffeine-induced convulsions in mice. In the group of class IV AADs, verapamil protected mice against PTZ-induced seizures and inhibited epileptogenesis in amygdala-kindled rats. Verapamil and diltiazem showed moderate anticonvulsant activity in genetically epilepsy prone rats. Additionally, numerous AADs potentiated the anticonvulsant action of AEDs in both experimental and clinical conditions. It should be mentioned, however, that many AADs showed proconvulsant effects in overdose. Moreover, intravenous esmolol and intra arterial verapamil induced seizures even at therapeutic dose ranges. PMID- 24948054 TI - The current approach into signaling pathways in pulmonary arterial hypertension and their implication in novel therapeutic strategies. AB - Many mediators and signaling pathways, with their downstream effectors, have been implicated in the pathogenesis of pulmonary hypertension. Currently approved drugs, representing an option of specific therapy, target NO, prostacyclin or ET 1 pathways and provide a significant improvement in the symptomatic status of patients and a slower rate of clinical deterioration. However, despite such improvements in the treatment, PAH remains a chronic disease without a cure, the mortality associated with PAH remains high and effective therapeutic regimens are still required. Knowledge about the role of the pathways involved in PAH and their interactions provides a better understanding of the pathogenesis of the disease and may highlight directions for novel therapeutic strategies for PAH. This paper reviews some novel, promising PAH-associated signaling pathways, such as RAAS, RhoA/ROCK, PDGF, PPAR, and TGF, focusing also on their possible interactions with well-established ones such as NO, ET-1 and prostacyclin pathways. PMID- 24948055 TI - Evaluation of the clinical indications, adverse drug reactions, and finasteride use in patients with benign prostatic hyperplasia in Poland. AB - BACKGROUND: Benign prostatic hyperplasia (LUTS/BPH) is one of the most common urinary disorders in elderly men. The symptoms of the disease include prostate gland enlargement, bladder outlet obstruction, and lower urinary tract symptoms (LUTSs). BPH predisposes patients to bladder infections and bladder stone formation and increases their risk of urinary retention, which in turn causes renal failure. Hence, the disease requires surgical treatment. However, over the recent years, the number of surgical interventions performed in pharmacotherapy has significantly reduced because of the increased efficacy of conservative therapy, including combination treatment mostly with 2 groups of drugs, namely, alpha-1-adrenolitics and other 5-alpha-reductase blockers, with a different pharmacological activity [5]. The aim of this study was to evaluate the clinical indications, adverse drug reactions, and finasteride use in patients with diagnosed BPH in Poland. MATERIALS AND METHODS: We conducted a clinical trial from November 2009 to November 2010 that included 5751 patients who were enrolled in 46 urological centres in Poland. The researchers who conducted the clinical trial were urologists from different regions of Poland. The clinical trial involved 6 follow-up visits. The mean age of the patients was 67 years (range, 45 93 years; median, 67.00; SD, 8.507). The inclusion criteria were as follows: LUTSs, finasteride therapy for at least 2 weeks, age>40 years, and BPH. RESULTS: Patients self-reported data on LUTSs, the symptom frequency, concurrent diseases, and intensification of urinary system symptoms. In addition, additional examinations were performed, including prostate-specific antigen test, urinary tract ultrasonography with evaluation of residual urine and prostate, and uroflowmetry. The study did not exclude data on the combined treatment with finasteride and alpha-1-adrenolitics. CONCLUSION: Finasteride was demonstrated to be effective, as evidenced by the significant decrease in TPV by 40% even after 12 months. It was also found to contribute to the attenuation of LUTSs, improvement in maximum flow rate, decrease in nocturia, and improvement in QoL. PMID- 24948056 TI - Epicutaneous immunization with phosphorylcholine conjugated to bovine serum albumin (PC-BSA) and TLR9 ligand CpG alleviates pneumococcal pneumonia in mice. AB - BACKGROUND: Epicutaneous (EC) immunization is a potential new strategy of a needle-free and self-administrable immunization by using a topically applied patch to deliver vaccine. We have previously shown that EC immunization with various protein antigens inhibits both Th1- and Tc1-mediated contact hypersensitivity (CHS) in mice. Our further work showed that maneuver of EC immunization with an antigen and Toll-like receptor (TLR) ligands prior to hapten sensitization reverses skin-induced suppression. METHODS: Animal model of pneumococcal pneumonia was used to study efficacy of EC induced immunopotentiation. RESULTS: Current work showed that EC immunization with phosphorylcholine conjugated to bovine serum albumin (PC-BSA) and CpG prior to Streptococcus pneumoniae infection results in smaller decrease of body weight when compared to PBS treated mice. Consistent with the behavioral observations and body weight, smaller numbers of bacteria were quantitated in lung homogenates of mice patched with PC-BSA and CpG prior inoculation with S. pneumonia when compared to mice patched with PBS alone. In vitro experiments showed that lymph node cells and spleen cells from mice EC immunized with PC-BSA plus CpG produced high levels of IFN-gamma and IL-17A when compared to PBS or PC-BSA or CpG treated mice. CONCLUSION: This work shows that EC immunization with PC-BSA plus TLR9 ligand CpG may be a potential tool to boost immunity to S. pneumoniae. PMID- 24948057 TI - Protection of differentiated neuronal NG108-15 cells from P2X7 receptor-mediated toxicity by taurine. AB - BACKGROUND: Strong P2X7 receptor (P2X7R) activation causes Ca(2+) overload and consequent cell death. We previously showed that depletion of Ca(2+) stores and endoplasmic reticulum (ER) stress in differentiated NG108-15 neuronal cells contributed to P2X7R-mediated cytotoxicity. In this work, we assessed whether taurine (2-aminoethanesulfonic acid) could prevent this P2X7R-mediated cytotoxicity in this neuronal cell line. METHODS: Cytotoxicity markers were assessed by MTT assay and Western blotting. Cytosolic Ca(2+) and mitochondrial Ca(2+) concentrations were measured microfluorimetrically using fura-2 and rhod 2, respectively. Intracellular reactive oxygen species (ROS) production was assayed by the indicator 2',7'-dichlorodihydrofluorescein diacetate. RESULTS: Selective P2X7R agonist BzATP treatment causes neuronal cell death by causing cytosolic Ca(2+) overload, depletion of Ca(2+) stores, endoplasmic reticulum (ER) stress, and caspase-3 activation (cleaved caspase 3). Remarkably, taurine (10mM) pretreatment could prevent P2X7R-mediated neuronal cell death by blocking BzATP mediated ER stress as determined by phosphorylated eukaryotic translation initiation factor 2alpha (peIF2alpha) and C/EBP-homologous protein (CHOP). However, taurine did not block BzATP-induced Ca(2+) overload and depletion of ER Ca(2+) stores. Interestingly, P2X7R activation did not result in mitochondrial Ca(2+) overload, nor did it affect mitochondrial membrane potential. BzATP induced generation of intracellular reactive oxygen species (ROS) was prevented by taurine. CONCLUSIONS: The neuroprotective effect by taurine is attributed to the suppression of P2X7R-mediated ER stress and ROS formation. PMID- 24948058 TI - Development of an alternative non-obese non-genetic rat model of type 2 diabetes using caffeine and streptozotocin. AB - BACKGROUND: The aim of the present study was to develop an alternative non-obese non-genetic rat model of type 2 diabetes (T2D). METHODS: Six-week-old male SD rats were randomly divided into six groups, namely: Normal Control (NC), Diabetic Control (DBC), Caffeine 5mg/kg BW+STZ (CAF5), Caffeine 10mg/kg BW+STZ (CAF10), Caffeine 20mg/kg BW+STZ (CAF20) and Caffeine 40mg/kg BW+STZ (CAF40) and were fed a normal rat pellet diet and drinking water ad libitum throughout the experimental period. After a one week acclimatization period, diabetes was induced in the animals in DBC and all CAF groups with an injection (i.p.) of the respective dosages of caffeine (mg/kg BW) 15min before the injection of STZ (65mg/kg BW) when normal saline was injected to the DBC group instead of caffeine. The NC group received normal saline and buffer instead of caffeine and STZ, respectively. One week after the STZ injection, animals with non-fasting blood glucose>300mg/dl were considered as diabetic. Three weeks after the STZ injection, the animals in the CAF5 and CAF10 groups were eliminated from the study due to the severity of diabetes and the experiment was continued with the remainder groups for a 13 weeks period. RESULTS AND CONCLUSION: The data of food and fluid intake, body weight, blood glucose, glucose tolerance test, HOMA-IR, HOMA-beta, serum insulin, fructosamine, lipid profile and organ specific enzymes, anti-diabetic drug response tests, and pancreatic histopathology suggest that CAF20 group can be a better alternative non-genetic model of non-obese T2D. PMID- 24948059 TI - Synergistic effect of the combination of gallic acid and famotidine in protection of rat gastric mucosa. AB - BACKGROUND: Antioxidant supplements with existing drugs may confer better therapeutic efficacy in oxidative stress related diseases. The purpose of the present work was to characterize the interaction and investigate the protective effect of H2 blocker famotidine and gallic acid in combination against experimentally induced peptic ulcer. METHODS: Preventive effect of gallic acid and famotidine in different combinations was investigated against aspirin plus pyloric ligation induced ulcer in rat. Ulcer index, gastric juice volume, pH, other biochemical parameters of gastric juice and antioxidant activity using stomach tissue were estimated. RESULTS: Pretreatment with gallic acid and famotidine in combinations for 7 days, protected the gastric mucosa significantly (p<0.05, 0.01), which was evidenced by decrease in ulcer index, gastric juice volume, free and total acidity, total protein, pepsin and DNA content, and increase in pH, carbohydrates concentration in gastric juice. Combination treatment increases levels of superoxide dismutase, catalase, reduced glutathione, glutathione reductase and glucose-6-phosphate dehydrogenase, and decreases lipid peroxidation, myloperoxidase in stomach tissue. Along with higher dose combination, lower dose combinations like gallic acid (50mg/kg) plus famotidine (10mg/kg) also offered better antiulcer activity than their individual effect. Histopathological studies confirmed their antiulcer activity. CONCLUSION: Combination treatments confer synergistic protective effect against peptic ulcer in rats, which was related to the gastroprotective, antisecratory and antioxidant activity of combination treatment. Results proved that use of gallic acid with existing antiulcer drug will be more useful in the prevention/management of peptic ulcer. PMID- 24948060 TI - Antinociceptive effect of D-Lys(2), Dab(4)N-(ureidoethyl)amide, a new cyclic 1-4 dermorphin/deltorphin analog. AB - BACKGROUND: A preliminary evaluation of antinociceptive activity of a new cyclic dermorphin/deltorphin tetrapeptide analog restricted via a urea bridge and containing C-terminal ureidoethylamid {[H-Tyr-d-Lys(&(1))-Phe-Dab(&(2)) CH2CH2NHCONH2][&(1)CO&(2)]} (cUP-1) revealed a significant and long-lasting increase of pain threshold to thermal stimulation after systemic application. The current studies were aimed at further evaluation of cUP-1 activity in animal models of somatic and visceral pain. The influence of cUP-1 on motor functions was also investigated. METHODS: The influence of cUP-1 (0.5-2mgkg(-1), iv) on nociceptive threshold to mechanical pressure and analgesic efficacy in formalin and acetic acid-induced writhing tests were estimated. The antinociceptive effect of cUP-1 was compared to that of morphine (MF). The influence of cUP-1 (1, 4 and 8mgkg(-1), iv) on locomotor activity, motor coordination and muscle strength was estimated using open field and rota-rod tests and a grip strength measurement. RESULTS: Administration of cUP-1 in doses of 1 and 2mgkg(-1) elicited a significant increase of nociceptive threshold to mechanical pressure. MF applied in the same doses induced an antinociceptive effect only at the higher dose (2mgkg(-1)). There were no marked differences between the effect of cUP-1 and MF at each dose, at relative time points. In the writhing test and both phases of the formalin test, cUP-1 showed a significant, dose-dependent antinociceptive effect which did not markedly differ from that of MF. cUP-1 did not significantly affect motor functions of mice. CONCLUSIONS: Systemic application of cUP-1 elicited a dose-dependent antinociceptive effect. The analgesic efficacy of cUP-1 on mechanical nociception, visceral and formalin-induced pain was comparable to that of MF. cUP-1 did not impair motor functions of mice. PMID- 24948062 TI - The prevalence of antipsychotic polypharmacy in schizophrenic patients discharged from psychiatric units in Poland. AB - BACKGROUND: The term antipsychotic polypharmacy (APP) refers to the concurrent use of two or more antipsychotic drugs in schizophrenia. The aim of this study was to investigate the range of APP in schizophrenic patients discharged from psychiatric units in Poland, and to determine its demographical and clinical correlates. METHODS: Data on the pharmacological treatment of 207 patients with a diagnosis of schizophrenia, discharged from six psychiatric hospitals from September-December 2011 were recorded by experienced psychiatrists. Clinical and demographical information was obtained on each patient. The severity of symptoms at admission, and their improvement during hospitalization were assessed using the Clinical Global Impression Scale. RESULTS: At discharge, 52.7% of the patients were prescribed one, 42.5% two and 4.8% three antipsychotic drugs (AP). When two AP were applied, it was usually a combination of two second generation antipsychotics (SGA) (46%), or of both first generation antipsychotics (FGA) and SGA (48%). The SGA's olanzapine and risperidone were those most commonly prescribed. Patients treated with two or more AP had a higher number of previous hospitalizations than patients receiving antipsychotic monotherapy. Mood stabilizers were prescribed for nearly one third of the patients, while antidepressants and benzodiazepines were prescribed for fewer than 10%. CONCLUSIONS: The prevalence of polypharmacy in Poland is similar to that reported in other countries. This may suggest that, in a substantial proportion of schizophrenic patients clinical response to the antipsychotic monotherapy is unsatisfactory. Further studies focusing on the efficacy and safety of strategies in the treatment of patients with schizophrenia not responding to antipsychotic monotherapy are necessary. PMID- 24948061 TI - Effect of trimethylgallic acid esters against chronic stress-induced anxiety-like behavior and oxidative stress in mice. AB - BACKGROUND: Many studies have shown that the levels of oxidative stress (increased lipid peroxidation, decreased glutathione levels and endogenous antioxidant enzyme activities) and proinflammatory cytokines (e.g., TNF-alpha) are increased in patients with chronic fatigue syndrome. Gallic acid and other phenolic compounds are potent antioxidants and inhibitor of cytokine production. The present study was designed to investigate the effect of newly synthesized conjugated esters of trimethylgallic acid in an experimental model of chronic stress. METHODS: The animals were forced to swim individually for a period of 6min every day for 15 days to induce chronic stress. The locomotor activity, anxiety-like behavior, and memory retention were evaluated in chronically stressed animals, followed by biochemical estimations and neuroinflammatory surge in the brain. RESULTS: Chronic treatment with trimethylgallic acid esters for 15 days significantly reversed the chronic stress-induced behavioral (impaired locomotor activity, anxiety-like behavior, and decreased percentage of memory retention), biochemical (increased lipid peroxidation and nitrite levels; decreased glutathione levels, superoxide dismutase and catalase activities), and inflammation surge (serum TNF-alpha) in stressed mice. CONCLUSIONS: The study revealed that trimethylgallic acid esters could ameliorate chronic stress-induced various behavioral and biochemical alterations in mice, showing protective effects against chronic stress. PMID- 24948063 TI - Metrifonate, like acetylcholine, up-regulates neurotrophic activity of cultured rat astrocytes. AB - BACKGROUND: Metrifonate is an inhibitor of acetylcholinesterase (AChE). Several studies confirmed its positive effects on cognitive impairment in Alzheimer's disease but it was due to adverse events withdrawn from clinical trials. Based on the importance of astrocytes in physiological and pathological brain activities we investigated the impact of metrifonate and, for comparison, acetylcholine on intrinsic neurotrophic activity in these cells. METHODS: Metabolic activity, intracellular adenosine 5'-triphosphate (ATP) levels and lactate dehydrogenase (LDH) release was measured to examine the impact of metrifonate on viability and integrity of cultured rat cortical astrocytes. The influence of metrifonate, acetylcholine and selective cholinergic ligands on nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) synthesis and secretion was determined by specific two-site enzyme immunoassays. RESULTS: Exposure of cultured astrocytes to metrifonate displayed no toxic effects on cell viability. Metrifonate and acetylcholine potently and transiently elevated NGF and BDNF, but not NT-3, protein levels and secretion with different intensity and time frame of their maximal response. Stimulatory effect on NGF was mimicked by selective nicotinic receptor agonist nicotine and completely blocked by nicotinic antagonist mecamylamine. The impact on BDNF synthesis was mimicked by muscarinic receptor agonist pilocarpine and abolished by selective muscarinic antagonist scopolamine. CONCLUSIONS: Metrifonate up-regulates astrocytic NGF and BDNF synthesis in the same manner as acetylcholine, their effect depends on different cholinergic pathways. These results suggest a trophic role of metrifonate, based on a well-known neurotrophic activity of NGF and BDNF in vivo. PMID- 24948064 TI - Interferon alpha and rapamycin inhibit the growth of carcinoid and medullary thyroid cancer in vitro. AB - Neuroendocrine tumors (NETs) are highly vascularized neoplasms characterized by rising incidence. Moreover, the neuroendocrine cells were shown to express vascular endothelial growth factor (VEGF) and VEGF receptors. Therefore, angiomodulators could be potentially a new group of drugs enhancing still unsatisfactory effectiveness of NET therapy. The aim of this study was to assess the direct influence of angiomodulators: VEGF and five endogenous and exogenous antiangiogenic compounds (endostatin, interferon alpha [IFNalpha], rapamycin, JV1 36, semaxinib [SU5416]) on the growth of two NET cell lines: lung carcinoid H727 cell line and medullary thyroid cancer TT cell line in vitro. IFNalpha and rapamycin induced the inhibitory effect on H727 and TT cell viability and proliferation, increasing apoptosis and arresting the cell cycle. Also semaxinib (10(-5)M) inhibited proliferation of both cell lines. VEGF and endostatin did not influence the growth of H727 and TT cells. The inhibitory effect of IFNalpha, rapamycin and semaxinib on carcinoid and medullary thyroid cancer growth was revealed in our in vitro study, although some other antiangiogenic agents did not directly influence H727 and TT cell growth. Thus, IFNalpha and mTOR inhibitors as multidirectionally acting drugs with antiangiogenic effect could be potentially efficient in treatment of neuroendocrine tumors and are worth further studies. PMID- 24948065 TI - The effect of active and passive intravenous cocaine administration on the extracellular signal-regulated kinase (ERK) activity in the rat brain. AB - According to a current hypothesis of learning processes, recent papers pointed out to an important role of the extracellular signal-regulated kinase (ERK), in drug addiction. We employed the Western blotting techniques to examine the ERK activity immediately after cocaine iv self-administration and in different drug free withdrawal periods in rats. To distinguish motivational vs. pharmacological effects of the psychostimulant intake, a "yoked" procedure was used. Animals were decapitated after 14 daily cocaine self-administration sessions or on the 1st, 3rd or 10th extinction days. At each time point the activity of the ERK was assessed in several brain structures, including the prefrontal cortex, hippocampus, dorsal striatum and nucleus accumbens. Passive, repeated iv cocaine administration resulted in a 45% increase in ERK phosphorylation in the hippocampus while cocaine self-administration did not change brain ERK activity. On the 1st day of extinction, the activity of the ERK in the prefrontal cortex was decreased in rats with a history of cocaine chronic intake: by 66% for "active" cocaine group and by 35% for "yoked" cocaine group. On the 3rd day the reduction in the ERK activity (25-34%) was observed in the hippocampus for both cocaine-treated groups, and also in the nucleus accumbens for "yoked" cocaine group (40%). On the 10th day of extinction there was no significant alteration in ERK activity in any group of rats. Our findings suggest that cortical ERK is involved in cocaine seeking behavior in rats. They also indicate the time and regional adaptations in this enzyme activity after cocaine withdrawal. PMID- 24948066 TI - A comparison of mecamylamine and bupropion effects on memory-related responses induced by nicotine and scopolamine in the novel object recognition test in mice. AB - BACKGROUND: The aim of the present study was to evaluate the involvement of the cholinergic receptors ligands in the memory-related responses in mice, using the novel object recognition (NOR) test. METHODS: The NOR test is based on natural, exploratory abilities of animals exposed to a new environment. In the first session, two copies of the same object were presented. In the next sessions (30min and 24h after), one of the familiar object and a new object were presented. RESULTS: The mice injected with nicotine (0.035 and 0.175mg/kg, free base, sc) before the first session spent more time exploring the new object than the familiar one at the second and third session, indicating that nicotine improved cognition. In turn, the mice injected with scopolamine (0.3 and 1mg/kg, ip) before the first session spent less time exploring the new object than the familiar one at the second and third trial, indicating that scopolamine impaired the memory performance. Additionally, the acute injection of drugs used in smoking cessation in humans: mecamylamine (0.5 and 1mg/kg) and bupropion (5 and 10mg/kg), prior to injections of nicotine (0.035mg/kg) or scopolamine (1mg/kg), significantly prevented nicotine-induced memory improvement or scopolamine induced memory impairment, at the second and third session. CONCLUSIONS: The results of our studies unveiling neuronal mechanisms for cholinergic system of memory processes, via both nicotinic and muscarinic cholinergic receptors, will be useful for development of more effective pharmacotherapies for memory impairment-like treatment of human disorders in which cholinergic pathways have been implicated. PMID- 24948067 TI - Protective effect of nimesulide against hepatic ischemia/reperfusion injury in rats: effects on oxidant/antioxidants, DNA mutation and COX-1/COX-2 levels. AB - BACKGROUND: Nimesulide is a pharmacological agent and selective COX-2 inhibitor. It has anti-inflammatory, analgesic and antipyretic properties. The purpose of this study was to investigate the effect of nimesulide on oxidant/antioxidant, DNA mutation and COX-1/COX-2 activities in rat liver tissue with induced ischemia/reperfusion (I/R). METHODS: Before the experiment, rats were divided into four groups; liver ischemia/reperfusion (LIR), 50mg/kg nimesulide+liver ischemia/reperfusion (NLIR50), 100mg/kg nimesulide+liver ischemia/reperfusion (NLIR100) and a control group to be given a sham operation (SG). Malondialdehyde (MDA), total glutathione (GSH) levels and myeloperoxidase (MPO), COX-1/COX-2 enzyme activities and DNA damage product level results from liver tissues and serum AST and ALT levels were determined. The data obtained were compared with the results from the liver ischemia/reperfusion and sham operation groups. RESULTS: MDA levels, MPO and COX-2 activities and products of DNA injury were significantly lower in the groups given nimesulide, and particularly the NLIR100 group, compared to the LIR group (p<0.05), while tGSH levels were significantly higher (p<0.05). There was no significant difference between the NLIR50 and NLIR100 groups and the LIR group in terms of COX-1 levels (p>0.05). AST and ALT levels were significantly lower in the other groups compared to the LIR group (p<0.05). CONCLUSIONS: Nimesulide at 100mg/kg prevented oxidative liver damage induced with I/R significantly better than at a dose of 50mg/kg. These experimental findings indicate that nimesulide may be useful in the treatment of hepatic I/R damage. PMID- 24948068 TI - Involvement of PKA, PKC, CAMK-II and MEK1/2 in the acute antidepressant-like effect of creatine in mice. AB - BACKGROUND: The aim of this study was to investigate the involvement of signaling pathways on the creatine antidepressant-like effect in the tail suspension test (TST) in mice. METHODS: The TST was used to assess the antidepressant-like properties of creatine. RESULTS: The anti-immobility effect of creatine (1mg/kg, p.o.) in the TST was blocked by i.c.v. pretreatment with H-89 (1MUg/site, PKA inhibitor), KN-62 (1MUg/site, CAMK-II inhibitor), chelerythrine (1MUg/site, PKC inhibitor), U0126 (5MUg/site, MEK1/2 inhibitor) or PD09058 (5MUg/site, MEK1/2 inhibitor). CONCLUSION: These results suggest that the antidepressant-like effect of creatine is dependent on PKA, CaMK-II, PKC and MEK 1/2 activation. PMID- 24948069 TI - The influence of AAV2-mediated gene transfer of human IL-10 on neurodegeneration and immune response in a murine model of Parkinson's disease. AB - BACKGROUND: The aim of this study was to examine the effect of AAV2-hIL-10 (vector containing cDNA for human interleukin 10) on dopaminergic system activity (measured as DA levels and TH mRNA expression in mouse striata), and other monoamine and amino acid neurotransmitters concentration as well as development of inflammatory processes (measured as TGF-beta, IFN-gamma and GFAP mRNA expression) in a murine MPTP neurotoxicant model of Parkinson's disease. METHODS: Male C57BL/6 mice 12 months-old were used in this study. AAV2-hIL-10 vector was bilaterally administered into striatum at 14, 21 or 28 days prior to MPTP intoxication. Animals were sacrificed at 7 days following MPTP injection. The expression of hIL-10 (human interleukin 10) was examined by ELISA. Striatal monoamine and amino acid neurotransmitters were measured by HPLC method. TH, TGF beta, IFN-gamma and GFAP mRNA expression was examined by RT-PCR method. RESULTS: MPTP treatment dramatically reduced DA levels and decreased TH mRNA expression in mouse striata, effects that were significantly impeded by AAV2-hIL-10 administration prior to MPTP intoxication. AAV2-hIL-10 infusion increased IFN gamma, TGF-beta and GFAP mRNA expression. CONCLUSIONS: Our data suggest that the transfer of AAV2-hIL-10 into the striatum may play a neuroprotective role in the mouse MPTP model of PD and these effects are mediated by the anti-inflammatory action of IL-10. PMID- 24948070 TI - Investigation into the role of Cu/Zn-SOD delivery system on its antioxidant and antiinflammatory activity in rat model of peritonitis. AB - BACKGROUND: The current study evaluated the role of delivery system (solution, conventional liposomes and PEG-ylated liposomes) on superoxide dismutase (SOD) antioxidant and antiinflammatory properties in a rat model of lipopolysaccharide (LPS)-induced peritonitis. METHODS: Fifty male albino rats (Wistar-Bratislava) were divided into five groups (n=10). Control group received saline and the other four groups received intraperitoneal injections of LPS (5mg/kg). Among the LPS injected groups, one was LPS control group and the other three groups received the endotoxin injection 30min after receiving the same dose of SOD (500U/kg, ip) in different delivery systems: saline solution (SOD-S), conventional liposomes (SOD-L) or PEG-ylated liposomes (SOD-PL). The animals were euthanized 6h after LPS injection, blood samples were collected and acute phase response (total and differential leukocytes count; tumor necrosis factor alpha), antioxidants (total antioxidants; reduced glutathione), oxidative stress (total oxidants; lipid peroxidation) and nitrosative stress (nitric oxide metabolites; nitrotyrosine) were evaluated. RESULTS: Intraperitoneal administration of LPS to rats induced a marked inflammatory and oxidative response in plasma. On the other hand, all SOD formulations had protective effect against endotoxin-induced inflammation and oxidative/nitrosative stress, but PEG-ylated liposomes had the most significant activity. Thus, SOD-PL administration significantly reduced the effects of LPS on bone marrow acute phase response, the oxidative status and production of nitric oxide metabolites, while increasing the markers of antioxidant response in a significant manner. CONCLUSION: SOD supplementation interferes both with inflammatory and oxidative pathways involved in LPS-induced acute inflammation, PEG-ylated liposomal formulation being of choice among the tested delivery systems. PMID- 24948071 TI - Comparison of cardioprotective effects of labeled and unlabeled oleanoic acids with new BOPIM dye on primary neonatal rat cardiomyocytes following hypoxia/reoxygenation injury. AB - BACKGROUND: It is well known that fluorescent labeling has recently become a major research tool in molecular and cellular biology for demonstrating therapeutic mechanisms and metabolic pathways. However, few studies have reported the use of fluorescent labeling of natural products. METHODS: We recently explored the boron 2-(2'-pyridyl) imidazole (BOPIM) derivative analogs, which are highly fluorescent, non-aggregated, and nontoxic. In the present study, the natural product oleanolic acid (OA) was functionalized and labeled with BOPIM, thus yielding a highly fluorescent probe, the comparison of cardioprotective effects of labeled and unlabeled OAs with BOPIM on primary neonatal rat cardiomyocytes with hypoxia/reoxygenation (H/R) injury were investigated. RESULTS: Pretreatment with OA and BOPIM-OA significantly prevented the H/R induced cell death in primary neonatal rat cardiomyocytes. However, BOPIM exhibited no improvements on the H/R injury cardiomyocytes, and which were similar to those of the H/R group. The results of comparison of cardioprotective effects between labeled and unlabeled OAs with BOPIM showed that introducing the BOPIM chromophore did not make a difference with H/R injury cardiomyocytes. CONCLUSION: BOPIM chromophore is a suitable probe for investigating the pharmacological mechanisms of natural products. PMID- 24948072 TI - Significance of the genetic polymorphism of CYP2D6 and NAT2 in patients with inflammatory bowel diseases. AB - BACKGROUND: The main types of inflammatory bowel diseases (IBD) are ulcerative colitis (UC) and Crohn's disease (CD). There is evidence that, in addition to immunological and environmental factors, genetic factors also play an important role in the pathogenesis of IBD. Determination of polymorphism of CYP2D6 and NAT2 genes encoding I and II phase enzymes of xenobiotic biotransformation may have clinical value as an indicator of individual predisposition to diseases, and also contribute to effective and safe pharmacotherapy. The aim of this study was to investigate the association between genetic polymorphism of CYP2D6 and NAT2 and the incidence of IBD, including UC and CD, among inhabitants of central Poland. METHODS: The study was performed in 258 individuals from central Poland (115 patients with IBD, including 65 patients with UC and 50 with CD; and in 143 healthy controls). The CYP2D6 genotypes of oxidation and NAT2 genotypes of acetylation were analyzed using the PCR-RFLP method. RESULTS: There were no statistically significant differences in the frequency of the CYP2D6 genotypes and alleles in patients with IBD, UC and CD in comparison with the control group. The relative risk (OR) of IBD, UC and CD was higher in carriers of the allele NAT2*7 and was OR=3.49 (p=0.0019), OR=3.86 (p=0.0019), and OR=3.02 (p=0.0247), respectively. CONCLUSIONS: Polymorphism of the gene encoding CYP2D6 does not affect the incidence of inflammatory bowel diseases. The carriers of the NAT2*7 allele which determines slow acetylation may be more predisposed to inflammatory bowel diseases, including ulcerative colitis and Crohn's disease. PMID- 24948074 TI - Involvement of leukotriene B4 in dermatophyte-related itch in mice. AB - BACKGROUND: Proteinase-activated receptor-2 (PAR2) is involved in dermatophyte induced scratching and leukotriene B4 (LTB4) release from keratinocytes. We investigated whether PAR2-mediated LTB4 production is involved in dermatophyte induced scratching. METHODS: Dermatophyte extract was injected intradermally and scratching was observed in mice. LTB4 was determined by enzyme immunoassay. RESULTS: Dermatophyte extract-induced scratching was inhibited by zileuton (5 lipoxygenase inhibitor), ONO-4057 (LTB4 antagonist), FSLLRY-NH2 (PAR2 antagonist), and anti-PAR2 antibody. Dermatophyte extract injection increased the cutaneous content of LTB4, which was inhibited by zileuton and FSLLRY-NH2. CONCLUSION: These results suggest the involvement of LTB4 in dermatophyte associated itch. LTB4 production might be due to PAR2 stimulation in the skin. PMID- 24948075 TI - Catalase activity in blood fractions of patients with sporadic ALS. AB - BACKGROUND: Oxidative stress may be a key element in pathogenesis of sporadic amyotrophic lateral sclerosis (sALS). Several studies proved that markers of peroxidation of lipids, proteins or nucleic acids are increased in postmortem tissue of sALS patients. However, much less is known about enzymatic antioxidant defense mechanism in sALS. OBJECTIVES: The aim of the study was to assess catalase (CAT) activity that is implicated in the defense against oxidative stress, in three blood fractions, i.e. erythrocytes, plasma and serum of sALS patients and healthy controls. METHODS: Altogether 46 sALS patients and 54 controls were enrolled in the study. CAT activity was estimated using a commercially available assay kit. RESULTS: CAT activity in erythrocytes of sALS patients was significantly decreased compared to neurologically healthy controls (p=0.04), whereas CAT activity in plasma and serum was similar in both studied groups. CONCLUSIONS: CAT activity in erythrocytes, in contrast to other blood fractions is reduced in sALS cases as compared to controls, which may indirectly indicate that antioxidant defense system in erythrocytes is involved in pathogenesis of sALS. PMID- 24948073 TI - Nitroxyl inhibits overt pain-like behavior in mice: role of cGMP/PKG/ATP sensitive potassium channel signaling pathway. AB - BACKGROUND: Several lines of evidence have indicated that nitric oxide (NO) plays complex and diverse roles in modulation of pain/analgesia. However, the roles of charged and uncharged congeners of NO are less well understood. In the present study, the antinociceptive effect of the nitroxyl (HNO) donor, Angeli's salt (Na2N2O3; AS) was investigated in models of overt pain-like behavior. Moreover, whether the antinociceptive effect of nitroxyl was dependent on the activation of cGMP (cyclic guanosine monophosphate)/PKG (protein kinase G)/ATP-sensitive potassium channels was addressed. METHODS: The antinociceptive effect of AS was evaluated on phenyl-p-benzoquinone (PBQ)- and acetic acid-induced writhings and via the formalin test. In addition, pharmacological treatments targeting guanylate cyclase (ODQ), PKG (KT5923) and ATP-sensitive potassium channel (glybenclamide) were used. RESULTS: PBQ and acetic acid induced significant writhing responses over 20min. The nociceptive response in these models were significantly reduced in a dose-dependent manner by subcutaneous pre-treatment with AS. Furthermore, AS also inhibited both phases of the formalin test. Subsequently, the inhibitory effect of AS in writhing and flinching responses were prevented by ODQ, KT5823 and glybenclamide, although these inhibitors alone did not alter the writhing score. Furthermore, pretreatment with L-cysteine, an HNO scavenger, confirmed that the antinociceptive effect of AS depends on HNO. CONCLUSION: The present study demonstrates the efficacy of a nitroxyl donor and its analgesic mechanisms in overt pain-like behavior by activating the cGMP/PKG/ATP-sensitive potassium channel (K(+)) signaling pathway. PMID- 24948076 TI - Evaluation of anticonvulsant activity of novel pyrrolidin-2-one derivatives. AB - BACKGROUND: The aim of this study was to examine the anticonvulsant activity of some novel pyrrolidin-2-one derivatives with considerable affinity to serotonin 5 HT1A and alpha1-adrenergic receptors. METHODS: The maximal electroshock-induced seizure (MES) and pentetrazole (PTZ)-induced seizure models in mice were performed. RESULTS: As a results of the conducted studies, three compounds showing anticonvulsant activity were selected. The EP-40 molecule significantly reduced incidence of seizures in the maximal electroshock test. The EP-42 and EP 46 compounds demonstrated activity in the pentetrazole-induced seizures. CONCLUSION: The results may indicate that the decrease in the susceptibility to seizures induced by the new pyrrolidin-2-one derivatives is related to the significant affinity to serotonergic or alpha1-adrenergic receptors. Also putative mechanism of action of the test compounds can be linked with their GABA ergic activity, because these novel derivatives are GABA analogs. PMID- 24948077 TI - HMG-CoA reductase inhibitors pravastatin, lovastatin and simvastatin suppress delayed rectifier K(+)-channel currents in murine thymocytes. AB - BACKGROUND: Since lymphocytes predominantly express delayed rectifier K(+) channels (Kv1.3) that trigger lymphocyte activation, statins, which exert immunosuppressive effects, would affect the channel currents. METHODS: Employing the patch-clamp technique in murine thymocytes, we examined the effects of statins on Kv1.3-channel currents and the membrane capacitance (Cm). RESULTS: Pravastatin significantly suppressed the pulse-end currents of the channels. Lovastatin and simvastatin also suppressed the peak currents, significantly decreasing the Cm. CONCLUSIONS: This study demonstrated for the first time that statins inhibit thymocyte Kv1.3-channels. The slow inactivation patterns induced by lovastatin and simvastatin may be associated with their accumulation in the plasma membranes. PMID- 24948078 TI - The effect of caffeine on MDMA-induced hydroxyl radical production in the mouse striatum. AB - BACKGROUND: The psychostimulant 3,4-methylenedioxymethamphetamine (MDMA) with a strong addictive potential is widely used as a recreational drug. Neurotoxicity of MDMA is related with the generation of highly reactive free radicals. METHODS: MDMA was given in doses of 20 and 40mg/kg ip alone or in combination with caffeine (CAF) 10mg/kg ip. Extracellular concentration of hydroxyl radical was measured using microdialysis in freely moving mice and was assayed by HPLC with electrochemical detection. RESULTS: MDMA dose-dependently increased production of hydroxyl radical in the mouse striatum and its effect was reversed by caffeine. CONCLUSIONS: The data show that caffeine may have neuroprotective properties as it decreased oxidative stress induced by MDMA. PMID- 24948079 TI - Partial effects of the protein kinase C inhibitor chelerythrine in a battery of tests for manic-like behavior in black Swiss mice. AB - BACKGROUND: The inhibition of protein kinase C (PKC) was recently suggested as a novel approach for the development of mood stabilizing drugs. METHODS: To further evaluate this possibility, the aim of the present study was to test the effects of peripheral (intraperitoneal) administration of chelerythrine in a battery of mania-related behavioral tests in black Swiss mice, a strain specific battery that was previously demonstrated to distinguish differential effects of mood stabilizing drugs. RESULTS: Sub-chronic administration of 1.0mg/kg or 2.0mg/kg chelerythrine had marginal effects to reduce spontaneous activity and sweet solution preference in black Swiss mice which naturally show mania-like behaviors. Chelerythrine had no effects on the behavior of these mice in the elevated plus-maze, the forced swim test and the amphetamine-induced hyperactivity test. CONCLUSIONS: The partial effects in the battery are not unique as previous studies showed that lithium, valproate and risperidone, all used in the treatment of bipolar disorder, have distinct profiles in the battery. It is therefore concluded that chelerythrine may have antimanic effects and additional dose and time response studies are warranted to further evaluate its range of activity. PMID- 24948080 TI - Predictors of quit attempts and successful quit attempts among individuals with alcohol use disorders in a nationally representative sample. AB - BACKGROUND: This study sought to identify predictors of attempting to quit and of successfully quitting alcohol abuse or dependence in the general population. METHODS: Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). RESULTS: Approximately 10% of individuals with alcohol abuse and 18% of those with dependence attempted to quit over the three year follow-up period. Of those who tried, 38% of individuals with abuse and 30% of those with dependence successfully quit. Among individuals with alcohol abuse or dependence, being single, younger than 40 years old, having low income, a co occurring psychiatric disorder and greater number of dependence symptoms increased the likelihood of attempting to quit. Among individuals with alcohol abuse, male gender and low educational attainment further increased the odds of quit attempts. However, greater severity of alcohol use disorder, having a co occurring drug use disorder and greater number of psychiatric disorders decreased the odds of success among individuals with alcohol abuse, while female gender, being married and older than 40 years old increased the odds of success. Among individuals with alcohol dependence, having nicotine dependence, greater number of psychiatric disorders and personality disorders decreased the odds of success. CONCLUSIONS: Predictors of attempts to quit are different and sometimes opposite from those leading to successful quitting probably indicating that some factors that increase motivation may decrease ability to quit. These findings may help in the development of more targeted and effective interventions for alcohol use disorders. PMID- 24948081 TI - High-yield electro-oxidative preparation of graphene oxide. AB - Herein, we report a green electrochemical oxidative approach to convert large quantities of graphite into graphene oxide (GO). The resulted GO flakes have been characterized using various analytical techniques. It was possible to control the degree of oxidation of the produced GO via controlling the electrochemical parameters of the process. PMID- 24948083 TI - Reduced glenohumeral rotation, external rotation weakness and scapular dyskinesis are risk factors for shoulder injuries among elite male handball players: a prospective cohort study. AB - AIM: To determine whether rotator cuff strength, glenohumeral joint range of motion and scapular control are associated with shoulder injuries among elite male handball players. METHODS: A total of 206 players in the Norwegian elite handball league for men were tested prior to the 2011-2012 season. Measures included: (1) glenohumeral internal and external rotation range of motion, (2) isometric internal rotation, external rotation and abduction strength and (3) assessment of scapular dyskinesis. Players were followed prospectively for the entire regular season (30 weeks), with shoulder problems registered bi-weekly using the Oslo Sports Trauma Research Center Overuse Injury Questionnaire. A cumulative severity score was calculated for each player based on their questionnaire responses. This was used as the outcome measure in risk factor analyses. RESULTS: The average prevalence of shoulder problems throughout the season was 28% (95% CI 25% to 31%). The prevalence of substantial shoulder problems, defined as those leading to moderate or severe reductions in handball participation or performance, or to time loss, was 12% (95% CI 11% to 13%). Significant associations were found between obvious scapular dyskinesis (OR 8.41, 95% CI 1.47 to 48.1, p<0.05), total rotational motion (OR 0.77 per 5 degrees change, 95% CI 0.56 to 0.995, p<0.05) and external rotation strength (OR 0.71 per 10 Nm change, 95% CI 0.44 to 0.99, p<0.05) and shoulder injury. CONCLUSIONS: Injury prevention programmes should incorporate interventions aimed at improving glenohumeral rotational range of motion, external rotation strength and scapular control. PMID- 24948082 TI - Cardiovascular screening in adolescents and young adults: a prospective study comparing the Pre-participation Physical Evaluation Monograph 4th Edition and ECG. AB - BACKGROUND: This study compares the accuracy of cardiovascular screening in active adolescents and young adults using a standardised history, physical examination and resting 12-lead ECG. METHODS: Participants were prospectively screened using a standardised questionnaire based on the Pre-participation Physical Evaluation Monograph 4th Edition (PPE-4), physical examination and ECG interpreted using modern standards. Participants with abnormal findings had focused echocardiography and further evaluation. Primary outcomes included disorders associated with sudden cardiac arrest (SCA). RESULTS: From September 2010 to July 2011, 1339 participants underwent screening: age 13-24 (mean 16) years, 49% male, 68% Caucasian, 17% African-American and 1071 (80%) participating in organised sports. Abnormal history responses were reported on 916 (68%) questionnaires. After physician review, 495/916 (54%) participants with positive questionnaires were thought to have non-cardiac symptoms and/or a benign family history and did not warrant additional evaluation. Physical examination was abnormal in 124 (9.3%) participants, and 72 (5.4%) had ECG abnormalities. Echocardiograms were performed in 586 (44%) participants for abnormal history (31%), physical examination (8%) or ECG (5%). Five participants (0.4%) were identified with a disorder associated with SCA, all with ECG-detected Wolff Parkinson-White. The false-positive rates for history, physical examination and ECG were 31.3%, 9.3% and 5%, respectively. CONCLUSIONS: A standardised history and physical examination using the PPE-4 yields a high false-positive rate in a young active population with limited sensitivity to identify those at risk for SCA. ECG screening has a low false-positive rate using modern interpretation standards and improves detection of primary electrical disease at risk of SCA. PMID- 24948084 TI - Descending the sanitation ladder in urban Uganda: evidence from Kampala Slums. AB - BACKGROUND: While the sanitation ladder is useful in analysing progressive improvements in sanitation, studies in Uganda have not indicated the sanitation barriers faced by the urban poor. There are various challenges in shared latrine use, cleaning and maintenance. Results from Kampala city indicate that, failure to clean and maintain sanitation infrastructure can lead to a reversal of the potential benefits that come with various sanitation facilities. METHODS: A cross sectional qualitative study was conducted between March and May 2013. Data were collected through 18 focus group discussions (FGDs) held separately; one with women, men and youth respectively. We also used pictorial methods; in addition, 16 key informant interviews were conducted. Data were analysed using content thematic approach. Relevant quotations per thematic area were identified and have been used in the presentation of the results. RESULTS: Whether a shared sanitation facility was improved or not, it was abandoned once it was not properly used and cleaned. The problem of using shared latrines began with the lack of proper latrine training when people do not know how to squat on the latrine hole. The constrained access and security concerns, obscure paths that were filthy especially at night, lack of light in the latrine cubicle, raised latrines sometimes up to two metres above the ground, coupled with lack of cleaning and emptying the shared facilities only made a bad situation worse. In this way, open defecation gradually substituted use of the available sanitation facilities. This paper argues that, filthy latrines have the same net effect as crude open defection. CONCLUSION: Whereas most sanitation campaigns are geared towards provision of improved sanitation infrastructure, these findings show that mere provision of infrastructure (improved or not) without adequate emphasis on proper use, cleaning and maintenance triggers an involuntary descent off the sanitation ladder. Understanding this reversal movement is critical in sustainable sanitation services and should be a concern for all actors. PMID- 24948086 TI - Gordonibacter faecihominis sp. nov., isolated from human faeces. AB - A novel actinobacterial strain, designated CAT-2(T), was isolated from human faeces as a bacterium capable of dehydroxylating (+)-catechin derivatives. Strain CAT-2(T) was found to be strictly anaerobic, Gram-positive, non-motile and non spore-forming coccobacilli. The major fatty acids were identified as C16:0 DMA (dimethy acetal), C16:0, C14:0, anteiso-C15:0 and iso-C14:0. The three predominant menaquinones were identified as MK-6 (menaquinene-6), MMK-6 (monomethylmenaquinone-6) and DMMK-6 (dimethylmenaquinone-6). The polar lipids were found to be diphosphatidylglycerol, phosphatidylglycerol and four unidentified glycolipid. The DNA G+C content of strain CAT-2(T) was 68.4 mol%. Phylogenetic analysis based on 16S rRNA gene sequence similarities showed that strain CAT-2(T) belongs to the genus Gordonibacter, sharing the highest level of sequence homology with Gordonibacter pamelaeae DSM 19378(T) (97.3 %). Combined phenotypic, chemotaxonomic and phylogenetic characteristics support the conclusion that the strain CAT-2(T) represents a novel species, for which the name Gordonibacter faecihominis sp. nov. is proposed. The type strain is CAT-2(T) (= KCTC 15204(T) = JCM 16058(T)). PMID- 24948085 TI - The novel globin protein fungoglobin is involved in low oxygen adaptation of Aspergillus fumigatus. AB - The human pathogenic fungus Aspergillus fumigatus normally lives as a soil saprophyte. Its environment includes poorly oxygenated substrates that also occur during tissue invasive growth of the fungus in the human host. Up to now, few cellular factors have been identified that allow the fungus to efficiently adapt its energy metabolism to hypoxia. Here, we cultivated A. fumigatus in an O2 controlled fermenter and analysed its responses to O2 limitation on a minute timescale. Transcriptome sequencing revealed several genes displaying a rapid and highly dynamic regulation. One of these genes was analysed in detail and found to encode fungoglobin, a previously uncharacterized member of the sensor globin protein family widely conserved in filamentous fungi. Besides low O2 , iron limitation also induced transcription, but regulation was not entirely dependent on the two major transcription factors involved in adaptation to iron starvation and hypoxia, HapX and SrbA respectively. The protein was identified as a functional haemoglobin, as binding of this cofactor was detected for the recombinant protein. Gene deletion in A. fumigatus confirmed that haem-binding fungoglobins are important for growth in microaerobic environments with O2 levels far lower than in hypoxic human tissue. PMID- 24948087 TI - Purity assessment of organic calibration standards using a combination of quantitative NMR and mass balance. AB - Quantitative NMR spectroscopy (qNMR) has been examined for purity assessment using a range of organic calibration standards of varying structural complexities, certified using the traditional mass balance approach. Demonstrated equivalence between the two independent purity values confirmed the accuracy of qNMR and highlighted the benefit of using both methods in tandem to minimise the potential for hidden bias, thereby conferring greater confidence in the overall purity assessment. A comprehensive approach to purity assessment is detailed, utilising, where appropriate, multiple peaks in the qNMR spectrum, chosen on the basis of scientific reason and statistical analysis. Two examples are presented in which differences between the purity assignment by qNMR and mass balance are addressed in different ways depending on the requirement of the end user, affording fit-for-purpose calibration standards in a cost-effective manner. PMID- 24948088 TI - Measurement of mercury species in human blood using triple spike isotope dilution with SPME-GC-ICP-DRC-MS. AB - The measurement of different mercury compounds in human blood can provide valuable information about the type of mercury exposure. To this end, our laboratory developed a biomonitoring method for the quantification of inorganic (iHg), methyl (MeHg), and ethyl (EtHg) mercury in whole blood using a triple spike isotope dilution (TSID) quantification method employing capillary gas chromatography (GC) and inductively coupled dynamic reaction cell mass spectrometry (ICP-DRC-MS). We used a robotic CombiPAL((r)) sample handling station featuring twin fiber-based solid-phase microextraction (SPME) injector heads. The use of two SPME fibers significantly reduces sample analysis cycle times making this method very suitable for high sample throughput, which is a requirement for large public health biomonitoring studies. Our sample preparation procedure involved solubilization of blood samples with tetramethylammonium hydroxide (TMAH) followed by the derivatization with sodium tetra(n-propyl)borate (NaBPr(4)) to promote volatility of mercury species. We thoroughly investigated mercury species stability in the blood matrix during the course of sample treatment and analysis. The method accuracy for quantifying iHg, MeHg, and EtHg was validated using NIST standard reference materials (SRM 955c level 3) and the Centre de Toxicologie du Quebec (CTQ) proficiency testing (PT) samples. The limit of detection (LOD) for iHg, MeHg, and EtHg in human blood was determined to be 0.27, 0.12, and 0.16 MUg/L, respectively. PMID- 24948089 TI - DNA methylation ratio variability may impede clinical application of cancer diagnostic markers. AB - Hypermethylation at promoter regions of tumour suppressor genes is diagnostic for many cancers. Many genomic regions that may be the targets for clinical diagnostic assays have been identified through use of measuring systems reliant on bisulphite conversion, but few of these promising markers are in clinical use. The comparability of a widely used DNA methylation measuring system involving bisulphite conversion was evaluated by supplying three experienced centres with methylated DNA reference material mixtures that were independently prepared and characterised by mass spectrometry and high-pressure liquid chromatography. A replication scheme was designed to evaluate reproducibility of key analytical steps within and between laboratories by regression analysis. In general, methylation was underestimated and methylation ratio values were highly variable. The difference in methylation ratio between CpG sites was the key contributor to variable results. The CpG site effect followed a similar pattern at all centres and at all methylation levels examined indicating that sequence context had a major effect on methylation ratio measurement using the bisulphite conversion process. The magnitude of underestimation combined with the variability of measurements between CpG sites compromises the concept of measuring genomic regional methylation by averaging the methylation ratios of many CpG sites. There were no significant differences in replicate bisulphite conversions or sample work-up and instrument analysis at each centre thus making this technique suitable for comparative intralaboratory investigations. However, it may not be suitable for a routine diagnostic assay without extensive standardisation efforts. PMID- 24948090 TI - Higher order structure characterization of protein therapeutics by hydrogen/deuterium exchange mass spectrometry. AB - Characterization of therapeutic drugs is a crucial step in drug development in the biopharmaceutical industry. Analysis of protein therapeutics is a challenging task because of the complexities associated with large molecular size and 3D structures. Recent advances in hydrogen/deuterium-exchange mass spectrometry (HDX MS) have provided a means to assess higher-order structure of protein therapeutics in solution. In this review, the principles and procedures of HDX-MS for protein therapeutics characterization are presented, focusing on specific applications of epitope mapping for protein-protein interactions and higher-order structure comparison studies for conformational dynamics of protein therapeutics. PMID- 24948091 TI - A quantitative HPLC-MS/MS method for studying internal concentrations and toxicokinetics of 34 polar analytes in zebrafish (Danio rerio) embryos. AB - An analytical method using high-performance liquid chromatography-tandem mass spectrometry was developed to determine internal concentrations of 34 test compounds such as pharmaceuticals and pesticides in zebrafish embryos (ZFE), among them, cimetidine, 2,4-dichlorophenoxyacetic acid, metoprolol, atropine and phenytoin. For qualification and quantification, multiple reaction monitoring mode was used. The linear range extends from 0.075 ng/mL for thiacloprid and metazachlor and 7.5 ng/mL for coniine and clofibrate to 250 ng/mL for many of the test compounds. Matrix effects were strongest for nicotine, but never exceeded +/ 20 % for any of the developmental stages of the ZFE. Method recoveries ranged from 90 to 110 % from an analysis of nine pooled ZFE. These findings together with the simple sample preparation mean this approach is suitable for the determination of internal concentrations from only nine individual ZFE in all life stages up to 96 h post-fertilization. Exemplarily, the time course of the internal concentrations of clofibric acid, metribuzin and benzocaine in ZFE was studied over 96 h, and three different patterns were distinguished, on the basis of the speed and extent of uptake and whether or not a steady state was reached. Decreasing internal concentrations may be due to metabolism in the ZFE. PMID- 24948093 TI - Identification and monitoring of thiabendazole transformation products in water during Fenton degradation by LC-QTOF-MS. AB - This work enabled the identification of major transformation products (TPs) of thiabendazole (TBZ) during the Fenton process. TBZ is a benzimidazole fungicide widely used around the world to prevent and/or treat a wide range of fruit and vegetable pathogens. The degradation of the parent molecule and the identification of the main TPs were carried out in demineralized water. The TPs were monitored and identified by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS/MS). Up to 12 TPs were tentatively identified. Most of them were eliminated after 15 min of treatment time and originated from numerous hydroxylations undergone by the aromatic ring during the initial stages of the process. PMID- 24948092 TI - Liquid chromatographic enantiomer separation with special focus on zwitterionic chiral ion-exchangers. AB - This article provides a condensed introduction to principles of chiral separation, gives a historic overview of the genesis of the most important concepts regarding chiral stationary phase (CSPs), and summarizes the state of the art in a concise manner. Some recent developments in the field of polysaccharide CSPs are outlined. Finally, the article focusses on the new concept of zwitterionic chiral stationary phases and their application profile and peculiarities. Some other trends in column technology, including sub-2 MUm and core-shell CSP particles and the emerging field of (UP)SFC, are briefly discussed. PMID- 24948094 TI - A miniaturized device for bioluminescence analysis of caspase-3/7 activity in a single apoptotic cell. AB - Caspases are key enzymes activated during the apoptotic machinery. Apoptosis as a way of programmed cell death becomes deregulated in some pathologies including cancer transformations, neurodegenerative, or autoimmune diseases. Most of the methods available for the detection of apoptosis and caspases provide qualitative information only or quantification data as an average from cell populations or cell lysates. Several reports point to the importance of more accurate single cell analyses in biomedical studies due to heterogeneity at tissue as well as cell level. To meet these requirements, we developed a miniaturized device enabling detection and quantification of active caspase-3/7 in individual cells at a femtogram level (10(-15) g). The active caspase-3/7 detection protocol is based on the bioluminescence chemistry commercially available as a Caspase-GloTM 3/7 reagent developed by Promega. As a model, we used human stem cells treated by camptothecin to induce apoptosis. Individual apoptotic cells were captured from a culture medium under a microscope and transferred by a micromanipulation system into a detection capillary containing 2 MUl of the reagent. Cells without activation by camptothecin served as negative controls. The detection limit of active caspase-3/7 achieved in the miniaturized system was determined as 0.20 and limit of quantification as 0.65 of the amount found in a single apoptotic human stem cell. Such a sensitive method could have a wide application potential in laboratory medicine and related clinically oriented research. PMID- 24948095 TI - Determination of methylisothiocyanate in soil and water by HS-SPME followed by GC MS-MS with a triple quadrupole. AB - Methylisothiocyanate (MITC) is the main degradation product of metam sodium, a soil disinfectant widely used in agriculture, and is responsible for its disinfectant properties. Because MITC is highly toxic and volatile, metam sodium has to be applied in a manner that tries to reduce atmospheric emissions but still maintains adequate concentration of MITC in soil to ensure its disinfectant effect. Thus, monitoring of MITC concentrations in soil is required, and to this end sensitive, fast, and reliable analytical methods must be developed. In this work, a headspace solid-phase microextraction (HS-SPME) method was developed for MITC determination in water and soil samples using gas chromatography-tandem mass spectrometry (GC-MS-MS) with a triple-quadrupole analyzer. Two MS-MS transitions were acquired to ensure the reliable quantification and confirmation of the analyte. The method had linear behavior in the range tested (0.026-2.6 ng mL(-1) in water, 1-100 ng g(-1) in soil) with r (2) over 0.999. Detection limits were 0.017 ng mL(-1) and 0.1 ng g(-1) in water and soil, respectively. Recoveries for five replicates were in the range 76-92 %, and RSD was below 7 % at the two spiking levels tested for each matrix (0.1 and 1 ng mL(-1) for water, 4 and 40 ng g(-1) for soil). The potential of using multiple HS-SPME for analyzing soil samples was also investigated, and its feasibility for quantification of MITC evaluated. The developed HS-SPME method was applied to soil samples from experimental plots treated with metam sodium following good agriculture practices. PMID- 24948096 TI - Validation of an assay for the determination of levoglucosan and associated monosaccharide anhydrides for the quantification of wood smoke in atmospheric aerosol. AB - Biomass burning is becoming an increasing contributor to atmospheric particulate matter, and concern is increasing over the detrimental health effects of inhaling such particles. Levoglucosan and related monosaccharide anhydrides (MAs) can be used as tracers of the contribution of wood burning to total particulate matter. An improved gas chromatography-mass spectrometry method to quantify atmospheric levels of MAs has been developed and, for the first-time, fully validated. The method uses an optimised, low-volume methanol extraction, derivitisation by trimethylsilylation and analysis with high-throughput gas chromatography-mass spectrometry (GC-MS). Recovery of approximately 90 % for levoglucosan, and 70 % for the isomers galactosan and mannosan, was achieved using spiked blank filters estimates. The method was extensively validated to ensure that the precision of the method over five experimental replicates on five repeat experimental occasions was within 15 % for low, mid and high concentrations and accuracy between 85 and 115 %. The lower limit of quantification (LLOQ) was 0.21 and 1.05 ng m(-3) for levoglucosan and galactosan/mannosan, respectively, where the assay satisfied precisions of <=20 % and accuracies 80-120 %. The limit of detection (LOD) for all analytes was 0.105 ng m(-3). The stability of the MAs, once deposited on aerosol filters, was high over the short term (4 weeks) at room temperature and over longer periods (3 months) when stored at -20 degrees C. The method was applied to determine atmospheric levels of MAs at an urban background site in Leicester (UK) for a month. Mean concentrations of levoglucosan over the month of May were 21.4 +/- 18.3 ng m(-3), 7.5 +/- 6.1 ng m(-3) mannosan and 1.8 +/- 1.3 ng m(-3) galactosan. PMID- 24948097 TI - Discrepancy between strength and function in adults with obstetric brachial plexus lesions. PMID- 24948098 TI - Albiziaflavane A: a new flavane from Albizia ferruginea (Mimosoideae). AB - A new polyhydroxylated flavane (1) was identified from Albizia ferruginea (Mimosoideae) along with 4',7-dihydroxyflavan-3,4-diol (2), julibrosides A1-A3 (3 5). The structures of the compounds were established based on their NMR and mass spectrometric data in conjunction with those previously reported in the literature. Compounds 1 and 5 displayed moderate antibacterial activities. PMID- 24948099 TI - Characterisation of acute respiratory infections at a United Kingdom paediatric teaching hospital: observational study assessing the impact of influenza A (2009 pdmH1N1) on predominant viral pathogens. AB - BACKGROUND: According to the World Health Organisation, influenza A (2009 pdmH1N1) has moved into the post-pandemic phase, but there were still high numbers of infections occurring in the United Kingdom in 2010-11. It is therefore important to examine the burden of acute respiratory infections at a large children's hospital to determine pathogen prevalence, occurrence of co-infection, prevalence of co-morbidities and diagnostic yield of sampling methods. METHODS: This was a retrospective study of respiratory virus aetiology in acute admissions to a paediatric teaching hospital in the North West of England between 1st April 2010 and 31st March 2011. Respiratory samples were analysed either with a rapid RSV test if the patient had symptoms suggestive of bronchiolitis, followed by multiplex PCR testing for ten respiratory viruses, or with multiplex PCR testing alone if the patient had suspected other ARI. Patient demographics and data regarding severity of illness, presence of co-morbidities and respiratory virus sampling method were retrieved from case notes. RESULTS: 645 patients were admitted during the study period. 82/645 (12.7%) patients were positive for 2009 pdmH1N1, of whom 24 (29.2%) required PICU admission, with 7.3% mortality rate. Viral co-infection occurred in 48/645 (7.4%) patients and was not associated with more severe disease. Co-morbidities were present more frequently in older children, but there was no significant difference in prevalence of co-morbidity between 2009 pdmH1N1 patients and those with other ARI. NPA samples had the highest diagnostic yield with 192/210 (91.4%) samples yielding an organism. CONCLUSIONS: Influenza A (2009 pdmH1N1) is an ongoing cause of occasionally severe disease affecting both healthy children and those with co-morbidities. Surveillance of viral pathogens provides valuable information on patterns of disease. PMID- 24948100 TI - Cumulative psychosocial stress, coping resources, and preterm birth. AB - Preterm birth constitutes a significant international public health issue, with implications for child and family well-being. High levels of psychosocial stress and negative affect before and during pregnancy are contributing factors to shortened gestation and preterm birth. We developed a cumulative psychosocial stress variable and examined its association with early delivery controlling for known preterm birth risk factors and confounding environmental variables. We further examined this association among subgroups of women with different levels of coping resources. Utilizing the All Our Babies (AOB) study, an ongoing prospective pregnancy cohort study in Alberta, Canada (n = 3,021), multinomial logistic regression was adopted to examine the independent effect of cumulative psychosocial stress and preterm birth subgroups compared to term births. Stratified analyses according to categories of perceived social support and optimism were undertaken to examine differential effects among subgroups of women. Cumulative psychosocial stress was a statistically significant risk factor for late preterm birth (OR = 1.73; 95 % CI = 1.07, 2.81), but not for early preterm birth (OR = 2.44; 95 % CI = 0.95, 6.32), controlling for income, history of preterm birth, pregnancy complications, reproductive history, and smoking in pregnancy. Stratified analyses showed that cumulative psychosocial stress was a significant risk factor for preterm birth at <37 weeks gestation for women with low levels of social support (OR = 2.09; 95 % CI = 1.07, 4.07) or optimism (OR = 1.87; 95 % CI = 1.04, 3.37). Our analyses suggest that early vulnerability combined with current anxiety symptoms in pregnancy confers risk for preterm birth. Coping resources may mitigate the effect of cumulative psychosocial stress on the risk for early delivery. PMID- 24948101 TI - Molecular characterization of Sarcocystis species from Polish roe deer based on ssu rRNA and cox1 sequence analysis. AB - Sarcocysts from four Polish roe deer were collected and examined by light microscopy, small subunit ribosomal RNA (ssu rRNA), and the subunit I of cytochrome oxidase (cox1) sequence analysis. This resulted in identification of Sarcocystis gracilis, Sarcocystis oviformis, and Sarcocystis silva. However, we were unable to detect Sarcocystis capreolicanis, the fourth Sarcocystis species found previously in Norwegian roe deer. Polish sarcocysts isolated from various tissues differed in terms of their shape and size and were larger than the respective Norwegian isolates. Analysis of ssu rRNA gene revealed the lack of differences between Sarcocystis isolates belonging to one species and a very low degree of genetic diversity between Polish and Norwegian sarcocysts, ranging from 0.1% for Sarcocystis gracilis and Sarcocystis oviformis to 0.44% for Sarcocystis silva. Contrary to the results of the ssu rRNA analysis, small intraspecies differences in cox1 sequences were found among Polish Sarcocystis gracilis and Sarcocystis silva isolates. The comparison of Polish and Norwegian cox1 sequences representing the same Sarcocystis species revealed similar degree of sequence identity, namely 99.72% for Sarcocystis gracilis, 98.76% for Sarcocystis silva, and 99.85% for Sarcocystis oviformis. Phylogenetic reconstruction and genetic population analyses showed an unexpected high degree of identity between Polish and Norwegian isolates. Moreover, cox1 gene sequences turned out to be more accurate than ssu rRNA when used to reveal phylogenetic relationships among closely related species. The results of our study revealed that the same Sarcocystis species isolated from the same hosts living in different geographic regions show a very high level of genetic similarity. PMID- 24948102 TI - Markers of oxidative stress in adipose tissue during Trypanosoma cruzi infection. AB - The protozoan parasite Trypanosoma cruzi causes Chagas disease. Cardiac and adipose tissues are among the early targets of infection and are sites of persistent infection. In the heart and adipose tissue, T. cruzi infection results in an upregulation of pro-inflammatory mediators. In the heart, infection is associated with an increase in the markers of oxidative stress. To date, markers of oxidative stress have not been evaluated in adipose tissue in this infection. Brown and white adipose tissues were obtained from CD-1 mice infected with the Brazil strain of T. cruzi for 15, 30, and 130 days post infection. Protein carbonylation and lipid peroxidation assays were performed on these samples. There was an upregulation of these markers of oxidative stress at all time-points in both white and brown adipose tissue. Determinants of anti-oxidative stress were downregulated at similar time-points. This increase in oxidative stress during T. cruzi infection most likely has a deleterious effect on host metabolism and on the heart. PMID- 24948103 TI - Aedes japonicus japonicus (Diptera: Culicidae) from Germany have vector competence for Japan encephalitis virus but are refractory to infection with West Nile virus. AB - The interplay between arthropod-borne (arbo) viruses and their vectors is usually complex and often exert unique relationships. Aedes japonicus japonicus (Hulecoeteomyia japonica or Ochlerotatus japonicus japonicus), an invasive mosquito species with laboratory proven vector competence for a number of emerging viruses has been newly introduced to Germany and is currently expanding its range throughout the country. On the other hand, West Nile virus (WNV), an emerging arbovirus originating from Africa, is already circulating in several European countries and might soon be introduced to Germany. Because newly introduced and rapidly expanding vector species pose a potential risk for public health in Germany, we assessed the vectorial capacity of German Ae. j. japonicus populations for WNV and Japanese encephalitis virus (JEV). The results indicate that German Ae. j. japonicus are susceptible for JEV but are refractory to infection with WNV. Of 67 Ae. j. japonicus females challenged by feeding of WNV containing blood, none had measurable amounts of WNV-RNA (0% infection rate) on day 14 post-infection. In contrast, all females challenged with JEV were positive for JEV-RNA (100% infection rate) on day 14 post-infection. The reason for WNV resistance remains to be determined but is independent from co-infection with other flaviviruses or the presence of endosymbiotic Wolbachia, since we found no evidence for other flavivirus infections within 1,033 tested A. j. japonicus females from the sampling region, nor detectable Wolbachia infection within 30 randomly selected individuals. PMID- 24948104 TI - Efficacy of herbal shampoo base on native plant against head lice (Pediculus humanus capitis De Geer, Pediculidae: Phthiraptera) in vitro and in vivo in Thailand. AB - Head lice infestation (or pediculosis) is an important public health problem in Thailand, especially in children between the ages 5 and 11 years. Head lice resistance is increasing, chemical pediculicides have lost their efficacy, and, therefore, alternative pediculicides such as herbal shampoos have been proposed to treat head lice infestation. Thus, the present study investigated the efficacy of three herbal shampoos based on native plants in Thailand (Acorus calamus Linn., Phyllanthus emblica Linn., and Zanthoxylum limonella Alston) against head lice and compared them with carbaryl shampoo (Hafif shampoo, 0.6% w/v carbaryl), malathion shampoo (A-Lice shampoo, 1.0% w/v malathion), and commercial shampoos (Babi Mild Natural' N Mild and Johnson's baby shampoo) in order to assess their in vitro and in vivo efficacy. For in vitro study, doses of 0.12 and 0.25 ml/cm(2) of each herbal shampoo were applied to filter paper, then 10 head lice were place on the filter paper. The mortalities of head lice were recorded at 5, 15, 30, and 60 min. The results revealed that all herbal shampoo were more effective on pediculicidal activity than chemical and commercial shampoos with 100% mortality at 15 min; LT50 values ranged from 0.25 to 1.90 min. Meanwhile, chemical shampoos caused 20-80% mortality, and LT50 values ranged from 6.50 to 85.43 min. On the other side, commercial shampoos showed 4.0% mortality. The most effective pediculicide was Z. limonella shampoo, followed by A. calamus shampoo, P. emblica shampoo, carbaryl shampoo, malathion shampoo, and commercial shampoo, respectively. In vivo results showed that all herbal shampoos were also more effective for head lice treatment than chemical and commercial shampoos with 94.67-97.68% of cure rate after the first treatment; the second treatment, 7 days later, revealed that the cure rate was 100%. Meanwhile, chemical shampoo showed 71.67-93.0% of cure rate and, unfortunately, commercial shampoos were nontoxic to head lice and showed 0% of cure rate after the first and the second treatments. Our data showed that three herbal shampoos of native plants in Thailand in this study are suitable to be used as pediculicides for Thai children since it is safe for children and there is no side-effect after application. PMID- 24948105 TI - Minimum effective concentrations of formalin and sodium percarbonate on the free living stages of an Australian isolate of Ichthyophthirius multifiliis. AB - Ichthyophthirius multifiliis Fouquet, 1876, a ciliate protozoan, is a common cosmopolitan parasite of freshwater teleosts and is a recurring problem during the summer months on Australian rainbow trout Oncorhynchus mykiss (Walbaum, 1792) farms. Preventative strategies include increasing water flow and filtration, but when an infection is established, chemical intervention is often required. Formalin (FOR) has been traditionally used on Australian trout farms as a treatment for I. multifiliis. Treatment using sodium percarbonate (SPC) that releases hydrogen peroxide when dissolved is being implemented on a number of farms. To assess anecdotal reports of low efficacy we evaluated 1 h exposures of FOR and SPC at 12 degrees C and 17 degrees C in both hard and soft water against free-living stages of I. multifiliis. Each free-living stage were exposed to FOR and SPC in vitro; theronts were exposed to 8, 16, 32 or 64 mg/l SPC or FOR every 15 min, for a maximum of 6 h, and the number of live theronts at each time point was recorded. Prototomonts and tomocysts were exposed to 64, 128, 256 and 512 mg/l SPC and 16, 32, 64 and 128 mg/l FOR for 1 h, incubated, with the percentage viability and the number of theronts produced recorded. Theronts were more sensitive to treatment than tomonts, and prototomonts were more sensitive to treatment than tomocysts. FOR and SPC killed all theronts within 15 min at 64 mg/l at both temperatures. FOR was effective against all prototomonts at >=64 mg/l at both temperatures and was effective against all tomocysts at 128 mg/l at 17 degrees C but did not achieve complete mortality in any doses tested at 12 degrees C. SPC was effective against prototomonts and tomocysts at 64 m/l at 17 degrees C but required >=256 mg/l at 12 degrees C. These results can be used to aid development of specific treatment strategies for the management of I. multifiliis on Australian rainbow trout farms. PMID- 24948106 TI - Effect of ozonide OZ418 against Schistosoma japonicum harbored in mice. AB - The in vitro and in vivo efficacies of ozonide carboxylic acid OZ418 against Schistosoma japonicum were investigated. For in vitro experiments, juvenile (14 day-old) and adult schistosomes were collected from mice infected with 80-100 S. japonicum cercariae for 14 and 35 days post-infection and the worms were maintained in Roswell Park Memorial Institute (RPMI) 1640 supplemented by 10% calf serum. Against 35-day-old adult S. japonicum, OZ418 resulted in weakened worm motor activity, injury to the worm body, emergence of vacuoles along the worm surface, and death. A similar outcome was seen in 14-day-old juvenile S. japonicum exposed to OZ418. Ineffective concentrations (1, 5, and 10 MUg/mL) of OZ418 also interacted with hemin to significantly increase the killing effect against adult schistosomes. The LC50 value of OZ418 against juvenile (14-day-old) and adult schistosomes were identical--16.2 MUg/mL, whereas the corresponding LC95 values were 30.7 and 22.7 MUg/mL, respectively. Treatment of adult and juvenile (14-day-old) S. japonicum-infected mice with single 200-400-mg/kg oral doses of OZ418 produced total worm burden reductions of 68.5-84.1 and 37.5-50.9%, respectively. Further study showed that in mice infected with various stages of schistosomes and treated with a single oral OZ418 400 mg/kg, poor efficacy was seen in the 3-h-old juvenile worm group, while 14-day-old and 21-day-old juvenile worm groups exhibited less efficacy with total worm burden reductions of 42.6 52.4%. On the other hand, similar and higher total worm burden reductions (64.2 76.0%) were seen in the 7-day-old juvenile worm group and 28-day-old as well as 35-day-old adult worm groups. Furthermore, the mean worm burden reductions of the 7-day-old juvenile worm group and 35-day-old adult worm group were statistically significantly higher than that of the 14-day-old or 21-day-old juvenile worm group (P < 0.01 or <0.05). These data suggest that OZ418 has promising efficacy against 7-day-old juvenile and adult S. japonicum. PMID- 24948107 TI - Description of two new Isospora species causing visceral coccidiosis in captive superb glossy starlings, Lamprotornis superbus (Aves: Sturnidae). AB - Isospora greineri sp. n. and Isospora superbusi sp. n. are described from captive superb glossy starlings, Lamprotornis superbus, from the Toronto Zoo succumbing to visceral coccidiosis. Sequence data from nuclear 18S recombinant DNA (rDNA) and mitochondrial cytochrome c oxidase subunit I (COI) loci from sporulated oocysts and infected tissues (liver, lung, or spleen) demonstrated two distinct Isospora sp. genotypes that varied in their relative abundance. In the tissues of one affected bird, as well as its associated fecal sample, two distinct COI sequences (1.7% divergence) and two distinct 18S rDNA sequences (0.6% divergence) were found at almost the same abundance; in other specimens, one of the 18S and one of the COI sequences were less abundant than the other. In the tissues of some birds, only a single COI and single 18S sequence were present. In all cases, the same pair of 18S rDNA and COI sequences fluctuated in abundance in parallel, indicating that there were two distinct species present rather than one species with more than one COI or 18S locus. The oocysts of these new species cannot be differentiated morphologically. Sporulated oocysts of both were spherical to subspherical measuring 17.7 +/- 0.22 MUm by 17.1 +/- 0.20 MUm with a mean L/W ratio of 1.03 +/- 0.004. Sporocysts were ovoid measuring 13.5 +/- 0.17 MUm by 9.3 +/- 0.15 MUm with a mean L/W ratio of 1.4 +/- 0.02. Sporocysts had a small Stieda body with indistinct sub-Stieda body; each sporocyst had a compact residuum. Two morphologically similar but genetically divergent Isospora species were shown to cause simultaneous enteric and extraintestinal infections in captive superb glossy starlings. PMID- 24948108 TI - Identification of two allelic variants of toxB gene and investigation of their distribution among Verocytotoxin-producing Escherichia coli. AB - Verocytotoxin-producing Escherichia coli (VTEC) are food borne pathogens causing severe human infections. The virulence genes asset of VTEC is complex and has not been completely defined yet. Nonetheless, all the virulence genes described so far have been described as conveyed by mobile genetic elements. A gene, termed toxB, has been identified in a large virulence plasmid of VTEC O157, later described in similar plasmids carried by VTEC O26 and O145. In this study we identified for the first time an intact copy of toxB gene in a plasmid present in a VTEC O111 strain and observed the existence of two allelic variants of the gene, that we termed toxB1 and toxB2. We investigated the distribution of the two alleles in a panel of VTEC strains belonging to different serogroups and demonstrated that this gene is present only in VTEC serogroups associated with the most severe forms of the infections such as those belonging to the five serogroups O157, O26, O111, O103 and O145 and that the two alleles segregate with the serogroup of the hosting strains. In particular the toxB1 variant was only present in VTEC O157 while the toxB2 allele was present in the remaining four VTEC serogroups. PMID- 24948109 TI - BrassicaTED - a public database for utilization of miniature transposable elements in Brassica species. AB - BACKGROUND: MITE, TRIM and SINEs are miniature form transposable elements (mTEs) that are ubiquitous and dispersed throughout entire plant genomes. Tens of thousands of members cause insertion polymorphism at both the inter- and intra- species level. Therefore, mTEs are valuable targets and resources for development of markers that can be utilized for breeding, genetic diversity and genome evolution studies. Taking advantage of the completely sequenced genomes of Brassica rapa and B. oleracea, characterization of mTEs and building a curated database are prerequisite to extending their utilization for genomics and applied fields in Brassica crops. FINDINGS: We have developed BrassicaTED as a unique web portal containing detailed characterization information for mTEs of Brassica species. At present, BrassicaTED has datasets for 41 mTE families, including 5894 and 6026 members from 20 MITE families, 1393 and 1639 members from 5 TRIM families, 1270 and 2364 members from 16 SINE families in B. rapa and B. oleracea, respectively. BrassicaTED offers different sections to browse structural and positional characteristics for every mTE family. In addition, we have added data on 289 MITE insertion polymorphisms from a survey of seven Brassica relatives. Genes with internal mTE insertions are shown with detailed gene annotation and microarray-based comparative gene expression data in comparison with their paralogs in the triplicated B. rapa genome. This database also includes a novel tool, K BLAST (Karyotype BLAST), for clear visualization of the locations for each member in the B. rapa and B. oleracea pseudo-genome sequences. CONCLUSIONS: BrassicaTED is a newly developed database of information regarding the characteristics and potential utility of mTEs including MITE, TRIM and SINEs in B. rapa and B. oleracea. The database will promote the development of desirable mTE-based markers, which can be utilized for genomics and breeding in Brassica species. BrassicaTED will be a valuable repository for scientists and breeders, promoting efficient research on Brassica species. BrassicaTED can be accessed at http://im-crop.snu.ac.kr/BrassicaTED/index.php. PMID- 24948113 TI - The role of autonomic testing in syncope. AB - Syncope is a common presenting complaint in both the inpatient and outpatient settings. The main goals in the clinical evaluation of syncope are to identify an underlying etiology, to stratify risk and to guide plans for therapeutic intervention. Testing begins with an initial electrocardiogram to screen for any cardiac rhythm abnormalities. Heart rate variability to paced breathing provides a standard measure of cardiac parasympathetic function and offers clues towards an autonomic cause of syncope. A Valsalva maneuver is used to evaluate for parasympathetic dysfunction through the Valsalva ratio. In addition, sympathetic adrenergic function is assessed through evaluation of blood pressure response during the Valsalva maneuver. Abnormalities to the Valsalva maneuver can suggest clues towards an autonomic cause of syncope. Head-up tilt table testing is an important part of the autonomic evaluation of patients with syncope, and can be diagnostic for many disorders that result in syncope including orthostatic hypotension, neurally mediated syncope, postural tachycardia syndrome or delayed orthostatic hypotension. Autonomic function testing provides a safe and controlled environment for evaluation of patients, and plays a pivotal role in the diagnosis of syncope, particularly in challenging cases. While the initial clinical evaluation of syncope involves a detailed history and physical examination; in situations where the diagnosis is unknown, the addition of autonomic testing is complementary and can lead to identification of autonomic causes of syncope. PMID- 24948112 TI - Linking signal fidelity and the efficiency costs of communication. AB - The handicap principle has been the overarching framework to explain the evolution and maintenance of communication. Yet, it is becoming apparent that strategic costs of signalling are not the only mechanism maintaining signal honesty. Rather, the fidelity of detecting signals can itself be strongly selected. Specifically, we argue that the fidelity of many signals will be constrained by the investment in signal generation and reception by the signaller and perceiver, respectively. Here, we model how investments in signal fidelity influence the emergence and stability of communication using a simple theoretical framework. The predictions of the model indicate that high-cost communication can be stable whereas low-cost intermediates are generally selected against. This dichotomy suggests that the most parsimonious route to the evolution of communication is for initial investment in communicative traits to be driven by noncommunicative functions. Such cues can appeal to pre-existing perceptual biases and thereby stimulate signal evolution. We predict that signal evolution will vary between systems in ways that can be linked to the economics of communication to the two parties involved. PMID- 24948110 TI - The MAPK pathway across different malignancies: a new perspective. AB - The mitogen-activated protein kinase/extracellular signal-regulated (MAPK/ERK) pathway is activated by upstream genomic events and/or activation of multiple signaling events in which information coalesces at this important nodal pathway point. This pathway is tightly regulated under normal conditions by phosphatases and bidirectional communication with other pathways, like the protein kinase B/mammalian target of rapamycin (AKT/m-TOR) pathway. Recent evidence indicates that the MAPK/ERK signaling node can function as a tumor suppressor as well as the more common pro-oncogenic signal. The effect that predominates depends on the intensity of the signal and the context or tissue in which the signal is aberrantly activated. Genomic profiling of tumors has revealed common mutations in MAPK/ERK pathway components, such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF). Currently approved for the treatment of melanoma, inhibitors of BRAF kinase are being studied alone and in combination with inhibitors of the MAPK and other pathways to optimize the treatment of many tumor types. Therapies targeted toward MAPK/ERK components have various response rates when used in different solid tumors, such as colorectal cancer and ovarian cancer. Understanding the differential nature of activation of the MAPK/ERK pathway in each tumor type is critical in developing single and combination regimens, because different tumors have unique mechanisms of primary and secondary signaling and subsequent sensitivity to drugs. PMID- 24948111 TI - ID1 promotes breast cancer metastasis by S100A9 regulation. AB - Metastasis is a major factor responsible for mortality in patients with breast cancer. Inhibitor of DNA binding 1 (Id1) has been shown to play an important role in cell differentiation, tumor angiogenesis, cell invasion, and metastasis. Despite the data establishing Id1 as a critical factor for lung metastasis in breast cancer, the pathways and molecular mechanisms of Id1 functions in metastasis remain to be defined. Here, we show that Id1 interacts with TFAP2A to suppress S100A9 expression. We show that expression of Id1 and S100A9 is inversely correlated in both breast cancer cell lines and clinical samples. We also show that the migratory and invasive phenotypes in vitro and metastasis in vivo induced by Id1 expression are rescued by reestablishment of S100A9 expression. S100A9 also suppresses the expression of known metastasis-promoting factor RhoC activated by Id1 expression. Our results suggest that Id1 promotes breast cancer metastasis by the suppression of S100A9 expression. IMPLICATIONS: Novel pathways by Id1 regulation in metastasis. PMID- 24948114 TI - Lipopolysaccharides (LPS) modulate the metabolism of deoxynivalenol (DON) in the pig. AB - Pigs might be exposed to lipopolysaccharides (LPS) and deoxynivalenol (DON) at the same time, and both toxins are thought to interactively affect the intestinal barrier, the innate immune system, and the xenobiotics metabolism. Hence, we aimed at examining the single and combined effects of both toxins on nutrient digestibility and DON metabolism. For this purpose, barrows (26 +/- 4 kg) were fed restrictedly either a control diet (CON) or a diet contaminated with 3.1 mg DON/kg (DON) for 37 days. At day 37 of the experiment, pigs were infused intravenously for 60 min either with 100 MUg DON/kg body weight (BW) (CON-DON), 7.5 MUg LPS/kg BW (CON-LPS, DON-LPS) or a combination of both substances (CON-DON + LPS), or physiological saline (CON-CON, DON-CON). Blood samples were collected frequently until 3.25 h before the pigs were sacrificed for bile, liver, and kidney collection. The apparent digestibility of N-free extractives was significantly increased by 1 % when the DON-contaminated diet was fed. The total DON content in blood was significantly higher in endotoxemic pigs (34.8 ng/mL; CON-DON + LPS) when compared to the pigs infused with DON alone (18.8 ng/mL; CON DON) while bile concentrations were not influenced by LPS. DON residue levels in liver and kidney closely reflected the treatment effects as described for blood. In contrast to DON infusion, the LPS challenge resulted in a significantly lower total DON concentration (13.2 vs. 7.5 ng/mL in groups DON-CON and DON-LPS, respectively) when the pigs were exposed to DON through the diet. The conjugation degree for DON in blood and bile was not influenced by treatments. In conclusion, endotoxemic pigs are characterized by higher DON residue levels in blood, liver, and kidney, probably by a compromised elimination. PMID- 24948115 TI - Production and applications of an N-terminally-truncated recombinant beta haemolysin from Staphylococcus aureus. AB - The beta-haemolysin of Staphylococcus aureus (SA-hlb) is a secreted neutral sphingomyelinase (nSMase) implicated in the pathogenesis of infection and responsible for the characteristic in vitro 'hot-cold' haemolytic ability of the bacterium. Here, we describe the production of a biologically active N-terminally truncated recombinant SA-hlb protein for use in in vitro assays and as a research tool. Using local isolates of S. aureus, we PCR-amplified an SA-hlb DNA sequence of 891 nucleotides, 99 nucleotides shorter than the full-length molecule, before cloning and sequencing (GenBank accession no. JN580071). The pQE.TriSystem vector (Qiagen, Germany) was used to express recombinant SA-hlb (r-SA-hlb) with a C terminal 8xHis tag in Escherichia coli JM107 cells. Both JM107 lysate and the purified r-SA-hlb possessed hot-cold lytic activity against sheep and buffalo erythrocytes, which was abolished by incubation at >=90 degrees C for 30 min or exposure to dithiothreitol, and could be neutralized by bovine immune sera. Purified r-SA-hlb was also cytotoxic to buffalo mononuclear cells and was effective as a coating antigen for indirect ELISA to screen for reactive sera. Importantly, the r-SA-hlb was suitable for use as a beta-toxin in the modified CAMP test. We conclude that the r-SA-hlb protein produced was functionally active and has numerous potential applications. PMID- 24948116 TI - Pigmented villonodular synovitis of 1st metatarsophalangeal joint: a case report and literature review. AB - Pigmented villonodular synovitis is a common disease entity particularly in the knee joint but its incidence in the foot is quite rare. A case of first metatarsophalangeal (MTP) joint pigmented villonodular synovitis (PVNS), presented to us with recurrence of symptoms after surgical excision done outside our institute. After histological confirmation of recurrence of the disease, repeat open surgical excision was performed. After being asymptomatic for two months she presented to us with recurrence of symptoms for which hyperkeratotic plaque at the ventral aspect of the first MTP joint was found to be responsible on physical examination. It was treated surgically by pairing it and now patient is symptom free for last 1 year. It signifies the importance of the histopathology in the diagnosis and recurrence of the PVNS and thorough physical examination in the management of the foot pathologies. PMID- 24948118 TI - Metabolic disorders: Pumping up muscle mitochondria. PMID- 24948117 TI - Enteropathogenic E. coli effectors EspG1/G2 disrupt microtubules, contribute to tight junction perturbation and inhibit restoration. AB - Enteropathogenic Escherichia coli (EPEC) uses a type 3 secretion system to transfer effector proteins into the host intestinal epithelial cell. Several effector molecules contribute to tight junction disruption including EspG1 and its homologue EspG2 via a mechanism thought to involve microtubule destruction. The aim of this study was to investigate the contribution of EspG-mediated microtubule disruption to TJ perturbation. We demonstrate that wild type EPEC infection disassembles microtubules and induces the progressive movement of occludin away from the membrane and into the cytosol. Deletion of espG1/G2 attenuates both of these phenotypes. In addition, EPEC infection impedes barrier recovery from calcium switch, suggesting that inhibition of TJ restoration, not merely disruption, prolongs barrier loss. TJs recover more rapidly following infection with DeltaespG1/G2 than with wild type EPEC, demonstrating that EspG1/G2 perpetuate barrier loss. Although EspG regulates ADP-ribosylation factor (ARF) and p21-activated kinase (PAK), these activities are not necessary for microtubule destruction or perturbation of TJ structure and function. These data strongly support a role for EspG1/G2 and its associated effects on microtubules in delaying the recovery of damaged tight junctions caused by EPEC infection. PMID- 24948119 TI - Alzheimer's disease: Abeta-fibrinogen interaction inhibitor improves cognition in AD. PMID- 24948121 TI - Anticancer drugs: Hitting SYK in B-ALL leukaemia. PMID- 24948122 TI - Continuous syntheses of Pd@Pt and Cu@Ag core-shell nanoparticles using microwave assisted core particle formation coupled with galvanic metal displacement. AB - Continuous synthesis of Pd@Pt and Cu@Ag core-shell nanoparticles was performed using flow processes including microwave-assisted Pd (or Cu) core-nanoparticle formation followed by galvanic displacement with a Pt (or Ag) shell. The core shell structure and the nanoparticle size were confirmed using high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) observation and EDS elemental mapping. The Pd@Pt nanoparticles with a particle size of 6.5 +/- 0.6 nm and a Pt shell thickness of ca. 0.25 nm were synthesized with appreciably high Pd concentration (Pd 100 mM). This shell thickness corresponds to one atomic layer thickness of Pt encapsulating the Pd core metal. The particle size of core Pd was controlled by tuning the initial concentrations of Na2[PdCl4] and PVP. Core-shell Cu@Ag nanoparticles with a particle size of 90 +/- 35 nm and an Ag shell thickness of ca. 3.5 nm were obtained using similar sequential reactions. Oxidation of the Cu core was suppressed by the coating of Cu nanoparticles with the Ag shell. PMID- 24948123 TI - Failure to fill a first prescription of a new medication is common in primary care settings. PMID- 24948124 TI - Combined oral contraceptives increase risk of venous thrombosis according to oestrogen dose and type of progestogen. PMID- 24948120 TI - Emerging targets in neuroinflammation-driven chronic pain. AB - Current analgesics predominately modulate pain transduction and transmission in neurons and have limited success in controlling disease progression. Accumulating evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of glial cells and production of inflammatory mediators in the peripheral and central nervous system, has an important role in the induction and maintenance of chronic pain. This Review focuses on emerging targets - such as chemokines, proteases and the WNT pathway - that promote spinal cord neuroinflammation and chronic pain. It also highlights the anti-inflammatory and pro-resolution lipid mediators that act on immune cells, glial cells and neurons to resolve neuroinflammation, synaptic plasticity and pain. Targeting excessive neuroinflammation could offer new therapeutic opportunities for chronic pain and related neurological and psychiatric disorders. PMID- 24948125 TI - Factors associated with treatment-seeking behavior for postpartum urinary incontinence. AB - PURPOSE: To identify the factors associated with treatment-seeking behavior for urinary incontinence (UI) among postpartum women. DESIGN: This is a cross sectional study. A total of 142 women with postpartum UI responded a telephone interview between August of 2010 and March of 2011. The association between the treatment-seeking and the predicting variables were measured through odds ratio and 95% confidence interval. RESULTS: The treatment-seeking percentage was 37.3% and the treatment percentage was 27.5%. The result of multiple logistic regressions indicated that: counseling about UI in pregnancy, postpartum physical exercise, and Spanish nationality predicted 47.8% of the variance in treatment seeking behavior CONCLUSIONS: The lack of counseling largely determines the low rates of treatment-seeking among Spanish mothers. CLINICAL RELEVANCE: Nursing counseling during pregnancy can contribute substantially to increasing the number of women treated for postpartum UI. PMID- 24948127 TI - Bent and planar structures of MU-eta2:eta2-N2 dinuclear early transition metal complexes. AB - This work studied the bent and planar structures of M2N2 cores of a series of dinuclear early transition-metal complexes (M = Zr, Hf, Nb, Ta, Mo and W) containing a side-on bridging dinitrogen ligand using DFT method. The calculated results propose three key factors favoring a bent structure: (1) the availability of a single electron in the metal centers which leads to the bonding interaction between two metal atoms, (2) no remarkable steric effect around the metal centers, and (3) the cis conformation of the ligands in the dinitrogen dinuclear complexes. In addition, the bent and planar structures of M2N2 could be transformed into each other if the steric hindrance was slight. PMID- 24948126 TI - Adverse events following implantable cardioverter defibrillator implantation: a systematic review. AB - PURPOSE: Implantable cardioverter defibrillators (ICDs) prevent sudden cardiac death, but patients need to be counseled about potential harms. We summarized the evidence on adverse events from ICDs with a focus on ICD use for primary prevention of sudden cardiac death. METHODS: We searched MEDLINE and Cochrane Central Register of Controlled Trials from 2002 through 2012 for reports of adverse events from ICDs implanted for primary prevention or mixed indications (primary and secondary prevention). Studies had to have >=500 patients and specify patient numerators and denominators. RESULTS: Data from 35 independent cohorts reported in 53 articles were included. Reports from one registry provided high quality evidence on adverse events during hospitalization for ICD implantation. Adverse events ranged from 2.8 to 3.6%. Serious adverse events ranged from 1.2 to 1.4%. The most frequent serious adverse events were pneumothorax (0.4-0.5%) and cardiac arrest (0.3%). The quality of the evidence for long-term adverse events was low. Frequency of adverse events post hospitalization was variable, as was follow-up: device-related complications <0.1 6.4% (2-49 months), lead-related complications <0.1-3.9% (1.5-40 months), infection 0.2-3.7% (1.5-49 months), and thrombosis 0.2-2.9% (1.5-49 months). Evidence for inappropriate shock was of moderate quality with 3-21% of patients experiencing at least one inappropriate shock during 1 to 5 years of follow-up. LIMITATIONS: The limitation of the evidence reviewed in this study is low quality evidence for adverse events post-hospitalization. Evidence is predominantly from mixed primary and secondary prevention populations. CONCLUSIONS: In-hospital adverse events after ICD implantation are infrequent. The estimates for long-term adverse events are uncertain. Up to one-fifth of patients receive inappropriate shocks. PMID- 24948128 TI - Global analysis for spread of infectious diseases via transportation networks. AB - We formulate an epidemic model for the spread of an infectious disease along with population dispersal over an arbitrary number of distinct regions. Structuring the population by the time elapsed since the start of travel, we describe the infectious disease dynamics during transportation as well as in the regions. As a result, we obtain a system of delay differential equations. We define the basic reproduction number R(0) as the spectral radius of a next generation matrix. For multi-regional systems with strongly connected transportation networks, we prove that if R(0) <= 1 then the disease will be eradicated from each region, while if R(0) > 1 there is a globally asymptotically stable equilibrium, which is endemic in every region. If the transportation network is not strongly connected, then the model analysis shows that numerous endemic patterns can exist by admitting a globally asymptotically stable equilibrium, which may be disease free in some regions while endemic in other regions. We provide a procedure to detect the disease free and the endemic regions according to the network topology and local reproduction numbers. The main ingredients of the mathematical proofs are the inductive applications of the theory of asymptotically autonomous semiflows and cooperative dynamical systems. We visualise stability boundaries of equilibria in a parameter plane to illustrate the influence of the transportation network on the disease dynamics. For a system consisting of two regions, we find that due to spatial heterogeneity characterised by different local reproduction numbers, R(0) may depend non-monotonically on the dispersal rates, thus travel restrictions are not always beneficial. PMID- 24948129 TI - Normal Solid Gastric Emptying Values Measured by Scintigraphy Using Asian-style Meal:A Multicenter Study in Healthy Volunteers. AB - BACKGROUND/AIMS: To report gastric emptying scintigraphy, normal values should be established for a specific protocol. The aim of this study was to provide normal gastric emptying values and determine factors affecting gastric emptying using Asian rice-based meal in healthy volunteers. METHODS: One hundred and ninety-two healthy volunteers were included at 7 tertiary care centers across Thailand. Gastric emptying scintigraphy was acquired in 45 degree left anterior oblique view immediately after ingestion of a 267 kcal steamed-rice with technetium-99m labeled-microwaved egg meal with 100 mL water for up to 4 hours. RESULTS: One hundred and eighty-nine volunteers (99 females, age 43 +/- 14 years) completed the study. The medians (5-95th percentiles) of lag time, gastric emptying half time (GE T1/2) and percent gastric retentions at 2 and 4 hours for all volunteers were 18.6 (0.5-39.1) minutes, 68.7 (45.1-107.8) minutes, 16.3% (2.7-49.8%) and 1.1% (0.2-8.8%), respectively. Female volunteers had significantly slower gastric emptying compared to male (GE T1/2, 74 [48-115] minutes vs. 63 (41-96) minutes; P < 0.05). Female volunteers who were in luteal phase of menstrual cycle had significantly slower gastric emptying compared to those in follicular phase or menopausal status (GE T1/2, 85 [66-102] mintes vs. 69 [50-120] minutes or 72 [47 109] minutes, P < 0.05). All of smoking volunteers were male. Smoker male volunteers had significantly faster gastric emptying compared to non-smoker males (GE T1/2, 56 [44-80] minutes vs. 67 [44-100] minutes, P < 0.05). Age, body mass index and alcohol consumption habits did not affect gastric emptying values. CONCLUSIONS: A steamed-rice with microwaved egg meal was well tolerated by healthy volunteers. Gender, menstrual status and smoking status were found to affect solid gastric emptying. PMID- 24948130 TI - A Study to Draw a Normative Database of Laryngopharynx pH Profile in Chinese. AB - BACKGROUND/AIMS: To draw a normative database of laryngopharynx pH profile in Chinese subjects. METHODS: Normal volunteers were recruited from "www.Ganji.com" and People's hospital between May 2008 and December 2009. The Restech pH Probes were calibrated in pH 7 and pH 4 buffer solutions according to the manufacturer's instructions. Each volunteer was asked to wear the device for a 24-hour period and was encouraged to participate in normal daily activities. RESULTS: The healthy volunteers consisted of 20 males and 9 females with a median age of 23 years (interquartile range, 21 to 32 years). The 95th percentiles for % total times at pH < 4, pH < 4.5, pH < 5.0 and pH < 5.5 for the oropharynx pH catheter were 0.06%, 1.01%, 7.23% and 27.34%, respectively. The 95th percentile for number of reflux events within the 24-hour period at pH < 4, pH < 4.5, pH < 5.0 and pH < 5.5 were 2.0, 18.0, 107.5 and 284.5, respectively. CONCLUSIONS: This is the first study to systematically assess the degree of reflux detected by the new pH probe in healthy asymptomatic Chinese volunteers and to report normative values in Chinese people. Using an oropharyngeal pH catheter to monitor laryngopharyngeal reflux indicated that in healthy Chinese, reflux should be considered normal if the percent time at pH less than 4.5 is no more than 1%. PMID- 24948132 TI - How to perform and interpret balloon expulsion test. AB - The balloon expulsion test is a simple and useful method for investigating a defecatory disorder assessing the subject's ability to evacuate a simulated stool. However, there is no standard methodology and varying interpretations have been reported. This review discusses the techniques, interpretation and clinical utility of the balloon expulsion test. PMID- 24948134 TI - The importance of being specific--a meta-analysis evaluating the effect of antibiotics in acute otitis media. AB - BACKGROUND: Whether acute otitis media (AOM) should be the cause for antibiotic treatment has been a matter of debate during the last decades. Treatment guidelines are based on less than twenty trials that have found the effect of antibiotics on symptomatic outcomes in AOM, such as pain, to be very modest. Two recent trials found a more substantial effect of antibiotics when they looked at treatment failure as the outcome. That the effect varies with the chosen outcome may not only be because the true effect is different but also because different outcomes are more or less specific for the disease in question. OBJECTIVE: The purpose of this study was to perform a meta-analysis to calculate a composite risk ratio for treatment failure in AOM and also to investigate whether the specificity of treatment failure as an outcome differs from that of symptomatic outcomes, such as pain. METHODS: Trials evaluating the effect of antibiotics in AOM and reporting the number of treatment failures were identified and a fixed effects meta-analysis was performed. In addition, the literature was searched for articles providing direct or indirect figures on the specificity of different outcomes in AOM trials. A hypothetical study was designed to show how differences in sensitivity/specificity of inclusion/outcome criteria affect the results of a trial. RESULTS: The meta-analysis yielded a composite risk ratio of 0.4 (95% CI 0.35-0.48), p<0.001 for the effect of antibiotics on treatment failure. Based on data from the literature, the specificity of treatment failure was estimated to 92-100%. The hypothetical study showed how a non-specific outcome biases the effect estimate towards the null, whereas other kinds of misclassification only decrease precision. CONCLUSION: Future trials should focus on improving diagnostic criteria to increase precision but primarily, they should focus on choosing a specific outcome in order not to get a biased effect estimate. PMID- 24948133 TI - Amiloride and SN-6 suppress audiogenic seizure susceptibility in genetically epilepsy-prone rats. AB - AIMS: We have recently reported that amiloride, a potent and nonselective blocker of acid-sensing ion channels, prevents the development of pilocarpine-induced seizures and status epilepticus. Amiloride is also known to suppress the activity of Na(+) /Ca(2+) and Na(+) /H(+) exchangers that have been implicated in the pathophysiology of seizures. Here, we evaluated the effects of amiloride, SN-6 (a potent blocker of Na(+) /Ca(2+) exchangers) and zoniporide (a potent blocker of Na(+) /H(+) exchangers) on acoustically evoked seizures (audiogenic seizures, AGS) in genetically epilepsy-prone rats (GEPR-3s), a model of inherited generalized epilepsy. METHODS: Male, six-week-old GEPR-3s were used. The GEPR-3s were tested for AGS susceptibility before and after treatment with various doses of amiloride, SN-6, and zoniporide (1, 3, 10, and 30 mg/kg; per os). RESULTS: We found that pretreatment with amiloride and SN-6 markedly reduced the incidence and severity of AGS in the GEPR-3s. In contrast, administration of zoniporide only minimally reduced the incidence and severity of AGS in the GEPR-3s. A combination of noneffective doses of SN-6 and zoniporide also suppressed AGS susceptibility in the GEPR-3s. CONCLUSIONS: These findings suggest acid-sensing ion channels and the Na(+) /Ca(2+) exchanger may play an important role in the pathophysiology of inherited AGS susceptibility in the GEPR-3s. PMID- 24948136 TI - Theme and variations: heterothermy in mammals. AB - This collection of articles is focused on the evolutionary dynamics of heterothermy in mammals, specifically torpor and hibernation. Topics cover a wide range from evolutionary genetics, physiology, ecology, and applications to human health. PMID- 24948135 TI - What are the patients' preferences for the Chronic Care Model? An application to the obstructive sleep apnoea syndrome. AB - CONTEXT: The Chronic Care Model (CCM) has been developed to improve the quality of medical care delivered by general practitioners to patients with multiple chronic conditions. Despite an increasing use of this model, it remains unclear to what extent the different recommendations are valued by the patients. OBJECTIVE: This study aims to identify the preferences of patients with multiple chronic conditions for recommendations of the Chronic Care Model. METHODS: The patients' preferences were identified with a discrete choice experiment. The hypothetical general practice cares were described using 10 recommendations of the Chronic Care Model (i.e. shared decision making; informational continuity (INF); regular follow-up; planned care; communication; collaboration with a nurse; advices on health habits; patient empowerment; psychological support; coordination). Respondents were consecutively recruited in a hospital setting during routine follow-up visits to their pulmonary specialist. The sample of respondents included 150 patients with multiple chronic conditions in addition to an obstructive sleep apnoea syndrome. RESULTS: The INF is highly valued by the patients. At the opposite, patients do not appear to value collaboration between nurses and GPs. To a large extent, the patients' preferences for the recommendations of the CCM depend on their gender, number of chronic conditions and self-perceived health condition. DISCUSSION: The INF appeared to be a minimal requirement to ensure high-quality general practice care. The significant interactions between the patients' socio-demographic characteristics and their preferences for the CCM highlighted the necessity to deliver personalized services. PMID- 24948131 TI - The significance of interstitial cells in neurogastroenterology. AB - Smooth muscle layers of the gastrointestinal tract consist of a heterogeneous population of cells that include enteric neurons, several classes of interstitial cells of mesenchymal origin, a variety of immune cells and smooth muscle cells (SMCs). Over the last number of years the complexity of the interactions between these cell types has begun to emerge. For example, interstitial cells, consisting of both interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor alpha-positive (PDGFRalpha(+)) cells generate pacemaker activity throughout the gastrointestinal (GI) tract and also transduce enteric motor nerve signals and mechanosensitivity to adjacent SMCs. ICC and PDGFRalpha(+) cells are electrically coupled to SMCs possibly via gap junctions forming a multicellular functional syncytium termed the SIP syncytium. Cells that make up the SIP syncytium are highly specialized containing unique receptors, ion channels and intracellular signaling pathways that regulate the excitability of GI muscles. The unique role of these cells in coordinating GI motility is evident by the altered motility patterns in animal models where interstitial cell networks are disrupted. Although considerable advances have been made in recent years on our understanding of the roles of these cells within the SIP syncytium, the full physiological functions of these cells and the consequences of their disruption in GI muscles have not been clearly defined. This review gives a synopsis of the history of interstitial cell discovery and highlights recent advances in structural, molecular expression and functional roles of these cells in the GI tract. PMID- 24948137 TI - Piwi and potency: PIWI proteins in animal stem cells and regeneration. AB - PIWI proteins are well known for their roles in the animal germline. They are essential for germline development and maintenance, and together with their binding partners, the piRNAs, they mediate transposon silencing. More recently, PIWI proteins have also been identified in somatic stem cells in diverse animals. The expression of PIWI proteins in these cells could be related to the ability of such cells to contribute to the germline. However, evaluation of stem cell systems across many different animal phyla suggests that PIWI proteins have an ancestral role in somatic stem cells, irrespective of their contribution to the germ cell lineage. Moreover, the data currently available reveal a possible correlation between the differentiation potential of a cell and its PIWI levels. PMID- 24948138 TI - Compensations during Unsteady Locomotion. AB - Locomotion in a complex environment is often not steady, but the mechanisms used by animals to power and control unsteady locomotion (stability and maneuverability) are not well understood. We use behavioral, morphological, and impulsive perturbations to determine the compensations used during unsteady locomotion. At the level both of the whole-body and of joints, quasi-stiffness models are useful for describing adjustments to the functioning of legs and joints during maneuvers. However, alterations to the mechanics of legs and joints often are distinct for different phases of the step cycle or for specific joints. For example, negotiating steps involves independent changes of leg stiffness during compression and thrust phases of stance. Unsteady locomotion also involves parameters that are not part of the simplest reduced-parameter models of locomotion (e.g., the spring-loaded inverted pendulum) such as moments of the hip joint. Extensive coupling among translational and rotational parameters must be taken into account to stabilize locomotion or maneuver. For example, maneuvers with morphological perturbations (increased rotational inertial turns) involve changes to several aspects of movement, including the initial conditions of rotation and ground-reaction forces. Coupled changes to several parameters may be employed to control maneuvers on a trial-by-trial basis. Compensating for increased rotational inertia of the body during turns is facilitated by the opposing effects of several mechanical and behavioral parameters. However, the specific rules used by animals to control translation and rotation of the body to maintain stability or maneuver have not been fully characterized. We initiated direct-perturbation experiments to investigate the strategies used by humans to maintain stability following center-of-mass (COM) perturbations. When walking, humans showed more resistance to medio-lateral perturbations (lower COM displacement). However, when running, humans could recover from the point of maximum COM displacement faster than when walking. Consequently, the total time necessary for recovery was not significantly different between walking and running. Future experiments will determine the mechanisms used for compensations during unsteady locomotion at the behavioral, joint, and muscle levels. Using reduced-parameter models will allow common experimental and analytical frameworks for the study of both stability and maneuverability and the determination of general control strategies for unsteady locomotion. PMID- 24948139 TI - Thermal transgenerational plasticity in natural populations of Daphnia. AB - Rising temperatures associated with global climatic change threaten the persistence of species. Determining how species adapt to environmental change is paramount. Much work has shown that environmental stressors have the potential to induce phenotypic changes that span multiple generations. Such transgenerational plasticity (TGP) represents a mechanism that may allow for rapid responses to global climatic change. Yet, our understanding of thermal TGP beyond the relationship between parent and offspring is limited. We evaluated thermal TGP in development across three generations (i.e., F0, F1, and F2) in zooplankton (Daphnia ambigua) from lakes in Connecticut. We found that the temperatures at which parents and grandparents were reared significantly influenced age at maturation in the grand-offspring. Comparisons between the F0 and F1 generation show that the offspring of parents reared at low temperatures matured significantly faster than the offspring of parents reared at a higher temperature. However, age at maturation in the grand-offspring was influenced by the interactive effects of parents and grandparents. Such an effect yielded trends that were not readily predicted from the previous generations and whose adaptive significance is unclear. Our results thus call for additional theoretical and empirical work to better understand the transgenerational effects of temperature. PMID- 24948140 TI - A new organismal systems biology: how animals walk the tight rope between stability and change. AB - The amount of knowledge in the biological sciences is growing at an exponential rate. Simultaneously, the incorporation of new technologies in gathering scientific information has greatly accelerated our capacity to ask, and answer, new questions. How do we, as organismal biologists, meet these challenges, and develop research strategies that will allow us to address the grand challenge question: how do organisms walk the tightrope between stability and change? Organisms and organismal systems are complex, and multi-scale in both space and time. It is clear that addressing major questions about organismal biology will not come from "business as usual" approaches. Rather, we require the collaboration of a wide range of experts and integration of biological information with more quantitative approaches traditionally found in engineering and applied mathematics. Research programs designed to address grand challenge questions will require deep knowledge and expertise within subfields of organismal biology, collaboration and integration among otherwise disparate areas of research, and consideration of organisms as integrated systems. Our ability to predict which features of complex integrated systems provide the capacity to be robust in changing environments is poorly developed. A predictive organismal biology is needed, but will require more quantitative approaches than are typical in biology, including complex systems-modeling approaches common to engineering. This new organismal systems biology will have reciprocal benefits for biologists, engineers, and mathematicians who address similar questions, including those working on control theory and dynamical systems biology, and will develop the tools we need to address the grand challenge questions of the 21st century. PMID- 24948141 TI - The utility of circulating markers to predict bone loss across the CKD spectrum. PMID- 24948142 TI - Race/ethnicity, age, and risk of hospital admission and length of stay during the first year of maintenance hemodialysis. AB - BACKGROUND AND OBJECTIVES: Although patients undergoing maintenance hemodialysis have exceptionally high hospitalization rates, the risk factors for hospitalizations are unclear. This study sought to examine hospitalization rates among hemodialysis patients in the United States according to both race/ethnicity and age. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: US Renal Data System data on 563,281 patients beginning maintenance hemodialysis between 1995 and 2009 were analyzed. Rates of hospital admission and number of hospital days for all-cause and cause-specific hospitalizations during the first year of dialysis were compared among blacks, whites, and Hispanics in the entire cohort and subgroups stratified by age. RESULTS: After multiple adjustments, compared with whites, Hispanics overall had lower rates of both all-cause hospital days (adjusted rate ratio [aRR], 0.91; 95% confidence interval [95% CI], 0.90 to 0.93; P<0.001) and hospital admissions (aRR, 0.89; 95% CI, 0.88 to 0.90; P<0.001), whereas blacks had a lower rate of all-cause admissions (aRR, 0.95; 95% CI, 0.94 to 0.96; P<0.001). The racial/ethnic differences, however, varied by age. Hispanics exhibited the lowest rates of hospital days and admissions for all age groups<=70 years, but those >80 years had higher rates than their white counterparts. The adjusted black-to-white rate ratios exhibited a U-shaped pattern with age, with higher rates for blacks in the younger and older age groups. Hospitalization rates for dialysis-related infections were markedly higher in blacks and Hispanics than whites, which were consistent in all age groups for blacks (aRRs for hospital days ranged from 1.09 to 1.36) and all ages>60 years for Hispanics (aRRs ranged from 1.20 to 1.38). CONCLUSIONS: There are significant racial/ethnic differences in hospitalization rates within first year of dialysis, which are not consistent across the age groups and also differ by causes of hospitalization. Overall, blacks and Hispanics had lower rates of all-cause hospital admissions than whites. However, younger and older blacks and older Hispanics were at greatest risk. PMID- 24948143 TI - Coding variants in nephrin (NPHS1) and susceptibility to nephropathy in African Americans. AB - BACKGROUND AND OBJECTIVES: Presumed genetic risk for diabetic and nondiabetic end stage renal disease is strong in African Americans. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Exome sequencing data from African Americans with type 2 diabetic end stage renal disease and nondiabetic, non-nephropathy controls in the T2D-GENES study (Discovery, n=529 patients and n=535 controls) were evaluated, focusing on missense variants in NPHS1. Associated variants were then evaluated in independent type 2 diabetic end stage renal disease (Replication, n=1305 patients and n=760 controls), nondiabetic end stage renal disease (n=1705), and type 2 diabetes-only, non-nephropathy samples (n=503). All participants were recruited from dialysis facilities and internal medicine clinics across the southeastern United States from 1991 to present. Additional NPHS1 missense variants were identified from exome sequencing resources, genotyped, and sequence kernel association testing was then performed. RESULTS: Initial analysis identified rs35238405 (T233A; minor allele frequency=0.0096) as associated with type 2 diabetic end stage renal disease (adjustment for admixture P=0.042; adjustment for admixture+APOL1 P=0.080; odds ratio, 2.89 and 2.36, respectively); with replication in independent type 2 diabetic end stage renal disease samples (P=0.018; odds ratio, 4.30) and nondiabetic end stage renal disease samples (P=0.016; odds ratio, 4.48). In a combined analysis (all patients with end stage renal disease versus all controls), T233A was associated with all cause end stage renal disease (P=0.0038; odds ratio, 2.82; n=3270 patients and n=1187 controls). A P-value of <0.001 was obtained after adjustment for admixture and APOL1 in sequence kernel association testing. Two additional variants (H800R and Y1174H) were nominally associated with protection from end stage renal disease (P=0.036; odds ratio, 0.44; P=0.0084; odds ratio, 0.040, respectively) in the locus-wide single-variant association tests. CONCLUSIONS: Coding variants in NPHS1 are associated with both risk for and protection from common forms of nephropathy in African Americans. PMID- 24948144 TI - Bone mineral density and serum biochemical predictors of bone loss in patients with CKD on dialysis. AB - BACKGROUND AND OBJECTIVES: Use of bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) is controversial for diagnosing bone loss in CKD patients on dialysis. The alternative quantitative computed tomography (QCT) is expensive and requires high radiation exposure. This study compared the two techniques and evaluated serum biochemical parameters for prediction of bone loss. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This prospective study enrolled patients from dialysis centers throughout Kentucky. BMD of the spine and hip was measured at baseline and after 1 year by DXA and QCT. Customary and novel serum biochemical parameters were obtained at the same times, including calcium, phosphorus, whole and intact parathyroid hormone, bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide, tartrate-resistant acid phosphatase-5b, Dickkopf-1, fibroblast growth factor, and sclerostin. Rates of detection of osteoporosis by DXA and QCT were compared. Correlations were calculated between baseline biochemical parameters and BMD at baseline and changes over 1 year. Multivariable regression was performed to adjust for age, sex, body mass index, and race. RESULTS: Eighty-one patients completed the study (mean age=52.6 +/- 12.3 years, 56% men, 53% African American, and median dialysis vintage=41 months). At baseline, QCT and DXA of the spine identified similar rates of osteoporosis (13.6% and 13.6%), but at the hip, DXA identified more osteoporosis (22.2% versus 13.6%). At any site and by either method, 33.3% of the patients were osteoporotic. Baseline BMD correlated with sclerostin, intact parathyroid hormone, bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase-5b, and fibroblast growth factor. At 1 year, hip QCT identified a higher number of patients experiencing bone loss (51.3%) than DXA (38.5%). After multivariable adjustment, baseline sclerostin and tartrate-resistant acid phosphatase-5b predicted bone loss measured by QCT of the hip; procollagen type 1 N-terminal propeptide predicted cortical spine bone gain by QCT. CONCLUSIONS: QCT identified prospectively more bone loss at the hip than DXA. The baseline serum biochemical parameters sclerostin and tartrate-resistant acid phosphatase-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis. PMID- 24948146 TI - Current management of migraine in US emergency departments: an analysis of the National Hospital Ambulatory Medical Care Survey. AB - BACKGROUND: Published data from 1998 revealed that most patients treated for migraine in an emergency department received opioids. Over the intervening years, a large body of evidence has emerged demonstrating the efficacy and safety of non opioid alternatives. Expert opinion during these years has cautioned against use of opioids for migraine. Our objectives were to compare current frequency of use of various medications for acute migraine in US emergency departments with use of these same medications in 1998 and to identify factors independently associated with opioid use. METHODS: We analyzed National Hospital Ambulatory Medical Care Survey data from 2010, the most current dataset available. The National Hospital Ambulatory Medical Care Survey is a public dataset collected and distributed by the Centers for Disease Control and Prevention. It is a multi-stage probability sample from randomly selected emergency departments across the country, designed to be representative of all US emergency department visits. We included in our analysis all patients with the ICD9 emergency department discharge diagnosis of migraine. We tabulated frequency of use of specific medications in 2010 and compared these results with the 1998 data. Using a logistic regression model, into which all of the following variables were entered, we explored the independent association between any opioid use in 2010 and sex, age, race/ethnicity, geographic region, type of hospital, triage pain score and history of emergency department use within the previous 12 months. RESULTS: In 2010, there were 1.2 (95% confidence interval 0.9, 1.4) million migraine visits to US emergency departments. Including opioid-containing oral analgesic combinations, opioids were administered in 59% of visits (95% confidence interval 51, 67). The most commonly used parenteral agent, hydromorphone, was used in 25% (95% confidence interval 19, 33) of visits in 2010 versus less than 1% (95% confidence interval 0, 3) in 1998. Conversely, use of meperidine had decreased markedly over the same timeframe. In 2010, it was used in just 7% (95% confidence interval 4, 12) of visits compared to 37% (95% confidence interval 29, 45) in 1998. Metoclopramide, the most commonly used anti-dopaminergic, was administered in 17% (95% confidence interval 12, 23) of visits in 2010 and 3% (95% confidence interval 1, 6) of visits in 1998. Use of any triptan was relatively uncommon in 2010 (7% (95% confidence interval 4, 11) of visits) and in 1998 (10% (95% confidence interval 6, 15) of visits). Of the predictor variables listed above, only emergency department use within the previous 12 months was associated with opioid administration (adjusted odds ratio: 2.87 (95% confidence interval 1.03, 7.97)). CONCLUSIONS: In spite of recommendations to the contrary, opioids are still used in more than half of all emergency department visits for migraine. Though use of meperidine has decreased markedly between 1998 and 2010, it has largely been replaced by hydromorphone. Opioid use in migraine visits is independently associated with prior visits to the same emergency department in the previous 12 months. PMID- 24948145 TI - Epigenetic regulation of the secreted frizzled-related protein family in human glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) are intracranial tumors of the central nervous system and the most lethal among solid tumors. Current therapy is palliative and is limited to surgical resection followed by radiation therapy and temozolomide treatment. Aberrant WNT pathway activation mediates not only cancer cell proliferation but also promotes radiation and chemotherapeutic resistance. WNT antagonists such as the secreted frizzled-related protein (sFRP) family have an ability to sensitize glioma cells to chemotherapeutics, decrease proliferation rate and induce apoptosis. During tumor development, sFRP genes (1-5) are frequently hypermethylated, causing transcriptional silencing. We investigated a possible involvement of methylation-mediated silencing of the sFRP gene family in human GBM using four human glioblastoma cell lines (U87, U138, A172 and LN18). To induce demethylation of the DNA, we inhibited DNA methyltransferases through treatment with 5-azacytidine. Genomic DNA, RNA and total protein were isolated from GBM cells before and after treatment. We utilized bisulfite modification of genomic DNA to examine the methylation status of the respective sFRP promoter regions. Pharmacological demethylation of the GBM cell lines demonstrated a loss of methylation in sFRP promoter regions, as well as an increase in sFRP gene specific mRNA abundance. Western blot analysis demonstrated an increased protein expression of sFRP-4 and increased levels of phosphorylated-beta-catenin. These data indicate an important role of methylation-induced gene silencing of the sFRP gene family in human GBM. PMID- 24948147 TI - Letter from the editors. PMID- 24948148 TI - Letter from the guest editor: update in cardiovascular nuclear medicine. PMID- 24948149 TI - New cardiac cameras: single-photon emission CT and PET. AB - Nuclear cardiology instrumentation has evolved significantly in the recent years. Concerns about radiation dose and long acquisition times have propelled developments of dedicated high-efficiency cardiac SPECT scanners. Novel collimator designs, such as multipinhole or locally focusing collimators arranged in geometries that are optimized for cardiac imaging, have been implemented to enhance photon-detection sensitivity. Some of these new SPECT scanners use solid state photon detectors instead of photomultipliers to improve image quality and to reduce the scanner footprint. These new SPECT devices allow dramatic up to 7 fold reduction in acquisition times or similar reduction in radiation dose. In addition, new hardware for photon attenuation correction allowing ultralow radiation doses has been offered by some vendors. To mitigate photon attenuation artifacts for the new SPECT scanners not equipped with attenuation correction hardware, 2-position (upright-supine or prone-supine) imaging has been proposed. PET hardware developments have been primarily driven by the requirements of oncologic imaging, but cardiac imaging can benefit from improved PET image quality and improved sensitivity of 3D systems. The time-of-flight reconstruction combined with resolution recovery techniques is now implemented by all major PET vendors. These new methods improve image contrast and image resolution and reduce image noise. High-sensitivity 3D PET without interplane septa allows reduced radiation dose for cardiac perfusion imaging. Simultaneous PET/MR hybrid system has been developed. Solid-state PET detectors with avalanche photodiodes or digital silicon photomultipliers have been introduced, and they offer improved imaging characteristics and reduced sensitivity to electromagnetic MR fields. Higher maximum count rate of the new PET detectors allows routine first-pass Rb 82 imaging, with 3D PET acquisition enabling clinical utilization of dynamic imaging with myocardial flow measurements for this tracer. The availability of high-end CT component in most PET/CT configurations enables hybrid multimodality cardiac imaging protocols with calcium scoring or CT angiography or both. PMID- 24948150 TI - Advances in cardiac processing software. AB - New software methods that incorporate iterative reconstruction, resolution recovery, and noise compensation now provide the ability to maintain or improve myocardial perfusion SPECT image quality with conventional sodium iodide cameras. Despite lower image counting statistics associated with significantly decreased injected radiopharmaceutical doses or shortened acquisition times or both, image quality is preserved or even improved compared with conventional processing methods. The ability to prescribe a desired myocardial count density by preselecting a SPECT acquisition time now avoids additional patient radiation exposure associated with "weight-based" dosing. More recent advancements, including temporal correlation among the gated perfusion frames and higher resolution SPECT acquisitions, hold promise to further improve image quality and diagnostic accuracy. Phase analysis of gated perfusion SPECT provides the ability to assess cardiac dyssynchrony and to select those patients who will most benefit from resynchronization therapy. In combination with the higher counting statistics afforded by the new solid-state dedicated cardiac cameras, these software advancements allow for even further decreased patient radiation doses or acquisition times or both. List-mode software allows for refinement of myocardial perfusion SPECT by interrogating particular data from selected cardiac cycles. Rejection of frames degraded by arrhythmic cardiac cycles or excessive extracardiac uptake can be excluded for reconstruction. Respiratory gating, which diminishes cardiac motion and potentially decreases diaphragmatic attenuation, has been demonstrated to improve diagnostic specificity. With high-count first pass list-mode acquisitions at rest and during pharmacologic vasodilatation, it may be possible to measure global and regional myocardial perfusion reserve to more accurately diagnose coronary artery disease and avoid false-negative studies owing to balanced ischemia. PMID- 24948151 TI - Quantitative assessment of myocardial blood flow--clinical and research applications. AB - Myocardial perfusion imaging with SPECT/CT or with PET/CT is a mainstay in clinical practice for the diagnostic assessment of downstream, flow-limiting effects of epicardial lesions during hyperemic flows and for risk stratification of patients with known or suspected coronary artery disease (CAD). In patients with multivessel CAD, the relative distribution of radiotracer uptake in the left ventricular myocardium during stress and rest accurately identifies flow-limiting epicardial lesions or the most advanced, so called culprit, lesion. Often, less severe obstructive CAD lesions may go undetected or underdiagnosed. The concurrent ability of PET/CT with radiotracer kinetic modeling to determine myocardial blood flow (MBF) in absolute terms (mL/g/min) at rest and during vasomotor stress allows the computation of regional myocardial flow reserve (MFR) as an adjunct to the visual interpretation of myocardial perfusion studies. Adding the noninvasive evaluation and quantification of MBF and MFR by PET imaging to the visual analysis of myocardial perfusion may (1) identify subclinical CAD, (2) better characterize the extent and severity of CAD burden, and (3) assess "balanced" decreases of MBF in all 3 major coronary artery vascular territories. Recent investigations have demonstrated that PET-determined reductions in hyperemic MBF or MFR in patients with subclinical or clinically manifest CAD are predictive of increased relative risk of future cardiovascular events and clinical outcome. Quantifying MFR with PET enables the identification and characterization of coronary vasodilator dysfunction as functional precursor of the CAD process, which offers the unique opportunity to monitor its response to lifestyle or risk factor modification by preventive medical care. Whether an improvement or even normalization of hyperemic MBF or the MFR in subclinical or in clinically manifest CAD confers an improved long-term cardiovascular outcome remains untested. Nonetheless, given the recent growth in the clinical utilization of myocardial perfusion PET, image-guided and personalized preventive care of vascular health may become a reality in the near future. PMID- 24948152 TI - Cardiac radionuclide imaging to assess patients with heart failure. AB - Heart failure (HF) is a major problem, with a high prevalence, morbidity, mortality, and cost, and is expected to become more widespread. Radionuclide imaging currently plays an important role in evaluating these patients, with much potential for increased utility. Myocardial perfusion imaging (MPI) with radiotracers is commonly used to differentiate an ischemic from a nonischemic etiology of HF and cardiomyopathy. In some instances, MPI effectively distinguishes among these, but often, standard MPI is deficient in that a nonischemic cardiomyopathy can have focal defects in tracer uptake and coronary artery disease with global balanced ischemia can result in a normal-appearing perfusion pattern. Developments in measuring quantitative blood flow promise to provide a more accurate determination of HF etiology. If coronary artery disease is established, MPI has long established use for assessment of myocardial viability and identification of patients likely to benefit from revascularization. Although a recent multicenter trial substudy has questioned the benefits of viability imaging, specific limitations of this study must be balanced against previously demonstrated utility. At the same time, viability imaging may need to be directed more skillfully toward carefully selected patients. In patients with HF who are not candidates for revascularization, myocardial remodeling often leads to poor patient outcome. Newer nuclear analyses of myocardial shape and of dyssynchronous contraction or relaxation can risk stratify patients and may help guide therapy. Investigative molecular imaging techniques promise to better understand underlying pathophysiology and guide therapy on an individual basis. Finally, recent approval of a tracer for cardiac autonomic innervation imaging should greatly expand the use of radionuclide imaging in HF, potentially guiding proper use of life saving but expensive and high-risk mechanical therapies. Given the molecular basis of much of the pathophysiology of HF, the contribution of cardiac radionuclide imaging to improve patient care should increase. PMID- 24948153 TI - Left ventricular dyssynchrony assessment using myocardial single-photon emission CT. AB - Myocardial SPECT using standard procedure for perfusion imaging and phase analysis is a novel approach to left ventricular dyssynchrony assessment. Preliminary data suggest excellent repeatability and potential utility for guiding cardiac resynchronization therapy and elucidating mechanisms. PMID- 24948154 TI - Clinical decision making with myocardial perfusion imaging in patients with known or suspected coronary artery disease. AB - Myocardial perfusion imaging (MPI) to diagnose coronary artery disease (CAD) is best performed in patients with intermediate pretest likelihood of disease; unfortunately, pretest likelihood is often overestimated, resulting in the inappropriate use of perfusion imaging. A good functional capacity often predicts low risk, and MPI for diagnosing CAD should be reserved for individuals with poor exercise capacity, abnormal resting electrocardiography, or an intermediate or high probability of CAD. With respect to anatomy-based testing, coronary CT angiography has a good negative predictive value, but stenosis severity correlates poorly with ischemia. Therefore decision making with respect to revascularization may be limited when a purely noninvasive anatomical test is used. Regarding perfusion imaging, the diagnostic accuracies of SPECT, PET, and cardiac magnetic resonance are similar, though fewer studies are available with cardiac magnetic resonance. PET coronary flow reserve may offer a negative predictive value sufficiently high to exclude severe CAD such that patients with mild to moderate reversible perfusion defects can forego invasive angiography. In addition, combined anatomical and perfusion-based imaging may eventually offer a definitive evaluation for diagnosing CAD, even in higher risk patients. Any remarkable findings on single-photon emission computed tomography and PET MPI studies are valuable for prognostication. Furthermore, assessment of myocardial blood flow with PET is particularly powerful for prognostication as it reflects the end result of many processes that lead to atherosclerosis. Decision making with respect to revascularization is limited for cardiac MRI and PET MPI. In contrast, retrospective radionuclide studies have identified an ischemic threshold, but randomized trials are needed. In patients with at least moderately reduced left ventricular systolic function, viable myocardium as assessed by PET or MRI, appears to identify patients who benefit from revascularization, but well executed randomized trials are lacking. PMID- 24948155 TI - Perceiving emotions in neutral faces: expression processing is biased by affective person knowledge. AB - According to a widely held view, basic emotions such as happiness or anger are reflected in facial expressions that are invariant and uniquely defined by specific facial muscle movements. Accordingly, expression perception should not be vulnerable to influences outside the face. Here, we test this assumption by manipulating the emotional valence of biographical knowledge associated with individual persons. Faces of well-known and initially unfamiliar persons displaying neutral expressions were associated with socially relevant negative, positive or comparatively neutral biographical information. The expressions of faces associated with negative information were classified as more negative than faces associated with neutral information. Event-related brain potential modulations in the early posterior negativity, a component taken to reflect early sensory processing of affective stimuli such as emotional facial expressions, suggest that negative affective knowledge can bias the perception of faces with neutral expressions toward subjectively displaying negative emotions. PMID- 24948156 TI - Neural patterns underlying social comparisons of personal performance. AB - Humans often evaluate their abilities by comparing their personal performance with that of others. For this process, it is critical whether the comparison turns out in one's favor or against it. Here, we investigate how social comparisons of performance are encoded and integrated on the neural level. We collected functional magnetic resonance images while subjects answered questions in a knowledge quiz that was related to their profession. After each question, subjects received a feedback about their personal performance, followed by a feedback about the performance of a reference group who had been quizzed beforehand. Based on the subjects' personal performance, we divided trials in downward and upward comparisons. We found that upward comparisons correlated with activity in the dorsolateral prefrontal cortex and the anterior insula. Downward comparisons were associated with increased activation in the ventral striatum (VS), the medial orbitofrontal cortex and the ventral anterior cingulate cortex (ACC). The extent to which subjects outperformed the reference group modulated the activity in the VS and in the dorsal ACC. We suggest that the co-activation of the VS and the dorsal ACC contributes to the integration of downward comparisons into the evaluation of personal performance. PMID- 24948159 TI - Reducing CO2 to methanol using frustrated Lewis pairs: on the mechanism of phosphine-borane-mediated hydroboration of CO2. AB - The full mechanism of the hydroboration of CO2 by the highly active ambiphilic organocatalyst 1-Bcat-2-PPh2-C6H4 (Bcat = catecholboryl) was determined using computational and experimental methods. The intramolecular Lewis pair was shown to be involved in every step of the stepwise reduction. In contrast to traditional frustrated Lewis pair systems, the lack of steric hindrance around the Lewis basic fragment allows activation of the reducing agent while moderate Lewis acidity/basicity at the active centers promotes catalysis by releasing the reduction products. Simultaneous activation of both the reducing agent and carbon dioxide is the key to efficient catalysis in every reduction step. PMID- 24948158 TI - Recurrent wheezing 36 months after bronchiolitis is associated with rhinovirus infections and blood eosinophilia. AB - AIM: Links between respiratory syncytial virus bronchiolitis and asthma are well known, but few studies have dealt with wheezing following bronchiolitis induced by other viruses. We assessed the risk factors for recurrent wheezing in infants hospitalised for acute viral bronchiolitis. METHODS: We followed 313 infants for three years after they were hospitalised for bronchiolitis, caused by 14 different viruses, to identify risk factors for recurrent wheezing. Parents provided feedback on wheezing episodes during telephone interviews 12 (n = 266), 24 (n = 242) and 36 (n = 230) months after hospitalisation. RESULTS: The frequency of wheezing episodes diminished during the follow-up period: 137 children (51.7%) at 12 months, 117 (48.3%) at 24 months and 93 (40.4%) at 36 months. The risk of wheeze after three years was OR = 7.2 (95% CI 3.9-13.3) if they had episodes of wheezing during the first year after bronchiolitis, 16.8 (8.7-32.7) if they had episodes of wheezing during the second year and 55.0 (22.7 133.2) if they wheezed during both years. Blood eosinophils >400 cells/MUL (OR 7.7; CI 1.4-41.8) and rhinovirus infections (3.1; 1.0-9.4) were the major risk factors for recurrent wheezing. CONCLUSION: Recurrent wheezing 36 months after infant bronchiolitis was associated with rhinoviruses and blood eosinophilia. PMID- 24948157 TI - Reward for food odors: an fMRI study of liking and wanting as a function of metabolic state and BMI. AB - Brain reward systems mediate liking and wanting for food reward. Here, we explore the differential involvement of the following structures for these two components: the ventral and dorsal striatopallidal area, orbitofrontal cortex (OFC), anterior insula and anterior cingulate. Twelve healthy female participants were asked to rate pleasantness (liking of food and non-food odors) and the desire to eat (wanting of odor-evoked food) during event-related functional magnetic resonance imaging (fMRI). The subjective ratings and fMRI were performed in hunger and satiety states. Activations of regions of interest were compared as a function of task (liking vs wanting), odor category (food vs non-food) and metabolic state (hunger vs satiety). We found that the nucleus accumbens and ventral pallidum were differentially involved in liking or wanting during the hunger state, which suggests a reciprocal inhibitory influence between these structures. Neural activation of OFC subregions was correlated with either liking or wanting ratings, suggesting an OFC role in reward processing magnitude. Finally, during the hunger state, participants with a high body mass index exhibited less activation in neural structures underlying food reward processing. Our results suggest that food liking and wanting are two separable psychological constructs and may be functionally segregated within the cortico-striatopallidal circuit. PMID- 24948160 TI - Star-shape redox-responsive PEG-sheddable copolymer of disulfide-linked polyethylene glycol-lysine-di-tocopherol succinate for tumor-triggering intracellular doxorubicin rapid release: head-to-head comparison. AB - A redox-responsive poly(ethylene glycol) (PEG)-sheddable copolymer of disulfide linked PEG 5000-lysine-di-tocopherol succinate (P(5k)SSLV) is developed which can self-assemble into nanomicelles in aqueous condition and trigger the rapid release of encapsulated drugs within tumor cells. The reduction-insensitive doxorubicin (DOX)-loaded P(5k)LV (P(5k)LV-DOX) nanomicelles are further prepared. Then head-to-head comparison of P(5k)SSLV-DOX, P(5k)LV-DOX and DOX-Sol is performed concerning in vitro release, cytotoxicity, cellular uptake and apoptosis. Results show that P(5k)SSLV-DOX nanomicelles have a faster DOX release, a higher anti-tumor activity and more DOX concentrating in the nucleus than P(5k)LV-DOX nanomicelles. In conclusion, the redox-responsive P(5k)SSLV nanomicelles might hold a great potential to improve chemotherapy by tumor triggering intracellular rapid release. The outcomes of this study also address the significance of such head-to-head comparison studies in translational research of nanomedicine. PMID- 24948161 TI - Common variants in BDNF, FAIM2, FTO, MC4R, NEGR1, and SH2B1 show association with obesity-related variables in Spanish Roma population. AB - OBJECTIVES: The objective of this study is to investigate the association between previously GWAS identified genetic variants predisposing to obesity in Europeans and obesity-related phenotypes in Roma population. METHODS: A total of 24 representative single nucleotide polymorphisms (SNPs) were genotyped in 372 individuals belonging to 50 extended families of Roma population. SNPs were tested for association with seven quantitative obesity-related phenotypes in the PLINK program. RESULTS: Risk variants in NEGR1, FAIM2, FTO, and SH2B1 genes were associated with increased adiposity accumulation in Roma population with effect sizes between 0.21 and 0.34 Z-scores for each copy of the BMI increasing allele. Additionally, variants in BDNF and MC4R were significantly associated with adiposity distribution but not with overall fatness. No significant association was detected between obesity-related phenotypes and variants in the first intron of the FTO gene (e.g., rs9939609). CONCLUSIONS: The results of this study suggest that SNPs in or near six genes (BDNF, FAIM2, FTO, MC4R, NEGR1, and SH2B1) are significantly associated with body fat accumulation and distribution in Roma people. However, the association observed among variants in the first intron of FTO and obesity in European derived populations is not evident in the analyzed Roma sample. PMID- 24948162 TI - Primates kept as pets: EFRACom calls for more data. PMID- 24948163 TI - TB controls: partial derestrictions to end in October. PMID- 24948164 TI - Defra seeks views on strengthening TB controls applied to cattle. PMID- 24948165 TI - Defra responds to BVA's e-petition on non-stun slaughter. PMID- 24948166 TI - FAO calls for more surveillance and research on MERS. PMID- 24948167 TI - National Sheep Association calls for reform of TSE legislation. PMID- 24948168 TI - Teaching fellowship for RVC lecturer. PMID- 24948169 TI - Collaboration to fight vector-borne diseases. PMID- 24948170 TI - RCVS to clarify its guidance on 24/7 emergency care. PMID- 24948171 TI - Unfortunate timing . . . AB - While researching a different subject in the archives of the RCVS, Bruce Vivash Jones discovered a box of pristine badges for the 10th International Veterinary Congress, which was to have been held in London in August 1914. Intrigued by why the badges were unused, he began to investigate the history of the congress. Reading official transcripts and contemporaneous news reports revealed how, despite meticulous planning and determined fundraising, the congress was overtaken by events. PMID- 24948172 TI - Disseminated idiopathic skeletal hyperostosis: diagnostic criteria and clinical significance. PMID- 24948173 TI - Vaccination against bluetongue. PMID- 24948174 TI - Availability of adder antivenom. PMID- 24948175 TI - Ritual slaughter. PMID- 24948177 TI - Primates as pets. PMID- 24948178 TI - Synthesis and characterization of bisoxazolines- and pybox-copper(II) complexes and their application in the coupling of alpha-carbonyls with functionalized amines. AB - Binuclear complexes [{(DMOX)CuCl}2(MU-Cl)2] (1), mononuclear complexes [(DMOX)CuBr2] (2) (DMOX = 4,5-dihydro-2-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-4,4 dimethyloxazole) and the pybox Cu(II) complex [(Dm-Pybox)CuBr2] (3) (Dm-Pybox = 2,6-bis[4',4'-dimethyloxazolin-2'-yl]pyridine) were obtained by reactions of CuX2 (X = Cl, Br) with DMOX and Dm-Pybox ligands, respectively. The molecular structures of 1, 2 and 3 have been determined by single-crystal X-ray diffraction analyses. The complexes 2 and 3 are efficient in catalyzing alpha-amination of ketones and esters through alpha-bromo carbonyl intermediate. The procedures are environmentally benign methods using molecular oxygen as an oxidant with water as the only byproduct. PMID- 24948180 TI - Seismic, satellite, and site observations of internal solitary waves in the NE South China Sea. AB - Internal solitary waves (ISWs) in the NE South China Sea (SCS) are tidally generated at the Luzon Strait. Their propagation, evolution, and dissipation processes involve numerous issues still poorly understood. Here, a novel method of seismic oceanography capable of capturing oceanic finescale structures is used to study ISWs in the slope region of the NE SCS. Near-simultaneous observations of two ISWs were acquired using seismic and satellite imaging, and water column measurements. The vertical and horizontal length scales of the seismic observed ISWs are around 50 m and 1-2 km, respectively. Wave phase speeds calculated from seismic observations, satellite images, and water column data are consistent with each other. Observed waveforms and vertical velocities also correspond well with those estimated using KdV theory. These results suggest that the seismic method, a new option to oceanographers, can be further applied to resolve other important issues related to ISWs. PMID- 24948181 TI - Evaluation of a depression screening and treatment program in primary care for patients with diabetes mellitus: insights and future directions. AB - PURPOSE: To evaluate a collaborative depression care program by assessing adherence to the program by internal medicine clinic (IMC) staff, and the program's effectiveness in treating depression in patients with diabetes mellitus. We also describe the rate of depression among patients with diabetes in the IMC. DATA SOURCES: Data for this program were obtained from a de-identified disease registry and included 1312 outpatient IMC visits in adult patients with diabetes between March 2011 and September 2011. CONCLUSIONS: Collaborative depression care results in high rates of screening for and identification of depression, high rates of antidepressant utilization, and improved depression scores; however, more focused interventions are needed to improve diabetes outcomes in patients with depression and diabetes. IMPLICATIONS FOR PRACTICE: The results indicate that the multidisciplinary IMC staff can work together with patients to identify and monitor depression within primary care. This study provides valuable information about models of depression care that can be implemented and evaluated in a clinical setting. PMID- 24948179 TI - Glutathione S-transferase M1 null genotype meta-analysis on gastric cancer risk. AB - BACKGROUND: Glutathione S-transferases (GSTs) have proved to be involved in the detoxifying several carcinogens and may play an important role in carcinogenesis of cancer. Previous studies on the association between Glutathione S-transferase M1 (GSTM1) polymorphism and gastric cancer (GC) risk reported inconclusive results. To get a precise result, we conducted this present meta-analysis through pooling all eligible studies. METHODS: A comprehensive databases of Pubmed, Embase, Web of Science, and the Chinese Biomedical Database (CBM) were searched for case-control studies investigating the association between GSTM1 null genotype and GC risk. Odds ratios (OR) and 95% confidence intervals (95% CI) were used to assess this possible association. A chi2-based Q-test was used to examine the heterogeneity assumption. Begg's and Egger's test were used to examine the potential publication bias. The leave-one-out sensitivity analysis was conducted to determine whether our assumptions or decisions have a major effect on the results of present work. Statistical analyses were performed with the software program STATA 12.0. RESULTS: A total of 47 eligible case-control studies were identified, including 6,678 cases and 12,912 controls. Our analyses suggested that GSTM1 null genotype was significantly associated with increased risk of GC (OR=1.186, 95% CI=1.057-1.329, Pheterogenetiy=0.000, P=0.004). Significant association was also found in Asians (OR=1.269, 95% CI=1.106-1.455, Pheterogenetiy=0.002, P=0.001). However, GSTM1 null genotype was not contributed to GC risk in Caucasians (OR=1.115, 95% CI=0.937-1.326, Pheterogenetiy=0.000, P=0.222). In the subgroup analysis stratified by sources of controls, significant association was detected in hospital-based studies (OR=1.355, 95% CI=1.179-1.557, Pheterogenetiy=0.001, P=0.000), while there was no significant association detected in population-based studies (OR=1.017, 95% CI=0.862-1.200, Pheterogenetiy=0.000, P=0.840). CONCLUSION: This meta-analysis showed the evidence that GSTM1 null genotype contributed to the development of GC. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1644180505119533. PMID- 24948182 TI - Type 1 diabetes mellitus and asthma: A follow-up study. PMID- 24948183 TI - Methacholine challenge test by wheezing and oxygen saturation in preschool children with asthma. AB - Methacholine challenge test (MCT) performed with spirometry is a commonly used test to evaluate bronchial hyperreactivity (BHR) in children. However, preschoolers do not usually collaborate. OBJECTIVES: To assess the usefulness of MCT through clinical evaluation (wheezing auscultation and decreased pulse arterial oxygen saturation [SpO2]) in recurrent wheezing preschoolers with asthma, in comparison to healthy controls. METHODS: We performed the MCT (modified Cockroft method) on healthy and on asthmatic preschoolers. The end point was determined by the presence of wheezing in the chest and/or tracheal auscultation (PCw) and/or a decrease in SpO2 of >=5 from the baseline value (PCSpO2). Maximal methacholine concentration was 8 mg/ml. RESULTS: The study population comprised 65 children: 32 healthy and 33 asthmatic children. There were no differences in demographic characteristics between the groups. The median methacholine doses for PCw and for PCSpO2 were significantly lower among asthmatic than healthy children: 0.5 mg/ml (0.25-0.5 mg/ml) vs. 2 mg/ml (1-4 mg/ml), respectively, p<0.001; and 0.25 mg/ml (0.25-0.5 mg/ml) and 2 mg/ml (0.5-4 mg/ml), respectively, p<0.001. The best cut-off point of PCw was observed at a methacholine concentration of 0.5 mg/ml (AUC=0.72 [95% CI=0.66-0.77]), its sensitivity was 91%, specificity 43%, PPV 16% and NPV 98%. For PCSpO2 the best cut-off point was a methacholine concentration of 1 mg/ml (AUC=0.85 [95% CI 0.81 0.89]), with sensitivity of 80%, specificity 74%, PPV 49%, and NPV 92%. There were no adverse reactions. CONCLUSION: MCT using clinical parameters such as wheezing auscultation and SpO2 measurement could be a useful and safe test to confirm BHR among preschoolers. PMID- 24948184 TI - Utility of bronchodilator response for asthma diagnosis in Latino preschoolers. AB - BACKGROUND: Asthma diagnosis in preschoolers is mostly based on clinical evidence, but a bronchodilator response could be used to help confirm the diagnosis. The objective of this study is to evaluate the utility of bronchodilator response for asthma diagnosis in preschoolers by using spirometry standardised for this specific age group. METHODS: A standardised spirometry was performed before and after 200 mcg of salbutamol in 64 asthmatics and 32 healthy control preschoolers in a case-control design study. RESULTS: The mean age of the population was 4.1 years (3-5.9 years) and 60% were females. Almost 95% of asthmatics and controls could perform an acceptable spirometry, but more asthmatics than controls reached forced expiratory volume in one second (FEV1) (57% vs. 23%, p=0.033), independent of age. Basal flows and FEV1 were significantly lower in asthmatics than in controls, but no difference was found between groups in forced vital capacity (FVC) and FEV in 0.5s (FEV0.5). Using receiver operating characteristic (ROC) curves, the variable with higher power to discriminate asthmatics from healthy controls was a bronchodilator response (% of change from basal above the coefficient of repeatability) of 25% in forced expiratory flow between 25% and 75% (FEF25-75) with 41% sensitivity, 80% specificity. The higher positive likelihood ratio for asthma equalled three for a bronchodilator response of 11% in FEV0.5 (sensitivity 30%, specificity 90%). CONCLUSIONS: In this sample of Chilean preschoolers, spirometry had a very high performance and bronchodilator response was very specific but had low sensitivity to confirm asthma diagnosis. PMID- 24948185 TI - The correlation between parental education and their knowledge of asthma. AB - OBJECTIVE: To evaluate the impact of parental education on the success of Asthma Educational Intervention (AEI). METHODS: AEI took place after the children's hospitalisation. Parental asthma knowledge was assessed at three time points: before AEI, immediately after, and 12 months later. The Intervention (I) group of parents (N=231) received complete AEI. The Control (C) group of parents (N=71) received instructions for proper use of asthma medications and the handbook. RESULTS: Asthma knowledge in I group increased immediately after the AEI (p<0.01), and had not changed (p>0.05) 12 months later. There were four subgroups in group I divided based on education level: elementary school, high school, college, and university degrees. Taking into account the parental education level, there were no differences in the baseline and final knowledge of asthma between subgroups (p>0.05). The number of asthma exacerbations decreased after AEI (5.96:2.50, p<0.01), regardless of the parental degree. Knowledge of asthma in group C did not improve during the study (p=0.17). Final asthma knowledge was higher in group I compared to group C (p<0.01). CONCLUSION: The parental education level did not influence the level of asthma knowledge after the AEI. The motivation and the type of asthma education had the greatest input on the final results. PRACTICE IMPLICATIONS: All parents should be educated about asthma regardless of their general education. PMID- 24948186 TI - Quality of sleep in allergic children and their parents. AB - BACKGROUND: Quality of sleep is essential for physical and mental health and influences the perception of the patient's well-being during the day. In patients with chronic allergic diseases sleep disorders may increase the severity of the condition, complicate the management and impair their quality of life. When children are concerned, their parents are also affected by the problem. We evaluated the presence of disrupted sleep in parents of children with atopic disorders, and its relationship with clinical features and the presence of disturbed sleep in children. METHODS: Parents of children suffering from allergic diseases were recruited from the Pediatric Allergy Units of Parma University. Evaluation of sleep in parents was based on the Pittsburg Sleep Quality Index (PSQI), while in children it was based on the Sleep Disturbance Scale for Children (SDSC). RESULTS: Of the 102 parents invited, 92 filled in the questionnaire. Only the questionnaires with more than a 95% completion rate were considered for analysis. PSQI mean score in parents was 6.6 (SD 2.6); 75.6% of them had a PSQI >= 5, indicating that most parents had a sleep quality perceived as bad. The PSQI >= 5 was more common in parents of children with asthma and rhinitis. In children, SDSC mean score was 42.1 (SD: 9.4); 62.3% had a total score >= 39. The quality of sleep in parents and children was significantly correlated (p<0.001). CONCLUSION: These findings make it apparent that an alteration of sleep in children can also affect the parents. Such effect further weighs the burden of respiratory allergy and needs to be considered in future studies. PMID- 24948187 TI - Prevalence and clinical profile of difficult-to-control severe asthma in children: results from pneumology and allergy hospital units in Spain. AB - BACKGROUND: Severe asthma is often poorly controlled and its prevalence in Spanish children is unknown. The aim was to determine the prevalence of difficult to-control severe asthma in children, the agreement of asthma control between physicians and Spanish Guidelines for Asthma Management (GEMA), and the health related quality of life (HRQoL) for children and parents. METHODS: Observational, cross-sectional, two-phase, multicentre study. In the first phase, all children who attended pneumology and allergy units during a three-month period were classified according to physicians' criteria as patients with: asthma, severe asthma, or difficult-to-control severe asthma. Patients aged 6-14 years with severe asthma (difficult-to-control or controlled) were included in the second phase. RESULTS: 12,376 asthmatic children were screened in the first phase. According to physicians' criteria, 8.8% (95% CI 8.3-9.3%) had severe asthma. Of these, 24.2% (95% CI, 21.7-26.8%) had difficult-to-control severe asthma. 207 patients with severe asthma (mean age 10.8 +/- 2.3 years; 61.4% male; mean of 5.5 +/- 3.4 years since asthma diagnosis) were included in the second phase. Compared to the patients with controlled asthma, children with difficult-to-control asthma had a higher number of exacerbations, emergency room or unscheduled primary care visits in the previous year (p<0.0001, all) and poor HRQoL (p<0.0001, both children and caregivers). 33.3% of patients with controlled asthma according to physicians' criteria were poorly controlled according to GEMA. CONCLUSIONS: Around one in four asthmatic children with severe disease had difficult-to control asthma, although one third was underestimated by physicians. Children with difficult-to-control severe asthma had a poor HRQoL that also affected their parents. PMID- 24948188 TI - Clinical, laboratory and imaging findings of the patients with disseminated bacilli Calmette-Guerin disease. AB - OBJECTIVES: In the present study, we reviewed 44 cases of disseminated BCG infection during a 10-year period in an Iranian referral children medical centre hospital. MATERIAL AND METHODS: In this study, all of the patients with clinical and laboratory findings that were compatible with a diagnosis of disseminated BCG were included. RESULTS: Through 10 years evaluation, 44 patients were found with disseminated BCG disease. Hepatomegaly and splenomegaly were seen in 68% and 66% of patients, respectively. Osteomyelitis was observed in 9% of our cases. Decrease in blood cells including anaemia, leucopoenia, neutropenia and thrombocytopenia were associated with more severe disease and even deaths. Moreover, 80% and 70% of patients who died had high level of C reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Among the dead patients, 80% had abnormal sonography. Thirty nine percent of patients had immunodeficiency, while more than half of the patients who died had no identified immunodeficiency. CONCLUSION: These findings confirm the need to do sonography as well as bone imaging immediately in all patients with BCGitis. Assessment of the inflammatory factors in order to predict the prognosis of the disease is recommended. Furthermore, complete blood count would provide important information and should perform in all patients with BCGitis. PMID- 24948189 TI - Timing isn't everything: A case of recurrent angio-oedema. PMID- 24948190 TI - Microwave spectroscopic observation of distinct electron solid phases in wide quantum wells. AB - In high magnetic fields, two-dimensional electron systems can form a number of phases in which interelectron repulsion plays the central role, since the kinetic energy is frozen out by Landau quantization. These phases include the well-known liquids of the fractional quantum Hall effect, as well as solid phases with broken spatial symmetry and crystalline order. Solids can occur at the low Landau filling termination of the fractional quantum Hall effect series but also within integer quantum Hall effects. Here we present microwave spectroscopy studies of wide quantum wells that clearly reveal two distinct solid phases, hidden within what in d.c. transport would be the zero diagonal conductivity of an integer quantum-Hall-effect state. Explanation of these solids is not possible with the simple picture of a Wigner solid of ordinary (quasi) electrons or holes. PMID- 24948191 TI - Identification of large intergenic non-coding RNAs in bovine muscle using next generation transcriptomic sequencing. AB - BACKGROUND: The advent of large-scale gene expression technologies has helped to reveal in eukaryotic cells, the existence of thousands of non-coding transcripts, whose function and significance remain mostly poorly understood. Among these non coding transcripts, long non-coding RNAs (lncRNAs) are the least well-studied but are emerging as key regulators of diverse cellular processes. In the present study, we performed a survey in bovine Longissimus thoraci of lincRNAs (long intergenic non-coding RNAs not overlapping protein-coding transcripts). To our knowledge, this represents the first such study in bovine muscle. RESULTS: To identify lincRNAs, we used paired-end RNA sequencing (RNA-Seq) to explore the transcriptomes of Longissimus thoraci from nine Limousin bull calves. Approximately 14-45 million paired-end reads were obtained per library. A total of 30,548 different transcripts were identified. Using a computational pipeline, we defined a stringent set of 584 different lincRNAs with 418 lincRNAs found in all nine muscle samples. Bovine lincRNAs share characteristics seen in their mammalian counterparts: relatively short transcript and gene lengths, low exon number and significantly lower expression, compared to protein-encoding genes. As for the first time, our study identified lincRNAs from nine different samples from the same tissue, it is possible to analyse the inter-individual variability of the gene expression level of the identified lincRNAs. Interestingly, there was a significant difference when we compared the expression variation of the 418 lincRNAs with the 10,775 known selected protein-encoding genes found in all muscle samples. In addition, we found 2,083 pairs of lincRNA/protein-encoding genes showing a highly significant correlated expression. Fourteen lincRNAs were selected and 13 were validated by RT-PCR. Some of the lincRNAs expressed in muscle are located within quantitative trait loci for meat quality traits. CONCLUSIONS: Our study provides a glimpse into the lincRNA content of bovine muscle and will facilitate future experimental studies to unravel the function of these molecules. It may prove useful to elucidate their effect on mechanisms underlying the genetic variability of meat quality traits. This catalog will complement the list of lincRNAs already discovered in cattle and therefore will help to better annotate the bovine genome. PMID- 24948192 TI - Percutaneous closure of an iatrogenic fistula from the left ventricle to the coronary sinus. AB - A patient with a history of rheumatic mitral valve disease and valve replacement in childhood presented with severe, persistent dyspnea. During an electrophyisiologic procedure, she was discovered to have a fistula from the left ventricle to the coronary sinus. She had severe pulmonary hypertension and elevated filling pressures, with a significant left-to-right shunt. Percutaneous closure of the fistula was performed using two vascular plugs. Subsequently the patient's hemodynamics improved and her symptoms subsided. Here, we describe the case and review the literature. PMID- 24948194 TI - Management of glia-mediated neuroinflammation and related patents. AB - Glia-mediated or glia-propagated inflammation, which acts as the central component in the progression of several brain diseases, is a milestone in the pathophysiological process contributing to the onset or progression of neurodegeneration. Excessive and prolonged neuroinflammation compromises cell and brain function, resulting in fatal brain anomalies. Glial research has garnered attention recently following breakthroughs in neuroinflammation-targeting therapeutics. Activation of microglia and astrocytes, and the attendant expression of proinflammatory cytokines and chemokines, is often associated with disease-, trauma-, and toxicant-induced damage to the central nervous system. A cause-and-effect relationship exists between neuroinflammation and neurotoxic outcomes. In clinical settings, pharmacological antagonists and immunosuppressive regimens can be used to prevent proinflammatory responses and attenuate subsequent neurotoxicity. Current research is focused on the exploration of existing drugs approved for other clinical purposes and on the development of novel synthetic compounds that may selectively downregulate neuroinflammation. The development of innovative therapeutic classes based on targeted selection of glial activation pathways and glia-mediated pathophysiology seems to be a promising approach, and may lead to more effective prevention and treatment of neuroinflammation and resulting maladies. This review focuses on recent patents and emerging therapeutics related to the management of glia-mediated neuroinflammation. PMID- 24948193 TI - Suppression of inflammatory and allergic responses by pharmacologically potent fungus Ganoderma lucidum. AB - Acute inflammation is the result of a complex signal transduction pathway that protects and heals our body and is necessary for our good health and normal wellbeing. Whereas, chronic inflammation can be correlated well with the onset of a plethora of autoimmune disorders; rheumatoid arthritis, systemic lupus and polymyalgia, rheumatic and other diseases like asthma, inflammatory bowel diseases, cardiovascular disorders, ulcerative colitis and Crohn's disease. Also, it has been reported to be associated with the onset of various cancers. An effective anti-inflammatory drug should be able to inhibit the development of chronic inflammation without interfering in normal homeostasis. A number of herbal drugs have been identified in the past that can target inflammatory cytokines. Among these, Ganoderma lucidum: a powerful medicinal mushroom has been found to possess immune-modulating and immune-potentiating capabilities and has been characterized as a wonder herb. This review mainly focuses on the molecular mechanism of anti-inflammatory and antiallergic action of this mushroom and also sheds light on various patent studies related to its pharmacological action. PMID- 24948195 TI - Arsenic immunotoxicity and immunomodulation by phytochemicals: potential relations to develop chemopreventive approaches. AB - Arsenic (As) contaminates drinking water worldwide, and As exposure, hypersensitivity and deficiency are involved in the immunopathogenesis of various health problems. Its chemoprevention thus has a high health impact. Given its oxidative potential, antioxidant compounds are good candidates to counteract arsenic's deleterious effects on humans. Phytochemicals (e.g., phenolics, carotenoids, etc.) act through free radical chelation activity and regulation of cellular targets. Consequently, they are appropriate for developing anti-As strategies derived from plants, and Argentinean flora is rich in useful species. Several molecular pathways involved in immune regulation are at the same time targets of exogenous agents, and oxidative stress itself is a modulating phenomenon of immunity. Since xenohormesis has been described as the organic enhancement of resistance to stress conditions (e.g., oxidation, pollution, etc.) by consuming xenobiotics, immunoxenohormesis implies also defense improvement. This review focuses on recent patents on the development of vegetable redox related immunomodulating agents, which might be applied in As-induced dysfunctions, with their scientific basis being reviewed. PMID- 24948196 TI - CEACAM2-L on spermatids interacts with poliovirus receptor on Sertoli cells in mouse seminiferous epithelium. AB - The removal of excess cytoplasm from elongated spermatids by Sertoli cells is the last essential step in spermatogenesis. It requires cell-to-cell recognition between a Sertoli cell and an elongating spermatid through protein-protein interactions. CEACAM2-L, an adhesion molecule of the immunoglobulin superfamily (IgSF), is present at the plasma membrane covering the excess cytoplasm of elongated spermatids, and is possibly involved in the cell-to-cell recognition. In this study, we investigated the interaction between CEACAM2-L and Poliovirus receptor (PVR), which is also from the IgSF and is expressed by Sertoli cells. Immunohistochemical analysis showed that CEACAM2-L expressed on elongated spermatids was in close contact with PVR-positive cell processes of Sertoli cells. Immunoprecipitation experiments both in vivo and in vitro demonstrated a direct heterophilic interaction between CEACAM2-L and PVR. We show that the N terminal Ig domain of CEACAM2-L was critical for its interaction with PVR. In addition, we found that CEACAM2-L formed heterophilic trans-tetramers with PVR in transfected COS-7 cells. From these data, we propose that Sertoli cells recognize the excess cytoplasm of elongated spermatids through the PVR-CEACAM2-L interaction in mouse testis. PMID- 24948197 TI - Anne D. Haffajee, D.D.S., 1947-2013. PMID- 24948199 TI - A general framework for time series data mining based on event analysis: application to the medical domains of electroencephalography and stabilometry. AB - There are now domains where information is recorded over a period of time, leading to sequences of data known as time series. In many domains, like medicine, time series analysis requires to focus on certain regions of interest, known as events, rather than analyzing the whole time series. In this paper, we propose a framework for knowledge discovery in both one-dimensional and multidimensional time series containing events. We show how our approach can be used to classify medical time series by means of a process that identifies events in time series, generates time series reference models of representative events and compares two time series by analyzing the events they have in common. We have applied our framework on time series generated in the areas of electroencephalography (EEG) and stabilometry. Framework performance was evaluated in terms of classification accuracy, and the results confirmed that the proposed schema has potential for classifying EEG and stabilometric signals. The proposed framework is useful for discovering knowledge from medical time series containing events, such as stabilometric and electroencephalographic time series. These results would be equally applicable to other medical domains generating iconographic time series, such as, for example, electrocardiography (ECG). PMID- 24948198 TI - Impaired decision-making under risk in individuals with alcohol dependence. AB - BACKGROUND: Alcohol dependence is associated with poor decision-making under ambiguity, that is, when decisions are to be made in the absence of known probabilities of reward and loss. However, little is known regarding decisions made by individuals with alcohol dependence in the context of known probabilities (decision under risk). In this study, we investigated the relative contribution of these distinct aspects of decision-making to alcohol dependence. METHODS: Thirty recently detoxified and sober asymptomatic alcohol-dependent individuals and 30 healthy control participants were tested for decision-making under ambiguity (using the Iowa Gambling Task[IGT]) and decision-making under risk (using the Cups Task and Coin Flipping Task). We also tested their capacities for working memory storage (digit span forward) and dual tasking (operation span task). RESULTS: Compared to healthy control participants, alcohol-dependent individuals made disadvantageous decisions on the IGT, reflecting poor decisions under ambiguity. They also made more risky choices on the Cups and Coin Flipping Tasks reflecting poor decision-making under risk. In addition, alcohol-dependent participants showed some working memory impairments, as measured by the dual tasking, and the degree of this impairment correlated with high-risk decision making, thus suggesting a relationship between processes subserving working memory and risky decisions. CONCLUSIONS: These results suggest that alcohol dependent individuals are impaired in their ability to decide optimally in multiple facets of uncertainty (i.e., both risk and ambiguity) and that at least some aspects of these deficits are linked to poor working memory processes. PMID- 24948200 TI - Is blood culture a reliable guide to diagnosing catheter-related bacteremia (CRB)? A case of CRB caused by fungi and seven types of bacteria in a hemodialysis patient. PMID- 24948201 TI - Does the KDIGO CKD risk stratification based on GFR and proteinuria predict kidney graft failure? AB - PURPOSE: The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines on chronic kidney disease (CKD) introduced risk classes for adverse outcome based on estimated glomerular filtration rate (eGFR) and albuminuria categories (low-LR, moderately-MR, high-HR, very high risk-VHR). We aimed to investigate if such risk stratification is suitable in kidney transplant (KTx) recipients. METHODS: This single-center prospective study enrolled 231 prevalent KTx recipients [36 (34-48) years, 62 % male, eGFR 53.7 (50.9-56.4) mL/min]. The patients were stratified in risk classes in January 2011; clinical and laboratory data were collected every 6 months till June 2013. Individual slope of linear regression of all eGFR and time averaged proteinuria (TAP) were computed. The composite endpoint was defined as >30 % decline in eGFR from 6 months after KTx to June 2013, dialysis initiation or death. RESULTS: Fifty-one patients reached the endpoint. They were younger, more often female, donor specific anti-HLA antibodies positive, noncompliant and smokers. TAP was 4 time greater (p < 0.0001) and eGFR abruptly declined [eGFR slope: -3.17 (-4.13 to -2.21) vs. 0.81 (0.45-1.3) mL/min per year, p < 0.0001] in the endpoint group. At baseline: 36 % LR, 23 % MR, 23 % HR and 18 % VHR, without differences between the groups. In the binary logistic regression model, VHR as compared to the other risk classes was an independent risk factor for poorer outcome. The final model also included female gender, cardiovascular events, smoking, GFR slope and BK virus infection. CONCLUSIONS: Risk group stratification according to KDIGO guideline on CKD may prove useful in predicting graft outcome, but this should be confirmed in larger cohorts. PMID- 24948202 TI - Preventing the progression of chronic kidney disease: two case reports and review of the literature. AB - A variety of therapeutic modalities are available to alter the abnormalities seen in patients with chronic kidney disease (CKD). A comprehensive plan can now be developed to slow the progression of CKD. Two clinical cases of delay in the need for renal replacement therapy are described. This delay was achieved by using recognized recommendations for optimal diabetes therapy (HbA1c target 7 %), goals for blood pressure levels, reduction of proteinuria, and the proper use of ACEI/ARB therapies. Recent recommendations include BP <140/90 mmHg for patients <60 years old and <150/90 mmHg for older patients unless they have CKD or diabetes. Limits on dietary sodium and protein intake and body weight reduction will decrease proteinuria. Proper treatment for elevated serum phosphorous and parathyroid hormone levels is now appreciated as well as the benefits of therapy for dyslipidemias and anemia. Concerns regarding unfavorable outcomes with excess ESA therapy have led to hemoglobin goals in the 10-12 g/dL range. Finally, new therapeutic considerations for the treatment of acidosis and hyperuricemia are presented with data available to suggest that increasing serum bicarbonate to >22 mmol/L is beneficial, while serum uric acid therapeutic goals are still uncertain. Also, two as yet insufficiently understood approaches to altering the course of CKD (FGF-23 level reduction and balancing gut microbiota) are noted. PMID- 24948203 TI - Impact of fatal cases on the epidemiology of traumatic spinal cord injury in Estonia. AB - BACKGROUND AND PURPOSE: Most epidemiological studies on traumatic spinal cord injury (TSCI) have not included patients who die before hospitalization. The aim of the research was to study the incidence of TSCI by including the individuals who die at the scene of the accident in addition to data retrieved from all hospitals in Estonia. METHODS: Medical records of patients with TSCI from all hospitals in Estonia from 2005 to 2007 were studied. With collaboration from the Estonian Forensic Science Institute the data of the victims of TSCI who died before hospitalization were included. RESULTS: From 2005 to 2007, 391 TSCI cases were identified: 183 patients were found retrospectively from medical records and 208 cases were detected from autopsy reports. Fifty-three per cent of patients died before hospitalization. The annual incidence rate was 97.0 per million population (95% confidence interval 87.4-106.6). The mean age at injury was 44.4 +/- 18.7 years. Motor vehicle accidents were the leading cause of TSCI amongst the individuals who died before hospitalization (75%). Falls accounted for the highest number of TSCIs (43%) amongst the patients who reached hospital. CONCLUSIONS: Our study shows that, when the cases that die at the scene of the accident are included, the incidence of TSCI in Estonia rises from 39.7 to 97.0 per million population. PMID- 24948205 TI - Prevalence of HTLV-I virus in blood donors and transfusion in Mali: Implications for blood safety. PMID- 24948204 TI - Evaluation of atazanavir and darunavir interactions with lipids for developing pH responsive anti-HIV drug combination nanoparticles. AB - We evaluated two human immunodeficiency virus (HIV) protease inhibitors, atazanavir (ATV) and darunavir (DRV), for pH-dependent solubility, lipid binding, and drug release from lipid nanoparticles (LNPs). Both ATV and DRV incorporated into LNPs composed of pegylated and non-pegylated phospholipids with nearly 100% efficiency, but only ATV-LNPs formed stable lipid-drug particles and exhibited pH dependent drug release. DRV-LNPs were unstable and formed mixed micelles at low drug-lipid concentrations, and thus are not suitable for lipid-drug particle development. When ATV-LNPs were prepared with ritonavir (RTV), a metabolic and cellular membrane exporter inhibitor, and tenofovir (TFV), an HIV reverse transcriptase inhibitor, stable, scalable, and reproducible anti-HIV drug combination LNPs were produced. Drug incorporation efficiencies of 85.5 +/- 8.2, 85.1 +/- 7.1, and 6.1 +/- 0.8% for ATV, RTV, and TFV, respectively, were achieved. Preliminary primate pharmacokinetic studies with these pH-responsive anti-HIV drug combination LNPs administered subcutaneously produced detectable plasma concentrations that lasted for 7 days for all three drugs. These anti-HIV LNPs could be developed as a long-acting targeted antiretroviral therapy. PMID- 24948206 TI - [Assessment of malaria screening management in blood donation control in the French Military Blood Institute]. AB - The French Military Blood Institute is responsible for the entire blood supply chain in the French Armed Forces. Considering, the high exposition rate of military to malaria risk, blood donation screening of plasmodium infection must be as efficient as possible. The main aim of our study was to assess our malaria testing strategy based on a single Elisa test compared with a two-step strategy implying immunofluorescence testing as confirmation test. The second goal was to describe characteristic of malaria Elisa positive donors. We conducted a prospective study: every malaria Elisa positive test was implemented by immunofluorescence testing and demographical data were recorded as usual by our medical software. We showed a significant risk of malaria ELISA positive tests among donor born in endemic area and we estimate the number of abusively 3-year rejected donors. However, based on our estimations, the two-step strategy is not relevant since the number of additionally collected blood products will be low. PMID- 24948208 TI - My vision for current problems in diagnostic radiology: 2014 and beyond. PMID- 24948207 TI - [Association of red blood cell and platelet allo-antibodies in platelet alloimmunized patients]. AB - PURPOSE OF THE STUDY: Use of matched red blood cell (RBC) concentrates is imperative in patients with RBC allo-antibodies (Abs) and when platelet (PLT) specific allo-Abs are present additional difficulties occur for PLT transfusions. In order to evaluate the prevalence of the PLT and RBC allo-Abs association, a study on patients with PLT specific allo-Acs was performed. This association is not a rare event. PATIENTS AND METHODS: In the database of a PLT immunohaematology laboratory, patients with PLT specific allo-Abs were selected and the presence and specificity of RBC allo-Abs was evaluated. RESULTS: Six hundred and eighty seven patients (673 females, 14 males) with PLT specific allo Abs were found. Six hundred and seventy-five patients (98.3%) had PLT specific allo-Abs with only one specificity. Anti-HPA-5b was the most frequent (539 cases). Twenty-nine (4.2%) patients had also RBC allo-Abs, including 27 females (93.1%) and two males. Seventy (58.6%) had RBC allo-Abs with only one specificity, 10 several and two unknown. Among the first, RBC allo-Abs directed against Rhesus blood group antigens were predominant (11 cases [64.7%]). Among the 29 patients with associated PLT and RBC allo-Abs, 15 (51.7%) were 50 or more years old and 14 (48.3%) under 50. CONCLUSION: In PLT specific alloimmunized patients, detection of RBC alloimmunization is not a rare event. When RBC and PLT transfusions are required, the supply of matched RBC and PLT concentrates is more difficult. PMID- 24948209 TI - Comparing the diagnostic accuracy of contrast-enhanced computed tomographic angiography and gadolinium-enhanced magnetic resonance angiography for the assessment of hemodynamically significant transplant renal artery stenosis. AB - To compare diagnostic accuracy of contrast-enhanced computed tomographic angiography (CTA) and gadolinium-enhanced magnetic resonance angiography (MRA) for the assessment of hemodynamically significant transplant renal artery stenosis (TRAS). After institutional review board approval, records of 27 patients with TRAS confirmed on digital subtraction angiography (DSA) were retrospectively reviewed. A total of 13 patients had MRA and 14 had CTA before DSA. Two board-certified fellowship-trained radiologists, one each from interventional radiology and body imaging blindly reviewed the DSA and CTA or MRA data, respectively. Sensitivity (SN), specificity (SP), positive predictive value, and negative predictive value of MRA and CTA were estimated using 50% stenosis as the detection threshold for significant TRAS. These parameters were compared between modalities using the Fisher exact test. Bias between MRA or CTA imaging and DSA was tested using the Wilcoxon signed-rank test. Two patients were excluded from the MRA group owing to susceptibility artifacts obscuring the TRAS. The correlation between MRA and DSA measurements of stenosis was r = 0.57 (95% CI:-0.02, 0.87; P = 0.052) and between CTA and DSA measurements was r = 0.63 (95% CI: 0.14, 0.87; P = 0.015); the difference between the 2 techniques was not significant (P = 0.7). Both imaging modalities tended to underestimate the degree of stenosis when compared with DSA. MRA group (SN and SP: 56% and 100%, respectively) and CTA group (SN and SP: 81% and 67%, respectively). There were no significant differences in detection performance between modalities (P>0.3 for all measures). We did not find that either modality had any advantage over the other in terms of measuring or detecting significant stenosis. Accordingly, MRA may be preferred over CTA after positive color Doppler ultrasound screening when not contraindicated owing to lack of ionizing radiation or nephrotoxic iodinated contrast. However, susceptibility of artifacts owing to surgical clips at the anastomosis may limit diagnostic utility of MRA as found in 2 of 13 patients. Trend towards no significant difference between the CTA and enhanced MRA in the detection of hemodynamically significant TRAS. PMID- 24948210 TI - Radiology peer-review feedback scorecards: optimizing transparency, accessibility, and education in a children's hospital. AB - Peer review is a requisite for a comprehensive quality assurance program. Although RADPEER implementations have been well documented, the feedback process has been underemphasized. Our radiology department developed feedback scorecards to address this gap. In this article, we describe our scorecard components, the software applications we independently created and utilize, and how they align missions of quality improvement and radiologist education. The result is a web based, comment-enhanced, monthly feedback scorecard that to our knowledge is the first of its kind described in the literature. PMID- 24948211 TI - Ophthalmic manifestations of systemic diseases--part 1: phakomatoses, hematologic malignancies, metastases, and histiocytosis. AB - The orbit can be secondarily involved in various systemic conditions. The ophthalmic involvement is often the first clue to the presence of an underlying systemic condition. The ophthalmic involvement in systemic diseases can be either ocular or extraocular. The extent of involvement can be well delineated by imaging modalities like computed tomography and magnetic resonance imaging. In the first part of the article, we provide an overview of systemic diseases affecting the orbit, briefly discuss the modalities for orbital imaging, and discuss the imaging appearances of ophthalmic involvement in (1) phakomatoses, (2) hematologic malignancies, (3) metastases, and (4) histiocytosis. At the end of the 2-part article, we discuss a pattern-based approach and differential diagnosis of orbital lesions in systemic diseases. PMID- 24948213 TI - Pictorial review of the role of multidetector computed tomography imaging in the postoperative evaluation of congenital heart disease. AB - Echocardiography and cardiac magnetic resonance imaging are the methods of choice for preoperative and postoperative assessments of most congenital heart diseases. However, multidetector computed tomographic angiography of the chest is a complementary imaging technique especially in postoperative evaluations. To accurately interpret those computed tomography examinations, an appropriate study protocol, knowledge of the details of surgical procedures, and their complications are essential. In this pictorial review, we discuss our computed tomography technique with a number of illustrative cases with varied postoperative appearances and complications after some of the commonly performed surgical procedures. PMID- 24948212 TI - The myriad of diseases that present with polyostotic bone lesions. AB - Many diseases result in polyostotic bone lesions including benign entities, benign entities with malignant potential, intermediate entities, and malignant entities. Imaging plays a key role in identifying complications of these disorders, most importantly malignant transformation of a benign lesion. The most common polyostotic bone lesions are reviewed and examples of malignant transformation are highlighted. PMID- 24948214 TI - Eponyms in cardiothoracic radiology--part II: vascular. AB - Eponyms serve the purpose of honoring individuals who have made important observations and discoveries. As with other fields of medicine, eponyms are frequently encountered in radiology, particularly in chest radiology. However, inappropriate use of an eponym may lead to potentially dangerous miscommunication. Moreover, an eponym may honor the incorrect person or a person who falls into disrepute. Despite their limitations, eponyms are still widespread in the medical literature. Furthermore, in some circumstances, more than one individual may have contributed to the description or discovery of a particular anatomical structure or disease, whereas in others, an eponym may have been incorrectly applied initially and propagated for years in the medical literature. Nevertheless, radiologic eponyms are a means of honoring those who have made lasting contributions to the field of radiology, and familiarity with these eponyms is critical for proper reporting and accurate communication. In addition, the acquisition of some historical knowledge about those whose names are associated with various structures or pathologic conditions conveys a sense of humanity in the science of medicine. In this second part of a multipart series, the authors discuss a number of chest radiology eponyms as they relate to the pulmonary vasculature, including relevant clinical and imaging features, as well biographic information of the respective eponym's namesake. PMID- 24948215 TI - Tumoral pulmonary emboli from angioinvasive hepatocellular carcinoma. AB - Tumoral pulmonary emboli from hepatocellular carcinoma (HCC) have rarely been described, although invasion of the portal and hepatic venous systems is a well known complication. HCC originating in a noncirrhotic liver in the absence of chronic hepatitis B infection is also uncommon. We present a case of a patient with chronic hepatitis C infection without hepatic cirrhosis who developed angioinvasive HCC with intracardiac extension and tumoral pulmonary emboli. Differential considerations, including combined HCC-cholangiocarcinoma, other hepatic mesenchymal tumors, and metastasis, are discussed. Owing to poor prognosis, no resection was attempted. Autopsy was performed because of the unusual clinical presentation, and immunohistochemistry of the hepatic tumor, the intracardiac extension, and the pulmonary emboli were concordant with hepatocellular origin. Even though definitive diagnosis may not affect patient outcome, it is important for radiologists and clinicians to be aware that angioinvasive HCC may arise in the absence of cirrhosis. PMID- 24948217 TI - Rational design of biotinylated probes: fluorescent turn-on detection of (strept)avidin and bioimaging in cancer cells. AB - Two fluorescent probes SPS1 and SPS2 were designed by connecting biotin to an environment-sensitive coumarin fluorophore. Streptavidin and avidin induced dramatical fluorescence changes in both probes. SPS2 has potential in fluorescent imaging of biotin receptor-enriched tumor cells. PMID- 24948218 TI - Abstracts of the Second European Conference on the Biology of Hydrogen Sulfide, Sep 8-11, 2013, Exeter, UK. PMID- 24948216 TI - Sporadic inclusion body myositis: the genetic contributions to the pathogenesis. AB - Sporadic inclusion body myositis (sIBM) is the commonest idiopathic inflammatory muscle disease in people over 50 years old. It is characterized by slowly progressive muscle weakness and atrophy, with typical pathological changes of inflammation, degeneration and mitochondrial abnormality in affected muscle fibres. The cause(s) of sIBM are still unknown, but are considered complex, with the contribution of multiple factors such as environmental triggers, ageing and genetic susceptibility. This review summarizes the current understanding of the genetic contributions to sIBM and provides some insights for future research in this mysterious disease with the advantage of the rapid development of advanced genetic technology. An international sIBM genetic study is ongoing and whole exome sequencing will be applied in a large cohort of sIBM patients with the aim of unravelling important genetic risk factors for sIBM. PMID- 24948329 TI - Acaricidal activity and sublethal effects of an oxymatrine-based biopesticide on two-spotted spider mite (Acari: Tetranychidae). AB - Lethal and sublethal effects of the biopesticide Kingbo (oxymatrine 0.2 % + psoralen 0.4 %) on the two-spotted spider mite (Tetranychus urticae Koch) were investigated in laboratory bioassays. The biopesticide was applied to bean leaf discs or primary leaves by using a Potter spray tower. Acute toxicity tests showed no significant ovicidal action: toxic effect (LC50 = 55.49 MUl/l) was the result of a residual activity against larvae that hatched from the treated eggs. Preovipositional females and female teleiochrysales showed similar susceptibility (LC50 = 52.68 and 59.03 MUl/l, respectively), whereas larvae, protonymphs and female deutonymphs were the most susceptible stages (LC50 = 6.88, 13.03, and 8.80 MUl/l, respectively). In a choice test, females preferred the untreated halves of leaves over the halves treated with 2,000, 1,000, and 500 MUl/l in the first 24 h, and their oviposition in those treatments was significantly greater on the untreated halves after 24 and 48 h, as well as the summed oviposition over 72 h. Viability and reproduction of survivors, as well as population growth, were strongly affected after the treatments of preovipositional females and female teleiochrysales with 100, 50 and 25 MUl/l. On the other hand, sublethal effects on the females that survived treatment at the egg stage or reached adulthood from the eggs laid on the treated surface (treatments with 50 and 25 MUl/l) were significantly weaker. Acaricidal and sublethal effects of the biopesticide Kingbo were discussed as a starting point for further research aimed to improve management of T. urticae populations. Regulatory issues and safety concerns regarding further commercialization of this biopesticide are addressed as well. PMID- 24948330 TI - A Markov chain model for studying suicide dynamics: an illustration of the Rose theorem. AB - BACKGROUND: High-risk strategies would only have a modest effect on suicide prevention within a population. It is best to incorporate both high-risk and population-based strategies to prevent suicide. This study aims to compare the effectiveness of suicide prevention between high-risk and population-based strategies. METHODS: A Markov chain illness and death model is proposed to determine suicide dynamic in a population and examine its effectiveness for reducing the number of suicides by modifying certain parameters of the model. Assuming a population with replacement, the suicide risk of the population was estimated by determining the final state of the Markov model. RESULTS: The model shows that targeting the whole population for suicide prevention is more effective than reducing risk in the high-risk tail of the distribution of psychological distress (i.e. the mentally ill). CONCLUSIONS: The results of this model reinforce the essence of the Rose theorem that lowering the suicidal risk in the population at large may be more effective than reducing the high risk in a small population. PMID- 24948331 TI - Functional mapping of community-acquired respiratory distress syndrome (CARDS) toxin of Mycoplasma pneumoniae defines regions with ADP-ribosyltransferase, vacuolating and receptor-binding activities. AB - Community-acquired respiratory distress syndrome (CARDS) toxin from Mycoplasma pneumoniae is a 591-amino-acid virulence factor with ADP-ribosyltransferase (ADPRT) and vacuolating activities. It is expressed at low levels during in vitro growth and at high levels during colonization of the lung. Exposure of experimental animals to purified recombinant CARDS toxin alone is sufficient to recapitulate the cytopathology and inflammatory responses associated with M. pneumoniae infection in humans and animals. Here, by molecular modelling, serial truncations and site-directed mutagenesis, we show that the N-terminal region is essential for ADP-ribosylating activity. Also, by systematic truncation and limited proteolysis experiments we identified a portion of the C-terminal region that mediates toxin binding to mammalian cell surfaces and subsequent internalization. In addition, the C-terminal region alone induces vacuolization in a manner similar to full-length toxin. Together, these data suggest that CARDS toxin has a unique architecture with functionally separable N-terminal and C terminal domains. PMID- 24948332 TI - Comparing bone microarchitecture by trabecular bone score (TBS) in Caucasian American women with and without osteoporotic fractures. AB - Several cross-sectional studies have shown the ability of the TBS to discriminate between those with and without fractures in European populations. The aim of this study was to assess the ability of TBS to discriminate between those with and without fractures in a large female Caucasian population in the USA. This was a case-control study of 2,165 Caucasian American women aged 40 and older. Patients with illness or taking medications known to affect bone metabolism were excluded. Those in the fracture group (n = 289) had at least one low-energy fracture. BMD was measured at L1-L4, TBS calculated directly from the same DXA image. Descriptive statistics and inferential tests for difference were used. Univariate and multivariate logistic regression models were created to investigate possible association between independent variables and the status of fracture. Odds ratios per standard deviation decrease (OR) and areas under the ROC curve were calculated for discriminating parameters. Weak correlations were observed between TBS and BMD and between TBS and BMI (r = 0.33 and -0.17, respectively, p < 0.01). Mean age, weight, BMD and TBS were significantly different between control and fracture groups (all p <= 0.05), whereas no difference was noted for BMI or height. After adjusting for age, weight, BMD, smoking, and maternal and family history of fracture, TBS (but not BMD) remained a significant predictor of fracture: OR 1.28[1.13-1.46] even after adjustment. In a US female population, TBS again was able to discriminate between those with and those without fractures, even after adjusting for other clinical risk factors. PMID- 24948333 TI - Rivaroxaban and stroke prevention in patients with atrial fibrillation: new evidence. AB - In the majority of patients with non-valvular atrial fibrillation (AF) anticoagulation is required to reduce the risk of stroke. Although vitamin K antagonists effectively reduce the risk of stroke, they have many disadvantages that limit their use. Rivaroxaban is a new once-daily oral anticoagulant that overcomes some of these limitations (i.e., no monitoring of anticoagulant effect required and fixed doses can be prescribed). In recent AF studies, rivaroxaban was reported to be at least as effective as warfarin for the prevention of stroke or systemic embolism but with a lesser risk of fatal bleeding and intracranial hemorrhage. More recent data have confirmed the beneficial effects of rivaroxaban, as originally described, and irrespective of the history of previous stroke, heart failure, myocardial infarction, diabetes, moderate renal dysfunction or age. In the present review the authors discuss current evidence regarding the efficacy and safety of rivaroxaban in patients with non-valvular AF. PMID- 24948334 TI - Corpus callosum alterations in pyridoxine-dependent epilepsy: a mirror image of an ongoing disease? PMID- 24948335 TI - A mutation in the H/ACA box of telomerase RNA component gene (TERC) in a young patient with myelodysplastic syndrome. AB - BACKGROUND: Telomeres are repeated sequences (the hexanucleotide TTAGGG in vertebrates) located at chromosome ends of eukaryotes, protecting DNA from end joining or degradation. Telomeres become shorter with each cell cycle, but telomerase, a ribonucleoprotein complex, alleviates this attrition. The telomerase RNA component (TERC) is an essential element of telomerase, serving as a template for telomere elongation. The H/ACA domain of TERC is indispensable for telomere biogenesis. Mutations in the telomerase components allow accelerated telomere loss, resulting in various disease manifestations, including bone marrow failure. To date, this is the first detailed report of an H-box mutation in TERC that is related to human disease. CASE PRESENTATION: A 26-year-old man with myelodysplastic syndrome (MDS) had very short telomeres. Sequencing identified a single heterozygous mutation in the H box of the patient's TERC gene. The same mutation was also present in his father and his son, demonstrating that it was germline in origin. The telomere length in the father's blood was shorter compared to age-matched healthy controls, while it was normal in the son and also in the sperm cells of the patient. In vitro experiments suggested that the mutation was responsible for the telomere shortening in the patient's leukocytes and contributed to the pathogenesis of bone marrow failure in our patient. CONCLUSION: We analyzed a mutation (A377G) in the H box of TERC in a young MDS patient who had significantly short-for-age telomeres. As telomeres protect chromosomes from instability, it is highly plausible that this genetic lesion was responsible for the patient's hematological manifestations, including marrow failure and aneuploidy in the hematopoietic stem cell compartment. PMID- 24948336 TI - Whole-grain intake in middle school students achieves dietary guidelines for Americans and MyPlate recommendations when provided as commercially available foods: a randomized trial. AB - In accordance with the 2010 Dietary Guidelines for Americans, at least half of total grain intake should be whole grains. Adolescents are currently not consuming the recommended daily intake of whole grains. Research is needed to determine whether whole grains are acceptable to adolescents and whether changing their food environment to include whole-grain foods will improve intake. The aim of this study was to determine the effect of providing refined-grain or whole grain foods to adolescents, with encouragement to eat three different grain-based foods per day, on total grain and whole-grain intakes. Middle school students (n=83; aged 11 to 15 years) were randomly assigned to either refined-grain or whole-grain foods for 6 weeks. Participants and their families were provided with weekly grains (eg, bread, pasta, and cereals), and participants were provided grain snacks at school. Intake of grains in ounce equivalents (oz eq) was determined through eight baseline and intervention targeted 24-hour diet recalls. Participants consumed 1.1+/-1.3 oz eq (mean+/-standard deviation) of whole grains at baseline, out of 5.3+/-2.4 oz eq of total grains. During intervention, whole grain intake increased in the whole-grain group (0.9+/-1.0 to 3.9+/-1.8 oz eq/day), whereas those in the refined-grain group reduced whole-grain intake (1.3+/-1.6 to 0.3+/-0.3 oz eq/day; P<0.002, group by time period interaction). Total grain intake achieved was 6.4+/-2.1 oz eq/day and did not differ across intervention groups. Providing adolescents with whole-grain foods in their school and home environments was an effective means of achieving recommendations. PMID- 24948337 TI - Tooth alterations in areas of bisphosphonate-induced osteonecrosis. AB - OBJECTIVE: Osteonecrosis of the jaw is a potential side effect when using bisphosphonates. Most studies on the effects of bisphosphonates on teeth have been conducted in vitro or in animal models of tooth development. Therefore, the aim of this study was to describe alterations found in human teeth extracted from areas of bisphosphonate-induced osteonecrosis. MATERIALS AND METHODS: Using a retrospective study design, 16 teeth from 13 patients were extracted from areas of bisphosphonate-induced osteonecrosis during surgical debridement. The specimens were decalcified and embedded in paraffin. A series of 5-MUm sections were prepared, stained with hematoxylin and eosin (H&E) and observed under a light microscope. RESULTS: The majority of the patients were female (53.85 %), with a mean age of 60.23 +/- 13.18 years. Zoledronate (IV) was the most common bisphosphonate used (92.3 %), over a mean period of 2 years. The commonest alteration observed was hypercementosis (87.5 %), followed by pulpar necrosis (81.25 %), pulp stones attached to the dentine and loose pulp stones in the pulp chamber and root canals in addition to linear calcifications (68.75 %), dentinoid/osteoid material formation (18.75 %), and dental ankylosis (6.25 %). CONCLUSIONS: Patients undergoing bisphosphonate therapy present diverse tooth alterations, which should be closely monitored by clinicians to prevent complications. CLINICAL RELEVANCE: It is paramount that the teeth involved in oral lesions are always examined. Attention should be drawn to the need to establish preventive measures, in terms of dental treatment, for patients prior to starting bisphosphonate therapy. PMID- 24948338 TI - The use of portable CO2 incubator for cross-border shipping of embryos in an international egg donation program. AB - Two groups of egg recipients were treated, one in situ (165 patients; 195 cycles) and one after cross-border embryo transportation (340 cycles; 340 cycles) using mobile CO(2) incubator. The positive pregnancy rate per cycle was 199/340 (58.6%) and 99/195 (50.7%) in the transportation and the traveling group, respectively (NS). The clinical pregnancy rate (fetal heart beat) was 48.1 and 43.1% per embryo transfer cycle, respectively (NS) and the delivery rate was 44.1 and 35.9% per embryo transfer cycle, respectively (p = 0.01). Long distance transportation of human pre-implantation embryos using portable CO(2) incubator is safe and do not jeopardize their developmental potential. PMID- 24948339 TI - Sequential protocol with urinary-FSH/recombinant-FSH versus standard protocol with recombinant-FSH in women of advanced age undergoing IVF. AB - A stimulation protocol mimicking the physiological pattern of FSH release may improve IVF outcome in women of advanced age. Urinary-FSH delivers a wider range of isoforms including the most acidic produced during the early follicular phase when oestradiol level is low, a common condition in women of advanced reproductive age. We hypothesized that a stimulation protocol using urinary-FSH during the early follicular phase and then shifting toward recombinant-FSH may improve oocyte quality and pregnancy rate in 35-40 years old patients in IVF program. A retrospective study was performed: after a standard down-regulation with GnRH-analogue, 115 women underwent stimulation with urinary-FSH for 6 days according to a step-down approach and then shifting to recombinant-FSH (group A), 115 women underwent a stimulation protocol with only recombinant-FSH (group B). Days of stimulation were lower in group A than in group B, a higher proportion of MII oocytes and of grade 1 embryos, higher implantation rate and pregnancy rate were observed in group A versus group B. We conclude that a sequential protocol using urinary-FSH in the early days of stimulation and subsequently recombinant FSH may improve the IVF outcome in patients of advanced reproductive age. PMID- 24948340 TI - Mayer-Rokitansky-Kuster-Hauser syndrome: complications, diagnosis and possible treatment options: a review. AB - Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a disorder in women that presents as Mullerian agenesis. These patients present internal genitalia abnormalities that include the absence of a uterus and the upper two-thirds of the vagina. In this review, current diagnostic methods, accompanying complications (congenital and psychological) and non-surgical and surgical treatments are summarized. Ultrasound and MRI have been the most documented options in MRKH syndrome diagnosis. Many women with MRKH syndrome have renal, skeletal, hearing or cardiac congenital anomalies and increased levels of psychological distress. Non-surgical interventions can be used to create a sexually functional neovagina through vaginal dilation, and surgical interventions provide alternate methods of creating a neovagina. Additionally, vaginal tissue engineering and gene therapy might provide more effective approaches in solving MRKH syndrome. PMID- 24948341 TI - Ketamine dosing in adolescents: sizing up the problem. PMID- 24948342 TI - Pneumatosis intestinalis. PMID- 24948343 TI - Bowel obstruction due to multiple retained foreign bodies in a Meckel diverticulum. PMID- 24948344 TI - Pulse oximetry screening for critical congenital heart disease in planned out-of hospital births. AB - OBJECTIVES: To describe the use of pulse oximetry screening (POS) for critical congenital heart disease (CCHD). STUDY DESIGN: This observational study of Wisconsin out-of-hospital births was performed from January to November, 2013. Licensed midwives, Amish birth attendants, and public health nurses were trained in the use of pulse oximetry to detect CCHD, supplied with pulse oximeters, and reported screening results and clinical outcomes. RESULTS: Results of POS in 440 newborns were reviewed; 173/440 births were from Amish or Mennonite communities. Prenatal ultrasonography was performed in less than one-half of the pregnancies and in only 13% of Amish and Mennonite women. A total of 432 babies passed the screening, 5 babies were incorrectly assigned to have passed or failed, and 3 babies failed the screening. Two of the babies who failed the screening were treated for sepsis and the third had congenital heart disease. There was 1 false negative result (coarctation of the aorta and ventricular septal defect). CONCLUSIONS: This study provides information on the use of POS for CCHD in out-of hospital births and shows that POS can be successfully implemented outside the hospital setting. Although the failure rate in this small sample was higher than reported in studies of hospital births, those babies failing the screening had significant disease processes that were identified more rapidly because of the screening. PMID- 24948345 TI - Effects of pump versus twice-daily injection delivery of synthetic parathyroid hormone 1-34 in children with severe congenital hypoparathyroidism. AB - OBJECTIVE: To compare the response with synthetic human parathyroid hormone (PTH) 1-34 delivered by twice-daily injection vs insulin pump in children with severe congenital hypoparathyroidism due to calcium receptor mutation or autoimmune polyglandular syndrome type 1. STUDY DESIGN: Children and young adults aged 7-20 years with congenital hypoparathyroidism (N = 12) were randomized to receive PTH 1-34, delivered either by twice-daily subcutaneous injection or insulin pump for 13 weeks, followed by crossover to the opposite delivery method. The principal outcome measures were serum and urine calcium levels. Secondary outcomes included serum and urine magnesium and phosphate levels and bone turnover markers. RESULTS: PTH 1-34 delivered via pump produced near normalization of mean serum calcium (2.02 +/- 0.05 [pump] vs 1.88 +/- 0.03 [injection] mmol/L, P < .05, normal 2.05-2.5 mmol/L), normalized mean urine calcium excretion (5.17 +/- 1.10 [pump] vs 6.67 +/- 0.76 mmol/24 h/1.73 m(2), P = .3), and significantly reduced markers of bone turnover (P < .02). Serum and urine calcium and magnesium showed a biphasic pattern during twice-daily injection vs minimal fluctuation during pump delivery. The PTH 1-34 dosage was markedly reduced during pump delivery (0.32 +/- 0.04 vs 0.85 +/- 0.11 MUg/kg/d, P < .001), and magnesium supplements were also reduced (P < .001). CONCLUSION: Compared with twice-daily delivery, pump delivery of PTH 1-34 provides more physiologic calcium homeostasis and bone turnover in children with severe congenital hypoparathyroidism. PMID- 24948346 TI - Current management of neonatal abstinence syndrome secondary to intrauterine opioid exposure. PMID- 24948347 TI - Quality of life is improved and kidney function preserved in patients with nephropathic cystinosis treated for 2 years with delayed-release cysteamine bitartrate. AB - OBJECTIVES: To determine the long-term effects of delayed-release cysteamine bitartrate (DR-CYS) based on our previous work that established the short-term noninferiority of DR-CYS every 12 hours compared with immediate-release cysteamine bitartrate every 6 hours. STUDY DESIGN: We conducted a prospective, controlled, open label, single-arm study of DR-CYS for 2 years in 40 patients to assess efficacy in depletion of cystine in peripheral white blood cells, to assess the dose required to maintain white blood cell content of cystine <1 nmol 1/2 cystine/mg protein, to measure quality of life using the Pediatric Quality of Life Inventory, change in estimated glomerular filtration rate, and change in height Z-score. RESULTS: Through 24 months of study, the mean white blood cell content of cystine was always <1 nmol 1/2 cystine/mg protein, and the dose of DR CYS decreased from 43.5-40.1 mg/kg/d (P = .05), and the significant improvement in social function, school function, and in total function scores on the Pediatric Quality of Life Inventory remained. The estimated glomerular filtration rate was maintained and growth velocity was maintained at 24 months compared with the baseline height Z-score. CONCLUSIONS: The use of a DR-CYS administered every 12 hours to patients with cystinosis is of great benefit to their quality of life and to important biomarkers of disease control, when studied in a prospective, controlled fashion. We suggest that DR-CYS should be considered for substrate depletion in patients with cystinosis. PMID- 24948349 TI - The time for a confirmative necrotizing enterocolitis probiotics prevention trial in the extremely low birth weight infant in North America is now! PMID- 24948350 TI - An infant with PELVIS (perineal hemangioma, external genital malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag) syndrome misdiagnosed as diaper rash. PMID- 24948351 TI - Feeding preterm infants during red blood cell transfusion is associated with a decline in postprandial mesenteric oxygenation. AB - OBJECTIVE: To evaluate the mesenteric tissue oxygenation response in preterm infants fed and not fed during red blood cell (RBC) transfusions. STUDY DESIGN: Prospective, observational comparison of mesenteric oxygenation using near infrared spectroscopy in preterm infants (<33 weeks' at birth) who were fed or not fed during RBC transfusion. Tissue oxygenation means were examined up to 48 hours after each transfusion event. RESULTS: Mean mesenteric regional oxygen saturation (rSO2) slopes during RBC transfusion of fed (n = 9) vs not fed (n = 8) infants ranged from -0.23 to +0.23 (mean 0.04) with no differences between groups (P = .480). However, following transfusions, postprandial mesenteric oxygenation means significantly declined in infants fed during transfusion compared with infants not fed during transfusion (P < .001). Infants fed during RBC transfusion had a mean 2.16 point decrease in rSO2 mesenteric oxygenation with each sequential feeding post-transfusion, whereas infants not fed during RBC transfusion increased their rSO2 postprandial mesenteric oxygenation by a mean of 2.09 points. CONCLUSIONS: Mesenteric tissue oxygenation during RBC transfusion is not influenced by feeding status. However, infants fed during RBC transfusion had, for the next 15 hours, decreasing postprandial mesenteric tissue oxygenation patterns compared with infants not fed during RBC transfusion. Feeding during RBC transfusions may increase the risk for mesenteric ischemia and the development of transfusion-related necrotizing enterocolitis in preterm infants. PMID- 24948352 TI - Sequence analysis reveals genomic factors affecting EST-SSR primer performance and polymorphism. AB - This study was to explore genomic factors affecting the performance and polymorphism of 340 randomly selected EST-SSR (expressed sequence tag-simple sequence repeat) primers through BLAST of primer sequences to a reference genome. Genotyping showed 111 failed and 229 succeeded. The failed types included "no peaks" (NP, 69 primers), "weak peaks" (WP, 30), and "multiple peaks" (MP, 12). The successful types were divided into HM (homozygous between two selected parents, 78 primers) and HT (heterozygous at least in one parent, 151 primers). The BLAST revealed primer alignment status, genomic amplicon size (GAS), and genomic and expressed amplicon size difference (ASD). The alignment status was categorized as: "no hits found" (NHF); "multiple partial alignments" (MPA); "single partial alignment" (SPA); "multiple full alignments" (MFA); and "single full alignment" (SFA). NHF and partial alignment (PA) mainly resulted from discrepant nucleotides in contig-derived primers. The ASD separated 247 non-NHF primers into: "deletion", "same size", "insertion", "intron (GAS <=500)", "intron (GAS >500)", and "error" categories. Most SFA primers were successful. About 88 % "error", 53 % NHF primers, and 47 % "intron (GAS >500)" failed. The "deletion" and "insertion" primers had the higher HT rates, and the "same size" had the highest HM rate. Optimized primer selection criteria are discussed. PMID- 24948353 TI - Associations between particulate matter elements and early-life pneumonia in seven birth cohorts: results from the ESCAPE and TRANSPHORM projects. AB - Evidence for a role of long-term particulate matter exposure on acute respiratory infections is growing. However, which components of particulate matter may be causative remains largely unknown. We assessed associations between eight particulate matter elements and early-life pneumonia in seven birth cohort studies (N total=15,980): BAMSE (Sweden), GASPII (Italy), GINIplus and LISAplus (Germany), INMA (Spain), MAAS (United Kingdom) and PIAMA (The Netherlands). Annual average exposure to copper, iron, potassium, nickel, sulfur, silicon, vanadium and zinc, each respectively derived from particles with aerodynamic diameters <= 10 MUm (PM10) and 2.5 MUm (PM2.5), were estimated using standardized land use regression models and assigned to birth addresses. Cohort-specific associations between these exposures and parental reports of physician-diagnosed pneumonia between birth and two years were assessed using logistic regression models adjusted for host and environmental covariates and total PM10 or PM2.5 mass. Combined estimates were calculated using random-effects meta-analysis. There was substantial within and between-cohort variability in element concentrations. In the adjusted meta-analysis, pneumonia was weakly associated with zinc derived from PM10 (OR: 1.47 (95% CI: 0.99, 2.18) per 20 ng/m(3) increase). No other associations with the other elements were consistently observed. The independent effect of particulate matter mass remained after adjustment for element concentrations. In conclusion, associations between particulate matter mass exposure and pneumonia were not explained by the elements we investigated. Zinc from PM10 was the only element which appeared independently associated with a higher risk of early-life pneumonia. As zinc is primarily attributable to non-tailpipe traffic emissions, these results may suggest a potential adverse effect of non-tailpipe emissions on health. PMID- 24948354 TI - Evaluation of the influence of electric nets on the behaviour of oviposition site seeking Anopheles gambiae s.s. AB - BACKGROUND: Electric nets (e-nets) are used to analyse the flight behaviour of insects and have been used extensively to study the host-oriented flight of tsetse flies. Recently we adapted this tool to analyse the oviposition behaviour of gravid malaria vectors, Anopheles gambiae s.s., orienting towards aquatic habitats and traps by surrounding an artificial pond with e-nets and collecting electrocuted mosquitoes on sticky boards on the ground next to the nets. Here we study whether e-nets themselves affect the responses of gravid An. gambiae s.s.. METHODS: Dual-choice experiments were carried out in 80 m2 screened semi-field systems where 200 gravid An. gambiae s.s. were released each night for 12 nights per experiment. The numbers of mosquito landing on or approaching an oviposition site were studied by adding detergent to the water in an artificial pond or surrounding the pond with a square of e-nets. We also assessed whether the supporting framework of the nets or the sticky boards used to retain electrocuted mosquitoes influenced the catch. RESULTS: Two similar detergent treated ponds presented in choice tests caught an equal proportion of the mosquitoes released, whereas a pond surrounded by e-nets caught a higher proportion than an open pond (odds ratio (OR) 1.7, 95% confidence interval (CI) 1.1 - 2.7; p<0.017). The separate evaluation of the impact of the square of electric nets and the yellow boards on the approach of gravid females towards a pond suggests that the tower like construction of the square of electric nets did not restrict the approach of females but the yellow sticky boards on the ground attract gravid females to a source of water (OR 2.7 95% CI 1.7 - 4.3; p<0.001). CONCLUSION: The trapping efficiency of the electric nets is increased when large yellow sticky boards are placed on the ground next to the e-nets to collect electrocuted mosquitoes, possibly because of increased visual contrast to the aquatic habitat. It is therefore important when comparing two treatments that the same trapping device is used in both. The importance of contrast around artificial habitats might be exploited to improve collections of An. gambiae s.s. in gravid traps. PMID- 24948348 TI - Relationships among stressful life events and physiological markers, treatment adherence, and psychosocial functioning among youth with type 2 diabetes. AB - OBJECTIVE: To examine the relationships between stressful life events and physiological measures, adherence to prescribed oral medication regimens, depressive symptoms, and impaired quality of life (QoL) in adolescents with recent-onset type 2 diabetes (T2D). STUDY DESIGN: Data were collected from 497 ethnically diverse participants (66% female) in the final year of the Treatment Options for Type 2 Diabetes in Adolescents and Youth multicenter clinical trial. Exposure to 32 possible events over the previous year and rating of subsequent distress were collected by self-report and summarized as a major stressors score. This score was analyzed for relationship to glycemic control (hemoglobin A1c and treatment failure), body mass index, diagnosis of hypertension or triglyceride dyslipidemia, adherence to a prescribed oral medication regimen, presence of depressive symptoms, and impaired QoL. RESULTS: The total number of major stressful life events in the adolescents with T2D was calculated, with 33% reporting none, 67% reporting >= 1, 47% reporting >= 2, 33% reporting >= 3, and 20% reporting >= 4. There were no associations between the major stressors score and physiological measures or diagnosis of comorbidities. The odds of medication nonadherence increased significantly from those reporting >= 1 major stressor (OR, 1.58; P = .0265) to those reporting >= 4 major stressors (OR, 2.70; P = .0009). Significant odds of elevated depressive symptoms and impaired QoL were also found with increased reporting of major stressors. CONCLUSION: Exposure to major stressful life events is associated with lower adherence to prescribed oral medication regimens and impaired psychosocial functioning in adolescents with T2D. PMID- 24948356 TI - Treatment for long bulbar urethral strictures with membranous involvement using urethroplasty with oral mucosa graft. AB - INTRODUCTION: Urethroplasty with oral mucosa grafting is the most popular technique for treating nontraumatic bulbar urethral strictures; however, cases involving the membranous portion are usually treated using progressive perineal anastomotic urethroplasty. We assessed the feasibility of performing dorsal (or ventral) graft urethroplasty on bulbar urethral strictures with mainly membranous involvement using a modified Barbagli technique. MATERIAL AND METHODS: This was a prospective study of 14 patients with bulbomembranous urethral strictures who underwent dilation urethroplasty with oral mucosa graft between 2005 and 2013, performed using a modified technique Barbagli, with proximal anchoring of the graft and securing of the graft to the tunica cavernosa in 12 cases (85.7%) and ventrally in 2 (14.3%). The minimum follow-up time was 1 year. We evaluated the subjective (patient satisfaction) and objective (maximum flow [Qmax] and postvoid residual volume [PVRV], preoperative and postoperative) results and complications. Failure was defined as the need for any postoperative instrumentation. RESULTS: A total of 14 patients (median age, 64+13 years) underwent surgery. The main antecedent of note was transurethral resection of the prostate in 9 cases (64.3%). The median length of the stenosis was 45+26.5mm. Prior to surgery, 50% of the patients had been subjected to dilatations and 4% to endoscopic urethrotomy. The mean surgical time and hospital stay were was 177+76min and 1.5+1 day, respectively. The preoperative Qmax and PVRV values were 4.5+4.45mL/sec and 212.5+130 cc, respectively. The postoperative values were 15.15+7.2mL/sec and 6+21.5cc, respectively (P<.01 for both comparisons). Surgery was successful in 13 cases (92.9%). None of the patients had major complications. There were minor complications in 1 (7.1%) patient, but reintervention was no required. CONCLUSION: The repair of long bulbar urethral strictures with membranous involvement using urethroplasty with free oral mucosa grafts represents a viable alternative for patients with nontraumatic etiology and little fibrosis. The dilation of the urethral lumen achieves good results with minimum failure rates and little probability of complications. For many of these patients, the length of the stricture is too long to perform the tension-free anastomosis technique. PMID- 24948355 TI - Interferon-gamma-induced inflammatory markers and the risk of cancer: the Hordaland Health Study. AB - BACKGROUND: It has been reported that interferon-gamma (IFN-gamma)-induced inflammatory markers, such as circulating neopterin and kynurenine-to-tryptophan ratio (KTR), are increased in patients with cancer and are also a predictor of poor prognosis. However, whether baseline levels of these makers are associated with subsequent cancer risk in the general population remains unknown. METHODS: We conducted a prospective analysis of the Hordaland Health Study in 6594 adults without known cancer at baseline who were enrolled between April 1998 and June 1999. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using multivariate Cox proportional hazards regression models adjusted for sex, age, body mass index, smoking status, and renal function. RESULTS: A total of 971 incident cancer cases (507 men and 464 women) were identified over a median follow-up time of 12 years. Baseline plasma neopterin, KTR and C-reactive protein (CRP) were significantly associated with an increased risk of overall cancer in models adjusted for covariates (P for trend across quartiles = .006 for neopterin, .022 for KTR, and .005 for CRP). The multivariate-adjusted HR (95% CI) per SD increment in similar models were 1.09 (1.03-1.16) for neopterin, 1.07 (1.01-1.14) for KTR, and 1.04 (0.98-1.10) for CRP. The associations between the inflammatory markers and risk of major specific cancer types were also provided. CONCLUSIONS: Our findings indicate that plasma neopterin, KTR, and CRP are associated with a significantly increased risk of overall cancer. Our study revealed novel evidence regarding the role of IFN-gamma-induced inflammation in human carcinogenesis. PMID- 24948359 TI - Ebstein's anomaly unmasked by accessory pathway ablation. PMID- 24948357 TI - Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis. AB - Although novel drugs have contributed immensely to improving outcomes of patients with multiple myeloma (MM), many patients develop drug resistance and ultimately succumb to MM. Here, we show that artesunate, an anti-malarial drug, reliably induces cell death in vitro in naive as well as drug-resistant MM cells at concentrations shown to be safe in humans. Artesunate induced apoptosis predominantly through the non-caspase mediated pathway by primarily targeting mitochondria and causing outer mitochondrial membrane permeabilization that led to cytosolic and subsequent nuclear translocation of mitochondrial proteins apoptosis inducing factor (AIF) and endonuclease G (EndoG). Nuclear translocation of AIF and EndoG was accompanied by low levels of reactive oxygen species (ROS) and increased mitochondrial production of superoxide. These effects were present before apoptosis was evident and were related to intracellular levels of bivalent iron (Fe+2). Artesunate's unique mechanism probably was at least partially responsible for, its ability to act synergistically with multiple anti-myeloma agents. Our findings suggest that artesunate acts through iron to affect the mitochondria and induce low ROS and non-caspase-mediated apoptosis. Its potency, toxicity profile, and synergism with other drugs make it an intriguing new candidate for MM treatment. PMID- 24948361 TI - Editorial overview: New constructs and expression of proteins: Making things better. PMID- 24948358 TI - Human APOE4 increases microglia reactivity at Abeta plaques in a mouse model of Abeta deposition. AB - BACKGROUND: Having the apolipoprotein E4 (APOE-epsilon4) allele is the strongest genetic risk factor for the development of Alzheimer's disease (AD). Accumulation of amyloid beta (Abeta) in the brain is influenced by APOE genotype. Transgenic mice co-expressing five familial AD mutations (5xFAD) in the presence of human APOE alleles (epsilon2, epsilon3 or epsilon4) exhibit APOE genotype-specific differences in early Abeta accumulation, suggesting an interaction between APOE and AD pathology. Whether APOE genotype affects Abeta-plaque-associated neuroinflammation remains unclear. In the current study, we address the role of APOE genotype on Abeta-associated microglial reactivity in the EFAD transgenic mouse model. METHODS: We analyzed Abeta-induced glial activation in the brains of 6-month-old EFAD transgenic mice (E2FAD, E3FAD and E4FAD). Region-specific morphological profiles of Abeta plaques in EFAD brain sections were compared using immunofluorescence staining. We then determined the degree of glial activation in sites of Abeta deposition while comparing levels of the inflammatory cytokine Interleukin-1beta (IL-1beta) by ELISA. Finally, we quantified parameters of Abeta-associated microglial reactivity using double stained EFAD brain sections. RESULTS: Characterization of Abeta plaques revealed there were larger and more intensely stained plaques in E4FAD mice relative to E2FAD and E3FAD mice. E4FAD mice also had a greater percentage of compact plaques in the subiculum than E3FAD mice. Reactive microglia and dystrophic astrocytes were prominent in EFAD brains, and primarily localized to two sites of significant Abeta deposition: the subiculum and deep layers of the cortex. Cortical levels of IL-1beta were nearly twofold greater in E4FAD mice relative to E3FAD mice. To control for differences in levels of Abeta in the different EFAD mice, we analyzed the microglia within domains of specific Abeta deposits. Morphometric analyses revealed increased measures of microglial reactivity in E4FAD mice, including greater dystrophy, increased fluorescence intensity and a higher density of reactive cells surrounding cortical plaques, than in E3FAD mice. CONCLUSIONS: In addition to altering morphological profiles of Abeta deposition, APOE genotype influences Abeta-induced glial activation in the adult EFAD cortex. These data support a role for APOE in modulating Abeta-induced neuroinflammatory responses in AD progression, and support the use of EFAD mice as a suitable model for mechanistic studies of Abeta-associated neuroinflammation. PMID- 24948363 TI - Signalling: a new master to rival NF-kappaB? PMID- 24948362 TI - Role of host GTPases in infection by Listeria monocytogenes. AB - The bacterial pathogen Listeria monocytogenes induces internalization into mammalian cells and uses actin-based motility to spread within tissues. Listeria accomplishes this intracellular life cycle by exploiting or antagonizing several host GTPases. Internalization into human cells is mediated by the bacterial surface proteins InlA or InlB. These two modes of uptake each require a host actin polymerization pathway comprised of the GTPase Rac1, nucleation promotion factors, and the Arp2/3 complex. In addition to Rac1, InlB-mediated internalization involves inhibition of the GTPase Arf6 and participation of Dynamin and septin family GTPases. After uptake, Listeria is encased in host phagosomes. The bacterial protein GAPDH inactivates the human GTPase Rab5, thereby delaying phagosomal acquisition of antimicrobial properties. After bacterial-induced destruction of the phagosome, cytosolic Listeria uses the surface protein ActA to stimulate actin-based motility. The GTPase Dynamin 2 reduces the density of microtubules that would otherwise limit bacterial movement. Cell-to-cell spread results when motile Listeria remodel the host plasma membrane into protrusions that are engulfed by neighbouring cells. The human GTPase Cdc42, its activator Tuba, and its effector N-WASP form a complex with the potential to restrict Listeria protrusions. Bacteria overcome this restriction through two microbial factors that inhibit Cdc42-GTP or Tuba/N-WASP interaction. PMID- 24948365 TI - T cells: IL-9 breaks down barriers. PMID- 24948364 TI - Follicular dendritic cells: dynamic antigen libraries. AB - Follicular dendritic cells (FDCs) are essential for high-affinity antibody production and for the development of B cell memory. Historically, FDCs have been characterized as 'accessory' cells that passively support germinal centre (GC) responses. However, recent observations suggest that FDCs actively shape humoral immunity. In this Review, we discuss recent findings concerning the antigen acquisition and retention functions of FDCs, and relevant implications for protective immunity. Furthermore, we describe the roles of FDCs within GCs in secondary lymphoid organs and discuss FDC development within this dynamic environment. Finally, we discuss how a better understanding of FDCs could facilitate the design of next-generation vaccines. PMID- 24948367 TI - ERK1/2 antagonize AMPK-dependent regulation of FcepsilonRI-mediated mast cell activation and anaphylaxis. AB - BACKGROUND: Extracellular signal-regulated kinases 1/2 (ERK1/2) make important contributions to allergic responses via their regulation of degranulation, eicosanoid production, and cytokine expression by mast cells, yet the mechanisms underlying their positive effects on FcepsilonRI-dependent signaling are not fully understood. Recently, we reported that mast cell activation and anaphylaxis are negatively regulated by AMP-activated protein kinase (AMPK). However, little is known about the relationship between ERK1/2-mediated positive and the AMPK mediated negative regulation of FcepsilonRI signaling in mast cells. OBJECTIVE: We investigated possible interactions between ERK1/2 and AMPK in the modulation of mast cell signaling and anaphylaxis. METHODS: Wild-type or AMPKalpha2(-/-) mice, or bone marrow-derived mast cells obtained from these mice, were treated with either chemical agents or small interfering RNAs that modulated the activity or expression of ERK1/2 or AMPK to evaluate the functional interplay between ERK1/2 and AMPK in FcepsilonRI-dependent signaling. RESULTS: The ERK1/2 pathway inhibitor U0126 and the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-4 ribofuranoside similarly inhibited FcepsilonRI-mediated mast cell signals in vitro and anaphylaxis in vivo. ERK1/2-specific small interfering RNA also mimicked this effect on FcepsilonRI signals. Moreover, AMPKalpha2 knockdown or deficiency led to increased FcepsilonRI-mediated mast cell activation and anaphylaxis that were insensitive to U0126 or activator 5-aminoimidazole-4 carboxamide-1-beta-4-ribofuranoside, suggesting that the suppression of FcepsilonRI signals by the inhibition of the ERK1/2 pathway relies largely on AMPK activation. ERK1/2 controlled AMPK activity by regulating its subcellular translocation. CONCLUSIONS: ERK1/2 ablated the AMPK-dependent negative regulatory axis, thereby activating FcepsilonRI signals in mast cells. PMID- 24948366 TI - Ectopic lymphoid-like structures in infection, cancer and autoimmunity. AB - Ectopic lymphoid-like structures often develop at sites of inflammation where they influence the course of infection, autoimmune disease, cancer and transplant rejection. These lymphoid aggregates range from tight clusters of B cells and T cells to highly organized structures that comprise functional germinal centres. Although the mechanisms governing ectopic lymphoid neogenesis in human pathology remain poorly defined, the presence of ectopic lymphoid-like structures within inflamed tissues has been linked to both protective and deleterious outcomes in patients. In this Review, we discuss investigations in both experimental model systems and patient cohorts to provide a perspective on the formation and functions of ectopic lymphoid-like structures in human pathology, with particular reference to the clinical implications and the potential for therapeutic targeting. PMID- 24948370 TI - Postmodification of PS-b-P4VP diblock copolymer membranes by ARGET ATRP. AB - The surfaces of polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP) diblock copolymer membranes were modified in order to obtain polymer brushes by using surface-initiated activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). Isoporous membranes were prepared by the combination of self-assembly of PS-b-P4VP diblock copolymers and the nonsolvent induced phase separation process, also known as "phase inversion". In order to allow further functionalization, the membranes were modified with an ATRP initiator, 2-bromoisobutyryl bromide (BIBB). Therefore, the mussel-inspired poly(dopamine) coating was used to attach BIBB on the membranes surface. In the next step the coated membranes were postmodified by using surface-initiated ARGET ATRP with the hydrophilic monomer 2-hydroxyethyl methacrylate (HEMA). HEMA as a hydrophilic methacrylate was chosen for the modification in order to enhance the membrane characteristics and to obtain a surface with antifouling properties. The surface-initiated ARGET ATRP reaction was carried out using different reaction times and environments. PHEMA could successfully incorporate on the membrane surface as confirmed by attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), (1)H nuclear magnetic resonance spectroscopy ((1)H NMR), scanning electron microscopy (SEM), and contact angle measurements. Furthermore, stability tests against heat and solvents were performed, and water flux was measured for the raw and modified membranes. Stability against heat and hydrophilicity could be increased with this type of modification for diblock copolymer membranes. PMID- 24948368 TI - Myeloid-derived suppressor cell function is diminished in aspirin-triggered allergic airway hyperresponsiveness in mice. AB - BACKGROUND: Myeloid-derived suppressor cells (MDSCs) have recently been implicated in the pathogenesis of asthma, but their regulation in patients with aspirin-intolerant asthma (AIA) remains unclear. OBJECTIVE: We sought to characterize MDSC accumulation and pathogenic functions in allergic airway inflammation mediated by COX-1 deficiency or aspirin treatment in mice. METHODS: Allergic airway inflammation was induced in mice by means of ovalbumin challenge. The distribution and function of MDSCs in mice were analyzed by using flow cytometry and pharmacologic/gene manipulation approaches. RESULTS: CD11b(+)Gr1(high)Ly6G(+)Ly6C(int) MDSCs (polymorphonuclear MDSCs [PMN-MDSCs]) recruited to the lungs are negatively correlated with airway inflammation in allergen-challenged mice. Aspirin-treated and COX-1 knockout (KO) mice showed significantly lower accumulation of PMN-MDSCs in the inflamed lung and immune organs accompanied by increased TH2 airway responses. The TH2-suppressive function of PMN-MDSCs was notably impaired by COX-1 deletion or inhibition, predominantly through downregulation of arginase-1. COX-1-derived prostaglandin E2 promoted PMN-MDSC generation in bone marrow through E prostanoid 2 and 4 receptors (EP2 and EP4), whereas the impaired arginase-1 expression in PMN-MDSCs in COX-1 KO mice was mediated by dysregulation of the prostaglandin E2/EP4/cyclic AMP/protein kinase A pathway. EP4 agonist administration alleviated allergy induced airway hyperresponsiveness in COX-1 KO mice. Moreover, the immunosuppressive function of PMN-MDSCs from patients with AIA was dramatically decreased compared with that from patients with aspirin-tolerant asthma. CONCLUSION: The immunosuppressive activity of PMN-MDSCs was diminished in both allergen-challenged COX-1 KO mice and patients with AIA, probably through an EP4 mediated signaling pathway, indicating that activation of PMN-MDSCs might be a promising therapeutic strategy for asthma, particularly AIA. PMID- 24948369 TI - The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. AB - In patients given a diagnosis of chronic spontaneous urticaria (CSU), there are no obvious external triggers, and the factors that initiate the clinical symptoms of wheal, flare, and itch arise from within the patient. Most patients with CSU have an autoimmune cause: some patients produce IgE autoantibodies against autoantigens, such as thyroperoxidase or double-stranded DNA, whereas other patients make IgG autoantibodies against FcepsilonRI, IgE, or both, which might chronically activate mast cells and basophils. In the remainder of patients with CSU, the nature of the abnormalities has not yet been identified. Accumulating evidence has shown that IgE, by binding to FcepsilonRI on mast cells without FcepsilonRI cross-linking, can promote the proliferation and survival of mast cells and thus maintain and expand the pool of mast cells. IgE and FcepsilonRI engagement can also decrease the release threshold of mast cells and increase their sensitivity to various stimuli through either FcepsilonRI or other receptors for the degranulation process. Furthermore, IgE-FcepsilonRI engagement potentiates the ability of mast cells to store and synthesize de novo inflammatory mediators and cytokines. Administration of omalizumab, by virtue of its ability to deplete IgE, attenuates the multiple effects of IgE to maintain and enhance mast cell activities and hence reduces the ability of mast cells to manifest inflammatory mechanisms in patients with CSU. PMID- 24948371 TI - Hybrid magnetic nanoparticle/nanogold clusters and their distance-dependent metal enhanced fluorescence effect via DNA hybridization. AB - To improve the metal-enhanced fluorescence (MEF) effect of nanogolds (AuNPs) and accurately detect specific DNA sequences via DNA hybridization, novel hybrid magnetic nanoparticles/nanogold clusters (HMNCs) were designed based on finite difference time-domain simulation results and prepared by using Fe3O4 and nanogolds. The nanogolds outside the HMNC were then conjugated with thiol terminated DNA molecules, thus DNA modified-HMNCs (DNA-HMNCs) were obtained. The size distributions of these nanostructures were measured by a Malvern size analyzer, and their morphology was observed via transmission electron microscopy (TEM). The ultraviolet (UV)-visible (vis) absorption spectra of the samples were recorded with a UV-2600 spectrophotometer. Fluorescence spectra and the MEF effect were recorded using a spectrophotofluorometer, and lifetimes were determined using a time-correlated single photon counting apparatus. The prepared HMNCs were stable in aqueous solutions and had an average diameter of 87 +/- 3.2 nm, with six to eight AuNPs around a single Fe3O4 nanoparticle. Fluorescein isothiocyanate (FITC) tagged DNA-HMNC conjugates exhibited a significant MEF effect and could accurately detect specific DNA sequences after DNA hybridization. This result indicates their various potential applications in sensors and biomedical fields. PMID- 24948372 TI - Factors influencing parents' decision to donate their healthy infant's DNA for minimal-risk genetic research. AB - PURPOSE: To examine factors that influence a parent's decision to donate their healthy infant's DNA for minimal-risk genetic research. DESIGN: Grounded theory, using semi-structured interviews conducted with 35 postpartum mother or mother father dyads in an urban teaching hospital. Data were collected from July 2011 to January 2012. METHODS: Audiorecorded semistructured interviews were conducted in private rooms with mothers or mother-father dyads 24 to 48 hr after the birth of their healthy, full-term infant. Data-driven content analysis using selected principles of grounded theory was performed. FINDINGS: Parents' willingness to donate their healthy infant's DNA for minimal-risk pediatric genetic research emerged as a process involving three interacting components: the parents, the scientist, and the comfort of the child embedded within the context of benefit to the child. The purpose of the study and parents' perception of their commitment of time and resources determined their willingness to participate. The scientist's ability to communicate trust in the research process influenced parents' decisions. Physical discomfort of the child shaped parents' decision to donate DNA. Parental perception of a direct benefit to their child affected their willingness to discuss genetic research and its outcomes. CONCLUSIONS: Significant gaps and misunderstandings in parental knowledge of pediatric genetic research may affect parental willingness to donate their healthy child's DNA. CLINICAL RELEVANCE: Nurses knowledgeable about the decision-making process parents utilize to donate their healthy infant's DNA for minimal-risk genetic research and the factors influencing that decision are well positioned to educate parents about the role of genetics in health and illness and reassure potential research participants of the value and safeguards in pediatric genetic research. PMID- 24948373 TI - Tissue-engineered membrane based on chitosan for repair of mechanically damaged corneal epithelium. AB - In this study, hydroxyethyl chitosan (HECTS), a water-soluble derivative of chitosan, was used to create a blend membrane and its function and application as a scaffold in repair of mechanically damaged corneal epethelia were examined. The results showed that HECTS significantly promoted growth of corneal epithelial cells (CEpCs) in vitro and that CEpCs grew well on the HECTS-based blend membrane. Fluorescent imaging showed that CEpCs were interconnected and formed layers on the membrane. After transplanting the CEpCs-seeded membranes onto the damaged corneal epithelium, we found that the epithelium was repaired faster compared with control. The repaired corneal epithelium with the membrane had a more compact structure and a smoother surface than control when observed by histology and scanning electron microscope. These results demonstrate an ability of the tissue-engineered scaffold to speed up the repair of mechanically damaged corneal epithelium. PMID- 24948374 TI - Treating orthopedic prosthesis with diamond-like carbon: minimizing debris in Ti6Al4V. AB - Prostheses are subject to various forms of failing mechanisms, including wear from ordinary patient motion. Superficial treatments can improve tribological properties of the contact pair, minimizing wear and increasing prostheses lifetime. One possibility is the diamond-like carbon (DLC) coating, where Carbon is deposited with variable ratio of sp(2)/sp(3) structures, leading to an increase in surface hardness. So in this research Ti6Al4V samples were coated with DLC using sputtering process to evaluate the debris release. The Ti6Al4V and Ti6Al4V plus DLC coating surfaces were analyzed using Raman spectroscopy and instrumented indentation (hardness). The wear behavior was tested using a reciprocating linear tribometer. The wear rate was smaller in the coated samples, producing less debris than the untreated Ti6Al4V alloy. Debris morphology was also evaluated, using scanning electronic microscopy, and it was observed that debris size from the coated samples were bigger than those observed from the uncoated Ti6Al4V alloy, above the size that generally triggers biological response from the host. PMID- 24948375 TI - Work instability in rheumatoid arthritis patients from Argentina: prevalence and associated factors. AB - To determine the prevalence of and associated factors to work instability (WI) in rheumatoid arthritis (RA) Argentinean patients. Observational cross-sectional study that assessing employment status in currently working RA patients. They answered the validated version of RA work instability scale (RA-WIS). High-risk WI was considered when RA-WIS was >=17. Factors associated with high-risk WI were examined by univariable and multivariable analysis. Four-hundred and fifty RA patients were enrolled; of these, 205 patients were currently employed, but only 172 have completed questionnaires required [RA-WIS and health assessment questionnaire (HAQ-A)]. Their mean age was 49.3 +/- 10.8 years; 81.3 % were female; and their mean disease duration was 8.1 +/- 7.2 years. Fifty-two percent of patients were doing manual work. The mean RA-WIS score was 11.4 +/- 6.8, and 41 % of patients had a high-risk WI. High-risk WI was associated with radiographic erosions (p < 0.001) and HAQ-A >0.87 (p < 0.001) in the univariable analysis, whereas in the multivariable logistic regression analysis the variables associated with a high-risk WI were as follows: HAQ-A >0.87 [odds ratio (OR) 12.31; 95 % CI 5.38-28.18] and the presence of radiographic erosions (OR 4.848; 95 % CI 2.22-10.5). In this model, having a higher monthly income (OR 0.301; 95 % CI 0.096-0.943) and a better functional class (OR 0.151; 95 % CI 0.036-0.632) were protective. Forty-one percent of RA working patients had high-risk WI. The predictors of high RA-WIS were HAQ-A >=0.87 and radiographic erosions, whereas having a better functional class and have higher incomes were protective. PMID- 24948377 TI - Polyaniline shell cross-linked Fe3O4 magnetic nanoparticles for heat activated killing of cancer cells. AB - Superparamagnetic Fe3O4 nanoparticles are appealing materials for heat activated killing of cancer cells. Here, we report a novel method to enhance the heat activated killing of cancer cells under an AC magnetic field (AMF) by introducing a polyaniline impregnated shell onto the surface of Fe3O4 nanoparticles. These polyaniline shell cross-linked magnetic nanoparticles (PSMN) were prepared by in situ polymerization of aniline hydrochloride on the surface of carboxyl PEGylated Fe3O4 nanoparticles. XRD and TEM analyses revealed the formation of single phase inverse spinel Fe3O4 nanoparticles of a size of about 10 nm. The successful growth of the polyaniline shell on the surface of carboxyl PEGylated magnetic nanoparticles (CPMN) is evident from FTIR spectra, DLS, TGA, zeta-potential and magnetic measurements. Both CPMN and PSMN show good colloidal stability, superparamagnetic behavior at room temperature and excellent heating efficacy under AMF. It has been observed that the heating efficacy of PSMN under AMF was slightly reduced as compared to that of CPMN. The enhanced toxicity of PSMN to cancer cells under AMF suggests their strong potential for magnetic hyperthermia. Furthermore, PSMN shows high loading affinity for an anticancer drug (doxorubicin), its sustained release and substantial internalization in tumor cells. PMID- 24948376 TI - Pneumocystis jirovecii pneumonia in mycophenolate mofetil-treated patients with connective tissue disease: analysis of 17 cases. AB - The association of Pneumocystis jirovecii pneumonia (PJP) with connective tissue disease (CTD) and mycophenolate mofetil's (MMF) potent activity against PJP have been separately reported. Until now, there have been no papers describing the occurrence of PJP following MMF treatment in CTD patients. The objective of this study was to describe the clinical features, risk factors, outcomes of PJP in patients with CTD and investigates the effects of MMF on the occurrence of PJP in China. In this retrospective cohort study, we performed a chart review, analyzing clinical features, treatment, and outcomes of PJP in patients with CTD in a single hospital. A total of 17 cases met the inclusion criteria of having PJP and a CTD diagnosis: systemic lupus erythematosus; polymyositis; dermatomyositis; rheumatoid arthritis; Wegener's granulomatosis; and microscopic polyangiitis. Sixteen patients were treated with glucocorticoids (GCs) plus immunosuppressive drugs. Only one patient had GCs without immunosuppressive drugs. Ten subjects (62.5 %) received MMF (1-1.5 g/day), and all ten had lymphopenia. The mortality rates of MMF and non-MMF patients were 50 and 14 %, respectively. This study is the first report of PJP following MMF plus GC treatment in patients with CTD. CTD itself may be a risk factor for PJP. When CTD patients receiving MMF therapy have low lymphocyte counts and/or CD4 lymphocyte counts <250/uL, we should be care of occurrence of PJP. PMID- 24948378 TI - Erythrocyte deformability responses to intermittent and continuous subhemolytic shear stress. AB - BACKGROUND: Previous studies have demonstrated that red blood cells (RBC) either lyse or at least experience mechanical damage following prolonged exposure to high shear stress (>=100 Pa). Conversely, prolonged shear stress exposure within the physiological range (5-20 Pa, 300 s) was recently reported to improve RBC deformability. This study investigated the relationships between shear stress and RBC deformability to determine the breakpoint between beneficial vs. detrimental exposure to shear stress (i.e., "subhemolytic threshold"). A second aim of the study was to determine whether the frequency of intermittent application of shear stress influenced the subhemolytic threshold. METHODS: RBC were exposed to various levels of shear stress (0-100 Pa) in a Couette type shearing system for 300 s. RBC deformability was then immediately measured via ektacytometry. Parallel experiments were conducted at the same shear stresses, except the application time differed while keeping constant the total exposure time: shear stress was applied either for 30 s and repeated 10 times (10*30 s) or applied for 15 s and repeated 20 times (20*15 s). RESULTS: For a range of donors, the subhemolytic threshold with constant shear stress application was between 30-40 Pa. When physiological shear stress was applied in an intermittent manner, more frequent applications tended to improve (i.e., increase) RBC deformability. However, when supra-physiological shear stress was applied, both continuous and intermittent protocols damaged RBC. Changes of RBC mechanical behavior occurred without increases of hemoglobin in the suspending media, thus attesting to the absence of hemolysis. CONCLUSION: Shear stress has a biphasic effect on the mechanical properties of RBC, with the duration and rate of exposure appearing to have minimal impact on the subhemolytic threshold when compared with the magnitude of applied shear stress. PMID- 24948379 TI - Characterization of the Campylobacter jejuni population in the barnacle geese reservoir. AB - Campylobacter spp. are the most common cause of bacterial gastroenteritis worldwide and have been isolated from a wide number of different hosts and environmental sources. Waterfowl is considered a natural reservoir for this zoonotic bacterium and may act as a potential infection source for human campylobacteriosis. In this study, faecal samples from 924 barnacle geese were tested for the presence of C. jejuni and C. coli. The resulting C. jejuni and C. coli populations were characterized by multilocus sequence typing (MLST), structure analysis by BAPS and phylogenetic analysis based on full genome sequences. The prevalences of C. jejuni in barnacle geese faeces were 11.5% and 23.1% in 2011 and 2012, respectively, and only 0.2% of the samples were positive for C. coli in both years. Furthermore, a possible adaption of the clonal complexes (CCs) ST-702 and ST-1034 to the barnacle geese reservoir was found, as these two CCs represented the majority of the typed isolates and were repeatedly isolated from different flocks at several time-points. Further core genome phylogenetic analysis using ClonalFrame revealed a formation of a distinct monophyletic lineage by these two CCs, suggesting a certain degree of clonality of the C. jejuni population adapted to barnacle geese. Therefore, although STs also commonly found in humans patients (e.g. ST-45) were among the barnacle geese C. jejuni isolates, this reservoir is probably an infrequent source for human campylobacteriosis. PMID- 24948380 TI - Turning on cGMP-dependent pathways to treat cardiac dysfunctions: boom, bust, and beyond. AB - cGMP inhibits hypertrophy, decreases fibrosis, and protects against cardiac ischemia-reperfusion (I/R) injury. Gene-targeting studies have not defined a clear role for its major downstream effector, cGMP-dependent protein kinase I (cGKI), in cardiac hypertrophy, but do implicate cGMP-cGKI signaling in fibrosis and I/R injury. No direct cGKI activators have advanced to clinical trials, whereas cardiac trials of agents that modulate cGMP via particulate or soluble guanylyl cyclases (GCs) and phosphodiesterase 5 (PDE5) are ongoing. Here we review concerns arising from preclinical and clinical studies that question whether targeting the cGMP pathway remains an encouraging concept for management of heart dysfunction. So far, trial results for GC modulators are inconclusive, and sildenafil, a PDE5 inhibitor, although cardioprotective in mouse models, has not shown positive clinical results. Preclinical cardioprotection observed for sildenafil may result from inhibition of PDE5 in non-cardiomyocytes or off-target effects, possibly on PDE1C. On the basis of such mechanistic considerations, re evaluation of the cellular localization of drug target(s) and intervention protocols for cGMP-elevating agents may be needed. PMID- 24948381 TI - Looking ahead: electroretinographic anomalies, glycogen synthase kinase-3, and biomarkers for neuropsychiatric disorders. PMID- 24948382 TI - Genetic mouse models of neuregulin 1: gene dosage effects, isoform-specific functions, and relevance to schizophrenia. PMID- 24948383 TI - Small cracks in the dam: rare genetic variants provide opportunities to delve into mechanisms of neuropsychiatric disorders. PMID- 24948384 TI - Parental feeding control in relation to feeding mode and growth pattern during early infancy. AB - AIM: A high level of parental control of feeding and disturbed energy self regulation has previously been suggested as a mechanism for the accelerated growth observed in formula-fed compared with breast-fed infants. This study explored factors associated with parental control of feeding in a population of formula-fed infants with high levels of self-regulation. METHODS: We included 141 formula-fed and 72 breast-fed infants from a randomised controlled trial, who were prospectively followed from under 2 months of age to 12 months of age. Anthropometry was recorded at baseline, 4, 6 and 12 months of age. Parental feeding control was assessed using a Child Feeding Questionnaire at 4 and 12 months. RESULTS: The formula-fed groups fully compensated for different energy and protein densities by regulating their volume intakes. Parents of formula-fed infants had a lower pressure to eat score at 12 months than parents of breast-fed infants. A high parental restrictive score at 12 months was associated with weight at 12 months and high parental pressure to eat score at 12 months with body mass index at 12 months. Neither were associated with feeding mode. CONCLUSION: Formula-fed infants had a high level of energy self-regulation and were subjected to low parental control. Parental control of feeding was mainly influenced by infant growth. PMID- 24948385 TI - On the importance of a rich embodiment in the grounding of concepts: perspectives from embodied cognitive science and computational linguistics. AB - The recent trend in cognitive robotics experiments on language learning, symbol grounding, and related issues necessarily entails a reduction of sensorimotor aspects from those provided by a human body to those that can be realized in machines, limiting robotic models of symbol grounding in this respect. Here, we argue that there is a need for modeling work in this domain to explicitly take into account the richer human embodiment even for concrete concepts that prima facie relate merely to simple actions, and illustrate this using distributional methods from computational linguistics which allow us to investigate grounding of concepts based on their actual usage. We also argue that these techniques have applications in theories and models of grounding, particularly in machine implementations thereof. Similarly, considering the grounding of concepts in human terms may be of benefit to future work in computational linguistics, in particular in going beyond "grounding" concepts in the textual modality alone. Overall, we highlight the overall potential for a mutually beneficial relationship between the two fields. PMID- 24948387 TI - An evidence-based quality improvement perspective for a chronic obstructive pulmonary disease case-finding program. AB - Chronic obstructive pulmonary disease (COPD) is a persistent progressive respiratory disease that is increasing in prevalence and cost in the United States health care system. Delays in recognition, diagnosis, and treatment are associated with poorer clinical outcomes. These delays are seen more often in populations experiencing economic hardship, lack of access to care, and lack of insurance, such as those seen in an indigent care clinic. The COPD case-finding program was planned as an evidence-based quality improvement project with a prospective, descriptive design generating a convenience sample of patients meeting modified screening criteria (i.e. patients 40 years of age with a smoking history and no pulmonary disease history) in a community-based indigent care clinic which was not screening for COPD. Practice change recommendations were guided by the Diffusion of Innovations Model. Descriptive statistics were used to describe the sample (i.e. age, ethnicity, race, gender, income, and selected comorbidities). Sensitivity, specificity, positive predictive value, negative predictive value, prevalence, and receiver operator characteristics curve COPD Questionnaire were calculated for this sample. PMID- 24948386 TI - Patient-centred care--what is it and how is it practised in the dental surgery? AB - OBJECTIVES: This paper explores the understanding and practice of patient-centred care (PCC) within dentistry. The aim of the research was to explore the nature of PCC, how PCC is taught and how it is practiced within a dental setting. METHODS: The results of a qualitative, interview-based study of dental professionals working across clinical and teaching positions within a dental school are presented. RESULTS: Results suggest that a shared understanding of PCC revolves round a basic sense of humanity ('being nice to patients'), giving information that is judged, by the clinician, to be in the patient's best interest and 'allowing' patient choice from a set of choices made available to patients by the clinicians themselves. CONCLUSIONS: This research suggests that significant work is needed if dentists are going to conform to the General Dental Council guidelines on patient-centred practice and a series of recommendations are made to this end. PMID- 24948389 TI - Thermotropic dynamic processes in multiphase polymer systems by (cryo-)AFM. AB - The structural (volume and enthalpy) relaxation of polymers during physical aging has a great relevance in materials science and engineering as it significantly changes the long-term material performance. In this article, we propose a methodological approach of (cryo-)atomic force microscopy (AFM) monitoring of macromolecular rearrangements which accompany structural relaxation within bulk of the polymer during physical aging. In contrast to conventional spectroscopic, scattering and thermal analysis techniques, high resolution topographical/phase imaging of the bulk cross-section over a large period of time and within a wide range of temperatures (-120 degrees C to +20 degrees C) yields unique information about the evolution of the polymer ultrastructure as a function of time and temperature in situ. PMID- 24948388 TI - Similar age-related decline in cortical activity over frontotemporal regions in schizophrenia: a multichannel near-infrared spectroscopy study. AB - OBJECTIVES: Although recent studies have demonstrated that patients with schizophrenia and healthy controls did not differ in the speed of age-related decline in cortical thickness and performances on cognitive tests, hemodynamic changes assessed by functional neuroimaging remain unclear. This study investigated age effects on regional brain cortical activity to determine whether there is similar age-related decline in cortical activity as those observed in cortical thickness and cognitive test performance. METHOD: A total of 109 patients with schizophrenia (age range: 16-59 y) and 106 healthy controls (age range: 16-59 y) underwent near-infrared spectroscopy (NIRS) while performing a verbal fluency test (VFT). Group comparison of cortical activity was examined using 2-tailed t tests, adopting the false discovery rate method. The relationship between age and cortical activity was investigated using correlational and multiple regression analyses, adjusting for potential confounding variables. A 2-way ANOVA was conducted to investigate differences in the age effects between diagnostic groups. RESULTS: The patient group exhibited significantly decreased cortical activity in several regions of the frontotemporal cortices. However, slopes of age-dependent decreases in cortical activity were similar between patients and healthy individuals at the bilateral frontotemporal regions. CONCLUSIONS: Our study showed no significant between group differences in the age-related decline in cortical activity, as measured by NIRS, over the frontotemporal regions during a VFT. The results of our study may indicate a decrease in cortical activity in a relatively limited period around illness onset rather than continuously progressing over the course of the illness. PMID- 24948390 TI - Wetting failure of hydrophilic surfaces promoted by surface roughness. AB - Wetting failure is of vital importance to many physical phenomena, such as industrial coating and drop emission. Here we show when and how the surface roughness promotes the destabilization of a moving contact line on a hydrophilic surface. Beyond the balance of the driving force and viscous resistance where a stable wetting interface is sustained, wetting failure occurs and is modified by the roughness of the surface. The promoting effect arises only when the wetting velocity is high enough to create a gas-liquid-solid composite interface in the vicinity of the moving contact line, and it is a function of the intrinsic contact angle and proportion of solid tops. We propose a model to explain splashes of rough solid spheres impacting into liquids. It reveals a novel concept that dynamic wetting on hydrophilic rough surfaces can be similar to that on hydrophobic surfaces, and brings a new way to design surfaces with specific wetting properties. PMID- 24948391 TI - Co-option of Sox3 as the male-determining factor on the Y chromosome in the fish Oryzias dancena. AB - Sex chromosomes harbour a primary sex-determining signal that triggers sexual development of the organism. However, diverse sex chromosome systems have been evolved in vertebrates. Here we use positional cloning to identify the sex determining locus of a medaka-related fish, Oryzias dancena, and find that the locus on the Y chromosome contains a cis-regulatory element that upregulates neighbouring Sox3 expression in developing gonad. Sex-reversed phenotypes in Sox3(Y) transgenic fish, and Sox3(Y) loss-of-function mutants all point to its critical role in sex determination. Furthermore, we demonstrate that Sox3 initiates testicular differentiation by upregulating expression of downstream Gsdf, which is highly conserved in fish sex differentiation pathways. Our results not only provide strong evidence for the independent recruitment of Sox3 to male determination in distantly related vertebrates, but also provide direct evidence that a novel sex determination pathway has evolved through co-option of a transcriptional regulator potentially interacted with a conserved downstream component. PMID- 24948392 TI - Production of a neutralizing antibody against envelope protein of dengue virus type 2 using the linear array epitope technique. AB - Dengue virus (DENV; genus Flavivirus) contains a positive-stranded RNA genome. Binding of DENV to host cells is mediated through domain III of the viral envelope protein. Many therapeutic mAbs against domain III have been generated and characterized because of its high antigenicity. We have previously established a novel PCR method named the linear array epitope (LAE) technique for producing monoclone-like polyclonal antibodies. To prove this method could be utilized to produce antibody against epitopes with low antigenicity, a region of 10 aa (V365NIEAEPPFG374) from domain III of the envelope protein in DENV serotype 2 (DENV2) was selected to design the primers for the LAE technique. A DNA fragment encoding 10 directed repeats of these 10 aa for producing the tandem repeated peptides was obtained and fused with glutathione S-transferase (GST) containing vector. This fusion protein (GST-Den EIII10-His6) was purified from Escherichia coli and used as antigen for immunizing rabbits to obtain the polyclonal antibody. Furthermore, the EIII antibody could recognize envelope proteins either ectopically overexpressed or synthesized by DENV2 infection using Western blot and immunofluorescence assays. Most importantly, this antibody was also able to detect DENV2 virions by ELISA, and could block viral entry into BHK 21 cells as shown by immunofluorescence and quantitative real-time PCR assays. Taken together, the LAE technique could be applied successfully for the production of antibodies against antigens with low antigenicity, and shows high potential to produce antibodies with good quality for academic research, diagnosis and even therapeutic applications in the future. PMID- 24948393 TI - Genome sequencing of two Neorhizobium galegae strains reveals a noeT gene responsible for the unusual acetylation of the nodulation factors. AB - BACKGROUND: The species Neorhizobium galegae comprises two symbiovars that induce nodules on Galega plants. Strains of both symbiovars, orientalis and officinalis, induce nodules on the same plant species, but fix nitrogen only in their own host species. The mechanism behind this strict host specificity is not yet known. In this study, genome sequences of representatives of the two symbiovars were produced, providing new material for studying properties of N. galegae, with a special interest in genomic differences that may play a role in host specificity. RESULTS: The genome sequences confirmed that the two representative strains are much alike at a whole-genome level. Analysis of orthologous genes showed that N. galegae has a higher number of orthologs shared with Rhizobium than with Agrobacterium. The symbiosis plasmid of strain HAMBI 1141 was shown to transfer by conjugation under optimal conditions. In addition, both sequenced strains have an acetyltransferase gene which was shown to modify the Nod factor on the residue adjacent to the non-reducing-terminal residue. The working hypothesis that this gene is of major importance in directing host specificity of N. galegae could not, however, be confirmed. CONCLUSIONS: Strains of N. galegae have many genes differentiating them from strains of Agrobacterium, Rhizobium and Sinorhizobium. However, the mechanism behind their ecological difference is not evident. Although the final determinant for the strict host specificity of N. galegae remains to be identified, the gene responsible for the species-specific acetylation of the Nod factors was identified in this study. We propose the name noeT for this gene to reflect its role in symbiosis. PMID- 24948394 TI - Initial experience with the novel patent foramen ovale occlusion device Nit Occlud(r) in patients with stroke or transient ischemic attack. AB - BACKGROUND: Patent foramen ovale (PFO) is associated with cryptogenic strokes and transient ischemic attacks (TIAs). This study examined the initial experience with a new PFO occluder, the Nit-Occlud(r) PFO Occlusion Device. METHODS: Sixty three patients with history of cryptogenic stroke or TIA and PFO underwent percutaneous closure of the defect with the Nit-Occlud(r) PFO Occlusion Device. The primary endpoint was successful implantation without recurrent event, device malfunction, embolization, or the need for a replacement device over 6 +/- 2 weeks. All patients underwent transesophageal echocardiography (TEE) at 6-weeks, and 42 patients had repeat TEE at 6-months. Clinical follow-up at 18.7 +/- 7.4 months was also performed. RESULTS: The device was successfully implanted in 62 (98.4%) patients with no relevant procedural complications. At 6-week follow-up, 60 (95.2%) patients met the primary endpoint. A residual shunt at rest and with Valsalva was noted in 8 (12.7%) and 31 (49.2%) patients respectively at 6-week TEE. At 6-months, 1 of 42 (2.4%) and 9 of 42 (21.4%) patients had a residual shunt at rest and with Valsava, respectively. At 18 months, 5/63 patients had recurrent events (3 TIAs, 2 strokes). No device-related complications occurred. One patient developed atrial fibrillation. CONCLUSION: In patients with cryptogenic stroke or TIA and a PFO, the Nit-Occlud(r) PFO Occlusion Device appears to be both a safe and effective means to occlude the PFO. It is associated with high procedural success and favorable rates of complete closure. PMID- 24948395 TI - Imaging findings of variable axillary mass and axillary lymphadenopathy. AB - The axilla is a triangular space that contains mesenchymal tissues such as fat, vessels, nerves and lymph nodes, from which various diseases can develop. This article describes axillary masses and axillary lymphadenopathies using imaging findings from techniques such as ultrasonography, mammography, computed tomography and magnetic resonance imaging. Awareness of the characteristic imaging findings of disease entities that cause axillary masses and various axillary lymphadenopathies will help in the accurate diagnosis of axillary lesions. PMID- 24948396 TI - Mechanical induction of interleukin-11 regulates osteoblastic/cementoblastic differentiation of human periodontal ligament stem/progenitor cells. AB - BACKGROUND AND OBJECTIVE: The periodontal ligament (PDL) is continually exposed to mechanical loading caused by mastication or occlusion. Physiological loading is thus considered a key regulator of PDL tissue homeostasis; however, it remains unclear how this occurs. We recently reported that an appropriate magnitude of mechanical stretch can maintain PDL tissue homeostasis via the renin-angiotensin system. In the present study, we investigated the expression of interleukin-11 (IL-11) in human primary PDL cells (HPDLCs) exposed to stretch loading, the contribution of angiotensin II (Ang II) to this event and the effects of IL-11 on osteoblastic/cementoblastic differentiation of human PDL progenitor cells (cell line 1-17). MATERIAL AND METHODS: Human primary PDL cells, derived from human tissues, with or without antagonists against the Ang II receptors AT1 or AT2, were subjected to cyclical stretch loading with 8% elongation for 1 h. Expression of IL-11 was measured by ELISA in these cultures and by immunohistochemistry in the sectioned maxillae of rats. The osteoblastic/cementoblastic potential of cell line 1-17 was determined using cell proliferation, gene expression and Alizarin Red staining. RESULTS: Positive staining for IL-11 was observed in the PDL of rat maxillae and in cultures of HPDLCs. In HPDLCs exposed to stretch, expression of the IL11 gene and the IL-11 protein were up-regulated, concomitant with an increase in Ang II and via AT2. Recombinant human IL-11 (rhIL-11) stimulated an increase in expression of mRNA for the cementoblast-specific marker, CP-23, and for the osteoblastic markers, osteopontin and bone sialoprotein, and promoted proliferation in cell line 1-17. In addition, rhIL-11 also increased the degree of mineralized nodule formation in cell line 1-17 cultures treated with CaCl2 . CONCLUSION: Mechanical loading appears to control proliferation and osteoblastic/cementoblastic differentiation of human PDL stem/progenitor cells through the regulation of Ang II and AT2 by IL-11. PMID- 24948397 TI - Elevated alcohol demand is associated with driving after drinking among college student binge drinkers. AB - BACKGROUND: Alcohol-impaired driving among college students represents a significant public health concern, yet little is known about specific theoretical and individual difference risk factors for driving after drinking among heavy drinking college students. This study evaluated the hypothesis that heavy drinkers with elevated alcohol demand would be more likely to report drinking and driving. METHOD: Participants were 207 college students who reported at least 1 heavy drinking episode (4/5 or more drinks in 1 occasion for a woman/man) in the past month. Participants completed an alcohol purchase task that assessed hypothetical alcohol consumption across 17 drink prices and an item from the Young Adult Alcohol Consequences Questionnaire that assessed driving after drinking. RESULTS: In binary logistic regression models that controlled for drinking level, gender, ethnicity, age, and sensation seeking, participants who reported higher demand were more likely to report driving after drinking. CONCLUSIONS: These results provide support for behavioral economics models of substance abuse that view elevated/inelastic demand as a key etiological feature of substance misuse. PMID- 24948398 TI - Blood biochemistry, thyroid hormones, and oxidant/antioxidant status of guinea pigs challenged with sodium arsenite or arsenic trioxide. AB - The present experiment aimed to compare the two most commonly used compounds of arsenic (sodium arsenite and arsenic trioxide) for their effect on blood metabolites, thyroid hormones, and oxidant/antioxidant status in guinea pigs. Twenty-one adult guinea pigs were randomly divided into three equal groups. Animals in group T1 (control) were fed a basal diet, whereas 50 ppm arsenic was added in the basal diet either as sodium arsenite (T2) or arsenic trioxide (T3) and fed for 11 weeks. Serum aspartate aminotransferase and alanine aminotransferase activities were significantly increased along with a decrease in blood hemoglobin level in both the arsenic-administered groups. The level of erythrocytic antioxidants (catalase, superoxide dismutase, reduced glutathione, glutathione-S-transferase, and glutathione reductase) was decreased and lipid peroxidation was elevated upon arsenic exposure. Serum thyroid hormone levels were reduced and arsenic levels in tissues increased in both the arsenic-exposed groups, irrespective of the arsenic compound. Thus, sodium arsenite and arsenic trioxide exerted similar adverse effects on blood metabolic profile, antioxidant status, and thyroid hormones in guinea pigs. PMID- 24948400 TI - Editor's Introduction. PMID- 24948401 TI - Identifying cut points for biomarker defined subset effects in clinical trials with survival endpoints. AB - The advancements in biotechnology and genetics lead to an increasing research interest in personalized medicine, where a patient's genetic profile or biological traits contribute to choosing the most effective treatment for the patient. The process starts with finding a specific biomarker among all possible candidates that can best predict the treatment effect. After a biomarker is chosen, identifying a cut point of the biomarker value that splits the patients into treatment effective and non-effective subgroups becomes an important scientific problem. Numerous methods have been proposed to validate the predictive marker and select the appropriate cut points either prospectively or retrospectively using clinical trial data. In trials with survival outcomes, the current practice applies an interaction testing procedure and chooses the cut point that minimizes the p-values for the tests. Such method assumes independence between the baseline hazard and biomarker value. In reality, however, this assumption is often violated, as the chosen biomarker might also be prognostic in addition to its predictive nature for treatment effect. In this paper we propose a block-wise estimation and a sequential testing approach to identify the cut point in biomarkers that can group the patients into subsets based on their distinct treatment outcomes without assuming independence between the biomarker and baseline hazard. Numerical results based on simulated survival data show that the proposed method could pinpoint accurately the cut points in biomarker values that separate the patient subpopulations into subgroups with distinctive treatment outcomes. PMID- 24948402 TI - Rationale and design of a multicenter randomized clinical trial with memantine and dextromethorphan in ketamine-responder patients. AB - The N-methyl-D-aspartate receptor plays an important role in central sensitization of neuropathic pain and N-methyl-D-aspartate receptor antagonists, such as ketamine, memantine and dextromethorphan may be used for persistent pain. However, ketamine cannot be repeated too often because of its adverse events. A drug relay would be helpful in the outpatient to postpone or even cancel the next ketamine infusion. This clinical trial evaluates if memantine and/or dextromethorphan given as a relay to ketamine responders may maintain or induce a decrease of pain intensity and have a beneficial impact on cognition and quality of life. This trial is a multi-center, randomized, controlled and single-blind clinical study (NCT01602185). It includes 60 ketamine responder patients suffering from neuropathic pain. They are randomly allocated to memantine, dextromethorphan or placebo. After ketamine infusion, 60 patients received either memantine (maximal dose 20 mg/day), or dextromethorphan (maximal dose 90 mg/day), or placebo for 12 weeks. The primary endpoint is pain measured on a (0-10) Numeric Rating Scale 1 month after inclusion. Secondary outcomes include assessment of neuropathic pain, sleep, quality of life, anxiety/depression and cognitive function at 2 and 3 months. Data analysis is performed using mixed models and the tests are two-sided, with a type I error set at alpha=0.05. This study will explore if oral memantine and/or dextromethorphan may be a beneficial relay in ketamine responders and may diminish ketamine infusion frequency. Preservation of cognitive function and quality of life is also a central issue that will be analyzed in these vulnerable patients. PMID- 24948403 TI - Influence of carbon-dioxide on the growth of Spirulina sp. (MCRC-A0003) isolated from Muttukadu backwaters, South India. AB - Growth of Spirulina sp. (MCRC-A0003), a cyanobacterium, was evaluated under different concentrations of carbon-dioxide (CO2) (4-50 %) in a closed glass photobioreactor. Although significant CO2 utilization by the cyanobacterial strain was observed up to 50 % concentration, complete utilization was observed only at 4, 10 and 20 % concentrations on 3rd, 6th and 8th day respectively. However, considerable reduction was witnessed in reactors containing 30-50 % CO2 only between 6th and 9th day. A corresponding increase in the biomass and primary metabolites like chlorophyll-a, carbohydrate and protein were observed. Biomass productivity of Spirulina in reactors sparged with 4, 10 and 20 % CO2 were 13.7, 43 and 44 % more than that in control reactor without CO2. While CO2 increased the levels of primary metabolites in the cyanobacterial cells, it was quite prominent in 10 % CO2 concentration with the chlorophyll-a, carbohydrate and protein contents were 64, 183 and 626 mg g(-1) respectively. While 10 and 6.6 % increase were noticed in chlorophyll-a and protein, 17 % increase in carbohydrate levels was observed in Spirulina cells, which could be attributed to the conversion of CO2 to carbohydrate by the cyanobacterium. PMID- 24948404 TI - Use of recombinant activated factor VII in patients with Glanzmann's thrombasthenia: a review of the literature. AB - Glanzmann's thrombasthenia (GT) is a rare bleeding disorder characterized by a quantitative or qualitative defect of glycoprotein IIb/IIIa on the platelet membrane. Managing bleeding episodes is often difficult, and a variety of modalities have been used, including platelet transfusions, recombinant factor VIIa (rFVIIa), and other supportive care. The aim of this review was to present the clinical experience with rFVIIa bolus infusion (rFVIIa BI) for treatment of bleeding episodes and prevention of bleeding during surgical procedures in patients with GT. A literature search was performed to identify rFVIIa-treated patients with GT. Overall, one international survey, one open-label study, and 40 case reports identified 172 bleeding episodes treated with rFVIIa and 62 procedures covered with rFVIIa. In the international survey, rFVIIa BI was used for 96 bleeding episodes in 59 patients. Recombinant FVIIa was effective in 76 bleeding episodes (79%). Of 34 surgical procedures, 25 procedures received rFVIIa BI with 92% bleeding-prevention efficacy. The open-label study reported 28 patients with 28 rFVIIa BI-treated bleeds, and 26 (93%) bleeding episodes responded to rFVIIa. Published case reports revealed that 25 (69%) of 36 bleeds and 27 (96%) of 28 surgeries responded to rFVIIa BI treatment. Overall, 26 adverse events were reported in 19 patients, including five thromboembolic events in two patients where a possible relationship with rFVIIa could not be excluded. Two large studies and 40 case reports provide a literature base to support the efficacy and safety of rFVIIa BI in patients with GT. PMID- 24948405 TI - First analysis of 10-year trends in national factor concentrates usage in haemophilia: data from CHARMS, the Canadian Hemophilia Assessment and Resource Management System. AB - The Canadian Hemophilia Assessment and Resource Management System (CHARMS) tracks factor concentrates (FC) from the sole suppliers, Canadian Blood Services (CBS) and Hema-Quebec (HQ), to hospitals and to patients' homes. Patients FC infusion data are entered into CHARMS at Canadian Hemophilia Treatment Centres (HTCs) then exported to the national database (CentrePoint). From 2000 to 2009, 2260 registered haemophilia A or B patients received FVIII (1,009,097,765 IU) and FIX (272,406,859 IU). Over 91% of FVIII and over 84% of FIX was infused at home. Utilization of FVIII progressively increased; this was accounted for by an increase in the number of patients treated (r = 0.97; P < 0.001), there being a linear relationship between the increase in utilization and the increase in number of patients treated (P < 0.001). There was also a correlation with the annual amount used per patient (r = 0.95; P < 0.001). Utilization of FIX did not increase over time. The highest proportional utilization of both FVIII and FIX was for prophylaxis, and this proportion progressively increased being, in year 10 (2009), 77% and 66% for FVIII and FIX respectively. The proportion used for bleeding remained steady; in year 10 that proportion was 14% for FVIII and 26% for FIX, the use per patient for bleeding decreasing. The HTC-based CHARMS tracking system is essential, in Canada, for analysing indications for infusion, for predicting utilization and planning for future needs. PMID- 24948406 TI - When is enough...enough? Developing consensus of definition of failure of immune tolerance induction in patients with haemophilia and inhibitors. AB - Immune tolerance induction (ITI) is the preferred management of haemophilia A patients who develop high titre inhibitors against factor VIII. However, the optimal ITI regimen, predictors of ITI outcome and definitions of successful and unsuccessful ITI remain unclear. The aim of this project was to develop a consensus on the definition of ITI treatment failure for Australian clinical practice using a modified Delphi approach. Three consecutive surveys were distributed to the directors of 17 haemophilia treatment centres in Australia. Participants were asked to rate their agreement with definitions of ITI treatment failure generated from a literature review. Thirty-five statements regarding ITI achieved consensus (majority agree or strongly agree) during the three survey rounds. After round 3, four statements achieved majority disagreement, and for two statements no consensus was reached. Our study demonstrates that clinicians in Australia necessitate an arbitrary time to assess ITI failure, but that clinical outcomes of ITI are important in assessing response. Assessment over any 3- to 6-month period without a 20% reduction in inhibitor titre is suggestive of failure, but a reduction in bleeding phenotype alone may be sufficient to continue ITI. Overall, a period of 3 or 5 years of ITI may be required to determine response to ITI. Documentation of improvement in clinical measures, supported by the laboratory features of factor VIII inhibitor levels and pharmacokinetics, is essential in assessing the success of failure of ITI in these patients. PMID- 24948399 TI - Epigenetic regulation of persistent pain. AB - Persistent or chronic pain is tightly associated with various environmental changes and linked to abnormal gene expression within cells processing nociceptive signaling. Epigenetic regulation governs gene expression in response to environmental cues. Recent animal model and clinical studies indicate that epigenetic regulation plays an important role in the development or maintenance of persistent pain and possibly the transition of acute pain to chronic pain, thus shedding light in a direction for development of new therapeutics for persistent pain. PMID- 24948407 TI - Acquired thrombin and FV inhibitors upon aortic bioprosthetic valve replacement. PMID- 24948408 TI - Life expectancy of Korean haemophiliacs, 1991-2012. PMID- 24948409 TI - Intermaxillary fixation screw for endotracheal tube fixation in the edentulous patient with facial burns. AB - Endotracheal tube fixation in patients with severe facial burns and edentulism is a challenge. We describe a simple and elegant method to secure the endotracheal tube in such patients by means of an intermaxillary fixation screw. PMID- 24948410 TI - Comparative assessment of the therapeutic effects of the topical and systemic forms of Hypericum perforatum extract on induced oral mucositis in golden hamsters. AB - Oral mucositis is a common and irritating complication of chemotherapy and radiotherapy for malignancies. Current treatments have failed to achieve complete remission of this complication. The St. John's wort plant (Hypericum perforatum) has long been known for its anti-inflammatory and antibacterial effects. The current study was designed to investigate the therapeutic efficacy of the topical and systemic administration of H. perforatum extract on oral mucositis. Oral mucositis was induced in 72 male golden hamsters by administration of 5 fluorouracil (60mg/kg), on days 0, 5, and 10 of the study. The cheek pouch was scratched with a sterile needle on days 1 and 2. On days 12-17, H. perforatum extract topical gel 10%, oral H. perforatum extract (300mg/kg), and gel base groups were treated and then compared with a control group. Weights and blood samples were evaluated, biopsies from buccal lesions were examined histopathologically, and tissue malondialdehyde (MDA) was measured. Both of the H. perforatum extract treatment groups saw a significant relief in oral mucositis compared to the control and base gel groups; the systemic form was superior to the topical form. H. perforatum extract, administered orally or topically, expedited the healing of chemotherapy-induced oral mucositis in hamsters. PMID- 24948411 TI - Maxillary squamous cell carcinoma: an 11-year retrospective study of one regional cancer centre. AB - Intraoral maxillary squamous cell carcinoma (IOMSCC) tumours are comparatively rare compared to those occurring at other oral sites. This has resulted in limited studies regarding their pattern of local and regional behaviour. In a review of the IOMSCC cohort (N=39) at the study institution, IOMSCC was found to demonstrate a pattern of levels 1-3 nodal disease in the N+ neck at presentation (33.3%), with a total metastatic rate of 46.1%, which is similar to that for other intraoral sites. IOMSCC demonstrated metastatic potential to the contralateral neck, with 20% of patients progressing to present with disease. This seems to occur irrespective of midline involvement. On observation of the N0 group patients who did not have surgical treatment of the neck, the rate of progression to disease development was similar to those with N+ necks on presentation (38.5%). An ipsilateral selective neck dissection in the N0 cohort appeared to have resolved ipsilateral neck disease, but the disease rate in the contralateral neck, although numbers are small, was >20%. This clinical review suggests the use of level 1-3 ipsilateral neck dissection in treating the N0 patient for IOMSCC and may indicate a role for sentinel node biopsy in the management of the contralateral neck. PMID- 24948412 TI - Designing and evaluating a balanced scorecard for a health information management department in a Canadian urban non-teaching hospital. AB - This report is a description of a balanced scorecard design and evaluation process conducted for the health information management department at an urban non-teaching hospital in Canada. The creation of the health information management balanced scorecard involved planning, development, implementation, and evaluation of the indicators within the balanced scorecard by the health information management department and required 6 months to complete. Following the evaluation, the majority of members of the health information management department agreed that the balanced scorecard is a useful tool in reporting key performance indicators. These findings support the success of the balanced scorecard development within this setting and will help the department to better align with the hospital's corporate strategy that is linked to the provision of efficient management through the evaluation of key performance indicators. Thus, it appears that the planning and selection process used to determine the key indicators within the study can aid in the development of a balanced scorecard for a health information management department. In addition, it is important to include the health information management department staff in all stages of the balanced scorecard development, implementation, and evaluation phases. PMID- 24948414 TI - Superiority of 5% NaHCO3 for preoperative hair removal in patients undergoing coronary artery bypass graft surgery with a limb vein: a randomized controlled trial?. AB - OBJECTIVES: Compared with a dry environment with talcum powder, a wet, alkaline environment with NaHCO3 solution is better for hair removal, as it can soften and expand the hair, decrease the friction and shear forces on the skin, and make hair removal easier and more efficient. The purpose of this study was to compare the effects of a preoperative skin preparation of 5% NaHCO3 with that of talcum powder for softening hair in patients undergoing coronary artery bypass graft (CABG) surgery with the saphenous vein. METHODS: A prospective randomized, single blinded, controlled study was established. Between March 2012 and June 2013, 120 patients who met the inclusion and exclusion criteria underwent elective CABG surgery with the saphenous vein in our hospital. The same doctor obtained the saphenous vein of each patient by a uniform method. CABG surgery was performed through an open or endoscopic technique, according to each patient's condition. Patients were divided into two groups of 60 patients each, according to whether the preoperative skin preparation procedure was performed with a 5% solution of NaHCO3 at 45-50 degrees C (experimental group) or with talcum powder (control group). Main outcome measures were the incision inflammation rate, skin preparation time, presence of shaving-induced macroscopic haemorrhagic spots, verbal rating scale (VRS) pain score and satisfaction. RESULTS: Neither group had any evidence of incision inflammation. The average (mean +/- standard deviation) skin preparation time of the experimental group was shorter than that of the control group (5.58 +/- 1.52 vs 9.74 +/- 1.23 min, P < 0.001). Three patients in the experimental group and 17 in the control group had shaving-induced macroscopic haemorrhagic spots after skin preparation (P = 0.001). The VRS pain scores were different between the two groups (P < 0.001). In the control group, 40% of patients and 37% of nurses were satisfied with the skin preparation procedure, compared with 95 and 90%, respectively, in the experimental group (both P < 0.001). CONCLUSIONS: Hair softening with a 5% NaHCO3 solution protected the skin integrity, alleviated pain and improved patient satisfaction to a greater extent than talcum powder. Nurses found the 5% NaHCO3 solution to be more convenient and less time-consuming to use. PMID- 24948415 TI - Enhancing quality control and performance monitoring in thoracic aortic surgery: a 10-year single institutional experience. AB - OBJECTIVES: The aim of the present study was to monitor performance and learning effects for thoracic aortic surgery. In addition, we evaluated the volume-outcome relationship of patients undergoing surgery of the thoracic aorta, comparing the results of two higher-volume surgeons (HVSs) with six lower volume surgeons. METHODS: A total of 867 thoracic aortic procedures (elective cases n = 753 and Type A acute dissection n = 114) were performed from 2003 to 2013 by eight surgeons (range 28-238 procedures) at our institution. Departmental and individual performance was monitored using control charts, with a predetermined acceptable failure rate of 10%. Perioperative death or one or more of four adverse events constituted failure. Moreover, results of two higher-volume operators (n = 460; 53%) were compared with those of six lower-volume operators (n = 407; 47%). RESULTS: The incidence rate of in-hospital mortality for elective cases was 2% and for Type A dissection repair 9.6%. Institutional control charts revealed that the surgical process was under control for all the study periods apart from small periods of worse than expected performance which were congruent with new surgeons joining the programme. The predominant surgical failure was reoperation for bleeding. There were differences between surgeons with regard to the learning curves and performance. No significant differences were observed between high- and low-volume surgeons in terms of mortality and morbidity for elective cases. However, high-volume surgeons presented a trend suggesting a higher mortality rate in Type A aortic dissection repair (17.1 vs 6.3%; P = 0.09). CONCLUSIONS: Thoracic aortic surgery can be performed with similar results by high- and low-volume surgeon. Control charts can facilitate learning effects and performance monitoring. Implementation of continuous departmental and individual performance monitoring is practicable. PMID- 24948413 TI - The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial. AB - OBJECTIVES: Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome. METHODS: In a prospective, randomized, double-blind, placebo controlled trial, patients at two centres were randomized to receive either oral perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided alpha value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometry-based metabolomics. RESULTS: Over a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56-1.50, P = 0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07-0.31, P = 0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34-0.89, P = 0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups on metabolomics analysis. CONCLUSIONS: Preoperative perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry-visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery. CLINICALTRIALSGOV ID: NCT00845364. PMID- 24948416 TI - Perceived psychosocial stress and glucose intolerance among pregnant Hispanic women. AB - AIM: Prior literature suggests a positive association between psychosocial stress and the risk of diabetes in non-pregnant populations, but studies during pregnancy are sparse. We evaluated the relationship between stress and glucose intolerance among 1115 Hispanic (predominantly Puerto Rican) prenatal care patients in Proyecto Buena Salud, a prospective cohort study in Western Massachusetts (2006-2011). METHODS: Cohen's Perceived Stress Scale (PSS-14) was administered in early (mean = 12.3 weeks gestation; range 4.1-18 weeks) and mid- (mean = 21.3 weeks gestation; range 18.1-26 weeks) pregnancy. Participants were classified as having a pregnancy complicated by gestational diabetes mellitus, impaired glucose tolerance, and abnormal glucose tolerance, based on the degree of abnormality on glucose tolerance testing between 24 and 28 weeks of gestation. RESULTS: The prevalence of gestational diabetes mellitus, impaired glucose tolerance, and abnormal glucose tolerance was 4.1%, 7.2%, and 14.5%, respectively. Absolute levels of early or mid-pregnancy stress were not significantly associated with glucose intolerance. However, participants with an increase in stress from early to mid-pregnancy had a 2.6-fold increased odds of gestational diabetes mellitus (95% confidence intervals: 1.0-6.9) as compared to those with no change or a decrease in stress after adjusting for age and pre pregnancy body mass index. In addition, every one-point increase in stress scores was associated with a 5.5mg/dL increase in screening glucose level (beta=5.5; standard deviation=2.8; P=0.05), after adjusting for the same variables. CONCLUSION: In this population of predominantly Puerto Rican women, stress patterns during pregnancy may influence the risk of glucose intolerance. PMID- 24948418 TI - Regulation of growth hormone induced JAK2 and mTOR signalling by hepatic protein tyrosine phosphatase 1B. AB - Protein tyrosine phosphatase 1B (PTP1B) regulates various signalling pathways including insulin, leptin, IGF-1 and growth hormone (GH) signalling. Transmission of the GH signal depends on Janus kinase 2 (JAK2), which is how PTP1B is thought to modulate GH signalling in the liver, based on studies utilising global PTP1B knockout mice (Ptp1b(-/-)). Here, we investigated the liver-specific role of PTP1B in GH signalling, using liver-specific Ptp1b(-/-) mice (alb-crePtp1b(-/-)), under physiological (chow) or insulin resistant (high-fat diet [HFD]) feeding conditions. Body weight and adiposity were comparable between female alb crePtp1b(-/-) and Ptp1b(fl/fl) control mice. On chow diet, under 48-hour fasting GH-resistant conditions, GH stimulation in vivo led to a robust stimulation of the JAK-STAT signalling pathway. Alb-crePtp1b(-/-) mice exhibited significantly higher GH-induced JAK2 phosphorylation and SOCS3 gene expression post-GH stimulation. However, STAT3, STAT5 and ERK1/2 phosphorylation and SOCS2 gene expression were similar between groups. Interestingly, GH-induced mTOR phosphorylation was significantly higher in alb-crePtp1b(-/-) mice 5-min post-GH stimulation compared to controls, revealing this part of the pathway under direct control of PTP1B. Under ad lib HFD-fed conditions, GH-induced STAT5 phosphorylation significantly increased in alb-crePtp1b(-/-) mice only, with no alterations in the controls. Overall, our data demonstrate that liver-specific PTP1B deletion leads to significant alterations in GH signalling with increased JAK2, STAT5 and mTOR phosphorylation and SOCS3 gene expression. PMID- 24948417 TI - Maternal diabetes, programming of beta-cell disorders and intergenerational risk of type 2 diabetes. AB - A substantial body of evidence suggests that an abnormal intra-uterine milieu elicited by maternal metabolic disturbances as diverse as malnutrition, placental insufficiency, diabetes and obesity may be able to programme susceptibility of the foetus to later develop chronic degenerative diseases such as obesity, hypertension, cardiovascular diseases and type 2 diabetes (T2D). As insulin producing cells have been placed centre stage in the development of T2D, this review examines developmental programming of the beta-cell mass (BCM) in various rodent models of maternal protein restriction, calorie restriction, overnutrition and diabetes. The main message is that whatever the initial maternal insult (F0 generation) and whether alone or in combination, it gives rise to the same programmed BCM outcome in the daughter generation (F1). The altered BCM phenotype in F1 females prohibits normal BCM adaptation during pregnancy and, thus, diabetes (gestational diabetes) ensues. This gestational diabetes is then passed from one generation (F1) to the next (F2, F3 and so on). This review highlights a number of studies that have identified epigenetic mechanisms that may contribute to altered BCM development and beta-cell failure, as observed in diabetes. In addition to their role in instilling the programmed defect, these non-genomic mechanisms may also be involved in its intergenerational transmission. PMID- 24948419 TI - Mutations in the 50S ribosomal subunit of Brachyspira hyodysenteriae associated with altered minimum inhibitory concentrations of pleuromutilins. AB - Brachyspira hyodysenteriae, the causative agent of swine dysentery, is responsible for severe mucohaemorrhagic colitis with considerable financial loss to worldwide swine production. Antimicrobial resistance against macrolides and lincosamides is widespread and the mechanisms are well known. Currently, the most common treatment for swine dysentery is the use of pleuromutilins and resistance to these drugs also is increasingly being reported. Although resistance mechanisms against pleuromutilins are less clear than for other drugs, they seem to involve alterations of the peptidyl transferase centre (PTC), including ribosomal RNA and the ribosomal protein L3. The present study was conducted to examine molecular mechanisms of resistance on a representative set of B. hyodysenteriae field strains with different resistance patterns. In total, we identified 24 single nucleotide polymorphisms (SNPs) in the 23S rRNA gene and genes of the ribosomal proteins L3, L4, L2 and L22. The SNP in the ribosomal protein gene L3 at position 443 led to an amino acid substitution of asparagine (Asn) by serine (Ser) at position 148, significantly associated with MICs for pleuromutilins. Based on this SNP a correct assignment of 71% of the strains with respect to a threshold of >0.625 MUg tiamulin/ml was reached. Unexpectedly low MICs in some of the Asn-strains were explained by a second SNP at position 2535 of the 23S rRNA. Our results clearly show the associations between MICs for pleuromutilins and mutations in their binding site. A complete list of SNPs that influence MICs of B. hyodysenteriae strains is needed to enable the interpretation of future molecular susceptibility testing. PMID- 24948420 TI - Polynorbornene derived 8-hydroxyquinoline paper strips for ultrasensitive chemical nerve agent surrogate sensing. AB - The detection of nerve agent simulants is achieved by the photoinduced electron transfer (PET) mechanism. A "turn-on" fluorescence response upon phosphorylation at 8-hydroxyquinoline of norbornene-based triazolyl functionalized 8 hydroxyquinoline () followed by intramolecular rearrangement provides very intense green emission. The detection limit of polymer () coated paper strips is 25 ppb with instantaneous response. PMID- 24948421 TI - Mucosal papules in a 9-year-old girl. PMID- 24948422 TI - Stigmatization of people with pedophilia: two comparative surveys. AB - Despite productive research on stigma and its impact on people's lives in the past 20 years, stigmatization of people with pedophilia has received little attention. We conducted two surveys estimating public stigma and determining predictors of social distance from this group. In both studies, pedophilia was defined as a "dominant sexual interest in children." The survey was comprised of items measuring agreement with stereotypes, emotions, and social distance (among others). Responses were compared with identical items referring to either people who abuse alcohol (Study 1), sexual sadists or people with antisocial tendencies (Study 2). Study 1 was conducted in two German cities (N = 854) and Study 2 sampled 201 English-speaking online participants. Both studies revealed that nearly all reactions to people with pedophilia were more negative than those to the other groups, including social distance. Fourteen percent (Study 1) and 28 % (Study 2) of the participants agreed that people with pedophilia should better be dead, even if they never had committed criminal acts. The strongest predictors of social distance towards people with pedophilia were affective reactions to this group (anger and, inversely, associated, pity) and the political attitude of right-wing authoritarianism (Study 1). Results strongly indicate that people with pedophilia are a stigmatized group who risk being the target of fierce discrimination. We discuss this particular form of stigmatization with respect to social isolation of persons with pedophilia and indirect negative consequences for child abuse prevention. PMID- 24948423 TI - How anomalous are paraphilic interests? PMID- 24948424 TI - Atherosclerosis in mummified human remains from Vilnius, Lithuania (18th-19th centuries AD): a computed tomographic investigation. AB - OBJECTIVE: Through the study of preserved human remains, it is now known that atherosclerosis, commonly thought to be a modern disease, also existed in historic and prehistoric periods. To date, however, little evidence of atherosclerosis has been reported in samples of tissues from spontaneously mummified bodies that are often found in European crypts and churches. METHODS: Within the framework of the Lithuanian Mummy Project, whole-body computed tomographic scans of seven spontaneous mummies from a crypt in Vilnius were obtained and assessed for indications of atherosclerosis. RESULTS: Three of the mummies investigated showed clear evidence of atherosclerosis, which was at times quite severe. Atherosclerosis is believed to have been prevalent among affluent members of Lithuanian society, which is corroborated by historical sources. CONCLUSIONS: In accordance with recent, significant data, this study further demonstrates the antiquity of this disease. Documentary and ethnographic data suggest that lifestyle may have played a role in the onset of atherosclerosis in these individuals. PMID- 24948425 TI - Classification and localization of early-stage Alzheimer's disease in magnetic resonance images using a patch-based classifier ensemble. AB - INTRODUCTION: Classification methods have been proposed to detect Alzheimer's disease (AD) using magnetic resonance images. Most rely on features such as the shape/volume of brain structures that need to be defined a priori. In this work, we propose a method that does not require either the segmentation of specific brain regions or the nonlinear alignment to a template. Besides classification, we also analyze which brain regions are discriminative between a group of normal controls and a group of AD patients. METHODS: We perform 3D texture analysis using Local Binary Patterns computed at local image patches in the whole brain, combined in a classifier ensemble.We evaluate our method in a publicly available database including very mild-to-mild AD subjects and healthy elderly controls. RESULTS: For the subject cohort including only mild AD subjects, the best results are obtained using a combination of large (30*30*30 and 40*40*40 voxels) patches. A spatial analysis on the best performing patches shows that these are located in the medial-temporal lobe and in the periventricular regions. When very mild AD subjects are included in the dataset, the small (10*10*10 voxels) patches perform best, with the most discriminative ones being located near the left hippocampus. CONCLUSION: We show that our method is able not only to perform accurate classification, but also to localize dis-criminative brain regions, which are in accordance with the medical literature. This is achieved without the need to segment-specific brain structures and without performing nonlinear registration to a template, indicating that the method may be suitable for a clinical implementation that can help to diagnose AD at an earlier stage. PMID- 24948426 TI - Salivary gland tumors of the parotid gland: CT and MR imaging findings with emphasis on intratumoral cystic components. AB - INTRODUCTION: The purpose of this study was to assess computed tomography (CT) and magnetic resonance (MR) imaging findings of salivary gland tumors of the parotid gland with emphasis on intratumoral cystic components. METHODS: Seventy two histopathologically confirmed salivary gland tumors of the parotid gland (44 benign and 28 malignant), which underwent both CT and MR imaging including contrast-enhanced study, were included in this study. We retrospectively reviewed images for the presence, number, occupying rate, margin characteristics, distribution, and predominant MR signal intensity of intratumoral cystic components. RESULTS: The prevalence of cystic components was greater in malignant than benign tumors (79 vs. 50%, p < 0.05). The number and occupying rate were similar between benign and malignant tumors. The irregular margins were more frequent in malignant than benign tumors (73 vs. 27%, p < 0.01). The frequency of eccentric location was greater in benign than malignant tumors (91 vs. 55%, p < 0.01), whereas the frequency of centric location was greater in malignant than benign tumors (32 vs. 0%, p < 0.01). On T1-weighted images, the frequency of hyperintensity was greater in benign than malignant tumors (50 vs. 9%, p < 0.01), whereas that of isointensity was greater in malignant than benign tumors (50 vs. 0%, p < 0.01). Multiple logistic regression analysis showed that the absence of irregular margins of cystic components only was significantly correlated with the presence of benign salivary gland tumors (p < 0.01). CONCLUSION: Imaging features of intratumoral cystic components may help to differentiate benign from malignant tumors of the parotid salivary gland. PMID- 24948427 TI - Computer-based analysis of general movements reveals stereotypies predicting cerebral palsy. PMID- 24948428 TI - The use of lisdexamfetamine dimesylate for the treatment of ADHD and other psychiatric disorders. AB - Lisdexamfetamine dimesylate (LDX) is a long-acting oral prodrug stimulant. It is inactive until enzymatically hydrolyzed in the blood to active D-amphetamine. The pharmacological action of this compound involves blocking norepinephrine (NE) and dopamine reuptake into presynaptic neurons and promoting the release of NE and dopamine into the extraneuronal space. LDX has been approved for treating ADHD, which is the most common psychiatric disorder in children and adolescents. Also, LDX has been proposed for other psychiatric conditions related with dopaminergic and NE CNS. LDX is the first long-acting oral prodrug indicated for the treatment of ADHD in children (6-12 years), adolescents (13-17 years) and in adults in the USA and Canada, whereas, in Europe, LDX is licensed in several countries for the treatment of children and adolescents with ADHD who have had a clinically inadequate response to methylphenidate. This article covers the most important pharmacological aspects of LDX as well as data on the efficacy, tolerability and safety of this long-acting amphetamine prodrug collected from clinical studies recently published in the literature. PMID- 24948429 TI - Statistical and methodological concerns about the beneficial effect of neuraminidase inhibitors on mortality. PMID- 24948430 TI - The role of macrolides in asthma: current evidence and future directions. AB - Macrolides, such as clarithromycin and azithromycin, possess antimicrobial, immunomodulatory, and potential antiviral properties. They represent a potential therapeutic option for asthma, a chronic inflammatory disorder characterised by airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. Results from clinical trials, however, have been contentious. The findings could be confounded by many factors, including the heterogeneity of asthma, treatment duration, dose, and differing outcome measures. Recent evidence suggests improved effectiveness of macrolides in patients with sub-optimally controlled severe neutrophilic asthma and in asthma exacerbations. We examine the evidence from clinical trials and discuss macrolide properties and their relevance to the pathophysiology of asthma. At present, the use of macrolides in chronic asthma or acute exacerbations is not justified. Further work, including proteomic, genomic, and microbiome studies, will advance our knowledge of asthma phenotypes, and help to identify a macrolide responsive subgroup. Future clinical trials should target this subgroup and place emphasis on clinically relevant outcomes such as asthma exacerbations. PMID- 24948431 TI - Statistical and methodological concerns about the beneficial effect of neuraminidase inhibitors on mortality. PMID- 24948433 TI - Statistical and methodological concerns about the beneficial effect of neuraminidase inhibitors on mortality. PMID- 24948434 TI - Statistical and methodological concerns about the beneficial effect of neuraminidase inhibitors on mortality. PMID- 24948432 TI - Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation. AB - BACKGROUND: Short telomere lengths are found in a subset of patients with idiopathic pulmonary fibrosis, but their clinical significance is unknown. Our aim was to investigate whether patients with various blood leucocyte telomere lengths had different overall survival. METHODS: In this observational cohort study, we enrolled patients with interstitial lung disease from Dallas, TX (primary cohort), and from Chicago, IL, and San Francisco, CA (replication cohorts). We obtained genomic DNA samples from unrelated healthy controls in Dallas, TX, and spouses of patients were also enrolled as an independent control group. Telomere lengths were measured in genomic DNA samples isolated from peripheral blood obtained at the time of the initial enrolment assessment. The primary endpoint was transplant-free survival (ie, time to death or lung transplantation) in the Dallas cohort. Findings were validated in the two independent idiopathic pulmonary fibrosis cohorts (Chicago and San Francisco). FINDINGS: 370 patients were enrolled into the Dallas cohort between June 17, 2003, and Aug 25, 2011. The 149 patients with idiopathic pulmonary fibrosis had shorter telomere lengths than did the 195 healthy controls (mean age-adjusted log transformed ratio of telomere to single copy gene was -0.16 [SD 0.23] vs 0.00 [0.18]; p<0.0001); however, telomere lengths of the Dallas patients with idiopathic pulmonary fibrosis (1.33 [SD 0.25]) were similar to the 221 patients with other interstitial lung disease diagnoses (1.46 [0.24]) after adjusting for age, sex, and ethnicity (p=0.47). Telomere length was independently associated with transplant-free survival time for patients with idiopathic pulmonary fibrosis (HR 0.22 [95% CI 0.08-0.63]; p=0.0048), but not for patients with interstitial lung disease diagnoses other than idiopathic pulmonary fibrosis (HR 0.73 [0.16-3.41]; p=0.69). The association between telomere length and survival in patients with idiopathic pulmonary fibrosis was independent of age, sex, forced vital capacity, or diffusing capacity of carbon monoxide, and was replicated in the two independent idiopathic pulmonary fibrosis replication cohorts (Chicago cohort, HR 0.11 [0.03-0.39], p=0.00066; San Francisco cohort, HR 0.25 [0.07-0.87], p=0.029). INTERPRETATION: Shorter leucocyte telomere lengths are associated with worse survival in idiopathic pulmonary fibrosis. Additional studies will be needed to establish clinically relevant thresholds for telomere length and how this biomarker might affect risk stratification of patients with idiopathic pulmonary fibrosis. FUNDING: US National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, Harroun Family Foundation, and Nina Ireland Lung Disease Program. PMID- 24948436 TI - Transposon mutagenesis of the extremely thermophilic bacterium Thermus thermophilus HB27. AB - Thermus thermophilus is an extremely thermophilic bacterium that grows between 50 and 80 degrees C and is an excellent model organism not only for understanding life at high temperature but also for its biotechnological and industrial applications. Multiple molecular capabilities are available including targeted gene inactivation and the use of shuttle plasmids that replicate in T. thermophilus and Escherichia coli; however, the ability to disrupt gene function randomly by transposon insertion has not been developed. Here we report a detailed method of transposon mutagenesis of T. thermophilus HB27 based on the EZ Tn5 system from Epicentre Biotechnologies. We were able to generate insertion mutations throughout the chromosome by in vitro transposition and transformation with mutagenized genomic DNA. We also report that an additional step, one that fills in single stranded gaps in donor DNA generated by the transposition reaction, was essential for successful mutagenesis. We anticipate that our method of transposon mutagenesis will enable further genetic development of T. thermophilus and may also be valuable for similar endeavors with other under developed organisms. PMID- 24948437 TI - White matter lesions and depression: a systematic review and meta-analysis. AB - We sought to determine if an association exists between overall, deep, and periventricular white matter hyperintensities and depression. We searched PubMed (Medline) and Scopus (Embase) from April-October 2012 using the MeSH terms: "White matter lesions" OR "white matter disease" OR "Cerebrovascular Disease" OR "Leukoencephalopathies" AND "Depressive Disorder" AND "magnetic resonance imaging," and "Depression" AND "leukoaraiosis." No language limits were implemented. Hand searching was performed of all included studies and relevant review articles. 913 PubMed and 188 Scopus citations were identified. Relevant, human, non-overlapping magnetic resonance imaging studies were eligible for inclusion if they reported generic data. We extracted the most adjusted odds ratios reported generated from comparing depression across severe (determined either volumetrically or visually) and mild/no white matter lesion groups. 19 reports were included. Cross-sectional subgroup analyses showed that deep white matter hyperintensities significantly associated with depression (N = 2261, odds ratio 1.02, 95% confidence interval 1.00-1.04, p = 0.02), whereas periventricular (N = 3813, odds ratio 1.08, 95% confidence interval 0.99-1.17, p = 0.07) and overall did not (N = 5876, odds ratio 1.12, 95% confidence interval 0.96-1.30, p = 0.14). Overall longitudinal analysis revealed a pooled odds ratio of 1.12 (N = 2015; 95% confidence interval 0.97-1.29; p = 0.13; Q = 7.19, p = 0.07; I2 = 58.3%). Longitudinal subgroup analyses revealed that overall white matter hyperintensities (N = 1882, odds ratio 1.22, 95% confidence interval, 1.06-1.4, p < 0.01) significantly associated with depression but deep did not (N = 660, odds ratio 2.02, 95% confidence interval, 0.56-7.22, p = 0.281). No significant heterogeneity was present in subgroup analyses. In conclusion, we found a significant, but weak association between white matter hyperintensities and depression. PMID- 24948439 TI - Early adoption of the human papillomavirus vaccine among Hispanic adolescent males in the United States. AB - BACKGROUND: Human papillomavirus (HPV) infection is common among Hispanic males, but to the authors' knowledge little is known regarding HPV vaccination in this population. The authors examined the early adoption of the HPV vaccine among a national sample of Hispanic adolescent males. METHODS: The authors analyzed provider-verified HPV vaccination data from the 2010 through 2012 National Immunization Survey-Teen (NIS-Teen) for Hispanic males aged 13 years to 17 years (n = 4238). Weighted logistic regression identified correlates of HPV vaccine initiation (receipt of >= 1 doses). RESULTS: HPV vaccine initiation was 17.1% overall, increasing from 2.8% in 2010 to 31.7% in 2012 (P < .0001). Initiation was higher among sons whose parents had received a provider recommendation to vaccinate compared with those whose parents had not (53.3% vs 9.0%; odds ratio, 8.77 [95% confidence interval, 6.05-12.70]). Initiation was also higher among sons who had visited a health care provider within the previous year (odds ratio, 2.42; 95% confidence interval, 1.39-4.23). Among parents with unvaccinated sons, Spanish-speaking parents reported much higher intent to vaccinate compared with English-speaking parents (means: 3.52 vs 2.54; P < .0001). Spanish-speaking parents were more likely to indicate lack of knowledge (32.9% vs 19.9%) and not having received a provider recommendation (32.2% vs 17.7%) as the main reasons for not intending to vaccinate (both P < .05). CONCLUSIONS: HPV vaccination among Hispanic adolescent males has increased substantially in recent years. Ensuring health care visits and provider recommendation will be key for continuing this trend. Preferred language may also be important for increasing HPV vaccination and addressing potential barriers to vaccination. PMID- 24948438 TI - The one-year attributable cost of post-stroke dysphagia. AB - With the recent emphasis on evidence-based practice and healthcare reform, understanding the cost of dysphagia management has never been more important. It is helpful for clinicians to understand and objectively report the costs associated with dysphagia when they advocate for their services in this economy. Having carefully estimated cost of illness, inputs are needed for cost effectiveness analyses that help support the value of treatments. This study sought to address this issue by examining the 1-year cost associated with a diagnosis of dysphagia post-stroke in South Carolina. Furthermore, this study investigated whether ethnicity and residence differences exist in the cost of dysphagia post-stroke. Data on 3,200 patients in the South Carolina Medicare database from 2004 who had ICD-9 codes for ischemic stroke, 434 and 436, were retrospectively included in this study. Differences between persons with and without dysphagia post-stroke were compared with respect to age, gender, ethnicity, mortality, length of stay, comorbidity, rurality, discharge disposition, and cost to Medicare. Univariate analyses and a gamma-distributed generalized linear multivariable model with a log link function were completed. We found that the 1-year cost to Medicare for persons with dysphagia post ischemic stroke was $4,510 higher than that for persons without dysphagia post ischemic stroke when controlling for age, comorbidities, ethnicity, and proportion of time alive. Univariate analysis revealed that rurality, ethnicity, and gender were not statistically significantly different in comparisons of individuals with or without dysphagia post-stroke. Post-stroke dysphagia significantly increases post-stroke medical expenses. Understanding the expenditures associated with post-stroke dysphagia is helpful for optimal allocation and use of resources. Such information is needed to conduct cost effectiveness studies. PMID- 24948441 TI - Efficient visible-light photocatalytic activity by band alignment in mesoporous ternary polyoxometalate-Ag2S-CdS semiconductors. AB - Porous multicomponent semiconductor materials show improved photocatalytic performance due to the large and accessible pore surface area and high charge separation efficiency. Here we report the synthesis of well-ordered porous polyoxometalate (POM)-Ag2S-CdS hybrid mesostructures featuring a controllable composition and high photocatalytic activity via a two-step hard-templating and topotactic ion-exchange chemical process. Ag2S compounds and polyoxometalate cluster anions with different reduction potentials, such as PW12O40(3-), SiW12O40(4-) and PMo12O40(3-), were employed as electron acceptors in these ternary heterojunction photocatalysts. Characterization by small-angle X-ray scattering, X-ray diffraction, transmission electron microscopy and N2 physisorption measurements showed hexagonal arrays of POM-Ag2S-CdS hybrid nanorods with large internal BET surface areas and uniform mesopores. The Keggin structure of the incorporated POM clusters was also verified by elemental X-ray spectroscopy microanalysis, infrared and diffuse-reflectance ultraviolet-visible spectroscopy. These new porous materials were implemented as visible-light-driven photocatalysts, displaying exceptional high activity in aerobic oxidation of various para-substituted benzyl alcohols to the corresponding carbonyl compounds. Our experiments show that the spatial separation of photogenerated electrons and holes at CdS through the potential gradient along the CdS-Ag2S-POM interfaces is responsible for the increased photocatalytic activity. PMID- 24948440 TI - Complex fractionated atrial electrograms related to left atrial wall thickness. AB - INTRODUCTION: The mechanism of complex fractionated atrial electrogram (CFAE) in patients with atrial fibrillation (AF) remains controversial. This study investigated the relationship between CFAE and left atrial (LA) wall thickness. METHODS AND RESULTS: LA muscular wall thickness (excluding fat) was measured by cardiac computed tomography in 31 patients with AF (12 paroxysmal, 19 persistent) prior to catheter ablation procedures. Measurements were performed at 31 distinct LA locations: 3 at roof, 3 at floor, 9 at anterior wall, 9 at posterior wall, 3 at lateral wall, 3 at septum, and 1 at base of the anterior appendage. The range of LA wall thickness (LAWT) varied widely (average 2.4 +/- 0.4 mm, range 1.5-3.1 mm) between patients. In addition, there were significant regional differences in LAWT. Each patient had an average of 7.3 +/- 3.5 CFAE sites. The LA wall was thicker at CFAE sites (227 sites, 3.0 +/- 1.0 mm) than at non-CFAE sites (734 sites, 2.2 +/- 0.9 mm, P < 0.001). In 23 of 31 (74%) patients, the LA wall was thicker at CFAE area than at non-CFAE area. There was no difference in LAWT between sites where CFAE vanished and those where CFAE persisted after pulmonary vein isolation (PVI) among sites with CFAE before PVI. The LAWT > 2.5 mm predicted CFAE with a sensitivity of 70% and a specificity of 70%. CONCLUSION: The LAWT correlates well with CFAE areas, suggesting that one of the mechanisms of CFAE might be related to LAWT. PMID- 24948442 TI - [The value of genetics in the era of hepatitis C triple therapy]. AB - Despite the introduction of protease inhibitors (PI) in the treatment of hepatitis C, the sensitivity of interferon continues to be essential to achieve a sustained virological response (SVR) and to eradicate the viral infection. Currently, pegylated interferon (PEG-IFN) and ribavirin (RBV) are required to avoid selection of PI-resistance mutations. The likelihood of obtaining an SVR with dual therapy in treatment-naive patients with genotype 1 infection varies from 40% to 50%. That is, almost half of these patients would not require a PI, thus avoiding their adverse effects and considerably reducing the cost of the treatment. Identifying which patients could potentially respond to dual therapy is one of the main challenges in clinical practice. The genetic variability of the host is one of the main factors affecting the sensitivity of PEG-IFN and therefore in the response to current treatment. Other baseline factors related to the host, the virus and, especially, to intratreatment factors such as rapid virological response (RVR) are strongly associated with the probability of achieving an SVR. The evidence on the decision to prescribe dual or triple therapy according to the factors predictive of response is based on retrospective studies or post-hoc analyses of pivotal studies on PI. Study of the polymorphisms of the IFNL3 gene (IL28B), ITPA, IFN-stimulated genes (ISGs), TT/DeltaG (ss469415590; IFNL4)) and RBV transporters could help in the decision to prescribe dual or triple therapy in treatment naive patients. PMID- 24948443 TI - [Diagnostic capability of carcinoembryonic antigen elevation]. AB - INTRODUCTION: There is little information on the oncologic diagnostic accuracy of carcinoembryonic antigen (CEA) levels more than 3-fold above normal. OBJETIVES: To determine the prevalence of underlying cancer in patients with mild CEA elevation and the mean cost per patient of CEA determination. METHODS: A retrospective study was carried out in all patients with CEA elevation (3-10 ng/ml) and suspicion of cancer referred to the gastroenterology or internal medicine outpatient units from 2001 to 2007. RESULTS: We studied 100 patients (60 men and 40 women), with a mean age of 67.4 +/- 14.2 years and baseline CEA of 5.8 +/- 1.7 ng/ml. The most important symptoms and signs were laboratory abnormalities (19 patients [19%]). Cancer was diagnosed in 4 patients (one gastric, 2 lung and one colon). Among patients without malignancies, 49 patients (49%) had no related processes, and 47 (47%) had benign diseases. During follow up, one laryngeal cancer, one acute myeloid leukemia, and one colon cancer were detected (54.3 +/- 24.6 months). We found no differences between baseline CEA levels in patients with and without cancer (6.6 +/- 2.4 vs. 5.8 +/- 1.7 ng/ml, p = 0.2). The mean cost per patient was 503.6 +/- 257.6 ?. CONCLUSIONS: Cancer was detected in a small proportion (7%) of patients with mild CEA elevation. The study of these patients is directly and indirectly associated with a not inconsiderable cost. PMID- 24948444 TI - [Early interruption of triple therapy with telaprevir in chronic hepatitis C due to severe adverse effects does not necessarily lead to treatment failure]. PMID- 24948445 TI - [Design of a preoperative predictive score for choledocholithiasis]. AB - INTRODUCTION: Choledocholithiasis is the most common cause of obstructive jaundice and occurs in 5-10% of patients with cholelithiasis. OBJECTIVES: To design a preoperative predictive score for choledocholithiasis. MATERIAL AND METHODS: A prospective study was carried out in 556 patients admitted to our department for biliary disease. Preoperative clinical, laboratory, and ultrasound variables were compared between patients without choledocholithiasis and 65 patients with this diagnosis. A multivariate logistic analysis was performed to obtain a predictive model of choledocholithiasis, determining sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Predictors of choledocholithiasis were the presence of a prior history of biliary disease (history of biliary colic, acute cholecystitis, choledocholithiasis or acute biliary pancreatitis) (p=0.021, OR=2.225, 95% CI: 1.130-4.381), total bilirubin values >4mg/dl (p=0.046, OR=2.403, 95% CI: 1.106 5.685), alkaline phosphatase values >150mg/dl (p=0.022 income, OR=2.631, 95%: 1.386-6.231), gamma-glutamyltransferase (GGT) values >100mg/dl (p=0.035, OR=2.10, 95% CI: 1.345-5.850), and an ultrasound finding of biliary duct >8mm (p=0.034, OR=3.063 95% CI: 1086-8649). A score superior to 5 had a specificity and PPV of 100% for detecting choledocholithiasis and a score less than 3 had a sensitivity and NPV of 100% for excluding this diagnosis. CONCLUSIONS: The preoperative score can exclude or confirm the presence of choledocholithiasis and allows patients to directly benefit from laparoscopic cholecystectomy (LC) or prior endoscopic retrograde cholangiopancreatography (ERCP). PMID- 24948446 TI - Prolonged acute migraine with aura and reversible brain MRI abnormalities after liquid sclerotherapy. AB - Transient visual disturbances constitute the most commonly reported neurological side effect during and immediately after sclerotherapy. A few studies, based on clinical and diffusion-weighted MRI assessments, have suggested that these transient neurological symptoms correspond to migraine with aura. Recently, it has been reported that brain magnetic resonance imaging can reveal transient T2* weighted abnormalities during the acute phase of migraine with aura. We reported a 36-year-old man who presented with transient neurological symptoms and concomitant T2*-weighted abnormalities on brain magnetic resonance imaging immediately after liquid sclerotherapy. We hypothesize that the reversible nature of the patient's T2*-weighted abnormalities may indicate a relationship with the post-sclerotherapy migraine with aura attack. PMID- 24948447 TI - Survival benefit of induction immunosuppression in cystic fibrosis lung transplant recipients. AB - BACKGROUND: Despite resistant microbes, induction immunosuppression is used in patients with cystic fibrosis (CF) undergoing lung transplantation (LTx). METHODS: To evaluate the effect of induction immunosuppression on survival, the United Network for Organ Sharing (UNOS) was queried restricting analysis to transplant patients 6-55years old from 2001 to 2012, who received induction agents (INDUCED) or did not (NONE). RESULTS: A total of 1721 CF patients who underwent LTx were included in the analysis; of these 791 (46%) were INDUCED. Of the INDUCED patients, 65% received basiliximab, 10% alemtuzumab, and 25% thymoglobulin/anti-lymphocyte globulin/anti-thymocyte globulin. Mean age was 28.0years (SD=9.7) and 28.5 (SD=9.5) for the INDUCED and NONE groups, respectively. The median survival in the INDUCED group was 93.8months (95% CI: 73.8, --) compared to 61.8months (95% CI: 55.8-73.8) for the NONE group (log rank p-value <0.001). CONCLUSIONS: Antibody-based induction immunosuppression had a survival benefit in CF patients undergoing LTx. PMID- 24948448 TI - Targeting eukaryotic Rab proteins: a smart strategy for chlamydial survival and replication. AB - Chlamydia, an obligate intracellular bacterium which passes its entire lifecycle within a membrane-bound vacuole called the inclusion, has evolved a variety of unique strategies to establish an advantageous intracellular niche for survival. This review highlights the mechanisms by which Chlamydia subverts vesicular transport in host cells, particularly by hijacking the master controllers of eukaryotic trafficking, the Rab proteins. A subset of Rabs and Rab interacting proteins that control the recycling pathway or the biosynthetic route are selectively recruited to the chlamydial inclusion membrane. By interfering with Rab-controlled transport steps, this intracellular pathogen not only prevents its own degradation in the phagocytic pathway, but also creates a favourable intracellular environment for growth and replication. Chlamydia, a highly adapted and successful intracellular pathogen, has several redundant strategies to re direct vesicles emerging from biosynthetic compartments that carry host molecules essential for bacterial development. Although current knowledge is limited, the latest findings have shed light on the role of Rab proteins in the course of chlamydial infections and could open novel opportunities for anti-chlamydial therapy. PMID- 24948449 TI - Strategies for human-driven robot comprehension of spatial descriptions by older adults in a robot fetch task. AB - This contribution presents a corpus of spatial descriptions and describes the development of a human-driven spatial language robot system for their comprehension. The domain of application is an eldercare setting in which an assistive robot is asked to "fetch" an object for an elderly resident based on a natural language spatial description given by the resident. In Part One, we describe a corpus of naturally occurring descriptions elicited from a group of older adults within a virtual 3D home that simulates the eldercare setting. We contrast descriptions elicited when participants offered descriptions to a human versus robot avatar, and under instructions to tell the addressee how to find the target versus where the target is. We summarize the key features of the spatial descriptions, including their dynamic versus static nature and the perspective adopted by the speaker. In Part Two, we discuss critical cognitive and perceptual processing capabilities necessary for the robot to establish a common ground with the human user and perform the "fetch" task. Based on the collected corpus, we focus here on resolving the perspective ambiguity and recognizing furniture items used as landmarks in the descriptions. Taken together, the work presented here offers the key building blocks of a robust system that takes as input natural spatial language descriptions and produces commands that drive the robot to successfully fetch objects within our eldercare scenario. PMID- 24948450 TI - In vitro evaluation of a multifunctional nano drug delivery system based on tigecycline-loaded calcium-phosphate/ poly-DL-lactide-co-glycolide. AB - Most drug delivery systems as treatment modalities for osteomyelitis have not been evaluated for resistant infections. Tigecycline (TG) is an antimicrobial agent that could be used in the treatment of multi-drug-resistant orthopedic infections. The objective of this in vitro study has been to determine what dosage of TG causes changes in the morphology and number of osteoblasts. We have also investigated whether nanoparticulate tigecycline-loaded calcium phosphate/poly-DL-lactide-co-glycolide is biocompatible and whether it could release bioactive TG in a controlled manner during the observation time. The cytotoxicity was tested by analyzing the release of lactate dehydrogenase from dead osteoblasts to the medium. Staphylococcus aureus was used to verify the antibacterial effect of the multifunctional drug delivery system. At concentrations as achieved by local application, TG caused high toxic effect and impaired the normal osteoblastic morphology. The nanoparticulate multifunctional drug delivery system showed good compatibility and antibacterial effect during the observation time and thus appears to be suitable for the treatment of osteomyelitis caused by multi-drug-resistant microbes. PMID- 24948451 TI - Riboflavin-sensitized photo-crosslinking of collagen using a dental curing light. AB - BACKGROUND: Photo-crosslinking of biomolecules such as collagen and fibrinogen is an emerging area of research interest. The use of a small dental curing light with a non-toxic photosensitizer represents a novel, practical approach to periodontal wound treatment. OBJECTIVE: This study evaluated the effects of riboflavin-sensitized photo-oxidation using a dental curing light on two collagenous biomaterials, as a preliminary step towards developing a medical technology for wound closure/healing. METHODS: A collagenous biomaterial (DBP) and type I collagen gels were treated by this photo-oxidative technique and characterized by hydrothermal isometric tension (HIT) analysis, amino acid analysis, SDS-PAGE, and rheology. RESULTS: HIT analysis suggested that dental curing light exposure for 300 s with riboflavin produced heavily crosslinked DBP. Dental curing light exposure for 300 s with riboflavin also showed a reduction in lysine concentration of DBP. SDS-PAGE showed that dental curing light exposure for 30 or 300 s with riboflavin resulted in crosslinked collagen gels. Dental curing light exposure for 30 s with riboflavin yielded a collagen gel with the strongest rheological characteristics. CONCLUSIONS: This novel approach to wound treatment has potential for wide adoption and clinical use, particularly because dental curing lights, riboflavin, and collagen biomaterials are all used clinically, but not yet combined together as one technology for broad application. PMID- 24948452 TI - Low-cost quasi-real-time elastography using B-mode ultrasound images. AB - A low cost, quasi real-time elastography system, displacement-gradient elastography (DGE), was developed by applying digital image correlation (DIC) method and smoothing algorithm to B-mode ultrasound images. In order to achieve quasi real-time elastogram display, a new fast pattern matching algorithm, decoupled cross-correlation (DCC), was proposed and validated. By applying the DGE to various phantoms, elastograms were generated to identify the lesion with wide variations of stiffness ratio and applied strain. The performance of DGE was qualitatively compared with those from a high-end ultrasound scanner using the elastograms of a commercial elastography breast phantom. DGE was also applied to the ultrasound images of human breast lesions in various BI-RADS categories. This study suggests that DGE may have comparable performance to conventional elastography in detecting breast cancer, while it can be easily implemented onto conventional ultrasound scanners. PMID- 24948453 TI - The deer femur--a morphological and biomechanical animal model of the human femur. AB - BACKGROUND: The need for continued refinement of animal models in orthopaedic studies persists despite decades of research. OBJECTIVE: This study investigates the merits of deer bone in comparison to the more commonly used pig and sheep bone as an animal model for the human femur. METHOD: A morphological and biomechanical comparison of deer, pig and sheep rear femurs to those of the human femur is presented. Morphological parameters measured include bone length, cortical and medullary diaphyseal diameters, cortical thickness, cortical cross sectional area and bone density along the diaphysis. Biomechanical tests included whole-bone four-point flexure tests to determine the bending stiffness (N/mm), Young's modulus of bending (GPa), and ultimate strength in bending (MPa). In addition torsional stiffness (Nm/degree) as well as mid-diaphyseal cortical compressive elastic modulus (GPa) and strength (MPa) is investigated. RESULTS: On average, deer bone was found to be the least dissimilar from human femur. However, no single bone type consistently resembled the human femur. CONCLUSION: Deer femora should be considered a suitable animal model for the human femur. PMID- 24948454 TI - Fabrication and functionalization of PCB gold electrodes suitable for DNA-based electrochemical sensing. AB - The request of high specificity and selectivity sensors suitable for mass production is a constant demand in medical research. For applications in point-of care diagnostics and therapy, there is a high demand for low cost and rapid sensing platforms. This paper describes the fabrication and functionalization of gold electrodes arrays for the detection of deoxyribonucleic acid (DNA) in printed circuit board (PCB) technology. The process can be implemented to produce efficiently a large number of biosensors. We report an electrolytic plating procedure to fabricate low-density gold microarrays on PCB suitable for electrochemical DNA detection in research fields such as cancer diagnostics or pharmacogenetics, where biosensors are usually targeted to detect a small number of genes. PCB technology allows producing high precision, fast and low cost microelectrodes. The surface of the microarray is functionalized with self assembled monolayers of mercaptoundodecanoic acid or thiolated DNA. The PCB microarray is tested by cyclic voltammetry in presence of 5 mM of the redox probe K3Fe(CN6) in 0.1 M KCl. The voltammograms prove the correct immobilization of both the alkanethiol systems. The sensor is tested for detecting relevant markers for breast cancer. Results for 5 nM of the target TACSTD1 against the complementary TACSTD1 and non-complementary GRP, MYC, SCGB2A1, SCGB2A2, TOP2A probes show a remarkable detection limit of 0.05 nM and a high specificity. PMID- 24948455 TI - Cytotoxic evaluation of biomechanically improved crosslinked ovine collagen on human dermal fibroblasts. AB - Earlier studies in our laboratory demonstrated that collagen extracted from ovine tendon is biocompatible towards human dermal fibroblast. To be able to use this collagen as a scaffold in skin tissue engineering, a mechanically stronger scaffold is required that can withstand manipulation before transplantation. This study was conducted to improve the mechanical strength of this collagen sponge using chemical crosslinkers, and evaluate their effect on physical, chemical and biocompatible properties. Collagen sponge was crosslinked with 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide (EDC) and glutaraldehyde (GA). Tensile test, FTIR study and mercury porosimetry were used to evaluate mechanical properties, chemical property and porosity, respectively. MTT assay was performed to evaluate the cytotoxic effect of crosslinked collagen sponge on human dermal fibroblasts. The FTIR study confirmed the successful crosslinking of collagen sponge. Crosslinking with EDC and GA significantly increased the mechanical strength of collagen sponge, with GA being more superior. Crosslinking of collagen sponge significantly reduced the porosity and the effect was predominant in GA crosslinked collagen sponge. The GA-crosslinked collagen showed significantly lower, 60% cell viability towards human dermal fibroblasts compared to that of EDC-crosslinked collagen, 80% and non-crosslinked collagen, 100%. Although the mechanical strength was better when using GA but the more toxic effect on dermal fibroblast makes EDC a more suitable crosslinker for future skin tissue engineering. PMID- 24948456 TI - Swelling behavior and morphological properties of semi-IPN hydrogels based on ionic and non-ionic components. AB - Semi-interpenetrating polymer network (IPN) hydrogels with different compositions of poly(vinyl alcohol) (PVA), poly(acrylic acid) (PAA) and poly(acrylamide) (PAAm) were synthesized via free radical polymerization using ethylene glycol dimethacrylate (EGDMA) as crosslinker. The variations of swelling percentages (S%) with time, temperature and pH were determined for all hydrogels. Average S% values at pH=7.4 and 37 degrees C were determined to be 1660% for PAA/PVA, the most swollen hydrogel, and 550% for PAAm/PVA, the least swollen IPN-hydrogel. Swelling behaviors based on ionic and non-ionic components were also explained with detailed SEM micrographs of the hydrogels. PMID- 24948457 TI - Measurement of electrode-tissue interface impedance for improvement of a transcutaneous data transmission using human body as transmission medium. AB - The electrical property between an electrode and skin or tissue is one of the important issues for communication performance of the transcutaneous communication system (TCS) using a human body as a conductive medium.In this study, we used a simple method to measure interface resistance between the electrode and skin on the surface of the body. The electrode-electrode impedance was measured by a commercially available LCR meter with changes in the distance between two electrodes on an arm of a healthy male subject, and we obtained the tissue resistivity and electrode-skin interface resistance using the cross sectional area of the arm.We also measured transmission gain of the TCS on the surface of the body, and we investigated the relationship between electrode-skin interface resistance and transmission gain. We examined four kinds of electrodes: a stainless steel electrode, a titanium electrode, an Ag-AgCl electrode and an Ag AgCl paste electrode. The stainless steel electrode, which had lower electrode skin resistance, had higher transmission gain.The results indicate that an electrode that has lower electrode-skin resistance will contribute to improvement of the performance of the TCS and that electrode-skin interface resistance is one of valuable evaluation parameters for selecting an optimum electrode for the TCS. PMID- 24948458 TI - An experimental study for syndiotactic polyvinyl alcohol spheres as an embolic agent: can it maintain spherical shape in vivo? AB - Syndiotactic polyvinyl alcohol (PVA) had been developed to overcome the drawbacks of atactic PVA spheres that deform easily, which can lead to non-target embolization. This study was performed to evaluate the in vivo stability of spherical shape of the syndiotactic PVA spheres. Selective arteriography and transarterial embolization (TAE) were performed in the main renal arteries of eight New Zealand white rabbits using syndiotactic PVA sphere that consisted of syndiotactic PVA skin and a copolymer core of vinyl acetate/vinyl pivalate. The size of the syndiotactic PVA spheres used for the TAE was 212-355 MUm. The rabbits were sacrificed 12-14 days after TAE. Gross and microscopic examinations of each kidney were performed. The microscopic examination showed infarction of all embolized kidneys. Syndiotactic PVA spheres were seen uniformly within the arterial lumen and appeared as round ring-like structures without any deformity. The syndiotactic PVA spheres exclusively occupied the arterial lumen. As a conclusion, syndiotactic PVA spheres maintained their spherical shape without significant deformation in this in vivo short-term experimental study. Further investigation is necessary for evaluation of detailed effects of physical stability in tumor embolization. PMID- 24948459 TI - Effect of sintering on the microstructural and mechanical properties of meleagris gallopova hydroxyapatite. AB - In this study, we obtained hydroxyapatite powders from the femur bones of meleagris gallopova at three steps and sintered at five different temperatures. The reactions, which occur during sintering of obtained powders, have been characterized by X-ray diffraction (XRD) patterns, scanning electron microscope (SEM), differential thermal analysis (DTA), thermo-gravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FTIR) techniques. The mechanical properties of meleagris gallopova hydroxyapatite powders were determined by the measurements of density, hardness, porosity, activation energy for grain growth, variation of average grain sizes, fracture toughness and compression strength. The Fourier transform infrared spectra and the thermogravimetric analysis/differential thermal analysis thermograms of meleagris gallopova hydroxyapatite powders indicated that the presence of organic compounds were completely removed from the matrice. The X-ray diffraction patterns showed that decomposition of meleagris gallopova hydroxyapatite into tricalcium phosphate and calcium oxide was observed for the sintered samples at 1300 degrees C. At the same temperature, formation of microcracks were also detected by scanning electron microscopy image. Mechanical tests showed that maximum hardness, fracture toughness and compression strength values were measured for the sintered samples at 1200 degrees C. PMID- 24948460 TI - Danish children born to parents with lower levels of education are more likely to become overweight. AB - AIM: Little is known about whether the socio-economic status of parents is linked to their children becoming overweight. This study examined the association between parents' educational level and overweight Danish children in a nationally representative sample. METHODS: Body mass index was calculated for a random sample of 512 children aged from four to 14 from the Danish National Survey of Diet and Physical Activity 2005-2008. Their parents provided weight and height data during an interview, together with details of their own educational level. Children were classified as overweight/obese in accordance with the International Obesity Task Force. Frequency estimates of prevalence and logistic regression models were used to correlate childhood overweight/obesity with the mothers' and fathers' educational levels as the main outcome measures. RESULTS: Danish mothers tended to be more highly educated than fathers and their educational level was inversely associated with their child being overweight, especially if it was a boy. However, the highest educational level of the parents was the only significant educational variable, suggesting that education was associated with overweight children irrespective of the gender of the parent. CONCLUSION: Public health initiatives should target parents with low educational levels to prevent, and reduce, social inequality in overweight children. PMID- 24948462 TI - Facile strain analysis of largely bending films by a surface-labelled grating method. AB - Mechanical properties of flexible films, for example surface strain of largely bending films, are key to design of stretchable electronic devices, wearable biointegrated devices, and soft microactuators/robots. However, existing methods are mainly based on strain-gauge measurements that require miniaturized array sensors, lead wires, and complicated calibrations. Here we introduce a facile method, based on surface-labelled gratings, for two-dimensional evaluation of surface strains in largely bending films. With this technique, we demonstrate that soft-matter mechanics can be distinct from the mechanics of hard materials. In particular, liquid-crystalline elastomers may undergo unconventional bending in three dimensions, in which both the inner and outer surfaces of the bending film are compressed. We also show that this method can be applied to amorphous elastomeric films, which highlights the general importance of this new mechanical evaluation tool in designing soft-matter-based electronic/photonic as well as biointegrated materials. PMID- 24948463 TI - Soft Janus particles: ideal building blocks for template-free fabrication of two dimensional exotic nanostructures. AB - The design and fabrication of two-dimensional (2D) well-ordered nanostructures by a facile and effective strategy remain a major scientific and technological challenge, hitherto achieved mainly through the aid of interfaces or substrates with an ordered arrangement. Here we introduce a new concept in achieving template-free fabrication of diverse 2D ordered nanostructures by utilizing anisotropic characteristics of soft triblock Janus particles. Our numerical investigation demonstrates how particle softness and controllable directional attraction interplay to generate a number of fascinating non-close-packed 2D nanostructures and even three-dimensional (3D) vesicles. These non-close-packed nanostructures are of great interest for scientific reasons and lead to promising applications in soft nanotechnology and biotechnology. PMID- 24948465 TI - Surrogate and clinical outcomes following ischemic postconditioning during primary percutaneous coronary intervention of ST--segment elevation myocardial infarction: a meta-analysis of 15 randomized trials. AB - OBJECTIVES: To conduct a meta-analysis on surrogate and clinical outcomes with myocardial ischemic postconditioning (IPoC) following revascularization with primary percutaneous intervention (PPCI) for ST-segment myocardial infarction (STEMI) compared with PPCI alone. BACKGROUND: Reperfusion injury remains an important problem following PPCI for STEMI. Trials of IPoC have mainly focused on cardiac biomarkers; the impact on clinical outcomes is unknown. METHODS: Clinical trials that randomized STEMI patients to IPoC as compared with conventional PPCI were included for analysis. RESULTS: A total of 15 randomized trials with 1,545 patients met our selection criteria (785 underwent IPoC + PPCI, 760 PPCI alone). Mean follow-up for clinical outcomes was 4.7 months. The mean ischemic time was 225 min. ST-segment resolution (Relative Risk [RR] = 0.98; 95% Confidence Intervals [CI] 0.85-1.13; P = 0.75) and infarct size (Weighted mean difference [WMD] = -2.53%, 95% CI -6.10 to 1.05; P = 0.17) were similar between the IPoC + PPCI vs. PPCI arms. Left ventricular ejection fraction at follow-up was marginally higher in the IPoC (WMD = 4.15%, 95% CI 0.19-8.12%, P = 0.04). No differences were noted in any of the clinical outcomes studied, including mortality (RR = 1.52; 95% CI 0.77-2.99; P = 0.23), recurrent MI (RR = 3.04; 95% CI 0.74-12.54; P = 0.12); stent thrombosis (RR = 1.24, 95% CI 0.51-3.04; P = 0.83) or the composite MACE outcome (RR = 1.53; 95% CI 0.89-2.63; P = 0.13). CONCLUSIONS: IPoC following PPCI is not associated with improvements in surrogate or clinical outcomes at 5 months as compared with PPCI alone. Our findings indicate no role for IPoC in the routine management of patients with STEMI. PMID- 24948464 TI - Sex- and tissue-specific profiles of chemosensory gene expression in a herbivorous gall-inducing fly (Diptera: Cecidomyiidae). AB - BACKGROUND: The chemical senses of insects mediate behaviors that are closely linked to survival and reproduction. The order Diptera contains two model organisms, the vinegar fly Drosophila melanogaster and the mosquito Anopheles gambiae, whose chemosensory genes have been extensively studied. Representing a third dipteran lineage with an interesting phylogenetic position, and being ecologically distinct by feeding on plants, the Hessian fly (Mayetiola destructor Say, Diptera: Cecidomyiidae) genome sequence has recently become available. Among plant-feeding insects, the Hessian fly is unusual in 'reprogramming' the plant to create a superior food and in being the target of plant resistance genes, a feature shared by plant pathogens. Chemoreception is essential for reproductive success, including detection of sex pheromone and plant-produced chemicals by males and females, respectively. RESULTS: We identified genes encoding 122 odorant receptors (OR), 28 gustatory receptors (GR), 39 ionotropic receptors (IR), 32 odorant binding proteins, and 7 sensory neuron membrane proteins in the Hessian fly genome. We then mapped Illumina-sequenced transcriptome reads to the genome to explore gene expression in male and female antennae and terminal abdominal segments. Our results reveal that a large number of chemosensory genes have up-regulated expression in the antennae, and the expression is in many cases sex-specific. Sex-specific expression is particularly evident among the Or genes, consistent with the sex-divergent olfactory-mediated behaviors of the adults. In addition, the large number of Ors in the genome but the reduced set of Grs and divergent Irs suggest that the short-lived adults rely more on long-range olfaction than on short-range gustation. We also report up-regulated expression of some genes from all chemosensory gene families in the terminal segments of the abdomen, which play important roles in reproduction. CONCLUSIONS: We show that a large number of the chemosensory genes in the Hessian fly genome have sex- and tissue-specific expression profiles. Our findings provide the first insights into the molecular basis of chemoreception in plant-feeding flies, representing an important advance toward a more complete understanding of olfaction in Diptera and its links to ecological specialization. PMID- 24948466 TI - The effect of age on the efficacy of maintenance bacillus Calmette-Guerin relative to maintenance epirubicin in patients with stage Ta T1 urothelial bladder cancer: results from EORTC genito-urinary group study 30911. AB - BACKGROUND: Although maintenance bacillus Calmette-Guerin (BCG) is the recommended treatment in high-risk non-muscle-invasive bladder cancer (NMIBC), its efficacy in older patients is controversial. OBJECTIVE: To determine the effect of age on prognosis and treatment outcome in patients with stage Ta T1 NMIBC treated with maintenance BCG. DESIGN, SETTING, AND PARTICIPANTS: A total of 957 patients with intermediate- or high-risk Ta T1 (without carcinoma in situ) NMIBC were randomized in European Organization for Research and Treatment of Cancer (EORTC) trial 30911 comparing six weekly instillations of epirubicin, BCG, and BCG plus isoniazid followed by three weekly maintenance instillations over 3 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox multivariate proportional hazards regression models were used to assess the relative importance of age for recurrence, progression, overall survival, and NMIBC-specific survival with adjustment for EORTC risk scores. RESULTS AND LIMITATIONS: Overall, 822 eligible patients were included: 546 patients in the BCG with or without INH arms and 276 in the epirubicin arm. In patients treated with BCG with or without INH, 34.1% were >70 yr of age and 3.7% were >80 yr. With a median follow-up of 9.2 yr, patients >70 yr had a shorter time to progression (p=0.028), overall survival (p<0.001), and NMIBC-specific survival (p=0.049) after adjustment for EORTC risk scores in the multivariate analysis. The time to recurrence was similar compared with the younger patients. BCG was more effective than epirubicin for all four end points considered, and there was no evidence that BCG was any less effective compared with epirubicin in patients >70 yr. CONCLUSIONS: In intermediate- and high-risk Ta T1 urothelial bladder cancer patients treated with BCG, patients >70 yr of age have a worse long-term prognosis; however, BCG is more effective than epirubicin independent of patient age. PATIENT SUMMARY: Intravesical bacillus Calmette-Guerin for non-muscle-invasive bladder cancer is less effective in patients >70 yr of age, but it is still more effective than epirubicin. TRIAL REGISTRATION: This study was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC 30911; http://www.cancer.gov/clinicaltrials/search/view?cdrid=77075&version=HealthProfes ional&protocolsearchid=12442243#StudyIdInfo_CDR0000077075). PMID- 24948467 TI - Structures of mesophilic and extremophilic citrate synthases reveal rigidity and flexibility for function. AB - Citrate synthase (CS) catalyses the entry of carbon into the citric acid cycle and is highly-conserved structurally across the tree of life. Crystal structures of dimeric CSs are known in both "open" and "closed" forms, which differ by a substantial domain motion that closes the substrate-binding clefts. We explore both the static rigidity and the dynamic flexibility of CS structures from mesophilic and extremophilic organisms from all three evolutionary domains. The computational expense of this wide-ranging exploration is kept to a minimum by the use of rigidity analysis and rapid all-atom simulations of flexible motion, combining geometric simulation and elastic network modeling. CS structures from thermophiles display increased structural rigidity compared with the mesophilic enzyme. A CS structure from a psychrophile, stabilized by strong ionic interactions, appears to display likewise increased rigidity in conventional rigidity analysis; however, a novel modified analysis, taking into account the weakening of the hydrophobic effect at low temperatures, shows a more appropriate decreased rigidity. These rigidity variations do not, however, affect the character of the flexible dynamics, which are well conserved across all the structures studied. Simulation trajectories not only duplicate the crystallographically observed symmetric open-to-closed transitions, but also identify motions describing a previously unidentified antisymmetric functional motion. This antisymmetric motion would not be directly observed in crystallography but is revealed as an intrinsic property of the CS structure by modeling of flexible motion. This suggests that the functional motion closing the binding clefts in CS may be independent rather than symmetric and cooperative. PMID- 24948469 TI - A molecular study of hemotropic mycoplasmas (hemoplasmas) in cats in Iran. AB - BACKGROUND: Three feline hemoplasma species are recognized: Mycoplasma haemofelis, 'Candidatus Mycoplasma haemominutum', and 'Candidatus Mycoplasma turicensis'. These species can cause anemia in cats and have a worldwide distribution. OBJECTIVES: There was no previous information on hemotropic mycoplasma spp in cats in Iran and the Middle East. Accordingly, we investigated the molecular presence, and clinical signs and hematological profile in cats infected with these microorganisms in Iranian cats. METHODS: Polymerase chain reaction (PCR) assays and cytology were performed on 100 blood samples collected from Iranian Shorthair cats. ACBC and case history were also collected for each sample. RESULTS: By PCR, 22 (22%; 14-30%, 95% CI) samples were positive. The prevalence of M haemofelis, 'Ca M haemominutum', and 'Ca M turicensis' was 63.63% (14/22), 54.54% (12/22), and 18.18% (4/22), respectively. Some double and triple co-infections were also found. Using PCR as the reference method, cytology had poor sensitivity (27%) and reasonable specificity (89.74%). Male cats were at a higher risk of infection (P = .001). Cats older than 8 years were more frequently infected than the younger cats (P = .0018). Lower HCT (P = .018), RBC count (P = .028) and HGB concentration (P = .003) were also associated with hemoplasma PCR positive status. CONCLUSIONS: Based on this study, the most prevalent feline hemoplasma species in Iranian cats was M haemofelis, but double and triple co infections are also documented. Age and sex, as well as reduced RBC parameters, were predisposing factors for hemoplasma infection. PMID- 24948470 TI - Dementia and well-being: A conceptual framework based on Tom Kitwood's model of needs. AB - The topic of well-being is becoming increasingly significant as a key outcome measure in dementia care. Previous work on personhood of individuals with dementia suggests that their subjective well-being can be described in terms of comfort, inclusion, identity, occupation and attachment The study aimed to examine Tom Kitwood's model of psychological needs and well-being in dementia based on the self-report of individuals with moderate or severe dementia and to differentiate and elaborate this model in the light of the empirical qualitative data. Nineteen inhabitants of a special long-term care unit were interviewed using a semi-structured interview. Data were analysed using content analysis. Thirty components within Kitwood's model have been identified. A conceptual framework of subjective well-being in dementia was developed based on a theoretical background. The study was able to find indications that Kitwood's model has empirical relevance. Nevertheless, it requires to be extended by the domain agency. Furthermore, the study suggests that individuals with dementia are important informants of their subjective well-being. PMID- 24948468 TI - Effects of the proteasome inhibitor, bortezomib, on cytodifferentiation and mineralization of periodontal ligament cells. AB - BACKGROUND AND OBJECTIVE: The proteasome inhibitor, bortezomib, is known to induce osteoblastic differentiation in a number of cell lines, such as mesenchymal stem cells and osteoblastic precursor cells. As periodontal ligament (PDL) cells are multipotent, we examined whether bortezomib may induce the differentiation of PDL cells into hard-tissue-forming cells. MATERIAL AND METHODS: A mouse PDL clone cell line, MPDL22 cells, was cultured in mineralization medium in the presence or absence of bortezomib. Expression of calcification-related genes and calcified-nodule formation were evaluated by real time PCR and Alizarin Red staining, respectively. RESULTS: Bortezomib increased the expression of calcification-related mRNAs, such as tissue nonspecific alkaline phosphatase isoenzyme (ALPase), bone sialoprotein (Bsp), runt-related transcription factor 2 (Runx2) and osteopontin, and calcified-nodule formation in MPDL22 cells. These effects were induced, in part, by increasing the cytosolic accumulation and nuclear translocation of beta-catenin, leading to an increase in expression of bone morphogenetic protein (Bmp)-2, -4 and -6 mRNAs. In addition, bortezomib enhanced BMP-2-induced expression of Bsp and osteopontin mRNAs and increased calcified-nodule formation in MPDL22 cells. CONCLUSION: Bortezomib induced cytodifferentiation and mineralization of PDL cells by enhancing the accumulation of beta-catenin within the cytosol and the nucleus and increasing the expression of Bmp-2, -4 and -6 mRNAs. Moreover, bortezomib enhanced the BMP-2 induced cytodifferentiation and mineralization of PDL cells, suggesting that bortezomib may be efficacious for use in periodontal regeneration therapy. PMID- 24948471 TI - Association of POLK polymorphisms with platinum-based chemotherapy response and severe toxicity in non-small cell lung cancer patients. AB - Lung cancer is the leading cause of tumor-derived death. Although target therapy is proven very efficient, traditionally platinum-based chemotherapies are still primary treatment for most patients. Platinum can suppress the tumor growth and impair normal cells together. The primary aim of the present study was to study the potential role of translesion synthesis (TLS) that might play in platinum chemotherapy tolerance and side-effect. In present study, a total of 663 patients who were newly histologically diagnosed with advanced NSCLC (aNSCLC) were enrolled. Treatment response was classified into four categories: complete response, partial response, stable disease, and progressive disease. Incidence of gastrointestinal and hematological toxicities was assessed twice a week during the whole first-line treatment. Eleven SNPs of POLK were genotyped. The associations between SNPs and treatment response or toxicity were analyzed with logistic regression model. Cox regression was used for survival analysis between SNPs and progression-free survival or overall survival. We identified that rs3213801 and rs5744533 showed complete linkage in the present study, and they were significantly associated with treatment response (adjusted P = 0.044), together with rs5744655 (adjusted P = 0.039). rs1018119 was correlated with gastrointestinal toxicity in smokers specially (adjusted P = 0.041). Besides, rs3756558 was associated with hematological toxicity and overall toxicity in smokers and combined cohort with additive model. We also identified the significant association between two SNPs, rs10077427 and rs5744545, and PFS. The polymorphism of POLK, an important gene in TLS, participates in platinum chemotherapy tolerance and side-effect. PMID- 24948472 TI - Edaravone protects neurons in the rat substantia nigra against 6-hydroxydopamine induced oxidative stress damage. AB - To investigate the mechanism of the neuroprotective effect of edaravone in substantia nigra (SN) of the 6-OHDA-induced rat model of Parkinson's disease. Animal model of Parkinson's disease was induced in male Sprague-Dawley rats by injecting 6-OHDA into the left medial forebrain bundle. Subsequently, rats were intraperitoneally injected with 0.3, 1, or 3 mg/kg of edaravone for 14 days or with 3 mg/kg edaravone for 14 days followed by 14 days of no treatment. We evaluated the effect of edaravone on the rotational and normal behavior of the rats, and on the number of tyrosine hydroxylase (TH)-positive cells, the amount of Nissl bodies, and the levels of glutathione (GSH), and malondialdehyde (MDA) in the SN. Edaravone treatment at 3 mg/kg significantly reduced apomorphine induced rotational behavior (P < 0.01), improved the spontaneous behavior, prevented the decrease in the levels of TH-positive cells, Nissl bodies and GSH, and inhibited the increase in the levels of MDA (P < 0.05) in SN of rats with 6 OHDA-induced PD. Edaravone exerted a long-term neuroprotective effects in 6-OHDA induced PD animal model by attenuating changes in the levels of GSH and MDA in SN, caused by oxidative stress. Edaravone prevented 6-OHDA-induced behavioral changes and de-pigmentation of SN that results from the loss of dopaminergic neurons. PMID- 24948473 TI - Hypothesis: exertional heat stroke-induced myopathy and genetically inherited malignant hyperthermia represent the same disorder, the human stress syndrome. AB - Exertional heat stroke is usually experienced as a result of a prolonged and intensive exercise. It is a life-threatening condition that is characterized by an increase in core body temperature and rhabdomyolysis. The associated hyperkalemia and metabolic acidosis may lead to an acute renal, cardiac, and hemostatic failure. Exactly, the same symptoms are noticed in case of the anesthesia-induced malignant hyperthermia (MH), an inherited disorder of the skeletal muscle ryanodine receptor. This receptor is a Ca(2+) channel that is activated by the volatile anesthetic agents and depolarizing muscle relaxant. The presence of MH-associated ryanodine receptor variant in the individuals who suffered from EH and improvement of the symptoms with dantrolene has frequently raised the question as to whether the two disorders actually represent one and the same disease. Nevertheless, an exact explanation of the susceptibility of the genetically predisposed MH individuals to ER remains elusive. We have attempted to review the published clinical reports to explore the possibility that ER and EH represent one and the same disorder. PMID- 24948474 TI - The interaction effects of temperature and humidity on emergency room visits for respiratory diseases in Beijing, China. AB - Few epidemiological studies have been reported as to whether there was any interactive effect between temperature and humidity on respiratory morbidity, especially in Asian countries. The present study used time-series analysis to explore the modification effects of humidity on the association between temperature and emergency room (ER) visits for respiratory, upper respiratory tract infection (URI), pneumonia, and bronchitis in Beijing between 2009 and 2011. Results showed that an obvious joint effect of temperature and humidity was revealed on ER visits for respiratory, URI, pneumonia, and bronchitis. Below temperature threshold, the temperature effect was stronger in low humidity level and presented a trend fall with humidity level increase. The effect estimates per 1 degrees C increase in temperature in low humidity level were -2.88 % (95 % confidence interval (CI) -3.08, -2.67) for all respiratory, -3.24 % (-3.59, 2.88) for URI, -1.48 % (-1.93, -1.03) for pneumonia, and -3.79 % (-4.37, -3.21) for bronchitis ER visits, respectively. However, above temperature threshold, temperature effect was greater in high humidity level and trending upward with humidity level increasing. In high humidity level, a 1 degrees C increase in temperature, the effect estimates were 1.84 % (1.55, 2.13) for all respiratory, 1.76 % (1.41, 2.11) for URI, and 7.48 % (4.41, 10.65) for bronchitis ER visits. But, there was no statistically significant for pneumonia. This suggests that the modifying effects of the humidity should be considered when analyzing health impacts of temperature. PMID- 24948475 TI - The histidine kinase CusS senses silver ions through direct binding by its sensor domain. AB - The Cus system of Escherichia coli aids in protection of cells from high concentrations of Ag(I) and Cu(I). The histidine kinase CusS of the CusRS two component system functions as a Ag(I)/Cu(I)-responsive sensor kinase and is essential for induction of the genes encoding the CusCFBA efflux pump. In this study, we have examined the molecular features of the sensor domain of CusS in order to understand how a metal-responsive histidine kinase senses specific metal ions. We find that the predicted periplasmic sensor domain of CusS directly interacts with Ag(I) ions and undergoes a conformational change upon metal binding. Metal binding also enhances the tendency of the domain to dimerize. These findings suggest a model for activation of the histidine kinase through metal binding events in the periplasmic sensor domain. PMID- 24948476 TI - SEVI, the semen enhancer of HIV infection along with fragments from its central region, form amyloid fibrils that are toxic to neuronal cells. AB - Semen-derived enhancer of viral infection (SEVI) is the term given to the amyloid fibrils formed by a 39-amino acid fragment (PAP248-286) of prostatic acidic phosphatase (PAP) found in human semen. SEVI enhances human immunodeficiency virus (HIV) infectivity by four to five orders of magnitude (Munch et al., 2007). Here, we show by various biophysical techniques including Thioflavin T fluorescence, circular dichroism spectroscopy and transmission electron microscopy that fragments encompassing the central region of SEVI, i.e. PAP248 271 and PAP257-267, form fibrils of similar morphology to SEVI. Our results show that the central region, residues PAP267-271, is crucially important in promoting SEVI fibril formation. Furthermore, SEVI and fibrillar forms of these peptide fragments are toxic to neuronal pheochromocytoma 12 cells but not to epithelial colon carcinoma cells. These findings imply that although SEVI assists in the attachment of HIV-1 to immune cells, it may not facilitate HIV entry by damaging the epithelial cell layer that presents a barrier to the HIV. PMID- 24948477 TI - Oral appliance to assist non-invasive ventilation in a patient with amyotrophic lateral sclerosis. AB - BACKGROUND: From the moment the respiratory muscle groups are affected in amyotrophic lateral sclerosis (ALS), respiratory complications will be the major cause of morbidity and mortality. Untreated respiratory muscle impairment leads to respiratory insufficiency and additionally to difficulties in airway secretion clearance. Non-invasive ventilation (NIV) is the first choice in treating respiratory insufficiency in ALS as it improves sleep-related symptoms, quality of life and life expectancy. Nevertheless, NIV is not always effective, probably due to bulbar dysfunction or anatomical abnormalities. As a result, tracheostomy ventilation (TV) may become necessary. METHODS: In this case report, we present a 60-year-old female with ALS, for whom it was not possible to provide a sufficient tidal volume with NIV. A chin lift was performed while the patient was awake to see if a more anterior jaw position would lead to an increased tidal volume. As this was the case, a mandibular advancement device (MAD) was fabricated. RESULTS: With a combination of a MAD and NIV, the upper airway obstructions were overcome and a good ventilation and adherence to therapy were seen. CONCLUSIONS: When there is the presumption of airway obstructions in combination with an ineffective NIV, we advise to perform a chin lift to assess whether the obstructions can be overcome by a more anterior jaw position. If that is the case, NIV may be combined with MAD to establish effective ventilation and avoid the use of TV. PMID- 24948478 TI - DNA element downstream of the kappaB site in the Lcn2 promoter is required for transcriptional activation by IkappaBzeta and NF-kappaB p50. AB - The nuclear protein IkappaBzeta activates transcription of a subset of NF-kappaB dependent innate immune genes such as Lcn2 encoding the antibacterial protein lipocalin-2. IkappaBzeta functions as a coactivator via its interaction with NF kappaB p50, which contains a DNA-binding Rel-homology domain but lacks a transcriptional activation domain. However cis-regulatory elements involved in IkappaBzeta function have remained unknown. Here, we show that, although IkappaBzeta by itself is unable to associate with the Lcn2 promoter, IkappaBzeta interacts with the promoter via p50 binding to the NF-kappaB-binding site (kappaB site) and the interaction also requires the pyrimidine-rich site (CCCCTC) that localizes seven bases downstream of the kappaB site. The pyrimidine-rich site is also essential for IkappaBzeta-mediated activation of the Lcn2 gene. Introduction of both sites into an IkappaBzeta-independent gene culminates in IkappaBzeta-p50 DNA complex formation and transcriptional activation. Furthermore, spacing between the two sites is crucial for both IkappaBzeta-DNA interaction and IkappaBzeta-mediated gene activation. Thus, the pyrimidine-rich IkappaBzeta responsive site plays an essential role in productive interaction of IkappaBzeta with the p50-DNA complex. PMID- 24948479 TI - [Social cooperatives in Italy]. AB - This paper describes the role of social cooperatives in Italy as a type of economic, non-profit organization and their role in contributing to the economic and social growth of the country. The purpose of this paper is to learn more about the experience of the Italian social cooperatives in promoting the work integration process of disadvantaged workers, especially those suffering from mental disorders, from a theoretical and an empirical point of view. Social enterprise is the most popular and consolidated legal and organizational model for social enterprises in Italy, introduced by Law 381/91. Developed during the early 1980s, and formally recognized by law in the early 1990s, social cooperatives aim at pursuing the general interest of the community to promote the human needs and social inclusion of citizens. They are orientated towards aims that go beyond the interest of the business owners, the primary beneficiary of their activities is the community, or groups of disadvantaged people. In Italy, Law 381/91 distinguishes between two categories of social cooperatives, those producing goods of social utility, such as culture, welfare and educational services (A-type), and those providing economic activities for the integration of disadvantaged people into employment (B-type). The main purpose of B-type social cooperatives is to integrate disadvantaged people into the open labour market. This goal is reached after a period of training and working experience inside the firm, during which the staff works to improve both the social and professional abilities of disadvantaged people. During the years, B-type social co-ops acquired a particular relevance in the care of people with mental disorders by offering them with job opportunities. Having a job is central in the recovery process of people suffering from mental diseases, meaning that B-type social co ops in Italy play an important rehabilitative and integrative role for this vulnerable population of workers. The recent literature has highlighted that difficulties with employment are a feature of mental disorders, with high unemployment rates and short job tenure. Yet, success in employment for this population can be expected when they are provided with adequate support and opportunities. B-type social cooperatives in Italy are found to be very useful in order to help this disadvantaged category of workers find and keep a job. The work environment is more flexible and allows a better integration with less stigma and better work accommodations compared to the open labour market and/or other public/private organizations. Results from B-type Italian social cooperatives studies show that mentally ill workers value the importance of working, are highly satisfied with their job, are motivated to continue working, are engaged in their job and willing to work in the competitive labour market. Also, studies show that environmental characteristics of the social cooperative, such as the implementation of work accommodations and the possibility to work in an environment that is highly supportive, have an impact on increasing the likelihood of being highly satisfied with the job, which in turn is positively related to job tenure. In sum, this article shed light on the historical background that led to the development of social cooperatives in Italy. Furthermore, the features of B-type co-ops that play a central role in facilitating the work integration of people with mental disorders are described in this paper. In general, Italian B-type social cooperatives are found to provide a meaningful work experience to people with mental disorders, that help them increase not only vocational outcomes, but also psycho-social outcomes, and generally to help them better integrate into society. PMID- 24948480 TI - [Disclosure of a mental disorder in the workplace and work accommodations: two factors associated with job tenure of people with severe mental disorders]. AB - Job tenure for people with severe mental disorders (e.g., schizophrenia) remains a stumbling-block to their work integration. However, the length of job tenure can vary according to the workplace (e.g., provided resources) and the work context (e.g., regular market, social firms). This gap can be explained in part by diverse organisational components, particularly the implementation of work accommodations, which is related to the disclosure of the mental disorder in the workplace. Indeed, in the scientific literature, the principal reason associated with disclosure is in regards to requesting work accommodations. The main objective of this paper is to increase our understanding of the relationships between these three concepts - disclosure of a mental disorder, work accommodations and natural supports, and job tenure - by reviewing the specialized literature and presenting the work of the authors of this paper. To do so, the authors will address the following questions: How do we define 'disclosure' of a mental disorder in the workplace and what are the strategies to consider before disclosing? What is the decision-making process related to disclosure in the workplace? How are the three concepts - disclosure of the mental disorder in the workplace, work accommodations and job tenure - intertwined? Finally, how can employment specialists facilitate the work integration of people with severe mental disorders by considering the three concepts mentioned above? Results from a review of the literature show that disclosure of a mental disorder is a dialectical process that goes beyond the question: to tell or not to tell? In fact, it is not a single binary decision. Several components are associated with the disclosure concept, and can be summarized by the questions: What, how, when and to whom to disclose his/her mental condition? Reasons for disclosing his/her mental disorder in the workplace are numerous, characterized by personal, interpersonal and work environmental factors, on one hand. On the other hand, disclosure has potential consequences, both positive (e.g., to obtain work accommodations) and negative (e.g., stigma). A decision-making process takes place when people with a severe mental disorder think about the possibility of disclosing their mental condition in the workplace - a complex decisional process involving the need to evaluate different aspects (i.e. individual, interpersonal and work environmental factors). Also, the literature supports the fact that requiring work accommodations is often related to the disclosure of the mental disorder, when natural supports in the workplace are not available. The literature is scarce regarding the correlations between the concepts of disclosure, implementation of work accommodations and job tenure; however, a more recent study demonstrated this significant relationship, in which the supervisor and co-worker supports are crucial. Employment specialists or counselors recognise the importance of planned disclosure as a means to obtain access to work adjustments in the workplace and to prevent stigma. The employment specialist working in supported employment programs for instance, could adopt with his/her clients a plan for managing the pros and cons of disclosure of the mental disorder in the workplace; this plan is entitled: Managing personal information. It consists of several steps - for example, to collect details of any sensitive information such as diagnosis, to identify work restrictions with the client, to have a common agreement (employment specialists and clients together) on terms to describe work restrictions - to help clients feel empowered and more confident as productive and valued workers. This plan allows employment specialists to work through the disclosure concept, often negatively connoted, and to adopt a more normalising strategy. Furthermore, additional tools for supporting the management of personal information plan could be used such as the Decision-Making About Disclosure Scale, the Barriers to Employment and Coping Efficacy Scale, and the Work Accommodation and Natural Support Scale, to name a few. To conclude, job tenure for people with severe mental disorders is not a pious vow, several pragmatic ingredients for intervening on this issue are now available. PMID- 24948481 TI - [Psychological barriers to professional inclusion of people with mental disabilities]. AB - Mental health in the workplace today are ubiquitous and cause significant dysfunction in organizations (turnover, absenteeism, presenteeism, early retirement, long sick...). Statements of professional unfitness for depression is of particular concern. The human and financial costs associated with the support of mental disability is important, in France it is estimated to 14 billion euros. Mental disorder in the workplace also has a significant impact on the individual. If not always leads to actual inability to work, it usually causes, from the disclosure of the disorder, professional inequalities related to perceived environmental work disability. Therefore, this type of public remains largely on the sidelines of a stable occupation and all forms of recognition and undergo disqualifications and some forms of exclusion. Instead of saving, the workplace can promote relapse and even constitute a real obstacle to improving health. These exclusionary behavior result in persistent employment resistance in France and elsewhere, especially because of the prejudice of employers. These resistances persist despite legal obligations in this regard (e.g. in France: Law of 11 February 2005 on Equal Rights and Opportunities). To address the issue of sustainable professional inclusion (recruitment, integration and job preservation) of people with mental disabilities, studies are especially developed for the rehabilitation in the workplace of this public or accompanying us in their professional reintegration into protected workplaces. We propose a reflection on the adaptation of knowledge about psychological processes of hiring discrimination in the particular employment situation of people with mental disabilities in ordinary workplaces. Researches on social representations, stereotypes and prejudices applied in the workplace help to understand the negative attitudes and resistance to the hiring of people with mental disabilities despite regulations. Representations of professional efficiency, cognitive bias in social perception, personological expectations and responsibilities about the success of the employment integration of new employees strongly impact the hiring and integration behaviors of actors of the company. Nevertheless, the influence of the organizational context was highlighted in the researches in psychology of organizations. Recruitment and integration practices implemented by organizations, the procedures used to recruit (procedural justice) and the quality of interpersonal treatment of individuals (interpersonal justice) are essential elements of socialization. Disability is recognized as a particularly salient dimension and effective in activating cognitive processes biased. Individual and/or collective courses of action as persuasive communication, suppression and dilution of stereotypes, self-regulation of prejudice, intergroup contact and the sharing of values, affirmative action, promoting diversity, are proposed to modify these psychological barriers. However, their effectiveness is moderated by various individual factors such as the level of prejudice of actors, their previous work experience of disabled workers, their commitment to the values promoted by the organization for example, or organizational and structural factors such as the characteristics of the organization, the degree of formalization of hiring procedures, social policy of the organization and how it is conveyed and received by workers... These studies support the conclusion that the process of professional inclusion of public considered as "non-standard" is complex. These tracks remain to be tested under the mental disability taking into account the type of company and characteristics of actors that constitute them. PMID- 24948482 TI - [A group cognitive behavioral intervention for people registered in supported employment programs: CBT-SE]. AB - INTRODUCTION: Supported employment programs are highly effective in helping people with severe mental illness obtain competitive jobs quickly. However, job tenure is often a problem for many. Of the various obstacles to job tenure documented, dysfunctional beliefs regarding the workplace and one's own abilities has been proposed as a therapeutic target. OBJECTIVES: The purpose of this article is threefold: (1) to describe the development and the content of a novel group cognitive behavioral intervention designed to increase job tenure for people receiving supported employment services; (2) to present the feasibility and acceptability of the intervention; and (3) to investigate some preliminary data regarding employment outcomes. A group CBT intervention offered during 8 sessions over the course of one month, in order to respect the rapid job search principle of IPS (individual placement and support), was developed. The content was tailored to facilitate the learning of skills specific to the workplace, such as recognizing and managing one's stressors at work, determining and modifying dysfunctional thoughts (e.g. not jumping to conclusions, finding alternatives, seeking facts), overcoming obstacles (e.g. problem solving), improving one's self esteem as a worker (recognizing strengths and qualities), dealing with criticism, using positive assertiveness, finding coping strategies (for symptoms and stress) to use at work, negotiating work accommodations and overcoming stigma. A trial is currently underway, with half the participants receiving supported employment as well as CBT-SE and the other half receiving only supported employment. METHODS: A subsample of the first 24 participants having completed the 12-month follow-up were used for the analyses, including 12 having received at least 3 sessions out of the 8 group sessions and 12 receiving only supported employment. Feasibility and acceptability were determined by the group therapists' feedback, the participants' feedback as well as attendance to group sessions. The work outcomes looked at with the preliminary sample only included the 12-month follow-up and involved: obtaining a competitive job, number of hours worked per week as well as number of weeks worked at the same job (>24hours). RESULTS: In terms of feasibility and acceptability, therapists and participants all mentioned appreciating the group, finding it useful and helpful, some even mentioning feeling grateful to have had the opportunity to receive the intervention. The only negative feedback received pertained to the frequency of the meetings, which could be brought down to one meeting per week of two hours instead of two one hour sessions per week. Participation was very good, with the average number of sessions attended being of 6/8. In terms of work outcomes, 50 % of all participants in both conditions found competitive work. Out of those working competitively, the number of participants working more than 24hours per week at the 12-month follow-up was higher in the CBT-SE group compared to the control condition (75 % vs. 50 %). Similarly, there was a trend towards the number of consecutive weeks worked at the same job being slightly superior at the 12-month follow-up for those who had received the CBT-SE intervention (22.5 weeks vs. 18.3 weeks). DISCUSSION: The preliminary results support previous studies where on average 50 % of people registered in supported employment programs obtain competitive work. We confirmed that the intervention was feasible and acceptable. Preliminary data suggest that the CBT-SE intervention might help people with severe mental illness use skills and gain the needed confidence enabling them to work longer hours and consecutive weeks. These results should be considered with caution given that only 24 participants were looked at whereas the final sample size will be of 160 participants. Nonetheless, these preliminary results are promising. Furthermore, additional information regarding the impact of the CBT-SE intervention on the capacity to overcome obstacles at work, self-esteem as a worker, as well as other work-related variables have been collected but have not been investigated here. Once the study is completed, the results should enlighten us regarding the usefulness of offering CBT-SE not only in terms of work outcomes but also in improving various psychosocial domains linked to workplace satisfaction. PMID- 24948483 TI - Determination of 15 sedative residues in mutton by rapid resolution liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: The use of xenobiotic compounds in animal husbandry has given rise to consumer anxieties regarding residual risk and food safety. Thus, animal tissues have become main samples for residue analysis and food safety for sedatives. In this study, a rapid resolution liquid chromatography-tandem mass spectrometry (RRLC-MS/MS) method was established for the determination of 15 sedatives residues in mutton. RESULTS: After enzymolysis, sedatives residues in mutton were extracted by ammonium hydroxide-acetonitrile (10:90, v/v) and determined by RRLC MS/MS with quantification by standard curve method. The calibration curves showed good linearity within the concentrations of 0.5-50 ug kg(-1) with the correlation coefficients (r(2)) ranged from 0.9639 to 0.9984. The limits of detection (LODs) and quantification (LOQs) were 0.25-2.5 and 0.5-5 ug kg(-1), respectively. The average recoveries of spikes samples were in the ranges of 74.1-116.8% with relative standard deviations of intra- and inter-day ranged from 2.6% to 11.2% and from 2.1% to 11.4%, respectively. CONCLUSION: This method is simple, sensitive and accurate in the determination of sedative residues. PMID- 24948484 TI - Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy. AB - The past decade has witnessed an explosion of knowledge on the impact of glia for the neurobiological foundation of schizophrenia. A plethora of studies have shown structural and functional abnormalities in all three types of glial cells. There is convincing evidence of reduced numbers of oligodendrocytes, impaired cell maturation and altered gene expression of myelin/oligodendrocyte-related genes that may in part explain white matter abnormalities and disturbed inter- and intra-hemispheric connectivity, which are characteristic signs of schizophrenia. Earlier reports of astrogliosis could not be confirmed by later studies, although the expression of a variety of astrocyte-related genes is abnormal in psychosis. Since astrocytes play a key role in the synaptic metabolism of glutamate, GABA, monoamines and purines, astrocyte dysfunction may contribute to certain aspects of disturbed neurotransmission in schizophrenia. Finally, increased densities of microglial cells and aberrant expression of microglia-related surface markers in schizophrenia suggest that immunological/inflammatory factors are of considerable relevance for the pathophysiology of psychosis. This review describes current evidence for the multifaceted role of glial cells in schizophrenia and discusses efforts to develop glia-directed therapies for the treatment of the disease. PMID- 24948485 TI - Neuroinflammation and white matter pathology in schizophrenia: systematic review. AB - BACKGROUND: Neuroinflammation and white matter pathology have each been independently associated with schizophrenia, and experimental studies have revealed mechanisms by which the two can interact in vitro, but whether these abnormalities simultaneously co-occur in people with schizophrenia remains unclear. METHOD: We searched MEDLINE, EMBASE, PsycINFO and Web of Science from inception through 12 January 2014 for studies reporting human data on the relationship between microglial or astroglial activation, or cytokines and white matter pathology in schizophrenia. RESULTS: Fifteen studies totaling 792 subjects (350 with schizophrenia, 346 controls, 49 with bipolar disorder, 37 with major depressive disorder and 10 with Alzheimer's disease) met all eligibility criteria. Five neuropathological and two neuroimaging studies collectively yielded consistent evidence of an association between schizophrenia and microglial activation, particularly in white rather than gray matter regions. Ultrastructural analysis revealed activated microglia near dystrophic and apoptotic oligodendroglia, demyelinating and dysmyelinating axons and swollen and vacuolated astroglia in subjects with schizophrenia but not controls. Two neuroimaging studies found an association between carrier status for a functional single nucleotide polymorphism in the interleukin-1beta gene and abnormal white as well as gray matter volumes in schizophrenia but not controls. A neuropathological study found that orbitofrontal white matter neuronal density was increased in schizophrenia cases exhibiting high transcription levels of pro inflammatory cytokines relative to those exhibiting low transcription levels and to controls. Schizophrenia was associated with decreased astroglial density specifically in subgenual cingulate white matter and anterior corpus callosum, but not other gray or white matter areas. Astrogliosis was consistently absent. Data on astroglial gene expression, mRNA expression and protein concentration were inconsistent. CONCLUSION: Neuroinflammation is associated with white matter pathology in people with schizophrenia, and may contribute to structural and functional disconnectivity, even at the first episode of psychosis. PMID- 24948486 TI - Ultrasonication assisted production of silver nanowires with low aspect ratio and their optical properties. AB - We investigated a facial method to produce silver nanowires with low aspect ratio by fragmentizing as produced long silver nanowires. The length of silver nanowires can be shortened in a controllable manner by increasing ultrasonication time or ultrasonication power. However, excessively large ultrasonication power caused a problem of agglomeration of nanowires. From UV absorption spectra, it was found that the UV absorption characteristic of silver nanowires is not affected by ultrasonication assisted fragmentation indicating that one dimensional structure of silver nanowires is maintained during the fragmentation process. PMID- 24948487 TI - Enhanced decolorization of methyl orange using zero-valent copper nanoparticles under assistance of hydrodynamic cavitation. AB - The rate of reduction reactions of zero-valent metal nanoparticles is restricted by their agglomeration. Hydrodynamic cavitation was used to overcome the disadvantage in this study. Experiments for decolorization of methyl orange azo dye by zero-valent copper nanoparticles were carried out in aqueous solution with and without hydrodynamic cavitation. The results showed that hydrodynamic cavitation greatly accelerated the decolorization rate of methyl orange. The size of nanoparticles was decreased after hydrodynamic cavitation treatment. The effects of important operating parameters such as discharge pressure, initial solution pH, and copper nanoparticle concentration on the degradation rates were studied. It was observed that there was an optimum discharge pressure to get best decolorization performance. Lower solution pH were favorable for the decolorization. The pseudo-first-order kinetic constant for the degradation of methyl orange increased linearly with the copper dose. UV-vis spectroscopic and Fourier transform infrared (FT-IR) analyses confirmed that many degradation intermediates were formed. The results indicated hydroxyl radicals played a key role in the decolorization process. Therefore, the enhancement of decolorization by hydrodynamic cavitation could due to the deagglomeration of nanoparticles as well as the oxidation by the in situ generated hydroxyl radicals. These findings greatly increase the potential of the Cu(0)/hydrodynamic cavitation technique for use in the field of treatment of wastewater containing hazardous materials. PMID- 24948488 TI - A copper-mediated oxidative N-cyanation reaction. AB - Copper-promoted N-cyanation of aliphatic sec-amine by CuCN is achieved via oxidative coupling. This procedure employs O2 as a clean oxidant. Notably, sulfoximines and 1,1,3,3-tetramethylguanidine also worked well in this procedure. Thus, it represents a key progress in the C-N bond formation reaction as well as in the cyanation reaction. PMID- 24948489 TI - Effect of left ventricular diastolic dysfunction on outcomes of atrial fibrillation ablation. AB - Left ventricular diastolic dysfunction (LVDD) is an important pathogenic factor for atrial fibrillation (AF). There are few data on the effect of LVDD on recurrence of AF after catheter ablation. A cohort of 124 patients (59.9 +/- 11.7 years, 73.9% male, and 55% with paroxysmal AF) with recalcitrant AF and normal left ventricular systolic function (left ventricular ejection fraction >=50%) undergoing ablation was studied. Each patient underwent transthoracic echocardiography, and LVDD was meticulously graded using rhythm-independent (AF or sinus rhythm) transmitral and tissue Doppler parameters. Patients underwent catheter ablation of AF using a stepwise protocol. All patients were followed up at 3, 6, and 12 months with recurrent AF (>30 seconds) captured by electrocardiography and/or 7-day monitor. Kaplan-Meier survival analysis and Cox proportional hazards model were used. There was no LVDD in 72 patients (58%), whereas 33 (26.6%), 10 (8.1%), and 9 (7.3%) patients had grades 1, 2, and 3 LVDD, respectively. AF recurred in 49 patients (39.5%) with median time to recurrence of 248 days. Patients with higher grade of LVDD were increasingly more likely to have recurrence (37.5% for no LVDD and 30.3%, 60%, and 66.7% for grades 1, 2, and 3 LVDD, respectively). Significant LVDD (grade 2 or 3) was an independent predictor of recurrence (hazard ratio 2.6, p = 0.009) after adjusting for persistent (vs paroxysmal) AF and left atrial volume. In conclusion, patients with more severe LVDD have a higher risk of AF recurrence after catheter ablation. These patients may derive less benefit from ablation or may require a more extensive ablation approach. PMID- 24948490 TI - Echocardiographic determinants of peak aerobic capacity and breathing efficiency in patients with undifferentiated dyspnea. AB - Diastolic function and E/e' correlate with peak aerobic capacity (VO2) in patients with heart failure, but the echocardiographic correlates of abnormal gas exchange in patients without heart failure are not well defined. We sought to determine the echocardiographic correlates of peak VO2 and breathing efficiency (estimated using the ratio of minute ventilation to carbon dioxide production, or VE/VCO2 nadir) in patients with unexplained dyspnea. We identified 232 patients with unexplained dyspnea who underwent echocardiography at rest followed by stress echocardiography with simultaneous measurement of peak VO2 and VE/VCO2 nadir. At baseline, 17 patients (5%) had an E/e' of >=15 while 31 patients (17%) had a right ventricular systolic pressure (RVSP) of >35 mm Hg. E/e' >=15 and RVSP >35 mm Hg were associated with lower peak VO2 (14.1 +/- 4.4 vs 21.0 +/- 6.9 and 15.2 +/- 3.6 vs 21.8 +/- 6.8 ml/kg/min, respectively, p <0.0001). E/e' >=15 (sensitivity 0.13, specificity 0.99, area under the curve 0.64) and RVSP >35 mm Hg (sensitivity 0.38, specificity 0.93, area under the curve 0.76) were highly specific for predicting limited peak VO2. Age and RVSP at rest were independent correlates with VE/VCO2, but diastolic function was not. However, the risk of having abnormal VE/VCO2 nadir was only elevated in subjects with elevated RVSP in the setting of abnormal diastolic function (hazard ratio 2.4, 95% confidence interval 1.3 to 4.6, p = 0.02). In conclusion, both E/e' >=15 and RVSP >35 mm Hg are highly specific markers of exercise limitation in patients without heart failure, but RVSP at rest may offer better overall diagnostic power than E/e' to predict low peak VO2 in this group. PMID- 24948491 TI - Relation between stroke volume index to risk of death in patients with low gradient severe aortic stenosis and preserved left ventricular function. AB - The aim of the present study was to evaluate whether assessment of stroke volume index (SVI) can be used to improve risk stratification among patients with low gradient severe aortic stenosis and preserved ejection fraction (EF). Study population comprised 409 patients with aortic valve area <=1.00 cm(2), mean gradient <40 mm Hg, and a normal EF (>=50%) who were followed up in a tertiary referral center from 2004 to 2012. Echocardiographic parameters and clinical data were collected. Multivariate Cox proportional hazards regression modeling was used to evaluate the association between SVI and the risk of all-cause mortality. Mean age of study patients was 78 +/- 11 years, and 42% were men. The mean SVI was 39 +/- 7 ml/m(2) (tertile 1 = 32 +/- 4 ml/m(2); tertile 2 = 39 +/- 1 ml/m(2); tertile 3 = 47 +/- 4 ml/m(2)). Multivariate analysis showed that the SVI was the most powerful echocardiographic parameter associated with long-term outcome: each 5 ml/m(2) reduction in SVI was associated with a 20% increase in adjusted mortality risk (p = 0.01). Consistently, Kaplan-Meier analysis showed that the cumulative probability of survival during 3 years of follow-up was 60%, 72%, and 73% among patients in the low-, intermediate-, and high-SVI groups, respectively (p = 0.012). Our findings suggest that in patients with low-gradient severe aortic stenosis and preserved EF, there is a graded inverse relation between SVI and the risk of long-term mortality. PMID- 24948492 TI - Left ventricular function in long-term survivors of childhood lymphoma. AB - Survivors of childhood lymphoma (CL) have markedly increased risk of developing heart failure. Echocardiographic studies after cardiotoxic treatment have primarily demonstrated left ventricular (LV) systolic dysfunction. In the present study, we hypothesized that longer follow-up and a more comprehensive echocardiographic examination would reveal more cardiac abnormalities. We conducted a cross-sectional study with echocardiography 20.4 +/- 8.6 years after diagnosis in 125 survivors of CL, grouped according to treatment methods, and compared with matched controls. Treatment included mediastinal radiotherapy (median 40.0 Gy) in 66 and anthracyclines (median dose 160 mg/m(2)) in 92 survivors of CL. Abnormal LV function, left-sided valve dysfunction, or both occurred in 62 patients (50%). Diastolic dysfunction occurred in 29%. Compared with control subjects, mitral annular early diastolic velocities (e') were reduced in patients (septal e' 0.09 +/- 0.03 vs 0.12 +/- 0.03 m/s, p <0.001), and the E/e' ratio was increased, particularly after mediastinal radiotherapy (10.6 +/- 6.4 vs 5.6 +/- 1.3, p <0.001). Survivors of CL had lower fractional shortening than control subjects (32 +/- 6 vs 36 +/- 7, p <0.001), but mean ejection fraction was equal and overt systolic dysfunction was infrequent. After mediastinal radiotherapy alone, global longitudinal myocardial strain was lower (p <0.05) compared with other treatment groups. Left-sided valvular dysfunction occurred in 55% of patients after mediastinal radiotherapy. In conclusion, survivors of CL had reduced LV diastolic function assessed by tissue Doppler imaging. This was more pronounced after mediastinal radiotherapy, which also frequently led to valvular disease. Systolic function was normal in most survivors of CL. PMID- 24948493 TI - Usefulness of the platelet-to-lymphocyte ratio in predicting angiographic reflow after primary percutaneous coronary intervention in patients with acute ST segment elevation myocardial infarction. AB - Impaired coronary flow after primary percutaneous coronary intervention (PPCI) is associated with short- and long-term morbidity and mortality in patients with acute ST-segment elevation myocardial infarction (STEMI). Recent studies have demonstrated that platelet-to-lymphocyte ratio (PLR) is associated with adverse cardiovascular outcomes. The aim of this study was to assess the relation between admission PLR and angiographic reflow after PPCI. A total of 520 patients with acute STEMI (age 60 +/- 13 years; 74% men) occurring within 12 hours of the onset of symptoms who underwent PPCI were enrolled. The PLR and other laboratory parameters were measured before PPCI. The patients were divided into 2 groups based on the postintervention Thrombolysis in Myocardial Infarction (TIMI) flow grade: normal-reflow group (defined as postintervention TIMI grade 3 flow) and none-reflow group (consisted of both patients with angiographic no-reflow defined as postintervention TIMI grades 0 to 1 flow and slow flow defined as postintervention TIMI grade 2 flow). There were 117 patients (22.5%) in the none reflow group (age 68 +/- 13 years and 77% men) and 403 patients in the normal reflow group (age 58 +/- 12 years and 63% men). The none-reflow group had significantly higher PLR compared with the normal-reflow group (219 +/- 79 vs 115 +/- 59, p <0.001). In logistic regression analysis, PLR (odds ratio 1.818, 95% confidence interval 1.713 to 1.980, p <0.001) and total stent length (OR 1.052, confidence interval 1.019 to 1.086, p = 0.002) were independent predictors of none-reflow after PPCI. In conclusion, preintervention PLR is a strong and independent predictor of slow flow/no-reflow after PPCI in patients with acute STEMI. PMID- 24948494 TI - Effect of myocardial perfusion pattern on frequency and severity of mitral regurgitation in patients with known or suspected coronary artery disease. AB - Mitral regurgitation (MR) is common with coronary artery disease as altered myocardial substrate can affect valve performance. Single-photon emission computed tomography myocardial perfusion imaging (MPI) enables assessment of myocardial perfusion alterations. This study examined perfusion pattern in relation to MR. A total of 2,377 consecutive patients with known or suspected coronary artery disease underwent stress MPI and echocardiography within 1.6 +/- 2.3 days. MR was present on echocardiography in 34% of patients, among whom 13% had advanced (moderate or more) MR. MR prevalence was higher in patients with abnormal MPI (44% vs 29%, p <0.001), corresponding to increased global ischemia (p <0.001). Regional perfusion varied in left ventricular segments adjacent to each papillary muscle: adjacent to the anterolateral papillary muscle, magnitude of baseline and stress-induced anterior/anterolateral perfusion abnormalities was greater in patients with MR (both p <0.001). Adjacent to the posteromedial papillary muscle, baseline inferior/inferolateral perfusion abnormalities were greater with MR (p <0.001), whereas stress inducibility was similar (p = 0.39). In multivariate analysis, stress-induced anterior/anterolateral and rest inferior/inferolateral perfusion abnormalities were independently associated with MR (both p <0.05) even after controlling for perfusion in reference segments not adjacent to the papillary muscles. MR severity increased in relation to magnitude of perfusion abnormalities in each territory adjacent to the papillary muscles, as evidenced by greater prevalence of advanced MR in patients with at least moderate anterior/anterolateral stress perfusion abnormalities (10.7% vs 3.6%), with similar results when MR was stratified based on rest inferior/inferolateral perfusion (10.4% vs 3.0%, both p <0.001). In conclusion, findings demonstrate that myocardial perfusion pattern in left ventricular segments adjacent to the papillary muscles influences presence and severity of MR. PMID- 24948495 TI - Usefulness of serial B-type natriuretic peptide assessment in asymptomatic aortic stenosis. AB - B-type natriuretic peptide (BNP) level may be a useful prognostic marker for the management of asymptomatic patients with aortic stenosis (AS). The aim of this study was to identify the echocardiographic determinants of BNP changes during follow-up in AS. We studied 61 asymptomatic patients with greater than moderate AS and preserved left ventricular (LV) ejection fraction who underwent rest and exercise Doppler echocardiography with concomitant BNP level measurement at baseline. BNP measurement was repeated after inclusion every 6 months. Patients were divided into 2 groups according to the median of BNP changes during follow up. According to parameters at rest, patients in the high BNP changes group had significantly higher E/e' ratio. Statistically significant correlations were found between BNP changes and E/e' ratio and indexed left atrial area. According to exercise parameters, patients in the high BNP changes group had significantly lower exercise-induced increase in LV ejection fraction. Statistically significant correlations were found between BNP changes and exercise-induced changes in LV ejection fraction. After adjustment for age, mean aortic pressure gradient, and BNP level at baseline, multivariate analysis identified indexed left atrial area, E/e' at rest, and exercise-induced increase in ejection fraction as independent determinants of BNP changes during follow-up. In conclusion, this study shows that, in asymptomatic patients with preserved LV function and moderate AS, serial BNP measurements may widely vary. Subclinical LV diastolic and systolic dysfunctions are frequently present in patients with higher serial BNP changes. PMID- 24948497 TI - Distinguishing imaging features between spinal hyperplastic hematopoietic bone marrow and bone metastasis. AB - BACKGROUND AND PURPOSE: Systematic investigations of the distinguishing imaging features between spinal hyperplastic hematopoietic bone marrow and bone metastasis have not been reported, to our knowledge. The purpose of this study was to determine the distinguishing imaging features of the 2 entities. MATERIALS AND METHODS: We retrospectively reviewed the radiologic images of 8 consecutive male patients (age range, 52-78 years; mean, 64 years) with suspected spinal metastasis on MR imaging and FDG-PET, which was later confirmed as hyperplastic hematopoietic bone marrow. MR imaging, FDG-PET, CT, and bone scintigraphy images were qualitatively and/or quantitatively evaluated. Imaging findings in 24 patients with spinal metastasis were compared, and differences were statistically analyzed. RESULTS: All 8 vertebral hyperplastic hematopoietic bone marrow lesions were hypointense on T1- and T2-weighted images; lesions contiguous with the adjacent vertebra were significantly more often seen in hyperplastic hematopoietic bone marrow than in metastasis (P = .035). T2 signal intensity of the lesion was significantly different between the 2 entities (P = .033). FDG-PET showed slightly higher uptake in all hyperplastic hematopoietic bone marrow lesions; their maximum standard uptake value was significantly lower than that of metastatic lesions (P = .037). CT attenuation of hyperplastic hematopoietic bone marrow was equal to or slightly higher than that of adjacent normal-appearing vertebra; the CT appearances of hyperplastic hematopoietic bone marrow and metastasis were significantly different (P < .01). Bone scintigraphy showed normal uptake for all vertebrae with hyperplastic hematopoietic bone marrow; the uptake was significantly different from that of metastasis (P < .01). CONCLUSIONS: If a lesion was isointense to hyperintense to normal-appearing marrow on MR imaging or had a maximum standard uptake value of >3.6, the lesion was considered metastatic. A normal appearance on CT or bone scintigraphy excluded metastasis. PMID- 24948496 TI - Incidental radiologic findings in the 22q11.2 deletion syndrome. AB - BACKGROUND AND PURPOSE: The 22q11.2 deletion syndrome is a common genetic microdeletion syndrome that results in cognitive delays and an increased risk of several psychiatric disorders, particularly schizophrenia. The current study investigates the prevalence of incidental neuroradiologic findings within this population and their relationships with psychiatric conditions. MATERIALS AND METHODS: Brain MR imaging from 58 individuals with 22q11.2 deletion syndrome was reviewed by board-certified radiologists by using standard clinical procedures. Intracranial incidental findings were classified into 8 categories and compared with a large typically developing cohort. RESULTS: The rate of incidental findings was significantly higher (P < .0001) in 22q11.2 deletion syndrome compared with typically developing individuals, driven by a high prevalence of cavum septum pellucidum (19.0%) and white matter abnormalities (10.3%). Both of these findings were associated with psychosis in 22q11.2 deletion syndrome. CONCLUSIONS: Cavum septum pellucidum and white matter hyperintensities are significantly more prevalent in patients with the 22q11.2 deletion syndrome and may represent biomarkers for psychosis. PMID- 24948498 TI - Flat detector angio-CT following intra-arterial therapy of acute ischemic stroke: identification of hemorrhage and distinction from contrast accumulation due to blood-brain barrier disruption. AB - BACKGROUND AND PURPOSE: Flat panel detector CT in the angiography suite may be valuable for the detection of intracranial hematomas; however, abnormal contrast enhancement frequently mimics hemorrhage. We aimed to assess the accuracy of flat panel detector CT in detecting/excluding intracranial bleeding after endovascular stroke therapy and whether it was able to reliably differentiate hemorrhage from early blood-brain barrier disruption. MATERIALS AND METHODS: Seventy-three patients were included for retrospective evaluation following endovascular stroke therapy: 32 after stent-assisted thrombectomy, 14 after intra-arterial thrombolysis, and 27 after a combination of both. Flat panel CT images were assessed for image quality and the presence and type of intracranial hemorrhage and BBB disruption by 2 readers separately and in consensus. Follow-up by multisection head CT, serving as the reference standard, was evaluated by a single reader. RESULTS: Conventional head CT revealed intracranial hematomas in 12 patients (8 subarachnoid hemorrhages, 7 cases of intracerebral bleeding, 3 SAHs plus intracerebral bleeding). Image quality of flat panel detector CT was considered sufficient in all cases supratentorially and in 92% in the posterior fossa. Regarding detection or exclusion of intracranial hemorrhage, flat panel detector CT reached a sensitivity, specificity, positive and negative predictive values, and accuracy of 58%, 85%, 44%, 91%, and 81%, respectively. Maximum attenuation measurements were not valuable for the differentiation of hemorrhage and BBB disruption. CONCLUSIONS: Flat panel CT after endovascular stroke treatment was able to exclude the rare event of an intracranial hemorrhage with a high negative predictive value. Future studies should evaluate the predictive value of BBB disruptions in flat panel detector CT for the development of relevant hematomas. PMID- 24948499 TI - Subdural hygromas in abusive head trauma: pathogenesis, diagnosis, and forensic implications. AB - Are subdural hygromas the result of abusive head trauma? CT and MR imaging represent important tools for the diagnosis of abusive head trauma in living infants. In addition, in-depth understanding of the pathogenesis of subdural hygromas is increasingly required by neuroradiologists, pediatricians, and forensic physicians. Therefore, the current knowledge on subdural hygromas is summarized and forensic conclusions are drawn. The most important diagnostic pitfalls, benign enlargement of the subarachnoid space, and chronic subdural hematoma, are discussed in detail. Illustrative cases from forensic practice are presented. Literature analysis indicates that subdural hygromas can occur immediately or be delayed. If other infrequent reasons can be excluded, the presence of subdural hygromas strongly suggests a posttraumatic state and should prompt the physician to search for other signs of abuse. To differentiate subdural hygromas from other pathologies, additional MR imaging of the infant's head is indispensable after initial CT scan. PMID- 24948500 TI - Preoperative prognostic value of dynamic contrast-enhanced MRI-derived contrast transfer coefficient and plasma volume in patients with cerebral gliomas. AB - BACKGROUND AND PURPOSE: The prognostic value of dynamic contrast-enhanced MR imaging-derived plasma volume obtained in tumor and the contrast transfer coefficient has not been well-established in patients with gliomas. We determined whether plasma volume and contrast transfer coefficient in tumor correlated with survival in patients with gliomas in addition to other factors such as age, type of surgery, preoperative Karnofsky score, contrast enhancement, and histopathologic grade. MATERIALS AND METHODS: This prospective study included 46 patients with a new pathologically confirmed diagnosis of glioma. The contrast transfer coefficient and plasma volume obtained in tumor maps were calculated directly from the signal-intensity curve without T1 measurements, and values were obtained from multiple small ROIs placed within tumors. Survival curve analysis was performed by dichotomizing patients into groups of high and low contrast transfer coefficient and plasma volume. Univariate analysis was performed by using dynamic contrast-enhanced parameters and clinical factors. Factors that were significant on univariate analysis were entered into multivariate analysis. RESULTS: For all patients with gliomas, survival was worse for groups of patients with high contrast transfer coefficient and plasma volume obtained in tumor (P < .05). In subgroups of high- and low-grade gliomas, survival was worse for groups of patients with high contrast transfer coefficient and plasma volume obtained in tumor (P < .05). Univariate analysis showed that factors associated with lower survival were age older than 50 years, low Karnofsky score, biopsy-only versus resection, marked contrast enhancement versus no/mild enhancement, high contrast transfer coefficient, and high plasma volume obtained in tumor (P < .05). In multivariate analysis, a low Karnofsky score, biopsy versus resection in combination with marked contrast enhancement, and a high contrast transfer coefficient were associated with lower survival rates (P < .05). CONCLUSIONS: In patients with glioma, those with a high contrast transfer coefficient have lower survival than those with low parameters. PMID- 24948501 TI - Effects of circle of Willis anatomic variations on angiographic and clinical outcomes of coiled anterior communicating artery aneurysms. AB - BACKGROUND AND PURPOSE: Anterior communicating artery aneurysms account for one fourth of all intracranial aneurysms and frequently occur in the context of A1 vessel asymmetry. The purpose of this study was to correlate circle of Willis anatomic variation association to angiographic and clinical outcomes of anterior communicating aneurysm coiling. MATERIALS AND METHODS: The Cerecyte Coil Trial provides a subgroup of 124 cases with anterior communicating artery aneurysms after endovascular coiling. One hundred seventeen of 124 anterior communicating artery aneurysms had complete imaging and follow-up for clinical outcome analysis, stability of aneurysm coil packing, and follow-up imaging between 5 and 7 months after treatment. Clinical outcomes were assessed by the mRS at 6 months. RESULTS: Anterior cerebral artery trunk-dominance was seen in 91 of 124 (73%) anterior communicating artery aneurysms and codominance in 33 of 124 (27%) anterior communicating artery aneurysms. There was no significant difference (P > .5) in treatment success at 5-7 months for anterior communicating artery aneurysms between the anterior cerebral artery trunk-dominant (49 of 86, 57%) and anterior cerebral artery trunk-codominant (19 of 31) groups. Angiographic follow up demonstrates a statistically significant increase in neck remnants and progressive aneurysm sac filling with the A1 dominant configuration (n = 21, 24% at follow-up versus n = 11, 12% at immediate posttreatment, P = .035). There was no statistically significant difference in clinical outcomes between types of anterior cerebral artery trunk configuration (P > .5). CONCLUSIONS: Anterior communicating artery aneurysms with anterior cerebral artery trunk-dominant circle of Willis configurations show less angiographic stability at follow-up than those with anterior cerebral artery trunk-codominance similar to other "termination" type aneurysms. This supports the hypothesis that anterior cerebral artery trunk-dominant flow contributes to aneurysm formation, growth, and instability after coiling treatment. PMID- 24948502 TI - Calvarial fracture patterns on CT imaging predict risk of a delayed epidural hematoma following decompressive craniectomy for traumatic brain injury. AB - BACKGROUND AND PURPOSE: The development of a delayed epidural hematoma as a result of decompressive craniectomy represents an urgent and potentially lethal complication in traumatic brain injury. The goal of this study was to determine the incidence of delayed epidural hematoma and whether patterns of skull fractures on the preoperative CT scan could predict risk of a delayed epidural hematoma. MATERIALS AND METHODS: We retrospectively evaluated medical records and imaging studies for patients with acute traumatic brain injury who underwent a decompressive craniectomy during a 9-year period. We compared patterns of skull fractures contralateral to the side of the craniectomy with the occurrence of a postoperative delayed epidural hematoma. RESULTS: In a series of 203 patients undergoing decompressive craniectomy for acute traumatic brain injury, the incidence of a delayed epidural hematoma complication was 6% (12 of 203). All 12 patients who developed a delayed epidural hematoma had a contralateral calvarial fracture on preoperative CT at the site where the delayed epidural hematoma subsequently formed. A contralateral calvarial fracture has perfect sensitivity (100%) for subsequent development of delayed epidural hematoma in our study population. Moreover, a contralateral calvarial fracture involving 2 or more bone plates had an especially high diagnostic odds ratio of 41 for delayed epidural hematoma. CONCLUSIONS: Recognition of skull fracture patterns associated with delayed epidural hematoma following decompressive craniectomy may reduce morbidity and mortality by prompting early postoperative intervention in high risk situations. PMID- 24948503 TI - Mechanical embolectomy for acute ischemic stroke in the anterior cerebral circulation: the Gothenburg experience during 2000-2011. AB - BACKGROUND AND PURPOSE: Intra-arterial treatment of proximal occlusions in the cerebral circulation have become an important tool in the management of acute ischemic stroke. Our goal was to evaluate the safety and efficacy of intra arterial acute ischemic stroke treatment performed in our institution in consecutive patients with anterior circulation occlusion during 2000-2011. MATERIALS AND METHODS: We identified, in our data base, 156 consecutive cases with anterior acute ischemic stroke treated intra-arterially during 2000-2011. Stroke severity was defined according to the National Institutes of Health Stroke Scale, the results of the procedure were defined according to the modified Thrombolysis in Cerebral Infarction score, and clinical outcome was defined according to the modified Rankin scale, with favorable outcome <=2 at 90 days. RESULTS: The mean admission NIHSS score was 19.4 (median, 20), with a mean time from stroke onset to groin puncture of 197 minutes (median, 171 minutes). The embolectomy tool of choice was the Amplatz GooseNeck snare (83%). Successful recanalization (modified TICI 2b +3) was seen in 74% of cases. A mRS <= 2 at 90 days was seen in 42% with a mortality rate of 17% and symptomatic intracerebral hemorrhage in 4%. CONCLUSIONS: A high recanalization rate was obtained with the Amplatz GooseNeck snare without any device-related complications. Favorable outcome, mortality, and symptomatic intracerebral hemorrhage are comparable with results of newer embolectomy devices. PMID- 24948504 TI - MRI characteristics of ependymoblastoma: results from 22 centrally reviewed cases. AB - BACKGROUND AND PURPOSE: Ependymoblastoma is a malignant embryonal tumor that develops in early childhood and has a dismal prognosis. Categorized by the World Health Organization as a subgroup of CNS-primitive neuroectodermal tumor, ependymoblastoma is histologically defined by "ependymoblastic rosettes." Because it is so rare, little is known about specific MR imaging characteristics of ependymoblastoma. We systematically analyzed and discussed MR imaging features of ependymoblastoma in a series of 22 consecutive patients. MATERIALS AND METHODS: Ependymoblastoma cases were obtained from the database of the German multicenter HIT trials between 2002 and 2013. All cases within this study were centrally reviewed for histopathology, MR imaging findings, and multimodal therapy. For systematic analysis of initial MR imaging scans at diagnosis, we applied standardized criteria for reference image evaluation of pediatric brain tumors. RESULTS: Ependymoblastomas are large tumors with well-defined tumor margins, iso- to hyperintense signal on T2WI, and diffusion restriction. Contrast enhancement is variable, with a tendency to mild or moderate enhancement. Subarachnoid spread is common in ependymoblastoma but can be absent initially. There was a male preponderance (1.75:1 ratio) for ependymoblastoma in our cohort. Mean age at diagnosis was 2.1 years. CONCLUSIONS: With this study, we add the largest case collection to the limited published database of MR imaging findings in ependymoblastoma, together with epidemiologic data. However, future studies are needed to systematically compare MR imaging findings of ependymoblastoma with other CNS-primitive neuroectodermal tumors and ependymoma, to delineate imaging criteria that might help distinguish these pediatric brain tumor entities. PMID- 24948505 TI - Ossification of the vascular pedicle in microsurgical fibular free flap reconstruction of the head and neck. AB - BACKGROUND AND PURPOSE: The fibular free flap, often used for osseous reconstruction following extirpation of head and neck malignancies, has been associated with heterotopic periosteal ossification. We aimed to determine the frequency and radiologic characteristics of this process and describe its clinical correlates. MATERIALS AND METHODS: Surgical records for 2 years and neck imaging reports for 10 years were evaluated to identify patients with fibular free flap reconstruction and CT and/or PET/CT imaging available for review. The images were evaluated for the quality, type, and contour of ossification, and the reports were reviewed for associated clinical findings and radiologic impressions. RESULTS: Of 32 patients with posttreatment CT or PET/CT imaging, ossification was evident in 16 patients (50%) as early as 1 month following fibular free flap reconstruction. In 8 patients, it mimicked a new bone; in 5, it appeared as linear attenuation; in 2, as multiple short segments; and in 1 patient, a mixed appearance was found. No associated FDG uptake was seen on PET/CT. On MR imaging, these findings were extremely subtle or not appreciable. In only 1 patient was new bone associated with symptoms. CONCLUSIONS: Periosteal ossification of the vascular pedicle is commonly evident on CT following fibular free flap, even as early as 1 month after reconstruction, though the finding is not typically noted on imaging. While symptoms related to new bone are uncommon, they may mimic recurrent tumor. The location and pattern of ossification and the absence of a soft-tissue mass or FDG uptake are useful distinguishing imaging features. PMID- 24948506 TI - Cranial arachnoid protrusions and contiguous diploic veins in CSF drainage. AB - BACKGROUND AND PURPOSE: Studies have suggested that arachnoid villi or granulations found in the walls of the cranial dural sinuses, olfactory mucosa, and cranial nerve sheaths function as outlets for intracranial CSF. However, their role as CSF outlets has not yet been verified. Here we show that arachnoid protrusions and contiguous diploic veins provide an alternative drainage route for intracranial CSF. MATERIALS AND METHODS: Four hundred patients with intact skull, dura mater, and dural sinuses underwent MR imaging to explore arachnoids protruding into the skull and diploic veins. Patients with symptoms of increased intracranial pressure or intracranial hypotension were excluded. For 15 patients undergoing craniotomy, both peripheral and diploic venous blood was collected. Albumin and the CSF-specific biomarkers were measured by enzyme-linked immunosorbent assay. RESULTS: With MR imaging, arachnoid protrusions into the skull and contiguous diploic veins were consistently identified throughout the cranium with their characteristic appearance depending on the cranial region. In addition, elevated amounts of prostaglandin D synthase and cystatin C were confirmed in diploic veins compared with peripheral venous blood. CONCLUSIONS: Diploic veins are distributed ubiquitously throughout the cranium. A portion of the intracranial CSF may be drained through arachnoid protrusions and contiguous diploic veins. PMID- 24948507 TI - Iron and volume in the deep gray matter: association with cognitive impairment in multiple sclerosis. AB - BACKGROUND AND PURPOSE: There is a well-established correlation between deep gray matter atrophy and cognitive dysfunction in MS. However, the cause of these signs of neurodegeneration is poorly understood. Iron accumulation in the deep gray matter is higher in patients with MS compared with age- and sex-matched healthy controls, and could contribute to disease progression. Our objective was to evaluate the relationship between iron and cognition in several deep gray matter structures while accounting for the influence of volume loss. MATERIALS AND METHODS: Eighty-five patients with MS and 27 healthy volunteers underwent 3T MR imaging and neuropsychological examination. We used SWI filtered phase to analyze the mean phase of low-phase voxels, indicative of abnormal iron accumulation. RESULTS: Correlations between mean phase of low-phase voxels and cognitive tests were found in the caudate nucleus (r = 0.240 and 0.232), putamen (r = 0.368, 0.252, and 0.238), globus pallidus (r = 0.235), and pulvinar nucleus of thalamus (r = 0.244, 0.255, and 0.251) (P < .05). However, correlations between structure volume and cognition were more robust. Furthermore, the introduction of structure volume into hierarchical regression analyses after iron metrics significantly improved most models, and mean phase of low-phase voxels did not account for significant variance after volume. CONCLUSIONS: These findings suggest that iron accumulation plays a significant, if minor, role in MS cognitive decline. PMID- 24948509 TI - The Impact of Computed Tomography of the Chest on the Management of Patients in a Medical Intensive Care Unit. AB - PURPOSE: To understand whether chest computed tomographies (CTs) have utility in a medical intensive care unit (MICU) population as previously noted in nonmedical critically ill patients. PATIENTS AND METHODS: We conducted a retrospective cohort study of patients receiving chest CTs in the MICU at an urban, academic institution. Indications for, findings on, and care changes made after chest CT were obtained. We identified patient characteristics associated with having a care change clearly related to the CT using multivariate regression. RESULTS: We evaluated 134 patients; 64 (47.8%) had a chest CT with intravenous contrast. Common findings included pulmonary consolidation (46.3%), nonconsolidative pulmonary parenchymal disease (29.1%), and pleural effusion (35.1%). Of the chest CTs, 23.9% were followed by changes in management clearly related to the study. Use of intravenous contrast was associated with increased odds of having a care change (adjusted odds ratio [95% confidence interval [CI] versus noncontrast study: 3.14 [1.18-8.37], P = .022) and having the CT performed 1 or 2 days after ICU admission versus on the day of ICU admission was associated with lower odds of a care change (odds ratio [95% CI]: 0.29 [0.09-0.99], P = .048). CONCLUSION: Less than one-quarter of chest CTs in the MICU result in management. Intravenous contrast-enhanced CTs and CTs done on the day of ICU admission have increased odds of utility. PMID- 24948508 TI - Patients prone to recurrence after endovascular treatment: periprocedural results of the PRET randomized trial on large and recurrent aneurysms. AB - BACKGROUND AND PURPOSE: Some patients with large or recurrent aneurysms may be at increased risk of recurrence postcoiling. The Patients Prone to Recurrence after Endovascular Treatment (PRET) trial was designed to assess whether hydrogel coils were superior to platinum coils in these high-risk patients. This article reports periprocedural safety and operator-assessed angiographic results from the PRET trial. MATERIALS AND METHODS: PRET was a pragmatic, multicenter, randomized controlled trial. Patients had >=10-mm aneurysms (PRET-1) or a major recurrence after coiling of an aneurysm of any size (PRET-2). Patients were randomly allocated to hydrogel or control arms (any platinum coil) by using concealed allocation with minimization. Assist devices could be used as clinically required. Aneurysms could be unruptured or recently ruptured. Analyses were on an intent-to-treat basis. RESULTS: Four hundred forty-seven patients were recruited (250 PRET-1; 197 PRET-2). Aneurysms were recently ruptured in 29% of PRET-1 and 4% of PRET-2 patients. Aneurysms were >=10 mm in all PRET-1 and in 50% of PRET-2 patients. They were wide-neck (>=4 mm) in 70% and in the posterior circulation in 24% of patients. Stents were used in 28% of patients (35% in PRET-2). Coiling was successful in 98%. Adverse events occurred in 28 patients with hydrogel and 23 with platinum coils. Mortality (n=2, unrelated to treatment) and morbidity (defined as mRS>2 at 1 month) occurred in 25 patients (5.6%; 12 hydrogel, 13 platinum), related to treatment in 10 (4 hydrogel; 6 platinum) (or 2.3% of 444 treated patients). No difference was seen between hydrogel and platinum for any of the indices used to assess safety up to at least 30 days after treatment. At 1 month, 95% of patients were home with a good outcome (mRS<=2 or unchanged). Operator-assessed angiographic outcomes were satisfactory (complete occlusion or residual neck) in 339 of 447 or 76.4% of patients, with no significant difference between groups. CONCLUSIONS: Endovascular treatment of large and recurrent aneurysms can be performed safely with platinum or hydrogel coils. PMID- 24948510 TI - A novel multi-alignment pipeline for high-throughput sequencing data. AB - Mapping reads to a reference sequence is a common step when analyzing allele effects in high-throughput sequencing data. The choice of reference is critical because its effect on quantitative sequence analysis is non-negligible. Recent studies suggest aligning to a single standard reference sequence, as is common practice, can lead to an underlying bias depending on the genetic distances of the target sequences from the reference. To avoid this bias, researchers have resorted to using modified reference sequences. Even with this improvement, various limitations and problems remain unsolved, which include reduced mapping ratios, shifts in read mappings and the selection of which variants to include to remove biases. To address these issues, we propose a novel and generic multi alignment pipeline. Our pipeline integrates the genomic variations from known or suspected founders into separate reference sequences and performs alignments to each one. By mapping reads to multiple reference sequences and merging them afterward, we are able to rescue more reads and diminish the bias caused by using a single common reference. Moreover, the genomic origin of each read is determined and annotated during the merging process, providing a better source of information to assess differential expression than simple allele queries at known variant positions. Using RNA-seq of a diallel cross, we compare our pipeline with the single-reference pipeline and demonstrate our advantages of more aligned reads and a higher percentage of reads with assigned origins. Database URL: http://csbio.unc.edu/CCstatus/index.py?run=Pseudo. PMID- 24948511 TI - Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. AB - BACKGROUND: Metformin is the recommended first-line pharmacotherapy for patients with type 2 diabetes. There is no consensus on the optimum second-line pharmacotherapy. We compared the efficacy and safety of the sodium glucose cotransporter 2 inhibitor empagliflozin and the sulfonylurea glimepiride as add on to metformin in patients with type 2 diabetes. METHODS: In this double-blind phase 3 trial, patients (aged >=18 years) with type 2 diabetes and HbA1c concentrations of 7-10%, despite metformin treatment and diet and exercise counselling, were randomly assigned in a 1:1 ratio with a computer-generated random sequence, stratified by HbA1c, estimated glomerular filtration rate (eGFR), and region, to empagliflozin (25 mg once daily, orally) or glimepiride (1 4 mg once daily, orally) as add-on to metformin for 104 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c levels at weeks 52 and 104. Differences in the primary endpoint were first tested for non-inferiority (based on a margin of 0.3%). If non-inferiority was shown, differences in the primary endpoint at week 104 were then tested for superiority. Analysis was done on the full-analysis set ie, patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is registered with ClinicalTrials.gov, number NCT01167881. A 104-week extension is ongoing. FINDINGS: Between August, 2010, and June, 2011, 1549 patients were randomly assigned to receive empagliflozin (n=769) or glimepiride (n=780); four patients in the empagliflozin group did not receive the assigned treatment. Empagliflozin was non-inferior to glimepiride at both timepoints. At week 104, adjusted mean difference in change from baseline in HbA1c with empagliflozin versus glimepiride was -0.11% (95% CI -0.19 to -0.02; p=0.0153 for superiority). Adverse events were reported in 661 (86%) patients treated with empagliflozin and 673 (86%) patients treated with glimepiride. Severe adverse events were reported in 72 (9%) patients in the empagliflozin group and 68 (9%) in the glimepiride group. Serious adverse events were reported in 119 (16%) patients in the empagliflozin group and 89 (11%) in the glimepiride group. Confirmed hypoglycaemic adverse events (plasma glucose <=3.9 mmol/L or requiring assistance) at week 104 were reported in 19 (2%) patients treated with empagliflozin and 189 (24%) patients treated with glimepiride. INTERPRETATION: Empagliflozin might be an effective and a well tolerated second-line treatment option for patients with type 2 diabetes who have not achieved good glycaemic control on metformin. FUNDING: Boehringer Ingelheim and Eli Lilly. PMID- 24948512 TI - SGLT-2 inhibitors as second-line therapy in type 2 diabetes. PMID- 24948513 TI - Intergenerational effects of early life nutrition: maternal leg length predicts offspring placental weight and birth weight among women in rural Luzon, Philippines. AB - OBJECTIVES: Leg length is the component of stature most sensitive to early life nutrition; as such, it provides an opportunity to retrospectively evaluate the relationship between a woman's infancy and early childhood nutrition and offspring birth weight (BW). Here we explore the relationship between maternal leg length and offspring BW in a rural Philippine community, while also investigating the potential role of placental size as a pathway. METHODS: Anthropometric and questionnaire data were obtained among pregnant women (ages 17 42 years) at a birthing clinic in Antipolo City, Philippines (n = 80). Offspring BW and placental weight were collected upon delivery. RESULTS: Maternal leg length, but not trunk length, was a positive predictor of infant BW. This relationship was strengthened after adjusting for gestational age and maternal body mass index (BMI). Further adjustment for placental weight attenuated the relationship between leg length and BW, while placental weight was unrelated to maternal trunk length. The relationship between maternal BMI and BW was also attenuated after adjustment for placental weight. CONCLUSION: Maternal leg length is the component of stature that most strongly predicts offspring placental weight and BW in this sample. These findings suggest that fetal nutrition and growth in the present generation are influenced, in part, by the mother's own early life growth conditions. Our results add to evidence that fetal nutrition tracks the mother's past nutritional experiences, while also suggesting that ensuring favorable growth conditions during infancy and early childhood may benefit not only the present generation, but future offspring. PMID- 24948514 TI - Relationship between level of independence in activities of daily living and estimated cardiovascular capacity in elderly women. AB - Elderly individuals undergo a progressive decline in functional capacity related to increased risk of dependency, loss of autonomy, and frailty. A lower cardiorespiratory fitness level is associated with cardiovascular disease events and mortality from all causes. The Veterans Specific Activity Questionnaire (VSAQ) was developed to facilitate prediction of the exercise capacity in older people with cardiovascular disease. However, few studies have investigated the relationship between the VSAQ and functional capacity in elderly women. This study investigated the relationship between functional capacity and the estimated cardiovascular capacity in elderly women, as assessed by the VSAQ. In this descriptive, observational, cross-sectional study, we evaluated 37 healthy elderly women (aged 70 +/- 7 years). The assessment protocols used were the following: Anamnesis, VSAQ and nomogram (age adjusted), Senior Fitness Test (30-s chair stand, to assess lower-body strength; 8-foot up-and-go test, to assess agility-dynamic balance; and 2-min step test, to assess aerobic endurance). The Spearman test showed a significant correlation (p<0.001) between the functional tests and the VSAQ (8-foot up-and-go test rs=-0.715; 2-min step test rs=0.567; 30 s chair stand rs=0.582). Adjustment of the results by age improved the correlation (8-foot up-and-go test rs=-0.760; 2-min step test rs=0.627; 30-s chair stand rs=0.601). The VSAQ seems to be a simple way to estimate functional capacity, particularly in older women. PMID- 24948515 TI - Auxin efflux by PIN-FORMED proteins is activated by two different protein kinases, D6 PROTEIN KINASE and PINOID. AB - The development and morphology of vascular plants is critically determined by synthesis and proper distribution of the phytohormone auxin. The directed cell-to cell distribution of auxin is achieved through a system of auxin influx and efflux transporters. PIN-FORMED (PIN) proteins are proposed auxin efflux transporters, and auxin fluxes can seemingly be predicted based on the--in many cells--asymmetric plasma membrane distribution of PINs. Here, we show in a heterologous Xenopus oocyte system as well as in Arabidopsis thaliana inflorescence stems that PIN-mediated auxin transport is directly activated by D6 PROTEIN KINASE (D6PK) and PINOID (PID)/WAG kinases of the Arabidopsis AGCVIII kinase family. At the same time, we reveal that D6PKs and PID have differential phosphosite preferences. Our study suggests that PIN activation by protein kinases is a crucial component of auxin transport control that must be taken into account to understand auxin distribution within the plant. PMID- 24948516 TI - Is the brain a decomposable or nondecomposable system? Comment on "Understanding brain networks and brain organization" by Pessoa. PMID- 24948517 TI - Properties of language networks and language systems: comment on "approaching human language with complex networks" by Cong and Liu. PMID- 24948518 TI - Social dimensions of pain. Comment on "Facing the experience of pain: a neuropsychological perspective" by Fabbro and Crescentini. PMID- 24948519 TI - Highly effective treatment of skull base chordoma with carbon ion irradiation using a raster scan technique in 155 patients: first long-term results. AB - BACKGROUND: The current study was conducted to evaluate the long-term results of irradiation with carbon ions in a raster scanning technique in patients with skull base chordomas. METHODS: Between 1998 and 2008, a total of 155 patients (76 men and 79 women) with a median age of 48 years (range, 15 years-85 years) were irradiated with carbon ions using a raster scan technique. The irradiation was performed at the Society for Heavy Ion Research in Darmstadt, Germany. The median total dose was 60 gray (relative biological effectiveness) at 3 gray (relative biological effectiveness) per fraction. The median boost planning target volume was 70 mL (range, 2 mL-294 mL). Local control (LC) and overall survival (OS) were evaluated using the Kaplan-Meier method, whereas long-term toxicity was evaluated via questionnaires. RESULTS: The median follow-up was 72 months (range, 12 months 165 months). All patients had residual macroscopic tumors at the initiation of radiotherapy. The authors observed 55 local recurrences during follow-up, as well as systemic disease progression in 4 patients. The resulting 3-year, 5-year, and 10-year LC rates were 82%, 72%, and 54%, respectively, whereas the 3-year, 5 year, and 10-year OS rates were 95%, 85%, and 75%, respectively. Age <48 years and a boost volume >75 mL were associated with a significantly improved LC and OS. Primary treatment resulted in a significantly better OS probability. No higher late toxicity could be detected after carbon ion treatment. CONCLUSIONS: Carbon ion therapy appears to be a safe and effective treatment for patients with skull base chordoma, resulting in high LC and OS rates. PMID- 24948521 TI - [Hospital-at-home in older patients: a scoping review on opportunities of developing comprehensive geriatric assessment based services]. AB - This scoping review focused on the opportunity of developing new hospital-at-home schemes in our health systems adapted to older patients with complex conditions due to acute illness. A review was conducted on articles including, randomized controlled trials, systematic reviews and meta-analysis in PubMed and Cochrane Library, from January 1990 to July 2013. Search terms were: hospital-at-home, Early Supported Discharge, hospital in the home and home hospitalization. An analysis was performed to include: the intervention model (admission avoidance or early discharge), age, diagnosis, main inclusion criteria and intervention characteristics (disciplines involved, duration of intervention, main outcomes and objectives). It is concluded that there are several models of hospital-at home care, with favorable clinical outcomes. The majority of teams in our country focused on acute health care in the less elderly with chronic diseases. Other schemes based on comprehensive geriatric assessment and interdisciplinary teams specialized in complex interventions are also highlighted. The development of comprehensive geriatric assessment based hospital-at-home care by teams led by geriatricians is an opportunity to develop alternatives to conventional hospitalization interventions tailored to older patients. PMID- 24948520 TI - Initial independent outcomes from focal impulse and rotor modulation ablation for atrial fibrillation: multicenter FIRM registry. AB - INTRODUCTION: The success of pulmonary vein isolation (PVI) for atrial fibrillation (AF) may be improved if stable AF sources identified by Focal Impulse and Rotor Mapping (FIRM) are also eliminated. The long-term results of this approach are unclear outside the centers where FIRM was developed; thus, we assessed outcomes of FIRM-guided AF ablation in the first cases at 10 experienced centers. METHODS: We prospectively enrolled n = 78 consecutive patients (61 +/- 10 years) undergoing FIRM guided ablation for persistent (n = 48), longstanding persistent (n = 7), or paroxysmal (n = 23) AF. AF recordings from both atria with a 64-pole basket catheter were analyzed using a novel mapping system (Rhythm View(TM) ; Topera Inc., CA, USA). Identified rotors/focal sources were ablated, followed by PVI. RESULTS: Each institution recruited a median of 6 patients, each of whom showed 2.3 +/- 0.9 AF rotors/focal sources in diverse locations. 25.3% of all sources were right atrial (RA), and 50.0% of patients had >=1 RA source. Ablation of all sources required a total of 16.6 +/- 11.7 minutes, followed by PVI. On >1 year follow-up with a 3-month blanking period, 1 patient lost to follow-up (median time to 1st recurrence: 245 days, IQR 145-354), single procedure freedom from AF was 87.5% (patients without prior ablation; 35/40) and 80.5% (all patients; 62/77) and similar for persistent and paroxysmal AF (P = 0.89). CONCLUSIONS: Elimination of patient-specific AF rotors/focal sources produced freedom-from-AF of ~80% at 1 year at centers new to FIRM. FIRM-guided ablation has a rapid learning curve, yielding similar results to original FIRM reports in each center's first cases. PMID- 24948522 TI - [Delirium and hip fracture. Anticipating is basic]. PMID- 24948523 TI - [RS3PE syndrome: A case description and a literature review]. PMID- 24948524 TI - Caregiver burden among primary caregivers of patients undergoing peripheral blood stem cell transplantation: a cross sectional study. AB - PURPOSE: This study aimed to identify caregiver burden and influencing factors on the burden in primary caregivers of peripheral blood stem cell transplantation patients within 2-12 months following transplant, indicating early recovery period after discharge. METHOD: This descriptive cross sectional study was carried out at hematopoietic stem cell transplantation outpatient units of three university hospitals in Turkey. A total of 55 patient and caregiver dyads were recruited and interviewed. The data were collected using questionnaires developed by the researchers and caregiver burden was measured with the Zarit Burden Interview. RESULTS: The mean score of Zarit Burden Interview was 28.41 (SD = 13.90). Patients' symptoms including nausea and self depreciation feeling were related to greater caregiver burden. Self-depreciation was referred to feeling undervalued. The mean score of the tool was significantly higher in caregivers who have not been educated beyond primary school and also caregivers who had lower income. Caregivers who supported their patients to fulfill physical needs and who did not receive help for meeting patients' psychological needs had statistically more elevated levels of burden. Moreover, the extent of care giving activities undertaken was positively correlated with caregiver burden scores. While positive impact of the care giving process on family relations decreased caregiver burden; negative effect increased the burden. CONCLUSIONS: This study suggests that caregiver burden of primary caregivers caring for peripheral blood stem cell transplantation patients varies by education, income status, and the extent of care giving activities undertaken. Changes in family ties and relations due to care giving effected caregiver burden. PMID- 24948526 TI - Complexity measure and quantum shape-phase transitions in the two-dimensional limit of the vibron model. AB - We obtain a characterization of quantum shape-phase transitions in the terms of complexity measures in the two-dimensional limit of the vibron model based on the spectrum generating algebra U(3). Complexity measures (in terms of the Renyi entropies) have been calculated for different values of the control parameter for the ground state of this model giving sharp signatures of the quantum shape-phase transition from linear to bent molecules. PMID- 24948525 TI - The regulatory role of icariin on apoptosis in mouse preimplantation embryos with reduced microRNA-21. AB - We constructed a model of apoptosis in mouse preimplantation embryos and investigated the effect of the flavonol icariin on embryonic development in vitro in embryos with reduced microRNA-21 (miR-21). The model was generated by microinjecting an miR-21 inhibitor into the cytoplasm of mouse pronuclear embryos, which were cultured in vitro using modified CZB (mCZB) basal medium (model group), or using mCZB medium with 0.6 MUg/mL icariin as an experimental group (model-Ica). These were compared with embryos collected in vivo (vivo group) or not microinjected (control group). Developmental rates in vitro of two- and four-cell embryos and blastocysts were observed, and Hoechst 33342 and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were used to count blastocyst cell numbers and apoptotic cell numbers and percentages. The transcriptional levels of miR-21, the apoptotic genes caspase 3 and phosphatase and tensin homolog deleted on chromosome ten (PTEN), and the antiapoptotic gene Bcl-2 were detected by quantitative polymerase chain reaction (qPCR). Western immunoblotting was used to detect the protein levels of caspase 3, PTEN, and Bcl 2. Compared with the model group, icariin treatment significantly improved blastocyst development in vitro (58.43 +/- 7.53% vs. 37.85 +/- 6.47%; P < 0.01), whereas it was not significantly different to the control group (60.34 +/- 9.86%). Icariin treatment significantly increased the blastocyst cell numbers (47.02 +/- 4.93 vs. 37.70 +/- 5.80; P < 0.01), and reduced the rates of apoptosis (5.51 +/- 2.35% vs. 10.11 +/- 4.21%; P < 0.01), whereas the blastocyst cell numbers and apoptotic rates revealed no significant differences between the vivo (46.06 +/- 6.50, 5.95 +/- 2.56%) and control groups (45.77 +/- 4.09, 6.18 +/- 2.41%). Icariin treatment significantly improved miR-21 expression in all embryo stages, reduced the transcriptional levels of caspase 3 and PTEN, and increased the levels of Bcl-2. The protein expression levels of caspase 3 and PTEN were decreased in blastocysts and the level of Bcl-2 was increased (P < 0.01). These had no significant differences with the vivo and control groups, and the protein levels revealed no significant differences between two- and four-cell embryos. Thus, miR-21 was necessary for preimplantation embryonic development, and embryo quality was closely associated with the apoptosis-related protein expression levels regulated by miR-21. Icariin upregulated miR-21 expression and reduced apoptosis in embryos with reduced miR-21. It also improved embryonic developmental quality in vitro, indicating an important regulatory role for miR 21 in blastocyst development in vitro. PMID- 24948527 TI - Theoretical studies on degradation mechanism for OH-initiated reactions with diuron in water system. AB - Diuron, a chlorine-substituted dimethyl herbicide, is widely used in agriculture. Though the degradation of diuron in water has been studied much with experiments, little is known about the detailed degradation mechanism from the molecular level. In this work, the degradation mechanisms for OH-induced reactions of diuron in water phase are investigated at the MPWB1K/6-311+G(3df,2p)//MPWB1K/6 31+G(d,p) level with polarizable continuum model (PCM) calculation. Three reaction types including H-atom abstraction, addition, and substitution are identified. For H-atom abstraction reactions, the calculation results show that the reaction abstracting H atom from the methyl group has the lowest energy barrier; the potential barrier of ortho- H (H1') abstraction is higher than the meta- H abstraction, and the reason is possibly that part of the potential energy is to overcome the side chain torsion for the H1' abstraction reaction. For addition pathways, the ortho- site (C (2) atom) is the most favorable site that OH may first attack; the potential barriers for OH additions to the ortho- sites (pathways R7 and R8) and the chloro-substituted para- site (R10) are lower than other sites, indicating the ortho- and para- sites are more favorable to be attacked, matching well with the -NHCO- group as an ortho-para directing group. PMID- 24948528 TI - Automatic detection of motor unit innervation zones of the external anal sphincter by multichannel surface EMG. AB - A method to detect automatically the location of innervation zones (IZs) from 16 channel surface EMG (sEMG) recordings from the external anal sphincter (EAS) muscle is presented in order to guide episiotomy during child delivery. The new algorithm (2DCorr) is applied to individual motor unit action potential (MUAP) templates and is based on bidimensional cross correlation between the interpolated image of each MUAP template and two images obtained by flipping upside-down (around a horizontal axis) and left-right (around a vertical axis) the original one. The method was tested on 640 simulated MUAP templates of the sphincter muscle and compared with previously developed algorithms (Radon Transform, RT; Template Match, TM). Experimental signals were detected from the EAS of 150 subjects using an intra-anal probe with 16 equally spaced circumferential electrodes. The results of the three algorithms were compared with the actual IZ location (simulated signal) and with IZ location provided by visual analysis (VA) (experimental signals). For simulated signals, the inter quartile error range (IQR) between the estimated and the actual locations of the IZ was 0.20, 0.23, 0.42, and 2.32 interelectrode distances (IED) for the VA, 2DCorr, RT and TM methods respectively. PMID- 24948531 TI - Putting the "family" back into family therapy. AB - In this article, we examine the field of family therapy by drawing a distinction between two forms of practice: Whole Family Therapy (WFT), defined as treating the whole family, and Relational Family Therapy (RFT), defined as working with a subsystem of the family or an individual while retaining a systemic lens. Our thesis is that the practice of WFT has been in decline for some time and steps must be taken to keep it from becoming a defunct practice. We consider the trajectory of WFT and RFT throughout the development of family therapy through reference to the people, the literature, training, and practice patterns associated with family therapy. We remind the reader of the many benefits of WFT and suggest that today WFT is likely to be practiced in conjunction with RFT and individual therapy. Since training of family therapists today is largely located in degree-granting programs, we identify constraints to including WFT in such programs. We conclude by offering suggestions that can enhance a program's ability to train students in WFT. PMID- 24948529 TI - Genetic research participation in a young adult community sample. AB - Opposed to large nationally sponsored health initiatives or biobanks, little is known about gathering genetic samples from young adults participating in academic community-based epidemiologic studies of mental health and substance use, especially samples with a large number of minority participants. This study describes our experience of establishing a genetic arm within a longitudinal study of a cohort of young adults (mean age 29, 75 % African American, 58 % female). In total, 75 % of those interviewed in the most recent wave donated a DNA sample (31.6 % blood and 68.4 % saliva) and over 90 % provided consent for storage and sharing. Current smokers were more likely to donate a sample than nonsmokers (adjusted odds ratio (aOR) = 1.59, 95 % confidence interval (CI) = 1.14, 2.22). The odds of obtaining a saliva sample were increased for those who were former cannabis smokers and who drank more regularly, but decreased among participants with less education and a history with drug use. Fewer minorities (aOR = 0.37, 95 % CI = 0.18, 0.75; p = 0.006) and cannabis users (aOR = 0.46, 95 % CI = 0.27, 0.77) consented to sharing their sample with other investigators. Findings also illustrate there are many study parameters that are important in planning biologic collection efforts. Building strong rapport and trust with subjects, minimizing the burden involved by the respondent to obtain a biological sample, offering a choice to provide blood or saliva, and offering an incentive will increase the likelihood of obtaining a sample and, importantly, increase the opportunity to store and share the sample for the future. PMID- 24948530 TI - Myb14, a direct activator of STS, is associated with resveratrol content variation in berry skin in two grape cultivars. AB - KEY MESSAGE: High and low resveratrol (Res) contents in two cultivars are correlated with the expression abundance of Myb14 , which could directly activate transcriptional expression of stilbene synthase gene ( STS ). Resveratrol (3,5,4' trihydroxystilbene) is one of the natural polyphenols produced by secondary metabolism in some plants. Stilbene synthase (STS) is the key enzyme for the final step of precursor formation of resveratrol (Res) in grapevines. In this study, we found that Res contents in ripe berry skin were completely different in two grape cultivars, namely, 'Z168' (Vitis monticola * Vitis riparia) with high Res and 'Jingzaojing' (Vitis vinifera) with low-Res. Moreover, the level of expression of STS gene was higher in the ripe berry skin of 'Z168' than in that of 'Jingzaojing'. To further investigate the underlying mechanisms, we conducted a co-expression analysis through transcriptomic data. We confirmed that Myb14, an R2R3 Myb transcription factor, is the direct regulator of STS by binding to Box L5 motif. Moreover, the expression pattern of Myb14 is associated with the variation of Res content. To test this prediction, we conducted a number of experiments in vivo and in vitro. The expression patterns of Myb14 and STS in grapevine leaves were identical under a series of stimulus. Myb14 showed higher expression in the ripe berry skin of 'Z168' than in that of 'Jingzaojing'. Yeast one-hybrid assay indicated that grapevine Myb14 could interact with the promoter of STS in vitro, and the transient overexpression of Myb14 promoted the expression of STS. Furthermore, co-expressing 35S::Myb14 in transgenic Arabidopsis could activate GUS expression promoted by STS promoter. Thus, Myb14 is the direct activator of STS, and its expression pattern is associated with Res content variation in grapes. PMID- 24948532 TI - A new method for nutrients removal and recovery from wastewater using a bioelectrochemical system. AB - Nutrients management is a key task of wastewater treatment and removal of nutrients is usually associated with significant energy/economic cost. A new bioelectrochemical system, named "R(2)-BES", was developed for removing and possibly recovering nutrients from wastewater. This R(2)-BES takes advantage of bioelectricity generation from oxidation of organic compounds to drive ammonium migration out of wastewater, and uses hydroxide ions produced from the cathode reaction as a medium to exchange phosphate ions from wastewater at the same time. Under an applied voltage of 0.8 V, the R(2)-BES removed 83.4 +/- 1.3% of ammonium nitrogen and 52.4 +/- 9.8% of phosphate, significantly higher than those (3.6 +/- 3.7% and 21.1 +/- 2.6%) under an open circuit condition. Applying an external voltage can increase current generation, COD removal, and nutrient removal. Those results demonstrate a proof of concept that the R(2)-BES may be potentially applied to remove and recover nutrients through appropriate integration into the existing treatment facilities. PMID- 24948533 TI - Reliability and validity of the C-BiLLT: a new instrument to assess comprehension of spoken language in young children with cerebral palsy and complex communication needs. AB - In clinical practice, a variety of diagnostic tests are available to assess a child's comprehension of spoken language. However, none of these tests have been designed specifically for use with children who have severe motor impairments and who experience severe difficulty when using speech to communicate. This article describes the process of investigating the reliability and validity of the Computer-Based Instrument for Low Motor Language Testing (C-BiLLT), which was specifically developed to assess spoken Dutch language comprehension in children with cerebral palsy and complex communication needs. The study included 806 children with typical development, and 87 nonspeaking children with cerebral palsy and complex communication needs, and was designed to provide information on the psychometric qualities of the C-BiLLT. The potential utility of the C-BiLLT as a measure of spoken Dutch language comprehension abilities for children with cerebral palsy and complex communication needs is discussed. PMID- 24948535 TI - Characteristics of U.S. veterans who begin and complete prolonged exposure and cognitive processing therapy for PTSD. AB - This retrospective chart-review study examined patient-level correlates of initiation and completion of evidence-based psychotherapy (EBP) for posttraumatic stress disorder (PTSD) among treatment-seeking U.S. veterans. We identified all patients (N = 796) in a large Veterans Affairs PTSD and anxiety clinic who attended at least 1 individual psychotherapy appointment with 1 of 8 providers trained in EBP. Within this group, 91 patients (11.4%) began EBP (either Cognitive Processing Therapy or Prolonged Exposure) and 59 patients (7.9%) completed EBP. The medical records of all EBP patients (n = 91) and a provider matched sample of patients who received another form of individual psychotherapy (n = 66) were reviewed by 4 independent raters. Logistic regression analyses revealed that Iraq and Afghanistan veterans were less likely to begin EBP than veterans from other service eras, OR = 0.48, 95% CI = [0.24, 0.94], and veterans who were service connected for PTSD were more likely than veterans without service connection to begin EBP, OR = 2.33, 95% CI = [1.09, 5.03]. Among those who began EBP, Iraq and Afghanistan veteran status, OR = 0.09, 95% CI = [0.03, 0.30], and a history of psychiatric inpatient hospitalization, OR = 0.13, 95% CI = [0.03, 0.54], were associated with decreased likelihood of EBP completion. PMID- 24948534 TI - The Abeta peptides-activated calcium-sensing receptor stimulates the production and secretion of vascular endothelial growth factor-A by normoxic adult human cortical astrocytes. AB - The excess vascular endothelial growth factor (VEGF) produced in the Alzheimer's disease (AD) brain can harm neurons, blood vessels, and other components of the neurovascular units (NVUs). But could astrocytes partaking in networks of astrocyte-neuron teams and connected to blood vessels of NVUs contribute to VEGF production? We have shown with cultured cerebral cortical normal (i.e., untransformed) adult human astrocytes (NAHAs) that exogenous amyloid-beta peptides (Abetas) stimulate the astrocytes to make and secrete large amounts of Abetas and nitric oxide by a mechanism mediated through the calcium-sensing receptor (CaSR). Here, we report that exogenous Abetas stimulate the NAHAs to produce and secrete even VEGF-A through a CaSR-mediated mechanism. This is indicated by the ability of Abetas to specifically bind the CaSR, and the capability of a CaSR activator, the "calcimimetic" NPS R-568, to imitate, and of the CaSR antagonist, "calcilytic" NPS 2143, to inhibit, the Abetas stimulation of VEGF-A production and secretion by the NAHAs. Thus, Abetas that accumulate in the AD brain may make the astrocytes that envelop and functionally collaborate with neurons into multi-agent AD-driving "machines" via a CaSR signaling mechanism(s). These observations suggest the possibility that CaSR allosteric antagonists such as NPS 2143 might impede AD progression. PMID- 24948536 TI - Assessing the association between childhood sexual abuse and adult sexual experiences in women with sexual difficulties. AB - Self-report instruments for assessing sexual well-being in women with sexual difficulties have not to date been explicitly validated among women with a history of childhood sexual abuse (CSA). Given an extensive literature suggesting psychological differences between women with and without a history of CSA, it is possible that sexual well-being has a different meaning for these groups. Without validated scales, it is difficult to evaluate the impact of early sexual trauma on adult sexuality. The present study assessed whether the factor structure of widely used measures of sexual well-being were consistent across women experiencing sexual difficulties, with and without an abuse history, and to estimate effect sizes for the statistical effect of CSA on sexual well-being in this population. A sample of women with and without a history of CSA (N = 238) completed the Female Sexual Function Index and the Sexual Satisfaction Scale for Women. Structural equation models indicated generally consistent factor structures across groups, suggesting good construct validity. Effect size estimates indicated medium to large (0.53-0.72) effects of CSA on sexual well being for women with sexual difficulties. These findings support and extend research regarding the potential effects of CSA that may inform treatment for this population. PMID- 24948538 TI - Psychiatric effects of protracted conflict and political life events exposure among adolescents in Israel: 1998-2011. AB - This cross-sectional study investigated relations between conflict exposure and psychiatric symptoms among 8,727 Jewish Israeli adolescents aged 12-17 years from 1998-2011. This 14-year span included periods of terrorism, missile attacks, wars, relocations, military operations, and relative quiet, reflecting a dynamically changing, primarily violent climate. Annual samples from the same cities, geographical regions, and schools throughout the country were assessed for personal political life events (PLE) exposure and for psychiatric symptoms using the Brief Symptom Inventory (BSI; Derogatis & Spencer, ). Data were divided into 8 exposure periods: (a) pre-Intifada 1998-2000, (b) Intifada peak 2001-2003, (c) Intifada recession 2004, (d) evacuation 2005, (e) missiles and the 2006 Lebanon war, (f) peak missiles 2006-2007, (g) Operation Cast Lead 2008-2009, and (h) global terrorism 2010-2011. Results confirmed a relation between type of exposure period, PLE exposure, and psychiatric symptoms. In addition, PLE exposure was positively correlated with psychiatric symptoms (beta = .49). A moderating effect of gender on the relationship between PLE exposure and the psychiatric index was found, with elevated symptoms among females (beta = .30). PMID- 24948537 TI - Inflamed by the flames? The impact of terrorism and war on immunity. AB - The physiological impact on citizens of prolonged exposure to violence and conflict is a crucial, yet underexplored, issue within the political science and biology literature. We examined the effect of high levels of exposure to rocket and terrorist attacks on biological markers of immunity and inflammation in a sample of 92 Israelis. A stratified random sample of individuals was drawn from a pool of subjects in Israel who had previously been interviewed regarding their stress exposure and psychological distress during a period of active rocket and terrorist attacks. These individuals were reinterviewed and blood samples were collected to assess antibodies to cytomegalovirus (CMV antibodies) and C-reactive protein (CRP). Posttraumatic stress disorder (PTSD) was significantly related to CRP, beta = .33, p = .034, with body mass index, depression, and exposure to terrorism included in the model. Depression scores were not significantly associated with CRP or CMV antibody levels. In contrast to the established convention that psychological distress is the sole outcome of terrorism exposure, these findings reveal that individuals exposed to terrorism experience higher levels of both PTSD/depression, and inflammation. This study has important ramifications for how policy makers and medical health professionals should formulate public health policies and medically treat individuals living in conflict zones. PMID- 24948539 TI - Severe stress and adjustment disorder diagnoses in the population of Denmark. AB - We created a registry of Danish-born citizens of Denmark with incident International Classification of Diseases (10th ed.; ICD-10) severe stress and adjustment disorder diagnoses between 1995 and 2011. A unique personal identifier was used to retrieve and merge data on demographic characteristics and diagnoses (ICD-10 codes F43.x). Here we report on the incidence of these disorders and the demographic characteristics of the subset of the Danish population who have received 1 of these diagnoses: 111,844 adults and children received a first diagnosis between 1995 and 2011. More women than men (60.1% vs. 39.9%) received a diagnosis. Diagnoses increased during the late teens through early 30s. Adjustment disorder was the most common diagnosis (65.7% of adults and 64% of children). Reaction to severe stress unspecified was the second most common (19.8% of adults and 23.8% of children), and there was a large increase in both, as well as acute stress reaction diagnoses, in 2007 (3,717-5,141, 1,248-2,520, and 348-1,024 in 2006 to 2007, respectively). Findings regarding gender and age of onset are similar to other westernized countries. This registry can be used for future research programs, contributing to the study of stress and trauma. PMID- 24948540 TI - Fever after redo Nissen fundoplication with hiatal hernia repair. AB - BACKGROUND: Fevers often arise after redo fundoplication with hiatal hernia repair. We reviewed our experience to evaluate the yield of a fever work-up in this population. METHODS: We performed a retrospective review of children undergoing redo Nissen fundoplication with hiatal hernia repair between December 2001 and September 2012. Temperatures and fever evaluations of those children receiving a mesh repair were compared with those without mesh. A fever defined as temperature >=38.4 degrees C. RESULTS: Fifty one children received 46 laparoscopic, 4 open, and 1 laparoscopic converted to open procedures. Biosynthetic mesh was used in 25 children whereas 26 underwent repair without mesh. A fever occurred in 56% of those repaired with mesh compared with 23.1% without mesh (P = 0.02). A fever evaluation was conducted in 32% of those with mesh compared with 11.5% without mesh (P = 0.52). A urinary tract infection was identified in one child after mesh use and an infection was identified in two children without mesh, one pneumonia and one wound infection (P = 1). In those repaired with mesh, there was no significant difference in maximum temperature. CONCLUSIONS: Fever is common after redo Nissen fundoplication with hiatal hernia repair and occurs more frequently, and with higher temperatures in those with mesh. Fever work-up in these patients is unlikely to yield an infectious source and is attributed to the extensive dissection during the redo procedure. PMID- 24948541 TI - Astaxanthin offers neuroprotection and reduces neuroinflammation in experimental subarachnoid hemorrhage. AB - BACKGROUND: Neuroinflammation has been proven to play a crucial role in early brain injury pathogenesis and represents a target for treatment of subarachnoid hemorrhage (SAH). Astaxanthin (ATX), a dietary carotenoid, has been shown to have powerful anti-inflammation property in various models of tissue injury. However, the potential effects of ATX on neuroinflammation in SAH remain uninvestigated. The goal of this study was to investigate the protective effects of ATX on neuroinflammation in a rat prechiasmatic cistern SAH model. METHODS: Rats were randomly distributed into multiple groups undergoing the sham surgery or SAH procedures, and ATX (25 mg/kg or 75 mg/kg) or equal volume of vehicle was given by oral gavage at 30 min after SAH. All rats were sacrificed at 24 h after SAH. Neurologic scores, brain water content, blood-brain barrier permeability, and neuronal cell death were examined. Brain inflammation was evaluated by means of expression changes in myeloperoxidase, cytokines (interleukin-1beta, tumor necrosis factor-alpha), adhesion molecules (intercellular adhesion molecule-1), and nuclear factor kappa B DNA-binding activity. RESULTS: Our data indicated that post-SAH treatment with high dose of ATX could significantly downregulate the increased nuclear factor kappa B activity and the expression of inflammatory cytokines and intercellular adhesion molecule-1 in both messenger RNA transcription and protein synthesis. Moreover, these beneficial effects lead to the amelioration of the secondary brain injury cascades including cerebral edema, blood-brain barrier disruption, neurological dysfunction, and neuronal degeneration. CONCLUSIONS: These results indicate that ATX treatment is neuroprotective against SAH, possibly through suppression of cerebral inflammation. PMID- 24948542 TI - Valproic acid protects septic mice from renal injury by reducing the inflammatory response. AB - BACKGROUND: Valproic acid (VPA), a histone deacetylase inhibitor, has extensive activities against inflammation, oxidation, and malignancy. This study was designed to investigate the protective effect of VPA on the systemic inflammatory response and renal injury in septic mice. MATERIALS AND METHODS: The septic model of mice was established using a cecal ligation-puncture technique. A single dose of VPA (300 mg/kg) was administered at 30 min postoperatively. RESULTS: We found that VPA reduced the tubular swelling and lowered the serum levels of blood urea nitrogen, creatinine, and C-reactive protein. After treatment with VPA, the renal level of malondialdehyde and the activity of myeloperoxidase decreased markedly; the activity of superoxide dismutase and the glutathione content increased accordingly; and the serum levels of tumor necrosis factor alpha, interleukin 1beta, and interleukin 6 decreased markedly. Furthermore, VPA suppressed the renal expression of cyclooxygenase 2 and inducible nitric oxide synthase and repressed the release of prostaglandin E2 and nitric oxide. CONCLUSIONS: Our results demonstrate that VPA reduces the inflammatory response in a septic model and protects mice from renal injury, showing substantial potential in the treatment of sepsis. PMID- 24948543 TI - Intraintestinal drainage as a damage control surgery adjunct in a hypothermic traumatic shock swine model with multiple bowel perforations. AB - BACKGROUND: Temporary bowel ligation (TL) has been proposed to prevent contamination as a damage control procedure in multiple bowel perforations. However, bacteria translocation and intestinal ischemia may develop in a prolonged duration. We here hypothesized that intraintestinal drainage combined with temporary ligation (D-TL) would decrease intestinal injury and improve survivals in a gunshot multiple bowel perforation swine model in the setting of a damage control surgery. MATERIALS AND METHODS: The abdomen was shot one time with an experimental modified gun whereas pigs were hemorrhaged to a mean arterial pressure of 40 mm Hg and maintained in shock for 40 min. Cold lactated Ringer solution was gradually infused to induce hypothermia. Animals were randomized to primary anastomosis, TL and intraintestinal D-TL groups (n = 8). Animals were resuscitated for 12 h with the shed blood and lactated Ringer solution. Delayed anastomosis was performed in TL and D-TL animals after resuscitation. Surviving animals were humanely killed 24 h after operation. Systemic hemodynamic parameters were recorded and blood samples were obtained for biochemical assays. Intra-abdominal pressure, portal vein and peripheral vein bacterial cultures, small intestine hematoxylin-eosin staining, and transmission electron microscopy examination were performed at 0, 2, 6, 12, and 24 h after the surgery. RESULTS: All animals suffered extreme physiologic conditions as follows: hypothermia, severe acidosis, hypotension, and depressed cardiac output. Compared with the primary anastomosis and TL group, D-TL animals required less resuscitation fluid, suffered a lower intra-abdominal hypertension and bacterial translocation, normalized lactate levels faster, had lower serum creatine kinase, aspartate aminotransferase levels and tissue TNF-alpha level, and nuclear factor-kB activations and thus had greater early survival. CONCLUSIONS: Compared with primary intestinal anastomosis and TL, rapid bowel ligation combined with intraintestinal drainage as a damage control adjunct improved survivals in a multiple bowel perforation swine model in the setting of damage control surgery. PMID- 24948544 TI - Augmenter of liver regeneration attenuates inflammatory response in the postischemic mouse liver in vivo. AB - BACKGROUND: Augmenter of Liver Regeneration (ALR), a protein synthesized in the liver is suggested to be protective against oxidative stress-induced cell death. Hepatic ischemia-reperfusion (I/R) injury is triggered by reactive oxygen species. Here, we tested the hypothesis that ALR attenuates hepatic I/R injury in vivo. METHODS: C57BL6 mice were subjected to warm hepatic ischemia for 90 min. Either recombinant ALR (100 MUg/kg) or vehicle were administered to mice prior ischemia. During reperfusion, neutrophil and CD4+ T cell migration and sinusoidal perfusion were analyzed using intravital microscopy. Alanine aminotransferase aspartate aminotransferase (plasma) and caspase-3 (tissue) activities were determined as markers of hepatocellular necrotic and apoptotic injury. RESULTS: Hepatic I/R led to dramatic enhancement of neutrophil and CD4+ T cell recruitment in hepatic microvessels, sinusoidal perfusion failure, and strong elevation of aspartate aminotransferase-alanine aminotransferase and caspase-3 activities. During early reperfusion (60 min), the pretreatment with ALR improved postischemic perfusion failure (P < 0.05) and attenuated liver enzyme activities. Recruitment of CD4+ T cells, but not of neutrophils was attenuated. After 240 min of reperfusion, the protective effect of ALR was stronger, since the liver enzyme activity, perfusion failure, and leukocyte influx were significantly attenuated. As shown by the measurement of caspase-3 activity, postischemic apoptosis was reduced in the ALR-treated group. CONCLUSIONS: Our in vivo data show that ALR has a therapeutic potential against postischemic liver injury. As a mechanism, we suggest a direct protective effect of ALR on apoptotic and necrotic death of hepatocytes and an attenuation of inflammatory cell influx into the postischemic tissue. PMID- 24948545 TI - Zoledronic acid infusion for lumbar interbody fusion in osteoporosis. AB - BACKGROUND: Clinical outcomes of intravenous (IV) infusion of zoledronic acid (ZOL) for lumbar interbody fusion surgery (LIFS) remain unknown. We investigated the efficacy of IV ZOL on clinical outcome and bone fusion after LIFS. MATERIALS AND METHODS: We retrospectively analyzed 64 patients with both degenerative lumbar spondylolisthesis and osteoporosis who underwent LIFS from January 2007 to April 2010. All patients were followed up for 2 y. Thirty-two were treated with an IV infusion of ZOL 3 d after surgery and a second injection 1 y later, and the other 32 patients did not receive ZOL. Preoperatively and every 3 mo postoperatively, oswestry disability index questionnaire and visual analog scale (VAS) scores for back and leg were compared. Preoperative and final postoperative follow-up to evaluate for subsequent compression fractures were also performed. Pedicle screw loosening, cage subsidence, and fusion rate were documented 2 y after surgery. RESULTS: At 2-y follow-up, a solid fusion was achieved in 75% of the ZOL group and only 56% of the control group. At final follow up, the incidence of final subsequent vertebral compression fractures (19% of the ZOL group and 51% of the control group, P = 0.006), pedicle screw loosening (18% of the ZOL group and 45% of the control group, P = 0.03), and cage subsidence >2 mm (28% of the ZOL group and only 54% of the control group, P = 0.04) were significantly lower in the ZOL group than in the control group. The ZOL group demonstrated improvement in VAS (for leg pain VAS, 2/10 for the ZOL group and 5/10 for the control group; for back pain VAS, 2/10 for the ZOL group and 6/10 for the control group) and oswestry disability index scores (7/25 for the ZOL group and 16/25 for the control group). CONCLUSIONS: ZOL treatment has beneficial effects on instrumented LIFS both radiographic and clinically. Thus, ZOL treatment can be recommended for osteoporosis patients undergoing LIFS. PMID- 24948547 TI - Colocation and role of polyphosphates and alkaline phosphatase in apatite biomineralization of elasmobranch tesserae. AB - Elasmobranchs (e.g. sharks and rays), like all fishes, grow continuously throughout life. Unlike other vertebrates, their skeletons are primarily cartilaginous, comprising a hyaline cartilage-like core, stiffened by a thin outer array of mineralized, abutting and interconnected tiles called tesserae. Tesserae bear active mineralization fronts at all margins and the tesseral layer is thin enough to section without decalcifying, making this a tractable but largely unexamined system for investigating controlled apatite mineralization, while also offering a potential analog for endochondral ossification. The chemical mechanism for tesserae mineralization has not been described, but has been previously attributed to spherical precursors, and alkaline phosphatase (ALP) activity. Here, we use a variety of techniques to elucidate the involvement of phosphorus-containing precursors in the formation of tesserae at their mineralization fronts. Using Raman spectroscopy, fluorescence microscopy and histological methods, we demonstrate that ALP activity is located with inorganic phosphate polymers (polyP) at the tessera-uncalcified cartilage interface, suggesting a potential mechanism for regulated mineralization: inorganic phosphate (Pi) can be cleaved from polyP by ALP, thus making Pi locally available for apatite biomineralization. The application of exogenous ALP to tissue cross sections resulted in the disappearance of polyP and the appearance of Pi in uncalcified cartilage adjacent to mineralization fronts. We propose that elasmobranch skeletal cells control apatite biomineralization by biochemically controlling polyP and ALP production, placement and activity. Previous identification of polyP and ALP shown previously in mammalian calcifying cartilage supports the hypothesis that this mechanism may be a general regulating feature in the mineralization of vertebrate skeletons. PMID- 24948546 TI - Polycyclic aromatic hydrocarbons in residential dust and risk of childhood acute lymphoblastic leukemia. AB - Several polycyclic aromatic hydrocarbons (PAHs) are known or probable human carcinogens. We evaluated the relationship between PAH exposure and risk of childhood acute lymphoblastic leukemia (ALL) using concentrations in residential dust as an exposure indicator. We conducted a population-based case-control study (251 ALL cases, 306 birth-certificate controls) in Northern and Central California from 2001 to 2007. We collected residential dust using a high volume small surface sampler (HVS3) (n=185 cases, 212 controls) or by sampling from participants' household vacuum cleaners (n=66 cases, 94 controls). We evaluated log-transformed concentrations of 9 individual PAHs, the summed PAHs, and the summed PAHs weighted by their carcinogenic potency (the toxic equivalence). We calculated odds ratios (ORs) and 95% confidence intervals (CI) using logistic regression adjusting for demographic characteristics and duration between diagnosis/reference date and dust collection. Among participants with HVS3 dust, risk of ALL was not associated with increasing concentration of any PAHs based on OR perln(ng/g). Among participants with vacuum dust, we observed positive associations between ALL risk and increasing concentrations of benzo[a]pyrene (OR perln[ng/g]=1.42, 95% CI=0.95, 2.12), dibenzo[a,h]anthracene (OR=1.98, 95% CI=1.11, 3.55), benzo[k]fluoranthene (OR=1.71, 95% CI=0.91, 3.22), indeno[1,2,3 cd]pyrene (OR=1.81, 95% CI=1.04, 3.16), and the toxic equivalence (OR=2.35, 95% CI=1.18, 4.69). The increased ALL risk among participants with vacuum dust suggests that PAH exposure may increase the risk of childhood ALL; however, reasons for the different results based on HVS3 dust samples deserve further study. PMID- 24948548 TI - Rifampicin-fosfomycin coating for cementless endoprostheses: antimicrobial effects against methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). AB - New strategies to decrease infection rates in cementless arthroplasty are needed, especially in the context of the growing incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections. The purpose of this study was to investigate the antimicrobial activity of a rifampicin-fosfomycin coating against methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA in a rabbit infection prophylaxis model. Uncoated or rifampicin-fosfomycin-coated K-wires were inserted into the intramedullary canal of the tibia in rabbits and contaminated with an inoculation dose of 10(5) or 10(6) colony-forming units of MSSA EDCC 5055 in study 1 and MRSA T6625930 in study 2, respectively. After 28days the animals were killed and clinical, histological and microbiological assessment, including pulse field gel electrophoresis, was conducted. Positive culture growth in agar plate testing and/or clinical signs and/or histological signs were defined positive for infection. Statistical evaluation was performed using Fisher's exact test. Both studies showed a statistically significant reduction of infection rates for rifampicin-fosfomycin-coated implants compared to uncoated K-wires (P=0.015). In both studies none of the 12 animals that were treated with a rifampicin fosfomycin-coated implant showed clinical signs of infection or a positive agar plate testing result. In both studies, one animal of the coating group showed the presence of sporadic bacteria with concomitant inflammatory signs in histology. The control groups in both studies exhibited an infection rate of 100% with clear clinical signs of infection and positive culture growth in all animals. In summary, the rifampicin-fosfomycin-coating showed excellent antimicrobial activity against both MSSA and MRSA, and therefore warrants further clinical testing. PMID- 24948549 TI - Mechanism of luminal patency of the self-expanding Sideguard sidebranch stent: evaluation by intravascular ultrasound and optical coherence tomography. AB - BACKGROUND: The Cappella Sideguard (CS) sidebranch stent is a self-expanding, thin-strut, nitinol device with anatomic flaring at the sidebranch ostium designed to treat bifurcation lesions. OBJECTIVE: To evaluate the mechanism of long-term lumen patency of the novel, self-expanding CS sidebranch stent compared with a balloon-expandable stent in the main vessel. METHODS: We performed intravascular ultrasound postintervention and at follow-up in 24 CS stents and in 28 balloon-expandable drug-eluting stents deployed in the corresponding main vessel. Thirteen patients also had optical coherence tomography (OCT) at follow up to evaluate neointimal hyperplasia and strut coverage. RESULTS: CS stent area at the sidebranch carina increased significantly from 3.8 +/- 1.2 mm(2) postintervention to 4.6 +/- 1.2 mm(2) at follow-up (P < 0.001), resulting in no change in lumen area (3.8 +/- 1.2 mm(2) to 3.7 +/- 1.2 mm(2) , P = 0.72) despite a neointimal area at follow-up of 0.9 +/- 0.8 mm(2) . Volumetric changes were similar, and the distribution of neointimal hyperplasia peaked 1-2 mm distal to the carina. Change of lumen volume inversely correlated to the neointimal volume (R = -0.48, P < 0.001), but correlated positively to the change in stent volume (R = 0.52, P < 0.0001). By OCT, most CS struts were covered (100% [98.9, 100]) at the bifurcation site, whereas 61% of floating DES struts that crossed the sidebranch were covered by smooth tissue with a similar texture compared with neointima. CONCLUSION: Although neointimal hyperplasia accumulates within the CS stent mainly 1-2 mm distal to the carina, the self-expanding CS stent may be effective in maintaining an adequate patency in the sidebranch by continued stent expansion noted at follow-up. PMID- 24948550 TI - Soybean flour induces a greater increase of the antioxidant defenses in rats fed with a normocaloric diet compared with a hypercaloric diet. AB - BACKGROUND: Soybeans, due to their antioxidant properties, present beneficial health effects. The objective was to evaluate if replacing casein with soy flour, modifies antioxidant defenses in rat liver, compared to animals that continued being fed with casein based diets (normocaloric and hypercaloric). RESULTS: Four groups of rats were used: CC (control casein), CS (control soy), HC (hypercaloric casein) and HS (hypercaloric soy). Malondialdehyde, in serum and liver, did not present differences. In liver, when comparing CS vs. CC: increased superoxide dismutase 1 (P < 0.001), catalase (P < 0.01) and glutathione reductase (P < 0.05) activities, the total glutathione (P < 0.001) and reduced glutathione (P < 0.05) content and decreased oxidized glutathione content (P < 0.05). In HS vs. HC: increased carbonyl groups (P < 0.01) and superoxide dismutase 1 activity (P < 0.05), and decreased glutathione peroxidase activity (P < 0.01), total glutathione (P < 0.05) and oxidized glutathione content (P < 0.001). In HS vs. CS: decreased glutathione reductase activity (P < 0.01), total glutathione (P < 0.001) and reduced glutathione (P < 0.01) content, and increased oxidized glutathione content (P < 0.05). CONCLUSION: Replacing casein by soybean flour improves antioxidant defenses, mainly in normocaloric diets. PMID- 24948551 TI - Ear pain following temporomandibular surgery originating from the temporomandibular joint or the cranial nervous tissue? A case report. AB - A patient presenting with local pain and limitation of movement in the temporomandibular region following surgery of the left temporomandibular joint (TMJ) is described. Manual techniques like distraction of the TMJ combined with motor control exercises to restore TMJ function were not sufficient to relieve the patient's symptoms and her orofacial functions. However, during manual assessment and treatment of cranial nervous tissue, in this case the auriculotemporal nerve and its interface, pain was relieved and orofacial functions improved. PMID- 24948552 TI - First-drug treatment failures in children with typical absence epilepsy. AB - BACKGROUND: Childhood absence epilepsy (CAE) is a well-known syndrome with onset in middle childhood and is characterized by multiple typical absences per day. Pharmacological treatment is specific and usually successful with a single medication. The goal of the study was to assess on risk factors associated with failure to respond to the initial antiepileptic drug (AED). METHODS: Fifty-two children with CAE were enrolled. Predictive factors were analyzed by survival methods. RESULTS: Among 52 patients, 32 patients (61.5%) were girls and the remaining 20 (38.5%) were boys and the mean age at the seizure onset was 6.5+/ 1.78 years old (3-11.5 years). Of the 52 patients, 42 (80.8%) were treated relatively successfully with the first AED treatment (Group A), and 10 (19.2%) were not responsed (Group B). Age of seizure onset, coexisting other types of seizures, and photoconvulsive EEG response were significantly associated with failure risk according to univariate analysis. In the multivariate analysis, only photoconvulsive EEG response was the risk factor influencing poor response to initial AED treatment. CONCLUSION: Factors predicting failure to respond to the AED were age of seizure onset, coexisting other types of seizures, and photoconvulsive EEG response in children with CAE. PMID- 24948553 TI - A novel missense mutation in GCH1 gene in a Korean family with Segawa disease. AB - Segawa disease is a rare disorder presenting gait disturbance and dystonia with marked fluctuation, and caused by GTP cyclohydrolase 1 (GCH1) deficiency. Our 15 year-old patient was admitted for fluctuating gait disturbance lasted for 4years. Administration of levodopa resulted in a dramatic improvement, and positron emission tomography using 18F-FP-CIT showed normal striatal dopamine transporter activity. Genetic study revealed a novel missense mutation in the exon 5 of GCH1 gene at c.623C>A in the proband and his father, and in silico analysis predicted that the protein function was probably damaged. Mutation analysis and searching with genetic databases might help diagnosing Segawa disease and predicting protein function. PMID- 24948556 TI - The interaction of the Arabidopsis response regulator ARR18 with bZIP63 mediates the regulation of PROLINE DEHYDROGENASE expression. AB - As the first and rate-limiting enzyme of proline degradation, PROLINE DEHYDROGENASE1 (PDH1) is tightly regulated during plant stress responses, including induction under hypoosmolarity and repression under water deficit. The plant receptor histidine kinases AHKs, elements of the two-component system (TCS) in Arabidopsis thaliana, are proposed to function in water stress responses by regulating different stress-responsive genes. However, little information is available concerning AHK phosphorelay-mediated downstream signaling. Here we show that the Arabidopsis type-B response regulator 18 (ARR18) functions as a positive osmotic stress response regulator in Arabidopsis seeds and affects the activity of the PDH1 promoter, known to be controlled by C-group bZIP transcription factors. Moreover, direct physical interaction of ARR18 with bZIP63 was identified and shown to be dependent on phosphorylation of the conserved aspartate residue in the ARR18 receiver domain. We further show that bZIP63 itself functions as a negative regulator of seed germination upon osmotic stress. Using reporter gene assays in protoplasts, we demonstrated that ARR18 interaction negatively interferes with the transcriptional activity of bZIP63 on the PDH1 promoter. Our findings provide new insight into the function of ARR18 and bZIP63 as antagonistic regulators of gene expression in Arabidopsis. PMID- 24948557 TI - Visceral adiposity is not associated with abdominal aortic aneurysm presence and growth. AB - Previous studies in rodent models and patients suggest that visceral adipose could play a direct role in the development and progression of abdominal aortic aneurysm (AAA). This study aimed to assess the association of visceral adiposity with AAA presence and growth. This study was a case-control investigation of patients that did (n=196) and did not (n=181) have an AAA who presented to The Townsville Hospital vascular clinic between 2003 and 2012. Cases were patients with AAA (infra-renal aortic diameter >30 mm) and controls were patients with intermittent claudication but no AAA (infra-renal aortic diameter <30 mm). All patients underwent computed tomography angiography (CTA). The visceral to total abdominal adipose volume ratio was estimated from CTAs by assessing total and visceral adipose deposits using an imaging software program. Measurements were assessed for reproducibility by repeat assessments on 15 patients. AAA risk factors were recorded at entry. Forty-five cases underwent two CTAs more than 6 months apart to assess AAA expansion. The association of visceral adiposity with AAA presence and growth was examined using logistic regression. Visceral adipose assessment by CTA was highly reproducible (mean coefficient of variation 1.0%). AAA was positively associated with older age and negatively associated with diabetes. The visceral to total abdominal adipose volume ratio was not significantly associated with AAA after adjustment for other risk factors. Patients with a visceral to total abdominal adipose volume ratio in quartile four had a 1.63-fold increased risk of AAA but with wide confidence intervals (95% CI 0.71-3.70; p=0.248). Visceral adiposity was not associated with AAA growth. In conclusion, this study suggests that visceral adiposity is not specifically associated with AAA presence or growth although larger studies are required to confirm these findings. PMID- 24948558 TI - Seeking health information online: does limited healthcare access matter? AB - Consumers facing barriers to healthcare access may use online health information seeking and online communication with physicians, but the empirical relationship has not been sufficiently analyzed. Our study examines the association of barriers to healthcare access with consumers' health-related information searching on the internet, use of health chat groups, and email communication with physicians, using data from 27,210 adults from the 2009 National Health Interview Survey. Individuals with financial barriers to healthcare access, difficulty getting timely appointments with doctors, and conflicts in scheduling during clinic hours are more likely to search for general health information online than those without these access barriers. Those unable to get timely appointments with physicians are more likely to participate in health chat groups and email physicians. The internet may offer a low-cost source of health information and could help meet the heightened demand for health-related information among those facing access barriers to care. PMID- 24948559 TI - The influence of the environment on the development of thyroid tumors: a new appraisal. AB - Most epidemiological studies concerning differentiated thyroid cancers (DTC) indicate an increasing incidence over the last two decades. This increase might be partially explained by the better access to health services worldwide, but clinicopathological analyses do not fully support this hypothesis, indicating that there are carcinogenetic factors behind this noticeable increasing incidence. Although we have undoubtedly understood the biology and molecular pathways underlying thyroid carcinogenesis in a better way, we have made very little progresses in identifying a risk profile for DTC, and our knowledge of risk factors is very similar to what we knew 30-40 years ago. In addition to ionizing radiation exposure, the most documented and established risk factor for DTC, we also investigated the role of other factors, including eating habits, tobacco smoking, living in a volcanic area, xenobiotics, and viruses, which could be involved in thyroid carcinogenesis, thus, contributing to the increase in DTC incidence rates observed. PMID- 24948560 TI - Complication rates of atrial fibrillation ablations: comparison of safety outcomes from real world to contemporary randomized control trials. PMID- 24948561 TI - Severe memory impairment following acute morphine intoxication. PMID- 24948562 TI - ApoE secretion modulating bromotyrosine derivative from the Australian marine sponge Callyspongia sp. AB - High throughput screening of a pre-fractionated natural product library identified 11 active fractions showing ApoE modulation activity. Mass-directed fractionation of one active crude extract from the Australian marine sponge Callyspongia sp. resulted in the isolation of 13 metabolites, including three new bromotyrosine derivatives, callyspongic acid (1), 3,5-dibromo-4 methoxyphenylpyruvic acid (2), N-acetyl-3-bromo-4-hydroxylphenylethamine (3), and ten known compounds (4-13). The structure elucidation of compounds 1-3 was based on their 1D and 2D NMR and MS spectroscopic data. 3,5-Dibromo-4 methoxyphenylpyruvic acid (2) showed weak activity in increasing the apolipoprotein E secretion from human CCF-STTG1 cells at the concentration of 40 MUM. PMID- 24948563 TI - Flow synthesis and biological activity of aryl sulfonamides as selective carbonic anhydrase IX and XII inhibitors. AB - A series of secondary and tertiary aryl sulfonamides were synthesized under flow conditions and evaluated for their ability to selectively inhibit tumor associated carbonic anhydrase isoforms IX and XII. The tested compounds revealed to be highly potent CA IX inhibitors in nanomolar range, and to inhibit CA XII activity with different ranks of potencies. Remarkably, 4-methyl-N-phenyl benzenesulfonamide was a selective nanomolar CA IX inhibitor with an IC50 of 90 nM. PMID- 24948564 TI - Structure based virtual screening of MDPI database: discovery of structurally diverse and novel DPP-IV inhibitors. AB - Inhibition of dipeptidyl peptidase IV (DPP-IV) has been emerged as a promising approach for the treatment of type 2 diabetes (T2D). Structure based virtual screening (SBVS) of Molecular Diversity Preservation International (MDPI) database was performed using Glide and Gold against DPP-IV enzyme. Six promising hits were identified and tested for DPP-IV inhibition. Three compounds were found to be active at low micromolar concentration. The 3-(1-hydrazinyl-1 (phenylamino)ethyl)-4-hydroxy-1-methylquinolin-2(1H)-one (compound A) was found to be the most potent hit with an IC50 of 0.73 MUM. These three compounds (A, B and D) were then assessed for their glucose lowering effects in glucose fed hyperglycemic female Wistar rats. The glucose lowering effects of compounds also confirms their potential as anti-diabetic agents. The present study demonstrates a successful utilization of in silico SBVS tools in identification of novel and potential DPP-IV inhibitor. PMID- 24948565 TI - Design and optimization of highly-selective fungal CYP51 inhibitors. AB - While the orally-active azoles such as voriconazole and itraconazole are effective antifungal agents, they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to various safety issues (e.g., drug drug interactions, liver toxicity). Herein, we describe rationally-designed, broad-spectrum antifungal agents that are more selective for the target fungal enzyme, CYP51, than related human CYP enzymes such as CYP3A4. Using proprietary methodology, the triazole metal-binding group found in current clinical agents was replaced with novel, less avid metal-binding groups in concert with potency enhancing molecular scaffold modifications. This process produced a unique series of fungal CYP51-selective inhibitors that included the oral antifungal 7d (VT 1161), now in Phase 2 clinical trials. This series exhibits excellent potency against key yeast and dermatophyte strains. The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases. PMID- 24948566 TI - Structural revision of kynapcin-12 by total synthesis, and inhibitory activities against prolyl oligopeptidase and cancer cells. AB - Kynapcin-12 is a prolyl oligopeptidase (POP) inhibitor isolated from Polyozellus multiplex, and its structure was assigned as 1 having a p-hydroquinone moiety by spectroscopic analyses and chemical means. This Letter describes the total syntheses of the proposed structure 1 for kynapcin-12 and 2',3'-diacetoxy 1,5',6',4"-tetrahydroxy-p-terphenyl 2 isolated from Boletopsis grisea, revising the structure of kynapcin-12 to the latter. These syntheses involved double Suzuki-Miyaura coupling, CAN oxidation, and LTA oxidation as key steps. The inhibitory activities of synthetic compounds against POP and cancer cells were also evaluated. PMID- 24948567 TI - Base-dependent formation of cis and trans olefins and their application in the synthesis of 5-oxo-ETE receptor antagonists. AB - 5-Oxo-ETE is the most potent eosinophil chemoattractant among lipid mediators. We have developed two 5-oxo-ETE receptor antagonists. In the course of the work, we have developed a procedure to selectively introduce a cis and trans double bond in an alkyl side chain. Reacting indolecarboxaldehydes with alkyl ylides using the Li base affords the trans olefins, whereas using the K base yields the cis olefins. PMID- 24948568 TI - 2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4 methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists. AB - A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4 methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode. PMID- 24948570 TI - Cytokine balance and cytokine-driven natural killer cell dysfunction in systemic juvenile idiopathic arthritis. AB - Systemic juvenile idiopathic arthritis (sJIA) is a severe inflammatory childhood disorder, characterized by a specific pattern of systemic features and a typical cytokine profile. Patients are at risk to develop macrophage activation syndrome (MAS), an acute life-threatening condition defined by excessive proliferation and activation of macrophages and T cells. Defects of unknown cause in the natural killer (NK) cell cytotoxic capacity are presumed to underlie the pathogenesis of MAS and have been detected in sJIA patients. Here, we provide an overview of the cytokine profiles in sJIA and related mouse models. We discuss the influence of cytokines on NK cell function, and hypothesize that NK cell dysfunction in sJIA is caused by altered cytokine profiles. PMID- 24948569 TI - On the underutilization of cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) is an exciting therapy that can treat patients with systolic heart failure and left ventricular dysfunction who have a wide QRS complex. Indications for its use have been refined and expanded based on recent clinical data and guidelines, yet the rate of new CRT implants in the United States has not changed much over the past 8 years. Many patients receiving implantable cardioverter-defibrillators can benefit from, but are not receiving, appropriately-indicated CRT devices. We summarize data on CRT use, discuss reasons for probable underutilization, and provide recommendations for augmenting proper and effective use of this highly beneficial therapy. PMID- 24948571 TI - Variability in premolar and molar root number in a modern population of Pan troglodytes verus. AB - While teeth are the most common fossil remains for hominoids, little is known of the tooth root morphology in Primates. With the exception of modern humans, the variability of the number of roots within a species is scarcely documented and not conclusively quantified. This lack of knowledge hinders the interpretation of observed evolutionary trends, such as the reduction of the number of roots of premolars within the hominins. Here, we present the first quantification of the variability of the number of roots in a nonhuman ape population including 405 specimens. Our sample is made of a single biological population of Pan troglodytes verus from Liberia, which is compared to other extant hominoids. Both permanent and deciduous teeth were analyzed and comprise premolars and molars from maxillaries and mandibles. The estimated variability is very low for each tooth position; more than 97% of the specimens displaying the same number of roots except for P4 (94%), M1 (89%), and P(4) (57%). No variability at all was observed for lacteal teeth. Males and females are statistically identical, and no difference linked to the tooth size (estimated by the occlusal surface) was observed. When compared to the observation in other hominoid species, these results emphasize that the difference of the number of roots observed between modern humans and apes is significant, and suggests that the evolution of premolar root number is mosaic, with the common ancestor of Pan and Homo probably displaying a reduced number of roots for P(4) and maybe P(3) , but a plesiomorphic morphology of the roots of lower premolars. PMID- 24948572 TI - The fibular collateral ligament of the knee: a detailed review. AB - The fibular collateral ligament (FCL) is one of the larger ligaments of the knee. The FCL, along with the popliteus tendon, arcuate popliteal ligament, and joint capsule, make up the posterolateral corner of the knee. Recently, there has there been an increased awareness and research on the structures of the posterolateral corner of the knee, particularly the FCL. Studying the detailed structure of the FCL may provide a better understanding that can lead to better diagnosis and treatments following injury. Therefore, this article reviews the FCL, which appears to be the primary restraint to varus rotation but is poorly oriented to resist external rotation of the knee. PMID- 24948573 TI - Thirty cases of human subcutaneous dirofilariasis reported in Rostov-on-Don (Southwestern Russian Federation). AB - INTRODUCTION: Different species of the genus Dirofilaria, mainly D. immitis and D. repens, are responsible for emergent vector borne transmitted zoonotic diseases in the Old World. Human D. repens infections are characterized by the appearance of benign subcutaneous nodules that mimic skin malignant tumors or due to live worms in the ocular area. METHODS: Thirty patients presenting superficial or deep nodules were treated at the Rostov Regional Diagnostic Center (Southwestern Russian Federation). Anatomical characteristics of the nodules were studied by non-invasive ultrasound and color and power Doppler techniques. Worms were surgically removed from every nodule and their DNA analyzed by polymerase chain reaction (PCR). RESULTS: Twenty-four out of the 30 nodules were located in the hypodermis, two in a retro-ocular location and four in scrotal location. Image techniques allowed the identification of the helminthic origin of all nodules, based on their oval and regular shape, peripheral vasculature, and the existence of internal linear winding hyperechoic structures with or without movements, indicating the presence of live or dead worms, respectively. Specific adscription to D. repens was achieved by the PCR analysis. CONCLUSION: The series described in the present paper confirms the increasing risk of infection by D. repens in humans living in endemic areas of Eastern Europe. The use of non invasive ultrasounds and Doppler techniques can contribute to an appropriate management of human dirofilariasis. Moreover, awareness of the medical community in the endemic areas influences the report of cases, and consequently the current epidemiological picture of human dirofilariasis. PMID- 24948574 TI - Breast cryoablation in patients with bone metastatic breast cancer. AB - PURPOSE: To assess retrospectively the safety and feasibility of palliative breast cryoablation to treat primary breast tumors in patients with stage IV breast cancer. MATERIALS AND METHODS: In 17 female patients (mean age +/- SD, 59 y +/- 13; range, 37-81 y) with 22 bone metastatic ductal invasive breast lesions (2.5 cm * 1.6 cm +/- 1.4 * 1.1; range, 1.0 cm * 0.5 cm to 6.7 cm * 5.5 cm), 19 computed tomography (CT)-guided percutaneous cryoablation sessions were performed for treatment of primary breast tumors. All patients had radiologic evidence (contrast-enhanced CT or magnetic resonance imaging) of persistence or progression of the primary breast cancer despite systemic therapy. The radiologic outcome was evaluated with a mean follow-up period of 13 months (range, 3-31 mo). Treatment of skeletal metastases was unnecessary during the follow-up period. RESULTS: All of the cryoablation sessions were completed and well tolerated. Complete regression of the disease was achieved in 15 (88%) patients 2 months after the cryoablation. Two (12%) patients underwent a second cryoablation treatment because of a minimal persistence of viable tumor (residual disease). No relapse of primary tumors was observed on breast imaging during the follow-up period. One patient (6%) developed a new lesion localized to the contralateral breast. CONCLUSIONS: These data suggest that palliative cryoablation of primary advanced breast cancer is a well-tolerated, feasible, and effective treatment option. Given the palliative effects of breast cryoablation demonstrated in this series, larger studies replicating these results are warranted. PMID- 24948575 TI - Sport psychology education for sport injury rehabilitation professionals: a systematic review. AB - Sport psychology education has been shown to have a positive impact on the practice of sport injury rehabilitation professionals (SIRPs). The purpose of this paper is to review recommendations relating to such education. The paper presents a review of existing literature relating to the content and mode of delivery for a sport psychology education programme for SIRPs. The review seeks to address four questions: (1) What topic areas do researchers suggest should be integrated into the sport psychology education of SIRPs? (2) What topic areas are currently being recommended by professional bodies? (3) What are the findings of research examining the impact of sport psychology education on SIRPs? and (4) What do researchers recommend to be the most appropriate mode of delivery for sport psychology education for SIRPs? The findings of the review suggest that in order to maximise adherence amongst already qualified SIRPs sport psychology education should be delivered in a flexible short duration package. Additionally three broad areas that sport psychology education should cover emerged: (1) understanding of the psychological impact of injury, (2) interventions and psychological skills/techniques, and (3) referral and professional boundaries. This has important implications for the future training of SIRPs. PMID- 24948576 TI - Computational fluid dynamics of the right ventricular outflow tract and of the pulmonary artery: a bench model of flow dynamics. AB - OBJECTIVES: The reconstruction of the right ventricular outflow tract (RVOT) with valved conduits remains a challenge. The reoperation rate at 5 years can be as high as 25% and depends on age, type of conduit, conduit diameter and principal heart malformation. The aim of this study is to provide a bench model with computer fluid dynamics to analyse the haemodynamics of the RVOT, pulmonary artery, its bifurcation, and left and right pulmonary arteries that in the future may serve as a tool for analysis and prediction of outcome following RVOT reconstruction. METHODS: Pressure, flow and diameter at the RVOT, pulmonary artery, bifurcation of the pulmonary artery, and left and right pulmonary arteries were measured in five normal pigs with a mean weight of 24.6 +/- 0.89 kg. Data obtained were used for a 3D computer fluid-dynamics simulation of flow conditions, focusing on the pressure, flow and shear stress profile of the pulmonary trunk to the level of the left and right pulmonary arteries. RESULTS: Three inlet steady flow profiles were obtained at 0.2, 0.29 and 0.36 m/s that correspond to the flow rates of 1.5, 2.0 and 2.5 l/min flow at the RVOT. The flow velocity profile was constant at the RVOT down to the bifurcation and decreased at the left and right pulmonary arteries. In all three inlet velocity profiles, low sheer stress and low-velocity areas were detected along the left wall of the pulmonary artery, at the pulmonary artery bifurcation and at the ostia of both pulmonary arteries. CONCLUSIONS: This computed fluid real-time model provides us with a realistic picture of fluid dynamics in the pulmonary tract area. Deep shear stress areas correspond to a turbulent flow profile that is a predictive factor for the development of vessel wall arteriosclerosis. We believe that this bench model may be a useful tool for further evaluation of RVOT pathology following surgical reconstructions. PMID- 24948577 TI - Long-term, low-dose erythromycin monotherapy for Mycobacterium avium complex lung disease: a propensity score analysis. AB - Multidrug regimens are initially withheld in mild cases of pulmonary Mycobacterium avium complex (MAC) disease. Based on the anti-inflammatory effects of macrolides, some patients are treated with erythromycin, which does not appear to exhibit cross-resistance with clarithromycin in MAC. The aim of this study was to evaluate the effects and adverse events of erythromycin monotherapy in patients with pulmonary MAC disease. This was a retrospective propensity score analysis consisting of 31 patients treated with erythromycin alone and 72 patients on conservative therapy, all of whom met the ATS/IDSA criteria for pulmonary MAC disease. The primary outcome was exacerbation requiring administration of a multidrug regimen. The secondary outcome was the rate of response to the multidrug regimens after exacerbation as a surrogate variable for cross-resistance to clarithromycin. As a result, erythromycin monotherapy was found to be likely to suppress exacerbation throughout the 7-year observation period after the diagnosis of pulmonary MAC disease (P=0.045, Breslow test). Multivariate analysis showed that erythromycin tended to prevent exacerbation, albeit statistically insignificantly (hazard ratio=0.495, 95% confidence interval 0.198-1.235; P=0.132). In addition, the rate of response to the multidrug regimens after exacerbation in the erythromycin group (56%; 5/9) was similar to that observed in the control group (62%; 13/21) (P=0.528). Erythromycin monotherapy for patients with pulmonary MAC disease may have the potential to suppress exacerbation without inducing cross-resistance to clarithromycin. However, further prospective studies are needed to microbiologically verify the effectiveness and potential for cross-resistance of these drugs. PMID- 24948578 TI - Phylogenetic and molecular insights into the evolution of multidrug-resistant porcine enterotoxigenic Escherichia coli in Australia. AB - This study investigated the phylogeny and molecular epidemiology of Australian porcine enterotoxigenic Escherichia coli (ETEC) isolates (n=70) by performing multilocus sequence typing (MLST), random amplified polymorphic DNA (RAPD) analysis, virulence gene analysis, plasmid, bacteriocin, integron and antimicrobial resistance gene typing, and antimicrobial susceptibility phenotyping. Isolates of the most commonly observed O serogroup (O149) were highly clonal with a lower frequency of antimicrobial resistance compared with the less common O141 serogroup isolates, which were more genetically diverse and resistant to a greater array of antimicrobials. The O149 and O141 isolates belonged to sequence types (STs) ST100 and ST1260, respectively. A small number of new STs were identified for the least common serogroups, including O157 (ST4245), O138 (ST4244), O139 (ST4246) and O8 (ST4247). A high frequency of plasmid replicons was observed among all ETEC isolates. However, O149 isolates predominantly carried IncFIB, I1, HI1 and FIC, whereas O141 isolates carried a more varied array, including IncI1, FIB, FIC, HI1, I1, Y and, most significantly, A/C. O141 isolates also possessed a greater diversity of bacteriocins, with almost one-half of the isolates carrying colicin E3 (44.4%; 12/27) and E7 (48.1%; 13/27). This study shows that Australian porcine ETEC are distinct from isolates obtained in other parts of the world with respect to the MLST profile and the absence of resistance to critically important antimicrobials, including third generation cephalosporins and fluoroquinolones. PMID- 24948579 TI - Cystic fibrosis in adult age. AB - AIM: To know the prevalence of the patients diagnosed of cystic fibrosis (CF) older than 18 years old of five specific Spanish Units and to analyze their clinical, genetic and microbiological characteristics. PATIENTS AND METHODS: Observational, cross-sectional, descriptive study of patients diagnosed with CF at age or older than 18 years. The variables analyzed were: current age, age at diagnosis, sex, nationality, lung function parameters, pathologies presented at diagnosis, microbiological features and genetic findings. RESULTS: Eigthy nine patients (14.8% of the total of 600 CF patients followed at the participating units), of which 45 patients were female (50.6%) and 44 were males (49.4%), were included with a mean age at diagnosis of 36.4 years. Eigthy one patients (91%) were Spaniards. The sweat test was diagnostic in 77 (86.5%) of the patients studied. The sweat test was diagnostic in 77 of the 89 patients studied (86.5%). The most frequently detected mutations were F508del/other and G542X/other, and the most frequent clinical findings at diagnosis were the presence of bronchiectasis in 33 patients (37.1%) followed by sterility in 12 patients (13.5%). The most common colonizing organisms were meticillin-sensitive Staphylococcus aureus (S.aureus) (23.6%) and Pseudomonas aeruginosa (P. aeruginosa) (13.5%). Most patients presented a mild obstructive ventilatory defect and had no pancreatic involvement. The sweat test used to be indeterminate. CONCLUSIONS: CF is also a disease which diagnosis can be in adulthood. CF patients diagnosed in adulthood have a mild lung function and lower incidence of pancreatic involvement, so their prognosis tends to be favorable. PMID- 24948580 TI - Fever and skin lesion. PMID- 24948581 TI - [Infection and pregnancy: a threat for mother and child]. PMID- 24948582 TI - Water scarcity conditions affect peach fruit size and polyphenol contents more severely than other fruit quality traits. AB - BACKGROUND: The literature abounds with the impacts of drought conditions on the concentration of non-structural compounds (NSC) in peach fruits without distinction as to the direct effect of drought on fruit metabolism and its indirect effect through dilution. Moreover, there is a need to investigate the sensitivity of the fruit composition to progressive water deficit in semi-arid conditions, as well as the origin of variations in fruit composition - not only in carbohydrates and organic acids, but also in secondary metabolites such as polyphenols. RESULTS: The increase in stress intensity resulted in smaller fruits and a reduction in yield. Drought increased fruit dry matter content, structural dry matter (SDM) content and firmness due to lower water import to fruits, although drought reduced fruit surface conductance and its transpiration. Drought significantly affected the concentrations of each NSC either through the decrease in dilution and/or modifications of their metabolism. The increase in hexoses and sorbitol concentrations of fruits grown under drought conditions resulted in an increase in the sweetness index but not near harvest. Malic acid concentration and content:SDM ratio increased as drought intensified, whereas those of citric and quinic acids decreased. Polyphenol concentration and content increased under severe drought. CONCLUSION: The increase in stress intensity strongly affected fruit mass. The concentration of total carbohydrates and organic acid at harvest increased mainly through a decrease in fruit dilution, whereas the concentrations of polyphenols were also strongly affected through an impact on their metabolism. PMID- 24948584 TI - Impact of mental health problems on self-perceived oral health needs in a Medicaid population. AB - The purpose of this study was to examine the prevalence of self-perceived oral health needs among Medicaid-enrolled adults with and without mental health problems and to identify factors predictive of enrollees' perceived oral health needs. The study involved a secondary analysis of 1,721 respondents to the Florida Health Services Survey. Contrary to the previous research, the findings from this study indicated that respondents with mental health problems (52.9%) did not differ significantly in their dental needs compared to those who did not have mental health problems (49.3%). The results from a logistic regression suggested that after controlling for demographic characteristics, substance abuse problems and functional needs increased the likelihood of self-reported oral health needs, whereas the receipt of Supplemental Security Income (SSI) was associated with decreased dental needs. The prevalence of unmet dental needs among these respondents (i.e., 23%) supported the conclusion that a significant gap exists in the accessibility of oral health services among this population. PMID- 24948583 TI - Non-locally regularized segmentation of multiple sclerosis lesion from multi channel MRI data. AB - Segmentation of multiple sclerosis (MS) lesion is important for many neuroimaging studies. In this paper, we propose a novel algorithm for automatic segmentation of MS lesions from multi-channel MR images (T1W, T2W and FLAIR images). The proposed method is an extension of Li et al.'s algorithm in [1], which only segments the normal tissues from T1W images. The proposed method is aimed to segment MS lesions, while normal tissues are also segmented and bias field is estimated to handle intensity inhomogeneities in the images. Another contribution of this paper is the introduction of a nonlocal means technique to achieve spatially regularized segmentation, which overcomes the influence of noise. Experimental results have demonstrated the effectiveness and advantages of the proposed algorithm. PMID- 24948585 TI - Double-Plug Autologous Osteochondral Transplantation Shows Equal Functional Outcomes Compared With Single-Plug Procedures in Lesions of the Talar Dome: A Minimum 5-Year Clinical Follow-up. AB - BACKGROUND: Autologous osteochondral transplantation (AOT) is used for large (>100-150 mm(2)) or cystic osteochondral lesions (OCLs) of the talus. Larger lesions may require using more than 1 graft to fill the defect. While patients with larger OCLs treated with microfracture exhibit inferior clinical outcomes, there is little evidence regarding the effect of lesion size and number of grafts required on clinical and radiological outcomes after AOT. HYPOTHESIS: Larger OCLs of the talar dome treated by double-plug AOT (dp-AOT) have inferior clinical and radiological MRI outcomes compared with smaller OCLs requiring single-plug AOT (sp-AOT). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Fourteen consecutive patients with a large OCL (mean, 208 +/- 54 mm(2)) treated using dp AOT with a minimum 5-year follow-up were matched by age and sex to a control cohort of 28 patients who underwent sp-AOT for a smaller OCL (mean, 74 +/- 26 mm(2)) over the same period. Functional outcomes were assessed both pre- and postoperatively using the Foot and Ankle Outcome Score (FAOS) and Short Form-12 (SF-12) general health questionnaire. Mean follow-up was 85 months (range, 65-118 months). Latest postoperative MRI was evaluated with modified magnetic resonance observation of cartilage repair tissue (MOCART) score. RESULTS: There was no significant difference between groups demographically (P > .05). All patients with dp-AOT and sp-AOT showed a significant pre- to postoperative increase in FAOS and SF-12 scores (P < .001). When comparing preoperative scores for both groups, there was no statistical significance between sp-AOT and dp-AOT scores (FAOS, P = .719; SF-12, P = .947). There was no significant difference in functional scores between the 2 groups postoperatively for both FAOS (P = .883) and SF-12 (P = .246). Mean MOCART scores did not exhibit any statistically significant difference between groups (P = .475). Two patients complained of knee donor site stiffness (4.8%), which later resolved. CONCLUSION: Patients with large OCLs treated using a dp-AOT procedure did not show inferior clinical or radiological outcomes compared with those treated with sp-AOT at a minimum 5-year follow-up. The dp-AOT procedure is as effective as sp-AOT in treating larger OCLs of the talar dome in the intermediate term, with similar high postoperative clinical and radiological outcomes. PMID- 24948586 TI - High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. AB - BACKGROUND: Relapsed multiple myeloma has no standard treatment, and the role of autologous stem-cell transplantation (ASCT) has not been fully defined. We aimed to compare high-dose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT. METHODS: This multicentre, randomised, open-label, phase 3 study recruited patients aged at least 18 years with multiple myeloma who needed treatment for first progressive or relapsed disease at least 18 months after a previous ASCT from 51 centres across the UK. Before randomisation, eligible patients received bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy and then underwent peripheral blood stem-cell mobilisation and harvesting if applicable. Eligible patients (with adequate stem-cell harvest) were randomly assigned (1:1), using an automated telephone randomisation line, to either high-dose melphalan 200 mg/m(2) plus salvage ASCT or oral cyclophosphamide (400mg/m(2) per week for 12 weeks). Randomisation was stratified by length of first remission or plateau and response to PAD re-induction therapy. The primary endpoint was time to disease progression, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and EudraCT, number 2006-005890-24. FINDINGS: Between April 16, 2008, and Nov 19, 2012, 297 patients were registered, of whom 293 received PAD re-induction therapy. Between Aug 26, 2008, and Nov 16, 2012, 174 patients with sufficient PBSCs were randomised to salvage ASCT (n=89) or cyclophosphamide (n=85). After a median follow-up of 31 months (IQR 19-42), median time to progression was significantly longer in the salvage ASCT than in the cyclophosphamide group (19 months [95% CI 16-25] vs 11 months [9-12]; hazard ratio 0.36 [95% CI 0.25-0.53]; p<0.0001). Frequently reported (in >10% of patients) grade 3-4 adverse events with PAD induction, salvage ASCT, and cyclophosphamide were: neutropenia (125 [43%] of 293 patients after PAD, and 63 [76%] of 83 patients in the salvage ASCT group vs 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, and 60 [72%] vs four [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none vs none, respectively). INTERPRETATION: This study provides evidence for the improved efficacy of high-dose melphalan plus salvage ASCT when compared with cyclophosphamide in patients with relapsed multiple myeloma eligible for intensive therapy, which might help to guide clinical decisions regarding the management of such patients. FUNDING: Cancer Research UK. PMID- 24948587 TI - Second transplant as a standard for multiple myeloma. PMID- 24948588 TI - Methodological challenges of validating a clinical decision-making tool in the practice environment. AB - Validating a measurement tool intended for use in the practice environment poses challenges that may not be present when validating a tool intended solely for research purposes. The aim of this article is to describe the methodological challenges of validating a clinical decision-making tool, the Oncology Acuity Tool, which nurses use to make nurse assignment and staffing decisions prospectively each shift. Data were derived from a larger validation study, during which several methodological challenges arose. Revisions to the tool, including conducting iterative feedback cycles with end users, were necessary before the validation study was initiated. The "true" value of patient acuity is unknown, and thus, two approaches to inter-rater reliability assessment were used. Discordant perspectives existed between experts and end users. Balancing psychometric rigor with clinical relevance may be achieved through establishing research-practice partnerships, seeking active and continuous feedback with end users, and weighing traditional statistical rules of thumb with practical considerations. PMID- 24948589 TI - Preferred Thinking Style, Symptom Recognition, and Response by Nursing Students During Simulation. AB - A better understanding of the relationships between symptom recognition, nursing response, and preferred thinking style is needed to improve nursing education practices. Final semester nursing students (N = 29) completed a high fidelity patient simulation (HFPS) scenario; recognized symptoms (i.e., dyspnea) and responses (i.e., apply oxygen) were recorded, and compared with students' preferred thinking style using the Rational-Experiential Inventory-40. Relationships between concepts were explored. Significant relationships were noted between preference for Rational thinking styles and symptom recognition (p < .05). Preferred thinking style was not related to numbers of therapeutic responses. Thirty percent of students delayed application of oxygen until directed to do so by members of the health care team. Students having a stronger preference for rational thinking demonstrate greater accuracy in cue recognition. More nursing research is needed to explore the cognitive processing during simulation. PMID- 24948592 TI - ICD role in preventing sudden cardiac death in Emery-Dreifuss muscular dystrophy with preserved myocardial function: 2013 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy. PMID- 24948590 TI - Two-site reproducibility of cerebellar and brainstem neurochemical profiles with short-echo, single-voxel MRS at 3T. AB - PURPOSE: To determine whether neurochemical concentrations obtained at two MRI sites using clinical 3T scanners can be pooled when a highly optimized, nonvendor short-echo, single-voxel proton MRS pulse sequence is used in conjunction with identical calibration and quantification procedures. METHODS: A modified semi LASER sequence (TE = 28 ms) was used to acquire spectra from two brain regions (cerebellar vermis and pons) on two Siemens 3T scanners using the same B0 and B1 calibration protocols from two different cohorts of healthy volunteers (N = 24-33 per site) matched for age and body mass index. Spectra were quantified with LCModel using water scaling. RESULTS: The spectral quality was very consistent between the two sites and allowed reliable quantification of at least 13 metabolites in the vermis and pons compared with 3-5 metabolites in prior multisite magnetic resonance spectroscopy trials using vendor-provided sequences. The neurochemical profiles were nearly identical at the two sites and showed the feasibility to detect interindividual differences in the healthy brain. CONCLUSION: Highly reproducible neurochemical profiles can be obtained on different clinical 3T scanners at different sites, provided that the same, optimized acquisition and analysis techniques are used. This will allow pooling of multisite data in clinical studies, which is particularly critical for rare neurological diseases. PMID- 24948591 TI - Prevalence of venous occlusion in patients referred for lead extraction: implications for tool selection. AB - AIMS: Data concerning the incidence of venous obstruction in patients referred for lead extraction is limited. Thus, we aimed to assess the incidence of venous obstruction in patients referred for lead extraction and the implications for tool selection. METHODS AND RESULTS: Contrast venography of the access vein was obtained in 202 patients (147 men; mean age, 62.4 +/- 14.5 years) scheduled for lead extraction. The indication for lead extraction included infection (n = 145, 72%) and other causes (n = 57, 28%). Two patients with device infection had superior vena caval occlusion. Access vein occlusion occurred in 6 (11%) patients without infection vs. 46 (32%) patients with infection [P = 0.002; odds ratio (OR) 3.94; 95% confidence interval (CI) 1.58-9.87]. No significant differences between occluded and non-occluded patients were seen for age, sex, device type, number of leads, time from implant of the initial lead, or anticoagulation therapy (all P>0.05). Procedural duration and fluoroscopy exposure time were significantly lower in the open group than in the occluded group (P < 0.05). Patients with venous occlusion required more advanced tools for lead extraction, such as dilator sheaths, evolution sheaths, and needle's eye snares (P = 0.019). CONCLUSION: Both systemic and local infections are associated with increased risk of access vein occlusion. We found no support for the hypothesis that venous occlusion increases with the number of leads present. Lead extraction was more difficult in patients with venous occlusion, requiring advanced tools and more time. PMID- 24948593 TI - Counterpublic health and the design of drug services for methamphetamine consumers in Melbourne. AB - This article is interested in how notions of the 'public' are conceived, marshalled and enacted in drug-treatment responses to methamphetamine use in Melbourne, Australia. After reviewing qualitative data collected among health care providers and methamphetamine consumers, we draw on the work of Michael Warner to argue that services for methamphetamine consumers in Melbourne betray ongoing tensions between 'public' and 'counterpublic' constituencies. Our analysis indicates that these tensions manifest in two ways: in the management of 'street business' in the delivery of services and in negotiating the meaning of health and the terms of its restoration or promotion. Reflecting these tensions, while the design of services for methamphetamine consumers is largely modelled on public health principles, the everyday experience of these services may be more accurately characterised in terms of what Kane Race has called 'counterpublic health'. Extending Race's analysis, we conclude that more explicit focus on the idea of counterpublic health may help local services engage with methamphetamine consumers in new ways, providing grounds for novel outreach, harm-reduction and treatment strategies. PMID- 24948594 TI - Being-in-dialysis: The experience of the machine-body for home dialysis users. AB - New Zealand leads the world in rates of home dialysis use, yet little is known about the experience of home dialysis from the patient's perspective. This article contributes to the literature on the self-care of dialysis patients by examining the relevance of the concept of the machine-body and cyborg embodiment for the lived experience of people with end-stage renal failure. The article, which presents a discussion of 24 in-depth interviews undertaken between 2009 and 2012, shows that although dialysis therapy is disruptive of being and time, study participants experience home dialysis in terms of flexibility, control and independence. While they do not use the term machine-body as a descriptor, the concept resonates with felt experience. Data also indicate that positive experience of home dialysis is relative to socio-economic positioning and the lived relation of patients to others, necessitating further research to examine these factors. PMID- 24948595 TI - Inflammasomes and intestinal homeostasis: regulating and connecting infection, inflammation and the microbiota. AB - Inflammasomes are large cytosolic protein complexes that detect infection and stress-associated signals and promote immediate inflammatory responses. In the intestine, activation of the inflammasome leads to an inflammatory response that is important for controlling enteric infections but can also result in pathological tissue damage. Recent studies have suggested that the inflammasome also regulates intestinal homeostasis through its effects on the intestinal microbiota. Notably, many conflicting studies have been published regarding the effect of inflammasome deficiencies on intestinal homeostasis. Here, we attempt to reconcile these contrasting data by highlighting the many ways that the inflammasome contributes to intestinal homeostasis and pathology and exploring the potential role of alterations in the microbiota in these conflicting studies. PMID- 24948596 TI - Glucocorticoids increase adipocytes in muscle by affecting IL-4 regulated FAP activity. AB - An increase in intramuscular adipocyte tissue (IMAT) is associated with glucose dysregulation, decreased muscle strength, and increased risk of disability. Unfortunately, the mechanisms stimulating intramuscular adipogenesis remain unclear. We found that dexamethasone (Dex) administration to mice with injured muscles stimulates the accumulation of IMAT. To identify precursors of these adipocytes, we isolated satellite cells and fibro/adipogenic progenitors (FAPs) from muscle; satellite cells did not differentiate into adipocytes even following Dex treatment. In contrast, Dex stimulated FAP differentiation into adipocytes. In vivo, we transplanted purified FAPs from transgenic, EGFP mice into the injured muscles of C57/BL6 mice and found that Dex administration stimulated adipogenesis from FAP-EGFP. The increase in adipogenesis depended on Dex-induced inhibition of interleukin-4 (IL-4). In the injured muscle of IL-4-knockout mice, the levels of adipocytes were increased, while in the injured muscles of Dex treated mice with IL-4 injections, adipogenesis was suppressed. In cultured FAPs, IL-4 inhibited Dex-induced conversion of FAPs into adipocytes; this did not occur in FAPs expressing knockdown of the IL-4 receptor. Thus, we concluded that glucocorticoids stimulate FAPs to differentiate into adipocytes in injured muscles. This process is blocked by IL-4, suggesting that interfering with IL-4 signaling could prevent adipogenesis in muscle. PMID- 24948597 TI - Overexpression of histone deacetylases in cancer cells is controlled by interplay of transcription factors and epigenetic modulators. AB - Histone deacetylases (HDACs) that deacetylate histone and nonhistone proteins play crucial roles in a variety of cellular processes. The overexpression of HDACs is reported in many cancer types and is directly linked to accelerated cell proliferation and survival. However, little is known about how HDAC expression is regulated in cancer cells. In this study, we found that HDAC1 and HDAC2 promoters are regulated through collaborative binding of transcription factors Sp1/Sp3 and epigenetic modulators, including histone H3K4 methyltransferase SET1 and histone acetyltransferase p300, whose levels are also elevated in colon cancer cell lines and patient samples. Interestingly, Sp1 and Sp3 differentially regulate HDAC1 and HDAC2 promoter activity. In addition, Sp1/Sp3 recruits SET1 and p300 to the promoters. SET1 knockdown (KD) results in a loss of the H3K4 trimethylation mark at the promoters, as well as destabilizes p300 at the promoters. Conversely, p300 also influences SET1 recruitment and H3K4me3 level, indicating a crosstalk between p300 and SET1. Further, SET1 KD reduces Sp1 binding to the HDAC1 promoter through the increase of Sp1 acetylation. These results indicate that interactions among transcription factors and epigenetic modulators orchestrate the activation of HDAC1 and HDAC2 promoter activity in colon cancer cells. PMID- 24948599 TI - Quantitative 4D analyses of epithelial folding during Drosophila gastrulation. AB - Understanding the cellular and mechanical processes that underlie the shape changes of individual cells and their collective behaviors in a tissue during dynamic and complex morphogenetic events is currently one of the major frontiers in developmental biology. The advent of high-speed time-lapse microscopy and its use in monitoring the cellular events in fluorescently labeled developing organisms demonstrate tremendous promise in establishing detailed descriptions of these events and could potentially provide a foundation for subsequent hypothesis driven research strategies. However, obtaining quantitative measurements of dynamic shapes and behaviors of cells and tissues in a rapidly developing metazoan embryo using time-lapse 3D microscopy remains technically challenging, with the main hurdle being the shortage of robust imaging processing and analysis tools. We have developed EDGE4D, a software tool for segmenting and tracking membrane-labeled cells using multi-photon microscopy data. Our results demonstrate that EDGE4D enables quantification of the dynamics of cell shape changes, cell interfaces and neighbor relations at single-cell resolution during a complex epithelial folding event in the early Drosophila embryo. We expect this tool to be broadly useful for the analysis of epithelial cell geometries and movements in a wide variety of developmental contexts. PMID- 24948600 TI - Sp8 plays a supplementary role to Pax6 in establishing the pMN/p3 domain boundary in the spinal cord. AB - Progenitor cells are segregated into multiple domains along the dorsoventral axis of the vertebrate neural tube, and each progenitor domain generates particular types of neurons. Selective cross-repressive interactions between pairs of class I and class II transcription factors play important roles in patterning neural progenitors into domains with clear boundaries. Here, we provide evidence that the zinc-finger protein Sp8 plays a supplementary role to Pax6 in establishing the pMN/p3 domain boundary through mutually repressive interactions with the class II protein Nkx2-2. The ventral limit of Sp8 expression is complementary to the dorsal limit of Nkx2-2 expression at the pMN/p3 boundary. Sp8 and Nkx2-2 exert cross-repressive interactions, and changing the expression of Sp8 and Nkx2 2 is coupled with pMN and p3 progenitor fate conversion. Sp8 exerts its neural patterning activities by acting as a transcriptional activator. The expression of a repressive form of Sp8 results in the selective inhibition of motor neuron generation and the ectopic induction of Nkx2-2 expression. Sp8 expression is positively regulated by, but not completely dependent on, Pax6. Furthermore, whereas loss of Pax6 function alone results in disruption of the pMN/p3 domain boundary only in the rostral levels of the spinal cord, loss of both Sp8 and Pax6 functions results in disruption of the pMN/p3 domain boundary along the whole rostrocaudal axis of the spinal cord. We conclude that Sp8 plays a supplementary role to Pax6 in specifying the pMN over p3 progenitor fate through cross repressive interactions with Nkx2-2. PMID- 24948601 TI - Initiation of Hippo signaling is linked to polarity rather than to cell position in the pre-implantation mouse embryo. AB - In the mouse embryo, asymmetric divisions during the 8-16 cell division generate two cell types, polar and apolar cells, that are allocated to outer and inner positions, respectively. This outer/inner configuration is the first sign of the formation of the first two cell lineages: trophectoderm (TE) and inner cell mass (ICM). Outer polar cells become TE and give rise to the placenta, whereas inner apolar cells become ICM and give rise to the embryo proper and yolk sac. Here, we analyze the frequency of asymmetric divisions during the 8-16 cell division and assess the relationships between cell polarity, cell and nuclear position, and Hippo signaling activation, the pathway that initiates lineage-specific gene expression in 16-cell embryos. Although the frequency of asymmetric divisions varied in each embryo, we found that more than six blastomeres divided asymmetrically in most embryos. Interestingly, many apolar cells in 16-cell embryos were located at outer positions, whereas only one or two apolar cells were located at inner positions. Live imaging analysis showed that outer apolar cells were eventually internalized by surrounding polar cells. Using isolated 8 cell blastomeres, we carefully analyzed the internalization process of apolar cells and found indications of higher cortical tension in apolar cells than in polar cells. Last, we found that apolar cells activate Hippo signaling prior to taking inner positions. Our results suggest that polar and apolar cells have intrinsic differences that establish outer/inner configuration and differentially regulate Hippo signaling to activate lineage-specific gene expression programs. PMID- 24948602 TI - Automated multidimensional image analysis reveals a role for Abl in embryonic wound repair. AB - The embryonic epidermis displays a remarkable ability to repair wounds rapidly. Embryonic wound repair is driven by the evolutionary conserved redistribution of cytoskeletal and junctional proteins around the wound. Drosophila has emerged as a model to screen for factors implicated in wound closure. However, genetic screens have been limited by the use of manual analysis methods. We introduce MEDUSA, a novel image-analysis tool for the automated quantification of multicellular and molecular dynamics from time-lapse confocal microscopy data. We validate MEDUSA by quantifying wound closure in Drosophila embryos, and we show that the results of our automated analysis are comparable to analysis by manual delineation and tracking of the wounds, while significantly reducing the processing time. We demonstrate that MEDUSA can also be applied to the investigation of cellular behaviors in three and four dimensions. Using MEDUSA, we find that the conserved nonreceptor tyrosine kinase Abelson (Abl) contributes to rapid embryonic wound closure. We demonstrate that Abl plays a role in the organization of filamentous actin and the redistribution of the junctional protein beta-catenin at the wound margin during embryonic wound repair. Finally, we discuss different models for the role of Abl in the regulation of actin architecture and adhesion dynamics at the wound margin. PMID- 24948603 TI - mTORC1 signaling controls mammalian skeletal growth through stimulation of protein synthesis. AB - Much of the mammalian skeleton is derived from a cartilage template that undergoes rapid growth during embryogenesis, but the molecular mechanism of growth regulation is not well understood. Signaling by mammalian target of rapamycin complex 1 (mTORC1) is an evolutionarily conserved mechanism that controls cellular growth. Here we report that mTORC1 signaling is activated during limb cartilage development in the mouse embryo. Disruption of mTORC1 signaling through deletion of either mTOR or the associated protein Raptor greatly diminishes embryonic skeletal growth associated with severe delays in chondrocyte hypertrophy and bone formation. The growth reduction of cartilage is not due to changes in chondrocyte proliferation or survival, but is caused by a reduction in cell size and in the amount of cartilage matrix. Metabolic labeling reveals a notable deficit in the rate of protein synthesis in Raptor-deficient chondrocytes. Thus, mTORC1 signaling controls limb skeletal growth through stimulation of protein synthesis in chondrocytes. PMID- 24948605 TI - Essential role of the ERK/MAPK pathway in blood-placental barrier formation. AB - The mammalian genome contains two ERK/MAP kinase kinase genes, Map2k1 and Map2k2, which encode dual-specificity kinases responsible for ERK activation. Loss of Map2k1 function in mouse causes embryonic lethality due to placental defects, whereas Map2k2 mutants have a normal lifespan. The majority of Map2k1(+/-) Map2k2(+/-) embryos die during gestation from the underdevelopment of the placenta labyrinth, demonstrating that both kinases are involved in placenta formation. Map2k1(+/-) Map2k2(+/-) mutants show reduced vascularization of the labyrinth and defective formation of syncytiotrophoblast layer II (SynT-II) leading to the accumulation of multinucleated trophoblast giant cells (MTGs). To define the cell type-specific contribution of the ERK/MAPK pathway to placenta development, we performed deletions of Map2k1 function in different Map2k1 Map2k2 allelic backgrounds. Loss of MAP kinase kinase activity in pericytes or in allantois-derived tissues worsens the MTG phenotype. These results define the contribution of the ERK/MAPK pathway in specific embryonic and extraembryonic cell populations for normal placentation. Our data also indicate that MTGs could result from the aberrant fusion of SynT-I and -II. Using mouse genetics, we demonstrate that the normal development of SynT-I into a thin layer of multinucleated cells depends on the presence of SynT-II. Lastly, the combined mutations of Map2k1 and Map2k2 alter the expression of several genes involved in cell fate specification, cell fusion and cell polarity. Thus, appropriate ERK/MAPK signaling in defined cell types is required for the proper growth, differentiation and morphogenesis of the placenta. PMID- 24948604 TI - The cortical hem regulates the size and patterning of neocortex. AB - The cortical hem, a source of Wingless-related (WNT) and bone morphogenetic protein (BMP) signaling in the dorsomedial telencephalon, is the embryonic organizer for the hippocampus. Whether the hem is a major regulator of cortical patterning outside the hippocampus has not been investigated. We examined regional organization across the entire cerebral cortex in mice genetically engineered to lack the hem. Indicating that the hem regulates dorsoventral patterning in the cortical hemisphere, the neocortex, particularly dorsomedial neocortex, was reduced in size in late-stage hem-ablated embryos, whereas cortex ventrolateral to the neocortex expanded dorsally. Unexpectedly, hem ablation also perturbed regional patterning along the rostrocaudal axis of neocortex. Rostral neocortical domains identified by characteristic gene expression were expanded, and caudal domains diminished. A similar shift occurs when fibroblast growth factor (FGF) 8 is increased at the rostral telencephalic organizer, yet the FGF8 source was unchanged in hem-ablated brains. Rather we found that hem WNT or BMP signals, or both, have opposite effects to those of FGF8 in regulating transcription factors that control the size and position of neocortical areas. When the hem is ablated a necessary balance is perturbed, and cerebral cortex is rostralized. Our findings reveal a much broader role for the hem in cortical development than previously recognized, and emphasize that two major signaling centers interact antagonistically to pattern cerebral cortex. PMID- 24948606 TI - A new, specular reflection-based, precorneal tear film stability measurement technique in a rabbit model: viscoelastic increases tear film stability. AB - PURPOSE: To develop a safe, noninvasive, noncontact, continuous in vivo method to measure the dehydration rate of the precorneal tear film and to compare the effectiveness of a viscoelastic agent in maintaining the precorneal tear film to that of a balanced salt solution. METHODS: Software was designed to analyze the corneal reflection produced by the operating microscope's coaxial illumination. The software characterized the shape of the reflection, which became distorted as the precorneal tear film evaporated; characterization was accomplished by fitting an ellipse to the reflection and measuring its projected surface area. Balanced salt solution Plus (BSS+) and a 2% hydroxypropylmethylcellulose viscoelastic were used as the test agents. The tear film evaporation rate was characterized and compared over a period of 20 minutes in 20 eyes from 10 New Zealand white rabbits. RESULTS: The ellipse axes ratio and surface area were found to decrease initially after each application of either viscoelastic or BSS+ and then to increase linearly as the tear film began to evaporate (P < 0.001) for eyes treated with BSS+ only. Eyes treated with BSS+ required 7.5 +/- 2.7 applications to maintain sufficient corneal hydration during the 20-minute test period, whereas eyes treated with viscoelastic required 1.4 +/- 0.5 applications. The rates of evaporation differed significantly (P < 0.043) between viscoelastic and BSS+. CONCLUSIONS: The shape and surface area of the corneal reflection are strongly correlated with the state of the tear film. Rabbits' corneas treated with viscoelastic remained hydrated significantly longer than corneas treated with BSS+. PMID- 24948607 TI - MPV17L2 is required for ribosome assembly in mitochondria. AB - MPV17 is a mitochondrial protein of unknown function, and mutations in MPV17 are associated with mitochondrial deoxyribonucleic acid (DNA) maintenance disorders. Here we investigated its most similar relative, MPV17L2, which is also annotated as a mitochondrial protein. Mitochondrial fractionation analyses demonstrate MPV17L2 is an integral inner membrane protein, like MPV17. However, unlike MPV17, MPV17L2 is dependent on mitochondrial DNA, as it is absent from rho(0) cells, and co-sediments on sucrose gradients with the large subunit of the mitochondrial ribosome and the monosome. Gene silencing of MPV17L2 results in marked decreases in the monosome and both subunits of the mitochondrial ribosome, leading to impaired protein synthesis in the mitochondria. Depletion of MPV17L2 also induces mitochondrial DNA aggregation. The DNA and ribosome phenotypes are linked, as in the absence of MPV17L2 proteins of the small subunit of the mitochondrial ribosome are trapped in the enlarged nucleoids, in contrast to a component of the large subunit. These findings suggest MPV17L2 contributes to the biogenesis of the mitochondrial ribosome, uniting the two subunits to create the translationally competent monosome, and provide evidence that assembly of the small subunit of the mitochondrial ribosome occurs at the nucleoid. PMID- 24948608 TI - Rps5-Rps16 communication is essential for efficient translation initiation in yeast S. cerevisiae. AB - Conserved ribosomal proteins frequently harbor additional segments in eukaryotes not found in bacteria, which could facilitate eukaryotic-specific reactions in the initiation phase of protein synthesis. Here we provide evidence showing that truncation of the N-terminal domain (NTD) of yeast Rps5 (absent in bacterial ortholog S7) impairs translation initiation, cell growth and induction of GCN4 mRNA translation in a manner suggesting incomplete assembly of 48S preinitiation complexes (PICs) at upstream AUG codons in GCN4 mRNA. Rps5 mutations evoke accumulation of factors on native 40S subunits normally released on conversion of 48S PICs to 80S initiation complexes (ICs) and this abnormality and related phenotypes are mitigated by the SUI5 variant of eIF5. Remarkably, similar effects are observed by substitution of Lys45 in the Rps5-NTD, involved in contact with Rps16, and by eliminating the last two residues of the C-terminal tail (CTT) of Rps16, believed to contact initiator tRNA base-paired to AUG in the P site. We propose that Rps5-NTD-Rps16-NTD interaction modulates Rps16-CTT association with Met-tRNAi (Met) to promote a functional 48S PIC. PMID- 24948609 TI - Dominant Rio1 kinase/ATPase catalytic mutant induces trapping of late pre-40S biogenesis factors in 80S-like ribosomes. AB - During eukaryotic ribosome biogenesis, members of the conserved atypical serine/threonine protein kinase family, the RIO kinases (Rio1, Rio2 and Rio3) function in small ribosomal subunit biogenesis. Structural analysis of Rio2 indicated a role as a conformation-sensing ATPase rather than a kinase to regulate its dynamic association with the pre-40S subunit. However, it remained elusive at which step and by which mechanism the other RIO kinase members act. Here, we have determined the crystal structure of the human Rio1-ATP-Mg(2+) complex carrying a phosphoaspartate in the active site indicative of ATPase activity. Structure-based mutations in yeast showed that Rio1's catalytic activity regulates its pre-40S association. Furthermore, we provide evidence that Rio1 associates with a very late pre-40S via its conserved C-terminal domain. Moreover, a rio1 dominant-negative mutant defective in ATP hydrolysis induced trapping of late biogenesis factors in pre-ribosomal particles, which turned out not to be pre-40S but 80S-like ribosomes. Thus, the RIO kinase fold generates a versatile ATPase enzyme, which in the case of Rio1 is activated following the Rio2 step to regulate one of the final 40S maturation events, at which time the 60S subunit is recruited for final quality control check. PMID- 24948610 TI - TET-mediated oxidation of methylcytosine causes TDG or NEIL glycosylase dependent gene reactivation. AB - The discovery of hydroxymethyl-, formyl- and carboxylcytosine, generated through oxidation of methylcytosine by TET dioxygenases, raised the question how these modifications contribute to epigenetic regulation. As they are subjected to complex regulation in vivo, we dissected links to gene expression with in vitro modified reporter constructs. We used an Oct4 promoter-driven reporter gene and demonstrated that in vitro methylation causes gene silencing while subsequent oxidation with purified catalytic domain of TET1 leads to gene reactivation. To identify proteins involved in this pathway we screened for TET interacting factors and identified TDG, PARP1, XRCC1 and LIG3 that are involved in base excision repair. Knockout and rescue experiments demonstrated that gene reactivation depended on the glycosylase TDG, but not MBD4, while NEIL1, 2 and 3 could partially rescue the loss of TDG. These results clearly show that oxidation of methylcytosine by TET dioxygenases and subsequent removal by TDG or NEIL glycosylases and the BER pathway results in reactivation of epigenetically silenced genes. PMID- 24948611 TI - Lynx web services for annotations and systems analysis of multi-gene disorders. AB - Lynx is a web-based integrated systems biology platform that supports annotation and analysis of experimental data and generation of weighted hypotheses on molecular mechanisms contributing to human phenotypes and disorders of interest. Lynx has integrated multiple classes of biomedical data (genomic, proteomic, pathways, phenotypic, toxicogenomic, contextual and others) from various public databases as well as manually curated data from our group and collaborators (LynxKB). Lynx provides tools for gene list enrichment analysis using multiple functional annotations and network-based gene prioritization. Lynx provides access to the integrated database and the analytical tools via REST based Web Services (http://lynx.ci.uchicago.edu/webservices.html). This comprises data retrieval services for specific functional annotations, services to search across the complete LynxKB (powered by Lucene), and services to access the analytical tools built within the Lynx platform. PMID- 24948612 TI - Serial number tagging reveals a prominent sequence preference of retrotransposon integration. AB - Transposable elements (TE) have both negative and positive impact on the biology of their host. As a result, a balance is struck between the host and the TE that relies on directing integration to specific genome territories. The extraordinary capacity of DNA sequencing can create ultra dense maps of integration that are being used to study the mechanisms that position integration. Unfortunately, the great increase in the numbers of insertion sites detected comes with the cost of not knowing which positions are rare targets and which sustain high numbers of insertions. To address this problem we developed the serial number system, a TE tagging method that measures the frequency of integration at single nucleotide positions. We sequenced 1 million insertions of retrotransposon Tf1 in the genome of Schizosaccharomyces pombe and obtained the first profile of integration with frequencies for each individual position. Integration levels at individual nucleotides varied over two orders of magnitude and revealed that sequence recognition plays a key role in positioning integration. The serial number system is a general method that can be applied to determine precise integration maps for retroviruses and gene therapy vectors. PMID- 24948613 TI - Caregiver burden is associated with disability in schizophrenia: results of a study from a rural setting of south India. AB - BACKGROUND: Taking care of patients with schizophrenia is a major source of burden to the family. Research on burden experienced by family members of patients living in rural communities is sparse. METHODS: Data were obtained from a community intervention program for psychoses in a rural community of south India, where persons with severe mental disorders were identified, treated and followed up. As part of the program, caregivers of 245 schizophrenia patients were interviewed using the Burden Assessment Schedule. Psychopathology (Positive and Negative Syndrome Scale; PANSS), treatment status and disability (Indian Disability Evaluation and Assessment Scale; IDEAS) experienced by the patients were also assessed. Univariate and multivariate analyses were used to study the influence of different factors on the caregiver burden. RESULTS: Level of burden had a significant direct correlation with disability (Pearson's r = .35; p < .01) and severity of psychopathology (r = .21; p < .01). Duration of treatment had an inverse correlation with burden (Pearson's r = -.16; p < .01). Multivariate analysis revealed that total IDEAS score (Beta = .28; t = 4.37; p <= .01), duration of treatment (Beta = -.17; t = -2.58; p = .01), age of the family caregiver (Beta = .15; t = 2.4; p = .02) and gender of the patient (Beta = -.13; t = -2.1; p = .04) were significant predictors of burden. The model including total IDEAS score explained 14% of variance (adjusted R (2) = .139; p < .01). CONCLUSION: Burden experienced by family caregivers of schizophrenia patients depends on the level of disability experienced by the patient, age of the family caregivers and gender of the patient. Interventions to reduce disability of the patients may reduce the caregiver burden. PMID- 24948614 TI - Psychological morbidity among co-residents of older people in rural South India: prevalence and risk factors. AB - OBJECTIVE: This study attempted to examine psychological morbidity among co residents of older people living in Vellore, Tamil Nadu, India. METHOD: This cross-sectional study evaluated psychological morbidity among co-residents using the Self-Reporting Questionnaire and psychiatric morbidity among older people using the 10/66 Dementia Research Group's population-based studies protocol. Socio-demographic data were also collected. Logistic regression was used for multivariate analysis. RESULTS: Of 807 residents evaluated, 73 (9.0%) had significant psychological morbidity. Such morbidity was associated with being older, female, poorer, illiterate, currently employed and being a spouse of the older person. A diagnosis of depression, neuropsychiatric symptoms and greater disability in older people were also associated with psychological morbidity among co-residents. CONCLUSION: Co-residents living with older people have significant psychological morbidity, which needs to be recognised and treated. PMID- 24948615 TI - Adele Bloch-Bauer (1881-1925): Possible diagnoses for Gustav Klimt's Lady in Gold. AB - One of the most famous works by the Austrian symbolist painter Gustav Klimt and one of the most widely reproduced works of art worldwide, Adele Bloch-Bauer I which portrays the beautiful wife of Austrian magnate Ferdinand Bloch-Bauer. Adele was the only woman painted by Klimt on more than one occasion. Apart from the beauty and value of the painting, the daring sea of gold that surrounds Adele and the gentle intimacy with which her fragile figure is portrayed have shrouded the history of this painting in mystery. Beyond speculation as to a special bond between artist and model, observation of the painting with a keener, clinical gaze yields evidence of potential illness in the model: facial erythema which, if not produced artificially by makeup, could represent a malar rash; pallor or cyanosis of the hands; and her draped fingers, which seemingly attempt to hide a deformity. This paper seeks to provide a biographical review both of the painter, Gustav Klimt, and of the subject, Adele Bloch-Bauer; to analyse Klimt's two portrayals of her in a search for evidence of a potential intimate relationship between artist and muse and, finally, to compile clinical evidence of possible diagnoses for the Lady in Gold. PMID- 24948616 TI - Big fat babies. PMID- 24948617 TI - Building Knowledge Structures by Testing Helps Children With Mathematical Learning Difficulty. AB - Mathematical learning difficulty (MLD) is prevalent in the development of mathematical abilities. Previous interventions for children with MLD have focused on number sense or basic mathematical skills. This study investigated whether mathematical performance of fifth grade children with MLD could be improved by developing knowledge structures by testing using a web-based curriculum learning system. A total of 142 children with MLD were recruited; half of the children were in the experimental group (using the system), and the other half were in the control group (not using the system). The children were encouraged to use the web based learning system at home for at least a 15-min session, at least once a week, for one and a half months. The mean accumulated time of testing on the system for children in the experimental group was 56.2 min. Children in the experimental group had significantly higher scores on their final mathematical examination compared to the control group. The results suggest that web-based curriculum learning through testing that promotes the building of knowledge structures for a mathematical course was helpful for children with MLD. PMID- 24948618 TI - Clinical trials have a home in Blood. PMID- 24948619 TI - Red cell island dances: switching hands. AB - In this issue of Blood, Toda et al present a shift in the paradigm of erythroid enucleation and provide novel tools to further study and optimize terminal erythroid maturation in vitro. PMID- 24948620 TI - Can Treg elimination enhance NK cell therapy for AML? AB - In this issue of Blood, Bachanova et al describe how modulation of the inhibitory tumor environment may enhance natural killer (NK) cell clinical activity and produce encouraging results in the treatment of refractory acute myeloid leukemia (AML). NK cells are highly proliferative, early responders of the innate immune response that in preclinical models can exert potent activity against a wide range of malignancies, including AML, and across HLA barriers. Considerable efforts have been made to exploit this activity in clinical trials but with only modest success. PMID- 24948621 TI - A GVHD kill switch helps immune reconstitution. AB - In this issue of Blood, Zhou et al report long-term follow-up and detailed analysis of immune reconstitution associated with a different suicide gene strategy to abrogate graft-versus-host disease (GVHD). PMID- 24948622 TI - Distinguishing CML LSCs from HSCs using CD26. AB - In this issue of Blood, Herrmann et al elegantly demonstrate that CD26 is a new, specific chronic myeloid leukemia (CML) stem cell biomarker that phenotypically distinguishes leukemic stem cells (LSCs) from normal hematopoietic stem cells (HSCs), and that it is a potential therapeutic target in CML. PMID- 24948623 TI - Survival trends in Waldenstrom macroglobulinemia: an analysis of the Surveillance, Epidemiology and End Results database. PMID- 24948624 TI - CD20 antibodies induce production and release of reactive oxygen species by neutrophils. PMID- 24948625 TI - Novel severe hemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions encompassing F8 and BRCC3 genes. PMID- 24948627 TI - Learning to cope with degraded sounds: female zebra finches can improve their expertise in discriminating between male voices at long distances. AB - Reliable transmission of acoustic information about individual identity is of critical importance for pair bond maintenance in numerous monogamous songbirds. However, information transfer can be impaired by environmental constraints such as external noise or propagation-induced degradation. Birds have been shown to use several adaptive strategies to deal with difficult signal transmission contexts. Specifically, a number of studies have suggested that vocal plasticity at the emitter's level allows birds to counteract the deleterious effects of sound degradation. Although the communication process involves both the emitter and the receiver, perceptual plasticity at the receiver's level has received little attention. Here, we explored the reliability of individual recognition by female zebra finches (Taeniopygia guttata), testing whether perceptual training can improve discrimination of degraded individual vocal signatures. We found that female zebra finches are proficient in discriminating between calls of individual males at long distances, and even more so when they can train themselves with increasingly degraded signals over time. In this latter context, females succeed in discriminating between males as far as 250 m. This result emphasizes that adaptation to adverse communication conditions may involve not only the emitter's vocal plasticity but also the receptor's decoding process through on-going learning. PMID- 24948628 TI - Hydrodynamics and energetics of jumping copepod nauplii and copepodids. AB - Within its life cycle, a copepod goes through drastic changes in size, shape and swimming mode. In particular, there is a stark difference between the early (nauplius) and later (copepodid) stages. Copepods inhabit an intermediate Reynolds number regime (between ~1 and 100) where both viscosity and inertia are potentially important, and the Reynolds number changes by an order of magnitude during growth. Thus we expect the life stage related changes experienced by a copepod to result in hydrodynamic and energetic differences, ultimately affecting the fitness. To quantify these differences, we measured the swimming kinematics and fluid flow around jumping Acartia tonsa at different stages of its life cycle, using particle image velocimetry and particle tracking velocimetry. We found that the flow structures around nauplii and copepodids are topologically different, with one and two vortex rings, respectively. Our measurements suggest that copepodids cover a larger distance compared to their body size in each jump and are also hydrodynamically quieter, as the flow disturbance they create attenuates faster with distance. Also, copepodids are energetically more efficient than nauplii, presumably due to the change in hydrodynamic regime accompanied with a well-adapted body form and swimming stroke. PMID- 24948629 TI - Leap and strike kinetics of an acoustically 'hunting' barn owl (Tyto alba). AB - Barn owls are effective hunters of small rodents. One hunting technique is a leap from the ground followed by a brief flight and a plummeting 'strike' onto an acoustically targeted - and potentially entirely hidden - prey. We used forceplate measurements to derive kinetics of the leap and strike. Leaping performance was similar to reported values for guinea fowl. This is likely achieved despite the owl's considerably smaller size because of its relatively long legs and use of wing upstroke. Strikes appear deliberately forceful: impulses could have been spread over larger periods during greater deflections of the centre of mass, as observed in leaping and an alighting landing measurement. The strike, despite forces around 150 times that of a mouse body weight, is not thought to be crucial to the kill; rather, forceful strikes may function primarily to enable rapid penetration of leaf litter or snow cover, allowing grasping of hidden prey. PMID- 24948630 TI - Thermal limitation of performance and biogeography in a free-ranging ectotherm: insights from accelerometry. AB - Theoretical and laboratory studies generally show that ectotherm performance increases with temperature to an optimum, and subsequently declines. Several physiological mechanisms probably shape thermal performance curves, but responses of free-ranging animals to temperature variation will represent a compromise between these mechanisms and ecological constraints. Thermal performance data from wild animals balancing physiology and ecology are rare, and this represents a hindrance for predicting population impacts of future temperature change. We used internally implanted accelerometers near the middle of a species' geographical distribution and gill-net catch data near the species' latitudinal extremes to quantify temperature-related activity levels of a wild predatory fish (Platycephalus fuscus). We examined our data in the context of established models of thermal performance, and the relationship between thermal performance thresholds and biogeography. Acceleration data approximated a thermal performance curve, with activity peaking at 23 degrees C but declining rapidly at higher temperatures. Gill-net catch data displayed a similar trend, with a temperature associated increase and decrease in catch rates in temperate and tropical regions, respectively. Extrapolated estimates of zero activity (CTmin and CTmax) from the accelerometers were similar to the minimum and maximum mean monthly water temperatures experienced at the southern and northern (respectively) limits of the species distribution, consistent with performance-limited biogeography in this species. These data highlight the fundamental influence of temperature on ectotherm performance, and how thermal performance limits may shape biogeography. Biologging approaches are rarely used to examine thermal performance curves in free-ranging animals, but these may be central to understanding the trade-offs between physiology and ecology that constrain species' biogeographies and determine the susceptibility of ectotherms to future increases in temperature. PMID- 24948632 TI - Encoding properties of the mechanosensory neurons in the Johnston's organ of the hawk moth, Manduca sexta. AB - Antennal mechanosensors play a key role in control and stability of insect flight. In addition to the well-established role of antennae as airflow detectors, recent studies have indicated that the sensing of antennal vibrations by Johnston's organs also provides a mechanosensory feedback relevant for flight stabilization. However, few studies have addressed how the individual units, or scolopidia, of the Johnston's organs encode these antennal vibrations and communicate it to the brain. Here, we characterize the encoding properties of individual scolopidia from the Johnston's organs in the hawk moth, Manduca sexta, through intracellular neurophysiological recordings from axons of the scolopidial neurons. We stimulated the flagellum-pedicel joint using a custom setup that delivered mechanical stimuli of various (step, sinusoidal, frequency and amplitude sweeps) waveforms. Single units of the Johnston's organs typically displayed phaso-tonic responses to step stimuli with short (3-5 ms) latencies. Their phase-locked response to sinusoidal stimuli in the 0.1-100 Hz frequency range showed high fidelity (vector strengths>0.9). The neurons were able to encode different phases of the stimulus motion and were also extremely sensitive to small amplitude (<0.05 deg) deflections with some indication of directional tuning. In many cases, the firing frequency of the neurons varied linearly as a function of the stimulus frequency at wingbeat and double wingbeat frequencies, which may be relevant to their role in flight stabilization. Iontophoretic fills of these neurons with fluorescent dyes showed that they all projected in the antennal mechanosensory and motor center (AMMC) area of the brain. Taken together, these results showcase the speed and high sensitivity of scolopidia of the Johnston's organs, and hence their ability to encode fine antennal vibrations. PMID- 24948633 TI - Thermal effects on the performance, motor control and muscle dynamics of ballistic feeding in the salamander Eurycea guttolineata. AB - Temperature strongly affects muscle contractile rate properties and thus may influence whole-organism performance. Movements powered by elastic recoil, however, are known to be more thermally robust than muscle-powered movements. We examined the whole-organism performance, motor control and muscle contractile physiology underlying feeding in the salamander Eurycea guttolineata. We compared elastically powered tongue projection with the associated muscle-powered retraction to determine the thermal robustness of each of these functional levels. We found that tongue-projection distance in E. guttolineata was unaffected by temperature across the entire 4-26 degrees C range, tongue projection dynamics were significantly affected by temperature across only the 4 11 degrees C interval, and tongue retraction was affected to a higher degree across the entire temperature range. The significant effect of temperature on projection dynamics across the 4-11 degrees C interval corresponds to a significant decline in projector muscle burst intensity and peak contractile force of the projector muscle across the same interval. Across the remaining temperature range, however, projection dynamics were unaffected by temperature, with muscle contractile physiology showing typical thermal effects and motor patterns showing increased activity durations and latencies. These results reveal that elastically powered tongue-projection performance in E. guttolineata is maintained to a higher degree than muscle-powered tongue retraction performance across a wide temperature range. These results further indicate that thermal robustness of the elastically powered movement is dependent on motor control and muscle physiology that results in comparable energy being stored in elastic tissues across a range of temperatures. PMID- 24948631 TI - Effects of feeding on in vivo motility patterns in the proximal intestine of shorthorn sculpin (Myoxocephalus scorpius). AB - This is the first study to catalogue the diverse array of in vivo motility patterns in a teleost fish and how they are affected by feeding. Video recordings of exteriorised proximal intestine from fasted and fed shorthorn sculpin (Myoxocephalus scorpius) were used to generate spatio-temporal maps to portray and quantify motility patterns. Propagating and non-propagating contractions were observed to occur at different frequencies and durations. The most apparent difference between the feeding states was that bands of relatively high amplitude contractions propagating slowly in the anal direction were observed in all fasted fish (N=10) but in only 35% of fed fish (N=11). Additionally, fed fish displayed a reduced frequency (0.21+/-0.03 versus 0.32+/-0.06 contractions min(-1)) and rhythmicity of these contractions compared with fasted fish. Although the underlying mechanisms of these slow anally propagating contractions differ from those of mammalian migrating motor complexes, we believe that they may play a similar role in shorthorn sculpin during the interdigestive period, to potentially remove food remnants and prevent the establishment of pathogens. 'Ripples' were the most prevalent contraction type in shorthorn sculpin and may be important during mixing and absorption. The persistence of shallow ripples and pendular movements of longitudinal muscle after tetrodotoxin (1 MUmol l(-1)) treatment suggests these contractions were myogenic in origin. The present study highlights both similarities and differences in motility patterns between shorthorn sculpin and other vertebrates, as well as providing a platform to examine other aspects of gastrointestinal functions in fish, including the impact of environmental changes. PMID- 24948635 TI - Hemolymph circulation in insect sensory appendages: functional mechanics of antennal accessory pulsatile organs (auxiliary hearts) in the mosquito Anopheles gambiae. AB - Mosquito antennae provide sensory input that modulates host-seeking, mating and oviposition behaviors. Thus, mosquitoes must ensure the efficient transport of molecules into and out of these appendages. To accomplish this, mosquitoes and other insects have evolved antennal accessory pulsatile organs (APOs) that drive hemolymph into the antennal space. This study characterizes the structural mechanics of hemolymph propulsion throughout the antennae of Anopheles gambiae. Using intravital video imaging, we show that mosquitoes possess paired antennal APOs that are located on each side of the head's dorsal midline. They are situated between the frons and the vertex in an area that is dorsal to the antenna but ventral to the medial-most region of the compound eyes. Antennal APOs contract in synchrony at 1 Hz, which is 45% slower than the heart. By means of histology and intravital imaging, we show that each antennal APO propels hemolymph into the antenna through an antennal vessel that traverses the length of the appendage and has an effective diameter of 1-2 MUm. When hemolymph reaches the end of the appendage, it is discharged into the antennal hemocoel and returns to the head. Because a narrow vessel empties into a larger cavity, hemolymph travels up the antenna at 0.2 mm s(-1) but reduces its velocity by 75% as it returns to the head. Finally, treatment of mosquitoes with the anesthetic agent FlyNap (triethylamine) increases both antennal APO and heart contraction rates. In summary, this study presents a comprehensive functional characterization of circulatory physiology in the mosquito antennae. PMID- 24948634 TI - Adult somatic progenitor cells and hematopoiesis in oysters. AB - Long-lived animals show a non-observable age-related decline in immune defense, which is provided by blood cells that derive from self-renewing stem cells. The oldest living animals are bivalves. Yet, the origin of hemocytes, the cells involved in innate immunity, is unknown in bivalves and current knowledge about mollusk adult somatic stem cells is scarce. Here we identify a population of adult somatic precursor cells and show their differentiation into hemocytes. Oyster gill contains an as yet unreported irregularly folded structure (IFS) with stem-like cells bathing into the hemolymph. BrdU labeling revealed that the stem like cells in the gill epithelium and in the nearby hemolymph replicate DNA. Proliferation of this cell population was further evidenced by phosphorylated histone H3 mitotic staining. Finally, these small cells, most abundant in the IFS epithelium, were found to be positive for the stemness marker Sox2. We provide evidence for hematopoiesis by showing that co-expression of Sox2 and Cu/Zn superoxide dismutase, a hemocyte-specific enzyme, does not occur in the gill epithelial cells but rather in the underlying tissues and vessels. We further confirm the hematopoietic features of these cells by the detection of Filamin, a protein specific for a sub-population of hemocytes, in large BrdU-labeled cells bathing into gill vessels. Altogether, our data show that progenitor cells differentiate into hemocytes in the gill, which suggests that hematopoiesis occurs in oyster gills. PMID- 24948637 TI - Functional characterization of a short neuropeptide F-related receptor in a lophotrochozoan, the mollusk Crassostrea gigas. AB - Members of the short neuropeptide F (sNPF) family of peptides and their cognate receptors play key roles in a variety of physiological processes in arthropods. In silico screening of GigasDatabase, a specific expressed sequence tag database from the Pacific oyster Crassostrea gigas, resulted in the identification of a receptor (Cg-sNPFR-like) phylogenetically closely related to sNPF receptors (sNPFRs) of insects. A reverse endocrinology approach was undertaken to identify the peptide ligand(s) of this orphan receptor. Though structurally distinct from insect sNPFs, three RFamide peptides derived from the same precursor, i.e. GSLFRFamide, SSLFRFamide and GALFRFamide, specifically activate the receptor in a dose-dependent manner, with respective EC50 values (half-maximal effective concentrations) of 1.1, 2.1 and 4.1 MUmol l(-1). We found that both Cg-sNPFR-like receptor and LFRFamide encoding transcripts are expressed in the oyster central nervous system and in other tissues as well, albeit at lower levels. Mass spectrometry analysis confirmed the wide distribution of LFRFamide mature peptides in several central and peripheral tissues. The Cg-sNPFR-like receptor was more abundantly expressed in ganglia of females than of males, and upregulated in starved oysters. In the gonad area, highest receptor gene expression occurred at the start of gametogenesis, when storage activity is maximal. Our results suggest that signaling of LFRFamide peptides through the Cg sNPFR-like receptor might play a role in the coordination of nutrition, energy storage and metabolism in C. gigas, possibly by promoting storage at the expense of reproduction. PMID- 24948636 TI - Altered regulation of sleep and feeding contributes to starvation resistance in Drosophila melanogaster. AB - Animals respond to changes in food availability by adjusting sleep and foraging strategies to optimize their fitness. Wild populations of the fruit fly, Drosophila melanogaster, display highly variable levels of starvation resistance that are dependent on geographic location, food availability and evolutionary history. How behaviors that include sleep and feeding vary in Drosophila with increased starvation resistance is unclear. We have generated starvation resistant flies through experimental evolution to investigate the relationship between foraging behaviors and starvation resistance. Outbred populations of D. melanogaster were selected for starvation resistance over 60 generations. This selection process resulted in flies with a threefold increase in total lipids that survive up to 18 days without food. We tested starvation-selected (S) flies for sleep and feeding behaviors to determine the effect that selection for starvation resistance has had on foraging behavior. Flies from three replicated starvation-selected populations displayed a dramatic reduction in feeding and prolonged sleep duration compared to fed control (F) populations, suggesting that modified sleep and feeding may contribute to starvation resistance. A prolonged larval developmental period contributes to the elevated energy stores present in starvation-selected flies. By preventing S larvae from feeding longer than F larvae, we were able to reduce energy stores in adult S flies to the levels seen in adult F flies, thus allowing us to control for energy storage levels. However, the reduction of energy stores in S flies fails to generate normal sleep and feeding behavior seen in F flies with similar energy stores. These findings suggest that the behavioral changes observed in S flies are due to genetic regulation of behavior rather than elevated lipid levels. Testing S-F hybrid individuals for both feeding and sleep revealed a lack of correlation between food consumption and sleep duration, indicating further independence in genetic factors underlying the sleep and feeding changes observed in S flies. Taken together, these findings provide evidence that starvation selection results in prolonged sleep and reduced feeding through a mechanism that is independent of elevated energy stores. These findings suggest that changes in both metabolic function and behavior contribute to the increase in starvation resistance seen in flies selected for starvation resistance. PMID- 24948638 TI - Does urban life change blood oxidative status in birds? AB - Cities may expose wild animals to new types of selection pressures, potentially leading to differentiation among urban and rural populations. One cellular mechanism likely important in determining the viability of vertebrate populations is resistance to oxidative stress, as tissue degradation resulting from oxidative stress may decrease reproductive performance and survival. We hypothesized that city-thriving Eurasian blackbirds (Turdus merula) would be more resistant to oxidative stress when exposed to stressful conditions than rural conspecifics. Hand-raised city and rural blackbirds kept under common garden conditions indeed differed in blood oxidative status when exposed to chronic stress: city birds had lower oxidative damage during stressful conditions compared with rural birds, but also tended to generally maintain lower levels of non-enzymatic and enzymatic antioxidants than rural birds. These findings show that individuals from urban and rural areas differ intrinsically in their blood oxidative status physiology, possibly as an adaptation to city life. PMID- 24948639 TI - Analyses of the mouthpart kinematics in Periplaneta americana (Blattodea, Blattidae) using synchrotron-based X-ray cineradiography. AB - The kinematics of the biting and chewing mouthparts of insects is a complex interaction of various components forming multiple jointed chains. The non invasive technique of in vivo cineradiography by means of synchrotron radiation was employed to elucidate the motion cycles of the mouthparts in the cockroach Periplaneta americana. Digital X-ray footage sequences were used in order to calculate pre-defined angles and distances, each representing characteristic aspects of the movement pattern. We were able to analyze the interactions of the mouthpart components and to generate a functional model of maxillary movement by integrating kinematic results, morphological dissections and fluorescence microscopy. During the opening and closing cycles, which take about 450-500 ms on average, we found strong correlations between the measured maxillary and mandibular angles, indicating a strong neural coordination of these movements. This is manifested by strong antiphasic courses of the maxillae and the mandibles, antiphasic patterns of the rotation of the cardo about its basic articulation at the head and by the deflection between the cardo and stipes. In our functional model of the maxilla, its movement pattern is explained by the antagonistic activity of four adductor-promotor muscles and two abductor-remotor muscles. However, beyond the observed intersegmental and bilateral stereotypy, certain amounts of variation across subsequent cycles within a sequence were observed with respect to the degree of correlation between the various mouthparts, the maximum, minimum and time course of the angular movements. Although generally correlated with the movement pattern of the mandibles and the maxillary cardo-stipes complex, such plastic behaviour was especially observed in the maxillary palpi and the labium. PMID- 24948640 TI - A whispering bat that screams: bimodal switch of foraging guild from gleaning to aerial hawking in the desert long-eared bat. AB - Echolocating bats have historically been classified as either loud aerial hawkers or whispering gleaners. Some bat species can forage in multiple ways and others have demonstrated limited flexibility in the amplitude of their echolocation calls. The desert long-eared bat, Otonycteris hemprichii, has been said to be a passive gleaning whispering bat preying on terrestrial arthropods such as scorpions. Using an acoustic tracking system, we recorded individuals flying at foraging and drinking sites and compared their flight height, flight speed, call duration, pulse interval and source levels with those of gleaning individuals previously recorded using the same setup. We found differences in all variables with the strongest difference in source levels, where bats called at a mean of 119 dB peSPL (compared with 75 dB peSPL when gleaning). Bat faecal analysis indicated that their diet differed from previous studies and that prey species were capable of flight. We conclude that the bats switched from passive gleaning to capturing airborne insects (aerial hawking). Although whispering bats have been known to opportunistically catch insects on the wing, in the present study we show a full bimodal switch between foraging guilds with the respective changes in source level to those typical of a true aerial hawker. PMID- 24948641 TI - Influence of substrate orientation on feeding kinematics and performance of algae grazing Lake Malawi cichlid fishes. AB - Lake Malawi cichlids have been studied extensively in an effort to elucidate the mechanisms underlying their adaptive radiation. Both habitat partitioning and trophic specialization have been suggested to be critical ecological axes underlying the exceptional diversification of these fishes, but the mechanisms facilitating this divergence are often unclear. For instance, in the rock dwelling mbuna of Lake Malawi, coexistence is likely tightly linked to how and where species feed on the algae coating all the surfaces of the rocky reefs they exclusively inhabit. Yet, although mbuna species often preferentially graze from particular substrate orientations, we understand very little about how substrate orientation influences feeding kinematics or feeding rates in any group of organisms. Therefore, for three species of mbuna, we quantified feeding kinematics and inferred the rates that algae could be ingested on substrates that mimicked the top, side and bottom of the algae-covered boulders these species utilize in Lake Malawi. A number of differences in feeding kinematics were found among species, and several of the kinematic variables were found to differ even within species when the fish grazed from different surface orientations. However, despite their preferences for particular microhabitats, we found no evidence for clear trade-offs in the rates that the three species were inferred to be able to obtain algae from different substrate orientations. Nevertheless, our results indicate microhabitat divergence linked to differences in feeding kinematics could have played a role in the origin and maintenance of the vast diversity of co-occurring Lake Malawi mbuna species. PMID- 24948642 TI - Tendon elastic strain energy in the human ankle plantar-flexors and its role with increased running speed. AB - The human ankle plantar-flexors, the soleus and gastrocnemius, utilize tendon elastic strain energy to reduce muscle fiber work and optimize contractile conditions during running. However, studies to date have considered only slow to moderate running speeds up to 5 m s(-1). Little is known about how the human ankle plantar-flexors utilize tendon elastic strain energy as running speed is advanced towards maximum sprinting. We used data obtained from gait experiments in conjunction with musculoskeletal modeling and optimization techniques to calculate muscle-tendon unit (MTU) work, tendon elastic strain energy and muscle fiber work for the ankle plantar-flexors as participants ran at five discrete steady-state speeds ranging from jogging (~2 m s(-1)) to sprinting (>=8 m s(-1)). As running speed progressed from jogging to sprinting, the contribution of tendon elastic strain energy to the positive work generated by the MTU increased from 53% to 74% for the soleus and from 62% to 75% for the gastrocnemius. This increase was facilitated by greater muscle activation and the relatively isometric behavior of the soleus and gastrocnemius muscle fibers. Both of these characteristics enhanced tendon stretch and recoil, which contributed to the bulk of the change in MTU length. Our results suggest that as steady-state running speed is advanced towards maximum sprinting, the human ankle plantar-flexors continue to prioritize the storage and recovery of tendon elastic strain energy over muscle fiber work. PMID- 24948644 TI - Aquaporin expression in the Japanese medaka (Oryzias latipes) in freshwater and seawater: challenging the paradigm of intestinal water transport? AB - We investigated the salinity-dependent expression dynamics of seven aquaporin paralogs (aqp1a, aqp3a, aqp7, aqp8ab, aqp10a, aqp10b and aqp11a) in several tissues of euryhaline Japanese medaka (Oryzias latipes). All paralogs except aqp7 and aqp10a had a broad tissue distribution, and several were affected by salinity in both osmoregulatory and non-osmoregulatory tissues. In the intestine, aqp1a, aqp7, aqp8ab and aqp10a decreased upon seawater (SW) acclimation in both long term acclimated fish and during 1-3 days of the transition period. In the gill, aqp3a was lower and aqp10a higher in SW than in freshwater (FW). In the kidney no aqps were affected by salinity. In the skin, aqp1a and aqp3a were lower in SW than in FW. In the liver, aqp8ab and aqp10a were lower in SW than in FW. Furthermore, six Na(+),K(+)-ATPase alpha-subunit isoform transcripts were analysed in the intestine but none showed a consistent response to salinity, suggesting that water transport is not regulated at this level. In contrast, mRNA of the Na(+),K(+),2Cl(-)-cotransporter type-2 strongly increased in the intestine in SW compared with FW fish. Using custom-made antibodies, Aqp1a, Aqp8ab and Aqp10a were localized in the apical region of enterocytes of FW fish. Apical staining intensity strongly decreased, vanished or moved to subapical regions, when fish were acclimated to SW, supporting the lower mRNA expression in SW. Western blots confirmed the decrease in Aqp1a and Aqp10a in SW. The strong decrease in aquaporin expression in the intestine of SW fish is surprising, and challenges the paradigm for transepithelial intestinal water absorption in SW fishes. PMID- 24948643 TI - Opsin expression in Limulus eyes: a UV opsin is expressed in each eye type and co expressed with a visible light-sensitive opsin in ventral larval eyes. AB - The eyes of the horseshoe crab, Limulus polyphemus, are a model for studies of visual function and the visual systems of euarthropods. Much is known about the structure and function of L. polyphemus photoreceptors, much less about their photopigments. Three visible-light-sensitive L. polyphemus opsins were characterized previously (LpOps1, 2 and 5). Here we characterize a UV opsin (LpUVOps1) that is expressed in all three types of L. polyphemus eyes. It is expressed in most photoreceptors in median ocelli, the only L. polyphemus eyes in which UV sensitivity was previously detected, and in the dendrite of eccentric cells in lateral compound eyes. Therefore, eccentric cells, previously thought to be non-photosensitive second-order neurons, may actually be UV-sensitive photoreceptors. LpUVOps1 is also expressed in small photoreceptors in L. polyphemus ventral larval eyes, and intracellular recordings from these photoreceptors confirm that LpUVOps1 is an active, UV-sensitive photopigment. These photoreceptors also express LpOps5, which we demonstrate is an active, long wavelength-sensitive photopigment. Thus small photoreceptors in ventral larval eyes, and probably those of the other larval eyes, have dual sensitivity to UV and visible light. Interestingly, the spectral tuning of small ventral photoreceptors may change day to night, because the level of LpOps5 in their rhabdoms is lower during the day than during the night, whereas LpUVOps1 levels show no diurnal change. These and previous findings show that opsin co-expression and the differential regulation of co-expressed opsins in rhabdoms is a common feature of L. polyphemus photoreceptors. PMID- 24948645 TI - Age at weaning, immunocompetence and ectoparasite performance in a precocial desert rodent. AB - We studied the effects of early weaning on immunocompetence and parasite resistance in a precocial rodent Acomys cahirinus. We hypothesized that if parasite resistance is energetically expensive and nutritional and immunological support from mothers are necessary for the long-term health of offspring, then early weaned animals would be immunologically weaker and less able to defend themselves against parasites than later weaned animals. We weaned pups at 14, 21 or 28 days after birth and assessed their immunocompetence and resistance against fleas Parapulex chephrenis when they attained adulthood. Immunocompetence was assessed using leukocyte concentration (LC) and a phytohaemagglutinin injection assay (PHA test). To estimate resistance against fleas, we measured performance of fleas via the number of produced eggs and duration of development and resistance to starvation of the flea offspring. We found a significant positive effect of weaning age on the PHA response but not on LC. The effect of age at weaning on flea egg production was manifested in male but not female hosts, with egg production being higher if a host was weaned at 14 than at 28 days. Weaning age of the host did not affect either duration of development or resistance to starvation of fleas produced by mothers fed on these hosts. We conclude that even in relatively precocial mammals, weaning age is an important indicator of future immunological responses and the ability of an animal to resist parasite infestations. Hosts weaned at an earlier age make easier, less-resistant targets for parasite infestations than hosts weaned later in life. PMID- 24948646 TI - Reproduction Symposium: does grazing on biosolids-treated pasture pose a pathophysiological risk associated with increased exposure to endocrine disrupting compounds? AB - Biosolids (processed human sewage sludge), which contain low individual concentrations of an array of contaminants including heavy metals and organic pollutants such as polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB), and polychlorinated dibenzodioxins/polychlorinated dibenzofurans known to cause physiological disturbances, are increasingly being used as an agricultural fertilizer. This could pose a health threat to both humans and domestic and wild animal species. This review summarizes results of a unique model, used to determine the effects of exposure to mixtures of environmentally relevant concentrations of pollutants, in sheep grazed on biosolids-treated pastures. Pasture treatment results in nonsignificant increases in environmental chemical (EC) concentrations in soil. Whereas EC concentrations were increased in some tissues of both ewes and their fetuses, concentrations were low and variable and deemed to pose little risk to consumer health. Investigation of the effects of gestational EC exposure on fetal development has highlighted a number of issues. The results indicate that gestational EC exposure can adversely affect gonadal development (males and females) and that these effects can impact testicular morphology, ovarian follicle numbers and health, and the transcriptome and proteome in adult animals. In addition, EC exposure can be associated with altered expression of GnRH, GnRH receptors, galanin receptors, and kisspeptin mRNA within the hypothalamus and pituitary gland, gonadotroph populations within the pituitary gland, and regional aberrations in thyroid morphology. In most cases, these anatomical and functional differences do not result in altered peripheral hormone concentrations or reproductive function (e.g., lambing rate), indicating physiological compensation under the conditions tested. Physiological compensation is also suggested from studies that indicate that EC effects may be greater when exposure occurs either before or during gestation compared with EC exposure throughout life. With regard to human and animal health, this body of work questions the concept of safe individual concentration of EC when EC exposure typically occurs as complex mixtures. It suggests that developmental EC exposure may affect many different physiological systems, with some sex-specific differences in EC sensitivity, and that EC effects may be masked under favorable physiological conditions. PMID- 24948647 TI - Relationships of feeding behaviors with efficiency in RFI-divergent Japanese Black cattle. AB - New approaches to limit expenses associated with input, without compromising profit, are needed in the beef industry. Residual feed intake (RFI) is an efficiency trait that measures variation in feed intake beyond maintenance, growth, and body composition. The addition of feeding behavior analysis to standard RFI tests may provide an approach to more readily identify feed efficient cattle. The current study analyzes 7 feeding behaviors (BVFREQ: bunk visit frequency, BVDUR: bunk visit duration, FBFREQ: feed bout frequency, FBDUR: feed bout duration, MFREQ: meal frequency, MDUR: meal duration, and AMINT: average meal intake) and their relationships with RFI, ADG, and DMI in Japanese Black (Wagyu) cattle. Three cohorts of yearling Wagyu animals were studied using a standard 70-d RFI test, and data from divergent ( +/- 0.5 SD from population RFI mean) subsets of animals were analyzed for feeding behaviors [n = 58, bulls on high-concentrate diet (C1); n = 36, bulls on a lower-concentrate diet (C2); n = 34, heifers on a lower-concentrate diet (C3)]. The following behaviors were correlated with ADG: BVFREQ (r = 0.32, P = 0.01; C1 bulls), BVDUR (r = 0.42, P = 0.01, C2 bulls), FBFREQ (r = 0.37, P < 0.01; C1 bulls), FBDUR (r = 0.46, P < 0.01, C1 bulls), and MFREQ (r = 0.42, P < 0.01, C2 bulls). Behaviors were trending or significantly correlated with DMI for all cases except for MFREQ for C3 and AMINT for C2. Residual feed intake was positively correlated with MDUR across all cohorts (r = 0.31, P = 0.02; r = 0.38, P = 0.02; r = 0.54, P >= 0.01, respectively). For C2 bulls and C3 heifers, RFI was positively correlated with behavior frequency categories (BVFREQ; r = 0.44, P = 0.01; r = 0.60, P <= 0.01, respectively, and FBFREQ r = 0.46, P <= 0.01; r = 0.60, P <= 0.01, respectively). Bunk visit frequency and FBFREQ were highly correlated with RFI status (high or low) in C2 bulls and C3 heifers. Behavior duration categories (BVDUR, FBDUR, and MDUR) were most correlated with efficiency status in C1 bulls. However, behavior frequency categories (BVFREQ and FBFREQ), as well as MDUR, were most correlated with efficiency status in C2 bulls and C3 heifers. Inclusion of meal duration measurements when evaluating RFI provides an additional tool in understanding the drivers of variation in this important trait in Wagyu cattle. The present study provides new insights into feed intake patterns of a beef breed for which there are few reports of feeding behavior. PMID- 24948648 TI - Genomic prediction in French Charolais beef cattle using high-density single nucleotide polymorphism markers. AB - The objective of the study was to develop a genomic evaluation for French beef cattle breeds and assess accuracy and bias of prediction for different genomic selection strategies. Based on a reference population of 2,682 Charolais bulls and cows, genotyped or imputed to a high-density SNP panel (777K SNP), we tested the influence of different statistical methods, marker densities (50K versus 777K), and training population sizes and structures on the quality of predictions. Four different training sets containing up to 1,979 animals and a unique validation set of 703 young bulls only known on their individual performances were formed. BayesC method had the largest average accuracy compared to genomic BLUP or pedigree-based BLUP. No gain of accuracy was observed when increasing the density of markers from 50K to 777K. For a BayesC model and 777K SNP panels, the accuracy calculated as the correlation between genomic predictions and deregressed EBV (DEBV) divided by the square root of heritability was 0.42 for birth weight, 0.34 for calving ease, 0.45 for weaning weight, 0.52 for muscular development, and 0.27 for skeletal development. Half of the training set constituted animals having only their own performance recorded, whose contribution only represented 5% of the accuracy. Using DEBV as a response brought greater accuracy than using EBV (+5% on average). Considering a residual polygenic component strongly reduced bias for most of the traits. The optimal percentage of polygenic variance varied across traits. Among the methodologies tested to implement genomic selection in the French Charolais beef cattle population, the most accurate and less biased methodology was to analyze DEBV under a BayesC strategy and a residual polygenic component approach. With this approach, a 50K SNP panel performed as well as a 777K panel. PMID- 24948649 TI - Dry fractionation creates fractions of wheat distillers dried grains and solubles with highly digestible nutrient content for grower pigs. AB - Nutrient digestibility in distillers dried grains with solubles (DDGS) is limited by constraints such as particle size and fiber. Wheat DDGS contains more fiber than corn DDGS that may reduce its nutritional value in swine feeds. Dry fractionation may create DDGS fractions with low and high fiber content; therefore, wheat DDGS was processed sequentially using a vibratory sifter and gravity table. Sufficient material was obtained from 3 wheat DDGS fractions that differed in particle size from fine to coarse (Fraction A [FA], Fraction C [FC], and Fraction D [FD]). Five cornstarch-based diets were mixed that contained either 40% wheat DDGS, 30% FA, 30% FC plus 10% soybean meal (SBM), 30% FD plus 15% SBM, or 35% SBM. A sixth, N-free diet served to subtract basal endogenous AA losses and as control for energy digestibility calculations. Six ileal-cannulated barrows (29 kg BW) were fed 6 diets at 2.8 times maintenance for DE in six 9-d periods as a 6 * 6 Latin square. Feces and ileal digesta were collected sequentially for 2 d each. Wheat DDGS FA, FC, and FD were 258, 530, and 723 MUm in mean particle size and contained 44.8, 39.3, and 33.8% CP and 29.1, 35.1, and 37.5% in NDF, respectively. The apparent total tract digestibility (ATTD) of GE was greater (P < 0.05) for SBM than wheat DDGS, was greater (P < 0.05) for FA than wheat DDGS, and did not differ between FC, FD, and wheat DDGS. The standardized ileal digestibility (SID) did not differ between SBM and wheat DDGS (P > 0.05) for most AA. The SID of Arg, Lys, Trp, and available Lys was greater (P < 0.05) for FD than wheat DDGS but was similar for FA, FC, and wheat DDGS and was greater (P < 0.05) for FD than SBM. The DE and NE value was greater (P < 0.05) for SBM, FA, and FC than wheat DDGS and did not differ between FD and wheat DDGS. The SID content of indispensable AA and available Lys was greater (P < 0.05) for SBM than wheat DDGS. The SID content of Ile, Leu, Met, Phe, and Val was greater (P < 0.05) for FA than wheat DDGS but did not differ for indispensable AA between FC and wheat DDGS. The SID content of His, Ile, Leu, Met, and Phe was lower (P < 0.05) for FD than wheat DDGS. In conclusion, dry fractionation creates DDGS fractions with a differing chemical composition. Fine particle fractions contain less fiber and more CP than coarse particle fractions, but their AA digestibility was lower, likely due to most of the solubles being fine particles that are more susceptible to AA damage than protein entrapped in particles of larger size. PMID- 24948650 TI - Effects of capsicum oleoresin, garlic botanical, and turmeric oleoresin on gene expression profile of ileal mucosa in weaned pigs. AB - This study was conducted to characterize the effects of feeding 3 plant extracts on gene expression in ileal mucosa of weaned pigs. Weaned pigs (n = 32, 6.3 +/- 0.2 kg BW, and 21 d old) were housed in individual pens for 9 d and fed 4 different diets: a nursery basal diet as control diet, basal diet supplemented with 10 mg/kg of capsicum oleoresin, garlic botanical, or turmeric oleoresin. Results reported elsewhere showed that the plant extracts reduced diarrhea and increased growth rate of weaning pigs. Total RNA (4 pigs/treatment) was extracted from ileal mucosa of pigs at d 9. Double-stranded cDNA was amplified, labeled, and further hybridized to the microarray. Microarray data were analyzed in R using packages from the Bioconductor project. Differential gene expression was tested by fitting a mixed linear model equivalent to ANOVA using the limma package. Bioinformatics analysis was conducted by DAVID Bioinformatics Resources. Three pairwise comparisons were used to compare each plant extract diet with the control diet. Quantitative real time PCR was applied to verify the mRNA expression detected by microarray. Compared with the control diet, feeding capsicum oleoresin altered (P < 0.05) the expression of 490 genes (280 up, 210 down), and feeding garlic botanical altered (P < 0.05) the expression of 64 genes (33 up, 31 down), while feeding turmeric oleoresin altered (P < 0.05) the expression of 327 genes (232 up, 95 down). Compared with the control diet, feeding capsicum oleoresin and turmeric oleoresin increased [Expression Analysis Systematic Explorer (EASE) < 0.05] the expression of genes related to integrity of membranes and tight junctions, indicating enhanced gut mucosa health, but decreased (EASE < 0.05) the cell cycle pathway. Feeding each of the 3 plant extracts enhanced (EASE < 0.05) the expression of genes associated with immune responses, indicating that feeding these plant extracts may stimulate the immune responses of pigs in the normal conditions. In conclusion, plant extracts regulated the expression of genes in ileal mucosa of pigs, perhaps providing benefits by enhancing the gut mucosa health and stimulating the immune system. PMID- 24948651 TI - Characterization of the adaptive immune response following immunization in pregnant sows (Sus scrofa) kept in two different housing systems. AB - Housing conditions might differentially affect the adaptive immune responses to a neoantigen in pregnant sows with possible consequences for the success of vaccinations. Therefore, this study aimed at characterizing antigen-specific T cell and B cell responses of pregnant sows (German Landrace) either housed in a social group (GP; n = 22) or confined in individual gestation crates (CR; n = 11). All sows were immunized with the neoantigen keyhole limpet hemocyanin (KLH) 7 and 5 wk prepartum. Blood samples were taken 7, 6, 4, and 2 wk prepartum, thus before and after the first as well as second immunization. This study aimed at identifying both the resulting cellular as well as humoral KLH-specific immune response in the pregnant sows. We therefore analyzed total IgG and anti-KLH IgG concentrations and the KLH-specific lymphocyte proliferation as well as the KLH specific production of the T helper cell type 1 (TH1)-related cytokines tumor necrosis factor (TNF) alpha and interferon (IFN) gamma in main T cell subsets before and after the immunization. Anti-KLH IgG titers significantly increased during the experimental procedure (P < 0.001) reflecting the activation and differentiation of KLH-specific B cells on immunization. However, CR-housed sows showed greater anti-KLH IgG concentrations compared to GP-housed sows (P < 0.05). Keyhole limpet hemocyanin-specific TNFalpha-producing cytotoxic T cells (CTL) and T helper (TH) cells were detectable in CR-housed sows not before the second immunization (both P < 0.05), whereas those cells were detectable already after the first immunization in GP-housed sows (CTL: P < 0.01 and TH: P < 0.05). Similarly, KLH-specific TNFalpha/IFNgamma-double producing CTL and TH cells were detectable earlier in GP-housed sows than in CR-housed sows (both P < 0.05). Keyhole limpet hemocyanin-induced lymphocyte proliferation and total IgG concentrations were not affected by the housing system. Our results show that housing conditions affect the adaptive immunity to a neoantigen in pregnant sows. Whereas GP housing of pregnant sows induced a rather TH1-mediated cellular response, individual housing in CR resulted in a T helper cell type 2 (TH2) pronounced humoral response to KLH. The greater anti-KLH IgG concentration and the delayed activation and differentiation of KLH-specific TH1 cells in CR-housed sows support the hypothesis of a shifted TH1:TH2 ratio in individually housed sows of this study. We presume differences in the stressfulness of the housing system to be mainly responsible for the occurring effects. PMID- 24948652 TI - Effects of calf weaning age and subsequent management systems on growth performance and carcass characteristics of beef steers. AB - Brahman * British crossbred steers (n = 40 and 38 in yr 1 and 2, respectively) were used to evaluate the effects of calf management systems following early weaning (EW) on growth performance, muscle gene expression, and carcass characteristics. On the day of EW (d 0), steers were stratified by BW and age (95 +/- 14 kg; 74 +/- 14 d) and randomly assigned to a control treatment that was normally weaned (NW) on d 180 (n = 10 steers/yr) or to 1 of 3 EW treatments: 1) EW and limit fed a high-concentrate diet at 3.5% of BW (as-fed basis) in drylot until d 180 (EW180; n = 10 steers/yr), 2) EW and limit fed a high-concentrate diet at 3.5% of BW (as-fed basis) in drylot until d 90 and then grazed on bahiagrass pastures until d 180 (EW90; n = 10 steers/yr), or 3) EW and grazed on annual ryegrass pastures until d 60 (yr 1; n = 10 steers) or 90 (yr 2; n = 8 steers) and then on bahiagrass pastures until d 180 (EWRG). Early-weaned steers on ryegrass and bahiagrass pastures were supplemented with high-concentrate diet at 1.0% of BW (as-fed basis) until d 180. From d 180 to 270 (yr 1), all EW steers remained in their respective treatments, whereas NW steers were provided high concentrate diet at 1.0% of BW (as-fed basis) on bahiagrass pastures. In yr 1, feedlot finishing period began on d 270. In yr 2, the study was terminated on d 180. In both years, EW180 steers were heaviest (P < 0.0001) on d 180. On d 180 of yr 1, EWRG steers were lightest (P < 0.0001) and EW90 steers were heavier (P = 0.05) than NW steers, whereas EW90, EWRG, and NW steers had similar BW on d 180 of yr 2 (P >= 0.14). On d 90, muscle PPARgamma mRNA expression tended (P = 0.07) to be greater for EW180 steers and was greater (P = 0.008) for EW90 vs. EWRG steers but similar (P = 0.25) between EW180 and NW steers. On d 180, PPARgamma mRNA was greater (P <= 0.06) for EW180 vs. NW, EW90, and EWRG steers. From d 274 to 302, EW180 steers had the least ADG (P <= 0.09), whereas EW90 steers had similar (P = 0.19) ADG compared with EWRG steers but greater (P = 0.03) ADG than NW steers. At slaughter, carcass characteristics did not differ (P >= 0.22) among treatments. In summary, EW steers provided a high-concentrate diet in drylot for at least 90 d were heavier at the time of normal weaning than NW steers and EW steers grazed on ryegrass pastures for 60 to 90 d and supplemented with concentrate at 1.0% of BW. Feeding a high-concentrate diet immediately after EW enhanced the muscle PPARgamma expression but did not enhance marbling at slaughter. PMID- 24948653 TI - Beef heifer growth and reproductive performance following two levels of pasture allowance during the fall grazing period. AB - The objective of this study was to compare heifer growth and reproductive performance following 2 levels of stockpiled fall forage allowance of orchardgrass (30.5%) and tall fescue (14.1%). Spring-born heifers (n = 203 and BW = 246 +/- 28.9 kg) of primarily Angus background were allocated to 2 grazing treatments during the fall period (November 12 to December 17 in yr 1, November 7 to January 4 in yr 2, and November 7 to January 14 in yr 3) each replicated 3 times per year for 3 yr. Treatments consisted of daily pasture DM allowance of 3.5% of BW (LO) or daily pasture DM allowance of 7.0% of BW (HI) under strip grazing management. Throughout the winter feeding period, mixed grass-legume haylage and soybean hulls were fed. Heifers were grazed as 1 group under continuous stocking after the winter period. Heifers in the LO group gained less than heifers in the HI group during the fall grazing period (0.12 vs. 0.40 kg/d; P < 0.0001). For each 1 10 g increase in NDF/kg fall pasture (DM basis), fall ADG decreased 0.14 kg (P = 0.01). During winter feeding, ADG was 0.30 and 0.39 kg/d for LO vs. HI heifers, respectively (P = 0.0008). During the spring grazing period (April 16 to May 24 in yr 1, April 22 to May 26 in yr 2, and April 5 to May 16 in yr 3), LO heifers had numerically greater ADG than HI heifers (1.38 vs. 1.30 kg/d; P = 0.64). Hip height (122.7 vs. 121.4 cm; P = 0.0055), BCS (5.8 vs. 5.6; P = 0.0057), and BW (356 vs. 335 kg; P < 0.0001) at the end of spring grazing was greater for HI than LO heifers. Heifers in the LO group compensated with greater summer ADG than heifers in the HI group (0.74 vs. 0.66 kg/d; P = 0.03). Total ADG from treatment initiation (November) through pregnancy diagnosis (August) was greater for HI than LO heifers (0.61 vs. 0.55 kg/d; P < 0.001) as was BW at pregnancy diagnosis (415 vs. 402 kg; P = 0.0055). Percentage of heifers reaching puberty by the time of AI was 34% for both groups (P = 0.93). Percentage of heifers becoming pregnant to AI tended (P = 0.13) to be greater for HI (44%) than for LO heifers (32%). Fall ADG across treatment groups affected the probability of a heifer becoming pregnant by AI (P = 0.01). Percentage pregnant by natural service (61% for LO vs. 59% for HI; P = 0.80) and final pregnancy rate (74% for LO vs. 77% for HI; P = 0.61) was not different for the 2 groups. These results indicate that altering fall forage allowance may delay the majority of BW gain until late in heifer development without negatively affecting overall pregnancy rates. PMID- 24948654 TI - Digestibility and retention of zinc, copper, manganese, iron, calcium, and phosphorus in pigs fed diets containing inorganic or organic minerals. AB - The objective of this experiment was to measure the apparent total tract digestibility (ATTD) and the retention rate of Zn, Cu, Mn, and Fe in pigs fed either inorganic or organic sources of Zn, Cu, Mn, and Fe. The experimental design was a randomized complete block design with a 2 * 3 factorial arrangement of treatments. There were 2 types of diets (corn grits-based or corn-soybean meal [SBM]-based diets) and 3 micromineral treatments (basal micromineral premix [BMM], inorganic micromineral premix [IMM], and organic micromineral premix [OMM]). The BMM contained no added Zn, Cu, Mn, or Fe; the IMM microminerals were provided as sulfates of Zn, Cu, Mn, and Fe at 40, 50, 20, and 100 mg/kg, respectively. The OMM contained the same levels of the 4 microminerals as IMM, but Zn, Cu, Mn, and Fe in this premix were provided by Zn(2-hydroxy-4-methylthio butanoic acid [HMTBa])2, Cu(HMTBa)2, Mn(HMTBa)2, and FeGly, respectively. Forty eight barrows (initial BW: 31.1 +/- 4.2 kg) were housed individually and allowed ad libitum access to the corn grits diet with BMM for 2 wk. All pigs were then moved to metabolism cages and randomly assigned to 1 of the 6 treatment diets with 8 replicates per diet. Fecal and urine samples were collected for 5 d following a 5-d adaptation period. Compared with corn grits diets, pigs fed corn SBM diets had greater (P < 0.05) absorption and retention of Zn, Cu, and Mn but less (P < 0.05) ATTD of Zn and Cu. Compared with BMM, supplementation of IMM or OMM increased (P < 0.05) absorption, retention, ATTD, and retention rate of Zn, Cu, Mn, and Fe. Compared with IMM, adding OMM to the corn-SBM diet improved (P < 0.05) the absorption and retention of Cu and Mn and the ATTD of Cu, but these differences were not observed in the corn grits diets (interaction, P < 0.05). In addition, adding OMM to the corn-SBM diet increased (P < 0.05) absorption and retention of Zn and Fe and ATTD of Zn, Mn, and Fe compared with adding IMM to the corn-SBM diet. Supplementation of OMM also increased (P < 0.05) the ATTD and retention rate of P in corn-SBM diets. Results indicate that Zn(HMTBa)2 has greater digestibility and Cu(HMTBa)2 and Mn(HMTBa)2 have greater digestibility and retention rates compared with their inorganic sulfates, if included in a corn SBM diet. Supplementation of organic microminerals also improves the digestibility of P in a corn-SBM diet. PMID- 24948655 TI - Identification of the STAC3 gene as a skeletal muscle-specifically expressed gene and a novel regulator of satellite cell differentiation in cattle. AB - Recent studies in mice and zebrafish suggest that the unannotated Src homology 3 and cysteine rich domain 3 (STAC3) gene plays an important role in skeletal muscle development and contraction. The objective of this study was to determine the tissue specificity of the bovine STAC3 gene and its potential role in the proliferation and differentiation of bovine satellite cells. The STAC3 mRNA was detected only in skeletal muscle among 18 bovine tissues examined by reverse transcription PCR. Western blotting revealed the expression of STAC3 protein in bovine skeletal muscle and the absence of it in 6 bovine tissues analyzed. Transfection of the bovine satellite cells with a pool of 2 STAC3 small interfering RNA (siRNA) caused a 90% reduction in STAC3 mRNA. Cell proliferation assays revealed that STAC3 knockdown had no effect on the proliferation rate of bovine satellite cells. Approximately 60% of bovine satellite cells transfected with STAC3 siRNA formed myotubes by 72 h of differentiation, whereas that percentage was 40% for those transfected with negative control siRNA (P < 0.05). At 24, 48, and 72 h of differentiation, bovine satellite cells transfected with STAC3 siRNA had greater mRNA expression of myogenin, myosin heavy chain 3, and myosin heavy chain 7, markers of myotubes, than those transfected with negative control siRNA (P < 0.05). These results suggest that the STAC3 gene is a negative regulator of the differentiation and fusion of bovine satellite cells into myotubes. However, STAC3 expression was increased during the differentiation of bovine satellite cells into myotubes. This suggests that STAC3 might have different functions in bovine myotubes than in bovine satellite cells. PMID- 24948656 TI - Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. AB - Patients in complete cytogenetic response (CCyR) with detectable BCR-ABL1 after >=2 years on imatinib were randomized to nilotinib (400 mg twice daily, n = 104) or continued imatinib (n = 103) in the Evaluating Nilotinib Efficacy and Safety in clinical Trials-Complete Molecular Response (ENESTcmr) trial. By 1 and 2 years, confirmed undetectable BCR-ABL1 was achieved by 12.5% vs 5.8% (P = .108) and 22.1% vs 8.7% of patients in the nilotinib and imatinib arms, respectively (P = .0087). Among patients without molecular response 4.5 (BCR-ABL1(IS) <=0.0032%; MR(4.5)) and those without major molecular response at study start, MR(4.5) by 2 years was achieved by 42.9% vs 20.8% and 29.2% vs 3.6% of patients in the nilotinib and imatinib arms, respectively. No patient in the nilotinib arm lost CCyR, vs 3 in the imatinib arm. Adverse events were more common in the nilotinib arm, as expected with the introduction of a new drug vs remaining on a well tolerated drug. The safety profile of nilotinib was consistent with other reported studies. In summary, switching to nilotinib enabled more patients with chronic myeloid leukemia in chronic phase (CML-CP) to sustain lower levels of disease burden vs remaining on imatinib. This trial was registered at www.clinicaltrials.gov as #NCT00760877. PMID- 24948657 TI - Two independent killing mechanisms of Candida albicans by human neutrophils: evidence from innate immunity defects. AB - Invasive fungal infections, accompanied by high rates of mortality, represent an increasing problem in medicine. Neutrophils are the major effector immune cells in fungal killing. Based on studies with neutrophils from patients with defined genetic defects, we provide evidence that human neutrophils use 2 distinct and independent phagolysosomal mechanisms to kill Candida albicans. The first mechanism for the killing of unopsonized C albicans was found to be dependent on complement receptor 3 (CR3) and the signaling proteins phosphatidylinositol-3 kinase and caspase recruitment domain-containing protein 9 (CARD9), but was independent of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The second mechanism for the killing of opsonized C albicans was strictly dependent on Fcgamma receptors, protein kinase C (PKC), and reactive oxygen species production by the NADPH oxidase system. Each of the 2 pathways of Candida killing required Syk tyrosine kinase activity, but dectin-1 was dispensable for both of them. These data provide an explanation for the variable clinical presentation of fungal infection in patients suffering from different immune defects, including dectin-1 deficiency, CARD9 deficiency, or chronic granulomatous disease. PMID- 24948659 TI - New models of healthcare will replace nearly three quarters of NHS by 2024, report says. PMID- 24948658 TI - Shear enhances thrombopoiesis and formation of microparticles that induce megakaryocytic differentiation of stem cells. AB - In vivo visualization of thrombopoiesis suggests an important role for shear flow in platelet biogenesis. In vitro, shear stress was shown to accelerate proplatelet formation from mature megakaryocytes (Mks). Yet, the role of biomechanical forces on Mk biology and platelet biogenesis remains largely unexplored. In this study, we investigated the impact of shear stress on Mk maturation and formation of platelet-like particles (PLPs), pro/preplatelets (PPTs), and Mk microparticles (MkMPs), and furthermore, we explored a physiological role for MkMPs. We found that shear accelerated DNA synthesis of immature Mks in an exposure time- and shear stress level-dependent manner. Both phosphatidylserine exposure and caspase-3 activation were enhanced by shear stress. Exposure to physiological shear dramatically increased generation of PLPs/PPTs and MkMPs by up to 10.8 and 47-fold, respectively. Caspase-3 inhibition reduced shear-induced PLP/PPT and MkMP formation. PLPs generated under shear flow displayed improved functionality as assessed by CD62P exposure and fibrinogen binding. Significantly, coculture of MkMPs with hematopoietic stem and progenitor cells promoted hematopoietic stem and progenitor cell differentiation to mature Mks synthesizing alpha- and dense-granules, and forming PPTs without exogenous thrombopoietin, thus identifying a novel and unexplored potential physiological role for MkMPs. PMID- 24948660 TI - Data quality: not selling ourselves short. AB - Routinely coded hospital data ('administrative data') have been criticised as invalid and unreliable, without due regard for how Australian data differ from those of other healthcare systems. The skills and education of coders, degree of professional coding supervision, and the existence and rigour of coding audits all strengthen Australian routine hospital data. PMID- 24948661 TI - Web-based geo-visualisation of spatial information to support evidence-based health policy: a case study of the development process of HealthTracks. AB - Place is of critical importance to health as it can reveal patterns of disease spread and clustering, associations with risk factors, and areas with greatest need for, or least access to healthcare services and promotion activities. Furthermore, in order to get a good understanding of the health status and needs of a particular area a broad range of data are required which can often be difficult and time consuming to obtain and collate. This process has been expedited by bringing together multiple data sources and making them available in an online geo-visualisation, HealthTracks, which consists of a mapping and reporting component. The overall aim of the HealthTracks project is to make spatial health information more accessible to policymakers, analysts, planners and program managers to inform decision-making across the Department of Health Western Australia. Preliminary mapping and reporting applications that have been utilised to inform service planning, increased awareness of the utility of spatial information and improved efficiency in data access were developed. The future for HealthTracks involves expanding the range of data available and developing new analytical capabilities in order to work towards providing external agencies, researchers and eventually the general public access to rich local area spatial data. PMID- 24948662 TI - Improving performance and agreement in injury coding using the Abbreviated Injury Scale: a training course helps. AB - The aim of this study was to determine the influence of a dedicated training course on the ability of participants to assign correct codes and their inter observer agreement using the Abbreviated Injury Scale (AIS98). Twelve participants followed a one-day training course in injury coding. Codes were recorded before, during and after the course. The number of correctly assigned codes and severity codes, as well as the Fleiss' kappas improved significantly during and after the course. This study emphasises the benefit of training in injury coding. Training improves the ability to assign correct codes and it reduces inter-observer variability. We advise all who are involved in injury coding to follow a dedicated training course. PMID- 24948663 TI - How do patients respond to violation of their information privacy? AB - The introduction of electronic medical records (EMRs) can expose patients to the risk of infringement of their privacy. The purpose of this study was to explore the relationship between patients' concerns about information privacy and their protective responses. A questionnaire survey conducted in a Taiwanese hospital revealed that, regarding information privacy, patients' concerns about the collection of information about themselves, the secondary use of this information and the possibility of errors in the recorded information were associated with their information privacy-protective responses, while concern for unauthorised access to their information by other staff in the medical facility was not. Medical facilities should devote every effort to alleviate patients' concerns about the invasion of their information privacy to avoid eroding the reputation of medical facilities and impeding the promotion of EMRs. PMID- 24948664 TI - Impact of documentation errors on accuracy of cause of death coding in an educational hospital in Southern Iran. AB - Accurate cause of death coding leads to organised and usable death information but there are some factors that influence documentation on death certificates and therefore affect the coding. We reviewed the role of documentation errors on the accuracy of death coding at Shahid Mohammadi Hospital (SMH), Bandar Abbas, Iran. We studied the death certificates of all deceased patients in SMH from October 2010 to March 2011. Researchers determined and coded the underlying cause of death on the death certificates according to the guidelines issued by the World Health Organization in Volume 2 of the International Statistical Classification of Diseases and Health Related Problems-10th revision (ICD-10). Necessary ICD coding rules (such as the General Principle, Rules 1-3, the modification rules and other instructions about death coding) were applied to select the underlying cause of death on each certificate. Demographic details and documentation errors were then extracted. Data were analysed with descriptive statistics and chi square tests. The accuracy rate of causes of death coding was 51.7%, demonstrating a statistically significant relationship (p=.001) with major errors but not such a relationship with minor errors. Factors that result in poor quality of Cause of Death coding in SMH are lack of coder training, documentation errors and the undesirable structure of death certificates. PMID- 24948665 TI - Only 15% of young men in England were tested for chlamydia last year despite recommendations. PMID- 24948666 TI - Initial experience with the Oncotype DX assay in decision-making for adjuvant therapy of early oestrogen receptor-positive breast cancer in Hong Kong. AB - OBJECTIVE: To examine the impact of the 21-gene Oncotype DX Breast Cancer Assay on the adjuvant treatment decision-making process for early-stage breast cancer in Hong Kong. DESIGN: Retrospective study. SETTING: Private hospital, Hong Kong. PATIENTS: Study included cases of early-stage breast cancer (T1-2N0-1M0, oestrogen receptor-positive, human epidermal growth factor receptor 2-negative) that were presented at a multidisciplinary breast meeting at a single site. Cases were selected for Oncotype DX testing with the assistance of Adjuvant! Online. The recommendations for adjuvant therapy before and after obtaining the Oncotype DX Recurrence Score results were analysed. RESULTS: A total of 154 cases that met the inclusion criteria were discussed at our multidisciplinary breast meeting. Of these, 64 cases with no clear recommendation by the Meeting Panel were selected for this study and reviewed. The distribution of Recurrence Score results was similar to that reported by others, with a somewhat higher proportion of low Recurrence Scores. Treatment recommendation was changed for 20 (31%) patients after the Oncotype DX result was received. Of the changes in treatment decisions, 16 (80%) were changes to lower-intensity regimens (either equipoise or hormonal therapy). The number of cases receiving an equipoise recommendation decreased by nine (82%), based on the additional information provided by the Oncotype DX test. CONCLUSION: The Oncotype DX Recurrence Score information impacts the decision making process for adjuvant therapy for early-stage breast cancer in the multidisciplinary care setting in Hong Kong. A larger-scale study is required to gain more experience, evaluate its impact more thoroughly, and assess its cost effectiveness. PMID- 24948667 TI - Three-year experience of using venovenous extracorporeal membrane oxygenation for patients with severe respiratory failure. AB - OBJECTIVE: To present the 3-year experience of using venovenous extracorporeal membrane oxygenation for patients with severe respiratory failure in a single centre in Hong Kong. DESIGN: Case series. SETTING: A 19-bed Intensive Care Unit of a tertiary hospital in Hong Kong. PATIENTS: All patients who were managed with venovenous extracorporeal membrane oxygenation from 1 July 2010 to 30 June 2013 in the Intensive Care Unit. RESULTS: Overall, 31 patients (mean age, 42.2 years, standard deviation, 14.1 years; 21 males) received venovenous extracorporeal membrane oxygenation for the treatment of severe respiratory failure. Of these, 90.3% (28 patients) presented with pneumonia as the cause of the respiratory failure, and 22 of them had identifiable causes. A total of nine (29.0%) patients were diagnosed to have H1N1 infection. The median Murray score was 3.5 (interquartile range, 3.0-3.5); the median duration of venovenous extracorporeal membrane oxygenation support was 5.0 (2.8-8.6) days; and the median duration of mechanical ventilator support was 18.2 (7.8-27.9) days. The overall intensive care unit mortality was 19.4% (n=6). The overall in-hospital mortality and the 28 day mortality were both 22.6% (n=7). Among the 22 patients who had identifiable infective causes, those suffering from viral infection had lower intensive care unit and hospital mortality than those who had bacterial infection (8.3% vs 20.0%). All the H1N1 patients survived. Complications related to extracorporeal membrane oxygenation included severe bleeding (n=2; 6.5%) and mechanical complications of the circuits (n=3; 9.7%). CONCLUSIONS: Venovenous extracorporeal membrane oxygenation is an effective adjunctive therapy and can be used as a life saving procedure for carefully selected patients with severe acute respiratory distress syndrome when the limits of standard therapy have been reached. PMID- 24948668 TI - Immunotherapy for peanut allergy. AB - Peanut allergy is one of the commonest food hypersensitivities causing fatal or near-fatal reactions. There is, currently, no preventive treatment and the incidence of severe allergic reactions during peanut desensitisation has limited its clinical use. Anti-immunoglobulin E therapy has been shown to be effective in preventing peanut-induced reactions but it does not result in long-term tolerance. Two important advances have recently been reported. One involves gradual oral introduction of peanut protein to desensitise, whereas the other approach uses a combination of anti-immunoglobulin E and oral peanut immunotherapy. Both approaches could offer a way to desensitise with a far greater margin of safety than has, hitherto, been reported. This article provides an overview of the literature on peanut immunotherapy and describes the experience in a small group of children in Hong Kong who were treated successfully using anti-immunoglobulin E combined with oral peanut desensitisation. PMID- 24948669 TI - Selenium addition alters mercury uptake, bioavailability in the rhizosphere and root anatomy of rice (Oryza sativa). AB - BACKGROUND AND AIMS: Mercury (Hg) is an extremely toxic pollutant, especially in the form of methylmercury (MeHg), whereas selenium (Se) is an essential trace element in the human diet. This study aimed to ascertain whether addition of Se can produce rice with enriched Se and lowered Hg content when growing in Hg contaminated paddy fields and, if so, to determine the possible mechanisms behind these effects. METHODS: Two cultivars of rice (Oryza sativa, japonica and indica) were grown in either hydroponic solutions or soil rhizobags with different Se and Hg treatments. Concentrations of total Hg, MeHg and Se were determined in the roots, shoots and brown rice, together with Hg uptake kinetics and Hg bioavailability in the soil. Root anatonmy was also studied. KEY RESULTS: The high Se treatment (5 MUg g(-1)) significantly increased brown rice yield by 48 % and total Se content by 2.8-fold, and decreased total Hg and MeHg by 47 and 55 %, respectively, compared with the control treatments. The high Se treatment also markedly reduced 'water-soluble' Hg and MeHg concentrations in the rhizosphere soil, decreased the uptake capacity of Hg by roots and enhanced the development of apoplastic barriers in the root endodermis. CONCLUSIONS: Addition of Se to Hg contaminated soil can help produce brown rice that is simultaneously enriched in Se and contains less total Hg and MeHg. The lowered accumulation of total Hg and MeHg appears to be the result of reduced bioavailability of Hg and production of MeHg in the rhizosphere, suppression of uptake of Hg into the root cells and an enhancement of the development of apoplastic barriers in the endodermis of the roots. PMID- 24948670 TI - Plant traits and ecosystem effects of clonality: a new research agenda. AB - BACKGROUND: Clonal plants spread laterally by spacers between their ramets (shoot root units); these spacers can transport and store resources. While much is known about how clonality promotes plant fitness, we know little about how different clonal plants influence ecosystem functions related to carbon, nutrient and water cycling. APPROACH: The response-effect trait framework is used to formulate hypotheses about the impact of clonality on ecosystems. Central to this framework is the degree of correspondence between interspecific variation in clonal 'response traits' that promote plant fitness and interspecific variation in 'effect traits', which define a plant's potential effect on ecosystem functions. The main example presented to illustrate this concept concerns clonal traits of vascular plant species that determine their lateral extension patterns. In combination with the different degrees of decomposability of litter derived from their spacers, leaves, roots and stems, these clonal traits should determine associated spatial and temporal patterns in soil organic matter accumulation, nutrient availability and water retention. CONCLUSIONS: This review gives some concrete pointers as to how to implement this new research agenda through a combination of (1) standardized screening of predominant species in ecosystems for clonal response traits and for effect traits related to carbon, nutrient and water cycling; (2) analysing the overlap between variation in these response traits and effect traits across species; (3) linking spatial and temporal patterns of clonal species in the field to those for soil properties related to carbon, nutrient and water stocks and dynamics; and (4) studying the effects of biotic interactions and feedbacks between resource heterogeneity and clonality. Linking these to environmental changes may help us to better understand and predict the role of clonal plants in modulating impacts of climate change and human activities on ecosystem functions. PMID- 24948671 TI - Cucurbits depicted in Byzantine mosaics from Israel, 350-600 ce. AB - BACKGROUND AND AIMS: Thousands of floor mosaics were produced in lands across the Roman and Byzantine empires. Some mosaics contain depictions of agricultural produce, potentially providing useful information concerning the contemporary presence and popularity of crop plants in a particular geographical region. Hundreds of floor mosaics produced in Israel during the Byzantine period have survived. The objective of the present work was to search these mosaics for Cucurbitaceae in order to obtain a more complete picture of cucurbit crop history in the eastern Mediterranean region. RESULTS AND CONCLUSIONS: Twenty-three mosaics dating from 350-600 ce were found that had images positively identifiable as cucurbits. The morphological diversity of the cucurbit fruits in the mosaics of Israel is greater than that appearing in mosaics from any other Roman or Byzantine provincial area. The depicted fruits vary in shape from oblate to extremely long, and some are furrowed, others are striped and others lack definite markings. The cucurbit taxa depicted in the mosaics are Cucumis melo (melon), Citrullus lanatus (watermelon), Luffa aegyptiaca (sponge gourd) and Lagenaria siceraria (bottle gourd). Cucumis melo is the most frequently found taxon in the mosaics and is represented by round dessert melons and long snake melons. Fruits of at least two cultivars of snake melons and of watermelons are represented. To our knowledge, images of sponge gourds have not been found in Roman and Byzantine mosaics elsewhere. Indeed, the mosaics of Israel contain what are probably the oldest depictions of Luffa aegyptiaca in Mediterranean lands. Sponge gourds are depicted often, in 11 of the mosaics at eight localities, and the images include both mature fruits, which are useful for cleaning and washing, and immature fruits, which are edible. Only one mosaic has images positively identifiable as of bottle gourds, and these were round-pyriform and probably used as vessels. PMID- 24948677 TI - An argument for a developmental approach in studying older adults' physical activity. PMID- 24948679 TI - Genome-wide identification and functional prediction of novel and drought responsive lincRNAs in Populus trichocarpa. AB - Protein-coding genes are considered to be a dominant component of the eukaryotic transcriptome; however, many studies have shown that intergenic, non-coding transcripts also play an important role. Long intergenic non-coding RNAs (lincRNAs) were found to play a vital role in human and Arabidopsis. However, lincRNAs and their regulatory roles remain poorly characterized in woody plants, especially Populus trichocarpa (P. trichocarpa). A large set of Populus RNA-Seq data were examined with high sequencing depth under control and drought conditions and a total of 2542 lincRNA candidates were identified. In total, 51 lincRNAs and 20 lincRNAs were identified as putative targets and target mimics of known Populus miRNAs, respectively. A total of 504 lincRNAs were found to be drought responsive, eight of which were confirmed by RT-qPCR. These findings provide a comprehensive view of Populus lincRNAs, which will enable in-depth functional analysis. PMID- 24948678 TI - Overexpression of the kiwifruit SVP3 gene affects reproductive development and suppresses anthocyanin biosynthesis in petals, but has no effect on vegetative growth, dormancy, or flowering time. AB - SVP-like MADS domain transcription factors have been shown to regulate flowering time and both inflorescence and flower development in annual plants, while having effects on growth cessation and terminal bud formation in perennial species. Previously, four SVP genes were described in woody perennial vine kiwifruit (Actinidia spp.), with possible distinct roles in bud dormancy and flowering. Kiwifruit SVP3 transcript was confined to vegetative tissues and acted as a repressor of flowering as it was able to rescue the Arabidopsis svp41 mutant. To characterize kiwifruit SVP3 further, ectopic expression in kiwifruit species was performed. Ectopic expression of SVP3 in A. deliciosa did not affect general plant growth or the duration of endodormancy. Ectopic expression of SVP3 in A. eriantha also resulted in plants with normal vegetative growth, bud break, and flowering time. However, significantly prolonged and abnormal flower, fruit, and seed development were observed, arising from SVP3 interactions with kiwifruit floral homeotic MADS-domain proteins. Petal pigmentation was reduced as a result of SVP3-mediated interference with transcription of the kiwifruit flower tissue specific R2R3 MYB regulator, MYB110a, and the gene encoding the key anthocyanin biosynthetic step, F3GT1. Constitutive expression of SVP3 had a similar impact on reproductive development in transgenic tobacco. The flowering time was not affected in day-neutral and photoperiod-responsive Nicotiana tabacum cultivars, but anthesis and seed germination were significantly delayed. The accumulation of anthocyanin in petals was reduced and the same underlying mechanism of R2R3 MYB NtAN2 transcript reduction was demonstrated. PMID- 24948680 TI - The challenges of commercializing second-generation transgenic crop traits necessitate the development of international public sector research infrastructure. AB - It has been 30 years since the first transformation of a gene into a plant species, and since that time a number of biotechnology products have been developed, with the most important being insect- and herbicide-resistant crops. The development of second-generation products, including nutrient use efficiency and tolerance to important environmental stressors such as drought, has, up to this time, been less successful. This is in part due to the inherent complexities of these traits and in part due to limitations in research infrastructure necessary for public sector researchers to test their best ideas. Here we discuss lessons from previous work in the generation of the first-generation traits, as well as work from our labs and others on identifying genes for nitrogen use efficiency. We then describe some of the issues that have impeded rapid progress in this area. Finally, we propose the type of public sector organization that we feel is necessary to make advances in important second-generation traits such as nitrogen use efficiency. PMID- 24948681 TI - Reassimilation of ammonium in Lotus japonicus. AB - This review summarizes the most recent results obtained in the analysis of two important metabolic pathways involved in the release of internal sources of ammonium in the model legume Lotus japonicus: photorespiratory metabolism and asparagine breakdown mediated by aparaginase (NSE). The use of photorespiratory mutants deficient in plastidic glutamine synthetase (GS2) enabled us to investigate the transcriptomics and metabolomic changes associated with photorespiratory ammonium accumulation in this plant. The results obtained indicate the existence of a coordinate regulation of genes involved in photorespiratory metabolism. Other types of evidence illustrate the multiple interconnections existing among the photorespiratory pathway and other processes such as intermediate metabolism, nodule function, and secondary metabolism in this plant, all of which are substantially affected in GS2-deficient mutants because of the impairment of the photorespiratory cycle. Finally, the importance of asparagine metabolism in L. japonicus is highlighted because of the fact that asparagine constitutes the vast majority of the reduced nitrogen translocated between different organs of this plant. The different types of NSE enzymes and genes which are present in L. japonicus are described. There is a particular focus on the most abundant K(+)-dependent LjNSE1 isoform and how TILLING mutants were used to demonstrate by reverse genetics the importance of this particular isoform in plant growth and seed production. PMID- 24948682 TI - Can current crop models be used in the phenotyping era for predicting the genetic variability of yield of plants subjected to drought or high temperature? AB - A crop model with genetic inputs can potentially simulate yield for a large range of genotypes, sites, and years, thereby indicating where and when a given combination of alleles confers a positive effect. We discuss to what extent current crop models, developed for predicting the effects of climate or cultivation techniques on a reference genotype, are adequate for ranking yields of a large number of genotypes in climatic scenarios with water deficit or high temperatures. We compare here the algorithms involved in 19 crop models. Marked differences exist in the representation of the combined effects of temperature and water deficit on plant development, and in the coordination of these effects with biomass production. The current literature suggests that these differences have a small impact on the yield prediction of a reference genotype because errors on the effects of different traits compensate each other. We propose that they have a larger impact if the crop model is used in a genetic context, because the model has to account for the genetic variability of studied traits. Models with explicit genetic inputs will be increasingly feasible because model parameters corresponding to each genotype can now be measured in phenotyping platforms for large plant collections. This will in turn allow prediction of parameter values from the allelic composition of genotypes. It is therefore timely to adapt crop models to this new context to simulate the allelic effects in present or future climatic scenarios with water or heat stresses. PMID- 24948683 TI - Identifying individuals with multiple sclerosis in an electronic medical record. AB - BACKGROUND: The increasing use of electronic medical records (EMRs) presents an opportunity to efficiently evaluate and improve quality of care for individuals with MS. OBJECTIVES: We aimed to establish an algorithm to identify individuals with MS within EMRs. METHODS: We used a sample of 73,003 adult patients from 83 primary care physicians in Ontario using the Electronic Medical Record Administrative data Linked Database (EMRALD). A reference standard of 247 individuals with MS was identified through chart abstraction. The accuracy of identifying individuals with MS in an EMR was assessed using information in the cumulative patient profile (CPP), prescriptions and physician billing codes. RESULTS: An algorithm identifying MS in the CPP performed well with 91.5% sensitivity, 100% specificity, 98.7% PPV and 100% NPV. The addition of prescriptions for MS-specific medications and physician billing code 340 used four times within any 12-month timeframe slightly improved the sensitivity to 92.3% with a PPV of 97.9%. CONCLUSIONS: Data within an EMR can be used to accurately identify patients with MS. This study has positive implications for clinicians, researchers and policy makers as it provides the potential to identify cohorts of MS patients in the primary care setting to examine quality of care. PMID- 24948684 TI - The aetiology of acute neurological decline in multiple sclerosis: experience from an open-access clinic. AB - BACKGROUND: Multiple sclerosis (MS) relapses contribute to disability and influence treatment decisions. Many centres now provide open access to specialist services for patients with new symptoms. However, there is scarce literature on the spectrum of presentations encountered in this setting. OBJECTIVE: The objective of this paper is to characterise presentations to an open, rapid-access MS relapse clinic and the impact on disease management. METHODS: A retrospective review of outpatient episodes over a three-year period was conducted. Demographic and service data, symptoms, disability, diagnosis and management were recorded according to a standardised proforma. RESULTS: A total of 371 attendances were analysed. A new MS relapse was diagnosed in 216 (58%) episodes, of which 56 (26%) patients had an additional diagnosis which had also contributed to their presentation. Of 266 reports of non-relapse-related symptoms, 73 were unrelated to MS. Treatment interventions were made in almost all relapsing patients and in 70% of patients presenting with acute, non-relapse-related symptoms of MS. Changes to disease-modifying therapies were considered in 28% of consultations. CONCLUSION: Diagnosing MS relapses is crucial for disease management and yet remains challenging. Clinicians should be aware of differential diagnoses and confounding factors. The high incidence of therapeutic interventions observed suggests that rapid-access clinics represent an effective platform for responsive disease management. PMID- 24948685 TI - Wasted tongue in neuromyelitis optica spectrum disorders due to hypoglossal nerve involvement. AB - We report two cases of neuromyelitis optica spectrum disorder with hypoglossal nerve involvement resulting in a wasted tongue associated with other brainstem symptoms of hypogeusia, hypersalivation, hiccough, increased sweating, hyperemesis and myelitis (in the second patient). This occurred due to involvement of the hypoglossal, tractus solitarius and dorsal vagal nuclei. Though the myelitis and other brainstem signs recovered the hypoglossal nerve involvement resulting in a unilateral wasted tongue did not. It is important to consider neuromyelitis optica and its spectrum disorders in the differential diagnosis of a wasted tongue though its occurrence is rare. PMID- 24948686 TI - An epidemiological study of neuromyelitis optica in Isfahan. PMID- 24948687 TI - Falls in people with MS--an individual data meta-analysis from studies from Australia, Sweden, United Kingdom and the United States. AB - BACKGROUND: Falls are common in people with multiple sclerosis (PwMS). Previous studies have generally included small samples and had varied methods. OBJECTIVES: The objectives of this paper are to compile fall rates across a broad range of ages and disease severity and to definitively assess the extent to which MS associated and demographic factors influence fall rates. METHODS: Individual data from studies in four countries that prospectively measured falls for three months were analyzed. We determined fall rates, prevalence of fallers (>=1 falls) and frequent fallers (>=2 falls), location and timing of falls, and fall-related demographic factors. RESULTS: A total of 537 participants reported 1721 falls: 56% were fallers and 37% frequent fallers. Most falls occurred indoors (65%) between 6 a.m. and 6 p.m. (75%). Primary progressive MS was associated with significantly increased odds of being a faller (odds ratio (OR) 2.02; CI 1.08 3.78). Fall risk peaked at EDSS levels of 4.0 and 6.0 with significant ORs between 5.30 (2.23-12.64) and 5.10 (2.08-12.47). The fall rate was lower in women than men (relative risk (RR) 0.80; CI 0.67-0.94) and decreased with increasing age (RR 0.97 for each year, CI 0.95-0.98). CONCLUSION: PwMS are at high risk of falls and there are important associations between falls and MS-associated disability, gender and age. PMID- 24948688 TI - Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria. AB - BACKGROUND: Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research. OBJECTIVE: An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials. METHODS: A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place. RESULTS: The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed. CONCLUSION: Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting. PMID- 24948689 TI - Uveitis as a prognostic factor in multiple sclerosis. AB - Uveitis is occasionally encountered in multiple sclerosis (MS) patients. The objective of this report is to investigate whether uveitis has a prognostic impact on the clinical course of MS. Several clinical and demographic features were compared between 41 MS patients with uveitis and 100 randomly selected MS patients without uveitis. While there were no significant differences by means of gender, age of MS onset, oligoclonal band positivity and disease duration, EDSS and progression index (PI) scores of MS patients with uveitis were significantly lower than those without uveitis (p = 0.004 and <0.001, respectively). Our results suggest that uveitis might be used as a good prognostic factor. PMID- 24948690 TI - Effects of natalizumab on oligoclonal bands in the cerebrospinal fluid of multiple sclerosis patients: a longitudinal study. AB - Retrospective studies show that natalizumab modifies oligoclonal immunoglobulin (IgG) bands (OCBs) in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. In this study, we prospectively analyzed both serum and CSF samples from 24 MS patients, before and after 2 years of natalizumab-based therapy. Our results showed complete (55%) or partial (27%) disappearance of the OCBs in CSF samples that were taken after 2 years of therapy. Intrathecal IgG production, represented by the IgG index and IgGLoc, was also quantitatively reduced. Our data showed that natalizumab substantially modulates both intrathecal polyclonal and oligoclonal IgG production: This effect was much more potent than was previously reported. PMID- 24948692 TI - Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous T cell lymphomas (CTCL) (Mycosis fungoides and Sezary syndrome). AB - BACKGROUND: Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients. RESULTS: All 144 patients had performance status 0-2. The median duration of CTCL from diagnosis was 53 months (5-516 months). The median number of pretreatments was 4 (range: 3 15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure. CONCLUSION: Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses. PMID- 24948694 TI - The management of atrial fibrillation: summary of updated NICE guidance. PMID- 24948693 TI - Whole-genome scans provide evidence of adaptive evolution in Malawian Plasmodium falciparum isolates. AB - BACKGROUND: Selection by host immunity and antimalarial drugs has driven extensive adaptive evolution in Plasmodium falciparum and continues to produce ever-changing landscapes of genetic variation. METHODS: We performed whole-genome sequencing of 69 P. falciparum isolates from Malawi and used population genetics approaches to investigate genetic diversity and population structure and identify loci under selection. RESULTS: High genetic diversity (pi = 2.4 * 10(-4)), moderately high multiplicity of infection (2.7), and low linkage disequilibrium (500-bp) were observed in Chikhwawa District, Malawi, an area of high malaria transmission. Allele frequency-based tests provided evidence of recent population growth in Malawi and detected potential targets of host immunity and candidate vaccine antigens. Comparison of the sequence variation between isolates from Malawi and those from 5 geographically dispersed countries (Kenya, Burkina Faso, Mali, Cambodia, and Thailand) detected population genetic differences between Africa and Asia, within Southeast Asia, and within Africa. Haplotype-based tests of selection to sequence data from all 6 populations identified signals of directional selection at known drug-resistance loci, including pfcrt, pfdhps, pfmdr1, and pfgch1. CONCLUSIONS: The sequence variations observed at drug resistance loci reflect differences in each country's historical use of antimalarial drugs and may be useful in formulating local malaria treatment guidelines. PMID- 24948696 TI - Rapid diagnostic tests for malaria. PMID- 24948695 TI - Rapid diagnostic tests to improve treatment of malaria and other febrile illnesses: patient randomised effectiveness trial in primary care clinics in Afghanistan. AB - OBJECTIVE: To assess the impact of rapid diagnostic tests on the diagnostic accuracy and treatment of malaria and non-severe fever in an Asian setting. DESIGN: Patient randomised trial in primary level clinics. SETTING: Two areas of Afghanistan where Plasmodium vivax and Plasmodium falciparum are endemic; one area with moderate transmission (eastern region) and one with low transmission (northern region). PARTICIPANTS: 5794 patients of all ages with suspected malaria enrolled by 80 clinicians in 22 clinics. INTERVENTIONS: Malaria rapid diagnostic tests were compared with clinical diagnosis where no parasite diagnostic test was available, longer established field microscopy, and recently introduced microscopy. MAIN OUTCOME MEASURES: Proportion of patients appropriately treated with an antimalarial, defined as patients with P vivax who received chloroquine, patients with P falciparum who received artemisinin based combination therapy, and patients with no malaria parasites who did not receive an antimalarial. Secondary outcomes included diagnostic test accuracy and the proportion of patients negative for malaria who received antibiotics and antimalarials. RESULTS: In the low transmission area, comparing rapid diagnostic tests with clinical diagnosis, 65% (212/325) versus 12% (40/321) of febrile patients were appropriately treated for malaria (adjusted odds ratio 92.7, 95% confidence interval 12.4 to 694.1, P<0.001). The proportion of patients who were negative for malaria and received an antibiotic was 57% (185/325) in the rapid diagnostic test arm compared with 14% (46/321) in the clinical diagnosis arm (16.9, 3.8 to 75.4, P<0.001). In the comparison of rapid diagnostic test with microscopy in the moderate transmission area, 83.6% (1696/2028) versus 76.3% (1512/1983) of patients were appropriately treated for malaria (1.70, 1.30 to 2.23, P<0.001). A higher proportion of P falciparum cases received appropriate treatment with artemisinin based combination therapy when malaria was diagnosed by rapid diagnostic test (82%, 58/71 v 32%, 24/76; 9.2, 3.88 to 21.66, P<0.001). CONCLUSIONS: In South and central Asian regions of low to moderate malaria transmission where clinics lack capacity for diagnosis with rapid diagnostic tests or microscopy, the introduction of the tests should be considered to improve clinical care, reduce the overuse of antimalarials, and improve disease surveillance. PMID- 24948697 TI - Legionnaires' disease in UK baby triggers warning over some home birth pools. PMID- 24948698 TI - Patients should have one point of contact for complaints, MPs are told. PMID- 24948699 TI - A Japanese region-wide survey of the knowledge, difficulties and self-reported palliative care practices among nurses. AB - OBJECTIVE: We investigated palliative care knowledge, difficulty and self reported practice among a region-wide sample of nurses who cared for cancer patients in Japan. METHODS: A cross-sectional questionnaire survey was distributed to 9 designated cancer centers, 17 community hospitals and 73 district nurse services across 4 regions in 2008. We used the Palliative Care Knowledge Test, the Palliative Care Difficulty Scale (five-point Likert scale) and the Palliative Care Self-Reported Practices Scale (five-point Likert scale). RESULTS: In total, 2378 out of 3008 nurses (79%) responded. The knowledge, difficulty and self-reported practice scores were 51 +/- 20%, 3.2 +/- 0.7 and 3.7 +/- 0.6, respectively. In the knowledge test, philosophy scored highest (88 +/- 26%) and psychiatric problems scored lowest (37 +/- 29%). In the difficulty test, alleviating symptoms scored most difficult (3.5 +/- 0.8) and providing expert support scored least difficult (2.9 +/- 1.3). In the self-reported practice questionnaire, pain and delirium relief were most frequently (4.0 +/- 0.8) and least frequently (3.1 +/- 0.9) provided, respectively. Knowledge was significantly poorer in community hospitals (P = 0.035); difficulty scores were significantly higher in community hospitals (P < 0.001) and district nurse services (P = 0.013); and self-reported practice scores were significantly poorer in community hospitals (P < 0.001) but superior in district nurse services (P < 0.001) than in designated cancer centers. CONCLUSIONS: Knowledge, difficulty and self-reported practice for symptom management, particularly psychological symptoms, were insufficient, particularly in community hospitals. Education, expert support and adequate clinical experiences would help provide quality palliative care. PMID- 24948700 TI - US drug regulator proposes social media guidelines for drug and medical device industry. PMID- 24948701 TI - Dexamethasone potentiates myeloid-derived suppressor cell function in prolonging allograft survival through nitric oxide. AB - Whereas GCs have been demonstrated to be beneficial for transplantation patients, the pharmacological mechanisms remain unknown. Herein, the role of GR signaling was investigated via a pharmacological approach in a murine allogeneic skin transplantation model. The GC Dex, a representative GC, significantly relieved allograft rejection. In Dex-treated allograft recipient mice, CD11b(+)Gr1(+) MDSCs prolonged graft survival and acted as functional suppressive immune modulators that resulted in fewer IFN-gamma-producing Th1 cells and a greater number of IL-4-producing Th2 cells. In agreement, Dex-treated MDSCs promoted reciprocal differentiation between Th1 and Th2 in vivo. Importantly, the GR is required in the Dex-induced MDSC effects. The blocking of GR with RU486 significantly diminished the expression of CXCR2 and the recruitment of CD11b(+)Gr1(+) MDSCs, thereby recovering the increased MDSC-suppressive activity induced by Dex. Mechanistically, Dex treatment induced MDSC iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated the MDSC suppressive function and the effects on T cell differentiation. This study shows MDSCs to be an essential component in the prolongation of allograft survival following Dex or RU486 treatment, validating the GC-GR-NO signaling axis as a potential therapeutic target in transplantation. PMID- 24948702 TI - Systemic antifungal treatment after posaconazole prophylaxis: results from the SEIFEM 2010-C survey. AB - OBJECTIVES: To investigate the incidence, treatment and outcome of breakthrough invasive fungal infections (IFIs) in adult acute myeloid leukaemia (AML) patients after posaconazole prophylaxis. METHODS: From January 2010 to April 2012, all consecutive patients with newly diagnosed AML were prospectively registered at 33 participating Italian centres. All cases of IFIs occurring within 30 days after the end of the first induction chemotherapy were recorded. The strategy of antifungal treatment (empirical, pre-emptive or targeted) and the drugs used were analysed. ClinicalTrials.gov code: NCT01315925. RESULTS: In total, 1192 patients with newly diagnosed AML were enrolled in the study, of whom 510 received posaconazole prophylaxis and were included in the present analysis. Of these patients, 140 (27%) needed systemic antifungal treatment. Among the 127 evaluable cases, an empirical approach was utilized in 102 patients (80%), a pre-emptive approach in 19 patients (15%) and targeted therapy in 6 patients (5%). Only five patients died of IFIs (three in the empirical group and two in the targeted group; 4%). A critical review of IFI diagnoses at 30 days demonstrated that among the patients treated empirically, ~30% were not affected by IFIs but rather only by fever of unidentified origin. A comparison between the empirical and the pre emptive groups showed no significant differences regarding the attributable and overall mortalities. CONCLUSIONS: This study confirms that posaconazole prophylaxis reduces the incidence of breakthrough IFIs and does not modify the efficacy of subsequent systemic antifungal treatment, regardless of the approach (empirical or pre-emptive) or the antifungal drug used. PMID- 24948703 TI - A single 2 g oral dose of extended-release azithromycin for treatment of gonococcal urethritis. AB - OBJECTIVES: We treated gonococcal urethritis in men with a single 2 g dose of azithromycin extended-release formulation (azithromycin-SR) to determine its microbiological outcomes and tolerability. PATIENTS AND METHODS: We enrolled 189 Japanese men with gonococcal urethritis between April 2009 and December 2013. The patients were given a single 2 g dose of azithromycin-SR. Microbiological efficacy was evaluated by the results of the post-treatment molecular testing of Neisseria gonorrhoeae. MIC testing was performed only for pretreatment isolates of N. gonorrhoeae collected from the patients. RESULTS: We evaluated 130 patients for microbiological outcomes. Of these patients, 122 (93.8%) were judged to be microbiologically cured on the basis of negative test results. All isolates for which the azithromycin MICs were <=0.25 mg/L were eradicated, whereas 5 of 12 isolates for which the MICs were 1 mg/L persisted after the treatment. Forty-six adverse events occurred in 41 patients. However, all adverse events were classified as mild. CONCLUSIONS: The eradication rate of N. gonorrhoeae was 93.8% in men with gonococcal urethritis treated with a single 2 g dose of azithromycin SR. The breakpoint MIC of a 2 g dose of azithromycin-SR for gonococcal urethritis associated with clinical treatment failures appeared to be 1 mg/L. With regard to side effects of higher doses of azithromycin, the 2 g dose of azithromycin-SR appeared to improve tolerability. However, the widespread use of a high-dose regimen of azithromycin might lead to the development of further resistance to azithromycin. PMID- 24948705 TI - Virological outcome at week 48 of three recommended first-line regimens using ultrasensitive viral load and plasma drug assay. AB - OBJECTIVES: To describe the virological and pharmacological outcomes of three different recommended once-daily first-line regimens in a cross-sectional analysis within an observational cohort using ultra-sensitive HIV quantification. PATIENTS AND METHODS: We enrolled all HIV-1-infected patients who initiated tenofovir/emtricitabine with efavirenz, darunavir/ritonavir or atazanavir/ritonavir as a first-line regimen between 1 November 2010 and 30 June 2012. An ultrasensitive viral load (VL) assay was performed and plasma drug concentrations at 24 h (C24) were determined at Week (W) 4, W12, W24, W36 and W48. RESULTS: Sixty patients initiated efavirenz, 81 darunavir/ritonavir and 27 atazanavir/ritonavir. A higher proportion of patients with a VL >100 000 copies/mL received darunavir/ritonavir (P = 0.022). At W48, 89%, 85% and 88% of the patients had a VL <50 copies/mL, 69%, 73% and 79% had a VL <20 copies/mL and 45%, 48% and 54% had a VL <1 copy/mL using the ultrasensitive assay in the efavirenz, darunavir/ritonavir and atazanavir/ritonavir groups, respectively. Patients with a detectable VL signal at W48 had a higher baseline VL than those with no detectable VL signal (P = 0.0001). A total of 92%, 93% and 91% of the efavirenz, darunavir and atazanavir C24 values were above the respective effective cut-offs. CONCLUSIONS: In this observational cohort, the choice of the regimen was related to the physicians' preferences and the patients' characteristics. The proportion of patients reaching VL <1 copy/mL at W48 was similar in the three regimens and was not associated with drug concentrations. PMID- 24948704 TI - A novel benzonitrile analogue inhibits rhinovirus replication. AB - OBJECTIVES: To study the characteristics and the mode of action of the anti rhinovirus compound 4-[1-hydroxy-2-(4,5-dimethoxy-2 nitrophenyl)ethyl]benzonitrile (LPCRW_0005). METHODS: The antiviral activity of LPCRW_0005 was evaluated in a cytopathic effect reduction assay against a panel of human rhinovirus (HRV) strains. To unravel its precise molecular mechanism of action, a time-of-drug-addition study, resistance selection and thermostability assays were performed. The crystal structure of the HRV14/LPCRW_0005 complex was elucidated as well. RESULTS: LPCRW_0005 proved to be a selective inhibitor of the replication of HRV14 (EC(50) of 2 +/- 1 MUM). Time-of-drug-addition studies revealed that LPCRW_0005 interferes with the earliest stages of virus replication. Phenotypic drug-resistant virus variants were obtained (>=30-fold decrease in susceptibility to the inhibitory effect of LPCRW_0005), which carried either an A150T or A150V amino acid substitution in the VP1 capsid protein. The link between the mutant genotype and drug-resistant phenotype was confirmed by reverse genetics. Cross-resistance studies and thermostability assays revealed that LPCRW_0005 has a similar mechanism of action to the capsid binder pleconaril. Elucidation of the crystal structure of the HRV14/LPCRW_0005 complex revealed the existence of multiple hydrophobic and polar interactions between the VP1 pocket and LPCRW_0005. CONCLUSIONS: LPCRW_0005 is a novel inhibitor of HRV14 replication that acts as a capsid binder. The compound has a chemical structure that is markedly smaller than that of other capsid binders. Structural studies show that LPCRW_0005, in contrast to pleconaril, leaves the toe end of the pocket in VP1 empty. This suggests that extended analogues of LPCRW_0005 that fill the full cavity could be more potent inhibitors of rhinovirus replication. PMID- 24948706 TI - Early selection of resistance-associated mutations in HIV-1 RT C-terminal domains across different subtypes: role of the genetic barrier to resistance. AB - OBJECTIVES: Interpretation of drug resistance mutation (DRM) has been based solely on HIV-1 subtype B. Reverse transcriptase (RT) C-terminal domains have been disregarded in resistance interpretation, as their clinical relevance is still controversial. We determined the emergence of DRM in RT C-terminal domains of different HIV-1 subtypes, the genetic barrier for the acquisition of these DRM and their temporal appearance with 'classical' RT inhibitor (RTI) mutations. METHODS: HIV-1 RT sequences were obtained from information from 6087 treatment naive and 3795 RTI-treated patients deposited in the Stanford HIV Resistance Database, including all major subtypes. DRM emergence was evaluated for subtype B, and was correlated with the number of DRM in the polymerase domain. Genetic barrier was calculated for each DRM studied and in each subtype. RESULTS: N348I, T369I and A360V were found at low prevalence in treatment-naive isolates of all subtypes. A371V was common to treatment-naive isolates. N348I was observed in all subtypes, while T369I was only selected in subtype C. A360V and T369V were selected by RTI treatment in several subtypes. A371V was selected in subtypes B and C, but is a signature in subtype A. RT C-terminal mutations were correlated with early drug resistance in subtype B. All subtypes have a low calculated genetic barrier towards C-terminal DRM acquisition, despite a few disparities having been observed. CONCLUSIONS: C-terminal mutations were selected in all HIV 1 subtypes, while some represent subtype-specific signatures. The selection of C terminal DRMs occurs early in RTI resistance failure in subtype B. PMID- 24948707 TI - S-nitrosoglutathione (GSNO) is cytotoxic to intracellular amastigotes and promotes healing of topically treated Leishmania major or Leishmania braziliensis skin lesions-authors' response. PMID- 24948708 TI - Systematical investigation on characteristics of a photocatalyst: tantalum oxynitrides. AB - Tantalum oxynitrides with various nitrogen contents were synthesized from Ta2O5 powder by nitridation under a flow of ammonia at 1123 K for various durations. X ray powder diffraction, transmission electron microscopy, Ultraviolet-visible spectroscopy, energy-dispersive spectroscopy, elemental analysis and photocatalytic reaction were performed to investigate these samples. Selected area electron diffraction analysis of the mixed crystalline phases of powder samples revealed that each particle had only one crystalline phase. This indicates that entire particles underwent a rapid structural transformation once their nitrogen content reached a critical value. We discovered a new intermediate crystalline phase of tantalum oxynitride, TaO(a > 1)N(b <1), appeared before the generation of the beta-TaON phase. The crystal structure of TaO(a > 1)N(b <1) is suggested to be monoclinic, with unit cell parameters of a = 5.1 A, b = 35.6 A, c = 5.4 A and beta = 93.5 degrees . The ratio of nitrogen to oxygen in the samples increased with increasing nitridation duration. The increasing rate is different in the different nitridation stage due to the different structure of the samples. Nitrogen entered the samples quickly during the initial 5 h of nitridation, and a monoclinic beta-TaON phase was formed. A mesoporous structure emerged in the nitrided particles during the phase transition, greatly increasing the surface area of the samples. The more the nitrogen entered one sample, the darker the color of it due to the narrower the band gap. H2 and O2 evolved by water splitting from the nitrided samples irradiated with visible light. Change in the evolution rate of H2 and O2 had a relation with the structure of the samples. PMID- 24948710 TI - Warming U.S.-Russia relations. PMID- 24948709 TI - Time to smoke first morning cigarette and lung cancer in a case-control study. AB - BACKGROUND: Targeting smokers at higher lung cancer risk can improve efficiency and reduce false-positive detection in lung cancer screening. We evaluated whether time to first cigarette after waking (TTFC), a single-item measure of nicotine dependency, could improve stratification of lung cancer risk beyond standard smoking metrics (intensity, duration, and pack-years). METHODS: In 3249 ever-smokers (n = 1812 case subjects; n = 1437 control subjects) from a population-based case-control study in Italy, we examined the association between TTFC and lung cancer using logistic regression and estimated lung cancer incidence by levels of TTFC, and intensity, duration, and pack-years using absolute risk regression. Significance tests were two-sided. RESULTS: Compared with smokers with TTFC greater than 60 minutes, the lung cancer odds ratios for TTFC of 31 to 60 minutes, 6 to 30 minutes, and 5 or fewer minutes (by increasing dependency) were 2.57 (95% confidence interval [CI] = 2.03 to 3.26), 2.27 (95% CI = 1.79 to 2.88), and 3.50 (95% CI = 2.64 to 4.64), respectively (P trend < .0001). The average lung cancer incidence rates for smokers of 1 to 10, 11 to 20, 21 to 30 and more than 30 cigarettes per day were consistently higher among smokers with TTFC of 60 or fewer minutes vs more than 60 minutes (64.1 vs 11.7; 125.6 vs 28.6; 130.1 vs 40.7; and 260.8 vs 108.9 per 100000 person-years, respectively). The slopes of increase in lung cancer rates with smoking duration and pack-years were statistically significantly greater among smokers with higher dependency (P interaction < .001). CONCLUSIONS: Lung cancer risk increases with shorter TTFC; this simple nicotine dependency measure increases lung cancer risk stratification beyond standard smoking measures. Assessing TTFC may improve lung cancer risk prediction and could be useful in lung cancer screening and smoking cessation programs. PMID- 24948713 TI - Funding. Just one proposal per year, please, NSF tells astronomers. PMID- 24948712 TI - Public health. NIH puts massive U.S. children's study on hold. PMID- 24948715 TI - Computer science. Quantum or not, controversial computer yields no speedup. PMID- 24948714 TI - Patient advocacy. 'Right to Try' laws bypass FDA for last-ditch treatments. PMID- 24948716 TI - History of science. Was America 'discovered' in medieval Central Asia? PMID- 24948717 TI - Scientific publishing. Secret bundles of profit. PMID- 24948718 TI - When the bat sings. PMID- 24948719 TI - Anthropology. How to build a Neandertal. PMID- 24948720 TI - Chemistry. Connecting the dots. PMID- 24948721 TI - Cell biology. A cell death avenue evolved from a life-saving path. PMID- 24948722 TI - Immunology. Teaching the immune system "self" respect and tolerance. PMID- 24948723 TI - Physics. Electronically erased. PMID- 24948724 TI - Genetics. How carrion and hooded crows defeat Linnaeus's curse. PMID- 24948726 TI - Biology's drones: undermined by fear. PMID- 24948727 TI - Biology's drones: new and improved. PMID- 24948728 TI - Investigative bioethics. PMID- 24948729 TI - Deep-sea protection: coordinate efforts. PMID- 24948731 TI - An electronic quantum eraser. AB - The quantum eraser is a device that illustrates the quantum principle of complementarity and shows how a dephased system can regain its lost quantum behavior by erasing the "which-path" information already obtained about it. Thus far, quantum erasers were constructed predominantly in optical systems. Here, we present a realization of a quantum eraser in a mesoscopic electronic device. The use of interacting electrons, instead of noninteracting photons, allows control over the extracted information and a smooth variation of the degree of quantum erasure. The demonstrated system can serve as a first step toward a variety of more complex setups. PMID- 24948725 TI - Research capacity. Enabling the genomic revolution in Africa. PMID- 24948730 TI - Neandertal roots: Cranial and chronological evidence from Sima de los Huesos. AB - Seventeen Middle Pleistocene crania from the Sima de los Huesos site (Atapuerca, Spain) are analyzed, including seven new specimens. This sample makes it possible to thoroughly characterize a Middle Pleistocene hominin paleodeme and to address hypotheses about the origin and evolution of the Neandertals. Using a variety of techniques, the hominin-bearing layer could be reassigned to a period around 430,000 years ago. The sample shows a consistent morphological pattern with derived Neandertal features present in the face and anterior vault, many of which are related to the masticatory apparatus. This suggests that facial modification was the first step in the evolution of the Neandertal lineage, pointing to a mosaic pattern of evolution, with different anatomical and functional modules evolving at different rates. PMID- 24948732 TI - Nanoscale imaging and control of domain-wall hopping with a nitrogen-vacancy center microscope. AB - The control of domain walls in magnetic wires underpins an emerging class of spintronic devices. Propagation of these walls in imperfect media requires defects that pin them to be characterized on the nanoscale. Using a magnetic microscope based on a single nitrogen-vacancy (NV) center in diamond, we report domain-wall imaging on a 1-nanometer-thick ferromagnetic nanowire and directly observe Barkhausen jumps between two pinning sites spaced 50 nanometers apart. We further demonstrate in situ laser control of these jumps, which allows us to drag the domain wall along the wire and map the pinning landscape. Our work demonstrates the potential of NV microscopy to study magnetic nano-objects in complex media, whereas controlling domain walls with laser light may find an application in spintronic devices. PMID- 24948733 TI - Ultralight, ultrastiff mechanical metamaterials. AB - The mechanical properties of ordinary materials degrade substantially with reduced density because their structural elements bend under applied load. We report a class of microarchitected materials that maintain a nearly constant stiffness per unit mass density, even at ultralow density. This performance derives from a network of nearly isotropic microscale unit cells with high structural connectivity and nanoscale features, whose structural members are designed to carry loads in tension or compression. Production of these microlattices, with polymers, metals, or ceramics as constituent materials, is made possible by projection microstereolithography (an additive micromanufacturing technique) combined with nanoscale coating and postprocessing. We found that these materials exhibit ultrastiff properties across more than three orders of magnitude in density, regardless of the constituent material. PMID- 24948734 TI - Long-range orientation and atomic attachment of nanocrystals in 2D honeycomb superlattices. AB - Oriented attachment of synthetic semiconductor nanocrystals is emerging as a route for obtaining new semiconductors that can have Dirac-type electronic bands such as graphene, but also strong spin-orbit coupling. The two-dimensional (2D) assembly geometry will require both atomic coherence and long-range periodicity of the superlattices. We show how the interfacial self-assembly and oriented attachment of nanocrystals results in 2D metal chalcogenide semiconductors with a honeycomb superlattice. We present an extensive atomic and nanoscale characterization of these systems using direct imaging and wave scattering methods. The honeycomb superlattices are atomically coherent and have an octahedral symmetry that is buckled; the nanocrystals occupy two parallel planes. Considerable necking and large-scale atomic motion occurred during the attachment process. PMID- 24948735 TI - Controlling low rates of cell differentiation through noise and ultrahigh feedback. AB - Mammalian tissue size is maintained by slow replacement of de-differentiating and dying cells. For adipocytes, key regulators of glucose and lipid metabolism, the renewal rate is only 10% per year. We used computational modeling, quantitative mass spectrometry, and single-cell microscopy to show that cell-to-cell variability, or noise, in protein abundance acts within a network of more than six positive feedbacks to permit pre-adipocytes to differentiate at very low rates. This reconciles two fundamental opposing requirements: High cell-to-cell signal variability is needed to generate very low differentiation rates, whereas low signal variability is needed to prevent differentiated cells from de differentiating. Higher eukaryotes can thus control low rates of near irreversible cell fate decisions through a balancing act between noise and ultrahigh feedback connectivity. PMID- 24948736 TI - HIV-1-induced AIDS in monkeys. AB - Primate lentiviruses exhibit narrow host tropism, reducing the occurrence of zoonoses but also impairing the development of optimal animal models of AIDS. To delineate the factors limiting cross-species HIV-1 transmission, we passaged a modified HIV-1 in pigtailed macaques that were transiently depleted of CD8(+) cells during acute infection. During adaptation over four passages in macaques, HIV-1 acquired the ability to antagonize the macaque restriction factor tetherin, replicated at progressively higher levels, and ultimately caused marked CD4(+) T cell depletion and AIDS-defining conditions. Transient treatment with an antibody to CD8 during acute HIV-1 infection caused rapid progression to AIDS, whereas untreated animals exhibited an elite controller phenotype. Thus, an adapted HIV-1 can cause AIDS in macaques, and stark differences in outcome can be determined by immunological perturbations during early infection. PMID- 24948738 TI - The genomic landscape underlying phenotypic integrity in the face of gene flow in crows. AB - The importance, extent, and mode of interspecific gene flow for the evolution of species has long been debated. Characterization of genomic differentiation in a classic example of hybridization between all-black carrion crows and gray-coated hooded crows identified genome-wide introgression extending far beyond the morphological hybrid zone. Gene expression divergence was concentrated in pigmentation genes expressed in gray versus black feather follicles. Only a small number of narrow genomic islands exhibited resistance to gene flow. One prominent genomic region (<2 megabases) harbored 81 of all 82 fixed differences (of 8.4 million single-nucleotide polymorphisms in total) linking genes involved in pigmentation and in visual perception-a genomic signal reflecting color-mediated prezygotic isolation. Thus, localized genomic selection can cause marked heterogeneity in introgression landscapes while maintaining phenotypic divergence. PMID- 24948739 TI - What it takes. PMID- 24948737 TI - Molecular basis for disruption of E-cadherin adhesion by botulinum neurotoxin A complex. AB - How botulinum neurotoxins (BoNTs) cross the host intestinal epithelial barrier in foodborne botulism is poorly understood. Here, we present the crystal structure of a clostridial hemagglutinin (HA) complex of serotype BoNT/A bound to the cell adhesion protein E-cadherin at 2.4 angstroms. The HA complex recognizes E cadherin with high specificity involving extensive intermolecular interactions and also binds to carbohydrates on the cell surface. Binding of the HA complex sequesters E-cadherin in the monomeric state, compromising the E-cadherin mediated intercellular barrier and facilitating paracellular absorption of BoNT/A. We reconstituted the complete 14-subunit BoNT/A complex using recombinantly produced components and demonstrated that abolishing either E cadherin- or carbohydrate-binding of the HA complex drastically reduces oral toxicity of BoNT/A complex in vivo. Together, these studies establish the molecular mechanism of how HAs contribute to the oral toxicity of BoNT/A. PMID- 24948740 TI - The cultural evolution of mind reading. AB - It is not just a manner of speaking: "Mind reading," or working out what others are thinking and feeling, is markedly similar to print reading. Both of these distinctly human skills recover meaning from signs, depend on dedicated cortical areas, are subject to genetically heritable disorders, show cultural variation around a universal core, and regulate how people behave. But when it comes to development, the evidence is conflicting. Some studies show that, like learning to read print, learning to read minds is a long, hard process that depends on tuition. Others indicate that even very young, nonliterate infants are already capable of mind reading. Here, we propose a resolution to this conflict. We suggest that infants are equipped with neurocognitive mechanisms that yield accurate expectations about behavior ("automatic" or "implicit" mind reading), whereas "explicit" mind reading, like literacy, is a culturally inherited skill; it is passed from one generation to the next by verbal instruction. PMID- 24948742 TI - Uterine cervical cancer displaying tumor-related leukocytosis: a distinct clinical entity with radioresistant feature. AB - BACKGROUND: Tumor-related leukocytosis (TRL) is occasionally found in patients with nonhematopoietic malignancies. We investigated the clinical implication of TRL and individualized treatment for TRL-positive cervical cancer, as well as the underlying biological mechanism. METHODS: Clinical data from 258 cervical cancer patients treated with definitive radiotherapy were analyzed to investigate the association between TRL and treatment outcome. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms responsible for TRL in cervical cancer, focusing on the role of tumor derived granulocyte colony-stimulating factor (G-CSF) and myeloid-derived suppressor cells (MDSCs). All statistical tests were two-sided. RESULTS: TRL was statistically significantly associated with younger age (Wilcoxon rank sum test, P = .03), larger tumor size (Wilcoxon rank sum test, P = .006), advanced clinical stage (chi(2) test, P = .01), and shorter overall survival (Cox proportional hazard modeling and Wald tests, P < .001). Among cervical cancer patients, TRL was associated with upregulated tumor G-CSF expression (chi(2) test, P < .001), elevated serum G-CSF levels (Student t test, P = .03), larger spleens (Student t test, P = .045), and increased MDSC frequencies in the blood (Student t test, P < .001) compared with the TRL-negative patients. In vitro and in vivo experiments revealed that tumor-derived G-CSF was involved in the underlying causative mechanism of TRL and MDSCs induced by tumor-derived G-CSF are responsible for the rapidly progressive and radioresistant nature of TRL-positive cervical cancer. The administration of anti-Gr-1 neutralizing antibody or the depletion of MDSCs by splenectomy (n = 6 per group) inhibited tumor growth and enhanced radiosensitivity in TRL-positive cervical cancer xenografts (Wilcoxon rank sum test, P = .008 and P = .02, respectively). CONCLUSIONS: TRL is associated with resistance to radiotherapy among cervical cancer patients, and MDSC-targeting treatments may have therapeutic potential in these patients. PMID- 24948741 TI - DNA double-strand break repair genes and oxidative damage in brain metastasis of breast cancer. AB - BACKGROUND: Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood. METHODS: Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two sided paired t test was performed to identify brain metastasis-specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB 231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group). RESULTS: Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74 fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression. CONCLUSIONS: BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species-mediated genotoxic stress in the metastatic brain. PMID- 24948745 TI - Preventive zinc supplementation for children, and the effect of additional iron: a systematic review and meta-analysis. AB - OBJECTIVE: Zinc deficiency is widespread, and preventive supplementation may have benefits in young children. Effects for children over 5 years of age, and effects when coadministered with other micronutrients are uncertain. These are obstacles to scale-up. This review seeks to determine if preventive supplementation reduces mortality and morbidity for children aged 6 months to 12 years. DESIGN: Systematic review conducted with the Cochrane Developmental, Psychosocial and Learning Problems Group. Two reviewers independently assessed studies. Meta analyses were performed for mortality, illness and side effects. DATA SOURCES: We searched multiple databases, including CENTRAL and MEDLINE in January 2013. Authors were contacted for missing information. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised trials of preventive zinc supplementation. Hospitalised children and children with chronic diseases were excluded. RESULTS: 80 randomised trials with 205 401 participants were included. There was a small but non-significant effect on all-cause mortality (risk ratio (RR) 0.95 (95% CI 0.86 to 1.05)). Supplementation may reduce incidence of all-cause diarrhoea (RR 0.87 (0.85 to 0.89)), but there was evidence of reporting bias. There was no evidence of an effect of incidence or prevalence of respiratory infections or malaria. There was moderate quality evidence of a very small effect on linear growth (standardised mean difference 0.09 (0.06 to 0.13)) and an increase in vomiting (RR 1.29 (1.14 to 1.46)). There was no evidence of an effect on iron status. Comparing zinc with and without iron cosupplementation and direct comparisons of zinc plus iron versus zinc administered alone favoured cointervention for some outcomes and zinc alone for other outcomes. Effects may be larger for children over 1 year of age, but most differences were not significant. CONCLUSIONS: Benefits of preventive zinc supplementation may outweigh any potentially adverse effects in areas where risk of zinc deficiency is high. Further research should determine optimal intervention characteristics and delivery strategies. PMID- 24948743 TI - Claudins and the kidney. AB - Claudins are tight-junction membrane proteins that function as both pores and barriers in the paracellular pathway in epithelial cells. In the kidney, claudins determine the permeability and selectivity of different nephron segments along the renal tubule. In the proximal tubule, claudins have a role in the bulk reabsorption of salt and water. In the thick ascending limb, claudins are important for the reabsorption of calcium and magnesium and are tightly regulated by the calcium-sensing receptor. In the distal nephron, claudins need to form cation barriers and chloride pores to facilitate electrogenic sodium reabsorption and potassium and acid secretion. Aldosterone and the with-no-lysine (WNK) proteins likely regulate claudins to fine-tune distal nephron salt transport. Genetic mutations in claudin-16 and -19 cause familial hypomagnesemic hypercalciuria with nephrocalcinosis, whereas polymorphisms in claudin-14 are associated with kidney stone risk. It is likely that additional roles for claudins in the pathogenesis of other types of kidney diseases have yet to be uncovered. PMID- 24948746 TI - Differences in socioeconomic position, lifestyle and health-related pregnancy characteristics between Pakistani and White British women in the Born in Bradford prospective cohort study: the influence of the woman's, her partner's and their parents' place of birth. AB - OBJECTIVE: To examine differences between Pakistani and White British women in relation to socioeconomic position, lifestyle and health-related pregnancy characteristics, and to determine whether these differences vary depending on the woman's, her partner's and both of their parents' place of birth. DESIGN: Prospective cohort study. SETTING: Bradford, UK PARTICIPANTS: 3656 Pakistani and 3503 White British women recruited to the Born in Bradford study. MAIN OUTCOME MEASURES: Socioeconomic position (employment status; level of education; receipt of benefits; housing tenure), lifestyle characteristics (body mass index (BMI) at the start of pregnancy; smoking during pregnancy) and health-related pregnancy characteristics (hypertensive disorders of pregnancy; gestational diabetes; fasting glucose, postload glucose and fasting insulin at ~27 weeks gestation). RESULTS: Fewer Pakistani women were employed (OR 0.17, 95% CI 0.15 to 0.19), the difference being markedly less for UK born women. UK born Pakistani women were more likely, and South Asian born less likely, to be educated post 16 than White British women. Smoking was uncommon among Pakistani women, though the difference comparing UK born Pakistani women to White British women was less than for other groups. BMI was lower among Pakistani compared to White British women (adjusted mean difference -1.12, 95% CI -1.43 to -0.81), the difference being greatest when partners were UK born irrespective of the woman's place of birth. Pakistani women had higher fasting and postload glucose (mean difference 0.20 mmol/L, 95% CI 0.17 to 0.24; 0.37, 95% CI 0.28 to 0.45), higher fasting insulin and were more likely to have gestational diabetes (GDM). CONCLUSIONS: Our results suggest that some socioeconomic, lifestyle and pregnancy characteristics could be beginning to change in response to migration to the UK, with generally beneficial changes, that is, improving education and employment prospects, lower BMI and no evidence that being UK born has further increased the risk of GDM, but some negative, that is, slight increases in smoking. PMID- 24948747 TI - Job burnout among critical care nurses from 14 adult intensive care units in Northeastern China: a cross-sectional survey. AB - OBJECTIVES: The shortage of qualified nurses is one of the critical challenges in the field of healthcare. Among the contributing factors, job burnout has been indicated as a risk factor for the intention to leave. The purpose of this study was to provide a better understanding of the local status and reference data for coping strategies for intensive care unit (ICU)-nurse burnout among Liaoning ICU nurses. DESIGN: Observational study. SETTING: 17 ICUs from 10 tertiary-level hospitals in Liaoning, China. PARTICIPANTS: 431 ICU nurses from 14 ICUs nested in 10 tertiary-level hospitals in Liaoning, China, were invited during October and November 2010. PRIMARY MEASURES: Burnout was measured using the 22-item Chinese version of Maslach Burnout Inventory-Health Service Survey (MBI-HSS) questionnaires. RESULTS: 14 ICUs responded actively and were included; the response rate was 87.7% among the 486 invited participants from these 17 ICUs. The study population was a young population, with the median age 25 years, IQR 23 28 years and female nurses accounted for the major part (88.5%). 68 nurses (16%) were found to have a high degree of burnout, earning high emotional exhaustion and depersonalisation scores together with a low personal accomplishment score. CONCLUSIONS: The present study indicated a moderate distribution of burnout among ICU nurses in Liaoning, China. An investigation into the burnout levels of this population could bring more attention to ICU caregivers. PMID- 24948748 TI - Epidemiology of injuries in hurling: a prospective study 2007-2011. AB - OBJECTIVES: Hurling is a stick handling game which, although native to Ireland, has international reach and presence. The aim of this study was to report incidence and type of injuries incurred by elite male hurling players over five consecutive playing seasons. DESIGN: Prospective cohort study. SETTING: Male intercounty elite sports teams participating in the National GAA Injury Database, 2007-2011. PARTICIPANTS: A total of 856 players in 25 county teams were enrolled. PRIMARY AND SECONDARY OUTCOMES: Incidence, nature and mechanism of injury were recorded by team physicians or physiotherapists to a secure online data collection portal. Time-loss injury rates per 1000 training and match play hours were calculated and injury proportions were expressed. RESULTS: In total 1030 injuries were registered, giving a rate of 1.2 injuries per player. These were sustained by 71% (n=608) of players. Injury incidence rate was 2.99 (95% CI 2.68 to 3.30) per 1000 training hours and 61.75 (56.75 to 66.75) per 1000 match hours. Direct player-to-player contact was recorded in 38.6% injuries, with sprinting (24.5%) and landing (13.7%) the next most commonly reported injury mechanisms. Median duration of time absent from training or games, where the player was able to return in the same season, was 12 days (range 2-127 days). The majority (68.3%) of injuries occurred in the lower limbs, with 18.6% in the upper limbs. The trunk and head/neck regions accounted for 8.6% and 4.1% injuries, respectively. The distribution of injury type was significantly different (p<0.001) between upper and lower extremities: fractures (upper 36.1%, lower 1.5%), muscle strain (upper 5.2%, lower 45.8%). CONCLUSIONS: These data provide stable, multiannual data on injury patterns in hurling, identifying the most common injury problems. This is the first step in applying a systematic, theory driven injury prevention model in the sport. PMID- 24948750 TI - Are statin trials in diabetes representative of real-world diabetes care: a population-based study on statin initiators in Finland. AB - OBJECTIVE: To assess the representativeness of the Heart Protection Study (HPS) and the Collaborative Atorvastatin Diabetes Study (CARDS) for incident statin users. DESIGN: A population-based analysis with linked register data. SETTING: Finland. POPULATION: 56 963 patients with diabetes initiating statin use from 2005 to 2008. MAIN OUTCOME MEASURES: We determined the proportions of real-world patients who fulfilled the eligibility criteria for HPS and CARDS trials and assessed the cardiovascular disease (CVD) event rates, assumed to reflect the background CVD risk, for those eligible and ineligible. We used descriptive statistics to identify the patient characteristics, lipid-lowering interventions and adherence to statin therapy. RESULTS: Of the real-world patients, 57% (N=32 582) fulfilled the eligibility criteria for HPS (DM) and 49% (N=20 499) of those without CVD for CARDS. The patients ineligible for HPS (DM) had a higher cumulative risk for CVD events than those eligible, whereas regarding CARDS the cumulative risks were of similar magnitude. The overall CVD event rates seemed to be comparable to those in the reviewed trials. Both trials were under representative of women and users of antihypertensive agents and metformin. 27% and 29% of real-world patients had an initial statin dose corresponding to <20 mg of simvastatin. The proportions of patients who were deemed adherent were 57% in the real world and 85% in both trials. CONCLUSIONS: Only half of the real-world patients would have qualified for the HPS (DM) and CARDS, limiting their representativeness for clinical practice. Women and users of antihypertensive agents and metformin were under-represented in both trials. These deviations reflect the changes in diabetes treatment over the years and are not expected to modify the average treatment effects of statins on CVD. Prescribing of lower statin doses in clinical practice than used in the trials and lower adherence may, however, attenuate the benefits in the real world. PMID- 24948751 TI - Drug efficacy in treating stable angina pectoris: a protocol for network meta analysis of randomised controlled trials. AB - INTRODUCTION: There were 11 pairwise meta-analysis on the efficacy of beta blockers (including atenolol, propranolol, bisoprolol, metoprolol and nadolol), calcium channel blockers (including amlodipine, diltiazem, felodipine, nifedipine and verapamil), and nitrates (including isosorbide dinitrate, isosorbide mononitrate and nitroglycerin) in treating stable angina pectoris. No network meta-analytic study has been published to evaluate the efficacies of these antianginal drugs. Current clinical guidelines (eg, National Institute of Health and Care Excellence (NICE) clinical guideline 126) are only based on the findings of limited clinical trials and pairwise meta-analysis. This study aims to fill this gap of research by conducting a Bayesian network meta-analysis to compare all these antianginal drugs. METHODS AND ANALYSES: Randomised controlled trials (RCT) on the drug therapy of stable angina pectoris with multiple outcome measures, selected from symptomatic relief, ECG tests, exercise tests, heart rates and blood pressures, etc, will be included. Overall effect sizes will be represented as mean differences with 95% credible intervals (CrI) for continuous outcome data and as ORs with 95% CrI for dichotomous outcome data. Bayesian network meta-analysis by WinBUGS will be conducted to compare the efficacies of these drugs. Sensitivity analysis on the quality of RCTs and subgroup analysis on the category of included drugs will be performed. ETHICS AND DISSEMINATION: Ethical approval is not required because this study includes no confidential personal data and interventions on the patients. Network meta-analysis is based on the RCT reports of eligible drugs in treating stable angina pectoris. The results of this study will be disseminated by an open access and peer-reviewed publication. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014007113. PMID- 24948753 TI - Genome sequence of abbey lake virus, a novel orthobunyavirus isolated from china. AB - The Orthobunyavirus genus of Bunyaviridae is a divergent group of medically important pathogens. Abbey Lake bunyavirus (Ab-BUNV) was newly isolated and identified in Xinjiang Province, northwestern China. The complete genome of Ab BUNV was sequenced and is reported here, revealing that Ab-BUNV may represent a novel genotype in the genus Orthobunyavirus. PMID- 24948752 TI - Analgesic use, pain and daytime sedation in people with and without dementia in aged care facilities: a cross-sectional, multisite, epidemiological study protocol. AB - INTRODUCTION: People living with dementia may experience and express pain in different ways to people without dementia. People with dementia are typically prescribed fewer analgesics than people without dementia indicating a potential difference in how pain is identified and treated in these populations. The objectives of this study are to (1) investigate the prevalence of analgesic load, pain and daytime sedation in people with and without dementia in Australian residential aged care facilities (RACFs), and (2) investigate the clinical and diagnostic associations between analgesic load, pain and daytime sedation in people with and without dementia in Australian RACFs. METHODS/ANALYSIS: This will be a cross-sectional study of 300 permanent residents of up to 10 low-level and high-level RACFs in South Australia with and without dementia. Trained study nurses will administer validated and dementia-specific assessments of self reported and clinician-observed pain, sedation and other clinical and humanistic outcomes. Medicine-use data will be extracted directly from each resident's medication administration chart. Binary and multinominal logistic regression will be used to compute unadjusted and adjusted ORs and 95% CIs for factors associated with pain, analgesic load and daytime sedation. These factors will include dementia severity, behavioural and psychological symptoms, quality of life, resident satisfaction, attitudes towards medicines, activities of daily living and nutritional status. ETHICS AND DISSEMINATION: Institutional ethics approval has been granted. The findings will be disseminated through public lectures, professional and scientific conferences and in peer-reviewed journal articles. The findings of this study will allow for a better understanding of the prevalence and factors associated with analgesic use, pain and other outcomes in residential care. The findings of this study will be used to inform the development and implementation of strategies to improve the quality of life of people with dementia. PMID- 24948754 TI - Genome Sequences of Nine Bordetella holmesii Strains Isolated in the United States. AB - An increasing number of pertussis-like cases are attributed to the emergent pathogen Bordetella holmesii. The genomes of 9 clinical isolates show that they are clonal, lack the virulence factors encoded by B. pertussis, and are more similar to nonpertussis bordetellae. New markers for B. holmesii can be developed using these sequences. PMID- 24948755 TI - Xiburema Virus, a Hitherto Undescribed Virus within the Family Rhabdoviridae Isolated in the Brazilian Amazon Region. AB - We report here the first complete open reading frame (ORF) genome sequence of Xiburema virus (XIBV), that of strain BE AR362159, isolated from mosquitoes (Sabethes intermedius) in Sena Madureira, Acre state, northern Brazil. All genes showed similarities with those belonging to members of the family Rhabdoviridae. PMID- 24948756 TI - Complete genome sequence of a bovine viral diarrhea virus strain isolated in southern china. AB - We report here the full-length RNA genomic sequence of the bovine viral diarrhea virus (BVDV) strain GX4, isolated from a cow in southern China. Studies indicate that BVDV GX4 belongs to the BVDV-1b subtype. This report will help in understanding the epidemiology and molecular characteristics of BVDV in southern China cattle. PMID- 24948757 TI - Genome Sequence of Arthrobacter siccitolerans 4J27, a Xeroprotectant-Producing Desiccation-Tolerant Microorganism. AB - We report the first genome sequence for Arthrobacter siccitolerans 4J27, a newly described desiccation-tolerant species. The complete genome of A. siccitolerans 4J27 has been sequenced and is estimated to be around 5.3 Mb in size, with an average GC content of 65.13%. We predict 4,480 protein-coding sequences (CDSs). PMID- 24948758 TI - Whole-Genome Sequence of Burkholderia sp. Strain RPE67, a Bacterial Gut Symbiont of the Bean Bug Riptortus pedestris. AB - Burkholderia sp. strain RPE67 is a bacterial symbiont isolated from a field collected bean bug, Riptortus pedestris. To understand the genetic basis of the insect-microbe symbiosis, we performed whole-genome sequencing of the Burkholderia strain, revealing an 8.69-Mb genome consisting of three chromosomes and three plasmids. PMID- 24948759 TI - Genome Sequences of Two Carbapenemase-Resistant Klebsiella pneumoniae ST258 Isolates. AB - Klebsiella pneumoniae, an ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogen, has acquired multiple antibiotic resistance genes and is becoming a serious public health threat. Here, we report the genome sequences of two representative strains of K. pneumoniae from the emerging K. pneumoniae carbapenemase (KPC) outbreak in northeast Ohio belonging to sequence type 258 (ST258) (isolates Kb140 and Kb677, which were isolated from blood and urine, respectively). Both isolates harbor a blaKPC gene, and strain Kb140 carries blaKPC-2, while Kb677 carries blaKPC-3. PMID- 24948760 TI - First full genome sequence of a human enterovirus a120, isolated in madagascar. AB - We report the first complete genome sequence of an enterovirus isolate belonging to the human enterovirus A species of the Picornaviridae family and to type A120 (EV-A120). The EV-A120 isolate MAD-2741-11 was obtained from the stool of a healthy child living on Madagascar Island. The isolate genome was amplified by a reverse transcription-PCR method, and the consensus sequence was determined. PMID- 24948761 TI - Full-Genome Analysis of Influenza A(H7N9) Virus from Shanghai, China, 2014. AB - We analyzed the complete genome sequence of the A/Shanghai/01/2014 (H7N9) strain, which will provide a better understanding of the evolution of influenza A(H7N9) virus. PMID- 24948762 TI - Complete genome sequences of the prototype isolates of genotypes 2, 3, and 4 of murray valley encephalitis virus. AB - Murray Valley encephalitis virus (MVEV) (Flaviviridae family, Flavivirus genus), a mosquito-borne pathogen of humans and horses, is endemic to the Australasian region. We report here the complete genomes of the prototype strains of MVEV genotypes 2, 3, and 4. PMID- 24948763 TI - Draft Genome Sequence of "Candidatus Cronobacter colletis" NCTC 14934T, a New Species in the Genus Cronobacter. AB - Members of the Cronobacter genus are associated with serious infections in neonates. This is the first report of the draft genome sequence for the newly proposed species Cronobacter colletis. PMID- 24948764 TI - Genome Sequence of meso-2,3-Butanediol-Producing Strain Serratia marcescens ATCC 14041. AB - Serratia marcescens strain ATCC 14041 was found to be an efficient meso-2,3 butanediol (meso-2,3-BD) producer from glucose and sucrose. Here we present a 5.0 Mb assembly of its genome. We have annotated 4 coding sequences (CDSs) for meso 2,3-BD fermentation and 2 complete operons including 6 CDSs for sucrose utilization. PMID- 24948765 TI - Complete Genome Sequence of the p-Nitrophenol-Degrading Bacterium Pseudomonas putida DLL-E4. AB - The first complete genome sequence of a p-nitrophenol (PNP)-degrading bacterium is reported here. Pseudomonas putida DLL-E4, a Gram-negative bacterium isolated from methyl-parathion-polluted soil, can utilize PNP as the sole carbon and nitrogen source. P. putida DLL-E4 has a 6,484,062 bp circular chromosome that contains 5,894 genes, with a G+C content of 62.46%. PMID- 24948766 TI - Complete genome sequence of a velogenic newcastle disease virus isolated from an apparently healthy village chicken in South India. AB - We report the complete genome sequence of a Newcastle disease virus (NDV) isolate, NDV-D1/1998, from an apparently healthy village chicken in South India. This class II, genotype II virus is 15,186 nucleotides in length with unique amino acid variations and was found to be a velogenic pathotype by standard pathogenicity tests. PMID- 24948767 TI - Complete genome sequence of a rabies virus isolated from a human in central african republic. AB - To validate the feasibility of using next-generation sequencing in an African context, the complete genome of a rabies virus isolated from a human patient was obtained by high-throughput sequencing after virus isolation in mice and random unbiased amplification. Phylogenetic analysis suggested that this virus belongs to the Africa II clade. PMID- 24948768 TI - Characterization of an Avian Influenza Virus H9N2 Strain Isolated from a Wild Bird in Southern China. AB - We isolated an avian influenza virus H9N2 strain from a wild bird in the Guangxi Province of southern China in 2013 named A/turtledove/Guangxi/49B6/2013(H9N2) (GX49B6). We aimed to understand the genetic characters of the GX49B6 strain by analyzing the complete genome sequence. The results showed that our isolated strain has features of low pathogenic avian influenza viruses and viruses that infect humans. The discovery of the complete genome sequence of the GX49B6 strain may be helpful to further the understanding of the epidemiology and surveillance of avian influenza viruses in the field. PMID- 24948769 TI - Draft Genome Sequence of a Legionella pneumophila Serogroup 4 Strain Causing Legionellosis. AB - Here, we report the draft genome sequence of the Legionella pneumophila Nagoya-1 strain, serogroup 4, which was isolated from a clinical sample from a patient with legionellosis. Several virulence-associated genes, including those encoding the type IV (Dot/Icm) secretion system and effector proteins, were highly conserved. PMID- 24948770 TI - Draft Genome Sequence of Kitasatospora cheerisanensis KCTC 2395, Which Produces Plecomacrolide against Phytopathogenic Fungi. AB - Kitasatospora cheerisanensis KCTC 2395, which produces antifungal metabolites with bafilomycin derivatives, including bafilomycin C1-amide, was isolated from a soil sample at Mt. Jiri, South Korea. Here, we report its draft genome sequence, which contains 8.04 Mb with 73.6% G+C content and 7,810 protein-coding genes. PMID- 24948771 TI - Draft Genome Sequence of Bacillus subtilis strain KATMIRA1933. AB - In this report, we present a draft sequence of Bacillus subtilis KATMIRA1933. Previous studies demonstrated probiotic properties of this strain partially attributed to production of an antibacterial compound, subtilosin. Comparative analysis of this strain's genome with that of a commercial probiotic strain, B. subtilis Natto, is presented. PMID- 24948772 TI - Draft Genome Sequences of Geomicrobium sp. Strains JCM 19037, JCM 19038, JCM 19039, and JCM 19055, Isolated from Aquatic Samples. AB - Haloalkaliphilic strains JCM 19037, JCM 19038, JCM 19039, and JCM 19055, closely related to Geomicrobium sediminis, were isolated from aquatic samples, and their draft genome sequences were determined. The genome information of these four strains will be useful for studies of their physiology and ecology. PMID- 24948774 TI - Draft Genome Sequence of Bacillus amyloliquefaciens B-1895. AB - In this report, we present a draft genome sequence of Bacillus amyloliquefaciens strain B-1895. Comparison with the genome of a reference strain demonstrated similar overall organization, as well as differences involving large gene clusters. PMID- 24948773 TI - Draft Genome Sequences of Vibrio sp. Strains Isolated from Tetrodotoxin-Bearing Scavenging Gastropod. AB - Vibrio sp. strains JCM 18905 and JCM 19053 were isolated from a tetrodotoxin (TTX)-bearing scavenging gastropod, and Vibrio sp. strain JCM 18904 was isolated from a sea cucumber. All these are closely related to Vibrio alginolyticus. Their comparative genome information is useful for studies of TTX production in bacteria. PMID- 24948775 TI - Draft Genome Sequence of Enterococcus faecalis MB5259. AB - In this study, we present a draft genome sequence of Enterococcus faecalis MB5259, a promising probiotic strain. The identified differences and common features between this strain and reference strains will assist in better understanding the mechanism of antibacterial action and in developing novel probiotics. PMID- 24948776 TI - Draft Genome Sequence of Penicillium expansum Strain R19, Which Causes Postharvest Decay of Apple Fruit. AB - Among the species that cause blue mold, isolates of Penicillium expansum are the most prevalent and virulent species, causing more than 50 percent of postharvest decay. We report the draft genome sequence of P. expansum R19 in order to identify fungal virulence factors and to understand the mechanism of infection. PMID- 24948777 TI - Draft Genome Sequence of the Lignin-Degrading Burkholderia sp. Strain LIG30, Isolated from Wet Tropical Forest Soil. AB - Burkholderia species are common soil Betaproteobacteria capable of degrading recalcitrant aromatic compounds and xenobiotics. Burkholderia sp. strain LIG30 was isolated from wet tropical forest soil and is capable of utilizing lignin as a sole carbon source. Here we report the draft genome sequence of Burkholderia sp. strain LIG30. PMID- 24948779 TI - Tracheoinnominate fistula: a rare acute complication of penetrating neck injury. AB - Penetrating injuries in the base of the neck are considered to be the most dangerous due to the potential combination of vascular and intrathoracic lesions. We describe an extremely rare case of combined injury of the trachea and innominate artery, which resulted in formation of a traumatic acute tracheoinnominate fistula. Previously, these fistulas have been described as an iatrogenic complication of tracheostomy, presenting with massive peristomal bleed or hemoptysis. This case demonstrates that a combination of lesions to vital anatomical structures in the neck can change their clinical presentation, making them extremely difficult to diagnose. PMID- 24948778 TI - Genome-wide linkage-disequilibrium profiles from single individuals. AB - Although the analysis of linkage disequilibrium (LD) plays a central role in many areas of population genetics, the sampling variance of LD is known to be very large with high sensitivity to numbers of nucleotide sites and individuals sampled. Here we show that a genome-wide analysis of the distribution of heterozygous sites within a single diploid genome can yield highly informative patterns of LD as a function of physical distance. The proposed statistic, the correlation of zygosity, is closely related to the conventional population-level measure of LD, but is agnostic with respect to allele frequencies and hence likely less prone to outlier artifacts. Application of the method to several vertebrate species leads to the conclusion that >80% of recombination events are typically resolved by gene-conversion-like processes unaccompanied by crossovers, with the average lengths of conversion patches being on the order of one to several kilobases in length. Thus, contrary to common assumptions, the recombination rate between sites does not scale linearly with distance, often even up to distances of 100 kb. In addition, the amount of LD between sites separated by <200 bp is uniformly much greater than can be explained by the conventional neutral model, possibly because of the nonindependent origin of mutations within this spatial scale. These results raise questions about the application of conventional population-genetic interpretations to LD on short spatial scales and also about the use of spatial patterns of LD to infer demographic histories. PMID- 24948780 TI - Reimplantation of left coronary artery from pulmonary artery in a 65-year-old. AB - Anomalous left coronary artery to the pulmonary artery is a rare pathology with a mortality rate of 90% in the first year of life, directly related to left ventricular function and coronary perfusion, although several adult cases have been reported. Surgical correction consists of ligation of the anomalous left coronary artery associated with coronary artery bypass grafting. We describe the exceptional case of a 65-year-old woman who underwent reimplantation of the left coronary artery in the anatomical position without bridging. PMID- 24948781 TI - Left common basal pyramid torsion following left upper lobectomy/segmentectomy. AB - Lobar or segmental lung torsion is a severe complication of lung resection. To the best of our knowledge, common basal pyramid torsion has never been reported. We describe a case of left basal pyramid torsion after left upper lobectomy and superior segmentectomy, which was successfully treated by thoracoscopic surgery. PMID- 24948782 TI - Lung cancer developing from tracheal bronchus. AB - Tracheal bronchus is a rare congenital anomaly of the bronchial tree, in which an aberrant bronchus originates in the trachea anywhere above the carina, but usually within 2 cm of it. Lung neoplasms that develop from tracheal bronchus have been identified only rarely. We present a case of tracheal bronchus that included a malignancy of the affected right upper lobe. The post-surgical histological stage was T4N0M0 stage IIIA. The patient was in good condition 24 months after the operation, and there was no evidence of recurrence. Before 2012, 14 cases of lung cancer that developed from tracheal bronchus had been reported. PMID- 24948783 TI - Non-BMPR2 mutation heritable pulmonary arterial hypertension in Southeast Asia. AB - A 29-year-old Thai man presented with progressive dyspnea and evidence of pulmonary hypertension. Computed tomography was negative for pulmonary embolism. Cardiac catheterization confirmed the diagnosis of pulmonary arterial hypertension (mean pulmonary artery pressure 54 mm Hg, left ventricular end diastolic pressure 4 mm Hg, and pulmonary vascular resistance 25 Wood units) without an intracardiac shunt. Two family members had been previously diagnosed with pulmonary hypertension. There was no evidence of left heart disease or respiratory disorders. Based on the definite diagnosis of pulmonary hypertension in 3 family members, heritable pulmonary arterial hypertension was confirmed. Genetic testing indicated no BMPR2 mutation. PMID- 24948785 TI - Corrigendum. PMID- 24948784 TI - Posterior pericardiotomy in cardiac surgery: systematic review and meta-analysis. AB - This systematic review with meta-analysis sought to determine the impact of posterior pericardiotomy on incidences of atrial fibrillation and supraventricular arrhythmias, pericardial effusion, pleural effusion, tamponade, and the length of hospital stay after cardiac surgery. We searched for randomized controlled trials, using Medline, Embase, Elsevier and Sciences online databases as well as Google Scholar literature. The effect sizes measured were odds ratio for categorical variables and standard mean difference with 95% confidence interval for calculating differences between mean values of hospital stay in intervention and control groups. A value of p < 0.1 for Q test or I(2 )> 50% indicated significant heterogeneity between the studies. The literature search of all major databases retrieved 20 studies. After screening, 12 suitable trials were identified, which reported outcomes of 2052 patients undergoing cardiac surgery. Posterior pericardiotomy had an odds ratio of 0.33 [95% confidence interval: 0.18-0.61] p < 0.001 for atrial fibrillation; odds ratio 0.32 [0.15 0.67] p = 0.003 for supraventricular arrhythmias; odds ratio 0.09 [0.04-0.19] p = 0.000 for early pericardial effusion and odds ratio 0.04 [0.02-0.08] p < 0.001 for late pericardial effusion; odds ratio 1.64 [1.23-2.20] p = 0.001 for pleural effusion, odds ratio 0.07 [0.02-0.27] p < 0.001 for tamponade, and standard mean difference = 0.01 [-0.12 to 0.14] p = 0.8 for hospital stay. Posterior pericardiotomy is a simple intraoperative technique that can improve postoperative clinical outcomes. However, the incidence of pleural effusion associated with posterior pericardiotomy might be higher. PMID- 24948786 TI - Histone H2B ubiquitination promotes the function of the anaphase-promoting complex/cyclosome in Schizosaccharomyces pombe. AB - Ubiquitination and deubiquitination of proteins are reciprocal events involved in many cellular processes, including the cell cycle. During mitosis, the metaphase to anaphase transition is regulated by the ubiquitin ligase activity of the anaphase-promoting complex/cyclosome (APC/C). Although the E3 ubiquitin ligase function of the APC/C has been well characterized, it is not clear whether deubiquitinating enzymes (DUBs) play a role in reversing APC/C substrate ubiquitination. Here we performed a genetic screen to determine what DUB, if any, antagonizes the function of the APC/C in the fission yeast Schizosaccharomyces pombe. We found that deletion of ubp8, encoding the Spt-Ada-Gcn5-Acetyl transferase (SAGA) complex associated DUB, suppressed temperature-sensitive phenotypes of APC/C mutants cut9-665, lid1-6, cut4-533, and slp1-362. Our analysis revealed that Ubp8 antagonizes APC/C function in a mechanism independent of the spindle assembly checkpoint and proteasome activity. Notably, suppression of APC/C mutants was linked to loss of Ubp8 catalytic activity and required histone H2B ubiquitination. On the basis of these data, we conclude that Ubp8 antagonizes APC/C function indirectly by modulating H2B ubiquitination status. PMID- 24948788 TI - Computer-aided detection system for chest radiography: reducing report turnaround times of examinations with abnormalities. AB - BACKGROUND: The ability to give high priority to examinations with pathological findings could be very useful to radiologists with large work lists who wish to first evaluate the most critical studies. A computer-aided detection (CAD) system for identifying chest examinations with abnormalities has therefore been developed. PURPOSE: To evaluate the effectiveness of a CAD system on report turnaround times of chest examinations with abnormalities. MATERIAL AND METHODS: The CAD system was designed to automatically mark chest examinations with possible abnormalities in the work list of radiologists interpreting chest examinations. The system evaluation was performed in two phases: two radiologists interpreted the chest examinations without CAD in phase 1 and with CAD in phase 2. The time information recorded by the radiology information system was then used to calculate the turnaround times. All chest examinations were reviewed by two other radiologists and were divided into normal and abnormal groups. The turnaround times for the examinations with pathological findings with and without the CAD system assistance were compared. RESULTS: The sensitivity and specificity of the CAD for chest abnormalities were 0.790 and 0.697, respectively, and use of the CAD system decreased the turnaround time for chest examinations with abnormalities by 44%. CONCLUSION: The turnaround times required for radiologists to identify chest examinations with abnormalities could be reduced by using the CAD system. This system could be useful for radiologists with large work lists who wish to first evaluate the most critical studies. PMID- 24948789 TI - Oncocytic adenomas of thyroid-mimicking benign or metastatic disease on 18F-FDG PET scan. AB - BACKGROUND: The literature is sparse concerning 18F-fluorodeoxyglucose (18F-FDG) accumulation in the Hurthle cell neoplasm (HCN) of the thyroid. Given the difficulty of accurately diagnosing HCN, even with ultrasound (US) and fine needle aspiration biopsy (FNAB), the ability to accurately characterize these lesions by 18F-FDG positron emission tomography (PET) would be of value. PURPOSE: To describe six cases of oncocytic proliferation in the thyroid gland that mimics the presence of metastatic disease and was detected incidentally by an 18F-FDG PET scan. MATERIAL AND METHODS: We conducted whole-body 18F-FDG PET examinations for cancer staging in 1862 oncological patients from 2012 to 2013. Among them, six subjects (4 women, 2 men; age range, 45-85 years) with focal-enhanced 18F-FDG accumulation in the thyroid gland were selected from the study population. This study group was further investigated using 99 m-Tc-pertechnetate scintigraphy, US, and FNAB. Two experienced nuclear physicians reviewed the images. Gray-scale US and color Doppler (CD) sonographic examinations of the thyroid were undertaken for all subjects using a sonographic device Logiq 5 Expert (GE Medical Systems, Osaka, Japan) equipped with a 7-12 MHz linear array transducer. RESULTS: In all six cases, abnormal 18F-FDG uptake was found locally in the thyroid. The average SUVmax of the HCN was 5.8 (range, 2.6-16). In all six cases, 99 m-Tc pertechnetate scintigraphy showed a cold spot. Compared with normal parenchymal vascularity, five of the six masses were shown to be hypervascular by CD ultrasonography. CONCLUSION: On PET scans, oncocytic proliferations of the thyroid may mimic metastases of other malignancies. The focal-enhanced uptake of 18F-FDG PET may be associated with a focal increase in the metabolic activity of the thyroid parenchyma due to the presence of oncocytes. Our study emphasizes the importance of obtaining cytological evidence before making a diagnosis of metastatic disease. PMID- 24948787 TI - Proteomic analysis reveals CACN-1 is a component of the spliceosome in Caenorhabditis elegans. AB - Cell migration is essential for embryonic development and tissue formation in all animals. cacn-1 is a conserved gene of unknown molecular function identified in a genome-wide screen for genes that regulate distal tip cell migration in the nematode worm Caenorhabditis elegans. In this study we take a proteomics approach to understand CACN-1 function. To isolate CACN-1-interacting proteins, we used an in vivo tandem-affinity purification strategy. Tandem-affinity purification tagged CACN-1 complexes were isolated from C. elegans lysate, analyzed by mass spectrometry, and characterized bioinformatically. Results suggest significant interaction of CACN-1 with the C. elegans spliceosome. All of the identified interactors were screened for distal tip cell migration phenotypes using RNAi. Depletion of many of these factors led to distal tip cell migration defects, particularly a failure to stop migrating, a phenotype commonly seen in cacn-1 deficient animals. The results of this screen identify eight novel regulators of cell migration and suggest CACN-1 may participate in a protein network dedicated to high-fidelity gonad development. The composition of proteins comprising the CACN-1 network suggests that this critical developmental module may exert its influence through alternative splicing or other post-transcriptional gene regulation. PMID- 24948790 TI - Dose reduction for chest CT: comparison of two iterative reconstruction techniques. AB - BACKGROUND: Lowering radiation dose in computed tomography (CT) scan results in low quality noisy images. Iterative reconstruction techniques are used currently to lower image noise and improve the quality of images. PURPOSE: To evaluate lesion detection and diagnostic acceptability of chest CT images acquired at CTDIvol of 1.8 mGy and processed with two different iterative reconstruction techniques. MATERIAL AND METHODS: Twenty-two patients (mean age, 60 +/- 14 years; men, 13; women, 9; body mass index, 27.4 +/- 6.5 kg/m(2)) gave informed consent for acquisition of low dose (LD) series in addition to the standard dose (SD) chest CT on a 128 - multidetector CT (MDCT). LD images were reconstructed with SafeCT C4, L1, and L2 settings, and Safire S1, S2, and S3 settings. Three thoracic radiologists assessed LD image series (S1, S2, S3, C4, L1, and L2) for lesion detection and comparison of lesion margin, visibility of normal structures, and diagnostic confidence with SD chest CT. Inter-observer agreement (kappa) was calculated. RESULTS: Average CTDIvol was 6.4 +/- 2.7 mGy and 1.8 +/- 0.2 mGy for SD and LD series, respectively. No additional lesion was found in SD as compared to LD images. Visibility of ground-glass opacities and lesion margins, as well as normal structures visibility were not affected on LD. CT image visibility of major fissure and pericardium was not optimal in some cases (n = 5). Objective image noise in some low dose images processed with SafeCT and Safire was similar to SD images (P value > 0.5). CONCLUSION: Routine LD chest CT reconstructed with iterative reconstruction technique can provide similar diagnostic information in terms of lesion detection, margin, and diagnostic confidence as compared to SD, regardless of the iterative reconstruction settings. PMID- 24948791 TI - The complex immunology of multiple sclerosis. PMID- 24948793 TI - Relationship between ICU nurses' moral distress with burnout and anticipated turnover. AB - BACKGROUND: Moral distress is one of intensive care unit nurses' major problems, which may happen due to various reasons, and has several consequences. Due to various moral distress outcomes in intensive care unit nurses, and their impact on nurses' personal and professional practice, recognizing moral distress is very important. RESEARCH OBJECTIVE: The aim of this study was to determine correlation between moral distress with burnout and anticipated turnover in intensive care unit nurses. RESEARCH DESIGN: This study is a descriptive-correlation research. PARTICIPANTS AND RESEARCH CONTEXT: A total of 159 intensive care unit nurses were selected from medical sciences universities in Iran. Data collection instruments included "demographic questionnaire," "ICU Nurses' Moral Distress Scale," "Copenhagen Burnout Inventory" and "Hinshaw and Atwood Turnover Scale." Data analysis was done by using SPSS19. ETHICAL CONSIDERATIONS: Informed consent from samples and research approval was obtained from Shahid Beheshti Medical Sciences University Research Ethics Board in Tehran. FINDINGS: The findings showed intensive care unit nurses' moral distress and anticipated turnover was high, but burnout was moderate. The results revealed that there was a positive statistical correlation between intensive care unit nurses' age, their work experience and the fraction of nurses' number to number of intensive care unit beds with their moral distress and burnout. However, there were no correlation between gender, marriage status, educational degree and work shift and moral distress. DISCUSSION: Some of the findings of this research are consistent with other studies and some of them are inconsistent. CONCLUSION: Similarly, moral distress with burnout and anticipated turnover did not have statistical correlation. However, a positive correlation was found between burnout and anticipated turnover. The results showed that increase in the recruitment of young nurses, and nursing personnel, and diminishing intensive care unit nurses' moral distress, burnout and their turnover intention are essential. PMID- 24948794 TI - Feature-specific clusters of neurons and decision-related neuronal activity. PMID- 24948795 TI - Adrenocortical status predicts the degree of age-related deficits in prefrontal structural plasticity and working memory. AB - Cognitive decline in aging is marked by considerable variability, with some individuals experiencing significant impairments and others retaining intact functioning. Whereas previous studies have linked elevated hypothalamo-pituitary adrenal (HPA) axis activity with impaired hippocampal function during aging, the idea has languished regarding whether such differences may underlie the deterioration of other cognitive functions. Here we investigate whether endogenous differences in HPA activity are predictive of age-related impairments in prefrontal structural and behavioral plasticity. Young and aged rats (4 and 21 months, respectively) were partitioned into low or high HPA activity, based upon averaged values of corticosterone release from each animal obtained from repeated sampling across a 24 h period. Pyramidal neurons in the prelimbic area of medial prefrontal cortex were selected for intracellular dye filling, followed by 3D imaging and analysis of dendritic spine morphometry. Aged animals displayed dendritic spine loss and altered geometric characteristics; however, these decrements were largely accounted for by the subgroup bearing elevated corticosterone. Moreover, high adrenocortical activity in aging was associated with downward shifts in frequency distributions for spine head diameter and length, whereas aged animals with low corticosterone showed an upward shift in these indices. Follow-up behavioral experiments revealed that age-related spatial working memory deficits were exacerbated by increased HPA activity. By contrast, variations in HPA activity in young animals failed to impact structural or behavioral plasticity. These data implicate the cumulative exposure to glucocorticoids as a central underlying process in age-related prefrontal impairment and define synaptic features accounting for different trajectories in age-related cognitive function. PMID- 24948796 TI - SkpA restrains synaptic terminal growth during development and promotes axonal degeneration following injury. AB - The Wallenda (Wnd)/dual leucine zipper kinase (DLK)-Jnk pathway is an evolutionarily conserved MAPK signaling pathway that functions during neuronal development and following axonal injury. Improper pathway activation causes defects in axonal guidance and synaptic growth, whereas loss-of-function mutations in pathway components impairs axonal regeneration and degeneration after injury. Regulation of this pathway is in part through the E3 ubiquitin ligase Highwire (Hiw), which targets Wnd/DLK for degradation to limit MAPK signaling. To explore mechanisms controlling Wnd/DLK signaling, we performed a large-scale genetic screen in Drosophila to identify negative regulators of the pathway. Here we describe the identification and characterization of SkpA, a core component of SCF E3 ubiquitin ligases. Mutants in SkpA display synaptic overgrowth and an increase in Jnk signaling, similar to hiw mutants. The combination of hypomorphic alleles of SkpA and hiw leads to enhanced synaptic growth. Mutants in the Wnd-Jnk pathway suppress the overgrowth of SkpA mutants demonstrating that the synaptic overgrowth is due to increased Jnk signaling. These findings support the model that SkpA and the E3 ligase Hiw function as part of an SCF-like complex that attenuates Wnd/DLK signaling. In addition, SkpA, like Hiw, is required for synaptic and axonal responses to injury. Synapses in SkpA mutants are more stable following genetic or traumatic axonal injury, and axon loss is delayed in SkpA mutants after nerve crush. As in highwire mutants, this axonal protection requires Nmnat. Hence, SkpA is a novel negative regulator of the Wnd-Jnk pathway that functions with Hiw to regulate both synaptic development and axonal maintenance. PMID- 24948797 TI - Ubiquitin-activating enzyme activity contributes to differential accumulation of mutant huntingtin in brain and peripheral tissues. AB - Huntington's disease (HD) belongs to a family of neurodegenerative diseases caused by misfolded proteins and shares the pathological hallmark of selective accumulation of misfolded proteins in neuronal cells. Polyglutamine expansion in the HD protein, huntingtin (Htt), causes selective neurodegeneration that is more severe in the striatum and cortex than in other brain regions, but the mechanism behind this selectivity is unknown. Here we report that in HD knock-in mice, the expression levels of mutant Htt (mHtt) are higher in brain tissues than in peripheral tissues. However, the expression of N-terminal mHtt via stereotaxic injection of viral vectors in mice also results in greater accumulation of mHtt in the striatum than in muscle. We developed an in vitro assay that revealed that extracts from the striatum and cortex promote the formation of high-molecular weight (HMW) mHtt compared with the relatively unaffected cerebellar and peripheral tissue extracts. Inhibition of ubiquitin-activating enzyme E1 (Ube1) increased the levels of HMW mHtt in the relatively unaffected tissues. Importantly, the expression levels of Ube1 are lower in brain tissues than peripheral tissues and decline in the nuclear fraction with age, which is correlated with the increased accumulation of mHtt in the brain and neuronal nuclei during aging. Our findings suggest that decreased targeting of misfolded Htt to the proteasome for degradation via Ube1 may underlie the preferential accumulation of toxic forms of mHtt in the brain and its selective neurodegeneration. PMID- 24948798 TI - Prolonged training at threshold promotes robust retinotopic specificity in perceptual learning. AB - Human perceptual learning is classically thought to be highly specific to trained stimuli's retinal location. Together with evidence that specific learning effects can result in corresponding changes in early visual cortex, researchers have theorized that specificity implies regionalization of learning in the brain. However, other research suggests that specificity can arise from learning readout in decision areas or through top-down processes. Notably, recent research using a novel double-training paradigm reveals dramatic generalization of perceptual learning to untrained locations when multiple stimuli are trained. These data provoked significant controversy in the field and challenged extant models of perceptual learning. To resolve this controversy, we investigated mechanisms that account for retinotopic specificity in perceptual learning. We replicated findings of transfer after double training; however, we show that prolonged training at threshold, which leads to a greater number of difficult trials during training, preserves location specificity when double training occurred at the same location or sequentially at different locations. Likewise, we find that prolonged training at threshold determines the degree of transfer in single training of a peripheral orientation discrimination task. Together, these data show that retinotopic specificity depends highly upon particularities of the training procedure. We suggest that perceptual learning can arise from decision rules, attention learning, or representational changes, and small differences in the training approach can emphasize some of these over the others. PMID- 24948799 TI - Balanced mTORC1 activity in oligodendrocytes is required for accurate CNS myelination. AB - The mammalian target of rapamycin (mTOR) pathway integrates multiple signals and regulates crucial cell functions via the molecular complexes mTORC1 and mTORC2. These complexes are functionally dependent on their raptor (mTORC1) or rictor (mTORC2) subunits. mTOR has been associated with oligodendrocyte differentiation and myelination downstream of the PI3K/Akt pathway, but the functional contributions of individual complexes are largely unknown. We show, by oligodendrocyte-specific genetic deletion of Rptor and/or Rictor in the mouse, that CNS myelination is mainly dependent on mTORC1 function, with minor mTORC2 contributions. Myelin-associated lipogenesis and protein gene regulation are strongly reliant on mTORC1. We found that also oligodendrocyte-specific overactivation of mTORC1, via ablation of tuberous sclerosis complex 1 (TSC1), causes hypomyelination characterized by downregulation of Akt signaling and lipogenic pathways. Our data demonstrate that a delicately balanced regulation of mTORC1 activation and action in oligodendrocytes is essential for CNS myelination, which has practical overtones for understanding CNS myelin disorders. PMID- 24948800 TI - Dynamic engagement of human motion detectors across space-time coordinates. AB - Motion detection is a fundamental property of the visual system. The gold standard for studying and understanding this function is the motion energy model. This computational tool relies on spatiotemporally selective filters that capture the change in spatial position over time afforded by moving objects. Although the filters are defined in space-time, their human counterparts have never been studied in their native spatiotemporal space but rather in the corresponding frequency domain. When this frequency description is back-projected to spatiotemporal description, not all characteristics of the underlying process are retained, leaving open the possibility that important properties of human motion detection may have remained unexplored. We derived descriptors of motion detectors in native space-time, and discovered a large unexpected dynamic structure involving a >2* change in detector amplitude over the first ~100 ms. This property is not predicted by the energy model, generalizes across the visual field, and is robust to adaptation; however, it is silenced by surround inhibition and is contrast dependent. We account for all results by extending the motion energy model to incorporate a small network that supports feedforward spread of activation along the motion trajectory via a simple gain-control circuit. PMID- 24948801 TI - Neuronal ensembles in amygdala, hippocampus, and prefrontal cortex track differential components of contextual fear. AB - Although the circuit mediating contextual fear conditioning has been extensively described, the precise contribution that specific anatomical nodes make to behavior has not been fully elucidated. To clarify the roles of the dorsal hippocampus (DH), basolateral amygdala (BLA), and medial prefrontal cortex (mPFC) in contextual fear conditioning, activity within these regions was mapped using cellular compartment analysis of temporal activity using fluorescence in situ hybridization (catFISH) for Arc mRNA. Rats were delay-fear conditioned or immediately shocked (controls) and thereafter reexposed to the shocked context to test for fear memory recall. Subsequent catFISH analyses revealed that in the DH, cells were preferentially reactivated during the context test, regardless of whether animals had been fear conditioned or immediately shocked, suggesting that the DH encodes spatial information specifically, rather then the emotional valence of an environment. In direct contrast, neuronal ensembles in the BLA were only reactivated at test if animals had been fear conditioned, suggesting that the amygdala specifically tracks the emotional properties of a context. Interestingly, Arc expression in the mPFC was consistent with both amygdala- and hippocampus-like patterns, supporting a role for the mPFC in both fear and contextual processing. Collectively, these data provide crucial insight into the region-specific behavior of neuronal ensembles during contextual fear conditioning and demonstrate a dissociable role for the hippocampus and amygdala in processing the contextual and emotional properties of a fear memory. PMID- 24948802 TI - Stage-specific regulation of oligodendrocyte development by Wnt/beta-catenin signaling. AB - Oligodendrocytes are myelin-forming glia that ensheath the axons of neurons in the CNS. Recent studies have revealed that Wnt/beta-catenin signaling plays important roles in oligodendrocyte development and myelin formation. However, there are conflicting reports on the specific function of Wnt signaling components in oligodendrocyte specification and differentiation. In the present study, we demonstrate that activation of beta-catenin in neural progenitor cells before gliogenesis inhibits the generation of oligodendrocyte progenitors (OLPs) in mice. Once OLPs are formed, beta-catenin becomes necessary for oligodendrocyte differentiation. Disruption of beta-catenin signaling instead leads to a significant delay of oligodendrocyte maturation. These findings suggest that Wnt/beta-catenin pathway regulates oligodendrocyte development in a stage dependent manner. PMID- 24948803 TI - Drosophila Syd-1, liprin-alpha, and protein phosphatase 2A B' subunit Wrd function in a linear pathway to prevent ectopic accumulation of synaptic materials in distal axons. AB - During synaptic development, presynaptic differentiation occurs as an intrinsic property of axons to form specialized areas of plasma membrane [active zones (AZs)] that regulate exocytosis and endocytosis of synaptic vesicles. Genetic and biochemical studies in vertebrate and invertebrate model systems have identified a number of proteins involved in AZ assembly. However, elucidating the molecular events of AZ assembly in a spatiotemporal manner remains a challenge. Syd-1 (synapse defective-1) and Liprin-alpha have been identified as two master organizers of AZ assembly. Genetic and imaging analyses in invertebrates show that Syd-1 works upstream of Liprin-alpha in synaptic assembly through undefined mechanisms. To understand molecular pathways downstream of Liprin-alpha, we performed a proteomic screen of Liprin-alpha-interacting proteins in Drosophila brains. We identify Drosophila protein phosphatase 2A (PP2A) regulatory subunit B' [Wrd (Well Rounded)] as a Liprin-alpha-interacting protein, and we demonstrate that it mediates the interaction of Liprin-alpha with PP2A holoenzyme and the Liprin-alpha-dependent synaptic localization of PP2A. Interestingly, loss of function in syd-1, liprin-alpha, or wrd shares a common defect in which a portion of synaptic vesicles, dense-core vesicles, and presynaptic cytomatrix proteins ectopically accumulate at the distal, but not proximal, region of motoneuron axons. Strong genetic data show that a linear syd-1/liprin-alpha/wrd pathway in the motoneuron antagonizes glycogen synthase kinase-3beta kinase activity to prevent the ectopic accumulation of synaptic materials. Furthermore, we provide data suggesting that the syd-1/liprin-alpha/wrd pathway stabilizes AZ specification at the nerve terminal and that such a novel function is independent of the roles of syd-1/liprin-alpha in regulating the morphology of the T-bar structural protein BRP (Bruchpilot). PMID- 24948804 TI - Differential longitudinal changes in cortical thickness, surface area and volume across the adult life span: regions of accelerating and decelerating change. AB - Human cortical thickness and surface area are genetically independent, emerge through different neurobiological events during development, and are sensitive to different clinical conditions. However, the relationship between changes in the two over time is unknown. Additionally, longitudinal studies have almost invariably been restricted to older adults, precluding the delineation of adult life span trajectories of change in cortical structure. In this longitudinal study, we investigated changes in cortical thickness, surface area, and volume after an average interval of 3.6 years in 207 well screened healthy adults aged 23-87 years. We hypothesized that the relationships among metrics are dynamic across the life span, that the primary contributor to cortical volume reductions in aging is cortical thinning, and that magnitude of change varies with age and region. Changes over time were seen in cortical area (mean annual percentage change [APC], -0.19), thickness (APC, -0.35), and volume (APC, -0.51) in most regions. Volume changes were primarily explained by changes in thickness rather than area. A negative relationship between change in thickness and surface area was found across several regions, where more thinning was associated with less decrease in area, and vice versa. Accelerating changes with increasing age was seen in temporal and occipital cortices. In contrast, decelerating changes were seen in prefrontal and anterior cingulate cortices. In conclusion, a dynamic relationship between cortical thickness and surface area changes exists throughout the adult life span. The mixture of accelerating and decelerating changes further demonstrates the importance of studying these metrics across the entire adult life span. PMID- 24948805 TI - Oxytocin reverses amphetamine-induced deficits in social bonding: evidence for an interaction with nucleus accumbens dopamine. AB - Drug addiction has devastating consequences on social behaviors and can lead to the impairment of social bonding. Accumulating evidence indicates that alterations in oxytocin (OT) and dopamine (DA) neurotransmission within brain reward circuitry may be involved. We investigated this possibility, as well as the therapeutic potential of OT for drug-induced social deficits, using the prairie vole (Microtus ochrogaster)-a socially monogamous rodent that forms enduring pair bonds between adult mates. We demonstrate that repeated exposure to the commonly abused psychostimulant amphetamine (AMPH) inhibits the formation of partner preferences (an index of pair bonding) in female prairie voles. AMPH exposure also altered OT and DA neurotransmission in regions that mediate partner preference formation: it decreased OT and DA D2 receptor immunoreactivity in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc), respectively, and increased NAcc DA levels. Administration of OT directly into the mPFC of AMPH exposed voles restored partner preferences, and altered NAcc DA levels, and this effect was dependent on OT receptor activation. Together, these data suggest that repeated AMPH exposure impairs pair bonding through an OT-mediated mechanism, and that OT and DA systems within brain reward circuitry may interact to mediate the complex relationship between drug abuse and social bonding. Further, these results provide empirical support for the idea that the central OT system may represent an important target for the treatment of social deficits in addiction. PMID- 24948807 TI - Coordinated within-trial dynamics of low-frequency neural rhythms controls evidence accumulation. AB - Higher cognitive functions, such as human perceptual decision making, require information processing and transmission across wide-spread cortical networks. Temporally synchronized neural firing patterns are advantageous for efficiently representing and transmitting information within and between assemblies. Computational, empirical, and conceptual considerations all lead to the expectation that the informational redundancy of neural firing rates is positively related to their synchronization. Recent theorizing and initial evidence also suggest that the coding of stimulus characteristics and their integration with behavioral goal states require neural interactions across a hierarchy of timescales. However, most studies thus have focused on neural activity in a single frequency range or on a restricted set of brain regions. Here we provide evidence for cooperative spatiotemporal dynamics of slow and fast EEG signals during perceptual decision making at the single-trial level. Participants performed three masked two-choice decision tasks, one each with numerical, verbal, or figural content. Decrements in posterior alpha power (8-14 Hz) were paralleled by increments in high-frequency (>30 Hz) signal entropy in trials demanding active sensory processing. Simultaneously, frontocentral theta power (4-7 Hz) increased, indicating evidence integration. The coordinated alpha/theta dynamics were tightly linked to decision speed and remarkably similar across tasks, suggesting a domain-general mechanism. In sum, we demonstrate an inverse association between decision-related changes in widespread low-frequency power and local high-frequency entropy. The cooperation among mechanisms captured by these changes enhances the informational density of neural response patterns and qualifies as a neural coding system in the service of perceptual decision making. PMID- 24948808 TI - The actual intrinsic excitability of granular cells determines the ruling neurovascular coupling mechanism in the rat dentate gyrus. AB - Paired-pulse stimulation of the perforant pathway was used to study the relation between granular cell activity and the resultant fMRI response in the rat dentate gyrus. By varying the interpulse interval (IPI), paired-pulse stimulations caused: a depression (20 ms IPI), a facilitation (100 ms IPI), a mixture of depression and facilitation (30 ms IPI), or no change (500 ms IPS) in the second response. Eight identical paired pulses were applied during one stimulation train and the evoked field potentials and generated fMRI responses were measured simultaneously. Application of consecutive stimulation trains caused time dependent variations in electrophysiological and fMRI responses, which were characteristic for each stimulus protocol. Depending on the IPI, the magnitude of the fMRI response either correlated strongly with or was apparently unrelated to the spiking or postsynaptic activity of the granular cells. A strong relation between spiking activity and resultant fMRI response was only found when the stimulation protocol caused an increase in the recorded population spike latency. If the latency was decreased, the fMRI response was more closely related to the applied input activity. Perforant pathway fibers monosynaptically activate granular cells, so variations in population spike latencies reflect changes in their intrinsic excitability. Therefore, during increased intrinsic excitability, signaling cascades upstream of the granular cells determine the fMRI response, whereas granular cell activity-related mechanisms control the fMRI response during decreased intrinsic excitability. PMID- 24948806 TI - An amino terminal phosphorylation motif regulates intranuclear compartmentalization of Olig2 in neural progenitor cells. AB - The bHLH transcription factor Olig2 is expressed in cycling neural progenitor cells but also in terminally differentiated, myelinating oligodendrocytes. Sustained expression of Olig2 is counterintuitive because all known functions of the protein in expansion of neural progenitors and specification of oligodendrocyte progenitors are completed with the formation of mature white matter. How are the biological functions of Olig2 suppressed in terminally differentiated oligodendrocytes? In previous studies, we have shown that a triple serine motif in the amino terminus of Olig2 is phosphorylated in cycling neural progenitors but not in their differentiated progeny. We now show that phosphorylation of the triple serine motif regulates intranuclear compartmentalization of murine Olig2. Phosphorylated Olig2 is preferentially localized to a transcriptionally active "open" chromatin compartment together with coregulator proteins essential for regulation of gene expression. Unphosphorylated Olig2, as seen in mature white matter, is localized mainly within a transcriptionally inactive, chromatin fraction characterized by condensed and inaccessible DNA. Of special note is the observation that the p53 tumor suppressor protein is confined to the open chromatin fraction. Proximity ligation assays show that phosphorylation brings Olig2 within 30 nm of p53 within the open chromatin compartment. The data thus shed light on previously noted promitogenic functions of phosphorylated Olig2, which reflect, at least in part, an oppositional relationship with p53 functions. PMID- 24948809 TI - Neurodegeneration by activation of the microglial complement-phagosome pathway. AB - Systemic inflammatory reactions have been postulated to exacerbate neurodegenerative diseases via microglial activation. We now demonstrate in vivo that repeated systemic challenge of mice over four consecutive days with bacterial LPS maintained an elevated microglial inflammatory phenotype and induced loss of dopaminergic neurons in the substantia nigra. The same total cumulative LPS dose given within a single application did not induce neurodegeneration. Whole-genome transcriptome analysis of the brain demonstrated that repeated systemic LPS application induced an activation pattern involving the classical complement system and its associated phagosome pathway. Loss of dopaminergic neurons induced by repeated systemic LPS application was rescued in complement C3-deficient mice, confirming the involvement of the complement system in neurodegeneration. Our data demonstrate that a phagosomal inflammatory response of microglia is leading to complement-mediated loss of dopaminergic neurons. PMID- 24948810 TI - Multiphasic modulation of cholinergic interneurons by nigrostriatal afferents. AB - The motor and learning functions of the striatum are critically dependent on synaptic transmission from midbrain dopamine neurons and striatal cholinergic interneurons (CINs). Both neural populations alter their discharge in vivo in response to salient sensory stimuli, albeit in opposite directions. Whereas midbrain dopamine neurons respond to salient stimuli with a brief burst of activity, CINs exhibit a distinct pause in firing that is often followed by a period of increased excitability. Although this "pause-rebound" sensory response requires dopaminergic signaling, the precise mechanisms underlying the modulation of CIN firing by dopaminergic afferents remain unclear. Here, we show that phasic activation of nigrostriatal afferents in a mouse striatal slice preparation is sufficient to evoke a pause-rebound response in CINs. Using a combination of optogenetic, electrophysiological, and pharmacological approaches, we demonstrate that synaptically released dopamine inhibits CINs through type 2 dopamine receptors, while another unidentified transmitter mediates the delayed excitation. These findings imply that, in addition to their direct effects on striatal projection neurons, midbrain dopamine neurons indirectly modulate striatal output by dynamically controlling cholinergic tone. In addition, our data suggest that phasic dopaminergic activity may directly participate in the characteristic pause-rebound sensory response that CINs exhibit in vivo in response to salient and conditioned stimuli. PMID- 24948811 TI - The role of visual area V4 in the discrimination of partially occluded shapes. AB - The primate brain successfully recognizes objects, even when they are partially occluded. To begin to elucidate the neural substrates of this perceptual capacity, we measured the responses of shape-selective neurons in visual area V4 while monkeys discriminated pairs of shapes under varying degrees of occlusion. We found that neuronal shape selectivity always decreased with increasing occlusion level, with some neurons being notably more robust to occlusion than others. The responses of neurons that maintained their selectivity across a wider range of occlusion levels were often sufficiently sensitive to support behavioral performance. Many of these same neurons were distinctively selective for the curvature of local boundary features and their shape tuning was well fit by a model of boundary curvature (curvature-tuned neurons). A significant subset of V4 neurons also signaled the animal's upcoming behavioral choices; these decision signals had short onset latencies that emerged progressively later for higher occlusion levels. The time course of the decision signals in V4 paralleled that of shape selectivity in curvature-tuned neurons: shape selectivity in curvature tuned neurons, but not others, emerged earlier than the decision signals. These findings provide evidence for the involvement of contour-based mechanisms in the segmentation and recognition of partially occluded objects, consistent with psychophysical theory. Furthermore, they suggest that area V4 participates in the representation of the relevant sensory signals and the generation of decision signals underlying discrimination. PMID- 24948812 TI - Nrf2 upregulates ATP binding cassette transporter expression and activity at the blood-brain and blood-spinal cord barriers. AB - Activation of nuclear factor E2-related factor-2 (Nrf2), a sensor of oxidative stress, is neuroprotective in animal models of cerebral ischemia, traumatic brain injury, subarachnoid hemorrhage, and spinal cord injury. We show here that Nrf2 activation with sulforaphane (SFN) in vivo or in vitro increases expression and transport activity of three ATP-driven drug efflux pumps at the blood-brain barrier [P-glycoprotein, ATP binding cassette b1 (Abcb1); multidrug resistance associated protein-2 (Mrp2), Abcc2; and breast cancer resistance protein (Bcrp), Abcg2]. Dosing rats with SFN increased protein expression of all three transporters in brain capillaries and decreased by 50% brain accumulation of the P-glycoprotein substrate verapamil. Exposing rat or mouse brain capillaries to SFN increased P-glycoprotein, Bcrp, and Mrp2 transport activity and protein expression; SFN increased P-glycoprotein activity in mouse spinal cord capillaries. Inhibiting transcription or translation abolished upregulation of P glycoprotein activity. No such effects were seen in brain capillaries from Nrf2 null mice, indicating Nrf2 dependence. Nrf2 signaled indirectly to increase transporter activity/expression. The p53 inhibitor pifithrin abolished the SFN induced increase in transporter activity/expression, and the p53-activator nutlin 3 increased P-glycoprotein activity. SFN did not alter P-glycoprotein transport activity in brain and spinal cord capillaries from p53-null mice. Inhibitors of p38 MAPK and nuclear factor kappaB (NF-kappaB) blocked the effects of SFN and nutlin-3 on P-glycoprotein activity. These results implicate Nrf2, p53, and NF kappaB in the upregulation of P-glycoprotein, Bcrp, and Mrp2 at blood-CNS barriers. They imply that the barriers are tightened selectively (efflux transporter upregulation) by oxidative stress, providing increased neuroprotection, but also reduced penetration of many therapeutic drugs. PMID- 24948813 TI - Altering spatial priority maps via reward-based learning. AB - Spatial priority maps are real-time representations of the behavioral salience of locations in the visual field, resulting from the combined influence of stimulus driven activity and top-down signals related to the current goals of the individual. They arbitrate which of a number of (potential) targets in the visual scene will win the competition for attentional resources. As a result, deployment of visual attention to a specific spatial location is determined by the current peak of activation (corresponding to the highest behavioral salience) across the map. Here we report a behavioral study performed on healthy human volunteers, where we demonstrate that spatial priority maps can be shaped via reward-based learning, reflecting long-lasting alterations (biases) in the behavioral salience of specific spatial locations. These biases exert an especially strong influence on performance under conditions where multiple potential targets compete for selection, conferring competitive advantage to targets presented in spatial locations associated with greater reward during learning relative to targets presented in locations associated with lesser reward. Such acquired biases of spatial attention are persistent, are nonstrategic in nature, and generalize across stimuli and task contexts. These results suggest that reward-based attentional learning can induce plastic changes in spatial priority maps, endowing these representations with the "intelligent" capacity to learn from experience. PMID- 24948814 TI - alpha2delta-1 signaling in nucleus accumbens is necessary for cocaine-induced relapse. AB - Relapse to cocaine seeking is associated with potentiated excitatory synapses in nucleus accumbens. alpha2delta-1 is an auxiliary subunit of voltage-gated calcium channels that affects calcium-channel trafficking and kinetics, initiates extracellular signaling cascades, and promotes excitatory synaptogenesis. Previous data demonstrate that repeated exposure to alcohol, nicotine, methamphetamine, and morphine upregulates alpha2delta-1 in reward-related brain regions, but it was unclear whether this alteration generalized to cocaine. Here, we show that alpha2delta-1 protein was increased in nucleus accumbens after cocaine self-administration and extinction compared with saline controls. Furthermore, the endogenous ligand thrombospondin-1, responsible for the synaptogenic properties of the alpha2delta-1 receptor, was likewise elevated. Using whole-cell patch-clamp recordings of EPSCs in nucleus accumbens, we demonstrated that gabapentin, a specific alpha2delta-1 antagonist, preferentially reduced the amplitude and increased the paired-pulse ratio of EPSCs evoked by electrical stimulation in slices from cocaine-experienced rats compared with controls. In vivo, gabapentin microinjected in the nucleus accumbens core attenuated cocaine-primed but not cue-induced reinstatement. Importantly, gabapentin's effects on drug seeking were not due to a general depression of spontaneous or cocaine-induced locomotor activity. Moreover, gabapentin had no effect on reinstatement of sucrose seeking. These data indicate that alpha2delta 1 contributes specifically to cocaine-reinstated drug seeking, and identifies this protein as a target for the development of cocaine relapse medications. These results also inform ongoing discussion in the literature regarding efficacy of gabapentin as a candidate addiction therapy. PMID- 24948815 TI - Gene-environment interactions: lifetime cognitive activity, APOE genotype, and beta-amyloid burden. AB - Carriers of the apolipoprotein E (APOE) epsilon4 allele, the major genetic risk for Alzheimer's disease (AD), harbor an increased load of beta-amyloid (Abeta) plaque burden that is felt to be a major instigator of AD development. Data has suggested that lifestyle factors may reduce AD risk by directly mitigating Abeta pathology, which could be particularly beneficial in APOE epsilon4 carriers. We therefore examined the interaction between lifetime cognitive activity and the APOE epsilon4 allele in relation to brain Abeta burden. We obtained measures of lifetime cognitive activity in 118 cognitively normal human individuals (mean age: 76.13 +/- 5.56 years, 70 women) using a validated questionnaire that included measures over early, middle, and current age epochs. Hierarchical regression models (adjusted for age, gender, and years of education) were conducted to examine effects of APOE epsilon4 carrier status, lifetime cognitive activity, and the interaction of the two factors with cortical Abeta deposition, quantified using [11C] Pittsburgh-compound-B (PIB)-PET. As expected, the epsilon4 carriers exhibited higher PIB retention compared with noncarriers. Lifetime cognitive activity moderated the APOE genotype effect such that cortical PIB retention was diminished in epsilon4 carriers that reported higher cognitive activity over the life course. The findings suggest that greater lifetime cognitive activity may forestall AD pathology, specifically in genetically susceptible individuals. The effect could imply that cognitive training promotes increased neural efficiency that might retard the lifelong neurally mediated deposition of Abeta. PMID- 24948816 TI - Presynaptic clathrin levels are a limiting factor for synaptic transmission. AB - To maintain communication, neurons must recycle their synaptic vesicles with high efficiency. This process places a huge burden on the clathrin-mediated endocytic machinery, but the consequences of this are poorly understood. We found that the amount of clathrin in a presynaptic terminal is not fixed. During stimulation, clathrin moves out of synapses as a function of stimulus strength and neurotransmitter release probability, which, together with membrane coat formation, transiently reduces the available pool of free clathrin triskelia. Correlative functional and morphological experiments in cholinergic autapses established by superior cervical ganglion neurons in culture show that presynaptic terminal function is compromised if clathrin levels fall by 20% after clathrin heavy chain knock down using RNAi. Synaptic transmission is depressed due to a reduction of cytoplasmic and readily releasable pools of vesicles. However, synaptic depression reverts after dialysis of exogenous clathrin, thus compensating RNAi-induced depletion. Lowering clathrin levels also reduces quantal size, which occurs concomitantly with a decrease in the size of synaptic vesicles. Large dense-core vesicles are unaffected by clathrin knock down. Together, our results show that clathrin levels are a dynamic property of presynaptic terminals that can influence short-term plasticity in a stimulus dependent manner. PMID- 24948817 TI - Modulation of GABAA receptor signaling increases neurogenesis and suppresses anxiety through NFATc4. AB - Correlative evidence suggests that GABAergic signaling plays an important role in the regulation of activity-dependent hippocampal neurogenesis and emotional behavior in adult mice. However, whether these are causally linked at the molecular level remains elusive. Nuclear factor of activated T cell (NFAT) proteins are activity-dependent transcription factors that respond to environmental stimuli in different cell types, including hippocampal newborn neurons. Here, we identify NFATc4 as a key activity-dependent transcriptional regulator of GABA signaling in hippocampal progenitor cells via an unbiased high throughput genome-wide study. Next, we demonstrate that GABAA receptor (GABAAR) signaling modulates hippocampal neurogenesis through NFATc4 activity, which in turn regulates GABRA2 and GABRA4 subunit expression via binding to specific promoter responsive elements, as assessed by ChIP and luciferase assays. Furthermore, we show that selective pharmacological enhancement of GABAAR activity promotes hippocampal neurogenesis via the calcineurin/NFATc4 axis. Importantly, the NFATc4-dependent increase in hippocampal neurogenesis after GABAAR stimulation is required for the suppression of the anxiety response in mice. Together, these data provide a novel molecular insight into the regulation of the anxiety response in mice, suggesting that the GABAAR/NFATc4 axis is a druggable target for the therapy of emotional disorders. PMID- 24948818 TI - Brain glycolipids suppress T helper cells and inhibit autoimmune demyelination. AB - The CNS is considered an immune privileged site because its repertoire of highly immunogenic molecules remains unseen by the immune system under normal conditions. However, the mechanism underlying the inhibition of immune reactions within the CNS environment is not known, particularly in regions containing myelin, which contains several potent proteins and lipids that are invariably recognized as foreign by immune system cells. Sulfatides constitute a major component of myelin glycolipids and are known to be capable of raising an immune response. In this study, the effect of sulfatides on mouse T cell function and differentiation was analyzed in vitro and in vivo. We found profound inhibition of sulfatide-dependent T cell proliferation which was particularly pronounced in naive T helper (Th) cells. The inhibitory effect of sulfatides on T cell function was CD1d-independent and was not related to apoptosis or necrosis but did involve the induction of anergy as confirmed by the upregulation of early growth response 2 transcription factor. A glycolipid 3-sulfate group was essential for the T cell suppression, and the T cell inhibition was galectin-4-dependent. Sulfatide stimulation in vitro led to prominent suppression of Th17 differentiation, and this was related to a decrease in susceptibility to disease in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis. Thus, we have defined a novel mechanism of negative regulation of T cell function by endogenous brain-derived glycolipids, a family of molecules traditionally deemphasized in favor of myelin proteins in studies of CNS autoimmunity. PMID- 24948820 TI - Xenia Forsselliana 2013. PMID- 24948821 TI - Complications After Facial Injections With Permanent Fillers: Important Limitations and Considerations of MRI Evaluation. AB - BACKGROUND: Soft-tissue fillers have become more prevalent for facial augmentation in the last 2 decades, even though complications of permanent fillers can be challenging to treat. An investigative imaging tool could aid in assessing the nature and extent of these complications when clinical findings are ambiguous. OBJECTIVES: The authors analyzed the value of magnetic resonance imaging (MRI) in the assessment of delayed-onset complications after injection of patients with permanent fillers. METHODS: Thirty-two patients with complications related to facial fillers were evaluated in this prospective cohort study. Their medical history was documented, and MRI was conducted before treatment of the complications. Radiologists were informed of the injection sites but were blinded to the results of other clinical evaluations. Levels of agreement between clinical and radiologic findings were calculated with the Jaccard similarity coefficient. RESULTS: A total of 107 site-specific clinicoradiologic evaluations were analyzed. The level of agreement was assessed as strong for deposits without complications and noninflammatory nodules (combined 85%), moderate for abscesses (60%), fair for low-grade inflammations (32%), and slight for migrations (9%). Results from the MRI examinations aided in subsequent treatment decisions in 11% of cases. CONCLUSIONS: Study results show that MRI may be useful for diagnosing complications associated with fillers that have migratory potential, for depiction of the extent of deposits before treatment, and for follow-up of low grade inflammation and abscesses after surgery. LEVEL OF EVIDENCE: 3. PMID- 24948822 TI - Pituitary incidentaloma found on O-(2-18F-fluoroethyl)-l-tyrosine PET. AB - Although incidental pituitary findings on (18)F-FDG PET are uncommon, there are several reports published in the literature. It is believed that this is the first reporting of incidental pituitary disease found on O-(2-(18)F-fluoroethyl) l-tyrosine ((18)F-FET) PET imaging. The case provides valuable insight into pathogenesis, diagnostic tools, and related pathology. The power of (18)F-FET in differentiating cerebral metastases and recurrence in patients who had previous surgical and radiation therapy is highlighted, and the incremental benefits over MR imaging and (18)F-FDG PET are outlined. The case represents an uncommon finding on MR imaging and (18)F-FDG PET and a rare finding on (18)F-FET PET. PMID- 24948823 TI - 18F-FDG PET and PET/CT in diagnosis and treatment monitoring of pyrexia of unknown origin due to tuberculosis with prominent hepatosplenic involvement. AB - The potential of (18)F-FDG PET/CT in the diagnosis and treatment response monitoring of fever of unknown origin (resulting from hepatosplenic tuberculosis) is demonstrated in this report. The patient was a 32-y-old woman who had presented to us with a history of pyrexia of unknown origin for the past 2 mo. On investigation, she was found to have hepatic and splenic granulomas, with whole body (18)F-FDG PET demonstrating abnormal (18)F-FDG-avid foci in the liver and spleen. Ultrasonography-guided liver biopsy was suggestive of granulomatous hepatitis. The patient was clinically nonresponsive to first-line antitubercular drugs, and second-line antitubercular medications were added subsequently in view of clinical nonresponse. The patient responded well to the treatment. The repeated CT scan at 11 mo demonstrated persistence of the splenic granulomas; however, follow-up (18)F-FDG PET/CT at the same time showed resolution of (18)F FDG-concentrating active disease foci with suggestion of complete metabolic response, commensurate with the patient's clinical improvement. PMID- 24948824 TI - Use of SPECT/CT with 99mTc-MDP bone scintigraphy to diagnose sacral insufficiency fracture. AB - Bone SPECT/CT offers additional information on pelvic insufficiency fractures, especially when there is incomplete formation of the H-sign on planar bone scanning. PMID- 24948825 TI - SNMMI and EANM practice guideline for meckel diverticulum scintigraphy 2.0. PMID- 24948826 TI - Second malignancies in patients with primary central nervous system lymphoma. AB - BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma with distinctive biological behaviors. The evolving treatment of PCNSL has greatly improved the outcome for patients with this disease and has stimulated interest in second malignancies (SMs) in patients diagnosed with PCNSL. METHODS: The records of 129 cases of PCNSL at Mayo Clinic, diagnosed between January 1, 1988, and November 26, 2012, were reviewed. Data on clinical characteristics, laboratory parameters, treatments, outcomes, and SMs were collected. The mean follow-up time was 44.8 months (range, 0.5-240 months; median, 28.0 months). RESULTS: Altogether, 28 cases with 30 (23.26%) SMs were identified. Twenty (15.50%) patients had prior or synchronous SM. Ten (7.76%) patients developed a subsequent primary cancer after PCNSL. The most common sites of prior or synchronous SMs were prostate (4/20), skin (4/20), and gastrointestinal (3/20). The most common site of the subsequent SM was skin (4/10). Two cases were identified with both prior SM and subsequent SM. CONCLUSIONS: Second malignancies in cases with PCNSL were not uncommon and occurred in nearly a quarter of our cohort. Nonmelanoma skin cancers were frequently seen. Therefore, screening for SMs should also be considered in long term follow-up of patients with PCNSL. In addition, the high incidence of subsequent cancer, synchronous cancer, and frequently seen nonmelanoma skin cancers may all indicate an immunosuppressed state in patients with PCNSL. PMID- 24948827 TI - Phytochrome B Nuclear Bodies Respond to the Low Red to Far-Red Ratio and to the Reduced Irradiance of Canopy Shade in Arabidopsis. AB - The current consensus is that plant responses to canopy shade involve the perception of low red to far-red ratios (R:FRs) by phytochrome B (phyB), which leads to the direct activation of auxin synthesis genes by PHYTOCHROME INTERACTING FACTORs (PIFs). In addition to its effect on R:FRs, shade also reduces irradiance, but whether shade-induced drops in irradiance affect phyB activity has not been demonstrated. To address this issue, we investigated whether irradiance and R:FRs have similar effects on the nuclear distribution of phyB in petiole cells of light-grown plants. Under high-irradiance white light, phyB formed large nuclear bodies. Lowering irradiance without changing R:FRs or lowering R:FRs by adding far-red light led to the appearance of small nuclear bodies containing phyB. Large nuclear bodies remained but with some concomitant reduction in diameter. The appearance of small nuclear bodies was rapid, stable, and reversible upon the return to high irradiance and high R:FRs. High levels of red light but not of blue light were enough to restrain the formation of small phyB nuclear bodies. Irradiance was effective within the range found in natural canopies and even under relatively low R:FRs. The promotion of leaf hyponasty by lowering irradiance was impaired in phyB and pif mutants, as previously reported for the response to R:FRs. The expression of auxin-related genes showed a similar hierarchy of response to low R:FRs and low irradiance. We propose that phyB is able to perceive not only the low R:FRs, but also the low irradiance of shade. PMID- 24948828 TI - Reversible Deformation of Transfusion Tracheids in Taxus baccata Is Associated with a Reversible Decrease in Leaf Hydraulic Conductance. AB - Declines in leaf hydraulic conductance (Kleaf) with increasing water stress have been attributed to cavitation of the leaf xylem. However, in the leaves of conifers, the reversible collapse of transfusion tracheids may provide an alternative explanation. Using Taxus baccata, a conifer species without resin, we developed a modified rehydration technique that allows the separation of declines in Kleaf into two components: one reversible and one irreversible upon relaxation of water potential to -1 MPa. We surveyed leaves at a range of water potentials for evidence of cavitation using cryo-scanning electron microscopy and quantified dehydration-induced structural changes in transfusion tracheids by cryo fluorescence microscopy. Irreversible declines in Kleaf did not occur until leaf water potentials were more negative than -3 MPa. Declines in Kleaf between -2 and -3 MPa were reversible and accompanied by the collapse of transfusion tracheids, as evidenced by cryo-fluorescence microscopy. Based on cryo-scanning electron microscopy, cavitation of either transfusion or xylem tracheids did not contribute to declines in Kleaf in the reversible range. Moreover, the deformation of transfusion tracheids was quickly reversible, thus acting as a circuit breaker regulating the flux of water through the leaf vasculature. As transfusion tissue is present in all gymnosperms, the reversible collapse of transfusion tracheids may be a general mechanism in this group for the protection of leaf xylem from excessive loads generated in the living leaf tissue. PMID- 24948829 TI - The Cellulase KORRIGAN Is Part of the Cellulose Synthase Complex. AB - Plant growth and organ formation depend on the oriented deposition of load bearing cellulose microfibrils in the cell wall. Cellulose is synthesized by a large relative molecular weight cellulose synthase complex (CSC), which comprises at least three distinct cellulose synthases. Cellulose synthesis in plants or bacteria also requires the activity of an endo-1,4-beta-d-glucanase, the exact function of which in the synthesis process is not known. Here, we show, to our knowledge for the first time, that a leaky mutation in the Arabidopsis (Arabidopsis thaliana) membrane-bound endo-1,4-beta-d-glucanase KORRIGAN1 (KOR1) not only caused reduced CSC movement in the plasma membrane but also a reduced cellulose synthesis inhibitor-induced accumulation of CSCs in intracellular compartments. This suggests a role for KOR1 both in the synthesis of cellulose microfibrils and in the intracellular trafficking of CSCs. Next, we used a multidisciplinary approach, including live cell imaging, gel filtration chromatography analysis, split ubiquitin assays in yeast (Saccharomyces cerevisiae NMY51), and bimolecular fluorescence complementation, to show that, in contrast to previous observations, KOR1 is an integral part of the primary cell wall CSC in the plasma membrane. PMID- 24948830 TI - It's complicated: intraroot system variability of respiration and morphological traits in four deciduous tree species. AB - Within branched root systems, a distinct heterogeneity of traits exists. Knowledge about the ecophysiology of different root types is critical to understand root system functioning. Classification schemes have to match functional root types as closely as possible to be used for sampling and modeling. Among ecophysiological root traits, respiration is of particular importance, consuming a great amount of carbon allocated. Root architecture differs between the four deciduous tree seedlings. However, two types of terminal root segments (i.e. first and second orders), white colored and brown colored, can be distinguished in all four species but vary in frequency, their morphology differing widely from each other and higher coarse root orders. Root respiration is related to diameter and tissue density. The use of extended root ordering (i.e. order and color) explains the variance of respiration two times as well as root diameter or root order classes alone. White terminal roots respire significantly more than brown ones; both possess respiration rates that are greater than those of higher orders in regard to dry weight and lower in regard to surface area. The correlation of root tissue density to respiration will allow us to use this continuous parameter (or easier to determine dry matter content) to model the respiration within woody root systems without having to determine nitrogen contents. In addition, this study evidenced that extended root orders are better suited than root diameter classes to picture the differences between root functional types. Together with information on root order class frequencies, these data allow us to calculate realistic, species-specific respiration rates of root branches. PMID- 24948831 TI - Proton Gradient Regulation5-Like1-Mediated Cyclic Electron Flow Is Crucial for Acclimation to Anoxia and Complementary to Nonphotochemical Quenching in Stress Adaptation. AB - To investigate the functional importance of Proton Gradient Regulation5-Like1 (PGRL1) for photosynthetic performances in the moss Physcomitrella patens, we generated a pgrl1 knockout mutant. Functional analysis revealed diminished nonphotochemical quenching (NPQ) as well as decreased capacity for cyclic electron flow (CEF) in pgrl1. Under anoxia, where CEF is induced, quantitative proteomics evidenced severe down-regulation of photosystems but up-regulation of the chloroplast NADH dehydrogenase complex, plastocyanin, and Ca2+ sensors in the mutant, indicating that the absence of PGRL1 triggered a mechanism compensatory for diminished CEF. On the other hand, proteins required for NPQ, such as light harvesting complex stress-related protein1 (LHCSR1), violaxanthin de-epoxidase, and PSII subunit S, remained stable. To further investigate the interrelation between CEF and NPQ, we generated a pgrl1 npq4 double mutant in the green alga Chlamydomonas reinhardtii lacking both PGRL1 and LHCSR3 expression. Phenotypic comparative analyses of this double mutant, together with the single knockout strains and with the P. patens pgrl1, demonstrated that PGRL1 is crucial for acclimation to high light and anoxia in both organisms. Moreover, the data generated for the C. reinhardtii double mutant clearly showed a complementary role of PGRL1 and LHCSR3 in managing high light stress response. We conclude that both proteins are needed for photoprotection and for survival under low oxygen, underpinning a tight link between CEF and NPQ in oxygenic photosynthesis. Given the complementarity of the energy-dependent component of NPQ (qE) and PGRL1 mediated CEF, we suggest that PGRL1 is a capacitor linked to the evolution of the PSII subunit S-dependent qE in terrestrial plants. PMID- 24948832 TI - MYB5 and MYB14 Play Pivotal Roles in Seed Coat Polymer Biosynthesis in Medicago truncatula. AB - In Arabidopsis (Arabidopsis thaliana), the major MYB protein regulating proanthocyanidin (PA) biosynthesis is TT2, named for the transparent testa phenotype of tt2 mutant seeds that lack PAs in their coats. In contrast, the MYB5 transcription factor mainly regulates seed mucilage biosynthesis and trichome branching, with only a minor role in PA biosynthesis. We here characterize MYB5 and MYB14 (a TT2 homolog) in the model legume Medicago truncatula. Overexpression of MtMYB5 or MtMYB14 strongly induces PA accumulation in M. truncatula hairy roots, and both myb5 and myb14 mutants of M. truncatula exhibit darker seed coat color than wild-type plants, with myb5 also showing deficiency in mucilage biosynthesis. myb5 mutant seeds have a much stronger seed color phenotype than myb14. The myb5 and myb14 mutants accumulate, respectively, about 30% and 50% of the PA content of wild-type plants, and PA levels are reduced further in myb5 myb14 double mutants. Transcriptome analyses of overexpressing hairy roots and knockout mutants of MtMYB5 and MtMYB14 indicate that MtMYB5 regulates a broader set of genes than MtMYB14. Moreover, we demonstrate that MtMYB5 and MtMYB14 physically interact and synergistically activate the promoters of anthocyanidin reductase and leucoanthocyanidin reductase, the key structural genes leading to PA biosynthesis, in the presence of MtTT8 and MtWD40-1. Our results provide new insights into the complex regulation of PA and mucilage biosynthesis in M. truncatula. PMID- 24948833 TI - Phycobilisome Mobility and Its Role in the Regulation of Light Harvesting in Red Algae. AB - Red algae represent an evolutionarily important group that gave rise to the whole red clade of photosynthetic organisms. They contain a unique combination of light harvesting systems represented by a membrane-bound antenna and by phycobilisomes situated on thylakoid membrane surfaces. So far, very little has been revealed about the mobility of their phycobilisomes and the regulation of their light harvesting system in general. Therefore, we carried out a detailed analysis of phycobilisome dynamics in several red alga strains and compared these results with the presence (or absence) of photoprotective mechanisms. Our data conclusively prove phycobilisome mobility in two model mesophilic red alga strains, Porphyridium cruentum and Rhodella violacea. In contrast, there was almost no phycobilisome mobility in the thermophilic red alga Cyanidium caldarium that was not caused by a decrease in lipid desaturation in this extremophile. Experimental data attributed this immobility to the strong phycobilisome photosystem interaction that highly restricted phycobilisome movement. Variations in phycobilisome mobility reflect the different ways in which light-harvesting antennae can be regulated in mesophilic and thermophilic red algae. Fluorescence changes attributed in cyanobacteria to state transitions were observed only in mesophilic P. cruentum with mobile phycobilisomes, and they were absent in the extremophilic C. caldarium with immobile phycobilisomes. We suggest that state transitions have an important regulatory function in mesophilic red algae; however, in thermophilic red algae, this process is replaced by nonphotochemical quenching. PMID- 24948834 TI - Dynamics of Male and Female Chromatin during Karyogamy in Rice Zygotes. AB - In angiosperms, the conversion of an egg cell into a zygote involves two sequential gametic processes: plasmogamy, the fusion of the plasma membranes of male and female gametes, and karyogamy, the fusion of the gametic nuclei. In this study, the nuclei and nuclear membranes of rice (Oryza sativa) gametes were fluorescently labeled using histones 2B-green fluorescent protein/red fluorescent protein and Sad1/UNC-84-domain protein2-green fluorescent protein, respectively, which were heterologously expressed. These gametes were fused in vitro to produce zygotes, and the nuclei and nuclear membranes in the zygotes were observed during karyogamy. The results indicated that the sperm nucleus migrates adjacent to the egg nucleus 5 to 10 min after plasmogamy via an actin cytoskelton, and the egg chromatin then appears to move unidirectionally into the sperm nucleus through a possible nuclear connection. The enlargement of the sperm nucleus accompanies this possible chromatin remodeling. Then, 30 to 70 min after fusion, the sperm chromatin begins to decondense with the completion of karyogamy. Based on these observations, the development of early rice zygotes from plasmogamy to karyogamy was divided into eight stages, and using reverse transcription PCR analyses, paternal and de novo synthesized transcripts were separately detected in zygotes at early and late karyogamy stages, respectively. PMID- 24948835 TI - Xyloglucan Endotransglucosylase-Hydrolase17 Interacts with Xyloglucan Endotransglucosylase-Hydrolase31 to Confer Xyloglucan Endotransglucosylase Action and Affect Aluminum Sensitivity in Arabidopsis. AB - Previously, we reported that although the Arabidopsis (Arabidopsis thaliana) Xyloglucan Endotransglucosylase-Hydrolase31 (XTH31) has predominately xyloglucan endohydrolase activity in vitro, loss of XTH31 results in remarkably reduced in vivo xyloglucan endotransglucosylase (XET) action and enhanced Al resistance. Here, we report that XTH17, predicted to have XET activity, binds XTH31 in yeast (Saccharomyces cerevisiae) two-hybrid and coimmunoprecipitations assays and that this interaction may be required for XTH17 XET activity in planta. XTH17 and XTH31 may be colocalized in plant cells because tagged XTH17 fusion proteins, like XTH31 fusion proteins, appear to target to the plasma membrane. XTH17 expression, like that of XTH31, was substantially reduced in the presence of aluminum (Al), even at concentrations as low as 10 um for 24 h or 25 um for just 30 min. Agrobacterium tumefaciens-mediated transfer DNA insertion mutant of XTH17, xth17, showed low XET action and had moderately shorter roots than the wild type but was more Al resistant than the wild type. Similar to xth31, xth17 had low hemicellulose content and retained less Al in the cell wall. These data suggest a model whereby XTH17 and XTH31 may exist as a dimer at the plasma membrane to confer in vivo XET action, which modulates cell wall Al-binding capacity and thereby affects Al sensitivity in Arabidopsis. PMID- 24948836 TI - Determination of the Structure and Catalytic Mechanism of Sorghum bicolor Caffeic Acid O-Methyltransferase and the Structural Impact of Three brown midrib12 Mutations. AB - Using S-adenosyl-methionine as the methyl donor, caffeic acid O-methyltransferase from sorghum (Sorghum bicolor; SbCOMT) methylates the 5-hydroxyl group of its preferred substrate, 5-hydroxyconiferaldehyde. In order to determine the mechanism of SbCOMT and understand the observed reduction in the lignin syringyl to-guaiacyl ratio of three brown midrib12 mutants that carry COMT gene missense mutations, we determined the apo-form and S-adenosyl-methionine binary complex SbCOMT crystal structures and established the ternary complex structure with 5 hydroxyconiferaldehyde by molecular modeling. These structures revealed many features shared with monocot ryegrass (Lolium perenne) and dicot alfalfa (Medicago sativa) COMTs. SbCOMT steady-state kinetic and calorimetric data suggest a random bi-bi mechanism. Based on our structural, kinetic, and thermodynamic results, we propose that the observed reactivity hierarchy among 4,5-dihydroxy-3-methoxycinnamyl (and 3,4-dihydroxycinnamyl) aldehyde, alcohol, and acid substrates arises from the ability of the aldehyde to stabilize the anionic intermediate that results from deprotonation of the 5-hydroxyl group by histidine-267. Additionally, despite the presence of other phenylpropanoid substrates in vivo, sinapaldehyde is the preferential product, as demonstrated by its low Km for 5-hydroxyconiferaldehyde. Unlike its acid and alcohol substrates, the aldehydes exhibit product inhibition, and we propose that this is due to nonproductive binding of the S-cis-form of the aldehydes inhibiting productive binding of the S-trans-form. The S-cis-aldehydes most likely act only as inhibitors, because the high rotational energy barrier around the 2-propenyl bond prevents S-trans-conversion, unlike alcohol substrates, whose low 2-propenyl bond rotational energy barrier enables rapid S-cis/S-trans-interconversion. PMID- 24948838 TI - Gamma frailty transformation models for multivariate survival times. AB - We propose a class of transformation models for multivariate failure times. The class of transformation models generalize the usual gamma frailty model and yields a marginally linear transformation model for each failure time. Nonparametric maximum likelihood estimation is used for inference. The maximum likelihood estimators for the regression coefficients are shown to be consistent and asymptotically normal, and their asymptotic variances attain the semiparametric efficiency bound. Simulation studies show that the proposed estimation procedure provides asymptotically efficient estimates and yields good inferential properties for small sample sizes. The method is illustrated using data from a cardiovascular study. PMID- 24948837 TI - The MADS-Domain Factors AGAMOUS-LIKE15 and AGAMOUS-LIKE18, along with SHORT VEGETATIVE PHASE and AGAMOUS-LIKE24, Are Necessary to Block Floral Gene Expression during the Vegetative Phase. AB - Multiple factors, including the MADS-domain proteins AGAMOUS-LIKE15 (AGL15) and AGL18, contribute to the regulation of the transition from vegetative to reproductive growth. AGL15 and AGL18 were previously shown to act redundantly as floral repressors and upstream of FLOWERING LOCUS T (FT) in Arabidopsis (Arabidopsis thaliana). A series of genetic and molecular experiments, primarily focused on AGL15, was performed to more clearly define their role. agl15 agl18 mutations fail to suppress ft mutations but show additive interactions with short vegetative phase (svp) mutations in ft and suppressor of constans1 (soc1) backgrounds. Chromatin immunoprecipitation analyses with AGL15-specific antibodies indicate that AGL15 binds directly to the FT locus at sites that partially overlap those bound by SVP and FLOWERING LOCUS C. In addition, expression of AGL15 in the phloem effectively restores wild-type flowering times in agl15 agl18 mutants. When agl15 agl18 mutations are combined with agl24 svp mutations, the plants show upward curling of rosette and cauline leaves, in addition to early flowering. The change in leaf morphology is associated with elevated levels of FT and ectopic expression of SEPALLATA3 (SEP3), leading to ectopic expression of floral genes. Leaf curling is suppressed by sep3 and ft mutations and enhanced by soc1 mutations. Thus, AGL15 and AGL18, along with SVP and AGL24, are necessary to block initiation of floral programs in vegetative organs. PMID- 24948839 TI - Transition into first intercourse, marriage, and childbearing among Ethiopian women. PMID- 24948841 TI - Optimal sampling ratios in comparative diagnostic trials. AB - A subjective sampling ratio between the case and the control groups is not always an efficient choice to maximize the power or to minimize the total required sample size in comparative diagnostic trials.We derive explicit expressions for an optimal sampling ratio based on a common variance structure shared by several existing summary statistics of the receiver operating characteristic curve. We propose a two-stage procedure to estimate adaptively the optimal ratio without pilot data. We investigate the properties of the proposed method through theoretical proofs, extensive simulation studies and a real example in cancer diagnostic studies. PMID- 24948840 TI - Markovian Interpretations of Dual Retrieval Processes. AB - A half-century ago, at the dawn of the all-or-none learning era, Estes showed that finite Markov chains supply a tractable, comprehensive framework for discrete-change data of the sort that he envisioned for shifts in conditioning states in stimulus sampling theory. Shortly thereafter, such data rapidly accumulated in many spheres of human learning and animal conditioning, and Estes' work stimulated vigorous development of Markov models to handle them. A key outcome was that the data of the workhorse paradigms of episodic memory, recognition and recall, proved to be one- and two-stage Markovian, respectively, to close approximations. Subsequently, Markov modeling of recognition and recall all but disappeared from the literature, but it is now reemerging in the wake of dual-process conceptions of episodic memory. In recall, in particular, Markov models are being used to measure two retrieval operations (direct access and reconstruction) and a slave familiarity operation. In the present paper, we develop this family of models and present the requisite machinery for fit evaluation and significance testing. Results are reviewed from selected experiments in which the recall models were used to understand dual memory processes. PMID- 24948842 TI - Bayesian sparse graphical models and their mixtures. AB - We propose Bayesian methods for Gaussian graphical models that lead to sparse and adaptively shrunk estimators of the precision (inverse covariance) matrix. Our methods are based on lasso-type regularization priors leading to parsimonious parameterization of the precision matrix, which is essential in several applications involving learning relationships among the variables. In this context, we introduce a novel type of selection prior that develops a sparse structure on the precision matrix by making most of the elements exactly zero, in addition to ensuring positive definiteness - thus conducting model selection and estimation simultaneously. More importantly, we extend these methods to analyze clustered data using finite mixtures of Gaussian graphical model and infinite mixtures of Gaussian graphical models. We discuss appropriate posterior simulation schemes to implement posterior inference in the proposed models, including the evaluation of normalizing constants that are functions of parameters of interest, which result from the restriction of positive definiteness on the correlation matrix. We evaluate the operating characteristics of our method via several simulations and demonstrate the application to real data examples in genomics. PMID- 24948843 TI - CALIBRATING NON-CONVEX PENALIZED REGRESSION IN ULTRA-HIGH DIMENSION. AB - We investigate high-dimensional non-convex penalized regression, where the number of covariates may grow at an exponential rate. Although recent asymptotic theory established that there exists a local minimum possessing the oracle property under general conditions, it is still largely an open problem how to identify the oracle estimator among potentially multiple local minima. There are two main obstacles: (1) due to the presence of multiple minima, the solution path is nonunique and is not guaranteed to contain the oracle estimator; (2) even if a solution path is known to contain the oracle estimator, the optimal tuning parameter depends on many unknown factors and is hard to estimate. To address these two challenging issues, we first prove that an easy-to-calculate calibrated CCCP algorithm produces a consistent solution path which contains the oracle estimator with probability approaching one. Furthermore, we propose a high dimensional BIC criterion and show that it can be applied to the solution path to select the optimal tuning parameter which asymptotically identifies the oracle estimator. The theory for a general class of non-convex penalties in the ultra high dimensional setup is established when the random errors follow the sub Gaussian distribution. Monte Carlo studies confirm that the calibrated CCCP algorithm combined with the proposed high-dimensional BIC has desirable performance in identifying the underlying sparsity pattern for high-dimensional data analysis. PMID- 24948844 TI - Nature, Nurture, and Expertise. AB - Rather than investigating the extent to which training can improve performance under experimental conditions ('what could be'), we ask about the origins of expertise as it exists in the world ('what is'). We used the twin method to investigate the genetic and environmental origins of exceptional performance in reading, a skill that is a major focus of educational training in the early school years. Selecting reading experts as the top 5% from a sample of 10,000 12 year-olds twins assessed on a battery of reading tests, three findings stand out. First, we found that genetic factors account for more than half of the difference in performance between expert and normal readers. Second, our results suggest that reading expertise is the quantitative extreme of the same genetic and environmental factors that affect reading performance for normal readers. Third, growing up in the same family and attending the same schools account for less than a fifth of the difference between expert and normal readers. We discuss implications and interpretations ('what is inherited is DNA sequence variation'; 'the abnormal is normal'). Finally, although there is no necessary relationship between 'what is' and 'what could be', the most far-reaching issues about the acquisition of expertise lie at the interface between them ('the nature of nurture: from a passive model of imposed environments to an active model of shaped experience'). PMID- 24948845 TI - Pathways of Peer Relationships from Childhood to Young Adulthood. AB - This study examined trajectories of peer social preference during childhood and personality assessed in early adolescence in relation to trajectories of friendship quality during early adulthood. Participants (N = 585) were followed from age 5 to age 23. At ages 5 to 8, peers provided sociometric nominations; at age 12 participants reported their own personality characteristics; from age 19 to 23 participants rated their friendship quality. Latent growth modeling revealed that trajectories characterized by high levels of childhood peer social preference were related to trajectories characterized by high levels of early adulthood friendship quality. Early adolescent personality characterized by extraversion and conscientiousness predicted higher friendship quality at age 19, and conscientiousness predicted change in friendship quality from age 19 to 23. This study demonstrates that peer relationships show continuity from childhood to early adulthood and that qualities of core personality are linked to the development of adult friendships. PMID- 24948847 TI - PMA induces vaccine adjuvant activity by the modulation of TLR signaling pathway. AB - Toll-like receptor (TLR) ligands are being developed for use as vaccine adjuvants and as immunomodulators because of their ability to stimulate innate and adaptive immune responses. Flagellin, a TLR5 ligand, was reported to show potent mucosal vaccine adjuvant activity. To identify ligands that potentiate the adjuvant activity of flagellin, we screened a plant library using HEK293T cells transiently cotransfected with phTLR5 and pNF- kappa B-SEAP plasmids. The 90% EtOH extract from Croton tiglium showed significant NF- kappa B transactivation in a TLR5-independent manner along with the increase of a flagellin activity. We have studied to characterize an active component from Croton tiglium and to elucidate the action mechanisms. Phorbol 12-myristate 13-acetate (PMA) was isolated as an active component of Croton tiglium by activity-guided fractionation, column chromatography, HPLC, NMR, and MS. PMA at a range of nM induced PKC-dependent NF- kappa B activation and IL-8 production in both TLR5- and TLR5+ assay systems. In in vivo mouse vaccination model, PMA induced antigen specific IgG and IgA antibody responses and increased IL-12 production corresponding to T cell responses in spleen lymphocytes. These results suggest that PMA would serve as an efficacious mucosal vaccine adjuvant. PMID- 24948846 TI - Recognition functions of pentameric C-reactive protein in cardiovascular disease. AB - C-reactive protein (CRP) performs two recognition functions that are relevant to cardiovascular disease. First, in its native pentameric conformation, CRP recognizes molecules and cells with exposed phosphocholine (PCh) groups, such as microbial pathogens and damaged cells. PCh-containing ligand-bound CRP activates the complement system to destroy the ligand. Thus, the PCh-binding function of CRP is defensive if it occurs on foreign pathogens because it results in the killing of the pathogen via complement activation. On the other hand, the PCh binding function of CRP is detrimental if it occurs on injured host cells because it causes more damage to the tissue via complement activation; this is how CRP worsens acute myocardial infarction and ischemia/reperfusion injury. Second, in its nonnative pentameric conformation, CRP also recognizes atherogenic low density lipoprotein (LDL). Recent data suggest that the LDL-binding function of CRP is beneficial because it prevents formation of macrophage foam cells, attenuates inflammatory effects of LDL, inhibits LDL oxidation, and reduces proatherogenic effects of macrophages, raising the possibility that nonnative CRP may show atheroprotective effects in experimental animals. In conclusion, temporarily inhibiting the PCh-binding function of CRP along with facilitating localized presence of nonnative pentameric CRP could be a promising approach to treat atherosclerosis and myocardial infarction. There is no need to stop the biosynthesis of CRP. PMID- 24948849 TI - Understanding interannual, decadal level variability in paralytic shellfish poisoning toxicity in the Gulf of Maine: the HAB Index. AB - A major goal in harmful algal bloom (HAB) research has been to identify mechanisms underlying interannual variability in bloom magnitude and impact. Here the focus is on variability in Alexandrium fundyense blooms and paralytic shellfish poisoning (PSP) toxicity in Maine, USA, over 34 years (1978 - 2011). The Maine coastline was divided into two regions -eastern and western Maine, and within those two regions, three measures of PSP toxicity (the percent of stations showing detectable toxicity over the year, the cumulative amount of toxicity per station measured in all shellfish (mussel) samples during that year, and the duration of measurable toxicity) were examined for each year in the time series. These metrics were combined into a simple HAB Index that provides a single measure of annual toxin severity across each region. The three toxin metrics, as well as the HAB Index that integrates them, reveal significant variability in overall toxicity between individual years as well as long-term, decadal patterns or regimes. Based on different conceptual models of the system, we considered three trend formulations to characterize the long-term patterns in the Index - a three-phase (mean-shift) model, a linear two-phase model, and a pulse-decline model. The first represents a "regime shift" or multiple equilibria formulation as might occur with alternating periods of sustained high and low cyst abundance or favorable and unfavorable growth conditions, the second depicts a scenario of more gradual transitions in cyst abundance or growth conditions of vegetative cells, and the third characterizes a "sawtooth" pattern in which upward shifts in toxicity are associated with major cyst recruitment events, followed by a gradual but continuous decline until the next pulse. The fitted models were compared using both residual sum of squares and Akaike's Information Criterion. There were some differences between model fits, but none consistently gave a better fit than the others. This statistical underpinning can guide efforts to identify physical and/or biological mechanisms underlying the patterns revealed by the HAB Index. Although A. fundyense cyst survey data (limited to 9 years) do not span the entire interval of the shellfish toxicity records, this analysis leads us to hypothesize that major changes in the abundance of A. fundyense cysts may be a primary factor contributing to the decadal trends in shellfish toxicity in this region. The HAB Index approach taken here is simple but represents a novel and potentially useful tool for resource managers in many areas of the world subject to toxic HABs. PMID- 24948848 TI - Protective effect of Laminaria japonica with probiotics on murine colitis. AB - Inflammatory bowel disease (IBD) is a chronically relapsing inflammatory disorder of the gastrointestinal tract. Most IBD treatments are unsatisfactory; therefore, various dietary supplements have emerged as promising interventions. Laminaria japonica (LJ) is an edible seaweed used to regulate digestive symptoms. Probiotics have been reported to improve digestive problems and their simultaneous administration with seaweeds has been shown to produce synergistic therapeutic effects. Here, we investigated the effect of LJ combination with probiotics on dextran sodium sulfate-induced colitis model in mice. Aqueous LJ extracts (LJE) at doses from 100 to 300 mg/kg and probiotics at a dose of 300 mg/kg were orally administered for 7 days. Body weight, colon length, histological score, macroscopic damage, and the levels of cytokines IFN- gamma , IL-1 beta , IL-6, IL-10, IL-12 (P40), IL-12 (P70), IL-17, and TNF- alpha were assessed. LJE alone caused a significant improvement of colitis signs such as colon length, histological score, and IL-1 beta and IL-6 production. LJE and probiotics demonstrated a synergistic effect by the histological score and levels of IL-1 beta , IL-6, and IL-12 (P40) but not IFN- gamma , IL-10, and IL-12 (P70). In conclusion, LJE was effective in inducing protection against colitis in mice and acted synergistically with probiotics. PMID- 24948850 TI - Long-term performance of modern coronary sinus leads in cardiac resynchronization therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) has become an important pillar of contemporary heart failure therapy. The efficacy of CRT, however, critically relies on proper LV lead placement and performance, which is why data regarding the long-term performance of CS leads are of considerable interest. Available studies are limited by a restricted variety of lead vendors, earlier lead models and / or very short follow-up periods. In the current study, we therefore investigated the long-term performance of modern LV leads in a large "real world" cohort of patients undergoing CRT implantation. METHODS AND RESULTS: All 193 patients who had successfullyundergone CRT implantation at the University Hospital Zurich between September 2003 and January 2010 were included in the study. An overall stable course of stimulation energy was observed over time; neither ischemic etiology, lead configuration, or severely reduced EF had an influence on the evolution of energy thresholds over time. Interestingly, patients with a high energy threshold at baseline experienced a significant reduction during follow-up. In contrast, a significant drop in impedance was seen following implantation, followed by a steady course for the rest of the observation period. Only 15 patients (9.7%) showed an impedance > 1000 Ohm at any time during their follow-up. Seven lead dislocations were observed during follow up. CONCLUSION: The current comprehensive analysis of long-term performance of modern coronary sinus leads demonstrates excellent stability, performance and safety. These data may have important implications for physicians involved in biventricular pacemaker implantations and in the follow-up care of these patients. PMID- 24948851 TI - Atrial Fibrillation and Beta Thalassemia Major: The Predictive Role of the 12 lead Electrocardiogram Analysis. AB - BACKGROUND: Paroxysmal atrial tachyarrhythmias frequently occur in beta thalassemia major (beta-TM) patients.The aim of our study was to investigate the role of maximum P-wave duration (P max) and dispersion (PD), calculated trough a new manually performed measurement with the use of computer software from all 12 ECG-leads,as predictors of atrial-fibrillation (AF) in beta-TM patients with conserved systolic or diastolic cardiac function during a twelve-months follow up. MATERIALS AND METHODS: 50 beta-TM-patients (age38.4+/-10.1; 38M) and 50 healthy subjects used as controls, matched for age and gender, were studied for the occurrence of atrial arrhythmias during a 1-year follow-up, through ECG Holter-monitoring performed every three months. The beta-TM-patients were divided into two groups according to number and complexity of premature-supraventricular complexes at the Holter-Monitoring (Group1: <30/h and no repetitive forms, n:35; Group2: >30/h or couplets, or run of supraventricular tachycardia and AF, n:15). RESULTS: Compared to the healthy control-group, beta-TM patients presented increased P-max (107.5+/- 21.2 vs 92.1+/-11ms, P=0.03) and PD-values (41.2+/-13 vs 25.1+/-5 ms,P=0.03). In the beta-TM population, the Group2 showed a statistically significant increase in PD (42.8+/-8.6 vs 33.2+/-6.5ms, P<0.001) and P-max (118.1+/-8.7 vs 103.1+/-7.5ms, P<0.001) compared to the Group1. Seven beta-TM patients who showed paroxysmal AF during this study had significantly increased P-max and PD than the other patients of the Group2. Moreover, P-max (OR:2.01; CI:1.12-3.59; P=0.01) and PD (OR=2.06;CI:1.17-3.64;P=0.01) demonstrated a statistically significant association with the occurrence of paroxysmal AF,P min was not associated with AF-risk (OR=0.99; CI:0.25-3.40; P=0.9) in beta-TM patients. A cut-off value of 111ms for P-max had a sensitivity of 80% and a specificity of 87%, a cut-off value of 35.5ms for PD had a sensitivity of 90% and a specificity of 85% in identifying beta-TM patients at risk for AF. CONCLUSION: Our results indicate that P-max and PD are useful electrocardiographic markers for identifying the beta-TM-high-risk patients for AF onset, even when the cardiac function is conserved. PMID- 24948853 TI - Envisioning AYUSH: Historic Opportunity for Innovation and Revitalization. PMID- 24948854 TI - Integrative approach for health care: time to review and change the paradigms. PMID- 24948852 TI - Reduced Penetrance and Variable Expression of SCN5A Mutations and the Importance of Co-inherited Genetic Variants: Case Report and Review of the Literature. AB - Mutations in the SCN5A gene are responsible for multiple phenotypical presentations including Brugada syndrome, long QT syndrome, progressive familial heart block, sick sinus syndrome, dilated cardiomyopathy, lone atrial fibrillation and multiple overlap syndromes. These different phenotypic expressions of a mutation in a single gene can be explained by variable expression and reduced penetrance. One of the possible explanations of these phenomena is the co-inheritance of genetic variants. We describe a family where the individuals exhibit a compound heterozygosity in the SCN5A gene including a mutation (R1632H) and a new variant (M858L). Individuals with both the mutation and new variant present with a more severe phenotype including spontaneous atrial tachyarrhythmia at young age. We give an overview of the different phenotypes of "SCN5A disease" and discuss the importance of co-inherited genetic variants in the expression of SCN5A disease. PMID- 24948855 TI - Anxiolytic, sedative, and hypnotic activities of aqueous extract of Morinda citrifolia fruit. AB - Morinda citrifolia (Indian mulberry or noni) fruit has been long used as a folk medicine for a wide range of health purposes as it is claimed to have analgesic, antiinflammatory, antioxidant, detoxifier, and cell-rejuvenator properties. A recent study has revealed central nervous system suppressant nature of its extract. Hence, the present study has evaluated the anxiolytic, sedative, and hypnotic effects of the aqueous extracts of Morinda citrifolia in rodents in comparison to diazepam. Anxiety was assessed by 'Isolation-induced aggression' model, sedation by 'Spontaneous locomotor activity using actophotometer' and hypnotic activity by 'Prolongation of ketamine-induced sleeping time'. Six male mice were used for each of the groups and postdose, all the six that received diazepam had shown an inhibition of aggression, whereas in the test group, five of six mice and none in the control group had shown an inhibition of aggression (P = 0.0007). Similarly, for the sedative activity, the total number of spontaneous locomotor activity at 30 min following drug administration was found to be 364.67 +/- 10.74, 123.16 +/- 8.33, and 196.67 +/- 3.7, while at 60 min it was found to be 209 +/- 12.98, 49 +/- 5.78, and 92 +/- 2.5 (mean +/- SD) for the control, standard, and test groups of mice respectively (P < 0.001). Hypnotic activity was measured by prolongation of ketamine-induced sleeping time wherein the onset and duration of loss of righting reflex were compared among each group of mice. The time in minutes for the onset in control, standard, and test groups was 4.01 +/- 0.22, 1.23 +/- 0.05, and 2.23 +/- 0.07, respectively. The duration of loss of righting reflex was 44.23 +/- 0.59, 56.03 +/- 1.34, and 50.57 +/- 0.36, respectively. Both these were statistically significant (P < 0.001). However, more clinical studies are needed to assess the long-term effects of the extract in humans. PMID- 24948856 TI - Does copper enhance the antihypertensive effect of Elaeocarpus ganitrus in experimentally induced hypertensive rats? AB - Ayurveda, one of the traditional systems of medicine of India, reports that the seeds of Elaeocarpus ganitrus Linn. (Tilaceae) can be used for the treatment of hypertension. The main aim is to evaluate the antihypertensive effect of Elaeocarpus ganitrus (Rudraksha) seeds. Powdered seeds were extracted by maceration, overnight, using water, in copper (E1) and glass vessel (E2) and analyzed for antihypertensive activity in cadmium chloride (1 mg/kg intraperitoneally, for a period of 15 days) induced hypertensive male Wistar rats at three dose levels. E1 was administered at the dose of 5, 10, and 15 mg/kg and E2 at dose of 10, 20, and 30 mg/kg. All the data were analyzed using one way analysis of variance (ANOVA) followed by Dunnett's multiple comparison test. E1 and E2 did not show any toxicity at the dose of 5 g/kg in rats. It was found that 15 mg/kg of E1 and 30 mg/kg of E2 decreases the blood pressure by 30.20 mmHg and 28.96 mmHg, respectively, in hypertensive rats. Thus, it can be said that 15 mg/kg of E1 produced similar decrease in blood pressure as was observed with 30 mg/kg of E2. Copper ions in E1 might be additively affecting the reduction in blood pressure with the usage of Elaeocarpus ganitrus extracts. PMID- 24948857 TI - A review on balya action mentioned in Ayurveda. AB - Medicinal and dietary substances have been used for various purposes including nutritional from time immemorial. Various activities such as immunomodulator, bulk promoting, nutritional, etc. that enhance strength, immunity, bulk of the body resulted by the use of medicinal or dietary substances are termed in total as Balya in Ayurveda. The term Balya originally stands for all those actions that enhance the "Bala". The word "Bala" refers to the strength and ability of the body or part of the body to cope up with various physical stressors. This term "Bala" refers to various body components and functions as per the science of Ayurveda. Even in the presence of modern scientific knowledge regarding body strength, Ayurveda concepts add varied dimensions to provide detailed explanation of Balya term. The balya action is critically analyzed and discussed in this review. PMID- 24948858 TI - Docosahexaenoic acid content is significantly higher in ghrita prepared by traditional Ayurvedic method. AB - BACKGROUND: Ghee (clarified butter) also known as ghrita, has been utilized for thousands of years in Ayurveda. Ghee is mostly prepared by traditional method in Indian households or by direct cream method at industry level. Ayurvedic classics mention that ghrita made from cow milk is superior. However, there is no scientific comparison available on preparation methods and essential fatty acids content of ghrita. OBJECTIVE: To investigate fatty acid composition of ghrita prepared by traditional/Ayurvedic method and commercial method (direct cream method). MATERIALS AND METHODS: Fatty Acid Methyl Esters (FAME) extracted from ghrita samples were analysed on Gas Chromatography (GC) Shimadzu B using capillary column BPX70 (0.32 mm*60 m, ID of 0.25 mm). The fatty acids in the samples were identified by comparing peaks with the external standard 68A (Nu Chek-Prep, Inc.USA). Significant differences between the experimental groups were assessed by analysis of variance. RESULTS: Distribution of fatty acids was compared in ghrita samples prepared by traditional method and direct cream method which is commercially used. Saturated fatty acids were predominant in both the groups. Mono unsaturated fatty acids and poly unsaturated fatty acids were in the range of 17-18% and 3-6% respectively. DHA content was significantly higher in ghee prepared by traditional method using curd starter fermentation. CONCLUSION: The findings suggested that ghrita prepared by traditional ayurvedic methods contains higher amount of DHA; Omega-3 long-chain polyunsaturated fatty acids, which is a major component of retinal and brain tissues and remains important in prevention of various diseases. PMID- 24948859 TI - Central nervous system activity of an aqueous acetonic extract of Ficus carica L. in mice. AB - BACKGROUND: Ficus carica Linn. is reported to possess variety of activities, but its potential in CNS disorders is still to be explored. OBJECTIVE: The present study was carried out to evaluate the CNS depressant activity of aqueous acetonic extract of Ficus carica Linn on different models in mice. MATERIALS AND METHODS: The aerial parts of the plant Ficus carica L. were extracted with aqueous acetone and the solvent was removed by rotary vacuum evaporator under reduced pressure. A crude extract was given orally and its effects were tested on ketamine-induced sleeping time, muscle-coordination, anxiety (elevated-plus maze and Staircase test), convulsions [maximal electroshock (MES) and pentylenetetrazole (PTZ) induced seizures], and nociception. In addition, we determined the levels of neurotransmitters, norepinephrine (NE) and 5-hydroxytryptamine (5-HT). RESULTS: RESULTS FROM THE EXPERIMENTAL MODELS TESTED SHOWED: (1) a delay on onset and prolongation of sleep of ketamine-induced sleeping time; (2) significant muscle relaxant activity; (3) a significant attenuation in the anxiety-response (4) a delay in the onset of seizures and reduction in duration of seizures and mortality induced by MES and PTZ; (5) a reduction in the licking time in nociception test and (6) increased levels of NE and 5-HT. CONCLUSION: This suggests that Ficus carica L. exerts its CNS depressive effect by modulating the neurotransmitters NE and 5-HT in the brain. PMID- 24948860 TI - Evaluation of anti-diabetic activity of Glucova Active Tablet on Type I and Type II diabetic model in rats. AB - BACKGROUND: Glucova Active Tablet is a proprietary Ayurvedic formulation with ingredients reported for anti-hyperglycemic, anti-hyperlipidemic activity and antioxidant properties. OBJECTIVE: Evaluation of anti-diabetic activity of Glucova Active Tablet on Type I and Type II diabetic model in rats. MATERIALS AND METHODS: Experimental Type I diabetes was induced in 24 albino rats with intra peritoneal injection of streptozotocin (50 mg/kg). Type II diabetes was induced in 18 albino rats by intra-peritoneal injection of streptozotocin (35 mg/kg) along with high fat diet. The rats were divided in 5 groups for Type I model and 4 groups for Type II model. Normal control group was kept common for both experimental models. Glucova Active Tablet (108 mg/kg) treatment was provided for 28 days twice daily orally. Fasting blood glucose level, serum lipid profile and liver anti-oxidant parameters like superoxide dismutase and reduced glutathione was carried out in both experimental models. Pancreas histopathology was also done. Statistical analysis were done by 'analysis of variance' test followed by post hoc Tukey's test, with significant level of P < 0.05. RESULTS AND DISCUSSION: Glucova Active Tablet showed significant effect on fasting blood glucose level. It also showed significant alteration in lipid profile and antioxidant parameters. Histopathology study revealed restoration of beta cells in pancreas in Glucova Active Tablet treated group. CONCLUSION: Finding of this study concludes that Glucova Active Tablet has shown promising anti-diabetic activity in Type I and Type II diabetic rats. It was also found showing good anti hyperlipidemic activity and anti-oxidant property. PMID- 24948861 TI - Comparative pharmacognosy of Pashanbhed. AB - BACKGROUND: Pashanbhed is a commercially available diuretic and lithotropic drug, used to treat renal problems. It is a controversial name as it is assigned to various plants such as Bergenia ligulata, Kalanchoe pinnata, Coleus aromaticus and Rotula aquatica. OBJECTIVE: To perform the comparative preliminary phytochemical screening, diuretic activity, and thin layer chromatography (TLC) finger printing profile of three plants (B. ligulata, C. aromaticus, and K. pinnata), most commonly used as Pashanbhed. MATERIALS AND METHODS: Diuretic potential of methanolic extract (ME) of three plants were evaluated at two dose levels (500 and 1,000 mg/kg p.o.), using normal Wistar rats (Lipschitz method). Furosemide (20 mg/kg p.o.) was used as a standard drug. The effect on urine output and electrolyte changes were measured for 24 h and compared. All MEs were screened preliminarily for their constituents and their TLC finger printing profiles were prepared. One-way analysis of variance (ANOVA) followed by Bonferroni's multiple comparison test. P < 0.05 was considered statistically significant. RESULTS: The MEs of all three plants have shown diuresis in normal rats. However, in intercomparison of the ME C. aromaticus (1,000 mg/kg p.o.) produced more significant diuresis (P < 0.05) and electrolyte excretion compared to other test groups, the effect was at par with furosemide. The ME of these plants showed presence of alkaloids, glycosides, steroids, terpenoids, saponins, flavonoids, etc. CONCLUSION: The ME of C. aromaticus (1,000 mg/kg p.o.) has showed highest diuretic action (4.2) among the tested extracts. This suggests the use of C. aromaticus leaves as "Pashanbhed"; the most effective diuretic drug. PMID- 24948862 TI - A randomized controlled clinical trial of Ocimum sanctum and chlorhexidine mouthwash on dental plaque and gingival inflammation. AB - BACKGROUND: Periodontal diseases are ubiquitous, affecting all dentate animals. Regular methods for controlling it have been found to be ineffective, which have paved the way for the use of herbal products as an adjunctive to mechanical therapy as they are free to untoward effects and hence can be used for a long period of time. Ocimum sanctum is a plant which has the greater medicinal value and enormous properties for curing and preventing disease. OBJECTIVE: In the present study we assessed the effectiveness of Ocimum sanctum on dental plaque, gingival inflammation and comparison with gold standard chlorhexidine and normal saline (placebo). MATERIALS AND METHODS: A triple blind randomized control trial was conducted among volunteered medical students. They were randomly allocated into three study groups: (1) Ocimum sanctum mouthwash (n = 36); (2) Chlorhexidine (active control) (n = 36); (3) normal saline (negative control) (n = 36). Assessment was carried out according to plaque score and gingival score. Statistical analysis was carried out later to compare the effect of both mouthwash. ANOVA (Analysis of variance) and post-hoc LSD tests were performed using software package used for statistical analysis (SPSS) version 17. P <=0.05 was considered as statistically significant. RESULTS: Our result showed that Ocimum sanctum mouthrinse is equally effective in reducing plaque and gingivitis as Chlorhexidine. The results demonstrated a significant reduction in gingival bleeding and plaque indices in both groups over a period of 15 and 30 days as compared to control group. CONCLUSION: The results of the present study indicate that Ocimum sanctum mouthrinse may prove to be an effective mouthwash owing to its ability in decreasing periodontal indices by reducing plaque accumulation, gingival inflammation and bleeding. It has no side effect as compared to chlorhexidine. PMID- 24948863 TI - Efficacy of a standardized herbal preparation (Roidosanal((r))) in the treatment of hemorrhoids: A randomized, controlled, open-label multicentre study. AB - BACKGROUND: Catechins and epicatechins are monomers of naturally occurring proanthocyanidins, which have been reported with free radical scavenging, antioxidant, antiinflammatory, antiallergic, and vasodilatory properties. Plant parts rich in proanthocyanidins have been used for years in treatment of various ano-rectal diseases. This study compares the efficacy of two herbal preparations, Daflon((r)) 500 mg and Roidosanal((r)), in ameliorating the signs and symptoms associated with hemorrhoids. OBJECTIVE: To evaluate the safety and to compare the efficacy of a herbal preparation, Roidosanal((r)) versus Daflon((r)) 500 mg, on signs and symptoms of hemorrhoidal disease. MATERIALS AND METHODS: In this pilot, active controlled, open-labeled multicentre study, 73 patients with proctoscopy proven hemorrhoids (Grade I to III) were randomly assigned to receive either Roidosanal((r)) (Gr R; n = 37) or Daflon((r)) 500 mg (Gr D; n = 36), for 15 days, at three centers in India. Assessment of hemorrhoidal symptoms was carried out in all patients at different time points. Intent-to-treat analysis was performed for both primary and secondary endpoints. RESULTS: Baseline characteristics were comparable between the two groups. Both products were found to be equally effective in improving the ano-rectal conditions in Grade I and Grade II hemorrhoids; however, Roidosanal((r)) demonstrated better efficacy in patients with Grade III hemorrhoids. Hemorrhoids associated symptoms like bleeding, pain, etc., improved in both groups, although intergroup comparisons were comparable. CONCLUSION: Both Roidosanal((r)) and Daflon((r)) 500 mg were equally effective in resolving signs and symptoms of hemorrhoids. Roidosanal((r)) can be tried as a safe and effective treatment option for treatment of hemorrhoids. Further randomized, double-blind and large multicentre studies are recommended. PMID- 24948864 TI - Pigment reduction in nevus of Ota following leech therapy. AB - Nevus of Ota is a congenital blue-gray color nevus afflicting unilaterally, the area near the eyes. It poses a huge cosmetic concern besides being a potential threat for developing melanoma sometime in the course of the disease. The treatment options are neither many nor promising besides they are too expensive. We have treated a case of nevus of Ota with leech therapy where leech was applied upon the lesion for five times spanned in a period of 2 months. The results in terms of change in the color of lesion were evaluated with the help of serial photographs following every treatment session to mark the level of color changes in the lesion. A substantial reduction in color of the nevus was reported following the completion of the therapy. The results were demonstrated with the photographs. Although, recommended as the classical Ayurvedic management for skin diseases, leech therapy is not reported earlier in such conditions. It proposes a novel approach to deal with such congenital pigment lesions where other options are not promising. PMID- 24948865 TI - Molecular and ayurvedic biology of inflammation 2014. PMID- 24948866 TI - Dubai ayu-con 2014: an international conference on ayurveda and yoga. PMID- 24948867 TI - Thinking beyond the mean: a practical guide for using quantile regression methods for health services research. PMID- 24948868 TI - Predicting Levels of Reading and Writing Achievement in Typically Developing, English-Speaking 2nd and 5th Graders. AB - Human traits tend to fall along normal distributions. The aim of this research was to evaluate an evidence-based conceptual framework for predicting expected individual differences in reading and writing achievement outcomes for typically developing readers and writers in early and middle childhood from Verbal Reasoning with or without Working Memory Components (phonological, orthographic, and morphological word storage and processing units, phonological and orthographic loops, and rapid switching attention for cross-code integration). Verbal Reasoning (reconceptualized as Bidirectional Cognitive-Linguistic Translation) plus the Working Memory Components (reconceptualized as a language learning system) accounted for more variance than Verbal Reasoning alone, except for handwriting for which Working Memory Components alone were better predictors. Which predictors explained unique variance varied within and across reading (oral real word and pseudoword accuracy and rate, reading comprehension) and writing (handwriting, spelling, composing) skills and grade levels (second and fifth) in this longitudinal study. Educational applications are illustrated and theoretical and practical significance discussed. PMID- 24948869 TI - Systemic Lupus Erythematosus (SLE) Complicated by Neuromyelitis Optica (NMO - Devic's Disease): Clinic-Pathological Report and Review of the Literature. AB - Neuromyelitis optica (NMO) is usually a relapsing demyelinating disease of the central nervous system associated with optic neuritis, transverse myelitis involving three or more contiguous spinal cord segments, and seropositivity for NMO-IgG antibody. NMO is often mistaken for multiple sclerosis and there are relatively sporadic publications about NMO and overlapping systemic or organ specific autoimmune diseases, such as systemic lupus erythematosus (SLE). We described a unique case of a 25-year-old Arab young woman who was diagnosed with SLE, depending on clinical, laboratory investigations and after she had fulfilled the diagnostic criteria for SLE and had presented the following findings: constitutional findings (fatigue, fever, and arthralgia); dermatologic finding (photosensitivity and butterfly rash); chronic renal failure (proteinuria up to 400 mg in 24 hours); hematologic and antinuclear antibodies (positivity for antinuclear factor (ANF), anti-double-stranded DNA antibodies, direct Coombs, ANA and anti-DNA, low C4 and C3, aCL by IgG and IgM). Recently, she presented with several episodes of transverse myelitis and optic neuritis. Clinical, radiological, and laboratory findings especially seropositivity for NMO-IgG were compatible with NMO. Accurate diagnosis is critical to facilitate initiation of immunosuppressive therapy for attack prevention. This case illustrates that NMO may be associated with SLE. PMID- 24948870 TI - Targeting androgen receptor action for prostate cancer treatment: does the post receptor level provide novel opportunities? AB - The standard of care for patients who suffer from non-organ confined prostate cancer (CaP) is androgen deprivation therapy (ADT). ADT exploits the reliance of CaP cells on androgen receptor (AR) signaling throughout CaP progression from androgen-stimulated (AS) to castration-recurrent (CR) disease. AR is a member of the nuclear receptor family of ligand-activated transcription factors. Ligand activated AR relocates from the cytoplasm to the nucleus, where it binds to Androgen Response Elements (AREs) to regulate transcription of target genes that control CaP cell behavior and progression. Current forms of ADT interfere at 2 levels along the AR signaling axis. At the pre-receptor level, ADT limits the availability of ligand for AR, while at the receptor level, ADT interrupts AR ligand interactions. Both forms of ADT induce remission, but are not curative and, because of extraprostatic actions, are associated with severe side effects. Here, the potential of interference with the molecular regulation of AR-dependent transcription and the action of AR target genes, at the post receptor level, as the foundation for the development of novel, more CaP- specific selective forms of ADT is explored. PMID- 24948871 TI - Androgen receptor as a driver of therapeutic resistance in advanced prostate cancer. AB - The role of the androgen receptor (AR) signaling axis in the progression of prostate cancer is a cornerstone to our understanding of the molecular mechanisms causing castration-resistant prostate cancer (CRPC). Resistance of advanced prostate cancer to available treatment options makes it a clinical challenge that results in approximately 30,000 deaths of American men every year. Since the historic discovery by Dr. Huggins more than 70 years ago, androgen deprivation therapy (ADT) has been the principal treatment for advanced prostate cancer. Initially, ADT induces apoptosis of androgen-dependent prostate cancer epithelial cells and regression of androgen-dependent tumors. However, the majority of patients with advanced prostate cancer progress and become refractory to ADT due to emergence of androgen-independent prostate cancer cells driven by aberrant AR activation. Microtubule-targeting agents such as taxanes, docetaxel and paclitaxel, have enjoyed success in the treatment of metastatic prostate cancer; although new, recently designed mitosis-specific agents, such as the polo-kinase and kinesin-inhibitors, have yielded clinically disappointing results. Docetaxel, as a first-line chemotherapy, improves prostate cancer patient survival by months, but tumor resistance to these therapeutic agents inevitably develops. On a molecular level, progression to CRPC is characterized by aberrant AR expression, de novo intraprostatic androgen production, and cross talk with other oncogenic pathways. Emerging evidence suggests that reactivation of epithelial mesenchymal-transition (EMT) processes may facilitate the development of not only prostate cancer but also prostate cancer metastases. EMT is characterized by gain of mesenchymal characteristics and invasiveness accompanied by loss of cell polarity, with an increasing number of studies focusing on the direct involvement of androgen-AR signaling axis in EMT, tumor progression, and therapeutic resistance. In this article, we discuss the current knowledge of mechanisms via which the AR signaling drives therapeutic resistance in prostate cancer metastatic progression and the novel therapeutic interventions targeting AR in CRPC. PMID- 24948872 TI - Roles for the backdoor pathway of androgen metabolism in prostate cancer response to castration and drug treatment. AB - Almost all men who present with advanced prostate cancer (CaP) and many men who fail potentially curative therapy are treated with androgen deprivation therapy (ADT). ADT is not curative and CaP recurs as the lethal phenotype. The goal of this review is to describe the evolution of adrenal androgen blockade, how new androgen measurement methods have furthered understanding of androgen metabolism, and how further understanding of the backdoor pathway of androgen metabolism may lead to interventions that extend survival even more. PMID- 24948873 TI - Beyond T and DHT - novel steroid derivatives capable of wild type androgen receptor activation. AB - While androgen deprivation therapy (ADT) remains the primary treatment for metastatic prostate cancer (PCa), castration does not eliminate androgens from the prostate tumor microenvironment, and residual intratumoral androgens are implicated in nearly every mechanism by which androgen receptor (AR)-mediated signaling promotes castration-resistant disease. The uptake and intratumoral (intracrine) conversion of circulating adrenal androgens such as dehydroepiandrosterone sulfate (DHEA-S) to steroids capable of activating the wild type AR is a recognized driver of castration resistant prostate cancer (CRPC). However, less well-characterized adrenal steroids, including 11 deoxcorticosterone (DOC) and 11beta-hydroxyandrostenedione (11OH-AED) may also play a previously unrecognized role in promoting AR activation. In particular, recent data demonstrate that the 5alpha-reduced metabolites of DOC and 11OH-AED are activators of the wild type AR. Given the well-recognized presence of SRD5A activity in CRPC tissue, these observations suggest that in the low androgen environment of CRPC, alternative sources of 5alpha-reduced ligands may supplement AR activation normally mediated by the canonical 5alpha-reduced agonist, 5alpha DHT. Herein we review the emerging data that suggests a role for these alternative steroids of adrenal origin in activating the AR, and discuss the enzymatic pathways and novel downstream metabolites mediating these effects. We conclude by discussing the potential implications of these findings for CRPC progression, particularly in context of new agents such as abiraterone and enzalutamide which target the AR-axis for prostate cancer therapy. PMID- 24948874 TI - Modulation of androgen receptor by FOXA1 and FOXO1 factors in prostate cancer. AB - Androgens and the androgen receptor (AR) are essential for growth and differentiation of the normal prostate gland as well as proliferation and survival of prostate cancer (PCa). Increasing evidence suggests that reactivation of the AR plays a pivotal role in disease progression to castration-resistant PCa (CRPC). Forkhead box (FOX) factors exert two distinct effects on AR function in PCa. The A-class of FOX proteins, especially FOXA1, functions as a pioneer factor to facilitate AR transactivation and PCa growth. In contrast, the O-class of FOX proteins such as FOXO1 and FOXO3, which are downstream effectors of the PTEN tumor suppressor, inhibit the transcriptional activity of either full-length AR or constitutively active splice variants of AR in a direct or indirect manner in PCa. FOXO1 also contributes to taxane-mediated inhibition of the AR and CRPC growth. Therefore, FOX family members not only have a tight relationship with AR, but also represent a pivotal group of proteins to be targeted for PCa therapy. The present review focuses primarily on recent advances in the epigenetic, mechanistic and clinical relevant aspects of regulation of the AR by FOXA1 and FOXO1 factors in PCa. PMID- 24948875 TI - Androgen receptor activation in castration-recurrent prostate cancer: the role of Src-family and Ack1 tyrosine kinases. AB - There is growing appreciation that castration-recurrent prostate cancer (CR-CaP) is driven by the continued expression of androgen receptor (AR). AR activation in CR-CaP through various mechanisms, including AR overexpression, expression of AR splice variants or mutants, increased expression of co-regulator proteins, and by post-translational modification, allows for the induction of AR-regulated genes in response to very low levels of tissue-expressed, so-called intracrine androgens, resulting in pathways that mediate CaP proliferation, anti-apoptosis and oncogenic aggressiveness. The current review focuses on the role played by Src-family (SFK) and Ack1 non-receptor tyrosine kinases in activating AR through direct phosphorylation, respectively, on tyrosines 534 or 267, and how these modifications facilitate progression to CR-CaP. The fact that SFK and Ack1 are central mediators for multiple growth factor receptor signaling pathways that become activated in CR-CaP, especially in the context of metastatic growth in the bone, has contributed to recent therapeutic trials using SFK/Ack1 inhibitors in monotherapy or in combination with antagonists of the AR activation axis. PMID- 24948876 TI - Conversion of androgen receptor signaling from a growth suppressor in normal prostate epithelial cells to an oncogene in prostate cancer cells involves a gain of function in c-Myc regulation. AB - In normal prostate, androgen-dependent androgen receptor (AR) signaling within prostate stromal cells induces their secretion of paracrine factors, termed "andromedins" which stimulate growth of the epithelial cells. The present studies demonstrate that androgen-dependent andromedin-driven growth stimulation is counter-balanced by androgen-induced AR signaling within normal adult prostate epithelial cells resulting in terminal G0 growth arrest coupled with terminal differentiation into DeltaNp63-negative, PSA-expressing secretory luminal cells. This cell autonomous AR-driven terminal differentiation requires DNA-binding of the AR protein, is associated with decreases in c-Myc m-RNA and protein, are coupled with increases in p21, p27, and SKP-2 protein expression, and does not require functional p53. These changes result in down-regulation of Cyclin D1 protein and RB phosphoryation. shRNA knockdown documents that neither RB, p21, p27 alone or in combination are required for such AR-induced G0 growth arrest. Transgenic expression of a constitutive vector to prevent c-Myc down-regulation overrides AR-mediated growth arrest in normal prostate epithelial cells, which documents that AR-induced c-Myc down-regulation is critical in terminal growth arrest of normal prostate epithelial cells. In contrast, in prostate cancer cells, androgen-induced AR signaling paradoxically up-regulates c-Myc expression and stimulates growth as documented by inhibition of both of these responses following exposure to the AR antagonist, bicalutamide. These data document that AR signaling is converted from a growth suppressor in normal prostate epithelial cells to an oncogene in prostate cancer cells during prostatic carcinogenesis and that this conversion involves a gain of function for regulation of c-Myc expression. PMID- 24948878 TI - Biological and clinical significance of androgens and androgen receptor in prostate cancer. PMID- 24948877 TI - Androgen receptor mutations and polymorphisms in African American prostate cancer. AB - The Androgen receptor (AR) plays a central role in the normal development of the prostate gland, in prostate carcinogenesis, and in the progression of prostate cancer (PCa) to advanced metastatic disease. African American (AA) men with PCa present with higher tumor volume, more advanced tumor stage, and higher Gleason score. This could be in part related to the AR expression or activity in the prostate tissue of AA men, or to unique mutations or polymorphisms of the AR. In Caucasian Americans (CAs), AR mutations are rare or infrequent in organ-confined tumors, but occur at a higher rate in advanced, metastatic, or castrate-recurrent disease. In AAs, the prevalence, clinical, and biological significance of AR mutations in PCa are unknown. In this study, we investigated the occurrence of somatic and germline AR mutations in patients with primary PCa in AAs compared with CAs. Due to very limited data available on allelic distribution of E213 (G/A) single nucleotide polymorphism (SNP), we also assessed this in patients with sporadic PCa and in unrelated healthy individuals from both ethnic populations. Somatic missense AR mutations were detected at a higher rate in AAs (17 out of 200 cases) than in CAs (2 out of 100 cases). In AAs, the majority of these mutations (41.1%) were from Gleason 7 tumors, a small portion (23.5%) from Gleason 8 tumors, and the rest (35.2%) from Gleason 6 tumors. Analysis of genomic DNAs extracted from white blood cells of patients with sporadic PCa revealed that the rate of germline AR mutations were also higher (~4 times) in AAs than in CAs. With respect to E213 (G/A) SNP, the E213 A-allele expression was 5.85 times higher in healthy unrelated AA men than in CA men. However, in AAs with somatic AR mutation, the E213 G-allele distribution was almost equal to the A-allele. Silencing of one of the somatic AR mutations (i.e., 597 Ser>Gly) in a primary AA PCa cell line (e.g., E006AA) revealed that similar AR mutation can be associated simultaneously with both "gain-of-function" phenotype (cell migration and invasion) and a "loss-of-function" phenotype (proliferation). Our data demonstrated a higher susceptibility for genetic alterations in the AR in the form of somatic mutations in sporadic PCa or in the form of germline mutations in AAs as compared with CAs. These data may support the idea that AR-specific hypermutator phenotype in combination with other genes, might serve as a contributing factor to ethnic differences in PCa and potentially different clinical outcome in AAs as a high-risk population. PMID- 24948879 TI - Genome-wide miRNA seeds prediction in Archaea. AB - Growing evidence indicates that miRNA genes exist in the archaeal genome, though the functional role of such noncoding RNA remains unclear. Here, we integrated the phylogenetic information of available archaeal genomes to predict miRNA seeds (typically defined as the 2-8 nucleotides of mature miRNAs) on the genomic scale. Finally, we found 2649 candidate seeds with significant conservation signal. Eleven of 29 unique seeds from previous study support our result (P value <0.01), which demonstrates that the pipeline is suitable to predict experimentally detectable miRNA seeds. The statistical significance of the overlap between the detected archaeal seeds and known eukaryotic seeds shows that the miRNA may evolve before the divergence of these two domains of cellular life. In addition, miRNA targets are enriched for genes involved in transcriptional regulation, which is consistent with the situation in eukaryote. Our research will enhance the regulatory network analysis in Archaea. PMID- 24948881 TI - What Would Your Journal Say if It Could Talk Back? Using Dialogue Journals as a Technique in Adolescent HIV/STI Prevention and Sexual Health Promotion Programs. AB - Dialogue journaling is a technique that is useful for enhancing the goals of sexual health promotion and HIV/STI prevention programs with 14 to 17 year old at risk youth. Included is a detailed lesson plan on how to implement dialogue journaling in this context; a discussion of advantages and concerns about using them; and future implications for its use. PMID- 24948880 TI - Understanding a Pacific Islander Young Adult Perspective on Access to Higher Education. AB - The Pacific Islander (PI) community suffers disproportionately from illnesses and diseases, including diabetes, heart disease and cancer. While there are tremendous health needs within the PI community, there are few health care providers from the community that exist to help address these particular needs. Many efforts have focused on health care workforce diversity to reduce and eliminate health disparities, but few have examined the issues faced in the health care work force pipeline. Understanding educational attainment among PI young adults is pivotal in speaking to a diverse health care workforce where health disparities among Pacific Islanders (PIs) may be addressed. This paper provides an in-depth, qualitative assessment of the various environmental, structural, socio-economic, and social challenges that prevent PIs from attaining higher education; it also discusses the various needs of PI young adults as they relate to psychosocial support, retention and recruitment, and health career knowledge and access. This paper represents a local, Southern California, assessment of PI young adults regarding educational access barriers. We examine how these barriers impact efforts to address health disparities and look at opportunities for health and health-related professionals to reduce and care for the high burden of illnesses and diseases in PI communities. PMID- 24948882 TI - Investigation of chemical transformations of thiophenylglycoside of muramyl dipeptide on the fumed silica surface using TPD-MS, FTIR spectroscopy and ES IT MS. AB - In this study, chemical transformations of benzyl ester of O-(phenyl-2-acetamido 2,3-dideoxy-1-thio-beta-d-glucopyranoside-3-yl)-d-lactoyl-l-alanyl-d-isoglutamine (SPhMDPOBn) on the fumed silica surface were examined, and the surface complex structure was characterized by temperature-programmed desorption mass spectrometry (TPD-MS), infrared spectroscopy (FTIR) and electrospray ion trap mass spectrometry (ES IT MS). Stages of pyrolysis of SPhMDPOBn in pristine state and on the silica surface have been determined. Probably, hydrogen-bonded complex forms between silanol surface groups and the C = O group of the acetamide moiety NH-(CH3)-C = O...H-O-Si=. The thermal transformations of such hydrogen-bonded complex result in pyrolysis of SPhMDPOBn immobilized on the silica surface under TPD-MS conditions. The shifts ?nu of amide I band (measured from 1,626 to 1,639 cm(-l) for SPhMDPOBn in pristine state) of 33 and 35 cm(-l) which occurred when SPhMDPOBn was immobilized on the silica surface may be caused by a weakening of the intramolecular hydrogen bonding of the SPhMDPOBn because the interaction with the silica surface as hydrogen bond with silanol groups is weaker than that in associates. PMID- 24948884 TI - Performance enhancement of multiple-gate ZnO metal-oxide-semiconductor field effect transistors fabricated using self-aligned and laser interference photolithography techniques. AB - The simple self-aligned photolithography technique and laser interference photolithography technique were proposed and utilized to fabricate multiple-gate ZnO metal-oxide-semiconductor field-effect transistors (MOSFETs). Since the multiple-gate structure could improve the electrical field distribution along the ZnO channel, the performance of the ZnO MOSFETs could be enhanced. The performance of the multiple-gate ZnO MOSFETs was better than that of the conventional single-gate ZnO MOSFETs. The higher the drain-source saturation current (12.41 mA/mm), the higher the transconductance (5.35 mS/mm) and the lower the anomalous off-current (5.7 MUA/mm) for the multiple-gate ZnO MOSFETs were obtained. PMID- 24948883 TI - Optical simulations of P3HT/Si nanowire array hybrid solar cells. AB - An optical simulation of poly(3-hexylthiophene) (P3HT)/Si nanowire array (NWA) hybrid solar cells was investigated to evaluate the optical design requirements of the system by using finite-difference time-domain (FDTD) method. Steady improvement of light absorption was obtained with increased P3HT coating shell thickness from 0 to 80 nm on Si NWA. Further increasing the thickness caused dramatic decrease of the light absorption. Combined with the analysis of ultimate photocurrents, an optimum geometric structure with a coating P3HT thickness of 80 nm was proposed. At this structure, the hybrid solar cells show the most efficient light absorption. The optimization of the geometric structure and further understanding of the optical characteristics may contribute to the development for the practical experiment of the promising hybrid solar cells. PMID- 24948885 TI - A catalyst-free growth of aluminum-doped ZnO nanorods by thermal evaporation. AB - The growth of Al:ZnO nanorods on a silicon substrate using a low-temperature thermal evaporation method is reported. The samples were fabricated within a horizontal quartz tube under controlled supply of O2 gas where Zn and Al powders were previously mixed and heated at 700 degrees C. This allows the reactant vapors to deposit onto the substrate placed vertically above the source materials. Both the undoped and doped samples were characterized using scanning electron microscopy (SEM), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectroscopy (EDX), high-resolution transmission electron microscopy (HRTEM) and photoluminescence (PL) measurements. It was observed that randomly oriented nanowires were formed with varying nanostructures as the dopant concentrations were increased from 0.6 at.% to 11.3 at.% with the appearance of 'pencil-like' shape at 2.4 at.%, measuring between 260 to 350 nm and 720 nm in diameter and length, respectively. The HRTEM images revealed nanorods fringes of 0.46 nm wide, an equivalent to the lattice constant of ZnO and correspond to the (0001) fringes with regard to the growth direction. The as-prepared Al:ZnO samples exhibited a strong UV emission band located at approximately 389 nm (E g = 3.19 eV) with multiple other low intensity peaks appeared at wavelengths greater than 400 nm contributed by oxygen vacancies. The results showed the importance of Al doping that played an important role on the morphology and optical properties of ZnO nanostructures. This may led to potential nanodevices in sensor and biological applications. PMID- 24948886 TI - Toxicity evaluation of zinc aluminium levodopa nanocomposite via oral route in repeated dose study. AB - Nanotechnology, through nanomedicine, allowed drugs to be manipulated into nanoscale sizes for delivery to the different parts of the body, at the same time, retaining the valuable pharmacological properties of the drugs. However, efficient drug delivery and excellent release potential of these delivery systems may be hindered by possible untoward side effects. In this study, the sub-acute toxicity of oral zinc aluminium nanocomposite with and without levodopa was assessed using the Organization for Economic Co-operation and Development guidelines. No sign or symptom of toxicity was observed in orally treated rats with the nanocomposite at 5 and 500 mg/kg concentrations. Body weight gain, feeding, water intake, general survival and organosomatic index were not significantly different between control and treatment groups. Aspartate aminotransferase (AST) in 500 mg/kg levodopa nanocomposite (169 +/- 30 U/L), 5 mg/kg levodopa nanocomposite (172 +/- 49 U/L), and 500 mg/kg layered double hydroxides (LDH) nanocomposite (175 +/- 25 U/L) were notably elevated compared to controls (143 +/- 05 U/L); but the difference were not significant (p > 0.05). However, the differences in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of 500 mg/kg levodopa nanocomposite (0.32 +/- 0.12) and 500 mg/kg LDH nanocomposite (0.34 +/- 0.12) were statistically significant (p < 0.05) compared to the control (0.51 +/- 0.07). Histology of the liver, spleen and brain was found to be of similar morphology in both control and experimental groups. The kidneys of 500-mg/kg-treated rats with levodopa nanocomposite and LDH nanocomposite were found to have slight inflammatory changes, notably leukocyte infiltration around the glomeruli. The ultra-structure of the neurons from the substantia nigra of nanocomposite-exposed group was similar to those receiving only normal saline. The observed result has suggested possible liver and renal toxicity in orally administered levodopa intercalated nanocomposite; it is also dose-dependent that needs further assessment. PMID- 24948887 TI - Coherent anti-Stokes Raman scattering enhancement of thymine adsorbed on graphene oxide. AB - Coherent anti-Stokes Raman scattering (CARS) of carbon nanostructures, namely, highly oriented pyrolytic graphite, graphene nanoplatelets, graphene oxide, and multiwall carbon nanotubes as well CARS spectra of thymine (Thy) molecules adsorbed on graphene oxide were studied. The spectra of the samples were compared with spontaneous Raman scattering (RS) spectra. The CARS spectra of Thy adsorbed on graphene oxide are characterized by shifts of the main bands in comparison with RS. The CARS spectra of the initial nanocarbons are definitely different: for all investigated materials, there is a redistribution of D- and G-mode intensities, significant shift of their frequencies (more than 20 cm(-1)), and appearance of new modes about 1,400 and 1,500 cm(-1). The D band in CARS spectra is less changed than the G band; there is an absence of 2D-mode at 2,600 cm(-1) for graphene and appearance of intensive modes of the second order between 2,400 and 3,000 cm(-1). Multiphonon processes in graphene under many photon excitations seem to be responsible for the features of the CARS spectra. We found an enhancement of the CARS signal from thymine adsorbed on graphene oxide with maximum enhancement factor about 10(5). The probable mechanism of CARS enhancement is discussed. PMID- 24948888 TI - RGD-conjugated silica-coated gold nanorods on the surface of carbon nanotubes for targeted photoacoustic imaging of gastric cancer. AB - Herein, we reported for the first time that RGD-conjugated silica-coated gold nanorods on the surface of multiwalled carbon nanotubes were successfully used for targeted photoacoustic imaging of in vivo gastric cancer cells. A simple strategy was used to attach covalently silica-coated gold nanorods (sGNRs) onto the surface of multiwalled carbon nanotubes (MWNTs) to fabricate a hybrid nanostructure. The cross-linked reaction occurred through the combination of carboxyl groups on the MWNTs and the amino group on the surface of sGNRs modified with a silane coupling agent. RGD peptides were conjugated with the sGNR/MWNT nanostructure; resultant RGD-conjugated sGNR/MWNT probes were investigated for their influences on viability of MGC803 and GES-1 cells. The nude mice models loaded with gastric cancer cells were prepared, the RGD-conjugated sGNR/MWNT probes were injected into gastric cancer-bearing nude mice models via the tail vein, and the nude mice were observed by an optoacoustic imaging system. Results showed that RGD-conjugated sGNR/MWNT probes showed good water solubility and low cellular toxicity, could target in vivo gastric cancer cells, and obtained strong photoacoustic imaging in the nude model. RGD-conjugated sGNR/MWNT probes will own great potential in applications such as targeted photoacoustic imaging and photothermal therapy in the near future. PMID- 24948889 TI - Hydrothermal epitaxy and resultant properties of EuTiO3 films on SrTiO3(001) substrate. AB - We report a novel epitaxial growth of EuTiO3 films on SrTiO3(001) substrate by hydrothermal method. The morphological, structural, chemical, and magnetic properties of these epitaxial EuTiO3 films were examined by scanning electron microscopy, transmission electron microscopy, high-resolution X-ray diffractometry, X-ray photoelectron spectroscopy, and superconducting quantum interference device magnetometry, respectively. As-grown EuTiO3 films with a perovskite structure were found to show an out-of-plane lattice shrinkage and room-temperature ferromagnetism, possibly resulting from an existence of Eu(3+). Postannealing at 1,000 degrees C could reduce the amount of Eu(3+), relax the out of-plane lattice shrinkage, and impact the magnetic properties of the films. PACS: 81.10.Aj; 81.15.-z; 61.05.-a. PMID- 24948890 TI - Diameter control of ultrathin zinc oxide nanofibers synthesized by electrospinning. AB - Electrospinning is a versatile technique, which can be used to generate nanofibers from a rich variety of materials. We investigate the variation of a zinc oxide (ZnO)-polyvinylpyrrolidone (PVP) composite structure in morphology by electrospinning from a series of mixture solutions of ZnO sol-gel and PVP. Calcination conditions for the crystallization of ZnO nanofibers and removal of the PVP component from the ZnO-PVP composite nanofibers were also studied. The progression of the ZnO-PVP composite structure from grains to nanofibers was observed, and ZnO-PVP nanofibers as thin as 29.9 +/- 0.8 nm on average were successfully fabricated. The size of the resultant ZnO-PVP composite nanofibers was considerably affected by two parameters: the concentrations of zinc acetate and PVP in the precursor solution. The concentration of zinc acetate particularly influenced the diameter distribution of the ZnO-PVP nanofibers. The ZnO-PVP nanofibers could be subsequently converted into ZnO nanofibers of a pure wurtzite phase via calcination in air at 500 degrees C for 2 h. PMID- 24948891 TI - Low-damage direct patterning of silicon oxide mask by mechanical processing. AB - To realize the nanofabrication of silicon surfaces using atomic force microscopy (AFM), we investigated the etching of mechanically processed oxide masks using potassium hydroxide (KOH) solution. The dependence of the KOH solution etching rate on the load and scanning density of the mechanical pre-processing was evaluated. Particular load ranges were found to increase the etching rate, and the silicon etching rate also increased with removal of the natural oxide layer by diamond tip sliding. In contrast, the local oxide pattern formed (due to mechanochemical reaction of the silicon) by tip sliding at higher load was found to have higher etching resistance than that of unprocessed areas. The profile changes caused by the etching of the mechanically pre-processed areas with the KOH solution were also investigated. First, protuberances were processed by diamond tip sliding at lower and higher stresses than that of the shearing strength. Mechanical processing at low load and scanning density to remove the natural oxide layer was then performed. The KOH solution selectively etched the low load and scanning density processed area first and then etched the unprocessed silicon area. In contrast, the protuberances pre-processed at higher load were hardly etched. The etching resistance of plastic deformed layers was decreased, and their etching rate was increased because of surface damage induced by the pre-processing. These results show that etching depth can be controlled by controlling the etching time through natural oxide layer removal and mechanochemical oxide layer formation. These oxide layer removal and formation processes can be exploited to realize low-damage mask patterns. PMID- 24948892 TI - Composite inorganic membranes containing nanoparticles of hydrated zirconium dioxide for electrodialytic separation. AB - The aim of the work was to elucidate the nature of charge-selective properties of macroporous composite inorganic membranes modified with nanoparticles of hydrated zirconium dioxide. The membranes have been investigated using methods of standard contact porosimetry, potentiometry, electron microscopy and small-angle X-ray scattering. The ion exchanger has been found to deposit inside pores of ceramics. Differential curves of pore volume distribution have been resolved using Lorentz functions; each maximum has been related to structure elements of the matrix and ion exchanger by means of calculations according to homogeneous and heterogeneous geometrical models. It was found that the voids, the radius of which is 4 to 8 nm, are responsible for charge selectivity of the composite membranes. These pores are formed due to blocking of macropores of ceramics with aggregates of nanoparticles of the ion exchanger; the radius of these aggregates is 20 to 24 nm. The membranes were applied to desalination of the solution containing NaCl. The removal degree of the salt from the solution reached 95% and 9% for the composite and unmodified membranes, respectively. PMID- 24948893 TI - Self-organized vanadium and nitrogen co-doped titania nanotube arrays with enhanced photocatalytic reduction of CO2 into CH4. AB - Self-organized V-N co-doped TiO2 nanotube arrays (TNAs) with various doping amount were synthesized by anodizing in association with hydrothermal treatment. Impacts of V-N co-doping on the morphologies, phase structures, and photoelectrochemical properties of the TNAs films were thoroughly investigated. The co-doped TiO2 photocatalysts show remarkably enhanced photocatalytic activity for the CO2 photoreduction to methane under ultraviolet illumination. The mechanism of the enhanced photocatalytic activity is discussed in detail. PMID- 24948894 TI - Microwave-induced fast crystallization of amorphous hierarchical anatase microspheres. AB - The fabrication of hierarchical anatase microspheres with potential photocatalytic properties eventually comprises a consolidation step in which a high degree of crystalline order is typically achieved through conventional electric heating treatments. This however entails a substantial reduction in the specific surface area and porosity of the powders, with the consequent deterioration in their photocatalytic response. Here, we have tested the employ of microwave heating as an alternative energy-saving sintering method to promote fast crystallization. The results obtained suggest that under the microwave radiation, the TiO2 hierarchical structures can effectively crystallize in a drastically reduced heating time, allowing the specific surface area and the porosity to be kept in the high values required for an improved photocatalytic performance. PMID- 24948896 TI - LiFePO4 microcrystals as an efficient heterogeneous Fenton-like catalyst in degradation of rhodamine 6G. AB - We present a novel heterogeneous Fenton-like catalyst of LiFePO4 (LFP). LFP has been widely used as an electrode material of a lithium ion battery, but we observed that commercial LFP (LFP-C) could act as a good Fenton-like catalyst to decompose rhodamine 6G. The catalytic activity of LFP-C microparticles was much higher than a popular catalyst, magnetite nanoparticles. Furthermore, we found that the catalytic activity of LFP-C could be further increased by increasing the specific surface area. The reaction rate constant of the hydrothermally synthesized LFP microcrystals (LFP-H) is at least 18 times higher than that of magnetite nanoparticles even though the particle size of LFP is far larger than magnetite nanoparticles. The LFP catalysts also exhibited a good recycling behavior and high stability under an oxidizing environment. The effects of the experimental parameters such as the concentration of the catalysts, pH, and the concentration of hydrogen peroxide on the catalytic activity of LFP were also analyzed. PMID- 24948895 TI - HAI-178 antibody-conjugated fluorescent magnetic nanoparticles for targeted imaging and simultaneous therapy of gastric cancer. AB - The successful development of safe and highly effective nanoprobes for targeted imaging and simultaneous therapy of in vivo gastric cancer is a great challenge. Herein we reported for the first time that anti-alpha-subunit of ATP synthase antibody, HAI-178 monoclonal antibody-conjugated fluorescent magnetic nanoparticles, was successfully used for targeted imaging and simultaneous therapy of in vivo gastric cancer. A total of 172 specimens of gastric cancer tissues were collected, and the expression of alpha-subunit of ATP synthase in gastric cancer tissues was investigated by immunohistochemistry method. Fluorescent magnetic nanoparticles were prepared and conjugated with HAI-178 monoclonal antibody, and the resultant HAI-178 antibody-conjugated fluorescent magnetic nanoparticles (HAI-178-FMNPs) were co-incubated with gastric cancer MGC803 cells and gastric mucous GES-1 cells. Gastric cancer-bearing nude mice models were established, were injected with prepared HAI-178-FMNPs via tail vein, and were imaged by magnetic resonance imaging and small animal fluorescent imaging system. The results showed that the alpha-subunit of ATP synthase exhibited high expression in 94.7% of the gastric cancer tissues. The prepared HAI-178-FMNPs could target actively MGC803 cells, realized fluorescent imaging and magnetic resonance imaging of in vivo gastric cancer, and actively inhibited growth of gastric cancer cells. In conclusion, HAI-178 antibody-conjugated fluorescent magnetic nanoparticles have a great potential in applications such as targeted imaging and simultaneous therapy of in vivo early gastric cancer cells in the near future. PMID- 24948897 TI - Suppression of dislocations by Sb spray in the vicinity of InAs/GaAs quantum dots. AB - The effect of Sb spray prior to the capping of a GaAs layer on the structure and properties of InAs/GaAs quantum dots (QDs) grown by molecular beam epitaxy (MBE) is studied by cross-sectional high-resolution transmission electron microscopy (HRTEM). Compared to the typical GaAs-capped InAs/GaAs QDs, Sb-sprayed QDs display a more uniform lens shape with a thickness of about 3 ~ 4 nm rather than the pyramidal shape of the non-Sb-sprayed QDs. Particularly, the dislocations were observed to be passivated in the InAs/GaAs interface region and even be suppressed to a large extent. There are almost no extended dislocations in the immediate vicinity of the QDs. This result is most likely related to the formation of graded GaAsSb immediately adjacent to the InAs QDs that provides strain relief for the dot/capping layer lattice mismatch. PACS: 81.05.Ea; 81.07. b; 81.07.Ta. PMID- 24948898 TI - Intensify the application of ZnO-based nanodevices in humid environment: O2/H2 plasma suppressed the spontaneous reaction of amorphous ZnO nanowires. AB - In this work, we have demonstrated that amorphous ZnO nanobranches (a-ZnO NBs) could spontaneously react from the crystalline ZnO NWs (c-ZnO NWs) at specific humid environment. The spontaneous reaction mechanism and result can be analyzed by humidity controlling and optical microscope (OM)/scanning electron microscope (SEM)/Kelvin probe force microscopy (KPFM)/transmission electron microscopy (TEM) system. We can make the c-ZnO NWs spontaneous reaction happen at different humid environments and suppress the a-ZnO NBs spontaneous reaction by oxygen/hydrogen plasma surface passivation. The hydrogen plasma surface treatment also can improve the UV sensing sensitivity more than twofold. This work provides the mechanism and methods of the a-ZnO NBs spontaneous growth and offers the passivation treatment for strengthening and enhancing ZnO-based nanodevice application in humid environment and UV light detection, respectively. PMID- 24948899 TI - Preparation of halloysite nanotube-supported gold nanocomposite for solvent-free oxidation of benzyl alcohol. AB - Gold nanoparticles supported on halloysite nanotubes (Au/HNTs) were prepared by a homogeneous deposition-precipitation method. The specific characteristics of the catalyst were characterized in detail, in relation to their performance for solvent-free oxidation of benzyl alcohol. The particular structure of the catalyst resulted in high catalytic activity and stability compared with other supported gold catalysts. The enhanced catalytic activity of the Au/HNTs catalyst was mainly attributed to the presence of a higher amount of oxidized gold species and the tubular structure of the HNTs. PMID- 24948900 TI - Surface modification and characterization of carbon spheres by grafting polyelectrolyte brushes. AB - Modified carbon spheres (CSPBs) were obtained by grafting poly(diallyl dimethyl ammonium chloride) (p-DMDAAC) on the surface of carbon spheres (CSs). It can be viewed as a kind of cation spherical polyelectrolyte brushes (CSPBs), which consist of carbon spheres as core and polyelectrolytes as shell. The method of synthesizing carbon spheres was hydrothermal reaction. Before the polyelectrolyte brushes were grafted, azo initiator [4,4'-Azobis(4-cyanovaleric acyl chloride)] was attached to the carbon spheres' surface through hydroxyl groups. CSPBs were characterized by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), gel permeation chromatography (GPC), conductivity meter, and system zeta potential. The results showed that compared with carbon spheres, the conductivity and zeta potential on CSPBs increased from 9.98 to 49.24 MUS/cm and 11.6 to 42.5 mV, respectively, after the polyelectrolyte brushes were grafted. The colloidal stability in water was enhanced, and at the same time, the average diameter of the CSPBs was found to be 173 nm, and the average molecular weight and grafted density of the grafted polyelectrolyte brushes were 780,138 g/mol and 4.026 * 10(9)/nm(2,) respectively. PMID- 24948901 TI - Mechanical characteristics of mesenchymal stem cells under impact of silica-based nanoparticles. AB - Silica-based nanoparticles (NPs) pose great potential for medical and biological applications; however, their interactions with living cells have not been investigated in full. The objective of this study was to analyze the mechanical characteristics of mesenchymal stem cells when cultured in the presence of silica (Si) and silica-boron (SiB) nanoparticles. Cell stiffness was measured using atomic force microscopy; F-actin structure was evaluated using TRITC-phalloidin by confocal microscopy. The obtained data suggested that the cell stiffness increased within the following line: 'Control' - 'Si' - 'SiB' (either after 1-h cultivation or 24-h incubation). Moreover, the cell stiffness was found to be higher after 1-h cultivation as compared to 24-h cultivation. This result shows that there is a two-phase process of particle diffusion into cells and that the particles interact directly with the membrane and, further, with the submembranous cytoskeleton. Conversely, the intensity of phalloidin fluorescence dropped within the same line: Control - Si - SiB. It could be suggested that the effects of silica-based particles may result in structural reorganization of cortical cytoskeleton with subsequent stiffness increase and concomitant F-actin content decrease (for example, in recruitment of additional actin-binding proteins within membrane and regrouping of actin filaments). PMID- 24948902 TI - Thermally controlled widening of droplet etched nanoholes. AB - We describe a method to control the shape of nanoholes in GaAs (001) which combines the technique of local droplet etching using Ga droplets with long-time thermal annealing. The cone-like shape of inverted nanoholes formed by droplet etching is transformed during long-time annealing into widened holes with flat bottoms and reduced depth. This is qualitatively understood using a simplified model of mass transport incorporating surface diffusion and evaporation. The hole diameter can be thermally controlled by varying the annealing time or annealing temperature which provides a method for tuning template morphology for subsequent nanostructure nucleation. We also demonstrate the integration of the combined droplet/thermal etching process with heteroepitaxy by the thermal control of hole depth in AlGaAs layers. PMID- 24948904 TI - Synthesis, Structural Characterization, and Biological Activity Studies of Ni(II) and Zn(II) Complexes. AB - Ni(II) and Zn(II) complexes were synthesized from tridentate 3-formyl chromone Schiff bases such as 3-((2-hydroxyphenylimino)methyl)-4H-chromen-4-one (HL1), 2 ((4-oxo-4H-chromen-3-yl)methylneamino)benzoic acid (HL2), 3-((3-hydroxypyridin-2 ylimino)methyl)-4H-chromen-4-one (HL3), and 3-((2-mercaptophenylimino)methyl)-4H chromen-4-one (HL4). All the complexes were characterized in the light of elemental analysis, molar conductance, FTIR, UV-VIS, magnetic, thermal, powder XRD, and SEM studies. The conductance and spectroscopic data suggested that, the ligands act as neutral and monobasic tridentate ligands and form octahedral complexes with general formula [M(L1-4)2].nH2O (M = Ni(II) and Zn(II)). Metal complexes exhibited pronounced activity against tested bacteria and fungi strains compared to the ligands. In addition metal complexes displayed good antioxidant and moderate nematicidal activities. The cytotoxicity of ligands and their metal complexes have been evaluated by MTT assay. The DNA cleavage activity of the metal complexes was performed using agarose gel electrophoresis in the presence and absence of oxidant H2O2. All metal complexes showed significant nuclease activity in the presence of H2O2. PMID- 24948903 TI - Quantitative secretome and glycome of primary human adipocytes during insulin resistance. AB - Adipose tissue is both an energy storage depot and an endocrine organ. The impaired regulation of the secreted proteins of adipose tissue, known as adipocytokines, observed during obesity contributes to the onset of whole-body insulin resistance and the pathobiology of type 2 diabetes mellitus (T2DM). In addition, the global elevation of the intracellular glycosylation of proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc) via either genetic or pharmacological methods is sufficient to induce insulin resistance in both cultured cells and animal models. The elevation of global O-GlcNAc levels is associated with the altered expression of many adipocytokines. We have previously characterized the rodent adipocyte secretome during insulin sensitive and insulin resistant conditions. Here, we characterize and quantify the secretome and glycome of primary human adipocytes during insulin responsive and insulin resistant conditions generated by the classical method of hyperglycemia and hyperinsulinemia or by the pharmacological manipulation of O-GlcNAc levels. Using a proteomic approach, we identify 190 secreted proteins and report a total of 20 up-regulated and 6 down-regulated proteins that are detected in both insulin resistant conditions. Moreover, we apply glycomic techniques to examine (1) the sites of N-glycosylation on secreted proteins, (2) the structures of complex N- and O-glycans, and (3) the relative abundance of complex N- and O-glycans structures in insulin responsive and insulin resistant conditions. We identify 91 N-glycosylation sites derived from 51 secreted proteins, as well as 155 and 29 released N- and O-glycans respectively. We go on to quantify many of the N- and O glycan structures between insulin responsive and insulin resistance conditions demonstrating no significant changes in complex glycosylation in the time frame for the induction of insulin resistance. Thus, our data support that the O-GlcNAc modification is involved in the regulation of adipocytokine secretion upon the induction of insulin resistance in human adipocytes. PMID- 24948905 TI - The Dynamic Association between Healthy Leisure and Substance Use in South African Adolescents: A State and Trait Perspective. AB - South Africa has an increasing adolescent substance use problem, lack of leisure opportunities and resources, and high adolescent discretionary time. How aspects of leisure relate to adolescent substance use is not well understood. Little research has been conducted on the leisure behaviors and experiences of South African adolescents, if and how those behaviors are associated with substance use, and ecological influences on those associations. By applying multi-level models to longitudinal data obtained from youth living in high-risk contexts, this research examines the association between state and trait healthy leisure and adolescent substance use and how perceived parental over-control moderates those associations. Results indicate healthy leisure protects against substance use at state and trait levels, provides empirical support that risk behavior can be addressed through leisure-based interventions, and emphasizes the importance of both short- and long-term processes when considering the context-dependent nature of adolescents' leisure experiences. PMID- 24948906 TI - An overview of antimicrobial resistance and its public health significance. AB - Multiple papers have been published regarding the bacterial resistance theme over the last years. A variety of information has reached general and scientific public, daily bringing up data on new resistant microorganisms, new drugs, outbreaks, epidemiological news, resistance gene dissemination, and the lack of information in a particular field has caught our attention: the public health department. Most of researchers, physicians and government employees interpret the public health field as a separate department, not linked to this antibiotic resistance era that we are living nowadays. In this paper we carefully tried to fill in the blanks between public health and the bacteria resistance issue, also considering historical, social, economical and biological problematic that come with this possible pre-antibiotic era. PMID- 24948907 TI - PCR and ELISA (VIDAS ECO O157((r))) Escherichia coli O157:H7 identification in Minas Frescal cheese commercialized in Goiania, GO. AB - Escherichia coli O157:H7 has been incriminated in food poisoning outbreaks and sporadic cases of hemorrhagic colitis and hemolytic uremic syndrome in many countries. Considering the high susceptibility of Minas Frescal cheese to contamination by E. coli O157:H7, the aim of this study was to determine the occurrence of this pathogen through PCR (Polymerase Chain Reaction) and ELISA (VIDAS ECO O157((r)), bioMerieux, Lyon, France) test. Thirty cheese samples manufactured by artisan farmhouse producers were collected from open-air markets in Goiania and thirty from industries under Federal Inspection located in Goias State which trade their products in supermarkets in Goiania. E. coli O157:H7 was detected in 6.67% samples collected in open air markets using ELISA, and 23,33% with PCR. The pathogen was not detected in samples from industries under Federal Inspection. PMID- 24948908 TI - Control of Listeria monocytogenes growth in soft cheeses by bacteriophage P100. AB - The purpose of this study was to determine the effect of bacteriophage P100 on strains of Listeria monocytogenes in artificially inoculated soft cheeses. A mix of L. monocytogenes 1/2a and Scott A was inoculated in Minas Frescal and Coalho cheeses (approximately 10(5) cfu/g) with the bacteriophage added thereafter (8.3 * 10(7) PFU/g). Samples were analyzed immediately, and then stored at 10 degrees C for seven days. At time zero, 30 min post-infection, the bacteriophage P100 reduced L. monocytogenes counts by 2.3 log units in Minas Frescal cheese and by 2.1 log units in Coalho cheese, compared to controls without bacteriophage. However, in samples stored under refrigeration for seven days, the bacteriophage P100 was only weakly antilisterial, with the lowest decimal reduction (DR) for the cheeses: 1.0 log unit for Minas Frescal and 0.8 log units for Coalho cheese. The treatment produced a statistically significant decrease in the counts of viable cells (p < 0.05) and in all assays performed, we observed an increase of approximately one log cycle in the number of viable cells of L. monocytogenes in the samples under refrigeration for seven days. Moreover, a smaller effect of phages was observed. These results, along with other published data, indicate that the effectiveness of the phage treatment depends on the initial concentration of L. monocytogenes, and that a high concentration of phages per unit area is required to ensure sustained inactivation of target pathogens on food surfaces. PMID- 24948909 TI - Occurrence of Salmonella spp. and generic Escherichia coli on beef carcasses sampled at a Brazilian slaughterhouse. AB - A total of 120 beef carcasses were analyzed during processing at a slaughterhouse in southern Brazil. The carcasses were sampled by swab at three different steps of the slaughter line and then they were tested for Salmonella and E. coli. The Salmonella isolates were also examined for antimicrobial susceptibility. Salmonella prevalence distribution was modeled and the probability of contamination was simulated using @Risk program and 10,000 interactions. Results demonstrated that 4 beef carcasses (3.3%) were positive for Salmonella only in the first point. The six isolates of Salmonella were classified: S. Newport (n = 3), S. Saintpaul (n = 2) and S. Anatum (n = 1). No Salmonella strains exhibited resistance to any of the antimicrobials tested. As expected, the most contaminated point with E. coli was the first point (hide), presenting counts from 0.31 to 5.07 log cfu/100 cm(2). Much smaller E. coli counts were observed in the other points. Results indicated low levels of Salmonella and E. coli on the beef carcasses analyzed and also low probability of contamination of the carcasses by Salmonella, suggesting adequate microbiological quality. PMID- 24948910 TI - Antibiotic resistance in lactic acid bacteria isolated from some pharmaceutical and dairy products. AB - A total of 244 lactic acid bacteria (LAB) strains were isolated from 180 dairy and pharmaceutical products that were collected from different areas in Minia governorate, Egypt. LAB were identified phenotypically on basis of morphological, physiological and biochemical characteristics. Lactobacillus isolates were further confirmed using PCR-based assay. By combination of phenotypic with molecular identification Lactobacillus spp. were found to be the dominant genus (138, 76.7%) followed by Streptococcus spp. (65, 36.1%) and Lactococcus spp. (27, 15%). Some contaminant organisms such as (Staphylococcus spp., Escherichia coli, Salmonella spp., mould and yeast) were isolated from the collected dairy samples but pharmaceutical products were free of such contaminants. Susceptibility of LAB isolates to antibiotics representing all major classes was tested by agar dilution method. Generally, LAB were highly susceptible to Beta-lactams except penicillin. Lactobacilli were resistant to vancomycin, however lactococci and streptococci proved to be very susceptible. Most strains were susceptible to tetracycline and showed a wide range of streptomycin MICs. The MICs of erythromycin and clindamycin for most of the LAB were within the normal range of susceptibility. Sixteen Lactobacillus, 8 Lactococcus and 8 Streptococcus isolates including all tetracycline and/or erythromycin resistant strains were tested for the presence of tetracycline and/or erythromycin resistant genes [tet(M) and/or erm(B)]. PCR assays shows that some resistant strains harbor tet(M) and/or erm(B) resistance genes. PMID- 24948911 TI - Comparison of the efficiency between two sampling plans for aflatoxins analysis in maize. AB - Variance and performance of two sampling plans for aflatoxins quantification in maize were evaluated. Eight lots of maize were sampled using two plans: manual, using sampling spear for kernels; and automatic, using a continuous flow to collect milled maize. Total variance and sampling, preparation, and analysis variance were determined and compared between plans through multifactor analysis of variance. Four theoretical distribution models were used to compare aflatoxins quantification distributions in eight maize lots. The acceptance and rejection probabilities for a lot under certain aflatoxin concentration were determined using variance and the information on the selected distribution model to build the operational characteristic curves (OC). Sampling and total variance were lower at the automatic plan. The OC curve from the automatic plan reduced both consumer and producer risks in comparison to the manual plan. The automatic plan is more efficient than the manual one because it expresses more accurately the real aflatoxin contamination in maize. PMID- 24948912 TI - Methods to preserve potentially toxigenic fungi. AB - Microorganisms are a source of many high-value compounds which are useful to every living being, such as humans, plants and animals. Since the process of isolating and improving a microorganism can be lengthy and expensive, preserving the obtained characteristic is of paramount importance, so the process does not need to be repeated. Fungi are eukaryotic, achlorophyllous, heterotrophic organisms, usually filamentous, absorb their food, can be either macro or microscopic, propagate themselves by means of spores and store glycogen as a source of storage. Fungi, while infesting food, may produce toxic substances such as mycotoxins. The great genetic diversity of the Kingdom Fungi renders the preservation of fungal cultures for many years relevant. Several international reference mycological culture collections are maintained in many countries. The methodologies that are most fit for preserving microorganisms for extended periods are based on lowering the metabolism until it reaches a stage of artificial dormancy. The goal of this study was to analyze three methods for potentially toxigenic fungal conservation (Castellani's, continuous subculture and lyophilization) and to identify the best among them. PMID- 24948913 TI - Survey of molds, yeast and Alicyclobacillus spp. from a concentrated apple juice productive process. AB - Bacteria and molds may spoil and/or contaminate apple juice either by direct microbial action or indirectly by the uptake of metabolites as off-flavours and toxins. Some of these microorganisms and/or metabolites may remain in the food even after extensive procedures. This study aim to identify the presence of molds (including heat resistant species) and Alicyclobacillus spp., during concentrated apple juice processing. Molds were isolated at different steps and then identified by their macroscopic and microscopic characteristics after cultivation on standard media at 5, 25 and 37 degrees C, during 7 days. Among the 19 isolated found, 63% were identified as Penicillium with 50% belonging to the P. expansum specie. With regards to heat resistant molds, the species Neosartorya fischeri, Byssochlamys fulva and also the genus Eupenicillium sp., Talaromyces sp. and Eurotium sp. were isolated. The thermoacidophilic spore-forming bacteria were identified as A. acidoterrestris by a further investigation based on 16S rRNA sequence similarity. The large contamination found indicates the need for methods to eliminate or prevent the presence of these microorganisms in the processing plants in order to avoid both spoilage of apple juice and toxin production. PMID- 24948914 TI - Simultaneous and successive inoculations of yeasts and lactic acid bacteria on the fermentation of an unsulfited Tannat grape must. AB - Interactions between yeasts and lactic acid bacteria are strain specific, and their outcome is expected to change in simultaneous alcoholic--malolactic fermentations from the pattern observed in successive fermentations. One Oenococcus oeni strain Lalvin VP41TM was inoculated with two Saccharomyces cerevisiae strains either simultaneously, three days after the yeast inoculation, or when alcoholic fermentation was close to finish. Early bacterial inoculations with each yeast strain allowed for the growth of the bacterial populations, and the length of malolactic fermentation was reduced to six days. Alcoholic fermentation by Lalvin ICV D80(r) yeast strain left the highest residual sugar, suggesting a negative effect of the bacterial growth and malolactic activity on its performance. In sequential inoculations the bacterial populations did not show actual growth with either yeast strain. In this strategy, both yeast strains finished the alcoholic fermentations, and malolactic fermentations took longer to finish. Lalvin ICV D80(r) allowed for higher viability and activity of the bacterial strain than Fermicru UY4(r) under the three inoculation strategies. This was beneficial for the sequential completion of both fermentations, but negatively affected the completion of alcoholic fermentation by Lalvin ICV D80(r) in the early bacteria additions. Conversely, Fermicru UY4(r), which was rather inhibitory towards the bacteria, favored the timely completion of both fermentations simultaneously. As bacteria in early inoculations with low or no SO2 addition can be expected to multiply and interact with fermenting yeasts, not only are the yeast-bacterium strains combination and time point of the inoculation to be considered, but also the amount of bacteria inoculated. PMID- 24948915 TI - Biofilm formation by Staphylococcus aureus from food contact surfaces in a meat based broth and sensitivity to sanitizers. AB - This study assessed the capacity of adhesion, the detachment kinetic and the biofilm formation by Staphylococcus aureus isolated from food services on stainless steel and polypropylene surfaces (2 * 2 cm) when cultivated in a meat based broth at 28 and 7 degrees C. It was also to study the efficacy of the sanitizers sodium hypochlorite (250 mg/L) and peracetic acid (30 mg/L) in inactivating the bacterial cells in the preformed biofilm. S. aureus strains adhered in high numbers regardless the assayed surface kind and incubation temperature over 72 h. Cells detachment of surfaces revealed high persistence over the incubation period. Number of cells needed for biofilm formation was noted at all experimental systems already after 3 days. Peracetic acid and sodium hypochlorite were not efficient in completely removing the cells of S. aureus adhered on polypropylene and stainless steel surfaces. From these results, the assayed strains revealed high capacity to adhere and form biofilm on polypropylene and stainless steel surfaces under different growth conditions. Moreover, the cells in biofilm matrix were resistant for total removal when submitted to the exposure to sanitizers. PMID- 24948916 TI - Campylobacter jejuni in commercial eggs. AB - This study evaluated the ability of Campylobacter jejuni to penetrate through the pores of the shells of commercial eggs and colonize the interior of these eggs, which may become a risk factor for human infection. Furthermore, this study assessed the survival and viability of the bacteria in commercial eggs. The eggs were placed in contact with wood shavings infected with C. jejuni to check the passage of the bacteria. In parallel, the bacteria were inoculated directly into the air chamber to assess the viability in the egg yolk. To determine whether the albumen and egg fertility interferes with the entry and survival of bacteria, we used varying concentrations of albumen and SPF and commercial eggs. C. jejuni was recovered in SPF eggs (fertile) after three hours in contact with contaminated wood shavings but not in infertile commercial eggs. The colonies isolated in the SPF eggs were identified by multiplex PCR and the similarity between strains verified by RAPD-PCR. The bacteria grew in different concentrations of albumen in commercial and SPF eggs. We did not find C. jejuni in commercial eggs inoculated directly into the air chamber, but the bacteria were viable during all periods tested in the wood shavings. This study shows that consumption of commercial eggs infected with C. jejuni does not represent a potential risk to human health. PMID- 24948917 TI - Optimization of nutritional and non--nutritional factors involved for production of antimicrobial compounds from Lactobacillus pentosus SJ65 using response surface methodology. AB - Bacteriocins from lactic acid bacteria are ribosomal synthesized antibacterial proteins/peptides having wide range of applications. Lactobacillus pentosus SJ65, isolated from fermented Uttapam batter (used to prepare south Indian pan cake), produces bacteriocin having a broad spectrum of activity against pathogens. Optimization studies are of utmost important to understand the source of utilization and the conditions to enhance the production of metabolites. In the present study, an attempt was made to identify the parameters involved for maximal production of antimicrobial compounds especially bacteriocin from the isolate L. pentosus SJ65. Initially, optimal conditions, such as incubation period, pH, and temperature were evaluated. Initial screening was done using methodology one-variable-at-a-time (OVAT) for various carbon and nitrogen sources. Further evaluation was carried out statistically using Plackett-Burman design and the variables were analyzed using response surface methodology using central composite design. The optimum media using tryptone or soy peptone, yeast extract, glucose, triammonium citrate, MnSO4, dipotassium hydrogen phosphate and tween 80 produced maximum bacteriocin activity. PMID- 24948918 TI - Use Carum copticum essential oil for controlling the Listeria monocytogenes growth in fish model system. AB - This study was conducted to evaluate the antibacterial effect of Carum copticum essential oil (Ajowan EO) against Listeria monocytogenes in fish model system. Ajowan EO chemical composition was determined by gas chromatography/mass spectral analysis and the highest concentration of Carum copticum essential oil without any significant changes on sensory properties of kutum fish (Rutilus frisii kutum) was assigned. Then the inhibitory effect of Ajowan EO at different concentrations in presence of salt and smoke component was tested on L. monocytogenes growth in fish peptone broth (FPB), kutum broth and cold smoked kutum broth at 4 degrees C for 12 days. Ajowan EO completely decreased the number of L. monocytogenes in FPB after 12 days of storage, however, antimicrobial effect of EO significantly reduced in kutum and cold smoked kutum broth. Addition of 4% NaCl and smoke component improved the anti-listerial activity of Ajowan EO in all fish model broths. PMID- 24948919 TI - Application of decolourized and partially purified polygalacturonase and alpha amylase in apple juice clarification. AB - Polygalacturonase and alpha-amylase play vital role in fruit juice industry. In the present study, polygalacturonase was produced by Aspergillus awamori Nakazawa MTCC 6652 utilizing apple pomace and mosambi orange (Citrus sinensis var mosambi) peels as solid substrate whereas, alpha-amylase was produced from A. oryzae (IFO 30103) using wheat bran by solid state fermentation (SSF) process. These carbohydrases were decolourized and purified 8.6-fold, 34.8-fold and 3.5-fold, respectively by activated charcoal powder in a single step with 65.1%, 69.8% and 60% recoveries, respectively. Apple juice was clarified by these decolourized and partially purified enzymes. In presence of 1% polygalacturonase from mosambi peels (9.87 U/mL) and 0.4% alpha-amylase (899 U/mL), maximum clarity (%T(660 nm) = 97.0%) of juice was attained after 2 h of incubation at 50 degrees C in presence of 10 mM CaCl2. Total phenolic content of juice was reduced by 19.8% after clarification, yet with slightly higher %DPPH radical scavenging property. PMID- 24948920 TI - Occurrence of Candida orthopsilosis in Brazilian tomato fruits (Lycopersicum esculentum Mill.). AB - We aimed to isolate and identify yeasts found in the tomato fruit in order to obtain isolates with biotechnological potential, such as in control of fungal diseases that damage postharvest fruits. We identified Candida orthopsilosis strains LT18 and LT24. This is the first report of this yeast on Lycopersicum esculentum fruits in Brazil. PMID- 24948921 TI - Prevalence and phenotypic characterization of Enterococcus spp. isolated from food in Brazil. AB - We evaluated the frequency of enterococci from food and found 95.2% of positivity, being E. faecium and E. faecalis the most frequent species. High level streptomycin resistance was observed, as well as gelatinase and hemolysis activity, showing the potential role of environmental strains as reservoir of virulence and resistance traits. PMID- 24948922 TI - Best conditions for biodegradation of diesel oil by chemometric tools. AB - Diesel oil biodegradation by different bacteria-yeast-rhamnolipids consortia was tested. Chromatographic analysis of post-biodegradation residue was completed with chemometric tools (ANOVA, and a novel ranking procedure based on the sum of ranking differences). These tools were used in the selection of the most effective systems. The best results of aliphatic fractions of diesel oil biodegradation were observed for a yeast consortia with Aeromonas hydrophila KR4. For these systems the positive effect of rhamnolipids on hydrocarbon biodegradation was observed. However, rhamnolipids addition did not always have a positive influence on the biodegradation process (e.g. in case of yeast consortia with Stenotrophomonas maltophila KR7). Moreover, particular differences in the degradation pattern were observed for lower and higher alkanes than in the case with C22. Normally, the best conditions for "lower" alkanes are Aeromonas hydrophila KR4 + emulsifier independently from yeasts and e.g. Pseudomonas stutzeri KR7 for C24 alkane. PMID- 24948923 TI - Aflatoxin detoxification by manganese peroxidase purified from Pleurotus ostreatus. AB - Manganese peroxidase (MnP) was produced from white rot edible mushroom Pleurotus ostreatus on the culture filtrate. The enzyme was purified to homogeneity using (NH4)2SO4 precipitation, DEAE-Sepharose and Sephadex G-100 column chromatography. The final enzyme activity achieved 81 U mL(-1), specific activity 78 U mg(-1) with purification fold of 130 and recovery 1.2% of the crude enzyme. SDS-PAGE indicated that the pure enzyme have a molecular mass of approximately 42 kDa. The optimum pH was between 4-5 and the optimum temperature was 25 degrees C. The pure MnP activity was enhanced by Mn(2+), Cu(2+), Ca(2+) and K(+) and inhibited by Hg(+2) and Cd(+2). H2O2 at 5 mM enhanced MnP activity while at 10 mM inhibited it significantly. The MnP-cDNA encoding gene was sequenced and determined (GenBank accession no. AB698450.1). The MnP-cDNA was found to consist of 497 bp in an Open Reading Frame (ORF) encoding 165 amino acids. MnP from P. ostreatus could detoxify aflatoxin B1 (AFB1) depending on enzyme concentration and incubation period. The highest detoxification power (90%) was observed after 48 h incubation at 1.5 U mL(-1) enzyme activities. PMID- 24948924 TI - Yeast diversity associated to sediments and water from two Colombian artificial lakes. AB - In Colombia, knowledge of the yeast and yeast-like fungi community is limited because most studies have focused on species with clinical importance. Sediments and water represent important habitats for the study of yeast diversity, especially for yeast species with industrial, biotechnological, and bioremediation potential. The main purpose of this study was to identify and compare the diversity of yeast species associated with sediment and water samples from two artificial lakes in Universidad del Valle (Cali-Colombia). Yeast samplings were performed from fifteen sediment samples and ten water samples. Grouping of similar isolates was initially based on colony and cell morphology, which was then complemented by micro/mini satellite primed PCR banding pattern analysis by using GTG5 as single primer. A representative isolate for each group established was chosen for D1/D2 domain sequencing and identification. In general, the following yeast species were identified: Candida albicans, Candida diversa, Candida glabrata, Candida pseudolambica, Cryptococcus podzolicus, Cryptococcus rajasthanensis, Cryptococcus laurentii, Williopsis saturnus, Hanseniaspora thailandica, Hanseniaspora uvarum, Rhodotorula mucilaginosa, Saccharomyces cerevisiae, Torulaspora delbrueckii, Torulaspora pretoriensis, Tricosporon jirovecii, Trichosporon laibachii and Yarrowia lypolitica. Two possible new species were also found, belonging to the Issatchenkia sp. and Bullera sp. genera. In conclusion, the lakes at the Universidad del Valle campus have significant differences in yeast diversity and species composition between them. PMID- 24948925 TI - Protozoans bacterivory in a subtropical environment during a dry/cold and a rainy/warm season. AB - In aquatic ecosystems, bacteria are controlled by several organisms in the food chain, such as protozoa, that use them as food source. This study aimed to quantify the ingestion and clearance rates of bacteria by ciliates and heterotrophic nanoflagellates (HNF) in a subtropical freshwater reservoir (Monjolinho reservoir - Sao Carlos - Brazil) during one year period, in order to verify their importance as consumers and controllers of bacteria in two seasons, a dry/cold and a rainy/warm one. For this purpose, in situ bacterivory experiments were carried out bimonthly using fluorescently labeled bacteria with 5-(4,6 diclorotriazin-2yl) aminofluorescein (DTAF). Although ciliates have shown the highest individual ingestion and clearance rates, bacterivory was dominated by HNF, who showed higher population ingestion rates (mean of 9,140 bacteria h( 1) mL(-1)) when compared to ciliates (mean of 492 bacteria h(-1) mL(-1)). The greater predation impact on bacterial communities was caused mainly by the small HNF (< 5 MUm) population, especially in the rainy season, probably due to the abundances of these organisms, the precipitation, trophic index state and water temperature that were higher in this period. Thus, the protozoan densities together with environmental variables were extremely relevant in determining the seasonal pattern of bacterivory in Monjolinho reservoir. PMID- 24948926 TI - Endophytic fungi from Myrcia guianensis at the Brazilian Amazon: distribution and bioactivity. AB - Beneficial interactions between plants and microorganisms have been investigated under different ecological, physiological, biochemical, and genetic aspects. However, the systematic exploration of biomolecules with potential for biotechnological products from this interaction still is relatively scarce. Therefore, this study aimed the evaluation of the diversity and antimicrobial activity of the endophytic fungi obtained from roots, stems and leafs of Myrcia guianensis (Myrtaceae) from the Brazilian Amazon. 156 endophytic fungi were isolated and above 80% were identified by morphological examination as belonging to the genera Pestalotiopsis, Phomopsis, Aspergillus, Xylaria, Nectria, Penicillium and Fusarium. Fermented broth of those fungi were assayed for antimicrobial activity and four inhibited the growth of Staphylococcus aureus, Enterococcus faecalis, Candida albicans and Penicillium avellaneum. As the strain named MgRe2.2.3B (Nectria haematococca) had shown the most promising results against those pathogenic strains, its fermented broth was fractioned and only its two low polar fractions demonstrated to be active. Both fractions exhibited a minimum bactericidal concentration of 50 MUg.mL(-1) against S. aureus and a minimum fungicidal concentration of 100 MUg.mL(-1) against P. avellaneum. These results demonstrate the diversity of fungal genera in M. guianensis and the potential of these endophytic fungi for the production of new antibiotics. PMID- 24948927 TI - A primary assessment of the endophytic bacterial community in a xerophilous moss (Grimmia montana) using molecular method and cultivated isolates. AB - Investigating the endophytic bacterial community in special moss species is fundamental to understanding the microbial-plant interactions and discovering the bacteria with stresses tolerance. Thus, the community structure of endophytic bacteria in the xerophilous moss Grimmia montana were estimated using a 16S rDNA library and traditional cultivation methods. In total, 212 sequences derived from the 16S rDNA library were used to assess the bacterial diversity. Sequence alignment showed that the endophytes were assigned to 54 genera in 4 phyla (Proteobacteria, Firmicutes, Actinobacteria and Cytophaga/Flexibacter/Bacteroids). Of them, the dominant phyla were Proteobacteria (45.9%) and Firmicutes (27.6%), the most abundant genera included Acinetobacter, Aeromonas, Enterobacter, Leclercia, Microvirga, Pseudomonas, Rhizobium, Planococcus, Paenisporosarcina and Planomicrobium. In addition, a total of 14 species belonging to 8 genera in 3 phyla (Proteobacteria, Firmicutes, Actinobacteria) were isolated, Curtobacterium, Massilia, Pseudomonas and Sphingomonas were the dominant genera. Although some of the genera isolated were inconsistent with those detected by molecular method, both of two methods proved that many different endophytic bacteria coexist in G. montana. According to the potential functional analyses of these bacteria, some species are known to have possible beneficial effects on hosts, but whether this is the case in G. montana needs to be confirmed. PMID- 24948929 TI - Tank bromeliad water: similar or distinct environments for research of bacterial bioactives? AB - The Atlantic Rainforest does not have a uniform physiognomy, its relief determines different environmental conditions that define the composition of its flora and fauna. Within this ecosystem, bromeliads that form tanks with their leaves hold water reservoirs throughout the year, maintaining complex food chains, based mainly on autotrophic and heterotrophic bacteria. Some works concluded that the water held by tank bromeliads concentrate the microbial diversity of their ecosystem. To investigate the bacterial diversity and the potential biotechnology of these ecosystems, tank bromeliads of the Neoregelia cruenta species from the Atlantic Rainforest in Brazil were used as models for this research. Bacteria isolated from these models were tested for production of bioactive compounds. DGGE of the water held by tank bromeliads was performed in different seasons, locations and sun exposure to verify whether these environmental factors affect bacterial communities. The DGGE bands profile showed no grouping of bacterial community by the environmental factors tested. Most of the isolates demonstrated promising activities in the tests performed. Collectively, these results suggest that tank bromeliads of the N. cruenta species provide important habitats for a diverse microbial community, suggesting that each tank forms a distinct micro-habitat. These tanks can be considered excellent sources for the search for new enzymes and/or new bioactive composites of microbial origin. PMID- 24948928 TI - Comparison of DNA extraction protocols for microbial communities from soil treated with biochar. AB - Many studies have evaluated the effects of biochar application on soil structure and plant growth. However, there are very few studies describing the effect of biochar on native soil microbial communities. Microbial analysis of environmental samples requires accurate and reproducible methods for the extraction of DNA from samples. Because of the variety among microbial species and the strong adsorption of the phosphate backbone of the DNA molecule to biochar, extracting and purifying high quality microbial DNA from biochar-amended soil is not a trivial process and can be considerably more difficult than the extraction of DNA from other environmental samples. The aim of this study was to compare the relative efficacies of three commercial DNA extraction kits, the FastDNA(r) SPIN Kit for Soil (FD kit), the PowerSoil(r) DNA Isolation Kit (PS kit) and the ZR Soil Microbe DNA Kit MiniprepTM (ZR kit), for extracting microbial genomic DNA from sand treated with different types of biochar. The methods were evaluated by comparing the DNA yields and purity and by analysing the bacterial and fungal community profiles generated by PCR-DGGE. Our results showed that the PCR-DGGE profiles for bacterial and fungal communities were highly affected by the purity and yield of the different DNA extracts. Among the tested kits, the PS kit was the most efficient with respect to the amount and purity of recovered DNA and considering the complexity of the generated DGGE microbial fingerprint from the sand-biochar samples. PMID- 24948930 TI - Screening of endoglucanase-producing bacteria in the saline rhizosphere of Rhizophora mangle. AB - In screening the culturable endoglucanase-producing bacteria in the rhizosphere of Rhizophora mangle, we found a prevalence of genera Bacillus and Paenibacillus. These bacteria revealed different activities in endoglucolysis and biofilm formation when exposed to specific NaCl concentrations, indicating modulated growth under natural variations in mangrove salinity. PMID- 24948931 TI - Development and assessment of a latex agglutination test based on recombinant MSP5 to detect antibodies against Anaplasma marginale in cattle. AB - The recombinant protein MSP5 has been established as an important antigen for serological diagnosis of Anaplasma marginale by enzyme-linked immunosorbent assay (ELISA). However, due to the high cost of specialized equipment, this technique is not accessible to all laboratories, especially in developing countries in areas where the disease is endemic. The present study describes the standardization of a latex agglutination test (LAT) to detect antibodies against A. marginale based on recombinant MSP5. Compared with indirect enzyme-linked immunosorbent assay (iELISA), the relative sensitivity and specificity of the LAT were 95.21% and 91.86% respectively, with an almost perfect agreement between tests (kappa index = 0.863). These results can be considered important for the serological diagnosis of A. marginale, as they indicate that the test represents a rapid and low cost alternative to ELISA. PMID- 24948932 TI - Isolation of Actinobacillus seminis from a goat with clinical epididymo-orchitis in Brazil. AB - The present study reports the first isolation of Actinobacillus seminis from a goat in Brazil. A four-year-old Moxoto breeding goat in a flock of 70 goats and 65 sheep reared together in the county of Patos, semiarid region of Northeastern Brazil, showed clinical signs of unilateral orchitis and epididymitis. Diagnosis of A. seminis infection was confirmed by association of clinical findings, bacterial isolation and 16S rRNA gene sequencing. This result suggests that A. seminis may be an additional cause of infertility in goats, and that sheep may be the source of infection because the mixed farming system allows the contact between sheep and goats in the semiarid region of Northeastern Brazil. PMID- 24948933 TI - In vitro inhibition of the bovine viral diarrhoea virus by the essential oil of Ocimum basilicum (basil) and monoterpenes. AB - The bovine viral diarrhoea virus (BVDV) is suggested as a model for antiviral studies of the hepatitis C virus (HCV). The antiviral activity of the essential oil of Ocimum basilicum and the monoterpenes camphor, thymol and 1,8-cineole against BVDV was investigated. The cytotoxicities of the compounds were measured by the MTT (3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide) test, and the antiviral activities were tested by the plaque reduction assay. The oil or compounds were added to the assay in three different time points: a) pre treatment of the virus (virucidal assay); b) pre-treatment of the cells; or c) post-treatment of the cells (after virus inoculation). The percentage of plaques inhibition for each compound was determined based on the number of plaques in the viral control. The results were expressed by CC50 (50% cytotoxic concentration), IC50 (inhibitory concentration for 50% of plaques) and SI (selectivity index = CC50/IC50). Camphor (CC50 = 4420.12 MUg mL(-1)) and 1,8-cineole (CC50 = 2996.10 MUg mL(-1)) showed the lowest cytotoxicities and the best antiviral activities (camphor SI = 13.88 and 1,8-cineol SI = 9.05) in the virucidal assay. The higher activities achieved by the monoterpenes in the virucidal assay suggest that these compounds act directly on the viral particle. PMID- 24948934 TI - Methicillin-resistant coagulase-negative staphylococci from healthy dogs in Nsukka, Nigeria. AB - The occurrence, resistance phenotype and molecular mechanisms of resistance of methicillin-resistant staphylococci from groin swabs of 109 clinically healthy dogs in Nsukka, Nigeria were investigated. The groin swab samples were cultured on mannitol salt agar supplemented with 10 MUg of cloxacillin. Sixteen methicillin-resistant coagulase negative staphylococci (MRCoNS), all harbouring the mecA gene were isolated from 14 (12.8%) of the 109 dogs studied. The MRCoNS isolated were: S. sciuri subspecies rodentium, S. lentus, S. haemolyticus, and S. simulans with S. sciuri subspecies rodentium (62.5%) being the predominant species. Thirteen (81.3%) of the MRCoNS were resistant to tetracycline while 12 (75%) and 10 (62.5%) were resistant to kanamycin and trimthoprim sulphamethoxazole respectively. None of the isolates was resistant to fusidic acid, linezolid and vancomycin. Thirteen (81.3%) of the MRCoNS were multi-drug resistance (MDR). Other antimicrobial genes detected were: blaZ, tet(K), tet(M), tet(L), erm(B), lnu(A), aacA-aphD, aphA3, str, dfr(G), cat pC221 , and cat pC223 . Methicillin-resistant staphylococci are common colonizers of healthy dogs in Nigeria with a major species detected being S. sciuri subsp. rodentium. PMID- 24948935 TI - Acute myonecrosis in horse caused by Clostridium novyi type A. AB - The objective of this study was to describe the first report involving a case of equine acute myonecrosis caused by C. novyi type A with an emphasis on clinical signs, the pathological and bacteriological analysis, and molecular identification of the microorganisms as the key of the definitive diagnosis. PMID- 24948936 TI - Thin layer microcolony culture associated with PCR for early identification of Mycobacterium bovis. AB - The initial growth of mycobacteria from 49 samples of cattle and buffalo organs collected in commercial slaughterhouses was compared between modified Middlebrook 7H11 thin layer microcolony culture and Stonebrink medium used in the isolation of Mycobacterium bovis. Aliquots were decontaminated by Petroff's method, processed and cultured in both media. The identity of the acid-fast bacilli stained by Ziehl-Neelsen was confirmed by PCR. Optical microscopy showed that results of the early observation of Mycobacterium bovis colonies in thin layer culture were similar to those obtained in macroscopic observation of the colonies in Stonebrink medium. However, early observation of the colonies enabled early confirmation by PCR, given the shorter time to the visualization of colonies when thin layer culture was used (between the 12(nd) and 25(th) day of culture). PMID- 24948937 TI - Canarypox virus expressing infectious bursal disease VP2 protein as immunogen for chickens. AB - Canarypox viruses (CNPV) carrying the coding sequence of VP2 protein from infectious bursal disease virus (IBDV) were obtained. These viruses were able to express VP2 protein in vitro and to induce IBDV-neutralizing antibodies when inoculated in specific pathogen-free chickens demonstrating that CNPV platform is usefulness to develop immunogens for chickens. PMID- 24948938 TI - Comparison of cefoxitin disk diffusion test and mecA gene PCR results for methicillin resistance detection in Staphylococcus intermedius group isolates from canine origin in Brazil. AB - The study evaluated cefoxitin disk diffusion tests breakpoints and their correlation to mecA gene PCR results for detecting Methicillin-resistant Staphylococcus intermedius Group (MRSP) isolates from dogs in Brazil. Agreement using proposed breakpoint (resistant <= 30 mm) was encouraging. The current study reinforces that an epidemiological breakpoint can be established to predict presence of MRSP. PMID- 24948940 TI - Paracoccidioidomycosis in southern Rio Grande do Sul: a retrospective study of histopathologically diagnosed cases. AB - Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the fungus Paracoccidioides brasiliensis and is endemic to Brazil. The aim of this study was to perform a retrospective analysis of the PCM cases in the countryside south of Rio Grande do Sul, Brazil. The files from four histopathology laboratories located in the city of Pelotas were obtained, and all of the epidemiological and clinical data from the PCM diagnosed cases were collected for analysis. A total of 123 PCM cases diagnosed between 1966 and 2009 were selected. Of these patients, 104 (84.5%) were male, and 17 were female. The patients ranged from 02 to 92 years of age. Fifty-two cases (41.9%) were obtained from the oral pathology laboratory, and the remaining 71 cases (58.1%) were obtained from the three general pathology laboratories. Of all of the patients studied, 65.2% lived in rural zones and worked in agriculture or other related fields. Data on the evolution of this disease was available for 43 cases, and the time frame ranged from 20 to 2920 days (mean = 572.3 days). An accurate diagnosis performed in less than 30 days only occurred in 21% of the cases. PCM is endemic to the countryside of Rio Grande do Sul. Therefore, it is recommended that PCM be included as a differential diagnosis, mainly for individuals between 30 and 60 years of age, living in rural zones and who have respiratory signs and associated-oropharyngeal lesions. PMID- 24948939 TI - Molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis clinical isolates. AB - To evaluate the molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis (MH) clinical strains isolated from urogenital specimens. 15 MH clinical isolates with different phenotypes of resistance to fluoroquinolones antibiotics were screened for mutations in the quinolone resistance-determining regions (QRDRs) of DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) in comparison with the reference strain PG21, which is susceptible to fluoroquinolones antibiotics. 15 MH isolates with three kinds of quinolone resistance phenotypes were obtained. Thirteen out of these quinolone-resistant isolates were found to carry nucleotide substitutions in either gyrA or parC. There were no alterations in gyrB and no mutations were found in the isolates with a phenotype of resistance to Ofloxacin (OFX), intermediate resistant to Levofloxacin (LVX) and Sparfloxacin (SFX), and those susceptible to all three tested antibiotics. The molecular mechanism of fluoroquinolone resistance in clinical isolates of MH was reported in this study. The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high level resistance to fluoroquinolones for MH is likely associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV. PMID- 24948941 TI - Antifungal activity of metabolites of the endophytic fungus Trichoderma brevicompactum from garlic. AB - The endophytic fungus strain 0248, isolated from garlic, was identified as Trichoderma brevicompactum based on morphological characteristics and the nucleotide sequences of ITS1-5.8S- ITS2 and tef1. The bioactive compound T2 was isolated from the culture extracts of this fungus by bioactivity-guided fractionation and identified as 4beta-acetoxy-12,13- epoxy-Delta(9)-trichothecene (trichodermin) by spectral analysis and mass spectrometry. Trichodermin has a marked inhibitory activity on Rhizoctonia solani, with an EC50 of 0.25 MUg mL( 1). Strong inhibition by trichodermin was also found for Botrytis cinerea, with an EC50 of 2.02 MUg mL(-1). However, a relatively poor inhibitory effect was observed for trichodermin against Colletotrichum lindemuthianum (EC50 = 25.60 MUg mL(-1)). Compared with the positive control Carbendazim, trichodermin showed a strong antifungal activity on the above phytopathogens. There is little known about endophytes from garlic. This paper studied in detail the identification of endophytic T. brevicompactum from garlic and the characterization of its active metabolite trichodermin. PMID- 24948942 TI - Evaluation of chromogenic media and seminested PCR in the identification of Candida species. AB - Identification of Candida cultured from various clinical specimens to the species level is increasingly necessary for clinical laboratories. Although sn PCR identifies the species within hours but its cost-effectiveness is to be considered. So there is always a need for media which help in the isolation and identification at the species level. The study aimed to evaluate the performance of different chromogenic media and to compare the effectiveness of the traditional phenotypic methods vs. seminested polymerase chain reaction (sn PCR) for identification of Candida species. One hundred and twenty seven Candida strains isolated from various clinical specimens were identified by conventional methods, four different chromogenic media and sn PCR. HiCrome Candida Differential and CHROMagar Candida media showed comparably high sensitivities and specificities in the identification of C. albicans, C. tropicalis, C. glabrata and C. krusei. CHROMagar Candida had an extra advantage of identifying all C. parapsilosis isolates. CHROMagar-Pal's medium identified C. albicans, C. tropicalis and C. krusei with high sensitivities and specificities, but couldn't identify C. glabrata or C. parapsilosis. It was the only medium that identified C. dubliniensis with a sensitivity and specificity of 100%. Biggy agar showed the least sensitivities and specificities. The overall concordance of the snPCR compared to the conventional tests including CHROMAgar Candida in the identification of Candida species was 97.5%. The use of CHROMAgar Candida medium is an easy and accurate method for presumptive identification of the most commonly encountered Candida spp. PMID- 24948943 TI - Newly-synthesized chalcones-inhibition of adherence and biofilm formation of methicillin-resistant Staphylococcus aureus. AB - Biofilm formation and adherence of bacteria to host tissue are one of the most important virulence factors of methicillin-resistant strains of Staphylococcus aureus (MRSA). The number of resistant strains is seriously increasing during the past years and bacteria have become resistant, not only to methicillin, but also to other commonly used antistaphylococcal antibiotics. There is a great need for discovering a novel antimicrobial agent for the treatment of staphylococcal infections. One of the most promising groups of compounds appears to be chalcones. In present study we evaluated the in vitro effect of three newly synthesized chalcones: 1,3- Bis-(2-hydroxy-phenyl)-propenone, 3-(3-Hydroxy phenyl)-1-(2-hydroxy-phenyl)-propenone and 3-(4-Hydroxy-phenyl)-1-(2-hydroxy phenyl)-propenone on glycocalyx production, biofilm formation and adherence to human fibronectin of clinical isolates and laboratory control strain of MRSA (ATCC 43300). Subinhibitory concentrations of the tested compounds reduced the production of glycocalyx, biofilm formation and adherence to human fibronectin of all MRSA strains. Inhibition of biofilm formation was dose dependent and the most effective was 1,3- Bis-(2-hydroxy-phenyl)-propenone. In our study we demonstrated that three newly-synthesized chalcones exhibited significant effect on adherence and biofilm formation of MRSA strains. Chalcones may be considered as promising new antimicrobial agents that can be used for prevention of staphylococcal infections or as adjunct to antibiotics in conventional therapy. PMID- 24948945 TI - A case of extensive chromoblastomycosis from North India. AB - A case of extensive chromoblastomycosis of the right leg and thigh with verruciform to nodular lesions evolving rapidly over five years duration is reported. The diagnosis was confirmed by visualizing pathognomonic pigmented muriform bodies with unique septate hyphae and mycological culture yielding Fonsecaea pedrosoi. PMID- 24948944 TI - Characterization of the virulence, growth temperature and antibiotic resistance of the Campylobacter jejuni IAL 2383 strain isolated from humans. AB - The objective of this study was to characterize the C. jejuni IAL2383 strain isolated from humans in Brazil. Transcripts for the racR, dnaJ and ciaB genes were found and flaA, plda and cadF genes were present in the genome and bacteria was sensitive to most of the important antimicrobials used to treat humans. C. jejuni IAL2383 is a good experimental model to analyze the interactions with cells. PMID- 24948946 TI - Filamentous fungi and media for cellulase production in solid state cultures. AB - Cellulase production was evaluated in two reference strains (T. reesei Rut-C30 and T. reesei QM9414), two strains isolated from a sugarcane cultivation area (Trichoderma sp. IPT778 and T. harzianum rifai IPT821) and one strain isolated in a program for biodiversity preservation in Sao Paulo state (Myceliophthora thermophila M77). Solid state cultures were performed using sugarcane bagasse (C), wheat bran (W) and/or soybean bran (S). The highest FPA was 10.6 U/gdm for M77 in SC (10:90) at 80% moisture, which was 4.4 times higher than production in pure W. C was a strong inducer of cellulase production, given that the production level of 6.1 U/gdm in WC (40:60) was 2.5 times higher than in pure W for strain M77; T. reesei Rut-C30 did not respond as strongly with about 1.6-fold surplus production. S advantageously replaced W, as the surplus production on SC (20:80) was 2.3 times relative to WC (20:80) for M77. PMID- 24948947 TI - Optimization of zofimarin production by an endophytic fungus, Xylaria sp. Acra L38. AB - To optimize the medium for high zofimarin production, sucrose maltose, glucose, tryptone and peptone were used in an orthogonal array design experiment, where the highest value of zofimarin produced was 25.6 MUg/mL. This value was about 3 times higher than that obtained with Czapek yeast extract (CzYE) culture medium. A study with Plackett-Burman design showed that sucrose, maltose, glucose and NaNO3 were significant factors in zofimarin production. Further studies using central composite design (CCD) showed the significance of glucose and the interactions of these critical components affecting zofimarin production. Multiple regression analysis of the data yielded a poor fit as shown by the mismatch of the model with these variable factors. When a polynomial equation was applied, the maximum zofimarin production was predicted to be 201.9 MUg/mL. Experimental verification yielded a much lower amount of zofimarin, at around 70 MUg/mL. Reconsideration of the CCD data and repetition of some runs with high zofimarin production resulted in reproducible zofimarin yield at 79.7 MUg/mL. Even though the amount was lower than the predicted value, the medium optimization study was considered to be quite successful as the yield increased to around 8 times that obtained with the original CzYE culture medium. PMID- 24948948 TI - Concentration, characterization and application of lipases from Sporidiobolus pararoseus strain. AB - Lipases produced by a newly isolated Sporidiobolus pararoseus strain have potential catalytic ability for esterification reactions. After production, the enzymatic extracts (conventional crude and precipitated, 'CC' and 'CP', and industrial crude and precipitated, 'IC' e 'IP') were partially characterized. The enzymes presented, in general, higher specificity for short chain alcohols and fatty acids. The precipitated extract showed a good thermal stability, higher than that for crude enzymatic extracts. The 'CC' and 'CP' enzymes presented high activities after exposure to pH 6.5 and 40 degrees C. On the other hand, the 'IC' and 'IP' extracts kept their activities in a wide range of pH memory but presented preference for higher reaction temperatures. Preliminary studies of application of the crude lipase extract in the enzymatic production of geranyl propionate using geraniol and propionic acid as substrates in solvent-free system led to a reaction conversion of 42 +/- 1.5%. PMID- 24948950 TI - Modulation of antimicrobial metabolites production by the fungus Aspergillus parasiticus. AB - Biosynthesis of active secondary metabolites by fungi occurs as a specific response to the different growing environments. Changes in this environment alter the chemical and biological profiles leading to metabolites diversification and consequently to novel pharmacological applications. In this work, it was studied the influence of three parameters (fermentation length, medium composition and aeration) in the biosyntheses of antimicrobial metabolites by the fungus Aspergillus parasiticus in 10 distinct fermentation periods. Metabolism modulation in two culturing media, CYA and YES was evaluated by a 2(2) full factorial planning (ANOVA) and on a 2(3) factorial planning, role of aeration, medium composition and carbohydrate concentration were also evaluated. In overall, 120 different extracts were prepared, their HPLC profiles were obtained and the antimicrobial activity against A. flavus, C. albicans, E. coli and S. aureus of all extracts was evaluated by microdilution bioassay. Yield of kojic acid, a fine chemical produced by the fungus A. parasiticus was determined in all extracts. Statistical analyses pointed thirteen conditions able to modulate the production of bioactive metabolites by A. parasiticus. Effect of carbon source in metabolites diversification was significant as shown by the changes in the HPLC profiles of the extracts. Most of the extracts presented inhibition rates higher than that of kojic acid as for the extract obtained after 6 days of fermentation in YES medium under stirring. Kojic acid was not the only metabolite responsible for the activity since some highly active extracts showed to possess low amounts of this compound, as determined by HPLC. PMID- 24948949 TI - Production of polypeptide antibiotic from Streptomyces parvulus and its antibacterial activity. AB - A highly potent secondary metabolite producing actinomycetes strain is isolated from marine soil sediments of Visakhapatnam sea coast, Bay of Bengal. Over all ten strains are isolated from the collected soil sediments. Among the ten actinomycetes strains the broad spectrum strain RSPSN2 was selected for molecular characterization, antibiotic production and its purification. The nucleotide sequence of the 1 rRNA gene (1261 base pairs) of the most potent strain evidenced a 96% similarity with Streptomyces parvulus 1044 strain, Streptomyces parvulus NBRC 13193 and Streptomyces parvulus BY-F. From the taxonomic features, the actinomycetes isolate RSPSN2 matches with Streptomyces parvulus in the morphological, physiological and biochemical characters. Thus, it was given the suggested name Streptomyces parvulus RSPSN2. The active metabolite was extracted using ethyl acetate (1:3, v/v) at pH 7.0. The separation of active ingredient and its purification was performed by using both thin layer chromatography (TLC) and column chromatography (CC) techniques. Spectrometric studies such as UV-visible, FTIR, and NMR and mass were performed. The antibacterial activity of pure compound was performed by cup plate method against some pathogenic bacteria including of streptomycin resistant bacteria like (Pseudomonas mirabilis, Pseudomonas putida and Bacillus cereus). In conclusion, the collected data emphasized the fact that a polypeptide antibiotic (Actinomycin D) was produced by Streptomyces parvulus RSPSN2. PMID- 24948951 TI - DesinFix TM 135 in fermentation process for bioethanol production. AB - Brazil has the world's largest ethanol production from sugarcane, but bacterial contamination decreases the ethanol yields. It was shown that the biocide DesinFixTM 135 can reduce the contamination without decreasing the yeasts' viability or negatively affecting the ethanol production. PMID- 24948952 TI - Molecular detection of virulence factors among food and clinical Enterococcus faecalis strains in South Brazil. AB - The present report aimed to perform a molecular epidemiological survey by investigating the presence of virulence factors in E. faecalis isolated from different human clinical (n = 57) and food samples (n = 55) in Porto Alegre, Brazil, collected from 2006 to 2009. In addition, the ability to form biofilm in vitro on polystyrene and the beta-haemolytic and gelatinase activities were determined. Clinical strains presented a higher prevalence of aggregation substance (agg), enterococcal surface protein (esp) and cytolysin (cylA) genes when compared with food isolates. The esp gene was found only in clinical strains. On the other hand, the gelatinase (gelE) and adherence factor (ace) genes had similar prevalence among the strains, showing the widespread occurrence of these virulence factors among food and clinical E. faecalis strains in South Brazil. More than three virulence factor genes were detected in 77.2% and 18.2% of clinical and food strains, respectively. Gelatinase and beta-haemolysin activities were not associated with the presence of gelE and cylA genes. The ability to produce biofilm was detected in 100% of clinical and 94.6% of food isolates, and clinical strains were more able to form biofilm than the food isolates (Student's t-test, p < 0.01). Results from the statistical analysis showed significant associations between strong biofilm formation and ace (p = 0.015) and gelE (p = 0.007) genes in clinical strains. In conclusion, our data indicate that E. faecalis strains isolated from clinical and food samples possess distinctive patterns of virulence factors, with a larger number of genes that encode virulence factors detected in clinical strains. PMID- 24948953 TI - Genome-wide transcription analyses in Mycobacterium tuberculosis treated with lupulone. AB - Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, still causes higher mortality than any other bacterial pathogen until now. With the emergence and spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR-TB) strains, it becomes more important to search for alternative targets to develop new antimycobacterial drugs. Lupulone is a compound extracted from Hops (Hurnulus lupulus), which exhibits a good antimicrobial activity against M. tuberculosis with minimal inhibitory concentration (MIC) value of 10 MUg/mL, but the response mechanisms of lupulone against M. tuberculosis are still poorly understood. In this study, we used a commercial oligonucleotide microarray to determine the overall transcriptional response of M. tuberculosis H37Rv triggered by exposure to MIC of lupulone. A total of 540 genes were found to be differentially regulated by lupulone. Of these, 254 genes were upregulated, and 286 genes were downregulated. A number of important genes were significantly regulated which are involved in various pathways, such as surface-exposed lipids, cytochrome P450 enzymes, PE/PPE multigene families, ABC transporters, and protein synthesis. Real-time quantitative RT-PCR was performed for choosed genes to verified the microarray results. To our knowledge, this genome-wide transcriptomics approach has produced the first insights into the response of M. tuberculosis to a lupulone challenge. PMID- 24948954 TI - Detection of enteric viruses in activated sludge by feasible concentration methods. AB - Human enteric viruses are responsible to cause several diseases, including gastroenteritis and hepatitis, and can be present in high amounts in sewage sludge. This study compared virus recovery efficiency of two feasible concentration methods used for detecting human adenovirus (HAdV), rotavirus species A (RV-A), norovirus genogroup II (NoV GII) and hepatitis A virus (HAV) in sewage sludge from an activated sludge process. Twelve sewage sludge samples were collected bi-monthly from January to July, 2011. Ultracentrifugation was compared with a simplified protocol based on beef extract elution for recovering enteric viruses. Viruses were quantified by quantitative real-time PCR assays and virus recovery efficiency and limits of detection were determined. Methods showed mean recovery rates lower than 7.5%, presenting critical limits of detection (higher than 10(2) - 10(3) genome copies - GC L(-1) for all viruses analyzed). Nevertheless, HAdV were detected in 90% of the analyzed sewage sludge samples (range: 1.8 * 10(4) to 1.1 * 10(5) GC L(-1)), followed by RV-A and NoV (both in 50%) and HAV (8%). Results suggesting that activated sludge is contaminated with high viral loads and HAdV are widely disseminated in these samples. The low virus recovery rates achieved, especially for HAV, indicate that other feasible concentration methods could be developed to improve virus recovery efficiency in these environmental matrices. PMID- 24948955 TI - Cloning, characterization and expression of a novel laccase gene Pclac2 from Phytophthora capsici. AB - Laccases are blue copper oxidases (E.C. 1.10.3.2) that catalyze the one-electron oxidation of phenolics, aromatic amines, and other electron-rich substrates with the concomitant reduction of O2 to H2O. A novel laccase gene pclac2 and its corresponding full-length cDNA were cloned and characterized from Phytophthora capsici for the first time. The 1683 bp full-length cDNA of pclac2 encoded a mature laccase protein containing 560 amino acids preceded by a signal peptide of 23 amino acids. The deduced protein sequence of PCLAC2 showed high similarity with other known fungal laccases and contained four copper-binding conserved domains of typical laccase protein. In order to achieve a high level secretion and full activity expression of PCLAC2, expression vector pPIC9K with the Pichia pastoris expression system was used. The recombinant PCLAC2 protein was purified and showed on SDS-PAGE as a single band with an apparent molecular weight ca. 68 kDa. The high activity of purified PCLAC2, 84 U/mL, at the seventh day induced with methanol, was observed with 2,2'-azino-di-(3-ethylbenzothialozin-6-sulfonic acid) (ABTS) as substrate. The optimum pH and temperature for ABTS were 4.0 and 30 degrees C, respectively. The reported data add a new piece to the knowledge about P. Capsici laccase multigene family and shed light on potential function about biotechnological and industrial applications of the individual laccase isoforms in oomycetes. PMID- 24948956 TI - Chemical management in fungicide sensitivity of Mycosphaerella fijiensis collected from banana fields in Mexico. AB - The chemical management of the black leaf streak disease in banana caused by Mycosphaerella fijiensis (Morelet) requires numerous applications of fungicides per year. However this has led to fungicide resistance in the field. The present study evaluated the activities of six fungicides against the mycelial growth by determination of EC50 values of strains collected from fields with different fungicide management programs: Rustic management (RM) without applications and Intensive management (IM) more than 25 fungicide application/year. Results showed a decreased sensitivity to all fungicides in isolates collected from IM. Means of EC50 values in mg L(-1) for RM and IM were: 13.25 +/- 18.24 and 51.58 +/- 46.14 for azoxystrobin, 81.40 +/- 56.50 and 1.8575 +/- 2.11 for carbendazim, 1.225 +/- 0.945 and 10.01 +/- 8.55 for propiconazole, 220 +/- 67.66 vs. 368 +/- 62.76 for vinclozolin, 9.862 +/- 3.24 and 54.5 +/- 21.08 for fludioxonil, 49.2125 +/- 34.11 and 112.25 +/- 51.20 for mancozeb. A molecular analysis for beta-tubulin revealed a mutation at codon 198 in these strains having an EC50 greater than 10 mg L(-1) for carbendazim. Our data indicate a consistency between fungicide resistance and intensive chemical management in banana fields, however indicative values for resistance were also found in strains collected from rustic fields, suggesting that proximity among fields may be causing a fungus interchange, where rustic fields are breeding grounds for development of resistant strains. Urgent actions are required in order to avoid fungicide resistance in Mexican populations of M. fijiensis due to fungicide management practices. PMID- 24948958 TI - Political determinants of Health: Lessons for Pakistan. AB - There is much concern about the capacity of the health system of Pakistan to meet its goals and obligations. Historically, the political thrust has been absent from the health policy formulation and this is reflected in the low and stagnant public allocations to health. Successive political leaderships have averred from considering healthcare is a common good rather than a market commodity and health has not been recognized as a constitutional right. Over 120 of world's nation states have accepted health as a constitutional right but the 1973 Constitution of Pakistan does not mandate health or education as a fundamental right and the recently adopted 18th constitutional amendment missed the opportunity to extend access to primary health care as an obligation of the State. It is argued in this communication that missing from the calculations of policy formulation and agenda setting is the political benefits of providing health and other social services to underserved populations. Across the developing world, many examples are presented of governments undertaking progressive health reforms that bring services where none existed and subsequently reaping electoral benefit. The political determinant of healthcare will be realized when the political leaders of poorly performing countries can be convinced that embracing distributive policies and successfully bringing healthcare to the poor can be major factors in their re-elections. PMID- 24948957 TI - Hump-nosed viper bite: an important but under-recognized cause of systemic envenoming. AB - Hump-nosed viper bites are common in the Indian subcontinent. In the past, hump nosed vipers (Hypnale species) were considered moderately venomous snakes whose bites result mainly in local envenoming. However, a variety of severe local effects, hemostatic dysfunction, microangiopathic hemolysis, kidney injury and death have been reported following envenoming by Hypnale species. We systematically reviewed the medical literature on the epidemiology, toxin profile, diagnosis, and clinical, laboratory and postmortem features of hump nosed viper envenoming, and highlight the need for development of an effective antivenom. PMID- 24948959 TI - Prescription patterns of general practitioners in peshawar, pakistan. AB - OBJECTIVES: To find out prescription patterns of general practitioners in Peshawar. METHODS: Cross-sectional survey of drug prescriptions was done at six major hospitals and pharmacies of Peshawar between April and May 2011. A total of 1097 prescriptions that included 3640 drugs, were analyzed to assess completeness, average number of drugs, prescription frequency of various drug classes, and number of brands prescribed. RESULTS: No prescription contained all essential components of a prescription. Legibility was poor in 58.5% prescriptions. Physician's name and registration number were not mentioned in 89% and 98.2% prescriptions respectively. Over 78% prescriptions did not have diagnosis or indication mentioned. Dosage, duration of use, signature of physician and directions for taking drugs were not written in 63.8%, 55.4%, 18.5% and 10.9% of prescriptions respectively. On average each prescription included 3.32 drugs. Most frequently prescribed drug classes included analgesics (61.7%), anti-infective agents (57.2%), multi-vitamins (37.8%) and gastrointestinal drugs (34.4%). We found 206, 130, 105 and 101 different brands of anti-infective agents, gastrointestinal drugs, analgesics and multivitamins being prescribed. CONCLUSION: We observed a high number of average drugs per prescription mostly using brand names, and over-prescription of analgesics, antimicrobials, multivitamins and anti-ulcer drugs. Quality of written prescriptions was poor in terms of completeness. PMID- 24948960 TI - Comparative Studies of Salivary and Blood Sialic Acid, Lipid Peroxidation and Antioxidative Status in Oral Squamous Cell Carcinoma (OSCC). AB - Objective : Oral squamous cell carcinoma (OSCC) is considered to be a serious life threatening issue for almost two decades. The objective of this study was to evaluate the over production of lipid peroxidation (LPO) byproducts and disturbances in antioxidant defense system in the pathogenesis of oral cancer. Methods : Lipid peroxidation and antioxidant status in OSCC patients were estimated and compared the sensitivity and specificity of circulating biomarkers (MDA, Sialic acid, Catalase, SOD, GSH and Neuraminidase) with beta-2 microglobulin (beta-2MG) at different thresholds in blood and saliva using receiver operating characteristics (ROC) curve design. R esults : Our results showed that the levels of MDA and Sialic acid were significantly increased in plasma of OSCC patients as compared to healthy subjects whereas antioxidant level was significantly decreased. Conclusion : ROC analysis indicated that MDA in saliva is a better diagnostic tool as compared to MDA in blood and beta-2MG in blood is better diagnostic marker as compared to beta-2MG level in saliva. PMID- 24948961 TI - Treatment of spontaneous ruptured hepatocellular carcinoma: A single-center study. AB - OBJECTIVES: Spontaneous rupture of hepatocarcinoma (HCC) is a fatal complication of advanced HCC and is associated with poor prognosis. However, there is no consensus on the best approach to treat hemoperitoneum due to ruptured HCC. In this paper, we evaluate and discuss the outcomes of different treatment methods employed at our center for ruptured HCC. METHODS: We reviewed the medical records of 132 patients diagnosed with ruptured HCC at our hospital from January 2003 to December 2012 and evaluated and compared the outcomes of five treatment methods for ruptured HCC: conservative treatment, surgical hemostasis, transarterial embolization (TAE), and one- and two-stage resections. RESULTS: There was no significant difference in the median survival time between the conservative treatment and surgical hemostasis groups. Patients in the TAE alone group had a better prognosis than those in the conservative treatment and surgical hemostasis groups. The survival time of the tumor resection group was obviously better than that of the conservative treatment, surgical hemostasis, and TAE alone groups, but no significant difference was observed between the one-stage and two-stage resection groups. CONCLUSIONS: One-stage hepatectomy is a better option for patients with preserved liver function, whereas TAE is a better option for those with poorly preserved liver function. PMID- 24948962 TI - Metabolic syndrome as a risk factor for elevated intraocular pressure. AB - OBJECTIVE: The aim of this study was to investigate the association between intraocular pressure and metabolic syndrome by comparing central corneal thicknesses. METHODS: One hundred sixty-two subjects were enrolled in this cross sectional study, with 89 subjects in a metabolic syndrome group and 73 subjects in a control group. Ophthalmological examinations, including intraocular pressure and central corneal thickness measurements, were performed on each subject. Serum fasting glucose, triglyceride and HDL cholesterol levels were measured, and waist circumference, systolic and diastolic blood pressure of all patients were recorded. RESULTS: Participants with metabolic syndrome had a significantly higher intraocular pressure than those without metabolic syndrome (p = 0.008), and there was no statistically significant difference between the central corneal thicknesses of the two groups (p = 0.553). Most of the metabolic syndrome components were associated with higher intraocular pressure (p < 0.05). CONCLUSIONS: There is a relationship between metabolic syndrome and intraocular pressure, but no association between metabolic syndrome and central corneal thicknesses. Intraocular pressure is affected by central corneal thicknesses, and intraocular pressure is used to correct according to the central corneal thicknesses measurement. To our knowledge, this is the first study that determines the positive relationship between metabolic syndrome and intraocular pressure by comparing the central corneal thicknesses of the groups. PMID- 24948963 TI - The clinical implications of ear canal debris in hearing aid users. AB - Objective : The ear irritations suffered by hearing aid (HA) users are yet to be related to the clinical state of canal. We undertook this study to examine the nature of debris and the microbial flora of ears of hearing aid users, as well as evaluate the determinant factors of ear irritation in this population. Methods : An observational clinical study was carried out involving 32 unilateral hearing aid users recruited from ENT clinic of a tertiary referral center. Each subject underwent otoscopic assessment of canal debris and microbial analysis of swab cultures taken from the hearing aid-wearing ear and contralateral normal ear without hearing aid. Results : Canal debris [wax (28%), fungal deposits (19%), bacteria exudates (13%)]. as well as microorganisms were identified in significant number of ears with hearing aids than ears without hearing aid (P = 0.003 and P = 0.006 respectively). Coagulase-negative staphylococci were the commonest identified bacteria. Others were Staphylococcus aureus, Pseudomonas aeruginosa, and Proteus species. Intolerable irritations of hearing aid wearing ears were significantly associated with bacterial and fungal otitis externa, and ear discharge (P = 0.005, 0.02, 0.03 respectively). Conclusions : This study demonstrates that using hearing aid alters the ear canal flora; increases risk of both fungal and bacterial otitis externa, as well as encourage wax debris formation, with resultant ear irritations. To ensure compliance their ears should periodically be attended to, by de-waxing or given topical antimicrobial agents where indicated. PMID- 24948964 TI - ERCC1 and BRCA1 mRNA expression predicts the clinical outcome of non-small cell lung cancer receiving platinum-based chemotherapy. AB - OBJECTIVE: We conducted a perspective study to investigate the association between mRNA expression quantities of ERCC1, BRCA1, RRM1 and RRM2 and response to chemotherapy and clinical outcome of advance Non-Small Cell Lung Cancer.(NSCLC). METHODS: Two hundred eight patients who were diagnosed as advanced stage NSCLC were included in our study. A fluorescence-based and real-time detection method was used to determine the relative cDNA quantification for ERCC1, BRCA1, RRM1 and RRM2, and beta-actin was used as the reference gene. RESULTS: The median expression levels of ERCC1, BRCA1, RRM1 and RRM2 mRNA were 0.67+/-0.17, 0.095+/ 0.012, 0.24+/-0.17 and 2.45+/-0.32, respectively. Our study found that the low ERCC1 (OR=1.82, 95% CI=1.01-3.20) and Low BRCA1 (OR=2.53, 95%CI=1.38-4.64) mRNA expression was more likely to response to chemotherapy when compared with high expression, respectively. Multivariate Cox regression analysis indicated that patients with low mRNA expression of ERCC1 and BRCA1 attained 0.43 (OR=0.43, 95%CI=0.27-0.89) and 0.37 (OR=0.37, 95%CI=0.22-0.66) fold risk of death from NSCLC. However, we found RMM1 and RRM2 mRNA expression could not influence the response to chemotherapy and clinical outcome of NSCLC. CONCLUSION: ERCC1 and BRCA1 mRNA expression could be important predictive markers for individualized platinum-based chemotherapy for NSCLC patients. PMID- 24948965 TI - Simple patch closure for perforated peptic ulcer in children followed by helicobacter pylori eradication. AB - OBJECTIVE: Peptic ulcer disease in children is rare. Therefore, the diagnosis can be missed until complications such as perforation or hemorrhage occur. Few reports have investigated the procedures and outcomes of children who have undergone operations for perforated duodenal ulcers. We report our experience with the modified Graham technique for perforated duodenal ulcers in nine children and review the literature. Methods : The records of patients operated on for a perforated duodenal ulcer in the last 8 years in two pediatric surgery centers were evaluated retrospectively. Patient demographics, symptoms, time to admission to hospital, operative findings, and postoperative clinical course were evaluated. Results : Nine children (mean age 13.2 years, range 6-170 years) were included. All patients were admitted in the first six hours after their abdominal pain started. In three patients, there was free air on plain x-rays, while the x rays were normal in six. All perforations were located on the anterior surface of the first part of the duodenum and repaired with primary suturing and Graham patch omentoplasty. The recovery was uneventful in all patients. In five patients, urea breath tests were performed postoperatively for Helicobacter Pylori, and the results were positive. All patients underwent triple therapy with lansoprazole, amoxicillin, and clarithromycin. The mean follow-up time was 58 (range 3-94) months. Conclusions : Peptic ulcer perforation should be suspected in children who have acute abdominal pain and peritoneal signs, especially when their suffering is intense. The simple patch repair and postoperative triple therapy for Helicobacter Pylori are safe and satisfactory for treating peptic ulcer perforation in children. PMID- 24948966 TI - Overweight and Obesity among Children (10-13 years) in Bahrain:A comparison between Two International Standards. AB - OBJECTIVE: Obesity has become one of the main public health problems worldwide. Childhood obesity rate is growing very fast in both developed and developing countries. This paper aimed to explore the prevalence of overweight and obesity among school children aged 10-13 years in Bahrain, and to find out the difference in this prevalence when using two international standards. METHODS: A multistage stratified sampling procedure was used to select 2146 students (1068 males, 1078 females) from public schools in Bahrain. Weight and height were measured and Body Mass Index for age and sex was calculated to determine the obesity levels. Both International Obesity Task Force (IOTF) and World Health Organization (WHO) references were used to determine the prevalence of overweight and obesity. RESULTS: The findings revealed that the prevalence of overweight and obesity ranged from 15.7% to 28.9% among males and from 21.1% to 30.7% among females. The WHO reference standard provided higher prevalence of overweight and obesity than IOTF reference. CONCLUSION: The study confirmed that obesity is a problem of concern in Bahraini school children and calls for intervention programme to combat obesity in schools. However, the standard used to determine obesity levels should be carefully selected and interpreted. PMID- 24948967 TI - The clinical & neurophysiological study of leprosy. AB - OBJECTIVES: The aim of this study was to evaluate neurological and neurophysiological features of leprosy. METHODS: Seventy seven hospitalized leprosy patients (52 male, 25 female) were examined neurological and neurophysiologically between 2010 and 2012. Standard procedures were performed for evaluating sensory and motor conduction studies to all patients. Motor studies were carried out on median, ulnar, tibial and common peroneal nerves. Sensory studies were carried out on median, ulnar and sural nerves. Sympathetic skin response (SSR) recordings on both hands and feet, and the heart rate (R-R) interval variation (RRIV) recordings on precordial region were done in order to evaluate the autonomic dysfunction. RESULTS: The mean age was 59.11+/-14.95 years ranging between 17 and 80 years. The mean duration of disease was 35.58+/-18.30 years. Clinically, the patients had severe deformity and disability. In neurophysiological examinations, sensory, motor conduction studies of the lower extremities were found to be more severely affected than upper, and sensory impairment predominated over motor. Abnormal SSRs were recorded in 63 (81.8%) cases of leprosy. Abnormal RRIVs were recorded in 41 (53.2%) cases and abnormal RRIVs with hyperventilation were recorded in 55 (71.4%) cases of leprosy. Significant differences were found between SSR and sensory conduction parameters of median, ulnar nerves as well as motor conduction parameters of median, ulnar and peroneal nerves (p<0.05). CONCLUSION: Peripheral nervous system dysfunction is accompanied by autonomic nervous system dysfunction in leprosy patients. Sympathetic involvement may predominate over parasympathetic involvement. PMID- 24948968 TI - The relationship between family history of cancer, coping style and psychological distress. AB - OBJECTIVE: To investigate the relationship between family history of cancer, coping style and psychological distress. METHODS: Total 80 patients with family history of cancer and 72 normal controls were analyzed using self-reporting inventory (SCL-90), coping style scale and impact of event scale-revised (IES-R). RESULTS: 1. Between the two groups of patients, there were significant differences in anxiety, depression, cancer-specific distress and coping style. 2. Psychological distress (anxiety, depression and cancer-specific distress) had positive correlation with negative coping style and family history. 3. Negative coping style played an intermediary role in the family history and psychological distress. CONCLUSION: The negative coping style will predispose to a more stronger psychological distress among the individuals with family history of cancer. PMID- 24948969 TI - Correlation between Microalbuminuria and Hypertension in Type 2 Diabetic Patients. AB - BACKGROUND: Hypertension is commonly found in patients with Diabetic Kidney Disease (DKD). Microalbuminuria is the first clinical sign of involvement of kidneys in patients with type 2 diabetes. Uncontrolled hypertension induces a higher risk of cardiovascular events, including death, increasing proteinuria and progression to kidney disease. OBJECTIVES: To determine the correlation between microalbuminuria and hypertension and their association with other risk factors in type 2 diabetic patients. METHODS: One hundred and thirteen type 2 diabetic patients attending the diabetic clinic of Shaikh Zayed Postgraduate Medical Institute, Lahore, Pakistan were screened for microalbuminuria and raised blood pressure. The study was conducted from November 2012 to June 2013. RESULTS: Patients were divided into two groups. Group 1, those with normoalbuminuria (n=63) and Group 2, those having microalbuminuria (n=50). Group 2 patients showed higher blood pressure values as compared to Group 1. The results were statistically significant and showed poor glycemic control as a contributing risk factor. CONCLUSION: The study concluded that there is high frequency of hypertension among type 2 diabetics but still much higher among those having microalbuminuria. So, early recognition of renal dysfunction through detection of microalbuminuria and to start treatment without any delay will confer future protection from end stage renal disease as well as hypertension and its complications in type 2 diabetic patients. PMID- 24948970 TI - Cardiovascular risk factors among retired attendees visiting primary care clinics. AB - OBJECTIVE: The aim of this study was to highlight cardiovascular risk factors among retired attendees attending a primary care clinic, Riyadh, Saudi Arabia. METHODS: A cross sectional study was conducted from Januaryto February 2013 at Primary Care Clinics of King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia. All retired attendees were interviewed by family physician, and their duration of retirement was determined. Their cardiovascular risk factors were confirmed from their medical records. The cardiovascular risk factors included history of diabetes mellitus, hypertension, dyslipidemia, obesity, and smoking. Their weight and height were recorded during the consultation and Body Mass Index was calculated to decide about those classified as obesity >= 30 All data were entered and analyzed using statistical package of social science SPSS version 17 software. RESULTS: The present study showed that 19.5% of retired attendees presenting at primary care clinic were early retired before the age of 60 years, while 80.5% were normally retired. The prevalence of cardiovascular risk factors showed: Hypertension among 73% attendees, Diabetes Mellitus in 67%, dyslipidemia in 71%, Obesity 29%, and Smoking 13% of the patients. CONCLUSION: This study concluded that cardiovascular risk factors among retired attendees of a primary care clinic are common, and need to be taken in to priority consideration while improving the health care of retired people. PMID- 24948971 TI - Association of Hepatitis C Virus Infection and Interleukin-28B Gene Polymorphism in Chinese Children. AB - OBJECTIVE: To preliminarily explore the association of rs12979860 and rs8099917 SNPs with chronic HCV infection in Chinese Han children. METHODS: Chronic HCV infection patients (n=277; 1-17 years old, 4.5 years old in average) and healthy subjects (n=150, children; 2-17 years old, 5.2 years old in average) were recruited and tested by PCR combining direct sequencing. The differences between the rs12979860 and rs8099917 genotypes in patients and healthy subjects were compared. RESULTS: The genetic variations at rs12979860 and rs8099917 in chronic hepatitis C (CHC) children and healthy subjects did not differ significantly. The frequency of spontaneous clearance in CHC children was higher (47%), which is related to the genetic variations. The histological changes of patients were more significant compared to their clinical and biochemical indices, but they did not correlate with the genetic mutations at rs12979860 and rs8099917 significantly. CONCLUSION: The rs12979860 and rs8099917 SNPs are independent factors predicting the spontaneous clearance of Chinese CHC children patients. The correlation between diseases outcomes are in need of further study. PMID- 24948972 TI - Impact of Duration of Macula off Rhegmatogenous Retinal Detachment on Visual Outcome. AB - OBJECTIVE: To assess impact of duration of macular detachment on visual outcome after scleral buckling for retinal detachment with macula off. METHODS: Prospective, descriptive case series was conducted at Ophthalmology Department Dow University of Health Sciences, Civil Hospital Karachi and Al Noor Eye Clinic Karachi from May 2012 to June 2013. Five groups were made according to period of macular detachment. Best corrected Visual acuity (BCVA) was main outcome measure. P value < 0.001 was considered significant. RESULTS: Mean duration of macula off was 17.0+/-4.0 (SD) days. Mean pre-operative VA in patients with immediate, early, intermediate, delayed or late group were 2/60, 2/60, Counting figure (CF) 3 meters (m), CF2 m and Hand Movement (HM) respectively. Only 48.48% patients of those repaired within 7 to15 days had significantly better (P < 0.001) BCVA (6/9 6/18) than the other groups. Only 19.35% patients of intermediate group achieved BCVA 6/18-6/24 (P < 0.001) which was comparatively better than the delayed and late group. CONCLUSIONS: Scleral buckle surgery for macular-off Rhegmatogenous Retinal Detachment has good post-operative visual outcomes if repaired within two weeks. PMID- 24948973 TI - Uterine closure with unlocked suture in cesarean section: Safety and Quality. AB - OBJECTIVE: Comparing locked and unlocked uterine closure techniques in terms of bleeding control and uterine incision healing. METHODS: The patients undergoing cesarean section in Sifa University Hospital between May - October 2012 were accepted to this prospective controlled study. Primarily, safety was evaluated. The hemoglobin count (HC) and serum creatine kinase (CK) levels of the patients in the locked (n = 47) and unlocked (n = 35) groups were measured just before and 24 hours after operation. Hemoglobin deficit, increase in CK and the additional hemostatic sutures were compared. Secondly, uterine scar healing was evaluated three months later. Scar thickness, niche and percentage of thinning of the scar region of the locked (n = 27) and unlocked (n = 32) groups were calculated and compared. RESULTS: The hemoglobin deficit was similar in two groups. CK rise was less in the unlocked group but it was not significant (P = 0.082). Unlocked group needed more additional sutures (P = 0.016). The thickness of the niche and the percentage of thinning of the scar region were significantly less in the unlocked group (P= 0.002, P=0.000). CONCLUSIONS: Unlocked uterine closure technique is safe and has less damage to the myometrium. PMID- 24948974 TI - Clinical pathologies of breast cancer in the elderly and youths and their prognosis. AB - OBJECTIVE: To explore the correlation between the clinical pathologies of breast cancer in the elderly and youths as well as their prognosis. METHODS: Two hundred and eighty breast cancer patients were divided into a youth group (<60, n=120) and an elderly group (>=60, n=160) according to the age. Their routine clinical pathological indices and immune indices were observed and determined, and the prognosis was observed after effective treatment. RESULTS: The positive expression rates of p63, CK5/6, CK14 and CK17 in the elderly group were significantly higher than those of the youth group (P<0.05). The tumor-free survival rate of the youth group (95.8%) was significantly higher than that of the elderly group (84.4%) (P<0.05). Multivariate Logistic regression analysis showed that the positive expressions of p63 and estrogen receptor, age, and postoperative chemotherapy were the independent risk factors of tumor-free survival rate (P<0.05). CONCLUSION: The immunohistochemical typing characteristics of the elderly and youths were different, and the prognosis of young patients was better, being correlated with the typing. PMID- 24948976 TI - Reference range of zinc in adult population (20-29 years) of Lahore, Pakistan. AB - OBJECTIVE: To determine the reference range of zinc in adult population (age range 20 to 29 years) of Lahore. METHODS: It was a descriptive cross sectional study which was carried out from Jan- August 2012 in Chemical Pathology Department of University of Health Sciences, Lahore. Serum zinc concentration was measured by flame atomic absorption spectrometry in randomly selected 450 healthy adults aged 20 to 29 years. After application of exclusion criteria reference values were determined in apparently healthy subjects according to guidelines of International Federation of Clinical Chemistry. The data was entered & analyzed using SPSS version 20.0. Serum Zn levels was expressed as Mean +/- SD. RESULTS: A total of 450 healthy subjects were included in this study. Out of these, 234 were females. Mean age was 25+/-0.13years. The mean concentration of zinc in serum of healthy individual was 24.02+/-7.03 umol/L (range11.47-36.72). The mean+/-SD for males subjects were 22.33+/-6.42 umol/L(range11.93-32.4). Similarly the mean+/-SD for females were 21.72+/-7.34 umol/L (range9.94-36.87). CONCLUSION: This study presents reference range for serum zinc concentration in adult population of Lahore. The results showed that there is significant difference in serum level of zinc among different countries. This study will help us in establishing reference ranges of trace elements on larger population in future. PMID- 24948975 TI - Acetylsalicylic Acid resistance in patients with type 2 diabetes mellitus, prediabetes & non-diabetic coronary artery disease. AB - Objective : Several studies have demonstrated the beneficial role of antiplatelet therapy with acetylsalicylic acid (ASA) at atherosclerotic vascular disease. Antiaggregant effect of ASA is not uniform in all patients. Purpose of the present study is to evaluate the prevalence of ASA resistance in patients with type 2 diabetes mellitus (T2DM), pre-diabetes and non-diabetic coronary artery disease (CAD). METHODS: Effect of ASA was assessed using the platelet function analyzer (PFA-100) system. Resistance to ASA was defined as a normal collagen/epinephrine induced closure time after one week of ASA therapy. Patients with non-diabetic CAD, pre-diabetes and T2DM were compared. RESULTS: ASA resistance was found in 26 (37.1%), 6 (17.6%) and 41 (26.5%) patients in the groups, respectively (p=0.154). ASA resistance was found to be significantly higher in men, smokers and insulin users, besides this it was found to be significantly lower in beta blocker (BB) users, angiotensin converting enzyme inhibitor (ACEI) users with univariate analysis. However insulin usage was found to be the single effective parameter on ASA resistance in multivariate analysis. CONCLUSION: There was no difference with regard to ASA resistance between groups. While ASA resistance was higher in men, smokers and insulin users, it was lower in patients using BBs and ACEIs. PMID- 24948977 TI - Comparing school lunch and canteen foods consumption of children in kayseri, Turkey. AB - OBJECTIVE: School Nutrition Programs (SNPs) may have positive effects on children's food choices through high nutritional quality meals. This cross sectional & descriptive study was conducted to determine nutritional quality of school lunch and to compare lunch consumption of students who participated in SNP and who did not, at the first governmental school serving school lunch in Kayseri, Turkey. METHODS: One hundred and sixteen students aged 9-14 years were divided into two groups after being matched according to gender, age, grade; 58 participants (school lunch group; SL-G) and 58 nonparticipants (school canteen group; SC-G) were recruited. Energy-nutrient content of 5-day school lunch was determined by recipes. Socio-demographic data and lunch consumption on 5 consecutive weekdays with weighed left overs were obtained. Lunch energy-nutrient intakes and anthropometric measurements were compared. RESULTS: School lunch was adequate for vitamins (E & C), fibre, iron, inadequate for energy, carbohydrate, folate, calcium. Contribution of fat (36.6+/-6.8%) and saturated fat (12.2+/ 3.5%) to energy and sodium content was high (1001 mg) in school lunch. SL-G consumed significantly higher protein, vitamin C, thiamine, vitamin B6, potassium, magnesium, iron, zinc (p<0.001 for each) than SC-G. Energy (p<0.001), carbohydrate (p<0.001), fat (p<0.05), vitamin E (p<0.001) intakes of SC-G were significantly higher than SL-G. Body weights, height, body mass index of groups were similar. CONCLUSIONS: Foodservice at school should be revised with collaboration of school management, catering firm, dietetic professionals. Policy should focus on reducing fat, saturated fat, sodium content and meeting energy nutrient requirements of school aged children. PMID- 24948978 TI - Postoperative nosocomial infections among children with congenital heart disease. AB - OBJECTIVE: To study the pathogen distribution, antimicrobial susceptibility and risk factors of postoperative nosocomial infections among children with congenital heart disease. METHODS: Three hundreds children with congenital heart disease admitted to our hospital to receive surgeries from February 2010 to February 2013 were selected. RESULTS: A total of 120 children were tested as positive by sputum culture, with the infection rate of 40.0%. The top five most common pathogenic microorganisms included Staphylococcus epidermidis, Staphylococcus aureus, Enterococcus, Pseudomonas aeruginosa, and Candida albicans. S. epidermidis, S. aureus and Enterococcus were highly resistant to penicillin, azithromycin and erythromycin, moderately susceptible to levofloxacin and cefazolin, and completely susceptible to vancomycin. Multivariate Logistic regression analysis showed that hospitalization stay length, combined use of antibiotics, systemic use of hormones, mechanical ventilation and catheter indwelling were the independent risk factors of postoperative nosocomial infections (P<0.05). CONCLUSION: Nosocomial infection, which was the most frequent postoperative complication of pediatric congenital heart disease, was predominantly induced by Gram-positive bacteria that were highly susceptible to cephalosporins and vancomycin. Particular attention should be paid to decrease relevant risk factors to improve the prognosis. PMID- 24948979 TI - Frequency of sexual dysfunction and its causative factors among diabetic women in Turkey. AB - OBJECTIVE: To determine the frequency of sexual dysfunction and its causative factors among the diabetic women. METHODS: The sample of the research was made up of 200 diabetic women selected using simple-random sampling who went to endocrinology poly clinics for counseling and treatment. The data were gathered with Data Collection Form for Women's Descriptive Characteristics designed by the researchers using the information in literature, Female Sexual Function Index and Beck Depression Inventory. The data were assessed with percentages, arithmetic means, standard deviation and ANOVA test in computer environment. RESULTS: Out of two hundred diabetic patients nearly halfof the participant women (48.0%) underwent depression and nearly one in four women experienced sexual dysfunction (26.2%). In the analysis, there was statistically significant correlation between women's sexual dysfunction and diabetes type, diabetes complications, HbA1C value, having a sexual problem and presence of depression. CONCLUSION: This study showed that one in two diabetic women suffered from depression while nearly one in four diabetic women expereienced sexual dysfunction. PMID- 24948980 TI - Otomycosis; clinical features, predisposing factors and treatment implications. AB - Objectives : The aim of this study was to determine the frequency of otomycosis, the clinical presentation, predisposing factors and treatment outcomes. METHODS: This observational study was conducted at ENT department of Combined Military Hospital Attock, from October, 2010 to September, 2012. Convenient sample comprising 180 patients of both sexes and all age groups were selected from ENT OPD. The frequency, predisposing factors and most common symptoms of otomycosis were recorded. The response to different antifungal agents was also observed. RESULTS were recorded in percentages. RESULTS: There were 180 patients with documented diagnosis of otomycosis. There were 107 (59%) males and 73 (41%) females. The age of patients ranged from 11/2 years to 75 years with a mean age of 38.5 years. Mean follow up time was 2 years. Most common presenting symptom was hearing loss (77.7%) followed by pruritis (68.8%) and otalgia (40%). We prescribed 1% clotrimazole drops or lotion in 58% patients and 2% salicylic acid in 31% cases. Both of these agents are effective. Topical 1% clotrimazole drops yielded highest resolution rate with lowest recurrent rate. Overall 149 (83%) patients were improved with initial treatment and 31 (17%) did not respond to initial treatment. Eight (4.4%) patients had a history of otological procedures. Four (2.2%) patients had canal wall down procedures that resulted in mastoid cavity. To analyse the efficacy of 1% clotrimazole and 2% salicylic acid we applied Z-Test to calculate the difference between 2 proportions of patients before treatment with those patients who remained uncured after treatment. CONCLUSION: Otomycosisis commonly presented with decreased hearing, pruritis, otalgia & otorrhoea. It usually resolves with local toilet of ear and instillation of antifungal agents. Eradication of disease is difficult in presence of a mastoid cavity and metabolic diseases like diabetes mellitus. PMID- 24948981 TI - The role of maternal serumbeta-HCG and PAPP-A levels at gestational weeks 10 to 14 in the prediction of pre-eclampsia. AB - OBJECTIVE: We aimed to detect whether maternal serum free beta-hCG and PAPP-A levels and NT measurements vary between normal pregnancies and those that subsequently develop pre-eclampsia and to evaluate the role of these screening serum analytes in the prediction of pre-eclampsia. METHODS: Using a case-control study design, we identified all women who had been screened by double test within 11+0 and 13+6 weeks of gestation and who had developed pre-eclampsia during the subsequent pregnancy course, over a 6-year period between January 2006 and December 2012 at two tertiary referral hospital. All women who had undergone a double test during that time, without a diagnosis of pre-eclampsia and who had not had any adverse obstetric outcomes, were also identified, and three women among them were randomly selected as controls for each case. Maternal and neonatal data were abstracted from the medical records and PAPP-A, beta-hCG, NT and CRL MoM values were compared between the two groups. RESULTS: Although beta hCG values show no statistically significant difference (p=0.882), PAPP-A levels were significantly reduced in the pre-eclampsia group compared to the control group (p<0.001). NT and CRL values showed no significant difference between the two groups (p=0.674 and p=0.558, respectively). CONCLUSION: Measuring PAPP-A in the first trimester may be useful in the prediction of pre-eclampsia. PMID- 24948982 TI - Management of upper gastrointestinal bleeding from portal hypertension: Elective or emergency operation? AB - Objective : To evaluate the clinical outcome of emergency and elective operation of splenectomy with periesophagogastric devascularization in treating upper gastrointestinal hemorrhage resulted from portal hypertension. Methods : We retrospectively reviewed 219 patients of upper gastrointestinal hemorrhage resulted from portal hypertension treated using emergency or elective operation between Jul 2002 and Aug 2010. The clinical data were collected and analyzed. Results : In the group of elective operation, four patients with grade B and three with grade C died, and in the group of emergency operation, two patients with Grade B and four with Grade C died. The Grade C patients treated using emergency operation presented with a higher mortality than those treated using elective operation, but no significant difference was found (p>0.05). In the two groups, no patients with Grade A died. 17 cases (11.1%) suffered from complications in the group of elective operation and 11 cases (16.7 %) in emergency operation (p>0.05). The complication rate in patients with Grade C is significantly higher than that in patients with Grade A or B in each group (p<0.05). The hospital stay and cost in group of elective operation are significantly higher than those in group of emergency operation (p<0.05). Conclusion : The patients with Grade A or B treated using emergency operation have similar clinical outcomes as those treated using elective operation, but emergency operation may result in higher rate of death and complication in patients with Grade C. PMID- 24948983 TI - Predictive Value of Soluble CD14, Interleukin-6 and Procalcitonin For Lower Extremity Amputation in People with Diabetes with Foot Ulcers: A Pilot Study. AB - OBJECTIVE: The aim of this pilot study was to determine clinical and laboratory factors that predict amputation surgery and to evaluate the predictive value of soluble CD14 (sCD14), interleukin-6 (IL-6), and procalcitonin (PCT) in patients with diabetic foot ulcers (DFUs). METHODS: Twenty-seven (20 males, 7 females) Diabetic Foot Ulcers (DFU) patients admitted to our department were consecutively enrolled. The patients' demographics and wound characteristics were noted. IL-6, PCT, and sCD14 were measured at admission. RESULTS: Six of the 27 patients (22%) eventually underwent lower extremity amputation. Compared to the non-amputation group, a previous history of amputation (p=0.017), the presence of gangrene (p=0.044), the Wagner grade (p=0.011), the IL-6 concentration (p=0.018), the white blood cell count (WBC) (p=0.036), and the erythrocyte sedimentation rate (ESR) (p=0.042) were significantly high in the amputation group. However, the sCD14 and PCT concentration were not significantly different. CONCLUSION: We have shown for the first time that IL-6 may have predictive value for lower extremity amputation in patients with DFU. Further studies are needed to confirm its predictive value in this patient group. PMID- 24948984 TI - Knowledge, attitude and practice regarding folic acid deficiency; A hidden hunger. AB - OBJECTIVES: To find the Knowledge Attitude and Practice regarding Folic Acid Deficiency among Women of Child Bearing Age (WPCBA). To find out the Association of Education Level with Practice of Folic Acid in WPCBA. METHODS: A Descriptive cross sectional study (Knowledge Practice and Attitude) was conducted at Military Hospital and Combined Hospital Rawalpindi from September 2012 to February 2013. About 400 married females of age group 21-42 years were included by convenient sampling technique. After taking informed verbal consent, a closed ended interviewer administered questionnaire was filled. Data was entered and analyzed using SPSS version 20. RESULTS: Mean age of the respondents was 30.31 + 5.280 years. Illiterate and literate were 165 (41.25%) and 235 (58.75%) respectively. The knowledge regarding folic acid need was 172 (43%). Only 161 (40.25%) thought that folic acid deficiency in pregnant women results in abnormality in newborn. In pregnancy, 205 (51.25%) had received folic acid supplementation. Association between education level and practice of folic acid was significant (p= 0.009) at 95% confidence level. CONCLUSION: Knowledge regarding folic acid deficiency among WOCBA was low along with the poor attitude. Practice was also not satisfactory. Education status plays important role in preventing micronutrient deficiency. PMID- 24948985 TI - Evaluation of Mean Platelet Volume values in lean women with polycystic ovary syndrome. AB - OBJECTIVE: Mean Platelet Volume (MPV) is an important indicator of platelet activation. It is known that MPV increases in patients with coronory artery disease, diabetes mellitus, atherosclerosis and Polycystic ovary syndrome (PCOS). Our aim was to measure the MPV in lean patients with polycystic ovary syndrome. METHODS: The present study was designed to examine the platelet function by measuring MPV in non-obese women with PCOS. A total of 50 outpatients with PCOS were included. The control group consisted of 50 healthy subjects. Serum platelet, MPV, and white blood cell (WBC) levels were compared and evaluated retrospectively in all participants. These values were compared by statistical analysis. RESULTS: There were no statistically significant difference in between groups regarding MPV (p?0.357), WBC (p?0,414) and platelet (p?0,666). CONCLUSION: There are studies implying MPV increase in PCOS patients, in our patients MPV levels did not correlate with PCOS except for patients with obesity. We think that PCOS itself has no effect on MPV levels and obesity changes MPV levels. PMID- 24948986 TI - ABO blood group frequency in Ischemic heart disease patients in Pakistani population. AB - OBJECTIVES: To determine if there is any significant association between ABO blood groups and ischemic heart disease (IHD). METHODS: The study was performed at Punjab Institute of Cardiology (PIC), Lahore. Study duration was from January 2012 to September 2012. This study included 200 IHD patients and 230 control individuals. Self design questionnaire was used to collect information regarding risk factors. Standard agglutination test was performed to determine the blood groups. Data was analyzed on SPSS 16. RESULTS: The prevalence of blood groups in IHD group was 34% in blood group A, 29% in blood group B, 14% in blood group AB and 23% in blood group O. In control group the distribution of B, A, AB and O blood groups were 34.4%, 20.9%, 12.6%, 32.2% respectively. Rh+ve factor was prevalent in 90.5% among IHD group and 92.6% in control subjects. The prevalence of IHD was more in males (63.5%) as compared to females (36.5%). Mean age was 56.4+/-0.86 (yrs) and BMI was 26.4+/-0.33 (kg/m(2)). The prevalence of hypertension was 58.5%, diabetes was 53%, family history of cardiac disease was 45%, 35.5% of patients were doing exercise regularly, 58.5% used ghee, and 58% were smokers. C onclusion: Subjects with blood group A had significantly (p< 0.05) higher risk of developing IHD as compare to other blood groups. PMID- 24948988 TI - Laparoscopic cholecystectomy in acute gallstone pancreatitis in index hospital admission: feasibility and safety. AB - BACKGROUND AND OBJECTIVE: Acute gallstone pancreatitis is quite common throughout the globe. Conventionally definitive cholecystectomy has been delayed in index hospital admission. Since the last decade timing of cholecystectomy is gradually shifting towards the earlier phase of disease and currently gallstone pancreatitis is being evaluated as a further indication for laparoscopic cholecystectomy. There is also great concern regarding compliance of patients for definitive surgery due to poverty, ignorance and illiteracy in developing countries. The aim of this study was to assess the feasibility and safety of laparoscopic cholecystectomy as a definitive treatment in patients with mild and resolving gall stone pancreatitis. METHODS: This was a prospective study from July 2009 to June 2012. Patients were diagnosed by clinical examination, biochemical tests, ultrasonography and contrast enhanced CT. Patients with mild form of the disease (Ranson Score <=3) and who showed clinical improvement were offered laparoscopic cholecystectomy in index hospital admission. Those who were unfit for surgery were referred for endoscopic sphincterotomy. Common bile duct stones were excluded preoperatively. RESULTS: A total of 38 patients were admitted with acute gallstone pancreatitis in the study period. The mean age of patients was 46.3 years with male to female ratio of 11/27. 22 (57.8%) patients were selected for laparoscopic cholecystectomy and procedure was completed successfully. Ten (26.3%) patients were referred for ERCP and endoscopic sphincterotomy and 11 (28.9%) were managed by conservative treatment and went without any definitive treatment. Mean duration of time from onset of symptoms and laparoscopic cholecystectomy was 7 days (range 4-10). Mean duration of operative time was 45 minutes and hospital stay was 7 days. There was no operative mortality. No major intra-operative or post-operative complication was recorded. two patients (9%) had minor complications. CONCLUSION: Laparoscopic cholecystectomy can be safely performed in selected cases of mild gallstone pancreatitis in order to prevent further attacks of acute pancreatitis and other consequences of delayed treatment. Furthermore it resolves the problem of noncompliance of patients in third world countries where many patients are lost for definitive treatment. PMID- 24948987 TI - Is atmospheric pressure change an Independent risk factor for hemoptysis? AB - OBJECTIVE: Hemoptysis is one of the most important and challenging symptoms in pulmonary medicine. Because of the increased number of patients with hemoptysis in certain periods of the year, we aimed to investigate whether atmospheric changes have an effect on the development of hemoptysis with or without a secondary cause. METHODS: The data of patients presenting with hemoptysis between January 2006 and December 2011 were analyzed. Data on the daily atmospheric pressure (hectopascal, hPa), relative humidity (%), and temperature ((o) C) during that time were obtained. RESULTS: A total of 232 patients with hemoptysis, 145 male (62.5%) and 87 female (37.5%) with an average age of 48.1(+/-17.6), were admitted to our hospital between 2006 and 2011. The highest admission rates were in the spring season, the highest in May (n=37, 15.9%), and the lowest admission rates were in December (n=10, 4.3%). A statistically significant negative correlation was found between the number of hemoptysis cases and mean atmospheric pressure but no relative humidity or outdoor temperature. CONCLUSION: Hemoptysis is very much influenced by weather factors; in particular, low atmospheric pressures significantly affect the development of hemoptysis. Fluctuations in atmospheric pressure may also play a role in hemoptysis. PMID- 24948989 TI - Can we use serum gamma-glutamyl transferase levels to predict early mortality in stroke? AB - OBJECTIVE: Serum gamma-glutamyl transferase (GGT) is a marker for alcohol consumption and hepatobiliary diseases. There are reports on the prognostic role of GGT in coronary artery diseases and stroke. The aim of our study was to identify the potential differences in GGT levels in different types of stroke, and to evaluate the correlation between GGT and 30-day mortality. METHOD: Patients diagnosed with stroke in emergency department between 01.01.2010 and 30.12.2012 was included in the study. Imaging techniques were used to distinguish between hemorrhagic and ischemic stroke. Ischemic strokes were further classified as either atherosclerotic/lacunar or embolic. Parameters including age, gender, vital signs (systolic and diastolic blood pressure), comorbid diseases (HT, DM, CAD, smoking and alcohol consumption), used medications, previous history of stroke, NIHSS score at the time of admission to emergency department, laboratory parameters (glucose, white blood cell count, hemoglobin, platelet, total cholesterol, creatinine) and duration of hospitalization were recorded. Death records were obtained from patients' medical records. RESULTS: One thousand eighty six patients were included in the study. GGT levels were not significantly different between ischemic and hemorrhagic strokes (p=0.435). On the other hand, GGT levels in embolic strokes were significantly higher compared to atherosclerotic/lacunar strokes (p=0.001). GGT levels [median 24.50 (16.00 43.00)] in Intensive Care Unit patients were significantly higher compared to GGT level [22.00 (15.00-34.25)] in admitted to service beds patients (p=0.015). Median GGT level of deceased patients was 24.00 (16.00-41.25) and median GGT level of alive patients was 22.00 (15.00-35.00). GGT level of deceased patients was significantly higher compared to GGT levels of alive patients (p=0.048). CONCLUSION: There was no difference in GGT levels between ischemic and hemorrhagic strokes; however, GGT levels in embolic strokes were significantly higher compared to atherosclerotic/lacunar strokes. High GGT levels are correlated with early mortality in stroke. We believe that GGT may be used as a predictor of mortality in future studies. PMID- 24948990 TI - Impact of an IEC (Information, Education and Communication) intervention on key family practices of mothers related to child health in Jamshoro, Sindh. AB - OBJECTIVE: To determine change in practice of mothers having children less than five years of age in five key areas related to child health, growth and development including immunization, feeding during illness, appropriate home treatment for infections and care seeking behavior. METHODS: This was a community based interventional study of Information, Education and Communication (IEC) intervention in the UC Jamshoro, Taluka Kotri, district Jamshoro of 15 months duration from March 2011 to June 2012. Ninety five mothers having children less than five years of age were selected by systematic random sampling for house hold based survey by questionnaire designed by EPP evaluation and health section of UNICEF during baseline and post-intervention phases. Base line data was collected from the interventional area then health education messages were given through written and pictorial material by LHWs for 9 months. To measure the impact helath education messages, data was again collected by same questionnaire are from the same union council during post-intervention phase. RESULTS: During baseline survey except immunization all other key family practices were poor. After 9 months of intervention of repeated heath education sessions through LHW during their routine visits all practices were improved with statistically significant difference. Regarding the comparison of the results between baseline and post intervention surveys we found that except immunization which was already better, all those practices which requires mother's knowledge and practice were improved after our intervention with significant P-values. CONCLUSIONS: Improving the mother's education level is very important, to empower the first care provider of child in the community. However, in the mean time, health educational messages related to the limited number of key family practices should be disseminated. PMID- 24948991 TI - Common Post-fitting Complications in Tooth-supported Fixed-Fixed Design Metal Ceramic Fixed Dental Prostheses. AB - OBJECTIVES: To report the frequency of common complications and their levels in metal-ceramic fixed dental prostheses (MC-FDPs). METHODS: A Descriptive Cross sectional study was conducted at the Prosthodontics Department, Khyber College of Dentistry Peshawar from January 2011 to October 2012. Using a structured proforma, data from 139 subjects fulfilling the inclusion and exclusion criteria for the study and reporting complications in their MC- FDPs were collected using the method of interview, clinical & radiographic examination. RESULTS: Of 139 subjects (Mean age = 34+ 6.4 Years), 81 (58.3%) were males and 58 (41.7%) were females with a male to female ratio of 1.4:1. De-cementation was the most common complication (41.7%). Least common complication was secondary caries (6.5%). Level-1 complications were more prevalent (77.7%) than level-2 complications (22.3%). In 91.4% cases, complications occurred before the FDP completed their fifth-years' service life with 25.2% of these occurring within the first years' service life. CONCLUSION: Irrespective of the type of complications, level-1 complications were more common with de-cementation being the most common complication. One-quarter of all the complications occurred within the first-year service life of the FDPs highlighting concern over the quality of the provided MC FDPs. . PMID- 24948992 TI - Maternal morbidity and perinatal outcome in preterm premature rupture of membranes before 37 weeks gestation. AB - OBJECTIVE: To assess the maternal morbidity and perinatal outcome in pre-term pre mature rupture of membranes between 24 to 37 weeks gestation. METHODS: This observational study was carried out in Gynaecology & Obstetrics Unit - I, at University Hospital Hyderabad, from October 2010 to October 2011. It included one hundred patients admitted through the outpatient department, as well as from casualty department of University Hospital Hyderabad. Detailed Clinical examination of the patient was done. Systemic review was also done to see any co morbidity. All patients had laboratory investigations. Inclusion criteria were all patients gestational age between 24 to 37 weeks with preterm premature rupture of membrane (PPROM) confirmed by ultrasound and clinical examination regardless of their age. Exclusion criteria were patients with congenital anomalies, multiple pregnancy, pre-eclampsia & eclampsia, diabetes mellitus, polyhydramnios1 intrauterine growth restriction and placenta abruption. Data was collected using a proforma. Detailed workup including history, general physical examination, abdomen and pelvic examination and relevant specific investigations were noted. RESULTS: Out of 100 patients included in this study Primigravida were 17% and multigravida 83%. There was wide variation of age ranging from a minimum of 20to >40 years. The mean age was 30+ 3.1 years. Mostly patients belonged to the poor class in 72% cases followed by middle class in 21% and upper class 7%. Analysis shows that out of 100 mothers 26% had PROM of <24 hrs duration and 74% had >24 hrs of duration. Maternal outcome in 16 cases of Preterm Premature Rupture of Membrane findings revealed septicemia in 12% cases and Chorioamnionitis in 12% cases. Fetal outcome in 27 cases of preterm premature rupture of membrane revealed prematurity in 5% cases, fetal distress in 4% cases, cord compression in 5% cases, necrotizing enterocolitis in 2% cases, hypoxia in 9% cases and pulmonary hypoplasia in 2% cases. CONCLUSION: Low socioeconomic status is associated with increased neonatal morbidity due to fetal distress, cord compression, necrotizing enterocolitis, hypoxia and pulmonary hypoplasia at the time of delivery. An appropriate and accurate diagnosis of PROM is critical to optimize pregnancy outcome. It is suggested that the timely diagnosis and management of preterm PROM will allow obstetric care providers to optimize perinatal outcome and minimize neonatal morbidity. PMID- 24948993 TI - Relationship between atrial fibrillation and coronary bypass surgery. AB - OBJECTIVE: Atrial fibrillation (AF) is the most common arrhythmia seen after coronary artery surgery. The purpose this study was to determine incidence of AF that develops after coronary surgery and the factors affecting its development. METHODS: Four hundred and forty eight patients who had coronary bypass surgery between February 2007 and September 2011 in the Cardiovascular Surgery Clinic were included in the study. Patients with history of chronic renal failure, redo coronary bypass surgery, valvular disease, thyroid disease, ventricular aneurysm and treatment with beta-blockers were excluded from the study of EF. RESULTS: Two hundred and ninety nine patients were male and 149 were female and their age varied between 38 and 85 and their mean age was 61+/-5. Surgery was performed on beating heart on 178 patients and the others were operated with cardiopulmonary bypass (CPB). Advanced age, male sex and history of hypertension was more in AF developed patient group. There was no difference between AF developed group and the other group in terms of diameter of left atrium, ejection fraction (EF), CPB time and cross clamp time. CONCLUSION: Advanced age, male sex, hypertension and prolonged P-wave duration are the factors that are associated with AF after coronary surgery. Avoidance of CPB does not decrease AF development. PMID- 24948994 TI - Vascular Endothelial Growth Factor expression in peripheral blood of patients with pregnancy induced hypertension syndrome and its clinical significance. AB - OBJECTIVE: This study was conducted was to detect vascular endothelial growth factor (VEGF) levels in peripheral blood of patients with pregnancy-induced hypertension (PIH) syndrome and to investigate VEGF correlation with PIH occurrence. METHODS: Double-antibody enzyme-linked immunosorbent assay and fluorescent quantitative polymerase chain reaction were used to detect VEGF levels in the peripheral blood of non-pregnant women (normal group, 30 cases), normal pregnant women (pregnancy group, 30 cases) and PIH patients (PIH group, 30 cases). RESULTS: VEGF level in the pregnancy group was significantly higher than in the normal group, and the difference between these two groups was significant (P < 0.001). In the pregnancy group, VEGF reached the maximum level at the metaphase stage of pregnancy and started to decrease at advanced pregnancy. VEGF level in the PIH group was significantly lower than in the pregnancy group at advanced pregnancy (P < 0.01), and VEGF level significantly and gradually decreased with PIH aggravation (P < 0.05). CONCLUSIONS: The significant decrease of VEGF level after pregnancy was possibly an important factor of PIH pathogenesis. PMID- 24948995 TI - Chronic scrotal pain caused by Mild Epididymitis:Report of a series of 44 cases. AB - OBJECTIVES: Patients with idiopathic chronic scrotal pain are challenging to both the general practioner and urologist. In this study, we tried to recognize mild epididymitis as an underrecogniczed cause of idiopathic chronic scrotal pain. Methods : We described a consecutive series of 44 patients with idiopathic chronic scrotal pain characterized by mild scrotal pain, mild to moderate tenderness of epididymis without abnormal swelling of epididymis. We obtained a detailed history and physical examination along with routine urinalysis and Doppler ultrasound to identify the characteristics of this new clinical entity. Results : A consecutive series of 44 patients who were primarily diagnosed as "idiopathic chronic scrotal pain" came to our hospital. All had the sign of mild to moderate tenderness on the affected epididymis without epididymis enlargement. Doppler ultrasound showed the affected epididymis with normal size and no abnormal change. We treated them with antibiotics orally along with cessation of strenuous activity and all fully recovered from scrotal pain. CONCLUSION: In this study, we recognized mild epididymitis as an underrecogniczed cause of idiopathic chronic scrotal pain. It was characterized by mild scrotal pain, mild to moderate tenderness of epididymis without abnormal enlargement of epididymis. PMID- 24948996 TI - Early stage effect of ischemic preconditioning for patients undergoing on-pump coronary artery bypass grafts surgery: systematic review and meta-analysis. AB - BACKGROUND: During the on-pump coronary artery bypass grafts surgery, ischemia/reperfusion injury would happen. Ischemia preconditioning could increase the tolerance against subsequent ischemia and reduce the ischemia/reperfusion injury. However the clinical outcomes of the available trials were different. Methods : We searched the Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 3, 2013), the Medline/PubMed and CNKI in March 2013. RevMan 5.1.6 and GRADEprofiler 3.6 were used for statistical analysis and evidence quality assessment. Heterogeneity was evaluated with significance set at P<=0.10. RESULTS: Eighteen randomized controlled trials were included. There were no differences on in-hospital mortality, postoperative myocardial infarction morbidity between ischemia preconditioning and control groups. The heterogeneity of creatine kinase-MB level 24 hours after surgery was obvious. The differences of 72 hours area under the curve of cardiac troponin T (mean differences of 14.50, 95% confidence interval of -21.71 to -7.28) and troponin I (mean differences -181.79, 95% confidence interval of -270.07 to -93.52) after surgery were observed. Conclusion s : All the 18 trails, the positive and the negative results were equal. The meta-analysis results should be interpreted with caution due to limited effective data. Because of high cost-effectiveness, ischemia preconditioning could not be denied completely. Large-scale randomized studies are needed, with the operation procedures and included criteria being more specific. PMID- 24948997 TI - Emerging 21(st) Century Medical Technologies. AB - Although several medical technologies have been around since decades and are in the continuous process of development, some latest technologies are changing the way medicine would be practiced in the future. These technologies would allow medical practice from anywhere, any time and from any device. These include smart phones, Tablet PCs, Touch screens, digital ink, voice recognition, Electronic Health Records (EHRs), Health Information Exchange (HIE), Nationwide Health Information Network (NwHIN), Personal Health Records (PHRs), patient portals, Nanomedicine, genome-based personalized medicine, Geographical Positioning System (GPS), Radiofrequency Identification (RFID), Telemedicine, clinical decision support (CDS), mobile home healthcare, cloud computing, and social media, to name a few significant. PMID- 24948998 TI - Can hospital promotional activities be more ethical? AB - At present, there exist a lot of violations of medical ethics in advertising and promotional activities, which have been infringing the rights of patients. Therefore, the ethical criteria should be established as soon as possible to regulate the hospital promotional activities, to regain the trust of people. PMID- 24948999 TI - How to deal with burden of critical illness: A comparison of strategies in different areas of China. AB - OBJECTIVES: This article aims to introduce, compare and analyze the design and development of Critical Illness Insurance systems in different parts of China under different social and economic conditions, to explain their characteristics and similarities. It may provide references to other countries, especially developing countries, to solve the problem of high medical costs. METHODS: According to the methods in Comparative Economics, 3 areas (Taicang in Jiangsu, Zhanjiang in Guangdong, Xunyi in Shanxi) which are in high, medium and low socio economic condition respectively were chosen in China. Their critical illness insurance systems were analyzed in the study. RESULTS: Each system shares several common points, including coordinating urban and rural medical insurance fund, financing from the basic medical insurance surplus, and exploring payment reform and so on. But in the way of management, Taicang and Zhanjiang cooperate with commercial insurance agencies, but Xunyi chooses autonomous management by government. In Xunyi, multi-channel financing is relatively more dispersed, while funds of Taicang and Zhanjiang are mainly from the basic medical insurance surplus. The specific method of payment is different among these three areas. CONCLUSION: Because of the differences in economic development, population structure, and sources of funds, each area took their own mode on health policy orientation, financing, payment, coverage, and fund management to design their Critical Illness Insurance systems. This might provide references to other areas in China and other developing countries in the world. PMID- 24949000 TI - A comparison of the scorings of real and standardized patients on physician communication skills. AB - OBJECTIVES: To compare the scorings of real and standardized patients on physician communication skills. METHODS: Patient scoring (n=183) on physicians' communication skills was determined by 93 real and 90 standardized patients. Eighty physicians (42 specialists and 38 general physicians) in private practice were enrolled. Data were analyzed using self administered questionnaires and checklists including 16 close ended questions. RESULTS: Twelve percent of patients were not satisfied with the physician communication skills. Poor communication skills were more reported by male patients and those with a higher educational level. The physician communication skill received a higher score with increase of age of patients. A good physician's communication skill was reported more by married patients. A good physician's communication skill was significantly more in female doctors, in general physicians and in doctors wearing a White Coat. Real patients scored physician's communication skills higher than standardized patients. CONCLUSION: It is important that physicians try to learn the principles of a good physician-patient communication skill. Therefore, providing medical educational programs on the role of a good doctor and patient relationship at all levels for the doctors and applying them in their clinical practice seem necessary to improve the physician communication skills. PMID- 24949001 TI - A case of hepatic cyst-induced inferior vena cava thrombosis. AB - A 92-year-old woman visited the hospital with edema of both lower extremities. Computed tomography revealed her inferior vena cava (IVC) was compressed by a massive hepatic cyst. A massive IVC thrombosis and pulmonary thromboembolism (PTE) were also observed. Medical treatment rather than radiologic intervention was preferred because of the patient's advanced age and poor performance status. IVC thrombosis and PTE disappeared after 6 months of anticoagulation therapy. To the best of our knowledge, this is the first study in the English literature to report IVC thrombosis caused by congenital hepatic cysts that was treated without vascular intervention. PMID- 24949002 TI - A rare case of critical illness polyneuropathy and literature review. AB - A 40- year-old Male was admitted to the first hospital of Jilin University with the complaint of 4 days of fever and headache and aggravation of weakness in his lower extremities accompanied with dysuria and disturbance of consciousness for one day. He had tachycardia, tachypnea and elevated white blood cell counts. General status of the patient got better day by day, while weakness and pain in his lower extremities had developed and gradually quadriplegia arose. When intensive care unit history, weaning difficulty from mechanical ventilator, clinical manifestations in intensive care unit associated with SIRS, symmetrical paresis pronounced in distal lower extremities, absence of deep tendon reflexes, evidence of distal sensory impairment, presence of electrophysiologic results indicating axonal sensorimotor polyneuropathy and muscle and nerve biopsy results were taken into consideration, he was diagnosed as critical illness polyneuropathy. PMID- 24949003 TI - Cardiorenal syndrome followed by acute hepatitis C in a patient with acute myeloid leukemia. AB - Cardiorenal syndrome involves altering cardiac and renal function. These patients frequently develop resistance to diuretic therapy, so that ultrafiltration should be applied in emergency for saving them. Concomitant presence of an active hematologic malignancy represents an important complicating factor. We present the case of an elderly patient with acute myeloid leukemia, appeared on the background of myelodysplastic syndrome who, during marrow aplasia occurred after the first course of induction chemotherapy, developed a cardiorenal syndrome, which required repeated sessions of hemodialysis. Complete hematologic remission and efficiency of fluid depletion therapy allowed the second course of polychemotherapy, after which the patient developed an acute hepatitis C. After 8 months of complete hematologic remission that persists, the patient will be put on the standard antivirusologic treatment. PMID- 24949004 TI - Study of non-syndromic thumb aplasia in six independent cases. AB - OBJECTIVES: To report on six independent and isolated cases demonstrating thumb aplasia as an essentially limb-specific phenotype. METHODS: The subjects were ascertained during 2011-2013 from six different geographic regions of Pakistan, and underwent detailed clinical and phenotypic examination. RESULTS: The affected arms of patients had complete absence of first digital rays, medial inclinations of second and fifth fingers, narrowing of palms, missing carpals, and shortening of zeugopod. All the subjects were presented with isolated and sporadic limb deficiencies, and five had no family history of limb or any other malformation. Parental consanguinity was denied in majority of the cases. We present detailed phenotypic manifestation of thumb apalsia in these subjects. CONCLUSION: Thumb aplasia markedly impairs the normal function of affected hand. Surgical procedures like pollicisation of the index finger should be employed to improve the quality of life of these subjects. There is so far no specific genetic factor known for isolated thumb aplasia, compromising an accurate genetic counseling. Collection of patients with similar phenotypic presentations could be useful in further molecular genetic investigations. PMID- 24949005 TI - Do the rates we report misinform the local programs? PMID- 24949006 TI - Atypical cause of a typical chest pain. PMID- 24949007 TI - Evaluation of the Potential Nephroprotective and Antimicrobial Effect of Camellia sinensis Leaves versus Hibiscus sabdariffa (In Vivo and In Vitro Studies). AB - Green tea and hibiscus are widely consumed as traditional beverages in Yemen and some regional countries. They are relatively cheap and the belief is that they improve health state and cure many diseases. The aim of this study was to evaluate the potential protective and antibacterial activity of these two famous plants in vitro through measuring their antibacterial activity and in vivo through measuring nonenzymatic kidney markers dysfunction after induction of nephrotoxicity by gentamicin. Gram positive bacteria like MRSA (methicillin resistant Staphylococcus aureus) were isolated from hospitalized patients' different sources (pus and wound) and Gram negative bacteria including E. coli and P. aeruginosa were used in vitro study. In addition, the efficacy of these plants was assessed in vivo through measuring nonenzymatic kidney markers including S. creatinine and S. urea. Green tea was shown antimicrobial activity against MRSA with inhibition zone 19.67 +/- 0.33 mm and MIC 1.25 +/- 0.00 mg/mL compared with standard reference (vancomycin) 18.00 +/- 0.00 mg/mL. Hibiscus did not exhibit a similar effect. Both Hibiscus- and green tea-treated groups had nephroprotective effects as they reduced the elevation in nonenzymatic kidney markers. We conclude that green tea has dual effects: antimicrobial and nephroprotective. PMID- 24949008 TI - Trends in the Rates of Pediatric Pyeloplasty for Ureteropelvic Junction Obstruction over 19 Years: A PHIS Database Study. AB - Background. Over the past 20 years, the management of ureteropelvic junction obstruction (UPJ) has shifted. While many urologists note a decrease in the number of pyeloplasties performed over time, the nature of the change in practice has yet to be defined. In the current study, we utilize a national, multi institutional database of children's hospitals to evaluate trends in patients undergoing pyeloplasty as well as the rate of surgical reconstruction over the past 20 years. Material/Methods. We queried the Pediatric Health Information System (PHIS) database for all children undergoing primary pyeloplasty between 1992 and 2011. Clinical variables, including age at time of surgery, gender, length of stay (LOS), and geographic region, were determined. Age-adjusted rate of repair was also calculated per 100,000 PHIS inpatients. Results. 6,013 patients were included in the study, of which 71.6% were male and 64.2% were under the age of 24 months at time of surgery. Over the study period, the median age at time of surgery increased from 2-4 months to 12-14 months (P < 0.01). LOS decreased from a median of 5 days to 2 days (P < 0.001). The rate of surgery increased by 10.6 pyeloplasties per 100,000 PHIS inpatients from 1992 to 2011 (P < 0.01). The highest rate of pyeloplasty was in the northeast. The increase in pyeloplasties performed from 1992 to 1999 was specific to children aged greater than 24 months, while rates stayed the same in infants younger than 2 years during the same time period. In contrast, from 1999 to 2011, the rate of pyeloplasty decreased in patients less than 2 years of age, while the rate remained constant in patients over age 2. Conclusion. The rate of pyeloplasty increased in PHIS hospitals from 1992 to 2011. Trends are due to an increase in surgery in infants younger than 2 years from 1992 to 1999, followed by a progressive surgical rate decline, characterized by a shift towards patients older than 2 years of age. PMID- 24949009 TI - Risk factors for anaplastic thyroid cancer. AB - Background. Anaplastic thyroid cancer (ATC) is a form of thyroid cancer with very poor prognosis, but is fortunately quite rare. Its aetiology is unknown and not well researched. Aim. The aim of this study was to identify potential risk factors for ATC. Material and Method. Case-control study of 126 ATC patients (77 females and 49 males) and 252 controls individually matched by gender, age, and place of abode. In statistical analysis we used a Cox regression model. Results. Univariate logistic regression showed that the risk factors for ATC are low education level, type B blood group, goitre, other nonthyroid malignancies, diabetes, late menarche, and an early first pregnancy. Multivariate logistic regression analysis showed that independent risk factors for ATC are low education level (OR = 1.42, 95% CI = 1.09-1.86), type B blood group (OR = 2.41, 95% CI = 1.03-5.66), and goitre (OR = 25-33, 95% CI = 5.66-126.65). Conclusion. Independent risk factors for ATC are: low education level, type B blood group, and goitre. PMID- 24949010 TI - Effects of Maternal Hypoxia during Pregnancy on Bone Development in Offspring: A Guinea Pig Model. AB - Low birth weight is associated with reduced bone mass and density in adult life. However, effects of maternal hypoxia (MH) on offspring bone development are not known. Objective. The current study investigated the effects of fetal growth restriction induced by MH during the last half of gestation on bone structure and volume in the offspring of the fetus near term and the pup in adolescence. Methods. During 35-62-day gestation (term, 69d), guinea pigs were housed in room air (21% O2; control) or 12% O2 (MH). Offspring femur and tibia were collected at 62d gestation and 120d after birth. Results. MH decreased fetal birth weight but did not affect osteogenic potential pools in the fetal bone marrow. Histological analysis showed no effects of MH on tibial growth plate thickness in either fetal or postnatal offspring, although there was increased VEGF mRNA expression in the growth plate of postnatal offspring. MH did not change primary spongiosa height but lowered collagen-1 mRNA expression in postnatal offspring. There was increased mRNA expression of adipogenesis-related gene (FABP4) in bone from the MH postnatal offspring. Conclusion. MH during late gestation did not change the pool of osteogenic cells before birth or growth plate heights before and after birth. However, MH reduced expression of bone formation marker (collagen-1) and increased expression of fat formation marker (FABP4) in postnatal offspring bone. PMID- 24949011 TI - Association of the apolipoprotein b/apolipoprotein a-I ratio, metabolic syndrome components, total cholesterol, and low-density lipoprotein cholesterol with insulin resistance in the population of georgia. AB - The study was designed to assess the association between insulin resistance (IR) and apolipoprotein B/apolipoprotein A-I ratio (ApoB/ApoA-I ratio), metabolic syndrome (MetS) components, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in the nondiabetic population of Georgia. The subjects were 1522 Georgians of Caucasian origin (mean age = 45 years, 653 women) without diabetes who had visited the clinics for a related health checkup between 2012 and 2013. IR was calculated using the computer homeostasis model assessment (HOMA2-IR) and was defined as the upper quartile. MetS was diagnosed using the updated ATP-III definition of the metabolic syndrome. Logistic and multiple regression models were used to estimate the association between IR and other components. IR was positively correlated with age, ApoB, ApoB/ApoA-I ratio, MetS components (excluding high-density lipoprotein cholesterol-HDL-C), LDL-C, fasting insulin, and TC and negatively correlated with HDL-C and ApoA-I in both sexes (all P < 0.001). In the logistic regression models, gender, age, ApoB/ApoA-I ratio, diastolic pressure, HDL-C, LDL-C, fasting glucose, and triglycerides were the covariates significantly associated with IR (OR: 8.64, 1.03, 17.95, 1.06, 0.13, 1.17, 3.75, and 2.29, resp.; all P < 0.05). Multiple regression models demonstrated that these components (except for HDL-C) made an independent contribution to the prediction of HOMA2 (all P < 0.05). PMID- 24949012 TI - Molar incisor hypomineralization, prevalence, and etiology. AB - Aim. To evaluate the prevalence and possible etiological factors associated with molar incisor hypomineralization (MIH) among a group of children in Jeddah, Saudi Arabia. Methods. A group of 8-12-year-old children were recruited (n = 267) from the Pediatric Dental Clinics at the Faculty of Dentistry, King Abdulaziz University. Children had at least one first permanent molar (FPM), erupted or partially erupted. Demographic information, children's medical history, and pregnancy-related data were obtained. The crowns of the FPM and permanent incisors were examined for demarcated opacities, posteruptive breakdown (PEB), atypical restorations, and extracted FPMs. Children were considered to have MIH if one or more FPM with or without involvement of incisors met the diagnostic criteria. Results. MIH showed a prevalence of 8.6%. Demarcated opacities were the most common form. Maxillary central incisors were more affected than mandibular (P = 0.01). The condition was more prevalent in children with history of illnesses during the first four years of life including tonsillitis (P = 0.001), adenoiditis (P = 0.001), asthma (P = 0.001), fever (P = 0.014), and antibiotics intake (P = 0.001). Conclusions. The prevalence of MIH is significantly associated with childhood illnesses during the first four years of life including asthma, adenoid infections, tonsillitis, fever, and antibiotics intake. PMID- 24949013 TI - Primary stability of self-drilling and self-tapping mini-implant in tibia of diabetes-induced rabbits. AB - Objective. This study aimed to evaluate effects of type 1 diabetes mellitus and mini-implant placement method on the primary stability of mini-implants by comparing mechanical stability and microstructural/histological differences. Methods. After 4 weeks of diabetic induction, 48 mini-implants (24 self-tapping and 24 self-drilling implants) were placed on the tibia of 6 diabetic and 6 normal rabbits. After 4 weeks, the rabbits were sacrificed. Insertion torque, removal torque, insertion energy, and removal energy were measured with a surgical engine on 8 rabbits. Remaining 4 rabbits were analyzed by microcomputed tomography (micro-CT) and bone histomorphometry. Results. Total insertion energy was higher in self-drilling groups than self-tapping groups in both control and diabetic groups. Diabetic groups had more trabecular separation in bone marrow than the control groups in both SD and ST groups. Micro-CT analysis showed deterioration of bone quality in tibia especially in bone marrow of diabetic rabbits. However, there was no statistically significant correlation between self drilling and self-tapping group for the remaining measurements in both control and diabetic groups. Conclusions. Type 1 diabetes mellitus and placement method of mini-implant did not affect primary stability of mini-implants. PMID- 24949014 TI - Cell death. PMID- 24949015 TI - Study of a Natural Mutant SHV-Type beta -Lactamase, SHV-104, from Klebsiella pneumoniae. AB - Klebsiella pneumoniae ML2011, a multiresistant isolate, was isolated from the Military Hospital of Tunis (Tunisia). The determination of the minimal inhibitory concentrations exhibited by K. pneumoniae ML2011 was performed by Etest. The crude extract of the isolates contains four different beta -lactamases with pI 5.5, 7.3, 7.6, and 8.6. Only the beta -lactamases with pI 7.3 and pI 8.6 were transferred by transformation and conjugation experiment. Molecular characterization of these genes was performed by PCR and sequencing. The chromosomal beta -lactamases are TEM (pI 5.5) and SHV-1 (7.6). CTX-M-28 (pI 8.6) and the novel variant of SHV named SHV-104 (pI 7.3) were encoded by bla gene located on a 50 kb highly conjugative plasmid. The SHV-104 beta -lactamase was produced in E. coli and purified. Its profile of activity was determined. Compared to SHV-1, SHV-104 contains one mutation, R202S. Their kinetic parameters were similar except for cefotaxime. The analysis of the predicted structure of SHV-104 indicated that the R202S mutation suppresses a salt bridge present in SHV 1. Therefore, the overall flexibility of the protein increased and might improve the hydrolysis of cefotaxime. We can conclude that the multiresistant phenotype of K. pneumoniae ML2011 strain is mainly linked to the production of CTX-M-28 since SHV-104 possesses a narrow spectrum of activity. PMID- 24949016 TI - Primary otomycosis in the Indian subcontinent: predisposing factors, microbiology, and classification. AB - Objective. To define otomycosis and determine the predisposing factors and microbiology in primary otomycosis. Study Design. Prospective study of two years and review of the literature. Setting. Academic Department of Otolaryngology in a coastal city in India. Patients. 150 immunocompetent individuals of whom 100 consecutive patients with a clinical diagnosis of otomycosis are considered as the study group and 50 consecutive patients with no otomycosis are considered as the control group. Results and Observations. Instillation of coconut oil (42%), use of topical antibiotic eardrops (20%), and compulsive cleaning of external ear with hard objects (32%) appeared to be the main predisposing factors in otomycosis. Aspergilli were the most common isolates (80%) followed by Penicillium (8%), Candida albicans (4%), Rhizopus (1%), and Chrysosporium (1%), the last being reported for the first time in otomycosis. Among aspergilli, A. niger complex (38%) was the most common followed by A. fumigatus complex (27%) and A. flavus complex (15%). Bacterial isolates associated with fungi in otomycosis were S. aureus, P. aeruginosa, and Proteus spp. In 42% of healthy external ears fungi were isolated. Conclusion. Aspergillus spp. were the most common fungi isolated, followed by Penicillium. Otomycotic ears are often associated with bacterial isolates when compared to normal ears. Fungi are also present in a significant number of healthy external auditory canals and their profiles match those in cases of otomycosis. The use of terms "primary" and "secondary" otomycosis is important to standardize reporting. PMID- 24949017 TI - Optimization of Amylase Production from B. amyloliquefaciens (MTCC 1270) Using Solid State Fermentation. AB - Demand for microbial amylase production persists because of its immense importance in wide spectrum industries. The present work has been initiated with a goal of optimization of solid state fermentation condition for amylase using agroindustrial waste and microbial strain like B. amyloliquefaciens (MTCC 1270). In an aim to improve the productivity of amylase, fermentation has been carried out in the presence of calcium (Ca(+2)), Nitrate (NO3 (-)), and chloride ions (Cl(-)) as well as in the presence of D-inositol and mannitol. Amylase needs calcium ion for the preservation of its structure, activity and stability that proves beneficial also for amylase production using solid state fermentation. The inclusion of ions and sugars in the SSF media is promising which can be explained by the protection offered by them against thermal decay of amylase at various incubation periods at 37 degrees C. PMID- 24949018 TI - Effect of environmental disturbance on the population of sandflies and leishmania transmission in an endemic area of Venezuela. AB - The exploitation of new wilderness areas with crops is increasing and traditional crop substitution has been modified by new more productive crops. The results show the anthropogenic disturbance effect on the sandflies population and Leishmania transmission in endemic areas of Venezuela. Three agroecosystems with variable degrees of ecological disturbance, forest (conserved), cacao (fragmented), and orangery (disturbed), were selected. Four methods to sandfly capture were used; the specimens were identified and infected with Leishmania. Diversity, population structure, ANOVA, Tukey test, and simple correlation analysis were carried out. Shannon traps were able to capture 94.7% of the total sandflies, while CDC light traps, Sticky traps, and direct suction just captured 2.2%, 1.2%, and 0.9%, respectively. The results showed the effect of ecological disturbance degree on the composition of sandflies and population structure, revealing a dominance level increased but decreased on the diversity and richness of sandflies species in the greatest ecological disturbance area in relation to areas with less organic disturbance. Environments more disturbed cause adaptability of certain species such as Lutzomyia gomezi and Lutzomyia walkeri. These changes on the composition of sandflies population and structure emerging species could cause increasing of leishmaniasis transmission. PMID- 24949019 TI - Meta-analysis of the efficacy of ectoine nasal spray in patients with allergic rhinoconjunctivitis. AB - Objectives. The meta-analysis aims to investigate the efficacy of ectoine nasal spray and eye drops in the treatment of allergic rhinitis and rhinoconjunctivitis symptoms. Design and Methods. This meta-analysis is based on yet unpublished data of four studies. Both nasal and eye symptoms were documented in patient diary cards. All scales were transformed into a 4-point scale: 0 = no, 1 = mild, 2 = moderate, and 3 = severe symptoms. Each symptom was analysed individually in a meta-analysis of the area under the curve values as well as in a meta-analysis of pre- and posttreatment comparison. Results. After seven days of treatment with ectoine nasal spray both nasal and ocular symptoms decreased significantly. A strong reduction of symptom severity was shown for the parameters rhinorrhoea (31.76% reduction) and nasal obstruction (29.94% reduction). Furthermore, the meta-analyses of individual symptoms to investigate the strength of effect after seven days of medication intake showed significant improvement for nasal obstruction, rhinorrhoea, nasal itching, sneezing, itching of eyes, and redness of eyes. The improvement of the symptom nasal obstruction was associated with a strong effect 0.53 (+/-0.26). Conclusions. The ectoine nasal spray and eye drops seem to be equally effective as guideline-recommended medication in the treatment of rhinoconjunctivitis symptoms. PMID- 24949021 TI - Growth parameters impairment in patients with food allergies. AB - Background and Aims. Food allergy (FA) is a common disease that is rapidly increasing in prevalence for reasons that remain unknown. Objective. The aim of this study was to analyze the clinical characteristics and anthropometric data of patients with food allergies followed in a tertiary centre of allergy and immunology. Methods. A retrospective study was performed that assessed the data records of patients with food allergy diagnosis, covering a period from February 2009 to February 2012. Results. 354 patients were evaluated in the period; 228 (69.1%) patients had a confirmed FA diagnosis. The z-scores for weight-for-age, height-for-age, and body mass indices-for-age showed lower significant values in the FA group compared with the non-FA group by Mann-Whitney test, with significance values of P = 0.0005, P = 0.0030, and P = 0.0066, respectively. There were no statistical differences in sex, gestational age, birth type, breastfeeding period, and age of introduction of complementary formulas based on cow milk protein between groups. Conclusion. FA patients had a lower growth rate in comparison with patients without FA. The early recognition of food allergies with the establishment of protein-implicated diet exclusion, in association with an adequate nutrient replenishment, is important to reduce the nutritional impact of food allergies. PMID- 24949020 TI - Immunochemical characterization of acacia pollen allergens and evaluation of cross-reactivity pattern with the common allergenic pollens. AB - Pollen from the Acacia has been reported as an important source of pollinosis in tropical and subtropical regions of the world. The aim of this study was to characterize the IgE binding protein of Acacia farnesiana pollen extract and evaluate cross-reactivity with the most allergenic pollens. In this study, pollen extract was fractionated by SDS-PAGE and the allergenic profile was determined by IgE-immunoblotting and specific ELISA using forty-two Acacia allergic patients. Potential cross-reactivity among Acacia and selected allergenic plants was evaluated with ELISA and immunoblotting inhibition experiments. There were several resolved protein fractions on SDS-PAGE which ranged from 12 to 85 kDa. Several allergenic protein bands with molecular weights approximately between 12 and 85 kDa were recognized by IgE-specific antibodies from Acacia allergic patients in the immunoblot assay. The inhibition by the Prosopis juliflora pollen extract was more than those by other pollen extracts. Moreover, the wheal diameters generated by the Acacia pollen extract were highly correlated with those of P. juliflora pollen extracts. The findings suggest that several proteins such as 15, 23, 45, and 50 kDa proteins could be used as diagnostic and therapeutic reagents for patients allergic to A. farnesiana and P. juliflora. PMID- 24949022 TI - Proteomic analysis allows for early detection of potential markers of metabolic impairment in very young obese children. AB - BACKGROUND: Early diagnosis of initial metabolic derangements in young obese children could influence their management; however, this impairment is frequently not overt, but subtle and undetectable by routinely used clinical assays. Our aim was to evaluate the ability of serum proteomic analysis to detect these incipient metabolic alterations in comparison to standard clinical methods and to identify new candidate biomarkers. METHODS: A cross-sectional study of fasting serum samples from twenty-two prepubertal, Caucasian obese (OB; 9.22 +/- 1.93 years; 3.43 +/- 1.08 BMI-SDS) and twenty-one lean controls (C; 8.50 +/- 1.98 years; 0.48 +/- 0.81 BMI-SDS) and a prospective study of fasting serum samples from twenty prepubertal, Caucasian obese children (11 insulin resistant [IR]) before (4.77 +/- 1.30 BMI-SDS) and after weight reduction (2.57 +/- 1.29 BMI-SDS) by conservative treatment in a reference hospital (Pros-OB) was performed. Proteomic analysis (two-dimension-eletrophoresis + mass spectrometry analysis) of serum and comparative evaluation of the sensitivity of routinely used assays in the clinics to detect the observed differences in protein expression level, as well as their relationship with anthropometric features, insulin resistance indexes, lipid profile and adipokine levels were carried out. RESULTS: Study of the intensity data from proteomic analysis showed a decrease of several isoforms of apolipoprotein-A1, apo-J/clusterin, vitamin D binding protein, transthyretin in OB vs. C, with some changes in these proteins being enhanced by IR and partially reversed after weight loss. Expression of low molecular weight isoforms of haptoglobin was increased in OB, enhanced in IR and again decreased after weight loss, being positively correlated with serum interleukin-6 and NAMPT/visfatin levels. After statistical correction for multiple comparisons, significance remained for a single isoform of low MW haptoglobin (OB vs. C and IR vs. non-IR) and Apo A1 (IR vs. non-IR). Assays routinely used in the clinical setting (ELISA/kinetic nephelometry), only partially confirmed the changes observed by proteomic analysis (ApoA1 and haptoglobin). CONCLUSION: Proteomic analysis can allow for the identification of potential new candidate biomarkers as a complement to routinely used assays to detect initial changes in serum markers of inflammation and lipid metabolism impairment in young obese children. PMID- 24949023 TI - Impact of primary food allergies on the introduction of other foods amongst Canadian children and their siblings. AB - BACKGROUND: Food-allergic children frequently avoid other highly allergenic foods. The NIAID 2010 guidelines state that individuals with an IgE-mediated food allergy should avoid their specific allergens and physicians should help patients to decide whether certain cross-reactive foods also should be avoided. Patients at risk for developing food allergy do not need to limit exposure to foods that may be cross-reactive with the major food allergens. The purpose of this study was to determine if parents of food-allergic children are given advice regarding introduction of allergenic foods; if these foods are avoided or delayed; if there is anxiety when introducing new foods; and if introducing other allergenic foods leads to any allergic reaction. The study also determined if there was a similar pattern seen amongst younger siblings. METHODS: An online survey was administered between December 2011 and March 2012 via Anaphylaxis Canada's website, available to Canadian parents and caregivers who are registered members of the organization and who have a child with a food allergy. RESULTS: 644 parents completed the online survey. 51% of families were given advice regarding the introduction of other allergenic foods. 72% were told to avoid certain foods, and 41% to delay certain foods. 58% of parents did avoid or delay other highly allergenic foods, mainly due to a fear of allergic reaction. 69% of children did not have an allergic reaction when these foods were subsequently introduced. 68% of parents felt moderate or high levels of anxiety when introducing other foods. A similar pattern was seen amongst the younger siblings. CONCLUSIONS: Canadian parents and caregivers of children with food allergies receive varied advice from health care professionals regarding the introduction of new allergenic foods, and feel moderate to high levels of anxiety. A similar pattern may be seen amongst younger siblings. While the majority of children in our study did not have an allergic reaction to a new food, a significant proportion of children did react. A more consistent approach to the advice given by health care professionals may decrease parental anxiety. Further research to support the 2010 NIAID guidelines may be necessary to clarify recommendations. PMID- 24949024 TI - Chronic kidney disease and aging: The theme of world kidney day in 2014; nephrologist will become the professional geriatrist. PMID- 24949025 TI - Association of GSTT1 and GSTM1 polymorphisms with blood pressure: A Bayesian modeling of continuous data. AB - BACKGROUND: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) are a multi-factorial traits and significantly heritable. Glutathione S-transferase (GST) enzyme is involved in detoxification of reactive oxygen species. The present study aimed at finding out the association between GSTM1 and GSTT1 polymorphisms and mean arterial pressure (MAP) in Iranian population. MAP, as the important indicator of blood pressure, is calculated by weighted averaging of SBP and DBP. MATERIALS AND METHODS: we randomly selected 72 healthy individuals from Isfahan Cohort Study (ICS). Polymerase chain reaction (PCR) was done to detect polymorphism of the GSTM1 and GSTT1 genes. The Bayesian Structured Regression model was used, adjusted for sex, age, body mass index (BMI), and smoking status. RESULTS: The results showed that both the GSTT1and GSTM1genotypes deletion had a significant effect on MAP increasing in our samples based on 95% Bayesian credible intervals. CONCLUSION: This study demonstrated that GSTT1 and GSTM1 gene increase the arterial pressure; hence, it can predict the susceptibility to cardiovascular disease. PMID- 24949026 TI - The correlation of anxiety and depression with obstructive sleep apnea syndrome. AB - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a common sleep disorder characterized by repeated upper airway obstruction during sleep. While respiratory pauses followed by loud snoring and daytime sleepiness are the main symptoms of OSAS, the patients may complain from sleep disruption, headache, mood disturbance, irritability, and memory impairment. However, the association of sleep apnea with anxiety and depression is not completely understood. Adherence to continuous positive airway pressure (CPAP), the treatment of choice for OSAS, may be influenced by psychological conditions, especially claustrophobia. The aim of this study was to evaluate the association of OSAS with anxiety and depression symptoms. This study also investigated the association of anxiety with body mass index (BMI) and the severity of OSAS. MATERIALS AND METHODS: We conducted a cross sectional study on 178 adult individuals diagnosed with OSAS at the sleep laboratory between September 2008 and May 2012. The participants were interviewed according to a checklist regarding both their chief complaints and other associated symptoms. The psychological status was assessed according to Beck anxiety inventory (BAI) and Beck depression inventory (BDI) scoring. The severity of breathing disorder was classified as mild, moderate, and severe based on apnea hypopnea index (AHI) which was ascertained by overnight polysomnography. Daytime sleepiness was assessed by Epworth sleepiness scale (ESS). RESULTS: The mean (SD) age of participants was 50.33 years. In terms of sex, 85.5% of the study population were males and14.4% were females. We found no relation between sex and the symptoms of OSAS. Regarding the frequency of anxiety and depression symptoms, 53.9% of the individuals had some degree of anxiety, while 46.1% demonstrated depressive symptoms. In terms of OSAS severity, this study showed that OSAS severity was associated with the frequency of anxiety, chocking, and sleepiness (P : 0.001). According to polysomnographic results, we found that the majority of patients suffering from anxiety and chocking (66.7% and 71.4%, respectively) had severe OSAS, while only 23.1% of patients with sleepiness had severe OSAS. CONCLUSION: Our study showed that the frequency of anxiety in OSAS patients is higher than in the general population regardless of the gender. Furthermore, it is more likely that OSAS patients present with anxiety and depression than the typical symptoms. PMID- 24949027 TI - Bronchial stump closure with amniotic membrane in animal model. AB - BACKGROUND: Coverage of the bronchial stumps (BSs) with adjacent tissues can improve healing and reduce bronchial complications in complex thoracic surgery. There is no evidence for the application of human amnion allograft for prevention of air leak from the BS. The comparison of the amniotic membrane (AM) and pleural patch for BS healing after lobectomy in dogs was our aim in this study. MATERIALS AND METHODS: A total of eight males and females 12-24-month-old dogs between 17 and 22 kg body-weight were used in this study in 2010, Isfahan University of Medical Sciences. Animals were separated into two groups: group A (n = 4; amniotic membrane) and group P (n = 4; pleural patch) according to the BS closure technique performed. After lobectomy of the right middle lobe, the BS was closed, while a small bronchopleural fistula (BPF) was created by inserting a catheter via edges of closed stump. Then, it was covered with a piece of AM3 * 3 cm in group A and with a pedicle graft of pleura in group P. Rethoracotomy was performed after 15 days of observation, and the BS was removed for histological examination. Histological healing was classified as complete or incomplete healing. Neoangiogenesis was measured by Von Willebrand expression using immunohistochemistry (IHC). Data were analyzed by SPSS version 15 using Fisher's exact test, Mann-Whitney test, and T tests. RESULTS: BPF complications were not seen during observation period. There was no significant difference in histological healing between two groups. Similarly, no significant difference was observed between the groups in terms of neoangiogenesis based on IHC examination (P value = 0.69). CONCLUSION: Human amnion allograft could be as effective as pleural patch for BS wrapping following pulmonary resections. PMID- 24949028 TI - Effects of pomegranate juice consumption on inflammatory markers in patients with type 2 diabetes: A randomized, placebo-controlled trial. AB - BACKGROUND: Diabetes causes the increased concentration of circulatory cytokines as a result of inflammation. Considering that pomegranate juice (PJ) is known to have antioxidant and anti-inflammatory properties, the purpose of this study was to determine the effects of PJ consumption on markers of inflammation in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: In a randomized, double-blind clinical trial study, 50 patients with T2D (40-65 years old) were randomly assigned to one of two groups. Participants in each group received either 250 mL/day PJ or a control beverage for 12 weeks. Biochemical markers including fasting plasma glucose (FPG), insulin and inflammatory markers were assayed on the baseline and follow-up blood samples. RESULTS: In all, 44 patients in two groups were included in the analysis: PJ (n = 22) and placebo (n = 22). After 12 weeks of intervention, in the PJ group, there were 32% and 30% significant decreases in plasma C-reactive protein (hs-CRP) and Interlukin-6, respectively (P < 0.05). The mean +/- SD plasma interlukin-6 (7.1 +/- 5.6 vs. 11.9 +/- 14.4 mg/L) and hs-CRP (1791 +/- 1657 and 1953 +/- 1561 ng/mL) concentrations in the PJ group were significantly lower than the placebo group after intervention (P < 0.05). CONCLUSION: PJ consumption by patients with T2D does not affect FPG or the insulin resistance index (HOMA-IR), whereas it does reduce Interlukin-6 and hs CRP concentrations in plasma. Therefore, PJ consumption may have an anti inflammatory effect in patients with T2D. PMID- 24949030 TI - Sexual dysfunction in women with multiple sclerosis: Dimensions and contributory factors. AB - BACKGROUND: Sexual dysfunction (SD) is a common reported problem in patients with multiple sclerosis (MS). AIMS: to examine frequency and distribution of SD dimensions and to determine whether SD is related to various clinical and demographic variables in female patients. MATERIALS AND METHODS: A total of 271 MS women (age: 19-50 years) participated in this cross-sectional study. We used a structured demographic and clinical interview and Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19). Disability was rated by Expanded Disability Status Score (EDSS). RESULTS: 63.5% (n = 173) of women had SD included 142 (52.4%) women with primary SD, 102 (37.5%) women with secondary SD and 120 (41%) women with tertiary SD. The most common SD-related complaint was orgasmic problem (41.2%). Women with primary SD were significantly older and had higher EDSS score. No significant relationship was found between primary SD and disease duration. Fatigue (OR = 2.69, 95% CI: 1.352-5.385, P = 0.005), memory and concentration complaints (OR = 1.915, 95% CI: 1.034-3.546, P = 0.039) and some of urinary symptoms such as frequency (OR = 2.108, 95% CI: 1.015-4.375, P = 0.045) were seem to be the significant predictors. Fatigue was also found to be the most powerful predicting factor for tertiary SD (OR = 2.793, 95% CI: 1.358-5.744 P = 0.005). CONCLUSION: SD, a common multifactorial problem among MS women, can arise at any time during the disease and with any level of disability. However, we found relationships between SD and some of clinical variables and symptoms. Understanding these relationships would help us to develop practical approach and treatment for SD. PMID- 24949029 TI - The effective comparison between emotion-focused cognitive behavioral group therapy and cognitive behavioral group therapy in children with separation anxiety disorder. AB - BACKGROUND: Emotion-focused cognitive behavioral therapy (ECBT) is a new form of CBT with emotion regulation components. This form of treatment is suggested to be employed to improve dysregulation of anxiety and other kind of emotions in anxious children. This study observed and compared the effectiveness of CBT and ECBT on anxiety symptoms; sadness and anger management; and cognitive emotion regulation strategies in children with separation anxiety disorder (SAD). MATERIALS AND METHODS: This study is a randomized clinical trial. Subjects were 30 children from 9 to 13-years-old (15 girls and 15 boys) with diagnosis of SAD, being randomly assigned to CBT, ECBT, and control groups (five girls and five boys in each group). Subject children in CBT group participated in 10-h weekly sessions within Coping Cat manual; whereas, subject children in ECBT group contributed in 12-h weekly sessions within ECBT. The control group received no treatment. The Screen for Child Anxiety Related Emotional Disorders (SCARED; child and parent forms), Children's Emotion Management Scale (CEMS; anger and sadness forms), and Cognitive Emotion Regulation Questionnaire (CERQ) tests administered to all subjects in pretest, posttest, and the follow-up measurement (3 months later). Analysis of covariance (ANCOVA) repeated measure and Kruskal Wallis were applied to analyze data by Statistical Package for Social Sciences (SPSS) software package (v. 20). RESULTS: CBT and ECBT; demonstrated no significant difference in reducing separation anxiety and total anxiety symptoms from parent and children's reports. ECBT effectively increased anger coping and decreased negative cognitive strategies and dysregulation of anger in children, both in posttest and follow-up. Also, ECBT reduced sadness dysregulation and increased sadness coping, though these significant advantages were lost in 3 months later follow-up. CBT reduced negative cognitive strategies in follow-up and increased sadness coping in posttest. None of treatments affected on anger and sadness inhibition and positive cognitive coping in separation anxious children. CONCLUSION: ECBT, in comparison with CBT; effectively improved emotion regulation strategies in children with separation anxiety. PMID- 24949031 TI - Sexual dimorphism in ratio of second and fourth digits and its relationship with metabolic syndrome indices and cardiovascular risk factors. AB - BACKGROUND: Ratio of second and fourth digit (2D:4D) is known to be germane in analyzing utero concentrations of testosterone and estrogen in human and other vertebrates. 2D:4D had been linked to several traits like athletes' abilities, reproductive success, risk of cancer and cardiovascular disease (CVD). Metabolic syndrome (MetS) is a clustering of several cardiovascular risk factors. Waist circumference (WC), neck circumference (NC), body mass index (BMI) and waist-to height ratio (WHtR) are important in measuring MetS. This study investigated sexual dimorphism in 2D:4D and its relationship with MetS indices and CVD factors among adult residing in Ilorin, North central Nigeria. MATERIALS AND METHODS: This is a cross-sectional, stratified multi-staged sampling study. Participants residing in different neighborhoods were visited at home where finger lengths and anthropometric traits were measured. Participants include 801 healthy adults aged 18-44 years (56% male) who had been living in the area for more than 3 years. RESULTS: Males showed significantly lower 2D:4D than females (unpaired t-test; t [699] = 11.49, P = 0.001). A significant positive correlation was observed in MetS markers and 2D:4D. WHtR showed the highest correlation with 2D:4D in male (r = 0.461, P <= 0.001) and female (r = 0.408, P <= 0.001) when compared with BMI, NC and WC. All positive correlations recorded in this study were high in male and right hand. CONCLUSION: Our results showed that 2D:4D is sexual dimorphic and right hand 2D:4D as a predictor of MetS is better. We concluded that 2D:4D is a proxy for MetS and CVD risk factors in Ilorin. PMID- 24949032 TI - Aftercare services for patients with severe mental disorder: A randomized controlled trial. AB - BACKGROUND: Although evidences emphasize on the importance of aftercare programs to achieve continuity of care, different studies have revealed controversial results about the outcome. The objective of this study was to investigate the effect of aftercare program on outcome measures of patients with severe mental disorders. MATERIALS AND METHODS: Of a total 123 eligible patients with severe mental disorders, 61 patients were randomly assigned to the intervention group and 62 patients to the control group. The interventions included follow-up phone calls, home visits, and psychoeducation for families. Assessments were performed on hospital admission, discharge and the following 3(rd), 6(th) and 12(th) month. Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), Clinical Global Impression (CGI), and the World Health Organization Quality of Life Questionnaire (WHO-QOL) were used. Data were analyzed through Chi square, t-test, Mann-Whitney-U, and Repeated Measures Analysis of Co-Variance. RESULTS: Mean of the HDRS scores revealed significant difference between the two groups when HDRS scores on the admission day were controlled (P = 0.028). The level of functioning was significantly different between the two groups based on the sequential assessments of GAF (P = 0.040). One year after the onset of trial, the number of psychiatric readmissions were significantly different between the two groups (P = 0.036). CONCLUSION: Readmission rates could be reduced by aftercare services, through the first year, after discharge of patients with severe mental disorders. On the other hand, higher levels of functioning would be expected after one year. PMID- 24949033 TI - Impacts of highly active antiretroviral therapy (HAART) on metabolic status of patients with AIDS: What happens from the initiation of AIDS to the initiation of treatment? AB - BACKGROUND: Our study aimed to determine if alteration of metabolic parameters is associated with the severity of human immunodeficiency virus (HIV) infection, progress to acquired immunodeficiency syndrome (AIDS), or with the type of antiretroviral treatment (ART). MATERIALS AND METHODS: In a cross-sectional study among 114 HIV infected patients, we measured hematological and biochemical parameters to assess metabolic alterations according to the disease process and anti-retroviral treatment. RESULTS: Of 114 HIV-positive patients, there were 82 AIDS patients receiving ART and 32 HIV patients without treatment. Alkaline phosphatase and parathyroid hormone (PTH) had lower serum levels in HIV patients with CD4(+) cell count <=250 (P < 0.01). CD4(+) cell count was higher in patients receiving Protease Inhibitors (PI) and Nucleoside Reverse Transcriptase Inhibitors (NRTI) regimen compared with those treated with Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) and NRTI or NRTI alone. Calcium (Ca) serum level was lower in patients with only NRTI regimen while Phosphorus (P) serum level was higher in patients on NNRTI and NRTI (P < 0.05). CONCLUSION: CD4(+) cell count <=250 cells/MUl in HIV-positive patients is associated with decreased level of triglyceride and PTH. Moreover, patients receiving NRTI regimen alone have lower Ca level while this regimen in combination with NNRTI or PI has a positive correlation with P serum level. PMID- 24949034 TI - Fordyce happiness program and postpartum depression. AB - BACKGROUND: Postpartum depression is endangering the health of mothers and has negative impacts on the evolution of social communication and newborns evolution. This study was conducted to determine the effects of Fordyce Happiness program on the postpartum depression. MATERIALS AND METHODS: This quasi-experimental intervention carried out on postpartum mothers that referred to 4 health centers in Isfahan. A total of 133 mothers were selected by convenient sampling and then randomly allocated in two groups (63 and 70 mothers for intervention and control respectively). Maternal depression 3 times before, immediate and 1 months after intervention in both groups was evaluated with Beck Depression Inventory-II Persian standardized questionnaires. Educational sessions based on the Fordyce happiness program were conducted for intervention group. Data was analyzed in SPSS17 (SPSS Inc, Chicago, Illinois) descriptive and analytic statistical tests at significance level of 0.05. RESULTS: No significant differences in demographic variables between the two groups (P >= 0.05). No significant differences in depression scores in the two groups before training. However after 2 months a significant difference in depression score was observed between two groups (control group: 19.38 +/- 3.94; intervention group: 16.24 +/- 4.8; P < 0.001). Furthermore in intervention group showed significant differences in depression scores before and after intervention (19.15 +/- 3.41 and 16.24 +/- 4.83; P < 0.001). However in the control group had not any significant change. CONCLUSION: Fordyce happiness program was effective in reducing postpartum depression in our study. With attention to the effectiveness and low cost of this program, it is recommended that this program might be considered for all mothers after childbirth in health centers or other community-based settings. PMID- 24949035 TI - The association between forced expiratory volume in one second (FEV1) and pulse oximetric measurements of arterial oxygen saturation (SpO2) in the patients with COPD: A preliminary study. AB - BACKGROUND: The study was aimed to explore the association between arterial oxygen saturation (SpO2) and spirometer parameters of disease severity in chronic obstructive pulmonary disease (COPD) patients with a view to identify whether the pulse oximetry can be used as an alternative to arterial values in the clinical management of COPD patients in a routine practice. MATERIALS AND METHODS: Thirty one patients with COPD were included in this study. After evaluation of each patient through history taking, physical examination and chest X-ray, SpO2 % and data regarding spirometry (FEV1% predicted and FEV1/FVC % predicted) in all patients were measured. Linear correlations among the variables were analyzed using the regression analysis. RESULTS: In total 31 COPD patients according to the criteria established by the Global Initiative for Chronic Obstructive Disease (GOLD) were included in the study. There was not statistically significant correlation between FEV1 % predicted and SpO2 values (P > 0.05), but a great correlation existed between FEV1/FVC % predicted and SpO2 values (r = 0.556, P < 0.001). Median SpO2 values did not differ between GOLD stages (Kruskal-Wallis test: P = 0.17). CONCLUSION: The study may demonstrate that oxygen saturation measured by pulse oximetry appears to be independent of the degree of airways obstruction as quantified by the FEV1; although further evidence needs to be assessed these preliminary findings. PMID- 24949036 TI - Serum uric acid level and its association with cardiometabolic risk factors in prediabetic subjects. AB - BACKGROUND: Excess serum uric acid (UA) accumulation can lead to various diseases. Increasing evidences reveal that UA may have a key role in the pathogenesis of metabolic syndrome. Little is known about the associations of UA levels with cardiometabolic risk factors in prediabetic individuals. This study was designed to evaluate the association between UA and cardiometabolic risk factors in prediabetic subjects with family history of diabetes compared with those with normal glucose tolerance (NGT). MATERIALS AND METHODS: In a cross sectional setting, a sample containing 643 (302 prediabetic subjects and 341 normal) of the first-degree relatives of diabetic patients aged 35-55-years old were investigated. Samples were assessed in prediabetic and normal groups using glucose tolerance categories. Prediabetes was defined based on American Diabetes Association (ADA) criteria. Body weight and height, systolic and diastolic blood pressure (SBP and DBP), UA, creatinine (Cr), albumin (Alb), fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and lipid profiles were measured and compared between two groups. RESULTS: Prediabetic persons were older and obese than normal persons. Also, prediabetic persons (5.2 +/- 1.3 mg/dl) had significantly higher UA than normal persons (4.9 +/- 1.4 mg/dl) (P < 0.05). FBG after 0, 30, 60, and 120 min in prediabetic were higher than normal persons (P < 0.001). With respect to metabolic parameters, the patients in the higher UA quartiles exhibited higher levels of body mass index (BMI), SBP, FBG and triglycerides (TG). The higher quartiles of UA tended to be associated with higher BMI and higher total cholesterol (TC) in females prediabetic persons. Based on logistic regression analysis in different models, UA was positively (odds ratio (OR) >1, P < 0.05) associated with glucose tolerance categories. This association remained statistically significant after adjusting the effects of age and BMI. Also, the association between glucose tolerance categories and UA were positively significant in both genders. CONCLUSION: High UA level was associated with some cardiometabolic risk factors in prediabetic individuals compared with normal person. UA level was also a significant predictor for prediabetes condition. PMID- 24949037 TI - Weight loss maintenance: A review on dietary related strategies. AB - BACKGROUND: Weight regain after weight loss is a common problem for all those obese or overweight who have had a recent weight loss. Different cures such as diet therapy, behavioral therapy, exercise or a mixture of them have been advised as solutions. The purpose of this review is to find the best diet or eating pattern to maintain a recent weight loss. MATERIALS AND METHODS: WE SEARCHED IN PUBMED AND SCOPUS BY USING THE FOLLOWING KEY WORDS: Overweight, obesity, weight maintenance, weight regain, and diet therapy. Finally, we assessed 26 articles in the present article. RESULTS: Meal replacement, low carbohydrate-low glycemic index (GI) diet, high protein intake, and moderate fat consumption have shown some positive effects on weight maintenance. However, the results are controversial. A Dietary Approach to Stop Hypertension (DASH)-type diet seems helpful for weight maintenance although the need for more study has remained. Some special behaviors were associated with less weight regain, such as, not being awake late at night, drinking lower amount of sugar-sweetened beverages, and following a healthy pattern. Some special foods have been suggested for weight maintenance. However, the roles of specific foods are not confirmed. CONCLUSION: Healthy diets recommend low carbohydrate, low GI, and moderate fat foods, but it is not clear whether they are useful in preventing weight gain. It seems that consuming fewer calories helps people to keep weight loss. Further research to find strategies in obesity management focusing on successful maintenance of weight loss is needed. PMID- 24949038 TI - Successful management of multiple small bowel perforations due to polyarteritis nodosa. AB - Classic Polyarteritis nodosa (PAN)) is a medium-sized vessel vasculitis that usually occurs in middle-aged men. One of the dramatic manifestations of PAN that requires surgical intervention is multiple small bowel perforations. Many studies have reported a high rate of mortality in PAN due to acute abdominal complications. We report here the case of multiple small bowel perforations in a 22-year-old man, who presented with an acute abdomen, and eventually, PAN was diagnosed. In our case, PAN led to multiple small bowel perforations and diffuse patchy necrosis. All perforations were primarily repaired and corticosteroids were prescribed. Using corticosteroid in patients with abdominal sepsis is injurious; however, laparostomy is the method we suggest, to achieve the purpose, including prevention of a short bowel and infection control. Our patient was discharged, well, after 48 days of hospitalization and referred to a rheumatologist. PMID- 24949039 TI - An isolated renal hydatid cyst in a 6-year-old child: A rare case report. AB - Isolated involvement of the kidney is rare in hydatid disease and is even rarer in children. We present a case of primary right renal hydatid cyst in 6-year-old female child who presented with pain right flank of 4 months duration. The patient was managed by nephrectomy. PMID- 24949040 TI - A new option for treatment of postoperative pancraticojejunal anstomosis leakage in pancraticoduodenectomy: Easy and safe. PMID- 24949041 TI - Coexistence of Takayasu's arteritis, ulcerative colitis, and stroke: A letter to the editor. PMID- 24949042 TI - Anesthesiological approach to a case with FAHR syndrome. PMID- 24949043 TI - Retraction notice. PMID- 24949044 TI - Posterior reversible encephalopathy syndrome in pediatric hematologic-oncologic disease: literature review and case presentation. AB - OBJECTIVE: Posterior reversible encephalopathy syndrome (PRES) is a cliniconeuroradiological disease entity, which is represented by characteristic magnetic resonance imaging (MRI) findings of subcortical/cortical hyperintensity in T2-weighted sequences. It is more often seen in parietaloccipital lobes, and is accompanied by clinical neurological changes. PRES is a rare central nervous system (CNS) complication in patients with childhood hematologic-oncologic disese and shows very different neurological symptoms between patients, ranging from numbness of extremities to generalized seizure. In this article, we will review PRES presentation in hematologic-oncologic patients. Then, we will present our patient, a 7-year-old boy with Evans syndrome on treatment with cyclosporine, mycophenolate mofetil (MMF) and prednisone, with seizure episodes and MRI finding in favour of PRES. PMID- 24949045 TI - Efficacy of chloral hydrate-hydroxyzine and chloral hydrate-midazolam in pediatric magnetic resonance imaging sedation. AB - OBJECTIVE: Magnetic resonance imaging (MRI) is a useful diagnostic tool for the evaluation of congenital or acquired brain lesions. But, in all of less than 8 year-old children, pharmacological agents and procedural sedation should be used to induce motionless conditions for imaging studies. The purpose of this study was to compare the efficacy and safety of combination of chloral hydrate hydroxyzine (CH+H) and chloral hydrate-midazolam (CH+M) in pediatric MRI sedation. MATERIALS & METHODS: In a parallel single-blinded randomized clinical trial, sixty 1-7-year-old children who underwent brain MRI, were randomly assigned to receive chloral hydrate in a minimum dosage of 40 mg/kg in combination with either 2 mg/kg of hydroxyzine or 0.5 mg/kg of midazolam. The primary outcomes were efficacy of adequate sedation (Ramsay sedation score of five) and completion of MRI examination. The secondary outcome was clinical side effects. RESULTS: Twenty-eight girls (46.7%) and 32 boys (53.3%) with the mean age of 2.72+/-1.58 years were studied. Adequate sedation and completion of MRI were achieved in 76.7% of CH+H group. Mild and transient clinical side-effects, such as vomiting of one child in each group and agitation in 2 (6.6 %) children of CH+M group, were also seen. The adverse events were more frequent in CH+M group. CONCLUSION: Combinations of chloral hydrate-hydroxyzine and chloral hydrate-midazolam were effective in pediatric MRI sedation; however, chloral hydrate-hydroxyzine was safer. PMID- 24949046 TI - Acquired CNS Demyelinating Syndrome in Children Referred to ShirazPediatric Neurology Ward. AB - OBJECTIVE: Incidence of CNS acquired demyelinating syndrome (ADS), especially multiple sclerosis (MS) in children, appears to be on the rise worldwide. The objective of this study was to determine prevalence, clinical presentation, neuroimaging features, and prognosis of different types of ADS in Iranian children. MATERIALS & METHODS: During the period 2002-2012, all the patients (aged 1-18 years) with ADS, such as MS, acute disseminated encephalomyelitis (ADEM), optic neurotic (ON), Devic disease, and transverse myelitis (TM), referred to the pediatric neurology ward, Nemazee Hospital, Shiraz University of Medical Sciences, were included in this study. Demographic data, clinical signs and symptoms, past and family history, preclinical findings, clinical course, and outcome were obtained. RESULTS: We identified 88 patients with ADS in our center. The most prevalent disease was MS with 36.5% (n=32), followed by AEDM 26.1% (n=31), ON 17% (n=13), TM 15.9% (n=14), and Devic disease 4.5% (n=4). MS, ON, TM were more common among females while ADEM was more common in males. Children with ADEM were significantly younger than those with other types of ADS. Family history was positive in 10% of patients with MS. Previous history of recent infection was considerably seen in cases with ADEM. Clinical presentation and prognosis in this study was in accordance with those in previous studies on children. CONCLUSION: In this study, the most common type of ADS was MS, which was more common in female and older age cases. ADEM was more common in male and younger children. ADEM and ON had the best and Devic disease had the worst prognosis. PMID- 24949047 TI - The Etiology, Clinical Type, and Short Outcome of Seizures in NewbornsHospitalized in Besat Hospital/Hamadan/ Iran. AB - OBJECTIVE: Seizures in neonates are very different from those of older children and adults. The aim of this study was to determine the etiology, clinical presentation, and outcome of seizures in hospitalized neonates of Besat Hospital, Hamadan, Iran. MATERIAL & METHODS: In this retrospective study, we evaluated all neonates with seizures (aged 0-28 days) admitted to the Besat hospital, Hamadan, over a period of three years from September 2008 to September 2011. The data were obtained from hospital records and analyzed using SPSS 12. RESULTS: Seizures were reported in 102/1112 (9.1%) neonatal admissions. Among neonates with seizures, 57% were male and 23.5% were preterm. The mean birth weight was 2936+/-677 grams and the mean gestational age was 37.60+/-1.94 weeks. 16.7% of them were LBW and 2.9% VLBW. In terms of seizure type, subtle seizures were observed in 38.2%, tonic in 29.4%, clonic in 26.4%, and myoclonic in 5.9% of cases. The main diagnosis in neonates with seizures included hypoxic-ischemic encephalopathy (HIE) (34.3%), infections (24.4%), intracranial hemorrhage (6.9%), hypoglycemia (5.9%), hypocalcemia (2.9%), inborn error of metabolism (1%), and unknown cause (24.5%). The mortality rate was 14.7%. CONCLUSION: Neonatal seizures indicate a significant underlying disease. HIE was the most common cause of neonatal seizures in our study. Therefore, efforts should be made to improve care during childbirth. PMID- 24949048 TI - Prevalence of epileptiform discharges in children with sensori-neural hearing loss and behavioral problems compared to their normal hearing peers. AB - OBJECTIVE: Overactivity and behavioral problems are common problems in children with prelingually profound sensorineural hearing loss (SNHL). Data on epileptiform electroencephalography (EEG) discharges in deaf children with psychological disorders are so limited. The primary focus of this study was to determine the prevalence of epileptiform discharges (EDs) in children with SNHL and overactivity or behavioral problems. MATERIALS & METHODS: A total of 262 patients with prelingually profound SNHL who were referred to our cochlear implantation center between 2008 and 2010 were enrolled in this study. Children with SNHL who had diagnosis of overactivity and/or behavioral problems by a pediatric psychiatrist, underwent electroencephalography (EEG). EEG analysis was carried out by a board-certified pediatric neurologist. The control group consisted of 45 cases with overactivity or behavioral problems and normal hearing. RESULTS: One hundred thirty-eight children with mean age of 3.5+/-1.23 year were enrolled in the case group, of whom 88 cases (63.7%) were boy. The control group consisted of 45 cases with mean age of 3.2+/-1.53 years, of whom 30 (66.6%) cases were male. EDs were detected in 28 (20.02%) children of the case group (with SNHL) in comparison with 4 (8.88%) in the control group (without SNHL), which was statistically significantly different. CONCLUSION: In this study, we obtained higher frequency of EDs in deaf children with overactivity and/or behavioral problem compared to the children without SNHL. Further studies are required to evaluate the possible association of SNHL with EDs in overactive children. PMID- 24949049 TI - A Study of Methadone-Poisoned Children Referred to Hamadan's Besat Hospital/Iran. AB - OBJECTIVE: Increasing use of methadone in withdrawal programs has increased methadone poisoning in children. This research aimed to study the causes of incidence of poisoning in children and its side-effects. MATERIALS & METHODS: In this research, The hospital records of all methadone-poisoned children referred to Hamadan's Be'sat Hospital from June 2007 to March 2013, were studied. Children with a definite history of methadone use or proven existence of methadone in their urine, were studied. RESULTS: During 5 years, 62 children with the mean age of 53.24+/-29.50 months were hospitalized due to methadone use. There was a significant relationship between delayed referral to hospital and increased bradypnea. According to their history, 25.8% and 58.1% of the children had been poisoned by methadone tablet and syrup, respectively. The most common initial complaint expressed by parents, was decreased consciousness (85.5%). During the initial examination, decreased consciousness, meiosis, and respiratory depression were observed in 91.9%, 82.3%, and 69.4% of the cases, respectively. Nine patients required mechanical ventilation. There was a significant relationship between the need for mechanical ventilation and seizure with initial symptom of emesis. There were two cases of death (3.2%), both of which were secondary to prolonged hypoxia and brain death. There was a significant relationship between poor patient prognosis (death) and presence of cyanosis in early symptoms, seizure, hypotension, duration of decreased consciousness, and duration of mechanical ventilation. CONCLUSION: This research indicated that the occurrence of seizure, hypotension, and cyanosis in the early stages of poisoning is associated with an increased risk of side effects and death and are serious warning signs. Early diagnosis and intervention can improve outcomes of methadone poisoned children. PMID- 24949050 TI - Iron-deficiency Anemia in Children with Febrile Seizure: A Case-Control Study. AB - OBJECTIVE: Considering the recurrence of febrile seizure and costs for families, many studies have attempted to identify its risk factors. Some recent studies have reported that anemia is more common in children with febrile convulsion, whereas others have reported that iron deficiency raises the seizure threshold. This study was done to compare iron-deficiency anemia in children with first FS with children having febrile illness alone and with healthy children. MATERIALS & METHODS: This case-control study evaluated 300 children in three groups (first FS, febrile without convulsion, and healthy) in Khoramabad Madani Hospital from September 2009 to September 2010. Body temperature on admission was measured using the tympanic method. CBC diff, MCV, MCH, MCHC, serum iron, plasma ferritin and TIBC tests were performed for all participants. Data were analyzed by frequency, mean, standard deviation, ANOVA, and chi-square statistical tests. Odds ratios were estimated by logistic regression at a confidence level of 95%. RESULTS: Forty percent of the cases with FS had iron-deficiency anemia, compared to 26% of children with febrile illness without seizure and 12% of healthy children. The Odds ratio for iron-deficiency anemia in the patients with FS was 1.89 (95% CI, 1.04-5.17) compared to the febrile children without convulsion and 2.21 (95% CI, 1.54-3.46) compared to the healthy group. CONCLUSION: Children with FS are more likely to be iron-deficient than those with febrile illness alone and healthy children. Thus, iron-deficiency anemia could be a risk factor for FS. PMID- 24949051 TI - Associations between Manual Abilities, Gross Motor Function, Epilepsy, and Mental Capacity in Children with Cerebral Palsy. AB - OBJECTIVE: This study aimed to evaluate gross motor function and hand function in children with cerebral palsy to explore their association with epilepsy and mental capacity. MATERIAL & METHODS: The research investigating the association between gross and fine motor function and the presence of epilepsy and/or mental impairment was conducted on a group of 83 children (45 girls, 38 boys). Among them, 41 were diagnosed with quadriplegia, 14 hemiplegia, 18 diplegia, 7 mixed form, and 3 athetosis. A neurologist assessed each child in terms of possible epilepsy and confirmed diagnosis in 35 children. A psychologist assessed the mental level (according to Wechsler) and found 13 children within intellectual norm, 3 children with mild mental impairment, 18 with moderate, 27 with severe, and 22 with profound. Children were then classified based on Gross Motor Function Classification System and Manual Ability Classification Scale. RESULTS: The gross motor function and manual performance were analysed in relation to mental impairment and the presence of epilepsy. Epilepsy was found to disturb conscious motor functions, but also higher degree of mental impairment was observed in children with epilepsy. CONCLUSION: The occurrence of epilepsy in children with cerebral palsy is associated with worse manual function. The occurrence of epilepsy is associated with limitations in conscious motor functions. There is an association between epilepsy in children with cerebral palsy and the degree of mental impairment. The occurrence of epilepsy, mainly in children with hemiplegia and diplegia is associated with worse mental capacities. PMID- 24949052 TI - Study on MRI changes in phenylketonuria in patients referred to mofid hospital/iran. AB - OBJECTIVE: Phenylketonuria is one of the most common metabolic disorders and the first known cause of mental retardation in pediatrics. As Screening for phenylketonuria (PKU) is not a routine neurometabolic screening test for neonates in Iran, many PKU cases may be diagnosed after developing the clinical symptoms. One of the findings of PKU is myelination disorders, which is seen as hypersignal regions in T2-weighted (T2W) and FLAIR sequences of brain MRI. The aim of our study was to assess MRI changes in PKU patients referred to Mofid Children's Hospital, 2010-2011. MATERIALS & METHODS: We studied all PKU cases referred to our clinic as a referral neurometabolic center in Iran for brain MRI and assessed the phenylalanine level at the time of Imaging. The mean phenylalanine level (in one year), clinical manifestations, and MRI pattern based on Thompson scoring, were evaluated. RESULTS: The mean age of our study group was 155+/-99 months and the mean diagnosis age was 37+/-27.85 months. There were 15 patients with positive and 15 with negative family history. The mean phenylalanine level at the time of imaging was 9.75+/-6.28 and the mean 1 year phenylalanine level was 10.28+/-4.82. Seventy percent of our patients had MRI involvement, in whom 20% showed atrophic changes, in addition to white matter involvement. Based on modified Thompson scoring, the score for our study group was 4.84. The maximum involvement in MRI was in occipital region, followed by parietal, frontal, and temporal zones. There was not any correlation between MRI score and patients' age. But we found significant relationship between MRI score and the age of regimen cessation. No correlation was seen between phenylalanine level (at the time of Imaging) and MRI score. But there was a relationship between mean 1 year phenylalanine level and MRI score. CONCLUSION: According to the results of this study, brain MRI and white matter involvement can be used for evaluation of long term control of phenylalanine level in PKU cases. PMID- 24949053 TI - Levatiracetam for the management of Lance-Adams syndrome. AB - Chronic post-hypoxic myoclonus, also known as Lance-Adams syndrome (LAS) is a neurological complication characterized by uncontrolled myoclonic jerks following cardiac arrest. In this article, clinical manifestation and symptomatic treatment options are discussed especially concerning the rationale of use of levatiracetam in patients with Lance-Adams syndrome. Clinical presentation is action myoclonus associated with cerebellar ataxia, postural imbalance, and very mild intellectual deficit. An 18-year-old female patient was admitted to our intensive care unit in a coma. She had a cardiorespiratory arrest after a splenectomy in a local hospital. Then, myoclonic movements were continuously observed over the entire body, including the face. On day 14 of hospitalization, we started levatiracetam 1000 mg daily. The frequency of convulsion movements was reduced. The patient level of consciousness was 15 on the Glasgow coma scale (GCS) on the Mini-Mental State Examination (MMSE) score was 23 out of 30. She was later transferred to the rehabilitation department. Vigilance is required to ensure early diagnosis and timely intervention for the myoclonic jerks. We would like to emphasize that LAS should be considered in patients with the myoclonic jerks following cardiac arrest and that levatiracetam therapy may be useful as treatment. PMID- 24949054 TI - The acrocallosal syndrome in a neonate with further widening of phenotypic expression. AB - The presentation of the typical characteristics of the acrocallosal syndrome (ACLS) are hypoplasia/agenesis of corpus callosum, moderate to severe mental retardation, characteristic craniofacial abnormalities, distinctive digital malformation, and growth retardation in a neonate. An Indian neonate presented on day 1 of life (youngest in the literature to be reported) with combination of abnormalities consistent with the acrocallosal syndrome and some additional findings. The baby, born to non-consanguineous, healthy parents, presented with macrocephaly, prominent forehead, hypertelorism, polydactyly of the hands and feet, duplication of hallux, hypotonia, recurrent cyanotic episodes, rib anomalies, dextro-positioning of heart, and delayed fall of umbilical cord. As the mode of inheritance of ACLS is autosomal recessive, the risk of recurrence is 25%. Genetic counselling is of prime importance, Polydactyly, and central nervous system malformations can be detected by ultrasonography in the second trimester, but due to variability of presentation, prenatal diagnosis may not always be possible. PMID- 24949055 TI - A Rare presentation of neurobrucellosis in a child with Recurrent transient ischemic attacks and pseudotumor cerebri (A case report and review of literature). AB - Brucellosis is a multi-system infectious disease that presents with various manifestations and complications. Neurobrucellosis is an uncommon but serious presentation of brucellosis that can be seen in all stages of the disease. High index of suspicion, especially in endemic areas is essential to prevent morbidity from this disease. The case was an 11- year -old female patient who was admitted with a severe headache that was worsening over a period of 2 months. The day after each attack, she experienced transient right hemiparesia that was lasting less than one hour (TIA) as well as blurred vision and bilateral papilledema. Laboratory findings revealed serum agglutination Wright test positive at 1/320 and 2ME test positive at 1/160. A lumbar puncture showed a clear CSF with increased opening pressure (32 cmH2O), CSF examination was within normal range (pseudotumor cerebri).To our knowledge, there has been no report for recurrent TIA in pediatric neurobrucellosis in the base of pseudotumor cerebri. In endemic areas like Iran, unexplained neurological signs or symptoms should be evaluated for brucellosis. PMID- 24949056 TI - A report of guillain-barre syndrome with myalgia and mild weakness. AB - We report a rare case that revealed severe myalgia as the chief complaint that is not mentioned in the list of frequent symptoms of Guillain Barre. Guillain-Barre syndrome (GBS) is an acute inflammatory demyelinating polyneuropathy (AIDP).Required features for diagnosis of GBS are progressive motor weakness of more than one limb and areflexia. We report an 11-yearold boy who was referred to the emergency department with complaints of generalized body pain and gate problem. It seems that if myalgias are the chief complaint and weakness is mentioned as a less important symptom, clinicians should consider GBS after ruling out other reasons for myalgia especially inflammatory myositis. PMID- 24949057 TI - The effectiveness of a supportive educative group intervention on family caregiver burden of patients with heart failure. AB - BACKGROUND: Living with heart failure patients is a complex situation for family caregivers. Few studies have been conducted to examine the effects of interventional programs to ease this condition. The purpose of this study was to determine the effectiveness of a supportive educative group intervention in reducing family caregivers' burden of caregiving. MATERIALS AND METHODS: This randomized clinical trail was conducted at a selective teaching hospital in Isfahan, Iran in 2012. The intervention consisted of four weekly multimedia training sessions of 2 h that included education and family support for 50 family caregivers. Caregiver burden was measured using the Zarit Burden Interview (ZBI). Paired t-test, Student's t-tests, and repeated measures analysis of variance (ANOVA) were used to test for significant differences of the mean scores of burden between the intervention and control groups over a 3-month period. RESULTS: The intervention was successful in reducing caregiver burden over time both at the end of the intervention period (P = 0.000) and 3 months after the intervention (P = 0.000). CONCLUSIONS: Nurses and other healthcare providers can use the findings of this study in order to implement effective programs to reduce family caregivers' challenges and to provide them more support. PMID- 24949058 TI - Nine centuries waiting: The experiences of Iranians surrogacy commissioning mothers. AB - BACKGROUND: There are a few studies about commissioning mothers' understanding from the surrogacy during 9 months of waiting for delivery in Iran and other countries. This study was conducted with an aim to explore and explain the nature of concerns (experiences) of commissioning mothers. MATERIALS AND METHODS: A qualitative design with a conventional content analysis approach was used to gather and analyze the experiences of commissioning mothers. They were selected from Royan Research Centre and other infertility centers in Iran. After purposive sampling for the selection of the participants, unstructured interviews were held for data collection. Twenty-four unstructured interviews were conducted with 12 commissioning mothers, 2 surrogate mothers, and 2 infertility center social workers who directly and continuously dealt with these mothers. RESULTS: TWO MAIN THEMES EMERGED FROM THE DATA ANALYSIS: 1. cultural dilemma (consisting of three subthemes: Social taboo, concerns about disclosure to others and the child, concerns about altering maternal and child's identity, and 2. uncertain waiting (consisting of three subthemes: Concerns about health of fetus and surrogate, concerns about an unfamiliar surrogate, and concerns about lack of preparation for maternal role). CONCLUSIONS: The study reveals the importance of maternal emotional care in this group and introduces a new arena for nurses' activity. These findings help the mothers by nurses' activities in health care clinics and anywhere they deliver nursing care. PMID- 24949059 TI - The effect of midwifery continuing care on childbirth outcomes. AB - BACKGROUND: Continuation of delivery care by a midwife, and establishing a relationship between the midwife and the delivering woman, is so important for women, and preserving such relationship increases woman's calmness and self confidence. The current research aims at studying the effect of midwifery continuing care during delivery on delivery outcomes. MATERIALS AND METHODS: This study was a quasi-experimental research conducted on childbearing women referring to Tabriz 29 Bahman Hospital. One hundred women were randomly assigned to either experimental (n = 50) or control (n = 50) group. In the experimental group, the women were cared exclusively with a midwife from the active phase continuously, while in the control group, women were cared with several midwifes conventionally. The birth outcomes were recorded in both valid and reliable groups (checklists). Data were analyzed using SPSS version 13.0. RESULTS: Type of delivery was the same in both the groups (P = 0.051). In the experimental group, grade of the perineal lacerations was lower (P = 0.001); also, in this group, less oxytocin was used in the labor stage (P = 0.001). CONCLUSIONS: The results showed that providing one-to-one delivery care and continuous attendance of the midwife on the bedside of delivering woman had positive effect on improvement of birth outcomes. So, providing the choice of one-to-one care for women in delivery rooms must be considered where it is logistically possible. PMID- 24949060 TI - The effect of recommended Azkar on anxiety, stress, and depression in families of patients undergoing open heart surgery. AB - INTRODUCTION: Admission of a family member to hospital would cause stress on other family members also. One of the most stressful treatment interventions imposing high level of anxiety to the families of patients is when the patients are undergoing a surgery, especially a cardiac surgery. So, we decided to investigate whether recommended Azkar could reduce stress, anxiety, and depression in families of the patients. MATERIALS AND METHODS: This study is a quasi-experimental study conducted on 120 immediate relatives of patients undergoing a cardiac surgery. Families of patients undergoing open heart surgery were randomly divided into two groups of study and control. The Depression, Anxiety, and Stress Scales (DASS 21) questionnaires were completed by both groups. Then, some explanations about how to use recommended prayers were given to the study group, and an hour later, the questionnaires were completed again. The data were analyzed by SPSS. P < 0.05 were considered significant. RESULTS: Stress, anxiety, and depression showed a significant difference in the study group before and after intervention. Similarly, there was a significant difference in the mean scores of anxiety, stress, and depression in the study and control groups after intervention. CONCLUSIONS: Findings of the present study showed that recommended religious prayers can significantly reduce anxiety, depression, and stress of families of the patients undergoing open heart surgery. PMID- 24949061 TI - Nursing students' spiritual well-being, spirituality and spiritual care. AB - BACKGROUND: Spiritual care should be considered an important part of holistic and multidisciplinary care and it has not been given much importance so far. We should begin with student nurses, who will soon be clinicians, to find out about potentiality of the nursing profession to put spiritual care into practice. Little has been known about spiritual well-being, spirituality, and spiritual care perspectives among nursing students. In this study, a comparison has been made in spiritual well-being, spirituality, and spiritual care perspectives between the first and fourth year baccalaureate nursing students. MATERIALS AND METHODS: This is a descriptive-comparative study that was carried out among 283 nursing students. All the students were Iranians studying in the universities of Iran, Tehran, and Shahid Beheshti medical sciences. They volunteered to participate in the study. There were 105 first year students and 178 fourth year students. The questionnaires used were on Spiritual Well-being (SWB) Scale, Spiritual Perspective Scale (SPS), and Nursing Spiritual Care Perspective Scale (NSCPS). The statistical analysis was performed using the SPSS software, version 10. The data were analyzed using descriptive statistics (distribution frequency, mean, and standard deviation). Mann-Whitney test was to compare each item and independent t-test to compare the mean values of two groups. RESULTS: Regarding spiritual well-being, there were no significant differences between the two groups. 98.8% of the first year students and 100% of the fourth year students were in the category of moderate spiritual well-being. Neither were there any significant differences between the two groups in spiritual perspective and spiritual care perspectives. CONCLUSIONS: The scores of fourth year nursing students were similar to those of first year students in spiritual well-being, spirituality, and spiritual care perspectives, though the fourth year students had already undergone 4-year nursing course. Including spiritual care in the curriculum of nursing students' courses will add to their understanding and provision of spiritual care. This will fill the present gap evident in the system in Iran. At present, the educational system here does not make use of spiritual care as part of its comprehensive curriculum. PMID- 24949062 TI - Experiences of role model instructors and nursing students about facilitator factors of role-modeling process: A qualitative research. AB - BACKGROUND: One of the key strategies in students' learning is the influence of models on them. Understanding the factors affecting the implementation of role modeling process in education will help to make greater use of this training strategy. This study aimed to understand the experiences of role model instructors and nursing students about the facilitator factors in the role modeling process. MATERIAL AND METHODS: This qualitative study was carried out by using thematic analysis method and purposeful sampling. Data were collected until saturation by using three focus group discussions (n = 20) and two individual interviews with nursing instructors, as well as six semi-structured face-to-face interviews with role model instructors from five nursing faculties of Tehran universities in 2011. RESULTS: Six themes, "effort for humanistic and professional growth of students," "individual and managerial empowerment of instructor," "instructor and student's modeling," "motivation and effort of student," "strategies governing the education system," and "appropriate facilities and equipment," were extracted as the facilitating factors. CONCLUSIONS: For development of role-modeling process in nursing education, paying attention to personal and environmental factors, especially effort for professional and humanistic growth of nursing students is necessary. PMID- 24949063 TI - Experiences of hospitalization in patients with multiple sclerosis: A qualitative study. AB - BACKGROUND: Patients with multiple sclerosis experience hospitalization several times in their lives. Certainly, providing efficient and high-quality care by healthcare professionals is not possible unless the experiences of patients' hospitalization are taken into consideration. This qualitative study was aimed to identify experiences of patients with multiple sclerosis in their hospitalization. MATERIALS AND METHODS: A qualitative content analysis method was used to conduct this study. The study participants were 25 patients with multiple sclerosis, who were chosen by purposeful sampling. Data were collected through non-structured interviews. RESULTS: The analysis resulted in the emergence of 4 themes and 11 subthemes. The main themes were: Religiosity, emotional reactions, seeking support, and feeling of being in a cage. CONCLUSIONS: Awareness of families and healthcare providers of the reactions of patients with multiple sclerosis to hospitalization will help them to deal effectively with patients and to improve relationships with them. However, by understanding the patients' experiences, the practitioners gain expertise and can join in the patients' health journey in a therapeutic way during the hospitalization period. In addition, the findings can serve to create a framework for developing nursing care processes including informational and supporting programs for multiple sclerosis patients during hospitalization while taking into consideration patients' needs and cultural backgrounds. PMID- 24949064 TI - Triple-blind, placebo-controlled trial of Ginkgo biloba extract on sexual desire in postmenopausal women in Tehran. AB - BACKGROUND: During the menopausal period, sexual desire may decrease. Therefore, restoring the sexual desire may help to improve sexual functioning in this group of women. The aim of this study was to examine the effect of Ginkgo biloba extract (GBE) on sexual desire in postmenopausal women. MATERIALS AND METHODS: In this triple-blind, randomized, placebo-controlled trial, 80 healthy female volunteers attending three healthcare centers of Tehran University of Medical Sciences (TUMS) were enrolled. The instrument of this study had two main parts. The first part covered the personal characteristics of the volunteers and the second part used the Sabbatsberg Sexual Rating Scale (SSRS) to subjectively evaluate sexual desire before and after intervention. The participants received GBE at a dose of 120-240 mg (n = 40) or received placebo (n = 40) daily for 30 days. The results were analyzed using Mann-Whitney test. All analyses were performed using SPSS software. RESULTS: The sexual desire was significantly improved in the GBE group compared to the placebo group (P = 0.02). CONCLUSIONS: In this study, we found that GBE had a positive effect on sexual desire of menopausal women; thus, these findings support the positive effect of GBE on the sexual function of menopausal women. PMID- 24949065 TI - What are the people's attitudes toward spinal cord injury victims (from common to elite). AB - BACKGROUND: One of the acutely fatal and prevalent crises in all societies is acute spinal cord injury. Individuals with a spinal cord injury are prone to numerous challenges, perturbation, and acute mental distresses. One of their concerns, often expressed generally and in the form of a complaint, is how people deal with them. The present study aims to analyze the experiences and interactions of the disabled with the society and to achieve a deep clarification of their internal attitudes and realistic approaches in various social classes (from common people to elite). MATERIALS AND METHODS: The present study is a part of a greater research with a classical grounded theory approach conducted on 12 successful and nationally and internationally popular disabled people. Sampling was firstly purposive and then continued with snowball sampling. The data were collected by open deep interviews which were recorded and transcribed verbatim. The obtained data were analyzed by Graneheim content analysis method. RESULTS: The findings obtained through analysis of the interviews yielded the theme of a socially suppressing attitude which contained four subthemes of compassionate attitude, disability attitude, inhuman attitude, and atonement attitude. CONCLUSIONS: The results showed that both groups of common, and educated and elite classes of Iranian society have identically suppressing attitudes and interactions toward spinal cord injury victims. It seems that traditional attitudes yet preponderate academic and scientific knowledge in Iranian society. This gap needs notable attention of all the Iranians, especially policy makers and social personalities. PMID- 24949066 TI - Developing a readiness assessment tool for weaning patients under mechanical ventilation. AB - BACKGROUND: Mechanical ventilation is one of the major supportive interventions in intensive care units. Weaning the patients from mechanical ventilation and its related criteria are of great importance due to the related complications. As there is no comprehensive standard to allocate the time of weaning and due to lack of local research in this field, development of a comprehensive tool to measure patients' readiness for weaning from mechanical ventilation is essential. Therefore, the present study was conducted with an aim to develop a readiness assessment tool for weaning patients from mechanical ventilation. MATERIALS AND METHODS: This was a qualitative study with Delphi multi-triangulation design. In the first stage, the related items were extracted from the textbook and through searching the databases. In the second stage, after primary development of the items and based on supervisors' indications, a questionnaire was made and used for assessment through Delphi methods. Twenty individuals, meeting the inclusion criteria, were selected through purposive sampling and their viewpoints concerning acceptability of the items were collected. In the third stage, the items with appropriateness over 70% were selected, and in the fourth stage, the final questionnaire was developed after a session with a panel of experts and supervisors. In the present study, in the first stage, the needed items were collected from various articles and books to provide items extraction. In stages two to four, manual calculation and investigation made by a panel of experts and the research team were adopted. RESULTS: In the first stage, 100 articles and 51 related books were selected. In the second stage, 87 items were extracted from the articles and books and were sent as semi-open questions of assessment. In the third stage, 28 items with consensus >70% were extracted, and in the fourth stage, 26 items were selected by a panel of experts and the finalized questionnaire with the title "Persian Weaning Tool" (PWT) was developed in three domains: Respiration with 9 items, cardiovascular with 4 items, and other related factors with 13 items. CONCLUSIONS: A three-domain questionnaire is the product of experts' consensus in the present study, which can be used to reduce the length of connection to mechanical ventilation and its complications. PMID- 24949067 TI - Compassion fatigue and burnout in Iranian nurses: The role of perceived social support. AB - BACKGROUND: Nurses are at risk for symptoms of compassion fatigue (CF) and burnout (BO). Social support plays an important role in predicting CF and BO. This study was performed to determine the prevalence of the symptoms of CF and BO and the role of perceived social support in predicting these symptoms in Iranian nurses. MATERIALS AND METHODS: Using a correlational descriptive survey research design, we selected 173 participants among the nurses working in public hospitals of Malayer, Iran. Professional Quality of Life (CF and BO subscales) and Multidimensional Scale of Perceived Social Support (MSPSS) were used for collecting the data. RESULTS: The obtained results indicated that the prevalence of CF and BO symptoms was 45.3% and 15.03%, respectively, in Iranian nurses. Social support (significant other, family, and friends) was negatively correlated to BO (P < 0.01). Also, there was a negative correlation between social support from family and CF (P < 0.01). According to hierarchical multiple regressions, social support from family was the significant predictor to CF (P < 0.005) and BO (P < 0.001) in nurses. CONCLUSIONS: Based on the obtained results, some nurses (especially emergency nurses) are at risk for CF and BO and social support negatively correlated to CF and BO in Iranian nurses. It is necessary to develop support systems for nurses who are at risk for CF and BO. PMID- 24949068 TI - The effect of expiratory rib cage compression before endotracheal suctioning on the vital signs in patients under mechanical ventilation. AB - BACKGROUND: In patients undergoing mechanical ventilation, mucus production and secretion is high as a result of the endotracheal tube. Because endotracheal suction in these patients is essential, chest physiotherapy techniques such as expiratory rib cage compression before endotracheal suctioning can be used as a means to facilitate mobilizing and removing airway secretion and improving alveolar ventilation. As one of the complications of mechanical ventilation and endotracheal suctioning is decrease of cardiac output, this study was carried out to determine the effect of expiratory rib cage compression before endotracheal suctioning on the vital signs in patients under mechanical ventilation. MATERIALS AND METHODS: This study was a randomized clinical trial with a crossover design. The study subjects included 50 mechanically ventilated patients, hospitalized in intensive care wards of Valiasr and Mousavi hospitals in Zanjan, Iran. Subjects were selected by consecutive sampling and randomly allocated to groups 1 and 2. The patients received endotracheal suctioning with or without rib cage compression, with a minimum of 3 h interval between the two interventions. Expiratory rib cage compression was performed for 5 min before endotracheal suctioning. Vital signs were measured 5 min before and 15 and 25 min after endotracheal suctioning. Data were recorded on a data recording sheet. Data were analyzed using paired t-tests. RESULTS: There were statistically significant differences in the means of vital signs measured 5 min before with 15 and 25 min after endotracheal suctioning with rib cage compression (P < 0. 01). There was no significant difference in the means of diastolic pressure measured 25 min after with baseline in this stage). But on the reverse mode, there was a significant difference between the means of pulse and respiratory rate 15 min after endotracheal suctioning and the baseline values (P < 0.002). This effect continued up to 25 min after endotracheal suctioning just for respiratory rate (P = 0.016). Moreover, there were statistically significant differences in the means of vital signs measured 5 min before and 15 min after endotracheal suctioning between the two methods (P <= 0001). CONCLUSIONS: Findings showed that expiratory rib cage compression before endotracheal suctioning improves the vital signs to normal range in patients under mechanical ventilation. More studies are suggested on performing expiratory rib cage compression before endotracheal suctioning in patients undergoing mechanical ventilation. PMID- 24949069 TI - Efficacy of group meaning centered hope therapy of cancer patients and their families on patients' quality of life. AB - BACKGROUND: Quality of life (QOL) is a multidimensional concept which has nowadays turned to a supportive interventional goal in chronic diseases like cancer. Numerous interventions have been carried out to improve the QOL in patients with cancer, but the effect of indirect interventions on the patients' QOL has not been investigated yet. This study aimed to compare the efficacy of group meaning centered hope therapy of cancer patients and their families on the patients' QOL. MATERIALS AND METHODS: This is a clinical trial conducted in three groups with a pre-test post-test design in which the effect of independent variable of meaning centered hope therapy on the dependent variable of QOL was investigated. The subjects were selected from the cancer patients who were aware of their diagnosis, were in primary stages of the disease, and had passed one period of chemotherapy. In this study, 42 patients (16 in control group, 14 in patients' group therapy, and 12 in patients' families' group therapy) were studied, and WHOQOL was adopted to investigate their QOL. Data were analyzed in two forms of descriptive and inferential statistical tests. RESULTS: The results obtained showed that group meaning centered hope therapy of cancer patients and their families had a positive effect on patients' QOL compared to the control group. The notable finding of the present study was that holding group sessions either for the patients or for their families equally improved patients' QOL. CONCLUSION: QOL of the cancer patients can be improved by either group meaning centered hope therapy for patients or group meaning centered hope therapy for their families. This finding is important for therapists, as when the patients cannot attend group therapy sessions due to complications of chemotherapy, these sessions can be held for their families to improve patients' QOL. This conclusion is very helpful in nurses' interaction with the patients and their families. PMID- 24949070 TI - A study of patient safety management in the framework of clinical governance according to the nurses working in the ICU of the hospitals in the East of Tehran. AB - BACKGROUND: The improvement of patient safety conditions in the framework of clinical service governance is one of the most important concerns worldwide. The importance of this issue and its effects on the health of patients encouraged the researcher to conduct this study to evaluate patient safety management in the framework of clinical governance according to the nurses working in the intensive care units (ICUs) of the hospitals of the east of Tehran, Iran in 2012. MATERIALS AND METHODS: This descriptive study, which was based on census method, was conducted on 250 nurses sampled from the hospitals located in the east of Tehran. For the collection of data, a researcher-made questionnaire in five categories, including culture, leadership, training, environment, and technology, as well as on safety items was used. To test the validity of the questionnaire, content validity test was conducted, and the reliability of the questionnaire was assessed by retest method, in which the value of alpha was equal to 91%. RESULTS: The results showed that safety culture was at a high level in 55% of cases, safety leadership was at a high level in 40% cases and at a low level in 2.04% cases, safety training was at a high level in 64.8% cases and at a low level in 4% cases, safety of environment and technology was at a high level in 56.8% cases and at a low level in 1.6% cases, and safety items of the patients in their reports were at a high level in approximately 44% cases and at a low level in 6.5% cases. The results of Student's t-test (P < 0.001) showed that the average score of all safety categories of the patients was significantly higher than the average points. CONCLUSIONS: Diligence of the management and personnel of the hospital is necessary for the improvement of safety management. For this purpose, the management of hospitals can show interest in safety, develop an events reporting system, enhance teamwork, and implement clinical governance plans. PMID- 24949071 TI - Influencing factors on professional commitment in Iranian nurses: A qualitative study. AB - BACKGROUND: Dissatisfaction and tending to leave are some of the major nursing problems around the world. Professional commitment is a key factor in attracting and keeping the nurses in their profession. Commitment is a cultural dependent variable. Some organizational and socio-cultural factors are counted as the drivers of professional commitment. This study aimed to explore factors influencing the professional commitment in Iranian nurses. MATERIALS AND METHODS: A qualitative content analysis was used to obtain rich data. We performed 21 in depth face-to-face semi-structured interviews. The sampling was based on the maximum variation with the staff nurses and managers in 5 university affiliated hospitals. Constant comparative method used for data analysis. RESULTS: TWO MAIN CATEGORIES WERE EMERGED: "Challenging with different feelings" and "Managers' role". Challenging with different feelings had two subcategories: "Burnout" and "sense of valuing". The other theme was composed of three subcategories: "Gratitude or punishment climate", "manager's view of caring" and "knowledge based vs. routine-based nursing". CONCLUSIONS: Findings revealed the burnout as a common sense in nurses. They also sensed being valued because of having a chance to help others. Impediments in the health care system such as work overload and having more concern in the benefits of organization rather than patient's care and wellbeing lead to a sense of humiliation and frustration. Congruence between the managers and nurses' perceived values of the profession would be a main driver to the professional commitment. Making a sense of support and gratitude, valuing the care and promoting the knowledge-based practice were among the other important factors for making the professional commitment. PMID- 24949072 TI - Association between shift working and musculoskeletal symptoms among nursing personnel. AB - BACKGROUND: Some health problems are more prevalent in shift workers than day workers. Musculoskeletal disorders are considered as one of the most common health-related problems that can cause disability among health care workers. The aim of this study was to assess the associations between shift working and the prevalence of musculoskeletal symptoms (MSs) among nursing personnel. MATERIALS AND METHODS: This study was conducted among 454 health care workers including nurses and nurses' aides in a general hospital in Iran. A Nordic musculoskeletal questionnaire was used to evaluate the prevalence of MSs. Logistic regression analysis with adjusting for confounding factors was performed to evaluate the associations between shift working and the prevalence of MSs. RESULTS: Lower back, knees, and upper back symptoms with the prevalence of 57.4%, 48.4%, and 47%, respectively, were the most common MSs. The prevalence of MSs in eight regions of the body (lower back, neck, knees, upper back, shoulder, wrist, buttock, and ankle) was higher among shift workers than day workers. The differences were statistically significant only in the lower back and ankle regions (P < 0.05). Odds Ratio for lower back symptoms in shift workers was 1.94 compared to day workers (P = 0.003). CONCLUSION: Findings of this study suggested that shift working could be associated with increased prevalence of lower back disorders among nursing personnel. This study emphasizes on the importance of proper work planning and regulating working hours for nursing personnel. PMID- 24949073 TI - Nurses' policy influence: A concept analysis. AB - BACKGROUND: Nurses' influence on health policy protects the quality of care by access to required recourses and opportunities. This is a new and important concept for nursing; however, research studies on policy influence of nurses in health care sector are lacking a basic conceptual understanding of what this concept represents. The aim of this paper is to clarify the concept of nurses' policy influence and to propose the definition of this concept, considering the context of Iran. MATERIALS AND METHODS: The eight stages of Walker and Avant approach was used to guide this concept analysis. Various databases and internet engines were searched to find all related information about the concept. Textbooks were also searched manually. English language literature reports published between 1990 and 2012 were reviewed. RESULTS: Based on the analysis undertaken, nurses' policy influence is nurses' ability in influencing decisions and affairs related to health through political knowledge, effective communication, and collaboration with other members of the health team, which results in the improvement of nurses' job environment and increases patient outcomes. This is a dynamic process situated on a spectrum and is accompanied with nurses' knowledge, competency, power, and advocacy, and also their ability to change. CONCLUSIONS: Nurses have individual views on health care issues and influence health care policies in different ways. With a common understanding of nurses' policy influence as a concept, nurses will recognize the importance of policy making in the health sector and their influence on this process and also on patients' outcomes. PMID- 24949074 TI - Experiences of the families concerning organ donation of a family member with brain death. AB - BACKGROUND: In recent years, the lack of organ for transplantation has resulted in health planners and authorities in all countries, including Iran, paying serious attention to the issue. Despite the above-mentioned fact, families with a member affected by brain death are not interested in organ donation. OBJECTIVE: This study is aimed at making an investigation into the decision-making process of organ donation in families with brain death. Also, the research is aimed at investigating how the deterrent and facilitating factors in the process of organ donation can be made. MATERIALS AND METHODS: The current research is a qualitative study with descriptive exploratory approach. Data were collected through unstructured interviews with 10 family members who gave consent to organ donation of their family members in 2012. Purposeful sampling processes began in March 2012 and lasted up to June 2012. Simultaneously, thematic approach was used in analyzing the data. RESULTS: Data analysis led to finding 24 categories and 11 themes, which fell into two categories: facilitating and deterrent factors. The five main deterrent themes included the five themes of prohibiting factors that were shock, hope for recovery, unknown process, and conflict of opinions, and worrying association. The six main facilitating themes included humanistic desires, immortality, culture making, satisfaction of the deceased, assurance, and eternal honor. CONCLUSION: The findings indicated that there is ambiguity and different interpretations on brain death. The research also showed that using the experiences of donator families can provide practical and applied solutions to facilitate the process of organ donation and solve the problems faced by the health care system. PMID- 24949075 TI - Do the pens used by nursing students in clinics cause bacterial contamination? AB - BACKGROUND: Health professionals and their medical equipment have long been known to act as vectors of infectious diseases. The aim of the present study was to evaluate the role of pens used by nursing students working in clinics in relation to transmission of bacteria. MATERIALS AND METHODS: The study was conducted in Sakarya University School of Health Sciences in March 2012, with the voluntary participation of 40 third-grade nursing students during their clinical practice. In total, 40 writing items were surveyed. RESULTS: Twenty-two (55%) of the students were doing their clinical practice at pediatrics department and 18 (45%) were at obstetrics and gynecology department. All the samples consisted of pens and bacterial contamination was observed in 5 (12.5%) of them. The microorganisms identified were: 1 (2.5%) sample was Staphylococcus hominis, 2 (5%) were Staphylococcus epidermidis, 1 (2.5%) was Staphylococcus haemolyticus, and 1 (2.5%) was Staphylococcus warneri. CONCLUSION: This study highlights the risks of nosocomial infections, especially in pediatric units, if not enough attention is paid to the cleanliness of the pens used in the clinics. PMID- 24949076 TI - Intrauterine Growth Retardation - A Developmental Model of Type 2 Diabetes. AB - Intrauterine growth retardation has been linked to the development of type 2 diabetes later in life and the mechanisms underlying this phenomena are unknown. Epidemiological studies in humans show a distinct link with the exposure to an intrauterine insult that results in low birth weight and the development of type 2 diabetes in adulthood. Intrauterine growth retardation can be induced in rodent models by exposing the pregnant rat to a low protein diet, total calorie restriction, high dose glucocorticoids or inducing uteroplacental insufficiency, all which result in abnormalities in glucose homeostasis in the offspring later in life. Animal models of intrauterine growth retardation allow for a better characterization of changes in glucose homeostasis and corresponding changes in gene expression that can provide insight in the mechanisms by which intrauterine growth retardation leads to type 2 diabetes. PMID- 24949077 TI - Action mechanism of fuzheng fangai pill combined with cyclophosphamide on tumor metastasis and growth. AB - Fuzheng Fangai pill (FZFA), a traditional Chinese formula, is widely used for cancer treatment. Compared with other anticancer drugs, it is characterized by moderate and persistent efficacy with few side effects. The present paper emphasizes antitumor effect of FZFA combined with cyclophosphamide (CTX) on C57BL/6 mice subcutaneously injected with Lewis lung cancer cells, Comparing it with that of CTX. On the 21st day, a set of biochemical parameters were studied: the tumor weight and tumor volume, the inhibition rate of lung metastasis, the percentage and ratio of spleen CD4(+)IL-17(+) Th17 (T helper cell 17, Th17 for short) and CD4(+)CD25(+)Foxp3(+) Treg (T regulatory cell, Treg for short) cells, and the concentrations of IL-6, TGF- beta , IL-17, IL-23, and IFN- gamma in culture supernatants of CD4(+) T lymphocytes were determined. The expression of the splenic Foxp3 and ROR gamma t mRNA and JAK2, STAT3, and SOCS3 protein as also determined. The results show that compared with the model control group and CTX group, FZFA+CTX restored the ratio of spleen CD4(+)IL-17(+) Th17 and CD4(+)CD25(+) Foxp3(+) Treg cells, and inhibited the inflammatory response including the nuclear SOCS3/JAK-STAT pathway, regulation of interleukins TGF- beta , IL-6, IL-17, IL-23, and IFN- gamma , and Foxp3 and ROR gamma t gene expression in CD4(+) T lymphocytes. We conclude that FZFA+CTX strongly reduced the growth and metastasis rate of Lewis lung cancer through inhibition of SOCS/JAK-STAT pathway and inflammatory cytokine responses. FZFA + CTX had greater activity than CTX alone. PMID- 24949078 TI - The effects of massage therapy on multiple sclerosis patients' quality of life and leg function. AB - Background. Massage therapy is a noninvasive treatment that many individuals with multiple sclerosis (MS) use to supplement their conventional treatment. Objective. We hypothesize that massage therapy will improve the leg function and overall quality of life (QoL) of MS patients. Design. A two-period (rest, massage) crossover design was used. Twenty-four individuals with MS ranging from 3.0 to 7.0 on the Expanded Disability Status Scale (EDSS) received Swedish massage treatments for four weeks. Exercise capacity and leg function as well as QoL were assessed using the Six-Minute Walk Test (6MWT) and the Hamburg Quality of Life in Multiple Sclerosis (HAQUAMS) instrument, respectively. Assessments were measured before and after a massage period and a rest period where no massages were employed. Results. The results displayed no significant changes in 6MWT distances or HAQUAMS scores. However, the participants perceived improvement in overall health as expressed in written comments. Conclusions. Massage is a safe, noninvasive treatment that may assist MS patients in managing the stress of their symptoms. Future studies with larger sample size and cortisol measures are warranted. PMID- 24949080 TI - Proteomic Identification of Nrf2-Mediated Phase II Enzymes Critical for Protection of Tao Hong Si Wu Decoction against Oxygen Glucose Deprivation Injury in PC12 Cells. AB - Chinese herbal medicine formula Tao Hong Si Wu decoction (THSWD) is traditionally used in China for cerebrovascular diseases. However, the molecular mechanisms of THSWD associated with the cerebral ischemia reperfusion injury are largely unknown. The current study applied the two-dimensional gel electrophoresis-based proteomics to investigate the different protein profiles in PC12 cells with and without the treatment of THSWD. Twenty-six proteins affected by THSWD were identified by MALDI-TOF mass spectrometry. Gene ontology analysis showed that those proteins participated in several important biological processes and exhibited diverse molecular functions. In particular, six of them were found to be phase II antioxidant enzymes, which were regulated by NF-E2-related factor-2 (Nrf2). Quantitative PCR further confirmed a dose-dependent induction of the six phase II enzymes by THSWD at the transcription level. Moreover, the individual ingredients of THSWD were discovered to synergistically contribute to the induction of phase II enzymes. Importantly, THSWD's protection against oxygen glucose deprivation-reperfusion (OGD-Rep) induced cell death was significantly attenuated by antioxidant response element (ARE) decoy oligonucleotides, suggesting the protection of THSWD may be likely regulated at least in part by Nrf2-mediated phase II enzymes. Thus, our data will help to elucidate the molecular mechanisms underlying the neuroprotective effect of THSWD. PMID- 24949079 TI - Comparison of Two Old Phytochemicals versus Two Newly Researched Plant-Derived Compounds: Potential for Brain and Other Relevant Ailments. AB - Among hundreds of formulae of Chinese herbal prescriptions and recently extracted active components from the herbs, some of which had demonstrated their functions on nervous system. For the last decade or more, Gingko biloba and Polygala tenuifolia were widely studied for their beneficial effects against damage to the brain. Two compounds extracted from Apium graveolens and Rhizoma coptidis, butylphthalide and berberine, respectively, received much attention recently as potential neuroprotective agents. In this review, the two traditionally used herbs and the two relatively new compounds will be discussed with regard to their potential advantages in alleviating brain and other relevant ailments. PMID- 24949081 TI - Diisocyanate-induced asthma in Switzerland: long-term course and patients' self assessment after a 12-year follow-up. AB - BACKGROUND: Isocyanates are among the most common causes of occupational asthma (OA) in Switzerland. Patients with OA have been shown to have unfavourable medical, socioeconomic and psychological outcomes. We investigated long-term asthma and the socio-economic outcomes of diisocyanate-induced asthma (DIA) in Switzerland. PATIENTS AND METHODS: We conducted an observational study on 49 patients with DIA and followed 35 of these patients over a mean exposure-free interval of 12 +/- 0.5 (range 11.0-13.0) years. At the initial and follow-up examinations, we recorded data on respiratory symptoms and asthma medication; measured the lung function; and tested for bronchial hyperreactivity. We allowed the patients to assess their state of health and overall satisfaction using a visual analogue scale (VAS) at these visits. RESULTS: The 35 patients whom we could follow had a median symptomatic exposure time of 12 months, interquartile range (IQR) 26 months and a median overall exposure time of 51 (IQR 104) months. Their subjective symptoms (p < 0.001) and the use of asthma medication (p = 0.002), particularly the use of inhaled corticosteroids (p < 0.001), decreased by nearly 50%. At the same time, the self-assessment of the patients' state of health and overall satisfaction increased considerably according to both symptomatology and income. In contrast, slight reductions in terms of FVC% predicted from 102% to 96% (p = 0.04), of FEV1% predicted from 91% to 87% (p = 0.06) and of the FEV1/FVC ratio of 3%; (p = 0.01) were observed while NSBHR positivity did not change significantly. In univariate as well as multivariate logistic analyses we showed significant associations between age, duration of exposure and FEV1/FVC ratio with persistent asthma symptoms and NSBHR. CONCLUSIONS: We found that the patients' symptoms, the extent of their therapy and the decrease in their lung volumes during the follow-up period were similar to the findings in the literature. The same hold true for some prognostic factors, whereas the patients' self-assessment of their state of health and overall satisfaction improved considerably. PMID- 24949082 TI - Identification of endoglin-dependent BMP-2-induced genes in the murine periodontal ligament cell line PDL-L2. AB - BACKGROUND: The periodontal ligament (PDL), connective tissue located between the cementum of teeth and alveolar bone of the mandibula, plays an important role in the maintenance and regeneration of periodontal tissues. We reported previously that endoglin was involved in the BMP-2-induced osteogenic differentiation of mouse PDL cells, which is associated with Smad-2 phosphorylation but not Smad 1/5/8 phosphorylation. In this study, to elucidate the detailed mechanism underlying the BMP-2 signalling pathway unique to PDL cells, we performed a microarray analysis to identify BMP-2-inducible genes in PDL-L2 cells, a mouse PDL-derived cell line, with or without endoglin knockdown. FINDINGS: Sixty-four genes were upregulated more than twofold by BMP-2 in PDL-L2 cells. Of these genes, 11 were endoglin-dependent, including Id4, which encodes ID4, a helix-loop helix transcription factor closely associated with TGF-beta signaling and osteoblast differentiation. The endoglin-dependent induction of ID4 by BMP-2 was also verified at a protein level. CONCLUSION: Our findings indicate that ID4 could be a signal mediator involved in the BMP-2-induced endoglin-dependent osteogenic differentiation of PDL cells. PMID- 24949083 TI - Associations between changes in the pattern of suicide methods and rates in Korea, the US, and Finland. AB - BACKGROUND: The lethality of the suicide method employed is a strong risk factor for the completion of suicide. We examined whether annual changes in the pattern of suicide methods is related to annual changes in suicide rates in South Korea, the United States (US), and Finland. METHODS: We analyzed annual data from 2000 2011 for South Korea and Finland, and 2000-2010 for the US in order to examine trends in the rates and methods of suicide. Data on suicide methods were obtained from the World Health Organization (WHO) mortality database. RESULTS: Along with an annual rapid increase in suicide rates, the incidence of hanging increased steadily while suicide by self-poisoning steadily decreased in South Korea. In the US, along with an annual increase in suicide rates, the proportion of suicides committed by hanging increased while those committed with the use of firearms steadily decreased. In Finland, annual changes in the suicide rate and suicide method were not statistically significant during the study period. CONCLUSIONS: Our present findings suggest that the increased use of specific lethal methods for suicide, namely hanging, is reflected in the increased suicide rates in the Korean and the US populations. The most effective approach for reducing overall suicide rates may be the implementation of population-based initiatives that reduce both the accessibility (e.g., access to firearms) and the social acceptability (e.g., effective and responsible regulations for reporting suicide) of lethal methods of suicide. PMID- 24949084 TI - "First and foremost the evangelist"? Mission and government priorities for the treatment of leprosy in Uganda, 1927-1948. AB - Early historiography on medicine in British colonial Africa suggests that colonial government and missionary medicine occupied two relatively distinct spheres, and that government officials viewed medical missionaries with suspicion and distrust. Contrary to this paradigm, this article suggests that missionaries and colonial government officials collaborated extensively and amicably in the treatment of leprosy in Uganda. Mission, medical, and government correspondence and reports are drawn upon in order to demonstrate that the suspicion and tension that characterised so many other interactions between British colonial government officials and missionaries was largely absent in the treatment of leprosy in Uganda. The mutual social and cultural priorities of missionaries and government administrators led to a system of isolated, in-patient leprosy care that was limited in scope and reflective not of a goal for the public health of Uganda, but rather a vision for the future of Uganda as a "civilised" and Christian country. PMID- 24949086 TI - Molecular cytogenetic characterization of chromosomal rearrangements - utility in genetic counseling and research. PMID- 24949085 TI - Exercise as an intervention for sedentary hazardous drinking college students: A pilot study. AB - Young adults 18-24 years have the highest rates of problems associated with alcohol use among all age groups, and substance use is inversely related to engagement in substance-free activities. This pilot study investigated the promotion of one specific substance-free activity, exercise, on alcohol use in college students. Thirty-one sedentary college students who engaged in hazardous drinking (Alcohol Use Disorders Identification Test scores >= 8) were randomized to one of two conditions: (a) one 50-minute session of motivational enhancement therapy (MET) focused on increasing exercise, or (b) one 50-minute session of MET focused on increasing exercise plus 8 weeks of contingency management (CM) for adhering to specific exercise activities. All participants completed evaluations at baseline and post-treatment (2-months later) assessing exercise participation and alcohol use. Results of the pilot study suggest the interventions were well received by participants, the MET+CM condition showed an increased self-reported frequency of exercise in comparison to the MET alone condition, but other indices of exercise, physical fitness, and alcohol use did not differ between the interventions over time. These results suggest that a larger scale trial could better assess efficacy of this well received combined intervention. Investigation in other clinically relevant populations is also warranted. PMID- 24949087 TI - Genetics of male infertility: Indian scenario. PMID- 24949088 TI - 3D facial phenotyping. PMID- 24949089 TI - Fertility options and challenges for patients with cytogenetic infertility & disorders of sex development. PMID- 24949090 TI - New paradigms in whole genome sequencing: from lab bench to cell phone. PMID- 24949091 TI - Personal genomes to precision medicine. PMID- 24949092 TI - Cytogenetic microarray in prenatal and postnatal diagnosis. PMID- 24949093 TI - New born screening program in India: ICMR multicentric experience. PMID- 24949094 TI - Molecular diagnosis of genodermatoses in india. PMID- 24949095 TI - Epigenetic regulation of double c2 like domain beta (Doc2b) in cervical cancer. PMID- 24949096 TI - The advantages of SNP arrays over CGH arrays. PMID- 24949097 TI - Neuroferritinopathy: iron in the brain. PMID- 24949098 TI - Next generation diagnostics on cardiomyopathy. PMID- 24949099 TI - Treatment of inborn errors of metabolism. PMID- 24949100 TI - Genetics of cardiovascular disorders: influence of maternal nutrition. PMID- 24949101 TI - Pharmacogenetics: polymorphism and genotype-phenotype correlation of drug response in indian population. PMID- 24949102 TI - Point of care testing for improving risk- benefit ratio of aspirin and warfarin. PMID- 24949103 TI - Vitiligo: a complex disease and a complex approach. PMID- 24949104 TI - Affordable diagnosis and prevention of genetic disease. PMID- 24949106 TI - Alveolar antral artery isolation during sinus lift procedure with the double window technique. AB - The sinus lift technique, introduced in 1976 by Tatum and subsequently described by Boyne in 1980, is nowadays considered a safe and reliable procedure for the rehabilitation of the atrophic upper posterior maxilla. The alveolar antral artery (AAA) is anastomoses between the posterior superior alveolar artery (PSAA) and the infraorbital artery (IOA) and may be present in the sinusal antrostomy. The haemorrhage of this vascular bundle represents the second intra-operatory complication in term of frequency during sinus lift procedure. Purpose of this study was to illustrate and describe a new technique allowing the AAA isolation during sinus lift procedure in cases in which the artery is clearly present inside the surgical area, detectable through CT scan exam. Presence, course and possible identification of the alveolar antral artery are also discussed, according to the studies present in the literature. PMID- 24949105 TI - Complement yourself: Transcomplementation rescues partially folded mutant proteins. AB - Cystic Fibrosis (CF) is an autosomal disease associated with malfunction in fluid and electrolyte transport across several mucosal membranes. The most common mutation in CF is an in-frame three-base pair deletion that removes a phenylalanine at position 508 in the first nucleotide-binding domain of the cystic fibrosis conductance regulator (CFTR) chloride channel. This mutation has been studied extensively and leads to biosynthetic arrest of the protein in the endoplasmic reticulum and severely reduced channel activity. This review discusses a novel method of rescuing DeltaF508 with transcomplementation, which occurs when smaller fragments of CFTR containing the wild-type nucleotide binding domain are co-expressed with the DeltaF508 deletion mutant. Transcomplementation rescues the processing and channel activity of DeltaF508 and reduces its rate of degradation in airway epithelial cells. To apply transcomplementation as a therapy would require that the cDNA encoding the truncated CFTR be delivered to cells. We also discuss a gene therapeutic approach based on delivery of a truncated form of CFTR to airway cells using adeno-associated viral vectors. PMID- 24949107 TI - Influence of an Intervention to Prevent Early Childhood Caries Initiated before Birth on Children's Use of Dental Services up to 7 Years of Age. AB - BACKGROUND: In a previously reported randomised controlled trial, advising first time mothers on the prevention of early childhood caries from before their child was born, decreased the prevalence of early childhood caries at 20 months of age 5-fold. OBJECTIVE: We examined the effect of the intervention on the frequency and nature of dental visits up to 7 years of age. METHODS: Of 649 expectant mothers who participated in the trial, 277 completed a "Child Oral Health Survey" 7 years later. Their answers were compared with those of a comparison group of 277 mothers selected at random among those living in the same area with a first child born in the same year enrolled with the South Australian School Dental Services (SA SDS). RESULTS: Only 1.5% of children had a dental visit before 12 months of age and only 4% before 2 years of age unless a dental problem had arisen. The age at the first visit did not differ among groups, but the reasons for the visit did as did the number of visits and the need for treatment under sedation or anaesthesia. In the trial group, 34% of first visits were for pain, 29% for injury, and 29% for concern with appearance. In the comparison group, pain was the main concern in 49%, injury in 9.5%, and appearance in 25% (p=0.019). Over time, children in the trial had an average of 2.2 visits compared with 3.1 in the comparison group. In the intervention group of the trial, no child had required treatment under sedation or general anaesthesia compared with 2.9% in the control group, and 6.5% in the comparison group. Only 15% of mothers reported that they had received any information on caries prevention from health care professionals other than dental care practitioners. CONCLUSION: Providing first-time mothers with guidance on the prevention of childhood caries decreased the use of dental services to deal with problems in preschool children. PMID- 24949108 TI - Molecular Detection, Quantification, and Toxigenicity Profiling of Aeromonas spp. in Source- and Drinking-Water. AB - Aeromonas is ubiquitous in aquatic environments and has been associated with a number of extra-gastrointestinal and gastrointestinal illnesses. This warrants monitoring of raw and processed water sources for pathogenic and toxigenic species of this human pathogen. In this study, a total of 17 different water samples [9 raw and 8 treated samples including 4 basin water (partial sand filtration) and 4 finished water samples] were screened for Aeromonas using selective culturing and a genus-specific real-time quantitative PCR assay. The selective culturing yielded Aeromonas counts ranging 0 - 2 x 10(3)CFU/ml and 15 Aeromonas isolates from both raw and treated water samples. The qPCR analysis indicated presence of a considerable nonculturable population (3.4 x 10(1) - 2.4 x 10(4) cells/ml) of Aeromonas in drinking water samples. Virulence potential of the Aeromonas isolates was assessed by multiplex/singleplex PCR-based profiling of the hemolysin and enterotoxin genes viz cytotoxic heat-labile enterotoxin (act), heat-labile cytotonic enterotoxin (alt), heat-stable cytotonic enterotoxin (ast), and aerolysin (aerA) genes. The water isolates yielded five distinct toxigenicity profiles, viz. act, alt, act+alt, aerA+alt, and aerA+alt+act. The alt gene showed the highest frequency of occurrence (40%), followed by the aerA (20%), act (13%), and ast (0%) genes. Taken together, the study demonstrated the occurrence of a considerable population of nonculturable Aeromonads in water and prevalence of toxigenic Aeromonas spp. potentially pathogenic to humans. This emphasizes the importance of routine monitoring of both source and drinking water for this human pathogen and role of the developed molecular approaches in improving the Aeromonas monitoring scheme for water. PMID- 24949109 TI - Highly Deviated Asymmetric Division in Very Low Proportion of Mycobacterial Mid log Phase Cells. AB - In this study, we show that about 20% of the septating Mycobacterium smegmatis and Mycobacterium xenopi cells in the exponential phase populationdivideasymmetrically, with an unusually high deviation (17 +/- 4%) in the division site from the median, to generate short cells and long cells, thereby generating population heterogeneity. This mode of division is very different from the symmetric division of themajority (about 80%) of the septating cells in the Mycobacterium smegmatis, Mycobacterium marinum, and Mycobacterium bovis BCG exponential phase population, with 5-10% deviation in the division site from the mid-cell site, as reported by recent studies. The short cells and the long cells further grew and divided to generate a population. We speculate that the generation of the short cells and the long cells through the highly deviated asymmetric divisionin the low proportions of mycobacterial population may have a role in stress tolerance. PMID- 24949110 TI - Clinical risk factors for poor anatomic response to ranibizumab in neovascular age-related macular degeneration. AB - PURPOSE: To identify OCT-based anatomical features and clinical characteristics for poor central retinal thickness (CRT) response to ranibizumab in neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: Investigating our electronic patient records (Eyeswide), patients with neovascular AMD treated with intravitreal injections of 0.5mg/0.05ml ranibizumab were identified and their notes reviewed. Data collected included gender, age, initial best-corrected visual acuity (BCVA), prior photodynamic therapy, lesion type (classic versus occult), type of macular edema (intraretinal fluid, subretinal fluid, pigment epithelium detachment) and the total number of previous ranibizumab injections. RESULTS: A total of 210 eyes of 182 patients with neovascular AMD were identified. Mean follow-up time was 1.34 years (SD +/- 0.77). Central retinal thickness reduction in women was significantly inferior to that in men (p=0.05). Patients with cystoid type macular edema had significantly greater reduction in CRT compared to patients with subretinal fluid (p<0.001) or pigment epithelium detachment (p<0.001). The percentage drop of CRT was no longer statistically significant after the sixth injection. Age, initial BCVA, prior photodynamic therapy and lesion type had no statistically effect on CRT response. CONCLUSION: Risk factors for poor central retinal thickness response to ranibizumab include female gender and patients with predominant subretinal fluid or pigment epithelium detachment. Furthermore, the anatomical response decreased after the sixth injection of ranibizumab. PMID- 24949111 TI - Death by water: precautionary water submersion for intravitreal injection of retinoblastoma eyes. AB - There is growing interest in intravitreal injections of chemotherapy for retinoblastoma. However, concerns for potential tumor seeding through the needle track has prompted the use of risk-reducing precautionary methods. Presented here is a novel technique, which can be easily replicated, requires minimal sophisticated equipment and with laboratory data supporting its concept. Sterile distilled water submersion for 3 minutes renders retinoblastoma cells nonviable and can be employed as a precautionary method following intravitreal injection in the technique described here. PMID- 24949112 TI - Understanding STI Risk and Condom Use Patterns by Partner Type Among Female Sex Workers in Peru. AB - While brothel-based sex work is regulated by the Peruvian government, there is little data on STI risk factors reported by female sex workers (FSW). This study compared high risk behaviors among 120 Peruvian FSW from government regulated brothels with both clients and non-commercial partners. Our study found that 12% of FSW reported unprotected vaginal sex with clients (compared to 75% with non commercial partners), and 42% reported unprotected anal sex with clients (compared to 87% with non-commercial partners). Group differences were observed in the expectation to have oral sex (32% for partners vs 60% for clients; p<0.01), and a history of anal sex (65% for partners vs 32% for clients; p<0.01) and both vaginal and anal sex with the same partners (46% for partners vs 25% for clients; p<0.001). These findings suggest that FSW constitute an important bridge population for STI/HIV transmission in Peru. PMID- 24949113 TI - Personalized approach to primary and secondary prevention of ischemic stroke. AB - Primary and secondary prevention of ischemic stroke represents a significant part of stroke management and health care. Although there are official guidelines concerning stroke management, new knowledge are introduced to them with a slight delay. This article provides an overview of current information on primary and secondary prevention of ischemic stroke. It summarizes information especially in the field of cardioembolic stroke, the use of new anticoagulants and the management of carotid stenosis based on the results of recent clinical studies. The optimal approach in stroke management is to follow these recommendations, to know new strategies and to apply an individual personalized approach in our clinical decisions. PMID- 24949114 TI - Lung cancer mimicking lung abscess formation on CT images. AB - PATIENT: Male, 64 FINAL DIAGNOSIS: Lung pleomorphic carcinoma Symptoms: Cough * fever MEDICATION: - Clinical Procedure: - Specialty: Oncology. OBJECTIVE: Unusual clinical course. BACKGROUND: The diagnosis of lung cancer is often made based on computed tomography (CT) image findings if it cannot be confirmed on pathological examinations, such as bronchoscopy. However, the CT image findings of cancerous lesions are similar to those of abscesses.We herein report a case of lung cancer that resembled a lung abscess on CT. CASE REPORT: We herein describe the case of 64-year-old male who was diagnosed with lung cancer using surgery. In this case, it was quite difficult to distinguish between the lung cancer and a lung abscess on CT images, and a lung abscess was initially suspected due to symptoms, such as fever and coughing, contrast-enhanced CT image findings showing a ring-enhancing mass in the right upper lobe and the patient's laboratory test results. However, a pathological diagnosis of lung cancer was confirmed according to the results of a rapid frozen section biopsy of the lesion. CONCLUSIONS: This case suggests that physicians should not suspect both a lung abscesses and malignancy in cases involving masses presenting as ring-enhancing lesions on contrast-enhanced CT. PMID- 24949115 TI - A 20-year-old female with hemoptysis and high blood pressure: An unusual case of papillary renal cell carcinoma. AB - PATIENT: Female, 20 FINAL DIAGNOSIS: Papillary renal cell carcinoma Symptoms: Hemopthysis Medication: Sutent Clinical Procedure: CT guided biopsy Specialty: Oncology. OBJECTIVE: Rare disease. BACKGROUND: Papillary renal cell carcinoma (PRCC) is a rare disease and is a carcinoma of the renal tubular epithelium, comprising only 10-15% of all renal cell carcinoma cases. The majority of cases occur in the sixth decade of life. PRCC rarely occurs before the fourth decade in the absence of family history. This paper describes an aggressive, sporadic case of PRCC in a 20-year-old female without family history and no risk factors. CASE REPORT: A 20-year-old African American female was admitted for hemoptysis with elevated blood pressure and was found to have left peri-hilar opacification on chest X-ray. Further radiological studies led to the discovery of a large complex left renal lesion within the collecting system, infiltrating the renal artery and causing severe hydronephrosis with para-aortic lymphadenopathy. An MRI also showed signal heterogeneity in the L2 and L3 vertebrae. Biopsies of the left renal mass and a right endobronchial lesion confirmed metastatic PRCC. Treatment was commenced with a tyrosine kinase inhibitor. Within a few weeks, the vertebral metastatic lesions progressed to cause spinal compression. After targeted radiotherapy, the patient was referred to Memorial Sloan Kettering Cancer Center for enrolment in a clinical trial. CONCLUSIONS: PRCC rarely occurs in the second decade of life and even then, most such early cases occur in family clusters. PRCC also has a relatively benign course, constituting less than 10% of all metastatic renal cell carcinomas, further making this case a unique presentation. PMID- 24949117 TI - Graduate medical education needs new ideas. PMID- 24949116 TI - Response to rotenone is glucose-sensitive in a model of human acute lymphoblastic leukemia: involvement of oxidative stress mechanism, DJ-1, Parkin, and PINK-1 proteins. AB - To establish the effect of low (11 mM) and high (55 mM) glucose concentrations (G11, G55) on Jurkat cells exposed to rotenone (ROT, a class 5 mitocan). We demonstrated that ROT induces apoptosis in Jurkat cells cultured in G11 by oxidative stress (OS) mechanism involving the generation of anion superoxide radical (O2(?-), 68%)/hydrogen peroxide (H2O2, 54%), activation of NF-kappaB (32%), p53 (25%), c-Jun (17%) transcription factors, and caspase-3 (28%), apoptosis-inducing factor (AIF, 36%) nuclei translocation, c-Jun N-terminal kinase (JNK) activation, and loss of mitochondria transmembrane potential (DeltaPsim, 62%) leading to nuclei fragmentation (~10% and ~40% stage I-II fragmented nuclei, resp.). ROT induces massive cytoplasmic aggregates of DJ-1 (93%), and upregulation of Parkin compared to untreated cells, but no effect on PINK-1 protein was observed. Cell death marker detection and DJ-1 and Parkin expression were significantly reduced when cells were cultured in G55 plus ROT. Remarkably, metformin sensitized Jurkat cells against ROT in G55. Our results indicate that a high-glucose milieu promotes resistance against ROT/H2O2-induced apoptosis in Jurkat cells. Our data suggest that combined therapy by using mitochondria-targeted damaging compounds and regulation of glucose (e.g., metformin) can efficiently terminate leukemia cells via apoptosis in hyperglycemic conditions. PMID- 24949118 TI - Technology in graduate medical education: shifting the paradigm and advancing the field. PMID- 24949119 TI - Smartphones, trainees, and mobile education: implications for graduate medical education. PMID- 24949120 TI - Toward a glossary of competency-based medical education terms. PMID- 24949121 TI - Snippets: an innovative method for efficient, effective faculty development. PMID- 24949122 TI - Can a simplified approach to emotional intelligence be the key to learner centered teaching? PMID- 24949123 TI - Surgical subspecialization: escape route for surgeons or added benefit for patients? PMID- 24949124 TI - Is subspecialty fellowship training emerging as a necessary component of contemporary orthopaedic surgery education? PMID- 24949125 TI - Motivational interviewing interventions in graduate medical education: a systematic review of the evidence. AB - BACKGROUND: Motivational interviewing (MI) is a patient-centered method of behavior change counseling. It has shown promise in enabling patients to identify and improve problem health behaviors. Incorporating MI education into residency training may be beneficial. OBJECTIVE: To review the current evidence regarding the impact of MI education in graduate medical education. RESULTS: Of the 9 studies of MI education in graduate medical education training, most noted favorable outcomes after MI education. Outcomes included improvements in residents' view of MI, MI skill use and competency, and resident satisfaction with MI interventions. Of the 5 studies that looked at residents' views of MI, 3 found improvements in resident assessments of the importance of and confidence in using MI. Of the 4 studies of MI skills, 3 reported improvements in residents' use of and competency in the MI skill. The quality of MI education in the graduate medical education literature is limited by overreliance on preintervention and postintervention analysis as a study design, the variable intensity of educational interventions, and limited use of validated assessment tools and quantitative outcome measures. CONCLUSIONS: Review of the literature shows that MI education can be successfully implemented within the residency education environment. The intensity of MI interventions, coupled with experiential learning and feedback, correlated with favorable outcomes in terms of resident use of MI skills and resident satisfaction. Further study is needed to determine which MI skills are most effectively taught to residents, the impact of MI training on resident behavior in clinical settings, and the impact on clinical outcomes. PMID- 24949126 TI - Residents-as-Teachers Publications: What Can Programs Learn From the Literature When Starting a New or Refining an Established Curriculum? AB - BACKGROUND: Teaching residents how to teach is a critical part of resident education because residents are often the major teachers of medical students. The importance of formal residents-as-teachers (RAT) curricula has been emphasized throughout the literature, yet not all residency programs have such a curriculum in place. OBJECTIVE: The purpose of our study was to (1) review the medical education literature for established RAT curricula, (2) assess published curricula's reproducibility, (3) evaluate the type of outcomes achieved using the Kirkpatrick model of evaluation, and (4) identify curricula that training programs could feasibly adopt. METHODS: We performed a literature review using PubMed, Medline, Scopus, PsycINFO, ERIC, and Embase. Key search words included residents, residents as teachers, teaching, internship and residency, and curriculum. In addition, a search of MedEdPORTAL was performed using the same key terms. Articles were evaluated based on the reproducibility of curricula and the assessment tools. Evaluation of educational outcomes was performed using the Kirkpatrick model. RESULTS: Thirty-nine articles were deemed appropriate for review. Interventions and evaluation techniques varied greatly. Only 1 article from the literature was deemed to have both curricula and assessments that would be fully reproducible by other programs. CONCLUSIONS: A literature review on RAT curricula found few articles that would be easily reproduced for residency programs that want to start or improve their own RAT curricula. It also demonstrated the difficulty and lack of rigorous outcome measurements for most curricula. PMID- 24949127 TI - Clinic design, key practice metrics, and resident satisfaction in internal medicine continuity clinics: findings of the educational innovations project ambulatory collaborative. AB - BACKGROUND: Internal medicine programs are redesigning ambulatory training to improve the resident experience and answer the challenges of conflicting clinical responsibilities. However, little is known about the effect of clinic redesign on residents' satisfaction. OBJECTIVE: We assessed residents' satisfaction with different resident continuity clinic models in programs participating in the Educational Innovations Project Ambulatory Collaborative (EPAC). METHODS: A total of 713 internal medicine residents from 12 institutions in the EPAC participated in this cross-sectional study. Each program completed a detailed curriculum questionnaire and tracked practice metrics for participating residents. Residents completed a 3-part satisfaction survey based on the Veterans Affairs Learners' Perception Survey, with additional questions addressing residents' perceptions of the continuous healing relationship and conflicting duties across care settings. RESULTS: THREE CLINIC MODELS WERE IDENTIFIED: traditional weekly experience, combination model with weekly experience plus concentrated ambulatory rotations, and a block model with distinct inpatient and ambulatory blocks. The satisfaction survey showed block models had less conflict between inpatient and outpatient duties than traditional and combination models. Residents' perceptions of the continuous healing relationship was higher in combination models. In secondary analyses, the continuity for physician measure was correlated with residents' perceptions of the continuous healing relationship. Panel size and workload did not have an effect on residents' overall personal experience. CONCLUSIONS: Block models successfully minimize conflict across care settings without sacrificing overall resident satisfaction or resident perception of the continuous healing relationship. However, resident perception of the continuous healing relationship was higher in combination models. PMID- 24949128 TI - Impact of protected sleep period for internal medicine interns on overnight call on depression, burnout, and empathy. AB - BACKGROUND: Patient safety and sleep experts advocate a protected sleep period for residents. OBJECTIVE: We examined whether interns scheduled for a protected sleep period during overnight call would have better end-of-rotation assessments of burnout, depression, and empathy scores compared with interns without protected sleep periods and whether the amount of sleep obtained during on call predicted end-of-rotation assessments. METHODS: We conducted a randomized, controlled trial with internal medicine interns at the Philadelphia Veterans Affairs Medical Center (PVAMC) and the Hospital of the University of Pennsylvania (HUP) in academic year 2009-2010. Four-week blocks were randomly assigned to either overnight call permitted under the 2003 duty hour standards or a protected sleep period from 12:30 am to 5:30 am. Participants wore wrist actigraphs. At the beginning and end of the rotations, they completed the Beck Depression Inventory (BDI-II), Maslach Burnout Inventory (MBI-HSS), and Interpersonal Reactivity Index (IRI). RESULTS: A total of 106 interns participated. There were no significant differences between groups in end-of-rotation BDI-II, MBI-HSS, or IRI scores at either location (P > .05). Amount of sleep while on call significantly predicted lower MBI-Emotional Exhaustion (P < .003), MBI-Depersonalization (P < .003), and IRI-Personal Distress (P < .006) at PVAMC, and higher IRI-Perspective Taking (P < .008) at HUP. CONCLUSIONS: A protected sleep period produced few consistent improvements in depression, burnout, or empathy, although depression was already low at baseline. Possibly the amount of protected time was too small to affect these emotional states or sleep may not be directly related to these scores. PMID- 24949129 TI - Use of Health Care Services by Pediatrics Residents: A CORNET Study. AB - BACKGROUND: The personal health practices of residents and their access to health care has not been well explored. Suboptimal personal health care habits and practices among many physicians may evolve during residency. OBJECTIVE: To identify the nature and extent of pediatrics resident health care use and the factors that restrict or facilitate use. METHODS: A web-based survey was sent to pediatrics residents from 19 continuity practice sites enrolled in the nationwide Continuity Research Network (CORNET) during April through June 2010. Outcome measures included self-report of health care use, involvement in an established care relationship with a primary care provider, and barriers residents encountered in receiving care. RESULTS: Of 1210 eligible residents, 766 (63%) completed the survey. Respondents were 73% women; each postgraduate training year was equally represented. More than one-half of residents (54%) stated they had an established care relationship (ECR) with a primary care provider. Interns were less likely to have an ECR when compared with upper level residents; female residents were twice as likely to have an ECR compared with male residents. Although 22% (172 of 766) of the respondents reported they had a chronic health condition, only 69% (118 of 172) of those individuals had an established care provider. The most significant barrier to obtaining health care was resident concern for time away from work and the potential increased workload for colleagues. CONCLUSIONS: A slight majority of pediatrics residents stated they had an established relationship with a primary care provider. The most common barriers to seeking routine and acute care were work related. PMID- 24949130 TI - Randomized controlled trial of spaced education for pediatric residency education. AB - BACKGROUND: Spaced education (SE) has shown promise as an instructional tool that uses repeated exposure to the same questions, but information on its utility in graduate medical education is limited, particularly in assessing knowledge gain with outcome measures that are different from repeat exposure to the intervention questions. OBJECTIVE: We examined whether SE is an effective instructional tool for pediatrics residents learning dermatology using an outcome measure that included both unique and isomorphic questions. METHODS: We randomized 81 pediatrics residents into 2 groups. Group A completed an SE course on atopic dermatitis and warts and molluscum. Group B completed an SE course on acne and melanocytic nevi. Each course consisted of 24 validated SE items (question, answer, and explanation) delivered 2 at a time in 2 e-mails per week. Both groups completed a pretest and posttest on all 4 topics. Each group served as the comparison for the other group. RESULTS: Fifty residents (60%) completed the study. The course did not have a statistically significant effect on the posttest scores for either group. Overall, test scores were low. Eighty-eight percent of residents indicated that they would like to participate in future SE courses. CONCLUSIONS: Using primarily novel posttest questions, this study did not demonstrate the significant knowledge gains that other investigators have found with SE. PMID- 24949131 TI - Repeated versus varied case selection in pediatric resident simulation. AB - BACKGROUND: Repeated exposure to pediatric emergency scenarios improves technical skills, but it is unclear whether repeated exposure to specific cases affects medical decision making in varied cases. OBJECTIVE: We sought to determine whether repeated exposure to 1 scenario would translate to improved performance and decision making in varied scenarios. METHODS: Senior pediatrics residents participated in 3 scenarios with scripted debriefing. Residents were randomized to repeated practice (RP) scenarios or mixed (MIX) scenarios. RP residents completed pulseless electrical activity (PEA) with different stems (Case 1, 2, 3). MIX residents completed PEA (Case 1), seizure (Case 2), and ventricular tachycardia (Case 3) scenarios. Four months later, participants returned to complete 3 more cases: PEA (Case 4), seizure (Case 5), and critical coarctation (Case 6). RESULTS: Twenty-three residents participated in the study and were randomized to either the RP or the MIX group. The RP group showed statistically significant improvement in time to start chest compressions, whereas the MIX group showed no improvement. Use of a backboard improved significantly in Case 4 for the RP group but not for the MIX group. Similarly, time to check glucose in the seizure scenario was significantly better in the MIX group that had previous exposure to a seizure scenario. No differences in performance were noted between groups in Case 6, which was new to both groups. CONCLUSIONS: Results of this study indicate that whereas repeated exposure may improve decision-making skills in similar scenarios, it may not translate to improved medical decision making in other scenarios. PMID- 24949132 TI - Reliability and validity of conversion formulas between comprehensive osteopathic medical licensing examination of the United States level 1 and United States medical licensing examination step 1. AB - BACKGROUND: The Comprehensive Osteopathic Medical Licensing Examination of the United States (COMLEX-USA) Level 1 and United States Medical Licensing Examination (USMLE) Step 1 scores are important factors in the selection process of medical students into US residency programs. OBJECTIVES: The goals of this study were to investigate the correlation between the COMLEX-USA Level 1 and the USMLE Step 1 and to assess the accuracy of the existing formulas in predicting USMLE scores from COMLEX-USA scores. METHODS: A retrospective study of 1016 paired COMLEX-USA Level 1 and USMLE Step 1 scores was conducted. Formulas by Sarko et al and by Slocum and Louder were used to estimate USMLE Step 1 scores from COMLEX-USA Level 1 scores, and a paired t test between calculated USMLE Step 1 scores and actual USMLE Step 1 scores was performed. RESULTS: During 2006-2012, 1016 of 1440 students (71%) took both the USMLE Step 1 and the COMLEX-USA Level 1 tests in the College of Osteopathic Medicine of the Pacific. The USMLE Step 1 scores were higher than those predicted by Slocum and Louder and by Sarko et al by an average of 14.16 +/- 11.69 (P < .001) and 7.80 +/- 12.48 (P < .001), respectively. A Pearson coefficient of 0.83 was observed. Regression analysis yielded the following formula: USMLE Step 1 = 0.2392 * COMLEX-USA Level 1 + 82.563 (R (2) = 0.69577). CONCLUSIONS: The USMLE Step 1 scores, on average, were higher than those predicted by the formulas derived by Slocum and Louder and by Sarko et al. Residency program directors should use caution when using formulas to derive USMLE Step 1 scores from COMLEX-USA Level 1 scores. PMID- 24949133 TI - Use of the Quality Improvement (QI) Knowledge Application Tool in Assessing Pediatric Resident QI Education. AB - BACKGROUND: Assessing the effectiveness of quality improvement curricula is important to improving this area of resident education. OBJECTIVE: To assess the ability of the Quality Improvement Knowledge Application Tool (QIKAT) to differentiate between residents who were provided instruction in QI and those who were not, when scored by individuals not involved in designing the QIKAT, its scoring rubric, or QI curriculum instruction. METHODS: The QIKAT and a 9-item self-assessment of QI proficiency were administered to an intervention and a control group. The intervention was a longitudinal curriculum consisting of 8 hours of didactic QI training and 6 workshops providing just-in-time training for resident QI projects. Two uninvolved faculty scored the QIKAT. RESULTS: A total of 33 residents in the intervention group and 27 in the control group completed the baseline and postcurriculum QIKAT and self-assessment. QIKAT mean intervention group scores were significantly higher than mean control group scores postcurriculum (P < .001). Absolute QIKAT differences were small (of 15 points, intervention group improved from a mean score of 12.8 to 13.2). Interrater agreement as measured by kappa test was low (0.09). Baseline self assessment showed no differences, and after instruction, the intervention group felt more proficient in QI knowledge than controls in 4 of 9 domains tested. CONCLUSIONS: The QIKAT detected a statistically significant improvement postintervention, but the absolute differences were small. Self-reported gain in QI knowledge and proficiency agreed with the results of the QIKAT. However, QIKAT limitations include poor interrater agreement and a scoring rubric that lacks specificity. Programs considering using QIKAT to assess curricula should understand these limitations. PMID- 24949134 TI - A multicenter study of the family educational rights and privacy act and the standardized letter of recommendation: impact on emergency medicine residency applicant and faculty behaviors. AB - BACKGROUND: Residency applicants have the right to see letters of recommendation written on their behalf. It is not known whether applicants are affected by waiving this right. OBJECTIVES: Our multicenter study assessed how frequently residency applicants waived their FERPA rights to view their letters of recommendation, and whether this affected the ratings they were given by faculty. METHODS: We reviewed all ERAS-submitted letters of recommendation to 14 ACGME accredited programs in 2006-2007. We collected ERAS ID, program name, FERPA declaration, standardized letter of recommendation (SLOR) use, and SLOR Global Assessment ranking. The percentage of applicants who waived their FERPA rights was determined. Chi-square tests of independence assessed whether applicants' decision to waive their FERPA rights was associated with their SLOR Global Assessment. RESULTS: We examined 1776 applications containing 6424 letters of recommendations. Of 2736 letters that specified a Global Assessment, 2550 (93%) applicants waived their FERPA rights, while 186 did not. Of the applicants who chose not to waive their rights, 45.6% received a ranking of Outstanding, 35.5% Excellent, 18.3% Very Good, and 1.6% Good. Of applicants who waived their FERPA rights, 35.1% received a ranking of Outstanding, 49.6% Excellent, 13.7% Very Good, and 1.6% Good. Applicants who did not waive their FERPA rights were more likely to receive an Outstanding Assessment (P = .003). CONCLUSIONS: The majority (93%) of residency applicants waived their FERPA rights. Those who did not waive their rights had a statistically higher chance of receiving an Outstanding Assessment than those who did. PMID- 24949135 TI - Dermatology curriculum for internal medicine residents: a randomized trial. AB - BACKGROUND: Physicians in specialties other than dermatology care for the majority of patients with skin diseases, yet most physicians receive little training in dermatology. OBJECTIVES: The primary objective of this study was to determine whether there would be a sizable (20%) improvement in posttraining scores for internal medicine residents after completing 1 of 3 assigned curricula. A secondary objective was to determine whether there were significant differences in improvement among the 3 resident cohorts after completing their curriculum. Finally, we explored the residents' change in perceived clinical knowledge postcurriculum. METHODS: Thirty-six postgraduate year 2 internal medicine residents were randomized to complete 1 of 3 one-month dermatology curricula (didactic, clinical, or combined). The main outcome measure was performance on different sets of Medical Knowledge Self-Assessment Program (MKSAP)-15 questions at study entry and completion. A secondary outcome was self rated performance in 3 clinical domains. RESULTS: All participants completed the study. All curricula led to an improvement in MKSAP-15 scores, but only students who completed the didactic curriculum demonstrated a 20% improvement in posttraining scores. A larger number of residents completing the clinical and didactic curricula rated their clinical performance as improved compared to those who completed the combined curriculum. CONCLUSIONS: While all 3 curricula led to improvement, as measured by a standardized assessment, a didactic curriculum in dermatology resulted in the largest improvement in knowledge as measured by a multiple-choice test. PMID- 24949136 TI - Council of emergency medicine residency directors standardized letter of recommendation writers' questionnaire. AB - BACKGROUND: The Council of Emergency Medicine Residency Directors (CORD) Standardized Letter of Recommendation (SLOR) has become the primary tool used by emergency medicine (EM) faculty to evaluate residency candidates. A survey was created to describe the training, beliefs, and usage patterns of SLOR writers. METHODS: The SLOR Task Force created the survey, which was circulated to the CORD listserv in 2012. RESULTS: Forty-six percent of CORD members (320 of 695) completed the survey. Of the respondents, 39% (125 of 320) had fewer than 5 years of experience writing SLOR letters. Most were aware of published guidelines, and most reported they learned how to write a SLOR on their own (67.4%, 182 of 270). Sixty-eight percent (176 of 258) admitted to not following the instructions for certain questions. Self-reported grade inflation occurred "rarely" 36% (97 of 269) of the time and not at all 40% (107 of 269) of the time. CONCLUSIONS: The CORD SLOR has become the primary tool used by EM faculty to evaluate candidates applying for residency in EM. The SLOR has been in use in the EM community for 16 years. However, our study has identified some problems with its use. Those issues may be overcome with a revised format for the SLOR and with faculty training in the writing and use of this document. PMID- 24949137 TI - Timely completion of paperwork: are some residents consistently late responders? AB - BACKGROUND: One element of competence in professionalism entails the timely completion of paperwork. Early identification of residents who are consistently late in completing their assignments might be the first step in helping them change this habit. OBJECTIVE: This study sought to determine if program coordinators' ratings of residents' response habits to completing assignments were associated with existing measures of resident response times tracked by the institution. METHODS: Program coordinators rated residents as early, mid, or late responders based on their experience with them. We compared coordinators' ratings with the response time of these same residents in returning orientation materials to the institution, completing a patient safety survey and duty hour logs, and providing their required countersignature on telephone and verbal orders. A total of 196 residents enrolled at this institution were eligible for this comparison in the 2012-2013 academic year. RESULTS: Program coordinators rated 23% (40 of 177) of the residents as late responders. These ratings were significantly associated with the response time of residents in returning orientation materials and the completed patient safety survey. Residents identified as late responders were 2.45 times (confidence interval, 1.09 +/- 5.64) more likely to have delinquent medical records. CONCLUSIONS: This exploratory study suggests that residents who are late responders can be identified as early as orientation and that they likely maintain this response habit in completing assignments throughout residency. To address this professionalism issue, programs should track and counsel residents on their timeliness in completing paperwork. PMID- 24949138 TI - Promoting quality care for recently resettled populations: curriculum development for internal medicine residents. AB - BACKGROUND: Residents report they lack preparation for caring for an increasingly diverse US population. In response, a variety of curricula have been developed to integrate cultural competency into medical training programs. To date, none of these curricula has specifically addressed members of recently resettled populations. METHODS: A preliminary assessment was conducted among internal medicine (IM) residents at 1 program (N = 147). Based on 2 conceptual frameworks and the survey results, a pilot curriculum was developed and integrated into the interns' ambulatory block education within the general IM track (n = 9). It included (1) online information made available to all hospital staff; (2) 4 interactive didactic sessions; and (3) increased exposure to newly arrived patients. The curriculum was qualitatively evaluated through 2 focus groups. RESULTS: The preliminary assessment was completed by 101 of 147 residents (69%), with 61% of respondents indicating they felt that they received less than adequate education in this area. Eight of the 9 interns exposed to the new curriculum participated in the focus groups. Overall, respondents reported they thought patient care had improved for recently resettled populations and across their patient panels after exposure to the curriculum. CONCLUSIONS: This study demonstrated that an intervention that included didactics and enhanced exposure to a diverse population improved IM interns' perceptions of care for all patients, including recently settled individuals. PMID- 24949139 TI - An ACGME Duty Hour Compliant 3-Person Night Float System for Neurological Surgery Residency Programs. AB - BACKGROUND: In 2003, the Accreditation Council for Graduate Medical Education (ACGME) instituted the 24+6-hour work schedule and 80-hour workweek, and in 2011, it enhanced work hour and supervision standards. INNOVATION: In response, Oregon Health & Science University's (OHSU) neurological surgery residency instituted a 3-person night float system. METHODS: We analyzed work hour records and operative experience for 1 year before and after night float implementation in a model that shortened a combined introductory research and basic clinical neurosciences rotation from 12 to 6 months. We analyzed residents' perception of the system using a confidential survey. The ACGME 2011 work hour standards were applied to both time periods. RESULTS: AFTER NIGHT FLOAT IMPLEMENTATION, THE NUMBER OF DUTY HOUR VIOLATIONS WAS REDUCED: 28-hour shift (11 versus 235), 8 hours off between shifts (2 versus 20), 80 hours per week (0 versus 17), and total violations (23 versus 275). Violations increased only for the less than 4 days off per 4-week interval rule (10 versus 3). No meaningful difference was seen in the number of operative cases performed per year at any postgraduate year (PGY) training level: PGY-2 (336 versus 351), PGY-3 (394 versus 354), PGY-4 (803 versus 802), PGY-5 (1075 versus 1040), PGY-7 (947 versus 913), and total (3555 versus 3460). Residents rated the new system favorably. CONCLUSIONS: To meet 2011 ACGME duty hour standards, the OHSU neurological surgery residency instituted a 3-person night float system. A nearly complete elimination of work hour violations did not affect overall resident operative experience. PMID- 24949140 TI - Fostering reciprocity in global health partnerships through a structured, hands on experience for visiting postgraduate medical trainees. AB - BACKGROUND: Global health programs that allow international experiences for US learners should also enable reciprocal learning experiences for international learners, particularly if that is a need identified by the partner institution. METHODS: A partnership between Indiana University and Moi University, Kenya, has successfully hosted 41 visiting Kenyan internal medicine and pediatrics registrars at Indiana University since 2006. The program's logistics, curriculum, and evaluation are described. RESULTS: The registrars rotated through nephrology, cardiology, hematology and oncology, infectious diseases, and intensive care, as well as related ambulatory experiences, functioning on a level comparable to fourth-year medical students. They showed significant improvement in pretest and posttest scores on a standardized National Board of Medical Examiners examination (P = .048). International learners experienced culture shock, yet they felt the Indiana University elective was helpful and would recommend it to future participants. CONCLUSIONS: Global health programs can reciprocate the benefits derived for US students and residents by offering learning experiences to international learners if that is an expressed need from the international partner. Barriers to those experiences can be overcome, and the hands-on, elective experience has the potential to positively affect the knowledge and attitudes of participants as well as the home nation. PMID- 24949141 TI - Use of a secure social media platform to facilitate reflection in a residency program. AB - BACKGROUND: Reflective writing is used to promote learning and professional growth in medical education. Sharing reflections with peers and supervisors facilitates feedback that enhances understanding. OBJECTIVE: We explored the feasibility of using a secure social media platform to share reflections and promote reflective discussions in an emergency medicine residency program. METHODS: This was a prospective pilot investigation evaluated with a poststudy opinion survey. Reflective discussions were also described using basic quantitative and qualitative methods. RESULTS: The 2-month, voluntary, pilot study included 21 faculty and 36 residents. Faculty posted reflections and replies (n = 146) more frequently than residents did (n = 48). Survey data suggested both groups found the platform engaging and easy to use, valued the security of the platform, and felt the conversations were valuable to their professional development. CONCLUSIONS: Secure social media offers a feasible option for sharing reflections and facilitating reflective discussions in medical education. PMID- 24949142 TI - Perceptions of internal medicine-pediatrics residents about autonomy during residency. AB - BACKGROUND: The development of autonomy is a key component of residency training. Although studies have examined levels of graduated autonomy within specialties, they have not, to our knowledge, examined how residents' perceptions of autonomy differ among specialties. OBJECTIVE: We surveyed residents in internal medicine pediatrics programs to determine their perceptions of the autonomy they experienced when they were serving on internal medicine (IM) and pediatrics inpatient rotations. METHODS: In 2012, we administered a 24-item online survey to residents in 36 internal medicine-pediatrics programs. RESULTS: Of 698 eligible residents, 143 (20.5%) participated. Participants were distributed equally among all 4 postgraduate years and between IM and pediatrics rotations. Participants were more likely to agree they experienced an appropriate level of autonomy when they were on IM rotations than when they were on pediatrics rotations (97.9% versus 34.3%, P < .001), were more likely to report experiencing frustration with too little oversight while on IM rotations (32.9% versus 2.2%, P < .001), and were more likely to report experiencing frustration with too much oversight while on pediatrics rotations (48.2% versus 0.7%, P < .001). Responses to items that described frequently encountered circumstances and hypothetical medical cases indicated participants were more likely to feel anxiety and discomfort with autonomous decision making while on pediatrics rotations. CONCLUSIONS: Residents in internal medicine-pediatrics programs perceive significant differences in the autonomy they experience during IM and pediatrics rotations. This may influence their confidence in medical decision making. PMID- 24949143 TI - Role of an audience response system in didactic attendance and assessment. AB - BACKGROUND: The Residency Review Committee for Emergency Medicine mandates conference participation, but tracking attendance is difficult and fraught with errors. Feedback on didactic sessions, if not collected in real time, is challenging to obtain. OBJECTIVE: We assessed whether an audience response system (ARS) would (1) encourage residents to arrive on time for lectures, and (2) increase anonymous real-time audience feedback. METHODS: The ARS (Poll Everywhere) provided date/time-stamped responses to polls from residents, including a question to verify attendance and questions to gather immediate, anonymous postconference evaluations. Fisher exact test was used to calculate proportions. RESULTS: The proportion of residents who completed evaluations prior to the institution of the ARS was 8.75, and it was 59.42 after (P < .001). The proportion of faculty who completed evaluations prior to using the ARS was 6.12, and it was 85.71 after (P < .001). The proportion of residents who reported they had attended the conference session was 55 for the 3 weeks prior to initiating the ARS, decreasing to 46.67 for the 3 weeks during which the ARS was used to take attendance (P = .46). The proportion of faculty who reported attending the conference was 5.56 for the 3 weeks prior to ARS initiation, decreasing to 4.44 for the 3 weeks while using the ARS (P = .81). CONCLUSIONS: Audience response systems are an effective way to verify attendance and tardiness, eliminating the subjective effect of attendance takers' leniency and increasing completion of evaluations for didactic sessions. PMID- 24949144 TI - Perceptions of internal medicine residency program candidates on the use of simulation in the selection process. AB - BACKGROUND: The recruitment of skilled candidates into internal medicine residency programs has relied on traditional interviewing techniques with varying degrees of success. The development of simulated medical technology has provided a new arena in which to assess candidates' clinical skills, knowledge base, situational awareness, and problem-solving dexterities within a standardized environment for educational and assessment purposes. OBJECTIVE: The purpose of this study was to investigate the interest of program candidates in incorporating simulation medicine into the internal medicine residency interview process. METHODS: As a prospective, survey-based analysis, potential candidates who completed an interview between October 2012 and January 2013 with an accredited internal medicine residency program were sent a postmatch survey that incorporated 3 additional questions relating to their prior experience with medical simulation and their views on incorporating the technology into the interview format. RESULTS: Of the 88 candidates who completed an interview, 92% (n = 81) were scheduled to graduate medical school in 2013 and were graduates of a US medical school. All survey responders described previous experience with medical simulation. Fifty-eight percent (n = 51) of responders described being "less likely" to interview with or join a residency program if they were required to participate in a 10-minute medical simulation during the interview process. CONCLUSIONS: The results of this study suggest that despite the increasing role of technology in medical education, its role in high-stakes evaluations (such as residency interviews) requires further maturation before general acceptance by residency candidates can be expected. PMID- 24949145 TI - Randomized Controlled Trial of RSS Reader Use and Resident Familiarity With Primary Literature. AB - BACKGROUND: Awareness of the primary literature is important for clinicians. Lack of time, poor access to information, and lack of personal initiative may be barriers for some trainees. Really Simple Syndication (RSS) readers aggregate web content, such as journal abstracts, in a single location for easy viewing. OBJECTIVE: We assessed whether use of an RSS reader would increase resident reading frequency, familiarity, and understanding of the primary literature. METHODS: We conducted a single-center, prospective, randomized, nonblinded, controlled trial of the effect of RSS reader use on knowledge of recent literature among pediatrics residents. Residents were randomly assigned to the RSS group (education in RSS use and receipt of the Pediatrics RSS feed) or a control group that followed standard reading practices. Outcome measures were differences on baseline and monthly surveys of reading frequency, familiarity with recent publications, and knowledge of recent articles (familiarity validation). RESULTS: Of 144 eligible residents, 79 (55%) were enrolled in the survey, with 81% (64 of 79) of participants completing all surveys. The RSS reader use was correlated with greater familiarity with selected articles, but not with improved understanding (as measured by ability to answer multiple-choice questions about content). Participants reported satisfaction with the RSS reader based on its ease of use, accessibility, and as an aid in supplementing reading. CONCLUSIONS: The RSS reader use was accepted by residents and associated with increased familiarity with the primary literature but not with increased understanding. PMID- 24949146 TI - A practical approach to conflict management for program directors. PMID- 24949147 TI - Responsible global health engagement: a road map to equity for academic partnerships. PMID- 24949149 TI - The Allopathic Program Director's Dilemma. PMID- 24949148 TI - Picking the right dose: the challenges of applying spaced testing to education. PMID- 24949150 TI - The CORD Standardized Letter of Evaluation: Have We Achieved Perfection or Just a Better Understanding of Our Limitations? PMID- 24949151 TI - Faculty development in narrative medicine: using stories to teach, learn, and thrive. PMID- 24949152 TI - A pragmatic approach to professional and ethical dilemmas. PMID- 24949153 TI - Utilization of a referral-based procedure clinic to improve procedure training and assessment in a family medicine residency. PMID- 24949154 TI - How bodies learn: a brief intervention using dance and dialogue. PMID- 24949155 TI - A longitudinal curriculum to address the gender gap in physician leadership. PMID- 24949156 TI - Morbidity, mortality, and improvement-moving ideas into action. PMID- 24949157 TI - All Hands on Deck-Structuring the CCC for Successful NAS Reporting. PMID- 24949158 TI - Introduction to outpatient medicine and the patient-centered medical home rotation: teaching interns to thrive in clinic. PMID- 24949160 TI - Meeting of the minds: a novel longitudinal ambulatory mental health rotation for internal medicine residents. PMID- 24949159 TI - The resident audio recording project: a 3-step process to improve clinical communication skills. PMID- 24949161 TI - Defense of the measures: a tool for engaging integrated care teams in outcomes measurement. PMID- 24949162 TI - Adapting ACGME-Accredited Training to Meet Changing Demands of the Workforce: The NuRad Pathway. PMID- 24949163 TI - Online surgical outcome database to improve resident cataract surgery performance. PMID- 24949164 TI - A Multidisciplinary, Experiential, Educational Curriculum in Child Abuse: The Pediatrician's Role in Early Recognition, Documentation, Management, and Legal Advocacy. PMID- 24949165 TI - Implementation of a monitored educational curriculum and impact on pediatrics resident in-training examination scores. PMID- 24949166 TI - Effectiveness of a mentored, longitudinal program fostering scholarly research by residents. PMID- 24949167 TI - The university of washington pediatric alaska track: a novel approach to training primary care pediatricians. PMID- 24949168 TI - PREDICT: Instituting an Educational Time Out in the Operating Room. PMID- 24949170 TI - Observations: the next accreditation system: a perspective. PMID- 24949169 TI - Observations: clinical revenue directly attributable to anesthesiology residents. PMID- 24949171 TI - Observations: milestones for combined training programs-innovation or burden? PMID- 24949172 TI - Comments: scholarly activities for residents: high expectations? PMID- 24949173 TI - Comments: defining the scholarly and scholarship common program requirements. PMID- 24949174 TI - Comments: the characteristics and purpose of resident scholarship. PMID- 24949175 TI - Comments: authors' response to letters regarding "defining the scholarly and scholarship common program requirements". PMID- 24949176 TI - Bereavement china and edge-work. PMID- 24949177 TI - Ambulatory training for primary care general internists: innovation with the affordable care act in mind. AB - BACKGROUND: Although primary care general internists (PCGIs) are essential to the physician workforce and the success of the Affordable Care Act, they are becoming an endangered species. OBJECTIVE: We describe an expanded program to educate PCGIs to meet the needs of a reformed health care system and detail the competencies PCGIs will need for their roles in team-based care. INTERVENTION: We recommended 5 initiatives to stabilize and expand the PCGI workforce: (1) caring for a defined patient population, (2) leading and serving as members of multidisciplinary health care teams, (3) participating in a medical neighborhood, (4) improving capacity for serving complex patients in group practices and accountable care organizations, and (5) finding an academic role for PCGIs, including clinical, population health, and health services research. A revamped approach to PCGI education based in teaching health centers formed by community health center and academic medical center partnerships would facilitate these curricular innovations. ANTICIPATED OUTCOMES: New approaches to primary care education would include multispecialty group practices facilitated by electronic consultation and clinical decision-support systems provided by the academic medical center partner. Multiprofessional and multidisciplinary education would prepare PCGI trainees with relevant skills for 21st century practice. The centers would also serve as sites for state and federal Medicaid graduate medical education (GME) expansion funding, making this funding more accountable to national health workforce priorities. CONCLUSIONS: The proposed innovative approach to PCGI training would provide an innovative educational environment, enhance general internist recruitment, provide team-based care for underserved patients, and ensure accountability of GME funds. PMID- 24949178 TI - Patterns of Change in ACGME-Accredited Residency Programs and Positions: Implication for the Adequacy of GME Positions and Supply of Physicians in the United States. AB - BACKGROUND: Recent studies suggest that the supply of primary care physicians and generalist physicians in other specialties may be inadequate to meet the needs of the US population. Data on the numbers and types of physicians-in-training, such as those collected by the Accreditation Council for Graduate Medical Education (ACGME), can be used to help understand variables affecting this supply. OBJECTIVE: We assessed trends in the number and type of medical school graduates entering accredited residencies, and the impact those trends could have on the future physician workforce. METHODS: Since 2004, the ACGME has published annually its data on accredited institutions, programs, and residents to help the graduate medical education community understand major trends in residency education, and to help guide graduate medical education policy. We present key results and trends for the period between academic years 2003-2004 and 2012-2013. RESULTS: The data show that increases in trainees in accredited programs are not uniform across specialties, or the types of medical school from which trainees graduated. In the past 10 years, the growth in residents entering training that culminates in initial board certification ("pipeline" specialties) was 13.0%, the number of trainees entering subspecialty education increased 39.9%. In the past 5 years, there has been a 25.8% increase in the number of osteopathic physicians entering allopathic programs. CONCLUSIONS: These trends portend challenges in absorbing the increasing numbers of allopathic and osteopathic graduates, and US international graduates in accredited programs. The increasing trend in subspecialization appears at odds with the current understanding of the need for generalist physicians. PMID- 24949180 TI - Short term efficacy and safety of low dose tolvaptan in patients with acute decompensated heart failure with hyponatremia: a prospective observational pilot study from a single center in South India. AB - BACKGROUND: In acute decompensated heart failure (ADHF), diuretic use, the mainstay therapy for congestion, is associated with electrolyte abnormalities and worsening renal function. Vasopressin mediates fluid retention in heart failure. In contrast to diuretics, the vasopressin antagonist tolvaptan may increase net volume loss in heart failure without adversely affecting electrolytes and renal function. Hyponatremia (serum sodium concentration, <135 mEq/L) is a predictor of death among patients with heart failure. OBJECTIVE: We prospectively observed the short term efficacy and safety of low dose (15 mg) tolvaptan in admitted patients with hyponatremia and ADHF in Indian population. METHODOLOGY: A total of 40 patients with ADHF along with hyponatremia (<125 mEq/L) on standard therapy were treated with 15 mg of tolvaptan at a single oral dose for 7 days. RESULTS: Serum sodium concentrations increased significantly after treatment with tolvaptan from baseline (P < 0.02). There was a significant improvement in symptoms and New York Heart Association (NYHA) class after starting tolvaptan (P <= 0.05). Total diuretic dose and mean body weight was reduced non-significantly at 7(th) day from the baseline. Side-effects associated with tolvaptan included increased thirst, dry mouth and increased urination. Few patients had worsening renal function. However, several patients developed hypernatremia. CONCLUSION: In this small observational study, tolvaptan initiation in patients with ADHF with hyponatremia in addition to standard therapy may hold promise in improvement in NYHA class and serum sodium. At the same time, we observed that serious adverse events such as renal function deterioration and hypernatremia developed after tolvaptan treatment, which needs to be addressed in future by randomized study with larger sample size. PMID- 24949182 TI - Expanding giant right coronary artery aneurysm: an acute need for new management strategies. AB - Angiography use has become increasingly common worldwide. Coronary artery aneurysm may be an incidental finding during angiography. Occasionally it might be symptomatic or may become symptomatic over the course of time. Rupture of aneurysm may lead to disastrous complications. Here we present a case in which aneurysm was asymptomatic but surgical intervention was done because of rapid increase in the size of aneurysm. This is to drive home the point that timely surgical intervention is instrumental in preventing complications associated with possible rupture of the aneurysm. PMID- 24949181 TI - Rationale, Design, Methodology and Hospital Characteristics of the First Gulf Acute Heart Failure Registry (Gulf CARE). AB - BACKGROUND: There is paucity of data on heart failure (HF) in the Gulf Middle East. The present paper describes the rationale, design, methodology and hospital characteristics of the first Gulf acute heart failure registry (Gulf CARE). MATERIALS AND METHODS: Gulf CARE is a prospective, multicenter, multinational registry of patients >18 year of age admitted with diagnosis of acute HF (AHF). The data collected included demographics, clinical characteristics, etiology, precipitating factors, management and outcomes of patients admitted with AHF. In addition, data about hospital readmission rates, procedures and mortality at 3 months and 1-year follow-up were recorded. Hospital characteristics and care provider details were collected. Data were entered in a dedicated website using an electronic case record form. RESULTS: A total of 5005 consecutive patients were enrolled from February 14, 2012 to November 13, 2012. Forty-seven hospitals in 7 Gulf States (Oman, Saudi Arabia, Yemen, Kuwait, United Gulf Emirates, Qatar and Bahrain) participated in the project. The majority of hospitals were community hospitals (46%; 22/47) followed by non-University teaching (32%; 15/47 and University hospitals (17%). Most of the hospitals had intensive or coronary care unit facilities (93%; 44/47) with 59% (28/47) having catheterization laboratory facilities. However, only 29% (14/47) had a dedicated HF clinic facility. Most patients (71%) were cared for by a cardiologist. CONCLUSIONS: Gulf CARE is the first prospective registry of AHF in the Middle East, intending to provide a unique insight into the demographics, etiology, management and outcomes of AHF in the Middle East. HF management in the Middle East is predominantly provided by cardiologists. The data obtained from this registry will help the local clinicians to identify the deficiencies in HF management as well as provide a platform to implement evidence based preventive and treatment strategies to reduce the burden of HF in this region. PMID- 24949183 TI - Recurrent myocardial infarction in a case of congenital afibrinogenemia. AB - Afibrinogenemia is a rare autosomal recessive bleeding disorder with an estimated prevalence of 1:1,000,000. Usual presentation of this disorder is spontaneous bleeding, bleeding after minor trauma and excessive bleeding during interventional procedures. Paradoxically, few patients with afibrinogenemia may also suffer from severe thromboembolic complications. The management of these patients is particularly challenging because they are not only at risk of thrombosis but also of bleeding. We are presenting a case of 33-year-old male patient of congenital afibrinogenemia who had two episodes myocardial infarction in a span of two years. The patient was managed conservatively with antiplatelet therapy and thrombolytic therapy was not given due to high risk for bleeding. PMID- 24949184 TI - Successful accessory renal artery denervation in a patient with resistant hypertension. AB - Renal sympathetic denervation is safe and effective in patients with resistant hypertension. In all of the studies of renal artery denervation, patients with accessory renal arteries are excluded. So there is not any data regarding renal sympathetic denervation applied to the accessory renal arteries. We present a young female patient with resistant hypertension despite use of five different antihypertensive drugs. The patient had a well developed (diameter >4 mm) left renal accessory. We believe that if we omitted the well developed accessory renal artery, we would not have maintained adequate blood pressure control. Thus, we applied radiofrequency ablation to both renal arteries and left accessory artery. Immediately after the procedure, the patient's blood pressure was reduced to 110/60 mmHg and this effect was continued during the first month of follow-up. PMID- 24949185 TI - Two cases of acute myocarditis with multiple intracardiac thrombi: the role of hypercoagulable States. AB - In acute myocarditis, thrombus formation is an important prognostic factor. Early diagnosis and treatment of intracardiac thrombus is critical, especially when there are multiple thrombi. When a patient presents with multiple cardiac thrombi not only cardiac disorders, but other diseases such as malignancies, rheumatologic disorders and thrombophilia must be considered in the differential diagnosis. Although the presence of hypercoagulable states does not generally affect the treatment choice, it may have an impact on continuation and duration of the anticoagulant therapy. In this paper, we present two cases of acute myocarditis with multiple intracardiac thrombi. Additionally, these cases had hypercoagulable states which might have contributed to the thrombus formation. PMID- 24949186 TI - Early Extracorporeal Membrane Oxygenation Support for 5-Fluorouracil-induced Acute Heart Failure with Cardiogenic Shock. AB - A 50-year-old man with no previous history of cardiovascular disease or risk factors was admitted for syncope and orthopnea. Importantly, he underwent recent chemotherapy with 5-fluorouracil (5-FU) until 1 day before his acute presentation. In the emergency room, patient developed asystole and was successfully resuscitated for 2 min. At coronary angiography, no signs of coronary artery disease were detectable, but transthoracic echocardiography showed a severely decreased left-ventricular systolic function. Due to the progressive cardiogenic shock, an extracorporeal membrane oxygenation (ECMO) support was used as bridge-to-recovery and to avoid the use of sympathomimetics with their known disadvantages. On ECMO support, hemodynamic stabilization was evident and medical heart failure treatment was commenced. Left-ventricular function recovered to normal values within a short period of time. Cardiac complications after chemotherapy with 5-FU are not rare and should be taken into consideration even in acute heart failure with cardiogenic shock. ECMO as the most potent form of acute cardiorespiratory support enables complete relief of cardiac workload and therefore recovery of cardiac function. PMID- 24949188 TI - Mechanical heart pump in the thorax. PMID- 24949187 TI - Aortic debranching and endovascular treatment of aortic arch aneurysm. PMID- 24949189 TI - Overcoming Nonlinear Partial Volume Effects in Known-Component Reconstruction of Cochlear Implants. AB - Nonlinear partial volume (NLPV) effects can be significant for objects with large attenuation differences and fine detail structures near the spatial resolution limits of a tomographic system. This is particularly true for small metal devices like cochlear implants. While traditional model-based approaches might alleviate these artifacts through very fine sampling of the image volume and subsampling of rays to each detector element, such solutions can be extremely burdensome in terms of memory and computational requirements. The work presented in this paper leverages the model-based approach called "known-component reconstruction" (KCR) where prior knowledge of a surgical device is integrated into the estimation. In KCR, the parameterization of the object separates the volume into an unknown background anatomy and a known component with unknown registration. Thus, one can model projections of an implant at very high spatial resolution while limiting the spatial resolution of the anatomy - in effect, modeling NLPV effects where they are most significant. We present modifications of the KCR approach that can be used to largely eliminate NLPV artifacts, and demonstrate the efficacy of the modified technique (with improved image quality and accurate implant position estimates) for the cochlear implant imaging scenario. PMID- 24949190 TI - Managing the potential and pitfalls during clinical translation of emerging stem cell therapies. AB - We are moving into a new era of stem cell research where many possibilities for treatment of degenerative, chronic and/or fatal diseases and injuries are becoming primed for clinical trial. These reports have led millions of people worldwide to hope that regenerative medicine is about to revolutionise biomedicine: either through transplantation of cells grown in the laboratory, or by finding ways to stimulate a patient's intrinsic stem cells to repair diseased and damaged organs. While major contributions of stem cells to drug discovery, safety and efficacy testing, as well as modelling 'diseases in a dish' are also expected, it is the in vivo use of stem cells that has captured the general public's attention. However, public misconceptions of stem cell potential and applications can leave patients vulnerable to the influences of profit driven entities selling unproven treatments without solid scientific basis or appropriate clinical testing or follow up. This review provides a brief history of stem cell clinical translation together with an overview of the properties, potential, and current clinical application of various stem cell types. In doing so it presents a clearer picture of the inherent risks and opportunities associated with stem cell research translation, and thus offers a framework to help realise invested expectations more quickly, safely and effectively. PMID- 24949191 TI - Lung ultrasound imaging in avian influenza A (H7N9) respiratory failure. AB - BACKGROUND: Lung ultrasound has been shown to identify in real-time, various pathologies of the lung such as pneumonia, viral pneumonia, and acute respiratory distress syndrome (ARDS). Lung ultrasound maybe a first-line alternative to chest X-ray and CT scan in critically ill patients with respiratory failure. We describe the use of lung ultrasound imaging and findings in two cases of severe respiratory failure from avian influenza A (H7N9) infection. METHODS: Serial lung ultrasound images and video from two cases of H7N9 respiratory failure requiring mechanical ventilation and extracorporeal membrane oxygenation in a tertiary care intensive care unit were analyzed for characteristic lung ultrasound findings described previously for respiratory failure and infection. These findings were followed serially, correlated with clinical course and chest X-ray. RESULTS: IN BOTH PATIENTS, CHARACTERISTIC LUNG ULTRASOUND FINDINGS HAVE BEEN OBSERVED AS PREVIOUSLY DESCRIBED IN VIRAL PULMONARY INFECTIONS: subpleural consolidations associated or not with local pleural effusion. In addition, numerous, confluent, or coalescing B-lines leading to 'white lung' with corresponding pleural line thickening are associated with ARDS. Extension or reduction of lesions observed with ultrasound was also correlated respectively with clinical worsening or improvement. Coexisting consolidated pneumonia with sonographic air bronchograms was noted in one patient who did not survive. CONCLUSIONS: Clinicians with access to point-of-care ultrasonography may use these findings as an alternative to chest X-ray or CT scan. Lung ultrasound imaging may assist in the efficient allocation of intensive care for patients with respiratory failure from viral pulmonary infections, especially in resource scarce settings or situations such as future respiratory virus outbreaks or pandemics. PMID- 24949192 TI - Diaphragm ultrasound as a new index of discontinuation from mechanical ventilation. AB - BACKGROUND: Predictive indexes of weaning from mechanical ventilation are often inaccurate. Among the many indexes used in clinical practice, the rapid shallow breathing index is one of the most accurate. We evaluated a new weaning index consisting in the diaphragm thickening fraction (DTF) assessed by ultrasound. METHODS: Forty-six patients were prospectively enrolled. All patients were ventilated in pressure support through a tracheostomy tube. Patients underwent a spontaneous breathing trial (SBT) when they met all the following criteria: FiO2 < 0.5, PEEP <=5 cmH2O, PaO2/FiO2 > 200, respiratory rate <30 breaths per minute, absence of fever, alert and cooperative, and hemodynamic stability without vaso active therapy support. During the trial, the right hemi-diaphragm was visualized in the zone of apposition using a 10-MHz linear ultrasound probe. The patient was then instructed to perform breathing to total lung capacity (TLC) and then exhaling to residual volume (RV). Diaphragm thickness was recorded at TLC and RV, and the DTF was calculated as percentage from the following formula: Thickness at end inspiration - Thickness at end expiration / Thickness at end expiration. Also, the rapid shallow breathing index (RSBI) was calculated. Weaning failure was defined as the inability to maintain spontaneous breathing for at least 48 h, without any form of ventilatory support. RESULTS: A significant difference between diaphragm thickness at TLC and RV was observed both in patients who succeeded SBT and patients who failed. DTF was significantly different between patients who failed and patients who succeeded SBT. A cutoff value of a DTF >36% was associated with a successful SBT with a sensitivity of 0.82, a specificity of 0.88, a positive predictive value (PPV) of 0.92, and a negative predictive value (NPV) of 0.75. By comparison, RSBI <105 had a sensitivity of 0.93, a specificity of 0.88, a PPV of 0.93, and a NPV of 0.88 for determining SBT success. CONCLUSIONS: This study shows that in our cohort of patients, the assessment of DTF by diaphragm ultrasound may perform similarly to other weaning indexes. If validated by other studies, this method may be used in clinical practice. PMID- 24949193 TI - A microsurgical procedure for middle cerebral artery occlusion by intraluminal monofilament insertion technique in the rat: a special emphasis on the methodology. AB - INTRODUCTION: Although there are many experimental studies describing the methodology of the middle cerebral artery occlusion (MCAO) in the literature, only limited data on these distinct anatomical structures and the details of the surgical procedure in a step by step manner. The aim of the present study simply is to examine the surgical anatomy of MCAO model and its modifications in the rat. MATERIALS AND METHODS: Forty Sprague-Dawley rats were used; 20 during the training phase and 20 for the main study. The monofilament sutures were prepared as described in the literature. All surgical steps of the study were performed under the operating microscope, including insertion of monofilament into middle cerebral artery through the internal carotid artery. RESULTS: After an extensive training period, we lost two rats in four weeks. The effects of MCAO were confirmed by the evidence of severe motor deficit during the recovery period, and histopathological findings of infarction were proved in all 18 surviving rats. CONCLUSION: In this study, a microsurgical guideline of the MCAO model in the rat is provided with the detailed description of all steps of the intraluminal monofilament insertion method with related figures. PMID- 24949194 TI - Mining characteristics of epidemiological studies from Medline: a case study in obesity. AB - BACKGROUND: The health sciences literature incorporates a relatively large subset of epidemiological studies that focus on population-level findings, including various determinants, outcomes and correlations. Extracting structured information about those characteristics would be useful for more complete understanding of diseases and for meta-analyses and systematic reviews. RESULTS: We present an information extraction approach that enables users to identify key characteristics of epidemiological studies from MEDLINE abstracts. It extracts six types of epidemiological characteristic: design of the study, population that has been studied, exposure, outcome, covariates and effect size. We have developed a generic rule-based approach that has been designed according to semantic patterns observed in text, and tested it in the domain of obesity. Identified exposure, outcome and covariate concepts are clustered into health related groups of interest. On a manually annotated test corpus of 60 epidemiological abstracts, the system achieved precision, recall and F-score between 79-100%, 80-100% and 82-96% respectively. We report the results of applying the method to a large scale epidemiological corpus related to obesity. CONCLUSIONS: The experiments suggest that the proposed approach could identify key epidemiological characteristics associated with a complex clinical problem from related abstracts. When integrated over the literature, the extracted data can be used to provide a more complete picture of epidemiological efforts, and thus support understanding via meta-analysis and systematic reviews. PMID- 24949195 TI - Intervention programs to increase influenza vaccination in Israel: which is the preferred one? AB - Influenza vaccine is the most effective method of preventing influenza and its complications, but coverage rates are not satisfactory. Therefore, an effective intervention is required to increase vaccination coverage. In a recent study published in IJHPR, Yamin et al. identified the need to target risk perception in the public, as a major intervention tool. Risk perception and compliance with vaccination guidelines was found to be mostly influenced by physician recommendations. These findings are in-line with similar findings in the literature, stressing the importance of patient-physician interaction in the patients' decision to comply with vaccination guidelines produced by the public health authorities. They also underscore the need to involve primary physicians in both the decision making process as well in the vaccination campaign. PMID- 24949196 TI - Choice of bacterial DNA extraction method from fecal material influences community structure as evaluated by metagenomic analysis. AB - BACKGROUND: In recent years, studies on the human intestinal microbiota have attracted tremendous attention. Application of next generation sequencing for mapping of bacterial phylogeny and function has opened new doors to this field of research. However, little attention has been given to the effects of choice of methodology on the output resulting from such studies. RESULTS: IN THIS STUDY WE CONDUCTED A SYSTEMATIC COMPARISON OF THE DNA EXTRACTION METHODS USED BY THE TWO MAJOR COLLABORATIVE EFFORTS: The European MetaHIT and the American Human Microbiome Project (HMP). Additionally, effects of homogenizing the samples before extraction were addressed. We observed significant differences in distribution of bacterial taxa depending on the method. While eukaryotic DNA was most efficiently extracted by the MetaHIT protocol, DNA from bacteria within the Bacteroidetes phylum was most efficiently extracted by the HMP protocol. CONCLUSIONS: Whereas it is comforting that the inter-individual variation clearly exceeded the variation resulting from choice of extraction method, our data highlight the challenge of comparing data across studies applying different methodologies. PMID- 24949197 TI - Isolation and antimicrobial susceptibility pattern of Staphylococcus aureus in patients with surgical site infection at Debre Markos Referral Hospital, Amhara Region, Ethiopia. AB - BACKGROUND: Staphylococcus aureus, especially Methicillin Resistant Staphylococcus Aureus (MRSA) is a major health problem recognized as the most important nosocomial pathogen, often causing postoperative wound infections. Antibiotic resistance by MRSA has grown to be common, and resistance to almost all antibiotics has been found among these strains. The aim of this study was to determine the prevalence, antimicrobial susceptibility patterns and associated risk factors of S. aureus in patients with surgical site infections in an Ethiopian hospital. METHODS: A cross-sectional study was conducted from December 1, 2011 to March 30, 2012 among patients with surgical site infections at Debre Markos Referral Hospital, Debre Markos, Ethiopia. All wound swabs obtained from patients with surgical site infections during the study period were cultured on mannitol salt agar media which is selective for S. aureus. Isolated strains of S. aureus were tested for antibiotic susceptibility patterns using standard disc diffusion technique, and interpretation of resistance was done based on Clinical and Laboratory Standard Institute criteria. Univariate and multivariable analyses were used to assess the risk factors. RESULTS: Of the 184 surgical patients who had developed surgical site infection, S. aureus was isolated from 73 (39.7%) cases. Out of the 73 isolates of S. aureus, 36 (49.7%) were MRSA. Among the study participants, prevalence of MRSA was found to be 19.6%. The clinical isolates showed >80% level of resistance to ampicillin, amoxicillin, penicillin G, erythromycin, gentamicin and cotrimoxazole whereas <50% level of resistance was observed against clindamycin, oxacillin, tetracycline and vancomycin. MRSA strains showed resistance ranging from 5.6% (vancomycin) to 100% (cotrimoxazole). Of the following risk factors: sex, age, pus consistency, duration of operation, type of surgery, ward and hospital stay, laparotomy type of surgery was identified as a risk factor for infection by S. aureus. CONCLUSION: The prevalence of S. aureus and/or MRSA infection in surgical and gynaecology & obstetrics wards of Debre Markos Referral Hospital was found to be high. The majority of isolates were highly resistant to major antimicrobial agents. PMID- 24949198 TI - Is the different time trend (1997-2008) of the obesity prevalence among adults in the three Belgian regions associated with lifestyle changes? AB - BACKGROUND: Obesity is a major public health issue with increasing prevalence among adults. However, in Belgium the regional time trends (1997-2008) differed: the prevalence of obesity increased in the Flemish and Brussels Regions, but remained stable in the Walloon Region, the latter still showing the highest prevalence. The purpose of the present study is to explore if the different time trends of obesity prevalence in the three Belgian regions is associated with lifestyle changes. METHODS: We used data from four successive cross-sectional waves (1997, 2001, 2004 and 2008) of the Belgian Health Interview Survey. The study was restricted to the adult population, resulting in samples of respectively 8,071, 9,391, 10,319 and 8,831 individuals. In line with the WHO definition, obesity was defined as having a BMI >= 30. Differences in regional trends of obesity were investigated through stratified analyses. The association between obesity and survey year, adjusted for lifestyle factors (alcohol consumption, smoking, fruit and vegetables consumption and leisure time physical activity), was assessed via logistic regression models. Interactions were added to the models to explore if the association between lifestyle factors and obesity varied over time. RESULTS: Obesity was associated with daily alcohol use in the Brussels (OR 0.66, 95% CI 0.50-0.88) and Walloon Regions (OR 0.8, 95% CI 0.6 0.9), with lower tendencies of being obese for daily drinkers. The probability of being obese was lower among smokers in the Flemish (OR 0.7, 95% CI 0.6-0.8) and Walloon Regions (OR 0.7, 95% CI 0.6-0.9) than among non-smokers. A lack of leisure time physical activity was associated with the probability of being obese in all regions (Brussels Region: OR 1.6, 95% CI 1.3-1.8; Flemish Region: OR 1.6, 95% CI 1.4-1.9; Walloon Region: OR 1.8, 95% CT 1.6-2.1). This association decreased significantly between 1997 and 2008 only in the Walloon Region. CONCLUSION: The decreasing association between obesity and a lack of leisure time physical activity in the Walloon Region between 1997 and 2008 could indicate that there is an increasing awareness of risk factors for obesity in the Walloon population, which may have resulted in a more favourable evolution of the obesity epidemic. PMID- 24949200 TI - Nanoscale Control of Silks for Nanofibrous Scaffold Formation with Improved Porous Structure. AB - Silk-based porous scaffolds have been used extensively in tissue engineering because of their excellent biocompatibility, tunable biodegradability and robust mechanical properties. Although many silk-based scaffolds have been prepared through freeze-drying, a challenge remains to effectively control porous structures during this process. In the present study silk fibroin with different nanostructures were self-assembled in aqueous solution by repeated drying dissolving process and then used to improve porous structure formation in lyophilization process. Viscosity, secondary structures and water interactions were also studied to exclude their influence on the formation and control of porous structures. Following nanofiber formation in aqueous solution, silk scaffolds with improved porous structure were directly formed after lyophilization and then stabilized with water or methanol annealing treatments. Compared to silk scaffolds derived from fresh solution, the nanofibrous scaffolds showed significantly better cell compatibility in vitro. Therefore, this nanoscale control of silk offers feasible way to regulate the matrix features including porous structure and nanostructure, which are important in regulating cell and tissue outcomes in tissue engineering and regeneration, and then achieve silk-based scaffolds with improved properties. PMID- 24949201 TI - Thermomechanical Properties, Antibiotic Release, and Bioactivity of a Sterilized Cyclodextrin Drug Delivery System. AB - Various local drug delivery devices and coatings are being developed as slow, sustained release mechanism for drugs, yet the polymers are typically not evaluated after commercial sterilization techniques. We examine the effect that commercial sterilization techniques have on the physical, mechanical, and drug delivery properties of polyurethane polymers. Specifically we tested cyclodextrin hexamethyl diisocyanate crosslinked polymers before and after autoclave, ethylene oxide, and gamma radiation sterilization processes. We found that there is no significant change in the properties of polymers sterilized by ethylene oxide and gamma radiation compared to non-sterilized polymers. Polymers sterilized by autoclave showed increased tensile strength (p<0.0001) compared to non-sterilized polymers . In the release of drugs, which were loaded after the autoclave sterilization process, we observed a prolonged release (p<0.05) and a prolonged therapeutic effect (p<0.05) but less drug loading (p<0.0001) compared to non sterilized polymers. The change in the release profile and tensile strength in polymers sterilized by autoclave was interpreted as being caused by additional crosslinking from residual, unreacted, or partially-reacted crosslinker contained within the polymer. Autoclaving therefore represents additional thermo-processing to modify rate and dose from polyurethanes and other materials. PMID- 24949199 TI - Relevance of Liver Failure for Anti-Infective Agents: From Pharmacokinetic Alterations to Dosage Adjustments. AB - The liver is a complex organ with great ability to influence drug pharmacokinetics. Due to its wide array of function, its impairment has the potential to affect bioavailability, enterohepatic circulation, drug distribution, metabolism, clearance, and biliary elimination. These alterations differ widely depending on the cause of the liver failure, if it is acute or chronic in nature, the extent of impairment, and comorbid conditions. In addition, effects on liver functions do not occur in a proportional or predictable manner for escalating degrees of liver impairment. The ability of hepatic alterations to influence PK is also dependent on drug characteristics, such as administration route, chemical properties, protein binding, and extraction ratio, among others. This complexity makes it difficult to predict what these effects have on drugs. Unlike certain classes of agents, efficacy of anti-infectives is most often dependent on fulfilling pharmacokinetic/pharmacodynamic targets, such as Cmax/MIC, AUC/MIC, T>MIC, IC50/EC50, or T>EC95. Loss of efficacy, or conversely, increased risk of toxicity may occur in certain circumstances of liver injury. Although important to consider these potential alterations and their effects on specific anti infectives, many lack data to constitute specific dosing adjustments, making it important to monitor patients for effectiveness and toxicities of therapy. PMID- 24949202 TI - Retinal-image quality and night-vision performance after alcohol consumption. AB - Purpose. To evaluate the influence of alcohol consumption on the retinal-image quality and visual performance under surrounding low-illumination conditions. Methods. A volunteer sample of 67 subjects was analyzed. Optical quality of the eye was evaluated by means of the Strehl ratio, the Objective Scattering Index (OSI), and the tear-film quality. We used the visual disturbance index (VDI) to evaluate visual performance under low-illumination conditions and we measured the pupil size under these conditions. The tear-film volume was also measured. All measurements were made before and after alcohol consumption and patients were classified into two groups depending on their breath alcohol content (BrAC): low alcohol (BrAC < 0.25 mg/L) and high-alcohol content (BrAC >= 0.25 mg/L). Results. The VDI was significantly higher after alcohol consumption: the higher the BrAC, the higher the deterioration of the visual discrimination capacity. The pupil size increased significantly for the high-BrAC group. Parameters evaluating optical quality deteriorated after alcohol consumption. Conclusion. The visual performance under low-illumination conditions and the retinal-image quality were deteriorated after alcohol consumption, especially for the high-alcohol group. Furthermore, some physiological changes were observed under effects for high alcohol contents, such as an increase in the pupil size and disturbances in the tear film, which deteriorated optical quality. PMID- 24949203 TI - Factors Associated with Neurologists' Provision of MS Patient Care. AB - Neurologists are central to providing quality care for individuals with MS. However, neurologist shortages may restrict access to care for MS patients. To examine factors influencing neurologists' provision of MS care, we surveyed 1,700 US neurologists to assess demographic/practice characteristics, training, and attitudes toward MS care. The study population consisted of 573 respondents: 87 (15.2%) MS subspecialists and 486 (84.8%) "other neurologists," including subspecialists in other neurology areas (i.e., non-MS) and general neurologists. MS subspecialists indicating they "enjoy interacting with MS patients" had a significantly greater rate of MS patients seen per week. In separate analyses of the "other neurologists" group, the rate of MS patients seen was lower among neurologists in university-based groups or those practicing in major cities; female neurologists; and neurologists who indicated lack of sufficient knowledge regarding MS patient care. Rates of MS patients seen were significantly greater for other neurologists who agreed that MS care involved "ability to improve patient outcomes and quality of life"; "dynamic area with evolving treatment options"; and "enjoy interacting with MS patients." Understanding factors influencing MS patient care by neurologists and developing policies for appropriate access to care is critical for optimal outcomes among this population. PMID- 24949204 TI - Sex Determination Using Inion-Opistocranium-Asterion (IOA) Triangle in Nigerians' Skulls. AB - Background. Determination of sex is an important concern to the forensic anthropologists as it is critical for individual identification. This study has investigated the existence of sexual dimorphism in the dimensions and the area of the IOA triangle. Methods. A total of 100 adult dry skulls, (78 males; 22 females) from departments of anatomy in Nigerian universities were used for this study. Automatic digital calliper was used for the measurement. Coefficient of variation, correlation, linear regression, percentiles, and sexual dimorphism ratio were computed from the IOA triangle measurements. The IOA triangle area was compared between sexes. Results. The male parameters were significantly (P < 0.05) higher than female parameters. The left opistocranium-asterion length was 71.09 +/- 0.56 and 61.68 +/- 3.35 mm and the right opistocranium-asterion length was 69.73 +/- 0.49 and 60.92 +/- 2.10 mm for male and female, respectively. A total area of IOA triangle of 1938.88 mm(2) and 1305.68 mm(2) for male and female, respectively, was calculated. The left IOA indices were 46.42% and 37.40% in males and females, respectively, while the right IOA indices for males and females were 47.19% and 38.87%, respectively. Conclusion. The anthropometry of inion-opistocranium-asterion IOA triangle can be a guide in gender determination of unknown individuals. PMID- 24949205 TI - Interpenetrating polymer networks as innovative drug delivery systems. AB - Polymers have always been valuable excipients in conventional dosage forms, also have shown excellent performance into the parenteral arena, and are now capable of offering advanced and sophisticated functions such as controlled drug release and drug targeting. Advances in polymer science have led to the development of several novel drug delivery systems. Interpenetrating polymer networks (IPNs) have shown superior performances over the conventional individual polymers and, consequently, the ranges of applications have grown rapidly for such class of materials. The advanced properties of IPNs like swelling capacity, stability, biocompatibility, nontoxicity and biodegradability have attracted considerable attention in pharmaceutical field especially in delivering bioactive molecules to the target site. In the past few years various research reports on the IPN based delivery systems showed that these carriers have emerged as a novel carrier in controlled drug delivery. The present review encompasses IPNs, their types, method of synthesis, factors which affects the morphology of IPNs, extensively studied IPN based drug delivery systems, and some natural polymers widely used for IPNs. PMID- 24949206 TI - Intraductal papillary neoplasms of the bile duct. AB - Intraductal papillary neoplasm of the bile duct (IPNB) is a rare variant of bile duct tumors characterized by papillary growth within the bile duct lumen and is regarded as a biliary counterpart of intraductal papillary mucinous neoplasm of the pancreas. IPNBs display a spectrum of premalignant lesion towards invasive cholangiocarcinoma. The most common radiologic findings for IPNB are bile duct dilatation and intraductal masses. The major treatment of IPNB is surgical resection. Ultrasonography, computed tomography, magnetic resonance image, and cholangiography are usually performed to assess tumor location and extension. Cholangioscopy can confirm the histology and assess the extent of the tumor including superficial spreading along the biliary epithelium. However, pathologic diagnosis by preoperative biopsy cannot always reflect the maximum degree of atypia, because IPNBs are often composed of varying degrees of cytoarchitectural atypia. IPNBs are microscopically classified into four epithelial subtypes, such as pancreatobiliary, intestinal, gastric, and oncocytic types. Most cases of IPNB are IPN with high-grade intraepithelial neoplasia or with an associated invasive carcinoma. The histologic types of invasive lesions are either tubular adenocarcinoma or mucinous carcinoma. Although several authors have investigated molecular genetic changes during the development and progression of IPNB, these are still poorly characterized and controversial. PMID- 24949207 TI - Comment on "complete androgen insensitivity syndrome: optimizing diagnosis and management". PMID- 24949208 TI - Primary hepatic lymphoma: a challenging diagnosis. AB - Introduction. Primary hepatic lymphoma is an unusual malignancy and is very difficult to diagnose promptly. An intrigue case presenting with cholestatic jaundice is reviewed and main disease characteristics are further discussed. Case Report. A 70-year-old male presented with dull right upper quadrant abdominal pain and mild cholestatic jaundice. Initial evaluation revealed mildly elevated liver function tests and normal tumor markers, while imaging with an abdominal CT scan showed multiple hypodense nodules in both liver lobes. First impression of metastatic deposits from gastrointestinal origin was not confirmed by endoscopic means. After CT-guided biopsy, primary diffuse large B-cells non-Hodgkin lymphoma was revealed. Appropriate chemotherapy improved patient's condition markedly. Discussion. Primary hepatic lymphoma is a rare form of extranodal lymphomas, accounting for less than 1% of all extranodal lymphomas in general. In order to define the condition as PHL, liver has to be the only site of lymphoma occurrence or to be involved in a major degree with minimal nonliver disease. Most PHLs are of B-cell origin with large cells as the main cell type. PMID- 24949209 TI - Cystoid Macular Edema in Bietti's Crystalline Retinopathy. AB - A 27-year-old man with progressive bilateral visual decline was diagnosed to have Bietti's crystalline dystrophy (BCD). Fluorescein angiography revealed bilateral petaloid type late hyperfluorescence implicating concurrent cystoid macular edema (CME). Optical coherence tomography exhibited cystoid foveal lacunas OU. During the follow-up of six years, intraretinal crystals reduced in amount but CME persisted angiographically and tomographically. CME is among the rare macular features of BCD including subfoveal sensorial detachment, subretinal neovascular membrane, and macular hole. PMID- 24949210 TI - Joint use of skull base surgery in a case of pediatric parotid gland carcinoma. AB - Parotid gland carcinoma is extremely rare in children. We report a case of pediatric parotid gland carcinoma with extensive infiltration into surrounding tissues including the skin and temporomandibular joint capsule at initial examination. Total resection of the parotid gland was conducted together with skull base surgery and mandibular dissection. The patient was a 14-year-old girl. In addition to the skin and temporomandibular joint, infiltration into the anterior wall of the external auditory meatus and masseter muscle was also seen, and T4N0M0 stage IV parotid carcinoma was diagnosed. Skin was resected together with the pinna, and temporal craniotomy and skull base surgery were performed to resect the temporomandibular joint capsule and external auditory meatus en bloc, and mandible dissection was conducted. Facial nerves were resected at the same time. Level I to level IV neck dissection was also conducted. A latissimus dorsi myocutaneous flap was used for reconstruction. The postoperative permanent pathology diagnosis was high-grade mucoepidermoid carcinoma with a low-grade component. Postoperatively, radiotherapy at 50 Gy alone has been conducted, with no recurrence or metastasis observed for over 4 years. PMID- 24949211 TI - Possible association of etanercept, venous thrombosis, and induction of antiphospholipid syndrome. AB - Tumor necrosis factor alpha (TNF alpha ) inhibitors are commonly used for treatment of aggressive rheumatoid arthritis and other rheumatic diseases. Etanercept is one of the medications approved for treatment of rheumatoid arthritis. Though many studies have documented the safety and efficacy of these medications, evidence for adverse effects is emerging including cancer, infections, and cardiovascular disease. There have been studies showing that these medications induce autoantibody production, including antinuclear antibodies and anti-dsDNA antibodies. Limited data exists, however, regarding induction of antiphospholipid antibodies (APLs) by TNF alpha inhibitors, including anticardiolipin antibodies (ACLs), lupus anticoagulant (LAC), and anti- beta 2-glycoprotein I (anti- beta 2 GPI), or an association between antibody development and clinical manifestations. In this case series, we describe five patients who developed venous thromboembolism (VTE) and APLs while receiving etanercept therapy. All five of our patients met the criteria for diagnosis of APS after receiving etanercept. Our case series supports the association between etanercept, APLs, and VTE. We believe that testing for APLs prior to initiation of anti-TNF therapy is reasonable, given this relationship and the risks associated with VTE. PMID- 24949212 TI - Gallbladder torsion: a diagnostic challenge. AB - 80-year-old female presented with clinical findings suggestive of acute cholecystitis. Intraoperatively we discovered a dusky gallbladder with gangrenous patches and gallbladder torsion with 270 degrees clockwise rotation along the longitudinal axis. Gallbladder torsion is a rare cause of acute cholecystitis with less than 500 cases published in the literature. Gallbladder torsion should be included in the list of differential diagnoses in patients suspected of having acute cholecystitis especially when there are inconsistencies between clinical features and imaging. It is worth noting that 3-dimensional reconstructed CT may be useful in preoperative diagnosis of gallbladder torsion. PMID- 24949213 TI - Age Differences in the Longitudinal Relationship between Work-Family Conflict and Alcohol Use. AB - Research on the relationship between work-family conflict and alcohol use has generally shown small effects possibly due to failure to include important individual differences relevant to the experience of work-family conflict and alcohol use, notably age. This study examined whether the relationships between aspects of work-family conflict and alcohol use variables differed by age. Participants were 543 individuals (51.2% women) from a community sample of working adults in the greater Chicagoland area who responded to a mail survey at three time points. Results showed important differences between age groups in several predictors of alcohol use. Strain versus time-based conflict had different effects on drinking, and strain-based forms of work-family conflict were related to increased problematic alcohol use depending on age. This study indicates that individual differences, particularly age, should be systematically accounted for when studying the relationship between work-family conflict and alcohol use. PMID- 24949214 TI - Altered proteolysis in fibroblasts of Alzheimer patients with predictive implications for subjects at risk of disease. AB - There is great interest in developing reliable biomarkers to support antemortem diagnosis of late-onset Alzheimer's disease (AD). Early prediction and diagnosis of AD might be improved by the detection of a proteolytic dysfunction in extracts from cultured AD fibroblasts, producing altered isoelectrophoretic forms of the enzyme transketolase (TK-alkaline bands). The TK profile and apolipoprotein E (APOE) genotype were examined in fibroblasts from 36 clinically diagnosed probable late-onset sporadic AD patients and 38 of their asymptomatic relatives, 29 elderly healthy individuals, 12 neurological non-AD patients, and 5 early onset AD patients. TK alterations occurred in (i) several probable AD patients regardless of age-of-onset and severity of disease; (ii) all early-onset AD patients and APOE epsilon 4/4 carriers; and (iii) nearly half of asymptomatic AD relatives. Normal subjects and non-AD patients were all negative. Notably, culture conditions promoting TK alterations were also effective in increasing active BACE1 levels. Overall, the TK assay might represent a low-cost laboratory tool useful for supporting AD differential diagnosis and identifying asymptomatic subjects who are at greater risk of AD and who should enter a follow-up study. Moreover, the cultured fibroblasts were confirmed as a useful in vitro model for further studies on the pathogenetic process of AD. PMID- 24949216 TI - Spontaneous regression together with increased calcification of incidental meningioma. AB - BACKGROUND: Regression of meningioma has been reported after hemorrhage or hormonal withdrawal. However, meningioma regression is rarely observed spontaneously. CASE DESCRIPTION: A right falx meningioma was incidentally diagnosed and was followed at every one-year by magnetic resonance imaging (MRI) for over 7 years. The tumor, with a maximum diameter of 4 cm, showed a slightly high density and was enhanced on computed tomography (CT), and a high intensity with a low-intensity core on T2 MRI, with significant edema. The meningioma gradually shrank together with a decrease of edema and increase of calcification. The initial volume, 25.5 cm(3), regressed linearly to less than half, 9.9 cm(3). CONCLUSION: Here, we report a case of an incidentally diagnosed meningioma that regressed spontaneously. The pattern of the regression was similar to that following gamma knife radiosurgery. PMID- 24949215 TI - Curcumin Inhibits Prostate Cancer Bone Metastasis by Up-Regulating Bone Morphogenic Protein-7 in Vivo. AB - A number of studies have focused on the beneficial properties of Curcumin (diferuloyl methane, used in South Asian cuisine and traditional medicine) such as the chemoprevention of cancer. Recent studies have also indicated that this material has significant benefits for the treatment of cancer and is currently undergoing several clinical trials. We have been interested in the application of this compound as a therapeutic agent for advanced prostate cancer, particularly the skeletal complications in this malignancy. Our earlier work indicated that this compound could inhibit the osteomimetic properties which occur in castration resistant prostate cancer cells, by interfering with the common denominators between these cancer cells and the bone cells in the metastatic tumor microenvironment, namely the osteoblasts and the osteoclast. We predicted that curcumin could break the vicious cycle of reciprocal stimulation that results in uncontrolled osteolysis in the bony matrix. In this work, we have evaluated the potential of this compound in inhibiting the bone metastasis of hormone refractory prostate cancer cells in an established animal model. Our results strongly suggest that curcumin modulates the TGF-beta signaling that occurs due to bone matrix degradation by up-regulating the metastasis inhibitory bone morphogenic protein-7 (BMP- 7). This enhancement of BMP-7 in the context of TGF betain the tumor microenvironment is shown to enhance the mesenchymal-to epithelial transition. Most importantly, we show that as a result of BMP-7 up regulation, a novel brown/beige adipogenic differentiation program is also up regu- lated which plays a role in the inhibition of bone metastasis. Our results suggest that curcumin may subvert the TGF-betasignaling to an alternative adipogenic differentiation program in addition to the previously established interference with the osteomimetic properties, thus inhibiting the bone metastatic processes in a chemopreventive as well as therapeutic setting. PMID- 24949217 TI - Visualization of luminal thrombosis and mural Iron accumulation in giant aneurysms with Ex vivo 4.7T magnetic resonance imaging. AB - BACKGROUND: Better diagnostic tools to identify rupture-prone saccular intracranial aneurysms (sIA) are needed. Inflammation and luminal thrombus associate with degeneration and rupture of the sIA wall. Iron-uptake has been detected in the inflammatory cells of the sIA wall and thrombus is the likely source of this iron. We investigated ex vivo the use of magnetic resonance imaging (MRI) to detect iron accumulation and luminal thrombus in giant sIAs. METHODS: Giant sIAs (n = 3) were acquired from microsurgical operations, fixed with formalin, embedded in agar and imaged at 4.7T. Samples were sectioned maintaining the orientation of the axial plane of MRI scans, and stained (hematoxylin-eosin and Prussian blue). RESULTS: All three giant sIAs showed a degenerated hypocellular wall with both mural and adventitial iron accumulation and displayed different degrees of luminal thrombus formation and thrombus organization. Signal intensity varied within the same sIA wall and associated with iron accumulation in all tested sequences. Wall areas with iron accumulation had significantly lower signal to noise ratio (SNR) compared with areas without iron accumulation (P = 0.002). Fresh and organizing thrombus differed in their MRI presentation and differed in signal intensity of the aneurysm wall (P = 0.027). CONCLUSION: MRI can detect ex vivo the accumulation of iron in giant sIA wall, as well as fresh and organizing luminal thrombus. These features have been previously associated with fragile, rupture-prone aneurysm wall. Further studies of iron accumulation as a marker of rupture-prone aneurysm wall are needed. PMID- 24949218 TI - Atypical teratoid/rhabdoid tumor in sellar turcica in an adult: A case report and review of the literature. AB - BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare central nervous system tumor composed of primitive rhabdoid cells that may differentiate along neuroectodermal, mesenchymal and epithelial lineages. AT/RT in adults is rare but not completely exceptional. It generally arises from the posterior fossa of infants, but the broad majority of the reported AT/RT in adults manifested supratentorially with the exception of four cases that arose in the cerebellum and two that arose in the spinal cord. CASE DESCRIPTION: A 44-year-old female complained of visual disturbance. We performed craniotomies twice and removed partially for each time, but any malignant cells were not found in the specimens. Finally, we determined histological diagnosis from the extended lesion. She died of respiratory failure 17 months after the initial treatment. CONCLUSION: AT/RT should be considered in the differential diagnosis of a sellar lesion in adult patients. However AT/RT is rare in adults, the appropriate immunohistochemical evaluation should be performed to diagnose this rare entity. PMID- 24949219 TI - Do neurosurgeons need Neuroanesthesiologists? Should every neurosurgical case be done by a Neuroanesthesiologist? AB - Neuroscience is exponentially growing and accompanied with everyday innovations and intriguing developments. There are new branches of science that are being developed within neuroscience. For instance, the fields of computer interface nanotechnology, molecular biology, ultra cellular, and gene therapy. The neuroscience programs have been established nationwide and worldwide. There is strong belief that better patient care is obtained through high volume and specialty physicians and hospitals. In fact, there are new subspecialties that already developed from within the specialty itself. Neuroanesthesia is one of the specialties that has contributed tremendously over the years to neuroscience yet it remained non-accredited and supported. In fact, there is a discouraging trend to pursue advocating the necessity of neurosurgery cases to be done by neuroanesthesiologists. It is one of the specialties that is lagging behind compared with other specialties and subspecialties in neuroscience. There is an ongoing debate within the neuroanesthesia society about the role of neuroanesthesiologists in neurosurgery. The author, being a neurosurgeon, neuroanesthesiologist, and neurointensivist, is presenting the topic, the views and expressing his opinion. PMID- 24949220 TI - Gross total resection: Do we want survival statistics or quality of life measurements. PMID- 24949221 TI - Midkine expression in high grade gliomas: Correlation of this novel marker with proliferation and survival in human gliomas. AB - BACKGROUND: High-grade primary glioma have poor prognosis and predictive biomarkers is very important. Midkine (MDK), a heparin-binding growth factor, is important in regulating carcinogenesis, cell proliferation, mitogenesis, and angiogenesis. This study aimed to identify over-expression of MDK in gliomas and correlate this with clinical outcomes. The authors put forward their hypothesis correlating proliferation and poor survival with over-expression of this novel protein. METHODS: Two datasets from Gene Expression Omnibus (GEO) included human data of 100 and 180 patients, respectively. The MDK expression, World Health Organization (WHO) pathological grade, sex, age, and survival time were identified for statistical analysis. RESULTS: A search of the GEO profile revealed that MDK expression level was statistically greater in the WHO grade IV compared with grade II (P = 0.002), in grades III and IV compared with nontumor control (P = 0.044 and P < 0.001, respectively) after adjustments using the Bonferroni method. By the Kaplan-Meier survival curve, the high MDK expression group had poorer survival outcome (2.38-fold hazard, 95% confidence interval: 1.22-4.63) than the low MDK expression group after adjustments for WHO grade and age. CONCLUSIONS: Taken together, there is a positive correlation between MDK expression and WHO grading of human gliomas. Moreover, MDK over-expression is significant correlated to poor survival outcome in high-grade, suggesting that MDK may be an important therapeutic target. PMID- 24949222 TI - Intraosseous Angiolipoma of the Cranium: Case report and review of the literature. AB - BACKGROUND: Angiolipomas are benign tumors that usually occur in patients during their late teens or early twenties. Most are found as multiple lesions and often located on the arm or trunk. Although predominantly subcutaneous lesions, intraosseous angiolipomas are primarily found in the mandible and ribs, with one case involving the calvarium reported in the literature. CASE DESCRIPTION: We report the case of a 55-year-old male who presented with headache, nausea, vomiting, and double vision and was found to a right frontal intraosseous lesion. He was also found to have invasive ductal breast carcinoma. The patient subsequently underwent a resection and the lesion was found to be an angiolipoma. CONCLUSION: We report a rare case of a calvarialangiolipoma in the setting of a male with invasive ductal breast carcinoma and a review of the literature. PMID- 24949223 TI - Magnetic resonance spectroscopy imaging characteristics of cerebral Blastomycosis. AB - BACKGROUND: Blastomycosis is a dimorphic fungus that is endemic to the midwest and southwestern United States. Involvement of the central nervous system (CNS) is thought to only represent 5-10% of cases of disseminated Blastomycosis. CASE DESCRIPTION: A 54-year-old Caucasian female presented to the Neurosurgery service with a 1-day history of progressive right sided hemiparesis. Magnetic resonance imaging (MRI) demonstrated a 2 * 4 cm heterogeneous intracranial mass lesion involving the left motor cortex and extending into the ipsilateral parietal lobe. Single-voxel magnetic resonance spectroscopy (MRS) over the enhancing area demonstrated diminished N-acetyl aspartate (NAA) to creatine ratio (1.10), normal choline to NAA ratio (0.82), normal choline to creatine ratio (0.9), and a diminished myoinositol to creatine ratio (0.39). There appeared to be peaks between 3.6 and 3.8 ppm over the enhancing area that were not present in the contralateral normal brain and thought to represent a "trehalose" peak. Due to worsening symptoms and uncertain preoperative diagnosis, the patient underwent a left fronto-parietal craniotomy for open surgical biopsy with possible resection approximately one month after presentation. Pathological analysis confirmed the diagnosis of Blastomycosis. CONCLUSION: We present the second documented case of intracranial Blastomycosis with MRS imaging. There appears to be a characteristic peak between 3.6 and 3.8 ppm that is thought to represent a "trehalose" peak. This peak is rather specific to fungi and can be helpful in differentiating fungal abscesses from pyogenic abscesses and malignant neoplasms. PMID- 24949224 TI - The policy implications of the cost structure of home health agencies. AB - PURPOSE: To examine the cost structure of home health agencies by estimating an empirical cost function for those that are Medicare-certified, ten years following the implementation of prospective payment. DESIGN AND METHODS: 2010 national Medicare cost report data for certified home health agencies were merged with case-mix information from the Outcome and Assessment Information Set (OASIS). We estimated a fully interacted (by tax status) hybrid cost function for 7,064 agencies and calculated marginal costs as percent of total costs for all variables. RESULTS: The home health industry is dominated by for-profit agencies, which tend to be newer than the non-profit agencies and to have higher average costs per patient but lower costs per visit. For-profit agencies tend to have smaller scale operations and different cost structures, and are less likely to be affiliated with chains. Our estimates suggest diseconomies of scale, zero marginal cost for contracting with therapy workers, and a positive marginal cost for contracting with nurses, when controlling for quality. IMPLICATIONS: Our findings suggest that efficiencies may be achieved by promoting non-profit, smaller agencies, with fewer contract nursing staff. This conclusion should be tested further in future studies that address some of the limitations of our study. PMID- 24949225 TI - What influences the awareness of physician quality information? Implications for Medicare. AB - OBJECTIVE: Examine the factors that are associated with awareness of physician quality information (PQI) among older people with one or more chronic illnesses and the implications for Medicare. DATA SOURCES/STUDY SETTING: Random digit-dial survey of adults with one or more chronic illnesses. RESEARCH DESIGN: Structural equation modeling to examine factors related to awareness of PQI. RESULTS: Awareness of PQI is low (13 percent), but comparable to findings in general population surveys. Age, race, education, and self-reported health status are associated with PQI awareness. Trust in the Internet as a source of health care information and not trusting one's physician as a source of information both are associated with a greater likelihood of being aware of PQI. Patients with high levels of activation have greater trust in physicians as information sources, but this is not associated with awareness, nor is degree of satisfaction with their care experience. CONCLUSIONS: Awareness of PQI among older persons with chronic illnesses is relatively low across all socio-economic and demographic subgroups. Changes in population characteristics over time are unlikely to improve awareness in this population, nor are changes in patient activation or satisfaction with care. Medicare would need a broad-based effort if it wishes to raise PQI awareness among Medicare beneficiaries in the near term. Before undertaking resource-intensive efforts to increase awareness, Medicare may want to consider what level of awareness actually is needed to accomplish the overall objective for PQI transparency, which is raising the quality of care received by beneficiaries. It may be that relatively low levels of awareness are sufficient. PMID- 24949226 TI - Post-discharge follow-up visits and hospital utilization by Medicare patients, 2007-2010. AB - OBJECTIVE: Document trends in time to post-discharge follow-up visit for Medicare patients with an index admission for heart failure (HF), acute myocardial infarction (AMI), or community-acquired pneumonia (CAP). Determine factors predicting whether the first post-discharge utilization event is a follow-up visit, treat-and-release emergency department (ED) visit, or readmission. METHODS: Using Medicare claims data from 2007-2010, we plotted annual cumulative incidence functions for the time frame post-discharge to follow-up visit, accounting for competing risks with censoring at 30 days. We used multinomial probit regression to determine factors predicting the probability of first occurring post-discharge utilization events within 30 days. RESULTS: For each cohort, the cumulative incidence of follow-up visits increased during the study period. For example, in 2010, 54.6% of HF patients had a follow-up visit within 10 days of discharge compared to 47.9% in 2007. Within each cohort, the largest increase in follow-up visits took place between 2008 and 2009. Follow-up visits were less likely for patients who were Black, Hispanic, and enrolled in Medicaid or Medicare Advantage, and they were more likely for patients with greater comorbidities and prior procedures as well as those with private or supplemental Medicare coverage. There were no changes in 30-day readmission rates. DISCUSSION: Although increases in follow-up visits may have been influenced by the introduction of publicly reported readmission rates in 2009, these increases did not continue in 2010 and were not associated with a change in readmissions. Patients who were Black, Hispanic, and/or enrolled in Medicaid or Medicare Advantage were less likely to have follow-up visits. PMID- 24949227 TI - Snake Venom Cytotoxins, Phospholipase A2s, and Zn2+-dependent Metalloproteinases: Mechanisms of Action and Pharmacological Relevance. AB - Snake venom toxins are responsible for causing severe pathology and toxicity following envenomation including necrosis, apoptosis, neurotoxicity, myotoxicity, cardiotoxicity, profuse hemorrhage, and disruption of blood homeostasis. Clinically, snake venom toxins therefore represent a significant hazard to snakebite victims which underscores the need to produce more efficient anti venom. Some snake venom toxins, however, have great potential as drugs for treating human diseases. In this review, we discuss the biochemistry, structure/function, and pathology induced by snake venom toxins on human tissue. We provide a broad overview of cobra venom cytotoxins, catalytically active and inactive phospholipase A2s (PLA2s), and Zn2+-dependent metalloproteinases. We also propose biomedical applications whereby snake venom toxins can be employed for treating human diseases. Cobra venom cytotoxins, for example, may be utilized as anti-cancer agents since they are efficient at destroying certain types of cancer cells including leukemia. Additionally, increasing our understanding of the molecular mechanism(s) by which snake venom PLA2s promote hydrolysis of cell membrane phospholipids can give insight into the underlying biomedical implications for treating autoimmune disorders that are caused by dysregulated endogenous PLA2 activity. Lastly, we provide an exhaustive overview of snake venom Zn2+-dependent metalloproteinases and suggest ways by which these enzymes can be engineered for treating deep vein thrombosis and neurodegenerative disorders. PMID- 24949229 TI - Compliance with vessel speed restrictions to protect North Atlantic right whales. AB - Environmental regulations can only be effective if they are adhered to, but the motivations for regulatory compliance are not always clear. We assessed vessel operator compliance with a December 2008 regulation aimed at reducing collisions with the endangered North Atlantic right whale that requires vessels 65 feet or greater in length to travel at speeds of 10 knots or less at prescribed times and locations along the U.S. eastern seaboard. Extensive outreach efforts were undertaken to notify affected entities both before and after the regulation went into effect. Vessel speeds of 201,862 trips made between November 2008 and August 2013 by 8,009 individual vessels were quantified remotely, constituting a nearly complete census of transits made by the regulated population. Of these, 437 vessels (or their parent companies), some of whom had been observed exceeding the speed limit, were contacted through one of four non-punitive information programs. A fraction (n = 26 vessels/companies) received citations and fines. Despite the efforts to inform mariners, initial compliance was low (<5% of the trips were completely <10 knots) but improved in the latter part of the study. Each notification/enforcement program improved compliance to some degree and some may have influenced compliance across the entire regulated community. Citations/fines appeared to have the greatest influence on improving compliance in notified vessels/companies, followed in order of effectiveness by enforcement office information letters, monthly summaries of vessel operations, and direct at sea radio contact. Trips by cargo vessels exhibited the greatest change in behavior followed by tanker and passenger vessels. These results have application to other regulatory systems, especially where remote monitoring is feasible, and any setting where regulatory compliance is sought. PMID- 24949228 TI - Childhood B-acute lymphoblastic leukemia: a genetic update. AB - In the pediatric population, B-acute lymphoblastic leukemia (B-ALL) is the most prevalent childhood hematological malignancy, as well as the leading cause of childhood cancer-related mortality. Advances in cytogenetics utilizing array based technologies and next-generation sequencing (NGS) techniques have revealed exciting insights into the genetic basis of this disease, with the hopes of developing individualized treatment plans for affected children. In this comprehensive review, we discuss our current understanding of childhood (pediatric) B-ALL and highlight the most recent genetic advances and their therapeutic implications. PMID- 24949230 TI - Stability of commercial glucanase and beta-glucosidase preparations under hydrolysis conditions. AB - The cost of enzymes makes enzymatic hydrolysis one of the most expensive steps in the production of lignocellulosic ethanol. Diverse studies have used commercial enzyme cocktails assuming that change in total protein concentration during hydrolysis was solely due to adsorption of endo- and exoglucanases onto the substrate. Given the sensitivity of enzymes and proteins to media conditions this assumption was tested by evaluating and modeling the protein concentration of commercial cocktails at hydrolysis conditions. In the absence of solid substrate, the total protein concentration of a mixture of Celluclast 1.5 L and Novozyme 188 decreased by as much as 45% at 50 degrees C after 4 days. The individual cocktails as well as a mixture of both were stable at 20 degrees C. At 50 degrees C, the protein concentration of Celluclast 1.5 was relatively constant but Novozyme 188 decreased by as much as 77%. It was hypothesized that Novozyme 188 proteins suffer a structural change at 50 degrees C which leads to protein aggregation and precipitation. Lyophilized beta-glucosidase (P-beta-glucosidase) at 50 degrees C exhibited an aggregation rate which was successfully modeled using first order kinetics (R (2) = 0.97). By incorporating the possible presence of chaperone proteins in Novozyme 188, the protein aggregation observed for this cocktail was successfully modeled (R (2) = 0.96). To accurately model the increasing protein stability observed at high cocktail loadings, the model was modified to include the presence of additives in the cocktail (R (2) = 0.98). By combining the measurement of total protein concentration with the proposed Novozyme 188 protein aggregation model, the endo- and exoglucanases concentration in the solid and liquid phases during hydrolysis can be more accurately determined. This methodology can be applied to various systems leading to optimization of enzyme loading by minimizing the excess of endo- and exoglucanases. In addition, the monitoring of endo- and exoglucanases concentrations can be used to build mass balances of enzyme recycling processes and to techno-economically evaluate the viability of enzyme recycling. PMID- 24949231 TI - Tree mortality from a short-duration freezing event and global-change-type drought in a Southwestern pinon-juniper woodland, USA. AB - This study documents tree mortality in Big Bend National Park in Texas in response to the most acute one-year drought on record, which occurred following a five-day winter freeze. I estimated changes in forest stand structure and species composition due to freezing and drought in the Chisos Mountains of Big Bend National Park using permanent monitoring plot data. The drought killed over half (63%) of the sampled trees over the entire elevation gradient. Significant mortality occurred in trees up to 20 cm diameter (P < 0.05). Pinus cembroides Zucc. experienced the highest seedling and tree mortality (P < 0.0001) (55% of pinon pines died), and over five times as many standing dead pines were observed in 2012 than in 2009. Juniperus deppeana vonSteudal and Quercus emoryi Leibmann also experienced significant declines in tree density (P < 0.02) (30.9% and 20.7%, respectively). Subsequent droughts under climate change will likely cause even greater damage to trees that survived this record drought, especially if such events follow freezes. The results from this study highlight the vulnerability of trees in the Southwest to climatic change and that future shifts in forest structure can have large-scale community consequences. PMID- 24949232 TI - Rape and the prevalence of hybrids in broadly sympatric species: a case study using albatrosses. AB - Conspecific rape often increases male reproductive success. However, the haste and aggression of forced copulations suggests that males may sometimes rape heterospecific females, thus making rape a likely, but undocumented, source of hybrids between broadly sympatric species. We present evidence that heterospecific rape may be the source of hybrids between Black-footed and Laysan Albatrosses (Phoebastria nigripes, and P. immutabilis, respectively). Extensive field studies have shown that paired (but not unpaired) males of both of these albatross species use rape as a supplemental reproductive strategy. Between species differences in size, timing of laying, and aggressiveness suggest that Black-footed Albatrosses should be more successful than Laysan Albatrosses in heteropspecific rape attempts, and male Black-footed Albatrosses have been observed attempting to force copulations on female Laysan Albatrosses. Nuclear markers showed that the six hybrids we studied were F1s and mitochondrial markers showed that male Black-footed Albatrosses sired all six hybrids. Long-term gene exchange between these species has been from Black-footed Albatrosses into Laysan Albatrosses, suggesting that the siring asymmetry found in our hybrids has long persisted. If hybrids are sired in heterospecific rapes, they presumably would be raised and sexually imprinted on Laysan Albatrosses, and two unmated hybrids in a previous study courted only Laysan Albatrosses. PMID- 24949233 TI - Swedish high-school pupils' attitudes towards drugs in relation to drug usage, impulsiveness and other risk factors. AB - Background. Illicit drug use influences people's lives and elicits unwanted behaviour. Current research shows that there is an increase in young people's drug use in Sweden. The aim was to investigate Swedish high-school pupils' attitudes, impulsiveness and gender differences linked to drug use. Risk and protective factors relative to drug use were also a focus of interest. Method. High school pupils (n = 146) aged 17-21 years, responded to the Adolescent Health and Development Inventory, Barratt Impulsiveness Scale and Knowledge, and the Attitudes and Beliefs. Direct logistic, multiple regression analyses, and Multivariate Analysis of Variance were used to analyze the data. Results. Positive Attitudes towards drugs were predicted by risk factors (odds ratio = 37.31) and gender (odds ratio = .32). Risk factors (odds ratio = 46.89), positive attitudes towards drugs (odds ratio = 4.63), and impulsiveness (odds ratio = 1.11) predicted drug usage. Risk factors dimensions Family, Friends and Individual Characteristic were positively related to impulsiveness among drug users. Moreover, although boys reported using drugs to a greater extent, girls expressed more positive attitude towards drugs and even reported more impulsiveness than boys. Conclusion. This study reinforces the notion that research ought to focus on gender differences relative to pro-drug attitudes along with testing for differences in the predictors of girls' and boys' delinquency and impulsiveness. Positive attitudes towards drugs among adolescents seem to be part of a vicious circle including risk factors, such as friendly drug environments (e.g., friends who use drugs) and unsupportive family environments, individual characteristics, and impulsiveness. PMID- 24949234 TI - Molecular cytogenetic analyses of Epinephelus bruneus and Epinephelus moara (Perciformes, Epinephelidae). AB - Genus Epinephelus (Perciformes, Epinephelidae), commonly known as groupers, are usually difficult in species identification for the lack and/or change of morphological specialization. In this study, molecular cytogenetic analyses were firstly performed to identify the closely related species Epinephelus bruneus and E. moara in this genus. The species-specific differences of both fish species showed in karyotype, chromosomal distribution of nucleolar organizer regions (NORs) and localization of 18S rDNA. The heterochromatin (interstitial C-bands) and distribution pattern of telomere (TTAGGG) n in E. bruneus revealed the chromosomal rearrangements and different karyotypic evolutionary characteristics compared to those in E. moara. The cytogenetic data suggested that the lineages of E. bruneus and E. moara were recently derived within the genus Epinephelus, and E. moara exhibited more plesiomorphic features than E. bruneus. All results confirmed that E. moara, which has long been considered a synonym of E. bruneus, is a distinct species in the family Epinephelidae. In addition, molecular cytogenetic analyses are useful in species differentiation and phylogenetic reconstruction in groupers. PMID- 24949235 TI - Regulation of KCa2.3 and endothelium-dependent hyperpolarization (EDH) in the rat middle cerebral artery: the role of lipoxygenase metabolites and isoprostanes. AB - Background and Purpose. In rat middle cerebral arteries, endothelium-dependent hyperpolarization (EDH) is mediated by activation of calcium-activated potassium (KCa) channels specifically KCa2.3 and KCa3.1. Lipoxygenase (LOX) products function as endothelium-derived hyperpolarizing factors (EDHFs) in rabbit arteries by stimulating KCa2.3. We investigated if LOX products contribute to EDH in rat cerebral arteries. Methods. Arachidonic acid (AA) metabolites produced in middle cerebral arteries were measured using HPLC and LC/MS. Vascular tension and membrane potential responses to SLIGRL were simultaneously recorded using wire myography and intracellular microelectrodes. Results. SLIGRL, an agonist at PAR2 receptors, caused EDH that was inhibited by a combination of KCa2.3 and KCa3.1 blockade. Non-selective LOX-inhibition reduced EDH, whereas inhibition of 12-LOX had no effect. Soluble epoxide hydrolase (sEH) inhibition enhanced the KCa2.3 component of EDH. Following NO synthase (NOS) inhibition, the KCa2.3 component of EDH was absent. Using HPLC, middle cerebral arteries metabolized (14)C-AA to 15- and 12-LOX products under control conditions. With NOS inhibition, there was little change in LOX metabolites, but increased F-type isoprostanes. 8-iso PGF2alpha inhibited the KCa2.3 component of EDH. Conclusions. LOX metabolites mediate EDH in rat middle cerebral arteries. Inhibition of sEH increases the KCa2.3 component of EDH. Following NOS inhibition, loss of KCa2.3 function is independent of changes in LOX production or sEH inhibition but due to increased isoprostane production and subsequent stimulation of TP receptors. These findings have important implications in diseases associated with loss of NO signaling such as stroke; where inhibition of sEH and/or isoprostane formation may of benefit. PMID- 24949236 TI - Ape duos and trios: spontaneous cooperation with free partner choice in chimpanzees. AB - The purpose of the present study was to push the boundaries of cooperation among captive chimpanzees (Pan troglodytes). There has been doubt about the level of cooperation that chimpanzees are able to spontaneously achieve or understand. Would they, without any pre-training or restrictions in partner choice, be able to develop successful joint action? And would they be able to extend cooperation to more than two partners, as they do in nature? Chimpanzees were given a chance to cooperate with multiple partners of their own choosing. All members of the group (N = 11) had simultaneous access to an apparatus that required two (dyadic condition) or three (triadic condition) individuals to pull in a tray baited with food. Without any training, the chimpanzees spontaneously solved the task a total of 3,565 times in both dyadic and triadic combinations. Their success rate and efficiency increased over time, whereas the amount of pulling in the absence of a partner decreased, demonstrating that they had learned the task contingencies. They preferentially approached the apparatus when kin or nonkin of similar rank were present, showing a preference for socially tolerant partners. The forced partner combinations typical of cooperation experiments cannot reveal these abilities, which demonstrate that in the midst of a complex social environment, chimpanzees spontaneously initiate and maintain a high level of cooperative behavior. PMID- 24949237 TI - Forms of Melanoplus bowditchi (Orthoptera: Acrididae) collected from different host plants are indistinguishable genetically and in aedeagal morphology. AB - The sagebrush grasshopper, Melanoplus bowditchi Scudder (Orthoptera: Acrididae), is a phytophilous species that is widely distributed in the western United States on sagebrush species. The geographical distribution of M. bowditchi is very similar to the range of its host plants and its feeding association varies in relation to sagebrush distribution. Melanoplus bowditchi bowditchi Scudder and M. bowditchi canus Hebard were described based on their feeding association with different sagebrush species, sand sagebrush and silver sagebrush, respectively. Recently, M. bowditchi have been observed feeding on other plant species in western Nebraska. We collected adult M. bowditchi feeding on four plant species, sand sagebrush, Artemisia filifolia, big sagebrush, A. tridentata, fringed sagebrush, A. frigidus, and winterfat, Krascheninnikovia lanata. We compared the specimens collected from the four plant species for their morphological and genetic differences. We observed no consistent differences among the aedeagal parameres or basal rings among the grasshoppers collected from different host plants. Amplified Fragment Length Polymorphism markers were used to test the genetic relationships among the grasshoppers. Analysis of Molecular Variance and distance-based Unweighted Pair Group Method with Arithmetic mean dendrogram failed to reveal significant differences. Although the forms showed behavioral and minor color and size differences, the genetic data suggest all forms under study likely interbreed, which indicates they are a single species instead of four species or subspecies. These results indicate that host plant use may influence melanopline phenotype and suggest the need of further genetic analysis of subspecies recognized based on morphology, distribution, and ecology. PMID- 24949238 TI - BALSA: integrated secondary analysis for whole-genome and whole-exome sequencing, accelerated by GPU. AB - This paper reports an integrated solution, called BALSA, for the secondary analysis of next generation sequencing data; it exploits the computational power of GPU and an intricate memory management to give a fast and accurate analysis. From raw reads to variants (including SNPs and Indels), BALSA, using just a single computing node with a commodity GPU board, takes 5.5 h to process 50-fold whole genome sequencing (~750 million 100 bp paired-end reads), or just 25 min for 210-fold whole exome sequencing. BALSA's speed is rooted at its parallel algorithms to effectively exploit a GPU to speed up processes like alignment, realignment and statistical testing. BALSA incorporates a 16-genotype model to support the calling of SNPs and Indels and achieves competitive variant calling accuracy and sensitivity when compared to the ensemble of six popular variant callers. BALSA also supports efficient identification of somatic SNVs and CNVs; experiments showed that BALSA recovers all the previously validated somatic SNVs and CNVs, and it is more sensitive for somatic Indel detection. BALSA outputs variants in VCF format. A pileup-like SNAPSHOT format, while maintaining the same fidelity as BAM in variant calling, enables efficient storage and indexing, and facilitates the App development of downstream analyses. BALSA is available at: http://sourceforge.net/p/balsa. PMID- 24949239 TI - Quantification of intraskeletal histovariability in Alligator mississippiensis and implications for vertebrate osteohistology. AB - Bone microanalyses of extant vertebrates provide a necessary framework from which to form hypotheses regarding the growth and skeletochronology of extinct taxa. Here, we describe the bone microstructure and quantify the histovariability of appendicular elements and osteoderms from three juvenile American alligators (Alligator mississippiensis) to assess growth mark and tissue organization within and amongst individuals, with the intention of validating paleohistological interpretations. Results confirm previous observations that lamellar and parallel fibered tissue organization are typical of crocodylians, and also that crocodylians are capable of forming woven tissue for brief periods. Tissue organization and growth mark count varies across individual skeletal elements and reveal that the femur, tibia, and humerus had the highest annual apposition rates in each individual. Cyclical growth mark count also varies intraskeletally, but data suggest these inconsistencies are due to differing medullary cavity expansion rates. There was no appreciable difference in either diaphyseal circumference or cyclical growth mark circumferences between left and right element pairs from an individual if diaphyses were sampled from roughly the same location. The considerable intraskeletal data obtained here provide validation for long-held paleohistology assumptions, but because medullary expansion, cyclical growth mark formation, and variable intraskeletal growth rates are skeletal features found in tetrapod taxa living or extinct, the validations presented herein should be considered during any tetrapod bone microanalysis. PMID- 24949240 TI - Oral health status among long-term hospitalized adults: a cross sectional study. AB - Background. Many Long-Term Care (LTC) institutionalized patients are the most frail and functionally dependent among the geriatric population and have significant oral health disparities.They often suffer from dental neglect due to limited access to appropriate professional dental care. These patients have chronic health situations and are treated with medications, which increase their risk of oral diseases. Despite the growth in elderly population in Israel, there is insufficient data regarding their oral health status and treatment needs. Objective. To describe the oral health status of the LTC hospitalized adults in a geriatric and psychiatric hospital in Israel. Methods. Data was recorded from LTC hospitalized adults with a physical and/or mental disabilities in a cross sectional research design, which included general health anamnesis and clinical oral examination. Variables included gender, medicines, oral hygiene (OH), using dentures, number of caries lesions and residual teeth. Univariate analyses included Pearson chi (2) and t-test analyses. Multivariate analyses included logistic and linear regressions while the outcome variables were categorical OH index and number of carious cavitations, number of residual teeth and carious teeth percentage. Results. 153 participants were included in the study with a mean age of 65.03 +/- 18.67 years. 31.3% of the patients were edentulous, and only 14% had partial or full dentures. Females had a significantly higher number of caries cavitation than males (P = 0.044). The number of caries cavitation was higher among patients with poor OH (P < 0.001) and when taking Clonazepam (P = 0.018). Number of residual teeth was higher in the fair OH group (P < 0.001). Carious teeth percentage was higher among the poor OH group (P < 0.001). PMID- 24949241 TI - First evidence of bryophyte diaspores in the plumage of transequatorial migrant birds. AB - Correlations between transequatorial migratory bird routes and bipolar biogeographic disjunctions in bryophytes suggest that disjunctions between northern and southern high latitude regions may result from bird-mediated dispersal; supporting evidence is, however, exclusively circumstantial. Birds disperse plant units (diaspores) internally via ingestion (endozoochory) or externally by the attachment of diaspores to the body (ectozoochory). Endozoochory is known to be the primary means of bird-mediated dispersal for seeds and invertebrates at local, regional, and continental scales. Data supporting the role of bird-mediated endozoochory or ectozoochory in the long distance dispersal of bryophytes remain sparse, however, despite the large number of bryophytes displaying bipolar disjunctions. To determine if transequatorial migrant shorebirds may play a role in the ectozoochory of bryophyte diaspores, we developed a method for screening feathers of wild birds. We provide the first evidence of microscopic bryophyte diaspores, as well as those from non-bryophyte lineages, embedded in the plumage of long distance transequatorial migrant birds captured in their arctic breeding grounds. The number of diaspores recovered suggests that entire migratory populations may be departing their northern breeding grounds laden with potentially viable plant parts and that they could thereby play significant roles in bipolar range expansions of lineages previously ignored in the migrant bird dispersal literature. PMID- 24949242 TI - FOCUS: an alignment-free model to identify organisms in metagenomes using non negative least squares. AB - One of the major goals in metagenomics is to identify the organisms present in a microbial community from unannotated shotgun sequencing reads. Taxonomic profiling has valuable applications in biological and medical research, including disease diagnostics. Most currently available approaches do not scale well with increasing data volumes, which is important because both the number and lengths of the reads provided by sequencing platforms keep increasing. Here we introduce FOCUS, an agile composition based approach using non-negative least squares (NNLS) to report the organisms present in metagenomic samples and profile their abundances. FOCUS was tested with simulated and real metagenomes, and the results show that our approach accurately predicts the organisms present in microbial communities. FOCUS was implemented in Python. The source code and web-sever are freely available at http://edwards.sdsu.edu/FOCUS. PMID- 24949243 TI - The salivary secretome of the biting midge, Culicoides sonorensis. AB - Culicoides biting midges (Diptera: Ceratopogonidae) are hematophagous insects with over 1400 species distributed throughout the world. Many of these species are of particular agricultural importance as primary vectors of bluetongue and Schmallenberg viruses, yet little is known about Culicoides genomics and proteomics. Detailed studies of members from other blood-feeding Dipteran families, including those of mosquito (Culicidae) and black fly (Simuliidae), have shown that protein components within the insect's saliva facilitate the blood feeding process. To determine the protein components in Culicoides sonorensis midges, secreted saliva was collected for peptide sequencing by tandem mass spectrometry. Forty-five secreted proteins were identified, including members of the D7 odorant binding protein family, Kunitz-like serine protease inhibitors, maltase, trypsin, and six novel proteins unique to C. sonorensis. Identifying the complex myriad of proteins in saliva from blood-feeding Dipteran species is critical for understanding their role in blood feeding, arbovirus transmission, and possibly the resulting disease pathogenesis. PMID- 24949244 TI - Interannual and spatial variability of maple syrup yield as related to climatic factors. AB - Sugar maple syrup production is an important economic activity for eastern Canada and the northeastern United States. Since annual variations in syrup yield have been related to climate, there are concerns about the impacts of climatic change on the industry in the upcoming decades. Although the temporal variability of syrup yield has been studied for specific sites on different time scales or for large regions, a model capable of accounting for both temporal and regional differences in yield is still lacking. In the present study, we studied the factors responsible for interregional and interannual variability in maple syrup yield over the 2001-2012 period, by combining the data from 8 Quebec regions (Canada) and 10 U.S. states. The resulting model explained 44.5% of the variability in yield. It includes the effect of climatic conditions that precede the sapflow season (variables from the previous growing season and winter), the effect of climatic conditions during the current sapflow season, and terms accounting for intercountry and temporal variability. Optimal conditions for maple syrup production appear to be spatially restricted by less favourable climate conditions occurring during the growing season in the north, and in the south, by the warmer winter and earlier spring conditions. This suggests that climate change may favor maple syrup production northwards, while southern regions are more likely to be negatively affected by adverse spring conditions. PMID- 24949245 TI - Diversity of introduced terrestrial flatworms in the Iberian Peninsula: a cautionary tale. AB - Many tropical terrestrial planarians (Platyhelminthes, Geoplanidae) have been introduced around the globe. One of these species is known to cause significant decline in earthworm populations, resulting in a reduction of ecological functions that earthworms provide. Flatworms, additionally, are a potential risk to other species that have the same dietary needs. Hence, the planarian invasion might cause significant economic losses in agriculture and damage to the ecosystem. In the Iberian Peninsula only Bipalium kewense Moseley, 1878 had been cited till 2007. From that year on, four more species have been cited, and several reports of the presence of these animals in particular gardens have been received. In the present study we have: (1) analyzed the animals sent by non specialists and also the presence of terrestrial planarians in plant nurseries and garden centers; (2) identified their species through morphological and phylogenetic molecular analyses, including representatives of their areas of origin; (3) revised their dietary sources and (4) used Species Distribution Modeling (SDM) for one species to evaluate the risk of its introduction to natural areas. The results have shown the presence of at least ten species of alien terrestrial planarians, from all its phylogenetic range. International plant trade is the source of these animals, and many garden centers are acting as reservoirs. Also, landscape restoration to reintroduce autochthonous plants has facilitated their introduction close to natural forests and agricultural fields. In conclusion, there is a need to take measures on plant trade and to have special care in the treatment of restored habitats. PMID- 24949246 TI - dDocent: a RADseq, variant-calling pipeline designed for population genomics of non-model organisms. AB - Restriction-site associated DNA sequencing (RADseq) has become a powerful and useful approach for population genomics. Currently, no software exists that utilizes both paired-end reads from RADseq data to efficiently produce population informative variant calls, especially for non-model organisms with large effective population sizes and high levels of genetic polymorphism. dDocent is an analysis pipeline with a user-friendly, command-line interface designed to process individually barcoded RADseq data (with double cut sites) into informative SNPs/Indels for population-level analyses. The pipeline, written in BASH, uses data reduction techniques and other stand-alone software packages to perform quality trimming and adapter removal, de novo assembly of RAD loci, read mapping, SNP and Indel calling, and baseline data filtering. Double-digest RAD data from population pairings of three different marine fishes were used to compare dDocent with Stacks, the first generally available, widely used pipeline for analysis of RADseq data. dDocent consistently identified more SNPs shared across greater numbers of individuals and with higher levels of coverage. This is due to the fact that dDocent quality trims instead of filtering, incorporates both forward and reverse reads (including reads with INDEL polymorphisms) in assembly, mapping, and SNP calling. The pipeline and a comprehensive user guide can be found at http://dDocent.wordpress.com. PMID- 24949247 TI - Immune stimulation reduces sleep and memory ability in Drosophila melanogaster. AB - Psychoneuroimmunology studies the increasing number of connections between neurobiology, immunology and behaviour. We demonstrate the effects of the immune response on two fundamental behaviours: sleep and memory ability in Drosophila melanogaster. We used the Geneswitch system to upregulate peptidoglycan receptor protein (PGRP) expression, thereby stimulating the immune system in the absence of infection. Geneswitch was activated by feeding the steroid RU486, to the flies. We used an aversive classical conditioning paradigm to quantify memory and measures of activity to infer sleep. Immune stimulated flies exhibited reduced levels of sleep, which could not be explained by a generalised increase in waking activity. Immune stimulated flies also showed a reduction in memory abilities. These results lend support to Drosophila as a model for immune-neural interactions and provide a possible role for sleep in the interplay between the immune response and memory. PMID- 24949248 TI - Modelling the impacts of an invasive species across landscapes: a step-wise approach. AB - We estimate the extent of ecological impacts of the invasive Asian paper wasp across different landscapes in New Zealand. We used: (i) a baseline distribution layer (modelled via MaxEnt); (ii) Asian paper wasp nest density (from >460 field plots, related to their preferences for specific land cover categories); and (iii) and their foraging intensity (rates of foraging success, and the time available to forage on a seasonal basis). Using geographic information systems this information is combined and modelled across different landscapes in New Zealand in a step-wise selection process. The highest densities of Asian paper wasps were in herbaceous saline vegetation, followed closely by built-up areas, and then scrub and shrubland. Nest densities of 34 per ha, and occupancy rates of 0.27 were recorded for herbaceous saline vegetation habitats. However, the extent of impacts of the Asian paper wasp remains relatively restricted because of narrow climate tolerances and spatial restriction of preferred habitats. A step wise process based on geographic information systems and species distribution models, in combination with factors such as distribution, density, and predation, create a useful tool that allows the extent of impacts of invasive species to be assessed across large spatial scales. These models will be useful for conservation managers as they provide easy visual interpretation of results, and can help prioritise where direct conservation action or control of the invader are required. PMID- 24949249 TI - How male sound pressure level influences phonotaxis in virgin female Jamaican field crickets (Gryllus assimilis). AB - Understanding female mate preference is important for determining the strength and direction of sexual trait evolution. The sound pressure level (SPL) acoustic signalers use is often an important predictor of mating success because higher sound pressure levels are detectable at greater distances. If females are more attracted to signals produced at higher sound pressure levels, then the potential fitness impacts of signalling at higher sound pressure levels should be elevated beyond what would be expected from detection distance alone. Here we manipulated the sound pressure level of cricket mate attraction signals to determine how female phonotaxis was influenced. We examined female phonotaxis using two common experimental methods: spherical treadmills and open arenas. Both methods showed similar results, with females exhibiting greatest phonotaxis towards loud sound pressure levels relative to the standard signal (69 vs. 60 dB SPL) but showing reduced phonotaxis towards very loud sound pressure level signals relative to the standard (77 vs. 60 dB SPL). Reduced female phonotaxis towards supernormal stimuli may signify an acoustic startle response, an absence of other required sensory cues, or perceived increases in predation risk. PMID- 24949250 TI - Continental variation in wing pigmentation in Calopteryx damselflies is related to the presence of heterospecifics. AB - Wing pigmentation in Calopteryx damselflies, caused by the deposition of melanin, is energetically expensive to produce and enhances predation risk. However, patterns of melanisation are used in species identification, greater pigmentation is an accurate signal of male immune function in at least some species, and there may be a role for pigment in thermoregulation. This study tested two potential hypotheses to explain the presence of, and variation in, this pigmentation based on these three potential benefits using 907 male specimens of Calopteryx maculata collected from 49 sites (34 discrete populations) across the geographical range of the species in North America: (i) pigmentation varies with the presence of the closely related species, Calopteryx aequabilis, and (ii) pigment increases at higher latitudes as would be expected if it enhances thermoregulatory capacity. No gradual latitudinal pattern was observed, as might be expected if pigmentation was involved in thermoregulation. However, strong variation was observed between populations that were sympatric or allopatric with C. aequabilis. This variation was characterised by dark wings through allopatry in the south of the range and then a step change to much lighter wings at the southern border of sympatry. Pigmentation then increased further north into the sympatric zone, finally returning to allopatry levels at the northern range margin. These patterns are qualitatively similar to variation in pigmentation in C. aequabilis, meaning that the data are consistent with what would be expected from convergent character displacement. Overall, the results corroborate recent research that has suggested sexual selection as a primary driver behind the evolution of wing pigmentation in this group. PMID- 24949252 TI - Artificial oxidative stress-tolerant Corynebacterium glutamicum. AB - We have reported a transcription profile of an adapted Corynebacterium glutamicum that showed enhanced oxidative stress resistance. To construct an artificial oxidative stress-resistant strain, gene clusters in the beta-ketoadipate pathway, which were up-regulated in the adapted strain, were artificially expressed in the wild-type C. glutamicum. The wild-type strain was unable to grow under 2 mM H2O2 containing minimal medium, while the strains expressing pca gene clusters restored growth under the same medium, and the pcaHGBC expression showed the most significant effect among the gene clusters. The expressions of pca gene clusters also enabled the wild-type to increase its resistance against oxidative stressors, such as diamide and cumene hydroperoxide, as well as H2O2. The oxidative stress tolerance of the strain was correlated to the reactive oxygen species (ROS)-scavenging activity of the cell extract. The reason for the enhanced oxidative stress-resistance of C. glutamicum and its applications on the synthetic strain development are discussed. PMID- 24949251 TI - Regulation of high-voltage-activated Ca2+ channel function, trafficking, and membrane stability by auxiliary subunits. AB - Voltage-gated Ca2+ (CaV) channels mediate Ca2+ ions influx into cells in response to depolarization of the plasma membrane. They are responsible for initiation of excitation-contraction and excitation-secretion coupling, and the Ca2+ that enters cells through this pathway is also important in the regulation of protein phosphorylation, gene transcription, and many other intracellular events. Initial electrophysiological studies divided CaV channels into low-voltage-activated (LVA) and high-voltage-activated (HVA) channels. The HVA CaV channels were further subdivided into L, N, P/Q, and R-types which are oligomeric protein complexes composed of an ion-conducting CaValpha1 subunit and auxiliary CaValpha2delta, CaVbeta, and CaVgamma subunits. The functional consequences of the auxiliary subunits include altered functional and pharmacological properties of the channels as well as increased current densities. The latter observation suggests an important role of the auxiliary subunits in membrane trafficking of the CaValpha1 subunit. This includes the mechanisms by which CaV channels are targeted to the plasma membrane and to appropriate regions within a given cell. Likewise, the auxiliary subunits seem to participate in the mechanisms that remove CaV channels from the plasma membrane for recycling and/or degradation. Diverse studies have provided important clues to the molecular mechanisms involved in the regulation of CaV channels by the auxiliary subunits, and the roles that these proteins could possibly play in channel targeting and membrane Stabilization. PMID- 24949254 TI - Increased biomass production and glycogen accumulation in apcE gene deleted Synechocystis sp. PCC 6803. AB - The effect of phycobilisome antenna-truncation in the cyanobacterium Synechocystis sp. PCC 6803 on biomass production and glycogen accumulation have not yet been fully clarified. To investigate these effects here, the apcE gene, which encodes the anchor protein linking the phycobilisome to the thylakoid membrane, was deleted in a glucose tolerant strain of Synechocystis sp. PCC 6803. Biomass production of the apcE-deleted strain under photoautotrophic and atmospheric air conditions was 1.6 times higher than that of strain PCC 6803 (1.32 +/- 0.01 versus 0.84 +/- 0.07 g cell-dry weight L(-1), respectively) after 15 days of cultivation. In addition, the glycogen content of the apcE-deleted strain (24.2 +/- 0.7%) was also higher than that of strain PCC 6803 (11.1 +/- 0.3%). Together, these results demonstrate that antenna truncation by deleting the apcE gene was effective for increasing biomass production and glycogen accumulation under photoautotrophic and atmospheric air conditions in Synechocystis sp. PCC 6803. PMID- 24949253 TI - Efficient fermentation of an improved synthetic grape must by enological and laboratory strains of Saccharomyces cerevisiae. AB - Grape must or freshly pressed grape juice is a complex chemical matrix that impacts the efficiency of yeast fermentation. The composition of natural grape must (NGM) can be variable; thus, to ensure reproducibility, a synthetic grape must (SGM) with defined composition is commonly used. The aim of this work was to create conditions to advance the use of Saccharomyces cerevisiae laboratory strains for wine fermentation studies, considering previous results obtained for enological strains fermenting NGM under simulated winery conditions. We designed a new SGM formulation, ISA-SGM, by introducing specific modifications to a commonly used formulation, putting together previous reports. We added glucose and fructose in equal amounts (125 g/l) and 50 parts per million (ppm) sulfur dioxide (SO2, corresponding to standard enological treatment), and we optimized the concentrations of malic acid (3 g/l), citric acid (0.3 g/l), and tartaric acid (3 g/l). Using ISA-SGM, we obtained similar fermentative profiles for the wine strain ISA1000, the prototrophic strain S288C, and its auxotrophic derivative BY4741. In this case, the concentrations of supplements were optimized to 120 mg/l L-uracil, 80 mg/l L-methionine, 400 mg/l L-leucine, and 100 mg/l L histidine. All these strains tested in ISA-SGM presented a similar fermentative performance as ISA1000 in NGM. ISA-SGM formulation is a promising new tool to allow the use of the auxotrophic BY strains in the detailed assessment of the alcoholic fermentation process under simulated winery conditions, and it provides a foundation to extract relevant physiological conclusions in future research on enological yeast traits. PMID- 24949255 TI - Disruption of pknG enhances production of gamma-aminobutyric acid by Corynebacterium glutamicum expressing glutamate decarboxylase. AB - Gamma-aminobutyric acid (GABA), a building block of the biodegradable plastic polyamide 4, is synthesized from glucose by Corynebacterium glutamicum that expresses Escherichia coli glutamate decarboxylase (GAD) B encoded by gadB. This strain was engineered to produce GABA more efficiently from biomass-derived sugars. To enhance GABA production further by increasing the intracellular concentration of its precursor glutamate, we focused on engineering pknG (encoding serine/threonine protein kinase G), which controls the activity of 2 oxoglutarate dehydrogenase (Odh) in the tricarboxylic acid cycle branch point leading to glutamate synthesis. We succeeded in expressing GadB in a C. glutamicum strain harboring a deletion of pknG. C. glutamicum strains GAD and GAD ?pknG were cultured in GP2 medium containing 100 g L(-1) glucose and 0.1 mM pyridoxal 5'-phosphate. Strain GAD?pknG produced 31.1 +/- 0.41 g L(-1) (0.259 g L(-1) h(-1)) of GABA in 120 hours, representing a 2.29-fold higher level compared with GAD. The production yield of GABA from glucose by GAD?pknG reached 0.893 mol mol(-1). PMID- 24949256 TI - Response surface modeling for hot, humid air decontamination of materials contaminated with Bacillus anthracis ?Sterne and Bacillus thuringiensis Al Hakam spores. AB - Response surface methodology using a face-centered cube design was used to describe and predict spore inactivation of Bacillus anthracis ?Sterne and Bacillus thuringiensis Al Hakam spores after exposure of six spore-contaminated materials to hot, humid air. For each strain/material pair, an attempt was made to fit a first or second order model. All three independent predictor variables (temperature, relative humidity, and time) were significant in the models except that time was not significant for B. thuringiensis Al Hakam on nylon. Modeling was unsuccessful for wiring insulation and wet spores because there was complete spore inactivation in the majority of the experimental space. In cases where a predictive equation could be fit, response surface plots with time set to four days were generated. The survival of highly purified Bacillus spores can be predicted for most materials tested when given the settings for temperature, relative humidity, and time. These predictions were cross-checked with spore inactivation measurements. PMID- 24949257 TI - Microbial community in microbial fuel cell (MFC) medium and effluent enriched with purple photosynthetic bacterium (Rhodopseudomonas sp.). AB - High power densities have been obtained from MFC reactors having a purple color characteristic of Rhodopseudomonas. We investigated the microbial community structure and population in developed purple MFC medium (DPMM) and MFC effluent (DPME) using 16S rRNA pyrosequencing. In DPMM, dominant bacteria were Comamonas (44.6%), Rhodopseudomonas (19.5%) and Pseudomonas (17.2%). The bacterial community of DPME mainly consisted of bacteria related to Rhodopseudomonas (72.2%). Hydrogen oxidizing bacteria were identified in both purple-colored samples: Hydrogenophaga and Sphaerochaeta in the DPMM, and Arcobacter, unclassified Ignavibacteriaceae, Acinetobacter, Desulfovibrio and Wolinella in the DPME. The methanogenic community of both purple-colored samples was dominated by hydrogenotrophic methanogens including Methanobacterium, Methanobrevibacter and Methanocorpusculum with significantly lower numbers of Methanosarcina. These results suggeste that hydrogen is actively produced by Rhodopseudomonas that leads to the dominance of hydrogen consuming microorganisms in both purple colored samples. The syntrophic relationship between Rhodopseudomonas and hydrogenotrophic microbes might be important for producing high power density in the acetate-fed MFC under light conditions. PMID- 24949258 TI - Cloning, expression and characterization of a versatile Baeyer-Villiger monooxygenase from Dietzia sp. D5. AB - A novel BVMO encoding gene was identified from a draft genome sequence of a newly isolated strain of Dietzia. Analysis of the protein sequence revealed that it belongs to a group of BVMOs whose most characterized member is cyclopentadecanone monooxygenase (CPDMO). The gene was PCR amplified, cloned and successfully expressed in E. coli. The expressed recombinant enzyme was purified using metal affinity chromatography. Characterization of the purified enzyme revealed that it has a broad substrate scope and oxidized different compounds including substituted and unsubstituted alicyclic, bicyclic-, aliphatic-ketones, ketones with an aromatic moiety, and sulfides. The highest activities were measured for 2 and 3-methylcyclohexanone, phenylacetone, bicyclo-[3.2.0]-hept-2-en-6-one and menthone. The enzyme was optimally active at pH 7.5 and 35 degrees C, a temperature at which its half-life was about 20 hours. The stability studies have shown that this enzyme is more stable than all other reported BVMOs except the phenylacetone monooxygenase from the thermophilic organism Thermobifida fusca. PMID- 24949259 TI - Characterization of newly isolated oleaginous yeasts - Cryptococcus podzolicus, Trichosporon porosum and Pichia segobiensis. AB - The yeast strains Cryptococcus podzolicus, Trichosporon porosum and Pichia segobiensis were isolated from soil samples and identified as oleaginous yeast strains beneficial for the establishment of microbial production processes for sustainable lipid production suitable for several industrial applications. When cultured in bioreactors with glucose as the sole carbon source C. podzolicus yielded 31.8% lipid per dry biomass at 20 degrees C, while T. porosum yielded 34.1% at 25 degrees C and P. segobiensis 24.6% at 25 degrees C. These amounts correspond to lipid concentrations of 17.97 g/L, 17.02 g/L and 12.7 g/L and volumetric productivities of 0.09 g/Lh, 0.1 g/Lh and 0.07 g/Lh, respectively. During the culture of C. podzolicus 30 g/l gluconic acid was detected as by product in the culture broth and 12 g/L gluconic acid in T. porosum culture. The production of gluconic acid was eliminated for both strains when glucose was substituted by xylose as the carbon source. Using xylose lipid yields were 11.1 g/L and 13.9 g/L, corresponding to 26.8% and 33.4% lipid per dry biomass and a volumetric productivity of 0.07 g/Lh and 0.09 g/Lh, for C. podzolicus and T. porosum respectively. The fatty acid profile analysis showed that oleic acid was the main component (39.6 to 59.4%) in all three strains and could be applicable for biodiesel production. Palmitic acid (18.4 to 21.1%) and linolenic acid (7.5 to 18.7%) are valuable for cosmetic applications. P. segobiensis had a considerable amount of palmitoleic acid (16% content) and may be suitable for medical applications. PMID- 24949260 TI - Assessment of packed bed bioreactor systems in the production of viral vaccines. AB - Vaccination is believed to be the most effective method for the prevention of infectious diseases. Thus it is imperative to develop cost effective and scalable process for the production of vaccines so as to make them affordable for mass use. In this study, performance of a novel disposable iCELLis fixed bed bioreactor system was investigated for the production of some viral vaccines like Rabies, Hepatitis-A and Chikungunya vaccines in comparison to conventional systems like the commercially available packed bed system and roller bottle system. Vero and MRC-5 cell substrates were evaluated for growth parameters in all the three systems maintaining similar seeding density, multiplicity of infection (MOI) and media components. It was observed that Vero cells showed similar growth in all the three bioreactors whereas MRC-5 cells showed better growth in iCELLis Nano system and roller bottle system. Subsequently, the virus infection and antigen production studies also revealed that for Hepatitis-A and Chikungunya iCELLis Nano bioreactor system was better to the commercial packed bed bioreactor and roller bottle systems. Although for rabies antigen production commercially available packed bed bioreactor system was found to be better. This study shows that different bioreactor platforms may be employed for viral vaccine production and iCELLis Nano is one of such new convenient and a stable platform for production of human viral vaccines. PMID- 24949261 TI - Identification and characterization of endophytic bacteria from corn (Zea mays L.) roots with biotechnological potential in agriculture. AB - Six endophytic bacteria of corn roots were identified as Bacillus sp. and as Enterobacter sp, by sequencing of the 16S rRNA gene. Four of the strains, CNPSo 2476, CNPSo 2477, CNPSo 2478 and CNPSo 2480 were positive for the nitrogen fixation ability evaluated through the acetylene reduction assay and amplification of nifH gene. Two Bacillus strains (CNPSo 2477 and CNPSo 2478) showed outstanding skills for the production of IAA, siderophores and lytic enzymes, but were not good candidates as growth promoters, because they reduced seed germination. However, the same strains were antagonists against the pathogenic fungi Fusarium verticillioides, Colletotrichum graminicola, Bipolaris maydis and Cercospora zea-maydis. As an indication of favorable bacterial action, Enterobacter sp. CNPSo 2480 and Bacillus sp. CNPSo 2481 increased the root volume by 44% and 39%, respectively, and the seed germination by 47% and 56%, respectively. Therefore, these two strains are good candidates for future testing as biological inoculants for corn. PMID- 24949262 TI - Xylanase (GH11) from Acremonium cellulolyticus: homologous expression and characterization. AB - Cellulosic materials constitute most of the biomass on earth, and can be converted into biofuel or bio-based materials if fermentable sugars can be released using cellulose-related enzymes. Acremonium cellulolyticus is a mesophilic fungus which produces a high amount of cellulose-related enzymes. In the genome sequence data of A. cellulolyticus, ORFs showing homology to GH10 and GH11 xylanases were found. The xylanases of A. cellulolyticus play an important role in cellulolytic biomass degradation. Search of a draft genome sequence of A. cellulolyticus for xylanase coding regions identified seven ORFs showing homology to GH 11 xylanase genes (xylA, xylB, xylC, xylD, xylE, xylF and xylG). These genes were cloned and their enzymes were prepared with a homologous expression system under the control of a glucoamylase promoter. Six of the seven recombinant enzymes were successfully expressed, prepared, and characterized. These enzymes exhibited optimal xylanase activity at pH 4.0 - 4.5. But this time, we found that only XylC had enormously higher relative activity (2947 U*mg (-1)) than the other xylanases at optimum pH. This result is surprising because XylC does not retain a carbohydrate-binding module 1 (CBM-1) that is necessary to bind tightly own substrate such as xylan. In this study, we discuss the relationship between activity, pH and sequence of seven xylanases in A. cellulolyticus. PMID- 24949263 TI - Production of (R)-3-hydroxybutyric acid by Burkholderia cepacia from wood extract hydrolysates. AB - (R)-hydroxyalkanoic acids (R-HAs) are valuable building blocks for the synthesis of fine chemicals and biopolymers because of the chiral center and the two active functional groups. Hydroxyalkanoic acids fermentation can revolutionize the polyhydroxyalkanoic acids (PHA) production by increasing efficiency and enhancing product utility. Modifying the fermentation conditions that promotes the in vivo depolymerization and secretion to fermentation broth in wild type bacteria is a novel and promising approach to produce R-HAs. Wood extract hydrolysate (WEH) was found to be a suitable substrate for R-3-hydroxybutyric acid (R-3-HB) production by Burkholderia cepacia. Using Paulownia elongate WEH as a feedstock, the R-3-HB concentration in fermentation broth reached as high as 14.2 g/L after 3 days of batch fermentation and the highest concentration of 16.8 g/L was obtained at day 9. Further investigation indicated that the composition of culture medium contributed to the enhanced R-3-HB production. PMID- 24949264 TI - Mushroom as a product and their role in mycoremediation. AB - Mushroom has been used for consumption as product for a long time due to their flavor and richness in protein. Mushrooms are also known as mycoremediation tool because of their use in remediation of different types of pollutants. Mycoremediation relies on the efficient enzymes, produced by mushroom, for the degradation of various types of substrate and pollutants. Besides waste degradation, mushroom produced a vendible product for consumption. However, sometimes they absorb the pollutant in their mycelium (biosorption process) and cannot be consumed due to absorbed toxicants. This article reviews the achievement and current status of mycoremediation technology based on mushroom cultivation for the remediation of waste and also emphasizes on the importance of mushroom as product. This critical review is also focused on the safety aspects of mushroom cultivation on waste. PMID- 24949265 TI - Michael hydratase alcohol dehydrogenase or just alcohol dehydrogenase? AB - The Michael hydratase - alcohol dehydrogenase (MhyADH) from Alicycliphilus denitrificans was previously identified as a bi-functional enzyme performing a hydration of alpha,beta-unsaturated ketones and subsequent oxidation of the formed alcohols. The investigations of the bi-functionality were based on a spectrophotometric assay and an activity staining in a native gel of the dehydrogenase. New insights in the recently discovered organocatalytic Michael addition of water led to the conclusion that the previously performed experiments to identify MhyADH as a bi-functional enzyme and their results need to be reconsidered and the reliability of the methodology used needs to be critically evaluated. PMID- 24949266 TI - Enzymatic synthesis of epothilone A glycosides. AB - Epothilones are extremely cytotoxic chemotherapeutic agents with epoxide, thiazole, and ketone groups that share equipotent kinetic similarity with taxol. The in vitro glycosylation catalyzed by uridine diphosphate glucosyltransferase (YjiC) from Bacillus licheniformis generated six novel epothilone A glycoside analouges including epothilone A 7-O-beta-D-glucoside, epothilone A 7-O-beta-D galactoside, epothilone A 3,7-O-beta-D-digalactoside, epothilone A 7-O-beta-D-2 deoxyglucoside, epothilone A 7-O-beta-L-rhamnoside, and epothilone A 7-O-beta-L fucoside. Epothilone A 7-O-beta-D-glucoside was structurally elucidated by ultra high performance liquid chromatography-photo diode array (UPLC-PDA) conjugated with high resolution quantitative time-of-flight-electrospray ionization mass spectroscopy (HR-QTOF ESI-MS/MS) supported by one-and two-dimensional nuclear magnetic resonance studies whereas other epothilone A glycosides were characterized by UPLC-PDA and HR-QTOF ESI-MS/MS analyses. The time dependent conversion study of epothilone A to epothilone A 7-O-beta-D-glucoside found to be maximum (~26%) between 3 h to 5 h incubation. PMID- 24949267 TI - Conversion of orange peel to L-galactonic acid in a consolidated process using engineered strains of Aspergillus niger. AB - Citrus processing waste is a leftover from the citrus processing industry and is available in large amounts. Typically, this waste is dried to produce animal feed, but sometimes it is just dumped. Its main component is the peel, which consists mostly of pectin, with D-galacturonic acid as the main monomer. Aspergillus niger is a filamentous fungus that efficiently produces pectinases for the hydrolysis of pectin and uses the resulting D-galacturonic acid and most of the other components of citrus peel for growth. We used engineered A. niger strains that were not able to catabolise D-galacturonic acid, but instead converted it to L-galactonic acid. These strains also produced pectinases for the hydrolysis of pectin and were used for the conversion of pectin in orange peel to L-galactonic acid in a consolidated process. The D-galacturonic acid in the orange peel was converted to L-galactonic acid with a yield close to 90%. Submerged and solid-state fermentation processes were compared. PMID- 24949268 TI - Erythritol production on wheat straw using Trichoderma reesei. AB - We overexpressed the err1 gene in the Trichoderma reesei wild-type and in the cellulase hyperproducing, carbon catabolite derepressed strain Rut-C30 in order to investigate the possibility of producing erythritol with T. reesei. Two different promoters were used for err1 overexpression in both strains, a constitutive (the native pyruvat kinase (pki) promoter) and an inducible one (the native beta-xylosidase (bxl1) promoter). The derived recombinant strains were precharacterized by analysis of err1 transcript formation on D-xylose and xylan. Based on this, one strain of each type was chosen for further investigation for erythritol production in shake flasks and in bioreactor experiments. For the latter, we used wheat straw pretreated by an alkaline organosolve process as lignocellulosic substrate. Shake flask experiments on D-xylose showed increased erythritol formation for both, the wild-type and the Rut-C30 overexpression strain compared to their respective parental strain. Bioreactor cultivations on wheat straw did not increase erythritol formation in the wild-type overexpression strain. However, err1 overexpression in Rut-C30 led to a clearly higher erythritol formation on wheat straw. PMID- 24949269 TI - Absolute quantification of individual biomass concentrations in a methanogenic coculture. AB - Identification of individual biomass concentrations is a crucial step towards an improved understanding of anaerobic digestion processes and mixed microbial conversions in general. The knowledge of individual biomass concentrations allows for the calculation of biomass specific conversion rates which form the basis of anaerobic digestion models. Only few attempts addressed the absolute quantification of individual biomass concentrations in methanogenic microbial ecosystems which has so far impaired the calculation of biomass specific conversion rates and thus model validation. This study proposes a quantitative PCR (qPCR) approach for the direct determination of individual biomass concentrations in methanogenic microbial associations by correlating the native qPCR signal (cycle threshold, Ct) to individual biomass concentrations (mg dry matter/L). Unlike existing methods, the proposed approach circumvents error-prone conversion factors that are typically used to convert gene copy numbers or cell concentrations into actual biomass concentrations. The newly developed method was assessed and deemed suitable for the determination of individual biomass concentrations in a defined coculture of Desulfovibrio sp. G11 and Methanospirillum hungatei JF1. The obtained calibration curves showed high accuracy, indicating that the new approach is well suited for any engineering applications where the knowledge of individual biomass concentrations is required. PMID- 24949270 TI - Family 1 carbohydrate binding-modules enhance saccharification rates. AB - Cellulose degrading enzymes usually have a two-domain structure consisting of a catalytic domain and a non-catalytic carbohydrate-binding module. Although it is well known the importance of those modules in cell wall degrading process, their function is not yet fully understood. Here, we analyze the cellulose-hydrolysis activity enhancement promoted by the cellobiohydrolase I carbohydrate-binding module from Trichoderma harzianum. It was cloned, expressed, purified and used in combination with either a commercial cellulase preparation, T. reesei cellobiohydrolase I or its separate catalytic domain to hydrolyze filter paper. In all cases the amount of glucose released was increased, reaching up to 30% gain when the carbohydrate-binding module was added to the reaction. We also show that this effect seems to be mediated by a decrease in the recalcitrance of the cellulosic substrate. This effect was observed both for crystalline cellulose samples which underwent incubation with the CBM prior to application of cellulases and for the ones incubated simultaneously. Our studies demonstrate that family 1 carbohydrate-binding modules are able to potentiate the enzymatic degradation of the polysaccharides and their application might contribute to diminishing the currently prohibitive costs of the lignocellulose saccharification process. PMID- 24949271 TI - Study of CFU for individual microorganisms in mixed cultures with a known ratio using MBRT. AB - Determination of metabolically active cell count is an important step in designing, operating and controlling fermentation processes. It's particularly relevant in processes involving mixed cultures, where multiple species contribute to the total growth. The motivation for the current study is to develop a methodology to estimate metabolically active cell counts for the individual species in a mixed culture with approximate equal numbers. Further, the methodology should indicate the presence of a contaminant in short time periods since in the agar plate methods used frequently it takes about 24 h. We present a methodology based on the rate of Methylene blue (MB) reduction to evaluate total count of metabolically active cells. The standard curve relating the slope of MB reduction and CFU of the individual species could be used to measure the metabolic activity of each species in the mixed culture. The slope of MB reduction could also be used to obtain the growth rate of individual species in a mixed culture and that of the total cell count. These measurements were achieved in less than 6 minutes during the growth of the cells. Evaluating the metabolic activity of individual species in a mixed culture is tedious, difficult and time consuming. The Methylene Blue dye Reduction Test (MBRT) presented here is capable of quickly estimating colony forming units (CFU) of individual species in a mixed culture if the ratio of the numbers of cells is known. The method was used to dynamically detect the occurrence of a contaminating microorganism during fermentation. The protocol developed here can be adapted to applications in processes involving mixed cultures. PMID- 24949272 TI - Phenotypic and metabolic traits of commercial Saccharomyces cerevisiae yeasts. AB - Currently, pursuing yeast strains that display both a high potential fitness for alcoholic fermentation and a favorable impact on quality is a major goal in the alcoholic beverage industry. This considerable industrial interest has led to many studies characterizing the phenotypic and metabolic traits of commercial yeast populations. In this study, 20 Saccharomyces cerevisiae strains from different geographical origins exhibited high phenotypic diversity when their response to nine biotechnologically relevant conditions was examined. Next, the fermentation fitness and metabolic traits of eight selected strains with a unique phenotypic profile were evaluated in a high-sugar synthetic medium under two nitrogen regimes. Although the strains exhibited significant differences in nitrogen requirements and utilization rates, a direct relationship between nitrogen consumption, specific growth rate, cell biomass, cell viability, acetic acid and glycerol formation was only observed under high-nitrogen conditions. In contrast, the strains produced more succinic acid under the low-nitrogen regime, and a direct relationship with the final cell biomass was established. Glucose and fructose utilization patterns depended on both yeast strain and nitrogen availability. For low-nitrogen fermentation, three strains did not fully degrade the fructose. This study validates phenotypic and metabolic diversity among commercial wine yeasts and contributes new findings on the relationship between nitrogen availability, yeast cell growth and sugar utilization. We suggest that measuring nitrogen during the stationary growth phase is important because yeast cells fermentative activity is not exclusively related to population size, as previously assumed, but it is also related to the quantity of nitrogen consumed during this growth phase. PMID- 24949273 TI - Effects of biosurfactants on the viability and proliferation of human breast cancer cells. AB - Biosurfactants are molecules with surface activity produced by microorganisms that can be used in many biomedical applications. The anti-tumour potential of these molecules is being studied, although results are still scarce and few data are available regarding the mechanisms underlying such activity. In this work, the anti-tumour activity of a surfactin produced by Bacillus subtilis 573 and a glycoprotein (BioEG) produced by Lactobacillus paracasei subsp. paracasei A20 was evaluated. Both biosurfactants were tested against two breast cancer cell lines, T47D and MDA-MB-231, and a non-tumour fibroblast cell line (MC-3 T3-E1), specifically regarding cell viability and proliferation. Surfactin was found to decrease viability of both breast cancer cell lines studied. A 24 h exposure to 0.05 g l(-1) surfactin led to inhibition of cell proliferation as shown by cell cycle arrest at G1 phase. Similarly, exposure of cells to 0.15 g l(-1) BioEG for 48 h decreased cancer cells' viability, without affecting normal fibroblasts. Moreover, BioEG induced the cell cycle arrest at G1 for both breast cancer cell lines. The biosurfactant BioEG was shown to be more active than surfactin against the studied breast cancer cells. The results gathered in this work are very promising regarding the biosurfactants potential for breast cancer treatment and encourage further work with the BioEG glycoprotein. PMID- 24949274 TI - Combining the effects of process design and pH for improved xylose conversion in high solid ethanol production from Arundo donax. AB - The impact of pH coupled to process design for the conversion of the energy crop Arundo donax to ethanol was assessed in the present study under industrially relevant solids loadings. Two main process strategies were investigated, i.e. the traditional simultaneous saccharification and co-fermentation (SSCF) and a HYBRID design, where a long high temperature enzymatic hydrolysis step was carried out prior to continued low temperature SSCF, keeping the same total reaction time. Since acetic acid was identified as the major inhibitor in the slurry, the scenarios were investigated under different fermentation pH in order to alleviate the inhibitory effect on, in particular, xylose conversion. The results show that, regardless of fermentation pH, a higher glucan conversion could be achieved with the HYBRID approach compared to SSCF. Furthermore, it was found that increasing the pH from 5.0 to 5.5 for the fermentation phase had a large positive effect on xylose consumption for both process designs, although the SSCF design was more favored. With the high sugar concentrations available at the start of fermentation during the HYBRID design, the ethanol yield was reduced in favor of cell growth and glycerol production. This finding was confirmed in shake flask fermentations where an increase in pH enhanced both glucose and xylose consumption, but also cell growth and cell yield with the overall effect being a reduced ethanol yield. In conclusion this resulted in similar overall ethanol yields at the different pH values for the HYBRID design, despite the improved xylose uptake, whereas a significant increase in overall ethanol yield was found with the SSCF design. PMID- 24949275 TI - Integrative gene transfer in the truffle Tuber borchii by Agrobacterium tumefaciens-mediated transformation. AB - Agrobacterium tumefaciens-mediated transformation is a powerful tool for reverse genetics and functional genomic analysis in a wide variety of plants and fungi. Tuber spp. are ecologically important and gastronomically prized fungi ("truffles") with a cryptic life cycle, a subterranean habitat and a symbiotic, but also facultative saprophytic lifestyle. The genome of a representative member of this group of fungi has recently been sequenced. However, because of their poor genetic tractability, including transformation, truffles have so far eluded in-depth functional genomic investigations. Here we report that A. tumefaciens can infect Tuber borchii mycelia, thereby conveying its transfer DNA with the production of stably integrated transformants. We constructed two new binary plasmids (pABr1 and pABr3) and tested them as improved transformation vectors using the green fluorescent protein as reporter gene and hygromycin phosphotransferase as selection marker. Transformants were stable for at least 12 months of in vitro culture propagation and, as revealed by TAIL- PCR analysis, integration sites appear to be heterogeneous, with a preference for repeat element-containing genome sites. PMID- 24949276 TI - Physiological and growth response of rice plants (Oryza sativa L.) to Trichoderma spp. inoculants. AB - Trichoderma spp., a known beneficial fungus is reported to have several mechanisms to enhance plant growth. In this study, the effectiveness of seven isolates of Trichoderma spp. to promote growth and increase physiological performance in rice was evaluated experimentally using completely randomized design under greenhouse condition. This study indicated that all the Trichoderma spp. isolates tested were able to increase several rice physiological processes which include net photosynthetic rate, stomatal conductance, transpiration, internal CO2 concentration and water use efficiency. These Trichoderma spp. isolates were also able to enhance rice growth components including plant height, leaf number, tiller number, root length and root fresh weight. Among the Trichoderma spp. isolates, Trichoderma sp. SL2 inoculated rice plants exhibited greater net photosynthetic rate (8.66 MUmolCO2 m(-2) s(-1)), internal CO2 concentration (336.97 ppm), water use efficiency (1.15 MUmoCO2/mmoH2O), plant height (70.47 cm), tiller number (12), root length (22.5 cm) and root fresh weight (15.21 g) compared to the plants treated with other Trichoderma isolates tested. We conclude that beneficial fungi can be used as a potential growth promoting agent in rice cultivation. PMID- 24949277 TI - The chemical nature of phenolic compounds determines their toxicity and induces distinct physiological responses in Saccharomyces cerevisiae in lignocellulose hydrolysates. AB - We investigated the severity of the inhibitory effects of 13 phenolic compounds usually found in spruce hydrolysates (4-hydroxy-3-methoxycinnamaldehyde, homovanilyl alcohol, vanillin, syringic acid, vanillic acid, gallic acid, dihydroferulic acid, p-coumaric acid, hydroquinone, ferulic acid, homovanillic acid, 4-hydroxybenzoic acid and vanillylidenacetone). The effects of the selected compounds on cell growth, biomass yield and ethanol yield were studied and the toxic concentration threshold was defined for each compound. Using Ethanol Red, the popular industrial strain of Saccharomyces cerevisiae, we found the most toxic compound to be 4-hydroxy-3-methoxycinnamaldehyde which inhibited growth at a concentration of 1.8 mM. We also observed that toxicity did not generally follow a trend based on the aldehyde, acid, ketone or alcohol classification of phenolic compounds, but rather that other structural properties such as additional functional groups attached to the compound may determine its toxicity. Three distinctive growth patterns that effectively clustered all the compounds involved in the screening into three categories. We suggest that the compounds have different cellular targets, and that. We suggest that the compounds have different cellular targets and inhibitory mechanisms in the cells, also compounds who share similar pattern on cell growth may have similar inhibitory effect and mechanisms of inhibition. PMID- 24949278 TI - Screening of liquid media and fermentation of an endophytic Beauveria bassiana strain in a bioreactor. AB - A novel approach for biological control of insect pests could be the use of the endophytic entomopathogenic Beauveria bassiana isolate ATP-02. For the utilization of the endophyte as a commercial biocontrol agent, the fungus has to be mass-produced. B. bassiana was raised in shake flask cultures to produce high concentrations of total spores (TS), which include blastospores (BS) and submerged conidiospores (SCS). The highest concentration of 1.33*10(9) TS/mL and the highest yield of 5.32*10(10) TS/g sucrose was obtained in the TKI broth with 5% sugar beet molasses which consists of 50% sucrose as a carbon source. In spite of the lower sugar concentration (2.5%) the amount of TS could be increased up to 11-times in contrast to the cultivation with 5% sucrose. The scale-up to a 2 L stirred tank reactor was carried out at 25 degrees C, 200-600 rpm and 1 vvm at pH 5.5. A TS yield of 5.2*10(10) TS/g sucrose corresponding to a SCS yield of 0.2*10(10) SCS/g sucrose was obtained after 216 h. With regards to the culture medium the cost of 10(12) TS amounts to 0.24 ?. Plutella xylostella larvae, which were fed with oilseed rape leaves treated with spores from fermentation resulted in 77 +/- 5% mortality. Moreover, spores from submerged cultivation were able to colonize oilseed rape leaves via leaf application. This is the first report of fermentation of an endophytic B. bassiana strain in a low-cost culture medium to very high yields of TS. PMID- 24949279 TI - Coronary artery bypass grafts and diagnosis related groups: patient classification and hospital reimbursement in 10 European countries. AB - BACKGROUND: The prospective reimbursement of hospitals through the grouping of patients into a finite number of categories (Diagnosis Related Groups, DRGs), is common to many European countries. However, the specific categories used vary greatly across countries, using different characteristics to define group boundaries and thus those characteristics which result in different payments for treatment. In order to assist in the construction and modification of national DRG systems, this study analyses the DRG systems of 10 European countries. AIMS: To compare the characteristics used to categorise patients receiving a coronary artery bypass graft (CABG) surgery into DRGs. Further, to compare the structure into which DRGs are placed and the relative price paid for patients across Europe. METHOD: Patients with a procedure of CABG surgery are analysed from Austria, England, Estonia, Finland, France, Germany, Ireland, Poland, Spain and Sweden. Diagrammatic algorithms of DRG structures are presented for each country. The price in Euros of seven typical case vignettes, each made up of a set of a hypothetical patient's characteristics, is also analysed for each country. In order to enable comparisons across countries the simplest case (index vignette) is taken as baseline and relative price levels are calculated for the other six vignettes, each representing patients with different combinations of procedures and comorbidities. RESULTS: European DRG payment structures for CABG surgery vary in terms of the number of different DRGs used and the types of distinctions which define patient categorisation. Based on the payments given to hospitals in different countries, the most resource intensive patient, relative to the index vignette, ranges in magnitude from 1.37 in Poland to 2.82 in Ireland. There is also considerable variation in how much different systems pay for particular circumstances, such as the occurrence of catheterisation or presence of comorbidity. CONCLUSION: Past experience of the construction of DRG systems for CABG patients demonstrates the variety of options available. It also highlights the importance of updating systems as frequently as possible, to incentivise best practice. PMID- 24949280 TI - A comparison of the cost-effectiveness of treatment of prolonged acute convulsive epileptic seizures in children across Europe. AB - In the majority of children and adolescents with epilepsy, optimal drug therapy adequately controls their condition. However, among the remaining patients who are still uncontrolled despite mono-, bi- or tri-therapy with chronic anti epileptic treatment, a rescue medication is required. In Western Europe, the licensed medications available for first-line treatment of prolonged acute convulsive seizures (PACS) vary widely, and so comparators for clinical and economic evaluation are not consistent. No European guidelines currently exist for the treatment of PACS in children and adolescents and limited evidence is available for the effectiveness of treatments in the community setting. The authors present cost-effectiveness data for BUCCOLAM(r) (midazolam oromucosal solution) for the treatment of PACS in children and adolescents in the context of the treatment pathway in seven European countries in patients from 6 months to 18 years. For each country, the health economic model consisted of a decision tree, with decision nodes informed by clinical data and expert opinion obtained via a Delphi methodology. The events modelled are those associated with a patient experiencing a seizure in the community setting. The model assessed the likelihood of medication being administered successfully and of seizure cessation. The associated resource use was also modelled, and ambulance call-outs and hospitalisations were considered. The patient's quality of life was estimated by clinicians, who completed a five-level EuroQol five dimensions questionnaire from the perspective of a child or adolescent suffering a seizure. Despite differences in current therapy, treatment patterns and healthcare costs in all countries assessed, BUCCOLAM was shown to be cost saving and offered increased health-related benefits for patients in the treatment of PACS compared with the current local standard of care. PMID- 24949281 TI - Factors associated with geographic variation in cost per episode of care for three medical conditions. AB - OBJECTIVE: To identify associations between market factors, especially relative reimbursement rates, and the probability of surgery and cost per episode for three medical conditions (cataract, benign prostatic neoplasm, and knee degeneration) with multiple treatment options. METHODS: We use 2004-2006 Medicare claims data for elderly beneficiaries from sixty nationally representative communities to estimate multivariate models for the probability of surgery and cost per episode of care as a function local market factors, including Medicare physician reimbursement for surgical versus non-surgical treatment and the availability of primary care and specialty physicians. We used Symmetry's Episode Treatment Groups (ETG) software to group claims into episodes for the three conditions (n = 540,874 episodes). RESULTS: Higher Medicare reimbursement for surgical episodes and greater availability of the relevant specialists are significantly associated with more surgery and higher cost per episode for all three conditions, while greater availability of primary care physicians is significantly associated with less frequent surgery and lower cost per episode. CONCLUSION: Relative Medicare reimbursement rates for surgical vs. non-surgical treatments and the availability of both primary care physicians and relevant specialists are associated with the likelihood of surgery and cost per episode. PMID- 24949282 TI - Feasibility of preoperative (125)I seed-guided tumoural tracer injection using freehand SPECT for sentinel lymph node mapping in non-palpable breast cancer. AB - BACKGROUND: This study was designed to explore the feasibility of replacing the conventional peri-/intratumoural ultrasound (US)-guided technetium-99m albumin nanocolloid ((99m)Tc-nanocolloid) administration by an injection of the same tracer guided by a freehand single-photon emission computed tomography (SPECT) device in patients with non-palpable breast cancer with an iodine-125 ((125)I) seed as tumour marker, who are scheduled for a sentinel lymph node biopsy (SLNB). This approach aimed to decrease the workload of the radiology department, avoiding a second US-guided procedure. METHODS: In ten patients, the implanted (125)I seed was primarily localised using freehand SPECT and subsequently verified by conventional US in order to inject the (99m)Tc-nanocolloid. The following 34 patients were injected using only freehand SPECT localisation. In these patients, additional SPECT/CT was acquired to measure the distance between the (99m)Tc-nanocolloid injection depot and the (125)I seed. In retrospect, a group of 21 patients with US-guided (99m)Tc-nanocolloid administrations was included as a control group. RESULTS: The depth difference measured by US and freehand SPECT in ten patients was 1.6 +/- 1.6 mm. In the following 36 (125)I seeds (34 patients), the average difference between the (125)I seed and the centre of the (99m)Tc-nanocolloid injection depot was 10.9 +/- 6.8 mm. In the retrospective study, the average distance between the (125)I seed and the centre of the (99m)Tc-nanocolloid injection depot as measured in SPECT/CT was 9.7 +/- 6.5 mm and was not significantly different compared to the freehand SPECT-guided group (two-sample Student's t test, p = 0.52). CONCLUSION: We conclude that using freehand SPECT for (99m)Tc-nanocolloid administration in patients with non palpable breast cancer with previously implanted (125)I seed is feasible. This technique may improve daily clinical logistics, reducing the workload of the radiology department. PMID- 24949284 TI - Assessing Older Adults' Obsessive-Compulsive Disorder Symptoms: Psychometric Characteristics of the Obsessive Compulsive Inventory-Revised. AB - The lack of Obsessive-Compulsive disorder (OCD) symptom measures validated for use with older adults has hindered research and treatment development for the age group. We evaluated the Obsessive-Compulsive Inventory-Revised (OCI-R; Foa et al., 2002) with participants aged 65 and older (N = 180) to determine if the measure was an effective tool for evaluating obsessional symptoms. Participants completed the OCI-R and a comprehensive assessment battery up to four times over approximately 18 months. Results supported the well-replicated latent structure of the OCI-R (i.e., Washing, Checking, Ordering, Obsessing, Hoarding, and Neutralizing.). OCI-R total score was robustly associated with OCD symptoms assessed 18 months later by clinical interview, while scores on self-report measures of worry, general anxiety, and depression were not. Results indicate the OCI-R is an effective OCD symptom measure for older adults, although replication with additional older adult samples is needed. PMID- 24949285 TI - The promise of mobile technologies and single case designs for the study of individuals in their natural environment. AB - Mobile technologies are growing rapidly around the world to broad demographics of society. These technologies hold great promise for their integration with Single Case Designs (SCDs) and the study of individuals in their natural environment. This paper discusses the theoretical, methodological and analytic implications of these tools for the advancement of the contextual behavioral etiology of behavioral disorders, and their remediation. We hope this paper will highlight the scientific advantages of combining mobile technologies and SCDs and encourage their adoption among CBS scientists. PMID- 24949283 TI - Dissociable effects of dopamine on learning and performance within sensorimotor striatum. AB - Striatal dopamine is an important modulator of current behavior, as seen in the rapid and dramatic effects of dopamine replacement therapy in Parkinson Disease (PD). Yet there is also extensive evidence that dopamine acts as a learning signal, modulating synaptic plasticity within striatum to affect future behavior. Disentangling these "performance" and "learning" functions is important for designing effective, long-term PD treatments. We conducted a series of unilateral drug manipulations and dopamine terminal lesions in the dorsolateral striatum of rats highly-trained to perform brief instructed head/neck movements (two alternative forced choice task). Reaction times and accuracy were measured longitudinally to determine if task behavior changed immediately, progressed over time, and/or persisted after drug withdrawal. Enhanced dopamine signaling with amphetamine caused an immediate, nonprogressive, and bilateral decrease in reaction times (RT). The altered RT distributions were consistent with reduced distance to threshold in the linear approach to threshold with ergodic rate (LATER) model of decision-making. Conversely, the dopamine antagonist flupenthixol caused experience-dependent, persistent changes in RT and accuracy indicative of a "learning" effect. These RT distributions were consistent with a slowed rate of approach to decision threshold. Our results show that dopaminergic signaling makes dissociable contributions to current and future behavior even within a single striatal subregion, and provide important clues for both models of normal decision-making and the design of novel drug therapies in PD. PMID- 24949286 TI - Can we use peroneus longus in addition to hamstring tendons for anterior cruciate ligament reconstruction? AB - BACKGROUND: The aim of this study is to evaluate the possible effects of removing the peroneus longus on the ankle and gait parameters, in order to add insufficient hamstring tendons for anterior cruciate ligament (ACL) reconstruction. MATERIALS AND METHODS: In this controlled clinical trial, 375 patients with ACL rupture who underwent ACL reconstruction arthroscopically using hamstring tendons in the orthopedic clinics of Isfahan University of Medical Sciences in 2010 and 2011 were selected. Fifteen patients were included because their hamstring tendon diameter was lower than 8 mm and peroneus longus was added. After 6 months, the patients were followed using "Kistler force plate" to detect 3D kinematics and kinetics of the ankles and spatiotemporal walking parameters. RESULTS: There was a significant difference between both operated and non-operated ankles in flexion/extension range of motion (P < 0.05). There was no significant difference between the moments of both ankles in sagittal and coronal planes (P > 0.05), but there was a significant difference between the moments of both ankles in the transverse plane (P = 0.006). There was a significant difference in the force of operated and non-operated ankles in all three planes (P < 0.05). There was no significant difference in the mean values of spatiotemporal gait parameters between operated and non-operated sides (P > 0.05). CONCLUSION: Removing the peroneus longus tendon has no effect on gait parameters and does not lead to instability of the ankle. So, it can be used as an autogenous graft in orthopedic surgeries. PMID- 24949287 TI - Diagnostic validity of the chemiluminescent method compared to polymerase chain reaction for hepatitis B virus detection in the routine clinical diagnostic laboratory. AB - BACKGROUND: Hepatitis B virus (HBV) is the most common significant chronic viral infection world-wide. Hepatitis B surface antigen (HBsAg) has been the principal target for laboratory testing to identify active infection by HBV. We aimed to find out diagnostic validity of the Liaison chemiluminescent method compared to the polymerase chain reaction (PCR) method for HBV detection in the routine clinical diagnostic laboratory. MATERIALS AND METHODS: From 350 patients suspicious of having infection with HBV, serum samples were separated and used for testing HBsAg by two methods of Liaison chemiluminescent immunoassay, with HBsAg confirmatory test and PCR method. RESULTS: According to the PCR results as assumed as gold standard method with 100% sensitivity and specificity, detection rate sensitivity of chemiluminescent with confirmatory test was 96% and its specificity was 100%, and for chemiluminescent without confirmatory test sensitivity and specificity were 100% and 70%, respectively. Also for chemiluminescent with confirmatory test, positive predictive value (PPV) was 100% and its negative predictive value (NPV) was 97%, compared to chemiluminescent without confirmatory test with PPV and NPV equal to 71% and 100%, respectively. CONCLUSIONS: It is possible to conclude that in the majority of the HBV cases, the diagnostic value of chemiluminescent method compared to the PCR method is acceptable, except in low indexes positive cases that need further investigation with the PCR method. PMID- 24949288 TI - Efflux pump regulatory genes mutations in multidrug resistance Pseudomonas aeruginosa isolated from wound infections in Isfahan hospitals. AB - BACKGROUND: Multidrug resistance Pseudomonas aeruginosa (MDR-P. aeruginosa) is a worldwide threat for public health. Hyperexpression of efflux pump systems (MexAB OprM and MexCD-OprJ), which is a well-known mechanisms for MDR emerging, is controlled by regulatory genes, mexR and nfxB, respectively. The aim of this study was to evaluate point mutations in mexR and nfxB genes in MDR- P. aeruginosa isolated from wound infections. MATERIALS AND METHODS: A total of 34 P. aeruginosa cultures obtained from wound infections were analyzed. Among them eight isolates identified as MDR-P. aeruginosa and were subjected to determination of mutations in mexR and nfxB genes. RESULTS: We detected eight point mutations in mexR and 12-point mutations in nfxB. The most common mutations were common G327-A (eight isolates), G384-A (eight isolates), G411-A (eight isolates). Mutations in A371-C and A372-C were the predominant substitution which was seen in nfxB. Amino acid substitutions were also found at position 124 and 126 for NfxB and MexR, respectively. CONCLUSIONS: P. aeruginosa isolates with mutation in efflux pump regulatory genes such as mexR and nfxB could be a main factor contributed to antibiotic resistance and must be considered in antibiotic treatment. PMID- 24949289 TI - Insertion/deletion polymorphism of the angiotensin-converting enzyme gene and the risk of hypertension among residents of two cities, South-South Nigeria. AB - BACKGROUND: Hypertension is a public health challenge due to its high prevalence, and is a major risk factor for cardiovascular diseases. This study was designed to determine the frequency of the I/D polymorphism of the angiotensin-converting enzyme gene and its association with hypertension in a sample population of Calabar and Uyo, South-South Nigeria. MATERIALS AND METHODS: A population-based case control design consisting of total of 1224 participants, 612 each of patients and controls, were randomly recruited from hypertension clinics and the general population. The I/D polymorphism was investigated using polymerase chain reaction. Multiple regression and odds ratio (OR) was applied to test whether the ID genotypes were predictors of hypertension. RESULTS: The I/D genotype frequencies were 73(12%), 262(43%) and 277(45%); 74(12%), 303(50%) and 235(38%) for the II, ID, DD genotype in patient and control groups, respectively. A higher frequency of the ID genotype was observed in controls of which 208(61%) were females. By multiple regression analysis, age was a predictor for SBP in patients, r = 0.596, and DBP in controls, r = 0.555. Gender, Body mass index, I/D genotypes were not significant predictors for hypertension but the I/D polymorpism was associated with an increased risk for hypertension with an OR of 1.15 95%CI (0.924-1.456). CONCLUSION: The I/D polymorphism of the angiotensin converting enzyme gene was a risk factor for hypertension in the sample population of Calabar and Uyo. This research will form baseline information for subsequent molecular studies in this population. PMID- 24949290 TI - Significance of the position of the proximal tip of the tibial nail: An important factor related to anterior knee pain. AB - BACKGROUND: Intramedullary nailing is the treatment of choice for the majority of tibial shaft fractures and anterior knee pain is the most common complication of this surgery; however, its etiology is still unknown. The purpose of this study was to assess the predicting factors related to anterior knee pain following tibial nailing. MATERIALS AND METHODS: Patients with isolated, unilateral tibial shaft fracture who had undergone tibial nailing were identified retrospectively. Data including age, sex, type of fracture, technique of surgery and location of the nail were collected and finally the association between the above variables and knee pain were analyzed via SPSS software. RESULTS: A total of 95 patients participated in the study. The mean age of the participants was 33.52 +/- 1.62, 87 (91.6%) of whom were male and 74 (77.9%) had close fractures respectively. The method of surgery in 60 (63.2%) patients was paratendinous approach and in 35 (36.8%) was transtendinous. Twenty six (27.4%) of the patients had anterior knee pain. There were no significant differences between the two groups of patients with and without knee pain by age, sex, type of fracture and type of surgery (P = 0.952, 0.502, 0.212 and 0.745, respectively). Patients with protrusion of the nail from the anterior cortex had higher risk of developing knee pain after surgery (odds ratio: 2.76, confidence interval: 1.08, 7.08, P = 0.031). CONCLUSION: The results revealed a higher risk of developing anterior knee pain after tibial nailing in patients with protrusion of the nail from the anterior cortex. PMID- 24949291 TI - Enumeration and identification of dust fungal elements from the weather inversion phenomenon in Isfahan, Iran. AB - BACKGROUND: Fungi are the major pathogens or allergens for which the air is the natural medium of their dispersal. Since the air pollution is associated with a wide range of adverse health outcomes, then identification of the type and population of fungi in these conditions will help the management of hygienic and control of fungal disease. MATERIALS AND METHODS: A total of 103 dust samples were collected from glass surfaces of different places by sedimentation method. Pollution standard indexes were provided by Environmental Protection Agency in Isfahan. All dust samples were mixed and homogenized in distilled water containing antibacterial agents. Serial cultures were done in 5 times experiments on two standard culture media. Isolated fungal colonies were identified by their standard morphologic and physiologic criteria. The analysis was performed by Mann Whitney test calculating by SPSS version 20 (SPSS Inc., Chicago, IL, USA). RESULTS: The real mean of total culture-able fungi in 1 g of sedimentation dust were account about 44800 colonies of different fungi. More than half of the viable fungi (62.8%) could grow out of 1 g of dust on Mycosel agar were the genera of Aspergillus, Penicillium and Cladosporium with 28.8%, 23.4% and 10.6% respectively. The dominant genus could grow on Sabouraud dextrose agar with chloramphenicol medium were the genera of Aspergillus, Cladosporium and Penicillium with 23.7%, 21.1% and 14.5% respectively. CONCLUSIONS: Our data show the amount and variety of viable colony-forming fungi, which we are faced with in Isfahan during the air pollution condition. The real abundance of fungal particles and non-cultivable fungi in dust are still poorly understood and remain for further study in the future. PMID- 24949292 TI - Heparin compared with normal saline to maintain patency of permanent double lumen hemodialysis catheters: A randomized controlled trial. AB - BACKGROUND: Heparin has long been used to prevent thrombosis in the permanent central venous hemodialysis catheters (PermCath). Other alternatives for heparin with fewer side-effects have recently been considered. We compared normal saline (0.9%) with heparin for flushing PermCath with regards to catheter patency and prevention of heparin complications. MATERIALS AND METHODS: Chronic kidney disease patients who were candidate of PermCath placement were randomly assigned into two groups of heparin and saline. In the heparin group, the PermCath was flushed with heparin (1000 IU), and in the saline group, it was flushed with saline 0.9%. Patients were followed for 24 hours, and outcomes included catheter thrombosis, maneuver needed to maintain catheter patency, and bleeding from catheter site. RESULTS: Ninety six patients were included (age = 63.1 +/- 11.2 years, 54.2% male). No one experienced catheter thrombosis. Two patient (4.2%) in the heparin and three ones (6.1%) in the saline group required catheter manipulation (P = 0.520). Four patients (8.5%) in the heparin and three ones (6.1%) in the saline group experienced bleeding (P = 0.476); differences between heparin and saline groups in the amount of bleeding (225.0 +/- 62.4 vs. 200.0 +/- 113.5 cc, P = 0.721) and bleeding time (6.5 +/- 1.2 vs. 5.3 +/- 1.5 min, P = 0.322) were not significant. In the heparin group, no significant increase was observed in PTT over time; baseline 30.9 +/- 3.4, 12 h 31.8 +/- 3.4, 24 h 31.2 +/ 6.6 (P = 0.628). CONCLUSIONS: Flushing PermCath with normal saline 0.9% is as effective as heparin in maintaining patency of the catheter, while it may reduce the risks associated with heparin. PMID- 24949293 TI - Comparing the effects of three different additional doses of propofol infusion on intubation condition and hemodynamic changes during general anesthesia under elective surgery: A randomized, placebo-controlled, double blind clinical trial. AB - BACKGROUND: Laryngoscopy and endotracheal intubation can induce unfavorable hemodynamic changes as propofol itself can induce hypotension. The aim of this study was to compare the effects of three different additional doses of propofol infusion on intubation conditions and hemodynamic changes occurred after intubation. MATERIALS AND METHODS: This double-blinded prospective study was performed on 140 patients aged 18-60 who received different additional doses of propofol and were randomly allocated into 4 groups as follows: A: Received additional dose of propofol 0.5 mg/kg infused after an initial dose 1.5 mg/kg. B: Received additional dose of propofol 1 mg/kg infused after an initial dose 1 mg/kg. C: Received additional dose of propofol 1.5 mg/kg after an initial dose 1 mg/kg. D: Received propofol 2 mg/kg as a bolus with no additional dose. RESULTS: Intubation conditions were acceptable in 91.4% of Group A patients, 94.2% of Group B patients, 97.1% of Group C patients and 68.5% of Group D patients. There were no significant differences in the mean of heart rate between four groups at any time before and after laryngoscopy. Mean arterial pressure (MAP) 3 min after laryngoscopy was significantly lower in Group D versus Group A (P = 0.015) while MAP was not different at any time between other groups. CONCLUSION: Infusion of propofol 1.5 mg/kg added to initial bolus dose of propofol 1 mg/kg improves intubation conditions significantly without inducing hemodynamic changes. PMID- 24949294 TI - Association of urinary transforming growth factor-beta1 with the ureteropelvic junction obstruction. AB - BACKGROUND: We aimed to compare the level of urinary transforming growth factor beta 1 (TGF-beta1) in children with ureteropelvic junction obstruction (UPJO) with the normal peers. MATERIALS AND METHODS: In this case-control study, we enrolled children with UPJO and matched normal peers. Sterile urine was collected from the subjects and urinary TGF-beta1 was measured by ELISA method. Also, degree of the UPJO and the magnitude of the renal injury were assessed by ultrasonography and measuring glomerular filtration rate (GFR), respectively. Study variables were then compared between the study groups regarding the level of urinary TGF-beta1. RESULTS: A total of 25 children with UPJO (age = 7.4 +/- 4.5 years; male = 16) were compared with 25 healthy peers (age = 6.8 +/- 5.6 years; male = 16). Mean GFR in the UPJO and the control group were 112.4 +/- 10.1 and 123.29 +/- 4.4, respectively. Mean urinary TGF-beta1 in the UPJO group was 87.1 +/- 12.6 pg/ml vs 30.5 +/- 14.5 pg/ml in the control group. The level of urinary TGF-beta1 was significantly associated with the degree of TGF-beta1 and patients with grade IV hydronephrosis had the highest level of urinary TGF-beta (P = 0.0001). CONCLUSION: Based on our findings, biomarkers such as TGF-beta1 can successfully be used for confirming UPJO. However, further studies are needed to determine the proper cut point for diagnosis confirmation. PMID- 24949295 TI - Evaluation of CD52 positive sperms in subfertile human semen samples: Is there any relationship with main semen parameters? AB - BACKGROUND: Sperm maturation and sperm membrane integration are the most important elements in male fertility. CD52 is one of the antigens. CD52 is a GPI (glycosylphosphatidylinositol) anchored that express on lymphocytes and epididymal cells. This antigen bind to sperm membrane during transition sperm from epididymal duct as well as its relationship with semenogelins in human seminal plasma. The aim of this study was to obtain any association between the percentage of CD52 positive sperms with main semen parameters such as percentage of motile sperms, percentage of sperm with normal morphology, and the presence of normal viscosity. MATERIALS AND METHODS: Semen samples from subfertile men were analyzed, the samples totally were 45 that divided according to their motility into three groups, first one, more than 40%, second one 10-40%, and the third one under 10% total motility. Fifteen samples in each group were evaluated by semen analysis according to WHO 2010 guidelines for infertility laboratory. Sperms were washed by Ham's F-10 and immunostaining with the monoclonal antibody CAMPATH-1G and then analyzed by flow cytometry. We compared each of the groups based on their motility and the data were analyzed by SPSS 20. RESULTS: Correlation between CD52 labeling and sperm motility was negatively significant, in the second group (r = -0.592, P = 0.020) and in the third group (r = -0.805, P = 0.00). CONCLUSION: Our results showed that the correlation between CD52 labeling and sperm motility was negatively significant, but we did not observe any relation with other semen parameters, such as sperm normal morphology, sperm concentration, and semen viscosity. PMID- 24949296 TI - Electrical stimulation of acupuncture points for analgesia during bone marrow aspiration and biopsy: A randomized double-blind placebo-controlled trial. AB - BACKGROUND: Bone marrow aspiration and biopsy (BMA/BMB) is a painful procedure mostly used in diagnosing and staging of a broad spectrum of hematological diseases. In spite of local anesthesia, the prevalence and intensity of the pain and patient discomfort caused by this procedure are considerable. The effect of acupuncture and electrical stimulation of acupoints (acupuncture points) in the treatment of many medical conditions, including pain, have been approved. The study is designed to evaluate the effect of electrical stimulation of acupoints to decrease the pain during BMA/BMB in adults. MATERIALS AND METHODS: In a double blind controlled clinical trial, 50 patients undergoing BMA/BMB were randomly allocated into two groups, to receive either true or placebo electrical stimulation of acupoints LI-4 (large intestine 4, Hegu) and LI-11 (large intestine 11, Quchi), bilaterally. Both groups received infiltrative local anesthesia. The pain level caused by BMA/BMB was measured using the Visual Analog Scale (VAS). RESULTS: The means of the VAS in the case and control groups were 41.84 +/- 20.54 and 69.40 +/- 20.06 respectively (P < 0.001). The systolic and diastolic blood pressure and pulse rate rose significantly in both the groups compared to the basal values. The rise was lower in the acupuncture group compared to the placebo group regarding systolic blood pressure and pulse rate (P = 0.018 and P < 0.001, respectively). CONCLUSIONS: The results of this study show that the electrical stimulation of acupoints significantly decreases the pain caused by BMA/BMB and some of the complications of the pain. PMID- 24949297 TI - Maternal serum cytokines in the prediction of preterm labor and response to tocolytic therapy in preterm labor women. AB - BACKGROUND: One of the most important challenges in health care system is prevention of preterm birth. The present study was aimed to investigate the relation between interleukins 6 and 8 (IL-6 and IL-8) with preterm labor and response to tocolytic therapy. MATERIALS AND METHODS: In the year 2012, 75 women with the symptoms of preterm labor (cases) in compare with 75 term women (controls) were randomly selected and evaluated. Baseline data and serum levels of IL-6 and IL-8 (using immunoassay method) recorded. Hence, tocolysis in women in case group was performed with the use of magnesium sulfate and then they were followed until delivery time to assess the response to treatment. RESULTS: In case group, 59 women response to tocolytic treatment and delivered at term but 16 of them delivered prematurely. The curve constructed cut-off value for IL-6 was >37.9 (area under the curve [AUC], 0.674; standard error [SE], 0.043; P < 0.0001), and > 9.5 for IL-8 (AUC, 0.773; SE, 0.038; P < 0.0001), indicating a significant relationship with preterm labor. Furthermore, there was a significant relationship between serum IL-6 and IL-8 levels with the response to the treatment in cut-off >45 for IL-6 (AUC, 0.894; SE, 0.042; P < 0.0001) and >171 for IL-8 (AUC, 0.864; SE, 0.059; P < 0.0001). CONCLUSION: In summary, our results suggest that the assessment of maternal serum concentrations of IL-6 and IL-8 can be used as appropriate biomarkers for predicting preterm labor and response to tocolytic therapy in these women. However, further studies needs to be done. PMID- 24949299 TI - Increased risk of diabetes with statin use: Reconsidering the use of high potency statins. PMID- 24949298 TI - Cytokines (interleukin-9, IL-17, IL-22, IL-25 and IL-33) and asthma. AB - Asthma is a reversible airway obstruction that is characterized by constriction of airway smooth muscle, hyper secretion of mucus, edema and airway hyper responsiveness (AHR), mucus secretion and thickening of the basement membrane underlying the airway epithelium. During the process of airway inflammation, complex interactions of innate and adaptive immune cells as well as structural cells and their cytokines have many important roles. It was believed that airway inflammation is orchestrated by allergen specific T helper (Th) 2 cells, which recruit and accumulate in the lungs and produce a range of different effector cytokines. However, more recent studies have revealed the potential collaboration of other helper T cells and their cytokines in this process. Th17 cell may have a role in severe asthma and chronic obstructive pulmonary disease (COPD). Interleukin (IL)-9-producing subset called Th9 cell, Th22 cells which primarily secrete IL-22, IL-13 and tumor necrosis factor-alpha and Th25 cells via producing IL-25 are believed to be important for initiating allergic reactions and developing airway inflammation. Cytokines are important in asthma and play a critical role in orchestrating the allergic inflammatory response, although the precise role of each cytokine remains to be determined. The aim of this review is to summarize the current knowledge about the possible roles of newly identified helper T cells derived cytokines (IL-9, 17, 22, 25 and IL-33) in asthma. The potential therapeutic applications emerging from the roles of these cytokines will be discussed as well. PMID- 24949300 TI - Metals and male reproduction: The possible mechanisms. PMID- 24949301 TI - Peroneus tertius: An inappropriate muscle for electromyographic studies of axonal polyneuropathy. PMID- 24949302 TI - The effect of Helicobacter pylori eradication on liver enzymes in patients referring with unexplained hypertransaminasemia. AB - BACKGROUND: Evidence has shown an association of Helicobacter pylori infection with liver dysfunction and damage. We investigated if H. pylori eradication affects liver enzymes in patients referring with unexplained hypertransaminasemia. MATERIALS AND METHODS: Patients with mild unexplained hypertransaminasemia accompanied with dyspepsia and confirmed H. pylori infection were studied. Viral, metabolic, autoimmune, and drug/toxin induced hepatitis as well as fatty liver were all ruled-out by appropriate tests. Patients received bismuth-containing quadruple-therapy for 2 weeks. Serum levels of liver enzymes (alanine transaminase (ALT) and aspartate transaminase (AST)) and successful eradication (with stool antigen test) were evaluated 4 weeks after the medication. RESULTS: A total number of 107 patients (55 males, mean age = 35.0 +/ 8.4 years) were studied. Eradication was successful in 93 patients (86.9%). Serum levels of AST (6.3 +/- 19.6 IU/L, P = 0.002) and ALT (7.8 +/- 24.9 IU/L, P = 0.001) were significantly decreased after eradication. Levels of AST and ALT decreased to normal range respectively in 46.6% and 45.7% of the cases who had baseline levels above the normal range. CONCLUSION: This study showed a decrease in liver enzymes after receiving eradication regimen of H. pylori, suggesting a role for H. pylori infection in at least some of patients with mild unexplained hypertransaminasemia. Further studies are warranted to find the underlying mechanisms by which H. pylori infection affects the liver and clinical importance of such effects. PMID- 24949303 TI - Androgen receptor expression and its relationship with clinicopathological parameters in an Iranian population with invasive breast carcinoma. AB - BACKGROUND: Androgen receptor (AR) status and its association with prognosis in Iranian breast cancer population are uncertain. We examined AR expression and its relationship with clinicopathological parameters among Iranian patients with invasive breast carcinoma. MATERIALS AND METHODS: This study was performed on formalin fixed and paraffin embedded tissue specimens with a diagnosis of invasive breast carcinoma archived at two University Hospitals in Isfahan city, Iran. Antibodies were used for evaluation of AR, human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR). Other data were gathered from patients' documents. RESULTS: A total of 70 cases were evaluated including 55 (78.6%) ductal, 9 (12.9%) lobular, 2 (2.9%) medullary, and 4 (5.7%) mucinous carcinomas. Overall, 48.6%, 42.9%, 64.3%, and 57.1% of the samples were positive for ER, PR, AR, and HER2, respectively. Thirty three (47.1%) cases were ER(-) PR(-) and 17.1% were triple negative. AR + cases were younger and more frequently positive for ER and showed less frequently tumor size of > 2 cm. Although tumor grade and stage were relatively higher among AR(-) cases compared to AR(+) ones, the difference between the two groups was not statistically significant. CONCLUSIONS: AR expression was found to be frequently present in breast carcinoma in the studied population. Since half of the ER negative and half of the triple negative tumors were found to be AR positive, AR positive cases may benefit from alternative endocrine therapeutic strategies other than the conventional endocrine-targeted medications. PMID- 24949304 TI - Prediction of difficult laryngoscopy: Extended mallampati score versus the MMT, ULBT and RHTMD. AB - BACKGROUND: Preoperative using of anatomical landmarks detects potentially difficult laryngoscopies. The main object of the present study was to evaluate the predictive power of Extended Mallampati Score (EMS) in comparison with modified Mallampati test (MMT), the ratio of height to thyromental distance (RHTMD) and the Upper-Lip-Bite test (ULBT) in isolation and combination. MATERIALS AND METHODS: Four hundred seventy sixadult patients who candidate for elective surgery under general anesthesia requiring endotracheal intubation were included in this study and evaluated based of all four factors before surgery. This study was randomized prospective double - blind. After that, laryngoscopy was performed by an anesthesiologist who didn't involve in preoperative airway assessment and graded based on Cormack and Lehane's classification. We calculated sensitivity, specificity, and area under receiver-operating characteristic (ROC) (AUC) for each score. RESULTS: The AUCof the ROC was significantly more for the ULBT (AUC = 0.820, P = 0.049) and RHTMD score (AUC = 0.845, P = 0.033) than the EMS (AUC = 0.703). This variable was significantly higher for the EMS compared with MMT (0.703 vs. 0.569, P = 0.046 respectively). There was no significant difference between the AUC of the ROC for the ULBT and the RHTMD score (P = 0.685). The optimalcut-off point for the RHTMD for predicting difficult laryngoscopy was 29.3. CONCLUSION: EMS predicted difficult laryngoscopy better than MMT while both ULBT and RHTMD had more power than EMS and MMT in this regard. ULBT and RHTMD had similar predictive value for prediction of difficult laryngoscopy in general population. PMID- 24949305 TI - A study on the anti-inflammatory effects of new derivatives of 3-hydroxy pyridine 4-one. AB - BACKGROUND: Derivatives of pyridine-4-one act as iron chelators and possess various pharmacological effects such as antifungal, antimalarial, antiviral, anti inflammatory, and analgesic effects. The aim of our study was to evaluate the anti-inflammatory effects of the three new derivatives of pyridine-4-one. MATERIALS AND METHODS: Carrageenan-induced paw edema in rats and croton oil induced ear edema in mice were used to evaluate the anti-inflammatry effects of three 3-hydroxy-pyridine-4-one derivatives (compounds A, B, and C). Compound A (10, 20 mg/kg), compound B (200, 400 mg/kg), and compound C (100, 200 mg/kg), vehicle (1 mL/kg), and indomethacin as standard drug (10 mg/kg) were injected intraperitoneally 30 min prior to carrageenan injection and 4 h later, the paw volume was measured using a mercury plethysmograph. The maximum dose of each test compound was used in the croton oil-induced ear edema test. RESULTS: All compounds showed significant anti-inflammatory activity in both tests. On a molar basis, compound A had the greatest potency, which may be due to the presence of a benzyl group substitution on the pyridine ring. CONCLUSIONS: Because cyclooxygenase and lipoxygenase as key enzymes of the inflammation pathway are heme-dependent, it seems that the anti-inflammatory effect of derivatives of pyridine-4-one may be related to their iron chelating properties. However, more investigations are needed to find out their exact mechanism of actions. PMID- 24949306 TI - Association of HOTAIR expression in gastric carcinoma with invasion and distant metastasis. AB - BACKGROUND: Gastric cancer is the second and fourth most common cancer in Iranian men and women, respectively, but it is the first leading cause of cancer deaths in Iran. Most Iranian patients with gastric cancer are diagnosed at an advanced stage of disease when the conventional treatments have no effect on improving the survival. So, early gastric cancer detection is of high priority in order to decrease its high mortality rate in Iran. HOTAIR is a long non-coding RNA which its overexpression has been documented in different types of human cancer and can be considered as a potential cancer biomarker. The aim of this study was to evaluate the clinicopathological relevance of the expression of HOTAIR gene in gastric carcinoma. MATERIALS AND METHODS: A total of 60 tumoral and non-tumoral gastric specimens were evaluated for HOTAIR gene expression using quantitative real-time PCR. RESULTS: The expression of HOTAIR was markedly increased in gastric cancer tissues compared with adjacent non-tumoral tissues. We further showed that there was a positive significant correlation between the HOTAIR gene expression, TNM staging, perineural invasion, and distant metastasis, but not with other clinicopathological features of gastric tumors. CONCLUSIONS: These results suggest that HOTAIR expression is modulated during gastric cancer progression and therefore may participate in molecular processes relevant to malignant transformation and metastasis in gastric carcinoma. PMID- 24949307 TI - Evaluation of effect of continuous positive airway pressure during cardiopulmonary bypass on cardiac de-airing after open heart surgery in randomized clinical trial. AB - BACKGROUND: Cardiac and pulmonary veins de-airing are of the most important steps during open heart surgery. This study evaluates the effect of continuous positive airway pressure (CPAP) on air trapping in pulmonary veins and on quality of de airing procedure. MATERIALS AND METHODS: This randomized prospective double blind clinical trial conducted on 40 patients. In the control group: During cardiopulmonary bypass (CPB), the ventilator was turned off and adjustable pressure limit (APL) valve was placed in SPONT position. In CPAP group: During CPB, after turning the ventilator off, the flow of oxygen flow was maintained at the rate of 0.5 L/min and the APL valve was placed in MAN position on 20 mbar. During cardiopulmonary bypass (CPB) weaning, the patients were observed for air bubbles in left atrium by using transesophageal echocardiography. RESULTS: The mean de-airing time after the start of mechanical ventilation in CPAP group (n = 20) was significantly lower than the control group (n = 20) (P = 0.0001). The mean time of the left atrium air bubbles occupation as mild (P = 0.004), moderate (P = 0.0001) and severe (P = 0.015) grading was significantly lower in CPAP group. CONCLUSIONS: By CPAP at 20 mbar during CPB in open heart surgery, de airing process can be down in better quality and in significantly shorter time. PMID- 24949308 TI - Stroke becomes the 3rd important cause of death in Korea; is it a time to toast? PMID- 24949309 TI - The primary goal of anticoagulation in atrial fibrillation to prevent stroke and not to offer the apparently cheapest treatment. PMID- 24949310 TI - Stroke: morbidity, risk factors, and care in taiwan. AB - Stroke is the third leading cause of death and the most common cause of complex disability in Taiwan. The annual age-standardized mortality rate of stroke is steadily decreasing between 2001 and 2012. The average years of potential life lost before age 70 for stroke is 13.8 years, ranked the fifth in the cause of death. Its national impact is predicted to be greater accompany aging population. The most common type of stroke was ischemic stroke in Taiwan. Small vessel occlusion was the majority of ischemic strokes subtype. Age, gender, hypertension, diabetes hyperlipidemia, obesity, atrial fibrillation, and smoking were important contributory factors to stroke morbidity. The standard treatment for acute ischemic stroke in Taiwan is providing the intravenous thrombolysis with recombinant tissue plasminogen activator (IV tPA) therapy for ischemic stroke patients within 3 hours of symptom onset. However, the rate of IV tPA therapy for patients with acute ischemic stroke is still low in Taiwan. Therefore, improving the public awareness of stroke warning signs and act on stroke and improving in-hospital critical pathway for thrombolysis would be the most important and urgent issues in Taiwan. To improve acute stroke care quality, a program of Breakthrough Series-Stroke activity was conducted from 2010 to 2011 and stroke centers were established in the medical centers. For the prevention of stroke, it was successful to increased annual smoke cessation rate through the 2009 Tobacco Hazards Prevention Act and decreased obesity rate through a nationwide weight-loss program conducted by Health Promotion Administration from 2011 to 2013 in Taiwan. PMID- 24949311 TI - Genetics and Biomarkers of Moyamoya Disease: Significance of RNF213 as a Susceptibility Gene. AB - Moyamoya disease is characterized by a progressive stenosis at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. Although its etiology is still unknown, recent genome-wide and locus-specific association studies identified RNF213 as an important susceptibility gene of moyamoya disease among East Asian population. A polymorphism in c.14576G>A in RNF213 was identified in 95% of familial patients with moyamoya disease and 79% of sporadic cases, and patients having this polymorphism were found to have significantly earlier disease onset and a more severe form of moyamoya disease, such as the presentation of cerebral infarction and posterior cerebral artery stenosis. The exact mechanism by which the RNF213 abnormality relates to moyamoya disease remains unknown, while recent reports using genetically engineered mice lacking RNF213 by homologous recombination provide new insight for the pathogenesis of this rare entity. Regarding biomarkers of moyamoya disease, moyamoya disease is characterized by an increased expression of angiogenic factors and pro-inflammatory molecules such as vascular endothelial growth factors and matrix metalloproteinase-9, which may partly explain its clinical manifestations of the pathologic angiogenesis, spontaneous hemorrhage, and higher incidence of cerebral hyperperfusion after revascularization surgery. More recently, blockade of these pro-inflammatory molecules during perioperative period is attempted to reduce the potential risk of surgical complication including cerebral hyperperfusion syndrome. In this review article, we focus on the genetics and biomarkers of moyamoya disease, and sought to discuss their clinical implication. PMID- 24949312 TI - New oral anticoagulants may be particularly useful for asian stroke patients. AB - Atrial fibrillation (AF) is an emerging epidemic in both high-income and low income countries, mainly because of global population aging. Stroke is a major complication of AF, and AF-related ischemic stroke is more disabling and more fatal than other types of ischemic stroke. However, because of concerns about bleeding complications, particularly intracranial hemorrhage, and the limitations of a narrow therapeutic window, warfarin is underused. Four large phase III randomized controlled trials in patients with non-valvular AF (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48) demonstrated that new oral anticoagulants (NOACs) are superior or non-inferior to warfarin as regards their efficacy in preventing ischemic stroke and systemic embolism, and superior to warfarin in terms of intracranial hemorrhage. Among AF patients receiving warfarin, Asians compared to non-Asians are at higher risk of stroke or systemic embolism and are also more prone to develop major bleeding complications, including intracranial hemorrhage. The extra benefit offered by NOACs over warfarin appears to be greater in Asians than in non-Asians. In addition, Asians are less compliant, partly because of the frequent use of herbal remedies. Therefore, NOACs compared to warfarin may be safer and more useful in Asians than in non-Asians, especially in stroke patients. Although the use of NOACs in AF patients is rapidly increasing, guidelines for the insurance reimbursement of NOACs have not been resolved, partly because of insufficient understanding of the benefit of NOACs and partly because of cost concerns. The cost-effectiveness of NOACs has been well demonstrated in the healthcare settings of developed countries, and its magnitude would vary depending on population characteristics as well as treatment cost. Therefore, academic societies and regulatory authorities should work together to formulate a scientific healthcare policy that will effectively reduce the burden of AF-related stroke in this rapidly aging society. PMID- 24949313 TI - Physicians' attitudes toward guidelines for stroke: a survey of korean neurologists. AB - BACKGROUND AND PURPOSE: Clinical practice guidelines (CPGs) are regarded as an essential guidance tool for practicing physicians. We surveyed physicians in Korea in order to evaluate their attitudes toward the Korean CPGs for stroke. METHODS: We obtained participation agreement for our survey from 27 centers of the 33 most actively contributing to the Korean Stroke Registry. A total of 174 neurologists participated in a questionnaire interview regarding their attitudes toward CPGs for stroke. RESULTS: Of 174 participating neurologists, 65 (37.4%) were stroke neurologists. The average age was 33.6+/-7.1 and 49 (28.2%) were female. Most of the respondents held positive attitudes and opinions regarding the use of the guidelines, whereas only a small percentage (14.9%) responded negatively. More than 60% of the physicians in the survey reported adherence to the Korean CPGs in dyslipidemia management for the secondary prevention of stroke. CONCLUSIONS: The positive attitudes and opinions toward the guidelines imply that physicians' attitudes should not be regarded as a potential barrier to the implementation of Korean CPGs for stroke practiced by general physicians. PMID- 24949314 TI - Smart phone applications as a source of information on stroke. AB - BACKGROUND AND PURPOSE: Smartphone applications have been increasingly identified as a novel platform for dissemination of healthcare related information. However, there have been no studies done to evaluate the availability and content of stroke related apps. PURPOSE: This study aims to identify and analyze stroke related applications available on the Apple iTunes and Android Google Play Store. METHODS: The Apple iTunes store and Android Google Play Store were searched for stroke-related applications on July 27, 2013 using keywords: stroke, brain attack, intracranial hemorrhage, subarachnoid hemorrhage, cerebral infarction. The content of the applications was analyzed by two independent investigators. RESULTS: A total of 93 relevant applications (46.2% android and 53.8% iPhone) were identified of which 47.3% were available free of cost. 92% of apps were identified as useful by users and over 60% had scientifically valid information. There is a significant participation of healthcare agencies in dissemination of stroke related information through apps with 47.3% apps being uploaded by them. Over half of all stroke related apps were aimed towards health care workers (51.6%), 75% of which could be utilized as bedside tools for patient care and remainder had information related to recent research advances. The difference in scientific validity between the apps aimed at general population versus healthcare professionals was statistically significant (P<0.01). There was no statistical association between cost of app and scientific validity or usefulness. CONCLUSIONS: Smartphone apps are a significant source of information related to stroke. An increasing participation of healthcare agencies should be encouraged to promote dissemination of scientifically valid information. PMID- 24949315 TI - Risk factors and biomarkers of ischemic stroke in cancer patients. AB - BACKGROUND AND PURPOSE: Stroke is common among cancer patients. However, risk factors and biomarkers of stroke in cancer patients are not well established. This study aimed to investigate risk factors and biomarkers as well as etiology of ischemic stroke in cancer patients. METHODS: A retrospective review was conducted in cancer patients with ischemic stroke who were admitted to a general hospital in Busan, Korea, between January 2003 and December 2012. The risk factors and biomarkers for stroke and stroke subtypes in cancer patients were compared with age- and sex-matched noncancer patients with ischemic stroke who were admitted to the same hospital during the same period. RESULTS: One hundred fifty-six cancer patients with ischemic stroke were identified. Cancer patients with ischemic stroke were found to have a significantly lower proportion of hypertension, atrial fibrillation, hyperlipidemia, and ischemic heart disease than noncancer patients with ischemic stroke. However, stroke biomarkers, such as erythrocyte sedimentation rate and high-sensitivity C-reactive protein, fibrinogen, pro-brain natriuretic peptide, and D-dimer levels, were significantly increased in cancer patients with ischemic stroke than in noncancer patients. Large-artery atherosclerosis and stroke of undetermined cause were more common in cancer patients with ischemic stroke than in noncancer patients with ischemic stroke. CONCLUSIONS: Cancer patients with ischemic stroke showed different risk factors, stroke biomarkers, and stroke etiology compared with noncancer patients with ischemic stroke. PMID- 24949317 TI - Prolonged ictal aphasia presenting as clinical-diffusion mismatch in a patient with acute ischemic stroke. PMID- 24949316 TI - Can STOP Trial Velocity Criteria Be Applied to Iranian Children with Sickle Cell Disease? AB - BACKGROUND AND PURPOSE: Sickle cell disease (SCD) is strongly linked to stroke across all haplotypes in the pediatric population. Transcranial Doppler (TCD) ultrasound is known to identify the highest risk group in African-Americans who need to receive and stay on blood transfusions, but it is unclear if the same flow velocity cut-offs can be applied to the Iranian population. We aimed to evaluate baseline TCD findings in Iranian children with SCD and no prior strokes. METHODS: Children with genetically confirmed SCD (Arabian haplotype, homozygote) and without SCD (controls) were prospectively recruited from pediatric outpatient clinic over a period of 9 months. We performed TCD in both groups to determine flow velocities in the middle cerebral (MCA) and terminal internal carotid arteries (TICA). RESULTS: Of 74 screened children, 60 met the inclusion/exclusion criteria (62% female; mean age 10+/-4 years). Baseline characteristics did not differ between the cases and controls, except hemoglobin (Hb) which was significantly lower in the SCD group (P<0.001). The right MCA TAMM (Time Averaged Maximum Mean) was significantly higher than in controls (125+5.52 cm/s vs. 92.5+1.63 cm/s, P<0.001). Left MCA did not show differences. The TICA TAMM was also different between cases and controls (P<0.05). CONCLUSIONS: Among Iranian children with asymptomatic SCD and without receiving recent transfusion TCD velocities are higher as compared to healthy controls but appear much lower than those observed in STOP (Stroke Prevention Trial in Sickle Cell Anemia) studies. We hypothesize that some children at high risk may be present with velocities lower than 170-200 cm/s thresholds. A prospective validation of ethnicity specific prognostic criteria is warranted. PMID- 24949318 TI - The risk factors of early recurrence after hepatectomy in hepatocellular carcinoma. AB - PURPOSE: Early recurrence after hepatectomy is a well-known poor prognostic factor in patients with hepatocellular carcinoma. This study was undertaken to identify the risk factors of early recurrence in patients with hepatocellular carcinoma after hepatectomy. METHODS: One hundred and sixty-seven patients that underwent hepatectomy for hepatocellular carcinoma from January 2005 to December 2010 were enrolled. The numbers of patients with or without early recurrence group were 40 and 127, respectively. Clinico-pathologic factors were retrospectively analyzed. RESULTS: Potential risk factors were classified as host, tumor, or surgical factors. Of the host factors examined, lobular hepatitis activity was found to be a significant risk factor of early recurrence, and of the tumor factors, infiltrative type of gross appearance, level of preoperative AFP and worst Edmondson-Steiner grade were significant. CONCLUSION: The present study shows that an infiltrative gross appearance, a high preoperative AFP level, high lobular hepatitis activity, and a poor Edmondson-Steiner grade are independent risk factors of early recurrence. Accordingly, patients with these risk factors should be followed closely after hepatectomy. PMID- 24949319 TI - Higher incidence of gastroesophageal reflux disease after gastric wedge resections of gastric submucosal tumors located close to the gastroesophageal junction. AB - PURPOSE: We hypothesized that gastroesophageal reflux disease (GERD) would be more prevalent after a gastric wedge resection of a submucosal tumor (SMT) located close to the gastroesophageal junction (GEJ) than after a gastric wedge resection of an SMT at other locations because of the damage to the lower esophageal sphincter during surgery. METHODS: Fifty-eight patients with gastric SMT who underwent open or laparoscopic gastric wedge resection between January 2000 and August 2012 at the Department of Surgery, Incheon St. Mary's Hospital were enrolled into this study. The patients were divided into 2 groups according to the location of the tumor, upper or lateral border of the tumor within 5 cm of the GEJ (GEJ <= 5 cm group) and upper or lateral border of the tumor greater than 5 cm distal to the GEJ (GEJ > 5 cm group). The surgical records, clinicopathologic findings, postoperative GERD symptoms, postoperative use of acid suppressive medications and preoperative and postoperative endoscopic findings were retrospectively reviewed and compared between the 2 groups. RESULTS: There was no difference in the frequency of the preoperative GERD symptoms between the 2 groups, whereas postoperative GERD symptoms and postoperative use of acid suppressive medications were more frequent in the GEJ <= 5 cm group (P = 0.045 and P = 0.031). However, there were no differences in the follow-up endoscopic findings in terms of reflux esophagitis and Hill's grade between the 2 groups. CONCLUSION: The incidence of GERD was higher after gastric wedge resection of SMTs located close to the GEJ. Hence, adequate care should be taken during the follow-up of these patients. PMID- 24949320 TI - Causes and outcomes of revisional bariatric surgery: initial experience at a single center. AB - PURPOSE: Bariatric surgery has become more prevalent owing to the worldwide obesity epidemic. With the growing number of bariatric procedures performed annually, the requirement for revisional and secondary operations is increasing accordingly. This study aimed to evaluate the initial experience of revisional bariatric surgery at a single specialized center. METHODS: A retrospective review of the prospectively established database identified all patients who underwent revisional bariatric surgery between January 2008 and August 2013. The causes, surgical outcomes, and efficacy of the revisional surgeries were analyzed. RESULTS: Twenty-two revisional surgeries were performed laparoscopically during the study period (13 laparoscopic adjustable gastric banding, 9 laparoscopic sleeve gastrectomy). The most common indication for revision was weight regain or insufficient weight loss (12/23, 52.2%), and Roux-en-Y gastric bypass (RYGB) was the most commonly performed secondary procedure (17/23, 73.9%, including four resectional RYGB procedures). Gastric pouch leak occurred in one patient following revisional RYGB, which required reoperation on the first postoperative day. The mean body mass index decreased from 35.9 to 28.8 kg/m(2) at a mean follow-up period of 10 months after revision. The percent excess weight losses at 1, 3, 6, and 12 months postoperatively were 18.8%, 41.1%, 40.1%, and 47.4%, respectively. CONCLUSION: Revisional bariatric surgery can be successfully performed via a laparoscopic approach with acceptable risk. Deliberate selection for the proper revisional procedure can efficiently manage undesirable results from the primary surgery. PMID- 24949321 TI - Relationship between 15-hydroxyprostaglandin dehydrogenase and gastric adenocarcinoma. AB - PURPOSE: Prostaglandin E2 (PGE2) is a contributory carcinogen in gastric adenocarcinoma. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catabolizes PGE2 by oxidizing its 15(s)-hydroxy group. The aim of this study was to investigate the expression of 15-PGDH in gastric adenocarcinoma tissue and the relationship between 15-PGDH expression and clinicopathologic features of gastric adenocarcinoma. METHODS: Ninety-nine patients who underwent surgical resection for gastric adenocarcinoma between January 2007 and December 2007 were enrolled and evaluated retrospectively. RESULTS: In 62 patients (62.6%), 15-PGDH expression was lower in gastric adenocarcinoma tissue than in nonneoplastic tissue. Regarding the relationship between 15-PGDH expression and clinicopathological features, 15-PGDH expression was significantly lower in tissues with poor differentiation (P = 0.002), advanced T stage (P = 0.0319), a higher number of lymph node metastases (P = 0.045), lymphatic invasion (P = 0.031), and vascular invasion (P = 0.036). CONCLUSION: 15-PGDH expression was associated with a subset of clinicopathologic features such as differentiation grade, T stage, lymphatic invasion, and vascular invasion. PMID- 24949323 TI - Long-term results of laparoscopic splenectomy in pediatric chronic immune thrombocytopenic purpura. AB - PURPOSE: Laparoscopic splenectomy (LS) for pediatric chronic immune thrombocytopenic purpura (ITP) patients has recently become widespread. However, its long-term result is rarely reported in children. METHODS: We retrospectively analyzed the patients who underwent LS for pediatric chronic ITP from June 1998 to April 2007. RESULTS: There were 18 patients (14 male and 4 female) with mean age 9.5 +/- 3.8 years. 14 complete response, 3 partial response, and 1 no response were occurred. During the 82-month median follow-up period, 9 patients maintained in a remission state without any additional treatment, and 9 patients relapsed. In a comparative analysis of the relapse group and no relapse group, hospital stays were longer in the relapse group and the preoperative platelet counts and platelet counts at 1 month post were lower in relapse group. A relapse free survival among 17 patients who achieved partial or complete responses following LS showed 76.5%, 61.8%, and 33.0% at 1-, 5-, and 10-year following LS, respectively. CONCLUSION: Although LS in pediatric chronic ITP patients had excellent results immediately after surgery, careful follow up is needed due to late relapse even when a complete response has been noted for several years. PMID- 24949322 TI - Inflammation-based score (Glasgow prognostic score) as an independent prognostic factor in colorectal cancer patients. AB - PURPOSE: This study was conducted to evaluate the systemic inflammatory response in colorectal cancer patients, and to estimate the usefulness of the Glasgow prognostic score (GPS) as a prognostic factor. METHODS: Patients with biopsy proven colorectal adenocarcinoma who were operated between April 2005 and December 2008 were enrolled in this study. The GPS was estimated based on the measurement of CRP and serum albumin level. The GPS was compared with other clinicopathological factors. Univariate and multivariate analyses were performed to evaluate the factors affecting cancer-specific survival. RESULTS: GPS was significantly higher in patients with anemia, thrombocytosis, a high neutrophil to lymphocyte ratio, tumor of the colon, and large tumor. Patient age, gender, serum CEA level, tumor gross appearance, TNM stage, and tumor differentiation were not related with the GPS. In univariate analysis, hemoglobin, CEA, gross appearance of tumor, TNM stage, tumor differentiation, and GPS were associated with cancer-specific survival. In multivariate analysis, TNM stage (III or IV : I or II; hazard ratio [HR], 12.322; P = 0.015), tumor differentiation (poorly differentiated : well or moderately differentiated; HR, 3.112; P = 0.021), and GPS (GPS 2 : GPS 0 or 1; HR, 5.168; P = 0.003) were identified as independent prognostic factors in colorectal cancer. CONCLUSION: Our study showed that the GPS was an independent variable from tumor stage and a good and convenient prognostic factor in colorectal cancer patients. PMID- 24949324 TI - Impact of a surgical intensivist on the clinical outcomes of patients admitted to a surgical intensive care unit. AB - PURPOSE: An intensivist is a key factor in the mortality of patients admitted to the intensive care unit (ICU). The aim of this study was to evaluate the effect of an intensivist on clinical outcomes of patients admitted to a surgical ICU. METHODS: During the study period, the surgical ICU was converted from an open ICU to an intensivist-directed ICU managed by an intensivist who was board certified in both general surgery and critical care medicine. We compared consecutive patients admitted to the surgical ICU before and after implementing the intensivist-directed care. The primary outcome was ICU mortality, and secondary outcomes were hospital mortality, 90-day mortality, length of hospital stay, ICU free days, ventilator-free days, and ICU readmission rate. RESULTS: A total of 441 patients were included in this study: 188 before implementation of the intensivist and 253 after implementation. Clinical characteristics were not different between the two groups. ICU mortality decreased from 11.7% to 6.3% (P = 0.047) after implementation, and 90-day mortality also decreased significantly (P = 0.008). The adjusted hazard ratio of the intensivist for ICU mortality was 0.43 (95% confidence interval, 0.22-0.87; P = 0.020). ICU-free days (P = 0.013) and the hospital length of stay (P = 0.032) were significantly improved after implementing the intensivist-directed care. Before implementation period, 16.0% of patients were readmitted, compared with only 9.9% after implementation (P = 0.05). CONCLUSION: Implementing intensivist-directed care in the surgical ICU was associated with significant improvements in ICU mortality and significant clinical outcomes. PMID- 24949325 TI - Peutz-Jeghers syndrome with germline mutation of STK11. AB - Peutz-Jeghers syndrome (PJS), also known as periorificial lentiginosis, is a rare autosomal dominant inherited disease with an incidence of 1/200,000 live-borns. Mutations in the serine-threonine kinase 11 (STK11) gene are considered the major cause of PJS. The most frequent complication at young age is recurrent intussusception due to multiple hamartomatous polyps, primarily in the small intestine. Although extremely rare, the small bowel should be fully examined to be certain additional intussusceptions are not present. Herein, we report on a case of PJS with germline mutation of STK11 in a 12-year-old young girl who presented as a rare case of two small intestinal intussusceptions and review the literature. PMID- 24949326 TI - Use of right lobe graft with type IV portal vein accompanied by type IV biliary tree in living donor liver transplantation: report of a case. AB - Anatomic variations of the portal vein (PV) and bile duct (BD) are more common on the right lobe as compared with left lobe grafts in living donor liver transplantation (LDLT). We recently experienced a case of LDLT for hepatocellular carcinoma combined with liver cirrhosis secondary to hepatitis B virus and hepatitis C virus infection. The only available donor had right lobe graft with type IV PV associated with type IV BD. The patient underwent relaparotomy for PV stenting due to PV stenosis. Percutaneous transhepatic biliary drainage was done for a stricture at the site of biliary reconstruction. Thereafter, the patient was discharged in good health. Our experience suggests that, the use of right lobe graft with type IV PV accompanied by type IV BD should be the last choice for LDLT, because of its technical difficulty and risks of associated complications. PMID- 24949328 TI - Welcome to your new journal: Endoscopic ultrasound. PMID- 24949327 TI - Mechanical thrombectomy-assisted thrombolysis for acute symptomatic portal and superior mesenteric venous thrombosis. AB - Acute portal vein and mesenteric vein thrombosis (PVMVT) can cause acute mesenteric ischemia and be fatal with mortality rate of 37%-76%. Therefore, early diagnosis and prompt venous revascularization are warranted in patients with acute symptomatic PVMVT. Due to advances in catheter-directed treatment, endovascular treatment has been used for revascularization of affected vessels in PVMVT. We report two cases of symptomatic PVMVT treated successfully by transhepatic percutaneous mechanical thrombectomy-assisted thrombolysis. PMID- 24949329 TI - EUS-guided choledochoduodenostomy for malignant distal biliary obstruction palliation: an article review. AB - The EUS-guided biliary drainage is a new tool for the palliation of distal obstructive biliary lesions. The EUS-guided access, which creates a fistulization between the duodenal bulb and distal common biliary duct, is an effective method to relieve jaundice and has low morbidity and mortality, in patients with distal biliary obstruction (pancreatic mass or papillary cancer). This technique is called choledochoduodenostomy and is presented promptly in this article. The EUS guided biliary drainage should be made within protocol conditions and done by very experienced endosonographers. PMID- 24949331 TI - Endoscopic ultrasound-guided fine needle aspiration cytology and biopsy in the evaluation of lymphoma. AB - Accurate diagnosis and subtyping of lymphoma have important prognostic implications and are generally required for treatment planning. Histological assessment, immunophenotyping, and genetic studies are usually necessary. Endoscopic ultrasound guided-fine needle aspiration cytology (EUS-FNAC) is a minimally invasive technique widely used for the evaluation of deep-seated benign and malignant lesions. However, the value of cytological samples in lymphoma diagnosis is still a matter of debate. Endoscopic ultrasound guided-fine needle biopsy (EUS-FNAB) can provide tissue core samples that may help overcome the limitations of cytology. The aim of this review is to summarize the available literature regarding EUS-FNAC and EUS-FNAB for the diagnosis and subtyping of lymphoma. In addition, we discuss its usefulness in the management of primary extra-nodal lymphomas, as well as technical issues that may influence sample quality. PMID- 24949330 TI - Endoscopic ultrasound elastography. AB - Endoscopic ultrasound (EUS) is a reference technique for diagnosing and staging several different diseases. EUS-guided biopsies and fine needle aspirations are used to improve diagnostic performance of cases where a definitive diagnosis cannot be obtained through conventional EUS. However, EUS-guided tissue sampling requires experience and is associated with a low but not negligible risk of complications. EUS elastography is a non-invasive method that can be used in combination with conventional EUS and has the potential for improving the diagnostic accuracy and reducing the need for EUS-guided tissue sampling in several situations. Elastography measures tissue stiffness by evaluating changes in the EUS image before and after the application of slight pressure to the target tissue by the ultrasonography probe. Pathologic processes such as cancerization and fibrosis alter tissue elasticity and therefore induce changes in elastographic appearance. Qualitative elastography depicts tissue stiffness using different colors, whereas quantitative elastography renders numerical results expressed as a strain ratio or hue histogram mean. EUS elastography has been proven to differentiate between benign and malignant solid pancreatic masses, as well as between benign and malignant lymph nodes with a high accuracy. Studies have also demonstrated that the early changes of chronic pancreatitis can be distinguished from normal pancreatic tissues under EUS elastography. In this article, we review the technical aspects and current clinical applications of qualitative and quantitative EUS elastography and emphasize the potential additional indications that need to be evaluated in future clinical studies. PMID- 24949333 TI - Endoscopic ultrasound-guided double stenting for biliary and duodenal obstruction. AB - Endoscopic biliary stenting for malignant biliary obstruction is currently the gold standard for biliary drainage. Biliary cancer treatment is crucial. Cases of gastric outlet obstruction that includes the duodenum because of cancer invasion and biliary obstruction are seldom observed. The required treatment for such cases is simple biliary stenting and a different treatment for duodenal obstruction. Hence, double stenting for bile duct and duodenal obstruction has drawn attention. In the present review, we state different treatment strategies for malignant duodenal obstruction and then describe double stenting in biliary obstruction that also includes non-biliary cancer malignant lesions and duodenal obstruction. PMID- 24949332 TI - Transrectal ultrasound - Techniques and outcomes in the management of intestinal endometriosis. AB - The widespread use of endoscopic ultrasound has facilitated the evaluation of subepithelial and surrounding lesions of the gastrointestinal tract. Deep pelvic endometriosis, with or without infiltration of the intestinal wall, is a frequent disease that can be observed in women in their fertile age. Patients of this disease may present nonspecific signs and symptoms or be completely asymptomatic. Laparoscopic surgical resection of endometriotic lesions is the treatment of choice in symptomatic patients. An accurate preoperative evaluation is indispensable for therapeutic decisions mainly in the suspicion of intestinal wall and/or urinary tract infiltration, and also in cases where we need to establish histological diagnosis or to rule out malignant disease. Diagnostic tools, including transrectal ultrasound, magnetic resonance image, transvaginal ultrasound, barium enema, and colonoscopy, play significant roles in determining the presence, depth, histology, and other relevant data about the extension of the disease. Diagnostic algorithm depends on the clinical presentation, the expertise of the medical team, and the technology available at each institution. This article reviews and discusses relevant clinical points in endometriosis, including techniques and outcomes of the study of the disease through transrectal ultrasound and fine-needle aspiration. PMID- 24949334 TI - Pilot trial of endoscopic ultrasound-guided interstitial chemoradiation of UICC T4 pancreatic cancer. AB - BACKGROUND AND AIMS: Both interstitial brachytherapy and interstitial chemotherapy are effective in improving local control in patients with local UICC T4 pancreatic cancer. In this study, we report the results of endoscopic ultrasound (EUS)-guided interstitial chemoradiation (EUS-ICR) in patients with advanced pancreatic cancer, with respect to tumor response, clinical response, safety, and complications. PATIENTS AND METHODS: A total of 8 patients (3 men, 5 women; median age of 69) with T4 pancreatic adenocarcinoma were the subjects of this study. A mean of 18 radioactive seeds and 36 intratumoral implants for sustained delivery of 5-fluorouracil in each patient were implanted into the tumors using EUS-guided needle puncture. The mean total implanted radioactive activity was 13.68 mCi, the mean total dose of intratumoral 5-fluorouracil was 3.6 g, and the mean volume of implants was 28 cm(3). The conditions of the patients were followed-up by examination and imaging tests every two months. Clinical endpoints included the Karnofsky performance status, pain response, tumor response (assessed by computed tomography and/or EUS), and survival. RESULTS: During a median follow-up period of 8.3 months, the objective tumor response was classified as "partial" in 1 of 8 patients (with a median duration of partial response of 3 months), "minimal" in 2 patients, and indicative of "stable disease", in 3 of 8 patients. Clinical benefit was shown in 4 of 8 patients, which was mostly due to pain reduction, and lasted for 3.5 months. No local complications or hematologic toxicity occurred. CONCLUSIONS: EUS-ICR had a moderate local anti-tumor effect, showed some clinical benefits in 4 of the 8 patients, and was well tolerated by all the patients in this study. PMID- 24949336 TI - Rupture of a duodenal stromal tumor during EUS-FNA: A case report. PMID- 24949335 TI - Ethanol lavage of 14 mucinous cysts of the pancreas: A retrospective study in two tertiary centers. AB - BACKGROUND: Mucinous cysts are lesions with malignant potential. Their management is stil difficult. Ethanol lavage under EUS can be used and could be a good alternative treatment. We report a bi-center experience of ethanol lavage in mucinous cysts of the pancreas. PATIENTS AND METHODS: A total of 13 patients in 2 tertiary centers (7 men, 6 women, mean age=68.5 years) underwent ethanol lavage for mucinous cysts under endoscopic ultrasound (EUS) from 2001 to 2010. One of the patients had 2 cysts treated during the same procedure. One patient underwent a second procedure of ethanol lavage. Mucinous cyst diagnosis required: (1) EUS showing cystic lesion without nodule and without communication with pancreatic branch duct. Six cysts were located in the isthmus of the pancreas, 3 in the head, 3 in the body, and 2 in the tail. The mean size was 24 mm (11-50); and (2) Intra-cystic ACE level >400 UI/l and/or histologic proof. Diagnosis of mucinous cyst was obtained using ACE levels in 5 cases, histology in 8 cases, and both in 1 case. RESULTS: No complication was reported. Complete responses were observed in 11 cases (85%), with no responses in 2 cases (15%). Mean follow-up was 26 months (4-118 months). Contact was lost with 1 patient. No recurrence was noticed in patients with complete responses. CONCLUSION: This study confirms the feasibility and effectiveness of a loco-regional treatment under EUS for pancreatic cysts. The good ratio of response is probably explained by the lack of septa and the small size of the cysts. The follow-up is still short and needs to be increased. Nethertheless loco-regional treatment of pancreatic cysts lesions under EUS should form a part of the management of pancreatic lesions. PMID- 24949338 TI - Aspiring to new levels of achievement: eus in the therapeutic endoscopy olympics. PMID- 24949337 TI - Cardiac rhabdomyosarcoma mimicking a mediastinal tumor and the role of endoscopic ultrasonography. AB - We report a case of cardiac rhabdomyosarcoma, with initial clinical features of "atrial rhythmic dysfunction", which was concluded as a mediastinal tumor by computed tomography (CT) scan. Endoscopic ultrasonography (EUS) and EUS-FNA (fine needle aspiration) were initially conducted to diagnose the isolated mediastinal mass. In this case, EUS re-assessed the previous diagnosis as a cardiac tumor, and the patient eventually achieved a 17-month survival rate after chemotherapy. In this paper, EUS findings obtained in our case are described and a review of literatures is briefly discussed. We also describe the advantages and limitations of this technique compared with other image diagnosis alternatives. PMID- 24949340 TI - Endobronchial ultrasound. AB - Endobronchial ultrasound (EBUS) has emerged as a routinely performed procedure in diagnostic bronchoscopy. Extending the view beyond the airway wall, EBUS provides evaluation of tumor involvement of tracheobronchial wall and mediastinum and plays an essential role as a guidance technique for peripheral pulmonary diseases. The latest development is the EBUS-transbronchial needle aspiration (TBNA) scope that allows performing real-time EBUS-TBNA of enlargerd hilar and mediastinal lymph nodes. PMID- 24949339 TI - Pancreatic fluid collection drainage by endoscopic ultrasound: new perspectives. AB - Since the introduction of endoscopic ultrasonography (EUS), many centers have utilized this imaging modality for transmural pancreatic fluid collection (PFC) drainage. The expanded use of EUS has resulted in increased safety and efficacy of endoscopic PFC drainage. The major procedural steps include EUS-guided transgastric or transduodenal fistula creation into the PFC, and stent placement or nasocystic drain deployment to decompress the collection. In this and other applications, EUS has become a major therapeutic advancement in the field of endoscopy and has figured in myriad diagnostic applications. Recent research indicates a number of situations in which EUS-guided PFC drainage is appropriate. These include unusual location of the collection, small window of entry, non bulging collections, coagulopathy, intervening varices, or failed conventional transmural drainage. In this study, we discuss the EUS-guided technique and review current literatures. PMID- 24949341 TI - Endoscopic ultrasound and pancreatic cystic lesions-diagnostic and therapeutic applications. AB - Pancreatic cystic lesions are being detected with an increasing frequency. Endoscopic ultrasound (EUS) provides both diagnostic and therapeutic means for pancreatic cystic lesions. Detailed imaging and EUS-guided fine-needle aspiration provide additional information on pancreatic cystic lesions. EUS-guided pseudocyst drainage has advantages over conventional drainage modalities. EUS guided cyst ablation is a promising therapeutic modality. PMID- 24949342 TI - Feasibility of Intratumoral Confocal Microscopy under Endoscopic Ultrasound Guidance. AB - The primary goal of this study was to develop descriptive image interpretation criteria and a classification of endoscopic ultrasound-confocal microscopy (EUS CM) findings in pancreatic masses and lymph nodes through a review of prospectively obtained EUS-CM videos from proven malignant and benign cases, and to propose diagnostic criteria for predicting malignancy. The material used was a 19-G EUS-needle in which the stylet was replaced by the confocal mini-probe. The mini-probe pre-loaded in the EUS-needle was guided endosonographically in the target then the mini-probe was pushed under EUS guidance into the lesion. Eleven patients mean age 62.3 years underwent EUS for the staging of a pancreatic mass (3 cystic and 4 solid) or for the diagnosis of celiac and/or mediastinal LN (n = 4). Benign intraductal papillary mucinous neoplasm (IPMN) was characterized by the aspect of finger-like projections which correspond to the villous changes of intestinal IPMN type. In pancreatic adenocarcinomas, EUS-CM found vascular leakage with irregular vessels with leakage of fluorescein into the tumor, large dark clumps which correspond to humps of malignant cells. Inflammatory lymph nodes were characterized by the presence of diffuse small cells into a homogeneous stroma with a normal vascularization. At the opposite, EUS-CM showed in malignant lymph node glandular structures with dark cells, large dark clumps and an important neo-vascularization with huge leakage of fluorescein. PMID- 24949343 TI - Can endoscopic ultrasound-guided fine needle aspiration offer clinical benefit for tumors of the ampulla of vater? -an initial study. AB - OBJECTIVE: No previous studies have described endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) only for intra-ampullary lesions of the papilla of Vater. We aimed to examine whether EUS-FNA can be used to diagnose such lesions. METHODS: This study included a subset of 10 consecutive patients in whom EUS-FNA targeted the ampulla of Vater. All the patients underwent biopsy and/or brushing cytology under endoscopic retrograde cholangiopancreatography (ERCP) prior to EUS FNA. The final diagnosis was based on pathological examinations of specimens obtained by surgical resection or clinical follow-up more than 1 year in case of evidence of benign lesions. RESULTS: Tissues from the ampulla of Vater could be obtained by EUS-FNA for all 10 patients. The final diagnosis was papillitis (n = 7) and intra-ampullary carcinoma (n = 3). Carcinoma of the ampulla of Vater showed neither exposure on the duodenal mucosal surface nor invasion to the pancreas. The diagnostic accuracy of surface biopsy with duodenoscopy, and intra ampullary biopsy and/or brush cytology with ERCP and/or intra-ampullary biopsy after endoscopic sphincterotomy (EST) in distinguishing between benign and malignancy was 70%. The diagnostic accuracy of EUS-FNA was 100%. No complications associated with EUS-FNA were encountered in this study. CONCLUSION: EUS-FNA for ampulla of Vater may be safely and accurately performed, and should be considered as a diagnostic modality before EST. PMID- 24949345 TI - Portal venous system and its tributaries: a radial endosonographic assessment. AB - The use of Color Doppler in endosonography has enabled detailed real-time assessment of the abdominal vasculature. Standard stations are used during the routine evaluation on endosonography. However, the imaging techniques do not describe the vascular imaging of the portal venous system and its tributaries, in detail. This article demonstrates the normal findings on the portal venous system and its tributaries using radial endosonography. PMID- 24949344 TI - Effect of Povidone-iodine Washing of Gastrointestinal Mucosa or Taking Proton Pump Inhibitors on Bacteremia after Endoscopic Ultrasonography-guided Fine Needle Aspiration. AB - OBJECTIVE: Few studies have evaluated the risk of bacteremia and infectious complications after endoscopic ultrasonography-guided fine needle aspiration (EUS FNA). Therefore, we aimed to study the frequency of bacteremia and search for a method to potentially reduce bacterial infection after EUS-FNA. We also investigated the effect of taking proton pump inhibitors (PPIs) before examination on the occurrence of bacteremia. METHODS: A total of 28 healthy adult dogs were randomly assigned into three groups: control group, povidone-iodine group and omeprazole group. The dogs in the povidone-iodine group were administered with 0.5% povidone-iodine solution (10 mL) to wash gastrointestinal mucosa, while the dogs in the omeprazole group were fed with 20 mg omeprazole orally twice a day for 3 days before the EUS-FNA procedure. Blood samples were collected for cultures before EUS examination, between EUS and FNA, and 5 min, 15 min and 30 min after FNA. RESULTS: There were 3 true-positive cases of bacteremia in the control group while there was 1 true-positive case of bacteremia in each of the two experiment groups. The differences in the occurrences of bacteremia between the control group and both experiment groups were not statistically significant. CONCLUSION: There are no statistically significant differences in the frequencies of bacteremia between the two experiment groups and the control group. Therefore, washing of the gastrointestinal mucosa with 0.5% povidone iodine solution may not reduce the risk of bacterial infection and taking the PPIs does not increase the risk of bacteremia after EUS-FNA. PMID- 24949346 TI - Endoscopic ultrasound-guided fine needle aspiration for the diagnosis of nonfunctional paragangliomas: a case report and review of the literature. AB - Paraganglioma is a rare tumor that should be included in the differential diagnosis of retroperitoneal tumors. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has emerged as an effective tool in the diagnosis of these lesions. A 37-year-old female patient with a history of microcytic anemia underwent EUS-FNA and was diagnosed with a neuroendocrine tumor by histopathological and immunohistochemical analysis. The tumor was surgically removed, and the final diagnosis was paraganglioma. This case report emphasizes the importance of EUS in the evaluation of this type of lesion. PMID- 24949347 TI - Treatment of Pancreatic Abscess with Endoscopic Ultrasound-guided Placement of a Covered Metal Stent Following Failed Balloon Dilation and Endoscopic Necrosectomy. AB - For the management of pancreatic abscess, endoscopic ultrasound (EUS)-guided puncture and drainage has become recognized as a safer and more effective alternative to surgery. Typically, a double-pigtail plastic stent is placed for drainage. When an abscess is complicated by infected necrosis, endoscopic evacuation is essential. However, endoscopic evacuation carries a high risk of hemorrhage and needs to be performed daily to be effective. We describe EUS guided endoscopic evacuation and placement of a fully covered metal stent following two failed evacuations. Patient recovery time was excellent, and no complications occurred. PMID- 24949348 TI - Is EUS Here to Stay? Accuracy Is Not an Indication.... PMID- 24949349 TI - Endoscopic Ultrasound-guided Bilio-pancreatic Drainage. AB - The echoendoscopic biliary drainage is an option to treat obstructive jaundices when endoscopic retrograde cholangiopancreatography (ERCP) drainage fails. These procedures compose alternative methods to the side of surgery and percutaneous transhepatic biliary drainage, and it was only possible by the continuous development and improvement of echoendoscopes and accessories. The development of linear sectorial array echoendoscopes in early 1990 brought a new approach to diagnostic and therapeutic dimension on echoendoscopy capabilities, opening the possibility to perform punction over direct ultrasonografic view. Despite of the high success rate and low morbidity of biliary drainage obtained by ERCP, difficulty could be found at the presence of stent tumor ingrown, tumor gut compression, periampullary diverticula and anatomic variation. The echoendoscopic technique starts performing punction and contrast of the left biliary tree. When performed from gastric wall, the access is made through hepatic segment III. From duodenum, direct common bile duct punction. Diathermic dilatation of the puncturing tract is required using a 6-Fr cystostome and a plastic or metal stent is introducted. The techincal success of hepaticogastrostomy is near 98%, and complications are present in 20%: pneumoperitoneum, choleperitoneum, infection and stent disfunction. To prevent bile leakage, we have used the 2-stent techniques. The first stent introduced was a long uncovered metal stent (8 or 10 cm) and inside this first stent a second fully covered stent of 6 cm was delivered to bridge the bile duct and the stomach. Choledochoduodenostomy overall success rate is 92%, and described complications include, in frequency order, pneumoperitoneum and focal bile peritonitis, present in 14%. By the last 10 years, the technique was especially performed in reference centers, by ERCP experienced groups, and this seems to be a general guideline to safer procedure execution. The ideal approach for pancreatic pseudocyst (PPC) puncture combines endos-copy with real time endosonography using an interventional echoendoscope. Several authors have described the use of endoscopic ultrasound (EUS) longitudinal scanners for guidance of transmural puncture and drainage procedures. The same technique could be used to access a dilated pancreatic duct in cases in which the duct cannot be drained by conventional ERCP because of complete obstruction. PMID- 24949350 TI - Contrast-enhanced endoscopic ultrasound. AB - The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) introduced guidelines on the use of contrast-enhanced ultrasound (CEUS) in 2004. This EFSUMB-document focused mainly on liver applications. However, new applications extending beyond the liver were developed thereafter. Increased interest in recent years in CEUS technique and in the application of CEUS in novel fields like endoscopic ultrasound (EUS) has revolutionized indications and applications. As a result, the EFSUMB initiated a new update of the guidelines in 2011 to include this additional knowledge. Some of the contrast-enhanced EUS (CE EUS) indications are established, whereas others are preliminary; these latter indications are categorized as emergent CEUS applications since the available evidence is insufficient for general recommendation. This article focuses on the use of CE-EUS in various clinical settings. The reader will get an overview of current indications and possible applications of CE-EUS. This involves the introduction of different contrast studies including color Doppler techniques (known as contrast-enhanced high mechanical index endosonography or CEHMI-EUS) as well as more modern high-resolution contrast-enhanced techniques (known as contrast-enhanced low mechanical index endosonography or CELMI EUS). PMID- 24949351 TI - A kit for eus-guided access and drainage of pancreatic pseudocysts: efficacy in a porcine model. AB - OBJECTIVE: Transluminal pseudocyst drainage with currently available tools remains technically challenging, time consuming and limited to fluid collections adherent to the GI tract. Multiple tools and steps are still required to achieve pseudocyst drainage. We evaluated a novel kit to facilitate endoscopic ultrasonography (EUS)-guided access, drainage and rapid decompression in a porcine model. METHODS: The kit consists of the NAVIX access device and the AXIOS stent delivery system. The NAVIX contains an inner trocar for puncture and an outer dual balloon catheter for anchorage and dilation. The AXIOS stent is a fully covered dual flanged stent. Both are inserted through the working channel of a curved linear array echoendoscope. In a porcine model, a gallbladder was used as a proxy for a pseudocyst. RESULTS: Six Yorkshire pigs underwent this procedure successfully without complication and 3 of them were kept alive. After a 4-week implantation period, the AXIOS stents were removed easily using a snare and the 3 animals were observed for an additional 4 weeks. The stents were well tolerated by the stomach and gallbladder tissues, as confirmed by weekly endoscopic inspection, gross necropsy and histopathology. CONCLUSION: EUS-guided transluminal access and drainage of the porcine gallbladder was technical feasible using a novel kit. This kit has the potential to simplify, streamline, and improve the safety of pancreatic pseudocyst drainage. PMID- 24949352 TI - Yield of Contrast-Enhanced Power Doppler Endoscopic Ultrasonography and Strain Ratio Obtained by EUS-Elastography in the Diagnosis of Focal Pancreatic Solid Lesions. AB - OBJECTIVE: Although endoscopic ultrasonography-guided fine needle aspiration (EUS FNA) is the gold standard for diagnosing pancreatic lesions, its negative predictive value is suboptimal. Our aim was to evaluate the yield of contrast enhanced EUS (CED-EUS) and of strain ratio EUS-elastography (SR-E-EUS) for differentiating pancreatic solid lesions. METHODS: Forty-seven patients (27 men, 20 women, 70 +/- 11 years) were consecutively involved in this single-center, prospective study. They were submitted to EUS, SR-E-EUS, CED-EUS with Sonovue((r)), and EUS-FNA. The final diagnosis was based on the histological assessment of EUS-FNA and/or surgical specimens when available, and on follow-up of at least 6 months. RESULTS: From the 47 focal pancreatic lesions included, 13 (28%) were benign and 34 (72%) malignant. Patients with malignancy were older (70 +/- 11 vs. 61 +/- 8, P = 0.003), and had larger lesions (34 +/- 12 mm vs. 22 +/- 11 mm, P = 0.03). Malignant lesions had higher SR-E-EUS (31 +/- 32 vs. 8 +/- 9, P = 0.001) and more hypovascular pattern (93% vs. 33%, P < 0.001). Logistic regression determined that only hypovascularity (OR = 2.6, 95%CI: 1.5-130, P = 0.02) was independently predictive of malignancy. ROC analysis for SR-E-EUS yielded an optimal cutoff of 8 (AUC 0.91, 95%CI: 0.74-0.98) for the best power distinction for malignancy. There was no significant difference concerning sensitivity (79%, 90%, 93%) and specificity rates (85%, 75%, 67%) of EUS-FNA, SR E-EUS, and CED-EUS, respectively. By analysis of the inconclusive EUS-FNA subset (9 patients, 19%), SR-E-EUS > 8 and hypovascularity showed sensitivity of 80% and 100%, and specificity of 67% and 67%, respectively. CONCLUSION: The clinical utility of CED-EUS and SR-E-EUS remains questionable. The accuracies of CED-EUS and SR-E-EUS are similar to EUS-FNA. Hypovascularity was independently predictive of malignancy. Patients with inconclusive EUS-FNA could benefit from CED-EUS due to the high sensitivity of hypovascularity for diagnosing malignancy. PMID- 24949353 TI - Power Doppler endoscopic ultrasound for the assessment of pancreatic neuroendocrine tumors. AB - OBJECTIVE: Pancreatic neuroendocrine tumors (PNET) represent rare, heterogeneous tumors with clinical, imaging and treatment particularities. The aim of this study was to assess the role of power Doppler endoscopic ultrasound (EUS) in the diagnosis and characterization of PNET. METHODS: All consecutive patients with PNET assessed by power Doppler EUS in the Research Centre of Gastroenterology and Hepatology Craiova, Romania, in the past 51 months were included in the study. All EUS examinations were performed initially in gray-scale mode, followed by power Doppler mode examinations, before and after contrast-enhancement. Each recorded EUS movie was further subjected to post-processing using a computer enhanced dynamic analysis using a special plug-in which permitted assessment of vascularity index (EUS-VI). RESULTS: Based on the analysis of all consecutive malignant focal pancreatic masses diagnosed in the study period, a total number of 131 consecutive patients were included: 14 patients with pancreatic neuroendocrine tumors and 117 patients with pancreatic adenocarcinoma. The sensitivity of the pre-contrast EUS-VI for the diagnosis of PNET was 71.43%, similar to EUS-FNA. After contrast enhancement, the EUS-VI is also higher in PNET (27.07%) as compared to pancreatic adenocarcinoma where it was significantly lower 9.82% (P < 0.001). However, the sensitivity of EUS-VI after contrast enhancement for the diagnosis of PNET was 100%, higher than pre-contrast EUS-VI, with an acceptable specificity (79.49%) and better accuracy (81.68%). CONCLUSION: Power Doppler EUS represents a useful method in the initial assessment of PNET. Using evaluation of vascularity through EUS-VI, the differentiation between PNET and pancreatic cancer could be possible, especially in the subgroup of patients where EUS-guided fine needle aspiration is falsely negative. PMID- 24949355 TI - Role of endoscopic ultrasonography in intramural bronchogenic cysts: case reports and review of the literature. AB - The differentiation between a solid and cystic lesion is not always easy. EUS has provided a minimally invasive approach to the diagnosis of benign mediastinal cysts. Our report describes two cases of intramural bronchogenic cysts and reviews the role of EUS in dealing with such cases. We conclude that the bronchogenic cysts are still a challenge despite evolution of the imaging studies. PMID- 24949356 TI - Communication of duodenal varix with pericholedochal venous plexus demonstrated by endoscopic ultrasound in a patient of portal biliopathy. PMID- 24949354 TI - A One-step Procedure by Using Linear Echoendoscope to Perform EUS-guided Choledochoduodenostomy and Duodenal Stenting in Patients with Irresectable Periampullary Cancer. AB - OBJECTIVE: Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CD) has become an alternative method after unsuccessful endoscopic retrograde cholangiopancreatography (ERCP) treatment. We present a case series study and its feasibility by using only a linear therapeutic channel echoendoscope to create both a biliary-enteral fistula and anatomic enteral recanalization. METHODS: We presented seven cases of unresectable periampullary cancer with both biliary and duodenal obstruction. In these cases, the EUS-guided technique might be an alternative to double stenting (biliary and enteral) in the same procedure and equipment. RESULTS: In all cases, the location of the biliary obstruction was in the distal common bile duct (CBD) and the grade of proximal dilation diameter varied from 15 mm to 20 mm. Two patients had type I (28.6%) and five had type II (71.4%) duodenal obstruction. Technical success of EUS-CD, by the stent placement, occurred in 100% of the cases. There were no early complications. Biliary drainage was effective clinically as well as in laboratory in 6 cases (6/7), by relieving obstructive jaundice and decreasing bilirubin levels. CONCLUSION: EUS equipment may offer an alternative to double stenting in the same procedure and with palliative propose. PMID- 24949357 TI - Splenic tuberculosis diagnosed by endoscopic ultrasound-guided fine needle aspiration. PMID- 24949358 TI - Endoscopic ultrasound-guided confocal microscopy: a new tool for the new year? PMID- 24949359 TI - Endobronchial ultrasound for peripheral lesions: a review. AB - Lung cancer is one of the most common tumors worldwide. Pulmonary lesions detected during screening for lung cancer need to be evaluated further and tissue should be obtained. Bronchoscopy is often the first step to secure a histological diagnosis. Differ-ent guidance techniques are available to increase the diagnostic yield. Over the last few years endobronchial ultrasound (EBUS) has been used increasingly to direct the sampling tools, often in combination with a guide sheath. This article offers a review of the literature of the use of EBUS in diagnosis of pulmonary peripheral lesions. PMID- 24949360 TI - Role of endoscopic ultrasound in the diagnosis of pancreas divisum. AB - OBJECTIVE: The published data on the accuracy of the detection of pancreas divisum by endoscopic ultrasound (EUS) is limited. In this study, we evaluate the accuracy of detection of pancreas divisum by radial EUS in patients with chronic pancreatitis. METHODS: We retrospectively evaluated patients with chronic pancreatitis who underwent EUS followed by endoscopic retrograde cholangiopancreatography (ERCP) in the last four years to identify patients with complete pancreas divisum. RESULTS: One hundred and forty six patients with chronic pancreatitis underwent EUS examination and 20 patients (13.6%) had pancreas divisum. The overall sensitivity, specificity, positive predictive value, negative predictive value and accuracy of absence of stack sign on EUS for the diagnosis of pancreas divisum were 50%, 97%, 73%, 93% and 91%, respectively and for the inability to trace pancreatic duct from the head to the body were 100%, 96%, 80%, 100% and 96%, respectively. CONCLUSION: EUS can diagnose pancreas divisum in a majority of patients. Pancreas divisum can be reliably excluded if pancreatic duct could be tracked backwards from the head to the body around the genu. PMID- 24949361 TI - Endoscopic Ultrasound-Assisted Tunnel-Type Endoscopic Submucosal Dissection for the Treatment of Esophageal Tumors Arising in the Muscularis Propria (with video). AB - OBJECTIVE: Esophageal tumors arising in the muscularis propria are difficult to be resected endoscopically using standard electro-surgical techniques, even the endoscopic submucosal dissection (ESD) technique appeared recently. Our purpose is to investigate the efficacy of endoscopic ultrasound (EUS)-assisted tunnel type ESD for resection of these tumors. METHODS: A total of 17 patients were included in this study. A standard endoscope was used. The submucosal tunnel was created with the triangle knife according to the standard ESD technique, about 5 cm proximal to the lesion. EUS was performed within the tunnel to detect the tumor, and then the tumor was separated both from the submucosal and the muscle layers. After the tumor was removed, several clips were used to close the mucosal defect. EUS was performed to evaluate the healing quality 1 week after the procedure. RESULT: In all the cases, the tumors were completely resected. Mean tumor size was 24.2 mm (12-50 mm) in diameter. The histo-logical diagnoses were leiomyoma (16/17) and gastrointestinal stromal tumor (GIST, 1/17). Subcutaneous emphysema was found in 2 patients after the procedure, but disappeared by the third day. No patients sustained perforation or developed significant hem orrhage, and there were no other immediate severe complications after the procedure. The healing quality was satisfying in 16/17 patients evaluated by EUS 1 week after the procedure. No recurrence has been found during follow-up (mean 7 months, range 3-13 months). CONCLUSION: EUS-assisted tunnel-type ESD is effective and safe in treatment of esophageal tumors arising in the muscularis pro-pria. PMID- 24949362 TI - Standard imaging techniques for assessment of portal venous system and its tributaries by linear endoscopic ultrasound: a pictorial essay. AB - Linear Endosonography has been used to image the Portal Venous System but no established standard guidelines exist. This article presents techniques to visualize the portal venous system and its tributaries by linear endosonography. Attempt has been made to show most of the first order tributaries and some second order tributaries of splenic vein, superior mesenteric vein and portal vein. PMID- 24949363 TI - Endoscopic ultrasound-guided fine needle aspiration for smooth benign appearing esophageal stricture due to metastatic breast cancer. AB - Metastatic breast cancer is an uncommon cause of esophageal stricture. We present an 80 year-old woman with past medical history of locally advanced breast cancer who admitted for evaluation of dysphagia. Barium swallow (i.g. esophageal fluoroscopy) demon-strated moderate irregular narrowing in the distal thoracic esophagus. Endoscopy revealed distal esophageal stricture with normal esophageal mucosa and computed tomography demonstrated thickened wall in the distal esophagus and the proximal stomach. Endoscopic biopsy of esophagus revealed no malignancy. Thus, we performed endoscopic ultrasound-guide fine needle aspiration (EUS-FNA) and cytological results were consistent with metastatic breast cancer. Diagnosis of malignant esophageal stricture due to metastasis from other primary is often challenging and requires a high index of suspicion. EUS-FNA is an alternative diagnostic technique in such cases when endoscopic biopsy fails to obtain adequate specimen. PMID- 24949364 TI - Pancreatic tuberculosis mimicking malignancy diagnosed with endoscopic ultrasound guided fine needle aspiration. AB - A female presented to the physician with a history of right upper quadrant pain. Abdominal computed tomography (CT) scan dem-onstrated a multi-loculated solid lesion in the head of the pancreas concerning for a primary malignancy. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of the lesion was performed and cytology revealed no evidence of malignancy. The acid-fast bacilli culture was found to be positive for Mycobacterium tuberculosis complex and pancreatic tuberculosis was diagnosed. PMID- 24949365 TI - Pancreatic Adenocarcinoma with Early Intense Enhancement in Harmonic Contrast Endoscopic Ultrasound and High Strain Ratio in Elastometry (with video). PMID- 24949366 TI - Endoscopic ultrasound-guided biliary drainage. PMID- 24949367 TI - Forward-view Endoscopic Ultrasound: A Systematic Review of Diagnostic and Therapeutic Applications. AB - Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) and therapeutic procedures have been performed by a curved linear array (CLA) echoendoscope since the early 1990's. This particular echoendoscope, allowing real time visualization of aspiration needles and of other devices, has substantially remained unchanged since its introduction to the market. In a context of rapidly expanding indications for EUS-guided procedures, a dedicated forward view (FV) echoendoscope has been developed and tested under different clinical conditions. The FV echoendoscope is equipped with front endoscopic and EUS view, allowing deployment of needles and other devices through the working channel in straight direction. Several new diagnostic and therapeutic applications may thereby potentially be feasible with the FV echoendoscope and the established ones may prove easier to accomplish. The published literature with the FV echoendoscope has been systematically reviewed and the results are presented analytically and discussed in detail. EUS-FNA and therapeutic procedures, including pancreatic pseudocyst drainage, treatment of gastric fundal varices, celiac plexus neurolysis, and duct drainage were reported. The FV echoendoscope showed some unique advantages, opening new possibilities such as EUS-FNA in difficult gastrointestinal tracts and combined endoscopic/EUS treatment with frontal approach. However, no statistically significant evidence of superiority of the FV echoendoscope vs. the CLA echoendoscope was found in pancreatic pseudocyst drainage. No complications specifically attributable to the use of the FV echoendoscope were reported. PMID- 24949368 TI - Role of endoscopic ultrasonography in the evaluation of extrahepatic cholangiocarcinoma. AB - Cholangiocarcinoma is a malignancy that arises from biliary epithelium and is associated with a poor prognosis. Accurate preopera-tive diagnosis and staging of cholangiocarcinoma continues to remain difficult. Endoscopic retrograde cholangiopancreatography (ERCP) is the most commonly performed procedure for cholangiocarcinoma and can provide a tissue diagnosis through brush cytology of the bile duct. However, the sensitivity of biliary brush cytology to diagnose cholangiocarcinoma may be as low as 30%. Endoscopic ultrasound (EUS) is a diagnostic modality which may overcome the limitations of other imaging and biopsy techniques in this setting. EUS can complement the role of ERCP and provide a tissue diagnosis through fine needle aspiration (FNA) and staging through ultrasound imaging. There is currently a paucity of data about the exact role of EUS for the diagnosis of cholan-giocarcinoma in patients with indeterminate extrahepatic biliary strictures. Although multiple studies have shown that EUS is more accurate than ERCP and radiologic imaging for identifying a biliary mass and diagnosing cholangiocarcinoma, the sensitivities are variable. More importantly, the incidence of false negative results is not negligible, though the specificity is close to 100%. There is also controversy regarding the role of EUS-FNA, since even though this may increase diagnosis, it can also lead to tumor seeding. PMID- 24949369 TI - Endoscopic ultrasound-guided fine needle aspiration: from the past to the future. AB - Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a technique which allows the study of cells obtained through aspiration in different locations near the gastrointestinal tract. EUS-FNA is used to acquire tissue from mucosal/submucosal tumors, as well as peri-intestinal structures including lymph nodes, pancreas, adrenal gland, gallbladder, bile duct, liver, kidney, lung, etc. The pancreas and lymph nodes are still the most common organs targeted in EUS FNA. The overall accuracy of EUS is superior to computed tomography scan and magnetic resonance imaging for detecting pancreatic lesions. In most cases it is possible to avoid unnecessary surgical interventions in advanced pancreatic cancer, and EUS is considered the preferred method for loco-regional staging of pancreatic cancer. FNA improved the sensitivity and specificity compared to EUS imaging alone in detection of malignant lymph nodes. The negative predictive value of EUS-FNA is relatively low. The presence of a cytopathologist during EUS FNA improves the diagnostic yield, decreasing unsatisfactory samples or need for additional passes, and consequently the procedural time. The size of the needle is another factor that could modify the diagnostic accuracy of EUS-FNA. Even though the EUS-FNA technique started in early nineteen's, there are many remarkable progresses culminating nowadays with the discovery and performance of needle-based confocal laser endomicroscopy. Last, but not least, identification and quantification of potential molecular markers for pancreatic cancer on cellular samples obtained by EUS-FNA could be a promising approach for the diagnosis of solid pancreatic masses. PMID- 24949370 TI - Expression of vascular endothelial growth factor and epidermal growth factor receptor in pancreatic ductal adenocarcinomas, neuroendocrine tumours and chronic pancreatitis. AB - OBJECTIVE: Angiogenesis is a crucial event for pancreatic carcinogenesis, and it also plays an important role in chronic pancreatitis. The aim of our study was to evaluate the mRNA expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) in chronic inflammatory or malignant pancreatic pathology in order to elucidate the differences in expression patterns and potential clinical implications. METHODS: Thirty-five patients who had undergone endoscopic ultrasonography followed by endoscipic ultrasound-guided fine needle aspiration (EUS-FNA) of focal pancreatic masses were included in the study. VEGF and EGFR mRNA expression levels in the samples collected by EUS-FNA were analyzed using quantitative real-time polymerase chain reaction (PCR). RESULTS: VEGF expression was detected in all chronic pancreatitis and adenocarcinoma samples and in only 62.5% of pancreatic neuroendocrine tumors. EGFR expression was detected in only 40% of the chronic pancreatitis cases, 76.9% of adenocarcinomas and in 50% of pancreatic neuroendocrine tumors. Both VEGF and EGFR mRNA levels were significantly higher in pancreatic ductal adenocarcinoma than those in normal tissue. VEGF expression inversely correlated with pancreatic ductal adenocarcinoma size, while EGFR expression was related to local invasiveness of adenocarcinoma. CONCLUSION: Both VEGF and EGFR mRNA expression in EUS-FNA samples may be used as a diagnostic marker associated with invasiveness in patients with pancreatic adenocarcinoma. PMID- 24949372 TI - Utility of Narrow Caliber Echo-bronchoscope in Pre-school Pediatric Population: A case series (with video). AB - The practical use of EUS in small children below the age of 4 years is not described. The aim of the study was to evaluate the feasibility, safety, and clinical utility of smaller caliber echo-bronchoscope in the management of gastrointestinal, pancreatobiliary, and mediastinal disease in children below 4 years. Consecutive children of age younger than 4 years where EUS was clinically considered useful were evaluated by echo-bronchoscopes. The findings showed that EUS by echo-bronchoscopes is feasible and safe in young children. PMID- 24949371 TI - Tuberculosis presenting as Dysphagia: clinical, endoscopic, radiological and endosonographic features. AB - OBJECTIVE: Dysphagia as a presenting manifestation of tuberculosis is rare and there is paucity of data on the clinical, endoscopic and endosonographic features of these patients. We present our data related to the features over last four years. METHODS: We analyzed retrospectively the clinical, endoscopic, radiological, endosonographic and cytological findings in 14 patients (male: 10; mean age: 37.7 +/- 10.4 years) with dysphagia due to tuberculosis presenting to us over last 4 years. RESULTS: Nine patients (64.3%) had Grade 1 dysphagia, 4 (28.6%) patients had Grade 2 and 1 patient (7.1%) had Grade 3. Mid esophagus was the commonest site of involvement. Endoscopic findings were extrinsic bulge (50%), linear ulcers (28.6%) and pol-ypoidal ulcerated lesion (7.1%). Endoscopic biopsies were inconclusive. Endoscopic ultrasound (EUS) demonstrated mediastinal lymph nodes being responsible for endoscopic bulge and their infiltration into esophageal wall leading on to ulcers. EUS-guided fine needle aspiration from these nodes established diagnosis in all patients. CONCLUSION: Dysphagia in tuberculosis is most commonly caused by compression by the surrounding mediastinal lymph nodes. EUS is a useful investigation for assessment of these patients. PMID- 24949373 TI - Role of EUS-FNA in Recurrent Lung Cancer: Maximum Results with Minimum (minimally invasive) Effort. AB - Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is an excellent method for primary lung cancer staging. We describe a 66-year-old male who underwent EUS-FNA for the diagnosis of recurrent lung cancer. Two years after initial radiation therapy followed by complete remission, routine follow-up imaging study revealed a mass in the right hilum. Trans-esophageal EUS revealed a 1.3-cm mass and the result of EUS-FNA was consistent with non-small lung cancer. EUS-FNA can play an important role in diagnosis of recurrent lung cancer as well as primary staging avoiding the more invasive diagnostic technique. PMID- 24949374 TI - Mediastinal paraganglioma: specific endoscopic ultrasound features. AB - Endoscopic ultrasound (EUS) features of mediastinal paraganglioma have not been described. In this paper, we report a female patient presented with cough and chest pain without any neuroendocrinal symptoms. Final diagnosis of mediastinal paraganglioma was made on thoracoscopic biopsy and immunohistochemistry after EUS guided fine needle aspiration. EUS features of mediastinal paraganglioma are described. PMID- 24949375 TI - Gastric ulcer penetration into the liver mimicking malignancy on endoscopic ultrasound. PMID- 24949376 TI - Pancreatic metastasis from colon carcinoma diagnosed by endoscopic ultrasound fine needle aspiration. PMID- 24949377 TI - Porcelain gall bladder on endoscopic ultrasound. PMID- 24949379 TI - Is endoscopic ultrasound-guided celiac Ganglia neurolysis superior to celiac plexus neurolysis? PMID- 24949378 TI - Endoscopic ultrasound-guided sampling in gastroenterology: European society of gastrointestinal endoscopy technical guidelines. AB - At present, the European Society of Gastrointestinal Endoscopy (ESGE) guidelines on endoscopic ultrasound-guided sampling are almost complete and express state of the art developments. However, future developments are anticipated. This editorial focuses on a few recently published papers with some additional information and on two important additional techniques, elastography and contrast enhanced ultrasound (CEUS), which are mentioned, but not explained in detail in the current ESGE guidelines. Elastography and CEUS might be of importance in the near future to improve the biopsy techniques. PMID- 24949380 TI - Endosonography-assisted diagnosis and therapy of gastrointestinal submucosal tumors. AB - Submucosal tumors (SMTs) are usually discovered fortuitously during routine endoscopy, including various non-neoplastic and neoplastic conditions. Endoscopic ultrasound (EUS) is considered to be the best imaging procedure to characterize SMTs and to determine the need for further treatment. In this review, the following issues will be addressed: The role of EUS in diagnosis for SMTs, tissue diagnosis for SMTs and the influence of EUS on endoscopic resection techniques for SMTs. PMID- 24949381 TI - Role of diagnostic and therapeutic endoscopic ultrasonography in benign pancreatic diseases. AB - Standard imaging of pancreas is generally obtained by computed tomography and magnetic resonance imaging. However endoscopic ultrasound (EUS) has become an indispensable tool for the diagnosis of various pancreatic diseases. Because of the close proximity of the EUS probe to the pancreas, EUS provides excellent images of the pancreas. In this review, we discuss the role of EUS in the clinical management of patients with benign pancreatic diseases, i.e., various forms of pancreatitis. PMID- 24949382 TI - Contrast-enhanced harmonic endoscopic ultrasonography of solid pancreatic lesions. AB - Endoscopic ultrasonography is the best modality for pancreatic lesion evaluation as its superior spatial resolution allows small lesions to be identified and fine needle aspiration (FNA) cytology performed under ultrasound-guidance. Despite this, differentiating benign from malignant lesions remains a challenge as conventional ultrasound imaging is unable to differentiate lesions accurately and tissue yield is poorly diagnostic or limited in patients with the chronic inflammation. Contrast-harmonic technology uses a wide-band transducer capable of inducing sufficient acoustic energy to create harmonic microbubble oscillations of the newer second-generation ultrasound contrast agents (UCAs). These microbubbles are more stable, remaining within the intravascular component longer and emit significantly more harmonic content than surrounding tissue, thus allowing pancreatic parenchymal differentiation and microvascular architecture visualization. The use of UCAs is generally safe, but should be especially avoided in patients with unstable ischemic heart disease. During CH endosonography, pancreatic adenocarcinoma is commonly seen as an inhomogenous hypoenhancing lesion, focal pancreatitis as a hypo- or iso-enhancing lesion and neuroendocrine tumor as a hyperenhancing lesion. The presence of hyperenhancement is a strong predictor of non-adenocarcinoma etiology. Furthermore, in patients with the chronic pancreatitis or biliary stents that may obscure pancreatic inspection, the addition of contrast-harmonic endosonography to guide FNA cytology improves its diagnostic yield and accuracy. Quantitative analysis of perfusion through the time intensity curve is promising as an objective and accurate method to differentiate pancreatic lesions. Furthermore, studies are required to fully determine the role of contrast harmonic endosonography in the differential diagnosis of solid pancreatic lesions. PMID- 24949383 TI - Distant lymph node metastases in gastroesophageal junction adenocarcinoma: impact of endoscopic ultrasound-guided fine-needle aspiration. AB - OBJECTIVE: Endoscopic ultrasound (EUS) is established as the most accurate technique for pre-operative locoregional staging of gastroesophageal junction (GEJ) adenocarcinoma, the purpose of the present study was to evaluate the distant lymph nodes (LNs) EUS-fine-needle aspiration (FNA) impact in therapeutic decision for patients with GEJ adenocarcinoma. MATERIALS AND METHODS: Retrospective study was made, with cross-sectional, non-probabilistic analysis from prospectively collected database for all GEJ adenocarcinoma staging patients referred between January 2009 and August 2012 in Paoli-Calmette Institute in Marseille-France. RESULTS: A total of 154 patients with GEJ adenocarcinoma were managed in our institution, of whom 113 (73.3%) had non-distant metastatic disease at computed tomography (CT) scan and underwent EUS for initial tumor staging prior to a treatment decision. On A total of 113 patients undergoing EUS, 8 (7%) patients underwent endoscopic resection and 6 (5.3%) underwent direct surgical resection. Of the remaining 99 patients (87.6%), 24 (21.2%) distant LN EUS-FNA were made. Seventeen LN had EUS malignant features, including 9 (52.9%) that were confirmed as malignant and underwent palliative treatment with chemotherapy. Ninety (79.6%) patients were treated with pre-operative neoadjuvant therapy and were revaluated after. 4 (4.4%) had metastatic disease at CT scan (underwent palliative treatment) and 65 (72.2%) underwent EUS restaging to treatment decision revaluation. Of these, twelve (18.4%) distant LN EUS-FNA were performed. Seven had LN EUS malignancy features, including 4 (57.1%) that were confirmed as malignant and underwent palliative treatment. The remaining 61 patients underwent surgery. As stated above, 21 patients (23.3%) did not undergo EUS restaging, including 10 (47.6%) that did not go to surgery because patient's age, poor general status and comorbidities, 6 (28.5%) had a loss of follow-up, 1 (4.7%) underwent to surgery due to chemotherapy collateral effects, 3 (14.2%) were still on pre-operative chemotherapy and 1 (4.7%) died for sepsis after mediastinal EUS-FNA, this was the only complication event evidenced. EUS-FNA changed clinical management in 54.2% of patients who met the criteria inclusion (distant LN with malignancies EUS features), which corresponds to 11.5% of patients with GEJ adenocarcinoma. CONCLUSION: EUS-FNA was able to provide a different tumor staging and these differences were associated with treatment received. EUS-FNA had a significant impact on treatment decision. PMID- 24949384 TI - Central is as effective as bilateral endoscopic ultrasound-guided celiac plexus neurolysis in patients with unresectable pancreatic cancer. AB - OBJECTIVE: The objective of this study is to compare the efficacy of central (single) vs bilateral (2-injections) endoscopic ultrasound (EUS)-celiac plexus neurolysis (CPN) for palliation of patients with pain related to pancreatic cancer. MATERIALS AND METHODS: Patients with unresectable pancreatic cancer were included. Central EUS CPN was used in the first group and bilateral EUS CPN in the second. The measurement of pain was made with a visual analog pain scale (VAPS) applied before and after the procedure. Follow-up was made at weeks 2 and 4 after the procedure. The use of morphine before and after EUS CPN was evaluated. Complications related to the procedure were recorded. RESULTS: A total of 53 patients underwent EUS CPN, 21 (39.6%) with the central technique and 32 (60.4%) with bilateral injection; 29 were women (54.7%) and the median age was 59 (30-85) years. The tumor was located in the head of the pancreas in 24 (45.3%) patients, the neck in 14 (26.4%), the body in 26 (49.1%) and in the tail of the pancreas in 8 (15.1%). Nearly, 14 (26.4%) patients had more than one pancreatic segment involved. There was no difference in the median (range) percent pain reduction from baseline-4 weeks later was 50% (0-100) vs 60% (0-100), for central and bilateral techniques, respectively; P = 0.18. In total, 60.4% of patients had a reduction of 50% punctuation in the VAPS. No major complications were detected. CONCLUSIONS: EUS CPN is useful for the management of pain in patients with unresectable pancreatic cancer, but there is no significant difference between central vs bilateral techniques. PMID- 24949385 TI - Surgical clips in the common bile duct suspected on endoscopic ultrasound and confirmed on endoscopic retrograde cholangiopancreatography. AB - We report a 56-year-old lady presented with cholangitis due to post-surgical clip migration associated choledocholithiasis. She under-went laparoscopic cholecystectomy 2 years ago. Endoscopic ultrasound revealed linear nature of hyper-echoic lesion casting acoustic shadow in the distal common bile duct suggestive of metallic surgical clip, which was later confirmed by endoscopic cholangiography. PMID- 24949386 TI - Heterotopic pancreas complicated by pseudocyst in the gastric wall diagnosed by endoscopic ultrasound-guided fine needle aspiration. AB - Heterotopic pancreas is usually asymptomatic and does not change throughout the patient's life, but sometimes it can present symp-toms and complications, which are rarely discrete in the literature. We present here a case of heterotopic pancreas in the gastric wall complicated with pseudocyst, and suggest that heterotopic pancreatic pseudocyst should be included in the differential diagnosis of gastric wall cysts. PMID- 24949387 TI - Endoscopic ultrasound assisted etiological localization in acute pancreatitis. AB - Hyperparathyroidism is an uncommon cause of pancreatitis and one should look for its telltale evidence on history (renal stone disease) and investigations (hypercalcemia). Endosonography has an upcoming role in the management of acute pancreatitis, especially in the presence of fluid collection. We report a case of parathyroid adenoma related acute pancreatitis complicated with pseudocyst, which was managed with percutaneous drainage and endosonographic localization of the adenoma to the left parathyroid gland. This patient underwent sestamibi scanning, which confirmed its presence and underwent surgical excision of the adenoma. Endosonography should be included in the work up of patients with unclear etiology and thyroids should be routinely scanned for parathyroid adenomas. One should always look outside the box to get clues for diseases inside the box. PMID- 24949389 TI - A retroperitoneal neuroendocrine tumor in ectopic pancreatic tissue. AB - Ectopic pancreas is the relatively uncommon presence of pancreatic tissue outside the normal location of the pancreas. We report a case of abdominal pain due to retroperitoneal neuroendocrine tumor arising from heterotopic pancreatic tissue between the duodenal wall and the head of the pancreas. Patient underwent surgical enucleation of the tumor. PMID- 24949388 TI - Esophageal duplication cyst in an adult masquerading as submucosal tumor. AB - Gastrointestinal duplications usually manifest in children and may involve the esophagus in 20% cases. Esophageal duplication cysts are a rare cause of dysphagia in adults. We report the case of a 35-year-old male who presented to us with progressive dysphagia of 6 months duration. Contrast enhanced computed tomography showed a soft-tissue lesion in right lateral wall of distal thoracic esophagus. On endoscopic ultrasound, a heterogeneously echotextured lesion with anechoic component present at intramural location in the lower esophagus was noted. The patient underwent surgical excision of the lesion and histopathology confirmed the diagnosis of esophageal duplication cyst. PMID- 24949390 TI - Shearing of the sheath of the guide wire: a complication of endoscopic ultrasound guided rendezvous procedure. PMID- 24949391 TI - Hyperparathyroidism: an unusual cause of acute pancreatitis detected by endoscopic ultrasound. PMID- 24949392 TI - Endobronchial ultrasound: first choice for the mediastinum. PMID- 24949393 TI - Role of endoscopic ultrasound in treatment of pancreatic cancer. AB - Endoscopic ultrasound (EUS) can help diagnose diseases with high accuracy because it overcomes the limitations of gastrointestinal gas and abdominal fat. The emergence of curved linear-array echoendoscopy has significantly promoted the applications of the technique to new levels. The advancement has appeared from EUS imaging to EUS-guided fine needle aspiration, drainage and injection. Computed tomography and magnetic resonance imaging present certain limitations for diagnosing pancreatic tumors due to the specificity of the location of such growths. In addition, traditional chemotherapy does not show ideal results because pancreatic cancer (PC) exhibits hypovascular characteristics. Interventional EUS can overcome these limitations and has potential to become the mainstream method of PC local treatment in the future. This paper reviews the use of interventional EUS in the treatment of PC based on previous studies. PMID- 24949394 TI - Endoscopic Ultrasound-Guided Fine Needle Aspiration versus Percutaneous Ultrasound-Guided Fine Needle Aspiration in Diagnosis of Focal Pancreatic Masses. AB - OBJECTIVE: Pancreatic carcinoma is one of the leading cancer morbidity and mortality world-wide. Controversy has arisen about whether the percutaneous approach with computed tomography/ultrasonography-guidance fine needle aspiration (US-FNA) or endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the preferred method to obtain diagnostic tissue. Our purpose of this study is to compare between the diagnostic accuracy of EUS-FNA and percutaneous US-FNA in diagnosis of pancreatic cancer. PATIENTS AND METHODS: A total of 197 patients with pancreatic masses were included in the study, 125 patients underwent US-FNA (Group 1) and 72 patients underwent EUS-FNA (Group 2). RESULTS: EUS-FNA has nearly the same accuracy (88.9%) as US-FNA (87.2%) in diagnosis of pancreatic cancer. The sensitivity, specificity, positive predictive value and negative predictive value for EUS-FNA was 84%, 100%, 100%, 73.3% respectively. It was 85.5%, 90.4%, 94.7%, 76% respectively for US-FNA. EUS-FNA had a lower complication rate (1.38%) than US-FNA (5.6%). CONCLUSION: EUS-FNA has nearly the same accuracy as US-FNA of pancreatic masses with a lower complication rate. PMID- 24949395 TI - Intramural pseudocysts of the upper gastrointestinal tract. AB - BACKGROUND: Intramural pseudocysts or pseudocysts occurring in the gastrointestinal tract (GIT) wall are rare and there is a paucity of data on their clinical features and management. PATIENTS AND METHODS: We retrospectively evaluated patients with intramural pseudocysts seen at our institution over the past 6 years. Intramural location was confirmed either on surgery or endoscopic ultrasound (EUS). Depending upon the symptoms, their control with the conservative medical therapy and procedural consent, the patients underwent EUS guided single time aspiration of the pseudocyst or transmural drainage or transpapillary drainage or surgery. RESULTS: A total of 9 patients with intra mural pseudocysts (male: n = 8; mean age +/- SD: 39.3 +/- 8.0 years; age range: 24-54 years; five patients having chronic and four patients having acute pancreatitis) were studied. The pseudocysts were located in the wall of the second part of the duodenum in five patients, in the gastric wall in three patients and in the lower esophageal wall in one patient. The size of the pseudocysts ranged from 8 mm to 8 cm and 3/9 (33%) patients had associated extra mural pancreatic pseudocysts. All patients had abdominal pain on presentation. Along with pain the patients with duodenal intramural pseduocysts also had symptoms suggestive of gastric outlet obstruction (3) or jaundice (1). The patient with esophageal intramural pseudocyst had dysphagia along with abdominal pain. Majority of these patients could be successfully treated endoscopically with no significant complications. CONCLUSIONS: Intramural pseudocysts of the upper GIT are very rare and EUS is a useful investigational modality for diagnosing and treating them. PMID- 24949396 TI - Endoscopic Ultrasound-guided Drainage of Pancreatic Pseudocysts: Medium-Term Assessment of Outcomes and Complications. AB - OBJECTIVE: Endoscopic ultrasound (EUS)-guided drainage is a widely used treatment modality for pancreatic pseudocysts (PPC). However, data on the clinical outcome and complication rates are conflicting. Our study aims to evaluate the rates of technical success, treatment success and complications of EUS-guided PPC drainage in a medium-term follow-up of 45 weeks. MATERIALS AND METHODS: A retrospective review was conducted for 55 patients with symptomatic PPC from December 2005 to August 2010 drained by EUS. Medium-term follow-up data were obtained by searching their medical history or by telephonic interview. RESULTS: A total of 61 procedures were performed. The symptoms that indicated drainage were abdominal pain (n = 43), vomiting (n = 7) and jaundice (n = 5). The procedure was technically successful in 57 of the 61 procedures (93%). The immediate complication rate was 5%. At a mean follow-up of 45 weeks, the treatment success was 75%. The medium term complications appeared in 25% of cases, which included three cases each of stent clogging, stent migration, infection and six cases of recurrence. There was no mortality. CONCLUSION: EUS-guided drainage is an effective treatment for PPC with a successful outcome in most of patients. Most of the complications require minimal invasive surgical treatment or repeated EUS guided drainage procedures. PMID- 24949397 TI - Pancreato-biliary Endoscopic Ultrasound in Opium Addicts Presenting with Abdominal Pain. AB - OBJECTIVE: Asymptomatic dilatation of bile duct and symptomatic sphincter of Oddi dysfunction have been reported in opium addicts. Except one case report, there is no report in the literature on endoscopic ultrasound (EUS) study of pancreato biliary system in opium addicts. The aim of the present study was to report the EUS features of pancreato-biliary system in opium addicts presenting with abdominal pain. PATIENTS AND METHODS: A total of 15 opium addicts presenting with upper abdominal pain and dilated common bile duct (CBD) and or pancreatic duct (PD) on abdominal ultrasound were included in this study. EUS findings of pancreato-biliary system were analyzed in these patients. RESULTS: All the 15 patients were males (mean age 53.3 years) presented with upper abdominal pain. Mean duration of opium addiction was 20.1 years. On EUS CBD was dilated in all the patients while PD was dilated in six patients. Gall bladder, liver and pancreatic parenchyma was normal in all these patients. Surface area of papilla of Vater (SPV) was increased in 12 patients. CONCLUSION: Opium addiction causes obstruction at ampulla and produces dilatation of bile duct and PD. Bile duct dilatation was seen in all the patients while PD dilatation was seen in few patients. Increase in SPV was a peculiar finding and appears to be as a result of direct effect of opium on ampulla. PMID- 24949398 TI - Endoscopic ultrasound practice survey in latin america. AB - OBJECTIVE: Endoscopic ultrasound (EUS) has become an important imaging modality for the diagnosis, staging and treatment of gastrointestinal disorders. However, no official data exists regarding clinical EUS practice in Latin America (LA). This study assessed current EUS practice and training. PATIENTS AND METHODS: A direct mail survey questionnaire was sent to 268 Capitulo Latino Americano de Ultrasonido Endoscopico members between August 2012 and January 2013. The questionnaire was sent out in English, Spanish and Portuguese languages and was available through the following site: http://www.cleus-encuesta.com. Responses were requested only from physicians who perform EUS. RESULTS: A total of 70 LA physicians answered the questionnaire until January 2013. Most of the participants were under 42 years of age (53%) and 80% were men. Most participants (45.7%) perform EUS in Brazil, 53% work in a private hospital. The majority (70%) also perform endoscopic retrograde cholangiopancreatography. A total 42% had performed EUS for 2 years or less and 22.7% for 11 years or more. Only 10% performed more than 5000 EUS. The most common indication was an evaluation of pancreatic-biliary-ampullary lesions. Regarding training, 48.6% had more than 6 months of dedicated hands-on EUS and 37% think that at least 6 months of formal training is necessary to acquire competence. Furthermore, 64% think that more than 50 procedures for pancreatic-biliary lesions are necessary. CONCLUSION: This survey provides insight into the status of EUS in LA. EUS is performed mostly by young endoscopists in LA. Diagnostic upper EUS is the most common EUS procedure. Most endosonographers believe that formal training is necessary to acquire competence. PMID- 24949399 TI - Uterine cervical cancer metastases to mediastinal lymph nodes diagnosed by endoscopic ultrasound-guided fine needle aspiration. AB - Utility of endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) for diagnosis of metastatic mediastinal lymph node (MLN) following an unproductive computed tomography (CT) guided-biopsy in a patient with cervical cancer. A 35 year-old woman with locally invasive cervical cancer was found to have a suspicious paraesophageal posterior MLN during the preliminary staging. Mediastinal metastasis from cervical cancer has been rarely reported. Mediastinal CT-guided-biopsy was non-diagnostic. Hence, patient underwent EUS guided-FNA of MLN confirming metastatic cervical cancer. Cervical cancer metastasis to MLN is rare. EUS can be safely and effectively used for FNA from paraesophageal lymph nodes. PMID- 24949400 TI - Solitary pancreatic metastasis from renal cell carcinoma 6 years after nephrectomy. AB - Metastatic cancer to the pancreas is rare and accounts for less than 2% of all pancreatic malignancies. Renal cell cancer, malignant melanoma, lung, colon and breast carcinoma are among the few tumors known to metastasize to the pancreas. The pancreas is a rare site of solitary metastasis, but it is often involved in diffuse metastatic disease. We report a case of a female patient with a solitary mass in the neck of the pancreas following right nephrectomy performed 6 years previously for renal cell carcinoma (RCC). An endoscopic ultrasound (EUS) revealed a well-defined lesion in the neck of the pancreas. Patient underwent EUS guided fine-needle aspiration and cytopathology confirmed the diagnosis of a metastatic RCC. Solitary pancreatic metachronous metastasis from RCC may rarely occur. The interval between nephrectomy and pancreatic metastasis may be long. PMID- 24949401 TI - Diagnosis of hydatid cyto-biliary disease by intraductal ultrasound (with video). AB - Hydatid disease is one of the relatively common infections in the Middle Eastern countries. It is seen in areas where dogs are used to raise livestock. In humans, the majority of Echinococcus cysts tends to develop in the liver (70%) and is asymptomatic. The two most common complications of hydatid cysts are abscess formation and rupture. Furthermore, in 5-25% of patients, rupture occurs into the biliary tract and patients may present with cholangitis, jaundice, abscess, or bilio-cutaneous fistula after surgery. Intraductal ultrasound (IDUS) is reportedly superior to conventional endoscopic ultrasound for the depiction of bile duct obstruction owing to its additional capability of providing higher resolution images due to the use of higher frequency transducers. Unfortunately IDUS is rarely used, possibly due to the limited availability of appropriate IDUS equipment, cost of the procedure and interventional endoscopists trained in its interpretation. IDUS with wire-guided, thin-caliber, high-frequency probes is a promising imaging modality, yet no previous reports discuss its usefulness in hydatid disease investigation. We hereby present the first report of biliary hydatid disease being diagnosed by IDUS. PMID- 24949402 TI - Portal hypertensive biliopathy developing after acute severe pancreatitis. PMID- 24949403 TI - Endoscopic ultrasound-guided fine-needle aspiration: Getting to the point. PMID- 24949405 TI - Training in endoscopic ultrasound-guided fine needle aspiration. AB - Like any other technique, fine needle aspiration (FNA) proficiency requires adequate experience. Although this technique is not difficult to master, formal training will allow endosonographers to achieve better results. The following article is derived in two parts: (1) To review current knowledge on endoscopic ultrasound (EUS)-FNA training, discuss the current recommendations on training guidelines, explore other training adjuncts and review the latest studies evaluating the validity of current recommendations; and (2) to provide some basic grounds on the EUS-FNA technique. EUS-FNA can be broken down into a series of steps. Proper execution of each step will make FNA easier and likely increase its diagnostic yield. Adequate positioning of the lesion in regards to the ultrasound probe is a key factor to obtain best results. The following will discuss useful tips in order to achieve maximal success rates. PMID- 24949404 TI - How good is fine needle aspiration? What results should you expect? AB - Tissue acquisition plays a key role before treatment decision in most of oncological pathologies but also in several benign diseases. By offering tissue sampling, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has become an essential tool in the diagnostic processes. One of the reasons for the success of the technique is related to its excellent diagnostic performance. The diagnostic accuracy of EUS-FNA is above 80% for most of the usual indications. These performances are however dependent on some factors related to both the disease and patient's medical history but also related to medical staff expertise. Endoscopist needs to know how to reach a lesion but also how to efficiently acquire good tissue samples. This review aims to report general recommendations available in the literature for high quality EUS-FNA. Sample processing and sample interpretation also influence diagnostic accuracy of FNA. This paper includes a discussion on sample processing and benefits of the on-site pathology examination. It also provides the results reported in the literature of sample adequacy and diagnostic performance of EUS-FNA for most common indications: Pancreatic diseases, sub-mucosal lesion, mucosal thickenings, lymph nodes, cystic lesion and free fluids. PMID- 24949406 TI - Basic techniques in endoscopic ultrasound-guided fine-needle aspiration: Role of a stylet and suction. AB - There are several variables that have been studied to optimize various outcomes of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) such as quality and adequacy of specimens, diagnostic yield of malignancy, accuracy and overall efficiency. Using an evidence-based approach, the objectives of this review are to discuss two key aspects of EUS-FNA: (a) Use of a stylet and (b) use of suction. Level 1 evidence available from randomized controlled trials demonstrates that the use of a stylet during EUS-FNA has no impact on the diagnostic yield of malignancy or the quality of specimens. Air flushing in a slow, controlled fashion is superior to reinsertion of a stylet to express EUS FNA aspirates. The use of suction should be considered during EUS-FNA of pancreatic masses. However, data from a randomized controlled trial suggest that suction should not be used during EUS-FNA of lymph nodes as it increases bloodiness of specimens obtained and has no impact on the overall diagnostic yield. PMID- 24949407 TI - Basic technique in endoscopic ultrasound-guided fine needle aspiration for solid lesions: How many passes? AB - Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has evolved to become an indispensable tool for tissue acquisition in patients with luminal and extra luminal gastrointestinal cancers. Despite the extensive use of EUS-FNA, there still exists a wide variation in the number of samples required to ensure acquisition of diagnostic material from different kind of lesions. There are several factors that may influence the number of fine needle passes made during EUS-FNA, but the main factor seems to be the presence of a Cytopathologist during the EUS procedure. The diagnostic yield of EUS-FNA with rapid on-site evaluation (ROSE) in most studies exceeds 90%. Nevertheless, ROSE is not available in many centers. Various studies have investigated the adequate number of needle passes that should be performed if ROSE is not used. Differences exist based on the nature of the target lesion: Five to seven passes for pancreatic masses, three passes for lymphnodes, only one pass for pancreatic cystic lesions. Consider using a core biopsy needle or a 19-G FNA needle for histology could improve the diagnostic yield. Even though EUS-FNA is widely available, some patients still do not receive conclusive diagnoses upon initial EUS-FNA. One way to maximize the benefits for patients might be to centralize cases to several well-equipped, high volume centers with experienced endosonographers that have universal availability of ROSE. PMID- 24949408 TI - Basic technique for solid lesions: Cytology, core, or both? AB - This chapter highlights key fundamentals relevant to post-procurement tissue handling of materials obtains by aspiration and/or biopsy and details the subtle techniques that can significantly impact patient management and practice patterns. A basic knowledge of tissue handling and processing is imperative for endosonographers who attempt to achieve a greater than 95% diagnostic accuracy with their tissue-acquisition procedures. PMID- 24949410 TI - Basic technique in endoscopic ultrasound-guided fine needle aspiration for solid lesions: What needle is the best? AB - Basic technique for endoscopic ultrasound (EUS) of solid lesions has developed during 30 years of EUS, as endoscopes and accessory equipment, particularly needles, have been developed. Systematic high-quality examinations require understanding and planning. Needles used for EUS-guided fine needle aspiration (FNA) have gone through many improvements; some 18 characteristics of any needle are presented and these come under consideration whenever choosing the best needle for each procedure. The bright future of EUS and FNA for solid lesions currently still leaves much room for continued developments. PMID- 24949409 TI - Basic techniques in endoscopic ultrasound-guided fine needle aspiration for solid lesions: Adverse events and avoiding them. AB - Endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) is often the preferred technique for tissue acquisition in the diagnosis of suspected intrathoracic and intraabdominal pathology. Although EUS FNA is a safe and accurate procedure, it has been associated with a low risk of adverse events. The unique properties of the echoendoscope and its ability to acquire tissue outside of the gastrointestinal lumen impart risks that are not associated with routine endoscopic procedures. In this review, we discuss the risk of perforation related to the echoendoscope itself and adverse events related to FNA of solid masses including infections, bleeding, pancreatitis and pancreatic duct leak, bile duct leak and tumor seeding. We also provide tips on how to avoid the most common adverse events related to EUS-FNA. PMID- 24949411 TI - Clinical, endoscopic and endoscopic ultrasound features of duodenal varices: A report of 10 cases. AB - BACKGROUND: Duodenal varices (DV) although an uncommon cause, are an important cause due to the severe nature of the bleed and associated adverse outcome. MATERIALS AND METHODS: We retrospectively evaluated patients with DV seen at our institution over past 4 years. RESULTS: A total of 10 patients (nine males; mean age was 35.8 +/- 7.68 years) with DV were studied. Five patients had underlying cirrhosis and five had DV because of non-cirrhotic portal hypertension (four patients had extra-hepatic portal venous obstruction and one patient had non cirrhotic portal fibrosis). Five patients presented with upper gastrointestinal (GI) bleed, whereas in the remaining five patients DV were detected on endoscopy performed for evaluation of portal hypertension. Endoscopy revealed submucosal lesion in nine patients, whereas in one patient an initial endoscopic diagnosis of Dieulafoy's lesion was made. However endoscopic ultrasound (EUS) could clearly identify DV in all patients. Of five patients presenting with upper GI bleed, three had the esophageal varices eradicated and two presented 1(st) time with bleed form DV and did not have esophagogastric varices. All patients with acute upper GI bleed were initially treated with intravenous terlipressin followed by glue (n-butyl cyanoacrylate) injection in 4/5 patients with one patient refusing further endoscopic therapy. The variceal obliteration was documented by EUS in all these four patients and there has been no recurrence of bleed in these four patients over a follow-up period of 4-46 months. The five non-bleeding DV were already on beta- blockers and the same were continued. Two of these five patients succumbed to progressive liver failure with none of these five patients having GI bleed on follow-up. CONCLUSION: EUS is a useful investigational modality for evaluating patients with DV and endoscopic injection of glue is an effective therapy for controlling and preventing recurrence of bleed from DV. PMID- 24949412 TI - Role of high resolution ultrasound/endosonography and elastography in predicting lymph node malignancy. AB - OBJECTIVE: The objective of this study is to evaluate the role of high resolution ultrasonography (US) and endoscopic ultrasound (EUS)-elastography in predicting malignant lymphadenopathy. PATIENTS AND METHODS: This prospective study included 88 patients who underwent EUS or US examination of different groups of lymph nodes (LNs). The classification as benign or malignant based on the real time elastography pattern and the B-mode US/EUS images was compared with the final diagnosis obtained by EUS or US guided fine-needle aspiration cytology (FNAC), tru-cut biopsy or excisional biopsy and follow-up in benign lesions not indicated for biopsy for at least 12 months. RESULTS: Regarding the echogenicity, 98.3% of the benign LNs were hyperechoic, 1.7% was hypoechoic while 89.7% of the malignant LNs were hypoechoic, 3.4% were heterogenous and 6.9% were hyperechoic. With cut off value of 1.93, the sensitivity of longitudinal to transverse ratio was 73% and the specificity was 100%. Score 1 elastography had specificity of 100% in diagnosis of benign LNs, sensitivity was 76.3%, positive predictive value (PPV) was 100%, negative predictive value (NPV) was 84.7% while score 2 had a sensitivity of 60%, specificity of 31.5%, PPV of 15.3%, NPV of 79.3%. Score 3 had a sensitivity of 70.2%, specificity of 100%, PPV of 13.8%, NPV of 100% in detecting malignancy while score 4 had a sensitivity of 85.5%, specificity of 100%, PPV of 100%, NPV of 65.5%. CONCLUSION: Elastography is a promising diagnostic modality that may complement standard ultrasound and EUS and help guide FNAC during staging of LNs. PMID- 24949413 TI - Endoscopic ultrasound for cavernous hemangioma of rectum. AB - Lower gastrointestinal (GI) bleed due to hemangioma in rectum is an uncommon problem. A 19-year-old female patient presented with history of recurrent episodes of lower GI bleeding 1-2 times/month for last 3 years. At the time of hospitalization her vital signs were normal and rectal examination revealed frank blood. Investigations revealed a hemoglobin level of 8.9 g/dL and normal coagulation parameters. Colonoscopy showed bluish reddish elevated nodular lesions limited to distal rectum. Magnetic resonance imaging and endoscopic ultrasound showed cavernous hemangioma. PMID- 24949414 TI - A rare case of incidental retroperitoneal seminoma diagnosed by endoscopic ultrasound-guided fine-needle aspiration. PMID- 24949415 TI - Purification, characterization, and potential of saline waste water remediation of a polyextremophilic alpha-amylase from an obligate halophilic Aspergillus gracilis. AB - An obligate halophilic Aspergillus gracilis which was isolated from a hypersaline man-made saltern from Thailand was screened for its potential of producing extracellular alpha -amylase in the previous studies. In this study the alpha amylase was extracted and purified by the help of column chromatography using Sephadex G-100 column. Presence of amylase was verified by SDS-PAGE analysis, showing a single band of approximately 35 kDa. The specific activity of the enzyme was found to be 131.02 U/mg. The Lineweaver-Burk plot showed the V max and K m values of 8.36 U/mg and 6.33 mg/mL, respectively. The enzyme was found to have the best activity at 5 pH, 60 degrees C, and 30% of NaCl concentration, showing its polyextremophilic nature. The use of various additives did not show much variation in the activity of enzyme, showing its resilience against inhibitors. The enzyme, when tested for its use for synthetic waste water remediation by comparing its activity with commercial amylase in different salt concentrations showed that the alpha -amylase from A. gracilis was having better performance at increasing salt concentrations than the commercial one. This shows its potential to be applied in saline waste water and other low water activity effluents for bioremediation. PMID- 24949416 TI - Quantifying cerebellum grey matter and white matter perfusion using pulsed arterial spin labeling. AB - To facilitate quantification of cerebellum cerebral blood flow (CBF), studies were performed to systematically optimize arterial spin labeling (ASL) parameters for measuring cerebellum perfusion, segment cerebellum to obtain separate CBF values for grey matter (GM) and white matter (WM), and compare FAIR ASST to PICORE. Cerebellum GM and WM CBF were measured with optimized ASL parameters using FAIR ASST and PICORE in five subjects. Influence of volume averaging in voxels on cerebellar grey and white matter boundaries was minimized by high probability threshold masks. Cerebellar CBF values determined by FAIR ASST were 43.8 +/- 5.1 mL/100 g/min for GM and 27.6 +/- 4.5 mL/100 g/min for WM. Quantitative perfusion studies indicated that CBF in cerebellum GM is 1.6 times greater than that in cerebellum WM. Compared to PICORE, FAIR ASST produced similar CBF estimations but less subtraction error and lower temporal, spatial, and intersubject variability. These are important advantages for detecting group and/or condition differences in CBF values. PMID- 24949417 TI - Toxicity evaluation following intratracheal instillation of iron oxide in a silica matrix in rats. AB - Iron oxide-silica nanoparticles (IOSi-NPs) were prepared from a mixture of ferrous chloride tetrahydrate and ferric chloride hexahydrate dropped into a silica xerogel composite. The structure and morphology of the synthesized maghemite nanoparticles into the silica xerogel were analysed by X-ray diffraction measurements, scanning electron microscopy equipped with an energy dispersive X-ray spectrometer, and transmission electron microscopy. The results of the EDAX analysis indicated that the embedded particles were iron oxide nanoparticles. The particle size of IOSi-NPs calculated from the XRD analysis was estimated at around 12.5 nm. The average size deduced from the particle size distribution is 13.7 +/- 0.6 nm, which is in good agreement with XRD analysis. The biocompatibility of IOSi-NPs was assessed by cell viability and cytoskeleton analysis. Histopathology analysis was performed after 24 hours and 7 days, respectively, from the intratracheal instillation of a solution containing 0.5, 2.5, or 5 mg/kg IOSi-NPs. The pathological micrographs of lungs derived from rats collected after the intratracheal instillation with a solution containing 0.5 mg/kg and 2.5 mg/kg IOSi-NPs show that the lung has preserved the architecture of the control specimen with no significant differences. However, even at concentrations of 5 mg/kg, the effect of IOSi-NPS on the lungs was markedly reduced at 7 days posttreatment. PMID- 24949418 TI - A quantitative ethnopharmacological documentation of natural pharmacological agents used by pediatric patients in Mauritius. AB - The pediatric population constitutes the most vulnerable patients due to a dearth of approved drugs. Consequently, there is a pressing need to probe novel natural pharmacological agents in an endeavour to develop new drugs to address pediatric illnesses. To date, no studies have explored the use of natural therapies for pediatric health care in Mauritius. Parents (n = 325) from different regions of the island were interviewed. Quantitative indexes such as fidelity level (FL), informant consensus factor (F IC), and use-value (UV) were calculated. Thirty-two plants were reported to be used by pediatric patients. Gastrointestinal disorders (F IC = 0.97) encompassing regurgitation, infantile colic, and stomach aches were the most common ailments managed with herbs. Matricaria chamomilla used for infantile colic and its pharmacological properties has previously been documented for pediatric patients. Product from A. mellifera (UV = 0.75) was the most utilized zootherapy for managing cough. Most plants and animal products reported in this study have bioactive constituents supported by existing scientific literature but their use for the pediatric population is scant. The present ethnopharmacological study has opened new perspectives for further research into their pharmacology, which can subsequently support and facilitate timely pediatric medicinal product development. PMID- 24949419 TI - Prevalence and correlation with clinical diseases of Helicobacter pylori cagA and vacA genotype among gastric patients from Northeast China. AB - Helicobacter pylori vacA and cagA genes have significant genetic heterogenicity, resulting in different clinical outcomes. Northeast part of China has reported high prevalence of H. pylori infections and gastric cancer. Hence, we investigated the H. pylori cagA and vacA genotypes with clinical outcomes in Northeast China. Gastric tissue samples (n = 169), chronic gastritis (GIs), gastric ulcer (GU), and gastric cancer (GC) were analysed for 16S rRNA ureA, cagA, and cagA genotypes by PCR. A total of 141 (84%) cases were found positive for H. pylori by 16S rRNA and ureA. GC showed high H. pylori infection (93%) compared with GIs (72%) and GU (84%). The vacAs1am1 was highly found in GC (40%) and GU (36%), vacAs1am2 in GIs (33%), vacAs1bm1 (14%) and vacAs1bm2 (8%) in GU cases, and s2m1 in normal cases (33%), while vacAs1cm1 showed low frequency in GIs (2%) and GU (3%) and GC showed negative result. The East-Asian cagA strain was highly observed in GC (43%), as compared to GIs (41%) and GU (20%). The East Asian cagA/vacAs1am1 was significantly higher in GC (23%) than in GU (22%) and GIs (145) patients. The East-Asian type cagA with vacAs1a and vacAm1 is the most predominant genotype in H. pylori strains of Northeast China. PMID- 24949420 TI - Nonlinear EEG decoding based on a particle filter model. AB - While the world is stepping into the aging society, rehabilitation robots play a more and more important role in terms of both rehabilitation treatment and nursing of the patients with neurological diseases. Benefiting from the abundant contents of movement information, electroencephalography (EEG) has become a promising information source for rehabilitation robots control. Although the multiple linear regression model was used as the decoding model of EEG signals in some researches, it has been considered that it cannot reflect the nonlinear components of EEG signals. In order to overcome this shortcoming, we propose a nonlinear decoding model, the particle filter model. Two- and three-dimensional decoding experiments were performed to test the validity of this model. In decoding accuracy, the results are comparable to those of the multiple linear regression model and previous EEG studies. In addition, the particle filter model uses less training data and more frequency information than the multiple linear regression model, which shows the potential of nonlinear decoding models. Overall, the findings hold promise for the furtherance of EEG-based rehabilitation robots. PMID- 24949421 TI - Examination of the compatibility of the photogrammetric method with the phenomenon of mora projection in the evaluation of scoliosis. AB - INTRODUCTION: The aim of this study was to evaluate the compatibility of external measurements of parameters characterizing scoliosis using the photogrammetric method. MATERIAL: The study involved 120 children between the ages of 7 and 11 years in Podkarpackie (Poland). METHOD: Measurements of body posture characteristics were performed using the photogrammetric method with mora projection. Each person was examined twice, once by two different therapists, with a time lapse of 20 minutes in between examinations. RESULTS: High accuracy and no statistical significance were found among different measurements of asymmetry parameters characterizing the shoulder blades and hips. Regularities were also found in the characteristic measurements of curves of scoliosis. The POSTI parameter showed a significant variation and lack of compatibility of results. CONCLUSIONS: (1) The photogrammetric method used to assess the pathological changes caused by scoliosis gives significant results in terms of parameters characterizing the position of the shoulder blades and shoulders, as well as pelvis rotation. (2) High compliance measurements are also characterized by the length of the right and left arcs of scoliosis. PMID- 24949422 TI - Long term follow-up in inferior alveolar nerve transposition: our experience. AB - INTRODUCTION: Inferior alveolar nerve transposition (IANT) is a surgical technique used in implantoprosthetic rehabilitation of the atrophic lower jaw which has not been well embraced because of the high risk of damage to the inferior alveolar nerve (IAN). There are cases in which this method is essential to obtain good morphologic and functional rebalancing of the jaw. In this paper, the authors present their experience with IANT, analyzing the various situations in which IANT is the only surgical preprosthetic option. METHODS: Between 2003 and 2011, 35 patients underwent surgical IANT at our center. Thermal and physical sensitivity were evaluated in each patient during follow-up. The follow-up ranged from 14 to 101 months. RESULTS AND CONCLUSION: Based on our experience, absolute indications of IANT are as follows: (1) class IV, V, or VI of Cawood and Howell with extrusion of the antagonist tooth and reduced prosthetic free space; (2) class V or VI of Cawood and Howell with presence of interforaminal teeth; (3) class V or VI of Cawood and Howell if patient desires fast implantoprosthetic rehabilitation with predictable outcomes; (4) class VI of Cawood and Howell when mandibular height increase with inlay grafts is advisable. PMID- 24949423 TI - Substituted hydroxyapatites with antibacterial properties. AB - Reconstructive surgery is presently struggling with the problem of infections located within implantation biomaterials. Of course, the best antibacterial protection is antibiotic therapy. However, oral antibiotic therapy is sometimes ineffective, while administering an antibiotic at the location of infection is often associated with an unfavourable ratio of dosage efficiency and toxic effect. Thus, the present study aims to find a new factor which may improve antibacterial activity while also presenting low toxicity to the human cells. Such factors are usually implemented along with the implant itself and may be an integral part of it. Many recent studies have focused on inorganic factors, such as metal nanoparticles, salts, and metal oxides. The advantages of inorganic factors include the ease with which they can be combined with ceramic and polymeric biomaterials. The following review focuses on hydroxyapatites substituted with ions with antibacterial properties. It considers materials that have already been applied in regenerative medicine (e.g., hydroxyapatites with silver ions) and those that are only at the preliminary stage of research and which could potentially be used in implantology or dentistry. We present methods for the synthesis of modified apatites and the antibacterial mechanisms of various ions as well as their antibacterial efficiency. PMID- 24949425 TI - Health-related quality of life and preferred health-seeking institutions among rural elderly individuals with and without chronic conditions: a population-based study in Guangdong Province, China. AB - The aim of this study was to examine health-related quality of life (HRQL) as measured by SF-36 and to identify these factors and the preferred health-seeking institutions of 12,800 persons aged 60 and older with and without chronic conditions in rural areas of Guangdong Province by multistage stratified cluster sampling method. HRQL among rural elderly subjects with chronic conditions was lower than that of elderly subjects with no chronic conditions. Multiple linear regression showed that marital status, living with children, cardiovascular disease, osteoporosis, cataract disease, and mental disease were the main affecting factors of HRQL. The main preferred health-seeking institutions selected by the rural elderly were community/town health service institutions, district hospitals, or secondary hospitals. Our findings indicate that the elderly in rural areas of Guangdong Province have a poor HRQL and incorrect health-seeking pathway. The healthcare policymakers should emphasize the need of developing effective and targeted community services strategies to improve the elderly individuals' HRQL in rural areas of China. PMID- 24949424 TI - The roles of biomarkers of oxidative stress and antioxidant in Alzheimer's disease: a systematic review. AB - PURPOSE: Oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD). This paper aims to examine whether biomarkers of oxidative stress and antioxidants could be useful biomarkers in AD, which might form the bases of future clinical studies. METHODS: PubMed, SCOPUS, and Web of Science were systematically queried to obtain studies with available data regarding markers of oxidative stress and antioxidants from subjects with AD. RESULTS AND CONCLUSION: Although most studies show elevated serum markers of lipid peroxidation in AD, there is no sufficient evidence to justify the routine use of biomarkers as predictors of severity or outcome in AD. PMID- 24949426 TI - Tools and databases of the KOMICS web portal for preprocessing, mining, and dissemination of metabolomics data. AB - A metabolome--the collection of comprehensive quantitative data on metabolites in an organism--has been increasingly utilized for applications such as data intensive systems biology, disease diagnostics, biomarker discovery, and assessment of food quality. A considerable number of tools and databases have been developed to date for the analysis of data generated by various combinations of chromatography and mass spectrometry. We report here a web portal named KOMICS (The Kazusa Metabolomics Portal), where the tools and databases that we developed are available for free to academic users. KOMICS includes the tools and databases for preprocessing, mining, visualization, and publication of metabolomics data. Improvements in the annotation of unknown metabolites and dissemination of comprehensive metabolomic data are the primary aims behind the development of this portal. For this purpose, PowerGet and FragmentAlign include a manual curation function for the results of metabolite feature alignments. A metadata specific wiki-based database, Metabolonote, functions as a hub of web resources related to the submitters' work. This feature is expected to increase citation of the submitters' work, thereby promoting data publication. As an example of the practical use of KOMICS, a workflow for a study on Jatropha curcas is presented. The tools and databases available at KOMICS should contribute to enhanced production, interpretation, and utilization of metabolomic Big Data. PMID- 24949427 TI - Suprascapular Notch asymmetry: a study on 311 patients. AB - The most important risk factor of suprascapular nerve entrapment is probably the shape of the suprascapular notch (SSN). The aim of the study was to perform a radiological study of the symmetry of SSN. Included in the study were 311 patients (137 women and 174 men) who underwent standard computed tomography investigation of the chest. A total of 622 computed tomography scans of scapulae were retrospectively analyzed to classify suprascapular notches into five types. Suprascapular notch was recognized as a symmetrical feature in 53.45% of the patients. Symmetry was more frequently seen in females (54.0% versus 52.9%), but not to any significant degree (P = 0.8413). Type III was the most commonly noted symmetrical feature (66.9%) and type II was less common (0.6%). Type III was the most symmetrical type of suprascapular notch, occurring significantly more often as a symmetrical feature in comparison with type I (P < 0.0001), type II (P = 0.00137), or type IV (P = 0.001). Our investigation did not show that the suprascapular notch is a symmetrical feature. However, symmetry was recognized more frequently in the case of type III SSN. No significant differences in symmetry were found with regard to sex. PMID- 24949428 TI - Progesterone attenuates experimental subarachnoid hemorrhage-induced vasospasm by upregulation of endothelial nitric oxide synthase via Akt signaling pathway. AB - Cerebral vasospasm is the leading cause of mortality and morbidity in patients after aneurysmal subarachnoid hemorrhage (SAH). However, the mechanism and adequate treatment of vasospasm are still elusive. In the present study, we evaluate the effect and possible mechanism of progesterone on SAH-induced vasospasm in a two-hemorrhage rodent model of SAH. Progesterone (8 mg/kg) was subcutaneously injected in ovariectomized female Sprague-Dawley rats one hour after SAH induction. The degree of vasospasm was determined by averaging the cross-sectional areas of basilar artery 7 days after first SAH. Expressions of endothelial nitric oxide synthase (eNOS) and phosphorylated Akt (phospho-Akt) in basilar arteries were evaluated. Prior to perfusion fixation, there were no significant differences among the control and treated groups in physiological parameters recorded. Progesterone treatment significantly (P < 0.01) attenuated SAH-induced vasospasm. The SAH-induced suppression of eNOS protein and phospho Akt were relieved by progesterone treatment. This result further confirmed that progesterone is effective in preventing SAH-induced vasospasm. The beneficial effect of progesterone might be in part related to upregulation of expression of eNOS via Akt signaling pathway after SAH. Progesterone holds therapeutic promise in the treatment of cerebral vasospasm following SAH. PMID- 24949429 TI - Coexpression of SFRP1 and WIF1 as a prognostic predictor of favorable outcomes in patients with colorectal carcinoma. AB - Colorectal tumorigenesis is ascribed to the activity of Wnt signaling pathway in a ligand-independent manner mainly through APC and CTNNB1 gene mutations and in a ligand-dependent manner through low expression of Wnt inhibitors such as WNT inhibitory factor 1 (WIF1) and secreted frizzled related protein 1 (SFRP1). In this study we found that WIF1 protein expression was increased and SFRP1 was decreased significantly in CRC tissue versus normal tissue, and high expression of WIF1 was associated with big tumor diameters and deep invasion, and loss of SFRP1 expression was associated with the left lesion site, deep invasion, and high TNM stage. Among the four expression patterns (WIF+/SFRP1+, WIF+/SFRP1-, WIF /SFRP1+, and WIF-/SFRP1-) only coexpression of WIF1 and SFRP1 (WIF+/SFRP1+) was associated with favorable overall survival, together with low TNM stage, as an independent prognostic factor as shown in a multivariate survival model. The results indicated that WIF1 seemed to play an oncogenic role, while SFRP1 seemed to play an oncosuppressive role although both of them are secreted Wnt antagonists. Coexpression of SFRP1 and WIF1, rather than SFRP1 or WIF1 alone, could be used, together with low TNM stage, as a prognostic predictor of favorable outcomes in CRC. PMID- 24949431 TI - A network biology approach to discover the molecular biomarker associated with hepatocellular carcinoma. AB - In recent years, high throughput technologies such as microarray platform have provided a new avenue for hepatocellular carcinoma (HCC) investigation. Traditionally, gene sets enrichment analysis of survival related genes is commonly used to reveal the underlying functional mechanisms. However, this approach usually produces too many candidate genes and cannot discover detailed signaling transduction cascades, which greatly limits their clinical application such as biomarker development. In this study, we have proposed a network biology approach to discover novel biomarkers from multidimensional omics data. This approach effectively combines clinical survival data with topological characteristics of human protein interaction networks and patients expression profiling data. It can produce novel network based biomarkers together with biological understanding of molecular mechanism. We have analyzed eighty HCC expression profiling arrays and identified that extracellular matrix and programmed cell death are the main themes related to HCC progression. Compared with traditional enrichment analysis, this approach can provide concrete and testable hypothesis on functional mechanism. Furthermore, the identified subnetworks can potentially be used as suitable targets for therapeutic intervention in HCC. PMID- 24949432 TI - A systematic analysis of miRNA-mRNA paired variations reveals widespread miRNA misregulation in breast cancer. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs that can regulate gene expression by binding to target mRNAs and induce translation repression or RNA degradation. There have been many studies indicating that both miRNAs and mRNAs display aberrant expression in breast cancer. Previously, most researches into the molecular mechanism of breast cancer examined miRNA expression patterns and mRNA expression patterns separately. In this study, we systematically analysed miRNA-mRNA paired variations (MMPVs), which are miRNA-mRNA pairs whose pattern of regulation can vary in association with biopathological features, such as the oestrogen receptor (ER), TP53 and human epidermal growth factor receptor 2 (HER2) genes, survival time, and breast cancer subtypes. We demonstrated that the existence of MMPVs is general and widespread but that there is a general unbalance in the distribution of MMPVs among the different biopathological features. Furthermore, based on studying MMPVs that are related to multiple biopathological features, we propose a potential crosstalk mechanism between ER and HER2. PMID- 24949433 TI - Detection of hepatitis C virus coinfection in patients with dengue diagnosis. AB - Coinfection produced by dengue virus (DENV) and hepatitis C virus (HCV) is a serious problem of public health in Mexico, as they both circulate in tropical zones and may lead to masking or complicating symptoms. In this research, we detected active coinfected patients by HCV residing in the endemic city of Merida, Yucatan, Mexico, with positive diagnosis to dengue during the acute phase. We performed a retrospective analysis of 240 serum samples from dengue patients. The IgM-ELISA serological test was used for dengue diagnosis, as well as viral isolation to confirm infection. DENV and HCV were detected by RT-PCR. Thus, 31 (12.9%) samples showed DENV-HCV coinfection, but interestingly the highest frequency of coinfection cases was found in male patients presenting hemorrhagic dengue in 19/31 (61.29%), with a predominance of 12 : 7 in males. Firstly, coinfection of DENV-HCV in Merida, Mexico, was detected in young dengue patients, between 11 and 20 years old (38.7%), followed by those between 21 and 30 years old (32%); only 16.13% were between 0 and 10 years of age. Diagnosis of HCV infection in patients with dengue is highly recommended in order to establish potential risk in clinical manifestations as well as dictate patients' special care. PMID- 24949434 TI - Gla-rich protein is a potential new vitamin K target in cancer: evidences for a direct GRP-mineral interaction. AB - Gla-rich protein (GRP) was described in sturgeon as a new vitamin-K-dependent protein (VKDP) with a high density of Gla residues and associated with ectopic calcifications in humans. Although VKDPs function has been related with gamma carboxylation, the Gla status of GRP in humans is still unknown. Here, we investigated the expression of recently identified GRP spliced transcripts, the gamma-carboxylation status, and its association with ectopic calcifications, in skin basal cell and breast carcinomas. GRP-F1 was identified as the predominant splice variant expressed in healthy and cancer tissues. Patterns of gamma carboxylated GRP (cGRP)/undercarboxylated GRP (ucGRP) accumulation in healthy and cancer tissues were determined by immunohistochemistry, using newly developed conformation-specific antibodies. Both GRP protein forms were found colocalized in healthy tissues, while ucGRP was the predominant form associated with tumor cells. Both cGRP and ucGRP found at sites of microcalcifications were shown to have in vitro calcium mineral-binding capacity. The decreased levels of cGRP and predominance of ucGRP in tumor cells suggest that GRP may represent a new target for the anticancer potential of vitamin K. Also, the direct interaction of cGRP and ucGRP with BCP crystals provides a possible mechanism explaining GRP association with pathological mineralization. PMID- 24949435 TI - Luminal DMSO: effects on detrusor and urothelial/lamina propria function. AB - DMSO is used as a treatment for interstitial cystitis and this study examined the effects of luminal DMSO treatment on bladder function and histology. Porcine bladder was incubated without (controls) or with DMSO (50%) applied to the luminal surface and the release of ATP, acetylcholine, and LDH assessed during incubation and in tissues strips after DMSO incubation. Luminally applied DMSO caused ATP, Ach, and LDH release from the urothelial surface during treatment, with loss of urothelial layers also evident histologically. In strips of urothelium/lamina propria from DMSO pretreated bladders the release of both ATP and Ach was depressed, while contractile responses to carbachol were enhanced. Detrusor muscle contractile responses to carbachol were not affected by DMSO pretreatment, but neurogenic responses to electrical field stimulation were enhanced. The presence of an intact urothelium/lamina propria inhibited detrusor contraction to carbachol by 53% and this inhibition was significantly reduced in DMSO pretreated tissues. Detection of LDH in the treatment medium suggests that DMSO permeabilised urothelial membranes causing leakage of cytosolic contents including ATP and Ach rather than enhancing release of these mediators. The increase in contractile response and high levels of ATP are consistent with initial flare up in IC/PBS symptoms after DMSO treatment. PMID- 24949430 TI - Autophagy in Drosophila: from historical studies to current knowledge. AB - The discovery of evolutionarily conserved Atg genes required for autophagy in yeast truly revolutionized this research field and made it possible to carry out functional studies on model organisms. Insects including Drosophila are classical and still popular models to study autophagy, starting from the 1960s. This review aims to summarize past achievements and our current knowledge about the role and regulation of autophagy in Drosophila, with an outlook to yeast and mammals. The basic mechanisms of autophagy in fruit fly cells appear to be quite similar to other eukaryotes, and the role that this lysosomal self-degradation process plays in Drosophila models of various diseases already made it possible to recognize certain aspects of human pathologies. Future studies in this complete animal hold great promise for the better understanding of such processes and may also help finding new research avenues for the treatment of disorders with misregulated autophagy. PMID- 24949436 TI - Propolis varnish: antimicrobial properties against cariogenic bacteria, cytotoxicity, and sustained-release profile. AB - Varnishes are preparations that differ in the polymeric matrix and therapeutical agents. In dentistry they are used to prevent caries. In this study we developed a propolis varnish, considering propolis properties against cariogenic bacteria. To a chitosan polymeric base (CHV) was added ethanolic propolis extract in different concentrations: PV1 (5%), PV2 (10%), and PV3 (15%). Antimicrobial activity was carried out against Streptococcus mutans (SM), Streptococcus sanguinis (SG), Streptococcus salivarius (SS), and Lactobacillus casei (LC) through agar diffusion method. The three propolis concentrations incorporated were effective in inhibiting the growth of all microorganisms, but without significant difference between the zones of inhibition observed. Cytotoxicity assay was done by MTT method. Data were analyzed by one-way ANOVA and Bonferroni test. None of the varnishes were cytotoxic, keeping 80% of viable cells, while CHV allowed cellular proliferation (120%). Sustained-release test was carried out by applying 40 MU L of each varnish in the buccal surface of bovine teeth and kept in an ethanol/water solution removed in regular times. According to the "independent model approach," the release profiles were distinct from each varnish and the most prolonged was PV3 (8 weeks). Varnish formulations had satisfactory antimicrobial activity against cariogenic bacteria and have a low cytotoxicity (<50%). PMID- 24949437 TI - Pathway bridge based multiobjective optimization approach for lurking pathway prediction. AB - Ovarian carcinoma immunoreactive antigen-like protein 2 (OCIAD2) is a protein with unknown function. Frequently methylated or downregulated, OCIAD2 has been observed in kinds of tumors, and TGFbeta signaling has been proved to induce the expression of OCIAD2. However, current pathway analysis tools do not cover the genes without reported interactions like OCIAD2 and also miss some significant genes with relatively lower expression. To investigate potential biological milieu of OCIAD2, especially in cancer microenvironment, a nova approach pbMOO was created to find the potential pathways from TGFbeta to OCIAD2 by searching on the pathway bridge, which consisted of cancer enriched looping patterns from the complicated entire protein interactions network. The pbMOO approach was further applied to study the modulator of ligand TGFbeta1, receptor TGFbetaR1, intermediate transfer proteins, transcription factor, and signature OCIAD2. Verified by literature and public database, the pathway TGFbeta1-TGFbetaR1 SMAD2/3-SMAD4/AR-OCIAD2 was detected, which concealed the androgen receptor (AR) which was the possible transcription factor of OCIAD2 in TGFbetasignal, and it well explained the mechanism of TGFbeta induced OCIAD2 expression in cancer microenvironment, therefore providing an important clue for the future functional analysis of OCIAD2 in tumor pathogenesis. PMID- 24949438 TI - Helical tomotherapy combined with capecitabine in the preoperative treatment of locally advanced rectal cancer. AB - The aim of this study was to evaluate the efficacy of helical tomotherapy plus capecitabine as a preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). Thirty-six LARC patients receiving preoperative CRT were analyzed. Radiotherapy (RT) consisted of 45 Gy to the regional lymph nodes and simultaneous-integrated boost (SIB) 50.4 Gy to the tumor, 5 days/week for 5 weeks. Chemotherapy consisted of capecitabine 850 mg/m(2), twice daily, during the RT days. Patients underwent surgery 6-8 weeks after completion of CRT. Information was collected for patient characteristics, treatment response, and acute and late toxicities. Grade 3/4 (G3+) toxicities occurred in 11.1% of patients (4/36). Sphincter preservation rate was 85.2% (23/27). Five patients (14.3%) achieved pathological complete response. Tumor, nodal, and ypT0-2N0 downstaging were noted in 60% (21/35), 69.6% (16/23), and 57.1% (20/35). Tumor regression grade 2~4 was achieved in 28 patients (80%). After a median follow-up time of 35 months, the most common G3+ late morbidity was ileus and fistula (5.7%, 2/35). The study showed that capecitabine plus helical tomotherapy with an SIB is feasible in treatment of LARC. The treatment modality can achieve a very encouraging sphincter preservation rate and a favorable ypT0-2N0 downstaging rate without excessive toxicity. PMID- 24949440 TI - Relationship between serum total cholesterol level and serum biochemical bone turnover markers in healthy pre- and postmenopausal women. AB - BACKGROUND: The presence of common risk factors suggests that there is a relationship between osteoporosis and cardiovascular disease, possibly via dyslipidemia and inflammation. We investigated the relationships among the lipid profile, the inflammation marker high-sensitivity C-reactive protein (hsCRP), bone turnover markers, and bone mineral density (BMD) to assess the correlation between osteoporosis and cardiovascular disease and identify factors predicting osteoporosis. METHODS: The study included 759 Korean women older than 20 years of age. The BMD, serum lipid profile, and levels of hsCRP, cross-linked C-terminal peptide (CTX), and osteocalcin were measured. We compared the serum biomarkers between groups with normal and low BMD and assessed the correlations between the levels of bone turnover markers and the lipid profile and hsCRP level. RESULTS: The concentrations of CTX, osteocalcin, and total cholesterol were significantly higher in the low BMD group than in the normal BMD group in premenopausal women group. However, hsCRP was not correlated with these parameters. Multivariate logistic regression analysis revealed that TC (OR, 1.647; 95% CI, 1.190-2.279) and osteocalcin (OR, 1.044; 95% CI, 1.002-1.088) had an increased risk of low BMD in premenopausal women. CONCLUSIONS: These results indicate that total cholesterol concentration is correlated with the levels of bone turnover markers, suggesting that it might predict osteoporosis in premenopausal women. PMID- 24949441 TI - Holoptelea integrifolia (Roxb.) Planch: a review of its ethnobotany, pharmacology, and phytochemistry. AB - Holoptelea integrifolia (Ulmaceae) is a versatile medicinal plant used in various indigenous systems of medicine for curing routine healthcare maladies. It is traditionally used in the treatment and prevention of several ailments like leprosy, inflammation, rickets, leucoderma, scabies, rheumatism, ringworm, eczema, malaria, intestinal cancer, and chronic wounds. In vitro and in vivo pharmacological investigations on crude extracts and isolated compounds showed antibacterial, antifungal, analgesic, antioxidant, anti-inflammatory, anthelmintic, antidiabetic, antidiarrhoeal, adaptogenic, anticancer, wound healing, hepatoprotective, larvicidal, antiemetic, CNS depressant, and hypolipidemic activities. Phytochemical analysis showed the presence of terpenoids, sterols, saponins, tannins, proteins, carbohydrates, alkaloids, phenols, flavonoids, glycosides, and quinines. Numerous compounds including Holoptelin-A, Holoptelin-B, friedlin, epifriedlin, beta -amyrin, stigmasterol, beta -sitosterol, 1, 4-napthalenedione, betulin, betulinic acid, hexacosanol, and octacosanol have been identified and isolated from the plant species. The results of several studies indicated that H. integrifolia may be used as an effective therapeutic remedy in the prevention and treatment of various ailments. However, further studies on chemical constituents and their mechanisms in exhibiting certain biological activities are needed. In addition, study on the toxicity of the crude extracts and the compounds isolated from this plant should be assessed to ensure their eligibility to be used as source of modern medicines. PMID- 24949439 TI - Circulating endothelial cells and chronic kidney disease. AB - Endothelial dysfunction may play a crucial role in initiation of the pathogenesis of vascular disease and atherosclerosis. The identification and quantification of circulating endothelial cells (CEC) have been developed as a novel marker of endothelial function. We describe, in great detail, mechanisms of endothelial dysfunction and CEC detachment. We also review the relationship between numbers of CEC and disease severity and response to treatment. In addition, we describe the possible clinical use of CEC in chronic kidney disease (CKD) and kidney transplantation. In summary, CEC have been developed as a novel approach to assess the endothelial damage. Measurement of the CEC level would provide an important diagnostic and prognostic value on the endothelium status and the long term outcome of vascular dysfunction. PMID- 24949442 TI - RhoA controls Wnt upregulation on microstructured titanium surfaces. AB - Rough topography enhances the activation of Wnt canonical signaling in vitro, and this mediates its effects on cell differentiation. However, the molecular mechanisms underlying topography-dependent control of Wnt signaling are still poorly understood. As the small GTPase RhoA controls cytoskeletal reorganization and actomyosin-induced tensional forces, we hypothesized that RhoA could affect the activation of Wnt signaling in cells on micropatterned titanium surfaces. G LISA assay revealed that RhoA activation was higher in C2C12 cells on rough (SLA) surfaces under basal conditions than on smooth (Polished) titanium. Transfection with dominant negative RhoA decreased Wnt activation by normalized TCF-Luc activity on SLA, whilst transfection with constitutively active RhoA increased TCF-Luc activation on Polished titanium. One mM Myosin II inhibitor Blebbistatin increased RhoA activation but decreased Wnt activation on SLA surfaces, indicating that tension-generating structures are required for canonical Wnt modulation on titanium surfaces. Actin inhibitor Cytochalasin markedly enhanced RhoA and TCF-Luc activation on both surfaces and increased the expression of differentiation markers in murine osteoblastic MC3T3 cells. Taken together, these data show that RhoA is upregulated in cells on rough surfaces and it affects the activation of Wnt canonical signaling through Myosin II modulation. PMID- 24949443 TI - Chagas' disease: pregnancy and congenital transmission. AB - Chagas disease is a chronic infection that kills approximately 12,000 people a year. Mass migration of chronically infected and asymptomatic persons has caused globalization of Chagas disease and has made nonvectorial infection, including vertical and blood-borne transmission, more of a threat to human communities than vectorial infection. To control transmission, it is essential to test all pregnant women living in endemic countries and all pregnant women having migrated from, or having lived in, endemic countries. All children born to seropositive mothers should be tested not only within the first month of life but also at ~6 months and ~12 months of age. The diagnosis is made by identification of the parasite in blood before the age of 6 months and by identification of the parasite in blood and/or positive serology after 10 months of age. Follow up for a year is essential as a significant proportion of cases are initially negative and are only detected at a later stage. If the condition is diagnosed and treated early, the clinical response is excellent and the majority of cases are cured. PMID- 24949444 TI - Are proteinase 3 and cathepsin C enzymes related to pathogenesis of periodontitis? AB - AIM: Cathepsin C is the activator of the polymorphonuclear leukocyte-derived proteinase 3, which contributes to inflammatory processes. The aim of the present study was to investigate gingival crevicular fluid (GCF) proteinase 3 and cathepsin C levels in periodontal diseases. DESIGN: Eighteen patients with chronic periodontitis (CP), 20 patients with generalized aggressive periodontitis (G-AgP), 20 patients with gingivitis, and 18 healthy subjects were included in the study. Periodontal parameters including probing depth, clinical attachment level, papilla bleeding index, and plaque index were assessed in all study subjects. GCF proteinase 3 and cathepsin C levels were analyzed by ELISA. RESULTS: GCF proteinase 3 total amount was significantly higher in diseased groups compared to control group, after adjusting age (P < 0.05). No differences were found in GCF cathepsin C levels among the study groups (P > 0.05). Periodontal parameters of sampling sites were positively correlated with GCF proteinase 3 total amounts (P < 0.01) but not with cathepsin C total amounts (P > 0.05). CONCLUSIONS: Elevated levels of GCF proteinase 3 in CP, G-AgP, and gingivitis might suggest that proteinase 3 plays a role during inflammatory periodontal events in host response. However, cathepsin C in GCF does not seem to have an effect on the pathogenesis of periodontal diseases. PMID- 24949445 TI - The analysis of genetic aberrations in children with inherited neurometabolic and neurodevelopmental disorders. AB - Inherited encephalopathies include a broad spectrum of heterogeneous disorders. To provide a correct diagnosis, an integrated approach including genetic testing is warranted. We report seven patients with difficult to diagnose inborn paediatric encephalopathies. The diagnosis could not be attained only by means of clinical and laboratory investigations and MRI. Additional genetic testing was required. Cytogenetics, PCR based tests, and array-based comparative genome hybridization were performed. In 4 patients with impaired language abilities we found the presence of microduplication in the region 16q23.1 affecting two dose sensitive genes: WWOX (OMIM 605131) and MAF (OMIM 177075) (1 case), an interstitial deletion of the 17p11.2 region (2 patients further diagnosed as Smith-Magenis syndrome), and deletion encompassing first three exons of Myocyte Enhancer Factor gene 2MEF2C (1 case). The two other cases represented progressing dystonia. Characteristic GAG deletion in DYT1 consistently with the diagnosis of torsion dystonia was confirmed in 1 case. Last enrolled patient presented with clinical picture consistent with Krabbe disease confirmed by finding of two pathogenic variants of GALC gene and the absence of mutations in PSAP. The integrated diagnostic approach including genetic testing in selected examples of complicated hereditary diseases of the brain is largely discussed in this paper. PMID- 24949446 TI - Circadian modulation of the Cl(-) equilibrium potential in the rat suprachiasmatic nuclei. AB - The suprachiasmatic nuclei (SCN) constitute a circadian clock in mammals, where gamma-amino-butyric acid (GABA) neurotransmission prevails and participates in different aspects of circadian regulation. Evidence suggests that GABA has an excitatory function in the SCN in addition to its typical inhibitory role. To examine this possibility further, we determined the equilibrium potential of GABAergic postsynaptic currents (E(GABA)) at different times of the day and in different regions of the SCN, using either perforated or whole cell patch clamp. Our results indicate that during the day most neurons in the dorsal SCN have an E(GABA) close to -30 mV while in the ventral SCN they have an E(GABA) close to 60 mV; this difference reverses during the night, in the dorsal SCN neurons have an E(GABA) of -60 mV and in the ventral SCN they have an E(GABA) of -30 mV. The depolarized equilibrium potential can be attributed to the activity of the Na(+) K(+)-2Cl(-) (NKCC) cotransporter since the equilibrium potential becomes more negative following addition of the NKCC blocker bumetanide. Our results suggest an excitatory role for GABA in the SCN and further indicate both time (day versus night) and regional (dorsal versus ventral) modulation of E(GABA) in the SCN. PMID- 24949447 TI - Micronuclei in bone marrow and liver in relation to hepatic metabolism and antioxidant response due to coexposure to chloroform, dichloromethane, and toluene in the rat model. AB - Genotoxicity in cells may occur in different ways, direct interaction, production of electrophilic metabolites, and secondary genotoxicity via oxidative stress. Chloroform, dichloromethane, and toluene are primarily metabolized in liver by CYP2E1, producing reactive electrophilic metabolites, and may also produce oxidative stress via the uncoupled CYP2E1 catalytic cycle. Additionally, GSTT1 also participates in dichloromethane activation. Despite the oxidative metabolism of these compounds and the production of oxidative adducts, their genotoxicity in the bone marrow micronucleus test is unclear. The objective of this work was to analyze whether the oxidative metabolism induced by the coexposure to these compounds would account for increased micronucleus frequency. We used an approach including the analysis of phase I, phase II, and antioxidant enzymes, oxidative stress biomarkers, and micronuclei in bone marrow (MNPCE) and hepatocytes (MNHEP). Rats were administered different doses of an artificial mixture of CLF/DCM/TOL, under two regimes. After one administration MNPCE frequency increased in correlation with induced GSTT1 activity and no oxidative stress occurred. Conversely, after three-day treatments oxidative stress was observed, without genotoxicity. The effects observed indicate that MNPCE by the coexposure to these VOCs could be increased via inducing the activity of metabolism enzymes. PMID- 24949449 TI - Role of microRNA-1 in human cancer and its therapeutic potentials. AB - While the mechanisms of human cancer development are not fully understood, evidence of microRNA (miRNA, miR) dysregulation has been reported in many human diseases, including cancer. miRs are small noncoding RNA molecules that regulate posttranscriptional gene expression by binding to complementary sequences in the specific region of gene mRNAs, resulting in downregulation of gene expression. Not only are certain miRs consistently dysregulated across many cancers, but they also play critical roles in many aspects of cell growth, proliferation, metastasis, apoptosis, and drug resistance. Recent studies from our group and others revealed that miR-1 is frequently downregulated in various types of cancer. Through targeting multiple oncogenes and oncogenic pathways, miR-1 has been demonstrated to be a tumor suppressor gene that represses cancer cell proliferation and metastasis and promotes apoptosis by ectopic expression. In this review, we highlight recent findings on the aberrant expression and functional significance of miR-1 in human cancers and emphasize its significant values for therapeutic potentials. PMID- 24949450 TI - Breast cancer prognosis risk estimation using integrated gene expression and clinical data. AB - BACKGROUND: Novel prognostic markers are needed so newly diagnosed breast cancer patients do not undergo any unnecessary therapy. Various microarray gene expression datasets based studies have generated gene signatures to predict the prognosis outcomes, while ignoring the large amount of information contained in established clinical markers. Nevertheless, small sample sizes in individual microarray datasets remain a bottleneck in generating robust gene signatures that show limited predictive power. The aim of this study is to achieve high classification accuracy for the good prognosis group and then achieve high classification accuracy for the poor prognosis group. METHODS: We propose a novel algorithm called the IPRE (integrated prognosis risk estimation) algorithm. We used integrated microarray datasets from multiple studies to increase the sample sizes (~ 2,700 samples). The IPRE algorithm consists of a virtual chromosome for the extraction of the prognostic gene signature that has 79 genes, and a multivariate logistic regression model that incorporates clinical data along with expression data to generate the risk score formula that accurately categorizes breast cancer patients into two prognosis groups. RESULTS: The evaluation on two testing datasets showed that the IPRE algorithm achieved high classification accuracies of 82% and 87%, which was far greater than any existing algorithms. PMID- 24949448 TI - Immunomodulation of nanoparticles in nanomedicine applications. AB - Nanoparticles (NPs) have promising applications in medicine. Immune system is an important protective system to defend organisms from non-self matters. NPs interact with the immune system and modulate its function, leading to immunosuppression or immunostimulation. These modulating effects may bring benefits or danger. Compositions, sizes, and surface chemistry, and so forth, affect these immunomodulations. Here we give an overview of the relationship between the physicochemical properties of NPs, which are candidates to be applied in medicine, and their immunomodulation properties. PMID- 24949451 TI - Punicalagin and ellagic acid demonstrate antimutagenic activity and inhibition of benzo[a]pyrene induced DNA adducts. AB - Punicalagin (PC) is an ellagitannin found in the fruit peel of Punica granatum. We have demonstrated antioxidant and antigenotoxic properties of Punica granatum and showed that PC and ellagic acid (EA) are its major constituents. In this study, we demonstrate the antimutagenic potential, inhibition of BP-induced DNA damage, and antiproliferative activity of PC and EA. Incubation of BP with rat liver microsomes, appropriate cofactors, and DNA in the presence of vehicle or PC and EA showed significant inhibition of the resultant DNA adducts, with essentially complete inhibition (97%) at 40 MU M by PC and 77% inhibition by EA. Antimutagenicity was tested by Ames test. PC and EA dose-dependently and markedly antagonized the effect of tested mutagens, sodium azide, methyl methanesulfonate, benzo[a]pyrene, and 2-aminoflourine, with maximum inhibition of mutagenicity up to 90 percent. Almost all the doses tested (50-500 MU M) exhibited significant antimutagenicity. A profound antiproliferative effect on human lung cancer cells was also shown with PC and EA. Together, our data show that PC and EA are pomegranate bioactives responsible for inhibition of BP-induced DNA adducts and strong antimutagenic, antiproliferative activities. However, these compounds are to be evaluated in suitable animal model to assess their therapeutic efficacy against cancer. PMID- 24949455 TI - Growth and replication of infectious bursal disease virus in the DF-1 cell line and chicken embryo fibroblasts. AB - Infectious bursal disease virus (IBDV) causes a highly contagious disease in young chicks and leads to significant economic losses in the poultry industry. To determine a suitable cell line for IBDV infection, replication, and growth kinetics of the virus, DF-1 cells and chicken embryo fibroblasts (CEF) were used. The population doubling per day (Pd/D) was found to be higher in DF-1 as compared to CEF cells. A suitable time of infection (TOI) was established for increased production of virus and greater infectivity titers. The DF-1 and CEF cells were found to be susceptible to infection by producing marked cytopathic effects (CPEs), and the growth curves of IBDV in DF-1 and CEF cells were evaluated by infectivity assay using tissue culture infectious dose (TCID50). The cytopathic effects of the virus in DF-1 and CEF cells were found to be similar, but higher viral titers were detected in the DF-1 cells as compared to CEF. Thus the DF-1 cell line had a higher growth potential and infectivity, which will be of advantage in vaccine production. PMID- 24949452 TI - Neuroimaging to investigate multisystem involvement and provide biomarkers in amyotrophic lateral sclerosis. AB - Neuroimaging allows investigating the extent of neurological systems degeneration in amyotrophic lateral sclerosis (ALS). Advanced MRI methods can detect changes related to the degeneration of upper motor neurons but have also demonstrated the participation of other systems such as the sensory system or basal ganglia, demonstrating in vivo that ALS is a multisystem disorder. Structural and functional imaging also allows studying dysfunction of brain areas associated with cognitive signs. From a biomarker perspective, numerous studies using diffusion tensor imaging showed a decrease of fractional anisotropy in the intracranial portion of the corticospinal tract but its diagnostic value at the individual level remains limited. A multiparametric approach will be required to use MRI in the diagnostic workup of ALS. A promising avenue is the new methodological developments of spinal cord imaging that has the advantage to investigate the two motor system components that are involved in ALS, that is, the lower and upper motor neuron. For all neuroimaging modalities, due to the intrinsic heterogeneity of ALS, larger pooled banks of images with standardized image acquisition and analysis procedures are needed. In this paper, we will review the main findings obtained with MRI, PET, SPECT, and nuclear magnetic resonance spectroscopy in ALS. PMID- 24949453 TI - Age modulates Fe3O4 nanoparticles liver toxicity: dose-dependent decrease in mitochondrial respiratory chain complexes activities and coupling in middle-aged as compared to young rats. AB - We examined the effects of iron oxide nanoparticles (IONPs) on mitochondrial respiratory chain complexes activities and mitochondrial coupling in young (3 months) and middle-aged (18 months) rat liver, organ largely involved in body iron detoxification. Isolated liver mitochondria were extracted using differential centrifugations. Maximal oxidative capacities (V(max), complexes I, III, and IV activities), V(succ) (complexes II, III, and IV activities), and V tmpd, (complex IV activity), together with mitochondrial coupling (V(max)/V0) were determined in controls conditions and after exposure to 250, 300, and 350 MU g/ml Fe3O4 in young and middle-aged rats. In young liver mitochondria, exposure to IONPs did not alter mitochondrial function. In contrast, IONPs dose dependently impaired all complexes of the mitochondrial respiratory chain in middle-aged rat liver: V(max) (from 30 +/- 1.6 to 17.9 +/- 1.5; P < 0.001), V(succ) (from 33.9 +/- 1.7 to 24.3 +/- 1.0; P < 0.01), V(tmpd) (from 43.0 +/- 1.6 to 26.3 +/- 2.2 umol O2/min/g protein; P < 0.001) using Fe3O4 350 ug/ml. Mitochondrial coupling also decreased. Interestingly, 350 MU g/ml Fe3O4 in the form of Fe(3+) solution did not impair liver mitochondrial function in middle aged rats. Thus, IONPs showed a specific toxicity in middle-aged rats suggesting caution when using it in old age. PMID- 24949454 TI - Antiproliferative and apoptotic effects of Sesbania grandiflora leaves in human cancer cells. AB - Natural phytochemicals and their derivatives are good drug candidates for anticancer therapeutic approaches against multiple targets. We report here the initial findings from our studies on the anticancer properties of the leaves of the medicinal plant Sesbania grandiflora. In the current study, five different solvent fractions from the leaves of S. grandiflora were tested on cancer cell lines such as MCF-7, HepG2, Hep-2, HCT-15, and A549. The methanolic fraction of S. grandiflora was found to exert potent antiproliferative effects especially in the human lung cancer cell line, A549. Caspase 3 was activated in the methanolic fraction treated A549 cells thereby leading to cell death by apoptosis. DAPI staining, DNA laddering, and decrease in mitochondrial membrane potential further confirmed the apoptotic mode of cell death. The high levels of ROS intermediates as evidenced by DCF-DA staining could have played a role in the apoptotic induction. Decrease in levels of cyclin D1 and decrease in the activation of NFkB were observed in A549 cells on treatment with methanolic fraction, giving a hint on the possible mechanism of action. These results prove that the medicinal plant S. grandiflora can be explored further for promising candidate molecules to combat cancer, especially lung cancer. PMID- 24949456 TI - Doctors' insights into the patient perspective: a qualitative study in the field of chronic pain. AB - PURPOSE: To strengthen the conceptualization of the patient perspective by identifying aspects that, from doctors' point of view, are important to address during a consultation to build a partnership with patients. METHOD: Semistructured interviews were conducted with 17 doctors who are experts in the field of chronic pain in Italy. The recordings of the interviews were transcribed verbatim and interpreted using thematic analysis. RESULTS: The participants agreed about the importance of doctors addressing aspects of the patient perspective that can lead to a difference of opinion with patients, namely, patients' views about their health condition (i.e., what they think they have and why and the perceived impact of the health condition on their life) and about treatments (i.e., what they have tried or have heard about and their expectations). CONCLUSIONS: Identifying patients' standpoints on their health condition and treatments offers an opportunity for critical discussion of differences of opinions and promotes communication exchange and agreement about the appropriate course of action. PMID- 24949457 TI - In vitro synergistic effect of curcumin in combination with third generation cephalosporins against bacteria associated with infectious diarrhea. AB - Diarrhea is one of the leading causes of morbidity and mortality in humans in developed and developing countries. Furthermore, increased resistance to antibiotics has resulted in serious challenges in the treatment of this infectious disease worldwide. Therefore, there exists a need to develop alternative natural or combination drug therapies. The aim of the present study was to investigate the synergistic effect of curcumin-1 in combination with three antibiotics against five diarrhea causing bacteria. The antibacterial activity of curcumin-1 and antibiotics was assessed by the broth microdilution method, checkerboard dilution test, and time-kill assay. Antimicrobial activity of curcumin-1 was observed against all tested strains. The MICs of curcumin-1 against test bacteria ranged from 125 to 1000 MU g/mL. In the checkerboard test, curcumin-1 markedly reduced the MICs of the antibiotics cefaclor, cefodizime, and cefotaxime. Significant synergistic effect was recorded by curcumin-1 in combination with cefotaxime. The toxicity of curcumin-1 with and without antibiotics was tested against foreskin (FS) normal fibroblast and no significant cytotoxicity was observed. From our result it is evident that curcumin-1 enhances the antibiotic potentials against diarrhea causing bacteria in in vitro condition. This study suggested that curcumin-1 in combination with antibiotics could lead to the development of new combination of antibiotics against diarrhea causing bacteria. PMID- 24949458 TI - Antimicrobial activity of coronarin D and its synergistic potential with antibiotics. AB - Coronarin D is a labdane-type diterpene from the rhizomes of Hedychium coronarium. In the view of our ongoing effort to explore its novel biological activity, antimicrobial activity study of coronarin D was performed. The results showed that coronarin D was active against tested Gram-positive bacteria, inactive for tested Gram-negative bacteria, and weakly active against tested fungi. The antibacterial effect of the combination of coronarin D with nine classical antibiotics against four Gram-positive bacteria was also evaluated. The fractional inhibitory concentration indices (FICI) of coronarin D-antibiotics combinations, calculated from the checkerboard assay, were used as synergism indicator. Out of 36 combinations, 47% showed total synergism, 33% had partial synergistic interaction, 17% showed no effect, and 3% showed antagonism. By combination with coronarin D at concentration of 0.25 minimal inhibitory concentration (MIC), the activities of antibiotics were boosted to 4- to 128 fold. These finding suggested an attractive approach to combat the infectious diseases by using coronarin D-antibiotic drug combination. PMID- 24949459 TI - Periodontal pathogens and atherosclerosis: implications of inflammation and oxidative modification of LDL. AB - Inflammation is well accepted to play a crucial role in the development of atherosclerotic lesions, and recent studies have demonstrated an association between periodontal disease and cardiovascular disease. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, causative agents of destructive chronic inflammation in the periodontium, can accelerate atheroma deposition in animal models. Emerging evidence suggests that vaccination against virulence factors of these pathogens and anti-inflammatory therapy may confer disease resistance. In this review, we focus on the role of inflammatory mechanisms and oxidative modification in the formation and activation of atherosclerotic plaques accelerated by P. gingivalis or A. actinomycetemcomitans in an ApoE-deficient mouse model and high-fat-diet-fed mice. Furthermore, we examine whether mucosal vaccination with a periodontal pathogen or the anti-inflammatory activity of catechins can reduce periodontal pathogen-accelerated atherosclerosis. PMID- 24949460 TI - A fast, reliable, and sensitive method for detection and quantification of Listeria monocytogenes and Escherichia coli O157:H7 in ready-to-eat fresh-cut products by MPN-qPCR. AB - In the present work we developed a MPN quantitative real-time PCR (MPN-qPCR) method for a fast and reliable detection and quantification of Listeria monocytogenes and Escherichia coli O157:H7 in minimally processed vegetables. In order to validate the proposed technique, the results were compared with conventional MPN followed by phenotypic and biochemical assays methods. When L. monocytogenes and E. coli O157:H7 were artificially inoculated in fresh-cut vegetables, a concentration as low as 1 CFU g(-1) could be detected in 48 hours for both pathogens. qPCR alone allowed a limit of detection of 10(1) CFU g(-1) after 2 hours of enrichment for L. monocytogenes and E. coli O157:H7. Since minimally processed ready-to-eat vegetables are characterized by very short shelf life, our method can potentially address the consistent reduction of time for microbial analysis, allowing a better management of quality control. Moreover, the occurrences of both pathogenic bacteria in mixed salad samples and fresh-cut melons were monitored in two production plants from the receipt of the raw materials to the early stages of shelf life. No sample was found to be contaminated by L. monocytogenes. One sample of raw mixed salad was found positive to an H7 enterohemorrhagic serotype. PMID- 24949461 TI - Association between arsenic exposure and diabetes mellitus in Cambodia. AB - Whereas studies in Taiwan found associations between arsenic exposure from drinking water and diabetes mellitus (DM), studies in other countries yielded inconsistent results, and diet might be a confounder. We conducted a study in Cambodia, where people have non-Western style diet, to evaluate the association. We measured well water and urine samples and examined skin signs of arsenicosis to assess arsenic exposure and used questionnaires to collect data on potential risk factors. We performed a fingertip blood glucose test followed by measurement of hemoglobin A1c to assess DM. The 43-male and 99-female participants had an average age of 40.4 years. We found that participants with skin signs of arsenicosis had a higher level of arsenic in the drinking water (1101.1 versus 972.2 MU g/L, P = 0.02). Drinking water with arsenic levels above the median (907.25 MU g/L) was associated with a nearly twofold increase in the risk of DM (odds ratio [OR] = 1.7, 95% confidence interval [CI]: 0.5-5.8), so was having skin sings of arsenicosis (OR = 1.7, 95% CI: 0.5-5.6). The ORs did not reach statistical significance most likely because of the small case number. Therefore, further studies with larger study populations are needed to confirm our findings. PMID- 24949462 TI - Neural decoding using a parallel sequential Monte Carlo method on point processes with ensemble effect. AB - Sequential Monte Carlo estimation on point processes has been successfully applied to predict the movement from neural activity. However, there exist some issues along with this method such as the simplified tuning model and the high computational complexity, which may degenerate the decoding performance of motor brain machine interfaces. In this paper, we adopt a general tuning model which takes recent ensemble activity into account. The goodness-of-fit analysis demonstrates that the proposed model can predict the neuronal response more accurately than the one only depending on kinematics. A new sequential Monte Carlo algorithm based on the proposed model is constructed. The algorithm can significantly reduce the root mean square error of decoding results, which decreases 23.6% in position estimation. In addition, we accelerate the decoding speed by implementing the proposed algorithm in a massive parallel manner on GPU. The results demonstrate that the spike trains can be decoded as point process in real time even with 8000 particles or 300 neurons, which is over 10 times faster than the serial implementation. The main contribution of our work is to enable the sequential Monte Carlo algorithm with point process observation to output the movement estimation much faster and more accurately. PMID- 24949463 TI - Growth curves for girls with Turner syndrome. AB - The objective of this study was to review the growth curves for Turner syndrome, evaluate the methodological and statistical quality, and suggest potential growth curves for clinical practice guidelines. The search was carried out in the databases Medline and Embase. Of 1006 references identified, 15 were included. Studies constructed curves for weight, height, weight/height, body mass index, head circumference, height velocity, leg length, and sitting height. The sample ranged between 47 and 1,565 (total = 6,273) girls aged 0 to 24 y, born between 1950 and 2006. The number of measures ranged from 580 to 9,011 (total = 28,915). Most studies showed strengths such as sample size, exclusion of the use of growth hormone and androgen, and analysis of confounding variables. However, the growth curves were restricted to height, lack of information about selection bias, limited distributional properties, and smoothing aspects. In conclusion, we observe the need to construct an international growth reference for girls with Turner syndrome, in order to provide support for clinical practice guidelines. PMID- 24949464 TI - Current and emerging biomarkers of cell death in human disease. AB - Cell death is a critical biological process, serving many important functions within multicellular organisms. Aberrations in cell death can contribute to the pathology of human diseases. Significant progress made in the research area enormously speeds up our understanding of the biochemical and molecular mechanisms of cell death. According to the distinct morphological and biochemical characteristics, cell death can be triggered by extrinsic or intrinsic apoptosis, regulated necrosis, autophagic cell death, and mitotic catastrophe. Nevertheless, the realization that all of these efforts seek to pursue an effective treatment and cure for the disease has spurred a significant interest in the development of promising biomarkers of cell death to early diagnose disease and accurately predict disease progression and outcome. In this review, we summarize recent knowledge about cell death, survey current and emerging biomarkers of cell death, and discuss the relationship with human diseases. PMID- 24949465 TI - Neuropathologic implication of peripheral neuregulin-1 and EGF signals in dopaminergic dysfunction and behavioral deficits relevant to schizophrenia: their target cells and time window. AB - Neuregulin-1 and epidermal growth factor (EGF) are implicated in the pathogenesis of schizophrenia. To test the developmental hypothesis for schizophrenia, we administered these factors to rodent pups, juveniles, and adults and characterized neurobiological and behavioral consequences. These factors were also provided from their transgenes or infused into the adult brain. Here we summarize previous results from these experiments and discuss those from neuropathological aspects. In the neonatal stage but not the juvenile and adult stages, subcutaneously injected factors penetrated the blood-brain barrier and acted on brain neurons, which later resulted in persistent behavioral and dopaminergic impairments associated with schizophrenia. Neonatally EGF-treated animals exhibited persistent hyperdopaminergic abnormalities in the nigro-pallido striatal system while neuregulin-1 treatment resulted in dopaminergic deficits in the corticolimbic dopamine system. Effects on GABAergic and glutamatergic systems were transient or limited. Even in the adult stage, intracerebral administration and transgenic expression of these factors produced similar but not identical behavioral impairments, although the effects of intracerebral administration were reversible. These findings suggest that dopaminergic development is highly vulnerable to circulating ErbB ligands in the pre- and perinatal stages. Once maldevelopment of the dopaminergic system is established during early development, dopamine-associating behavioral deficits become irreversible and manifest at postpubertal stages. PMID- 24949466 TI - Evaluation of three formulations of culture media for isolation of Brucella spp. regarding their ability to inhibit the growth of contaminating organisms. AB - Three culture media (Brucella agar, Farrell medium, and CITA) were compared for their effectiveness in inhibiting contamination and for isolating Brucella spp. One hundred lymph nodes from pigs (n = 50) and wild boars (n = 50) with lymphadenitis were collected in slaughterhouses in the State of Sao Paulo and were assessed on these three selective media for Brucella spp. All of the samples were negative for Brucella spp. on the three culture media. On the agar medium, fungal (70 plates) and Gram-positive bacterial (59 plates) contaminants were observed; in the CITA medium, the absence of fungal and Gram-positive bacteria on 15 plates was observed; no bacterial or fungal growth was observed on the Farrell media. The results demonstrated that the CITA and Farrell media inhibited the growth of contaminants better than the Brucella agar. PMID- 24949468 TI - Fish and crayfish toxicology. PMID- 24949467 TI - Extracellular matrix modulates angiogenesis in physiological and pathological conditions. AB - Angiogenesis is a multistep process driven by a wide range of positive and negative regulatory factors. Extracellular matrix (ECM) plays a crucial role in the regulation of this process. The degradation of ECM, occurring in response to an angiogenic stimulus, leads to degradation or partial modification of matrix molecules, release of soluble factors, and exposure of cryptic sites with pro- and/or antiangiogenic activity. ECM molecules and fragments, resulting from proteolysis, can also act directly as inflammatory stimuli, and this can explain the exacerbated angiogenesis that drives and maintains several inflammatory diseases. In this review we have summarized some of the more recent literature data concerning the molecular control of ECM in angiogenesis in both physiological and pathological conditions. PMID- 24949469 TI - Biological characterization and pluripotent identification of sheep dermis derived mesenchymal stem/progenitor cells. AB - Dermis-derived mesenchymal stem/progenitor cells (DMS/PCs) were a multipotential stem cell population, which has potential applications in the tissue damage repair and skin transplant. Although a large number of studies deal with the human DMS/PCs self-renewal and regulation, however, the study of livestock derived DMS/PCs has rarely been reported. Here, sheep DMS/PCs were isolated from one-month-old sheep embryos and studied at the cellular and molecular level. And then the DMS/PCs biological characteristics were analysed by RT-PCR and immunofluorescence. Experimental results showed that DMS/PCs could be expanded for 48 passages and the cells viability and hereditary character were steady. In addition, the DMS/PCs maker beta -integrin, CD71, CD44, and CD73 were expressed positively through RT-PCR and immunofluorescence. Passage 3 DMS/PCs were successfully induced to differentiate into adipocytes, osteoblasts, chondrocytes, and neurocytes, respectively. The above results suggest that DMS/PCs not only have strong self-renewal capacity but also have the potential to differentiate into adipocytes, osteoblasts, chondrocytes, and neurocytes. The study provides theoretical basis and experimental evidence for potential clinical application. PMID- 24949470 TI - Gremlin activates the Smad pathway linked to epithelial mesenchymal transdifferentiation in cultured tubular epithelial cells. AB - Gremlin is a developmental gene upregulated in human chronic kidney disease and in renal cells in response to transforming growth factor-beta (TGF-beta). Epithelial mesenchymal transition (EMT) is one process involved in renal fibrosis. In tubular epithelial cells we have recently described that Gremlin induces EMT and acts as a downstream TGF-beta mediator. Our aim was to investigate whether Gremlin participates in EMT by the regulation of the Smad pathway. Stimulation of human tubular epithelial cells (HK2) with Gremlin caused an early activation of the Smad signaling pathway (Smad 2/3 phosphorylation, nuclear translocation, and Smad-dependent gene transcription). The blockade of TGF-beta, by a neutralizing antibody against active TGF-beta, did not modify Gremlin-induced early Smad activation. These data show that Gremlin directly, by a TGF-beta independent process, activates the Smad pathway. In tubular epithelial cells long-term incubation with Gremlin increased TGF-beta production and caused a sustained Smad activation and a phenotype conversion into myofibroblasts-like cells. Smad 7 overexpression, which blocks Smad 2/3 activation, diminished EMT changes observed in Gremlin-transfected tubuloepithelial cells. TGF-beta neutralization also diminished Gremlin-induced EMT changes. In conclusion, we propose that Gremlin could participate in renal fibrosis by inducing EMT in tubular epithelial cells through activation of Smad pathway and induction of TGF beta. PMID- 24949471 TI - Solanine induces mitochondria-mediated apoptosis in human pancreatic cancer cells. AB - Steroid alkaloids have been suggested as potential anticancer compounds. However, the underlying mechanisms of how steroid alkaloids inhibit the tumor growth are largely unknown. Here, we reported that solanine, a substance of steroid alkaloids, has a positive effect on the inhibition of pancreatic cancer cell growth in vitro and in vivo. In pancreatic cancer cells and nu/nu nude mice model, we found that solanine inhibited cancer cells growth through caspase-3 dependent mitochondrial apoptosis. Mechanically, solanine promotes the opening of mitochondrial membrane permeability transition pore (MPTP) by downregulating the Bcl-2/Bax ratio; thereafter, Cytochrome c and Smac are released from mitochondria into cytosol to process the caspase-3 zymogen into an activated form. Moreover, we found that the expression of tumor metastasis related proteins, MMP-2 and MMP 9, was also decreased in the cells treated with solanine. Therefore, our results suggested that solanine was an effective compound for the treatment of pancreatic cancer. PMID- 24949472 TI - Norovirus Narita 104 virus-like particles expressed in Nicotiana benthamiana induce serum and mucosal immune responses. AB - Narita 104 virus is a human pathogen belonging to the norovirus (family Caliciviridae) genogroup II. Noroviruses cause epidemic gastroenteritis worldwide. To explore the potential of developing a plant-based vaccine, a plant optimized gene encoding Narita 104 virus capsid protein (NaVCP) was expressed transiently in Nicotiana benthamiana using a tobacco mosaic virus expression system. NaVCP accumulated up to approximately 0.3 mg/g fresh weight of leaf at 4 days postinfection. Initiation of hypersensitive response-like symptoms followed by tissue necrosis necessitated a brief infection time and was a significant factor limiting expression. Transmission electron microscopy of plant-derived NaVCP confirmed the presence of fully assembled virus-like particles (VLPs). In this study, an optimized method to express and partially purify NaVCP is described. Further, partially purified NaVCP was used to immunize mice by intranasal delivery and generated significant mucosal and serum antibody responses. Thus, plant-derived Narita 104 VLPs have potential for use as a candidate subunit vaccine or as a component of a multivalent subunit vaccine, along with other genotype-specific plant-derived VLPs. PMID- 24949474 TI - Benchmarking B-cell epitope prediction with quantitative dose-response data on antipeptide antibodies: towards novel pharmaceutical product development. AB - B-cell epitope prediction can enable novel pharmaceutical product development. However, a mechanistically framed consensus has yet to emerge on benchmarking such prediction, thus presenting an opportunity to establish standards of practice that circumvent epistemic inconsistencies of casting the epitope prediction task as a binary-classification problem. As an alternative to conventional dichotomous qualitative benchmark data, quantitative dose-response data on antibody-mediated biological effects are more meaningful from an information-theoretic perspective in the sense that such effects may be expressed as probabilities (e.g., of functional inhibition by antibody) for which the Shannon information entropy (SIE) can be evaluated as a measure of informativeness. Accordingly, half-maximal biological effects (e.g., at median inhibitory concentrations of antibody) correspond to maximally informative data while undetectable and maximal biological effects correspond to minimally informative data. This applies to benchmarking B-cell epitope prediction for the design of peptide-based immunogens that elicit antipeptide antibodies with functionally relevant cross-reactivity. Presently, the Immune Epitope Database (IEDB) contains relatively few quantitative dose-response data on such cross reactivity. Only a small fraction of these IEDB data is maximally informative, and many more of them are minimally informative (i.e., with zero SIE). Nevertheless, the numerous qualitative data in IEDB suggest how to overcome the paucity of informative benchmark data. PMID- 24949473 TI - Phytochemical, therapeutic, and ethnopharmacological overview for a traditionally important herb: Boerhavia diffusa Linn. AB - Boerhavia diffusa (BD) is a plant of rasayana category as per ayurvedic claims. It is reported to possess antiaging, disease prevention, and life strengthening activities which hold enormous influence in disease burden and affordability/availability of healthcare in the world. Objective. This paper has been compiled to comment on the studies reported for BD to highlight its chemical and therapeutic potential along with its ethnopharmacological considerations. METHODS: In the present paper, a detailed account of chemical constituents and pharmacological activities has been presented. All the findings were correlated with modern pharmacological activities to appraise the value of BD. RESULTS: Chemical analysis of BD gives a wide variety of chemical constituents, namely, rotenoids, flavonoids, xanthones, purine nucleoside, lignans, and steroids. Various ethnopharmacological reports emphasize its role in disorders of reproductive system, gastrointestinal system, respiratory system, urinary system, hepatic system/jaundice, cardiovascular system, and cancer. CONCLUSIONS: The studies on the therapeutic activities of BD range from studies on crude extracts to isolated compounds; however some of the studies require sophistication and validated results. BD is a plant of enormous importance in the purview of its chemical and therapeutic properties. PMID- 24949475 TI - Atypical enteropathogenic Escherichia coli secretes plasmid encoded toxin. AB - Plasmid encoded toxin (Pet) is a serine protease originally described in enteroaggregative Escherichia coli (EAEC) prototype strain 042 whose entire characterization was essentially obtained from studies performed with the purified toxin. Here we show that Pet is not exclusive to EAEC. Atypical enteropathogenic Escherichia coli (aEPEC) strains, isolated from diarrhea cases, express Pet and its detection in supernatants of infected HEp-2 cells coincides with the appearance of cell damage, which, in turn, were similar to those described with purified Pet. Pet secretion and the cytotoxic effects are time and culture medium dependent. In presence of DMEM supplemented with tryptone cell rounding and detachment were observed after just 5 h of incubation with the bacteria. In the absence of tryptone, the cytotoxic effects were detected only after 24 h of infection. We also show that, in addition to the prototype EAEC, other pet+ EAEC strains, also isolated from diarrhea cases, induce cellular damage in the same degree as the aEPEC. The cytotoxic effects of EAEC and aEPEC strains were significantly reduced in the presence of a serine protease inhibitor or anti-Pet IgG serum. Our results show a common aspect between the aEPEC and EAEC and provide the first evidence pointing to a role of Pet in aEPEC pathogenesis. PMID- 24949476 TI - Endoscopic evacuation of basal ganglia hemorrhage via keyhole approach using an adjustable cannula in comparison with craniotomy. AB - Neuroendoscopic (NE) surgery as a minimal invasive treatment for basal ganglia hemorrhage is a promising approach. The present study aims to evaluate the efficacy and safety of NE approach using an adjustable cannula to treat basal ganglia hemorrhage. In this study, we analysed the clinical and radiographic outcomes between NE group (21 cases) and craniotomy group (30 cases). The results indicated that NE surgery might be an effective and safe approach for basal ganglia haemorrhage, and it is also suggested that NE approach may improve good functional recovery. However, NE approach only suits the selected patient, and the usefulness of NE approach needs further randomized controlled trials (RCTs) to evaluate. PMID- 24949477 TI - Synthesis and characterization of poly(lactic-co-glycolic) acid nanoparticles loaded chitosan/bioactive glass scaffolds as a localized delivery system in the bone defects. AB - The functionality of tissue engineering scaffolds can be enhanced by localized delivery of appropriate biological macromolecules incorporated within biodegradable nanoparticles. In this research, chitosan/58 S-bioactive glass (58 S-BG) containing poly(lactic-co-glycolic) acid (PLGA) nanoparticles has been prepared and then characterized. The effects of further addition of 58 S-BG on the structure of scaffolds have been investigated to optimize the characteristics of the scaffolds for bone tissue engineering applications. The results showed that the scaffolds had high porosity with open pores. It was also shown that the porosity decreased with increasing 58 S-BG content. Furthermore, the PLGA nanoparticles were homogenously distributed within the scaffolds. According to the obtained results, the nanocomposites could be considered as highly bioactive bone tissue engineering scaffolds with the potential of localized delivery of biological macromolecules. PMID- 24949478 TI - The antiacetylcholinesterase and antileishmanial activities of Canarium patentinervium Miq. AB - In continuation of our natural and medicinal research programme on tropical rainforest plants, a bioassay guided fractionation of ethanolic extract of leaves of Canarium patentinervium Miq. (Burseraceae Kunth.) led to the isolation of scopoletin (1), scoparone (2), (+)-catechin (3), vomifoliol (4), lioxin (5), and syringic acid (6). All the compounds exhibited antiacetylcholinesterase activity with syringic acid, a phenolic acid exhibiting good AChE inhibition (IC50 29.53 +/- 0.19 MU g/mL). All compounds displayed moderate antileishmanial activity with scopoletin having the highest antileishmanial activity (IC50 163.30 +/- 0.32 MU g/mL). Given the aforementioned evidence, it is tempting to speculate that Canarium patentinervium Miq. represents an exciting scaffold from which to develop leads for treatment of neurodegenerative and parasitic diseases. PMID- 24949479 TI - Induction of antibodies and T cell responses by a recombinant influenza virus carrying an HIV-1 TatDelta51-59 protein in mice. AB - Recombinant influenza viruses hold promise as vectors for vaccines to prevent transmission of mucosal pathogens. In this study, we generated a recombinant WSN/TatDelta(51-59) virus in which Tat protein lacking residues 51 to 59 of the basic domain was inserted into the N-terminus of the hemagglutinin (HA) of A/WSN/33 virus. The TatDelta(51-59) insertion into the viral HA caused a 2-log reduction in viral titers in cell culture, compared with the parental A/WSN/33 virus, and severely affected virus replication in vivo. Nevertheless, Tat specific antibodies and T cell responses were elicited upon a single intranasal immunization of BALB/c mice with WSN/TatDelta(51-59) virus. Moreover, Tat specific immune responses were also detected following vaccine administration via the vaginal route. These data provide further evidence that moderately large HIV antigens can be delivered by chimeric HA constructs and elicit specific immune responses, thus increasing the options for the potential use of recombinant influenza viruses, and their derivatives, for prophylactic and therapeutic vaccines. PMID- 24949480 TI - Spider silk as guiding biomaterial for human model neurons. AB - Over the last years, a number of therapeutic strategies have emerged to promote axonal regeneration. An attractive strategy is the implantation of biodegradable and nonimmunogenic artificial scaffolds into injured peripheral nerves. In previous studies, transplantation of decellularized veins filled with spider silk for bridging critical size nerve defects resulted in axonal regeneration and remyelination by invading endogenous Schwann cells. Detailed interaction of elongating neurons and the spider silk as guidance material is unknown. To visualize direct cellular interactions between spider silk and neurons in vitro, we developed an in vitro crossed silk fiber array. Here, we describe in detail for the first time that human (NT2) model neurons attach to silk scaffolds. Extending neurites can bridge gaps between single silk fibers and elongate afterwards on the neighboring fiber. Culturing human neurons on the silk arrays led to an increasing migration and adhesion of neuronal cell bodies to the spider silk fibers. Within three to four weeks, clustered somata and extending neurites formed ganglion-like cell structures. Microscopic imaging of human neurons on the crossed fiber arrays in vitro will allow for a more efficient development of methods to maximize cell adhesion and neurite growth on spider silk prior to transplantation studies. PMID- 24949481 TI - Novel molecular biomarkers at the blood-brain barrier in ALS. AB - Recently neuroinflammation has gained a particular focus as a key mechanism of ALS. Several studies in vivo as well as in vitro have nominated immunoglobulin G (IgG) isolated from ALS patients as an active contributor to disease onset and progression. We have shown that ALS IgG affects astroglial Ca(2+) excitability and induces downstream activation of phosphatidylinositol 3-kinase. These studies were hampered by a lack of knowledge of the pathway of entry of immune factors in the CNS. Our MRI data revealed the blood-brain barrier BBB leakage and T cell infiltration into brain parenchyma in ALS G93A rats. Since astrocyte ensheathes blood vessel wall contributing to BBB stability and plays an important role in ALS pathogenesis, we have studied astrocytic membrane proteins water channel aquaporin-4 and the inwardly rectifying potassium channel. In this review, we will summarize data related to BBB disruption with particular emphasis on impaired function of astrocytes in ALS. We will discuss implication of membrane proteins expressed on astrocytic endfeet, aquaporin-4, and inwardly rectifying potassium channel in the pathology of ALS. In addition to ALS-specific IgGs, these membrane proteins are proposed as novel biomarkers of the disease. PMID- 24949482 TI - Differential macrophage response to slow- and fast-growing pathogenic mycobacteria. AB - Nontuberculous mycobacteria (NTM) have recently been recognized as important species that cause disease even in immunocompetent individuals. The mechanisms that these species use to infect and persist inside macrophages are not well characterised. To gain insight concerning this process we used THP-1 macrophages infected with M. abscessus, M. fortuitum, M. celatum, and M. tuberculosis. Our results showed that slow-growing mycobacteria gained entrance into these cells with more efficiency than fast-growing mycobacteria. We have also demonstrated that viable slow-growing M. celatum persisted inside macrophages without causing cell damage and without inducing reactive oxygen species (ROS), as M. tuberculosis caused. In contrast, fast-growing mycobacteria destroyed the cells and induced high levels of ROS. Additionally, the macrophage cytokine pattern induced by M. celatum was different from the one induced by either M. tuberculosis or fast-growing mycobacteria. Our results also suggest that, in some cases, the intracellular survival of mycobacteria and the immune response that they induce in macrophages could be related to their growth rate. In addition, the modulation of macrophage cytokine production, caused by M. celatum, might be a novel immune-evasion strategy used to survive inside macrophages that is different from the one reported for M. tuberculosis. PMID- 24949483 TI - Minimally invasive transforaminal lumbar interbody fusion with unilateral pedicle screw fixation: comparison between primary and revision surgery. AB - Minimally invasive surgery with a transforaminal lumbar interbody fusion (MIS TLIF) is an important minimally invasive fusion technique for the lumbar spine. Lumbar spine reoperation is challenging and is thought to have greater complication risks. The purpose of this study was to compare MIS TLIF with unilateral screw fixation perioperative results between primary and revision surgeries. This was a prospective study that included 46 patients who underwent MIS TLIF with unilateral pedicle screw. The patients were divided into two groups, primary and revision MIS TLIF, to compare perioperative results and complications. The two groups were similar in age, sex, and level of operation, and were not significantly different in the length of follow-up or clinical results. Although dural tears were more common with the revision group (primary 1; revision 4), operation time, blood loss, total perioperative complication, and fusion rates were not significantly different between the two groups. Both groups showed substantial improvements in VAS and ODI scores one year after surgical treatment. Revision MIS TLIF performed by an experienced surgeon does not necessarily increase the risk of perioperative complication compared with primary surgery. MIS TLIF with unilateral pedicle screw fixation is a valuable option for revision lumbar surgery. PMID- 24949484 TI - NGS nominated CELA1, HSPG2, and KCNK5 as candidate genes for predisposition to Balkan endemic nephropathy. AB - Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression leading to terminal renal failure. The results of molecular biological investigations propose that BEN is a multifactorial disease with genetic predisposition to environmental risk agents. Exome sequencing of 22 000 genes with Illumina Nextera Exome Enrichment Kit was performed on 22 DNA samples (11 Bulgarian patients and 11 Serbian patients). Software analysis was performed via NextGene, Provean, and PolyPhen. The frequency of all annotated genetic variants with deleterious/damaging effect was compared with those of European populations. Then we focused on nonannotated variants (with no data available about them and not found in healthy Bulgarian controls). There is no statistically significant difference between annotated variants in BEN patients and European populations. From nonannotated variants with more than 40% frequency in both patients' groups, we nominated 3 genes with possible deleterious/damaging variants--CELA1, HSPG2, and KCNK5. Mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN. PMID- 24949485 TI - Vomiting and dysphagia predict delayed gastric emptying in diabetic and nondiabetic subjects. AB - BACKGROUND: Gastroparesis is a heterogeneous disorder most often idiopathic, diabetic, or postsurgical in nature. The demographic and clinical predictors of gastroparesis in Israeli patients are poorly defined. METHODS: During the study period we identified all adult patients who were referred to gastric emptying scintigraphy (GES) for the evaluation of dyspeptic symptoms. Of those, 193 patients who were referred to GES from our institution were retrospectively identified (76 (39%) males, mean age 60.2 +/- 15.6 years). Subjects were grouped according to gastric half-emptying times (gastric T 1/2). Demographic and clinical data were extracted from electronic medical records or by a phone interview. KEY RESULTS: Gastric emptying half-times were normal (gastric T 1/2 0 99 min) in 101 patients, abnormal (gastric T 1/2 100-299 min) in 67 patients, and grossly abnormal (gastric T 1/2 >= 300 min) in 25 patients. Vomiting and dysphagia, but neither early satiety nor bloating, correlated with delayed gastric emptying. Diabetes was associated with grossly abnormal gastric T 1/2. Idiopathic gastroparesis was associated with a younger age at GES. No correlation was observed between gastric T 1/2 values and gender, smoking, H. pylori infection, HBA1C, or microvascular complication of diabetes. CONCLUSIONS INFERENCES: Vomiting and dysphagia are predictive of delayed gastric emptying in both diabetic and nondiabetic subjects. Diabetes is associated with more severe gastroparesis. PMID- 24949487 TI - Retracted: Skeletal muscle-specific CPT1 deficiency elevates lipotoxic intermediates but preserves insulin sensitivity. PMID- 24949486 TI - Insulin increases ceramide synthesis in skeletal muscle. AB - AIMS: The purpose of this study was to determine the effect of insulin on ceramide metabolism in skeletal muscle. METHODS: Skeletal muscle cells were treated with insulin with or without palmitate for various time periods. Lipids (ceramides and TAG) were isolated and gene expression of multiple biosynthetic enzymes were quantified. Additionally, adult male mice received daily insulin injections for 14 days, followed by muscle ceramide analysis. RESULTS: In muscle cells, insulin elicited an increase in ceramides comparable to palmitate alone. This is likely partly due to an insulin-induced increase in expression of multiple enzymes, particularly SPT2, which, when knocked down, prevented the increase in ceramides. In mice, 14 days of insulin injection resulted in increased soleus ceramides, but not TAG. However, insulin injections did significantly increase hepatic TAG compared with vehicle-injected animals. CONCLUSIONS: This study suggests that insulin elicits an anabolic effect on sphingolipid metabolism in skeletal muscle, resulting in increased ceramide accumulation. These findings reveal a potential mechanism of the deleterious consequences of the hyperinsulinemia that accompanies insulin resistance and suggest a possible novel therapeutic target to mitigate its effects. PMID- 24949489 TI - Approaches to modelling the human immune response in transition of candidates from research to development. AB - This review considers the steps required to evaluate a candidate biodefense vaccine or therapy as it emerges from the research phase, in order to transition it to development. The options for preclinical modelling of efficacy are considered in the context of the FDA's Animal Rule. PMID- 24949490 TI - A Pilot Study of Clinical Measures to Assess Mind-Body Intervention Effects for those with and without PTSD. AB - OBJECTIVE: Assess measures for future mind-body interventions in those with and without PTSD. METHODS: Psychological and immune measures were assessed at baseline in three age and gender-matched groups: 1) 15 combat veterans with PTSD, 2) 15 combat veterans without PTSD, and 3) 15 non-combat veterans without PTSD. Physiological measures were assessed at baseline, during relaxation and stress conditions. RESULTS: The PTSD group had increased PTSD and depression severity, anxiety, and mood disturbance, and decreased quality of life scores. Respiration, heart rate variability, heart rate, and blood pressure differed significantly between conditions but not between groups. CONCLUSIONS: Respiration and heart rate variability may be useful measures for future mind-body intervention trials. PMID- 24949491 TI - Optimization of power utilization in multimobile robot foraging behavior inspired by honeybees system. AB - Deploying large numbers of mobile robots which can interact with each other produces swarm intelligent behavior. However, mobile robots are normally running with finite energy resource, supplied from finite battery. The limitation of energy resource required human intervention for recharging the batteries. The sharing information among the mobile robots would be one of the potentials to overcome the limitation on previously recharging system. A new approach is proposed based on integrated intelligent system inspired by foraging of honeybees applied to multimobile robot scenario. This integrated approach caters for both working and foraging stages for known/unknown power station locations. Swarm mobile robot inspired by honeybee is simulated to explore and identify the power station for battery recharging. The mobile robots will share the location information of the power station with each other. The result showed that mobile robots consume less energy and less time when they are cooperating with each other for foraging process. The optimizing of foraging behavior would result in the mobile robots spending more time to do real work. PMID- 24949488 TI - Hapten-induced contact hypersensitivity, autoimmune reactions, and tumor regression: plausibility of mediating antitumor immunity. AB - Haptens are small molecule irritants that bind to proteins and elicit an immune response. Haptens have been commonly used to study allergic contact dermatitis (ACD) using animal contact hypersensitivity (CHS) models. However, extensive research into contact hypersensitivity has offered a confusing and intriguing mechanism of allergic reactions occurring in the skin. The abilities of haptens to induce such reactions have been frequently utilized to study the mechanisms of inflammatory bowel disease (IBD) to induce autoimmune-like responses such as autoimmune hemolytic anemia and to elicit viral wart and tumor regression. Hapten induced tumor regression has been studied since the mid-1900s and relies on four major concepts: (1) ex vivo haptenation, (2) in situ haptenation, (3) epifocal hapten application, and (4) antigen-hapten conjugate injection. Each of these approaches elicits unique responses in mice and humans. The present review attempts to provide a critical appraisal of the hapten-mediated tumor treatments and offers insights for future development of the field. PMID- 24949492 TI - UV spectrophotometric simultaneous determination of paracetamol and ibuprofen in combined tablets by derivative and wavelet transforms. AB - The application of first-order derivative and wavelet transforms to UV spectra and ratio spectra was proposed for the simultaneous determination of ibuprofen and paracetamol in their combined tablets. A new hybrid approach on the combined use of first-order derivative and wavelet transforms to spectra was also discussed. In this application, DWT (sym6 and haar), CWT (mexh), and FWT were optimized to give the highest spectral recoveries. Calibration graphs in the linear concentration ranges of ibuprofen (12-32 mg/L) and paracetamol (20-40 mg/L) were obtained by measuring the amplitudes of the transformed signals. Our proposed spectrophotometric methods were statistically compared to HPLC in terms of precision and accuracy. PMID- 24949493 TI - Soft congruence relations over rings. AB - Molodtsov introduced the concept of soft sets, which can be seen as a new mathematical tool for dealing with uncertainty. In this paper, we initiate the study of soft congruence relations by using the soft set theory. The notions of soft quotient rings, generalized soft ideals and generalized soft quotient rings, are introduced, and several related properties are investigated. Also, we obtain a one-to-one correspondence between soft congruence relations and idealistic soft rings and a one-to-one correspondence between soft congruence relations and soft ideals. In particular, the first, second, and third soft isomorphism theorems are established, respectively. PMID- 24949494 TI - Towards an optimal energy consumption for unattended mobile sensor networks through autonomous sensor redeployment. AB - Energy hole is an inherent problem caused by heavier traffic loads of sensor nodes nearer the sink because of more frequent data transmission, which is strongly dependent on the topology induced by the sensor deployment. In this paper, we propose an autonomous sensor redeployment algorithm to balance energy consumption and mitigate energy hole for unattended mobile sensor networks. First, with the target area divided into several equal width coronas, we present a mathematical problem modeling sensor node layout as well as transmission pattern to maximize network coverage and reduce communication cost. And then, by calculating the optimal node density for each corona to avoid energy hole, a fully distributed movement algorithm is proposed, which can achieve an optimal distribution quickly only by pushing or pulling its one-hop neighbors. The simulation results demonstrate that our algorithm achieves a much smaller average moving distance and a much longer network lifetime than existing algorithms and can eliminate the energy hole problem effectively. PMID- 24949495 TI - SERS of molecules that do not adsorb on Ag surfaces: a metal-organic framework based functionalization strategy. AB - The potential for discriminating between analytes by their unique vibrational signature makes surface-enhanced Raman scattering (SERS) extremely interesting for chemical detection. However, for molecules that weakly adsorb to non functionalized plasmonic materials, detection by SERS remains a key challenge. Here we present an approach to SERS-based detection where a polycrystalline metal organic framework (MOF) film is used to recruit a range of structurally similar volatile organic compounds for detection by SERS. MOF films were grown on the surface of Ag "films-over-nanospheres" (FONs), which have previously been shown to enhance Raman signals of surface adsorbates by a factor of 10(7). Upon exposing the MOF-coated FON to benzene, toluene, nitrobenzene, or 2,6-di-tert butylpyridine, the MOF film traps the vapors at the FON surface, allowing the unique Raman spectrum of each vapor to be recorded. By contrast, these analytes do not adsorb to a bare FON surface and thus cannot be detected by conventional SERS substrates. Pyridine was also tested as a Ag-adsorbing control analyte. Concentration dependence and time resolved measurements provide evidence for the hypothesis that the vapors are reversibly adsorbed on the surfaces of MOF nanocrystals exposed at grain boundaries. This represents a generalized approach for confining aromatic molecules through interactions with the MOF surface, which can be applied for future SERS-based sensors. PMID- 24949496 TI - Differential pulse voltammetry detection of dopamine and ascorbic acid by permselective silica mesochannels vertically attached to the electrode surface. AB - A thin film consisting of highly ordered and vertically oriented silica mesochannels (SMCs) was prepared on the indium tin oxide (ITO) coated glass electrode surface by chronopotentiometry. The mesochannel has a uniform pore size of 2-3 nm in diameter and a positively charged surface due to grafted ammonium groups. The electrostatic and steric effects resulted from control of the surface charge and the ionic buffer concentration make the SMCs permselective, favoring the mass transport of oppositely charged species and repelling that of similarly charged ones. By using differential pulse voltammetry (DPV), the SMCs with this charge selectivity can be employed for permselective detection of ascorbic acid (AA) and dopamine (DA) that are oppositely charged compounds. The obtained linear detection range was 49-2651 MUM for AA and 20-226 MUM for DA, respectively. AA and DA in real samples were also determined by the SMC film modified electrode. PMID- 24949497 TI - Poly(ethylene glycol) hydrogels with adaptable mechanical and degradation properties for use in biomedical applications. AB - Requirements of hydrogels for drug delivery, wound dressings, and surgical implantation can be extensive, including suitable mechanical properties and tailorable degradation time frames. Herein, an adaptable PEG-based hydrogel, whose mechanical properties and degradation rate can be systematically adjusted to meet these criteria by altering simple variables such as the PEG molecular weight, is described. The performance of these hydrogels in three physical manipulations (pushing, pulling, and folding), representative of manipulations that they may undergo during typical biomedical use, is also assessed. While not all of these formulations can withstand these manipulations, a subset did, and it is intended to further optimize these formulations for specific clinical applications. Additionally, the outcomes of the physical manipulation tests indicate that simply having a high modulus does not correlate with biomedical applicability. PMID- 24949499 TI - Moving beyond "me-too" respiratory drugs. PMID- 24949498 TI - Cerulomycin Caerulomycin [corrected] A: a potent novel immunosuppressive agent. PMID- 24949500 TI - Antibiotics for respiratory infections: too much, too soon. PMID- 24949501 TI - MMR lowers infection-related hospital admissions in children. PMID- 24949503 TI - Obituary: Dr. Barry Fitzgerald. PMID- 24949502 TI - Pulmonary hypertension of sickle cell disease: new guidelines. PMID- 24949505 TI - Obituary: Professor Robert M. Kenney. PMID- 24949506 TI - Obituary: Dr John Steiner. PMID- 24949504 TI - Obituary: Dr John Hurtgen. PMID- 24949507 TI - Disseminated cryptococcosis in bone marrow. PMID- 24949508 TI - Obituary: Dr Gordon Leon Woods. PMID- 24949509 TI - Acute basophilic leukemia. PMID- 24949510 TI - Tribute to the Joint Honorary Chairman: Douglas Mitchell, BSc, MRCVS, DipACT Joint Honorary Chairman of the 10th International Symposium on Equine Reproduction, Lexington, Kentucky, USA, July 2010. PMID- 24949511 TI - Tribute to the Joint Honorary Chairman: B.W. Pickett, PhD Joint Honorary Chairman of the Tenth International Symposium on Equine Reproduction, Lexington, KY, USA, July 2010. PMID- 24949512 TI - Pregnant woman. PMID- 24949513 TI - Determinants of children's oral-health-related quality of life over time. AB - OBJECTIVE: To identify clinical and psychosocial predictors of oral-health related quality of life (OHQoL) in Thai children over time. METHODS: OHQoL data were collected from 510 students aged 10-14 years at baseline and 3, 6 and 9 month follow-up using the Child Perceptions Questionnaire (CPQ11-14), and sense of coherence (SOC), dental coping beliefs (DCB) and socioeconomic status (maternal educational attainment, paternal educational attainment and parental income), together with clinical variables (untreated caries, gingival health, malocclusion, dental opacities), were collected at baseline. The data were analysed with structural equation modelling (SEM) guided by the Wilson and Cleary model (J Am Med Assoc 1995;273:59). RESULTS: Mean DMFT was 1.97 (SD=1.81). Most students had healthy gingivae (54.3%) and 68.9% scored IOTN 1-4. The SEM model fitted the data well [CMIN/DF=2.574, SRMR=0.0561, CFI=0.974 and RMSEA=0.059 (90% CIs=0.039-0.079)]. Higher SOC, DCB and socioeconomic status (SES) at baseline consistently predicted better OHQoL at all three time points. Untreated caries at baseline predicted worse OHQoL at 6-month follow-up only. Malocclusion and dental opacities were unrelated to OHQoL at any time point. CONCLUSIONS: Individual factors, particularly SOC, were important influences on OHQoL, suggesting that interventions designed to promote SOC may present an opportunity to enhance children's experience of oral health in their daily lives. Clinical factors were not consistently related to OHQoL. This could be attributed to weak relationships between the two, the low level of disease and/or the sensitivity and discriminant validity of the CPQ11-14. PMID- 24949514 TI - Subjective well-being in dentists: the role of intrinsic aspirations. AB - OBJECTIVES: To take a motivational approach, testing an idea derived from self determination theory (SDT) that the pursuit of intrinsic life and professional aspirations is associated with enhanced subjective well-being. METHODS: A cross sectional survey of a cluster sample of 583 dentists in England provided data on the subjective importance of their intrinsic and extrinsic aspirations and their perceived likelihood of achieving those aspirations. The dependent variable was a four-domain measure of subjective well-being. RESULTS: Controlling measures of core self-evaluations and trait emotional intelligence, the perceived importance and likelihood of achieving intrinsic aspirations were uniquely related to positive affect; the perceived likelihood of achieving intrinsic aspirations was uniquely related to job and life satisfaction and positive affect, and the perceived likelihood of achieving extrinsic aspirations was uniquely related to life satisfaction. No aspiration variables uniquely predicted negative affect. CONCLUSIONS: These findings lend support to self-determination theory and provide a platform for the future development of interventions that can promote and maintain well-being in dentists. PMID- 24949515 TI - Equity in access to health care services in Italy. AB - OBJECTIVE: To provide new evidence on whether and how patterns of health care utilization deviate from horizontal equity in a country with a universal and egalitarian public health care system: Italy. DATA SOURCES: Secondary analysis of data from the Health Conditions and Health Care Utilization Survey 2005, conducted by the Italian National Institute of Statistics on a probability sample of the noninstitutionalized Italian population. STUDY DESIGN: Using multilevel logistic regression, we investigated how the probability of utilizing five health care services varies among individuals with equal health status but different SES. DATA COLLECTION/EXTRACTION: Respondents aged 18 or older at the interview time (n = 103,651). PRINCIPAL FINDINGS: Overall, we found that use of primary care is inequitable in favor of the less well-off, hospitalization is equitable, and use of outpatient specialist care, basic medical tests, and diagnostic services is inequitable in favor of the well-off. Stratifying the analysis by health status, however, we found that the degree of inequity varies according to health status. CONCLUSIONS: Despite its universal and egalitarian public health care system, Italy exhibits a significant degree of SES-related horizontal inequity in health services utilization. PMID- 24949516 TI - Largest publicly traded healthcare providers. Ranked by 2013 revenue, based on filings with the U.S. Securities and Exchange Commission. PMID- 24949517 TI - Matters of the spirit. PMID- 24949518 TI - Caring for children who are dying. PMID- 24949519 TI - Copper and silver complexes of tris(triazole)amine and tris(benzimidazole)amine ligands: evidence that catalysis of an azide-alkyne cycloaddition ("click") reaction by a silver tris(triazole)amine complex arises from copper impurities. AB - The synthesis and characterization of a silver complex of the tripodal triazole ligand, tris(benzyltriazolylmethyl)amine (TBTA, L(1)), that is used as promoter to enhance Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions is reported. X-ray analysis of the silver(I) complex with L(1) reveals a dinuclear cation, [Ag2(L(1))2](2+), that is essentially isostructural to the copper(I) analogue. While the [Ag2(L(1))2](BF4)2 complex provides catalysis for the azide alkyne cycloaddition process, evidence is presented that this arises from trace copper contamination. The synthesis of silver(I), copper(II), and copper(I) complexes of a second tripodal ligand, tris(2-benzimidazolymethyl)amine (L(2)), which is used to enhance the rate of CuAAC reactions, is also reported. X-ray crystallography of the Cu(I) complex [Cu(I)3(L(2))2(CH3CN)2](BF4)3 offers structural insight into previous mechanistic speculation about the role of this ligand in the CuAAC reaction. PMID- 24949520 TI - Depression is linked to uncontrolled hypertension: a case-control study from Karachi, Pakistan. AB - BACKGROUND: High blood pressure is an important risk factor for cardiovascular disease and may be more prevalent in persons with psychopathology. OBJECTIVE: To determine the association between uncontrolled hypertension with depressive and anxiety disorders in two tertiary care centers in Karachi. METHODS: It was a case control study conducted in two hospitals in Karachi. Cases were patients with uncontrolled hypertension and controls were patients with controlled hypertension. History of anxiety or depression as measured by Hospital Anxiety and Depression Scale (HADS) was the exposure. HADS of >8 was suggestive of having anxiety or depression. RESULTS: A total of 700 participants were approached, out of whom 590 fulfilled the inclusion criteria and consented to participate, 323 (54.7%) participants were enrolled as cases and 267 (45.3%) as controls. Mean (SD) age was 54.98 (12.38) years, 229 (38%) were males. Odds ratio (OR) (95% CI) of having uncontrolled hypertension and being depressed (HADS-D > 8) was 2.02 (1.44-2.83), p value <= 0.001. The association remained significant even after adjusting for age and gender in Model 1 OR (95% CI): 1.82 (1.27-2.60), p value = 0.001, ethinicity and education in Model 2 OR (95% CI): 1.87 (1.29-2.71), p value = 0.001 and comorbids, history of hospitalization body mass index in Model 3 OR (95% CI): 1.94 (1.31-2.85), p value = 0.001. CONCLUSION: There is association between uncontrolled hypertension and depression that is independent of sociodemographic factors, comorbids and history of hospitalization. PMID- 24949521 TI - Carboxylated glucuronic poly-amido-saccharides as protein stabilizing agents. AB - The synthesis of novel carbohydrate-based polymers allows the structure to be tailored at the monomer level for a specific property and expands the range of available structures beyond those found in nature. Using a controlled anionic polymerization, a new type of carbohydrate polymer is synthesized in which glucose-derived monomers are joined by an alpha-1,2 amide linkage to give enantiopure poly-amido-saccharides (PASs). To investigate the effect of adding ionizable carboxylic acid groups, such as those found in natural polysaccharides containing glucuronic acid, the oxidation of the primary alcohol at the C6 position of the repeat unit to a carboxylic acid is reported. TEMPO-mediated oxidation provides control over the degree of oxidation in excellent yield. Based on circular dichroism, the oxidized polymers possess an ordered helical secondary structure in aqueous solution. Finally, oxidized PASs stabilize lysozyme toward dehydration and freezing stresses better than a current, widely used protein stabilizing agent, trehalose. PMID- 24949522 TI - Transition-metal-free synthesis of substituted pyridines via ring expansion of 2 allyl-2H-azirines. AB - A new strategy to open the 2-allyl-2H-azirines by 1,8-diazabicyclo[5.4.0]undec-7 ene (DBU) promotion in metal-free conditions affording 1-azatrienes that in situ electrocyclize to the pyridines in good to excellent yields is reported. The reaction displays a broad substrate scope and good tolerance to a variety of substituents including aryl, alkyl, and heterocyclic groups. In addition, one-pot synthesis of pyridines from oximes via in situ formation of 2H-azirines was achieved. PMID- 24949524 TI - Low-temperature thermal reduction of graphene oxide nanobrick walls: unique combination of high gas barrier and low resistivity in fully organic polyelectrolyte multilayer thin films. AB - Layer-by-layer assembly from aqueous solutions was used to construct multilayer thin films (<200 nm) comprising polyethylenimine and graphene oxide. Low temperature (175 degrees C) thermal reduction of these films improved gas barrier properties (e.g., lower permeability than SiOx), even under high humidity conditions, and enhanced their electrical conductivity to 1750 S/m. The flexible nature of the aforementioned thin films, along with their excellent combination of transport properties, make them ideal candidates for use in a broad range of electronics and packaging applications. PMID- 24949523 TI - Imaging mass spectrometry of diversified cardiolipin molecular species in the brain. AB - MALDI imaging mass spectrometry (MALDI-IMS) has been used successfully in mapping different lipids in tissue sections, yet existing protocols fail to detect the diverse species of mitochondria-unique cardiolipins (CLs) in the brain which are essential for cellular and mitochondrial physiology. We have developed methods enabling the imaging of individual CLs in brain tissue. This was achieved by eliminating ion suppressive effects by (i) cross-linking carboxyl/amino containing molecules on tissue with 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide hydrochloride and (ii) removing highly abundant phosphatidylcholine head groups via phospholipase C treatment. These treatments allowed the detection of CL species at 100 MUm resolution and did not affect the amount or molecular species distribution of brain tissue CLs. When combined with augmented matrix application, these modifications allowed the visualization and mapping of multiple CL species in various regions of the brain including the thalamus, hippocampus, and cortex. Areas such as the dentate and stratum radiatum exhibited higher CL signals than other areas within the hippocampal formation. The habenular nuclear (Hb)/dorsal third ventricle (D3 V) and lateral ventricle (LV) areas were identified as CL "hot spots". Our method also allowed structural MS/MS fragmentation and mapping of CLs with identified fatty acid residues and demonstrated a nonrandom distribution of individual oxidizable (polyunsaturated fatty acid containing) and nonoxidizable (nonpolyunsaturated containing) CLs in different anatomical areas of the brain. To our knowledge, this method is the first label-free approach for molecular mapping of diversified CLs in brain tissue. PMID- 24949525 TI - Initial step of pH-jump-induced lamellar to bicontinuous cubic phase transition in dioleoylphosphatidylserine/monoolein. AB - Electrostatic interactions (EI) are an important factor for phase transitions between lamellar liquid-crystalline (L(alpha)) and inverse bicontinuous cubic (Q(II)) phases. We investigated the low pH-induced L(alpha) to double-diamond cubic (Q(II)(D)) phase transition in dioleoylphosphatidylserine (DOPS)/monoolein (MO) using time-resolved small-angle X-ray scattering. Using a stopped-flow apparatus, a suspension of liposomes (multilamellar vesicles (MLVs) or large unilamellar vesicles (LUVs)) of 20%-DOPS/80%-MO membrane at neutral pH was rapidly mixed with a low pH buffer, and then the structural change of the membranes in the resultant suspension was observed as a function of time (i.e., pH-jump experiment). At the initial step, the L(alpha) phase was directly transformed into the hexagonal II (H(II)) phase, and subsequently, the H(II) phase slowly converted into the Q(II)(D) phase. We obtained the rate constants of the initial step (i.e., the L(alpha) to H(II) phase transition) and of the second step (i.e., the H(II) to Q(II)(D) phase transition) using the non-negative matrix factorization method. The rate constant of the initial step was independent of the MLV concentration, indicating that single MLVs can convert into the HII phase without any interaction with other MLVs. On the other hand, the rate constant of the initial step increased with a decrease in pH, 0.041 s(-1) at pH 2.6 and 0.013 s(-1) at pH 2.8, and also exhibited a size dependence; for smaller vesicles such as LUVs and smaller MLVs with diameters of ~1 MUm, the rate constant was smaller. They were reasonably explained by the classical nucleation theory. These results provide the first experimental evidence of the total kinetics of EI-induced L(alpha)/Q(II) phase transitions. PMID- 24949528 TI - Time-dependent wave-packet quantum dynamics study of the Ne + D2(+) (v0 = 0-2, j0 = 0) -> NeD(+) + D reaction: including the coriolis coupling. AB - The dynamics of the Ne + D2(+) (v0 = 0-2, j0 = 0) -> NeD(+) + D reaction has been investigated in detail by using an accurate time-dependent wave-packet method on the ground 1(2)A' potential energy surface. Comparisons between the Coriolis coupling results and the centrifugal-sudden ones reveal that Coriolis coupling effect can influence reaction dynamics of the NeD2(+) system. Integral cross sections have been evaluated for the Ne + D2(+) reaction and its isotopic variant Ne + H2(+), and a considerable intermolecular isotopic effect has been found. Also obvious is the great enhancement of the reactivity due to the reagent vibrational excitation. Besides, a comparison with previous theoretical results is also presented and discussed. PMID- 24949527 TI - Cognitive impairments at high altitudes and adaptation. AB - High altitude hypoxia has been shown to have significant impact on cognitive performance. This article reviews the aspects in which, and the conditions under which, decreased cognitive performance has been observed at high altitudes. Neural changes related to high altitude hypoxia are also reviewed with respect to their possible contributions to cognitive impairments. In addition, potential adaptation mechanisms are reviewed among indigenous high altitude residents and long-term immigrant residents, with discussions about methodological concerns related to these studies. PMID- 24949529 TI - Electron and hole mobilities in single-layer WSe2. AB - Single-layer transition metal dichalcogenide WSe2 has recently attracted a lot of attention because it is a 2D semiconductor with a direct band gap. Due to low doping levels, it is intrinsic and shows ambipolar transport. This opens up the possibility to realize devices with the Fermi level located in the valence band, where the spin/valley coupling is strong and leads to new and interesting physics. As a consequence of its intrinsically low doping, large Schottky barriers form between WSe2 and metal contacts, which impede the injection of charges at low temperatures. Here, we report on the study of single-layer WSe2 transistors with a polymer electrolyte gate (PEO:LiClO4). Polymer electrolytes allow the charge carrier densities to be modulated to very high values, allowing the observation of both the electron- and the hole-doped regimes. Moreover, our ohmic contacts formed at low temperatures allow us to study the temperature dependence of electron and hole mobilities. At high electron densities, a re entrant insulating regime is also observed, a feature which is absent at high hole densities. PMID- 24949530 TI - Investigational therapies targeting the ErbB family in oesophagogastric cancer. AB - INTRODUCTION: The prognosis for patients with oesophagogastric (OG) cancer remains poor, with a median survival of approximately 9 - 11 months for patients with metastatic disease. However, a more personalised approach to treatment, using drugs tailored to the molecular characteristics of patients' tumours, has the potential to improve patient outcomes. Drugs targeting the ErbB family of receptors have been developed, but these have had varying degrees of success in clinical practice. AREAS COVERED: The authors provide an overview of the ErbB receptor family with regard to OG cancers. Furthermore, they evaluate the evidence from preclinical and clinical trials of therapeutics targeting this family, including monoclonal antibodies, tyrosine kinase inhibitors and novel agents. EXPERT OPINION: Drugs targeting the ErbB family have been evaluated in OG cancer, with a notable success story in the case of trastuzumab, although there have been disappointing failures with anti-EGFR therapy. The response to targeted treatment remains variable and further biomarker research is essential to identify patients most likely to benefit from these therapies. The treatment of OG cancer remains challenging, but new anti-HER2 therapies and combination therapies hold promise for the future. PMID- 24949531 TI - Bicycle helmet size, adjustment, and stability. AB - OBJECTIVES: One of the main requirements of a protective bicycle helmet is to provide and maintain adequate coverage to the head. A poorly fitting or fastened helmet may be displaced during normal use or even ejected during a crash. The aims of the current study were to identify factors that influence the size of helmet worn, identify factors that influence helmet position and adjustment, and examine the effects of helmet size worn and adjustment on helmet stability. METHODS: Recreational and commuter cyclists in Sydney were surveyed to determine how helmet size and/or adjustment affected helmet stability in the real world. Anthropometric characteristics of the head were measured and, to assess helmet stability, a test analogous to the requirements of the Australian bicycle helmet standard was undertaken. RESULTS: Two hundred sixty-seven cyclists were recruited across all age groups and 91% wore an AS/NZS 2063-compliant helmet. The main ethnic group was Europeans (71%) followed by Asians (18%). The circumferences of the cyclists' heads matched well the circumference of the relevant ISO headform for the chosen helmet size, but the head shapes differed with respect to ISO headforms. Age and gender were associated with wearing an incorrectly sized helmet and helmet adjustment. Older males (>55 years) were most likely to wear an incorrectly sized helmet. Adult males in the 35-54 year age group were most likely to wear a correctly adjusted helmet. Using quasistatic helmet stability tests, it was found that the correctness of adjustment, rather than size, head dimensions, or shape, significantly affected helmet stability in all test directions. CONCLUSIONS: Bicycle helmets worn by recreational and commuter cyclists are often the wrong size and are often worn and adjusted incorrectly, especially in children and young people. Cyclists need to be encouraged to adjust their helmets correctly. Current headforms used in standards testing may not be representative of cyclists' head shapes. This may create challenges to helmet suppliers if on one hand they optimize the helmet to meet tests on ISO-related headforms while on the other seeking to offer greater range of sizes. PMID- 24949532 TI - It's not what you say, it's how you say it: language use on Facebook impacts employability but not attractiveness. AB - The expansion and increasing diversity of the Internet has seen a growth in user generated online content, and an escalation in incorrect and nonstandardized language use (e.g., text speak). This evolution has been exemplified by social networking sites such as Facebook. In our experiment, participants viewed six Facebook profiles whose walls contained status updates that were either spelled correctly, incorrectly, or using text speak, and then rated the profile owners on measures of attractiveness and employability. It was shown that language use had no impact on attractiveness, but users who used correct language were seen as more intelligent, competent, and employable. These results highlight the need to control language in this area of research by demonstrating the variables' seemingly elevated importance to employers compared to peers. The findings also pave the way for further exploration of the Warranting Theory of impression formation online and the role of language in social media-based identity statements and behavioral residue. PMID- 24949533 TI - Two functional sequence variants of the GATA6 gene promoter in patients with indirect inguinal hernia. AB - Inguinal hernia is a common surgical disease, majority of which are indirect inguinal hernia (IIH). A positive family history has indicated that genetic factors play important roles in the IIH development. To date, genetic causes and underlying mechanisms for inguinal hernia remain largely unknown. During the embryonic development, GATA transcription factor 6 (GATA6) plays an essential role. Mutations in GATA6 gene and changed GATA6 levels have been associated with human diseases. As GATA6 acts in a dosage-dependent manner, we speculated that changed GATA6 levels, resulting from DNA sequence variants (DSVs) within the gene regulatory regions, may mediate the IIH development. In this study, the GATA6 gene promoter was genetically and functionally analyzed in IIH patients and ethnic-matched controls. Eleven DNA sequence variants (DSVs), including four SNPs and seven new variants, within the GATA6 gene promoter were identified. Two heterozygous DSVs, g.22168361C>A and g.22169106C>T, were identified in two IIH patients, but in none of controls. In cultured human fibroblast, these DSVs significantly reduced the GATA6 gene promoter activities. In addition, three heterozygous DSVs were only found in three controls. Five DSVs, including four SNPs and one new variant, were found in both IIH patients and controls with similar frequencies. Therefore, the DSVs within the GATA6 gene promoter may contribute to the IIH development as a risk factor by changing the GATA6 levels. PMID- 24949534 TI - Understanding pathogenic Burkholderia glumae metabolic and signaling pathways within rice tissues through in vivo transcriptome analyses. AB - Burkholderia glumae is a causal agent of rice grain and sheath rot. Similar to other phytopathogens, B. glumae adapts well to the host environment and controls its biology to induce diseases in the host plant; however, its molecular mechanisms are not yet fully understood. To gain a better understating of the actual physiological changes that occur in B. glumae during infection, we analyzed B. glumae transcriptome from infected rice tissues using an RNA-seq technique. To accomplish this, we analyzed differentially expressed genes (DEGs) and identified 2653 transcripts that were significantly altered. We then performed KEGG pathway and module enrichment of the DEGs. Interestingly, most genes involved bacterial chemotaxis-mediated motility, ascorbate and trehalose metabolisms, and sugar transporters including l-arabinose and d-xylose were found to be highly enriched. The in vivo transcriptional profiling of pathogenic B. glumae will facilitate elucidation of unknown plant-pathogenic bacteria interactions, as well as the overall infection processes. PMID- 24949535 TI - Comparison of mechanical properties of beta-titanium wires between leveled and unleveled brackets: an in vitro study. AB - BACKGROUND: The objective of this study is to evaluate the force-deflection behavior of beta-titanium alloy wires between two leveled and unleveled bracket alignment scenarios using a three-point bending test. METHODS: Six groups of ten beta-titanium alloy wire segments (0.017 * 0.025-in. diameter) of different manufacturers (Orthometric, Ortho Organizers, GAC, Morelli, and Ormco) were used. Both brackets were bonded to an acrylic jig with a 10-mm interbracket distance. A 1-mm deflection test in two hypothetical conditions (with aligned brackets and by simulating a 2-mm horizontal displacement of the brackets) was explored. Forces of activation and deactivation of the wires during both tests were compared by an analysis of variance (ANOVA) tests followed by a Tukey test. RESULTS: A statistically significant difference was found in the force-deflection behavior between some of the wires in both simulated in vitro conditions. For the leveled type alignment scenario, the differences between wires were up to 70 g (range 110 to 179 g). For the unleveled-type alignment scenario, these differences were up to 65 g (range 111 to 175 g). CONCLUSIONS: The study showed some significant differences in forces generated during activation and deactivation among the five types of beta-titanium wires tested. In comparing leveled and unleveled brackets during activation, only Orthometric Beta Flexy and Ormco Beta-titanium were different between them. PMID- 24949536 TI - Effect of maternal intravenous fluid therapy on external cephalic version at term: a prospective cohort study. AB - OBJECTIVE: We sought to analyze whether maternal intravenous fluid therapy prior to external cephalic version (ECV) increases the amount of amniotic fluid and the success rate of the procedure. STUDY DESIGN: This was a prospective single-center cohort study of 200 women with a consecutive cohort of 100 pregnant women with a breech presentation at term who were administered intravenous fluid therapy with 2 L of hypotonic saline before the version attempt, compared to a control cohort of 100 pregnant women not given hydration treatment. RESULTS: The mean increase in the amniotic fluid index (AFI) after intravenous maternal hydration was 3.75 +/- 2.71 cm. The amount of fluid before hydration was the only variable found to be associated with increases in amniotic fluid levels, both in absolute and relative terms (odds ratio, -0.21; 95% confidence interval, -0.37 to -0.05 and odds ratio, -4.62; 95% confidence interval, -6.17 to -3.06; P < .01, respectively). We did not observe any severe complications secondary to the intravenous fluid therapy. The ECV success rate was 43% in the study group compared to 47% in the control group (P = .67). The success rate was significantly lower the larger the relative increase in the AFI, although no correlation was found in absolute terms (chi(2) for linear trend = 0.03 and 0.34, respectively). CONCLUSION: Maternal intravenous fluid therapy with 2 L of hypotonic saline prior to ECV is an effective and safe technique for increasing the AFI. However, its use in ECV does not increase the success rate of the procedure. PMID- 24949537 TI - Hydatidiform mole and subsequent pregnancy outcome: a population-based cohort study. AB - OBJECTIVE: The objective of the study was to investigate whether a history of hydatidiform mole (HM) is associated with an increased risk of adverse outcomes in subsequent pregnancies. STUDY DESIGN: This was a nationwide cohort study with data from population-based registers. The study population consisted of all children registered in the Swedish Medical Birth Register 1973-2009 (n = 3,730,825). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated for adverse maternal and offspring pregnancy outcomes by maternal history of HM prior to the delivery, with children to women with no maternal history of HM as the reference. Risk estimates were adjusted for maternal age at delivery and maternal country of birth. RESULTS: A history of HM was not associated with an increased risk of adverse maternal outcomes in subsequent pregnancies (n = 5186). Women exposed to a molar pregnancy prior to the index birth were at an almost 25% increased risk of preterm birth (OR, 1.23; 95% CI, 1.06-1.43), whereas women with at least 1 birth between the HM and the index birth were at an increased risk of a large-for-gestational-age birth and stillbirth (OR, 1.35; 95% CI, 1.10-1.67 and OR, 1.81; 95% CI, 1.11-2.96, respectively). The risk of repeat mole was 0.4%. CONCLUSION: Women with a history of HM are at no increased risk of adverse maternal outcomes in subsequent pregnancies but have an increased risk of large for-gestational-age birth, stillbirth, and preterm birth. However, in absolute terms, the risk of subsequent adverse offspring outcomes is very low. PMID- 24949538 TI - A population-based study of associations between preeclampsia and later cardiovascular risk factors. AB - OBJECTIVE: Women with a history of preeclampsia are at increased lifetime risk for cardiovascular disease. Their offspring may carry similar risks. The aim was to study cardiovascular and metabolic risk factors 11 years after the delivery among women who were diagnosed with mild, moderate, or severe preeclampsia, and their offspring, compared with women without preeclampsia and their offspring. STUDY DESIGN: In a follow-up 11 years after a nested case-control study at birth, we studied 611 mother-offspring dyads, including 228 dyads with preeclampsia in the index pregnancy and 383 dyads without preeclampsia. Cardiovascular and metabolic risk profiles were assessed by serum lipids (total cholesterol, high density lipoprotein [HDL] cholesterol, non-HDL cholesterol), insulin-related factors (glucose, insulin, and homeostasis assessment model for insulin resistance) and blood pressure in mothers and children. RESULTS: Among mothers with mild or moderate preeclampsia, levels of glucose, insulin, and homeostasis assessment model for insulin resistance were higher than in the nonpreeclampsia group and also higher compared with mothers with severe preeclampsia (all P < .05). HDL cholesterol was lower in mothers with mild or moderate preeclampsia (all P < .05), but other lipids did not substantially differ between the groups. Body mass index and blood pressure (systolic and diastolic) were also higher in the mild and moderate preeclampsia group compared with mothers without preeclampsia (all P < .05). Among the offspring, we found no clear differences in any blood analytes between the groups. CONCLUSION: Women with a previous diagnosis of mild or moderate, but not severe, preeclampsia may have an adverse metabolic and cardiovascular risk profile 11 years after the delivery. PMID- 24949539 TI - Resident participation in laparoscopic hysterectomy: impact of trainee involvement on operative times and surgical outcomes. AB - OBJECTIVE: The purpose of this study was to determine the impact of resident involvement on morbidity after total laparoscopic hysterectomy for benign disease. STUDY DESIGN: We performed a retrospective review of a National Surgical Quality Improvement Program database of total laparoscopic hysterectomy for benign disease that was performed with resident involvement vs attending alone between Jan. 1, 2008, and Dec. 31, 2011. Surgical operative times and morbidity and mortality rates were compared. Binary logistic regression was used to control for covariates that were significant on univariate analysis (P < .05). RESULTS: A total of 3441 patients were identified as having undergone a total laparoscopic hysterectomy for benign disease. The mean age of patients was 47.4 +/- 11.1 years; the mean body mass index was 30.6 +/- 7.9 kg/m(2). A resident participated in 1591 of cases (46.2%); 1850 of the procedures (53.8%) were done by an attending physician alone. Cases with resident involvement had higher mean age, Charlson morbidity scoring, and American Society of Anesthesiologists classification and were more likely to be inpatient cases. With resident involvement, the mean operative time was increased (179.29 vs 135.46 minutes; P < .0001). There were no differences in the rates of experiencing at least 1 complication (6.8% for resident involvement vs 5.4% for attending alone; P = .5), composite severe morbidity (1.3% resident vs 1.0% attending alone), or 30-day mortality rate (0% resident vs 0.1% attending alone). Additionally, there were no differences between groups in the infectious, wound, neurorenal, thromboembolic, septic, and cardiopulmonary complications. Cases with resident involvement had significantly increased rates of postoperative transfusion of packed red blood cells (2% vs 0.4%; P < .0001), reoperation (2.2% vs 1.3%; P = .048), and a 30-day readmission (5.5% vs 2.9%; P = .015). In models that were adjusted for factors that differed between the 2 groups, cases with resident involvement had increased odds of receiving postoperative blood transfusion (odds ratio [OR], 4.98; 95% confidence interval [CI], 2.18-11.33), reoperation (OR, 1.7, 95% CI, 1.01-2.89) and readmission (OR, 1.93, 95% CI, 1.09-3.42). CONCLUSION: Resident involvement in total laparoscopic hysterectomy for benign disease was associated with clinically appreciable longer surgical time and small differences in the rates of postoperative transfusions, reoperation, and readmission. However, the rates of overall complications, severe complications, and 30-day mortality rate remain comparable. PMID- 24949540 TI - Management of stage Ia1 squamous cervical cancer and the importance of excision margins: a retrospective study of long-term outcome after 25 years of follow-up. AB - OBJECTIVE: The aim of this study was to assess the effect of the excision margin after cone for stage Ia1 cervical cancer on long-term outcomes. STUDY DESIGN: Retrospective observational study. Patients were divided into 3 groups. Group A underwent immediate reflex hysterectomy; group B had cervical intraepithelial neoplasia (CIN) at the margins but were followed up; group C had clear margins. RESULTS: We identified 111 women: 19 (17.1%) in group A; 29 (26.1%) in group B; and 63 (56.8%) in group C. Women in group A were older (median, 40 years vs 35 years; P = .0001) with higher rate of endocervical margin involvement (89.5 vs 48.1%, P = .007) than in group B. The women had been followed for a total of 960 woman-years with median follow-up of 398 weeks (quartiles: 258,612). Women with clear margins in the initial excision were more likely to remain free of disease than those with involved (P < .0001). Further surgery was required due to abnormal cytology in 9 (31.0%) women from group B and 7 (11.1%) from group C (P = .04). The cumulative rate of recurrent CIN2+ was 6.4% in group B and 2.7% in group C (P = .17). In group B, recurrences were more common in positive endocervical rather than ectocervical margins (66.6% vs 33.4%, P < .05); all had high-grade CIN at the margins. CONCLUSION: The risk of posttreatment CIN2+ is substantially reduced when complete excision is achieved at first treatment. Conservative management is contraindicated in women with microinvasion at the margin. When CIN involves the margin, there is a greater risk of residual disease and of further treatment. PMID- 24949541 TI - Risk of selected structural abnormalities in infants after increased nuchal translucency measurement. AB - OBJECTIVE: We sought to examine the association between increased first-trimester fetal nuchal translucency (NT) measurement and major noncardiac structural birth defects in euploid infants. STUDY DESIGN: Included were 75,899 singleton infants without aneuploidy or critical congenital heart defects born in California in 2009 through 2010 with NT measured between 11-14 weeks of gestation. Logistic binomial regression was employed to estimate relative risks (RRs) and 95% confidence intervals (CIs) for occurrence of birth defects in infants with an increased NT measurement (by percentile at crown-rump length [CRL] and by >=3.5 mm compared to those with measurements <90th percentile for CRL). RESULTS: When considered by CRL adjusted percentile and by measurement >=3.5 mm, infants with a NT >=95th percentile were at risk of having >=1 major structural birth defects (any defect, RR, 1.6; 95% CI, 1.3-1.9; multiple defects, RR, 2.1; 95% CI, 1.3 3.4). Infants with a NT measurement >=95th percentile were at particularly high risk for pulmonary, gastrointestinal, genitourinary, and musculoskeletal anomalies (RR, 1.6-2.7; 95% CI, 1.1-5.4). CONCLUSION: Our findings demonstrate that risks of major pulmonary, gastrointestinal, genitourinary, and musculoskeletal structural birth defects exist for NT measurements >=95th percentile. The >=3-fold risks were observed for congenital hydrocephalus; agenesis, hypoplasia, and dysplasia of the lung; atresia and stenosis of the small intestine; osteodystrophies; and diaphragm anomalies. PMID- 24949542 TI - Neonatal encephalopathy and the association to asphyxia in labor. AB - OBJECTIVE: In cases with moderate and severe neonatal encephalopathy, we aimed to determine the proportion that was attributable to asphyxia during labor and to investigate the association between cardiotocographic (CTG) patterns and neonatal outcome. STUDY DESIGN: In a study population of 71,189 births from 2 Swedish university hospitals, 80 cases of neonatal encephalopathy were identified. Cases were categorized by admission CTG patterns (normal or abnormal) and by the presence of asphyxia (cord pH, <7.00; base deficit, >=12 mmol/L). Cases with normal admission CTG patterns and asphyxia at birth were considered to experience asphyxia related to labor. CTG patterns were assessed for the 2 hours preceding delivery. RESULTS: Admission CTG patterns were normal in 51 cases (64%) and abnormal in 29 cases (36%). The rate of cases attributable to asphyxia (ie, hypoxic ischemic encephalopathy) was 48 of 80 cases (60%), most of which evolved during labor (43/80 cases; 54%). Both severe neonatal encephalopathy and neonatal death were more frequent with an abnormal, rather than with a normal, admission CTG pattern (13 [45%] vs 11 [22%]; P = .03), and 6 [21%] vs 3 [6%]; P = .04), respectively. Comparison of cases with an abnormal and a normal admission CTG pattern also revealed more frequently observed decreased variability (12 [60%] and 8 [22%], respectively) and more late decelerations (8 [40%] and 1 [3%], respectively). CONCLUSION: Moderate and severe encephalopathy is attributable to asphyxia in 60% of cases, most of which evolve during labor. An abnormal admission CTG pattern indicates a poorer neonatal outcome and more often is associated with pathologic CTG patterns preceding delivery. PMID- 24949543 TI - Interpreting category II fetal heart rate tracings: does meconium matter? AB - OBJECTIVE: Category II fetal heart rate (FHR) tracings are considered indeterminate; thus, improved risk stratification of category II FHR tracings is needed. We estimated whether the presence of meconium increased the risk of adverse neonatal outcomes. STUDY DESIGN: This study was conducted within a prospective cohort of 5000 women with singleton pregnancies who were admitted in labor at term. Pregnancies with category II FHR in the 60 minutes before delivery were included. FHR data were extracted by trained nurses who were blinded to clinical outcome. The exposure was the presence of meconium. The primary outcome was a composite neonatal morbidity defined as >=1 of the following: neonatal death, neurologic morbidity, respiratory morbidity, hypotension that required treatment, and sepsis. Secondary outcomes were nursery admission, cord pH, 5 minute Apgar score, and components of the composite. Logistic regression was used to adjust for confounders. RESULTS: Of the 3257 women with category II FHR tracings, 693 women (21.3%) had meconium, and 2564 women (78.7%) did not. Meconium was associated with higher risk of the composite morbidity (adjusted odds ratio, 2.49; 95% confidence interval, 1.78-3.48) and increased risks of the secondary outcomes. The associations remained significant when infants with meconium aspiration syndrome were excluded. Thick meconium was associated significantly with the composite morbidity. CONCLUSION: The presence of meconium is associated with an increased risk of neonatal morbidity in women with category II FHR pattern. This clinical factor may assist clinicians in managing category II FHR patterns in labor. PMID- 24949545 TI - Nomogram to predict recurrence in patients with early- and advanced-stage mucinous and serous borderline ovarian tumors. AB - OBJECTIVE: Recurrence prediction is a cornerstone of patient management for borderline ovarian tumors. This study aimed to develop a nomogram predicting the recurrence probability in individual patients who had received primary surgical treatment. STUDY DESIGN: This retrospective multicenter study included 186 patients with borderline ovarian tumor diagnosed from January 1980 through December 2008. A multivariate logistic regression analysis of selected prognostic features was performed and a nomogram to predict recurrence was constructed. The nomogram was internally validated. RESULTS: The overall recurrence rate was 34.4% (64/186), with noninvasive and invasive forms in 29% (54/186) and 5.4% (10/186) of cases, respectively. International Federation of Gynecology and Obstetrics stage, age at diagnosis, histologic subtype, completeness of surgery, and type of surgery (radical vs fertility sparing) were associated with an increased risk of recurrence and were included in the nomogram. The predictive model had a concordance index of 0.78 (95% confidence interval, 0.76-0.80) and 0.77 (95% confidence interval, 0.75-0.79) before and after the 200 repetitions of bootstrap sample corrections, respectively, and showed good calibration. CONCLUSION: Our results support the use of the present nomogram based on 5 clinical and pathological characteristics to predict recurrence probability with a high concordance, hence to inform patients on surgical management. External validation is required to recommend this nomogram in routine practice. PMID- 24949544 TI - A blinded, randomized controlled trial of high-dose vitamin D supplementation to reduce recurrence of bacterial vaginosis. AB - OBJECTIVE: Low serum vitamin D levels have been associated with increased prevalence of the reproductive tract condition bacterial vaginosis (BV). The objective of this trial was to evaluate the effect of high-dose vitamin D supplementation on BV recurrence. STUDY DESIGN: This randomized, placebo controlled, double-blinded trial enrolled 118 women with symptomatic BV from an urban sexually transmitted disease clinic (clinicaltrials.gov registration NCT01450462). All participants received 500 mg of oral metronidazole twice daily for 7 days. Intervention participants (n = 59) also received 9 doses of 50,000 IU of cholecalciferol (vitamin D3) over 24 weeks; control women (n = 59) received matching placebo. Recurrent BV was assessed via Nugent scoring after 4, 12, and 24 weeks. We assessed the effect of the intervention using an intention-to-treat approach, fitting Cox proportional hazards models to evaluate recurrent BV over the follow-up period. RESULTS: Most participants (74%) were black, with a median age of 26 years. Median presupplementation serum 25-hydroxyvitamin D [25(OH)D] was similar across randomization arms: 16.6 ng/mL in the vitamin D arm and 15.8 ng/mL in the control arm. At trial completion, median 25(OH)D among women receiving vitamin D was 30.5 ng/mL, vs 17.8 ng/mL in control women; 16% of women receiving vitamin D and 57% receiving placebo remained vitamin D deficient (<20 ng/mL). BV prevalence among women randomized to vitamin D was very similar to those randomized to placebo at the 4- and 12-week visits, but by the 24-week visit, BV prevalence was 65% among women in the vitamin D arm and 48% among control women. BV recurrence was not reduced by vitamin D supplementation (intention-to-treat hazard ratio, 1.11; 95% confidence interval, 0.68-1.81). Among women experiencing recurrent BV, median time to recurrence was 13.7 weeks in the vitamin D arm and 14.3 weeks in the control arm. CONCLUSION: Women receiving vitamin D experienced significant increases in serum 25(OH)D, but this increase was not associated with decreased BV recurrence in this high-risk sexually transmitted disease clinic population. PMID- 24949546 TI - Does pregnancy and/or shifting positions create more room in a woman's pelvis? AB - OBJECTIVE: The purpose of this study was to assess the impact of different positions on pelvic diameters by comparing pregnant and nonpregnant women who assumed a dorsal supine and kneeling squat position. STUDY DESIGN: In this cohort study from a tertiary referral center in Germany, we enrolled 50 pregnant women and 50 nonpregnant women. Pelvic measurements were obtained with obstetric magnetic resonance imaging pelvimetry with the use of a 1.5-T scanner. We compared measurements of the depth (anteroposterior (AP) and width (transverse diameters) of the pelvis between the 2 positions. RESULTS: The most striking finding was a significant 0.9-1.9 cm increase (7-15%) in the average transverse diameters in the kneeling squat position in both pregnant and nonpregnant groups. The average bispinous diameter in the pregnant group increased from 12.6 cm +/- 0.65 cm in the supine dorsal to 14.5 cm +/- 0.64 cm (P < .0001) in the kneeling squat; in the nonpregnant group the increase was from 12 cm +/- 0.76 cm to 13.9 cm +/- 1.04 cm (P < .0001). The average bituberous diameter in the pregnant group increased from 13.6 cm +/- 0.93 cm in the supine dorsal to 14.5 cm +/- 0.83 cm (P < .0001) in the kneeling squat position; in the nonpregnant women the increase was from 12.6 cm +/- 0.92 cm to 13.5 cm +/- 0.88 cm (P < .0001). CONCLUSION: A kneeling squat position significantly increases the bony transverse and anteroposterior dimension in the mid pelvic plane and the pelvic outlet. Because this indicates that pelvic diameters change when women change positions, the potential for facilitation of delivery of the fetal head suggests further research that will compare maternal delivery positions is warranted. PMID- 24949547 TI - Inclusion of pork meat in the diets of young women reduces their intakes of energy-dense, nutrient-poor foods: results from a randomized controlled trial. AB - Adherence of young women to dietary recommendations has been examined predominantly by surveys. This study aimed to determine the quality of women's diets relative to the Australian Guide to Healthy Eating (AGHE); and to evaluate dietary changes during an intervention trial with pork meat or an iron supplement. A 12-week randomized trial was conducted in young women who were assigned to one of three groups. They maintained three, seven-day food diaries while continuing their routine diet (CG); taking an iron supplement (SG); or incorporating into their diets 500 g/week of pork (PG). Participants (n = 58) provided dietary information on 1218 diary-days. The serves consumed from the vegetable, fruit and dairy groups were lower (p < 0.001), and from the meat and alternatives group greater (p < 0.001) than the recommended serves. PG consumed significantly fewer (p < 0.001) serves of "extra" foods, and ate fruit more frequently (p < 0.001) than CG and SG. The participants' dietary self-assessment showed poor agreement with the AGHE description of "serve". The inclusion of pork in the diets of young women is associated with the reduced consumption of energy dense nutrient-poor "extra" foods and increased frequency of fruit intake. The effect may be explained by diverse factors such as increased food knowledge, cooking skills and the effect of pork on satiety. PMID- 24949548 TI - Development and pilot testing of 24-hour multiple-pass recall to assess dietary intake of toddlers of Somali- and Iraqi-born mothers living in Norway. AB - The aim of this study was to develop, test, and evaluate a 24-h recall procedure to assess the dietary intake of toddlers of Somali- and Iraqi-born mothers living in Norway. A protocol for a 24-h multiple-pass recall procedure, registration forms, and visual tools (a picture library for food identification and portion size estimation) was developed and tested in 12 mothers from Somalia and Iraq with children aged 10-21 months. Five female field workers were recruited and trained to conduct the interviews. Evaluation data for the 24-h recall procedure were collected from both the mothers and the field workers. Nutrient intake was calculated using a Norwegian dietary calculation system. Each child's estimated energy intake was compared with its estimated energy requirement. Both the mothers and the field workers found the method feasible and the visual tools useful. The estimated energy intake corresponded well with the estimated energy requirement for most of the children (within mean +/- 2 SD, except for three). The pilot study identified the need for additional foods in the picture library and some crucial aspects in training and supervising the field workers to reduce sources of error in the data collection. PMID- 24949549 TI - Dietary supplementation with a superoxide dismutase-melon concentrate reduces stress, physical and mental fatigue in healthy people: a randomised, double blind, placebo-controlled trial. AB - BACKGROUND: We aimed to investigate effects of superoxide dismutase (SOD)-melon concentrate supplementation on psychological stress, physical and mental fatigue in healthy people. METHODS: A randomized, double-blind, placebo-controlled trial was performed on 61 people divided in two groups: active supplement (n = 32) and placebo (n = 29) for 12 weeks. Volunteers were given one small hard capsule per day. One capsule contained 10 mg of SOD-melon concentrate (140 U of SOD) and starch for the active supplement and starch only for the placebo. Stress and fatigue were evaluated using four psychometric scales: PSS-14; SF-36; Stroop tests and Prevost scale. RESULTS: The supplementation with SOD-melon concentrate significantly decreased perceived stress, compared to placebo. Moreover, quality of life was improved and physical and mental fatigue were reduced with SOD-melon concentrate supplementation. CONCLUSION: SOD-melon concentrate supplementation appears to be an effective and natural way to reduce stress and fatigue. TRIAL REGISTRATION: trial approved by the ethical committee of Poitiers (France), and the ClinicalTrials.gov Identifier is NCT01767922. PMID- 24949550 TI - Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model. AB - Androgens are key factors involved in the development and progression of prostate cancer (PCa), and PCa growth can be suppressed by androgen deprivation therapy. In a considerable proportion of men receiving androgen deprivation therapy, however, PCa progresses to castration-resistant PCa (CRPC), making the development of efficient therapies challenging. We used an orthotopic VCaP human PCa xenograft model to study cellular and molecular changes in tumors after androgen deprivation therapy (castration). Tumor growth was monitored through weekly serum prostate-specific antigen measurements, and mice with recurrent tumors after castration were randomized to treatment groups. Serum prostate specific antigen concentrations showed significant correlation with tumor volume. Castration-resistant tumors retained concentrations of intratumoral androgen (androstenedione, testosterone, and 5alpha-dihydrotestosterone) at levels similar to tumors growing in intact hosts. Accordingly, castration induced up-regulation of enzymes involved in androgen synthesis (CYP17A1, AKR1C3, and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration resistant xenografts. The AR antagonists enzalutamide (MDV3100) and ARN-509 suppressed PSA production of castration-resistant tumors, confirming the androgen dependency of these tumors. Taken together, the findings demonstrate that our VCaP xenograft model exhibits the key characteristics of clinical CRPC and thus provides a valuable tool for identifying druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC. PMID- 24949551 TI - Rational improvement of the affinity and selectivity of integrin binding of grafted lasso peptides. AB - Integrins moderate diverse important functions in the human body and are promising targets in cancer therapy. Hence, the selective inhibition of specific integrins is of great medicinal interest. Here, we report the optimization of a grafted lasso peptide, yielding MccJ25(RGDF), which is a highly potent and selective alphavbeta3 integrin inhibitor. Furthermore, its NMR structure was elucidated and employed in a molecular dynamics approach, revealing information about the integrin binding mode and selectivity profile of MccJ25(RGDF). PMID- 24949552 TI - Interindividual variation in response to xenobiotic exposure established in precision-cut human liver slices. AB - Large differences in toxicity responses occur within the human population. In this study we evaluate whether interindividual variation in baseline enzyme activity (EA)/gene expression (GE) levels in liver predispose for the variation in toxicity responses by assessing dose-response relationships for several prototypical hepatotoxicants. Baseline levels of cytochrome-P450 (CYP) GE/EA were measured in precision-cut human liver slices. Slices (n=4-5/compound) were exposed to a dose-range of acetaminophen, aflatoxin B1, benzo(alpha) pyrene or 2 nitrofluorene. Interindividual variation in induced genotoxicity (COMET-assay and CDKN1A/p21 GE) and cytotoxicity (lactate dehydrogenase-leakage), combined with NQO1- and GSTM1-induced GE-responses for oxidative stress and GE-responses of several CYPs was evaluated. The benchmark dose-approach was applied as a tool to model exposure responses on an individual level. Variation in baseline CYP levels, both GE and EA, can explain variation in compound exposure-responses on an individual level. Network analyses enable the definition of key parameters influencing interindividual variation after compound exposure. For 2 nitrofluorene, this analysis suggests involvement of CYP1B1 in the metabolism of this compound, which represents a novel finding. In this study, GSTM1 which is known to be highly polymorphic within the human population, but so far could not be linked to toxicity in acetaminophen-poisoned patients, is suggested to cause interindividual variability in acetaminophen-metabolism, dependent on the individual's gene expression-responses of CYP-enzymes. This study demonstrates that using interindividual variation within network modelling provides a source for the definition of essential and even new parameters involved in compound related metabolism. This information might enable ways to make more quantitative estimates of human risks. PMID- 24949553 TI - Personal semantic memory: insights from neuropsychological research on amnesia. AB - This paper provides insight into the cognitive and neural mechanisms of personal semantic memory, knowledge that is specific and unique to individuals, by reviewing neuropsychological research on stable amnesia secondary to medial temporal lobe damage. The results reveal that personal semantic memory does not depend on a unitary set of cognitive and neural mechanisms. Findings show that autobiographical fact knowledge reflects an experience-near type of personal semantic memory that relies on the medial temporal lobe for retrieval, albeit less so than personal episodic memory. Additional evidence demonstrates that new autobiographical fact learning likely relies on the medial temporal lobe, but the extent to which remains unclear. Other findings show that retrieval of personal traits/roles and new learning of personal traits/roles and thoughts/beliefs are independent of the medial temporal lobe and thus may represent highly conceptual types of personal semantic memory that are stored in the neocortex. PMID- 24949554 TI - The posterior parietal cortex: comparing remember/know and source memory tests of recollection and familiarity. AB - Numerous neuroimaging studies have shown a dissociation within the left posterior parietal cortex (PPC) between recollection and familiarity, with dorsal regions routinely active during familiarity and ventral regions active during recollection. The two most common methods for separating the neural correlates of these retrieval states are the remember/know paradigm and tests probing source memory. While relatively converging results have been found using these methods, the literature is lacking an adequate and direct comparison of the two procedures. We directly compared these two methodologies and found differences in both the magnitude and extent of activation within the left PPC. During familiarity, dorsal PPC regions were more strongly activated by the source test, while the remember/know test led to stronger recollection-related activations within the ventral regions of the PPC. This modulation of PPC activity is particularly important because it suggests that the neural correlates of familiarity and recollection depend on how they are operationalized. Previous assumptions that remember/know and source memory tests are functionally equivalent should therefore be re-evaluated. Additionally, any theories attempting to explain the functional role of the PPC during memory retrieval must take these differences into account. PMID- 24949555 TI - Visual areas PPA and pSTS diverge from other processing modules during perceptual closure: functional dichotomies within category selective networks. AB - The nature of neural processing within category-preferring visual networks remains an open topic in human neuroscience. Although the topography of face, scene, and object-preferring modules in the human brain is well established, the functional characterization, in terms of dynamic selectivity across their nodes is still elusive. Here, we use long trials of perceptually impoverished images of faces and objects to assess the dynamics of BOLD activity and selectivity induced by perceptual closure within these regions of interest. Departing from paradigms involving immediate percepts, we used ambiguous images favoring holistic search and independence from low level stimulus properties. By assessing the neural responses to images that go beyond the preferred category of the studied ROIs we could dissect the specificity of these processes as a function of the timing of perceptual closure and contribute to the debate regarding specialization of these modules. We found that pSTS is a notable exception to the observation that category selective high-level visual areas also participate on the perceptual closure of their non-preferred category. A similar observation was found for PPA responses to faces. Most importantly, these observations directly link the pSTS region with the social processing network, which cannot be engaged by object stimuli. PMID- 24949556 TI - Activation of alpha7nAChR by nicotine reduced the Th17 response in CD4(+)T lymphocytes. AB - BACKGROUND: nAChRs play an important role in the regulation and modulation of immune cell proliferation, differentiation, migration and cell-cell interactions. The present study was to characterize the expression of alpha7nAChR on human peripheral blood mononuclear cells (hPBMC) and CD4(+)T lymphocytes, and to explore the change of Th17 expression after activation of alpha7nAChR on human CD4(+)T lymphocytes. METHODS: A Ficoll gradient was used to separate hPBMC from whole blood, and then CD4(+)T lymphocytes were isolated by magnetic bead separation. The expression of alpha7nAChR on PBMC and CD4(+)T lymphocytes was analyzed using flow cytometry before and after stimulation with phytohemagglutinin (PHA). The effect of alpha7nAChR stimulation by nicotine or inhibition by alpha-bungarotoxin (alpha-BTX), as well as Th17 expression on the phenotype of CD4(+)T cells was evaluated using flow cytometric analysis. RESULTS: The percentage of CD4(+)T cells in reduced PBMC, while the expression of alpha7nAChR increased when cells were stimulated by nicotine. This effect vanished when co-treated with nicotine and alpha-BTX. alpha7nAChR was found to expressed in about 90% of CD4(+)T cells. However, alpha7nAChR expression reduced to 80% on CD4(+)T cells after stimulation with PHA for 24 h. Stimulation of alpha7nAChR with nicotine increased the expression of Th17 cells, and this upregulation reduced when AChRalpha7 was inhibited by alpha-BTX. CONCLUSION: alpha7nAChR was ubiquitously expressed by CD4(+)T lymphocytes, which was correlated with the cell activation status. Meanwhile, activation of nAChRalpha7 by nicotine in CD4 cells reduced the Th17 response. PMID- 24949557 TI - Comparison of automated home-cage monitoring systems: emphasis on feeding behaviour, activity and spatial learning following pharmacological interventions. AB - BACKGROUND: Different automated systems have been developed to facilitate long term and continuous assessment of behaviours including locomotor activity, feeding behaviour and circadian activity. NEW METHOD: This study assessed the effectiveness of three different observation systems as methods for determining strain and pharmacological induced differences in locomotor activity, feeding behaviour and spatial learning. The effect of the CB1 antagonist AM251 on feeding behaviour was determined in the PhenoMaster and PhenoTyper. Next, effects of cholinergic (scopolamine) and glutamatergic (Phenylcyclidine, PCP) receptor antagonism and dopaminergic agonism (apomorphine) on activity were assessed in the PhenoTyper and IntelliCage. Finally, the IntelliCage was utilised to determine differences in activity and spatial learning of C57BL/6 and DBA/2 mouse strains following pharmacological intervention. RESULTS: AM251 induced a suppression of food intake, feeding behaviour and a reduction in body weight in both the PhenoTyper and PhenoMaster. Apomorphine reduced activity in both the PhenoTyper and IntelliCage. Whereas, decreased activity was evident with PCP in the PhenoTyper, but not IntelliCage and Scopolamine induced a trend towards elevated levels of activity in the IntelliCage but not PhenoTyper. Strain differences in activity and spatial learning were also evident, with increased corner visits and drug induced impairments only observed with C57BL/6 mice. COMPARISON WITH EXISTING METHOD: The automated home cage observation systems determined similar drug and strain effects on behaviour to those observed using traditional methods. CONCLUSIONS: All three observation systems reported drug induced changes in behaviour however, they differ in their application of spatial learning tasks and utilisation of single versus group housed recordings. PMID- 24949558 TI - Detection of motor imagery of brisk walking from electroencephalogram. AB - Rehabilitation of lower limbs is equally as important as that of upper limbs. This paper presented a study to detect motor imagery of walking (MI-Walking) from background idle state. Broad overlapping neuronal networks involved in reorganization following motor imagery introduce redundancy. We hypothesized that MI-Walking could be robustly detected by constraining dependency among selected features and class separations. Hence, we proposed to jointly select channels and frequency bands involved in MI-Walking by optimizing/regularizing the objective function formulated on the dependency between features and class labels, redundancy between to-be-selected with selected features, and separations between classes, namely, "regularized maximum dependency with minimum redundancy-based joint channel and frequency band selection (RMDR-JCFS)". Evaluated on electroencephalography (EEG) data of 11 healthy subjects, the results showed that the selected channels were mainly located at premotor cortex, mid-central area overlaying supplementary motor area (SMA), prefrontal cortex, foot area sensory cortex and leg and arm sensorimotor representation area. Broad frequencies of alpha, mu and beta rhythms were involved. Our proposed method yielded an averaged accuracy of 76.67%, which was 9.08%, 5.03%, 7.03%, 14.15% and 3.88% higher than that obtained by common spatial pattern (CSP), filter-bank CSP, sliding window discriminate CSP, filter-bank power and maximum dependency and minimum redundancy methods, respectively. Further, our method yielded significantly superior performance compared with other channel selection methods, and it yielded an averaged session-to-session accuracy of 70.14%. These results demonstrated the potentials of detecting MI-Walking using proposed method for stroke rehabilitation. PMID- 24949559 TI - Comparison of QoL-AD and DQoL in elderly with Alzheimer's disease. AB - OBJECTIVE: The Dementia Quality of Life (DQoL) and the Quality of Life in Alzheimer's Disease (QoL-AD) are the two most widely used dementia-specific QoL instruments in the world. We aimed to compare the psychometric properties of these two instruments and identify which is most adapted to use in geriatric consultations. METHODS: To evaluate the psychometric properties of the French language validation of DQoL and QoL-AD, 123 patients aged 65 years and over suffering from AD (Mini Mental State Examination score >=10) were recruited in seven French hospitals and one Switzerland hospital. The DQoL comprises 29 items, ranked on a five-point Likert scale and measuring five QoL domains: self-esteem, positive affect, negative affect, feeling of belonging and sense of aesthetics. The QoL-AD contains 13 items giving an overall score ranging from 13 to 52 and evaluating the domains of interpersonal relationships, financial difficulties, physical condition, memory, mood and overall health. RESULTS: Both questionnaires showed adequate reproducibility at 2 weeks interval (intra-class correlation coefficient >0.80), good internal consistency (Cronbach's alpha coefficient >0.70) and good convergent validity with the general health dimension of the Duke Health Profile. The time required to complete the QoL-AD was significantly shorter (p < 0.0001). DQoL had better discriminant capacity (with at least one dimension significant for each subgroup of severity of cognitive decline, dependency, presence of depression or behavioural disorders). CONCLUSIONS: For quick evaluation of QoL during consultations in geriatric care, the QoL-AD is preferable, whereas for the purposes of research and more in-depth evaluation, the DQoL is more suitable. PMID- 24949560 TI - Unconventional protein secretion (UPS) pathways in plants. AB - As in yeast and mammalian cells, novel unconventional protein secretion (UPS) or unconventional membrane trafficking pathways are now known to operate in plants. UPS in plants is generally associated with stress conditions such as pathogen attack, but little is known about its underlying mechanism and function. Here, we present an update on the current knowledge of UPS in the plants in terms of its transport pathways, possible functions and its relationship to autophagy. PMID- 24949561 TI - Forensic aspect of cremations on wooden pyre. AB - Three cases of cremation on open-air pyres are described. One was classified as a suicide and two as homicides. Fire duration was estimated at approximately 1 h, close to 2 h and more than 3 h, respectively. The position of the remains, the colour alteration of bone and the burned bone fractures biomechanics are discussed. Knowledge of normal burn patterns in fire and detection of perimortem lesions are essential. These three cases highlight the specific thermal alterations and burning processes in accordance with fire duration. In each case, careful investigation yielded clues as to the manner of death. Close cooperation between law enforcement and forensic pathology investigators is required in order to correctly identify the circumstances of death. PMID- 24949562 TI - Altered discharges of spinal neurons parallel the behavioral phenotype shown by rats with bortezomib related chemotherapy induced peripheral neuropathy. AB - Bortezomib is a first generation proteasome inhibitor that is the frontline chemotherapy for multiple myeloma with the chief dose-limiting side effect of painful peripheral neuropathy. The goal of this study was to define the behavioral phenotype in a preclinical model of bortezomib chemotherapy-induced peripheral neuropathy (CIPN) and to test whether this is matched by changes in the physiological responses of spinal wide dynamic range neurons. Sprague-Dawley rats were treated with four injections of bortezomib at four doses, 0.05mg/kg, 0.10mg/kg, 0.15mg/kg, 0.20mg/kg, or equal volume of saline. All doses of bortezomib above 0.05mg/kg produced showed significant dose-dependent mechanical hyperalgesia that was fully established at 30 days after treatment and that recovered to baseline levels by day 69 after treatment. Thermal, cold, and motor testing were all unaffected by treatment with bortezomib. Spinal wide dynamic range (WDR) neurons in rats with confirmed bortzomib-related CIPN showed an increase in number of evoked discharges to mechanical stimuli and exaggerated after-discharges in rats with bortezomib CIPN. PMID- 24949563 TI - YAC128 Huntington's disease transgenic mice show enhanced short-term hippocampal synaptic plasticity early in the course of the disease. AB - Huntington's disease (HD) is a progressive and fatal neurodegenerative disorder caused by a polyglutamine expansion in the gene encoding the protein huntingtin. The disease progresses over decades, but often patients develop cognitive impairments that precede the onset of the classical motor symptoms. Similar to the disease progression in humans, the yeast artificial chromosome (YAC) 128 HD mouse model also exhibits cognitive dysfunction that precedes the onset of the neuropathological and motor impairments characteristic of HD. Thus, the purpose of this study was to evaluate whether short- and long-term synaptic plasticity in the hippocampus, two related biological models of learning and memory processes, were altered in YAC128 mice in early stages of disease progression. We show that the YAC128 hippocampal dentate gyrus (DG) displays marked reductions in paired pulse depression both at 3 and 6 months of age. In addition, significantly enhanced post-tetanic and short-term potentiation are apparent in YAC128 mice after high-frequency stimulation at this time. Early and late forms of long-term plasticity were not altered at this stage. Together these findings indicate that there may be elevated neurotransmitter release in response to synaptic stimulation in YAC128 mice during the initial phase of disease progression. These abnormalities in short-term plasticity detected at this stage in YAC128 HD transgenic mice indicate that aberrant information processing at the level of the synapses may contribute, at least in part, to the early onset of cognitive deficits that are characteristic of this devastating neurodegenerative disorder. PMID- 24949565 TI - Fascia iliaca compartment block for hip fractures: experience of integrating a new protocol across two hospital sites. AB - OBJECTIVE: Fascia iliaca compartment block (FICB) administered through the loss of resistance technique effectively reduces pain and opiate requirement in elderly patients with hip fractures. FICB is a simple technique and is easily taught. This paper plots the implementation of FICB in two hospitals. METHODS: A continuous audit process of two separate sites recorded the uptake of the FICB on an organizational level. An additional control group (CG) of 100 patients were analysed to compare pain scores (using the Numerical Rating Scale) and opiate requirements between groups of patients receiving fascia iliaca block and those receiving standard care. Documentation habits and adverse drug reactions were monitored over the audit process. RESULTS: There were 434 patients audited, with 326 (75.1%) receiving the FICB. The uptake of the FICB and documentation improved over time. The FICB significantly reduced pain scores (P<0.001) and also opiate requirement (P<0.0001) compared with those in the CG. Acute length of stay reduced to 9.9 days (FICB group) from 15 days (CG). Inpatient mortality was 5.5% in the FICB group and 15% in the CG (P=0.0024). CONCLUSION: Organizational learning of this simple procedure can be achieved through a multidisciplinary approach, and committed departmental education and feedback. The impact on length of stay and mortality were striking; however, there may be other confounding factors. Only two cases of true anaesthetic toxicity occurred in 1586 patients. The authors conclude that FICB is a safe procedure and a useful adjunct for preoperative pain control in patients with hip fractures. PMID- 24949564 TI - Varenicline, naltrexone, and their combination for heavy-drinking smokers: preliminary neuroimaging findings. AB - RATIONALE: Heavy drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available. OBJECTIVE: The present study used a double-blind, randomized, 2 * 2 medication design, testing varenicline alone (VAR; 1 mg twice daily), naltrexone alone (NTX; 25 mg once daily), varenicline plus naltrexone, and placebo for effects on neural activation to cigarette cues in a sample (n = 40) of heavy drinking daily smokers (>=10 cigarettes/day). METHODS: All participants were tested after a 10-12-day titration period designed to reach steady state on the target medication. Participants underwent functional neuroimaging (fMRI) for examination of brain responses to visual smoking-related (vs. neutral) cues. RESULTS: Region of interest (ROI) analyses of brain responses to Cigarette vs. Neutral Cues indicated that the combination of VAR + NTX was associated with reduced activation of the bilateral anterior cingulate cortex as compared to placebo and to NTX alone. Exploratory whole-brain analyses also indicated significant differences in brain activation during cigarette cues in the active medications versus placebo condition. All medications suppressed left nucleus accumbens activation relative to placebo, suggesting the possibility that both medications, either alone or in combination, reduce neural signals associated with appetitive behavior. CONCLUSIONS: Although preliminary, these neuroimaging findings indicate that clinical studies of the combination of VAR + NTX for heavy drinkers trying to quit smoking may be warranted. PMID- 24949567 TI - The portion size effect on food intake. An anchoring and adjustment process? AB - People consistently over-eat when served a large compared with a small (appropriate) portion of food. However, the mechanism underlying this so-called portion size effect is not well understood. We argue that the process of anchoring and adjustment naturally describes this effect, such that the size of a presented portion works as an anchor that strongly influences consumption. The classical anchoring and adjustment paradigm was applied to six hypothetical eating situations. Participants were asked to imagine being served either a small or a large portion of food (i.e., low and high anchor) and to indicate whether they would consume more or less than this amount. Then, they indicated how much they would eat. These estimates were compared with a no-anchor condition where participants did not imagine a specific portion size but only indicated how much they would eat. In addition, half of participants in the anchoring conditions received a discounting instruction stating that the portion size they had been asked to imagine was randomly selected and thus not informative for their consumption estimate. As expected, participants who imagined to be served larger portions estimated to consume significantly more food than participants in the no anchor condition, and participants who imagined to be served smaller portions estimated to consume significantly less food than participants in the no-anchor condition. The discounting manipulation did not reduce this effect of the anchors. We suggest that the process of anchoring and adjustment may provide a useful framework to understand the portion size effect and we discuss implications of this perspective. PMID- 24949566 TI - Inhibitory control effects in adolescent binge eating and consumption of sugar sweetened beverages and snacks. AB - Inhibitory control and sensitivity to reward are relevant to the food choices individuals make frequently. An imbalance of these systems can lead to deficits in decision-making that are relevant to food ingestion. This study evaluated the relationship between dietary behaviors - binge eating and consumption of sweetened beverages and snacks - and behavioral control processes among 198 adolescents, ages 14 to 17. Neurocognitive control processes were assessed with the Iowa Gambling Task (IGT), a generic Go/No-Go task, and a food-specific Go/No Go task. The food-specific version directly ties the task to food cues that trigger responses, addressing an integral link between cue-habit processes. Diet was assessed with self-administered food frequency and binge eating questionnaires. Latent variable models revealed marked gender differences. Inhibitory problems on the food-specific and generic Go/No-Go tasks were significantly correlated with binge eating only in females, whereas inhibitory problems measured with these tasks were the strongest correlates of sweet snack consumption in males. Higher BMI percentile and sedentary behavior also predicted binge eating in females and sweet snack consumption in males. Inhibitory problems on the generic Go/No-Go, poorer affective decision-making on the IGT, and sedentary behavior were associated with sweetened beverage consumption in males, but not females. The food-specific Go/No-Go was not predictive in models evaluating sweetened beverage consumption, providing some initial discriminant validity for the task, which consisted of sweet/fatty snacks as no-go signals and no sugar-sweetened beverage signals. This work extends research findings, revealing gender differences in inhibitory function relevant to behavioral control. Further, the findings contribute to research implicating the relevance of cues in habitual behaviors and their relationship to snack food consumption in an understudied population of diverse adolescents not receiving treatment for eating disorders. PMID- 24949569 TI - Effect of environmental cues on the behavioral efficacy of haloperidol, olanzapine, and clozapine in rats. AB - Previous studies have reported that context can powerfully modulate the inhibitory effect of an antipsychotic drug on phencyclidine (PCP)-induced hyperlocomotion (a behavioral test used to evaluate putative antipsychotic drugs). The present study investigated the experimental conditions under which environmental stimuli exert their influence through associative conditioning processes. Experiment 1 examined the extent to which previous antipsychotic treatment in the home cages affected a drug's ability to inhibit PCP-induced hyperlocomotion in novel motor activity test apparatus. Five days of repeated haloperidol (0.05 mg/kg, subcutaneously) and olanzapine (2.0 mg/kg, subcutaneously) treatment in the home cages still potentiated their inhibition of PCP-induced hyperlocomotion (i.e. sensitization) assessed in a new environment, whereas the clozapine (10.0 mg/kg, subcutaneously) treatment enhanced the development of clozapine tolerance, indicating a lack of environmental modulation of antipsychotic efficacy. Experiment 2 assessed the impact of different numbers of antipsychotic administrations (e.g. 4, 2 or 0), in either the home environment or test environment, on a drug's ability to inhibit PCP-induced hyperlocomotion. Repeated administration of clozapine (5.0 mg/kg, subcutaneously) or olanzapine (1.0 mg/kg, subcutaneously) for 4 consecutive days, irrespective of where these treatments occurred, led to a similar level of inhibition of PCP-induced hyperlocomotion. However, 4-day haloperidol (0.03 mg/kg, subcutaneously) treatment in the test apparatus led to significantly higher inhibition than a 4 day home-cage treatment. Thus, more exposures to the test environment under the influence of haloperidol (but not clozapine or olanzapine) caused a stronger inhibition than fewer exposures, indicating a strong environmental modulation. Collectively, these findings suggest that previous antipsychotic treatment in one environment could alter later antipsychotic-like response assessed in a different environment under certain test conditions. Therefore, whether the circumstances surrounding antipsychotic drug administration have a powerful effect on the expression of antipsychotic-like efficacy is dependent on specific experimental and drug treatment factors. PMID- 24949570 TI - Effects of chronic mild stress on the development of drug dependence in rats. AB - There is high comorbidity between depression and addiction. Features of addiction relevant to depression have been studied extensively, but less is known about features of depression relevant to addiction. Here, we have studied the effects of chronic mild stress (CMS), a valid animal model of depression, on measures of physical and psychological dependence resulting from subchronic treatment of rats with three drugs of abuse that act through disparate neurobiological mechanisms: morphine, nicotine and diazepam. In animals not treated subchronically with drugs of abuse, CMS increased the withdrawal-like effects of the opiate antagonist naloxone, but not those of the nicotinic antagonist mecamylamine or the benzodiazepine antagonist flumazenil. In animals treated subchronically with drugs of abuse, CMS exacerbated, precipitated and conditioned withdrawal effects associated with all three antagonists. CMS also potentiated withdrawal-induced and cue-induced place aversions associated with all three antagonists. All of the effects of CMS were reversed by chronic treatment with the specific serotonin reuptake inhibitor citalopram. These results suggest that treatment of comorbid depression, although not a primary treatment for addiction, may facilitate other treatments for addiction, by decreasing the severity of withdrawal symptoms and the likelihood of relapse. PMID- 24949568 TI - CaMKII-dependent phosphorylation of cardiac ryanodine receptors regulates cell death in cardiac ischemia/reperfusion injury. AB - Ca(2+)-calmodulin kinase II (CaMKII) activation is deleterious in cardiac ischemia/reperfusion (I/R). Moreover, inhibition of CaMKII-dependent phosphorylations at the sarcoplasmic reticulum (SR) prevents CaMKII-induced I/R damage. However, the downstream targets of CaMKII at the SR level, responsible for this detrimental effect, remain unclear. In the present study we aimed to dissect the role of the two main substrates of CaMKII at the SR level, phospholamban (PLN) and ryanodine receptors (RyR2), in CaMKII-dependent I/R injury. In mouse hearts subjected to global I/R (45/120min), phosphorylation of the primary CaMKII sites, S2814 on cardiac RyR2 and of T17 on PLN, significantly increased at the onset of reperfusion whereas PKA-dependent phosphorylation of RyR2 and PLN did not change. Similar results were obtained in vivo, in mice subjected to regional myocardial I/R (1/24h). Knock-in mice with an inactivated serine 2814 phosphorylation site on RyR2 (S2814A) significantly improved post ischemic mechanical recovery, reduced infarct size and decreased apoptosis. Conversely, knock-in mice, in which CaMKII site of RyR2 is constitutively activated (S2814D), significantly increased infarct size and exacerbated apoptosis. In S2814A and S2814D mice subjected to regional myocardial ischemia, infarct size was also decreased and increased respectively. Transgenic mice with double-mutant non-phosphorylatable PLN (S16A/T17A) in the PLN knockout background (PLNDM) also showed significantly increased post-ischemic cardiac damage. This effect cannot be attributed to PKA-dependent PLN phosphorylation and was not due to the enhanced L-type Ca(2+) current, present in these mice. Our results reveal a major role for the phosphorylation of S2814 site on RyR2 in CaMKII-dependent I/R cardiac damage. In contrast, they showed that CaMKII-dependent increase in PLN phosphorylation during reperfusion opposes rather than contributes to I/R damage. PMID- 24949571 TI - Eating high fat chow and the behavioral effects of direct-acting and indirect acting dopamine receptor agonists in female rats. AB - Eating high fat chow increases the sensitivity of male rats to some behavioral effects of the direct-acting dopamine receptor agonist quinpirole; it is not known whether sensitivity to quinpirole is similarly enhanced in female rats eating high fat chow. Female Sprague-Dawley rats had free access to standard chow (5.7% fat) or either free or restricted access (i.e. body weight matched to rats eating standard chow) to high fat (34.3% fat) chow. Quinpirole (0.0032-0.32 mg/kg) produced hypothermia and a low frequency of yawning. Eating high fat chow produced insulin resistance without affecting quinpirole-induced yawning or hypothermia. Pretreatment with the dopamine D2 receptor antagonist L-741,626 failed to increase quinpirole-induced yawning, indicating that the low frequency of yawning was not due to enhanced D2 receptor sensitivity. Compared with younger (postnatal day 75), drug-naive female rats in a previous study, rats in the present study (postnatal day 275) were more sensitive to cocaine-elicited (1-17.8 mg/kg) locomotion and the development of sensitization across 5 weeks; however, eating high fat chow did not further enhance these effects. These results suggest that drug history and age might modulate the effects of diet on sensitivity to drugs acting on dopamine systems. PMID- 24949573 TI - Serum metabolomics reveals betaine and phosphatidylcholine as potential biomarkers for the toxic responses of processed Aconitum carmichaelii Debx. AB - We recently reported that processed Aconitum carmichaelii Debx (Bai-Fu-Pian in Chinese, BFP) elicits differential toxic responses in rats under various health conditions. The present study aimed to determine the graded toxicity of BFP so as to derive a safe therapeutic rationale in clinical practice. Sensitive and reliable biomarkers of toxicity were also identified, with the corresponding metabolic pathways being unveiled. Thirty male Sprague-Dawley rats were divided into five groups (n = 6) and received oral administration of BFP extract (0.32, 0.64, 1.28 or 2.56 g kg(-1) per day) or an equal volume of drinking water (control) for 15 days. The metabolomic profiles of rat serum were analyzed by liquid chromatography quadruple time-of-flight mass spectrometry (LC-Q-TOF-MS). Linear regression analysis and Ingenuity Pathway Analysis (IPA) were used to elucidate the differentiated altered metabolites and associated network relationships. Results from biochemical and histopathological examinations revealed that BFP could induce prominent toxicity in the heart, liver and kidneys at a dose of 2.56 g kg(-1) per day. Betaine up-regulation and phosphatidylcholine down-regulation were detected in the serum samples of drug-treated groups in a dose-dependent manner. In summary, betaine and phosphatidylcholine could be regarded as sensitive biomarkers for the toxic responses of BFP. Perturbations of RhoA signaling, choline metabolism and free radical scavenging were found to be partly responsible for the toxic effects of the herbal drug. Based on the metabolomics findings, we could establish a safe therapeutic range in the clinical use of BFP, with promising predictions of possible drug toxicity. PMID- 24949574 TI - Comparison of pediatric patients with status epilepticus lasting 5-29 min versus >=30 min. AB - The most common thresholds for considering prolonged seizures as status epilepticus (SE) are 5 and 30 min. It is unknown whether these different thresholds (5 or 30 min) identify patient populations with different electroclinical characteristics. We compared the characteristics of patients with SE lasting 5-29 min (SE5-29) with those with SE lasting >=30 min (SE>=30). Inclusion criteria were the following: 1) 1 month to 21 years of age at the time of SE, 2) convulsive seizures, and 3) seizure duration >=5 min. Exclusion criteria were the following: 1) exclusively neonatal seizures, 2) psychogenic nonepileptic seizures, or 3) incomplete information about seizure duration. Four hundred forty-five patients (50.1% male) with a median (p25-p75) age at SE of 5.5 (2.8-10.5) years were enrolled. Status epilepticus lasted for 5-29 min in 296 (66.5%) of subjects and for >=30 min in 149 (33.5%). Patients with SE>=30 were younger than the patients with SE5-29 at the time of seizure onset (median: 1 versus 2.1 years, p=0.0007). Status epilepticus as the first seizure presentation was more frequent in patients with SE>=30 (24.2% versus 12.2%, p=0.002). There was a tendency towards a higher rate of abnormalities in the magnetic resonance imaging at baseline in patients with SE>=30 (70.5% versus 57.1%, p=0.061). Differences were not detected in seizure frequency, seizure types, presence of developmental delay, and electroencephalogram abnormalities at baseline. In the pediatric population, SE thresholds of either 5 or 30 min identify groups of patients with very similar electroclinical characteristics, which may influence future definitions of pediatric SE. PMID- 24949575 TI - Impact of family support on psychiatric disorders and seizure control in patients with juvenile myoclonic epilepsy. AB - OBJECTIVE: Psychiatric disorders (PDs) are frequently observed in patients with juvenile myoclonic epilepsy (JME). In this study, we aimed to assess factors associated with PDs in patients with JME. METHODS: Retrospective analysis of data of 90 consecutive patients with JME was performed. Assessment of DSM-IV Axis I clinical disorders was done using Structured Clinical Interview for Axis I. Diagnosis of PDs is made when the score exceeds the threshold provided by the DSM IV. We also applied the Global Assessment of Functioning (GAF) scale which is part of the multiaxial evaluation of the DSM-IV (Axis-V). Using seizure frequency score at presentation, we classified subjects into controlled and uncontrolled groups. RESULTS: In the current cohort, 29 (32.2%) patients were diagnosed with PDs. Fewer patients with PDs had family support (48.3% vs. 83.6%; p=0.001). Lifetime prevalence of PDs was higher among patients with current PDs (96.6% vs. 18.0%; p<0.0001). Subthreshold illness was not different between the groups (17.2% vs. 27.9%; p=0.204). Mean GAF was higher in patients without PDs than in patients with PDs (89.19+/-6.92 vs. 64.22+/-9.76; p<0.0001). Patients with PDs had lower seizure control (7.8% vs. 73.1%; p<0.0001) compared with patients without PDs. Logistic regression analysis for factors associated with diagnosis of PDs revealed that none of the factors significantly affected the odds of seizure control. Patients with lack of family support had poor seizure control (0% vs. 36.9%; p<0.0001); 51.7% of patients with JME with PDs reported lack of family support. Patients with family support had lower lifetime prevalence of PDs (30.8% vs. 76.0%; p<0.0001), whereas patients with JME without family support had lower levels of education (8.0% vs. 35.4%; p=0.009). CONCLUSION: Lack of family support is associated with poor seizure control and higher incidence of PDs in patients with JME. Lack of family support increases neither the odds of PDs nor seizure control. PMID- 24949576 TI - Withdrawal-related adverse events from clinical trials of clobazam in Lennox Gastaut syndrome. AB - To assess withdrawal-related adverse event (AE) rates following abrupt clobazam discontinuation in Phase I trials and gradual clobazam tapering (2-3 weeks) following discontinuation from III trials met the criteria for potential/III trials, we evaluated AE data from four multiple-dosage Phase I trials (duration: 8-34 days). Therapeutic (20 and 40 mg/day) and supratherapeutic clobazam dosages (120 and 160 mg/day) were administered. Adverse events (AEs) were also assessed for patients with Lennox-Gastaut syndrome enrolled in Phase II (OV-1002) and Phase III (OV-1012) studies (duration <=15 weeks) and in the open-label extension (OLE) trial OV-1004 (<=5 years). Potential withdrawal-related AEs were identified by preferred terms, provided that the AEs occurred >=1 day following and <=30 days after the last clobazam doses, or were deemed withdrawal symptoms by investigators. Clinical Institute Withdrawal Assessment for Benzodiazepines (CIWA B) scale was used to evaluate withdrawal intensity in three of the four Phase I trials. A total of 207 participants in Phase I trials received steady-state clobazam dosages of 20-160 mg/day, 182 received clobazam dosages of >=40 mg/day, and 94 received clobazam dosages of >=120 mg/day. Abrupt clobazam discontinuation led to 193 withdrawal-related AEs for 68 Phase I participants. Nearly 50% of AEs occurred after discontinuation of clobazam dosages of >=120 mg/day. Adverse events were mild or moderate and included headache (14% of Phase I participants), insomnia (12.6%), tremor (10.1%), and anxiety (8.7%). The CIWA-B scores varied (range: 0-59). Most scores were <30, indicating possible mild benzodiazepine withdrawal. III trials met the criteria for potential/III patients received clobazam dosages of <=40 mg/day, and those in the OLE trial received clobazam dosages of <=80 mg/day. Eighty-seven patients discontinued clobazam and were gradually tapered. No withdrawal-related AEs or incidences of status epilepticus were reported. Withdrawal-related AEs observed in Phase I studies following abrupt clobazam discontinuation at therapeutic and supratherapeutic dosages were generally mild. No withdrawal-related AEs occurred when dosages were tapered over 3 weeks, after short- or long-term clobazam use (<=5 years). PMID- 24949577 TI - Genetic predictors of Stevens-Johnson syndrome and toxic epidermal necrolysis induced by aromatic antiepileptic drugs among the Chinese Han population. AB - BACKGROUND: Previous studies suggested that one or more HLA alleles participate in the pathogenesis of AED-induced SJS/TEN, but most of these studies focused only on the HLA-B alleles. PURPOSE: The aim of this study was to investigate the pathogenesis of AED-induced SJS/TEN across a broader spectrum of HLA alleles, including the HLA-A, -B and -DRB1 alleles, to further explore the association between each HLA allele and SJS/TEN induced by aromatic AEDs. METHODS: A total of 27 patients exhibiting AED-induced SJS/TEN (16 CBZ-SJS/TEN, seven LTG-SJS/TEN, two PHT-SJS/TEN, and two PB-SJS/TEN patients) and 64 patients who exhibited tolerance to AEDs were recruited. High-resolution HLA genotyping was performed to estimate the prevalence of the HLA-A, -B and -DRB1 alleles for each subject. RESULTS: Fifteen subjects in the SJS/TEN group (12 exhibiting CBZ-SJS/TEN, two exhibiting LTG-SJS, and one exhibiting PB-SJS) carried the HLA-B*15:02 allele, whereas only 4/64 subjects in the AED-tolerant group carried this allele; the carrier rate of HLA-B*15:02 was significantly different between the groups (P<0.001). Nine patients in the SJS/TEN group carried the HLA-DRB1*15:01 allele, while 12/64 subjects in the tolerant group carried this allele; considering that two patients in the SJS/TEN group (one exhibiting LTG-SJS and one exhibiting PB SJS) were homozygous for this allele, the prevalence of HLA-DRB1*15:01 expression between the two groups was significantly different (P=0.041). Furthermore, the carrier rates of HLA-A*33:03, HLA-B*58:01, and HLA-DRB1*03:01 were lower in the SJS/TEN group compared with the AED-tolerant group. The carrier rates of these alleles between the two groups were significantly different (P=0.009, 0.016, and 0.009, respectively). CONCLUSIONS: The HLA-DRB1*15:01 allele may represent a risk factor for AED-induced SJS/TEN among Han Chinese. The HLA-A*33:03, HLA-B*58:01, and HLA-DRB1*03:01 alleles may be "protectors" against AED-induced SJS/TEN, especially CBZ-SJS/TEN. PMID- 24949572 TI - Stress, sex, and addiction: potential roles of corticotropin-releasing factor, oxytocin, and arginine-vasopressin. AB - Stress sensitivity and sex are predictive factors for the development of neuropsychiatric disorders. Life stresses are not only risk factors for the development of addiction but also are triggers for relapse to drug use. Therefore, it is imperative to elucidate the molecular mechanisms underlying the interactions between stress and drug abuse, as an understanding of this may help in the development of novel and more effective therapeutic approaches to block the clinical manifestations of drug addiction. The development and clinical course of addiction-related disorders do appear to involve neuroadaptations within neurocircuitries that modulate stress responses and are influenced by several neuropeptides. These include corticotropin-releasing factor, the prototypic member of this class, as well as oxytocin and arginine-vasopressin that play important roles in affiliative behaviors. Interestingly, these peptides function to balance emotional behavior, with sexual dimorphism in the oxytocin/arginine-vasopressin systems, a fact that might play an important role in the differential responses of women and men to stressful stimuli and the specific sex-based prevalence of certain addictive disorders. Thus, this review aims to summarize (i) the contribution of sex differences to the function of dopamine systems, and (ii) the behavioral, neurochemical, and anatomical changes in brain stress systems. PMID- 24949578 TI - Solvent evaporation versus proton transfer in nucleobase-Pt(CN)(4,6)2- dianion clusters: a collisional excitation and electronic laser photodissociation spectroscopy study. AB - Isolated molecular clusters of adenine, cytosine, thymine and uracil with Pt(CN)6(2-) and Pt(CN)4(2-) were studied for the first time to characterize the binding and reactivity of isolated transition metal complex ions with nucleobases. These clusters represent model systems for understanding metal complex-DNA adducts, as a function of individual nucleobases. Collisional excitation revealed that the clusters decay on the ground electronic surface by either solvent evaporation (i.e. loss of a nucleobase unit from the cluster) or via proton transfer from the nucleobase to the dianion. The Pt(CN)6(2-) nucleobase clusters decay only by solvent evaporation, while the Pt(CN)4(2-) clusters fragment by both pathways. The enhanced proton-transfer reactivity of Pt(CN)4(2-) is attributed to the higher charge-density of the ligands in this transition metal anion. % fragmentation curves of the clusters reveal that the adenine clusters display distinctively higher fragmentation onsets, which are traced to the propensity of adenine to form the shortest intercluster H-bond. We also present laser electronic photodissociation measurements for the Pt(CN)6(2 ).Ur, Pt(CN)4(2-).Ur and Pt(CN)4(2-).Ur2 clusters to illustrate the potential of exploring metal complex DNA photophysics as a function of nucleobase within well defined gaseous clusters. The spectra reported herein represent the first such measurements. We find that the electronic excited states decay with production of the same fragments (associated with solvent evaporation and proton transfer) observed upon collisional excitation of the electronic ground state, indicating ultrafast deactivation of the excited-state uracil-localized chromophore followed by vibrational predissociation. PMID- 24949579 TI - Dynamics of brain activity underlying working memory for music in a naturalistic condition. AB - We aimed at determining the functional neuroanatomy of working memory (WM) recognition of musical motifs that occurs while listening to music by adopting a non-standard procedure. Western tonal music provides naturally occurring repetition and variation of motifs. These serve as WM triggers, thus allowing us to study the phenomenon of motif tracking within real music. Adopting a modern tango as stimulus, a behavioural test helped to identify the stimulus motifs and build a time-course regressor of WM neural responses. This regressor was then correlated with the participants' (musicians') functional magnetic resonance imaging (fMRI) signal obtained during a continuous listening condition. In order to fine-tune the identification of WM processes in the brain, the variance accounted for by the sensory processing of a set of the stimulus' acoustic features was pruned from participants' neurovascular responses to music. Motivic repetitions activated prefrontal and motor cortical areas, basal ganglia, medial temporal lobe (MTL) structures, and cerebellum. The findings suggest that WM processing of motifs while listening to music emerges from the integration of neural activity distributed over cognitive, motor and limbic subsystems. The recruitment of the hippocampus stands as a novel finding in auditory WM. Effective connectivity and agglomerative hierarchical clustering analyses indicate that the hippocampal connectivity is modulated by motif repetitions, showing strong connections with WM-relevant areas (dorsolateral prefrontal cortex - dlPFC, supplementary motor area - SMA, and cerebellum), which supports the role of the hippocampus in the encoding of the musical motifs in WM, and may evidence long-term memory (LTM) formation, enabled by the use of a realistic listening condition. PMID- 24949580 TI - Identification of p.Gln858* in ATP13A2 in two EOPD patients and presentation of their clinical features. AB - We present results of homozygosity mapping in two siblings affected with early onset Parkinson's disease (EOPD) and mutation screening of ATP13A2 in these and other Iranian EOPD patients. Genome-wide SNP homozygosity analysis revealed linkage to a locus that included ATP13A2, and sequencing of the gene revealed a novel p.Gln858*-causing mutation in the homozygous state in the siblings. Sequencing of the gene in seven other unrelated EOPD patients previously shown not to have mutations in PRKN, DJ-1, PINK1, and LRRK2 identified the same homozygous p. Gln858*-causing mutation in another patient. Haplotype analysis revealed that two alleles harboring the mutation were not identical by decent. The variation identified represents the 13th known disease causing mutation in ATP13A2. The clinical features of the patients who harbored the mutation are compared to those of previously reported patients with mutations in ATP13A2. Bradykinesia and rigidity, but not tremor, were reported in nearly all the patients. l-dopa administration, though initially effective, usually caused dyskinesia upon prolonged usage. Eye movement abnormalities including saccades and supranuclear gaze palsy, were almost always observed. Dystonia and bulbar anomalies were common but more variable manifestations. Although a degree of cognitive decline was found in most of the patients, the decline was often mild and absent in one patient. Age at onset of symptoms was usually in the second decade of life, and sometimes in the third decade. PMID- 24949581 TI - Evaluation of radiation hazard potential of TENORM waste from oil and natural gas production. AB - In this study, a potential radiation hazard from TENORM sludge wastes generated during exploration and extraction processes of oil and gas was evaluated. The activity concentration of natural radionuclides (238)U, (226)Ra and (232)Th were determined in TENORM sludge waste. It was found that sludge waste from oil and gas industry is one of the major sources of (226)Ra in the environment. Therefore, some preliminary chemical treatment of sludge waste using Triton X-100 was also investigated to reduce the radioactivity content as well as the risk of radiation hazard from TENORM wastes. The activity concentrations of (226)Ra and (228)Ra in petroleum sludge materials before and after chemical treatment were measured using gamma-ray spectrometry. The average values of the activity concentrations of (226)Ra and (228)Ra measured in the original samples were found as 8908 Bq kg(-1) and 933 Bq kg(-1), respectively. After chemical treatment of TENORM samples, the average values of the activity concentrations of (226)Ra and (228)Ra measured in the samples were found as 7835 Bq kg(-1) and 574 Bq kg(-1), respectively. Activity concentration index, internal index, absorbed gamma dose rate and the corresponding effective dose rate were estimated for untreated and treated samples. PMID- 24949582 TI - Lightweight aerial vehicles for monitoring, assessment and mapping of radiation anomalies. AB - The Fukushima Daiichi nuclear power plant (FDNPP) incident released a significant mass of radioactive material into the atmosphere. An estimated 22% of this material fell out over land following the incident. Immediately following the disaster, there was a severe lack of information not only pertaining to the identity of the radioactive material released, but also its distribution as fallout in the surrounding regions. Indeed, emergency aid groups including the UN did not have sufficient location specific radiation data to accurately assign exclusion and evacuation zones surrounding the plant in the days and weeks following the incident. A newly developed instrument to provide rapid and high spatial resolution assessment of radionuclide contamination in the environment is presented. The device consists of a low cost, lightweight, unmanned aerial platform with a microcontroller and integrated gamma spectrometer, GPS and LIDAR. We demonstrate that with this instrument it is possible to rapidly and remotely detect ground-based radiation anomalies with a high spatial resolution (<1 m). Critically, as the device is remotely operated, the user is removed from any unnecessary or unforeseen exposure to elevated levels of radiation. PMID- 24949583 TI - Does pharmacotherapy influence the inflammatory responses during cardiopulmonary bypass in children? AB - Cardiopulmonary bypass (CPB) induces a systemic inflammatory response syndrome (SIRS) by factors such as contact of the blood with the foreign surface of the extracorporeal circuit, hypothermia, reduction of pulmonary blood flow during CPB and endotoxemia. SIRS is maintained in the postoperative phase, co-occurring with a counter anti-inflammatory response syndrome. Research on the effects of drugs administered before the surgery, especially in the induction phase of anesthesia, as well as drugs used during extracorporeal circulation, has revealed that they greatly influence these postoperative inflammatory responses. A better understanding of these processes may not only improve postoperative recovery but also enable tailor-made pharmacotherapy, with both health and economic benefits. In this review, we describe the pathophysiology of SIRS and counter anti inflammatory response syndrome in the light of CPB in children and the influence of drugs used on these syndromes. PMID- 24949584 TI - Cardioprotection afforded by sour cherry seed kernel: the role of heme oxygenase 1. AB - Cardiovascular diseases are primary cause of death worldwide, particularly among populations with sedentary lifestyles and diets rich in animal products and processed foods. Currently, public health countermeasures to these disorders focus on costly and often marginally effective interventions administered only after the development of disease. These countermeasures are mainly palliative and fail to address the underlying causes of cardiac pathologies. Previously, the authors of this report have demonstrated that sour cherry seed kernel extract (SCSE), a nontoxic low-cost plant material, strongly preserves tissues through induction of heme oxygenase-1 (HO-1), a critical host antioxidant defense enzyme. This investigation seeks to characterize underlying mechanisms of SCSE-mediated tissue protection. Isolated hearts from Sprague-Dawley rats fed 30 mg.kg.d SCSE for 8 weeks, and untreated controls were mounted in a "working heart" apparatus and subjected to ischemia and reperfusion. A panel of cardiac functional evaluations was conducted on each heart. Infarct size assessments were made along with Western blot and immunohistochemical analysis for selected proteins involved in cardiovascular homeostasis. SCSE treatment was observed to improve postischemic cardiac functions and suppress infarct size. Analysis of the outcomes produced by this study is consistent with SCSE cardioprotection that involve interaction of Bcl-2 and HO-1. PMID- 24949585 TI - Asleep or awake: rethinking "safety". PMID- 24949586 TI - Think before you inject: understanding electrophysiological radiofrequency principles and the importance of the local tissue environment. PMID- 24949587 TI - Maximum effective needle-nerve distance: what did we really find? PMID- 24949588 TI - Reply to Drs Bhatt and Hofmann. PMID- 24949589 TI - Questions regarding a comparison of techniques for piriformis muscle injection. PMID- 24949590 TI - Reply to Dr Bhatia. PMID- 24949591 TI - Comparing the efficacy of 2 techniques for piriformis muscle injection proceed with caution. PMID- 24949592 TI - Reply to Drs Moriggl et al. PMID- 24949593 TI - Pneumothorax case caveat: always visualize needle tip. PMID- 24949594 TI - Continuous paravertebral blocks for analgesia following mastectomy: the jury is still out. PMID- 24949595 TI - Raising a red flag over TAP blocks. PMID- 24949597 TI - Atomic resolution mapping of phonon excitations in STEM-EELS experiments. AB - Atomically resolved electron energy-loss spectroscopy experiments are commonplace in modern aberration-corrected transmission electron microscopes. Energy resolution has also been increasing steadily with the continuous improvement of electron monochromators. Electronic excitations however are known to be delocalized due to the long range interaction of the charged accelerated electrons with the electrons in a sample. This has made several scientists question the value of combined high spatial and energy resolution for mapping interband transitions and possibly phonon excitation in crystals. In this paper we demonstrate experimentally that atomic resolution information is indeed available at very low energy losses around 100meV expressed as a modulation of the broadening of the zero loss peak. Careful data analysis allows us to get a glimpse of what are likely phonon excitations with both an energy loss and gain part. These experiments confirm recent theoretical predictions on the strong localization of phonon excitations as opposed to electronic excitations and show that a combination of atomic resolution and recent developments in increased energy resolution will offer great benefit for mapping phonon modes in real space. PMID- 24949596 TI - Dialect awareness and lexical comprehension of mainstream american english in african american english-speaking children. AB - PURPOSE: This study was designed to examine the relationships among minority dialect use, language ability, and young African American English (AAE)-speaking children's understanding and awareness of Mainstream American English (MAE). METHOD: Eighty-three 4- to 8-year-old AAE-speaking children participated in 2 experimental tasks. One task evaluated their awareness of differences between MAE and AAE, whereas the other task evaluated their lexical comprehension of MAE in contexts that were ambiguous in AAE but unambiguous in MAE. Receptive and expressive vocabulary, receptive syntax, and dialect density were also assessed. RESULTS: The results of a series of mixed-effect models showed that children with larger expressive vocabularies performed better on both experimental tasks, relative to children with smaller expressive vocabularies. Dialect density was a significant predictor only of MAE lexical comprehension; children with higher levels of dialect density were less accurate on this task. CONCLUSIONS: Both vocabulary size and dialect density independently influenced MAE lexical comprehension. The results suggest that children with high levels of nonmainstream dialect use have more difficulty understanding words in MAE, at least in challenging contexts, and suggest directions for future research. PMID- 24949598 TI - Expression of amyloid-beta protein and amyloid-beta precursor protein after primary brain-stem injury in rats. AB - Amyloid-beta (Abeta) protein and its precursor, amyloid-beta precursor protein (beta-APP), have traditionally been used in the diagnosis of Alzheimer disease. Their use in diagnosis of traumatic brain injury by forensic analysis is becoming more widespread. However, to date, no reliable small animal model exists to evaluate these brain injury indicators. To address this, we have studied primary brain-stem injury in rats to assess the appearance of diffuse axonal injury in brain sections and correlate these findings with appearance of Abeta and relative beta-APP mRNA levels. Using an EnVision 2-step immunohistochemical staining method to measure axon diameter, we found that there was significant difference in axon diameters within the medulla oblongata and several time points after brain injury, ranging from 3 to 24 hours. In addition, mRNA expression levels of beta-APP increased following brain injury, peaking 3 hours following injury and decreasing back to baseline levels by 24 hours after injury. These results suggest that using immunohistochemistry and reverse transcription-polymerase chain reaction to detect changes in Abeta-associated axonal changes and beta-APP mRNA levels, respectively, can be useful for the diagnosis of diffuse axonal injury during autopsy at early time points following fatal brain injury. PMID- 24949599 TI - Endoscopic retroflexion treats bleed within duodenal bulb. PMID- 24949600 TI - A rare cause of dysphagia. PMID- 24949601 TI - Cross-talk between the liver, heart and kidney - another piece in the puzzle. PMID- 24949602 TI - Drug rediscovery to prevent off-label prescription reduces health care costs: the case of tioguanine in the Netherlands. PMID- 24949604 TI - Patient tolerability of bowel preparation is associated with polyp detection rate during colonoscopy. AB - BACKGROUND & AIMS: A number of factors have been identified that influence the yield of screening colonoscopy. The perceived tolerability of bowel preparation has not been studied as a predictor of quality outcomes in colonoscopy. We aimed to characterize the association between patient-perceived tolerability of bowel preparation and polyp detection during colonoscopy. METHODS: We performed a cross sectional cohort study of 413 consecutive adult patients presenting for outpatient colonoscopy at two outpatient endoscopy centers at our institution. We developed a standardized questionnaire to assess the patient's experience with bowel preparation. Bowel preparation quality was measured using the validated Ottawa scale and colonoscopic findings were recorded for each patient. The primary outcome was polyp detection and the secondary outcome was the quality of bowel preparation. RESULTS: Patient-reported clarity of effluent during bowel preparation correlated poorly with Ottawa score during colonoscopy, K=0.15. Female gender was an independent risk factor for a poorly tolerated bowel prep (OR 3.93, 95% CI 2.30 - 6.72, p<0.001). Report of a poorly tolerated bowel prep was independently associated with the primary outcome, polyp detection (OR 0.39, 95% CI 0.18 - 0.84, p=0.02) and also with the secondary outcome, lower quality bowel preparation (OR 2.39, 95% CI 1.17 - 4.9, p=0.02). CONCLUSIONS: A patient perceived negative experience with bowel preparation independently predicted both a lower quality bowel preparation and a lower rate of polyp of detection. Assessment of the tolerability of bowel preparation before colonoscopy may be a clinically useful predictor of quality outcomes during colonoscopy. PMID- 24949603 TI - Increased IgA glycoprotein-2 specific antibody titres in refractory celiac disease. AB - BACKGROUND & AIMS: In most cases celiac disease (CD) is successfully treated with a gluten-free diet (GFD). However, some patients become refractory to the GFD. Refractory CD (RCD) patients have an increased risk for developing enteropathy associated T-cell lymphoma and early diagnosis is therefore of importance. Currently, RCD diagnosis relies on endoscopy and adequate serological markers are lacking. Antibodies against glycoprotein-2 (GP2A) were described in Crohn's disease (CrD) and active CD but not in ulcerative colitis (UC), suggesting this is a specific marker for small intestinal lesions. METHODS: Sera obtained from patients visiting our outpatient clinic for routine serological tests for diagnosis and/or follow-up of inflammatory bowel disease (n=78), active CD (n=45), GFD (n=34) and RCD (n=15) were analysed for GP2A titres. RESULTS: Increased GP2A-IgA levels in CrD and active CD as compared to controls (p<0.001) and lack thereof in UC was confirmed. However, we could not confirm the association with small bowel localization within the CrD patient group. Within CD patients, we demonstrated a significant decrease of GP2A-IgA titres upon a GFD and increased levels in RCD patients as compared to patients on a GFD. Although GP2A-IgA was not associated with the degree of villous atrophy, GP2A-IgA levels were able to distinguish RCD patients from GFD patients (ROC AUC=0.79, p=0.002). CONCLUSION: Follow-up of GP2A-IgA titres in CD patients on a GFD may help to identify patients at risk for developing RCD. PMID- 24949605 TI - A single or split dose picosulphate/magnesium citrate before colonoscopy: comparison regarding tolerance and efficacy with polyethylene glycol. A randomized trial. AB - BACKGROUND & AIMS: To compare the efficacy and tolerance of sodium picosulphate/magnesium citrate (PMC) and polyethylene glycol (PEG) in a single or split dose regimen for colonoscopy bowel preparation. METHODS: A prospective, randomized, endoscopist-blinded, multicenter study. The patients were randomly assigned to receive PMC (PMC4/0) or PEG (PEG4/0) in a single dose 4L day before colonoscopy or a split dose 2+2L PMC (PMC2/2) or 3+1L PEG (PEG3/1) one day before and in the morning before the colonoscopy. Each patient was interviewed to determine his/her subjective tolerance of the preparation before the procedure. The quality of bowel cleansing was assessed in a blinded test performed by multiple endoscopists using the Aronchick scale. RESULTS: A total of 600 patients were enrolled, 88.2% were included in the analysis. Satisfactory bowel cleansing (Aronchick score 1 and 2) was significantly more frequent when a split dose was used irrespective of the solution type (81.6% PMC2/2, 87.3% PEG3/1 vs. 73.0% PEG4/0, p = 0.024). In single dose regimens, PMC performed better than PEG (82.6% vs. 73.0%). Single or split dose PMC preparations were comparable. A PMC based solution was generally better tolerated than PEG regardless of the regimen used (p < 0.001). Nausea was reported mostly after the 4L PEG (32.8%, p < 0.001), incontinence after a split PMC dose (34.4%, p = 0.002), and bloating after the 4L PEG (38.0%, p < 0.001). There was no significant difference in the prevalence of vomiting. CONCLUSION: Colonic preparation with PMC yields similar results as a split PEG dose, regardless of whether PMC is administered in single or separate doses. PMC is better tolerated than any PEG-based preparation. A single 4L PEG the day before the colonoscopy is less appropriate for bowel cleansing. PMID- 24949606 TI - Increasing prevalence of right-sided colonic adenomas in a high-volume endoscopy department in Romania: implications for colorectal cancer screening. AB - BACKGROUND & AIMS: A gradual shift of colorectal adenoma and carcinoma location toward the proximal colon has been recently observed both in the United States and Europe. We aimed to study the polyp and adenoma detection rate in a major endoscopy center of northwestern Romania over a 16-year period, and to characterize the distribution and the pathological features of the removed polyps according to age and sex, in order to assess the trend of proximal adenoma prevalence in our population. METHODS: We retrospectively analyzed 9,230 consecutive colonoscopies performed between 1996 and 2011 in a high-volume outpatient clinic in Cluj-Napoca, Romania. We analyzed 2,436 complete colonoscopies that detected 3,642 polyps in two time periods: 1996 to 2003 and 2004 to 2011. We compared the number, size and histopathological features of the polyps removed from the right-sided colon and the left sided-colon in the two periods. RESULTS: An increasing trend of polyp detection rate in the right-sided colon was observed, from 9.36% in the first period to 12.17% in the second period (p<0.001). The prevalence of right-sided colon adenomas also presented an increased trend (OR 1.45; CI95% 1.02-2.05; p=0.03). High-grade dysplasia (HGD) was found in 8.6% of the adenomas and in 4.1% of the diminutive polyps. Advanced neoplasia was detected in 1.5% of persons younger than 50 years. Multivariate logistic regression analysis evidenced that the right-sided polyps were significantly associated with the last time period (OR 1.3; p=0.001; CI95% 1.12 1.56), male gender (OR-1.3; p=0.001; CI95% 1.1-1.5) and age above 48 years (OR 1.3; p=0.006: CI95% 1-1.6). CONCLUSION: An increasing trend of polyp detection rate in the right-sided colon was documented, with an increasing prevalence of right-sided adenomas. The evaluation of the proximal colon is particularly important in males aged over 48. A clear-cut risk of HGD in the diminutive polyps and in the middle age subjects has been also observed. PMID- 24949607 TI - Open-access flexible sigmoidoscopy frequently leads to additional colonoscopy in symptomatic patients over 50 years. AB - BACKGROUND & AIMS: General practitioners (GPs) in the Netherlands have open access to flexible sigmoidoscopy (FS) for patients with lower gastrointestinal symptoms, but not to colonoscopy. This study was performed to investigate the yield of FS in GP-referred patients, to evaluate the proportion of patients in whom additional colonoscopy was performed and to investigate whether there was a subgroup of patients referred for symptoms with a low risk of detecting significant findings. METHODS: All patients undergoing FS in 2008 and 2009 who were referred by GPs were analyzed. Indications for additional colonoscopy were the presence of polyps and/or colorectal cancer (CRC), polyp screening or surveillance, incomplete FS or other reasons. RESULTS: In total, 916 patients underwent FS. A cause for the symptoms was found in 44.2% of patients. In patients aged 50 years or older, additional colonoscopy was more frequently performed than in younger patients (27.5% vs. 9.6%, OR=3.6 [95% CI 2.4-5.4]), mainly due to a higher prevalence of adenomatous polyps (29.9% vs. 10.5%, OR=3.6 [95% CI 2.4-5.4]) and CRC (7.5% vs. 1.3%, OR=6.2 [95% CI 2.2-17.5]) during FS. In 7.8% patients undergoing FS for abdominal pain as the presenting symptom, a probable cause for the symptoms was found, mainly diverticular disease. CONCLUSION: Due to the high prevalence of polyps and CRC in symptomatic patients aged 50 years or older undergoing FS, an additional colonoscopy is performed frequently. In patients referred with abdominal pain, FS is unlikely to reveal a relevant cause for the symptoms. PMID- 24949608 TI - CD133/CD166/Ki-67 triple immunofluorescence assessment for putative cancer stem cells in colon carcinoma. AB - BACKGROUND & AIMS: Colorectal cancer represents the third most common malignancy and the fourth most common cause of cancer death worldwide. The existence of drug resistant colon cancer stem cells is thought to be one of the most important reasons behind treatment failure in colon cancer, their existence putatively leading to metastasis and recurrences. The aim of our study was to investigate the immunoexpression patterns of CD133 and CD166 in colon carcinoma, both individually and in combination, assessing their significance as prognostic markers. METHODS: A total of 45 retrospective colon adenocarcinoma cases were investigated by enzymatic and multiple fluorescence immunohistochemistry for their CD133 and CD166 expression and colocalization. RESULTS: Both CD133 and CD166 were expressed to different extents in all cancer specimens, with a predominant cytoplasmic pattern for CD133 and a more obvious membranous-like pattern for CD166. Overall, when comparing their reactivity for the tumoral tissue, CD166 expression areas seemed to be smaller than those of CD133. However, there was a direct correlation between CD133 and CD166 expression levels throughout the entire spectrum of lesions, with higher values for dysplastic lesions. Colocalization of CD133/CD166 was obvious at the level of cells membranes, with higher coefficients in high grade dysplasia, followed by well and moderate differentiated tumours. : CD133/CD166 colocalization is an early event occurring in colon tumorigenesis, with the highest coefficients recorded for patients with high grade dysplasia, followed by well differentiated tumours. Thus, we consider that the coexpression of these two markers could be useful for further prognostic and therapeutically stratification of patients with colon cancer. PMID- 24949609 TI - Neoadjuvant conformal chemoradiation with induction chemotherapy for rectal adenocarcinoma. A prospective observational study. AB - BACKGROUND & AIMS: The purpose of this prospective observational study was to evaluate the rate and the prognostic factors for down-staging and complete response for rectal adenocarcinoma after induction chemotherapy and neoadjuvant chemoradiation followed by surgery, and to analyze the rate of sphincter-saving surgery. METHODS: We included from March 2011 to October 2013 a number of 88 patients hospitalized with locally advanced rectal adenocarcinoma in the Prof. Dr. Ion Chiricuta Institute of Oncology, Cluj. The treatment schedule included 2 4 cycles of Oxaliplatin plus a fluoropyrimidine followed by concomitant chemoradiation with a dose of 50 Gy in 25 fractions combined with a fluoropyrimidine monotherapy. RESULTS: The rate of T down-staging was 49.4% (40/81 evaluable patients). Independent prognostic factors for T down-staging were: age >57 years (p<0.01), cN0 (p<0.01), distance from anal verge >5 cm (p<0.01), initial CEA <6.2 ng/ml (p<0.01), higher number of chemotherapy cycles with Oxaliplatin (pROC=0.05) and protraction of radiotherapy of >35 days (p<0.01). Nine patients from 81 (11.1%) presented complete response (7 pathological and 2 clinical); the independent prognostic factors were stage cT2 versus cT3-4 (p<0.01), initial tumor size <=3.5 cm and distance from anal verge >5 cm (p=0.03). Sixty-eight patients (79.1%) underwent radical surgery and among them 35 patients (51.5 %) had a sphincter saving procedure. CONCLUSIONS: Induction chemotherapy with neoadjuvant chemoradiation produced important down staging in rectal adenocarcinoma. Independent prognostic factors for T down staging were: age, cN0, distance from anal verge, initial CEA, the number of Oxaliplatin cycles and duration of radiotherapy; for complete response: cT2, initial tumor size and distance from the anal verge. PMID- 24949610 TI - Autoimmune pancreatitis - diagnosis, management and longterm follow-up. AB - BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is a fibroinflammatory condition affecting the pancreas and could present as a multisystem disorder. Diagnosis and management can pose a diagnostic challenge in certain groups of patients. We report our experience of managing this condition in a tertiary pancreaticobiliary centre in the North East of England. METHODS: Patients were identified from a prospectively maintained database of patients diagnosed with AIP between 2005 and 2013. Diagnosis of definite/probable AIP was based on the revised HISORt criteria. When indicated, patients were treated with steroids and relapses were treated with azathioprine. All patients have been followed up to date. RESULTS: Twenty-two patients were diagnosed with AIP during this period. All patients had pancreatic protocol CT performed while some patients had either MR or EUS as part of the work up. Fourteen out of 22 (64%) had an elevated IgG4 level (mean: 10.9 g/L; range 3.4 - 31 g/L). Four (18%) patients underwent surgery. Extrapancreatic involvement was seen in 15 (68%) patients, with biliary involvement being the commonest. Nineteen (86%) were treated with steroids and five (23%) required further immunosuppression for treatment of relapses. The mean follow up period was 36.94 months (range 7 - 94). CONCLUSION: Autoimmune pancreatitis is being increasingly recognized in the British population. Extrapancreatic involvement, particularly extrahepatic biliary involvement seems to be a frequent feature. Diagnosis should be based on accepted criteria as this significantly reduces the chances of overlooking malignancy. Awareness of this relatively rare condition and a multi-disciplinary team approach will help us to diagnose and treat this condition more effectively thereby reducing unnecessary interventions. PMID- 24949612 TI - Population-based screening in colorectal cancer - current practice and future developments: faecal biomarkers review. AB - BACKGROUND & AIMS: Colorectal cancer (CRC) is the second most common form of malignancy in Europe and North America, and is one of the major causes of cancer death, with a 50.7% 5 year mortality rate. The majority of cases are of a sporadic nature and develop from a pre-cancerous lesion. Screening programmes have been introduced in many countries to detect and treat the condition. These mostly rely on a combination of faecal occult blood tests and endoscopy to guide diagnosis. They are expensive to establish and run, have a potential for false negatives (especially for high risk adenomas and right sided cancers) and they are often unacceptable to a significant percentage of the at-risk population. Consequently many groups have sought sensitive and specific diagnostic biomarkers for CRC and adenomas. These biomarkers form three broad categories: cytogenetic, enzymatic/protein and metabolomic. METHODS: Pubmed and Medline databases were searched to identify relevant articles concerning colorectal cancer screening. CONCLUSION: Here we provide a review of the current population-based screening possibilities and faecal biomarkers currently under investigation, an assessment of their cost-effectiveness, their efficacy and suggestions for the future of large scale screening in CRC. PMID- 24949611 TI - Endogenous heparinoids detected by anti-Xa activity are present in blood during acute variceal bleeding in cirrhosis. A prospective study. AB - BACKGROUND & AIMS: Endogenous heparinoids have been detected by thromboelastography and quantified by clotting based anti-Xa activity assays in patients with cirrhosis, but their presence in variceal bleeding has not been established yet. METHODS: Clotting based anti-Xa activity was measured in A) 30 cirrhotics with variceal bleeding, B) 15 non-cirrhotics with peptic ulcer bleeding, C) 10 cirrhotics without infection or bleeding, and D) 10 cirrhotics with hepatocellular carcinoma (HCC). RESULTS: Anti-Xa activity was not detected in ulcer bleeders or in cirrhotics without infection or bleeding but was present in seven (23%) variceal bleeders (median levels: 0.03 u/mL (0.01-0.07)) and was quantifiable for 3 days in six of seven patients. Four of seven variceal bleeders with anti-Xa activity present had HCC (p=0.023). Age, creatinine, platelet count and total infections the second day from admission were significantly correlated with the presence of measureable anti-Xa levels (p=0.014, 0.032, 0.004 and 0.019, respectively). In the HCC group, anti-Xa activity was present in three patients (30%) [median levels: 0.05 u/mL (0.01-0.06)]. CONCLUSIONS: In this study, variceal bleeders and 30% of the patients with HCC had endogenous heparinoids that were detected by a clotting based anti-Xa activity assay, whereas there was no anti Xa activity present in patients with cirrhosis without infection, or bleeding or HCC, nor in those with ulcer bleeding. Thus, the anti Xa activity is likely to be a response to bacterial infection and/or presence of HCC in cirrhosis. PMID- 24949613 TI - A case of cap polyposis remission by betamethasone enema after antibiotics therapy including Helicobacter pylori eradication. AB - We report the case of a 58-year-old woman who was referred to our hospital due to frequent bloody mucus diarrhea. She was diagnosed with cap polyposis based on typical endoscopic and histological findings. Colonoscopy revealed multiple, reddish, mucus-capped polypoid lesions from the rectum to the sigmoid colon. A pathological examination revealed that the polyps were covered by erosive and inflamed granulation tissue with decreased crypt cells. Laboratory data indicated positive values for Helicobacter pylori immunoglobulin G antibody and hypoproteinemia. Metronidazole, H. pylori eradication, and levofloxacin therapies were not effective; however, the subsequent administration of betamethasone enema dramatically improved the clinical symptoms and endoscopic findings. The hypoproteinemia was normalized after the therapy. The dose of the betamethasone enema was tapered gradually, and no recurrence was observed 6 months after discontinuation of the treatment. This case suggests that betamethasone enema may be considered as the second treatment choice for cap polyposis patients after H. pylori eradication, metronidazole or levofloxacin therapy. PMID- 24949614 TI - Ciliated foregut cyst of the gallbladder. A diagnostic challenge and management quandary. AB - Ciliated foregut cysts are rare anomalies due to aberrant embryological development. Only a small number of gallbladder ciliated foregut cysts have been reported. We report the case of a 29-year-old woman presenting with epigastric pain associated with diarrhoea and vomiting, who was found to have raised serum bilirubin levels and abnormal liver function tests. Following a diagnostic pathway including abdominal ultrasound, magnetic resonance cholangiopancreatography and endoscopic ultrasound the gallbladder cyst was provisionally diagnosed to be a cyst arising from the cystic duct or a duplicated gallbladder. A laparoscopic cholecystectomy was carried out and histopathology identified a ciliated foregut gallbladder cyst. The postoperative course was uneventful. In this report we offer what we believe to be an optimal diagnostic pathway and therapeutic strategy for this rare congenital cyst. PMID- 24949615 TI - Hepatic arterioportal fistula presenting as gastric variceal hemorrhage. AB - Hepatic arterioportal fistulae (APF) are abnormal communications between the hepatic artery and the portal vein. In this report, we present the second case in the literature of a symptomatic APF presenting as a gastric variceal bleeding. A 55-year-old female presented to our facility with hematemesis. Upper endoscopy revealed a bleeding gastric varix. A computed tomography scan identified a large left hepatic lobe APF between the left hepatic artery and the left portal vein. Through angiography coil embolization was performed and with resultant loss of arterial flow, the APF was decompressed. On hospital day 3, the patient developed new melena. Portovenogram was performed and a TIPS stent was deployed. The patient subsequently did well. Hepatic arterioportal fistulae can result in portal hypertension secondary to arterial blood flowing directly into the portal vein bypassing the hepatic sinusoids. Iatrogenic causes (e.g. percutaneous liver biopsy) represent more than 50% of published cases of APFs. Most APFs resolve spontaneously as they are small and peripherally located. In rare instances, when APFs are centrally located, clinical symptoms develop. There have been 30 reported cases of symptomatic intrahepatic APFs following percutaneous liver biopsy. Of those, only one case presented as a gastric variceal bleed. Digital subtraction angiography is the gold standard in the diagnosis and treatment of APFs. In addition to initial embolization, we elected to treat the patient with TIPS due to the magnitude of her bleed. Although rare, intrahepatic APF should be kept on the differential of a patient presenting with isolated gastric varices. PMID- 24949616 TI - Partial splenic embolization for hypersplenism in cirrhotic patients. A case series. AB - The prognosis of liver cirrhosis depends on the presence of its major complications as well as on other factors such as hypersplenism with thrombocytopenia. Partial splenic embolization is an effective interventional procedure performed in liver cirrhosis complicated with portal hypertension to improve the low platelet count. This technique represents an efficient alternative to splenectomy, which has major drawbacks and is associated with a high morbidity. We report a series of patients with liver cirrhosis and portal hypertension who presented with severe thrombocytopenia and were treated with partial splenic embolization eventually having a favourable outcome. PMID- 24949617 TI - Concomitant CMV and Clostridium difficile colitis in an immunocompetent patient treated with Ganciclovir and fecal transplantation. PMID- 24949618 TI - The first report of oxcarbazepine-induced vanishing bile duct syndrome. PMID- 24949619 TI - Is spleen stiffness a predictor of clinical decompensation in cirrhotic patients? PMID- 24949620 TI - Autologous fascia lata repair of hiatal hernia. PMID- 24949621 TI - An improved experimental method for simulating erosion processes by concentrated channel flow. AB - Rill erosion is an important process that occurs on hill slopes, including sloped farmland. Laboratory simulations have been vital to understanding rill erosion. Previous experiments obtained sediment yields using rills of various lengths to get the sedimentation process, which disrupted the continuity of the rill erosion process and was time-consuming. In this study, an improved experimental method was used to measure the rill erosion processes by concentrated channel flow. By using this method, a laboratory platform, 12 m long and 3 m wide, was used to construct rills of 0.1 m wide and 12 m long for experiments under five slope gradients (5, 10, 15, 20, and 25 degrees) and three flow rates (2, 4, and 8 L min(-1)). Sediment laden water was simultaneously sampled along the rill at locations 0.5 m, 1 m, 2 m, 3 m, 4 m, 5 m, 6 m, 7 m, 8 m, 10 m, and 12 m from the water inlet to determine the sediment concentration distribution. The rill erosion process measured by the method used in this study and that by previous experimental methods are approximately the same. The experimental data indicated that sediment concentrations increase with slope gradient and flow rate, which highlights the hydraulic impact on rill erosion. Sediment concentration increased rapidly at the initial section of the rill, and the rate of increase in sediment concentration reduced with the rill length. Overall, both experimental methods are feasible and applicable. However, the method proposed in this study is more efficient and easier to operate. This improved method will be useful in related research. PMID- 24949622 TI - Internet-delivered cognitive behavior therapy for adolescents with obsessive compulsive disorder: an open trial. AB - BACKGROUND: International guidelines recommend Cognitive Behavior Therapy (CBT) as the first line treatment for pediatric obsessive-compulsive disorder (OCD). However, a substantial proportion of patients do not have access to such treatment. We developed and tested the feasibility, efficacy and acceptability of a novel therapist-guided, Internet-delivered CBT (ICBT) platform for adolescents with OCD. METHODS: An interactive, age-appropriate ICBT platform ("BiP OCD") was developed. Twenty-one adolescents (12-17 years) with a DSM-IV diagnosis of OCD and their parents were enrolled in the study. All participants received 12 weeks of ICBT with therapist support. The primary outcome measure was the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Acceptability was assessed at post-treatment. RESULTS: Participants completed on average 8.29 (SD = 3.0) of the 12 treatment chapters. Treatment yielded significant improvements on all clinician-, parent- and most self-administered outcome measures, with a large effect size of d = 2.29 (95% CI 1.5-3.07) on the CY-BOCS. Patients continued to improve at follow-up. At 6-month follow-up, 71% were classified as responders (>=35% decrease on the CY-BOCS) and 76% as being in remission (CY-BOCS score <=12). Average clinician support time was less than 20 minutes per patient per week. The majority of participants felt that BiP OCD was age-appropriate and rated the treatment as good or very good. CONCLUSIONS: ICBT could be efficacious, acceptable, and cost-effective for adolescents with OCD. More rigorously controlled studies are needed to further evaluate the treatment. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01809990. PMID- 24949623 TI - Morphine enhances HIV-1SF162-mediated neuron death and delays recovery of injured neurites. AB - HIV-1 enters the CNS soon after initial systemic infection; within the CNS parenchyma infected and/or activated perivascular macrophages, microglia and astrocytes release viral and cellular toxins that drive secondary toxicity in neurons and other cell types. Our previous work has largely modeled HIV neuropathology using the individual viral proteins Tat or gp120, with murine striatal neurons as targets. To model disease processes more closely, the current study uses supernatant from HIV-1-infected cells. Supernatant from HIV-1SF162 infected differentiated-U937 cells (HIV+sup) was collected and p24 level was measured by ELISA to assess the infection. Injection drug abuse is a significant risk factor for HIV-infection, and opiate drug abusers show increased HIV neuropathology, even with anti-retroviral treatments. We therefore assessed HIV+sup effects on neuronal survival and neurite growth/pruning with or without concurrent exposure to morphine, an opiate that preferentially acts through u opioid receptors. Effects of HIV+sup +/- morphine were assessed on neuronal populations, and also by time-lapse imaging of individual cells. HIV+sup caused dose-dependent toxicity over a range of p24 levels (10-500 pg/ml). Significant interactions occurred with morphine at lower p24 levels (10 and 25 pg/ml), and GSK3beta was implicated as a point of convergence. In the presence of glia, selective neurotoxic measures were significantly enhanced and interactions with morphine were also augmented, perhaps related to a decreased level of BDNF. Importantly, the arrest of neurite growth that occurred with exposure to HIV+sup was reversible unless neurons were continuously exposed to morphine. Thus, while reducing HIV-infection levels may be protective, ongoing exposure to opiates may limit recovery. Opiate interactions observed in this HIV-infective environment were similar, though not entirely concordant, with Tat/gp120 interactions reported previously, suggesting unique interactions with virions or other viral or cellular proteins released by infected and/or activated cells. PMID- 24949625 TI - Weighted road density and allergic disease in children at high risk of developing asthma. AB - BACKGROUND: Evidence for an association between traffic-related air pollution and allergic disease is inconsistent, possibly because the adverse effects may be limited to susceptible subgroups and these have not been identified. This study examined children in the Childhood Asthma Prevention Study (CAPS), potentially susceptible to air pollution effects because of a family history of asthma. METHODS: We examined cross-sectional associations at age eight years between road density within 75 m and 50 m of home address weighted by road type (traffic density), as a proxy for traffic-related air pollution, on the following allergic and respiratory outcomes: skin prick tests (SPTs), total and specific serum IgE, pre- and post-bronchodilator lung function, airway hyperresponsiveness, exhaled NO, and reported asthma and rhinitis. RESULTS: Weighted road density was positively associated with allergic sensitisation and allergic rhinitis. Adjusted relative risk (RR) for house dust mite (HDM) positive SPT was 1.25 (95% CI: 1.06 1.48), for detectable house dust mite-specific IgE was 1.19 (95% CI: 1.01-1.41) and for allergic rhinitis was 1.30 (95% CI: 1.03-1.63) per 100 m local road or 33.3 m motorway within 50 m of home. Associations were also seen with small decrements of peak and mid-expiratory flows and increased risk of asthma, current wheeze and rhinitis in atopic children. CONCLUSION: Associations between road density and allergic disease were found in a potentially susceptible subgroup of children at high risk of developing atopy and asthma. PMID- 24949628 TI - Developing and validating the Youth Conduct Problems Scale-Rwanda: a mixed methods approach. AB - This study developed and validated the Youth Conduct Problems Scale-Rwanda (YCPS R). Qualitative free listing (n = 74) and key informant interviews (n = 47) identified local conduct problems, which were compared to existing standardized conduct problem scales and used to develop the YCPS-R. The YCPS-R was cognitive tested by 12 youth and caregiver participants, and assessed for test-retest and inter-rater reliability in a sample of 64 youth. Finally, a purposive sample of 389 youth and their caregivers were enrolled in a validity study. Validity was assessed by comparing YCPS-R scores to conduct disorder, which was diagnosed with the Mini International Neuropsychiatric Interview for Children, and functional impairment scores on the World Health Organization Disability Assessment Schedule Child Version. ROC analyses assessed the YCPS-R's ability to discriminate between youth with and without conduct disorder. Qualitative data identified a local presentation of youth conduct problems that did not match previously standardized measures. Therefore, the YCPS-R was developed solely from local conduct problems. Cognitive testing indicated that the YCPS-R was understandable and required little modification. The YCPS-R demonstrated good reliability, construct, criterion, and discriminant validity, and fair classification accuracy. The YCPS R is a locally-derived measure of Rwandan youth conduct problems that demonstrated good psychometric properties and could be used for further research. PMID- 24949626 TI - IIS--Integrated Interactome System: a web-based platform for the annotation, analysis and visualization of protein-metabolite-gene-drug interactions by integrating a variety of data sources and tools. AB - BACKGROUND: High-throughput screening of physical, genetic and chemical-genetic interactions brings important perspectives in the Systems Biology field, as the analysis of these interactions provides new insights into protein/gene function, cellular metabolic variations and the validation of therapeutic targets and drug design. However, such analysis depends on a pipeline connecting different tools that can automatically integrate data from diverse sources and result in a more comprehensive dataset that can be properly interpreted. RESULTS: We describe here the Integrated Interactome System (IIS), an integrative platform with a web-based interface for the annotation, analysis and visualization of the interaction profiles of proteins/genes, metabolites and drugs of interest. IIS works in four connected modules: (i) Submission module, which receives raw data derived from Sanger sequencing (e.g. two-hybrid system); (ii) Search module, which enables the user to search for the processed reads to be assembled into contigs/singlets, or for lists of proteins/genes, metabolites and drugs of interest, and add them to the project; (iii) Annotation module, which assigns annotations from several databases for the contigs/singlets or lists of proteins/genes, generating tables with automatic annotation that can be manually curated; and (iv) Interactome module, which maps the contigs/singlets or the uploaded lists to entries in our integrated database, building networks that gather novel identified interactions, protein and metabolite expression/concentration levels, subcellular localization and computed topological metrics, GO biological processes and KEGG pathways enrichment. This module generates a XGMML file that can be imported into Cytoscape or be visualized directly on the web. CONCLUSIONS: We have developed IIS by the integration of diverse databases following the need of appropriate tools for a systematic analysis of physical, genetic and chemical-genetic interactions. IIS was validated with yeast two-hybrid, proteomics and metabolomics datasets, but it is also extendable to other datasets. IIS is freely available online at: http://www.lge.ibi.unicamp.br/lnbio/IIS/. PMID- 24949629 TI - Mechanism for adhesion G protein-coupled receptor GPR56-mediated RhoA activation induced by collagen III stimulation. AB - GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) family. Despite the importance of GPR56 in brain development, where mutations cause a devastating human brain malformation called bilateral frontoparietal polymicrogyria (BFPP), the signaling mechanism(s) remain largely unknown. Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); however, the biological significance of this cleavage is elusive. Taking advantage of the recent identification of a GPR56 ligand and the presence of BFPP-associated mutations, we investigated the molecular mechanism of GPR56 signaling. We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation. Furthermore, one of the BFPP-associated mutations, L640R, does not affect collagen III-induced lipid raft association of GPR56. Instead, it specifically abolishes collagen III-mediated RhoA activation. Together, these findings reveal a novel signaling mechanism that may apply to other members of the adhesion GPCR family. PMID- 24949633 TI - Validation of airway wall measurements by optical coherence tomography in porcine airways. AB - Examining and quantifying changes in airway morphology is critical for studying longitudinal pathogenesis and interventions in diseases such as chronic obstructive pulmonary disease and asthma. Here we present fiber-optic optical coherence tomography (OCT) as a nondestructive technique to precisely and accurately measure the 2-dimensional cross-sectional areas of airway wall substructure divided into the mucosa (WAmuc), submucosa (WAsub), cartilage (WAcart), and the airway total wall area (WAt). Porcine lung airway specimens were dissected from freshly resected lung lobes (N = 10). Three-dimensional OCT imaging using a fiber-optic rotary-pullback probe was performed immediately on airways greater than 0.9 mm in diameter on the fresh airway specimens and subsequently on the same specimens post-formalin-fixation. The fixed specimens were serially sectioned and stained with H&E. OCT images carefully matched to selected sections stained with Movat's pentachrome demonstrated that OCT effectively identifies airway epithelium, lamina propria, and cartilage. Selected H&E sections were digitally scanned and airway total wall areas were measured. Traced measurements of WAmuc, WAsub, WAcart, and WAt from OCT images of fresh specimens by two independent observers found there were no significant differences (p>0.05) between the observer's measurements. The same wall area measurements from OCT images of formalin-fixed specimens found no significant differences for WAsub, WAcart and WAt, and a small but significant difference for WAmuc. Bland-Altman analysis indicated there were negligible biases between the observers for OCT wall area measurements in both fresh and formalin-fixed specimens. Bland-Altman analysis also indicated there was negligible bias between histology and OCT wall area measurements for both fresh and formalin-fixed specimens. We believe this study sets the groundwork for quantitatively monitoring pathogenesis and interventions in the airways using OCT. PMID- 24949630 TI - Integrating EMR-linked and in vivo functional genetic data to identify new genotype-phenotype associations. AB - The coupling of electronic medical records (EMR) with genetic data has created the potential for implementing reverse genetic approaches in humans, whereby the function of a gene is inferred from the shared pattern of morbidity among homozygotes of a genetic variant. We explored the feasibility of this approach to identify phenotypes associated with low frequency variants using Vanderbilt's EMR based BioVU resource. We analyzed 1,658 low frequency non-synonymous SNPs (nsSNPs) with a minor allele frequency (MAF)<10% collected on 8,546 subjects. For each nsSNP, we identified diagnoses shared by at least 2 minor allele homozygotes and with an association p<0.05. The diagnoses were reviewed by a clinician to ascertain whether they may share a common mechanistic basis. While a number of biologically compelling clinical patterns of association were observed, the frequency of these associations was identical to that observed using genotype permuted data sets, indicating that the associations were likely due to chance. To refine our analysis associations, we then restricted the analysis to 711 nsSNPs in genes with phenotypes in the On-line Mendelian Inheritance in Man (OMIM) or knock-out mouse phenotype databases. An initial comparison of the EMR diagnoses to the known in vivo functions of the gene identified 25 candidate nsSNPs, 19 of which had significant genotype-phenotype associations when tested using matched controls. Twleve of the 19 nsSNPs associations were confirmed by a detailed record review. Four of 12 nsSNP-phenotype associations were successfully replicated in an independent data set: thrombosis (F5,rs6031), seizures/convulsions (GPR98,rs13157270), macular degeneration (CNGB3,rs3735972), and GI bleeding (HGFAC,rs16844401). These analyses demonstrate the feasibility and challenges of using reverse genetics approaches to identify novel gene phenotype associations in human subjects using low frequency variants. As increasing amounts of rare variant data are generated from modern genotyping and sequence platforms, model organism data may be an important tool to enable discovery. PMID- 24949634 TI - iTRAQ-based proteomics reveals novel members involved in pathogen challenge in sea cucumber Apostichopus japonicus. AB - Skin ulceration syndrome (SUS) is considered to be a major constraint for the stable development of Apostichopus japonicus culture industries. In this study, we investigated protein changes in the coelomocytes of A. japonicus challenged by Vibrio splendidus using isobaric tags for relative and absolute quantification (iTRAQ) over a 96 h time course. Consequently, 228 differentially expressed proteins were identified in two iTRAQs. A comparison of the protein expression profiles among different time points detected 125 proteins primarily involved in response to endogenous stimuli at 24 h. At 48 h, the number of differentially expressed proteins decreased to 67, with their primary function being oxidation reduction. At the end of pathogen infection, proteins responsive to amino acid stimuli and some metabolic processes were classified as the predominant group. Fifteen proteins were differentially expressed at all time points, among which eight proteins related to pathologies in higher animals were shown to be down regulated after V. splendidus infection: paxillin, fascin-2, aggrecan, ololfactomedin-1, nesprin-3, a disintegrin-like and metallopeptidase with thrombospondin type 1 motif (Adamts7), C-type lectin domain family 4 (Clec4g) and n-myc downstream regulated gene 1 (Ndrg1). To gain more insight into two SUS related miRNA (miR-31 and miR-2008) targets at the protein level, all 129 down regulated proteins were further analyzed in combination with RNA-seq. Twelve and eight proteins were identified as putative targets for miR-31 and miR-2008, respectively, in which six proteins (5 for miR-31 and 1 for miR-2008) displayed higher possibilities to be regulated at the level of translation. Overall, the present work enhances our understanding of the process of V. splendidus challenged sea cucumber and provides a new method for screening miRNAs targets at the translation level. PMID- 24949635 TI - Shell extracts from the marine bivalve Pecten maximus regulate the synthesis of extracellular matrix in primary cultured human skin fibroblasts. AB - Mollusc shells are composed of more than 95% calcium carbonate and less than 5% of an organic matrix consisting mostly of proteins, glycoproteins and polysaccharides. Previous studies have elucidated the biological activities of the shell matrices from bivalve molluscs on skin, especially on the expression of the extracellular matrix components of fibroblasts. In this work, we have investigated the potential biological activities of shell matrix components extracted from the shell of the scallop Pecten maximus on human fibroblasts in primary culture. Firstly, we demonstrated that shell matrix components had different effects on general cellular activities. Secondly, we have shown that the shell matrix components stimulate the synthesis of type I and III collagens, as well as that of sulphated GAGs. The increased expression of type I collagen is likely mediated by the recruitment of transactivating factors (Sp1, Sp3 and human c-Krox) in the -112/-61 bp COL1A1 promoter region. Finally, contrarily to what was obtained in previous works, we demonstrated that the scallop shell extracts have only a small effect on cell migration during in vitro wound tests and have no effect on cell proliferation. Thus, our research emphasizes the potential use of shell matrix of Pecten maximus for dermo-cosmetic applications. PMID- 24949637 TI - Pathogenicity of Shigella in chickens. AB - Shigellosis in chickens was first reported in 2004. This study aimed to determine the pathogenicity of Shigella in chickens and the possibility of cross-infection between humans and chickens. The pathogenicity of Shigella in chickens was examined via infection of three-day-old SPF chickens with Shigella strain ZD02 isolated from a human patient. The virulence and invasiveness were examined by infection of the chicken intestines and primary chicken intestinal epithelial cells. The results showed Shigella can cause death via intraperitoneal injection in SPF chickens, but only induce depression via crop injection. Immunohistochemistry and transmission electron microscopy revealed the Shigella can invade the intestinal epithelia. Immunohistochemistry of the primary chicken intestinal epithelial cells infected with Shigella showed the bacteria were internalized into the epithelial cells. Electron microscopy also confirmed that Shigella invaded primary chicken intestinal epithelia and was encapsulated by phagosome-like membranes. Our data demonstrate that Shigella can invade primary chicken intestinal epithelial cells in vitro and chicken intestinal mucosa in vivo, resulting in pathogenicity and even death. The findings suggest Shigella isolated from human or chicken share similar pathogenicity as well as the possibility of human-poultry cross-infection, which is of public health significance. PMID- 24949636 TI - Proteomics analysis of the non-muscle myosin heavy chain IIa-enriched actin myosin complex reveals multiple functions within the podocyte. AB - MYH9 encodes non-muscle myosin heavy chain IIA (NMMHCIIA), the predominant force generating ATPase in non-muscle cells. Several lines of evidence implicate a role for MYH9 in podocytopathies. However, NMMHCIIA's function in podocytes remains unknown. To better understand this function, we performed immuno-precipitation followed by mass-spectrometry proteomics to identify proteins interacting with the NMMHCIIA-enriched actin-myosin complexes. Computational analyses revealed that these proteins belong to functional networks including regulators of cytoskeletal organization, metabolism and networks regulated by the HIV-1 gene nef. We further characterized the subcellular localization of NMMHCIIA within podocytes in vivo, and found it to be present within the podocyte major foot processes. Finally, we tested the effect of loss of MYH9 expression in podocytes in vitro, and found that it was necessary for cytoskeletal organization. Our results provide the first survey of NMMHCIIA-enriched actin-myosin-interacting proteins within the podocyte, demonstrating the important role of NMMHCIIA in organizing the elaborate cytoskeleton structure of podocytes. Our characterization of NMMHCIIA's functions goes beyond the podocyte, providing important insights into its general molecular role. PMID- 24949639 TI - EPMOSt: an energy-efficient passive monitoring system for wireless sensor networks. AB - Monitoring systems are important for debugging and analyzing Wireless Sensor Networks (WSN). In passive monitoring, a monitoring network needs to be deployed in addition to the network to be monitored, named the target network. The monitoring network captures and analyzes packets transmitted by the target network. An energy-efficient passive monitoring system is necessary when we need to monitor a WSN in a real scenario because the lifetime of the monitoring network is extended and, consequently, the target network benefits from the monitoring for a longer time. In this work, we have identified, analyzed and compared the main passive monitoring systems proposed for WSN. During our research, we did not identify any passive monitoring system for WSN that aims to reduce the energy consumption of the monitoring network. Therefore, we propose an Energy-efficient Passive MOnitoring SysTem for WSN named EPMOSt that provides monitoring information using a Simple Network Management Protocol (SNMP) agent. Thus, any management tool that supports the SNMP protocol can be integrated with this monitoring system. Experiments with real sensors were performed in several scenarios. The results obtained show the energy efficiency of the proposed monitoring system and the viability of using it to monitor WSN in real scenarios. PMID- 24949638 TI - Active optical sensors for tree stem detection and classification in nurseries. AB - Active optical sensing (LIDAR and light curtain transmission) devices mounted on a mobile platform can correctly detect, localize, and classify trees. To conduct an evaluation and comparison of the different sensors, an optical encoder wheel was used for vehicle odometry and provided a measurement of the linear displacement of the prototype vehicle along a row of tree seedlings as a reference for each recorded sensor measurement. The field trials were conducted in a juvenile tree nursery with one-year-old grafted almond trees at Sierra Gold Nurseries, Yuba City, CA, United States. Through these tests and subsequent data processing, each sensor was individually evaluated to characterize their reliability, as well as their advantages and disadvantages for the proposed task. Test results indicated that 95.7% and 99.48% of the trees were successfully detected with the LIDAR and light curtain sensors, respectively. LIDAR correctly classified, between alive or dead tree states at a 93.75% success rate compared to 94.16% for the light curtain sensor. These results can help system designers select the most reliable sensor for the accurate detection and localization of each tree in a nursery, which might allow labor-intensive tasks, such as weeding, to be automated without damaging crops. PMID- 24949640 TI - Detection and tracking of a moving target using SAR images with the particle filter-based track-before-detect algorithm. AB - A novel approach to detecting and tracking a moving target using synthetic aperture radar (SAR) images is proposed in this paper. Achieved with the particle filter (PF) based track-before-detect (TBD) algorithm, the approach is capable of detecting and tracking the low signal-to-noise ratio (SNR) moving target with SAR systems, which the traditional track-after-detect (TAD) approach is inadequate for. By incorporating the signal model of the SAR moving target into the algorithm, the ambiguity in target azimuth position and radial velocity is resolved while tracking, which leads directly to the true estimation. With the sub-area substituted for the whole area to calculate the likelihood ratio and a pertinent choice of the number of particles, the computational efficiency is improved with little loss in the detection and tracking performance. The feasibility of the approach is validated and the performance is evaluated with Monte Carlo trials. It is demonstrated that the proposed approach is capable to detect and track a moving target with SNR as low as 7 dB, and outperforms the traditional TAD approach when the SNR is below 14 dB. PMID- 24949642 TI - A new surface plasmon resonance-based immunoassay for rapid, reproducible and sensitive quantification of pentraxin-3 in human plasma. AB - A new immunoassay based on surface plasmon resonance (SPR) for the rapid, reproducible and sensitive determination of pentraxin-3 (PTX3) levels in human plasma has been developed and characterized. The method involves a 3-min flow of plasma over a sensor chip pre-coated with a monoclonal anti-PTX3 antibody (MNB4), followed by a 3-min flow of a polyclonal anti-PTX3 antibody (pAb), required for specific recognition of captured PTX3. The SPR signal generated with this secondary antibody linearly correlates with the plasma PTX3 concentration, in the range of 5-1500 ng/mL, with a lowest limit of detection of 5 ng/mL. The PTX3 concentrations determined with the SPR-based immunoassay in the plasma of 21 patients with sepsis, ranging 15-1600 ng/mL, were superimposable to those found in a classic ELISA immunoassay. Since the PTX3 concentration in the plasma of healthy subjects is <2 ng/mL, but markedly rises in certain medical conditions, the method is useful to quantify pathological levels of this important biomarker, with important diagnostic applications. In comparison with the classic ELISA, the SPR-based approach is much faster (30 min versus 4-5 h) and could be exploited for the development of new cost-effective SPR devices for point-of-care diagnosis. PMID- 24949641 TI - Isolation and epitope mapping of staphylococcal enterotoxin B single-domain antibodies. AB - Single-domain antibodies (sdAbs), derived from the heavy chain only antibodies found in camelids such as llamas have the potential to provide rugged detection reagents with high affinities, and the ability to refold after denaturation. We have isolated and characterized sdAbs specific to staphylococcal enterotoxin B (SEB) which bind to two distinct epitopes and are able to function in a sandwich immunoassay for toxin detection. Characterization of these sdAbs revealed that each exhibited nanomolar binding affinities or better. Melting temperatures for the sdAbs ranged from approximately 60 degrees C to over 70 degrees C, with each demonstrating at least partial refolding after denaturation and several were able to completely refold. A first set of sdAbs was isolated by panning the library using adsorbed antigen, all of which recognized the same epitope on SEB. Epitope mapping suggested that these sdAbs bind to a particular fragment of SEB (VKSIDQFLYFDLIYSI) containing position L45 (underlined), which is involved in binding to the major histocompatibility complex (MHC). Differences in the binding affinities of the sdAbs to SEB and a less-toxic vaccine immunogen, SEBv (L45R/Y89A/Y94A) were also consistent with binding to this epitope. A sandwich panning strategy was utilized to isolate sdAbs which bind a second epitope. This epitope differed from the initial one obtained or from that recognized by previously isolated anti-SEB sdAb A3. Using SEB-toxin spiked milk we demonstrated that these newly isolated sdAbs could be utilized in sandwich-assays with each other, A3, and with various monoclonal antibodies. PMID- 24949643 TI - Optical characteristic research on fiber Bragg gratings utilizing finite element and eigenmode expansion methods. AB - Compared with coupled-mode theory (CMT), which is widely used for studies involving optical fiber Bragg gratings (FBGs), the proposed investigation scheme is visualized, diagrammatic, and simple. This method combines the finite element method (FEM) and eigenmode expansion method (EEM). The function of the FEM is to calculate all guided modes that match the boundary conditions of optical fiber waveguides. Moreover, the FEM is used for implementing power propagation for HE11 in optical fiber devices. How the periodic characteristic of FBG causes this novel scheme to be substantially superior to CMT is explained in detail. Regarding current numerical calculation techniques, the scheme proposed in this paper is the only method capable of the 3D design and analysis of large periodic components. Additionally, unlike CMT, in which deviations exist between the designed wavelength lambda(D) and the maximal reflection wavelength lambdamax, the proposed method performs rapid scans of the periods of optical FBG. Therefore, once the operating wavelength is set for the component design, the maximal reflection wavelength of the final products can be accurately limited to that of the original design, such as lambda = 1550 nm. Furthermore, a comparison between the period scan plot and the optical spectra plot for FBG indicated an inverse relationship between the periods and wavelengths. Consequently, this property can be used to predict the final FBG spectra before implementing time consuming calculations. By employing this novel investigation scheme involving a rigorous design procedure, the graphical and simple calculation method reduces the studying time and professional expertise required for researching and applying optical FBG. PMID- 24949645 TI - Application of wireless power transmission systems in wireless capsule endoscopy: an overview. AB - Wireless capsule endoscopy (WCE) is a promising technology for direct diagnosis of the entire small bowel to detect lethal diseases, including cancer and obscure gastrointestinal bleeding (OGIB). To improve the quality of diagnosis, some vital specifications of WCE such as image resolution, frame rate and working time need to be improved. Additionally, future multi-functioning robotic capsule endoscopy (RCE) units may utilize advanced features such as active system control over capsule motion, drug delivery systems, semi-surgical tools and biopsy. However, the inclusion of the above advanced features demands additional power that make conventional power source methods impractical. In this regards, wireless power transmission (WPT) system has received attention among researchers to overcome this problem. Systematic reviews on techniques of using WPT for WCE are limited, especially when involving the recent technological advancements. This paper aims to fill that gap by providing a systematic review with emphasis on the aspects related to the amount of transmitted power, the power transmission efficiency, the system stability and patient safety. It is noted that, thus far the development of WPT system for this WCE application is still in initial stage and there is room for improvements, especially involving system efficiency, stability, and the patient safety aspects. PMID- 24949646 TI - Computational intelligence techniques for tactile sensing systems. AB - Tactile sensing helps robots interact with humans and objects effectively in real environments. Piezoelectric polymer sensors provide the functional building blocks of the robotic electronic skin, mainly thanks to their flexibility and suitability for detecting dynamic contact events and for recognizing the touch modality. The paper focuses on the ability of tactile sensing systems to support the challenging recognition of certain qualities/modalities of touch. The research applies novel computational intelligence techniques and a tensor-based approach for the classification of touch modalities; its main results consist in providing a procedure to enhance system generalization ability and architecture for multi-class recognition applications. An experimental campaign involving 70 participants using three different modalities in touching the upper surface of the sensor array was conducted, and confirmed the validity of the approach. PMID- 24949648 TI - Detection of Legionella pneumophila at high altitude in Tibetan plateau. PMID- 24949647 TI - The photochemical route to octahedral iron(V). Primary processes and quantum yields from ultrafast mid-infrared spectroscopy. AB - Recently, the complex cation [(cyclam-ac)Fe(III)(N3)](+) has been used in solid matrices under cryogenic conditions as a photochemical precursor for an octahedral iron nitride containing the metal at the remarkably high oxidation state +5. Here, we study the photochemical primary events of this complex cation in liquid solution at room temperature using femtosecond time-resolved mid infrared (fs-MIR) spectroscopy as well as step-scan Fourier-transform infrared spectroscopy, both of which were carried out with variable-wavelength excitation. In stark contrast to the cryomatrix experiments, a photooxidized product cannot be detected in liquid solution when the complex is excited through its putative LMCT band in the visible region. Instead, only a redox-neutral dissociation of azide anions is seen under these conditions. However, clear evidence is found for the formation of the highly oxidized iron nitride product when the photolysis is carried out in liquid solution with UV light. Yet, the photooxidation must compete with photoreductive Fe-N bond cleavage leading to azide radicals and an iron(II) complex. Both, redox-neutral and photoreductive Fe-N bond breakage as well as photooxidative N-N bond breakage occur on a time scale well below a few hundred femtoseconds. The majority of fragments suffer from geminate recombination back to the parent complex on a time scale of 10 ps. Upper limits of the primary quantum yield for photooxidation are derived from the fs-MIR data, which increase with increasing energy of the photolysis photon. PMID- 24949644 TI - The theory and fundamentals of bioimpedance analysis in clinical status monitoring and diagnosis of diseases. AB - Bioimpedance analysis is a noninvasive, low cost and a commonly used approach for body composition measurements and assessment of clinical condition. There are a variety of methods applied for interpretation of measured bioimpedance data and a wide range of utilizations of bioimpedance in body composition estimation and evaluation of clinical status. This paper reviews the main concepts of bioimpedance measurement techniques including the frequency based, the allocation based, bioimpedance vector analysis and the real time bioimpedance analysis systems. Commonly used prediction equations for body composition assessment and influence of anthropometric measurements, gender, ethnic groups, postures, measurements protocols and electrode artifacts in estimated values are also discussed. In addition, this paper also contributes to the deliberations of bioimpedance analysis assessment of abnormal loss in lean body mass and unbalanced shift in body fluids and to the summary of diagnostic usage in different kinds of conditions such as cardiac, pulmonary, renal, and neural and infection diseases. PMID- 24949649 TI - The Nano-X Linear Accelerator: A Compact and Economical Cancer Radiotherapy System Incorporating Patient Rotation. AB - Rapid technological improvements in radiotherapy delivery results in improved outcomes to patients, yet current commercial systems with these technologies on board are costly. The aim of this study was to develop a state-of-the-art cancer radiotherapy system that is economical and space efficient fitting with current world demands. The Nano-X system is a compact design that is light weight combining a patient rotation system with a vertical 6 MV fixed beam. In this paper, we present the Nano-X system design configuration, an estimate of the system dimensions and its potential impact on shielding cost reductions. We provide an assessment of implementing such a radiotherapy system clinically, its advantages and disadvantages compared to a compact conventional gantry rotating linac. The Nano-X system has several differentiating features from current radiotherapy systems, it is [1] compact and therefore can fit into small vaults, [2] light weight, and [3] engineering efficient, i.e., it rotates a relatively light component and the main treatment delivery components are not under rotation (e.g., DMLCs). All these features can have an impact on reducing the costs of the system. In terms of shielding requirements, leakage radiation was found to be the dominant contributor to the Nano-X vault and as such no primary shielding was necessary. For a low leakage design, the Nano-X vault footprint and concrete volume required is 17 m2 and 35 m3 respectively, compared to 54 m2 and 102 m3 for a conventional compact linac vault, resulting in decreased costs in shielding. Key issues to be investigated in future work are the possible patient comfort concerns associated with the patient rotation system, as well as the magnitude of deformation and subsequent adaptation requirements. PMID- 24949650 TI - Syntheses, structures, and physical properties of CsRE(2)Ag(3)Te(5) (RE = Pr, Nd, Sm, Gd-Er) and RbR(2)Ag(3)Te(5) (RE = Sm, Gd-Dy). AB - A new series of quaternary CsRE2Ag3Te5 (RE = Pr, Nd, Sm, Gd-Er) and RbRE2Ag3Te5 (RE = Sm, Gd-Dy), which have been synthesized from the elemental mixtures in ACl flux (A = Rb, Cs) and crystallized in the orthorhombic space group Cmcm, with a = 4.620(2)-4.504(2) A, b = 16.232(8)-16.027(8) A, c = 18.84(1)-18.32(2) and Z = 4, are isostructural to RbSm2Ag3Se5. These isostructural ARE2Ag3Te5 feature a three dimensional tunnel framework constructed by ionically bound RETe6 octahedron and covalently bound AgTe4 tetrahedron in which tunnels are filled by A. Typical semiconducting behavior is revealed by the electrical conductivity, Seebeck coefficient, optical band gap measurement, and the theoretical calculations. The undoped sintered polycrystalline pellets of CsRE2Ag3Te5 (containing 1.1-1.7% CsCl impurity) show very low electrical conductivity (sigmar.t. = 0.5-2.4 S/cm), very low thermal conductivity (kr,t = 0.66-0.53 W/(m.K)), and moderate Seebeck coefficient (160-200 MUV/K at 700 K). PMID- 24949652 TI - Varying TiO2 macroscopic fiber morphologies toward tuning their photocatalytic properties. AB - In a context of volatile organic compound photodecomposition, we have addressed TiO2-based macroscoscpic fiber generation. We have extruded hybrid sols of amorphous titania nanoparticles, latex nanoparticles, and nonionic surfactant (Tergitol) as structure-directing agents into a poly(vinyl alcohol) (PVA) solution bearing salts acting as a flocculating medium. The resulting nanocomposite TiO2/latex/PVA macroscopic fibers were thermally treated in air to open porosity by organic removal while generating the photocatalytically active anatase phase of TiO2 along with residual brookite. Considering the synthetic paths, we have varied both the diameter of the latex particles as well as their concentration within the starting sol. These parameters allow tuning both the voids created through the applied thermal treatment and the fiber final diameters. For gas-phase photocatalysis, we have shown that the fiber diameters, mesoscopic roughness, and macroscopic topological defects represent indeed important morphological parameters acting cooperatively toward both acetone degradation and its mineralization processes. Particularly, triggering the fiber morphological characteristics, we have increased their efficiency toward acetone degradation of around 550% when compared with previous work. PMID- 24949651 TI - Modulators of erythrocyte glutathione peroxidase activity in healthy adults: an observational study. AB - The aim of this study was to investigate the potential modulators of erythrocyte glutathione peroxidase (GPx) activity in young and apparently healthy individuals. One hundred one individuals (53 women and 48 men) were evaluated for anthropometric measurements, biochemical markers, clinical, dietary, and endogenous and exogenous components of the antioxidant defense system. Statistical analysis was performed to detect differences among subjects by the median of GPx activity. A linear regression model and Spearman correlation coefficients were used to screen the associations between GPx activity and interest variables. Individuals with higher GPx enzymatic activity were older and higher circulating levels of oxidized low-density lipoprotein (ox-LDL) values, but conversely lower nail concentrations of selenium and copper (P < 0.05). The GPx activity was positively correlated to truncal fat percentage values (r = 0.24, P = 0.016), circulating levels of ox-LDL (r = 0.28, P = 0.004), and daily vitamin C intake (r = 0.28, P = 0.007), and negatively correlated to the nail concentration of selenium (r = -0.24, P = 0.026). Interesting, it was noticed that the truncal fat percentage and circulating levels of ox-LDL explained 5.9 and 7.4% of the GPx enzymatic activity. Thus, preventive measures such as adequate antioxidant intake and proper fat percentage would be a priority in the nutritional care of young and apparently healthy individuals. PMID- 24949653 TI - Examining physiological responses across different driving maneuvers during an on road driving task: a pilot study comparing older and younger drivers. AB - OBJECTIVE: This pilot study aimed to investigate physiological responses during an on-road driving task for older and younger drivers. METHODS: Five older drivers (mean age = 74.60 years [2.97]) and 5 younger drivers (mean age = 30.00 years [3.08]) completed a series of cognitive assessments (Montreal Cognitive Assessment [MoCA], Mini Mental Status Examination [MMSE]; Trail Making Test [Trails A and Trails B]) and an on-road driving task along a predetermined, standardized urban route in their own vehicle. Driving performance was observed and scored by a single trained observer using a standardized procedure, where driving behaviors (appropriate and inappropriate) were scored for intersection negotiation, lane changing, and merging. During the on-road driving task, participants' heart rate (HR) was monitored with an unobtrusive physiological monitor. RESULTS: Younger drivers performed significantly better on all cognitive assessments compared to older drivers (MoCA: t(8) = 3.882, P <.01; MMSE: t(8) = 2.954, P <.05; Trails A: t(8) = -2.499, P <.05; Trails B: t(8) = -3.262, P <.05). Analyses of participants' performance during the on-road driving task revealed a high level of appropriate overall driving behavior (M = 87%, SD = 7.62, range = 73-95%), including intersection negotiation (M = 89%, SD = 8.37%), lane changing (M = 100%), and merging (M = 53%, SD = 28.28%). The overall proportion of appropriate driving behavior did not significantly differ across age groups (younger drivers: M = 87.6%, SD = 9.04; older drivers: M = 87.0%, SD = 6.96; t(8) = 0.118, P =.91). CONCLUSIONS: Although older drivers scored lower than younger drivers on the cognitive assessments, there was no indication of cognitive overload among older drivers based on HR response to the on-road driving task. The results provide preliminary evidence that mild age-related cognitive impairment may not pose a motor vehicle crash hazard for the wider older driver population. To maintain safe mobility of the aging population, further research into the specific crash risk factors in the older driver population is warranted. PMID- 24949655 TI - Interaction of mixed-ligand monolayer-protected Au144 clusters with biomimetic membranes as a function of the transmembrane potential. AB - Understanding the interaction of nanoparticles with cell membranes is a high priority research area for possible biomedical applications. We describe our findings concerning the interaction of Au144 monolayer-protected clusters (MPCs) with biomimetic membranes and their permeabilizing effect as a function of the transmembrane potential. We synthesized Au144(SCH2CH2Ph)60 and modified the capping monolayer with 8-mercaptooctanoic acid (Au144OctA) or thiolated trichogin (Au144TCG), a channel-forming peptide. The interactions of these MPCs with mercury-supported lipid mono- and bilayers were studied with a combination of electrochemical techniques specifically sensitive to changes in the properties of biomimetic membranes and/or charge-transfer phenomena. Permeabilization effects were evaluated through the influence of MPC uptake on the reduction of cadmium(II) ions. The nature and properties of the Au144 capping molecules play a crucial role in controlling how MPCs interact with membranes. The native MPC causes a small effect, whereas both Au144OctA and Au144TCG interact significantly with the lipid monolayer and show electroactivity. Whereas Au144OctA penetrates the membrane, Au144TCG pierces the membrane with its peptide appendage while remaining outside of it. Both clusters promote Cd(2+) reduction but with apparently different mechanisms. Because of the different way that they interact with the membrane, Au144OctA is more effective in Cd(2+) reduction when interacting with the lipid bilayer and Au144TCG performs particularly well when piercing the lipid monolayer. PMID- 24949654 TI - Efficacy of adding once-daily insulin glulisine in Japanese type 2 diabetes patients treated with insulin glargine and sitagliptin. AB - BACKGROUND: Glucose fluctuation often remains to be corrected under basal supported oral therapy. We investigated the efficacy of adding once-daily rapid acting insulin in Japanese diabetes patients treated with basal-supported oral therapy. SUBJECTS AND METHODS: In this 8-week, parallel-group, randomized, open label trial, 62 Japanese adults with type 2 diabetes treated with insulin glargine and 50 mg of sitagliptin were randomized into the following two arms: the single-bolus group, in which once-daily insulin glulisine was initiated at a main meal at a fifth (i.e., 20%) the dose of insulin glargine, and the control group, in which the dose of sitagliptin was maximized to 100 mg. The primary end point was the change of glycemic fluctuation assessed with the M-value. RESULTS: Baseline hemoglobin A1c levels, mean blood glucose profiles, and M-value were 7.2 +/- 0.6%, 9.3 +/- 1.7 mmol/L, and 21 +/- 13 units, respectively. At the end of the study, the single-bolus group had a greater reduction of M-value than the control group (P=0.02); the difference was 6.5 units (95% confidence interval, 1.1-11.9 units). The single-bolus group also had a greater reduction of mean blood glucose levels (P=0.01). There were no significant differences in the incidence of hypoglycemia or the weight change between the two groups (P>0.05). CONCLUSIONS: Adding once-daily insulin glulisine was more effective in controlling the glycemic fluctuation in Japanese type 2 diabetes patients treated with insulin glargine together with sitagliptin. PMID- 24949656 TI - Synthesis of cross-linked DNA containing oxidized abasic site analogues. AB - DNA interstrand cross-links are an important family of DNA damage that block replication and transcription. Recently, it was discovered that oxidized abasic sites react with the opposing strand of DNA to produce interstrand cross-links. Some of the cross-links between 2'-deoxyadenosine and the oxidized abasic sites, 5'-(2-phosphoryl-1,4-dioxobutane) (DOB) and the C4-hydroxylated abasic site (C4 AP), are formed reversibly. Chemical instability hinders biochemical, structural, and physicochemical characterization of these cross-linked duplexes. To overcome these limitations, we developed methods for preparing stabilized analogues of DOB and C4-AP cross-links via solid-phase oligonucleotide synthesis. Oligonucleotides of any sequence are attainable by synthesizing phosphoramidites in which the hydroxyl groups of the cross-linked product were orthogonally protected using photochemically labile and hydrazine labile groups. Selective unmasking of a single hydroxyl group precedes solid-phase synthesis of one arm of the cross linked DNA. The method is compatible with commercially available phosphoramidites and other oligonucleotide synthesis reagents. Cross-linked duplexes containing as many as 54 nt were synthesized on solid-phase supports. Subsequent enzyme ligation of one cross-link product provided a 60 bp duplex, which is suitable for nucleotide excision repair studies. PMID- 24949657 TI - Aptamer-functionalized gold nanoparticles as photoresponsive nanoplatform for co drug delivery. AB - Various platforms have been developed as innovative nanocarriers to deliver therapeutic agents to the diseased sites. Multifunctional surface modification allows an enhanced recognition and uptake of drug carriers by targeted cells. However, the development of drug resistance in some tumor cells plays a major role in the failure of chemotherapy. Drugs given in combination, called multidrug delivery approach, was designed to improve the therapeutic efficacy and has become an increasingly used strategy that is of great importance in clinical cancer treatments. In this study, aptamer-functionalized gold nanoparticles (Au NPs) have been used as a nanoplatform to codeliver two different anticancer drugs for improving the drug effectiveness. The surface of Au NPs (13 nm in diameter) was assembled with AS1411 aptamers, which tethered with 21-base pairs of (CGATCGA)3 sequence approached to the Au NPs. Both the photosensitizer 5,10,15,20 tetrakis(1-methylpyridinium-4-yl) porphyrin (TMPyP4) and the chemotherapeutic drug doxorubicin (Dox) were then physically attached to the AS1411-conjugated Au NPs (T/D:ds-NPs) and delivered to the target tumor cells such as HeLa and Dox resistant MCF-7R cell lines. When exposed to a 632 nm light, reactive oxygen species induced by TMPyP4 molecules were generated inside the living cells, followed by cell damage. In addition, triggered release of the complementary drugs also occurred simultaneously during the photodynamic reaction. In the presence of Dox molecules, the toxicity toward the target cells was superior to individual drug treatment. Overall, a co-drug delivery platform was successfully established to improve the therapeutic efficacy in tumor cells. The improvement of the photodynamic-stimulated triggered release was enhanced, thus highly promising precise drug release in targeted drug delivery. PMID- 24949658 TI - The PVH as a site of CB1-mediated stimulation of thermogenesis by MC4R agonism in male rats. AB - The present study was designed to investigate the involvement of the cannabinoid receptor 1 (CB1) in the stimulating effects of the melanocortin-4 receptor (MC4R) agonism on whole-body and brown adipose tissue (BAT) thermogenesis. In a first series of experiments, whole-body and BAT thermogenesis were investigated in rats infused in the third ventricle of the brain with the MC4R agonist melanotan II (MTII) and the CB1 agonist delta9-tetrahydrocannabinol (delta(9)-THC) or the CB1 antagonist AM251. Whole-body thermogenesis was measured by indirect calorimetry and BAT thermogenesis assessed from interscapular BAT (iBAT) temperature. delta(9)-THC blunted the effects of MTII on energy expenditure and iBAT temperature, whereas AM251 tended to potentiate the MTII effects. delta(9)-THC also blocked the stimulating effect of MTII on (14)C-bromopalmitate and (3)H deoxyglucose uptakes in iBAT. Additionally, delta(9)-THC attenuated the stimulating effect of MTII on the expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (Pgc1alpha), type II iodothyronine deiodinase (Dio2), carnitine palmitoyltransferase 1B (Cpt1b), and uncoupling protein 1 (Ucp1). In a second series of experiments, we addressed the involvement of the paraventricular hypothalamic nucleus (PVH) in the CB1-mediated effects of MTII on iBAT thermogenesis, which were assessed following the infusion of MTII in the PVH and delta(9)-THC or AM251 in the fourth ventricle of the brain. We demonstrated the ability of delta(9)-THC to blunt MTII-induced iBAT temperature elevation. delta(9)-THC also blocked the PVH effect of MTII on (14)C-bromopalmitate uptake as well as on Pgc1alpha and Dio2 expression in iBAT. Altogether the results of this study demonstrate the involvement of the PVH in the CB1-mediated stimulating effects of the MC4R agonist MTII on whole-body and BAT thermogenesis. PMID- 24949659 TI - Liraglutide enhances insulin sensitivity by activating AMP-activated protein kinase in male Wistar rats. AB - We investigated the effects of liraglutide on insulin sensitivity and glucose metabolism in male Wistar rats. The rats were fed a normal chow diet (NCD) or a 60% high-fat diet (HFD) for a total of 4 weeks. After 3 weeks of feeding, they were injected with liraglutide once a day for 7 days. Subsequently, euglycemic hyperinsulinemic clamp studies were performed after fasting the animals for 8 hours. During the clamp studies on the NCD-fed rats, the glucose infusion rate required for euglycemia was significantly higher in the liraglutide group than in the control group. The clamp hepatic glucose output was significantly lower in the liraglutide group than in the control group, but the insulin-stimulated glucose disposal rate did not change significantly in the liraglutide groups. The clamp studies on the HFD-fed rats revealed that the glucose infusion rate required to achieve euglycemia was significantly higher in the liraglutide group than in the control HFD group, and the insulin-stimulated glucose disposal rate increased significantly in the liraglutide groups. The clamp hepatic glucose output decreased significantly in the liraglutide groups. Consistent with the clamp data, the insulin-stimulated phosphorylation of Akt and AMP-activated protein kinase was enhanced in the livers of the NCD- and HFD-fed rats and in the skeletal muscles of the HFD-fed rats. Oil red O staining indicated that liraglutide also improved hepatic steatosis. In summary, our studies suggest that in normal glucose tolerance states, liraglutide enhances insulin sensitivity in the liver but not in skeletal muscles. However, in insulin-resistant states, liraglutide improves insulin resistance in the liver and muscles and improves fatty liver. PMID- 24949662 TI - An early reduction in GH peak amplitude in preproghrelin-deficient male mice has a minor impact on linear growth. AB - Ghrelin is a gut hormone processed from the proghrelin peptide acting as the endogenous ligand of the GH secretagogue receptor 1a. The regulatory role of endogenous ghrelin on pulsatile GH secretion and linear growth had to be established. The aim of the present study was to delineate the endogenous actions of preproghrelin on peripheral and central components of the GH axis. Accordingly, the ultradian pattern of GH secretion was measured in young and old preproghrelin-deficient males. Blood samples were collected by tail bleeding every 10 minutes over a period of 6 hours. Analysis of the GH pulsatile pattern by deconvolution showed that GH was secreted in an ultradian manner in all genotypes, with major secretory peaks occurring at about 3-hour intervals. In older mice, the peak number was reduced and secretion was less irregular compared with younger animals. Remarkably, in young Ghrl(-/-) mice, the amplitude of GH secretory bursts was significantly reduced. In older mice, however, genotype differences were less significant. Changes in GH pulsatility in young Ghrl(-/-) mice were associated with a tendency for reduced GH pituitary contents and plasma IGF-I concentrations, but with only a minor impact on linear growth. In Ghrl(+/-) mice, despite reduced Acyl ghrelin to des-acyl ghrelin ratio, GH secretion was not impaired. Ghrelin deficiency was not associated with a reduction in hypothalamic GHRH content or altered response to GHRH stimulation. Therefore, reduction in GHRH production and/or sensitivity do not primarily account for the altered GH pulsatile secretion of young Ghrl(-/-) mice. Instead, GHRH expression was elevated in young but not old Ghrl(-/-) mice, suggesting that differential compensatory responses resulting from the absence of endogenous ghrelin is occurring according to age. These results show that endogenous ghrelin is a regulator of GH pulse amplitude in growing mice but does not significantly modulate linear growth. PMID- 24949661 TI - Long term exendin-4 treatment reduces food intake and body weight and alters expression of brain homeostatic and reward markers. AB - Repeated administration of the long-acting glucagon-like peptide 1 receptor agonist exendin-4 (EX-4) has been shown to reduce food intake and body weight and do so without a rebound increase in food intake after treatment termination. The current study examines the neural mechanisms underlying these actions. After 6 weeks of maintenance on a standard chow or a high-fat (HF) diet, male Sprague Dawley rats were treated with EX-4 (3.2 MUg/kg, i.p., twice a day) or vehicle for 9 consecutive days. Food intake and body weight (BW) were monitored daily. Expression of the genes for the hypothalamic arcuate nucleus (ARC) peptides proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti gene-related protein was determined. Expression of the dopamine precursor tyrosine hydroxylase (TH) gene in the ventral tegmental area and genes for dopamine receptors 1 (D1R) and dopamine receptor 2 in the nucleus accumbens were also determined. Pair-fed groups were included to control for the effects of reduced food intake and BW. Treatment with EX-4 significantly decreased food intake and BW over the 9-day period in both the standard chow and HF groups. HF feeding decreased POMC without changing NPY/agouti gene-related protein gene expression in the ARC. Treatment with EX-4 increased POMC and decreased NPY expression independent of the reduction of food intake and BW. Mesolimbic TH and D1R gene expression were decreased significantly in chronic HF diet-fed rats, and these changes were reversed in both EX-4 and pair-fed conditions. These results suggest a role for increased POMC and decreased NPY expression in the ARC in the effects of EX-4 on food intake and BW. Our findings also suggest that EX-4 induced the recovery of mesolimbic TH and D1R expression in HF diet-fed rats may be secondary to HF intake reduction and/or weight loss. PMID- 24949660 TI - The vitamin D receptor (VDR) is expressed in skeletal muscle of male mice and modulates 25-hydroxyvitamin D (25OHD) uptake in myofibers. AB - Vitamin D deficiency is associated with a range of muscle disorders, including myalgia, muscle weakness, and falls. In humans, polymorphisms of the vitamin D receptor (VDR) gene are associated with variations in muscle strength, and in mice, genetic ablation of VDR results in muscle fiber atrophy and motor deficits. However, mechanisms by which VDR regulates muscle function and morphology remain unclear. A crucial question is whether VDR is expressed in skeletal muscle and directly alters muscle physiology. Using PCR, Western blotting, and immunohistochemistry (VDR-D6 antibody), we detected VDR in murine quadriceps muscle. Detection by Western blotting was dependent on the use of hyperosmolar lysis buffer. Levels of VDR in muscle were low compared with duodenum and dropped progressively with age. Two in vitro models, C2C12 and primary myotubes, displayed dose- and time-dependent increases in expression of both VDR and its target gene CYP24A1 after 1,25(OH)2D (1,25 dihydroxyvitamin D) treatment. Primary myotubes also expressed functional CYP27B1 as demonstrated by luciferase reporter studies, supporting an autoregulatory vitamin D-endocrine system in muscle. Myofibers isolated from mice retained tritiated 25-hydroxyvitamin D3, and this increased after 3 hours of pretreatment with 1,25(OH)2D (0.1 nM). No such response was seen in myofibers from VDR knockout mice. In summary, VDR is expressed in skeletal muscle, and vitamin D regulates gene expression and modulates ligand-dependent uptake of 25-hydroxyvitamin D3 in primary myofibers. PMID- 24949663 TI - Glucagon is essential for adaptive thermogenesis in brown adipose tissue. AB - Glucagon, a counterregulatory hormone to insulin, serves as a regulator of glucose homeostasis and acts in response to hypoglycemia. Earlier studies have shown that glucagon administration induces thermogenesis in experimental animal models. However, it is not known whether endogenous glucagon is involved in the regulation of brown adipose tissue (BAT) function. Here we investigated the role of glucagon in cold-induced thermogenesis in male mice deficient in proglucagon derived peptides (GCGKO mice). Upon exposure to cold, GCGKO mice exhibited a greater decrease in rectal temperature than control mice. The cold exposure induced increase in oxygen consumption in GCGKO mice was less than that seen in control mice. Moreover, the increase in oxygen consumption after administration of a beta3-adrenergic receptor agonist, CL-316,243, was also lesser in GCGKO than in control mice. Expression of thermogenic genes, including the gene encoding uncoupling protein 1 (Ucp1), was reduced in the BAT of GCGKO mice under ambient as well as cold conditions. Administration of glucagon restored the expression of Ucp1 mRNA in the BAT as well as the expression of the fibroblast growth factor 21 gene (Fgf21) in the liver. Supplementation with glucagon for 2 weeks resulted in higher plasma Fgf21 levels and improved responses to CL-316,243 in GCGKO mice. These results indicated that endogenous glucagon is essential for adaptive thermogenesis and that it regulates BAT function, most likely by increasing hepatic Fgf21 production. PMID- 24949664 TI - Life without the iodothyronine deiodinases. AB - The three iodothyronine deiodinases (D1, D2, and D3) play major roles in determining the tissue and cellular content of the active thyroid hormone, T3. The D1 and D2 5'-deiodinate T4 to T3 and the D3 5-deiodinates T4 and T3 to inactive forms. 5'-Deiodinase-deficient mice (D1/D2KO) have a mild gross phenotype, whereas D3-deficient mice (D3KO) exhibit significant phenotypic abnormalities of the hypothalamic/pituitary/thyroid axis and other organ systems and are not viable in some background strains. The goal of this study was to perform an initial assessment of the phenotype of mice devoid of all deiodinases (D1/D2/D3KO) and determine whether the marked phenotypic abnormalities of the D3KO mouse are exacerbated or mitigated by the absence of the D1 and D2. Relative to D3KO mutants, survival, growth, and fertility were improved in the D1/D2/D3KO mice, although considerably impaired relative to wild-type and D1/D2KO animals. The triple deiodinase-deficient mice also demonstrated normal brain T3 content at postnatal day 6, normal cerebellar expression of the T3-responsive gene hairless at postnatal day 21, and near normalization of their serum thyroid hormone levels as adults, parameters that are abnormal in either the D3KO or the D1/D2KO mutants. These studies demonstrate that within the supportive environment of a research vivarium, mice lacking all three deiodinases can be bred and survive and that at least some of the phenotypic abnormalities resulting from a deficiency of either the D3 5-deiodinase, or the D1 and D2 5'-deiodinase, are mitigated by the simultaneous lack of all three enzymes. PMID- 24949666 TI - Atmospheric gas phase chemistry of CH2?NH and HNC. A first-principles approach. AB - Quantum chemical methods were used to investigate the OH initiated atmospheric degradation of methanimine, CH2?NH, the major primary product in the atmospheric photo-oxidation of methylamine, CH3NH2. Energies of stationary points on potential energy surfaces of reaction were calculated using multireference perturbation theory and coupled cluster theory. The results show that hydrogen abstraction dominates over the addition route in the CH2?NH + OH reaction, and that the major primary product is HCN, while HNC and CHONH2 are minor primary products. HNC is found to react with OH exclusively via addition to the carbon atom followed by O-H scission leading to HNCO; N2O is not a product in the atmospheric photo-oxidation of HNC. Additional G4 calculations of the CH2?NH + O3 reaction show that this is too slow to be of importance at atmospheric conditions. Rate coefficients for the CH2?NH + OH and HNC + OH reactions were calculated as a function of temperature and pressure using a master equation model based on the coupled cluster theory results. The rate coefficients for OH reaction with CH2?NH and HNC at 1000 mbar and room temperature are calculated to be 3.0 * 10(-12) and 1.3 * 10(-11) cm(3) molecule(-1) s(-1), respectively. The atmospheric fate of CH2?NH is discussed and a gas phase photo-oxidation mechanism is presented. PMID- 24949665 TI - The Sirtuin1 activator SRT3025 down-regulates sclerostin and rescues ovariectomy induced bone loss and biomechanical deterioration in female mice. AB - Estrogen deficiency leads to rapid bone loss and skeletal fragility. Sclerostin, encoded by the sost gene, and a product of the osteocyte, is a negative regulator of bone formation. Blocking sclerostin increases bone mass and strength in animals and humans. Sirtuin1 (Sirt1), a player in aging and metabolism, regulates bone mass and inhibits sost expression by deacetylating histone 3 at its promoter. We asked whether a Sirt1-activating compound could rescue ovariectomy (OVX)-induced bone loss and biomechanical deterioration in 9-week-old C57BL/6 mice. OVX resulted in a substantial decrease in skeletal Sirt1 expression accompanied by an increase in sclerostin. Oral administration of SRT3025, a Sirt1 activator, at 50 and 100 mg/kg.d for 6 weeks starting 6 weeks after OVX fully reversed the deleterious effects of OVX on vertebral bone mass, microarchitecture, and femoral biomechanical properties. Treatment with SRT3025 decreased bone sclerostin expression and increased cortical periosteal mineralizing surface and serum propeptide of type I procollagen, a bone formation marker. In vitro, in the murine long bone osteocyte-Y4 osteocyte-like cell line SRT3025 down-regulated sclerostin and inactive beta-catenin, whereas a reciprocal effect was observed with EX-527, a Sirt1 inhibitor. Sirt1 activation by Sirt1 activating compounds is a potential novel pathway to down-regulate sclerostin and design anabolic therapies for osteoporosis concurrently ameliorating other metabolic and age-associated conditions. PMID- 24949668 TI - Reflections on the Theories of Aging, of Oxidative Stress, and of Science in General. Is It Time to Abandon the Free Radical (Oxidative Stress) Theory of Aging? AB - SIGNIFICANCE: Aging and oxidative stress are complex phenomena, and their understanding is of enormous theoretical and practical significance. RECENT ADVANCES: Numerous hypotheses and theories that attempt to explain these phenomena have been developed. These hypotheses and theories compete with each other, with each claiming to be the correct one, while significantly contradicting each other. CRITICAL ISSUES: It is important to develop a maximally correct theory that may then trigger significant practical breakthroughs. FUTURE DIRECTIONS: None of these theories is entirely correct or close enough to the truth. However, most of them contain many correct elements (CE). Finding these CE is possible by analysis of these theories. Once the CE are found, they can be merged by synthesis in a better new theory. An analysis of some of the theories of aging followed by synthesis is attempted. PMID- 24949667 TI - Dual effects of tumor necrosis factor alpha on myocardial injury following prolonged hypoperfusion of the heart. AB - OBJECTIVE: To examine the dose response of TNFalpha in an ex vivo rat model of myocardial ischemia reperfusion. METHODS AND RESULTS: Seventy-two rat hearts were mounted on Langendorff apparatus and perfused with oxygenated Krebs-Henseleit solutions. Ischemia was induced by reducing the perfusate flow rate. During reperfusion, incremental doses of recombinant TNFalpha were infused as a part of perfusate. TNFalpha was blocked with monoclonal TNFalpha antibody. Myocardial function was measured by dP/dT and relaxation time (IVRT). Cellular injury was assessed by released myoglobin and tissue concentration of malondialdehyde activity of the heart homogenates. Baseline +dP/dT was 1645 +/- 125 mmHg/sec, dP/dT was 945 +/- 73 mmHg/sec and IVRT was 65 +/- 5 msec. At the conclusion of reperfusion period, lower doses of TNFalpha increased +dP/dT and lowered IVRT. In contrast, the higher doses of TNFalpha decreased +dP/dT and prolonged IVRT. Pretreating the hearts with monoclonal TNFalpha antibody completely abolished the effects of TNFalpha on myocardial contractility and relaxation comparable to ischemia controls. CONCLUSION: Low dose TNFalpha improved myocardial function and decreased resultant cellular injury while high dose TNFalpha decreased myocardial function and increased myocardial injury following ischemia and reperfusion. PMID- 24949669 TI - Alcohol use, externalizing problems, and depressive symptoms among American Indian youth: the role of self-efficacy. AB - BACKGROUND: There is a need to understand resiliency factors which can be used to inform and design interventions to prevent externalizing problems, substance use, and depressive symptoms among American Indian (AI) youth. OBJECTIVES: The present study examined the role of self-efficacy in externalizing problems, alcohol use, and depressive symptoms among AI youth from the North American plains. METHODS: Participants for this study included 146 (53 boys and 93 girls) adolescents, with an age range of 13-18 (M = 14.5) years of age. RESULTS: High self-efficacy for resisting negative peer influences predicted both lower rates of alcohol use and fewer externalizing behaviors. Furthermore, higher levels of both academic and social self-efficacy predicted fewer depressive symptoms. The hypothesis that academic self-efficacy would predict depressive symptoms was not supported. CONCLUSION: As expected, the best-fitting path model showed self-efficacy for resisting negative peer influences predicting both alcohol use and externalizing problems, and social self-efficacy (as well as being female) predicting depressive symptoms among AI youth. Therefore, this study supports the importance of self-efficacy beliefs for alcohol use and externalizing problems, as well as depressive symptoms, among AI youth. PMID- 24949671 TI - The reaction of CH3O2 radicals with OH radicals: a neglected sink for CH3O2 in the remote atmosphere. PMID- 24949673 TI - Editorial: see one, simulate fifty, then do one? PMID- 24949672 TI - Superior performance of cone-beam CT angiography in characterization of intracranial atherosclerosis. AB - OBJECT: Intracranial atherosclerotic disease (ICAD) carries a high risk of stroke. Evaluation of ICAD has focused on assessing the absolute degree of stenosis, although plaque morphology has recently demonstrated increasing relevance. The authors provide the first report of the use of ultra-high resolution C-arm cone-beam CT angiography (CBCT-A) in the evaluation of vessel stenosis as well as plaque morphology. METHODS: Between August 2009 and July 2012, CBCT-A was used in all patients with ICAD who underwent catheter-based angiography at the authors' institution (n = 18). Lesions were evaluated for maximum degree of stenosis as well as plaque morphological characteristics (ulcerated, calcified, dissected, or spiculated) via digital subtraction angiography (DSA), 3D-rotational angiography (3DRA), and CBCT-A. The different imaging modalities were compared in their assessment of absolute stenosis as well as their ability to resolve different plaque morphologies. RESULTS: Lesions were found to have similar degrees of stenosis when utilizing CBCT-A compared with 3DRA, but both 3DRA and CBCT-A differed from DSA in their assessment of the absolute degree of stenosis. CBCT-A provided the most detailed resolution of plaque morphology, identifying a new plaque characteristic in 61% of patients (n = 11) when compared with DSA and 50% (n = 9) when compared with 3DRA. CBCT-A identified all lesion characteristics visualized on DSA and 3DRA. CONCLUSIONS: CBCT-A provides detailed spatial resolution of plaque morphology and may add to DSA and 3DRA in the evaluation of ICAD. Further prospective study is warranted to determine any benefit CBCTA-A may provide in clinical decision making and risk stratification over existing conventional imaging modalities. PMID- 24949670 TI - Development of N-methyl-(2-arylquinolin-4-yl)oxypropanamides as leads to PET radioligands for translocator protein (18 kDa). AB - Translocator protein (18 kDa), known as TSPO, is a recognized biomarker of neuroinflammation. Radioligands with PET accurately quantify TSPO in neuroinflammatory conditions. However, the existence of three human TSPO genotypes that show differential affinity to almost all useful TSPO PET radioligands hampers such studies. There is an unmet need for genotype insensitive, high-affinity, and moderately lipophilic TSPO ligands that may serve as leads for PET radioligand development. To address this need, we varied the known high-affinity TSPO ligand (l)-N,N-diethyl-2-methyl-3-(2-phenylquinolin-4 yl)propanamide in its aryl scaffold, side chain tether, and pendant substituted amido group while retaining an N-methyl group as a site for labeling with carbon 11. From this effort, oxygen-tethered N-methyl-aryloxypropanamides emerged as new high-affinity TSPO ligands with attenuated lipophilicity, including one example with attractive properties for PET radioligand development, namely N-methyl-N phenyl-2-{[2-(pyridin-2-yl)quinolin-4-yl]oxy}propanamide (22a; rat Ki=0.10 nM; human TSPO genotypes Ki=1.4 nM; clogD=4.18). PMID- 24949674 TI - Sensory recovery after cell therapy in peripheral nerve repair: effects of naive and skin precursor-derived Schwann cells. AB - OBJECT: Cell therapy is a promising candidate among biological or technological innovations sought to augment microsurgical techniques in peripheral nerve repair. This report describes long-term functional regenerative effects of cell therapy in the rat injury model with a focus on sensory recovery. METHODS: Schwann cells were derived from isogenic nerve or skin precursor cells and injected into the transected and immediately repaired sciatic nerve distal to the injury site. Sensory recovery was assessed at weeks 4, 7, and 10. Axonal regeneration was assessed at Week 11. RESULTS: By Week 10, thermal sensitivity in cell therapy groups returned to a level indistinguishable from the baseline (p > 0.05). Immunohistochemistry at 11 weeks after injury showed improved regeneration of NF+ and IB4+ axons. CONCLUSIONS: The results of this study show that cell therapy significantly improves thermal sensation and the number of regenerated sensory neurons at 11 weeks after injury. These findings contribute to the view of skin-derived stem cells as a reliable source of Schwann cells with therapeutic potential for functional recovery in damaged peripheral nerve. PMID- 24949675 TI - Case-control studies in neurosurgery. AB - OBJECT: Observational studies, such as cohort and case-control studies, are valuable instruments in evidence-based medicine. Case-control studies, in particular, are becoming increasingly popular in the neurosurgical literature due to their low cost and relative ease of execution; however, no one has yet systematically assessed these types of studies for quality in methodology and reporting. METHODS: The authors performed a literature search using PubMed/MEDLINE to identify all studies that explicitly identified themselves as "case-control" and were published in the JNS Publishing Group journals (Journal of Neurosurgery, Journal of Neurosurgery: Pediatrics, Journal of Neurosurgery: Spine, and Neurosurgical Focus) or Neurosurgery. Each paper was evaluated for 22 descriptive variables and then categorized as having either met or missed the basic definition of a case-control study. All studies that evaluated risk factors for a well-defined outcome were considered true case-control studies. The authors sought to identify key features or phrases that were or were not predictive of a true case-control study. Those papers that satisfied the definition were further evaluated using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. RESULTS: The search detected 67 papers that met the inclusion criteria, of which 32 (48%) represented true case-control studies. The frequency of true case-control studies has not changed with time. Use of odds ratios (ORs) and logistic regression (LR) analysis were strong positive predictors of true case-control studies (for odds ratios, OR 15.33 and 95% CI 4.52-51.97; for logistic regression analysis, OR 8.77 and 95% CI 2.69-28.56). Conversely, negative predictors included focus on a procedure/intervention (OR 0.35, 95% CI 0.13-0.998) and use of the word "outcome" in the Results section (OR 0.23, 95% CI 0.082-0.65). After exclusion of nested case-control studies, the negative correlation between focus on a procedure/intervention and true case control studies was strengthened (OR 0.053, 95% CI 0.0064-0.44). There was a trend toward a negative association between the use of survival analysis or Kaplan-Meier curves and true case-control studies (OR 0.13, 95% CI 0.015-1.12). True case-control studies were no more likely than their counterparts to use a potential study design "expert" (OR 1.50, 95% CI 0.57-3.95). The overall average STROBE score was 72% (range 50-86%). Examples of reporting deficiencies were reporting of bias (28%), missing data (55%), and funding (44%). CONCLUSIONS: The results of this analysis show that the majority of studies in the neurosurgical literature that identify themselves as "case-control" studies are, in fact, labeled incorrectly. Positive and negative predictors were identified. The authors provide several recommendations that may reverse the incorrect and inappropriate use of the term "case-control" and improve the quality of design and reporting of true case-control studies in neurosurgery. PMID- 24949676 TI - Analysis of subarachnoid hemorrhage using the Nationwide Inpatient Sample: the NIS-SAH Severity Score and Outcome Measure. AB - OBJECT: Studies using the Nationwide Inpatient Sample (NIS), a large ICD-9-based (International Classification of Diseases, Ninth Revision) administrative database, to analyze aneurysmal subarachnoid hemorrhage (SAH) have been limited by an inability to control for SAH severity and the use of unverified outcome measures. To address these limitations, the authors developed and validated a surrogate marker for SAH severity, the NIS-SAH Severity Score (NIS-SSS; akin to Hunt and Hess [HH] grade), and a dichotomous measure of SAH outcome, the NIS-SAH Outcome Measure (NIS-SOM; akin to modified Rankin Scale [mRS] score). METHODS: Three separate and distinct patient cohorts were used to define and then validate the NIS-SSS and NIS-SOM. A cohort (n = 148,958, the "model population") derived from the 1998-2009 NIS was used for developing the NIS-SSS and NIS-SOM models. Diagnoses most likely reflective of SAH severity were entered into a regression model predicting poor outcome; model coefficients of significant factors were used to generate the NIS-SSS. Nationwide Inpatient Sample codes most likely to reflect a poor outcome (for example, discharge disposition, tracheostomy) were used to create the NIS-SOM. Data from 716 patients with SAH (the "validation population") treated at the authors' institution were used to validate the NIS SSS and NIS-SOM against HH grade and mRS score, respectively. Lastly, 147,395 patients (the "assessment population") from the 1998-2009 NIS, independent of the model population, were used to assess performance of the NIS-SSS in predicting outcome. The ability of the NIS-SSS to predict outcome was compared with other common measures of disease severity (All Patient Refined Diagnosis Related Group [APR-DRG], All Payer Severity-adjusted DRG [APS-DRG], and DRG). RESULTS The NIS SSS significantly correlated with HH grade, and there was no statistical difference between the abilities of the NIS-SSS and HH grade to predict mRS-based outcomes. As compared with the APR-DRG, APSDRG, and DRG, the NIS-SSS was more accurate in predicting SAH outcome (area under the curve [AUC] = 0.69, 0.71, 0.71, and 0.79, respectively). A strong correlation between NIS-SOM and mRS was found, with an agreement and kappa statistic of 85% and 0.63, respectively, when poor outcome was defined by an mRS score > 2 and 95% and 0.84 when poor outcome was defined by an mRS score > 3. CONCLUSIONS: Data in this study indicate that in the analysis of NIS data sets, the NIS-SSS is a valid measure of SAH severity that outperforms previous measures of disease severity and that the NIS-SOM is a valid measure of SAH outcome. It is critically important that outcomes research in SAH using administrative data sets incorporate the NIS-SSS and NIS-SOM to adjust for neurology-specific disease severity. PMID- 24949677 TI - Role of oxidized LDL and lectin-like oxidized LDL receptor-1 in cerebral vasospasm after subarachnoid hemorrhage. AB - OBJECT: Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a serious complication. Free radicals derived from subarachnoid clotting are recognized to play an important role. Oxidized low-density lipoprotein (ox-LDL) and lectin-like oxidized LDL receptor-1 (LOX-1) have been shown to be related to the pathogenesis of atherosclerosis and may increase in cerebral arteries after SAH, due to the action of free radicals derived from a subarachnoid clot. These molecules may also affect the pathogenesis of vasospasm, generating intracellular reactive oxygen species and downregulating the expression of endothelial NO synthase (eNOS). If so, apple polyphenol might be effective in the prevention of vasospasm due to an abundant content of procyanidins, which exhibit strong radical scavenging effects, and the ability to suppress ox-LDL and LOX-1. The purposes of this study were to investigate changes in levels of ox-LDL and LOX-1 after SAH and whether administering apple polyphenol can modify cerebral vasospasm. METHODS: Forty Japanese white rabbits were assigned randomly to 4 groups: an SAH group (n = 10); a shamoperation group (n = 10), which underwent intracisternal saline injection; a low-dose polyphenol group (n = 10) with SAH and oral administration of apple polyphenol at 10 mg/kg per day from Day 0 to Day 3; and a high-dose polyphenol group (n = 10) with SAH and oral administration of apple polyphenol at 50 mg/kg per day. At Day 4, the basilar artery and brain was excised from each rabbit. The degree of cerebral vasospasm was evaluated by measuring the cross-sectional area of each basilar artery, and the expression of ox-LDL, LOX-1, and eNOS was examined for each basilar artery by immunohistochemical staining and reverse transcriptase polymerase chain reaction. In addition, neuronal apoptosis in the cerebral cortex was evaluated by TUNEL. RESULTS: Compared with the sham group, the expression of ox-LDL and LOX-1 in the basilar arterial wall was significantly increased in the SAH group, the expression of eNOS was significantly decreased, and the cross-sectional area of basilar artery was significantly decreased. Compared with the SAH group, the cross-sectional area of basilar artery was increased in the polyphenol groups, together with the decreased expression of ox-LDL and LOX-1 and the increased expression of eNOS. In the high-dose polyphenol group, those changes were statistically significant compared with the SAH group. In the low-dose polyphenol group, those changes were smaller than in the high-dose polyphenol group. No apoptosis and no changes were seen in the cerebral cortex in all groups. CONCLUSIONS: This is the first study suggesting that ox-LDL and LOX-1 increase due to SAH and that they may play a role in the pathogenesis of vasospasm. It is assumed that procyanidins in apple polyphenol may inhibit a vicious cycle of ox LDL, LOX-1, and ROS in a dose-dependent manner. Apple polyphenol is a candidate for preventive treatment of cerebral vasospasm. PMID- 24949678 TI - Prediction of methylguanine methyltransferase promoter methylation in glioblastoma using dynamic contrast-enhanced magnetic resonance and diffusion tensor imaging. AB - OBJECT: The methylation status of the methylguanine methyltransferase (MGMT) promoter has been associated with treatment response in glioblastoma. The authors aimed to assess whether MGMT methylation status can be predicted by dynamic contrast-enhanced (DCE) MRI and diffusion tensor imaging (DTI). METHODS: This retrospective study included 43 patients with pathologically diagnosed glioblastoma who had undergone preoperative DCE-MRI and DTI and whose MGMT methylation status was available. The imaging features were qualitatively assessed using conventional MR images. Regions of interest analyses for DCE-MRI permeability parameters (transfer constant [Ktrans], rate transfer coefficient [Kep], and volume fraction of extravascular extracellular space [Ve]) and DTI parameters (apparent diffusion coefficient [ADC] and fractional anisotropy [FA]) were performed on the enhancing solid portion of the glioblastoma. Chi-square or Mann-Whitney tests were used to evaluate relationships between MGMT methylation and imaging parameters. The authors performed receiver operating characteristic curve analysis to find the optimal cutoff value for the presence of MGMT methylation. RESULTS: MGMT methylation was not significantly associated with any imaging features on conventional MR images. Ktrans values were significantly higher in the MGMT methylated group (median 0.091 vs 0.053 min(-1), p = 0.018). However, Kep, Ve, ADC, and FA were not significantly different between the 2 groups. The optimal cutoff value for the presence of MGMT methylation was Ktrans > 0.086 min(-1) with an area under the curve of 0.756, a sensitivity of 56.3%, and a specificity of 85.2%. CONCLUSIONS: Ktrans may serve as a potential imaging biomarker to predict MGMT methylation status preoperatively in glioblastoma; however, further investigation with a larger cohort is necessary. PMID- 24949679 TI - Major Harvey Cushing's difficulties with the British and American armies during World War I. AB - This historical review explores Harvey Cushing's difficulties with both the British and American armies during his World War I service to definitively examine the rumor of his possible court martial. It also provides a further understanding of Cushing the man. While in France during World War I, Cushing was initially assigned to British hospital units. This service began in May 1917 and ended abruptly in May 1918 when the British cashiered him for repeated censorship violations. Returning to American command, he feared court martial. The army file on this matter (retrieved from the United States National Archives) indicates that US Army authorities recommended that Cushing be reprimanded and returned to the US for his violations. The army carried out neither recommendation, and no evidence exists that a court martial was considered. Cushing's army career and possible future academic life were protected by the actions of his surgical peers and Merritte Ireland, Chief Surgeon of the US Army in France. After this censorship episode, Cushing was made a neurosurgical consultant but was also sternly warned that further rule violations would not be tolerated by the US Army. Thereafter, despite the onset of a severe peripheral neuropathy, probably Guillian Barre's syndrome, Cushing was indefatigable in ministering to neurosurgical needs in the US sector in France. Cushing's repeated defying of censorship regulations reveals poor judgment plus an initial inability to be a "team player." The explanations he offered for his censorship violations showed an ability to bend the truth. Cushing's war journal is unclear as to exactly what transpired between him and the British and US armies. It also shows no recognition of the help he received from others who were instrumental in preventing his ignominious removal from service in France. Had that happened, his academic future and ability to train future neurosurgical leaders may have been seriously threatened. Cushing's foibles notwithstanding, all realized that he contributed greatly to both British and US war neurosurgery. United States Army surgeons who operated upon brain wounds in France recognized Cushing as their leader. PMID- 24949681 TI - Ultrafast on-site selective visual detection of TNT at sub-ppt level using fluorescent gold cluster incorporated single nanofiber. AB - In this communication, a fluorescent gold cluster incorporated electrospun nanofibrous membrane and single nanofiber for selective and sensitive detection of TNT at sub-ppt level are demonstrated. PMID- 24949680 TI - The use of simulation in neurosurgical education and training. A systematic review. AB - OBJECT: There is increasing evidence that simulation provides high-quality, time effective training in an era of resident duty-hour restrictions. Simulation may also permit trainees to acquire key skills in a safe environment, important in a specialty such as neurosurgery, where technical error can result in devastating consequences. The authors systematically reviewed the application of simulation within neurosurgical training and explored the state of the art in simulation within this specialty. To their knowledge this is the first systematic review published on this topic to date. METHODS: The authors searched the Ovid MEDLINE, Embase, and PsycINFO databases and identified 4101 articles; 195 abstracts were screened by 2 authors for inclusion. The authors reviewed data on study population, study design and setting, outcome measures, key findings, and limitations. RESULTS: Twenty-eight articles formed the basis of this systematic review. Several different simulators are at the neurosurgeon's disposal, including those for ventriculostomy, neuroendoscopic procedures, and spinal surgery, with evidence for improved performance in a range of procedures. Feedback from participants has generally been favorable. However, study quality was found to be poor overall, with many studies hampered by nonrandomized design, presenting normal rather than abnormal anatomy, lack of control groups and long term follow-up, poor study reporting, lack of evidence of improved simulator performance translating into clinical benefit, and poor reliability and validity evidence. The mean Medical Education Research Study Quality Instrument score of included studies was 9.21 +/- 1.95 (+/- SD) out of a possible score of 18. CONCLUSIONS: The authors demonstrate qualitative and quantitative benefits of a range of neurosurgical simulators but find significant shortfalls in methodology and design. Future studies should seek to improve study design and reporting, and provide long-term follow-up data on simulated and ideally patient outcomes. PMID- 24949683 TI - [Brucine inhibits the proliferation of human lung cancer cell line PC-9 ?via arresting cell cycle]. AB - BACKGROUND: It has been proven that Cyclin D1 and Cyclin E are the important positive regulators of cell cycle, they are closely related to the tumor proliferation. The aim of this study is to explore the relationship between Brucine and the proliferation in human lung cancer cell line PC-9, and the effect of it on the expression of Cyclin D1 and Cyclin E. METHODS: PC-9 cells were divided to 4 groups: the normal control group, the DMSO control group (20/00), the 150 MUM Brucine group, and the 300 MUM Brucine group. The proliferation rate of PC-9 cells was determined by The CellTiter-Glo Luminescent Cell Viability Assay and Colony Formation assay. The change of cell cycle was detected by Flow cytome try. Expressions of cell cycle regulators Cyclin D1, Cyclin E mRNA were determined by qRT-PCR. Protein expression of cell cycle regulators Cyclin D1, Cyclin E were determined by Western blot. RESULTS: Compared with the control, Brucine remarkably inhibited the proliferation of PC-9 cells in a dose- and time dependent manner (P<0.01); Flow cytome try showed that Brucine blocked the cell cycle of PC-9 cells at G0/G1, and the differences were statistically significant (P<0.01); qRT-PCR showed that the expression of Cyclin D1, Cyclin E mRNA were down-regulated; Western blot showed that the protein expression of Cyclin D1, Cyclin E were down-regulated. CONCLUSIONS: Brucine can inhibit the proliferation of human lung cancer cell line PC-9 mainly by blocking the cell cycle at G0/G1 via down-regulating the expression of Cyclin D1, Cyclin E. PMID- 24949684 TI - [Value of immunohistochemical staining with mutation-specific antibodies in detecting EGFR mutations: a meta-analysis]. AB - BACKGROUND: It has been proven that epidermal growth factor receptor (EGFR) mutation is the most important predictive factor for determining the effect of EGFR tyrosine kinase inhibitors (TKIs) applied to non-small cell lung cancer (NSCLC) patients. The patients with EGFR mutations response better to TKIs. To detect EGFR mutation has been particularly essential to select first-line treatment for lung cancer patients. To research and analyze the sensitivity and specificity of immunohistochemistry (IHC) using mutation specific antibodies in detecting EGFR mutations compared with DNA sequencing, and further evaluate the accuracy and clinical application value of IHC. METHODS: All required articles in Pubmed database were searched. The deadline of retrieval was March 26, 2013. Then further screening the articles based on the inclusion and exclusion criteria. Meta analysis of diagnostic test was applied to analyze the sensitivity and specificity of IHC compared with DNA sequencing for the detection of EGFR mutations. RESULTS: Ten articles were included in the meta analysis, there were 1,679 samples in L858R group and 1,041 samples in E746-A750del group. The DOR were 225.17 (95%CI: 55.67-910.69) and 267.16 (95%CI: 132.45-538.88) respectively; the AUC of SROC were 0.948,4 (SEAUC=0.014,4) and 0.981,3 (SEAUC=0.009,9) respectively; the Q values were 0.888,3 (SEQ*=0.019,2) and 0.939,7 (SEQ*=0.019,1) respectively. CONCLUSIONS: The specificity and sensitivity of IHC method using these two mutation-specific antibodies were relatively high. As a screening method for EGFR mutations, the IHC with mutation specific antibodies is of clinical value. PMID- 24949682 TI - [Screening and identification of novel drug-resistant genes in CD133+ and CD133- lung adenosarcoma cells using cDNA microarray]. AB - BACKGROUND: Cancer stem cells (CSCs) are responsible for multi-drug resistance in tumors. CD133 is a known biomarker of CSCs. The aim of this study is to screen for drug-resistant differentially expressed genes in CD133+ and CD133- lung cancer cells and to identify novel lung tumor drug-resistant genes. METHODS: Magnetic activated cell sorting was used to isolate CD133+ and CD133- cells from human lung cancer cell line A549, and drug-resistant microarray was used to detect drug-resistant genes in the these cells. RT-qPCR was used to examine the expression of six lung tumor drug-resistant genes in pre- and post chemotherapeutic A549 cells. RESULTS: A total of 31 differentially expressed genes were screened by microarray analysis. Of these genes, 30 were upregulated and one was downregulated in CD133+ cells compared with CD133- cells. Results were verified by RT-qPCR. CYP2C19, CYP2D6, CYP2E1, GSK3alpha, PPARalpha, and PPARbeta/delta were significantly upregulated after the A549 cells were treated with 1.97 MUg/mL DDP or 0.61 MUg/mL doxorubicin for 48 h. CONCLUSIONS: The drug resistance of lung adenosarcoma may be correlated with 31 differentially expressed genes screened by drug-resistant microarray. CYP2C19, CYP2D6, CYP2E1, GSK3alpha, PPARalpha, and PPARbeta/delta might be novel lung adenosarcoma drug resistant genes. PMID- 24949685 TI - [Radiofrequency ablation for lung neoplasms with isolated postsurgical local ?recurrences or metastases of non-small cell lung cancer]. AB - BACKGROUND: Primary lung cancer is one of the most common malignancies worldwide. Surgical resection remains the first choice for the treatment of early stage non small cell lung cancer (NSCLC). Relapse after surgery sharply reduces the patient's life expectancy. This relapse is referred to as isolated postsurgical local recurrences or metastases (IPSLROM), which can be treated via local therapy to achieve long-term survival or cure. In recent years, radiofrequency ablation (RFA) has been increasingly used as a non-surgical treatment option for patients with primary and metastatic lung tumors. This study aims to evaluate the efficacy of RFA among patients with IPSLROM of NSCLC. METHODS: A total of 20 patients underwent computerd tomograghy (CT)-guided RFA for lung neoplasm with IPSLROM of NSCLC (with unresectable disease because of poor lung reserve or multifocality) in our hospital between December 2008 and November 2013. These patients comprised 15 males and 5 females with a mean age of 69.2 years (range: 45-85). All patients exhibited pathological evidence of neoplastic lesion (14 tumors were adenocarcinoma, and six were squamous cell carcinoma). The mean size of the lesions was 3.9 cm (range: 2.0 cm to 8.0 cm). Treatment complications, progression-free survival (PFS), and survival parameters were retrospectively analyzed. RESULTS: RFA was well tolerated by all patients with an average time of 34.3 min (range: 15 min to 60 min). Intraprocedural complications included eight cases of chest pain (40%). No procedure-related deaths occurred in all of the 20 ablation procedures. The median PFS was 25 months in all of the patients who received RFA. The median overall survival for the entire group of patients was 27.0 months. No differences were observed in the overall survival between patients with IPSLROM. The overall survival rates at 1 and 2 years after RFA were 92.9% and 57.0%, respectively. CONCLUSIONS: RFA is a safe and effective procedure in unresectable lung tumors with IPSLROM of NSCLC. PMID- 24949686 TI - [Clinicopathological characteristics of 130 cases of lung cancer in the youth]. AB - BACKGROUND: It has been proven that lung cancer in the youth exhibited rapid progression, thus timely and accurate diagnosis is crucial. The aim of this study is to explore the clinicopathological characteristics of lung cancer in the youth, so as to provide clues for diagnosis. METHODS: The study enrolled patients aged younger than 40 years with lung cancer diagnosed with histology or cytology in our hospital between 1995-2012. We retrospectively analyzed sex, age, symptoms, smoking history, histology, stage and misdiagnosis. RESULTS: One hundred and thirty patients with lung cancer in the youth were enrolled, which comprise 5.2% of all cases of lung cancer in that period. Among them, 68.5% were male; 53.8% were aged between 36 and 40 years. Common symptoms included cough and hemoptysis, and systematic symptoms were relatively uncommon; and 11.8% showed no symptoms. 63.3% had a smoking history, and the time between initial symptom and final diagnosis averaged 3.9 months. The misdiagnosis rate was 51.5%, with tuberculosis as the leading misdiagnosis. 85.4% were staged III/IV. Primary lesion often located in upper lobes. Adenocarcinoma was the commonest histology, and 72.3% of the whole group was poorly differentiated. CONCLUSIONS: Lung cancer in the youth showed some special clinicopathological characteristics. Doctors should consider the possibility of lung cancer in patients with seemly diagnosis of tuberculosis, especially in those without symptomatic symptoms, and perform histological or cytological examinations. The absence of smoking history cannot rule out the possibility of lung cancer in youth patients. PMID- 24949687 TI - [A highly efficient in vitro site-directed mutagenesis protocol for introducing multiple-site mutations into target genes]. AB - BACKGROUND: The methods for introducing point mutations into target genes are important for dissecting the relationship of gene structure and function. Up to date, there are numbers of protocols available for the purpose. However, many of them are suited for introducing single site mutation into the target gene. For introducing multiple-site mutations simultaneously into the target genes, it is required to further improve the related methods. METHODS: In this report, we describe an improvement on the type IIs restriction enzyme-dependent site directed mutagenesis method and the improved protocol is highly efficient for multiple-site mutagenesis. In our method, a pair of mutagenic primers are synthesized for each desired site and each mutagenic primer contains a selected type IIs restriction site. The DNA fragments between two neighboring sites are amplified with PCR. All amplified fragments are then digested by the selected Type IIs restriction enzyme. The expected mutant is eventually generated by ligation of these digested DNA fragments. RESULTS: The improved protocol is very easy and can be achieved in just one day. As a proof of principle, we have introduced multiple-site, i.e., 3-site or 4-site mutations into the fusion gene of nm23 and EGFP (enhanced green fluorecence protein). The mutagenic frequencies are almost reached 100%. CONCLUSIONS: Our protocol provides a useful tool for gene function research. PMID- 24949688 TI - [Advances of immunotherapy in small cell lung cancer]. AB - Small cell lung cancer (SCLC) is complex heterogeneous due to unclear biological characteristics in terms of cell origin, pathogenesis and driver genes etc. Diagnosis and treatment of SCLC has been slowly improved and few breakthroughs have been discovered up to now. Therefore new strategies are urgently needed to improve the efficacy of SCLC treatment. Tumor immunotherapy has potential to restore and trigger the immune system to recognize and eliminate tumor cells, notably it has only minimal adverse impact on normal tissue. Cancer vaccine, adoptive immunotherapy, cytokines and checkpoint inhibitors have now been launched for clinical treatment of SCLC. Ipilimumab is the most promising medicine of immunotherapy. Immunotherapy is expected to bring new vision to the treatment of SCLC. And further researches are needed on such problems affecting efficacy of immunotherapy as the heterogeneity of SCLC, the uncertainty of target for immunotherapy, the immune tolerance, etc. PMID- 24949689 TI - [Driver genes and its clinical significance in non-small cell lung cancer]. AB - With the development of molecular biology technology and the transforming patterns of drug research, guiding molecular targeted therapy according to the drive gene mutation spectrum in lung cancer has gradually become a reality. Definition of the mutation incidence and whether existing advantage population groups in non-small cell lung cancer (NSCLC) have important guiding significance in clinical practice. The purpose of this paper will draw a summary on the general characteristics, demographic features and clinical significance of driver genes in NSCLC. PMID- 24949690 TI - [Research status of molecular targeted therapy in thymic epithelial tumors]. AB - In recent years, as the study of molecular mechanism and signal transduction pathways of tumors, molecular target therapy in many solid tumors has made great progress. At present, more and more studies focus on molecular target drugs in thymic epithelial tumors and people have got some experience. Molecular target therapy may be a new therapeutic option for patients of thymic epithelial tumor. PMID- 24949691 TI - [Research progress of thyroid transcription factor-1 as molecular marker in lung carcinoma]. AB - Lung cancer is the leading cause of cancer-related death worldwide. The majority of cases, the diagnosis is made at an advanced stage. The prognosis is poor with a 5-year survival rate less than 16% and the median overall survival 1 year or so. In recent years, research has focused on the potential role of new biological factors involved in the carcinogenic process. It's well known that thyroid transcription factor 1 (TTF-1) was a special lineage-survival oncogene in lung cancer according to recent researches. It has become apparent that TTF-1 expression has biological and clinical functions in the opposite direction that act in tumor progression. Herein, we summarize the role of this transcription factor in the development, diagnosis, and prognosis of lung cancer in the hope of providing insights into the utility of TTF-1 as a novel biomarker of lung cancer. PMID- 24949692 TI - [Clinical significance of ERCC1, RRM1 and TS in non-small cell lung cancer]. PMID- 24949693 TI - [Advance of postoperative adjuvant therapy in non-small cell lung cancer]. AB - Lung cancer including non-small cell lung cancer (NSCLC) and SCLC is the most commonly diagnosed cancer and leading cause of cancer-related death worldwide. This review focuses on progress of the effect, indications, regimens and the related biological markers of postoperative adjuvant chemotherapy in NSCLC. PMID- 24949694 TI - [Significance of immunohistochemical indicators in diagnosis and prognosis of ?squamous cell carcinoma and adenocarcinoma of lung]. PMID- 24949695 TI - [A case report of combined small cell lung cancer with EGFR mutation and treatment experience]. PMID- 24949696 TI - Splenic artery aneurysm presenting with clinical features of a bleeding gastric gastrointestinal stromal tumour. AB - Gastrointestinal stromal tumours often present with insidious upper gastrointestinal symptoms. Initial definitive diagnosis can be difficult and therefore misdiagnosis is not infrequent. Here we report a case of upper GI bleeding caused by a splenic artery aneurysm that was misdiagnosed as a gastric GIST. This rare presentation of splenic artery aneurysm highlights the potential pitfalls of investigation in upper gastrointestinal disease. PMID- 24949697 TI - Sphenoid sinus metastatic lesion from a pyriform fossa squamous cell carcinoma. AB - Head and neck cancers represent a significant proportion of all malignancies; comparatively few occur in the nasal sinuses, and fewer still of these are metastatic in origin. This case describes the presentation and management of a sphenoid sinus metastasis from a primary squamous cell carcinoma of the pyriform fossa. PMID- 24949699 TI - Post-radiotherapy vesicocutaneous fistula presenting as gas/fluid-filled groin swelling. AB - We report an interesting and rare case of a vesicocutaneous fistula, which was diagnosed only one year following radiotherapy. A 71 year old gentleman presented with a gangrenous swelling of his left thigh. A copius amount of urine was seen to be draining from the site after initial incision and drainage. Computed tomography with contrast confirmed the diagnosis of a vesicocutaneous fistula. Bilateral nephrostomies were inserted to aid spontaneous closure of the fistula. Previous case reports of vesicocutaneous fistulae involving radiotherapy have described the complication of a fistula occurring many years after the intervention. PMID- 24949698 TI - Adult intussusception in the Democratic Republic of Congo. AB - Adult intussusception is a relatively infrequent, but well documented entity in the Western surgical literature, where the majorities of cases is caused by tumors and require resection. In Africa and other tropical locations, however, other causes of adult intussusceptions predominate and must be considered. As Western trained surgeons increasingly volunteer in developing countries it is imperative to become familiar with the complex presentation and differential diagnosis of this disease. We present an illustrative case of adult intussusception with a complex differential diagnosis that we recently treated during a surgical mission to the Democratic Republic of Congo. PMID- 24949700 TI - Acute diaphragmatic rupture following open type IV paraesophageal hernia repair. AB - Open primary transthoracic repair is a well established treatment for large paraesophageal hernias. The rate of major post-operative complications has been reported to be low, and no cases of acute diaphragmatic injury have previously been reported. Here we present a case of open primary transthoracic repair of a type IV paraesophageal hernia that was complicated by rupture of the left diaphragm in the immediate post-operative period, and was successfully repaired with Gore DualMesh(r) (W.L Gore and Assoc. Flagstaff, AZ). PMID- 24949701 TI - Perinatal use of aripiprazole: plasma levels, placental transfer, and child outcome in 3 new cases. AB - The use of new agents of second-generation antipsychotics in childbearing women is increasing and poses an unknown risk to the fetus; thus, information of pregnancy and child outcome are urgently needed. We reviewed the literature of 12 patients, 3 of them were exposed during the first trimester, and added 3 new cases of peripartum use of aripiprazole. No teratogenesis was observed despite all 3 women having received the substance during part or full first trimester. All 3 pregnancies were uncomplicated with spontaneous birth. Dosage had to be changed during the course of gestation from 2.5 to 15 mg and plasma levels (PL) were below recommended levels, although all 3 women remained in stable remission throughout pregnancy and postpartum period.The extent of placental transfer of aripiprazole (mean ratio of 56.2%) is comparable with that of other second generation antipsychotics.Our observations have clinical implications: antipsychotic PLs show large-scale decreases, which may require dose adjustments during pregnancy. Pregnant women may require lower PLs. In our cases, a PL of one third of the previous effective PL was effective and safe. Repeated therapeutic drug monitoring during late gestation based on individual, previous effective PLs seems to be a feasible way for safe and effective antipsychotic therapy in unplanned pregnancy. PMID- 24949703 TI - Bilateral gynecomastia in a preadolescent boy while under treatment with methylphenidate and paroxetine. PMID- 24949704 TI - Estimating dopamine D(2) receptor occupancy for doses of 8 antipsychotics: a meta analysis: a reply. PMID- 24949702 TI - Impact of lithium treatment on FGF-23 serum concentrations in depressive patients. PMID- 24949705 TI - Proactive policy planning for unexpected student distress during simulation. AB - Stress reactions resulting from participation in simulation scenarios are seldom reported in the literature but are often informally discussed by simulation faculty seeking guidance to manage the occurrences. Although simulation faculty members often describe events where a single learner's distress interrupted learning for all involved, no examples of policies to plan for this kind of occurrence are available in the simulation literature. This article offers suggested best practices for identifying and assisting students who exhibit uncontrolled stress in simulation and includes a sample policy for planning. PMID- 24949706 TI - Early decrease in dietary protein:energy ratio by fat addition and ontogenetic changes in muscle growth mechanisms of rainbow trout: short- and long-term effects. AB - As the understanding of the nutritional regulation of muscle growth mechanisms in fish is fragmentary, the present study aimed to (1) characterise ontogenetic changes in muscle growth-related genes in parallel to changes in muscle cellularity; (2) determine whether an early decrease in dietary protein:energy ratio by fat addition affects the muscle growth mechanisms of rainbow trout (Oncorhynchus mykiss) alevins; and (3) determine whether this early feeding of a high-fat (HF) diet to alevins had a long-term effect on muscle growth processes in juveniles fed a commercial diet. Developmental regulation of hyperplasia and hypertrophy was evidenced at the molecular (expression of myogenic regulatory factors, proliferating cell nuclear antigen and myosin heavy chains (MHC)) and cellular (number and diameter of white muscle fibres) levels. An early decrease in dietary protein:energy ratio by fat addition stimulated the body growth of alevins but led to a fatty phenotype, with accumulation of lipids in the anterior part, and less caudal muscle when compared at similar body weights, due to a decrease in both the white muscle hyperplasia and maximum hypertrophy of white muscle fibres. These HF diet-induced cellular changes were preceded by a very rapid down-regulation of the expression of fast-MHC. The present study also demonstrated that early dietary composition had a long-term effect on the subsequent muscle growth processes of juveniles fed a commercial diet for 3 months. When compared at similar body weights, initially HF diet-fed juveniles indeed had a lower mean diameter of white muscle fibres, a smaller number of large white muscle fibres, and lower expression levels of MyoD1 and myogenin. These findings demonstrated the strong effect of early feed composition on the muscle growth mechanisms of trout alevins and juveniles. PMID- 24949707 TI - Acquired atopic disease after liver transplantation in children; similarities to and differences from adults: a preliminary study. AB - OBJECTIVE: The aim of this study was to determine the similarities and differences in the frequency and follow-ups of newly diagnosed atopic diseases after liver transplantation in pediatric and adult patients. MATERIALS AND METHODS: Patients who underwent liver transplants between 2005 and 2013 and who are still alive were enrolled in the study. Patients who came for checkups filled out a survey evaluating atopic diseases. Those who had an atopic disease before transplantation were excluded from the study. RESULTS: A total of 165 patients were enrolled in this study; 114 (69.1%) were males and 29 (17.6%) were children. The average transplantation age was 40.8 (0.3-67) years, and the most frequent reason for transplantation was chronic viral hepatitis. In 22 patients, atopic diseases [allergic rhinitis in nine patients (5.5%), asthma in six patients (3.9%), atopic eczema in six patients (3.9%), food allergy in six patients (3.9%), and drug allergy in one patient (0.6%)] developed after transplantation. Atopic diseases after transplantation were more common in children (P=0.03). When the atopic diseases were examined on a case-by-case basis, there were no differences between children and adults with respect to asthma (P=0.284), allergic rhinitis (P=1.0), or atopic eczema (P=0.284), but food allergy (P=0.009) and peripheral eosinophilia (P=0.002) were more common in children. The periodicity of allergic diseases after transplantation (P=0.192) and total IgE levels (P=0.086) were similar. CONCLUSION: Atopic diseases developed after liver transplantation and had a greater impact on children than adults. Therefore, after undergoing liver transplantation, patients should be monitored closely for signs of atopic diseases. PMID- 24949711 TI - Social challenges when implementing information systems in everyday work in a nursing context. AB - Implementation of information systems in healthcare has become a lengthy process where healthcare staff (eg, nurses) are expected to put information into systems without getting the overall picture of the potential usefulness for their own work. The aim of this study was to explore social challenges when implementing information systems in everyday work in a nursing context. Moreover, this study aimed at putting perceived social challenges in a theoretical framework to address them more constructively when implementing information systems in healthcare. Influenced by institutional ethnography, the findings are based on interviews, observations, and written reflections. Power (changing the existing hierarchy, alienation), professional identity (calling on hold, expert becomes novice, changed routines), and encounter (ignorant introductions, preconceived notions) were categories (subcategories) presented in the findings. Social Cognitive Theory, Diffusion of Innovations, organizational culture, and dramaturgical analysis are proposed to set up a theoretical framework. If social challenges are not considered and addressed in the implementation process, it will be affected by nurses' solidarity to existing power structures and their own professional identity. Thus, implementation of information systems affects more aspects in the organization than might have been intended. These aspects need to be taken in to account in the implementation process. PMID- 24949708 TI - Fourier ptychographic microscopy for filtration-based circulating tumor cell enumeration and analysis. AB - Circulating tumor cells (CTCs) are recognized as a candidate biomarker with strong prognostic and predictive potential in metastatic disease. Filtration based enrichment technologies have been used for CTC characterization, and our group has previously developed a membrane microfilter device that demonstrates efficacy in model systems and clinical blood samples. However, uneven filtration surfaces make the use of standard microscopic techniques a difficult task, limiting the performance of automated imaging using commercially available technologies. Here, we report the use of Fourier ptychographic microscopy (FPM) to tackle this challenge. Employing this method, we were able to obtain high resolution color images, including amplitude and phase, of the microfilter samples over large areas. FPM's ability to perform digital refocusing on complex images is particularly useful in this setting as, in contrast to other imaging platforms, we can focus samples on multiple focal planes within the same frame despite surface unevenness. In model systems, FPM demonstrates high image quality, efficiency, and consistency in detection of tumor cells when comparing corresponding microfilter samples to standard microscopy with high correlation (R2 = 0.99932). Based on these results, we believe that FPM will have important implications for improved, high throughput, filtration-based CTC analysis, and, more generally, image analysis of uneven surfaces. PMID- 24949710 TI - Ischemic preconditioning improves oxygen saturation and attenuates hypoxic pulmonary vasoconstriction at high altitude. AB - Exposure to hypoxic environments is associated with decreased arterial oxygen saturation and increased pulmonary artery pressures. Ischemic preconditioning of an extremity (IPC) is a procedure that stimulates vasoactive and inflammatory pathways that protect remote organ systems from ongoing or future ischemic injury. To test the effects of IPC on oxygen saturation and pulmonary artery pressures at high altitude, 12 healthy adult volunteers were evaluated in a randomized cross-over trial. IPC was administered utilizing a standardized protocol. IPC or placebo was administered daily for 5 days prior to ascent to altitude. All participants were evaluated twice at 4342 m altitude (placebo and IPC conditions separated by 4 weeks, randomized). The pulmonary artery systolic pressure (PASP) at 4342 m was significantly lower in the IPC condition than the placebo condition (36 +/- 6.0 mmHg vs. 38.1 +/- 7.6 mmHg, respectively, p = 0.035). Oxygen saturation at 4342 m was significantly higher with IPC compared to placebo (80.3 +/- 8.7% vs. 75.3 +/- 9.6%, respectively, p = 0.003). Prophylactic IPC treatment is associated with improved oxygen saturation and attenuation of the normal hypoxic increase in pulmonary artery pressures following ascent to high altitude. PMID- 24949712 TI - Perceived sense of community, cognitive engagement, and learning outcomes among undergraduate nursing students enrolled in an internet-based learning course. AB - Internet-based learning environments are a popular instructional delivery method that provides flexibility, easy access, convenience, and self-directed learning. There is concern that Internet-based learning creates a loss of community and lacks the power to fully engage the student, leading to negative learning outcomes. This descriptive, correlational study evaluated the relationship among a perceived sense of community, cognitive engagement, and learner outcomes among undergraduate nursing students enrolled in an Internet-based learning course. A convenience sample of 96 undergraduate nursing students enrolled in an online health informatics course participated in this study. Findings indicated a moderate sense of community and a positive relationship between student engagement and learning outcomes. A variety of group activities such as wikis, blogs, and discussion board were helpful in promoting a sense of community, but students emphasized a desire for more faculty feedback and interaction. Nursing is a collaborative profession where community building is a critical skill; therefore, innovative teaching/learning techniques that promote a sense of belonging and community are needed to improve learning outcomes, prepare students to provide quality patient care, and interact with an interprofessional team. PMID- 24949713 TI - Use of computer and cellular phone technology by older rural adults. AB - The objective of this study was to explore the use of computer and cellular phone technology among older adults living in the rural Appalachian region of North Carolina. A 21-item questionnaire on access to and use of computer and cellular phone technology was administered to 43 older adults, using dichotomous and frequency-rated questions. The sample was recruited from two rural senior centers in the Appalachian region of North Carolina. Forty percent of the participants earned $20 000 or less annually. The majority owned a cellular phone (79.9%), and nearly half had a desktop computer (44.2%). High-speed Internet coverage was the most frequent type (42%) of in-home coverage. This study provides insights into the needs and challenges of older rural Appalachians with regard to technology. Computer technology may be more accessible and have fewer barriers by older adults than other forms of technology. Future research should explore the levels of computer literacy of older adults. PMID- 24949714 TI - A comparison of two nursing program exit exams that predict first-time NCLEX-RN outcome. AB - This retrospective descriptive correlational study compared the predictive accuracy of the Health Education Systems, Inc, Exit Exam (Elsevier) and Assessment Technologies Institute's RN Comprehensive Predictor, both of which were administered to nursing students in an upper-division baccalaureate nursing program during their final semester of study. Using logistic regression analyses, it was determined that the two examinations were statistically significant but weak predictors of success on the RN licensure examination. The RN Comprehensive Predictor had a slightly better odds ratio; however, both examinations had similar sensitivity, specificity, and overall accuracy. Because the RN Comprehensive Predictor was included in the Assessment Technologies Institute's Comprehensive Assessment and Review Program already being used by the BSN program, based on the results of this study, the nursing faculty decided to use only the RN Comprehensive Predictor during its NCLEX-RN preparation course. PMID- 24949715 TI - Attitudes of RN-to-BSN students regarding teaching strategies utilized in online courses. AB - In this descriptive study, researchers examined RN-to-BSN students' attitudes regarding different teaching/learning strategies incorporated in courses offered utilizing the online delivery format. A semantic differential scale was used to measure attitudes regarding the use of wikis, podcasts, video capture, talking PowerPoint, and discussion boards. The results indicated that students had the most favorable attitude toward tegrity lectures as a teaching strategy. This was followed by talking PowerPoint lectures and discussion board. PMID- 24949716 TI - Retinal toxicities of cancer therapy drugs: biologics, small molecule inhibitors, and chemotherapies. AB - PURPOSE: To review reported retinal side effects from current cancer therapy drugs. METHODS: Retinal toxicities from ophthalmologic or oncologic case reports, case series, and clinical trials were identified by a systematic literature search using Lexicomp and PubMed. RESULTS: Four biologics, 8 small molecule inhibitors, and 17 traditional chemotherapy agents had reported retinal side effects. For biologics, interferon alpha 2b was associated with retinopathy, denileukin diftitiox with pigmentary retinopathy, ipilimumab with a Vogt-Koyanagi Harada-like syndrome, and trastuzumab with retinal ischemia. For small molecule inhibitors, v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors were associated with uveitis, mitogen-activated protein kinase/extracellular signal regulated kinase inhibitors with pigment epithelium detachments, and tyrosine kinase inhibitors with macular edema. Steroid antagonists were associated with crystalline retinopathy and macular edema. Nitrosoureas, platinum analogs, and cytosine arabinoside were associated with retinal vascular occlusions. Antimicrotubular agents were associated with cystoid macular edema but without fluorescein leakage. Retinoic acid derivatives were associated with impaired night vision, and mitotane was associated with a pigmentary retinopathy and papilledema. CONCLUSION: Certain agents used in the treatment of systemic cancer are associated with ocular complications. Awareness of these complications will allow early detections and maybe reversal of some of the ocular problems. PMID- 24949717 TI - Scleral fixation of posterior chamber intraocular lenses using gore-tex suture with concurrent 23-gauge pars plana vitrectomy. PMID- 24949718 TI - A new vitreous cutter blade engineered for constant flow vitrectomy. PMID- 24949719 TI - Bilateral contusion-compression model of incomplete traumatic cervical spinal cord injury. AB - Despite the increasing incidence and prevalence of cervical spinal cord injury (cSCI), we lack clinically relevant animal models that can be used to study the pathomechanisms of this injury and test new therapies. Here, we characterize a moderate cervical contusion-compression model in rats that is similar to incomplete traumatic cSCI in humans. We characterized the effects of 18-g clip compression injury at cervical level C6 over an 8-week recovery period. Using Luxol fast blue/hematoxylin-eosin staining in combination with quantitative stereology, we determined that 18-g injury results in loss of gray matter (GM), white matter (WM), as well as in cavity formation. Magnetization transfer and T2 weighted magnetic resonance imaging were used to analyze lesion dynamics in vivo. This analysis demonstrated that both techniques are able to differentiate between the injury epicenter, subpial rim, and WM distal to the injury. Neurobehavioral assessment of locomotor function using Basso, Beattie, and Bresnahan (BBB) scoring and CatWalk revealed limited recovery from clip-compression injury at C6. Testing of forelimb function using grip strength demonstrated significant forelimb dysfunction, similar to the loss of upper-limb motor function observed in human cSCI. Sensory-evoked potentials recorded from the forelimb and Hoffman reflex recorded from the hindlimb confirmed the fore- and hindlimb deficits observed in our neurobehavioral analysis. Here, we have characterized a clip compression model of incomplete cSCI that closely models this condition in humans. This work directly addresses the current lack of clinically relevant models of cSCI and will thus contribute to improved success in the translation of putative therapies into the clinic. PMID- 24949725 TI - Oxidative balance in lymphocytes from patients with nonalcoholic steatohepatitis. AB - Oxidative stress is linked to several human diseases, including nonalcoholic steatohepatitis (NASH). In this study, lymphocytes were used as a model to study this disease. These cells offer several advantages for cellular and molecular studies such as easy accessibility, and they are easily accessible and constitute a "time-persistent" system capable of reflecting the condition of the whole organism. Lymphocytes from patients with NASH display oxidative stress features. Among the possible causes for the overproduction of reactive oxygen species in NASH lymphocytes, there might be alterations of enzymatic pathways, auto oxidation of glucose and mitochondrial superoxide production, which, in turn, would lead to protein oxidative damage. Increased oxidative stress in lymphocytes from patients with NASH may result in a pro-oxidative environment, which, in turn, could modify the pathway of the enzymatic activities. The data confirm that an imbalance between pro-oxidant and antioxidant defense mechanisms may be an important factor in NASH. PMID- 24949726 TI - Prolonged international normalized ratio during the first year of warfarin treatment. AB - OBJECTIVE: Oral anticoagulants (OAC) are effective in the prevention of thromboembolic events but are underused. The 1st year following the beginning of vitamin K antagonists is associated with higher bleeding rate, especially in patients with international normalized ratio (INR) of >4, leading to discontinuation of OAC. We hypothesized that the decision to discontinue OAC during the 1st year in patients with events of overanticoagulation is not fully justified. SETTING: A retrospective study of the association between warfarin overanticoagulation during the 1st year of treatment and the outcome and complications in patients admitted to an internal medicine department with INR>4. SUBJECTS: A cohort of 249 patients was divided according to OAC treatment duration: <=12 months (group I, n=72; mean age, 79.1 years) and >12 months (group II, n=177; mean age, 78.3 years). RESULTS: International normalized ratio upon admission was higher in group I (INR, 6.88 versus 6.16; P=0.003). Patients in group I were overanticoagulated for a longer period (46.4% versus 18.5%; P<0.001) but had lower time in therapeutic range (39.0% versus 60.2%; P=0.001). The frequency of INR monitoring was higher in group I. The incidence of major and minor bleeding events and survival was similar. CONCLUSIONS: Patients who are admitted with INR>4 during the 1st year of OAC therapy are overanticoagulated for a longer period, have lower time in therapeutic range, but do not present with higher incidence of bleeding events, all compared with patients treated for longer than 12 months. Stricter INR monitoring and careful patient selection may prevent the discontinuation of OAC. PMID- 24949720 TI - mTORC2 phosphorylation of Akt1: a possible mechanism for hydrogen sulfide-induced cardioprotection. AB - Hydrogen sulfide (H2S) is known to have cardiac protective effects through Akt activation. Akt acts as a 'central sensor' for myocyte survival or death; its activity is regulated by multiple kinases including PI3K, mTORC2, PDK1 and phosphatases including PTEN, PP2A and PHLPPL. Based on the previous finding that PI3K inhibitor LY294002 abolishes H2S-induced Akt phosphorylation and cardioprotection, it is accepted that PI3K is the mediator of H2S-induced Akt phosphorylation. However, LY294002 inhibits both PI3K and mTOR, and PI3K only recruits Akt to the membrane where Akt is phosphorylated by Akt kinases. We undertook a series of experiments to further evaluate the role of mTORC2, PDK1, PTEN, PP2A and PHLPPL in H2S-induced Akt phosphorylation and cardioprotection, which, we believe, has not been investigated before. Hearts from adult Sprague Dawley rats were isolated and subjected to (i) normoxia, (ii) global ischemia and (iii) ischemia/reperfusion in the presence or absence of 50 uM of H2S donor NaHS. Cardiac mechanical function and lactate dehydrogenase (LDH) release were assessed. All hearts also were Western analyzed at the end of perfusion for Akt and a panel of appropriate Akt regulators and targets. Hearts pretreated with 50 uM NaHS had improved function at the end of reperfusion (Rate pressure product; 19+/-4*10(3) vs. 10+/-3*10(3) mmHg/min, p<0.05) and reduced cell injury (LDH release 19+/-10 vs. 170+/-87 mU/ml p<0.05) compared to untreated hearts. NaHS significantly increased phospho-Akt, phospho-mTOR, phospho-Bim and Bcl-2 in reperfused hearts (P<0.05). Furthermore using H9c2 cells we demonstrate that NaHS pretreatment reduces apoptosis following hypoxia/re-oxygenation. Importantly, PP242, a specific mTOR inhibitor, abolished both cardioprotection and protein phosphorylation in isolated heart and reduced apoptotic effects in H9c2 cells. Treating hearts with NaHS only during reperfusion produced less cardioprotection through a similar mechanism. These data suggest mTORC2 phosphorylation of Akt is a key mediator of H2S-induced cardioprotection in I/R. PMID- 24949728 TI - Comparison of conventional tacrolimus versus prolong release formula as initial therapy in heart transplantation. AB - BACKGROUND: A new formulation of tacrolimus that is characterized by prolonged release has been developed to facilitate treatment and patient compliance. Initial therapy with prolonged release formula in heart transplantation is not widely accepted. MATERIAL AND METHODS: We enrolled 19 patients into a randomized analysis divided into 2 groups with different initial regimens. There were 8 patients with a mean age of 44 +/- 13 years treated by Advagraf, and 11 patients with a mean age of 41 +/- 9 years treated by Prograf. Serum concentration of immunosuppressive drug was followed by its oral dosage and endomyocardial biopsy results. Arterial hypertension, kidney function, and incidence of diabetes mellitus were recorded. RESULTS: There were no perioperative deaths. The risk of acute rejection within 6 months following surgery was 1 (2%) in the Advagraf group and 1 (1.5%) in the Prograf group. Although the serum tacrolimus results were comparable between groups, the drug's daily dosages were different after 6 months of therapy (3 +/- 1 mg in the Advagraf group and 6 +/- 2 mg in the Prograf group (p<0.05). The low rate of adverse effects throughout the study was noted. CONCLUSIONS: Prolonged-release tacrolimus formula is an efficient immunosuppressant in heart transplantation. Its initial application after surgery has low risk of adverse effects with similar results to conventional formula. PMID- 24949727 TI - PTPRT regulates high-fat diet-induced obesity and insulin resistance. AB - Obesity is a risk factor for many human diseases. However, the underlying molecular causes of obesity are not well understood. Here, we report that protein tyrosine phosphatase receptor T (PTPRT) knockout mice are resistant to high-fat diet-induced obesity. Those mice avoid many deleterious side effects of high-fat diet-induced obesity, displaying improved peripheral insulin sensitivity, lower blood glucose and insulin levels. Compared to wild type littermates, PTPRT knockout mice show reduced food intake. Consistently, STAT3 phosphorylation is up regulated in the hypothalamus of PTPRT knockout mice. These studies implicate PTPRT-modulated STAT3 signaling in the regulation of high-fat diet-induced obesity. PMID- 24949729 TI - Genetic spectrum of autosomal recessive non-syndromic hearing loss in Pakistani families. AB - The frequency of inherited bilateral autosomal recessive non-syndromic hearing loss (ARNSHL) in Pakistan is 1.6/1000 individuals. More than 50% of the families carry mutations in GJB2 while mutations in MYO15A account for about 5% of recessive deafness. In the present study a cohort of 30 ARNSHL families was initially screened for mutations in GJB2 and MYO15A. Homozygosity mapping was performed by employing whole genome single nucleotide polymorphism (SNP) genotyping in the families that did not carry mutations in GJB2 or MYO15A. Mutation analysis was performed for the known ARNSHL genes present in the homozygous regions to determine the causative mutations. This allowed the identification of a causative mutation in all the 30 families including 9 novel mutations, which were identified in 9 different families (GJB2 (c.598G>A, p.Gly200Arg); MYO15A (c.9948G>A, p.Gln3316Gln; c.3866+1G>A; c.8767C>T, p.Arg2923* and c.8222T>C, p.Phe2741Ser), TMC1 (c.362+18A>G), BSND (c.97G>C, p.Val33Leu), TMPRSS3 (c.726C>G, p.Cys242Trp) and MSRB3 (c.20T>G, p.Leu7Arg)). Furthermore, 12 recurrent mutations were detected in 21 other families. The 21 identified mutations included 10 (48%) missense changes, 4 (19%) nonsense mutations, 3 (14%) intronic mutations, 2 (9%) splice site mutations and 2 (9%) frameshift mutations. GJB2 accounted for 53% of the families, while mutations in MYO15A were the second most frequent (13%) cause of ARNSHL in these 30 families. The identification of novel as well as recurrent mutations in the present study increases the spectrum of mutations in known deafness genes which could lead to the identification of novel founder mutations and population specific mutated deafness genes causative of ARNSHL. These results provide detailed genetic information that has potential diagnostic implication in the establishment of cost-efficient allele-specific analysis of frequently occurring variants in combination with other reported mutations in Pakistani populations. PMID- 24949733 TI - Reusable and mediator-free cholesterol biosensor based on cholesterol oxidase immobilized onto TGA-SAM modified smart bio-chips. AB - A reusable and mediator-free cholesterol biosensor based on cholesterol oxidase (ChOx) was fabricated based on self-assembled monolayer (SAM) of thioglycolic acid (TGA) (covalent enzyme immobilization by dropping method) using bio-chips. Cholesterol was detected with modified bio-chip (Gold/Thioglycolic acid/Cholesterol-oxidase i.e., Au/TGA/ChOx) by reliable cyclic voltammetric (CV) technique at room conditions. The Au/TGA/ChOx modified bio-chip sensor demonstrates good linearity (1.0 nM to 1.0 mM; R = 0.9935), low-detection limit (~0.42 nM, SNR~3), and higher sensitivity (~74.3 uA uM(-1) cm(-2)), lowest-small sample volume (50.0 MUL), good stability, and reproducibility. To the best of our knowledge, this is the first statement with a very high sensitivity, low detection limit, and low-sample volumes are required for cholesterol biosensor using Au/TGA/ChOx-chips assembly. The result of this facile approach was investigated for the biomedical applications for real samples at room conditions with significant assembly (Au/TGA/ChOx) towards the development of selected cholesterol biosensors, which can offer analytical access to a large group of enzymes for wide range of biomedical applications in health-care fields. PMID- 24949734 TI - High efficient differentiation of functional hepatocytes from porcine induced pluripotent stem cells. AB - Hepatocyte transplantation is considered to be a promising therapy for patients with liver diseases. Induced pluripotent stem cells (iPSCs) provide an unlimited source for the generation of functional hepatocytes. In this study, we generated iPSCs from porcine ear fibroblasts (PEFs) by overexpressing Sox2, Klf4, Oct4, and c-Myc (SKOM), and developed a novel strategy for the efficient differentiation of hepatocyte-like cells from porcine iPSCs by following the processes of early liver development. The differentiated cells displayed the phenotypes of hepatocytes, exhibited classic hepatocyte-associated bio-functions, such as LDL uptake, glycogen storage and urea secretion, as well as possessed the metabolic activities of cytochrome P-450 (CYP) 3A and 2C. Furthermore, we compared the hepatocyte differentiation efficacy of our protocol with another published method, and the results demonstrated that our differentiation strategy could significantly improve the generation of morphological and functional hepatocyte like cells from porcine iPSCs. In conclusion, this study establishes an efficient method for in vitro generation of functional hepatocytes from porcine iPSCs, which could represent a promising cell source for preclinical testing of cell based therapeutics for liver failure and for pharmacological applications. PMID- 24949735 TI - Landscape suitability in Botswana for the conservation of its six large African carnivores. AB - Wide-ranging large carnivores often range beyond the boundaries of protected areas into human-dominated areas. Mapping out potentially suitable habitats on a country-wide scale and identifying areas with potentially high levels of threats to large carnivore survival is necessary to develop national conservation action plans. We used a novel approach to map and identify these areas in Botswana for its large carnivore guild consisting of lion (Panthera leo), leopard (Panthera pardus), spotted hyaena (Crocuta crocuta), brown hyaena (Hyaena brunnea), cheetah (Acinonyx jubatus) and African wild dog (Lycaon pictus). The habitat suitability for large carnivores depends primarily on prey availability, interspecific competition, and conflict with humans. Prey availability is most likely the strongest natural determinant. We used the distribution of biomass of typical wild ungulate species occurring in Botswana which is preyed upon by the six large carnivores to evaluate the potential suitability of the different management zones in the country to sustain large carnivore populations. In areas where a high biomass of large prey species occurred, we assumed interspecific competition between dominant and subordinated competitors to be high. This reduced the suitability of these areas for conservation of subordinate competitors, and vice versa. We used the percentage of prey biomass of the total prey and livestock biomass to identify areas with potentially high levels of conflict in agricultural areas. High to medium biomass of large prey was mostly confined to conservation zones, while small prey biomass was more evenly spread across large parts of the country. This necessitates different conservation strategies for carnivores with a preference for large prey, and those that can persist in the agricultural areas. To ensure connectivity between populations inside Botswana and also with its neighbours, a number of critical areas for priority management actions exist in the agricultural zones. PMID- 24949738 TI - Forced convective heat transfer in boundary layer flow of Sisko fluid over a nonlinear stretching sheet. AB - The major focus of this article is to analyze the forced convective heat transfer in a steady boundary layer flow of Sisko fluid over a nonlinear stretching sheet. Two cases are studied, namely (i) the sheet with variable temperature (PST case) and (ii) the sheet with variable heat flux (PHF case). The heat transfer aspects are investigated for both integer and non-integer values of the power-law index. The governing partial differential equations are reduced to a system of nonlinear ordinary differential equations using appropriate similarity variables and solved numerically. The numerical results are obtained by the shooting method using adaptive Runge Kutta method with Broyden's method in the domain[Formula: see text]. The numerical results for the temperature field are found to be strongly dependent upon the power-law index, stretching parameter, wall temperature parameter, material parameter of the Sisko fluid and Prandtl number. In addition, the local Nusselt number versus wall temperature parameter is also graphed and tabulated for different values of pertaining parameters. Further, numerical results are validated by comparison with exact solutions as well as previously published results in the literature. PMID- 24949737 TI - Could local dynamic stability serve as an early predictor of falls in patients with moderate neurological gait disorders? A reliability and comparison study in healthy individuals and in patients with paresis of the lower extremities. AB - Falls while walking are frequent in patients with muscular dysfunction resulting from neurological disorders. Falls induce injuries that may lead to deconditioning and disabilities, which further increase the risk of falling. Therefore, an early gait stability index would be useful to evaluate patients in order to prevent the occurrence of future falls. Derived from chaos theory, local dynamic stability (LDS), defined by the maximal Lyapunov exponent, assesses the sensitivity of a dynamic system to small perturbations. LDS has already been used for fall risk prediction in elderly people. The aim of the present study was to provide information to facilitate future researches regarding gait stability in patients with neurological gait disorders. The main objectives were 1) to evaluate the intra-session repeatability of LDS in patients and 2) to assess the discriminative power of LDS to differentiate between healthy individuals and neurological patients. Eighty-three patients with mild to moderate neurological disorders associated with paresis of the lower extremities and 40 healthy controls participated in the study. The participants performed 2*30 s walking wearing a 3D accelerometer attached to the lower back, from which 2*35 steps were extracted. LDS was defined as the average exponential rate of divergence among trajectories in a reconstructed state-space that reflected the gait dynamics. LDS assessed along the medio-lateral axis offered the highest repeatability and discriminative power. Intra-session repeatability (intraclass correlation coefficient between the two repetitions) in the patients was 0.89 and the smallest detectable difference was 16%. LDS was substantially lower in the patients than in the controls (33% relative difference, standardized effect size 2.3). LDS measured in short over-ground walking tests seems sufficiently reliable. LDS exhibits good discriminative power to differentiate fall-prone individuals and opens up the possibility of future clinical applications for better prediction of fall risk in neurological patients. PMID- 24949740 TI - A new instrument to measure sexual competence and interaction competence in youth: psychometric properties in female adolescents. AB - The Sexual Competence and Interaction Competence in Youth is a self-report questionnaire that aims to measure sexual competence and interaction competence in adolescents. The study sample consisted of 276 female undergraduate students (M = 20.95 years, SD = 2.00 years). The factor structure of the questionnaire was calculated on full sample data. A subsample was used to calculate the validity and internal consistency (N = 236; M = 20.88 years, SD = 1.96). The test-retest reliability was also calculated in a subsample (N = 82; M = 21.45 years, SD = 1.74 years). On the basis of an exploratory factor analysis, 8 factors were extracted: (a) communication about sex, (b) refusing sex, (c) positive sexual attitudes, (d) male role in sexual interaction, (e) contraceptive use, (f) not suppressing problems and desires regarding sex, (g) sexual assertiveness, and (h) sexual hedonism. The subscales possess adequate internal consistency and moderate to excellent test-retest reliability. A higher order principal component analysis revealed a 2-factor structure that appears to adequately represent the sexual competence and interaction competence constructs. Furthermore, convergent and discriminant validity were considered to be good. The results indicate that the Sexual Competence and Interaction Competence in Youth may be a useful instrument to measure sexual and interaction competence among adolescents. PMID- 24949739 TI - The global response regulator RegR controls expression of denitrification genes in Bradyrhizobium japonicum. AB - Bradyrhizobium japonicum RegSR regulatory proteins belong to the family of two component regulatory systems, and orthologs are present in many Proteobacteria where they globally control gene expression mostly in a redox-responsive manner. In this work, we have performed a transcriptional profiling of wild-type and regR mutant cells grown under anoxic denitrifying conditions. The comparative analyses of wild-type and regR strains revealed that almost 620 genes induced in the wild type under denitrifying conditions were regulated (directly or indirectly) by RegR, pointing out the important role of this protein as a global regulator of denitrification. Genes controlled by RegR included nor and nos structural genes encoding nitric oxide and nitrous oxide reductase, respectively, genes encoding electron transport proteins such as cycA (blr7544) or cy2 (bll2388), and genes involved in nitric oxide detoxification (blr2806-09) and copper homeostasis (copCAB), as well as two regulatory genes (bll3466, bll4130). Purified RegR interacted with the promoters of norC (blr3214), nosR (blr0314), a fixK-like gene (bll3466), and bll4130, which encodes a LysR-type regulator. By using fluorescently labeled oligonucleotide extension (FLOE), we were able to identify two transcriptional start sites located at about 35 (P1) and 22 (P2) bp upstream of the putative translational start codon of norC. P1 matched with the previously mapped 5'end of norC mRNA which we demonstrate in this work to be under FixK2 control. P2 is a start site modulated by RegR and specific for anoxic conditions. Moreover, qRT-PCR experiments, expression studies with a norC-lacZ fusion, and heme c-staining analyses revealed that anoxia and nitrate are required for RegR dependent induction of nor genes, and that this control is independent of the sensor protein RegS. PMID- 24949741 TI - Identification of tyrosine-phosphorylated peptides using cold ion spectroscopy. AB - The accurate and unambiguous detection of post-translational modifications in proteins and peptides remains a challenging task. We report here the use of cold ion spectroscopy for the identification of phosphorylated tyrosine residues in peptides. This approach employs the wavelength-specific UV fragmentation of cryogenically cooled protonated peptides in the gas phase. In addition to the appearance of specific photofragments, the phosphorylation of tyrosine induces large spectral shifts of the peptide electronic band origins. Quantum chemical calculations and experiments together suggest a certain generality of the use of such shifts in the spectroscopic identification of phosphotyrosines. The enhanced selectivity offered by the joint application of wavelength-specific fragmentation and mass spectrometry of cold molecules can also be used in the identifications of aromatic residues in protonated peptides and, potentially, of other UV absorbing groups in a variety of large polyatomic ions. PMID- 24949743 TI - Yield-enhancing heterotic QTL transferred from wild species to cultivated rice Oryza sativa L. AB - Utilization of "hidden genes" from wild species has emerged as a novel option for enrichment of genetic diversity for productivity traits. In rice we have generated more than 2000 lines having introgression from 'A' genome-donor wild species of rice in the genetic background of popular varieties PR114 and Pusa44 were developed. Out of these, based on agronomic acceptability, 318 lines were used for developing rice hybrids to assess the effect of introgressions in heterozygous state. These introgression lines and their recurrent parents, possessing fertility restoration ability for wild abortive (WA) cytoplasm, were crossed with cytoplasmic male sterile (CMS) line PMS17A to develop hybrids. Hybrids developed from recurrent parents were used as checks to compare the performance of 318 hybrids developed by hybridizing alien introgression lines with PMS17A. Seventeen hybrids expressed a significant increase in yield and its component traits over check hybrids. These 17 hybrids were re-evaluated in large size replicated plots. Of these, four hybrids, viz., ILH299, ILH326, ILH867 and ILH901, having introgressions from O. rufipogon and two hybrids (ILH921 and ILH951) having introgressions from O. nivara showed significant heterosis over parental introgression line, recurrent parents and check hybrids for grain yield related traits. Alien introgressions were detected in the lines taken as male parents for developing six superior hybrids, using a set of 100 polymorphic simple sequence repeat (SSR) markers. Percent introgression showed a range of 2.24 from in O. nivara to 7.66 from O. rufipogon. The introgressed regions and their putative association with yield components in hybrids is reported and discussed. PMID- 24949745 TI - Thermalization and revivals after a quantum quench in conformal field theory. AB - We consider a quantum quench in a finite system of length L described by a 1+1 dimensional conformal field theory (CFT), of central charge c, from a state with finite energy density corresponding to an inverse temperature beta?L. For times t such that l/2A, p. Gly630Ser) in exon 29 of COL2A1 in the Gly-X-Y domain, in a Chinese family affected by LCPD and ANFH. Our findings provide significant clues to the phenotype-genotype relationships in these syndromes and may be helpful in clinical diagnosis. Furthermore, these results should assist further studies of the mechanisms underlying collagen diseases. CONCLUSION: Our data add new variants to the repertoire of COL2A1 mutation resulting in related collagenopathies. PMID- 24949747 TI - Real-space decoupling transformation for quantum many-body systems. AB - We propose a real-space renormalization group method to explicitly decouple into independent components a many-body system that, as in the phenomenon of spin charge separation, exhibits separation of degrees of freedom at low energies. Our approach produces a branching holographic description of such systems that opens the path to the efficient simulation of the most entangled phases of quantum matter, such as those whose ground state violates a boundary law for entanglement entropy. As in the coarse-graining transformation of Vidal [Phys. Rev. Lett. 99, 220405 (2007). PMID- 24949746 TI - Experimental realization of a compressed quantum simulation of a 32-spin Ising chain. AB - Certain n-qubit quantum systems can be faithfully simulated by quantum circuits with only O(log(n)) qubits [B. Kraus, Phys. Rev. Lett. 107, 250503 (2011)]. Here we report an experimental realization of this compressed quantum simulation on a one-dimensional Ising chain. By utilizing an nuclear magnetic resonance quantum simulator with only five qubits, the property of ground-state magnetization of an open-boundary 32-spin Ising model is experimentally simulated, prefacing the expected quantum phase transition in the thermodynamic limit. This experimental protocol can be straightforwardly extended to systems with hundreds of spins by compressing them into up to merely 10-qubit systems. Our experiment paves the way for exploring physical phenomena in large-scale quantum systems with quantum simulators under current technology. PMID- 24949748 TI - Fluctuating interfaces subject to stochastic resetting. AB - We study one-dimensional fluctuating interfaces of length L, where the interface stochastically resets to a fixed initial profile at a constant rate r. For finite r in the limit L->infinity, the system settles into a nonequilibrium stationary state with non-Gaussian interface fluctuations, which we characterize analytically for the Kardar-Parisi-Zhang and Edwards-Wilkinson universality class. Our results are corroborated by numerical simulations. We also discuss the generality of our results for a fluctuating interface in a generic universality class. PMID- 24949749 TI - Nonequilibrium glassy dynamics of self-propelled hard disks. AB - We analyze the collective dynamics of self-propelled particles in the large density regime where passive particles undergo a kinetic arrest to an amorphous glassy state. We capture the competition between self-propulsion and crowding effects using a two-dimensional model of self-propelled hard disks, which we study using Monte Carlo simulations. Although the activity drives the system far from equilibrium, self-propelled particles undergo a kinetic arrest, which we characterize in detail and compare with its equilibrium counterpart. In particular, the critical density for dynamic arrest continuously shifts to larger densities with increasing activity, and the relaxation time is surprisingly well described by an algebraic divergence resulting from the emergence of highly collective dynamics. These results show that dense assemblies of active particles undergo a nonequilibrium glass transition that is profoundly affected by self propulsion mechanisms. PMID- 24949750 TI - Kerr black holes with scalar hair. AB - We present a family of solutions of Einstein's gravity minimally coupled to a complex, massive scalar field, describing asymptotically flat, spinning black holes with scalar hair and a regular horizon. These hairy black holes (HBHs) are supported by rotation and have no static limit. Besides mass M and angular momentum J, they carry a conserved, continuous Noether charge Q measuring the scalar hair. HBHs branch off from the Kerr metric at the threshold of the superradiant instability and reduce to spinning boson stars in the limit of vanishing horizon area. They overlap with Kerr black holes for a set of (M, J) values. A single Killing vector field preserves the solutions, tangent to the null geodesic generators of the event horizon. HBHs can exhibit sharp physical differences when compared to the Kerr solution, such as J/M^{2}>1, a quadrupole moment larger than J^{2}/M, and a larger orbital angular velocity at the innermost stable circular orbit. Families of HBHs connected to the Kerr geometry should exist in scalar (and other) models with more general self-interactions. PMID- 24949751 TI - Clear and measurable signature of modified gravity in the galaxy velocity field. AB - The velocity field of dark matter and galaxies reflects the continued action of gravity throughout cosmic history. We show that the low-order moments of the pairwise velocity distribution v_{12} are a powerful diagnostic of the laws of gravity on cosmological scales. In particular, the projected line-of-sight galaxy pairwise velocity dispersion sigma_{12}(r) is very sensitive to the presence of modified gravity. Using a set of high-resolution N-body simulations, we compute the pairwise velocity distribution and its projected line-of-sight dispersion for a class of modified gravity theories: the chameleon f(R) gravity and Galileon gravity (cubic and quartic). The velocities of dark matter halos with a wide range of masses would exhibit deviations from general relativity at the (5 10)sigma level. We examine strategies for detecting these deviations in galaxy redshift and peculiar velocity surveys. If detected, this signature would be a "smoking gun" for modified gravity. PMID- 24949752 TI - Quantum Monte Carlo calculations of neutron matter with nonlocal chiral interactions. AB - We present fully nonperturbative quantum Monte Carlo calculations with nonlocal chiral effective field theory (EFT) interactions for the ground-state properties of neutron matter. The equation of state, the nucleon chemical potentials, and the momentum distribution in pure neutron matter up to one and a half times the nuclear saturation density are computed with a newly optimized chiral EFT interaction at next-to-next-to-leading order. This work opens the way to systematic order by order benchmarking of chiral EFT interactions and ab initio prediction of nuclear properties while respecting the symmetries of quantum chromodynamics. PMID- 24949754 TI - Falsifying high-scale leptogenesis at the LHC. AB - Measuring a nonzero value for the cross section of any lepton number violating (LNV) process would put a strong lower limit on the washout factor for the effective lepton number density in the early Universe at times close to the electroweak phase transition and thus would lead to important constraints on any high-scale model for the generation of the observed baryon asymmetry based on LNV. In particular, for leptogenesis (LG) models with masses of the right-handed neutrinos heavier than the mass scale observed at the LHC, the implied large washout factors would lead to a violation of the out-of-equilibrium condition and exponentially suppress the net lepton number produced in such LG models. We thus demonstrate that the observation of LNV processes at the LHC results in the falsification of high-scale LG models. However, no conclusions about the viability of LG models can be drawn from the nonobservation of LNV processes. PMID- 24949753 TI - Value of H(0) in the inhomogeneous universe. AB - Local measurements of the Hubble expansion rate are affected by structures like galaxy clusters or voids. Here we present a fully relativistic treatment of this effect, studying how clustering modifies the mean distance- (modulus-)redshift relation and its dispersion in a standard cold dark matter universe with a cosmological constant. The best estimates of the local expansion rate stem from supernova observations at small redshifts (0.01h_{1}h_{1}, a_{1}a_{1} and chi_{1}chi_{1}, however. As an illustration, we study the decay topology: h_{2}->chi_{1}chi_{2}, where the binolike chi_{2} decays to h_{1}chi_{1} or a_{1}chi_{1}, and h_{1}/a_{1}->ff[over -], with ff[over ]=MU^{+}MU^{-}, bb[over -]. In the dimuon case (m_{h_{1}/a_{1}}~1 GeV), a statistical sensitivity of S/sqrt[B]>6sigma can be achieved easily at the 8 TeV LHC, assuming sigma(pp->Wh_{2})/sigma(pp->Wh_{SM})Br(h_{2}->MU^{+}MU^{ }chi_{1}chi_{1})=0.1. In the bb[over -] case (m_{h_{1}/a_{1}}~45 GeV), 600 fb^{ 1} data at the 14 TeV LHC can lead to a statistical sensitivity of S/sqrt[B]>5sigma, assuming sigma(pp->Zh_{2})/sigma(pp->Zh_{SM})Br(h_{2}->bb[over ]chi_{1}chi_{1})=0.5. These exotic decays open a new avenue for exploring new physics couplings with the 125 GeV Higgs boson at colliders. PMID- 24949757 TI - Search at the Mainz Microtron for light massive gauge bosons relevant for the muon g-2 anomaly. AB - A massive, but light, Abelian U(1) gauge boson is a well-motivated possible signature of physics beyond the standard model of particle physics. In this Letter, the search for the signal of such a U(1) gauge boson in electron-positron pair production at the spectrometer setup of the A1 Collaboration at the Mainz Microtron is described. Exclusion limits in the mass range of 40 MeV/c^{2} to 300 MeV/c^{2}, with a sensitivity in the squared mixing parameter of as little as epsilon^{2}=8*10^{-7} are presented. A large fraction of the parameter space has been excluded where the discrepancy of the measured anomalous magnetic moment of the muon with theory might be explained by an additional U(1) gauge boson. PMID- 24949759 TI - Selection rules for hadronic transitions of XYZ mesons. AB - Many of the XYZ mesons discovered in the last decade can be identified as bound states of a heavy quark and antiquark in Born-Oppenheimer (BO) potentials defined by the energy of gluon and light-quark fields in the presence of static color sources. The mesons include quarkonium hybrids, which are bound states in excited flavor-singlet BO potentials, and quarkonium tetraquarks, which are bound states in BO potentials with light-quark+antiquark flavor. The deepest hybrid potentials are known from lattice QCD calculations. The deepest tetraquark potentials can be inferred from lattice QCD calculations of static adjoint mesons. Selection rules for hadronic transitions are derived and used to identify XYZ mesons that are candidates for ground-state energy levels in the BO potentials for charmonium hybrids and tetraquarks. PMID- 24949763 TI - Complete photoionization experiments via ultrafast coherent control with polarization multiplexing. AB - Photoelectron angular distributions (PADs) obtained from ionization of potassium atoms using moderately intense femtosecond IR fields (~10^{12} W cm^{-2}) of various polarization states are shown to provide a route to "complete" photoionization experiments. Ionization occurs by a net three-photon absorption process, driven via the 4s->4p resonance at the one-photon level. A theoretical treatment incorporating the intrapulse electronic dynamics allows for a full set of ionization matrix elements to be extracted from 2D imaging data. 3D PADs generated from the extracted matrix elements are also compared to experimental, tomographically reconstructed, 3D photoelectron distributions, providing a sensitive test of their validity. Finally, application of the determined matrix elements to ionization via more complex, polarization-shaped, pulses is demonstrated, illustrating the utility of this methodology towards detailed understanding of complex ionization control schemes and suggesting the utility of such "multiplexed" intrapulse processes as powerful tools for measurement. PMID- 24949762 TI - Observation of the beta-delayed gamma-proton decay of (56)Zn and its impact on the Gamow-Teller strength evaluation. AB - We report the observation of a very exotic decay mode at the proton drip line, the beta-delayed gamma-proton decay, clearly seen in the beta decay of the T_{z}= 2 nucleus ^{56}Zn. Three gamma-proton sequences have been observed after the beta decay. Here this decay mode, already observed in the sd shell, is seen for the first time in the fp shell. Both gamma and proton decays have been taken into account in the estimation of the Fermi and Gamow-Teller strengths. Evidence for fragmentation of the Fermi strength due to strong isospin mixing is found. PMID- 24949764 TI - Harnessing vacuum forces for quantum sensing of graphene motion. AB - Position measurements at the quantum level are vital for many applications but also challenging. Typically, methods based on optical phase shifts are used, but these methods are often weak and difficult to apply to many materials. An important example is graphene, which is an excellent mechanical resonator due to its small mass and an outstanding platform for nanotechnologies, but it is largely transparent. Here, we present a novel detection scheme based upon the strong, dispersive vacuum interactions between a graphene sheet and a quantum emitter. In particular, the mechanical displacement causes strong changes in the vacuum-induced shifts of the transition frequency of the emitter, which can be read out via optical fields. We show that this enables strong quantum squeezing of the graphene position on time scales that are short compared to the mechanical period. PMID- 24949766 TI - Synchronized switching in a josephson junction crystal. AB - We consider a superconducting coplanar waveguide resonator where the central conductor is interrupted by a series of uniformly spaced Josephson junctions. The device forms an extended medium that is optically nonlinear on the single photon level with normal modes that inherit the full nonlinearity of the junctions but are nonetheless accessible via the resonator ports. For specific plasma frequencies of the junctions, a set of normal modes clusters in a narrow band and eventually becomes entirely degenerate. Upon increasing the intensity of a red detuned drive on these modes, we observe a sharp and synchronized switching from low-occupation quantum states to high-occupation classical fields, accompanied by a pronounced jump from low to high output intensity. PMID- 24949765 TI - Scalable spatial superresolution using entangled photons. AB - N00N states-maximally path-entangled states of N photons-exhibit spatial interference patterns sharper than any classical interference pattern. This is known as superresolution. However, even given perfectly efficient number resolving detectors, the detection efficiency of all previous measurements of such interference would decrease exponentially with the number of photons in the N00N state, often leading to the conclusion that N00N states are unsuitable for spatial measurements. A technique known as the "optical centroid measurement" has been proposed to solve this and has been experimentally verified for photon pairs; here we present the first extension beyond two photons, measuring the superresolution fringes of two-, three-, and four-photon N00N states. Moreover, we compare the N00N-state interference to the corresponding classical superresolution interference. Although both provide the same increase in spatial frequency, the visibility of the classical fringes decreases exponentially with the number of detected photons. Our work represents an essential step forward for quantum-enhanced measurements, overcoming what was believed to be a fundamental challenge to quantum metrology. PMID- 24949767 TI - How lasing localized structures evolve out of passive mode locking. AB - We investigate the relationship between passive mode locking and the formation of time-localized structures in the output intensity of a laser. We show how the mode-locked pulses transform into lasing localized structures, allowing for individual addressing and arbitrary low repetition rates. Our analysis reveals that this occurs when (i) the cavity round-trip is much larger than the slowest medium time scale, namely the gain recovery time, and (ii) the mode-locked solution coexists with the zero intensity (off) solution. These conditions enable the coexistence of a large quantity of stable solutions, each of them being characterized by a different number of pulses per round-trip and with different arrangements. Then, each mode-locked pulse becomes localized, i.e., individually addressable. PMID- 24949768 TI - Superfilamentation in air. AB - The interaction between a large number of laser filaments brought together using weak external focusing leads to the emergence of few filamentary structures reminiscent of standard filaments, but carrying a higher intensity. The resulting plasma is measured to be 1 order of magnitude denser than for short-scale filaments. This new propagation regime is dubbed superfilamentation. Numerical simulations of a nonlinear envelope equation provide good agreement with experiments. PMID- 24949769 TI - Intrinsic power oscillations generated by the backaction of continuum on solitons and its implications on the transfer functions of a mode-locked laser. AB - Soliton mode locking is an essential technique for building compact mode-locked lasers with multigigahertz repetition rates. In this scheme, pulses behave like dissipative solitons due to the presence of gain, loss, frequency filtering, and nonlinear absorption in the cavity. The continuum waves that radiate from the perturbed soliton act back on the soliton, resulting in periodic changes in the electric field of the pulse. We find that, in the presence of gain filtering or two-photon absorption, this field modulation is converted to power modulation, which is observable from the radio-frequency spectrum of the laser's output power. We investigate its physical origin in the context of soliton perturbation theory. For comparison, we also perform numerical simulations and experiments. PMID- 24949770 TI - Dynamic wavelength conversion in copropagating slow-light pulses. AB - Dynamic wavelength conversion (DWC) is obtained by controlling copropagating slow light signal and control pulse trajectories. Our method is based on the understanding that conventional resonator-based DWC can be generalized, and is linked to cross-phase modulation. Dispersion-engineered Si photonic crystal waveguides produce such slow-light pulses. Free carriers generated by two-photon absorption of the control pulse dynamically shift the signal wavelength. Matching the group velocities of the two pulses enhances the shift, elongating the interaction length. We demonstrate an extremely large wavelength shift in DWC (4.9 nm blueshift) for the signal wavelength. Although DWC is similar to the Doppler effect, we highlight their essential differences. PMID- 24949771 TI - Coherence and incoherence in an optical comb. AB - We demonstrate a coexistence of coherent and incoherent modes in the optical comb generated by a passively mode-locked quantum dot laser. This is experimentally achieved by means of optical linewidth, radio frequency spectrum, and optical spectrum measurements and confirmed numerically by a delay-differential equation model showing excellent agreement with the experiment. We interpret the state as a chimera state. PMID- 24949772 TI - Muon cooling: longitudinal compression. AB - A 10 MeV/c positive muon beam was stopped in helium gas of a few mbar in a magnetic field of 5 T. The muon "swarm" has been efficiently compressed from a length of 16 cm down to a few mm along the magnetic field axis (longitudinal compression) using electrostatic fields. The simulation reproduces the low energy interactions of slow muons in helium gas. Phase space compression occurs on the order of microseconds, compatible with the muon lifetime of 2 MUs. This paves the way for the preparation of a high-quality low-energy muon beam, with an increase in phase space density relative to a standard surface muon beam of 10^{7}. The achievable phase space compression by using only the longitudinal stage presented here is of the order of 10^{4}. PMID- 24949756 TI - Measurement of B(t->Wb)/B(t->Wq) in top-quark-pair decays using dilepton events and the full CDF Run II data set. AB - We present a measurement of the ratio of the top-quark branching fractions R=B(t >Wb)/B(t->Wq), where q represents any quark flavor, in events with two charged leptons, imbalance in total transverse energy, and at least two jets. The measurement uses proton-antiproton collision data at center-of-mass energy 1.96 TeV, corresponding to an integrated luminosity of 8.7 fb^{-1} collected with the Collider Detector at Fermilab during Run II of the Tevatron. We measure R to be 0.87+/-0.07, and extract the magnitude of the top-bottom quark coupling to be |V_{tb}|=0.93+/-0.04, assuming three generations of quarks. Under these assumptions, a lower limit of |V_{tb}|>0.85(0.87) at 95% (90%) credibility level is set. PMID- 24949773 TI - Detection of lower tropospheric responses to solar energetic particles at midlatitudes. AB - Solar energetic particles (SEPs) occasionally contribute additional atmospheric ionization beyond that arising from the usual galactic cosmic ray background. During an SEP event associated with a solar flare on April 11, 2013, the vertical ionization rate profile obtained using a balloon-borne detector showed enhanced ionization with a 26% increase at 20 km, over Reading, United Kingdom. Fluctuations in atmospheric electrical parameters were also detected at the surface, beneath the balloon's trajectory. As no coincident changes in geomagnetism occurred, the electrical fluctuations are very likely to be associated with increased ionization, as observed by the balloon measurements. The lack of response of surface neutron monitors during this event indicates that energetic particles that are not detected at the surface by neutron monitors can nevertheless enter and influence the atmosphere's weather-generating regions. PMID- 24949775 TI - Critical exponents of the superfluid-Bose-glass transition in three dimensions. AB - Recent experimental and numerical studies of the critical-temperature exponent phi for the superfluid-Bose-glass universality in three-dimensional systems report strong violations of the key quantum critical relation, phi=nuz, where z and nu are the dynamic and correlation-length exponents, respectively; these studies question the conventional scaling laws for this quantum critical point. Using Monte Carlo simulations of the disordered Bose-Hubbard model, we demonstrate that previous work on the superfluid-to-normal-fluid transition temperature dependence on the chemical potential (or the magnetic field, in spin systems), T_{c}?(MU-MU_{c})^{phi}, was misinterpreting transient behavior on approach to the fluctuation region with the genuine critical law. When the model parameters are modified to have a broad quantum critical region, simulations of both quantum and classical models reveal that the phi=nuz law [with phi=2.7(2), z=3, and nu=0.88(5)] holds true, resolving the phi-exponent "crisis." PMID- 24949774 TI - Observation of a reflected shock in an indirectly driven spherical implosion at the national ignition facility. AB - A 200 MUm radius hot spot at more than 2 keV temperature, 1 g/cm^{3} density has been achieved on the National Ignition Facility using a near vacuum hohlraum. The implosion exhibits ideal one-dimensional behavior and 99% laser-to-hohlraum coupling. The low opacity of the remaining shell at bang time allows for a measurement of the x-ray emission of the reflected central shock in a deuterium plasma. Comparison with 1D hydrodynamic simulations puts constraints on electron ion collisions and heat conduction. Results are consistent with classical (Spitzer-Harm) heat flux. PMID- 24949778 TI - Diffusion on demand to control precipitation aging: application to Al-Mg-Si alloys. AB - We demonstrate experimentally that a part-per-million addition of Sn solutes in Al-Mg-Si alloys can inhibit natural aging and enhance artificial aging. The mechanism controlling the aging is argued to be vacancy diffusion, with solutes trapping vacancies at low temperature and releasing them at elevated temperature, which is supported by a thermodynamic model and first-principles computations of Sn-vacancy binding. This "diffusion on demand" solves the long-standing problem of detrimental natural aging in Al-Mg-Si alloys, which is of great scientific and industrial importance. Moreover, the mechanism of controlled buffering and release of excess vacancies is generally applicable to modulate diffusion in other metallic systems. PMID- 24949777 TI - Emergent structure of multidislocation ground States in curved crystals. AB - We study the structural features and underlying principles of multidislocation ground states of a crystalline spherical cap. In the continuum limit where the ratio of crystal size to lattice spacing W/a diverges, dislocations proliferate and ground states approach a characteristic sequence of structures composed of radial grain boundaries ("neutral scars"), extending radially from the boundary and terminating in the bulk. Employing a combination of numerical simulations and asymptotic analysis of continuum elasticity theory, we prove that an energetic hierarchy gives rise to a structural hierarchy, whereby dislocation number and scar number diverge as a/W->0 while scar length and dislocation number per scar become independent of lattice spacing. We characterize a secondary transition occurring as scar length grows, where the n-fold scar symmetry is broken and ground states are characterized by polydisperse, forked-scar morphologies. PMID- 24949776 TI - Towards template-assisted assembly of nematic colloids. AB - Colloidal crystals belong to a new class of materials with unusual properties in which the big challenge is to grow large-scale structures of a given symmetry in a well-controlled and inexpensive way. Recently, template-assisted crystallization was successfully exploited experimentally in the case of colloidal particles dispersed in isotropic fluids. In liquid crystal (LC) colloids, particles are subjected to long-range anisotropic elastic forces originating from the anisotropic deformation of the underlying order parameter. These effective interactions are easily tunable by external electric or magnetic fields, light, temperature, or confinement and, thus, provide additional handles for better control of colloidal assembly. Here we use the coupling between microsculptured bounding surfaces and LC elasticity in order to guide the self assembly of large-scale colloidal structures. We present explicit numerical calculations of the free energy landscape of colloidal particles in the presence of convex protrusions modeled as squared pyramids comparable to the size of the particles. We show the existence of strong trapping potentials that are able to efficiently localize the colloidal particles and withstand thermal fluctuations. Three-dimensional optical imaging experiments support the theoretical predictions. PMID- 24949779 TI - Critical exponents of strongly correlated fermion systems from diagrammatic multiscale methods. AB - Self-consistent dynamical approximations for strongly correlated fermion systems are particularly successful in capturing the dynamical competition of local correlations. In these, the effect of spatially extended degrees of freedom is usually only taken into account in a mean field fashion or as a secondary effect. As a result, critical exponents associated with phase transitions have a mean field character. Here we demonstrate that diagrammatic multiscale methods anchored around local approximations are indeed capable of capturing the non-mean field nature of the critical point of the lattice model encoded in a nonvanishing anomalous dimension and of correctly describing the transition to mean-field-like behavior as the number of spatial dimensions increases. PMID- 24949781 TI - Giant fluctuations of local magnetoresistance of organic spin valves and the non Hermitian 1D Anderson model. AB - Motivated by recent experiments, where the tunnel magnetoresitance (TMR) of a spin valve was measured locally, we theoretically study the distribution of TMR along the surface of magnetized electrodes. We show that, even in the absence of interfacial effects (like hybridization due to donor and acceptor molecules), this distribution is very broad, and the portion of area with negative TMR is appreciable even if on average the TMR is positive. The origin of the local sign reversal is quantum interference of subsequent spin-rotation amplitudes in the course of incoherent transport of carriers between the source and the drain. We find the distribution of local TMR exactly by drawing upon formal similarity between evolution of spinors in time and of the reflection coefficient along a 1D chain in the Anderson model. The results obtained are confirmed by the numerical simulations. PMID- 24949780 TI - Importance of charge fluctuations for the topological phase in SmB(6). AB - Typical Kondo insulators (KIs) can have a nontrivial Z_{2} topology because the energy gap opens at the Fermi energy (E_{F}) by a hybridization between odd- and even-parity bands. SmB_{6} deviates from such KI behavior, and it has been unclear how the insulating phase occurs. Here, we demonstrate that charge fluctuations are the origin of the topological insulating phase in SmB_{6}. Our angle-resolved photoemission spectroscopy results reveal that with decreasing temperature the bottom of the d-f hybridized band at the X[over -] point, which is predicted to have odd parity and is required for a topological phase, gradually shifts from below to above E_{F}. We conclude that SmB_{6} is a charge fluctuating topological insulator. PMID- 24949782 TI - Enhanced thermoelectric performance and anomalous seebeck effects in topological insulators. AB - Improving the thermoelectric figure of merit zT is one of the greatest challenges in material science. The recent discovery of topological insulators (TIs) offers new promise in this prospect. In this work, we demonstrate theoretically that zT is strongly size dependent in TIs, and the size parameter can be tuned to enhance zT to be significantly greater than 1. Furthermore, we show that the lifetime of the edge states in TIs is strongly energy dependent, leading to large and anomalous Seebeck effects with an opposite sign to the Hall effect. These striking properties make TIs a promising material for thermoelectric science and technology. PMID- 24949783 TI - Evidence of van Hove singularities in ordered grain boundaries of graphene. AB - It has long been under debate whether the electron transport performance of graphene could be enhanced by the possible occurrence of van Hove singularities in grain boundaries. Here, we provide direct experimental evidence to confirm the existence of van Hove singularity states close to the Fermi energy in certain ordered grain boundaries using scanning tunneling microscopy. The intrinsic atomic and electronic structures of two ordered grain boundaries, one with alternative pentagon and heptagon rings and the other with alternative pentagon pair and octagon rings, are determined. It is firmly verified that the carrier concentration and, thus, the conductance around ordered grain boundaries can be significantly enhanced by the van Hove singularity states. This finding strongly suggests that a graphene nanoribbon with a properly embedded ordered grain boundary can be a promising structure to improve the performance of graphene based electronic devices. PMID- 24949785 TI - Effect of disorder on the resistivity anisotropy near the electronic nematic phase transition in pure and electron-doped BaFe(2)As(2). AB - We show that the strain-induced resistivity anisotropy in the tetragonal state of the representative underdoped Fe arsenides BaFe_{2}As_{2}, Ba(Fe_{1 x}Co_{x})_{2}As_{2} and Ba(Fe_{1-x}Ni_{x})_{2}As_{2} is independent of disorder over a wide range of defect and impurity concentrations. This result demonstrates that the anisotropy in the in-plane resistivity in the paramagnetic orthorhombic state of this material is not due to elastic scattering from anisotropic defects. Conversely, our result can be most easily understood if the resistivity anisotropy arises primarily from an intrinsic anisotropy in the electronic structure. PMID- 24949784 TI - Self-referenced single-electron quantized current source. AB - The future redefinition of the international system of units in terms of natural constants requires a robust, high-precision quantum standard for the electrical base unit ampere. However, the reliability of any single-electron current source generating a nominally quantized output current I=ef by delivering single electrons with charge e at a frequency f is eventually limited by the stochastic nature of the underlying quantum mechanical tunneling process. We experimentally explore a path to overcome this fundamental limitation by serially connecting clocked single-electron emitters with multiple in situ single-electron detectors. Correlation analysis of the detector signatures during current generation reveals erroneous pumping events and enables us to determine the deviation of the output current from the nominal quantized value ef. This demonstrates the concept of a self-referenced single-electron source for electrical quantum metrology. PMID- 24949786 TI - Superfluid spin transport through easy-plane ferromagnetic insulators. AB - Superfluid spin transport-dissipationless transport of spin-is theoretically studied in a ferromagnetic insulator with easy-plane anisotropy. We consider an open geometry where the spin current is injected into the ferromagnet from one side by a metallic reservoir with a nonequilibrium spin accumulation and ejected into another metallic reservoir located downstream. Spin transport is studied using a combination of magnetoelectric circuit theory, Landau-Lifshitz-Gilbert phenomenology, and microscopic linear-response theory. We discuss how spin superfluidity can be probed in a magnetically mediated negative electron-drag experiment. PMID- 24949787 TI - Extreme harmonic generation in electrically driven spin resonance. AB - We report the observation of multiple harmonic generation in electric dipole spin resonance in an InAs nanowire double quantum dot. The harmonics display a remarkable detuning dependence: near the interdot charge transition as many as eight harmonics are observed, while at large detunings we only observe the fundamental spin resonance condition. The detuning dependence indicates that the observed harmonics may be due to Landau-Zener transition dynamics at anticrossings in the energy level spectrum. PMID- 24949788 TI - Consequences of anomalous diffusion in disordered systems under cyclic forcing. AB - We study the particle scale response of a 2D frictionless disk system to bulk forcing via cyclic shear with reversal amplitude gamma_{r}. We find a subdiffusive gamma_{r}-dependent regime, which is consistent with models of anomalous diffusion with scale-invariant cage dynamics, and a crossover to diffusive grain motion at high gamma_{r}. Analysis of local displacements of a particle relative to its cage of neighbors reveals a key distinction from thermal systems. Particles are moved by fluctuations of their cage of neighbors rather than rattling in their cage, indicating a distinct cage-breaking mechanism. PMID- 24949761 TI - Azimuthal-angle dependence of charged-pion-interferometry measurements with respect to second- and third-order event planes in Au+Au collisions at ?[S(NN)]=200 GeV. AB - Charged-pion-interferometry measurements were made with respect to the second- and third-order event plane for Au+Au collisions at sqrt[s_{NN}]=200 GeV. A strong azimuthal-angle dependence of the extracted Gaussian-source radii was observed with respect to both the second- and third-order event planes. The results for the second-order dependence indicate that the initial eccentricity is reduced during the medium evolution, which is consistent with previous results. In contrast, the results for the third-order dependence indicate that the initial triangular shape is significantly reduced and potentially reversed by the end of the medium evolution, and that the third-order oscillations are largely dominated by the dynamical effects from triangular flow. PMID- 24949789 TI - Granular dynamics during impact. AB - We study the impact of a projectile onto a bed of 3 mm grains immersed in an index-matched fluid. We vary the amount of prestrain on the sample, strengthening the force chains within the system. We find this affects only the prefactor of the linear depth-dependent term in the stopping force. We propose a simple model to account for the strain dependence of this term, owing to increased pressure in the pile. Interestingly, we find that the presence of the fluid does not affect the impact dynamics, suggesting that dynamic friction is not a factor. Using a laser sheet scanning technique to visualize internal grain motion, we measure the trajectory of each grain throughout an impact. Microscopically, our results indicate that weaker initial force chains result in more irreversible, plastic rearrangements, suggesting static friction between grains does play a substantial role in the energy dissipation. PMID- 24949790 TI - Possible origin of stagnation and variability of earth's biodiversity. AB - The magnitude and variability of Earth's biodiversity have puzzled scientists ever since paleontologic fossil databases became available. We identify and study a model of interdependent species where both endogenous and exogenous impacts determine the nonstationary extinction dynamics. The framework provides an explanation for the qualitative difference of marine and continental biodiversity growth. In particular, the stagnation of marine biodiversity may result from a global transition from an imbalanced to a balanced state of the species dependency network. The predictions of our framework are in agreement with paleontologic databases. PMID- 24949791 TI - Charge-transfer excited states in aqueous DNA: Insights from many-body Green's function theory. AB - Charge-transfer (CT) excited states play an important role in the excited-state dynamics of DNA in aqueous solution. However, there is still much controversy on their energies. By ab initio many-body Green's function theory, together with classical molecular dynamics simulations, we confirm the existence of CT states at the lower energy side of the optical absorption maximum in aqueous DNA as observed in experiments. We find that the hydration shell can exert strong effects (~1 eV) on both the electronic structure and CT states of DNA molecules through dipole electric fields. In this case, the solvent cannot be simply regarded as a macroscopic screening medium as usual. The influence of base stacking and base pairing on the CT states is also discussed. PMID- 24949792 TI - Comment on "lithium synthesis in microquasar accretion". PMID- 24949793 TI - Iocco and Pato reply:. PMID- 24949794 TI - Assessment of genetic associations between common single nucleotide polymorphisms in RIG-I-like receptor and IL-4 signaling genes and severe respiratory syncytial virus infection in children: a candidate gene case-control study. AB - The majority of cases of severe pediatric respiratory syncytial virus (RSV) infection occur in otherwise healthy infants who have no identifiable risk factors, suggesting that additional subclinical factors, such as population genetic variation, influence the course of RSV infection. The objective of this study was to test if common single nucleotide polymorphisms (SNPs) in genes encoding for immune signalling components of the RIG-I-like receptor (RLR) and IL 4-signalling pathways affect the outcome of RSV infection in early life. We genotyped 8 SNPs using allele-specific probes combined with real-time PCR. Each of the SNPs tested had previously been established to have a functional impact on immune responsiveness and two of the SNPs in the IL4 and IL4R genes had previously been associated with severe RSV bronchiolitis. Association with susceptibility to severe RSV infection was tested by statistically comparing genotype and allele frequencies in infants and young children hospitalized with severe RSV bronchiolitis (n = 140) with two control groups-children who tested positive for RSV but did not require hospitalization (n = 100), and a general population control group (n = 285). Our study was designed with sufficient power (>80%) to detect clinically-relevant associations with effect sizes >=1.5. However, we detected no statistically significant differences in allele and genotype frequencies of the investigated SNPs between the inpatient and control groups. To conclude, we could not replicate the previously reported association with SNPs in the IL4 and IL4R genes in our independent cohort, nor did we find that common SNPs in genes encoding for RLRs and the downstream adapter MAVS were associated with susceptibility to severe RSV infections. Despite the existing evidence demonstrating a functional immunological impact of these SNPs, our data suggest that the biological effect of each individual SNP is unlikely to affect clinical outcomes of RSV infection. PMID- 24949795 TI - In older men, lower plasma 25-hydroxyvitamin D is associated with reduced incidence of prostate, but not colorectal or lung cancer. AB - CONTEXT AND OBJECTIVE: Prostate, colorectal and lung cancers are common in men. In this study, we aimed to determine whether vitamin D status is associated with the incidence of these cancers in older men. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: 4208 older men aged 70-88 years in Perth, Western Australia. MAIN OUTCOME MEASURES: Plasma 25-hydroxyvitamin D [25(OH)D] concentration was measured by immunoassay. New diagnoses of prostate, colorectal and lung cancers were determined via electronic record linkage. RESULTS: During a mean follow-up of 6.7+/-1.8 years, there were 315, 117 and 101 new diagnoses of prostate, colorectal and lung cancer. In multivariate competing risks proportional hazards models, every 10 nmol/l decrease in 25(OH)D concentration was associated with a 4% reduction in prostate cancer incidence (sub-hazard ratio [SHR] 0.96, 95% confidence interval [CI] 0.92-1.00). Every halving of 25(OH)D concentration was associated with a 21% reduction in incident prostate cancer in multivariate analysis (SHR 0.79, 95% CI 0.63-0.99). Following exclusion of prostate cancer cases diagnosed within 3 years of blood sampling, low 25(OH)D <50 nmol/l was associated with lower incident prostate cancer, and higher 25(OH)D >75 nmol/l was associated with higher incidence, when compared to the reference range 50-75 nmol/l, respectively (p = 0.027). Significant associations were also observed when 25(OH)D was modeled as a quantitative variable. No associations were observed between plasma 25(OH)D concentration with incidence of colorectal or lung cancer. CONCLUSION: Lower levels of vitamin D may reduce prostate cancer risk in older men. By contrast, levels of vitamin D did not predict incidence of colorectal or lung cancers. Further studies are needed to determine whether a causal relationship exists between vitamin D and prostate cancer in ageing men. PMID- 24949797 TI - A new glutarimide derivative from marine sponge-derived Streptomyces anulatus S71. AB - Four glutarimide-derived compounds including a new 3-[2-[2-hydroxy-3-methylphenyl 5-(hydroxymethyl)]-2-oxoethyl] glutarimide (1) and three known 3-[2-(2-hyroxy-3,5 dimethylphenyl)-2-oxoethyl] glutarimide (2, actiphenol), 3-hydroxy-3-[2-(2 hydroxy-3,5-dimethylphenyl)-2-oxoethyl] glutarimide (3) and 3-[2-[2-hydroxy-3 (hydroxymethyl)-5-methylphenyl]-2-oxoethyl] glutarimide (4), along with a known indole alkaloid 3-(hydroxyacetyl) indole (5), were isolated from ethyl acetate extract of the fermentation broth of the marine sponge-derived Streptomyces anulatus S71. Their structures were deduced by extensive studies of NMR and mass spectra. PMID- 24949796 TI - Microstructural integrity of the superior cerebellar peduncle is associated with an impaired proprioceptive weighting capacity in individuals with non-specific low back pain. AB - INTRODUCTION: Postural control is a complex sensorimotor task that requires an intact network of white matter connections. The ability to weight proprioceptive signals is crucial for postural control. However, research into central processing of proprioceptive signals for postural control is lacking. This is specifically of interest in individuals with non-specific low back pain (NSLBP), because impairments in postural control have been observed as possible underlying mechanisms of NSLBP. Therefore, the objective was to investigate potential differences in sensorimotor white matter microstructure between individuals with NSLBP and healthy controls, and to determine whether the alterations in individuals with NSLBP are associated with the capacity to weight proprioceptive signals for postural control. METHODS: The contribution of proprioceptive signals from the ankle and back muscles to postural control was evaluated by local muscle vibration in 18 individuals with NSLBP and 18 healthy controls. Center of pressure displacement in response to muscle vibration was determined during upright standing on a stable and unstable support surface. Diffusion magnetic resonance imaging was applied to examine whether this proprioceptive contribution was associated with sensorimotor white matter microstructure. RESULTS: Individuals with NSLBP showed a trend towards a reduced fractional anisotropy along the left superior cerebellar peduncle compared to healthy controls (p = 0.039). The impaired microstructural integrity of the superior cerebellar peduncle in individuals with NSLBP was significantly correlated with the response to ankle muscle vibration (p<0.003). CONCLUSIONS: In individuals with NSLBP, a decreased integrity of the superior cerebellar peduncle was associated with an increased reliance on ankle muscle proprioception, even on unstable support surface, which implies an impaired proprioceptive weighting capacity. Our findings emphasize the importance of the superior cerebellar peduncle in proprioceptive weighting for postural control in individuals with NSLBP. PMID- 24949799 TI - Editors' note. PMID- 24949798 TI - Membrane environment can enhance the interaction of glycan binding protein to cell surface glycan receptors. AB - The binding of lectins to glycan receptors on the host cell surface is a key step contributing to the virulence and species specificity of most viruses. This is exemplified by the viral protein hemagglutinin (HA) of the influenza A virus, whose binding specificity is modulated by the linkage pattern of terminal sialic acids on glycan receptors of host epithelial cells. Such specificity dictates whether transmission is confined to a particular animal species or jumps between species. Here, we show, using H5N1 avian influenza as a model, that the specific binding of recombinant HA to alpha2-3 linked sialic acids can be enhanced dramatically by interaction with the surface of the lipid membrane. This effect can be quantitatively accounted for by a two-stage process in which weak association of HA with the membrane surface precedes more specific and tighter binding to the glycan receptor. The weak protein-membrane interaction discovered here in the model system may play an important secondary role in the infection and pathogenesis of the influenza A virus. PMID- 24949800 TI - Carotid artery stenting: it's all about appropriate patient selection and keeping to the indications. AB - With increasing carotid artery stenting (CAS) expertise and improved CAS equipment, recent trials have demonstrated better results for CAS compared with earlier studies. As a result, it may be argued that CAS is currently non-inferior to carotid endarterectomy (CEA), at least in some patient subgroups. Consequently, there have been recent calls for extending CAS indications to include average surgical risk patients with symptomatic or asymptomatic carotid stenosis. However, CAS remains a less cost-effective option than CEA. Opening the floodgates to unrestricted CAS for both symptomatic and asymptomatic carotid patients would have considerable cost implications for any health system. Appropriate patient selection and keeping to the indications are crucial to optimize CAS outcomes. PMID- 24949802 TI - The predictive power of the annellation theory: the case of the C32H16 benzenoid polycyclic aromatic hydrocarbons. AB - The positions of maximum absorbance for the p and beta bands of the UV-vis spectra of the benzenoid polycyclic aromatic hydrocarbons, PAHs, with molecular formula C32H16 have been predicted by means of the annellation theory. In the C32H16 PAH group there are 46 isomers, 39 of which have not been synthesized so far, thus their characterization and possible presence in the environment remains unknown. The methodology has been validated using literature information for 7 isomers in this PAH group. The results have been satisfactorily substantiated by means of semi-empirical calculations using the ZINDO/S approach. It has been concluded that the annellation theory is a powerful tool for the prediction of the positions of maximum absorbance of aromatic compounds with unknown UV-vis spectra. It is the first time that the UV-vis spectral information on these 39 benzenoid C32H16 PAHs has been predicted. PMID- 24949801 TI - Currently available methodologies for the processing of intravascular ultrasound and optical coherence tomography images. AB - Optical coherence tomography and intravascular ultrasound are the most widely used methodologies in clinical practice as they provide high resolution cross sectional images that allow comprehensive visualization of the lumen and plaque morphology. Several methods have been developed in recent years to process the output of these imaging modalities, which allow fast, reliable and reproducible detection of the luminal borders and characterization of plaque composition. These methods have proven useful in the study of the atherosclerotic process as they have facilitated analysis of a vast amount of data. This review presents currently available intravascular ultrasound and optical coherence tomography processing methodologies for segmenting and characterizing the plaque area, highlighting their advantages and disadvantages, and discusses the future trends in intravascular imaging. PMID- 24949803 TI - Rh(III)-catalyzed C-H activation/cyclization of indoles and pyrroles: divergent synthesis of heterocycles. AB - We report herein a new strategy of the Rh(III)-catalyzed C-H activation/cyclization of indoles and pyrroles, for the divergent synthesis of privileged heterocycles. A simple derivation of indoles and pyrroles to N carboxamides with oxidative bidentate directing group could enable rhodacycle formation and late-stage redox-neutral cyclization with alkynes, alkenes and diazo compounds, for access to five- and six-membered fused heterocycles, such as pyrimido[1,6-a]indol-1(2H)-one, 3,4-dihydropyrimido[1,6-a]indol-1(2H)-one, and 1H imidazo[1,5-a]indol-3(2H)-ones. Kinetic isotope effect study was conducted, and a plausible mechanism was proposed. Furthermore, this protocol was applied to concise synthesis of 5-HT3 receptor antagonist in gram-scale. PMID- 24949806 TI - Choriocarcinoma of the testis. PMID- 24949808 TI - Isothermal nucleic acid amplification strategy by cyclic enzymatic repairing for highly sensitive microRNA detection. AB - Technologies enabling highly sensitive and selective detection of microRNAs (miRNAs) are critical for miRNA discovery and clinical theranostics. Here we develop a novel isothermal nucleic acid amplification technology based on cyclic enzymatic repairing and strand-displacement polymerase extension for highly sensitive miRNA detection. The enzymatic repairing amplification (ERA) reaction is performed via replicating DNA template using lesion bases by DNA polymerase and cleaving the DNA replicate at the lesions by repairing enzymes, uracil-DNA glycosylase, and endonuclease IV, to prime a next-round replication. By utilizing the miRNA target as the primer, the ERA reaction is capable of producing a large number of reporter sequences from the DNA template, which can then be coupled to a cyclic signal output reaction mediated by endonuclease IV. The ERA reaction can be configured as a single-step, close-tube, and real-time format, which enables highly sensitive and selective detection of miRNA with excellent resistance to contaminants. The developed technology is demonstrated to give a detection limit of 0.1 fM and show superb specificity in discriminating single-base mismatch. The results reveal that the ERA reaction may provide a new paradigm for efficient nucleic acid amplification and may hold the potential for miRNA expression profiling and related theranostic applications. PMID- 24949809 TI - Dual role of serotonin in the acquisition and extinction of reward-driven learning: involvement of 5-HT1A, 5-HT2A and 5-HT3 receptors. AB - Serotonin (5-HT) has been proposed as a possible encoder of reward. Nevertheless, the role of this neurotransmitter in reward-based tasks is not well understood. Given that the major serotonergic circuit in the rat brain comprises the dorsal raphe nuclei and the medial prefrontal cortex (mPFC), and because the latter structure is involved in the control of complex behaviors and expresses 1A (5 HT1A), 2A (5-HT2A), and 3 (5-HT3) receptors, the aim was to study the role of 5 HT and of these receptors in the acquisition and extinction of a reward-dependent operant conditioning task. Long Evans rats were trained in an operant conditioning task while receiving fluoxetine (serotonin reuptake inhibitor, 10mg/kg), tianeptine (serotonin reuptake enhancer, 10mg/kg), buspirone (5-HT1A partial agonist, 10mg/kg), risperidone (5-HT2A antagonist, 1mg/kg), ondansetron (5-HT3 antagonist, 2mg/kg) or vehicle. Then, animals that acquired the operant conditioning without any treatment were trained to extinct the task in the presence of the pharmacological agents. Fluoxetine impaired acquisition but improved extinction. Tianeptine administration induced the opposite effects. Buspirone induced a mild deficit in acquisition and had no effects during the extinction phase. Risperidone administration resulted in learning deficits during the acquisition phase, although it promoted improved extinction. Ondansetron treatment showed a deleterious effect in the acquisition phase and an overall improvement in the extinction phase. These data showed a differential role of 5 HT in the acquisition and extinction of an operant conditioning task, suggesting that it may have a dual function in reward encoding. PMID- 24949810 TI - Moisture distribution during conventional or electrical resistance oven baking of bread dough and subsequent storage. AB - Electrical resistance oven (ERO) baking processes bread dough with little temperature gradient in the baking dough. Heating of the dough by means of an ERO is based on the principles of Joule's first law and Ohm's law. This study compared the changes in moisture distribution and physical changes in starch of breads conventionally baked or using an ERO. The moisture contents in fresh ERO breads are generally lower than those in conventional breads. During storage of conventionally baked breads, water migrates from the crumb to the crust and moisture contents decrease throughout the bread crumb. Evidently, less moisture redistribution occurs in ERO breads. Also, the protons of ERO bread constituents were less mobile than their counterparts in conventional bread. Starch retrogradation occurs to similar extents in conventional and ERO bread. As a result, the changes in proton mobility cannot be attributed to differences in levels of retrograded starch and seem to be primarily determined by the overall lower moisture content. PMID- 24949811 TI - Trends in asthma readmissions among children and adolescents over time by age, gender and season. AB - OBJECTIVES: Little is known about asthma readmissions within 28 days over time by age or gender. We explored trends in childhood asthma hospital readmission rates over time by age, gender and season. METHODS: Using a large database of 53,156 childhood admissions with a primary diagnosis of asthma from the Department of Health Victoria Australia for 1997-2009, we explored asthma hospital readmissions rates by seasonality, gender and age (2-18 years) using chi square tests, logistic regression models and graphical techniques. RESULTS: Approximately 9459 (28%) of the children had two or more admissions over the whole study period, contributing to 55% (29,056/53,156) of all admissions. Approximately 5% of admissions were repeat admission within 28 days. Over time, despite a decline in asthma incidence, the rate of readmission within 28 days increased, particularly in the 2-12 year age groups. Girls were at greater risk of readmission within 28 days (odds ratio [OR] = 1.15; 95% CI: 1.004-1.32; p = 0.04) and 12 months (OR = 1.11; 95% CI: 1.05-1.19; p = 0.001). Grass pollen season was associated with readmissions within 28 days, but only in boys (p = 0.01). CONCLUSION: Over time, despite a fall in asthma incidence, readmission rates for childhood asthma significantly increased in younger age groups with girls at a higher risk of being readmitted than boys. Increased risk of repeat admission for boys was observed during the grass pollen season. These findings highlight high-risk groups, which has implications for both clinical services and patient care. More detailed monitoring of readmission rates amongst various risk groups over time is required. PMID- 24949812 TI - Contribution of weak S-H . . . O hydrogen bonds to the side chain motions in D,L homocysteine on cooling. AB - Sulfhydryl groups play an important role in the formation of native structures of proteins and their biological functions. In the present work, we report for the first time the crystal structure of D,L-homocysteine and the results of a detailed study of the dynamics of its sulfhydryl group on cooling by precise single-crystal X-ray diffraction combined with polarized Raman spectroscopy of oriented single crystals. Although the crystal structures of both D,L-cysteine and D,L-homocysteine are layered, hydrogen bonds formed by -SH groups differ. In contrast with the crystal structure of D,L-cysteine with weak S-H . . . S hydrogen bonds between layers, D,L-homocysteine resembles the structures of amino acids with hydrophobic aliphatic side chains with no hydrogen bonds between the layers. The side chain of D,L-homocysteine forms a three-centered S-H . . . O hydrogen bond with carboxylate groups of two neighboring zwitterions. On cooling down, despite the shortening of the two S . . . O distances in the bifurcated S-H . . . O hydrogen bond, the wavenumber of the stretching vibrations of -SH groups increases. The same effect was also observed previously for other sulfhydryl containing amino acids, L-cysteine, and N-acetyl-L-cysteine on increasing pressure and is related to the strengthening of a three-centered bifurcated S-H . . . O hydrogen bond. PMID- 24949813 TI - Metal concentrations in surface water and sediments from Pardo River, Brazil: human health risks. AB - Pardo River (Brazil) is suffering from an important anthropogenic impact due to the pressure of highly populated areas and the influence of sugarcane cultivation. The objective of the present study was to determine the levels of 13 trace elements (As, Be, Cd, Cr, Cu, Pb, Mn, Hg, Ni, Tl, Sn, V and Zn) in samples of surface water and sediments from the Pardo River. Furthermore, the human health risks associated with exposure to those metals through oral intake and dermal absorption were also evaluated. Spatial and seasonal trends of the data were closely analyzed from a probabilistic approach. Manganese showed the highest mean concentrations in both water and sediments, remarking the incidence of the agricultural activity and the geological characteristics within the basin. Thallium and arsenic were identified as two priority pollutants, being the most important contributors to the Hazard Index (HI). Since non-carcinogenic risks due to thallium exposure slightly exceeded international guidelines (HI>1), a special effort should be made on this trace element. However, the current concentrations of arsenic, a carcinogenic element, were in accordance to acceptable lifetime risks. Nowadays, there is a clear increasing growth in human population and economic activities in the Pardo River, whose waters have become a serious strategic alternative for the potential supply of drinking water. Therefore, environmental monitoring studies are required not only to assure that the current state of pollution of Pardo River does not mean a risk for the riverside population, but also to assess the potential trends in the environmental levels of those elements. PMID- 24949760 TI - Observation of the resonant character of the Z(4430)(-) state. AB - Resonant structures in B^{0}->psi^{'}pi^{-}K^{+} decays are analyzed by performing a four-dimensional fit of the decay amplitude, using pp collision data corresponding to 3 fb^{-1} collected with the LHCb detector. The data cannot be described with K^{+}pi^{-} resonances alone, which is confirmed with a model independent approach. A highly significant Z(4430)^{-}->psi^{'}pi^{-} component is required, thus confirming the existence of this state. The observed evolution of the Z(4430)^{-} amplitude with the psi^{'}pi^{-} mass establishes the resonant nature of this particle. The mass and width measurements are substantially improved. The spin parity is determined unambiguously to be 1^{+}. PMID- 24949814 TI - Asthma, respiratory symptoms and lung function in children living near a petrochemical site. AB - Residential proximity to environmental hazards has been related to adverse health outcomes. Respiratory health and allergies in children living near petrochemical sites have not been extensively studied. We evaluated the association between residential proximity to the petrochemical site of Tarragona (Catalonia, Spain) and the prevalence of asthma, respiratory symptoms and lung function in children. Children aged 6-7 (n=2672) and adolescents aged 13-14 (n=2524) residing near two large petrochemical sites and those living in a city with medium vehicular traffic were cross-sectionally compared with children from an area with low vehicular traffic and without industry. The prevalence of symptoms was measured using the International Study of Asthma and Allergies in Childhood written and video questionnaires. Lung function measurements were done in a subsample of 959 adolescents in the four areas. Multivariable analyses were done to estimate the effects of the residential area on symptoms and lung function adjusted for potential confounders. Crude prevalence of symptoms was similar across the studied areas. After adjustment, children and adolescents living near a petrochemical site had a statistically significant higher prevalence of respiratory hospitalizations in the previous year (Prevalence Ratio (PR)=1.49; 95%CI, 1.06-2.09) and of nocturnal cough (PR=1.29; 95%CI 1.05-1.57), respectively. Reduced lung function values among adolescents residing near the petrochemical areas were not observed. Although a higher prevalence of asthma in children and adolescents living near the petrochemical sites could not be demonstrated, as described in other studies, respiratory hospitalizations and nocturnal cough could be related to short-term exposures to pollutants. Other clinical and sub-clinical respiratory health effects in the petrochemical industry areas should be investigated. PMID- 24949815 TI - Oxidative stress biomarkers and metallothionein in Folsomia candida--responses to Cu and Cd. AB - Folsomia candida (Collembola) is a standard soil ecotoxicological species; effect assessment includes survival and reproduction as endpoints. In the present study, and for the first time, a range of oxidative stress biomarkers measurement was optimized and validated. The antioxidant capacity was measured by the activities of catalase (CAT), glutathione reductase (GR), glutathione-s-transferase (GST) and content of total glutathione (TG). The oxidative damage in the lipid membranes was estimated by lipid peroxidation (LPO) and metallothionein (MT) levels. The exposure included the essential and non-essential metals Cu and Cd, in LUFA 2.2 natural standard soil, using a series of sampling times along a 10 days period (0, 2, 4, 6 and 10 days). Exposure concentrations were selected based on their reproduction EC50 values, 60 and 1000 mg/kg soil DW, for Cd and Cu respectively. The protocols were optimized and results show that oxidative stress biomarkers can be successfully used in F. candida, this being highly relevant as complementary information to the mechanistic level. The selected sampling times gave a good indication of the markers dynamic and can be reduced/adapted in future testing. Results showed that both metals caused an increase in the MT levels after 6 days but Cd acted as a stronger oxidant agent compared to Cu, i.e. causing higher damage. In sum, Cd mobilized/activated more antioxidant enzymes, but the increased activities were not enough to prevent LPO. This study confirms that the oxidative stress caused by Cd is higher despite the use of same reproduction EC50 indicating that toxicity seems more reversible for Cu than for Cd. Among others, GST and MT would be a good selection of biomarkers for Cd effect. PMID- 24949817 TI - Andrographolide attenuates interleukin-1beta-stimulated upregulation of chemokine CCL5 and glial fibrillary acidic protein in astrocytes. AB - Andrographolide is a bioactive molecule isolated from Andrographis paniculata with anticancer and anti-inflammatory activities. In this study, we tested the effects of andrographolide on astrocyte-mediated neuroinflammatory responses. Cultured rat primary astrocytes were treated with proinflammatory cytokine interleukin 1beta with or without pretreatment with andrographolide, and then processed for measurements of chemokine C-C motif ligand 5 (CCL5) and glial fibrillary acidic protein. The activation status of nuclear factor-kappaB activation that may underlie CCL5 upregulation was also measured. Andrographolide pretreatment was found to attenuate the upregulation of CCL5 and glial fibrillary basic protein as well as reduce the phosphorylation of nuclear factor-kappaB p65 and IkappaBalpha after interleukin 1beta stimulation. These data suggest that andrographolide should be evaluated further as a therapeutic for central nervous system diseases characterized by astrocyte-mediated neuroinflammatory processes. PMID- 24949818 TI - The relationship between uncinate fasciculus white matter integrity and verbal memory proficiency in children. AB - During childhood, verbal learning and memory are important for academic performance. Recent functional MRI studies have reported on the functional correlates of verbal memory proficiency, but few have reported the underlying structural correlates. The present study sought to test the relationship between fronto-temporal white matter integrity and verbal memory proficiency in children. Diffusion weighted images were collected from 17 Black children (age 8-11 years) who also completed the California Verbal Learning Test. To index white matter integrity, fractional anisotropy values were calculated for bilateral uncinate fasciculus. The results revealed that low anisotropy values corresponded to poor verbal memory, whereas high anisotropy values corresponded to significantly better verbal memory scores. These findings suggest that a greater degree of myelination and cohesiveness of axonal fibers in uncinate fasciculus underlie better verbal memory proficiency in children. PMID- 24949816 TI - Persistent organic pollutant levels in human visceral and subcutaneous adipose tissue in obese individuals--depot differences and dysmetabolism implications. AB - BACKGROUND: The role of persistent organic pollutants (POPs) with endocrine disrupting activity in the aetiology of obesity and other metabolic dysfunctions has been recently highlighted. Adipose tissue (AT) is a common site of POPs accumulation where they can induce adverse effects on human health. OBJECTIVES: To evaluate the presence of POPs in human visceral (vAT) and subcutaneous (scAT) adipose tissue in a sample of Portuguese obese patients that underwent bariatric surgery, and assess their putative association with metabolic disruption preoperatively, as well as with subsequent body mass index (BMI) reduction. METHODS: AT samples (n=189) from obese patients (BMI >= 35) were collected and the levels of 13 POPs were determined by gas chromatography with electron-capture detection (GC-ECD). Anthropometric and biochemical data were collected at the time of surgery. BMI variation was evaluated after 12 months and adipocyte size was measured in AT samples. RESULTS: Our data confirm that POPs are pervasive in this obese population (96.3% of detection on both tissues), their abundance increasing with age (RS=0.310, p<0.01) and duration of obesity (RS=0.170, p<0.05). We observed a difference in AT depot POPs storage capability, with higher levels of SigmaPOPs in vAT (213.9 +/- 204.2 compared to 155.1 +/- 147.4 ng/g of fat, p<0.001), extremely relevant when evaluating their metabolic impact. Furthermore, there was a positive correlation between POP levels and the presence of metabolic syndrome components, namely dysglycaemia and hypertension, and more importantly with cardiovascular risk (RS=0.277, p<0.01), with relevance for vAT (RS=0.315, p<0.01). Finally, we observed an interesting relation of higher POP levels with lower weight loss in older patients. CONCLUSION: Our sample of obese subjects allowed us to highlight the importance of POPs stored in AT on the development of metabolic dysfunction in a context of obesity, shifting the focus to their metabolic effects and not only for their recognition as environmental obesogens. PMID- 24949819 TI - Development and validation of a LC-MS/MS method for assessment of an anti inflammatory indolinone derivative by in vitro blood-brain barrier models. AB - The compound (E,Z)-3-(4-hydroxy-3,5-dimethoxybenzylidene)indolin-2-one (indolinone) was identified from lipophilic woad extracts (Isatis tinctoria L., Brassicaceae) as a compound possessing potent histamine release inhibitory and anti-inflammatory properties [1]. To further evaluate the potential of indolinone in terms of crossing the blood-brain barrier (BBB), we screened the compound in several in vitro cell-based human and animal BBB models. Therefore, we developed a quantitative LC-MS/MS method for the compound in modified Ringer HEPES buffer (RHB) and validated it according to FDA and EMA guidelines [2,3]. The calibration curve of indolinone in the range between 30.0 and 3000ng/ml was quadratic, and the limit of quantification was 30.0ng/ml. Dilution of samples up to 100-fold did not affect precision and accuracy. The carry-over was within acceptance criteria. Indolinone proved to be stable in RHB for 3h at room temperature (RT), and for three successive freeze/thaw cycles. The processed samples could be stored in the autosampler at 10 degrees C for at least 28h. Moreover, indolinone was stable for at least 16 days in RHB when stored below -65 degrees C. This validation study demonstrates that our method is specific, selective, precise, accurate, and capable to produce reliable results. In the immortalized human BBB mono-culture model, the apparent permeability coefficient from apical to basolateral (PappA >B), and the Papp from basolateral to apical (PappB->A) were 19.2+/-0.485*10( 6)cm/s and 21.7+/-0.326*10(-6)cm/s, respectively. For the primary rat/bovine BBB co-culture model a PappA->B of 27.1+/-1.67*10(-6)cm/s was determined. In the primary rat BBB triple co-culture model, the PappA->B and the PappB->A were 56.2+/-3.63*10(-6)cm/s and 34.6+/-1.41*10(-6)cm/s, respectively. The data obtained with the different models showed good correlation and were indicative of a high BBB permeation potential of indolinone confirmed by in silico prediction calculations. P-glycoprotein (P-gp) interaction for indolinone was studied with the aid of a calcein-AM uptake assay, and by calculation of the efflux ratio (ER) from the bidirectional permeability assays. For both bidirectional BBB models an ER below 2 was calculated, indicating that no active mediated transport mechanism is involved for indolinone. In porcine brain capillary endothelial cells (PBCECs), the calcein-AM uptake assay demonstrated that indolinone is neither a P gp substrate nor a P-gp inhibitor and is accumulated into cells at high extent. PMID- 24949821 TI - A packaged paper fluidic-based microdevice for detecting gene expression of influenza A virus. AB - Pathotyping and subtyping of influenza A virus were performed with a packaged paper fluidic-based analytical microdevice (PFAM) after one-step reverse transcription-polymerase chain reaction (RT-PCR). The PFAM contains two test lines: one for detecting M gene to identify the influenza A virus and another for haemagglutinin subtyping to determine the viral strain among H1N1, H3N2, and H5N1. The M gene and the haemagglutinin gene (H1, H3, and H5 genes) were amplified by using the Digoxigenin and the Texas Red modified primers, respectively, in the multiplex RT-PCR. The amplicon products were loaded in the conjugate pad of the PFAM in which the streptavidin coated gold nanoparticles were linked with the biotin moieties that were incorporated in the middle of the DNA strands, and then captured by the anti-Digoxigenin and anti-Texas Red immobilized on the test lines. Influenza A H1N1, H3N2, and H5N1 could be identified with a limit of detection of 10(2) copies of RNA templates in 10 min. Pathotyping and subtyping of the clinical nasopharyngeal swab samples were also analyzed whose results were confirmed by real-time RT-PCR. PMID- 24949822 TI - Brief review of monitoring methods for loop-mediated isothermal amplification (LAMP). AB - The loop-mediated isothermal amplification (LAMP) technique has the potential to revolutionize molecular biology because it allows DNA amplification under isothermal conditions and is highly compatible with point-of-care analysis. To achieve efficient genetic analysis of samples, the method of real-time or endpoint determination selected to monitor the biochemical reaction is of great importance. In this paper we briefly review progress in the development of monitoring methods for LAMP. PMID- 24949820 TI - Delayed patchy choroidal filling in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). AB - PURPOSE: To determine the relationship between delayed patchy choroidal filling and morphologic and functional outcomes among eyes treated with ranibizumab or bevacizumab. DESIGN: Cohort study. METHODS: Comparison of Age-related Macular Degeneration Treatment Trials participants were assigned randomly to ranibizumab or bevacizumab on a monthly or as-needed schedule. Presence of delayed patchy choroidal filling and morphologic and functional outcomes were evaluated among eyes with gradable fluorescein angiography at baseline (n = 973) and at 1 year (n = 860) eyes. RESULTS: Delayed filling was present in 75 (7.7%) of 973 eyes at baseline. Eyes with incident delayed filling at 1 year (23 [2.9%] of 798) showed a mean decrease of 1.7 letters in visual acuity, whereas eyes without incident delayed filling had a mean improvement of 8.1 letters (difference [Delta], -9.8; 95% confidence interval [CI] , -15.8 to -3.9; P < .01). Eyes with incident delayed filling had a larger increase in mean total lesion area of choroidal neovascularization (3.00 mm(2)) than eyes without incident delayed filling (0.56 mm(2); Delta , 2.4; 95% CI, 0.4 to 4.4; P = .02). The proportion with incident delayed filling at 1 year was similar among eyes treated with ranibizumab (10 [2.4%] of 413) or bevacizumab (13 [3.3%] of 385; P = .53) and among eyes treated monthly (12 [3.1%] of 388) or as needed (11 [2.7%] of 410; P = .83). CONCLUSIONS: Delayed patchy choroidal filling was uncommon at baseline. Although only a small percentage of eyes demonstrated delayed filling during the first year of anti vascular endothelial growth factor treatment, these eyes had worse visual acuity and a larger increase in total lesion area of choroidal neovascularization. PMID- 24949823 TI - Enhanced photocatalytic hydrogen production activity via dual modification of MOF and reduced graphene oxide on CdS. AB - A Ternary composite UiO-66/CdS/1% reduced graphene oxide (RGO) was successfully prepared, with a photocatalytic hydrogen evolution rate 13.8 times as high as that of pure commercial CdS. It shows great advantages over the perfect composite photocatalyst-P25/CdS/1%RGO. PMID- 24949824 TI - Recombination kinetics in a silicon solar cell at low concentration: electro analytical characterization of space-charge and quasi-neutral regions. AB - The present work reports a detailed electro-analytical framework for studying commercially available mono-crystalline silicon solar cells under varying illumination conditions to explore their application in the up-and-coming field of low concentration photovoltaics (LCPVs). The effect of low concentration illumination (>1-12 suns) on performance indicating parameters, i.e., short circuit current, open circuit voltage, fill factor, efficiency and ideality factor, was investigated using DC characterization. The same framework can be used for AC characterization in order to explore diffusion capacitance, transition capacitance, diffusion resistance and recombination kinetics under varying illumination. Recent developments in the impedance spectroscopy technique have broadened its horizon and have allowed its use in addressing unexplored material and performance aspects of mono-crystalline Si solar cells under non equilibrium conditions. The obtained DC and AC experimental results are coupled with theoretical treatment to demonstrate the characteristic features of charge recombination in the space-charge region and the quasi-neutral region. PMID- 24949825 TI - Integrating analysis reveals microRNA-mediated pathway crosstalk among Crohn's disease, ulcerative colitis and colorectal cancer. AB - Inflammatory bowel disease (IBD), which can increase the risk of colorectal cancer (CRC), includes two primary subtypes, ulcerative colitis (UC) and Crohn's disease (CD). Although several individual genes involved in inflammation or cancer characterization have been identified, it is still difficult to elucidate functional relationship details between the molecules underlying pathogenesis at the system level. The global effect of miRNAs on genes or their involved functions is also poorly understood. We first integrated genome-wide gene expression profiles and biological pathway information to explore the underlying associations among UC, CD and CRC at the function and gene level. After identifying the pathways regulated by miRNAs, a global map of miRNA-mediated pathway crosstalk shared by the three diseases was further constructed to vertically explain the links of three level alterations. The three types of diseases have close associations with each other at the levels of function, gene and miRNA regulation. Several key biological pathways are involved in the three diseases, related to the immune system and inflammation, metabolism, or cell proliferation and apoptosis etc. Moreover, miRNAs exhibit dominant effects on multiple pathways. It is worth noting that UC shows relatively close associations with CD and CRC at the three levels. Finally, the miRNAs could mediate the crosstalk within or between pathways. For example, hsa-miR-125b, hsa-miR-335 and hsa-miR-155 mediated the crosstalk between three metabolic pathways. The crosstalk within the Toll-like receptor signaling pathway could be mediated by hsa-miR-124, hsa-miR-146a and hsa-mir-221/222. Our results make sense for the prevention and treatment of intestinal-related chronic inflammation or cancer. PMID- 24949826 TI - Electronic properties of meso-superstructured and planar organometal halide perovskite films: charge trapping, photodoping, and carrier mobility. AB - Solution-processed organometal trihalide perovskite solar cells are attracting increasing interest, leading to high performances over 15% in thin film architectures. Here, we probe the presence of sub gap states in both solid and mesosuperstructured perovskite films and determine that they strongly influence the photoconductivity response and splitting of the quasi-Fermi levels in films and solar cells. We find that while the planar perovskite films are superior to the mesosuperstructured films in terms of charge carrier mobility (in excess of 20 cm(2) V(-1) s(-1)) and emissivity, the planar heterojunction solar cells are limited in photovoltage by the presence of sub gap states and low intrinsic doping densities. PMID- 24949827 TI - Effects of cryopreservation on the characteristics of dental pulp stem cells of intact deciduous teeth. AB - OBJECTIVES: The aim of this study was to isolate and cultivate cells from the pulp of 7-day-cryopreserved intact deciduous human teeth and evaluate the effect of cryopreservation on dental pulp stem cell (DPSC) characteristics. DESIGN: Twenty-six deciduous teeth were collected and allocated in two groups: immediate cell isolation (non-cryopreserved group) and intact cryopreserved (cryopreserved group). The teeth were cryopreserved in dimethylsulfoxide solution and recovered after 7 days. The success rate of isolation, proliferation, surface markers (CD14, CD29, CD34, CD45, CD73, CD90, and HLA-DR), differentiation capacity, and morphology were evaluated. RESULTS: Isolation success rate was 61% and 30% for the non-cryopreserved and cryopreserved groups, respectively. There were no statistical differences between the groups for the tested surface markers. The cells in both groups were capable of differentiating into three mesenchymal lineages. No statistical differences between the groups were observed through the time course proliferation assay (0, 1, 3, 5, and 7 days); however, the mean time between isolation and the fifth passage was shorter for the non-cryopreserved group (p=0.035). The morphology of the cells was considered altered in the cryopreserved group. CONCLUSION: DPSCs were obtained from cryopreserved intact deciduous teeth without changes in the immunophenotypical characteristics and differentiation ability; however, lower culture rates, proliferation potential, and morphological alterations were observed in relation to the control group. PMID- 24949828 TI - Colonisation of gingival epithelia by subgingival biofilms in vitro: role of "red complex" bacteria. AB - OBJECTIVES: Biofilm formation on tooth surface results in colonisation and invasion of the juxtaposed gingival tissue, eliciting strong inflammatory responses that lead to periodontal disease. This in vitro study investigated the colonisation of human gingival multi-layered epithelium by multi-species subgingival biofilms, and evaluated the relative effects of the "red complex" species (Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola). METHODS: The grown biofilm consisted of Fusobacterium nucleatum, Campylobacter rectus, Veillonella dispar, P. gingivalis, Prevotella intermedia, T. forsythia, T. denticola, Actinomyces oris, Streptococcus anginosus and Streptococcus oralis, or its variant lacking the "red complex". After 48h in co-culture with the gingival epithelia, the bacterial species in the biofilm were quantified, whereas their localisation on the cell surface was investigated by combining confocal laser scanning microscopy (CLSM) and fluorescence in situ hybridisation (FISH), as well as by scanning electron microscopy (SEM). RESULTS: Exclusion of the "red complex" quantitatively affected S. oralis, but not other species. The "red complex" species were all able to colonise the gingival epithelial cells. A co localisation trend was observed between P. gingivalis and T. denticola, as determined by FISH. However, in the absence of all three "red complex" bacteria from the biofilm, an immense colonisation of streptococci (potentially S. oralis) was observed on the gingival epithelia, as confirmed by both CLSM and SEM. CONCLUSIONS: While the "red complex" species synergise in colonizing gingival epithelia, their absence from the biofilm enhances streptococcal colonisation. This antagonism with streptococci reveals that the "red complex" may regulate biofilm virulence, with potential implications in periodontal pathogenesis. PMID- 24949829 TI - Effects of 100-km ultramarathon on acute kidney injury. AB - OBJECTIVE: To evaluate the prevalence and characteristics of acute kidney injury (AKI) in 100-km ultramarathon runners. DESIGN: Prospective observational study. SETTING: The 2011 Soochow University ultramarathon, in which each athlete ran for 100 km. PARTICIPANTS: All Taiwanese entrants who participated in the 100-km race and lived in the northern part of Taiwan were invited to participate in the study. MAIN OUTCOME MEASURES: Acute kidney injury was defined using the Acute Kidney Injury Network criteria. Blood and urine samples were collected 1 week before, immediately after, and 1 day after the race. RESULTS: Immediately after the race, 85% (22) of the 26 subjects were diagnosed with AKI, 65% (16) with moderate dehydration, 23% (6) with muscle cramps, and 12% (3) with hematuria. Body weight was significantly decreased from prerace to all postrace measurements. Plasma levels of potassium ion, creatinine, renin, and aldosterone were significantly elevated immediately after the race and then significantly reduced 1 day after the race. Changes in plasma levels of sodium, creatine kinase, and creatine kinase-MB, as well as urine potassium and creatinine, were indicative of AKI. CONCLUSIONS: Transient AKI and muscle cramps are very common in 100-km ultramarathon runners. All transient ultra-runners who developed AKI in this study recovered their renal function 1 day later. CLINICAL RELEVANCE: Ultramarathon running is associated with a wide range of significant changes in hematological parameters, several of which can be associated with potentially serious renal and physiological abnormalities. PMID- 24949830 TI - The most cut-resistant neck guard for preventing lacerations to the neck. AB - OBJECTIVE: To evaluate the effectiveness of a variety of neck guard brands when contacted by a sharpened hockey skate blade. DESIGN: Analytic experimental. SETTING: Laboratory. PARTICIPANTS: Neck surrogate. INTERVENTIONS: Forty-six samples of 14 different types of neck guards were tested on a custom-made laceration machine using a neck surrogate. Closed-cell polyethylene foam was placed between the neck surrogate and the protective device. MAIN OUTCOME MEASURES: The effectiveness of the neck guard was evaluated by observation of the foam after the simulated slicing action of the skate blade. Two sets of tests were performed on each device sample including low and high force. For low-force tests, initial compression loads of 100, 200, and 300 N were applied between the neck surrogate for each of 2 orientations of the blade at 45 and 90 degrees. For high-force tests, representing a more severe simulation, the applied load was increased to 600 N and a blade angle fixed at 45 degrees. All tests were performed at a blade speed of 5 m/s. RESULTS: Only 1 product, the Bauer N7 Nectech, failed during the 300-N compression tests. All of the neck guards failed during 600-N test condition except for the Skate Armor device and 1 of the 3 Reebok 11K devices. CONCLUSIONS: A skate blade angle of 45 degrees increased the likelihood of a neck laceration compared with a skate blade angle of 90 degrees due to decreased contact area. Damage to the neck guard is not an indicator of the cut resistance of a neck guard. Neck protectors with Spectra fibers were the most cut resistant. CLINICAL RELEVANCE: The study provides data for the selection of neck guards and neck guard materials that can reduce lacerations to the neck. PMID- 24949831 TI - Why university athletes choose not to reveal their concussion symptoms during a practice or game. AB - OBJECTIVE: To determine why athletes decide not to seek medical attention during a game or practice when they believe they have suffered a concussion. DESIGN: A retrospective survey. SETTING: University Sport Medicine Clinic. PARTICIPANTS: A total of 469 male and female university athletes from several varsity team sports were participated in the study. MAIN OUTCOME MEASURES: Athletes were surveyed about the previous 12 months to identify specific reasons why those athletes who believed they had suffered a concussion during a game or practice decided not to seek attention at that time, how often these reasons occurred, and how important these reasons were in the decision process. RESULTS: Ninety-two of the 469 athletes (19.6%) believed they had suffered a concussion within the previous 12 months while playing their respective sport, and 72 of these 92 athletes (78.3%) did not seek medical attention during the game or practice at least once during that time. Sports in which athletes were more likely to not reveal their concussion symptoms were football and ice hockey. The reason "Did not feel the concussion was serious/severe and felt you could still continue to play with little danger to yourself," was listed most commonly (55/92) as a cause for not seeking medical attention for a presumed concussion. CONCLUSIONS: A significant percentage of university athletes who believed they had suffered a concussion chose not to seek medical attention at the time of injury. Improved education of players, parents, and coaches about the dangers of continuing to play with concussion symptoms may help improve reporting. CLINICAL RELEVANCE: Medical staff should be aware that university athletes who believe they have suffered a concussion may choose not to volunteer their symptoms during a game or practice for a variety of personal and athletic reasons. PMID- 24949832 TI - Sec6 regulated cytoplasmic translocation and degradation of p27 via interactions with Jab1 and Siah1. AB - p27 has essential roles in cellular proliferation and migration, and reduced or cytoplasmic p27 is associated with poor clinical outcomes in a variety of human tumours. Jun activation domain-binding protein (Jab1)/constitutive photomorphogenic-9 signalosome 5 (CSN5) directly interacts with p27 promoting its translocation and cytoplasmic degradation. Sec6 is a component of the exocyst complex. Recently, several studies revealed that Sec6 has specific functions in migration, adhesion, and cell differentiation. However, how Sec6 is involved in the regulation of cell cycle progression is unknown. The present study shows that Sec6 regulates cytoplasmic translocation of p27 through p27 phosphorylation at Thr157, thereby promoting p27 degradation in the cytoplasm via interaction with Jab1 and Siah1 and suppressing cell cycle progression. PMID- 24949833 TI - Mechanism of SB431542 in inhibiting mouse embryonic stem cell differentiation. AB - SB431542 (SB) is an established small molecular inhibitor that specifically binds to the ATP binding domains of the activin receptor-like kinase receptors, ALK5, ALK4 and ALK7, and thus specifically inhibits Smad2/3 activation and blocks TGF beta signal transduction. SB maintains the undifferentiated state of mouse embryonic stem cells. However, the way of SB in maintaining the undifferentiated state of mouse embryonic stem cells remains unclear. Considering that SB could not maintain embryonic stem cells pluripotency when leukemia inhibitory factor was withdrawn, we sought to identify the mechanism of SB on pluripotent maintenance. Transcripts regulated by SB, including message RNAs and small non coding RNAs were examined through microarray and deep-sequence experiments. After examination, Western blot analysis, and quantitative real-time PCR verification, we found that SB regulated the transcript expressions related to self-renewal and differentiation. SB mainly functioned by inhibiting differentiation. The key pluripotent factors expression were not significantly affected by SB, and intrinsic differentiation-related transcripts including fibroblast growth factor family members, were significantly down-regulated by SB. Moreover, SB could partially inhibit the retinoic acid response to neuronal differentiation of mouse embryonic stem cells. PMID- 24949834 TI - A simulation comparing the cost-effectiveness of adult incontinence products. AB - PURPOSE: To compare leak point volumes and cost-effectiveness of a variety of adult incontinence products. METHODS: Adult incontinence products were purchased from local retail stores and categorized into moderate absorbency pads, moderate absorbency briefs, maximum absorbency pads, and maximum absorbent briefs. The leak point for each product was determined by applying fluid to the pad until the first drop of leakage from the pad or brief occurred. Cost-effectiveness was calculated by dividing the cost per product by the amount of fluid absorbed prior to the leak point. The leak points and cost-effectiveness of incontinence products were compared within and between categories. RESULTS: Significant differences in leak point volumes were present within all product categories except moderate absorbency pads. When comparing product categories, moderate absorbency pads were the least cost-effective, followed by maximum absorbency pads and absorbent briefs (P < .01). CONCLUSIONS: As a group, absorbent briefs are more cost-effective than incontinence pads, although products of similar absorbency category and design demonstrated varying leak points and cost effectiveness. These findings may influence physician assessment of urinary incontinence as well as patient selection of incontinence products. PMID- 24949835 TI - Stomal and peristomal complications: prioritizing management approaches in adults. AB - PURPOSE: The objectives of this study were to establish additional content validation data for proposed stomal and peristomal complications interventions and to identify optimal interventions for the specified complications based on experts' clinical judgment. SUBJECTS AND SETTING: Following pilot testing of the researcher-designed instrument, the survey was mailed to 1000 systematically randomly selected expert WOC nurses via a national mailing to a representative sample of participants who identified in their WOCN Society description as having ostomy certification and/or clinical expertise. Two hundred eighty-one nurses returned the survey, comprising a response rate of 28%. METHODS: A cross sectional, quantitative descriptive design with qualitative components was used for this study. Respondents were asked to quantify degree of validity (relevance or appropriateness) of the survey's stated stomal and peristomal complications interventions. They were asked to rank interventions for each stomal and peristomal complication for being first-line (most preferred), second-line, and third-line treatment. Hand-written qualitative comments of the participants were transcribed and analyzed, and themes were derived. RESULTS: On a scale of 1 to 4, the mean score for all interventions was 3.47 +/- 0.29 (relevant/very relevant, mean +/- SD). The overall survey's Content Validity Index was 0.84 out of 1.00. Some items had lower mean scores and content validity index scores, especially peristomal interventions. Ranking of most preferred treatments revealed clearly preferred approaches in some clinical situations and some less so. Qualitative analysis of participants' comments about each stomal and peristomal complication intervention and about the whole instrument and research process was conducted generating positive and negative themes. CONCLUSION: The proposed stomal and peristomal interventions were rated as generally valid substantiating results of our earlier study. The ranking of most preferred treatments for stomal and peristomal complications provides, to the authors' knowledge, the world's first research support for prioritized approaches and evidence-based practice in ostomy care. PMID- 24949836 TI - The chorioretinal damage caused by different half parameters of photodynamic therapy in rabbits. AB - PURPOSE: To compare the chorioretinal tissue response after different half strength parameters of photodynamic therapy (PDT) in rabbits. METHODS: The study included 4 groups, and each group contained 4 animals. The full dose served as the control group: verteporfin (4 mg/kg) with 600 mW/cm(2) irradiance from a diode laser at 689 nm applied to the retina for 8 s. One parameter was changed to half-strength in the other 3 groups. The HLaser group received half-strength laser irradiance. The HTime group was exposed to photosensitization for half the time, and the HDose group received half the drug dose. Six laser spots were generated in each of the eyes of every rabbit and documented graphically. The lesions were examined on days 1, 7, and 42 after PDT treatment using color fundus imaging, fluorescein angiography (FA), and histopathology analysis. RESULTS: PDT treatment in rabbits caused chorioretinal damage in all 4 groups. FA on day 1 showed that the use of half the laser irradiance, half the drug dose, or half the photosensitizing time tended to decrease the damage to the chorioretinal tissue in terms of the number of occlusions and the area of occlusion, but only the results from half the laser irradiance were significantly different. In addition, the HLaser and HDose groups showed significantly less apoptosis by TUNEL staining on day 1. CONCLUSIONS: Among these PDT parameters, decreasing the laser irradiance by half showed the greatest decrease in chorioretinal damage in an experimental animal model. PMID- 24949837 TI - Fucosylated chondroitin sulfate from sea cucumber improves glucose metabolism and activates insulin signaling in the liver of insulin-resistant mice. AB - This study investigated the effects of fucosylated chondroitin sulfate (CHS) isolated from sea cucumber on glucose metabolism and insulin signaling in the liver of insulin-resistant C57BL/6 mice fed a high-fat, high-sucrose diet (HFSD). Male C57BL/6J mice were randomly assigned into six groups: control; HFSD; 1 mg RSG/kg.body weight (RSG); 80 mg CHS/kg . body weight (CHS); 20 mg CHS+1 mg RSG/kg . body weight (20 CHS+RSG); and 80 mg CHS+1 mg RSG/kg . body weight (80 CHS+RSG). Blood glucose, insulin parameters, glucose metabolism-related enzymes activities and insulin-signaling transducers in the liver were analyzed at 19 weeks. Results showed that CHS significantly decreased body weight gain, adipose tissue weight, and fasting blood glucose and serum insulin levels in insulin-resistant mice. Rosiglitazone (RSG) is an effective thiazolidinedione hypoglycemic agent, and CHS synergistically enhanced the effect of RSG. CHS feeding normalized the activities of hexokinase, pyruvate kinase, glycogen phosphorylase, glucose-6-phosphatase, and increased glycogen reserves in the liver. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis showed that CHS promoted the mRNA expression of insulin receptors (IR), insulin receptor substrate 2 (IRS-2), phosphatidylinositol 3 kinase (PI3K), protein kinase B (PKB), and glycogen synthase (GS) in the liver of insulin resistant mice, and inhibited glycogen synthase kinase-3 (GSK-3beta) mRNA expression. The results suggested that CHS treatment improved glucose metabolism by modulating metabolic enzymes and promoting the PI3K/PKB/GSK-3beta signaling pathway mediated by insulin at the transcriptional level. These results provided strong justification for the development of CHS as a functional food. PMID- 24949838 TI - Psychometric properties of the motor diagnostics in the German football talent identification and development programme. AB - The utilisation of motor performance tests for talent identification in youth sports is discussed intensively in talent research. This article examines the reliability, differential stability and validity of the motor diagnostics conducted nationwide by the German football talent identification and development programme and provides reference values for a standardised interpretation of the diagnostics results. Highly selected players (the top 4% of their age groups, U12 U15) took part in the diagnostics at 17 measurement points between spring 2004 and spring 2012 (N = 68,158). The heterogeneous test battery measured speed abilities and football-specific technical skills (sprint, agility, dribbling, ball control, shooting, juggling). For all measurement points, the overall score and the speed tests showed high internal consistency, high test-retest reliability and satisfying differential stability. The diagnostics demonstrated satisfying factorial-related validity with plausible and stable loadings on the two empirical factors "speed" and "technical skills". The score, and the technical skills dribbling and juggling, differentiated the most among players of different performance levels and thus showed the highest criterion-related validity. Satisfactory psychometric properties for the diagnostics are an important prerequisite for a scientifically sound rating of players' actual motor performance and for the future examination of the prognostic validity for success in adulthood. PMID- 24949839 TI - Does the legalization of medical marijuana increase completed suicide? AB - INTRODUCTION: Suicide is among the 10 most common causes of death in the United States. Researchers have identified a number of factors associated with completed suicide, including marijuana use, and increased land elevation. Colorado is an ideal state to test the strength of these associations. The state has a completed suicide rate well above the national average and over the past 15 years has permitted first the medical and, as 2014, the recreational use of marijuana. OBJECTIVES: To determine if there is a correlation between medical marijuana use, as assessed by the number of medical marijuana registrants and completed suicides per county in Colorado. METHODS: The number of medical marijuana registrants was used as a proxy for marijuana use. Analysis variables included total medical marijuana registrants, medical marijuana dispensaries per county, total suicide deaths, mechanism of suicide death, gender, total suicide hospitalizations, total unemployment, and county-level information such as mean elevation and whether the county was urban or rural. Analysis was performed with mixed model Poisson regression using generalized linear modeling techniques. RESULTS: We found no consistent association between the number of marijuana registrants and completed suicide after controlling for multiple known risk factors for completed suicide. CONCLUSION: The legalization of medical marijuana may not have an adverse impact on suicide rates. Given the concern for the increased use of marijuana after its legalization, our negative findings provide some reassurance. However, this conclusion needs to be examined in light of the limitations of our study and may not be generalizable to those with existing severe mental illness. This finding may have significant public health implications for the presumable increase in marijuana use that may follow legalization. PMID- 24949842 TI - Studies on lipidification of streptokinase: a novel strategy to enhance the stability and activity. AB - Thrombotic disorders and their associated problems are extensively prevalent in developed and developing countries. Streptokinase (SK) is a well-known thrombolytic agent, which is very useful in treating coronary thrombosis and acute myocardial infarction. Several attempts have been made to date to make improvements of this wonderful molecule in terms of reducing or eliminating the problems of eliciting immunogenicity and enhancing the half-life of the molecule. The present research is focused to produce a recombinant SK with enhanced stability and biological activity by the methodology of lipid modification. SK was targeted successfully to the membrane with the help of modified apyrase signal sequence. Higher expression was reported for GJ1158 strain in LBON medium when compared with BL21 (DE3). The obtained recombinant SK was tested for its biological activity by the method of caseinolytic assay. The higher clearance zone was observed in recombinant lipid-modified streptokinase, which denotes the enhanced activity of the protein. The present trial of lipid modification of therapeutics, particularly SK, could help for its superior use as a thrombolytic agent and also paves way for many of the other clinical applications. PMID- 24949844 TI - Exercise and weight loss: no sex differences in body weight response to exercise. AB - There is a view that exercise is less effective for weight loss in women compared with men. This systematic review examines the evidence for sex-based differences in the effect of exercise on body weight. We hypothesize that, when energy expenditure is equivalent, there will be no evidence for sex differences in body weight response to exercise. PMID- 24949841 TI - Targeted overexpression of mitochondrial catalase prevents radiation-induced cognitive dysfunction. AB - AIMS: Radiation-induced disruption of mitochondrial function can elevate oxidative stress and contribute to the metabolic perturbations believed to compromise the functionality of the central nervous system. To clarify the role of mitochondrial oxidative stress in mediating the adverse effects of radiation in the brain, we analyzed transgenic (mitochondrial catalase [MCAT]) mice that overexpress human catalase localized to the mitochondria. RESULTS: Compared with wild-type (WT) controls, overexpression of the MCAT transgene significantly decreased cognitive dysfunction after proton irradiation. Significant improvements in behavioral performance found on novel object recognition and object recognition in place tasks were associated with a preservation of neuronal morphology. While the architecture of hippocampal CA1 neurons was significantly compromised in irradiated WT mice, the same neurons in MCAT mice did not exhibit extensive and significant radiation-induced reductions in dendritic complexity. Irradiated neurons from MCAT mice maintained dendritic branching and length compared with WT mice. Protected neuronal morphology in irradiated MCAT mice was also associated with a stabilization of radiation-induced variations in long-term potentiation. Stabilized synaptic activity in MCAT mice coincided with an altered composition of the synaptic AMPA receptor subunits GluR1/2. INNOVATION: Our findings provide the first evidence that neurocognitive sequelae associated with radiation exposure can be reduced by overexpression of MCAT, operating through a mechanism involving the preservation of neuronal morphology. CONCLUSION: Our article documents the neuroprotective properties of reducing mitochondrial reactive oxygen species through the targeted overexpression of catalase and how this ameliorates the adverse effects of proton irradiation in the brain. PMID- 24949843 TI - The protective effect of baicalin against UVB irradiation induced photoaging: an in vitro and in vivo study. AB - OBJECTIVE: This study was aimed to evaluate the anti-photoaging effects of baicalin on Ultraviolet B (UVB)-induced photoaging in the dorsal skin of hairless mice and premature senescence in human dermal fibroblasts. METHODS: We established in vivo and in vitro photoaging models by repeated exposures to UVB irradiation. By HE staining, masson staining, immunohistostaing and real-time RT PCR, we analyzed epidermal thickness, collagen expression and the mRNA and protein levels of type I collagen, type III collagen, interstitial collagenase (MMP-1 and MMP-3) in UVB exposed dorsal mice skin. The aging condition in human dermal fibroblasts was determined by senescence-associated beta-galactosidase (SA beta-gal) staining. Cell viability was determined using the Cell Counting Kit-8 (CCK-8). The G1 phase cell growth arrest was analyzed by flow cytometry. The senescence-related protein levels of p16INK-4a, p21WAF-1, and p53 and protein levels of phosphorylated histone H2AX were estimated by Western blotting. RESULTS: Topically application of baicalin treatment reduced UVB-induced epidermal thickening of mouse skin and also result in an increase in the production of collagen I and III, and a decrease in the expression of MMP-1 and MMP-3. Compared with the UVB-irradiated group, we found that the irradiated fibroblasts additionally treated with baicalin demonstrated a decrease in the expression of SA-beta-gal, a increase in the cell viability, a decrease in the G1 phase cell proportion, a downregulation in the level of senescence-associated and gamma-H2AX proteins. However, Baicalin had no difference in the normal fibroblasts without UVB irradiation and long-term Baicalin incubation of UVB-SIPS fibroblasts gave no effects on the cell proliferation. CONCLUSIONS: Taken together, these results suggest that baicalin significantly antagonizes photoaging induced by UVB in vivo and in vitro, indicating the potential of baicalin application for anti-photoaging treatment. PMID- 24949845 TI - ATP signaling in skeletal muscle: from fiber plasticity to regulation of metabolism. AB - Tetanic electrical stimulation releases adenosine triphosphate (ATP) from muscle fibers through pannexin-1 channels in a frequency-dependent manner; extracellular ATP activates signals that ultimately regulate gene expression and is able to increase glucose transport through activation of P2Y receptors, phosphatidylinositol 3-kinase, Akt, and AS160. We hypothesize that this mechanism is an important link between exercise and the regulation of muscle fiber plasticity and metabolism. PMID- 24949846 TI - Dynamic ultrasound imaging applications to quantify musculoskeletal function. AB - Advances in imaging methods have led to new capability to study muscle and tendon motion in vivo. Direct measurements of muscle and tendon kinematics using imaging may lead to improved understanding of musculoskeletal function. This review presents quantitative ultrasound methods for muscle dynamics that can be used to assess in vivo musculoskeletal function when integrated with other conventional biomechanical measurements. PMID- 24949847 TI - Sarcolipin provides a novel muscle-based mechanism for adaptive thermogenesis. AB - The sarco(endo)plasmic reticulum Ca-ATPase (SERCA) transports Ca into the sarcoplasmic reticulum lumen and contributes significantly to skeletal muscle metabolic rate. Sarcolipin (SLN) has been shown recently to uncouple Ca transport from adenosine triphosphate hydrolysis by SERCA. We have hypothesized that SLN provides a novel mechanism of adaptive thermogenesis within skeletal muscle and protects against diet-induced obesity. PMID- 24949848 TI - The effects of Eph-ephrin mutations on pre-pulse inhibition in mice. AB - Eph-ephrin signaling is known to be important in directing topographic projections in the afferent auditory pathway, including connections to various subdivisions of the inferior colliculus (IC). The acoustic startle-response (ASR) is a reliable reflexive behavioral response in mammals elicited by an unexpected intense acoustic startle-eliciting stimulus (ES). It is mediated by a sub cortical pathway that includes the IC. The ASR amplitude can be measured with an accelerometer under the subject and can be decreased in amplitude by presenting a less intense, non-startling stimulus 5-300ms before the ES. This reflexive decrement in ASR is called pre-pulse inhibition (PPI) and indicates that the relatively soft pre-pulse was heard. PPI is a general trait among mammals. Mice have been used recently to study this response and to reveal how genetic mutations affect neural circuits and hence the ASR and PPI. In this experiment, we measured the effect of Eph-ephrin mutations using control mice (C57BL/6J), mice with compromised EphA4 signaling (EphA4(lacZ/+), EphA4(lacZ/lacZ)), and knockout ephrin-B3 mice (ephrin-B3 (+/-, -/-)). Control and EphA4(lacZ/+s)trains showed robust PPI (up to 75% decrement in ASR) to an offset of a 70dB SPL background noise at 50ms before the ES. Ephrin-B3 knockout mice and EphA4 homozygous mutants were only marginally significant in PPI (<25% decrement and <33% decrement, respectively) to the same conditions. This decrement in PPI highlights the importance of ephrin-B3 and EphA4 interactions in ordering auditory behavioral circuits. Thus, different mutations in certain members of the signaling family produce a full range of changes in PPI, from minimal to nearly maximal. This technique can be easily adapted to study other aspects of hearing in a wider range of mutations. Along with ongoing neuroanatomical studies, this allows careful quantification of how the auditory anatomical, physiological and now behavioral phenotype is affected by changes in Eph-ephrin expression and functionality. PMID- 24949850 TI - Regenerative medicine for the youngest: customized therapies for rare diseases. PMID- 24949849 TI - The community balance and mobility scale alleviates the ceiling effects observed in the currently used gait and balance assessments for the community-dwelling older adults. AB - BACKGROUND AND PURPOSE: Currently used balance assessments show a ceiling effect and lack activities essential for community mobility in higher-functioning older adults. The aim of this study was to investigate the reliability and validity of the Community Balance and Mobility (CB&M) Scale in a high-functioning community dwelling older adult population since the CB&M Scale includes assessment of several challenging tasks and may alleviate the ceiling effects observed in commonly used gait and balance assessments for this cohort. METHODS: A convenience sample of 40 older adults (73.4 +/- 6.9 years) participated in this cross-sectional study. Previously standardized balance and mobility assessments measuring similar constructs as the CB&M were used for validation. Outcomes included Timed Up and Go Test, Berg Balance Scale (BBS), Dynamic Gait Index (DGI), Functional Reach Test (FRT), Short Physical Performance Battery (SPPB), 6 Minute Walk Test (6MWT), Activities Specific Balance Confidence scale (ABC), gait speed, and intraindividual gait variability. A falls questionnaire documented the history of falls. RESULTS: Rater reliability (ICC > 0.95) and internal consistency (alpha= .97) of the CB&M scale were high. CB&M scores demonstrated strong correlations with DGI, BBS, SPPB, and 6MWT (rho= 0.70-0.87; P < .01); moderate correlations with falls history, TUG, ABC, and gait speed (rho= 0.44 0.65; P < .01); and low correlations with FRT, swing and stance time variability (rho= 0.34-0.37; P < .05). Dynamic Gait Index, BBS, SPPB, and ABC assessments demonstrated ceiling effects (7.5%-32.5%), while no floor or ceiling effects were noted on the CB&M. Logistic regression model showed that the CB&M scores significantly predicted falls history (chi(2) = 6.66, odds ratio = 0.92; P < .01). Area under the curve for the CB&M scale was 0.80 (95% CI: 0.65-0.95). A score of CB&M <= 39 was the optimal trade-off between sensitivity and specificity (sensitivity = 79%, specificity = 76%) and a score of CB&M <= 45 maximized sensitivity (sensitivity = 93%, specificity = 60%) to discriminate persons with 2 or more falls from those with fewer than 2 falls in the past year. DISCUSSION AND CONCLUSIONS: CB&M scale is reliable and valid to evaluate gait, balance, and mobility in community-dwelling older adults. Unlike some currently used balance and mobility assessments for the community-dwelling older adults, the CB&M scale did not show a ceiling in detection of balance and mobility deficits. In addition, cutoff scores have been proposed that might serve as criteria to discriminate older adults with balance and mobility deficits. The CB&M scale might enable assessment of balance and mobility limitations masked by other assessments and help design interventions to improve community mobility and sustain independence in the higher-functioning community-dwelling older adult. PMID- 24949851 TI - Simulation of Swanson's literature-based discovery: anandamide treatment inhibits growth of gastric cancer cells in vitro and in silico. AB - Swanson's literature-based discovery focus on resurrecting previously published but neglected knowledge. In this study, we propose a two-step model of the discovery process and generate a hypothesis between anandamide and gastric cancer. Further, the potential relationship was confirmed by follow-up experimentation. The anandamide treatment resulted in cell cycle redistribution of gastric cancer cells. Most importantly, the variation of cell cycle was mediated by some genes from the B-terms of the closed discovery, indicating the potential role of the B-terms. Swanson's literature-based discovery not only collates data for possible interactions, but also provides the potential to observe the larger background behind these direct links and is an invaluable discovery tool for investigators. PMID- 24949852 TI - Concerted versus stepwise mechanism in thymidylate synthase. AB - Thymidylate synthase (TSase) catalyzes the intracellular de novo formation of thymidylate (a DNA building block) in most living organisms, making it a common target for chemotherapeutic and antibiotic drugs. Two mechanisms have been proposed for the rate-limiting hydride transfer step in TSase catalysis: a stepwise mechanism in which the hydride transfer precedes the cleavage of the covalent bond between the enzymatic cysteine and the product and a mechanism where both happen concertedly. Striking similarities between the enzyme-bound enolate intermediates formed in the initial and final step of the reaction supported the first mechanism, while QM/MM calculations favored the concerted mechanism. Here, we experimentally test these two possibilities using secondary kinetic isotope effect (KIE), mutagenesis study, and primary KIEs. The findings support the concerted mechanism and demonstrate the critical role of an active site arginine in substrate binding, activation of enzymatic nucleophile, and the hydride transfer studied here. The elucidation of this reduction/substitution sheds light on the critical catalytic step in TSase and may aid future drug or biomimetic catalyst design. PMID- 24949853 TI - Sorption kinetics and equilibrium of the herbicide diuron to carbon nanotubes or soot in absence and presence of algae. AB - Carbon nanotubes (CNT) are strong sorbents for organic micropollutants, but changing environmental conditions may alter the distribution and bioavailability of the sorbed substances. Therefore, we investigated the effect of green algae (Chlorella vulgaris) on sorption of a model pollutant (diuron, synonyms: 3-(3,4 Dichlorophenyl)-1,1-dimethylurea, DCMU) to CNT (multi-walled purified, industrial grade, pristine, and oxidized; reference material: Diesel soot). In absence of algae, diuron sorption to CNT was fast, strong, and nonlinear (Freundlich coefficients: 10(5.79)-10(6.24) MUg/kgCNT.(MUg/L)(-n) and 0.62-0.70 for KF and n, respectively). Adding algae to equilibrated diuron-CNT mixtures led to 15-20% (median) diuron re-dissolution. The relatively high amorphous carbon content slowed down ad-/desorption to/from the high energy sorption sites for both industrial grade CNT and soot. The results suggest that diuron binds readily, but - particularly in presence of algae - partially reversibly to CNT, which is of relevance for environmental exposure and risk assessment. PMID- 24949856 TI - Gene therapies for inherited retinal disorders. AB - Significant advances have been made over the last decade or two in the elucidation of the molecular pathogenesis of inherited ocular disorders. In particular, remarkable successes have been achieved in exploration of gene-based medicines for these conditions, both in preclinical and in clinical studies. Progress in the development of gene therapies targeted toward correcting the primary genetic defect or focused on modulating secondary effects associated with retinal pathologies are discussed in the review. Likewise, the recent utilization of genes encoding light-sensing molecules to provide new functions to residual retinal cells in the degenerating retina is discussed. While a great deal has been learned over the last two decades, the next decade should result in an increasing number of preclinical studies progressing to human clinical trial, an exciting prospect for patients, those active in research and development and bystanders alike. PMID- 24949855 TI - A systems biology approach to the analysis of subset-specific responses to lipopolysaccharide in dendritic cells. AB - Dendritic cells (DCs) are critical for regulating CD4 and CD8 T cell immunity, controlling Th1, Th2, and Th17 commitment, generating inducible Tregs, and mediating tolerance. It is believed that distinct DC subsets have evolved to control these different immune outcomes. However, how DC subsets mount different responses to inflammatory and/or tolerogenic signals in order to accomplish their divergent functions remains unclear. Lipopolysaccharide (LPS) provides an excellent model for investigating responses in closely related splenic DC subsets, as all subsets express the LPS receptor TLR4 and respond to LPS in vitro. However, previous studies of the LPS-induced DC transcriptome have been performed only on mixed DC populations. Moreover, comparisons of the in vivo response of two closely related DC subsets to LPS stimulation have not been reported in the literature to date. We compared the transcriptomes of murine splenic CD8 and CD11b DC subsets after in vivo LPS stimulation, using RNA-Seq and systems biology approaches. We identified subset-specific gene signatures, which included multiple functional immune mediators unique to each subset. To explain the observed subset-specific differences, we used a network analysis approach. While both DC subsets used a conserved set of transcription factors and major signalling pathways, the subsets showed differential regulation of sets of genes that 'fine-tune' the network Hubs expressed in common. We propose a model in which signalling through common pathway components is 'fine-tuned' by transcriptional control of subset-specific modulators, thus allowing for distinct functional outcomes in closely related DC subsets. We extend this analysis to comparable datasets from the literature and confirm that our model can account for cell subset-specific responses to LPS stimulation in multiple subpopulations in mouse and man. PMID- 24949857 TI - Helicobacter pylori-related diffuse large B-cell lymphoma of the stomach: a distinct entity with lower aggressiveness and higher chemosensitivity. AB - We recently showed that Helicobacter pylori (HP)-positive gastric 'pure' diffuse large B-cell lymphoma (DLBCL) may respond to HP eradication therapy. However, whether these HP-related 'pure' DLBCL of the stomach may differ fundamentally from those unrelated to HP remains unclear. In this study, we compared the clinicopathologic features of these two groups of patients who had been uniformly treated by conventional chemotherapy. Forty-six patients were designated HP positive and 49 were HP-negative by conventional criteria. HP-positive patients had a lower International Prognostic Index score (0-1, 65% vs 43%, P=0.029), a lower clinical stage (I-IIE1, 70% vs 39%, P=0.003), a better tumor response to chemotherapy (complete pathologic response, 76% vs 47%, P=0.004) and significantly superior 5-year event-free survival (EFS) (71.7% vs 31.8%, P<0.001) and overall survival (OS) (76.1% vs 39.8%, P<0.001). To draw a closer biologic link with HP, HP-positive tumors were further examined for CagA expression in lymphoma cells. Compared with CagA-negative cases (n=16), CagA-positive cases (n=27) were associated with high phosphorylated SHP-2 expression (P=0.016), and even better 5-year EFS (85.2% vs 46.3%, P=0.002) and OS (88.9% vs 52.9%, P=0.003). HP-related gastric 'pure' DLBCL may be a distinct tumor entity, which is less aggressive, and responds better to conventional chemotherapy. PMID- 24949858 TI - KIF14 binds tightly to microtubules and adopts a rigor-like conformation. AB - The mitotic kinesin motor protein KIF14 is essential for cytokinesis during cell division and has been implicated in cerebral development and a variety of human cancers. Here we show that the mouse KIF14 motor domain binds tightly to microtubules and does not display typical nucleotide-dependent changes in this affinity. It also has robust ATPase activity but very slow motility. A crystal structure of the ADP-bound form of the KIF14 motor domain reveals a dramatically opened ATP-binding pocket, as if ready to exchange its bound ADP for Mg.ATP. In this state, the central beta-sheet is twisted ~10 degrees beyond the maximal amount observed in other kinesins. This configuration has only been seen in the nucleotide-free states of myosins-known as the "rigor-like" state. Fitting of this atomic model to electron density maps from cryo-electron microscopy indicates a distinct binding configuration of the motor domain to microtubules. We postulate that these properties of KIF14 are well suited for stabilizing midbody microtubules during cytokinesis. PMID- 24949861 TI - Titanium-oxo cluster with 9-anthracenecarboxylate antennae: a fluorescent and photocurrent transfer material. AB - Attention has been paid to titanium-oxo clusters (TOCs) modified with functional molecules, because they can be considered as model systems for dye-sensitized titanium oxides in terms of their information in structures and electron transfer. We select 9-anthracenecarboxylate (9-AC) as a photoactive ligand and prepare two model compounds, [Ti6O6(O(i)Pr)6(9-AC)6] (1) and [Ti6O4(O(i)Pr)6(cat)4(9-AC)2] (2) (where cat = catecholate). Structures of the TOCs and the dye-TOC linkage are characterized by single-crystal analysis. Solvent-induced fluorescence change is observed for the cluster solution, and the fluorescence can be turned off by irradiating and on by oxygen bubbling. Photoinduced Ti(III) is responsible for the fluorescence extinction. The photocurrent conversion property of the clusters is examined by use of a three electrode cell with cluster-coated indium tin oxide (ITO) electrodes. The results indicate that 9-AC is an effective photosensitizer and cluster 1 shows higher photocurrent intensity for its multiantenna structure in comparison with that of 2. Density of states for cluster 1 is calculated, in which the discrete energy bands of Ti6O24 include a number of new energy levels for the contribution of 9 AC molecules. PMID- 24949862 TI - Method Development for the Detection of Human Myostatin by High-Resolution and Targeted Mass Spectrometry. AB - Myostatin, a highly conserved secretory protein, negatively regulates muscle development, affecting both the proliferation and differentiation of muscle cells. Proteolytic processing of the myostatin precursor protein generates a myostatin pro-peptide and mature protein. Dimerization of the mature myostatin protein creates the active form of myostatin. Myostatin dimer activity can be inhibited by noncovalent binding of two monomeric myostatin pro-peptides. This ability for myostatin to self-regulate as well as the altered expression of myostatin in states of abnormal health (e.g., muscle wasting) support the need for specific detection of myostatin forms. Current protein detection methods (e.g., Western blot) rely greatly on antibodies and are semiquantitative at best. Tandem mass spectometry (as in this study) provides a highly specific method of detection, enabling the characterization of myostatin protein forms through the analysis of discrete peptides fragments. Utilizing the scheduled high-resolution multiple reaction monitoring paradigm (sMRMHR; AB SCIEX 5600 TripleTOF) we identified the lower limit of quantitation (LLOQ) of both mature (DFGLDCDEHSTESR) and pro-peptide regions (ELIDQYDVQR) as 0.19 nmol/L. Furthermore, scheduled multiple reaction monitoring (sMRM; AB SCIEX QTRAP 5500) identified a LLOQ for a peptide of the pro-peptide region (LETAPNISK) as 0.16 nmol/L and a peptide of the mature region (EQIIYGK) as 0.25 nmol/L. PMID- 24949860 TI - In vivo near-infrared fluorescence imaging of apoptosis using histone H1 targeting peptide probe after anti-cancer treatment with cisplatin and cetuximab for early decision on tumor response. AB - Early decision on tumor response after anti-cancer treatment is still an unmet medical need. Here we investigated whether in vivo imaging of apoptosis using linear and cyclic (disulfide-bonded) form of ApoPep-1, a peptide that recognizes histone H1 exposed on apoptotic cells, at an early stage after treatment could predict tumor response to the treatment later. Treatment of stomach tumor cells with cistplatin or cetuximab alone induced apoptosis, while combination of cisplatin plus cetuximab more efficiently induced apoptosis, as detected by binding with linear and cyclic form of ApoPep-1. However, the differences between the single agent and combination treatment were more remarkable as detected with the cyclic form compared to the linear form. In tumor-bearing mice, apoptosis imaging was performed 1 week and 2 weeks after the initiation of treatment, while tumor volumes and weights were measured 3 weeks after the treatment. In vivo fluorescence imaging signals obtained by the uptake of ApoPep-1 to tumor was most remarkable in the group injected with cyclic form of ApoPep-1 at 1 week after combined treatment with cisplatin plus cetuximab. Correlation analysis revealed that imaging signals by cyclic ApoPep-1 at 1 week after treatment with cisplatin plus cetuximab in combination were most closely related with tumor volume changes (r2 = 0.934). These results demonstrate that in vivo apoptosis imaging using Apopep-1, especially cyclic ApoPep-1, is a sensitive and predictive tool for early decision on stomach tumor response after anti-cancer treatment. PMID- 24949859 TI - Mismatch negativity in recent-onset and chronic schizophrenia: a current source density analysis. AB - Mismatch negativity (MMN) is a component of the event-related potential elicited by deviant auditory stimuli. It is presumed to index pre-attentive monitoring of changes in the auditory environment. MMN amplitude is smaller in groups of individuals with schizophrenia compared to healthy controls. We compared duration deviant MMN in 16 recent-onset and 19 chronic schizophrenia patients versus age- and sex-matched controls. Reduced frontal MMN was found in both patient groups, involved reduced hemispheric asymmetry, and was correlated with Global Assessment of Functioning (GAF) and negative symptom ratings. A cortically-constrained LORETA analysis, incorporating anatomical data from each individual's MRI, was performed to generate a current source density model of the MMN response over time. This model suggested MMN generation within a temporal, parietal and frontal network, which was right hemisphere dominant only in controls. An exploratory analysis revealed reduced CSD in patients in superior and middle temporal cortex, inferior and superior parietal cortex, precuneus, anterior cingulate, and superior and middle frontal cortex. A region of interest (ROI) analysis was performed. For the early phase of the MMN, patients had reduced bilateral temporal and parietal response and no lateralisation in frontal ROIs. For late MMN, patients had reduced bilateral parietal response and no lateralisation in temporal ROIs. In patients, correlations revealed a link between GAF and the MMN response in parietal cortex. In controls, the frontal response onset was 17 ms later than the temporal and parietal response. In patients, onset latency of the MMN response was delayed in secondary, but not primary, auditory cortex. However amplitude reductions were observed in both primary and secondary auditory cortex. These latency delays may indicate relatively intact information processing upstream of the primary auditory cortex, but impaired primary auditory cortex or cortico-cortical or thalamo-cortical communication with higher auditory cortices as a core deficit in schizophrenia. PMID- 24949863 TI - Identification of novel small RNAs and characterization of the 6S RNA of Coxiella burnetii. AB - Coxiella burnetii, an obligate intracellular bacterial pathogen that causes Q fever, undergoes a biphasic developmental cycle that alternates between a metabolically-active large cell variant (LCV) and a dormant small cell variant (SCV). As such, the bacterium undoubtedly employs complex modes of regulating its lifecycle, metabolism and pathogenesis. Small RNAs (sRNAs) have been shown to play important regulatory roles in controlling metabolism and virulence in several pathogenic bacteria. We hypothesize that sRNAs are involved in regulating growth and development of C. burnetii and its infection of host cells. To address the hypothesis and identify potential sRNAs, we subjected total RNA isolated from Coxiella cultured axenically and in Vero host cells to deep-sequencing. Using this approach, we identified fifteen novel C. burnetii sRNAs (CbSRs). Fourteen CbSRs were validated by Northern blotting. Most CbSRs showed differential expression, with increased levels in LCVs. Eight CbSRs were upregulated (>=2 fold) during intracellular growth as compared to growth in axenic medium. Along with the fifteen sRNAs, we also identified three sRNAs that have been previously described from other bacteria, including RNase P RNA, tmRNA and 6S RNA. The 6S regulatory sRNA of C. burnetii was found to accumulate over log phase-growth with a maximum level attained in the SCV stage. The 6S RNA-encoding gene (ssrS) was mapped to the 5' UTR of ygfA; a highly conserved linkage in eubacteria. The predicted secondary structure of the 6S RNA possesses three highly conserved domains found in 6S RNAs of other eubacteria. We also demonstrate that Coxiella's 6S RNA interacts with RNA polymerase (RNAP) in a specific manner. Finally, transcript levels of 6S RNA were found to be at much higher levels when Coxiella was grown in host cells relative to axenic culture, indicating a potential role in regulating the bacterium's intracellular stress response by interacting with RNAP during transcription. PMID- 24949864 TI - Improving ethical and participatory practice for marginalized populations in biomedical HIV prevention trials: lessons from Thailand. AB - BACKGROUND: This paper presents findings from a qualitative investigation of ethical and participatory issues related to the conduct of biomedical HIV prevention trials among marginalized populations in Thailand. This research was deemed important to conduct, as several large-scale biomedical HIV prevention trials among marginalized populations had closed prematurely in other countries, and a better understanding of how to prevent similar trial closures from occurring in the future was desired. METHODS: In-depth key informant interviews were held in Bangkok and Chiang Mai, Thailand. Interviews were audio recorded, transcribed, translated and thematically analyzed. The Good Participatory Practice Guidelines for Biomedical HIV Prevention Trials (GPP) guided this work. RESULTS: Fourteen interviews were conducted: 10 with policymakers, academic and community-based researchers and trial staff and four with representatives of non governmental organizations (NGOs). Suggested ways to improve ethical and participatory practice centered on standards of HIV prevention, informed consent, communication and human rights. In particular, the need to overcome language and literacy differences was identified. Key informants felt communication was the basis of ethical understanding and trust within biomedical HIV prevention trial contexts, and thus fundamental to trial participants' ability to exercise free will. DISCUSSION: Biomedical HIV prevention trials present opportunities for inclusive and productive ethical and participatory practice. Key informants suggested that efforts to improve practice could result in better relationships between research stakeholders and research investigative teams and by extension, better, more ethical participatory trials. This research took place in Thailand and its findings apply primarily to Thailand. However, given the universality of many ethical considerations, the results of this study can inform the improvement of ethical and participatory practice in other parts of the world where biomedical HIV prevention trials occur, and where clinical trials in marginalized populations continue. PMID- 24949865 TI - The expression of VEGF and Dll4/Notch pathway molecules in ovarian cancer. AB - BACKGROUND: VEGF and Dll4/Notch pathways play important roles in tumor angiogenesis. The purpose of this study is to investigate the expression of these two pathway molecules in ovarian cancer and their possible relationships in carcinogenesis. METHODS: Twenty-eight specimens of human ovarian carcinoma, 18 of benign ovarian and 20 of healthy ovarian tissues were subjected to immunohistochemical analysis for VEGF, VEGFR1, and VEGFR2, Dll4, Notch1, and Notch3 expression. Microvessel density (MVD) was evaluated by counting the number of CD34-stained microvessels in each pathologic specimen. RESULTS: The expression of VEGF, VEGFR1, Dll4, Notch1, or Notch3 in ovarian tumor tissues was higher than that in normal ovary tissues as well as that in benign ovarian tumor tissues (P<0.05). In the tumor tissues, Dll4 was positively correlated with VEGFR1 expression and Notch1 was positively associated with VEGFR2 and MVD. Moreover, VEGFR2 expression was positively associated with ascites and distant metastasis (R=0.401, P=0.034). CONCLUSIONS: Dll4 represents a potential biomarker and therapeutic target for ovarian angiogenesis. VEGFR2 is significantly related to ovarian metastasis and invasion. Therefore testing the key molecules of these two pathways expression may have some diagnostic and prognostic value for ovarian cancer. PMID- 24949866 TI - Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics. AB - BACKGROUND: Metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5) are novel therapeutic targets for major depression (MD), bipolar disorder (BD) and schizophrenia. We aimed to determine whether mGluR2/3 and mGluR5 binding in the anterior cingulate cortex (ACC), a brain region essential for the regulation of mood, cognition and emotion, were differentially altered in these pathologies. METHODS: Using postmortem human brains derived from 2 cohorts, [(3)H]LY341495 binding to mGluR2/3 and [(3)H]MPEP binding to mGluR5 were measured by receptor autoradiography in the ACC. The first cohort comprised samples from individuals who had MD with psychosis (MDP), MD without psychosis (MDNP) and matched controls (n = 11-12 per group). The second cohort comprised samples from individuals who had MDNP, BD, schizophrenia and matched controls (n = 15 per group). RESULTS: No differences in mGluR2/3 or mGluR5 binding were observed in the MDP, MDNP, BD or schizophrenia groups compared with the control group (all p > 0.05). Importantly, there were also no differences in binding densities between the psychiatric disorders (p > 0.05). We did, however, observe age-related effects, with consistent negative associations between mGluR2/3 and age in the control group (r < -0.575, p < 0.025) and the psychotic disorder groups (MDP and schizophrenia: r = -0.765 to -0.515, p < 0.05), but not in the mood disorder groups (MDNP, BD). LIMITATIONS: Replication in larger independent cohorts and medication-naive individuals would strengthen these findings. CONCLUSION: Our findings suggest that mGluRs are unaltered in the ACC; however, the presence of altered receptor function cannot be discounted and requires further investigation. Taken together with previous studies, which report differential changes in mGluR2, 3 and 5 across these disorders, we suggest mGluRs may be affected in a brain region specific manner. PMID- 24949868 TI - Clinically relevant correlates of accurate perception of patients' thoughts and feelings. AB - The goal was to explore the clinical relevance of accurate understanding of patients' thoughts and feelings. Between 2010 and 2012, four groups of participants (nursing students, medical students, internal medicine residents, and undergraduate students) took a test of accuracy in understanding the thoughts and feelings of patients who were videorecorded during their actual medical visits and who afterward reviewed their video to identify their thoughts and feelings as they occurred (Test of Accurate Perception of Patients' Affect, or TAPPA). Participants' accuracy scores were then correlated with participants' attitudes toward patient-centered care, clinical course background, recall of clinical conversation, evaluations of clinical performance made by preceptors, evaluations of interpersonal skill made by standardized patients in clinical encounters, and independent coding of behavior in a clinical encounter. Accuracy in understanding patients' thoughts and feelings was significantly correlated with nursing students' clinical course experience, clinicians' favorable attitudes to psychosocial discussion, standardized patients' evaluations of medical students' interpersonal skill, independent coding of medical students' patient-centered behavior while taking a social history, and undergraduates' more accurate recall of what an actor-physician said on video. Accuracy in perceiving patients' thoughts and feelings can be objectively measured and is a skill relevant to clinical performance. PMID- 24949867 TI - Brain grey matter volume alterations in late-life depression. AB - BACKGROUND: Voxel-based morphometry (VBM) studies have demonstrated that grey matter abnormalities are involved in the pathophysiology of late-life depression (LLD), but the findings are inconsistent and have not been quantitatively reviewed. The aim of the present study was to conduct a meta-analysis that integrated the reported VBM studies, to determine consistent grey matter alterations in individuals with LLD. METHODS: A systematic search was conducted to identify VBM studies that compared patients with LLD and healthy controls. We performed a meta-analysis using the effect size signed differential mapping method to quantitatively estimate regional grey matter abnormalities in patients with LLD. RESULTS: We included 9 studies with 11 data sets comprising 292 patients with LLD and 278 healthy controls in our meta-analysis. The pooled and subgroup meta-analyses showed robust grey matter reductions in the right lentiform nucleus extending into the parahippocampus, the hippocampus and the amygdala, the bilateral medial frontal gyrus and the right subcallosal gyrus as well as a grey matter increase in the right lingual gyrus. Meta-regression analyses showed that mean age and the percentage of female patients with LLD were not significantly related to grey matter changes. LIMITATIONS: The analysis techniques, patient characteristics and clinical variables of the studies included were heterogeneous, and most participants were medicated. CONCLUSION: The present meta-analysis is, to our knowledge, the first to overcome previous inconsistencies in the VBM studies of LLD and provide robust evidence for grey matter alterations within fronto-striatal-limbic networks, thereby implicating them in the pathophysiology of LLD. The mean age and the percentage of female patients with LLD did not appear to have a measurable impact on grey matter changes, although we cannot rule out the contributory effects of medication. PMID- 24949870 TI - Whole body vibration improves cognition in healthy young adults. AB - This study investigated the acute effects of passive whole body vibration (WBV) on executive functions in healthy young adults. Participants (112 females, 21 males; age: 20.5+/-2.2 years) underwent six passive WBV sessions (frequency 30 Hz, amplitude approximately 0.5 mm) and six non-vibration control sessions of two minutes each while sitting on a chair mounted on a vibrating platform. A passive WBV session was alternated with a control session. Directly after each session, performance on the Stroop Color-Block Test (CBT), Stroop Color-Word Interference Test (CWIT), Stroop Difference Score (SDS) and Digit Span Backward task (DSBT) was measured. In half of the passive WBV and control sessions the test order was CBT-CWIT-DSBT, and DSBT-CBT-CWIT in the other half. Passive WBV improved CWIT (p = 0.009; effect size r = 0.20) and SDS (p = 0.034; r = 0.16) performance, but only when the CBT and CWIT preceded the DSBT. CBT and DSBT performance did not change. This study shows that two minutes passive WBV has positive acute effects on attention and inhibition in young adults, notwithstanding their high cognitive functioning which could have hampered improvement. This finding indicates the potential of passive WBV as a cognition-enhancing therapy worth further evaluation, especially in persons unable to perform active forms of exercise. PMID- 24949869 TI - A cost-minimization analysis of tissue-engineered constructs for corneal endothelial transplantation. AB - Corneal endothelial transplantation or endothelial keratoplasty has become the preferred choice of transplantation for patients with corneal blindness due to endothelial dysfunction. Currently, there is a worldwide shortage of transplantable tissue, and demand is expected to increase further with aging populations. Tissue-engineered alternatives are being developed, and are likely to be available soon. However, the cost of these constructs may impair their widespread use. A cost-minimization analysis comparing tissue-engineered constructs to donor tissue procured from eye banks for endothelial keratoplasty was performed. Both initial investment costs and recurring costs were considered in the analysis to arrive at a final tissue cost per transplant. The clinical outcomes of endothelial keratoplasty with tissue-engineered constructs and with donor tissue procured from eye banks were assumed to be equivalent. One-way and probabilistic sensitivity analyses were performed to simulate various possible scenarios, and to determine the robustness of the results. A tissue engineering strategy was cheaper in both investment cost and recurring cost. Tissue engineered constructs for endothelial keratoplasty could be produced at a cost of US$880 per transplant. In contrast, utilizing donor tissue procured from eye banks for endothelial keratoplasty required US$3,710 per transplant. Sensitivity analyses performed further support the results of this cost-minimization analysis across a wide range of possible scenarios. The use of tissue-engineered constructs for endothelial keratoplasty could potentially increase the supply of transplantable tissue and bring the costs of corneal endothelial transplantation down, making this intervention accessible to a larger group of patients. Tissue engineering strategies for corneal epithelial constructs or other tissue types, such as pancreatic islet cells, should also be subject to similar pharmacoeconomic analyses. PMID- 24949871 TI - Self-reported parental exposure to pesticide during pregnancy and birth outcomes: the MecoExpo cohort study. AB - The MecoExpo study was performed in the Picardy region of northern France, in order to investigate the putative relationship between parental exposures to pesticides (as reported by the mother) on one hand and neonatal parameters on the other. The cohort comprised 993 mother-newborn pairs. Each mother completed a questionnaire that probed occupational, domestic, environmental and dietary sources of parental exposure to pesticides during her pregnancy. Multivariate regression analyses were then used to test for associations between the characteristics of parental pesticide exposure during pregnancy and the corresponding birth outcomes. Maternal occupational exposure was associated with an elevated risk of low birth weight (odds ratio (OR) [95% confidence interval]: 4.2 [1.2, 15.4]). Paternal occupational exposure to pesticides was associated with a lower than average gestational age at birth (-0.7 weeks; p = 0.0002) and an elevated risk of prematurity (OR: 3.7 [1.4, 9.7]). Levels of domestic exposure to veterinary antiparasitics and to pesticides for indoor plants were both associated with a low birth weight (-70 g; p = 0.02 and -160 g; p = 0.005, respectively). Babies born to women living in urban areas had a lower birth length and a higher risk of low birth length (-0.4 cm, p = 0.006 and OR: 2.9 [1.5, 5.5], respectively). The present study results mainly demonstrate a negative correlation between fetal development on one hand and parental occupational and domestic exposure to pesticides on the other. Our study highlights the need to perform a global and detailed screening of all potential physiological effects when assessing in utero exposure to pesticides. PMID- 24949874 TI - Loss of stromal caveolin-1 expression: a novel tumor microenvironment biomarker that can predict poor clinical outcomes for pancreatic cancer. AB - AIMS: Cancer development and progression is not only associated with the tumor cell proliferation but also depends on the interaction between tumor cells and the stromal microenvironment. A new understanding of the role of the tumor microenvironment suggests that the loss of stromal caveolin-1 (Cav-1) as a key regulator may become a potential therapy target. This study aims to elucidate whether stromal Cav-1 expression in pancreatic cancer can be a strong prognosis biomarker. METHODS: Tissue samples from 45 pancreatic cancer patients were studied. Parenchyma and stroma were separated and purified using laser capture microdissection. Stromal Cav-1 expression was measured from pancreatic cancer, paraneoplastic, and normal tissue using immunohistochemistry. We analyzed the correlation of stromal Cav-1 expression with clinicopathologic features and prognostic indicators, such as tumor marker HER-2/neu gene. RESULTS: Specimens from six patients (13.3%) showed high levels of stromal Cav-1 staining, those from eight patients (17.8%) showed a lower, intermediate level of staining, whereas those from 31 patients (68.9%) showed an absence of staining. Cav-1 expression in cancer-associated fibroblasts was lower than that in paracancer associated and in normal fibroblasts. Stromal Cav-1 loss was associated with TNM stage (P = 0.018), lymph node metastasis (P = 0.014), distant metastasis (P = 0.027), and HER-2/neu amplification (P = 0.007). The relationships of age, sex, histological grade, and tumor size with stromal Cav-1 expression were not significant (P>0.05). A negative correlation was found between circulating tumor cells and stromal Cav-1 expression (P<0.05). CONCLUSION: The loss of stromal Cav 1 in pancreatic cancer was an independent prognostic indicator, thus suggesting that stromal Cav-1 may be an effective therapeutic target for patients with pancreatic cancer. PMID- 24949875 TI - Tissue distribution of amino acid- and lipid-brevetoxins after intravenous administration to C57BL/6 mice. AB - Brevetoxins produced during algal blooms of the dinoflagellate Karenia are metabolized by shellfish into reduction, oxidation, and conjugation products. Brevetoxin metabolites comprising amino acid- and lipid conjugates account for a large proportion of the toxicity associated with the consumption of toxic shellfish. However, the disposition of these brevetoxin metabolites has not been established. Using intravenous exposure to C57BL/6 mice, we investigated the disposition in the body of three radiolabeled brevetoxin metabolites. Amino acid brevetoxin conjugates represented by S-desoxy-BTX-B2 (cysteine-BTX-B) and lipid brevetoxin conjugates represented by N-palmitoyl-S-desoxy-BTX-B2 were compared to dihydro-BTX-B. Tissue concentration profiles were unique to each of the brevetoxin metabolites tested, with dihydro-BTX-B being widely distributed to all tissues, S-desoxy-BTX-B2 concentrated in kidney, and N-palmitoyl-S-desoxy-BTX-B2 having the highest concentrations in spleen, liver, and lung. Elimination patterns were also unique: dihydro-BTX-B had a greater fecal versus urinary elimination, whereas urine was a more important elimination route for S-desoxy BTX-B2, and N-palmitoyl-S-desoxy-BTX-B2 persisted in tissues and was eliminated equally in both urine and feces. The structures particular to each brevetoxin metabolite resulting from the reduction, amino acid conjugation, or fatty acid addition of BTX-B were likely responsible for these tissue-specific distributions and unique elimination patterns. These observed differences provide further insight into the contribution each brevetoxin metabolite class has to the observed potencies. PMID- 24949876 TI - Post-transcriptional regulation of the human reduced folate carrier as a novel adaptive mechanism in response to folate excess or deficiency. AB - The RFC (reduced folate carrier) is the principal mechanism by which folates and clinically used antifolates are delivered to mammalian cells. hRFC (human RFC) is subject to complex transcriptional controls and exists as homo-oligomer. To explore the post-transcriptional regulation of hRFC by exogenous folates, hRFC null HeLa cells were stably transfected with hRFC under control of a constitutive promoter. hRFC transcripts and the total membrane protein increased with increasing LCV [(6R,S)5-formyl tetrahydrofolate (leucovorin)] with a maximum at 20 nM LCV, attributable to reduced turnover of hRFC transcripts. hRFC homo oligomerization was unaffected by increasing LCV. Cell surface hRFC paralleled [3H]methotrexate transport and increased from 0.5 to 2 nM LCV, and then decreased (~2-fold) with increasing LCV up to 20 nM. hRFC was localized to the cell surface at low LCV concentrations (0.5-1.5 nM). However, at higher LCV concentrations, significant intracellular hRFC was localized to the ER (endoplasmic reticulum), such that at 20 nM LCV, intracellular hRFC was predominated. Our results demonstrate a novel post-transcriptional regulation of hRFC involving: (i) increased hRFC transcripts and proteins, accompanying increased extracellular folates, attributable to differences in hRFC transcript stabilities; and (ii) increased retention of hRFC in the ER under conditions of folate excess, because of impaired intracellular trafficking and plasma membrane targeting. PMID- 24949877 TI - Multilevel hierarchical kernel spectral clustering for real-life large scale complex networks. AB - Kernel spectral clustering corresponds to a weighted kernel principal component analysis problem in a constrained optimization framework. The primal formulation leads to an eigen-decomposition of a centered Laplacian matrix at the dual level. The dual formulation allows to build a model on a representative subgraph of the large scale network in the training phase and the model parameters are estimated in the validation stage. The KSC model has a powerful out-of-sample extension property which allows cluster affiliation for the unseen nodes of the big data network. In this paper we exploit the structure of the projections in the eigenspace during the validation stage to automatically determine a set of increasing distance thresholds. We use these distance thresholds in the test phase to obtain multiple levels of hierarchy for the large scale network. The hierarchical structure in the network is determined in a bottom-up fashion. We empirically showcase that real-world networks have multilevel hierarchical organization which cannot be detected efficiently by several state-of-the-art large scale hierarchical community detection techniques like the Louvain, OSLOM and Infomap methods. We show that a major advantage of our proposed approach is the ability to locate good quality clusters at both the finer and coarser levels of hierarchy using internal cluster quality metrics on 7 real-life networks. PMID- 24949878 TI - Toxin diversity revealed by a transcriptomic study of Ornithoctonus huwena. AB - Spider venom comprises a mixture of compounds with diverse biological activities, which are used to capture prey and defend against predators. The peptide components bind a broad range of cellular targets with high affinity and selectivity, and appear to have remarkable structural diversity. Although spider venoms have been intensively investigated over the past few decades, venomic strategies to date have generally focused on high-abundance peptides. In addition, the lack of complete spider genomes or representative cDNA libraries has presented significant limitations for researchers interested in molecular diversity and understanding the genetic mechanisms of toxin evolution. In the present study, second-generation sequencing technologies, combined with proteomic analysis, were applied to determine the diverse peptide toxins in venom of the Chinese bird spider Ornithoctonus huwena. In total, 626 toxin precursor sequences were retrieved from transcriptomic data. All toxin precursors clustered into 16 gene superfamilies, which included six novel superfamilies and six novel cysteine patterns. A surprisingly high number of hypermutations and fragment insertions/deletions were detected, which accounted for the majority of toxin gene sequences with low-level expression. These mutations contribute to the formation of diverse cysteine patterns and highly variable isoforms. Furthermore, intraspecific venom variability, in combination with variable transcripts and peptide processing, contributes to the hypervariability of toxins in venoms, and associated rapid and adaptive evolution of toxins for prey capture and defense. PMID- 24949879 TI - Antiretroviral treatment outcomes amongst older adults in a large multicentre cohort in South Africa. AB - INTRODUCTION: Increasing numbers of patients are starting antiretroviral treatment (ART) at advanced age or reaching advanced age while on ART. We compared baseline characteristics and ART outcomes of older adults (aged >=55 years) vs. younger adults (aged 25-54 years) in routine care settings in South Africa. METHODS: A multicentre cohort study of ART-naive adults starting ART at 89 public sector facilities was conducted. Mortality, loss to follow-up (LTFU), immunological and virological outcomes until five years of ART were compared using competing-risks regression, generalised estimating equations and mixed effects models. RESULTS: 4065 older adults and 86,006 younger adults were included. There were more men amongst older adults; 44.7% vs. 33.4%; RR = 1.34 (95% CI: 1.29-1.39). Mortality after starting ART was substantially higher amongst older adults, adjusted sub-hazard ratio (asHR) = 1.44 over 5 years (95% CI: 1.26-1.64), particularly for the period 7-60 months of treatment, asHR = 1.73 (95% CI: 1.44-2.10). LTFU was lower in older adults, asHR = 0.87 (95% CI: 0.78 0.97). Achievement of virological suppression was greater in older adults, adjusted odds ratio = 1.42 (95% CI: 1.23-1.64). The probabilities of viral rebound and confirmed virological failure were both lower in older adults, adjusted hazard ratios = 0.69 (95% CI: 0.56-0.85) and 0.64 (95% CI: 0.47-0.89), respectively. The rate of CD4 cell recovery (amongst patients with continuous viral suppression) was 25 cells/6 months of ART (95% CI: 17.3-33.2) lower in older adults. CONCLUSIONS: Although older adults had better virological outcomes and reduced LTFU, their higher mortality and slower immunological recovery warrant consideration of age-specific ART initiation criteria and management strategies. PMID- 24949881 TI - Antitumoural activity of viniferin-enriched extracts from Vitis vinifera L. cell cultures. AB - The aim of this work was to evaluate the effect of stilbenes from different cultivars of Vitis vinifera on tumour proliferation. Extracts were obtained from elicited V. vinifera cell cultures and characterised by HPLC/DAD/MS. Cell growth was evaluated in four human cancer cell lines and in normal human fibroblasts. The cells were exposed to the extracts or to trans-resveratrol, used as reference molecule, for 48 h, at 1-10 MUM concentrations of total stilbenoids. All the extracts exhibited antiproliferative activity, mediated by modulation of the cell cycle and induction of cytotoxicity in cancer but not in normal cell lines, and positively correlated with the content in dimeric stilbenoids. The Alphonse Lavallee extract was the most active, and the obtained stilbenoid fraction resulted 8-10 times more active than trans-resveratrol. Extracts from V. vinifera cell cultures could represent new sources of active stilbenoid compounds to be further assayed in in vivo studies for their antitumoural properties. PMID- 24949882 TI - Effects of olfactory stimulation with perilla essential oil on prefrontal cortex activity. AB - OBJECTIVES: To clarify the effect of olfactory stimulation with perilla essential oil on human prefrontal cortex activity using near-infrared time-resolved spectroscopy. DESIGN: Single-center prospective study. METHODS: Nineteen female university students (mean age, 21.6 +/- 1.5 years) participated in the study. Perilla essential oil was used as an olfactory stimulant and air as a control. Oxyhemoglobin concentrations in the prefrontal cortex were measured by using near infrared time-resolved spectroscopy when the participants were presented with the stimulant or control. Emotional effects were subjectively evaluated by using a modified semantic differential method. RESULTS: Olfactory stimulation with the perilla essential oil significantly reduced the oxyhemoglobin concentration in the prefrontal cortex. No significant differences in the feelings of comfort or relaxation, which strongly reflect human mental status, were observed between the perilla essential oil and control periods. CONCLUSIONS: Olfactory stimulation with perilla essential oil reduced prefrontal cortex activity, thereby inducing physiologic relaxation. PMID- 24949883 TI - Interfacing microsampling droplets and mass spectrometry by paper spray ionization for online chemical monitoring of cell culture. AB - In this work, the establishment of a microdialysis-paper spray ionization-mass spectrometry (MS) system was described. A homemade microdialysis module was employed for sampling, and microdroplets were generated at the outlet of the capillary conducting the dialysate. Online MS analysis of each microdroplet was immediately accomplished, interfacing by paper spray ionization. Analytical performance of the method was investigated and improved through the introduction of thinner capillary tubes and the optimization of spray solvent and paper substrate. For microdroplets with concentrated salt at 50 nL, the limit of detection at 0.8 ppm (or 40 pg absolute) and a highest resolution at about 1.5 s were achieved. The integrated system was applied into the online monitoring of glucose concentration in cell culture mediums. A satisfactory linearity of the calibration curve between the relative MS intensity and the glucose concentration was observed. Furthermore, as a model, hormone regulation of the glucose concentration was investigated. This work demonstrated the potential application of the label-free, online "MS sensor" into studies on cellular metabolism. PMID- 24949884 TI - Insulin receptor antibody-sulfamidase fusion protein penetrates the primate blood brain barrier and reduces glycosoaminoglycans in Sanfilippo type A cells. AB - Mutations in the lysosomal enzyme, N-sulfoglucosamine sulfohydrolase (SGSH), also called sulfamidase, cause accumulation of lysosomal inclusion bodies in the brain of children born with mucopolysaccharidosis type IIIA, also called Sanfilippo type A syndrome. Enzyme replacement therapy with recombinant SGSH does not treat the brain because the enzyme is a large molecule drug that does not cross the blood-brain barrier (BBB). A BBB-penetrating form of SGSH was produced by re engineering the enzyme as an IgG fusion protein, where the IgG domain is a monoclonal antibody (mAb) against the human insulin receptor (HIR). The HIRMAb domain of the HIRMAb-SGSH fusion protein acts as a molecular Trojan horse to ferry the fused enzyme across the BBB. The HIRMAb-SGSH was produced in stably transfected host cells and purified to homogeneity by protein A chromatography. The fusion protein reacted with antibodies against either human IgG or SGSH on Western blotting. High affinity binding to the HIR was retained following SGSH fusion to the HIRMAb, with an EC50 of 0.33 +/- 0.05 nM in an HIR binding ELISA. The SGSH enzyme activity of the HIRMAb-SGSH fusion protein was 4712 +/- 388 units/mg protein based on a two-step fluorometric enzyme assay. The HIRMAb-SGSH was taken up by lysosomes in MPSIIIA fibroblasts, and treatment of these cells with the fusion protein caused an 83% reduction in sulfate incorporation into lysosomal glycosoaminoglycans. The HIRMAb-SGSH fusion protein was radiolabeled with the [(125)I]-Bolton-Hunter reagent and injected intravenously in the Rhesus monkey. The brain uptake of the fusion protein was high, ~1% injected dose/brain. Calculations, based on this level of brain uptake, suggest normalization of brain SGSH enzyme activity is possible following administration of therapeutic doses of the fusion protein. These studies describe a novel IgG-SGSH fusion protein that is a new noninvasive treatment of the brain in MPS type IIIA. PMID- 24949885 TI - Pathogenesis of immune-mediated neuropathies. AB - Autoimmune neuropathies occur when immunologic tolerance to myelin or axonal antigens is lost. Even though the triggering factors and the underling immunopathology have not been fully elucidated in all neuropathy subsets, immunological studies on the patients' nerves, transfer experiments with the patients' serum or intraneural injections, and molecular fingerprinting on circulating autoantibodies or autoreactive T cells, indicate that cellular and humoral factors, either independently or in concert with each other, play a fundamental role in their cause. The review is focused on the main subtypes of autoimmune neuropathies, mainly the Guillain-Barre syndrome(s), the Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), the Multifocal Motor Neuropathy (MMN), and the IgM anti-MAG-antibody mediated neuropathy. It addresses the factors associated with breaking tolerance, examines the T cell activation process including co-stimulatory molecules and key cytokines, and discusses the role of antibodies against peripheral nerve glycolipids or glycoproteins. Special attention is given to the newly identified proteins in the nodal, paranodal and juxtaparanodal regions as potential antigenic targets that could best explain conduction failure and rapid recovery. New biological agents against T cells, cytokines, B cells, transmigration and transduction molecules involved in their immunopathologic network, are discussed as future therapeutic options in difficult cases. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. PMID- 24949888 TI - Methods for the development of tumor-targeting bacteria. AB - INTRODUCTION: For at least two centuries, there have been reports that cancer patients infected with various bacteria had what appeared to be spontaneous remission. In the late nineteenth and early twentieth centuries, W.B. Coley, of what is now the Memorial Sloan-Kettering Cancer Center, pioneered bacterial therapy of cancer in the clinic with considerable success. After Coley died in 1936, bacterial therapy of cancer started to go out of favor. In the current twenty-first century, there is great resurgent interest in developing bacterial therapy for treating cancer using either obligate or facultative anaerobic bacteria. There is also controversy about which bacteria are optimum for cancer treatment and whether bacteria should be used as tumor-targeting vectors, immune stimulators, or for direct tumor killing. AREAS COVERED: This review covers various types of bacteria currently used for tumor targeting. It also covers methods used to develop maximal tumor targeting and minimally attenuated bacteria, which grow in viable as well as necrotic areas of tumors and directly kill cancer cells. EXPERT OPINION: The current paradigm of cancer chemotherapy lacks sufficient efficacy, and a new paradigm is needed. Bacterial therapy is a candidate for a 'new' approach to cancer treatment. In the authors' opinion, the current revival of bacterial therapy of cancer is one of the most promising approaches to treatment. PMID- 24949890 TI - Amplification of single molecule translocation signal using beta-strand peptide functionalized nanopores. AB - Changes in ionic current flowing through nanopores due to binding or translocation of single biopolymer molecules enable their detection and characterization. It is, however, much more challenging to detect small molecules due to their rapid and small signal signature. Here we demonstrate the use of de novo designed peptides for functionalization of nanopores that enable the detection of a small analytes at the single molecule level. The detection relies on cooperative peptide conformational change that is induced by the binding of the small molecule to a receptor domain on the peptide. This change results in alteration of the nanopore effective diameter and hence induces current perturbation signal. On the basis of this approach, we demonstrate here the detection of diethyl 4-nitrophenyl phosphate (paraoxon), a poisonous organophosphate molecule. Paraoxon binding is induced by the incorporation of the catalytic triad of acetylcholine esterase in the hydrophilic domain of a short amphiphilic peptide and promotes beta-sheet assembly of the peptide both in solution and for peptide molecules immobilized on solid surfaces. Nanopores coated with this peptide allowed the detection of paraoxon at the single molecule level revealing two binding arrangements. This unique approach, hence, provides the ability to study interactions of small molecules with the corresponding engineered receptors at the single molecule level. Furthermore, the suggested versatile platform may be used for the development of highly sensitive small analytes sensors. PMID- 24949891 TI - Reduction of PP2A Calpha stimulates adipogenesis by regulating the Wnt/GSK 3beta/beta-catenin pathway and PPARgamma expression. AB - Serine/threonine protein phosphatase 2A (PP2A) regulates several physiological processes such as the cell cycle, cell growth, apoptosis, and signal transduction. In this study, we examined the expression and role of PP2A Calpha in adipocyte differentiation. PP2A Calpha expression and PP2A activity decreased during adipocyte differentiation in C3H10T1/2 and 3T3-L1 cells and the expression of adipocyte marker genes such as PPARgamma and adiponectin increased. To further clarify the role of PP2A Calpha in adipocyte differentiation, we constructed PP2A knockdown cells by infecting C3H10T1/2 cells with a lentivirus expressing a shRNA specific for the PP2A Calpha (shPP2A cells). Silencing of PP2A Calpha in C3H10T1/2 cells dramatically stimulated adipocyte differentiation and lipid accumulation, which were accompanied by expression of adipocyte marker genes. Silencing of PP2A Calpha suppressed Wnt10b expression and reduced the levels of the inactivated form of GSK-3beta (phospho-GSK-3beta), leading to the reduction of beta-catenin levels in the nucleus and its transcriptional activity. Treatment with LiCl, a GSK-3beta inhibitor, and inhibition of PPARgamma expression suppressed the accelerated adipogenesis of shPP2A cells. Our data indicate that PP2A Calpha plays an important role in the regulation of adipocyte differentiation by regulating the Wnt/GSK-3beta/beta-catenin pathway and PPARgamma expression. PMID- 24949887 TI - Effect of the English familial disease mutation (H6R) on the monomers and dimers of Abeta40 and Abeta42. AB - The self-assembly of the amyloid beta (Abeta) peptides into senile plaques is the hallmark of Alzheimer's disease. Recent experiments have shown that the English familial disease mutation (H6R) speeds up the fibril formation process of alloforms Abeta40 and Abeta42 peptides altering their toxicity to cells. We used all-atom molecular dynamics simulations at microsecond time scales with the OPLS AA force field and TIP4P explicit water model to study the structural dynamics of the monomer and dimer of H6R sequences of both peptides. The reason behind the self-assembly acceleration is common that upon mutation the net charge is reduced leading to the weaker repulsive interaction between chains that facilitates the peptide association. In addition, our estimation of the solvation free energy shows that the mutation enhances the hydrophobicity of both peptides speeding up their aggregation. However, we can show that the acceleration mechanisms are different for different peptides: the rate of fibril formation of Abeta42 increases due to increased beta-structure at the C-terminal in both monomer and dimer and enhanced stability of salt bridge Asp23-Lys28 in monomer, while the enhancement of turn at residues 25-29 and reduction of coil in regions 10-13, 26 19, and 30-34 would play the key role for Abeta40. Overall, our study provides a detailed atomistic picture of the H6R-mediated conformational changes that are consistent with the experimental findings and highlights the important role of the N-terminal in Abeta peptide aggregation. PMID- 24949892 TI - Controlling the charge transfer in D-A-D chromophores based on pyrazine derivatives. AB - A series of symmetrical donor-acceptor-donor (D-A-D) chromophores bearing various electron-withdrawing groups, such as quinoxaline (Qx), benzo[g]quinoxaline (BQ), phenazine (Pz), benzo[b]phenazine (BP), thieno[3,4-b]pyrazine (TP), and thieno[3,4-b]quinoxaline (TQ), has been designed and synthesized. Intramolecular charge transfer (ICT) interactions can be found for all the chromophores due to the electron-withdrawing properties of the two imine nitrogens in the pyrazine ring and the electron-donating properties of the other two amine nitrogens in the two triphenylamines. Upon the fusion of either benzene or thiophene ring on the pyrazine acceptor unit, the ICT interactions are strengthened, which results in the bathochromically shifted ICT band. Moreover, the thiophene ring is superior to the benzene ring in enlarging the ICT interaction and expanding the absorption spectrum. Typically, when a thiophene ring is fused on the Qx unit in DQxD, a near-infrared dye is realized in simple chromophore DTQD, which displays the maximum absorption wavelength at 716 nm with the threshold over 900 nm. This is probably due to the enhanced charge density on the acceptor moiety and better orbital overlap, as revealed by theoretical calculation. These results suggest that extending the conjugation of a pyrazine acceptor in an orthogonal direction to the D-A-D backbone can dramatically improve the ICT interactions. PMID- 24949893 TI - Different aggregation dynamics of benzene-water mixtures. AB - All-atom molecular dynamics simulations for benzene-water mixtures are performed, aiming to explore the relationship between the microscopic structures and the thermodynamic properties, in particular, the transformation dynamics from the mutually soluble state to the phase-separated state. We find that the molecular aggregation of benzene in the water-rich mixture is distinctly different from that of water in the benzene-rich mixture. This aggregation difference is attributed to the different intermolecular interactions: the clustering of benzene molecules in the water-rich mixture is primarily driven by weak short distance pi-pi interactions; while the formation of water clusters in the benzene rich solution is triggered by long-range dipole-dipole electrostatic interactions. Moreover, the molecular aggregations show double-scaled features: firstly assembling in a quasi-plane at a low concentration, then bulking in three dimensions with an increase in concentration. PMID- 24949886 TI - Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain. AB - Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. Epidemiological data show that the incidence of AD increases with age and doubles every 5 years after 65 years of age. From a neuropathological point of view, amyloid-beta peptide (Abeta) leads to senile plaques, which, together with hyperphosphorylated tau-based neurofibrillary tangles and synapse loss, are the principal pathological hallmarks of AD. Abeta is associated with the formation of reactive oxygen (ROS) and nitrogen (RNS) species, and induces calcium-dependent excitotoxicity, impairment of cellular respiration, and alteration of synaptic functions associated with learning and memory. Oxidative stress was found to be associated with type 2 diabetes mellitus (T2DM), which (i) represents another prevalent disease associated with obesity and often aging, and (ii) is considered to be a risk factor for AD development. T2DM is characterized by high blood glucose levels resulting from increased hepatic glucose production, impaired insulin production and peripheral insulin resistance, which close resemble to the brain insulin resistance observed in AD patients. Furthermore, growing evidence suggests that oxidative stress plays a pivotal role in the development of insulin resistance and vice versa. This review article provides molecular aspects and the pharmacological approaches from both preclinical and clinical data interpreted from the point of view of oxidative stress with the aim of highlighting progresses in this field. PMID- 24949894 TI - In situ synthesis of peptide nucleic acids in porous silicon for drug delivery and biosensing. AB - Peptide nucleic acids (PNA) are a unique class of synthetic molecules that have a peptide backbone and can hybridize with nucleic acids. Here, a versatile method has been developed for the automated, in situ synthesis of PNA from a porous silicon (PSi) substrate for applications in gene therapy and biosensing. Nondestructive optical measurements were performed to monitor single base additions of PNA initiated from (3-aminopropyl)triethoxysilane attached to the surface of PSi films, and mass spectrometry was conducted to verify synthesis of the desired sequence. Comparison of in situ synthesis to postsynthesis surface conjugation of the full PNA molecules showed that surface mediated, in situ PNA synthesis increased loading 8-fold. For therapeutic proof-of-concept, controlled PNA release from PSi films was characterized in phosphate buffered saline, and PSi nanoparticles fabricated from PSi films containing in situ grown PNA complementary to micro-RNA (miR) 122 generated significant anti-miR activity in a Huh7 psiCHECK-miR122 cell line. The applicability of this platform for biosensing was also demonstrated using optical measurements that indicated selective hybridization of complementary DNA target molecules to PNA synthesized in situ on PSi films. These collective data confirm that we have established a novel PNA-PSi platform with broad utility in drug delivery and biosensing. PMID- 24949896 TI - Recognizing the signs and symptoms of aneurysmal subarachnoid hemorrhage. AB - Subarachnoid hemorrhage (SAH) is a devastating neurologic condition with a high mortality and long term neurological morbidity in 50% of survivors. In addition, SAH commonly affects young patients causing substantial loss of productive life years and resulting in significant long term healthcare costs. Early recognition of the signs and symptoms of SAH is absolutely critical to earlier intervention, and delays in diagnosis can have devastating consequences. To avoid such delays in SAH diagnosis, the medical provider should recognize its signs and symptoms. Neuroimgaging, cerebrospinal fluid examination and angiography (invasive or non invasive) facilitate early diagnosis of SAH. The purpose of this review is not to provide an exhaustive critique of the available literature, rather, it is to provide an overview that will better enable a provider to recognize and initiate the workup of patients with SAH. PMID- 24949897 TI - Periodic table-based descriptors to encode cytotoxicity profile of metal oxide nanoparticles: a mechanistic QSTR approach. AB - Nanotechnology has evolved as a frontrunner in the development of modern science. Current studies have established toxicity of some nanoparticles to human and environment. Lack of sufficient data and low adequacy of experimental protocols hinder comprehensive risk assessment of nanoparticles (NPs). In the present work, metal electronegativity (chi), the charge of the metal cation corresponding to a given oxide (chiox), atomic number and valence electron number of the metal have been used as simple molecular descriptors to build up quantitative structure toxicity relationship (QSTR) models for prediction of cytotoxicity of metal oxide NPs to bacteria Escherichia coli. These descriptors can be easily obtained from molecular formula and information acquired from periodic table in no time. It has been shown that a simple molecular descriptor chiox can efficiently encode cytotoxicity of metal oxides leading to models with high statistical quality as well as interpretability. Based on this model and previously published experimental results, we have hypothesized the most probable mechanism of the cytotoxicity of metal oxide nanoparticles to E. coli. Moreover, the required information for descriptor calculation is independent of size range of NPs, nullifying a significant problem that various physical properties of NPs change for different size ranges. PMID- 24949895 TI - Metabolic regulation of redox status in stem cells. AB - SIGNIFICANCE: Metabolism-dependent generation of reactive oxygen species (ROS) and associated oxidative damage have been traditionally linked to impaired homeostasis and cellular death. Beyond the adverse effects of ROS accumulation, increasing evidence implicates redox status as a regulator of vital cellular processes. RECENT ADVANCES: Emerging studies on the molecular mechanisms guiding stem cell fate decisions indicate a role for energy metabolism in regulating the fundamental ability of maintaining stemness versus undergoing lineage-specific differentiation. Stem cells have evolved protective metabolic phenotypes to minimize reactive oxygen generation through oxidative metabolism and support antioxidant scavenging through glycolysis and the pentose phosphate pathway. CRITICAL ISSUES: While the dynamics in ROS generation has been correlated with stem cell function, the intimate mechanisms by which energy metabolism regulates ROS to impact cellular fate remain to be deciphered. FUTURE DIRECTIONS: Decoding the linkage between nutrient sensing, energy metabolism, and ROS in regulating cell fate decisions would offer a redox-dependent strategy to regulate stemness and lineage specification. PMID- 24949898 TI - Effects of field metal-contaminated soils submitted to phytostabilisation and fly ash-aided phytostabilisation on the avoidance behaviour of the earthworm Eisenia fetida. AB - The earthworm Eisenia fetida avoidance behaviour test was used to assess the quality recovery of metal-contaminated soils from lands submitted for 10 years to remediation. Soils were from plots located in the surroundings of a former lead smelter plant of Northern France. Metal concentrations in the soils ranged from 93 to 1231, 56 to 1424, 0.3 to 20 and 15 to 45.5mg metal/kg dry soil for Pb, Zn, Cd and Cu, respectively. Several former agricultural plots were treated either by a single phytostabilisation process involving the plantation of a tree mix or by fly ash aided-phytostabilisation. Silico-aluminous or sulfo-calcic ashes used were ploughed up to a 25- to 30-cm soil depth at a rate of 23.3kg/m(2) (i.e., 6 percent W/W). E. fetida was shown to avoid significantly the 10 years ash-treated soils whose habitat function has to be considered as limited. This avoidance would relate to a change of the texture of soils induced by the addition of ashes and consisting in an increased level of fine silts together with a decreased level of clays. By contrast, afforested metal-contaminated soils appeared for E. fetida as more attractive than unplanted ones. Regarding the influence of the metal contamination of the soils on E. fetida, none of the soils tested even the highest contaminated one was significantly avoided by worms. This lack of reaction would result from the low bioavailability of the metals in the soils tested. At the lights of our results and those previously published on both these ashes and these ash-treated soils, the usefulness of these soil treatments is discussed. PMID- 24949899 TI - Toxic potential of paracetamol to freshwater organisms: a headache to environmental regulators? AB - Paracetamol is one of the most prescribed drugs globally, due to its antipyretic and analgesic properties. However, it is highly toxic at elevated doses, with involvement of an already described oxidative stress pathway. Despite this, the number of ecotoxicological studies on potential effects of paracetamol in wild organisms is still scarce. The present article presents a comprehensive series of standardized assays for the assessment of paracetamol effects in freshwater organisms. The results show that paracetamol toxicity is widely variable among species, even when these species are phylogenetically related. Furthermore, comparisons between data from the literature and our results reinforce this conclusion, providing evidence of the inadequacy of standardized toxicity testing guidelines for pharmaceutical compounds in wild organisms. Paracetamol toxicity can be modulated by unpredictable physiological conditions that might compromise extrapolations and comparisons of responsiveness among species. The ecological relevance of data obtained from classical tests for this compound is further discussed. PMID- 24949900 TI - Continuous colorimetric screening assay for detection of d-amino acid aminotransferase mutants displaying altered substrate specificity. AB - D-Amino acid aminotransferase (DAAT) catalyzes the synthesis of numerous d-amino acids, making it an attractive biocatalyst for the production of enantiopure d amino acids. To bolster its biocatalytic applicability, improved variants displaying increased activity toward non-native substrates are desired. Here, we report the development of a high-throughput, colorimetric, continuous coupled enzyme assay for the screening of DAAT mutant libraries that is based on the use of d-amino acid oxidase (DAAO). In this assay, the d-amino acid product of DAAT is oxidized by DAAO with concomitant release of hydrogen peroxide, which is detected colorimetrically by the addition of horseradish peroxidase and o dianisidine. Using this assay, we measured apparent KM and kcat values for DAAT and identified mutants displaying altered substrate specificity via the screening of cell lysates in 96-well plates. The DAAO coupled assay is sensitive in that it allowed the detection of a DAAT mutant displaying an approximately 2000-fold decrease in kcat/KM relative to wild type. In addition, the DAAO assay enabled the identification of two DAAT mutants (V33Y and V33G) that are more efficient than wild type at transaminating the non-native acceptor phenylpyruvate. We expect that this assay will be useful for the engineering of additional mutants displaying increased activity toward non-native substrates. PMID- 24949902 TI - Adaptive remodeling at the pedicle due to pars fracture: a finite element analysis study. AB - OBJECT: Spondylolysis is a common condition among the general population and a major cause of back pain in young athletes. This condition can be difficult to detect with plain radiography and has been reported to lead to contralateral pars fracture or pedicle fracture in the terminal stages. Interestingly, some patients with late-stage spondylolysis are observed to have radiographic or CT evidence of a sclerotic pedicle on the side contralateral to the spondylolysis. Although computational studies have shown stress elevation in the contralateral pedicle after a pars fracture, it is not known if these changes would cause sclerotic changes in the contralateral pedicle. The objective of this study was to investigate the adaptive remodeling process at the pedicle due to a contralateral spondylolysis using finite element analysis. METHODS: A multiscale finite element model of a vertebra was obtained by combining a continuum model of the posterior elements with a voxel-based pedicle section. Extension loading conditions were applied with or without a fracture at the contralateral pars to analyze the stresses in the contralateral pedicle. A remodeling algorithm was used to simulate and assess density changes in the contralateral pedicle. RESULTS: The remodeling algorithm demonstrated an increase in bone formation around the perimeter of the contralateral pedicle with some localized loss of mass in the region of cancellous bone. CONCLUSIONS: The authors' results indicated that a pars fracture results in sclerotic changes in the contralateral pedicle. Such a remodeling process could increase overall bone mass. However, focal bone loss in the region of the cancellous bone of the pedicle might predispose the pedicle to microfractures. This phenomenon explains, at least in part, the origin of pedicle stress fractures in the sclerotic contralateral pedicles of patients with unilateral spondylolysis. PMID- 24949901 TI - A mass spectrometry-based approach to host cell protein identification and its application in a comparability exercise. AB - Host cell proteins (HCPs) are process-related impurities present in biopharmaceuticals and are generally considered to be critical quality attributes. Changes in a biopharmaceutical production process may result in qualitative shifts in the HCP population. These shifts are not necessarily detectable when overall HCP levels are measured with traditional approaches such as enzyme-linked immunosorbent assays (ELISAs). Thus, the development of techniques that complement the ELISA's functionality is desirable. Here, a mass spectrometry (MS)-based approach for the analysis of HCP populations in biopharmaceuticals is presented. It consists of (i) the generation of exclusion lists that represent the masses of the active pharmaceutical ingredient (API), (ii) the compilation of inclusion lists based on an HCP catalog derived from the analysis of protein A-purified samples, and (iii) the analysis of purified biopharmaceuticals using the generated exclusion and inclusion lists. With this approach, it was possible to increase sensitivity for HCP detection compared with a standard liquid chromatography tandem MS (LC-MS/MS) run. The workflow was successfully implemented in a comparability exercise assessing HCP populations in drug substance samples before and after a process change. Furthermore, the results suggest that size can be an important factor in the copurification of HCPs and API. PMID- 24949903 TI - Biomechanical evaluation of a simulated T-9 burst fracture of the thoracic spine with an intact rib cage. AB - OBJECT: Classic biomechanical models have used thoracic spines disarticulated from the rib cage, but the biomechanical influence of the rib cage on fracture biomechanics has not been investigated. The well-accepted construct for stabilizing midthoracic fractures is posterior instrumentation 3 levels above and 2 levels below the injury. Short-segment fixation failure in thoracolumbar burst fractures has led to kyphosis and implant failure when anterior column support is lacking. Whether shorter constructs are viable in the midthoracic spine is a point of controversy. The objective of this study was the biomechanical evaluation of a burst fracture at T-9 with an intact rib cage using different fixation constructs for stabilizing the spine. METHODS: A total of 8 human cadaveric spines (C7-L1) with intact rib cages were used in this study. The range of motion (ROM) between T-8 and T-10 was the outcome measure. A robotic spine testing system was programmed to apply pure moment loads (+/- 5 Nm) in lateral bending, flexion-extension, and axial rotation to whole thoracic specimens. Intersegmental rotations were measured using an optoelectronic system. Flexibility tests were conducted on intact specimens, then sequentially after surgically induced fracture at T-9, and after each of 4 fixation construct patterns. The 4 construct patterns were sequentially tested in a nondestructive protocol, as follows: 1) 3 above/2 below (3A/2B); 2) 1 above/1 below (1A/1B); 3) 1 above/1 below with vertebral body augmentation (1A/1B w/VA); and 4) vertebral body augmentation with no posterior instrumentation (VA). A repeated-measures ANOVA was used to compare the segmental motion between T-8 and T-10 vertebrae. RESULTS: Mean ROM increased by 86%, 151%, and 31% after fracture in lateral bending, flexion-extension, and axial rotation, respectively. In lateral bending, there was significant reduction compared with intact controls for all 3 instrumented constructs: 3A/2B (-92%, p = 0.0004), 1A/1B (-63%, p = 0.0132), and 1A/1B w/VA (-66%, p = 0.0150). In flexion-extension, only the 3A/2B pattern showed a significant reduction (-90%, p = 0.011). In axial rotation, motion was significantly reduced for the 3 instrumented constructs: 3A/2B (-66%, p = 0.0001), 1A/1B (-53%, p = 0.0001), and 1A/1B w/VA (-51%, p = 0.0002). Between the 4 construct patterns, the 3 instrumented constructs (3A/2B, 1A/1B, and 1A/1B w/VA) showed comparable stability in all 3 motion planes. CONCLUSIONS: This study showed no significant difference in the stability of the 3 instrumented constructs tested when the rib cage is intact. Fractures that might appear more grossly unstable when tested in the disarticulated spine may be bolstered by the ribs. This may affect the extent of segmental spinal instrumentation needed to restore stability in some spine injuries. While these initial findings suggest that shorter constructs may adequately stabilize the spine in this fracture model, further study is needed before these results can be extrapolated to clinical application. PMID- 24949904 TI - Leakage detection on CT myelography for targeted epidural blood patch in spontaneous cerebrospinal fluid leaks: calcified or ossified spinal lesions ventral to the thecal sac. AB - OBJECT: The purpose of this study was to describe significant CT myelography findings for determination of the leak site and outcome of targeted epidural blood patch (EBP) in patients with spontaneous CSF leaks. METHODS: During 2005 2013, spontaneous CSF leaks were diagnosed for 12 patients with orthostatic headaches. The patients received targeted EBP on the basis of CT myelography assessments. RESULTS: Computed tomography myelograms revealed ventral extradural collection of contrast medium distributed over multiple spinal levels (average 16 levels). Intraforaminal contrast medium extravasations were observed at multiple spinal levels (average 8.2 levels). For 8 (67%) of 12 patients, spinal lesions were noted around the thecal sac and included calcified discs with osteophytes, an ossified posterior longitudinal ligament, and an ossified yellow ligament; lesions were mostly located ventral to the thecal sac and were in close contact with the dura mater. The levels of these spinal lesions were considered potential leak sites and were targeted for EBP. For the remaining 4 patients who did not have definite spinal lesions around the thecal sac, leak site determination was based primarily on the contrast gradient hypothesis. The authors hypothesized that the concentration of extradural contrast medium would be the greatest and the same as that of intradural contrast medium at the leak site but that it would decrease with increased distance from the leak site according to the contrast gradient. Epidural blood patch was placed at the level of spinal lesions and/or of the greatest and same concentration of contrast medium between the intradural and extradural spaces. For 10 of the 12 patients, the orthostatic headaches decreased significantly within a week of EBP and disappeared within a month. For the remaining 2 patients, headaches persisted and medical treatment was required for several months. For 3 patients, thick chronic subdural hematomas caused severe headaches and/or disturbed consciousness because of the mass effect of the hematomas, which were removed by bur hole drainage surgery. For 1 patient, bur hole drainage before EBP on the day of admission to hospital resulted in subdural tension pneumocephalus. The patient's headache immediately disappeared after EBP, and the hematoma did not recur. The other 2 patients underwent EBP followed by bur hole drainage, which resulted in improvements and disappearance of the hematomas. Over the follow-up period (mean 39 months), no CSF leaks or chronic subdural hematomas had recurred in any patient after EBP; by the final follow-up visit, all patients had returned to their jobs. CONCLUSIONS: The most significant finding of this study was that spinal ventral calcified or ossified lesions, which may be associated with a dural tear, were present in approximately 70% of patients. Targeted EBP to these lesions resulted in good outcomes. PMID- 24949905 TI - Recombinant human bone morphogenetic protein-2-induced ossification of the ligamentum flavum in rats and the associated global modification of histone H3. AB - OBJECT: The primary object of this investigation was to study recombinant human bone morphogenetic protein-2 (rhBMP-2)-induced ossification of the ligamentum flavum and associated histone H3 modification in a rat model. In an additional set of studies the authors investigated spinal cord and behavioral changes in the same model. METHODS: The authors report on 2 separate sets of studies. A total of 90 rats were used for the 2 sets of studies (45 each); in each study, a lyophilized rhBMP-2 and collagen mixture (20 MUg rhBMP-2 and 200 MUl collagen) was implanted in the lumbar extradural space in 18 rats; another 18 animals were used for a sham-operation control group and underwent implantation of lyophilized collagen without rhBMP-2 at the same level; an additional 9 animals were used as untreated controls. Lumbar spinal samples were harvested from the rhBMP-2 groups and the shamoperation control groups at 1 week, 3 weeks, and 9 weeks after the operation. Samples were also obtained from untreated controls at the same time points. All samples were scanned using micro-CT and then made into paraffinembedded sections. The sections from the first set of 45 rats were stained using elastica van Gieson and toluidine blue, and the expression of histone modifications (H3K9ac, H3K18ac, H3K4me3, and H3K36me3) and osteogenic transcription factors (osterix, Runx2) was detected by immunohistochemistry. In the second set of studies, hindlimb motor function was assessed at 1 week, 3 weeks, and 9 weeks after surgery. After behavioral evaluation, samples were harvested, scanned using micro-CT, and then made into paraffin-embedded sections. The sections were stained using Luxol fast blue. The expression of NeuN was also detected using immunohistochemistry. RESULTS: Ossification was seen in the rhBMP 2 group from 1 week after insertion, and the volume of ossified mass increased at 3 and 9 weeks. There was no ossification seen in the sham-surgery and normal controls. The pathological changes of ossification involved ligament degeneration, cartilage formation, and, finally, bone replacement. Spinal cord evaluation showed a significant decrease in white matter content and number of neurons at 9 weeks after operation in the rhBMP-2-treated group (compared with findings in the sham-surgery and control groups as well as findings at the earlier time points in the rhBMP-2 group). Using immunohistochemical staining, histone modifications (H3K9ac, H3K18ac, H3K4me3, and H3K36me3) and osteogenic transcription factors (osterix, Runx2) all were found to be expressed in the fibrocartilage area of the rat ossified ligamentum flavum samples (rhBMP2 group). CONCLUSIONS: This rhBMP-2-induced OLF is a typical endochondral ossification, which is similar to clinical OLF. The compressed spinal cord around the ossification site showed signs of a chronic degenerative process. Histone H3 modifications (H3K9ac, H3K18ac, H3K4me3, and H3K36me3) may play an important role in OLF. PMID- 24949906 TI - Spondylolysis outcomes in adolescents after direct screw repair of the pars interarticularis. AB - OBJECT: Isthmic spondylolysis can significantly decrease functional abilities, especially in adolescent athletes. Although treatment can range from observation to surgery, direct screw placement through the fractured pars, or Buck's procedure, may be a more minimally invasive procedure than the more common pedicle screw-hook construct. METHODS: Review of surgical databases identified 16 consecutive patients treated with Buck's procedure from 2004 to 2010. Twelve patients were treated at Miami Children's Hospital and 4 at Barrow Neurological Institute. Demographics and clinical and radiographic outcomes were recorded and analyzed retrospectively. RESULTS: The 16 patients had a median age of 16 years, and 14 were 20 years or younger at the time of treatment. Symptoms included axial back pain in 100% of patients with concomitant radiculopathy in 38%. Pars defects were bilateral in 81% and unilateral in 19% for a total of 29 pars defects treated using Buck's procedure. Autograft or allograft augmented with recombinant human bone morphogenetic protein as well as postoperative bracing was used in all cases. Postoperatively, symptoms resolved completely or partially in 15 patients (94%). Of 29 pars defects, healing was observed in 26 (89.6%) prior to 1 revision surgery, and an overall fusion rate of 97% was observed at last radiological follow-up. There were no implant failures. All 8 athletes in this group had returned to play at last follow-up. CONCLUSIONS: Direct screw repair of the pars interarticularis defect as described in this series may provide a more minimally invasive treatment of adolescent patients with satisfactory clinical and radiological outcomes, including return to play of adolescent athletes. PMID- 24949908 TI - Clinical effectiveness and cost-effectiveness of Internet- vs. group-based cognitive behavior therapy for social anxiety disorder: 4-year follow-up of a randomized trial. AB - Social anxiety disorder (SAD) is common, debilitating and associated with high societal costs. The disorder can be effectively treated with Internet-based cognitive behavior therapy (ICBT), but no previous study has investigated the long-term clinical or health economic effects of ICBT for SAD in comparison to an evidence-based control treatment. The aim of the study was to investigate the clinical effectiveness and cost-effectiveness of ICBT compared to cognitive behavioral group therapy (CBGT) four years post-treatment. We conducted a 4-year follow-up study of participants who had received ICBT or CBGT for SAD within the context of a randomized controlled non-inferiority trial. The cost-effectiveness analyses were conducted taking a societal perspective. Participants in both treatment groups made large improvements from baseline to 4-year follow-up on the primary outcome measure (d = 1.34-1.48) and the 95% CI of the mean difference on the primary outcome was well within the non-inferiority margin. ICBT and CBGT were similarly cost-effective and both groups reduced their indirect costs. We conclude that ICBT for SAD yields large sustainable effects and is at least as long-term effective as CBGT. Intervention costs of both treatments are offset by net societal cost reductions in a short time. PMID- 24949909 TI - A unique copper-catalyzed cross-coupling reaction by hydrogen (H2) removal for the stereoselective synthesis of 3-phosphoindoles. AB - The first Cu(i)-catalyzed cross-coupling reaction by hydrogen (H2) removal for the stereoselective synthesis of 3-phosphoindoles is reported. Going beyond the oxidative dehydrogenative coupling reactions reported recently, this reaction completely omits the oxidant and base, producing hydrogen (H2) as the only byproduct. PMID- 24949907 TI - The effects of an anxiety sensitivity intervention on anxiety, depression, and worry: mediation through affect tolerances. AB - Recently there has been increased interest in emotional and physical tolerance risk factors for mood and anxiety disorders. Three tolerance risk factors that have been shown to be related are anxiety sensitivity (AS), distress tolerance (DT), and discomfort intolerance (DI). Although previous research has demonstrated these constructs are malleable, no research has investigated the effects of an AS intervention on DT or DI. Further, no studies have investigated whether changes in DT or DI play a role in mood and anxiety symptom amelioration due to an AS intervention. Participants (N = 104), who were selected for elevated levels of AS, completed a single-session computer-assisted AS intervention or a control intervention and follow-up assessments at 1-week and 1-month post intervention. Results revealed that the intervention reduced AS and increased DT, but did not affect DI at the 1-week follow-up. Mediation analyses revealed that changes in AS and DT both mediated changes in symptoms (depression, anxiety, worry) due to the intervention at 1-month follow-up, however, when AS and DT were considered in the same model only the effect via AS remained significant. These results have important implications for the nature of the relationships between AS, DT, and DI as well as the specific mechanistic pathways through which an AS intervention ameliorates symptoms. PMID- 24949910 TI - Evaluation of salivary total oxidant-antioxidant status and DNA damage of children undergoing fixed orthodontic therapy. AB - OBJECTIVE: To determine the total oxidant status (TOS), total antioxidant status (TAS), and the 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and their interrelationship in the saliva of children undergoing fixed orthodontic therapy. MATERIALS AND METHODS: Thirty children were randomly divided into three groups. The attachments were bonded to all of the teeth using three different orthodontic composites: Transbond XT, Kurasper F, and GrenGloo. The salivary levels of TOS, TAS, and 8-OHdG were determined three times, as follows: before treatment (T1) and at 1 month (T2) and 3 months (T3) following appliance placement. All data were statistically analyzed. RESULTS: There were no significant differences in TOS, TAS, and 8-OHdG within the same time periods among the three different orthodontic composites (P > .05). TAS in all composite groups decreased over time. These decreases were found to be significant for Kurasper F and GrenGloo at the T1-T3 and T2-T3 time periods (P < .05). In all composite groups 8-OHdG decreased between T1 and T2 (P < .05). However, 8-OHdG in all composite groups increased from T2 to T3. These differences in 8-OHdG were significant in Kurasper F and GrenGloo (P < .05). CONCLUSIONS: Fixed orthodontic appliances bonded with the tested composites did not increase the cytotoxicity markers in saliva. PMID- 24949912 TI - Advanced multiresponsive comploids: from design to possible applications. AB - We extend the commonly used synthesis strategies for responsive microgels to the design of novel multiresponsive and multifunctional nanoparticles that combine inorganic magnetic, metallic/catalytic and thermoresponsive organic moieties. Magnetic responsiveness is implemented through the integration of silica-coated maghemite nanoparticles into fluorescently labeled crosslinked poly(N isopropylmethacrylamide) microgels. These particles are then employed as templates for the in situ reduction of catalytically active gold nanoparticles. In order to tune the reactivity of the catalyst through a thermally controlled barrier, an additional layer of crosslinked poly(N-isopropylacrylamide) is added in the final step. We subsequently demonstrate that these particles can be employed as smart catalysts. We show that the thermoresponsive nature of the outer particle shell not only provides control over the catalytic activity, but when combined with a magnetic core allows for very efficient removal of the catalytic system through temperature-controlled reversible coagulation and subsequent magnetophoresis in an applied magnetic field gradient. We finally discuss the use of this design principle for the synthesis of complex hybrid particles for various applications that would all profit from their multiresponsive and multifunctional nature. PMID- 24949911 TI - Chiral dicarboxamide scaffolds containing a sulfiliminyl moiety as potential ryanodine receptor activators. AB - To search for new environmentally benign insecticides with high activity, low toxicity, and low residue, novel chiral configurations introduced into dicarboxamide scaffolds containing N-cyano sulfiliminyl moieties were first studied. Four series of phthalamides with sulfur-containing side chains were designed, synthesized, and evaluated against oriental armyworm (Pseudaletia separata Walker) and diamondback moth (Plutella xylostella (L.)) for their insecticidal activities. All structures were characterized by (1)H NMR, (13)C NMR, and HRMS (or elemental analysis), and their configurations were confirmed by optical polarimetry. The biological assessment indicated that some title compounds exhibited significant insecticidal activities. For oriental armyworm, these stereoisomers exerted different impacts on biological activity following the sequence (Sc, Ss) >= (Sc, Rs) ? (Rc, Ss) > (Rc, Rs), and carbon chirality influenced the activities more strongly than sulfur. Compounds Ia and IIa reached as high an activity as commercial flubendiamide, with LC50 values of 0.0504 and 0.0699 mg L(-1), respectively, lower than that of flubendiamide (0.1230 mg L( 1)). For diamondback moth, the sequence of activity was (Sc, Ss) > (Sc, Rs), and the sulfur chirality influenced the activities more greatly than carbon. Compound IIe exhibited even higher activity than flubendiamide, whereas Ie and Ic,d reached the activity of the latter. The results indicated that the improvement of insecticidal activity probably required a coordination of both carbon and sulfur chirality. Comparative molecular field analysis calculation indicated that stereoisomers with Sc configurations containing strong electron-withdrawing groups such as as CN are important in maintaining the high activity. The chiral scaffolds containing the N-cyano sulfiliminyl moiety are also essential for high larvicidal activity. Some title compounds could be considered as potential candidates for ryanodine receptor activators. PMID- 24949915 TI - Multicenter evaluation of renography with an automated physical phantom. AB - PURPOSE: The diversity of the dynamic radionuclide renal imaging (renography) study protocols sets challenges for the overall study quality, therefore raising a need for national quality control. The aim of this study was to encourage the standardization of renography in Finland and to evaluate the development after a previous study performed in 1997. METHODS: The new Heikkinen phantom was imaged in each of the 20 participating nuclear medicine laboratories. The results were interpreted in the manner of a regular patient study, and reconstructions and printouts were made according to the clinical routines of each laboratory. Four quantitative parameters were calculated and compared between laboratories. The reports were also assessed in a blind test. RESULTS: The average error in T(max) values ranged from -5 to 7% (-29 to +18% in 1997), in T(1/2) from 0 to 35% (-43 to +66%), in RCA20 from -20 to +28% (-50 to +82%) and in relative uptake from -3 to 5%. The difference from average in relative uptake ranged from -4 to 5% (-21 to +36%). CONCLUSION: The results showed that the errors in T(max) and relative uptake were generally within quite acceptable margins, and the variation in quantitative parameters between laboratories was shown to be smaller than 14 years earlier. The reason might be the use of new software packages as well as increased efforts to improve the quality of the studies. PMID- 24949916 TI - A new PET resolution measurement method through Monte-Carlo simulations. AB - OBJECTIVE: The aim of this study was to propose a novel method for image quality assessment in PET scanners through estimation of the modulation transfer function (MTF) of a plane source. The simulation was implemented using the previously validated Monte-Carlo model. A comparison of the proposed method with the more traditional technique, based on a line source, was also performed. MATERIALS AND METHODS: The Geant4 application for tomographic emission (GATE) Monte-Carlo package was used for model development, and reconstructed images were obtained using software for tomographic image reconstruction (STIR) with cluster computing. A novel plane source consisting of a radioactive ((18)F fluorodeoxyglucose) thin-layer chromatography plate was simulated (total source activity: 44.4 MBq) to assess image quality through the MTF. All images were reconstructed with the three-dimensional filtered back projection (FBP3DRP) and ordered-subsets expectation maximization (OSEM) reprojection algorithms. RESULTS: The MTFs obtained using ordered-subsets expectation maximization show, in all cases, that higher frequencies are preserved compared with those obtained using the FBP3DRP. In addition, the plane source method is less prone to noise than the conventional line source method (SD=0.0031 and 0.0203, respectively). CONCLUSION: The thin-layer chromatography-based plane source presented requires materials commonly found in a clinical environment and could be used to assess image quality in nuclear medicine departments and to further develop PET and single photon emission computed tomography scanners through Monte-Carlo simulations. PMID- 24949913 TI - Vascular L-type Ca2+ channel blocking activity of sulfur-containing indole alkaloids from Glycosmis petelotii. AB - In the search for novel natural compounds endowed with potential antihypertensive activity, a new sulfur-containing indole alkaloid, N-demethylglypetelotine (2), and its known analogue glypetelotine (1), were isolated from the leaves of Glycosmis petelotii. Their structures were established on the basis of spectroscopic evidence. The two alkaloids were assessed for vasorelaxing activity on rat aorta rings and for L-type Ba(2+) current [I(Ba(L))] blocking activity on single myocytes isolated from rat tail artery. Both glypetelotine and N demethylglypetelotine inhibited phenylephrine-induced contraction with IC50 values of 20 and 50 MUM, respectively. The presence of endothelium did not modify their spasmolytic effect. Neither glypetelotine nor N-demethylglypetelotine affected Ca(2+) release from the sarcoplasmic reticulum induced by phenylephrine. The spasmolytic effect of glypetelotine increased with membrane depolarization. In the presence of 60 mM K(+), both compounds inhibited, in a concentration dependent manner, the contraction induced by cumulative addition of Ca(2+), this inhibition being inversely related to Ca(2+) concentration. Glypetelotine and, less efficiently N-demethylglypetelotine, inhibited I(Ba(L)), the former compound also affecting I(Ba(L)) kinetics. In conclusion, glypetelotine is a novel vasorelaxing agent which antagonizes L-type Ca(2+) channels. PMID- 24949919 TI - Measurement of radionuclide activities induced in target components of an IBA CYCLONE 18/9 by gamma-ray spectrometry with HPGe and LaBr3: Ce detectors. AB - Cyclotrons are used worldwide to produce radiopharmaceuticals by proton irradiation of a suitable target. The intense secondary neutron beam generated by proton interactions with the target induce high radionuclide activities in the target assembly parts that may result in an exposure to high dose levels of the operators during maintenance. The main goal of this work is to evaluate gamma emitting radionuclide activities induced in Havar foils and titanium windows of a target assembly and carousel stripper forks of an IBA CYCLONE 18/9 cyclotron. The knowledge of radionuclide inventory for each component is required by many companies to assess risk for operators before waste handling and disposal. Gamma ray spectrometric analyses were carried out with High Purity Germanium (HPGe) and Lanthanum bromide (LaBr3:Ce) scintillation detectors. HPGe is the most used detector for its high energy resolution although it is more suitable for use in a laboratory. The use of LaBr3:Ce can be considered a viable option, particularly in realizing a portable spectrometric system to perform "on-site" measurements and a fast dose rate evaluation before the disposal of activated parts. Due to a high activity of target assembly components replaced after a typical irradiation cycle (about 5000 MUAh integrated beam current), gamma-ray spectrometric measurements were performed at a large distance from the detector, even more than 100 cm, or by using a purposely realized Lead-walled collimator. The identification of some key-radionuclides allows to evaluate through simple formulations the dose rate behavior for each component as function of decay time from the last irradiation. The knowledge of the dose rate behavior is a significant piece of information to health physicists for waste handling with safety at work. For an HavarTM foil, the dose rate will be reduced to about 1/1,000 of the starting value after a decay period of approximately 4 y (about 1,500 d), with a relatively safety at product disposal work. For a longer time, only long-lived radionuclides (57)Co, (60)Co, and (54)Mn contribute to dose rate. PMID- 24949918 TI - RSO interview with Jennifer Cerecero. PMID- 24949917 TI - The role of Ki-67 in the proliferation and prognosis of breast cancer molecular classification subtypes. AB - The Ki-67 antigen was identified in the early steps of polymerase I-dependent ribosomal RNA synthesis. Although it seems that this protein has an important function in cell division, its exact role is still unclear and there is little published work on its overall function. The aim of the present study was to evaluate the contribution of the level of Ki-67 with respect to tumor recurrence in molecularly classified groups of breast cancer patients. Ki-67 was divided into the percentage levels up to and including 20% and over 20%. Immunohistochemistry and fluorescence in-situ hybridization are described for the results of estrogen receptor, progesterone receptor, c-erb-B2, and Ki-67 biomarkers. Formaldehyde-fixed breast samples were paraffin wax embedded and processed for paraffin sections. The protocol of the present study started in 1995 and finished in 2010. Nine hundred and sixteen patients with breast cancer were examined: 291 were grouped as luminal A, 228 as luminal B, 221 as the Her-2 subtype, and 107 as basal cell (triple negative). Follow-up ranged from 3 to 15 years following diagnosis. It was found that in luminal A patients, only one had a Ki-67 level higher than 20%. In luminal B, the Ki-67 was higher than 20% in 51.16% of the patients and recurrence occurred in 23.68%. In the Her-2 subtype, the Ki-67 level was more than 20% in 48.63%. In basal cell triple-negative patients, Ki-67 was more than 20% in 63.86%. The data presented here indicate that the level of Ki-67 may be considered one of the valuable biomarkers in breast cancer patients with respect to process and recurrence. PMID- 24949920 TI - An updated radiation protection program prospectus based on 20 years of data describing program drivers and activities. AB - In 1992, the University of Texas Health Science Center at Houston (UTHSCH) Radiation Safety Program began assembling data on a monthly basis that described various program drivers and associated activities. At the end of calendar year 2002, a decade of data had been collected, so the information was summarized into a novel program prospectus, displaying various program indicator parameters in a format similar to that used in a commercial enterprise prospectus provided to potential investors. The consistent formatting of the data afforded a succinct and easily digestible snapshot of program activities and trends. Feedback from various program stakeholders, even those unfamiliar with radiation safety matters, was overwhelmingly positive. By the end of 2012, a total of 20 years of data had been collected, so an updated and slightly modified prospectus was created. The summary document has helped to describe the drivers of the program, revealed some interesting trends, and has aided in maintaining program support even in challenging economic times. The data summary has also proved to be useful in making future projections regarding program needs. PMID- 24949921 TI - Measurement of activity distribution using photostimulable phosphor imaging plates in decommissioned 10 MV medical linear accelerator. AB - Photonuclear reactions generate neutrons in the head of the linear accelerator. Therefore, some parts of the linear accelerator can become activated. Such activated materials must be handled as radioactive waste. The authors attempted to investigate the distribution of induced radioactivity using photostimulable phosphor imaging plates. Autoradiographs were produced from some parts of the linear accelerator (the target, upper jaw, multileaf collimator and shielding). The levels of induced radioactivity were confirmed to be non-uniform within each part from the autoradiographs. The method was a simple and highly sensitive approach to evaluating the relative degree of activation of the linear accelerators, so that appropriate materials management procedures can be carried out. PMID- 24949922 TI - Internal contamination of an irradiator discovered during security enhancement. AB - High-risk radioactive sources regulated under Increased Controls Regulations have been protected by licensed facilities, but the federal government has placed significant emphasis on these sources and has developed initiatives to assist radioactive material licensees. The Department of Energy's Global Threat Reduction Initiative (GTRI) Domestic Threat Reduction Program is a voluntary federally funded program for security enhancements of high-risk radiological material. During the hardening or security enhancement process by the United States Department of Energy (U.S. DOE) contractors, a small amount of radioactive contamination was discovered in a Cesium irradiator. Ultimately, it was decided to pursue disposal with U.S. DOE's Off-Site Recovery Program (OSRP). Radiological devices may have a leaking source or known internal contamination that may cause difficulty during security enhancement. If the licensee understands this, it may provide facilities the opportunity to plan and prepare for unusual circumstances. PMID- 24949924 TI - N-Acyl Chain in Ceramide and Sphingomyelin Determines Their Mixing Behavior, Phase State, and Surface Topography in Langmuir Films. AB - Sphingolipids are membrane lipids composed by a long chain aminediol base, usually sphingosine, with a N-linked fatty acyl chain whose quality depends on the membrane type. The effect of length and unsaturation of the N-acyl chain on the mixing behavior of different sphingolipids has scarcely been studied, and in this work this issue is addressed employing Langmuir monolayers at the air-water interface, in order to assess the surface mixing in binary mixtures of different species of sphingomyelins and ceramides. The dependence on the monolayer composition of the mean molecular area, perpendicular dipole moment, domain segregation, and surface topography, as well as the film elasticity and optical thickness were studied. The results indicate that composition-dependent favorable interactions among sphingomyelin and ceramide occur as a consequence of complementary lateral packing and increased acyl chain ordering; the phase state of the components appears as a major factor determining miscibility among sphingomyelins and ceramides even in cases where the lipids have a considerable hydrocarbon chain length mismatch. PMID- 24949923 TI - Exposure levels associated with Na(131)I thyroid cancer patients: correlation with initial activity and clinical physical parameters. AB - Initial radiation exposure levels X (0) at 1 m from the navel of thyroid cancer patients were measured for 165 individuals at the time of ingestion. Some 61 patients had previously signed informed consent so only those patients could be assayed with regard to body parameters. While the activity was in the stomach, resultant X (0) values were seen to be linearly correlated with the total (131)I activity (A) given orally. Yet large differences in X (0) were seen; e.g., at A = 7.4 GBq, variations of a factor of four were found between the largest and smallest exposure rates. Correlation analyses were performed between normalized rate X (0)A-1 and several patient physical parameters. These included age, sex, height, weight, and BMI (body mass index). Only weight and BMI had significant linear correlation (p < 0.05) with normalized exposure rate. In the former case, the correlation coefficient rho (weight) was -0.296 (p = 0.02). Using BMI as the independent variable, rho (BMI) was -0.386 (p = 0.0021). With further analysis of the BMI variation, 95% confidence intervals could be determined at various BMI levels. For example, at 28 kg m(-2), the normalized rate varied between 0.039 and 0.0446 MUGy h(-1) MBq(-1)-approximately a +/-6.5% variation on the mean value of 0.0419 MUGy h(-1) MBq(-1) at this BMI. Given such clinical information, differences in normalized exposure rate can be reduced to values on the order of +/-10% or less for BMI values over the clinically relevant interval 20 to 40 kg m(-2). PMID- 24949925 TI - Rwandan young people's perceptions on sexuality and relationships: results from a qualitative study using the 'mailbox technique'. AB - This study aimed to gain more insight into young Rwandans' perceptions on sex and relationships, which is essential for formulating effective sexual and reproductive health (SRH) promotion interventions. Using a 'mailbox technique', this paper studies the spontaneous thoughts of Rwandan young people on sexuality. Mailboxes were installed in five secondary schools in the Bugesera district and students were invited to write about their ideas, secrets, wishes, desires and fears on sexuality and relationships. Of the 186 letters collected, 154 addressed SRH topics. The letters were analysed in NVivo 9 using a theoretical model on vulnerability. Two stereotypical sexual interactions co-exist: experimental sex, taking place unprepared, driven by desire among young people of the same age, and transactional sex, occurring after negotiation between older men/women and younger girls/boys in exchange for money or goods. Both types expose young people to poor, though different, SRH outcomes. Young people have little capacity to manage their vulnerability in these relationships: they have limited knowledge on SRH topics, lack adult guidance or support and have difficult access to condoms. They apply seemingly contradictory norms and behaviours concerning sexuality. In conclusion, we have formulated several recommendations for SRH interventions. PMID- 24949926 TI - Evidence for seasonal patterns in the relative abundance of avian influenza virus subtypes in blue-winged teal (Anas discors). AB - Seasonal dynamics of influenza A viruses (IAVs) are driven by host density and population immunity. Through an analysis of subtypic data for IAVs isolated from Blue-winged Teal (Anas discors), we present evidence for seasonal patterns in the relative abundance of viral subtypes in spring and summer/autumn. PMID- 24949927 TI - Surveillance of avian coronaviruses in wild bird populations of Korea. AB - We examined the role of wild birds in the epidemiology of avian coronaviruses by studying oropharyngeal swabs from 32 wild bird species. The 14 avian coronaviruses detected belonged to the gamma-coronaviruses and shared high nucleotide sequence identity with some previously identified strains in wild waterfowl, but not with infectious bronchitis viruses. PMID- 24949928 TI - Serum leptin as an indicator of fat levels in white-tailed deer (Odocoileus virginianus) in the southeastern USA. AB - Leptin is a hormone that plays a key role in regulating energy intake, appetite, and metabolism. In some mammals, leptin has been shown to circulate at levels proportional to body fat, which could make it useful for nonlethal evaluation of body condition. Leptin's usefulness for estimating fat levels (i.e., body condition) of white-tailed deer (Odocoileus virginianus) is unknown. We quantified serum leptin concentrations in a sample of free-ranging, female deer collected in July 2008 and March 2009 from coastal North Carolina, USA. We compared leptin concentrations with kidney fat index, femur marrow fat index, and kidney fat mass. Additionally, we assessed differences in leptin concentrations between the two seasons, lactating and nonlactating females, and gestating and nongestating females. Leptin concentrations were similar between seasons but were lower in lactating and gestating females. We did not detect significant relationships between leptin and the body fat metrics, indicating that leptin may have limited value for estimating fat reserves in white-tailed deer. PMID- 24949929 TI - Sensorineural hearing loss in very low birth weight infants with histological chorioamnionitis. AB - OBJECTIVE: Histological chorioamnionitis (HCAM) has been associated with inflammatory diseases of preterm infants. Recently we have observed that it increased the risk of speech delay and hearing loss. So the aim of this study was to evaluate the relationship between sensorineural hearing loss (SNHL) of VLBW infants and HCAM. METHODS: We performed an observational study on VLBW infants admitted to the NICU of Padua. Each patient with HCAM was matched with one control without HCAM. All infants underwent hearing screening before discharge by means of automated transient-evoked otoacustic emissions and automated auditory brainstem responses, which were repeated at 3 and 6 months of age with tympanometry measurement. Incidence of SNHL at 6 months of age was compared in the 2 groups and risk factors for hearing loss were studied. RESULTS: Two of 77 (2.6%) newborns with HCAM e 6/73 (8.2%) without it presented SNHL at 6 months of corrected age (p = 0.16). Multivariable logistic regression analysis identified surgical ligation of patent ductus arteriosus (PDA) as independent predictors of SNHL (OR: 5.75, 95% CI 1.34-24.84, p = 0.02), whereas the effect of HCAM on SNHL was only near to statistical significance level. CONCLUSIONS: Surgical ligation of PDA is associated with an increased risk of SNHL in VLBW infants, regardless of HCAM. PMID- 24949930 TI - Prediction of neonatal outcome in women with gestational hypertension or mild preeclampsia after 36 weeks of gestation. AB - BACKGROUND: There is little knowledge about neonatal complications in GH and PE and induction at term, we aim to assess whether they can be predicted from clinical data. METHODS: We used data of the HYPITAT trial and evaluated whether adverse neonatal outcome (Apgar score < 7, pH < 7.05, NICU admission) could be predicted from clinical data. Logistic regression, ROC analysis and calibration were used to identify predictors and evaluate the predictive capacity in an antepartum and intrapartum model. RESULTS: We included 1153 pregnancies, of whom 76 (6.6%) had adverse neonatal outcome. Parity (primipara OR 2.75), BMI (OR 1.06), proteinuria (dipstick +++ OR 2.5), uric acid (OR 1.4) and creatinine (OR 1.02) were independent antepartum predictors; In the intrapartum model, meconium stained amniotic fluid (OR 2.2), temperature (OR 1.8), duration of first stage of labour (OR 1.15), proteinuria (dipstick +++ OR 2.7), creatinine (OR 1.02) and uric acid (OR 1.5) were predictors of adverse neonatal outcome. Both models showed good discrimination (AUC 0.75 and 0.78), but calibration was limited (Hosmer-Lemeshow p = 0.41, and p = 0.20). CONCLUSIONS: In women with GH or PE at term, it is difficult to predict neonatal complications, possibly since they are rare in the term pregnancy. However, the identified individual predictors may guide physicians to anticipate requirements for neonatal care. PMID- 24949931 TI - Ultrasonographic visceral fat thickness measurement may be a good scan test for prediction of gestational diabetes mellitus. PMID- 24949932 TI - Neonatal hypoglycemia associated with the antenatal corticosteroids may be secondary to fetal adrenal suppression. PMID- 24949933 TI - FAR1 and FAR2 regulate the expression of genes associated with lipid metabolism in the rice blast fungus Magnaporthe oryzae. AB - The rice blast fungus Magnaporthe oryzae causes plant disease via specialised infection structures called appressoria. These dome-shaped cells are able to generate enormous internal pressure, which enables penetration of rice tissue by invasive hyphae. Previous studies have shown that mobilisation of lipid bodies and subsequent lipid metabolism are essential pre-requisites for successful appressorium-mediated plant infection, which requires autophagic recycling of the contents of germinated spores and germ tubes to the developing appressorium. Here, we set out to identify putative regulators of lipid metabolism in the rice blast fungus. We report the identification of FAR1 and FAR2, which encode highly conserved members of the Zn2-Cys6 family of transcriptional regulators. We generated Deltafar1, Deltafar2 and Deltafar1Deltafar2 double mutants in M. oryzae and show that these deletion mutants are deficient in growth on long chain fatty acids. In addition, Deltafar2 mutants are also unable to grow on acetate and short chain fatty acids. FAR1 and FAR2 are necessary for differential expression of genes involved in fatty acid beta-oxidation, acetyl-CoA translocation, peroxisomal biogenesis, and the glyoxylate cycle in response to the presence of lipids. Furthermore, FAR2 is necessary for expression of genes associated with acetyl-CoA synthesis. Interestingly, Deltafar1, Deltafar2 and Deltafar1Deltafar2 mutants show no observable delay or reduction in lipid body mobilisation during plant infection, suggesting that these transcriptional regulators control lipid substrate utilization by the fungus but not the mobilisation of intracellular lipid reserves during infection-related morphogenesis. PMID- 24949934 TI - The evolution of nonsteroidal antiestrogens to become selective estrogen receptor modulators. AB - The discovery of the first nonsteroidal antiestrogen ethamoxytriphetol (MER25) in 1958, opened the door to a wide range of clinical applications. However, the finding that ethamoxytriphetol was a "morning after" pill in laboratory animals, energized the pharmaceutical industry to discover more potent derivatives. In the wake of the enormous impact of the introduction of the oral contraceptive worldwide, contraceptive research was a central focus in the early 1960's. Numerous compounds were discovered e.g., clomiphene, nafoxidine, and tamoxifen, but the fact that clinical studies showed no contraceptive actions, but, in fact, induced ovulation, dampened enthusiasm for clinical development. Only clomiphene moved forward to pioneer an application to induce ovulation in subfertile women. The fact that all the compounds were antiestrogenic made an application in patients to treat estrogen responsive breast cancer, an obvious choice. However, toxicities and poor projected commercial returns severely retarded clinical development for two decades. In the 1970's a paradigm shift in the laboratory to advocate long term adjuvant tamoxifen treatment for early (non-metastatic) breast cancer changed medical care and dramatically increased survivorship. Tamoxifen pioneered that paradigm shift but it became the medicine of choice in a second paradigm shift for preventing breast cancer during the 1980's and 1990's. This was not surprising as it was the only medicine available and there was laboratory and clinical evidence for the eventual success of this application. Tamoxifen is the first medicine to be approved by the Food and Drug Administration (FDA) to reduce the risk of breast cancer in women at high risk. But it was the re evaluation of the toxicology of tamoxifen in the 1980's and the finding that there was both carcinogenic potential and a significant, but small, risk of endometrial cancer in postmenopausal women that led to a third paradigm shift to identify applications for selective estrogen receptor (ER) modulation. This idea was to establish a new group of medicines now called selective ER modulators (SERMs). Today there are 5 SERMs FDA approved (one other in Europe) for applications ranging from the reduction of breast cancer risk and osteoporosis to the reduction of menopausal hot flashes and improvements in dyspareunia and vaginal lubrication. This article charts the origins of the current path for progress in women's health with SERMs. PMID- 24949936 TI - Selective impairment of attentional networks of alerting in Wilson's disease. AB - Wilson's disease (WD) is typically affected by attention, which is one of the cognitive domains. The Attention Network Test (ANT) was developed to measure the functioning of the following three individual attentional networks: orienting, alerting, and executive control. The ANT has been used in a variety of neuropsychiatric conditions; however, it has not been used in WD. The aim of this study was to investigate the attentional function of WD patients, and 35 patients with early and moderate neurological WD, as well as 35 gender-, age-, and education-matched healthy controls performed the ANT. Remarkable differences between the patients and healthy controls were observed in the alerting network (p = 0.007) in contrast the differences in the orienting (p = 0.729) and executive control (p = 0.888) networks of visual attention. The mean reaction time in the ANT was significantly longer in the WD patients than in the controls (p<0.001, 0.001). In the WD patients, there was an effect specifically on the alerting domain of the attention network, whereas the orienting and executive control domains were not affected. PMID- 24949935 TI - Myogenic differential methylation: diverse associations with chromatin structure. AB - Employing a new algorithm for identifying differentially methylated regions (DMRs) from reduced representation bisulfite sequencing profiles, we identified 1972 hypermethylated and 3250 hypomethylated myogenic DMRs in a comparison of myoblasts (Mb) and myotubes (Mt) with 16 types of nonmuscle cell cultures. DMRs co-localized with a variety of chromatin structures, as deduced from ENCODE whole genome profiles. Myogenic hypomethylation was highly associated with both weak and strong enhancer-type chromatin, while hypermethylation was infrequently associated with enhancer-type chromatin. Both myogenic hypermethylation and hypomethylation often overlapped weak transcription-type chromatin and Polycomb repressed-type chromatin. For representative genes, we illustrate relationships between DNA methylation, the local chromatin state, DNaseI hypersensitivity, and gene expression. For example, MARVELD2 exhibited myogenic hypermethylation in transcription-type chromatin that overlapped a silenced promoter in Mb and Mt while TEAD4 had myogenic hypomethylation in intronic subregions displaying enhancer-type or transcription-type chromatin in these cells. For LSP1, alternative promoter usage and active promoter-type chromatin were linked to highly specific myogenic or lymphogenic hypomethylated DMRs. Lastly, despite its myogenesis-associated expression, TBX15 had multiple hypermethylated myogenic DMRs framing its promoter region. This could help explain why TBX15 was previously reported to be underexpressed and, unexpectedly, its promoter undermethylated in placentas exhibiting vascular intrauterine growth restriction. PMID- 24949937 TI - Impact of fatigue on outcome of selective serotonin reuptake inhibitor treatment: secondary analysis of STAR*D. AB - OBJECTIVE: To explore relationships between baseline and changes in fatigue during treatment with outcomes in patients with major depressive disorder (MDD) receiving citalopram monotherapy. RESEARCH DESIGN AND METHODS: Secondary analyses of data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Level 1 treatment phase (<=14 weeks citalopram monotherapy). Fatigue was assessed with item 14 on energy level from the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16; scored 0-3: 0 = no fatigue, 3 = maximal fatigue); prospective fatigue: assessment of fatigue at Level 1 entry and exit (no fatigue, treatment-emergent fatigue, remitted fatigue, or residual fatigue). CLINICAL TRIAL REGISTRATION: Http://clinicaltrials.gov, NCT00021528. MAIN OUTCOME MEASURES: Remission of depressive symptoms (17-item Hamilton Rating Scale for Depression <=7 or QIDS-SR16 <=5); Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form; Short-Form Health Survey Mental and Physical subscales; and Work and Social Adjustment Scale (WSAS). RESULTS: At baseline, of 2868 patients included in the analyses, 5.5% had a QIDS-SR16 item 14 score of 0; 22.9%, a score of 1; 53.6%, a score of 2; and 18.0%, a score of 3. During Level 1 treatment, 3.5% of patients had no prospective fatigue, 2.1% had treatment emergent fatigue, 33.6% had fatigue remitting during treatment, and 60.8% had residual fatigue. Female gender, unemployment, fewer years of education, and lower monthly income were significantly associated with higher rates of baseline fatigue (all P < 0.0001). Higher levels of baseline or prospective fatigue were associated with reduced likelihood of remission, decreased overall satisfaction (P < 0.0001), and reduced mental and physical function at outcome (P <= 0.05). Patients with higher baseline or prospective fatigue reported higher WSAS total scores (P < 0.0001), indicative of more severe functional impairment. CONCLUSIONS: Lower baseline fatigue and remission of fatigue during antidepressant treatment in patients with MDD are associated with higher rates of remission of depressive symptoms and better function and quality of life. Study limitations include use of the STAR*D Level 1 sample (citalopram as only antidepressant), use of a proxy measure of energy/fatigue (item 14 from the QIDS SR16), and the secondary post-hoc analysis design. PMID- 24949939 TI - Cdc42 is required in a genetically distinct subset of cardiac cells during Drosophila dorsal vessel closure. AB - The embryonic heart tube is formed by the migration and subsequent midline convergence of two bilateral heart fields. In Drosophila the heart fields are organized into two rows of cardioblasts (CBs). While morphogenesis of the dorsal ectoderm, which lies directly above the Drosophila dorsal vessel (DV), has been extensively characterized, the migration and concomitant fundamental factors facilitating DV formation remain poorly understood. Here we provide evidence that DV closure occurs at multiple independent points along the A-P axis of the embryo in a "buttoning" pattern, divergent from the zippering mechanism observed in the overlying epidermis during dorsal closure. Moreover, we demonstrate that a genetically distinct subset of CBs is programmed to make initial contact with the opposing row. To elucidate the cellular mechanisms underlying this process, we examined the role of Rho GTPases during cardiac migration using inhibitory and overexpression approaches. We found that Cdc42 shows striking cell-type specificity during DV formation. Disruption of Cdc42 function specifically prevents CBs that express the homeobox gene tinman from completing their dorsal migration, resulting in a failure to make connections with their partnering CBs. Conversely, neighboring CBs that express the orphan nuclear receptor, seven-up, are not sensitive to Cdc42 inhibition. Furthermore, this phenotype was specific to Cdc42 and was not observed upon perturbation of Rac or Rho function. Together with the observation that DV closure occurs through the initial contralateral pairing of tinman-expressing CBs, our studies suggest that the distinct buttoning mechanism we propose for DV closure is elaborated through signaling pathways regulating Cdc42 activity in this cell type. PMID- 24949940 TI - miR-365 promotes cutaneous squamous cell carcinoma (CSCC) through targeting nuclear factor I/B (NFIB). AB - Aberrant expression of microRNAs plays vital roles in tumor development and progression. As transcription factors (TFs) are the critical components of signaling cascades, specific targeting effects of microRNAs to specific TFs may determine the role of microRNAs in different cancers. In this study, we identified Nuclear Factor I/B (NFIB) as one of the targets of miR-365 which was previously verified as an onco-miR in cutaneous squamous cell carcinoma (CSCC). Down-regulation of NFIB was a general feature in both CSCC cell lines and tumors from patients which show drastically up-regulated miR-365 expression levels. The siRNA-based knockdown of NFIB mimic the carcinogenic transformation of normal cells by ectopically expression of miR-365 which indicates depletion of NFIB is necessary for miR-365 to exert its pro-carcinogenic function. NFIB may represent a functional barrier targeted by miR-365 to the development of CSCC. Further studies also discovered a conserved feedback regulatory circuitry formed by NFIB and miR-365 in CSCC development which may be potentially utilized as therapeutic target to improve the clinical CSCC treatment. PMID- 24949941 TI - The Handan Eye Study: comparison of screening methods for primary angle closure suspects in a rural Chinese population. AB - OBJECTIVE: To evaluate the van Herick test, anterior segment optical coherence tomography (AS-OCT), Pentacam and scanning peripheral anterior chamber depth analyzer (SPAC) for detecting primary angle-closure suspect (PACS) in a rural Chinese population. METHODS: Eligible subjects aged >=40 years were examined at the 5-year follow-up of the Handan Eye Study. PACS was defined as non-visibility of the posterior pigmented trabecular meshwork for >=180 degrees of the angle. Sensitivity, specificity, predictive values and receiver operating characteristic curves were used to assess the tests. RESULTS: A total of 425 right eyes of 431 eligible subjects were analyzed. The area under the curve (AUC) for the van Herick test and AS-OCT were 0.711 and 0.799, respectively. The AUC for Pentacam anterior chamber depth was 0.834, while anterior chamber angle and anterior chamber volume had AUCs of 0.680 and 0.800, respectively. The AUC for SPAC was 0.779. AS-OCT had a specificity of 87% with a sensitivity of 73%. The best specificity of 92% (sensitivity 19%) was achieved by the van Herrick test at the 15% cut-off. CONCLUSIONS: None of the tests evaluated achieved the combination of specificity and sensitivity needed for population-based screening and their current capability does not realize the objective of case detection in the setting of an ophthalmology clinic. PMID- 24949938 TI - Multiple tissue-specific requirements for the BMP antagonist Noggin in development of the mammalian craniofacial skeleton. AB - Proper morphogenesis is essential for both form and function of the mammalian craniofacial skeleton, which consists of more than twenty small cartilages and bones. Skeletal elements that support the oral cavity are derived from cranial neural crest cells (NCCs) that develop in the maxillary and mandibular buds of pharyngeal arch 1 (PA1). Bone Morphogenetic Protein (BMP) signaling has been implicated in most aspects of craniofacial skeletogenesis, including PA1 development. However, the roles of the BMP antagonist Noggin in formation of the craniofacial skeleton remain unclear, in part because of its multiple domains of expression during formative stages. Here we used a tissue-specific gene ablation approach to assess roles of Noggin (Nog) in two different tissue domains potentially relevant to mandibular and maxillary development. We found that the axial midline domain of Nog expression is critical to promote PA1 development in early stages, necessary for adequate outgrowth of the mandibular bud. Subsequently, Nog expression in NCCs regulates craniofacial cartilage and bone formation. Mice lacking Nog in NCCs have an enlarged mandible that results from increased cell proliferation in and around Meckel's cartilage. These mutants also show complete secondary cleft palate, most likely due to inhibition of posterior palatal shelf elevation by disrupted morphology of the developing skull base. Our findings demonstrate multiple roles of Noggin in different domains for craniofacial skeletogenesis, and suggest an indirect mechanism for secondary cleft palate in Nog mutants that may be relevant to human cleft palate as well. PMID- 24949942 TI - Oral exposure to the organophosphorus insecticide, Monocrotophos induces intestinal dysfunction in rats. AB - There is limited experimental evidence to imply the role of organophosphorus insecticides on intestinal dysfunctions. Residues of Monocrotophos (MCP), above maximum residue limits (MRL), have been reported in fruits and vegetables from various parts of India. Hence, in this study, we investigated the potential of MCP to induce intestinal dysfunction in rats. MCP was administered orally to rats at sublethal doses (0.45, 0.9 and 1.8 mg/kgb.w/d) for 30 days. MCP at the highest dose significantly increased the unit weight of the small intestine. MCP increased the activities of intestinal brush border disaccharidases, intestinal alkaline phosphatase, glycyl-glycine dipeptidase, and Na(+)/K(+)-ATPase while it decreased cholesterol: phospholipid ratio. Histology and scanning electron microscopy of small intestine of MCP treated rats revealed disruption in terms of congestion, increased length of villi, goblet cell hyperplasia, infiltration of inflammatory cells and necrotic villi tip. Further, the intestinal transit rate was found to be increased in MCP treated rats. Collectively, our findings provide evidence that repeated oral intake of MCP has the propensity to alter small intestinal structure and functions, which might lead to intestinal dysfunctions and abnormal nutrient uptake and thereby affect the human health. Although we have employed doses, which are higher than those likely to be encountered as residues, we speculate that further studies should be performed to determine whether MCP residues in foods in the long-term will interfere with the digestive capacity of the small intestine and thus exert adverse effects on the health of human. PMID- 24949943 TI - Hepatotoxicity and genotoxicity of patulin in mice, and its modulation by green tea polyphenols administration. AB - Patulin (PAT) is a mycotoxin produced by certain species of Penicillium, Aspergillus, and Byssochlamys. Previous studies demonstrated its cytotoxic, genotoxic, and mutagenic effects in different cell lines. However, there is little information available concerning its toxic behavior in vivo. In the present study, we investigated PAT-induced hepatotoxicity and genotoxicity in mice. We also investigated the antioxidant and anti-genotoxicity efficiency of green tea polyphenols (GTP) against PAT-induced toxicity. We found that PAT treatment induced serum alanine transaminase (ALT) and aspartate transaminase (AST) activities significantly. PAT-induced lipid peroxidation was confirmed with the elevation of thiobarbituric acid-reactive substances (TBARS). Moreover, the increasing of reactive oxygen species (ROS) and decreasing of GSH level implied its oxidative damage mechanism. In bone marrow cell, PAT was found to induce micronucleus and chromosomal aberration formation. In addition, our result suggested that GTP administration has dose-dependent antioxidative and antigenotoxic effect in against PAT-induced hepatotoxicity and genotoxicity. PMID- 24949944 TI - Interleukin-17 mediates triptolide-induced liver injury in mice. AB - Triptolide (TP)-induced liver injury can be attributed to the Th17/Treg imbalance with the enhancement of the expansion of Th17 cells and suppression of the production of Tregs, especially the significant increase of interleukin (IL)-17 secreted by helper T (Th) 17 cells. To further investigate the involvement of IL 17-mediated immune response in the TP-induced hepatotoxicity, we examined the plasma transaminase, histopathological changes, hepatic frequencies of Th17 cells, hepatic expression of transcriptional factors and cytokines genes and plasma IL-17 levels after administration of TP (600 MUg/kg) by oral gavage to female C57BL/6 mice. Mice treated with TP displayed acute liver injury with significantly increased hepatic frequencies of Th17 cells, mRNA expression of retinoid-related orphan receptor (ROR)-gammat and plasma IL-17 level as well as the plasma ALT and AST. Neutralization study using anti-IL-17 antibody ameliorated TP-induced liver injury. In contrast, when challenged by coadministration of recombinant IL-17, hepatotoxicity was exacerbated in the triptolide-administered mice. In summary, this report was demonstrated for the first time that IL-17-mediated immune response is involved in the pathogenesis of TP-induced liver injury in mice, which may shed light on the mechanisms of TP induced liver injury. PMID- 24949945 TI - Biochemical and histopathological effects of subchronic oral exposure of rats to a mixture of five toxic elements. AB - Arsenic, cadmium, lead, chromium and mercury are toxic elements that occur with high frequency in the soil and thus in agricultural products in China. To explore their combined effects, thirty male and thirty female Sprague-Dawley rats were orally exposed to a mixture of these elements at high dose (2.11, 6.47, 72.82, 2.26 and 2.71 mg/kg bw/day), medium dose (1/10 of the high dose) and low dose (1/100 of the high dose) via their drinking water for 90 days. The results revealed that BUN increased in all rats given the high dose, and serum creatinine increased in female rats given the medium dose. Decreased ALP levels in all treated male rats accompanied decreased RBC counts. In the high dose group, serum albumin, globulin and total protein content decreased in male rats, whereas serum ALT levels increased in female rats. Pathological changes were observed in the hepatocytes and renal tubules of all rats given the high dose, and the numbers of spermatogenic cells and sperm significantly decreased in both the epididymides and testes of the rats given the high dose. Abnormalities were observed earlier and more clearly in the males than in the females under combined exposure. PMID- 24949946 TI - Light-induced magnetization changes in a coordination polymer heterostructure of a Prussian blue analogue and a Hofmann-like Fe(II) spin crossover compound. AB - Coordination polymer thin film heterostructures of the Prussian blue analogue Ni(II)b[Cr(III)(CN)6](0.7).nH2O (NiCr-PBA) and the 3D Hofmann-like spin crossover compound Fe(azpy)[Pt(CN)4].xH2O {azpy = 4,4'-azopyridine} have been developed, and spin transition properties have been characterized via SQUID magnetometry and Raman spectroscopy. The magnetic response of the ferromagnetic NiCr-PBA layer (T(c) ~ 70 K) can be altered by inducing the LIESST effect (light-induced excited spin state trapping) in the coupled paramagnetic Fe(II) spin crossover material. Whereas an increase in magnetization is measured for the single-phase Fe(azpy)[Pt(CN)4].xH2O, a decrease in magnetization is observed for the heterostructure. These results indicate the LIESST effect alone cannot account for the sign and magnitude of the magnetization change in the heterostructure, but the temperature profile of the magnetization shows that significant changes in the NiCr-PBA network are correlated to the spin state of the Hofmann-like SCO network. PMID- 24949947 TI - ImmunoFISH is a reliable technique for the assessment of 1p and 19q status in oligodendrogliomas. AB - OBJECTIVE: To develop a new ImmunoFISH technique for the study of oligodendrogliomas by combining a standard immunohistochemical stain using MIB-1 antibody with a standard FISH technique using commercial 1p36 and 19q13 chromosomal probes. METHODS: Validation was performed by two observers on a series of 36 pre-selected oligodendrogliomas and compared to the results previously determined by FISH alone. RESULTS: The ImFISH technique is easy to perform and to analyze and is no more time-consuming than the usual FISH technique. Our results show that the inter-observer reliability of ImFISH is high (kappa = 0.86 and 0.95 respectively for 1p and 19q). Compared to FISH, the ImFISH exhibits a very high sensitivity (~100%) and specificity (~90%) for 1p and/or 19q deleted cases. The sensitivity is high for normal cases (~85%) and imbalanced cases (~90%) with a specificity ranging between 50 and 85%. Finally, there were no significant differences between FISH and ImFISH results calculated on 60, 40 or 20 cells. CONCLUSION: Our study demonstrates the reliability of the ImFISH technique in oligodendrogliomas and emphasizes its advantage in poorly cellular tumoral specimen. PMID- 24949948 TI - Variation in BAS-BIS profiles across categories of cigarette use. AB - Cigarette smoking is a major health concern, especially among college students. Research suggests a number of individual difference variables may be useful for identifying people at risk of becoming smokers and their likelihood of successfully quitting. The current study focuses on individual differences relating to Behavioral Inhibition System sensitivity (BIS) and the fun seeking, reward responsiveness, and drive aspects of Behavioral Approach System sensitivity (BAS). The former relates to mitigation of potential threat, whereas the latter three relate to different motivations for approach. Noting that existing literature suggests the considerations influencing whether a person experiments with cigarettes differ from those influencing who becomes a habitual smoker which in turn differ from those influencing whether a person quits smoking, we hypothesized that never smokers, experimenters, smokers, and former smokers would differ from each other on BIS, fun seeking, reward responsiveness, and drive in predictable ways. Moreover, we predicted these groups would differ from each other in terms of member profiles across these four variables. We assessed these predictions in a sample of college students from geographically diverse institutions within the United States (N=1840). The profile for never smokers was characterized by high BIS and low fun seeking, that of experimenters by moderately high BIS, high fun seeking, and moderate reward responsiveness, and that of former smokers by moderate BIS, high fun seeking, high reward responsiveness, and high drive. Contrary to expectations, current smokers were low on all four of these characteristics. PMID- 24949950 TI - The effectiveness of an integrated multicomponent program for adolescent smoking cessation in Taiwan. AB - If adolescents do not receive appropriate assistance in quitting smoking, they are highly likely to become regular smokers when they enter adulthood. Thus, an effective smoking-cessation program is required. A program was designed based on both the smoking-cessation barriers reported by students and effective strategies derived from the literature. We assigned 143 student smokers from 6 vocational high schools to intervention (n=78) and comparison groups (n=65). Data were collected at the baseline, the end of the program, and 1- and 4-month follow-up time points. For the intervention group, the smoking-abstinence rates confirmed using the urine cotinine test were 22.73% at the end of the program and 20.75% at the 4-month follow-up point. Days smoked in the past month, number of cigarettes smoked per day, and the Fagerstrom Test for Nicotine Dependence score of the intervention group decreased at all of the time points. The group differences in these variables were statistically significant; the magnitude of effect sizes ranged from 0.44 to 0.95. Multicomponent programs addressing smoking-cessation barriers that students encounter can help adolescents quit smoking. PMID- 24949949 TI - The impact of pre-cessation varenicline on behavioral economic indices of smoking reinforcement. AB - BACKGROUND: Varenicline was developed to aid smoking cessation by reducing smoking reinforcement. The present study tests this reinforcement-reduction hypothesis among smokers preparing to quit. METHOD: After a one-week baseline, treatment-seeking smokers were randomized to receive three weeks of varenicline or placebo (Weeks 2-4). During each of the four weeks of the study, smokers completed a hypothetical cigarette purchase task (CPT) via handheld devices in their natural environment. Behavioral economic measures of simulated smoking if cigarettes were free (demand intensity), sensitivity of consumption to increasing price (elasticity), and price at which purchases would drop to 0 (breakpoint) were estimated. RESULTS: The exponential demand equation fit the purchase task data well across subjects and time. As predicted, demand intensity decreased and sensitivity to price (elasticity) increased over time. However, changes in demand intensity did not differ by treatment group. Contrary to our hypothesis that varenicline would increase sensitivity to price, the placebo group tended to become more elastic in their purchases during Weeks 2 and 3; the groups did not differ in elasticity at Week 4. Breakpoint did not vary by group, time, or their interaction. CONCLUSION: Simulated smoking demand can be validly assessed in the natural environment of treatment-seeking smokers. Simulated demand indices of smoking reinforcement diminished as smokers approached their target quit date. However, there was no evidence that varenicline facilitated these changes over a three-week period, leaving open the mechanisms by which varenicline reduces smoking rate prior to cessation and improves long-term abstinence. PMID- 24949951 TI - Metastasis-associated in colon cancer 1 is a novel survival-related biomarker for human patients with renal pelvis carcinoma. AB - Metastasis-associated in colon cancer 1 (MACC1) has recently been identified as a novel independent prognostic indicator for metastasis occurrence, overall survival and cancer-free survival for patients with colon cancer and other solid tumors. In this study, we investigated the role of MACC1 in the development and progression of renal pelvis carcinoma, a form of upper tract urothelial carcinomas. MACC1 protein has been found in the cytoplasm as well as in the nucleus of the transitional epithelial cells of the normal renal pelvis in immunohistochemical (IHC) assays. Quantitative IHC examinations revealed that MACC1 abnormal abundance in cancerous tissues might represent a biological indicator clinically suggestive of tumor malignancy in the renal pelvis. Furthermore, investigation of the association of MACC1 protein levels with clinicopathological parameters in this study has suggested a correlation of MACC1 expression with tumor-node-metastasis stage and histopathological grade of patients with renal pelvis carcinoma, with elevated MACC1 protein levels frequently associated with higher aggressiveness of the disease. Moreover, both disease-free survival and overall survival for the patients in the high MACC1 expression group were significantly lower than those in the low expression group. Multivariate analysis with a Cox proportional-hazards model suggested that MACC1 is indeed an independent prognostic indicator of overall survival and cancer-free survival for patients with renal pelvis carcinoma. Thus, MACC1 may represent a promising prognostic biomarker candidate, as well as a potential therapeutic target for this disease. PMID- 24949952 TI - Biochemical characterization of quinolinic acid phosphoribosyltransferase from Mycobacterium tuberculosis H37Rv and inhibition of its activity by pyrazinamide. AB - Quinolinic acid phosphoribosyltransferase (QAPRTase, EC 2.4.2.19) is a key enzyme in the de novo pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis and a target for the development of new anti-tuberculosis drugs. QAPRTase catalyzes the synthesis of nicotinic acid mononucleotide from quinolinic acid (QA) and 5-phosphoribosyl-1-pyrophosphate (PRPP) through a phosphoribosyl transfer reaction followed by decarboxylation. The crystal structure of QAPRTase from Mycobacterium tuberculosis H37Rv (MtQAPRTase) has been determined; however, a detailed functional analysis of MtQAPRTase has not been published. Here, we analyzed the enzymatic activities of MtQAPRTase and determined the effect on catalysis of the anti-tuberculosis drug pyrazinamide (PZA). The optimum temperature and pH for MtQAPRTase activity were 60 degrees C and pH 9.2. MtQAPRTase required bivalent metal ions and its activity was highest in the presence of Mg2+. Kinetic analyses revealed that the Km values for QA and PRPP were 0.08 and 0.39 mM, respectively, and the kcat values for QA and PRPP were 0.12 and 0.14 [s-1], respectively. When the amino acid residues of MtQAPRTase, which may interact with QA, were substituted with alanine residues, catalytic activity was undetectable. Further, PZA, which is an anti-tuberculosis drug and a structural analog of QA, markedly inhibited the catalytic activity of MtQAPRTase. The structure of PZA may provide the basis for the design of new inhibitors of MtQAPRTase. These findings provide new insights into the catalytic properties of MtQAPRTase. PMID- 24949954 TI - The influence of physical factors on kelp and sea urchin distribution in previously and still grazed areas in the NE Atlantic. AB - The spatial distribution of kelp (Laminaria hyperborea) and sea urchins (Strongylocentrotus droebachiensis) in the NE Atlantic are highly related to physical factors and to temporal changes in temperature. On a large scale, we identified borders for kelp recovery and sea urchin persistence along the north south gradient. Sea urchin persistence was also related to the coast-ocean gradient. The southern border corresponds to summer temperatures exceeding about 10 degrees C, a threshold value known to be critical for sea urchin recruitment and development. The outer border along the coast-ocean gradient is related to temperature, wave exposure and salinity. On a finer scale, kelp recovery occurs mainly at ridges in outer, wave exposed, saline and warm areas whereas sea urchins still dominate in inner, shallow and cold areas, particularly in areas with optimal current speed for sea urchin foraging. In contrast to other studies in Europe, we here show a positive influence of climate change to presence of a long-lived climax canopy-forming kelp. The extent of the coast-ocean gradient varies within the study area, and is especially wide in the southern part where the presence of islands and skerries increases the area of the shallow coastal zone. This creates a large area with intermediate physical conditions for the two species and a mosaic of kelp and sea urchin dominated patches. The statistical models (GAM and BRT) show high performance and indicate recovery of kelp in 45 60% of the study area. The study shows the value of combining a traditional (GAM) and a more complex (BRT) modeling approach to gain insight into complex spatial patterns of species or habitats. The results, methods and approaches are of general ecological relevance regardless of ecosystems and species, although they are particularly relevant for understanding and exploring the corresponding changes between algae and grazers in different coastal areas. PMID- 24949953 TI - Comparative transcriptome profiling of two Tibetan wild barley genotypes in responses to low potassium. AB - Potassium (K) deficiency is one of the major factors affecting crop growth and productivity. Development of low-K tolerant crops is an effective approach to solve the nutritional deficiency in agricultural production. Tibetan annual wild barley is rich in genetic diversity and can grow normally under poor soils, including low-K supply. However, the molecular mechanism about low K tolerance is still poorly understood. In this study, Illumina RNA-Sequencing was performed using two Tibetan wild barley genotypes differing in low K tolerance (XZ153, tolerant and XZ141, sensitive), to determine the genotypic difference in transcriptome profiling. We identified a total of 692 differentially expressed genes (DEGs) in two genotypes at 6 h and 48 h after low-K treatment, including transcription factors, transporters and kinases, oxidative stress and hormone signaling related genes. Meanwhile, 294 low-K tolerant associated DEGs were assigned to transporter and antioxidant activities, stimulus response, and other gene ontology (GO), which were mainly involved in starch and sucrose metabolism, lipid metabolism and ethylene biosynthesis. Finally, a hypothetical model of low K tolerance mechanism in XZ153 was presented. It may be concluded that wild barley accession XZ153 has a higher capability of K absorption and use efficiency than XZ141 under low K stress. A rapid response to low K stress in XZ153 is attributed to its more K uptake and accumulation in plants, resulting in higher low K tolerance. The ethylene response pathway may account for the genotypic difference in low-K tolerance. PMID- 24949955 TI - Fracture prevention by prophylactic femoroplasty of the proximal femur--metallic compared with cemented augmentation. AB - OBJECTIVES: To compare 2 different femoral neck augmentation techniques at improving the mechanical strength of the femoral neck. METHODS: Twenty pairs of human cadaveric femora were randomly divided into 2 groups. In 1 group, the femora were augmented with a steel spiral; the other group with the cemented technique. The untreated contralateral side served as an intraindividual control. Fracture strength was evaluated using an established biomechanical testing scenario mimicking a fall on the greater trochanter (Hayes fall). RESULTS: The peak load to failure was significantly higher in the steel spiral group (P = 0.0024) and in the cemented group (P = 0.001) compared with the intraindividual controls. The peak load to failure showed a median of 3167 N (1825-5230 N) in the spiral group and 2485 N (1066-4395 N) in the spiral control group. The peak load to failure in the cemented group was 3698 N (SD +/- 1249 N) compared with 2763 N (SD +/- 1335 N) in the cement control group. Furthermore, fracture displacement was clearly reduced in the steel spiral group. CONCLUSIONS: Femoral augmentations using steel spirals or cement-based femoroplasty are technically feasible procedures. Our results demonstrate that a prophylactic reinforced proximal femur has higher strength when compared with the untreated contralateral limb. Prophylactic augmentation has potential to become an auxiliary treatment option to protect the osteoporotic proximal femur against fracture. PMID- 24949956 TI - In response. PMID- 24949957 TI - Skeletal muscle expression of the adhesion-GPCR CD97: CD97 deletion induces an abnormal structure of the sarcoplasmatic reticulum but does not impair skeletal muscle function. AB - CD97 is a widely expressed adhesion class G-protein-coupled receptor (aGPCR). Here, we investigated the presence of CD97 in normal and malignant human skeletal muscle as well as the ultrastructural and functional consequences of CD97 deficiency in mice. In normal human skeletal muscle, CD97 was expressed at the peripheral sarcolemma of all myofibers, as revealed by immunostaining of tissue sections and surface labeling of single myocytes using flow cytometry. In muscle cross-sections, an intracellular polygonal, honeycomb-like CD97-staining pattern, typical for molecules located in the T-tubule or sarcoplasmatic reticulum (SR), was additionally found. CD97 co-localized with SR Ca2+-ATPase (SERCA), a constituent of the longitudinal SR, but not with the receptors for dihydropyridine (DHPR) or ryanodine (RYR), located in the T-tubule and terminal SR, respectively. Intracellular expression of CD97 was higher in slow-twitch compared to most fast-twitch myofibers. In rhabdomyosarcomas, CD97 was strongly upregulated and in part more N-glycosylated compared to normal skeletal muscle. All tumors were strongly CD97-positive, independent of the underlying histological subtype, suggesting high sensitivity of CD97 for this tumor. Ultrastructural analysis of murine skeletal myofibers confirmed the location of CD97 in the SR. CD97 knock-out mice had a dilated SR, resulting in a partial increase in triad diameter yet not affecting the T-tubule, sarcomeric, and mitochondrial structure. Despite these obvious ultrastructural changes, intracellular Ca2+ release from single myofibers, force generation and fatigability of isolated soleus muscles, and wheel-running capacity of mice were not affected by the lack of CD97. We conclude that CD97 is located in the SR and at the peripheral sarcolemma of human and murine skeletal muscle, where its absence affects the structure of the SR without impairing skeletal muscle function. PMID- 24949959 TI - No positive selection for G allele in a p53 response element in Europeans. PMID- 24949958 TI - Epidemiology of visceral leishmaniasis in Algeria: an update. AB - Visceral leishmaniasis (VL), a zoonotic disease caused by Leishmania infantum, is endemic in Algeria. This report describes a retrospective epidemiological study conducted on human VL to document the epidemiological profile at national level. All human VL cases notified by the National Institute of Public Health between 1998 and 2008 were investigated. In parallel all VL cases admitted to the university hospitals of Algiers were surveyed to estimate the underreporting ratio. Fifteen hundred and sixty-two human VL cases were reported in Algeria between 1998-2008 with an average annual reported incidence rate of 0.45 cases per 100,000 inhabitants, of which 81.42% were in the age range of 0-4 years. Cases were detected year-round, with a peak notification in May and June. One hundred and seventy patients were admitted to the university hospitals in Algiers in the same period, of which less than one in ten had been officially notified. Splenomegaly, fever, pallor and pancytopenia were the main clinical and laboratory features. Meglumine antimoniate was the first-line therapy for paediatric VL whereas the conventional amphotericin B was used for adult patients. Visceral leishmaniasis in Algeria shows the epidemiological profile of a paediatric disease with a decrease of the annual reported incidence rate. However, vigilance is required because of huge underreporting and an apparent propagation towards the south. PMID- 24949960 TI - Shedding "UV" light on endogenous opioid dependence. AB - Excessive sun tanning can result in addictive behavior. In this issue of Cell, Fell et al. utilize a combination of behavioral pharmacology and transgenic mice to demonstrate that chronic UV light exposure recruits p53 signaling in keratinocytes, subsequently increasing beta-endorphin signaling at opioid receptors, and produces an endogenous opioid-dependent state. PMID- 24949961 TI - Assembling cell ensembles. AB - The way the hippocampus processes information and encodes memories in the form of "cell assemblies" is likely determined in part by how its circuits are wired up during development. In this issue, Xu et al. now provide new insight into how neurons arising from a single common precursor migrate to their final destination and form functionally synchronous ensembles. PMID- 24949962 TI - The angiotensin II type 2 receptor for pain control. AB - All well-known deleterious effects of angiotensin (Ang) II, including vasoconstriction, inflammation, water and salt retention, and vascular remodeling, are mediated via its type 1 (AT1) receptor. This explains why AT1 receptor blockers (ARBs) and inhibitors of Ang II synthesis, such as ACE inhibitors and renin inhibitors, are beneficial for cardiovascular disease. Yet, Ang II has a second receptor, the Ang II type 2 (AT2) receptor, the function of which, even after over 20 years of research, remains largely unknown. In this issue, Marion et al. provide a new chapter to the AT2 receptor story. PMID- 24949963 TI - Designer proteins to trigger cell death. AB - Efforts to generate biologically active proteins by de novo computational design have been limited to creating functional sites within pre-existing scaffolds. Procko et al. use an innovative computational design approach coupled with in vitro-targeted evolution to produce a potent polypeptide inhibitor of a viral Bcl 2-like protein. This novel inhibitor triggers apoptosis of virus-infected cells. PMID- 24949964 TI - From cancer genomics to precision oncology--tissue's still an issue. AB - Rapidly evolving genome technology has enabled extensive molecular analysis of limited tumor biopsy material, thereby facilitating the broader implementation of personalized cancer medicine. However, genomics-based patient stratification across diverse tumor types is unlikely to supplant tissue-of-origin considerations in addressing clinical needs, including the development and application of novel "rationally targeted" cancer therapies. PMID- 24949965 TI - The search for antiaging interventions: from elixirs to fasting regimens. AB - The phenomenon of aging is an intrinsic feature of life. Accordingly, the possibility to manipulate it has fascinated humans likely since time immemorial. Recent evidence is shaping a picture where low caloric regimes and exercise may improve healthy senescence, and several pharmacological strategies have been suggested to counteract aging. Surprisingly, the most effective interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy. Here, we critically examine drugs and behaviors to which life- or healthspan-extending properties have been ascribed and discuss the underlying molecular mechanisms. PMID- 24949966 TI - Skin beta-endorphin mediates addiction to UV light. AB - UV light is an established carcinogen, yet evidence suggests that UV-seeking behavior has addictive features. Following UV exposure, epidermal keratinocytes synthesize proopiomelanocortin (POMC) that is processed to melanocyte-stimulating hormone, inducing tanning. We show that, in rodents, another POMC-derived peptide, beta-endorphin, is coordinately synthesized in skin, elevating plasma levels after low-dose UV. Increases in pain-related thresholds are observed and reversed by pharmacologic opioid antagonism. Opioid blockade also elicits withdrawal signs after chronic UV exposure. This effect was sufficient to guide operant behavioral choices to avoidance of opioid withdrawal (conditioned place aversion). These UV-induced nociceptive and behavioral effects were absent in beta-endorphin knockout mice and in mice lacking p53-mediated POMC induction in epidermal keratinocytes. Although primordial UV addiction, mediated by the hedonic action of beta-endorphin and anhedonic effects of withdrawal, may theoretically have enhanced evolutionary vitamin D biosynthesis, it now may contribute to the relentless rise in skin cancer incidence in humans. PMID- 24949967 TI - Natural neural projection dynamics underlying social behavior. AB - Social interaction is a complex behavior essential for many species and is impaired in major neuropsychiatric disorders. Pharmacological studies have implicated certain neurotransmitter systems in social behavior, but circuit-level understanding of endogenous neural activity during social interaction is lacking. We therefore developed and applied a new methodology, termed fiber photometry, to optically record natural neural activity in genetically and connectivity-defined projections to elucidate the real-time role of specified pathways in mammalian behavior. Fiber photometry revealed that activity dynamics of a ventral tegmental area (VTA)-to-nucleus accumbens (NAc) projection could encode and predict key features of social, but not novel object, interaction. Consistent with this observation, optogenetic control of cells specifically contributing to this projection was sufficient to modulate social behavior, which was mediated by type 1 dopamine receptor signaling downstream in the NAc. Direct observation of deep projection-specific activity in this way captures a fundamental and previously inaccessible dimension of mammalian circuit dynamics. PMID- 24949968 TI - Distinct lineage-dependent structural and functional organization of the hippocampus. AB - The hippocampus, as part of the cerebral cortex, is essential for memory formation and spatial navigation. Although it has been extensively studied, especially as a model system for neurophysiology, the cellular processes involved in constructing and organizing the hippocampus remain largely unclear. Here, we show that clonally related excitatory neurons in the developing hippocampus are progressively organized into discrete horizontal, but not vertical, clusters in the stratum pyramidale, as revealed by both cell-type-specific retroviral labeling and mosaic analysis with double markers (MADM). Moreover, distinct from those in the neocortex, sister excitatory neurons in the cornu ammonis 1 region of the hippocampus rarely develop electrical or chemical synapses with each other. Instead, they preferentially receive common synaptic input from nearby fast-spiking (FS), but not non-FS, interneurons and exhibit synchronous synaptic activity. These results suggest that shared inhibitory input may specify horizontally clustered sister excitatory neurons as functional units in the hippocampus. PMID- 24949969 TI - Mycobacterial toxin induces analgesia in buruli ulcer by targeting the angiotensin pathways. AB - Mycobacterium ulcerans, the etiological agent of Buruli ulcer, causes extensive skin lesions, which despite their severity are not accompanied by pain. It was previously thought that this remarkable analgesia is ensured by direct nerve cell destruction. We demonstrate here that M. ulcerans-induced hypoesthesia is instead achieved through a specific neurological pathway triggered by the secreted mycobacterial polyketide mycolactone. We decipher this pathway at the molecular level, showing that mycolactone elicits signaling through type 2 angiotensin II receptors (AT2Rs), leading to potassium-dependent hyperpolarization of neurons. We further validate the physiological relevance of this mechanism with in vivo studies of pain sensitivity in mice infected with M. ulcerans, following the disruption of the identified pathway. Our findings shed new light on molecular mechanisms evolved by natural systems for the induction of very effective analgesia, opening up the prospect of new families of analgesics derived from such systems. PMID- 24949971 TI - Polar body genome transfer for preventing the transmission of inherited mitochondrial diseases. AB - Inherited mtDNA diseases transmit maternally and cause severe phenotypes. Currently, there is no effective therapy or genetic screens for these diseases; however, nuclear genome transfer between patients' and healthy eggs to replace mutant mtDNAs holds promises. Considering that a polar body contains few mitochondria and shares the same genomic material as an oocyte, we perform polar body transfer to prevent the transmission of mtDNA variants. We compare the effects of different types of germline genome transfer, including spindle chromosome transfer, pronuclear transfer, and first and second polar body transfer, in mice. Reconstructed embryos support normal fertilization and produce live offspring. Importantly, genetic analysis confirms that the F1 generation from polar body transfer possesses minimal donor mtDNA carryover compared to the F1 generation from other procedures. Moreover, the mtDNA genotype remains stable in F2 progeny after polar body transfer. Our preclinical model demonstrates polar body transfer has great potential to prevent inherited mtDNA diseases. PMID- 24949970 TI - The diabetes susceptibility gene Clec16a regulates mitophagy. AB - Clec16a has been identified as a disease susceptibility gene for type 1 diabetes, multiple sclerosis, and adrenal dysfunction, but its function is unknown. Here we report that Clec16a is a membrane-associated endosomal protein that interacts with E3 ubiquitin ligase Nrdp1. Loss of Clec16a leads to an increase in the Nrdp1 target Parkin, a master regulator of mitophagy. Islets from mice with pancreas specific deletion of Clec16a have abnormal mitochondria with reduced oxygen consumption and ATP concentration, both of which are required for normal beta cell function. Indeed, pancreatic Clec16a is required for normal glucose stimulated insulin release. Moreover, patients harboring a diabetogenic SNP in the Clec16a gene have reduced islet Clec16a expression and reduced insulin secretion. Thus, Clec16a controls beta cell function and prevents diabetes by controlling mitophagy. This pathway could be targeted for prevention and control of diabetes and may extend to the pathogenesis of other Clec16a- and Parkin associated diseases. PMID- 24949973 TI - Programmed -1 frameshifting by kinetic partitioning during impeded translocation. AB - Programmed -1 ribosomal frameshifting (-1PRF) is an mRNA recoding event utilized by cells to enhance the information content of the genome and to regulate gene expression. The mechanism of -1PRF and its timing during translation elongation are unclear. Here, we identified the steps that govern -1PRF by following the stepwise movement of the ribosome through the frameshifting site of a model mRNA derived from the IBV 1a/1b gene in a reconstituted in vitro translation system from Escherichia coli. Frameshifting occurs at a late stage of translocation when the two tRNAs are bound to adjacent slippery sequence codons of the mRNA. The downstream pseudoknot in the mRNA impairs the closing movement of the 30S subunit head, the dissociation of EF-G, and the release of tRNA from the ribosome. The slippage of the ribosome into the -1 frame accelerates the completion of translocation, thereby further favoring translation in the new reading frame. PMID- 24949972 TI - Programmed translational readthrough generates antiangiogenic VEGF-Ax. AB - Translational readthrough, observed primarily in less complex organisms from viruses to Drosophila, expands the proteome by translating select transcripts beyond the canonical stop codon. Here, we show that vascular endothelial growth factor A (VEGFA) mRNA in mammalian endothelial cells undergoes programmed translational readthrough (PTR) generating VEGF-Ax, an isoform containing a unique 22-amino-acid C terminus extension. A cis-acting element in the VEGFA 3' UTR serves a dual function, not only encoding the appended peptide but also directing the PTR by decoding the UGA stop codon as serine. Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 binds this element and promotes readthrough. Remarkably, VEGF-Ax exhibits antiangiogenic activity in contrast to the proangiogenic activity of VEGF-A. Pathophysiological significance of VEGF-Ax is indicated by robust expression in multiple human tissues but depletion in colon adenocarcinoma. Furthermore, genome-wide analysis revealed AGO1 and MTCH2 as authentic readthrough targets. Overall, our studies reveal a novel protein regulated PTR event in a vertebrate system. PMID- 24949974 TI - A computationally designed inhibitor of an Epstein-Barr viral Bcl-2 protein induces apoptosis in infected cells. AB - Because apoptosis of infected cells can limit virus production and spread, some viruses have co-opted prosurvival genes from the host. This includes the Epstein Barr virus (EBV) gene BHRF1, a homolog of human Bcl-2 proteins that block apoptosis and are associated with cancer. Computational design and experimental optimization were used to generate a novel protein called BINDI that binds BHRF1 with picomolar affinity. BINDI recognizes the hydrophobic cleft of BHRF1 in a manner similar to other Bcl-2 protein interactions but makes many additional contacts to achieve exceptional affinity and specificity. BINDI induces apoptosis in EBV-infected cancer lines, and when delivered with an antibody-targeted intracellular delivery carrier, BINDI suppressed tumor growth and extended survival in a xenograft disease model of EBV-positive human lymphoma. High specificity-designed proteins that selectively kill target cells may provide an advantage over the toxic compounds used in current generation antibody-drug conjugates. PMID- 24949975 TI - Conservation of Ca2+/calmodulin regulation across Na and Ca2+ channels. AB - Voltage-gated Na and Ca2+ channels comprise distinct ion channel superfamilies, yet the carboxy tails of these channels exhibit high homology, hinting at a long shared and purposeful module. For different Ca2+ channels, carboxyl-tail interactions with calmodulin do elaborate robust and similar forms of Ca2+ regulation. However, Na channels have only shown subtler Ca2+ modulation that differs among reports, challenging attempts at unified understanding. Here, by rapid Ca2+ photorelease onto Na channels, we reset this view of Na channel regulation. For cardiac-muscle channels (NaV1.5), reported effects from which most mechanistic proposals derive, we observe no Ca2+ modulation. Conversely, for skeletal-muscle channels (NaV1.4), we uncover fast Ca2+ regulation eerily similar to that of Ca2+ channels. Channelopathic myotonia mutations halve NaV1.4 Ca2+ regulation, and transplanting the NaV1.4 carboxy tail onto Ca2+ channels recapitulates Ca2+ regulation. Thus, we argue for the persistence and physiological relevance of an ancient Ca2+ regulatory module across Na and Ca2+ channels. PMID- 24949976 TI - Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8. AB - Most E3 ligases use a RING domain to activate a thioester-linked E2~ubiquitin like protein (UBL) intermediate and promote UBL transfer to a remotely bound target protein. Nonetheless, RING E3 mechanisms matching a specific UBL and acceptor lysine remain elusive, including for RBX1, which mediates NEDD8 ligation to cullins and >10% of all ubiquitination. We report the structure of a trapped RING E3-E2~UBL-target intermediate representing RBX1-UBC12~NEDD8-CUL1-DCN1, which reveals the mechanism of NEDD8 ligation and how a particular UBL and acceptor lysine are matched by a multifunctional RING E3. Numerous mechanisms specify cullin neddylation while preventing noncognate ubiquitin ligation. Notably, E2-E3 target and RING-E2~UBL modules are not optimized to function independently, but instead require integration by the UBL and target for maximal reactivity. The UBL and target regulate the catalytic machinery by positioning the RING-E2~UBL catalytic center, licensing the acceptor lysine, and influencing E2 reactivity, thereby driving their specific coupling by a multifunctional RING E3. PMID- 24949977 TI - Glucocorticoid receptor function regulated by coordinated action of the Hsp90 and Hsp70 chaperone cycles. AB - The glucocorticoid receptor (GR), like many signaling proteins, depends on the Hsp90 molecular chaperone for in vivo function. Although Hsp90 is required for ligand binding in vivo, purified apo GR is capable of binding ligand with no enhancement from Hsp90. We reveal that Hsp70, known to facilitate client delivery to Hsp90, inactivates GR through partial unfolding, whereas Hsp90 reverses this inactivation. Full recovery of ligand binding requires ATP hydrolysis on Hsp90 and the Hop and p23 cochaperones. Surprisingly, Hsp90 ATP hydrolysis appears to regulate client transfer from Hsp70, likely through a coupling of the two chaperone's ATP cycles. Such coupling is embodied in contacts between Hsp90 and Hsp70 in the GR:Hsp70:Hsp90:Hop complex imaged by cryoelectron microscopy. Whereas GR released from Hsp70 is aggregation prone, release from Hsp90 protects GR from aggregation and enhances its ligand affinity. Together, this illustrates how coordinated chaperone interactions can enhance stability, function, and regulation. PMID- 24949978 TI - A chromatin-based mechanism for limiting divergent noncoding transcription. AB - In addition to their annotated transcript, many eukaryotic mRNA promoters produce divergent noncoding transcripts. To define determinants of divergent promoter directionality, we used genomic replacement experiments. Sequences within noncoding transcripts specified their degradation pathways, and functional protein-coding transcripts could be produced in the divergent direction. To screen for mutants affecting the ratio of transcription in each direction, a bidirectional fluorescent protein reporter construct was introduced into the yeast nonessential gene deletion collection. We identified chromatin assembly as an important regulator of divergent transcription. Mutations in the CAF-I complex caused genome-wide derepression of nascent divergent noncoding transcription. In opposition to the CAF-I chromatin assembly pathway, H3K56 hyperacetylation, together with the nucleosome remodeler SWI/SNF, facilitated divergent transcription by promoting rapid nucleosome turnover. We propose that these chromatin-mediated effects control divergent transcription initiation, complementing downstream pathways linked to early termination and degradation of the noncoding RNAs. PMID- 24949981 TI - Stronger, but not (yet) an equal. The use of quality improvement instruments and strategies by patient organisations in the Netherlands. AB - This article deals with the questions what the benefits and limitations are of the instruments and strategies that patient organisations use to influence quality of care. The advocacy of patients' interests has become more important for patient organisations in recent years, which is partly due to Dutch health care policy reform. Thirty state funded quality improvement projects run by patient organisations between 2009 and 2012 have been analysed. The quality improvement instruments developed and used in these projects are concerned with: standardization and standard setting (What is good care?); consultation, comparison and checking (What is the state of the care given?); and negotiating and advising (How can quality of care be improved?). The choice for these instruments is partly based on patient organisations' strategies of scientization, valuing institutionalized methods and valuing good relationships. We see that the development and use of these quality improvement instruments do strengthen patient organisation and therefore have internal identity and organisational effects. However, the external effects patient organisations can have by using these instruments and strategies is limited or at least insecure by lack of economic capital after the development phase and lack of negotiating power. The external effects of these instruments and strategies depend largely on a patient organisation's network and the willingness, degree of openness and policy of other stakeholders to cooperate. Therefore, these forms of patient participation remain vulnerable. PMID- 24949980 TI - SnapShot: receptor dynamics at plastic synapses. AB - The dynamic synapse is represented by the constant mobility and exchange of components at both the cell surface and at intracellular sites. This includes thermally powered Brownian diffusion movement, followed by reversible trapping through receptor-scaffold interactions and active transport of cargo vesicles through cytoskeletal motors. PMID- 24949979 TI - High-sensitivity measurements of multiple kinase activities in live single cells. AB - Increasing evidence has shown that population dynamics are qualitatively different from single-cell behaviors. Reporters to probe dynamic, single-cell behaviors are desirable yet relatively scarce. Here, we describe an easy-to implement and generalizable technology to generate reporters of kinase activity for individual cells. Our technology converts phosphorylation into a nucleocytoplasmic shuttling event that can be measured by epifluorescence microscopy. Our reporters reproduce kinase activity for multiple types of kinases and allow for calculation of active kinase concentrations via a mathematical model. Using this technology, we made several experimental observations that had previously been technicallyunfeasible, including stimulus-dependent patterns of c Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-kappaB) activation. We also measured JNK, p38, and ERK activities simultaneously, finding that p38 regulates the peak number, but not the intensity, of ERK fluctuations. Our approach opens the possibility of analyzing a wide range of kinase-mediated processes in individual cells. PMID- 24949982 TI - Sialosignaling: sialyltransferases as engines of self-fueling loops in cancer progression. AB - BACKGROUND: Glycosylation is increasingly recognized as one of the most relevant postranslational modifications. Sialic acids are negatively charged sugars which frequently terminate the carbohydrate chains of glycoproteins and glycolipids. The addition of sialic acids is mediated by sialyltransferases, a family of glycosyltransferases with a crucial role in cancer progression. SCOPE OF THE REVIEW: To describe the phenotypic and clinical implications of altered expression of sialyltransferases and of their cognate sialylated structures in cancer. To propose a unifying model of the role of sialyltransferases and sialylated structures on cancer progression. MAJOR CONCLUSIONS: We first discuss the biosynthesis and the role played by the major cancer-associated sialylated structures, including Thomsen-Friedenreich-associated antigens, sialyl Lewis antigens, alpha2,6-sialylated lactosamine, polysialic acid and gangliosides. Then, we show that altered sialyltransferase expression in cancer, consequence of genetic and epigenetic alterations, generates a flow of information toward the membrane through the biosynthesis of aberrantly sialylated molecules (inside-out signaling). In turn, the presence of aberrantly sialylated structures on cell membrane receptors generates a flow of information toward the nucleus, which can exacerbate the neoplastic phenotype (outside-in signaling). We provide examples of self-fueling loops generated by these flows of information. GENERAL SIGNIFICANCE: Sialyltransferases have a wide impact on the biology of cancer and can be the target of innovative therapies. Our unified view provides a conceptual framework to understand the impact of altered glycosylation in cancer. PMID- 24949983 TI - Altered ubiquitin-proteasome system leads to neuronal cell death in a spontaneous obese rat model. AB - BACKGROUND: Obesity is associated with various progressive age-related diseases, including neurological disorders. However, underlying molecular basis for increased risk of neurodegeneration in obesity is unknown. A suitable animal model would immensely help in understanding the obesity-linked neurological problems. METHODS: A spontaneously developed obese rat (WNIN/Ob) which is highly vulnerable for a variety of degenerative diseases was isolated from the existing WNIN stock rats. Ultrastructure of neurons in the cerebral cortex of 12-month old obese rats was evaluated by transmission electron microscopy. qRT-PCR and immunoblotting of ubiquitin C-terminal hydrolases (UCHs), ubiquitin, proteasomal sub-units, markers of ER stress and apoptosis were performed in the cerebral cortex. Proteasome activity was assayed by fluorometric method. Immunohistochemistry was performed for mediators of apoptosis, which was further confirmed by TUNEL assay. These investigations were also carried in high-fat diet induced obese rat model. RESULTS: Neurons in the cerebral cortex of 12-month obese rats showed swollen mitochondria, disrupted ER and degenerating axons, nucleus and finally neurons. Results showed altered UPS, existence of ER stress, up-regulation of apoptotic markers and apoptosis in the cerebral cortex of obese rats. It appears that UCHL-1 mediated apoptosis through stabilizing p53 might play a role in neuronal cell death in obese rat. Similar changes were observed in the brain of diet-induced obese WNIN rats. CONCLUSION: Altered UPS could be one of the underlying mechanisms for the neuronal cell death in obese conditions. GENERAL SIGNIFICANCE: This is the first report to highlight the role of altered UPS in neurodegeneration due to obesity. PMID- 24949984 TI - Prevalence of self-reported metal allergy in patients undergoing primary total knee arthroplasty. AB - No validated screening method exists to identify patients at risk for metal allergy complications following total knee arthroplasty (TKA). Select use of implants that do not contain nickel, cobalt, and chromium may be considered in patients at risk. This study was performed to determine the rate of self-reported cutaneous metal allergy, or sensitivity, in patients undergoing knee replacement, and to evaluate whether there is a higher prevalence in females. A retrospective chart review was performed on 194 consecutive patients who underwent primary knee arthroplasty with a single surgeon between 2010 and 2011. During this period, all patients, except those with a previous well-functioning orthopedic device, were asked preoperatively about a history of metal allergy or sensitivity. The prevalence of self-reported cutaneous metal allergy, or sensitivity, was 14%; 22% (19/86) of females and 2% (1/53) of males reported a positive history. Fourteen percent of patients undergoing TKA self-identify as having a cutaneous metal allergy or sensitivity. Until validated screening tests are developed to identify patients "at risk" of symptomatic metal allergy after TKA, selective use of prostheses that do not contain cobalt, chromium, or nickel in individuals who self-identify with metal sensitivity may be considered. As most of these patients are female, manufacturers should consider optimizing availability of these implants in smaller sizes. PMID- 24949985 TI - Anterior cruciate ligament and medial collateral ligament injuries. AB - The diagnosis and treatment of combined anterior cruciate ligament (ACL) and medial collateral ligament (MCL) injuries have evolved over the past 30 years. A detailed physical examination along with careful review of the magnetic resonance imaging and stress radiographs will guide decision making. Early ACL reconstruction and acute MCL repair are recommended when there is increased medial joint space opening with valgus stress in extension, a significant meniscotibial deep MCL injury (high-riding medial meniscus), or a displaced tibial-sided superficial MCL avulsion (stener lesion of the knee). Delayed ACL reconstruction to allow for MCL healing is advised when increased valgus laxity is present only at 30 degrees of flexion and not at 0 degree. However, at the time of ACL surgery, medial stability has to be re-assessed after the reconstruction is completed. In patients with neutral alignment in the chronic setting, graft reconstruction of both the ACL and MCL is recommended. PMID- 24949986 TI - Combined anterior cruciate ligament and posterolateral reconstruction of the knee using allograft tissue in chronic knee injuries. AB - Combined anterior cruciate ligament (ACL) and posterolateral injury of the knee can result in significant functional instability for the affected individual. Both components of the instability must be treated to maximize the probability of success for the surgical procedure. Higher failure rates of the ACL reconstruction have been reported when the posterolateral instability has been left untreated. The purpose of this article is to describe our surgical technique, and present the results of 34 chronic combined ACL posterolateral reconstructions in 34 knees using allograft tissue, and evaluating these patient outcomes with KT 1000 knee ligament arthrometer, Lysholm, Tegner, and Hospital for Special Surgery knee ligament rating scales. In addition, observations regarding patient demographics with combined ACL posterolateral instability, postoperative range of motion loss, postinjury degenerative joint disease, infection rate, return to function, and the use of radiated and nonirradiated allograft tissues will be presented. PMID- 24949988 TI - Thin film flow in MHD third grade fluid on a vertical belt with temperature dependent viscosity. AB - In this work, we have carried out the influence of temperature dependent viscosity on thin film flow of a magnetohydrodynamic (MHD) third grade fluid past a vertical belt. The governing coupled non-linear differential equations with appropriate boundary conditions are solved analytically by using Adomian Decomposition Method (ADM). In order to make comparison, the governing problem has also been solved by using Optimal Homotopy Asymptotic Method (OHAM). The physical characteristics of the problem have been well discussed in graphs for several parameter of interest. PMID- 24949991 TI - Personal Beliefs about Experiences in those at Clinical High Risk for Psychosis. AB - BACKGROUND: Negative beliefs about illness in early psychosis have been shown to have an unfavourable impact on one's quality of life. A shift of focus in psychosis research has been on the detection of individuals considered to be at clinical high risk (CHR) of developing psychosis. Little is known about the impact that beliefs about psychotic like experiences or attenuated psychotic symptoms may have on CHR individuals. AIM: To explore these beliefs in a large sample of young people at CHR of developing psychosis using the Personal Beliefs about Experiences Questionnaire (PBEQ). METHOD: Beliefs about unusual experiences were assessed in 153 CHR individuals with the PBEQ. Prodromal symptoms (measured by the SIPS) and depression (measured by the CDSS) were also assessed. RESULTS: In CHR individuals, holding more negative beliefs was associated with increased severity in depression and negative symptoms. Higher scores on suspiciousness were associated with increased negative beliefs, and higher levels of grandiosity were associated with decreased negative beliefs. Those who later transitioned to psychosis agreed significantly more with statements concerning control over experiences (i.e. "my experiences frighten me", "I find it difficult to cope). CONCLUSIONS: The results suggest that targeting negative beliefs and other illness related appraisals is an important objective for intervention strategies. PMID- 24949989 TI - Root resorption after leveling with super-elastic and conventional steel arch wires: a prospective study. AB - BACKGROUND: The aim of this prospective study was to compare root resorption after the leveling phase of treatment, performed by either super-elastic or conventional multi-stranded stainless steel arch wires. METHODS: From a total of 156 future orthodontic patients in a private clinic, 82 were included in the study after excluding those who earlier had orthodontic or endodontic treatment or signs of resorption. Patients were equally arbitrary allocated into two groups, where leveling was performed either with super-elastic heat-activated or conventional multi-stranded stainless steel arch wires. Root length loss was calculated using pre-treatment and post-leveling periapical radiographs. RESULTS: The use of super-elastic arch wires did not significantly increase the severity of root resorption, except for tooth 31, while it reduced leveling time compared to conventional stainless steel wires. Crossbite of maxillary lateral incisors seemed to be a risk factor for resorption. CONCLUSION: Incisor root resorption after leveling did not differ significantly between patients treated with super elastic and conventional stainless steel arch wires, except for a mandibular incisor. PMID- 24949992 TI - Preparation, characterization, cytotoxicity, and genotoxicity evaluations of thiolated- and s-nitrosated superparamagnetic iron oxide nanoparticles: implications for cancer treatment. AB - Iron oxide magnetic nanoparticles have been proposed for an increasing number of biomedical applications, such as drug delivery. To this end, toxicological studies of their potent effects in biological media must be better evaluated. The aim of this study was to synthesize, characterize, and examine the potential in vitro cytotoxicity and genotoxicity of thiolated (SH) and S-nitrosated (S-NO) iron oxide superparamagnetic nanoparticles toward healthy and cancer cell lines. Fe3O4 nanoparticles were synthesized by coprecipitation techniques and coated with small thiol-containing molecules, such as mercaptosuccinic acid (MSA) or meso-2,3-dimercaptosuccinic acid (DMSA). The physical-chemical, morphological, and magnetic properties of thiol-coating Fe3O4 nanoparticles were characterized by different techniques. The thiol groups on the surface of the nanoparticles were nitrosated, leading to the formation of S-nitroso-MSA- or S-nitroso-DMSA Fe3O4 nanoparticles. The cytotoxicity and genotoxicity of thiolated and S nitrosated nanoparticles were more deeply evaluated in healthy (3T3, human lymphocytes cells, and chinese hamster ovary cells) and cancer cell lines (MCF 7). The results demonstrated that thiol-coating iron oxide magnetic nanoparticles have few toxic effects in cells, whereas S-nitrosated-coated particles did cause toxic effects. Moreover, due to the superaramagnetic behavior of S-nitroso-Fe3O4 nanoparticles, those particles can be guided to the target site upon the application of an external magnetic field, leading to local toxic effects in the tumor cells. Taken together, the results suggest the promise of S-nitroso magnetic nanoparticles in cancer treatment. PMID- 24949993 TI - A set of descriptors for identifying the protein-drug interaction in cellular networking. AB - The study of protein-drug interactions is a significant issue for drug development. Unfortunately, it is both expensive and time-consuming to perform physical experiments to determine whether a drug and a protein are interacting with each other. Some previous attempts to design an automated system to perform this task were based on the knowledge of the 3D structure of a protein, which is not always available in practice. With the availability of protein sequences generated in the post-genomic age, however, a sequence-based solution to deal with this problem is necessary. Following other works in this area, we propose a new machine learning system based on several protein descriptors extracted from several protein representations, such as, variants of the position specific scoring matrix (PSSM) of proteins, the amino-acid sequence, and a matrix representation of a protein. The prediction engine is operated by an ensemble of support vector machines (SVMs), with each SVM trained on a specific descriptor and the results of each SVM combined by sum rule. The overall success rate achieved by our final ensemble is notably higher than previous results obtained on the same datasets using the same testing protocols reported in the literature. MATLAB code and the datasets used in our experiments are freely available for future comparison at http://www.dei.unipd.it/node/2357. PMID- 24949995 TI - Ablation of coactivator Med1 switches the cell fate of dental epithelia to that generating hair. AB - Cell fates are determined by specific transcriptional programs. Here we provide evidence that the transcriptional coactivator, Mediator 1 (Med1), is essential for the cell fate determination of ectodermal epithelia. Conditional deletion of Med1 in vivo converted dental epithelia into epidermal epithelia, causing defects in enamel organ development while promoting hair formation in the incisors. We identified multiple processes by which hairs are generated in Med1 deficient incisors: 1) dental epithelial stem cells lacking Med 1 fail to commit to the dental lineage, 2) Sox2-expressing stem cells extend into the differentiation zone and remain multi-potent due to reduced Notch1 signaling, and 3) epidermal fate is induced by calcium as demonstrated in dental epithelial cell cultures. These results demonstrate that Med1 is a master regulator in adult stem cells to govern epithelial cell fate. PMID- 24949994 TI - Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents. AB - Clindamycin is commonly prescribed to treat children with skin and skin-structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA)), yet little is known about its pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving i.v. clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA-MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. A one-compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (l/h) = 13.7 * (weight/70)(0.75) * (PMA(3.1)/(43.6(3.1) + PMA(3.1))); V (l) = 61.8 * (weight/70). Maturation reached 50% of adult CL values at ~44 weeks PMA. Our findings support age-based dosing. PMID- 24949996 TI - Neuropsychological Assessment Battery-Screening Module (S-NAB): performance in treatment-seeking cocaine users. AB - Abstract Background: Cocaine use is associated with cognitive impairments, which can have a negative effect on treatment retention and drug use. Thus, there is an increasing demand for a screening cognitive battery can be used by clinicians to detect such impairments in cocaine patients so that treatment can be adapted to patients' specific cognitive strengths and deficits. The Neuropsychological Assessment Battery-Screening Module (S-NAB) test for adults takes approximately 35-45 min to administer, and assesses attention, language, memory (verbal and visual), visual spatial reasoning, and executive functioning. OBJECTIVE: The purpose of this descriptive study was to present S-NAB score results for a sample of treatment seeking adult cocaine users to determine its potential utility for detecting cognitive impairments in this population. METHODS: In the present sample, 145 adult cocaine users participated in screening to enroll in an intervention to decrease cocaine use (59% male; 73.1% African American); screening included the S-NAB and self-report questionnaires. RESULTS: A substantial proportion of the sample (44%) met criteria for impairment, i.e. composite scores of one or more standard deviations below the mean. Furthermore, memory scores were significantly lower than language and spatial scores (p < 0.007). CONCLUSIONS: The impairments detected by the S-NAB were generally consistent with those previously observed in samples of cocaine users completing other batteries, as well in other substance abusing samples completing the S-NAB. This suggests that the S-NAB can be considered an additional appropriate battery, as an alternative to other existing batteries, for assessment of the cognitive functioning of adult cocaine users. PMID- 24949997 TI - Focused ultrasound simultaneous irradiation/MRI imaging, and two-stage general kinetic model. AB - Many studies have investigated how to use focused ultrasound (FUS) to temporarily disrupt the blood-brain barrier (BBB) in order to facilitate the delivery of medication into lesion sites in the brain. In this study, through the setup of a real-time system, FUS irradiation and injections of ultrasound contrast agent (UCA) and Gadodiamide (Gd, an MRI contrast agent) can be conducted simultaneously during MRI scanning. By using this real-time system, we were able to investigate in detail how the general kinetic model (GKM) is used to estimate Gd penetration in the FUS irradiated area in a rat's brain resulting from UCA concentration changes after single FUS irradiation. Two-stage GKM was proposed to estimate the Gd penetration in the FUS irradiated area in a rat's brain under experimental conditions with repeated FUS irradiation combined with different UCA concentrations. The results showed that the focal increase in the transfer rate constant of Ktrans caused by BBB disruption was dependent on the doses of UCA. Moreover, the amount of in vivo penetration of Evans blue in the FUS irradiated area in a rat's brain under various FUS irradiation experimental conditions was assessed to show the positive correlation with the transfer rate constants. Compared to the GKM method, the Two-stage GKM is more suitable for estimating the transfer rate constants of the brain treated with repeated FUS irradiations. This study demonstrated that the entire process of BBB disrupted by FUS could be quantitatively monitored by real-time dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). PMID- 24949998 TI - Assessment of PALB2 as a candidate melanoma susceptibility gene. AB - Partner and localizer of BRCA2 (PALB2) interacts with BRCA2 to enable double strand break repair through homologous recombination. Similar to BRCA2, germline mutations in PALB2 have been shown to predispose to Fanconi anaemia as well as pancreatic and breast cancer. The PALB2/BRCA2 protein interaction, as well as the increased melanoma risk observed in families harbouring BRCA2 mutations, makes PALB2 a candidate for melanoma susceptibility. In order to assess PALB2 as a melanoma predisposition gene, we sequenced the entire protein-coding sequence of PALB2 in probands from 182 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, and BAP1. In addition, we interrogated whole-genome and exome data from another 19 kindreds with a strong family history of melanoma for deleterious mutations in PALB2. Here we report a rare known deleterious PALB2 mutation (rs118203998) causing a premature truncation of the protein (p.Y1183X) in an individual who had developed four different cancer types, including melanoma. Three other family members affected with melanoma did not carry the variant. Overall our data do not support a case for PALB2 being associated with melanoma predisposition. PMID- 24950001 TI - Prevalence of dyslipidaemia in patients treated with lipid-lowering agents in China: results of the DYSlipidemia International Study (DYSIS). AB - BACKGROUND: Despite clear guideline recommendations, there is a paucity of data regarding the prevalence and type of persistent lipid profile abnormalities in patients on stable lipid-lowering therapy in China. METHODS: This cross-sectional trial included 25,697 patients treated with lipid-lowering agents from 122 centres between April 2012 and October 2012; all underwent clinical examination and had their latest fasting lipid profiles while on lipid-lowering therapy recorded. Logistic regression was performed to assess predictors for lipid abnormalities classified according to current Chinese guidelines. FINDINGS: Overall, 29.1% of patients had no lipid abnormalities, and 38.5% of patients did not achieve the therapeutic goal for low-density lipoprotein cholesterol (LDL-C), either as a single lipid anomaly or associated with low high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, or both. Subjects with low risk were more likely than those with very high and high risk to be at target LDL-C levels. Furthermore, 10.4% of very high-risk patients and 11.1% of high-risk patients who attained the LDL-C goal failed to attain non-HDL-C goals. Diabetes was shown to be a strong predictor of failure in attaining non-HDL-C and both goals (OR 3.03; 3.22, 95% CI 2.58-3.55; 2.73-3.79, respectively). CONCLUSION: Although great improvements have been made over the past decade, the large majority of very high risk and high-risk patients treated with lipid-lowing agents still had one or more manifestations of dyslipidaemia. Further clinical evidence is needed to clarify whether adding other lipid-lowering agents to a statin will be associated with additional cardiovascular risk reduction. PMID- 24949999 TI - Clathrin-mediated endocytosis is impaired in type A-B Niemann-Pick disease model cells and can be restored by ICAM-1-mediated enzyme replacement. AB - Drugs often use endocytosis to achieve intracellular delivery, either by passive uptake from the extracellular fluid or by active targeting of cell surface features such as endocytic receptors. An example is enzyme replacement therapy, a clinically practiced treatment for several lysosomal storage diseases where glycosylated recombinant enzymes naturally target the mannose-6-phosphate receptor and are internalized by clathrin mediated endocytosis (CME). However, lysosomal substrate accumulation, a hallmark of these diseases, has been indirectly linked to aberrant endocytic activity. These effects are poorly understood, creating an obstacle to therapeutic efficiency. Here we explored endocytic activity in fibroblasts from patients with type A Niemann-Pick disease, a lysosomal storage disease characterized by acid sphingomyelinase (ASM) deficiency. The uptake of fluid phase markers and clathrin-associated ligands, formation of endocytic structures, and recruitment of intracellular clathrin to ligand binding sites were all altered, demonstrating aberrant CME in these cells. Model polymer nanocarriers targeted to intercellular adhesion molecule-1 (ICAM 1), which are internalized by a clathrin-independent route, enhanced the intracellular delivery of recombinant ASM more than 10-fold compared to free enzyme. This strategy reduced substrate accumulation and restored clathrin endocytic activity to wild-type levels. There appears to be a relationship between lysosomal storage and diminished CME, and bypassing this pathway by targeting ICAM-1 may enhance future therapies for lysosomal storage diseases. PMID- 24950000 TI - CETP inhibitors downregulate hepatic LDL receptor and PCSK9 expression in vitro and in vivo through a SREBP2 dependent mechanism. AB - BACKGROUND: CETP inhibitors block the transfer of cholesteryl ester from HDL-C to VLDL-C and LDL-C, thereby raising HDL-C and lowering LDL-C. In this study, we explored the effect of CETP inhibitors on hepatic LDL receptor (LDLR) and PCSK9 expression and further elucidated the underlying regulatory mechanism. RESULTS: We first examined the effect of anacetrapib (ANA) and dalcetrapib (DAL) on LDLR and PCSK9 expression in hepatic cells in vitro. ANA exhibited a dose-dependent inhibition on both LDLR and PCSK9 expression in CETP-positive HepG2 cells and human primary hepatocytes as well as CETP-negative mouse primary hepatocytes (MPH). Moreover, the induction of LDLR protein expression by rosuvastatin in MPH was blunted by cotreatment with ANA. In both HepG2 and MPH ANA treatment reduced the amount of mature form of SREBP2 (SREBP2-M). In vivo, oral administration of ANA to dyslipidemic C57BL/6J mice at a daily dose of 50 mg/kg for 1 week elevated serum total cholesterol by approximately 24.5% (p < 0.05%) and VLDL-C by 70% (p < 0.05%) with concomitant reductions of serum PCSK9 and liver LDLR/SREBP2-M protein. Finally, we examined the in vitro effect of two other strong CETP inhibitors evacetrapib and torcetrapib on LDLR/PCSK9 expression and observed a similar inhibitory effect as ANA in a concentration range of 1-10 MUM. CONCLUSION: Our study revealed an unexpected off-target effect of CETP inhibitors that reduce the mature form of SREBP2, leading to attenuated transcription of hepatic LDLR and PCSK9. This negative regulation of SREBP pathway by ANA manifested in mice where CETP activity was absent and affected serum cholesterol metabolism. PMID- 24950005 TI - Complexity in the therapeutic delivery of RNAi medicines: an analytical challenge. AB - INTRODUCTION: Nucleic acids have witnessed a dramatic acceleration in their therapeutic exploitation and currently represent a growing number of applications in drug development pipelines. However, a more wide-spread development of therapeutics based on nucleic acids is restricted by their poor chemical and enzymatic stability in vivo, lack of cellular uptake and insufficient capability to reach intracellular targets. AREAS COVERED: Advanced formulation of nucleic acids in nano-sized carriers may help unlocking their potential as therapeutic agents. Nano-sized matters own specific features responsible for inducing characteristic interactions with biological molecules and tissues. These properties enable for the enhancement of the nano-formulation's therapeutic efficacy, but on the other hand, the nanomatters interactions in biological fluids are also responsible for adverse effects. The purpose of this review is to reflect on the complexity in the therapeutic delivery of RNA interference-based drugs emerging from the recent clinical experiences and report the actual technological and analytical advances introduced to solve it. EXPERT OPINION: The complexity in the therapeutic delivery of nucleic acids and the heterogeneity of side effects make the interpretation of the therapeutic outcome difficult. Hence the development of analytical approaches applicable in the field of nucleic acid delivery is becoming a major challenge. PMID- 24950003 TI - Influence of storage condition on properties of MCC II-based pellets with theophylline-monohydrate. AB - Microcrystalline cellulose II (MCC II(1)) is a polymorph of commonly used MCC I; in 2010 it was introduced as new pelletization aid in wet extrusion/spheronization leading to fast disintegrating pellets. Previous investigations suggested that the storage of the resulting pellets affect the disintegration behavior, the non-hygroscopic substance chloramphenicol that showed no polymorphism or hydrate formation due to relative humidity was used for the investigations. Therefore, theophylline-monohydrate that can dehydrate during storage, but also during manufacturing and drying was used for this study to confirm the results of the previous study and give a more detailed overview of the influence of recrystallization of theophylline monohydrate on disintegration. Storage recommendations should be derived. MCC II-based pellets were prepared of binary mixtures containing 10%, 20% or 50% MCCII as pelletization aid and theophylline-monohydrate as API. These pellets were stored at different relative humidity (0-97%rH; 20 degrees C); the influence on their disintegration and drug release was investigated. The storage conditions had an impact on pellet disintegration. Low relative humidities (? 40%rH) led to a conversion of the monohydrate to the anhydrous form. Newly grown crystals formed a kind of network around the pellet and inhibited the disintegration. High relative humidity (>80%rh) affected the disintegration caused by changes in the MCCII as already seen in the previous study. Due to the changed disintegration behavior also the drug release and release kinetic changed. Therefore, for theophylline containing pellets a storage humidity of 55%rH to 80%rH (20 degrees C) is recommended. All in all, these investigations substantiate the knowledge of MCCII-based pellets providing a better basis for adequate storage conditions of MCCII based pellets. PMID- 24950002 TI - A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production. AB - OBJECTIVE: We report a novel apolipoprotein (apo) A-I truncation (apoA-IMytilene) due to a heterozygous nonsense mutation (c.718C > T, p.Gln216*) in a 68-year-old male proband with premature coronary heart disease (CHD), corneal arcus, and very low plasma concentrations of HDL cholesterol (HDL-C) and apoA-I. Two family members also had the same mutation. Our objectives were to characterize the kindred and to examine the kinetics of apoA-I, as well as cellular cholesterol efflux capacity in the proband. METHODS: We carried out the kinetic studies using a primed constant infusion of [5,5,5-D3]L-leucine and isotopic enrichment was determined by gas chromatography mass spectrometry in the proband and seven controls with low HDL-C. To assess cellular cholesterol efflux capacity, we used a validated ex vivo system that involved incubation of J774 macrophages with apoB depleted serum from the proband, five controls with normal HDL-C, and two controls with low HDL-C. RESULTS: Stable isotope kinetic studies indicated that the proband had an apoA-I production rate (PR) that was 41% lower than the mean PR observed in low HDL-C controls (n = 7). The cellular cholesterol efflux capacity assessment showed normalized cholesterol efflux capacity in the proband was decreased by 36% compared to the mean normalized cholesterol efflux capacity of normal controls (n = 5). CONCLUSIONS: Our data indicate that this novel heterozygous apoA-I truncation is associated with markedly decreased levels of HDL-C, plasma apoA-I, and apoA-I in large alpha-1 HDL particles, as well as decreased total cellular cholesterol efflux and decreased apoA-I production. PMID- 24950006 TI - Flexible chains of ferromagnetic nanoparticles. AB - We report the fabrication of flexible chains of ferromagnetic Ni nanoparticles that possess the ability to adapt other than the typically observed rigid (nearly) straight configurations in the absence of an external magnetic field. The dynamic mobility of the ferromagnetic chains originates from a layer of densely grafted polyethylene glycol macromolecules enveloping each nanoparticle in the chain. While ferromagnetic chains of unmodified Ni nanoparticles behave as stiff nickel nanorods, the chains made of the grafted nanoparticles demonstrate extreme flexibility. Upon changing the direction of the field, and inevitably going through a zero-field point, the shorter chains undergo chain-globule-chain transformation. The longer chains can bend to a high degree, attaining "snake like" configurations. PMID- 24950007 TI - A simple optical configuration for cell tracking by dark-field microscopy. AB - We describe a simple optical configuration for dark-field microscopy at low magnification, realized with the use of standard microscope components. An inherent high contrast makes this method attractive for computer-assisted tracking and counting of microorganisms. We applied this setup for dark-field microscopy to measure the speed of migrating Dictyostelium amoebae. PMID- 24950009 TI - Spin-semiconducting properties in silicene nanoribbons. AB - We have investigated the relative stabilities and electronic properties of silicene nanoribbons with sawtooth edges (SSiNRs) by first-principles calculations. The SSiNR is more stable than the zigzag silicene nanoribbon (ZSiNR) and has a ferromagnetic ground state with an intrinsic energy gap between majority and minority spin-polarized bands, which shows that SSiNR is a spin semiconductor. Under an external transverse electric field, the energy gap decreases and even vanishes. Meanwhile, the charge densities of the two edge bands near the Fermi level become spatially separated at different edges. We find also that the electric field-induced features can be achieved by a suitable uniaxial compressive strain. This can be understood from the effect of the Wilson transition. At last, the electronic structures of SSiNRs tuned by electric field and strain together are studied, showing that a small tensile strain makes the SSiNRs more sensitive to the electric field. These results suggest that the electric field or/and strain modulated SSiNRs have potential applications in silicon-based spintronic nanodevices. PMID- 24950008 TI - DABCO-based ionic liquids: recyclable catalysts for aza-Michael addition of alpha,beta-unsaturated amides under solvent-free conditions. AB - An array of novel 1,4-diazobicyclo[2.2.2]octane (DABCO) based ionic liquids were developed and used as recyclable catalysts for the aza-Michael addition at room temperature without any organic solvent. [DABCO-PDO][OAc] was found to be the most efficient catalyst, and the amount of catalyst was only 10 mol %. Various amines reacted with a wide range of alpha,beta-unsaturated amides, smoothly affording target products in good to excellent yields within hours. Moreover, the catalyst could be reused up to eight times, still maintaining a high catalytic activity. Finally, a plausible mechanism was proposed. FTIR and computational chemistry were used to verify the catalytic mechanism. PMID- 24950010 TI - Treatment of early Parkinson's disease. AB - PURPOSE OF REVIEW: This review summarizes currently available treatment options and treatment strategies, investigational treatments, and the importance of exercise for early Parkinson's disease. RECENT FINDINGS: The available treatment options for early Parkinson's disease have changed little in the past decade and include carbidopa/levodopa, dopamine agonists, and monoamine oxidase type B (MAO B) inhibitors. However, we discuss changes in treatment strategies, including dosing and the use of combination therapy used in an attempt to reduce or delay the appearance of motor complications and other adverse events. We will also review several investigational treatments that have shown promise for the treatment of early Parkinson's disease, including a new extended release formulation of carbidopa/levodopa (IPX066), safinamide which inhibits MAO-B, dopamine uptake and glutamate and pardoprunox which is a 5HT-1A agonist and a partial dopamine agonist. Finally, we discuss recent studies focusing on exercise as an important component in the management of early Parkinson's disease. SUMMARY: Advances in the management of early Parkinson's disease include evolving treatment strategies, new investigational treatments, and earlier implementation of various forms of exercise. PMID- 24950012 TI - Neuroimaging of therapy-associated brain tissue abnormalities. AB - PURPOSE OF REVIEW: This study summarizes recent advances in neuroimaging of therapy-related brain tissue abnormalities. RECENT FINDINGS: Pseudoprogression constitutes a typical posttherapeutic phenomenon in patients with glioblastoma treated with radiochemotherapy with temozolomide. Advanced MRI techniques, such as diffusion MRI and perfusion MRI, can be helpful to distinguish it from true tumor progression. In clinical trials on amyloid-modifying therapies in Alzheimer's disease patients, previously unknown, characteristic nonhemorrhagic and hemorrhagic amyloid-related imaging abnormalities have been observed. Awareness of this phenomenon is essential for therapy monitoring. Posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome can both occur as a complication of a variety of systemic drug therapies and present with a wide spectrum of clinical and imaging findings. The pathomechanisms underlying these different therapy-related brain tissue changes are only poorly understood. SUMMARY: Neuroimaging, including advanced MRI techniques, plays a key role in the identification and monitoring of therapy associated brain tissue abnormalities. However, future imaging studies should focus on the pathomechanism underlying these phenomena. PMID- 24950013 TI - Update on SPECT and PET in parkinsonism - part 1: imaging for differential diagnosis. AB - PURPOSE OF REVIEW: To give an update on recent findings concerning the use of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) for differential diagnosis and prognosis of neurodegenerative parkinsonism and related disorders. RECENT FINDINGS: Several studies confirmed the very high diagnostic accuracy and clinical impact of imaging nigrostriatal function (most notably with [I]FP-CIT-SPECT) for diagnosing neurodegenerative parkinsonism and dementia with Lewy bodies. Accurate differential diagnosis of neurodegenerative parkinsonism can be achieved by imaging disease-specific patterns of cerebral glucose metabolism with [18F]fluorodeoxyglucose-PET, which surpasses the diagnostic accuracy of other currently available radionuclide imaging techniques. SUMMARY: SPECT and PET are established methods for the differential diagnosis of parkinsonism with significant therapeutic and prognostic impact. Given the limited accuracy of the clinical diagnosis as the reference standard, future studies with post-mortem verification are needed for validation of diagnostic imaging pattern, particularly in tauopathies. PMID- 24950011 TI - Essential tremor: from bedside to bench and back to bedside. AB - PURPOSE OF REVIEW: The last several years have witnessed a remarkable increase in research on essential tremor, with consequent advances in our understanding of this entity. An attempt to both summarize and frame this work has not been undertaken. RECENT FINDINGS: Here, I show that observations on essential tremor arising from clinical practice/clinical studies have guided scientific studies of this disorder. In turn, the results of scientific studies are beginning to be translated back to the bedside to improve treatment. Recent essential tremor research has given rise to several novel and intriguing ideas about the disease. These include the following: essential tremor may represent a family of diseases rather than a single disease; essential tremor seems to be a disease of the cerebellum or cerebellar system; essential tremor may be neurodegenerative; low gamma aminobutyric acid tone seems to be a central feature of essential tremor. As with many emerging ideas, there is significant discussion and debate over these emerging ideas, and this fuels additional scientific studies. SUMMARY: The flow of ideas from clinical observations about essential tremor, to their translation into scientific studies, and their translation back to the bedside, is expected to eventually lead to improvements at the patient interface. PMID- 24950014 TI - Predicting disabilities in daily functioning in older people with intellectual disabilities using a frailty index. AB - Frailty is a state of increased vulnerability to adverse health outcomes compared to others of the same age. People with intellectual disabilities (ID) are more frequently and earlier frail compared to the general population. Frailty challenges much of health care, which will likely further increase due to the aging of the population. Before effective interventions can start, more information is necessary about the consequences of frailty in this, already disabled, population. Here we report whether frailty predicts disabilities in daily functioning. Frailty was measured with a frailty index (FI). At baseline and follow-up activities of daily living (ADL), instrumental activities of daily living (IADL) and mobility were collected by informant report. For 703 older people with ID (>=50 yr) baseline and follow-up measures were known. Multivariate linear regression models were used to predict ADL, IADL and mobility at follow up. The FI was significantly associated with disabilities in daily functioning independent of baseline characteristics (age, gender, level of ID, Down syndrome) and baseline ADL, IADL or mobility. The FI showed to be most predictive for those with relative high independence at baseline. These results stress the importance for interventions that limit the progression of frailty and, thereby, help to limit further disability. PMID- 24950015 TI - Physical fitness is predictive for a decline in daily functioning in older adults with intellectual disabilities: results of the HA-ID study. AB - A high incidence of limitations in daily functioning is seen in older adults with intellectual disabilities (ID), along with poor physical fitness levels. The aim of this study was to assess the predictive value of physical fitness for daily functioning after 3 years, in 602 older adults with borderline to profound ID (>= 50 years). At baseline, physical fitness levels and daily functioning (operationalized as basic activities of daily living [ADL] and mobility) were assessed. After 3 years, the measurements of daily functioning were repeated. At follow-up, 12.6% of the participants were completely independent in ADL and 48.5% had no mobility limitations. More than half of the participants (54.8%) declined in their ability to perform ADL and 37.5% declined in their mobility. Manual dexterity, visual reaction time, balance, comfortable and fast gait speed, muscular endurance, and cardiorespiratory fitness were significant predictors for a decline in ADL. For a decline in mobility, manual dexterity, balance, comfortable and fast walking speed, grip strength, muscular endurance, and cardiorespiratory fitness were all significant predictors. This proves the predictive validity of these physical fitness tests for daily functioning and stresses the importance of using physical fitness tests and implementing physical fitness enhancing programs in the care for older adults with ID. PMID- 24950017 TI - An overview of the state of the art of automated capture of dietary intake information. AB - Significant benefits arise from being able to capture dietary or nutritional intake information automatically or semi-automatically. These include the ability for individuals to know and understand their nutritional intake and hence improve their diet and health. To date, only highly manual processes such as 24-hour recall, food diaries, and food journals have been utilized which have been overly cumbersome for widespread adoption. Emerging informatics, computer vision, mobile computing, and sensor-based approaches are likely to play a role in further automating the capture of dietary intake information and these are becoming increasingly utilizable through such advents as the rapid and ubiquitous uptake of smartphones with built-in digital cameras and other sensors. In this paper, we review the state of the art of technologies for automatic capture of dietary intake information and identify significant outstanding research problems and promising directions. PMID- 24950016 TI - SDF-1 signaling: a promising target in rheumatic diseases. AB - INTRODUCTION: Stromal cell-derived factor 1 (SDF-1) is a potent chemoattractant cytokine with various biological functions such as stem cell mobilization, inflammatory cell infiltration and angiogenesis. Therefore, it has also been implicated in several pathological processes, from ischemic conditions to cancer. Remarkably, SDF-1 and its receptors, CXCR4 and CXCR7, are also present in joint tissues, where they play a role in the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA). AREAS COVERED: This review summarizes the physiological and pathological role of SDF-1 signaling and its involvement in RA and OA. That includes synovial inflammation, bone erosion, cartilage degradation and increased bone turnover. Although this cytokine could play different roles in these rheumatic diseases, specific and differentiated therapeutic targets in each process can be identified. Current therapeutic strategies to block SDF-1 signaling in several diseases and their possible use in rheumatic diseases are also discussed. EXPERT OPINION: Emerging drugs that block CXCR4 or CXCR7 in different disorders may represent promising therapies for rheumatic disease via inhibition of key pathological events involved in the progression of RA and OA. PMID- 24950018 TI - Understanding the economic impacts of disruptions in water service. AB - Over the past decade, there has been much attention focused on community readiness for catastrophic emergency events, such as major natural disasters or terrorist attacks. However, though the economic costs associated with experiencing such an event are high, the probability of such events occurring is quite low. At the same time, less catastrophic events that temporarily disrupt essential services to local areas, such as water and electricity, are quite common. However, there is little research that documents residents' actual economic costs when their water service is disrupted. In this paper, we contribute to the growing literature assigning economic value to residential water service by documenting the economic costs residents report from routine, small-scale water disruptions through focus groups and in-person interviews. We find that residential impacts ranged from over $1400 in savings (from working more hours than usual and eating out less than usual) to a cost of over $1000, with an overall average of $93.96. These costs, particularly when multiplied over a substantial population, become quite significant and demonstrate the importance of studying the economic costs of such events. PMID- 24950019 TI - Teaching teens about sex: a fidelity assessment model for Making Proud Choices. AB - Given the increased necessity for local program administrators to operate evidenced-based programs developed for different target populations and community settings, we present evidence about the effectiveness of a specific adolescent health intervention, Making Proud Choices (MPC). MPC was originally designed for inner city, African-American youth in high HIV communities, but implemented recently in diverse settings shown to be at high risk of teen-pregnancy in Missouri. In light of the pressures for local adaptation of the comprehensive sexual education curriculum, we created a three-pronged fidelity assessment tool. We find that significant gains are reported in terms of knowledge as well as intent to use a condom. Furthermore, these findings are consistently achieved in both urban and rural settings, with foster care youth, and for Whites and African Americans. PMID- 24950020 TI - An expedient approach to pyrrolo[3,2-c]quinolines via regioselective formation of the pyrrole nucleus over indoles. AB - An efficient approach for the synthesis of pyrrolo[3,2-c]quinolines (the core nucleus of the natural product martinellic acid) from protected 2-alkynylanilines via the regioselective formation of pyrroles followed by Heck and intramolecular Michael addition has been described. PMID- 24950021 TI - Determination of expression and activity of genes involved in starch metabolism in Lactobacillus plantarum A6 during fermentation of a cereal-based gruel. AB - Traditional fermented gruels prepared from cereals are widely used for complementary feeding of young children in Africa and usually have a low energy density. The amylase activity of some lactic acid bacteria (LAB) helps increase the energy content of gruels through partial hydrolysis of starch, thus enabling the incorporation of more starchy material while conserving the desired semi liquid consistency for young children. Even if this ability is mainly related to the production of alpha-amylase (E.C. 3.2.1.1), in a recent molecular screening, genes coding for enzymes involved in starch metabolism were detected in the efficient amylolytic LAB Lactobacillus plantarum A6: alpha-glucosidase (E.C. 3.2.1.20), neopullulanase (E.C. 3.2.1.135), amylopectin phosphorylase (E.C. 2.4.1.1) and maltose phosphorylase (E.C. 2.4.1.8). The objective of this study was to investigate the expression of these genes in a model of starchy fermented food made from pearl millet (Pennisetum glaucum). Transcriptional and enzymatic analyses were performed during the 18-h fermentation period. Liquefaction was mainly caused by an extracellular alpha amylase encoded by the amyA gene specific to the A6 strain among L. plantarum species and found in both Lactobacillus amylovorus and Lactobacillus manihotivorans. The second most active enzyme was neopullulanase. Other starch metabolizing enzymes were less often detected. The dynamic detection of transcripts of gene during starch fermentation in pearl millet porridge suggests that the set of genes we investigated was not expressed continuously but transiently. PMID- 24950022 TI - Neurogenins in brain development and disease: an overview. AB - The production of neurons, astrocytes and oligodendrocytes is regulated by a group of transcription factors, which determine cell fates and specify subtype identities in the nervous system. Here we focus on profiling the distinct roles of Neurogenin (Ngn or Neurog) family members during the neuronal development. Ngn proteins are tightly regulated to be expressed at defined times and positions of different progenitor cell pools. In addition to their well-elucidated proneural function, Ngn proteins play various critical roles to specify or maintain cell fate and regulate neurite outgrowth and targeting in the central nervous system. Finally, Ngns have been associated with neuronal disorders. Therefore understanding the function and regulation of Ngns will not only improve the understanding of the molecular mechanism underlying the development of nervous system, but may also provide insight into neuronal disease. PMID- 24950023 TI - Central genes, pathways and modules that regulate bone mass. AB - Bones are structures that give the shape and defined features to vertebrates, protect several soft organs and perform multiple endocrine influences on other organs. To achieve these functions bones are first modeled early during life and then constantly remodeled throughout life. The process of bone (re)modeling happens simultaneously at multitude of locations in the skeleton and ensures that vertebrates have a mechanically strong yet a flexible skeleton to the most part of their life. Given the extent of its occurrence in the body, bone remodeling is a highly energy demanding process and is co-ordinated with other physiological processes as diverse as energy metabolism, sleep-wake cycle and reproduction. Neuronal circuits in the brain play a very important role in the coordination of bone remodeling with other organ system functions, and perform this function in sync with environmental and peripheral hormonal cues. In this review, we will focus on the roles of hormonal signals and neural circuits that originate in, or impinge on, the brain in the regulation of bone mass. We will provide herein an updated view of how advances in molecular genetics have refined the neural circuits involved in the regulation of bone mass, from the whole brain level to the specific neuronal populations and their neurotransmitters. This will help to understand the mechanisms whereby vertebrate brain regulates bone mass by fine tuning metabolic signals that originate in the brain or elsewhere in the body. PMID- 24950024 TI - Expression and induction of small heat shock proteins in rat heart under chronic hyperglycemic conditions. AB - The induction of small heat shock proteins (sHsp) is observed under various stress conditions to protect the cells and organisms from adverse events including diabetes. Diabetic cardiomyopathy is a common complication of diabetes. Therefore, in this study, we investigated the expression of sHsp under chronic hyperglycemic conditions in rat heart. Hyperglycemia was induced in WNIN rats by intraperitoneal injection of streptozotocin and maintained for a period of 12weeks. Expression of sHsp, phosphorylation and translocation of phosphoforms of Hsp27 and alphaB-crystallin (alphaBC) from cytosolic fraction to cytoskeletal fraction was analyzed. While the expression of MKBP, HspB3, alphaBC was found to be increased in diabetic heart, expression of Hsp20 was decreased. Chronic hyperglycemia further induced phosphorylation of alphaBC at S59, S45, Hsp27 at S82, p38MAPK and p44/42MAPK. However, pS59-alphaBC and pS82-Hsp27 were translocated from detergent-soluble to detergent-insoluble fraction under hyperglycemic conditions. Furthermore, the interaction of pS82-Hsp27 and pS59 alphaBC with desmin was increased under hyperglycemia. However, the interaction of alphaBC and pS59-alphaBC with Bax was impaired by chronic hyperglycemia. These results suggest up regulation of sHsp (MKBP, HspB3 and alphaBC), phosphorylation and translocation of Hsp27 and alphaBC to striated sarcomeres and impaired interaction of alphaBC and pS59-alphaBC with Bax under chronic hyperglycemia. PMID- 24950025 TI - The spectrum of lung disease due to chronic occult aspiration. AB - RATIONALE: Chronic aspiration of small volumes of oral and gastric contents can lead to lung disease. This process is less familiar than the acute aspiration syndromes, which can create confusion in terminology as well as with radiologic and pathologic definitions. OBJECTIVES: In this study we analyze a series of cases of patients with chronic occult aspiration to better define the disease process. METHODS: Twenty-five patients with chronic occult aspiration as defined pathologically on lung biopsy were studied by means of retrospective review of their case records. Clinical associations and radiologic and pathologic patterns were noted. MEASUREMENTS AND MAIN RESULTS: Among patients with chronic occult aspiration, there was a high prevalence of gastroesophageal reflux disease (96%), esophageal dysfunction (40%), oropharyngeal/laryngeal dysfunction (40%), hiatal hernias (32%), obstructive sleep apnea (32%), and obesity (52%). The radiologic presentation was typically one of multilobar centrilobular nodularity, tree-in bud, and airway thickening, with a subset of patients having evidence of fibrosis. The disease presented pathologically with exogenous lipoid pneumonia, poorly formed granulomas, and foreign body-type multinucleated giant cells with or without foreign material. Pathologic fibrosis was also seen. CONCLUSION: In this study, chronic occult aspiration was associated with a number of comorbid conditions and a spectrum of radiologic and pathologic patterns, which in some patients included fibrosis. PMID- 24950027 TI - Cord blood CD4(+)CD25(+) regulatory T cells fail to inhibit cord blood NK cell functions due to insufficient production and expression of TGF-beta1. AB - Although CD4(+)CD25(+) Treg (Treg) cells are known to modulate NK cell functions, the modulation mechanism of these cells in cord blood has not been fully clarified. The purpose of this study was to clarify the mechanism whereby cord blood Treg cells modulate cord NK cells. By performing various cultures of purified NK cells with or without autologous Treg cells, diminished inhibitory effects of cord Treg cells towards cord NK cell functions, including activation, cytokine production, and cytotoxicity, were observed. We also observed lower secretion of sTGF-beta1 and lower expression of mTGF-beta1 by cord Treg cells than by adult Treg cells. These data revealed the capability of adult Treg cells to suppress rhIL-2-stimulated NK cell function by TGF-beta1, both membrane-bound and soluble types. The reduced inhibitory capabilities of cord Treg cells compared with adult Treg cells is thought to be due to insufficient expression of TGF-beta1. PMID- 24950028 TI - Metabolomic analysis of Entamoeba: applications and implications. AB - Entamoeba histolytica is an enteric protozoan parasite that causes hemorrhagic dysentery and extraintestinal abscesses in millions of inhabitants of endemic areas. The genome of E. histolytica has already been sequenced and used to predict the metabolic potential of the organism. Since nearly 56% of the E. histolytica genes remain unannotated, correlative 'omics' analyses of genomics, transcriptomics, proteomics, and biochemical metabolic profiling are essential in uncovering new, or poorly understood metabolic pathways. Metabolomics aims at understanding biology by comprehensive metabolite profiling. In this review, we discuss recent metabolomics approaches to elucidate unidentified metabolic systems of this pathogen and also discuss future applications of metabolomics to understand the biology and pathogenesis of E. histolytica. PMID- 24950026 TI - ADAM10 is required for SCF-induced mast cell migration. AB - A Disintegrin and Metalloproteinase (ADAM)-10 plays critical roles in neuronal migration and distribution. Recently, ADAM10 deletion was shown to disrupt myelopoiesis. We found that inducible deletion of ADAM10 using Mx1-driven Cre recombinase for a period of three weeks resulted in mast cell hyperplasia in the skin, intestine and spleen. Mast cells express surface ADAM10 in vitro and in vivo, at high levels compared to other immune cells tested. ADAM10 is important for mast cell migration, since ADAM10-deficiency reduced c-Kit-mediated migration. As with some mast cell proteases, ADAM10 expression could be altered by the cytokine microenvironment, being inhibited by IL-10 or TGFbeta1, but not by several other T cell-derived cytokines. Collectively these data show that the ADAM10 protease is an important factor in mast cell migration and tissue distribution, and can be manipulated by environmental cues. PMID- 24950030 TI - Sequestered fulvinol-related polyacetylenes in Peltodoris atromaculata. AB - The Mediterranean dorid nudibranch Peltodoris atromaculata that had been collected while feeding on Haliclona fulva was shown to sequester long-chain fulvinol-like polyacetylene metabolites (compounds 2-5) from the prey. They were isolated along with previously reported bromorenierins from the diethyl ether extracts of both the mollusk and the sponge. Their structures were elucidated by NMR spectroscopy and tandem FABMS analysis. Compound 5 exhibited in vitro growth inhibitory effects against the SKMEL-28 melanoma cell line. PMID- 24950031 TI - Nutrition and age-related macular degeneration: research evidence in practice. AB - Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment in developed countries. In the absence of effective treatments to slow AMD progression, it is predicted that the prevalence of AMD will double over the next 20 years. One area of significant interest is the potential role that nutrition may play in preventing and/or delaying the progression of AMD. Specifically, is there any benefit in oral antioxidant and/or mineral supplementation? This review critically evaluates the currently available evidence relating to nutrition and AMD, with particular reference to the key findings of two large National Eye Institute-sponsored clinical studies, namely, the Age-Related Eye Disease Study (AREDS) and AREDS2. Topical controversies relating to nutrition and AMD are considered and analyzed in the context of the published literature to guide practitioners through assessing the merit, or otherwise, of common claims. This article provides a foundation for clinicians to provide informed advice to AMD patients based on available research evidence. PMID- 24950032 TI - Reticular pseudodrusen in age-related macular degeneration. AB - Historically, drusen, which are recognized as the hallmark of age-related macular degeneration (AMD), have been described in terms of size, margins, and texture, and several studies have emphasized the importance of large soft drusen particularly when combined with focal pigmentary irregularities in determining the risk of progression to neovascular AMD. However, recent developments in imaging over the past decade have revealed a further distinct phenotype strongly associated with the development of late AMD, namely, reticular pseudodrusen (RPD) or reticular drusen. Reticular pseudodrusen appear as yellowish interlacing networks in the fundus and, although visible on color photography, are better visualized using infrared imaging or spectral domain optical coherence tomography. Studies correlating spectral domain optical coherence tomography and confocal scanning laser ophthalmoscopy have shown that RPD are subretinal deposits located internal to the retinal pigment epithelium in contrast to traditional drusen, which are located external to the retinal pigment epithelium. As multiple longitudinal studies have revealed RPD are strong predictors for progression to both neovascular AMD and geographic atrophy, the interest in understanding the role that RPD play in the pathogenesis of AMD has grown. This review focuses on the current literature concerning RPD and considers what is currently known regarding their epidemiology, risk factors, appearance in both retinal imaging and histology, impact on visual function, relationship to other AMD lesions, and association with the development of late AMD. PMID- 24950029 TI - Serum lipoprotein composition and vitamin D metabolite levels in clinically isolated syndromes: Results from a multi-center study. AB - CONTEXT: High serum cholesterol is adversely associated with clinical and imaging disease progression outcomes in multiple sclerosis (MS) and in clinically isolated syndrome (CIS), the earliest stage of MS. Low vitamin D levels are associated with an increased risk of disease progression. OBJECTIVES: To investigate the mechanisms mediating the adverse effects of cholesterol in CIS and to determine the role of the nexus between the vitamin D3 (D3) and cholesterol pathways. DESIGN: Multi-center, prospective, longitudinal prospective study. SETTING: University hospital multiple sclerosis centers. INTERVENTION: Serum samples were obtained prior to any treatment from study subjects. METHODS: Serum obtained prior to any treatment from 172 CIS patients enrolled in a multi center, prospective, longitudinal study (119 females: 53 males, age: 28.1 +/- SD 8.1 years) were analyzed for high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein AI (ApoAI), ApoAII, ApoB, ApoE, and lipoprotein-a. Levels of 25-hydroxy vitamin D3 (25(OH)D3), 1,25 dihydroxy D3, and 24,25-dihydroxy D3 were measured using liquid chromatography mass spectrometry. RESULTS: Greater levels of HDL-C biomarkers (e.g., HDL-C itself, ApoAI, ApoAII and paroxonase arylesterase activity) and LDL-C biomarkers (e.g., LDL-C itself, Apo B) were associated with greater 25(OH)D3. The effects of HDL-C biomarkers were stronger than those of LDL-C. Free cholesterol and cholesteryl ester levels were positively associated with higher 25(OH)D3 levels. Cholesterol palmitate was particularly potent. The nexus between the D3 and cholesterol pathways was proximal to, or in linkage disequilibrium with, 7 dehydrocholesterol reductase DHCR7 rs1790349, endothelial lipase LIPG rs4939883 and proprotein convertase subtilisin/kexin type 9 PCSK9 rs11206510. CONCLUSIONS: The associations between cholesterol biomarkers and vitamin D metabolite levels in CIS are consistent with the biochemical inter-dependence between the two pathways. Cholesterol biomarkers should be considered for inclusion as covariates when assessing vitamin D levels in CIS. PMID- 24950033 TI - Abstracts of the 3rd Regional IGCS Meeting 2014, May 16-18, 2014, Cape Town, South Africa. PMID- 24950034 TI - Osteogenesis imperfecta types I-XI: implications for the neonatal nurse. AB - Osteogenesis imperfecta (OI), also called "brittle bone disease," is a rare heterozygous connective tissue disorder that is caused by mutations of genes that affect collagen. Osteogenesis imperfecta is characterized by decreased bone mass, bone fragility, and skin hyperlaxity. The phenotype present is determined according to the mutation on the affected gene as well as the type and location of the mutation. Osteogenesis imperfecta is neither preventable nor treatable. Osteogenesis imperfecta is classified into 11 types to date, on the basis of their clinical symptoms and genetic components. This article discusses the definition of the disease, the classifications on the basis of its clinical features, incidence, etiology, and pathogenesis. In addition, phenotype, natural history, diagnosis and management of this disease, recurrence risk, and, most importantly, the implications for the neonatal nurse and management for the family are discussed. PMID- 24950035 TI - Neonatal peripherally inserted central catheter practices and their association with demographics, training, and radiographic monitoring: results from a national survey. AB - The goal of this secondary analysis of results from a national survey of peripherally inserted central catheters (PICCs) practices in neonates was to determine whether demographics and types of training were associated with differing radiographic confirmation practices of these catheters. Correlational analyses were performed on the 2010 national database of neonatal PICC practices. The sample consisted of 187 respondents, representing 25% of the level III neonatal intensive care units (NICUs) of more than 20 beds in the United States. The key factors examined were geographic location, size of NICU, academic affiliation, and type of training related to radiographic confirmation of the catheter tip position, routine monitoring and reconfirmation of the catheter tip position following adjustments, and associated patient positioning practices for consistent evaluation of the catheter tip position. Formal training and annual retraining were statistically significantly associated with consistent patient positioning practices for more accurate monitoring of the catheter tip position and acceptable tip location. Size of NICU and academic affiliation were not associated with differences in practices. Adherence to specific national guidelines and recommendations for care of infants with PICCs is significantly impacted by formal training and annual retraining. This underscores the importance of education and annual retraining in preventing PICC-related complications beyond the crucial prevention of central line-associated bloodstream infections. PMID- 24950036 TI - Simulating Hydrogen-Bond Structure and Dynamics in Glassy Solids Composed of Imidazole Oligomers. AB - We simulated structural and dynamical properties of imidazoles tethered to aliphatic backbones to determine how chain length influences the competition between extended hydrogen-bond networks and imidazole reorientation dynamics. We performed molecular dynamics simulations on hypothetical solids using the GAFF Amber force field over the temperature range 300-800 K, for chain lengths varying from monomers to pentamers. We investigated the effect of heterogeneity by simulating monodisperse and polydisperse solids with the same average chain length. We computed hydrogen-bond cluster sizes and percolation ratios; orientational order parameters associated with imidazole rings, tethering linkers, and backbones; and orientational correlation functions for imidazole rings. We found the surprising result that chain-length heterogeneity negligibly affects system density at standard pressure, the fraction of percolating hydrogen bonded clusters, and the order parameters for backbone, linker, and imidazole ring. Decreasing oligomer chain length from pentamers to shorter chains decreases the tendency to form percolating hydrogen-bond networks while dramatically decreasing imidazole ring reorientation times from a broad range of 100-700 ps for pentamers down to 20 ps for monomers, hence quantifying the competition between hydrogen-bond cluster size and reorientation rate. The computed orientational order parameters suggest the following hierarchy of structural excitations: imidazole ring reorientation in the range 400-500 K, linker motion around 500-600 K, and backbone relaxation at 600-700 K in this model. The question remains for this class of systems which of these motions is crucial for facile proton transport. PMID- 24950039 TI - Leiomyosarcoma of the breast. AB - Leiomyosarcomas of the breast are rare tumors. Less than 16 such cases have been reported in the literature so far. We present a case of a 44 year female patient who was found to have primary leiomyosarcoma of the breast. PMID- 24950040 TI - Mucin lakes or perforation? AB - We are reporting two cases with similar appearances on post chemo radiotherapy MRI scan of the mucinous adenocarcinoma. There was high signal on T2-weighted sequences of the mucin pools within and beyond the rectal wall. Does this imply that wall tissues become less resistant to cancer pools intrusion after chemo radiation? Does the high intramural pressure have an impact on the protrusion of the cancer pools beyond the muscularis propria? Final histology reports differ from predicted MRI staging. It highlights the difficulty of the final MRI staging and outcome for mucinous adenocarcinomas. The presence of acellular mesothelial reaction, acellular mucin pools and inflammation extending to the serosal surface causes considerable confusion and may result in over staging or under staging of mucinous adenocarcinoma. Pathogenesis and prediction of the mucin lakes behaviour prior and post chemoradiotherapy is unclear and requires future study but may impact surgical management. PMID- 24950037 TI - Decreased Langerhans cell responses to IL-36gamma: altered innate immunity in patients with recurrent respiratory papillomatosis. AB - Recurrent respiratory papillomatosis (RRP) is a rare, chronic disease caused by human papillomaviruses (HPVs) types 6 and 11 that is characterized by the polarization of adaptive immune responses that support persistent HPV infection. Respiratory papillomas express elevated mRNA levels of IL-36gamma, a proinflammatory cytokine in comparison to autologous clinically normal laryngeal tissues; however there is no evidence of inflammation in these lesions. Consistent with this, respiratory papillomas do not contain TH1-like CD4(+) T cells or cytotoxic CD8(+) T-cells, but instead contain a predominance of TH2-like and T regulatory cells (Tregs). In addition, papillomas also are infiltrated with immature Langerhans cells (iLCs). In this study, we show that papilloma cells express IL-36gamma protein, and that human keratinocytes transduced with HPV11 have reduced IL-36gamma secretion. We now provide the first evidence that peripheral blood-derived iLCs respond to IL-36gamma by expressing inflammatory cytokines and chemokines. When stimulated with IL-36gamma, iLCs from patients with RRP had lower expression levels of the TH2-like chemokine CCL-20 as compared with controls. Patients' iLCs also had decreased steady state levels of CCL-1, which is a proinflammatory chemokine. Moreover, CCL-1 levels in iLCs inversely correlated with the severity of RRP. The combined decrease of TH1- and a TH2-like chemokines by iLCs from patients could have consequences in the priming of IFN gamma expression by CD8(+) T-cells. Taken together, our results suggest that, in RRP, there is a defect in the proinflammatory innate immune responses made by iLCs in response to IL-36gamma. The consequence of this defect may lead to persistent HPV infection by failing to support an effective HPV-specific, TH1 like and/or Tc1-like adaptive response, thus resulting in the predominant TH2 like and/or Treg micromilieu present in papillomas. PMID- 24950041 TI - A pain in the neck: a rare case of isolated hyoid bone trauma. AB - We report the first case of dislocation of the symphysis between the great cornu and the body of the hyoid bone following strangulation in survivors. The present paper presents a rare case of injury to the hyoid bone and reviews the current knowledge on hyoid bone injuries in survivors. PMID- 24950042 TI - Laparoscopic partial splenectomy for littoral cell angioma. AB - Littoral cell angioma (LCA) is a rare benign splenic vascular neoplasm. We report a case of a 58-year-old man with a 5.5-cm lesion in the upper pole of the spleen. A laparoscopic partial splenectomy was performed. He was discharged on the second postoperative day. Pathology revealed LCA. Laparoscopic partial splenectomy can be performed safely in selected cases and is an appropriate option in patients with benign conditions as it enables preservation of the immunologic function of the spleen. Long-term follow up in patients with LCA is important given its high association with other malignancies. PMID- 24950043 TI - A strange case of ingrown toenail treated with phenol. AB - We experienced a strange case of ingrown toenail, which had developed as a huge mass and enveloped the nail of the left first toe. The patient had self-treated his ingrown toenail for a period of one year with an ointment available over the counter. However, the granulation tissue on both sides of the nail had increased gradually and advanced over the nail plate in the medial direction. Finally, the granulation tissue on both sides had adhered to the nail and epithelial cells advanced over the granulation tissue completely. During surgery, the epithelized granulation tissue was excised at the bilateral terminal base point, and the posterior nail fold and the nail matrix were cauterized completely with phenol. Eighteen months after the operation there was no recurrence of the ingrown toenail. PMID- 24950044 TI - Delayed presentation of post traumatic diaphragmatic hernia. AB - Blunt traumatic diaphragmatic rupture is an uncommon but severe problem that is usually seen in polytraumatized patients including blunt abdomino-thoracic trauma due to road traffic accidents, fall from height and penetrating injuries. Regardless of the mechanism, diagnosis is often missed and high index of suspicion is vital. Late presentations are associated with increased morbidity. We report an interesting case of blunt traumatic diaphragmatic hernia in a 32 year-old man presenting 4 years after the initial abdomino-thoracic injury due to fall from height. He had herniation of the spleen and stomach. Through a left sub costal incision, the herniated organs were reduced and diaphragmatic defect closed with interrupted prolene suture. PMID- 24950045 TI - Superior vena cava syndrome secondary to thyroid cancer. AB - It is uncommon for thyroid cancer to present with superior vena cava syndrome. Obstruction of superior vena cava can develop as a result of intrinsic and extrinsic spread of the thyroid cancer. The usual presentation of this disease entity is a neck mass with symptoms and signs suggestive of superior vena cava obstruction. Superior vena cava obstruction is commonly caused by lung cancer and lymphoma. However, thyroid cancer can cause superior vena cava obstruction by downward tumour spread into the mediastinum causing extrinsic compression, which will lead to narrowing and thrombosis of the major venous system in the chest. Paraganglioma can also present with superior vena cava obstruction and it mimics thyroid cancer microscopically. Proper staining should be performed to differentiate between the two diseases. This could be the first case of this kind reported in the literature. PMID- 24950046 TI - The Thomas Repair of the strangulated femoral hernia - one skin incision for all. AB - Several methods of femoral hernia repair have been described. It is the one most likely to strangulate, its repair must often be accompanied by examination of, and sometimes resection of, bowel or omentum. We describe a new method to repair such a hernia. PMID- 24950048 TI - Unraveling the mechanisms involved in zearalenone-mediated toxicity in permanent fish cell cultures. AB - The world-wide occurrence of zearalenone (ZEN) as a contaminant in feed for farm animals and fish requires the evaluation of toxicity mechanisms of action of ZEN. The present study investigates possible metabolization of ZEN in fish cell lines suggesting that mainly glucuronidation takes place. It demonstrates that concentrations up to 20,000 ng ml(-1) ZEN are capable of influencing cell viability in permanent fish cell cultures in a dose-response manner with different response patterns between the five tested cell lines, whereby lysosomes appeared to be the main target of ZEN. ZEN toxicity is often discussed in the context of oxidative stress. Our study shows a biphasic response of the cell lines when reactive oxygen species (ROS) production is monitored. Damage in cells was observed by measuring lipid peroxidation, DNA strand breaks, and alterations of intracellular glutathione levels. Metabolization of ZEN, especially at concentrations above 7500 ng ml(-1) ZEN, does not prevent cytotoxicity. ZEN as an estrogenic compound may involve processes mediated by binding to estrogen receptors (ER). Since one cell line showed no detectable expression of ER, an ER mediated pathway seems to be unlikely in these cells. This confirms a lysosomal pathway as a main target of ZEN in fish cells. PMID- 24950047 TI - Pleiotropic effect of AccD5 and AccE5 depletion in acyl-coenzyme A carboxylase activity and in lipid biosynthesis in mycobacteria. AB - Mycobacteria contain a large variety of fatty acids which are used for the biosynthesis of several complex cell wall lipids that have been implicated in the ability of the organism to resist host defenses. The building blocks for the biosynthesis of all these lipids are provided by a fairly complex set of acyl-CoA carboxylases (ACCases) whose subunit composition and roles within these organisms have not yet been clearly established. Previous biochemical and structural studies provided strong evidences that ACCase 5 from Mycobacterium tuberculosis is formed by the AccA3, AccD5 and AccE5 subunits and that this enzyme complex carboxylates acetyl-CoA and propionyl-CoA with a clear substrate preference for the latest. In this work we used a genetic approach to unambiguously demonstrate that the products of both accD5 and accE5 genes are essential for the viability of Mycobacterium smegmatis. By obtaining a conditional mutant on the accD5-accE5 operon, we also demonstrated that the main physiological role of this enzyme complex was to provide the substrates for fatty acid and mycolic acid biosynthesis. Furthermore, enzymatic and biochemical analysis of the conditional mutant provided strong evidences supporting the notion that AccD5 and/or AccE5 have an additional role in the carboxylation of long chain acyl-CoA prior to mycolic acid condensation. These studies represent a significant step towards a better understanding of the roles of ACCases in mycobacteria and confirm ACCase 5 as an interesting target for the development of new antimycobacterial drugs. PMID- 24950049 TI - Toxin gene determination and evolution in scorpaenoid fish. AB - In this study, we determine the toxin genes from both cDNA and genomic DNA of four scorpaenoid fish and reconstruct their evolutionary relationship. The deduced protein sequences of the two toxin subunits in Sebastapistes strongia, Scorpaenopsis oxycephala, and Sebastiscus marmoratus are about 700 amino acid, similar to the sizes of the stonefish (Synanceia horrida, and Synanceia verrucosa) and lionfish (Pterois antennata and Pterois volitans) toxins previously published. The intron positions are highly conserved among these species, which indicate the applicability of gene finding by using genomic DNA template. The phylogenetic analysis shows that the two toxin subunits were duplicated prior to the speciation of Scorpaenoidei. The precedence of the gene duplication over speciation indicates that the toxin genes may be common to the whole family of Scorpaeniform. Furthermore, one additional toxin gene has been determined in the genomic DNA of Dendrochirus zebra. The phylogenetic analysis suggests that an additional gene duplication occurred before the speciation of the lionfish (Pteroinae) and a pseudogene may be generally present in the lineage of lionfish. PMID- 24950051 TI - Toxicity of Bothrops sp snake venoms from Ecuador and preclinical assessment of the neutralizing efficacy of a polyspecific antivenom from Costa Rica. AB - The toxicological profile of the venoms of the snakes Bothrops asper and Bothrops atrox from Ecuador was investigated, together with the venom of a population of B. asper formerly classified as 'Bothrops xanthogrammus'. The three venoms exerted lethal, hemorrhagic, myotoxic, coagulant and defibrinogenating effects, in agreement with the characteristic toxicological profile of Bothrops sp venoms. A polyspecific antivenom (bothropic-crotalic-lachesic) manufactured in Costa Rica was assessed for its preclinical efficacy against the toxic activities of these Ecuadorian venoms. Antivenom was effective in the neutralization of the five activities tested in the three venoms. These observations are in agreement with previous reports on the extensive cross-reactivity and paraspecific neutralization of antivenoms manufactured in Latin America against the venoms of Bothrops sp snakes. PMID- 24950050 TI - Prevention and treatment of Clostridium perfringens epsilon toxin intoxication in mice with a neutralizing monoclonal antibody (c4D7) produced in Nicotiana benthamiana. AB - Epsilon toxin (ETX), produced by Clostridium perfringens types B and D, is among the most lethal toxins known. ETX is a potential bioterrorism threat that was listed as a Category B agent by the U.S. Centers for Disease Control until 2012 and it still remains a toxin of interest for several government agencies. We produced a monoclonal antibody (MAb) against ETX (ETX MAb c4D7) in Nicotiana benthamiana and characterized its preventive and therapeutic efficacy in mice. The ETX preparation used was highly lethal for mice (LD50 = 1.6 MUg/kg) and resulted in a mean time from inoculation to death of 18 and 180 min when administered intravenously or intraperitoneally, respectively. High lethal challenge resulted in dramatic increases of a variety of pro-inflammatory cytokines in serum, while lower, but still lethal doses, did not elicit such responses. ETX MAb c4D7 was highly effective prophylactically (ED50 = 0.3 mg/kg; ED100 = 0.8 mg/kg) and also provided protection when delivered 15-30 min post-ETX intoxication. These data suggest that ETX MAb c4D7 may have use as a pre- and post-exposure treatment for ETX intoxication. PMID- 24950053 TI - Flapless versus conventional flapped dental implant surgery: a meta-analysis. AB - The aim of this study was to test the null hypothesis of no difference in the implant failure rates, postoperative infection, and marginal bone loss for patients being rehabilitated by dental implants being inserted by a flapless surgical procedure versus the open flap technique, against the alternative hypothesis of a difference. An electronic search without time or language restrictions was undertaken in March 2014. Eligibility criteria included clinical human studies, either randomized or not. The search strategy resulted in 23 publications. The I2 statistic was used to express the percentage of the total variation across studies due to heterogeneity. The inverse variance method was used for random-effects model or fixed-effects model, when indicated. The estimates of relative effect were expressed in risk ratio (RR) and mean difference (MD) in millimeters. Sixteen studies were judged to be at high risk of bias, whereas two studies were considered of moderate risk of bias, and five studies of low risk of bias. The funnel plots indicated absence of publication bias for the three outcomes analyzed. The test for overall effect showed that the difference between the procedures (flapless vs. open flap surgery) significantly affect the implant failure rates (P = 0.03), with a RR of 1.75 (95% CI 1.07 2.86). However, a sensitivity analysis revealed differences when studies of high and low risk of bias were pooled separately. Thus, the results must be interpreted carefully. No apparent significant effects of flapless technique on the occurrence of postoperative infection (P = 0.96; RR 0.96, 95% CI 0.23-4.03) or on the marginal bone loss (P = 0.16; MD -0.07 mm, 95% CI -0.16-0.03) were observed. PMID- 24950054 TI - The effect of parent involvement in the treatment of anxiety disorders in children: a meta-analysis. AB - Among clinicians, it is common practice to include parents in treatment, and it has been taken for granted that parents' involvement in their children's treatment is beneficial for therapy outcome, although research on this issue is far from clear. A meta-analysis was carried out in order to investigate whether parent involvement potentiates the outcome for children with anxiety disorders when treated with cognitive-behavior therapy. Sixteen studies, which directly compared parent-involved treatments with child-only treatments, were included in the meta-analysis. The results showed a small, nonsignificant effect size of - 0.10 in favor of the child-only treatments. There was no indication of publication bias in the analysis. Implications of the results are discussed. PMID- 24950052 TI - Lifetime-dependent effects of bisphenol A on asthma development in an experimental mouse model. AB - BACKGROUND: Environmental factors are thought to contribute significantly to the increase of asthma prevalence in the last two decades. Bisphenol A (BPA) is a xenoestrogen commonly used in consumer products and the plastic industry. There is evidence and an ongoing discussion that endocrine disruptors like BPA may affect human health and also exert alterations on in the immune system. The aim of this study was to investigate age-dependent effects of BPA on the asthma risk using a murine model to explain the controversial results reported till date. METHODS: BALB/c mice were exposed to BPA via the drinking water for different time periods including pregnancy and breastfeeding. To induce an asthma phenotype, mice were sensitized to ovalbumin (OVA), followed by an intrapulmonary allergen challenge. RESULTS: BPA exposure during pregnancy and breastfeeding had no significant effect on asthma development in the offspring. In contrast, lifelong exposure from birth until the last antigen challenge clearly increased eosinophilic inflammation in the lung, airway hyperreactivity and antigen specific serum IgE levels in OVA-sensitized adult mice compared to mice without BPA exposure. Surprisingly, BPA intake during the sensitization period significantly reduced the development of allergic asthma. This effect was reversed in the presence of a glucocorticoid receptor antagonist. CONCLUSIONS: Our results demonstrate that the impact of BPA on asthma risk is strongly age dependent and ranges from asthma-promoting to asthma-reducing effects. This could explain the diversity of results from previous studies regarding the observed health impact of BPA. PMID- 24950055 TI - Self-reported comfort treating severe mental illnesses among pre-doctoral graduate students in clinical psychology. AB - BACKGROUND: One possible explanation for the dearth of psychologists working in severe mental illness (SMI) areas is a lack of training opportunities. Recent studies have shown that while training opportunities have increased, there remain fewer resources available for SMI training compared to other disorders. AIM: Examines whether students express discomfort working with this population and whether they are satisfied with their level of training in SMI. METHODS: One hundred sixty-nine students currently enrolled in doctoral programs in clinical psychology in the United States and Canada were surveyed for their comfort treating and satisfaction with training related to a number of disorders. RESULTS: RESULTS indicate that students are significantly less comfortable treating and finding a referral for a patient with schizophrenia as well as dissatisfied with their current training in SMI and desirous of more training. Regression analyses showed that dissatisfaction with training predicted a desire for more training; however, discomfort in treating people with SMI did not predict a desire for more training in this sample. This pattern generally held across disorders. CONCLUSIONS: Our results suggest general discomfort among students surveyed in treating SMI compared to other disorders. PMID- 24950056 TI - Socioeconomic status and trajectory of overweight from birth to mid-childhood: the Early Childhood Longitudinal Study-Birth Cohort. AB - OBJECTIVE: Our objective was to use longitudinal data from a US birth cohort to test whether the probability of overweight or obesity during the first 6 years of life varied according to socioeconomic status. DESIGN AND METHODS: Using six waves of longitudinal data from full-term children in the Early Childhood Longitudinal Study-Birth Cohort (2001-2007; n~4,950), we examined the prevalence of overweight or obesity (Body Mass Index (BMI)>2 standard deviations above age- and sex- specific WHO Childhood Growth Standard reference mean; henceforth, "overweight/obesity") according to age, socioeconomic status, and race/ethnicity using generalized estimating equation models. RESULTS: The association between socioeconomic status and overweight/obesity varied significantly by race/ethnicity, but not by sex. Overweight/obesity was significantly associated with socioeconomic status among whites, Hispanics and Asians; the adjusted odds of overweight/obesity began to diverge according to SES after the first 9 months of life. By approximately 4 years, children with the highest SES had a significantly lower odds of overweight/obesity. SES was not significantly related to overweight/obesity among African Americans and American Indians during early childhood. CONCLUSIONS: Few studies have assessed the associations between SES and overweight/obesity within racial/ethnic groups in the US. We find that in contemporary, US-born children, SES was inversely associated with overweight/obesity among more racial/ethnic groups (whites, Hispanics, and Asians) than previously reported. PMID- 24950057 TI - Ultrafast charge carrier recombination and trapping in hematite photoanodes under applied bias. AB - Transient absorption spectroscopy on subpicosecond to second time scales is used to investigate photogenerated charge carrier recombination in Si-doped nanostructured hematite (alpha-Fe2O3) photoanodes as a function of applied bias. For unbiased hematite, this recombination exhibits a 50% decay time of ~6 ps, ~10(3) times faster than that of TiO2 under comparable conditions. Anodic bias significantly retards hematite recombination dynamics, and causes the appearance of electron trapping on ps-MUs time scales. These ultrafast recombination dynamics, their retardation by applied bias, and the associated electron trapping are discussed in terms of their implications for efficient water oxidation. PMID- 24950058 TI - Poor compliance with community-acquired pneumonia antibiotic guidelines in a large Australian private hospital emergency department. AB - AIMS: This study evaluated guideline concordance and time to administration of antibiotics in community-acquired pneumonia (CAP) in a private Australian emergency department (ED). Two key components in the management of CAP are timely administration and appropriate choice of antibiotic therapy. The use of antibiotics outside of guidelines can potentially increase rates of antibiotic resistance. Previous studies that evaluate guideline concordance have largely been conducted in Australian public hospitals; however, private hospitals comprise a significant portion of Australian health care. METHODS: One hundred and thirty patients admitted to a private Brisbane hospital between 01/01/2011 and 28/03/2012 with an admission diagnosis of CAP were included. Data were collected on administration time and choice of antibiotic therapy in the ED. This was compared with local and national CAP guidelines. RESULTS: Concordance with antibiotic guidelines was low (6.9%). Antibiotics with broader spectrum of action than that recommended in guidelines were frequently prescribed. Eighty-one percent of patients received their first antibiotic within 4 hours of arriving in the ED. Mortality was low at 0.9% in a cohort where 31% of patients were aged under 65. CONCLUSIONS: We found low rates of concordance with CAP antibiotic guidelines and high use of broad-spectrum antibiotics. This has the potential to lead to increased rates of antibiotic resistance. A subtle alteration to the restrictions within the pharmaceutical benefit scheme formulary could potentially decrease the high usage of broad-spectrum antibiotics. However, the low mortality rate, nontoxic nature of these antibiotics, and the ease of their administration pose a challenge to convincing clinicians to alter their practice. PMID- 24950060 TI - Aspergers--different, not less: occupational strengths and job interests of individuals with Asperger's Syndrome. AB - Rooted in the neurodiversity approach, this study provides an overview of the strengths and interests of individuals with Asperger's Syndrome. We interviewed 136 individuals with Asperger's Syndrome and 155 neurotypical individuals via an online survey with regards to (a) demography, (b) occupational strengths, (c) general self-efficacy, (d) occupational self-efficacy, and (e) the job interest profile according to Holland. The vocational and educational fields of the individuals with Asperger's in the sample are more diverse than and surpass those classical fields stated in research and biographical literature. The comparison of both groups in cross-tables showed that the indicated strengths differ in several areas (PhiCramer = .02-.47), which means that a specific strength profile can be derived, and this profile goes beyond the clinical view of the diagnostic criteria. Individuals with Asperger's indicate lower self-efficacy, both general and occupational. Furthermore, a high concentration of individuals with Asperger's can be found in the areas I (Investigative) and C (Conventional) of Holland's RIASEC model. PMID- 24950059 TI - BRCA1 haploinsufficiency leads to altered expression of genes involved in cellular proliferation and development. AB - The assessment of BRCA1 and BRCA2 coding sequences to identify pathogenic mutations associated with inherited breast/ovarian cancer syndrome has provided a method to identify high-risk individuals, allowing them to seek preventative treatments and strategies. However, the current test is expensive, and cannot differentiate between pathogenic variants and those that may be benign. Focusing only on one of the two BRCA partners, we have developed a biological assay for haploinsufficiency of BRCA1. Using a series of EBV-transformed cell lines, we explored gene expression patterns in cells that were BRCA1 wildtype compared to those that carried (heterozygous) BRCA1 pathogenic mutations. We identified a subset of 43 genes whose combined expression pattern is a sensitive predictor of BRCA1 status. The gene set was disproportionately made up of genes involved in cellular differentiation, lending credence to the hypothesis that single copy loss of BRCA1 function may impact differentiation, rendering cells more susceptible to undergoing malignant processes. PMID- 24950061 TI - Evaluating the impact of environmental temperature on global highly pathogenic avian influenza (HPAI) H5N1 outbreaks in domestic poultry. AB - The emergence and spread of highly pathogenic avian influenza (HPAI) A virus subtype H5N1 in Asia, Europe and Africa has had an enormously socioeconomic impact and presents an important threat to human health because of its efficient animal-to-human transmission. Many factors contribute to the occurrence and transmission of HPAI H5N1 virus, but the role of environmental temperature remains poorly understood. Based on an approach of integrating a Bayesian Cox proportional hazards model and a Besag-York-Mollie (BYM) model, we examined the specific impact of environmental temperature on HPAI H5N1 outbreaks in domestic poultry around the globe during the period from 1 December 2003 to 31 December 2009. The results showed that higher environmental temperature was a significant risk factor for earlier occurrence of HPAI H5N1 outbreaks in domestic poultry, especially for a temperature of 25 degrees C. Its impact varied with epidemic waves (EWs), and the magnitude of the impact tended to increase over EWs. PMID- 24950062 TI - Humidity and gravimetric equivalency adjustments for nephelometer-based particulate matter measurements of emissions from solid biomass fuel use in cookstoves. AB - Great uncertainty exists around indoor biomass burning exposure-disease relationships due to lack of detailed exposure data in large health outcome studies. Passive nephelometers can be used to estimate high particulate matter (PM) concentrations during cooking in low resource environments. Since passive nephelometers do not have a collection filter they are not subject to sampler overload. Nephelometric concentration readings can be biased due to particle growth in high humid environments and differences in compositional and size dependent aerosol characteristics. This paper explores relative humidity (RH) and gravimetric equivalency adjustment approaches to be used for the pDR-1000 used to assess indoor PM concentrations for a cookstove intervention trial in Nepal. Three approaches to humidity adjustment performed equivalently (similar root mean squared error). For gravimetric conversion, the new linear regression equation with log-transformed variables performed better than the traditional linear equation. In addition, gravimetric conversion equations utilizing a spline or quadratic term were examined. We propose a humidity adjustment equation encompassing the entire RH range instead of adjusting for RH above an arbitrary 60% threshold. Furthermore, we propose new integrated RH and gravimetric conversion methods because they have one response variable (gravimetric PM2.5 concentration), do not contain an RH threshold, and is straightforward. PMID- 24950064 TI - A novel light-dependent activation of DAGK and PKC in bovine photoreceptor nuclei. AB - In this work, we describe a selective light-dependent distribution of the lipid kinase 1,2-diacylglycerol kinase (EC 2.7.1.107, DAGK) and the phosphorylated protein kinase C alpha (pPKCalpha) in a nuclear fraction of photoreceptor cells from bovine retinas. A nuclear fraction enriched in small nuclei from photoreceptor cells (PNF), was obtained when a modified nuclear isolation protocol developed by our laboratory was used. We measured and compared DAGK activity as phosphatidic acid (PA) formation in PNF obtained from retinas exposed to light and in retinas kept in darkness using [gamma-(32)P]ATP or [(3)H]DAG. In the absence of exogenous substrates and detergents, no changes in DAGK activity were observed. However, when DAGK activity assays were performed in the presence of exogenous substrates, such as stearoyl arachidonoyl glycerol (SAG) or dioleoyl glycerol (DOG), and different detergents (used to make different DAGK isoforms evident), we observed significant light effects on DAGK activity, suggesting the presence of several DAGK isoforms in PNF. Under conditions favoring DAGKzeta activity (DOG, Triton X-100, dioleoyl phosphatidylserine and R59022) we observed an increase in PA formation in PNF from retinas exposed to light with respect to those exposed to darkness. In contrast, under conditions favoring DAGKE (SAG, octylglucoside and R59022) we observed a decrease in its activity. These results suggest different physiological roles of the above-mentioned DAGK isoforms. Western blot analysis showed that whereas light stimulation of bovine retinas increases DAGKzeta nuclear content, it decreases DAGKE and DAGKbeta content in PNF. The role of PIP2-phospholipase C in light-stimulated DAGK activity was demonstrated using U73122. Light was also observed to induce enhanced pPKCalpha content in PNF. The selective distribution of DAGKzeta and E in PNF could be a light-dependent mechanism that in vertebrate retina promotes selective DAG removal and PKC regulation. PMID- 24950063 TI - Environmental factors and multiple sclerosis severity: a descriptive study. AB - Growing evidence suggests that environmental factors play a key role in the onset of multiple sclerosis (MS). This study was conducted to examine whether environmental factors may also be associated with the evolution of the disease. We collected data on smoking habits, sunlight exposure and diet (particularly consumption of vitamin D-rich foods) from a sample of 131 MS patients. We also measured their serum vitamin D concentration. The clinical impact of MS was quantified using the Multiple Sclerosis Severity Score (MSSS); MS was considered "severe" in patients with MSSS >= 6, and "mild" in patients with MSSS <= 1. The results showed a strong association between serum vitamin D concentration and both sunlight exposure (26.4 +/- 11.9 ng/mL vs. 16.5 +/- 12.1 ng/mL, p = 0.0004) and a fish-rich diet (23.5 +/- 12.1 ng/mL vs. 16.1 +/- 12.4 ng/mL, p = 0.005). Patients reporting frequent sunlight exposure had a lower MSSS (2.6 +/- 2.4 h vs. 4.6 +/- 2.6 h, p < 0.001). The mild MS patients reported much more frequent sunlight exposure (75% mild MS vs. 25% severe MS p = 0.004, Chi square test). A higher serum vitamin D concentration determined a lower risk of developing severe MS, adjusted for sunlight exposure (OR = 0.92 for one unit increase in vitamin D, 95% CI: 0.86-0.97, p = 0.005). A stronger inverse association emerged between frequent sunlight exposure and the risk of severe MS (OR = 0.26, 95% CI: 0.09 0.71, p = 0.009). Our data show that an appropriate diet and adequate expose to sunlight are associated with less aggressive MS. PMID- 24950066 TI - Prediction of survival with alternative modeling techniques using pseudo values. AB - BACKGROUND: The use of alternative modeling techniques for predicting patient survival is complicated by the fact that some alternative techniques cannot readily deal with censoring, which is essential for analyzing survival data. In the current study, we aimed to demonstrate that pseudo values enable statistically appropriate analyses of survival outcomes when used in seven alternative modeling techniques. METHODS: In this case study, we analyzed survival of 1282 Dutch patients with newly diagnosed Head and Neck Squamous Cell Carcinoma (HNSCC) with conventional Kaplan-Meier and Cox regression analysis. We subsequently calculated pseudo values to reflect the individual survival patterns. We used these pseudo values to compare recursive partitioning (RPART), neural nets (NNET), logistic regression (LR) general linear models (GLM) and three variants of support vector machines (SVM) with respect to dichotomous 60 month survival, and continuous pseudo values at 60 months or estimated survival time. We used the area under the ROC curve (AUC) and the root of the mean squared error (RMSE) to compare the performance of these models using bootstrap validation. RESULTS: Of a total of 1282 patients, 986 patients died during a median follow-up of 66 months (60-month survival: 52% [95% CI: 50%-55%]). The LR model had the highest optimism corrected AUC (0.791) to predict 60-month survival, followed by the SVM model with a linear kernel (AUC 0.787). The GLM model had the smallest optimism corrected RMSE when continuous pseudo values were considered for 60-month survival or the estimated survival time followed by SVM models with a linear kernel. The estimated importance of predictors varied substantially by the specific aspect of survival studied and modeling technique used. CONCLUSIONS: The use of pseudo values makes it readily possible to apply alternative modeling techniques to survival problems, to compare their performance and to search further for promising alternative modeling techniques to analyze survival time. PMID- 24950065 TI - Assessing postzygotic isolation using zygotic disequilibria in natural hybrid zones. AB - Hybrid zones as windows on evolutionary processes provide a natural laboratory for studying the genetic basis and mechanisms of postzygotic isolation. One resultant pattern in hybrid zones is the Hardy-Weinberg disequilibrium (HWD) for a single locus or the linkage disequilibrium (LD) for multiple loci produced by natural selection against hybrids. However, HWD and the commonly used low-order gametic or composite digenic LD cannot fully reflect the pattern of the high order genotypic interactions. Here we propose the use of zygotic LD to elucidate the selection mechanisms of postzygotic isolation, and its calculation is based on genotypic frequencies only, irrespective of the type of mating system. We numerically and analytically show that the maximum composite digenic LD is always greater than the maximum absolute zygotic LD under the linear-additive selection, but is comparable to or smaller than the maximum absolute zygotic LD under the strong epistatic selection. Selection mechanisms can be inferred by testing such differences. We analyze a previously reported mouse hybrid zone assayed with genome-wide SNPs, and confirm that the composite digenic LD cannot appropriately indicate all possible significant genotypic interactions for a given SNP pair. A large proportion of significant zygotic LDs, ~75% in general in the mouse hybrid zone, cannot be revealed from the composite digenic LD analysis. Statistical tests indicate that epistatic selection occurred among multiple loci in the mouse hybrid zone. The results highlight that the joint patterns of the composite digenic and zygotic LDs can help to elucidate the selection mechanism that is potentially involved in postzygotic isolation. PMID- 24950067 TI - Celecoxib sensitizes Staphylococcus aureus to antibiotics in macrophages by modulating SIRT1. AB - We have previously shown that celecoxib in combination with an antibiotic, increase the bacterial sensitivity to antibiotics. However, the underlying molecular mechanism remained elusive. Efficacy of the combinatorial treatment of celecoxib and ampicillin in vitro was evaluated on macrophage-phagocytosed S. aureus. To elucidate the mechanism, signaling pathway of infection and inflammation involving TLR2, JNK, SIRT1 and NF-kappaB was studied by FACS, Western blot, ELISA and activity assays. Combinatorial treatment of ampicillin and celecoxib reduced the bacterial load in the macrophages. Further studies clearly suggested the activation of the master regulator of oxidative stress and inflammation SIRT1, by celecoxib when used alone and/or in combination with ampicillin. Also, the results indicated that celecoxib inhibited JNK phosphorylation thereby stabilizing and activating SIRT1 protein that inhibited the COX-2 gene transcription with a significant decrease in the levels of protein inflammatory cytokines like IL-6, MIP-1alpha and IL-1beta via inhibition of NF kappaB. SIRT1 activation by celecoxib also resulted in increase of catalase and peroxidase activity with a decrease in Nitric oxide levels. In conclusion, we demonstrate a novel role of celecoxib in controlling inflammation as an enhancer of antibiotic activity against bacteria by modulating SIRT1. PMID- 24950071 TI - What is medical education for? The challenges in global medical education today. PMID- 24950070 TI - Prevalence of metabolic syndrome in COPD patients and its consequences. AB - BACKGROUND: The prevalence of metabolic syndrome in COPD patients and its impact on patient related outcomes has been little studied. We evaluated the prevalence of metabolic syndrome and clinical and functional characteristics in patients with COPD and healthy subjects. METHODS: 228 COPD patients and 156 healthy subjects were included. Metabolic syndrome was defined using criteria of the IDF. In all patients spirometry, body composition, functional exercise performance, and mood and health status were assessed. Groups were stratified for BMI and gender. RESULTS: Metabolic syndrome was present in 57% of the COPD patients and 40% of the healthy subjects. After stratification for BMI, presence of metabolic syndrome in patients with a BMI >=25 kg/m2 was higher than in healthy peers. Patients with metabolic syndrome and a BMI <25 kg/m2 had higher BMI, fat free mass index and bone mineral density, and a lower 6MWD than the BMI matched patients without metabolic syndrome. Spirometry, maximal ergometry, mood and health status, and blood gases were not different between those groups. In COPD patients with metabolic syndrome self-reported co-morbidities and medication use were higher than in those without. CONCLUSION: Metabolic syndrome is more prevalent in overweight or obese COPD patients than in BMI matched healthy subjects. Metabolic syndrome did not additionally impact patients' functional outcomes, but did impact the prevalence of co-morbidities. PMID- 24950069 TI - Metformin impairs mitochondrial function in skeletal muscle of both lean and diabetic rats in a dose-dependent manner. AB - Metformin is a widely prescribed drug for the treatment of type 2 diabetes. Previous studies have demonstrated in vitro that metformin specifically inhibits Complex I of the mitochondrial respiratory chain. This seems contraindicative since muscle mitochondrial dysfunction has been linked to the pathogenesis of type 2 diabetes. However, its significance for in vivo skeletal muscle mitochondrial function has yet to be elucidated. The aim of this study was to assess the effects of metformin on in vivo and ex vivo skeletal muscle mitochondrial function in a rat model of diabetes. Healthy (fa/+) and diabetic (fa/fa) Zucker diabetic fatty rats were treated by oral gavage with metformin dissolved in water (30, 100 or 300 mg/kg bodyweight/day) or water as a control for 2 weeks. After 2 weeks of treatment, muscle oxidative capacity was assessed in vivo using 31P magnetic resonance spectroscopy and ex vivo by measuring oxygen consumption in isolated mitochondria using high-resolution respirometry. Two weeks of treatment with metformin impaired in vivo muscle oxidative capacity in a dose-dependent manner, both in healthy and diabetic rats. Whereas a dosage of 30 mg/kg/day had no significant effect, in vivo oxidative capacity was 21% and 48% lower after metformin treatment at 100 and 300 mg/kg/day, respectively, independent of genotype. High-resolution respirometry measurements demonstrated a similar dose-dependent effect of metformin on ex vivo mitochondrial function. In conclusion, metformin compromises in vivo and ex vivo muscle oxidative capacity in Zucker diabetic fatty rats in a dose-dependent manner. PMID- 24950072 TI - Reform in medical and health sciences educational system: a Delphi study of faculty members' views at Shiraz University of Medical Sciences. AB - Despite the strengths in the Iranian medical and health sciences educational system, areas in need of improvement have been noted. The purpose of this study was to understand the views of faculty members at Shiraz University of Medical Sciences about current and future needs for medical and health sciences education, with the goal of improving the quality of the educational system. The data were collected using a Delphi consensus method. Analysis of the findings identified the following key themes among the factors likely to contribute to medical and health sciences education and training: adding and/or increasing student numbers in higher degrees in preference to associate degrees; providing more interactive, student-centred teaching methods; improving the educational content with more practical and research-based courses tailored to society's needs; and an emphasis on outcome-based student evaluation techniques. These changes aim to respond to health trends in society and enhance the close relationship between medical education and the needs of the Iranian society. PMID- 24950073 TI - Factors influencing parental consent for participation in clinical research involving their children in Egypt. AB - Factors affecting parents' decision to involve their children in clinical research have not been studied in all cultural backgrounds. We aimed to explore the attitudes and beliefs influencing parents' decision to involve their children in clinical research in Mansoura, Egypt. Of 523 families approached, 357 filled the questionnaire. Only 98 (27.5%) parents consented to involve their child in clinical research. The children of consenters were significantly older than refusers: 8.6 (SD 7.2) versus 2.6 (SD 1.2) years. Factors favouring consent were: research of benefit to child (84.7%), enough explanation about the benefits (40.8%) and to learn more about child's condition (29.6%). Factors favouring refusal were: use of new drugs or vaccines (89.6%) and invasive procedures (84.2%). Parents' rate of consent was positively correlated with the research being non-invasive and the belief that research was of benefit to their child and negatively correlated with belief that refusal may negatively affect the care provided to their child. PMID- 24950074 TI - Epidemiological survey on pandemic influenza A (H1N1) virus infection in Kurdistan province, Islamic Republic of Iran, 2009. AB - This study evaluated the epidemiology of suspected cases of pandemic influenza A (H1N1) virus infection in 2009-2010 in Kurdistan province, a frontier province of the Islamic Republic of Iran. A questionnaire covering demographic characteristics, clinical presentation and outcome, and history of exposure and travel was completed by patients attending health centres and hospitals in the province. Nasal and throat swabs were analysed by RT-PCR. A total of 1059 suspected cases were assessed; H1N1 influenza A was confirmed in 157 (14.8%). The highest proportion of confirmed cases was 30.0%, among children aged < 1 year. In multivariate analysis, previous contact with symptomatic influenza patients (OR = 2.17) and hospitalization (OR = 3.88) were the only significant risk factors for confirmed H1N1 infection. Age, sex, residency, presenting symptoms and history of national or international travel were not significant. Influenza A (H1N1) virus has spread in Islamic Republic of Iran; probably transmitted by travellers to Kurdistan. PMID- 24950075 TI - Pregnancy outcomes in Benghazi, Libya, before and during the armed conflict in 2011. AB - Stressful life events experienced by pregnant women may lead to adverse obstetric outcomes. This study in Benghazi compared the rates of preterm, low-birth-weight and caesarean-section births at Al-Jamhouria hospital in the months before and during the armed conflict in Libya in 2011. Data were collected on all women admitted to the delivery ward during February to May 2011 (the months of the most active fighting in the city) (n = 7096), and October to December 2010 (the months immediately before the war) (n = 5935). Compared with the preceding months there was a significant rise during the conflict in the rate of deliveries involving preterm (3.6% versus 2.5%) and low-birth-weight (10.1% versus 8.5%) infants and caesarean sections (26.9% versus 25.3%). Psychosocial stress may have been a factor (among others) in an increase in negative pregnancy outcomes, and obstetric hospitals should be aware of these issues in times of war. PMID- 24950076 TI - Rate and correlates of depression among elderly people attending primary health care centres in Al-Dakhiliyah governorate, Oman. AB - This study determined the rates and correlates of depression among community dwelling elderly people, based on data from the comprehensive health assessment conducted in Al-Dakhiliyah governorate in Oman in 2008-2010. Data covered sociodemographic characteristics, medical and nutrition status, functional abilities, depression and dementia. The rate of depression was 16.9%, higher among women than men (19.3% versus 14.3%). Depression was independently predicted by the presence of social risk (OR = 3.44), dementia (OR = 3.17), impairment in activities of daily living (OR = 2.19), joint problems (OR = 1.52) and mobility restriction (OR = 1.43). If dementia was excluded from the model, depression was additionally predicted by poor perception of health (OR = 2.09), impairment in instrumental activities of daily living (OR = 1.47) and older ages of 70-< 80 years (OR = 1.63) and >= 80 years (OR = 1.75). Although not presenting as a complaint, depression in not uncommon among elderly people. PMID- 24950077 TI - Reliability and validity of the Persian (Farsi) version of the Risk Perception Survey-Diabetes Mellitus. AB - Knowledge of patients' risk perceptions is essential for the management of chronic diseases. This study aimed to assess the reliability and validity of a Persian (Farsi) language translation of the Risk Perception Survey-Diabetes Mellitus. After forward-backward translation the RPS-DM was randomly administered to 106 adult patients with diabetes who were enrolled in a teaching referral clinic in the north of the Islamic Republic of Iran (Rasht). Internal consistency and exploratory factor analysis were applied. The minimum value for internal consistency was 0.50 for risk knowledge and the highest value was 0.88 on the optimistic bias subscale. Principal component analysis showed that the items of the composite risk score matched with the same items in the English language version, except for question numbers 16, 24 and 25. The Persian version of RPS-DM is the first standardized tool for measuring risk perception and knowledge about diabetes complications in the Islamic Republic of Iran. PMID- 24950078 TI - Knowledge of and attitudes towards periodontal health among adults in Tehran. AB - Determining what people know and believe about periodontal health and disease is important in order to establish prevention practices. This study aimed to assess knowledge of and attitudes towards periodontal health among adults in Tehran, Islamic Republic of Iran. We conducted a cross-sectional face-to-face interview survey in 2011 of 791 adults aged 18-50 years using a stratified, multistage sampling method. We recorded demographic characteristics including age, sex, education, marital status, employment and economic status (housing density). The lowest percentage of correct answers was related to the definition of dental plaque (11.6%) and the highest was for the role of the dental visit in prevention (92.8%). Female sex, university education and higher economic status were significantly associated with a higher mean score on periodontal health knowledge. The regression analysis showed that positive attitudes were associated with higher periodontal health knowledge and having university education. In this study positive attitudes towards prevention were related to better knowledge. PMID- 24950079 TI - Phenotypic characterization of Acinetobacter baumannii isolates from intensive care units at a tertiary-care hospital in Egypt. AB - Multi-drug resistant (MDR) strains of Acinetobacter baumannii are responsible for an increasing number of opportunistic infections in hospitals. This study determined the prevalence of MDR A. baumannii isolates from intensive care units in a large tertiary-care hospital in Ismailia, Egypt, and the occurrence of different beta-lactamases in these isolates. Biotyping and antimicrobial susceptibility profile was done for isolated strains. Respiratory, urine, burn wound and blood specimens were collected from 350 patients admitted to different units; 10 strains (2.9%) of A. baumannii were isolated. All isolates showed resistance to more than 3 classes of antibiotics. Among the isolates, 6 isolates were carbapenemase producers, 2 were AmpC beta-lactamase producers and no isolates were metallo-beta-lactamase producers. Despite the low prevalence of A. baumannii infection in this hospital, the antibiotic resistance profile suggests that prevention of health-care-associated transmission of MDR Acinetobacter spp. infection is essential. PMID- 24950080 TI - Hepatitis A and E: not to be forgotten. PMID- 24950081 TI - Microbiological and physicochemical characterization of dry-cured Halal goat meat. Effect of salting time and addition of olive oil and paprika covering. AB - The objective of this work was to define a simple technological process for dry cured Halal goat meat elaboration. The aims of this study were to analyze physicochemical parameters and to enumerate the microbial population at the end of the different manufacturing processes (two salting times and the addition of olive oil and paprika covering) on 36 units of meat product. A total of 532 strains were isolated from several selective culture media and then identified using classical and molecular methods. In general, salt effect and the addition of olive oil and paprika were significant for all the studied microbial groups as well as on NaCl content and water activity. Molecular analysis proves that staphylococci, especially Staphylococcus xylosus and Staphylococcus equorum, were the most common naturally occurring microbiota. The best manufacturing process would be obtained with a longer salting time and the addition of the olive oil and paprika covering. PMID- 24950082 TI - The impact of supplementing lambs with algae on growth, meat traits and oxidative status. AB - The current study examined the effect of supplementing lambs with algae. Forty, three month old lambs were allocated to receive a control ration based on oats and lupins (n=20) or the control ration with DHA-GoldTM algae (~2% of the ration, n=20). These lambs came from dams previously fed a ration based on either silage (high in omega-3) or oats and cottonseed meal (OCSM: high in omega-6) at joining (dam nutrition, DN). Lamb performance, carcase weight and GR fat content were not affected by treatment diet (control vs algae) or DN (silage vs OSCM). Health claimable omega-3 fatty acids (EPA+DHA) were significantly greater in the LL of lambs fed algae (125+/-6mg/100g meat) compared to those not fed algae (43+/ 6mg/100g meat) and this effect was mediated by DN. Supplementing with algae high in DHA provides a means of improving an aspect of the health status of lamb meat. PMID- 24950083 TI - The use of power ultrasound for accelerating the curing of pork. AB - Power ultrasound (10, 25 or 40min at US intensities of 4.2, 11 or 19Wcm(-2)) was assessed for accelerating brine transfer into meat. Sample analysis included NaCl content, water content, water-binding capacity, colour and texture. Water content (g/100g) was increased by 19Wcm(-2) for 10 or 25min (p<=0.05). NaCl content (g/100g) was increased by all ultrasonic treatments (p<=0.001). Decreased cohesiveness (p<=0.05) and gumminess (p<=0.05) were evident in sonicated samples. Ultrasonic curing can assist brine transfer, reducing processing times with minimal impact on product quality. PMID- 24950085 TI - Retraction of "Development of Fe/Fe3O4 core-shell nanocubes as a promising magnetic resonance imaging contrast agent". PMID- 24950084 TI - Effect of olive leaf (Olea europea L.) extracts on protein and lipid oxidation of long-term frozen n-3 fatty acids-enriched pork patties. AB - Our previous study has demonstrated the protective effects of olive leaf extracts on the oxidation of pork patties from n-3 fatty acid-enriched meat during refrigerated storage. The target of the present study was to examine these effects during frozen storage. Results showed that frozen storage accelerated (P=0.05) both lipid and protein oxidation in pork patties, but an addition of olive leaf extract at 200mg gallic acid equivalent/kg improved sensory attributes by delaying oxidation of lipids (reduction (P=0.05) of conjugated dienes, hydroperoxides and malondialdehyde), and of proteins (reduction (P=0.05) of protein carbonyls and inhibition (P=0.05) of the decrease of protein sulfhydryls). PMID- 24950087 TI - Gene therapy briefs. PMID- 24950086 TI - Vector integration and tumorigenesis. PMID- 24950088 TI - The first adeno-associated virus gene transfer experiment, 1983. PMID- 24950091 TI - Long-term storage of aerobic granules in liquid media: viable but non-culturable status. AB - Long-term storage and successful reactivation after storage are essential for practical applications of aerobic granules on wastewater treatment. This study cultivated aerobic granules (SI) in sequencing batch reactors and then stored the granules at 4 degrees C in five liquid media (DI water (SW), acetone (SA), acetone/isoamyl acetate mix (SAA), saline water (SS), and formaldehyde (SF)) for over 1 year. The first four granules were then successfully reactivated in 24h cultivation. The specific oxygen uptake rates (SOUR) of the granules followed SI>SS>SA>SAA>SW>SF; and the corresponding granular strengths (10 min ultrasound) followed SI>SA=SS>SAA>SW>>SF. During storage the granular cells secreted excess quantities of cyclic-diguanylate (c-di-GMP) and pentaphosphate (ppGpp) as responses to the stringent challenges. We proposed that to force cells in granules (Alphaproteobacteria, Flavobacteria, Betaproteobacteria, Gammaproteobacteria, Actinobacteria, Sphingobacteria, and Clostridia) entering viable but non-culturable (VBNC) status is the key of success for extended period storage of granules. PMID- 24950092 TI - Glycerol as an ionic liquid co-solvent for pretreatment of rice hulls to enhance glucose and xylose yield. AB - Rice hulls, a widely-available secondary agricultural residue, can be pretreated with ionic liquids (IL) prior to enzymatic hydrolysis to enhance glucose and xylose yields. The high cost of ILs is a deterrent to commercial deployment at present. ILs 1-ethyl-3-methylimidazolium acetate, 1-ethyl-3-methylimidazolium formate, 1,3-dimethylimidazolium dimethylphosphate, and 1-ethyl-3 methylimidazolium diethylphosphate were investigated for rice hull pretreatment. Effects of diluting ILs with glycerol were investigated for biomass pretreatment efficacy, and for solvent recovery. When diluted with 50% glycerol, rice hulls treated in 1-ethyl-3-methylimidazolium formate was found to give glucose and xylose yields after enzymatic hydrolysis better than rice hulls treated in pure 1 ethyl-3-methylimidazolium formate. Dilution in glycerol resulted in an increased rate of solvent recovery after pretreatment, as much as six times that when pure 1-ethyl-3-methylimidazolium formate was used. Diluting 1-ethyl-3 methylimidazolium formate with 50% glycerol was found to decrease solvent viscosity at the pretreatment temperature (110 degrees C) helping explain improved biomass pretreatment. PMID- 24950093 TI - Fatty acid metabolism and population dynamics in a wet biowaste digester during re-start after revision. AB - Volatile fatty acid (VFA) metabolism and population changes during re-start of a wet anaerobic digester for treatment of biowaste suspensions were investigated. Initially acetate and propionate accumulated. However, VFA degradation rates improved within 2 weeks, reaching a balanced metabolism with constantly low VFA concentrations. The total microbial population consisted of 60% acidogenic+acetogenic and 40% methanogenic bacteria. Maximally 5.1% of all bacteria in the digester were propionate-oxidizing bacteria. Pelotomaculum species were dominant, followed by much lower numbers of Smithella species and Syntrophobacter species. Pelotomaculum and Smithella spec. decreased during acetate and propionate accumulation and recovered later on, whereas Syntrophobacter spec. was steadily increasing during start-up. A nearly constant proportion of Methanosaeta spec. was present all time, while Methanosarcina spec. decreased and Methanomicrobiales increased during accumulation and degradation of acetate and propionate. During steady state proportions as in the inoculum were obtained. PMID- 24950094 TI - Utilization of carbon dioxide in industrial flue gases for the cultivation of microalga Chlorella sp. AB - The biomass and lipid productivity of Chlorella sp. MTF-15 cultivated using aeration with flue gases from a coke oven, hot stove or power plant in a steel plant of the China Steel Corporation in Taiwan were investigated. Using the flue gas from the coke oven, hot stove or power plant for cultivation, the microalgal strain obtained a maximum specific growth rate and lipid production of (0.827 d( 1), 0.688 g L(-1)), (0.762 d(-1), 0.961 g L(-1)), and (0.728 d(-1), 0.792 g L( 1)), respectively. This study demonstrated that Chlorella sp. MTF-15 could efficiently utilize the CO2, NOX and SO2 present in the different flue gases. The results also showed that the growth potential, lipid production and fatty acid composition of the microalgal strain were dependent on the composition of the flue gas and on the operating strategy deployed. PMID- 24950095 TI - Black liquor fractionation for biofuels production - a techno-economic assessment. AB - The hemicelluloses fraction of black liquor is an underutilized resource in many chemical pulp mills. It is possible to extract and separate the lignin and hemicelluloses from the black liquor and use the hemicelluloses for biochemical conversion into biofuels and chemicals. Precipitation of the lignin from the black liquor would consequently decrease the thermal load on the recovery boiler, which is often referred to as a bottleneck for increased pulp production. The objective of this work is to techno-economically evaluate the production of sodium-free lignin as a solid fuel and butanol to be used as fossil gasoline replacement by fractionating black liquor. The hydrolysis and fermentation processes are modeled in Aspen Plus to analyze energy and material balances as well as to evaluate the plant economics. A mathematical model of an existing pulp and paper mill is used to analyze the effects on the energy performance of the mill subprocesses. PMID- 24950096 TI - Development and validation of an LC-MS/MS method for determination of the L-type voltage-gated calcium channel/NMDA receptor antagonist NGP1-01 in mouse serum. AB - NGP1-01 (8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane) is a heterocyclic cage compound with multifunctional calcium channel blocking activity that has been demonstrated to be neuroprotective in several neurodegenerative models. A sensitive internal standard LC-MS/MS method was developed and validated to quantify NGP1-01 in mouse serum. The internal standard (IS) was 8-(2-phenylethylamino)-8,11 oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane. Sample preparation involved a protein precipitation procedure by addition of acetonitrile. Chromatographic separation was carried out on a Phenomenex Kinetex phenyl-hexyl column (100 mm*2.1mm, 2.6 MUm) employing a gradient (45% isocratic 3 min, 45-95% linear gradient 6 min, 95% isocratic 3 min) of an elution mobile phase of 5mM ammonium acetate in 100% acetonitrile mixing with an application mobile phase of 5mM ammonium acetate in 2% acetonitrile. Detection was achieved by a QTrap 5500 mass spectrometer (AB Sciex) employing electrospray ionization in the positive mode with multiple-reaction-monitoring (MRM) for NGP1-01 (m/z 266->91) and IS (m/z 280 >105). The method validation was carried out in accordance with Food and Drug Administration (FDA) guidelines. The method had a linear range of at least 0.5-50 ng/mL with a correlation coefficient 0.999. The intra-assay and inter-assay precisions (%CV) were equal to or within the range of 1.0-4.3% and the accuracies (% relative error) equal to or within -2.5% to 3.4%. The analyte was stable for at least 2 months at -20 degrees C, for at least 8h at room temperature and for at least three freeze-thaw cycles. The extraction recovery was 94.9 to 105.0%, with a %CV <= 9.5%. The technique was found to be free of any matrix effects as determined by experiments involving five different lots of mouse serum. Cross talk interferences were not present. Two different gradient slope chromatography runs were done on dosed mouse serum samples to assess a possible positive error in peak area determination from in-source fragmentation of metabolites generating the same MRM transitions as the parent drug or IS. No such interference was found in the NGP1-01 peak, while a minor interference was identified in the IS peak. The optimized method was applied to the measurement of NGP1-01 in serum of dosed mice. PMID- 24950097 TI - Trapping of NAPQI, the intermediate toxic paracetamol metabolite, by aqueous sulfide (S2-) and analysis by GC-MS/MS. AB - NAPQI, i.e., N-acetyl-p-benzoquinone imine, is considered the toxic metabolite of the widely used analgesic drug paracetamol (acetaminophen, APAP). Due to its high reactivity towards nucleophiles both in low- and high-molecular-mass biomolecules, NAPQI is hardly detectable in its native form. Upon conjugation with glutathione, NAPQI is finally excreted in the urine as the paracetamol mercapturic acid. Thus, determination of paracetamol mercapturate may provide a measure of in vivo NAPQI formation. In this work, we propose the use of Na2S in aqueous solution to trap NAPQI and to analyze the reaction product, i.e., 3-thio paracetamol, together with paracetamol by GC-MS/MS in the electron-capture negative-ion chemical ionization mode after solvent extraction with ethyl acetate and derivatization with pentafluorobenzyl bromide. In mechanistic studies, we used newly synthesized N-acetyl-p-[2,3,5,6-(2)H4]benzoquinone imine (d4-NAPQI). In quantitative analyses, N-(4-hydroxyphenyl)-[2,3,5,6-(2)H4]acetamide (d4-APAP) was used as the internal standard both for NAPQI and APAP. 3-Thio-d3-paracetamol, prepared from d4-NAPQI and Na2S, may also be useful as an internal standard. We showed NAPQI in vitro formation from APAP by recombinant cyclooxygenase-1 as well as by dog liver homogenate. In vivo formation of NAPQI was demonstrated in mice given paracetamol intraperitoneally (about 150 mg/kg). PMID- 24950098 TI - Quantitative liquid chromatography-tandem mass spectrometry method for determination of microcystin-RR and its glutathione and cysteine conjugates in fish plasma and bile. AB - A rapid and sensitive liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for the simultaneous determination of microcystin-RR (MC RR) and its glutathione and cysteine conjugates (MC-RR-GSH and MC-RR-Cys, respectively) in fish plasma and bile. The analytes were extracted using methanol, followed by an Oasis mixed-mode cation-exchange polymeric sorbent. The separation was performed on a reversed-phase Waters XBridge C18 column with the gradient mobile phase, consisting of water and acetonitrile (both acidified with 0.50/00 formic acid). Mean recoveries of MC-RR, MC-RR-GSH and MC-RR-Cys ranged from 80.7 to 93.7%, 81.1 to 93.1% and 80.3 to 93.2%, respectively, at three concentrations (0.2, 1.0 and 5.0 MUg mL(-1)). Limits of detection (LODs) for MC RR, MC-RR-GSH and MC-RR-Cys were 6, 12 and 9 ng mL(-1), respectively. Limits of quantification (LOQs) were 15, 30 and 22.5 ng mL(-1) for MC-RR, MC-RR-GSH and MC RR-Cys, respectively. This method makes it feasible for the identification and quantification of MC-RR, MC-RR-GSH and MC-RR-Cys in limited and complex biological fluid samples (such as plasma and bile, typically 50 MUL), which were previously excluded or difficult to study due to the relatively large sample volumes. PMID- 24950100 TI - Promiscuity breeds diversity: the role of polyketide synthase in natural product biosynthesis. AB - Secondary metabolites are often highly biologically active molecules and are widely used from antibacterial to anticancer drugs. In this issue of Chemistry and Biology, Zaehle and coworkers describe the gene cluster and biosynthesis of the polyketide terrein, a secondary metabolite produced by the soil-borne fungus Aspergillus terreus. PMID- 24950101 TI - Timing protein assembly in neurons. AB - Integration of two fluorescence imaging methods enables tracking of the formation of fibrillar Abeta peptide amyloid aggregates in neurons, as discussed by Esbjorner and colleagues in this issue of Chemistry & Biology. This approach has the potential to fundamentally improve our understanding of the onset and therapeutic intervention of neurodegenerative diseases. PMID- 24950099 TI - Cell wall modifications during conidial maturation of the human pathogenic fungus Pseudallescheria boydii. AB - Progress in extending the life expectancy of cystic fibrosis (CF) patients remains jeopardized by the increasing incidence of fungal respiratory infections. Pseudallescheria boydii (P. boydii), an emerging pathogen of humans, is a filamentous fungus frequently isolated from the respiratory secretions of CF patients. It is commonly believed that infection by this fungus occurs through inhalation of airborne conidia, but the mechanisms allowing the adherence of Pseudallescheria to the host epithelial cells and its escape from the host immune defenses remain largely unknown. Given that the cell wall orchestrates all these processes, we were interested in studying its dynamic changes in conidia as function of the age of cultures. We found that the surface hydrophobicity and electronegative charge of conidia increased with the age of culture. Melanin that can influence the cell surface properties, was extracted from conidia and estimated using UV-visible spectrophotometry. Cells were also directly examined and compared using electron paramagnetic resonance (EPR) that determines the production of free radicals. Consistent with the increased amount of melanin, the EPR signal intensity decreased suggesting polymerization of melanin. These results were confirmed by flow cytometry after studying the effect of melanin polymerization on the surface accessibility of mannose-containing glycoconjugates to fluorescent concanavalin A. In the absence of melanin, conidia showed a marked increase in fluorescence intensity as the age of culture increased. Using atomic force microscopy, we were unable to find rodlet-forming hydrophobins, molecules that can also affect conidial surface properties. In conclusion, the changes in surface properties and biochemical composition of the conidial wall with the age of culture highlight the process of conidial maturation. Mannose-containing glycoconjugates that are involved in immune recognition, are progressively masked by polymerization of melanin, an antioxidant that is commonly thought to allow fungal escape from the host immune defenses. PMID- 24950102 TI - Casting a wide net for endocrine disruptors. AB - The number of chemicals identified as endocrine disruptors continues to rise, and, yet, many assays intended to prioritize them for further action cannot gauge their impact on cells. Stossi and colleagues present new high-throughput screening methods that inform estrogen receptor biology, leading to questions about "safe alternatives" for one compound, bisphenol A. PMID- 24950103 TI - Results of cervical recapping laminoplasty: gross anatomical changes, biomechanical evaluation at different time points and degrees of level involvement. AB - BACKGROUND: Recapping laminoplasty has become the frequently-used approach to the spinal canal when bone decompression of the vertebral canal is not the goal. However, what changes will occur after surgery, and whether recapping laminoplasty can actually reduce the risk of delayed deformities remains unknown. METHODOLOGY: We designed an animal experiment using a caprine model, and partitioned the animals into in vitro and in vivo surgical groups. We performed recapping laminoplasty on one group and laminectomy on another group. These animals were sacrificed six months after operating, cervical spines removed, biomechanically tested, and these data were compared to determine whether the recapping laminoplasty technique leads to subsequent differences in range of motion. Image data were also obtained before the surgery and when the animals were killed. Besides, we investigated the initial differences in kinetics between recapping laminoplasty and laminectomy. We did this by comparing data obtained from biomechanical testing of in vitro-performed recapping laminoplasty and laminectomy. Finally, we investigated the effect that longitudinal distance has on cervical mechanics. This was determined by performing a two-level recapping laminoplasty, and then extending the laminoplasty to the next level and repeating the mechanical testing at each step. PRINCIPAL FINDINGS: There were three mainly morphological changes at the six months after laminoplasty: volume reduction and bone nonunion of the recapping laminae, irregular fibrosis formation around the facet joints and re-implanted lamina-ligamentous complex. In the biomechanical test, comparing with laminectomy, recapping laminoplasty didn't show significant differences in the immediate postoperative comparison, while recapping laminoplasty demonstrated significantly decreased motion in flexion/extension six months later. Inclusion of additional levels in the laminotomy procedure didn't lead to changes in immediate biomechanics. CONCLUSIONS: Recapping laminoplasty can't fully restore the posterior structure, but still reduced the risk of delayed cervical instability in a caprine model. PMID- 24950104 TI - Japanese encephalitis among patients with acute encephalitic syndrome admitted to a tertiary hospital in Chitwan, Nepal--a prospective observational study. AB - INTRODUCTION: The reported incidence of JE among patients with acute encephalitic syndrome (AES) in Nepal ranges between 20% to 62%. In light of the lack of up-to date data, we sought to describe the epidemiology of JE in Chitwan, Nepal. METHODS: A prospective observational study was conducted during 2010-2012 in the College of Medical Science in the Chitwan District. Patients with suspected JE were tested for anti-JE IgM in serum and cerebrospinal fluid (CSF). RESULTS: Of 227 all patients tested, 18 (7.9%) were found positive for JE. 17/202 (8.4%) patients with AES had JE. All, with the exception of two patients, were diagnosed on the basis of positive a serologic test, both in serum and CSF samples. Patients with JE were significantly older (42.1+/-27.6 years) than patients without JE (25.6+/-25.2 years, p = 0.02). Half of JE cases occurred in adults older than 50. More of the JE cases (11/18, 61.1%) occurred during the rainy season when compared to the JE negative patients [71/209, (34%), p = 0.01]. None of the JE patients had a relevant travel history, and one recalled having been immunized against JE. There was a variation in the geographic distribution of cases across the districts of the central Terai. CONCLUSIONS: In this cohort, the proportion of patients with AES who had JE was lower than in previous studies. In addition, most patients were adults, and cases were not distributed uniformly across the central Terai region. The risk of acquiring JE by short-term travelers in the area is likely to be low. Vector-control programs and the promotion of mosquito avoidance behavior in the Terai region should continue. The high proportions of adults among patients with JE may suggest recent changes in the epidemiology of JE in the central Terai region, and routine immunization of all adults should be considered. PMID- 24950105 TI - Radiological outcome of reconstructive hip surgery in children with gross motor function classification system IV and V cerebral palsy. AB - Hip subluxation is common in children with cerebral palsy (CP). The aim of this study was to describe the radiological outcome of reconstructive hip surgery in children with CP, gross motor function classification system (GMFCS) level IV and V, and determine whether the GMFCS level plays a predictive role in outcome. This was a retrospective cohort study conducted at a tertiary-level pediatric hospital with a CP hip surveillance program. Of 110 children with GMFCS IV and V CP registered for hip surveillance, 45 underwent reconstructive hip surgery between 1997 and 2009, defined as varus derotational proximal femoral osteotomy with or without additional pelvic osteotomy. Eleven children were excluded because of lack of 12-month follow-up (n=10) or missing clinical records (n=1). Thus, 21 GMFCS IV children (median age 6 years at surgery) and 13 GMFCS V children (median age 5 years at surgery), who underwent 58 index surgeries, were included in the study. Clinical records and radiology were reviewed. The two surgical groups were femoral osteotomy (varus derotational femoral osteotomy with an AO blade plate or femoral locking plate fixation), or femoral ostetotomy with additional pelvic osteotomy. Reimer's migration percentage (MP) was calculated from anteroposterior pelvis radiographs to determine the outcome for each hip independently. Failure was defined as MP of greater than 60% or further operation on the hip. Reconstructive surgeries were performed for 58 hips with a median preoperative MP of 55%. There were 15 failures at a median of 62 months, including nine failures in 35 GMFCS IV hips and six failures in 23 GMFCS V hips. Overall, GMFCS V hips tended to fail earlier, (hazard ratio 2.3) with a median time to failure of 78 and 39 months for GMFCS IV and V hips, respectively. Combined femoral and pelvic osteotomies had the lowest failure rates in both groups of patients. The GMFCS classification may have some predictive value for outcomes following reconstructive hip surgery, with surgery for GMFCS V hips tending to fail earlier. PMID- 24950106 TI - Propofol pretreatment induced place preference and self-administration of the tiletamine-zolazepam combination: implication on drug of abuse substitution. AB - BACKGROUND: Propofol and the tiletamine-zolazepam combination are anesthetics with both sedative-hypnotic and hallucinogenic effects. In South Korea, propofol is controlled while the tiletamine-zolazepam combination is not. Thus, there is a possibility that this drug combination might be used as a substitute drug by propofol-abusers. OBJECTIVE: In the present study we evaluated whether repeated pre-exposure to propofol predisposes to the use/abuse of the tiletamine-zolazepam combination. METHODS: Rats (8-10 animals/group) were pre-treated with saline (control) or propofol at different dosages (10, 30, 60 mg/kg, i.p.), for 14 days, then conditioned place preference (CPP) and self-administration (SA) for the tiletamine-zolazepam combination were evaluated. RESULTS: Rats pretreated with saline exhibited neither CPP nor SA for the tiletamine-zolazepam combination. On the other hand, rats pretreated with propofol, in all dosages, demonstrated significant CPP and SA for the tiletamine-zolazepam combination. CONCLUSION: These results suggest that tiletamine-zolazepam combinations might be used as a "substitute drug" by abusers of propofol. The careful use, dispensation, and monitoring of tiletamine-zolazepam combinations are advocated. PMID- 24950108 TI - The niche of an invasive marine microbe in a subtropical freshwater impoundment. AB - Growing attention in aquatic ecology is focusing on biogeographic patterns in microorganisms and whether these potential patterns can be explained within the framework of general ecology. The long-standing microbiologist's credo 'Everything is everywhere, but, the environment selects' suggests that dispersal is not limiting for microbes, but that the environment is the primary determining factor in microbial community composition. Advances in molecular techniques have provided new evidence that biogeographic patterns exist in microbes and that dispersal limitation may actually have an important role, yet more recent study using extremely deep sequencing predicts that indeed everything is everywhere. Using a long-term field study of the 'invasive' marine haptophyte Prymnesium parvum, we characterize the environmental niche of P. parvum in a subtropical impoundment in the southern United States. Our analysis contributes to a growing body of evidence that indicates a primary role for environmental conditions, but not dispersal, in the lake-wide abundances and seasonal bloom patterns in this globally important microbe. PMID- 24950107 TI - Coral transcriptome and bacterial community profiles reveal distinct Yellow Band Disease states in Orbicella faveolata. AB - Coral diseases impact reefs globally. Although we continue to describe diseases, little is known about the etiology or progression of even the most common cases. To examine a spectrum of coral health and determine factors of disease progression we examined Orbicella faveolata exhibiting signs of Yellow Band Disease (YBD), a widespread condition in the Caribbean. We used a novel combined approach to assess three members of the coral holobiont: the coral-host, associated Symbiodinium algae, and bacteria. We profiled three conditions: (1) healthy-appearing colonies (HH), (2) healthy-appearing tissue on diseased colonies (HD), and (3) diseased lesion (DD). Restriction fragment length polymorphism analysis revealed health state-specific diversity in Symbiodinium clade associations. 16S ribosomal RNA gene microarrays (PhyloChips) and O. faveolata complimentary DNA microarrays revealed the bacterial community structure and host transcriptional response, respectively. A distinct bacterial community structure marked each health state. Diseased samples were associated with two to three times more bacterial diversity. HD samples had the highest bacterial richness, which included components associated with HH and DD, as well as additional unique families. The host transcriptome under YBD revealed a reduced cellular expression of defense- and metabolism-related processes, while the neighboring HD condition exhibited an intermediate expression profile. Although HD tissue appeared visibly healthy, the microbial communities and gene expression profiles were distinct. HD should be regarded as an additional (intermediate) state of disease, which is important for understanding the progression of YBD. PMID- 24950110 TI - Hydration strategies, weight change and performance in a 161 km ultramarathon. AB - To examine controversies about hydration strategies, participants (383 starters) of a 161 km ultramarathon (maximum temperature 39.0 degrees C) underwent body weight measurements before, during and after the race; and completed a post-race questionnaire on drinking strategies and sodium supplementation use during 4 race segments. Drinking to thirst was the most common (p < 0.01) drinking strategy (used by 67.0% during at least one segment) and most runners (95.6%) used sodium supplementation during at least one segment. There was no difference in the extent of weight loss (mean 2.0-3.1%) or the weight change pattern when comparing groups using different hydration strategies. Among top-10 finishers, half had lost more than 2% of starting body weight by 90 km. We conclude that weight loss greater than 2% does not necessarily have adverse consequences on performance, and use of sodium supplements or drinking beyond thirst is not required to maintain hydration during ultra-endurance events with high thermal stress. PMID- 24950109 TI - Unveiling microbial activities along the halocline of Thetis, a deep-sea hypersaline anoxic basin. AB - Deep-sea hypersaline anoxic basins (DHABs) in the Eastern Mediterranean Sea are considered some of the most hostile environments on Earth. Little is known about the biochemical adaptations of microorganisms living in these habitats. This first metatranscriptome analysis of DHAB samples provides significant insights into shifts in metabolic activities of microorganisms as physicochemical conditions change from deep Mediterranean sea water to brine. The analysis of Thetis DHAB interface indicates that sulfate reduction occurs in both the upper (7.0-16.3% salinity) and lower (21.4-27.6%) halocline, but that expression of dissimilatory sulfate reductase is reduced in the more hypersaline lower halocline. High dark-carbon assimilation rates in the upper interface coincided with high abundance of transcripts for ribulose 1,5-bisphosphate carboxylase affiliated to sulfur-oxidizing bacteria. In the lower interface, increased expression of genes associated with methane metabolism and osmoregulation is noted. In addition, in this layer, nitrogenase transcripts affiliated to uncultivated putative methanotrophic archaea were detected, implying nitrogen fixation in this anoxic habitat, and providing evidence of linked carbon, nitrogen and sulfur cycles. PMID- 24950111 TI - Substance use and misuse and potential doping behaviour in rugby union players. AB - The aims of this investigation were to compile evidence on substance-use-and misuse (SUM) and to identify factors related to potential-doping-behaviour (PDB) in rugby union. The subjects were 105 rugby athletes (all males; 23.4 +/- 4.1 years; 99% respondents). The variables included socio-demographic factors, SUM data, sport-factors, knowledge-on-doping (KD), and PDB. Data showed high alcohol consumption, with more than 30% of the athletes binge drinking at least once per week. Approximately 52% of the subjects used dietary-supplementation (DS) and 23% reported PDB, whereas 55% believed that doping is present in rugby. Forward conditional logistic regression revealed that less rugby experience (OR:1.286; 95%CI:1.058-1.563; p < 0.05), less smoking (OR:2.034; 95%CI:1.100-3.760; p < 0.05), higher DS usage (OR:5.543; 95%CI:1.666-18.444; p < 0.01), and a stronger belief that doping is present in rugby (OR:0.305; 95%CI:0.066-0.638; p < 0.01) were significant predictors of PDB. The high PDB and alcohol consumption warrant a serious intervention on these problems in rugby. PMID- 24950112 TI - Effects of acute exposure to mild simulated hypoxia on hormonal responses to low intensity resistance exercise in untrained men. AB - This study examined hormonal responses to low-intensity resistance exercise under mild simulated hypoxia. Ten resistance untrained men performed five sets of 15 repetitions of squat exercise at 30% of 1RM under normobaric hypoxia (FiO2 = 15%) and normoxia in a cross-over and counter-balanced design. Blood lactate (LAC), growth hormone (GH), total testosterone (T) and cortisol (C) were measured at pre exercise, immediately post-exercise and 15 minutes post-exercise. LAC, GH and T significantly increased immediately after squat exercise in both trials (p < 0.05). While T returned to baseline, GH remained significantly greater at 15 minutes post-exercise. Cortisol significantly decreased immediately after and 15 minutes post-exercise in both trials (p < 0.05). No significant differences were observed between two trials in LAC, GH, T and C. It was concluded that low intensity resistance exercise performed under mild simulated hypoxia does not induce greater anabolic hormonal responses in resistance untrained men. PMID- 24950113 TI - Acute effect of caffeine intake on hemodynamics after resistance exercise in young non-hypertensive subjects. AB - This study aimed to examine the effect of caffeine on hemodynamics after a resistance exercise session. Fifteen subjects completed two randomly ordered experimental resistance exercise sessions 45 min after the ingestion of either caffeine (4 mg.kg(-1)) or placebo. Systolic (SBP), diastolic (DBP) and mean (MAP) blood pressures were measured before consuming caffeine; SBP, DBP, MAP, heart rate, stroke volume, cardiac output and peripheral vascular resistance (PVR) were measured immediately before and after each of the sessions; SBP, DBP and MAP were measured for 9 hours after sessions. Caffeine increased (p < 0.05) pre-exercise DBP and MAP. In caffeine and placebo conditions significant decreases (p < 0.05) were noted in SBP, MAP, and PVR between the pre- and post-exercise time points. Notwithstanding, the mean values for SBP, DBP and MAP during the 9 h of post exercise monitoring were increased (p < 0.05) for the caffeine. In conclusion, the cardiovascular effects of caffeine are different over the post-exercise period after resistance exercise in normotensive young adults. PMID- 24950114 TI - A comparison of two anaerobic test measurement systems using an upper body Wingate test. AB - This study aimed to compare performance measures acquired by two different Wingate Anaerobic Test systems; Cranlea and Monark. Twenty participants undertook 58 Wingate tests against a 4% body mass resistive load on a cycle ergometer adapted for arm cranking. Corrected peak power output (PP; W) was recorded using 1 rev min(-1), 0.5, 1 and 5 s averages and mean power output (MP; W). The Cranlea system recorded the greatest PP (589 +/- 267 W) compared with the Monark (546 +/- 267 W; P < 0.001). The PP using all other methods was also greater for the Cranlea compared with the Monark system (P < 0.001) with mean differences of 55 +/- 18 W for 1 s averages and 22 +/- 18 W for MP. Correlations between all PPs were strong (r = 0.99 - 0.97; P < 0.001). In conclusion, although the Cranlea system provides a consistently greater corrected PP it may not be enough to substantially differentiate between systems. PMID- 24950115 TI - A review of the physics of ice surface friction and the development of ice skating. AB - Our walking and running movement patterns require friction between shoes and ground. The surface of ice is characterised by low friction in several naturally occurring conditions, and compromises our typical locomotion pattern. Ice skates take advantage of this slippery nature of ice; the first ice skates were made more than 4000 years ago, and afforded the development of a very efficient form of human locomotion. This review presents an overview of the physics of ice surface friction, and discusses the most relevant factors that can influence ice skates' dynamic friction coefficient. It also presents the main stages in the development of ice skating, describes the associated implications for exercise physiology, and shows the extent to which ice skating performance improved through history. This article illustrates how technical and materials' development, together with empirical understanding of muscle biomechanics and energetics, led to one of the fastest forms of human powered locomotion. PMID- 24950116 TI - Effects of whole-body vibration with stochastic resonance on balance in persons with balance disability and falls history - a systematic review. AB - The aim of this systematic review was to identify and evaluate the evidence of the efficacy of stochastic resonance whole-body vibration (SR-WBV) on static, dynamic and functional balance in the elderly and in patients with neurodegenerative diseases. English and German studies were consulted in the CINAHL, Cochrane Central Register of Controlled Trials, ISI Web of Knowledge, PEDro and PubMed databases. Eight of 138 eligible studies were included, involving 381 participants. The included studies showed a low to high risk of bias. Three studies focused on long-term effects after SR-WBV. One study evaluated SR-WBV impact over three days while four studies examined its immediate effects. There is only limited evidence that SR-WBV may be effective in improving static, dynamic and functional balance among elderly individuals and patients with neurodegenerative diseases. In the future, more studies of high methodological quality are needed to improve the level of evidence. PMID- 24950117 TI - A consideration of the paradigm of exercise physiology. AB - Exercise physiology, in terms of the history of biological sciences, is quite young and has a rather tumultuous history - as it spans physical education, health & medicine, sport science, and biology. This has led to the development of differing definitions, research approaches, practices and goals. This is easily seen in the presence of competing and non-universally adopted definitions of fitness. Such internal inconsistencies portray to the outside world a discipline experiencing the problems associated with a changing paradigm. Every science requires the presence of a paradigm that both describes and guides the evolution of thinking, experimentation, and the application of such. It is argued here that exercise physiology has been operating without benefit of a satisfactory and relevant paradigm. A further proposition is that the required disciplinary definitions derived from an articulated paradigm are also absent. A paradigmatic scheme based on biological dogma is presented along with proposed definitions. PMID- 24950118 TI - Highlighting the ratio of sodium to potassium in population-level dietary assessments: cross-sectional data from New York City, USA. AB - OBJECTIVE: To contrast mean values of Na:K with Na and K mean intakes by demographic factors, and to calculate the prevalence of New York City (NYC) adults meeting the WHO guideline for optimal Na:K (<1 mmol/mmol, i.e. <0.59 mg/mg) using 24 h urinary values. DESIGN: Data were from the 2010 Community Health Survey Heart Follow-Up Study, a population-based, representative study including data from 24 h urine collections. SETTING: Participants were interviewed using a dual-frame sample design consisting of random-digit dial telephone exchanges that cover NYC. Data were weighted to be representative of NYC adults as a whole. SUBJECTS: The final sample of 1656 adults provided 24 h urine collections and self-reported health data. RESULTS: Mean Na:K in NYC adults was 1.7 mg/mg. Elevated Na:K was observed in young, minority, low-education and high-poverty adults. Only 5.2 % of NYC adults had Na:K in the optimal range. CONCLUSIONS: Na intake is high and K intake is low in NYC adults, leading to high Na:K. Na:K is a useful marker and its inclusion for nutrition surveillance in populations, in addition to Na and K intakes, is indicated. PMID- 24950119 TI - Cocaine modulates mammalian circadian clock timing by decreasing serotonin transport in the SCN. AB - Cocaine abuse disrupts reward and homeostatic processes through diverse processes, including those involved in circadian clock regulation. Recently we showed that cocaine administration to mice disrupts nocturnal photic phase resetting of the suprachiasmatic (SCN) circadian clock, whereas administration during the day induces non-photic phase shifts. Importantly, the same effects are seen when cocaine is applied to the SCN in vitro, where it blocks photic-like (glutamate-induced) phase shifts at night and induces phase advances during the day. Furthermore, our previous data suggest that cocaine acts in the SCN by enhancing 5-HT signaling. For example, the in vitro actions of cocaine mimic those of 5-HT and are blocked by the 5-HT antagonist, metergoline, but not the dopamine receptor antagonist, fluphenazine. Although our data are consistent with cocaine acting through enhanced 5-HT signaling, the nonselective actions of cocaine as an antagonist of monoamine transporters raises the question of whether inhibition of the 5-HT transporter (SERT) is key to its circadian effects. Here we investigate this issue using transgenic mice expressing a SERT that exhibits normal 5-HT recognition and transport but significantly reduced cocaine potency (SERT Met172). Circadian patterns of SCN behavioral and neuronal activity did not differ between wild-type (WT) and SERT Met172 mice, nor did they differ in the ability of the 5-HT1A,2,7 receptor agonist, 8-OH-DPAT to reset SCN clock phase, consistent with the normal SERT expression and activity in the transgenic mice. However, (1) cocaine administration does not induce phase advances when administered in vivo or in vitro in SERT Met172 mice; (2) cocaine does not block photic or glutamate-induced phase shifts in SERT Met172 mice; and (3) cocaine does not induce long-term changes in free-running period in SERT Met172 mice. We conclude that SERT antagonism is required for the phase shifting of the SCN circadian clock induced by cocaine. PMID- 24950120 TI - MicroRNA-922 promotes tau phosphorylation by downregulating ubiquitin carboxy terminal hydrolase L1 (UCHL1) expression in the pathogenesis of Alzheimer's disease. AB - Decreased levels of soluble ubiquitin carboxy-terminal hydrolase L1 (UCHL1) have been reported in the brains of sporadic Alzheimer's disease (AD) patients, and the introduction of UCHL1 rescued the synaptic and cognitive function of AD model mice. Obviously, a reduction in the levels of UCHL1 may play a role in the pathogenesis of AD. However, the mechanisms underlying the regulation of UCHL1 levels in AD have not been fully elucidated. MicroRNAs (miRs) have been shown to participate in the process of AD. In our study, we discovered that microRNA-922 decreased the levels of UCHL1. Neurofibrillary tangles (NFTs) mainly consisting of the hyperphosphorylated microtubule-associated protein tau are the defining pathological features of AD. In the present study, we found the levels of UCHL1 affected the levels of phosphorylated tau: the phosphorylated tau levels increased after knockdown of UCHL1 expression, and the phosphorylated tau levels decreased when UCHL1 was overexpressed. Furthermore, overexpression of microRNA 922 increased the phosphorylated tau levels. In conclusion, miR-922 increasing the levels of phosphorylated tau by regulating UCHL1 levels contributed to the pathogenesis of AD. Our study partly explained one of the mechanisms underlying the downregulation of UCHL1 levels in AD patients and could enrich the content of tau pathology in the pathogenesis of AD. PMID- 24950122 TI - High electrochemical performances of microsphere C-TiO2 anode for sodium-ion battery. AB - High-power, long-life carbon-coated TiO2 microsphere electrodes were synthesized by a hydrothermal method for sodium ion batteries, and the electrochemical properties were evaluated as a function of carbon content. The carbon coating, introduced by sucrose addition, had an effect of suppressing the growth of the TiO2 primary crystallites during calcination. The carbon coated TiO2 (sucrose 20 wt % coated) electrode exhibited excellent cycle retention during 50 cycles (100%) and superior rate capability up to a 30 C rate at room temperature. This cell delivered a high discharge capacity of 155 mAh g(composite)(-1) at 0.1 C, 149 mAh g(composite)(-1) at 1 C, and 82.7 mAh g(composite)(-1) at a 10 C rate, respectively. PMID- 24950121 TI - Colorimetric detection of copper(II) ion using click chemistry and hemin/G quadruplex horseradish peroxidase-mimicking DNAzyme. AB - G-quadruplex-forming sequence can be formed through a copper(I) ion (Cu(+)) catalyzed click chemistry between azide- and alkyne-modified short G-rich sequences in aqueous solution, eliminating immobilization and washing steps of conventional assays. The source for Cu(+) was generated from the reduction of Cu(2+) with the reductant of sodium ascorbate. In the presence of hemin and K(+), the self-assembly of hemin/G-quadruplex structure has the activity of horseradish peroxidase (HRP), which can catalyze its colorless substrate tetrazmethyl benzidine (TMB) into a colored product. Hence, the concentration of Cu(2+) can be evaluated visually for qualitative analysis according to the color change of the solution, and the optical density (OD) value of the resulting solution at 450 nm was also recorded using a microplate reader for quantitative analysis. PMID- 24950123 TI - A review on the role of laparoscopic sacrocervicopexy. AB - PURPOSE OF REVIEW: To provide an update on the outcomes and complications of laparoscopic (or robot-assisted) sacrocervicopexy with and without supracervical hysterectomy, and highlight the differences with sacrocolpopexy technique based on the most recent evidence. RECENT FINDINGS: Laparoscopic and robot-assisted sacrocervicopexy with supracervical hysterectomy and sacrohysteropexy have good success rates, with a mean objective success rate of 96% (range 90-100%), subjective success rates of 80-95% and mean reoperation rate of 3%. Also, pelvic symptoms and quality of life improved after laparoscopic sacrocervicopexy. These results are similar to laparoscopic and abdominal sacrocolpopexy, and are confirmed by the results of two comparative studies. Mesh erosion risk is very low in patients treated with laparoscopic sacrocervicopexy. Studies that compare laparoscopic sacrocolpopexy with concomitant total hysterectomy and sacrocervicopexy with subtotal hysterectomy show that total hysterectomy is associated with a greater prevalence of vaginal mesh exposure when compared with a subtotal hysterectomy. In case of sacralpexy, if it is decided to proceed with a hysterectomy, it is recommended to limit this to a subtotal. SUMMARY: The benefits of laparoscopic sacrocervicopexy with or without supracervical hysterectomy in terms of outcomes and reduced risk of mesh erosion in comparison with sacrocolpopexy and concomitant total hysterectomy have to be confirmed by randomized controlled trials. Moreover, standardization of surgical technique is mandatory. PMID- 24950124 TI - New hysteroscopic techniques for submucosal uterine fibroids. AB - PURPOSE OF REVIEW: To review the preoperative preparation, intraoperative equipment and techniques to facilitate hysteroscopic resection of submucous fibroids. RECENT FINDINGS: The use of preoperative ultrasound can guide safe resection of submucous fibroids and should be an integral part of a preoperative workup. The data regarding misoprostol use for cervical dilation prior to hysteroscopy is somewhat conflicting and the decision to preoperatively administer misoprostol should be on a case-by-case basis. Hysteroscopic resection of submucous intrauterine fibroids can now be performed under low-dose spinal anesthesia and with the development of smaller instruments and bipolar technology, in an office-based setting without any anesthesia and, sometimes, analgesia. Although the complete removal of type 1 and 2 submucous fibroids remain a challenge, the development of newer techniques such as office preparation of partially intramural myomas and cold-loop myomectomy can result in better removal of these submucous fibroids with an intramural component. SUMMARY: Hysteroscopic resection of submucous uterine fibroids should be a simple, well tolerated and effective procedure. Innovations to the existing hysteroscopic techniques and the development of the hysteroscopic morcellator will hopefully result in a greater number of gynecologic surgeons being able to safely perform hysteroscopic resection of submucous uterine fibroids. PMID- 24950125 TI - Selective progesterone receptor modulators. AB - PURPOSE OF REVIEW: Review of recent data from clinical trials and descriptions of endometrial morphology with administration of selective progesterone receptor modulators (SPRMs). RECENT FINDINGS: Recent reports concerning administration of SPRMs, specifically the efficacy of ulipristal acetate in reducing fibroid size and rapid control of menstrual blood loss, have renewed clinical interest in this class of compound. Histological data from studies with SPRMs report that this class of drugs is associated with progesterone receptor modulator-associated endometrial changes. Data on mechanisms of action are lacking. The antagonistic progesterone effect of SPRMs has shown promising results in animal studies with endometriosis. Sex steroid receptor effects of PRMs outside the reproductive tract raise the potential for use in neurology and oncology, and although there are several randomized trials in these areas, there are limited small studies published to date. SUMMARY: The SPRM ulipristal acetate is an effective treatment for preoperative treatment of fibroids and a reliable emergency contraceptive. This class of compounds holds the potential for long-term effective medical management of fibroids and may have utility in the management of other sex steroid-dependent conditions. PMID- 24950126 TI - The ultrastructure of Chlorobaculum tepidum revealed by cryo-electron tomography. AB - Chlorobaculum (Cba) tepidum is a green sulfur bacterium that oxidizes sulfide, elemental sulfur, and thiosulfate for photosynthetic growth. As other anoxygenic green photosynthetic bacteria, Cba tepidum synthesizes bacteriochlorophylls for the assembly of a large light-harvesting antenna structure, the chlorosome. Chlorosomes are sac-like structures that are connected to the reaction centers in the cytoplasmic membrane through the BChl alpha-containing Fenna-Matthews-Olson protein. Most components of the photosynthetic machinery are known on a biophysical level, however, the structural integration of light harvesting with charge separation is still not fully understood. Despite over two decades of research, gaps in our understanding of cellular architecture exist. Here we present an in-depth analysis of the cellular architecture of the thermophilic photosynthetic green sulfur bacterium of Cba tepidum by cryo-electron tomography. We examined whole hydrated cells grown under different electron donor conditions. Our results reveal the distribution of chlorosomes in 3D in an unperturbed cell, connecting elements between chlorosomes and the cytoplasmic membrane and the distribution of reaction centers in the cytoplasmic membrane. PMID- 24950127 TI - Orthodontic apps at fingertips. AB - BACKGROUND: Smartphone usage has spread to many settings including that of healthcare and dentistry with numerous potential and realized benefits. The ability to download custom-built software applications (apps) has created new opportunities for orthodontists to integrate technology into clinical practice and patients to collect the information about orthodontics and help them during their treatment. The purpose of this study is to provide a summary of the orthodontic apps currently available for orthodontic patients as well as 'practicing clinicians'. METHOD: Three smartphones and two tablets were used to search three operating systems (Android, Apple, and Windows) using the keywords 'braces', 'orthodontist', 'model analysis', and 'orthodontics'. RESULTS: Android and Apple operating systems accumulate all of the apps that are thought to be related to orthodontic clinicians and patients. Clinician's apps (17) are those related to orthodontic news (2), publication (4), products (3), and diagnosis (4) and practice management (3) while patient apps (17) are those related to orthodontic education (4), simulator (5), related to reminding patients about elastic wear (3), progress tracker of treatment (4), and orthodontic products (1). CONCLUSION: In the generation of technology, the use of smartphones and tablets has made life simple. The use of these technologies can be a boon both for the orthodontist and the patients as it aids both in treatment planning and progress in enhancing the treatment outcome. PMID- 24950129 TI - Exploring the impact of a dedicated streetcar right-of-way on pedestrian motor vehicle collisions: a quasi experimental design. AB - BACKGROUND AND OBJECTIVES: The frequency of pedestrian collisions is strongly influenced by the built environment, including road width, street connectivity and public transit design. In 2010, 2159 pedestrian collisions were reported in the City of Toronto, Canada with 20 fatalities. Previous studies have reported that streetcars operating in mixed traffic pose safety risks to pedestrians; however, few studies evaluate the effects on pedestrian-motor vehicle collisions (PMVC). The objective of this study was to examine changes in the rate and spatial patterning of PMVC, pre to post right-of-way (ROW) installation of the St. Clair Avenue West streetcar in the City of Toronto, Canada. METHODS: A quasi experimental design was used to evaluate changes in PMVC rate, following implementation of a streetcar ROW. Collision data were extracted from all police reported PMVC, complied and verified by the City of Toronto, from January 1, 2000 to December 31, 2011. A zero-inflated Poisson regression analysis estimated the change in PMVC, pre to post ROW. Age and injury severity were also examined. Changes in the spatial pattern of collisions were examined by applying the G function to describe the proportion of collision events that shared a nearest neighbor distance less than or equal to a threshold distance. RESULTS: A total of 23,607 PMVC occurred on roadways during the study period; 441 occurring on St. Clair Ave, 153 during the period of analysis. There was a 48% decrease in the rate of collisions on St. Clair [Incidence rate ratio (IRR)=0.52, 95% CI: 0.37 0.74], post ROW installation. There were also decreases noted for children (IRR=0.13, 95% CI: 0.04-0.44), adults (IRR=0.61, 95% CI: 0.38-0.97), and minor injuries (IRR=0.56, 95% CI: 0.40-0.80). Spatial analyses indicated increased dispersion of collision events across each redeveloped route segment following the changes in ROW design. CONCLUSIONS/IMPLICATIONS: Construction of a raised ROW operating on St. Clair Ave. was associated with a reduction in the rate of collisions. Differences in pre- and post collision spatial structure indicated changes in collision locations. Results from this study suggest that a streetcar ROW may be a safer alternative for pedestrians compared to a mixed traffic streetcar route and should be considered by city planners where appropriate to the street environment. PMID- 24950128 TI - Augmented reality cues to assist older drivers with gap estimation for left turns. AB - The objective of this study was to assess the effects of augmented reality (AR) cues designed to assist middle-aged and older drivers with a range of UFOV impairments, judging when to make left-turns across oncoming traffic. Previous studies have shown that AR cues can help middle-aged and older drivers respond to potential roadside hazards by increasing hazard detection without interfering with other driving tasks. Intersections pose a critical challenge for cognitively impaired drivers, prone to misjudge time-to-contact with oncoming traffic. We investigated whether AR cues improve or interfere with hazard perception in left turns across oncoming traffic for drivers with age-related cognitive decline. Sixty-four middle-aged and older drivers with a range of UFOV impairment judged when it would be safe to turn left across oncoming traffic approaching the driver from the opposite direction in a rural stop-sign controlled intersection scenario implemented in a static base driving simulator. Outcome measures used to evaluate the effectiveness of AR cueing included: Time-to-Contact (TTC), Gap Time Variation (GTV), Response Rate, and Gap Response Variation (GRV). All drivers estimated TTCs were shorter in cued than in uncued conditions. In addition, drivers responded more often in cued conditions than in uncued conditions and GRV decreased for all drivers in scenarios that contained AR cues. For both TTC and response rate, drivers also appeared to adjust their behavior to be consistent with the cues, especially drivers with the poorest UFOV scores (matching their behavior to be close to middle-aged drivers). Driver ratings indicated that cueing was not considered to be distracting. Further, various conditions of reliability (e.g., 15% miss rate) did not appear to affect performance or driver ratings. PMID- 24950130 TI - Integrated traffic conflict model for estimating crash modification factors. AB - Crash modification factors (CMFs) for road safety treatments are usually obtained through observational models based on reported crashes. Observational Bayesian before-and-after methods have been applied to obtain more precise estimates of CMFs by accounting for the regression-to-the-mean bias inherent in naive methods. However, sufficient crash data reported over an extended period of time are needed to provide reliable estimates of treatment effects, a requirement that can be a challenge for certain types of treatment. In addition, these studies require that sites analyzed actually receive the treatment to which the CMF pertains. Another key issue with observational approaches is that they are not causal in nature, and as such, cannot provide a sound "behavioral" rationale for the treatment effect. Surrogate safety measures based on high risk vehicle interactions and traffic conflicts have been proposed to address this issue by providing a more "causal perspective" on lack of safety for different road and traffic conditions. The traffic conflict approach has been criticized, however, for lacking a formal link to observed and verified crashes, a difficulty that this paper attempts to resolve by presenting and investigating an alternative approach for estimating CMFs using simulated conflicts that are linked formally to observed crashes. The integrated CMF estimates are compared to estimates from an empirical Bayes (EB) crash-based before-and-after analysis for the same sample of treatment sites. The treatment considered involves changing left turn signal priority at Toronto signalized intersections from permissive to protected permissive. The results are promising in that the proposed integrated method yields CMFs that closely match those obtained from the crash-based EB before-and after analysis. PMID- 24950131 TI - A human body model with active muscles for simulation of pretensioned restraints in autonomous braking interventions. AB - OBJECTIVE: The aim of this work is to study driver and passenger kinematics in autonomous braking scenarios, with and without pretensioned seat belts, using a whole-body finite element (FE) human body model (HBM) with active muscles. METHODS: Upper extremity musculature for elbow and shoulder flexion-extension feedback control was added to an HBM that was previously complemented with feedback controlled muscles for the trunk and neck. Controller gains were found using a radial basis function metamodel sampled by making 144 simulations of an 8 ms(-2) volunteer sled test. The HBM kinematics, interaction forces, and muscle activations were validated using a second volunteer data set for the passenger and driver positions, with and without 170 N seat belt pretension, in 11 ms(-2) autonomous braking deceleration. The HBM was then used for a parameter study in which seat belt pretension force and timing were varied from 170 to 570 N and from 0.25 s before to 0.15 s after deceleration onset, in an 11 ms(-2) autonomous braking scenario. RESULTS: The model validation showed that the forward displacements and interaction forces of the HBM correlated with those of corresponding volunteer tests. Muscle activations and head rotation angles were overestimated in the HBM when compared with volunteer data. With a standard seat belt in 11 ms(-2) autonomous braking interventions, the HBM exhibited peak forward head displacements of 153 and 232 mm for the driver and passenger positions. When 570 N seat belt pretension was applied 0.15 s before deceleration onset, a reduction of peak head displacements to 60 and 75 mm was predicted. CONCLUSIONS: Driver and passenger responses to autonomous braking with standard and pretensioned restraints were successfully modeled in a whole-body FE HBM with feedback controlled active muscles. Variations of belt pretension force level and timing revealed that belt pretension 0.15 s before deceleration onset had the largest effect in reducing forward head and torso movement caused by the autonomous brake intervention. The displacement of the head relative to the torso for the HBM is quite constant for all variations in timing and belt force; it is the reduced torso displacements that lead to reduced forward head displacements. PMID- 24950132 TI - Making sense of all the conflict: a theoretical review and critique of conflict related ERPs. AB - Cognitive control theory suggests that goal-directed behavior is governed by a dynamic interplay between areas of the prefrontal cortex. Critical to cognitive control is the detection and resolution of competing stimulus or response representations (i.e., conflict). Event-related potential (ERP) research provides a window into the nature and precise temporal sequence of conflict monitoring. We critically review the research on conflict-related ERPs, including the error related negativity (ERN), Flanker N2, Stroop N450 and conflict slow potential (conflict SP or negative slow wave [NSW]), and provide an analysis of how these ERPs inform conflict monitoring theory. Overall, there is considerable evidence that amplitude of the ERN is sensitive to the degree of response conflict, consistent with a role in conflict monitoring. It remains unclear, however, to what degree contextual, individual, affective, and motivational factors influence ERN amplitudes and how ERN amplitudes are related to regulative changes in behavior. The Flanker N2, Stroop N450, and conflict SP ERPs represent distinct conflict-monitoring processes that reflect conflict detection (N2, N450) and conflict adjustment or resolution processes (N2, conflict SP). The investigation of conflict adaptation effects (i.e., sequence or sequential trial effects) shows that the N2 and conflict SP reflect post-conflict adjustments in cognitive control, but the N450 generally does not. Conflict-related ERP research provides a promising avenue for understanding the effects of individual differences on cognitive control processes in healthy, neurologic and psychiatric populations. Comparisons between the major conflict-related ERPs and suggestions for future studies to clarify the nature of conflict-related neural processes are provided. PMID- 24950133 TI - The role of encoding and attention in facial emotion memory: an EEG investigation. AB - Facial expressions are encoded via sensory mechanisms, but meaning extraction and salience of these expressions involve cognitive functions. We investigated the time course of sensory encoding and subsequent maintenance in memory via EEG. Twenty-nine healthy participants completed a facial emotion delayed match-to sample task. P100, N170 and N250 ERPs were measured in response to the first stimulus, and evoked theta power (4-7Hz) was measured during the delay interval. Negative facial expressions produced larger N170 amplitudes and greater theta power early in the delay. N170 amplitude correlated with theta power, however larger N170 amplitude coupled with greater theta power only predicted behavioural performance for one emotion condition (very happy) out of six tested (see Supplemental Data). These findings indicate that the N170 ERP may be sensitive to emotional facial expressions when task demands require encoding and retention of this information. Furthermore, sustained theta activity may represent continued attentional processing that supports short-term memory, especially of negative facial stimuli. Further study is needed to investigate the potential influence of these measures, and their interaction, on behavioural performance. PMID- 24950135 TI - Nucleophilic conjugate 1,3-addition of phosphines to oligoynoates. AB - Herein we have elucidated unusual and unique nucleophilic conjugate 1,3-addition reactions of surveyed oligoynoates toward phosphines through spectroscopic and single crystal X-ray diffraction analyses of three-component reaction products of oligoynoates, phosphines and aldehydes. PMID- 24950134 TI - Intracellular delivery of recombinant arginine deiminase (rADI) by heparin binding hemagglutinin adhesion peptide restores sensitivity in rADI-resistant cancer cells. AB - Recombinant arginine deiminase (rADI) has been used in clinical trials for arginine-auxotrophic cancers. However, the emergence of rADI resistance, due to the overexpression of argininosuccinate synthetase (AS), has introduced an obstacle in its clinical application. Here, we have proposed a strategy for the intracellular delivery of rADI, which depletes both extracellular and intracellular arginine, to restore the sensitivity of rADI-resistant cancer cells. In this study, the C terminus of heparin-binding hemagglutinin adhesion protein from Mycobacterium tuberculosis (HBHAc), which contains 23 amino acids, was used to deliver rADI into rADI-resistant human breast adenocarcinoma cells (MCF-7). Chemical conjugates (l- and d-HBHAc-SPDP-rADI) and a recombinant fusion protein (rHBHAc-ADI) were produced. l- and d-HBHAc-SPDP-rADI showed a significantly higher cellular uptake of rADI by MCF-7 cells compared to that of rADI alone. Cell viability was significantly decreased in a dose-dependent manner in response to l- and d-HBHAc-SPDP-rADI treatments. In addition, the ratio of intracellular concentration of citrulline to arginine in cells treated with l- and d-HBHAc-SPDP-rADI was significantly increased by 1.4- and 1.7-fold, respectively, compared with that obtained in cells treated with rADI alone (p < 0.001). Similar results were obtained with the recombinant fusion protein rHBHAc ADI. Our study demonstrates that the increased cellular uptake of rADI by HBHAc modification can restore the sensitivity of rADI treatment in MCF-7 cells. rHBHAc ADI may represent a novel class of antitumor enzyme with an intracellular mechanism that is independent of AS expression. PMID- 24950136 TI - Powder and crack cocaine use among opioid users: is all cocaine the same? AB - OBJECTIVES: Problematic cocaine use is highly prevalent and is a significant public health concern. However, few investigations have distinguished between the 2 formulations of cocaine (ie, powder and crack cocaine) when examining the characteristics of cocaine use. Moreover, research has yet to assess the patterns of powder and crack cocaine use among opioid users, a clinical population in which problematic cocaine use is increasingly common. Using a within-subjects design, this study examined whether opioid users reported different patterns and features of powder and crack cocaine use, along with distinct trajectories and consequences of use. METHODS: Seventy-three clients enrolled in a low-threshold methadone maintenance treatment were interviewed regarding their lifetime use of powder and crack cocaine. RESULTS: Compared with crack cocaine, initiation and peak use of powder cocaine occurred at a significantly younger age. In relation to recent cocaine use, participants were significantly more likely to report using crack cocaine than using powder cocaine. Differences in routes of administration, polysubstance use, and criminal activity associated with cocaine use were also found between the 2 forms of cocaine. CONCLUSIONS: Results suggest that it may not be appropriate to consider powder and crack cocaine as diagnostically and clinically equivalent. As such, researchers may wish to distinguish explicitly between powder and crack cocaine when assessing the characteristics and patterns of cocaine use among substance users and treat these 2 forms of cocaine separately in analyses. PMID- 24950137 TI - Longitudinal assessment of mental disorders, smoking, and hazardous drinking among a population-based cohort of US service members. AB - OBJECTIVES: Combat exposure is known to increase the risk for mental disorders; however, less is known about the temporal relationship between mental disorders and alcohol misuse or smoking. To better understand these interrelationships, this study investigated mental disorders in association with hazardous drinking and cigarette smoking. METHODS: Using data from a large population-based military cohort, standardized instruments were used to screen for posttraumatic stress disorder, depression, panic, and other anxiety syndromes. Self-reported use of cigarettes and hazardous drinking was also assessed. Subjects were classified as having "new-onset," "persistent," or "resolved" mental disorders and health risk behaviors on the basis of screening results from baseline to follow-up (n = 50,028). Multivariable logistic regression models were used to investigate temporal patterns between the development of mental disorders and the uptake of smoking or hazardous drinking. RESULTS: The strongest associations of new-onset mental disorders were among those who newly reported smoking or hazardous drinking (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.28-2.59 and OR, 2.49; 95% CI, 2.15-2.89, respectively), even after adjustment for combat deployment experience. In addition, persistent smokers and hazardous drinkers had elevated odds for developing a mental disorder at follow-up. CONCLUSIONS: This study demonstrates a positive association between the onset of mental disorders with the uptake of smoking and hazardous drinking and the likelihood that multiple temporal sequence patterns exist to explain the relationship between mental disorders and hazardous drinking and smoking. Clinical approaches to mitigate deployment-related mental disorders should include alcohol and tobacco related assessments and interventions. PMID- 24950138 TI - Intravenous administration and abuse of bupropion: a case report and a review of the literature. AB - INTRODUCTION: Bupropion is an effective and well-tolerated second-generation antidepressant generally assumed to be without abuse potential. In the past years, several case reports about the recreational use of bupropion, mainly via nasal insufflation, have been published. Last year, a first case of intravenous bupropion dependence was reported. CASE PRESENTATION: We present another case of intravenous administration of and dependence on bupropion in a 29-year-old woman with a history of polysubstance dependence, who consumed an extremely high daily dose of about 2400 mg of bupropion together with a daily oral dose of 2400 to 3600 mg of pregabalin. DISCUSSION: The possible impact of bupropion on subjects with a history of polysubstance dependence is discussed; physicians should be careful when prescribing bupropion in these cases. PMID- 24950140 TI - Myospherulosis in Temporal Bone After Surgery Resembles Cholesteatoma on Imaging. PMID- 24950139 TI - Effects of antagonist of retinoid X receptor (UVI3003) on morphology and gene profile of Xenopus tropicalis embryos. AB - We exposed Xenopus tropicalis embryos to a selective antagonist of retinoid X receptor (UVI3003). UVI3003 induced multiple malformations at the concentrations of 200-1000 MUg/L after 48 h exposure. The most prominent malformations affected brains, eyes, cement gland and fins. UVI3003 also induced variable and divergent malformations at 250-1500 MUg/L after 0-24 and 24-48 h exposure. Microarray analysis showed that seven genes (rps15, serp2, fmr1, cyp2e1, lrrc9, ugtla6 and LOC100490188) were differentially regulated in all three treatment groups after 0 24h exposure. The most significantly affected pathway was galactose metabolism. In 24-48 h exposure groups, 18 genes were differentially regulated, mainly comprising components of the PPAR signaling pathway. These results suggested that UVI3003 is teratogenic in amphibian embryos. Differential gene expression suggests that galactose metabolism and PPAR signaling pathways may provide underlying mechanistic detail accounting for the observed malformations. PMID- 24950141 TI - Cartilage tympanoplasty in children with cleft palate repair. AB - OBJECTIVE: To determine outcomes of type 1 cartilage tympanoplasty in a cohort of pediatric patients with a history of cleft palate repair. PATIENTS AND OUTCOME MEASURES: Retrospective chart review and comparison with a historical control group of patients with no cleft palate anomaly undergoing the same procedure by the same surgeon at a tertiary care pediatric hospital. A total of 37 patients between ages 4 and 19 years inclusive (45 ears), with a history of repaired cleft palate, underwent type 1 cartilage tympanoplasty with or without primary tube insertion from September 2004 to October 2012. Demographics, type of cleft palate, surgical indication, middle ear status, complications, history of myringotomy tube insertion, and auditory outcomes were collected. Results were compared with those for a non-cleft palate cohort that had undergone the same procedure, which had been previously published. RESULTS: The unadjusted average preoperative and postoperative pure-tone averages for patients with a history of cleft palate were 22.06 and 7.29, respectively, compared with 18.34 and 8.32, respectively, for non-cleft patients. Despite significantly worse preoperative hearing levels among the cleft palate group, there was no statistically significant difference in outcomes with regard to hearing results between the two groups. One patient in the cleft palate group required revision type 1 cartilage tympanoplasty for graft failure, which is comparable to that reported for non cleft palate patients. Post-tympanoplasty secondary tympanostomy intubation was slightly higher for the cleft palate population. CONCLUSION: Type 1 cartilage tympanoplasty, when performed in a pediatric population with a history of cleft palate, can achieve closure and hearing results that are comparable of those in patients with no such anomaly. PMID- 24950142 TI - Functional characterization of canine interferon-lambda. AB - In this study, we provide the first comprehensive annotation of canine interferon lambda (CaIFN-lambda, type III IFN). Phylogenetic analysis based on genomic sequences indicated that CaIFN-lambda is located in the same branch with Swine IFN-lambda1 (SwIFN-lambda), Bat IFN-lambda1 (BaIFN-lambda), and human IFN-lambda1 (HuIFN-lambda1). CaIFN-lambda was cloned, expressed in Escherichia coli, and purified to further investigate the biological activity in vitro. The recombinant CaIFN-lambda (rCaIFN-lambda) displayed potent antiviral activity on both homologous and heterologous animal cells in terms of inhibiting the replication of the New Jersey serotype of vesicular stomatitis virus (VSV), canine parvovirus, and influenza virus A/WSN/33 (H1N1), respectively. In addition, we also found that rCaIFN-lambda exhibits a significant antiproliferative response against A72 canine tumor cells and MDCK cells in a dose-dependent manner. Furthermore, CaIFN-lambda activated the JAK-STAT signaling pathway. To evaluate the expression of CaIFN-lambda induced by virus and the expression of IFN stimulated genes (ISGs) induced by rCaIFN-lambda in the MDCK cells, we measured the relative mRNA level of CaIFN-lambda and ISGs (ISG15, Mx1, and 2'5'-OAS) by quantitative real-time PCR and found that the mRNA level of CaIFN-lambda and the ISGs significantly increased after treating the MDCK cells with viruses and rCaIFN-lambda protein, respectively. Finally, to evaluate the binding activity of rCaIFN-lambda to its receptor, we expressed the extracellular domain of the canine IFN-lambda receptor 1 (CaIFN-lambdaR1-EC) and determined the binding activity via ELISA. Our results demonstrated that rCaIFN-lambda bound tightly to recombinant CaIFN-lambdaR1-EC (rCaIFN-lambdaR1-EC). PMID- 24950143 TI - Enantioselective skin permeation of ibuprofen enantiomers: mechanistic insights from ATR-FTIR and CLSM studies based on synthetic enantiomers as naphthalimide fluorescent probes. AB - OBJECTIVE: The aim of this study was to investigate the mechanisms of different skin permeability of ibuprofen racemate and enantiomers. METHODS: The percutaneous permeation of ibuprofen racemate and enantiomers through rabbit normal skin and damaged skin (without stratum corneum [SC]) was investigated in vitro using side-by-side diffusion cells. With the melting temperature-membrane transport model, the flux ratio of enantiomer/racemate was calculated from their thermodynamic properties obtained by differential scanning calorimetry. Attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) study was performed to evaluate the interaction between the enantiomers and the SC. New fluorescent probes were designed and utilized in confocal laser scanning microscopy (CLSM) study for visualization of the enantioselective permeation of the enantiomers through the intact rabbit skin. RESULT: The flux of (S)-ibuprofen through normal skin was significantly higher than that of (RS)-ibuprofen and (R) ibuprofen (p < 0.05), whereas in damaged skin, there was no significant difference (p > 0.05). The predicted flux ratio of (S)-ibuprofen/(RS)-ibuprofen (2.50) was in close agreement with the experimentally determined ratio (2.48). These results were supported by ATR-FTIR and CLSM studies that indicated that a chiral environment of the skin led to the enantioselective permeation of enantiomers. CONCLUSIONS: The chiral nature of the SC and the different physicochemical properties of the enantiomers should be taken into account in the assessment of different skin permeability of the racemate and enantiomers. The synthetic fluorescent probes used in this study could visualize the enantioselective permeation of the chiral compounds across the skin. PMID- 24950144 TI - Determination of protein binding affinities within hydrogel-based molecularly imprinted polymers (HydroMIPs). AB - Hydrogel-based molecularly imprinted polymers (HydroMIPs) were prepared for several proteins (haemoglobin, myoglobin and catalase) using a family of acrylamide-based monomers. Protein affinity towards the HydroMIPs was investigated under equilibrium conditions and over a range of concentrations using specific binding with Hill slope saturation profiles. We report HydroMIP binding affinities, in terms of equilibrium dissociation constants (Kd) within the micro-molar range (25 +/- 4 MUM, 44 +/- 3 MUM, 17 +/- 2 MUM for haemoglobin, myoglobin and catalase respectively within a polyacrylamide-based MIP). The extent of non-specific binding or cross-selectivity for non-target proteins has also been assessed. It is concluded that both selectivity and affinity for both cognate and non-cognate proteins towards the MIPs were dependent on the concentration and the complementarity of their structures and size. This is tentatively attributed to the formation of protein complexes during both the polymerisation and rebinding stages at high protein concentrations. We have used atomic force spectroscopy to characterize molecular interactions in the MIP cavities using protein-modified AFM tips. Attractive and repulsive force curves were obtained for the MIP and NIP (non-imprinted polymer) surfaces (under protein loaded or unloaded states). Our force data suggest that we have produced selective cavities for the template protein in the MIPs and we have been able to quantify the extent of non-specific protein binding on, for example, a non imprinted polymer (NIP) control surface. PMID- 24950145 TI - Food and nutrient intake of Irish community-dwelling elderly subjects: who is at nutritional risk? AB - OBJECTIVES: To assess the dietary intakes of Irish community-dwelling elderly individuals, participating in the ELDERMET project. DESIGN: Cross-sectional study. SETTING: Cork city and county region of southern Ireland. PARTICIPANTS: Two hundred and eight (94 males, 114 females) community-dwelling subjects aged 64 93 yrs. MEASUREMENTS: Dietary intake was assessed using a validated semi quantitative food frequency questionnaire (FFQ). Anthropometric data were recorded. Nutritional status was assessed using the Mini Nutritional Assessment (MNA). RESULTS: A high rate of overweight/obesity was observed in this population group. Consumption of energy-dense, low-nutrient foods was excessive among this population group. Older elderly subjects (>=75 yrs) consumed significantly (P<0.01) more desserts/sweets than younger elderly (64-74 yrs). Intakes of dietary fat and saturated fat were high while dairy food consumption was inadequate in both males and females. Elderly females typically had a more nutrient-dense diet than males. A considerable proportion of subjects, particularly males, had inadequate intakes of calcium, magnesium, vitamin D, folate, zinc and vitamin C. CONCLUSION: The data indicate that the diet of Irish community-dwelling elderly individuals is sub-optimal with respect to nutrient intake, and excessive in terms of fat intake, with implications for the health status of this population group. Reductions in dietary fat and increased low fat dairy food intakes are recommended for the prevention of diet-related disease in older persons. In addition, strategies to improve a number of sub-optimal micronutrient intakes need to be developed and implemented, particularly among elderly males. PMID- 24950146 TI - Fruit and vegetable consumption, ethnicity and risk of fatal ischemic heart disease. AB - OBJECTIVE: Mortality rates from ischemic heart disease vary among ethnic groups. Dietary intake of fruits and vegetables has been associated with a lower risk of ischemic heart disease, but ethnic-specific data are limited. DESIGN: Prospective cohort study. SETTING: Hawaii and Los Angeles County, between 1993 and 1996. PARTICIPANTS: These analyses included 164,617 adults age 45 to 75, representing five ethnic groups who were enrolled in the Multiethnic Cohort Study. Dietary data were collected at baseline using a validated food frequency questionnaire and fatal ischemic heart disease cases were identified up to December 31, 2001. Associations between fruit and vegetable consumption and fatal ischemic heart disease were examined using multivariate Cox proportional hazard models. RESULTS: The associations between fruit and vegetable intake and fatal ischemic heart disease were similar among the five ethnic groups. When data for the ethnic groups were combined, higher vegetable intake was associated with a protective effect against ischemic heart disease in men with all intake levels above 3.4 servings per day (over 6.6 servings per day: hazard ratio, 0.73; 95% confidence interval, 0.58-0.92). Inconsistent results were observed for women, where the protective association was observed only at mid-level vegetable intake levels, but not among women with the highest level of vegetable intake. There was no evidence of an association for fruit intake. CONCLUSIONS: Associations between fruit and vegetable intake and fatal IHD do not appear to vary among ethnic groups. Additional research is needed to clarify associations for fruit versus vegetable intake and impact on cardiovascular outcomes. PMID- 24950147 TI - Applicability of ultrasound muscle thickness measurements for predicting fat-free mass in elderly population. AB - OBJECTIVE: This study aimed to examine the applicability of ultrasound muscle thickness (MT) measurements for predicting whole body fat-free mass (FFM) in elderly individuals. DESIGN AND SETTING: Cross-sectional study of 77 healthy elderly individuals. METHODS: MTs at nine sites of the body and FFM were determined using B-mode ultrasound and dual-energy x-ray absorptiometry (DXA), respectively, in 44 women and 33 men aged 52 to 78 yrs. Stepwise multiple regression analysis produced two equations for predicting DXA-based FFM with sex (dummy: woman = 0 and man = 1) and either MTs at the anterior and posterior of thigh and lower leg (Eq1) or the product of MT and limb length (MT*LL) at thigh anterior and posterior, lower leg posterior, and upper arm anterior (Eq2) as independent variables. RESULTS: The R2 and SEE for each of the two equations were 0.929 and 2.5 kg for Eq1 and 0.955 and 2.0 kg for Eq2. The estimated FFM from each of Eq1 (44.4 +/- 8.9 kg) and Eq2 (44.4 +/- 9.0 kg) did not significantly differ from that of the DXA-based FFM (44.4 +/- 9.2 kg), without systematic error. However, the absolute value of the difference between the DXA-based and estimated FFM was significantly greater with Eq1 (2.0 +/- 1.5 kg) than with Eq2 (1.5 +/- 1.3 kg). CONCLUSION: The current results indicate that ultrasound MT measurement is useful to predict FFM in the elderly, and its accuracy is improved by using the product of MT and limb length as an independent variable. PMID- 24950148 TI - A comparison of prediction equations for the estimation of body fat percentage in non-obese and obese older Caucasian adults in the United States. AB - OBJECTIVES: The predictive capabilities of skinfold regression equations are limited across populations and current equations may not be well suited for the prediction of body fat in older adults or obese Americans. The goal of this study was to compare percent body fat (%BF) predicted by several skinfold regression equations to %BF determined by Dual-Energy X-ray Absorptiometry (DXA) in obese and non-obese Caucasian men and women in the United States over the age of 65 years. DESIGN: A block design was used with two blocks: obesity (non-obese/obese) and gender (male/female). All subjects underwent the same testing procedures in one visit. SETTING: University of Pittsburgh Clinical and Translation Research Center. PARTICIPANTS: Seventy-eight older healthy adults were recruited for participation. MEASUREMENTS: Actual percent body fat was determined from a whole body DXA scan. Estimated percent body fat (%BF) was calculated using skinfold measurements and established regression equations. The predictive accuracy of the regression equations was evaluated by comparing the estimated %BF to the actual %BF measured with DXA using a within subject ANOVA (alpha=0.05). This was done within subgroups: obese males, obese females, non-obese males and non-obese females. RESULTS: Durnin and Womersly and Jackson and Pollock had reasonably good agreement with DXA in older Caucasian American females and males, respectively. The remaining equations significantly overestimated %BF in older Caucasian American males. Mixed results were found in females with Gause-Nilsson and Jackson and Pollock significantly underestimating %BF, while Visser and Kwok overestimated %BF. CONCLUSION: Numerous factors of a population including age, race, ethnicity, gender and obesity should be considered when selecting a skinfold regression equation to estimate %BF. While Durnin and Womersly and Jackson and Pollock are recommended for predicting %BF in older Caucasian American females and males, respectively, there exists a need to develop accurate regression models that consider obesity, gender, race or ethnicity when predicting %BF in a diverse geriatric American population. PMID- 24950149 TI - Precision of total and regional body fat estimates from dual-energy X-ray absorptiometer measurements. AB - OBJECTIVES: To evaluate the precision of both total %fat and all the regional %fat measures acquired from both the Lunar Prodigy and Lunar iDXA software. DESIGN: Cross-sectional study. SETTING: University-based research laboratory. PARTICIPANTS: The sample consisted of 300 individual test records from men and women who had volunteered to participate in dual-energy x-ray absorptiometer (DXA) technician precision training studies. Subjects ranged in age from 20-84 years and in body mass index from 15.7-52.0 kg.m-2. MEASUREMENTS: A total of 27 different technicians performed three total body scan measurements on 10-15 different subjects. The Lunar Prodigy and Lunar iDXA were used for 253 and 47 precision training evaluations, respectively. The regions of interest (ROI) were automatically determined by the enCORE software (autoROI) for total body, android, gynoid, trunk, legs, and arms regions and the region %fat data were used for analyses. RESULTS: The CV for total body %fat was 1.9% and 0.9% for the Prodigy and iDXA, respectively. CV's for %fat measures at regional sites ranged from 1.2-4.4% for the Prodigy measures and 0.9-2.4% for the iDXA measures. The ICC for both devices ranged from 0.990 to 0.999. CONCLUSION: Monitoring the status of body composition changes with age is gaining more clinical acceptance. Thus, it is important that practitioners use measures that are both precise and accurate. The findings from the current study add support that DXA measurements can be used with a high level of confidence for serial testing of patients. PMID- 24950150 TI - Malnutrition in care home residents with dementia. AB - OBJECTIVES: To investigate the malnutrition prevalence in Dutch care home residents with dementia over the years. Secondly, to examine the relationship of malnutrition and dementia and the role of care dependency and co-morbidity within this relationship. DESIGN: This study is a secondary analysis of data of the annual independent Dutch National Prevalence Measurement of Care Problems of Maastricht University. The design involves a cross-sectional, multicenter point prevalence measurement. SETTING: Care homes. PARTICIPANTS: 75399 residents older than 65 years (4523 resident with dementia) participated over 5 years (2006 2010). Sixty organizations measured 4 times, 31 organizations 3 times, 68 organizations 2 times, 511 organizations 1 time. MEASUREMENTS: A standardized questionnaire was used to register amongst others data of weight, height, nutritional intake, undesired weight loss, comorbidity, dementia, and care dependency. RESULTS: The study was able to show that there is a significant decline in malnutrition prevalence in the group of non-demented residents over the years (Non-demented group p <0.001). The prevalence of malnutrition in the demented group showed no significant reduction over the years. GEE analysis showed that malnutrition and dementia are related and that care dependency and age are important influencing factors in this relation. CONCLUSION: The results show that compared to the non-demented residents, the prevalence of malnutrition does not decline in demented care home residents over the years. Moreover, the findings of this study stress that malnutrition and dementia are related, while care dependency and age are confounding factors in this relationship. PMID- 24950151 TI - The nutritional status of Dutch elderly patients with Parkinson's disease. AB - OBJECTIVES: To assess the prevalence of (risk of) undernutrition in Dutch elder Parkinson's disease patients as well as it's risk factors. DESIGN: Observational cross-sectional study. SETTING: An outpatient clinic at the department Neurology of Medical Centre Leeuwarden, a large teaching hospital. PARTICIPANTS: 102 outpatients with Parkinson's disease aged 65 years and older were recruited. MEASUREMENTS: Data regarding various aspects of undernutrition including socio demographic aspect, disease characterisitics, nutritional status, appetite and overall-physical and psychological functioning were collected. RESULTS: Undernutrition was diagnosed in 2.0% and 20.5% of the patients were categorized as being at risk of undernutrition. Care dependency and appetite were the two risk factors with the highest predictive value for an unfavorable nutritional status. CONCLUSION: Of Dutch elderly patients with Parkinson's Disease 22.5% had an unfavourable nutritional status. Dependency and appetite were the two risk factors with the highest predictive value fort his outcome. Because undernutrition can be regarded as a geriatric syndrome a comprehensive nutritional assessment should be done followed by nutritional interventions next to interventions focused on the risk factors. Further studies are needed to evaluate these interventions. PMID- 24950153 TI - Physical performance measures and polypharmacy among hospitalized older adults: results from the CRIME study. AB - OBJECTIVE: To investigate the association of polypharmacy and physical performance measures in a sample of elderly patients aged >=65 years admitted to acute care hospitals. DESIGN, SETTING AND PARTICIPANTS: Prospective study conducted among 1123 hospitalized older adults participating to the CRiteria to Assess Appropriate Medication Use among Elderly Complex Patients (CRIME) project. MEASUREMENTS: Physical performance was measured at hospital admission by the 4 meter walking speed (WS) and the grip strength (GS). Polypharmacy was defined as the use of >=10 drugs during hospital stay. RESULTS: Mean age of 1123 participants was 81.5+/-7.4 years and 576 (51.3%) were on polypharmacy. Prevalence of polypharmacy was higher in patients with low WS and GS. After adjusting for potential confounders, participants in the highest tertile of WS were less likely to be on polypharmacy as compared with those in the lowest tertile (OR 0.58; 95% CI 0.35 - 0.96). Similarly, participants in the highest tertile of GS had a significantly lower likelihood of polypharmacy as compared with those in the lowest tertile (OR 0.55; 95% CI 0.36 - 0.84). When examined as continuous variables, WS and GS were inversely associated with polypharmacy (WS: OR 0.77 per 1 SD increment; 95% CI 0.60 - 0.98; GS: OR 0.71 per 1 SD increment; 95% CI 0.56 - 0.90). CONCLUSION: Among hospitalized older adults WS and GS are inversely related to polypharmacy. These measures should be incorporated in standard assessment of in-hospital patients. PMID- 24950152 TI - Exercise-induced lowering of chemerin is associated with reduced cardiometabolic risk and glucose-stimulated insulin secretion in older adults. AB - OBJECTIVE: To determine the effect of exercise on chemerin in relation to changes in fat loss, insulin action, and dyslipidemia in older adults. PARTICIPANTS: Thirty older (65.9+/-0.9yr) obese adults (BMI:34.5+/-0.7kg/m2). SETTING: Single center, Cleveland Clinic. DESIGN: Prospective clinical trial. INTERVENTION: Twelve-weeks of exercise training (60minutes/day, 5day/week at ~85% HRmax). Subjects were instructed to maintain habitual nutrient intake. MEASUREMENTS: Plasma chemerin was analyzed using an enzyme-linked immunosorbent assay. Peripheral and hepatic insulin sensitivity was assessed using a euglycemic hyperinsulinic clamp with glucose kinetics. First-phase and total glucose stimulated insulin secretion (GSIS) was calculated from an oral glucose tolerance test. Fasting blood lipids (cholesterol, triglycerides), total/visceral fat (dual x-ray absorptiometry and computerized tomography) and cardiorespiratory fitness (treadmill test) were also tested pre and post intervention. RESULTS: Exercise increased fitness and reduced total/visceral fat, blood lipids, and first-phase GSIS (P<0.05). Training also increased peripheral insulin sensitivity and lowered basal/insulin-related hepatic glucose production (P<0.01). The intervention reduced chemerin (87.1+/-6.0 vs. 78.1+/-5.8ng/ml; P=0.02), and the reduction correlated with decreased visceral fat (r=0.50, P=0.009), total body fat (r=0.42, P=0.02), cholesterol (r=0.38, P=0.04), triglycerides (r=0.36, P=0.05), and first phase and total GSIS (r=0.39, P=0.03 and r=0.43, P=0.02, respectively). CONCLUSIONS: Lower chemerin appears to be an important hormone involved in cardiometabolic risk and GSIS reduction following exercise in older adults. PMID- 24950154 TI - Age, frailty, disability, institutionalization, multimorbidity or comorbidity. Which are the main targets in older adults? AB - OBJECTIVES: Age, frailty, disability, institutionalization, multimorbidity or comorbidity are main risk factors for serious health adverse outcomes in older adults. However, the adjusted relevance of each of them in order to determine which characteristics must be of importance for health policies in this population group, has not been established. DESIGN: Concurrent population-based cohort study. SETTING: Albacete city, Spain. PARTICIPANTS: 842 participants over age 70 from the FRADEA Study. MEASUREMENTS: Age, gender, institutionalization, frailty (Fried's criteria), previous disability in basic activities of daily living (BADL) (Barthel index), comorbidity (Charlson index), and multimorbidity (>= 2 from 14 selected diseases) were recorded in the basal visit. The combined event of mortality or incident disability in BADL was determined in the follow-up visit. The risk of presenting adverse events was determined by Kaplan-Meier analysis and logistic regression adjusted for age, sex, and institutionalization. RESULTS: Mean follow-up 520 days. 63 participants died (7.5%). Among the remaining 779, 191 lost at least one BADL (24.5%). The combined event of mortality or disability was present in 254 participants (30.2%). Age (OR 1.10, 95%CI 1.06-1.14), frailty (OR 3.07, 95%CI 1.63-5.77), disability (OR 2.19, 95%CI 1.43-3.36) and institutionalization (OR 2.73, 95%CI 1.68-4.44) were independently associated with the combined adverse event, but not comorbidity or multimorbidity. In subjects younger than 80, only frailty, disability and institutionalization were risk factors, and in those aged >= 80, only age, disability and institutionalization were. CONCLUSIONS: Health policies for older adults must take into account mainly frailty and disability in subjects younger than 80 and disability in those older than 80. PMID- 24950156 TI - Relationship of the 2011 Global Initiative for Chronic Obstructive Lung Disease strategy to clinically relevant outcomes in individuals with alpha1-antitrypsin deficiency. AB - RATIONALE: It is not known how the 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy predicts clinical course of alpha1-antitrypsin deficiency (AATD). OBJECTIVES: To determine how the new strategy relates to outcomes (i.e., mortality, lung function decline, and exacerbations) in patients with AATD. METHODS: All PiZZ patients (patients with ZZ genotype causing severe AATD) on the AATD registry with a physiological diagnosis of chronic obstructive pulmonary disease were grouped into four GOLD categories (A, B, C, and D) on the basis of their combined risk. We then compared mortality and lung function decline in these categories and also assessed the predictive ability of exacerbation history in the patients. MEASUREMENTS AND MAIN RESULTS: Mortality (GOLD categories A: 6 [5.8%]; B: 7 [5.93%]; C: 11 [9.32%]; D: 94 [79.66%]) was greatest in high-symptom, high-risk category D (P = 0.0001), which also showed a faster decline in Kco (mmol/min/kPa/L/yr, mean [SD], A: -0.021 [0.03]; B: -0.022 [0.03]; C: -0.032 [0.03]; D: -0.031 [0.03]) (P = 0.012). The fastest mean decline in FEV1 (ml/yr, mean [SD], A: -66.59 [61.39]; B: -53.00 [47.09]; C: -56.96 [48.87]; D: -41.25 [62.09]) was observed in category A and least in category D (P = 0.002). Multivariate analysis showed that GOLD category was significant for all outcomes (P < 0.05). CONCLUSIONS: The new strategy performs well in identifying patients with increased risk of poorer outcomes in AATD. This has therapeutic implications enabling more aggressive therapy to be directed to those in the highest-risk group. Further studies to identify subgroups of patients most likely to benefit from augmentation therapy are indicated. PMID- 24950159 TI - Psychological problems of Iranian children and adolescents: parent report form of Strengths and Difficulties Questionnaire. AB - OBJECTIVE: The aim of this study was to evaluate the degree of psychological problems Iranian children and adolescents have, using parent report form of the Strengths and Difficulties Questionnaire (SDQ). METHODS: In a community-based study, 9636 children and adolescents aged 6-17 years were selected using the multistage cluster random sampling method from five provinces of Iran: Tehran, Isfahan, Fars, Razavi Khorasan and East Azerbaijan. The parents completed the SDQ, which consisted of five subscales including emotional problems, conduct problems, hyperactivity, peer problems and prosocial behaviors. RESULT: The results revealed 21.4% of emotional problems, 32.9% of conduct problems, 20% of hyperactivity, 25.6% of peer problems, 7.6% of problems in prosocial behaviors and 16.7% of total difficulties among Iranian children and adolescents. We found that emotional problems were more prevalent among girls, while conduct problems, hyperactivity, total difficulties and problems in prosocial behaviors were more prevalent among boys. High educational level of parents was a protective factor against some psychological problems. CONCLUSION: Considering the proportion of psychological problems in Iranian children and adolescents, we need to develop and implement special policies and programs to provide appropriate mental health services. PMID- 24950158 TI - Water behavior in bacterial spores by deuterium NMR spectroscopy. AB - Dormant bacterial spores are able to survive long periods of time without nutrients, withstand harsh environmental conditions, and germinate into metabolically active bacteria when conditions are favorable. Numerous factors influence this hardiness, including the spore structure and the presence of compounds to protect DNA from damage. It is known that the water content of the spore core plays a role in resistance to degradation, but the exact state of water inside the core is a subject of discussion. Two main theories present themselves: either the water in the spore core is mostly immobile and the core and its components are in a glassy state, or the core is a gel with mobile water around components which themselves have limited mobility. Using deuterium solid state NMR experiments, we examine the nature of the water in the spore core. Our data show the presence of unbound water, bound water, and deuterated biomolecules that also contain labile deuterons. Deuterium-hydrogen exchange experiments show that most of these deuterons are inaccessible by external water. We believe that these unreachable deuterons are in a chemical bonding state that prevents exchange. Variable-temperature NMR results suggest that the spore core is more rigid than would be expected for a gel-like state. However, our rigid core interpretation may only apply to dried spores whereas a gel core may exist in aqueous suspension. Nonetheless, the gel core, if present, is inaccessible to external water. PMID- 24950160 TI - Health effects of multi-pollutant profiles. AB - BACKGROUND: The association between exposure to particle mass and mortality is well established; however, there are still uncertainties as to whether certain chemical components are more harmful than others. Moreover, understanding the health effects associated with exposure to pollutant mixtures may lead to new regulatory strategies. OBJECTIVES: Recently we have introduced a new approach that uses cluster analysis to identify distinct air pollutant mixtures by classifying days into groups based on their pollutant concentration profiles. In Boston during the years 1999-2009, we examined whether the effect of PM2.5 on total mortality differed by distinct pollution mixtures. METHODS: We applied a time series analysis to examine the association of PM2.5 with daily deaths. Subsequently, we included an interaction term between PM2.5 and the pollution mixture clusters. RESULTS: We found a 1.1% increase (95% CI: 0.0, 2.2) and 2.3% increase (95% CI: 0.9-3.7) in total mortality for a 10 MUg/m(3) increase in the same day and the two-day average of PM2.5 respectively. The association is larger in a cluster characterized by high concentrations of the elements related to primary traffic pollution and oil combustion emissions with a 3.7% increase (95% CI: 0.4, 7.1) in total mortality, per 10 MUg/m(3) increase in the same day average of PM2.5. CONCLUSIONS: Our study shows a higher association of PM2.5 on total mortality during days with a strong contribution of traffic emissions, and fuel oil combustion. Our proposed method to create multi-pollutant profiles is robust, and provides a promising tool to identify multi-pollutant mixtures which can be linked to the health effects. PMID- 24950161 TI - Monitoring chlorinated persistent organic pollutants in adolescents in Flanders (Belgium): concentrations, trends and dose-effect relationships (FLEHS II). AB - BACKGROUND: In 2007, the second cycle of the Flemish human biomonitoring survey started, with a main focus on 14-15 year-old adolescents. OBJECTIVES: The main objectives were generating reference values for exposure markers, determining the pollution pressure in industrial hotspots and establishing dose-effect relationships between exposure to pollutants and hormone levels, sexual development, asthma and allergy, genotoxic and hematological markers. METHODS: Geometric means with 95% confidence intervals (CI) were calculated for a reference population of 200 14-15 year-old adolescents. Stepwise multiple regression analyses with correction for confounders and covariates were performed to establish dose-effect relationships. RESULTS: Geometric mean concentrations (with 95% CI) of 49.6 (45.7, 53.8), 70.8 (63.6, 78.8) and 8.34 (7.76, 8.97) n gg( 1) lipid for the sum of PCB 138, 153 and 180, p,p'-DDE and HCB were respectively 23%, 26% and 60% lower than those obtained five years earlier. Geometric mean concentrations of 108 (101, 114) and 32.1 (30.1, 34.2) pgCALUX-BEQg(-1) lipid were observed for the PCDD/Fs and dioxin-like PCBs, respectively. Multiple dose effect relationships were observed between POPs and several effect markers, including positive (boys) and negative (girls) associations with data on sexual development and positive associations with asthma, animal allergy and free thyroxine (boys and girls). CONCLUSIONS: Our findings suggest that chlorinated POP concentrations are decreasing over time and that even relatively low concentrations are associated with biological effects. PMID- 24950168 TI - A 2-year-old Japanese girl with TNF receptor-associated periodic syndrome: A case report of the youngest diagnosed proband in Japan. AB - We report a 2-year-old girl with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) who is the youngest proband diagnosed in Japan. Recurrent fever had started at her 6 months of age, and she had the familial history of recurrent fever, suggesting underlying genetic disorder, in her father and grandfather. Careful clinical observation of characteristics of fever with disease course and the familial history of recurrent fever may lead to diagnosis of TRAPS in early infancy. PMID- 24950163 TI - Case scenario: a patient on dual antiplatelet therapy with an intracranial hemorrhage after percutaneous coronary intervention. PMID- 24950164 TI - Down-regulation of microRNA-21 is involved in the propofol-induced neurotoxicity observed in human stem cell-derived neurons. AB - BACKGROUND: Recent studies in various animal models have suggested that anesthetics such as propofol, when administered early in life, can lead to neurotoxicity. These studies have raised significant safety concerns regarding the use of anesthetics in the pediatric population and highlight the need for a better model to study anesthetic-induced neurotoxicity in humans. Human embryonic stem cells are capable of differentiating into any cell type and represent a promising model to study mechanisms governing anesthetic-induced neurotoxicity. METHODS: Cell death in human embryonic stem cell-derived neurons was assessed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling staining, and microRNA expression was assessed using quantitative reverse transcription polymerase chain reaction. miR-21 was overexpressed and knocked down using an miR-21 mimic and antagomir, respectively. Sprouty 2 was knocked down using a small interfering RNA, and the expression of the miR-21 targets of interest was assessed by Western blot. RESULTS: Propofol dose and exposure time dependently induced significant cell death (n = 3) in the neurons and down-regulated several microRNAs, including miR-21. Overexpression of miR-21 and knockdown of Sprouty 2 attenuated the increase in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling-positive cells following propofol exposure. In addition, miR-21 knockdown increased the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling-positive cells by 30% (n = 5). Finally, activated signal transducer and activator of transcription 3 and protein kinase B (Akt) were down-regulated, and Sprouty 2 was up-regulated following propofol exposure (n = 3). CONCLUSIONS: These data suggest that (1) human embryonic stem cell-derived neurons represent a promising in vitro human model for studying anesthetic-induced neurotoxicity, (2) propofol induces cell death in human embryonic stem cell-derived neurons, and (3) the propofol-induced cell death may occur via a signal transducer and activator of transcription 3/miR 21/Sprouty 2-dependent mechanism. PMID- 24950169 TI - Obstacles to the implementation of the treat-to-target strategy for rheumatoid arthritis in clinical practice in Japan. AB - OBJECTIVE: To clarify the obstacles preventing the implementation of the treat-to target (T2T) strategy for rheumatoid arthritis (RA) in clinical practice. METHODS: A total of 301 rheumatologists in Japan completed a questionnaire. In the first section, participants were indirectly questioned on the implementation of basic components of T2T, and in the second section, participants were directly questioned on their level of agreement and application. RESULTS: Although nearly all participants set treatment targets for the majority of RA patients with moderate to high disease activity, the proportion who set clinical remission as their target was 59%, with only 45% of these using composite measures. The proportion of participants who monitored X-rays and Health Assessment Questionnaires for all their patients was 44% and 14%, respectively. The proportion of participants who did not discuss treatment strategies was 44%, with approximately half of these reasoning that this was due to a proportion of patients having a lack of understanding of the treatment strategy or inability to make decisions. When participants were directly questioned, there was a high level of agreement with the T2T recommendations. CONCLUSION: Although there was a high level of agreement with the T2T recommendations, major obstacles preventing its full implementation still remain. PMID- 24950170 TI - Spontaneous flexor tendon rupture in systemic lupus erythematosus: A case report. AB - Spontaneous flexor tendon rupture is an unusual complication of systemic lupus erythematosus (SLE) and has not previously been reported. While tendon ruptures in association with SLE have been focused on the previous studies, upper extremity tendon ruptures are infrequently reported in the literature. Here, we present an uncommon case of spontaneous flexor tendon rupture of the ring and little fingers in a patient with SLE and discuss the mechanism of injury and its surgical treatment. PMID- 24950172 TI - Being bad in a video game can make us more morally sensitive. AB - Several researchers have demonstrated that the virtual behaviors committed in a video game can elicit feelings of guilt. Researchers have proposed that such guilt could have prosocial consequences. However, this proposition has not been supported with empirical evidence. The current study examined this issue in a 2*2 (video game play vs. real world recollection*guilt vs. control) experiment. Participants were first randomly assigned to either play a video game or complete a memory recall task. Next, participants were randomly assigned to either a guilt inducing condition (game play as a terrorist/recall of acts that induce guilt) or a control condition (game play as a UN soldier/recall of acts that do not induce guilt). Results of the study indicate several important findings. First, the current results replicate previous research indicating that immoral virtual behaviors are capable of eliciting guilt. Second, and more importantly, the guilt elicited by game play led to intuition-specific increases in the salience of violated moral foundations. These findings indicate that committing "immoral" virtual behaviors in a video game can lead to increased moral sensitivity of the player. The potential prosocial benefits of these findings are discussed. PMID- 24950157 TI - Weighing the Evidence of Common Beliefs in Obesity Research. AB - Obesity is a topic on which many views are strongly held in the absence of scientific evidence to support those views, and some views are strongly held despite evidence to contradict those views. We refer to the former as "presumptions" and the latter as "myths." Here, we present nine myths and 10 presumptions surrounding the effects of rapid weight loss; setting realistic goals in weight loss therapy; stage of change or readiness to lose weight; physical education classes; breastfeeding; daily self-weighing; genetic contribution to obesity; the "Freshman 15"; food deserts; regularly eating (versus skipping) breakfast; eating close to bedtime; eating more fruits and vegetables; weight cycling (i.e., yo-yo dieting); snacking; built environment; reducing screen time in childhood obesity; portion size; participation in family mealtime; and drinking water as a means of weight loss. For each of these, we describe the belief and present evidence that the belief is widely held or stated, reasons to support the conjecture that the belief might be true, evidence to directly support or refute the belief, and findings from randomized controlled trials, if available. We conclude with a discussion of the implications of these determinations, conjecture on why so many myths and presumptions exist, and suggestions for limiting the spread of these and other unsubstantiated beliefs about the obesity domain. PMID- 24950174 TI - Investigation of the profile control mechanisms of dispersed particle gel. AB - Dispersed particle gel (DPG) particles of nano- to micron- to mm-size have been prepared successfully and will be used for profile control treatment in mature oilfields. The profile control and enhanced oil recovery mechanisms of DPG particles have been investigated using core flow tests and visual simulation experiments. Core flow test results show that DPG particles can easily be injected into deep formations and can effectively plug the high permeability zones. The high profile improvement rate improves reservoir heterogeneity and diverts fluid into the low permeability zone. Both water and oil permeability were reduced when DPG particles were injected, but the disproportionate permeability reduction effect was significant. Water permeability decreases more than the oil permeability to ensure that oil flows in its own pathways and can easily be driven out. Visual simulation experiments demonstrate that DPG particles can pass directly or by deformation through porous media and enter deep formations. By retention, adsorption, trapping and bridging, DPG particles can effectively reduce the permeability of porous media in high permeability zones and divert fluid into a low permeability zone, thus improving formation profiles and enhancing oil recovery. PMID- 24950171 TI - Thermodynamic mechanism for the evasion of antibody neutralization in flaviviruses. AB - Mutations in the epitopes of antigenic proteins can confer viral resistance to antibody-mediated neutralization. However, the fundamental properties that characterize epitope residues and how mutations affect antibody binding to alter virus susceptibility to neutralization remain largely unknown. To address these questions, we used an ensemble-based algorithm to characterize the effects of mutations on the thermodynamics of protein conformational fluctuations. We applied this method to the envelope protein domain III (ED3) of two medically important flaviviruses: West Nile and dengue 2. We determined an intimate relationship between the susceptibility of a residue to thermodynamic perturbations and epitope location. This relationship allows the successful identification of the primary epitopes in each ED3, despite their high sequence and structural similarity. Mutations that allow the ED3 to evade detection by the antibody either increase or decrease conformational fluctuations of the epitopes through local effects or long-range interactions. Spatially distant interactions originate in the redistribution of conformations of the ED3 ensembles, not through a mechanically connected array of contiguous amino acids. These results reconcile previous observations of evasion of neutralization by mutations at a distance from the epitopes. Finally, we established a quantitative correlation between subtle changes in the conformational fluctuations of the epitope and large defects in antibody binding affinity. This correlation suggests that mutations that allow viral growth, while reducing neutralization, do not generate significant structural changes and underscores the importance of protein fluctuations and long-range interactions in the mechanism of antibody-mediated neutralization resistance. PMID- 24950175 TI - Profiling animal toxicants by automatically mining public bioassay data: a big data approach for computational toxicology. AB - In vitro bioassays have been developed and are currently being evaluated as potential alternatives to traditional animal toxicity models. Already, the progress of high throughput screening techniques has resulted in an enormous amount of publicly available bioassay data having been generated for a large collection of compounds. When a compound is tested using a collection of various bioassays, all the testing results can be considered as providing a unique bio profile for this compound, which records the responses induced when the compound interacts with different cellular systems or biological targets. Profiling compounds of environmental or pharmaceutical interest using useful toxicity bioassay data is a promising method to study complex animal toxicity. In this study, we developed an automatic virtual profiling tool to evaluate potential animal toxicants. First, we automatically acquired all PubChem bioassay data for a set of 4,841 compounds with publicly available rat acute toxicity results. Next, we developed a scoring system to evaluate the relevance between these extracted bioassays and animal acute toxicity. Finally, the top ranked bioassays were selected to profile the compounds of interest. The resulting response profiles proved to be useful to prioritize untested compounds for their animal toxicity potentials and form a potential in vitro toxicity testing panel. The protocol developed in this study could be combined with structure-activity approaches and used to explore additional publicly available bioassay datasets for modeling a broader range of animal toxicities. PMID- 24950176 TI - Evaluation of an injectable thermosensitive hydrogel as drug delivery implant for ocular glaucoma surgery. AB - In this study, a biodegradable thermo-sensitive hydrogel from poly(trimethylene carbonate)15-F127-poly(trimethylene carbonate)15 (PTMC15-F127-PTMC15) was designed and evaluated as an injectable implant during ocular glaucoma filtration surgery in vivo and in vitro. Mitomycin C (MMC) was loaded into this hydrogel for controlled released to prolong the efficacy and to reduce the long-term toxicity. The properties of the hydrogel were confirmed using 1H NMR and gel permeation chromatography (GPC). Compared to the Pluronic F127 hydrogel, the PTMC15-F127 PTMC15 hydrogel showed a good solution-gel transition temperature at 37 degrees C, a lower work concentration of 5% w/v and a longer mass loss time of more than 2 weeks. The in vitro study showed that the drug could be released from PTMC15 F127-PTMC15 (5% w/v) hydrogel for up to 16 days with only 57% of drug released in the first day. Moreover, the cell toxicity, which was tested via LDH and ANNEXIN V/PI, decreased within 72 h in human tenon's fibroblast cells (HTFs). The in vivo behavior in a rabbit glaucoma filtration surgery model indicated that this hydrogel loaded with 0.1 mg/ml MMC led to a better functional bleb with a prolonged mean bleb survival time (25.5+/-2.9 days). The scar tissue formation, new collagen deposition and myofibroblast generation appeared to be reduced upon histological and immunohistochemistry examinations, with no obvious side effects and inflammatory reactions. The in vitro and in vivo results demonstrated that this novel hydrogel is a safe and effective drug delivery candidate in ocular glaucoma surgery. PMID- 24950177 TI - A single nucleotide polymorphism in the stromal cell-derived factor 1 gene is associated with coronary heart disease in Chinese patients. AB - Coronary heart disease (CHD) is highly prevalent globally and a major cause of mortality. Genetic predisposition is a non-modifiable risk factor associated with CHD. Eighty-four Chinese patients with CHD and 253 healthy Chinese controls without CHD were recruited. Major clinical data were collected, and a single nucleotide polymorphism (SNP) in the stromal cell-derived factor 1 (SDF-1) gene at position 801 (G to A, rs1801157) in the 3'-untranslated region was identified. The correlation between rs1801157 genotypes and CHD was evaluated by a multivariate logistic regression analysis. The allele frequency in the CHD and control groups was in Hardy-Weinberg equilibrium (HWE) (p>0.05). The frequency of the GG genotype in the CHD group (59.5%) was significantly higher than that in the control group (49.8%) (p=0.036). A number of variables, including male sex, age, presence of hypertension, and the levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), uric acid, and total bilirubin, were associated with CHD in a primary univariate analysis. In a multivariable logistic regression analysis, the GG genotype (GG:AA, odds ratio (OR)=2.31, 95% confidence interval (CI)=1.21-5.23), male sex, advanced age (>=60 years), presence of hypertension, LDL-C level>=3.33 mg/dL, HDL-C level<1.03 mg/dL, and TG level>=1.7 mg/dL were independent risk factors for CHD. PMID- 24950178 TI - Does prop-2-ynylideneamine, HC=CCH=NH, exist in space? A theoretical and computational investigation. AB - MP2, DFT and CCSD methods with 6-311++G** and aug-cc-pvdz basis sets have been used to probe the structural changes and relative energies of E-prop-2 ynylideneamine (I), Z-prop-2-ynylideneamine (II), prop-1,2-diene-1-imine (III) and vinyl cyanide (IV). The energy near-equivalence and provenance of preference of isomers and tautomers were investigated by NBO calculations using HF and B3LYP methods with 6-311++G** and aug-cc-pvdz basis sets. All substrates have Cs symmetry. The optimized geometries were found to be mainly theoretical method dependent. All elected levels of theory have computed I/II total energy of isomerization (DeltaE) of 1.707 to 3.707 kJ/mol in favour of II at 298.15 K. MP2 and CCSD methods have indicated clearly the preference of II over III; while the B3LYP functional predicted nearly similar total energies. All tested levels of theory yielded a global II/IV tautomerization total energy (DeltaE) of 137.3 148.4 kJ/mol in support of IV at 298.15 K. The negative values of DeltaS indicated that IV is favoured at low temperature. At high temperature, a reverse tautomerization becomes spontaneous and II is preferred. The existence of II in space was debated through the interpretation and analysis of the thermodynamic and kinetic studies of this tautomerization reaction and the presence of similar compounds in the Interstellar Medium (ISM). PMID- 24950181 TI - Special issue on stem cells: "the end of the beginning". PMID- 24950179 TI - The structure and dynamics of BmR1 protein from Brugia malayi: in silico approaches. AB - Brugia malayi is a filarial nematode, which causes lymphatic filariasis in humans. In 1995, the disease has been identified by the World Health Organization (WHO) as one of the second leading causes of permanent and long-term disability and thus it is targeted for elimination by year 2020. Therefore, accurate filariasis diagnosis is important for management and elimination programs. A recombinant antigen (BmR1) from the Bm17DIII gene product was used for antibody based filariasis diagnosis in "Brugia Rapid". However, the structure and dynamics of BmR1 protein is yet to be elucidated. Here we study the three dimensional structure and dynamics of BmR1 protein using comparative modeling, threading and ab initio protein structure prediction. The best predicted structure obtained via an ab initio method (Rosetta) was further refined and minimized. A total of 5 ns molecular dynamics simulation were performed to investigate the packing of the protein. Here we also identified three epitopes as potential antibody binding sites from the molecular dynamics average structure. The structure and epitopes obtained from this study can be used to design a binder specific against BmR1, thus aiding future development of antigen-based filariasis diagnostics to complement the current diagnostics. PMID- 24950180 TI - Coactivator recruitment of AhR/ARNT1. AB - A common feature of nuclear receptors (NRs) is the transformation of external cell signals into specific transcriptions of the signal molecule. Signal molecules function as ligands for NRs and, after their uptake, activated NRs form homo- or heterodimers at promoter recognition sequences of the specific genes in the nucleus. Another common feature of NRs is their dependence on coactivators, which bridge the basic transcriptional machinery and other cofactors to the target genes, in order to initiate transcription and to unwind histone-bound DNA for exposing additional promoter recognition sites via their histone acetyltransferase (HAT) function. In this review, we focus on our recent findings related to the recruitment of steroid receptor coactivator 1 (SRC1/NCoA1) by the estrogen receptor-alpha (ERalpha) and by the arylhydrocarbon receptor/arylhydrocarbon receptor nuclear translocator 1 (AhR/ARNT1) complex. We also describe the extension of our previously published findings regarding the binding between ARNT1.1 exon16 and SRC1e exon 21, via in silico analyses of androgen receptor (AR) NH2-carboxyl-terminal interactions, the results of which were verified by in vitro experiments. Based on these data, we suggest a newly derived tentative binding site of nuclear coactivator 2/glucocorticoid receptor interacting protein-1/transcriptional intermediary factor 2 (NCOA-2/ GRIP-1/TIF 2) for ARNT1.1 exon 16. Furthermore, results obtained by immunoprecipitation have revealed a second leucine-rich binding site for hARNT1.1 exon 16 in SRC1e exon 21 (LSSTDLL). Finally, we discuss the role of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as an endocrine disruptor for estrogen related transcription. PMID- 24950183 TI - Epidermal growth factor/heat shock protein 27 pathway regulates vasculogenic mimicry activity of breast cancer stem/progenitor cells. AB - Tumor vascularization, which is mainly contributed by angiogenesis and vascularization, is necessary for tumor maintenance and progression. Vasculogenic mimicry (VM), vascular-like channels which are lack of the involvement of endothelial cells, has been observed in aggressive cancers and also involves in tumor vascularization. Breast cancer stem/progenitor cells (BCSCs) have been identified as a subpopulation of breast cancer cells with markers of CD24( )CD44(+), high aldehyde dehydrogenase activity (ALDH(+)) or could be enriched by mammosphere cultivation. These cells have been proven to be associated with tumor vascularization. Here we investigated the molecular mechanisms in VM activity of BCSCs. By periodic acid-Schiff or hematoxylin-eosin stain, we found that there were VM structures in two xenografted human breast cancer tissues established from CD24(-)CD44(+) or ALDH(+) cells. Only ALDH(+) or mammosphere-forming BCSCs could form tube structures on matrigel-coated surface as similar as microvascular endothelial cells. Inhibition of the phosphorylation of epidermal growth factor receptor (EGFR) by gefitinib or knockdown of EGFR by lentiviral shRNA abolished the in vitro VM activity of BCSCs. By quercetin treatment, a plant flavonoid compound which is known to suppress heat shock proteins, or siRNA-mediated gene silencing, both Hsp27 expression and VM capability of BCSCs were suppressed. Forced expression of phosphor-mimic form of Hsp27 in ALDH(+) BCSCs could overcome the inhibitory effect of gefitinib. In conclusion, our data demonstrate that VM activity of BCSCs is mediated by EGF/Hsp27 signaling and targeting this pathway may benefit to breast cancer therapy. PMID- 24950182 TI - Eukarya associated with the stony coral Oculina patagonica from the Mediterranean Sea. AB - Oculina patagonica is a putative alien scleractinian coral from the Southwest Atlantic that inhabits across the Mediterranean Sea. Here, we have addressed the diversity of Eukarya associated with this coral and its changes related to the environmental conditions and coral status. A total of 46 colonies of O. patagonica were taken from Alicante coast (Spain) and Pietra Ligure coast (Italy) and analyzed using denaturing gradient gel electrophoresis (DGGE) of the small subunit 18S rRNA and 16S plastid rRNA genes, internal transcribed spacer region 2 (ITS 2) analyses, and electron microscopy. Our results show that Eukarya and plastid community associated to O. patagonica change with environmental conditions and coral status. Cryptic species, which can be difficult to identify by optical methods, were distinguished by 18S rRNA gene DGGE: the barnacle Megatrema anglicum, which was detected at two locations, and two boring sponges related to Cliona sp. and Siphonodictyon coralliphagum detected in samples from Tabarca and Alicante Harbour, respectively. Eukaryotic phototrophic community from the skeletal matrix of healthy corals was dominated by Ochrosphaera sp. while bleached corals from the Harbour and Tabarca were associated to different uncultured phototrophic organism. Differences in ultrastructural morphologies of the zooxanthellae between healthy and bleached corals were observed. Nevertheless, no differences were found in Symbiodinium community among time, environments, coral status and location, showing that O. patagonica hosted only one genotype of Symbiodinium belonging to clade B2. The fact that this clade has not been previously detected in other Mediterranean corals and is more frequent in the tropical Western Atlantic, is a new evidence that O. patagonica is an alien species in the Mediterranean Sea. PMID- 24950184 TI - An eye-tracking paradigm for analyzing the processing time of sentences with different linguistic complexities. AB - An eye-tracking paradigm was developed for use in audiology in order to enable online analysis of the speech comprehension process. This paradigm should be useful in assessing impediments in speech processing. In this paradigm, two scenes, a target picture and a competitor picture, were presented simultaneously with an aurally presented sentence that corresponded to the target picture. At the same time, eye fixations were recorded using an eye-tracking device. The effect of linguistic complexity on language processing time was assessed from eye fixation information by systematically varying linguistic complexity. This was achieved with a sentence corpus containing seven German sentence structures. A novel data analysis method computed the average tendency to fixate the target picture as a function of time during sentence processing. This allowed identification of the point in time at which the participant understood the sentence, referred to as the decision moment. Systematic differences in processing time were observed as a function of linguistic complexity. These differences in processing time may be used to assess the efficiency of cognitive processes involved in resolving linguistic complexity. Thus, the proposed method enables a temporal analysis of the speech comprehension process and has potential applications in speech audiology and psychoacoustics. PMID- 24950185 TI - The cost of providing combined prevention and treatment services, including ART, to female sex workers in Burkina Faso. AB - BACKGROUND: Female Sex workers (FSW) are important in driving HIV transmission in West Africa. The Yerelon clinic in Burkina Faso has provided combined preventative and therapeutic services, including anti-retroviral therapy (ART), for FSWs since 1998, with evidence suggesting it has decreased HIV prevalence and incidence in this group. No data exists on the costs of such a combined prevention and treatment intervention for FSW. This study aims to determine the mean cost of service provision per patient year for FSWs attending the Yerelon clinic, and identifies differences in costs between patient groups. METHODS: Field-based retrospective cost analyses were undertaken using top-down and bottom up costing approaches for 2010. Expenditure and service utilisation data was collated from primary sources. Patients were divided into groups according to full-time or occasional sex-work, HIV status and ART duration. Patient specific service use data was extracted. Costs were converted to 2012 US$. Sensitivity analyses considered removal of all research costs, different discount rates and use of different ART treatment regimens and follow-up schedules. RESULTS: Using the top-down costing approach, the mean annual cost of service provision for FSWs on or off ART was US$1098 and US$882, respectively. The cost for FSWs on ART reduced by 29%, to US$781, if all research-related costs were removed and national ART monitoring guidelines were followed. The bottom-up patient-level costing showed the cost of the service varied greatly across patient groups (US$505-US$1117), primarily due to large differences in the costs of different ART regimens. HIV-negative women had the lowest annual cost at US$505. CONCLUSION: Whilst FSWs may require specialised services to optimise their care and hence, the public health benefits, our study shows that the cost of ART provision within a combined prevention and treatment intervention setting is comparable to providing ART to other population groups in Africa. PMID- 24950186 TI - Is the conditioned pain modulation paradigm reliable? A test-retest assessment using the nociceptive withdrawal reflex. AB - The aim of this study was to determine the reliability of the conditioned pain modulation (CPM) paradigm assessed by an objective electrophysiological method, the nociceptive withdrawal reflex (NWR), and psychophysical measures, using hypothetical sample sizes for future studies as analytical goals. Thirty-four healthy volunteers participated in two identical experimental sessions, separated by 1 to 3 weeks. In each session, the cold pressor test (CPT) was used to induce CPM, and the NWR thresholds, electrical pain detection thresholds and pain intensity ratings after suprathreshold electrical stimulation were assessed before and during CPT. CPM was consistently detected by all methods, and the electrophysiological measures did not introduce additional variation to the assessment. In particular, 99% of the trials resulted in higher NWR thresholds during CPT, with an average increase of 3.4 mA (p<0.001). Similarly, 96% of the trials resulted in higher electrical pain detection thresholds during CPT, with an average increase of 2.2 mA (p<0.001). Pain intensity ratings after suprathreshold electrical stimulation were reduced during CPT in 84% of the trials, displaying an average decrease of 1.5 points in a numeric rating scale (p<0.001). Under these experimental conditions, CPM reliability was acceptable for all assessment methods in terms of sample sizes for potential experiments. The presented results are encouraging with regards to the use of the CPM as an assessment tool in experimental and clinical pain. Trial registration: Clinical Trials.gov NCT01636440. PMID- 24950187 TI - Hearts from mice fed a non-obesogenic high-fat diet exhibit changes in their oxidative state, calcium and mitochondria in parallel with increased susceptibility to reperfusion injury. AB - RATIONALE: High-fat diet with obesity-associated co-morbidities triggers cardiac remodeling and renders the heart more vulnerable to ischemia/reperfusion injury. However, the effect of high-fat diet without obesity and associated co morbidities is presently unknown. OBJECTIVES: To characterize a non-obese mouse model of high-fat diet, assess the vulnerability of hearts to reperfusion injury and to investigate cardiac cellular remodeling in relation to the mechanism(s) underlying reperfusion injury. METHODS AND RESULTS: Feeding C57BL/6J male mice high-fat diet for 20 weeks did not induce obesity, diabetes, cardiac hypertrophy, cardiac dysfunction, atherosclerosis or cardiac apoptosis. However, isolated perfused hearts from mice fed high-fat diet were more vulnerable to reperfusion injury than those from mice fed normal diet. In isolated cardiomyocytes, high-fat diet was associated with higher diastolic intracellular Ca2+ concentration and greater damage to isolated cardiomyocytes following simulated ischemia/reperfusion. High-fat diet was also associated with changes in mitochondrial morphology and expression of some related proteins but not mitochondrial respiration or reactive oxygen species turnover rates. Proteomics, western blot and high-performance liquid chromatography techniques revealed that high-fat diet led to less cardiac oxidative stress, higher catalase expression and significant changes in expression of putative components of the mitochondrial permeability transition pore (mPTP). Inhibition of the mPTP conferred relatively more cardio-protection in the high-fat fed mice compared to normal diet. CONCLUSIONS: This study shows for the first time that high-fat diet, independent of obesity-induced co-morbidities, triggers changes in cardiac oxidative state, calcium handling and mitochondria which are likely to be responsible for increased vulnerability to cardiac insults. PMID- 24950188 TI - Frequency of autoantibodies and connective tissue diseases in Chinese patients with optic neuritis. AB - BACKGROUND: Optic neuritis (ON) is often associated with other clinical or serological markers of connective tissue diseases (CTDs). To date, the effects of autoantibodies on ON are not clear. PURPOSE: To assess the prevalence, clinical patterns, and short outcomes of autoantibodies and Sjogren's syndrome (SS) involvement in Chinese ON patients and evaluate the relationship between ON, including their subtypes, and autoantibodies. METHODS: A total of 190 ON patients were divided into recurrent ON (RON), bilateral ON (BON), and isolated monocular ON (ION). Demographic, clinical, and serum autoantibodies data were compared between them with and without SS involvement. Serum was drawn for antinuclear antibody (ANA), extractable nuclear antigen antibodies (SSA/SSB), rheumatoid factor (RF), anticardiolipin antibodies (ACA), and anti-double-stranded DNA antibody (A-ds DNA), anticardiolipin antibody (ACLs), anti-beta2-glycoprotein I (beta2-GPI) and Aquaporin-4 antibodies (AQP4-Ab). Spectral-domain optical coherence tomography (SD-OCT) was used to evaluate the atrophy of the optic nerve. RESULTS: 68 patients (35.79%) had abnormal autoantibodies, 26(13.68%) patients met diagnostic criteria for CTDs, including 15(7.89%) patients meeting the criteria for SS. Antibodies including SSA/SSB 23 (30.26%) (p1 and p 2<0.001) and AQP4-Ab10 (13.16%) (p1 = 0.044, p2 = 0.01) were significantly different in patients in the RON group when compared with those in the BON (P1 = RON VS ION) and ION (p2 = RON VS ION) groups. SS was more common in RON patients (p1 = 0.04, p2 = 0.028). There was no significant difference between SSA/SSB positive and negative patients in disease characteristics or severity. Similar results were obtained when SS was diagnosed in SSA/SSB positive patients. CONCLUSION: RON and BON were more likely associated with abnormal autoantibodies; furthermore, AQP4 antibody, SSA/SSB and SS were more common in the RON patients. AQP4 antibody determination is crucial in RON patients who will develop NMO. However, when compared with other autoantibodies, SSA/SSB detected in patients was not significantly associated with disease characteristics or severity. PMID- 24950189 TI - Notch signaling regulates the lifespan of vascular endothelial cells via a p16 dependent pathway. AB - Evolutionarily conserved Notch signaling controls cell fate determination and differentiation during development, and is also essential for neovascularization in adults. Although recent studies suggest that the Notch pathway is associated with age-related conditions, it remains unclear whether Notch signaling is involved in vascular aging. Here we show that Notch signaling has a crucial role in endothelial cell senescence. Inhibition of Notch signaling in human endothelial cells induced premature senescence via a p16-dependent pathway. Conversely, over-expression of Notch1 or Jagged1 prolonged the replicative lifespan of endothelial cells. Notch1 positively regulated the expression of inhibitor of DNA binding 1 (Id1) and MAP kinase phosphatase 1 (MKP1), while MKP1 further up-regulated Id1 expression by inhibiting p38MAPK-induced protein degradation. Over-expression of Id1 down-regulated p16 expression, thereby inhibiting premature senescence of Notch1-deleted endothelial cells. These findings indicate that Notch1 signaling has a role in the regulation of endothelial cell senescence via a p16-dependent pathway and suggest that activation of Notch1 could be a new therapeutic target for treating age associated vascular diseases. PMID- 24950191 TI - Stability of the resistance to the thiosemicarbazone derived from 5,6-dimethoxy-1 indanone, a non-nucleoside polymerase inhibitor of bovine viral diarrhea virus. AB - Bovine viral diarrhea virus (BVDV) is the prototype Pestivirus. BVDV infection is distributed worldwide and causes serious problems for the livestock industry. The thiosemicarbazone of 5,6-dimethoxy-1-indanone (TSC) is a non-nucleoside polymerase inhibitor (NNI) of BVDV. All TSC-resistant BVDV variants (BVDV-TSCr T1 5) present an N264D mutation in the NS5B gene (RdRp) whereas the variant BVDV TSCr T1 also presents an NS5B A392E mutation. In the present study, we carried out twenty passages of BVDV-TSCr T1-5 in MDBK cells in the absence of TSC to evaluate the stability of the resistance. The viral populations obtained (BVDV R1 5) remained resistant to the antiviral compound and conserved the mutations in NS5B associated with this phenotype. Along the passages, BVDV R2, R3 and R5 presented a delay in the production of cytopathic effect that correlated with a decrease in cell apoptosis and intracellular accumulation of viral RNA. The complete genome sequences that encode for NS2 to NS5B, Npro and Erns were analyzed. Additional mutations were detected in the NS5B of BVDV R1, R3 and R4. In both BVDV R2 and R3, most of the mutations found were localized in NS5A, whereas in BVDV R5, the only mutation fixed was NS5A V177A. These results suggest that mutations in NS5A could alter BVDV cytopathogenicity. In conclusion, the stability of the resistance to TSC may be due to the fixation of different compensatory mutations in each BVDV-TSCr. During their replication in a TSC-free medium, some virus populations presented a kind of interaction with the host cell that resembled a persistent infection: decreased cytopathogenicity and viral genome synthesis. This is the first report on the stability of antiviral resistance and on the evolution of NNI-resistant BVDV variants. The results obtained for BVDV-TSCr could also be applied for other NNIs. PMID- 24950192 TI - Classification of four-class motor imagery employing single-channel electroencephalography. AB - With advances in brain-computer interface (BCI) research, a portable few- or single-channel BCI system has become necessary. Most recent BCI studies have demonstrated that the common spatial pattern (CSP) algorithm is a powerful tool in extracting features for multiple-class motor imagery. However, since the CSP algorithm requires multi-channel information, it is not suitable for a few- or single-channel system. In this study, we applied a short-time Fourier transform to decompose a single-channel electroencephalography signal into the time frequency domain and construct multi-channel information. Using the reconstructed data, the CSP was combined with a support vector machine to obtain high classification accuracies from channels of both the sensorimotor and forehead areas. These results suggest that motor imagery can be detected with a single channel not only from the traditional sensorimotor area but also from the forehead area. PMID- 24950194 TI - Gene expression in B-1 cells from lupus-prone mice. AB - New Zealand Black X New Zealand White F1 [(NZB/NZW)F1] mice develop an autoimmune condition with similarities to human systemic lupus erythematosus (SLE). In this study, we demonstrate that B-1 cells, which have previously been reported to be involved in several autoimmune diseases, have altered gene expression in these mice. RNA was extracted from purified B-1 cells of disease-free C57BL/6 mice and lupus-prone (NZB/NZW)F1 mice. Gene expression was analysed using DNA microarray techniques and validated by real time reverse transcriptase polymerase chain reaction (RT-PCR). In (NZB/NZW)F1 mice, some genes had altered expression patterns compared to disease-free controls. Specifically, the upregulation of Ifitm1, Pvrl2 and Ifi202b and downregulation of Trp53bp1 mRNA were observed in (NZB/NZW)F1 mice. These genes are known to be associated with autoimmune diseases. This pattern of gene expression in B-1 cells could understanding of the pathogenesis of SLE. Thus, it is reasonable to hypothesise that the altered gene expression observed in B-1 cells in our experimental model is important for SLE prognosis and therapy, and these implications are discussed herein. PMID- 24950195 TI - Mathematical model formulation and validation of water and solute transport in whole hamster pancreatic islets. AB - Optimization of cryopreservation protocols for cells and tissues requires accurate models of heat and mass transport. Model selection often depends on the configuration of the tissue. Here, a mathematical and conceptual model of water and solute transport for whole hamster pancreatic islets has been developed and experimentally validated incorporating fundamental biophysical data from previous studies on individual hamster islet cells while retaining whole-islet structural information. It describes coupled transport of water and solutes through the islet by three methods: intracellularly, intercellularly, and in combination. In particular we use domain decomposition techniques to couple a transmembrane flux model with an interstitial mass transfer model. The only significant undetermined variable is the cellular surface area which is in contact with the intercellularly transported solutes, Ais. The model was validated and Ais determined using a 3*3 factorial experimental design blocked for experimental day. Whole islet physical experiments were compared with model predictions at three temperatures, three perfusing solutions, and three islet size groups. A mean of 4.4 islets were compared at each of the 27 experimental conditions and found to correlate with a coefficient of determination of 0.87+/-0.06 (mean +/- SD). Only the treatment variable of perfusing solution was found to be significant (p<0.05). We have devised a model that retains much of the intrinsic geometric configuration of the system, and thus fewer laboratory experiments are needed to determine model parameters and thus to develop new optimized cryopreservation protocols. Additionally, extensions to ovarian follicles and other concentric tissue structures may be made. PMID- 24950196 TI - Kyasanur Forest disease virus infection in mice is associated with higher morbidity and mortality than infection with the closely related Alkhurma hemorrhagic fever virus. AB - BACKGROUND: Kyasanur Forest disease virus (KFDV) and Alkhurma hemorrhagic fever virus (AHFV) are closely related members of the Flavivirus genus and are important causes of human disease in India and the Arabian Peninsula, respectively. Despite high genetic similarity, the viruses have distinctly different host ranges and ecologies. Human cases of KFDV or AHFV develop a spectrum of disease syndromes ranging from liver pathology to neurologic disease. Case reports suggest KFDV is more commonly associated with hepatic and gastrointestinal manifestations whereas AHFV is more commonly associated with neurologic disease. METHODOLOGY/PRINCIPAL FINDINGS: Inoculation of three immunocompetent laboratory mouse strains revealed that KFDV was consistently more lethal than AHFV. In subsequent studies utilizing C57BL/6J mice, we demonstrated that KFDV infection was associated with higher viral loads and significantly higher mortality. KFDV-infected mice rapidly developed more severe disease than AHFV-infected mice, as evidenced by significant abnormalities on clinical chemistry panels and more severe pathology in the brain and gastrointestinal tract. CONCLUSIONS/SIGNIFICANCE: Infections of C57BL/6J mice with KFDV or AHFV resulted in clinical disease syndromes that closely approximate the diseases seen in human cases. Despite high genetic similarity, there were clear differences in survival, viral kinetics, clinical chemistry data and histology. These results suggest that distinct mouse models for AHFV and KFDV are necessary in order to gain a better understanding of the unique pathogenesis of each virus, as well as to provide platforms for testing promising vaccines and therapeutics. PMID- 24950198 TI - Criteria of radon risk of territories and methods for their determination. AB - The paper analyzes the values used in the assessment of radon potential of territories. It was shown that the most reliable criterion in the assessment of radon risk of territories can be the value of radon activity concentration fixed at large depths. The authors proposed a simple method to assess this value and radon flux density from the soil surface, based on the measurement of radon activity concentration in soil gas at two twice differing depths and the diffusion model of transport. PMID- 24950197 TI - Inherited polymorphisms in hyaluronan synthase 1 predict risk of systemic B-cell malignancies but not of breast cancer. AB - Genetic variations in the hyaluronan synthase 1 gene (HAS1) influence HAS1 aberrant splicing. HAS1 is aberrantly spliced in malignant cells from multiple myeloma (MM) and Waldenstrom macroglobulinemia (WM), but not in their counterparts from healthy donors. The presence of aberrant HAS1 splice variants predicts for poor survival in multiple myeloma (MM). We evaluated the influence of inherited HAS1 single nucleotide polymorphisms (SNP) on the risk of having a systemic B cell malignancy in 1414 individuals compromising 832 patients and 582 healthy controls, including familial analysis of an Icelandic kindred. We sequenced HAS1 gene segments from 181 patients with MM, 98 with monoclonal gammopathy of undetermined significance (MGUS), 72 with Waldenstrom macroglobulinemia (WM), 169 with chronic lymphocytic leukemia (CLL), as well as 34 members of a monoclonal gammopathy-prone Icelandic family, 212 age-matched healthy donors and a case-control cohort of 295 breast cancer patients with 353 healthy controls. Three linked single nucleotide polymorphisms (SNP) in HAS1 intron3 are significantly associated with B-cell malignancies (range p = 0.007 to p = 10(-5)), but not MGUS or breast cancer, and predict risk in a 34 member Icelandic family (p = 0.005, Odds Ratio = 5.8 (OR)), a relatively homogeneous cohort. In contrast, exon3 SNPs were not significantly different among the study groups. Pooled analyses showed a strong association between the linked HAS1 intron3 SNPs and B-cell malignancies (OR = 1.78), but not for sporadic MGUS or for breast cancer (OR<1.0). The minor allele genotypes of HAS1 SNPs are significantly more frequent in MM, WM, CLL and in affected members of a monoclonal gammopathy-prone family than they are in breast cancer, sporadic MGUS or healthy donors. These inherited changes may increase the risk for systemic B cell malignancies but not for solid tumors. PMID- 24950199 TI - The characteristics of a low background germanium gamma ray spectrometer at China JinPing Underground Laboratory. AB - A low background germanium gamma ray spectrometer, GeTHU, has been installed at China JinPing Underground Laboratory (CJPL). The integral background count rate of the spectrometer was 0.629 cpm between 40 and 2700 keV, the origins of which were studied by Monte Carlo simulation. Detection limits and efficiencies were calculated for selected gamma peaks. Some samples of rare event experiments were measured and (137)Cs contamination was found in boric acid. GeTHU will be mainly used to measure environmental samples and screen materials in dark matter and double beta decay experiments. PMID- 24950200 TI - A highly functional synthetic phage display library containing over 40 billion human antibody clones. AB - Several synthetic antibody phage display libraries have been created and used for the isolation of human monoclonal antibodies. The performance of antibody libraries, which is usually measured in terms of their ability to yield high affinity binding specificities against target proteins of interest, depends both on technical aspects (such as library size and quality of cloning) and on design features (which influence the percentage of functional clones in the library and their ability to be used for practical applications). Here, we describe the design, construction and characterization of a combinatorial phage display library, comprising over 40 billion human antibody clones in single-chain fragment variable (scFv) format. The library was designed with the aim to obtain highly stable antibody clones, which can be affinity-purified on protein A supports, even when used in scFv format. The library was found to be highly functional, as >90% of randomly selected clones expressed the corresponding antibody. When selected against more than 15 antigens from various sources, the library always yielded specific and potent binders, at a higher frequency compared to previous antibody libraries. To demonstrate library performance in practical biomedical research projects, we isolated the human antibody G5, which reacts both against human and murine forms of the alternatively spliced BCD segment of tenascin-C, an extracellular matrix component frequently over expressed in cancer and in chronic inflammation. The new library represents a useful source of binding specificities, both for academic research and for the development of antibody-based therapeutics. PMID- 24950201 TI - Mining the human gut microbiota for effector strains that shape the immune system. AB - The gut microbiota codevelops with the immune system beginning at birth. Mining the microbiota for bacterial strains responsible for shaping the structure and dynamic operations of the innate and adaptive arms of the immune system represents a formidable combinatorial problem but one that needs to be overcome to advance mechanistic understanding of microbial community and immune system coregulation and to develop new diagnostic and therapeutic approaches that promote health. Here, we discuss a scalable, less biased approach for identifying effector strains in complex microbial communities that impact immune function. The approach begins by identifying uncultured human fecal microbiota samples that transmit immune phenotypes to germ-free mice. Clonally arrayed sequenced collections of bacterial strains are constructed from representative donor microbiota. If the collection transmits phenotypes, effector strains are identified by testing randomly generated subsets with overlapping membership in individually housed germ-free animals. Detailed mechanistic studies of effector strain-host interactions can then be performed. PMID- 24950202 TI - Finding the missing links among metabolites, microbes, and the host. AB - The unexpected diversity of the human microbiome and metabolome far exceeds the complexity of the human genome. Although we now understand microbial taxonomic and genetic repertoires in some populations, we are just beginning to assemble the necessary computational and experimental tools to understand the metabolome in comparable detail. However, even with the limited current state of knowledge, individual connections between microbes and metabolites, between microbes and immune function, and between metabolites and immune function are being established. Here, we provide our perspective on these connections and outline a systematic research program that could turn these individual links into a broader network that allows us to understand how these components interact. This program will enable us to exploit connections among the microbiome, metabolome, and host immune system to maintain health and perhaps help us understand how to reverse the processes that lead to a wide range of immune and other diseases. PMID- 24950203 TI - Diet, metabolites, and "western-lifestyle" inflammatory diseases. AB - One explanation for the increased incidence of allergies, asthma, and even some autoimmune diseases has been the hygiene hypothesis. However, recent studies also highlight an important role for diet and bacterial metabolites in controlling various immune pathways, including gut and immune homeostasis, regulatory T cell biology, and inflammation. Dietary-related metabolites engage "metabolite sensing" G-protein-coupled receptors, such as GPR43, GPR41, GPR109A, GPR120, and GPR35. These receptors are expressed on immune cells and some gut epithelial cells and generally mediate a direct anti-inflammatory effect. Insufficient intake of "healthy foodstuffs" adversely affects the production of bacterial metabolites. These metabolites and those derived directly from food drive beneficial downstream effects on immune pathways. We propose that insufficient exposure to dietary and bacterial metabolites might underlie the development of inflammatory disorders in Western countries. This review highlights what is currently known about diet, metabolites, and their associated immune pathways in relation to the development of inflammatory disease. PMID- 24950205 TI - Jarid2 links MicroRNA and chromatin in Th17 cells. AB - In this issue of Immunity, Escobar et al. (2014) bring microRNAs and chromatin together by showing how activation-induced miR-155 targets the chromatin protein Jarid2 to regulate proinflammatory cytokine production in T helper 17 cells. PMID- 24950206 TI - Of worms and men: HLH-30 and TFEB regulate tolerance to infection. AB - In this issue of Immunity, Visvikis et al. (2014) use the model host Caenorhabditis elegans to discover a role in innate immunity for the basic helix loop-helix transcription factor, HLH-30. The finding inspires study of the mammalian ortholog TFEB, in which a similar role in immune response is ascertained. PMID- 24950204 TI - Inflammatory bowel disease as a model for translating the microbiome. AB - The inflammatory bowel diseases (IBDs) are among the most closely studied chronic inflammatory disorders that involve environmental, host genetic, and commensal microbial factors. This combination of features has made IBD both an appropriate and a high-priority platform for translatable research in host-microbiome interactions. Decades of epidemiology have identified environmental risk factors, although most mechanisms of action remain unexplained. The genetic architecture of IBD has been carefully dissected in multiple large populations, identifying several responsible host epithelial and immune pathways but without yet a complete systems-level explanation. Most recently, the commensal gut microbiota have been found to be both ecologically and functionally perturbed during the disease, but with as-yet-unexplained heterogeneity among IBD subtypes and individual patients. IBD thus represents perhaps the most comprehensive current model for understanding the human microbiome's role in complex inflammatory disease. Here, we review the influences of the microbiota on IBD and its potential for translational medicine. PMID- 24950207 TI - An uncommon tail about the common gamma-chain. AB - The common gamma-chain (gammac) is a key component of multiple cytokine receptors. In this issue of Immunity, Hong et al. (2014) demonstrate a unique function of gammac as a secreted protein capable of inhibiting cytokine responses and promoting autoimmunity. PMID- 24950208 TI - A stay of execution: type I interferons pardon T cells from death by natural killers. AB - In this issue of Immunity, Crouse et al., (2014) and Xu et al., (2014), show that by modulating the expression of natural killer (NK) cell receptor ligands, type I interferons protect responding T cells against culling by NK cells. PMID- 24950209 TI - AHR: making the keratinocytes thick skinned. AB - Dysregulated signals from the external environment and/or the internal milieu of the skin can lead to pathological conditions such as psoriasis. Di Meglio et al. (2014) show that the environment-responsive transcription factor AhR acts in keratinocytes to suppress psoriatic lesions. PMID- 24950210 TI - Five crop seasons' records of greenhouse gas fluxes from upland fields with repetitive applications of biochar and cattle manure. AB - The application of char to agricultural land is recognized as a potential way to sequester atmospheric carbon (C) assimilated by plants in soil, thus decelerating global warming. Such a process would also be expected to improve plant growth and the physical and chemical properties of soil. However, field investigations of the effects of continuous char application have not been reported. In the present study, the effects of repetitive bamboo char application on CO2, CH4, and N2O flux from soil, soil C content, and crop yield were investigated at two upland fields over five crop seasons. Three treatments: chemical fertilizer (CF) applied plots (Control plot); cattle manure (CM) (10 t ha(-1)) and CF applied plot (CM plot); and bamboo char (20 t ha(-1)), cattle manure (10 t ha(-1)), and CF applied plot (Char/CM plot), were arranged in each field. After three crop seasons, the fourth treatment with char was applied without CF (Char plot) was given to one of the fields. CM and/or char were applied every crop season. Gas fluxes were measured using the static chamber method. Seasonal variations in CO2 flux and total CO2 emissions were consistently similar between the CM and Char/CM plots and between the Char and Control plots. As such, the decomposition rate of bamboo char was quite small, and the positive or negative effect of char on CM decomposition was not significant in the fields. Soil C analysis provided confirmation of this. CM application enhanced N2O emission mainly in the summer crop season. The differences in total N2O emission between the Char/CM and CM plots as well as between the Char and Control plots were insignificant in most cases. Total CH4 flux was negligibly small in all cases. Although the yield of winter crop (broccoli) in the Char/CM plots was twice observed to be higher than that in the Control and CM plots at one of the fields, in general, the char application had no effect on overall crop yield. Thus, the repeated application of bamboo char had no significant influence on greenhouse gas emissions and crop yields, but a high C accumulating function was found. PMID- 24950211 TI - Quality of trace element contaminated soils amended with compost under fast growing tree Paulownia fortunei plantation. AB - The use of fast growing trees could be an alternative in trace element contaminated soils to stabilize these elements and improve soil quality. In this study we investigate the effect of Paulownia fortunei growth on trace element contaminated soils amended with two organic composts under semi-field conditions for a period of 18 months. The experiment was carried out in containers filled with tree different soils, two contaminated soils (neutral AZ and acid V) and a non contaminated soil, NC. Three treatments per soil were established: two organic amendments (alperujo compost, AC, and biosolid compost, BC) and a control without amendment addition. We study parameters related with fertility and contamination in soils and plants. Paulownia growth and amendments increased pH in acid soils whereas no effect of these factors was observed in neutral soils. The plant and the amendments also increased organic matter and consequently, soil fertility. Positive results were also found in soils that were only affected by plant growth (without amendment). A general improvement of "soil biochemical quality" was detected over time and treatments, confirming the positive effect of amendments plus paulownia. Even in contaminated soils, except for Cu and Zn, trace element concentrations in leaves were in the normal range for plants. Results of this mid-term study showed that Paulownia fortunei is a promising species for phytoremediation of trace element polluted soils. PMID- 24950212 TI - Frequency of behavior witnessed and conformity in an everyday social context. AB - Conformity is thought to be an important force in human evolution because it has the potential to stabilize cultural homogeneity within groups and cultural diversity between groups. However, the effects of such conformity on cultural and biological evolution will depend much on the particular way in which individuals are influenced by the frequency of alternative behavioral options they witness. In a previous study we found that in a natural situation people displayed a tendency to be 'linear-conformist'. When visitors to a Zoo exhibit were invited to write or draw answers to questions on cards to win a small prize and we manipulated the proportion of text versus drawings on display, we found a strong and significant effect of the proportion of text displayed on the proportion of text in the answers, a conformist effect that was largely linear with a small non linear component. However, although this overall effect is important to understand cultural evolution, it might mask a greater diversity of behavioral responses shaped by variables such as age, sex, social environment and attention of the participants. Accordingly we performed a further study explicitly to analyze the effects of these variables, together with the quality of the information participants' responses made available to further visitors. Results again showed a largely linear conformity effect that varied little with the variables analyzed. PMID- 24950215 TI - Visualization of hierarchical nanodomains in polymer/fullerene bulk heterojunction solar cells. AB - Traditional electron microscopy techniques such as bright-field imaging provide poor contrast for organic films and identification of structures in amorphous material can be problematic, particularly in high-performance organic solar cells. By combining energy-filtered corrected transmission electron microscopy, together with electron energy loss and X-ray energy-dispersive hyperspectral imaging, we have imaged PTB7/PC61BM blended polymer optical photovoltaic films, and were able to identify domains ranging in size from several hundred nanometers to several nanometers in extent. This work verifies that microstructural domains exist in bulk heterojunctions in PTB7/PC61BM polymeric solar cells at multiple length scales and expands our understanding of optimal device performance providing insight for the design of even higher performance cells. PMID- 24950214 TI - Spatial distributions of red blood cells significantly alter local haemodynamics. AB - Although bulk changes in red blood cell concentration between vessels have been well characterised, local distributions are generally overlooked. Red blood cells aggregate, deform and migrate within vessels, forming heterogeneous distributions which have considerable effect on local haemodynamics. The present study reports data on the local distribution of human red blood cells in a sequentially bifurcating microchannel, representing the branching geometry of the microvasculature. Imaging methodologies with simple extrapolations are used to infer three dimensional, time-averaged velocity and haematocrit distributions under a range of flow conditions. Strong correlation between the bluntness of the velocity and haematocrit profiles in the parent branch of the geometry is observed and red blood cell aggregation has a notable effect on the observed trends. The two branches of the first bifurcation show similar characteristics in terms of the shapes of the profiles and the extent of plasma skimming, despite the difference in geometric configuration. In the second bifurcation, considerable asymmetry between the branches in the plasma skimming relationship is observed, and elucidated by considering individual haematocrit profiles. The results of the study highlight the importance of considering local haematocrit distributions in the analysis of blood flow and could lead to more accurate computational models of blood flow in microvascular networks. The experimental approaches developed in this work provide a foundation for further examining the characteristics of microhaemodynamics. PMID- 24950216 TI - Characterization of the ectodomain of the envelope protein of dengue virus type 4: expression, membrane association, secretion and particle formation in the absence of precursor membrane protein. AB - BACKGROUND: The envelope (E) of dengue virus (DENV) is the major target of neutralizing antibodies and vaccine development. After biosynthesis E protein forms a heterodimer with precursor membrane (prM) protein. Recent reports of infection enhancement by anti-prM monoclonal antibodies (mAbs) suggest anti-prM responses could be potentially harmful. Previously, we studied a series of C terminal truncation constructs expressing DENV type 4 prM/E or E proteins and found the ectodomain of E protein alone could be recognized by all 12 mAbs tested, suggesting E protein ectodomain as a potential subunit immunogen without inducing anti-prM response. The characteristics of DENV E protein ectodomain in the absence of prM protein remains largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the expression, membrane association, glycosylation pattern, secretion and particle formation of E protein ectodomain of DENV4 in the presence or absence of prM protein. E protein ectodomain associated with membrane in or beyond trans-Golgi and contained primarily complex glycans, whereas full-length E protein associated with ER membrane and contained high mannose glycans. In the absence of prM protein, E protein ectodomain can secrete as well as form particles of approximately 49 nm in diameter, as revealed by sucrose gradient ultracentrifugation with or without detergent and electron microscopy. Mutational analysis revealed that the secretion of E protein ectodomain was affected by N-linked glycosylation and could be restored by treatment with ammonia chloride. CONCLUSIONS/SIGNIFICANCE: Considering the enhancement of DENV infectivity by anti-prM antibodies, our findings provide new insights into the expression and secretion of E protein ectodomain in the absence of prM protein and contribute to future subunit vaccine design. PMID- 24950217 TI - Modulation of CYP1A1 and CYP1A2 hepatic enzymes after oral administration of Chios mastic gum to male Wistar rats. AB - Chios mastic gum (CMG), a resin derived from Pistacia lentiscus var. chia, is known since ancient times for its pharmacological activities. CYP1A1 and CYP1A2 enzymes are among the most involved in the biotransformation of chemicals and the metabolic activation of pro-carcinogens. Previous studies referring to the modulation of these enzymes by CMG have revealed findings of unclear biological and toxicological significance. For this purpose, the modulation of CYP1A1 and CYP1A2 enzymes in the liver of male Wistar rats following oral administration of CMG extract (CMGE), at the levels of mRNA and CYP1A1 enzyme activity, was compared to respective enzyme modulation following oral administration of a well known bioactive natural product, caffeine, as control compound known to involve hepatic enzymes in its metabolism. mRNA levels of Cyp1a1 and Cyp1a2 were measured by reverse transcription real-time polymerase chain reaction and their relative quantification was calculated. CYP1A1 enzyme induction was measured through the activity of ethoxyresorufin-O-deethylase (EROD). The results indicated that administration of CMGE at the recommended pharmaceutical dose does not induce significant transcriptional modulation of Cyp1a1/2 and subsequent enzyme activity induction of CYP1A1 while effects of the same order of magnitude were observed in the same test system following the administration of caffeine at the mean daily consumed levels. The outcome of this study further confirms the lack of any toxicological or biological significance of the specific findings on liver following the administration of CMGE. PMID- 24950218 TI - Activity monitor intervention to promote physical activity of physicians-in training: randomized controlled trial. AB - BACKGROUND: Physicians are expected to serve as role models for healthy lifestyles, but long work hours reduce time for healthy behaviors. A hospital based physical activity intervention could improve physician health and increase counseling about exercise. METHODS: We conducted a two-phase intervention among 104 medical residents at a large hospital in Boston, Massachusetts. Phase 1 was a 6-week randomized controlled trial comparing daily steps of residents assigned to an activity monitor displaying feedback about steps and energy consumed (intervention) or to a blinded monitor (control). Phase 2 immediately followed and was a 6-week non-randomized team steps competition in which all participants wore monitors with feedback. Phase 1 outcomes were: 1) median steps/day and 2) proportion of days activity monitor worn. The Phase 2 outcome was mean steps/day on days monitor worn (>=500 steps/day). Physiologic measurements were collected at baseline and study end. Median steps/day were compared using Wilcoxon rank-sum tests. Mean steps were compared using repeated measures regression analyses. RESULTS: In Phase 1, intervention and control groups had similar activity (6369 vs. 6063 steps/day, p = 0.16) and compliance with wearing the monitor (77% vs. 77% of days, p = 0.73). In Phase 2 (team competition), residents recorded more steps/day than during Phase 1 (CONTROL: 7,971 vs. 7,567, p = 0.002; INTERVENTION: 7,832 vs. 7,739, p = 0.13). Mean compliance with wearing the activity monitor decreased for both groups during Phase 2 compared to Phase 1 (60% vs. 77%, p<0.001). Mean systolic blood pressure decreased (p = 0.004) and HDL cholesterol increased (p<0.001) among all participants at end of study compared to baseline. CONCLUSIONS: Although the activity monitor intervention did not have a major impact on activity or health, the high participation rates of busy residents and modest changes in steps, blood pressure, and HDL suggest that more intensive hospital-based wellness programs have potential for promoting healthier lifestyles among physicians. TRIAL REGISTRATION: Clinicaltrials.gov NCT01287208. PMID- 24950220 TI - High-resolution quantification of hepatitis C virus genome-wide mutation load and its correlation with the outcome of peginterferon-alpha2a and ribavirin combination therapy. AB - Hepatitis C virus (HCV) is a highly mutable RNA virus and circulates as a heterogeneous population in individual patients. The magnitude of such population heterogeneity has long been proposed to be linked with diverse clinical phenotypes, including antiviral therapy. Yet data accumulated thus far are fairly inconclusive. By the integration of long RT-PCR with 454 sequencing, we have built a pipeline optimized for the quantification of HCV genome-wide mutation load at 1% resolution of mutation frequency, followed by a retrospective study to examine the role of HCV mutation load in peginterferon-alpha2a and ribavirin combination antiviral therapy. Genome-wide HCV mutation load varied widely with a range from 92 to 1639 mutations and presented a Poisson distribution among 56 patients (Kolmogorov-Smirnov statistic = 0.078, p = 0.25). Patients achieving sustained virological response (n = 26) had significantly lower mutation loads than that in null responders (n = 30) (mean and standard derivation: 524+/-279 vs. 805+/-271, p = 0.00035). All 36,818 mutations detected in 56 patients displayed a power-law distribution in terms of mutation frequency in viral population. The low-frequency mutation load, but not the high-frequency load, was proportional firmly to the total mutation load. In-depth analyses revealed that intra-patient HCV population structure was shaped by multiple factors, including immune pressure, strain difference and genetic drift. These findings explain previous conflicting reports using low-resolution methods and highlight a dominant role of natural selection in response to therapeutic intervention. By attaining its signatures from complex interaction between host and virus, the high-resolution quantification of HCV mutation load predicts outcomes from interferon-based antiviral therapy and could also be a potential biomarker in other clinical settings. PMID- 24950219 TI - Cardiorespiratory anomalies in mice lacking CB1 cannabinoid receptors. AB - Cannabinoid type 1 (CB1) receptors are expressed in the nervous and cardiovascular systems. In mice, CB1 receptor deficiency protects from metabolic consequences of a high-fat diet (HFD), increases sympathetic activity to brown fat, and entails sleep anomalies. We investigated whether sleep-wake and diet dependent cardiorespiratory control is altered in mice lacking CB1 receptors. CB1 receptor knock-out (KO) and intact wild-type (WT) mice were fed standard diet or a HFD for 3 months, and implanted with a telemetric arterial pressure transducer and electrodes for sleep scoring. Sleep state was assessed together with arterial pressure and heart rate (home cage), or breathing (whole-body plethysmograph). Increases in arterial pressure and heart rate on passing from the light (rest) to the dark (activity) period in the KO were significantly enhanced compared with the WT. These increases were unaffected by cardiac (beta1) or vascular (alpha1) adrenergic blockade. The breathing rhythm of the KO during sleep was also more irregular than that of the WT. A HFD increased heart rate, impaired cardiac vagal modulation, and blunted the central autonomic cardiac control during sleep. A HFD also decreased cardiac baroreflex sensitivity in the KO but not in the WT. In conclusion, we performed the first systematic study of cardiovascular function in CB1 receptor deficient mice during spontaneous wake-sleep behavior, and demonstrated that CB1 receptor KO alters cardiorespiratory control particularly in the presence of a HFD. The CB1 receptor signaling may thus play a role in physiological cardiorespiratory regulation and protect from some adverse cardiovascular consequences of a HFD. PMID- 24950221 TI - Correction: In Vivo Expression Technology Identifies a Novel Virulence Factor Critical for Borrelia burgdorferi Persistence in Mice. AB - Analysis of the transcriptome of Borrelia burgdorferi, the causative agent of Lyme disease, during infection has proven difficult due to the low spirochete loads in the mammalian tissues. To overcome this challenge, we have developed an In Vivo Expression Technology (IVET) system for identification of B. burgdorferi genes expressed during an active murine infection. Spirochetes lacking linear plasmid (lp) 25 are non-infectious yet highly transformable.Mouse infection can be restored to these spirochetes by expression of the essential lp25-encoded pnc A gene alone. Therefore, this IVET-based approach selects for in vivo-expressed promoters that drive expression of pncA resulting in the recovery of infectious spirochetes lacking lp25 following a three week infection in mice.Screening of approximately 15,000 clones in mice identified 289 unique in vivo-expressed DNA fragments from across all 22 replicons of the B. burgdorferi B31 genome. The in vivo-expressed candidate genes putatively encode proteins in various functional categories including antigenicity, metabolism, motility, nutrient transport and unknown functions. Candidate gene bbk46 on essential virulence plasmid lp36 was found to be highly induced in vivo and to be RpoS-independent. The bbk46 gene was dispensable for B. burgdorferi infection in mice. Our findings highlight the power of the IVET-based approach for identification of B. burgdorferi in vivo expressed genes, which might not be discovered using other genome-wide gene expression methods. Further investigation of the novel in vivo-expressed candidate genes will contribute to advancing the understanding of molecular mechanisms of B.burgdorferi survival and pathogenicity in the mammalian host. PMID- 24950222 TI - Functional dissection of sugar signals affecting gene expression in Arabidopsis thaliana. AB - BACKGROUND: Sugars modulate expression of hundreds of genes in plants. Previous studies on sugar signaling, using intact plants or plant tissues, were hampered by tissue heterogeneity, uneven sugar transport and/or inter-conversions of the applied sugars. This, in turn, could obscure the identity of a specific sugar that acts as a signal affecting expression of given gene in a given tissue or cell-type. METHODOLOGY/PRINCIPAL FINDINGS: To bypass those biases, we have developed a novel biological system, based on stem-cell-like Arabidopsis suspension culture. The cells were grown in a hormone-free medium and were sustained on xylose as the only carbon source. Using functional genomics we have identified 290 sugar responsive genes, responding rapidly (within 1 h) and specifically to low concentration (1 mM) of glucose, fructose and/or sucrose. For selected genes, the true nature of the signaling sugar molecules and sites of sugar perception were further clarified using non-metabolizable sugar analogues. Using both transgenic and wild-type A. thaliana seedlings, it was shown that the expression of selected sugar-responsive genes was not restricted to a specific tissue or cell type and responded to photoperiod-related changes in sugar availability. This suggested that sugar-responsiveness of genes identified in the cell culture system was not biased toward heterotrophic background and resembled that in whole plants. CONCLUSIONS: Altogether, our research strategy, using a combination of cell culture and whole plants, has provided an unequivocal evidence for the identity of sugar-responsive genes and the identity of the sugar signaling molecules, independently from their inter-conversions or use for energy metabolism. PMID- 24950224 TI - The impact of recovery of visuo-spatial neglect on motor recovery of the upper paretic limb after stroke. AB - The aim of the current study was to investigate the longitudinal relationship between improvements of synergism and strength of the upper paretic limb and severity of visuo-spatial neglect during the first 52 weeks post-stroke. The longitudinal association between severity of VSN and motor impairment using Fugl Meyer motor score and Motricity Index of the arm was measured in an intensive repeated measurement design including 18 measurement sessions for each subject. Neglect was assessed using the letter cancellation test applied in a prospective cohort of 101 ischemic, first-ever, hemispheric stroke patients. All time dependent measures were taken weekly, starting within 14 days post-stroke. From week 10 to 20 biweekly measurements are obtained. The longitudinal relationship of (bi)weekly time on improvement of motor functions and severity of neglect was investigated using random coefficient analysis and trend analyses. Fifty-one of the 101 stroke patients showed neglect at stroke onset. Less improvement of synergism and strength of the upper paretic limb was associated with more severe neglect. This association was most pronounced in the first 10 weeks post-stroke. The seemingly suppressive effect of neglect on upper-limb motor recovery appears to take place mainly during spontaneous neurological recovery of first 10 weeks post-stroke. This finding suggests that damage to large-scale white matter tracts of especially the perceptual-attention networks suppress recovery of other networks at distance in the brain suggesting a common underlying mechanism. PMID- 24950225 TI - Speed, force, and power values produced from nonmotorized treadmill test are related to sprinting performance. AB - The relationships between 30-m sprint time and performance on a nonmotorized treadmill (TM) test and a vertical jump test were determined in this investigation. Seventy-eight physically active men and women (22.9 +/- 2.7 years; 73.0 +/- 14.7 kg; 170.7 +/- 10.4 cm) performed a 30-second maximal sprint on the curve nonmotorized TM after 1 familiarization trial. Pearson product-moment correlation coefficients produced significant (p <= 0.05) moderate to very strong relationships between 30-m sprint time and body mass (r = -0.37), %fat (r = 0.79), peak power (PP) (r = -0.59), relative PP (r = -0.42), time to peak velocity (r = -0.23) and TM sprint times at 10 m (r = 0.48), 20 m (r = 0.59), 30 m (r = 0.67), 40 m (r = 0.71), and 50 m (r = 0.75). Strong relationships between 30-m sprint time and peak (r = -0.479) and mean vertical jump power (r = -0.559) were also observed. Subsequently, stepwise regression was used to produce two 30 m sprint time prediction models from TM performance (TM1: body mass + TM data and TM2: body composition + TM data) in a validation group (n = 39), and then crossvalidated against another group (n = 39). As no significant differences were observed between these groups, data were combined (n = 72) and used to create the final prediction models (TM1: r = 0.75, standard error of the estimate (SEE) = 0.27 seconds; TM2: r = 0.84, SEE = 0.22 seconds). These final movement-specific models seem to be more accurate in predicting 30-m sprint time than derived peak (r = 0.23, SEE = 0.48 seconds) and mean vertical jump power (r = 0.31, SEE = 0.45 seconds) equations. Consequently, sprinting performance on the TM can significantly predict short-distance sprint time. It, therefore, may be used to obtain movement-specific measures of sprinting force, velocity, and power in a controlled environment from a single 30-second maximal sprinting test. PMID- 24950223 TI - Mixed species flock, nest height, and elevation partially explain avian haemoparasite prevalence in Colombia. AB - The high avian biodiversity present in the Neotropical region offers a great opportunity to explore the ecology of host-parasite relationships. We present a survey of avian haemoparasites in a megadiverse country and explore how parasite prevalences are related to physical and ecological host characteristics. Using light microscopy, we documented the presence of haemoparasites in over 2000 individuals belonging to 246 species of wild birds, from nine localities and several ecosystems of Colombia. We analysed the prevalence of six avian haemoparasite taxa in relation to elevation and the following host traits: nest height, nest type, foraging strata, primary diet, sociality, migratory behaviour, and participation in mixed species flocks. Our analyses indicate significant associations between both mixed species flocks and nest height and Haemoproteus and Leucocytozoon prevalence. The prevalence of Leucocytozoon increased with elevation, whereas the prevalence of Trypanosoma and microfilariae decreased. Plasmodium and Haemoproteus prevalence did not vary significantly with elevation; in fact, both parasites were found up to 3300 m above sea level. The distribution of parasite prevalence across the phylogeny of bird species included in this study showed little host phylogenetic signal indicating that infection rates in this system are evolutionarily labile. Vector distribution as well as the biology of transmission and the maintenance of populations of avian haemoparasites deserve more detailed study in this system. PMID- 24950226 TI - An evaluation of upper-body muscle activation during coupled and uncoupled instability resistance training. AB - Recently, there has been a growth in the popularity of resistance exercises performed on unstable surfaces. However, the relationship between unstable surface training and load coupling on muscle activation is unclear. The purpose of this study was to evaluate changes in muscle activation during a barbell (BB) (coupled) and dumbbell (DB) (uncoupled) chest press exercise performed on an unstable surface. The 3 specific chest press conditions included 50% 1 repetition maximum (RM) with BB (50% BB), 50% 1RM with DBs (50% DB), and 25% 1RM with DBs (25% DB). Ten male subjects participated in the study (age, 23.9 +/- 2.6 years; body weight, 82.8 +/- 10.2 kg). During testing, mean electromyographic activity was assessed for pectoralis major (PM), triceps brachii, anterior deltoid (AD), and rectus abdominis (RA) and was presented as a percent change across the lifting conditions. It was observed that muscle activation increased by 15% in both the PM and RA from the 50% BB condition to the 50% DB condition. Also, the greatest percent difference in muscle activation between the 50 and 25% DB conditions occurred for PM and AD (+54% during 50% DB). These results suggest that demands on the core musculature to provide stability are increased with the use of DBs (uncoupled) as opposed to a BB (coupled). Where instability training provides a sufficient hypertrophy stimulus in prime mover muscle groups, there may be the added benefit of core stability training. Specifically, this type of training may benefit both untrained persons and those engaged in active rehabilitation. PMID- 24950227 TI - The "grep" command but not FusionMap, FusionFinder or ChimeraScan captures the CIC-DUX4 fusion gene from whole transcriptome sequencing data on a small round cell tumor with t(4;19)(q35;q13). AB - Whole transcriptome sequencing was used to study a small round cell tumor in which a t(4;19)(q35;q13) was part of the complex karyotype but where the initial reverse transcriptase PCR (RT-PCR) examination did not detect a CIC-DUX4 fusion transcript previously described as the crucial gene-level outcome of this specific translocation. The RNA sequencing data were analysed using the FusionMap, FusionFinder, and ChimeraScan programs which are specifically designed to identify fusion genes. FusionMap, FusionFinder, and ChimeraScan identified 1017, 102, and 101 fusion transcripts, respectively, but CIC-DUX4 was not among them. Since the RNA sequencing data are in the fastq text-based format, we searched the files using the "grep" command-line utility. The "grep" command searches the text for specific expressions and displays, by default, the lines where matches occur. The "specific expression" was a sequence of 20 nucleotides from the coding part of the last exon 20 of CIC (Reference Sequence: NM_015125.3) chosen since all the so far reported CIC breakpoints have occurred here. Fifteen chimeric CIC-DUX4 cDNA sequences were captured and the fusion between the CIC and DUX4 genes was mapped precisely. New primer combinations were constructed based on these findings and were used together with a polymerase suitable for amplification of GC-rich DNA templates to amplify CIC-DUX4 cDNA fragments which had the same fusion point found with "grep". In conclusion, FusionMap, FusionFinder, and ChimeraScan generated a plethora of fusion transcripts but did not detect the biologically important CIC-DUX4 chimeric transcript; they are generally useful but evidently suffer from imperfect both sensitivity and specificity. The "grep" command is an excellent tool to capture chimeric transcripts from RNA sequencing data when the pathological and/or cytogenetic information strongly indicates the presence of a specific fusion gene. PMID- 24950229 TI - Reaction mechanism of adenylyltransferase DrrA from Legionella pneumophila elucidated by time-resolved fourier transform infrared spectroscopy. AB - Modulation of the function of small GTPases that regulate vesicular trafficking is a strategy employed by several human pathogens. Legionella pneumophila infects lung macrophages and injects a plethora of different proteins into its host cell. Among these is DrrA/SidM, which catalyzes stable adenylylation of Rab1b, a regulator of endoplasmatic reticulum to Golgi trafficking, and thereby alters the function and interactions of this small GTPase. We employed time-resolved FTIR spectroscopy to monitor the DrrA-catalyzed AMP-transfer to Tyr77 of Rab1b. A transient complex between DrrA, adenylylated Rab1b, and the pyrophosphate byproduct was resolved, allowing us to analyze the interactions at the active site. Combination of isotopic labeling and site-directed mutagenesis allowed us to derive the catalytic mechanism of DrrA from the FTIR difference spectra. DrrA shares crucial residues in the ATP-binding pocket with similar AMP-transferring enzymes such as glutamine synthetase adenylyltransferase or kanamycin nucleotidyltransferase, but provides the complete active site on a single subunit. We determined that Asp112 of DrrA functions as the catalytic base for deprotonation of Tyr77 of Rab1b to enable nucleophilic attack on the ATP. The study provides detailed understanding of the Legionella pneumophila protein DrrA and of AMP-transfer reactions in general. PMID- 24950228 TI - Microbial community responses to organophosphate substrate additions in contaminated subsurface sediments. AB - BACKGROUND: Radionuclide- and heavy metal-contaminated subsurface sediments remain a legacy of Cold War nuclear weapons research and recent nuclear power plant failures. Within such contaminated sediments, remediation activities are necessary to mitigate groundwater contamination. A promising approach makes use of extant microbial communities capable of hydrolyzing organophosphate substrates to promote mineralization of soluble contaminants within deep subsurface environments. METHODOLOGY/PRINCIPAL FINDINGS: Uranium-contaminated sediments from the U.S. Department of Energy Oak Ridge Field Research Center (ORFRC) Area 2 site were used in slurry experiments to identify microbial communities involved in hydrolysis of 10 mM organophosphate amendments [i.e., glycerol-2-phosphate (G2P) or glycerol-3-phosphate (G3P)] in synthetic groundwater at pH 5.5 and pH 6.8. Following 36 day (G2P) and 20 day (G3P) amended treatments, maximum phosphate (PO4(3-)) concentrations of 4.8 mM and 8.9 mM were measured, respectively. Use of the PhyloChip 16S rRNA microarray identified 2,120 archaeal and bacterial taxa representing 46 phyla, 66 classes, 110 orders, and 186 families among all treatments. Measures of archaeal and bacterial richness were lowest under G2P (pH 5.5) treatments and greatest with G3P (pH 6.8) treatments. Members of the phyla Crenarchaeota, Euryarchaeota, Bacteroidetes, and Proteobacteria demonstrated the greatest enrichment in response to organophosphate amendments and the OTUs that increased in relative abundance by 2-fold or greater accounted for 9%-50% and 3% 17% of total detected Archaea and Bacteria, respectively. CONCLUSIONS/SIGNIFICANCE: This work provided a characterization of the distinct ORFRC subsurface microbial communities that contributed to increased concentrations of extracellular phosphate via hydrolysis of organophosphate substrate amendments. Within subsurface environments that are not ideal for reductive precipitation of uranium, strategies that harness microbial phosphate metabolism to promote uranium phosphate precipitation could offer an alternative approach for in situ sequestration. PMID- 24950230 TI - beta-Adrenergic agonist and antagonist regulation of autophagy in HepG2 cells, primary mouse hepatocytes, and mouse liver. AB - Autophagy recently has been shown to be involved in normal hepatic function and in pathological conditions such as non-alcoholic fatty liver disease. Adrenergic signalling also is an important regulator of hepatic metabolism and function. However, currently little is known about the potential role of adrenergic signaling on hepatic autophagy, and whether the beta-adrenergic receptor itself may be a key regulator of autophagy. To address these issues, we investigated the actions of the beta2-adrenergic receptor agonist, clenbuterol on hepatic autophagy. Surprisingly, we found that clenbuterol stimulated autophagy and autophagic flux in hepatoma cells, primary hepatocytes and in vivo. Similar effects also were observed with epinephrine treatment. Interestingly, propranolol caused a late block in autophagy in the absence and presence of clenbuterol, both in cell culture and in vivo. Thus, our results demonstrate that the beta2 adrenergic receptor is a key regulator of hepatic autophagy, and that the beta blocker propranolol can independently induce a late block in autophagy. PMID- 24950231 TI - Does the ORF in the control region of Mytilus mtDNA code for a protein product? AB - The control region of the mtDNA of Mytilus is known to contain sequences that determine whether the genome will be paternally or maternally transmitted. An open reading frame (ORF) in this region raised suspicion that it may code for a protein involved in this mechanism. An analysis of the mtDNA transcriptome failed to produce evidence for this hypothesis. PMID- 24950232 TI - Significant other half of a glycoconjugate: contributions of scaffolds to lectin glycoconjugate interactions. AB - The glycan epitopes of natural and synthetic glycoconjugates exist as covalent attachments of well-defined inner structures or scaffolds. Macromolecules such as proteins, peptides, lipids, and saccharides and synthetic structures serve as scaffolds of glycoconjugates. It is generally perceived that the biological activities of glycoconjugates are determined mainly by the attached glycans, while the seemingly inert inner scaffolds play a passive role by providing physical support to the attached glycan epitopes. However, our data show that scaffolds actively influence lectin recognition and can potentially modulate lectin-mediated signaling properties of glycoconjugates. Through in vitro experiments, we found that the scaffolds significantly altered the thermodynamic binding properties of the covalently attached glycan epitopes. When a free glycan was attached to a scaffold, its lectin binding entropy became more positive. The level of positive entropic gain was dependent on the types of scaffolds tested. For example, protein scaffolds of glycoproteins were found to generate more positive entropy of binding than synthetic scaffolds. Certain scaffolds were found to have limiting effects on glycoconjugate affinity. We also found that scaffold-bearing glycans with a similar affinity or an identical valence demonstrated different kinetics of lattice formation with lectins, when the scaffold structures were different. Our data support the view that scaffolds of glycoconjugates (i) help the covalently attached glycans become more spontaneous in lectin binding and (ii) help diversify the lattice forming or cross-linking properties of glycoconjugates. PMID- 24950233 TI - The effect of learning on feedback-related potentials in adolescents with dyslexia: an EEG-ERP study. AB - INTRODUCTION: Individuals with dyslexia exhibit associated learning deficits and impaired executive functions. The Wisconsin Card Sorting Test (WCST) is a learning-based task that relies heavily on executive functioning, in particular, attention shift and working memory. Performance during early and late phases of a series within the task represents learning and implementation of a newly learned rule. Here, we aimed to examine two event-related potentials associated with learning, feedback-related negativity (FRN)-P300 complex, in individuals with dyslexia performing the WCST. METHODS: Adolescents with dyslexia and age-matched typical readers performed the Madrid card sorting test (MCST), a computerized version of the WCST. Task performance, reading measures, and cognitive measures were collected. FRN and the P300 complex were acquired using the event-related potentials methodology and were compared in early vs late errors within a series. RESULTS: While performing the MCST, both groups showed a significant reduction in average reaction times and a trend toward decreased error rates. Typical readers performed consistently better than individuals with dyslexia. FRN amplitudes in early phases were significantly smaller in dyslexic readers, but were essentially equivalent to typical readers in the late phase. P300 amplitudes were initially smaller among readers with dyslexia and tended to decrease further in late phases. Differences in FRN amplitudes for early vs late phases were positively correlated with those of P300 amplitudes in the entire sample. CONCLUSION: Individuals with dyslexia demonstrate a behavioral and electrophysiological change within single series of the MCST. However, learning patterns seem to differ between individuals with dyslexia and typical readers. We attribute these differences to the lower baseline performance of individuals with dyslexia. We suggest that these changes represent a fast compensatory mechanism, demonstrating the importance of learning strategies on reading among individuals with dyslexia. PMID- 24950234 TI - Citicoline in addictive disorders: a review of the literature. AB - BACKGROUND: Citicoline is a dietary supplement that has been used as a neuroprotective agent for neurological disorders such as stroke and dementia. Citicoline influences acetylcholine, dopamine, and glutamate neurotransmitter systems; serves as an intermediate in phospholipid metabolism; and enhances the integrity of neuronal membranes. Interest has grown in citicoline as a treatment for addiction since it may have beneficial effects on craving, withdrawal symptoms, and cognitive functioning, as well as the ability to attenuate the neurotoxic effects of drugs of abuse. OBJECTIVES: To review the literature on citicoline's use in addictive disorders. METHODS: Using PubMed we conducted a narrative review of the clinical literature on citicoline related to addictive disorders from the years 1900-2013 using the following keywords: citicoline, CDP choline, addiction, cocaine, alcohol, substance abuse, and substance dependence. Out of approximately 900 first hits, nine clinical studies have been included in this review. RESULTS: Most addiction research investigated citicoline for cocaine use. The findings suggest that it is safe and well tolerated. Furthermore, citicoline appears to decrease craving and is associated with a reduction in cocaine use, at least at high doses in patients with both bipolar disorder and cocaine dependence. Limited data suggest citicoline may also hold promise for alcohol and cannabis dependence and in reducing food consumption. CONCLUSIONS: Currently, there is limited research on the efficacy of citicoline for addictive disorders, but the available literature suggests promising results. Future research should employ larger sample sizes, increased dosing, and more complex study designs. PMID- 24950237 TI - Prenatal therapy in developmental disorders: drug targeting via intra-amniotic injection to treat X-linked hypohidrotic ectodermal dysplasia. PMID- 24950238 TI - Cell-free synthetic biology special issue. PMID- 24950236 TI - Pluronics and MDR reversal: an update. AB - Multidrug resistance (MDR) remains one of the biggest obstacles for effective cancer therapy. Currently there are only few methods that are available clinically that are used to bypass MDR with very limited success. In this review we describe how MDR can be overcome by a simple yet effective approach of using amphiphilic block copolymers. Triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), arranged in a triblock structure PEO-PPO-PEO, Pluronics or "poloxamers", raised a considerable interest in the drug delivery field. Previous studies demonstrated that Pluronics sensitize MDR cancer cells resulting in increased cytotoxic activity of Dox, paclitaxel, and other drugs by 2-3 orders of magnitude. Pluronics can also prevent the development of MDR in vitro and in vivo. Additionally, promising results of clinical studies of Dox/Pluronic formulation reinforced the need to ascertain a thorough understanding of Pluronic effects in tumors. These effects are extremely comprehensive and appear on the level of plasma membranes, mitochondria, and regulation of gene expression selectively in MDR cancer cells. Moreover, it has been demonstrated recently that Pluronics can effectively deplete tumorigenic intrinsically drug-resistant cancer stem cells (CSC). Interestingly, sensitization of MDR and inhibition of drug efflux transporters is not specific or selective to Pluronics. Other amphiphilic polymers have shown similar activities in various experimental models. This review summarizes recent advances of understanding the Pluronic effects in sensitization and prevention of MDR. PMID- 24950241 TI - Screening for rumination and brooding may be a feasible method of identifying adolescents at high risk for depression. AB - The purpose of this study was to explore the usefulness of a standardized measure of rumination and brooding (Ruminative Response Scale [RRS]), to accurately identify adolescents at risk for depression. Participants (N=111; mean age=13.06 years) completed standardized measures in a cross-sectional study. ROC analyses yielded high area under the curve estimates for the RRS (.94, p<.001) and the brooding subscale (.91, p<.001), indicating both are excellent at discriminating between adolescents at high and low risk for depressive symptoms. Findings suggest depression prevention may benefit from screening for and targeting rumination or brooding with adolescence. PMID- 24950240 TI - Interferon-induced genes of the expanded IFIT family show conserved antiviral activities in non-mammalian species. AB - Interferon-induced proteins with tetratricopeptide repeats (IFITs) are involved in the protective response to viral infection, although the precise mechanism of IFITs for reducing viral proliferation is currently unknown. The interaction with the translation initiation factor eIF-3 or viral proteins and the sequestering of viral RNA have been proposed as potential antiviral functions for these proteins. In humans, four members of this family have been characterized. Nevertheless, information about these proteins in fish is almost non-existent. Exploiting the conservation of synteny between human and zebrafish genomes, we have identified ten members of the IFIT family located on four different chromosomes. The induction of these genes was examined both in vitro and in vivo after interferon (IFN) administration and rhabdovirus challenge. Whereas an induction of IFIT genes was observed after interferon treatments (IFNPhi1, IFNPhi2 and IFNPhi3), the viral infection did not affect these IFN-induced genes in vitro, and even reduced the IFN-induced expression of these genes. The response was largely different in vivo, with a broad up-regulation of IFIT genes after viral challenge. In addition, three selected IFITs were cloned in an expression vector and microinjected into zebrafish larvae to examine the protective effect of IFITs upon viral infection. Reduction in the mortality rate was observed confirming a conserved antiviral function in non-mammalian species. PMID- 24950242 TI - On SHiPs and safety: a journey of safe patient handling in pediatrics. AB - Nursing personnel have consistently been ranked among the top ten professions impacted by musculoskeletal injuries. Inpatient pediatric nurses witnessed an increase in injuries and upon discovering limited evidence applicable to pediatrics, conducted a research study to evaluate the effectiveness of a safe patient handling program. Surveys were distributed to assess risk and workplace safety perceptions. Post-implementation, surveys revealed a statistically significant (p>0.0001) increase in staff perception of workplace safety, reduction in risk perception for several nursing tasks, and reduction in injury related costs. As a result of this program, workplace safety was improved through education and equipment provision. PMID- 24950244 TI - Expression of concern: Arsenic sulfide promotes apoptosis in retinoid acid resistant human acute promyelocytic leukemic NB4-R1 cells through downregulation of SET protein. PMID- 24950243 TI - Theta-burst stimulation of hippocampal slices induces network-level calcium oscillations and activates analogous gene transcription to spatial learning. AB - Over four decades ago, it was discovered that high-frequency stimulation of the dentate gyrus induces long-term potentiation (LTP) of synaptic transmission. LTP is believed to underlie how we process and code external stimuli before converting it to salient information that we store as 'memories'. It has been shown that rats performing spatial learning tasks display theta-frequency (3-12 Hz) hippocampal neural activity. Moreover, administering theta-burst stimulation (TBS) to hippocampal slices can induce LTP. TBS triggers a sustained rise in intracellular calcium [Ca2+]i in neurons leading to new protein synthesis important for LTP maintenance. In this study, we measured TBS-induced [Ca2+]i oscillations in thousands of cells at increasing distances from the source of stimulation. Following TBS, a calcium wave propagates radially with an average speed of 5.2 um/s and triggers multiple and regular [Ca2+]i oscillations in the hippocampus. Interestingly, the number and frequency of [Ca2+]i fluctuations post TBS increased with respect to distance from the electrode. During the post tetanic phase, 18% of cells exhibited 3 peaks in [Ca2+]i with a frequency of 17 mHz, whereas 2.3% of cells distributed further from the electrode displayed 8 [Ca2+]i oscillations at 33 mHz. We suggest that these observed [Ca2+]i oscillations could lead to activation of transcription factors involved in synaptic plasticity. In particular, the transcription factor, NF-kappaB, has been implicated in memory formation and is up-regulated after LTP induction. We measured increased activation of NF-kappaB 30 min post-TBS in CA1 pyramidal cells and also observed similar temporal up-regulation of NF-kappaB levels in CA1 neurons following water maze training in rats. Therefore, TBS of hippocampal slice cultures in vitro can mimic the cell type-specific up-regulations in activated NF-kappaB following spatial learning in vivo. This indicates that TBS may induce similar transcriptional changes to spatial learning and that TBS triggered [Ca2+]i oscillations could activate memory-associated gene expression. PMID- 24950245 TI - Spectroscopic and calorimetric studies on trazodone hydrochloride phosphatidylcholine liposome interactions in the presence and absence of cholesterol. AB - The interaction of antidepressant drug trazodone hydrochloride (TRZ) with dipalmitoyl phosphatidylcholine (DPPC) multilamellar liposomes (MLVs) in the presence and absence of cholesterol (CHO) was investigated as a function of temperature by using Electron Paramagnetic Resonance (EPR) spin labeling, Fourier Transform Infrared (FTIR) Spectroscopy and Differential Scanning Calorimetry (DSC) techniques. These interactions were also examined for dimyristoyl phosphatidylcholine (DMPC) multilamellar liposomes by using Electron Paramagnetic Resonance (EPR) spin labeling technique. In the EPR spin labeling studies, 5- and 16-doxyl stearic acid (5-DS and 16-DS) spin labels were used to monitor the head group and alkyl chain region of phospholipids respectively. The results indicated that TRZ incorporation causes changes in the physical properties of PC liposomes by decreasing the main phase transition temperature, abolishing the pre transition, broadening the phase transition profile, and disordering the system around the head group region. The interaction of TRZ with unilamellar (LUV) DPPC liposomes was also examined. The most pronounced effect of TRZ on DPPC LUVs was observed as the further decrease of main phase transition temperature in comparison with DPPC MLVs. The mentioned changes in lipid structure and dynamics caused by TRZ may modulate the biophysical activity of membrane associated receptors and in turn the pharmacological action of TRZ. PMID- 24950247 TI - MCLIP, an effective method to detect interactions of transmembrane proteins of the nuclear envelope in live cells. AB - Investigating interactions of proteins in the nuclear envelope (NE) using co immunoprecipitation (Co-IP) has previously been difficult or even impossible due to their inherent resistance to extraction. We have developed a novel method, MCLIP (Membrane protein Cross-Link ImmunoPrecipitation), which takes advantage of a cell permeable crosslinker to enable effective detection and analysis of specific interactions of NE proteins in live cells using Western blot. Using MCLIP we show that, in U2OS cells, the integral inner nuclear membrane protein Samp1 interacts with Lamin B1, the LINC (Linker of nucleoskeleton and cytoskeleton) complex protein, Sun1 and the soluble small GTPase Ran. The results show that the previously detected in vitro interaction between Samp1 and Emerin also takes place in live cells. In vitro pull down experiments show, that the nucleoplasmic domains of Samp1 and Emerin can bind directly to each other. We also, show that MCLIP is suitable to coprecipitate protein interactions in different stages of the cell cycle. PMID- 24950246 TI - Measuring localization and diffusion coefficients of basolateral proteins in lateral versus basal membranes using functionalized substrates and kICS analysis. AB - Micropatterning enabled semiquantitation of basolateral proteins in lateral and basal membranes of the same cell. Lateral diffusion coefficients of basolateral aquaporin-3 (AQP3-EGFP) and EGFP-AQP4 were extracted from "lateral" and "basal" membranes using identical live-cell imaging and k-space Image Correlation Spectroscopy (kICS). To simultaneously image proteins in "lateral" and "basal" membranes, micropatterning with the extracellular domain of E-cadherin and collagen, to mimic cell-cell and cell-extracellular matrix (ECM) adhesion, respectively, was used. In kidney collecting duct principal cells AQP3 localizes lateral and basal whereas AQP4 localizes mainly basal. On alternating stripes of E-cadherin and collagen, AQP3-EGFP was predominantly localized to "lateral" compared to "basal" membranes, whereas Orange-AQP4 was evenly distributed. Average diffusion coefficients were extracted via kICS analysis of rapid time lapse sequences of AQP3-EGFP and EGFP-AQP4 on uniform substrates of either E cadherin or collagen. AQP3-EGFP was measured to 0.022+/-0.010MUm(2)/s on E cadherin and 0.019+/-0.004MUm(2)/s on collagen, whereas EGFP-AQP4 was measured to 0.044+/-0.009MUm(2)/s on E-cadherin and 0.037+/-0.009MUm(2)/s on collagen, thus, diffusion did not differ between substrates. Cholesterol depletion by methyl-beta cyclodextrin (MBCD) reduced the AQP3-EGFP diffusion coefficient by 43% from 0.024+/-0.007MUm(2)/s (water) to 0.014+/-0.003MUm(2)/s (MBCD) (p<0.05) on collagen surfaces, and by 41% from 0.023+/-0.011MUm(2)/s (water) to 0.014+/ 0.005MUm(2)/s (MBCD) (p<0.05) on E-cadherin surfaces. Thus, protein patterning enables the semiquantitation of protein distribution between the "lateral" and "basal" membranes as well as measurements of lateral diffusion coefficients. PMID- 24950248 TI - Bilayer undulation dynamics in unilamellar phospholipid vesicles: effect of temperature, cholesterol and trehalose. AB - We report a combined dynamic light scattering (DLS) and neutron spin-echo (NSE) study on the local bilayer undulation dynamics of phospholipid vesicles composed of 1,2-dimyristoyl-glycero-3-phosphatidylcholine (DMPC) under the influence of temperature and the additives cholesterol and trehalose. The additives affect vesicle size and self-diffusion. Mechanical properties of the membrane and corresponding bilayer undulations are tuned by changing lipid headgroup or acyl chain properties through temperature or composition. On the local length scale, changes at the lipid headgroup influence the bilayer bending rigidity kappa less than changes at the lipid acyl chain: We observe a bilayer softening around the main phase transition temperature Tm of the single lipid system, and stiffening when more cholesterol is added, in concordance with literature. Surprisingly, no effect on the mechanical properties of the vesicles is observed upon the addition of trehalose. PMID- 24950249 TI - Whole genome and exome sequencing of monozygotic twins with trisomy 21, discordant for a congenital heart defect and epilepsy. AB - Congenital heart defects (CHD) occur in 40% of patients with trisomy 21, while the other 60% have a structurally normal heart. This suggests that the increased dosage of genes on chromosome 21 is a risk factor for abnormal heart development. Interaction of genes on chromosome 21 or their gene products with certain alleles of genes on other chromosomes could contribute to CHD. Here, we identified a pair of monozygotic twins with trisomy 21 but discordant for a ventricular septal defect and epilepsy. Twin-zygosity was confirmed by microsatellite genotyping. We hypothesized that some genetic differences from post-twinning mutations caused the discordant phenotypes. Thus, next generation sequencing (NGS) technologies were applied to sequence both whole genome and exome of their leukocytes. The post-analyses of the sequencing data revealed 21 putative discordant exonic variants between the twins from either genome or exome data. However, of the 15 variants chosen for validation with conventional Sanger sequencing, these candidate variants showed no differences in both twins. The fact that no discordant DNA variants were found suggests that sequence differences of DNA from leukocytes of monozygotic twins might be extremely rare. It also emphasizes the limitation of the current NGS technology in identifying causative genes for discordant phenotypes in monozygotic twins. PMID- 24950250 TI - Selective enrichment yields robust ethene-producing dechlorinating cultures from microcosms stalled at cis-dichloroethene. AB - Dehalococcoides mccartyi strains are of particular importance for bioremediation due to their unique capability of transforming perchloroethene (PCE) and trichloroethene (TCE) to non-toxic ethene, through the intermediates cis dichloroethene (cis-DCE) and vinyl chloride (VC). Despite the widespread environmental distribution of Dehalococcoides, biostimulation sometimes fails to promote dechlorination beyond cis-DCE. In our study, microcosms established with garden soil and mangrove sediment also stalled at cis-DCE, albeit Dehalococcoides mccartyi containing the reductive dehalogenase genes tceA, vcrA and bvcA were detected in the soil/sediment inocula. Reductive dechlorination was not promoted beyond cis-DCE, even after multiple biostimulation events with fermentable substrates and a lengthy incubation. However, transfers from microcosms stalled at cis-DCE yielded dechlorination to ethene with subsequent enrichment cultures containing up to 10(9) Dehalococcoides mccartyi cells mL(-1). Proteobacterial classes which dominated the soil/sediment communities became undetectable in the enrichments, and methanogenic activity drastically decreased after the transfers. We hypothesized that biostimulation of Dehalococcoides in the cis-DCE-stalled microcosms was impeded by other microbes present at higher abundances than Dehalococcoides and utilizing terminal electron acceptors from the soil/sediment, hence, outcompeting Dehalococcoides for H2. In support of this hypothesis, we show that garden soil and mangrove sediment microcosms bioaugmented with their respective cultures containing Dehalococcoides in high abundance were able to compete for H2 for reductive dechlorination from one biostimulation event and produced ethene with no obvious stall. Overall, our results provide an alternate explanation to consolidate conflicting observations on the ubiquity of Dehalococcoides mccartyi and occasional stalling of dechlorination at cis-DCE; thus, bringing a new perspective to better assess biological potential of different environments and to understand microbial interactions governing bioremediation. PMID- 24950251 TI - The composite of bone marrow concentrate and PRP as an alternative to autologous bone grafting. AB - One possible alternative to the application of autologous bone grafts represents the use of autologous bone marrow concentrate (BMC). The purpose of our study was to evaluate the potency of autologous platelet-rich plasma (PRP) in combination with BMC. In 32 mini-pigs a metaphyseal critical-size defect was surgically created at the proximal tibia. The animals were allocated to four treatment groups of eight animals each (1. BMC+CPG group, 2. BMC+CPG+PRP group, 3. autograft group, 4. CPG group). In the BMC+CPG group the defect was filled with autologous BMC in combination with calcium phosphate granules (CPG), whereas in the BMC+CPG+PRP group the defect was filled with the composite of autologous BMC, CPG and autologous PRP. In the autograft group the defect was filled with autologous cancellous graft, whereas in the CPG group the defect was filled with CPG solely. After 6 weeks radiological and histomorphometrical analysis showed significantly more new bone formation in the BMC+CPG+PRP group compared to the BMC+CPG group and the CPG group. There were no significant differences between the BMC+CPG+PRP group and the autograft group. In the PRP platelets were enriched significantly about 4.7-fold compared to native blood. In BMC the count of mononuclear cells increased significantly (3.5-fold) compared to the bone marrow aspirate. This study demonstrates that the composite of BMC+CPG+PRP leads to a significantly higher bone regeneration of critical-size defects at the proximal tibia in mini-pigs than the use of BMC+CPG without PRP. Furthermore, within the limits of the present study the composite BMC+CPG+PRP represents a comparable alternative to autologous bone grafting. PMID- 24950253 TI - Incidence of hospital-admitted severe traumatic brain injury and in-hospital fatality rates in a Pacific Island country: a 5-year retrospective study. AB - BACKGROUND: Epidemiology of severe traumatic brain injury (TBI) is poorly defined in the Pacific region, including in New Caledonia. The aim of this study was to assess the incidence, causes and outcome of hospital-admitted severe TBI in the whole population of New Caledonia. METHODS: A retrospective study on patients with severe TBI admitted to the only trauma centre during the 5-year period (2008 2012) was performed. The electronic patient register was searched for diagnoses of intracranial injuries to identify patients. Severe TBI was defined as a Glasgow Coma Scale Score <= 8 during the first 24 hours after injury. RESULTS: The annual incidence ranged from 10/100 000 in 2010 to 15/100 000 in 2011. Road traffic accidents (n = 109; 71%), falls (n = 26; 17%) and assaults (n = 19; 12%) were causes of severe TBI. Young Melanesian adults (median age = 26 [19-36]) were the most affected. In ICU, the overall case-fatality rate was 25%. The mortality rate was the highest among victims of assaults (47%). CONCLUSIONS: The high incidence of hospital-admitted patients with severe TBI in this study combined with high in-ICU mortality rates supports the need for targeted public health action to prevent assaults and traffic road accidents in this vulnerable population. PMID- 24950252 TI - Identification of novel surface-exposed proteins of Rickettsia rickettsii by affinity purification and proteomics. AB - Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever, is the most pathogenic member among Rickettsia spp. Surface-exposed proteins (SEPs) of R. rickettsii may play important roles in its pathogenesis or immunity. In this study, R. rickettsii organisms were surface-labeled with sulfo-NHS-SS-biotin and the labeled proteins were affinity-purified with streptavidin. The isolated proteins were separated by two-dimensional electrophoresis, and 10 proteins were identified among 23 protein spots by electrospray ionization tandem mass spectrometry. Five (OmpA, OmpB, GroEL, GroES, and a DNA-binding protein) of the 10 proteins were previously characterized as surface proteins of R. rickettsii. Another 5 proteins (Adr1, Adr2, OmpW, Porin_4, and TolC) were first recognized as SEPs of R. rickettsii herein. The genes encoding the 5 novel SEPs were expressed in Escherichia coli cells, resulting in 5 recombinant SEPs (rSEPs), which were used to immunize mice. After challenge with viable R. rickettsii cells, the rickettsial load in the spleen, liver, or lung of mice immunized with rAdr2 and in the lungs of mice immunized with other rSEPs excluding rTolC was significantly lower than in mice that were mock-immunized with PBS. The in vitro neutralization test revealed that sera from mice immunized with rAdr1, rAdr2, or rOmpW reduced R. rickettsii adherence to and invasion of vascular endothelial cells. The immuno electron microscopic assay clearly showed that the novel SEPs were located in the outer and/or inner membrane of R. rickettsii. Altogether, the 5 novel SEPs identified herein might be involved in the interaction of R. rickettsii with vascular endothelial cells, and all of them except TolC were protective antigens. PMID- 24950254 TI - Cochlear dead regions constrain the benefit of combining acoustic stimulation with electric stimulation. AB - OBJECTIVE: The aims of this study were to (1) detect the presence and edge frequency (fe) of a cochlear dead region in the ear with residual acoustic hearing for bimodal cochlear implant users, and (2) determine whether amplification based on the presence or absence of a dead region would improve speech understanding and sound quality. DESIGN: Twenty-two listeners with a cochlear implant in one ear and residual acoustic hearing in the nonimplanted ear were tested. Eleven listeners had a cochlear dead region in the acoustic-hearing ear and 11 did not. Dead regions were assessed with the threshold-equalizing noise (TEN) and the sweeping noise, psychophysical tuning curve tests. Speech understanding was assessed with monosyllabic words and the AzBio sentences at +10 dB signal-to-noise ratio. Speech- and music-quality judgments were obtained with the Judgment of Sound Quality questionnaire. RESULTS: Using shifted tips of the psychophysical tuning curve as a basis for diagnosis, the TEN had high sensitivity (0.91) and poor specificity (0.55) for this population. The value of fe was lower when estimated with the sweeping noise, psychophysical tuning curve test than with the TEN test. For the listeners with cochlear dead regions, speech understanding, speech quality and music quality were best when no amplification was applied for frequencies within the dead region. For listeners without dead regions, speech understanding was best with full-bandwidth amplification and was reduced when amplification was not applied when the audiometric threshold exceeded 80 dB HL. CONCLUSION: The data from this study suggest that, to improve bimodal benefit for listeners who combine electric and acoustic stimulation, audiologists should routinely test for the presence of cochlear dead regions and determine amplification bandwidth accordingly. PMID- 24950255 TI - Letter to the editor. PMID- 24950256 TI - What is the adequate stimulus for the oVEMP n10 to bone-conducted vibration? A reply to the letter by Todd and Colebatch (2014). PMID- 24950257 TI - Cytotoxic enhancement of hexapeptide-conjugated micelles in EGFR high-expressed cancer cells. AB - OBJECTIVES: The aim of this study was to develop the hexapeptide-conjugated active targeting micelles for delivery of doxorubicin (DOX) and paclitaxel (PTX) to EGFR high-expressed cancer cells. METHODS: A hexapeptide, which mimicked the EGFR, was applied as a targeting ligand. The active targeting micelles were prepared using the synthesized poly(D,L-lactide-co-glycolide)-PEG copolymer conjugated with the hexapeptide. The micelles were used for encapsulating DOX and/or PTX, and the cellular uptake, in vitro drug release and cellular viability of drug-loaded peptide-conjugated and peptide-free micelles were investigated. RESULTS: The particle size of drug-loaded peptide-conjugated and peptide-free micelles was < 150 nm with narrow size distribution. The uptake of peptide conjugated micelles was more efficient in EGFR high-expressed MDA-MB-468 and SKOV3 cells than in EGFR low-expressed HepG2 cells. The in vitro release of DOX and PTX was faster in pH 4.0 (500 U lipase) than in pH 7.4 release medium. The cytotoxicity in terms of IC50 of DOX/PTX-loaded peptide-conjugated micelles was 4.8-folds lower than that of peptide-free micelles and 18.2-folds lower than DOX/PTX drug solution in SOKV3 cells. CONCLUSION: The peptide-conjugated micelles acted as a nanocarrier to increase intracellular accumulation of anticancer drugs in EGFR high-expressed SKOV3 cancer cells to enhance cell cytotoxicity. PMID- 24950258 TI - Rapid and ultrasensitive electrochemical detection of multidrug-resistant bacteria based on nanostructured gold coated ITO electrode. AB - Rapid and ultrasensitive detection of pathogenic bacteria and their relevant multidrug resistance is particularly important in clinical diagnosis, disease control, and environmental monitoring. In this contribution, we have explored the possibility to rapidly detect some important disease related bacteria based on a nanostructured Au modified indium tin oxide electrode through the antibiotic agents such as doxorubicin. The rapid and real-time electrochemical detection of multidrug resistant bacteria like Escherichia coli and Staphylococcus aureus could be readily realized through the nanostructured Au based biosensor with high sensitivity. The observations of surface-enhanced Raman spectroscopy and laser confocal fluorescence microscopy also demonstrate the effectiveness of the relevant new strategy for the rapid and ultrasensitive electrochemical detection of some disease related bacteria. PMID- 24950260 TI - Individual differences in in-person and social media television coviewing: the role of emotional contagion, need to belong, and coviewing orientation. AB - The popularity of social media television coviewing is growing, but little is known about why people engage in these connected viewing experiences or how they differ from in-person coviewing. This study investigated how engaging in in person and social media coviewing is predicted by individual differences: emotional contagion, need to belong, and three dimensions of a coviewing orientation scale created for this research (need for company, need for solitude, and audience monitoring). On Amazon Mechanical Turk, 451 people were recruited for an online survey. The mean age was 34.64 years (SD=13.16 years), and 52% of the sample was female. Emotional contagion predicted in-person coviewing only. Need to belong predicted several mediated co-viewing activities. Need for solitude negatively predicted in-person coviewing, but need for company positively predicted in-person coviewing. Results indicate that viewers have different motivations for engaging in various coviewing activities. Findings also suggest that social media coviewing can provide valuable opportunities for social connection among viewers who watch television in physical solitude. PMID- 24950259 TI - Quantitative evaluation of enhancement patterns in focal solid liver lesions with Gd-EOB-DTPA-enhanced MRI. AB - PURPOSE: The objective was to investigate the dynamic enhancement patterns in focal solid liver lesions after the administration of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) by means of dynamic magnetic resonance imaging (MRI) including hepatobiliary phase (HP) images 20 min after Gd EOB-DTPA administration. MATERIALS AND METHODS: Non-enhanced T1/T2-weighted as well as dynamic magnetic resonance (MR) images during the arterial phase (AP), the portal venous phase (PVP), the late phase (LP), and the HP (20 min) were obtained from 83 patients (54 male, 29 female, mean age 62.01 years) with focal solid liver lesions. MRI was conducted by means of a 1.5-T system for 63 patients with malignant liver lesions (HCCs: n = 34, metastases: n = 29) and for 20 patients with benign liver lesions (FNH lesions: n = 14, hemangiomas: n = 3, adenomas: n = 3). For quantitative analysis, signal-to-noise ratios (SNR), contrast enhancement ratios (CER), lesion-to-liver contrast ratios (LLC), and signal intensity (SI) ratios were measured. RESULTS: The SNR of liver parenchyma significantly increased in each dynamic phase after Gd-EOB-DTPA administration compared to the SNR of non-enhanced images (p<0.001). The CER of HCCs and metastases significantly decreased between LP and HP images (p = 0.0011, p<0.0001). However, FNH lesions did not show any significant difference, whereas an increased CER was found in hemangiomas. The mean LLCs of FNH lesions were significantly higher than those of HCCs and metastases. The LLC values of hemangiomas remained negative during the entire time course, whereas the LLC of adenomas indicated hyperintensity from the AP to the LP. Furthermore, adenomas showed hypointensity in HP images. CONCLUSION: Gd-EOB-DTPA-enhanced MRI may help diagnose focal solid liver lesions by evaluating their enhancement patterns. PMID- 24950261 TI - Natural history of preoperative subcentimeter pulmonary nodules in patients with resectable pancreatic adenocarcinoma: a retrospective cohort study. AB - OBJECTIVE: To determine the detection rate, radiologic characteristics, and natural history of incidental subcentimeter pulmonary nodules (SCPN) among patients with resectable pancreatic adenocarcinoma and to clarify whether further preoperative evaluation should be considered. BACKGROUND: The clinical significance of SCPN detected by routine preoperative abdominal imaging in patients with pancreatic adenocarcinoma is unknown. METHODS: Patients who underwent resection for pancreatic adenocarcinoma between 2000 and 2010 were queried from a prospectively maintained database at a single institution. Pre- and postoperative computed tomographic (CT) imaging was independently reviewed and the presence and radiologic features of SCPNs were analyzed for associations with overall survival (OS). RESULTS: Of the 463 patients who met inclusion criteria, 329 (71%) had reviewable preoperative imaging. Preoperative SCPNs were described in 59 patients (18%), and 41 patients had follow-up imaging available for review. Only increasing age (67.1 vs 63.5 years; P = 0.005) was associated with the presence of SCPN. Six patients (1.8%) had new or enlarging nodules after surgery, of whom 5 (1.5%) had confirmed metastatic adenocarcinoma. There was no difference in OS between patients with or without preoperative SCPN (16.1 vs 19.1 months; P = 0.201). No radiographic criterion of SCPN (including number, size, laterality, calcification, or contour) was associated with OS. CONCLUSIONS: Neither the presence of preoperative SCPN nor nodule characteristics was associated with OS among patients who underwent pancreaticoduodenectomy (PD) for pancreatic cancer. These data do not support routine additional workup of preoperative SCPN in patients with resectable pancreatic adenocarcinoma. PMID- 24950262 TI - Progression and Management of Duodenal Neoplasia in Familial Adenomatous Polyposis: A Cohort Study. AB - OBJECTIVE: To describe the natural history and outcomes of surveillance of duodenal neoplasia in familial adenomatous polyposis (FAP). BACKGROUND: Duodenal cancer is the most common cause of death in FAP. METHODS: Cohort study of patients prospectively enrolled in an upper endoscopic surveillance protocol from 1982 to 2012. The duodenum was assessed by side-viewing endoscopy and classified as stage 1 to 5 disease. Endoscopic and/or operative interventions were performed according to stage. RESULTS: There were 218 patients in the protocol (98 with advanced stage). They had a median of 9 endoscopies (range: 2-25) over a median of 11 years (range: 1-26). Median age at diagnosis of stage 3 disease (adenoma: 2.1-10 mm) was 41 years and stage 4 disease (adenoma >10 mm) was 45 years. Median time from first esophagogastroduodenoscopy to stage 4 disease was 22.4 years. The risk of stage 4 disease was 34.3% [95% confidence interval (CI) 23.8-43.4] at 15 years. In multivariate analysis, sex, type of colorectal surgery, years since colorectal surgery, and stage were significantly associated with risk of progression to stage 4 disease. Five of 218 (2.3%) patients developed duodenal cancer at median age of 58 years (range: 51-65). The risk of developing duodenal cancer was 2.1% (95% CI: 0-5.2) at 15 years. CONCLUSIONS: Patients with advanced duodenal polyposis progress in the severity of disease (size and degree of dysplasia); however, the rate of progression to carcinoma is slow. Aggressive endoscopic and surgical intervention, especially in the presence of large polyps and high-grade dysplasia, appears to be effective in preventing cancer deaths in FAP. PMID- 24950264 TI - Sarcopenia Impacts on Short- and Long-term Results of Hepatectomy for Hepatocellular Carcinoma. AB - OBJECTIVE: To evaluate the prevalence of sarcopenia among European patients with resectable hepatocellular carcinoma (HCC) and to assess its prognostic impact on overall and disease-free survival. BACKGROUND: Identification of preoperative prognostic factors in liver surgery for HCC is required to better select patients and improve survival. Recent studies have shown that preoperative discrimination of patients with low skeletal muscle mass (sarcopenic patients) using computed tomography was associated with morbidity and mortality after liver and colorectal surgery. Assessment of sarcopenia could be used to evaluate patients before hepatectomy for HCC. METHODS: All consecutive patients who underwent hepatectomy for HCC in our institution, between February 2006 and September 2012, were included. Univariate and multivariate analyses evaluating prognostic factors of postoperative mortality and cancer recurrence were performed, including preoperative, surgical, and histopathological factors. RESULTS: Among 198 patients who underwent hepatectomy for HCC, 109 patients had an available computed tomographic scan and represent the study cohort. After a median follow up of 21.23 months, 27 patients (24.8%) died. There were 20 deaths among the 59 patients who had sarcopenia and only 7 deaths in the nonsarcopenic group. Sarcopenic patients had significantly shorter median overall survival than nonsarcopenic patients (52.3 months vs 70.3 months; P = 0.015). On multivariate analysis, sarcopenia was found to be an independent predictor of poor overall survival (hazard ratio = 3.19; P = 0.013) and disease-free survival (hazard ratio = 2.60; P = 0.001). CONCLUSIONS: Sarcopenia was found to be a strong and independent prognostic factor for mortality after hepatectomy for HCC in European patients and could be used to evaluate eligibility of patients with HCC before surgery. PMID- 24950263 TI - The impact of preoperative serum anti-TNFalpha therapy levels on early postoperative outcomes in inflammatory bowel disease surgery. AB - OBJECTIVE: Assess the impact of preoperative serum antitumor necrosis factor alpha (anti-TNFalpha) drug levels on 30-day postoperative morbidity in inflammatory bowel disease (IBD) patients. BACKGROUND: Studies on the association of anti-TNFalpha drugs and postoperative outcomes in IBD are conflicting due to variable pharmacokinetics of anti-TNFalpha drugs. It remains to be seen whether preoperative serum anti-TNFalpha drug levels correlate with postoperative morbidity. METHODS: Thirty-day postoperative outcomes of consecutive IBD surgical patients with serum drawn within 7 days preoperatively were studied. The total serum level of 3 anti-TNFalpha drugs (infliximab, adalimumab, and certolizumab) was measured, with >= 0.98 MUg/mL considered as detected. Data were also reviewed according to a clinical cutoff value of 3 MUg/mL. RESULTS: A total of 217 patients [123 with Crohn disease (CD) and 94 with ulcerative colitis (UC)] were analyzed; 75 of 150 (50%) treated with anti-TNFalpha therapy did not have detected levels at the time of surgery. In the UC cohort, adverse postoperative outcome rates between the undetectable and detectable groups were similar when stratified according to type of UC surgery. In the CD cohort, there was a higher but statistically insignificant rate of adverse outcomes in the detectable versus undetectable groups. Using a cut off level of 3 MUg/mL, postoperative morbidity (odds ratio [OR] = 2.5, P = 0.03) and infectious complications (OR = 3.0, P = 0.03) were significantly higher in the >= 3 MUg/mL group. There were higher rates of postoperative morbidity (P = 0.047) and hospital readmissions (P = 0.04) in the >= 8 MUg/mL compared with <3 MUg/mL group. CONCLUSIONS: Increasing preoperative serum anti-TNFalpha drug levels are associated with adverse postoperative outcomes in CD but not UC patients. PMID- 24950265 TI - Nonsteroidal anti-inflammatory drugs are associated with reduced risk of early hepatocellular carcinoma recurrence after curative liver resection: a nationwide cohort study. AB - PURPOSE: The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in reducing the risk of various de novo cancers has been reported; however, its role in reducing hepatocellular carcinoma (HCC) recurrence after liver resection still remains unknown. METHODS: We have conducted a nationwide cohort study by recruiting all patients with a newly diagnosed HCC who had received curative liver resection as their initial treatment. The use of NSAIDs and the risk of early HCC recurrence have been examined by multivariate and stratified analyses. To avoid immortal time bias, the use of NSAIDs has been treated as a time dependent variable in Cox proportional hazard ratio models. RESULTS: Between January 1997 and December 2010, a total of 15,574 HCC patients who had received liver resection were enrolled in this study. The 1-, 3-, and 5-year overall survival rates were 90.4%, 73.2%, and 59.8%, respectively. The 1-, 3-, and 5-year disease-free survival rates were 80.5%, 59.4%, and 50.2%, respectively. NSAID use (hazard ratio, 0.81; 95% confidence interval, 0.73-0.90) and minor liver resection (hazard ratio, 0.83; 95% confidence interval, 0.78-0.89) were independently associated with a reduced risk of early HCC recurrence after liver resection. In the stratified analyses, NSAID usage was universally associated with reduced risks in most subgroups, particularly for those aged younger than 65 years, male, with underlying diabetes mellitus and receiving major liver resection. CONCLUSIONS: The use of NSAIDs can be associated with a reduced risk of early HCC recurrence within 2 years after curative liver resection, regardless of patients' age, extent of liver resection, viral hepatitis status, underlying diabetes, and liver cirrhosis. PMID- 24950266 TI - Reply to Letter: "Anastomotic Leak Increases Distant Recurrence and Long-term Mortality After Curative Resection for Colonic Cancer". PMID- 24950267 TI - Anastomotic Leak Increases Distant Recurrence and Long-term Mortality After Curative Resection for Colonic Cancer. PMID- 24950268 TI - Surgical Ward Round Quality and Impact on Variable Patient Outcomes. PMID- 24950269 TI - What Ingredients Have You Used to Prepare This Delicious Lunch? A Critical Look Behind a Meta-analysis. PMID- 24950271 TI - Vascularized lymph node transfer for treatment of lymphedema: a comprehensive literature review. AB - OBJECTIVE: A comprehensive literature review of VLNT with updates and comparisons on current application, techniques, results, studies and possible future implications. BACKGROUND: Lymphedema is a debilitating condition that often results secondary to treatment of cancer. Unfortunately there is no cure. However, microsurgical procedures such as VLNT has gained popularity as there have been increasing reports that VLNT may help alleviate the severity of lymphedema. METHODS: A review of literature was conducted over major medical indices (PubMed-MEDLINE, Factiva, Scopus, Sciencedirect, EMBASE). Search terms were focused on vascularized, lymph node transfer (also autologous, lymph node transplant) to cover both human and animal studies. Each study was verified for the nature of the procedure; a free microsurgical flap containing lymph nodes for the purpose of relieving lymphedema. RESULTS: There are human and animal studies that individually report clear benefits, but because of methodological shortcomings comparative studies with uniform patient selection and monitoring are lacking. CONCLUSIONS: Although the results with the use of VLNT for treatment of lymphedema have been largely positive, further exploration into standardized protocols for diagnosis, treatment optimization, and patient outcomes assessment is needed. PMID- 24950270 TI - Perineal transanal approach: a new standard for laparoscopic sphincter-saving resection in low rectal cancer, a randomized trial. AB - BACKGROUND: Laparoscopic sphincter preservation for low rectal cancer is challenging because of the high risk of positive circumferential resection margin. We hypothesized that perineal dissection of the distal rectum may improve quality of surgery, compared with the conventional abdominal dissection. METHODS: Between 2008 and 2012, 100 patients with low rectal cancer (< 6 cm from the anal verge) suitable for sphincter preservation were randomized between perineal and abdominal low rectal dissection. Surgery included laparoscopic mobilization of the left colon with high rectal dissection. Distal rectal dissection was performed laparoscopically in the abdominal group and transanally in the perineal group. The primary endpoint was quality of surgery (circumferential resection margin, mesorectum grade, and lymph nodes). Secondary end points were morbidity and conversion. RESULTS: The rate of positive circumferential resection margin decreased significantly after perineal compared with abdominal low rectal dissection, 4% versus 18% (P = 0.025). The mesorectum grade and the number of lymph nodes analyzed did not differ between the 2 groups. There was no difference in surgical morbidity (12% vs 14%; P = 0.766) and conversion (4% vs 10%; P = 0.436) between perineal and abdominal rectal dissection. Multivariate analysis showed that abdominal rectal dissection was the only independent factor of positive circumferential resection margin (odds ratio = 5.25; 95% confidence interval: 1.03-26.70; P = 0.046). CONCLUSIONS: Perineal rectal dissection reduces the risk of positive circumferential resection margin, as compared with the conventional abdominal dissection in low rectal cancer. This suggests the perineal rectal dissection as a new standard in laparoscopic sphincter-saving resection for low rectal cancer. PMID- 24950272 TI - Contralateral prophylactic mastectomy after unilateral breast cancer: a systematic review and meta-analysis. AB - OBJECTIVE: To examine whether contralateral prophylactic mastectomy (CPM) is associated with improved survival, incidence of contralateral breast cancer (CBC), and recurrence in patients with unilateral breast cancer (UBC). BACKGROUND: Despite conflicting data, CPM rates continue to increase. Here we present the first meta-analysis to assess post-CPM outcomes in women with UBC. METHODS: We searched 5 databases and retrieved papers' bibliographies for relevant studies published through March 2012. Fixed- and random-effects meta analyses were conducted on the basis of tests of study heterogeneity. We examined potential confounding via stratification and meta-regression. We report pooled relative risks (RRs) and risk differences (RDs) with 95% confidence intervals (CIs) at 2-tailed P < 0.05 significance. RESULTS: Of 93 studies reviewed, 14 were included in meta-analyses. Compared with nonrecipients, CPM recipients had higher rates of overall survival [OS; RR = 1.09 (95% CI: 1.06, 1.11)] and lower rates of breast cancer-specific mortality [BCM; RR = 0.69 (95% CI: 0.56, 0.85)] but saw no absolute reduction in risk of metachronous CBC (MCBC). Among patients with elevated familial/genetic risk (FGR, ie, BRCA carrier status and/or family history of breast cancer), both relative and absolute risks of MCBC were significantly decreased among CPM recipients [RR = 0.04 (95% CI: 0.02, 0.09); RD = -24.0% (95% CI: -35.6%, -12.4%)], but there was no improvement in OS or BCM. CONCLUSIONS: CPM is associated with decreased MCBC incidence but not improved survival among patients with elevated FGR. The superior outcomes observed when comparing CPM recipients with nonrecipients in the general population are likely not attributable to a CPM-derived decrease in MCBC incidence. UBC patients without known FGR should not be advised to undergo CPM. PMID- 24950273 TI - Safety and durability of one-stage repair of abdominal wall defects with enteric fistulas. AB - OBJECTIVE: To evaluate the safety and long-term durability of 1-stage repair of enteric fistulas in the presence of an abdominal wall defect. BACKGROUND: Patients with enteric fistulas and an abdominal wall defect present an extreme challenge to surgeons and have been associated with significant morbidity and mortality. Durability of repair is unknown as studies fail to report this or use limited follow-up periods. METHODS: Chart review was done of consecutive patients who underwent 1-stage repair. Short-term outcomes included morbidity (wound and medical) and mortality. Long-term durability of repair was determined by prospective outpatient follow-up at least 3 years after surgery. RESULTS: Thirty nine patients were included with a mean age of 61.2 years, a mean BMI of 24.4 kg/m2, and a mean abdominal wall defect size of 247.9 cm2. Component separation technique was used in 34 (87.2%) and synthetic mesh in 13 (33.3%) patients. There was 1 (2.6%) postoperative death. Twenty-four wound complications developed in 18 (46.2%) patients, including surgical-site infection in 8 (20.5%) patients. Two (5.1%) enteric fistulas recurred and were treated conservatively resulting in closure. Medical complications were seen 36 times in 23 (59%) patients. Twelve of 33 (36.4%) living patients developed a recurrent hernia after a mean follow-up of 62.7 months (range: 36-130). CONCLUSIONS: One-stage abdominal wall reconstruction with enteric fistula takedown is feasible at the cost of considerable morbidity. Our treatment strategy including component separation technique with synthetic mesh on-demand results in a durable repair in 6 to 7 of 10 patients. PMID- 24950274 TI - Surgery and jazz: the art of improvisation in the evidence-based medicine era. PMID- 24950275 TI - The right treatment at the right time in the right place: a population-based, before-and-after study of outcomes associated with implementation of an all inclusive trauma system in a large Canadian province. AB - OBJECTIVE: To evaluate the implementation of an all-inclusive philosophy of trauma care in a large Canadian province. BACKGROUND: Challenges to regionalized trauma care may occur where transport distances to level I trauma centers are substantial and few level I centers exist. In 2008, we modified our predominantly regionalized model to an all-inclusive one with the hopes of increasing the role of level III trauma centers. METHODS: We conducted a population-based, before-and after study of patient admission and transfer practices and outcomes associated with implementation of an all-inclusive provincial trauma system using multivariable Poisson and linear regression and Cox proportional hazard models. RESULTS: In total, 21,772 major trauma patients were included. Implementation of the all-inclusive model of trauma care was associated with a decline in transfers directly to level I trauma centers [risk ratio (RR) = 0.91; 95% confidence interval (CI): 0.88-0.94; P < 0.001] and an increase in transfers from level III to level I centers (RR = 1.10; 95% CI: 1.00-1.21; P = 0.04). These changes in trauma care occurred in conjunction with a 12% reduction in the hazard of mortality (hazard ratio = 0.88; 95% CI: 0.84-0.98; P = 0.003) and a decrease in mean trauma patient hospital length of stay by 1 day (95% CI: 1.02-1.11; P = 0.02) after adjustment for differences in case mix. CONCLUSIONS: In this study, introduction of an all-inclusive provincial trauma system was associated with an increased number of injured patients cared for in their local systems and improved trauma patient mortality and hospital length of stay. PMID- 24950276 TI - Prognostic nomograms for prediction of recurrence and survival after curative liver resection for hepatocellular carcinoma. AB - OBJECTIVE: To develop clinical predictive nomograms generating per-patient numerical probabilities of postoperative recurrence-free and overall survival at specific times. BACKGROUND: The prognosis after surgical resection is diverse in patients with early-stage hepatocellular carcinoma (HCC). METHODS: In a retrospective review, we evaluated data from 1085 mostly early-stage patients newly diagnosed with HCC who were subsequently treated by curative resection. We randomly divided the subjects into derivation (n = 760) and validation (n = 325) samples. Multivariate Cox proportional hazards models were developed and separately validated on the basis of pre- and postoperative clinical and pathological covariates assessed for association with 2-year recurrence and 5 year HCC-specific death. The discriminatory accuracy of the models was compared with traditional tools by analyzing receiver operating characteristic curves. RESULTS: The statistical nomograms built on the basis of sex, serum albumin, platelet count, microvascular invasion, and calculated tumor volume had good calibration and discriminatory abilities, with c-indices of 0.69 (2-year recurrence) and 0.66 (5-year survival), respectively. These models showed satisfactory goodness-of-fit and discrimination abilities in the independent validation cohort (c-index, 0.66 for 2-year recurrence; and 0.67 for 5-year survival). The areas under the receiver operating characteristic curve using our methods were greater than those of conventional staging systems in the validation patients, indicating better discriminatory capability (corresponding c-indices, 0.55-0.56; and 0.55-0.61, respectively). CONCLUSIONS: Our simple user-friendly calculators, which present graphically postsurgical prognostic models for recurrence and survival outcomes in patients with curatively resectable HCC, offer useful guidance to clinicians and patients for individually planning recurrence surveillance and adjuvant therapy. PMID- 24950277 TI - Ambulatory varicosity avulsion later or synchronized (AVULS): a randomized clinical trial. AB - OBJECTIVE: A randomized clinical trial assessing the difference in quality of life and clinical outcomes between delayed and simultaneous phlebectomies in the context of endovenous truncal vein ablation. BACKGROUND: Endovenous ablation has replaced open surgery as the treatment of choice for truncal varicose veins. Timing of varicosity treatment is controversial with delayed and simultaneous pathways having studies advocating their benefits. A previous small randomized study has shown improved outcomes for simultaneous treatment. METHODS: Patients undergoing local anesthetic endovenous thermal ablation were randomized to either simultaneous phlebectomy or delayed varicosity treatment. Patients were reviewed at 6 weeks, 6 months, and 1 year with clinical and quality of life scores completed, and were assessed at 6 weeks for need for further varicosity intervention, which was completed with either ultrasound-guided foam sclerotherapy or local anesthetic phlebectomy. Duplex ultrasound assessment of the treated trunk was completed at 6 months. RESULTS: 101 patients were successfully recruited and treated out of 221 suitable patients from a screened population of 393. Patients in the simultaneous group (n = 51) showed a significantly improved Venous Clinical Severity Score at all time points, 36% of the delayed group required further treatment compared with 2% of the simultaneous group (P < 0.001). There were no deep vein thromboses, with 1 superfificial venous thrombosis in each group. CONCLUSIONS: Combined endovenous ablation and phlebectomy delivers improved clinical outcomes and a reduced need for further procedures, as well as early quality of life improvements. PMID- 24950279 TI - Quality of reporting on patient and public involvement within surgical research: a systematic review. AB - BACKGROUND: Recruitment difficulties are a well-reported concern in surgical literature, which may be improved by patient and public involvement (PPI). PPI within research has been defined as being conducted "with" or "by" patients or members of the public rather than being "about" or "for" them. However, the extent to which PPI is used within surgical research is unknown. METHODS: Surgical literature was systematically reviewed using EMBASE, MEDLINE, PsycINFO, the Cochrane Central Register of Controlled Trials, and PubMed. Search terms related to (i) patients, (ii) involvement, (iii) perioperative care, and (iv) impact. Quality of PPI reporting was evaluated using the GRIPP (Guidance for Reporting Involvement of Patients and Public checklist and the guidelines developed by Wright and Foster. A patient representative advised on the purpose and analysis of this systematic review. RESULTS: Eight articles described PPI in surgical trials to improve the identification of research topics, study design, recruitment, retention, and data collection. Quality of PPI reporting was suboptimal, as none of the articles provided a clear account of how PPI was conceptualized. Training and support for patients, their involvement in dissemination, and a critique of the limitations of PPI were not reported. However, it was not clear whether this represents an underutilization of PPI or purely suboptimal reporting in surgery. CONCLUSIONS: There is a paucity of surgical research reporting upon PPI, and the quality of reporting is low. Further research to define appropriate standards for reporting on PPI activities may facilitate broadening the utilization and impact of PPI in surgical research. PMID- 24950278 TI - Prediction of multiple infections after severe burn trauma: a prospective cohort study. AB - OBJECTIVE: To develop predictive models for early triage of burn patients based on hypersusceptibility to repeated infections. BACKGROUND: Infection remains a major cause of mortality and morbidity after severe trauma, demanding new strategies to combat infections. Models for infection prediction are lacking. METHODS: Secondary analysis of 459 burn patients (>=16 years old) with 20% or more total body surface area burns recruited from 6 US burn centers. We compared blood transcriptomes with a 180-hour cutoff on the injury-to-transcriptome interval of 47 patients (<=1 infection episode) to those of 66 hypersusceptible patients [multiple (>=2) infection episodes (MIE)]. We used LASSO regression to select biomarkers and multivariate logistic regression to built models, accuracy of which were assessed by area under receiver operating characteristic curve (AUROC) and cross-validation. RESULTS: Three predictive models were developed using covariates of (1) clinical characteristics; (2) expression profiles of 14 genomic probes; (3) combining (1) and (2). The genomic and clinical models were highly predictive of MIE status [AUROCGenomic = 0.946 (95% CI: 0.906-0.986); AUROCClinical = 0.864 (CI: 0.794-0.933); AUROCGenomic/AUROCClinical P = 0.044]. Combined model has an increased AUROCCombined of 0.967 (CI: 0.940-0.993) compared with the individual models (AUROCCombined/AUROCClinical P = 0.0069). Hypersusceptible patients show early alterations in immune-related signaling pathways, epigenetic modulation, and chromatin remodeling. CONCLUSIONS: Early triage of burn patients more susceptible to infections can be made using clinical characteristics and/or genomic signatures. Genomic signature suggests new insights into the pathophysiology of hypersusceptibility to infection may lead to novel potential therapeutic or prophylactic targets. PMID- 24950280 TI - Chemotherapy or liver transplantation for nonresectable liver metastases from colorectal cancer? AB - OBJECTIVE: The primary objective was to compare overall survival (OS) in patients with colorectal cancer (CRC) with nonresectable liver-only metastases treated by liver transplantation or chemotherapy. BACKGROUND: CRC is the third most common cancer worldwide. About 50% of patients will develop metastatic disease primarily to the liver and the lung. The majority of patients with liver metastases receive palliative chemotherapy, with a median OS of trial patients of about 2 years, and less than 10% are alive at 5 years. METHODS: Patients with nonresectable liver only CRC metastases underwent liver transplantation in the SECA study (n = 21). Disease-free survival (DFS) and OS of patients included in the SECA study were compared with progression-free survival (PFS) and OS in a similar cohort of CRC patients with liver-only disease included in a first-line chemotherapy study, the NORDIC VII study (n = 47). PFS/DFS and OS were estimated by the Kaplan-Meier method. RESULTS: DFS/PFS in both groups were 8 to 10 months. However, a dramatic difference in OS was observed. The 5-year OS rate was 56% in patients undergoing liver transplantation compared with 9% in patients starting first-line chemotherapy. The reason for the large difference in OS despite similar DFS/PFS is likely different metastatic patterns at relapse/progression. Relapse in the liver transplantation group was often detected as small, slowly growing lung metastases, whereas progression of nonresectable liver metastases was observed in the chemotherapy group. CONCLUSIONS: Compared with chemotherapy, liver transplantation resulted in a marked increased OS in CRC patients with nonresectable liver-only metastases. PMID- 24950281 TI - Chemotherapy before liver resection of colorectal metastases: friend or foe? PMID- 24950282 TI - Reply to letter: "chemotherapy before liver resection of colorectal metastases: friend or foe?". PMID- 24950283 TI - Trends in the frequency and quality of parathyroid surgery: analysis of 17,082 cases over 10 years. AB - OBJECTIVE: To examine trends in the frequency and quality of surgery for primary hyperparathyroidism (PHPT) in California during the period of 1999 to 2008. BACKGROUND: The quality of surgery for PHPT can be measured by the complication rate and the success rate of surgery. A fraction of patients with failed initial surgery undergo reoperation. METHODS: Data on patients undergoing parathyroidectomy (PTx) were obtained from the California Office of Statewide Health Planning and Development. Renal transplant recipients and dialysis patients were excluded. Hospitals were categorized by case volume: Very low: 1 to 4 operations annually; Low: 5 to 9; Medium, 10 to 19; High: 20 to 49; Very high: 50 or more. Complication rates and the percentage of cases requiring reoperation were analyzed. RESULTS: A total of 17,082 cases were studied. Annual case volume grew from 990 to 2746 (177% increase) over the study period, corresponding to a 147% increase in the per capita PTx rate. The proportion of cases performed by very high-volume hospitals increased from 6.4% to 20.5% (P < 0.001). The overall complication rate declined from 8.7% to 3.8% (P < 0.001). Complication rates were inversely related to hospital volume (very high volume, 3.9% vs very low volume, 5.2%, P < 0.05). Reoperation was performed in 363 patients (2.1%). The reoperation rate increased from 0.91% to 2.73% during the study period (P < 0.01). The reoperation rate was inversely and nonlinearly related to hospital volume, as described by the equation % reoperation = 100/(total hospital case volume). CONCLUSIONS: Surgery for PHPT has grown safer and more common over time. High-volume centers have lower rates of complication and reoperation. PMID- 24950284 TI - Complex Liver Resection Using Standard Total Vascular Exclusion, Venovenous Bypass, and In Situ Hypothermic Portal Perfusion: An Audit of 77 Consecutive Cases. AB - OBJECTIVE: To identify independent predictors of 90-day mortality after liver resection for patients undergoing standard total vascular exclusion (TVE) with hypothermic portal perfusion and venovenous bypass. The secondary endpoint was to evaluate the long-term outcomes. BACKGROUND: Tumors invading the vena cava and/or the hepatocaval confluence are indications for standard TVE. The inclusion of liver hypothermic perfusion permits safe TVE. There are a limited number of reports focusing on this complex technique and no relevant analysis of short-term and long-term results. METHODS: Seventy-seven consecutive liver resections performed using standard TVE with hypothermic portal perfusion and venovenous bypass between 1998 and 2010 were analyzed. The independent predictors and rates of 90-day mortality, morbidity, and long-term survival were evaluated. RESULTS: The 90-day mortality rate was 19.5% (15 cases). Three independent predictors of mortality were identified: age-adjusted Charlson Comorbidity Index 3 or more (P = 0.0231; odds ratio = 47.565; 95% confidence interval = 1.701-1330.414), tumor size 10 cm or more (P = 0.0442; odds ratio = 6.374; 95% confidence interval = 1.049-38.734), and the presence of 50/50 criteria (P = 0.0407; odds ratio = 6.217; 95% confidence interval = 1.080-35.782). The overall 5-year survival rate was 30.4%. CONCLUSIONS: Liver resection using standard TVE with hypothermic portal perfusion and venovenous bypass is associated with a high mortality rate. The identification of preoperative predictors of mortality should improve the selection of patients for this aggressive surgery. Compared with nonsurgical management, the long-term results are acceptable and justify this aggressive surgery in selected patients. PMID- 24950285 TI - Simvastatin reduces burn injury-induced splenic apoptosis via downregulation of the TNF-alpha/NF-kappaB pathway. AB - OBJECTIVE: Recent studies have suggested that epidermal burn injuries are associated with inflammation and immune dysfunction. Simvastatin has been shown to possess potent anti-inflammatory properties. Thus, we hypothesized that simvastatin protects against burn-induced apoptosis in the spleen via its anti inflammatory activity. METHODS: Wild-type, tumor necrosis factor alpha knockout (TNF-alpha KO) and NF-kappaB KO mice were subjected to full-thickness burn injury or sham treatment. The mice then were treated with or without simvastatin, and the spleen was harvested to measure the extent of apoptosis. Expression levels of TNF-alpha and NF-kappaB were also determined in spleen tissue and serum. RESULTS: Burn injury induced significant splenic apoptosis and systemic cytokine production. Simvastatin protected the spleen from apoptosis, reduced cytokine production in the serum, and increased the survival rate. Simvastatin decreased burn-induced TNF-alpha and NF-kappaB expression in the spleen and serum. TNF alpha and NF-kappaB KO mice demonstrated lower levels of apoptosis in spleen in response to burn injury. Simvastatin did not further decrease burn-caused apoptosis and mortality in either strain of KO mice. CONCLUSIONS: Simvastatin reduces burn-induced splenic apoptosis via downregulation of the TNF-alpha/NF kappaB pathway. PMID- 24950286 TI - Reply to Letter: "A Randomized Study on 1-week Versus 4-week Prophylaxis for Venous Thromboembolism After Laparoscopic Surgery for Colorectal Cancer". PMID- 24950287 TI - Management of Acute Appendicitis in Ambulatory Surgery: Is It Possible? How to Select Patients? AB - OBJECTIVE: Establish a protocol of management of acute appendicitis (AA) in ambulatory surgery (AmbSurg) on the basis of preoperative criteria. BACKGROUND: Ambulatory laparoscopic appendectomy (LA) for AA has not been yet reported. METHODS: All patients who underwent LA between 2010 and 2012 were reviewed. A multivariate analysis was performed to create a predictive score of discharge within the first 24 hours. The score was prospectively used on every AA from January 1, 2013, to December 15, 2013. All patients with 5 or 4 points were proposed for AmbSurg. RESULTS: A total of 468 patients were included retrospectively, 181(38.7%) were discharged within the first 24 hours. In multivariate analysis, predictive factors of early discharge were body mass index less than 28 kg/m, white cell count less than 15,000/mL, C-reactive protein less than 30 mg/L, no radiological signs of perforation, and appendix diameter of 10 mm or smaller. Rate of discharge at day 1 was 72%, 45%, 39%, 21%, 0%, and 0% according to the score 5 to 0 (P < 0.0001). Prospectively, 184 patients had AA and 103 (56%) had a score of 4 or 5. Thirty-eight underwent ambulatory LA [16 (42%) patients were postponed to the next day and went back home]. All patients were directly discharged from recovery room, except 1 (2.6%) patient, after a mean hospital stay of 8.4 hours +/- 6.9 hours. A total of 146 patients underwent LA in conventional surgery and 58% were discharged at day 1. Rate of early discharge was significantly associated with the score ranging from 0% to 92% for a score 0 or 5, validating prospectively the score (P < 0.0001). CONCLUSIONS: We establish a simple validated predictive score of early discharge. When applied to AmbSurg, it allowed us to select patients eligible with a success rate of 97%. PMID- 24950288 TI - What should be the gold standard for the surgical component in the treatment of locally advanced esophageal cancer: transthoracic versus transhiatal esophagectomy. AB - OBJECTIVE: To analyze survival differences between transthoracic esophagectomy (TTE) and limited transhiatal esophagectomy (THE) in clinically (cT3) and pathologically (pT3) staged advanced tumors without neoadjuvant treatment. BACKGROUND: Debate exists whether in the type of resection in locally advanced cancer plays a role in prognosis and whether THE is a valuable alternative to TTE regarding oncological doctrine and overall survival. METHODS: In a retrospective study of 2 high-volume centers, 468 patients with cT3NXM0 esophageal cancer, including 242 (51.7%) squamous cell carcinomas (SCCs) and 226 (48.3%) adenocarcinomas (ACs), were analyzed. A total of 341 (72.9%) TTE and 127 (27.1%) THE were performed. We used the propensity score matching to build comparable groups. Primary endpoint was the overall survival; secondary endpoints included resection status and lymph node yield. RESULTS: TTE achieved a higher rate of R0 resections (86.2% vs 73.2%; P = 0.001) and a higher median lymph node yield (27.0 +/- 12.4 vs 17.0 +/- 6.4; P < 0.001) than THE. Thirty-day mortality rate was 6.6% (8/121) for TTE and 7.4% (9/121) for THE (P = 0.600). In the matched groups, TTE was beneficial for pT3 SCC (P = 0.004), pT3 AC (P = 0.029), cT3 SCC (P = 0.018), and cT3 AC (P = 0.028) patients. TTE was either beneficial in pN2 disease for cT3 AC + SCC or pT3 SCC but not for pT3 AC patients, without nodal stratification in pT3 and cT3 SCC node-positive patients. On multivariable analysis, TTE remained an independent factor for survival. CONCLUSIONS: Extended TTE achieved a higher rate of R0 resections, a higher lymph node yield, and resulted in a prolonged survival than THE in pT3, cT3, and node-positive patients. PMID- 24950289 TI - Risk of acute appendicitis in and around pregnancy: a population-based cohort study from England. AB - OBJECTIVE: To determine the absolute and relative risk of acute appendicitis during the antepartum and postpartum periods compared with the time outside pregnancy among women of childbearing age. BACKGROUND: Acute appendicitis is the most common nonobstetric surgical emergency during pregnancy. Estimates of the incidence of acute appendicitis in pregnancy remain imprecise and inconsistent. METHODS: All potential fertile women aged 15 to 44 years registered within Clinical Practice Research Datalink with linkages to the Hospital Episodes Statistics between 1997 and 2012 were identified. Absolute rates of acute appendicitis were calculated during the antepartum and postpartum periods and were compared with the time outside pregnancy in terms of incidence rate ratio (IRR) using a Poisson regression model. RESULTS: Among 1,624,804 women, there were 362,219 pregnancies resulting in live or stillbirths. Compared with the time outside pregnancy, the rate of acute appendicitis was 35% lower during the antepartum period [IRR, 0.65; 95% confidence interval (CI), 0.55-0.76], with the lowest rate reported during the third trimester (IRR, 0.47; 95% CI, 0.35-0.64) for all ages; no increased risk of acute appendicitis was observed in the postpartum period compared with the time outside pregnancy among women aged 15 to 34 years but an 84% increased risk for women older than 35 years (IRR, 1.84; 95% CI, 1.18-2.86). The highest and lowest rates of negative appendectomy were encountered in the second and the third trimesters, respectively. CONCLUSIONS: Pregnant women are less likely to be diagnosed with acute appendicitis than nonpregnant women, with the lowest risk reported during the third trimester. PMID- 24950291 TI - Behavioral heterogeneity of adult mouse lung epithelial progenitor cells. AB - The existence and identity of multipotent stem cells in the adult lung is currently highly debated. At present, it remains unclear whether candidate stem/progenitor cells are located in the airways, alveoli, or throughout the epithelial lining of the lung. Here, we introduce a method of airway microdissection, which enabled us to study the progenitor behavior of pulmonary epithelial cells in region-specific contexts. The progenitor characteristics of epithelial cells isolated from the trachea, proximal and distal airways, and lung parenchyme were evaluated in vitro and in vivo. We identified a population of airway-derived basal-like epithelial cells with the potential to self-renew and differentiate into airway and alveolar lineages in culture and in vivo after subcutaneous transplantation. The multipotent candidate progenitors originated from a minor fraction of the airway epithelial cell population characterized by high expression of alpha6 integrin. Results of the current study provide new insights into the regenerative potential of region-specific integrin alpha6 positive pulmonary epithelial cells. PMID- 24950290 TI - FoxO3a nuclear localization and its association with beta-catenin and Smads in IFN-alpha-treated hepatocellular carcinoma cell lines. AB - Interferon-alpha2b (IFN-alpha2b) reduces proliferation and increases apoptosis in hepatocellular carcinoma cells by decreasing beta-catenin/TCF4/Smads interaction. Forkhead box O-class 3a (FoxO3a) participates in proliferation and apoptosis and interacts with beta-catenin and Smads. FoxO3a is inhibited by Akt, IkappaB kinase beta (IKKbeta), and extracellular-signal-regulated kinase (Erk), which promote FoxO3a sequestration in the cytosol, and accumulates in the nucleus upon phosphorylation by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase (p38 MAPK). We analyzed FoxO3a subcellular localization, the participating kinases, FoxO3a/beta-catenin/Smads association, and FoxO3a target gene expression in IFN-alpha2b-stimulated HepG2/C3A and Huh7 cells. Total FoxO3a and Akt phosphorylated FoxO3a levels decreased in the cytosol, whereas total FoxO3a levels increased in the nucleus upon IFN-alpha2b stimulus. IFN-alpha2b reduced Akt, IKKbeta, and Erk activation, and increased JNK and p38 MAPK activation. p38 MAPK inhibition blocked IFN-alpha2b-induced FoxO3a nuclear localization. IFN alpha2b enhanced FoxO3a association with beta-catenin and Smad2/3/7. Two-step coimmunoprecipitation experiments suggest that these proteins coexist in the same complex. The expression of several FoxO3a target genes increased with IFN alpha2b. FoxO3a knockdown prevented the induction of these genes, suggesting that FoxO3a acts as mediator of IFN-alpha2b action. Results suggest a beta catenin/Smads switch from TCF4 to FoxO3a. Such events would contribute to the IFN alpha2b-mediated effects on cellular proliferation and apoptosis. These results demonstrate new mechanisms for IFN-alpha action, showing the importance of its application in antitumorigenic therapies. PMID- 24950292 TI - Linking eye design with host symbiont relationships in pontoniine shrimps (Crustacea, Decapoda, Palaemonidae). AB - Symbiosis is prevalent in the marine environment with many studies examining the effects of such interactions between host and symbiont. Pontoniine shrimps are a group whose ecology is characterised by symbiotic interactions. This investigation examines the gross morphology of Pontoniinae compound eyes and superficial optical parameters with reference to their symbiotic relationship or lifestyle category; free-living, ectosymbiont, endosymbiont (bivalves) or endosymbiont (non-bivalves). The eye morphologies of free-living and ectosymbiotic species are very similar, yet differ from both forms of endosymbiotic species. Endosymbionts have significantly smaller and simpler eyes with larger facets and bigger interommatidial angles and eye parameters for increased sensitivity levels. However bivalve endosymbionts form an intermediary group between non-bivalve endosymbionts and ectosymbionts as a result of their more active lifestyle. The accessory eye or "nebenauge", although of uncertain function, commonly occurs in free-living Pontoniinae species but rarely in endosymbionts apart from in more primitive species. The variation in morphology reflects tensions between functional requirements and ecological pressures that have strongly influenced eye design in Pontoniinae. PMID- 24950293 TI - Erucin, the major isothiocyanate in arugula (Eruca sativa), inhibits proliferation of MCF7 tumor cells by suppressing microtubule dynamics. AB - Consumption of cruciferous vegetables is associated with reduced risk of various types of cancer. Isothiocyanates including sulforaphane and erucin are believed to be responsible for this activity. Erucin [1-isothiocyanato-4 (methylthio)butane], which is metabolically and structurally related to sulforaphane, is present in large quantities in arugula (Eruca sativa, Mill.), kohlrabi and Chinese cabbage. However, its cancer preventive mechanisms remain poorly understood. We found that erucin inhibits proliferation of MCF7 breast cancer cells (IC50 = 28 uM) in parallel with cell cycle arrest at mitosis (IC50 = 13 uM) and apoptosis, by a mechanism consistent with impairment of microtubule dynamics. Concentrations of 5-15 uM erucin suppressed the dynamic instability of microtubules during interphase in the cells. Most dynamic instability parameters were inhibited, including the rates and extents of growing and shortening, the switching frequencies between growing and shortening, and the overall dynamicity. Much higher erucin concentrations were required to reduce the microtubule polymer mass. In addition, erucin suppressed dynamic instability of microtubules reassembled from purified tubulin in similar fashion. The effects of erucin on microtubule dynamics, like those of sulforaphane, are similar qualitatively to those of much more powerful clinically-used microtubule-targeting anticancer drugs, including taxanes and the vinca alkaloids. The results suggest that suppression of microtubule dynamics by erucin and the resulting impairment of critically important microtubule-dependent cell functions such as mitosis, cell migration and microtubule-based transport may be important in its cancer preventive activities. PMID- 24950294 TI - Siphonaxanthin, a green algal carotenoid, as a novel functional compound. AB - Siphonaxanthin is a specific keto-carotenoid in green algae whose bio-functional properties are yet to be identified. This review focuses on siphonaxanthin as a bioactive compound and outlines the evidence associated with functionality. Siphonaxanthin has been reported to potently inhibit the viability of human leukemia HL-60 cells via induction of apoptosis. In comparison with fucoxanthin, siphonaxanthin markedly reduced cell viability as early as 6 h after treatment. The cellular uptake of siphonaxanthin was 2-fold higher than fucoxanthin. It has been proposed that siphonaxanthin possesses significant anti-angiogenic activity in studies using human umbilical vein endothelial cells and rat aortic ring. The results of these studies suggested that the anti-angiogenic effect of siphonaxanthin is due to the down-regulation of signal transduction by fibroblast growth factor receptor-1 in vascular endothelial cells. Siphonaxanthin also exhibited inhibitory effects on antigen-induced degranulation of mast cells. These findings open up new avenues for future research on siphonaxanthin as a bioactive compound, and additional investigation, especially in vivo studies, are required to validate these findings. In addition, further studies are needed to determine its bioavailability and metabolic fate. PMID- 24950295 TI - Electricity generation and microbial community in microbial fuel cell using low pH distillery wastewater at different external resistances. AB - Single chamber MFC (SMFC) consisted of two separator-electrode assemblies (SEA) using low-pH distillery wastewater (DW) was operated under continuous mode. The electricity generation and microbial community were analyzed according to the external resistance (Rext; 0.1, 0.5, 1, and 5 kOmega). The two SEAs exhibited different electricity generations, despite sharing the same anodic chamber. The SMFC showed the largest maximum power density (PDmax) of 3.7 W/m(3) (SEA 1) and 12.9 W/m(3) (SEA 2) at 5 kOmega. These results demonstrated that low-pH wastewater could be sufficiently used as fuels for electricity generation. Pyrosequencing analysis showed that microbial communities at the phylum level were significantly different according to the Rext. The communities of SEA 1 were slightly different from those of SEA 2. In both SEAs, Firmicutes (>45%) were the most dominant at 0.1 kOmega, while Firmicutes (>34%) and Caldiserica (>34%) were dominant at 5 kOmega. Caldiserica sp. might significantly contribute to electricity generation under low-pH and high-Rext. PMID- 24950296 TI - Integrated continuous dissolution, refolding and tag removal of fusion proteins from inclusion bodies in a tubular reactor. AB - An integrated continuous tubular reactor system was developed for processing an autoprotease expressed as inclusion bodies. The inclusion bodies were suspended and fed into the tubular reactor system for continuous dissolving, refolding and precipitation. During refolding, the dissolved autoprotease cleaves itself, separating the fusion tag from the target peptide. Subsequently, the cleaved fusion tag and any uncleaved autoprotease were precipitated out in the precipitation step. The processed exiting solution results in the purified soluble target peptide. Refolding and precipitation yields performed in the tubular reactor were similar to batch reactor and process was stable for at least 20 h. The authenticity of purified peptide was also verified by mass spectroscopy. Productivity (in mg/l/h and mg/h) calculated in the tubular process was twice and 1.5 times of the batch process, respectively. Although it is more complex to setup a tubular than a batch reactor, it offers faster mixing, higher productivity and better integration to other bioprocessing steps. With increasing interest of integrated continuous biomanufacturing, the use of tubular reactors in industrial settings offers clear advantages. PMID- 24950297 TI - The impact of implementing a rapid response system: a comparison of cardiopulmonary arrests and mortality among four teaching hospitals in Australia. AB - AIMS: To compare clinical outcomes between a teaching hospital with a mature rapid response system (RRS), with three similar teaching hospitals without a RRS in Sydney, Australia. METHODS: For the period 2002-2009, we compared a teaching hospital with a mature RRS, with three similar teaching hospitals without a RRS. Two non-RRS hospitals began implementing the system in 2009 and a third in January 2010. We compared the rates of in-hospital cardiopulmonary arrest (IHCA), IHCA-related mortality, overall hospital mortality and 1-year post discharge mortality after IHCA between the RRS hospital and the non-RRS hospitals based on three separate analyses: (1) pooled analysis during 2002-2008; (2) before-after difference between 2008 and 2009; (3) after implementation in 2009. RESULTS: During the 2002-2008 period, the mature RRS hospital had a greater than 50% lower IHCA rate, a 40% lower IHCA-related mortality, and 6% lower overall hospital mortality. Compared to 2008, in their first year of RRS (2009) two hospitals achieved a 22% reduction in IHCA rate, a 22% reduction in IHCA-related mortality and an 11% reduction in overall hospital mortality. During the same time, the mature RRS hospital showed no significant change in those outcomes but, in 2009, it still achieved a crude 20% lower IHCA rate, and a 14% lower overall hospital mortality rate. There was no significant difference in 1-year post-discharge mortality for survivors of IHCA over the study period. CONCLUSIONS: Implementation of a RRS was associated with a significant reduction in IHCA, IHCA related mortality and overall hospital mortality. PMID- 24950298 TI - Head impact exposure in youth football: middle school ages 12-14 years. AB - The head impact exposure experienced by football players at the college and high school levels has been well documented; however, there are limited data regarding youth football despite its dramatically larger population. The objective of this study was to investigate head impact exposure in middle school football. Impacts were monitored using a commercially available accelerometer array installed inside the helmets of 17 players aged 12-14 years. A total of 4678 impacts were measured, with an average (+/-standard deviation) of 275 +/- 190 impacts per player. The average of impact distributions for each player had a median impact of 22 +/- 2 g and 954 +/- 122 rad/s2, and a 95th percentile impact of 54 +/- 9 g and 2525 +/- 450 rad/s2. Similar to the head impact exposure experienced by high school and collegiate players, these data show that middle school football players experience a greater number of head impacts during games than practices. There were no significant differences between median and 95th percentile head acceleration magnitudes experienced during games and practices; however, a larger number of impacts greater than 80 g occurred during games than during practices. Impacts to the front and back of the helmet were most common. Overall, these data are similar to high school and college data that have been collected using similar methods. These data have applications toward youth football helmet design, the development of strategies designed to limit head impact exposure, and child-specific brain injury criteria. PMID- 24950299 TI - Generation and characterization of an Nse-CreERT2 transgenic line suitable for inducible gene manipulation in cerebellar granule cells. AB - We created an Nse-CreERT2 mouse line expressing the tamoxifen-inducible CreERT2 recombinase under the control of the neuron-specific enolase (Nse) promoter. By using Cre reporter lines we could show that this Nse-CreERT2 line has recombination activity in the granule cells of all cerebellar lobules as well as in postmitotic granule cell precursors in the external granular layer of the developing cerebellum. A few hippocampal dentate gyrus granule cells showed Cre mediated recombination as well. Cre activity could be induced in both the developing and adult mouse brain. The established mouse line constitutes a valuable tool to study the function of genes expressed by cerebellar granule cells in the developing and adult brain. In combination with reporter lines it is a useful model to analyze the development and maintenance of the cerebellar architecture including granule cell distribution, migration, and the extension of granule cell fibers in vivo. PMID- 24950300 TI - Mapping glaucoma patients' 30-2 and 10-2 visual fields reveals clusters of test points damaged in the 10-2 grid that are not sampled in the sparse 30-2 grid. AB - PURPOSE: To cluster test points in glaucoma patients' 30-2 and 10-2 visual field (VF) (Humphrey Field Analyzer: HFA, Carl Zeiss Meditec, Dublin, CA) in order to map the different regions damaged by the disease. METHOD: This retrospective study included 128 eyes from 128 patients. 142 total deviation (TD) values (74 from the 30-2 VF and 68 from the 10-2 VF) were clustered using the 'Hierarchical Ordered Partitioning And Collapsing Hybrid-Partitioning Around Medoids' algorithm. The stability of the identified clusters was evaluated using bootstrapping. RESULTS: 65 sectors were identified in total: 38 sectors were located outside the 10-2 VF whereas 29 sectors were located inside the 10-2 VF (two sectors overlap in both grids). The mapping of many sectors appeared to follow the distribution of retinal nerve fiber bundles. The results of bootstrapping suggested clusters were stable whether they were outside or inside the 10-2 VF. CONCLUSION: A considerable number of sectors were identified in the 10-2 VF area, despite the fact that clustering was carried out on all points in both the 30-2 VF and 10-2 VF simultaneously. These findings suggest that glaucomatous central VF deterioration cannot be picked up by the 30-2 test grid alone, because of poor spatial sampling; denser estimation of the central ten degrees, than offered by the 30-2 test grid alone, is needed. It may be beneficial to develop a new VF test grid that combines test points from 30-2 and 10-2 VFs--the results of this study could help to devise this test grid. PMID- 24950302 TI - Can virtues enhance the benefits of expressive writing among healthy Chinese? A pilot study. AB - OBJECTIVE: This study aims to explore the relationship between virtues and self disclosure via a cross-sectional study and an intervention study among Chinese. METHODS: In study one, 144 healthy individuals completed the Chinese Virtues Questionnaire (CVQ) and the short version of Jourard Self-Disclosure Questionnaire. In study two, 41 undergraduates voluntarily attended a nine-week intervention. Satisfaction with Life Scale (SWLS) was adopted as the well-being indicator. They were asked to complete the vitality sub-scale of CVQ and SWLS at week one for obtaining the virtue scores and baseline scores of well-being. After an eight-week intervention, SWLS was completed again to examine the intervention efficacy. RESULTS: Among the three virtues, only vitality had the significant and positive relation with self-disclosure. After eight weeks, the high-vitality group obtained the significant growth of satisfaction with life. The change degree of satisfaction among high vitality individuals was significantly higher than the low vitality group. CONCLUSION: Prescreening of individual vitality may be helpful for identifying the sensitive targets of expressive writing intervention. However, considering that this is a preliminary study, more rigorous randomized controlled trials will be helpful to test this conclusion in future. PMID- 24950301 TI - Prostatic inflammation induces fibrosis in a mouse model of chronic bacterial infection. AB - Inflammation of the prostate is strongly correlated with development of lower urinary tract symptoms and several studies have implicated prostatic fibrosis in the pathogenesis of bladder outlet obstruction. It has been postulated that inflammation induces prostatic fibrosis but this relationship has never been tested. Here, we characterized the fibrotic response to inflammation in a mouse model of chronic bacterial-induced prostatic inflammation. Transurethral instillation of the uropathogenic E. coli into C3H/HeOuJ male mice induced persistent prostatic inflammation followed by a significant increase in collagen deposition and hydroxyproline content. This fibrotic response to inflammation was accompanied with an increase in collagen synthesis determined by the incorporation of 3H-hydroxyproline and mRNA expression of several collagen remodeling-associated genes, including Col1a1, Col1a2, Col3a1, Mmp2, Mmp9, and Lox. Correlation analysis revealed a positive correlation of inflammation severity with collagen deposition and immunohistochemical staining revealed that CD45+VIM+ fibrocytes were abundant in inflamed prostates at the time point coinciding with increased collagen synthesis. Furthermore, flow cytometric analysis demonstrated an increased percentage of these CD45+VIM+ fibrocytes among collagen type I expressing cells. These data show-for the first time-that chronic prostatic inflammation induces collagen deposition and implicates fibrocytes in the fibrotic process. PMID- 24950303 TI - Diagnostic significance of serum osteopontin level for pancreatic cancer: a meta analysis. AB - OBJECTIVE: This meta-analysis aimed to identify the significance of serum osteopontin (OPN) level for the diagnosis of pancreatic cancer (PC). METHODS: Through searching the following electronic databases-the Cochrane Library Database (Issue 12, 2013), Web of Science (1945-2013), PubMed (1966-2013), CINAHL (1982-2013), EMBASE (1980-2013), and the Chinese Biomedical Database (CBM) (1982 2013)-related articles were determined without any language restrictions. The STATA statistical software (version 12.0; Stata Corporation, College Station, TX) was chosen to deal with statistical data. Standard mean difference (SMD) and its corresponding 95% confidence interval (95% CI) was calculated. Eleven clinical case-control studies, which recruited 491 PC patients and 481 healthy controls, were selected for statistical analysis. RESULTS: Combined SMD of OPN suggested that the serum OPN level in PC patients was significantly higher than that in healthy controls (SMD=3.58, 95% CI=2.42-4.74, p<0.001). Ethnicity stratified analysis indicated a higher serum OPN level in PC patients compared with control subjects among both Caucasians and Asians (Caucasians: SMD=2.62, 95% CI=1.33 3.91, p<0.001; Asians: SMD=4.54, 95% CI=2.80-6.27, p<0.001; respectively). CONCLUSION: The main finding of our meta-analysis revealed that an elevated serum OPN level may be used as a promising diagnostic tool for early identification of PC. PMID- 24950304 TI - Disposable paper-based bipolar electrode for sensitive electrochemiluminescence detection of a cancer biomarker. AB - A disposable paper-based bipolar electrode (BPE) was reported for the first time for the sensitive electrochemiluminescence detection of a prostate specific antigen (PSA). PMID- 24950305 TI - Computational analysis of nitric oxide biotransport to red blood cell in the presence of free hemoglobin and NO donor. AB - Red blood cells (RBCs) modulate nitric oxide (NO) bioavailability in the vasculature. Extracellular free hemoglobin (Hb) in the vascular lumen can cause NO bioavailability related complications seen in pathological conditions such as pancreatitis, sickle cell disease and malaria. In addition, the role of extracellular free Hb has been critical to estimate kinetic and transport properties of NO-RBCs interactions in 'competition experiments'. We recently reported a strong dependence of NO transport on RBC membrane permeability and hematocrit. NO donors combined with anti-inflammatory drugs are an emergent treatment for diseases like cancer, cardiovascular complications and wound healing. However, the role of RBCs in transport NO from NO donors is not clearly understood. To understand the significance of extracellular free Hb in pathophysiology on NO availability and estimation of the NO-RBC interactions, we developed a computational model to simulate NO biotransport to the RBC in the presence of extracellular free Hb. Using this model, we studied the effect of hematocrit, RBC membrane permeability and NO donors on NO-RBC interactions in the presence and absence of extracellular free Hb. The plasma NO concentration gradients and average plasma NO concentrations changed minimally with increase in extracellular free Hb concentrations at the higher hematocrit as compared to those at the lower hematocrit irrespective of the NO delivery method, indicating that the presence of extracellular free Hb affects the NO transport only at a low hematocrit. We also observed that NO concentrations increased with NO donor concentrations in the absence as well as in the presence of extracellular free Hb. In addition, NO donor supplementation may increase NO availability in the plasma in the event of loss of endothelium-derived NO activity. PMID- 24950306 TI - Oxygen activation and CO oxidation over size-selected Pt(n)/alumina/Re(0001) model catalysts: correlations with valence electronic structure, physical structure, and binding sites. AB - Oxidation of CO over size-selected Ptn clusters (n = 1, 2, 4, 7, 10, 14, 18) supported on alumina thin films grown on Re(0001) was studied using temperature programmed reaction/desorption (TPR/TPD), X-ray and ultraviolet photoelectron spectroscopy (XPS/UPS), and low energy ion scattering spectroscopy (ISS). The activity of the model catalysts was found to vary by a factor of five with deposited Ptn size during the first reaction cycle (TPR) and by a factor of two during subsequent cycles, with Pt2 being the least active and Pt14 the most active. The limiting step in the reaction appears to be the binding of oxygen; however, this does not appear to be an activated process as reaction is equally efficient for 300 K and 180 K oxidation temperatures. Size-dependent shifts in the valence band onset energy correlate strongly with CO oxidation activity, and there is also an apparent correlation with the availability of a particular binding site, as probed by CO TPD. The morphology of the clusters also becomes more three dimensional over the same size range, but with a distinctly different size-dependence. The results suggest that both electronic structure and the availability of particular binding sites control activity. PMID- 24950307 TI - Deletion of Ptp4a3 reduces clonogenicity and tumor-initiation ability of colitis associated cancer cells in mice. AB - The PTP4A3 gene is highly expressed in human colon cancer and often associates with enhanced metastatic potential. Genetic disruption of the mouse Ptp4a3 gene reduces the frequency of colon tumor formation in mice treated in a colitis associated cancer model. In the current study, we have examined the role of Ptp4a3 in the tumor-initiating cell population of mouse colon tumors using an in vitro culture system. Tumors generated in vivo following AOM/DSS treatment were isolated, dissociated, and expanded on a feeder layer resulting in a CD133(+) cell population, which expressed high levels of Ptp4a3. Tumor cells deficient for Ptp4a3 exhibited reduced clonogenicity and growth potential relative to WT cells as determined by limiting dilution analysis. Importantly, expanded tumor cells from WT mice readily formed secondary tumors when transplanted into nude mice, while tumor cells without Ptp4a3 expression failed to form secondary tumors and thus were not tumorigenic. These results demonstrate that Ptp4a3 contributes to the malignant phenotype of tumor-initiating cells and supports its role as a potential therapeutic target to inhibit tumor self-renewal and metastasis. PMID- 24950309 TI - Extraction, antioxidant and antilisterial activities of polysaccharides from the flower of viper's bugloss. AB - The objective of the present research was to investigate the effect of microwave assisted extraction (MAE) conditions on the extraction yield, antioxidant properties and antilisterial activities of the polysaccharides from the flowers of viper's bugloss (Echium vulgare L.). The four extraction variables, time (40 100min), microwave power (200-800W), temperature (30-70 degrees C), and the ratio of water to raw material (10-70), were optimized using response surface methodology. The experimental data were matched to a second-order polynomial equation. The optimal conditions for MAE of polysaccharides (EVFP) were time 73.8min, microwave power 769.2W, temperature 42.3 degrees C and the ratio of water to raw material 61.4, where the actual yield of EVFP 25.11+/-0.87% was obtained (versus the value predicted by the model 25.36%). The results indicated that EVFP has significant radical (.OH and .DPPH) scavenging abilities in vitro assay. Moreover, the antilisterial activity was confirmed against four species of Listeria. EVFP, at a concentration of 5mg/mL, demonstrated great antilisterial properties against Listeria ivanovii and Listeria monocytogenes, with inhibition zones of 10.76+/-0.32mm and 8.64+/-0.47mm, respectively. PMID- 24950308 TI - Adsorption property of Rhodamine 6G onto chitosan-g-(N-vinyl pyrrolidone)/montmorillonite composite. AB - A series of chitosan-g-(N-vinyl pyrrolidone)/montmorillonite hydrogel composites were synthesized by in situ intercalative polymerization. The properties of the composites were investigated by FTIR, XRD, scanning electron microscopy and differential scanning calorimetry. The morphologies of the hydrogel composites were sponge like with a homogeneous structure. The effects of clay on the swelling, morphology, glass transition (Tg), and water structure were studied. The swelling of the hydrogel composites formed was found to be affected by the pH of the medium and the electrolyte. Maximum swelling was observed in the hydrogel containing low percentage of clay (H-0.2) and was used to investigate the adsorption of a water soluble cationic dye Rhodamine 6G (Rh6G). The results show that the adsorption capacity for the dye increased with increase in dose, contact time but there was no change observed with respect to increase in temperature. The adsorption kinetics of Rh6G followed Pseudo second order model and the equilibrium data was found to fit Freundlich model. PMID- 24950311 TI - Effect of the organic loading rate on the production of polyhydroxyalkanoates in a multi-stage process aimed at the valorization of olive oil mill wastewater. AB - Mixed microbial culture polyhydroxyalkanoates (PHA) production has been investigated by using olive oil mill wastewater (OMW) as no-cost feedstock in a multi-stage process, also involving phenols removal and recovery. The selection of PHA-storing microorganisms occurred in a sequencing batch reactor (SBR), fed with dephenolized and fermented OMW and operated at different organic loading rates (OLR), ranging from 2.40 to 8.40gCOD/Ld. The optimal operating condition was observed at an OLR of 4.70gCOD/Ld, which showed the highest values of storage rate and yield (339+/-48mgCOD/gCODh and 0.56+/-0.05 COD/COD, respectively). The OLR applied to the SBR largely affected the performance of the PHA-accumulating reactor, which was fed through multiple pulsed additions of pretreated OMW. From an overall mass balance, involving all the stages of the process, an abatement of about 85% of the OMW initial COD (chemical oxygen demand) was estimated whereas the conversion of the influent COD into PHA was about 10% (or 22% by taking into account only the COD contained in the pretreated OMW, which is directly fed to the PHA production stages). Overall, polymer volumetric productivity (calculated from the combination of both the SBR and the accumulation reactor) accounted for 1.50gPHA/Ld. PMID- 24950310 TI - Chitosan cross-linked docetaxel loaded EGF receptor targeted nanoparticles for lung cancer cells. AB - Lung cancer, associated with the up-regulated epidermal growth factor receptor (EGFR) led to the development of EGFR targeted anticancer therapeutics. The biopolymeric nanoparticles form an outstanding system for the targeted delivery of therapeutic agents. The present work evaluated the in vitro effects of chitosan cross-linked gamma-poly(glutamic acid) (gamma-PGA) nanoparticles (Nps) loaded with docetaxel (DTXL) and decorated with Cetuximab (CET), targeted to EGFR over-expressing non-small-cell-lung-cancer (NSCLC) cells (A549). CET-DTXL-gamma PGA Nps was prepared by ionic gelation and CET conjugation via EDC/NHS chemistry. EGFR specificity of targeted Nps was confirmed by the higher uptake rates of EGFR +ve A549 cells compared to that of EGFR -ve cells (NIH3T3). The cytotoxicity of Nps quantified using cell based (MTT/LDH) and flowcytometry (Cell-cycle analysis, Annexin V/PI and JC-1) assays showed superior antiproliferative activity of CET DTXL-gamma-PGA Nps over DTXL-gamma-PGA Nps. The A549 cells treated with CET-DTXL gamma-PGA NPs underwent a G2/M phase cell cycle arrest followed by reduction in mitochondrial membrane potential of A549 cells, inducing apoptosis and necrosis resulting in enhanced cancer cell death. CET-DTXL-gamma-PGA Nps exhibited enhanced cellular internalization and therapeutic activity, by actively targeting EGFR on NSCLC cells and hence could be an effective alternative to non-specific, conventional chemotherapy by increasing its efficiency by many folds. PMID- 24950312 TI - In vitro and in vivo evaluation of novel interpenetrated polymer network microparticles containing repaglinide. AB - Interpenetrated polymer network (IPN) microparticles of sterculia gum and sodium alginate loaded with repaglinide were developed by ionic gelation and emulsion crosslinking method. The drug entrapment efficiency was as high as 91%. FTIR and TG analyses confirmed the crosslinking and IPN formation. Microparticles have demonstrated the drug release up to 24h depending upon type of crosslinking agents; the glutaraldehyde treatment of ionically crosslinked microparticles has resulted in decreased drug release rate. The in-vivo anti-diabetic activity performed on streptozotocin induced diabetic rats indicated that the pristine repaglinide has shown maximum percentage reduction of elevated blood glucose within 3h and then the percentage reduction in blood glucose was decreased. In the case of rats treated with KA8 IPN microparticles, percentage reduction of elevated glucose was slow as compared to pristine drug within 3h, but it was gradually increased to 81.27% up to 24h. PMID- 24950313 TI - Chitin extraction from shrimp shell using enzymatic treatment. Antitumor, antioxidant and antimicrobial activities of chitosan. AB - Chitin was recovered through enzymatic deproteinization of the shrimp processing by-products. Different microbial and fish viscera proteases were tested for their deproteinization efficiency. High levels of protein removal of about 77+/-3% and 78+/-2% were recorded using Bacillus mojavensis A21 and Balistes capriscus proteases, respectively, after 3h of hydrolysis at 45 degrees C using an enzyme/substrate ratio of 20U/mg. Therefore, these two crude proteases were used separately for chitin extraction and then chitosan preparation by N deacetylation. Chitin and chitosan samples were then characterized by 13 Cross polarization magic angle spinning nuclear magnetic resonance (CP/MAS)-NMR spectroscopy and compared to samples prepared through chemical deproteinization. All chitins and chitosans showed identical spectra. Chitosans prepared through enzymatic deproteinization have practically the same acetylation degree but higher molecular weights compared to that obtained through chemical process. Antimicobial, antioxidant and antitumoral activitities of chitosan-M obtained by treatment with A21 proteases and chitosan-C obtained by alkaline treatment were investigated. Results showed that both chitosans inhibited the growth of most Gram-negative, Gram-positive bacteria and fungi tested. Furthermore, both chitosans exhibited antioxidant and antitumor activities which was dependent on the molecular weight. PMID- 24950315 TI - The write stuff. PMID- 24950314 TI - Chiral encoding may provide a simple solution to the origin of life. AB - The route by which the complex and specific molecules of life arose from the 'prebiotic soup' remains an unsolved problem. Evolution provides a large part of the answer, but this requires molecules that can carry information (that is, exist in many variants) and can replicate themselves. The process is commonplace in living organisms, but not so easy to achieve with simple chemical systems. It is especially difficult to contemplate in the chemical chaos of the prebiotic world. Although popular in many quarters, the notion that RNA was the first self replicator carries many difficulties. Here, we present an alternative view, suggesting that there may be undiscovered self-replication mechanisms possible in much simpler systems. In particular, we highlight the possibility of information coding through stereochemical configurations of substituents in organic polymers. We also show that this coding system leads naturally to enantiopurity, solving the apparent problem of biological homochirality. PMID- 24950321 TI - Ligand discovery: Docking points. PMID- 24950322 TI - C-C bond formation: Rethinking cross-coupling. PMID- 24950323 TI - Bioelectronics: A positive future for squid proteins. PMID- 24950324 TI - Covalent organic frameworks: Crossing the channel. PMID- 24950325 TI - Virus engineering: Fighting HIV at its own game. PMID- 24950327 TI - Enantiospecific sp(2)-sp(3) coupling of secondary and tertiary boronic esters. AB - The cross-coupling of boronic acids and related derivatives with sp(2) electrophiles (the Suzuki-Miyaura reaction) is one of the most powerful C-C bond formation reactions in synthesis, with applications that span pharmaceuticals, agrochemicals and high-tech materials. Despite the breadth of its utility, the scope of this Nobel prize-winning reaction is rather limited when applied to aliphatic boronic esters. Primary organoboron reagents work well, but secondary and tertiary boronic esters do not (apart from a few specific and isolated examples). Through an alternative strategy, which does not involve using transition metals, we have discovered that enantioenriched secondary and tertiary boronic esters can be coupled to electron-rich aromatics with essentially complete enantiospecificity. As the enantioenriched boronic esters are easily accessible, this reaction should find considerable application, particularly in the pharmaceutical industry where there is growing awareness of the importance of, and greater clinical success in, creating biomolecules with three-dimensional architectures. PMID- 24950326 TI - Incorporation of protein flexibility and conformational energy penalties in docking screens to improve ligand discovery. AB - Proteins fluctuate between alternative conformations, which presents a challenge for ligand discovery because such flexibility is difficult to treat computationally owing to problems with conformational sampling and energy weighting. Here we describe a flexible docking method that samples and weights protein conformations using experimentally derived conformations as a guide. The crystallographically refined occupancies of these conformations, which are observable in an apo receptor structure, define energy penalties for docking. In a large prospective library screen, we identified new ligands that target specific receptor conformations of a cavity in cytochrome c peroxidase, and we confirm both ligand pose and associated receptor conformation predictions by crystallography. The inclusion of receptor flexibility led to ligands with new chemotypes and physical properties. By exploiting experimental measures of loop and side-chain flexibility, this method can be extended to the discovery of new ligands for hundreds of targets in the Protein Data Bank for which similar experimental information is available. PMID- 24950328 TI - Oxidation of ethane to ethanol by N2O in a metal-organic framework with coordinatively unsaturated iron(II) sites. AB - Enzymatic haem and non-haem high-valent iron-oxo species are known to activate strong C-H bonds, yet duplicating this reactivity in a synthetic system remains a formidable challenge. Although instability of the terminal iron-oxo moiety is perhaps the foremost obstacle, steric and electronic factors also limit the activity of previously reported mononuclear iron(IV)-oxo compounds. In particular, although nature's non-haem iron(IV)-oxo compounds possess high-spin S = 2 ground states, this electronic configuration has proved difficult to achieve in a molecular species. These challenges may be mitigated within metal-organic frameworks that feature site-isolated iron centres in a constrained, weak-field ligand environment. Here, we show that the metal-organic framework Fe2(dobdc) (dobdc(4-) = 2,5-dioxido-1,4-benzenedicarboxylate) and its magnesium-diluted analogue, Fe0.1Mg1.9(dobdc), are able to activate the C-H bonds of ethane and convert it into ethanol and acetaldehyde using nitrous oxide as the terminal oxidant. Electronic structure calculations indicate that the active oxidant is likely to be a high-spin S = 2 iron(IV)-oxo species. PMID- 24950329 TI - Bulk protonic conductivity in a cephalopod structural protein. AB - Proton-conducting materials play a central role in many renewable energy and bioelectronics technologies, including fuel cells, batteries and sensors. Thus, much research effort has been expended to develop improved proton-conducting materials, such as ceramic oxides, solid acids, polymers and metal-organic frameworks. Within this context, bulk proton conductors from naturally occurring proteins have received somewhat less attention than other materials, which is surprising given the potential modularity, tunability and processability of protein-based materials. Here, we report proton conductivity for thin films composed of reflectin, a cephalopod structural protein. Bulk reflectin has a proton conductivity of ~2.6 * 10(-3) S cm(-1) at 65 degrees C, a proton transport activation energy of ~0.2 eV and a proton mobility of ~7 * 10(-3) cm(2) V(-1) s(-1). These figures of merit are similar to those reported for state-of the-art artificial proton conductors and make it possible to use reflectin in protein-based protonic transistors. Our findings may hold implications for the next generation of biocompatible proton-conducting materials and protonic devices. PMID- 24950330 TI - Single-molecule analysis of chirality in a multicomponent reaction network. AB - Single-molecule approaches to chemical reaction analysis can provide information that is not accessible by studying ensemble systems. Changes in the molecular structures of compounds tethered to the inner wall of a protein pore are known to affect the current carried through the pore by aqueous ions under a fixed applied potential. Here, we use this approach to study the substitution reactions of arsenic(III) compounds with thiols, stretching the limits of the protein pore technology to track the interconversion of seven reaction components in a network that comprises interconnected Walden cycles. Single-molecule pathway analysis of 'allowed' and 'forbidden' reactions reveals that sulfur-sulfur substitution occurs with stereochemical inversion at the arsenic centre. Hence, we demonstrate that the nanoreactor approach can be a valuable technique for the analysis of dynamic reaction systems of relevance to biology. PMID- 24950331 TI - Design and synthesis of the first triply twisted Mobius annulene. AB - As long as 50 years ago theoretical calculations predicted that Mobius annulenes with only one pi surface and one edge would exhibit peculiar electronic properties and violate the Huckel rules. Numerous synthetic attempts notwithstanding, the first singly twisted Mobius annulene was not prepared until 2003. Here we present a general, rational strategy to synthesize triply or even more highly twisted cyclic pi systems. We apply this strategy to the preparation of a triply twisted [24]dehydroannulene, the structure of which was confirmed by X-ray analysis. Our strategy is based on the topological transformation of 'twist' into 'writhe'. The advantage is twofold: the product exhibits a lower degree of strain and precursors can be designed that inherently include the writhe, which, after cyclization, ends up in the Mobius product. With our strategy, triply twisted systems are easier to prepare than their singly twisted counterparts. PMID- 24950332 TI - Imaging the intracellular distribution of tyrosine kinase inhibitors in living cells with quantitative hyperspectral stimulated Raman scattering. AB - ABL1 tyrosine-kinase inhibitors (TKI) are front-line therapy for chronic myelogenous leukaemia and are among the best-known examples of targeted cancer therapeutics. However, the dynamic uptake into cells of TKIs of low molecular weight and their intracellular behaviour is unknown because of the difficulty of observing non-fluorescent small molecules at subcellular resolution. Here we report the direct label-free visualization and quantification of two TKI drugs (imatinib and nilotinib) inside living cells using hyperspectral stimulated Raman scattering imaging. Concentrations of both drugs were enriched over 1,000-fold in lysosomes as a result of their lysosomotropic properties. In addition, low solubility appeared to contribute significantly to the surprisingly large accumulation of nilotinib. We further show that the lysosomal trapping of imatinib was reduced more than tenfold when chloroquine is used simultaneously, which suggests that chloroquine may increase the efficacy of TKIs through lysosome-mediated drug-drug interaction in addition to the commonly proposed autophagy-inhibition mechanism. PMID- 24950333 TI - Mechanically triggered heterolytic unzipping of a low-ceiling-temperature polymer. AB - Biological systems rely on recyclable materials resources such as amino acids, carbohydrates and nucleic acids. When biomaterials are damaged as a result of aging or stress, tissues undergo repair by a depolymerization-repolymerization sequence of remodelling. Integration of this concept into synthetic materials systems may lead to devices with extended lifetimes. Here, we show that a metastable polymer, end-capped poly(o-phthalaldehyde), undergoes mechanically initiated depolymerization to revert the material to monomers. Trapping experiments and steered molecular dynamics simulations are consistent with a heterolytic scission mechanism. The obtained monomer was repolymerized by a chemical initiator, effectively completing a depolymerization-repolymerization cycle. By emulating remodelling of biomaterials, this model system suggests the possibility of smart materials where aging or mechanical damage triggers depolymerization, and orthogonal conditions regenerate the polymer when and where necessary. PMID- 24950334 TI - Genetically encoded reporters for hyperpolarized xenon magnetic resonance imaging. AB - Magnetic resonance imaging (MRI) enables high-resolution non-invasive observation of the anatomy and function of intact organisms. However, previous MRI reporters of key biological processes tied to gene expression have been limited by the inherently low molecular sensitivity of conventional (1)H MRI. This limitation could be overcome through the use of hyperpolarized nuclei, such as in the noble gas xenon, but previous reporters acting on such nuclei have been synthetic. Here, we introduce the first genetically encoded reporters for hyperpolarized (129)Xe MRI. These expressible reporters are based on gas vesicles (GVs), gas binding protein nanostructures expressed by certain buoyant microorganisms. We show that GVs are capable of chemical exchange saturation transfer interactions with xenon, which enables chemically amplified GV detection at picomolar concentrations (a 100- to 10,000-fold improvement over comparable constructs for (1)H MRI). We demonstrate the use of GVs as heterologously expressed indicators of gene expression and chemically targeted exogenous labels in MRI experiments performed on living cells. PMID- 24950336 TI - Reactions of xenon with iron and nickel are predicted in the Earth's inner core. AB - Studies of the Earth's atmosphere have shown that more than 90% of the expected amount of Xe is depleted, a finding often referred to as the 'missing Xe paradox'. Although several models for a Xe reservoir have been proposed, whether the missing Xe could be contained in the Earth's inner core has not yet been answered. The key to addressing this issue lies in the reactivity of Xe with Fe/Ni, the main constituents of the Earth's core. Here, we predict, through first principles calculations and unbiased structure searching techniques, a chemical reaction of Xe with Fe/Ni at the temperatures and pressures found in the Earth's core. We find that, under these conditions, Xe and Fe/Ni can form intermetallic compounds, of which XeFe3 and XeNi3 are energetically the most stable. This shows that the Earth's inner core is a natural reservoir for Xe storage and provides a solution to the missing Xe paradox. PMID- 24950335 TI - Development of a minimal saponin vaccine adjuvant based on QS-21. AB - Adjuvants are materials added to vaccines to enhance the immunological response to an antigen. QS-21 is a natural product adjuvant under investigation in numerous vaccine clinical trials, but its use is constrained by scarcity, toxicity, instability and an enigmatic molecular mechanism of action. Herein we describe the development of a minimal QS-21 analogue that decouples adjuvant activity from toxicity and provides a powerful platform for mechanistic investigations. We found that the entire branched trisaccharide domain of QS-21 is dispensable for adjuvant activity and that the C4-aldehyde substituent, previously proposed to bind covalently to an unknown cellular target, is also not required. Biodistribution studies revealed that active adjuvants were retained preferentially at the injection site and the nearest draining lymph nodes compared with the attenuated variants. Overall, these studies have yielded critical insights into saponin structure-function relationships, provided practical synthetic access to non-toxic adjuvants, and established a platform for detailed mechanistic studies. PMID- 24950342 TI - Nobelium non-believers. PMID- 24950344 TI - A microfluidic system for studying ageing and dynamic single-cell responses in budding yeast. AB - Recognition of the importance of cell-to-cell variability in cellular decision making and a growing interest in stochastic modeling of cellular processes has led to an increased demand for high density, reproducible, single-cell measurements in time-varying surroundings. We present ALCATRAS (A Long-term Culturing And TRApping System), a microfluidic device that can quantitatively monitor up to 1000 cells of budding yeast in a well-defined and controlled environment. Daughter cells are removed by fluid flow to avoid crowding allowing experiments to run for over 60 hours, and the extracellular media may be changed repeatedly and in seconds. We illustrate use of the device by measuring ageing through replicative life span curves, following the dynamics of the cell cycle, and examining history-dependent behaviour in the general stress response. PMID- 24950346 TI - Unambiguous Assignment of Reduction Potentials in Diheme Cytochromes. AB - Perturbed matrix method calculations are performed on a diheme cytochrome c (DHC) protein, in order to assign previously experimentally detemined reduction potentials (E0) to their corresponding heme groups. Very good agreement between calculated values to experimental data prove that the present approach can be used as a predictive tool of redox thermodynamic properties of multicenter redox proteins in the absence of experimental data, or in synergy with state-of-the art spectroscopic and electrochemical approaches to obtain a detailed picture of electron transfer processes within these complex systems. PMID- 24950345 TI - The walking environment in Lima, Peru and pedestrian-motor vehicle collisions: an exploratory analysis. AB - OBJECTIVE: Pedestrians comprise 78% of the road fatalities in Peru. The objective of this study was to explore the relationship between the walking environment and pedestrian-motor vehicle collisions. METHODS: A matched case-control study was used to detect the odds of a pedestrian-motor vehicle collision at a pedestrian crossing location. Data were collected from 11 sampled police commissaries in Lima, Peru. RESULTS: In a multivariable model adjusting for vehicle and pedestrian flow, pedestrian collisions were less likely in the presence of a curb and sidewalk on both roadway sides (odds ratio [OR] = 0.19, 95% confidence interval [CI], 0.11-0.33) or a pedestrian barricade (OR = 0.11, 95% CI, 0.01 0.81). There was a greater risk of collisions for each street vendor present (OR = 2.82, 95% CI, 1.59-5.00) or whether any parked vehicles (OR = 3.67, 95% CI, 1.18-11.4) were present. CONCLUSIONS: Improving or addressing these potentially modifiable features of the walking environment could improve pedestrian safety in Lima and in similar urban settings in low- and middle-income countries. PMID- 24950343 TI - Extracellularly activatable nanocarriers for drug delivery to tumors. AB - INTRODUCTION: Nanoparticles (NPs) for drug delivery to tumors need to satisfy two seemingly conflicting requirements: they should maintain physical and chemical stability during circulation and be able to interact with target cells and release the drug at desired locations with no substantial delay. The unique microenvironment of tumors and externally applied stimuli provide a useful means to maintain a balance between the two requirements. AREAS COVERED: We discuss nanoparticulate drug carriers that maintain stable structures in normal conditions but respond to stimuli for the spatiotemporal control of drug delivery. We first define the desired effects of extracellular activation of NPs and frequently used stimuli and then review the examples of extracellularly activated NPs. EXPERT OPINION: Several challenges remain in developing extracellularly activatable NPs. First, some of the stimuli-responsive NPs undergo incremental changes in response to stimuli, losing circulation stability. Second, the applicability of stimuli in clinical settings is limited due to the occasional occurrence of the activating conditions in normal tissues. Third, the construction of stimuli-responsive NPs involves increasing complexity in NP structure and production methods. Future efforts are needed to identify new targeting conditions and increase the contrast between activated and nonactivated NPs while keeping the production methods simple and scalable. PMID- 24950347 TI - Surviving out-of-hospital cardiac arrest: just a matter of defibrillators? AB - Out-of-hospital sudden cardiac arrest (OHCA) is a leading cause of death all over the world. Although the outcome of OHCA resulting from 'nonshockable' rhythms (asystole and pulseless electrical activity) is poor regardless of resuscitation efforts, 'shockable' rhythms such as ventricular tachycardia or fibrillation may carry a good prognosis if early defibrillation is performed. At present, simplified cardiopulmonary resuscitation techniques (hands-only cardiopulmonary resuscitation) and automated external defibrillators (AEDs) offer lay people the possibility to provide lifesaving treatment to OHCA victims in the critical minutes before the arrival of the emergency medical system. Programs aimed at increasing provision of cardiopulmonary resuscitation and use of AEDs by lay people have been set up in different countries, including Italy, and have contributed to improve survival rates. However, success of these programs critically depends on appropriate planning and design, and on cultural predisposition of witnesses to undertake immediate measures of resuscitation in the case of OHCA. Placement of a large number of AEDs may carry high costs and little benefits if it is uncoordinated and not preceded by educational campaigns to spread widely the 'culture of resuscitation' in the population. PMID- 24950348 TI - Does temporal preparation facilitate visual processing in a selective manner? Evidence from attentional capture. AB - The present study addressed the question of whether temporal preparation influences perceptual stimulus processing in a selective manner. In three visual search experiments, we examined whether temporal preparation aids spatial selection and thus reduces distraction caused by the onset of a task-irrelevant item. In each trial, participants had to detect a target amongst five non-targets and report a basic feature of the target. In some trials, an additional task irrelevant singleton item (abrupt onset) appeared on the screen which distracted attention away from the target. To manipulate the degree of distraction, we varied the spatial distance and the stimulus-onset asynchrony between target and singleton. Temporal preparation for the target varied by means of constant foreperiods of different lengths. Though we observed overall faster responding in the case of high temporal preparation in all three experiments, temporal preparation did not reduce spatial distraction by the abrupt onset, even when the spatial position of the target was predictable. In sum, this pattern of results does not provide support for an influence of temporal preparation on spatial selection. Instead, it indicates that temporal preparation affects early visual processing in a non-selective manner. PMID- 24950349 TI - An innovative cycling exergame to promote cardiovascular fitness in youth with cerebral palsy. AB - OBJECTIVE: To evaluate the effects of an internet-platform exergame cycling programme on cardiovascular fitness of youth with cerebral palsy (CP). METHODS: In this pilot prospective case series, eight youth with bilateral spastic CP, Gross Motor Functional Classification System (GMFCS) level III, completed a six week exergame programme. Outcomes were obtained at baseline and post intervention. The primary outcome measure was the GMFCS III-specific shuttle run test (SRT-III). Secondary outcomes included health-related quality of life (HQL) as measured by the KIDSCREEN-52 questionnaire, six-minute walk test, Wingate arm cranking test and anthropomorphic measurements. RESULTS: There were significant improvements in the SRT-III (t = -2.5, p = 0.04, d = 0.88) post-intervention. There were no significant changes in secondary outcomes. CONCLUSION: An exergame cycling programme may lead to improvement in cardiovascular fitness in youth with CP. This study was limited by small sample size and lack of a comparison group. Future research is warranted. PMID- 24950350 TI - 3D FEM comparison of lingual and labial orthodontics in en masse retraction. AB - BACKGROUND: The aim of this study was to compare displacements and stress after en masse retraction of mandibular dentition with lingual and labial orthodontics using three-dimensional (3D) finite element models (FEM). METHODS: A 3D FEM of each lower tooth was constructed and located as appropriate to Roth's prescription. The 0.018-in. GAC Roth Ovation labial and Ormco 7th Generation lingual brackets were virtually bonded to the lower teeth and threaded with 0.018 * 0.025- and 0.016 * 0.022-in. SS labial (Tru-Arch form, small size) and lingual (mushroom) archwires. En masse retraction was simulated by applying 300 g of distal force from the canine to the second premolar on the 0.016 * 0.022-in. SS labial and lingual archwires. The type of finite element used in the analysis was an eight-noded brick element. The Algor program (Algor Inc., Pittsburgh, PA, USA) was used to calculate the strains and displacements at each nodal point. RESULTS: Lingual tipping and extrusion of the anterior dentition occurred with both archwires. At the premolars and first molars, intrusion, lingual movements, and lingual tipping were seen with the labial archwire, while intrusion was accompanied by labial movements, mesial tipping, and buccal rotation with lingual mechanics. CONCLUSIONS: Lingual vs. labial bracket placement influences the pattern of tooth movement, but the stress that occurs around the teeth can be accurately mapped using a 3D FEM model. PMID- 24950352 TI - Five year follow-up after a first booster vaccination against tick-borne encephalitis following different primary vaccination schedules demonstrates long term antibody persistence and safety. AB - Long-term vaccination programs are recommended for individuals living in regions endemic for tick-borne encephalitis (TBE). Current recommendations suggest a first booster vaccine be administered 3 years after a conventional regimen or 12 18 months after a rapid regimen. However, the research supporting subsequent booster intervals is limited. The aim of this study was thus to evaluate the long term persistence of TBE antibodies in adults and adolescents after a first booster dose with Encepur((r)). A total of 323 subjects aged 15 years and over, who had received one of four different primary TBE vaccination series in a parent study, participated in this follow-up Phase IV trial. Immunogenicity and safety were assessed for up to five years after a first booster dose, which was administered three years after completion of the primary series. One subset of subjects was excluded from the booster vaccination since they had already received their booster prior to enrollment. For comparison, immune responses were still recorded for these subjects on Day 0 and on an annual basis until Year 5, but safety information was not collected. Following a booster vaccination, high antibody titers were recorded in all groups throughout the study. Neutralization test (NT) titers of >= 10 were noted in at least 94% of subjects at every time point post-booster (on Day 21 and through Years 1-5). These results demonstrated that a first booster vaccination following any primary immunization schedule results in high and long-lasting (>5 years) immune responses. These data lend support to the current belief that subsequent TBE booster intervals could be extended from the current recommendation. NCT00387634. PMID- 24950351 TI - Haloarchaeal gas vesicle nanoparticles displaying Salmonella SopB antigen reduce bacterial burden when administered with live attenuated bacteria. AB - Innovative vaccines against typhoid and other Salmonella diseases that are safe, effective, and inexpensive are urgently needed. In order to address this need, buoyant, self-adjuvating gas vesicle nanoparticles (GVNPs) from the halophilic archaeon Halobacterium sp. NRC-1 were bioengineered to display the highly conserved Salmonella enterica antigen SopB, a secreted inosine phosphate effector protein injected by pathogenic bacteria during infection into the host cell. Two highly conserved sopB gene segments near the 3'-coding region, named sopB4 and B5, were each fused to the gvpC gene, and resulting GVNPs were purified by centrifugally accelerated flotation. Display of SopB4 and B5 antigenic epitopes on GVNPs was established by Western blotting analysis using antisera raised against short synthetic peptides of SopB. Immunostimulatory activities of the SopB4 and B5 nanoparticles were tested by intraperitoneal administration of recombinant GVNPs to BALB/c mice which had been immunized with S. enterica serovar Typhimurium 14028 DeltapmrG-HM-D (DV-STM-07), a live attenuated vaccine strain. Proinflammatory cytokines IFN-gamma, IL-2, and IL-9 were significantly induced in mice boosted with SopB5-GVNPs, consistent with a robust Th1 response. After challenge with virulent S. enterica serovar Typhimurium 14028, bacterial burden was found to be diminished in spleen of mice boosted with SopB4-GVNPs and absent or significantly diminished in liver, mesenteric lymph node, and spleen of mice boosted with SopB5-GVNPs, indicating that the C-terminal portions of SopB displayed on GVNPs elicit a protective response to Salmonella infection in mice. SopB antigen-GVNPs were found to be stable at elevated temperatures for extended periods without refrigeration in Halobacterium cells. The results all together show that bioengineered GVNPs are likely to represent a valuable platform for the development of improved vaccines against Salmonella diseases. PMID- 24950353 TI - Evaluation of immunogenicity and protective efficacy of a plasmid DNA vaccine encoding ribosomal protein L9 of Brucella abortus in BALB/c mice. AB - Brucellosis is a worldwide zoonotic disease. No Brucella vaccine is available for use in humans and existing animal vaccines have limitations. We have previously described the ribosomal protein L9 to have the vaccine potential. In this study, L9 based DNA vaccine (pVaxL9) was generated and evaluated in mouse model. Intramuscular immunisation of pVaxL9 was able to elicit the anti-L9 IgG antibody response of both IgG1 and IgG2a isotypes when compared with PBS and pVax immunised control animals. Heightened antibody response was observed in mice groups immunised with pVaxL9 priming and recombinant L9 boosting (PB) and where pDNA immunisation was carried out by in vivo electroporation (EP). The vaccine groups proliferated splenocytes and released Th1 type cytokines e.g. IFN-gamma, TNF-alpha, IL-2. Further, flow cytometric analysis revealed that IFN-gamma was released by both by CD4+ and CD8+ T cells particularly in PB and EP groups when compared with mice immunised with empty control vector. The L9 based pDNA vaccine was able to confer significant protection in mice against challenge with virulent B. abortus with PB and EP groups offering better protection. Taken together, it can be concluded that L9 based DNA vaccine is immunogenic and confer protection in mouse model. PMID- 24950354 TI - A rationally designed form of the TLR5 agonist, flagellin, supports superior immunogenicity of Influenza B globular head vaccines. AB - Previously, we demonstrated that for H1N1 and H5N1 influenza strains, the globular head of the hemagglutinin (HA) antigen fused to flagellin of Salmonella typhimurium fljB (STF2) is highly immunogenic in preclinical models and man (Song et al. (2008) [13]; Song et al. (2009) [14]; Taylor et al. (2012) [12]). Further we showed that the vaccine format, or point of attachment of the vaccine antigen to flagellin, can dramatically affect the immunogenicity and safety profile of the vaccine. However, Influenza B vaccines based on these formats are poor triggers of TLR5 and consequently are poorly immunogenic. Through rational design, here we show that we have identified a fusion position within domain 3 of flagellin that improves TLR5 signaling and consequently, immunogenicity of multiple influenza B vaccines. Our results demonstrate that, similar to influenza A strains, the protective subunit of the influenza B HA can be fused to flagellin and produced in a standard prokaryotic expression system thereby allowing for cost and time efficient production of multivalent seasonal influenza vaccines. PMID- 24950356 TI - TRANSVAC workshop on standardisation and harmonisation of analytical platforms for HIV, TB and malaria vaccines: 'how can big data help?'. AB - High-throughput analyses of RNA and protein expression are increasingly used for better understanding of vaccine-induced immunity and protection against infectious disease. With an increasing number of vaccine candidates in clinical development, it is timely to consider standardisation and harmonisation of sample collection, storage and analysis to ensure results of highest quality from these precious samples. These challenges were discussed by a group of international experts during a workshop organised by TRANSVAC, a European Commission-funded Research Infrastructure project. The main conclusions were: Platforms are rarely standardised for use in preclinical and clinical studies. Coordinated efforts should continue to harmonise the experimental set up of these studies, as well as the establishment of internal standards and controls. This will ensure comparability, efficiency and feasibility of the global analyses performed on preclinical and clinical data sets. PMID- 24950355 TI - A single dose of whole inactivated H7N9 influenza vaccine confers protection from severe disease but not infection in ferrets. AB - The H7N9 influenza virus caused significant mortality and morbidity in infected humans during an outbreak in China in 2013 stimulating vaccine development efforts. As previous H7-based vaccines have been poorly immunogenic in humans we sought to determine the immunogenic and protective properties of an inactivated whole virus vaccine derived from a 2013 H7N9 virus in ferrets. As whole virus vaccine preparations have been shown to be more immunogenic in humans, but less likely to be used, than split or surface antigen formulations, we vaccinated ferrets with a single dose of 15, 30, or 50 MUg of the vaccine and subsequently challenged with wild-type A/Anhui/1/2013 (H7N9) either by direct instillation or by contact with infected animals. Although ferrets vaccinated with higher doses of vaccine had higher serum hemagglutinin inhibition (HI) titers, the titers were still low. During subsequent instillation challenge, however, ferrets vaccinated with 50 MUg of vaccine showed no illness and shed significantly less virus than mock vaccinated controls. All vaccinated ferrets had lower virus loads in their lungs as compared to controls. In a separate study where unvaccinated-infected ferrets were placed in the same cage with vaccinated-uninfected ferrets, vaccination did not prevent infection in the contact ferrets, although they showed a trend of lower viral load. Overall, we conclude that inactivated whole virus H7N9 vaccine was able to reduce the severity of infection and viral load, despite the lack of hemagglutinin-inhibiting antibodies. PMID- 24950357 TI - Serum IgG titres, but not avidity, correlates with neutralizing antibody response after H5N1 vaccination. AB - BACKGROUND: Influenza H5N1 virus constitutes a pandemic threat and development of effective H5N1 vaccines is a global priority. Anti-influenza antibodies directed towards the haemagglutinin (HA) define a correlate of protection. Both antibody concentration and avidity may be important for virus neutralization and resolving influenza disease. METHODS: We conducted a phase I clinical trial of a virosomal H5N1 vaccine adjuvanted with the immunostimulating complex Matrix MTM. Sixty adults were intramuscularly immunized with two vaccine doses (21 days apart) of 30 MUg HA alone or 1.5, 7.5 or 30 MUg HA adjuvanted with Matrix MTM. Serum H5 HA1 specific antibodies and virus neutralization were determined at days 0, 21, 42, 180 and 360 and long-term memory B cells at day 360 post-vaccination. The binding of the HA specific antibodies was measured by avidity NaSCN-elution ELISA and surface plasmon resonance (SPR). RESULTS: The H5 HA1-specific IgG response peaked after the second dose (day 42), was dominated by IgG1 and IgG3 and was highest in the adjuvanted vaccine groups. IgG titres correlated significantly with virus neutralization at all time points (Spearman r>=0.66, p<0.0001). By elution ELISA, serum antibody avidity was highest at days 180 and 360 post vaccination and did not correlate with virus neutralization. Long-lasting H5 HA1-specific memory B cells produced high IgG antibody avidity similar to serum IgG. CONCLUSIONS: Maturation of serum antibody avidity continued up to day 360 after influenza H5N1 vaccination. Virus neutralization correlated with serum H5 HA1-specific IgG antibody concentrations and not antibody avidity. PMID- 24950358 TI - Sequential Phase 1 and Phase 2 randomized, controlled trials of the safety, immunogenicity and efficacy of combined pre-erythrocytic vaccine antigens RTS,S and TRAP formulated with AS02 Adjuvant System in healthy, malaria naive adults. AB - In an attempt to improve the efficacy of the candidate malaria vaccine RTS,S/AS02, two studies were conducted in 1999 in healthy volunteers of RTS,S/AS02 in combination with recombinant Plasmodium falciparum thrombospondin related anonymous protein (TRAP). In a Phase 1 safety and immunogenicity study, volunteers were randomized to receive TRAP/AS02 (N=10), RTS,S/AS02 (N=10), or RTS,S+TRAP/AS02 (N=20) at 0, 1 and 6-months. In a Phase 2 challenge study, subjects were randomized to receive either RTS,S+TRAP/AS02 (N=25) or TRAP/AS02 (N=10) at 0 and 1-month, or to a challenge control group (N=8). In both studies, the combination vaccine had an acceptable safety profile and was acceptably tolerated. Antigen-specific antibodies, lymphoproliferative responses, and IFN gamma production by ELISPOT assay elicited with the combination vaccine were qualitatively similar to those generated by the single component vaccines. However, post-dose 2 anti-CS antibodies in the RTS,S+TRAP/AS02 vaccine recipients were lower than in the RTS,S/AS02 vaccine recipients. After challenge, 10 of 11 RTS,S+TRAP/AS02 vaccinees, 5 of 5 TRAP/AS02 vaccinees, and 8 of 8 infectivity controls developed parasitemia, with median pre-patent periods of 13.0, 11.0, and 12.0 days, respectively. The absence of any prevention or delay of parasitemia by TRAP/AS02 suggests no apparent added value of TRAP/AS02 as a candidate vaccine. The absence of significant protection or delay of parasitemia in the 11 RTS,S+TRAP/AS02 vaccine recipients contrasts with previous 2 dose studies of RTS,S/AS02. The small sample size did not permit identifying statistically significant differences between the study arms. However, we speculate, within the constraints of the challenge study, that the presence of the TRAP antigen may have interfered with the vaccine efficacy previously observed with this regimen of RTS,S/AS02, and that any future TRAP-based vaccines should consider employing alternative vaccine platforms. PMID- 24950359 TI - Association between human papillomavirus vaccine status and other cervical cancer risk factors. AB - Little is known about the relationship between HPV vaccine uptake and other risk factors for cervical cancer. This study aimed to measure the association between vaccine status and cervical cancer risk factors in adolescent girls. Girls (15-16 years) from the first two cohorts to be offered routine HPV vaccination in the NHS immunisation programme completed a survey 3 years post-vaccination. Recruitment took place at 13 schools in London. Of 2768 girls registered in Year 11, 1912 (69%) took part and provided analysable data. Questions assessed vaccine status, demographic characteristics, smoking status, sexual behaviour and intention to attend cervical screening. Overall, 78% had completed the three-dose vaccine course. There was no association between vaccine status and smoking behaviour or sexual experience. In adjusted analyses, girls from black or 'other' ethnic backgrounds were less likely to be fully-vaccinated than those from white backgrounds. Those with low intentions to attend cervical screening were less likely to be fully vaccinated than those with high intentions. Efforts will be needed to ensure that unvaccinated women understand the importance of cervical screening when they reach the age that screening begins. Ethnic inequalities in vaccine coverage need to be explored further. PMID- 24950360 TI - Evaluation of single-round infectious, chimeric dengue type 1 virus as an antigen for dengue functional antibody assays. AB - Dengue fever and dengue hemorrhagic fever are endemic throughout tropical and subtropical countries. Four serotypes of dengue viruses (DENV-1 to DENV-4), each with several genotypes including various subclades, are co-distributed in most endemic areas. Infection-neutralizing and -enhancing antibodies are believed to play protective and pathogenic roles, respectively. Measurement of these functional antibodies against a variety of viral strains is thus important for evaluating coverage and safety of dengue vaccine candidates. Although transportation of live virus materials beyond national borders is increasingly limited, this difficulty may be overcome using biotechnology that enables generation of an antibody-assay antigen equivalent to authentic virus based on viral sequence information. A rapid system to produce flavivirus single-round infectious particles (SRIPs) was recently developed using a Japanese encephalitis virus (JEV) subgenomic replicon plasmid. This system allows production of chimeric SRIPs that have surface proteins of other flaviviruses. In the present study, SRIPs of DENV-1 (D1-SRIPs) were evaluated as an antigen for functional antibody assays. Inclusion of the whole mature capsid gene of JEV into the replicon plasmid provided higher D1-SRIP yields than did its exclusion in cases where a DENV-1 surface-protein-expressing plasmid was used for co-transfection of 293T cells with the replicon plasmid. In an assay to measure the balance between neutralizing and enhancing activities, dose (antibody dilution)-dependent activity curves in dengue-immune human sera or mouse monoclonal antibodies obtained using D1-SRIP antigen were equivalent to those obtained using DENV-1 antigen. Similar results were obtained using additional DENV-2 and DENV-3 systems. In a conventional Vero-cell neutralization test, a significant correlation was shown between antibody titers obtained using D1-SRIP and DENV-1 antigens. These results demonstrate the utility of D1-SRIPs as an alternative antigen to authentic DENV-1 in functional antibody assays. SRIP antigens may contribute to dengue vaccine candidate evaluation, understanding of dengue pathogenesis, and development of serodiagnostic systems. PMID- 24950361 TI - Heterologous prime-boost immunization with live attenuated B. pertussis BPZE1 followed by acellular pertussis vaccine in mice. AB - Pertussis is a severe and life-threatening infectious disease. Two successive generations of vaccines have strongly reduced its incidence over the last 70 years. However, despite excellent global vaccine coverage, it is still not under control and constitutes today the most frequent vaccine-preventable childhood disease. New vaccination approaches are therefore needed. Here, we provide preclinical proof of concept for a heterologous prime-boost strategy, using the live attenuated Bordetella pertussis vaccine candidate BPZE1 to prime infant and neonatal mice intranasally and a currently available acellular pertussis vaccine (aPV) as a booster. Intranasal vaccination with BPZE1 provided strong protection against challenge in neonatal mice, which could be boosted with a single dose of aPV. Furthermore, BPZE1 priming induced a strong Th1/Th17 response, which was maintained after repeated aPV administrations, in contrast to non-primed mice, in which aPV administrations resulted in Th2 skewing. In addition to T cell responses, intranasal administration of BPZE1 to infant or neonatal mice also primed antibody responses to B. pertussis antigens, with a strong preference of the IgG2a over the IgG1 isotypes, which was not seen in non-primed animals. Finally, neonatal BPZE1 priming strongly enhanced aPV-induced protection against B. pertussis challenge. These results lend support for a heterologous prime-boost strategy to control pertussis by using BPZE1 early in life and considering the current aPV administrations as booster vaccinations, thereby bridging the gap from birth to the first aPV immunizations and avoiding aPV-mediated Th2 skewing. A first-in-man clinical trial on BPZE1 has recently been successfully completed, which provides hope that these findings may be translated into human applications in the future. PMID- 24950363 TI - A virus-like particle based bivalent vaccine confers dual protection against enterovirus 71 and coxsackievirus A16 infections in mice. AB - Enterovirus 71(EV71) and coxsackievirus A16 (CA16) are responsible for hand, foot and mouth disease which has been prevalent in Asia-Pacific regions, causing significant morbidity and mortality in young children. Co-circulation of and co infection by both viruses underscores the importance and urgency of developing vaccines against both viruses simultaneously. Here we report the immunogenicity and protective efficacy of a bivalent combination vaccine comprised of EV71 and CA16 virus-like particles (VLPs). We show that monovalent EV71- or CA16-VLPs elicited serum antibodies exhibited potent neutralization effect on the homotypic virus but little or no effect on the heterotypic one, whereas the antisera against the bivalent vaccine formulation were able to efficiently neutralize both EV71 and CA16, indicating there is no immunological interference between the two antigens with respect to their ability to induce virus-specific neutralizing antibodies. Passive immunization with monovalent VLP vaccines protected mice against a homotypic virus challenge but not heterotypic infection. Surprisingly, antibody-dependent enhancement (ADE) of disease was observed in mice passively transferred with mono-specific anti-CA16 VLP sera and subsequently challenged with EV71. In contrast, the bivalent VLP vaccine conferred full protection against lethal challenge by either EV71 or CA16, thus eliminating the potential of ADE. Taken together, our results demonstrate for the first time that the bivalent VLP approach represents a safe and efficacious vaccine strategy for both EV71 and CA16. PMID- 24950362 TI - Factors associated with humoral immune response to pandemic A/H1N1(v) 2009 influenza vaccine in cystic fibrosis. AB - Influenza vaccination is recommended in cystic fibrosis patients. The objective of this study was to assess the immunogenicity of vaccination against 2009 pandemic A/H1N1 influenza and to study the factors associated with the immune response in patients with cystic fibrosis. 122 patients with cystic fibrosis were enrolled in a prospective study and received 1 dose of 2009/H1N1v adjuvanted vaccine, or for children <2 years and lung-transplanted patients, two doses of non-adjuvanted 2009/H1N1v vaccine administered 21 days apart. Hemagglutination inhibition antibodies were assessed before and 21 days after vaccination and at least 6 months after vaccination. After vaccination, 85% of the patients had an influenza antibody titer >=1:40 and 69% seroconverted. 13% of the transplanted patients seroconverted compared with 72% of the non-transplanted patients. In this latter group, non-adjuvanted vaccine and low body mass index were independently associated with lower response to vaccination. 86% of the non transplanted patients with normal BMI and receiving adjuvanted vaccine seroconverted. Persistence of seroprotection 10 months after vaccination was found in 50% of the patients. In patients with cystic fibrosis, malnutrition and receipt of non-adjuvanted vaccine were associated with lower immune response to pandemic influenza vaccination. Our data also suggest a potential defect in the immune response to influenza vaccination of patients with cystic fibrosis and raise the question of whether a different immunization strategy is needed. PMID- 24950364 TI - Stabilisation of amorphous ibuprofen in Upsalite, a mesoporous magnesium carbonate, as an approach to increasing the aqueous solubility of poorly soluble drugs. AB - One attractive approach to increase the aqueous solubility and thus the bioavailability of poorly soluble drugs is to formulate them in their amorphous state since amorphous compounds generally exhibit higher apparent solubilities than their crystalline counterparts. In the current work, mesoporous magnesium carbonate was used to stabilise the amorphous state of the model substance ibuprofen. Crystallisation of the drug was completely supressed in the formulation, resulting in both a higher apparent solubility and a three times faster dissolution rate of the drug where the drug release was shown to be diffusion controlled. It was also shown that the formulation is stable for at least three months when stored at 75% relative humidity. The simple synthesis together with a high loading capacity and narrow pore size distribution of the mesoporous magnesium carbonate is foreseen to offer great advantages in formulations of poorly soluble drugs. PMID- 24950365 TI - Anginex lipoplexes for delivery of anti-angiogenic siRNA. AB - Angiogenesis is one of the hallmarks of cancer which renders it an attractive target for therapy of malignancies. Tumor growth suppression can be achieved by inhibiting angiogenesis since it would deprive tumor cells of oxygen and vital nutrients. Activation of endothelial cells of tumor vasculature is the first step in angiogenesis which is mediated by various factors. One of the major triggers in this process is vascular endothelial growth factor (VEGF) which binds to VEGF receptors on endothelial cells of tumor vessels. This induces a series of signaling cascades leading to activation of cellular processes involved in angiogenesis, and therefore down-regulation of VEGF receptor-2 (VEGFR-2) expression seems a viable option to inhibit angiogenesis. In our investigations, this aim has been pursued by using siRNA interfering with the expression of VEGFR 2. Since the discovery of RNA interference (RNAi) as a gene regulation process, successful delivery of small non-coding RNA has presented itself as a major challenge. In the current study, we have characterized a galectin-1 targeted anginex-coupled lipoplex (Angiplex) containing siRNA against the gene of VEGFR-2 as an angiostatic therapeutic. Angiplex particles had a size of approximately 120 nm with a net negative charge and were stable in vitro. These particles were internalized in a specific manner by HUVECs compared to a non-targeted lipoplex system, and their uptake was higher than Lipofectamine 2000. Gene silencing efficiency of Angiplex was shown to be 61%. PMID- 24950366 TI - A review of monitoring methods for pharmaceutical wet granulation. AB - High-shear wet granulation is commonly used in the pharmaceutical industry to improve powder properties for downstream processes such as tabletting. Granule growth, however, is difficult to predict because the process is sensitive to raw material properties and operating conditions. Development of process analytical technologies is encouraged by regulatory bodies to improve process understanding and monitor quality online. The primary technologies investigated for high-shear wet granulation monitoring include power consumption, near-infrared spectroscopy, Raman spectroscopy, capacitance measurements, microwave measurements, imaging, focused beam reflectance measurements, spatial filter velocimetry, stress and vibration measurements, as well as acoustic emissions. This review summarizes relevant research related to each of these technologies and discusses the challenges associated with each approach as a possible process analytical technology tool for high-shear wet granulation. PMID- 24950367 TI - Thermoresponsive polymers: insights into decisive hydrogel characteristics, mechanisms of gelation, and promising biomedical applications. AB - Thermally induced gelling systems have gained enormous attention over the last decade. They consist of hydrophilic homopolymers or block copolymers in water that present a sol at room temperature and form a gel after administration into the body. This article reviews the main types of thermoresponsive polymers, with special focus on decisive hydrogel characteristics, mechanisms of gelation, and biocompatibility. Promising biomedical applications are described with a focus on injectable formulations, which include solubilization of small hydrophobic drugs, controlled release, delivery of labile biopharmaceutics, such as proteins and genes, cell encapsulation, and tissue regeneration. Furthermore, combinations of thermoresponsive hydrogels and various nanocarriers as promising systems for sustained drug delivery are discussed through selected examples from the literature. Finally, there is a brief overview of current progress in nano-sized systems incorporating thermoresponsive properties. PMID- 24950368 TI - Instability of bacteriophages in spray-dried trehalose powders is caused by crystallization of the matrix. AB - Spray drying is a valuable technique in pharmaceutical dosage formulation, capable of producing amorphous, spherical powders, suitable for pulmonary deposition and further downstream processing. In this study, we show that spray drying bacteriophages together with trehalose results in an amorphous powder matrix with high glass transition temperature (between 116 and 118 degrees C), typical for amorphous trehalose. These powders are stable at low temperatures (4 degrees C) and relative humidity (0%). However, high humidity causes crystallization of the amorphous matrix, destroying the embedded phages. Furthermore, storage at higher temperature (25 degrees C) causes thermal instability of the embedded phages. The results show that storage conditions are important parameters to take into account in phage therapy development. The resulting particles are hollow spheres, with suitable aerodynamic diameters for deposition into the deep lungs. This opens possibilities to use these phage containing powder formulations to tackle pulmonary infectious diseases, especially caused by antibiotic resistant pathogens. PMID- 24950370 TI - Modulating the lateral tension of solvent-free pore-spanning membranes. AB - The plasma membrane of animal cells is attached to the cytoskeleton, which significantly contributes to the lateral tension of the membrane. Lateral membrane tension has been shown to be an important physical regulator of cellular processes such as cell motility and morphology as well as exo- and endocytosis. Here, we report on lipid bilayers spanning highly ordered pore arrays, where we can control the lateral membrane tension by chemically varying the surface functionalization of the porous substrate. Surface functionalization was achieved by a gold coating on top of the pore rims of the hexagonal array of pores in silicon nitride substrates with pore radii of 600 nm followed by subsequent incubation with various n-propanolic mixtures of 6-mercapto-1-hexanol (6MH) and O cholesteryl N-(8'-mercapto-3',6'-dioxaoctyl)carbamate (CPEO3). Pore-spanning membranes composed of 1,2-diphytanoyl-sn-glycero-3-phosphocholine were prepared by spreading giant unilamellar vesicles on these functionalized porous silicon nitride substrates. Different mixtures of 6MH and CPEO3 provided self-assembled monolayers (SAMs) with different compositions as analyzed by contact angle and PM IRRAS measurements. Site specific force-indentation experiments on the pore spanning membranes attached to the different SAMs revealed a clear dependence of the amount of CPEO3 in the monolayer on the lateral membrane tension. While bilayers on pure 6MH monolayers show an average lateral membrane tension of 1.4 mN m(-1), a mixed monolayer of CPEO3 and 6MH obtained from a solution with 9.1 mol % CPEO3 exhibits a lateral tension of 5.0 mN m(-1). From contact angle and PM IRRAS results, the mole fraction of CPEO3 in solution can be roughly translated into a CPEO3 surface concentration of 40 mol %. Our results clearly demonstrate that the free energy difference between the supported and freestanding part of the membrane depends on the chemical composition of the SAM, which controls the lateral membrane tension. PMID- 24950369 TI - CYP3A4*22 (c.522-191 C>T; rs35599367) is associated with lopinavir pharmacokinetics in HIV-positive adults. AB - The CYP3A4*22 (c.522-191 C>T; rs35599367) single nucleotide polymorphism has been associated with lower CYP3A4 mRNA expression and activity. We investigated the association of CYP3A4*22 with the pharmacokinetics of lopinavir through a population pharmacokinetic approach. The minor allele frequency for CYP3A4*22 was 0.035, and seven of 375 patients had a combination of CYP3A4*22 and SLCO1B1 521T>C alleles. Lack of information on the ethnicity in this cohort should be considered as a limitation. However, in the final model, the population clearance was 5.9 l/h and patients with CYP3A4*22/*22 had 53% (P=0.023) lower clearance compared with noncarriers. In addition, the combined effect of CYP3A4*22 with SLCO1B1 521T>C (previously shown to be associated with lopinavir plasma concentration) was analysed. We observed a 2.3-fold higher lopinavir trough concentration (Ctrough) in individuals with CYP3A4*22/*22, a 1.8-fold higher Ctrough with SLCO1B1 521CC and a 9.7-fold higher Ctrough in individuals homozygous for both single nucleotide polymorphisms, compared with noncarriers. A simulated dose-reduction scenario showed that 200/100 mg lopinavir/ritonavir was adequate to achieve therapeutic concentration in individuals with CYP3A4*22/*22 alone or in combination with SLCO1B1 521CC. These data further our understanding of the genetic basis for variability in the pharmacokinetics of lopinavir. PMID- 24950371 TI - Laboratory study of non-aqueous phase liquid and water co-boiling during thermal treatment. AB - In situ thermal treatment technologies, such as electrical resistance heating and thermal conductive heating, use subsurface temperature measurements in addition to the analysis of soil and groundwater samples to monitor remediation performance. One potential indication of non-aqueous phase liquid (NAPL) removal is an increase in temperature following observations of a co-boiling plateau, during which subsurface temperatures remain constant as NAPL and water co-boil. However, observed co-boiling temperatures can be affected by the composition of the NAPL and the proximity of the NAPL to the temperature measurement location. Results of laboratory heating experiments using single-component and multi component NAPLs showed that local-scale temperature measurements can be mistakenly interpreted as an indication of the end of NAPL-water co-boiling, and that significant NAPL saturations (1% to 9%) remain despite observed increases in temperature. Furthermore, co-boiling of multi-component NAPL results in gradually increasing temperature, rather than a co-boiling plateau. Measurements of gas production can serve as a complementary metric for assessing NAPL removal by providing a larger-scale measurement integrated over multiple smaller-scale NAPL locations. Measurements of the composition of the NAPL condensate can provide ISTT operators with information regarding the progress of NAPL removal for multi component sources. PMID- 24950372 TI - Solute transport in a single fracture involving an arbitrary length decay chain with rock matrix comprising different geological layers. AB - A model is developed to describe solute transport and retention in fractured rocks. It accounts for advection along the fracture, molecular diffusion from the fracture to the rock matrix composed of several geological layers, adsorption on the fracture surface, adsorption in the rock matrix layers and radioactive decay chains. The analytical solution, obtained for the Laplace-transformed concentration at the outlet of the flowing channel, can conveniently be transformed back to the time domain by the use of the de Hoog algorithm. This allows one to readily include it into a fracture network model or a channel network model to predict nuclide transport through channels in heterogeneous fractured media consisting of an arbitrary number of rock units with piecewise constant properties. More importantly, the simulations made in this study recommend that it is necessary to account for decay-chains and also rock matrix comprising at least two different geological layers, if justified, in safety and performance assessment of the repositories for spent nuclear fuel. PMID- 24950373 TI - The diagnostic vibrational signature of pentacoordination in heme carbonyls. AB - Heme-carbonyl complexes are widely exploited for the insight they provide into the structural basis of function in heme-based proteins, by revealing the nature of their bonded and nonbonded interactions with the protein. This report presents two novel results which clearly establish a FeCO vibrational signature for crystallographically verified pentacoordination. First, anisotropy in the NRVS density of states for nu(Fe-C) and delta(FeCO) in oriented single crystals of [Fe(OEP)(CO)] clearly reveals that the Fe-C stretch occurs at higher frequency than the FeCO bend and considerably higher than any previously reported heme carbonyl. Second, DFT calculations on a series of heme carbonyls reveal that the frequency crossover occurs near the weak trans O atom donor, furan. As nu(Fe-C) occurs at lower frequencies than delta(FeCO) in all heme protein carbonyls reported to date, the results reported herein suggest that they are all hexacoordinate. PMID- 24950374 TI - 2',6'-Dihalostyrylanilines, pyridines, and pyrimidines for the inhibition of the catalytic subunit of methionine S-adenosyltransferase-2. AB - Inhibition of the catalytic subunit of the heterodimeric methionine S-adenosyl transferase-2 (MAT2A) with fluorinated N,N-dialkylaminostilbenes (FIDAS agents) offers a potential avenue for the treatment of liver and colorectal cancers where upregulation of this enzyme occurs. A study of structure-activity relationships led to the identification of the most active compounds as those with (1) either a 2,6-difluorostyryl or 2-chloro-6-fluorostyryl subunit, (2) either an N methylamino or N,N-dimethylamino group attached in a para orientation relative to the 2,6-dihalostyryl subunit, and (3) either an N-methylaniline or a 2-(N,N dimethylamino)pyridine ring. These modifications led to FIDAS agents that were active in the low nanomolar range, that formed water-soluble hydrochloride salts, and that possessed the desired property of not inhibiting the human hERG potassium ion channel at concentrations at which the FIDAS agents inhibit MAT2A. The active FIDAS agents may inhibit cancer cells through alterations of methylation reactions essential for cancer cell survival and growth. PMID- 24950375 TI - Nuclear PI5P, Uhrf1, and the road not taken. AB - In this issue of Molecular Cell, Gelato et al. (2014) identify the signaling molecule phosphatidylinositol 5-phosphate (PI5P) as an allosteric regulator that determines the mode of chromatin binding for the DNA methylation maintenance factor Uhrf1. This work links nuclear lipids to chromatin signaling in the maintenance of DNA methylation and epigenetic regulation. PMID- 24950376 TI - Networking in an alternative splicing world. AB - Using Caenorhabditis elegans as a model system, Norris et al. (2014) define complex combinatorial regulation of alternative splicing at single-neuron resolution and illustrate functional coherence among components of a splicing regulatory network controlled by a neuronal splicing factor. PMID- 24950378 TI - Interaction of CD5 and CD72 is involved in regulatory T and B cell homeostasis. AB - Regulatory IL-10-producing CD1d(high)CD5(+)CD19(+) B cells and CD4(+)CD25(+)Foxp3(+) T cells have been found to modulate immune responses in autoimmunity, infection, and cancer, but the interaction between these two cell subsets remains unclear. Through cell culture and flow cytometry (FACS), we analyzed the interaction of regulatory T cells (Tregs) and regulatory B cells (Bregs). A neutralizing antibody was used to determine the role of CD5 and CD72 in maintaining regulatory T and B cell homeostasis. We found that CD19(+)CD5(+)CD1d(hi) Bregs induced expansion of CD4(+)Foxp3(+) Tregs, and CD4(+)CD25(+) Tregs also induced expansion of IL-10-expressing Bregs. Once CD72 or CD5 was blocked, both IL-10-expressing Bregs and CD4(+)Foxp3(+)Tregs were reduced in the different cultures. Finally, FACS analysis demonstrated that Foxp3(+)CD4(+)Treg cells were reduced in CD19(Cre) mice defective of CD5 on the surface of B cells. The study suggests that the interaction of CD5 and CD72 plays a critical role in maintaining regulatory T and B cell homeostasis. PMID- 24950377 TI - PKA-mediated phosphorylation of ATR promotes recruitment of XPA to UV-induced DNA damage. AB - The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals. PMID- 24950379 TI - Variants close to NTRK2 gene are associated with birth weight in female twins. AB - Low weight at birth has previously been shown to be associated with a number of adult diseases such as type 2 diabetes, cardiovascular disease, high blood pressure, and obesity later in life. Genome-wide association studies (GWAS) have been published for singleton-born individuals, but the role of genetic variation in birth weight (BW) in twins has not yet been fully investigated. A GWAS was performed in 4,593 female study participants with BW data available from the TwinsUK cohort. A genome-wide significant signal was found in chromosome 9, close to the NTRK2 gene (OMIM: 600456). QIMR, an Australian twin cohort (n = 3,003), and UK-based singleton-birth individuals from the Hertfordshire cohort (n = 2,997) were used as replication for the top two single nucleotide polymorphism (SNPs) underpinning this signal, rs12340987 and rs7849941. The top SNP, rs12340987, was found to be in the same direction in the Australian twins and in the singleton-born females (fixed effects meta-analysis beta = -0.13, SE = 0.02, and p = 1.48 * 10-8) but not in the singleton-born males tested. These findings provide an important insight into the genetic component of BW in twins who are normally excluded due to their lower BW when compared with singleton births, as well as the difference in BW between twins. The NTRK2 gene identified in this study has previously been associated with obesity. PMID- 24950380 TI - Copper and selenium: auxiliary measure to control infection by Haemonchus contortus in lambs. AB - The aim of this study was to evaluate the effects of selenium and copper on oxidative stress and its performance in lambs experimentally infected with Haemonchus contortus. Twenty-eight five-months old lambs were experimentally infected by the oral route with 5000 third-stage infective larvae and allocated into four groups, i.e., untreated animals, animals treated intramuscularly with sodium selenite (0.2 mg kg(-1)), animals treated subcutaneously with copper (3.5 mg kg(-1)), and animals treated with sodium selenite (IM; 0.2 mg kg(-1)) and copper (SC; 3.5 mg kg(-1)). These animals received oat hay (Avena sativa) and commercial concentrate, totaling 15% of crude protein, 30% being derived from oat hay and 70% of the concentrate. Lipid peroxidation, antioxidant enzymes, eggs per gram of feces (EPG) and body weight were assessed on the day of infection and after 20, 40, 60 and 80 days post-infection. The number of H. contortus adults was assessed at the end of the experiment. The selenium associated or not with copper reduced the effects of oxidative stress caused by infection. The groups supplemented with copper had increased body weight, and the combination of these two minerals reduced the EPG and number of H. contortus adults in lambs. The use of selenium associated with copper may help the control of infection by H. contortus. PMID- 24950381 TI - Mianserin, an antidepressant kills Leishmania donovani by depleting ergosterol levels. AB - In the present study, we have investigated the antileishmanial potential of mianserin, an antidepressant. Mianserin was found to inhibit both the promastigote and amastigote forms of the parasite in a dose dependant manner. The IC50 values for promastigotes and amastigotes were 21 MUM and 46 MUM respectively. Interestingly, mianserin failed to inhibit THP-1 differentiated macrophages up to 100 MUM concentration thus, exhibiting parasite selectivity. When mianserin was incubated with recombinant Leishmania donovani 3-hydroxy-3 methylglutaryl coenzyme A reductase (HMGR) enzyme, it exhibited an IC50 value of 19.8 MUM. Inhibition kinetics revealed competitive mode of enzyme inhibition as the Km increased with no change in Vmax. Further structural investigation of enzyme-inhibitor interaction revealed quenching of HMGR tryptophan intrinsic fluorescence with a K(sv) value of 3.025+/-0.37 M(-1) and an apparent binding constant of 0.0954 mM. We further estimated ergosterol levels which is a major component of Leishmania cell membrane. It is synthesized by HMGR enzyme, the first rate limiting enzyme of the sterol biosynthetic pathway. Analysis of ergosterol levels by HPLC revealed ~2.5-fold depletion in mianserin treated promastigotes with respect to untreated parasites. This data was further validated by exogenous supplementation of mianserin treated cells with ergosterol and cholesterol. Reversal of growth inhibition was observed only upon ergosterol addition though it was refractory to cholesterol supplementation. Overall, our results demonstrate the possibility of repositioning of an antidepressant for the treatment of Visceral Leishmaniasis. PMID- 24950382 TI - Estimation of Eu(3+) in bulk uranium by ligand sensitized fluorescence in dimethyl sulphoxide. AB - Ligand sensitized fluorescence of europium ion using thenoyltrifluoroacetone (TTA) as a sensitizing ligand and dimethyl sulphoxide (DMSO) as a solvent is studied for the first time. TTA ligand enhances the fluorescence of Eu(3+) by a factor of 40000 in DMSO. Linearity is obtained for a concentration range of 0.076 7.6ng/mL of Eu(3+) with a detection limit of 7.6pg/mL. The quenching of Eu(3+) TTA fluorescence by uranium matrix was studied in different solvents and found to be less in DMSO. Consequently, estimation of Eu(3+) in a large excess of uranium becomes a possibility without the need to separate uranium from the solution, which has been demonstrated in this paper. Satisfactory results are obtained when Eu(3+) is present at a concentration of 0.6MUg/g in uranium. PMID- 24950383 TI - Structural, morphological and optical studies of l-cysteine modified silver nanoparticles and its application as a probe for the selective colorimetric detection of Hg(2+). AB - We report an extensive study on the evolution of a highly facile, selective colorimetric probe for Hg(2+) detection using cysteine modified silver nanoparticles. The nanoparticles are stable in a basic medium and the Surface Enhanced Raman Spectrum (SERS) reveal that the cysteine is bound to the Ag surface through the thiolate moiety with the charged carboxylate group pointing outwards in a morphology that lends itself to sensor applications. In the presence of Hg(2+), the absorption peak is quenched resulting in a drastic colour change. The sensor displays high selectivity to Hg(2+) over other metallic ions. PMID- 24950384 TI - The impact of synthetic analogs of histidine on copper(II) and nickel(II) coordination properties to an albumin-like peptide. Possible leads towards new metallodrugs. AB - The purpose of our research was to obtain peptidomimetics possessing Cu(II) and Ni(II) binding properties, which would be useful for biomedical applications. In this context we used potentiometry, UV-VIS and CD spectroscopies to characterize the Cu(II) and Ni(II) binding properties of pentapeptide analogs of the N terminal sequence of histatin 5. The peptides investigated had a general sequence DSXAK-am (am stands for C-terminal amide), with X including His and its three synthetic analogs, (4-thiazolyl)-L-alanine (1), (2-pyridyl)-L-alanine (2), and (pyrazol-1-yl)-L-alanine (3). The heterocyclic nitrogens present in these analogs were significantly more acidic than that of the His imidazole. We found that DSXAK-am peptides were able to bind Cu(II) and Ni(II) and form 4N complexes in a cooperative fashion, with similar affinities. These results indicate that acidic heterocyclic amino acids provide a viable alternative for histidine in peptidomimetics designed for metal ion binding. PMID- 24950385 TI - Mechanistic basis for the enantioselectivity of the anaerobic hydroxylation of alkylaromatic compounds by ethylbenzene dehydrogenase. AB - The enantioselectivity of reactions catalyzed by ethylbenzene dehydrogenase, a molybdenum enzyme that catalyzes the oxygen-independent hydroxylation of many alkylaromatic and alkylheterocyclic compounds to secondary alcohols, was studied by chiral chromatography and theoretical modeling. Chromatographic analyses of 22 substrates revealed that this enzyme exhibits remarkably high reaction enantioselectivity toward (S)-secondary alcohols (18 substrates converted with >99% ee). Theoretical QM:MM modeling was used to elucidate the structure of the catalytically active form of the enzyme and to study the reaction mechanism and factors determining its high degree of enantioselectivity. This analysis showed that the enzyme imposes strong stereoselectivity on the reaction by discriminating the hydrogen atom abstracted from the substrate. Activation of the pro(S) hydrogen atom was calculated to be 500 times faster than of the pro(R) hydrogen atom. The actual hydroxylation step (i.e., hydroxyl group rebound reaction to a carbocation intermediate) does not appear to be enantioselective enough to explain the experimental data (the calculated rate ratios were in the range of only 2-50 for pro(S): pro(R)-oriented OH rebound). PMID- 24950386 TI - Interaction of Pd(2+) complexes of 2,6-disubstituted pyridines with nucleoside 5' monophosphates. AB - To learn more about the underlying principles of metal-ion-mediated recognition of nucleic acid bases, PdCl(+) complexes of six 2,6-disubstituted pyridines, viz. pyridine-2,6-dicarboxamide, its N(2),N(6)-dimethyl and N(2),N(6)-diisopropyl derivatives, 6-carbamoylpyridine-2-carboxylic acid, 6-aminomethylpyridine-2 carboxamide and its N(2)-methyl derivative, were prepared and their interaction with nucleoside 5'-monophosphate (NMP) was studied by (1)H NMR spectroscopy in D2O at pH7.2. The binding sites within the nucleobases were assigned on the basis of Pd(2+) induced changes in chemical shifts of the base moiety proton resonances. The mole fractions of NMPs engaged in mono- or dinuclear Pd(2+) complexes were determined at various concentrations by comparing the intensities of the aromatic and anomeric protons of the complexed and uncomplexed NMPs. Some of the pyridine complexes showed moderate discrimination between the NMPs. PMID- 24950387 TI - Mechanism of the electrocatalytic reduction of protons with diaryldithiolene cobalt complexes. AB - A series of dimeric cobalt-diaryldithiolene complexes [Co(S2C2Ar2)2]2, possessing various aryl para substituents (OMe, F, Cl, and Br), were studied as electrocatalysts for proton reduction in nonaqueous media, in an effort to correlate dithiolene donor strength with catalyst activity. Cyclic voltammetry data acquired for the cobalt-diaryldithiolene dimers guided the isolation of chemically reduced monoanionic ([Co(S2C2Ar2)2](-)) and dianionic ([Co(S2C2Ar2)2](2-)) monomers. The potassium and tetrabutylammonium salts of dianionic cobalt-diaryldithiolene complexes have been characterized by single crystal X-ray crystallography. Treatment of the dianionic species with stoichiometric quantities of a weak acid afforded H2 and the monoanionic cobalt diaryldithiolene species. Density functional theory (BP86) suggests that hydrogen elimination proceeds through a diprotonated intermediate with a Co-H bond and a protonated S center. A transition state for transfer of the S-H proton to the metal center was located with a computed free energy of 5.9 kcal/mol, in solution (DMF via C-PCM approach). PMID- 24950388 TI - Pre-hospital core temperature measurement in accidental and therapeutic hypothermia. AB - Core temperature (T core) measurement is the only diagnostic tool to accurately assess the severity of hypothermia. International recommendations for management of accidental hypothermia encourage T core measurement for triage, treatment, and transport decisions, but they also recognize that lack of equipment may be a limiting factor, particularly in the field. The aim of this nonsystematic review is to highlight the importance of field measurement of T core and to provide practical guidance for clinicians on pre-hospital temperature measurement in accidental and therapeutic hypothermia. Clinicians should recognize the difference between alternative measurement locations and available thermometers, tailoring their decision to the purpose of the measurement (i.e., intermittent vs. continual measurement), and the impact on management decisions. The importance of T core measurement in therapeutic hypothermia protocols during early cooling and monitoring of target temperature is discussed. PMID- 24950389 TI - The complex interplay between semantics and grammar in impression formation. AB - We sought to bridge findings showing that (a) describing a person's behavior with the perfective verb aspect (did), compared to the imperfective aspect (was doing), increases processing of semantic knowledge unrelated to the target's action such as stereotypes and (b) an increased recognition of stereotypical thoughts often promotes a judgment correction for the stereotypes. We hypothesized an interplay between grammar (verb conjugation) and semantic information (gender) in impression-formation. Participants read a resume, attributed to a male or female, for a traditionally masculine job. When the resume was written in the imperfective, people rated a male (vs. female) more positively. When the resume was in the perfective, this pattern reversed. Only these latter effects of gender were influenced by cognitive load. Further, people more quickly indicated the applicant's gender in the perfective condition, suggesting an enhanced focus on gender during processing. PMID- 24950390 TI - HKOCl-2 series of green BODIPY-based fluorescent probes for hypochlorous acid detection and imaging in live cells. AB - A HKOCl-2 series of new fluorescent probes for hypochlorous acid (HOCl) detection in live cells is reported. The probes exhibit excellent selectivity, sensitivity, and chemostability toward HOCl. In particular, HKOCl-2b rapidly and selectively detects endogenous HOCl in both human and mouse macrophages. These probes could therefore serve as promising discovery tools to help elucidate biological functions of HOCl. PMID- 24950391 TI - Functionality of aryl hydrocarbon receptors (AhR1 and AhR2) of white sturgeon (Acipenser transmontanus) and implications for the risk assessment of dioxin-like compounds. AB - Worldwide, populations of sturgeons are endangered, and it is hypothesized that anthropogenic chemicals, including dioxin-like compounds (DLCs), might be contributing to the observed declines in populations. DLCs elicit their toxic action through activation of the aryl hydrocarbon receptor (AhR), which is believed to regulate most, if not all, adverse effects associated with exposure to these chemicals. Currently, risk assessment of DLCs in fishes uses toxic equivalency factors (TEFs) developed for the World Health Organization (WHO) that are based on studies of embryo-lethality with salmonids. However, there is a lack of knowledge of the sensitivity of sturgeons to DLCs, and it is uncertain whether TEFs developed by the WHO are protective of these fishes. Sturgeons are evolutionarily distinct from salmonids, and the AhRs of sturgeons differ from those of salmonids. Therefore, this study investigated the sensitivity of white sturgeon (Acipenser transmontanus) to DLCs in vitro via the use of luciferase reporter gene assays using COS-7 cells transfected with AhR1 or AhR2 of white sturgeon. Specifically, activation and relative potencies (RePs) of 2,3,7,8 tetrachloro-dibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachloro-dibenzofuran, 2,3,7,8 tetrachloro-dibenzofuran, 3,3',4,4',5-pentachlorobiphenyl, 3,3',4,4' tetrachlorobiphenyl, and 2,3,3',4,4'-pentachlorobiphenyl were determined for each AhR. It was demonstrated that white sturgeon expresses AhR1s and AhR2s that are both activated by DLCs with EC50 values for 2,3,7,8-TCDD that are lower than those of any other AhR of vertebrates tested to date. Both AhRs of white sturgeon had RePs for polychlorinated dibenzofurans more similar to TEFs for birds, while RePs for polychlorinated biphenyls were most similar to TEFs for fishes. Measured concentrations of select DLCs in tissues of white sturgeon from British Columbia, Canada, were used to calculate toxic equivalents (TEQs) by use of TEFs for fishes used by the WHO and TCDD equivalents (TCDD-EQs) via the use of RePs for AhR2 of white sturgeon as determined by transfected COS-7 cells. TCDD-EQs calculated for endangered populations of white sturgeon were approximately 10-fold greater than TEQs and were within ranges known to cause adverse effects in other fishes, including other species of sturgeons. Therefore, TEFs used by the WHO might not adequately protect white sturgeon, illuminating the need for additional investigation into the sensitivity of these fish to DLCs. PMID- 24950392 TI - 'Doctor, there is a lump in my heart' - A rare case of a ventricular myxoma. AB - Myxomas are the commonest primary cardiac tumours. They may be asymptomatic, and picked up incidentally, or be the cause of congestive heart failure, arrhythmias and/or murmurs. Echocardiography is necessary for diagnosis. Surgical resection is recommended to prevent further complications. A rare symptomatic ventricular myxoma is presented in this case report. PMID- 24950393 TI - Gossypiboma presented as abdominal lump seven years after open cholecystectomy. AB - Gossypiboma is very rare in clinical practice. Despite its clinical importance, it carries some medico legal implications. We report a case of gossypiboma in a 54 years old female who presented with pain and a slowly growing lump in the abdomen 7 years after open cholecystectomy. Computed tomography (CT) scan of the abdomen showed a mass with enhanced internal septae and a radio-opaque marker within it, raising the suspicion of a foreign body. She underwent excision of the mass along with a segment of densely adherent transverse colon. Post-operative recovery was uneventful and the patient was well at 19-month follow up. PMID- 24950394 TI - Schwannoma of the ansa cervicalis. AB - Schwannomas are rare neoplasms that originate from Schwann cells. We present a case report of schwannoma of the ansa cervicalis in a patient where preoperative imaging suggested thyroid pathology. A 25-year-old man presented to the otolaryngology department with a one-year history of an asymptomatic, anterior triangle neck swelling. Imaging and FNA suggested a cystic lesion of the thyroid. However, intraoperatively, the lesion was found between the right sternohyoid and thyrohoid and histology showed findings consistent with a diagnosis of schwannoma, determined to originate from the ansa cervicalis based on its anatomical position. Schwannoma of the ansa cervicalis is extremely rare and there have only been four reported cases in the literature. Schwannomas are often misdiagnosed and confused for other lesions. In our case report we add to the sparse literature on this pathology and highlight common pitfalls in diagnosis and discuss the principles of management of this rare condition. PMID- 24950395 TI - Parathyroid cyst: the forgotten diagnosis of a neck mass. AB - The differential diagnosis of cystic cervical masses includes cystic thyroid disease or some embryological diseases. Parathyroid cyst is one of the less common causes of the cervical masses. The Swedish anatomist Sandstrom reported the first description of parathyroid cyst in 1880. Up to date, only about 300 cases have been reported in the world literature. They may be functional or nonfunctional, depending on the presence or absence of the hyperparathyroidism and treatment options vary for both presentations. Particularly, nonfunctional cysts are often considered as thyroid cysts. Diagnosis is best made by monitoring serum calcium levels and sending cyst fluid for parathormone analysis. We herein report a patient diagnosed with a parathyroid cyst who had received the diagnosis of goitre at other institute; including a review of the literature. PMID- 24950396 TI - Ovarian strumal carcinoid presenting as severe progressive constipation. AB - Strumal carcinoid develops in a germ cell tumor characterized by an intimate mixture of thyroid and carcinoid. Unlike other carcinoid tumors, most patients with strumal carcinoid have no symptoms of carcinoid syndrome; few are reported to cause severe constipation. We report a case of a 60-year-old female patient presenting with severe progressive constipation and painful defecation for last few years. A right ovarian tumor was discovered during clinical examination. CT scan revealed a large lobulated solid cystic right adenexal mass suggestive of monomorphic teratoma, which was successfully removed surgically. The histopathology confirmed the diagnosis of strumal carcinoid tumor. Her constipation completely disappeared post surgery. These tumors are known to produce a biologically active substance like peptide YY, which has a pharmacologic inhibitory action on intestinal motility. This was presumably the cause of the constipation in this patient rather than a mechanical effect of the tumor. PMID- 24950397 TI - Adenomyoma of ampulla: a rare cause of obstructive jaundice. AB - Adenomyoma is a rare benign lesion occurring commonly in the fundus of the gallbladder in the biliary tract. Ampullary adenomyoma is rarer still, presenting as obstructive jaundice due to its location at the ampulla and may mimic malignancy on clinical and radiological examination. Endoscopic biopsy may not be always diagnostic if the lesion is deep seated. Histologically these lesions show a combination of diverse benign epithelial and mesenchymal elements, which should not be confused with an invasive tumor because of its arrangement. We report three cases of adenomyoma located at the ampulla presenting as obstructive jaundice. The diagnosis was confirmed on pacreaticoduodenectomy resection specimens. PMID- 24950398 TI - Inflammatory myofibroblastic tumour of liver masquerading as hilar cholangiocarcinoma. AB - There is a wide variety of inflammatory and benign neoplastic disorders of the biliary system that mimic cholangiocarcinoma in terms of clinical manifestations and imaging findings. Inflammatory myofibroblastic tumour of the bilary tract is one such condition, which is extremely rare but benign. Like cholangiocarcinoma this condition presents as painless progressive obstructive jaundice and it is often difficult to differentiate between the two prior to laparotomy, with the usual investigative modalities. Diagnosis is usually established by the characteristic histopathology findings in biopsy specimen. Newer diagnostic modalities directed at obtaining preoperative biopsy of the lesion appear promising in differentiating benign from malignant biliary lesions, but their routine use is yet to become standardised. Until then, awareness of doctors about the existence of such benign entities might prompt a less aggressive treatment approach while dealing with atypical hilar lesions of liver. PMID- 24950400 TI - Giant urethral calculus. AB - Primary urethral calculus is rarely seen and is usually encountered in men with urethral stricture or diverticulum. We present a case of giant urethral calculus secondary to a urethral stricture in a man. The patient was treated with calculus extraction with end to end urethroplasty. PMID- 24950399 TI - Isolated right atrial tear following blunt trauma. AB - Cardiac chamber rupture in blunt trauma is uncommon and is associated with a high mortality rate. We report a patient involved in a motor vehicle collision with an isolated right atrial injury resulting in a pericardial effusion associated with hemodynamic compromise. A 20 year-old intoxicated female was transported after sustaining a collision in her vehicle. The patient remained mildly hypotensive and tachycardic despite volume resuscitation. FAST was negative showing good cardiac motion and no fluid in her abdomen. A CT scan revealed a mediastinal hematoma and free intra-abdominal fluid, and trans-thoracic echocardiogram (TTE) identified a mass within the right atrium associated with a pericardial effusion. In the operating room, clot was removed from within the pericardium. Hypothermic circulatory arrest and cardiopulmonary bypass were performed and a single laceration involving the right atrium was repaired after removing a large intra atrial clot. A negative concurrent exploratory laparotomy was performed. The patient was discharged from the hospital postoperative day 6. This report presents an isolated right atrial tear associated with pericardial tamponade following blunt trauma and we discuss the role of early diagnosis and treatment. PMID- 24950401 TI - Digital ischaemia in the digital age. AB - After the accidental injection of epinephrine into a digit, various techniques to try and reverse the ensuing ischaemia were unsuccessful. To identify a further treatment strategy and as members of the admitting team were unfamiliar with digital injection of epinephrine a Google search was performed. Previous cases were described and separate sources indicated appropriate management protocols utilising phentolamine. After administration, an almost immediate reversal of ischaemic symptoms occurred. This highlights the role of the internet as an adjunct in managing unfamiliar situations and practising evidence based medicine. PMID- 24950402 TI - Ribosomal protein L19 overexpression activates the unfolded protein response and sensitizes MCF7 breast cancer cells to endoplasmic reticulum stress-induced cell death. AB - Although first identified for their roles in protein synthesis, certain ribosomal proteins exert pleiotropic physiological functions in the cell. Ribosomal protein L19 is overexpressed in breast cancer cells by amplification and copy number variation. In this study, we examined the novel pro-apoptotic role of ribosomal protein L19 in the breast cancer cell line MCF7. Overexpression of RPL19 sensitized MCF7 cells to endoplasmic reticulum stress-induced cell death. RPL19 overexpression itself was not cytotoxic; however, cell death induction was enhanced when RPL19 overexpressing cells were incubated with endoplasmic reticulum stress-inducing agents, and this sensitizing effect was specific to MCF7 cells. Examination of the cell signaling pathways that mediate the unfolded protein response (UPR) revealed that overexpression of RPL19 induced pre activation of the UPR, including phosphorylation of pERK-like ER kinase (PERK), phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2alpha), and activation of p38 MAPK-associated stress signaling. Our findings suggest that upregulation of RPL19 induces ER stress, resulting in increased sensitivity to ER stress and enhanced cell death in MCF7 breast cancer cells. PMID- 24950403 TI - Role of genomics in translational research for Parkinson's disease. AB - Research on Parkinson's disease (PD) has made remarkable progress in recent decades, due largely to new genomic technologies, such as high throughput sequencing and microarray analyses. Since the discovery of a linkage of a missense mutation of the alpha-synuclein (alphaS) gene to a rare familial dominant form of PD in 1996, positional cloning and characterization of a number of familial PD risk factors have established a hypothesis that aggregation of alphaS may play a major role in the pathogenesis of PD. Furthermore, dozens of sensitizing alleles related to the disease have been identified by genome wide association studies (GWAS) and meta-GWAS, contributing to a better understanding of the pathological mechanisms of sporadic PD. Thus, the knowledge obtained from the association studies will be valuable for "the personal genome" of PD. Besides summarizing such progress, this paper focuses on the role of microRNAs in the field of PD research, since microRNAs might be promising as a biomarker and as a therapeutic reagent for PD. We further refer to a recent view that neurodegenerative diseases, including PD, coexist with metabolic disorders and are stimulated by type II diabetes, the most common disease among elderly populations. The development of genomic approaches may potentially contribute to therapeutic intervention for PD. PMID- 24950404 TI - Isorhynchophylline protects against pulmonary arterial hypertension and suppresses PASMCs proliferation. AB - Increased pulmonary arterial smooth muscle cells (PASMCs) proliferation is a key pathophysiological component of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Isorhynchophylline (IRN) is a tetracyclic oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla. It has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether IRN can influence the development of PAH. Here we examined the effect of IRN on monocrotaline (MCT) induced PAH in rats. Our data demonstrated that IRN prevented MCT induced PAH in rats, as assessed by right ventricular (RV) pressure, the weight ratio of RV to (left ventricular+septum) and RV hypertrophy. IRN significantly attenuated the percentage of fully muscularized small arterioles, the medial wall thickness, and the expression of smooth muscle alpha-actin (alpha-SMA) and proliferating cell nuclear antigen (PCNA). In vitro studies, IRN concentration-dependently inhibited the platelet-derived growth factor (PDGF)-BB-induced proliferation of PASMCs. Fluorescence-activated cell-sorting analysis showed that IRN caused G0/G1 phase cell cycle arrest. IRN-induced growth inhibition was associated with downregulation of Cyclin D1 and CDK6 as well as an increase in p27Kip1 levels in PDGF-BB-stimulated PASMCs. Moreover, IRN negatively modulated PDGF-BB-induced phosphorylation of PDGF-Rbeta, ERK1/2, Akt/GSK3beta, and signal transducers and activators of transcription 3 (STAT3). These results demonstrate that IRN could inhibit PASMCs proliferation and attenuate pulmonary vascular remodeling after MCT induction. These beneficial effects were at least through the inhibition of PDGF-Rbeta phosphorylation and its downstream signaling pathways. Therefore, IRN might be a potential candidate for the treatment of PAH. PMID- 24950405 TI - Mutational analysis of the pumpkin (Cucurbita maxima) phloem exudate lectin, PP2 reveals Ser-104 is crucial for carbohydrate binding. AB - The pumpkin phloem lectin (PP2) is an RNA-binding, defense-related, chitooligosaccharide-specific, homodimeric lectin of Mr 48 kDa expressed at high concentrations in the sieve elements and companion cells of pumpkin (Cucurbita maxima). In the present study, PP2 was expressed in the methylotrophic yeast Pichia pastoris with the Saccharomyces alpha-factor sequence to direct the recombinant protein into the secretory pathway as a prerequisite for unimpaired folding and posttranslational glycosylation of recombinant PP2. Previous computational modeling and ligand docking studies predicted a putative chitooligosaccharide-binding site on the PP2 surface, which was divided into three subsites, with two amino acid residues in each subsite identified as possible candidates for interaction with chitooligosaccharides (CHOs). In this work, mutational analysis and hemagglutination assays were employed to verify the role of the predicted residues in the carbohydrate binding activity of the protein. The results obtained revealed that mutation of Ser-104 to Ala (S104A) at subsite-2 resulted in about 90% loss of agglutination activity of the protein, indicating that Ser-104 is crucial for the binding of CHOs to PP2. Also, L100A (at subsite-1) and K200A (at subsite-3) independently decreased the lectin activity by about 40%, indicating that these two residues also contribute significantly to sugar binding by PP2. Together, these findings confirm that all the three subsites contribute to varying degrees toward PP2-carbohydrate interaction, and confirm the validity of the computational model, as proposed earlier. PMID- 24950406 TI - Engineering and characterization of a humanized antibody targeting TNF-alpha and RANKL. AB - To neutralize the pathological activities of tumor necrosis factor-alpha (TNF alpha) and receptor activator of NF-kappaB ligand (RANKL), we engineered and characterized a humanized 8G12 (h8G12) antibody that targeted TNF-alpha and RANKL. Standard molecular biological and complementarity determining region (CDR) grafting techniques were used to engineer the h8G12 antibody, and enzyme-linked immunosorbent assays (ELISAs) and Western blotting were employed to determine its binding activation and specificity. TNF-alpha-mediated cytotoxicity and RANKL induced osteoclastogenesis assays were used to evaluate the neutralizing effects of the antibody. The cDNA sequences were established by grafting the murine monoclonal antibody (mAb) 8G12 CDRs into the heavy and light chain (HC and LC) variable regions (VH and VL) of the human mAbs 3DGG_B and 1I9R_L, respectively. The recombinant plasmids were transfected into Chinese hamster ovary (CHO) cells to produce the h8G12 antibody, which could simultaneously recognize TNF-alpha and RANKL. In addition, the h8G12 antibody reduced the TNF-alpha-mediated apoptosis of L929 cells by 25.84%. Furthermore, the h8G12 antibody significantly inhibited leukocyte infiltration in a murine allergic contact inflammation model. Concurrent with the inhibition of apoptosis, the h8G12 antibody significantly reduced the number of osteoclast-like cells in a dose-dependent manner. These results demonstrated that the h8G12 antibody neutralized the activities of TNF alpha and RANKL and that it might be a potential candidate for the treatment of inflammatory bone diseases, such as rheumatoid arthritis (RA). PMID- 24950407 TI - Structural characterization of the BH3-like motif of hepatitis B virus X protein. AB - Hepatitis B virus X protein (HBx) is a multifunctional protein, which is considered to be an essential molecule for viral replication and the development of liver diseases. Recently, it has been demonstrated that HBx can directly interact with Bcl-2 and Bcl-xL through a sequence (termed the BH3-like motif) that is related to the BH3 motif of pro-apoptotic BH3-only proteins. Here, we present the first structural characterization of the HBx BH3-like motif by circular dichroism and NMR spectroscopies. Our results demonstrated that the HBx BH3-like motif has the ability to form an alpha-helix, and the potential helical region involves residues L108-L134. This is a common characteristic among the BH3 peptides of pro-apoptotic BH3-only proteins, implying that HBx may interact with Bcl-2 and Bcl-xL, by forming an alpha-helix, similar to the interaction mode of other BH3 peptides with Bcl-2 and Bcl-xL. PMID- 24950409 TI - Lithium potentiates GSK-3beta activity by inhibiting phosphoinositide 3-kinase mediated Akt phosphorylation. AB - Accumulating evidence has pointed to the direct inhibitory action of lithium, an anti-depressant, on GSK-3beta. The present study investigated further insight into lithium signaling pathways. In the cell-free assay Li2CO3 significantly inhibited phosphoinositide 3-kinase (PI3K)-mediated phosphorylation of Akt1 at Ser473, but Li2CO3 did not affect PI3K-mediated PI(3,4,5)P3 production and 3 phosphoinositide-dependent protein kinase 1 (PDK1)-mediated phosphorylation of Akt1 at Thr308. This indicates that lithium could enhance GSK-3beta activity by suppressing Akt-mediated Ser9 phosphorylation of GSK-3beta in association with inhibition of PI3K-mediated Akt activation. There was no direct effect of Li2CO3 on Akt1-induced phosphorylation of GSK-3beta at Ser9, but otherwise Li2CO3 significantly reduced GSK-3beta-mediated phosphorylation of beta-catenin at Ser33/37 and Thr41. This indicates that lithium directly inhibits GSK-3beta in an Akt-independent manner. In rat hippocampal slices Li2CO3 significantly inhibited phosphorylation of Akt1/2 at Ser473/474, GSK-3beta at Ser9, and beta-catenin at Ser33/37 and Thr41. Taken together, these results indicate that lithium exerts its potentiating and inhibiting bidirectional actions on GSK-3beta activity. PMID- 24950408 TI - Continuous wave W- and D-band EPR spectroscopy offer "sweet-spots" for characterizing conformational changes and dynamics in intrinsically disordered proteins. AB - Site-directed spin labeling (SDSL) electron paramagnetic resonance (EPR) spectroscopy is a powerful tool for characterizing conformational sampling and dynamics in biological macromolecules. Here we demonstrate that nitroxide spectra collected at frequencies higher than X-band (~9.5 GHz) have sensitivity to the timescale of motion sampled by highly dynamic intrinsically disordered proteins (IDPs). The 68 amino acid protein IA3, was spin-labeled at two distinct sites and a comparison of X-band, Q-band (35 GHz) and W-band (95 GHz) spectra are shown for this protein as it undergoes the helical transition chemically induced by tri fluoroethanol. Experimental spectra at W-band showed pronounced line shape dispersion corresponding to a change in correlation time from ~0.3 ns (unstructured) to ~0.6 ns (alpha-helical) as indicated by comparison with simulations. Experimental and simulated spectra at X- and Q-bands showed minimal dispersion over this range, illustrating the utility of SDSL EPR at higher frequencies for characterizing structural transitions and dynamics in IDPs. PMID- 24950410 TI - Higher frequency of C.3435 of the ABCB1 gene in patients with tramadol dependence disorder. AB - BACKGROUND: Polymorphic variation at the ABCB1 gene has been shown to affect the pharmacodynamics and kinetics of various drugs. AIM: This study aimed to determine the frequency of occurrence of Single Nucleotide Polymorphism (SNP) in position A118G OPRM1 (rs1799971) gene and C.3435 (rs1045642) gene in tramadol users in comparison with normal controls. METHODS: This was a cross sectional case-control outpatient study. The study sample consisted of 127 subjects (74 tramadol-dependents and 50 healthy controls). All patients fulfilled the Diagnostic and Statistical Manual IV Criteria for substance dependence (on tramadol). Genotyping of the OPRM1 gene 118 SNP and ABCB1 genes C.3435 SNP was performed by PCR, followed by restriction fragment length polymorphism identification. RESULTS: A significant association was found between the ABCB1 gene T allele at the polymorphic site 3435 and tramadol dependence. No significant association was observed with the A118G OPRM1 gene. CONCLUSION: The high frequency of ABCB1 gene T allele present at the polymorphic site 3435 could provide a protective mechanism from tramadol dependence disorder. Further study, using a larger sample, would be useful in further evaluating the possible role of ABCB1 gene polymorphisms. PMID- 24950411 TI - Graphene surface plasmon induced optical field confinement and lasing enhancement in ZnO whispering-gallery microcavity. AB - Fundamental physics under the surface plasmon (SP) of graphene and the functional application beyond ultraviolet (UV) lasing of ZnO are both fascinating research areas. Herein, the optical field confinement induced by graphene SP was simulated theoretically in a graphene-coated ZnO microrod, which acted as a whispering gallery microcavity for lasing resonance. Distinct optical field confinement and photoluminescence (PL) enhancement were observed experimentally. Stable and transient spectra were employed to analyze the PL enhancement and the coupling dynamics between graphene SP and ZnO interband emission. As a functional application, the graphene-coated ZnO microcavities presented the obviously improved whispering-gallery mode (WGM) lasing performance. These results would be valuable for designing novel optical and photoelectronic devices based on SP coupling in graphene-semiconductor hybrid materials. PMID- 24950412 TI - Work stress and subsequent risk of internet addiction among information technology engineers in Taiwan. AB - Work stress, as defined by the Demand-Control-Support (DCS) model and the Effort Reward Imbalance (ERI) model, has been found to predict risks for depression, anxiety, and substance addictions, but little research is available on work stress and Internet addiction. The aims of this study are to assess whether the DCS and ERI models predict subsequent risks of Internet addiction, and to examine whether these associations might be mediated by depression and anxiety. A longitudinal study was conducted in a sample (N=2,550) of 21-55 year old information technology engineers without Internet addiction. Data collection included questionnaires covering work stress, demographic factors, psychosocial factors, substance addictions, Internet-related factors, depression and anxiety at wave 1, and the Internet Addiction Test (IAT) at wave 2. Ordinal logistic regression was used to assess the associations between work stress and IAT; path analysis was adopted to evaluate potentially mediating roles of depression and anxiety. After 6.2 months of follow-up, 14.0% of subjects became problematic Internet users (IAT 40-69) and 4.1% pathological Internet users (IAT 70-100). Job strain was associated with an increased risk of Internet addiction (odds ratio [OR] of having a higher IAT outcome vs. a lower outcome was 1.53); high work social support reduced the risk of Internet addiction (OR=0.62). High ER ratio (OR=1.61) and high overcommitment (OR=1.68) were associated with increased risks of Internet addiction. Work stress defined by the DCS and ERI models predicted subsequent risks of Internet addiction. PMID- 24950413 TI - Pain assessment using the adolescent pediatric pain tool: a systematic review. AB - BACKGROUND: The Adolescent Pediatric Pain Tool (APPT) is a multidimensional pain assessment tool designed to assess pain location (body outline diagram), intensity (word graphic rating scale) and quality (list of pain descriptors) in hospitalized children eight to 17 years of age. OBJECTIVES: To identify the age range, health conditions, settings and purpose for which APPT has been used; the components of the APPT that have been used; and the reported clinical and research utility of the APPT. METHODS: A systematic review of published studies using the APPT was performed. Studies were identified through electronic searches in CINAHL, Medline, PubMed, SciELO and PsycInfo. RESULTS: Twenty-three studies were analyzed. APPT has been used in patients between two and 68 years of age, with various acute and chronic conditions, in and out of hospital. All but six studies used the three components of the APPT. Most of the studies used the total number of sites marked, mean pain intensity and mean number of pain descriptors selected as main outcome measures; however, scoring methods varied. Studies report that the use of the APPT is relevant for clinical practice and for research. CONCLUSION: Obtaining self-report of pain using the APPT may help clinicians to tailor pain management interventions. It may also be used in studies to provide a deeper understanding of the pain experience and to examine the effectiveness of pain management interventions. However, outcome measures and methods of scoring the different components of the APPT need to be clearly identified. PMID- 24950414 TI - Reactive oxygen species generated by a heat shock protein (Hsp) inducing product contributes to Hsp70 production and Hsp70-mediated protective immunity in Artemia franciscana against pathogenic vibrios. AB - The cytoprotective role of heat shock protein (Hsp70) described in a variety of animal disease models, including vibriosis in farmed aquatic animals, suggests that new protective strategies relying upon the use of compounds that selectively turn on Hsp genes could be developed. The product Tex-OE(r) (hereafter referred to as Hspi), an extract from the skin of the prickly pear fruit, Opuntia ficus indica, was previously shown to trigger Hsp70 synthesis in a non-stressful situation in a variety of animals, including in a gnotobiotically (germ-free) cultured brine shrimp Artemia franciscana model system. This model system offers great potential for carrying out high-throughput, live-animal screens of compounds that have health benefit effects. By using this model system, we aimed to disclose the underlying cause behind the induction of Hsp70 by Hspi in the shrimp host, and to determine whether the product affects the shrimp in inducing resistance towards pathogenic vibrios. We provide unequivocal evidences indicating that during the pretreatment period with Hspi, there is an initial release of reactive oxygen species (hydrogen peroxide and/or superoxide anion), generated by the added product, in the rearing water and associated with the host. The reactive molecules generated are the triggering factors responsible for causing Hsp70 induction within Artemia. We have also shown that Hspi acts prophylactically at an optimum dose regimen to confer protection against pathogenic vibrios. This salutary effect was associated with upregulation of two important immune genes, prophenoloxidase and transglutaminase of the innate immune system. These findings suggest that inducers of stress protein (e.g. Hsp70) are potentially important modulator of immune responses and might be exploited to confer protection to cultured shrimp against Vibrio infection. PMID- 24950415 TI - Sequence diversity and evolution of antimicrobial peptides in invertebrates. AB - Antimicrobial peptides (AMPs) are evolutionarily ancient molecules that act as the key components in the invertebrate innate immunity against invading pathogens. Several AMPs have been identified and characterized in invertebrates, and found to display considerable diversity in their amino acid sequence, structure and biological activity. AMP genes appear to have rapidly evolved, which might have arisen from the co-evolutionary arms race between host and pathogens, and enabled organisms to survive in different microbial environments. Here, the sequence diversity of invertebrate AMPs (defensins, cecropins, crustins and anti-lipopolysaccharide factors) are presented to provide a better understanding of the evolution pattern of these peptides that play a major role in host defense mechanisms. PMID- 24950416 TI - Molecular cloning, functional identification and expressional analyses of FasL in Tilapia, Oreochromis niloticus. AB - FasL is the most extensively studied apoptosis ligand. In 2000, tilapia FasL was identified using anti-human FasL monoclonal antibody by Evans's research group. Recently, a tilapia FasL-like protein of smaller molecule weight was predicted in Genbank (XM_003445156.2). Based on several clues drawn from previous studies, we cast doubt on the authenticity of the formerly identified tilapia FasL. Conversely, using reverse transcription polymerase chain reaction (RT-PCR), the existence of the predicted FasL-like was verified at the mRNA level (The Genbank accession number of the FasL mRNA sequence we cloned is KM008610). Through multiple alignments, this FasL-like protein was found to be highly similar to the FasL of the Japanese flounder. Moreover, we artificially expressed the functional region of the predicted protein and later confirmed its apoptosis-inducing activity using a methyl thiazolyl tetrazolium (MTT) assay, Annexin-V/Propidium iodide (PI) double staining, and DNA fragment detection. Supported by these evidences, we suggest that the predicted protein is the authentic tilapia FasL. To advance this research further, tilapia FasL mRNA and its protein across different tissues were quantified. High expression levels were identified in the tilapia immune system and sites where active cell turnover conservatively occurs. In this regard, FasL may assume an active role in the immune system and cell homeostasis maintenance in tilapia, similar to that shown in other species. In addition, because the distribution pattern of FasL mRNA did not synchronize with that of the protein, post-transcriptional expression regulation is suggested. Such regulation may be dominated by potential adenylate- and uridylate-rich elements (AREs) featuring AUUUA repeats found in the 3' untranslated region (UTR) of tilapia FasL mRNA. PMID- 24950417 TI - Morphological findings of deep cutaneous fungal infections. AB - Cutaneous fungal infections used to be rare in most developed countries. However, they have become more common due to immunosuppression and globalization. In this report, we summarize the histopathologic findings of the main cutaneous fungal infections that are commonly seen in daily practice, including eumycetoma, sporotrichosis, histoplasmosis, cryptococcosis, coccidioidomycosis, aspergillosis, zygomycosis, phaeohyphomycosis, alternariosis, blastomycosis, paracoccidioidomycosis, lobomycosis, and chromoblastomycosis. We also include protothecosis (despite the fact that the infectious agent of this disease is algal and not fungal) and rhinosporidiosis (despite being caused by mesomycetozoea, which are not fungi). PMID- 24950418 TI - Histological features associated with vemurafenib-induced skin toxicities: examination of 141 cutaneous lesions biopsied during therapy. AB - Dermatologic toxicities (DTs) associated with vemurafenib therapy include actinic keratosis (AK), verruca vulgaris (VV), keratoacanthoma (KA), and invasive squamous cell carcinoma (SCC), which may share histological features. The authors report the histological features to aid in distinguishing among these DTs. A 3 year retrospective examination of the authors' surgical pathology database was conducted and 141 cases of vemurafenib-associated DTs from 33 patients were identified. DTs were categorized into 3 groups: (1) cutaneous epithelial proliferations (CEP), (2) melanocytic lesions, and (3) inflammatory dermatoses. The authors compared the groups using analysis of variance, and P<0.05 was considered significant. CEP (n=120) accounted for 85% of all DTs biopsied. The most frequent diagnosis in the CEP category was VV (40%), followed by invasive SCC (24%) and AK (21%). KA was diagnosed in 3% of CEP. Histologically, AK, VV, KA, and invasive SCC may demonstrate similar morphological features in superficial sampled specimens. The mitotic rate was significantly higher in invasive SCC than other CEP (P<0.003). The median tumor thickness of SCC was 2.60 mm. Evaluating the base of the keratinized lesion will aid in distinguishing the histological type of CEP and the management of the DTs; thus, a deep shave or punch biopsy may be warranted for patients who received vemurafenib therapy. PMID- 24950419 TI - Two cases of primary cutaneous lymphoma with a gamma/delta+ phenotype and an indolent course: further evidence of heterogeneity of cutaneous gamma/delta+ T cell lymphomas. AB - Cutaneous gamma/delta+ T-cell lymphoma (CGD-TCL) is a rare but aggressive lymphoma associated with a poor prognosis in most patients. The clinicopathological spectrum is variable including predominantly epidermotropic infiltrates manifesting with patches and plaques or tumors with dermal and/or subcutaneous infiltrates. The diagnosis of CGD-TCL requires the demonstration of a gamma/delta+ phenotype by immunohistochemistry. We report 2 patients with epidermotropic cutaneous T-cell lymphomas displaying a gamma/delta+ phenotype, but exhibiting an indolent course. In one patient, the clinical presentation was similar to mycosis fungoides in patch and plaque stage, but recurrent blister formation within the lesions was observed accompanied by fever and arthralgias, whereas the second patient presented with 2 localized erosive plaques on the left temple and dense epidermotropic and dermal diffuse and folliculotropic infiltrates of atypical small-to-medium-sized lymphocytes. These cases corroborate the view that expression of a gamma/delta+ phenotype in cutaneous T cell lymphomas per se does not portend a worse prognosis and that CGD-TCL may represent a clinically and prognostically heterogeneous group. PMID- 24950420 TI - Eosinophilic ulcer of the oral mucosa: report of a case with multiple synchronous lesions. AB - Eosinophilic ulcer of the oral mucosa is considered to be a benign, reactive, and self-limiting lesion, with unclear pathogenesis, manifesting as a rapidly developing solitary ulcer. We report the case of a 52-year-old man who presented with 4 synchronous ulcerations of the tongue. Histopathological examination showed polymorphic inflammatory infiltrate, rich in eosinophils, involving the superficial mucosa and the deeper muscle layer. Immunohistochemical analysis revealed single CD30 cells scattered within an inflammatory infiltrate. All the lesions began to regress spontaneously within 1 week after biopsy. A 4-year follow-up showed no recurrence. PMID- 24950421 TI - Disseminated noninterstitial granulomatous dermatitis as a cutaneous manifestation of the preleukemic state in a patient with myelodysplasia and ulcerative colitis--apropos a case and review of the literature. AB - The authors describe a patient with a lesion on the right forearm. Her past medical history was significant for ulcerative colitis (UC, status post-colectomy six months prior). Eleven months earlier, she was diagnosed with myelodysplastic syndrome (MDS), a finding confirmed by bone marrow biopsy showing refractory anemia with excess blasts. The forearm lesion was biopsied. Within 2 weeks, the lesions spread to involve both arms. A month later, another lesion on the left elbow was biopsied. Histopathologic findings of both the biopsies revealed similar findings of multiple, superficial and deep, noncaseating granulomas. Including our case, the total number of reported cases of noninterstitial granulomatous dermatitis in a setting of MDS with impending leukemic transformation totals two. In contrast to the other, a confounding variable in ours was the history of UC. However, the development of the lesions after colectomy argued against them being a manifestation of UC. The authors present this case to increase awareness of the noninterstitial granulomatous dermatitis granulomatous reaction pattern as a possible histopathologic clue to the preleukemic state in a patient with MDS. PMID- 24950422 TI - Secondary diffuse large B-cell lymphoma after chemotherapy for acute myeloid leukemia: looking for the unexpected diagnosis. AB - Development of Epstein-Barr virus (EBV) positive lymphoproliferative disorders in patients with immunosuppression has become more frequently reported. A patient with acute myeloid leukemia was treated to remission, when on follow-up 9 months after his initial diagnosis, he was noted to have a generalized rash and lymphadenopathy. Evaluation of skin and bone marrow biopsies was suggestive of a relapsed leukemia, and treatment was initiated. Fever evaluation revealed a high load of EBV in his blood. A lymph node biopsy and retrospective examination of his skin and bone marrow revealed an EBV-positive diffuse large B-cell lymphoma with no recurrence of acute myeloid leukemia. His chemotherapy-induced immunosuppression likely predisposed him to develop this EBV-positive diffuse large B-cell lymphoma. This case highlights the need to consider a broader differential and immunohistochemical profiling of these neoplasms to avoid misdiagnosing complex oncology patients. PMID- 24950423 TI - Assessment of dietary phytoestrogen intake via plant-derived foods in China. AB - The potential influence of dietary phytoestrogen exposure on human health during different life phases including early childhood is a matter of scientific debate. In order to improve the risk-benefit assessment of exposure to dietary phytoestrogen, reliable and age-stratified exposure data are desirable. For contributing to the database on phytoestrogen exposure, in the present study plant-derived foods from the Chinese market were analysed by LC-MS/MS for their contents of phytoestrogens, including daidzein, genistein, secoisolariciresinol, glycitein and coumestrol. The analytical data showed the presence of phytoestrogens in a concentration range of less than 0.1 to about 50 MUg g(-1). Dietary intake was assessed on the basis of average food intake data obtained from interviewing 1000 randomly selected people with the help of food frequency questionnaires. Based on the overall population sampled, the average total phytoestrogen intake was estimated at 232 MUg kg(-1) day(-1). Genistein contributed to about 66%, secoisolariciresinol and glycitein to about 10% each, and daidzein to about 7% of the overall intake. Coumestrol was present only in trace amounts. Age-related exposure assessment indicated that pre-pubertal children (aged 0-14 years) were exposed at the highest level with an average total phytoestrogen intake of 621 MUg kg(-1) day(-1). The substantially higher average exposure of children as compared with adults should trigger further research into the potential health effects of early life exposure to phytoestrogen. PMID- 24950424 TI - Risk and protective factors for symptoms of anxiety and depression in parents of children with autism spectrum disorder. AB - OBJECTIVE: The severity of symptoms of anxiety and depression was evaluated in 102 parents of children with autism spectrum disorders (ASD) and correlated with the severity of their child's behavioral symptoms. DESIGN: An observational, cross-sectional study. METHODS: The Portuguese versions of the Hospital Anxiety and Depression Scale and the Aberrant Behavior Checklist were used to assess symptoms in the parents and in their children. MAIN OUTCOMES AND RESULTS: Depression was present in 26.7% of parents and anxiety in 33.7%. Severe behavioral symptoms in the child increased the likelihood of severe anxiety and depression symptoms in the parents by a factor of 35. If the child had severe behavioral symptoms and the father lived in the family home, the likelihood of severe symptoms of anxiety and depression in the parents was 95.2% lower. CONCLUSION: The presence of the father living in the family home acted as a buffer against parents' symptoms. PMID- 24950425 TI - Developmental hematopoiesis: ontogeny, genetic programming and conservation. AB - Hematopoietic stem cells (HSCs) sustain blood production throughout life and are of pivotal importance in regenerative medicine. Although HSC generation from pluripotent stem cells would resolve their shortage for clinical applications, this has not yet been achieved mainly because of the poor mechanistic understanding of their programming. Bone marrow HSCs are first created during embryogenesis in the dorsal aorta (DA) of the midgestation conceptus, from where they migrate to the fetal liver and, eventually, the bone marrow. It is currently accepted that HSCs emerge from specialized endothelium, the hemogenic endothelium, localized in the ventral wall of the DA through an evolutionarily conserved process called the endothelial-to-hematopoietic transition. However, the endothelial-to-hematopoietic transition represents one of the last steps in HSC creation, and an understanding of earlier events in the specification of their progenitors is required if we are to create them from naive pluripotent cells. Because of their ready availability and external development, zebrafish and Xenopus embryos have enormously facilitated our understanding of the early developmental processes leading to the programming of HSCs from nascent lateral plate mesoderm to hemogenic endothelium in the DA. The amenity of the Xenopus model to lineage tracing experiments has also contributed to the establishment of the distinct origins of embryonic (yolk sac) and adult (HSC) hematopoiesis, whereas the transparency of the zebrafish has allowed in vivo imaging of developing blood cells, particularly during and after the emergence of HSCs in the DA. Here, we discuss the key contributions of these model organisms to our understanding of developmental hematopoiesis. PMID- 24950426 TI - Isostericity and tautomerism of base pairs in nucleic acids. AB - The natural bases of nucleic acids form a great variety of base pairs with at least two hydrogen bonds between them. They are classified in twelve main families, with the Watson-Crick family being one of them. In a given family, some of the base pairs are isosteric between them, meaning that the positions and the distances between the C1' carbon atoms are very similar. The isostericity of Watson-Crick pairs between the complementary bases forms the basis of RNA helices and of the resulting RNA secondary structure. Several defined suites of non Watson-Crick base pairs assemble into RNA modules that form recurrent, rather regular, building blocks of the tertiary architecture of folded RNAs. RNA modules are intrinsic to RNA architecture are therefore disconnected from a biological function specifically attached to a RNA sequence. RNA modules occur in all kingdoms of life and in structured RNAs with diverse functions. Because of chemical and geometrical constraints, isostericity between non-Watson-Crick pairs is restricted and this leads to higher sequence conservation in RNA modules with, consequently, greater difficulties in extracting 3D information from sequence analysis. Nucleic acid helices have to be recognised in several biological processes like replication or translational decoding. In polymerases and the ribosomal decoding site, the recognition occurs on the minor groove sides of the helical fragments. With the use of alternative conformations, protonated or tautomeric forms of the bases, some base pairs with Watson-Crick-like geometries can form and be stabilized. Several of these pairs with Watson-Crick-like geometries extend the concept of isostericity beyond the number of isosteric pairs formed between complementary bases. These observations set therefore limits and constraints to geometric selection in molecular recognition of complementary Watson-Crick pairs for fidelity in replication and translation processes. PMID- 24950427 TI - Genome wide functional genetics in haploid cells. AB - Some organisms such as yeast or males of social insects are haploid, i.e. they carry a single set of chromosomes, while haploidy in mammals is exclusively restricted to mature germ cells. A single copy of the genome provides the basis for genetic analyses where any recessive mutation of essential genes will show a clear phenotype due to the absence of a second gene copy. Most prominently, haploidy in yeast has been utilized for recessive genetic screens that have markedly contributed to our understanding of development, basic physiology, and disease. Somatic mammalian cells carry two copies of chromosomes (diploidy) that obscure genetic analysis. Near haploid human leukemic cells however have been developed as a high throughput screening tool. Although deemed impossible, we and others have generated mammalian haploid embryonic stem cells from parthenogenetic mouse embryos. Haploid stem cells open the possibility of combining the power of a haploid genome with pluripotency of embryonic stem cells to uncover fundamental biological processes in defined cell types at a genomic scale. Haploid genetics has thus become a powerful alternative to RNAi or CRISPR based screens. PMID- 24950429 TI - Molecular cloning and characterization of three cDNAs encoding 1-deoxy-d-xylulose 5-phosphate synthase in Aquilaria sinensis (Lour.) Gilg. AB - Agarwood is an expensive resinous heartwood derived from Aquilaria plants that is widely used in traditional medicines, incense and perfume. The major constituents of agarwood oils are sesquiterpenes, which are obtained from isopentenyl diphosphate and dimethylallyl diphosphate precursors through the plastidial methylerythritol phosphate (MEP) pathway and/or the cytosolic mevalonate pathway. 1-deoxy-d-xylulose-5-phosphate synthase (DXS) is the first rate-limiting enzyme for sesquiterpene synthesis in the MEP pathway. In this study, 3 cDNAs of DXS genes were cloned and characterized from the Aquilaria sinensis (Lour.) Gilg. These genes represent 3 phylogenetically distinct clades conserved among plants. Functional complementation in a DXS-deficient Escherichia coli strain EcAB4-2 demonstrated that they are active DXS, which rescued the E. coli mutant. Their expression profiles in different tissues and in response to different treatments were analyzed by real-time PCR. All 3 genes are highly expressed in stem, followed by leaf and root. AsDXS1 was significantly stimulated by mechanical, chemical, and H2O2 treatment, whereas AsDXS2 and AsDXS3 only responded to chemical treatment and mechanical treatment, respectively. All three genes were oscillation in respond to MJ treatment, with expression peaks occurring at different time points. Our results suggest the conservation of DXS in evolution and imply their distinct functions in primary and defensive sesquiterpene metabolism in A. sinensis. PMID- 24950428 TI - Solution phase dynamics of the DNA repair enzyme spore photoproduct lyase as probed by H/D exchange. AB - Spore photoproduct lyase (SPL) catalyzes the repair of the UV lesion spore photoproduct (SP) in a reaction dependent on S-adenosyl-L-methionine (SAM). We have utilized H/D exchange to show that in the presence of SAM, a significant reduction in H/D exchange is observed upon binding SPTpT or undamaged oligonucleotide, indicating a shift of 20 or 10 amide protons, respectively, from a rapidly-exchangable state to a fully-protected conformation. In the absence of SAM, neither the oligonucleotide nor the SPTpT produce a significant perturbation in H/D exchange, indicating SAM is a requisite binding partner. Performing the same experiments in aerobic conditions reduced the magnitude of ligand-induced structural changes, consistent with the importance of the oxygen-sensitive iron sulfur cluster for SAM and substrate binding. PMID- 24950430 TI - On-demand antimicrobial release from a temperature-sensitive polymer - comparison with ad libitum release from central venous catheters. AB - Antimicrobial releasing biomaterial coatings have found application for instance in the fixation of orthopedic joint prostheses and central venous catheters. Most frequently, the release kinetics is such that antimicrobially-effective concentrations are only reached within the first days to weeks after implantation, leaving no local antimicrobial release available when a biomaterial associated infection occurs later. Here we compare the ad libitum release of chlorhexidine and silver-sulfadiazine from a central venous catheter with their release from a new, on-demand release coating consisting of a temperature sensitive copolymer of styrene and n-butyl (meth)acrylate. The copolymer can be loaded with an antimicrobial, which is released when the temperature is raised above its glass transition temperature. Ad libitum release of chlorhexidine and silver-sulfadiazine from a commercially-purchased catheter and associated antimicrobial efficacy against Staphylococcus aureus was limited to 16days. Consecutive temperature-triggers of our on-demand coating yielded little or no antimicrobial efficacy of silver-acetate release, but antimicrobially-effective chlorhexidine concentrations were observed over a time period of 60-80days. This attests to the clear advantage of on-demand coatings above ad libitum releasing coatings, that may have released their antimicrobial content before it is actually needed. Importantly, glass transition temperature of chlorhexidine loaded copolymers was lower (48 degrees C) than of silver loaded ones (61 degrees C), facilitating their clinical use. PMID- 24950431 TI - Transdermal iontophoretic delivery of a liquid lipophilic drug by complexation with an anionic cyclodextrin. AB - Iontophoresis is now established as one of the methods of enhancing transdermal delivery of drugs. However, its application to enhance the delivery of highly lipophilic compounds is limited due to lack of any charge and poor water solubility of molecules. Propofol, a sedative and anesthetic drug was chosen as a model lipophilic drug in this study. Propofol was complexed with sulfobutyl ether beta-cyclodextrin (SCD), a beta-cyclodextrin derivative carrying ionizable groups to render propofol amenable to iontophoresis. The phase solubility studies of propofol with SCD revealed an AL type curve indicating a stoichiometry of 1:1. The complex was characterized by UV-spectrophotometry and (1)HNMR. Transport studies were performed using Franz diffusion cells across porcine epidermis. The passive permeation flux of propofol was enhanced by fourfold due to complexation with SCD. Application of iontophoresis (0.5mA/cm(2)) to SCD-propofol solution enhanced the transport of propofol by an additional fourfold. The enhancement in the transport of propofol after complexation was found to be due to multiple mechanisms such as transport of intact complex, enhanced thermodynamic activity of drug at the interface and prolonged recovery of barrier disrupted due to iontophoresis. The pharmacokinetic studies were performed in Sprague-Dawley rats to assess the feasibility of transdermal iontophoretic delivery in vivo, of a lipophilic drug complexed with SCD. PMID- 24950432 TI - Maternal exercise during pregnancy reduces risk of mammary tumorigenesis in rat offspring. AB - Breast cancer is the most common cancer among women. Emerging research indicates that modifying lifestyle factors during pregnancy may convey long-term health benefits to offspring. This study was designed to determine whether maternal exercise during pregnancy leads to reduced mammary tumorigenesis in female offspring. Pregnant rats were randomly assigned to exercised and sedentary groups, with the exercised group having free access to a running wheel and the sedentary group housed with a locked wheel during pregnancy. Female pups from exercised or sedentary dams were weaned at 21 days of age and fed a high fat diet without access to a running wheel. At 6 weeks, all pups were injected with the carcinogen N-methyl-N-nitrosourea. Mammary tumor development in all pups was monitored for 15 weeks. Pups from exercised dams had a substantially lower tumor incidence (42.9%) compared with pups from sedentary dams (100%). Neither tumor latency nor histological grade differed between the two groups. These data are the first to demonstrate that exercise during pregnancy potentiates reduced tumorigenesis in offspring. This study provides an important foundation towards developing more effective modes of behavior modification for cancer prevention. PMID- 24950433 TI - A new esthetic fiber-reinforced polymer composite resin archwire: a comparative atomic force microscope (AFM) and field-emission scanning electron microscope (FESEM) study. AB - BACKGROUND: Fiber-reinforced polymer composite (FRPC) archwires could provide an esthetic solution to conventional orthodontic archwires. This study was carried out with the following aims: (1) to compare the sliding friction of FRPC archwire with nickel titanium archwire using various archwire-bracket combinations and (2) to determine the correlation between surface roughness and friction of the FRPC and NiTi archwires. METHODS: Four different brackets (Gemini(r) (Gemini-3M Unitek, St. Paul, MN, USA), ICE(r) (ICE-Ormco- Orange, CA, USA), Clarity(r) (Clarity-3M Unitek, St. Paul, MN, USA), and SmartClip(r) (SmartClip-3M Unitek, St. Paul, MN, USA)) in combination with FRPC wires and NiTi wires (0.018 in) were studied for archwire friction with simulated wear and surface roughness using scanning electron microscope (SEM) and atomic force microscope (AFM), respectively. Statistical analysis of frictional wear generated and surface roughness between the various archwire and bracket groups was evaluated by one way ANOVA at 5% level. Least significant difference (LSD) multiple comparisons were used to determine the archwire-bracket group difference. RESULTS: Gemini(r) FRPC group generated the highest frictional wear (mean, 313.10; SD, 802.59) and ICE(r)-FRPC group produced the highest roughness values among all the groups tested (Ra = 496.13 nm, RMS = 635.49 nm). No correlation was found between frictional wear and surface roughness of the archwires of the various groups. CONCLUSIONS: FRPC archwire shows promise in its application as an esthetic aligning archwire. However, further research and refinement in its manufacture would be necessary to fully realize its potential as an esthetic archwire. PMID- 24950435 TI - Reduced graphene oxide/Ni(1-x)Co(x)Al-layered double hydroxide composites: preparation and high supercapacitor performance. AB - Reduced graphene oxide (rGO) sheet and ternary-component Ni(1-x)Co(x)Al-layered double hydroxide (Ni(1-x)Co(x)Al-LDH) hybrid composites with an interesting sandwich structure have been fabricated by an in situ growth route. The as obtained composite displays a sandwich architecture constructed by the self assembly of sheet-like LDH crystals on both sides of the rGO sheets. It was found that the Co content doped in Ni(1-x)Co(x)Al-LDH plays an important role in the shape and structure of the final products. When the Co doped content is 17%, the rGO/Ni(0.83)Co(0.17)Al-LDH has a high surface area (171.5 m(2) g(-1)) and exhibits a perfect sandwich structure. In addition, this structure and morphology is favorable for a supercapacitor electrode material with a high performance. The influence of cobalt content on the electrochemical behavior of rGO/Ni(1-x)Co(x)Al LDH has been systematically studied. The results indicate that the rGO/Ni(0.83)Co(0.17)Al-LDH composite exhibits the highest electrochemical performance, with a specific capacitance of 1902 F g(-1) at 1 A g(-1), and an excellent cycling stability. The markedly improved electrochemical performance is superior to undoped rGO/NiAl-LDH and can be attributed to the enhanced conductivity achieved through cobalt doping. Such composites could be used as a type of potential energy storage/conversion material for supercapacitors. PMID- 24950434 TI - Cost-effectiveness of add-on treatments to metformin in a Swedish setting: liraglutide vs sulphonylurea or sitagplitin. AB - OBJECTIVE: To evaluate long-run cost-effectiveness in a Swedish setting for liraglutide compared with sulphonylureas (glimepiride) or sitagliptin, all as add on to metformin for patients with type 2 diabetes insufficiently controlled with metformin in monotherapy. METHODS: The IHE Cohort Model of Type 2 Diabetes was used to evaluate clinical and economic outcomes from a societal perspective. Model input data were obtained from two clinical trials, the Swedish National Diabetes Register and the literature. Cost data reflected year 2013 price level. The robustness of results was checked with one-way-sensitivity analysis and probability sensitivity analysis. RESULTS: The cost per QALY gained for liraglutide (1.2 mg) compared to SU (glimepiride 4 mg), both as add-on to metformin, ranged from SEK 226,000 to SEK 255,000 in analyzed patient cohorts. The cost per QALY for liraglutide (1.2 mg) vs sitagliptin (100 mg) as second-line treatment was lower, ranging from SEK 149,000 to SEK 161,000. Costs of preventive treatment were driving costs, but there was also a cost offset from reduced costs of complications of ~ 20%. Notable cost differences were found for nephropathy, stroke, and heart failure. The predicted life expectancy with liraglutide increased the cost of net consumption for liraglutide. LIMITATIONS: The analysis was an ex-ante analysis using model input data from clinical trials which may not reflect effectiveness in real-world clinical practice in broader patient populations. This limitation was explored in the sensitivity analysis. The lack of specific data on loss of production due to diabetes complications implied that these costs may be under-estimated. CONCLUSIONS: Treatment strategies with liraglutide 1.2 mg improved the expected quality-of-life and increased costs when compared to SU and to sitagliptin for second-line add-on treatments. The cost per QALY for liraglutide was in the range considered medium by Swedish authorities. PMID- 24950436 TI - Evidence for the involvement of spinal cord-inhibitory and cytokines-modulatory mechanisms in the anti-hyperalgesic effect of hecogenin acetate, a steroidal sapogenin-acetylated, in mice. AB - Hecogenin is a steroidal sapogenin largely drawn from the plants of the genus Agave, commonly known as 'sisal', and is one of the important precursors used by the pharmaceutical industry for the synthesis of steroid hormones. Hecogenin acetate (HA) is a steroidal sapogenin-acetylated that produces antinociceptive activity. Thus, we evaluate the antihyperalgesic profile of HA in mice in inflammatory models, as well as its possible involvement with c-fos expression on spinal cord area and cytokines to produces analgesic profile. Acute pretreatment with HA (5, 10, or 20 mg/kg; i.p.) inhibited the development of mechanical hyperalgesia induced by carrageenan, TNF-alpha, dopamine and PGE2. Additionally, the immunofluorescence data demonstrated that acute pretreatment with HA, at all doses tested, significantly inhibited Fos-like expression in the spinal cord dorsal horn normally observed after carrageenan-inflammation. Moreover, HA did not affect the motor performance of the mice as tested in the Rota rod test. This antinociceptive profile seems to be related, at least in part, to a reduction of pro-inflammatory cytokines, as IL-1beta. The present results suggest that HA attenuates mechanical hyperalgesia by blocking the neural transmission of pain at the spinal cord levels and by cytokines-inhibitory mechanisms. PMID- 24950437 TI - Xanthenedione derivatives, new promising antioxidant and acetylcholinesterase inhibitor agents. AB - Natural and synthetic xanthone derivatives are well-known for their ability to act as antioxidants and/or enzyme inhibitors. This paper aims to present a successful synthetic methodology towards xanthenedione derivatives and the study of their aromatization to xanthones. Additionally their ability to reduce Fe(III), to scavenge DPPH radicals and to inhibit AChE was evaluated. The results demonstrated that xanthenedione derivative 5e, bearing a catechol unit, showed higher reduction capacity than BHT and similar to quercetin, strong DPPH scavenging activity (EC50 = 3.79 +/- 0.06 uM) and it was also showed to be a potent AChEI (IC50 = 31.0 +/- 0.09 uM) when compared to galantamine (IC50 = 211.8 +/- 9.5 uM). PMID- 24950438 TI - Sulfur amino acids in diet-induced fatty liver: a new perspective based on recent findings. AB - The relationship of sulfur amino acids to diet-induced fatty liver was established 80 years ago, with cystine promoting the condition and methionine preventing it. This relationship has renewed importance today because diet induced fatty liver is relevant to the current epidemics of obesity, non alcoholic fatty liver disease, metabolic syndrome, and type 2 diabetes. Two recent papers provide the first evidence linking sulfane sulfur to diet-induced fatty liver opening a new perspective on the problem. This review summarizes the early data on sulfur amino acids in fatty liver and correlates that data with current knowledge of sulfur metabolism. Evidence is reviewed showing that the lipotropic effect of methionine may be mediated by sulfane sulfur and that the hepatosteatogenic effect of cystine may be related to the removal of sulfane sulfur by cysteine catabolites. Possible preventive and therapeutic strategies are discussed. PMID- 24950439 TI - RNA interference of 1-aminocyclopropane-1-carboxylic acid oxidase (ACO1 and ACO2) genes expression prolongs the shelf life of Eksotika (Carica papaya L.) papaya fruit. AB - The purpose of this study was to evaluate the effectiveness of using RNA interference in down regulating the expression of 1-aminocyclopropane-1 carboxylic acid oxidase gene in Eksotika papaya. One-month old embryogenic calli were separately transformed with Agrobacterium strain LBA 4404 harbouring the three different RNAi pOpOff2 constructs bearing the 1-aminocyclopropane-1 carboxylic acid oxidase gene. A total of 176 putative transformed lines were produced from 15,000 calli transformed, selected, then regenerated on medium supplemented with kanamycin. Integration and expression of the targeted gene in putatively transformed lines were verified by PCR and real-time RT-PCR. Confined field evaluation of a total of 31 putative transgenic lines planted showed a knockdown expression of the targeted ACO1 and ACO2 genes in 13 lines, which required more than 8 days to achieve the full yellow colour (Index 6). Fruits harvested from lines pRNAiACO2 L2-9 and pRNAiACO1 L2 exhibited about 20 and 14 days extended post-harvest shelf life to reach Index 6, respectively. The total soluble solids contents of the fruits ranged from 11 to 14 degrees Brix, a range similar to fruits from non-transformed, wild type seed-derived plants. PMID- 24950440 TI - Properties for sourcing Nigerian larvicidal plants. AB - Aedes aegypti is the primary vector of chikungunya, yellow and dengue fevers. Dengue fever is the major cause of child morbidity and hospitalisation in some Asian and African countries, while yellow fever is prevalent in Nigeria. The development of resistance to the available insecticides has necessitated the continued search for safer ones from plants. Eighteen plant extracts with ethnomedical claims of or demonstrated febrifuge, antimalarial, insecticidal and insect repellent biological activities were tested for activity against the fourth instar larvae of Aedes aegypti. About 61% of the eighteen extracts demonstrated high to moderate larvicidal activity. Extracts of Piper nigrum and Abrus precatorius seeds were the most active and the larvicidal constituent(s) of the latter should be determined. PMID- 24950441 TI - alpha-Glucosidase inhibitory activity of polyphenols from the burs of Castanea mollissima Blume. AB - Polyphenol extracts from the burs of Castanea mollissima Blume (CMPE) exhibited potential antioxidant and hypoglycemic activities. The alpha-glucosidase inhibitory activities of CMPE were assessed as a means of elucidating the mechanism behind its hypoglycemic activities. In vitro studies showed that CMPE significantly inhibited both yeast alpha-glucosidase, through a noncompetitive mode with an IC50 of 0.33 MUg/mL, and rat intestinal alpha-glucosidase. In vivo studies revealed that oral administration of CMPE at doses of 600 mg/kg significantly reduced postprandial blood glucose levels by 27.2% in normal rats following sucrose challenges. Gel permeation chromatography revealed that CMPE exhibited typical characteristics of high-molecular-mass polymers with mean (Mn) and weight (Mw) average molecular weights of 35.4 and 50.7 kDa, respectively, and a polydispersity (Mw/Mn) of 1.432. Acid hydrolysis analysis indicated the presence of ellagitannins. These data suggest that CMPE, enriched with ellagitannins, would be an efficacious dietary supplement for diabetes management through the inhibition of alpha-glucosidase. PMID- 24950442 TI - Microwave resonant and zero-field absorption study of doped magnetite prepared by a co-precipitation method. AB - Fe3O4 and ZnxFe3-xO4 pure and doped magnetite magnetic nanoparticles (NPs) were prepared in aqueous solution (Series A) or in a water-ethyl alcohol mixture (Series B) by the co-precipitation method. Only one ferromagnetic resonance line was observed in all cases under consideration indicating that the materials are magnetically uniform. The shortfall in the resonance fields from 3.27 kOe (for the frequency of 9.5 GHz) expected for spheres can be understood taking into account the dipolar forces, magnetoelasticity, or magnetocrystalline anisotropy. All samples show non-zero low field absorption. For Series A samples the grain size decreases with an increase of the Zn content. In this case zero field absorption does not correlate with the changes of the grain size. For Series B samples the grain size and zero field absorption behavior correlate with each other. The highest zero-field absorption corresponded to 0.2 zinc concentration in both A and B series. High zero-field absorption of Fe3O4 ferrite magnetic NPs can be interesting for biomedical applications. PMID- 24950443 TI - Palladium catalyzed heck arylation of 2,3-dihydrofuran-effect of the palladium precursor. AB - Heck arylation of 2,3-dihydrofuran with iodobenzene was carried out in systems consisting of different palladium precursors (Pd2(dba)3, Pd(acac)2, PdCl2(cod), [PdCl(allyl)]2, PdCl2(PhCN)2, PdCl2(PPh3)2) and ionic liquids (CILs) with L prolinate or L-lactate anions. All the tested CILs caused remarkable increases of the conversion values and in all of the reactions 2-phenyl-2,3-dihydrofuran (3) was obtained as the main product with a yield of up to 59.2%. The highest conversions of iodobenzene were achieved for the [PdCl(allyl)]2 precursor. Formation of Pd(0) nanoparticles, representing the resting state of the catalyst, was evidenced by TEM. PMID- 24950444 TI - Synthesis, crystal structure, DFT studies and evaluation of the antioxidant activity of 3,4-dimethoxybenzenamine schiff bases. AB - Schiff bases of 3,4-dimethoxybenzenamine 1-25 were synthesized and evaluated for their antioxidant activity. All the synthesized compounds were characterized by various spectroscopic techniques. In addition, the characterizations of compounds 13, 15 and 16 were supported by crystal X-ray determinations and their geometrical parameters were compared with theoretical DFT calculations at the B3LYP level of theory. Furthermore, the X-ray crystal data of two non-crystalline compounds 8 and 18 were theoretically calculated and compared with the practical values of compounds 13, 15, 16 and found a good agreement. The compounds showed good DPPH scavenging activity ranging from 10.12 to 84.34 MUM where compounds 1-4 and 6 showed stronger activity than the standard n-propyl gallate. For the superoxide anion radical assay, compounds 1-3 showed better activity than the standard. PMID- 24950445 TI - Behavioral effect of dipeptide NGF mimetic GK-2 in an in vivo model of rat traumatic brain injury and its neuroprotective and regenerative properties in vitro. AB - A protective behavioral effect of a nerve growth factor dipeptide mimetic GK-2 in the model of open focal trauma of rat brain sensorimotor cortex and its antioxidative and regenerative properties in cultures of rat cerebellar granule cells and mouse embryonal spinal ganglion, respectively, were studied. Intraperitoneal injections of GK-2 (1 mg/kg) for 5 days daily after traumatic brain injury improved significantly motor function of limbs. Moreover, supplementation the incubation medium with GK-2 (0.5-1.5 mg/l) decreased neuronal death induced by H2O2 in cerebellar granule cell cultures and stimulated neurite outgrowth from cultured mouse embryonal spinal ganglia. Our results suggest that GK-2 exhibits pronounced positive behavioral effect in vivo as well as neuroprotective and regenerative effects in vitro, and that these neuroprotective properties probably associated with cell survival but not with cell differentiation pathway. PMID- 24950446 TI - Bioactive components on immuno-enhancement effects in the traditional Chinese medicine Shenqi Fuzheng Injection based on relevance analysis between chemical HPLC fingerprints and in vivo biological effects. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Shenqi Fuzheng Injection (SFI) is an injectable traditional Chinese herbal formula comprised of two Chinese herbs, Radix codonopsis and Radix astragali, which were commonly used to improve immune functions against chronic diseases in an integrative and holistic way in China and other East Asian countries for thousands of years. MATERIALS AND METHODS: This present study was designed to explore the bioactive components on immuno enhancement effects in SFI using the relevance analysis between chemical fingerprints and biological effects in vivo. According to a four-factor, nine level uniform design, SFI samples were prepared with different proportions of the four portions separated from SFI via high speed counter current chromatography (HSCCC). SFI samples were assessed with high performance liquid chromatography (HPLC) for 23 identified components. For the immunosuppressed murine experiments, biological effects in vivo were evaluated on spleen index (E1), peripheral white blood cell counts (E2), bone marrow cell counts (E3), splenic lymphocyte proliferation (E4), splenic natural killer cell activity (E5), peritoneal macrophage phagocytosis (E6) and the amount of interleukin-2 (E7). Based on the hypothesis that biological effects in vivo varied with differences in components, multivariate relevance analysis, including gray relational analysis (GRA), multi linear regression analysis (MLRA) and principal component analysis (PCA), were performed to evaluate the contribution of each identified component. RESULTS: The results indicated that the bioactive components of SFI on immuno-enhancement activities were calycosin-7-O-beta-d-glucopyranoside (P9), isomucronulatol-7,2' di-O-glucoside (P11), biochanin-7-glucoside (P12), 9,10-dimethoxypterocarpan-3-O xylosylglucoside (P15) and astragaloside IV (P20), which might have positive effects on spleen index (E1), splenic lymphocyte proliferation (E4), splenic natural killer cell activity (E5), peritoneal macrophage phagocytosis (E6) and the amount of interleukin-2 (E7), while 5-hydroxymethyl-furaldehyde (P5) and lobetyolin (P13) might have negative effects on E1, E4, E5, E6 and E7. Finally, the bioactive HPLC fingerprint of SFI based on its bioactive components on immuno enhancement effects was established for quality control of SFI. CONCLUSIONS: In summary, this study provided a perspective to explore the bioactive components in a traditional Chinese herbal formula with a series of HPLC and animal experiments, which would be helpful to improve quality control and inspire further clinical studies of traditional Chinese medicines. PMID- 24950447 TI - The ear under pressure. PMID- 24950448 TI - Development of spatial release from masking in mandarin-speaking children with normal hearing. AB - PURPOSE: This study investigated the development of spatial release from masking in children using closed-set Mandarin disyllabic words and monosyllabic words carrying lexical tones as test stimuli and speech spectrum-weighted noise as a masker. METHOD: Twenty-six children ages 4-9 years and 12 adults, all with normal hearing, participated in speech recognition tests under 2 conditions: (a) speech and noise spatially mixed and presented from the front (NF), and (b) speech presented from the front with noise spatially separated and presented from the side (NS) with different signal-to-noise ratios (SNRs). Performance-SNR psychometric functions were obtained that generated the SNR for a 50% correct score (SNR-50%) as the outcome measure. RESULTS: In the child participants, SNR 50% improved with age in NS but not NF. The difference in SNR-50% between NS and NF-the spatial release from masking (SRM)-increased with age with an average improvement of 0.1-0.15 dB per month. CONCLUSIONS: SRM has a long developmental time, at least up to 9 years of age, which is significantly longer than some previous developmental studies have suggested. The child participants had not yet reached the adult SRM performance level. SRM is a potential clinical measure to reflect the maturation of spatial auditory processing. PMID- 24950449 TI - A compartment model of alveolar-capillary oxygen diffusion with ventilation perfusion gradient and dynamics of air transport through the respiratory tract. AB - This paper presents a model of alveolar-capillary oxygen diffusion with dynamics of air transport through the respiratory tract. For this purpose electrical model representing the respiratory tract mechanics and differential equations representing oxygen membrane diffusion are combined. Relevant thermodynamic relations describing the mass of oxygen transported into the human body are proposed as the connection between these models, as well as the influence of ventilation-perfusion mismatch on the oxygen diffusion. The model is verified based on simulation results of varying exercise intensities and statistical calculations of the results obtained during various clinical trials. The benefit of the approach proposed is its application in simulation-based research aimed to generate quantitative data of normal and pathological conditions. Based on the model presented, taking into account many essential physiological processes and air transport dynamics, comprehensive and combined studies of the respiratory efficiency can be performed. The impact of physical exercise, precise changes in respiratory tract mechanics and alterations in breathing pattern can be analyzed together with the impact of various changes in alveolar-capillary oxygen diffusion. This may be useful in simulation of effects of many severe medical conditions and increased activity level. PMID- 24950450 TI - Thermodynamic factors impacting the peptide-driven self-assembly of perylene diimide nanofibers. AB - Synthetic peptides offer enormous potential to encode the assembly of molecular electronic components, provided that the complex range of interactions is distilled into simple design rules. Here, we report a spectroscopic investigation of aggregation in an extensive series of peptide-perylene diiimide conjugates designed to interrogate the effect of structural variations. By fitting different contributions to temperature dependent optical absorption spectra, we quantify both the thermodynamics and the nature of aggregation for peptides by incrementally varying hydrophobicity, charge density, length, as well as asymmetric substitution with a hexyl chain, and stereocenter inversion. We find that coarse effects like hydrophobicity and hexyl substitution have the greatest impact on aggregation thermodynamics, which are separated into enthalpic and entropic contributions. Moreover, significant peptide packing effects are resolved via stereocenter inversion studies, particularly when examining the nature of aggregates formed and the coupling between pi electronic orbitals. Our results develop a quantitative framework for establishing structure-function relationships that will underpin the design of self-assembling peptide electronic materials. PMID- 24950451 TI - Involvement of both sodium influx and potassium efflux in ciguatoxin-induced nodal swelling of frog myelinated axons. AB - Ciguatoxins, mainly produced by benthic dinoflagellate Gambierdiscus species, are responsible for a complex human poisoning known as ciguatera. Previous pharmacological studies revealed that these toxins activate voltage-gated Na+ channels. In frog nodes of Ranvier, ciguatoxins induce spontaneous and repetitive action potentials (APs) and increase axonal volume that may explain alterations of nerve functioning in intoxicated humans. The present study aimed determining the ionic mechanisms involved in Pacific ciguatoxin-1B (P-CTX-1B)-induced membrane hyperexcitability and subsequent volume increase in frog nodes of Ranvier, using electrophysiology and confocal microscopy. The results reveal that P-CTX-1B action is not dependent on external Cl- ions since it was not affected by substituting Cl- by methylsulfate ions. In contrast, substitution of external Na+ by Li+ ions suppressed spontaneous APs and prevented nodal swelling. This suggests that P-CTX-1B-modified Na+ channels are not selective to Li+ ions and/or are blocked by these ions, and that Na+ influx through Na+ channels opened during spontaneous APs is required for axonal swelling. The fact that the K+ channel blocker tetraethylammonium modified, but did not suppress, spontaneous APs and greatly reduced nodal swelling induced by P-CTX-1B indicates that K+ efflux might also be involved. This is supported by the fact that P-CTX-1B, when tested in the presence of both tetraethylammonium and the K+ ionophore valinomycin, produced the characteristic nodal swelling. It is concluded that, during the action of P CTX-1B, water movements responsible for axonal swelling depend on both Na+ influx and K+ efflux. These results pave the way for further studies regarding ciguatera treatment. PMID- 24950452 TI - Regionally selective activation of ERK and JNK in morphine paradoxical hyperalgesia: a step toward improving opioid pain therapy. AB - In addition to analgesia, opioid agonists may increase pain sensitivity under different conditions varying dose and administration pattern. While opioid hyperalgesia induced by tolerance and withdrawal is largely studied, little is known on the mechanisms underlying ultra-low dose morphine hyperalgesia. This pronociceptive response appears to play an opposing role in morphine analgesia and might have clinical relevance. Ultra-low dose morphine elicited thermal hyperalgesia through activation of MU opioid receptors. To elucidate the intracellular mechanism of morphine nociceptive behaviour, we investigated the mitogen-activated protein kinase (MAPK), crucial pathways in pain hypersensitivity. The catalytic activity of extracellular signal-regulated kinase (ERK), p38, c-Jun-N-terminal kinase (JNK), upstream modulators and transcription factors was investigated in the mouse periaqueductal grey matter (PAG), thalamus and prefrontal cortex by western blotting. Ultra-low dose morphine intensively increased pERK1 contents in the PAG and cortex and, to a lesser extent, increased cortical ERK2 and JNK phosphorylation. No involvement of p38 was detected. Morphine exposure also increased phosphorylation of cortical c-Jun whereas levels of phosphorylated cAMP response element-binding protein (CREB) remained unmodified. Blockade of protein kinase C (PKC) prevented increases in phosphorylation showing a PKC-dependent mechanism of activation. Pharmacological inhibitors of PKC, ERK, and JNK activity prevented morphine hyperalgesia. No modulation of MAPK and transcription factors' activity was detected in the thalamus. These results support the concept that selective activation of ERK and JNK on descending pathways plays an important role in ultra-low dose morphine hyperalgesia. The modulation of these signalling processes might improve pain management with opiate analgesics. PMID- 24950454 TI - Two rare variations, D478N and D478E, that occur at the same amino acid residue in nicotinic acetylcholine receptor (nAChR) alpha2 subunit influence nAChR function. AB - There occur two rare variations, Asp(D)478Asn(N) and Asp(D)478Glu(E), in the putative cytoplasmic amphipathic alpha-helices of human nicotinic acetylcholine receptor (nAChR) alpha2 subunit as a result of mutation in the 1st (G -> A: rs141072985) and 3rd (C -> A: rs56344740) nucleotide of its 478th triplet codon (GAC). We assessed the effects of these two variations on the function of alpha2beta2- and alpha2beta4-nAChRs as they could alter the electronegativity and/or the structure of the cytoplasmic 'portals' (framed by subunit amphipathic alpha-helices) necessary for obligate ion permeation from extracellular space to cytoplasm. We injected decreasing ratio of subunit cRNAs (alpha:beta; 10:1, 1:1 and 1:10) into Xenopus oocytes to express putative low-sensitivity (LS; 10:1), intermediate-sensitivity (IS; 1:1) and high sensitivity (HS; 1:10) isoforms of wild type and variant alpha2beta2- and alpha2beta4-nAChRs. Two-electrode voltage clamp analyses indicate that the agonist (ACh or nicotine) induced peak current responses (Imax) of alpha2beta2-nAChR isoforms and those of alpha2beta4-nAChR isoforms are increased (1.3-4.7-fold) as a result of D478E variation. The alpha2 subunit D478N variation only increases the Imax of IS (~2-fold) or HS (1.4-2.1 fold) alpha2beta2-nAChRs. Concentration-response curves constructed indicate no effect on agonist sensitivities of LS and HS isoforms of alpha2beta2- or alpha2beta4-nAChRs as a result of either variation in alpha2 subunit. Between the two variant nAChRs, alpha2(D478E)*-nAChR isoforms generally yield higher Imax than those of respective alpha2(D478N)*-nAChR isoforms. These effects could be attributed to alteration in cytoplasmic 'portals' and/or ion permeation through it owing to change in amino acid electronegativity (D -> N) and side chain length (D -> E) in nAChR alpha2 subunit. PMID- 24950453 TI - Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes. AB - Methamphetamine (METH) is abused by about 5% of the United States population with approximately 10-15% of human immunodeficiency virus-1 (HIV-1) patients reporting its use. METH abuse accelerates the onset and severity of HIV-associated neurocognitive disorders (HAND) and astrocyte-induced neurotoxicity. METH activates G-protein coupled receptors such as trace amine associated receptor 1 (TAAR1) increasing intracellular cyclic adenosine monophosphate (cAMP) levels in presynaptic cells of monoaminergic systems. In the present study, we investigated the effects of METH and HIV-1 on primary human astrocyte TAAR1 expression, function and glutamate clearance. Our results demonstrate combined conditions increased TAAR1 mRNA levels 7-fold and increased intracellular cAMP levels. METH and beta-phenylethylamine (beta-PEA), known TAAR1 agonists, increased intracellular cAMP levels in astrocytes. Further, TAAR1 knockdown significantly reduced intracellular cAMP levels in response to METH/beta-PEA, indicating signaling through astrocyte TAAR1. METH+/-HIV-1 decreased excitatory amino acid transporter-2 (EAAT-2) mRNA and significantly decreased glutamate clearance. RNA interference for TAAR1 prevented METH-mediated decreases in EAAT-2. TAAR1 knockdown significantly increased glutamate clearance, which was further heightened significantly by METH. Moreover, TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance that were further reduced by METH. Taken together, our data show that METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. To our knowledge this is the first report implicating astrocyte TAAR1 as a novel receptor for METH during combined injury in the context of HAND. PMID- 24950456 TI - Enhancement of enzymatic colorimetric response by silver island films on high throughput screening microplates. AB - In this study, we report the use of an enzyme-based hybrid platform, which is comprised of silver island films, enzymes (HRP and AP) and high-throughput screening (HTS) microplates, to enhance the colorimetric response of enzymatic reactions. The hybrid platform was designed in a two-step process: (i) deposition of SIFs onto HTS microplates with low, medium, and high loading (refers to the extent of the surface plasmon resonance peak of SIFs at 460 nm) using Tollen's reaction scheme; and (ii) attachment of b-BSA or BEA as linkers for the immobilization of enzymes. The presence of SIFs within the wells of the HTS microplates was confirmed using an optical spectrophotometer and real-color photography. Control experiments, where SIFs were omitted from the surfaces were carried out to confirm the effect of SIFs on the enzymatic colorimetric response. Significant colorimetric signal enhancement was observed for HRP or AP on SIFs (high loading) deposited HTS microplates using b-BSA (up to ~3-fold for AP and ~6 fold HRP) or BEA (up to ~7-fold for both HRP and AP), as compared to our control samples. The observed increase in colorimetric response can be attributed to the nature of BEA, which exposes surface-bound enzymes to the substrate present in bulk more efficiently than b-BSA. This study proves that SIFs can serve as a valuable tool to improve the signal output of existing bioassays carried out in HTS microplates, which can be applicable to the field biosensors and plasmonics. PMID- 24950455 TI - Neonatal nicotine exposure increases excitatory synaptic transmission and attenuates nicotine-stimulated GABA release in the adult rat hippocampus. AB - Developmental exposure to nicotine has been linked to long-lasting changes in synaptic transmission which may contribute to behavioral abnormalities seen in offspring of women who smoke during pregnancy. Here, we examined the long-lasting effects of developmental nicotine exposure on glutamatergic and GABAergic neurotransmission, and on acute nicotine-induced glutamate and GABA release in the adult hippocampus, a structure important in cognitive and emotional behaviors. We utilized a chronic neonatal nicotine treatment model to administer nicotine (6 mg/kg/day) to rat pups from postnatal day (P) 1-7, a period that falls developmentally into the third human trimester. Using whole-cell voltage clamp recordings from CA1 pyramidal neurons in hippocampal slices, we measured excitatory and inhibitory postsynaptic currents in neonatally control- and nicotine-treated young adult males. Neonatal nicotine exposure significantly increased AMPA receptor-mediated spontaneous and evoked excitatory signaling, with no change in glutamate release probability in adults. Conversely, there was no increase in spontaneous GABAergic neurotransmission in nicotine-males. Chronic neonatal nicotine treatment had no effect on acute nicotine-stimulated glutamate release in adults, but acute nicotine-stimulated GABA release was significantly attenuated. Thus, neonatal nicotine exposure results in a persistent net increase in excitation and a concurrent loss of nicotinic acetylcholine receptor (nAChR) mediated regulation of presynaptic GABA but not glutamate release, which would exacerbate excitation following endogenous or exogenous nAChR activation. Our data underscore an important role for nAChRs in hippocampal excitatory synapse development, and suggest selective long-term changes at specific presynaptic nAChRs which together could explain some of the behavioral abnormalities associated with maternal smoking. PMID- 24950458 TI - Formation of nitroanthracene and anthraquinone from the heterogeneous reaction between NO2 and anthracene adsorbed on NaCl particles. AB - Oxidative derivatives of polycyclic aromatic hydrocarbons (PAHs), that is, nitro PAHs and quinones, are classed as hazardous semivolatile organic compounds but their formation mechanism from the heterogeneous reactions of PAHs adsorbed on atmospheric particles is not well understood. The heterogeneous reaction of NO2 with anthracene adsorbed on NaCl particles under different relative humidity (RH 0-60%) was investigated under dark conditions at 298 K. The formation of the major products, 9,10-anthraquinone (9,10-AQ) and 9-nitroanthracene (9-NANT), were determined to be second-order reactions with respect to NO2 concentration. The rate of formation of 9,10-AQ under low RH (0-20%) increased as the RH increased but decreased when the RH was further increased in high RH (40-60%). In contrast, the rate of formation of 9-NANT across the whole RH range (0-60%) decreased significantly with increasing RH. Two different reaction pathways are discussed for the formation of 9,10-AQ and 9-NANT, respectively, and both are considered to be coupled to the predominant reaction of NO2 with the NaCl substrate. These results suggest that relative humidity, which controls the amount of surface adsorbed water on NaCl particles, plays an important role in the heterogeneous reaction of NO2 with adsorbed PAHs. PMID- 24950457 TI - Amuvatinib has cytotoxic effects against NRAS-mutant melanoma but not BRAF-mutant melanoma. AB - Effective targeted therapy strategies are still lacking for the 15-20% of melanoma patients whose melanomas are driven by oncogenic NRAS. Here, we report on the NRAS-specific behavior of amuvatinib, a kinase inhibitor with activity against c-KIT, Axl, PDGFRalpha, and Rad51. An analysis of BRAF-mutant and NRAS mutant melanoma cell lines showed the NRAS-mutant cohort to be enriched for targets of amuvatinib, including Axl, c-KIT, and the Axl ligand Gas6. Increasing concentrations of amuvatinib selectively inhibited the growth of NRAS-mutant, but not BRAF-mutant melanoma cell lines, an effect associated with induction of S phase and G2/M-phase cell cycle arrest and induction of apoptosis. Mechanistically, amuvatinib was noted to either inhibit Axl, AKT, and MAPK signaling or Axl and AKT signaling and to induce a DNA damage response. In three dimensional cell culture experiments, amuvatinib was cytotoxic against NRAS mutant melanoma cell lines. Thus, we show for the first time that amuvatinib has proapoptotic activity against melanoma cell lines, with selectivity observed for those harboring oncogenic NRAS. PMID- 24950459 TI - Impact of influent COD/N ratio on disintegration of aerobic granular sludge. AB - Disintegration of aerobic granular sludge (AGS) is a challenging issue in the long-term operation of an AGS system. Chemical oxygen demand (COD)-to-nitrogen (N) ratio (COD/N), often variable in industrial wastewaters, could be a destabilizing factor causing granule disintegration. This study investigates the impact of this ratio on AGS disintegration and identifies the key causes, through close monitoring of AGS changes in its physical and chemical characteristics, microbial community and treatment performance. For specific comparison, two lab scale air-lift type sequencing batch reactors, one for aerobic granular and the other for flocculent sludge, were operated in parallel with three COD/N ratios (4, 2, 1) applied in the influent of each reactor. The decreased COD/N ratios of 2 and 1 strongly influenced the stability of AGS with regard to physical properties and nitrification efficiency, leading to AGS disintegration when the ratio was decreased to 1. Comparatively the flocculent sludge maintained relatively stable structure and nitrification efficiency under all tested COD/N ratios. The lowest COD/N ratio resulted in a large microbial community shift and extracellular polymeric substances (EPS) reduction in both flocculent and granular sludges. The disintegration of AGS was associated with two possible causes: 1) reduction in net tyrosine production in the EPS and 2) a major microbial community shift including reduction in filamentous bacteria leading to the collapse of granule structure. PMID- 24950460 TI - Changes of the corrosion potential of iron in stagnation and flow conditions and their relationship with metal release. AB - This study examined the behavior of corrosion potential (Ecorr) of iron exposed to drinking water during episodes of stagnation and flow. These measurements showed that during stagnation episodes, Ecorr values decrease prominently and consistently. This decrease is initially rapid but it becomes slower as the stagnation time increases. During flow episodes, the Ecorr values increase and reach a quasi-steady state. Experiments with varying concentrations of dissolved oxygen showed that the decrease of Ecorr values characteristic for stagnation is likely to be associated with the consumption of dissolved oxygen by the exposed metal. The corrosion potential of iron and its changes during stagnation were sensitive to the concentrations of sulfate and chloride ions. Measurements of iron release showed that both the absolute values of Ecorr measured prior to or after stagnation episodes were well correlated with the logarithms of concentrations of total iron. The slope of this dependence showed that the observed correlations between Ecorr values and Fe concentrations corresponded to the coupling between the oxidant consumption and changes of Fe redox status. These results demonstrate that in situ Ecorr measurements can be a sensitive method with which to ascertain effects of hydrodynamic conditions and short-term variations of water chemistry on metal release and corrosion in drinking water. This approach is valuable practically because Ecorr measurements are precise, can be carried out in situ with any desired time resolution, do not affect the state of exposed surface in any extent and can be carried out with readily available equipment. PMID- 24950461 TI - Successful recruitment to a study of first-episode psychosis by clinicians: a qualitative account of outcomes and influences on process. AB - Abstract Background: Strategies proposed to promote recruitment of representative samples to trials and mental health research have focused on researchers external to clinical services. How clinicians approach recruitment as researchers and particularities of recruiting people with first episode of psychosis warrant investigation. AIMS: To describe recruitment, by clinicians, of people with first episode psychosis (FEP) and factors influencing process and enrolment. METHODS: Observational study nested within longitudinal examination of trauma and outcomes for patients experiencing first psychotic episode. Data collected during 20 scheduled meetings of clinicians recruiting from services in Australia. RESULTS: Timely recruitment of 60 young people demonstrates that clinicians can successfully engage patients in research. Success depends on satisfaction of organisational preconditions and clinician motivation grounded in considering the study worthwhile. Pre-selection of participants was informed by judgments about health, insight and quality of the therapeutic alliance. Patients' decisions were influenced by family support, acceptance of diagnosis and altruism. Honoraria had variable effect. CONCLUSIONS: Clinicians are well placed to recruit when appropriately supported, and people with FEP are willing to engage in research that fits their personal circumstances. Research should examine the meaning of participation in such studies and ways participation could support recovery. PMID- 24950466 TI - The Still-Face Paradigm and bidirectionality: associations with maternal sensitivity, self-esteem and infant emotional reactivity. AB - The Still-Face Paradigm (SFP) is a structured stressful event within which researchers have investigated the influence of maternal psychological and behavioral characteristics on infant behavior. The present investigation contributes to this body of work by examining the joint contributions of maternal and child behavioral and affective characteristics on subsequent behaviors and affectations following the SFP. A sample of non-clinically depressed mothers and their infants (n=31) engaged in a modified Still-Face Paradigm (SFP), followed by a period of toy play. These interactions were videotaped and behaviorally coded along the following dimensions: maternal sensitivity prior to the SFP and during toy play, infant negative emotional reactivity during the still-face, and infant resistance during the reunion phase. Additionally, mothers reported global self esteem and this was examined as a predictor of infant behavior. Results revealed significant bidirectional influences such that maternal self-esteem predicted infant emotional reactivity, maternal sensitivity pre-SFP predicted infant resistance during the reunion phase, and infant resistance predicted subsequent levels of maternal sensitivity. Indirect effects were also examined, and provided additional support for bidirectionality in mother-infant interactions. Implications for clinical practice are discussed in light of these findings. PMID- 24950467 TI - Advances in patient-derived tumor xenografts: from target identification to predicting clinical response rates in oncology. AB - Most oncology compounds entering clinical development have passed stringent preclinical pharmacology evaluation criteria. However, only a small fraction of experimental agents induce meaningful antitumor activities in the clinic. Low predictability of conventional preclinical pharmacology models is frequently cited as a main reason for the unusually high clinical attrition rates of therapeutic compounds in oncology. Therefore, improvement in the predictive values of preclinical efficacy models for clinical outcome holds great promise to reduce the clinical attrition rates of experimental compounds. Recent reports suggest that pharmacology studies conducted with patient derived xenograft (PDX) tumors are more predictive for clinical outcome compared to conventional, cell line derived xenograft (CDX) models, in particular when therapeutic compounds were tested at clinically relevant doses (CRDs). Moreover, the study of the most malignant cell types within tumors, the tumor initiating cells (TICs), relies on the availability of preclinical models that mimic the lineage hierarchy of cells within tumors. PDX models were shown to more closely recapitulate the heterogeneity of patient tumors and maintain the molecular, genetic, and histological complexity of human tumors during early stages of sequential passaging in mice, rendering them ideal tools to study the responses of TICs, tumor- and stromal cells to therapeutic intervention. In this commentary, we review the progress made in the development of PDX models in key areas of oncology research, including target identification and validation, tumor indication search and the development of a biomarker hypothesis that can be tested in the clinic to identify patients that will benefit most from therapeutic intervention. PMID- 24950469 TI - Poor correlation between head circumference and cranial ultrasound findings in premature infants with intraventricular hemorrhage. AB - OBJECT: Intraventricular hemorrhage (IVH) is the most common cause of hydrocephalus in the pediatric population and is particularly common in preterm infants. The decision to place a ventriculoperitoneal shunt or ventricular access device is based on physical examination findings and radiographic imaging. The authors undertook this study to determine if head circumference (HC) measurements correlated with the Evans ratio (ER) and if changes in ventricular size could be detected by HC measurements. METHODS: All cranial ultrasound (CUS) reports at the authors' institution between 2008 and 2011 were queried for terms related to hydrocephalus and IVH, from which a patient cohort was determined. A review of radiology reports, HC measurements, operative interventions, and significant clinical events was performed for each patient in the study. Additional radiographic measurements, such as an ER, were calculated by the authors. Significance was set at a statistical threshold of p < 0.05 for this study. RESULTS: One hundred forty-four patients were studied, of which 45 (31%) underwent CSF diversion. The mean gestational age and birth weight did not differ between patients who did and those who did not undergo CSF diversion. The CSF diversion procedures were reserved almost entirely for patients with IVH categorized as Grade III or IV. Both initial ER and HC were significantly larger for patients who underwent CSF diversion. The average ER and HC at presentation were 0.59 and 28.2 cm, respectively, for patients undergoing CSF diversion, and 0.34 and 25.2 cm for those who did not undergo CSF diversion. There was poor correlation between ER and HC measurements regardless of gestational age (r = 0.13). Additionally, increasing HC was not found to correlate with increasing ERs on consecutive CUSs (phi = -0.01, p = 0.90). Patients who underwent CSF diversion after being followed with multiple CUSs (10 of 45 patients) presented with smaller ERs and HC than those who underwent CSF diversion after a single CUS. Just prior to CSF diversion surgery, the patients who received multiple CUSs had ERs, but not HC measurements, that were similar to those in patients who underwent CSF diversion after a single CUS. CONCLUSIONS: The HC measurement does not correlate with the ER or with changes in ER and therefore does not appear to be an adequate surrogate for serial CUSs. In patients who are followed for longer periods of time before CSF shunting procedures, the ER may play a larger role in the decision to proceed with surgery. Clinicians should be aware that the ER and HC are not surrogates for one another and may reflect different pathological processes. Future studies that take into account other physical examination findings and long-term clinical outcomes will aid in developing standardized protocols for evaluating preterm infants for ventriculoperitoneal shunt or ventricular access device placement. PMID- 24950468 TI - Hypericin suppresses osteoclast formation and wear particle-induced osteolysis via modulating ERK signalling pathway. AB - Osteoclast-induced bone resorption and wear-particle-induced osteolysis leads to prosthetic loosening, one of the most common causes of joint implant failure, resulting in revision surgery. Thus, inhibition of osteoclastic bone resorption, which further prevents wear particle-induced osteolysis, is a potential treatment strategy for prosthetic loosening. Here, we examined the therapeutic effect of hypericin (HP), which was photosensitive, on osteoclastogenesis and wear particle induced osteolysis in the absence of visible light. HP inhibited RANKL-induced osteoclast differentiation in bone marrow macrophages (BMMs) and RAW264.7 cell line without any evidence of cytotoxicity. The bone-resorbing activity of mature osteoclasts was significantly inhibited by HP. As HP has been previously reported to inhibit signalling pathway such as ERK and NF-kappaB in other cells, which is also important in osteoclast differentiation. We thus examined the molecular mechanism and showed that HP significantly inhibited the ERK/mitogen-activated protein kinase (MAPK) signalling pathway without affecting nuclear factor kappaB (NF-kappaB), c-Jun N-terminal kinase (JNK) and p38 signalling in RANKL-stimulated BMMs. Further in vivo studies revealed HP attenuated osteoclast formation and subsequently prevented wear particle-induced bone erosion. Taken together, the results suggest that HP inhibits RANKL-mediated osteoclastogenesis via affecting ERK signalling in vitro and suppresses wear particle-induced osteolysis in vivo. We therefore conclude that HP may be an innovative and safe alternative treatment for osteoclast-related prosthetic loosening. PMID- 24950470 TI - Use of a customized 3D "basket" to create a solitary split-thickness cranial graft from numerous split fragments in an infant. AB - While autologous split calvaria remains the preferred material for use in pediatric cranioplasty, it may be difficult to split the bone neatly into two distinct pieces, especially in infants and young children. In this paper, the authors present a technique in which numerous split pieces of bone can be readily joined together and conformed to the shape of the specific defect using a customized template and 3D trellis-like basket. PMID- 24950471 TI - Meningeal fibroma: a rare meningioma mimic. AB - Meningeal fibromas are rare intracranial tumors that mimic meningiomas radiologically as well as histologically. The authors report 2 cases of meningeal fibroma with detailed clinical, radiological, histopathological, and immunohistochemical features, and discuss the differential diagnosis of this entity. Knowledge of this rare tumor is essential for pathologists to be able distinguish it from more common meningeal tumors, especially in younger patients. This knowledge is also essential for neurosurgeons, as incomplete resection may lead to tumor recurrence, and such patients require close follow-up. PMID- 24950472 TI - Cognitive disorders in pediatric medulloblastoma: what neuroimaging has to offer. AB - Medulloblastomas are the most common malignant childhood brain tumors arising in the posterior fossa. Treatment improvements for these tumors have meant that there are a greater number of survivors, but this long-term patient survival has increased the awareness of resulting neurocognitive deficits. Impairments in attention, memory, executive functions, and intelligence quotient demonstrate that the cerebellum likely plays a significant role in numerous higher cognitive functions such as language, cognitive, and emotional functions. In addition, children with medulloblastoma not only have cerebellar lesions but also brain white matter damages due to radiation and chemotherapy. Functional neuroimaging, a noninvasive method with many advantages, has become the standard tool in clinical and cognitive neuroscience research. By reviewing functional neuroimaging studies, this review aims to clarify the role of the cerebellum in cognitive function and explain more clearly cognitive sequelae due to polytherapy in children with medulloblastoma. This review suggests that the posterior cerebellar lobes are crucial to maintaining cognitive performance. Clinical investigations could help to better assess the involvement of these lobes in cognitive functions. PMID- 24950473 TI - Analysis of childhood leukemia mortality trends in Brazil, from 1980 to 2010. AB - OBJECTIVE: Leukemias comprise the most common group of cancers in children and adolescents. Studies conducted in other countries and Brazil have observed a decrease in their mortality.This study aimed to evaluate the trend of mortality from leukemia in children under 19 years of age in Brazil, from 1980 to 2010. METHODS: This was an ecological study, using retrospective time series data from the Mortality Information System, from 1980 to 2010. Calculations of mortality rates were performed, including gross, gender-specific, and age-based. For trend analysis, linear and semi-log regression models were used. The significance level was 5%. RESULTS: Mortality rates for lymphoid and myeloid leukemias presented a growth trend, with the exception of lymphoid leukemia among children under 4 years of age (percentage decrease: 1.21% annually), while in the sub-group "Other types of leukemia", a downward trend was observed. Overall, mortality from leukemia tended to increase for boys and girls, especially in the age groups 10 14 years (annual percentage increase of 1.23% for males and 1.28% for females) and 15-19 years (annual percentage increase of 1.40% for males and 1.62% for females). CONCLUSIONS: The results for leukemia generally corroborate the results of other similar studies. A detailed analysis by subgroup of leukemia, age, and gender revealed no trends shown in other studies, thus indicating special requirements for each variable in the analysis. PMID- 24950474 TI - Bone densitometry by dual-energy X-ray absorptiometry (DXA) in preterm newborns compared with full-term peers in the first six months of life. AB - OBJECTIVES: To longitudinally assess bone mineral content (BMC), bone mineral density (BMD), and whole-body lean mass obtained through bone densitometry by dual-energy X-ray absorptiometry (DXA) in preterm newborns (PTNs) and compare them with full-term newborns (FTNs) from birth to 6 months of corrected postnatal age. METHODS: A total of 28 adequate for gestational age (AGA) newborns were studied: 14 preterm and 14 full-term newborns. DXA was used to determine BMC, BMD, and lean mass in three moments: 40 weeks corrected post-conceptual age, as well as 3 and 6 months of corrected postnatal age. PTNs had gestational age <= 32 weeks at birth and were fed their mother's own milk or milk from the human milk bank. RESULTS: All infants had an increase in BMC, BMD, and lean body mass values during the study. PTNs had lower BMC, BMD, and lean mass at 40 weeks of corrected post-conceptual age in relation to FTNs (p<0.001, p<0.001, p=0.047, respectively). However, there was an acceleration in the mineralization process of PTNs, which was sufficient to achieve the normal values of FTNs at 6 months of corrected age. CONCLUSIONS: This study suggests that bone densitometry by dual energy X-ray absorptiometry is a good method for the assessment of body composition parameters at baseline, and at the follow-up of these PTNs. PMID- 24950475 TI - Impact of chronic kidney disease on quality of life, lung function, and functional capacity. AB - OBJECTIVES: To evaluate the impact of the chronic kidney disease (CKD) on quality of life, from the children's and their parents' perspective, respiratory muscle strength, lung function, and functional capacity in children and adolescents. METHOD: Cross-sectional study of children with CKD aged 8 to 17 years. Those incapable of taking the tests were excluded. After an interview, quality of life by Pediatric Quality of Life Inventory) (PedsQL(TM)), muscular strength, pulmonary function tests, and the 6-minute walking test (6MWT) were applied. Student's t-test, ANOVA (difference in means), and Pearson's coefficient of correlation were used. The level of significance was set at 5%. RESULTS: Of the 40 patients, the mean distance walked at the 6MWT was 396 meters, and the mean final score at the quality of life test as perceived by the children and parents was 50.9 and 51, respectively. From the children's perspective, the transplanted patients had a higher quality of life score when compared to those undergoing hemodialysis (p<0.001); those who practiced physical activity had better quality of life when compared to the sedentary children (p<0.001). From the children's and the parents' perspectives, the male gender had a higher quality of life score (p<0.05). There was a positive correlation between the distance walked at the 6MWT and age, height, final PedsQL(TM), forced vital capacity (FVC), and forced expiratory volume in the first second (FEV1), as well as a negative correlation between FEV1/FVC and the distance walked. CONCLUSION: A significant reduction in the quality of life and the functional capacity was observed in children with CKD, influenced by the type of treatment, gender, and sedentary life style. PMID- 24950476 TI - Refining and integrating schizophrenia pathophysiology - relevance of the allostatic load concept. AB - Adaptation to stress leads to the activation of several biological systems that maintain homeostasis and enable effective coping with challenges. These adaptive processes have been designated as 'allostasis'. However, overactivation or aberrant performance of allostatic mechanisms due to chronic stress exposure may exert systemic deleterious effects. This condition has been called 'allostatic load' (AL). The AL concept is a useful framework allowing to understand the mulitisystem physiological dysregulation due to cumulative stressful demands over the lifespan. In the recent years, the AL paradigm has emerged as a novel concept explaining the morbidity and mortality with respect to several mental disorders. In this article, we suggest that AL provides a useful framework to describe schizophrenia - its etiology, course, outcome and comorbidities. Schizophrenia is a severe mental illness that is characterized by multidimensional psychopathology including positive and negative symptoms, affective symptoms and cognitive impairment with several known risk factors and accompanying pathophysiological correlates. However, there is a great need to refine and integrate the plethora of findings reported from various research perspectives. We propose that AL is a meaningful concept integrating findings on pathophysiological underpinnings, factors influencing course of the disorder and the development of co-occurring physical health impairments as well as substance use disorders in schizophrenia. Furthermore, there is an urgent necessity to investigate AL and its correlates in schizophrenia as no studies in this field have been performed so far. PMID- 24950477 TI - Do alcohol excise taxes affect traffic accidents? Evidence from Estonia. AB - OBJECTIVE: This article examines the association between alcohol excise tax rates and alcohol-related traffic accidents in Estonia. METHODS: Monthly time series of traffic accidents involving drunken motor vehicle drivers from 1998 through 2013 were regressed on real average alcohol excise tax rates while controlling for changes in economic conditions and the traffic environment. Specifically, regression models with autoregressive integrated moving average (ARIMA) errors were estimated in order to deal with serial correlation in residuals. Counterfactual models were also estimated in order to check the robustness of the results, using the level of non-alcohol-related traffic accidents as a dependent variable. RESULTS: A statistically significant (P <.01) strong negative relationship between the real average alcohol excise tax rate and alcohol-related traffic accidents was disclosed under alternative model specifications. For instance, the regression model with ARIMA (0, 1, 1)(0, 1, 1) errors revealed that a 1-unit increase in the tax rate is associated with a 1.6% decrease in the level of accidents per 100,000 population involving drunk motor vehicle drivers. No similar association was found in the cases of counterfactual models for non alcohol-related traffic accidents. CONCLUSIONS: This article indicates that the level of alcohol-related traffic accidents in Estonia has been affected by changes in real average alcohol excise taxes during the period 1998-2013. Therefore, in addition to other measures, the use of alcohol taxation is warranted as a policy instrument in tackling alcohol-related traffic accidents. PMID- 24950479 TI - Engineering cellulosic bioreactors by template assisted DNA shuffling and in vitro recombination (TADSir). AB - The current study focuses on development of a bioreactor engineering strategy based on exploitation of the Arabidopsis thaliana genome. Chimeric A. thaliana glycosyl hydrolase (GH) gene libraries were assembled using a novel directed evolution strategy (TADSir: template assisted DNA shuffling and in vitro recombination) that promotes DNA recombination by reassembly of DNA fragments on unique gene templates. TADSir was modeled using a set of algorithms designed to simulate DNA interactions based on nearest neighbor base stacking interactions and Gibb's free energy differences between helical coil and folded DNA states. The algorithms allow for target gene prediction and for in silica analysis of chimeric gene library composition. Further, the study investigated utilization of A. thaliana GH sequence space for bioreactor design by evolving 20 A. thaliana genes representing the GH1, GH3, GH5, GH9 and GH10 gene families. Notably, TADSir achieved streamlined engineering of Saccharomyces cerevisiae and spinach mesophyll protoplast bioreactors capable of processing CM cellulose, Avicel and xylan. PMID- 24950478 TI - Mixed valence copper(I,II) binuclear complexes with unexpected structure: synthesis, biological properties and anticancer activity. AB - We have synthesized and characterized a panel of new binuclear mixed valence Cu(I,II) complexes containing substituted 2-alkylthio-5-arylmethylene-4H imidazolin-4-ones with unusual structure. These complexes are shown to be cytotoxic for various cell lines. We have found that these compounds did not intercalate DNA, inhibited number of polymerases (telomerase predominantly), accumulated in the cell nucleus, and caused DNA degradation. Preliminary studies revealed that lead compound inhibited human breast adenocarcinoma growth in mice model. PMID- 24950480 TI - Tuning of photocatalytic activity by creating a tridentate coordination sphere for palladium. AB - The synthesis and characterisation of an asymmetric potential bridging ligand bmptpphz (bmptpphz = 2,17-bis(4-methoxyphenyl)tetrapyrido[3,2-a:2',3'-c:3'',2'' h:2''',3'''-j] phenazine) is presented. This ligand contains a 1,10 phenanthroline (phen) and a 2,9-disubstituted phen sphere and possesses a strong absorbance in the visible. Facile coordination of the phen sphere to a Ru(tbbpy)2 core leads to Ru(bmptpphz) ([(tbbpy)2Ru(bmptpphz)](PF6)2; tbbpy = 4,4'-di-tert butyl-2,2'-bipyridine). UV-vis, emission, resonance Raman and theoretical investigations show that this complex possesses all properties associated with a Ru(tpphz) ([(tbbpy)2Ru(tpphz)](PF6)2; tpphz = tetrapyrido[3,2-a:2',3'-c:3'',2'' h:2''',3'''-j] phenazine) moiety and that the ligand based absorbances in the vis part also populate an MLCT like state. The coordination of a Pd-core in the new 2,9-disubstituted phen sphere is possible, leading to a cyclometallation. The tridentate complexation leads to changes in the UV-vis and emission behaviour. Furthermore, the stability of the Pd-coordination is significantly enhanced if compared to the unsubstituted Ru(tpphz). Ru(bmptpphz)PdCl proved to be an active photocatalyst for H2 evolution, albeit with lower activity than the mother compound Ru(tpphz)PdCl2. PMID- 24950481 TI - Reply to: "pre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantation". PMID- 24950483 TI - How predictive quantitative modelling of tissue organisation can inform liver disease pathogenesis. AB - From the more than 100 liver diseases described, many of those with high incidence rates manifest themselves by histopathological changes, such as hepatitis, alcoholic liver disease, fatty liver disease, fibrosis, and, in its later stages, cirrhosis, hepatocellular carcinoma, primary biliary cirrhosis and other disorders. Studies of disease pathogeneses are largely based on integrating -omics data pooled from cells at different locations with spatial information from stained liver structures in animal models. Even though this has led to significant insights, the complexity of interactions as well as the involvement of processes at many different time and length scales constrains the possibility to condense disease processes in illustrations, schemes and tables. The combination of modern imaging modalities with image processing and analysis, and mathematical models opens up a promising new approach towards a quantitative understanding of pathologies and of disease processes. This strategy is discussed for two examples, ammonia metabolism after drug-induced acute liver damage, and the recovery of liver mass as well as architecture during the subsequent regeneration process. This interdisciplinary approach permits integration of biological mechanisms and models of processes contributing to disease progression at various scales into mathematical models. These can be used to perform in silico simulations to promote unravelling the relation between architecture and function as below illustrated for liver regeneration, and bridging from the in vitro situation and animal models to humans. In the near future novel mechanisms will usually not be directly elucidated by modelling. However, models will falsify hypotheses and guide towards the most informative experimental design. PMID- 24950484 TI - Pre-retrieval reperfusion decreases cancer recurrence after rat ischemic liver graft transplantation. PMID- 24950482 TI - Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. AB - BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a frequent syndrome (30% prevalence), characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. This study develops and validates a specific prognostic score for ACLF patients. METHODS: Data from 1349 patients included in the CANONIC study were used. First, a simplified organ function scoring system (CLIF Consortium Organ Failure score, CLIF-C OFs) was developed to diagnose ACLF using data from all patients. Subsequently, in 275 patients with ACLF, CLIF-C OFs and two other independent predictors of mortality (age and white blood cell count) were combined to develop a specific prognostic score for ACLF (CLIF Consortium ACLF score [CLIF-C ACLFs]). A concordance index (C-index) was used to compare the discrimination abilities of CLIF-C ACLF, MELD, MELD-sodium (MELD-Na), and Child-Pugh (CPs) scores. The CLIF-C ACLFs was validated in an external cohort and assessed for sequential use. RESULTS: The CLIF-C ACLFs showed a significantly higher predictive accuracy than MELDs, MELD-Nas, and CPs, reducing (19-28%) the corresponding prediction error rates at all main time points after ACLF diagnosis (28, 90, 180, and 365 days) in both the CANONIC and the external validation cohort. CLIF-C ACLFs computed at 48 h, 3-7 days, and 8-15 days after ACLF diagnosis predicted the 28-day mortality significantly better than at diagnosis. CONCLUSIONS: The CLIF-C ACLFs at ACLF diagnosis is superior to the MELDs and MELD-Nas in predicting mortality. The CLIF-C ACLFs is a clinically relevant, validated scoring system that can be used sequentially to stratify the risk of mortality in ACLF patients. PMID- 24950485 TI - Black physicians and the struggle for civil rights: lessons from the Mississippi experience: part 2: their lives and experiences. AB - Little information is available on the lives and experiences of black physicians who practiced in the South during the Jim Crow era of legalized segregation. In Mississippi and elsewhere, it is a story of disenfranchised professionals who risked life, limb, and personal success to improve the lot of those they served. In this second article on this topic, we present the stories of some of the physicians who were leaders in the civil rights movement in Mississippi as examples. Because the health disparities they sought to address have, not of their own making, been passed on to the next generation of physicians, the lessons learned from their experience are worthy of consideration. PMID- 24950487 TI - The lungs in acute mountain sickness: victim, perpetrator, or both? PMID- 24950486 TI - The comparative safety of tumor necrosis factor inhibitors in rheumatoid arthritis: a meta-analysis update of 44 trials. AB - OBJECTIVE: The study objective was to evaluate and update the safety data from randomized controlled trials of tumor necrosis factor inhibitors in patients treated for rheumatoid arthritis. METHODS: A systematic literature search was conducted from 1990 to May 2013. All studies included were randomized, double blind, controlled trials of patients with rheumatoid arthritis that evaluated adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab treatment. The serious adverse events and discontinuation rates were abstracted, and risk estimates were calculated by Peto odds ratios (ORs). RESULTS: Forty-four randomized controlled trials involving 11,700 subjects receiving tumor necrosis factor inhibitors and 5901 subjects receiving placebo or traditional disease modifying antirheumatic drugs were included. Tumor necrosis factor inhibitor treatment as a group was associated with a higher risk of serious infection (OR, 1.42; 95% confidence interval [CI], 1.13-1.78) and treatment discontinuation due to adverse events (OR, 1.23; 95% CI, 1.06-1.43) compared with placebo and traditional disease-modifying antirheumatic drug treatments. Specifically, patients taking adalimumab, certolizumab pegol, and infliximab had an increased risk of serious infection (OR, 1.69, 1.98, and 1.63, respectively) and showed an increased risk of discontinuation due to adverse events (OR, 1.38, 1.67, and 2.04, respectively). In contrast, patients taking etanercept had a decreased risk of discontinuation due to adverse events (OR, 0.72; 95% CI, 0.55-0.93). Although ORs for malignancy varied across the different tumor necrosis factor inhibitors, none reached statistical significance. CONCLUSIONS: These meta-analysis updates of the comparative safety of tumor necrosis factor inhibitors suggest a higher risk of serious infection associated with adalimumab, certolizumab pegol, and infliximab, which seems to contribute to higher rates of discontinuation. In contrast, etanercept use showed a lower rate of discontinuation. These data may help guide clinical comparative decision making in the management of rheumatoid arthritis. PMID- 24950488 TI - A topical matter: toxic epidermal necrolysis. PMID- 24950489 TI - Synthesis and biological evaluation of imidazo[1,2-a]pyrimidines and imidazo[1,2 a]pyridines as new inhibitors of the Wnt/beta-catenin signaling. AB - Wnt/beta-catenin signaling plays an important role in the regulation of embryonic development and tumorigenesis. Since its deregulation results in severe human diseases, especially cancer, the Wnt signaling pathway constitutes a promising platform for pharmacological targeting of cancer. In this study we synthesized a series of imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyridines and identified some derivatives that were able to inhibit the Wnt/beta-catenin signaling pathway in a luciferase reporter assay and cell proliferation in selected cancer cell lines, endowed with APC or beta-catenin gene mutations. The most active compounds significantly downregulate the expression of Wnt target genes such as c-myc and cyclin D1. Further studies indicated that these compounds function independently of GSK-3beta activity. More importantly, in vivo experiments, carried out on a Wnt-reporter zebrafish model indicate, in particular for compounds 4c and 4i as the most active compounds, an activity comparable to that of the reference compound IWR1, suggesting their potential use not only as small molecule inhibitors of the Wnt/beta-catenin signal in Wnt driven cancers, but also in other Wnt-related diseases. PMID- 24950492 TI - Effects of the teach-model-coach-review instructional approach on caregiver use of language support strategies and children's expressive language skills. AB - PURPOSE: In this study, the authors examined the effects of the Teach-Model-Coach Review instructional approach on caregivers' use of four enhanced milieu teaching (EMT) language support strategies and on their children's use of expressive language. METHOD: Four caregiver-child dyads participated in a single-subject, multiple-baseline study. Children were between 24 and 42 months of age and had language impairment. Interventionists used the Teach-Model-Coach-Review instructional approach to teach caregivers to use matched turns, expansions, time delays, and milieu teaching prompts during 24 individualized clinic sessions. Caregiver use of each EMT language support strategy and child use of communication targets were the dependent variables. RESULTS: The caregivers demonstrated increases in their use of each EMT language support strategy after instruction. Generalization and maintenance of strategy use to the home was limited, indicating that teaching across routines is necessary to achieve maximal outcomes. All children demonstrated gains in their use of communication targets and in their performance on norm-referenced measures of language. CONCLUSION: The results indicate that the Teach-Model-Coach-Review instructional approach resulted in increased use of EMT language support strategies by caregivers. Caregiver use of these strategies was associated with positive changes in child language skills. PMID- 24950490 TI - Discovery of anxiolytic 2-ferrocenyl-1,3-thiazolidin-4-ones exerting GABAA receptor interaction via the benzodiazepine-binding site. AB - Herein, we report on the synthesis, spectral, crystallographic and electrochemical properties of a small library of N-substituted 2-ferrocenyl-1,3 thiazolidin-4-ones, designed as novel GABAA benzodiazepine-binding site ligands. The anxiolytic properties of the title compounds were evaluated in several different in vivo models, whereas the involvement of the GABAA receptor complex in the activity of the most potent compound, 2-ferrocenyl-3-(4 methoxyphenylethyl)-1,3-thiazolidin-4-one, was inferred from experiments with known GABAA-targeting agents. Ligand docking experiments revealed that the high, dose-dependent, anxiolytic activity of the new compounds might be due to their favorable interactions with the benzodiazepine-binding site of the GABAA receptor complex. The incorporation of the ferrocene core and fine tuning of the distance between the thiazolidinone core and an additional aromatic ring were judged to be crucial structural requirements for the observed anxiolytic effect. PMID- 24950493 TI - Investigating apical adverse effects of four endocrine active substances in the freshwater gastropod Lymnaea stagnalis. AB - The hermaphroditic gastropod Lymnaea stagnalis is proposed as a candidate species for the development of OECD guidelines for testing of the reprotoxicity of chemicals, including endocrine active substances (EASs). Up to now, only a few putative EASs have been tested for their reproductive toxicity in this species. In this study, we investigate the effects of four EASs with different affinities to the vertebrate estrogen and androgen receptors (chlordecone as an estrogen; cyproterone acetate, fenitrothion and vinclozolin as anti-androgens) on the reproduction of L. stagnalis in a 21-day semi-static test. Testosterone and 17alpha-ethinylestradiol (EE2) were used as the reference compounds. The tested EASs had no significant effect on growth and survival at the tested concentration ranges (ng to MUg/L). Classical reproduction endpoints (i.e., oviposition and fecundity) were not responsive to the tested chemicals, except for chlordecone and 17alpha-ethinylestradiol, which hampered reproduction from 19.6 MUg/L and 17.6 MUg/L, respectively. The frequency of polyembryonic eggs, used as an additional endpoint, demonstrated the effects of all compounds except EE2. The molecular pathways, which are involved in such reproduction impairments, remain unknown. Our results suggest that egg quality is a more sensitive endpoint as compared to other reproductive endpoints commonly assessed in mollusk toxicity tests. PMID- 24950494 TI - Evaluation of sensitizers found in wastewater from paper recycling areas, and their activation of the aryl hydrocarbon receptor in vitro. AB - The in vitro potential of sensitizers and related compounds (SRCs) originating from impurities in waste paper in activating the human aryl hydrocarbon receptor (AhR) alpha was assessed using yeast reporter gene as well as cytochrome P450 (CYP)1A1 and ethoxyresorufin O-deethylase (EROD) assays. In the yeast assay, eight compounds exhibited agonist activity, and their activity relative to beta naphthoflavone (BNF) ranged from 1.4 * 10(-4) to 8.3 * 10(-2), with the highest activity observed for benzyl 2-naphthyl ether (BNE). In the EROD assay, six compounds caused a more significant induction of CYP1A-dependent activity than did the vehicle control at 50 MUM (p<0.01), and their induction levels were 5.1- to 11-fold more potent; 1,2-bis(3-methylphenoxy)ethane (BME) was the most effective inducer. The water from the waste paper recycling area was fractioned using solid-phase extraction (SPE) combined with a C18 disk and florisil cartridge. In gas chromatography-mass spectrometry (GC-MS) analysis, SRCs were detected in the first fraction, at a total concentration of 5.5 MUg/L. This fraction also activated AhR, and its activity, expressed as a BNF equivalent value, was 0.42 nM in the yeast assay. The contribution ratio of active compounds accounted for up to 34% and 4.4% observed activity of the fraction and total samples, respectively. To our knowledge, this is the first study to show that paper industry-related compounds, namely aromatic sensitizers, activate AhR by using a yeast assay and HepG2 cells. PMID- 24950495 TI - Apportionment of urban aerosol sources in Cork (Ireland) by synergistic measurement techniques. AB - The sources of ambient fine particulate matter (PM2.5) during wintertime at a background urban location in Cork city (Ireland) have been determined. Aerosol chemical analyses were performed by multiple techniques including on-line high resolution aerosol time-of-flight mass spectrometry (Aerodyne HR-ToF-AMS), on line single particle aerosol time-of-flight mass spectrometry (TSI ATOFMS), on line elemental carbon-organic carbon analysis (Sunset_EC-OC), and off-line gas chromatography/mass spectrometry and ion chromatography analysis of filter samples collected at 6-h resolution. Positive matrix factorization (PMF) has been carried out to better elucidate aerosol sources not clearly identified when analyzing results from individual aerosol techniques on their own. Two datasets have been considered: on-line measurements averaged over 2-h periods, and both on line and off-line measurements averaged over 6-h periods. Five aerosol sources were identified by PMF in both datasets, with excellent agreement between the two solutions: (1) regional domestic solid fuel burning--"DSF_Regional," 24-27%; (2) local urban domestic solid fuel burning--"DSF_Urban," 22-23%; (3) road vehicle emissions--"Traffic," 15-20%; (4) secondary aerosols from regional anthropogenic sources--"SA_Regional" 9-13%; and (5) secondary aged/processed aerosols related to urban anthropogenic sources--"SA_Urban," 21-26%. The results indicate that, despite regulations for restricting the use of smoky fuels, solid fuel burning is the major source (46-50%) of PM2.5 in wintertime in Cork, and also likely other areas of Ireland. Whilst wood combustion is strongly associated with OC and EC, it was found that peat and coal combustion is linked mainly with OC and the aerosol from these latter sources appears to be more volatile than that produced by wood combustion. Ship emissions from the nearby port were found to be mixed with the SA_Regional factor. The PMF analysis allowed us to link the AMS cooking organic aerosol factor (AMS_PMF_COA) to oxidized organic aerosol, chloride and locally produced nitrate, indicating that AMS_PMF_COA cannot be attributed to primary cooking emissions only. Overall, there are clear benefits from factor analysis applied to results obtained from multiple techniques, which allows better association of aerosols with sources and atmospheric processes. PMID- 24950496 TI - Evaluation of the efficiency of the photo Fenton disinfection of natural drinking water source during the rainy season in the Sahelian region. AB - The photo-disinfection of water from two different wells (W1, pH: 4.6-5.1 +/- 0.02) and (W2 pH: 5.6-5.7 +/- 0.02) was carried out during the rainy season at Ouagadougou-Burkina Faso, West Africa. The weather variation during the rainy season significantly affects the photo-disinfection processes (solar disinfection and photo-Fenton). The dilution of the water by rainwater highly affected the chemical composition of the wells' water used in this study; very low iron contents Compared to the ones recorded during the dry season were recorded in all water samples. Both photo-disinfection processes were used to treat 25 L of water in a compound parabolic collector (CPC). None of them have shown the total inactivation of both wild enteric bacteria strains (total coliforms/E. coli and Salmonella spp.) involved in the treatment. However, the total coliforms/E. coli strains were totally inactivated during the exposure under most of the photo Fenton treatment. Also, the remaining strains, especially those of Salmonella spp. were achieved during the subsequent 24h of dark storage under the action of the Fenton process. Under uniquely solar radiation, total inactivation was recorded only in the total coliforms/E. coli strains. The impact of the available irradiance on the efficiency of the photo-Fenton disinfection of natural water was highlighted during the exposure under high intermittent solar radiation. The impact of the HCO3(-) concentration of both wells' water on the evolution of the pH during the photo-disinfection was recorded. Drastic decrease was noticed after the initial fast increase in presence of low HCO3(-) concentration while a steady state was observed after the increase in presence of higher concentration. The redox activities of the nitrogen components of the water during both photo disinfection processes have led to increased concentration of nitrite in all the cases and variations were noticed in that of nitrate and ammonia. PMID- 24950498 TI - Short and medium-term effects of a wildfire and two emergency stabilization treatments on the availability of macronutrients and trace elements in topsoil. AB - In NW Spain, a European region with very high fire incidence and erosion risks, the effects on soils of a medium-to-high severity wildfire and two emergency stabilization techniques were studied. In burned plots (control, BS; seeded with cereal, BSS; straw mulched, BSM) and adjacent unburned plots (US), the topsoil (0 2 cm) pH and thirteen NH4Ac-DTPA extractable elements were evaluated at t = 0, 4, 8 and 12 months after the fire. Compared to US, fire increased by 0.3-0.5 units the soil pH which decrease slowly over time, but remaining significantly higher at t = 12 (BS, BSM, BSS>US). Ammonium nitrogen (N) levels were higher (p<0.05) in burned plots than in US, difference decreasing progressively from 48-fold (t = 0) to 25-fold (t = 12). Although no significant effect of fire was immediately observed, the extractable sodium (Na) and potassium (K) were higher (p<0.05) in burned plots than in US at t = 4 and t = 8, probably due to cation leaching from the overlying ash. Fire did not modify the extractable magnesium (Mg), but at t = 0 the extractable calcium (Ca) and phosphorous (P) were transiently and significantly higher in burned plots than in US. Extractable aluminum (Al), iron (Fe), copper (Cu), cobalt (Co) and zinc (Zn) were lower and manganese (Mn) was higher in burned plots than in US. Neither seeding nor mulching significantly modified the topsoil concentrations of the elements considered. The PCA revealed that BS, BSM and BSS became more similar to US over the study period due to a rapid decrease in extractable Ca and Mg and a slow decrease in extractable Mn and NH4(+)-N. At t = 12, the most notable differences between burned plots and US were in the concentrations of extractable Al and Zn. Data suggest that at least another 4-8 months will be required for full recovery of the burned plots to unburned conditions. PMID- 24950497 TI - Conceptualizing and assessing the effects of installation and operation of photovoltaic power plants on major hydrologic budget constituents. AB - This study addresses the effects of land use change from agricultural to photovoltaic parks (PVPs) on the hydrology of an area. Although many environmental effects have been identified and analyzed, only minor attention has been given to the hydrologic effects of the installation and operation of PVPs. The effects of current PVP installation and operation practices on major hydrologic budget constituents (surface runoff, evapotranspiration and percolation) were identified, conceptualized, quantified and simulated using SWAT model. Vosvozis river basin located in north Greece was selected as a test site. Additionally, long-term effects were simulated using dynamically downscaled climate projections by a Regional Climate Model (RCM) driven by 5 different General Circulation Models (GCMs) for the period 2011-2100. Results indicate that surface runoff and percolation potential are significantly increased at the local scale and have to be considered during PVP siting, especially when sensitive and protected ecosystems are involved. PMID- 24950499 TI - The association of LUR modeled PM2.5 elemental composition with personal exposure. AB - BACKGROUND AND AIMS: Land use regression (LUR) models predict spatial variation of ambient concentrations, but little is known about the validity in predicting personal exposures. In this study, the association of LUR modeled concentrations of PM2.5 components with measured personal concentrations was determined. The elements of interest were copper (Cu), iron (Fe), potassium (K), nickel (Ni), sulfur (S), silicon (Si), vanadium (V) and zinc (Zn). METHODS: In Helsinki (Finland), Utrecht (the Netherlands) and Barcelona (Spain) five participants from urban background, five from suburban background and five from busy street sites were selected in each city (15 participants per city). Outdoor, indoor and personal 96-hour PM2.5 samples were collected by the participants over periods of two weeks in three different seasons (winter, summer and spring/autumn) and the overall average was calculated. Elemental composition was measured by ED-XRF spectrometry. The LUR models for the average ambient concentrations of each element were developed by the ESCAPE project. RESULTS: LUR models predicted the within-city variation of average outdoor Cu and Fe concentrations moderately well (range in R(2) 27-67% for Cu and 24-54% for Fe). The outdoor concentrations of the other elements were not well predicted. The LUR modeled concentration only significantly correlated with measured personal Fe exposure in Utrecht and Ni and V in Helsinki. The LUR model predictions did not correlate with measured personal Cu exposure. After excluding observations with an indoor/outdoor ratio of >1.5, modeled Cu outdoor concentrations correlated with indoor concentrations in Helsinki and Utrecht and personal concentrations in Utrecht. The LUR model predictions were associated with measured outdoor, indoor and personal concentrations for all elements when the data for the three cities was pooled. CONCLUSIONS: Within-city modeled variation of elemental composition of PM2.5 did not predict measured variation in personal exposure well. PMID- 24950501 TI - Impact of myeloid cells on the efficacy of anticancer chemotherapy. AB - Tumors are not immunologically silent but evolve and respond to therapy in the context of a continuous, bi-directional interaction with the host immune system. In line with this notion, several clinically successful chemotherapeutics have been shown to mediate antineoplastic effects as they (re)activate an anticancer immune response that is generally executed by lymphoid cells. Myeloid cells play a central role in this process, not only because they critically regulate the activity of T and B lymphocytes, but also because they exert direct tumoricidal effects, at least in some settings. Here, we discuss the impact of various myeloid cell populations, including macrophages, dendritic cells and myeloid derived suppressor cells, on the efficacy of anticancer chemotherapy. PMID- 24950502 TI - A delayed presentation of cardiac tamponade after blunt trauma. AB - Cardiac tamponade is a recognised complication of blunt trauma to the chest. It usually presents at the time of the acute event but there are rare cases of delayed presentations. We present such a case where the tamponade occurred six weeks following the trauma to the chest wall. PMID- 24950500 TI - Conscious awareness is required for holistic face processing. AB - Investigating the limits of unconscious processing is essential to understand the function of consciousness. Here, we explored whether holistic face processing, a mechanism believed to be important for face processing in general, can be accomplished unconsciously. Using a novel "eyes-face" stimulus we tested whether discrimination of pairs of eyes was influenced by the surrounding face context. While the eyes were fully visible, the faces that provided context could be rendered invisible through continuous flash suppression. Two experiments with three different sets of face stimuli and a subliminal learning procedure converged to show that invisible faces did not influence perception of visible eyes. In contrast, surrounding faces, when they were clearly visible, strongly influenced perception of the eyes. Thus, we conclude that conscious awareness might be a prerequisite for holistic face processing. PMID- 24950503 TI - Duodenal perforation in a patient with non-small cell lung cancer receiving Pemetrexed-Cisplatin combination. AB - Pemetrexed is increasingly used in combination with platinum antineoplastic agents for the treatment of certain lung malignancies. Its use was associated with favorable hematological adverse reaction compared to standard regimens. Non hematological life-threatening complications such as gastrointestinal perforations are extremely rare with pemetrexed use and tend to develop in the distal bowel in patients at risk. We report the case of a 56-years old Arab male, heavy smoker newly diagnosed with Stage IV non-small cell lung cancer with no comorbidities, treated with pemetrexed-cisplatin combination. Four days after the first cycle of chemotherapy, the patient developed a small duodenal perforation that required emergency laparoscopy repair. Clinicians should have a high index of suspicion should be taken for alimentary tract perforation in patients presenting with acute abdominal pain during pemetrexed therapy. PMID- 24950504 TI - Diaphragm disease of the ileum: an unexpected cause of small bowel obstruction. AB - Diaphragm disease of the intestine is a rare entity that is commonly associated with long-term non-steroidal anti-inflammatory drug (NSAID) usage. There are reports on those that also occur without appreciable NSAID usage. Resection and anastomosis of the affected segment is the approved treatment. PMID- 24950505 TI - Periampullary carcinoma in a patient with agenesis of dorsal pancreas. AB - Agenesis of dorsal pancreas is a rare developmental anomaly. We here report a case of agenesis of dorsal pancreas in a patient of periampullary carcinoma and highlight its implications on the management. PMID- 24950506 TI - Hyperplastic sublingual gland in association with a congenitally missing ipsilateral submandibular gland. AB - A congenitally absent unilateral submandibular gland is a rare condition. We present such a case with an associated ipsilateral benign hyperplastic sublingual gland. The enlarged sublingual gland may well represent a compensatory response to the missing submandibular gland, but it is known that sublingual gland tumours are malignant in approximately 90% of cases and so a sublingual gland swelling is viewed with a high degree of suspicion. Clinical diagnosis of sublingual hyperplasia becomes a challenge if there is a missing unilateral submandibular gland, but a full investigation is important to rule out a more sinister pathology. PMID- 24950507 TI - Episodic cauda equina compression from an intradural lumbar herniated disc: a case of 'floppy disc'. AB - Intradural disc herniation (IDDH) is a rare complication of intervertebral disc disease and comprises 0.26-0.30% of all herniated discs, with 92% of them located in the lumbar region (1). We present a case of IDDH that presented with intermittent symptoms and signs of cauda equina compression. We were unable to find in the literature, any previously described cases of intermittent cauda equina compression from a herniated intradural disc fragment leading to a "floppy disc syndrome". PMID- 24950508 TI - An unusual case of severe haematemesis: a cautionary tale. AB - We present a case of pancreatitis with secondary pseudoaneurysm formation in a branch of the hepatic artery, which fistulated into the common bile duct following endoscopic retrograde cholangiopancreatography. This aneurysm manifested itself clinically with recurrent haematemesis, and was treated by embolisation of the anterior and posterior branches of the right hepatic artery. PMID- 24950509 TI - Incidentally detected squamous cell carcinoma in non-functioning kidney presenting as multi-cystic mass. AB - Squamous cell carcinoma (SCC) of urinary tract is a rarely encountered tumor. The incidence of this tumor is 1.4 per cent of all renal malignancies (1). We present a case of 52 years male with squamous cell carcinoma of renal pelvis, presenting as chronic pyelonephritis transforming the kidney into non-functioning multicystic cavitatory mass without any renal calculi. The case highlights the rarity of tumor in absence of calculi or any other predisposing factor. Moreover, histology of resected specimen detected features of SCC giving importance to careful and exhaustive assessment of specimen and of histologic sections, when there is no suspicion of malignancy clinically. PMID- 24950510 TI - Gastric outlet obstruction caused by a pyloric submucosal fibroepithelial tumour. AB - A 57 year old male patient presented to our hospital with vomiting, epigastric discomfort, and loss of appetite over a 24hr period. Subsequent investigations demonstrated a submucosal lesion causing gastric outlet obstruction. The patients deteriorating condition mandated laparotomy and a pathologic diagnosis was made of a pyloric submucosal fibroepithelial lesion from the resected distal stomach and adherent transverse colon; no malignant features were found. This is to our knowledge the first instance of a fibroepithelial neoplasm occurring within the gastrointestinal tract. PMID- 24950511 TI - Duplication of the inferior vena cava. AB - We highlight the case of a double Inferior Vena Cava (IVC) encountered in a multi visceral recovery operation on a deceased donor. In such cases pre-operative abdominal cross sectional imaging is usually not available hence the procurement surgeon needs to rely on vigilance and awareness of other potential anatomical variations that are associated with the condition. We outline our operative approach, summarize the embryological development of IVC and present the case as a reminder of this rare anatomical variation. PMID- 24950512 TI - Thyroid-stimulating hormone reference range and factors affecting it in a nationwide random sample. AB - BACKGROUND: Previous studies with mainly selected populations have proposed contradicting reference ranges for thyroid-stimulating hormone (TSH) and have disagreed on how screening, age and gender affect them. This study aimed to determine a TSH reference range on the Abbott Architect ci8200 integrated system in a large, nationwide, stratified random sample. To our knowledge this is the only study apart from the NHANES III that has addressed this issue in a similar nationwide setting. The effects of age, gender, thyroid peroxidase antibody (TPOAb)-positivity and medications on TSH reference range were also assessed. METHODS: TSH was measured from 6247 participants randomly drawn from the population register to represent the Finnish adult population. TSH reference ranges were established of a thyroid-healthy population and its subpopulations with increasing and cumulative rigour of screening: screening for overt thyroid disease (thyroid-healthy population, n=5709); screening for TPOAb-positivity (risk factor-free subpopulation, n=4586); and screening for use of any medications (reference subpopulation, n=1849). RESULTS: The TSH reference ranges of the thyroid-healthy population, and the risk factor-free and reference subpopulations were 0.4-4.4, 0.4-3.7 and 0.4-3.4 mU/L (2.5th-97.5th percentiles), respectively. Although the differences in TSH between subgroups for age (p=0.002) and gender (p=0.005) reached statistical significance, the TSH distribution curves of the subgroups were practically superimposed. CONCLUSIONS: We propose 0.4-3.4 mU/L as a TSH reference range for adults for this platform, which is lower than those presently used in most laboratories. Our findings suggest that intensive screening for thyroid risk factors, especially for TPOAb-positivity, decreases the TSH upper reference limit. PMID- 24950514 TI - Time for a prospective study to evaluate the Amber Care Bundle. PMID- 24950517 TI - Circles of care: should community development redefine the practice of palliative care? AB - Specialist palliative care, within hospices in particular, has historically led and set the standard for caring for patients at end of life. The focus of this care has been mostly for patients with cancer. More recently, health and social care services have been developing equality of care for all patients approaching end of life. This has mostly been done in the context of a service delivery approach to care whereby services have become increasingly expert in identifying health and social care need and meeting this need with professional services. This model of patient centred care, with the impeccable assessment and treatment of physical, social, psychological and spiritual need, predominantly worked very well for the latter part of the 20th century. Over the last 13 years, however, there have been several international examples of community development approaches to end of life care. The patient centred model of care has limitations when there is a fundamental lack of integrated community policy, development and resourcing. Within this article, we propose a model of care which identifies a person with an illness at the centre of a network which includes inner and outer networks, communities and service delivery organisations. All of these are underpinned by policy development, supporting the overall structure. Adoption of this model would allow individuals, communities, service delivery organisations and policy makers to work together to provide end of life care that enhances value and meaning for people at end of life, both patients and communities alike. PMID- 24950518 TI - Can palliative care reduce futile treatment? A systematic review. AB - BACKGROUND: Palliative care interventions have the potential to lower health service costs by reducing the intensity of treatments intended to have curative effect while concentrating on quality of life and, in due course, quality of death. A patient receiving treatment inspired by curative intent during the end stage of their life is potentially exposed to medical futility. AIM: To conduct a systematic review of the evidence for palliative interventions reducing health service costs without impacting on quality of care. METHOD: An electronic search of MEDLINE, EMBASE, AMED and CINAHL databases, augmented by hand-searching techniques, was performed. Only research where palliative care was the intervention or observation, and cost, together with either quality of life or patient satisfaction with care were outcome measures, was included in results. RESULTS: Of 1964 sources identified, only 12 measured both cost and an appropriate quality outcome. Evidence supported existing research that palliative care interventions generally reduce health service costs. Evidence of concurrent improvement in quality-of-life outcomes was limited; little available evidence derives from randomised trial designs. Small sample sizes and disparate outcome measures hamper statistical assessments. CONCLUSIONS: Evidence that palliative interventions cut costs, without reducing quality of life, by minimising futile medical acts is limited. Further research, including both observational studies and controlled trials, should be conducted to collect empirical data in this field. Future research should examine palliative interventions earlier in chronic progressive illness, and incorporate standardised outcome measures to allow meta analysis. PMID- 24950519 TI - Assessing the uptake of the Liverpool Care Pathway for dying patients: a systematic review. AB - Improving the care of the dying is regarded as a national priority and current guidelines stipulate the need to provide holistic palliative care. Despite this, many dying patients and carers report low levels of comfort and satisfaction with care. Reasons include poor coordination of care, variability in communication and crisis-driven interventions. Integrated care pathways aim to support care coordination and open communication with patients and carers. One example is the Liverpool Care Pathway (LCP). Using the LCP entails assessment of eligibility criteria which requires skills, knowledge and clinical judgement about its timing. This can be problematic, and little is known about actual uptake, characteristics of assessed patients and reasons for inclusion/exclusion. A comprehensive systematic review was conducted for papers published between January 1990 and July 2012 providing information on LCP uptake. 17 papers met inclusion criteria. A total of 18 052 patients were placed on the LCP, in a variety of inpatient and primary care settings, and cancer and non-cancer diagnoses. 47.4% of dying patients identified were placed on the LCP. Although the LCP is widely recommended, it is only used for around half of dying patients. Reasons may include lack of knowledge, high staff turnover and concerns about applicability particularly for unpredictable dying trajectories. The proportion of patients who meet the eligibility criteria and the reasons surrounding low uptake remain unclear. Research is urgently required to further quantify the variable use of the LCP, and to investigate whether alternative approaches should be developed for non-cancer groups. PMID- 24950520 TI - Information transfer to out-of-hours co-operatives: a survey of general practitioners' views in relation to palliative patients. AB - BACKGROUND: In Ireland, weekend and night medical cover for community based patients is largely provided by general practice co-operatives. Doctors working in this service do not have direct access to patients' medical records which challenges continuity of care. OBJECTIVES: This study investigates the opinion of general practitioners (GPs) on the potential value of a formalised method of information transfer regarding their palliative patients to out-of-hours GP co operatives. The survey was designed to identify the information that is necessary to offer appropriate anticipated end-of-life care. METHODS: A questionnaire was sent to all 414 GPs registered in the Irish Medical Directory in the southwest of Ireland. Data were analysed with Microsoft Excel and SPSS V.12.0. RESULTS: 52% response rate with exclusion of incomplete questionnaires allowed analysis of 212 data sets. Currently, 82% of GPs do not routinely transfer information pertaining to end-of-life issues to the out-of-hours service. Despite this, 96% would value a standardised way of transferring information. 67% felt they sometimes refer unnecessarily to hospital emergency departments due to lack of information. The most important items of information identified by study participants are as follows: ? Diagnosis (97%) ? Medications (94%) ? Patient insight (91%) ? Patient wishes regarding end-of-life care (90%) ? Anticipated problems and suggested management(90%). CONCLUSIONS: A structured format for information transfer regarding end-of-life care is deemed important by GPs when working on-call at night and weekends. Diagnosis, patient preference and management plans are valued. PMID- 24950521 TI - Discontinuity of care at end of life: a qualitative exploration of OOH end of life care. AB - OBJECTIVE: This study aimed to understand the experiences of palliative care patients when accessing or making decisions about out of hours (OOH) services. It also aimed to illuminate barriers and enablers to accessing appropriate and timely care following the introduction of the 2004 New General Medical Services Contract. METHOD: Longitudinal prospective qualitative study using semi structured interviews and telephone interviews over 6 months and analysed for thematic content. 32 patients defined as receiving palliative care in six General Practices and three hospices selected on the basis of size and rural/urban location in Southern England were recruited. RESULTS: Continuity of care was highly valued. Participants described the importance of being known by the healthcare team, and the perceived positive implications continuity could have for the quality of care they received and the trust they had in their care. Various factors prevented participants from seeking help or advice from OOH services, despite having health concerns that may have benefitted from medical assistance. Prior poor experience, limited knowledge of services and knowing who to call and, indeed, when to call were all factors that reportedly shaped participants' use of OOH services. CONCLUSIONS: Interpersonal or relationship continuity and management continuity are vital to the process of optimising the patient experience of OOH palliative care. While recent service innovations are tackling some of the issues highlighted, this research reinforces the value patients with palliative care needs places on continuity and the need to improve this aspect of care management. PMID- 24950522 TI - Effect of a home-based end-of-life nursing service on hospital use at the end of life and place of death: a study using administrative data and matched controls. AB - OBJECTIVE: To assess the effect of routinely delivered home-based end-of-life care on hospital use at the end of life and place of death. DESIGN: Retrospective analysis using matched controls and administrative data. SETTING: Community-based care in England. PARTICIPANTS: 29,538 people aged over 18 who received Marie Curie nursing support compared with 29,538 controls individually matched on variables including: age, socioeconomic deprivation, prior hospital use, number of chronic conditions and prior diagnostic history. INTERVENTION: Home-based end of-life nursing care delivered by the Marie Curie Nursing Service (MCNS), compared with end-of-life care available to those who did not receive MCNS care. MAIN OUTCOME MEASURES: Proportion of people who died at home; numbers of emergency and elective inpatient admissions, outpatient attendances and attendances at emergency departments in the period until death; and notional costs of hospital care. RESULTS: Intervention patients were significantly more likely to die at home and less likely to die in hospital than matched controls (unadjusted OR 6.16, 95% CI 5.94 to 6.38, p<0.001). Hospital activity was significantly lower among intervention than matched control patients (emergency admissions: 0.14 vs 0.44 admissions per person, p<0.001) and average costs across all hospital services were lower (unadjusted average costs per person, L610 (intervention patients) vs L1750 (matched controls), p<0.001). Greater activity and cost differences were seen in those patients who had been receiving home nursing for longer. CONCLUSIONS: Home-based end-of-life care offers the potential to reduce demand for acute hospital care and increase the number of people able to die at home. PMID- 24950523 TI - Is home-based palliative care cost-effective? An economic evaluation of the Palliative Care Extended Packages at Home (PEACH) pilot. AB - OBJECTIVE: The aim of this study was to evaluate the cost-effectiveness of a home based palliative care model relative to usual care in expediting discharge or enabling patients to remain at home. DESIGN: Economic evaluation of a pilot randomised controlled trial with 28 days follow-up. METHODS: Mean costs and effectiveness were calculated for the Palliative Care Extended Packages at Home (PEACH) and usual care arms including: days at home; place of death; PEACH intervention costs; specialist palliative care service use; acute hospital and palliative care unit inpatient stays; and outpatient visits. RESULTS: PEACH mean intervention costs per patient ($3489) were largely offset by lower mean inpatient care costs ($2450) and in this arm, participants were at home for one additional day on average. Consequently, PEACH is cost-effective relative to usual care when the threshold value for one extra day at home exceeds $1068, or $2547 if only within-study days of hospital admission are costed. All estimates are high uncertainty. CONCLUSIONS: The results of this small pilot study point to the potential of PEACH as a cost-effective end-of-life care model relative to usual care. Findings support the feasibility of conducting a definitive, fully powered study with longer follow-up and comprehensive economic evaluation. PMID- 24950524 TI - Community pharmacists: a forgotten resource for palliative care. AB - Timely access to medicines within the community is important for palliative patients where their preferred place of care is the home environment. The objective of this observational study is to establish baseline data to quantify the issue of poor access to medicines for symptom control in the last few days of life. The list of 13 medicines was generated from medicine use within a metropolitan palliative care unit. A survey was designed to determine which of these 13 medicines community pharmacies stock, the expiry date of this stock, awareness of palliative care patients by community pharmacists and basic demographic characteristics of the community pharmacies. Surveys were distributed, by post, to all community pharmacies in South Australia. The response rate was 23.7%, and was representative of all socioeconomic areas. Each pharmacy stocked a median of 3 medicines (range 0-12) with 1 in 8 pharmacies having none of the 13 medicines listed in the survey. When the data was combined to identify the range of medicines from all pharmacies within a geographical postcode region, the median number of medicines increased to 5 medicines per postcode. Just over 1 in 5 pharmacies reported learning about the palliative status of a patient through another health practitioner. Community pharmacies remain an underused resource to support timely access to medicines for community based palliative patients. Palliative care services and government agencies can develop new strategies for better access to medicines that will benefit community patients and their carers. PMID- 24950525 TI - What tools are available to identify patients with palliative care needs in primary care: a systematic literature review and survey of European practice. AB - BACKGROUND: It can be difficult to identify when a palliative care approach should be started both in malignant, and particularly, in non-malignant disease, ideally to run alongside disease-modifying care. A structured method or tool may be useful to help general practitioners (GPs) identify patients for early palliative care and trigger assessment and care planning. AIMS: To document what tools for identification of patients with palliative care needs are available in the published literature and to ascertain how GPs in Europe currently identify patients for palliative care. METHODS: A systematic literature search using PubMed and Embase, and a questionnaire survey among key informants in 14 European countries requesting data on methods used to identify patients with palliative care needs. RESULTS: The literature search identified four tools. The questionnaire survey identified a further three in current use and found that in current practice identification is largely based on a GP's own clinical judgement and information received from the hospital: tools are rarely used. CONCLUSIONS: Although several identification tools have been developed, none of these have been validated or widely implemented in Europe. Further collaborative international development, implementation and evaluation of such tools are recommended. PMID- 24950526 TI - Use of a structured palliative care summary in patients with established cancer is associated with reduced hospital admissions by out-of-hours general practitioners in Grampian. AB - OBJECTIVES: Palliative care summaries are used by general practices to provide structured anticipatory care information to those providing care during the out of-hours period. We hypothesised that the availability of a palliative care summary for individuals with established cancer would influence emergency hospital admission during the out-of-hours period. METHODS: Each consultation with Grampian Medical Emergency Department (GMED) is recorded on the ADASTRA software system and the nature of the consultation is Read coded. We retrospectively reviewed consultations between 1 January 2011 and 31 December 2011 which had been coded as 'neoplasm' or 'terminal care'. The availability of a palliative care summary on ADASTRA and admission status were recorded. chi(2) Test of association was performed. Binary logistic regression was used for multivariate analysis exploring the effect of a palliative care summary on admission, while adjusting for important confounders. RESULTS: 401 patients with established cancer were identified who had presented to GMED in 2011. 35.7% had a palliative care summary available on ADASTRA. Of the 401 contacts, 100 patients were admitted to hospital. Not having a palliative care summary made admission significantly more likely; chi(2)=12.480, p=0.001. (OR 2.425, 95% CI 1.412 to 4.165). CONCLUSIONS: Availability of a structured palliative care plan can aid decision making in the out-of-hours period and prevent unplanned hospital admissions. PMID- 24950527 TI - Response to: Defining the palliative care patient: its challenges and implications for service delivery. PMID- 24950528 TI - Patients want to be involved in end-of-life care research. PMID- 24950529 TI - Erroneous assumptions about deep palliative sedation and euthanasia. PMID- 24950531 TI - Examining rating scales using Rasch and Mokken models for rater-mediated assessments. AB - A variety of methods for evaluating the psychometric quality of rater-mediated assessments have been proposed, including rater effects based on latent trait models (e.g., Engelhard, 2013; Wolfe, 2009). Although information about rater effects contributes to the interpretation and use of rater-assigned scores, it is also important to consider ratings in terms of the structure of the rating scale on which scores are assigned. Further, concern with the validity of rater assigned scores necessitates investigation of these quality control indices within student subgroups, such as gender, language, and race/ethnicity groups. Using a set of guidelines for evaluating the interpretation and use of rating scales adapted from Linacre (1999, 2004), this study demonstrates methods that can be used to examine rating scale functioning within and across student subgroups with indicators from Rasch measurement theory (Rasch, 1960) and Mokken scale analysis (Mokken, 1971). Specifically, this study illustrates indices of rating scale effectiveness based on Rasch models and models adapted from Mokken scaling, and considers whether the two approaches to evaluating the interpretation and use of rating scales lead to comparable conclusions within the context of a large-scale rater-mediated writing assessment. Major findings suggest that indices of rating scale effectiveness based on a parametric and nonparametric approach provide related, but slightly different, information about the structure of rating scales. Implications for research, theory, and practice are discussed. PMID- 24950532 TI - Differential item functioning analysis using a multilevel Rasch mixture model: investigating the impact of disability status and receipt of testing accommodations. AB - The assessment of differential item functioning (DIF) remains an area of active research in psychometrics and educational measurement. In recent years, methodological innovations involving mixture Rasch models have provided researchers with an additional set of tools for more deeply understanding the root causes of DIF, while at the same time increased interest in the role of disabilities and accommodations has also made itself felt in the measurement community. The current study furthered work in both areas by using the newly described multilevel mixture Rasch model to investigate the presence of DIF associated with disability and accommodation status at both examinee and school levels for a 3rd grade language assessment. Results of the study found that indeed DIF was present at both levels of analysis, and that it was associated with the presence of disabilities and the receipt of accommodations. Implications of these results for both practitioners and researchers are discussed. PMID- 24950533 TI - Rater effect comparability in local independence and rater bundle models. AB - A large body of literature exists describing how rater effects may be detected in rating data. In this study, we compared the flag and agreement rates for several rater effects based on calibration of a real data under two psychometric models the Rasch rating scale model (RSM) and the Rasch testlet-based rater bundle model (RBM). The results show that the RBM provided more accurate diagnoses of rater severity and leniency than do the RSM which is based on the local independence assumption. However, the statistical indicators associated with rater centrality and inaccuracy remain consistent between these two models. PMID- 24950534 TI - Improving the Individual Work Performance Questionnaire using Rasch analysis. AB - Recently, the Individual Work Performance Questionnaire (IWPQ) version 0.2 was developed using Rasch analysis. The goal of the current study was to improve targeting of the IWPQ scales by including additional items. The IWPQ 0.2 (original) and 0.3 (including additional items) were examined using Rasch analysis. Additional items that showed misfit or did not improve targeting were removed from the IWPQ 0.3, resulting in a final IWPQ 1.0. Subsequently, the scales showed good model fit and reliability, and were examined for key measurement requirements (e.g., category ordening, unidimensionality, and differential item functioning). Finally, calculation and interpretability of scores were addressed. Compared to its previous version, the final IWPQ 1.0 showed improved targeting for two out of three scales. As a result, it can more reliably measure workers at all levels of ability, discriminate between workers at a wider range on each scale, and detect changes in individual work performance. PMID- 24950535 TI - Influence of DIF on differences in performance of Italian and Asian individuals on a reading comprehension test of Spanish as a foreign language (negative emotionality) in Hong Kong. AB - Research into Differential Item Functioning (DIF) has been an active research area in language testing (Ferne and Rupp, 2007). In this study we analyzed the DIF of two groups with different types of native language (927 Italians and 280 Asians) in a reading comprehension task forming part of an exam in Spanish as a foreign language. The Mantel-Haenszel (MH) and Rasch procedures for the detection of uniform and nonuniform DIF were used. The results reveal that the Rasch model and MH converge substantially on the results. Uniform DIF was detected in 6.6 per cent of the items and nonuniform DIF in 16.7 per cent. Half of the items affected by DIF favored the focal group (Asians) and the other half favored the reference group (Italians). The difference in test performance of the two groups did not appear to be affected by the elimination of items with DIF. PMID- 24950536 TI - Rasch rating scale analysis of the Attitudes Toward Research Scale. AB - College students may view research methods courses with negative attitudes, however, few studies have investigated this issue due to the lack of instruments that measure the students' attitudes towards research. Therefore, the purpose of this study was to examine the psychometric properties of a Attitudes Toward Research Scale using Rasch rating scale analysis. Assessment of attitudes toward research is essential to determine if students have negative attitudes towards research and assist instructors in better facilitation of learning research methods in their courses. The results of this study have shown that a thirty item Attitudes Toward Research Scale yielded scores with high person and item reliability. PMID- 24950537 TI - Measuring the ability of military aircrews to adapt to perceived stressors when undergoing centrifuge training. AB - This study assessed the ability of military aircrews to adapt to stressors when undergoing centrifuge training and determined what equipment items caused perceived stress and needed to be upgraded. We used questionnaires and the Rasch model to measure aircrew personnel's ability to adapt to centrifuge training. The measurement items were ranked by 611 military aircrew personnel. Analytical results indicated that the majority of the stress perceived by aircrew personnel resulted from the lightproof cockpit without outer reference. This study prioritized the equipment requiring updating as the lightproof cockpit design, the dim lighting of the cockpit, and the pedal design. A significant difference was found between pilot and non-pilot subjects' stress from the pedal design; and considerable association was discernible between the seat angle design and flight hours accrued. The study results provide aviators, astronauts, and air forces with reliable information as to which equipment items need to be urgently upgraded as their present physiological and psychological effects can affect the effectiveness of centrifuge training. PMID- 24950539 TI - Primary Non-Hodgkins Lymphoma of the prostate presenting as haematuria. AB - We report a rare case of Primary Non-Hodgkins lymphoma of prostate presenting as an emergency with gross haematuria. A review of literature is also discussed. A 71 year old man presented to Emergency department with gross haematuria and was found to have grossly enlarged right lobe of the prostate on digital rectal examination. Histology confirmed a diffuse large B-cell lymphoma of the prostate. CT scan revealed a para-aortic lymphadenopathy which resolved with chemotherapy followed by radiotherapy. The patient remains disease free more than 5 years after initial diagnosis. The treatment and prognosis of primary lymphoma of prostate is same as with other nodal lymphomas. Primary or secondary lymphoma of the prostate should also be considered in patients presenting with haematuria. Cystoscopy and prostate biopsies should be taken to confirm the diagnosis. Treatment with chemo-radiotherapy can provide lasting benefit. PMID- 24950538 TI - New insights in the regulation of Rab GTPases by G protein-coupled receptors. AB - Cargo-mediated regulation of vesicular transport has received great attention lately. Rab GTPases, forming the largest branch of the Ras GTPase superfamily, regulate almost every step of vesicle-mediated trafficking. Growing evidence suggests that mutations, aberrant expression, and altered post-translational modifications of Rab GTPases are associated with human diseases. However, their regulatory mechanisms and how they are connected to cargo proteins are still poorly understood. Accumulating data indicate that G protein-coupled receptors (GPCRs) directly associate with Rab GTPases and that these interactions dictate receptor trafficking. Yet, it remained unclear whether the receptors could regulate the targeting and activity of Rab GTPases in various cell compartments. It is only in recent years that experimental studies showed that GPCR signaling and interaction with Rab-associated regulatory proteins modulate the localization and activity of Rab GTPases. This research is revealing novel regulatory mechanisms of these small GTPases and should contribute to the progress in effective drug development. Recently published in the Journal of Cell Science, Lachance et al. present a novel role for ubiquitylation of Rab11a by a beta2AR/HACE1 complex in regulating Rab11a activity and beta2AR trafficking. PMID- 24950540 TI - Ameloblastoma of the frontal sinuses: a rare site for recurrence. AB - Ameloblastoma is a benign odontogenic tumour which commonly recurs after initial surgery; most recurrences occur at the site of the primary tumour. A rare case of recurrence of a maxillary ameloblastoma in the frontal sinuses is presented. To our knowledge there are no previous reports in the literature of a benign maxillary ameloblastoma extending into the frontal sinuses. PMID- 24950541 TI - A rare case of surgical pathway implantation of clival chordoma presenting as a neck mass. AB - Chordomas are rare, locally-aggressive tumours with a high rate of local recurrence. Recurrence along the route of surgical entry is an uncommon form of treatment failure. We report a case of a 59-year-old female who presented with a 3 cm neck mass in the left mid-sternocleidomastoid region. She had a history of a large clival chordoma resected via a transcervical, transparotid and transoral approach along with endoscopic intranasal exposure and a palatal split 4.5 years previously, followed by radiation to the primary site. Biopsy of the neck mass confirmed the diagnosis of chordoma recurrence following implantation in the surgical pathway. This case illustrates that while surgical pathway recurrence is a rare entity, it requires a high index of suspicion and should be considered in the differential diagnosis of a patient with a history of chordoma resection presenting with a mass more than two years after undergoing initial treatment. PMID- 24950542 TI - A rare presentation of TB: Osteomyelitis of distal ulna. AB - Tuberculosis (TB) is a major health issue in both developing and developed countries such as the UK. Healthy individuals who contract the infection have only 5-10% chance of converting to the active disease over their lifetime. We present the clinical history of a 76 year old female who attended the emergency department complaining of wrist pain, and was only diagnosed with TB after three years. This case report emphasises the importance of including TB in the differential diagnosis when treating patients with an infection resistant to conventional antibiotics, even though risk factors for TB may not be evident or special stains for TB are negative. PMID- 24950543 TI - Meckels diverticulum and intestinal ischaemia. AB - We report an exceptional case of intestinal ischaemia requiring resection, secondary to torsion around a long Meckel's diverticulum. Meckel's diverticulum is an uncommon congenital abnormality of the small bowel. Meckel's diverticulum giving rise to intestinal ischaemia that requires resection is very rare but potentially fatal complication. A 62 year old woman presented as an emergency with sudden onset upper abdominal pain and vomiting. Clinical suspicion of cholecystitis prompted an ultrasound scan which revealed a distended gallbladder with multiple gallstones and an otherwise normal abdomen. Laparoscopy revealed a large volume of free blood in all four quadrants and a loop of gangrenous small bowel. The case was converted to laparotomy and a 640 mm loop of infarcted small bowel, torted around a Meckel's diverticulum, was resected. Detection of a complication arising from a Meckel's diverticulum presents a diagnostic challenge and can be mistaken for more common surgical presentations. PMID- 24950544 TI - Perihepatic abscess secondary to retained appendicolith: A rare complication managed laparoscopically. AB - Appendicectomy is one of the commonest emergency operations performed worldwide. In cases of perforated appendicitis, the prevalence of post-operative abscess formation is up to 20 per cent (1). Most cases can be managed with drainage and antibiotics. However, a minority of these will leave a retained appendicolith. We present a case of a 17 year old female patient who presented 1 year after laparoscopic appendicectomy for perforated appendicitis, with right upper quadrant pain and sepsis. Computed tomography (CT) of the abdomen was performed and revealed a retained appendicolith with perihepatic abscess formation in the right upper quadrant. She underwent laparoscopic drainage of this perihepatic abscess and removal of the faecolith. She was discharged home the following day and remains well. PMID- 24950545 TI - Leukaemic infiltration of gall bladder - unusual presentation of occult chronic lymphocytic leukaemia. AB - Extramedullary involvement in early stage chronic lymphocytic leukaemia (CLL) is rare. We report the first case of an incidental finding of gall bladder infiltration in a patient who underwent a cholecystectomy for gallstone pancreatitis with no preceding history of CLL. This case reiterates the importance of subjecting even routine cholecystectomy specimens for histopathology examination in the context of this unusual presentation. PMID- 24950546 TI - Retroperitoneal schwannoma. AB - Retroperitoneal schwannomas are rare tumors and a correct pre-operative diagnosis is often not possible. They are usually identified incidentally via cross sectional imaging. Diagnosis is based on histopathologic examination and immunohistochemistry. A 57-year-old man with a retroperitoneal schwannoma, as an unusual localisation, is presented. PMID- 24950547 TI - Pregnancy following gastric bypass surgery (Roux-en-Y) for morbid obesity. AB - Morbidly obese women are at increased risk of obstetric complications and poor neonatal outcomes. Gastric bypass surgery is being performed with increased frequency in reproductive-aged women to treat morbid obesity. Both maternal and fetal complications have been reported in women who underwent gastric bypass surgery. Current recommendations advise delaying pregnancy for at least 1 year following bariatric surgery. This guideline is meant to discourage women from becoming pregnant during the rapid weight loss phase of the first post-surgical year. Pregnancy during this time could lead to a malnourished fetus, due to some protein malnutrition, possibly resulting in complications such as low birth weight or malformation. However, data validating this concern are lacking. We report a case of 37-year-old woman who had laparoscopic bypass surgery, as treatment for morbid obesity, 6 months prior to her pregnancy with good outcome despite the short duration between gastric bypass surgery and pregnancy. PMID- 24950548 TI - Small bowel ischaemia resulting from delayed presentation of an incarcerated right-sided diaphragmatic hernia. AB - A 51 year old man presented with a short history of severe upper abdominal pain and vomiting. An initial chest radiograph demonstrated gas in the right subphrenic space and a subsequent CT scan demonstrated a hernia through the mid part of the right hemi-diaphragm, containing small bowel and omentum. A detailed history revealed that there had been trauma to the right side of the chest approximately 12 years previously. An emergency laparoscopy revealed a right sided diaphragmatic hernia containing non-viable small bowel and omentum. After converting to a small midline laparotomy, a small bowel resection and primary anastomosis was performed. The patient was discharged from hospital 12 days later. In any patient presenting with symptoms of upper abdominal pain, with a prior history of trauma, the diagnosis of diaphragmatic hernia should therefore be considered. PMID- 24950549 TI - An unusual cause of perianal fistula. AB - Anal pain is a common presentation in colorectal clinic. Accurate diagnosis often requires examination under anaesthesia as pain prevents careful assessment. This report intends to highlight a rare cause of a superficial perianal fistula caused by an ingested foreign body. A 36-year-old Afro-Caribbean gentleman underwent examination under anaesthesia of rectum. He had a 2-week history of perianal pain and discharge. Intra-operatively, a piece of bone from a pork spare rib was found embedded within the superficial subcutaneous fistula. There was an associated abscess cavity adjacent to the fistula, which was curetted. The fistula was laid open and the bone was removed. The cavity was successfully left to heal by secondary intention. Ingested foreign body is a very unusual cause of perianal sepsis and subsequent fistula formation. Incision and drainage of the abscess along with removal of foreign body is the key to immediate pain relief and cure. PMID- 24950550 TI - Retropharyngeal haematoma - an unusual cause of airway obstruction. AB - Retropharyngeal haematoma is a rare and potentially fatal cause of airway obstruction. The treatment of retropharyngeal haematoma is contentious. We report a case of an 84 year old woman on aspirin and warfarin who developed a retropharyngeal haematoma following minor blunt head and neck trauma. The patient presented insidiously with Capp's triad and developed delayed airway obstruction necessitating emergency fibreoptic endoscopic intubation. Both tracheostomy and surgical drainage were avoided and she recovered well. PMID- 24950551 TI - Non-Hodgkins Lymphoma presenting as Garcin's Syndrome. AB - An 80 year old man presented with a twelve month history of progressive multiple unilateral cranial nerve palsies. A gadolinium enhanced MRI scan of his head and neck was performed. This showed an extra-axial enhancing lesion, which enveloped the hemi-mandible at the level of the left inferior alveolar nerve, and a dumbbell shaped lesion within the cerebellopontine angle. An incisional biopsy was performed to gain a tissue diagnosis, which demonstrated a Non-Hodgkin's Lymphoma. The combination of signs, symptoms and radiological findings enabled a diagnosis of Garcin's Syndrome secondary to Non-Hodgkin's Lymphoma. PMID- 24950552 TI - A case of complete spontaneous regression of extremely advanced Merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is a rare locally malignant cutaneous tumor of neuroendocrine origin, most often occurring on the head and neck of the elderly. MCC is a highly aggressive tumor with a high percentage of recurrence, metastatic spread and mortality. Despite the highly malignant course of MCC, there have been several reports of spontaneous regression or resolution. We report the clinical course of a 71-year-old man with MCC. The tumor initially occurred in the left lower eyelid and advanced to encompass nearly half the face. Despite its large size, complete spontaneous regression of the tumor occurred. This is the most advanced case of complete spontaneous regression of MCC to be reported. PMID- 24950553 TI - Delayed diagnosis of pseudoaneurysm formation in a patient with diaphyseal aclasis. AB - A 15 year old boy, with known diaphyseal aclasis, presented with a swollen left leg. The diagnosis of popliteal pseudoaneurysm, a known and well understood vascular complication, was delayed due to presentation suggestive of a chondrosarcoma. In this age group, sarcomatous change is more common and a potentially sinister complication of diaphyseal aclasis. Following a sarcoma MDT referral, the correct diagnosis was confirmed by ultrasound and CT angiogram. This case identifies one of the largest, non-ruptured popliteal pseudoaneurysms reported and illustrates an unusual complication of a rare orthopaedic genetic condition, which is potentially limb threatening. PMID- 24950554 TI - An unusual shoulder injury. AB - Traumatic pseudoaneurysm of the axillary artery is a rare sequel of shoulder injury. We report here a unique phenomenon of delayed presentation axillary pseudoaneurysm some time after an initial blunt injury, with no evidence of gross bony injury. The gentleman presented again some weeks later after a failure of rehabilitation and progressive neurological deficit in the affected arm. Ultimate management of the lesion was by endovascular insertion of a covered stent, and decompression of the axilla. Unfortunately the lack of subsequent neurological recovery parallels some of the findings in the literature, from cases where relief of the brachial plexus was not undertaken soon enough. PMID- 24950555 TI - Smooth muscle hyperplasia of the epididymis. AB - Benign smooth muscle cell proliferation commonly involves a variety of body organs, yet is a rare finding in the spermatic cord or paratesticular tissue of the male genital tract. Here we discuss a case of smooth muscle hyperplasia of the epididymis which presented as an intrascrotal mass. This is a very rare condition and should be considered in the differential diagnosis of any paratesticular mass. PMID- 24950556 TI - Thigh subcutaneous emphysema: is that a clear indication for thigh exploration? AB - Thigh subcutaneous emphysema is an usual orthopaedic presentation normally associated with musculoskeletal problems or penetrating wounds. But, sometimes it can be related to abdominal pathology. We present a case of subcutaneous emphysema of the thigh secondary to para-caecal abscess. PMID- 24950557 TI - Pseudo-lyre sign. AB - Carotid body tumours cause characteristic splaying of the internal and external carotid arteries, known as 'Lyre Sign'. Vagal paragangliomas are rare tumours that arise from glomus cells along the length of the vagus nerve. We present a case in which a vagal paraganglioma has arisen from the vagus nerve at the carotid bifurcation, and has mimicked the 'Lyre Sign' of a carotid body tumour. PMID- 24950558 TI - Appendiceal duplication with simultaneous acute appendicitis and appendicular perforation causing small bowel obstruction. AB - Acute appendicitis, as well as intestinal obstruction, is a common surgical emergencies. Both the conditions can present as an acute abdomen, however the diagnosis of acute appendicitis can be overlooked when it presents as a small bowel obstruction. Difficulties in correctly identifying the cause of pain can be hazardous to the patient and care needs to be taken in obtaining a prompt and accurate diagnosis enabling the most appropriate management. Appendiceal duplication although rare and difficult to diagnose preoperatively, should be checked while operating for appendicular pathology in order to avoid serious clinical and medicolegal implications. We hereby report a case of appendiceal duplication presenting as small bowel obstruction with one appendix having acute appendicitis and the other one perforated in the middle third. PMID- 24950559 TI - Submucosal lipoma of the large intestine masquerading as a colonic malignancy. AB - Lipomas of the alimentary tract are rare tumours that can mimic malignant lesions. They are often small and asymptomatic although larger tumours can present with intusussception or as abdominal masses. We present a case of a transverse colon submucosal lipoma masquerading as a colonic adenocarcinoma leading to resection. A 74 year-old-man was referred urgently for assessment with altered bowel habits, and lower abdominal discomfort along with a positive Faecal Occult-Blood sample. Colonoscopy demonstrated a large polypoidal lesion at the hepatic flexure with ulceration. Biopsies were inconclusive. A staging CT scan confirmed a 3.3 x 4.3 x 3.4cm Polyp with colonic wall thickening suspicious of malignancy. An extended right hemi-colectomy was performed. Histology showed a large submucosal lipoma with 12 reactive lymph nodes. Colonic lipoma often present as incidental findings detected on either imaging or endoscopically whilst investigating other symptoms. Their appearances can mimic colonic malignancy and surgical resection may be required. PMID- 24950560 TI - A rare case of necrotising epiglottitis. AB - We report a case of an acute necrotizing supraglottitis in a healthy patient. Only seven cases of necrotizing epiglottitis/supraglottitis have been reported in medical literature; all in immunocompromised patients. The features and characteristics of necrotizing epiglottitis are discussed with review of all previously reported cases. PMID- 24950561 TI - The surgical management of intercostal lung herniation using bioprosthesis. AB - Lung hernia is a rare occurrence. Consequently there is little literature providing guidance to effective management. Classified as congenital or acquired, there are fewer than 300 cases described in current literature (1). We describe a unique method for the management of spontaneous rib fractures and, resulting posterior lung herniation in a 65 year old man following a bout of coughing. PMID- 24950562 TI - Rare benign pathologies mimicking malignancy: A cautionary tale for Whipple's resections. AB - Benign pathologies demonstrated after a Whipple's resection (pancreatoduodenectomy) for pancreatic and peri-ampullary lesions are relatively uncommon. Here we report two cases where a Whipple's procedure was undertaken for suspected pancreaticobiliary cancer and where the final histology revealed, in each case, a rare benign lesion. The first case confirmed a cholesterol polyp in the distal common bile duct whilst the second case revealed ampullary intramural ectopic gland hyperplasia. Although pre-operative imaging helps in differentiating some benign lesions from malignant lesions, rare benign pathology may still mimic malignant conditions leading to a Whipple's resection. PMID- 24950563 TI - Operative repair of an incidentally diagnosed giant hepatic artery aneurysm. AB - Hepatic Artery Aneurysms (HAA) are rare vascular lesions which are associated with significant morbidity and mortality in the event of rupture. Early diagnosis and expedient management are therefore important to optimise outcome. Here we report a case of a giant Hepatic Artery Aneurysms (HAA) found incidentally on Computerised Tomography, successfully managed without complication by elective surgical repair. PMID- 24950564 TI - Giant colonic mucocele following palliative surgery for metastatic adenocarcinoma. AB - We report an unusual case of a giant colonic mucocele following ileo-sigmoid bypass surgery in a patient with advanced adenocarcinoma of the splenic flexure. The formation of a giant colonic mucocele resulted from distal splenic flexure obstruction due to tumour relapse and proximal caecal obstruction due to peritoneal disease with subsequent accumulation of mucus in the closed loop. PMID- 24950565 TI - Laparoscopic repair of a large interstitially incarcerated inguinal hernia. AB - A 68 year old female presented for elective repair of an abdominal wall hernia. Preoperative CT imaging revealed a right inguinal hernia defect with hernia contents coursing cephalad between the external and internal abdominal oblique muscles. This was consistent with an interstitial inguinal hernia, a rare entity outside of post- traumatic hernias. At operation the hernia contents were reduced laparoscopically. The hernia was then repaired by transitioning to the totally extraperitoneal (TEP) approach using a 15cm X 15cm piece of polyester mesh. The patient had an uneventful recovery. Interstitial hernias are rare, difficult to diagnose and potentially dangerous if left untreated. There is no consensus on the ideal repair of these unique hernias. This represents a minimally invasive repair of an unusual hernia, with a novel approach to diagnose and manage the hernia and its redundant sac. PMID- 24950566 TI - Upper limb compartment syndrome secondary to streptococcus pyogenes (Group A streptococcus) infection. AB - Compartment syndrome caused by Streptococcus pyogenes (Group A streptococcus) has rarely been described. We report a case of a healthy 44-year-old male who presented with compartment syndrome of the right forearm and subsequent acute respiratory distress syndrome. The patient received antibiotics and urgent surgical decompression, followed by delayed wound closure without the need for skin grafting. The patient recovered with no loss of power, sensation or range of movement. High index of suspicion, early intervention and excellent post operative management were essential in recovery. PMID- 24950568 TI - Torsion of the gallbladder. AB - Torsion of the gallbladder is an uncommon condition that is rarely diagnosed pre operatively. Here, we present the case of a 76 year old male who was found to have a complete torsion of the gallbladder, and was successfully treated with cholecystectomy. PMID- 24950567 TI - Pseudoaneurysm of the right hepatic artery and bile duct necrosis as a complication of acute cholecystitis in a diabetic patient. AB - A very uncommon complication of acute cholecystitis is the development of a pseudoaneurysm in an arterial branch of the hepatic artery. We report a rare case of a patient with acute cholecystitis who presented with a pseudoaneurysm of the right anterior hepatic artery complicated by necrosis of the bile duct and hepatic infarction. A 70-year-old woman attended the emergency department with an unusual presentation of acute cholecystitis involving abdominal discomfort and a mass in the right upper quadrant. CT demonstrated a pseudoaneurysm of the right hepatic artery. Emergency selective transcatheter arterial embolization and cholecystectomy were performed. Subsequently, bile duct necrosis and hepatic ischemic damage made it necessary to perform a right hepatectomy and bile duct resection. Once a hepatic artery pseudoaneurysm is confirmed, its embolization may be useful to ensure the patient's safety. However, in our experience such pseudoaneurysms may be associated with hepatic and biliary ischemia. PMID- 24950569 TI - Biliary stent migration presenting as transdiverticular sigmoid perforation. AB - The authors present a case report of a patient with distal plastic biliary stent migration resulting in perforation through a sigmoid diverticulum. The perforation was contained by a loop of ileum that had descended into the pelvis allowing for a sigmoid resection with primary anastomosis. This rare complication of biliary stent placement should be included in differential diagnosis of any patient that presents with lower quadrant abdominal pain after endoscopic retrograde cholangiopancreatography with stent placement. PMID- 24950570 TI - An unusual case of dysphagia following routine electrical DC cardioversion. AB - Dysphagia can arise from a multitude of underlying pathologies affecting any of the three stages of swallowing; oral, pharyngeal and or oesophageal; and can be further classified as intraluminal, intramural or extramural. We discuss an unusual case of acute dysphagia secondary to haematoma formation within one of a number of potential neck spaces. We report on a novel precipitant; routine electrical cardioversion. A review of relevant anatomical boundaries, symptoms, precipitants and treatment options will be discussed. PMID- 24950571 TI - Naso-pharyngeal entrapment. An unusual complication of naso-jejunal feeding tube insertion using a guidewire. AB - We present the case of an unusual complication of insertion of a naso-jejunal feeding tube (NJT) using a guidewire, where the guidewire formed an alpha-loop in the naso-pharynx, becoming entrapped after cutting into the soft palate. This required ENT input and a general anaesthetic to rectify the situation. PMID- 24950572 TI - Upper intestinal obstruction due to inverted intraduodenal diverticulum. AB - Inverted intraduodenal diverticulum is a rare congenital abnormality usually arising near the ampulla of Vater. We describe a case of an inverted duodenal diverticulum in a patient that presented with an upper recurrent intestinal obstruction that required surgery. Recognition of the entity and its anatomic relationships to the ampulla of Vater is essential to the prevention of iatrogenic complications. The inverted intraduodenal diverticulum must be considered in the management of upper intestinal obstruction of unclear origin. PMID- 24950573 TI - Signet ring adenocarcinoma of a urethral diverticulum. AB - Urethral diverticula are a rare entity. Carcinoma in a urethral diverticulum is a particularly unusual finding with only a little over 200 cases in the reported literature. Adenocarcinoma is the most common carcinoma to occur in a urethral diverticulum. To our knowledge, there are only a handful of cases of signet ring cell adenocarcimona of the urethra and no cases of signet ring adenocarcinoma found in a urethral diverticulum. We present a case report of an incidentally found signet ring cell adenocarcinoma of a female urethral diverticulum. PMID- 24950574 TI - Herniation of the gallbladder within a hernia of the abdominal wall associated with Mirizzi Syndrome. AB - A gallbladder incarcerated hernia associated with Mirizzi syndrome is a very rare entity and to our knowledge this is the first case ever described in literature. An 85-year-old man presented at the emergency department with a tender right upper quadrant mass. Computed Tomography (CT) revealed the presence of a gallbladder lithiasis with signs of acute cholecystitis, herniated through the abdominal wall with an associated Mirizzi syndrome. Laparoscopic cholecystectomy and repair of the abdominal wall defect were performed. The patient recovered very well and the postoperative period was uneventful. PMID- 24950575 TI - A case of tension pneumothorax mimicking spontaneous rupture of the diaphragm. AB - A 40 year old asthmatic presented with acute respiratory distress. Chest radiograph appeared to show loops of bowel within the thorax and a diagnosis of spontaneous/effort rupture of the diaphragm was made. Emergency laparotomy revealed an intact diaphragm and chest drain was inserted relieving a tension pneumothorax. PMID- 24950576 TI - Allantoic cyst - an unusual umbilical cord swelling. AB - We report a baby with an unusual umbilical cord swelling. On the antenatal scans, a cystic area within the umbilical cord near its insertion onto the abdominal wall was detected. Postnatally an unusually thick umbilical cord with a yellow fluid filled cyst at the base was noted. The fluid from the cyst was confirmed as urine and ultrasound confirmed patent urachus. The baby underwent a cystoscopy and excision of patent urachus with associated allantoic cyst. Allantoic cyst is a rare swelling formed at the base of umbilicus associated with a patent urachus which results from an allantoic remnant. Paediatricians need to be aware about this condition as investigation is required to differentiate allantois cysts from umbilical pseudocysts. A patent urachus with allantoic cyst requires surgical excision. PMID- 24950577 TI - Just a simple case of tonsillitis? Lemierre's Syndrome and thrombosis of the external jugular vein. AB - Oropharyngeal infections are routinely encountered within general practice and accident and emergency departments. Most settle with simple analgesia and antibiotics; occasionally such patients may develop Lemierre's syndrome (LS) a rare and potentially fatal sequela that can be easily overlooked. We aim to highlight the main symptoms, pathology, investigations and management. PMID- 24950578 TI - A rare case of pyomyositis due to swine flu. AB - Pyomyositis is a bacterial infectious disease of the large skeletal muscles, mostly seen in tropical regions. A case with such a multitude of abscesses has never been described in the western world, nor following an H1N1 infection. We report of a 31 year old man who presented himself with complaints of muscle pain and fever. His complaints were attributed to a proven H1N1 infection. However, despite proper therapy his condition worsened. He had developed multiple abscesses in both arms and legs. After surgical and radiologic drainage and antibiotic treatment our patient healed without any symptoms. Pyomositis is related with immuno-compromisation. Our patient might have been immunocompromised due to the H1N1 infection. Rhabdomyolysis following influenza has been described before, however a relation with H1N1 never was. Imaging studies help detect and confirm the diagnosis. When missed, serious complications may arise. PMID- 24950579 TI - Congenital bladder diverticulum - a rare adult presentation. AB - Congenital bladder diverticula usually present during childhood. They are solitary and present with infection, haematuria and abdominal pain. They are associated with a smooth walled bladder without bladder outlet obstruction. An adult male presented with voiding symptoms and lower abdominal pain. On evaluation he had a grossly distended bladder extending from the hypogastrium up to the right hypochondrium. Investigations revealed a large bladder diverticulum and left hydronephrosis with a non-functioning left kidney. Left nephroureterectomy and diverticulectomy were carried out. We report this case because of its unusual adult presentation. PMID- 24950580 TI - Oesophageal xanthalasma with Barrett's Oesophagus and Menetrier's Disease. AB - This case report describes three conditions; oesophageal xanthalasma, Menetrier's disease and Barrett's oesophagus, none of which have ever been seen together, diagnosed in one patient. Further to the details of the case the endoscopic, radiological and histological findings are discussed. Any links between these three conditions are currently unclear. PMID- 24950581 TI - A rare case of an aberrant anterior mitral valve chord resulting in severe mitral regurgitation. AB - A 49 year old female presented with severe dyspnoea due to mitral regurgitation. Echocardiography revealed an aberrant mitral valve chord causing severe mitral regurgitation. The aberrant chord extended between the anterior mitral valve leaflet (AMVL) and the atrial septum causing AMVL prolapse. Resection of the aberrant chord and correction of the AMVL using synthetic Gore-Tex sutures was performed. The patient made an uneventful recovery with post-op echocardiography demonstrating normal mitral valve function. PMID- 24950582 TI - Brunner's gland hyperplasia: an unusual cause of hemorrhagic shock. AB - Brunner's gland hyperplasia is a very rare lesion of the duodenum, which is usually asymptomatic and diagnosed incidentally during upper gastrointestinal endoscopy. It can cause gastrointestinal bleeding but hemorrhagic shock is a rare clinical presentation of Brunner's gland hyperplasia. The authors present a case of a patient with hemorrhagic shock due to a bleeding Brunner's gland hyperplasia, treated by urgent laparotomy and polypectomy. PMID- 24950583 TI - Retroperitoneal sarcoma: a rare cause of intestinal perforation in two cases. AB - Retroperitoneal sarcoma is a rare malignancy often insidious in onset. At initial presentation, abdominal mass, pain or obstructive symptoms are the most common complaints. Here we present two patients who presented with abdominal discomfort and were discovered to have retroperitoneal sarcomas with secondary intestinal perforation. Perforation is a rare complication of retroperitoneal sarcoma, but one with the potential to significantly affect patient outcomes. Both patients underwent surgical resection and pathological characterization of their malignancies. The discovery of intestinal perforation during workup necessitates initiation of empirical antibiotic coverage and prompt surgical intervention. PMID- 24950584 TI - Sarcomatous carcinoma with osteosarcomatoid differentiation of the bladder with simultaneous sigmoid colon adenocarcinoma. AB - Sarcomatoid carcinoma is a rare tumor of the urinary bladder and accounts for approximately 0.3% of all bladder malignancies. In these tumors, histogenesis and biological behaviour remains controversial. Herein, we report a case of sarcomatoid carcinoma with osteosarcomatoid differentiation of the urinary bladder with simulataneous sigmoid colon adenocarcinoma. PMID- 24950585 TI - Tension faecopneumothorax: a rare presentation of colonic diverticular perforation. AB - Tension faeco-pneumothorax is rare, typically occurring following strangulation of a diaphragmatic hernia. We report the case of a 69-year-old gentleman with a previous history of thoraco-abdominal oesophagectomy, who presented with an acute abdomen and respiratory distress. Initial investigations revealed pneumoperitoneum and left-sided pneumothorax. The patient rapidly deteriorated with development of tension pneumothorax. Following tube thoracostomy, feculent fluid was drained. At laparotomy, gross faecal peritonitis secondary to colonic diverticular perforation was encountered, with no evidence of intestinal diaphragmatic herniation. This case report highlights the rarity of this clinical entity as well as the possible complications of hiatal surgery. PMID- 24950586 TI - Malignant otitis externa with skull base osteomyelitis. AB - Malignant otitis externa associated with skull base osteomyelitis is a condition seen classically in the elderly, diabetic patient. This disease is difficult to manage, often requiring long-term antibiotic therapy. Here we present such a case, seen in a 74- year-old lady. Initially, she was treated for a number of years in the outpatient department with intermittent ear complaints, but eventually required a hospital admission that lasted for 6 months due to a severe malignant otitis externa complicated by skull base osteomyelitis. We will discuss the clinical features, diagnostic criteria, imaging and management of this life threatening clinical entity. PMID- 24950587 TI - Cocoon within an abdominal cocoon. AB - Intestinal obstruction is a fairly common surgical emergency that usually occurs due to herniae, adhesions, or bands. Rarely, uncommon causes such as an abdominal cocoon are encountered, where part or all of the small intestine is encased within a thin membrane. We report one such case of abdominal cocoon, in whom, further encasement of the distal ileum was seen within a separate membrane. PMID- 24950589 TI - The Birth Memories and Recall Questionnaire (BirthMARQ): development and evaluation. AB - BACKGROUND: Childbirth is a challenging and emotive experience that is accompanied by strong positive and/or negative emotions. Memories of birth may be associated with how women cognitively process birth events postpartum and potentially their adaptation to parenthood. Characteristics of memories for birth may also be associated with postnatal psychological wellbeing. This paper reports the development and evaluation of a questionnaire to measure characteristics of memories of childbirth and to examine the relationship between memories for birth and mental health. METHODS: The Birth Memories and Recall Questionnaire (BirthMARQ) was developed by generating items from literature reviews and general measures of memory characteristics to cover dimensions relevant to childbirth. Fifty nine items were administered to 523 women in the first year after childbirth (M = 23.7 weeks) as part of an online study of childbirth. Validity of the final scale was checked by examining differences between women with and without probable depression and PTSD. RESULTS: Principal components analysis identified 23 items representing six aspects of memory accounting for 64% of the variance. These were: Emotional memory, Centrality of memory to identity, Coherence, Reliving, Involuntary recall, and Sensory memory. Reliability was good (M alpha = .80). Women with probable depression or PTSD reported more emotional memory, centrality of memories and involuntary recall. Women with probable depression also reported more reliving, and those with probable PTSD reported less coherence and sensory memory. CONCLUSION: The results suggest the BirthMARQ is a coherent and valid measure of the characteristics of memory for childbirth which may be important in postnatal mood and psychopathology. While further testing of its reliability and validity is needed, it is a measure capable of becoming a valuable tool for examining memory characteristics in the important context of childbirth. PMID- 24950588 TI - Immune modulation to improve tissue engineering outcomes for cartilage repair in the osteoarthritic joint. AB - Osteoarthritis (OA), the most common form of arthritis, is a disabling degenerative joint disease affecting synovial joints and is associated with cartilage destruction, inflammation of the synovial membrane, and subchondral bone remodeling. Inflammation of the synovial membrane may arise secondary to degenerative processes in articular cartilage (AC), or may be a primary occurrence in OA pathogenesis. However, synovial inflammation plays a key role in the pathogenesis and disease progression of OA through the production of pro inflammatory mediators, and is associated with cartilage destruction and pain. The triggers that initiate activation of the immune response in OA are unknown, but crosstalk between osteoarthritic chondrocytes, cartilage degradation products, and the synovium may act to perpetuate this response. Increasing evidence has emerged highlighting an important role for pro-inflammatory mediators and infiltrating inflammatory cell populations in the progression of the disease. Tissue engineering strategies hold great potential for the repair of damaged AC in an osteoarthritic joint. However, an in-depth understanding of how OA-associated inflammation impacts chondrocyte and progenitor cell behavior is required to achieve efficient cartilage regeneration in a catabolic osteoarthritic environment. In this review, we will discuss the role of inflammation in OA, and investigate novel immune modulation strategies that may prevent disease progression and facilitate successful cartilage regeneration for the treatment of OA. PMID- 24950590 TI - SOLD1 is expressed in bovine trophoblast cell lines and regulates cell invasiveness. AB - BACKGROUND: Secreted protein of Ly-6 domain 1 (SOLD1), a secretory-type member of the Ly-6 superfamily, is expressed in both fetal and maternal tissues throughout gestation. SOLD1 mRNA is expressed in the endometrium and in trophoblast mononucleate and binucleate cells, suggesting it plays an important role not only in placental architecture at early gestation, but also in remodeling the endometrium at late gestation. Here, we investigate the expression of SOLD1 mRNA and protein in trophoblast cell lines. In addition, we examine the effect of SOLD1 on the invasive ability of trophoblast cells. METHODS: We measured SOLD1 gene expression in thirteen bovine trophoblast (BT) cell lines by using quantitative reverse transcription PCR (qRT-PCR). SOLD1 protein levels were examined in two cell lines, BT-C and BT-K, by using Western blotting and immunocytochemistry. In addition, we measured the invasive activity of BT cells in the presence or absence of anti-bovine SOLD1 antibodies. RESULTS: At variable levels, SOLD1 was expressed in all thirteen cell lines; however, expression remained below that of proximal fetal membrane tissue. SOLD1 protein, which was approximately 28 kDa in size, was detected in perinuclear area of the cytoplasm in BT cells. Treatment with anti-bovine SOLD1 antibody had a dose-dependent suppressive effect on the invasiveness of BT-K cell lines. CONCLUSIONS: The present study is the first to investigate SOLD1 expression in vitro, in trophoblastic cell lines. Our data suggested that SOLD1 is involved in the regulation of the trophoblast invasiveness. Therefore, SOLD1 may play an active and crucial role in mediating communication at the fetomaternal interface. PMID- 24950591 TI - Paraproteinemic maculopathy. AB - PURPOSE: Paraproteinemia relates to monoclonal gammopathy-producing pathologic antibodies with serous macular detachment being an uncommon ocular manifestation. We ascertained the clinical course of maculopathy in paraproteinemia and investigated the effect of various therapeutic methods on the resolution of subretinal deposits. DESIGN: Multicenter, retrospective, observational case series. PARTICIPANTS: The records of patients with paraproteinemia with optical coherence tomography (OCT) documentation of serous macular detachment were reviewed. METHODS: Data collection included coexisting morbidity, rheology data (immunoglobulin level, hematocrit, and blood viscosity), clinical examination results, and OCT findings. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), height and basal area of the serous macular detachment, and systemic versus local therapies. RESULTS: A total of 33 cases were collected: 10 new and 23 previously reported in the literature. Diabetes was present in 7 patients, systemic hypertension in 9 patients, and anemia in 18. Mean initial immunoglobulin level was 6497 mg/dl, and mean serum viscosity was 5.5 centipoise (cP). Mean logarithm of the minimum angle of resolution initial vs. final BCVA was 0.55 (Snellen equivalent, 20/71) vs. 0.45 (20/56) in the right eye and 0.38 (20/48) vs. 0.50 (20/63) in the left eye. After mean follow-up of 7 months (range, 0-51 months). Systemic therapies included plasmapheresis (18), chemotherapy (30), blood transfusions (2), transplantation of progenitor hematopoietic cells (2), and oral rituximab (10). Immunoglobulin levels normalized in 8 patients and were unchanged in 1 after plasmapheresis, chemotherapy, or both. Ocular therapy in 8 patients included vitrectomy (1), laser photocoagulation (4), intravitreal bevacizumab (5), intravitreal triamcinolone (2), intravitreal dexamethasone implant (1), intravitreal rituximab (1), and sub-Tenon corticosteroid (1). The maculopathy resolved partially or completely in 17 patients and worsened or remained unchanged in 14 patients over median follow-up of 7 months. Maculopathy was unilateral in 9 cases and occurred at a lower initial immunoglobulin level in diabetics. There was a positive correlation between area of the detachment and serum viscosity. CONCLUSIONS: Paraproteinemic maculopathy can be unilateral. Decreasing the blood immunoglobulin level is the primary goal of therapy for paraproteinemic maculopathy, and this can be achieved by a systemic route. Coexisting diabetes facilitates leakage of immunoglobulins at lower levels than in nondiabetics. PMID- 24950592 TI - Ethnic differences of intraocular pressure and central corneal thickness: the Singapore Epidemiology of Eye Diseases study. AB - PURPOSE: To determine the ethnic differences in the distribution of intraocular pressure (IOP) and central corneal thickness (CCT) in a multi-ethnic Asian population by self-reported ethnicity and genetic ancestry. DESIGN: Population based, cross-sectional study. PARTICIPANTS: A total of 10 033 adults (3353 Chinese, 3280 Malays, and 3400 Indians) aged >40 years. METHODS: Participants underwent standardized systemic and ocular examinations and interviewer administered questionnaires for risk factor assessment. The IOP readings were obtained by Goldmann applanation tonometry (Haag-Streit, Konig, Switzerland) before pupil dilation. The CCT was measured with ultrasound pachymetry. Genetic ancestry was derived using principal component (PC) analysis. Regression models were used to investigate the association of IOP and CCT with potential risk factors and genetic ancestry. MAIN OUTCOME MEASURES: Intraocular pressure and CCT. RESULTS: After excluding participants with a history of glaucoma surgery or medication, refractive surgery, corneal edema, or corneal dystrophy, IOP and CCT readings were available for 3251 Chinese, 3232 Malays, and 3317 Indians. The mean IOP readings in the Chinese, Malay, and Indian participants were 14.3+/-3.1, 15.3+/-3.7, and 15.8+/-2.9 mmHg, respectively (P < 0.001). The prevalence of participants with IOP >=21 mmHg was 2.6% in Chinese, 6.2% in Malays, and 4% in Indians (P < 0.001). In the multivariate regression analysis, the Malay and Indian participants on average had 0.81 and 1.43 mmHg higher IOP levels, respectively, than Chinese (P < 0.001). The mean CCT reading was 552.3+/-33.4 MUm in Chinese, 540.9+/-33.6 MUm in Malays, and 540.4+/-33.6 MUm in Indians (P < 0.001). The percentage of participants with CCT <555 MUm was 52.8% in Chinese, 68.5% in Malays, and 66.2% in Indians (P < 0.001). The IOP and CCT levels are significantly correlated with genetic ancestry in our South East Asian population. CONCLUSIONS: Chinese have the thickest CCT but lowest IOP among the 3 major ethnic groups. In addition, there is a higher proportion of Malays with IOP >=21 mmHg and CCT <555 MUm compared with the Chinese or Indians. This disparity across ethnic groups should be taken into account by future studies investigating IOP and CCT as risk factors or diagnostic tests for glaucoma in Asian populations. PMID- 24950593 TI - Evaluation of the long-term efficacy and safety of infliximab treatment for uveitis in Behcet's disease: a multicenter study. AB - PURPOSE: To evaluate the long-term efficacy and safety of infliximab for the treatment of uveitis in Behcet's disease (BD). DESIGN: Retrospective multicenter study using a questionnaire. PARTICIPANTS: A total of 164 consecutive patients with BD treated with infliximab for more than 1 year were studied. The mean age at initiation of infliximab treatment was 42.6+/-11.7 years, and the mean treatment duration was 32.9+/-14.4 months. METHODS: Data before and at the last visit during infliximab treatment were analyzed in 4 groups divided by duration of treatment: group A (n = 43, 12-<24 months), group B (n = 62, 24-<36 months), group C (n = 42, 36-<48 months), and group D (n = 17, >=48 months). MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), relapse of ocular inflammation, numbers of ocular inflammatory attacks per year, and adverse effects of infliximab therapy. RESULTS: The frequency of ocular attacks decreased in all groups (from 5.3+/-3.0 to 1.0+/-0.3 in group A, 4.8+/-4.6 to 1.4+/-0.3 in group B, 4.1+/-2.9 to 0.9+/-0.3 in group C, and 9.5+/-5.8 to 1.6+/-0.5 in group D; all P < 0.05). The BCVA was improved in approximately 55% of the eyes after treatment. Mean BCVA converted to logarithm of the minimum angle of resolution was improved after treatment with infliximab in groups A to C (from 0.79+/-1.04 to 0.59+/-0.94 in group A, 0.59+/-1.07 to 0.41+/-1.04 in group B, and 1.15+/-1.77 to 0.92+/-1.73 in group C; all P < 0.05) but not in group D. Uveitis relapsed in 59.1% of all patients after infliximab treatment, and no difference in duration until relapse was observed between individual groups. Approximately 80% of relapses occurred within 1 year after the initiation of infliximab treatment in all groups, 90% of which were controlled by increasing doses of topical corticosteroids and shortening the interval of infliximab infusion. Adverse effects were observed in 65 cases or 35% of all subjects. Infliximab treatment was continued in 85% of the patients, but 15% of the patients discontinued infliximab treatment because of adverse effects or insufficient efficacy. CONCLUSIONS: Infliximab reduced the frequency of ocular attacks and improved visual acuity in patients with BD-related uveitis and was generally well tolerated with few serious adverse events. PMID- 24950595 TI - Evaluation of the 'Fitting to Outcomes eXpert' (FOX(r)) with established cochlear implant users. AB - OBJECTIVES: To evaluate the possible impact of 'Fitting to Outcomes eXpert (FOX((r)))' on cochlear implant (CI) fitting in a clinic with extensive experience of fitting a range of CI systems, as a way to assess whether a software tool such as FOX is able to complement standard clinical procedures. METHODS: Ten adult post-lingually deafened and unilateral long-term users of the Advanced Bionics(TM) CI system (Clarion CII or HiRes 90K(TM)) underwent speech perception assessment with their current clinical program. One cycle 'iteration' of FOX optimization was performed and the program adjusted accordingly. After a month of using both clinical and FOX programs, a second iteration of FOX optimization was performed. Following this, the assessments were repeated without further acclimatization. RESULTS: FOX prescribed programming modifications in all subjects. Soundfield-aided thresholds were significantly lower for FOX than the clinical program. Group speech scores in noise were not significantly different between the two programs but three individual subjects had improved speech scores with the FOX MAP, two had worse speech scores, and five were the same. CONCLUSION: FOX provided a standardized approach to fitting based on outcome measures rather than comfort alone. The results indicated that for this group of well-fitted patients, FOX improved outcomes in some individuals. There were significant changes, both better and worse, in individual speech perception scores but median scores remained unchanged. Soundfield-aided thresholds were significantly improved for the FOX group. PMID- 24950594 TI - Nutritional and health status among nursing home residents in Lebanon: comparison across gender in a national cross sectional study. AB - BACKGROUND: This study described the differences between elderly men and women living in Lebanese long-term care nursing homes on socio-economic, health and nutritional status. METHODS: This study used a cross-sectional design. Field researchers obtained data from 221 residents; 148 (67%) women and 73 (33%) men, living in 36 nursing homes. Data on health conditions; nutritional, psychological, and functional status; socio-demographic characteristics, as well as social relations were collected. The analysis used both chi-square and t-test tests. RESULTS: The majority of elderly had low socio-economic and poor health status. In comparison to men, women were significantly less educated, had lower occupational status, had no partner, relied financially on their children and relatives, and enjoyed better social relations and health behaviours. Furthermore, the prevalence of both; malnutrition, and at risk of malnutrition, were at 3.2% and 27.6% respectively. There was no statistically significant difference between women and men on Mini Nutritional Assessment, Activities of Daily Living, Geriatric Depression Scale, Body Mass Index, and chronic diseases. While women reported "good" health status compared to men, they continued to have higher prevalence of diseases and chronic pain. CONCLUSIONS: This study explored the socio-demographic, health, and nutritional status of elderly residing in Lebanese nursing homes and compared these characteristics across gender. The results indicated the need of health support and institutional interventions for elderly women residents. PMID- 24950596 TI - Coronary intervention for acute coronary syndrome in a 51-year-old man with immune thrombocytopenic purpura: a case report. AB - INTRODUCTION: Treatment of the rare cases of patients with chronic idiopathic thrombocytopenic purpura with acute coronary syndrome can be a significant problem. The patient in our case report was treated successfully with percutaneous coronary intervention. CASE PRESENTATION: A 51-year-old man of Turkish origin who had idiopathic thrombocytopenic purpura was admitted to our hospital with severe chest pain. His electrocardiography was normal on admission but dynamic ischemic changes were observed during follow-up. He underwent immediate coronary angiography. In his angiography, left anterior descending artery stenosis was 90% together with the diagonal ostium. Percutaneous coronary intervention was performed successfully. Bleeding complications were not observed after the procedure. CONCLUSIONS: We report the presence of a rare case of chronic idiopathic thrombocytopenic purpura in a patient with acute coronary syndrome. In this situation a serious multidisciplinary approach is required before coronary intervention. PMID- 24950597 TI - Pre-diagnostic smoking behaviour and poorer prognosis in a German breast cancer patient cohort - Differential effects by tumour subtype, NAT2 status, BMI and alcohol intake. AB - BACKGROUND: Inconsistent associations of smoking and breast cancer-specific mortality might be explained by subgroups of patients with different susceptibility to harmful effects of smoking. METHODS: We used a prospective cohort of 3340 postmenopausal breast cancer patients aged 50-74 and diagnosed with invasive tumours 2001-2005 in Germany, with a median follow-up time of 6 years. The effect of pre-diagnostic smoking behaviour on mortality outcomes and risk of recurrence was investigated using delayed entry Cox regression analysis. Differential effects according to N-acetyltransferase (NAT2) status, BMI, alcohol consumption, and tumour subtypes were assessed. RESULTS: Overall, smoking at time of breast cancer diagnosis versus never/former smoking was non-significantly associated with increased breast cancer-specific mortality and risk of recurrence (HR 1.23, 95% CI 0.93-1.64, and HR 1.29, 95% CI 0.95-1.75, respectively). Associations were consistently stronger in NAT2 slow than in fast acetylators for all mortality outcomes. Breast cancer-specific mortality was significantly increased in smokers with NAT2 slow acetylating status (HR 1.77, 95% CI 1.13 2.79) but not in those with fast acetylating status (HR 1.09, 95% CI 0.60-1.98; Pheterogeneity=0.19). Smoking was associated with significantly poorer outcomes for triple negative and luminal A-like tumours (e.g. all-cause mortality: HR 1.93, 95% CI 1.02-3.65, and HR 2.08, 95% CI 1.40-3.10, respectively). Risk of recurrence was significantly increased for women with HER2 positive tumours (HR 3.64, 95% CI 1.22-10.8). There was significant heterogeneity by BMI for non breast cancer-specific mortality (<25 kg/m(2): HR 2.52, 95% CI 1.52-4.15 vs. >=25 kg/m(2): HR 0.94, 95% CI 0.38-2.36; Pheterogeneity=0.04). CONCLUSION: The harmful effects of smoking may be particularly relevant for certain subgroups of breast cancer patients. This may include patients with NAT2 slow acetylation status or with tumour subtypes other than luminal B, such as luminal A tumours who usually have a rather good prognosis. Emphasis on smoking cessation programmes for all cancer patients should be strengthened. PMID- 24950598 TI - Multi-locus phylogeny of lethal amanitas: implications for species diversity and historical biogeography. AB - BACKGROUND: Lethal amanitas (Amanita section Phalloideae) are a group of wild, fatal mushrooms causing many poisoning cases worldwide. However, the diversity and evolutionary history of these lethal mushrooms remain poorly known due to the limited sampling and insufficient gene fragments employed for phylogenetic analyses. In this study, five gene loci (nrLSU, ITS, rpb2, ef1-alpha and beta tubulin) with a widely geographic sampling from East and South Asia, Europe, North and Central America, South Africa and Australia were analysed with maximum likelihood, maximum-parsimony and Bayesian inference methods. Biochemical analyses were also conducted with intention to detect amatoxins and phalloidin in 14 representative samples. RESULT: Lethal amanitas were robustly supported to be a monophyletic group after excluding five species that were provisionally defined as lethal amanitas based on morphological studies. In lethal amanitas, 28 phylogenetic species were recognised by integrating molecular phylogenetic analyses with morphological studies, and 14 of them represented putatively new species. The biochemical analyses indicated a single origin of cyclic peptide toxins (amatoxins and phalloidin) within Amanita and suggested that this kind of toxins seemed to be a synapomorphy of lethal amanitas. Molecular dating through BEAST and biogeographic analyses with LAGRANGE and RASP indicated that lethal amanitas most likely originated in the Palaeotropics with the present crown group dated around 64.92 Mya in the early Paleocene, and the East Asia-eastern North America or Eurasia-North America-Central America disjunct distribution patterns were primarily established during the middle Oligocene to Miocene. CONCLUSION: The cryptic diversity found in this study indicates that the species diversity of lethal amanitas is strongly underestimated under the current taxonomy. The intercontinental sister species or sister groups relationships among East Asia and eastern North America or Eurasia-North America-Central America within lethal amanitas are best explained by the diversification model of Palaeotropical origin, dispersal via the Bering Land Bridge, followed by regional vicariance speciation resulting from climate change during the middle Oligocene to the present. These findings indicate the importance of both dispersal and vicariance in shaping the intercontinental distributions of these ectomycorrhizal fungi. PMID- 24950599 TI - Alterations in proton leak, oxidative status and uncoupling protein 3 content in skeletal muscle subsarcolemmal and intermyofibrillar mitochondria in old rats. AB - BACKGROUND: We considered of interest to evaluate how aging affects mitochondrial function in skeletal muscle. METHODS: We measured mitochondrial oxidative capacity and proton leak, together with lipid oxidative damage, superoxide dismutase specific activity and uncoupling protein 3 content, in subsarcolemmal and intermyofibrillar mitochondria from adult (six months) and old (two years) rats. Body composition, resting metabolic rate and plasma non esterified fatty acid levels were also assessed. RESULTS: Old rats displayed significantly higher body energy and lipids, while body proteins were significantly lower, compared to adult rats. In addition, plasma non esterified fatty acid levels were significantly higher, while resting metabolic rates were found to be significantly lower, in old rats compared to adult ones. Significantly lower oxidative capacities in whole tissue homogenates and in intermyofibrillar and subsarcolemmal mitochondria were found in old rats compared to adult ones. Subsarcolemmal and intermyofibrillar mitochondria from old rats exhibited a significantly lower proton leak rate, while oxidative damage was found to be significantly higher only in subsarcolemmal mitochondria. Mitochondrial superoxide dismutase specific activity was not significantly affected in old rats, while significantly higher content of uncoupling protein 3 was found in both mitochondrial populations from old rats compared to adult ones, although the magnitude of the increase was lower in subsarcolemmal than in intermyofibrillar mitochondria. CONCLUSIONS: The decrease in oxidative capacity and proton leak in intermyofibrillar and subsarcolemmal mitochondria could induce a decline in energy expenditure and thus contribute to the reduced resting metabolic rate found in old rats, while oxidative damage is present only in subsarcolemmal mitochondria. PMID- 24950601 TI - Energy harvesting for the implantable biomedical devices: issues and challenges. AB - The development of implanted devices is essential because of their direct effect on the lives and safety of humanity. This paper presents the current issues and challenges related to all methods used to harvest energy for implantable biomedical devices. The advantages, disadvantages, and future trends of each method are discussed. The concept of harvesting energy from environmental sources and human body motion for implantable devices has gained a new relevance. In this review, the harvesting kinetic, electromagnetic, thermal and infrared radiant energies are discussed. Current issues and challenges related to the typical applications of these methods for energy harvesting are illustrated. Suggestions and discussion of the progress of research on implantable devices are also provided. This review is expected to increase research efforts to develop the battery-less implantable devices with reduced over hole size, low power, high efficiency, high data rate, and improved reliability and feasibility. Based on current literature, we believe that the inductive coupling link is the suitable method to be used to power the battery-less devices. Therefore, in this study, the power efficiency of the inductive coupling method is validated by MATLAB based on suggested values. By further researching and improvements, in the future the implantable and portable medical devices are expected to be free of batteries. PMID- 24950600 TI - From molecule to mind: an integrative perspective on odor intensity. AB - A fundamental problem in systems neuroscience is mapping the physical properties of a stimulus to perceptual characteristics. In vision, wavelength translates into color; in audition, frequency translates into pitch. Although odorant concentration is a key feature of olfactory stimuli, we do not know how concentration is translated into perceived intensity by the olfactory system. A variety of neural responses at several levels of processing have been reported to vary with odorant concentration, suggesting specific coding models. However, it remains unclear which, if any, of these phenomena underlie the perception of odor intensity. Here, we provide an overview of current models at different stages of olfactory processing, and identify promising avenues for future research. PMID- 24950602 TI - Posttraumatic stress disorder and incidence of type-2 diabetes: a prospective twin study. AB - Growing evidence has linked posttraumatic stress disorder (PTSD) to insulin resistance and type-2 diabetes, but most previous studies were cross-sectional. We examined the association between PTSD and incidence of diabetes in a prospective study of middle-aged male twins from the Vietnam Era Twin Registry. Lifetime PTSD was diagnosed at baseline with the Diagnostic Interview Schedule (DIS) according to DSM-III-R criteria. Subthreshold PTSD was defined by meeting some, but not all, criteria for PTSD. A total of 4340 respondents without self reported diabetes at baseline were included. Of these, 658 reported a new diagnosis of treated diabetes over a median of 19.4 years of follow-up. At baseline, twins with PTSD showed more behavioral and metabolic risk factors such as overweight and hypertension. The age-adjusted cumulative incidence of diabetes was significantly higher in twins with PTSD (18.9%) than those without PTSD (14.4%), [odds ratio (OR) = 1.4, 95% confidence interval (CI) 1.03-1.8], and intermediate in those with subthreshold PTSD (16.4%) (OR = 1.2, 95% CI 0.9-1.5, p for trend = 0.03). Adjustment for military, lifestyle and metabolic factors diminished the association. No significant association was found comparing twin pairs discordant for PTSD. In conclusion, PTSD was prospectively associated with a 40% increased risk of new-onset type-2 diabetes which was partially explained by a cluster of metabolic and behavioral risk factors known to influence insulin resistance. Shared biological or behavioral precursors which occur within families may lead to both PTSD and insulin resistance/diabetes. Thus, PTSD could be a marker of neuroendocrine and metabolic dysregulation which may lead to type 2 diabetes. PMID- 24950603 TI - Can magnetic resonance imaging findings predict the degree of knee joint laxity in patients undergoing anterior cruciate ligament reconstruction? AB - BACKGROUND: The present study was performed to determine whether MRI findings can predict the degree of knee joint laxity in patients undergoing ACL reconstruction and whether the accuracy of the prediction is affected by the MRI acquisition time. METHODS: We assessed prospectively collected data of 154 knees with ACL tears. The presence or absence of four primary findings of ACL tears, i.e., nonvisualization, discontinuity, abnormal signal intensity, and abnormal shape of the ACL, and five secondary findings, i.e., anterior translation of the tibia relative to the femur (>=7 mm), posterior cruciate ligament angle (<105 degrees ), bone contusion, Segond fracture, and the deep sulcus sign, were determined. Knee joint laxity was assessed using the Lachman and pivot shift tests. The associations between MRI findings and clinically assessed knee joint laxity were analyzed and compared between subgroups (<=3 months from injury to MRI, 89 knees; >3 months, 65 knees). RESULTS: Nonvisualization was related to the results of the Lachman test [Odds ratio (OR), 2.6; 95% confidence interval (CI), 1.2-5.5]. Anterior translation of the tibia relative to the femur was related to the results of the pivot shift test (OR, 3.8; 95% CI, 1.6-9.4). In subgroup comparisons of the early and late MRI groups, anterior translation of the tibia relative to the femur was related to the results of the pivot shift test in the early MRI group (OR, 4.5; 95% CI, 1.4-14.4). In contrast, no MRI findings had statistically significant relationships with physical findings in the late MRI group. CONCLUSIONS: Our study indicates that MRI findings may have some usefulness for predicting the grade of knee laxity in patients with symptomatic ACL injury, but its value is limited, especially in patients with a longer time interval between injury and the performance of MRI. PMID- 24950604 TI - Validation of the diagnostic utility of salivary interleukin 8 in the differentiation of potentially malignant oral lesions and oral squamous cell carcinoma in a region with high endemicity. AB - OBJECTIVE: To evaluate the clinical utility of salivary interleukin 8 (IL-8) in the differential diagnosis of potentially malignant lesions (PMLs) and oral squamous cell carcinoma (OSCC) in a region with high oral cancer prevalence. STUDY DESIGN: Saliva and blood samples were collected from 100 participants in each group (OSCC, PMLs, and healthy controls). Serum and salivary IL-8 levels were measured by enzyme-linked immunosorbent assay. The data were subjected to appropriate statistical analysis. RESULTS: A significant increase in levels of serum and salivary IL-8 was found in OSCC compared with PMLs and healthy controls. Receiver operating characteristic curve analysis found salivary IL-8 to have superior sensitivity in detecting OSCC. A significant increase in IL-8 levels based on the histologic grading of OSCC was also observed. CONCLUSIONS: This study confirms that salivary IL-8 can be a potent marker that can be used as a tool in the differential diagnosis of PMLs and OSCC. PMID- 24950605 TI - An incidentally discovered radiolucency in the posterior maxilla. PMID- 24950606 TI - Apically extruded dentin debris by reciprocating single-file and multi-file rotary system. AB - OBJECTIVES: This study aims to evaluate the apical extrusion of debris by the two reciprocating single-file systems: WaveOne and Reciproc. Conventional multi-file rotary system was used as a reference for comparison. The hypotheses tested were (i) the reciprocating single-file systems extrude more than conventional multi file rotary system and (ii) the reciprocating single-file systems extrude similar amounts of dentin debris. MATERIALS AND METHODS: After solid selection criteria, 80 mesial roots of lower molars were included in the present study. The use of four different instrumentation techniques resulted in four groups (n = 20): G1 (hand-file technique), G2 (ProTaper), G3 (WaveOne), and G4 (Reciproc). The apparatus used to evaluate the collection of apically extruded debris was typical double-chamber collector. Statistical analysis was performed for multiple comparisons. RESULTS: No significant difference was found in the amount of the debris extruded between the two reciprocating systems. In contrast, conventional multi-file rotary system group extruded significantly more debris than both reciprocating groups. Hand instrumentation group extruded significantly more debris than all other groups. CONCLUSION: The present results yielded favorable input for both reciprocation single-file systems, inasmuch as they showed an improved control of apically extruded debris. CLINICAL RELEVANCE: Apical extrusion of debris has been studied extensively because of its clinical relevance, particularly since it may cause flare-ups, originated by the introduction of bacteria, pulpal tissue, and irrigating solutions into the periapical tissues. PMID- 24950607 TI - Photodynamic killing of Enterococcus faecalis in dentinal tubules using mTHPC incorporated in liposomes and invasomes. AB - OBJECTIVES: The present in vitro study investigates the antimicrobial photodynamic efficiency of the photosensitizer 5,10,15,20-tetra(m hydroxyphenyl)chlorin (mTHPC) incorporated in liposomes (LIP) and highly flexible invasomes (INV) on the endodontopathogenic species Enterococcus faecalis in infected dental root canals. MATERIALS AND METHODS: A total of 48 root canals were prepared mechanically to file size ISO 50 and inoculated with E. faecalis for 48 h. In the test groups, the infected root canals were subjected to aPDT with either mTHPC linked to LIP or INV. The controls were either incubated with 1 % chlorohexidine gel (CHX, positive control) or root canals were irrigated with normal saline (NaCl, negative control). After treatment all canals were mechanically enlarged (ISO 50-110), and the debris of each filing process was subjected to bacterial culture analysis. RESULTS: Both mTHPC formulations showed a significant antimicrobial effect. A bacterial reduction by up to 3.6 log-steps was ascertained for INV directly at the root canal wall. aPDT using INV (ISO 60) was more effective than CHX, which caused a decrease in only 1.2 log-steps. It was found that both liposomal mTHPC formulations were capable to suppress E. faecalis inside the dentinal tubules up to 300 MUm. CONCLUSIONS: The results show that mTHPC linked to LIP and INV is capable of efficiently reducing E. faecalis in dental root canals. CLINICAL RELEVANCE: As evidenced, E. faecalis is resistant to several conventional antibacterial treatment measures. In this context, photodynamic treatment with mTHPC delivered by INV is superior to temporary dressing with 1 % CHX gel applied for 24 h. PMID- 24950608 TI - Color stability of adhesive resin cements after immersion in coffee. AB - OBJECTIVES: Marginal discoloration of luting cement may affect the appearance of esthetic restorations. This study evaluated the color stability of current adhesive resin cements after immersion in coffee. MATERIALS AND METHODS: Four dual-cured resin cements (Clearfil SA cement Automix Universal, Maxcem Elite Clear, Maxcem Elite Yellow, and RelyX Unicem2 Automix A2) and two chemical-cured resin cements (Super-Bond C&B Clear and Super-Bond C&B Esthetic) were examined. The CIE L*a*b* of 2.0-mm-thick disc-shaped specimens was measured using a spectrophotometer on a white background (n = 6). The color differences (?E) after 1-day and 1-week immersion in 37 degrees C water or coffee were analyzed by two way ANOVA by selecting immersion solution and product as main factors, followed by Tukey's HSD test (alpha = 0.05). Water sorption and solubility were also evaluated. RESULTS: The two-way ANOVA of the ?Es suggested that the two main factors and their interaction were significant. The ?Es after coffee immersion were significantly greater than those after water immersion, except for Super Bond C&B Esthetic. The ?Es after water immersion were not significantly different among the products; those of Maxcem Elite Clear and Maxcem Elite Yellow after coffee immersion were significantly greater than the others. The water sorption and solubility significantly correlated with the ?Es. CONCLUSIONS: The ?Es of the adhesive resin cements examined after 1-week coffee immersion were significantly different among the products. The product showing greater water sorption and solubility displayed greater color change. CLINICAL RELEVANCE: Adhesive resin cements should be carefully selected when the marginal appearance of the ceramic restoration is important. PMID- 24950609 TI - Exponential convergence analysis of uncertain genetic regulatory networks with time-varying delays. AB - This study is concerned with the problem of exponential convergence of uncertain genetic regulatory networks with time-varying delays in the case of the unknown equilibrium point. The system's uncertainties are modeled as a structured linear fractional form. Novel stability criteria are obtained by using the lower bound lemma together with Jensen inequality lemma. In order to get rid of the rigorous constraint that the derivatives of time-varying delays must be less than one, a new approach is introduced by improving Lyapunov-Krasovskii functional rather than using the traditional free-weighting matrices. Finally, numerical examples are presented to demonstrate the effectiveness of the theoretical results. PMID- 24950610 TI - Gyroidal mesoporous multifunctional nanocomposites via atomic layer deposition. AB - We demonstrate the preparation of rationally designed, multifunctional, monolithic and periodically ordered mesoporous core-shell nanocomposites with tunable structural characteristics. Three-dimensionally (3D) co-continuous gyroidal mesoporous polymer monoliths are fabricated from a solution-based triblock terpolymer-resol co-assembly and used as the functional templates for the fabrication of free-standing core-shell carbon-titania composites using atomic layer deposition (ALD). The deposition depth into the torturous gyroidal nanonetwork is investigated as a function of ALD conditions and the resulting composites are submitted to different thermal treatments. Results suggest that ALD can homogenously coat mesoporous templates with well defined pore sizes below 50 nm and thicknesses above 10 MUm. Structural tunability like titania shell thickness and pore size control is demonstrated. The ordered nanocomposites exhibit triple functionality; a 3D continuous conductive carbon core that is coated with a crystalline titania shell that in turn is in contact with a 3D continuous mesopore network in a compact monolithic architecture. This materials design is of interest for applications including energy conversion and storage. Gyroidal mesoporous titania monoliths can be obtained through simultaneous titania crystallization and template removal in air. PMID- 24950612 TI - [Are STI/HIV centers effective in reducing late HIV diagnosis?]. PMID- 24950611 TI - The effects of chemical and physical penetration enhancers on the percutaneous permeation of lidocaine through equine skin. AB - BACKGROUND: The effect of physical and chemical permeation enhancers on in vitro transdermal permeation of lidocaine was investigated in the horse.Therefore, the effect of six vehicles (phosphate-buffered saline (PBS), 50% ethanol, 50% propylene glycol, 50% isopropylalcohol, 50% isopropylalcohol/isopropylmyristate and 50% dimethylsulfoxide) was examined as well as the effect of microneedle pretreatment with different needle lengths on transdermal drug delivery of lidocaine.The skin was obtained from the thorax of six Warmblood horses and was stored up to two weeks at - 20 degrees C. Franz-type diffusion cells were used to study the transdermal permeation through split skin (600 MUm thickness). The amount of lidocaine in the receptor fluid was determined by UV-VIS high performance liquid chromatography. RESULTS: All investigated vehicle supplementations diminished the transdermal flux of lidocaine through equine skin in comparison to pure PBS except dimethylsulfoxide, which resulted in comparable permeation rates to PBS. The maximum flux (Jmax) was 1.6-1.8 fold lower for lidocaine applied in 50% ethanol, propylene glycol, isopropylalcohol and isopropylalcohol/isopropylmyristate. A significant higher Jmax of lidocaine was observed when lidocaine was applied in PBS onto microneedle pretreated skin with similar permeation rates in both needle lengths. After 6 hours, 1.7 fold higher recovery rates were observed in the microneedle pretreated skin samples than in the untreated control samples. The lagtimes were reduced to 20-50% in the microneedle pretreated skin samples. CONCLUSION: Microneedles represent a promising tool for transdermal lidocaine application in the horse with a rapid systemic bioavailability. PMID- 24950613 TI - [Nosocomial infection in patients receiving a solid organ transplant or haematopoietic stem cell transplant]. AB - Bacterial infections are the most common infections in solid organ transplant recipients. These infections occur mainly in the first month after transplantation and are hospital-acquired. Nosocomial infections cause significant morbidity and are the most common cause of mortality in this early period of transplantation. These infections are caused by multi-drug resistant (MDR) microorganisms, mainly Gram-negative enterobacteria, non-fermentative Gram negative bacilli, enterococci, and staphylococci. The patients at risk of developing nosocomial bacterial infections are those previously colonized with MDR bacteria while on the transplant waiting list. Intravascular catheters, the urinary tract, the lungs, and surgical wounds are the most frequent sources of infection. Preventive measures are the same as those applied in non immunocompromised, hospitalized patients except in patients at high risk for developing fungal infection. These patients need antifungal therapy during their hospitalization, and for preventing some bacterial infections in the early transplant period, patients need vaccinations on the waiting list according to the current recommendations. Although morbidity and mortality related to infectious diseases have decreased during the last few years in haematopoietic stem cell transplant recipients, they are still one of the most important complications in this population. Furthermore, as occurs in the general population, the incidence of nosocomial infections has increased during the different phases of transplantation. It is difficult to establish general preventive measures in these patients, as there are many risk factors conditioning these infections. Firstly, they undergo multiple antibiotic treatments and interventions; secondly, there is a wide variability in the degree of neutropenia and immunosuppression among patients, and finally they combine hospital and home stay during the transplant process. However, some simple measures could be implemented to improve the current situation. PMID- 24950614 TI - Real exposure: field measurement of chemical plumes in headwater streams. AB - In fluvial systems, organismic exposure to nonpoint source pollutants will fluctuate in frequency (exposure events), intensity (concentration), and duration. The reliance on lethal concentrations and static exposure in many laboratory studies does not adequately represent nor address exposure to in situ chemical plumes of fluvial habitats. To adequately address field exposure in a laboratory setting, one needs an understanding of the physics of chemical transmission within moving fluids. Because of the chaotic nature of turbulence, chemical plumes introduced to fluvial systems have a spatial and temporal microstructure with fluxes in chemical concentration. Consequently, time-averaged static exposure models are not ecologically relevant for the major reason of in situ distribution. The purpose of this study was to quantify in situ chemical distribution and dispersion within two physically different streams. Dopamine was introduced as a chemical tracer mimicking groundwater runoff. Chemical fluxes and stream hydrodynamics were simultaneously measured using a microelectrode and an acoustic Doppler velocimeter, respectively, at three heights of three downstream locations at each research site. Fine-scale measurements of the dopamine plume microstructure showed that organisms could be exposed to chemical fluctuations where concentrations are significantly greater than the overall time-averaged concentration. These measurements demonstrate that rather than relying on static exposure, standards for pollution must consider the concept of exposure being interdependently linked to flow of the fluid medium. The relationship between fluid dynamics, pollution exposure, and organism physiology are complex and must be evaluated in ways to mimic natural systems. PMID- 24950615 TI - Preparation and characterization of magnetic gold nanoparticles to be used as doxorubicin nanocarriers. AB - Magnetic targeted drug delivery (MTD), using magnetic gold nanoparticles (Fe3O4@Au NPs) conjugated with an anti-cancer drug is a promise modality for cancer treatment. In this study, Fe3O4@Au NPs were prepared and functionalized with thiol-terminated polyethylene glycol (PEG), then loaded with anti-cancer drug doxorubicin (DOX). The physical properties of the prepared NPs were characterized using different techniques. Transmission electron microscopy (TEM) revealed the mono dispersed nature of Fe3O4@Au NPs with an average size of 20 nm which was confirmed using Dynamic light scattering (DLS) measurements. Zeta potential measurements along with UV-VIS spectroscopy demonstrated surface DOX loading on Fe3O4@Au NPs. Energy Dispersive X-ray Spectroscopy (EDX) assured the existence of both iron and gold elements in the prepared NPs. The paramagnetic properties of the prepared NPs were assessed by vibrating sample magnetometer (VSM). The maximum DOX-loading capacity was 100 MUg DOX/mg of Fe3O4@Au NPs. It was found that DOX released more readily at acidic pH. In vitro studies on MCF-7 cell line elucidated that DOX loaded Fe3O4@Au NPs (Fe3O4@Au-PEG-DOX) have more potent therapeutic effect than free DOX. Knowledge gained in this study may open the door to pursue Fe3O4@Au NPs as a viable nanocarriers for different molecules delivery in many diagnostic and therapeutic applications. PMID- 24950616 TI - The influence of continuous vs. pulsed laser excitation on single quantum dot photophysics. AB - The impact of pulsed versus continuous wave (cw) laser excitation on the photophysical properties of single quantum dots (QDs) has been investigated in an experiment in which all macroscopic variables are identical except the nature of laser excitation. Pulsed excitation exaggerates the effects of photobleaching, results in a lower probability of long ON fluorescence blinking events, and leads to shorter fluorescence lifetimes with respect to cw excitation at the same wavelength and average intensity. Spectral wandering, biexciton quantum yields, and power law exponents that describe fluorescence blinking are largely insensitive to the nature of laser excitation. These results explicitly illustrate important similarities and differences in fluorescence dynamics between pulsed and cw excitation, enabling more meaningful comparisons between literature reports and aiding in the design of new experiments to mitigate possible influences of high photon flux on QDs. PMID- 24950617 TI - Characterization of fetal growth by repeated ultrasound measurements in the wild guinea pig (Cavia aperea). AB - Fetal growth during pregnancy has previously been studied in the domesticated guinea pig (Cavia aperea f. porcellus) after dissecting pregnant females, but there are no studies describing the fetal growth in their wild progenitor, the wild guinea pig (C aperea). In this study, 50 pregnancies of wild guinea pig sows were investigated using modern ultrasound technique. The two most common fetal growth parameters (biparietal diameter [BPD] and crown-rump-length [CRL]) and uterine position were measured. Data revealed similar fetal growth patterns in the wild guinea pig and domesticated guinea pig in the investigated gestation period, although they differ in reproductive milestones such as gestation length (average duration of pregnancy 68 days), average birth weight, and litter mass. In this study, pregnancy lasted on average 60.2 days with a variance of less than a day (0.96 days). The measured fetal growth parameters are strongly correlated with each (R = 0.91; P < 0.001) other and with gestational age (BPD regression equation y = 0.04x - 0.29; P < 0.001 and CRL regression equation y = 0.17x - 2.21; P < 0.01). Furthermore, fetuses in the most frequent uterine positions did not differ in their growth parameters and were not influenced by the mother ID. Our results imply that ultrasound measurement of a single fetal growth parameter is sufficient to reliably estimate gestational age in the wild guinea pig. PMID- 24950618 TI - Use of commercial extenders and alternatives to prevent sperm agglutination for cryopreservation of brown bear semen. AB - The objective of this study was to evaluate different bovine and canine commercial semen extenders for cryopreservation of brown bear ejaculates and the effect of semen collection directly into extender on sperm agglutination. Semen samples were obtained by electroejaculation from 13 adult males. In experiment 1, eleven ejaculates from eight bears were used to evaluate Bioxcell and Andromed as extenders, whereas in experiment 2, nine ejaculates from six bears were used to evaluate Triladyl canine, CaniPro, and Extender 2 as extenders. An extender specifically developed for brown bears (Test-Tris-fructose-egg yolk-glycerol, TTF ULE/bear) served as a control extender in both experiments. After thawing, total and progressive sperm motility and sperm viability were greater (P < 0.05) for TTF-ULE/bear and Andromed extenders than for Bioxcell in experiment 1 and greater (P < 0.05) for TTF-ULE/bear extender than for Triladyl Canine, CaniPro, and Extender 2 in experiment 2. In experiment 3, addition of handling extender (TTF H) to the semen collection tube for eight ejaculates from seven bears resulted in less (P < 0.05) sperm agglutination in fresh samples (score 0.5 +/- 0.2 vs. 1.8 +/- 0.4 in diluted and control samples, respectively) with no effect on pre freeze and post-thawing semen quality. In conclusion, TTF-ULE/bear is the most suitable extender for brown bear semen cryopreservation, but comparable results can be obtained with the commercial extender Andromed. In addition, collection of ejaculates directly in TTF-H extender decreases sperm agglutination in fresh samples. PMID- 24950620 TI - High throughput monoclonal antibody generation by immunizing multiple antigens. AB - Recognizing proteins via the production of highly specific monoclonal antibodies (mAbs) is crucial to identifying proteins for proteomic research. However, traditional mAb generation is time-consuming with low efficiency. In this study, we assessed the high throughput method of producing mAbs by immunizing mice with multiple antigens in order to obtain hybridomas against these multiple antigens in one cell fusion. We selected eight proteins that play important roles in human physiological or pathological processes. These proteins were mixed and simultaneously administered to one mouse. We observed the immunizing period for 10 d, and determined the effect of liquid medium and semi-solid medium in hybridoma generation. As a result, all eight immunogens induced antibodies in the immunized mouse in one cell fusion, we obtained hybridomas specific to all eight proteins by enzyme-linked immuno sorbent assay (ELISA) screening, hybridomas against five out of eight showed specific positive in Western-blotting assays. This indicates that we generated mAbs specific to eight proteins in one cell fusion, greatly increasing the efficiency of mAb generation. Furthermore, we observed that hybridomas selected from the liquid medium and semi-solid medium showed different reactivity to antigens. Our study established high-throughput and time-saving methods for production of mAbs. These results provide alternative approaches for increasing the efficacy of mAb generation. PMID- 24950621 TI - Has the cardiac stem cell controversy settled down? PMID- 24950619 TI - Enhanced vasoconstriction to alpha1 adrenoceptor autoantibody in spontaneously hypertensive rats. AB - Autoimmune activities have been implicated in the pathogenesis of hypertension. High levels of autoantibodies against the second extracellular loop of alpha1 adrenoceptor (alpha1-AR autoantibody, alpha1-AA) are found in patients with hypertension, and alpha1-AA could exert a alpha1-AR agonist-like vasoconstrictive effect. However, whether the vasoconstrictive effect of alpha1-AA is enhanced in hypertension is unknown. Using aortic rings of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, we observed the vasoconstrictive responses to alpha1-AA with phenylephrine (alpha1-AR agonist) as a positive control drug. Aortic nitrotyrosine levels were also measured by ELISA and immunohistochemistry. The results showed that the aortic constrictive responses to alpha1-AA and phenylephrine (both 1 nmol L(-1)-10 MUmol L(-1)) were greater in SHR than in WKY rats. Endothelial denudation or L-NAME (a non-selective NOS inhibitor) (100 MUmol L(-1)) increased alpha1-AA- or phenylephrine-induced vasoconstrictions both in SHR and WKY. However, selective iNOS inhibitor 1400 W (10 MUmol L(-1)) enhanced the alpha1-AA-induced aortic constriction in WKY, but not in SHR. The aortic nitrotyrosine level was significantly higher in SHR than WKY, as shown by both ELISA and immunohistochemistry. These results indicate that the vasoconstrictive response to alpha1-AA is enhanced in SHR, and this altered responsiveness is due to endothelial dysfunction and decreased NO bioavailability. The study suggests an important role of alpha1-AR autoimmunity in the pathogenesis and management of hypertension especially in those harboring high alpha1-AA levels. PMID- 24950622 TI - Biased ligand bonds to make right calls--laboratory of signal transduction reveals molecular mechanism for functional selectivity of GPCR. PMID- 24950623 TI - Genetic variants and evolutionary analyses of heparin cofactor II. AB - Heparin cofactor II (HCII) belongs to serpin superfamily and it acts as a thrombin inhibitor in the coagulation cascade, in a glycosaminoglycan-dependent pathway using the release of a sequestered hirudin-like N-terminal tail for interaction with thrombin. This serpin belongs to multiple member group V2 of vertebrate serpin classification. However, there is no comprehensive study illustrating the exact phylogenetic history of HCII, to date. Herein, we explored phylogenetic traits of HCII genes. Structures of HCII gene from selected ray finned fishes and lamprey varied in exon I and II with insertions of novel introns of which one in core domain for ray-finned fishes in exon II at the position 241c. We found HCII remain nested in the largest intron of phosphatidylinositol (PI) 4-kinase (PIK4CA) gene (genetic variants of this gene cause schizophrenia) at the origin of vertebrates, dated about 500MY old. We found that sequence features such as two acidic repeats (AR1-II), GAG-binding helix-D, three serpin motifs and inhibitory reactive center loop (RCL) of HCII protein are highly conserved in 55 vertebrates analyzed. We identified 985 HCII variants by analysis of 1092 human genomes with top three variation classes belongs to SNPs (84.3%), insertion (7.1%) and deletion (5.0%). We identified 37 deleterious mutations in the human HCII protein and we have described these mutations in relation to HCII sequence-structure-function relationships. These understandings may have clinical and medical importance as well. PMID- 24950624 TI - Jumonji family histone demethylases in neural development. AB - Central nervous system (CNS) development is driven by coordinated actions of developmental signals and chromatin regulators that precisely regulate gene expression patterns. Histone methylation is a regulatory mechanism that controls transcriptional programs. In the last 10 years, several histone demethylases (HDM) have been identified as important players in neural development, and their implication in cell fate decisions is beginning to be recognized. Identification of the physiological roles of these enzymes and their molecular mechanisms of action will be necessary for completely understanding the process that ultimately generates different neural cells in the CNS. In this review, we provide an overview of the Jumonji family of HDMs involved in neurodevelopment, and we discuss their roles during neural fate establishment and neuronal differentiation. PMID- 24950625 TI - [On the 25th anniversary of the PAPPS ]. PMID- 24950626 TI - [EUROPREV (European Network for Prevention and Health Promotion]. PMID- 24950628 TI - [Recommendations on lifestyle]. PMID- 24950627 TI - [Cardiovascular preventive recommendations]. PMID- 24950629 TI - [Recommendations for cancer prevention]. PMID- 24950630 TI - [Prevention of infectious diseases]. PMID- 24950632 TI - [Preventive activities in the elderly]. PMID- 24950631 TI - [Recommendations for the prevention of mental disorders in primary care]. PMID- 24950633 TI - [Preventive activities in women]. PMID- 24950635 TI - Gaining improved chemical composition by exploitation of Compton-to-Rayleigh intensity ratio in XRF analysis. AB - The high specificity of the coherent (Rayleigh), as well as incoherent (Compton) X-ray scattering to the mean atomic number of a specimen to be analyzed by X-ray fluorescence (XRF), is exploited to gain more information on the chemical composition. Concretely, the evaluation of the Compton-to-Rayleigh intensity ratio from XRF spectra and its relation to the average atomic number of reference materials via a calibration curve can reveal valuable information on the elemental composition complementary to that obtained from the reference-free XRF analysis. Particularly for matrices of lower mean atomic numbers, the sensitivity of the approach is so high that it can be easily distinguished between specimens of mean atomic numbers differing from each other by 0.1. Hence, the content of light elements which are "invisible" for XRF, particularly hydrogen, or of heavier impurities/additives in light materials can be calculated "by difference" from the scattering calibration curve. The excellent agreement between such an experimental, empirical calibration curve and a synthetically generated one, on the basis of a reliable physical model for the X-ray scattering, is also demonstrated. Thus, the feasibility of the approach for given experimental conditions and particular analytical questions can be tested prior to experiments with reference materials. For the present work a microfocus X-ray source attached on an SEM/EDX (scanning electron microscopy/energy dispersive X-ray spectroscopy) system was used so that the Compton-to-Rayleigh intensity ratio could be acquired with EDX spectral data for improved analysis of the elemental composition. PMID- 24950634 TI - [Childhood and adolescence program]. PMID- 24950637 TI - Photodynamic inactivation of oropharyngeal Candida strains. AB - Oropharyngeal candidiasis (OPC) is an infection frequent in immunocompromised patients. Photodynamic therapy is an alternative to conventional treatments, based on the utilization of compounds that inhibit or kill microorganisms only under the effect of light, process known as Photodynamic Inactivation (PDI). In the present study, PDI of Candida spp. by the natural product alpha-terthienyl (alpha-T) was investigated following the guidelines of CLSI M27-A3, under UV-A light irradiation. The optimal values of two variables, exposure irradiation time (ET) and distance to the irradiation source (DIS) were established by employing Design Expert Software (DES). For this purpose, a panel of Candida strains isolated from OPC (C. albicans, C. tropicalis, C. parapsilosis and C. krusei) was employed and optimal values were 5 min (ET) and between 6.06 and 6.43 cm (DIS) with a desirability factor of 0.989. alpha-T plus UV-A light in the optimal conditions caused a complete reduction in viable cells in 5 min which was demonstrated by viable cells reduction assays and confocal microscopy after vital staining (propidium iodide/fluorescein diacetate). The germ tube formation of C. albicans was inhibited by alpha-T at sub-inhibitory concentrations. Results showed that alpha-T plus UV-A light could constitute an alternative for OPC treatments at the optimal conditions determined here. PMID- 24950639 TI - Per-oral endoscopic myotomy white paper summary. PMID- 24950638 TI - Regularly drinking alcohol before sex in the United States: effects of relationship status and alcohol use disorders. AB - BACKGROUND: Drinking alcohol before sex increases the likelihood of engaging in sexual risk behaviors and risk for HIV infection. Relationship status (single versus partnered) and alcohol use disorders (AUD) are associated with each other and sexual risk behaviors, yet have not been examined as predictors of drinking alcohol before sex, using national data. This study examined whether relationship status and AUD increased the likelihood of regularly drinking alcohol before sex in a nationally representative sample. METHODS: The main and additive interaction effects of relationship status and AUD on regularly drinking alcohol before sex were analyzed among sexually active drinkers (N=17,491) from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Regularly drinking alcohol before sex was defined as drinking alcohol most or all of the time before sex. RESULTS: After adjustment for controls, relationship status (AOR=3.51; CI=2.59-4.75) and AUD (AOR=6.24; CI=5.16-7.53) increased the likelihood of regularly drinking alcohol before sex and interacted to differentially increase this risk, with the effect of being single on the likelihood of regularly drinking alcohol before sex increased among participants with AUD (p<.001). CONCLUSIONS: This study reinforces the importance of relationship status and AUD to the risk for regularly drinking alcohol before sex. Public health efforts should target alcohol and HIV prevention messages to single adults, particularly those with AUD, highlighting their risk for regularly drinking alcohol before sex. PMID- 24950640 TI - Entrustable professional activities for gastroenterology fellowship training. PMID- 24950641 TI - Impact of socioeconomic status on incidence, mortality, and survival of colorectal cancer patients: a systematic review. PMID- 24950642 TI - Consent: Can it be more informed? PMID- 24950643 TI - Complaints against gastroenterology fellows. PMID- 24950644 TI - EUS-guided angiotherapy. PMID- 24950645 TI - Endoscopic percutaneous pancreatic necrosectomy. PMID- 24950646 TI - Avulsion: a novel technique to achieve complete resection of difficult colon polyps. PMID- 24950647 TI - Percutaneous placement of a biliary self-expandable metallic stent for severe post-ERCP bleeding. PMID- 24950648 TI - Helicobacter pylori-related metabolic syndrome might justify earlier colorectal cancer screening. PMID- 24950649 TI - Response. PMID- 24950650 TI - Cost-effectiveness of Barrett's surveillance: a conceptual error. PMID- 24950651 TI - Response. PMID- 24950652 TI - Wireless endoscopy capsules should not be released in the environment. PMID- 24950653 TI - Response. PMID- 24950654 TI - Esophageal luminal restoration for a patient with a long lye-induced stricture via tunnel endoscopic therapy during a rendezvous procedure followed by self dilation (with video). PMID- 24950655 TI - Gastric duplication cyst presenting as acquired pyloric stenosis. PMID- 24950656 TI - Two-year prospective cohort study on quality of life outcomes among people living with HIV after initiation of antiretroviral therapy in Guangxi, China. AB - The long-term impact of antiretroviral therapy (ART) on quality of life (QOL) is not well understood in China. From 2007-2008, 332 treatment-naive, HIV-infected adults from five hospitals in Guangxi were enrolled in a 2-year prospective cohort study. Information was collected at the time of ART initiation and during 6-, 12-, and 24-month follow-up visits. Significant improvements were observed across all QOL domains during the first 6 months on ART as measured using the WHOQOL-HIV BREF instrument. These were closely tracked by increases in CD4+ T cell counts, total lymphocyte counts, and the Karnofsky performance scores (p < .05). After 6 months, improvements were smaller and uneven across QOL domains; social relationships was the only domain to not significantly improve at 24 months compared to baseline. Poorer and socially isolated participants had lower QOL outcomes. Strengthening ART program interventions to increase social support for patients may increase QOL outcomes. PMID- 24950657 TI - Interleukin-1 beta guides the migration of cortical neurons. AB - BACKGROUND: Proinflammatory cytokine interleukin-1beta (IL-1beta) is expressed at high levels in the developing brain and declines to low constitutive levels in the adult. However, the pathophysiological function of IL-1beta during brain development remains elusive. In this study, we investigated the role of IL-1beta in neuronal migration. METHODS: The Boyden transwell assay was used to examine the effects of IL-1beta on the migration of dissociated primary cortical neurons. To determine the role of IL-1beta in neuron leading process pathfinding, we employed a growth cone turning assay. In utero electroporation combined with RNAi technology was used to examine the neuronal migration in vivo during brain development in Sprague-Dawley rats. RESULTS: IL-1beta at concentrations ranging from 0.1 to 10 ng/mL in the lower chamber of a transwell induced a significant increase in the number of migrating neurons in a dose-dependent manner. When IL 1beta was simultaneously put in both the upper and lower chambers to eliminate the gradient, no significant differences in cell migration were observed. IL-1 receptor antagonist IL-1RA dose-dependently blocked the attractive effect of IL 1beta on neuronal migration. Microscopic gradients of IL-1beta were created near the growth cones of isolated neurons by repetitive pulsatile application of picoliters of a IL-1beta-containing solution with a micropipette. We found that growth cones exhibited a clear bias toward the source of IL-1beta at the end of a one hour period in the IL-1beta gradient. No significant difference was observed in the rate of neurite extension between IL-1beta and controls. We electroporated specific siRNA constructs against IL-1R1 mRNA into cortical progenitors at embryonic day 16 and examined the position and distribution of transfected cells in the somatosensory cortex at postnatal day 5. We found that neurons transfected with IL-1R1-siRNA displayed a severe retardation in radial migration, with about 83% of total cells unable to arrive at the upper cortical layers. CONCLUSIONS: Our study suggests an essential contribution of IL-1beta to neuronal migration during brain development, which provides a basis to understand the physiological roles of IL-1beta in the developing brain and could have significant implications for the prevention of some neurodevelopment disorders due to abnormal neuronal migration. PMID- 24950658 TI - A quantitative analysis of microcirculation in sore-prone pressure areas on conventional and pressure relief hospital mattresses using laser Doppler flowmetry and tissue spectrophotometry. AB - BACKGROUND: Pressure ulcers are associated with severe impairment for the patients and high economic load. With this study we wanted to gain more insight to the skin perfusion dynamics due to external loading. Furthermore, we evaluated the effect of different types of pressure relief mattresses. METHODS: A total of 25 healthy volunteers were enrolled in the study. Perfusion dynamics of the sacral and the heel area were assessed using the O2C-device, which combines a laser light, to determine blood flow, and white light to determine the relative amount of hemoglobin. Three mattresses were evaluated compared to a hard surface: a standard hospital foam mattress bed, a visco-elastic foam mattress, and an air fluidized bed. RESULTS: In the heel area, only the air-fluidized bed was able to maintain the blood circulation (mean blood flow of 13.6 +/- 6 versus 3.9 +/- 3 AU and mean relative amount of hemoglobin of 44.0 +/- 14 versus 32.7 +/- 12 AU.) In the sacral area, all used mattresses revealed an improvement of blood circulation compared to the hard surface. CONCLUSION: The results of this study form a more precise pattern of perfusion changes due to external loading on various pressure relief mattresses. This knowledge may reduce the incidence of pressure ulcers and may be an influencing factor in pressure relief mattress selection. PMID- 24950660 TI - Ryanodine myopathies without central cores--clinical, histopathologic, and genetic description of three cases. AB - BACKGROUND: Mutations in ryanodine receptor 1 gene (RYR1) are frequent causes of myopathies. They classically present with central core disease; however, clinical variability and histopathologic overlap are being increasingly recognized. PATIENTS: Patient 1 is a 15-year-old girl with mild proximal, four-limb weakness from age 5, presenting with a progressive scoliosis starting at age 10. Patient 2 is an 18-year-old girl with progressively worsening muscle hypotrophy and mild proximal, four-limb weakness. She developed a rapidly progressive scoliosis from age 11 and needed surgical treatment at age 14 years. Patient 3 is an 11-year-old boy with moderate proximal limb weakness and progressive neck flexor weakness, first noticed at age 2. Muscle biopsies revealed type 1 fiber predominance (Patients 1 and 2) or abnormal type 1 fiber uniformity (Patient 3). Different RYR1 variants were identified in all patients. In Patients 1 and 3, these changes were validated as being pathogenic. CONCLUSIONS: These patients illustrate early onset, progressive myopathies with predominant axial involvement. Histopathologic findings were abnormal but not specific for a diagnosis, particularly central core myopathy. Genetic testing helped broaden the range of phenotypes included in the RYR1-related myopathies. Our patients reinforce the need to recognize the broad histopathologic variability of RYR1-related myopathies and sometimes lack of pathognomonic findings that may reduce the diagnostic threshold of this disease. We suggest that the predominance of type 1 fibers and involvement of axial muscles may be an important element to consider the RYR1 gene as candidate. PMID- 24950659 TI - Surfactant protein A genetic variants associate with severe respiratory insufficiency in pandemic influenza A virus infection. AB - INTRODUCTION: Inherited variability in host immune responses influences susceptibility and outcome of Influenza A virus (IAV) infection, but these factors remain largely unknown. Components of the innate immune response may be crucial in the first days of the infection. The collectins surfactant protein (SP)-A1, -A2, and -D and mannose-binding lectin (MBL) neutralize IAV infectivity, although only SP-A2 can establish an efficient neutralization of poorly glycosylated pandemic IAV strains. METHODS: We studied the role of polymorphic variants at the genes of MBL (MBL2), SP-A1 (SFTPA1), SP-A2 (SFTPA2), and SP-D (SFTPD) in 93 patients with H1N1 pandemic 2009 (H1N1pdm) infection. RESULTS: Multivariate analysis showed that two frequent SFTPA2 missense alleles (rs1965708 C and rs1059046-A) and the SFTPA2 haplotype 1A(0) were associated with a need for mechanical ventilation, acute respiratory failure, and acute respiratory distress syndrome. The SFTPA2 haplotype 1A(1) was a protective variant. Kaplan-Meier analysis and Cox regression also showed that diplotypes not containing the 1A(1) haplotype were associated with a significantly shorter time to ICU admission in hospitalized patients. In addition, rs1965708-C (P = 0.0007), rs1059046-A (P = 0.0007), and haplotype 1A(0) (P = 0.0004) were associated, in a dose-dependent fashion, with lower PaO2/FiO2 ratio, whereas haplotype 1A(1) was associated with a higher PaO2/FiO2 ratio (P = 0.001). CONCLUSIONS: Our data suggest an effect of genetic variants of SFTPA2 on the severity of H1N1pdm infection and could pave the way for a potential treatment with haplotype-specific (1A(1)) SP-A2 for future IAV pandemics. PMID- 24950661 TI - A case of startle epilepsy associated with IL1RAPL1 gene deletion. AB - BACKGROUND: Startle epilepsy is a type of reflex epilepsy in which the seizures are mainly precipitated by unexpected sensory stimuli. PATIENT: We present an 18 month-old boy with global developmental delay and multiple episodes of loss of tone after auditory cues. RESULTS: The neurophysiologic study (video electroencephalographic monitoring) revealed the epileptic nature of the stimulus induced drop attacks, and the comparative genomic hybridization analysis revealed a microdeletion encompassing the interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene. The drop attacks were refractory to initial antiepileptic treatment, but they had a satisfactory response to a synthetic adrenocorticotropic hormone analogue. CONCLUSIONS: The IL1RAPL1 gene is located on Xp21.2-p21.3 and codes a synaptic adhesion protein involved in neuronal differentiation and synapse localization, stabilization, and maturation. The coexistence of startle epilepsy and IL1RAPL1 gene deletion in this child may not be coincidental and suggests a possible involvement of IL1RAPL1 in the dysregulation of excitatory synapses and the pathogenesis of startle epilepsy. PMID- 24950662 TI - Diagnostic yield of electromyography in children with myopathic disorders. AB - BACKGROUND: Interpretation of pediatric electromyography interpretation in myopathic disorders is technically challenging. We assessed our electromyographic experience with respect to sensitivity and specificity in pediatric myopathy. METHODS: We did a retrospective chart review of patients <=18 years between 2009 and 2013. Two hundred twenty-four electromyographic studies were reviewed with the following referral diagnoses: myopathy, muscle weakness, neuromuscular disorders, myositis, myalgia, myoglobinuria, myasthenia, myotonia, cramps, periodic paralysis, hypotonia, and developmental delay. Only children who had an electromyography and muscle biopsy were included for analysis. Patients with neurogenic electromyography and neuromuscular junction disorders were excluded. Myopathic electromyography was defined as short duration, low amplitude, polyphasic motor unit potentials with rapid recruitment. RESULTS: Seventy-two patients were included (age range, 6 months-18 years). The following observations were made: group A: myopathic electromyography or pathognomonic of muscle disease and biopsy or genetically confirmed myopathy (32 cases); group B: myopathic electromyography but biopsy normal or nondiagnostic (12 cases); group C: normal electromyography but biopsy or genetically confirmed myopathy (three cases, all with metabolic myopathy); and group D: electromyography normal and biopsy normal or nondiagnostic (25 cases). The most common diagnoses were congenital myopathy (seven cases), metabolic myopathy (six cases), muscular dystrophy (six cases), genetically confirmed myopathy (five cases), myopathy, undefined (five cases), and inflammatory myopathy (four cases). CONCLUSIONS: Pediatric electromyography was 91% sensitive and 67% specific in myopathic disorders. The metabolic myopathies were commonly missed by electromyography. PMID- 24950663 TI - Telemedicine in pediatric neurology. PMID- 24950664 TI - Effects of hyperglycemia on the developing brain in newborns. AB - BACKGROUND: Hyperglycemia is a common problem in preterm neonates and is associated with increased risk of mortality and severe morbidities such as brain damage. However, available data about the effects of severity of hyperglycemia on the developing brain in the early life is limited. Therefore, we evaluated the effects of moderate and severe hyperglycemia on the developing brain. METHOD: Thirty newborn Sprague-Dawley rats were randomly divided into three groups as control, moderate hyperglycemia (30% dextrose), and severe hyperglycemia (50% dextrose). Pups in the hyperglycemia groups were administered subcutaneous sterile dextrose solution at a dose of 4 mL/kg daily from the second day to the eleventh day of life. Blood glucose levels were measured every day in all study groups. Rat brain tissues were removed at the end of the study. Histopathologic and immunohistochemical (caspase-9, -8, and -3) examination and biochemical analysis including xanthine oxidase, total antioxidant status, total oxidant status, and malondialdehyde activities were performed. RESULTS: Weight of the brain tissues in rats with hyperglycemia groups was significantly lower than the control group (P < 0.05). Weight of the brain tissues in rats with moderate hyperglycemia was lower than that of the severe hyperglycemia (P < 0.05). In the histopathologic and immunochemical evaluation, severity of brain damage and apoptosis were significantly higher in the severe hyperglycemia group, especially at the level of the hippocampus (P < 0.05). Tissue malondialdehyde, xanthine oxidase levels, and total oxidant status were significantly increased in the severe hyperglycemia group, whereas total antioxidant status was significantly decreased in the severe hyperglycemia group (P < 0.001). CONCLUSION: Brain damaging effects of severe hyperglycemia were observed in the developing brains of the rat pups. It might be inferred that severe hyperglycemia can damage the developing brain especially in preterm infants. PMID- 24950665 TI - A case of acute cerebellitis with a unique sequential change on magnetic resonance imaging. AB - BACKGROUND: Acute cerebellitis with unilateral onset is rare, and magnetic resonance imaging (MRI) is a useful method for demonstrating cerebellar involvement. PATIENT: We report a 12-year-old girl with acute cerebellitis with a unique sequential change on her MRI. RESULTS: The patient's brain MRI first revealed cortical lesions mainly in the right cerebellar hemisphere. These subsequently disappeared, and at the same time, new lesions appeared in the opposite cerebellar hemisphere. All the lesions were confined to gray matter in the cerebellum and were isotense on diffusion-weighted imaging and had high signal intensity on the apparent diffusion coefficient map, consistent with the characteristic of vasogenic edema. CONCLUSION: The sequential MRI demonstrates conversion of hemicerebellitis to bilateral cerebellitis during subacute phase, and vasogenic edema might be contributing to the pathogenesis of acute cerebellitis in this patient. PMID- 24950667 TI - Mortality trends and risk of dying from pulmonary tuberculosis in the 7 socioeconomic regions and the 32 States of Mexico, 2000-2009. AB - INTRODUCTION: Tuberculosis (TB) is a world public health problem that still has a high morbidity and mortality rate mainly in countries with significant wealth gaps. Poverty, malnutrition, HIV infection, drug resistance, diabetes and addictions (mainly alcoholism) have been seen to contribute to the persistence of TB as an important health problem in Mexico. METHODS: Death certificates associated with pulmonary tuberculosis (PTB) for 2000-2009 were obtained from the National Information System of the Secretariat of Health. Rates of mortality nationwide, by state, and by socioeconomic region were calculated. The strength of association between states where individuals resided, socioeconomic regions, and education with mortality from PTB was determined. RESULTS: Age-adjusted mortality rates per 100,000 inhabitants who died from PTB decreased from 4.1 to 2 between 2000 and 2009. Men (67.7%) presented higher mortality than women (32.3%). Individuals failing to complete elementary education presented a higher risk of dying from PTB (RR 1.08 [95%CI: 1.05-1.12]). The socioeconomic region and the entities with the strongest association were region 1, 5, Chiapas and Baja California. Region 1 in 2007 presented RR 7.34 (95%CI: 5.32-10.13), and region 5 in 2009 had RR 10.08 (95%CI: 6.83-14.88). CONCLUSIONS: In Mexico, the annual mortality rate from PTB decreased. Men presented higher mortality than women. Individuals failing to complete elementary education showed a higher risk of dying from PTB. The states and regions of Mexico that presented a stronger association with mortality from PTB were Chiapas and Baja California, region 1 and 5. PMID- 24950666 TI - A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase. AB - Taliglucerase alfa is a beta-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9-60U/kg body weight) and regimen of administration (every 2weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348. PMID- 24950668 TI - Clinical and molecular study of 4 cases of pulmonary hypertension associated with sarcoidosis. AB - Sarcoidosis is a pleomorphic disease that can present with pulmonary hypertension (PH). What little information is available about the association of these two diseases comes mainly from small series of patients scheduled for transplant. We present 4 cases of mild pulmonary involvement in whom right catheterisation was performed and PH-specific therapy was administered. After obtaining written consent, a genetic study was performed that showed mutations in PH-related genes in 3 of the patients. This is the first study of its kind to yield genetic information for this type of PH. PMID- 24950670 TI - Professor Vincenzo de Luca. PMID- 24950669 TI - Report of the NIH Task Force on Research Standards for Chronic Low Back Pain. AB - Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement. PERSPECTIVE: A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. PMID- 24950671 TI - Rotors as drivers of atrial fibrillation and targets for ablation. AB - Atrial fibrillation (AF) is the most common arrhythmia targeted by catheter ablation. Despite significant advances in our understanding of AF, ablation outcomes remain suboptimal, and this is due in large part to an incomplete understanding of the underlying sustaining mechanisms of AF. Recent developments of patient-tailored and physiology-based computational mapping systems have identified localized electrical spiral waves, or rotors, and focal sources as mechanisms that may represent novel targets for therapy. This report provides an overview of Focal Impulse and Rotor Modulation (FIRM) mapping, which reveals that human AF is often not actually driven by disorganized activity but instead that disorganization is secondary to organized rotors or focal sources. Targeted ablation of such sources alone can eliminate AF and, when added to pulmonary vein isolation, improves long-term outcome compared with conventional ablation alone. Translating mechanistic insights from such patient-tailored mapping is likely to be crucial in achieving the next major advances in personalized medicine for AF. PMID- 24950673 TI - Role of HDL in those with diabetes. AB - Low levels of high-density lipoprotein cholesterol (HDL-C) have been associated with an increased risk of coronary heart disease in prospective population studies and clinical trials of high-risk patients treated with a low to moderate intensity statin. As a result, therapeutic targets were developed to increase concentrations of HDL-C. Subsequently, clinical trials of high-intensity statins have not supported this previously well-established association. In trials of high-intensity statin therapy, low HDL particle concentration (HDL-P) has been associated with an increased risk of future cardiovascular events. Therefore, strategies that increase HDL-C without expanding the pool of HDL-P with its rich proteome/lipidome do not seem to be an effective strategy. In this review, we discuss potential mechanisms of action for the anti-atherogenic effect of HDL and the impact of current and emerging therapies on the functional capacity of HDL-P. Finally, we discuss emerging therapies that increase the concentration and functional properties of HDL. PMID- 24950672 TI - Arrhythmias in structural heart disease. AB - The presence of structural heart disease is often associated with the development of electrical abnormalities of the heart, manifesting as atrial and ventricular arrhythmias. These can occur in those with ischemic and nonischemic cardiomyopathies, congenital heart disease, and various acquired and intrinsic structural abnormalities of the myocardium. Treatment of these arrhythmias generally involves treatment of the underlying disorder first, if possible, such as with surgical or catheter-based intervention. Other therapies, including medical therapy with beta-blockers and anti-arrhythmic agents, pacemakers and implantable cardioverter-defibrillators (ICDs), and ablation may be offered both as prophylactic therapy or if arrhythmias have developed. In some instances, therapy is undertaken regardless of whether there are symptoms. ICDs provide support for those patients at risk for malignant, life-threatening arrhythmias, but appropriate patient and device selection are vital to improve mortality and to limit adverse events. PMID- 24950674 TI - Biomarkers of coronary artery disease: the promise of the transcriptome. AB - The last years have witnessed tremendous technical advances in the field of transcriptomics that enable the simultaneous assessment of nearly all transcripts expressed in a tissue at a given time. These advances harbor the potential to gain a better understanding of the complex biological systems and for the identification and development of novel biomarkers. This article will review the current knowledge of transcriptomics biomarkers in the cardiovascular field and will provide an overview about the promises and challenges of the transcriptomics approach for biomarker identification. PMID- 24950676 TI - Assessment and impact of cardiac fibrosis on atrial fibrillation. AB - Fibrosis is an essential component of structural remodeling that accompanies different cardiovascular disease conditions. In cardiac arrhythmias, fibrosis plays an important role in creating the necessary substrate for these arrhythmias to persist. Non-invasive evaluation of the arrhythmia substrate has seen significant advancements in the past several years. Cardiac MRI characterizes tissue changes including fibrosis and scarring and has seen its role expand significantly in cardiac electrophysiology. We have used late-gadolinium enhancement MRI (LGE-MRI) to study tissue changes in the left atrium of patients with atrial fibrillation (AF) and demonstrated its utility in identifying poor responders to catheter ablation, as well as its association with stroke risk and significant sinus node dysfunction. Following ablation, we also studied atrial scarring and demonstrated the utility of scar imaging in guiding repeat ablation procedures. PMID- 24950677 TI - Relation of digoxin use in atrial fibrillation and the risk of all-cause mortality in patients >=65 years of age with versus without heart failure. AB - Previous studies on digoxin use in patients with atrial fibrillation (AF) and the risk of all-cause mortality found conflicting results. We conducted a population based, retrospective, cohort study of patients aged >=65 years admitted to a hospital with a primary or secondary diagnosis of AF, in Quebec province, Canada, from 1998 to 2012. The AF cohort was grouped into patients with and without heart failure (HF) and into digoxin and no-digoxin users according to the first prescription filled for digoxin within 30 days after AF hospital discharge. We derived propensity score-matched digoxin and no-digoxin treatment groups for the groups of patients with and without HF, respectively, and conducted multivariable Cox proportional hazards regression analyses to determine association between digoxin use and all-cause mortality. The AF propensity score-matched cohorts of patients with and without HF were well balanced on baseline characteristics. In the propensity score-matched HF group, digoxin use was associated with a 14% greater risk of all-cause mortality (adjusted hazard ratio 1.14, 95% confidence interval 1.10 to 1.17). In the propensity score-matched no-HF group, digoxin use was associated with a 17% greater risk of all-cause mortality (adjusted hazard ratio 1.17, 95% confidence interval 1.14 to 1.19). In conclusion, our retrospective analyses found that digoxin use was associated with a greater risk for all-cause mortality in patients aged >=65 years with AF regardless of concomitant HF. Large, multicenter, randomized controlled trials or prospective cohort studies are required to clarify this issue. PMID- 24950678 TI - Board certification scams. PMID- 24950675 TI - Role of the gut in modulating lipoprotein metabolism. AB - The intestinal production of lipoproteins is one of the key processes by which the body prepares dietary lipid for dissemination to locations throughout the body where they are required. Paramount to this is the relationship between dietary lipid and the enterocytes that line the gut, along with the processes which prepare this lipid for efficient uptake by these cells. These include those which occur in the mouth and stomach along with those which occur within the intestinal lumen itself. Additionally, the interplay between digested lipid, dual avenues for lipid uptake by enterocytes (passive and lipid transporter proteins), a system of intercellular lipid resynthesis and transport, and a complex system of lipoprotein synthesis yield a system open to significant modulation. In this review, we will attempt to outline the processes of lipid digestion, lipoprotein synthesis and the exogenous and endogenous factors which exert their influence. PMID- 24950679 TI - Secreted adiponectin as a marker to evaluate in vitro the adipogenic differentiation of human mesenchymal stromal cells. AB - BACKGROUND AIMS: Multipotency is one of the hallmarks of mesenchymal stromal cells (MSCs). Given the widespread adoption of MSC-based clinical applications, the need for rapid and reliable methods to estimate MSC multipotency is demanding. Adipogenic potential is commonly evaluated by staining cell lipid droplets with oil red O. This cytochemical assay is performed at the terminal stage of adipogenic induction (21-28 days) and necessitates the destruction of the specimen. In this study, we investigated whether it is possible to assess MSC adipogenic differentiation in a more efficient, timely and non-destructive manner, while monitoring in vitro secretion of adiponectin, a hormone specifically secreted by adipose tissue. METHODS: A commercially available enzyme linked immunosorbent assay kit was used to quantify adiponectin secreted in the culture medium of adipo-induced human bone marrow-derived MSCs. Oil red O staining was used as a reference method. RESULTS: Adiponectin is detectable after 10 days of induction at a median concentration of 5.13 ng/mL. The secretion of adiponectin steadily increases as adipogenesis proceeds. Adiponectin is undetectable when adipogenic induction is pharmacologically blocked, inefficient or when human MSCs are induced to differentiate toward the osteogenic lineage, proving the specificity of the assay. Furthermore, the results of adiponectin secretion strongly correlate with oil red O quantification at the end of induction treatment. CONCLUSIONS: Our results demonstrate that quantification of secreted adiponectin can be used as a reliable and robust method to evaluate adipogenic potential without destroying samples. This method provides a useful tool for quality control in the laboratory and in clinical applications of human MSCs. PMID- 24950680 TI - Effect of exposure to interleukin-21 at various time points on human natural killer cell culture. AB - BACKGROUND AIMS: Interleukin-21 (IL-21) can enhance the effector function of natural killer (NK) cells but also limits their proliferation when continuously combined with IL-2/IL-15. Paradoxically, membrane-bound (mb)-IL-21 has been shown to improve human NK cell proliferation when cultured with IL-2/mb-IL-15. To clarify the role of IL-21, we investigated the effect of the timing of IL-21 addition to NK cell culture. METHODS: IL-2/IL-15-activated NK cells were additionally treated with IL-21 according to the following schedules; (i) control (without IL-21); (ii) first week (day 0 to day 7); (iii) intermittent (the first 3 days of each week for 7 weeks); (iv) after 1 week (day 8 to day 14); and (v) continuous (day 0 to day 49). The expression of NK receptors, granzyme B, perforin, CD107a, interferon-gamma, telomere length and NK cell death were measured by flow cytometry. RESULTS: Compared with the control (2004.2-fold; n = 10 healthy donors) and intermittent groups (2063.9-fold), a strong proliferative response of the NK cells on day 42 was identified in the "first week" group (3743.8-fold) (P < 0.05). NK cells treated with IL-21 in the "first week" group showed cytotoxicity similar to that in control cells. On day 28, there was a significant increase in cytotoxicity of "first week" NK cells that received IL-21 treatment for an additional 2 days compared with the "first week" NK cells (P < 0.05). CONCLUSIONS: These data suggest that controlling temporal exposure of IL 21 during NK cell proliferation can be a critical consideration to improve the yields and cytotoxicity of NK cells. PMID- 24950681 TI - Outcomes of an open autologous osteochondral plug graft for capitellar osteochondritis dissecans: time to return to sports. AB - BACKGROUND: Autologous osteochondral plug grafts have been used for capitellar osteochondritis dissecans (OCD), and good clinical results have been described. However, little is known about the optimal timing of return to sports. PURPOSE: To investigate the clinical outcomes of open autologous osteochondral plug grafts for capitellar OCD and to address the timing of return to sports. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Thirty-three male patients with a mean age at the time of surgery of 13.6 years (range, 11-17 years) and with advanced lesions of capitellar OCD underwent a procedure using open autologous osteochondral plug grafts. All patients played baseball, and the lesion affected their throwing side. Thirteen lesions were arthroscopically classified as International Cartilage Repair Society (ICRS) OCD III and 20 lesions as ICRS OCD IV. The mean size of the lesions (sagittal * coronal) was 16 * 14 mm. One to 3 osteochondral plug grafts, with a mean diameter of 7 mm (range, 5-9 mm), were harvested from the lateral femoral condyle and transplanted to the defects. Patients were allowed to begin throwing after 3 months and to return to sports after 6 months. The mean follow-up was 28.4 months (range, 12-76 months), during which elbow pain, Timmerman and Andrews scores, return to sports, and radiographs were evaluated. RESULTS: After surgery, 30 patients (91%) had no elbow pain, and 3 patients (9%) had occasional mild throwing pain. The mean total arc of elbow motion increased significantly from 116 degrees to 133 degrees (P < .05). The mean Timmerman and Andrews score improved significantly from 143 to 190 (P < .05). All except 2 patients returned to a competitive level at which they had previously played after a mean of 6.9 months (range, 6-14 months). One patient chose another sport, and another retired from baseball after high school graduation. All patients achieved graft incorporation, and there was no postoperative enlargement of osteophytes on radiographs. One patient had mild anterior knee pain at the donor site during exercise. The remaining patients had no knee pain. The mean Lysholm score was 99.8. CONCLUSION: The results of this study indicate that an open autologous osteochondral plug graft allows a return to the previous competitive level of throwing by a mean of 7 months postoperatively. PMID- 24950682 TI - Pilonidal abscess in the breast: a case report. AB - Pilonidal sinus is a common entity, most often occurring in the natal cleft. Pilonidal sinus with abscess formation has also been described in hairdressers in the interdigital space. We report a case of pilonidal abscess of the breast in a hairdresser, a rarely reported site, which requires awareness on the clinician's part of this occupational risk, for appropriate management and post-surgery advice on prevention. It is particularly important to impart such information to the reporting pathologist who is key to making this histological diagnosis. PMID- 24950684 TI - A non-participant observational study of health and social care waste disposal behaviour in the South West of England. AB - INTRODUCTION: The National Health Service in England has a large carbon footprint. Waste production and disposal contributes to this carbon footprint and costs the National Health Service England over L82 million per annum. This study builds on existing work regarding health care waste management in the United Kingdom where the potential for recycling has begun to be studied. The study focuses on a private hospital and social care organizations, and provides a more detailed study of the behaviour of individuals across a variety of waste management systems. METHODS: The study was an overt observational study at four health and social care sites in the South West of England. Systematic observations were made of the waste disposed of by employees in which the observer recorded: a description of the waste item; the bin into which the waste was placed; the type of employee who disposed of the waste; the material the waste comprised and the appropriateness of the disposal behaviour. RESULTS: The domestic waste bin was found to be most commonly used by employees to dispose of waste (51%), and the materials observed being disposed of most often were paper (26%), organic wastes (19%) and plastic (19%). There were significant differences between the four sites indicating that the activities performed at each site may have been influencing the waste being disposed of. CONCLUSION: It was concluded that the transfer of waste from the domestic waste stream to the recycling waste stream should be a central focus for the design of new health and social care waste management systems. Employees will require guidance and training in identifying and classifying waste materials for recycling. PMID- 24950683 TI - A feasibility study to develop a diabetes prevention program for young adults with prediabetes by using digital platforms and a handheld device. AB - PURPOSE: The purpose of this pilot study was to examine the feasibility and preliminary efficacy of an age-specific diabetes prevention program in young adults with prediabetes. METHODS: A one-group pretest-posttest design was used. The inclusion criteria were age 18 to 29 years and the presence of prediabetes (either impaired fasting glucose of 100-125 mg/dL [5.55-6.94 mmol/L] or A1C of 5.7%-6.4%). Fifteen participants were enrolled in the study. A technology-based lifestyle coaching program focused on diet and physical activity and incorporating a handheld device and digital platforms was developed and tested. Psychosocial factors (health literacy, illness perception, self-efficacy, therapeutic efficacy) based on social cognitive theory, changes in diet and physical activity, and cardiometabolic risk factors were assessed at baseline and week 12 after the intervention. A paired-samples t test was performed to examine changes between baseline and postintervention on each psychosocial and physical variable. RESULTS: Participants' (n = 13 completers) mean age was 24.4 +/- 2.2 years, 23.1% were male, and 53.8% were African American. Overall, the participants were satisfied with the intervention (mean score, 4.15 on a 5-point, Likert-type scale). Between pre- and posttesting, mean body mass index and mean A1C decreased from 41.0 +/- 7.3 kg/m(2) and 6.0 +/- 0.5% to 40.1 +/- 7.0 kg/m(2) and 5.6 +/- 0.5%, respectively, whereas mean fasting glucose did not significantly change (from 92.6 +/- 11 to 97.6 +/- 14.3 mg/dL [5.14 +/- 0.61 to 5.42 +/- 0.79 mmol/L]). CONCLUSIONS: The intervention resulted in reduced A1C and a trend toward decreased body mass index in obese sedentary young adults with prediabetes after 12 weeks. Further study through a randomized clinical trial with a longer intervention period is warranted. PMID- 24950686 TI - Drugs for dementia should receive accelerated approval, says world envoy. PMID- 24950685 TI - Effects of the environmental contaminants DEHP and TCDD on estradiol synthesis and aryl hydrocarbon receptor and peroxisome proliferator-activated receptor signalling in the human granulosa cell line KGN. AB - Environmental contaminants binding to transcription factors, such as the aryl hydrocarbon receptor (AhR) and the alpha and gamma peroxisome proliferator activated receptors (PPARs), contribute to adverse effects on the reproductive system. Expressing both the AhR and PPARs, the human granulosa cell line KGN offers the opportunity to investigate the regulatory mechanisms involved in receptor crosstalk, independent of overriding hormonal control. The aim of the present study was to investigate the impact of two environmental contaminants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an AhR ligand) and di-(2-ethylhexyl) phthalate (DEHP, a PPAR ligand), on gonadotrophin sensitivity and estrogen synthesis in KGN cells. Accumulation of the DEHP metabolite mono-(2-ethylhexyl) phthalate (MEHP) in DEHP-exposed cells was measured by high-performance liquid chromatography mass spectrometry, thereby demonstrating DEHP metabolism to MEHP by KGN cells. By employing TCDD ( an AhR agonist), rosiglitazone (a PPARgamma agonist) or bezafibrate (a PPARalpha agonist), the presence of a functional AhR and PPAR cascade was confirmed in KGN cells. Cytotoxicity testing revealed no effect on KGN cell proliferation for the concentrations of TCDD and DEHP used in the current study. FSH-stimulated cells were exposed to TCDD, DEHP or a mix of both and estradiol synthesis was measured by enzyme-linked immunosorbent assay and gene expression by quantitative RT-PCR. Exposure decreased estradiol synthesis (TCDD, DEHP, mix) and reduced the mRNA expression of CYP19 aromatase (DEHP, mix) and FSHR (DEHP). DEHP induced the expression of the alpha and gamma PPARs and AhR, an effect which was inhibited by selective PPAR antagonists. Studies in the human granulosa cell line KGN show that the action of endocrine disrupting chemicals may be due to a direct activation of AhR, for example by TCDD, and by a transactivation via PPARs, for example by DEHP, inducing subsequent transcriptional changes with a broad range of effects on granulosa cell function. PMID- 24950687 TI - Breast cancer classification: linking molecular mechanisms to disease prognosis. AB - Breast cancer was traditionally perceived as a single disease; however, recent advances in gene expression and genomic profiling have revealed that breast cancer is in fact a collection of diseases exhibiting distinct anatomical features, responses to treatment and survival outcomes. Consequently, a number of schemes have been proposed for subtyping of breast cancer to bring out the biological and clinically relevant characteristics of the subtypes. Although some of these schemes capture underlying molecular differences, others predict variations in response to treatment and survival patterns. However, despite this diversity in the approaches, it is clear that molecular mechanisms drive clinical outcomes, and therefore an effective scheme should integrate molecular as well as clinical parameters to enable deeper understanding of cancer mechanisms and allow better decision making in the clinic. Here, using a large cohort of ~550 breast tumours from The Cancer Genome Atlas, we systematically evaluate a number of expression-based schemes including at least eight molecular pathways implicated in breast cancer and three prognostic signatures, across a variety of classification scenarios covering molecular characteristics, biomarker status, tumour stages and survival patterns. We observe that a careful combination of these schemes yields better classification results compared with using them individually, thus confirming that molecular mechanisms and clinical outcomes are related and that an effective scheme should therefore integrate both these parameters to enable a deeper understanding of the cancer. PMID- 24950688 TI - Efficient induction of antitumor immunity by synthetic toll-like receptor ligand peptide conjugates. AB - Chemical conjugates comprising synthetic Toll-like receptor ligands (TLR-L) covalently bound to antigenic synthetic long peptides (SLP) are attractive vaccine modalities, which can induce robust CD8(+) T-cell immune responses. Previously, we have shown that the mechanism underlying the power of TLR-L SLP conjugates is improved delivery of the antigen together with a dendritic cell activation signal. In the present study, we have expanded the approach to tumor specific CD4(+) as well as CD8(+) T-cell responses and in vivo studies in two nonrelated aggressive tumor models. We show that TLR2-L SLP conjugates have superior mouse CD8(+) and CD4(+) T-cell priming capacity compared with free SLPs injected together with a free TLR2-L. Vaccination with TLR2-L SLP conjugates leads to efficient induction of antitumor immunity in mice challenged with aggressive transplantable melanoma or lymphoma. Our data indicate that TLR2-L SLP conjugates are suitable to promote integrated antigen-specific CD8(+) and CD4(+) T-cell responses required for the antitumor effects. Collectively, these data show that TLR2-L SLP conjugates are promising synthetic vaccine candidates for active immunotherapy against cancer. PMID- 24950689 TI - Palato-pharyngo-laryngeal myoclonus ... an unusual cause of dysphagia. AB - Dysphagia is a common problem in the elderly patient. Palato-pharyngo-laryngeal myoclonus, however, is a rare cause of this. We report a case of a 78-year-old man with dysphagia due to palato-pharngo-laryngeal myoclonus that was ultimately managed conservatively with a good functional outcome. PMID- 24950690 TI - Cost-effectiveness of telecare for people with social care needs: the Whole Systems Demonstrator cluster randomised trial. AB - PURPOSE OF THE STUDY: to examine the costs and cost-effectiveness of 'second generation' telecare, in addition to standard support and care that could include 'first-generation' forms of telecare, compared with standard support and care that could include 'first-generation' forms of telecare. DESIGN AND METHODS: a pragmatic cluster-randomised controlled trial with nested economic evaluation. A total of 2,600 people with social care needs participated in a trial of community based telecare in three English local authority areas. In the Whole Systems Demonstrator Telecare Questionnaire Study, 550 participants were randomised to intervention and 639 to control. Participants who were offered the telecare intervention received a package of equipment and monitoring services for 12 months, additional to their standard health and social care services. The control group received usual health and social care. PRIMARY OUTCOME MEASURE: incremental cost per quality-adjusted life year (QALY) gained. The analyses took a health and social care perspective. RESULTS: cost per additional QALY was L297,000. Cost effectiveness acceptability curves indicated that the probability of cost effectiveness at a willingness-to-pay of L30,000 per QALY gained was only 16%. Sensitivity analyses combining variations in equipment price and support cost parameters yielded a cost-effectiveness ratio of L161,000 per QALY. IMPLICATIONS: while QALY gain in the intervention group was similar to that for controls, social and health services costs were higher. Second-generation telecare did not appear to be a cost-effective addition to usual care, assuming a commonly accepted willingness to pay for QALYs. TRIAL REGISTRATION NUMBER: ISRCTN 43002091. PMID- 24950691 TI - LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice. AB - A key step in plasma HDL maturation from discoidal to spherical particles is the esterification of cholesterol to cholesteryl ester, which is catalyzed by LCAT. HDL-like lipoproteins in cerebrospinal fluid (CSF) are also spherical, whereas nascent lipoprotein particles secreted from astrocytes are discoidal, suggesting that LCAT may play a similar role in the CNS. In plasma, apoA-I is the main LCAT activator, while in the CNS, it is believed to be apoE. apoE is directly involved in the pathological progression of Alzheimer's disease, including facilitating beta-amyloid (Abeta) clearance from the brain, a function that requires its lipidation by ABCA1. However, whether apoE particle maturation by LCAT is also required for Abeta clearance is unknown. Here we characterized the impact of LCAT deficiency on CNS lipoprotein metabolism and amyloid pathology. Deletion of LCAT from APP/PS1 mice resulted in a pronounced decrease of apoA-I in plasma that was paralleled by decreased apoA-I levels in CSF and brain tissue, whereas apoE levels were unaffected. Furthermore, LCAT deficiency did not increase Abeta or amyloid in APP/PS1 LCAT(-/-) mice. Finally, LCAT expression and plasma activity were unaffected by age or the onset of Alzheimer's-like pathology in APP/PS1 mice. Taken together, these results suggest that apoE-containing discoidal HDLs do not require LCAT-dependent maturation to mediate efficient Abeta clearance. PMID- 24950693 TI - The need for independent evaluations of government-led health information technology initiatives. PMID- 24950692 TI - Apolipoprotein M modulates erythrocyte efflux and tubular reabsorption of sphingosine-1-phosphate. AB - Sphingosine-1-phosphate (S1P) mediates several cytoprotective functions of HDL. apoM acts as a S1P binding protein in HDL. Erythrocytes are the major source of S1P in plasma. After glomerular filtration, apoM is endocytosed in the proximal renal tubules. Human or murine HDL elicited time- and dose-dependent S1P efflux from erythrocytes. Compared with HDL of wild-type (wt) mice, S1P efflux was enhanced in the presence of HDL from apoM transgenic mice, but not diminished in the presence of HDL from apoM knockout (Apom(-/-)) mice. Artificially reconstituted and apoM-free HDL also effectively induced S1P efflux from erythrocytes. S1P and apoM were not measurable in the urine of wt mice. Apom(-/-) mice excreted significant amounts of S1P. apoM was detected in the urine of mice with defective tubular endocytosis because of knockout of the LDL receptor related protein, chloride-proton exchanger ClC-5 (Clcn5(-/-)), or the cysteine transporter cystinosin. Urinary levels of S1P were significantly elevated in Clcn5(-/-) mice. In contrast to Apom(-/-) mice, these mice showed normal plasma concentrations for apoM and S1P. In conclusion, HDL facilitates S1P efflux from erythrocytes by both apoM-dependent and apoM-independent mechanisms. Moreover, apoM facilitates tubular reabsorption of S1P from the urine, however, with no impact on S1P plasma concentrations. PMID- 24950694 TI - Pre-specified vs. post-hoc subgroup analyses: are we wiser before or after a trial has been performed? PMID- 24950696 TI - E-cigarette use in air transit: self-reported data from US flight attendants. PMID- 24950697 TI - Implementation of graphic health warning labels on tobacco products in India: the interplay between the cigarette and the bidi industries. AB - OBJECTIVES: To understand the competition between and among tobacco companies and health groups that led to graphical health warning labels (GHWL) on all tobacco products in India. METHODS: Analysis of internal tobacco industry documents in the Legacy Tobacco Document Library, documents obtained through India's Right to Information Act, and news reports. RESULTS: Implementation of GHWLs in India reflects a complex interplay between the government and the cigarette and bidi industries, who have shared as well as conflicting interests. Joint lobbying by national-level tobacco companies (that are foreign subsidiaries of multinationals) and local producers of other forms of tobacco blocked GHWLs for decades and delayed the implementation of effective GHWLs after they were mandated in 2007. Tobacco control activists used public interest lawsuits and the Right to Information Act to win government implementation of GHWLs on cigarette, bidi and smokeless tobacco packs in May 2009 and rotating GHWLs in December 2011. CONCLUSIONS: GHWLs in India illustrate how the presence of bidis and cigarettes in the same market creates a complex regulatory environment. The government imposing tobacco control on multinational cigarette companies led to the enforcement of regulation on local forms of tobacco. As other developing countries with high rates of alternate forms of tobacco use establish and enforce GHWL laws, the tobacco control advocacy community can use pressure on the multinational cigarette industry as an indirect tool to force implementation of regulations on other forms of tobacco. PMID- 24950695 TI - Silencing of CCR2 in myocarditis. AB - BACKGROUND: Myocarditis is characterized by inflammatory cell infiltration of the heart and subsequent deterioration of cardiac function. Monocytes are the most prominent population of accumulating leucocytes. We investigated whether in vivo administration of nanoparticle-encapsulated siRNA targeting chemokine (C-C motif) receptor 2 (CCR2)-a chemokine receptor crucial for leucocyte migration in humans and mice--reduces inflammation in autoimmune myocarditis. METHODS AND RESULTS: In myocardium of patients with myocarditis, CCL2 mRNA levels and CCR2(+) cells increased (P < 0.05), motivating us to pursue CCR2 silencing. Flow cytometric analysis showed that siRNA silencing of CCR2 (siCCR2) reduced the number of Ly6C(high) monocytes in hearts of mice with acute autoimmune myocarditis by 69% (P < 0.05), corroborated by histological assessment. The nanoparticle-delivered siRNA was not only active in monocytes but also in bone marrow haematopoietic progenitor cells. Treatment with siCCR2 reduced the migration of bone marrow granulocyte macrophage progenitors into the blood. Cellular magnetic resonance imaging (MRI) after injection of macrophage-avid magnetic nanoparticles detected myocarditis and therapeutic effects of RNAi non-invasively. Mice with acute myocarditis showed enhanced macrophage MRI contrast, which was prevented by siCCR2 (P < 0.05). Follow-up MRI volumetry revealed that siCCR2 treatment improved ejection fraction (P < 0.05 vs. control siRNA-treated mice). CONCLUSION: This study highlights the importance of CCR2 in the pathogenesis of myocarditis. In addition, we show that siCCR2 affects leucocyte progenitor trafficking. The data also point to a novel therapeutic strategy for the treatment of myocarditis. PMID- 24950698 TI - The serotonin transporter gene polymorphism is associated with the susceptibility and the pain severity in idiopathic trigeminal neuralgia patients. AB - BACKGROUND: To investigate the possible association between the serotonin transporter gene (5-HTTLPR) and rs 25531 polymorphism and the susceptibility and the pain severity in Trigeminal Neuralgia patients. METHODS: A total of 244 TN patients and 280 age and sex matched healthy volunteer were recruited. 5-HTTLPR and rs 25531 genotyping were performed. All patients received the carbamazepine treatment and the treatment response was evaluated at 6 months. RESULTS: The genotype distribution of 5-HTTLPR between TN patients and controls were significantly different. The TN Patients had a higher prevalence of short-short genotype than controls. The short-short genotype carriers are also significantly associated with higher pain severity and poorer carbamazepine treatment response compared to the long-long genotype carriers. In contrast, the rs 25531 polymorphism was not associated with the susceptibility to TN, neither with the pain severity and the treat response to carbamazepine. CONCLUSION: The 5-HTTLPR polymorphism is associated with the susceptibility to TN and pain severity of TN. PMID- 24950701 TI - Health and social support services to HIV/AIDS infected individuals in Tanzania: employees and employers perceptions. AB - BACKGROUND: HIV is a major public health problem in the world, especially in sub Saharan Africa. It often leads to loss of productive labour and disruption of existing social support system which results in deterioration of population health. This poses a great challenge to infected people in meeting their essential goods and services. This paper examines health and social support services provided by employers to HIV/AIDS infected employees in Tanzania. METHODS: This was a cross-sectional study, which employed qualitative and quantitative methods in data collection and analysis. Structured questionnaires and in-depth interviews were used to assess the health and social support services provision at employers and employees perspectives. The study participants were employees and employers from public and private organizations. RESULTS: A total of 181 employees and 23 employers from 23 workplaces aged between 18-68 years were involved. The results show that 23.8% (i.e., 20.4% males and 27.3% females) of the employees had at least one member of the family or close relatives living with HIV at the time of the study. Fifty six percent of the infected employees reported to have been receiving health or social support from their employers. Employees' responses were consistent with those reported by their employers. A total of 12(52.2%) and 11(47.8%) employers reported to have been providing health and social supports respectively. Female employees (58.3%) from the private sector (60.0%) were more likely to receive supports than male employees (52.6%) and than those from the public sector (46.2%). The most common health and social support received by the employees were treatment, and nutritional support and reduction of workload, respectively. CONCLUSIONS: HIV/AIDS infected employees named treatment and nutritional support, and soft loans and reduced workload respectively, as the most important health and social supports they needed from their employers. This study provides baseline information for further studies on provision of health and social support services by employers to HIV/AIDS infected employees in the context of a developing economy like Tanzania. PMID- 24950700 TI - Improving audiologic performance with partial insertion of a compressed array despite intracochlear retention of four electrodes during revision cochlear implant surgery: A case report. AB - OBJECTIVE AND IMPORTANCE: To report a case of partial extraction of the electrode array during revision cochlear implant surgery and to discuss the surgical management of this rare complication. Clinical presentation The safety of revision cochlear implant surgery has long been demonstrated. Only five cases of partial extraction of the electrode array with intracochlear retention have been reported in the literature. In this report, we describe the case of a 12-year-old boy with post-meningitis deafness who suffered this complication. INTERVENTION: Despite intracochlear retention of four electrodes, the surgical team was able to perform partial insertion of a Med-El compressed array: a total of 8 electrodes out of 12 were implanted in the same scala tympani. Five months after the surgery, the patient had access for the first time to open-set speech recognition. He could recognize 77% of open-set sentences in silence compared to 14% after initial implant activation. Seven months after the surgery, the patient was implanted in his contralateral ear with a Med-El Pulsar split array and now benefits from bilateral auditory stimulation. CONCLUSION: Partial insertion of a compressed array represents a viable option when facing incomplete extraction of a cochlear implant electrode array. Indeed, our patient's audiologic performance improved significantly and the results seem to surpass those obtained with partial insertion of a conventional electrode array. PMID- 24950699 TI - Gene expression identifies heterogeneity of metastatic behavior among high-grade non-translocation associated soft tissue sarcomas. AB - BACKGROUND: The biologic heterogeneity of soft tissue sarcomas (STS), even within histological subtypes, complicates treatment. In earlier studies, gene expression patterns that distinguish two subsets of clear cell renal carcinoma (RCC), serous ovarian carcinoma (OVCA), and aggressive fibromatosis (AF) were used to separate 73 STS into two or four groups with different probabilities of developing metastatic disease (PrMet). This study was designed to confirm our earlier observations in a larger independent data set. METHODS: We utilized these gene sets, hierarchical clustering (HC), and Kaplan-Meier analysis, to examine 309 STS, using Affymetrix chip expression profiling. RESULTS: HC using the combined AF-, RCC-, and OVCA-gene sets identified subsets of the STS samples. Analysis revealed differences in PrMet between the clusters defined by the first branch point of the clustering dendrogram (p = 0.048), and also among the four different clusters defined by the second branch points (p < 0.0001). Analysis also revealed differences in PrMet between the leiomyosarcomas (LMS), dedifferentiated liposarcomas (LipoD), and undifferentiated pleomorphic sarcomas (UPS) (p = 0.0004). HC of both the LipoD and UPS sample sets divided the samples into two groups with different PrMet (p = 0.0128, and 0.0002, respectively). HC of the UPS samples also showed four groups with different PrMet (p = 0.0007). HC found no subgroups of the LMS samples. CONCLUSIONS: These data confirm our earlier studies, and suggest that this approach may allow the identification of more than two subsets of STS, each with distinct clinical behavior, and may be useful to stratify STS in clinical trials and in patient management. PMID- 24950702 TI - COX-2 overexpression in resected pancreatic head adenocarcinomas correlates with favourable prognosis. AB - BACKGROUND: Overexpression of cyclooxygenase-2 (COX-2) has been implicated in oncogenesis and progression of adenocarcinomas of the pancreatic head. The data on the prognostic importance of COX expression in these tumours is inconsistent and conflicting. We evaluated how COX-2 overexpression affected overall postoperative survival in pancreatic head adenocarcinomas. METHODS: The study included 230 consecutive pancreatoduodenectomies for pancreatic cancer (PC, n = 92), ampullary cancer (AC, n = 62) and distal bile duct cancer (DBC, n = 76). COX 2 expression was assessed by immunohistochemistry. Associations between COX-2 expression and histopathologic variables including degree of differentiation, histopathologic type of differentiation (pancreatobiliary vs. intestinal) and lymph node ratio (LNR) were evaluated. Unadjusted and adjusted survival analysis was performed. RESULTS: COX-2 staining was positive in 71% of PC, 77% in AC and 72% in DBC. Irrespective of tumour origin, overall patient survival was more favourable in patients with COX-2 positive tumours than COX-2 negative (p = 0.043 in PC, p = 0.011 in AC, p = 0.06 in DBC). In tumours of pancreatobiliary type of histopathological differentiation, COX-2 expression did not significantly affect overall patient survival. In AC with intestinal differentiation COX-2 expression significantly predicted favourable survival (p = 0.003). In PC, COX-2 expression was significantly associated with high degree of differentiation (p = 0.002). COX 2 and LNR independently predicted good prognosis in a multivariate model. CONCLUSIONS: COX-2 is overexpressed in pancreatic cancer, ampullary cancer and distal bile duct cancer and confers a survival benefit in all three cancer types. In pancreatic cancer, COX-2 overexpression is significantly associated with the degree of differentiation and independently predicts a favourable prognosis. PMID- 24950703 TI - Clinical course and implications of congenital nasal pyriform stenosis and solitary median maxillary central incisor in a newborn: a case report. AB - INTRODUCTION: Congenital nasal pyriform aperture stenosis and solitary median maxillary central incisor are uncommon anomalies and are associated with further malformations. Solitary median maxillary central incisor itself has initially no impact on a child's health, but congenital nasal pyriform aperture stenosis is a potentially life-threatening condition. CASE PRESENTATION: A Caucasian baby boy showed severe dyspnoea and was intubated orotracheally. Multiple anomalies were detected, including urogenital and craniofacial malformations. Computed tomography scans revealed congenital nasal pyriform aperture stenosis with a diameter of 4.9mm and a solitary median maxillary central incisor. A 3.0mm tube was inserted in his left nasal cavity, and the baby was able to breathe sufficiently and spontaneously. The nasal tube was removed after seven days, and the baby was discharged under application of decongestant drops. After seven months, the baby was readmitted with respiratory distress, and surgery was carried out using an intraoral sublabial approach. The stenotic area of the pyriform aperture was widened, and 3.0mm tubes were inserted in both nasal cavities for 10 days. Over a period of six months, no further respiratory distress has occurred. CONCLUSIONS: The decision to perform surgery was delayed since the baby's nasal breathing was adequate as a result of the insertion of a nasal tube. Since treatment depends on the severity of symptoms, it is appropriate in some cases to take a conservative approach at first, and to keep surgery as a last resort. Once a conservative approach has been selected for congenital nasal pyriform aperture stenosis, awareness of the life-threatening nature of the condition should be kept in mind, and a surgical approach must still be taken into account. PMID- 24950705 TI - Diagnostic proficiency and reporting of Lassa fever by physicians in Osun State of Nigeria. AB - BACKGROUND: Lassa fever is highly contagious and commonly results in death. It is therefore necessary to diagnose and report any suspected case of Lassa fever to facilitate preventive strategies. This study assessed the preparedness of physicians in the diagnosis and reporting of Lassa fever. METHODS: The study design was descriptive cross-sectional. The consenting medical doctors completed a self-administered questionnaire on the diagnosis and reporting of Lassa fever. Descriptive and inferential statistics were used in data analyses. RESULTS: One hundred seventy-five physicians participated in the study. The mean age was 41.5 +/- 10.9 years (range, 24-75 years). Most of the physicians were male (78.9%) and had practiced medicine >= 20 years (51.5%). Most of the physicians had a good knowledge regarding the diagnosis and reporting of Lassa fever; however, none of the physicians had ever diagnosed or reported a suspected case. Predictors of good knowledge include male sex, not practicing at a secondary health care level and post graduation year more than 20 years. CONCLUSION: There is disparity in knowledge and practices of physicians regarding the diagnosis and reporting of Lassa fever. Thus, it is necessary to improve the knowledge and practices of physicians regarding the diagnosis and reporting of Lassa fever. PMID- 24950704 TI - Fabrication and in vitro evaluation of an articular cartilage extracellular matrix-hydroxyapatite bilayered scaffold with low permeability for interface tissue engineering. AB - BACKGROUND: Osteochondral interface regeneration is challenging for functional and integrated cartilage repair. Various layered scaffolds have been used to reconstruct the complex interface, yet the influence of the permeability of the layered structure on cartilage defect healing remains largely unknown. METHODS: We designed and fabricated a novel bilayered scaffold using articular cartilage extracellular matrix (ACECM) and hydroxyapatite (HAp), involving a porous, oriented upper layer and a dense, mineralised lower layer. By optimising the HAp/ACECM ratio, differing pore sizes and porosities were obtained simultaneously in the two layers. To evaluate the effects of permeability on cell behaviour, rabbit chondrocytes were seeded. RESULTS: Morphological observations demonstrated that a gradual interfacial region was formed with pore sizes varying from 128.2 +/- 20.3 to 21.2 +/- 3.1 MUm. The permeability of the bilayered scaffold decreased with increasing compressive strain and HAp content. Mechanical tests indicated that the interface was stable to bearing compressive and shear loads. Accordingly, the optimum HAp/ACECM ratio (7 w/v%) in the layer to mimic native calcified cartilage was found. Chondrocytes could not penetrate the interface and resided only in the upper layer, where they showed high cellularity and abundant matrix deposition. CONCLUSIONS: Our findings suggest that a bilayered scaffold with low permeability, rather than complete isolation, represents a promising candidate for osteochondral interface tissue engineering. PMID- 24950706 TI - Case report: nocardia infection associated with ectopic cushings. AB - BACKGROUND: Cushing's syndrome results from exposure to excess glucocorticoids. Ectopic Cushings is endogenous ACTH dependant form of Cushing's associated with markedly raised ACTH and cortisol levels. This leads to an impaired immune response, setting the stage for occurrence of opportunistic infections. Nocardiosis is a gram positive bacterial infection caused by aerobic actinomycetes in genus Nocardia. We report a series of patients diagnosed with ectopic Cushings, having pneumonia with Nocardia spp. In one of these cases, the manifestations of Cushing's disappeared with treatment for Nocardia. CASE PRESENTATION: Two middle aged men of Asian descent presented to the Endocrine clinic: the first with history of exertional shortness of breath, and weight loss for 1 year, the other with facial swelling, disturbed sleep and lethargy for a month. The third case was a young Asian male who presented with progressive weakness & weight loss for 2 months. All three patients had uncontrolled hypertension, high blood sugars & were hypokalemic (K: 2.52, 2.9, 1.5 mmol/l); 24 hour urine cortisol was elevated at 2000, 27216 and 9088 (32-243 ug/24 hours); ACTH 68.5, 159, 255 [0-48 pg/ml), respectively. Their MRI pituitary was normal, inferior petrosal sinus sampling revealed no central peripheral gradient. CT chest of these subjects demonstrated cavitatory lung lesions; microscopic analysis of respiratory samples was suggestive of infection with Nocardia spp. Histopathology of bronchoscopic-guided biopsy revealed no malignancy. Antihypertensives, insulin, potassium replacement, ketoconazole & trimethoprim sulphamethoxazole (TS) were initiated. The patients' symptomatology improved & cavitatory lesions resolved with treatment. The primary source for the ectopic cushings remained unknown. The first case required bilateral adrenalectomy. The second case followed a progressively downhill course leading to death. In the third case, we were able to completely taper off ketoconazole, potassium, insulin & antihypertensives, after starting TS. CONCLUSION: Opportunistic infections are known to be associated with Cushing's syndrome, and higher levels of glucocorticoid secretion are found in patients with ectopically produced ACTH. Pulmonary nocardiosis is important differential to consider. This series includes the first case reported in which signs and symptoms of cushings subsided after treatment of Nocardia. PMID- 24950707 TI - Calculation of exact p-values when SNPs are tested using multiple genetic models. AB - BACKGROUND: Several methods have been proposed to account for multiple comparisons in genetic association studies. However, investigators typically test each of the SNPs using multiple genetic models. Association testing using the Cochran-Armitage test for trend assuming an additive, dominant, or recessive genetic model, is commonly performed. Thus, each SNP is tested three times. Some investigators report the smallest p-value obtained from the three tests corresponding to the three genetic models, but such an approach inherently leads to inflated type 1 errors. Because of the small number of tests (three) and high correlation (functional dependence) among these tests, the procedures available for accounting for multiple tests are either too conservative or fail to meet the underlying assumptions (e.g., asymptotic multivariate normality or independence among the tests). RESULTS: We propose a method to calculate the exact p-value for each SNP using different genetic models. We performed simulations, which demonstrated the control of type 1 error and power gains using the proposed approach. We applied the proposed method to compute p-value for a polymorphism eNOS -786T>C which was shown to be associated with breast cancer risk. CONCLUSIONS: Our findings indicate that the proposed method should be used to maximize power and control type 1 errors when analyzing genetic data using additive, dominant, and recessive models. PMID- 24950709 TI - Bimetallic alloys in action: dynamic atomistic motifs for electrochemistry and catalysis. AB - Bimetallic alloys show great promise for applications in a wide range of technologies related to electrochemistry and heterogeneous catalysis. The alloyed nature of these materials supports the existence of surface phenomena and structural motifs not present in single-component materials. These novel features result in electrochemical and catalytic behaviors, requiring entirely new categories of explanations. In this perspective concrete examples are used to illustrate several of these chemical and structural features, which are unique to multi-component metal surfaces. The influence of the surface's structure and surroundings (e.g. adsorbates) on each other provides a common thread, with the emergence of dynamic surfaces as its terminus. In considering three model systems (PtRu, PtNi and AuPd), we discuss not only a selection of surface phenomena relevant to each, but also the implications of these alloy-related behaviors for the electrochemical and catalytic properties of each surface. PMID- 24950708 TI - Community-based implementation and effectiveness in a randomized trial of a risk reduction intervention for HIV-serodiscordant couples: study protocol. AB - BACKGROUND: The HIV/AIDS epidemic continues to disproportionately affect African American communities in the US, particularly those located in urban areas. Despite the fact that HIV is often transmitted from one sexual partner to another, most HIV prevention interventions have focused only on individuals, rather than couples. This five-year study investigates community-based implementation, effectiveness, and sustainability of 'Eban II,' an evidence-based risk reduction intervention for African-American heterosexual, serodiscordant couples. METHODS/DESIGN: This hybrid implementation/effectiveness implementation study is guided by organizational change theory as conceptualized in the Texas Christian University Program Change Model (PCM), a model of phased organizational change from exposure to adoption, implementation, and sustainability. The primary implementation aims are to assist 10 community-based organizations (CBOs) to implement and sustain Eban II; specifically, to partner with CBOs to expose providers to the intervention; facilitate its adoption, implementation and sustainment; and to evaluate processes and determinants of implementation, effectiveness, fidelity, and sustainment. The primary effectiveness aim is to evaluate the effect of Eban II on participant (n = 200 couples) outcomes, specifically incidents of protected sex and proportion of condom use. We will also determine the cost-effectiveness of implementation, as measured by implementation costs and potential cost savings. A mixed methods evaluation will examine implementation at the agency level; staff members from the CBOs will complete baseline measures of organizational context and climate, while key stakeholders will be interviewed periodically throughout implementation. Effectiveness of Eban II will be assessed using a randomized delayed enrollment (waitlist) control design to evaluate the impact of treatment on outcomes at posttest and three-month follow-up. Multi-level hierarchical modeling with a multi-level nested structure will be used to evaluate the effects of agency- and couples-level characteristics on couples-level outcomes (e.g., condom use). DISCUSSION: This study will produce important information regarding the value of the Eban II program and a theory-guided implementation process and tools designed for use in implementing Eban II and other evidence-based programs in demographically diverse, resource-constrained treatment settings. TRIAL REGISTRATION: NCT00644163. PMID- 24950710 TI - Significant head accelerations can influence immediate neurological impairments in a murine model of blast-induced traumatic brain injury. AB - Although blast-induced traumatic brain injury (bTBI) is well recognized for its significance in the military population, the unique mechanisms of primary bTBI remain undefined. Animate models of primary bTBI are critical for determining these potentially unique mechanisms, but the biomechanical characteristics of many bTBI models are poorly understood. In this study, we examine some common shock tube configurations used to study blast-induced brain injury in the laboratory and define the optimal configuration to minimize the effect of torso overpressure and blast-induced head accelerations. Pressure transducers indicated that a customized animal holder successfully reduced peak torso overpressures to safe levels across all tested configurations. However, high speed video imaging acquired during the blast showed significant head accelerations occurred when animals were oriented perpendicular to the shock tube axis. These findings of complex head motions during blast are similar to previous reports [Goldstein et al., 2012, "Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model," Sci. Transl. Med., 4(134), 134ra160; Sundaramurthy et al., 2012, "Blast-Induced Biomechanical Loading of the Rat: An Experimental and Anatomically Accurate Computational Blast Injury Model," J. Neurotrauma, 29(13), pp. 2352-2364; Svetlov et al., 2010, "Morphologic and Biochemical Characterization of Brain Injury in a Model of Controlled Blast Overpressure Exposure," J. Trauma, 69(4), pp. 795-804]. Under the same blast input conditions, minimizing head acceleration led to a corresponding elimination of righting time deficits. However, we could still achieve righting time deficits under minimal acceleration conditions by significantly increasing the peak blast overpressure. Together, these data show the importance of characterizing the effect of blast overpressure on head kinematics, with the goal of producing models focused on understanding the effects of blast overpressure on the brain without the complicating factor of superimposed head accelerations. PMID- 24950711 TI - The regulatory toll-like receptor 4 genetic polymorphism rs11536889 is associated with renal, coagulation and hepatic organ failure in sepsis patients. AB - BACKGROUND: Toll-like receptor 4 (TLR4), a lipopolysaccharide (LPS) receptor complex signal-transducing molecule, plays a crucial role in sensing LPS from gram-negative bacteria. TLR4 signaling pathway activation by LPS plays a major role in sepsis pathogenesis. A single nucleotide polymorphism, rs11536889, in the 3'-untranslated region of the TLR4 gene is thought to affect TLR4 translation. This study aimed to investigate whether organ failure in sepsis patients is related to the TLR4 rs11536889 genotype. METHODS: Adult Caucasian patients with sepsis from the intensive care unit of a university medical center were followed up for 90 days, and organ failure was recorded as the primary outcome variable. Blood samples were collected at enrollment for TLR4 rs11536889 genotyping. Sepsis related organ failure assessment (SOFA) scores were quantified at sepsis onset and throughout the observational period to monitor organ failure. RESULTS: A total of 210 critically ill patients with sepsis were enrolled into this study. Wild-type GG was compared to GC/CC. During their stay in the intensive care unit, GG patients presented significantly higher SOFA scores than did C allele carriers (7.9 +/- 4.5 and 6.8 +/- 4.2, respectively; p = 0.0005). Analysis of organ specific SOFA sub-scores revealed significant differences in three organ systems: renal, coagulation and hepatic (p = 0.0005, p = 0.0245 and p < 0.0001, respectively). Additionally, the rs11536889 polymorphism was associated with a higher incidence of gram-negative infections. CONCLUSIONS: These results offer the first evidence that TLR4 rs11536889 is a useful marker of organ failure in patients with sepsis. PMID- 24950712 TI - Practitioners' perspectives on the functioning of school-age children with cochlear implants. AB - OBJECTIVE: The availability of cochlear implants has increased the number of children with profound deafness educated in classrooms alongside peers with normal hearing. The purpose of this research was to better understand the functioning of these children from the perspective of their service providers. METHODS: Semi-structured focus group interviews were conducted with 28 practitioners to elicit their perceptions of children's abilities in oral communication, academic, and social functioning. Data were coded inductively and examined through content analysis. RESULTS: The central theme was that cochlear implantation has improved school functioning for children both in hearing and related spoken language abilities and beyond hearing in academic and social development. While these benefits were a consistent theme, a wide range of performance was identified across all areas of functioning. In particular, areas of concern included full participation in classroom activities and social interaction with peers. CONCLUSIONS: The findings provide insights into functioning for children with cochlear implants from the perspective of those who interact with them in everyday settings. These findings underscore the challenges for children in achieving full participation despite improvements in communication skills. Practitioners identified areas where intervention is required to facilitate the inclusion of children in school programs. PMID- 24950713 TI - Parental perceived neighborhood attributes: associations with active transport and physical activity among 10-12 year old children and the mediating role of independent mobility. AB - BACKGROUND: During the last decades, the use of active travel modes declined in all age groups. Childhood is a critical time to establish lifelong healthy patterns. To develop effective interventions in this age group, insight in the correlates of health behaviors and the possible mediating factors is necessary. Among children, the role of parents may not be overlooked. Therefore, this study aimed to examine the associations of parental perceptions of neighborhood environmental attributes with active transport and total physical activity in 10 12 year old Belgian boys and girls. Furthermore, this study examined the potential mediating effect of independent mobility on these associations. METHODS: In the present study, 736 10-12 year old children and their parents from 44 elementary schools in Flanders, Belgium, participated. The children were asked to wear an activity monitor and to fill in a survey questioning demographic factors and the Flemish Physical Activity Questionnaire. The parents filled in a survey concerning demographic factors, the child's level of independent mobility and environmental perceptions (Neighborhood Environmental Walkability Scale). RESULTS: Overall, boys reported more active transport when parents perceived more land use mix diversity, shorter distances to school, good land use mix access, higher residential density and less pleasing neighborhood aesthetics. Higher total physical activity levels were reported when parents perceived shorter distances to school and availability of walking/cycling infrastructure. None of the associations was mediated by independent mobility in boys. Girls reported more active transport when parents perceived higher residential density, more land use mix diversity, shorter distances to school, good land use mix access, available walking/cycling infrastructure and convenient recreational facilities. Girls reported higher total physical activity levels when parents perceived high residential density, good land use mix access, well-maintained and high quality walking/cycling infrastructures and more traffic safety. Independent mobility was found to be an important mediator of these associations in girls. CONCLUSIONS: Neighborhood environmental interventions to increase children's active transport and physical activity can be effective when combined with awareness raising programs for parents. Furthermore, among girls encouraging independent mobility may contribute to behavior change. PMID- 24950715 TI - The influence of emotion on keyboard typing: an experimental study using visual stimuli. AB - BACKGROUND: Emotion recognition technology plays the essential role of enhancement in Human-Computer Interaction (HCI). In recent years, a novel approach for emotion recognition has been reported, which is by keystroke dynamics. This approach can be considered to be rather desirable in HCI because the data used is rather non-intrusive and easy to obtain. However, there were only limited investigations about the phenomenon itself in previous studies. This study aims to examine the source of variance in keystroke typing patterns caused by emotions. METHODS: A controlled experiment to collect subjects' keystroke data in different emotional states induced by International Affective Picture System (IAPS) was conducted. Two-way Valence (3) * Arousal (3) ANOVAs were used to examine the collected dataset. RESULTS: The results of the experiment indicate that the effect of emotion is significant (p<.001) in the keystroke duration, keystroke latency, and accuracy rate of the keyboard typing. However, the size of the emotional effect is small, compare to the individual variability. CONCLUSIONS: Our findings support the conclusion that the keystroke duration, keystroke latency, and also the accuracy rate of typing, are influenced by emotional states. Notably, the finding about the size of effect suggests that the accuracy rate of the emotion recognition could be further improved if personalized models are utilized. On the other hand, the finding also provides an explanation of why real-world applications which authenticate the identity of users by monitoring keystrokes may not be interfered by the emotional states of users. The experiment was conducted using standard instruments and hence is expected to be highly reproducible. PMID- 24950714 TI - Expression of integrin alpha3beta1 and cyclooxygenase-2 (COX2) are positively correlated in human breast cancer. AB - BACKGROUND: Expression of integrin alpha3beta1 is associated with tumor progression, metastasis, and poor prognosis in several cancers, including breast cancer. Moreover, preclinical studies have revealed important pro-tumorigenic and pro-metastatic functions for this integrin, including tumor growth, survival, invasion, and paracrine induction of angiogenesis. Our previously published work in a preclinical breast cancer model showed that integrin alpha3beta1 promotes expression of cyclooxygenase-2 (COX2/PTGS2), a known driver of breast cancer progression. However, the clinical significance of this regulation was unknown. The objective of the current study was to assess the clinical relevance of the relationship between integrin alpha3beta1 and COX2 by testing for their correlated expression among various forms of human breast cancer. METHODS: Immunohistochemistry was performed to assess co-expression of alpha3 and COX2 in specimens of human invasive ductal carcinoma (IDC), either on a commercial tissue microarray (n = 59 samples) or obtained from Albany Medical Center archives (n = 68 samples). Immunostaining intensity for the integrin alpha3 subunit or COX2 was scored, and Spearman's rank correlation coefficient analysis was performed to assess their co-expression across and within different tumor subtypes or clinicopathologic criteria. RESULTS: Although expression of integrin alpha3 or COX2 varied among clinical IDC samples, a statistically significant, positive correlation was detected between alpha3 and COX2 in both tissue microarrays (r(s) = 0.49, p < 0.001, n = 59) and archived samples (r(s) = 0.59, p < 0.0001, n = 68). In both sample sets, this correlation was independent of hormone receptor status, histological grade, or disease stage. CONCLUSIONS: COX2 and alpha3 are correlated in IDC independently of hormone receptor status or other clinicopathologic features, supporting the hypothesis that integrin alpha3beta1 is a determinant of COX2 expression in human breast cancer. These results support the clinical relevance of alpha3beta1-dependent COX2 gene expression that we reported previously in breast cancer cells. The findings also suggest that COX2 positive breast carcinomas of various subtypes might be vulnerable to therapeutic strategies that target alpha3beta1, and that alpha3 expression might serve as an independent prognostic biomarker. PMID- 24950716 TI - Association between harmful alcohol use and periodontal status according to gender and smoking. AB - BACKGROUND: the aim of this study is to assess the association of harmful alcohol use based on the alcohol use disorders identification test (AUDIT) score with periodontal status according to gender and smoking in a representative sample of Korean adults. METHODS: This study analyzed 5,291 participants older than 19 years whose data of harmful alcohol use and periodontal status were available. Harmful alcohol use was defined by the WHO guidelines for the administration of AUDIT. The periodontal status was assessed by the Community Periodontal Index (CPI). Multivariate logistic regression analysis was performed with adjustment for socio-demographic variables, oral and general health behavior, oral health status and systemic conditions. All analyses considered a complex sampling design, and multivariate analysis was also performed in the subgroups. RESULTS: Multivariate logistic regression analysis revealed a marginal association between harmful alcohol use and higher CPI in the total sample. The adjusted odds ratio (OR) of harmful alcohol use was 1.16 (0.97 to 1.38) for higher CPI. Higher CPI was significantly associated with harmful alcohol use in men (OR: 1.28; 95% CI: 1.03-1.60) and non-smokers (OR: 1.29; 95% CI: 1.06-1.57). CONCLUSION: Periodontal status is significantly associated with harmful alcohol use in men and non smokers in a representative sample of Korean adults. PMID- 24950717 TI - Genome-wide identification of pathogenicity factors of the free-living amoeba Naegleria fowleri. AB - BACKGROUND: The free-living amoeba Naegleria fowleri is the causative agent of the rapidly progressing and typically fatal primary amoebic meningoencephalitis (PAM) in humans. Despite the devastating nature of this disease, which results in > 97% mortality, knowledge of the pathogenic mechanisms of the amoeba is incomplete. This work presents a comparative proteomic approach based on an experimental model in which the pathogenic potential of N. fowleri trophozoites is influenced by the compositions of different media. RESULTS: As a scaffold for proteomic analysis, we sequenced the genome and transcriptome of N. fowleri. Since the sequence similarity of the recently published genome of Naegleria gruberi was far lower than the close taxonomic relationship of these species would suggest, a de novo sequencing approach was chosen. After excluding cell regulatory mechanisms originating from different media compositions, we identified 22 proteins with a potential role in the pathogenesis of PAM. Functional annotation of these proteins revealed, that the membrane is the major location where the amoeba exerts its pathogenic potential, possibly involving actin-dependent processes such as intracellular trafficking via vesicles. CONCLUSION: This study describes for the first time the 30 Mb-genome and the transcriptome sequence of N. fowleri and provides the basis for the further definition of effective intervention strategies against the rare but highly fatal form of amoebic meningoencephalitis. PMID- 24950718 TI - Development of quality indicators for antimicrobial treatment in adults with sepsis. AB - BACKGROUND: Outcomes in patients with sepsis are better if initial empirical antimicrobial use is appropriate. Several studies have shown that adherence to guidelines dictating appropriate antimicrobial use positively influences clinical outcome, shortens length of hospital stay and contributes to the containment of antibiotic resistance.Quality indicators (QIs) can be systematically developed from these guidelines to define and measure appropriate antimicrobial use. We describe the development of a concise set of QIs to assess the appropriateness of antimicrobial use in adult patients with sepsis on a general medical ward or Intensive Care Unit (ICU). METHODS: A RAND-modified, five step Delphi procedure was used. A multidisciplinary panel of 14 experts appraised and prioritized 40 key recommendations from within the Dutch national guideline on antimicrobial use for adult hospitalized patients with sepsis (http://www.swab.nl/guidelines). A procedure to select QIs relevant to clinical outcome, antimicrobial resistance and costs was performed using two rounds of questionnaires with a face-to-face consensus meeting between the rounds over a period of three months. RESULTS: The procedure resulted in the selection of a final set of five QIs, namely: obtain cultures; prescribe empirical antimicrobial therapy according to the national guideline; start intravenous drug therapy; start antimicrobial treatment within one hour; and streamline antimicrobial therapy. CONCLUSION: This systematic, stepwise method, which combined evidence and expert opinion, led to a concise and therefore feasible set of QIs for optimal antimicrobial use in hospitalized adult patients with sepsis. The next step will entail subjecting these quality indicators to an applicability test for their clinimetric properties and ultimately, using these QIs in quality-improvement projects. This information is crucial for antimicrobial stewardship teams to help set priorities and to focus improvement. PMID- 24950720 TI - Comparison of a standard CO2 pressure pneumoperitoneum insufflator versus AirSeal: study protocol of a randomized controlled trial. AB - BACKGROUND: AirSeal is a novel class of valve-free insufflation system that enables a stable pneumoperitoneum with continuous smoke evacuation and carbon dioxide (CO2) recirculation during laparoscopic surgery. Comparison data to standard CO2 pressure pneumoperitoneum insufflators is scarce. The aim of this study is to evaluate the potential advantages of AirSeal compared to a standard CO2 insufflator. METHODS/DESIGN: This is a single center randomized controlled trial comparing elective laparoscopic cholecystectomy, colorectal surgery and hernia repair with AirSeal (group A) versus a standard CO2 pressure insufflator (group S). Patients are randomized using a web-based central randomization and registration system. Primary outcome measures will be operative time and level of postoperative shoulder pain by using the visual analog score (VAS). Secondary outcomes include the evaluation of immunological values through blood tests, anesthesiological parameters, surgical side effects and length of hospital stay. Taking into account an expected dropout rate of 5%, the total number of patients is 182 (n = 91 per group). All tests will be two-sided with a confidence level of 95% (P <0.05). DISCUSSION: The duration of an operation is an important factor in reducing the patient's exposure to CO2 pneumoperitoneum and its adverse consequences. This trial will help to evaluate if the announced advantages of AirSeal, such as clear sight of the operative site and an exceptionally stable working environment, will facilitate the course of selected procedures and influence operation time and patients clinical outcome. TRIAL REGISTRATION: ClinicalTrials.gov NCT01740011, registered 23 November 2012. PMID- 24950721 TI - Tai chimpanzees anticipate revisiting high-valued fruit trees from further distances. AB - The use of spatio-temporal memory has been argued to increase food-finding efficiency in rainforest primates. However, the exact content of this memory is poorly known to date. This study investigated what specific information from previous feeding visits chimpanzees (Pan troglodytes verus), in Tai National Park, Cote d'Ivoire, take into account when they revisit the same feeding trees. By following five adult females for many consecutive days, we tested from what distance the females directed their travels towards previously visited feeding trees and how previous feeding experiences and fruit tree properties influenced this distance. To exclude the influence of sensory cues, the females' approach distance was measured from their last significant change in travel direction until the moment they entered the tree's maximum detection field. We found that chimpanzees travelled longer distances to trees at which they had previously made food grunts and had rejected fewer fruits compared to other trees. In addition, the results suggest that the chimpanzees were able to anticipate the amount of fruit that they would find in the trees. Overall, our findings are consistent with the hypothesis that chimpanzees act upon a retrieved memory of their last feeding experiences long before they revisit feeding trees, which would indicate a daily use of long-term prospective memory. Further, the results are consistent with the possibility that positive emotional experiences help to trigger prospective memory retrieval in forest areas that are further away and have fewer cues associated with revisited feeding trees. PMID- 24950719 TI - Design, implementation, and evaluation of a knowledge translation intervention to increase organ donation after cardiocirculatory death in Canada: a study protocol. AB - BACKGROUND: A shortage of transplantable organs is a global problem. There are two types of organ donation: living and deceased. Deceased organ donation can occur following neurological determination of death (NDD) or cardiocirculatory death. Donation after cardiocirculatory death (DCD) accounts for the largest increments in deceased organ donation worldwide. Variations in the use of DCD exist, however, within Canada and worldwide. Reasons for these discrepancies are largely unknown. The purpose of this study is to develop, implement, and evaluate a theory-based knowledge translation intervention to provide practical guidance about how to increase the numbers of DCD organ donors without reducing the numbers of standard NDD donors. METHODS: We will use a mixed method three-step approach. In step one, we will conduct semi-structured interviews, informed by the Theoretical Domains Framework, to identify and describe stakeholders' beliefs and attitudes about DCD and their perceptions of the multi-level factors that influence DCD. We will identify: determinants of the evidence-practice gap; specific behavioural changes and/or process changes needed to increase DCD; specific group(s) of clinicians or organizations (e.g., provincial donor organizations) in need of behaviour change; and specific targets for interventions. In step two, using the principles of intervention mapping, we will develop a theory-based knowledge translation intervention that encompasses behavior change techniques to overcome the identified barriers and enhance the enablers to DCD. In step three, we will roll out the intervention in hospitals across the 10 Canadian provinces and evaluate its effectiveness using a multiple interrupted time series design. DISCUSSION: We will adopt a behavioural approach to define and test novel, theory-based, and ethically-acceptable knowledge translation strategies to increase the numbers of available DCD organ donors in Canada. If successful, this study will ultimately lead to more transplantations, reducing patient morbidity and mortality at a population-level. PMID- 24950722 TI - Visual perspective taking by dogs (Canis familiaris) in a Guesser-Knower task: evidence for a canine theory of mind? AB - We tested domestic dogs (N = 16) in a Guesser-Knower task in which they chose between possible locations for hidden food indicated by human informants. In four experiments, the perceptual access of the Guesser and Knower to the hidden food baiting was manipulated. When informants had differing perceptual access to the baiting, dogs preferred the location indicated by the Knower from the start of testing (Experiment 1), even when baiting was done by a third experimenter (Experiments 2-3). However, when there was no difference in perceptual access and both informants either knew or did not know the food location, dogs had no preference between the informants (Experiment 4). Controls ruled out alternative explanations in terms of associative learning, unintentional and olfactory cues. Analysis of individual data showed no significant heterogeneity across dogs, and results were not correlated with age or sex. Dogs' performances were superior to those of nonhuman primates in previous studies. Although a mentalistic explanation is not required, results add to evidence that dogs have a remarkable sensitivity to cues related to humans' attentional state, which enables them to respond as if they had a functional theory of mind in the Guesser-Knower task with human informants. PMID- 24950723 TI - Ultrahigh sensitivity endoscopic camera using a new CMOS image sensor: providing with clear images under low illumination in addition to fluorescent images. AB - BACKGROUND: We developed a new ultrahigh-sensitive CMOS camera using a specific sensor that has a wide range of spectral sensitivity characteristics. The objective of this study is to present our updated endoscopic technology that has successfully integrated two innovative functions; ultrasensitive imaging as well as advanced fluorescent viewing. METHODS: Two different experiments were conducted. One was carried out to evaluate the function of the ultrahigh sensitive camera. The other was to test the availability of the newly developed sensor and its performance as a fluorescence endoscope. In both studies, the distance from the endoscopic tip to the target was varied and those endoscopic images in each setting were taken for further comparison. RESULTS: In the first experiment, the 3-CCD camera failed to display the clear images under low illumination, and the target was hardly seen. In contrast, the CMOS camera was able to display the targets regardless of the camera-target distance under low illumination. Under high illumination, imaging quality given by both cameras was quite alike. In the second experiment as a fluorescence endoscope, the CMOS camera was capable of clearly showing the fluorescent-activated organs. CONCLUSIONS: The ultrahigh sensitivity CMOS HD endoscopic camera is expected to provide us with clear images under low illumination in addition to the fluorescent images under high illumination in the field of laparoscopic surgery. PMID- 24950724 TI - Patient-reported outcomes of symptomatic cholelithiasis patients following cholecystectomy after at least 5 years of follow-up: a long-term prospective cohort study. AB - BACKGROUND: Up to 41% of patients report pain after cholecystectomy and in most studies follow-up for these symptoms did not exceed 5 years. The episodic nature of abdominal pain associated with symptomatic cholelithiasis warrants long-term follow-up studies. We assessed which patient and surgical factors were associated with absence of pain and patient-reported success of surgery after >= 5 years of follow-up. METHODS: Patients of >= 18 years of age with symptomatic cholelithiasis, classified as ASA I or II, who had previously returned a preoperative questionnaire were sent a questionnaire consisting of the gastrointestinal quality of life index (GIQLI) and patient ratings of current versus presurgical abdominal symptoms and of surgery result. Logistic regression analysis was performed to determine associations. RESULTS: Questionnaires were sent to 197 patients and returned by 126 (64.0%) patients (73.8 % female, mean age at surgery 47.5 +/- 12.2 years) at a mean of 10.0 +/- 1.0 years after cholecystectomy. Absence of abdominal pain was reported by 60.3% of the patients. Patients classified as ASA II as opposed to ASA I were less likely to report absence of pain (OR 0.41, 95% CI 0.17-0.99). A positive rating of long-term postsurgical versus presurgical abdominal symptoms was given by 89.7% of the patients and 90.5% considered the cholecystectomy result to be good. No variables were significantly associated with these latter two outcome measures. CONCLUSIONS: We found a high patient-reported surgery success rate after >5 years of follow-up after cholecystectomy despite residual abdominal pain in some of these patients. None of the patient and surgery-related characteristics were consistently associated with all three outcome measures. This discrepancy between patient' outcomes highlights the need for realistic expectations prior to cholecystectomy. PMID- 24950725 TI - Predicting the pathological features of the mesorectum before the laparoscopic approach to rectal cancer. AB - Pelvic anatomy and tumour features play a role in the difficulty of the laparoscopic approach to total mesorectal excision in rectal cancer. The aim of the study was to analyse whether these characteristics also influence the quality of the surgical specimen. We performed a prospective study in consecutive patients with rectal cancer located less than 12 cm from the anal verge who underwent laparoscopic surgery between January 2010 and July 2013. Exclusion criteria were T1 and T4 tumours, abdominoperineal resections, obstructive and perforated tumours, or any major contraindication for laparoscopic surgery. Dependent variables were the circumferential resection margin (CMR) and the quality of the mesorectum. Sixty-four patients underwent laparoscopic sphincter preserving total mesorectal excision. Resection was complete in 79.1% of specimens and CMR was positive in 9.7%. Univariate analysis showed tumour depth (T status) (P = 0.04) and promontorium-subsacrum angle (P = 0.02) independently predicted CRM (circumferential resection margin) positivity. Tumour depth (P < 0.05) and promontorium-subsacrum axis (P < 0.05) independently predicted mesorectum quality. Multivariate analysis identified the promontorium-subsacrum angle (P = 0.012) as the only independent predictor of CRM. Bony pelvis dimensions influenced the quality of the specimen obtained by laparoscopy. These measurements may be useful to predict which patients will benefit most from laparoscopic surgery and also to select patients in accordance with the learning curve of trainee surgeons. PMID- 24950727 TI - Using qualitative comparative analysis (QCA) in systematic reviews of complex interventions: a worked example. AB - BACKGROUND: Systematic reviews that address policy and practice questions in relation to complex interventions frequently need not only to assess the efficacy of a given intervention but to identify which intervention - and which intervention components - might be most effective in particular situations. Here, intervention replication is rare, and commonly used synthesis methods are less useful when the focus of analysis is the identification of those components of an intervention that are critical to its success. METHODS: Having identified initial theories of change in a previous analysis, we explore the potential of qualitative comparative analysis (QCA) to assist with complex syntheses through a worked example. Developed originally in the area of political science and historical sociology, a QCA aims to identify those configurations of participant, intervention and contextual characteristics that may be associated with a given outcome. Analysing studies in these terms facilitates the identification of necessary and sufficient conditions for the outcome to be obtained. Since QCA is predicated on the assumption that multiple pathways might lead to the same outcome and does not assume a linear additive model in terms of changes to a particular condition (that is, it can cope with 'tipping points' in complex interventions), it appears not to suffer from some of the limitations of the statistical methods often used in meta-analysis. RESULTS: The worked example shows how the QCA reveals that our initial theories of change were unable to distinguish between 'effective' and 'highly effective' interventions. Through the iterative QCA process, other intervention characteristics are identified that better explain the observed results. CONCLUSIONS: QCA is a promising alternative (or adjunct), particularly to the standard fall-back of a 'narrative synthesis' when a quantitative synthesis is impossible, and should be considered when reviews are broad and heterogeneity is significant. There are very few examples of its use with systematic review data at present, and further methodological work is needed to establish optimal conditions for its use and to document process, practice, and reporting standards. PMID- 24950726 TI - Radiofrequency ablation for Barrett's-associated intramucosal carcinoma: a multi center follow-up study. AB - BACKGROUND: Radiofrequency ablation (RFA), with or without endoscopic mucosal resection (EMR), has been validated as a safe, effective and durable treatment option for dysplastic Barrett's esophagus. Its durability in eradicating Barrett's-associated intramucosal carcinoma (IMC), however, is unclear. We set out to assess the long-term safety and efficacy of RFA for IMC. METHODS: Retrospective review of two tertiary care facility records for patients undergoing RFA, with or without EMR, for biopsy-proven IMC. Our primary outcome of interest was to quantify the rate of durable complete eradication for intestinal metaplasia and for IMC and associated dysplasia. A multi-variate regression analysis was performed to identify features which correlate with durable eradication of IMC/dysplasia. Our secondary outcome of interest was treatment-related complications. RESULTS: 36 patients (26 male; mean age 64 +/- 12 years), with a mean Barrett's length of 3.5 +/- 2.5 cm, underwent RFA for biopsy-proven IMC. EMR was performed in 31 (86%) prior to or during RFA. Complete eradication of IMC/dysplasia was achieved in 32/36 (89%) and patients required a mean of 1 +/- 1 EMR and 2 +/- 1 RFA sessions to achieve eradication. During a mean follow-up period of 24 +/- 19 months, durable complete eradication of IMC/dysplasia was achieved in 29/36 (81%) patients. On multi-variate regression analysis, undergoing an EMR prior to RFA was associated with an increased likelihood of maintaining durable eradication of IMC/dysplasia (p = 0.03). Treatment-related complications included: bleeding (3%) and stricture formation (19%). CONCLUSION: RFA is an effective and durable treatment option for Barrett's associated IMC. Greater than 80% of patients will achieve and maintain complete eradication of IMC at a mean of 2 years follow-up. PMID- 24950728 TI - Ryanodine receptor mutations presenting as idiopathic ventricular fibrillation: a report on two novel familial compound mutations, c.6224T>C and c.13781A>G, with the clinical presentation of idiopathic ventricular fibrillation. AB - Idiopathic ventricular fibrillation (IVF) is a rare genetically determined disease causing unexpected cardiac death in otherwise healthy individuals. This study identified two novel, functional heterozygous mutations in the ryanodine receptor 2 (RyR2) gene in a family with IVF. In the presented case all the patients received a thorough diagnostic workup to exclude structural heart disease. Blood was drawn from the patients, and genetic testing was performed including amplification and sequencing of splice locations in two exons of the RyR2 gene. The mutations were detected in five symptomatic family members. The genetic status of the five affected family members remains unclear. No clinically affected patient is without mutation. At this writing, one family member with confirmed mutation is asymptomatic. The differentiation between catecholaminergic polymorphic ventricular tachycardia (CPVT) and IVF remains a difficult issue, mainly based on clinical characteristics and gross genetic classification. In our case, the family history, exercise testing, and epinephrine stress testing do not suggest an association of arrhythmia and adrenergic triggers, which makes CPVT rather unlikely despite the fact that genetic testing showed RyR2 mutations. Currently, knowledge concerning the functional meaning of genetic mutations is growing. Future exploration of these functional aspects might give further impetus to allocation of these patients to a specific diagnosis. PMID- 24950730 TI - The multiple associations of Klippel-Feil syndrome. PMID- 24950729 TI - Assessment of right ventricular geometry and mechanics in chronic obstructive pulmonary disease patients living at high altitude. AB - Degree of increase in pulmonary artery pressure (PAP) and adaptive responses in right ventricular morphology and mechanics play an important role in the prognosis of chronic obstructive pulmonary disease (COPD) patients. Three dimensional echocardiography and deformation imaging are recent advancements in echocardiography that allow more through assessment of right ventricle. We aimed to investigate right ventricular geometry and mechanics in a stable COPD population living at moderately high altitude. A total of 26 stable COPD patients with variable disease severity were included to this study. Pulmonary function tests, six minutes walking test (6MWT) and two- and three-dimensional echocardiography were performed for evaluation and data collection. Both systolic (43.06 +/- 11.79 mmHg) and mean (33.38 +/- 9.75 mmHg) PAPs were significantly higher in COPD patients compared to controls (p < 0.05, p < 0.001; respectively). Right ventricular volumes were similar between groups, although right ventricular free wall thickness was significantly increased in COPD group. The number of subjects with a sub-normal (<40 %) right ventricular ejection fraction was significantly higher in COPD group (45.8 vs. 17.4 %, p < 0.05), and the mean right ventricular strain was significantly lower (-21.05 +/- 3.80 vs. -24.14 +/- 5.37; p < 0.05). Only mean PAP and body surface area were found as independent predictors for 6MWT distance. Increased PAP and reduced right ventricular contractility were found in COPD patients living at moderately high altitude, although right ventricular volumes were normal. Similar findings can be expected in other COPD patients with high PAP, since these findings probably represents the effect of increased PAP on right ventricular mechanics. PMID- 24950731 TI - Drug interactions and antiretroviral drug monitoring. AB - Owing to the improved longevity afforded by combination antiretroviral therapy (cART), HIV-infected individuals are developing several non-AIDS-related comorbid conditions. Consequently, medical management of the HIV-infected population is increasingly complex, with a growing list of potential drug-drug interactions (DDIs). This article reviews some of the most relevant and emerging potential interactions between antiretroviral medications and other agents. The most common DDIs are those involving protease inhibitors or non-nucleoside reverse transcriptase inhibitors, which alter the cytochrome P450 enzyme system and/or drug transporters such as p-glycoprotein. Of note are the new agents for the treatment of chronic hepatitis C virus infection. These new classes of drugs and others drugs that are increasingly used in this patient population represent a significant challenge with regard to achieving the goals of effective HIV suppression and minimization of drug-related toxicities. Awareness of DDIs and a multidisciplinary approach are imperative in reaching these goals. PMID- 24950735 TI - Bibliometric analysis of regional Latin America's scientific output in Public Health through SCImago Journal & Country Rank. AB - BACKGROUND: In the greater framework of the essential functions of Public Health, our focus is on a systematic, objective, external evaluation of Latin American scientific output, to compare its publications in the area of Public Health with those of other major geographic zones. We aim to describe the regional distribution of output in Public Health, and the level of visibility and specialization, for Latin America; it can then be characterized and compared in the international context. METHODS: The primary source of information was the Scopus database, using the category "Public Health, Environmental and Occupational Health", in the period 1996-2011. Data were obtained through the portal of SCImago Journal and Country Rank. Using a set of qualitative (citation based), quantitative (document recount) and collaborative (authors from more than one country) indicators, we derived complementary data. The methodology serves as an analytical tool for researchers and scientific policy-makers. RESULTS: The contribution of Latin America to the arsenal of world science lies more or less midway on the international scale in terms of its output and visibility. Revealed as its greatest strengths are the high level of specialization in Public Health and the sustained growth of output. The main limitations identified were a relative decrease in collaboration and low visibility. CONCLUSIONS: Collaboration is a key factor behind the development of scientific activity in Latin America. Although this finding can be useful for formulating research policy in Latin American countries, it also underlines the need for further research into patterns of scientific communication in this region, to arrive at more specific recommendations. PMID- 24950732 TI - Immune reconstitution disorders in patients with HIV infection: from pathogenesis to prevention and treatment. AB - An immune reconstitution disorder occurs in up to 40 % of severely immunodeficient HIV patients who commence antiretroviral therapy (ART), with an immune reconstitution inflammatory syndrome (IRIS) being encountered most commonly. Differences in the immunopathogenesis of an IRIS associated with different types of pathogen have become apparent but common features have also been defined. These include severe immunodeficiency prior to commencing ART associated with a high pathogen load and 'compensatory' immune responses, particularly innate immune responses, which inadequately control the pathogen and increase the risk of immunopathology as the immune system recovers on ART. Prevention of an IRIS may be achieved by optimising therapy for opportunistic infections before ART is commenced, delaying ART or using immunomodulatory therapy to prevent or suppress the immune response that causes the immunopathology. However, further clinical studies are required to examine these options in a systematic manner for the various types of IRIS. PMID- 24950734 TI - Genome-wide identification and expression profiling of DNA methyltransferase gene family in maize. AB - KEY MESSAGE: In this study, we identified eight DNA MTase genes in maize and the diversity of expression patterns of them was presented by EST mining, microarray and semi-quantitative expression profile analyses. DNA methylation plays a pivotal role in promoting genomic stability through diverse biological processes including regulation of gene expression during development and chromatin organization. Although this important biological process is mainly regulated by several conserved Cytosine-5 DNA methyltransferases encoded by a smaller multigene family in plants, investigation of the plant C5-MTase-encoding gene family will serve to elucidate the epigenetic mechanism diversity in plants. Recently, genome-wide identification and evolutionary analyses of the C5-MTase encoding gene family have been characterized in multiple plant species including Arabidopsis, rice, carrot and wheat. However, little is known regarding the C5 MTase-encoding genes in the entire maize genome. Here, genome-wide identification and expression profile analyses of maize C5-MTase-encoding genes (ZmMETs) were performed from the latest version of the maize (B73) genome. Phylogenetic analysis indicated that the orthologs from the three species (maize, Arabidopsis and rice) were categorized into four classes. Chromosomal location of these genes revealed that they are unevenly distributed on 6 of all 10 chromosomes with three chromosomal/segmental duplication events, suggesting that gene duplication played a key role in expansion of the maize C5-MTase-encoding gene family. Furthermore, EST expression data mining, microarray data and semi-quantitative expression profile analyses detected in the leaves by two different abiotic stress treatments have demonstrated that these genes had temporal and spatial expression pattern and exhibited different expression levels in stress treatments, suggesting that functional diversification of ZmMET genes family. Overall, our study will serve to present signification insights to explore the plant C5-MTase encoding gene expression and function and also be beneficial for future experimental research to further unravel the mechanisms of epigenetic regulation in plants. PMID- 24950736 TI - A-site size effect in a family of unfilled ferroelectric tetragonal tungsten bronzes: Ba4R(0.67)Nb10O30 (R = La, Nd, Sm, Gd, Dy and Y). AB - The effect of A-cation size on the structural and electrical properties in a family of ferroelectric tetragonal tungsten bronzes (TTBs) Ba4R(0.67)?(1.33)Nb10O30 (R = La, Nd, Sm, Gd, Dy and Y; ? = vacancy) was investigated. In each case, the crystal structure, as determined from lab-based ambient powder X-ray diffraction (PXRD), is metrically tetragonal and can be refined in the P4bm space group. XRD data show an increased splitting of hk0 00l reflections with decreasing R cation size indicating an increasing tetragonal distortion (measured by tetragonality c/a). Dielectric data and ferroelectric measurements indicate that the ferroelectric Curie temperature, T(C), increases with decreasing R size and so a direct correlation between T(C) and tetragonality/ionic radius of R is demonstrated. Rietveld refinements show that the large A2-site is fully occupied by Ba(2+) and, in addition to the R cation size, the presence of vacancies at the A1-site (perovskite-like site) is also shown to strongly affect the stability of ferroelectricity in this structure type. PMID- 24950733 TI - Side population cells of pancreatic cancer show characteristics of cancer stem cells responsible for resistance and metastasis. AB - Cancer stem cells (CSCs) have been proposed to underlie the initiation and maintenance of tumor growth and the development of chemoresistance in solid tumors. The identification and role of these important cells in pancreatic cancer remains controversial. Here, we isolate side population (SP) cells from the highly aggressive and metastatic human pancreatic cancer cell line L3.6pl and evaluate their potential role as models for CSCs. SP cells were isolated following Hoechst 33342 staining of L3.6pl cells. SP, non-SP, and unsorted L3.6pl cells were orthotopically xenografted into the pancreas of nude mice and tumor growth observed. RNA was analyzed by whole genome array and pathway mapping was performed. Drug resistant variants of L3.6pl were developed and examined for SP proportions and evaluated for surface expression of known CSC markers. A distinct SP with the ability to self-renew and differentiate into non-SP cells was isolated from L3.6pl (0.9 % +/- 0.22). SP cells showed highly tumorigenic and metastatic characteristics after orthotopic injection. Transcriptomic analysis identified modulation of gene networks linked to tumorigenesis, differentiation, and metastasization in SP cells relative to non-SP cells. Wnt, NOTCH, and EGFR signaling pathways associated with tumor stem cells were altered in SP cells. When cultured with increasing concentrations of gemcitabine, the proportion of SP cells, ABCG2(+), and CD24(+) cells were significantly enriched, whereas 5 fluorouracil (5-FU) treatment lowered the percentage of SP cells. SP cells were distinct from cells positive for previously postulated pancreatic CSC markers. The Hoechst-induced side population in L3.6pl cells comprises a subset of tumor cells displaying aggressive growth and metastasization, increased gemcitabine-, but not 5-FU resistance. The cells may act as a partial model for CSC biology. PMID- 24950737 TI - Cochlear implant extrusion secondary to keloid formation. AB - OBJECTIVE AND IMPORTANCE: The goal of this paper is to describe a previously unreported etiology for cochlear implant extrusion. A short literature review is included. This paper represents the first reported case of cochlear implant extrusion secondary to keloid formation. CLINICAL PRESENTATION: We present the case of a 40-year-old male who underwent cochlear implant insertion approximately 5 years prior who later developed a 5 cm post-auricular soft tissue swelling and partial extrusion which interfered with implant function. INTERVENTION: He subsequently underwent wound debridement, cochlear implant removal, and rotational skin flap closure. Final pathology revealed keloid scar. CONCLUSION: Cochlear implant extrusion is a rare complication which has been attributed to various causes. This report identifies keloid formation as another possible source. PMID- 24950739 TI - Involving patient in the early stages of health technology assessment (HTA): a study protocol. AB - BACKGROUND: Public and patient involvement in the different stages of the health technology assessment (HTA) process is increasingly encouraged. The selection of topics for assessment, which includes identifying and prioritizing HTA questions, is a constant challenge for HTA agencies because the number of technologies requiring an assessment exceeds the resources available. Public and patient involvement in these early stages of HTA could make assessments more relevant and acceptable to them. Involving them in the development of the assessment plan is also crucial to optimize their influence and impact on HTA research. The project objectives are: 1) setting up interventions to promote patient participation in three stages of the HTA process: identification of HTA topics, prioritization, and development of the assessment plan of the topic prioritized; and 2) assessing the impact of patient participation on the relevance of the topics suggested, the prioritization process, and the assessment plan from the point of view of patients and other groups involved in HTA. METHODS: Patients and their representatives living in the catchment area of the HTA Roundtable of Universite Laval's Integrated University Health Network (covering six health regions of the Province of Quebec, Canada) will be involved in the following HTA activities: 1) identification of potential HTA topics in the field of cancer; 2) revision of vignettes developed to inform the prioritization of topics; 3) participation in deliberation sessions for prioritizing HTA topics; and 4) development of the assessment plan of the topic prioritized. The research team will coordinate the implementation of these activities and will evaluate the process and outcomes of patient involvement through semi-structured interviews with representatives of the different stakeholder groups, structured observations, and document analysis, mainly involving the comparison of votes and topics suggested by various stakeholder groups. DISCUSSION: This project is designed as an integrated approach to knowledge translation and will be conducted through a close collaboration between researchers and knowledge users at all stages of the project. In response to the needs expressed by HTA producers, the knowledge produced will be directly useful in guiding practices regarding patient involvement in the early phases of HTA. PMID- 24950738 TI - Analyses of Catharanthus roseus and Arabidopsis thaliana WRKY transcription factors reveal involvement in jasmonate signaling. AB - BACKGROUND: To combat infection to biotic stress plants elicit the biosynthesis of numerous natural products, many of which are valuable pharmaceutical compounds. Jasmonate is a central regulator of defense response to pathogens and accumulation of specialized metabolites. Catharanthus roseus produces a large number of terpenoid indole alkaloids (TIAs) and is an excellent model for understanding the regulation of this class of valuable compounds. Recent work illustrates a possible role for the Catharanthus WRKY transcription factors (TFs) in regulating TIA biosynthesis. In Arabidopsis and other plants, the WRKY TF family is also shown to play important role in controlling tolerance to biotic and abiotic stresses, as well as secondary metabolism. RESULTS: Here, we describe the WRKY TF families in response to jasmonate in Arabidopsis and Catharanthus. Publically available Arabidopsis microarrays revealed at least 30% (22 of 72) of WRKY TFs respond to jasmonate treatments. Microarray analysis identified at least six jasmonate responsive Arabidopsis WRKY genes (AtWRKY7, AtWRKY20, AtWRKY26, AtWRKY45, AtWRKY48, and AtWRKY72) that have not been previously reported. The Catharanthus WRKY TF family is comprised of at least 48 members. Phylogenetic clustering reveals 11 group I, 32 group II, and 5 group III WRKY TFs. Furthermore, we found that at least 25% (12 of 48) were jasmonate responsive, and 75% (9 of 12) of the jasmonate responsive CrWRKYs are orthologs of AtWRKYs known to be regulated by jasmonate. CONCLUSION: Overall, the CrWRKY family, ascertained from transcriptome sequences, contains approximately 75% of the number of WRKYs found in other sequenced asterid species (pepper, tomato, potato, and bladderwort). Microarray and transcriptomic data indicate that expression of WRKY TFs in Arabidopsis and Catharanthus are under tight spatio-temporal and developmental control, and potentially have a significant role in jasmonate signaling. Profiling of CrWRKY expression in response to jasmonate treatment revealed potential associations with secondary metabolism. This study provides a foundation for further characterization of WRKY TFs in jasmonate responses and regulation of natural product biosynthesis. PMID- 24950740 TI - High efficiency of alphaviral gene transfer in combination with 5-fluorouracil in a mouse mammary tumor model. AB - BACKGROUND: The combination of virotherapy and chemotherapy may enable efficient tumor regression that would be unachievable using either therapy alone. In this study, we investigated the efficiency of transgene delivery and the cytotoxic effects of alphaviral vector in combination with 5-fluorouracil (5-FU) in a mouse mammary tumor model (4 T1). METHODS: Replication-deficient Semliki Forest virus (SFV) vectors carrying genes encoding fluorescent proteins were used to infect 4 T1 cell cultures treated with different doses of 5-FU. The efficiency of infection was monitored via fluorescence microscopy and quantified by fluorometry. The cytotoxicity of the combined treatment with 5-FU and alphaviral vector was measured using an MTT-based cell viability assay. In vivo experiments were performed in a subcutaneous 4 T1 mouse mammary tumor model with different 5 FU doses and an SFV vector encoding firefly luciferase. RESULTS: Infection of 4 T1 cells with SFV prior to 5-FU treatment did not produce a synergistic anti proliferative effect. An alternative treatment strategy, in which 5-FU was used prior to virus infection, strongly inhibited SFV expression. Nevertheless, in vivo experiments showed a significant enhancement in SFV-driven transgene (luciferase) expression upon intratumoral and intraperitoneal vector administration in 4 T1 tumor-bearing mice pretreated with 5-FU: here, we observed a positive correlation between 5-FU dose and the level of luciferase expression. CONCLUSIONS: Although 5-FU inhibited SFV-mediated transgene expression in 4 T1 cells in vitro, application of the drug in a mouse model revealed a significant enhancement of intratumoral transgene synthesis compared with 5-FU untreated mice. These results may have implications for efficient transgene delivery and the development of potent cancer treatment strategies using alphaviral vectors and 5-FU. PMID- 24950742 TI - Significant cross reactive antibodies to influenza virus in adults and children during a period of marked antigenic drift. AB - BACKGROUND: Little is known about the development of cross-reactive antibodies following natural exposure to pathogens. Such knowledge is critical in the development of new universal influenza vaccines. METHODS: To study the possibility of the presence of cross-reactive antibodies to influenza viruses which underwent a major antigenic drift between the years 1999 and 2007 sera from samples of 80 children and 400 adults were selected at random from the Israeli national serum bank. The sera was obtained in 2002 and in 2007, two time points that followed a major drift in the infectious H3N2 influenza virus strain (A/Panama/2007/99 to A/Wisconsin/67/2005). RESULTS: In the summer of 2002, 13% of the children had Hemagglutination Inhibition (HI) antibody titers of at least 40 and these antibodies recognized both A/Panama/2007/99 and A/Wisconsin/67/2005, where the latter strain only began to circulate in Israel in 2006. In 2007, 29% of the children had HI antibody titers of at least 40 directed against both A/Wisconsin/67/2005 and A/Panama/2007/99, even though they had never been exposed to the latter virus. Anti-A/Panama/2007/99 antibodies were detected in 58% and 68% of the 2002 and 2007 adult samples, respectively, while 8% and 39% had antibodies against A/Wisconsin/67/2005, respectively. CONCLUSIONS: The presence of naturally occurring cross-reactive influenza virus antibodies in a significant percentage of children has important implications for the development of a universal influenza vaccine. PMID- 24950741 TI - Bortezomib treatment causes long-term testicular dysfunction in young male mice. AB - BACKGROUND: With increased long-term survivors of childhood cancer patients, therapy-associated infertility has become one of the most common late side effects and significantly affects their life-quality. Therefore, evaluation of anti-cancer agents on male reproduction and infertility prevention are urgently demanding. The proteasome inhibitor bortezomib has been launched in clinical trials for childhood cancers, however, its potential side effects on reproduction have so far been neither investigated experimentally nor reported in treated children. Thus the present study is designed to explore the impact of bortezomib on male reproductive function and to gain insights into how bortezomib exerts its adverse effects on man gonad, thereby providing pediatric oncologists relevant information. METHODS: 35 day-old male mice were treated with one 11-day cycle of bortezomib and then sacrificed 2 days, 45 days, or 6 months later. A mating study was performed in the group followed for 6 months, and their pups were analyzed on postnatal day 50. Serum follicle-stimulating hormone (FSH) and testicular testosterone levels were measured. Testicular morphology was evaluated by light- and electron microscopy, and the underlying mechanisms and pathways of testis damage were investigated. RESULTS: Testicular damage was visible already 2 days after stopping bortezomib and increased in severity by day 45. Then 80% of seminiferous tubules exhibited hypospermatogenesis with arrest at the levels of spermatogonia, spermatocytes and round spermatids. Germ cells were specifically targeted by bortezomib as evidenced by increased apoptosis mediated through activation of p53 and caspases. Even six months after the bortezomib treatment, testis weight, sperm concentration and seminiferous tubule length remained at a decreased level, indicating that spermatogenesis and tubular outgrowth could not fully recover. Combined with persistently increased serum levels of FSH in these mice, our results demonstrate that bortezomib can have long-term effects on testicular function, although fertility of bortezomib-exposed males remained and their offspring looked healthy. CONCLUSION: Bortezomib treatment causes long-term gonadal dysfunction in male mice. Careful monitoring of gonadal function in male childhood cancer patients treated with bortezomib is thus strongly recommended. PMID- 24950743 TI - ADAMTS13 and its variants promote angiogenesis via upregulation of VEGF and VEGFR2. AB - Severe plasma ADAMTS13 deficiency results in the clinical disorder thrombotic thrombocytopenic purpura. However, other potential pathophysiological roles of ADAMTS13 in endothelial cell biology remain unexplored. The goals of this study were to understand the angiogenic pathways ADAMTS13 activates and to identify the important structural components of ADAMTS13 that stimulate angiogenesis. Incubation of human umbilical vein endothelial cells (HUVEC) with 150 ng/mL (1 nM) of recombinant human ADAMTS13 induced VEGF expression by 53 % and increased VEGF mRNA by over sixfold, both within 10 min; the measured VEGF levels steadily decreased over 2 h, as shown by Western blot and ELISA. Phosphorylation of VEGFR2 was significantly enhanced in HUVEC after incubation with ADAMTS13 (1 nM). Structure-function analysis showed that an ADAMTS13 variant containing thrombospondin type 1 (TSP1) 2-8 repeats (TSP1 2-8), TSP1 2-8 plus CUB domains (TSP1 2-8 plus CUB), or TSP1 5-8 repeats plus CUB domains (TSP1 5-8 plus CUB) increased HUVEC proliferation by 41-54 % as compared to the EBM-2 controls. Chemotaxis assays further demonstrated that the TSP1 domains of ADAMTS13 increased HUVEC migration by 2.65-fold. Incubation of HUVEC with both ADAMTS13 variants containing TSP1 repeats and anti-VEGF IgG abrogated the enhanced effect of ADAMTS13 on proliferation, migration, and VEGFR2 phosphorylation. In conclusion, ADAMTS13-induced endothelial cell angiogenesis occurs via the upregulation of VEGF and phosphorylation of VEGFR2. This angiogenic activity depends on the C-terminal TSP1 repeats of ADAMTS13. PMID- 24950744 TI - Apoptotic effect of pheophorbide a-mediated photodynamic therapy on DMBA/TPA induced mouse papillomas. AB - Pheophorbide a (Pa) is a chlorine-based photosensitizer, and Pa-mediated photodynamic therapy (PDT) reportedly exhibits antitumor activity against various malignancies. The aim of our study was to investigate the therapeutic effect of Pa-mediated PDT on 7,12-dimethylbenz[a]anthracene (DMBA)/12-O tetradecanoylphorobol-13-acetate (TPA)-induced mouse papillomas. Thirty mice received a topical application of DMBA/TPA on their backs to induce mouse papillomas. One week after two sessions of Pa-mediated PDT, immunohistochemical stains and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were performed to evaluate the apoptotic effects thereof on the papillomas. Among 63 mouse papillomas treated with Pa-mediated PDT, 17.5% of the lesions were completely removed 1 week after the first treatment, while 31.7% disappeared 1 week after the second treatment. Statistical analyses revealed significant differences in therapeutic outcomes for the Pa-mediated PDT group in comparison to a solvent-PDT group and a Pa group. Additionally, a marked downregulation of proliferating cell nuclear antigen expression, as well as upregulation of cleaved caspase 3 and cleaved poly(ADP-ribose) polymerase expression, was noted in the Pa PDT group, compared to the solvent-PDT group and Pa group. TUNEL assay revealed higher apoptotic cell counts in the Pa-PDT group, although the difference was not statistically significant. Our data demonstrated that Pa-mediated PDT is effective in treating DMBA/TPA-induced mouse papillomas. PMID- 24950745 TI - Comparison of the hemodynamic effects of nitroprusside and remifentanil for controlled hypotension during endoscopic sinus surgery. AB - PURPOSE: Controlled hypotension (CH) is a well-established technique to decrease blood loss and improve surgical visibility. Although nitroprusside and remifentanil have been safely and effectively used for this purpose, the hemodynamic changes that occur during CH are unclear. This study compared the effects of nitroprusside and remifentanil on hemodynamics using a noninvasive cardiac output monitor (Cheetah NICOM((r)); Cheetah Medical Inc., Maidenhead, Berkshire, UK) for endoscopic sinus surgery (ESS). METHODS: Twenty-eight adult patients scheduled for ESS were randomly assigned to the nitroprusside group (n = 14) or remifentanil group (n = 14). After anesthesia induction, hypotension was induced with continuous infusion of nitroprusside or remifentanil at a target mean arterial blood pressure (MAP) of 60-70 mmHg. Cardiac index (CI), stroke volume index (SVI) and total peripheral resistance index (TPRI) were measured at 10-min intervals. RESULTS: The heart rate was higher and SVI was lower in the nitroprusside group than in the remifentanil group during CH. There were no significant differences in MAP, CI or TPRI between the two groups. Both nitroprusside and remifentanil reduced MAP and TPRI during CH compared with baseline values. However, there was no significant change in CI. CONCLUSIONS: Both nitroprusside and remifentanil were effective to induce CH and maintain CI during CH. PMID- 24950746 TI - Development and testing of an endoscopic pseudo-viewpoint alternating system. AB - PURPOSE: An endoscopic system is needed that presents informative images irrespective of the surgical situation and the number of degrees of freedom in endoscopic manipulation. This goal may be achieved with a virtual reality view for a region of interest from an arbitrary viewpoint. An endoscopic pseudo viewpoint alternation system for this purpose was developed and tested. METHOD: Surgical experts and trainees from an endoscopic surgery training course at the minimally invasive surgery training center of Kyushu University were enrolled in a trial of a virtual reality system. The initial viewpoint was positioned to approximate the horizontal view often seen in laparoscopic surgery, with [Formula: see text] between the optical axis of the endoscope and the task surface. A right-to-left suturing task with right hand, based on a task from the endoscopic surgery training course, was selected for testing. We compared task outcomes with and without use of a new virtual reality-viewing system. RESULT: There was a 0.37 mm reduction in total error ([Formula: see text]) with use of the proposed system. Error reduction was composed of 0.1 mm reduction on the y axis and 0.27 mm reduction on the x-axis. Experts benefited more than novices from use of the proposed system. Most subjects worked at a pseudo-viewpoint of around 34[Formula: see text]. DISCUSSION: Suturing performance improved with the new virtual reality endoscopic display system. Viewpoint alternation resulted in an overview that improved depth perception and allowed subjects to better aim the marker. This suggests the proposed method offers users better visualization and control in endoscopic surgery. PMID- 24950750 TI - Interest of sentinel node biopsy in apparently intrathyroidal medullary thyroid cancer: a pilot study. AB - PURPOSE: Initial surgery for medullary thyroid cancer (MTC) with no evidence of lymph node involvement in neck compartments consists of total thyroidectomy and prophylactic central neck dissection. This study evaluated the reliability of a radiotracer technique for the intraoperative detection of sentinel lymph nodes (SLNs) in lateral compartments in patients with early MTC. METHODS: Patients with limited (cT1 N0) MTC entered the study (2009-2012). A 0.1-0.3 ml suspension of macrocolloidal technetium-99-labeled human albumin was injected (under echo guide) in the tumor 5 h before surgery. Preoperative lymphoscintigraphy confirmed the identification of SLNs in the lateral neck. The operation consisted of total thyroidectomy and central neck dissection, and a hand-held gamma-probe (Neoprobe) guide was used to remove the SLNs from the lateral neck. RESULTS: Four patients were recruited. The tracer always indicated a SLN. Pathology reports indicated micrometastases from MTC in SLN in three patients. At a mean follow-up of 30.5 months, all patients were biochemically cured. The technique we describe to detect and remove neck SLN from MTC seemed to be very accurate. It always showed the SLNs (usually two) in the lateral compartments. Micrometastases were detected in three of four patients, allowing their correct staging. CONCLUSIONS: The method described here for the detection of SLNs in early MTC seems effective and reliable and can be used for a more precise N staging of the patients. It could play a role, alone or combined with other techniques, in driving the extent of prophylactic neck dissection or other potential applications. PMID- 24950749 TI - Achieving universal access and moving towards elimination of new HIV infections in Cambodia. AB - INTRODUCTION: In the mid-1990s, Cambodia faced one of the fastest growing HIV epidemics in Asia. For its achievement in reversing this trend, and achieving universal access to HIV treatment, the country received a United Nations millennium development goal award in 2010. This article reviews Cambodia's response to HIV over the past two decades and discusses its current efforts towards elimination of new HIV infections. METHODS: A literature review of published and unpublished documents, including programme data and presentations, was conducted. RESULTS AND DISCUSSION: Cambodia classifies its response to one of the most serious HIV epidemics in Asia into three phases. In Phase I (1991-2000), when adult HIV prevalence peaked at 1.7% and incidence exceeded 20,000 cases, a nationwide HIV prevention programme targeted brothel-based sex work. Voluntary confidential counselling and testing and home-based care were introduced, and peer support groups of people living with HIV emerged. Phase II (2001-2011) observed a steady decline in adult prevalence to 0.8% and incidence to 1600 cases by 2011, and was characterized by: expanding antiretroviral treatment (coverage reaching more than 80%) and continuum of care; linking with tuberculosis and maternal and child health services; accelerated prevention among key populations, including entertainment establishment-based sex workers, men having sex with men, transgender persons, and people who inject drugs; engagement of health workers to deliver quality services; and strengthening health service delivery systems. The third phase (2012-2020) aims to attain zero new infections by 2020 through: sharpening responses to key populations at higher risk; maximizing access to community and facility-based testing and retention in prevention and care; and accelerating the transition from vertical approaches to linked/integrated approaches. CONCLUSIONS: Cambodia has tailored its prevention strategy to its own epidemic, established systematic linkages across different services and communities, and achieved nearly universal coverage of HIV services nationwide. Still, the programme must continually (re)prioritize the most effective and efficient interventions, strengthen synergies between programmes, contribute to health system strengthening, and increase domestic funding so that the gains of the previous two decades are sustained, and the goal of zero new infections is reached. PMID- 24950751 TI - Prone-position acquisition of myocardial (123)I-metaiodobenzylguanidine (MIBG) SPECT reveals regional uptake similar to that found using (11)C-hydroxyephedrine PET/CT. AB - OBJECTIVES: (123)I-metaiodobenzylguanidine (MIBG) has been used to estimate cardiac sympathetic nervous innervation. Heterogeneous MIBG distribution is mainly associated with high physiological MIBG uptakes in the liver. We postulate that prone position acquisition might be especially effective for MIBG, providing for separation from high liver uptake similar to that provided by perfusion single-photon emission computed tomography (SPECT). We investigated whether prone position acquisition improved MIBG image quality by comparing our results to those acquired using supine MIBG and high-quality (11)C-hydroxyephedrine (HED) positron emission tomography/computed tomography PET/CT. METHODS: Ten male volunteers (body mass index (BMI) 22.7 +/- 3.4) underwent prone and supine MIBG and HED PET. Relative regional tracer uptake was estimated in early MIBG and HED. Acquired images were divided into 17 segments and were grouped into 4 regions: anterior, inferior, septum, and lateral. For each patient, the inferior/anterior ratio was calculated. RESULTS: The quality of images acquired using prone MIBG was better than that using supine MIBG (p < 0.05). Inferior and septum relative MIBG uptake was reduced in comparison with anterior or lateral MIBG uptake in the supine position (inferior vs. anterior: 69.0 +/- 5.6 vs. 82.3 +/- 4.6 %, p < 0.01; septum vs. lateral: 66.2 +/- 5.1 vs. 81.9 +/- 5.4 %, p < 0.01). Prone MIBG showed a significantly higher inferior/anterior uptake ratio in comparison with supine MIBG (n = 24, seg: 92.2 +/- 7.2 vs. 83.6 +/- 5.7 %, p < 0.05). However, intergroup differences in uptake ratio were demonstrated among prone and supine MIBG and HED. HED PET/CT still showed a higher uptake ratio in comparison with prone MIBG SPECT (103.9 +/- 8.0 vs. 92.2 +/- 7.2 %, p < 0.05). CONCLUSION: Even in normal male subjects, standard supine MIBG imaging showed reduced inferior and septum uptake. Uptake with prone MIBG imaging showed a significant improvement over that with supine imaging and was closer to uptake for HED PET/CT. This improvement may be the result of preventing intense uptake by the liver. Prone data acquisition may be a viable alternative in evaluating regional abnormalities using MIBG SPECT in men. PMID- 24950747 TI - Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial. AB - BACKGROUND: Pharmacologic treatment options for posttraumatic stress disorder (PTSD) are limited in number and effectiveness. Medications currently in use to treat PTSD were originally approved based on their efficacy in other disorders, such as major depression. Substantial research in PTSD suggests that increased activity of corticotropin releasing hormone (CRH)-containing circuits are involved in the pathophysiology of the disease. This Phase II trial aims to evaluate the efficacy of a CRH type 1 receptor (CRHR1) antagonist in the treatment of PTSD. METHODS/DESIGN: Currently untreated adult women, ages 18 to 65 years, with a primary psychiatric diagnosis of PTSD of at least 3 months' duration, are being enrolled in a parallel-group, double-blind, placebo controlled, randomized clinical trial evaluating the efficacy and safety of GSK561679, a novel CRHR1 receptor antagonist. GSK561679 (or matching placebo) is prescribed at a fixed dose of 350 mg nightly for six weeks. The primary trial hypothesis is that GSK561679 will reduce symptoms of PTSD, as measured by the Clinician-Administered PTSD Scale (CAPS), significantly more than placebo after six weeks of treatment. Putative biological markers of PTSD which may influence treatment response are measured prior to randomization and after five weeks' exposure to the study medication, including: fear conditioning and extinction using psychophysiological measures; variants of stress-related genes and gene expression profiles; and indices of HPA axis reactivity. In addition, the impact of PTSD and treatment on neuropsychological performance and functional capacity are assessed at baseline and after the fifth week of study medication. After completion of the six-week double blind treatment period, subjects enter a one month follow-up period to monitor for sustained response and resolution of any adverse effects. DISCUSSION: Considerable preclinical and human research supports the hypothesis that alterations in central nervous system CRH neuronal activity are a potential mediator of PTSD symptoms. This study is the first to assess the efficacy of a specific antagonist of a CRH receptor in the treatment of PTSD. Furthermore, the biological and neuropsychological measures included in this trial will substantially inform our understanding of the mechanisms of PTSD. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01018992.Registered 6 November 2009. First patient randomized 14 January 2010. PMID- 24950752 TI - Benefit of cardiac N-13 PET CFR for combined anatomical and functional diagnosis of ischemic coronary artery disease: a pilot study. AB - BACKGROUND: Cardiac positron emission tomography (PET) can lead to flow impairment quantification using PET coronary flow reserve (CFRp: ratio of stress flow to rest flow) and is superior to the current standard, single-photon emission computed tomography. In this study, our first aim was to assess the benefit of CFRp in place of invasive CFR (CFRi) by comparing the correlations of each of the indices with combined pressure and flow index CDP, and combined functional (pressure-flow) and anatomical (%area stenosis, %AS) index, LFC. The second aim was to test the correlation between CFRp and CFRi. METHODS: N-13 ammonia PET scans were performed and CFRp was obtained using a 1-compartment 2K dynamic volume (DV)-constant kinetic model in Flowquant. During catheterization, simultaneous pressure and flow readings were obtained in 10 vessels (three vessels in one patient, one vessel each in 7 patients) using a dual sensor tipped Combowire, and CFRi, CDP, LFC, and FFR were computed. %AS was obtained using quantitative coronary angiography. CDP was correlated with invasive pressure index (FFR) and CFRp and with FFR and CFRi. LFC was correlated with the %AS, FFR, and CFRp/CFRi, individually and in combination. Correlation analysis was done in SAS; p < 0.05 was used for statistical significance. RESULTS: The correlations between CDP vs FFR and CFRp (r = 0.62, p = 0.19) in combination, as well as CDP vs FFR and CFRi in combination (r = 0.58, p = 0.24) remained similar. The correlation between LFC vs FFR, CFRp and %AS in combination improved (r = 0.82) with a near-significant p = 0.06, in comparison to the correlation between LFC vs FFR, CFRi and %AS in combination (r = 0.75, p = 0.15). CFRp correlated strongly and significantly (r = 0.82, p = 0.003) with CFRi, and the values were within 11 %. CONCLUSION: The novelty of the PET procedure in this study is that the noninvasive CFRp can be used instead of invasive CFRi for the functional diagnosis of CAD. Therefore, a PET scan can reduce procedure time and cost while simplifying the diagnostic protocol for assessing coronary artery disease, thus benefitting both the patients and clinicians. PMID- 24950753 TI - Accuracy of amplitude-based respiratory gating for PET/CT in irregular respirations. AB - OBJECTIVE: We evaluated the accuracy of amplitude gating PET (AG-PET) compared with phase gating PET (PG-PET) in relation to respiratory motion patterns based on a phantom analysis. METHOD: We used a NEMA IEC body phantom filled with an (18)F solution with a 4:1 sphere-to-background radioactivity ratio (12.6 and 2.97 kBq/mL). PET/CT scans were acquired in a motionless and moving state on a Biograph mCT. The respiratory movements were simulated by four different waveform patterns consisting of ideal breathing, breathing with a pause period, breathing with a variable amplitude and breathing with a changing baseline. AG-PET selects the narrow bandwidth containing 20 % of the respiratory cycle. PG-PET was reconstructed with five gates. The image quality was physically assessed using the percent contrast (Q H,10mm), background variability (N 10mm) recovery coefficient (RC), and sphere volumes. RESULT: In regular motion patterns with ideal breathing and breathing with a pause period, the Q H,10mm, RC and sphere volumes were not different between AG-PET and PG-PET. In the variable amplitude pattern, the Q H,10mm of AG-PET was higher than that of PG-PET (35.8 vs 28.2 %), the RC of AG-PET was higher than that of PG-PET and sphere volume of AG-PET was smaller than that of PG-PET (6.4 vs 8.6 mL). In the changing baseline pattern, the Q H,10mm of AG-PET was higher than that of PG-PET (42.4 vs 16.7 %), the RC of AG-PET was higher than that of PG-PET and sphere volume of AG-PET was smaller than that of PG-PET (6.2 vs 9.8 mL). The N 10mm did not differ between AG-PET and PG-PET, irrespective of the motion pattern. CONCLUSION: Amplitude gating PET is considered to be more accurate than phase gating PET for examining unstable respiratory motion patterns, such as those involving a variable amplitude or changing baseline. PMID- 24950754 TI - Investigating bacterial populations in styrene-degrading biofilters by 16S rDNA tag pyrosequencing. AB - Microbial biofilms are essential components in the elimination of pollutants within biofilters, yet still little is known regarding the complex relationships between microbial community structure and biodegradation function within these engineered ecosystems. To further explore this relationship, 16S rDNA tag pyrosequencing was applied to samples taken at four time points from a styrene degrading biofilter undergoing variable operating conditions. Changes in microbial structure were observed between different stages of biofilter operation, and the level of styrene concentration was revealed to be a critical factor affecting these changes. Bacterial genera Azoarcus and Pseudomonas were among the dominant classified genera in the biofilter. Canonical correspondence analysis (CCA) and correlation analysis revealed that the genera Brevundimonas, Hydrogenophaga, and Achromobacter may play important roles in styrene degradation under increasing styrene concentrations. No significant correlations (P > 0.05) could be detected between biofilter operational/functional parameters and biodiversity measurements, although biological heterogeneity within biofilms and/or technical variability within pyrosequencing may have considerably affected these results. Percentages of selected bacterial taxonomic groups detected by fluorescence in situ hybridization (FISH) were compared to results from pyrosequencing in order to assess the effectiveness and limitations of each method for identifying each microbial taxon. Comparison of results revealed discrepancies between the two methods in the detected percentages of numerous taxonomic groups. Biases and technical limitations of both FISH and pyrosequencing, such as the binding of FISH probes to non-target microbial groups and lack of classification of sequences for defined taxonomic groups from pyrosequencing, may partially explain some differences between the two methods. PMID- 24950757 TI - Facile synthesis of biocompatible cysteine-coated CuS nanoparticles with high photothermal conversion efficiency for cancer therapy. AB - The semiconductor compounds have been proven to be promising candidates as a new type of photothermal therapy agent, but unsatisfactory photothermal conversion efficiencies limit their widespread application in photothermal therapy (PTT). Herein, we synthesized cysteine-coated CuS nanoparticles (Cys-CuS NPs) as highly efficient PTT agents by a simple aqueous solution method. The Cys-CuS NPs have a good biocompatibility owing to their biocompatible cysteine coating and exhibit a strong absorption in the near-infrared region due to the localized surface plasma resonances of valence-band free carriers. The photothermal conversion efficiency of Cys-CuS NPs reaches 38.0%, which is much higher than that of the recently reported Cu9S5 and Cu(2-x)Se nanocrystals. More importantly, tumor growth can be efficiently inhibited in vivo by the fatal heat arising from the excellent photothermal effect of Cys-CuS NPs at a low concentration under the irradiation of a 980 nm laser with a safe power density of 0.72 W cm(-2). Therefore, the Cys CuS NPs have great potential as ideal photothermal agents for cancer therapy. PMID- 24950755 TI - An Aspergillus nidulans beta-mannanase with high transglycosylation capacity revealed through comparative studies within glycosidase family 5. AB - beta-Mannanases are involved in the conversion and modification of mannan-based saccharides. Using a retaining mechanism, they can, in addition to hydrolysis, also potentially perform transglycosylation reactions, synthesizing new glyco conjugates. Transglycosylation has been reported for beta-mannanases in GH5 and GH113. However, although they share the same fold and catalytic mechanism, there may be differences in the enzymes' ability to perform transglycosylation. Three GH5 beta-mannanases from Aspergillus nidulans, AnMan5A, AnMan5B and AnMan5C, which belong to subfamily GH5_7 were studied. Comparative studies, including the GH5_7 TrMan5A from Trichoderma reesei, showed some differences between the enzymes. All the enzymes could perform transglycosylation but AnMan5B stood out in generating comparably higher amounts of transglycosylation products when incubated with manno-oligosaccharides. In addition, AnMan5B did not use alcohols as acceptor, which was also different compared to the other three beta mannanases. In order to map the preferred binding of manno-oligosaccharides, incubations were performed in H2 (18)O. AnMan5B in contrary to the other enzymes did not generate any (18)O-labelled products. This further supported the idea that AnMan5B potentially prefers to use saccharides as acceptor instead of water. A homology model of AnMan5B showed a non-conserved Trp located in subsite +2, not present in the other studied enzymes. Strong aglycone binding seems to be important for transglycosylation with saccharides. Depending on the application, it is important to select the right enzyme. PMID- 24950758 TI - En bloc transurethral resection with 2-micron continuous-wave laser for primary non-muscle-invasive bladder cancer: a randomized controlled trial. AB - PURPOSE: To evaluate the practicability of en bloc transurethral resection with 2 micron continuous-wave laser as treatment for primary non-muscle-invasive bladder cancer (NMIBC). METHODS: This was a single-center, randomized, controlled trial involving 142 patients with newly diagnosed NMIBC. All patients were randomly assigned in a 1:1 ratio to receive either laser treatment or conventional transurethral resection of bladder tumor (TURBT). All patients received intravesical chemotherapy. Follow-up was performed in 18 months. Primary outcome measure was difference of tumor recurrence rate at the end of study. RESULTS: Baseline characteristics did not differ between patients in two groups. Operation time was longer in laser group than in TURBT group (56.5 +/- 37.4 vs. 41.0 +/- 29.4 min, P = 0.017). Obturator nerve reflection was noted during TURBT in 18 patients, whereas none was noted during laser resection. Number of T1 tumors was higher in the laser group (25 vs. 15, P = 0.047). According to Kaplan-Meier survival curves, there was no statistical difference in the rate of recurrence in 18 months (P = 0.383). All recurrences were out of the site of first resection, and there was no progression in tumor grade. CONCLUSION: Two-micron continuous wave laser did not diminish tumor recurrence rate in primary NMIBC for 18-months observation. However, T1 tumors were significantly higher among laser group. Clear and complete tumor bases were easily conserved by laser resection, which may enable pathologists to distinguish the T stages of bladder cancer more easily. Further studies need to be done in future. PMID- 24950760 TI - Swelling around the implant body: A late complication of cochlear implantation. How to deal? AB - OBJECTIVE: In this retrospective review, we aimed to determine the most appropriate management of the complication of late swelling around the implant body following cochlear implantation. METHODS: The medical records of 516 patients who underwent cochlear implantation between January 2008 and June 2013 were reviewed for a history of swelling around the implant body. RESULTS; Of the 516 patients, 16 (8 males and 8 females) had a history of swelling around the implant body following implantation. The onset of swelling was from 1 to 60 months (median 21.2 months) after implantation. Three of the 16 patients had a history of manifest trauma to the head, and the remaining 13 had experienced an upper respiratory tract infection just before the swelling arose. Discussion In the light of our clinical experiences, we may suggest that late swelling around the implant body seems associated with a manifest or hidden head trauma or upper respiratory tract infections. CONCLUSION: After the initial assessment of swelling, surgeons should be aware of the possibility of abscess formation. As a general rule, any kind of pus collection should be drained surgically. However, in the case of pus collection without abscess formation, conservative measurements can often achieve satisfactory results. PMID- 24950759 TI - Growth effects of exclusive breastfeeding promotion by peer counsellors in sub Saharan Africa: the cluster-randomised PROMISE EBF trial. AB - BACKGROUND: In this multi-country cluster-randomized behavioural intervention trial promoting exclusive breastfeeding (EBF) in Africa, we compared growth of infants up to 6 months of age living in communities where peer counsellors promoted EBF with growth in those infants living in control communities. METHODS: A total of 82 clusters in Burkina Faso, Uganda and South Africa were randomised to either the intervention or the control arm. Feeding data and anthropometric measurements were collected at visits scheduled 3, 6, 12 and 24 weeks post partum. We calculated weight-for-length (WLZ), length-for-age (LAZ) and weight for-age (WAZ) z-scores. Country specific adjusted Least Squares Means with 95% confidence intervals (CI) based on a longitudinal analysis are reported. Prevalence ratios (PR) for the association between peer counselling for EBF and wasting (WLZ < -2), stunting (LAZ < -2) and underweight (WAZ < -2) were calculated at each data collection point. RESULTS: The study included a total of 2,579 children. Adjusting for socio-economic status, the mean WLZ at 24 weeks were in Burkina Faso -0.20 (95% CI -0.39 to -0.01) and in Uganda -0.23 (95% CI 0.43 to -0.03) lower in the intervention than in the control arm. In South Africa the mean WLZ at 24 weeks was 0.23 (95% CI 0.03 to 0.43) greater in the intervention than in the control arm. Differences in LAZ between the study arms were small and not statistically significant. In Uganda, infants in the intervention arm were more likely to be wasted compared to those in the control arm at 24 weeks (PR 2.36; 95% CI 1.11 to 5.00). Differences in wasting in South Africa and Burkina Faso and stunting and underweight in all three countries were small and not significantly different. CONCLUSIONS: There were small differences in mean anthropometric indicators between the intervention and control arms in the study, but in Uganda and Burkina Faso, a tendency to slightly lower ponderal growth (weight-for-length z-scores) was found in the intervention arms. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00397150. PMID- 24950762 TI - KIF2A silencing inhibits the proliferation and migration of breast cancer cells and correlates with unfavorable prognosis in breast cancer. AB - BACKGROUND: Kinesin family member 2a (KIF2A), a type of motor protein found in eukaryotic cells, is associated with development and progression of various human cancers. The role of KIF2A during breast cancer tumorigenesis and progression was studied. METHODS: Immunohistochemical staining, real time RT-PCR and western blot were used to examine the expression of KIF2A in cancer tissues and adjacent normal tissues from breast cancer patients. Patients' survival in relation to KIF2A expression was estimated using the Kaplan-Meier survival and multivariate analysis. Breast cancer cell line, MDA-MB-231 was used to study the proliferation, migration and invasion of cells following KIF2A-siRNA transfection. RESULTS: The expression of KIF2A in cancer tissues was higher than that in normal adjacent tissues from the same patient (P < 0.05). KIF2A expression in cancer tissue with lymph node metastasis and HER2 positive cancer were higher than that in cancer tissue without (P < 0.05). A negative correlation was found between KIF2A expression levels in breast cancer and the survival time of breast cancer patients (P < 0.05). In addition, multivariate analysis indicated that KIF2A was an independent prognostic for outcome in breast cancer (OR: 16.55, 95% CI: 2.216-123.631, P = 0.006). The proliferation, migration and invasion of cancer cells in vitro were suppressed by KIF2A gene silencing (P < 0.05). CONCLUSIONS: KIF2A may play an important role in breast cancer progression and is potentially a novel predictive and prognostic marker for breast cancer. PMID- 24950763 TI - David and Goliath: a clash of flows in apical hypertrophic cardiomyopathy. PMID- 24950761 TI - Role of the fast kinetics of pyroglutamate-modified amyloid-beta oligomers in membrane binding and membrane permeability. AB - Membrane permeability to ions and small molecules is believed to be a critical step in the pathology of Alzheimer's disease (AD). Interactions of oligomers formed by amyloid-beta (Abeta) peptides with the plasma cell membrane are believed to play a fundamental role in the processes leading to membrane permeability. Among the family of Abetas, pyroglutamate (pE)-modified Abeta peptides constitute the most abundant oligomeric species in the brains of AD patients. Although membrane permeability mechanisms have been studied for full length Abeta1-40/42 peptides, these have not been sufficiently characterized for the more abundant AbetapE3-42 fragment. Here we have compared the adsorbed and membrane-inserted oligomeric species of AbetapE3-42 and Abeta1-42 peptides. We find lower concentrations and larger dimensions for both species of membrane associated AbetapE3-42 oligomers. The larger dimensions are attributed to the faster self-assembly kinetics of AbetapE3-42, and the lower concentrations are attributed to weaker interactions with zwitterionic lipid headgroups. While adsorbed oligomers produced little or no significant membrane structural damage, increased membrane permeabilization to ionic species is understood in terms of enlarged membrane-inserted oligomers. Membrane-inserted AbetapE3-42 oligomers were also found to modify the mechanical properties of the membrane. Taken together, our results suggest that membrane-inserted oligomers are the primary species responsible for membrane permeability. PMID- 24950765 TI - Toll-like receptor 4 knockout protects against isoproterenol-induced cardiac fibrosis: the role of autophagy. AB - BACKGROUND: Toll-like receptor 4 participates in the process of acute heart injury. The underlying mechanisms of its protection are multifactorial, but we hypothesized that toll-like receptor-mediated autophagy control plays a vital role. The purpose of this study was to clarify the effect of autophagy on cardiac fibrosis. METHODS: Cardiac fibrosis was induced by subcutaneous isoproterenol (ISO) injection, and rapamycin was simultaneously administered orally for 14 days. Animal echocardiography was then used to evaluate the success of the cardiac fibrosis model, and the mice were killed after the echocardiography examination. RESULTS: Toll-like receptor 4 knockout (TLR4 KO) mice had better heart function than did wild-type (WT) mice (P < .05). Rapamycin treatment reduced the left ventricular ejection fraction to 23.5% (P < .05), and the collagen volume fraction of the ISO and ISO plus rapamycin groups was 5.9% and 25.9%, respectively, in TLR4 KO mice. Compared with the WT mice, Beclin 1 and autophagy were downregulated in TLR4 KO mice (P < .05); however, the ISO plus rapamycin group had higher autophagy activity than did the ISO group in TLR4 KO mice (P < .05). CONCLUSIONS: Our results suggest that TLR4 KO-induced cardioprotection against ISO-induced cardiac fibrosis is associated with reduced autophagy induction. Cardiac fibroblast autophagy participates in its own activation. The moderate inhibition of autophagic activity may be a new strategy for treating cardiac fibrosis. PMID- 24950766 TI - Cut winter fuel payments for wealthy to provide more care for poor elderly, says think tank. PMID- 24950764 TI - Atorvastatin helps preserve pancreatic beta cell function in obese C57BL/6 J mice and the effect is related to increased pancreas proliferation and amelioration of endoplasmic-reticulum stress. AB - BACKGROUND: 3-Hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitors or statins are competitive inhibitors of the rate-limiting enzyme in cholesterol biosynthesis. Currently, statins are used as first-line therapy in the treatment of diabetic dyslipidemia. However, effects of statins on beta cell function remains unclear. This study aims to examine effects of atorvastatin treatment on pancreatic beta cell function in obese C57BL/6 J mice and the possible mechanisms. METHODS: Diet-induced obesity (DIO) C57BL/6 J mice were treated with atorvastatin (30 mg/kg/day) for 58 days. beta cell function was assessed by hyperglycemic clamp and the area of insulin-positive beta cells was examined by immunofluorescence. Gene expression was assessed by RT-PCR, and endoplasmic reticulum (ER) stress related proteins were examined by Western blot. Additionally, cell viability and apoptosis of the cholesterol-loaded NIT-1 cells were investigated after atorvastatin treatment. RESULTS: Hyperglycemic clamp study revealed that glucose infusion rate (GIR) and insulin stimulation ratio in atorvastatin-treated DIO mice were markedly higher than control mice (P < 0.05, P < 0.01 vs. con), indicating preserved beta-cell sensitivity to glucose. Lipid profiles of plasma triglyceride (TG), pancreas TG and plasma cholesterol (CHO) were improved. Pancreas weight and weight index were improved significantly after atorvastatin treatment (P < 0.05 vs. con). Immunofluorescence results showed that atorvastatin-treated mice had significantly larger insulin-positive beta cell area (P < 0.05 vs. con). Furthermore, RT-PCR and western blot showed that the mRNA and protein expression of pancreatic and duodenal homeobox 1 (Pdx1) in the pancreas were upregulated (P < 0.001, P < 0.01 vs. con). Moreover, the expression level of ER stress markers of activating transcription factor 4 (ATF4), CCAAT enhancer-binding protein homologous protein (CHOP) and phosphorylated eukaryotic initiation factor 2alpha (eIF2alpha) were downregulated in the pancreas of atorvastatin-treated mice (P < 0.001, P < 0.01, P < 0.01 vs. con). Besides, atorvastatin protected the pancreatic beta cell line of NIT-1 from cholesterol induced apoptosis. Western blot showed increased expression of anti-apoptotic protein of B-cell lymphoma 2 (Bcl-2). CONCLUSION: Pancreatic beta cell function of obese C57BL/6 J mice was preserved after atorvastatin treatment, and this improvement may be attributed to enhanced pancreas proliferation and amelioration of pancreatic ER stress. PMID- 24950767 TI - Controlled and uncontrolled asthma display distinct alveolar tissue matrix compositions. AB - OBJECTIVE: Whether distal inflammation in asthmatics also leads to structural changes in the alveolar parenchyma remains poorly examined, especially in patients with uncontrolled asthma. We hypothesized that patients who do not respond to conventional inhaled corticosteroid therapy have a distinct tissue composition, not only in central, but also in distal lung. METHODS: Bronchial and transbronchial biopsies from healthy controls, patients with controlled atopic and patients with uncontrolled atopic asthma were processed for immunohistochemical analysis of fibroblasts and extracellular matrix molecules: collagen, versican, biglycan, decorin, fibronectin, EDA-fibronectin, matrix metalloproteinase (MMP)-9 and tissue-inhibitor of matrix metalloproteinase (TIMP) 3. RESULTS: In central airways we found increased percentage areas of versican and decorin in patients with uncontrolled asthma compared to both healthy controls and patients with controlled asthma. Percentage area of biglycan was significantly higher in both central airways and alveolar parenchyma of patients with uncontrolled compared to controlled asthma. Ratios of MMP-9/TIMP-3 were decreased in both uncontrolled and controlled asthma compared to healthy controls. In the alveolar parenchyma, patients with uncontrolled asthma had increased percentage areas of collagen, versican and decorin compared to patients with controlled asthma. Patients with uncontrolled asthma had significantly higher numbers of myofibroblasts in both central airways and alveolar parenchyma compared to patients with controlled asthma. CONCLUSIONS: Tissue composition differs, in both central and distal airways, between patients with uncontrolled and controlled asthma on equivalent doses of ICS. This altered structure and possible change in tissue elasticity may lead to abnormal mechanical properties, which could be a factor in the persistent symptoms for patients with uncontrolled asthma. PMID- 24950768 TI - Intradiaphragmatic extralobar pulmonary sequestration in adult. AB - Extralobar pulmonary sequestrations may be located in intrathoracic or extrathoracic areas. Extrathoracic intradiaphragmatic extralobar pulmonary sequestrations are an extremely rare subset of bronchopulmonary sequestrations and there have been very few reported cases until now. We describe a 48-year-old Korean woman found to have left peridiaphragmatic lesion on computed tomography. We performed thoracoscopic surgery and successfully resected the tumor. Based on the histological findings, it was diagnosed as an intradiaphragmatic extralobar pulmonary sequestration. Postoperative course was uneventful. Intradiaphragmatic extralobar pulmonary sequestration in adult is extremely rare, so we report the case with a literature review. PMID- 24950769 TI - Five novel mutations in the ADAR1 gene associated with dyschromatosis symmetrica hereditaria. AB - BACKGROUND: Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominantly inherited skin disease associated with mutations of ADAR1, the gene that encodes a double-stranded RNA-specific adenosine deaminase. The purpose of this study was to investigate the potential mutations in ADAR1 in seven Chinese families with DSH. METHODS: All the coding exons including adjacent intronic as well as 5' and 3' untranslated region (UTR) of ADAR1 were screened by direct sequencing. Moreover, quantitative reverse-transcription polymerase chain (qRT PCR) and Western blot were applied to determine the pathogenic effects associated with the mutations. RESULTS: Molecular genetic investigations detected five novel mutations (c.556C > T, c.3001C > T, c.1936_1937insTG, c.1065_1068delGACA and c.1601G > A resulting in p.Gln186X, p.Arg1001Cys, p.Phe646LeufsX16, p.Asp357ArgfsX47 and p.Gly471AspfsX30 protein changes, respectively) as well as two previously reported (c.2744C > T and c.3463C > T causing p.Ser915Phe and p.Arg1155Trp protein changes, respectively). Among them, we found that the substitution c.1601G > A at the last nucleotide of exon 2 compromised the recognition of the splice donor site of intron 2, inducing an aberrant transcript with 190-bp deletion in exon 2 and causing an approximately 50% reduction of ADAR1 mRNA level in affected individual. In addition, consistent with the predicted results, the expression patterns of other novel mutations were detected by Western blot. CONCLUSION: We identified five novel and two recurrent mutations of the ADAR1 gene in seven Chinese families with DSH and investigated potential effects of the novel mutations in this study. Our study expands the database on mutations of ADAR1 and for the first time, demonstrates the importance of exonic nucleotides at exon-intron junctions for ADAR1 splicing. PMID- 24950771 TI - A new joystick technique for unsuccessful closed reduction of supracondylar humeral fractures: minimum trauma. AB - BACKGROUND: The purpose of this study was to compare operation duration, radiological and functional results of the open reduction with either posterior or lateral approach and closed reduction with joystick method in unsuccessful closed reduction of displaced (Gartland type III) supracondylar humeral fractures. METHODS: Between February 2010 and August 2011, 37 patients who were not obtained satisfactory reduction with classic closed reduction attempts for three times in operating room were included in this study. Patients were treated with three different surgical methods. Group I have 13 patients who had joystick and lateral K-wire-assisted closed reduction, group II have 12 patients who had open reduction by lateral approach, and group III have 12 patients who had open reduction by posterior approach. In final follow-up, AP and lateral radiographs of both elbows were taken and bilateral Baumann angles, lateral humerocapitellar angles, carrying angles, and elbow range of motion were measured. These angles and operation times compared between the groups. The functional and cosmetic outcome of surgery was evaluated by criteria of Flynn et al. RESULTS: There was no statistical significance difference between Baumann angles, lateral humerocapitellar angles, and carrying angles of fractured and uninjured sides in between three groups (respectively, p = 0.761, p = 0.354, p = 0.750). In group I, operation duration is shorter than the other groups. Functional scoring showed that in group I and group II, all patients have satisfactory results; however, in group III, three patients (25%) had poor results. In the perspective of cosmetic results, all three groups have satisfactory results. CONCLUSIONS: When classical closed reduction fail, lateral joystick and K-wire-assisted reduction is a useful way to make and maintain the reduction. Functional and radiological results are as good as lateral and posterior open approaches. Short operation time is an advantage. This method reduces the risk of complications due to repeated closed reduction and open reduction in unsuccessful closed reduction in pediatric supracondylar humeral fractures. LEVEL OF EVIDENCE: Level III. PMID- 24950770 TI - Chronic pain patients' treatment preferences: a discrete-choice experiment. AB - OBJECTIVE: The objective of this study was to identify, document, and weight attributes of a pain medication that are relevant from the perspective of patients with chronic pain. Within the sub-population of patients suffering from "chronic neuropathic pain", three groups were analyzed in depth: patients with neuropathic back pain, patients with painful diabetic polyneuropathy, and patients suffering from pain due to post-herpetic neuralgia. The central question was: "On which features do patients base their assessment of pain medications and which features are most useful in the process of evaluating and selecting possible therapies?" METHODS: A detailed literature review, focus groups with patients, and face-to-face interviews with widely recognized experts for pain treatment were conducted to identify relevant treatment attributes of a pain medication. A pre-test was conducted to verify the structure of relevant and dominant attributes using factor analyses by evaluating the most frequently mentioned representatives of each factor. The Discrete-Choice Experiment (DCE) used a survey based on self-reported patient data including socio-demographics and specific parameters concerning pain treatment. Furthermore, the neuropathic pain component was determined in all patients based on their scoring in the painDETECT((r)) questionnaire. For statistical data analysis of the DCE, a random effect logit model was used and coefficients were presented. RESULTS: A total of 1,324 German patients participated in the survey, of whom 44 % suffered from neuropathic back pain (including mixed pain syndrome), 10 % complained about diabetic polyneuropathy, and 4 % reported pain due to post-herpetic neuralgia. A total of 36 single quality aspects of pain treatment, detected in the qualitative survey, were grouped in 7 dimensions by factor analysis. These 7 dimensions were used as attributes for the DCE. The DCE model resulted in the following ranking of relevant attributes for treatment decision: "no character change", "less nausea and vomiting", "pain reduction" (coefficient: >0.9 for all attributes, "high impact"), "rapid effect", "low risk of addiction" (coefficient ~0.5, "middle impact"), "applicability with comorbidity" (coefficient ~0.3), and "improvement of quality of sleep" (coefficient ~0.25). All attributes were highly significant (p < 0.001). CONCLUSIONS: The results were intended to enable early selection of an individualized pain medication. The results of the study showed that DCE is an appropriate means for the identification of patient preferences when being treated with specific pain medications. Due to the fact that pain perception is subjective in nature, the identification of patients' preferences will enable therapists to better develop and implement patient-oriented treatment of chronic pain. It is therefore essential to improve the therapists' understanding of patient preferences in order to make decisions concerning pain treatment. DCE and direct assessment should become valid instruments to elicit treatment preferences in chronic pain. PMID- 24950772 TI - Impact of warming and drought on carbon balance related to wood formation in black spruce. AB - BACKGROUND AND AIMS: Wood formation in trees represents a carbon sink that can be modified in the case of stress. The way carbon metabolism constrains growth during stress periods (high temperature and water deficit) is now under debate. In this study, the amounts of non-structural carbohydrates (NSCs) for xylogenesis in black spruce, Picea mariana, saplings were assessed under high temperature and drought in order to determine the role of sugar mobilization for osmotic purposes and its consequences for secondary growth. METHODS: Four-year-old saplings of black spruce in a greenhouse were subjected to different thermal conditions with respect to the outside air temperature (T0) in 2010 (2 and 5 degrees C higher than T0) and 2011 (6 degrees C warmer than T0 during the day or night) with a dry period of about 1 month in June of each year. Wood formation together with starch, NSCs and leaf parameters (water potential and photosynthesis) were monitored from May to September. KEY RESULTS: With the exception of raffinose, the amounts of soluble sugars were not modified in the cambium even if gas exchange and photosynthesis were greatly reduced during drought. Raffinose increased more than pinitol under a pre-dawn water potential of less than -1 Mpa, presumably because this compound is better suited than polyol for replacing water and capturing free radicals, and its degradation into simple sugar is easier. Warming decreased the starch storage in the xylem as well the available hexose pool in the cambium and the xylem, probably because of an increase in respiration. CONCLUSIONS: Radial stem growth was reduced during drought due to the mobilization of NSCs for osmotic purposes and due to the lack of cell turgor. Thus plant water status during wood formation can influence the NSCs available for growth in the cambium and xylem. PMID- 24950774 TI - Response to the letter to the editor by Genc et al. PMID- 24950773 TI - Medial open transversus abdominis plane (MOTAP) catheters for analgesia following open liver resection: study protocol for a randomized controlled trial. AB - BACKGROUND: The current standard for pain control following liver surgery is intravenous, patient-controlled analgesia (IV PCA) or epidural analgesia. We have developed a modification of a regional technique called medial open transversus abdominis plane (MOTAP) catheter analgesia. The MOTAP technique involves surgically placed catheters through the open surgical site into a plane between the internal oblique muscle and the transverse abdominis muscle superiorly. The objective of this trial is to assess the efficacy of this technique. METHODS/DESIGN: This protocol describes a multicentre, prospective, blinded, randomized controlled trial. One hundred and twenty patients scheduled for open liver resection through a subcostal incision will be enrolled. All patients will have two MOTAP catheters placed at the conclusion of surgery. Patients will be randomized to one of two parallel groups: experimental (local anaesthetic through MOTAP catheters) or placebo (normal saline through MOTAP catheters). Both groups will also receive IV PCA. The primary endpoint is mean cumulative postoperative opioid consumption over the first 2 postoperative days (48 hours). Secondary outcomes include pain intensity, patient functional outcomes, and the incidence of complications. DISCUSSION: This trial has been approved by the ethics boards at participating centres and is currently enrolling patients. Data collection will be completed by the end of 2014 with analysis mid-2015 and publication by the end of 2015. TRIAL REGISTRATION: The study is registered with http://clinicaltrials.gov ( NCT01960049; 23 September 2013). PMID- 24950775 TI - Laparoscopic approach to appendectomy reduces the incidence of short- and long term post-operative bowel obstruction: systematic review and pooled analysis. AB - BACKGROUND: The aim of this meta-analysis was to determine the effect of laparoscopic appendectomy (LA) compared to open appendectomy (OA) on short-term and long-term post-operative bowel obstruction. METHODS: Medline, Embase, trial registries, conference proceedings and reference lists were searched. Subset analysis was performed for paediatric patients, patients who presented with perforated appendicitis and studies with long-term follow-up and surveillance for bowel obstruction and with surgery for bowel obstruction. RESULTS: Overall, 29 studies comprising 159,729 patients (60,875 LA versus 98,854 OA) were included. LA was associated with a significant reduction in the incidence of post-operative bowel obstruction in the general population (pooled odds ratio (POR) = 0.43 [95 %C.I. 0.3-0.63]). Subset analysis demonstrated that LA significantly reduced the incidence of post-operative bowel obstruction in paediatric patients (POR = 0.48 [95 %C.I. 0.3-0.78]) and patients with perforated appendicitis (POR = 0.44 [95 %C.I. 0.26-0.74]). Furthermore, LA was associated with a significantly reduced incidence of long-term bowel obstruction (POR = 0.33 [95 %C.I. 0.19-0.56]) and bowel obstruction requiring surgery (POR = 0.31 [95 %C.I. 0.2-0.48]). DISCUSSIONS: This present meta-analysis provides evidence to clearly demonstrate the benefits of a laparoscopic approach to appendectomy as reflected by a reduction in short- and long-term adhesive bowel obstruction. Important future areas for assessment include the influence of surgical approach on long-term quality of life following appendectomy. PMID- 24950777 TI - The 'Five Point Plan': a successful tool for reducing lameness in sheep. PMID- 24950776 TI - Determinants of repeat curative intent surgery in colorectal liver metastasis. AB - INTRODUCTION: Following curative intent surgery (CIS) for colorectal liver metastasis (CRLM), repeat CIS for recurrence improves survival. The factors associated with repeat CIS are not widely reported. METHODS: An institutional database (January 2002-December 2012) was reviewed to evaluate factors influencing repeat CIS. RESULTS: One hundred sixty-three patients with colorectal liver metastasis (CRLM) underwent successful CIS. Median follow-up and disease free interval (DFI) was 33 and 16 months, respectively. After initial CIS, 102 patients (63%) recurred. Fifty-three patients (52%) underwent a repeat CIS. After repeat CIS, 33 patients (62%) developed a second recurrence, and in 13 patients (39%), a third CIS was possible. DFI decreased following initial CIS (first CIS vs. second CIS vs. third CIS [20 vs. 15 vs. 8.5 months], p < 0.001). Overall 5 year survival in all patients was 55%; patients who recurred had a 5-year survival of 67% if they underwent repeat CIS vs. 7.8% if they were managed palliatively. Second CIS was less likely with a postoperative complication, other/multifocal recurrence, or DFI <12 months. CONCLUSION: Despite high recurrence and decreasing DFI, repeat CIS provides a survival benefit. Postoperative complications, DFI, number, and pattern of recurrence influence the decision to pursue repeat CIS. PMID- 24950778 TI - Impact of the healthcare payment system on patient access to oral anticancer drugs: an illustration from the French and United States contexts. AB - BACKGROUND: Oral anticancer drugs (OADs) allow treating a growing range of cancers. Despite their convenience, their acceptance by healthcare professionals and patients may be affected by medical, economical and organizational factors. The way the healthcare payment system (HPS) reimburses OADs or finances hospital activities may impact patients' access to such drugs. We discuss how the HPS in France and USA may generate disincentives to the use of OADs in certain circumstances. DISCUSSION: French public and private hospitals are financed by National Health Insurance (NHI) according to the nature and volume of medical services provided annually. Patients receiving intravenous anticancer drugs (IADs) in a hospital setting generate services, while those receiving OADs shift a part of service provision from the hospital to the community. In 2013, two million outpatient IADs sessions were performed, representing a cost of ?815 million to the NHI, but positive contribution margin of ?86 million to hospitals. Substitution of IADs by OADs mechanically induces a shortfall in hospital income related to hospitalizations. Such economic constraints may partially contribute to making physicians reluctant to prescribe OADs. In the US healthcare system, coverage for OADs is less favorable than coverage for injectable anticancer drugs. In 2006, a Cancer Drug Coverage Parity Act was adopted by several states in order to provide patients with better coverage for OADs. Nonetheless, the complexity of reimbursement systems and multiple reimbursement channels from private insurance represent real economic barriers which may prevent patients with low income being treated with OADs. From an organizational perspective, in both countries the use of OADs generates additional activities related to physician consultations, therapeutic education and healthcare coordination between hospitals and community settings, which are not considered in the funding of hospitals activities so far. SUMMARY: Funding of healthcare services is a critical factor influencing in part the choice of cancer treatments and this is expected to become increasingly important as economic constraints grow. Drug reimbursement systems and hospital financing changes, coupled with other accompanying measures, should contribute to improve equal and safe patient access to appropriate anticancer drugs and improve the management and care pathway of cancer patients. PMID- 24950780 TI - Orientin inhibits high glucose-induced vascular inflammation in vitro and in vivo. AB - Vascular inflammation plays a key role in the initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Orientin, a C glycosyl flavonoid, is known to have anxiolytic and antioxidative activity. In this study, we assessed whether orientin can suppress vascular inflammation induced by high glucose (HG) in human umbilical vein endothelial cells (HUVECs) and mice. Our data indicate that HG markedly increased vascular permeability, monocyte adhesion, the expression of cell adhesion molecules (CAMs), the formation of reactive oxygen species (ROS), and the activation of nuclear factor kappa B (NF-kappaB). Remarkably, the vascular inflammatory effects of HG were attenuated by pretreatment with orientin. Since vascular inflammation induced by HG is critical in the development of diabetic complications, our results suggest that orientin may have significant benefits in the treatment of diabetic complications and atherosclerosis. PMID- 24950781 TI - Mast cells kill Candida albicans in the extracellular environment but spare ingested fungi from death. AB - Mast cells (MCs) reside in tissues that are common targets of Candida spp. infections, and can exert bactericidal activity, but little is known about their fungicidal activity. MCs purified from rat peritoneum (RPMC) and a clinical isolate of C. albicans, were employed. Ingestion was evaluated by flow cytometry (FACS) and optical microscopy. The killing activity was assayed by FACS analysis and by colony forming unit method. RPMC degranulation was evaluated by beta hexosaminidase assay and phosphatidylserine externalization by FACS. Phagocytosing RPMC were also analyzed by transmission electron microscopy. Herein, we show that the killing of C. albicans by RPMC takes place in the extracellular environment, very likely through secreted granular components. Ultrastructural analysis of the ingestion process revealed an unusual RPMC-C. albicans interaction that could allow fungal survival. Our findings indicate that MCs have a positive role in the defense mechanism against Candida infections and should be included among the cell types involved in host-defense against this pathogen. PMID- 24950779 TI - Flutamide and biomarkers in women at high risk for ovarian cancer: preclinical and clinical evidence. AB - We hypothesized that (i) preclinical biologic evidence exists for the role of androgens in ovarian cancer development and (ii) flutamide treatment of women at high risk for ovarian cancer may identify meaningful tissue biomarkers of androgen action and of ovarian cancer initiation. We showed that androgen ablation of male mice led to a 24-fold decrease in tumor burden from serous ovarian cells. In a phase II study, we studied the effect of preoperative flutamide treatment (125 mg/day * 6 weeks) in 12 women versus 47 controls, 47% with BRCA mutation. We analyzed immunohistochemical scores of candidate proteins CSF-1, CSF-1R, and ErbB4 in the epithelium and stroma of fallopian tube, ovary, and ovarian endosalpingiosis. Flutamide decreased the levels, notably, of CSF-1 and ErbB4 in ovarian stroma (P <= 0.0006) and ovarian endosalpingiosis (P <= 0.01), ErbB4 in ovarian epithelium (P = 0.006), and CSF-1R in ovarian endosalpingiosis (P = 0.009). Our logistic regression model clearly distinguished the flutamide patients from controls (P <= 0.0001). Our analysis of the precision of this model of CSF-1 and ErbB4 expression in ovarian stroma achieved 100% sensitivity and 97% specificity (AUC = 0.99). Thus, our data suggest that a short 6-week exposure of flutamide reversed elevated levels of CSF-1 and ErbB4 (both of which we had previously found correlated with high risk status). CSF-1 and ErbB4 in ovarian stroma led to a model with high predictive value for flutamide sensitivity. The effect of flutamide on marker expression in ovarian endosalpingiosis, previously associated with BRCA carrier status, suggests that ovarian endosalpingiosis may be a latent precursor to pelvic serous cancers. PMID- 24950784 TI - Development of a concentration method for detection of tobacco mosaic virus in irrigation water. AB - Tobacco mosaic virus (TMV) causes significant yield loss in susceptible crops irrigated with contaminated water. However, detection of TMV in water is difficult owing to extremely low concentrations of the virus. Here, we developed a simple method for the detection and quantification of TMV in irrigation water. TMV was reliably detected at concentrations as low as 10 viral copies/MUL with real-time PCR. The sensitivity of detection was further improved using polyethylene glycol 6000 (PEG6000, MW 6000) to concentrate TMV from water samples. Among the 28 samples from Shaanxi Province examined with our method, 17 were tested positive after virus concentration. Infectivity of TMV in the original water sample as well as after concentration was confirmed using PCR. The limiting concentration of TMV in water to re-infect plants was determined as 10(2) viral copies/mL. The method developed in this study offers a novel approach to detect TMV in irrigation water, and may provide an effective tool to control crop infection. PMID- 24950782 TI - Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model. AB - Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and transforming growth factor (TGF)-beta1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin. PMID- 24950783 TI - Unusual outcome of in utero infection and subsequent postnatal super-infection with different PCV2b strains. AB - VC2002, isolated from postweaning multisystemic wasting syndrome (PMWS)-affected pig, is a mixture of two porcine circovirus genotype 2b (PCV2b) viruses, K2 and K39. Preliminary experiments disclosed short-term adverse effects of K39, but not K2, on porcine foetuses. These findings led to the hypothesis that infection of immuno-incompetent foetuses with K2 confers a status of immunotolerance, and postnatal super-infection with K39 triggers PMWS. To explore this hypothesis, nine 55-day-old foetuses were inoculated in utero (three with K2-10(4.3)TCID50, three with K39-10(4.3)TCID50 and three with medium), and foeto-pathogenicity examined. At 21 days post-inoculation (dpi), K2 did not induce pathology, whereas pathological effects of K39 were evident. Twenty-four 45-day-old foetuses were subsequently inoculated to examine the long-term effect of K2, including six with K2-high dose-10(4.3)TCID50, six with K2-low dose-10(2.3)TCID50 and 12 mock inoculated controls. Both doses resulted in five mummified foetuses and one live born piglet each (69dpi). K2 was recovered from all mummies. K2 and K2-specific antibodies were not detected in serum of the two live-born piglets at birth, indicating full control of K2 infection. The K2-low dose-infected piglet was immunostimulated at day 2, but not the K2-high dose-infected piglet. Both non stimulated and stimulated K2-infected piglets were super-inoculated with K39 at day 6 or 8 (taken as 0 days post super-inoculation). Low viral replication was observed in the non-stimulated K2-K39 piglet (up to 10(3.3)TCID50/g; identified as K39). In contrast, viral replication was extremely high in the stimulated K2 K39 piglet (up to 10(5.6)TCID50/g) and identified as K2, indicating that K2 infection is controlled during foetal life, but emerges after birth upon immunostimulation. However, none of the piglets showed any signs of PMWS. PMID- 24950785 TI - Analysis of molecular variation in porcine reproductive and respiratory syndrome virus in China between 2007 and 2012. AB - In the present study, 89 porcine reproductive and respiratory syndrome virus (PRRSV) isolates in China during 2007 to 2012 were randomly selected from the GenBank genetic sequence database. Evolutionary characteristics of these isolates were analyzed based on the sequences of non-structural protein 2 (Nsp2) and glycoprotein 5 (GP5). The genetic variations of the isolates were also compared with six representative strains. The results showed that a high degree of genetic diversity exists among the PRRSV population in China. Highly pathogenic PRRSV isolates, with a discontinuous deletion of a 30 amino acid residue in the Nsp2 region, remained the most dominant virus throughout 2007-2012 in China. Owing to the extensive use of representative vaccine strains, natural recombination events occurred between strains. Three isolates - HH08, DY, and YN-2011 - were more closely related to vaccine strains than the other isolates. Both YN-2011 and DY were the evolutionary products of recombination events between strains SP and CH 1R. The results of the present study provide useful information for the epidemiology of PRRSV as well as for vaccine development. PMID- 24950786 TI - Conservation of T cell epitopes between seasonal influenza viruses and the novel influenza A H7N9 virus. AB - A novel avian influenza A (H7N9) virus recently emerged in the Yangtze River delta and caused diseases, often severe, in over 130 people. This H7N9 virus appeared to infect humans with greater ease than previous avian influenza virus subtypes such as H5N1 and H9N2. While there are other potential explanations for this large number of human infections with an avian influenza virus, we investigated whether a lack of conserved T-cell epitopes between endemic H1N1 and H3N2 influenza viruses and the novel H7N9 virus contributes to this observation. Here we demonstrate that a number of T cell epitopes are conserved between endemic H1N1 and H3N2 viruses and H7N9 virus. Most of these conserved epitopes are from viral internal proteins. The extent of conservation between endemic human seasonal influenza and avian influenza H7N9 was comparable to that with the highly pathogenic avian influenza H5N1. Thus, the ease of inter-species transmission of H7N9 viruses (compared with avian H5N1 viruses) cannot be attributed to the lack of conservation of such T cell epitopes. On the contrary, our findings predict significant T-cell based cross-reactions in the human population to the novel H7N9 virus. Our findings also have implications for H7N9 virus vaccine design. PMID- 24950787 TI - Psychophysiology-informed (multimodal) imaging. AB - Electroencephalography (EEG) and magnetic resonance imaging are two popular methodologies for brain research. While EEG has a high temporal resolution, yet a low spatial resolution, MRI has the complete opposite, a high spatial resolution, yet a low temporal resolution. Obviously therefore, researchers have been searching for ways combining the two methodologies, for more than two decades. However, there are many issues that have to be solved before the methodologies can be successfully and, more importantly reliably, combined. Here, we give an overview of these issues, and present strategies that have been used over the past two decades to overcome them. We start with a general description of EEG and (f)MRI methodology, then present the difficulties involved in combining both methodologies, and lastly present and discuss the most popular strategies that have been used over the past two decades to solve these problems. We conclude that in spite of the many issues, the two methodologies can be combined successfully, provided that the correct procedures are followed. PMID- 24950789 TI - Leadership style and culturally competent care: Nurse leaders' views of their practice in the multicultural care settings of the United Arab Emirates. AB - Abstract It is well recognised that nurse leader managers play an important role in facilitating the quality and nature of hospital care, the improvement of work performance and work satisfaction. In the United Arab Emirates (UAE) they face the additional challenge of working within a context of significant linguistic and cultural diversity where leadership in the provision of culturally competent care is a major requirement. With this goal at the fore, a sample of 153 nurse leader-managers, including matrons, nursing directors, supervisors, nurses-in charge and in-service education staff from four private and six government hospitals completed the Multifactor Leadership Questionnaire (Bass & Avolio, 2004). The survey also explored participants' perceptions of the characteristics of good leaders and what they needed to do in their particular work place to enhance culturally competent care. The results showed nurseleader-managers used both transformational and transactional leadership attributes but in different combinations across the two hospital types. PMID- 24950791 TI - Outcomes of implementation of sacral nerve stimulation on urination, defecation, and sexual function in patients with spinal cord injury. PMID- 24950788 TI - Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. AB - A hexanucleotide (GGGGCC) expansion in C9ORF72 gene is the most common genetic change seen in familial Frontotemporal Lobar Degeneration (FTLD) and familial Motor Neurone Disease (MND). Pathologically, expansion bearers show characteristic p62 positive, TDP-43 negative inclusion bodies within cerebellar and hippocampal neurons which also contain dipeptide repeat proteins (DPR) formed from sense and antisense RAN (repeat associated non ATG-initiated) translation of the expanded repeat region itself. 'Inappropriate' formation, and aggregation, of DPR might therefore confer neurotoxicity and influence clinical phenotype. Consequently, we compared the topographic brain distribution of DPR in 8 patients with Frontotemporal dementia (FTD), 6 with FTD + MND and 7 with MND alone (all 21 patients bearing expansions in C9ORF72) using a polyclonal antibody to poly-GA, and related this to the extent of TDP-43 pathology in key regions of cerebral cortex and hippocampus. There were no significant differences in either the pattern or severity of brain distribution of DPR between FTD, FTD + MND and MND groups, nor was there any relationship between the distribution of DPR and TDP-43 pathologies in expansion bearers. Likewise, there were no significant differences in the extent of TDP-43 pathology between FTLD patients bearing an expansion in C9ORF72 and non-bearers of the expansion. There were no association between the extent of DPR pathology and TMEM106B or APOE genotypes. However, there was a negative correlation between the extent of DPR pathology and age at onset. Present findings therefore suggest that although the presence and topographic distribution of DPR may be of diagnostic relevance in patients bearing expansion in C9ORF72 this has no bearing on the determination of clinical phenotype. Because TDP-43 pathologies are similar in bearers and non-bearers of the expansion, the expansion may act as a major genetic risk factor for FTLD and MND by rendering the brain highly vulnerable to those very same factors which generate FTLD and MND in sporadic disease. PMID- 24950792 TI - Combined analysis of biomarkers of proliferation and apoptosis in colon cancer: an immunohistochemistry-based study using tissue microarray. AB - BACKGROUND: Disturbance of the balance between proliferation and apoptosis is an important hallmark of tumor development. The goal of this study was to develop a descriptive parameter that represents this imbalance and relate this parameter to clinical outcome in all four stages of colon cancer. MATERIAL AND METHODS: The study population consisted of 285 stage I-IV colon cancer patients of which a tumor tissue microarray (TMA) was available. TMA sections were immunohistochemically stained and quantified for the presence of Ki67 and cleaved caspase-3 tumor expression. These results were used to develop the combined apoptosis proliferation (CAP) parameter and correlated to patient outcome. RESULTS: The CAP parameter was significantly related to clinical outcome; patients with CAP ++ (high level of both apoptosis and proliferation) showed the best outcome perspectives (overall survival (OS), p = 0.004 and disease-free survival (DFS), p = 0.009). The effect of the CAP parameter was related to tumor microsatellite status and indirectly to tumor location, where left-sided tumors with CAP + - (high level of proliferation, low level of apoptosis) showed a worse prognosis (DFS p value 0.02) and right-sided tumors with CAP + - had a better prognosis (DFS p value 0.032). With stratified analyses, the CAP parameter remained significant in stage II tumors only. CONCLUSIONS: The CAP parameter, representing outcome of the balance between the level of apoptosis and proliferation, can be used as a prognostic marker in colon cancer patients for both DFS and OS, particularly in left-sided, microsatellite stable tumors when tumor-node-metastasis (TNM) stage is taken into account. PMID- 24950793 TI - Extralevator abdominoperineal excision (ELAPE) for rectal cancer--short-term results from the Swedish Colorectal Cancer Registry. Selective use of ELAPE warranted. AB - PURPOSE: Local recurrences are more common after abdominoperineal excision (APE) than after anterior resection of rectal cancer. Extralevator APE was introduced to address this problem. This prospective registry-based population study aims to investigate the efficacy of extralevator APE (ELAPE) in improving short-term oncological outcome. METHODS: All Swedish patients operated with any kind of abdominoperineal excision and registered in the Swedish Rectal Cancer Registry 2007-2009 were included (n = 1,397) and analyzed with emphasis on the perineal part of the operation. Short-term perioperative and oncological results were collected from the registry. RESULTS: Extralevator APE did not result in fewer intraoperative perforations or involved circumferential resection margins as compared to standard APE for the entire group. Intraoperative perforations were significantly fewer for patients with low tumours (<=4 cm) (ELAPE: n = 28/386 versus APE: n = 9/58) (p = 0.043) and for early (T0-T2) T-stages (ELAPE: n = 3/172 versus APE: n = 6/75) (p = 0.025). There were significantly more post operative wound infections for ELAPE than for APE (n = 106 (20.4 %) versus n = 25 (12.0 %), p = 0.011). CONCLUSIONS: The short-term results indicate that selective use of extralevator APE can be warranted, for example, for subgroups with low tumours. In conclusion, selective use of the extralevator APE is advocated as not all patients seem to benefit from the technique, and there are significantly more short-term complications after extralevator APE. PMID- 24950794 TI - Limitations of somatostatin scintigraphy in primary small bowel neuroendocrine tumors. AB - BACKGROUND: Somatostatin receptor scintigraphy (SRS; octreoscan) is used in neuroendocrine tumors to locate the primary tumor site and delineate the extent of disease. SRS has decreased sensitivity for small bowel neuroendocrine tumors (SBNETs). The reasons for SRS nonlocalization are not clear. We sought to determine factors that correlate with successful primary tumor localization by SRS in patients with resected SBNETs, and also identify factors that confound interpretation of SRS reports. METHODS: Records of patients with resected SBNETs were reviewed for SRS results, tumor size, multifocality, N, and M status. Somatostatin receptor 2 (SSTR2) expression was analyzed in resected tumors by quantitative polymerase chain reaction. SRS reports were reviewed and categorized as localizing the primary tumor or not. A nuclear medicine physician independently reviewed available images. RESULTS: Of 37 patients with preoperative SRS, the primary tumor was localized in 37%. Of all the factors tested, only small tumor size correlated significantly with SRS nonlocalization. Overexpression of SSTR2 was not significantly different between tumors that were or were not localized by SRS, regardless of tumor size. There were three instances where the SRS report did not agree with the nuclear medicine physician's interpretation as to whether SRS localized the primary tumor. In each case, uptake in mesenteric nodes was a confounding factor. CONCLUSIONS: SBNETs <2 cm are most likely to be missed by SRS. SSTR2 expression did not correlate with SRS nonlocalization of the primary tumor. Uptake in mesenteric nodes may help indicate an SBNET primary but can also interfere with its visualization within the small bowel. PMID- 24950795 TI - Parathyroidectomy in dialysis patients. AB - BACKGROUND: The optimal surgical treatment for secondary hyperparathyroidism is not well defined. Subtotal parathyroidectomy and total parathyroidectomy (tPTX) with autotransplant are accepted options; treatment method is left to surgeon preference. We sought to describe different characteristics of patients with secondary hyperparathyroidism receiving surgical treatment and to compare outcomes between the two treatment strategies. METHODS: We conducted a retrospective cohort study of patients aged >18 y and on dialysis who received a parathyroidectomy (Current Procedural Terminology code = 60500) using the American College of Surgeons National Surgical Quality Improvement Program Participant Use File (2008-2011). Procedures were classified as subtotal if no autotransplant was performed and total if autotransplant was performed. Descriptive statistics were performed. The primary outcome variable of interest was 30-day morbidity. Secondary outcome variables studied were operative time, postoperative length of stay (LOS), 30-day mortality, and 30-day readmission. Univariate analyses were performed. RESULTS: A total of 898 patients studied; of which, 236 patients (26.4%) received a tPTX and 662 (73.7%) received a subtotal parathyroidectomy. The median age was 49 y (interquartile range [IQR]: 38, 59), and majority of patients were American Society of Anesthesiologists class III (629, 70%). Nearly half of the patients were black (447, 49.8%); blacks were more likely to receive a tPTX than whites (30.2% versus 19.9%, P = 0.01). Median operative time (133 min, IQR: 92, 160 versus 120 min, IQR: 103, 181; P < 0.01) and median LOS (4 d, IQR: 3, 7 versus 4 d, IQR: 2, 6; P < 0.01) were longer after a tPTX. There was no difference in the 30-day morbidity, mortality, or readmission rates between the two treatments. CONCLUSIONS: We used a national multi-institutional data set to show that despite the high-risk patient cohort and difference in operative duration, there is no difference in the more general postoperative complication rates. PMID- 24950796 TI - Resident participation and postoperative outcomes in adrenal surgery. AB - BACKGROUND: The changing paradigm of surgical residency training has raised concerns about the effects on the quality of training. The purpose of this study is to identify if resident participation in laparoscopic adrenalectomy (LA) and open adrenalectomy (OA) cases is associated with deleterious outcomes. MATERIALS AND METHODS: This is a retrospective study using the American College of Surgeons National Surgical Quality Improvement Program database. Data from patients undergoing LA and OA from 2005 to 2010 were queried. Preoperative variables as well as intra- and post-operative outcomes for each procedure were evaluated. Multivariate logistic regression was used to analyze if resident participation was associated with significant differences in outcomes, compared with no resident participation. Subset analysis was done to determine possible differences in outcomes based on the level of resident participating, divided into junior (Post Graduate Year [PGY]1-3), senior (PGY4-5), or fellow (>=PGY6) levels. RESULTS: A total of 3219 adrenalectomies were performed. Of these, 735 (22.8%) were OAs and 2484 (77.2%) were LAs. Residents were involved in 2582 (80.2%) surgeries, which comprised 1985 (76.9%) LAs and 597 (23.1%) OAs. Senior residents or fellows performed majority of the cases (85.2%). Mean operative time was significantly higher with resident participation in LA (P < 0.0001) and OA group (P < 0.0001). On multivariate analysis, resident participation was not associated with significant differences in the operative outcomes of 30-d mortality or postoperative complications after laparoscopic or OA. CONCLUSIONS: Although resident participation does increase operative time in LA and OA, this does not appear to be clinically significant and does not result in adverse patient outcomes. PMID- 24950797 TI - Massive transfusion in paediatric and adolescent trauma patients: incidence, patient profile, and outcomes prior to a massive transfusion protocol. AB - OBJECTIVES: The purpose of this study was to quantify the incidence, patient profile, and outcomes associated with massive transfusion in paediatric trauma patients prior to establishing a massive transfusion protocol. METHODS: We performed a retrospective review of paediatric trauma patients treated at London Heath Sciences Centre between January 1, 2006, and December 31, 2011. Inclusion criteria were Injury Severity Score (ISS) greater than 12 and age less than 18 years. RESULTS: 435 patients met the inclusion criteria. Three hundred and fifty six (82%) did not receive packed red blood cells in the first 24h, 66 (15%) received a non-massive transfusion (<40mL/kg), and 13 (3%) received a massive transfusion (>40mL/kg). Coagulopathy of any kind was more common in massive transfusion (11/13; 85%) than non-massive (32/66; 49%) (p=0.037). Hyperkalemia (18% versus 23%; p=0.98) and hypocalcemia (41% versus 46%; p=1.00) were similar in both groups. Of the 13 massively transfused patients, 9 had multisystem injuries due to a motor vehicle collision, 3 had non-accidental head injuries requiring surgical evacuation, and 1 had multiple stab wounds. In the absence of a massive transfusion protocol, only 8 of the 13 patients received both fresh frozen plasma and platelets in the first 24h. Massive transfusion occurred in patients from across the age spectrum and was associated with severe injuries (mean ISS=33), a higher incidence of severe head injuries (92%), longer hospital stay (mean=36 days), and increased mortality (38%). CONCLUSIONS: This study is the first to describe the incidence, complications, and outcomes associated with massive transfusion in paediatric trauma patients prior to a massive transfusion protocol. Massive transfusion occurred in 3% of patients and was associated with coagulopathy and poor outcomes. Protocols are needed to ensure that resuscitation occurs in a coordinated fashion and that patients are given appropriate amounts of fresh frozen plasma, platelets, and cryoprecipitate. PMID- 24950799 TI - Strong Lewis acid air-stable cationic titanocene perfluoroalkyl(aryl)sulfonate complexes as highly efficient and recyclable catalysts for C-C bond forming reactions. AB - A series of strong Lewis acid air-stable titanocene perfluoroalkyl(aryl)sulfonate complexes Cp2Ti(OH2)2(OSO2X)2.THF (X = C8F17, 1.THF; X = C4F9, 2.H2O.THF; X = C6F5, 3) were successfully synthesized by the treatment of Cp2TiCl2 with C8F17SO3Ag, C4F9SO3Ag and C6F5SO3Ag, respectively. In contrast to well-known titanocene bis(triflate), these complexes showed no change in open air over three months. TG-DSC analysis showed that 1.THF, 2.H2O.THF and 3 were thermally stable at 230 degrees C, 220 degrees C and 280 degrees C, respectively. Conductivity measurements showed that these complexes underwent ionic dissociation in CH3CN solution. X-ray analysis results confirmed that 2.H2O.THF and 3 were cationic. ESR spectra showed that the Lewis acidity of 1.THF (1.06 eV) was higher than that of Sc(3+) (1.00 eV) and Y(3+) (0.85 eV). UV/Vis spectra showed a significant red shift due to the strong complex formation between 10-methylacridone and 2.H2O.THF. Fluorescence spectra showed that the Lewis acidity of 2 (lambda(em) = 477 nm) was higher than that of Sc(3+) (lambda(em) = 474 nm). These complexes showed high catalytic ability in various carbon-carbon bond forming reactions. Moreover, they show good reusability. Compared with 1.THF, 2.H2O.THF and 3 exhibit higher solubility and better catalytic activity, and will find broad applications in organic synthesis. PMID- 24950798 TI - Predicting in-hospital death among patients injured in traffic crashes in Saudi Arabia. AB - INTRODUCTION: Traffic-related injuries are a major cause of premature death in developing countries. Saudi Arabia has struggled with high rates of traffic related deaths for decades, yet little is known about health outcomes of motor vehicle victims seeking medical care. This study aims to develop and validate a model to predict in-hospital death among patients admitted to a large-urban trauma centre in Saudi Arabia for treatment following traffic-related crashes. METHODS: The analysis used data from King Abdulaziz Medical City (KAMC) in Riyadh, Saudi Arabia. During the study period 2001-2010, 5325 patients met the inclusion criteria of being injured in traffic crashes and seen in the Emergency Department (ED) and/or admitted to the hospital. Backward stepwise logistic regression, with in-hospital death as the outcome, was performed. Variables with p<0.05 were included in the final model. The Bayesian Information Criterion (BIC) was employed to identify the most parsimonious model. Model discrimination was evaluated by the C-statistic and calibration by the Hosmer-Lemeshow Goodness of Fit statistic. Bootstrapping was used to assess overestimation of model performance and obtain a corrected C-statistic. RESULTS: 457 (8.5%) patients died at some time during their treatment in the ED or hospital. Older age, the Triage Revised Trauma Scale (T-RTS), and Injury Severity Score were independent risk factors for in-hospital death: T-RTS was best modelled with linear and quadratic terms to capture a flattening of the relationship to death in the more severe range. The model showed excellent discrimination (C-statistic=0.96) and calibration (H-L statistic 4.29 [p>0.05]). Internal bootstrap validation gave similar results (C-statistic=0.96). CONCLUSIONS: The proposed model can predict in-hospital death accurately. It can facilitate the triage process among injured patients, and identify unexpected deaths in order to address potential pitfalls in the care process. Conversely, by identifying high-risk patients, strategies can be developed to improve trauma care for these patients and reduce case fatality. This is the first study to develop and validate a model to predict traffic-related mortality in a developing country. Future studies from developing countries can use this study as a reference for case fatality achievable for different risk profiles at a well-equipped trauma centre. PMID- 24950800 TI - Long shift patterns to end for Scottish junior doctors. PMID- 24950802 TI - Fate and effects of veterinary antibiotics in soil. AB - Large amounts of veterinary antibiotics are applied worldwide to farm animals and reach agricultural fields by manure fertilization, where they might lead to an increased abundance and transferability of antibiotic-resistance determinants. In this review we discuss recent advances, limitations, and research needs in determining the fate of veterinary antibiotics and resistant bacteria applied with manure to soil, and their effects on the structure and function of soil microbial communities in bulk soils and the rhizosphere. The increased abundance and mobilization of antibiotic-resistance genes (ARGs) might contribute to the emergence of multi-resistant human pathogens that increasingly threaten the successful antibiotic treatment of bacterial infections. PMID- 24950803 TI - Microbial lactate utilization: enzymes, pathogenesis, and regulation. AB - Lactate utilization endows microbes with the ability to use lactate as a carbon source. Lactate oxidizing enzymes play key roles in the lactate utilization pathway. Various types of these enzymes have been characterized, but novel ones remain to be identified. Lactate determination techniques and biocatalysts have been developed based on these enzymes. Lactate utilization has also been found to induce pathogenicity of several microbes, and the mechanisms have been investigated. More recently, studies on the structure and organization of operons of lactate utilization have been carried out. This review focuses on the recent progress and future perspectives in understanding microbial lactate utilization. PMID- 24950801 TI - Synergism between inhibitors of Aurora A and KIF11 overcomes KIF15-dependent drug resistance. AB - The mitotic kinesin KIF11 (also called Eg5) plays critical roles in spindle functions. Although a number of small-molecule inhibitors of KIF11 are currently in clinical development, drug-resistance could be developed through compensation by another kinesin called KIF15. Using a newly developed infrared-based cell system, we discovered that the effectiveness of one of the latest generations of KIF11 inhibitor (SB743921) could be enhanced with several inhibitors of Aurora A kinase. Evidence including live-cell imaging and isobologram analysis indicated that targeting KIF11 and Aurora A together promoted monoastral spindle formation and mitotic catastrophe synergistically, supporting a model of parallel pathways of centrosome regulation by Aurora A and KIF11. We also developed a KIF15 dependent SB743921-resistance cell model. Significantly, the drug-resistance could also be overcome with Aurora A inhibitors. These results provide a molecular basis for increasing the effectiveness of Aurora A and KIF11 inhibitors and tackling problems of drug resistance. PMID- 24950804 TI - Synthesis of none Bisphenol A structure dimethacrylate monomer and characterization for dental composite applications. AB - OBJECTIVE: In this study, new dimethacrylate monomer SiMA without Bisphenol A (BPA) structure was synthesized and used as base resin of dental composite materials with the aim of reducing human exposure to BPA derivatives. METHODS: SiMA was synthesized through ring-opening addition reaction between 1,3-bis[2(3,4 epoxycyclohex-1-yl)ethyl]tetra-methyldisiloxane and methacrylic acid, and its structure was confirmed by FT-IR and (1)H NMR spectra. SiMA was mixed with TEGDMA (50/50, wt/wt) and photoinitiation system (0.7 wt% of CQ and 0.7 wt% of DMAEMA) to form resin system. Experimental composite EC was then prepared by SiMA based resin loading with BaAlSiO2 microfillers (72wt%). Double bond conversion (DC) was determined by FT-IR analysis. Volume shrinkage (VS) was measured through variation of density before and after irradiation. Water sorption (WS) and solubility (SL) were obtained until the mass variation of polymer in distilled water kept stable. Flexural strength (FS) and modulus (FM) of the polymer were measured using a three-point bending set up. Extract of composite was used to evaluate its cytotoxic effect on humane dental pulp cells, and relative growth rate (RGR) was obtained by CCK-8 assay. Bis-GMA/TEGDMA (50/50, wt/wt) resin system and universal dental restorative materials 3M ESPE FiltekTM Z250 were used as references for neat resin system and composite material, respectively. RESULTS: FT-IR and (1)H NMR spectra showed that structure of SiMA was the same as designed. For the neat resin systems: DC of SiMA based resin was higher than that of Bis-GMA based resin (p<0.05); SiMA based resin had lower VS than Bis-GMA based resin; WS of SiMA based resin was lower than that of Bis-GMA based resin (p<0.05), while SL of SiMA based resin was nearly the same as that of Bis-GMA based resin (p>0.05); FS and FM of SiMA based resin were lower than those of Bis GMA based resin (p<0.05). For the composite materials: DC of EC was higher than that of Z250 (p<0.05); EC and Z250 had same VS; WS of EC was lower than that of Z250 (p<0.05), and SL of EC was higher than that of Z250 (p<0.05); FS and FM of EC were lower than those of Z250 (p<0.05); RGRs of EC were lower than those of Z250 after the cells were incubated with relative extract for 24h and 48h (p<0.05), while after being incubated for 72 h, RGR of EC and Z250 had no obvious difference (p>0.05). SIGNIFICANCE: SiMA had potential to replace Bis-GMA as base resin of dental composite materials. However, formulation of SiMA based resin and composite should be optimized in terms of mechanical strength to satisfy the requirements of resin based dental materials for clinical application. PMID- 24950805 TI - Effect of heat treatment and in vitro aging on the microstructure and mechanical properties of cold isostatic-pressed zirconia ceramics for dental restorations. AB - OBJECTIVES: The temperature variations during the veneering firing cycles of a zirconia dental ceramic can negatively affect its mechanical properties. A possible synergistic effect of both heat-treatment and aging while exposed to the oral environment could result to catastrophic failure. The aim of the present study was to investigate the effect of heat treatment followed during veneering and in vitro aging on the mechanical and microstructural properties of zirconia dental ceramics. METHODS: Three specimens from each of two zirconia blocks (Ivoclar IPS e.max ZirCAD (IV) and Wieland ZENO Zr (WI)) were cut by CAD/CAM technology, fully sintered and polished. Each one was cut in four equal parts. One part was used as control (C), one was heat-treated (H), one was aged (A) (134 degrees C, 2bar, 10h) and one was heat-treated and subsequently aged (HA). The mechanical properties (nano-hardness (H) and elastic modulus (E*)) were investigated by nano-indentation tests while the surface characterization was carried out with XRD, FTIR and SEM. RESULTS: Different treatments on IV and WI samples resulted in a reduction of both H and E* values, however the differences were not statistically significant (p>0.05). The combination of treatments imposes an overall effect (p<0.001), enhancing the influence on both H and E* values. This reduction in mechanical properties was followed by an increase of monoclinic content. Greater variations in both H and E* values were recorded for WI samples. SIGNIFICANCE: The clinical performance of zirconia dental ceramics may be affected during firing and aging resulting in increased probability of failure. PMID- 24950806 TI - FEA and microstructure characterization of a one-piece Y-TZP abutment. AB - OBJECTIVES: The most important drawback of dental implant/abutment assemblies is the need for a fixing screw. This study aimed to develop an esthetic one-piece Y TZP abutment to suppress the use of the screw. METHODS: Material characterization was performed using a bar-shaped specimen obtained by slip-casting to validate the method prior to prototype abutment fabrication by the same process. The mechanical behavior of the prototype abutment was verified and compared with a conventional abutment by finite element analysis (FEA). The abutment was evaluated by micro-CT analysis and its density was measured. RESULTS: FEA showed stress concentration at the first thread pitch during installation and in the cervical region during oblique loading for both abutments. However, stress concentration was observed at the base of the screw head and stem in the conventional abutment. The relative density for the fabricated abutment was 95.68%. Micro-CT analysis revealed the presence of elongated cracks with sharp edges over the surface and porosity in the central region. SIGNIFICANCE: In the light of these findings, the behavior of a one-piece abutment is expected to be better than that of the conventional model. New studies should be conducted to clarify the performance and longevity of this one-piece Y-TZP abutment. PMID- 24950807 TI - Chemical characterization and bioactivity of epoxy resin and Portland cement based sealers with niobium and zirconium oxide radiopacifiers. AB - OBJECTIVE: The purpose of this study was to characterize and to evaluate the bioactivity potential of experimental root canal sealers (ES) based on Portland cement, epoxy resin with nano- and micro-particles of niobium or zirconium oxide used as radiopacifiers in comparison to AH Plus and MTA Fillapex. METHODS: Specimens of the sealers (10 mm in diameter*1 mm thick) were prepared and the radiopacity was evaluated according to ISO 6876 (2012) specifications. Characterization of the sealers was performed under the scanning electron microscope (SEM) immediately after setting and after immersion for 28 days in Hank's balanced salt solution (HBSS). In addition X-ray energy dispersive spectroscopy (EDS), X-ray diffraction (XRD) and Fourier transform infrared (FT IR) spectroscopy were also performed. The pH and calcium ion release were measured after 1, 7, 14, 21 and 28 days after completion of seating using a digital pH meter and an atomic absorption spectrophotometer, respectively. RESULTS: The experimental sealers exhibited an average radiopacity of 2.5 mm thickness of aluminum, which was similar to MTA Fillapex (P>0.05) and inferior to AH Plus (P<0.05). AH Plus did not show bioactivity. Although the experimental sealers did not exhibit the formation of hydration product, they encouraged the deposition of crystalline spherical structures of calcium deficient phosphate. The highest pH and calcium release values were observed with the experimental sealers (P<0.01). ES-Nb-micro was the only sealer to present hexagonal shaped crystal deposition. SIGNIFICANCE: Novel root canal sealers based on a mixture of Portland cement, epoxy resin and radiopacifier exhibited a degree of bioactivity although no evidence of cement hydration was demonstrated on material characterization. The radiopacifier particle size had limited effect on the sealer microstructure and chemical properties. PMID- 24950808 TI - Biodegradation of composite resin with ester linkages: identifying human salivary enzyme activity with a potential role in the esterolytic process. AB - OBJECTIVES: The ester linkages contained within dental resin monomers (such as Bisphenol A-glycidylmethacrylate (BisGMA) and triethylene glycol dimethacrylate (TEGDMA)) are susceptible to hydrolytic degradation by salivary esterases, however very little is known about the specific esterase activities implicated in this process. The objective of this work was to isolate and identify the dominant proteins from saliva that are associated with the esterase activities shown to be involved in the degradation of BisGMA. METHODS: Human whole saliva was collected and processed prior to separation in a HiPrep 16/60 Sephacryl S-200 HR column. The fraction with the highest esterase activity was further separated by an anion exchange column (Mono-Q (10/100G)). Isolated fractions were then separated by gel electrophoresis, and compared to a common bench marker esterase, cholesterol esterase (CE), and commercial albumin which has been reported to express esterase activity. Proteins suspected of containing esterase activity were analyzed by Mass Spectroscopy (MS). Commercially available proteins, similar to the salivary esterase proteins identified by MS, were used to replicate the enzymatic complexes and confirm their degradation activity with respect to BisGMA. RESULTS: MS data suggested that the enzyme fraction with the highest esterase activity was contained among a group of proteins consisting of albumin, Zn-alpha2 glycoprotein, alpha-amylase, TALDO1 protein, transferrin, lipocalin2, and prolactin-induced protein. Studies concluded that the main esterase bands on the gels in each fraction did not overlap with CE activity, and that albumin activity emerged as a lead candidate with significant esterase activity relative to BisGMA degradation, particularly when it formed a complex with Zn-alpha2-glycoprotein, under slightly basic conditions. SIGNIFICANCE: These enzyme complexes can be used as a physiologically relevant formulation to test the biostability of composite resins. PMID- 24950809 TI - A method for calculating the compliance of bonded-interfaces under shrinkage: validation for Class I cavities. AB - OBJECTIVE: The compliance for tooth cavity preparations is not yet fully described in the literature. Thus, the objectives were to present a finite element (FE) method for calculating compliance and to apply this to peak shrinkage stress regions in model cavities restored with resin-composite. METHODS: Three groups of FE-models were created, with all materials considered linear, homogeneous, elastic and isotropic: (a) a pair of butt-joint bonded cubic prisms (dentin/resin-composite), with dentin of known compliance (0.0666 MUm/N). Free ends were fixed in the Z-axis direction. A 1% volumetric shrinkage was simulated for the resin-composite. Mean displacements in the Z direction at each node at the dentin-resin interface were calculated and divided by the sum of normal contact forces in Z for each node. (b) A series of more complex restored cavity configurations for which their compliances were calculated. (c) A set of 3D-FE beam models, of 4 mm * 2 mm cross-section with lengths from 2 to 10mm, were also analyzed under both tensile and bending modes. RESULTS: The compliance calculated by FEM for the butt-joint prisms was 0.0652 MUm/N and corresponded well to the analytical value (0.0666 MUm/N). For more accurate representations of the phenomenon, such as the compliance of a cavity or any other complex structure, the use of the displacement-magnitude was recommended, as loading by isotropic contraction also produces transversal deformations. For the beam models, the compliance was strongly dependent upon the loading direction and was greater under bending than in tension. SIGNIFICANCE: The method was validated for the compliance calculation of complex structures subjected to shrinkage stress such as Class I 'cavities'. The same FEM parameters could be applied to calculate the real compliance of any interface of complex structures. The compliance concept is improved by considering specific load directions. PMID- 24950810 TI - Adhesion of resin-modified glass-ionomer cements may affect the integrity of tooth structure in the open sandwich technique. AB - OBJECTIVE: To study the interfaces between model cavities prepared in teeth and four glass ionomer cements (two conventional and two resin-modified). METHODS: Ten non-cavitated molars and premolars were used and, in each, two 3mm deep slot preparations were created on opposing sides of the tooth. The teeth were conditioned as appropriate, then restored using the open sandwich technique, using a conventional glass ionomer (Fuji IX, Ketac Molar) or resin modified glass ionomer (Fuji II LC or N100), followed by completion with composite resin. The teeth were then embedded in a transparent acrylic resin and cut parallel to the long axis through both restorations, using a low speed diamond wheel saw. Samples were evaluated using a metallographic light microscope (100*). Three areas were assessed: the axial wall, the axial gingival line angle and the cavo-surface line angle. Bonding was categorized as inadequate or adequate based on the appearance and inadequate bonding was further studied and classified. Data were analysed statistically using the McNamara analysis. RESULTS: The majority of materials failed to make adequate contact with the axial wall, and there were also flaws at the axial/gingival line angle in several samples. By contrast, the cavo-surface line angle was generally soundly filled and the materials showed intimate contact with the tooth surface in this region. The most serious inadequacy, though, was not lack of intimate contact and/or adhesive bond, but the presence of perpendicular cracks in 30% of the Fuji II LC samples which extended into the underlying dentin. SIGNIFICANCE: The problems of placement and dentin cracking experienced with these materials demonstrate that adhesive bond strength alone cannot be used as the criterion of success for restorative materials. In fact good adhesion can, in certain cases, promote cracking of the dentin due to stresses within the material, an outcome which is undesirable. PMID- 24950811 TI - BEETL-fastq: a searchable compressed archive for DNA reads. AB - MOTIVATION: FASTQ is a standard file format for DNA sequencing data, which stores both nucleotides and quality scores. A typical sequencing study can easily generate hundreds of gigabytes of FASTQ files, while public archives such as ENA and NCBI and large international collaborations such as the Cancer Genome Atlas can accumulate many terabytes of data in this format. Compression tools such as gzip are often used to reduce the storage burden but have the disadvantage that the data must be decompressed before they can be used. Here, we present BEETL fastq, a tool that not only compresses FASTQ-formatted DNA reads more compactly than gzip but also permits rapid search for k-mer queries within the archived sequences. Importantly, the full FASTQ record of each matching read or read pair is returned, allowing the search results to be piped directly to any of the many standard tools that accept FASTQ data as input. RESULTS: We show that 6.6 terabytes of human reads in FASTQ format can be transformed into 1.7 terabytes of indexed files, from where we can search for 1, 10, 100, 1000 and a million of 30 mers in 3, 8, 14, 45 and 567 s, respectively, plus 20 ms per output read. Useful applications of the search capability are highlighted, including the genotyping of structural variant breakpoints and 'in silico pull-down' experiments in which only the reads that cover a region of interest are selectively extracted for the purposes of variant calling or visualization. AVAILABILITY AND IMPLEMENTATION: BEETL-fastq is part of the BEETL library, available as a github repository at github.com/BEETL/BEETL. PMID- 24950812 TI - Protective effect of tetanus antibodies. PMID- 24950813 TI - Population normalization with ammonium in wastewater-based epidemiology: application to illicit drug monitoring. AB - Fluctuations in ammonium (NH4+), measured as NH4-N loads using an ion-selective electrode installed at the inlet of a sewage treatment plant, showed a distinctive pattern which was associated to weekly (i.e., commuters) and seasonal (i.e., holidays) fluctuations of the population. Moreover, population size estimates based on NH4-N loads were lower compared to census data. Diurnal profiles of benzoylecgonine (BE) and 11-nor-9-carboxy-Delta9-tetrahydrocannabinol (THC-COOH) were shown to be strongly correlated to NH4-N. Characteristic patterns, which reflect the prolonged nocturnal activity of people during the weekend, could be observed for BE, cocaine, and a major metabolite of MDMA (i.e., 4-hydroxy-3-methoxymethamphetamine). Additional 24 h composite samples were collected between February and September 2013. Per-capita loads (i.e., grams per day per 1000 inhabitants) were computed using census data and NH4-N measurements. Normalization with NH4-N did not modify the overall pattern, suggesting that the magnitude of fluctuations in the size of the population is negligible compared to those of illicit drug loads. Results show that fluctuations in the size of the population over longer periods of time or during major events can be monitored using NH4-N loads: either using raw NH4-N loads or population size estimates based on NH4-N loads, if information about site-specific NH4-N population equivalents is available. PMID- 24950815 TI - Somatostatin ameliorates lipopolysaccharide-induced tight junction damage via the ERK-MAPK pathway in Caco2 cells. AB - Dysfunction of the epithelial barrier is an important pathogenic factor of inflammatory bowel disease and other inflammatory conditions of the gut. Somatostatin (SST) has been demonstrated to reduce local and systemic inflammation reactions and maintain the integrity of the blood-brain barrier (BBB). To determine the beneficial effect of SST on lipopolysaccharide (LPS) induced damage of the tight junction (TJ) and its mechanisms, Caco2 cells pretreated with SST (1nM) or MEK inhibitor U0126 (10MUM) were exposed to LPS. LPS significantly reduced the expression of TJ proteins in a dose-dependent way. LPS (100MUg/ml) greatly induced Caco2 monolayer barrier dysfunction by decreasing transepithelial resistance and increasing epithelial permeability. Pretreatment with SST effectively improved the barrier dysfunction of Caco2 cells. SST significantly increased the expression of TJ proteins occludin and ZO-1 and inhibited the redistribution of TJ proteins due to LPS stimulation. Furthermore, SST decreased the LPS-induced phosphorylation of ERK1/2, and a selective MEK inhibitor markedly protected the barrier function against LPS disturbance by blocking the activation of the ERK-MAPK pathway in Caco2 cells. Besides, LPS significantly increased the mRNA level of SSTR5, which was partly inhibited by pretreatment with SST. In conclusion, the present study indicates that SST protects the Caco2 monolayer barrier against LPS-induced tight junction breakdown by down-regulating the activation of the ERK-MAPK pathway and suppression the activation of SSTR5. PMID- 24950814 TI - The Chlamydomonas genome project: a decade on. AB - The green alga Chlamydomonas reinhardtii is a popular unicellular organism for studying photosynthesis, cilia biogenesis, and micronutrient homeostasis. Ten years since its genome project was initiated an iterative process of improvements to the genome and gene predictions has propelled this organism to the forefront of the omics era. Housed at Phytozome, the plant genomics portal of the Joint Genome Institute (JGI), the most up-to-date genomic data include a genome arranged on chromosomes and high-quality gene models with alternative splice forms supported by an abundance of whole transcriptome sequencing (RNA-Seq) data. We present here the past, present, and future of Chlamydomonas genomics. Specifically, we detail progress on genome assembly and gene model refinement, discuss resources for gene annotations, functional predictions, and locus ID mapping between versions and, importantly, outline a standardized framework for naming genes. PMID- 24950816 TI - [Pancreatic ultrasonography]. AB - Despite the recent technological advances in imaging, abdominal ultrasonography continues to be the first diagnostic test indicated in patients with a suspicion of pancreatic disease, due to its safety, accessibility and low cost. It is an essential technique in the study of inflammatory processes, since it not only assesses changes in pancreatic parenchyma, but also gives an indication of the origin (bile or alcoholic). It is also essential in the detection and tracing of possible complications as well as being used as a guide in diagnostic and therapeutic punctures. It is also the first technique used in the study of pancreatic tumors, detecting them with a sensitivity of around 70% and a specificity of 90%. PMID- 24950818 TI - Where now for schizophrenia research? AB - Schizophrenia continues to pose a serious challenge to neuroscience and psychiatry as well as to health care systems and to the patients and families who suffer this terrible and disabling illness. Major developments in the past few months in both genetics and drug development oblige us to consider novel drug discovery tactics for future schizophrenia research. Here we review what we consider to be the key issues and some suggested solutions. PMID- 24950817 TI - Exploiting large-scale drug-protein interaction information for computational drug repurposing. AB - BACKGROUND: Despite increased investment in pharmaceutical research and development, fewer and fewer new drugs are entering the marketplace. This has prompted studies in repurposing existing drugs for use against diseases with unmet medical needs. A popular approach is to develop a classification model based on drugs with and without a desired therapeutic effect. For this approach to be statistically sound, it requires a large number of drugs in both classes. However, given few or no approved drugs for the diseases of highest medical urgency and interest, different strategies need to be investigated. RESULTS: We developed a computational method termed "drug-protein interaction-based repurposing" (DPIR) that is potentially applicable to diseases with very few approved drugs. The method, based on genome-wide drug-protein interaction information and Bayesian statistics, first identifies drug-protein interactions associated with a desired therapeutic effect. Then, it uses key drug-protein interactions to score other drugs for their potential to have the same therapeutic effect. CONCLUSIONS: Detailed cross-validation studies using United States Food and Drug Administration-approved drugs for hypertension, human immunodeficiency virus, and malaria indicated that DPIR provides robust predictions. It achieves high levels of enrichment of drugs approved for a disease even with models developed based on a single drug known to treat the disease. Analysis of our model predictions also indicated that the method is potentially useful for understanding molecular mechanisms of drug action and for identifying protein targets that may potentiate the desired therapeutic effects of other drugs (combination therapies). PMID- 24950820 TI - In regard to Boyle et al. PMID- 24950819 TI - Limbic versus cognitive target for deep brain stimulation in treatment-resistant depression: accumbens more promising than caudate. AB - High-frequency deep brain stimulation (DBS) represents a major stake for treatment for treatment-resistant depression (TRD). We describe a preliminary trial of DBS of two potential brain targets in chronic TRD: the nucleus accumbens (Acb) and, in the event of failure, the caudate nucleus. Patients were followed for 6 months before surgery (M0). From M1 to M5, they underwent stimulation of the Acb target. PET scans allowed us to track metabolic modifications resulting from this stimulation. The caudate target of nonresponders was stimulated between M5 and M9. Patients then entered an extension phase, in which it was possible to adapt stimulation parameters and treatments. Six patients were included and four were operated on. At M5, none of the patients were either responders or remitters, but we did observe a decrease in Hamilton Depression Rating Scale (HDRS) scores. Three patients were switched to caudate stimulation, but no improvement was observed. During the extension phase, the Acb target was stimulated for all patients, three of whom exhibited a significant response. A decrease in glucose metabolism was observed after Acb stimulation, in the posterior cingulate gyrus, left frontal lobe, superior and medial gyrus, and bilateral cerebellum. An increase in metabolism was observed in the bilateral frontal lobe (superior gyrus), left frontal lobe (medial gyrus), and right limbic lobe (anterior cingulate gyrus). The results of this trial suggest that Acb is a more promising target than the caudate. NCT01569711. PMID- 24950821 TI - Monte Carlo dosimetry of the eye plaque design used at the St. Erik Eye Hospital for (125)I brachytherapy. AB - PURPOSE: At St. Erik Eye Hospital in Stockholm, Sweden, ocular tumors of apical height above 6 mm are treated with brachytherapy, using iodine-125 seeds attached to a gold alloy plaque while the treatment planning is performed assuming homogeneous water surroundings. The aim of this work was to investigate the dose modifying effects of the plaque and the seed fixating silicone rubber glue. METHODS AND MATERIALS: The impact of the gold plaque and silicone rubber glue was studied with the Monte Carlo N-particle transport code, version 5. RESULTS: For the 2 cm most proximal to the plaque surface along the plaque's central axis, the eyeball received 104.6-93.0% of the dose in all-water conditions. CONCLUSIONS: The 0.3 mm thick layer of silicone rubber glue, used for seed fixation, attenuates photons little enough to allow characteristic X-rays from the gold alloy plaque to reach the eyeball. Close to the plaque, the dose rates were higher with the plaque and glue present, than in homogeneous water conditions. This is in contrast to what has been reported for more commonly used eye plaques, demonstrating the importance of investigating the dosimetry of individual treatment systems. PMID- 24950822 TI - Long-term followup of breast preservation by re-excision and balloon brachytherapy after ipsilateral breast tumor recurrence. AB - PURPOSE: To report our long-term experience with balloon brachytherapy in retreatment of the breast after ipsilateral breast tumor recurrence. METHODS AND MATERIALS: Between March 2004 and June 2012, 18 patients previously treated with external beam radiotherapy were retreated using either the MammoSite (Hologic Corporation, Marlborough, MA), MammoSite ML (Hologic Corporation), or the Contura (Bard Peripheral Vascular, Inc., Tempe, AZ) brachytherapy devices. Sixteen patients were treated for an ipsilateral breast tumor recurrence after breast conservation surgery and postoperative irradiation (11 with infiltrating ductal carcinoma [IDC] and 6 with ductal carcinoma in situ [DCIS]), whereas 2 patients developed an in-field breast cancer likely associated with Hodgkin disease mantle irradiation (27 and 17 years prior, respectively). The recurrent histology of seven was IDC, with seven others recurring as DCIS, three as a combination of IDC/DCIS, and one as infiltrating lobular carcinoma. All patients received a twice-daily tumor dose of 3400 cGy at 340 cGy per fraction. Acute and chronic side effects were graded by the Common Terminology Criteria for Adverse Events, version 4.0. Cosmesis was graded by both the Harvard Cosmesis Scale and the Allegheny General Modification of the Harvard Scale. RESULTS: With a mean of followup of 39.6 months, only 2 patients developed a local recurrence. One patient developed an inflammatory recurrence from what was identified as a moderately differentiated T1N0M0 estrogen receptor-positive recurrence, and the second developed a recurrence immediately adjacent to the implant site. Both patients were treated locally by salvage mastectomy. The patient who developed an inflammatory recurrence rapidly developed visceral metastases including brain lesions and succumbed to her progressive disease. The second patient was successfully salvaged with uncomplicated mastectomy, and she survives to this date. One patient developed a chronic abscess in the sinus tract of the balloon, which required mastectomy, and one developed a post-treatment infection in the catheter tract, which was successfully treated with oral antibiotics. Cosmesis as graded by the Harvard cosmesis criteria and the Allegheny General Modification Score diminished one grade in only 2 patients. All other patients had stable cosmetic scores. CONCLUSIONS: Use of balloon brachytherapy devices in the treatment of the previously irradiated breast is feasible and may provide adequate local control and acceptable cosmesis in carefully selected patients. Further study and refinement of this therapy is required for more definitive results. PMID- 24950823 TI - [KiGGS: the second wave]. PMID- 24950824 TI - [The first KiGGS follow-up (KiGGS Wave 1): study conduct, sample design, and response]. AB - The "German Health Interview and Examination Survey for Children and Adolescents" (KiGGS) is part of the health monitoring system of the Robert Koch Institute (RKI). Following the KiGGS baseline study (2003 - 06), which comprised interviews and physical examinations of 0- to 17-year-old participants, KiGGS Wave 1 (2009 - 2012) was carried out as a telephone-based survey. In addition to providing longitudinal data, a second essential aim of KiGGS is to regularly provide population-based cross-sectional data on the health situation of children and adolescents aged 0-17 years living in Germany. Therefore, the study population of KiGGS Wave 1 consists of re-invited participants from the baseline study (KiGGS cohort), supplemented by newly invited children aged 0-6 years. The newly invited participants were randomly chosen from local population registries in the 167 baseline sample points. This method was chosen to supplement the sample with younger age groups. This article focuses on the age groups from 0 to 17 years, which are relevant for prevalence estimations among children and adolescents. In total 12,368 children and adolescents took part; among them 4,455 newly invited and 7,913 re-invited participants (response 38.8 and 72.9%, respectively). A comparison of the net sample with the resident German population (0-17 years) regarding particular population characteristics and an analysis of the relationship between the re-participation rate and certain characteristics collected in the baseline study (7-17 years) suggest a mostly unbiased sample. To account for certain aspects of the population and nonresponse, cross-sectional and trend analyses were partially corrected by weighting factors. PMID- 24950825 TI - [Measurement of socioeconomic status in the KiGGS study: first follow-up (KiGGS Wave 1)]. AB - This article describes the measurement of socioeconomic status in the first follow-up of the KiGGS study (KiGGS Wave 1) conducted from 2009 to 2012. A multidimensional index score was used. The score is the sum of three metric components: Education and Occupational Qualification, Occupational Status, and Net Income. Compared with the approach in the KiGGS baseline study, some modifications were made in accordance with changes in the other components of the health-monitoring program at the Robert Koch Institute, i.e., the German Health Update (GEDA) and the German Health Interview and Examination Survey for Adults (DEGS1). These changes facilitate the analysis of temporal developments and trends, ensure international comparability of the data, and support the transfer of the results into politics and practice. In order to demonstrate the application of the revised instrument, we report on exemplary results of KiGGS Wave 1 regarding the relationship between socioeconomic status and the general health status of children and adolescents aged 3-17 years. PMID- 24950826 TI - [Prevalence of common allergies in children and adolescents in Germany: results of the KiGGS study: first follow-up (KiGGS Wave 1)]. AB - The first follow-up of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS Wave 1) was conducted from 2009 to 2012 as a combined cross-sectional and longitudinal study and provides, among other things, data on allergic diseases. Data collection was carried out by telephone interviews. In total, 6,093 girls and 6,275 boys were included, among them 4,455 newly recruited 0- to 6-year-olds (response 38.8%) and 7,913 KiGGS follow-up participants aged 7-17 years (response 72.9%). Based on parent reports, 15.6% (95% confidence interval 14.7-16.5) of children and adolescents aged 0-17 years were currently affected by at least one atopic disease. The 12-month prevalence rates of hay fever, atopic dermatitis, and asthma were 9.1% (8.4-9.8), 6.0% (5.4 6.6), and 4.1% (3.6-4.6), respectively. In all, 2.2% (1.9-2.6) of the children and adolescents were currently suffering from contact dermatitis. Compared with the baseline KiGGS survey from 2003 to 2006, a higher percentage of participants reported the occurrence of asthma within the past 12 months in the recent KiGGS Wave 1 (4.1 vs. 3.2%; p = 0.0034). The total increase is mainly due to higher prevalence rates among 0- to 6-year-olds, especially in girls. Higher 12-month prevalence rates can be also observed for hay fever among 0- to 6-year-olds, especially in girls, although the total increase is not statistically significant (9.1 vs. 8.3%; p = 0.08). There was a declining trend for atopic dermatitis: 6.8% (2003-2006) vs. 5.4% (2009-2012); p = 0.0015. PMID- 24950827 TI - [Chronic and vaccine-preventable diseases in children and adolescents in Germany: results of the KiGGS study: first follow up (KiGGS wave 1)]. AB - The German Health Interview and Examination Survey for Children and Adolescents (KiGGS) 2003-2006 is the first nationwide comprehensive study on the health of children and adolescents living in Germany. The KiGGS first interview follow-up is a telephone interview study that collected, among other things, data on a number of chronic and vaccine-preventable diseases in 2009-2012 and is a combined cross-sectional and longitudinal study based on a population registry sample from the 167 KiGGS study points. The analysis is based on 12,368 respondents (7913 KiGGS follow-up participants aged 7-17 years, response 72 % and 4455 newly recruited 0- to 6-year-olds, response 42 %). Based on parent reports the lifetime prevalence of both chickenpox and pertussis has decreased in the population targeted by recently changed vaccination recommendations. For measles the prevalence remained unsatisfactorily high in each investigated age group. Of the children and adolescents aged 0-17 years 16 % (95 % confidence interval CI 15.2 17.0 %) had a long-standing chronic health condition according to the parents. Of these, however, only one in five was affected in their routine daily activities. The lifetime prevalence in 7- to 17-year-olds was 1.2 % (0.9-1.6) for epilepsy (0.4 % for the past 12 months), 5.0 % (4.4-5.7) for migraine, 0.2 % (0.1-0.3) for diabetes and in 0 to 6-year-olds 2.0 % (1.5-2.6) for heart conditions and 3.1 % (2.5-3.8) for febrile seizures with a -prevalence in 0 to 2-year-olds which are most affected of 1.0 % (0.6-1.6) in the past 12 months. The vast majority of children and adolescents in Germany are in good or very good health as suggested by other results reported in this issue; however, chronic conditions are not rare and need continuous monitoring. These results confirm that implementation of the vaccination recommendations of the German Standing Committee on Vaccination (STIKO) can lead to effective prevention of infectious diseases in Germany. PMID- 24950828 TI - [Unintentional injuries in childhood and adolescence: current prevalence, determinants, and trends: results of the KiGGS study: first follow-up (KiGGS Wave 1)]. AB - BACKGROUND: In Germany and worldwide, unintentional injuries (UI) are a major health threat for children and adolescents. The first follow-up of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS Wave 1, 2009-2012) continued the national UI monitoring that started with the KiGGS baseline study (2003-2006). The present analysis provides updated information and for the first time gives indications on time trends. METHODS: KiGGS Wave 1 is a combined nationwide cross-sectional and longitudinal survey by the Robert Koch Institute (RKI) providing information about 12,368 participating children and adolescents (0-17 years old; response rates: 38.8% first time invited, 72.9% reinvited). Parents were asked about their children's UI and poisonings via telephone interviews. Information on UI is available for 11,665 children and adolescents (1-17 years old). The 12-month prevalence rate and 95% confidence interval were calculated, and KiGGS Wave 1 was compared with the KiGGS baseline study. The Rao-Scott chi-square test corrected over the F distribution was used to test for the statistical significance of subgroup differences and trend effects. RESULTS: Within the previous 12 months, 15.5% of all children and adolescents aged 1-17 years were medically treated for UI. UI were significantly more prevalent among boys (17.0%) than among girls (14.0%), and 3.4% of the subjects had more than one accident leading to UI. One in eight children and adolescents who suffered UI stayed in hospital (12.3%) for inpatient treatment for at least one night. The home, childcare and educational institutions, and sports facilities/playgrounds were the predominant accident locations. Compared to the baseline study, neither the overall prevalence of UI nor the gender- and age-specific patterns changed significantly. CONCLUSION: Since a large proportion of UI is avoidable, knowledge of high-risk subgroups and accident locations is of particular use for prevention. KiGGS Wave 1 makes an important contribution to the comprehension of these issues. The transfer of research into practice is of particular importance for the avoidance of UI. PMID- 24950829 TI - [Health-related quality of life in children and adolescents in Germany: results of the KiGGS study: first follow-up (KiGGS Wave 1)]. AB - In recent years, there has been a change in the health and disease spectrum among children and adolescents, with an increase in mental health problems and a shift from acute to chronic illness. In this phase, the health-related quality of life (HRQoL) has increased in importance as a dimension of subjective health. The aim of this study is to describe the HRQoL of children and adolescents measured with the internationally standardized screening instrument KIDSCREEN-10. In the follow up of the KiGGS study in 2009-2012 (KiGGS Wave 1), 2,567 parents of children aged 7-10 years and 4,878 adolescents aged 11 years or older completed the KIDSCREEN 10 questionnaire. In all, 94% of parents of 7- to 10-year-old girls and boys estimate the HRQoL of their children to be "very good" or "good." Of the 11- to 17-year-old adolescents, 96% report their HRQoL as "very good" or "good." Somatic diseases and pain as well as mental health problems and a low social status are included in the HRQoL in only a limited way. Potential differences in HRQoL by social status were not confirmed in multivariate models. The HRQoL of the examined children and adolescents is predominantly very good or good. Interventions to improve the HRQoL of children and adolescents with diseases and psychopathological problems are necessary, regardless of their social status. PMID- 24950830 TI - [Psychopathological problems and psychosocial impairment in children and adolescents aged 3-17 years in the German population: prevalence and time trends at two measurement points (2003-2006 and 2009-2012): results of the KiGGS study: first follow-up (KiGGS Wave 1)]. AB - Child and adolescent mental health problems burden not only the individual, but also their families and their social environment and may, therefore, be regarded as a highly relevant public health issue. The data on mental health problems of children and adolescents from the KiGGS Wave 1 study (sample period 2009-2012) make it possible to report on both current prevalence rates and time trends over the 6-year period beginning with the KiGGS baseline survey (2003-2006). The assessment of emotional and behavioral problems in KiGGS Wave 1 was carried out with the symptoms questionnaire of the Strengths and Difficulties Questionnaire (SDQ) in a telephone interview with 10,353 guardians of children and adolescents aged 3-17 years. Moreover, using the SDQ impact supplement, the KIGGS Wave 1 data provide information on psychosocial impairment following child and adolescent mental health problems. Subjects with a borderline or abnormal SDQ score, according to German normative data, were considered at risk. A total of 20.2% (95% CI: 18.9-21.6%) of the study subjects were identified as being at risk for a mental health disorder, compared with 20.0% (19.1-20.9%) during the KiGGS baseline study (age-standardized based on population from 12 December 2010). Thus, no significant changes over time in the prevalence of mental health problems were detected. Also, there were no statistically significant differences in prevalence by sex, age group, or socioeconomic status between the KiGGS baseline survey and KiGGS Wave 1. The statistical comparison of the subscale mean values for both girls and boys showed higher values with respect to the subscales for emotional problems, behavioral problems, and prosocial behavior and lower mean values for the peer problems subscale in KiGGS Wave 1. These partly small temporal trends, however, may be due to possible mode effects (written questionnaire in the KiGGS baseline study versus telephone interview in KiGGS Wave 1). The hyperactivity subscale remained stable across the two sample periods. Regarding impairments following mental health problems at the second sample period, boys were more affected in the areas of chronicity, family burden, and impact score. The high and stable prevalence rates and magnitude of emotional and behavioral problems should prompt increased preventive efforts. PMID- 24950831 TI - [Has the prevalence of parent-reported diagnosis of attention deficit hyperactivity disorder (ADHD) in Germany increased between 2003-2006 and 2009 2012? Results of the KiGGS-study: first follow-up (KiGGS Wave 1)]. AB - Recent international studies have reported a considerable increase in the diagnosis of attention deficit hyperactivity disorder (ADHD). Data from German statutory health insurance companies suggest a comparable trend for Germany. Based on data from the nationally representative study KiGGS Wave 1 (2009-2012) it was the aim of this study to report on the prevalence rates of parent-reported ADHD diagnoses in children and adolescents aged 3-17 years as well as to report on time trends in comparison with the KiGGS baseline study (2003-2006). ADHD caseness was met if a parent reported that a physician or a psychologist diagnosed their child with ADHD. Participants without a reported ADHD diagnosis but who scored >= 7 (clinical range) on the parent-rated hyperactivity subscale of the Strengths and Difficulties Questionnaire (SDQ) were considered as potential ADHD cases. The prevalence of diagnosed ADHD was 5.0% (prevalence of potential ADHD cases 6.0%). An ADHD diagnosis was more than four and a half times more likely to be reported among boys than girls. Children from families with low socioeconomic status (SES) were more than two and a half times more likely to be diagnosed with ADHD than children from families with high SES. Among potential cases, boys were twice as common as girls, and children from families with low SES were approximately three times more common compared with those from high SES families. The proportion of lifetime ADHD diagnoses increased with age and was highest in 11- to 17-year-olds. In every fifth child with ADHD the initial diagnosis was made by the age of 6 years and in 1 out of 11 children with ADHD the initial diagnosis was made by the age of 5 years. In total, we observed no significant changes regarding the frequency of ADHD diagnosis compared to the KiGGS baseline study. Increases reported using data from German statuary health insurance companies were not reflected in the KiGGS data. PMID- 24950833 TI - [Physical activity and electronic media use in children and adolescents: results of the KiGGS study: first follow-up (KiGGS wave 1)]. AB - Physical activity during childhood and adolescence has numerous health benefits, while sedentary behavior, especially electronic media use, is associated with the development of overweight. Therefore, the promotion of physical activity during childhood and adolescence is an integral part of national public health efforts. The aim of this article is to describe the physical activity behavior of German children and adolescents based on the nationwide data of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS wave 1). Furthermore, the association between physical activity and sports participation and use of screen-based media in youth aged 11 to 17 years was analyzed. The analyses included data from 10,426 children and adolescents aged 3-17 years collected by telephone interviews. Children older than 11 years answered the questions by themselves, whereas a parent was interviewed for younger children. The descriptive analyses were performed under consideration of social and demographic factors. According to the results of KiGGS wave 1 a total of 77.5% (95% Cl 76.0-78.9 %) of the children and adolescents participated in sports activities, and 59.7% (58.1-61.3 %) were members of a sports club. The recommendation of the World Health Organization (WHO) to be physically active at least 60 min per day was achieved by 27.5% (26.0-28.9 %). Children and adolescents with a low socioeconomic status (SES) participated less in sports activities than children of higher SES groups. Excessive use of screen-based media was more likely to be associated with lack of sports participation than with a lack of physical activity. In the future, preventive measures should promote the daily physical activity of children and adolescents and additionally encourage children and adolescents with low SES to participate in sports activities. PMID- 24950832 TI - [Tobacco and alcohol consumption among 11- to 17-year-old adolescents: results of the KiGGS study: first follow-up (KiGGS Wave 1)]. AB - In this paper, tobacco and alcohol consumption among adolescents in Germany was analyzed. In addition to the current situation, we report temporal developments and trends. Data were obtained from the first follow-up of the KiGGS study (KiGGS Wave 1) conducted from 2009 to 2012. All girls and boys aged 11-17 years (n = 5,258) were included. The results show that currently 12.0% of 11- to 17-year-old adolescents in Germany smoke, 5.4% of them on a daily basis. At-risk drinking (AUDIT-C total score) was prevalent among 15.8% of adolescents, heavy episodic drinking (six or more alcoholic standard drinks on a single occasion at least once a month) among 11.5%. No significant gender differences were found for most indicators. However, among adolescents aged 14-17 years, boys revealed a greater inclination toward heavy episodic drinking than girls did (23.1 vs. 16.5 %, p < 0.01). Regarding smoking, distinct socioeconomic differences were observed. For example, adolescents from families with a low socioeconomic status (SES) smoke significantly more often on a regular or daily basis compared with their peers from high-SES families (OR = 1.95, 95% CI = 1.16-3.27 and OR = 3.71, 95% CI = 2.05-6.69, respectively). The relationship between SES and alcohol consumption is rather weak. Significant differences emerged only regarding lifetime prevalence of alcohol consumption, and indicate lower consumption rates among low-SES compared with high-SES adolescents (OR = 0.47, 95% CI = 0.33-0.68). Consideration of the KiGGS baseline study data (2003-2006) shows that smoking prevalence has dropped almost by half from 20.4 to 12.0%. The percentage of adolescents who have ever drunk alcohol has decreased from 62.8 to 54.4%. These results are consistent with the findings of other studies on adolescent tobacco and alcohol consumption and should be considered in the context of preventive efforts that have been strengthened in recent years, especially regarding tobacco use. PMID- 24950834 TI - [Factors influencing the prevalence and duration of breastfeeding in Germany: results of the KiGGS study: first follow up (KiGGS Wave 1)]. AB - Breastfeeding is the natural way of feeding infants in the first months of their lives and has been proven to have health benefits for both infants and mothers. Breastfeeding initiation and duration are affected by social, demographic and health factors. The aim of this study was to describe the current rates of breastfeeding initiation and duration in Germany, and to identify potential factors that underline these rates. Additionally, results are compared with the KiGGS basic (2003-2006; birth cohorts 1996-2002) study in order to reveal the development in the trends of breastfeeding initiation and duration in Germany. The KiGGS wave 1 (2009-2012) includes data on the breastfeeding behavior of mothers of 4410 children aged between 0 and 6 years (birth cohorts 2002-2012). Altogether, 82% (95% confidence interval 79.8-84.2 %) of children were ever breastfed, and the average breastfeeding duration was 7.5 months (7.2-7.8). There was a slight increase in the breastfeeding initiation in Germany over the last several years. Breastfeeding initiation among children aged 0-6 years increased by 4% points compared to 0- to 6-year-olds (birth cohorts 1996-2002) from the KiGGS basic study. The breastfeeding duration stayed unchanged. The breastfeeding behavior was mainly related to the age of the mother at birth, the mother's education level, smoking during pregnancy, and multiple or premature birth. Despite the overall increasing trend in breastfeeding initiation, there is still a growing need for breastfeeding promotion and support for young and less educated mothers, mothers who smoke during pregnancy, and also for mothers with premature babies or multiple births. PMID- 24950836 TI - [HPV vaccination coverage in German girls: results of the KiGGS study: first follow-up (KiGGS Wave 1)]. AB - OBJECTIVES: In Germany, vaccination against HPV infection has been recommended for girls aged 12-17 years since 2007. The aim of this paper was to provide an overview of the current status and determinants of HPV vaccination uptake in Germany. METHODS: Analyses included data from 14- to 17-year-old girls (n =1,337) of the German Health Interview and Examination Survey for Children and Adolescents - First Follow-up Survey (KiGGS Wave 1). Standardized telephone interviews included questions for girls on the number of HPV vaccine doses and visits to a gynecologist. Parents were asked about their socioeconomic status (SES) and the girls' participation in the J1 adolescent health check-up. Descriptive analyses of the HPV vaccination status with respect to social, demographic, and health-care utilization factors were performed. Factors associated with vaccination were identified and odds ratios (OR) were estimated by means of logistic regression analysis. RESULTS: The prevalence of vaccination with at least one HPV vaccine dose was 52.6% (95% confidence interval 48.5-56.6). Three-dose HPV vaccination coverage was 39.5% (35.3-43.9). Vaccine uptake increased with age, was higher in girls with middle and low SES compared with high SES, with residence in eastern Germany, in those who had already seen a gynecologist, and who participated in the J1. Multivariable logistic regression revealed a twofold increased chance of being vaccinated for girls with middle SES (OR 1.9) compared with high-SES girls and for those who had yet seen a gynecologist (OR 2.1). CONCLUSIONS: School-based vaccination programs and multi tier vaccination campaigns have led to high vaccination rates in some European and non-European countries. In Germany, however, such high vaccination rates have not been achieved. To fully realize the potential of HPV vaccinations to reduce HPV-related cancer incidence at the population level, vaccination coverage in Germany must be increased. In absence of school-based vaccination programs, medical doctors should use each visit to check and complete the girl's vaccination status. PMID- 24950835 TI - [Health of children and adolescents in single-parent, step-, and nuclear families: results of the KiGGS study: first follow-up (KiGGS Wave 1)]. AB - On the basis of data from KiGGS Wave 1, the following manuscript investigates potential differences in the health status of children and adolescents aged 3-17 years according to the family form they live in: nuclear, single-parent, or stepfamily (n = 10,298). Additionally, we investigate whether differences persist after controlling for age, gender, living area, parental social status, and getting along in the family. Parent-rated health, chronic diseases, emotional or behavior problems, health-related quality of life, and daily consumption of fruits and vegetables were analyzed (prevalence, odds ratios). While the parent rated health was independent of the family form, the prevalence of the other outcomes differed significantly according to the family form. Emotional or behavior problems were measured more often among children and adolescents growing up in single-parent families (OR 1.62; 95% CI 1.17-2.26) or stepfamily households (OR 2.36; 95% CI 1.63-3.41) than among those growing up in nuclear families, after adjusting for age, gender, living area, social status, and getting along in the family. Additionally, children and adolescents from single-parent families had chronic diseases (OR 1.53; 95% CI 1.20-1.96) more often than their counterparts who lived together with both parents. Compared with those growing up in nuclear families, children and adolescents from stepfamilies showed a greater risk of lower health-related quality of life (OR 2.91; 95% CI 1.76-4.80) and of lower daily consumption of fruits and vegetables (OR 1.30; 95% CI 1.01-1.67). The results indicate the importance of the family context for the health of children and adolescents. PMID- 24950837 TI - [Trends in the utilization of outpatient medical care in childhood and adolescence: results of the KiGGS study - a comparison of baseline and first follow up (KiGGS Wave 1)]. AB - This article provides information on trends in the utilization of outpatient medical care in childhood and adolescence in Germany on the basis of data from two waves of the KiGGS study (prevalences and odds ratios). In the period 2009 2012, 91.9% (95% CI 91.1-92.7%) of children and adolescents used outpatient medical services at least once a year. In the 12 months prior to the interview, 67.9% (95% CI 65.9-69.8%) of the 0- to 17-year-olds consulted a pediatrician and 34.1% (95% CI 31.6-36.3%) a general practitioner. Whereas there was no change in the use of either overall outpatient or general practice medical care compared to 2003-2006, a significant increase of 8.7% points in the utilization of pediatricians was found. This could be explained by, among other factors, an expansion of pediatric services (additional vaccinations and health screening examinations) in recent years. It may also be related to a significantly greater participation in the health screening program in early childhood (U3-U9 examinations), which was seen especially when comparing the youngest birth cohorts and in children from families with low social status (from U7 onwards). The increased use of health screening examinations can probably be attributed to the invitation, reminding and reporting procedures that have been introduced in recent years. Whereas at KiGGS baseline urban-rural differences in participation in health screening examinations could be seen, these were no longer apparent in KiGGS Wave 1. Similarly, differences between rural and urban regions in the use of general and pediatric medical services have also diminished. Nevertheless, currently children and young people in rural areas use outpatient general medical care to a greater extent than those in urban areas. PMID- 24950838 TI - [Promotion of next generation primary care physicians: initiatives in the university training of medical students]. AB - BACKGROUND: There is, and will be a serious shortage of young primary care physicians in Germany. Initiatives at medical faculties focusing on primary care may increase the recruitment of young primary care physicians. OBJECTIVES: The present report describes national and international university initiatives, as well as programs for the recruitment of primary care physicians, and reports on their evaluation. METHODS: We searched medical data bases, journals and the internet using corresponding key words in the sense of a pragmatic review article. We also contacted experts who were questioned on this topic. RESULTS: Initiatives for increasing the recruitment of young general practitioners were identified at nine medical faculties in Germany. The underlying hypothesis of the existing programs is that the decision to become a primary care physician depends on the time point, extent and quality of the training at medical school. The decisive limitation of existing programs is that they have been sparsely evaluated. The available results from evaluations consistently indicate quite large positive effects on the recruitment rates; however, the underlying study designs are highly prone to bias. CONCLUSION: The identified initiatives can be grouped into three different models: (1) postgraduate studies, (2) specialized curricula for selected students with high interest in primary care and (3) longitudinal integration of primary care teaching in the obligatory curriculum. Different aspects, such as selection of the curricular model, definition of content, reimbursement of personnel and material expenses as well as evaluation are relevant to the planning and implementation of such initiatives. PMID- 24950840 TI - Systematic review of outcome measures in trials of pediatric anaphylaxis treatment. AB - BACKGROUND: Considerable heterogeneity has been observed in the selection and reporting of disease-specific pediatric outcome measures in randomized controlled trials (RCTs). This makes interpretation of results and comparison across trials challenging. Outcome measures in pediatric anaphylaxis trials have never previously been systematically assessed. This systematic review (SR) identified and assessed outcome measures used in RCTs of anaphylaxis treatment in children. As a secondary objective, this SR assessed the evidence for current treatment modalities for anaphylaxis in the pediatric population. METHODS: We searched MEDLINE, EMBASE, The Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL from 2001 until December 2012. We also searched websites listing ongoing trials. We included randomized and controlled trials of anaphylaxis treatment in patients 0-18 years of age. Two authors independently assessed articles for inclusion. RESULTS: No published studies fulfilled the inclusion criteria. CONCLUSIONS: There is an alarming absence of RCTs evaluating the treatments for anaphylaxis in children. High quality studies are needed and are possible to design, despite the severe and acute nature of this condition. Consensus about the selection and validation of appropriate outcome measures will enhance the quality of research and improve the care of children with anaphylaxis. TRIAL REGISTRATION: CRD42012002685. PMID- 24950841 TI - Efficacy of electroacupuncture for symptoms of menopausal transition: study protocol for a randomized controlled trial. AB - BACKGROUND: Previous studies have shown that acupuncture can alleviate postmenopausal symptoms, such as hot flashes, but few studies have assessed symptoms during the menopausal transition (MT) period. Thus, the effect of acupuncture upon MT symptoms is unclear. We designed a large-scale trial aimed at evaluating the efficacy of electroacupuncture for MT symptoms compared with sham electroacupuncture and at observing the safety of electroacupuncture. METHODS/DESIGN: In this multicenter randomized controlled trial, 360 women will be randomized to either an electroacupuncture group or a sham electroacupuncture group. During the 8-week-long treatment, a menopause rating scale, average 24 hour hot flash score, Menopause-Specific Quality of Life Questionnaire score, and level of female hormones will be observed. Follow-ups at the 20th and 32nd week will be made. DISCUSSION: Though there is no completely inert placebo acupuncture and blinding is difficult in acupuncture trials, the placebo effect of EA can still be partially excluded in this study. For the placebo control, we use non points and a tailor-made sham needle. This needle is different from a retractable needle, which is usually used for sham acupuncture. The needle in this trial is more simply constructed and more acceptable to Chinese people. We expect to evaluate the efficacy of electroacupuncture for MT symptoms and clarify its effect on these symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01849172 (Date of registration: 05/05/2013). PMID- 24950842 TI - Unlocking the stress-allergy puzzle: need for a more comprehensive stress model. PMID- 24950843 TI - Allergic contact dermatitis. PMID- 24950845 TI - What affects quality of life among caregivers of food-allergic children? AB - BACKGROUND: Food allergy is associated with decreased caregiver quality of life (QoL). The influence of accurate reaction perception, allergen, and sociodemographic factors on caregiver QoL is poorly understood. OBJECTIVE: To determine factors influencing caregiver food allergy QoL within an academic center cohort. METHODS: Caregivers of children allergic to milk, egg, peanut, or tree nut evaluated from 2009 to 2011 completed a questionnaire assessing the details of the children's most severe food reaction and caregiver QoL using the Food Allergy Quality of Life-Parental Burden index. Survey responses were verified through chart review. A multiple linear regression model was used to determine factors influencing QoL score. RESULTS: Of 305 caregivers surveyed, 65% had accurate reaction perception. This was higher in caregivers of children with provider-confirmed anaphylaxis (P = .008). Milk or egg allergy was associated with higher total and independent domain-specific QoL scores compared with peanut or tree nut allergy, and an income lower than $50,000 was associated with higher total QoL scores and higher scores for 5 of 17 individual domains. In a linear regression model, age at most severe reaction (-0.02, P = .01), peanut or tree nut allergy (-0.81, P = .004) and milk allergy (-1.12, P = .001) vs egg allergy, income higher than $50,000 (-0.53, P = .04), multiple food allergies (0.45, P = .007), accurate reaction perception (-0.37, P = .04), eczema (+0.49, P = .004), and caregiver report that the child had anaphylaxis (+0.48, P = .02) were significantly associated with QoL score. CONCLUSION: Food allergen, having multiple food allergies, age at reaction, income, eczema, parent-reported anaphylaxis, and reaction perception can significantly affect caregiver food allergy QoL. Milk or egg allergy was associated with worse total and domain specific caregiver QoL scores vs peanut or tree nut allergy, representing a high risk subgroup. PMID- 24950844 TI - Serum specific IgG response to toluene diisocyanate-tissue transglutaminase conjugate in toluene diisocyanate-induced occupational asthmatics. AB - BACKGROUND: Tissue transglutaminase (tTG) is a post-translational modifying enzyme located in airway epithelial cells. A potential contribution of serum specific IgG (sIgG) to tTG in airway inflammation of toluene diisocyanate (TDI) induced occupational asthma (OA) has been suggested. OBJECTIVE: To prepare a TDI tTG conjugate and detect serum specific antibodies in sera of patients with TDI OA to understand this mechanism. METHODS: Ninety-nine patients with TDI-OA, 76 asymptomatic exposed controls, 208 patients with non-OA, and 74 unexposed controls were enrolled for this study. The TDI-tTG conjugate was prepared and confirmed by a native gel. Serum sIgG and/or sIgE antibodies to tTG, TDI-tTG, TDI conjugated to human serum albumin, cytokeratin 19, and serum cytokine levels, such as interleukin-8, transforming growth factor-beta1, and tissue inhibitor of metalloproteinase-1, were measured by enzyme-linked immunosorbent assay. The level of interleukin-8 produced from airway epithelial cells (A549) treated with tTG was evaluated to investigate the inflammatory effect of tTG and TDI-tTG. RESULTS: In the TDI-OA group, the prevalence of serum sIgG to TDI-tTG (17.2%) was higher than that of sIgG to tTG (11.1%), which were significantly higher than those of the 3 control groups (P < .05 for all groups). TDI-exposed subjects with high levels of serum sIgG to TDI-tTG had a high prevalence of sIgG to cytokeratin 19 and higher serum levels of transforming growth factor-beta1 and tissue inhibitor of metalloproteinase-1. The tTG and TDI-tTG dose-dependently increased interleukin-8 production from A549 cells. CONCLUSION: These findings suggest that TDI exposure in the workplace binds to tTG to form a conjugate that can induce serum sIgG antibody production, airway inflammation, and airway remodeling in patients with TDI-OA. PMID- 24950847 TI - Omalizumab effectively prevents recurrent refractory anaphylaxis in a patient with monoclonal mast cell activation syndrome. PMID- 24950846 TI - Maternal consumption of dairy products, calcium, and vitamin D during pregnancy and infantile allergic disorders. AB - BACKGROUND: Epidemiologic evidence of the association between maternal intake of dairy foods, calcium, and vitamin D during pregnancy and childhood allergic disorders is inconclusive. OBJECTIVE: To examine the association between maternal intake of dairy foods, calcium, and vitamin D during pregnancy and childhood allergic disorders in Japanese children aged 23 to 29 months. METHODS: Study participants were 1,354 mother-child pairs. Maternal intake during pregnancy was assessed with a validated diet history questionnaire administered between April 2007 and March 2008. Wheeze and eczema, defined according to criteria of the International Study of Asthma and Allergies in Childhood, and physician-diagnosed asthma and atopic eczema were assessed via a questionnaire completed by mothers. RESULTS: Higher maternal intake of total dairy products during pregnancy was significantly associated with a reduced risk of infantile eczema (adjusted odds ratio [OR] between extreme quartiles, 0.64; 95% confidence interval [CI], 0.42 0.98). Higher maternal intake of cheese during pregnancy was significantly related to a reduced risk of physician-diagnosed infantile asthma (adjusted OR between extreme quartiles, 0.44; 95% CI, 0.18-0.97). Maternal intake levels of yogurt and calcium during pregnancy were significantly inversely associated with physician-diagnosed infantile atopic eczema (adjusted ORs between extreme quartiles, 0.49 and 0.34; 95% CI, 0.20-1.16 and 0.12-0.84; P for trend = .01 and .03, respectively). Maternal intake of vitamin D during pregnancy was significantly positively associated with infantile eczema (adjusted OR between extreme quartiles, 1.63; 95% CI, 1.07-2.51). CONCLUSION: Higher maternal intake of total dairy products, cheese, yogurt, and calcium during pregnancy may reduce the risk of infantile eczema, physician-diagnosed asthma, physician-diagnosed atopic eczema, and physician-diagnosed atopic eczema, respectively. Higher maternal intake of vitamin D during pregnancy may increase the risk of infantile eczema. PMID- 24950848 TI - A case of transient acquired C1 inhibitor deficiency. PMID- 24950849 TI - Fractional exhaled nitric oxide of at least 100 ppb and implications for future asthma research. PMID- 24950850 TI - Contact hypersensitivity to triclosan. PMID- 24950851 TI - The dry needle technique. PMID- 24950852 TI - Allergen of the month--meadow fescue. PMID- 24950853 TI - Canine rangeliosis due to Rangelia vitalii: from first report in Brazil in 1910 to current day - a review. AB - Canine rangeliosis (popular names: "nambi-uvu", i.e. ''bleeding ears''; "peste de sangue", i.e. ''bleeding plague''; and "febre amarela dos caes", i.e. ''yellow fever of dogs'') is a tick-borne haemolytic and haemorrhagic disease caused by the protozoan parasite Rangelia vitalii which infects erythrocytes, leukocytes, and endothelial cells of blood capillaries. Rangelia vitalii was first reported as a novel piroplasm of dogs in 1910 in Brazil, a discovery that was met with skepticism at that time. Canine rangeliosis has been diagnosed in domestic dogs not only in Brazil but also in other South American countries (Argentina and Uruguay). Rangelia vitalii infection has also been found incidentally in Brazil in wild dogs (Cerdocyon thous, the crab-eating fox). Despite the fact that researchers in the early 1900s suggested that R. vitalii was a hitherto unidentified piroplasm that would be transmitted by the tick Amblyomma aureolatum, it was not until 2012 that these hypotheses were actually confirmed by PCR and transmission studies. Molecular studies have shown that R. vitalii is related to the Babesia sensu strictu clade, but genetically different from other morphologically similar species of Babesia that infect dogs. Another difference between Babesia spp. and R. vitalii is the ability of R. vitalii to invade endothelial cells, erythrocytes, and leukocytes. Experimental infection in dogs has successfully reproduced the clinical picture and pathology of the natural disease. In this article, epidemiology, clinical signs, laboratory findings, pathogenetic mechanisms including oxidative stress and immune response, necropsy findings, microscopic lesions, diagnosis, and treatment of canine rangeliosis are reviewed. What is currently known about this protozoal disease since its first report over a century ago is presented herein. PMID- 24950854 TI - Discovery of Rickettsia species in Dermacentor niveus Neumann ticks by investigating the diversity of bacterial communities. AB - Ticks (Dermacentor niveus Neumann) were collected from Tacheng, Xinjiang Uygur Autonomous Region, and their bacterial diversity was investigated using the 16S RNA gene library method from one pooled sample. A total of 452 clones was successfully sequenced and assigned to 4 phyla. The dominant phylum was the Proteobacteria, accounting for 62.8% of all the clones of the 16S rRNA gene at the confidence level 80%. The other sequences were assigned to the phyla Bacteroidetes, Firmicutes, Actinobacteria and accounted for 13.5%, 12.4%, and 11.3%, respectively. These results provide an insight into the bacterial diversity associated with D. niveus ticks in the natural environment of Tacheng. They indicate the occurrence of Rickettsia raoultii and Rickettsia slovaca in D. niveus ticks in this area, and as a consequence, cases of TIBOLA/DEBONEL may occur (tick-borne lymphadenopathy/Dermacentor-borne necrosis erythema and lymphadenopathy). PMID- 24950855 TI - Transcriptomic analysis of candidate osmoregulatory genes in the eastern oyster Crassostrea virginica. AB - BACKGROUND: The eastern oyster, Crassostrea virginica, is a euryhaline species that can thrive across a wide range of salinities (5-35). As with all estuarine species, individual oysters must be able to regulate their osmotic balance in response to constant temporal variation in salinity. At the population level, recurrent viability selection may be an additional mechanism shaping adaptive osmoregulatory phenotypes at the margins of oyster salinity tolerance. To identify candidate genes for osmoregulation, we sequenced, assembled, and annotated the transcriptome of wild juvenile eastern oysters from 'high' and 'low' salinity regimes. Annotations and candidates were mostly based on the Pacific oyster (Crassostrea gigas) genome sequence so osmoregulatory relevance in C. virginica was explored by testing functional enrichment of genes showing spatially discrete patterns of expression and by quantifying coding sequence divergence. RESULTS: The assembly of sequence reads and permissive clustering of potentially oversplit alleles resulted in 98,729 reftigs (contigs and singletons). Of these, 50,736 were annotated with 9,307 belonging to a set of candidate osmoregulatory genes identified from the C. gigas genome. A total of 218,777 SNPs (0.0185 SNPs/bp) were identified in annotated reftigs of C. virginica. Amino acid divergence between translations of C. virginica annotated reftigs and C. gigas coding sequence averaged 23.2 % with an average dN/dS ratio of 0.074, suggesting purifying selection on protein sequences. The high and low salinity source oysters each expressed a subset of genes unique to that group, and the functions for these annotated genes were consistent with known molecular mechanisms for osmotic regulation in molluscs. CONCLUSIONS: Most of the osmoregulatory gene candidates experimentally identified in C. gigas are present in this C. virginica transcriptome. In general these congeners show coding sequence divergence too high to make the C. gigas genome a useful reference for C. virginica bioinformatics. However, strong purifying selection is characteristic of the osmoregulatory candidates so functional annotations are likely to correspond. An initial examination of C. virginica presence/absence expression patterns across the salinity gradient in a single estuary suggests that many of these candidates have expression patterns that co-vary with salinity, consistent with osmoregulatory function in C. virginica. PMID- 24950856 TI - Right atrial pressure alterations during echocardiography-guided-catheterization predict tricuspid valvular impairment: a novel method for the creation of a rabbit model of Staphylococcus aureus endocarditis. AB - BACKGROUND: We previously reported the use of a catheter system to damage the tricuspid valve and create infectious endocarditis (IE) in an animal model. The current study aims to create a faint IE model suitable for antibiotic prophylaxis using a low bacterial inoculum. We also aim to explore a way to quantitatively assess valvular impairment and to predict the success of the IE models during catheterization. METHODS: Ninety rabbits were assigned to two groups according to the density of bacteria inoculated (1 * 10(5) CFU for Group A and 1 * 10(4) CFU for Group B). A catheter system consisting of a polyethylene catheter and a guide wire were used to damage the valve. The catheter system was passed through the rabbits' tricuspid valves under echocardiographic guidance. A pressure transducer was used to assess right atrial pressure (P(RA)) before and just after valvular damage to calculate the pressure alterations (DeltaP(RA)). The animals in group A and B were divided into 3 subgroups according to the DeltaP(RA) (0-5 mmHg for Groups A1 and B1; 5-10 mmHg for Groups A2 and B2; 10-15 mmHg for Groups A3 and B3). Staphylococcus aureus (ATCC 29213) inoculation was performed 24 hr after cardiac catheterization. RESULTS: Faint IE was confirmed in 20%, 93.3%, 26.7%, 6.7%, 20%, and 33.3% of the rabbits in Groups A1, A2, A3, B1, B2, and B3, respectively. There was no difference in the LV/RV ratio and VTR of the No-IE, faint-IE, and severe IE animals. Faint IE rabbits had a larger DeltaPRA than No IE rabbits (7.81 +/- 1.21 vs. 2.48 +/- 1.0, P < 0.01, for Group A; 7.60 +/- 1.32 vs. 2.98 +/- 1.08, P < 0.01, for Group B). The DeltaPRA of severe IE and faint IE rabbits was significantly different (13.11 +/- 1.31 vs. 7.81 +/- 1.21, P < 0.01, for Group A; 12.73 +/- 1.44 vs.7.60 +/- 1.32, P < 0.01, for Group B). CONCLUSION: DeltaP(RA) could be used to assess valvular impairment. Controlling the value of DeltaP(RA) during catheterization and inoculating of an appropriate dose of bacteria was associated with a successful IE model. PMID- 24950857 TI - Clinical implication of SGLT2 inhibitors in type 2 diabetes. AB - Treatment of type 2 diabetes mellitus (T2DM) continues to present challenges, with many patients failing to achieve glycemic targets. Despite the availability of many oral and injectable anti-diabetic agents, therapeutic efficacy is often offset by undesirable side effects such as hypoglycemia, weight gain and cardiovascular complications. Therefore, the search for new therapeutic agents with an improved benefit-risk profile continues. Recent research has focused on the kidney as a potential therapeutic target, especially because maximal renal glucose reabsorption is increased in T2DM. Under normal physiological conditions, nearly all filtered glucose is reabsorbed in the proximal tubule of the nephron via the sodium/glucose co-transporter 2 (SGLT2). SGLT2-inhibitors are a new class of oral anti-diabetes, which reduce hyperglycemia by increasing urinary glucose excretion independently of insulin secretion or action. Canagliflozin and dapagliflozin in US market, and ipragliflozin and luseogliflozin in Japan market are now available for glycemic control in type 2 diabetics. There are several phase III clinical ongoing trials involving this new class of medications. This review examines some of the key efficacy and safety data from clinical trials of the SGLT2 inhibitors approved, and their future perspectives in the treatment of T2DM. PMID- 24950858 TI - Stroke incidence and risk factors in Havana and Matanzas, Cuba. AB - INTRODUCTION: Cerebrovascular disease is the third-leading cause of death and the second-leading cause of disability and dementia. OBJECTIVE: Determine stroke incidence and risk factors in a population of adults aged 65 and over in Cuba (Havana and Matanzas). MATERIAL AND METHODS: This prospective longitudinal study, completed between April 2008 and Abril 2011, re-evaluated 2916 elderly adults with an average follow-up time of 4 years. Cases included 2316 living subjects and 600 verbal autopsies. Study variables were age, sex, educational level, self reported health, and description of chronic diseases and substance abuse. Laboratory tests included genotyping APOE. Stroke was diagnosed based on the World Health Organization definition. We calculated the global incidence rate for stroke, broken down by sex, age group, and risk factors for incident stroke. RESULTS: Stroke incidence was 786.2 in 100000 persons/year (95% CI: 672.3-906.4). History of alcohol consumption (HR: 3.5; 95% CI: 3.3-3.7), dementia (HR: 3.0; 95% CI, 1.6-5.5) and male sex (HR: 1.8; 95% CI, 1.2-2.8) were shown to be risk factors for incident stroke. CONCLUSIONS: Stroke incidence was similar to rates reported in developed countries and lower than that in low- to middle-income countries. Given that diabetes mellitus, heart disease, arterial hypertension, smoking, APOE4, etc. are associated with higher mortality rates, they will require separate analysis in a study of stroke risk factors. PMID- 24950860 TI - [Stomatology and oral pathology histo-seminar for pathologists to avoid pitfalls!]. PMID- 24950859 TI - Heart rate changes in partial seizures: analysis of influencing factors among refractory patients. AB - BACKGROUND: We analyzed the frequency of heart rate (HR) changes related to seizures, and we sought to identify the influencing factors of these changes during partial seizures, to summarize the regularity of the HR changes and gain some insight into the mechanisms involved in the neuronal regulation of cardiovascular function. To date, detailed information on influencing factors of HR changes related to seizures by multiple linear regression analysis remains scarce. METHODS: Using video-electroencephalograph (EEG)-electrocardiograph (ECG) recordings, we retrospectively assessed the changes in the HR of 81 patients during a total of 181 seizures, including 27 simple partial seizures (SPS), 110 complex partial seizures (CPS) and 44 complex partial seizures secondarily generalized (CPS-G). The epileptogenic focus and the seizure type, age, gender, and sleep/wakefulness state of each patient were evaluated during and after the seizure onset. The HR changes were evaluated in the stage of epilepsy as time varies. RESULTS: Of the 181 seizures from 81 patients with ictal ECGs, 152 seizures (83.98%) from 74 patients were accompanied by ictal tachycardia (IT). And only 1 patient was accompanied by ictal bradycardia (IB). A patient has both IT and IB. We observed that HR difference was independently correlated with side, type and sleep/wakefulness state. In this analysis, the HR changes were related to the side, gender, seizure type, and sleep/wakefulness state. Right focus, male, sleep, and CPS-G showed more significant increases than that were observed in left, female, wakefulness, SPS and CPS. HR increases rapidly within 10 seconds before seizure onset and ictus, and typically slows to normal with seizure offset. CONCLUSION: CPS-G, sleep and right focus led to higher ictal HR. The HR in the stage of epilepsy has regularly been observed to change to become time varying. The risk factors of ictal HR need to be controlled along with sleep, CPS G and right focus. Our study first explains that the HR in seizures has a regular evolution varying with time. Our study might help to further clarify the basic mechanisms of interactions between heart and brain, making seizure detection and closed-loop systems a possible therapeutic alternative in refractory patients. PMID- 24950862 TI - [Oral and stomatological pathology. Introduction]. PMID- 24950861 TI - [What place and what future for the pathology of infectious and tropical diseases in France?]. AB - The management of tissues and cellular samples by the pathologists in the infectious and tropical diseases pathology field in 2014 needs a strong knowledge of both morphological and molecular domains which includes the good control: (i) of the taxonomy of infectious and tropical diseases pathology leading to the pathogens identification and (ii) of the ancillary methods which can be used in fixed samples in order to detect or better identify these pathogens. There is a recent paradox in France concerning the frequency of infectious diseases to be diagnosed in pathology laboratories and the progressive loss of pathologist's expertise in this domain. Different reasons could explain this statement including the omnipresence of the tumour lesions to be managed in a pathology laboratory as well as the recent constraints associated with the different biomarkers that are mandatory to be detected by immunohistochemistry and/or by molecular biology. Even if the microbiologists play a pivotal role for identifying the different pathogens as well as for the assessment of their sensitivity to the anti-microbial drugs, a large number of infectious diseases can be diagnosed only on fixed tissue and/or cells by the pathologists. The purpose of this review is to describe the current and future issues of infectious and tropical diseases diagnoses in pathology laboratories, in particular in France. PMID- 24950863 TI - [Oral and stomatological pathology. Pre-test]. PMID- 24950865 TI - [Oral and stomatological pathology. Case 1: congenital dentigerous odontogenic cyst with inflammatory reaction]. PMID- 24950866 TI - [Oral and stomatological pathology. Case 2: unicystic ameloblastoma with a plexiform tumoral contingent]. PMID- 24950867 TI - [Oral and stomatological pathology. Case 3: odontogenic keratocyst]. PMID- 24950868 TI - [Oral and stomatological pathology. Case 4: oral intra-epithelial neoplasia (OIN)]. PMID- 24950869 TI - [Oral and stomatologycial pathology. Case 5: verrucous keratosis, smokeless tobacco lesion]. PMID- 24950871 TI - [Oral and stomatological pathology. Case 7. Ossifying fibroma of the mandibule]. PMID- 24950870 TI - [Oral and stomatological pathology. Case 6: ameloblastic fibroma]. PMID- 24950872 TI - [Malignant meningioma with adenocarcinoma-like metaplasia: a rare entity to be not misdiagnosed]. AB - We report on a 51-year-old woman who presented with a cervical spinal cord tumor clinically suspected to be a metastasis. Histological examination revealed an anaplastic meningioma containing epithelial nests arranged in a gland-like pattern suggestive of adenocarcinoma. This component strongly expressed cytokeratins whereas the meningothelial component was vimentin--epithelial membrane antigen--and progesterone receptor-immunoreactive, suggesting either anaplastic meningioma with adenocarcinoma-like metaplasia, or adenocarcinoma metastasis in a meningioma, but the search for a primitive neoplasia including thoracic-abdominal-pelvic computed tomography and mammography was negative. Anaplastic meningiomas with adenocarcinoma-like metaplasia are uncommon lesions, 4 cases having been reported in the literature so far. Their immunohistochemical and chromosomal characteristics are similar to those observed in secretory meningiomas. When available, fluorescence in situ hybridization detects the same chromosomal alterations in the two components, confirming a common clonal origin. This observation demonstrates the necessity to perform the correct diagnosis of malignant meningioma with adenocarcinomatous metaplasia, whose prognosis and treatment radically differ from those of metastatic adenocarcinoma located in a meningioma. PMID- 24950874 TI - [Prostatic stromal tumors of uncertain malignant potential (STUMP): a case report]. AB - We report the case of a patient affected by a voluminous prostatic tumor for which the histological analysis conclude in a stromal tumor of uncertain malignant potential. This type of tumor is rare, but requires to be individualized to differentiate it from a benign prostatic hyperplasia or a sarcoma of the prostate. The therapeutic care must be made keeping in mind the risk of degeneration towards a malignant shape. PMID- 24950875 TI - [A granulomatous colitis?]. PMID- 24950873 TI - [A letal case of gastro-intestinal basidiobolomycosis]. AB - We report here the case of a 55-year-old man from Mali, who presented with abdominal pain. Radiological exploration revealed an ileo-colonic mass surrounding the appendix. A biopsy was taken and on histology, transmural granulomatous inflammation of numerous eosinophils, lymphocytes, plasmocytes and giant cells was seen. Tuberculosis was suspected clinically and an antibiotic treatment was initiated. Two months later, the patient died of septic complications. Basidiobolus ranarum was identified by PCR. Pathogens were retrospectively highlighted on biopsies. These elements were between 10 and 15 MUm in diameter, occasionally pseudo-septated, and were surrounded by a thick eosinophilic cuff. The thick eosinophilic cuff was identified as the Splendore Hoeppli phenomenon. Basidiobolomycosis is a well-known infection in the tropical areas. Basidiobolus sp., fungus of the order Entomophtorales are a known cause of chronic subcutaneous mycosis. Gastro-intestinal basidiobolomycosis is rare and presents considerable diagnostic difficulty. This infection needs to be diagnosed because surgical resection and prolonged antifungal treatment are curable in most cases. PMID- 24950876 TI - [A rare form of primary cutaneous lymphoma]. PMID- 24950877 TI - [Unusual tumor of the inferior vena cava]. PMID- 24950878 TI - Clinical mentorship to improve pediatric quality of care at the health centers in rural Rwanda: a qualitative study of perceptions and acceptability of health care workers. AB - BACKGROUND: Despite evidence supporting Integrated Management of Childhood Illness (IMCI) as a strategy to improve pediatric care in countries with high child mortality, its implementation faces challenges related to lack of or poor post-didactic training supervision and gaps in necessary supporting systems. These constraints lead to health care workers' inability to consistently translate IMCI knowledge and skills into practice. A program providing mentoring and enhanced supervision at health centers (MESH), focusing on clinical and systems improvement was implemented in rural Rwanda as a strategy to address these issues, with the ultimate goal of improving the quality of pediatric care at rural health centers. We explored perceptions of MESH from the perspective of IMCI clinical mentors, mentees, and district clinical leadership. METHODS: We conducted focus group discussions with 40 health care workers from 21 MESH supported health centers. Two FGDs in each district were carried out, including one for nurses and one for director of health centers. District medical directors and clinical mentors had individual in-depth interviews. We performed a hermeneutic analysis using Atlas.ti v5.2. RESULTS: Study participants highlighted program components in five key areas that contributed to acceptability and impact, including: 1) Interactive, collaborative capacity-building, 2) active listening and relationships, 3) supporting not policing, 4) systems improvement, and 5) real-time feedback. Staff turn-over, stock-outs, and other facility/systems gaps were identified as barriers to MESH and IMCI implementation. CONCLUSION: Health care workers reported high acceptance and positive perceptions of the MESH model as an effective strategy to build their capacity, bridge the gap between knowledge and practice in pediatric care, and address facility and systems issues. This approach also improved relationships between the district supervisory team and health center-based care providers. Despite some challenges, many perceived a strong benefit on clinical performance and outcomes. This study can inform program implementers and policy makers of key components needed for developing similar health facility-based mentorship interventions and potential barriers and resistance which can be proactively addressed to ensure success. PMID- 24950879 TI - Importance of MRI in the diagnosis of vertebral involvement in generalized cystic lymphangiomatosis. AB - A 9-year-old boy presented with the sudden onset of pleuritic chest pain and on CT was found to have a large pleural effusion, mediastinal fluid, splenic lesions and multiple apparently sclerotic vertebral bodies. Subsequent MRI showed that those vertebral bodies that appeared sclerotic were in fact normal, and the vertebral bodies initially interpreted as normal had an abnormal T1 and T2 hyperintense signal on MRI and were relatively lucent on CT. MRI also demonstrated abnormal heterogeneous T2 hyperintense paraspinal tissue and several multicystic soft tissue masses. Biopsy of two adjacent vertebral bodies, one relatively sclerotic and one lucent, demonstrated findings of bony remodeling without a specific diagnosis. Biopsy of an infiltrative mediastinal mass confirmed the diagnosis of generalized cystic lymphangiomatosis. MRI should be included in the assessment of vertebral involvement in this condition because CT and biopsy findings may be nonspecific. PMID- 24950880 TI - A novel esterase from Paenibacillus sp. PBS-2 is a new member of the beta lactamase belonging to the family VIII lipases/esterases. AB - Screening of a gene library from Paenibacillus sp. PBS-2 generated in Escherichia coli led to the identification of a clone with lipolytic activity. Sequence analysis showed an open reading frame encoding a polypeptide of 378 amino acid residues with a predicted molecular mass of 42 kDa. The esterase displayed 69% and 42% identity with the putative beta-lactamases from Paenibacillus sp. JDR-2 and Clostridium sp. BNL1100, respectively. The esterase contained a Serx- x-Lys motif that is conserved among all beta-lactamases found to date. The protein PBS 2 was produced in both soluble and insoluble forms when E. coli cells harboring the gene were cultured at 18 degrees C. The enzyme is a serine protein and was active against p-nitrophenyl esters of C2, C4, C8, and C10. The optimum pH and temperature for enzyme activity were pH 9.0 and 30 degrees C, respectively. Relative activity of 55% remained at up to 5 degrees C with an activation energy of 5.84 kcal/mol, which indicates that the enzyme is cold-adapted. Enzyme activity was inhibited by Cd(2+), Cu(2+), and Hg(2+) ions. As expected for a serine esterase, activity was inhibited by phenylmethylsulfonyl fluoride. The enzyme was remarkably active and stable in the presence of commercial detergents and organic solvents. This cold-adapted esterase has potential as a biocatalyst and detergent additive for use at low temperatures. PMID- 24950881 TI - Effect of antibiotic down-regulatory gene wblA ortholog on antifungal polyene production in rare actinomycetes Pseudonocardia autotrophica. AB - The rare actinomycete Pseudonocardia autotrophica was previously shown to produce a solubilityimproved toxicity-reduced novel polyene compound named Nystatin-like Pseudonocardia Polyene (NPP). The low productivity of NPP in P. autotrophica implies that its biosynthetic pathway is tightly regulated. In this study, wblApau was isolated and identified as a novel negative regulatory gene for NPP production in P. autotrophica, which showed approximately 49% amino acid identity with a global antibiotic down-regulatory gene, wblA, identified from various Streptomycetes species. Although no significant difference in NPP production was observed between P. autotrophica harboring empty vector and the S. coelicolor wblA under its native promoter, approximately 12% less NPP was produced in P. autotrophica expressing the wblA gene under the strong constitutive ermE(*) promoter. Furthermore, disruption of the wblApau gene from P. autotrophica resulted in an approximately 80% increase in NPP productivity. These results strongly suggest that identification and inactivation of the global antibiotic down-regulatory gene wblA ortholog are a critical strategy for improving secondary metabolite overproduction in not only Streptomyces but also non Streptomyces rare actinomycete species. PMID- 24950882 TI - Spatial abundance and diversity of bacterioplankton in a typical stream-forming ecosystem, Huangqian Reservoir, China. AB - The specific freshwater environment of reservoirs formed by streams has not been well studied. In this paper, the bacterioplankton community in such a reservoir, the Huangqian Reservoir in eastern China, was described using culture-independent molecular methods. We found that the most dominant bacterioplankton were affiliated with Cyanobacteria, followed by Betaproteobacteria, Bacteroidetes, Gammaproteobacteria, and Actinobacteria. Both bacterial abundance and diversity increased along the direction of water flow, and the 16S rRNA gene copy number in the water outlet was nearly an order of magnitude higher than that in the water inlet. Pearson correlation analyses indicated that nitrate had a significantly negative correlation with the bacterial abundance (p < 0.05) and that ammonium was positively correlated with bacterial abundance (p < 0.05). Interestingly, owing to a remarkably negative correlation (p < 0.01), the ratio of nitrate and ammonium might serve as a good pre dictor of the relative abundance of bacterioplankton. According to redundancy analysis, nitrate and dissolved oxygen were the major factors influencing the bacterial communities. In addition, we attempted to determine the reasons why such a reservoir could maintain good ecological balance for a period of decades, and we found that the environmental factors and bacterial communities both played critical roles. This research will benefit our understanding of bacterial communities and their surrounding environments in freshwater ecosystems. PMID- 24950883 TI - Development of a single nucleotide polymorphism DNA microarray for the detection and genotyping of the SARS coronavirus. AB - Severe acute respiratory syndrome (SARS), a disease that spread widely in the world during late 2002 to 2004, severely threatened public health. Although there have been no reported infections since 2004, the extremely pathogenic SARS coronavirus (SARS-CoV), as the causative agent of SARS, has recently been identified in animals, showing the potential for the re-emergence of this disease. Previous studies showed that 27 single nucleotide polymorphism (SNP) mutations among the spike (S) gene of this virus are correlated closely with the SARS pathogenicity and epidemicity. We have developed a SNP DNA microarray in order to detect and genotype these SNPs, and to obtain related information on the pathogenicity and epidemicity of a given strain. The microarray was hybridized with PCR products amplified from cDNAs obtained from different SARS-CoV strains. We were able to detect 24 SNPs and determine the type of a given strain. The hybridization profile showed that 19 samples were detected and genotyped correctly by using our microarray, with 100% accuracy. Our microarray provides a novel method for the detection and epidemiological surveillance of SARS-CoV. PMID- 24950884 TI - Institute of medicine recommendations for improving the quality of cancer care: what do they mean for the general internist? AB - In order to evaluate and address the deficiencies in the U.S. cancer care system, particularly affecting the growing elderly population, the Institute of Medicine (IOM) convened a panel representing oncology providers, surgeons, primary care providers, researchers, policy makers and patients. The Committee concluded that cancer care is on the brink of crisis and issued recommendations targeting all stakeholders involved in cancer care. General internists play a critical role in the care of cancer patients, from the time of diagnosis, through treatment, survivorship and end of life care. We review the IOM recommendations, highlight those that are particularly relevant to the general internist, and outline clinical, research and educational opportunities where general internists should take an expanded role. PMID- 24950886 TI - Phylogenetic evidence of a new canine distemper virus lineage among domestic dogs in Colombia, South America. AB - Canine distemper virus (CDV) is a highly contagious viral disease of carnivores affecting both wild and domestic populations. The hemagglutinin gene, encoding for the attachment protein that determines viral tropism, shows high heterogeneity among strains, allowing for the distinction of ten different lineages distributed worldwide according to a geographic pattern. We obtained the sequences of the full-length H gene of 15 wild-type CDV strains circulating in domestic dog populations from the Aburra Valley, Colombia. A phylogenetic analysis of H gene nucleotide sequences from Colombian CDV viruses along with field isolates from different geographic regions and vaccine strains was performed. Colombian wild-type viruses formed a distinct monophyletic cluster clearly separated from the previously identified wild-type and vaccine lineages, suggesting that a novel genetic variant, quite different from vaccines and other lineages, is circulating among dog populations in the Aburra Valley. We propose naming this new lineage as "South America 3". This information indicates that there are at least three different CDV lineages circulating in domestic and wild carnivore populations in South America. The first one, renamed Europe/South America 1, circulates in Brazil and Uruguay; the second, South America 2, appears to be restricted to Argentina; and the third, South America 3, which comprises all the strains characterized in this study, may also be circulating in other northern countries of South America. PMID- 24950885 TI - [French guidelines for diagnosis and treatment of cluster headache (French Headache Society)]. PMID- 24950887 TI - The spinal posture of computing adolescents in a real-life setting. AB - BACKGROUND: It is assumed that good postural alignment is associated with the less likelihood of musculoskeletal pain symptoms. Encouraging good sitting postures have not reported consequent musculoskeletal pain reduction in school based populations, possibly due to a lack of clear understanding of good posture. Therefore this paper describes the variability of postural angles in a cohort of asymptomatic high-school students whilst working on desk-top computers in a school computer classroom and to report on the relationship between the postural angles and age, gender, height, weight and computer use. METHODS: The baseline data from a 12 month longitudinal study is reported. The study was conducted in South African school computer classrooms. 194 Grade 10 high-school students, from randomly selected high-schools, aged 15-17 years, enrolled in Computer Application Technology for the first time, asymptomatic during the preceding month, and from whom written informed consent were obtained, participated in the study. The 3D Posture Analysis Tool captured five postural angles (head flexion, neck flexion, cranio-cervical angle, trunk flexion and head lateral bend) while the students were working on desk-top computers. Height, weight and computer use were also measured. Individual and combinations of postural angles were analysed. RESULTS: 944 Students were screened for eligibility of which the data of 194 students are reported. Trunk flexion was the most variable angle. Increased neck flexion and the combination of increased head flexion, neck flexion and trunk flexion were significantly associated with increased weight and BMI (p = 0.0001). CONCLUSIONS: High-school students sit with greater ranges of trunk flexion (leaning forward or reclining) when using the classroom computer. Increased weight is significantly associated with increased sagittal plane postural angles. PMID- 24950888 TI - Factors associated with lack of effective contraception among obese women in the United States. AB - OBJECTIVE: To identify factors associated with contraceptive nonuse and use of less effective methods among obese women in the US. STUDY DESIGN: We analyzed data from sexually active obese women (body mass index >30 kg/m2) age 20-44 using the 2006-2010 National Survey of Family Growth. We conducted multinomial logistic regression to assess associations between current contraceptive use and demographic, reproductive and health services factors. Specifically, we compared contraceptive nonusers, behavioral method users (withdrawal and fertility awareness) and barrier method users (condoms) to prescription method users (pill, patch, ring, injection, implant and intrauterine device). RESULTS: Of 1345 obese respondents, 21.5% used no method, 10.3% behavioral methods, 20.8% barrier methods and 47.4% prescription methods. Only 42.4% of respondents overall and 20.4% of nonprescription method users reported discussing contraception with a provider in the past year. Similar to findings in the general population, behavioral method users were more likely to have previously discontinued a contraceptive method due to dissatisfaction [adjusted RR (aRR), 1.93; 95% confidence interval (CI), 1.09-3.44], and nonusers were more likely to perceive difficulty becoming pregnant (aRR, 3.86; 95% CI, 2.04-7.29), compared to prescription method users. Respondents using nonprescription methods were significantly less likely to have discussed contraception with a healthcare provider (nonusers: aRR, 0.16; 95% CI, 0.10-0.27; behavioral methods: aRR, 0.13; 95% CI, 0.06-0.25, barrier methods: aRR, 0.15; 95% CI, 0.09-0.25) than prescription method users. CONCLUSIONS: Obese women who discuss contraception with a provider are more likely to use effective contraception and may be less likely to experience unintended pregnancy; however, over half report no recent discussion of contraception with a provider. IMPLICATIONS: Efforts are needed to increase contraceptive counseling for obese women, who face increased risks of morbidity from unintended pregnancy. PMID- 24950889 TI - Evaluation of physiological FDG uptake in the skeleton in adults: is it uniformly distributed? AB - AIM: The aim of this study was to study whether FDG was uniformly distributed throughout the skeleton and whether age and gender affected this biodistribution. MATERIAL AND METHODS: A total of 158 patients were included in this retrospective study. None of the patients had received prior treatment that had affected the bone marrow and patients with bone metastases, trauma, benign and/or malignant hematologic disorders were excluded from the study. The SUVmax from the 24 different locations in the skeleton was obtained and all the values were compared with each other. RESULTS: FDG uptake in the skeleton was not uniform in both sexes. While the highest FDG uptake was seen in the L3 vertebra, the lowest glucose metabolism was observed in the diaphysis of the femur. Concerning the vertebral column, FDG uptakes were also non-uniform and the SUVmax gradually increased from the cervix to the lumbar spine. The mean skeletal SUVmax was decreased in accordance with age in both genders. CONCLUSION: FDG was not uniformly distributed throughout the skeleton in both sexes. It had a tendency to increase from the appendicular to axial skeleton and from cervical to lumbar spine in the vertebral column that may be related with the normal distribution of the red bone marrow. Additionally, the glycolytic metabolism of the whole skeleton was gradually decreased in accordance with the age in both sexes. PMID- 24950891 TI - [PET-CT with 18F-FDG in the diagnosis of Takayasu's arteritis and the assessment of response to therapy]. AB - We present a patient without specific symptoms of vasculitis, with normal acute phase reactants, but with the pathological diagnosis of Takayasu' arteritis that was referred for a PET-CT with (18)F-FDG. Scan findings showed inflammatory activity in the vessel walls of the aorta and after the appropriate treatment, a second scan with (18)F-FDG, correctly assessed the therapeutic response. We discuss the contributions of PET-CT with (18)F-FDG in the management of this pathological entity. PMID- 24950890 TI - Estimation of the collective ionizing dose in the Portuguese population for the years 2011 and 2012, due to nuclear medicine exams. AB - OBJECTIVES: In 2009-2010 a Portuguese consortium was created to implement the methodologies proposed by the Dose Datamed II (DDM2) project, aiming to collect data from diagnostic X-ray and nuclear medicine (NM) procedures, in order to determine the most frequently prescribed exams and the associated ionizing radiation doses for the Portuguese population. The current study is the continuation of this work, although it focuses only on NM exams for the years 2011 and 2012. MATERIAL AND METHODS: The annual frequency of each of the 28 selected NM exams and the average administered activity per procedure was obtained by means of a nationwide survey sent to the 35 NM centres in Portugal. RESULTS: The results show a reduction of the number of cardiac exams performed in the last two years compared with 2010, leading to a reduction of the annual average effective dose of Portuguese population due to NM exams from 0.08 mSv +/- 0.017 mSv/caput to 0.059 +/- 0.011 mSv/caput in 2011 and 0.054 +/- 0.011 mSv/caput in 2012. Portuguese total annual average collective effective dose due to medical procedures was estimated to be 625.6 +/- 110.9 manSv in 2011 and 565.1 +/- 117.3 manSv in 2012, a reduction in comparison with 2010 (840.3 +/- 183.8 manSv). CONCLUSIONS: The most frequent exams and the ones that contributed the most for total population dose were the cardiac and bone exams, although a decrease observed in 2011 and in 2012 was verified. The authors intend to perform this study periodically to identify trends in the annual Portuguese average effective dose and to help to raise awareness about the potential dose optimization. PMID- 24950893 TI - Genetic dissection of a genomic region with pleiotropic effects on domestication traits in maize reveals multiple linked QTL. AB - The domesticated crop maize and its wild progenitor, teosinte, have been used in numerous experiments to investigate the nature of divergent morphologies. This study examines a poorly understood region on the fifth chromosome of maize associated with a number of traits under selection during domestication, using a quantitative trait locus (QTL) mapping population specific to the fifth chromosome. In contrast with other major domestication loci in maize where large effect, highly pleiotropic, single genes are responsible for phenotypic effects, our study found the region on chromosome five fractionates into multiple-QTL regions, none with singularly large effects. The smallest 1.5-LOD support interval for a QTL contained 54 genes, one of which was a MADS MIKC(C) transcription factor, a family of proteins implicated in many developmental programs. We also used simulated trait data sets to investigate the power of our mapping population to identify QTL for which there is a single underlying causal gene. This analysis showed that while QTL for traits controlled by single genes can be accurately mapped, our population design can detect no more than ~4.5 QTL per trait even when there are 100 causal genes. Thus when a trait is controlled by >=5 genes in the simulated data, the number of detected QTL can represent a simplification of the underlying causative factors. Our results show how a QTL region with effects on several domestication traits may be due to multiple linked QTL of small effect as opposed to a single gene with large and pleiotropic effects. PMID- 24950894 TI - A C++ template library for efficient forward-time population genetic simulation of large populations. AB - fwdpp is a C++ library of routines intended to facilitate the development of forward-time simulations under arbitrary mutation and fitness models. The library design provides a combination of speed, low memory overhead, and modeling flexibility not currently available from other forward simulation tools. The library is particularly useful when the simulation of large populations is required, as programs implemented using the library are much more efficient than other available forward simulation programs. PMID- 24950892 TI - Regulation of inflorescence branch development in rice through a novel pathway involving the pentatricopeptide repeat protein sped1-D. AB - Panicle type has a direct bearing on rice yield. Here, we characterized a rice clustered-spikelet mutant, sped1-D, with shortened pedicels and/or secondary branches, which exhibits decreased pollen fertility. We cloned sped1-D and found that it encodes a pentatricopeptide repeat protein. We investigated the global expression profiles of wild-type, 9311, and sped1-D plants using Illumina RNA sequencing. The expression of several GID1L2 family members was downregulated in the sped1-D mutant, suggesting that the gibberellin (GA) pathway is involved in the elongation of pedicels and/or secondary branches. When we overexpressed one GID1L2, AK070299, in sped1-D plants, the panicle phenotype was restored to varying degrees. In addition, we analyzed the expression of genes that function in floral meristems and found that RFL and WOX3 were severely downregulated in sped1-D. These results suggest that sped1-D may prompt the shortening of pedicels and secondary branches by blocking the action of GID1L2, RFL, and Wox3. Moreover, overexpression of sped1-D in Arabidopsis resulted in the shortening of pedicels and clusters of siliques, which indicates that the function of sped1-D is highly conserved in monocotyledonous and dicotyledonous plants. Sequence data from this article have been deposited with the miRBase Data Libraries under accession no. MI0003201. PMID- 24950895 TI - Do sequentially-presented answer options prevent the use of testwiseness cues on continuing medical education tests? AB - Testwiseness--that is, the ability to find subtle cues towards the solution by the simultaneous comparison of the available answer options--threatens the validity of multiple-choice (MC) tests. Discrete-option multiple-choice (DOMC) has recently been proposed as a computerized alternative testing format for MC tests, and presumably allows for a better control of testwiseness. It is based on a sequential rather than simultaneous presentation of answer options. The test taker has to decide on the correctness of one option after another, until the item has been answered either correctly or incorrectly. Test items that have been criticized for being susceptible to testwiseness strategies are used in continuing medical education (CME) programs aimed at developing and maintaining the knowledge of medical professionals. In Experiment 1 with 48 adults without a special medical education, presenting answer options sequentially reduced the use of testwiseness cues on a CME test compared to their simultaneous presentation as shown by a significant interaction of answer format and the availability of cues (p = .01, eta(2) = 0.13). This result was not dependent on a hint towards potential cues to the solution, as it also held when another 86 adults were not informed of the presence of testwiseness cues in Experiment 2 (p < .001, eta(2) = 0.14). The result could be replicated with 106 medical students and medical doctors in Experiment 3. Items were answered correctly more often in the MC condition (71%) than in the DOMC condition (47%), but only when items contained cues to their solution. A significant interaction between answer format and the availability of cues (p = .02, eta(2) = 0.05) showed that the sequential DOMC answer format allows for a better control of testwiseness than traditional MC testing. PMID- 24950896 TI - An Aboriginal nurse-led working model for success in graduating Indigenous Australian nurses. AB - Abstract Australia needs more Indigenous nurses. This is widely recognised in both academic literature and government policy. In 2012, only 0.8 percent of the Australian nursing workforce was Indigenous (AIHW, 2012). In spite of the clear need, there is little discussion about how to successfully recruit, retain and graduate Indigenous nursing students. This paper describes a successful program being implemented at the University of Southern Queensland (USQ). Between 2000 and 2012, USQ graduated 80 Indigenous nurses and midwives, at both undergraduate and postgraduate levels. In this paper, the authors outline the journey they undertook to develop the successful program at USQ: the Indigenous Nursing Support (INS) Model: Helping Hands. They argue that four elements underpin success for Indigenous nursing students: the availability of Indigenous academics, Indigenous health content in the nursing curriculum, Indigenous specific recruitment materials, and individual mentoring and nurturing of Indigenous students. PMID- 24950897 TI - Simultaneous concentration and detection of biomarkers on paper. AB - The lateral-flow immunoassay (LFA) is an inexpensive point-of-care (POC) paper based diagnostic device with the potential to rapidly detect disease biomarkers in resource-poor settings. Although LFA is inexpensive, easy to use, and requires no laboratory equipment, it is limited by its sensitivity, which remains inferior to that of gold standard laboratory-based assays. Our group is the only one to have previously utilized various aqueous two-phase systems (ATPSs) to enhance LFA detection. In those studies, the sample was concentrated by an ATPS in a test tube and could only be applied to LFA after it had been extracted manually. Here, we bypass the extraction step by seamlessly integrating a polyethylene glycol potassium phosphate ATPS with downstream LFA detection in a simple, inexpensive, power-free, and portable all-in-one diagnostic device. We discovered a new phenomenon in which the target biomarkers simultaneously concentrate as the ATPS solution flows through the paper membranes, and our device features a 3-D paper well that was designed to exploit this phenomenon. Studies with this device, which were performed at room temperature in under 25 min, demonstrated a 10-fold improvement in the detection limit of a model protein, transferrin. Our next generation LFA technology is rapid, affordable, easy-to-use, and can be applied to existing LFA products, thereby providing a new platform for revolutionizing the current state of disease diagnosis in resource-poor settings. PMID- 24950898 TI - How reliable is the classification of cognitive impairment across different criteria in early and late stages of multiple sclerosis? AB - BACKGROUND: Prevalence rates of cognitive impairment (CI) in multiple sclerosis (MS) vary between 40% and 80%. Differences in classification criteria for CI may explain this variance. OBJECTIVE: This study reviewed and compared classification criteria for CI in patients with early and late MS. METHODS: The paper consists of two parts: a systematic review of published classification criteria and the presentation of new data. Criteria were reviewed in respect to percentage of abnormal parameters and cut-offs concerning standard deviations. Thereafter, criteria were applied to cognitive data of 25 patients with early MS (duration <= 2 y), 52 matched patients with late MS (>= 12 y), and 75 matched controls. The test battery assessed alertness, divided attention, mental flexibility, verbal and visual learning, memory, and visuospatial abilities. RESULTS: Seventy classification criteria were revealed and grouped into 20 distinct approaches that can be subdivided into three basic classification strategies. Most commonly, CI was defined as performing 1.5 SD or 2 SD below the normative mean in 18-30% of test parameters (n=42). Other criteria utilized cognitive domains (n=6), composite indices (n=8), or combinations of cut-offs and strategies. The stringency of the criteria was correlated with the prevalence rate of CI (r=-.43) and disease duration (r=.48). In the new data, a substantial effect of classification criteria was found with a prevalence rate ranging from 0 to 68% in early and 4 to 81% in late MS. Increased rates of CI in patients vs. controls were found following 18 out of 20 criteria in the sample of late MS. In early MS, an increased rate of CI was only found following a liberal 1.5 SD cut-off criterion. Inter-rater reliability between all criteria was moderate. However, between criteria of comparable stringency the inter-rater reliability was found to be strong. CONCLUSION: Classification based on different published criteria is not fully comparable and criteria need to be better homogenized. PMID- 24950899 TI - Guillain-Barre syndrome in Arab countries: a systematic review. AB - Systematic review of the frequency and clinical pattern of Guillain-Barre syndrome (GBS) in Arab countries was initiated by a keyword search of PubMed, Medline and Embase and examination of references in all relevant papers. Seven articles were included from Iraq (n=1), Kuwait (n=1), Libya (n=2), and Saudi Arabia (n=3). The only incidence report from the Arab world, a 1987 study from Libya, gives an incidence of 1.7 per 100,000 person-years. Some studies reported that GBS was more common in males and in people in their twenties and thirties. Five studies showed that GBS occurred more frequently during the colder months, and antecedent infection was reported in 26-76% of cases. Most patients had an ascending pattern of weakness and almost all patients had lower limb weakness and reduced or absent reflexes. Facial weakness was the most common cranial nerve involvement. Only one study classified the GBS patients according to electrophysiological findings and reported that 68% of the patients had demyelination type and 15% axonal type. Protein level in cerebrospinal fluid is elevated in most of the GBS patients. Mortality rate from GBS was up to 8%. This systematic review shows an immense deficit in epidemiological data on GBS in Arab countries. The limited data show that clinical pattern, sex and age distribution, reported antecedent infection, and GBS subtypes are similar to those in Western countries. However, further well-designed epidemiological studies on GBS in the Arab world are needed. PMID- 24950900 TI - A wide spectrum of variably periictal MRI abnormalities induced by a single or a cluster of seizures. AB - BACKGROUND: Although predominantly reported in patients with status epilepticus, periictal MRI abnormalities have been reported in patients with a single or a cluster of seizures. Clinicians are often presented with a dilemma concerning the features of MRI abnormalities induced by a single or a cluster of seizures, as they may represent the effect of seizure activity rather than its structural cause. METHODS: A retrospective review of clinical and neuroimaging charts of 14 patients diagnosed with a single or a cluster of seizure-related MR-signal changes from the database of our unit (approximately 300 patients diagnosed with a single or a cluster of seizures underwent brain-MRI within 14 days from a seizure) was conducted. Extensive clinical work-up and follow-up, ranging from 3 months to 5 years, ruled out infection or other possible causes of brain damage. Site, characteristics and reversibility of MRI changes, and association with characteristics of seizures were determined. RESULTS: MRI showed unilateral abnormalities in 14 patients, with hyperintensities on T2-signal (12/14), fluid attenuated inversion-recovery (FLAIR) (12/14), and restricted diffusion (6/8). Location of abnormality was cortical (4/14), subcortical (6/14), thalamus (2/14), corpus callosum (1/14), and bordering an old encephaloclastic lesion (1/14). Periictal MRI abnormalities and electroclinical findings in 10 patients showed an almost complete topographic concordance, which was not consistent in 4 patients. Reversibility of MRI changes was complete in 11 patients, partially disappeared in 1 patient, and irreversible on MRI in 2 patients. CONCLUSIONS: A single or a cluster of seizures cannot only induce transient, variably reversible MRI brain abnormalities, but also irreversible changes. These seizure-induced MRI abnormalities pose a broad differential diagnosis; increased awareness may reduce the risk of misdiagnosis and unnecessary intervention. PMID- 24950901 TI - Different patterns of brain activation in normal aging and Alzheimer's disease from cognitional sight: meta analysis using activation likelihood estimation. AB - Alzheimer disease (AD) is a chronic neurological disease, frequently affecting cognitional functions. Recently, a large body of neuro-imaging studies have aimed at finding reliable biomarkers of AD for early diagnosis of disease in contrast with healthy elderlies. We intended to have a meta-analytical study on recent functional neuroimaging studies to find the relationship between cognition in AD patients and normal elderlies. A systematic search was conducted to collect functional neuroimaging studies such as positron emission therapy (PET) and functional magnetic resonance imaging (fMRI) in AD patients and healthy elderlies. The coordinates of regions related to cognition were meta-analyzed using the activation likelihood estimation (ALE) method and Sleuth software. P value map at the false discovery rate (FDR) of P<0.05 thresholds and the clusters with a minimum size of 200 mm(3) were considered. Data were visualized with MANGO software. Forty-one articles that explored the areas activated during cognition in normal elderly subjects and AD patients were found. According to the findings, left middle frontal gyrus and left precuneus are the most activated areas in cognitional tasks in healthy elderlies and AD patients respectively. In normal elderly subjects and AD patients, comparison of ALE maps and reverse contrast showed that insula and left precuneus were the most activated areas in cognitional aspects respectively. With respect to unification of left precuneus activation in cognitional tasks, it seems that this point can be a hallmark in primary differentiation of AD and healthy individuals. PMID- 24950902 TI - Clinical characteristics of Parkinson's disease patients in Greece: a multicenter, nation-wide, cross-sectional study. AB - Parkinson's disease is a neurodegenerative disease, with a constantly increasing prevalence and a high global financial impact arising from direct and indirect costs. Large-scale, observational studies provide data that support the better comprehension of disease aspects, constitute a baseline reference for future studies and assist comparisons among different patient populations, allowing the recognition of distinctive characteristics and special needs. The present study is the first to depict the clinical characteristics and their interplay in a large sample of Parkinson's disease (PD) patients in Greece. Nine hundred eighty six consecutive PD outpatients were recruited from 17 centers around Greece in the time period from 8/2007 to 7/2009 and were examined and interviewed by movement disorders experts. Multiple clinical characteristics were recorded including age at diagnosis, disease severity, patients' self classification of PD symptoms and their relevance to physician's global clinical impression, smoking, alcohol consumption, presence of family history for PD, dementia, depression, hypertension, cancer and other comorbidities. Associations of high clinical significance were found between certain clinical characteristics. PMID- 24950903 TI - A decrease in N-acetylaspartate and an increase in myoinositol in the anterior cingulate gyrus are associated with behavioral and psychological symptoms in Alzheimer's disease. PMID- 24950904 TI - Immunotherapy-responsive limbic encephalitis with antibodies to glutamic acid decarboxylase. AB - Glutamic acid decarboxylase (GAD) has been recently identified as a target of humoral autoimmunity in a small subgroup of patients with non-paraneoplastic limbic encephalitis (NPLE). We present a patient with NPLE and positive anti-GAD antibodies who showed significant improvement after long-term immunotherapy. A 48 year old female was admitted with a two-year history of anterograde amnesia and seizures. Brain MRI revealed bilateral lesions of medial temporal lobes. Screening for anti-neuronal antibodies showed high anti-GAD titers in both serum and cerebrospinal fluid (CSF) with strong evidence of intrathecal production. The patient received treatment with prednisolone and long-term plasma exchange. During a 12-month follow-up, she exhibited complete seizure remission and an improvement in memory and visuo-spatial skills. Anti-GAD antibodies may serve as a useful marker to identify a subset of NPLE patients that respond to immunoregulatory treatment. PMID- 24950905 TI - Choroidal thickness in relation to sex, age, refractive error, and axial length in healthy Turkish subjects. AB - The aim of this study was to investigate the association between choroidal thickness (CT) and sex, age, refractive error (RE), and axial length in healthy subjects. This is a study of 154 eyes in 154 healthy subjects. CT measurements were performed by the same experienced technician using a spectral domain optical coherence tomography device. CT was measured perpendicularly from the outer edge of the retinal pigment epithelium to the choroid-sclera boundary at the fovea and at six more points which are located at, respectively, 500 um nasal to the fovea, 1,000 um nasal to the fovea, and 1,500 MUm nasal to the fovea, 500 MUm temporal to the fovea, 1,000 MUm temporal to the fovea, and 1,500 MUm temporal to the fovea. The RE was measured by autorefractometry, and the axial length was measured by interferometry. Statistical analysis was performed to evaluate CT at each location, and to the correlations of CT with sex, age, RE, and axial length. The mean subfoveal CT was 265.86 +/- 60.32 um, the mean age was 49.01 +/- 19.19 years, the mean RE was -0.17 +/- 1.20 diopters (D), and the mean axial length was 23.39 +/- 0.76 mm. CT profile indicated that the choroid was thicker at the fovea than at temporal and nasal locations. Univariable linear regression analysis showed that subfoveal CT decreased 3.14 um for each year of age and decreased 79.33 um for each mm of axial length (P = 0.000, R(2) = 0.249; P = 0.000, R(2) = 0.487, respectively). In a similar analysis, subfoveal CT was found to decrease by 50.24 um/D myopia-shifted change in refraction (P = 0.000, R (2) = 0.201). The subfoveal choroid was 99.16 um (39.22 %) thicker in men than women when adjusting for age and axial length (P = 0.000, R(2) = 0.249). CT decreases with increasing myopia, age, and axial length. Men had thicker choroid than women, and CT varies depending on location. PMID- 24950906 TI - Pleomorphic xanthoastrocytomas: institutional experience of 18 patients. AB - Pleomorphic xanthoastrocytoma (PXA) is a rare, low-grade glioma (World Health Organization Grade II) that most often presents in the first two decades of life. We summarize and present our institutional experience in the management of these tumors. All patients managed for PXA at the University of California San Francisco were retrospectively identified through chart review. Patient demographics, tumor characteristics, management, and follow-up were extracted using medical records. Primary endpoints were overall (OS) and progression-free survival (PFS). In total, nineteen patients were treated for PXA from 1993-2011. Clinical data were available for analysis in 18 patients. Median OS was 209.0 months after date of surgery, with both 5 year and 10 year survival rates of 94%. In this patient cohort, tumor grade (p=0.07), age (p=0.32), and extent of resection (p=0.58) did not predict OS. The majority of tumors (78%) recurred. Median PFS was 21.7 months, with 5 year and 10 year recurrence-free rates of 28% and 22%. On univariate analysis, tumor grade (p=0.01), but not age (p=0.51), size (p=0.30), or extent of resection (p=0.21), was the only covariate predictive of PFS. In patients presenting with higher tumor grade, however, earlier recurrence was demonstrated. Furthermore, the majority of recurrences (36%) occurred within the first 6 months post-operatively, which indicates the need to closely follow patients for that time. PMID- 24950907 TI - Pelvic packing with vaginal traction for the management of intractable hemorrhage. AB - OBJECTIVE: To present clinical cases examining the effectiveness and safety of pelvic packing with vaginal traction for inhibiting obstetric hemorrhage among women receiving treatment at a public obstetrics and gynecology tertiary care hospital in Mexico. METHODS: In a retrospective observational descriptive study, eight cases of obstetric hemorrhage treated by pelvic packing with vaginal traction between January 2012 and December 2013 at Hospital de la Mujer, Mexico City, Mexico, were reviewed. RESULTS: The mean patient age was 28.8+/-6.8 years. The average blood loss was 4535+/-897 mL. Uterine atony was the cause of bleeding among six patients: histopathologic examination revealed two cases of placenta accreta, one case of placenta percreta, two cases of uteroplacental apoplexy, and one case of myomatosis. For two patients, placental separation was difficult and required surgical management. The packing technique was effective for all patients. No patients presented with infection or required re-operation for bleeding management. No deaths occurred. CONCLUSION: For management of bleeding among patients with underlying coagulation disorders, pelvic packing can be useful when standard techniques such as hysterectomy, tubal hypogastric ligation, and/or pharmacologic therapy are unsuccessful. PMID- 24950908 TI - Knowledge of Lynch syndrome among obstetrician/gynecologists and general surgeons. AB - OBJECTIVE: To determine comfort and knowledge among obstetrician/gynecologists and general surgeons regarding recommendations for cancer screening for women with Lynch syndrome. METHODS: A questionnaire on Lynch syndrome was administered to all obstetrician/gynecologists and general surgeons at a hospital in New York, USA. RESULTS: Fifty obstetrician/gynecologists and 62 general surgeons completed the survey (67% response rate). Physicians were more comfortable counseling on colon cancer than endometrial cancer screening (51% vs 28%; P<0.001). Obstetrician/gynecologists were more comfortable than general surgeons counseling patients on endometrial cancer screening (36% vs 21%; P=0.090) but less comfortable counseling patients on colon cancer screening (36% vs 63%; P=0.008). There was no significant difference between the specialties in the number of knowledge-based questions answered correctly. Furthermore, there was no correlation between a physician's perceived knowledge and number of correct answers. CONCLUSION: Most physicians did not report being comfortable counseling about recommendations for endometrial cancer screening. While obstetrician/gynecologists reported greater comfort than general surgeons, we found no significant difference in disease knowledge between the groups. Because appropriate cancer screening can improve the outcomes of patients with Lynch syndrome, physicians must be knowledgeable and comfortable with screening recommendations for both endometrial and colon cancer, regardless of clinical specialty. PMID- 24950910 TI - Pentraxin 3: a novel biomarker for predicting progression from prostatic inflammation to prostate cancer. AB - Pentraxin-3 (PTX3) is a member of the pentraxin family of innate immune regulators, which includes C-reactive protein (CRP). PTX3 has been implicated in angiogenesis, proliferation, and immune escape in cancer. In the present study, we evaluated PTX3 tissue expression and serum concentration as a biomarker to discriminate prostatic inflammation and benign prostatic hyperplasia (BPH) from prostate cancer, and to determine whether PTX3 status may predict progression from BPH to prostate cancer. We analyzed 40 patients with biopsy-proven BPH who underwent a second prostate biopsy 12 to 36 months later when they were diagnosed with prostate cancer or inflammation/BPH (n = 20 patients each group). Furthermore, we evaluated PTX3 serum concentrations in an independent set of patients with biopsy-proven inflammation/BPH (n = 61) and prostate cancer (n = 56). We found reduced PTX3 tissue expression in patients with prostatic inflammation/BPH compared with patients who developed prostate cancer. In the latter group, there was an increase in PTX3 tissue expression between the first and second prostate biopsy. PTX3 serum levels were also higher in patients with prostate cancer than in patients with inflammation/BPH. In contrast, there was no difference in serum PSA or CRP levels in these two groups. ROC curve analysis confirmed the reliability of PTX3 serum levels in predicting prostate cancer development, identifying a cutoff value of 3.25 ng/mL with a sensitivity and a specificity of 89.3% and 88.5%, respectively. In summary, our results encourage further evaluation of PTX3 as a tissue biopsy and blood-borne biomarker to discriminate BPH from prostate cancer. PMID- 24950911 TI - Use of cheaper eye drug would save billions, says US study. PMID- 24950913 TI - Contributions of fat content and oxidation to the changes in physicochemical and sensory attributes of pork dumpling filler during frozen storage. AB - This study was conducted to evaluate the contributions of fat addition levels and storage duration at -18 degrees C to the oxidation and physicochemical changes of frozen pork dumpling filler. With an increase in the fat addition, thiobarbituric acid-reactive substances and carbonyl production increased (P < 0.05), the transition temperatures (Tmax) shifted to lower temperatures, and the total enthalpy (DeltaH) of protein denaturation reduced (P < 0.05). Dynamic rheological measurements revealed a compromised viscoelastic network in filler protein gels with increased fat levels and storage time. Increasing the fat level also increased cooking loss and decreased breaking strength (P < 0.05). The sensory results showed that the dumplings with a high fat level had significantly higher texture, juiciness, and overall acceptability scores (P < 0.05). The results suggest that the dumplings with a high fat level stored for long periods enhanced oxidation and cooking loss and decreased breaking strength; however, it is important to add proper fat considering the palatability. PMID- 24950909 TI - TRIM29 suppresses TWIST1 and invasive breast cancer behavior. AB - TRIM29 (ATDC) exhibits a contextual function in cancer, but seems to exert a tumor-suppressor role in breast cancer. Here, we show that TRIM29 is often silenced in primary breast tumors and cultured tumor cells as a result of aberrant gene hypermethylation. RNAi-mediated silencing of TRIM29 in breast tumor cells increased their motility, invasiveness, and proliferation in a manner associated with increased expression of mesenchymal markers (N-cadherin and vimentin), decreased expression of epithelial markers (E-cadherin and EpCAM), and increased expression and activity of the oncogenic transcription factor TWIST1, an important driver of the epithelial-mesenchymal transition (EMT). Functional investigations revealed an inverse relationship in the expression of TRIM29 and TWIST1, suggesting the existence of a negative regulatory feedback loop. In support of this relationship, we found that TWIST1 inhibited TRIM29 promoter activity through direct binding to a region containing a cluster of consensus E box elements, arguing that TWIST1 transcriptionally represses TRIM29 expression. Analysis of a public breast cancer gene-expression database indicated that reduced TRIM29 expression was associated with reduced relapse-free survival, increased tumor size, grade, and metastatic characteristics. Taken together, our results suggest that TRIM29 acts as a tumor suppressor in breast cancer through its ability to inhibit TWIST1 and suppress EMT. PMID- 24950914 TI - Leaving home in Slovenia: a quantitative exploration of residential independence among young adults. AB - The present paper analyzes and contextualizes the phenomenon of prolonged co residence of parents and young adult children in Slovenia. It analyzes the process of moving out or staying at home on the basis of a subsample of young people between 19 and 29 who are no longer at school included in the representative Slovenian field survey Youth 2010. Young people still living in the household of their parents or (legal) guardians are compared with those who have already left. The analysis considers factors associated with the status transitions from youth to adulthood; the demographic, social and economic background; and the perception of the parent-child relationship quality and parenting style by the children. Our findings point to the importance of possibilities for independent housing and the economic capacity of young people and their family. The most important factor behind moving out seems to be a stable partnership. PMID- 24950912 TI - Electronic monitoring of symptoms and lung function to assess asthma control in children. AB - BACKGROUND: Asthma remains poorly controlled in children. Home monitoring of asthma control may help to improve the level of asthma control. OBJECTIVES: To compare 2 methods to assess asthma control: (1) prospective home monitoring, based on daily assessment of forced expiratory volume in 1 second (FEV1) and electronic symptom score, and (2) Asthma Control Questionnaire (ACQ) with retrospective assessment of symptoms and FEV1. METHODS: Ninety-six children with asthma were prospectively followed up during 1 year. Asthma control was assessed by home monitoring, including an electronic symptom score based on Global Initiative for Asthma (GINA) criteria and FEV1 measurements. In the hospital, the ACQ was completed and FEV1 was measured. Kappa analysis was performed to assess levels of agreement between the 2 methods. RESULTS: Agreement between the 2 methods was low (kappa coefficient of 0.393). In 29 children (37%), prospective home monitoring was less optimistic than the retrospective assessment of asthma control by the ACQ. CONCLUSION: This study found low agreement between asthma control based on GINA criteria by means of prospective home monitoring and the hospital ACQ. The prospective home monitor detected more cases of less well controlled asthma than the ACQ. However, optimization of adherence to home monitor use is necessary. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01239238. PMID- 24950915 TI - Influence of psychiatric comorbidities in migraineurs in the emergency department. AB - OBJECTIVE: To examine how psychiatric comorbidities in migraineurs in the emergency department (ED) affect healthcare utilization and treatment tendencies. METHOD: This is a cross-sectional analysis of 2872 patients who visited our ED over a 10-year period and were given a principal diagnosis of migraine. RESULTS: Compared to migraineurs without a psychiatric comorbidity, migraineurs with a psychiatric comorbidity had about three times more ED visits, six times more inpatient hospital stays and four times more outpatient visits. Migraineurs with psychiatric comorbidities received narcotics in the ED more often than migraineurs without psychiatric comorbidities (P<0.0001). In addition, migraineurs with psychiatric disorders were more likely to have a computed tomography scan of the head [Risk Ratio (RR) 1.42 (95% confidence interval (CI)=1.28-1.56, P<0.001)] or a magnetic resonance image of the brain [RR 1.53 (95% CI=1.33-1.76, P<0.001)] than patients without a psychiatric disorder when visiting our hospital center. CONCLUSIONS: Migraineurs with psychiatric comorbidity who visit the ED have different healthcare utilization tendencies than migraineurs without psychiatric comorbidity who visit the ED. This is seen in the frequency of ED visits, outpatient visits and inpatient stays, in the medications administered to them and in the radiology tests they undergo. PMID- 24950916 TI - Could clomiphene kindle acute manic episode in a male patient? A case report. AB - Psychiatric adverse effects associated with the use of clomiphene are relatively uncommon. Though case reports link mood swings to be associated with clomiphene, it is not known to be associated with a syndromal affective episode. Being a selective estrogen receptor modulator, clomiphene affects the hypothalamus pituitary-gonadal axis and can have potential neuropsychiatric effects in vulnerable persons. Herein we report a case of clomiphene-induced manic episode in a known bipolar male patient. PMID- 24950918 TI - A meta-analysis of critically ill patients reveals several potential risk factors for delirium. AB - OBJECTIVE: To investigate potential risk factors for delirium in critically ill patients through a meta-analysis of clinical observational studies. METHOD: A literature search was conducted of MEDLINE and Embase databases. Studies that reported risk factors for delirium in a critical care setting were included. Data were independently extracted by two reviewers and pooled using a fixed-effect or random effects model according to the result of a heterogeneity test. RESULTS: Twenty-five studies were included. The combined odds ratio (95% confidence interval) for each potential risk factor estimated by meta-analysis was as follows (univariate/multivariate): alcohol use, 1.47 (0.79-2.72)/2.34 (1.56 3.49); smoking, 1.01 (0.81-1.25)/1.61 (0.83-3.10); hypertension, 1.64 (1.30 2.06)/1.98 (1.44-2.72); age (per year), 1.03 (1.001-1.05)/1.04 (1.02-1.05); age >65 years, 2.52 (1.55-4.10)/2.59 (1.93-3.47); mechanical ventilation, 3.09 (1.43 6.66)/4.51 (1.41-14.39); and Acute Physiology and Chronic Health Evaluation (APACHE) II score (per point), 1.13 (1.06-1.21) (multivariate only). There was no evidence of publication bias except for APACHE II score. CONCLUSION: Age, history of hypertension, clinical use of mechanical ventilation and higher APACHE II score are associated with increased risk of delirium in critically ill patients. PMID- 24950917 TI - Hyperlipidemia, statin use and the risk of developing depression: a nationwide retrospective cohort study. AB - OBJECTIVE: Depression is a highly prevalent disorder that is associated with disability. The aim of this study was to determine the relationship between depression and hyperlipidemia and whether the onset of depression is associated with administering statins to patients with hyperlipidemia. MATERIAL AND METHODS: The data analyzed in this study were retrieved from the National Health Insurance Research Database in Taiwan. We identified newly diagnosed hyperlipidemia in 26,852 patients without a history of depression as the exposure group in the period of 2000-2002, and a comparison group comprised 107,408 patients. The differences between the exposure group and the comparison group were examined using a chi-square test to calculate categorical variables. The hazard ratio and the 95% confidence interval for depression were used in the logistic regression. RESULTS: The hyperlipidemia patients demonstrated a high risk for depression and comorbidities, such as hypertension, diabetes and sleep disorder, which indicated synergistic effects related to a high risk of depression in hyperlipidemia patients. Hyperlipidemia patients who had received statins exhibited a lower risk of depression than did those who had not received statins. CONCLUSION: Our results suggested that hyperlipidemia increases the risk of depression and that using statins is associated with a decreased risk of depression in patients with hyperlipidemia. PMID- 24950919 TI - Reevaluating the role of antidepressants in cancer-related depression: a systematic review and meta-analysis. AB - OBJECTIVE: Prior reviews evaluating the role of antidepressants in cancer-related depression have drawn conflicting conclusions. These reviews have also not explored differences in efficacy and tolerability between antidepressants. We conducted a meta-analysis to address these limitations. METHOD: We searched Medline (1948-2013), the Cochrane Library (1800-2013), the Cumulative Index to Nursing and Allied Health Literature (1986-2013), ClinicalTrials.gov (2013) and meeting abstracts. We included randomized trials comparing antidepressants to placebo or no treatment for cancer-related depression. We used random effects to calculate standardized mean differences (SMD). RESULTS: Of 5178 potentially eligible citations, 9 trials (1169 subjects) met inclusion criteria. Trials of mianserin found a robust reduction in depression scores at >=4 weeks of treatment (SMD: 0.60, 95% confidence interval (CI): 0.24-0.95). Similar, but less robust, results were observed with paroxetine (SMD: 0.22, 95% CI: 0.01-0.42) and fluoxetine (SMD 0.34, 95% CI: 0.02-0.66). Conversely, there was no advantage with amitriptyline or desipramine. Compared to placebo, the odds of dropping out due to side effect were higher with fluoxetine and paroxetine and lower with mianserin. Methodological quality was moderate. CONCLUSIONS: Paroxetine, fluoxetine and mianserin improve cancer-related depression but may vary in efficacy and tolerability. High-quality, randomized trials of newer antidepressant agents are needed to identify optimal treatments for managing cancer-related depression. PMID- 24950920 TI - Evaluation of low tidal volume with positive end-expiratory pressure application effects on arterial blood gases during laparoscopic surgery. AB - BACKGROUND: Pneumoperitoneum (PNP) and patient positions required for laparoscopy can induce pathophysiological changes that complicate anesthetic management during laparoscopic procedures. This study investigated whether low tidal volume and positive end-expiratory pressure (PEEP) application can improve ventilatory and oxygenation parameters during laparoscopic surgery. METHODS: A total of 60 patients undergoing laparoscopic surgery were randomized to either the conventional group (n = 30, tidal volume = 10 mL/kg, rate = 12/minute, PEEP = 0 cm H(2)O) or the low tidal group with PEEP group (n = 30, tidal volume = 6 mL/kg, rate = 18/minute, PEEP = 5 cm H(2)O) at maintenance of anesthesia. Hemodynamic parameters, peak plateau pressure (Pplat) and arterial blood gases results were recorded before and after PNP. RESULTS: There was a significant increase in the partial pressure of arterial carbon dioxide (PaCO(2)) values after PNP in the conventional group in the reverse Trendelenburg (41.28 mmHg) and Trendelenburg positions (44.80 mmHg;p = 0.001), but there was no difference in the low tidal group at any of the positions (36.46 and 38.56, respectively). We saw that PaO(2) values recorded before PNP were significantly higher than the values recorded 1 hour after PNP in the two groups at all positions. No significant difference was seen in peak inspiratory pressure (Ppeak) at the reverse Trendelenburg position before and after PNP between the groups, but there was a significant increase at the Trendelenburg position in both groups (conventional; 21.67 cm H(2)O, p = 0.041, low tidal; 23.67 cm H(2)O, p = 0.004). However, Pplat values did not change before and after PNP in the two groups at all positions. CONCLUSION: The application of low tidal volume + PEEP + high respiratory rate during laparoscopic surgeries may be considered to improve good results of arterial blood gases. PMID- 24950921 TI - Rapid containment of coincident outbreaks with 2 carbapenem-resistant Klebsiella pneumoniae strains in an intensive care unit. AB - In our intensive care unit, coincident outbreaks were caused by concomitant cross transmission of 2 carbapenem-resistant Klebsiella pneumoniae strains harboring distinct mechanisms of resistance. One strain produced extended-spectrum beta lactamase in combination with reduced permeability. The other produced oxacillinase-48 carbapenemase. Rapid phenotypic detection of carbapenemase production allowed timely implementation of appropriate infection control measures. PMID- 24950922 TI - Perceptions of methicillin-resistant Staphylococcus aureus and hand hygiene provider training and patient education: results of a mixed method study of health care providers in Department of Veterans Affairs spinal cord injury and disorder units. AB - BACKGROUND: The goal of this study was to assess current practices for training of spinal cord injury and disorder (SCI/D) health care workers and education of veterans with SCI/D in Department of Veterans Affairs (VA) spinal cord injury (SCI) centers on methicillin-resistant Staphylococcus aureus (MRSA) prevention. METHODS: Mixed methods. A Web-based survey was distributed to 673 VA SCI/D providers across 24 SCI centers; 21 acute care and 1 long-term care facility participated. There were 295 that responded, 228 had complete data and were included in this analysis. Semistructured interviews were conducted with 30 SCI/D providers across 9 SCI centers. RESULTS: Nurses, physicians, and therapists represent most respondents (92.1%, n = 210); over half (56.6%, n = 129) were nurses. Of providers, 75.9% (n = 173) reported receiving excellent or good training on how to educate patients about MRSA. However, nurses were more likely to report having excellent or good training for how to educate patients about MRSA (P = .005). Despite this, only 63.6% (n = 82) of nurses perceived the education they provide patients on how MRSA is transmitted as excellent or good. CONCLUSION: Despite health care workers reporting receiving excellent or good training on MRSA-related topics, this did not translate to excellent or good education for patients, suggesting that health care workers need additional training for educating patients. Population-specific MRSA prevention educational materials may also assist providers in educating patients about MRSA prevention for individuals with SCI/D. PMID- 24950923 TI - SSPACE-LongRead: scaffolding bacterial draft genomes using long read sequence information. AB - BACKGROUND: The recent introduction of the Pacific Biosciences RS single molecule sequencing technology has opened new doors to scaffolding genome assemblies in a cost-effective manner. The long read sequence information is promised to enhance the quality of incomplete and inaccurate draft assemblies constructed from Next Generation Sequencing (NGS) data. RESULTS: Here we propose a novel hybrid assembly methodology that aims to scaffold pre-assembled contigs in an iterative manner using PacBio RS long read information as a backbone. On a test set comprising six bacterial draft genomes, assembled using either a single Illumina MiSeq or Roche 454 library, we show that even a 50* coverage of uncorrected PacBio RS long reads is sufficient to drastically reduce the number of contigs. Comparisons to the AHA scaffolder indicate our strategy is better capable of producing (nearly) complete bacterial genomes. CONCLUSIONS: The current work describes our SSPACE-LongRead software which is designed to upgrade incomplete draft genomes using single molecule sequences. We conclude that the recent advances of the PacBio sequencing technology and chemistry, in combination with the limited computational resources required to run our program, allow to scaffold genomes in a fast and reliable manner. PMID- 24950924 TI - Antiretroviral treatment associated hyperglycemia and dyslipidemia among HIV infected patients at Burayu Health Center, Addis Ababa, Ethiopia: a cross sectional comparative study. AB - BACKGROUND: The effects of highly active antiretroviral therapy (HAART) on glucose and lipid metabolism among sub-Saharan Africans, for whom access to antiretroviral therapy is expanding, remain largely unknown. Therefore, the aim of this study was to assess antiretroviral treatment associated hyperglycemia and dyslipidemia among HIV infected patients at Burayu health center, Addis Ababa, Ethiopia. METHODS: A cross-sectional comparative study was conducted among HIV infected adults at Burayu Health Center, Addis Ababa, Ethiopia from September, 2011 to May, 2012. Equal number of HAART naive and HAART initiated patients (n = 126 each) were included in the study. Demographic data were collected using a well-structured questionnaire. Total cholesterol (TC), Triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL C) and glucose were determined. The data were analyzed using SPSS version 20 software. RESULT: Of 252 study participants, 72.2% were females; mean age was 35.3 years; mean Body Mass Index (BMI) was 21.4(kg/m2); mean time living with the virus was 20.6 months and 15.5% were TB-HIV co-infected. The prevalence of hyperglycemia, increased LDL-C hypercholesterolemia, hypertriglyceridemia and decreased HDL-C were 7.9%, 23%, 42.1%, 46.8% and 50.8% in HAART and 5.6%, 7.1%, 11.1%, 31% and 73% in non-HAART groups, respectively. First line antiretrovirals were drugs containing 2 nucleoside backbones (from Zidovudine/Stavudine/Lamivudine/Tenofovir) with either Nevirapine or Efavirenz. There was statistically significant increase in serum lipid profile levels among HAART initiated patients than HAART naive individuals (p =0.01 for TG and <0.001 for others). CONCLUSION: First-line HAART is associated with potentially atherogenic lipid profile levels in patients with HIV infection compared to untreated patients. This indicates glucose and lipid profile levels need to be monitored regularly in HIV infected patients taking antiretroviral treatment. PMID- 24950926 TI - Ischemia-reperfusion in the renal allograft: new clues in a cold-case. PMID- 24950927 TI - Innate and adaptive immune responses subsequent to ischemia-reperfusion injury in the kidney. AB - Understanding innate immune responses and their correlation to alloimmunity after solid organ transplantation is key to optimizing long term graft outcome. While Ischemia/Reperfusion injury (IRI) has been well studied, new insight into central mechanisms of innate immune activation, i.e. chemokine mediated cell trafficking and the role of Toll-like receptors have evolved recently. The mechanistic implications of Neutrophils, Macrophages/Monocytes, NK-cells, Dendritic cells in renal IRI has been proven by selective depletion of these cell types, thereby offering novel therapeutic interventions. At the same time, the multi-faceted role of different T-cell subsets in IRI has gained interest, highlighting the dichotomous effects of differentiated T-cells and suggesting more selective therapeutic approaches. Targeting innate immune cells and their activation and migration pathways, respectively, has been promising in experimental models holding translational potential. This review will summarize the effects of innate immune activation and potential strategies to interfere with the immunological cascade following renal IRI. PMID- 24950925 TI - [The EFS metrology: From the production to the reason]. AB - In order to answer statutory requirements and to anticipate the future needs and standards, the EFS is committed, since a few years, in a process of harmonization of its metrology function. In particular, the institution has opted for the skills development by internalizing the metrological traceability of the main critical quantities (temperature, volumetric) measurements. The development of metrology so resulted in a significant increase in calibration and testing activities. Methods are homogenized and improved through accreditations. The investment strategies are based on more and more demanding specifications. The performance of the equipments is better known and mastered. Technical expertise and maturity of the national metrology function today are assets to review in more informed ways the appropriateness of the applied periodicities. Analysis of numerous information and data in the calibration and testing reports could be pooled and operated on behalf of the unique establishment. The objective of this article is to illustrate these reflections with a few examples from of a feedback of the EFS Pyrenees Mediterranee. The analysis of some methods of qualification, the exploitation of the historical metrology in order to quantify the risk of non compliance, and to adapt the control strategy, analysis of the criticality of an instrument in a measurement process, risk analyses are tools that deserve to be more widely exploited for that discipline wins in efficiency at the national level. PMID- 24950928 TI - Angiogenic response following renal ischemia reperfusion injury: new players. AB - Ischemia-reperfusion (IR) injury can negatively influence the short- and long term outcomes of kidney transplantation because it promotes acute tubular necrosis and tissue scarring and activates innate alloimmunity. The adaptive responses to IR are centrally involved in reducing tissue damage but can also be deleterious when they activate programmed cell death and inflammation. The HIF 1alpha-mediated angiogenic responses following IR at early and late stages are complex and poorly understood. The early stages of IR seem to be associated with an antiangiogenic response, whereas the hypoxia that follows IR at later stages may activate angiogenic factors such as vascular endothelial growth factor (VEGF) and may be beneficial by stabilizing the microvasculature and favoring local blood supply. In addition to HIF-1alpha, new players in angiogenesis, including mTOR and the unfolded protein response, may lead to innovative therapeutic strategies for treating patients with ischemia- and reperfusion-associated tissue inflammation and organ dysfunction. PMID- 24950929 TI - Pharmacological strategy designed to limit ischemia-reperfusion injury in brain dead donor kidneys. AB - Ischemia-reperfusion injury is a complex physiological process responsible for delayed renal function or primary graft non-function, explicitly when kidney allograft are issued from expanded criteria donor. The purpose of this review is to detail the detrimental phenomenons altering kidney allograft's integrity in brain dead donor, therefore suggesting pharmacological interventions aiming to reduce ischemia-reperfusion injuries and improving transplantation outcome. This ischemia-reperfusion phenomenon must therefore be anticipated through the whole procedure starting at the stage of conditioning of the potential donor. Hormonal and haemodynamic consequences of brain death modify perfusion and oxygenation conditions of the organs Thus, after describing the autonomic, metabolic, endocrine and chemokine storm occurring during brain death, the authors focus on strategies to prevent hemodynamic instability in the donor and to limit the consequences of hormonal and immunological changes on organs that will eventually be transplanted. PMID- 24950930 TI - Additives to preservation solutions. AB - As the impact of ischemia reperfusion injury on graft outcome is now well defined, efforts are made towards decreasing these lesions, typically through the improvement of preservation techniques. The use of pharmacological supplements which could be compatible with any preservation solution used by the transplant center and target specific pathways of IR is an interesting strategy to improve graft quality. However, the extensive number of studies showing the benefits a molecule in an animal model of IR without thorough mechanistic determination of the effects of this agent make it difficult to opt for specific pharmaceutical intervention. Herein we expose studies which demonstrate the benefits of several molecules relying on a thorough mechanical analysis of the events occurring during preservation, both at the cellular and the systemic levels. We believe this approach is the most appropriate to truly understand the potential benefits of a molecule and particularly to design a comprehensive pharmaceutical regiment, with several agents acting synergistically against IR, to improve organ preservation and graft outcome. PMID- 24950931 TI - Polyethylene glycols and organ protection against I/R injury. AB - During the organ transplantation process, conservation solutions must address responses to the physiologic organ preservation and prevent ischemia-reperfusion injuries. The use of colloids seems beneficial especially for long ischemia time compared to the impermeant molecules used for short time. The colloids family includes molecules as hydroxyethyl starch (HES), albumin, dextran or polyethylene glycol (PEG). In this review, the authors describe the rational for PEG use, its potential immunomodulatory effect and the main results of its experimental and clinical use. PMID- 24950932 TI - Ischemia-reperfusion: From cell biology to acute kidney injury. AB - Ischemia reperfusion injury occurs in the kidney when blood supply is interrupted in clinical settings such as kidney transplantation or nephron sparing surgery for renal tumors. These lesions lead to acute kidney injury (AKI) a detrimental situation associated with impaired short-term allograft function (delayed graft function or primary non function) but also long-term transplant survival through the onset of chronic allograft nephropathy. The present review details the cellular and molecular consequences of ischemia reperfusion in a native kidney as well as in a kidney graft after cold ischemia time, giving a comprehensive description of biological pathways involved during the phase of ischemia and during the reperfusion period where the rapid return to normoxia leads to a large burst of reactive oxygen species along with a dramatic reduction in antioxidant defenses. This work also focuses on the distinct susceptibilities of kidney cells to ischemia (endothelial vs epithelial) and the outcome of acute kidney injury. PMID- 24950933 TI - Does machine perfusion decrease ischemia reperfusion injury? AB - In 1990's, use of machine perfusion for organ preservation has been abandoned because of improvement of preservation solutions, efficient without perfusion, easy to use and cheaper. Since the last 15 years, a renewed interest for machine perfusion emerged based on studies performed on preclinical model and seems to make consensus in case of expanded criteria donors or deceased after cardiac death donations. We present relevant studies highlighted the efficiency of preservation with hypothermic machine perfusion compared to static cold storage. Machines for organ preservation being in constant evolution, we also summarized recent developments included direct oxygenation of the perfusat. Machine perfusion technology also enables organ reconditioning during the last hours of preservation through a short period of perfusion on hypothermia, subnormothermia or normothermia. We present significant or low advantages for machine perfusion against ischemia reperfusion injuries regarding at least one primary parameter: risk of DFG, organ function or graft survival. PMID- 24950934 TI - Ischemia/reperfusion during normothermic perfusion. AB - INTRODUCTION: Cold storage of organs for preservation and transplantation is reaching its limits especially with extended criteria for heart beating donors and donation after cardiac death. We will discuss recent findings and perspectives in normothermic kidney preservation. METHODS: A literature review was performed from original articles and syntheses selected by the search engine PubMed. Keywords used were: cold ischemia; warm ischemia, normothermic, organ preservation, preconditioning, organ perfusion. RESULTS: We identified several ways to improve kidney preservation: Ischemic normothermic preconditioning; Pharmacologic normothermic preconditioning; Ex vivo normothermic reperfusion; Remote ischemic transplantation preconditioning; Ischemic postconditioning. In clinical practice, only uses of ECMO for organ preconditioning or ex vivo normothermic organ perfusion were used. CONCLUSION: Promising experimental and clinical results make challenge cold preservation. The most suitable and physiological method seems to be a normothermic perfusion and conservation with autologous oxygenated blood using Extra Corporeal Membrane Oxygenation or Regional Normothermic Circulation. PMID- 24950935 TI - Ischemic pre- and post-conditioning: current clinical applications. AB - Ischemic conditioning is a phenomenon through which short sequences of ischemia reperfusion applied to an organ confer some degree of protection towards future ischemic insults. This phenomenon was first observed in the mid-1980s in cardiac surgery, and has been since widely studied in different settings. Different sort of ischemic conditioning exist: local vs remote, direct or pharmacological, and with different timeframes of protection. Ischemic conditioning seems especially suited to applications in transplantation since schedules of both cold and warm ischemia, as well as reperfusion, are carefully and easily controlled, and the benefits of protecting fragile organs against ischemia-reperfusion injuries might help widen the pool of possible grafts and ensure better graft function and survival. The pathways through which ischemic conditioning work are many, offering both preservation of cell energy, protection against oxidative stress, better blood flow to organs and protection against apoptosis. In the field of pharmacological conditioning, which tries to mimic the protective effects of traditional ischemic conditioning without the potential side-effects associated with vessel clamping, many common-use drugs including anesthetics have been shown to be effective. Significant results have been obtained in small animal models, but while ischemic conditioning is successfully used in cardiac surgery, studies in large animal models and human applications in liver and kidney transplantation are still inconclusive. PMID- 24950936 TI - Associations between perceived and observational physical environmental factors and the use of walking paths: a cross-sectional study. AB - BACKGROUND: How to promote physical activity is an important public health problem that is attracting increasing attention. Although the application of environmental approaches is believed to promote resident walking, there remains insufficient evidence of the effectiveness of these interventions. METHODS: This study employed direct observation and questionnaires. Observations were performed on each Tuesday, Thursday, Saturday, and Sunday from April 13th to May 16th. Fourteen trained observers observed six community walking paths, and an additional walking path in a park. The trained observers filled out 2388 observation forms in the field, including 228 forms rating the permanent environment, and 1080 forms assessing the current environment and counting the number of walkers. A total of 1800 questionnaires were administered to community residents. RESULTS: The results of both observation and questionnaires showed good association regarding the characteristics of walking path users (for observation, female = 54.4%; for questionnaire interviews, female, OR = 1.441), and the environmental features associated with walking path utilization (for observation, positive associations were observed between the utilization index and observational environmental variables; for questionnaire interviews, roads and aesthetics were important, OR = 1.044). There were positive associations between path use and time, a preference for brisk walking, and the observed current and permanent environmental variables. Female participants were more likely to use walking paths than males (OR = 1.441, 95% confidence interval [CI] 1.126-1.846). BMI and traffic hazard safety were significantly negatively associated with walking path use (OR = 0.948, 95% CI 0.915-0.981, and OR = 0.933, 95% CI 0.887-0.981, respectively). Roads, aesthetics, and knowledge of physical activity were significantly positively correlated with use of walking paths (OR = 1.044, 95% CI 1.017-1.072, and OR = 1.175, 95% CI 1.043-1.323). Participants that resided further than 1 km from the park were less likely to use walking paths (OR = 0.703, 95% CI 0.530-0.933). Gender-specific associations were also found. CONCLUSIONS: Both perceived and objective environmental factors were associated with walking path use. Data suggested that the permanent and current conditions of the paths might influence walking path utilization, and that gender-specific promotion strategies should be considered. PMID- 24950937 TI - Diagnostic criteria in renal and hepatic cyst infection. AB - Cyst infection is a severe complication of renal and hepatic cystic disease that frequently leads to hospitalization. In most cases the diagnosis of cyst infection is made empirically as a cyst aspirate is frequently unavailable. This study aims to evaluate diagnostic criteria, microbiological findings and imaging modalities needed to diagnose cyst infection. In order to do so, we evaluated reports that characterize cyst infection cases published in the English language between 1948 and January 2014. We identified 70 articles documenting a total of 215 cyst infection cases (renal n = 119; hepatic n = 96). Six studies, including 74 cases of renal and 61 cases of hepatic cyst infection, used diagnostic criteria. The criteria that led to a definite cyst infection diagnosis were consistent, whereas criteria for a 'probable diagnosis' varied considerably. Cyst infection cases commonly have abdominal pain, fever and elevated serum inflammatory markers. Urine and blood cultures frequently remained negative, even in definite cases. The diagnostic properties of (18)fluorodeoxyglucose positron emission computed tomography ((18)F-FDG PET/CT) are probably best to diagnose cyst infection. Cyst aspirate indicating infection is currently the gold standard in diagnosing cyst infection. If not available, a combination of clinical and biochemical parameters is necessary to make a well-considered diagnosis, preferably including (18)F-FDG PET/CT. PMID- 24950938 TI - Interventions to improve medication adherence in adult kidney transplant recipients: a systematic review. AB - BACKGROUND: In kidney transplantation, adherence to immunosuppressive therapy is paramount for long-term graft survival. This systematic review aimed to assess the effectiveness of interventions to improve medication adherence in adult kidney transplantation. METHODS: Eight electronic databases were searched from inception to November 2013. Only primary intervention studies, which reported measurement of adherence to immunosuppressive medications after kidney transplantation, were included. The quality of all studies was assessed using the Consolidated Standards of Reporting Trials and Transparent Reporting of Evaluations with Non-randomized Designs checklists. A synthesis was undertaken to tease out the domains targeted by interventions: (i) educational/cognitive, (ii) counselling/behavioural, (iii) psychologic/affective and (iv) financial support. For each study, key information, such as population, location, methods of measurements, comparison group, type of intervention and outcomes, were extracted and tabulated. RESULTS: Twelve intervention studies were identified. Quality of studies ranged from 16.0 to 80.5%. Effective interventions were implemented for 3, 6 and 12 months. Medication adherence rates were greatly enhanced when multidimensional interventions were implemented whereas one-off feedback from a nurse and financial assistance programmes offered little improvement. Dose administration aids when used in conjunction with self-monitoring also improved adherence. The number of patients who had a drug holiday (at least 1-day interval without a dose) was higher in a once-daily regimen than a twice-daily regimen. CONCLUSIONS: The findings of this review suggest an intervention targeting behavioural risk factors or a combination of behavioural, educational and emotional changes is effective in enhancing medication adherence. Effectiveness of an intervention may be further enhanced if patients are encouraged to participate in the development process. PMID- 24950941 TI - Management of bleeding liver tumors. AB - Liver tumors bleed rarely; management has changed radically during the last 20years, advancing from emergency surgery with poor results to multidisciplinary management. The first steps are the diagnosis and control of bleeding. Abdominopelvic CT scan should be performed as soon as patient hemodynamics allow. When active bleeding is visualized, arterial embolization, targeted as selectively as possible, is preferable to surgery, which should be reserved for severe hemodynamic instability or failure of interventional radiology. When surgery is unavoidable, abbreviated laparotomy (damage control) with perihepatic packing is recommended. The second step is determination of the etiology and treatment of the underlying tumor. Adenoma and hepatocellular carcinoma (HCC) are the two most frequently encountered tumors in this context. Liver MRI after control of the bleeding episode generally leads to the diagnosis although sometimes the analysis can be difficult because of the hematoma. Prompt resection is indicated for HCC, atypical adenoma or lesions at risk for degeneration to hepatocellular carcinoma. For adenoma with no suspicion of malignancy, it is best to wait for the hematoma to resorb completely before undertaking appropriate therapy. PMID- 24950942 TI - Infectious sacroiliitis. PMID- 24950943 TI - FiO2 delivered by a turbine portable ventilator with an oxygen concentrator in an Austere environment. AB - BACKGROUND: Management of critically ill patients in austere environments is a logistic challenge. Availability of oxygen cylinders for the mechanically ventilated patient may be difficult in such a context. A solution is to use a ventilator able to function with an oxygen concentrator. OBJECTIVES: We tested the SeQual IntegraTM (SeQual, San Diego, CA) 10-OM oxygen concentrator paired with the Pulmonetic System((r)) LTV 1000 ventilator (Pulmonetic Systems, Minneapolis, MN) and evaluated the delivered fraction of inspired oxygen (FiO2) across a range of minute volumes and combinations of ventilator settings. METHODS: Two LTV 1000 ventilators were tested. The ventilators were attached to a test lung and FiO2 was measured by a gas analyzer. Continuous-flow oxygen was generated by the OC from 0.5 L/min to 10 L/min and injected into the oxygen inlet port of the LTV 1000. Several combinations of ventilator settings were evaluated to determine the factors affecting the delivered FiO2. RESULTS: The LTV 1000 ventilator is a turbine ventilator that is able to deliver high FiO2 when functioning with an oxygen concentrator. However, modifications of the ventilator settings such as increase in minute ventilation affect delivered FiO2 even if oxygen flow is constant on the oxygen concentrator. CONCLUSIONS: The ability of an oxygen concentrator to deliver high FiO2 when used with a turbine ventilator makes this method of oxygen delivery a viable alternative to cylinders in austere environments when used with a turbine ventilator. However, FiO2 has to be monitored continuously because delivered FiO2 decreases when minute ventilation is increased. PMID- 24950945 TI - Genotoxicological response of the common carp (Cyprinus carpio) exposed to spring water in Tlaxcala, Mexico. AB - This study evaluated the genotoxic impact of anthropic activities in Huactzinco Spring, using Cyprinus carpio as a biomonitor. In situ and in vivo experimental designs were compared by means of simultaneous 2-week exposures. The water from the spring generated mean micronuclei frequency values (108.6 +/- 32 MN/1,000) and DNA fragmentation values (143.4 +/- 35 au) which were statistically higher than those for the negative control (10.9 +/- 6 MN/1,000 and 67.6 +/- 23 au). The in situ and in vivo experiments supported one another. The comet assay proved to be the most sensitive test, with an EC50 value (11.4 % +/- 3.4 %) being less than that determined for the micronuclei test (54.8 % +/- 3.2 %). The results of this study confirm the usefulness of C. carpio as an environmental contamination biomonitor, and suggest that Huactzinco Spring water constitutes a latent risk to human health and the environment. PMID- 24950944 TI - Glutamate and GABA-metabolizing enzymes in post-mortem cerebellum in Alzheimer's disease: phosphate-activated glutaminase and glutamic acid decarboxylase. AB - Enzymes of glutamate and GABA metabolism in postmortem cerebellum from patients with Alzheimer's disease (AD) have not been comprehensively studied. The present work reports results of original comparative study on levels of phosphate activated glutaminase (PAG) and glutamic acid decarboxylase isoenzymes (GAD65/67) in autopsied cerebellum samples from AD patients and matched controls (13 cases in each group) as well as summarizes published evidence for altered levels of PAG and GAD65/67 in AD brain. Altered (decreased) levels of these enzymes and changes in links between amounts of these enzymes and other glutamate-metabolizing enzymes (such as glutamate dehydrogenase and glutamine synthetase-like protein) in AD cerebella suggest significantly impaired glutamate and GABA metabolism in this brain region, which was previously regarded as not substantially involved in AD pathogenesis. PMID- 24950946 TI - Inhaled beta-2-agonists/muscarinic antagonists and acute myocardial infarction in COPD patients. AB - OBJECTIVE: Empirical results indicate an increased risk for cardiovascular (CV) adverse drug events (ADE) in chronic obstructive pulmonary disease (COPD) patients treated with beta-2-agonists (B2A) and muscarinic antagonists (MA). A systematic review (including a meta-analysis for drug classes with sufficient sample size) was conducted assessing the association between B2A or MA and acute myocardial infarctions (MI) in COPD patients. METHODS: Comprehensive literature search in electronic databases (MEDLINE, Cochrane database) was performed (January 1, 1946-April 1, 2013). Results were presented by narrative synthesis including a comprehensive quality assessment. In the meta-analysis, a random effects model was used for estimating relative risk estimates for acute MI. RESULTS: Eight studies (two systematic reviews, two randomized controlled trials, and four observational studies) were comprised. Most studies comparing tiotropium vs. placebo showed a decreased MI risk for tiotropium, whereas for studies with active control arms no clear tendency was revealed. For short-acting B2A, an increased MI risk was shown after first treatment initiation. For all studies, a good quality was found despite some shortcomings in ADE-specific criteria. A meta analysis could be conducted for tiotropium vs. placebo only, showing a relative risk reduction of MI (0.74 [0.61-0.90]) with no evidence of statistical heterogeneity among the included trials (I(2) = 0%; p = 0.8090). CONCLUSIONS: An MI-protective effect of tiotropium compared to placebo was found, which might be attributable to an effective COPD treatment leading to a decrease in COPD-related cardiovascular events. Further studies with effective control arms and minimal CV risk are required determining precisely tiotropium's cardiovascular risk. PMID- 24950947 TI - The treatment of clavicular shaft fractures with an innovative locked intramedullary device. AB - BACKGROUND: Displaced and shortened clavicular shaft fractures can be treated by intramedullary fixation; however, hardware migration and soft tissue irritation at the insertion site have complicated its use. The aim of this study was to determine whether the new Sonoma CRx intramedullary device (Sonoma Orthopedic Products Inc, Santa Rosa, CA, USA) could be used successfully to treat displaced and shortened clavicular shaft fractures and restore the functional capacity of shoulder without the development of secondary complications. METHODS: Displaced and shortened clavicular shaft fractures in 47 consecutive patients were treated with the CRx device. Incision size was captured during the surgical procedure. The union rate was evaluated postoperatively. Shoulder function was assessed by Disabilities of the Arm, Shoulder and Hand (DASH) score, the Constant Shoulder Score, and a range of motion score. Patients were assessed after 3 to 6 months (group I), 6 to 9 months (group II), or 9 to 12 months (group III) postoperatively. RESULTS: Union was achieved in all patients at the time of review, without any incidence of hardware migration. Postoperative complications developed in 3 patients, comprising infection in 1 and hardware failure in 2. No differences among the groups were found for the DASH score (P = .33), Constant Shoulder Score (P = .38), and range of motion score (P = .96). The DASH, Constant Shoulder, and range of motion scores were similar to other successful treatment options, such as plating. CONCLUSION: The Sonoma CRx is a good alternative device to treat displaced and shortened clavicular shaft fractures and restore the functional capacity of the shoulder. Future research should focus on when nailing and plating should be used to treat clavicular shaft fractures most optimally. PMID- 24950948 TI - 2014 Neer Award Paper: neuromonitoring the Latarjet procedure. AB - BACKGROUND: We used intraoperative neuromonitoring to define the stages of the Latarjet procedure during which the nerves are at greatest risk. METHODS: Thirty four patients with a mean age of 28.4 years were included. The Latarjet procedure was divided into 9 defined stages. Bilateral median and ulnar somatosensory evoked responses and transcranial motor evoked potentials from all arm myotomes were continuously monitored. A "nerve alert" was defined as averaged 50% amplitude attenuation or 10% latency prolongation of ipsilateral somatosensory evoked responses and transcranial motor evoked potentials. For each nerve alert, the surgeon altered retractor placement, and if there was no response to this, the position of the operative extremity was then changed. RESULTS: Of 34 patients, 26 (76.5%) had 45 separate nerve alert episodes. The most common stages of the procedure for a nerve alert to occur were glenoid exposure and graft insertion. The axillary nerve was involved in 35 alerts; the musculocutaneous nerve, in 22. Of the 34 patients, 7 (20.6%) had a clinically detectable nerve deficit postoperatively, all correlated with an intraoperative nerve alert. All cases involved the axillary nerve, and all resolved completely from 28 to 165 days postoperatively. Prior surgery and body mass index were not predictive of a neurologic deficit postoperatively. However, total operative time (P = .042) and duration of the stage of the procedure in which the concordant nerve alert occurred (P = .010) were statistically significant predictors of a postoperative nerve deficit. CONCLUSIONS: The nerves, in particular the axillary and musculocutaneous nerves, are at risk during the Latarjet procedure, especially during glenoid exposure and graft insertion. PMID- 24950949 TI - Outcome and determinants of prognosis in patients undergoing isolated tricuspid valve surgery: retrospective single center analysis. AB - AIMS: Although tricuspid valve (TV) surgery has become more popular, isolated TV surgery is infrequently performed. The aims of this study were (1) to evaluate the postoperative and long-term mortality of patients undergoing isolated TV surgery, (2) to compare the outcomes of patients undergoing their first TV surgery or TV reoperation, and (3) to assess the additive value of echocardiographic and invasive hemodynamic evaluations for predicting postoperative outcome. METHODS: We followed a contemporary cohort of patients undergoing isolated TV surgery from January 1, 1995, through December 31, 2011. Preoperative demographic, echocardiographic, hemodynamic, and operative data were included. Outcome was all-cause mortality. RESULTS: Ninety-two patients (38% male; mean age: 56+/-14 years) were included. Kaplan-Meier survival analyses showed that 30-day, 3-month, 5-year, and 10-year mortality were 7.9%, 15.2%, 25.7%, and 53.7%, respectively. No difference in outcome was found between patients undergoing first TV surgery (n=61) and TV reoperation (n=31) (p=0.669). Univariable Cox analysis identified age (p<0.0001), extracardiac vascular disease (p=0.001), glomerular filtration rate (p=0.022), NYHA classification (p=0.010), and mean pulmonary artery pressure (p=0.005) as predictors of mortality. Multivariable analysis identified significant associations with outcome, only for age (p=0.010) and NYHA functional class (p=0.044). In younger patients (<59 years), mean pulmonary artery pressure was associated with the worse outcome (p=0.024). CONCLUSIONS: Isolated TV surgery is still associated with important postoperative and long-term mortality, both for first TV surgery and TV reoperation. Pre-operative NYHA functional class and, in younger patients, pulmonary hypertension appear to determine prognosis. PMID- 24950950 TI - [Impact of new Spanish smoke-free legislation on the business activity of bars, cafes and restaurants]. AB - OBJECTIVE: to analyze the impact of Spanish smoke-free legislation (Law 42/2010) on the business activity of bars, cafes, and restaurants. METHODS: we used the micro-data from the Household Budget Survey for 2010 and 2011. The linking files allowed close follow-up of the households that remained in the sample for 2 consecutive years. Taking the year 2010 as the base reference for our analyses, we quantified how levels of consumption expenses on hospitality venues have changed over the years, differentiating between smoking households and non smoking households. RESULTS: the marginal effects of the first stage of the two part model showed that the mean probability of expenditure on hospitality venues was 96% in smoking households and was 86% in non-smoking households. There were no statistically significant variations in the probability of expenditure between 2010 and 2011. The proportion of expenditure on hospitality venues in total household consumption expenditure in smoking households was 7.961% and 7.796% in 2010 and 2011, respectively. These proportions were 7.25% in 2010 and 7.272% in 2011 for non-smoking households. The difference in differences estimator, which takes into account both differences between years and households, showed no statistically significant differences in levels of household consumption. CONCLUSIONS: the introduction of the Law 42/2010 has had no impact on the levels of household consumption expenses on hospitality venues. Changes in consumption expenses could be explained by sociodemographic characteristics (such as the number of children per household) and the impact of the economic crisis (unemployment and a decrease in household income). PMID- 24950956 TI - Semi-supervised word polarity identification in resource-lean languages. AB - Sentiment words, as fundamental constitutive parts of subjective sentences, have a substantial effect on analysis of opinions, emotions and beliefs. Most of the proposed methods for identifying the semantic orientations of words exploit rich linguistic resources such as WordNet, subjectivity corpora, or polarity tagged words. Shortage of such linguistic resources in resource-lean languages affects the performance of word polarity identification in these languages. In this paper, we present a method which exploits a language with rich subjectivity analysis resources (English) to identify the polarity of words in a resource-lean foreign language. The English WordNet and a sparse foreign WordNet infrastructure are used to create a heterogeneous, multilingual and weighted semantic network. To identify the semantic orientation of foreign words, a random walk based method is applied to the semantic network along with a set of automatically weighted English positive and negative seeds. In a post-processing phase, synonym and antonym relations in the foreign WordNet are used to filter the random walk results. Our experiments on English and Persian languages show that the proposed method can outperform state-of-the-art word polarity identification methods in both languages. PMID- 24950951 TI - Outcome predictors of intra-articular glucocorticoid treatment for knee synovitis in patients with rheumatoid arthritis - a prospective cohort study. AB - INTRODUCTION: Intra-articular glucocorticoid treatment (IAGC) is widely used for symptom relief in arthritis. However, knowledge of factors predicting treatment outcome is limited. The aim of the present study was to identify response predictors of IAGC for knee synovitis in patients with rheumatoid arthritis (RA). METHODS: In this study 121 RA patients with synovitis of the knee were treated with intra-articular injections of 20 mg triamcinolone hexacetonide. They were followed for six months and the rate of clinical relapse was studied. Non responders (relapse within 6 months) and responders were compared regarding patient characteristics and knee joint damage as determined by the Larsen-Dale index. In addition, matched samples of serum and synovial fluid were analysed for factors reflecting the inflammatory process (C-reactive protein, interleukin 6, tumour necrosis factor alpha, vascular endothelial growth factor), joint tissue turnover (cartilage oligomeric matrix protein, metalloproteinase 3), and autoimmunity (antinuclear antibodies, antibodies against citrullinated peptides, rheumatoid factor). RESULTS: During the observation period, 48 knees relapsed (40%). Non-responders had more radiographic joint damage than responders (P = 0.002) and the pre-treatment vascular endothelial growth factor (VEGF) level in synovial fluid was significantly higher in non-responders (P = 0.002). CONCLUSIONS: Joint destruction is associated with poor outcome of IAGC for knee synovitis in RA. In addition, higher levels of VEGF in synovial fluid are found in non-responders, suggesting that locally produced VEGF is a biomarker for recurrence of synovial hyperplasia and the risk for arthritis relapse. PMID- 24950957 TI - Identification, characterization, and utilization of single copy genes in 29 angiosperm genomes. AB - BACKGROUND: Single copy genes are common across angiosperm genomes. With the sufficiently high quality sequenced genomes, the identification of large-scale single copy genes among multiple species is possible. Although some characteristics have been reported, our study provides novel insights into single copy genes. RESULTS: We identified single copy genes across 29 angiosperm genomes. A significant negative correlation was found between the number of duplicate blocks and the number of single copy genes. We found that a considerable number of single copy genes are located in organelles, showing a preference for binding and catalytic activity. The analysis of effective number of codons (Nc) illustrates that single copy genes have a stronger codon bias than non-single copy genes in eudicots. The relative high expression level of single copy genes was partially confirmed by the RNA-seq data, rather than the Codon Adaptation Index (CAI). Unlike in most other species, a strongly negatively correlation occurs between Nc and GC3 among single copy genes in grass genomes. When compared to all non-single copy genes, single copy genes indicate more conservation (as indicated by Ka and Ks values). But our alternative splicing (AS) results reveal that selective constraints are weaker in single copy genes than in low copy family genes (1-10 in-paralogs) and stronger than high copy family genes (>10 in-paralogs). Using concatenated shared single copy genes, we obtained a well-resolved phylogenetic tree. With the addition of intron sequences, the branch support is improved, but striking incongruences are also evident. Therefore, it is noteworthy that inclusion of intron sequences seems more appropriate for the phylogenetic reconstruction at lower taxonomic levels. CONCLUSIONS: Our analysis provides insight into the evolutionary characteristics of single copy genes across 29 angiosperm genomes. The results suggest that there are key differences in evolutionary constraints between single copy genes and non single copy genes. And to some extent, these evolutionary constraints show some species-specific differences, especially between eudicots and monocots. Our preliminary evidence also suggests that the concatenated shared single copy genes are well suited for use in resolving phylogenetic relationships. PMID- 24950958 TI - HIV/AIDS status disclosure increases support, behavioural change and, HIV prevention in the long term: a case for an Urban Clinic, Kampala, Uganda. AB - BACKGROUND: Disclosure of HIV status supports risk reduction and facilitates access to prevention and care services, but can be inhibited by the fear of negative repercussions. We explored the short and long-term outcomes of disclosure among clients attending an urban HIV clinic in Uganda. METHODS: Qualitative semi-structured interviews were administered to a purposeful sample of 40 adult HIV clients that was stratified by gender. The information elicited included their lived experiences and outcomes of disclosure in the short and long term. A text data management software (ATLAS.ti) was used for data analysis. Codes were exported to MS Excel and pivot tables, and code counts made to generate statistical data. RESULTS: Of the 134 short-term responses elicited during the interview regarding disclosure events, most responses were supportive including encouragement, advice and support regarding HIV care and treatment. The results show on-disclosing to spouse, there was more trust, and use of condoms for HIV prevention. Only one third were negative responses, like emotional shock and feeling of distress. The negative reactions to the spouses included rejection, shock and distress in the short term. Even then, none of these events led to drastic change such as divorce. Other responses reflected HIV prevention and call for behavioural change and advice to change sexual behaviour, recipient seeking HIV testing or care. Women reported more responses of encouragement compared to men. Men reported more preventive behaviour compared to women. Of the 137 long-term outcomes elicited during disclosure, three quarters were positive followed by behavioral change and prevention, and then negative responses. Men reported increased care and support when they disclosed to fellow men compared to when women disclosed to women. There was better or not change in relationship when women disclosed to women than when women disclosed to men. CONCLUSIONS: There is overwhelming support to individuals that disclose their HIV status, especially in the long term. Besides, gender appears to influence responses to HIV disclosure, highlighting the need for gender specific disclosure support strategies. PMID- 24950959 TI - Experimental evaluation of the sustainability of dwarf bamboo (Pseudosasa usawai) sprout-harvesting practices in Yangminshan National Park, Taiwan. AB - Sustainable harvest of natural products that meets the needs of local people has been viewed by many as an important means for sustaining conservation projects. Although plants often respond to tissue damage through compensatory growth, it may not secure long-term sustainability of the populations because many plants enhance individual well-being at the expense of propagation. Sustainability may further be threatened by infrequent, large-scale events, especially ill documented ones. We studied the impacts of sprout harvesting on sprout growth in a dwarf bamboo (Pseudosasa usawai) population that has seemingly recovered from an infrequent, large-scale masting event. Experimental results suggest that although a single sprout harvest did not significantly alter the subsequent abundance and structure of sprouts, culm damage that accompanied sprout harvesting resulted in shorter, thinner, and fewer sprouts. Weaker recovery was found in windward, continually harvested, and more severely damaged sites. These findings suggest that sprout growth of damaged dwarf bamboos is likely non compensatory, but is instead supported through physiological integration whose strength is determined by the well-being of the supplying ramets. Healthy culms closer to the damage also provided more resources than those farther away. Sustainable harvesting of sprouts could benefit from organized community efforts to limit the magnitude of culm damage, provide adequate spacing between harvested sites, and ensure sufficient time interval between harvests. Vegetation boundaries relatively resilient to infrequent, large-scale events are likely maintained by climatic factors and may be sensitive to climate change. Continual monitoring is, therefore, integral to the sustainability of harvesting projects. PMID- 24950960 TI - Effects of cryoablation and radiofrequency ablation on endothelial and blood clotting activation. AB - Cryoablation (CA) emerged as an alternative procedure to radiofrequency (RF). The aim of this study was to compare haemostatic system alterations in patients undergoing RF or CA for atrioventricular nodal reentrant tachycardia ablation. von Willebrand factor (vWF), spontaneous whole blood platelet aggregation, prothrombin fragment F1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), plasminogen activator inhibitor type-1 (PAI-1), and clot lysis time (CLT) were determined in 48 patients (27 CA; 21 RF; 19M/29F, mean age 49.6 +/- 17.6 years). Blood samples were obtained before the procedure (T0), immediately after (T1), and 24 h later (T2). At T1 both procedures were associated with a significant increase in levels of the endothelial activation marker vWF. At T2 vWF levels were lower in CA than in RF group. No changes in whole blood platelet aggregation before and after ablation procedures were observed. At T1 both groups determined an increase in blood clotting activation markers, F1 + 2, TAT, and DD. At T2 F1 + 2, TAT and DD levels were similar to baseline values. The comparison between RF and CA showed no significant differences in F1 + 2 and TAT levels, whereas at T1 DD levels were higher in CA group than in RF group. Both procedures induced a significant decrease in CLT, whereas no changes in PAI-1 levels were found. There were no significant differences in CLT and PAI-1 levels. The fibrinolytic efficiency analysis showed that at T1 DD/TAT and DD/F1 + 2 ratios were lower in RF group and remained lower in RF than in CA group at T2. CA procedure may be associated with a lower degree of endothelial damage and with a higher fibrinolytic capacity respect to RF. PMID- 24950961 TI - An 85-year-old man with acute-onset of confusion and dyspnea after a fall: a diagnostic challenge. PMID- 24950962 TI - Unusual presentation of primary T-cell lymphoblastic lymphoma: description of two cases. AB - BACKGROUND: T-cell lymphoblastic lymphoma comprises approximately 85-90% of all lymphoblastic lymphomas. It often arises as a mediastinal mass, and with bone marrow involvement. Presentation at other sites without nodal or mediastinal localization is uncommon. CASE REPORT: We describe clinical, histologic, immunohistochemical, and molecular features of two cases of primary T-cell lymphoblastic lymphoma arising respectively in uterine corpus and testis. The tumors were composed by medium to large cells, exhibiting a diffuse pattern of growth but sometimes forming indian files or pseudo-rosettes. The neoplastic cells strongly expressed TdT and T-cell markers in both uterine corpus and testis. However, the testis case also showed aberrant expression of B-cell markers, thus molecular biology was necessary to achieve a final diagnosis. T cell receptor gene rearrangement analysis identified a T-cell origin. CONCLUSIONS: To the best of our knowledge, only one doubtful previous case of primary uterine T-cell lymphoblastic lymphoma and no previous cases of primary testicular T-cell lymphoblastic lymphoma have been reported. Due to the morphology of neoplastic cells, a challenging differential diagnosis with all the tumors belonging to the so-called small round blue cell tumor category is mandatory. In ambiguous lineage cases, molecular biology may represent an adequate tool to confirm diagnosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1559880973128230. PMID- 24950963 TI - Genetic control of heterochrony in Eucalyptus globulus. AB - A change in the timing or rate of developmental events throughout ontogeny is referred to as heterochrony, and it is a major evolutionary process in plants and animals. We investigated the genetic basis for natural variation in the timing of vegetative phase change in the tree Eucalyptus globulus, which undergoes a dramatic change in vegetative morphology during the juvenile-to-adult transition. Quantitative trait loci analysis in an outcross F2 family derived from crosses between individuals from a coastal population of E. globulus with precocious vegetative phase change and individuals from populations in which vegetative phase change occurs several years later implicated the microRNA EglMIR156.5 as a potential contributor to this heterochronic difference. Additional evidence for the involvement of EglMIR156.5 was provided by its differential expression in trees with early and late phase change. Our findings suggest that changes in the expression of miR156 underlie natural variation in vegetative phase change in E. globulus, and may also explain interspecific differences in the timing of this developmental transition. PMID- 24950964 TI - G-protein-coupled receptor signaling and polarized actin dynamics drive cell-in cell invasion. AB - Homotypic or entotic cell-in-cell invasion is an integrin-independent process observed in carcinoma cells exposed during conditions of low adhesion such as in exudates of malignant disease. Although active cell-in-cell invasion depends on RhoA and actin, the precise mechanism as well as the underlying actin structures and assembly factors driving the process are unknown. Furthermore, whether specific cell surface receptors trigger entotic invasion in a signal-dependent fashion has not been investigated. In this study, we identify the G-protein coupled LPA receptor 2 (LPAR2) as a signal transducer specifically required for the actively invading cell during entosis. We find that G12/13 and PDZ-RhoGEF are required for entotic invasion, which is driven by blebbing and a uropod-like actin structure at the rear of the invading cell. Finally, we provide evidence for an involvement of the RhoA-regulated formin Dia1 for entosis downstream of LPAR2. Thus, we delineate a signaling process that regulates actin dynamics during cell-in-cell invasion. PMID- 24950966 TI - Primary Epstein-Barr virus infection diffusing F18-fluorodeoxyglucose-positron emission tomography/computed tomography response monitoring of Hodgkin's disease: a case report. AB - INTRODUCTION: Hodgkin's disease is highly curable by radiotherapy and/or chemotherapy, but refractory disease or early relapses are rarely cured by conventional salvage therapy. CASE PRESENTATION: We report a case of a 20-year old Caucasian man, with a biopsy-proven intrapulmonary relapse of Hodgkin's disease, for whom salvage chemotherapy was administered. During salvage chemotherapy intense increased F18-fluorodeoxyglucose uptake was noticed in multiple lymph nodes and diffuse increased splenic uptake, suggesting chemotherapy-refractory disease. However, additional information obtained from the patient revealed he recently had met his first girlfriend. An asymptomatic primary Epstein-Barr virus infection was considered proven. CONCLUSIONS: Interim F18-fluorodeoxyglucose-positron emission tomography/computed tomography is a strong prognostic factor for advanced Hodgkin's and may better identify those patients needing intensified chemotherapy. Related to the nonspecificity of F18 fluorodeoxyglucose, clinical awareness of the potential interference of intercurrent asymptomatic viral infections with treatment and remission status monitoring continues to be important in the interpretation of equivocal medical imaging results. PMID- 24950965 TI - A molecular model for the role of SYCP3 in meiotic chromosome organisation. AB - The synaptonemal complex (SC) is an evolutionarily-conserved protein assembly that holds together homologous chromosomes during prophase of the first meiotic division. Whilst essential for meiosis and fertility, the molecular structure of the SC has proved resistant to elucidation. The SC protein SYCP3 has a crucial but poorly understood role in establishing the architecture of the meiotic chromosome. Here we show that human SYCP3 forms a highly-elongated helical tetramer of 20 nm length. N-terminal sequences extending from each end of the rod like structure bind double-stranded DNA, enabling SYCP3 to link distant sites along the sister chromatid. We further find that SYCP3 self-assembles into regular filamentous structures that resemble the known morphology of the SC lateral element. Together, our data form the basis for a model in which SYCP3 binding and assembly on meiotic chromosomes leads to their organisation into compact structures compatible with recombination and crossover formation. PMID- 24950967 TI - Video Q & A: The impact of stress. An interview with George Chrousos. AB - In this video Q & A, we talk to George Chrousos about stress and its impact on chronic non-communicable disorders (NCDs) and early life development. Professor Chrousos also discusses the effects of psychological and economical stressors on health, and suggests ways in which we can learn to cope with stress. PMID- 24950968 TI - Selection for narrow gate of emergence results in correlated sex-specific changes in life history of Drosophila melanogaster. AB - Since the ability to time rhythmic behaviours in accordance with cyclic environments is likely to confer adaptive advantage to organisms, the underlying clocks are believed to be selected for stability in timekeeping over evolutionary time scales. Here we report the results of a study aimed at assessing fitness consequences of a long-term laboratory selection for tighter circadian organisation using fruit fly Drosophila melanogaster populations. We selected flies emerging in a narrow window of 1 h in the morning for several generations and assayed their life history traits such as pre-adult development time, survivorship, adult lifespan and lifetime fecundity. We chose flies emerging during the selection window (in the morning) and another window (in the evening) to represent adaptive and non-adaptive phenotypes, respectively, and examined the correlation of emergence time with adult fitness traits. Adult lifespan of males from the selected populations does not differ from the controls, whereas females from the selected populations have significantly shorter lifespan and produce more eggs during their mid-life compared to the controls. Although there is no difference in the lifespan of males of the selected populations, whether they emerge in morning or evening window, morning emerging females live slightly shorter and lay more eggs during the mid-life stage compared to those emerging in the evening. Interestingly, such a time of emergence dependent difference in fitness is not seen in flies from the control populations. These results, therefore, suggest reduced lifespan and enhanced mid-life reproductive output in females selected for narrow gate of emergence, and a sex-dependent genetic correlation between the timing of emergence and key fitness traits in these populations. PMID- 24950970 TI - Smed-dynA-1 is a planarian nervous system specific dynamin 1 homolog required for normal locomotion. AB - Dynamins are GTPases that are required for separation of vesicles from the plasma membrane and thus are key regulators of endocytosis in eukaryotic cells. This role for dynamin proteins is especially crucial for the proper function of neurons, where they ensure that synaptic vesicles and their neurotransmitter cargo are recycled in the presynaptic cell. Here we have characterized the dynamin protein family in the freshwater planarian Schmidtea mediterranea and showed that it possesses six dynamins with tissue specific expression profiles. Of these six planarian homologs, two are necessary for normal tissue homeostasis, and the loss of another, Smed-dynA-1, leads to an abnormal behavioral phenotype, which we have quantified using automated center of mass tracking. Smed-dynA-1 is primarily expressed in the planarian nervous system and is a functional homolog of the mammalian Dynamin I. The distinct expression profiles of the six dynamin genes makes planarians an interesting new system to reveal novel dynamin functions, which may be determined by their differential tissue localization. The observed complexity of neurotransmitter regulation combined with the tools of quantitative behavioral assays as a functional readout for neuronal activity, renders planarians an ideal system for studying how the nervous system controls behavior. PMID- 24950969 TI - An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells. AB - Embryonic Stem cells derived from the epiblast tissue of the mammalian blastocyst retain the capability to differentiate into any adult cell type and are able to self-renew indefinitely under appropriate culture conditions. Despite the large amount of knowledge that we have accumulated to date about the regulation and control of self-renewal, efficient directed differentiation into specific tissues remains elusive. In this work, we have analysed in a systematic manner the interaction between the dynamics of loss of pluripotency and Activin/Nodal, BMP4 and Wnt signalling in fate assignment during the early stages of differentiation of mouse ES cells in culture. During the initial period of differentiation, cells exit from pluripotency and enter an Epi-like state. Following this transient stage, and under the influence of Activin/Nodal and BMP signalling, cells face a fate choice between differentiating into neuroectoderm and contributing to Primitive Streak fates. We find that Wnt signalling does not suppress neural development as previously thought and that it aids both fates in a context dependent manner. Our results suggest that as cells exit pluripotency they are endowed with a primary neuroectodermal fate and that the potency to become endomesodermal rises with time. We suggest that this situation translates into a "race for fates" in which the neuroectodermal fate has an advantage. PMID- 24950972 TI - Retraction notice. PMID- 24950971 TI - Comparative cation dependency of sugar transport by crustacean hepatopancreas and intestine. AB - Glucose is transported in crustacean hepatopancreas and intestine by Na(+) dependent co-transport, while Na(+)-dependent D-fructose influx has only been described for the hepatopancreas. It is still unclear if the two sugars are independently transported by two distinct cation-dependent co-transporter carrier systems. In this study, lobster (Homarus americanus) hepatopancreas brush border membrane vesicles (BBMV) were used to characterize, in detail, the cation dependency of both D-[(3)H]-glucose and D-[(3)H]-fructose influxes, while in vitro perfused intestines were employed to determine the nature of cation dependent sugar transport across this organ. Over the sodium concentration range of 0-100 mM, both [(3)H]-glucose and [(3)H]-fructose influxes (0.1 mM; 1 min uptakes) by hepatopancreatic BBMV were hyperbolic functions of [Na(+)]. [(3)H] glucose and [(3)H]-fructose influxes by hepatopancreatic BBMV over a potassium concentration range of 15-100 mM were hyperbolic functions of [K(+)]. Both sugars displayed significant (p<0.01) Na(+)/K(+)-dependent and cation-independent uptake processes. Transepithelial 25 uM [(3)H]-glucose and [(3)H]-fructose fluxes across lobster intestine over luminal sodium and potassium concentration ranges of 0-50 mM and 5-100 mM, respectively, were hyperbolic functions of luminal [Na(+)] and [K(+)]. As with hepatopancreatic sugar transport, transepithelial intestinal sugar transport exhibited both significant (p<0.01) Na(+)/K(+)-dependent and cation-independent processes. Results suggest that both D-glucose and D-fructose are transported by a single SGLT-type carrier in each organ with sodium being the "preferred", high affinity, cation for both sugars in the hepatopancreas, and potassium being the "preferred", high affinity, cation for both sugars in the intestine. PMID- 24950974 TI - The Last Page: Answers to questions from issue 54(2). PMID- 24950975 TI - The Last Page: Question. PMID- 24950976 TI - Proteome-scale identification of outer membrane proteins in Mycobacterium avium subspecies paratuberculosis using a structure based combined hierarchical approach. AB - Outer membrane proteins (OMPs) in eubacteria have several important roles, which range from membrane transport to the host-pathogen interactions. These are directly involved in pathogen attachment, entry and activation of several pathogen-induced signaling cascades in the cell. The cardinal structural features of OMPs include the presence of a beta-barrel, a signal peptide and the absence of the transmembrane helix. This is the first report on proteome-wide identification of OMPs of ruminant pathogen, Mycobacterium avium subsp. paratuberculosis (MAP). The complete proteome of MAP was analyzed using a pipeline of algorithms, which screens the amino acid sequences and structural features shared by OMPs in other bacteria. Secondary structure of these proteins is also analyzed and scores are calculated for amphiphilic beta-strands. From the set of 588 exported proteins, 264 proteins are predicted to be inner membrane proteins while 83 proteins are identified as potential OMPs in MAP. Finally, this study identified 57 proteins as top candidates, on the basis of computed isoelectric points, as the core set of OMPs. Significantly, the resulting data for OMPs are not only useful in designing novel vaccines but may also open avenues for the development of early serodiagnostic tools for MAP. PMID- 24950977 TI - The immunogenicity of breast cancer--molecular subtypes matter. PMID- 24950978 TI - Carboplatin's fourth decade: still searching for its sweet spot. PMID- 24950979 TI - Delivering precision medicine in oncology today and in future-the promise and challenges of personalised cancer medicine: a position paper by the European Society for Medical Oncology (ESMO). PMID- 24950980 TI - Immunoscoring breast cancer: TILs remember what they target. PMID- 24950981 TI - Intensive care in patients with lung cancer: a multinational study. AB - BACKGROUND: Detailed information about lung cancer patients requiring admission to intensive care units (ICUs) is mostly restricted to single-center studies. Our aim was to evaluate the clinical characteristics and outcomes of lung cancer patients admitted to ICUs. PATIENTS AND METHODS: Prospective multicenter study in 449 patients with lung cancer (small cell, n = 55; non-small cell, n = 394) admitted to 22 ICUs in six countries in Europe and South America during 2011. Multivariate Cox proportional hazards frailty models were built to identify characteristics associated with 30-day and 6-month mortality. RESULTS: Most of the patients (71%) had newly diagnosed cancer. Cancer-related complications occurred in 56% of patients; the most common was tumoral airway involvement (26%). Ventilatory support was required in 53% of patients. Overall hospital, 30 day, and 6-month mortality rates were 39%, 41%, and 55%, respectively. After adjustment for type of admission and early treatment-limitation decisions, determinants of mortality were organ dysfunction severity, poor performance status (PS), recurrent/progressive cancer, and cancer-related complications. Mortality rates were far lower in the patient subset with nonrecurrent/progressive cancer and a good PS, even those with sepsis, multiple organ dysfunctions, and need for ventilatory support. Mortality was also lower in high-volume centers. Poor PS predicted failure to receive the initially planned cancer treatment after hospital discharge. CONCLUSIONS: ICU admission was associated with meaningful survival in lung cancer patients with good PS and non recurrent/progressive disease. Conversely, mortality rates were very high in patients not fit for anticancer treatment and poor PS. In this subgroup, palliative care may be the best option. PMID- 24950982 TI - Endometrial beta3 integrin profile reflects endometrial receptivity defects in women with unexplained recurrent pregnancy loss. AB - BACKGROUND: The pathophysiology of recurrent pregnancy loss (RPL) is still unknown in 50% of the cases. Herein we measure the expression of beta3 integrin subunit, a well-known implantation marker, in women with or without RPL and correlate it with the histological dating of the endometrial tissue. METHODS: LH timed endometrial biopsies were obtained from cases (RPL; n = 21, age 33.9+/-4.7) and healthy controls (n = 29; age 29.8+/-4.1) during the mid-secretory phase (post ovulatory day: 8 to 10). Endometrial samples were timed histologically according to Noyes' criteria and underwent immunohistochemical staining for beta3 integrin expression. For statistical analysis the semi-quantitative HSCORE was assessed. Type I (beta3 negative in an out-of-phase endometrium) and Type II defect (beta3 negative in an in-phase endometrium) were also analysed. Statistical analysis was done with Student t-test, Mann Whitney U test, ANCOVA and chi square for trend. Significance was set as P < 0.05. RESULTS: The mean (SD) age in controls was lower compared to cases [(29.8 (4.1) vs. 33.9 (4.7) - P = 0.001; Student t-test)]. The median (range) expression of beta3 integrin in controls and cases was 1.94 (0 to 3.5) vs. 0.82 (0 to 3.6), respectively (P = 0.001; Mann Whitney U test). Significance was still significant after adjusting for age (P = 0.03;ANCOVA). The normal positive staining > =0.7 of beta3 integrin subunit and in-phase endometrium was seen in 24 out of 29 (82.8%) controls, but in only 6 out of 21 (28.6%) of cases with RPL; Type I and II defects were seen in 10.3 and 6.9% of controls, while present in 52.4 and 19.1% of cases, respectively (P = 0.0005; chi-square). CONCLUSIONS: Women with unexplained RPL had significantly reduced integrin expression compared to controls. Our findings underline the need for further molecular analysis of endometrial tissue in affected women. PMID- 24950983 TI - Development of a novel neuroprotective strategy: combined treatment with hypothermia and valproic acid improves survival in hypoxic hippocampal cells. AB - BACKGROUND: Therapeutic hypothermia and histone deacetylase inhibitors, such as valproic acid (VPA), independently have been shown to have neuroprotective properties in models of cerebral ischemic and traumatic brain injury. However, the depth of hypothermia and the dose of VPA needed to achieve the desired result are logistically challenging. It remains unknown whether these two promising strategies can be combined to yield synergistic results. We designed an experiment to answer this question by subjecting hippocampal-derived HT22 cells to severe hypoxia in vitro. METHODS: Mouse hippocampal HT22 cells were exposed to 200 MUM cobalt chloride (CoCl(2)), which created hypoxic conditions in vitro. Cells were incubated for 6 or 30 hours under the following conditions: (1) Dulbecco's Modified Eagle Medium; (2) 200 MUM CoCl(2); (3) 200 MUM CoCl(2) plus 1 mmol/L VPA; (4) 200 MUM CoCl(2) plus 32 degrees C hypothermia; and (5) 200 MUM CoCl(2) plus both 1 mmol/L VPA and 32 degrees C hypothermia. Cellular viability was evaluated by (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) and lactate dehydrogenase release assays at 30 hours after treatment. Levels of acetylated histone H3, hypoxia-inducible factor-1alpha, phospho-GSK-3beta, beta catenin, and high-mobility group box-1 were measured by Western blotting. RESULTS: High levels of acetylated histone H3 were detected in the VPA-treated cells. The release of lactate dehydrogenase was greatly suppressed after the combined hypothermia + VPA treatment (0.269 +/- 0.003) versus VPA (0.836 +/- 0.026) or hypothermia (0.451 +/- 0.005) treatments alone (n = 3, P = .0001). (3 (4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay showed that the number of viable cells was increased by 17.6 % when VPA and hypothermia were used in combination (n = 5, P = .0001). Hypoxia-inducible factor-1alpha and phospho-GSK-3beta expression were synergistically affected by the combination treatment, whereas high-mobility group box-1 was increased by VPA treatment, and inhibited by the hypothermia. CONCLUSION: This is the first study to demonstrate that the neuroprotective effects of VPA and hypothermia are synergistic. This novel approach can be used to develop more effective therapies for the prevention of neuronal death. PMID- 24950984 TI - Trebananib: an alternative anti-angiogenic strategy. PMID- 24950985 TI - Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA 1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial. AB - BACKGROUND: Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. METHODS: For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m(2)) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (>=0 and <=6 months vs >6 and <=12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients. FINDINGS: 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7.2 months [5.8-7.4] vs 5.4 months [95% CI 4.3-5.5], respectively, hazard ratio 0.66, 95% CI 0.57-0.77, p<0.0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 [54%] of 452 patients in the placebo group vs 258 [56%] of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 [17%] patients vs 27 [6%], respectively) and higher incidences of oedema (294 [64%] patients had any-grade oedema in the trebananib group vs 127 [28%] patients in the placebo group). Grade 3 or higher adverse events included ascites (34 [8%] in the placebo group vs 52 [11%] in the trebananib group), neutropenia (40 [9%] vs 26 [6%]), and abdominal pain (21 [5%] vs 22 [5%]). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 [17%] vs 46 [10%]). INTERPRETATION: Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti VEGF associated adverse events were not prominent. FUNDING: Amgen. PMID- 24950986 TI - Gefitinib for oesophageal cancer: a cog in need of a wheel? PMID- 24950988 TI - "A Western diet side story": the effects of transitioning to a Western-type diet on fertility. PMID- 24950987 TI - Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. AB - BACKGROUND: Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer. METHODS: For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0-2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179. FINDINGS: Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3.73 months, 95% CI 3.23 4.50, for gefitinib vs 3.67 months, 95% CI 2.97-4.37, for placebo; hazard ratio [HR] 0.90, 95% CI 0.74-1.09, p=0.29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference -8.61, 95% CI -14.49 to -2.73; n=227; p=0.004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2.69, 95% CI -2.33 to 7.72, n=231, p=0.293), dysphagia (-3.18, 95% CI -8.36 to 2.00, n=231, p=0.228), and eating (-4.11, 95% CI -9.96 to 1.75, n=229, p=0.168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1.57 months, 95% CI 1.23-1.90 in the gefitinib group vs 1.17 months, 95% CI 1.07-1.37 in the placebo group; HR 0.80, 95% CI 0.66-0.96, p=0.020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3-4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0.023). INTERPRETATION: The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients. FUNDING: Cancer Research UK. PMID- 24950989 TI - The genetics of obesity meets basic cell biology through prohormone convertase 1/3. PMID- 24950990 TI - Neurokinin B: a new player in immune/inflammatory stress-mediated suppression of reproduction. PMID- 24950991 TI - Usefulness of a new inflammation-based scoring system for prognostication of patients with hepatocellular carcinoma after hepatectomy. AB - BACKGROUND: We investigated whether a preoperative scoring system (the "CRP-AFP Score [CAS]") based on the serum levels of C-reactive protein and alpha fetoprotein would predict outcome in patients undergoing hepatectomy for hepatocellular carcinoma. METHODS: The CAS was defined as follows: patients with an elevated level of both C-reactive protein (>.3 mg/dL) and alpha-fetoprotein (>20 ng/mL) were assigned a score of 2, and patients showing one or none of these abnormalities were assigned a score of 1 or 0, respectively. RESULTS: A total of 349 patients were identified. Pathologic findings, in terms of tumor size, histologic grade, vascular invasion, intrahepatic metastasis, and recurrence rate, worsened as the CAS increased. CAS 2 patients had a poorer 5-year overall survival than CAS 0 or 1 patients (32.2% vs 59.7% vs 49.2%, respectively; P < .001). CONCLUSIONS: The CAS is an informative scoring system that can predict outcome in patients with hepatocellular carcinoma after hepatectomy. PMID- 24950992 TI - Mesoscopic structures of triglyceride nanosuspensions studied by small-angle X ray and neutron scattering and computer simulations. AB - Aqueous suspensions of platelet-like shaped tripalmitin nanocrystals are studied here at high tripalmitin concentrations (10 wt % tripalmitin) for the first time by a combination of small-angle X-ray and neutron scattering (SAXS and SANS). The suspensions are stabilized by different lecithins, namely, DLPC, DOPC, and the lecithin blend S100. At such high concentrations the platelets start to self assemble in stacks, which causes interference maxima at low Q-values in the SAXS and SANS patterns, respectively. It is found that the stack-related interference maxima are more pronounced for the suspension stabilized with DOPC and in particular DLPC, compared to suspensions stabilized by S100. By use of the X-ray and neutron powder pattern simulation analysis (XNPPSA), the SAXS and SANS patterns of the native tripalmitin suspensions could only be reproduced simultaneously when assuming the presence of both isolated nanocrystals and stacks of nanocrystals of different size in the simulation model of the dispersions. By a fit of the simulated SAXS and SANS patterns to the experimental data, a distribution of the stack sizes and their volume fractions is determined. The volume fraction of stacklike platelet assemblies is found to rise from 70% for S100-stabilized suspensions to almost 100% for the DLPC-stabilized suspensions. The distribution of the platelet thicknesses could be determined with molecular resolution from a combined analysis of the SAXS and SANS patterns of the corresponding diluted tripalmitin (3 wt %) suspensions. In accordance with microcalorimetric data, it could be concluded that the platelets in the suspensions stabilized with DOPC, and in particular DLPC, are significantly thinner than those stabilized with S100. The DLPC-stabilized suspensions exhibit a significantly narrower platelet thickness distribution compared to DOPC- and S100-stabilized suspensions. The smaller thicknesses for the DLPC- and DOPC stabilized platelets explain their higher tendency to self-assemble in stacks. The finding that the nanoparticles of the suspension stabilized by the saturated lecithin DLPC crystallize in the stable beta-tripalmitin modification with its characteristic platelet-like shape is surprising and can be explained by the fact that the main phase transformation temperature for DLPC is, as for unsaturated lecithins like DOPC and S100, well below the crystallization temperature of the supercooled tripalmitin emulsion droplets. PMID- 24950994 TI - Critical age affecting 1-year functional outcome in elderly patients aged >= 70 years with aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: While advanced age is already recognized as an independent risk factor for a poor functional outcome following an aneurysmal subarachnoid hemorrhage (SAH), it is also important to investigate the critical age for defining a higher risk population among elderly patients and the clinical grade at admission in order to provide a prognostic description and help guide the management of patients aged >= 70 years. METHODS: This retrospective study included 165 patients aged 70-90 years who underwent surgical or endovascular treatment for a ruptured aneurysm. In addition to medical and radiological data, telephone interviews were used to obtain the 1-year functional outcome. RESULTS: A multivariate analysis revealed age (p = 0.001) and the World Federation of Neurological Surgeons (WFNS) grade (p = 0.001), regardless of the treatment modalities (surgical versus endovascular), as significant risk factors for a poor outcome, while a receiver operating characteristic analysis revealed 75 years as an appropriate cutoff value for the patient age to predict a poor 1-year functional outcome (area under the curve: 0.683). For the patients aged 70-75 years with good (1-3) and poor (4-5) WFNS grades, 81.9 % and 42.9 % achieved a favorable outcome (modified Rankin Scale 0-3), respectively, whereas for the patients over the critical age (> 75 years) with good and poor WFNS grades, 54.8 % and 5.9 % achieved a favorable outcome, respectively. CONCLUSIONS: The long term outcome for elderly patients with an aneurysmal SAH is affected primarily by the clinical condition at admission and the patient's age in relation to the critical age (> 75 years), regardless of the treatment modalities, including surgical clipping and endovascular coiling. PMID- 24950995 TI - The effect of videotape augmented feedback on drop jump landing strategy: Implications for anterior cruciate ligament and patellofemoral joint injury prevention. AB - BACKGROUND: Modification of high-risk movement strategies such as dynamic knee valgus is key to the reduction of anterior cruciate ligament (ACL) and patellofemoral joint (PFJ) injuries. Augmented feedback, which includes video and verbal feedback, could offer a quick, simple and effective alternative to training programs for altering high-risk movement patterns. It is not clear whether feedback can reduce dynamic knee valgus measured using frontal plane projection angle (FPPA). METHODS: Vertical ground reaction force (vGRF), two dimensional FPPA of the knee, contact time and jump height of 20 recreationally active university students were measured during a drop jump task pre- and post- an augmented feedback intervention. A control group of eight recreationally active university students were also studied at baseline and repeat test. RESULTS: There was a significant reduction in vGRF (p=0.033), FPPA (p<0.001) and jump height (p<0.001) and an increase in contact time (p<0.001) post feedback in the intervention group. No changes were evident in the control group. CONCLUSION: Augmented feedback leads to significant decreases in vGRF, FPPA and contact time which may help to reduce ACL and PFJ injury risk. However, these changes may result in decreased performance. CLINICAL RELEVANCE: Augmented feedback reduces dynamic knee valgus, as measured via FPPA, and forces experienced during the drop jump task and therefore could be used as a tool for helping decrease ACL and PFJ injury risk prior to, or as part of, the implementation of injury prevention training programs. PMID- 24950993 TI - Anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis show distinct patterns of brain glucose metabolism in 18F fluoro-2-deoxy-d-glucose positron emission tomography. AB - BACKGROUND: Pathogenic autoantibodies targeting the recently identified leucine rich glioma inactivated 1 protein and the subunit 1 of the N-methyl-D-aspartate receptor induce autoimmune encephalitis. A comparison of brain metabolic patterns in 18F-fluoro-2-deoxy-d-glucose positron emission tomography of anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis patients has not been performed yet and shall be helpful in differentiating these two most common forms of autoimmune encephalitis. METHODS: The brain 18F-fluoro-2 deoxy-d-glucose uptake from whole-body positron emission tomography of six anti-N methyl-D-aspartate receptor encephalitis patients and four patients with anti leucine rich glioma inactivated 1 protein encephalitis admitted to Hannover Medical School between 2008 and 2012 was retrospectively analyzed and compared to matched controls. RESULTS: Group analysis of anti-N-methyl-D-aspartate encephalitis patients demonstrated regionally limited hypermetabolism in frontotemporal areas contrasting an extensive hypometabolism in parietal lobes, whereas the anti-leucine rich glioma inactivated 1 protein syndrome was characterized by hypermetabolism in cerebellar, basal ganglia, occipital and precentral areas and minor frontomesial hypometabolism. CONCLUSIONS: This retrospective 18F-fluoro-2-deoxy-d-glucose positron emission tomography study provides novel evidence for distinct brain metabolic patterns in patients with anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis. PMID- 24950996 TI - Mobile-bearing total knee arthroplasty: More rotation is evident during more demanding tasks. AB - BACKGROUND: Some reports showed few but significant more axial femorotibial rotation in favor of mobile-bearing (MB) versus fixed-bearing (FB) total knee arthroplasty (TKA), mostly during knee bend fluoroscopic studies. The goal of the current study was to submit MB and FB groups of TKA patients to a turning activity, in which additional rotation was to be expected. METHODS: Two consecutive cohorts of patients after TKA (10 FB and 11 MB knees in a total of 18 patients) were assessed using motion analysis five year postoperatively, while performing gait and sit-to-walk (STW) movements with and without turning steps. RESULTS: Mean range of rotation in the FB group increased from 9.7 degrees during gait, to 11.7 degrees during STW straight, and to 14.3 degrees during STW turning. Mean range of rotation in the MB group increased from 13.4 degrees during gait to 21.0 degrees during STW straight, and stayed at 21.1 degrees during STW turning. CONCLUSIONS: Too many uncontrolled variables in the current study hinder a meaningful discrimination of MB from FB TKA rotation. However, the study does illustrate how more demanding task loads could be helpful in exploring the geometric constraints of TKA variants. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 24950999 TI - Clinical pearls often contain key concepts that are boiled into a pithy comment by an expert clinician. Foreword. PMID- 24950998 TI - Gonadotropin stimulation using P.G. 600(r) on reproductive success of non lactating anestrous ewes. AB - The effect of stimulation with a gonadotropin preparation with combined follicle stimulating and luteininzing hormone like activity on reproductive success in anestrous ewes was evaluated. In Experiment 1, ewes of mixed breeding were treated with CIDR inserts (0.3g progesterone) for 5 days and were assigned randomly to receive either gonadotropin stimulation (3mL i.m. injection of P.G. 600(r), 240IU eCG and 120IU hCG) at CIDR removal or no further treatment. Intact raddled rams were joined at insert removal for 30-35 days, and ewes were observed for indications of estrus after 4 days of ram exposure. Pregnancy diagnosis was conducted via transrectal ultrasonography at the time of ram removal and again 20 25 days. The second experiment was similar to Experiment 1, except treated ewes received the gonadotropin 1 day prior to insert removal. In Experiment 1, incidence of estrus was greater for treated ewes (P=0.01), and prolificacy tended to be greater in treated ewes (P=0.06). In Experiment 2, treated ewes had greater conception rates (P=0.01), pregnancy rates to first service (P=0.0007), and tended to have greater overall pregnancy rates than control ewes (P=0.07). A greater percentage of ewes lambed in the gonadotropin treated ewes than in ewes in the control group (P<0.0001), and overall lambing rates in treated ewes were greater than non-treated controls (P<0.0001). In conclusion, gonadotropin treatment 1 day prior to CIDR removal increased reproductive success in progesterone-treated anestrous ewes. PMID- 24951001 TI - Clinical pearls in gastroenterology 2012. PMID- 24950997 TI - Ovulation-inducing factor (OIF/NGF) from seminal plasma origin enhances Corpus Luteum function in llamas regardless the preovulatory follicle diameter. AB - Ovulation-inducing factor (OIF) is a protein present in llama seminal plasma that has recently been identified as beta-Nerve Growth Factor (NGF) and it induces not only a high rate of ovulation but also appears to have luteotrophic properties in this species. A 2-by-2 experimental design was used to determine the effect of treatments (OIF/NGF vs GnRH) and categories of preovulatory follicle diameter (7 10 vs >10mm) on ovulation rate, CL diameter and function in llamas. Llamas (n=32 llamas per group) were randomly assigned to receive an intramuscular dose of: (a) 1mg purified OIF/NGF in the presence of a follicle of 7-10mm in diameter; (b) 50 MUg of GnRH in the presence of a follicle of 7-10mm in diameter; (c) 1mg purified OIF/NGF in the presence of a follicle >10mm in diameter; (d) 50 MUg of GnRH in the presence of a follicle >10mm in diameter. Llamas were examined by ultrasonography every 12h from treatment to Day 2 (Day 0=treatment) to detect ovulation, and again on Day 8 to determine CL diameter. Ovulation rates did not differ among groups. There was an effect of preovulatory follicle size on Corpus Luteum diameter at Day 8 (P<0.001), however plasma progesterone concentration (n=15/per group) was higher (P<0.05) in the OIF/NGF - than that of the GnRH - treated group by the same day. We conclude that OIF/NGF treatment enhances CL function regardless preovulatory follicle size at the time of treatment. PMID- 24951002 TI - Clinical pearls in rheumatology. PMID- 24951003 TI - Clinical pearls in complementary and integrative medicine (CIM). PMID- 24951004 TI - Clinical pearls in dermatology 2013. PMID- 24951005 TI - Clinical pearls in gastroenterology (2013). PMID- 24951006 TI - Clinical pearls in pulmonary medicine (2013). PMID- 24951007 TI - Clinical pearls in women's health. PMID- 24951008 TI - Clinical pearls in dermatology 2014. PMID- 24951009 TI - Clinical pearls in gastroenterology 2014. PMID- 24951010 TI - Clinical pearls in infectious diseases. PMID- 24951011 TI - Clinical pearls in perioperative medicine. PMID- 24951012 TI - Clinical pearls in pulmonary medicine. PMID- 24951013 TI - Prevalence and long-term predictors of persistent chronic widespread pain in the general population in an 11-year prospective study: the HUNT study. AB - BACKGROUND: Chronic widespread pain (CWP) is common and associated with prominent negative consequences. The aim of this study was to assess the prevalence of persistent CWP in an 11-year prospective cohort study in the general population, and to examine anxiety, depression, alcohol use, poor sleep, body mass index (BMI) and chronic disease, along with demographic, lifestyle and other health related variables as possible predictors for the assumed CWP persistence. METHODS: CWP was defined as having pain at three or more predefined sites (involving the trunk and upper and lower limbs) for at least three months in the last year. We used a Norwegian general population cohort of 28,367 individuals who responded to both the second (1995-1997) and the third (2006-2008) waves of the Nord-Trondelag Health Study (HUNT2 and HUNT3, respectively). Data were analysed with logistic regression models. RESULTS: CWP prevalence in HUNT2 was 17%. Of those reporting CWP in HUNT2, 53% still reported CWP at follow-up in HUNT3. Adjusted analyses revealed that depression and alcohol consumption were not substantially associated with the 11-year prospective CWP outcome. Poor sleep, obesity and chronic disease predicted persistent CWP, and being male and/or 60 years or older was protective. CONCLUSIONS: This cohort study revealed that nearly half of the participants with baseline CWP resolved from CWP 11 years later. Among those whose CWP did not resolve, obesity, sleeping problems and chronic disease predicted CWP persistence, while aging and male sex was protective. Anxiety, mixed anxiety and depression, former smoking, and overweight were weakly associated, while depression, moderate exercise, and alcohol use were not associated with persistent CWP. PMID- 24951014 TI - Reliability and validity of a new measurement of lumbar foraminal volume using a computed tomography. AB - PURPOSE: Measuring foraminal stenosis is generally determined by an area calculation. It is difficult to know exactly where it is most appropriate to measure. No precise data are available on a method for calculating the foraminal volume using a CT. To develop a new method for measuring lumbar foraminal volume, we analyzed repeatability and reliability for measuring methods for foraminal volume using CT. METHODS: The measurements were performed using a CT scan from ten healthy patients, with a mean age of 26.3 years. L3-L4, L4-L5 and L5-S1 foramen were studied, to obtain 60 foraminal measurements. Inter- and intra observer reproducibility was calculated. Each series was analyzed using the VitreaCore(r) reconstruction software for volume calculation. RESULTS: Average volume measurements of 60 foramina and 20 L4-L5 foramina were, respectively, 1.17 and 1.25 mm(3) for observer 1 and 1.21 and 1.29 for observer 2. The intra observer correlation coefficients for observer 1 when measuring all foramina and L4-L5 foramina were 0.98 and 0.99, respectively. For observer 2, coefficients were 0.90 and 0.92, respectively. The inter-observer correlation coefficients for observer 1 when measuring all foramina and L4-L5 foramina were 0.78 and 0.83, respectively. For observer 2, coefficients were 0.77 and 0.8, respectively. The average differences in intra- and inter-observer measurements regardless of the evaluator group were less than 0.2 mm(3). CONCLUSIONS: This is the first study measuring lumbar foraminal volume using CT. The excellent reproducibility of this simple measure can supplement a range of foramen measurement tools. PMID- 24951015 TI - Evaluation of the zygomatic bone by cone beam computed tomography. AB - PURPOSE: The zygomatic bone (ZB) has been an effective option in the rehabilitation of the atrophic edentulous maxilla, in restoration of the low projection of the maxilla and in insertion of miniplates in maxillofacial fracture; it is situated near to air cells. In this way, the aim of this study was to evaluate the ZB by means of cone beam computed tomography (CBCT) images to determine if this bone can present characteristics similar to pneumatizations (CSPZB) and, in affirmative case, to determine its distribution concerning the age, gender, laterality and type. MATERIALS AND METHODS: CBCT of 698 patients (1.396 ZB) were evaluated to determine the presence of CSPZB. The age and gender were recorded for all patients and, for the cases of CSPZB, laterality and type (unilocular or multilocular) were noted. Its prevalence was correlated with gender, age and laterality by statistical analyses (Chi-squared test). RESULTS: 3.3% of individuals presented CSPZB. If we consider all zygomatic bones, CSPZB was in 2.8%. Of these cases, 30.5% were unilateral and 69.5% bilateral; all presented multilocular pattern. There was no statistical correlation between CSPZB and gender or age (p = 0.15 and 0.63, respectively), neither between CSPZB and laterality (p = 0.39). CONCLUSION: It was found an altered pattern similar to pneumatization in ZB; however, its prevalence was low (3.3% of the studied population). Our results indicate that the ZB should be evaluated in tomographic images prior to surgical treatments carefully. PMID- 24951016 TI - Crowd knowledge based community in radiotherapy: in response to Yartev et al. PMID- 24951019 TI - Tropheryma whipplei endocarditis: the value of valve polymerase chain reaction in cardiac surgery. PMID- 24951017 TI - Integrated models for the prediction of late genitourinary complaints after high dose intensity modulated radiotherapy for prostate cancer: making informed decisions. AB - BACKGROUND AND PURPOSE: To develop predictive models for late radiation-induced hematuria and nocturia allowing a patient individualized estimation of pre treatment risk. MATERIALS AND METHODS: We studied 262 PCa patients treated with curative intensity modulated radiotherapy to the intact prostate or prostate bed. A total of 372 variables were used for prediction modeling, among which 343 genetic variations. Toxicity was scored using an in-house developed toxicity scale. Predictor selection is achieved by the EMLasso procedure, a penalized logistic regression method with an EM algorithm handling missing data and crossvalidation avoiding overfit. Model performance was expressed by the area under the curve (AUC) and by sensitivity and specificity. RESULTS: Variables of the model predicting late hematuria (36/262) are bladder volume receiving ?75 Gy, prostatic transurethral resection and four polymorphisms. (AUC = 0.80, sensitivity = 83.3%, specificity = 61.5%). The AUC drops to 0.67 when the genetic markers are left out. The model that predicts for late nocturia (29/262) contains the minimal clinical target volume (CTV) dose, the CTV volume and three polymorphisms (AUC = 0.76, sensitivity = 75.9%, specify = 67.4%). This model is a better predictor for nocturia compared to the nongenetic model (AUC of 0.60). CONCLUSIONS: We were able to develop models that predict for the occurrence of late radiation-induced hematuria and nocturia, including genetic factors which might improve the prediction of late urinary toxicity. PMID- 24951018 TI - Extracorporeal membrane oxygenation in patients undergoing superior cavopulmonary anastomosis. AB - OBJECTIVE: Patients who have undergone the superior cavopulmonary anastomosis (Glenn procedure) have unique cardiopulmonary-cerebral physiology that may limit the success of cardiopulmonary resuscitation and extracorporeal membrane oxygenation (ECMO). Limited data published to date suggest grim morbidity and mortality when ECMO is used. We utilized the Extracorporeal Life Support Organization registry database to more thoroughly assess outcomes in these patients. METHODS: Data from the Extracorporeal Life Support Organization registry from 1999 to 2012 for children with Glenn physiology aged 3 months to 1 year were retrospectively analyzed. Demographics and ECMO characteristics were compared between survivors and nonsurvivors. Factors associated with mortality were evaluated using multivariate logistic regression. RESULTS: Of 103 infants, 42 (41%) survived to hospital discharge. Neurologic complications (eg, seizure, hemorrhage, or embolic stroke) were documented in 23% of patients (24 of 103) and 14% of survivors (6 of 42). In univariate analysis, inotropic requirement before ECMO, duration of ECMO, mechanical complications with the ECMO circuit, renal failure, and pulmonary hemorrhage or pneumothorax were predictors of mortality. In multivariate logistic regression, inotrope requirement (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.3-9.8), longer duration of ECMO support (OR, 7.2; 95% CI, 1.8-28), combined cardiopulmonary indication for ECMO (OR, 3.7; 95% CI, 1.4-9.7), and renal failure (OR, 4.2; 95% CI, 1.5-12) were associated with mortality. CONCLUSIONS: Mortality in infants with Glenn physiology supported with ECMO is lower than that previously reported, but the incidence of neurologic injury is high. These data support use of ECMO in patients with Glenn physiology with refractory cardiopulmonary failure. PMID- 24951020 TI - Hemostatic effects of fibrinogen concentrate compared with cryoprecipitate in children after cardiac surgery: a randomized pilot trial. AB - OBJECTIVES: Acute acquired hypofibrinogenemia in children undergoing cardiac surgery is a major concern because it often results in perioperative bleeding and high rates of allogeneic blood transfusion. Fibrinogen concentrate has been proposed as an alternative to cryoprecipitate (the gold standard therapy), with minimal infectious and immunologic risks. Our objective was to investigate the efficacy and safety of fibrinogen concentrate in children undergoing cardiac surgery. METHODS: In this randomized pilot study, patients were allocated to receive fibrinogen concentrate (60 mg/kg) or cryoprecipitate (10 mL/kg) if bleeding was associated with fibrinogen levels<1 g/dL after cardiopulmonary bypass weaning. The primary outcome was postoperative blood losses during the 48 hours after surgery. RESULTS: A total of 63 patients were included in the study, 30 in the fibrinogen concentrate group and 33 in the cryoprecipitate group. The median 48-hour blood loss was not significantly different between the 2 groups (320 mL [interquartile range, 157-750] vs 410 mL [interquartile range, 215-510], respectively; P=.672). After treatment, plasma fibrinogen concentration increased similarly following administration of both products. There were no differences in allogeneic blood transfusion after intervention treatment. CONCLUSIONS: A large trial comparing fibrinogen concentrate and cryoprecipitate in the management of children with acute acquired hypofibrinogenemia during heart surgery is feasible. The preliminary results of our study showed that the use of fibrinogen concentrate was as efficient and safe as cryoprecipitate in the management of bleeding children undergoing cardiac surgery. PMID- 24951021 TI - Neurologic and psycho-intellectual outcome related to structural brain imaging in adolescents and young adults after neonatal arterial switch operation for transposition of the great arteries. AB - OBJECTIVE: We studied brain structure abnormalities in adolescents and young adults who had undergone the neonatal arterial switch operation for transposition of the great arteries and related them to the neurologic and psycho-intellectual outcomes. METHODS: In a prospective longitudinal study, 60 unselected adolescents and young adults who had undergone surgery with combined deep hypothermic circulatory arrest and low flow cardiopulmonary bypass were re-evaluated at a mean age of 16.9+/-1.7 years to determine their clinical neurologic status, intellectual development, and psychological condition. The results were related to population norms and anatomic structural abnormalities assessed by brain magnetic resonance imaging, with consideration of the risk factors in the preoperative and perioperative periods. RESULTS: Neurologic impairment was more frequent (10%) than in the normal population. Although the average full-scale, verbal, and performance intelligence quotients were not reduced, scores>2 standard deviations less than the expected mean were increased. Above average scores were found for analytical thinking, but the orthography testing results were reduced. The self-rated psychological condition was better than expected. Magnetic resonance imaging demonstrated moderate or severe structural brain abnormalities in 32% of the patients. Periventricular leukomalacia was detected in >50%; its severity correlated with the grade of neurologic impairment, which correlated significantly with reduced intelligence, analytical thinking, and orthography. Preoperative acidosis and hypoxia were the only independent patient related risk factors for neurologic dysfunction, reduced intelligence, periventricular leukomalacia, and reduced brain volume. CONCLUSIONS: Despite encouraging overall neurodevelopmental outcomes, a significant minority had performances below the expected level, emphasizing the need for ongoing surveillance. Considering the high frequency of structural brain abnormalities, prospective long-term studies are needed to define their prognostic value with respect to the neuropsychological outcomes in childhood and adolescence. PMID- 24951023 TI - Symptoms mimicking dementia in a 60-year-old woman with bipolar disorder: a case report. AB - BACKGROUND: Dementia is generally considered an irreversible process of cognitive decline that can be caused by different neurodegenerative diseases. However, in some cases, dementia is caused by a non-neurodegenerative disease, such as an affective disorder. In these cases, the dementia can be reversible. Nevertheless, cognitive symptoms due to an affective disorder are often difficult to distinguish from a depressed mood due to a neurodegenerative disease. Especially in elderly patients with a history of affective disorder, a potentially reversible cause can be missed. CASE PRESENTATION: We describe a 60-year-old white woman with bipolar disorder, depressive symptoms, a movement disorder and severe cognitive impairment, in whom a neurodegenerative disease was seriously considered. She was referred to our clinic for further investigation because initial treatment of the depressive episode with antidepressants, mood stabilizers and electroconvulsive therapy (ECT) had not been successful. However, despite extensive evaluation, we could not find evidence for a neurodegenerative disease and the patient mostly recovered after discontinuation of different psychotropic medications and treatment with nortriptyline. CONCLUSIONS: Our case shows that improvement of severe cognitive impairment in individual cases is possible. In our opinion, this underlines the necessity of a careful re evaluation of the patient's symptoms at presentation and the course of the disease as well as a critical review of the prescribed medications. PMID- 24951022 TI - Outcome after surgery for prosthetic valve endocarditis and the impact of preoperative treatment. AB - OBJECTIVES: This study examined the outcomes of surgery for active prosthetic valve endocarditis in a recent decade, with special interest in preoperative treatment and predictors for early and late events. METHODS: From 2000 to 2010, a cohort of 149 consecutive patients (mean age, 64+/-13.9 years; 72% were male) underwent redo-surgery for prosthetic valve endocarditis and were reviewed regarding early (<=60 days) and late (>60 days) events (death, reinfection, reoperation). Kaplan-Meier survival curves and Cox regression analysis were used to investigate the impact of preoperative intervals and predictors for events, respectively. RESULTS: Preoperative status was critical (European System for Cardiac Operative Risk Evaluation>20%) in 121 patients (81.2%). Staphylococci were the most common infecting microorganisms (27.5%). The median interval between onset of symptoms and diagnosis and between diagnosis and operation was 2 days (interquartile range, 1-5) and 8 days (interquartile range, 2-23), respectively. Operative mortality (<=30 days) was 12.8%. Mean follow-up was 4+/ 2.9 years. In 53 patients, 47 early (24 deaths, 14 recurrences, 9 reoperations) and 22 late events (11 deaths, 9 recurrences, 2 reoperations) occurred. Overall and event-free survivals at 10 years were 75%+/-3.8% and 64%+/-4.0%, respectively. Freedom from recurrent infection and reoperation at 10 years were 81%+/-3.6% and 91%+/-2.6%, respectively. In multivariate Cox regression, mechanical circulatory support, prolongation between onset of symptoms and diagnosis more than 30 days, and preoperative presence of renal failure predicted early events, and double valve replacement predicted late events. CONCLUSIONS: Cardiac and renal function, need for double valve replacement, and preoperative treatment predicted outcomes. A prolonged interval in which patients were left untreated while symptomatic, but not prolongation of preoperative antibiotic treatment, increased risk. PMID- 24951024 TI - "We are people too": consumer participation and the potential transformation of therapeutic relations within drug treatment. AB - BACKGROUND: While there is growing recognition of the benefits of user involvement within drug treatment there is scant literature documenting the actual implementation of such initiatives. Nonetheless, the extant research is remarkably consistent in identifying poor relationships between service users and staff as a principal barrier to the successful implementation of consumer participation. Focussing on participants' accounts of change within the 'therapeutic alliance', this paper investigates a consumer participation initiative introduced within three Australian drug treatment services. METHODS: In 2012, the New South Wales Users and AIDS Association (NUAA), a state-based drug user organisation, introduced a consumer participation initiative within three treatment facilities across the state. This paper draws on 57 semi structured interviews with staff and service-user project participants. Approximately ten participants from each site were recruited and interviewed at baseline and six months later at evaluation. RESULTS: The enhanced opportunities for interaction enabled by the consumer participation initiative fostered a sense of service users and staff coming to know one another beyond the usual constraints and limitations of their relationship. Both sets of participants described a diminution of adversarial relations: an unsettling of the 'them and us' treatment divide. The routine separation of users and staff was challenged by the emergence of a more collaborative ethos of 'working together'. Participants noted 'seeing' one another--the other--differently; as people rather than simply an identity category. CONCLUSION: For service users, the opportunity to have 'a voice' began to disrupt the routine objectification or dehumanisation that consistently, if unintentionally, characterises the treatment experience. Having a voice, it seemed, was synonymous with being human, with having ones' 'humanness' recognised. We contend that not only did the introduction of consumer participation appear to empower service users and enhance the therapeutic alliance, it may have also improved service quality and health outcomes. PMID- 24951026 TI - Thyroid cancer. PMID- 24951027 TI - Proposed new clinicopathological surrogate definitions of luminal A and luminal B (HER2-negative) intrinsic breast cancer subtypes. AB - INTRODUCTION: The St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 recognized substantial progress in the pathological characterization of breast cancer subtypes. A useful surrogate definition was developed to distinguish luminal A-like breast cancer from luminal B-like disease based on a combination of estrogen receptor (ER), progesterone receptor (PgR) and Ki-67 status, without a requirement for molecular diagnostics. Differences depend upon the choice of the threshold value for Ki-67 and the requirement for substantial PgR positivity. We aimed to verify the suitability of the new surrogate definitions of luminal subtypes in terms of distant disease control in a large series of patients. METHODS: We studied 9,415 women with a median follow up of 8.1 years who (1) had ER-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer and (2) had undergone surgery at the European Institute of Oncology between 1994 and 2006. We evaluated distant disease-free survival of patients with "low" (<14%), "intermediate" (14% to 19%) or "high" (>=20%) Ki-67 positivity stratified by PgR expression (negative or low versus high). We calculated the cumulative incidence of distant events, considered competing events and performed multivariable analysis adjusted for pathologic tumor stage, pathologic node stage, tumor grade, peritumoral vascular invasion and menopausal status. RESULTS: Lack of substantial PgR positivity was associated with poorer outcomes only for patients with an intermediate Ki-67 level (P<0.001). The 4,890 patients (51.9%) with low Ki-67 level (any PgR expression level) or with intermediate Ki-67 level but substantial PgR positivity had comparably good outcomes and thus may represent a most advantageous grouping of those with luminal A-like disease. CONCLUSIONS: The updated pathological definition of intrinsic molecular subtypes may maximize the number of patients classified as having the luminal A-like intrinsic subtype of breast cancer and for whom the use of cytotoxic drugs could mostly be avoided. PMID- 24951025 TI - Within-prison drug injection among HIV-infected Ukrainian prisoners: prevalence and correlates of an extremely high-risk behaviour. AB - BACKGROUND: In Ukraine, HIV-infection, injection drug use, and incarceration are syndemic; however, few services are available to incarcerated people who inject drugs (PWIDs). While data are limited internationally, within-prison drug injection (WP-DI) appears widespread and may pose significant challenges in countries like Ukraine, where PWIDs contribute heavily to HIV incidence. To date, WP-DI has not been specifically examined among HIV-infected prisoners, the only persons that can transmit HIV. METHODS: A convenience sample of 97 HIV-infected adults recently released from prison within 1-12 months was recruited in two major Ukrainian cities. Post-release surveys inquired about WP-DI and injection equipment sharing, as well as current and prior drug use and injection, mental health, and access to within-prison treatment for HIV and other comorbidities. Logistic regression identified independent correlates of WP-DI. RESULTS: Complete data for WP-DI were available for 95 (97.9%) respondents. Overall, 54 (56.8%) reported WP-DI, among whom 40 (74.1%) shared injecting equipment with a mean of 4.4 (range 0-30) other injectors per needle/syringe. Independent correlates of WP DI were recruitment in Kyiv (AOR 7.46, p=0.003), male gender (AOR 22.07, p=0.006), and active pre-incarceration opioid use (AOR 8.66, p=0.005). CONCLUSIONS: Among these recently released HIV-infected prisoners, WP-DI and injection equipment sharing were frequent and involved many injecting partners per needle/syringe. The overwhelming majority of respondents reporting WP-DI used opioids both before and after incarceration, suggesting that implementation of evidence-based harm reduction practices, such as opioid substitution therapy and/or needle/syringe exchange programmes within prison, is crucial to addressing continuing HIV transmission among PWIDs within prison settings. The positive correlation between Kyiv site and WP-DI suggests that additional structural interventions may be useful. PMID- 24951028 TI - Closure of large defects after microcystic lymphatic malformations using lateral intercostal artery perforator flap. AB - BACKGROUND AND AIM: The surgical treatment of microcystic lymphatic malformations (LMs) has historically been difficult and frustrating because of a high recurrence rate due to incomplete resection. However, complete removal of the multifocal and extensive lesions rely on accurate imaging diagnosis and effective repair methods for the resulting large defect. The purpose of this study was to repair large skin defects due to complete resection of microcystic LMs using lateral intercostal artery perforator (LICAP) flap. PATIENTS AND METHODS: Between January 2009 and June 2012, tissue defects in the axillary chest wall region of eight patients aged 13-22 years after microcystic LMs resections were closed using the LICAP flap. Flap donor sites in all patients were closed primarily except in one patient who underwent skin grafting. Before surgery, ultrasound and magnetic resonance imaging (MRI) examination were used to confirm the diagnosis and determine the scope and level of the abnormality for complete resection. RESULTS: All defects after microcystic LM excision were successfully closed using LICAP flaps. The follow-up period ranged from 1 to 3 years (mean 2.1 years). All flaps survived postoperatively. No recurrence occurred. Ultrasound and MRI follow up also demonstrated flap survival without recurrence of microcystic LMs. No functional loss attributable to the LICAP flap harvest was identified in any case. CONCLUSIONS: Surgical resection is necessary for microcystic LMs. Imaging assists in the diagnosis and identification of the scope and level of lesions. The LICAP flap provides good coverage for the large defects and achieves acceptable morphology without functional deficits at flap donor sites. Ultrasound and MRI are safe and accurate diagnostic imaging methods for the pre- and postoperative evaluation of microcystic LMs in patients undergoing surgery. PMID- 24951029 TI - Contralateral C7 transfer to lower trunk via the prespinal route in the repair of brachial plexus injury: an experimental study in rats. AB - Contralateral C7 (cC7) root transfer to reconstruct brachial plexus injury (BPI) has been widely used. A revised technique that cC7 root was transferred to lower trunk via the prespinal route with direct neurorrhaphy has been reported clinically. The aim of this experimental study was to develop an animal model of the modified surgical approach in order to obtain quantification index of postoperative nerve regeneration and muscle morphology. Sixty adult Sprague Dawley rats randomized into experimental and control groups of 30 each. In the experimental group, after total brachial plexus injury (BPI) the cC7 root was transferred to lower trunk via the prespinal route with direct neurorrhaphy, and in the control group the brachial plexus was only exposed without intervention. Electrophysiological study, muscle tension test, neuromorphology, muscle wet weight, and muscle fiber cross-sectional area measurements were obtained 4, 8, and 12 weeks postoperatively. Median and ulnar nerve regeneration and the forearm flexor muscles functional recovery were obtained by cC7 root transfer to lower trunk via the prespinal route when measured at 12 weeks following the operation though the parameters had not recovered to normal value. We concealed the control and experimental groups from those who did the evaluations. PMID- 24951030 TI - The "Chicken Hand": a training model for hand surgery. PMID- 24951031 TI - Engineering of synthetic cellular microenvironments: implications for immunity. AB - In this article, we discuss novel synthetic approaches for studying the interactions of cells with their microenvironment. Notably, critical cellular processes such as growth, differentiation, migration, and fate determination, are tightly regulated by interactions with neighboring cells, and the surrounding extracellular matrix. Given the huge complexity of natural cellular environments, and their rich molecular and physical diversity, the mission of understanding "environmental signaling" at a molecular-mechanistic level appears to be extremely challenging. To meet these challenges, attempts have been made in recent years to design synthetic matrices with defined chemical and physical properties, which, artificial though they may be, could reveal basic "design principles" underlying the physiological processes. Here, we summarize recent developments in the characterization of the chemical and physical properties of cell sensing and adhesion, as well as the design and use of engineered, micro- to nanoscale patterned and confined environments, for systematic, comprehensive modulation of the cells' environment. The power of these biomimetic surfaces to highlight environmental signaling events in cells, and in immune cells in particular, will be discussed. PMID- 24951032 TI - Lumbar spine texture enhances 10-year fracture probability assessment. AB - We found that lumbar spine texture analysis using trabecular bone score (TBS) is a risk factor for MOF and a risk factor for death in a retrospective cohort study from a large clinical registry for the province of Manitoba, Canada. INTRODUCTION: FRAX(r) estimates the 10-year probability of major osteoporotic fracture (MOF) using clinical risk factors and femoral neck bone mineral density (BMD). Trabecular bone score (TBS), derived from texture in the spine dual X-ray absorptiometry (DXA) image, is related to bone microarchitecture and fracture risk independently of BMD. Our objective was to determine whether TBS provides information on MOF probability beyond that provided by the FRAX variables. METHODS: We included 33,352 women aged 40-100 years (mean 63 years) with baseline DXA measurements of lumbar spine TBS and femoral neck BMD. The association between TBS, the FRAX variables, and the risk of MOF or death was examined using an extension of the Poisson regression model. RESULTS: During the mean of 4.7 years, 1,754 women died and 1,872 sustained one or more MOF. For each standard deviation reduction in TBS, there was a 36 % increase in MOF risk (HR 1.36, 95 % CI 1.30-1.42, p < 0.001) and a 32 % increase in death (HR 1.32, 95 % CI 1.26 1.39, p < 0.001). When adjusted for significant clinical risk factors and femoral neck BMD, lumbar spine TBS was still a significant predictor of MOF (HR 1.18, 95 % CI 1.12-1.23) and death (HR 1.20, 95 % CI 1.14-1.26). Models for estimating MOF probability, accounting for competing mortality, showed that low TBS (10th percentile) increased risk by 1.5-1.6-fold compared with high TBS (90th percentile) across a broad range of ages and femoral neck T-scores. CONCLUSIONS: Lumbar spine TBS is able to predict incident MOF independent of FRAX clinical risk factors and femoral neck BMD even after accounting for the increased death hazard. PMID- 24951033 TI - Exercise preconditioning-induced late phase of cardioprotection against exhaustive exercise: possible role of protein kinase C delta. AB - The objective of this study was to investigate the late cardiac effect of exercise preconditioning (EP) on the exhaustive exercise-induced myocardial injury in rats and the role of protein kinase C (PKC) in EP. Rats were subjected to a run on the treadmill for four periods of 10 min each at 30 m/min with intervening periods of rest of 10 min as an EP protocol. The exhaustive exercise was performed 24 h after EP. PKC inhibitor chelerythrine (CHE) was injected before EP. The results showed that EP increased the running ability of rats, and alleviated the exhaustive exercise-induced injury in cardiomyocytes, but pretreatment with PKC inhibitor CHE did not abolish the late phase cardioprotection of EP. A significant increase of PKCdelta, both at the protein level and the mRNA level in the left ventricular myocardium of rats, accompanied by its activated form (phosphorylated on Thr507, p-PKCdeltaThr507) translocated to intercalated disks and was found in the late phase of EP. This circumstance was not attenuated by CHE. These results suggested that a high level of PKCdelta might be involved in cardioprotection against myocardial damage, but if activated PKCdelta at reperfusion took on a key role in cardioprotection was still an outstanding question. PMID- 24951036 TI - Giant Gartner duct cyst and elevated CA-125. AB - BACKGROUND: Gartner duct cysts represent vestigial remnants of the caudal end of the mesonephric (Wolffian) ducts. They are often associated with ureteral and renal abnormalities. In most cases they are solitary, less than 2 cm in diameter. Giant Gartner duct cysts are extremely rare. CASE: We present a girl with a giant Gartner duct cyst, without notable associated abnormalities or pathology, successfully treated by surgical excision. Preoperative aspiration revealed elevated level of CA-125 in the cyst fluid, with normal serum level of the same marker. CONCLUSION: Analyzing the aspirated fluid for CA-125 may be a useful tool for evaluation of cystic lesions in this region. PMID- 24951034 TI - Fine-tuning T cell receptor signaling to control T cell development. AB - T cell development from immature CD4(+)CD8(+) double-positive (DP) thymocytes to the mature CD4 or CD8 single-positive (SP) stage requires proper T cell receptor (TCR) signaling. The current working model of thymocyte development is that the strength of the TCR-mediated signal - from little-or-none, through intermediate, to strong - received by the immature cells determines whether they will undergo death by neglect, positive selection, or negative selection, respectively. In recent years, several developmentally regulated, stage-specifically expressed proteins and miRNAs have been found that act like fine-tuners for signal transduction and propagation downstream of the TCR. This allows them to govern thymocyte positive selection. Here, we summarize recent findings on these molecules and suggest new concepts of TCR positive-selection signaling. PMID- 24951035 TI - Neonatal cytokines and chemokines and risk of Autism Spectrum Disorder: the Early Markers for Autism (EMA) study: a case-control study. AB - BACKGROUND: Biologic markers of infection and inflammation have been associated with Autism Spectrum Disorders (ASD) but prior studies have largely relied on specimens taken after clinical diagnosis. Research on potential biologic markers early in neurodevelopment is required to evaluate possible causal pathways and screening profiles. OBJECTIVE: To investigate levels of cytokines and chemokines in newborn blood specimens as possible early biologic markers for autism. METHODS: We conducted a population-based case-control study nested within the cohort of infants born from July 2000 to September 2001 to women who participated in the prenatal screening program in Orange County, California, USA. The study population included children ascertained from the California Department of Developmental Services with Autism Spectrum Disorder (ASD, n = 84), or developmental delay but not ASD (DD, n = 49), and general population controls randomly sampled from the birth certificate files and frequency matched to ASD cases on sex, birth month and birth year (GP, n = 159). Cytokine and chemokine concentrations were measured in archived neonatal blood specimens collected for routine newborn screening. RESULTS: Cytokines were not detected in the vast majority of newborn samples regardless of case or control status. However, the chemokine monocyte chemotactic protein-1 (MCP-1) was elevated and the chemokine Regulated upon Activation Normal T-Cell Expressed and Secreted (RANTES) was decreased in ASD cases compared to GP controls. The chemokines macrophage inflammatory protein-1alpha (MIP-1alpha) and RANTES were decreased in children with DD compared to GP controls. CONCLUSION: Measurement of immune system function in the first few days of life may aid in the early identification of abnormal neurodevelopment and shed light on the biologic mechanisms underlying normal neurodevelopment. PMID- 24951038 TI - Employee knowledge of value-based insurance design benefits. AB - BACKGROUND: Value-based insurance designs (VBD) incorporate evidence-based medicine into health benefit design. Consumer knowledge of new VBD benefits is important to assessing their impact on health care use. PURPOSE: To assess knowledge of features of a VBD. METHODS: The eligible study population was employees receiving healthcare benefits in an integrated care system in the U.S. Pacific Northwest. In 2010, participants completed a web-based survey 2 months after rollout of the plan, including three true/false questions about benefit design features including copays for preventive care visits and chronic disease medications and premium costs. Analysis was completed in 2012. Knowledgeable was defined as correct response to all three questions; self-reported knowledge was also assessed. RESULTS: A total of 3,463 people completed the survey (response rate=71.7%). The majority of respondents were female (80.1%) Caucasians (79.6%) aged 35-64 years (79.0%), reflecting the overall employee population. A total of 45.7% had at least a 4-year college education, and 69.1% were married. About three quarters of respondents correctly answered each individual question; half (52.1%) of respondents answered all three questions correctly. On multivariate analysis, knowledge was independently associated with female gender (OR=1.80, 95% CI=1.40, 2.31); Caucasian race (OR=1.72, 95% CI=1.28, 2.32); increasing household income (OR for >=$100,000=1.86, 95% CI=1.29, 2.68); nonunion job status (OR compared to union status=1.63, 95% CI=1.17, 2.26); and high satisfaction with the health plan (OR compared to low satisfaction=1.26; 95% CI=1.00, 1.57). CONCLUSIONS: Incomplete knowledge of benefits is prevalent in an employee population soon after VBD rollout. PMID- 24951037 TI - Fecal-based colorectal cancer screening among the uninsured in northern Manhattan. AB - BACKGROUND: Colorectal cancer (CRC) screening reduces CRC mortality; however, for many reasons, uninsured individuals are less likely to utilize CRC screening tests. PURPOSE: To compare CRC screening behaviors and outcomes with guaiac fecal occult blood testing (gFOBT) from 1998 to 2006 and fecal immunochemical testing (FIT) from 2006 to 2010 in a community-based program serving uninsured patients in northern Manhattan. METHODS: In 2013, we conducted a retrospective record review of individuals aged >=50 years who received fecal-based CRC screening at the Northern Manhattan Cancer Screening Partnership between 1998 and 2010. Included were those with household income <=250% of the federal poverty level, no medical insurance coverage, and who were not up to date with CRC screening. We assessed screening positivity rate, positive predictive value, differences in the use of diagnostic colonoscopy, colonoscopic findings, and adenoma detection rates for gFOBT versus FIT. RESULTS: In total, 7,710 patients completed CRC screenings (4,951 gFOBT and 2,759 FIT). The majority were female, Hispanic, foreign born, and young at age of first screening. Compared to gFOBT, FIT detected twice as many positive tests (3.2% vs 1.5%, p<=0.001) and had a higher adenoma detection rate (18.2 vs 11.8, p=0.002). CONCLUSIONS: The improved positivity and adenoma detection rates with greater number of screening tests over time favor the use of FIT over gFOBT for colorectal screening among uninsured populations in northern Manhattan. PMID- 24951040 TI - Gambling with our health: smoke-free policy would not reduce tribal casino patronage. AB - BACKGROUND: Tribal sovereignty exempts tribal casinos from statewide smoking bans. PURPOSE: To conduct a tribally-led assessment to identify the characteristics of casino patrons at Lake of the Torches Resort Casino in Lac du Flambeau WI and their preferences for a smoke-free casino. METHODS: A survey was administered from April to August 2011 to a stratified random sample of 957 members of the casino players club to assess their preferences for a smoke-free casino. These members were categorized into three groups: those who reported being likely to (1) visit more; (2) visit less; or (3) visit the same if the casino prohibited smoking. They were characterized by age, education, sex, race/ethnicity, annual income, players club level, and reasons for visiting the casino. Statistical analyses were conducted on weighted data in October to December 2011. Weighted logistic regression was calculated to control for potential confounding of patron characteristics. RESULTS: Of the 957 surveyed patrons, 520 (54%) patrons were likely to visit more; 173 (18%) patrons to visit less; and 264 (28%) patrons were indifferent to the smoke-free status. Patrons more likely to prefer a smoke-free casino tended to be white, elderly, middle class and above, and visit the casino restaurants. Patrons within the lower tiers of the players club, almost half of the players club members, also showed a higher preference for a smoke-free casino. CONCLUSIONS: This tribal casino would likely realize increased patronage associated with smoke-free status while also contributing to improved health for casino workers and patrons. PMID- 24951042 TI - Sexual and reproductive health care: adolescent and adult men's willingness to talk and preferred approach. AB - INTRODUCTION: Sexually active adolescent and adult men have substantial sexual and reproductive health (SRH) needs, but little is known about their willingness and preferred approach to talk about SRH with their healthcare provider. PURPOSE: To examine participants' willingness to talk about 11 SRH topics, including sexually transmitted disease (STD) risk; human papilloma virus (HPV) vaccine; condom use; female birth control methods; emergency contraception; concerns about sexual performance or making someone pregnant; being a father; relationships; testicular cancer; and acne, with their healthcare provider and their preferred approach (provider- or self-initiated). METHODS: This cross-sectional clinic based survey of 346 men aged 16-35 years was conducted in 2011. Bivariate analyses conducted in 2012 examined variation in study outcomes by participants' predisposing (age, race/ethnicity); enabling (education, past provider SRH discussion); and need factors (SRH concern). RESULTS: Almost all participants (84%-98%) were willing to talk about all SRH topics. The top three topics included STD risk (98%); testicular cancer (98%); and HPV vaccine (97%). Among those willing to talk, the majority preferred their provider initiate the discussion (52%-88%). Participants reporting past provider discussions were more likely to prefer that their provider initiate discussions on condom use, female birth control methods, concerns about sexual performance and making someone pregnant, and relationships. Study outcomes did not vary by any other participant predisposing, enabling, or need factors. CONCLUSIONS: These findings indicate that adolescent and adult men are willing to discuss a wide range of SRH topics with their healthcare provider. Providers need to move beyond whether male patients want to talk about these topics and instead proactively promote these conversations. PMID- 24951041 TI - Influenza vaccination among persons with work-related asthma. AB - BACKGROUND: Seasonal influenza vaccination is recommended for all asthma patients. Persons with work-related asthma may have more severe disease than those with non-work-related asthma and may particularly benefit from receiving influenza vaccination. PURPOSE: To determine if influenza vaccination coverage differs among individuals aged 18-64 years with work-related and non-work-related asthma. METHODS: Data from the 2006-2009 Behavioral Risk Factor Surveillance System Asthma Call-Back Survey collected in 38 states and the District of Columbia were analyzed in 2013. Multivariable logistic regression and predictive marginal analyses were conducted to identify factors independently associated with influenza vaccination among respondents aged 18-64 years with work-related asthma. RESULTS: Among adults aged 18-64 years with current asthma, an estimated 42.7% received influenza vaccination in the past 12 months. Although influenza vaccination coverage was significantly higher among adults with work-related asthma than those with non-work-related asthma (48.5% vs 42.8%), this association became non-significant after adjustment for demographic and clinical characteristics (prevalence ratio=1.08, 95% CI=0.99, 1.20). Among individuals with work-related asthma, receiving the influenza vaccine was associated with being 50-64 years old, being unemployed in the prior year, and seeking urgent treatment for worsening asthma symptoms. CONCLUSIONS: Among persons with work related and non-work-related asthma, less than half received influenza vaccination in the prior year, both below the Healthy People 2010 target of 60%. These results suggest the need for strengthening current vaccination interventions to meet the updated Healthy People 2020 objective of achieving at least 70% influenza vaccination coverage. PMID- 24951039 TI - Quantifying cardiometabolic risk using modifiable non-self-reported risk factors. AB - BACKGROUND: Sensitive general cardiometabolic risk assessment tools of modifiable risk factors would be helpful and practical in a range of primary prevention interventions or for preventive health maintenance. PURPOSE: To develop and validate a cumulative general cardiometabolic risk score that focuses on non-self reported modifiable risk factors such as glycosylated hemoglobin (HbA1c) and BMI so as to be sensitive to small changes across a span of major modifiable risk factors, which may not individually cross clinical cut-off points for risk categories. METHODS: We prospectively followed 2,359 cardiovascular disease (CVD) free subjects from the Framingham offspring cohort over a 14-year follow-up. Baseline (fifth offspring examination cycle) included HbA1c and cholesterol measurements. Gender-specific Cox proportional hazards models were considered to evaluate the effects of non-self-reported modifiable risk factors (blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking, BMI, and HbA1c) on general CVD risk. We constructed 10-year general cardiometabolic risk score functions and evaluated its predictive performance in 2012-2013. RESULTS: HbA1c was significantly related to general CVD risk. The proposed cardiometabolic general CVD risk model showed good predictive performance as determined by cross-validated discrimination (male C-index=0.703, 95% CI=0.668, 0.734; female C-index=0.762, 95% CI=0.726, 0.801) and calibration (lack-of-fit chi-square=9.05 [p=0.338] and 12.54 [p=0.128] for men and women, respectively). CONCLUSIONS: This study presents a risk factor algorithm that provides a convenient and informative way to quantify cardiometabolic risk on the basis of modifiable risk factors that can motivate an individual's commitment to prevention and intervention. PMID- 24951044 TI - UPMC MyHealth: managing the health and costs of U.S. healthcare workers. AB - BACKGROUND: Workplace wellness programs hold promise for managing the health and costs of the U.S. workforce. These programs have not been rigorously tested in healthcare worksites. PURPOSE: To evaluate the impact of MyHealth on the health and costs of UPMC healthcare workers. DESIGN: Five-year observational study conducted in 2013 with subgroup analyses and propensity-matched pair comparisons to more accurately interpret program effects. SETTING/PARTICIPANTS: UPMC, an integrated health care delivery and financing system headquartered in Pittsburgh, Pennsylvania. Participants included 13,627 UPMC employees who were continuously enrolled in UPMC-sponsored health insurance during the study period and demonstrated participation in MyHealth by completing a Health Risk Assessment in both 2007 and 2011, as well as 4,448 other healthcare workers employed outside of UPMC who did not participate in the program. INTERVENTION: A comprehensive wellness, prevention, and chronic disease management program that ties achievement of health and wellness requirements to receipt of an annual credit on participants' health insurance deductible. MAIN OUTCOME MEASURES: Health-risk levels, medical, pharmacy, and total healthcare costs, and Healthcare Effectiveness Data and Information Set performance rates for prevention and chronic disease management. RESULTS: Significant improvements in health-risk status and increases in use of preventive and chronic disease management services were observed in the intervention group. Although total healthcare costs increased significantly, reductions in costs were significant for those who moved from higher- to the lowest-risk levels. The contrast differences in costs between reduced- and maintained-risk groups was also significant. Matched pair comparisons provided further evidence of program effects on observed reductions in costs and improvements in prevention, but not improvements in chronic disease management. CONCLUSIONS: Incorporating incentivized health management strategies in employer-sponsored health insurance benefit designs can serve as a useful, though not sufficient, tool for managing the health and costs of the U.S. healthcare workforce. PMID- 24951045 TI - What happened to hypersexual disorder? PMID- 24951043 TI - Acculturation and maternal health behaviors: findings from the Massachusetts birth certificate. AB - BACKGROUND: Although prior studies have shown disparities in maternal health behaviors according to race/ethnicity and acculturation, whether these patterns are evident among new immigrant populations remains unclear. PURPOSE: To examine the associations among proxies of acculturation and maternal smoking during pregnancy and breastfeeding initiation within each major ethnic group in Massachusetts. METHODS: Data were from the Standard Certificate of Live Births on 1,067,375 babies by mothers from 31 ethnic groups for 1996-2009. Mothers reported whether they smoked during pregnancy and the birth facility recorded whether mothers started breastfeeding. The acculturation proxy combined mothers' country of birth and language preference: U.S.-born, foreign-born English-speaking, and foreign-born non-English speaking. For each ethnic group, adjusted logistic regression models were used to examine associations between the acculturation proxy and whether mothers smoked or initiated breastfeeding. Data were analyzed from 2012 to 2013. RESULTS: A lower proportion of foreign-born mothers had a high school degree or private insurance than U.S.-born mothers. However, foreign-born mothers who were English (range of AORs=0.07-0.93) or non-English speakers (AORs=0.01-0.36) were less likely to smoke during pregnancy than their U.S.-born counterparts. Foreign-born mothers who were English (AORs=1.22-6.52) or non English speakers (AORs=1.35-10.12) were also more likely to initiate breastfeeding compared to U.S.-born mothers, except for some mothers with Asian ethnicities. CONCLUSIONS: The consistency of the associations of being foreign born with less smoking and more breastfeeding suggests that for the majority of ethnic groups studied, acculturation in the U.S. results in poorer maternal health behaviors. PMID- 24951046 TI - Citation analysis of the prognosis of Haux et al. for the year 2013. AB - In 2002, Haux, Ammenwerth, Herzog, and Knaup published a prognosis about health care in the information society. In contrast to other prognoses, they underpinned their 30 theses with 71 quantitative statements that could be easily checked. A citation analysis was performed to assess the perception of this work in the medical informatics community. The ISI Web of Science was used for the citation search. From 55 hits, 38 articles were finally included in the metadata analysis, 33 articles in the qualitative analysis. The most prominent statement citing the paper of Haux et al. was identified in each article, divided into statements about the present and those about the future. Each statement was tagged with one keyword out of a convenient list. One article provided a statement about the present and the future. Most of the references were published in English as journal articles between 2006 and 2009. The majority of the first authors were from Europe. Twenty-two articles offered a statement about the present, 12 about the future. There was a shift from the present emphasis on electronic medical records and information and communication technologies to challenges in the future because of an aging population and the advent of personalized medicine. The citing papers seemed to be representative of medical informatics in terms of journals and the authors' countries of origin. The statements relating the citing literature with the paper of Haux et al. corresponded well with current notions about medical informatics. However, there was no debate about the concrete theses and prognoses offered in the cited paper. Therefore, the medical informatics community needs to rethink its own citation strategy. PMID- 24951047 TI - Targetable micelleplex hydrogel for long-term, effective, and systemic siRNA delivery. AB - We developed a targetable micelleplex hydrogel as a new efficient systemic siRNA delivery material that functions as a targetable gene carrier, and a hydrogel capable of controlled release to overcome drawbacks of multiple administrations of systemic siRNA carriers due to decreased fluctuation of them in the serum. The micelleplexes, complexes between polymeric micelles and siRNAs could turn into gel after subcutaneous injection and be slowly released from the gel. The released micelleplexes selectively accumulated in the tumor and showed anti-tumor effect due to gene silencing for an extended period of time with only one injection in anywhere in vivo model. Moreover, the duration of therapy can be controlled by adjusting the amount and properties of the hydrogel. Therefore, this micelleplex hydrogel is expected to be a new effective siRNA delivery material for systemic long-term gene silencing. PMID- 24951049 TI - FAS and FAS ligand gene polymorphisms in Egyptian females with preeclampsia. AB - We aimed to evaluate the association of Fas polymorphism and the Fas ligand with preeclampsia, investigating whether the G 670 Fas gene variant and the Fas Ligand INV2nt 124 G variant had a differential distribution in patients with preeclampsia. The preeclamptic group consisted of 50 pregnant women who developed preeclampsia, while the control group consisted of 50 age-matched pregnant women with uncomplicated pregnancies. Fas and Fas ligand gene polymorphisms were tested using polymerase chain reaction-restriction fragment length polymorphism. Regarding the Fas 670 A>G polymorphism, statistically significant differences were found between the two groups regarding the AA and GG/AG genotypes as well as the A, G allele frequency, while no statistically significant differences were found regarding AG or GG genotypes. Regarding the FasLG IVS2nt 124 A>G polymorphism, no statistically significant differences were found between the two groups studied. Concerning the Fas 670 A>G gene, no statistically significant differences between the severe and mild preeclampsia groups regarding the A allele frequency were found. Concerning the FasLG IVS2nt 124 A>G gene, there were no statistically significant differences between the severe and mild preeclampsia groups regarding the A allele frequency or the G allele frequency. The presence of the Fas gene polymorphism Fas A670G is associated with an increased risk of preeclampsia, while the presence of FasLG IVS2nt 124 A>G gene may be protective against preeclampsia. PMID- 24951048 TI - In vivo monitoring of structural and mechanical changes of tissue scaffolds by multi-modality imaging. AB - Degradable tissue scaffolds are implanted to serve a mechanical role while healing processes occur and putatively assume the physiological load as the scaffold degrades. Mechanical failure during this period can be unpredictable as monitoring of structural degradation and mechanical strength changes at the implant site is not readily achieved in vivo, and non-invasively. To address this need, a multi-modality approach using ultrasound shear wave imaging (USWI) and photoacoustic imaging (PAI) for both mechanical and structural assessment in vivo was demonstrated with degradable poly(ester urethane)urea (PEUU) and polydioxanone (PDO) scaffolds. The fibrous scaffolds were fabricated with wet electrospinning, dyed with indocyanine green (ICG) for optical contrast in PAI, and implanted in the abdominal wall of 36 rats. The scaffolds were monitored monthly using USWI and PAI and were extracted at 0, 4, 8 and 12 wk for mechanical and histological assessment. The change in shear modulus of the constructs in vivo obtained by USWI correlated with the change in average Young's modulus of the constructs ex vivo obtained by compression measurements. The PEUU and PDO scaffolds exhibited distinctly different degradation rates and average PAI signal intensity. The distribution of PAI signal intensity also corresponded well to the remaining scaffolds as seen in explant histology. This evidence using a small animal abdominal wall repair model demonstrates that multi-modality imaging of USWI and PAI may allow tissue engineers to noninvasively evaluate concurrent mechanical stiffness and structural changes of tissue constructs in vivo for a variety of applications. PMID- 24951050 TI - Extent of maxillary deficiency in patients with complete UCLP and BCLP. AB - OBJECTIVES: Primary surgery in patients with complete unilateral and bilateral cleft lip and palate restricts transverse and sagittal maxillary growth. Additional surgical maxillary advancement might become necessary after completion of growth. The aim of this study was to determine the extent of maxillary deficiency at an early stage during the transitory dentition, and to identify factors that might indicate the need for a later maxillary advancement. MATERIALS AND METHODS: Lateral head films and casts of 40 non-syndromatic patients with complete UCLP (n=29) and BCLP (n=11) were evaluated. This retrospective evaluation included measurements of casts and lateral head films from all patients at the beginning of orthodontic treatment during the transitory dentition (T1), after completion of orthodontic treatment (T2) and after completion of growth (T3). The statistic analysis comprised t-tests (Anova) and correlation analyses (Pearson). RESULTS: SNA decreased significantly between T1 and T2. At T3, 27.5% of the patients showed a sagittal maxillary deficiency with need for osteotomy. There were no statistical differences between patients with UCLP and BCLP. Significant positive correlations occurred between SNA and WITS appraisal (+0.62), and significant negative correlations between SNA and NL/NS ( 0.66). CONCLUSIONS: During craniofacial growth patients with complete UCLP and BCLP experience sagittal growth inhibition of the maxilla after primary surgery. A later need for maxillary advancement after completion of growth occurs equally in both cleft types. There are no correlations regarding the need for osteotomy with gender or number of primary surgical measures. It is impossible to predict a need for later maxillary osteotomy during the transitory dentition. CLINICAL RELEVANCE: Patients with clefts typically receive long-term treatment. The present results provide useful information for treatment planning and implementation. PMID- 24951051 TI - ZnT-1 extrudes zinc from mammalian cells functioning as a Zn(2+)/H(+) exchanger. AB - ZnT-1 is a Cation Diffusion Facilitator (CDF) family protein, and is present throughout the phylogenetic tree from bacteria to humans. Since its original cloning in 1995, ZnT-1 has been considered to be the major Zn(2+) extruding transporter, based on its ability to protect cells against zinc toxicity. However, experimental evidence for ZnT-1 induced Zn(2+) extrusion was not convincing. In the present study, based on the 3D crystal structure of the ZnT-1 homologue, YiiP, that predicts a homodimer that utilizes the H(+) electrochemical gradient to facilitate Zn(2+) efflux, we demonstrate ZnT-1 dependent Zn(2+) efflux from HEK 293T cells using FluoZin-3 and Fura 2 by single cell microscope based fluorescent imaging. ZnT-1 facilitates zinc efflux in a sodium-independent, pH-driven and calcium-sensitive manner. Moreover, substitution of two amino acids in the putative zinc binding domain of ZnT-1 led to nullification of Zn(2+) efflux and rendered the mutated protein incapable of protecting cells against Zn(2+) toxicity. Our results demonstrate that ZnT-1 extrudes zinc from mammalian cells by functioning as a Zn(2+)/H(+) exchanger. PMID- 24951052 TI - Vitamin D receptor is highly expressed in precancerous lesions and esophageal adenocarcinoma with significant sex difference. AB - Bile acid reflux into the esophagus is important in the development of esophageal adenocarcinoma (EAC). Recently, vitamin D receptor (VDR) was recognized as a bile acid receptor as well as a vitamin receptor. Expression of VDR is reported to influence the development of various types of cancer, such as those of the breast, liver, and colon. However, little is known about the role of VDR in esophageal neoplasms. We investigated the clinicopathological role of VDR in esophageal tumors. We analyzed genomic DNA from 116 EACs for copy number aberrations. The VDR locus was amplified in 7% of EACs. Expression of the VDR protein was also detected by immunohistochemistry from tissue microarrays created from tissues of Barrett esophagus (BE), low-grade (LGD) and high-grade dysplasia (HGD), columnar cell metaplasia (CCM), squamous epithelium (SE), EAC, and esophageal squamous cell carcinoma (ESCC). The protein was highly expressed in 88% of CCM (58/66), 95% of BE (35/37), 100% of the 19 LGD, 94% of HGD (15/16), and 79% of EAC (86/109), but expression in SE and ESCC was rare. Female patients with EAC and CCM were significantly less likely to have high VDR expression than male patients. The overall survival rate was significantly different for patients with tumors exhibiting VDR amplification versus nonamplification. Our findings suggest that VDR plays a role in the early development of EAC through a bile acid ligand. The sex difference in VDR expression may help to explain why men have a high incidence of EAC. PMID- 24951053 TI - The HIV epidemic and prevention response in Tigrai, Ethiopia: a synthesis at sub national level. AB - BACKGROUND: This study, the first of its kind carried out at sub-national level in Ethiopia, was conducted in order to understand the dynamics of HIV transmission at regional and district level in Tigrai, Ethiopia; and to assess the adequacy of the HIV prevention response. METHODS: Routine data from health centres, data from available published and grey literature and studies, and primary qualitative information were triangulated to draw an updated picture of the HIV epidemic, HIV response and resource allocation in Tigrai. RESULTS: HIV prevalence in Tigrai was 1.8% in 2011 (EDHS). ANC data show that there has been a continuous decline in the prevalence of HIV in both urban and rural areas (urban: 14.9% in 2001 to 5.0% in 2009; rural: 5.2% in 2001 to 1.3% in 2009, ANC surveillance data). Variability in prevalence by zone and by district was observed. Possible reasons for higher prevalence include the presence of mobile seasonal workers, highly urbanized centres, a high concentration of economic activity and connecting roads and large commercial farms. Sex workers, seasonal farm workers and HIV negative partners in discordant couples were identified as being at higher risk. There is no evidence that programme planning is done on the basis of geographical variations in HIV prevalence and there are gaps in programmes and services for certain high risk population groups. CONCLUSION: Considerable efforts have been invested in the HIV prevention response in Tigrai however, these efforts do not fully respond to the actual needs. For a more effective and targeted HIV prevention response, studies and data syntheses need to be carried out at sub-national level in order to accurately identify local specificities and plan accordingly. Resources should be targeted towards areas where transmission is linked to sex work, mobility and the mobile labour workforce. PMID- 24951054 TI - Meta-ethnography 25 years on: challenges and insights for synthesising a large number of qualitative studies. AB - Studies that systematically search for and synthesise qualitative research are becoming more evident in health care, and they can make an important contribution to patient care. Our team was funded to complete a meta-ethnography of patients' experience of chronic musculoskeletal pain. It has been 25 years since Noblit and Hare published their core text on meta-ethnography, and the current health research environment brings additional challenges to researchers aiming to synthesise qualitative research. Noblit and Hare propose seven stages of meta ethnography which take the researcher from formulating a research idea to expressing the findings. These stages are not discrete but form part of an iterative research process. We aimed to build on the methods of Noblit and Hare and explore the challenges of including a large number of qualitative studies into a qualitative systematic review. These challenges hinge upon epistemological and practical issues to be considered alongside expectations about what determines high quality research. This paper describes our method and explores these challenges. Central to our method was the process of collaborative interpretation of concepts and the decision to exclude original material where we could not decipher a concept. We use excerpts from our research team's reflexive statements to illustrate the development of our methods. PMID- 24951057 TI - Intestinal cholesterol embolism resulting from intra-aortic balloon pumping: a case report. AB - INTRODUCTION: Intra-aortic balloon pumping is used in elective percutaneous coronary intervention for increasing coronary blood flow. However, intra-aortic balloon pumping may decrease visceral blood flow and cause mesenteric ischemia by visceral artery obstruction. CASE PRESENTATION: We report the case of a 79-year old Asian man in whom elective percutaneous coronary intervention was performed with intra-aortic balloon pumping. He died from mesenteric ischemia 25 hours after the procedure. Microscopic findings showed that intra-aortic balloon pumping had detached the aortic plaque, breaking it into systemic emboli, leading to subsequent intestinal ischemia and necrosis. CONCLUSIONS: We conclude that intra-aortic balloon pumping can cause an intestinal cholesterol embolism. PMID- 24951055 TI - What we think we learn from watching others: the moderating role of ability on perceptions of learning from observation. AB - Despite increased interest in the processes guiding action observation and observational learning, we know little about what people think they learn from watching, how well perceptions of learning marry with actual ability and how ability perceptions develop across multiple observation trials. Based on common coding ideas, we would think that ability and perceptions of ability from watching should be well matched. We conducted two studies to answer these questions that involved repeated observation of a 2-ball juggling task. After each video observation, observers judged if they could perform the skill and gave a confidence score (0-100%). In Experiment 1, an Observe-only group was compared to an Observe + Physical practice and No-practice group. Both observer groups showed a better physical approximation of the juggling action after practice and in retention and their confidence increased in a linear fashion. Confidence showed a small, yet significant relationship to actual success. In Experiment 2, we limited physical practice to 5 attempts (across 50 observation trials). In general, people who had high perceptions of ability following a demonstration were overconfident, whereas those with lower perceptions of ability were accurate in their assessments. Confidence generally increased across practice, particularly for trials following observation rather than physical practice. We conclude that while perceptions of ability and actual ability show congruence across trials and individuals, observational practice increases people's confidence in their ability to perform a skill, even despite physical experiences to the contrary. PMID- 24951058 TI - The first metabolic and bariatric surgery accreditation and quality improvement program quality initiative: decreasing readmissions through opportunities provided. PMID- 24951056 TI - Analysis of embryo morphokinetics, multinucleation and cleavage anomalies using continuous time-lapse monitoring in blastocyst transfer cycles. AB - BACKGROUND: Time-lapse imaging combined with embryo morphokinetics may offer a non-invasive means for improving embryo selection. Data from clinics worldwide are necessary to compare and ultimately develop embryo classifications models using kinetic data. The primary objective of this study was to determine if there were kinetic differences between embryos with limited potential and those more often associated with in vitro blastocyst formation and/or implantation. We also wanted to compare putative kinetic markers for embryo selection as proposed by other laboratories to what we were observing in our own laboratory setting. METHODS: Kinetic data and cycle outcomes were retrospectively analyzed in patients age 39 and younger with 7 or more zygotes cultured in the Embryoscope. Timing of specific events from the point of insemination were determined using time-lapse (TL) imaging. The following kinetic markers were assessed: time to syngamy (tPNf), t2, time to two cells (c), 3c (t3), 4c ( t4), 5c (t5), 8c (t8), morula (tMor), start of blastulation (tSB); tBL, blastocyst (tBL); expanded blastocyst (tEBL). Durations of the second (cc2) and third (cc3) cell cycles, the t5-t2 interval as well as time to complete synchronous divisions s1, s2 and s3 were calculated. Incidence and impact on development of nuclear and cleavage anomalies were also assessed. RESULTS: A total of 648 embryos transferred on day 5 were analyzed. The clinical pregnancy and implantation rate were 72% and 50%, respectively. Morphokinetic data showed that tPNf, t2,t4, t8, s1, s2,s3 and cc2 were significantly different in embryos forming blastocysts (ET or frozen) versus those with limited potential either failing to blastulate or else forming poor quality blastocysts ,ultimately discarded. Comparison of embryo kinetics in cycles with all embryos implanting (KID+) versus no implantation (KID-) suggested that markers of embryo competence to implant may be different from ability to form a blastocyst. The incidence of multinucleation and reverse cleavage amongst the embryos observed was 25% and 7%, respectively. Over 40% of embryos exhibiting these characteristics did however form blastocysts meeting our criteria for freezing. CONCLUSIONS: These data provide us with a platform with which to potentially enhance embryo selection for transfer. PMID- 24951059 TI - Why readmissions matter.... PMID- 24951061 TI - Readmissions after bariatric surgery: does operative technique and procedure choice matter? PMID- 24951060 TI - Working together: regional collaboration and readmissions. PMID- 24951062 TI - Decreasing bariatric surgery: readmissions with preoperative education. PMID- 24951063 TI - Decreasing readmission through psychological evaluation and treatment. PMID- 24951064 TI - Preventing readmissions: Geisinger: how we do it. PMID- 24951065 TI - Three-year weight outcomes from a bariatric surgery registry in a large integrated healthcare system. AB - BACKGROUND: A registry was created for patients having procedures for weight loss from 2004 to the present time at a large integrated healthcare system. The objective of this study was to compare findings to the literature and national quality monitoring databases and present 3-year weight loss outcomes. METHODS: Patients are passively enrolled in the registry with the following characteristics: a bariatric procedure for weight loss after January 1, 2004 and actively enrolled in the health plan at the time of surgery. RESULTS: Compared to national surgical quality databases, the registry (n = 20,296) has a similar proportion of Roux-en-Y gastric bypass (RYGB; 58%), more vertical sleeve gastrectomy (SG; 40%), fewer banding (2%) procedures, more Hispanic patients (35%), and higher rates of 1 year follow-up (78%). RYGB patients lost more weight at every time point up to 3 years after surgery compared with SG patients (P<.001). Non-Hispanic white RYGB patients had a higher percent excess weight loss than non-Hispanic black (P<.001) and Hispanic (P<.001) RYGB patients. There were no differences between SG racial/ethnic groups in percent excess weight loss throughout the 3-year follow-up period. CONCLUSION: We are one of the first groups to publish comparison weight outcomes for RYGB and SG in a diverse patient population, showing that the responses to RYGB and not SG vary by race/ethnicity. PMID- 24951066 TI - Comment on: Three-year weight outcomes from a bariatric surgery registry in a large integrated healthcare system. PMID- 24951068 TI - Comment on: Hiatal hernia and gastroesophageal reflux disease in gastric banding patients: analysis of a national database. PMID- 24951067 TI - Is esophagogastroduodenoscopy before Roux-en-Y gastric bypass or sleeve gastrectomy mandatory? AB - BACKGROUND: Roux-Y Gastric Bypass is a frequently used technique in bariatric surgery. Postoperative anatomy is altered by exclusion of the stomach, which makes this organ inaccessible for future esophagogastroduodenoscopy (EGD). The value of preoperative assessment of the stomach is unclear. Some institutions choose to investigate the future remnant stomach by EGD, others do not. Aim of the present study is to quantify the yield of preoperative EGD in our institution. METHODS: Patients, planned for primary laparoscopic Roux-Y Gastric Bypass (LRYGB) or laparoscopic sleeve gastrectomy from December 2007 until August 2012, were screened by EGD in advance. Results of EGD and patient characteristics were retrospectively analyzed and categorized according to a classification system based on intervention needed. RESULTS: 523 patients (122 male, 401 female, mean age 44.3 years, average BMI 46.6) underwent preoperative EGD. In 257 patients (48.9%) no abnormality was found (group A), 117 patients (17.2%) had abnormalities without treatment consequences (B1), 84 patients (of the 326 tested [comment #1, reviewer #1, 26.8%] were H. Pylori positive (B2), in 75 (14.3%) treatment with proton pump inhibitors was required (B3), 6 (1.1%) required follow up EGD before surgery (C). For1 patient (0.2%) the operation was canceled because preoperative EGD presented with Barrett's esophagus with carcinoma (D). When all abnormalities were taken into account, baselines did show a significant difference for age, gender and reflux symptoms. CONCLUSION: Standard preoperative assessment by EGD in patients who are planned for bariatric surgery is not indicated. The number needed to screen to find clinically significant abnormalities is high. PMID- 24951069 TI - Patient expectations of bariatric surgery are gender specific--a prospective, multicenter cohort study. AB - BACKGROUND: The effect of bariatric surgery on weight loss and improvement of co morbidities is no longer doubted. However, little attention has been given to the treatment goals from the patient's point of view (patient expectations). The objective of this study was to examine patients' expectations of bariatric surgery and identify gender differences. METHODS: Bariatric patients were asked to complete a questionnaire. Statistical analysis was performed using chi-square, Pearson correlation coefficient, and Wilcoxon rank sum test. RESULTS: Overall, 248 patients participated in this study (69.4% females). The male patients (45.2 yr, SD+/-11.1) were significantly older than the female (41.8 yr, SD+/-12.0; P = .04) and suffered significantly more often from diabetes, hypertension, hypercholesterolemia, and sleep apnea. One hundred thirty patients (52.4%) expected to lose at least 45 kg and 39 patients (15.7%)>70 kg. The mean expected excess weight loss was 71.8%. Females expected significantly more often that surgery alone would induce weight loss (P = .03). "Improved co-morbidity" was by far the highest ranked parameter. CONCLUSION: The male bariatric surgery patients were older and suffered from more co-morbidities. Most of the patients had unrealistic weight loss goals and overestimated the effect of the surgical intervention. However, for both female and male patients, "improved co-morbidity" was the most important issue. PMID- 24951071 TI - Wernicke's encephalopathy after sleeve gastrectomy. Where do we stand today? A reappraisal. PMID- 24951070 TI - Laparoscopic Roux-en-Y gastric bypass with hand-sewn gastrojejunostomy using an absorbable bidirectional monofilament barbed suture: review of the literature and illustrative case video. PMID- 24951073 TI - Jerky spontaneous movements at term age in preterm infants who later developed cerebral palsy. AB - BACKGROUND: Assessment of spontaneous movements in infants has been a powerful predictor of cerebral palsy (CP). Recent advancements on computer-based video analysis can provide detailed information about the properties of spontaneous movements. AIMS: The aim of this study was to investigate the relationship between spontaneous movements of the 4 limbs at term age and the development of CP at 3 years of age by using a computer-based video analysis system. STUDY DESIGN AND SUBJECTS: We analyzed video recordings of spontaneous movements at 36 44 weeks postmenstrual age (PMA) for 145 preterm infants who were born preterm (22-36 weeks PMA with birthweights of 460-1498g). Sixteen of the infants developed CP by 3 years of age, while 129 developed normally. We compared 6 movement indices calculated from 2-dimensional trajectories of all limbs between the 2 groups. RESULTS: We found that the indices of jerkiness were higher in the CP group than in the normal group (p<0.1 for arms and p<0.01 for legs). No decline was observed in the average velocity and number of movement units in the CP group compared with to the normal group. CONCLUSIONS: Jerkiness of spontaneous movements at term age provides additional information for predicting CP in infants born preterm. PMID- 24951074 TI - Neonatal line on fetus and infant teeth: An indicator of live birth and mode of delivery. AB - BACKGROUND: The neonatal line (NL) is an important issue in forensic odontology. It is the sign of a developmental birth defect, which is caused by the effect of metabolic stress on tooth structures when the fetus passes to extrauterine life. AIMS: The aim of this research is to determine the existence and thickness of NL in teeth, as it is a legal necessity to indicate the signs of viability at birth in a forensic examination of a fetus or infant case. STUDY DESIGN AND SUBJECTS: This research was conducted on 48 lower left and right lateral teeth, which were taken from 24 autopsy cases (46% female and 54% male). Left lateral teeth were sectioned in a vertical plane and right lateral teeth were sectioned in a horizontal plane. The NL thickness was measured with a scanning electron microscope (SEM). These cases comprised three conditions as: 70.3% normal birth, 16.7% caesarean sections, and 12.5% still birth cases under the legal and ethical permission. OUTCOME MEASURES: The mean NL thickness of normal birth cases was higher than caesarean cases as 7.7MUm and 2.5MUm, respectively. RESULTS AND CONCLUSIONS: The results showed a statistical significance between all birth conditions. NL does not exist in still birth cases (p<0.001). Not only is the presence of NL a sign of live birth, but also its thickness is an indicator of the delivery mode where NL thickness of normal birth was found thicker than the caesarean cases. PMID- 24951075 TI - Preschool regulatory problems and attention-deficit/hyperactivity and cognitive deficits at school age in children born at risk: different phenotypes of dysregulation? AB - BACKGROUND: Early regulatory problems (RP), i.e., excessive crying, feeding, and sleeping difficulties, have been reported to be predictors of cognitive and attention-deficit/hyperactivity problems. However, previous studies had limitations such as small sample size or retrospective design. AIM: To investigate whether persistent RP from infancy until preschool age are precursors of ADHD problems and cognitive deficits at school age. STUDY DESIGN: A prospective study from birth to 8.5years of age. SUBJECTS: 1120 infants born at risk. MEASURES: RP were assessed at 5months (i.e., excessive crying, feeding, and sleeping problems), 20, and 56months (i.e., eating and sleeping problems) via parent interviews and neurological examination. At 8.5years of age, IQ was assessed by a standard test (K-ABC), and ADHD problems by direct observations in the test situation and by the Mannheimer Parent Interview (MPI, DSM-IV diagnosis of ADHD). RESULTS: 23.8% of the sample born at risk had RP at least at two measurement points until preschool age. Persistent RP predicted lower IQ (beta= .17; 95% CI (-.21; -.10)), behaviour problems (beta=-.10; 95% CI (-.15; -.03)), attention (OR 2.43; 95% CI (1.16; 5.09)) and hyperactivity problems (OR 3.10; 95% CI (1.29; 7.48)), and an ADHD diagnosis (OR 3.32; 95% CI (1.23; 8.98)) at school age, even when controlled for psychosocial and neurological confounders. CONCLUSIONS: Early persistent RP increased the odds of ADHD and associated problems at school age, indicating a cascade model of development, i.e., infant behaviour problems provide the starting point of a trajectory of dysregulation through time. PMID- 24951076 TI - Feeding regimens in VLBW infants. PMID- 24951077 TI - Transitional hemodynamics in preterm infants with a respiratory management strategy directed at avoidance of mechanical ventilation. AB - BACKGROUND: Early respiratory management of very low birth weight infants has changed over recent years to a practice of early use of CPAP with early selective surfactant administration, and decreased use of mechanical ventilation. One strategy is to use the combination of surfactant and prompt extubation to nasal continuous positive airway pressure (INtubate, SURfactant, Extubate, or INSURE). The aim of this study is to describe blood flow and ductal flow in a prospective cohort during the transitional period when this respiratory management strategy is used. METHODS: Inborn infants <29week gestation underwent INSURE within 30min of birth using 200mg/kg Curosurf. Blood pressure and blood flow parameters (RVO, LVO, SVC flow, ductus arteriosus) were measured at 6, 24 and 72h of age and information on morbidity was collected. RESULTS: Sixty-eight infants with a median (range) weight of 940 (450-1380) g were studied. 13 (19%) patients needed mechanical ventilation within 72h of life (INSURE failure). Blood flows and blood pressure were within reported ranges. Eleven (16%) patients had a blood pressure 34 weeks (group 2, n=41), and according to ethnic origin: Caucasians (group A, n=49) and non-Caucasians (group B, n=36). Statistical analysis, using Pearson's correlation coefficient (r) and Bland-Altman analysis were performed to evaluate correlation and agreement between TSB and TcB values. Multiple linear regression was used to control for confounders for TSB values. RESULTS: Correlation between TSB and TcB was high. Pearson's correlation coefficients were over 0.9 in all groups (0.910, 0.908, 0.916 and 0.934, p<0.0001 in groups 1, 2, A, and B respectively). Bland-Altman plots showed acceptable and close limits of agreements (56.8/-57.7, 54.2/-67.2, 57.7/-55.8, and 51.3/-69.9MUmol/L in groups 1, 2, A and B respectively) with a trend for TcB to overestimate TSB in groups 2 and B. Birth term and skin color were not identified as confounding factors for predicting TSB in multiple linear regression. CONCLUSIONS: TcB measurements using the Draeger JM-103(r) device correlate significantly with TSB, regardless of term and skin color. Transcutaneous bilirubinometry seems to be a safe and cost-effective screening method for severe hyperbilirubinemia in newborns of different terms and ethnic origins. PMID- 24951082 TI - Serum bilirubin as a predictor of incident metabolic syndrome: a 4-year retrospective longitudinal study of 6205 initially healthy Korean men. AB - AIM: Serum bilirubin is an endogenous antioxidant with anti-inflammatory properties. Several cross-sectional studies have reported that bilirubin was negatively associated with oxidative stress-mediated diseases, including the metabolic syndrome (MetS). However, the clinical relevance of bilirubin as a risk factor for incident MetS remains controversial. For this reason, the longitudinal effects of baseline serum bilirubin concentrations on incident MetS were evaluated in Korean men. METHODS: This 4-year retrospective longitudinal observational study involved 6205 Korean men without MetS. Subjects underwent routine health examinations in 2007 and returned for a follow-up examination in 2011. Baseline serum bilirubin concentrations were determined using the vanadate oxidation method. RESULTS: During the 4-year period, 936 cases of incident MetS (15.1%) were identified. Its incidence decreased across baseline bilirubin quartile categories (P<0.001), with an odds ratio (OR) for developing MetS being significantly lower in the highest quartile group (>= 1.40 mg/dL) compared with the lowest (<= 0.90 mg/dL) after adjusting for all confounding variables [OR=0.70, 95% confidence interval (CI) 0.54-0.90; P for trend=0.019]. Among individual components of MetS, bilirubin was found to be negatively associated with only the risk of incident hypertriglyceridaemia. The OR (95% CI) for incident hypertriglyceridaemia in the highest vs lowest quartile was 0.75 (0.61 0.91; P for trend=0.002). CONCLUSION: Serum total bilirubin level was negatively associated with incidence of MetS in healthy Korean men over a 4-year period. PMID- 24951081 TI - Cranial shape, size and cervical motion in normal newborns. AB - BACKGROUND: Deformational plagiocephaly (DP) and torticollis are commonly seen in infants and they often co-occur, but little is known of the prevalence and relationship of these conditions in the immediate newborn period. No previous studies focusing on the relationship between cranial shape and cervical motion in newborns can be found. OBJECTIVES: Determining the incidence rates and characteristics of DP and torticollis and examining the relationship between cervical range of motion (ROM), cranial size and cranial shape in neonates. METHODS: A single-center, descriptive cross-sectional study including 155 healthy neonates was conducted. Participants were examined during their birth hospitalization. Oblique Cranial Length Ratio (OCLR) and Cephalic Index (CI), indicating cranial asymmetry and shape, were measured from standardized digital photographs with a computer-based cephalometric method. Cervical ROM was measured with goniometry. RESULTS: 7.7% of the newborns had DP and 3.9% had torticollis. 46.4% presented lesser cervical imbalances. DP was associated with gestational diabetes (adjusted OR 5.6; p<0.01) and vacuum assisted delivery (adjusted OR 6.8; p<0.01), but not at all with torticollis. CI correlated strongly with cervical ROM in all directions, while no definite association between cranial asymmetry and cervical motion could be found. CONCLUSIONS: DP and torticollis are common and minor cervical imbalances very common in normal newborns. Our results support the theory that in most cases neither DP nor torticollis is congenital, but rather develops and worsens synergistically in early infancy. Still, although no direct association between DP and torticollis was found, cranial shape is linked to cervical motion at birth. PMID- 24951080 TI - Frequency of anomalies and hospital outcomes in infants with gastroschisis and omphalocele. AB - BACKGROUND: Gastroschisis and omphalocele are the most common anterior abdominal wall defects affecting infants. There are few large cohort studies describing the frequency of associated anomalies in infants with these 2 conditions. We describe associated anomalies and outcomes in infants with these defects using a large, multi-center clinical database. METHODS: We identified all infants with gastroschisis or omphalocele from a prospectively collected database of infants discharged from 348 neonatal intensive care units in North America from 1997 to 2012. Maternal and patient demographic data, associated anomalies, and outcome data were compared between infants with gastroschisis and omphalocele. RESULTS: A total of 4687 infants with gastroschisis and 1448 infants with omphalocele were identified. Infants with omphalocele were more likely to be diagnosed with at least 1 other anomaly compared with infants with gastroschisis (35% vs. 8%, p<0.001). Infants with omphalocele were more likely to develop pulmonary hypertension compared with those with gastroschisis (odds ratio [OR] 7.78; 95% confidence interval 5.81, 10.41) and had higher overall mortality (OR 6.81 [5.33, 8.71]). CONCLUSION: Infants with omphalocele were more likely to have other anomalies, be diagnosed with pulmonary hypertension, and have higher mortality than infants with gastroschisis. PMID- 24951083 TI - Nurses' involvement in physician-assisted dying under the euthanasia law in Belgium. PMID- 24951084 TI - Attitudes and perceptions of adults of 60 years and older towards in-home monitoring of the activities of daily living with contactless sensors: an explorative study. AB - BACKGROUND AND OBJECTIVES: Contactless monitoring is increasingly used to enhance qualitative and cost-effective care for older persons. Succesful integration of this technology in older peoples' daily lives, depends on their acceptance of these systems. The primary purpose was to explore attitudes and perceptions of adults of 60 years and older towards contactless monitoring of the activities of daily living. DESIGN, PARTICIPANTS AND METHODS: A questionnaire was developed, validated and used in a cross-sectional survey with a convenience sample (n=245). The results were presented using descriptive statistics and bivariate analyses to explore variables associated with willingness to install the technology. RESULTS: Descriptive statistics indicate that adults of 60 years and older find contactless monitoring useful for various purposes (e.g. to remain living at home longer, safely and independently; for timely detection of emergency situations and gradually emerging health problems). They agree to share collected information with professional caregivers and own access to the data is valued. Respondents like to take part in diverse decisions about the monitoring (e.g. about the rooms in which it is installed, the type of sensors used and access of third parties to collected information). However, several concerns were expressed related to the functioning and financing of contactless monitoring. Bivariate analyses show that both socio-demographic factors (e.g. age, receiving professional home care) and attitudes and perceptions towards contactless monitoring (e.g. on its potential usefulness, on the availability of collected information, on the functional requirements and financial costs of the system and on the use of video cameras) can promote or impede acceptance of the technology. CONCLUSIONS: This explorative study indicates that older adults are willing to incorporate contactless monitoring in later life or when their health declines. They agree to share collected information with professional caregivers and clearly demand for participation in decisions about the technology. Various concerns and requirements provide implications for clinical practice and future research. Thereby, technology developpers, policy makers and professional caregivers can promote the implementation of contactless monitoring in the care for older adults. PMID- 24951085 TI - Psychometric testing of a Mandarin Chinese Version of the Clinically Useful Depression Outcome Scale for patients diagnosed with type 2 diabetes mellitus. AB - BACKGROUND: The Clinically Useful Depression Outcome Scale (CUDOS) is a self report instrument that assesses symptoms and the severity of depression, but its psychometric properties in patients with type 2 diabetes mellitus in Chinese Speaking populations are unknown. OBJECTIVES: To examine the psychometric properties of the Mandarin Chinese version of the CUDOS (CUDOS-Chinese). DESIGN: A methodological research design. SETTING: Endocrinology and metabolism outpatient clinics at 2 university-affiliated hospitals in northern Taiwan. PARTICIPANTS: Two-hundred and fourteen type 2 diabetic patients with the mean age of 62.6 years were enrolled, and two-hundred and twelve of them completed the study. METHODS: Internal consistency, test-retest reliability, concurrent, and contrasted-groups validity were assessed. A receiver operating characteristic curve analysis was performed to assess sensitivity and specificity. Construct validity by means of confirmatory factor analysis was conducted. RESULTS: Internal consistency (Cronbach alpha of total scale and four subscales=0.93, 0.80, 0.66, 0.80, and 0.83, respectively), test-retest reliability (intra-class correlation coefficients of total scale and four subscales=0.92, 0.89, 0.94, 0.89, and 0.91, respectively), and strong correlations with the Beck Depression Inventory-II (r=0.87) suggested good reliability and validity. The confirmatory factor analysis supported a four-factor model. A cut-off score of 19/20 yielded 77.8% sensitivity and 75.6% specificity. CONCLUSIONS: The CUDOS-Chinese demonstrated satisfactory validity and reliability for detecting depression in type 2 diabetic patients in Taiwan. PMID- 24951086 TI - Urinary nerve growth factor in patients with detrusor overactivity. AB - BACKGROUND: Detrusor overactivity (DO) is one of the most frequent bladder dysfunctions in children up to the age of 18. Nowadays, the only way to confirm DO is by urodynamic investigation, which is an invasive procedure. Among the many mediators influencing bladder function, nerve growth factor (NGF) plays an important role. The present study was designed to measure urinary NGF (uNGF) levels in patients with DO diagnosed by urodynamic study in comparison with healthy controls. METHODS: The investigation was conducted on 44 children, divided into two groups (24 patients with DO, 20 healthy children). Uroflowmetry was performed in all enrolled to the study and cystometry only to patients. uNGF levels were estimated in both studied groups. RESULTS: The median uNGF level in patients with DO before treatment was higher compared with healthy controls. There were no differences between uNGF levels in patients after anticholinergic treatment and the controls. We found differences in uroflowmetry parameters between the reference group and the patients. We found correlations between uroflowmetry parameters and uNGF/cr. level. CONCLUSIONS: 1. The uNGF level could be used for detecting DO in children and adolescents. 2. Measuring uNGF level is a simple, noninvasive procedure and very useful for choosing therapy in patients with DO in various clinical conditions. PMID- 24951088 TI - Diffusion of water inside carbon nanotubes studied by pulsed field gradient NMR spectroscopy. AB - Diffusion dynamics of guest molecules in nanopores has been studied intensively because diffusion is center on a number of research fields such as separation, drug delivery, chemical reactions, and sensing. In the present work, we report an experimental investigation of the self-diffusion of water inside carbon nanotube (CNT) channels using a pulsed field gradient (PFG) NMR method. The dispersion of CNTs homogeneously in water and cooling to temperatures below the melting point of bulk water allow us to probe the translational motion of confined water molecules. The results demonstrate that the self-diffusion coefficient of water in CNTs is highly dependent on the diffusion time and CNT diameter. In particular, the diffusivity of water in double-walled carbon nanotubes (DWNTs) with an average inner diameter of 2.3 +/- 0.3 nm is twice that in multiwalled carbon nanotubes (MWNTs) with an average inner diameter of 6.7 +/- 0.8 nm in the temperature range of 263-223 K. In addition, the effective self-diffusion coefficient in DWNTs is 1 order of magnitude higher than that reported for mesoporous silica materials with a similar pore size. The faster diffusivity of water in CNTs could be attributed to the ordered hydrogen bonds formed between water molecules within the confined channels of CNTs and the weak interaction between water and the CNT walls. PMID- 24951087 TI - Percutaneous balloon compression (PBC) of trigeminal ganglion for recurrent trigeminal neuralgia after microvascular decompression (MVD). AB - BACKGROUND: Although microvascular decompression (MVD) has become the best surgical treatment for trigeminal neuralgia, it does not achieve 100% cure rate. Re-exploration of the posterior fossa may carry increased risk over first-time MVD and is not always successful, so other treatments are needed. AIMS: In this study, we evaluate the effectiveness of the patients with recurrent trigeminal neuralgia after MVD treated with percutaneous balloon compression (PBC). METHODS: The clinical data of 52 recurrent trigeminal neuralgia patients after MVD who underwent PBC between November 2007 and March 2012 were retrospectively reviewed and analyzed. RESULTS: After the PBC, 50 patients (96.2%) experienced immediate pain relief; 1 patient had occasional pain, and did not require medication; and 1 patient had no pain relief. The total efficiency was 98.1%. With a mean length of follow-up of 37.6 months, ranging from 12 to 64 months after surgery, 43 (82.7%) patients remained pain-free, 4 patients (7.7%) had mild recurrence, and 3 patients (5.8%) had severe recurrence. The mean time to recurrence was 25.1 months (5-60 months). PBC was repeated a second time in three patients, a third time in one patient. Postoperative complications included facial numbness in 51 patients (98.1%), masseter muscle weakness in 31 patients (59.6%), paresthesia in 5 patients (9.6%), and diplopia secondary to abducens nerve palsy in 1 patient (1.9%). None of the patients had serious surgical morbidities. CONCLUSIONS: PBC is a minimally invasive, safe and effective procedure which can be regarded as an optimized choice for recurrent trigeminal neuralgia after MVD. PMID- 24951089 TI - Brain iron accumulation in dysmetabolic iron overload syndrome with restless legs syndrome. PMID- 24951092 TI - [Hypertension and pregnancy in Lome (sub-Saharan Africa): epidemiology, diagnosis and risk factors]. AB - AIM: Describe the epidemiology, diagnosis and risk factors of hypertension in pregnant women in Lome. METHODS: It was a prospective, descriptive and comparative study during 12 months (October 1st, 2011 to September 31st, 2012) on 200 cases of hypertension among 1620 pregnant women, in the department of gynecology and obstetrics at the Tokoin teaching hospital of Lome. RESULTS: We had 200 cases of hypertension on 1620 pregnant women. The prevalence of hypertension in pregnant women in Lome was 12.3%. The average age of pregnant women was 30+/-7 years, with extremes of 15 and 44 years. Hypertension was more common (50%) in ages of 30-39 years. The society the most represented were housewives (33.33%), civil servants (16.67%) and traders (16.66%). Hypertension was found incidentally or during a complication especially during the third trimester of pregnancy. Preeclampsia (44%) and pregnancy-induced hypertension (33%) were the most represented. The main risk factors where primiparity (especially older primipars >30ans), nulliparity, familial history of hypertension, low economic level, history of pregnancy-induced hypertension, age >30 years, twinning, obesity and stress. CONCLUSION: Hypertension in pregnancy is frequent in Lome. A regular follow-up before and after delivery is important according to fetal and maternal complications, and the risk of heart and kidney disease at mild and long outcome. PMID- 24951093 TI - An exploration of influences on women's birthplace decision-making in New Zealand: a mixed methods prospective cohort within the Evaluating Maternity Units study. AB - BACKGROUND: There is worldwide debate surrounding the safety and appropriateness of different birthplaces for well women. One of the primary objectives of the Evaluating Maternity Units prospective cohort study was to compare the clinical outcomes for well women, intending to give birth in either an obstetric-led tertiary hospital or a free-standing midwifery-led primary maternity unit. This paper addresses a secondary aim of the study--to describe and explore the influences on women's birthplace decision-making in New Zealand, which has a publicly funded, midwifery-led continuity of care maternity system. METHODS: This mixed method study utilised data from the six week postpartum survey and focus groups undertaken in the Christchurch area in New Zealand (2010-2012). Christchurch has a tertiary hospital and four primary maternity units. The survey was completed by 82% of the 702 study participants, who were well, pregnant women booked to give birth in one of these places. All women received midwifery-led continuity of care, regardless of their intended or actual birthplace. RESULTS: Almost all the respondents perceived themselves as the main birthplace decision makers. Accessing a 'specialist facility' was the most important factor for the tertiary hospital group. The primary unit group identified several factors, including 'closeness to home', 'ease of access', the 'atmosphere' of the unit and avoidance of 'unnecessary intervention' as important. Both groups believed their chosen birthplace was the right and 'safe' place for them. The concept of 'safety' was integral and based on the participants' differing perception of safety in childbirth. CONCLUSIONS: Birthplace is a profoundly important aspect of women's experience of childbirth. This is the first published study reporting New Zealand women's perspectives on their birthplace decision-making. The groups' responses expressed different ideologies about childbirth. The tertiary hospital group identified with the 'medical model' of birth, and the primary unit group identified with the 'midwifery model' of birth. Research evidence affirming the 'clinical safety' of primary units addresses only one aspect of the beliefs influencing women's birthplace decision-making. In order for more women to give birth at a primary unit other aspects of women's beliefs need addressing, and much wider socio-political change is required. PMID- 24951091 TI - Rethinking stimulation of the brain in stroke rehabilitation: why higher motor areas might be better alternatives for patients with greater impairments. AB - Stimulating the brain to drive its adaptive plastic potential is promising to accelerate rehabilitative outcomes in stroke. The ipsilesional primary motor cortex (M1) is invariably facilitated. However, evidence supporting its efficacy is divided, indicating that we may have overgeneralized its potential. Since the M1 and its corticospinal output are frequently damaged in patients with serious lesions and impairments, ipsilesional premotor areas (PMAs) could be useful alternates instead. We base our premise on their higher probability of survival, greater descending projections, and adaptive potential, which is causal for recovery across the seriously impaired. Using a conceptual model, we describe how chronically stimulating PMAs would strongly affect key mechanisms of stroke motor recovery, such as facilitating the plasticity of alternate descending output, restoring interhemispheric balance, and establishing widespread connectivity. Although at this time it is difficult to predict whether PMAs would be "better," it is important to at least investigate whether they are reasonable substitutes for the M1. Even if the stimulation of the M1 may benefit those with maximum recovery potential, while that of PMAs may only help the more disadvantaged, it may still be reasonable to achieve some recovery across the majority rather than stimulate a single locus fated to be inconsistently effective across all. PMID- 24951094 TI - Treatment for those who need it most. PMID- 24951090 TI - Molecular evolution of NASP and conserved histone H3/H4 transport pathway. AB - BACKGROUND: NASP is an essential protein in mammals that functions in histone transport pathways and maintenance of a soluble reservoir of histones H3/H4. NASP has been studied exclusively in Opisthokonta lineages where some functional diversity has been reported. In humans, growing evidence implicates NASP miss regulation in the development of a variety of cancers. Although a comprehensive phylogenetic analysis is lacking, NASP-family proteins that possess four TPR motifs are thought to be widely distributed across eukaryotes. RESULTS: We characterize the molecular evolution of NASP by systematically identifying putative NASP orthologs across diverse eukaryotic lineages ranging from excavata to those of the crown group. We detect extensive silent divergence at the nucleotide level suggesting the presence of strong purifying selection acting at the protein level. We also observe a selection bias for high frequencies of acidic residues which we hypothesize is a consequence of their critical function(s), further indicating the role of functional constraints operating on NASP evolution. Our data indicate that TPR1 and TPR4 constitute the most rapidly evolving functional units of NASP and may account for the functional diversity observed among well characterized family members. We also show that NASP paralogs in ray-finned fish have different genomic environments with clear differences in their GC content and have undergone significant changes at the protein level suggesting functional diversification. CONCLUSION: We draw four main conclusions from this study. First, wide distribution of NASP throughout eukaryotes suggests that it was likely present in the last eukaryotic common ancestor (LECA) possibly as an important innovation in the transport of H3/H4. Second, strong purifying selection operating at the protein level has influenced the nucleotide composition of NASP genes. Further, we show that selection has acted to maintain a high frequency of functionally relevant acidic amino acids in the region that interrupts TPR2. Third, functional diversity reported among several well characterized NASP family members can be explained in terms of quickly evolving TPR1 and TPR4 motifs. Fourth, NASP fish specific paralogs have significantly diverged at the protein level with NASP2 acquiring a NNR domain. PMID- 24951095 TI - An index of orthognathic functional treatment need (IOFTN). AB - OBJECTIVE: To design a new index categorizing the functional need for orthognathic treatment. DESIGN: Laboratory-based study. SETTING: Records were obtained from two UK hospital-based orthodontic departments. PARTICIPANTS: A panel of four consultant orthodontists, experienced in providing orthognathic care, devised a new index of Orthognathic Functional Treatment Need (IOFTN) with the aid of the membership of the British Orthodontic Society Consultant Orthodontists Group (COG). Twenty-three consultants and post-CCST level specialists took part in the study as raters to test the validity and reliability of the new index. METHODS: A total of 163 start study models of patients who had previously undergone orthognathic treatment were assessed by the panel of four consultant orthodontists using the new index (IOFTN) and the agreed category was set as the 'gold standard'. Twenty-one consultants and post-CCST level specialists then scored the models on one occasion and two scored 50 sets of models twice to determine the test-re-test reliability. RESULTS: Kappa scores for inter-rater agreement with the expert panel for the major categories (1-5) demonstrated good to very good agreement (kappa: 0.64-0.89) for all raters. The percentage agreement ranged from 68.1 to 92% in all cases. Intra-rater agreement for the major categories was moderate to good (kappa: 0.53-0.80). CONCLUSIONS: A new index, the IOFTN, has been developed to help in the prioritization of severe malocclusions not amenable to orthodontic treatment alone. It demonstrates good content validity and good inter-rater and moderate to good intra-rater reliability. As a result of being an evolution of the IOTN, the familiar format should make it easy to determine functional treatment need within daily orthognathic practice. PMID- 24951100 TI - Synthesis of (R)- or (S)-valinol using omega-transaminases in aqueous and organic media. AB - Valinol is part of numerous pharmaceuticals and has various other important applications. Optically pure valinol (ee >99%) was prepared employing different omega-transaminases from the corresponding prochiral hydroxy ketone. By the choice of the enzyme the (R)- as well as the (S)-enantiomer were accessible. Reductive amination was performed in organic solvent (MTBE) using 2-propyl amine as amine donor whereas alanine was applied in or in aqueous medium. Transformations in phosphate buffer were successfully performed even at 200 mM substrate concentration (20.4 g/L) leading to 99% (R) and 94% (S) conversion with perfect optical purity (>99% ee). PMID- 24951101 TI - Effects of isoflavones and amino acid therapies for hot flashes and co-occurring symptoms during the menopausal transition and early postmenopause: a systematic review. AB - AIMS: Review controlled clinical trials of isoflavones and amino acid preparation effects on hot flashes and at least one other symptom including mood, sleep, pain, and cognitive function that women report during the menopausal transition and early postmenopause. METHODS: An experienced reference librarian searched PubMed/Medline, CINAHL Plus, PsycInfo, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, EMBASE, AMED, and Alt-Health Watch for English-language randomized controlled trials between 2004 and July 2011. Seventeen trials of isoflavones and amino acid effects on hot flashes and one additional symptom were identified. RESULTS: In five trials of soy isoflavone preparations, two (6g soy germ extract and 25 g soy protein in soy nuts) significantly decreased hot flashes, but no other symptoms. In the seven trials of other isoflavones, six significantly reduced hot flashes; in addition, red clover (80 mg) significantly reduced mood symptoms; Rexflavone (350 mg) for women with Kupperman Index>20 significantly reduced sleep symptoms; two trials had significant reductions for pain: isoflavone powder (90 mg) and red clover (80 mg). The only trial in this systematic review that significantly reduced cognitive symptoms was red clover (80 mg). In one trial, red clover isoflavone (80 mg/day) significantly relieved hot flashes, mood, pain, and cognitive symptoms. Amino acids yielded no significant results. Equol supplements of 30 mg/day for non-Equol producing women significantly reduced mood symptoms in one trial. The magnolia bark extract combination significantly reduced hot flashes, mood, and sleep symptoms. CONCLUSIONS: Isoflavone trials yielded significant reductions on hot flashes and co-occurring symptoms during the menopausal transition and postmenopause, but studies require replication with larger sample sizes and attention to measurement of outcomes. PMID- 24951102 TI - Menopause and depression: is there a link? AB - AIM: Depression is common and may have significant implications for the individual, their families and work and for the health care system. The menopause transition (MT) may be an 'at risk' time for the development of depression. This review aims to explore the relationship between depression and MT and the complex interaction between the biological, psychological and social factors that inform it. METHODS: The literature on depressive disorders and MT is reviewed. RESULTS AND CONCLUSIONS: Longitudinal studies have demonstrated an association between the menopause transition (MT) and an increase in depressive symptoms. A trend towards higher rates of depressive disorders during the MT, has also been shown, although not always reaching statistical significance. Risk factors for the development of depressive symptoms and depression in the MT include the presence of vasomotor symptoms (VMS), a personal history of depression (particularly depression that is related to pregnancy or hormonal changes through the menstrual cycle), surgical menopause, adverse life events, and negative attitudes to menopause and ageing. A treatment approach to depression during the MT exploits the biological as well as the psychosocial factors that are likely to be contributing in an individual. PMID- 24951103 TI - Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). AB - OBJECTIVES: Despite advances in systemic lupus erythematosus (SLE) treatment, many patients suffer from the disease and side effects. Atacicept is a fusion protein that blocks B-lymphocyte stimulator and a proliferation-inducing ligand, which are increased in patients with SLE. METHODS: In this double-blind, placebo controlled study, patients with moderate-to-severe SLE were randomised to atacicept 75 mg or atacicept 150 mg administered subcutaneously, or placebo twice weekly for 4 weeks, then weekly for 48 weeks. Primary and secondary efficacy measures were the proportion of patients experiencing at least one flare of British Isles Lupus Assessment Group A or B, and time to first flare, respectively. RESULTS: Enrolment in the atacicept 150 mg arm was discontinued prematurely due to two deaths. In the intention-to-treat population (n=461), there was no difference in flare rates or time to first flare between atacicept 75 mg and placebo. Analysis of patients treated with atacicept 150 mg suggested beneficial effect versus placebo in flare rates (OR: 0.48, p=0.002) and time to first flare (HR: 0.56, p=0.009). Both atacicept doses were associated with reductions in total Ig levels and anti-dsDNA antibodies, and increases in C3 and C4 levels. Most treatment-emergent adverse events were mild or moderate. CONCLUSIONS: There was no difference between atacicept 75 mg and placebo for flare rate or time to first flare. Analysis of atacicept 150 mg suggested benefit. TRIAL REGISTRATION NUMBER: EudraCT: 2007-003698-13; NCT00624338. PMID- 24951104 TI - State-mandated reporting of health care-associated infections in the United States: trends over time. AB - Over the past decade, most US states and territories began mandating that acute care hospitals report health care-associated infections (HAIs) to their departments of health. Trends in state HAI law enactment and data submission requirements were determined through systematic legal review; state HAI coordinators were contacted to confirm collected data. As of January 31, 2013, 37 US states and territories (71%) had adopted laws requiring HAI data submission, most of which were enacted and became effective in 2006 and 2007. Most states with HAI laws required reporting of central line-associated bloodstream infections in adult intensive care units (92%), and about half required reporting of methicillin-resistant Staphylococcus aureus and Clostridium difficile infections (54% and 51%, respectively). Overall, data submission requirements were found to vary across states. Considering the facility and state resources needed to comply with HAI reporting mandates, future studies should focus on whether these laws have had the desired impact of reducing infection rates. PMID- 24951105 TI - Organizational characteristics and patient experiences with hospital care: a survey study of hospital chief patient experience officers. AB - Beginning in fiscal year 2013, scores based on the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) constitute 30% of incentive-based payments from Medicare's Value-Based Purchasing (VBP) initiative. Yet there is little empirical work to understand hospital approaches to improving the patient experience. In this study, chief patient experience officers at 416 VHA hospitals were surveyed to assess the relationship between organizational characteristics and publicly reported HCAHPS scores. Of 416 institutions, 143 (34.4%) participated. Respondents reported that boards (68%) and chief executive officers (81%) viewed the patient experience as extremely important. In contrast, they reported that in only 15% and 34% of hospitals, respectively, physicians and nurses were supportive of efforts to improve the patient experience. Hospitals with collaborative cultures and higher physician engagement had higher VBP total HCAHPS scores (6.9 points and 8.2 points higher, respectively; both P < .05). These areas should be addressed to improve the patient experience in provider organizations. PMID- 24951106 TI - Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia. AB - Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors (38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assess TERT promoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH deficiency. TERT promoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%), and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines. TERT promoter mutations preferentially occurred in a SDH-deficient setting (P=0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact tumors. We conclude that TERT promoter mutations occur in ACCs and ea PGLs. In addition, preliminary evidence indicates a potential association with the acquisition of TERT promoter mutations in SDH-deficient tumors. PMID- 24951107 TI - Complexities of androgen receptor signalling in breast cancer. AB - While the clinical benefit of androgen-based therapeutics in breast cancer has been known since the 1940s, we have only recently begun to fully understand the mechanisms of androgen action in breast cancer. Androgen signalling pathways can have either beneficial or deleterious effects in breast cancer depending on the breast cancer subtype and intracellular context. This review discusses our current knowledge of androgen signalling in breast cancer, including the relationship between serum androgens and breast cancer risk, the prognostic significance of androgen receptor (AR) expression in different breast cancer subtypes and the downstream molecular pathways mediating androgen action in breast cancer cells. Intracrine androgen metabolism has also been discussed and proposed as a potential mechanism that may explain some of the reported differences regarding dichotomous androgen actions in breast cancers. A better understanding of AR signalling in this disease is critical given the current resurgence in interest in utilising contemporary AR-directed therapies for breast cancer and the need for biomarkers that will accurately predict clinical response. PMID- 24951108 TI - Understanding experiences of participating in a weight loss lifestyle intervention trial: a qualitative evaluation of South Asians at high risk of diabetes. AB - OBJECTIVE: To explore the reasons for enrolling, experiences of participating and reasons for remaining in a family-based, cluster randomised controlled trial of a dietitian-delivered lifestyle modification intervention aiming to reduce obesity in South Asians at high risk of developing diabetes. DESIGN: Qualitative study using narrative interviews of a purposive sample of trial participants following completion of the intervention. Data were thematically analysed. SETTING: The intervention was conducted in Scotland and resulted in a modest decrease in weight, but did not statistically reduce the incidence of diabetes. PARTICIPANTS: We conducted 21 narrative interviews with 24 participants (20 trial participants and four family volunteers). RESULTS: Many participants were motivated to participate because of: known family history of diabetes and the desire to better understand diabetes-related risks to their own and their family's health; ways to mitigate these risks and to benefit from personalised monitoring. Home-based interventions, communication in the participant's chosen language(s) and continuity in dietitians supported their continuing engagement with the trial. Adaptations in food choices were initially accommodated by participants, although social and faith-based responsibilities were reported as important barriers to persevering with agreed dietary goals. Many participants reported that increasing their level of physical activity was difficult given their long working hours, physically demanding employment and domestic commitments; this being compounded by Scotland's challenging climate and a related reluctance to exercise in the outdoors. CONCLUSIONS: Although participants had strong personal interests in participation and found the information provided by dietitians useful, they nonetheless struggled to incorporate the dietary and exercise recommendations into their daily lives. In particular, increasing levels of physical exercise was described as an additional and in some cases unachievable burden. Consideration needs to be given to strengthening and supporting lifestyle interventions with community-based approaches in order to help overcome wider social and environmental factors. PMID- 24951110 TI - Lifestyle risk factors for invasive pneumococcal disease: a systematic review. AB - OBJECTIVE: To systematically review the literature for evidence of smoking and alcohol intake as independent risk factors for invasive pneumococcal disease (IPD). DESIGN: Systematic review. METHODS: MEDLINE (1946-May 2012) and EMBASE (1947-May 2012) were searched for studies investigating alcohol or smoking as risk factors for acquiring IPD and which reported results as relative risk. Studies conducted exclusively in clinical risk groups, those assessing risk factors for outcomes other than acquisition of IPD and studies describing risk factors without quantifying a relative risk were excluded. RESULTS: Seven observational studies were identified and reviewed; owing to the heterogeneity of study design, meta-analysis was not attempted. Five of six studies investigating smoking reported an increased risk of IPD in the range 2.2-4.1. Four of the six studies investigating alcohol intake reported a significant increased risk for IPD ranging from 2.9 to 11.4, while one reported a significant protective effect. CONCLUSIONS: Overall, these observational data suggest that smoking and alcohol misuse may increase the risk of IPD in adults, but the magnitude of this risk remains unclear and should be explored with further research. The findings of this review will contribute to the debate on whether pneumococcal vaccine should be offered to smokers and people who misuse alcohol in addition to other clinically defined risk groups. PMID- 24951109 TI - Association of lifestyle factors and suboptimal health status: a cross-sectional study of Chinese students. AB - OBJECTIVES: Suboptimal health status (SHS) is considered to be an intermediate status between disease and health, and is characterised by a decline in vitality, in physiological function and in the capacity for adaptation. Although the incidence of SHS is high, the underlying causes remain unclear. Lifestyle is one of the most important factors affecting health status; however, the relationship between SHS and lifestyle has not been elucidated. DESIGN: Cross-sectional survey. SETTING: A questionnaire, based on 'Health Promoting Lifestyle Profile-II (HPLP-II)' and 'Sub-Health Measurement Scale V1.0 (SHMS V1.0)', was sent to four colleges in four districts (Guangzhou, Foshan, Zhanjiang and Shaoguan) of China between May and July 2013. PARTICIPANTS: A total of 12 429 questionnaires were distributed during the study period, and 11 144 completed responses were received. RESULTS: The prevalence rates for the 'healthy', 'SHS' and 'disease' groups of respondents (students) were 22.81% (2542), 55.9% (6234) and 21.25% (2368), respectively. Most of the students reported a 'moderate' or 'good' lifestyle. There were significant differences in lifestyle and health status between the two genders. It was notable that health status was significantly positively correlated with lifestyle (r=0.563). For every dimension of the HPLP II model, the mean values were lower for those participants who reported as 'SHS' or 'disease' than for those who reported that they were 'healthy'. The individual dimensions of the HPLP-II model, including 'spiritual growth', 'health responsibility', 'physical activity', 'interpersonal relations' and 'stress management' were all related to SHS. CONCLUSIONS: Health status is significantly positively correlated with lifestyle. Poor lifestyle is a risk factor for SHS. Conversely, adopting a healthier lifestyle can improve SHS. TRIAL REGISTRATION NUMBER: ChiCTR-OCH-12002317. PMID- 24951113 TI - Is the volume of low-grade glioma measurable and is it clinically relevant? PMID- 24951111 TI - Measures of vitamin K antagonist control reported in atrial fibrillation and venous thromboembolism studies: a systematic review. AB - OBJECTIVE: To aid trialists, systematic reviewers and others, we evaluated the degree of standardisation of control measure reporting that has occurred in atrial fibrillation (AF) and venous thromboembolism (VTE) studies since 2000; and attempted to determine whether the prior recommendation of reporting >=2 measures per study has been employed. DESIGN: Systematic review. SEARCH STRATEGY: We searched bibliographic databases (2000 to June 2013) to identify AF and VTE studies evaluating dose-adjusted vitamin K antagonists (VKAs) and reporting >=1 control measure. The types of measures reported, proportion of studies reporting >=2 measures and mean (+/-SD) number of measures per study were determined for all studies and compared between subgroups. DATA EXTRACTION: Through the use of a standardised data extraction tool, we independently extracted all data, with disagreements resolved by a separate investigator. RESULTS: 148 studies were included, 57% of which reported >=2 control measures (mean/study=2.13+/-1.36). The proportion of time spent in the target international normalised ratio range (TTR) was most commonly reported (79%), and was frequently accompanied by time above/below range (52%). AF studies more frequently reported >=2 control measures compared with VTE studies (63% vs 37%; p=0.004), and reported a greater number of measures per study (mean=2.36 vs 1.53; p<0.001). Observational studies were more likely to provide >=2 measures compared with randomised trials (76% vs 33%; p<0.001) and report a greater number of measures (mean=2.58 vs 1.63; p<0.001). More recent studies (2004-2013) reported >=2 measures more often than older (2000 2003) studies (59% vs 35%; p=0.05) and reported more measures per study (mean=2.23 vs 1.48; p=0.02). CONCLUSIONS: While TTR was often utilised, studies reported >=2 measures of VKA control only about half of the time and lacked consistency in the types of measures reported. A trend towards studies reporting greater numbers of VKA control measures over time was observed over our review time horizon, particularly, with AF and observational studies. PMID- 24951112 TI - MicroRNA-377 inhibited proliferation and invasion of human glioblastoma cells by directly targeting specificity protein 1. AB - BACKGROUND: Increasing evidence has indicated that microRNAs (miRNAs) are strongly implicated in the initiation and progression of glioblastoma multiforme (GBM). Here, we identified a novel tumor suppressive miRNA, miR-377, and investigated its role and therapeutic effect for GBM. METHODS: MiRNA global screening was performed on GBM patient samples and adjacent nontumor brain tissues. The expression of miR-377 was detected by real-time reverse transcription PCR. The effects of miR-377 on GBM cell proliferation, cell cycle progression, invasion, and orthotopic tumorigenicity were investigated The therapeutic effect of miR-377 mimic was explored in a subcutaneous GBM model. Western blot and luciferase reporter assay were used to identify the direct and functional target of miR-377. RESULTS: MiR-377 was markedly downregulated in human GBM tissues and cell lines. Overexpression of miR-377 dramatically inhibited cell growth both in culture and in orthotopic xenograft tumor models, blocked G1/S transition, and suppressed cell invasion in GBM cells. Importantly, introduction of miR-377 could strongly inhibit tumor growth in a subcutaneous GBM model. Subsequent investigation revealed that specificity protein 1 (Sp1) was a direct and functional target of miR-377 in GBM cells. Silencing of Sp1 recapitulated the antiproliferative and anti-invasive effects of miR-377, whereas restoring the Sp1 expression antagonized the tumor-suppressive function of miR 377. Finally, analysis of miR-377 and Sp1 levels in human GBM tissues revealed that miR-377 is inversely correlated with Sp1 expression. CONCLUSION: These findings reveal that miR-377/Sp1 signaling that may be required for GBM development and may consequently serve as a therapeutic target for the treatment of GBM. PMID- 24951114 TI - Targeted treatment for sonic hedgehog-dependent medulloblastoma. AB - Novel treatment options, including targeted therapies, are needed for patients with medulloblastoma (MB), especially for those with high-risk or recurrent/relapsed disease. Four major molecular subgroups of MB have been identified, one of which is characterized by activation of the sonic hedgehog (SHH) pathway. Preclinical data suggest that inhibitors of the hedgehog (Hh) pathway could become valuable treatment options for patients with this subgroup of MB. Indeed, agents targeting the positive regulator of the pathway, smoothened (SMO), have demonstrated efficacy in a subset of patients with SHH MB. However, because of resistance and the presence of mutations downstream of SMO, not all patients with SHH MB respond to SMO inhibitors. The development of agents that target these resistance mechanisms and the potential for their combination with traditional chemotherapy and SHH inhibitors will be discussed. Due to its extensive molecular heterogeneity, the future of MB treatment is in personalized therapy, which may lead to improved efficacy and reduced toxicity. This will include the development of clinically available tests that can efficiently discern the SHH subgroup. The preliminary use of these tests in clinical trials is also discussed herein. PMID- 24951117 TI - Cytoplasmic dynein pushes the cytoskeletal meshwork forward during axonal elongation. AB - During development, neurons send out axonal processes that can reach lengths hundreds of times longer than the diameter of their cell bodies. Recent studies indicate that en masse microtubule translocation is a significant mechanism underlying axonal elongation, but how cellular forces drive this process is unknown. Cytoplasmic dynein generates forces on microtubules in axons to power their movement through 'stop-and-go' transport, but whether these forces influence the bulk translocation of long microtubules embedded in the cytoskeletal meshwork has not been tested. Here, we use both function-blocking antibodies targeted to the dynein intermediate chain and the pharmacological dynein inhibitor ciliobrevin D to ask whether dynein forces contribute to en bloc cytoskeleton translocation. By tracking docked mitochondria as fiducial markers for bulk cytoskeleton movements, we find that translocation is reduced after dynein disruption. We then directly measure net force generation after dynein disruption and find a dramatic increase in axonal tension. Taken together, these data indicate that dynein generates forces that push the cytoskeletal meshwork forward en masse during axonal elongation. PMID- 24951115 TI - ERM proteins at a glance. AB - The cell cortex is a dynamic and heterogeneous structure that governs cell identity and behavior. The ERM proteins (ezrin, radixin and moesin) are major architects of the cell cortex, and they link plasma membrane phospholipids and proteins to the underlying cortical actin cytoskeleton. Recent studies in several model systems have uncovered surprisingly dynamic and complex molecular activities of the ERM proteins and have provided new mechanistic insight into how they build and maintain cortical domains. Among many well-established and essential functions of ERM proteins, this Cell Science at a Glance article and accompanying poster will focus on the role of ERMs in organizing the cell cortex during cell division and apical morphogenesis. These examples highlight an emerging appreciation that the ERM proteins both locally alter the mechanical properties of the cell cortex, and control the spatial distribution and activity of key membrane complexes, establishing the ERM proteins as a nexus for the physical and functional organization of the cell cortex and making it clear that they are much more than scaffolds. This article is part of a Minifocus on Establishing polarity. PMID- 24951118 TI - The hand knife: a forgotten tool in plastic surgery training. PMID- 24951116 TI - Multivariate signaling regulation by SHP2 differentially controls proliferation and therapeutic response in glioma cells. AB - Information from multiple signaling axes is integrated in the determination of cellular phenotypes. Here, we demonstrate this aspect of cellular decision making in glioblastoma multiforme (GBM) cells by investigating the multivariate signaling regulatory functions of the protein tyrosine phosphatase SHP2 (also known as PTPN11). Specifically, we demonstrate that the ability of SHP2 to simultaneously drive ERK1/2 and antagonize STAT3 pathway activities produces qualitatively different effects on the phenotypes of proliferation and resistance to EGFR and c-MET co-inhibition. Whereas the ERK1/2 and STAT3 pathways independently promote proliferation and resistance to EGFR and c-MET co inhibition, SHP2-driven ERK1/2 activity is dominant in driving cellular proliferation and SHP2-mediated antagonism of STAT3 phosphorylation prevails in the promotion of GBM cell death in response to EGFR and c-MET co-inhibition. Interestingly, the extent of these SHP2 signaling regulatory functions is diminished in glioblastoma cells that express sufficiently high levels of the EGFR variant III (EGFRvIII) mutant, which is commonly expressed in GBM. In cells and tumors that express EGFRvIII, SHP2 also antagonizes the phosphorylation of EGFRvIII and c-MET and drives expression of HIF-1alpha and HIF-2alpha, adding complexity to the evolving understanding of the regulatory functions of SHP2 in GBM. PMID- 24951120 TI - Introduction to JCPT Focused Issue on "Stem Cells and Cardiac Regenerative Medicine" PMID- 24951119 TI - Diagnostic value of procalcitonin in burn septic patients. PMID- 24951121 TI - Measurement of air dose rates over a wide area around the Fukushima Dai-ichi Nuclear Power Plant through a series of car-borne surveys. AB - A series of car-borne surveys using the Kyoto University RAdiation MApping (KURAMA) and KURAMA-II survey systems has been conducted over a wide area in eastern Japan since June 2011 to evaluate the distribution of air dose rates around the Fukushima Dai-ichi Nuclear Power Plant and to evaluate the time dependent trend of decrease in air dose rates. An automated data processing system for the KURAMA-II system was established, which enabled rapid analysis of large amounts of data obtained using about 100 KURAMA-II units. The initial data used for evaluating the migration status of radioactive cesium were obtained in the first survey, followed by other car-borne surveys conducted over more extensive and wider measurement ranges. By comparing the measured air dose rates obtained in each survey (until December 2012), the decreasing trend of air dose rates measured through car-borne surveys was found to be more pronounced than those expected on the basis of the physical decay of radioactive cesium and of the air dose rates measured using NaI (Tl) survey meters in the areas surrounding the roadways. In addition, it was found that the extent of decrease in air dose rates depended on land use, wherein it decreased faster for land used as building sites than for forested areas. PMID- 24951122 TI - Primary prophylaxis of invasive fungal infections in patients with haematologic malignancies. 2014 update of the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. AB - Invasive fungal infections cause substantial morbidity and mortality in immunocompromised patients, particularly in those with haematological malignancies and recipients of allogeneic haematopoietic stem cell transplantation. Difficulties in diagnosing invasive fungal infections and subsequent delays in treatment initiation lead to unfavourable outcomes and emphasise the importance of prophylaxis. Since the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology in 2009, results of 14 additional clinical studies have been published comprising 2,899 patients and initiating this update. Key recommendations for adult patients are as follows: Posaconazole remains the drug of choice during remission-induction chemotherapy in acute myeloid leukaemia, myelodysplastic syndrome and allogeneic haematopoietic stem cell transplantation with graft versus host disease (AI). In the pre-engraftment period of allogeneic transplantation, several antifungals are appropriate and can be recommended with equal strength: voriconazole (BI), micafungin (BI), fluconazole (BI) and posaconazole (BII). There is poor evidence regarding antifungal prophylaxis in the post-engraftment period of allogeneic haematopoietic stem cell transplantation if no steroids for treatment of graft versus host disease are required. Aerosolised liposomal amphotericin B inhalation in conjunction with fluconazole can be used in patients with prolonged neutropenia (BII). PMID- 24951124 TI - Lymphocyte recovery is impaired in patients with chronic lymphocytic leukemia and indolent non-Hodgkin lymphomas treated with bendamustine plus rituximab. AB - The immune system has the potential to either attenuate tumor growth or to promote tumor progression. The goal of cancer immunotherapy is to shift the balance in favor of tumor immunosurveillance, so that the immune system can recognize the tumor, eliminate it, and prevent its recurrence. Bendamustine plus rituximab is generally considered effective and safe in patients with previously untreated chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphomas. To evaluate the effects of bendamustine-rituximab and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on the recuperation of immune system, we analyze the distribution of CD4+ and CD8+ T cells, B cells, and NK cells in peripheral blood of 18 patients who received 4-6 cycles of rituximab-bendamustine (BR) or six R-CHOP before therapy and 6 months after completing treatment. Our results indicate that lymphocyte recovery is impaired in patients with chronic lymphocytic leukemia and indolent lymphomas treated with bendamustine plus rituximab. Low CD4 T cells (<200 cells/MUl) induced by bendamustine (BR) suggest prophylaxis should be applied against opportunistic infections. Asymptomatic EBV and CMV reactivations support a negative effect of BR on the immune system. If cellular immune therapy such as lymphokine-activated killer (LAK) or effector lymphocytes infusion is planned, regimes other than BR should be the first choice. PMID- 24951123 TI - Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group. AB - Data on efficacy and safety of azacitidine in acute myeloid leukemia (AML) with >30 % bone marrow (BM) blasts are limited, and the drug can only be used off label in these patients. We previously reported on the efficacy and safety of azacitidine in 155 AML patients treated within the Austrian Azacitidine Registry (clinicaltrials.gov identifier NCT01595295). We herein update this report with a population almost twice as large (n = 302). This cohort included 172 patients with >30 % BM blasts; 93 % would have been excluded from the pivotal AZA-001 trial (which led to European Medicines Agency (EMA) approval of azacitidine for high-risk myelodysplastic syndromes (MDS) and AML with 20-30 % BM blasts). Despite this much more unfavorable profile, results are encouraging: overall response rate was 48 % in the total cohort and 72 % in patients evaluable according to MDS-IWG-2006 response criteria, respectively. Median OS was 9.6 (95 % CI 8.53-10.7) months. A clinically relevant OS benefit was observed with any form of disease stabilization (marrow stable disease (8.1 months), hematologic improvement (HI) (9.7 months), or the combination thereof (18.9 months)), as compared to patients without response and/or without disease stabilization (3.2 months). Age, white blood cell count, and BM blast count at start of therapy did not influence OS. The baseline factors LDH >225 U/l, ECOG >=2, comorbidities >=3, monosomal karyotype, and prior disease-modifying drugs, as well as the response related factors hematologic improvement and further deepening of response after first response, were significant independent predictors of OS in multivariate analysis. Azacitidine seems effective in WHO-AML, including patients with >30 % BM blasts (currently off-label use). Although currently not regarded as standard form of response assessment in AML, disease stabilization and/or HI should be considered sufficient response to continue treatment with azacitidine. PMID- 24951125 TI - Clinical outcome of HCV-positive patients with diffuse large B-cell lymphoma treated with rituximab-based chemotherapy. AB - The influence of rituximab therapy on prognosis and hepatic toxicity (HT) in patients with hepatitis C virus (HCV)-positive diffuse large B-cell lymphoma (DLBCL) is unclear. Thus, we assessed HT and clinical outcome in patients with DLBCL and HCV infection who received rituximab-containing immunochemotherapy. We carried out a prospective analysis on a total of 280 HCV-positive patients with DLBCL, 200 of whom received chemotherapy plus rituximab (R-CHT), 80 received chemotherapy (CHT)-only. Survival outcomes and HT were compared according to rituximab administration. The median follow-up was 41 months. Addition of rituximab did not significantly affect prognosis (median progression-free survival, 40 vs 35 months, P = 0.26; median overall survival, 51 vs 43 months P = 0.09). Of 200 patients who received rituximab, 53 (26.5 %) had severe HT (grade 3 4), compared with 11 of 80 (13.75 %) patients who received rituximab-free regimens (P = 0.033). Among patients treated with rituximab, 50 patients (25 %) did not complete planned course of therapy, 14 patients because of hepatic toxicity and 36 patients because of progressive disease. Pretreatment liver function impairment was predictive of severe HT. These results raise concerns regarding the routine use of rituximab with chemotherapy in individuals with HCV positive DLBCL. However, more studies are warranted before a definitive conclusion can be made. PMID- 24951126 TI - Transcervical sterilization: population sterilization rates overestimated. PMID- 24951127 TI - Clinical correlates of prescription opioid analgesic use in pregnancy. AB - A 2012 committee opinion from the American College of Obstetricians and Gynecologists highlights the considerable increase in opioid addiction in recent years, yet little is known about clinical correlates of prescribed opioids among pregnant women. This study examines clinical and demographic factors associated with the use of opioid analgesics in pregnancy. Data were derived from a prospective cohort study of pregnant women. Participants were administered the Composite International Diagnostic Interview to identify depressive and anxiety disorders and data on medication use were gathered at three assessment points and classified according to the Anatomical Therapeutic Chemical Code (ATC) classification system ATC group N02A. Participants included 2,748 English or Spanish speaking pregnant women. Six percent (n = 165) of women used opioid analgesics at any point in pregnancy. More pregnant women using opioids met diagnostic criteria for major depressive disorder (16 vs. 8 % for non users), generalized anxiety disorder (18 vs. 9 % for non users), post-traumatic stress disorder (11 vs. 4 % for non users) and panic disorder (6 vs. 4 % for non users). Women who reported opioid use were also significantly more likely than non users to report using illicit drugs and almost three times as likely to report smoking cigarettes in the second or third trimester of pregnancy (4 and 23 %, respectively) as compared to non-opioid users (0.5 and 8 %). The use of opioids in pregnancy was associated with higher levels of psychiatric comorbidity and use of other substances as compared to non-opioid users. PMID- 24951128 TI - Indicators of successful implementation of programs to promote healthy weight among women. AB - Obesity rates have steadily increased over the past two decades. To address the epidemic in women, the Health Resources and Services Administration's Maternal and Child Health Bureau, Division of Healthy Start and Perinatal Services (HRSA/MCHB/DHSPS) awarded 14 demonstration grants to community health centers, health departments, universities and community-based organizations in 12 states to develop innovative approaches aimed at reducing the prevalence of overweight and obesity, specifically in women of childbearing age. Grantees implemented modified or existing evidence-based programs (EBP) or promising practices tailored to the geographic locations, cultures and traditional values of the communities. A review of the 15 programs implemented from 2004 to 2007 was conducted using the methodology outlined in the Transparent Reporting of Evaluations with Nonrandomized Designs Statement to identify indicators of successful program implementation. The six indicators identified were: (1) supportive organizational culture with adequate resources and appropriate staff; (2) attention to the needs of the service population; (3) a referral system that links participants to appropriate services; (4) flexible schedules; (5) support for child care and transportation; and (6) formal and informal support systems to keep participants engaged and motivated. Two of the programs that reported improved participant outcomes are available for replication: La Vida Sana, La Vida Feliz in Illinois was designated as a promising practice by the Association of Maternal and Child Health Programs and Sisters in Action in Michigan was rated as a moderate evidence-based program by the Agency for Healthcare Research and Quality. PMID- 24951130 TI - The heterogeneity in financial and time burden of caregiving to children with chronic conditions. AB - We examine the financial and time burdens associated with caring for children with chronic conditions, focusing on disparities across types of conditions. Using linked data from the 2003 to 2006 National Health Interview Survey and 2004 2008 Medical Expenditure Panel Survey, we created measures of financial burden (out-of-pocket healthcare costs, the ratio of out-of-pocket healthcare costs to family income, healthcare costs paid by insurance, and total healthcare costs) and time burden (missed school time due to illness or injury and the number of doctor visits) associated with 14 groups of children's chronic conditions. We used the two-part model to assess the effect of condition on financial burden and finite mixture/latent class model to analyze the time burden of caregiving. Controlling for the influences of other socio-demographic characteristics on caregiving burden, children with chronic conditions have higher financial and time burdens relative to caregiving burdens for healthy children. Levels of financial burden and burden sharing between families and insurance system also vary by type of condition. For example, children with pervasive developmental disorder or heart disease have a relatively low financial burden for families, while imposing a high cost on the insurance system. In contrast, vision difficulties are associated with a high financial burden for families relative to the costs borne by others. With respect to time burden, conditions such as cerebral palsy and heart disease impose a low time burden, while conditions such as pervasive developmental disorder are associated with a high time burden. This study demonstrates that differences exist in caregiving burden for children by type of chronic condition. Each condition has a unique profile of time and financial cost burden for families and the insurance system. These results have implications for policymakers and for families' savings and employment decisions. PMID- 24951131 TI - Continuous vs. segmented second-dimension system gradients for comprehensive two dimensional liquid chromatography of sugarcane (Saccharum spp.). AB - A comprehensive two-dimensional liquid chromatography system in combination with photodiode array and mass spectrometry detection was developed for analysis of polyphenols in sugarcane (Saccharum spp.) leaf extracts. To achieve this, a micro cyano column and a partially porous octodecylsilica column were used in the first and the second dimension, respectively. The choice of the cyano column over other reversed-phase columns tested for the first-dimension separation was due to its lower correlation selectivity with respect to the octodecylsilica column, which was used for the second-dimension separation. Even when reversed-phase mode was used in both dimensions, a satisfactory degree of orthogonality was achieved by use of different gradient elution modes in the second dimension. By means of the setup investigated, 38 polyphenolic compounds were detected, and among them 24 were positively identified by means of complementary data from photodiode array and mass spectrometry detection and an in-house database. This is the first time such a powerful analytical technique has been used for polyphenolic characterization of sugarcane extracts. PMID- 24951129 TI - Plasmodium falciparum infection is associated with Epstein-Barr virus reactivation in pregnant women living in malaria holoendemic area of Western Kenya. AB - The role of Plasmodium falciparum malaria in Epstein-Barr virus (EBV) transmission among infants early in life remain elusive. We hypothesized that infection with malaria during pregnancy could cause EBV reactivation leading to high EBV load in circulation, which could subsequently enhance early age of EBV infection. Pregnant women in Kisumu, where P. falciparum malaria is holoendemic, were actively followed monthly through antenatal visits (up to 4 per mother) and delivery. Using real-time quantitative (Q)-PCR, we quantified and compared EBV and P. falciparum DNA levels in the blood of pregnant women with and without P. falciparum malaria. Pregnant women that had malaria detected during pregnancy were more likely to have detectable EBV DNA than pregnant women who had no evidence of malaria infection during pregnancy (64 vs. 36 %, p = 0.01). EBV load as analyzed by quantifying area under the longitudinal observation curve (AUC) was significantly higher in pregnant women with P. falciparum malaria than in women without evidence of malaria infection (p = 0.01) regardless of gestational age of pregnancy. Increase in malaria load correlated with increase in EBV load (p < 0.0001). EBV load was higher in third trimester (p = 0.04) than first and second trimester of pregnancy independent of known infections. Significantly higher frequency and elevated EBV loads were found in pregnant women with malaria than in women without evidence of P. falciparum infection during pregnancy. The loss of control of EBV latency following P. falciparum infection during pregnancy and subsequent increase in EBV load in circulation could contribute to enhanced shedding of EBV in maternal saliva and breast milk postpartum, but further studies are needed. PMID- 24951132 TI - Asymmetrical flow field-flow fractionation with multi-angle light scattering and quasi-elastic light scattering for characterization of polymersomes: comparison with classical techniques. AB - Polymersomes formed from amphiphilic block copolymers, such as poly(ethyleneoxide b-epsilon-caprolactone) (PEO-b-PCL) or poly(ethyleneoxide-b-methylmethacrylate), were characterized by asymmetrical flow field-flow fractionation coupled with quasi-elastic light scattering (QELS), multi-angle light scattering (MALS), and refractive index detection, leading to the determination of their size, shape, and molecular weight. The method was cross-examined with more classical ones, like batch dynamic and static light scattering, electron microscopy, and atomic force microscopy. The results show good complementarities between all the techniques; asymmetrical flow field-flow fractionation being the most pertinent one when the sample exhibits several different types of population. PMID- 24951133 TI - Growth factor expression after lesion creation in the avascular zone of the meniscus: a quantitative PCR study in rabbits. AB - PURPOSE: To define the variations in the expression of 5 growth factor genes in meniscal tissue after a lesion is created in the avascular zone of the medial meniscus of the rabbit. METHODS: A longitudinal lesion was created in the avascular zone of the anterior horn of the medial meniscus in 42 rabbits. Six animals were killed at 0, 1, 3, 7, 14, 21, and 120 days after lesion creation. Meniscal tissue from the avascular and vascular zones was harvested. A quantitative polymerase chain reaction analysis was performed to evaluate the expression levels of 5 different growth factors: vascular endothelial growth factor A (VEGF-A), insulin-like growth factor 1 (IGF-1), transforming growth factor beta1 (TGF-beta1), platelet-derived growth factor beta (PDGF-beta), and interleukin 1beta. RESULTS: The basal expression levels of all the growth factors studied were similar in the avascular and vascular zones. There was an increase in VEGF-A expression in the avascular zone on the 14th day, an increase in IGF-1 expression in the vascular zone on the 14th day, a decrease in PDGF-beta expression in both zones in the first week, an increase in interleukin 1beta expression in both zones on the first day, and a decrease in TGF-beta1 expression in the vascular zone in the first week. At 120 days, the expression levels of all 5 growth factors returned to basal levels. CONCLUSIONS: There are significant variations in the expression of the growth factors studied during the first weeks after meniscal lesion creation. The preinjury expression levels are similar in the avascular and vascular zones and are not significantly different from the basal levels 4 months after injury. CLINICAL RELEVANCE: This study identifies potential therapeutic molecular targets (VEGF-A, IGF-1, TGF-beta1, and PDGF-beta) that can be used in the treatment of meniscal tears. PMID- 24951135 TI - Anterior hip dislocation 5 months after hip arthroscopy. AB - Hip dislocation subsequent to hip arthroscopy is a rare complication. We report on a case of low-energy anterior hip dislocation that occurred 5 months after hip arthroscopy, a period notably longer than any previously reported event. The patient was a track and field athlete who presented and received treatment for a labral tear and cam lesion. The athlete then dislocated her hip postoperatively during competitive jumping, a motion that requires significant hip flexion and extension. The most likely cause of the anterior dislocation was failure to close the capsule at the completion of surgery, lending credibility to recent trends in the literature suggesting routine capsular closure. We believe that a partial psoas release also contributed to dynamic hip instability because of increased femoral anteversion in this patient. This case suggests that hip capsule closure should be considered at the completion of every procedure and that a psoas release should be avoided in patients with significant anteversion. Furthermore, the biomechanics of competitive jumping may make these athletes more prone to dislocation and require more conservative return-to-sport recommendations. PMID- 24951134 TI - Are magnetic resonance imaging recovery and laxity improvement possible after anterior cruciate ligament rupture in nonoperative treatment? AB - PURPOSE: This study aimed to determine whether anterior cruciate ligament (ACL) features on magnetic resonance imaging (MRI) and knee laxity are improved 2 years after ACL rupture treated nonoperatively and to analyze the relation between changes in scores of ACL features and changes in laxity. METHODS: One hundred fifty-four eligible patients were included in a prospective multicenter cohort study with 2-year follow-up. Inclusion criteria were (1) ACL rupture diagnosed by physical examination and MRI, (2) MRI within 6 months after trauma, and (3) age 18 to 45 years. Laxity tests and MRI were performed at baseline and at 2-year follow-up. Fifty of 143 patients, for whom all MRI data was available, were treated nonoperatively and were included for this study. Nine ACL features were scored using MRI: fiber continuity, signal intensity, slope of ACL with respect to the Blumensaat line, distance between the Blumensaat line and the ACL, tension, thickness, clear boundaries, assessment of original insertions, and assessment of the intercondylar notch. A total score was determined by summing scores for each feature. RESULTS: Fiber continuity improved in 30 patients (60%), and the empty intercondylar notch resolved for 22 patients (44%). Improvement in other ACL features ranged from 4% to 28%. Sixteen patients (32%) improved on the Lachman test (change from soft to firm end points [n = 14]; decreased anterior translation [n = 2]), one patient (2%) showed improvement with the KT-1000 arthrometer (MEDmetric, San Diego, CA) and 4 patients (8%) improved on the pivot shift test. Improvement on the Lachman test was moderately negatively associated with the total score of ACL features at follow-up. Analyzing ACL features separately showed that only signal intensity improvement, clear boundaries, and intercondylar notch assessment were positively associated with improvement on the Lachman test. CONCLUSIONS: Two years after ACL rupture and nonoperative management, patients experienced partial recovery on MRI, and some knee laxity improvement was present. Improvement of ACL features on MRI correlates moderately with improved laxity. LEVEL OF EVIDENCE: Level II, Prospective comparative study. PMID- 24951136 TI - Near infrared spectroscopy for rapid determination of Mankin score components: a potential tool for quantitative characterization of articular cartilage at surgery. AB - PURPOSE: The purpose of this study was to demonstrate the potential of near infrared (NIR) spectroscopy for characterizing the health and degenerative state of articular cartilage based on the components of the Mankin score. METHODS: Three models of osteoarthritic degeneration induced in laboratory rats by anterior cruciate ligament (ACL) transection, meniscectomy (MSX), and intra articular injection of monoiodoacetate (1 mg) (MIA) were used in this study. Degeneration was induced in the right knee joint; each model group consisted of 12 rats (N = 36). After 8 weeks, the animals were euthanized and knee joints were collected. A custom-made diffuse reflectance NIR probe of 5-mm diameter was placed on the tibial and femoral surfaces, and spectral data were acquired from each specimen in the wave number range of 4,000 to 12,500 cm(-1). After spectral data acquisition, the specimens were fixed and safranin O staining (SOS) was performed to assess disease severity based on the Mankin scoring system. Using multivariate statistical analysis, with spectral preprocessing and wavelength selection technique, the spectral data were then correlated to the structural integrity (SI), cellularity (CEL), and matrix staining (SOS) components of the Mankin score for all the samples tested. RESULTS: ACL models showed mild cartilage degeneration, MSX models had moderate degeneration, and MIA models showed severe cartilage degenerative changes both morphologically and histologically. Our results reveal significant linear correlations between the NIR absorption spectra and SI (R(2) = 94.78%), CEL (R(2) = 88.03%), and SOS (R(2) = 96.39%) parameters of all samples in the models. In addition, clustering of the samples according to their level of degeneration, with respect to the Mankin components, was also observed. CONCLUSIONS: NIR spectroscopic probing of articular cartilage can potentially provide critical information about the health of articular cartilage matrix in early and advanced stages of osteoarthritis (OA). CLINICAL RELEVANCE: This rapid nondestructive method can facilitate clinical appraisal of articular cartilage integrity during arthroscopic surgery. PMID- 24951137 TI - An engineered co-sensitization system for highly efficient dye solar cells. AB - Novel co-sensitizers have been structurally tailored and implemented in multi sensitized devices demonstrating synergic efficiency enhancement attributable to improved light-harvesting as well as prevention of charge recombination. PMID- 24951138 TI - [Paradoxal cultures]. PMID- 24951139 TI - [Paradoxical reactions and responses during antibiotic treatment for Mycobacterium ulcerans infection (Buruli ulcer). Four cases from French Guiana]. AB - BACKGROUND: In recent years, first-line therapy for Mycobacterium ulcerans infection in French Guiana has consisted of antibiotics active against this organism. Two regimens are used comprising rifampicin associated with clarithromycin or amikacin. PATIENTS AND METHODS: We describe four patients presenting apparent worsening of their lesions during treatment: ulceration of a nodular lesion in a 32-year-old woman and worsening of an ulcerated lesion in three patients aged 16, 27 and 79 years. DISCUSSION: In these 4 patients, we concluded that the symptoms were caused by a paradoxical response or a reaction, a phenomenon already described in tuberculosis and leprosy. Such worsening is transient and must not be misinterpreted as failure to respond to treatment. The most plausible pathophysiological hypothesis involves the re-emergence of potentially necrotizing cellular immunity secondary to the loss of mycolactone, a necrotizing and immunosuppressive toxin produced by M. ulcerans, resulting from the action of the antibiotics. PMID- 24951141 TI - [Nail-fold capillaroscopy in dermatology]. AB - Nail-fold capillaroscopy is a non-invasive tool to study the microcirculation and is increasingly being used in dermatology, angiology and rheumatology. More recently, the use of video-capillaroscopy has allowed computer storage of capillaroscopic images (video-capillaroscopy), enabling evaluation of changes in capillaroscopic abnormalities during the follow-up of patients with systemic sclerosis or mixed connective tissue disease. Qualitative and quantitative assessment of the nail-fold dermal capillaries and of their organization can readily distinguish between a normal capillaroscopic pattern in primary Raynaud phenomenon and a specific sclerodermic pattern in secondary Raynaud phenomenon carrying a very high risk of systemic sclerosis. Apart from its important role as a diagnostic tool for distinguishing between primary and secondary Raynaud phenomenon, capillaroscopy is now used to predict the risk of development of digital ulcers and of future visceral complications in patients with systemic sclerosis. Moreover, nail-fold capillaroscopy is essential for differential diagnosis between connective tissue diseases, for the etiologic diagnosis of digital necrosis and diffuse interstitial lung disease, and in sclerodermiform syndromes. PMID- 24951140 TI - [Port-wine stains treated by pulsed-dye laser with sedation: A retrospective observational efficacy and safety in 18 children]. AB - BACKGROUND: Pulsed-dye laser (PDL) is the gold standard treatment for port-wine stains but it is painful. To limit pain in small children, sedation may be given. OBJECTIVE: We sought to determine the efficacy of this approach and the risks of sedation, as well as the level of satisfaction of parents. PATIENTS AND METHODS: A retrospective study was conducted in our dermatology department in children treated with PDL while under sedation. The efficacy of treatment was evaluated by comparing pictures of lesions before and after treatment and using a questionnaire sent to the parents. RESULTS: 18 children were included between 2003 and 2011. In all, 111 laser sessions were performed with sedation. Comparison of photographs showed an improvement rate of 6.2/10 (in terms of colour and area). The mean parent satisfaction score was 6.6/10. Adverse events were reported in 27.8 % of children and for 4.5 % of PDL sessions, with one case of severe hypoxemia that resolved without sequelae. DISCUSSION: In our study, PDL for port-wine stains was effective, with good improvement of lesions. Pain was controlled thanks to sedation with one serious adverse event. The parents indicated a positive impression. This study suggests that the procedure may be proposed for small children in order to reduce pain, with a good risk-benefit ratio for sedation. More studies are needed to better qualify pain management for children under PDL treatment. PMID- 24951142 TI - [Pseudocyst of the scalp: two cases]. AB - BACKGROUND: Pseudocysts of the scalp are a poorly known entity. Herein we present two new cases. CASE REPORT: Two male patients aged respectively 42 and 33 years had been presenting a small number of pseudocystic lesions on the scalp, as well as alopecia limited to the same region, for a number of years. Inflammatory episodes had occurred in certain lesions. In one case, biopsy showed an aspect typical of pseudocyst of the scalp and the lesions appeared to stabilize on treatment with doxycycline. DISCUSSION: Pseudocysts of the scalp are also known as aseptic nodules of the scalp, a term that appears to us to be less appropriate. They form lesions involving alopecia and they may be inflammatory to various degrees. Following incision of these lesions, a deep yellow fluid liquid is released that may be shown by microbiological analysis to be sterile. Histological analysis reveals a pseudocystic wall associated with perilesional inflammatory remodelling. The cysts are frequently confused with dissecting cellulitis of the scalp, but the prognosis is more encouraging. Treatment involves surgical excision, and intralesional injections of corticosteroids or doxycycline. PMID- 24951143 TI - [Acquired haemophilia A: two cases]. AB - BACKGROUND: Acquired haemophilia A (AH) is an uncommon bleeding disorder that presents as multiple, disseminated spontaneous subcutaneous bleeds. Diagnosis may be made on the basis of prolonged activated partial thromboplastin time (aPTT). The severity of the disease is associated with the low risk of haemoglobin levels and with potential links with other diseases. OBSERVATIONS: Two men were hospitalized for extensive and spontaneous subcutaneous hematoma. In both cases, the International Normalized Ratio (INR) was normal, but aPTT was 3 times higher than normal. Autoantibodies against coagulation factor VIII confirmed the diagnosis of AH. The patients received immunomodulatory treatment. In one patient, diffuse large B-cell lymphoma was discovered one year after successful treatment of AH. DISCUSSION: AH may be revealed by areas of bruising, subutaneous haematomas mimicking erythema nodosum, and muscle pain. APTT results alone can prompt the biologist to screen for factor VIII inhibitors. Aside from the risk of fatal bleeding, in half of all cases, the prognosis is determined by associated disorders such as blood dyscrasias, solid tumours, autoimmune diseases, use of certain medicines and pregnancy. After treatment for bleeding complications, therapy focuses on restoring the coagulation time. The aim of immunomodulatory therapy is to stem production of autoantibodies against coagulation factor VIII. CONCLUSION: AH must be considered rapidly in order to reduce the risk of bleeding emergencies and to screen for potential related diseases. PMID- 24951144 TI - [Clinical and capillaroscopic regression of CD30 anaplastic lymphoma associated with limited cutaneous systemic sclerosis following autologous bone marrow transplantation]. AB - BACKGROUND: In rare cases, tumors are associated with secondary Raynaud's phenomenon in systemic sclerosis (SSc). We report the case of a patient presenting cutaneous limited SSc associated with CD30 anaplastic lymphoma with cutaneous and lymph node involvement in whom the capillaroscopic scleroderma pattern regressed completely after autologous bone marrow transplantation, with complete remission of the lymphoma. CASE REPORT: A 37-year-old man presented bilateral Raynaud's phenomenon associated with digital ulcers contracted one year earlier but subsequently neglected. Right axillary lymph nodes and regional cutaneous tumors were present, leading to the diagnosis of CD30+ anaplastic lymphoma with cutaneous and lymph node involvement. Chemotherapy containing cyclophosphamide achieved only partial remission of the lymphoma. Clinical examination showed bilateral Raynaud's phenomenon, sclerodactyly, a right axillary subcutaneous nodule and a pathological Allen's test for the right hand. Antinuclear antibodies were positive without any other immunological abnormalities, and capillaroscopy showed an SSc pattern with numerous megacapillaries. Digital blood pressure was reduced in the right index and the left middle fingers, in which ulcers of the pulp were observed. Bone marrow transplantation was performed, resulting in complete remission of the lymphoma and disappearance of the sclerodactyly, with no recurrence of the pulp ulcers and complete normalization of capillaroscopic appearance and digital pressure. DISCUSSION: This case raises the question of authentic SSc and neoplasia and highlights the importance of capillaroscopy in the follow-up of SSc. The complete regression of SSc and of capillaroscopic abnormalities could be explained by the paraneoplastic nature of SSc or by the direct action of the chemotherapy and bone marrow transplantation. PMID- 24951145 TI - [Two cases of proliferation of monoclonal and monotypic lymphocytes and plasma cells corresponding to acrodermatitis chronica atrophicans]. AB - BACKGROUND: While a dermal proliferation of monotypic monoclonal lymphocytes and plasma cells suggests above all cutaneous marginal zone lymphoma (CMZL) or plasmacytoma, it may also correspond to a Borrelia infection of which the clinic picture is evocative, as demonstrated in the cases presented herein. PATIENTS AND METHODS: The files of two patients were submitted for discussion at the regional multidisciplinary staff meeting on cutaneous lymphomas after review of the skin biopsies led to a diagnosis of plasmacytoma and CMZL on the basis of infiltrate containing abundant plasma cells. The infiltrates of both patients showed a kappa monotypic light chain and cutaneous B-cell clones were detected. However, the clinical features, with monomelic maculopapular rash, were evocative primarily of Borrelia infection. Diagnosis was confirmed by positive serology and clinical cure was achieved after 3 weeks of oral tetracycline, without relapse. COMMENTS: A link between Borrelia infection and cutaneous lymphomas has long been thought to exist. Further, it is recommended that antibiotics be considered in CMZL before undertaking systemic therapy. The classic histological appearance of the tertiary phase of early-stage Lyme's disease shows perivascular and periadnexal infiltrate comprising lymphocytes and plasma cells. At the later stages, epidermal atrophy occurs with thinning of the dermis. The monoclonal and monotypic nature of skin proliferation points above all to CMZL or plasmacytoma. However, clinicopathological correlation is an essential step before such a diagnosis may be made. In the event of monomelic erythema, as in our patients, it is important to screen for Borrelia infection, which responds well to appropriate treatment. PMID- 24951146 TI - [Dermatoscopy and reflectance confocal microscopy aspects of a "nested melanoma of the elderly"]. AB - BACKGROUND: We report a case of a nested melanoma of the elderly, a recently described entity, and we describe its aspect under confocal reflectance microscopy. PATIENTS AND METHODS: A 70-year-old woman presented a pigmented lesion of the left leg measuring 2 * 2.5 cm in diameter which was increasing in size. Dermatoscopic examination showed a predominantly globular pattern, with globules of irregular color and distribution. Reflectance confocal microscopy revealed the presence of dense nests at the dermo-epidermal junction with cytologic atypia and pagetoid cells. The histological appearance was overlapping and a diagnosis of nested melanoma of the elderly was made. COMMENTS: The presence in an older subject of a large pigmented lesion with an irregular globular pattern should be suspected of nested melanoma of the elderly. Reflectance confocal microscopy may be useful in the case of such difficult lesions to proceed with more confidence to surgical excision. PMID- 24951147 TI - [Improvement of idiopathic Raynaud's phenomenon following local infusion of botulinum toxin]. PMID- 24951148 TI - [An alternative pain relief method in PDT]. PMID- 24951149 TI - [Male genital psoriasis]. PMID- 24951150 TI - [Surgical management of localized trichoblastic carcinoma of the conchal bowl by means of a retroauricular revolving door island flap]. PMID- 24951151 TI - [VZV infection]. PMID- 24951152 TI - [Hereditary fibrosing poikiloderma with contractures, myopathy and pulmonary fibrosis: The role of mutations in FAM111B]. PMID- 24951153 TI - [Pseudocyst of the scalp in a child]. PMID- 24951154 TI - [Mycosis fungoides associated with follicular mucinosis manifested by lichen spinulosus in skinfolds]. PMID- 24951155 TI - [Median nail dystrophy and ritonavir]. PMID- 24951156 TI - What is the importance of zoonotic trichomonads for human health? AB - Trichomonads are common parasites of many vertebrate and invertebrate species, with four species classically recognized as human parasites: Dientamoeba fragilis, Pentatrichomonas hominis, Trichomonas vaginalis, and Trichomonas tenax. The latter two species are considered human-specific; by contrast, D. fragilis and P. hominis have been isolated from domestic and farm mammals, demonstrating a wide host range and potential zoonotic origin. Several new studies have highlighted the zoonotic dimension of trichomonads. First, species typically known to infect birds and domestic mammals have been identified in human clinical samples. Second, several phylogenetic analyses have identified animal-derived trichomonads as close sister taxa of the two human-specific species. It is our opinion, therefore, that these observations prompt further investigation into the importance of zoonotic trichomonads for human health. PMID- 24951157 TI - Qualitative insights into women's personal experiences of perinatal depression and anxiety. AB - BACKGROUND AND AIM: Symptoms of perinatal depression and anxiety are usually described and understood from a nosological perspective. This research sought to gain insight into women's lived experience of postnatal depression and anxiety, the factors that contribute to these symptoms and the context in which they develop. METHOD: Face to face and telephone interviews were conducted with 28 women from metropolitan and rural areas across Australia, who had experienced postnatal depression and/or anxiety within the last five years. Analysis was conducted from a grounded theory perspective. FINDINGS: Particular symptoms of anxiety and depression develop in the context of the numerous changes inherent to the transition to motherhood and contribute to a common experience of frustration and loss. Symptoms were also associated with feelings of dissatisfaction with the pregnancy and motherhood experience. CONCLUSIONS: The findings provide useful insights into women's experiences of mental health symptoms during the perinatal period, how these symptoms present and the factors involved in their development and maintenance. The need to consider women's perspectives to develop resources and health promotions strategies, as well as within the context of relationships with health professionals is highlighted. The study emphasizes the need for greater, more accurate information surrounding perinatal depression and the need to increase the profile and awareness of anxiety disorders. PMID- 24951158 TI - Construction of a microrobot system using magnetotactic bacteria for the separation of Staphylococcus aureus. AB - Magnetotactic bacteria exhibit superiority over other bacteria in fabricating microrobots because of their high motility and convenient controllability. In this study, a microrobot system is constructed using magnetotactic bacteria MO-1 and applied in pathogenic separation. The feasibility of this approach is demonstrated using Staphylococcus aureus. The MO-1 magnetotactic bacterial microrobots are fabricated by binding magnetotactic bacteria MO-1 with their rabbit anti-MO-1 polyclonal antibodies. The efficient binding of MO-1 magnetotactic bacterial microrobots to Staphylococcus aureus is corroborated by phase contrast microscopic and transmission electron microscopic analyses. Further, a microfluidic chip is designed and produced, and the MO-1 microrobots are magnetically guided toward a sample pool in the chip. In the sample pool, Staphylococcus aureus samples are loaded on the microrobots and then carried away to a detection pool in the chip, suggesting the microrobots have successfully carried and separated pathogen. This study is the first to demonstrate bacterial microrobots carrying pathogens and more importantly, it reflects the great potential of using magnetotactic bacteria to develop magnetic-guided, auto propelled microrobots for pathogen isolation. PMID- 24951159 TI - Reply to comment on "Renoprotective effect of combining pentoxifylline with angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker in advanced chronic kidney disease". PMID- 24951160 TI - Three-parent embryo: The therapeutic future for inherited mitochondrial diseases. PMID- 24951161 TI - The relationship between sleep and drug use characteristics in participants with cocaine or methamphetamine use disorders. AB - The goal of this project was to evaluate the relationship between self-reported sleep habits, daytime sleepiness, and drug use variables in individuals with cocaine and methamphetamine (METH) use disorders. Participants with a cocaine or meth use disorder completed questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and a demographic/drug use form. Participants with a cocaine (N=51) or meth use disorder (N=85) were separated into those with either high or low sleep deficits. In participants with a cocaine use disorder, ANOVA revealed significantly higher ESS scores among those defined as "poor sleepers" (with a PSQI score >5) when compared to those defined as "good sleepers" (with a PSQI score <=5). In addition, poor sleepers reported using cocaine for more days out of the past 30 when compared to good sleepers. Interestingly, good sleepers reported using more grams of cocaine/day compared to poor sleepers. In participants with a METH use disorder, ANOVA revealed significantly higher ESS scores among poor sleepers when compared to good sleepers. Finally, individuals with a METH use disorder that endorsed elevated daytime sleepiness also had significantly higher PSQI scores when compared to those with normal daytime sleepiness. The results indicate that drug use variables, such as recent and daily use, may affect sleep quality and daytime sleepiness in individuals with stimulant use disorders; however, further investigations (i.e. in cocaine and METH users that do not meet criteria for a cocaine or METH use disorder) must be conducted in order to provide more conclusive evidence of the impact these usage variables may have on these sleep characteristics. PMID- 24951162 TI - Comparative cross-sectional study of masticatory performance and mastication predominance for patients with missing posterior teeth. AB - PURPOSE: Missing posterior teeth can decrease masticatory function and cause horizontal mastication deviation, i.e., mastication predominance. Mastication predominance may lead to abnormal tooth attrition and temporomandibular disorders. This study evaluated masticatory performance and mastication predominance in patients with missing posterior teeth to investigate effects of missing posterior teeth on masticatory performance and mastication predominance. METHODS: Thirty volunteers with normal dentition (control group), 30 patients with unilateral missing posterior teeth (unilateral group), and 23 patients with bilateral missing posterior teeth (bilateral group) participated. Gummy jellies were used to evaluate participants' masticatory performance, and electromyography was used to assess the degree of mastication predominance. Chewing gums, gummy jellies, and peanuts were used as foods of various hardnesses for evaluating mastication predominance. RESULTS: Compared with the control group, masticatory performance did not differ in the unilateral group but was significantly decreased in the bilateral group. With chewing gum and gummy jellies, the degree of mastication predominance was significantly increased in both unilateral and bilateral groups than the control group. With peanuts, the degree of mastication predominance was significantly increased in the unilateral group than the control group. CONCLUSIONS: Although masticatory performance was not decreased in the unilateral group, the degree of mastication predominance was increased. Decreased masticatory performance was observed in the bilateral group, and for foods with normal hardness and soft foods, the degree of mastication predominance was increased. These results suggested that mastication predominance should be considered in the recovery of masticatory performance in patients with missing posterior teeth. PMID- 24951163 TI - Case report of recurrent temporomandibular joint open lock associated with abrupt reduction of displaced articular disk. AB - PATIENT: This report describes the case of a 51-year-old male patient who initially presented at age 23 with a habitual intermittent open lock (at >35mm) in the left temporomandibular joint (TMJ). The patient was able to manage this affliction through rapid-repetition jaw opening and closing. Tomography of the joint showed no irregular morphology, but intraoral examination revealed an occlusal interference at the mandibular left third molar during leftwards excursion. For this patient, alteration of lateral guidance using a palatal plate attached to the maxillary left canine precluded this intermittent open lock, but at 22 years of age, the open lock recurred and could not be relieved by the patient, who was unable to assume an occlusal position. Because conservative treatment was ineffective, a pumping manipulation technique was applied to reduce the open lock, after which the patient has maintained good jaw function. MRI taken before and after repositioning indicated that abrupt reduction of a displaced articular disk was the cause of the open lock, and that this articular disk was restored to its proper position during the manipulation. DISCUSSION: Most TMJ open locks occur as anterior dislocation, where the mandibular head becomes trapped anterior to the articular eminences, causing excessive opening and difficulty closing. Our clinical findings from this patient indicate that open lock can occur through abrupt reduction of a displaced articular disk, particularly in patients with chronic internal derangement of the TMJ. CONCLUSION: TMJ open lock can occur following abrupt reduction of a displaced articular disk. PMID- 24951164 TI - Increased cardio and cerebrovascular mortality in breast cancer patients treated with postmastectomy radiotherapy--25 year follow-up of a randomised trial from the South Sweden Breast Cancer Group. AB - AIM OF THE STUDY: To analyse late morbidity and mortality in pre and post menopausal breast cancer patients treated with postmastectomy radiotherapy, with emphasis on side-effects from the heart, cerebrovascular and respiratory systems. METHODS: Long term follow-up of two randomised, clinical trials with 1100 patients was carried out. Pre-menopausal women were allocated to radiotherapy (RT), RT+oral cyclophosphamide (RT+C) or cyclophosphamide only (C). Post menopausal women were allocated to RT, RT+Tamoxifen for one year (RT+Tam) or tamoxifen only (Tam). Information on admission to hospital, mortality and causes of death was obtained from national registers. RESULTS: After 25 years, adding RT to cyclophosphamide in pre-menopausal women raised the mortality from heart disease from zero to 0.8% (p=0.04). In post-menopausal women, adding RT to Tam raised the mortality from heart disease from 10.5% to 18.4% (p=0.005). In post menopausal women mortality due to cerebrovascular disease increased from 3.4% to 8.7% by adding RT to Tam (p=0.015). The differences were not evident until in the second decade of follow-up. In spite of differences in specific causes of death, there were no significant differences between the treatment arms concerning morbidity or overall mortality. CONCLUSION: Postmastectomy radiotherapy to the chest wall and loco-regional lymph nodes including the parasternal lymph nodes as delivered in the end of the seventies did not reduce overall mortality, but gave a significantly increased risk of death from heart and cerebrovascular disease, which appeared during the second decade after radiotherapy. PMID- 24951165 TI - Acanthamoeba everywhere: high diversity of Acanthamoeba in soils. AB - Acanthamoeba is a very abundant genus of soil protists with fundamental importance in nutrient cycling, but several strains can also act as human pathogens. The systematics of the genus is still unclear: currently 18 small subunit (SSU or 18S) ribosomal RNA sequence types (T1-T18) are recognized, which sometimes contain several different morphotypes; on the other hand, some morphological identical strains belong to different sequence types, sometimes appearing in paraphyletic positions. In this study, we cultivated 65 Acanthamoeba clones from soil samples collected under grassland at three separate locations in the Netherlands, in Sardinia and at high altitude mountains in Tibet. We obtained 24 distinct partial sequences, which predominantly grouped within sequence type T4 followed by T2, T13, T16 and "OX-1" (in the T2/T6 clade). Our sequences were 98-99% similar, but none was identical to already known Acanthamoeba sequences. The community composition of Acanthamoeba strains differed between locations, T4 being the dominant sequence type in Sardinia and Tibet, but represented only half of the clones from soils in the Netherlands. The other half of clones from the Dutch soils was made up by T2, T16 and "OX-1", while T13 was only found in Sardinia and Tibet. None of the sequences was identical between localities. Several T4 clones from all three localities and all T13 clones grew at 37 degrees C while one T4 clone was highly cytopathogenic. PMID- 24951166 TI - Serum aca-mir-146a is a potential biomarker for early diagnosis of Angiostrongylus cantonensis infection. AB - Infection with Angiostrongylus cantonensis can cause eosinophilic meningoencephalitis, but it lacks an effective early diagnostic tool for the disease. Recently, growing number of serum microRNAs (miRNAs) were investigated to serve as potentially noninvasive biomarkers for various diseases. However, it is unclear if the molecule can considered a biomarker for diagnosing the infection of A. cantonensis. Here, we attempted to identify potential A. cantonensis-derived miRNAs for the early diagnosis of angiostrongyliasis. Through Solexa deep sequencing and GO "biological process" classifications, we found that there were 18 miRNAs of significantly differential expression in the fourth-stage larvae (L4) larva of A. cantonensis when compared with the third-stage larvae (L3) larva of A. cantonensis. Among the 18 miRNAs, the sequences of 6 miRNAs, including aca-miR-29a, aca-miR-124, aca-miR-125a, aca-miR-146a, aca-miR-101, and aca-miR-185, were different from human- and mouse-derived miRNAs (both are the nonpermissive hosts of A. cantonensis). The expression patterns of the six A. cantonensis-derived miRNAs in serum were investigated by polymerase chain reaction on the A. cantonensis-infected mice and their controls. We found that aca-miR-146a had a significantly higher expression level in every experimental positive group, which suggested that this miRNA might be useful for early diagnosis. Receiver operating characteristic (ROC) curve analysis showed that aca miR-146a was an effective biomarker for discriminating A. cantonensis-infected mice from healthy control cases, with an area under the ROC curve (AUC) of 0.90. Its diagnostic accuracy was assessed on patients (n = 30) and healthy controls (n = 30), and the sensitivity and specificity reached 83 and 86.7 %, respectively. Our study revealed that aca-mir-146a in serum is an effective biomarker to track infection of A. cantonensis. PMID- 24951167 TI - Acanthamoeba DNA can be directly amplified from corneal scrapings. AB - This study evaluated the performance of direct amplification of Acanthamoeba-DNA bypassing DNA extraction in the diagnosis of Acanthamoeba keratitis in clinically suspected cases in comparison to direct microscopic examination and in vitro culture. Corneal scrapings were collected from 110 patients who were clinically suspected to have Acanthamoeba keratitis, 63 contact lens wearers (CLW), and 47 non-contact lens wearers (NCLW). Taken samples were subjected to direct microscopic examination, cultivation onto the non-nutrient agar plate surface seeded with Escherichia coli, and PCR amplification. The diagnostic performance of these methods was statistically compared. The results showed that Acanthamoeba infection was detected in 21 (19.1%) of clinically suspected cases (110); 17 (81%) of them were CLW and the remaining 4 (19%) positive cases were NCLW. Regarding the used diagnostic methods, it was found that direct amplification of Acanthamoeba DNA bypassing nucleic acid extraction was superior to microscopy and culture in which 21 cases (19.1%) were positive for Acanthamoeba by PCR compared to 19 positive cases by culture (17.3%) and one case (0.9%) by direct smear. The difference in detection rates between culture and direct smear was highly statistically significant (P = 0.001). On the other hand, there was no significant difference in detection rates between culture and PCR (P = 0.86). On using culture as the gold standard, PCR showed three false-positive samples that were negative by culture and one false-negative sample that was positive by culture. At the same time, direct smear showed 18 false-negative samples. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of PCR were 94.7, 96.7, 85.7, 98.9, and 96.4, respectively, while those of direct smear were 5.3, 100, 100, 83.5, and 83.6, respectively. In conclusion, direct amplification of Acanthamoeba-DNA bypassing DNA extraction is a reliable, specific, sensitive method in the diagnosis of Acanthamoeba keratitis in clinically suspected cases. It should set up in ophthalmological centers as an easy diagnostic tool. PMID- 24951168 TI - First findings and prevalence of adult heartworms (Dirofilaria immitis) in wild carnivores from Serbia. AB - Heartworm (Dirofilaria immitis) is a parasitic roundworm that causes a zoonotic disease known as dirofilariosis. Little is known about the role of wild carnivores serving as reservoirs in nature. Therefore, we examined 738 hearts and lungs of free ranging wild carnivores from Serbia to determine the presence of adult heartworms. During the period 2009-2013, the prevalence in golden jackals (Canis aureus) was 7.32%, in red foxes (Vulpes vulpes) 1.55%, in wolves (Canis lupus) 1.43%, and in wild cats (Felis silvestris) 7.69%. No adult heartworm specimens were found in beech martens (Martes foina), stone martens (Martes martes), European polecats (Mustela putorius), badgers (Meles meles) or otter (Lutra lutra). The highest recorded prevalence was in 2013 (7.30%) and the lowest in 2012 (1.6%). In jackals, the prevalence was higher in males (10%) than in females (4.06%), while in foxes the prevalence was 1.75% in males and 1.26% in females. The most infected host was a wolf in which 37 adult specimens were found. Because of the potentially significant role in the life cycle of D. immitis, populations of wild carnivores in Europe should be further examined and tested for heartworm infections. PMID- 24951169 TI - Two new gonad-infecting species of Philometra (Nematoda: Philometridae) parasitic in Lutjanus spp. (Osteichthyes: Lutjanidae) in the Bay of Bengal, India. AB - Based on light and scanning electron microscopical studies, two new gonad infecting species of Philometra Costa, 1845 (Nematoda: Philometridae) are described from marine fishes of the genus Lutjanus Bloch (Lutjanidae, Perciformes) in the Bay of Bengal, off the eastern coast of India: Philometra argentimaculati sp. n. and Philometra fulvi sp. n. from the mangrove red snapper Lutjanus argentimaculatus (Forsskal) and blacktail snapper Lutjanus fulvus (Foerster), respectively. P. argentimaculati is mainly characterised by the body length of male 2.56-3.07 mm, needle-like spicules 183-228 MUm long, length of the gubernaculum at 90-120 MUm, distal end of the gubernaculum with lamellar structures without a dorsal protuberance and by the dorsally non-interrupted male caudal mound. P. fulvi differs from all Philometra spp. with described males in the rectangular shape of the distal tip of the gubernaculum and is noted for the length of needle-like spicules 123-138 MUm, that of the gubernaculum 69-93 MUm and for the presence of a dorsal protuberance and lamella-like structures on the gubernaculum distal end. These are the first nominal species of philometrids reported from fishes of the family Lutjanidae in the region of the Indian Ocean. A necessity of further detailed studies on philometrids parasitising marine fishes worlwide is stressed. PMID- 24951170 TI - Immunomodulation of liver injury by Ascaris suum extract in an experimental model of autoimmune hepatitis. AB - Adult worm extract from Ascaris suum (Asc) has immunosuppressive activity and elicits Th2/IL-4/IL-10 response. This study evaluated the prophylactic and therapeutic effect of Asc in a murine model of concanavalin A (ConA)-induced autoimmune hepatitis (AIH). BALB/c mice received ConA, iv, (20 mg/kg), and three groups of animals were formed: (1) AIH, received only ConA; (2) AIH + Asc prophylactic, treated with Asc (1 mg/ml), ip, 30 min before of the AIH; and (3) AIH + Asc therapeutic, treated with Asc 2 h after the AIH. Plasma transaminase and immunoglobulins (measured at 8 and 24 h and 7 days after treatment) and cytokine production (IL-4, IL-10, IL-13, and IFN-gamma) by splenocytes upon ConA and Asc stimulus were compared. The livers were weighed and examined histologically. In the AIH group, there was an increase in liver weight, transaminase levels, and total immunoglobulins. These parameters were reduced by 8-24 h and 7 days in the prophylactic group, but in the therapeutic group, only on day 7. The survival rate of mice in the AIH group was 38.5%, compared to 67% in the therapeutic Asc group. The survival rate of the animals with AIH that were prophylactically treated with Asc was 100%. A decrease of cellular infiltration and high levels of IL-4, IL-10, and IL-13 were induced by Asc. An increase of liver fibrosis was also observed, but with less intensity with prophylactic treatment. Thus, the Ascaris components have an inhibitory effect on AIH, with an intense Th2 immune response. PMID- 24951171 TI - Association of maternal KIR and fetal HLA-C genes with the risk of preeclampsia in the Chinese Han population. AB - INTRODUCTION: This study is to investigate the distribution of inhibitory and activating killer-cell immunoglobulin-like receptors (KIRs) and the combination of KIR/human leukocyte antigen (HLA)-C in women with preeclampsia in the Chinese Han population. METHODS: A total of 271 patients and 295 controls were enrolled in our study. The inhibitory/activating KIR and HLA-C genes were detected using the PCR-SSP (polymerase chain reaction with sequence-specific primers) method. RESULTS: Our result showed that decreased numbers of individual activating KIR genes (2DS2, 2DS3, and 2DS5) were observed in women with preeclampsia. Furthermore, the gene frequency of total activating KIRs was significantly lower in patients compared with that of the controls (P = 0.03). The frequency of the KIR2DL1 gene was increased in women with preeclampsia when a homozygous HLA-C2 allele appeared in the fetus. CONCLUSION: The results suggest that a KIR genetic variation might influence the risk of preeclampsia. The lack of activating KIRs could possibly lower uterine natural killer (uNK) cell activation, thereby contributing to the pathogenesis of preeclampsia. Moreover, the imbalance of the inhibitory or activating signals at the maternal-fetal interface seems to play a regulatory role in the occurrence of preeclampsia. PMID- 24951172 TI - Expression of serum amyloid A4 in human trophoblast-like choriocarcinoma cell lines and human first trimester/term trophoblast cells. AB - Trophoblast invasion into uterine tissues represents a hallmark of first trimester placental development. As expression of serum amyloid A4 (SAA4) occurs in tumorigenic and invasive tissues we here investigated whether SAA4 is present in trophoblast-like human AC1-M59/Jeg-3 cells and trophoblast preparations of human first trimester and term placenta. SAA4 mRNA was expressed in non stimulated and cytokine-treated AC1-M59/Jeg-3 cells. In purified trophoblast cells SAA4 mRNA expression was upregulated at weeks 10 and 12 of pregnancy. Western-blot and immunohistochemical staining of first trimester placental tissue revealed pronounced SAA4 expression in invasive trophoblast cells indicating a potential role of SAA4 during invasion. PMID- 24951173 TI - Association between reduced fetal movements at term and first trimester markers of impaired placental development. PMID- 24951175 TI - Uncultured undifferentiated adipose-derived nucleated cell fractions combined with inside-out artery graft accelerate sciatic nerve regeneration and functional recovery. AB - Effects of transplantation of adipose-derived nucleated cell fractions (ADNCs) on sciatic nerve regeneration were studied. A 10-mm sciatic nerve defect was bridged using artery graft filled with ADNCs. In control group, artery graft was filled with saline alone. Regenerated nerve fibres were studied for 12 weeks. In sham operated group, sciatic nerve was only exposed and manipulated. Behavioural and functional studies confirmed faster recovery of regenerated axons in ADNCs transplanted animals than in control group (P<0.05). At the end of study period, animals in ADNCs transplanted group achieved a sciatic functional index (SFI) value of -31.6 +/- -3.14, whereas in control group a value of -42.5 +/- -3.7 was found. Gastrocnemius muscle mass in ADNCs transplanted animals was found to be significantly higher than that in control group (P=0.001). Morphometric indices of regenerated fibres showed the number and diameter of myelinated fibres to be significantly higher in ADNCs transplanted animals than in control group (P=0.001). On immunohistochemistry, there was more positive staining of S100 in the ADNCs transplanted animals than in control group. ADNCs transplantation into an artery graft could be considered a readily accessible technique that improves functional recovery of sciatic nerve. PMID- 24951174 TI - Banking placental tissue: an optimized collection procedure for genome-wide analysis of nucleic acids. AB - INTRODUCTION: Banking of high-quality placental tissue specimens will enable biomarker discovery and molecular studies on diseases involving placental dysfunction. Systematic studies aimed at developing feasible standardized methodology for placental collection in a typical clinical setting are lacking. METHODS: To determine the acceptable timeframe for placental collection, we collected multiple samples from first and third trimester placentas at serial timepoints in a 2-h window after delivery, simultaneously comparing the traditional snap-freeze technique to commercial solutions designed to preserve RNA (RNAlaterTM), and DNA (DNAgard((r))). The performance of RNAlater for preserving DNA was also tested. Nucleic acid quality was assessed by determining the RNA integrity number (RIN) and genome-wide microarray profiling for gene expression and DNA methylation. RESULTS: We found that samples collected in RNAlater had higher and more consistent RINs compared to snap-frozen tissue. Similar RINs were obtained for tissue collected in RNAlater as large (1 cm(3)) and small (~0.1 cm(3)) pieces. RNAlater appeared to better stabilize the time zero gene expression profile compared to snap-freezing for first trimester placenta. DNA methylation profiles remained quite stable over a 2 h time period after removal of the placenta from the uterus, with DNAgard being superior to other treatments. DISCUSSION AND CONCLUSION: The collection of placental samples in RNAlater and DNAgard is simple, and eliminates the need for liquid nitrogen or a freezer on-site. Moreover, the quality of the nucleic acids and the resulting data from samples collected in these preservation solutions is higher than samples collected using the snap-freeze method and easier to implement in busy clinical environments. PMID- 24951176 TI - External carotid artery pseudoaneurysm following microvascular free flap reconstruction. The role of endovascular thrombin injection in embolization: a case report and review. AB - Pseudoaneurysm at the anastomosis of the free flap following ablative head and neck surgery is uncommon. We present a case of external carotid artery pseudoaneurysm in a patient who had previously undergone a subtotal glossectomy, neck dissection, and radial forearm free flap reconstruction. The traditional treatment for pseudoaneurysm has been open surgical repair. Our patient underwent successful treatment with an endovascular embolization utilizing thrombin injection of the aneurysmal sac. This case highlights the role of interventional radiology in the management of this rare but important complication of microvascular reconstructive surgery. PMID- 24951177 TI - A plea for the systematic preservation of the deltopectoralis (Bakamjian) flap in pectoralis major flap harvesting. PMID- 24951178 TI - Age-related changes in anatomic bases for the insertion of zygomatic implants. AB - The objectives of this study were to verify whether Chinese patients are well suited for zygomatic implantation and to observe age-related changes in the linear and angular anatomic bases of the maxilla and zygoma. Using three dimensional images selected from maxillofacial cone beam computed tomography (CBCT) scans generated by SimPlant, linear and angular measurements were obtained by simulating zygomatic implantation. The edentulous group comprised 40 subjects aged between 62 and 65 years. A total of 120 dentate cases were divided into three groups based on age: the established occlusion group (n=40; 12-15 years old), the adult group (n=40; 37-40 years old), and the elderly group (n=40; 62-65 years old). The mean potential insertion length of the ordinary and additional zygomatic implants became longer with age in the dentate groups. For both zygomatic implant insertion areas, the anteroposterior lengths of the maxilla and zygoma were thicker in the older dentate groups (P<0.05). Significant differences were verified in the installation direction among the dentate groups. Gender was not a significant factor. The zygomatic skeleton changes with age, which results in linear and angular variations in the zygomatic implant insertion area. Therefore, the anatomic bases in Chinese adults are suitable for zygomatic implants. PMID- 24951179 TI - Arthrocentesis followed by intra-articular autologous blood injection for the treatment of recurrent temporomandibular joint dislocation. AB - Temporomandibular joint (TMJ) dislocation is an excessive forward movement of the condyle beyond the articular eminence with complete separation of the articular surfaces and fixation in that position. This study was conducted to assess autologous blood injection to the TMJ for the treatment of chronic recurrent TMJ dislocation. Fifteen patients with bilateral chronic recurrent condylar dislocation were included in the study. Bilateral TMJ arthrocentesis was performed on each patient, followed by the injection of 2ml of autologous blood into the superior joint compartment and 1ml onto the outer surface of the joint capsule. Preoperative and postoperative assessment included a thorough history and physical examination to determine the maximal mouth opening, presence of pain and sounds, frequency of luxation, recurrence rate, and presence of facial nerve paralysis. Eighty percent of the subjects (12 patients) had a successful outcome with no further episodes of dislocation and required no further treatment at their 1-year follow-up, whereas three patients had recurrent dislocation as early as 2 weeks after treatment. Autologous blood injection is a safe, simple, and cost-effective treatment for chronic recurrent TMJ dislocation. PMID- 24951180 TI - An individually-tailored multifactorial intervention program for older fallers in a middle-income developing country: Malaysian Falls Assessment and Intervention Trial (MyFAIT). AB - BACKGROUND: In line with a rapidly ageing global population, the rise in the frequency of falls will lead to increased healthcare and social care costs. This study will be one of the few randomized controlled trials evaluating a multifaceted falls intervention in a low-middle income, culturally-diverse older Asian community. The primary objective of our paper is to evaluate whether individually tailored multifactorial interventions will successfully reduce the number of falls among older adults. METHODS: Three hundred community-dwelling older Malaysian adults with a history of (i) two or more falls, or (ii) one injurious fall in the past 12 months will be recruited. Baseline assessment will include cardiovascular, frailty, fracture risk, psychological factors, gait and balance, activities of daily living and visual assessments. Fallers will be randomized into 2 groups: to receive tailored multifactorial interventions (intervention group); or given lifestyle advice with continued conventional care (control group). Multifactorial interventions will target 6 specific risk factors. All participants will be re-assessed after 12 months. The primary outcome measure will be fall recurrence, measured with monthly falls diaries. Secondary outcomes include falls risk factors; and psychological measures including fear of falling, and quality of life. DISCUSSION: Previous studies evaluating multifactorial interventions in falls have reported variable outcomes. Given likely cultural, personal, lifestyle and health service differences in Asian countries, it is vital that individually-tailored multifaceted interventions are evaluated in an Asian population to determine applicability of these interventions in our setting. If successful, these approaches have the potential for widespread application in geriatric healthcare services, will reduce the projected escalation of falls and fall-related injuries, and improve the quality of life of our older community. TRIAL REGISTRATION: ISRCTN11674947. PMID- 24951182 TI - Older age is associated with rapid remission of depression after electroconvulsive therapy: a latent class growth analysis. AB - OBJECTIVES: This study aims to empirically identify latent course trajectories of depressive symptoms during electroconvulsive therapy (ECT) within a cohort of patients suffering from a depressive disorder and to examine putative predictors of course. METHODS: Using a prospective cohort multicenter collaborative ECT design, 120 patients fulfilling the Mini International Neuropsychiatric Interview criteria for major depressive disorder and referred for ECT were selected. Ratings of the 17-item Hamilton Rating Scale for Depression (HRSD) were obtained weekly during the course of ECT. Latent class growth analysis was used to identify trajectories of course during 6-week follow-up, based on weekly total HRSD scores. Characteristics of the identified classes were examined, and putative predictors for class membership were tested. RESULTS: Data-driven techniques identified distinct course trajectories during 6-week follow-up ECT treatment, consisting of "rapid remission," "moderate response," and "nonremitting" course trajectories. Remission rates were as high as 80.1% in the rapid remission class. Older age was associated with rapid remission, even after adjustment for putative confounders. CONCLUSION: Our results strongly confirm the favorable outcome of ECT among elderly depressed inpatients. PMID- 24951183 TI - Plant DNA-damage repair/toleration 100 protein repairs UV-B-induced DNA damage. AB - We report the characterization of VvDRT100-L, a grape DNA-damage repair/toleration 100 protein. VvDRT100-L has nine leucine-rich repeats and belongs to the plant DRT100 protein family. VvDRT100-L is expressed abundantly in green organs of grapevines, including tendrils, leaves, and green berry skins. The overexpression of VvDRT100-L in Arabidopsis plants decreased the number of abasic sites and the frequency of DNA single-strand breaks in the DNA damaged by UV-B irradiation, whereas UV-B irradiation markedly increased the number of abasic sites and the frequency of DNA single-strand breaks in T-DNA insertion mutant drt100 plants. VvDRT100-L-overexpressing plants remained viable and noticeably healthy under lethal UV doses, suggesting that VvDRT100-L may enhance UV tolerance in plant. Taken together, we concluded that VvDRT100-L might play an important role in the repair and toleration of UV-B-induced DNA damage. These findings would help us better understand how plants acquire UV stress acclimation, tolerance and DNA repair. PMID- 24951185 TI - [Bartholin's gland carcinoma]. AB - Bartholin gland carcinoma is a rare tumor. Treatment is not consensual due to the absence of prospective and randomized controlled trials. Bartholin gland carcinoma is actually treated similarly to primary median squamous cell carcinoma of the vulva. Here we report two cases of 42- and 67-year-old females who developed respectively an adenoid cystic carcinoma, and a squamous carcinoma of Bartholin gland. PMID- 24951184 TI - [Satisfaction with obstetrical care: development and validation of a scale on quality of care]. AB - OBJECTIVES: To develop and validate a subjective and multidimensional scale to measure satisfaction in obstetrical care (SSO) during labour, delivery and two hours postpartum, which is relevant to the French-speaking context. PATIENTS ET METHODS: Forty partially directed patient interviews during the 48 hours after delivery and four care-giver interviews were conducted to build up the questionnaire. After a prior feasibility study on 40 patients, the psychometric validity of the questionnaire was evaluated by calculating the Cronbach coefficient of reliability for 432 patients. RESULTS: Hundred and eighty items were initially obtained after content analysis of the patient interviews. Expert meetings finally selected 49 items classified within 5 dimensions. The feasibility study showed that the questionnaire was easily accepted and understood with a mean time of 15 minutes to answer it. Cronbach coefficients were respectively at 0.941, 0.949, 0.808, 0.814 et 0.869 for the 5 dimensions. DISCUSSION AND CONCLUSION: SSO questionnaire is a reliable and relevant scale to measure immediate postpartum quality of care in French. PMID- 24951181 TI - The SOLUTIONS project: challenges and responses for present and future emerging pollutants in land and water resources management. AB - SOLUTIONS (2013 to 2018) is a European Union Seventh Framework Programme Project (EU-FP7). The project aims to deliver a conceptual framework to support the evidence-based development of environmental policies with regard to water quality. SOLUTIONS will develop the tools for the identification, prioritisation and assessment of those water contaminants that may pose a risk to ecosystems and human health. To this end, a new generation of chemical and effect-based monitoring tools is developed and integrated with a full set of exposure, effect and risk assessment models. SOLUTIONS attempts to address legacy, present and future contamination by integrating monitoring and modelling based approaches with scenarios on future developments in society, economy and technology and thus in contamination. The project follows a solutions-oriented approach by addressing major problems of water and chemicals management and by assessing abatement options. SOLUTIONS takes advantage of the access to the infrastructure necessary to investigate the large basins of the Danube and Rhine as well as relevant Mediterranean basins as case studies, and puts major efforts on stakeholder dialogue and support. Particularly, the EU Water Framework Directive (WFD) Common Implementation Strategy (CIS) working groups, International River Commissions, and water works associations are directly supported with consistent guidance for the early detection, identification, prioritisation, and abatement of chemicals in the water cycle. SOLUTIONS will give a specific emphasis on concepts and tools for the impact and risk assessment of complex mixtures of emerging pollutants, their metabolites and transformation products. Analytical and effect-based screening tools will be applied together with ecological assessment tools for the identification of toxicants and their impacts. The SOLUTIONS approach is expected to provide transparent and evidence-based candidates or River Basin Specific Pollutants in the case study basins and to assist future review of priority pollutants under the WFD as well as potential abatement options. PMID- 24951186 TI - [Interest of emergency endocervical specimens]. AB - OBJECTIVE: To estimate the diagnosis profitability of endocervical specimen (ES) within the framework of a teaching gynecological emergency department by studying the circumstances of realization and its bacteriological results. PATIENTS AND METHODS: We included in our study all the patients who had a gynecological exam with an ES during a consultation in our gynecological teaching emergency department of Tours between January 1st, 2012 and December 31st, 2012. We estimated the diagnosis profitability of realization of the ES (positivity rate within the population with ES, diagnosis correction in case of pelvic inflammatory disease). RESULTS: Over the study period, 614 (12.4%) women consulting in our emergency department had an ES, which was positive among 102 (16.6%) of them, and a diagnosis of pelvic inflammatory disease in 64 patients. ES had a higher pertinence in case of abdominal pain and a lesser one in case of pregnancy for whom ES realisation must be limited. The diagnosis correction due to ES was observed in 46.8% of pelvic inflammatory disease. CONCLUSION: The diagnostic profitability of the endocervical specimen in our emergency department was low, taking into account the whole cohort, but ES permitted to correct the diagnosis in about half of diagnosed pelvic inflammatory diseases. The endocervical specimens seem to have no profit in pregnant women. PMID- 24951189 TI - Guest editorial: the Figley Fellowship--a window for junior radiologists into the inner workings of the AJR. PMID- 24951187 TI - [How can we nowadays select the best embryo to transfer?]. AB - Multiple pregnancies stand as the most common adverse outcome of assisted reproduction technologies (ART) and the dangers associated with those pregnancies have been reduced by doing elective single embryo transfers (e-SET). Many studies have shown that e-SET is compatible with a continuously high pregnancy rate per embryo transfer. Yet, it still becomes necessary to improve the selection process in order to define the quality of individual embryos - so that the ones we choose for transfer are more likely to implant. First, analysis of embryo morphology has greatly helped in this identification and remains the most relevant criterion for choosing the embryo. The introduction of time-lapse imaging provides new criteria predictive of implantation potential, but the real contribution of this system - including the benefit/cost ratio - seems to be not yet properly established. In this context, extended culture until blastocyst stage is an essential practice but it appears wise to keep it for a population showing a good prognosis. Then, the failure of aneuploid embryos to implant properly led to achieve preimplantation genetic screening (PGS) in order to increase pregnancy and delivery rates after ART. However, PGS by fluorescence in situ hybridization (FISH) at day 3 is a useless process - and may even be harmful. Another solution involves using comparative genomic hybridisation (CGH) and moving to blastocyst biopsy. Finally, it is envisaged that morphology will also be significantly aided by non-invasive analysis of biomarkers in the culture media that give a better reflection of whole-embryo physiology and function. PMID- 24951188 TI - The impact of natural transformation on adaptation in spatially structured bacterial populations. AB - BACKGROUND: Recent studies have demonstrated that natural transformation and the formation of highly structured populations in bacteria are interconnected. In spite of growing evidence about this connection, little is known about the dynamics of natural transformation in spatially structured bacterial populations. RESULTS: In this work, we model the interdependency between the dynamics of the bacterial gene pool and those of environmental DNA in space to dissect the effect of transformation on adaptation. Our model reveals that even with only a single locus under consideration, transformation with a free DNA fragment pool results in complex adaptation dynamics that do not emerge in previous models focusing only on the gene shuffling effect of transformation at multiple loci. We demonstrate how spatial restriction on population growth and DNA diffusion in the environment affect the impact of transformation on adaptation. We found that in structured bacterial populations intermediate DNA diffusion rates predominantly cause transformation to impede adaptation by spreading deleterious alleles in the population. CONCLUSION: Overall, our model highlights distinctive evolutionary consequences of bacterial transformation in spatially restricted compared to planktonic bacterial populations. PMID- 24951190 TI - Off-site smartphone reading of CT images for patients with inconclusive diagnoses of appendicitis from on-call radiologists. AB - OBJECTIVE: The purpose of this study was to simulate a mobile consultation in patients with inconclusive diagnosis of appendicitis made by on-call radiologists, as well as to measure the diagnostic confidence and performance of the mobile consultation. MATERIALS AND METHODS: Two off-site abdominal radiologists interpreted the CT images from 68 patients (including 29 patients with confirmed appendicitis) on a smart-phone for whom the preliminary CT reports by 25 in-house on-call radiologists were inconclusive. The smartphone readings were compared with the preliminary reports by on-call radiologists and with the original final reports by in-house abdominal radiologists. Heat maps, kappa statistics, Wilcoxon signed-rank tests, and ROC curves were used for data analysis. RESULTS: The heat maps and kappa statistics showed that the smartphone readings were more similar to the final reports than to the preliminary reports. In diagnosing or ruling out appendicitis, the smartphone readings were more confident than the preliminary reports (p <= 0.01) and did not significantly differ in diagnostic confidence from the final reports (p >= 0.19). The AUCs of the smartphone readings (0.91 and 0.92) did not differ significantly from those of the preliminary (0.85) or final (0.97) reports (p >= 0.09). CONCLUSION: With the given study sample, the diagnostic performance of the off-site smartphone readings did not differ significantly from that of the in-house preliminary reports. However, the smartphone readings provided higher diagnostic confidence than the preliminary reports. PMID- 24951191 TI - Gastric band slippage: a case-controlled study comparing new and old radiographic signs of this important surgical complication. AB - OBJECTIVE: The purpose of this study was to compare the diagnostic performance of four radiographic signs of gastric band slippage: abnormal phi angle, the "O sign," inferior displacement of the superolateral gastric band margin, and presence of an air-fluid level above the gastric band. MATERIALS AND METHODS: A search of the electronic medical record identified 21 patients with a surgically proven slipped gastric band and 63 randomly-selected asymptomatic gastric band patients who had undergone barium swallow studies. These studies were evaluated for the four signs of band slippage by two independent radiologists who were blinded to clinical data. Sensitivity, specificity, and positive and negative predictive values were calculated for each radiographic sign of band slippage. Interobserver agreement between radiologists was assessed using the Fleiss kappa statistic. RESULTS: In evaluating for gastric band slippage, an abnormal phi angle greater than 58 degrees was 91-95% sensitive and 52-62% specific (kappa = 0.78), the O sign was 33-48% sensitive but 97% specific (kappa = 0.84), inferior displacement of the superolateral band margin by more than 2.4 cm from the diaphragm was 95% sensitive and 97-98% specific (kappa = 0.97), and the presence of an air-fluid level was 95% sensitive and 100% specific (kappa = 1.00). CONCLUSION: We report two previously undescribed radiographic signs of gastric band slippage that are both sensitive and specific for this important surgical complication and recommend that these signs should be incorporated into the imaging evaluation of gastric band patients. PMID- 24951192 TI - Abnormalities of the distal common bile duct and ampulla: diagnostic approach and differential diagnosis using multiplanar reformations and 3D imaging. AB - OBJECTIVE: The distal common bile duct (CBD) and ampulla are extremely difficult sites to evaluate on CT. This article seeks to provide the reader with a framework and algorithmic approach to the evaluation of abnormalities involving the distal CBD and ampulla, including an emphasis on the use of multiplanar reformations and 3D imaging, the morphologic features on CT that suggest the presence of malignancy, and a differential diagnosis for abnormalities in this location. CONCLUSION: In our experience, both the distal CBD and ampulla are common sites of missed diagnoses for radiologists. Avoiding mistakes in interpreting imaging findings in this location requires a systematic approach especially in the setting of unexplained biliary ductal dilatation. Rather than simply suggesting that MRCP or ERCP be performed for the ultimate diagnosis, radiologists can perform a careful CT evaluation using multiplanar reformations and 3D imaging to determine the correct diagnosis prospectively. A timely and correct diagnosis is imperative because lesions in the ampulla and CBD can be very aggressive despite their small size. PMID- 24951193 TI - Imaging findings and clinical features of abdominal vascular compression syndromes. AB - OBJECTIVE: This article describes the typical imaging findings and clinical features that are associated with four abdominal vascular compression syndromes. We explain the underlying pathophysiology that results in these clinical syndromes so that the patient subset who will benefit from treatment can be identified. CONCLUSION: The abdominal vascular compression syndromes discussed here are uncommon and are potentially easily missed on a cursory review of radiologic examinations, particularly in a nonspecific and vague clinical setting. Hence, knowledge of the typical imaging findings and associated clinical symptoms is essential so that the they can be carefully sought and excluded. However, because these findings may also exist in healthy individuals as anatomic variants, it is important to correlate radiologic findings with clinical symptoms to identify the subset of patients who will benefit from treatment. PMID- 24951194 TI - Clinical guidelines for imaging and reporting ingested foreign bodies. AB - OBJECTIVE: The purpose of this article is to familiarize radiologists with the specific characteristics of foreign bodies, obtained from image interpretation, to guide further management. Details of object morphologic characteristics and location in the body gained through imaging form the backbone of the classification used in the treatment of ingested foreign bodies. CONCLUSION: The characteristics of foreign bodies and predisposing bowel abnormalities affect the decision to follow ingested objects radiographically, perform additional imaging, or proceed with endoscopic or surgical removal. PMID- 24951195 TI - Acute mesenteric vein thrombosis: factors associated with evolution to chronic mesenteric vein thrombosis. AB - OBJECTIVE: Acute mesenteric venous thrombosis signs at MDCT are well described, but the literature lacks studies assessing their evolution. We aimed to describe the radiologic evolution of isolated acute mesenteric venous thrombosis and associated prognostic factors. MATERIALS AND METHODS: Patients with isolated acute mesenteric venous thrombosis with follow-up for a minimum of 1 month with MDCT were selected. Images at the acute phase and on follow-up were reviewed in consensus reading. For acute mesenteric venous thrombosis, we searched for low attenuated intraluminal filling defect. For chronic mesenteric venous thrombosis, we searched for vessel stenosis or occlusion associated with collateral mesenteric veins. Treatment, thrombosis risk factor, symptoms, location, and length and diameter of mesenteric venous thrombosis were reported and correlated with evolution over time. RESULTS: Twenty patients (nine women and 11 men; mean age, 52 years) were selected. Four patients recovered without radiologic sequelae, and 16 developed chronic mesenteric venous thrombosis signs. Anticoagulation did not influence recovery (p = 1). Patients with recovery compared with patients with chronic mesenteric venous thrombosis showed more frequent central lesions (p = 0.03). At diagnosis, the thrombosed segment was shorter and larger in the complete radiologic recovery group compared with the chronic mesenteric venous thrombosis signs group: mean length (+/- SD) 6.25 +/- 3.21 cm and 12.81 +/- 5.96 cm, respectively (p = 0.01); mean transverse diameter 1.82 +/- 0.42 cm and 1.12 +/- 0.34 cm, respectively (p = 0.01). Mesenteric fat infiltration at diagnosis was more frequent in the chronic mesenteric venous thrombosis signs group than in the complete recovery group (p = 0.03). CONCLUSION: Most cases of acute mesenteric venous thrombosis evolve toward the chronic form with vein stenosis or occlusion and development of collateral veins. Location, length of mesenteric venous thrombosis, transverse diameter of the vein, and mesenteric fat infiltration at diagnosis are determinant factors for mesenteric venous thrombosis evolution. PMID- 24951197 TI - Postablation assessment using follow-up registration of CT images before and after radiofrequency ablation (RFA): prospective evaluation of midterm therapeutic results of RFA for hepatocellular carcinoma. AB - OBJECTIVE: The purpose of this study was to prospectively evaluate the diagnostic impact of prototypic software that allows registration of CT images before and after radiofrequency ablation (RFA) for safety margin assessment, as well as to determine the therapeutic impact of this software on local tumor progression in comparison with the conventional method of side-by-side CT comparison. SUBJECTS AND METHODS: One-hundred fifty patients with a single hepatocellular carcinoma (HCC) referred for RFA were enrolled. CT scans were obtained before and after RFA, and all CT images were analyzed with and without the use of nonrigid registration software. Thereafter, local tumor progression in the study group (n = 150) was compared with that in a matched control group (n = 90) in which side by-side comparison of CT images before and after RFA was used for safety margin assessment. RESULTS: RFA using registration software-assisted diagnoses to decide whether additional RFA was necessary resulted in a 10.67% local tumor progression rate 42 months after the procedure, which was significantly better than that in the matched control group (23.33%) (p = 0.01). After registration software was used, 15.33% (23/150) of patients had conflicting assessments on the safety margin and the necessity for additional RFAs compared with the initial visual comparison of the CT scans. CONCLUSION: The addition of follow-up registration of CT images before and after RFA resulted in significantly improved assessment of safety margins, simplifying the decision of whether to perform additional treatments and reducing local tumor progression of HCCs after RFA. PMID- 24951198 TI - Ratios of peripheral-to-central airway lumen area and percentage wall area as predictors of severity of chronic obstructive pulmonary disease. AB - OBJECTIVE: The purpose of this study was to assess the ability of the ratios of peripheral-to-central airway lumen area (hereafter referred to as LA) and percentage wall area (hereafter referred to as %WA) to predict the severity of chronic obstructive pulmonary disease (COPD) according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. SUBJECTS AND METHODS: We examined 32 patients (27 men and five women; mean age +/- SD, 70.0 +/- 6.8 years; seven GOLD stage 0 [at risk for COPD], 19 GOLD stage 1-2 [mild to moderate airflow limitation], and six GOLD stage 3-4 [severe to very severe airflow limitation]) using inspiratory CT. Mean LA and %WA were measured for the first (main bronchi), third, and fifth generations of five bronchi in each lobe and the ratios of peripheral to central airways were calculated (third to first, fifth to first, and fifth to third) and statistically compared. RESULTS: The fifth generation LA, LA fifth to first, and LA fifth to third significantly decreased and fifth %WA, %WA fifth to first, and %WA fifth to third also increased with progression of GOLD stage (p < 0.05), but central measurements, including first and third generations, did not. There were significant differences between GOLD 0 and GOLD 1-2 for %WA fifth to third and LA fifth to third and between GOLD 0 and GOLD 3-4 for all six parameters (p < 0.05); %WA fifth to third had the best cutoff value of 1.02 (sensitivity, 92%; specificity, 86%) for diagnosis of COPD (GOLD 1-4). The %WA fifth to first of 1.51 (sensitivity, 83%; specificity, 89%) was best for diagnosis of GOLD 3-4. CONCLUSION: Ratios of peripheral-to-central airway LA and %WA show improved correlation with COPD severity. PMID- 24951196 TI - Prevalence and clinical importance of mesenteric venous thrombosis in the Swiss Inflammatory Bowel Disease Cohort. AB - OBJECTIVE: The purpose of this study was to evaluate the prevalence of mesenteric venous thrombosis (MVT) in the Swiss Inflammatory Bowel Disease Cohort Study and to correlate MVT with clinical outcome. MATERIALS AND METHODS: Abdominal portal phase CT was used to examine patients with inflammatory bowel disease (IBD). Two experienced abdominal radiologists retrospectively analyzed the images, focusing on the superior and inferior mesenteric vein branches and looking for signs of acute or chronic thrombosis. The location of abnormalities was registered. The presence of MVT was correlated with IBD-related radiologic signs and complications. RESULTS: The cases of 160 patients with IBD (89 women, 71 men; Crohn disease [CD], 121 patients; ulcerative colitis [UC], 39 patients; median age at diagnosis, 27 years for patients with CD, 32 years for patients with UC) were analyzed. MVT was detected in 43 patients with IBD (26.8%). One of these patients had acute MVT; 38, chronic MVT; and four, both. The prevalence of MVT did not differ between CD (35/121 [28.9%]) and UC (8/39 [20.5%]) (p = 0.303). The location of thrombosis was different between CD and UC (CD, jejunal or ileal veins only [p = 0.005]; UC, rectocolic veins only [p = 0.001]). Almost all (41/43) cases of thrombosis were peripheral. MVT in CD patients was more frequently associated with bowel wall thickening (p = 0.013), mesenteric fat hypertrophy (p = 0.005), ascites (p = 0.002), and mesenteric lymph node enlargement (p = 0.036) and was associated with higher rate of bowel stenosis (p < 0.001) and more intestinal IBD-related surgery (p = 0.016) in the outcome. Statistical analyses for patients with UC were not relevant because of the limited population (n = 8). CONCLUSION: MVT is frequently found in patients with IBD. Among patients with CD, MVT is associated with bowel stenosis and CD-related intestinal surgery. PMID- 24951199 TI - High-resolution diffusion-weighted imaging of the prostate. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of increasing the spatial resolution of the prostate DWI protocol on image quality and lesion conspicuity. SUBJECTS AND METHODS: Twenty-nine patients with biopsy-proven prostate cancer undergoing MRI examinations were imaged with two diffusion weighted imaging (DWI) protocols: current standard clinical protocol (6.7 mm(3) voxels) and a new high-resolution protocol (3.1 mm(3) voxels). Diffusion-weighted images were independently and subjectively scored on lesion conspicuity, internal architecture definition, and overall image quality by two radiologists. Average apparent diffusion coefficient (ADC) values were measured in normal tissue and cancerous lesions on both sequences. Reader scores and ADC and contrast values were compared between the two protocols. Cancer ADC values were correlated with Gleason scores. RESULTS: The signal-to-noise ratio of the new high-resolution DWI protocol was 40% lower than that of the standard protocol. The reader scores were higher by 0.73 (range, 0.29-1.16) grades, or 19% (range, 7-32%), on average, for the new protocol, indicating better image quality. The average ADC values were 8% higher with the new protocol, with ADC contrast values between cancer and normal prostate unchanged. There was marginally significant correlation of cancer ADC values with Gleason scores (p = 0.05, r ~ -0.36). CONCLUSION: We showed that for DWI of the prostate at 3-7 mm(3) voxel sizes the benefits of higher spatial resolution outweigh the effects of reduced signal-to-noise and contrast-to-noise ratios, potentially improving the sensitivity to small or sparse prostate cancers. Radiologists can consider using higher-spatial-resolution DWI sequences in their practices. PMID- 24951200 TI - MRI of the epididymis: can the outcome of vasectomy reversal be predicted preoperatively? AB - OBJECTIVE: The purpose of this study is to describe the MRI findings seen with tubular ectasia of the epididymis and investigate whether MRI may predict vasal/epididymal tubular occlusion before vasectomy reversal. MATERIALS AND METHODS: First, we compared epididymal T1 signal intensity (measured as percentage change relative to ipsilateral testis) in 24 patients with sonographically established tubular ectasia compared with 22 control patients (sonographically normal epididymides). Second, in a subset of patients with tubular ectasia who subsequently underwent surgery to restore fertility (n = 10), we examined the relationship between epididymal T1 signal intensity and surgical outcome. Vasovasostomy (simple vas deferens reanastomosis with high success rate) was possible when viable sperm were detected in the vas deferens intraoperatively. When no sperm were detected, vasal/epididymal tubular occlusion was inferred and vasoepididymostomy (vas deferens to epididymal head anastomosis, a technically challenging procedure with poorer outcome) was performed. RESULTS: In tubular ectasia, we found increased epididymal T1 signal intensity (0-77%) compared with normal epididymides (-27 to 20%) (p < 0.0001). In patients with tubular ectasia who underwent surgery (n = 10), we found higher T1 epididymal signal intensity in cases of vasal/epididymal occlusion (0-70%) relative to cases in which vasal/epididymal patency was maintained (0-10%) (p = 0.01). By logistic regression, relative epididymal T1 signal intensity increase above 19.4% corresponded to greater than 90% probability of requiring vasoepididymostomy. CONCLUSION: Increased epididymal T1 signal intensity (likely due to proteinaceous material lodged within the epididymal tubules) at preoperative MRI in patients undergoing vasectomy reversal suggests vasal/epididymal tubular occlusion and requirement for vasoepididymostomy rather than vasovasostomy. PMID- 24951201 TI - Combined chemical shift imaging with early dynamic serial gadolinium-enhanced MRI in the characterization of adrenal lesions. AB - OBJECTIVE: The purpose of this study was to retrospectively evaluate early dynamic serial gadolinium-enhanced and chemical-shift imaging (CSI) MRI to distinguish benign from malignant adrenal tumors. MATERIALS AND METHODS: Between July 2007 and December 2011, 205 patients with 239 adrenal lesions (177 adenomas, 54 metastases, 5 pheochromocytomas, and 3 adrenal cortical carcinomas) underwent early dynamic serial gadolinium-enhanced MRI and CSI. CSI was assessed qualitatively and by calculating the adrenal index, and enhancement patterns were evaluated qualitatively and quantitatively. Statistical analyses were performed. RESULTS: Most adenomas exhibited either an arterial blush or homogeneous enhancement, whereas most metastases showed early peripheral or heterogeneous enhancement. Visualization of higher enhancement on arterial and venous phases enabled differentiation of adenomas from metastases in most cases. Moderate to high signal intensity drop on CSI was seen in 95.4% of adenomas and 14.8% of metastases. In lesions with this level of signal intensity drop, 87 of 88 lesions with a capillary blush were adenomas. Early dynamic serial imaging alone was a significant (p < 0.0001) indicator of nonadenoma (area under the curve [AUC], 0.912) with optimal sensitivity of 81% and specificity of 93% for differentiating adenomas from nonadenomas. Combined analysis (CSI and early dynamic serial imaging) was also significant (p < 0.0001 and p=0.0014, respectively) for diagnosing nonadenomas (AUC, 0.983) with optimal sensitivity of 94% and specificity of 98%. CONCLUSION: Early dynamic serial gadolinium-enhanced MRI aids in characterization of adrenal tumors, especially lesions that are categorized as indeterminate on the basis of CSI. PMID- 24951202 TI - Providing formal reports for outside imaging and the rate of repeat imaging. AB - OBJECTIVE: The purpose of this study is to assess whether providing a formal report for outside imaging reduces repeat imaging. MATERIALS AND METHODS: From January 1, 2006, through December 31, 2011, patients transferred with an abdominal CT from another ("outside") institution that was imported to our institution's PACS within 60 days of the original CT were considered. Repeat imaging was defined as when an abdominal CT performed at another institution was followed by the same study at our institution in the 14 days after import to PACS. The rate of repeat imaging was compared between patients whose outside imaging did and did not receive a formal report from our radiologists. RESULTS: Consecutive patients (n = 10,330) who imported an outside abdominal CT to our PACS were considered. Thirty-six percent (3719/10,330) received a formal report. These patients were 32% less likely than the other patients to undergo repeat imaging (9.4% [350/3719] vs 14% [919/6611]; p < 0.001). The odds of repeat imaging were statistically significantly lower for patients who received a formal report after adjusting for potential confounding variables, including the age of the outside imaging study and the referring specialty (multivariate odds ratio, 0.53; 95% CI, 0.47-0.61; p < 0.001). CONCLUSION: Patients who received a formal report for their outside abdominal CT examinations were less likely to have repeat imaging. Institutions, payers, and policy makers should consider providing and supporting formal reports for outside imaging. PMID- 24951203 TI - A (gentle) introduction to behavioral economics. AB - OBJECTIVE: The article will introduce radiologists to decision making under uncertainty to foster a better understanding of the overutilization of imaging. CONCLUSION: Understanding the precepts of the expanding field of behavioral economics has relevance for health care in general and radiology in particular. PMID- 24951204 TI - What is the minimal radiation dose that can be used for detecting pleural effusion? AB - OBJECTIVE: The objective of our study was to assess the effect of radiation dose reduction on the detection of pleural effusions, thickening, and calcifications. MATERIALS AND METHODS: Forty-five human cadavers (mean age at death, 60 +/- 17 [SD] years; male-female ratio, 29:16; mean body mass index, 29 +/- 5.7 [SD] kg/m(2)) were scanned at seven different dose levels (CT Dose Index volume [CTDIvol] = 20, 12, 10, 6, 4, 2, and 0.8 mGy) on a 128-MDCT unit (Definition FLASH). Images were reconstructed at a 3-mm slice thickness and 2-mm increment with filtered back projection (FBP) technique. Two chest radiologists independently reviewed all image series for the detection of pleural effusion, pleural calcification, and adjacent parenchymal opacification from atelectasis or consolidation. Objective image noise was measured at each dose level on the pleural effusion using ImageJ software. Data analysis was performed with the Student t test and kappa test. RESULTS: Pleural effusions were seen in 39 of 45 cadavers on image series acquired at 2-20 mGy. Only 14 of 39 pleural effusions were identified at 0.8 mGy. Pleural effusions were not detected in 25 of 39 cadavers at 0.8 mGy because of photon starvation and increased image noise. Patient size was significantly larger in subjects with undetected pleural effusion than in those with detectable pleural effusion at 0.8 mGy (p < 0.01). Pleural calcifications and thickening (seen at 2-10 mGy images in three of three cadavers) were not identified on 0.8-mGy FBP images. On the other hand, adjacent parenchymal opacification could be assessed at all dose levels. The mean CT numbers of the pleural effusion were significantly lower on 0.8-mGy images than on images obtained at all other dose levels (-21 +/- 55 [SD] vs 17.6 +/- 19 HU, respectively) (p < 0.001). CONCLUSION: Pleural effusions, thickening, and calcifications can be seen on FBP images reconstructed at a CTDIvol as low as 2 mGy (32-cm body phantom). CT at 0.8 mGy may provide suboptimal information on very small pleural effusions, pleural thickening, and calcifications. PMID- 24951205 TI - Effect of patient centering on patient dose and image noise in chest CT. AB - OBJECTIVE: The objective of our study was to evaluate the effect of vertical centering on dose and image noise in chest MDCT of different-sized patients using anthropomorphic phantoms and retrospectively studying examinations of clinical patients. MATERIALS AND METHODS: Three different anthropomorphic phantoms were scanned using different vertical centering (offset +/- 6 cm) and were assessed with radiation dose-monitoring software. The effect of vertical positioning on the radiation dose was studied using the volume CT dose index, dose-length product, and size-specific dose estimates for different-sized phantoms. Image noise was determined from CT number histograms. Vertical positioning for chest CT examinations of 112 patients ranging from neonates to adults were retrospectively assessed. RESULTS: Radiation doses were highest when using the posteroanterior scout image for automatic exposure control (AEC) and when phantoms were set in the lowest table position, and radiation doses were lowest when phantoms were set in the uppermost table position. For the adult phantom, relative doses increased by 38% in the lowest table position and decreased by 23% in the highest table position. Similarly, doses for pediatric 5-year-old and newborn phantoms were 21% and 12% higher in the lowest table position and 12% and 8% lower in the highest table position, respectively. The effect decreased when a lateral scout image was used for AEC. The relative noise was lowest when the phantoms were properly centered and increased with vertical offset. In clinical patients, we observed offset with a median value varying from 25 to 35 mm below the isocenter. CONCLUSION: Regardless of patient size, most patients in this study were positioned too low, which negatively affected both patient dose and image noise. Miscentering was more pronounced in smaller pediatric patients. PMID- 24951206 TI - Imaging of Kienbock disease. AB - OBJECTIVE: The purpose of this article is to provide an overview of Kienbock disease focusing on imaging findings, including the relevant anatomy, pathophysiology, and treatment of Kienbock disease and the differential diagnoses (pseudo-Kienbock lesions). CONCLUSION: Kienbock disease is a condition marked by avascular necrosis of the lunate bone. MRI is useful in diagnosis and staging and should be considered, after conventional radiography, for patients with suspected Kienbock disease. PMID- 24951207 TI - Outcome of traumatic intervertebral disk lesions after stabilization by internal fixator. AB - OBJECTIVE: The optimal treatment of intervertebral disk lesions accompanying thoracolumbar fractures remains controversial. To evaluate short- and medium-term progression of intervertebral disk lesions accompanying vertebral fractures, MRI scans obtained after trauma were compared with scans obtained at an average follow-up of 1 year, by means of our clinically useful classification of traumatic intervertebral disk lesions. MATERIALS AND METHODS: MRI scans of 54 disks in patients with trauma-induced single-level thoracolumbar fractures were analyzed retrospectively. All patients underwent posterior stabilization using a titanium internal fixator. Exclusion criteria were malignant vertebral collapse, spondylodiskitis, osteoporotic fractures, and degenerative disk disease in the uninjured disks. Morphologic changes and signal alterations of the adjacent disks were compared using routine MRI scans obtained after trauma and at an average follow-up of 1 year. Disks were divided according to their signals into four categories, from grade 0 to grade 3. RESULTS: Of the disks studied after trauma (n = 54), 27.8% were determined to be grade 0, 31.5% were grade 2, and 40.7% were grade 3. In the follow-up examination, MRI detected grade 0 in 13% of disks. Hence, more than 50% of the disks with grade 0 after trauma changed into grade 2 lesions, resulting in 46.3% grade 2 lesions. Grade 3 disk lesions (40.7%) remained the same without any sign of recovery. CONCLUSION: In the current study, we found progressive disk degradation and creeping in instrumented and nonfused segments in thoracolumbar fractures. For further validation, randomized controlled long-term outcome investigations seem mandatory as the next step in future clinical research. PMID- 24951208 TI - The role of imaging in diagnosing diseases of the distal radioulnar joint, triangular fibrocartilage complex, and distal ulna. AB - OBJECTIVE: The purpose of this article is to review the anatomy, biomechanics, and multimodality imaging findings of common and uncommon distal radioulnar joint (DRUJ), triangular fibrocartilage complex, and distal ulna abnormalities. CONCLUSION: The DRUJ is a common site for acute and chronic injuries and is frequently imaged to evaluate chronic wrist pain, forearm dysfunction, and traumatic forearm injury. Given the complex anatomy of the wrist, the radiologist plays a vital role in the diagnosis of wrist pain and dysfunction. PMID- 24951209 TI - Clinical implementation of MRI of joint arthroplasty. AB - OBJECTIVE: The purpose of this article is to explain the basic physics of imaging patients with metal implants, explain conflicting information regarding MRI scanning of "MR Conditional" devices, and relate our experience of scanning total joint arthroplasty (TJA) at our institution. CONCLUSION: MRI near TJA is effective with appropriate imaging protocols and standardized safety precautions. Strict adherence to MR Conditional labeling may preclude broad use of MRI for TJA assessment. PMID- 24951210 TI - Video: Common upper extremity injections utilizing musculoskeletal ultrasound. AB - OBJECTIVE: The purpose of this video article is to demonstrate the use of ultrasound for upper extremity musculoskeletal injections, covering general guidelines, preprocedure planning, needle selection, and basic technique. Several different upper-extremity injections are shown, including joint injections and aspirations, tendon sheath and bursal injections, and percutaneous treatment of calcific tendinitis. CONCLUSION: Musculoskeletal ultrasound is well suited for imaging-guided injections of the upper extremities. It is readily available, allows for high-resolution real-time imaging of the soft tissues and joints, and is adaptable for patient comfort and positioning. After viewing this video article, the observer should have an understanding of the applications for ultrasound in upper-extremity musculoskeletal interventions and should be able to apply that knowledge to advance their clinical practice. PMID- 24951211 TI - Gradient of apparent diffusion coefficient values in peritumoral edema helps in differentiation of glioblastoma from solitary metastatic lesions. AB - OBJECTIVE: Glioblastoma and solitary metastatic lesions can be difficult to differentiate with conventional MRI. The use of diffusion-weighted MRI to better characterize peritumoral edema has been explored for this purpose, but the results have been conflicting. The purpose of this study was to test the hypothesis that the gradient of apparent diffusion coefficient (ADC) values in peritumoral edema--that is, the difference in ADC values from the region closest to the enhancing tumor and the one closest to the normal-appearing white matter- may be a marker for differentiating glioblastoma from a metastatic lesion. MATERIALS AND METHODS: Forty patients, 20 with glioblastoma and 20 with a solitary metastatic lesion, underwent diffusion-weighted brain MRI before surgical resection. The ADC values were retrospectively collected in the peritumoral edema in three positions: near, an intermediate distance from, and far from the core enhancing tumor (G1, G2, and G3). The ADC gradient in the peritumoral edema was calculated as the subtractions ADCG3 - ADCG1, ADCG3 - ADCG2, and ADCG2 - ADCG1. The ADC values in the enhancing tumor, peritumoral edema, ipsilateral normal-appearing white matter, contralateral healthy white matter, and CSF were also collected. RESULTS: A gradient of ADC values was found in the peritumoral edema of glioblastoma. The ADC values increased from the region close to the enhancing tumor (1.36 +/- 0.24 * 10(-3) mm(2)/s) to the area near the normal-appearing white matter (1.57 +/- 0.34 * 10(-3) mm(2)/s). In metastatic lesions, however, those values were nearly homogeneous (p = 0.04). CONCLUSION: The ADC gradient in peritumoral edema appears to be a promising tool for differentiating glioblastoma from a metastatic lesion. PMID- 24951212 TI - Axial diffusivity of the corona radiata correlated with ventricular size in adult hydrocephalus. AB - OBJECTIVE: Hydrocephalus causes changes in the diffusion-tensor properties of periventricular white matter. Understanding the nature of these changes may aid in the diagnosis and treatment planning of this relatively common neurologic condition. Because ventricular size is a common measure of the severity of hydrocephalus, we hypothesized that a quantitative correlation could be made between the ventricular size and diffusion-tensor changes in the periventricular corona radiata. In this article, we investigated this relationship in adult patients with hydrocephalus and in healthy adult subjects. MATERIALS AND METHODS: Diffusion-tensor imaging metrics of the corona radiata were correlated with ventricular size in 14 adult patients with acute hydrocephalus, 16 patients with long-standing hydrocephalus, and 48 consecutive healthy adult subjects. Regression analysis was performed to investigate the relationship between ventricular size and the diffusion-tensor metrics of the corona radiata. Subject age was analyzed as a covariable. RESULTS: There is a linear correlation between fractional anisotropy of the corona radiata and ventricular size in acute hydrocephalus (r = 0.784, p < 0.001), with positive correlation with axial diffusivity (r = 0.636, p = 0.014) and negative correlation with radial diffusivity (r = 0.668, p = 0.009). In healthy subjects, axial diffusion in the periventricular corona radiata is more strongly correlated with ventricular size than with patient age (r = 0.466, p < 0.001, compared with r = 0.058, p = 0.269). CONCLUSION: Axial diffusivity of the corona radiata is linearly correlated with ventricular size in healthy adults and in patients with hydrocephalus. Radial diffusivity of the corona radiata decreases linearly with ventricular size in acute hydrocephalus but is not significantly correlated with ventricular size in healthy subjects or in patients with long-standing hydrocephalus. PMID- 24951213 TI - Potential role of 18F-FDG PET/CT in patients with fungal infections. AB - OBJECTIVE: Combined anatomic and functional imaging with (18)F-FDG PET/CT is slowly gaining foothold in the management of various infective pathologic abnormalities. However, limited literature is available regarding the role of FDG PET/CT in patients with fungal infections. CONCLUSION: Here, we briefly review the available literature and highlight the potential role that FDG PET/CT can play in the diagnosis and management of fungal infections. PMID- 24951214 TI - Transphyseal involvement of pyogenic osteomyelitis is considerably more common than classically taught. AB - OBJECTIVE: Radiologists are taught that pyogenic osteomyelitis in children rarely crosses the growth plate because terminal vessels of nutrient arteries loop at the physis, predisposing the metaphysis to hematogenous infection. However, we note that MRI frequently shows osteomyelitis involving both sides of the physis. The purpose of this article is to document our observation that pyogenic osteomyelitis crosses the growth plate more frequently in the pediatric patient population than is classically taught. MATERIALS AND METHODS: All pediatric patients (age, 2-16 years) with clinically suspected osteomyelitis from 2004 to 2009 were reviewed for transphyseal disease on a consensus basis. To reveal the statistical significance, we applied a z test to our results. We quantified rare as 20% or less and used a z test to determine whether 27 of 32 (81%) differed from rare. RESULTS: Of 32 subjects, 81% showed transphyseal infection. In our study, the z test revealed that transphyseal infection occurred significantly more often than what would be considered rare (z = 4.75, p < 0.01). CONCLUSION: In our pediatric patient population, we have documented a higher frequency of transphyseal osteomyelitis (81%) than metaphyseal osteomyelitis in pyogenic infections. When our findings are statistically compared with an expected rate of 20%, they cannot be attributed to chance alone. This raises some doubt regarding the conventional understanding of pediatric pyogenic osteomyelitis. PMID- 24951215 TI - CT-guided nerve block for pudendal neuralgia: diagnostic and therapeutic implications. AB - OBJECTIVE: The objective of our study was to help clarify the role of CT-guided pudendal nerve blocks in the problematic and poorly understood entity of pudendal neuralgia (PN). SUBJECTS AND METHODS: Over a 1-year period, 52 CT-guided pudendal nerve blocks were performed in 31 patients (28 women, three men; age range, 22-80 years) who suffered from chronic pelvic pain with a presumed diagnosis of PN. A combination of anesthetic and steroid was injected into the pudendal (Alcock) canal. Pre- and postprocedural pain scores (0-10) were tallied and assessed by Student t tests. A p value < 0.05 was indicative of a significant difference. RESULTS: All procedures were successful technically, which was defined as contrast material filling the pudendal canal on CT and subsequent infusion of anesthetic and steroid. Pre- and postprocedural pain scores ranged from 2 to 10 (mean score, 6.13) and 0-10 (mean score, 2.14), respectively; the difference was statistically significant for each nerve block session (first session, p < 0.001; second session, p < 0.001; third session, p = 0.049). Of the 31 patients, two had long-term relief with pudendal nerve blocks alone. Fourteen had subsequent surgery based on initial improvement with block(s), and all 14 patients improved with surgical nerve release. Two patients had no diagnostic response and the diagnosis of PN was excluded. The gynecologic service followed the remaining 13 patients clinically. CONCLUSION: CT-guided pudendal nerve blocks appear to be valuable diagnostically for PN and uncommonly therapeutically. On the basis of these preliminary results, we have developed an algorithm for the role of the procedure for PN. PMID- 24951216 TI - Sonographic analysis of the intercostal spaces for the application of high intensity focused ultrasound therapy to the liver. AB - OBJECTIVE: The purposes of this study were to assess the widths of the intercostal spaces of the right inferior human rib cage through which high intensity focused ultrasound therapy would be applied for treating liver cancer and to elucidate the demographic factors associated with intercostal space width. SUBJECTS AND METHODS: From March 2013 to June 2013, the widths of the intercostal spaces and the ribs at six areas of the right inferior rib cage (area 1, lowest intercostal space on anterior axillary line and the adjacent upper rib; area 2, second-lowest intercostal space on anterior axillary line and the adjacent upper rib; areas 3 and 4, lowest and second-lowest spaces on midaxillary line; areas 5 and 6, lowest and second-lowest spaces on posterior axillary line) were sonographically measured in 466 patients (214 men, 252 women; mean age, 53.0 years) after an abdominal sonographic examination. Demographic factors and the presence or absence of chronic liver disease were evaluated by multivariate analysis to investigate which factors influence intercostal width. RESULTS: The width of the intercostal space was 19.7 +/- 3.7 mm (range, 9-33 mm) at area 1, 18.3 +/- 3.4 mm (range, 9-33 mm) at area 2, 17.4 +/- 4.0 mm (range, 7-33 mm) at area 3, 15.4 +/- 3.5 mm (range, 5-26 mm) at area 4, 17.2 +/- 3.7 mm (range, 7-28 mm) at area 5, and 14.5 +/- 3.6 mm (range, 4-26 mm) at area 6. The corresponding widths of the ribs were 15.2 +/- 2.3 mm (range, 8-22 mm), 14.5 +/- 2.3 mm (range, 9-22 mm), 13.2 +/- 2.0 mm (range, 9-20), 14.3 +/- 2.2 mm (range, 9-20 mm), 15.0 +/- 2.2 mm (range, 10-22 mm), and 15.1 +/- 2.3 mm (range, 8-21 mm). Only female sex was significantly associated with the narrower intercostal width at areas 1, 2, 3, and 5 (regression coefficient, 1.124-1.885; p = 0.01-0.04). CONCLUSION: There was substantial variation in the widths of the intercostal spaces of the right inferior rib cage such that the anterior and inferior aspects of the intercostal space were relatively wider. Women had significantly narrower intercostal spaces than men. PMID- 24951217 TI - Inter- and intrareader agreement for categorization of background parenchymal enhancement at baseline and after training. AB - OBJECTIVE: Background parenchymal enhancement (BPE) refers to enhancing fibroglandular tissue on initial contrast-enhanced MR images. BPE appears to impact the rate of abnormal MRI interpretation and may correlate with breast cancer risk. There are now minimal data as to the uniformity of radiologists' BPE assessments and no data as to whether training improves agreement. Therefore, for this study, we sought to assess interreader agreement for BPE at baseline and after dedicated training. MATERIALS AND METHODS: This study included 119 breast MRI examinations performed in 119 patients (mean age, 47 years; age range, 25-79 years) in 2008. One week before training, four fellowship-trained breast imagers with 2-12 years' experience independently recorded BPE on a 4-point scale as follows: 1 (minimal, <= 25%), 2 (mild, 26-50%), 3 (moderate, 51-75%), or 4 (marked, > 75%). The same 119 cases were reread in a new random order within 1 week and at least 3 weeks after training. Interreader agreement and intrareader agreement were assessed using kappa coefficients. RESULTS: With training, interreader agreement increased from fair (kappa = 0.36) to moderate (kappa = 0.48). Improvement was sustained at 3 weeks after training (kappa = 0.45). Intrareader agreement between time points 2 and 3 (kappa: mean, 0.79; range, 0.56 0.98) was greater than between time points 1 and 2 (kappa: mean, 0.62; range, 0.45-0.84), indicating readers learned and retained. CONCLUSION: Initial interreader agreement for BPE was fair among breast radiologists but achieved sustained improvement with training, highlighting the importance of education and inclusion of standardized BPE categories in a reference atlas. PMID- 24951218 TI - Detection of mammographically occult architectural distortion on digital breast tomosynthesis screening: initial clinical experience. AB - OBJECTIVE: Digital breast tomosynthesis (DBT) has been shown to improve the sensitivity of screening mammography. DBT may have the most potential impact in cases of subtle mammographic findings such as architectural distortion (AD). The objective of our study was to determine whether DBT provides better visualization of AD than digital mammography (DM) and whether sensitivity for cancer detection is increased by the addition of DBT as it relates to cases of mammographically occult AD. MATERIALS AND METHODS: Retrospective review of BI-RADS category 0 reports from 9982 screening DM examinations with adjunct DBT were searched for the term "architectural distortion" and were reviewed in consensus by three radiologists. ADs were classified by whether they were seen better on DM or DBT, were seen equally well on both, or were occult on either modality. The electronic medical record was reviewed to identify additional imaging studies, biopsy results, and surgical excision pathology results. RESULTS: Review identified 26 cases of AD, 19 (73%) of which were seen only on the DBT images. Of the remaining seven ADs, six were seen better on DBT than DM. On diagnostic workup, nine lesions were assigned to BI-RADS category 4 or 5. Surgical pathology revealed two invasive carcinomas, two ductal carcinoma in situ lesions, three radial scars, and two lesions showing atypia. The cancer detection rate of DBT in mammographically occult AD was 21% (4/19). The positive predictive value of biopsy was 44%. CONCLUSION: DBT provides better visualization of AD than DM and identifies a subset of ADs that are occult on DM. Identification of additional ADs on DBT increases the cancer detection rate. PMID- 24951219 TI - Breast-specific gamma imaging: correlations with mammographic and clinicopathologic characteristics of breast cancer. AB - OBJECTIVE: The purpose of this article is to evaluate the correlations between breast-specific gamma imaging (BSGI) findings and mammographic and clinicopathologic characteristics of breast cancer. MATERIALS AND METHODS: Our study included 56 breast cancers that had undergone BSGI between August 2010 and December 2012. We reviewed imaging findings (BSGI and mammography) with histopathologic findings, including tumor size, histologic type, nuclear grade, presence of ductal carcinoma in situ (DCIS), and presence of extensive intraductal component (EIC); and immunochemical features, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (ERBB2, formerly HER2), Ki67, and p53. We classified cancers into positive or negative groups on the basis of BSGI visibility and investigated the statistical differences in mammographic and histopathologic characteristics between the BSGI positive and -negative groups. RESULTS: Among 56 malignancies, 48 (85.7%) were shown to be BSGI positive. Patients in the BSGI-positive group were statistically significantly older than those in the BSGI-negative group (p = 0.027). BSGI positive cancers were statistically significantly larger than BSGI-negative cancers (p = 0.002). Cancers 1.0 cm or larger, unlike those of subcentimeter size, were statistically significantly more visible on BSGI (p = 0.004). The mammographic findings and mammographic densities did not statistically significantly differ between the BSGI-positive and -negative groups. Invasiveness of cancer showed no statistically significant difference on BSGI finding. Cancers with a DCIS component tended to be BSGI positive, but without statistical significance (p = 0.051). Visibility on BSGI was not statistically significantly associated with EIC, nuclear grade, ER, PR, ERBB2, Ki67, and p53. CONCLUSION: The sensitivity of BSGI for breast cancer was 85.7%. Breast cancers in older patients, cancers larger than 1.0 cm, and cancers with the DCIS component tended to be visible on BSGI. BSGI was an equally sensitive tool to detect the breast cancer in women with fatty and dense breast. PMID- 24951220 TI - Understanding (and explaining) imaging performance metrics. PMID- 24951221 TI - Artifacts in dual-energy CT gout protocol: a review of 50 suspected cases with an artifact identification guide. AB - OBJECTIVE: The objective of our study was to discover the types and incidence of artifacts in dual-energy CT (DECT) using datasets of 50 consecutive patients who underwent a four-limb DECT protocol for the evaluation of suspected gout. Identification of artifacts and techniques for artifact reduction are discussed. CONCLUSION: Artifacts commonly occur in DECT performed for gout assessment but are usually readily recognizable. For 90% of the patients in our study who underwent imaging for suspected gout, DECT showed some type of artifact, with nail bed and skin artifacts being the most common. PMID- 24951222 TI - Doppler ultrasound velocities and resistive indexes immediately after pediatric liver transplantation: normal ranges and predictors of failure. AB - OBJECTIVE: We sought to determine the ranges of Doppler ultrasound findings immediately after pediatric liver transplantation that are associated with successful outcomes or postoperative complications. MATERIALS AND METHODS: This study included consecutive children who underwent Doppler ultrasound less than 48 hours after liver transplantation from 2001 to 2011. Operative reports and clinical outcome data were recorded. We had 110 patients (54% girls) with mean age at transplantation of 2.9 years (median, 1.3 years; range, 0-14 years) and a median follow-up interval of 3.5 years. Two pediatric radiologists reviewed ultrasound images in consensus. We computed descriptive statistics, interindex correlations, and analysis of variance. RESULTS: Twenty-four of 110 patients had a vascular complication, most commonly hepatic arterial thrombosis (seven patients). Compared with published adult normal values, normal pediatric Doppler parameters at postoperative day 1 trended toward higher normal velocities and resistive indexes (up to 0.95). Absent or low-velocity common hepatic artery flow less than 50 cm/s or a common hepatic artery resistive index less than 0.50 were significantly associated with hepatic artery thrombosis, whereas absent or low velocity portal venous flow less than 30 cm/s or low-velocity hepatic venous flow less than 25 cm/s were significantly associated with vascular complications and a monotonic hepatic venous waveform was significantly associated with venous complications. CONCLUSION: Flow in a pediatric liver on the first day after transplantation is normally hyperdynamic, especially in the youngest transplant recipients, and, as a result, low velocities or resistive indexes are particularly concerning for complications. The pediatric-specific ranges of expected posttransplantation Doppler ultrasound findings presented in this article should assist in identifying normal variation and potentially life threatening complications. PMID- 24951223 TI - Anteverted retroflexed uterus: a common consequence of cesarean delivery. AB - OBJECTIVE: The purpose of this study was to determine in a sequential unselected sample of nonpregnant women whether an anteverted retroflexed uterine position develops after cesarean delivery and to see whether the amount of myometrial thinning related to cesarean delivery affects the development of an anteverted retroflexed uterine position. MATERIALS AND METHODS: Images from 641 consecutive transvaginal ultrasound examinations performed between 2008 and 2011 in which a uterus was present were reviewed and archived. The series was analyzed in three groups: patients who underwent cesarean delivery, patients who were parous but had not undergone cesarean delivery, and patients who were nulliparous. The uterine axis was categorized as anteverted, anteverted and anteflexed, retroverted, retroverted and retroflexed, anteverted and retroflexed, retroverted and anteflexed, and axial, that is, in the same axis as the vagina. RESULTS: An anteverted retroflexed uterine position was found in 27% of women after cesarean delivery. It was rare when no cesarean section had been performed, being found in 1% of those women, and was not seen in nulliparous women. CONCLUSION: An anteverted retroflexed uterine position is a common consequence of cesarean delivery but is rarely seen in other parous women. PMID- 24951224 TI - Medicolegal-malpractice and ethical issues in radiology. Is there a reptile in the courtroom? PMID- 24951225 TI - Visual presentation of statistical concepts in diagnostic testing: the 2 * 2 diagram. AB - OBJECTIVE: The purpose of this article is to present a visual conceptual framework for important statistical concepts in radiology, and to provide an online application to facilitate this visualization. CONCLUSION: Statistical measures such as sensitivity, specificity, and predictive values are ubiquitous in medical literature, yet thinking fluidly about these concepts is not always easy. The 2 * 2 diagram is a helpful guide. PMID- 24951227 TI - Gastrointestinal tract filling defects in pediatric patients. PMID- 24951226 TI - Surgical resection of a malignant liver lesion: what the surgeon wants the radiologist to know. AB - OBJECTIVE: Hepatic malignancy is a common and lethal disease, whether due to a primary tumor or metastasis. There are numerous treatment options available depending on the stage of the disease and medical condition of the patient, including systemic chemotherapy, transcatheter embolization, thermal ablation, and surgical resection. In a subset of patients with liver malignancy, surgical resection can offer the best chance of long-term survival and potentially even cure. This article reviews the major indications and contraindications for resection, basic surgical techniques and terminology, key clinical and imaging preoperative workup, and pertinent interventional oncology procedures in the management of hepatic malignancy. CONCLUSION: Diagnostic and interventional radiology plays an important role in the assessment and treatment of malignant hepatic lesions. Radiologists should be familiar with how surgeons select, work up, and treat candidates for liver resection to provide the most clinically valuable service. PMID- 24951228 TI - Hepatocellular carcinoma in the noncirrhotic liver. AB - OBJECTIVE: Hepatocellular carcinomas (HCCs) that arise in noncirrhotic livers have several histologic and biochemical features that distinguish them from HCCs occurring in the setting of cirrhosis. Because the presentation, management, and prognosis of these entities are distinct, the accurate preoperative characterization of these lesions is of great clinical significance. We review the pathogenesis, imaging appearance, and clinical implications of noncirrhotic HCCs as they pertain to the clinical radiologist. CONCLUSION: HCCs that develop in noncirrhotic patients have distinct etiologic, cytogenetic, histopathologic, and clinical features. Despite a larger tumor burden at the time of HCC diagnosis, noncirrhotic patients with HCC have better overall survival and disease-free survival than cirrhotic patients with HCC. Knowledge of the precise clinical and imaging features of this entity and of other diagnostic considerations for the noncirrhotic liver is essential for improved patient care. PMID- 24951229 TI - LI-RADS categorization of benign and likely benign findings in patients at risk of hepatocellular carcinoma: a pictorial atlas. AB - OBJECTIVE: The purpose of this article is to review the imaging features and Liver Imaging Reporting and Data System (LI-RADS) categorization of benign and likely benign entities, including typical cirrhotic nodules, distinctive nodular observations, and benign entities that may simulate hepatocellular carcinoma. CONCLUSION: LI-RADS is a system of standardized criteria for interpreting liver CT and MR images of patients at risk of hepatocellular carcinoma. Most of the observations in these patients are not malignant. With the development of fibrosis and cirrhosis, these benign entities may take on an altered appearance. PMID- 24951230 TI - Incremental value of pharmacological stress cardiac dual-energy CT over coronary CT angiography alone for the assessment of coronary artery disease in a high-risk population. AB - OBJECTIVE: The purpose of this article is to prospectively determine the value of stress dual-energy CT (DECT) myocardial perfusion imaging to coronary CT angiography (CTA) for the assessment of coronary artery disease (CAD) in a high risk population. SUBJECTS AND METHODS: We prospectively enrolled 29 consecutive patients who were referred for cardiac SPECT examinations for known or suspected CAD to also undergo pharmacologic stress cardiac DECT. In 25 patients, cardiac catheterization was available as the reference standard for morphologically significant stenosis. The performance of coronary CTA alone, DECT myocardial perfusion alone, and the combination of both was assessed by calculating sensitivity, specificity, and AUC values. RESULTS: For morphologically significant stenosis, coronary CTA alone and myocardial DECT assessment alone had 95% sensitivity and 50% specificity. The combined approach yielded 100% sensitivity and 33% specificity if either was positive and 90% sensitivity and 67% specificity if both were positive. The AUC value was highest (0.78) if both were positive. For hemodynamically significant lesions, coronary CTA alone had 91% sensitivity and 38% specificity, and DECT alone had 95% sensitivity and 75% specificity. The combined approach yielded 100% sensitivity and 38% specificity if either was positive and 86% sensitivity and 75% specificity if both were positive. AUC values were highest for DECT alone (0.85) and the "both positive" evaluation (0.80). CONCLUSION: The combined analysis of coronary CTA and DECT myocardial perfusion reduces the number of false-positives in a high-risk population for CAD and outperforms the purely anatomic test of coronary CTA alone for the detection of morphologically and hemodynamically significant CAD. PMID- 24951231 TI - Subtype differentiation of renal cell carcinoma using diffusion-weighted and blood oxygenation level-dependent MRI. AB - OBJECTIVE: The purpose of this article is to evaluate the utility of diffusion weighted imaging (DWI) and blood oxygenation level-dependent (BOLD) MRI for characterizing renal cell carcinoma (RCC) subtypes at 3 T. MATERIALS AND METHODS: Seventy-seven patients underwent 3-T DWI and BOLD MRI. Apparent diffusion coefficient (ADC; * 10(-3) mm(2)/s) and rate of spin dephasing (R2*, which equals 1 / T2* relaxation time, or 1/s) values were measured in the three RCC subtypes and normal renal parenchyma, and the results were compared. Statistical analyses were performed using analysis of variance, Student t test, and ROC curve analysis. RESULTS: Clear cell RCCs showed statistically significantly greater ADC values (1.81 * 10(-3) mm(2)/s) than did papillary (1.29 * 10(-3) mm(2)/s) and chromophobe (1.55 * 10(-3) mm(2)/s) RCCs (p < 0.01); however, no statistically significant differences between papillary and chromophobe RCCs were observed (p = 0.26). Chromophobe RCCs showed the greatest mean R2* (33.6 1/s) of the three subtypes (p < 0.01); however, no statistically significant differences between clear cell RCCs and papillary RCCs were seen (p = 0.48). Low-grade clear cell RCCs showed statistically significantly higher ADC value (1.97 * 10(-3) mm(2)/s) than did high-grade clear cell RCCs (1.66 * 10(-3) mm(2)/s; p = 0.021). For differentiating clear cell RCCs from non-clear cell RCCs, the AUCs of ADC and R2* values were 0.756 * 10(-3) mm(2)/s and 0.607 (1/s), respectively (p = 0.047): cutoff values of ADC (1.4 * 10(-3) mm(2)/s) and R2* (26.3 1/s) resulted in sensitivities and specificities of 85% and 73%, and 86% and 47%, respectively. CONCLUSION: For characterizing RCC subtypes, DWI and BOLD MRI at 3 T may be useful, but the current technique of BOLD MRI seems to have a limited diagnostic accuracy. PMID- 24951232 TI - Relationships of pediatric anthropometrics for CT protocol selection. AB - OBJECTIVE: Determining the optimal CT technique to minimize patient radiation exposure while maintaining diagnostic utility requires patient-specific protocols that are based on patient characteristics. This work develops relationships between different anthropometrics and CT image noise to determine appropriate protocol classification schemes. MATERIALS AND METHODS: We measured the image noise in 387 CT examinations of pediatric patients (222 boys, 165 girls) of the chest, abdomen, and pelvis and generated mathematic relationships between image noise and patient lateral and anteroposterior dimensions, age, and weight. RESULTS: At the chest level, lateral distance (ld) across the body is strongly correlated with weight (ld = 0.23 * weight + 16.77; R(2) = 0.93) and is less well correlated with age (ld = 1.10 * age + 17.13; R(2) = 0.84). Similar trends were found for anteroposterior dimensions and at the abdomen level. Across all studies, when acquisition-specific parameters are factored out of the noise, the log of image noise was highly correlated with lateral distance (R(2) = 0.72) and weight (R(2) = 0.72) and was less correlated with age (R(2) = 0.62). Following first-order relationships of image noise and scanner technique, plots were formed to show techniques that could achieve matched noise across the pediatric population. CONCLUSION: Patient lateral distance and weight are essentially equally effective metrics to base maximum technique settings for pediatric patient-specific protocols. These metrics can also be used to help categorize appropriate reference levels for CT technique and size-specific dose estimates across the pediatric population. PMID- 24951233 TI - Multimodality imaging of foreign bodies of the musculoskeletal system. AB - OBJECTIVE: The purpose of this article is to clarify the most relevant points in managing suspected foreign bodies of the musculoskeletal system on the basis of a literature review and published reports with cases to illustrate each type on different imaging modalities. CONCLUSION: Foreign bodies of the musculoskeletal system are a common problem in emergency departments, with more than a third missed in the initial clinical evaluation. These retained objects may result in various complications and also offer fertile ground for litigation. PMID- 24951234 TI - Effects of a standing and three dynamic workstations on computer task performance and cognitive function tests. AB - Sedentary work entails health risks. Dynamic (or active) workstations, at which computer tasks can be combined with physical activity, may reduce the risks of sedentary behaviour. The aim of this study was to evaluate short term task performance while working on three dynamic workstations: a treadmill, an elliptical trainer, a bicycle ergometer and a conventional standing workstation. A standard sitting workstation served as control condition. Fifteen Dutch adults performed five standardised but common office tasks in an office-like laboratory setting. Both objective and perceived work performance were measured. With the exception of high precision mouse tasks, short term work performance was not affected by working on a dynamic or a standing workstation. The participant's perception of decreased performance might complicate the acceptance of dynamic workstations, although most participants indicate that they would use a dynamic workstation if available at the workplace. PMID- 24951236 TI - Myth: When it comes to drugs and devices, newer is always better. PMID- 24951235 TI - Temporomandibular dysfunction post-craniotomy: evaluation between pre- and post operative status. AB - OBJECTIVE: To identify risk factors associated with post-operative temporomandibular joint dysfunction after craniotomy. METHODS: The study sample included 24 patients, mean age of 37.3 +/- 10 years; eligible for surgery for refractory epilepsy, evaluated according to RDC/TMD before and after surgery. The primary predictor was the time after the surgery. The primary outcome variable was maximal mouth opening. Other outcome variables were: disc displacement, bruxism, TMJ sound, TMJ pain, and pain associated to mandibular movements. Data analyses were performed using bivariate and multiple regression methods. RESULTS: The maximal mouth opening was significantly reduced after surgery in all patients (p = 0.03). In the multiple regression model, time of evaluation and pre operative bruxism were significantly (p < .05) associated with an increased risk for TMD post-surgery. CONCLUSION: A significant correlation between surgery follow-up time and maximal opening mouth was found. Pre-operative bruxism was associated with increased risk for temporomandibular joint dysfunction after craniotomy. PMID- 24951237 TI - Diagnostic tools for hypersensitivity to platinum drugs and taxanes: skin testing, specific IgE, and mast cell/basophil mediators. AB - Hypersensitivity reactions (HSRs) to platinum drugs and taxanes are increasing in cancer patients, and rapid drug desensitization has emerged as a safe and effective method to reintroduce these drugs in reactive patients. Optimal management of patients presenting HSRs to chemotherapy depends on the use of various diagnostic tools, which include measurement of mast cell/basophil mediator release following a HSR and skin testing. Serum tryptase should be measured in patients presenting chemotherapy HSRs, and its elevation would support mast cell/basophil activation. Skin testing to platinum drugs has a high sensitivity and specificity and is critical to guide the management of platinum reactive patients. Taxane skin testing is also emerging as a useful diagnostic and risk stratification tool in the evaluation of patients with HSRs to taxanes. Platinum sIgE assays have been recently developed and can be helpful in combination with skin testing or as an alternative when skin testing is not available. PMID- 24951238 TI - Perioperative anaphylaxis. AB - Perioperative anaphylaxis is a life-threatening condition with an estimated prevalence of 1:3,500 to 1:20,000 procedures and a mortality rate of up to 9 %. Clinical presentation involves signs such as skin rash, urticaria, angioedema, bronchospasm, tachycardia, bradycardia, and hypotension. Prompt recognition and treatment is of utmost importance to the patient's prognosis, since clinical deterioration can develop rapidly. Epinephrine is the main treatment drug, and its use should not be postponed, since delayed administration is associated with increased mortality. Elevated levels of serum tryptase help to confirm the diagnosis. The main agents involved in IgE-mediated perioperative anaphylaxis are neuromuscular blocking agents, latex, antibiotics, hypnotics, opioids, and colloids. Specific investigation should be conducted 4 to 6 weeks after the reaction and relies on skin tests, serum-specific IgE, and challenge procedures. This review aims to discuss the main aspects of perioperative anaphylaxis: risk factors, diagnosis, treatment, culprit agents, specific investigation, and preventive measures. PMID- 24951239 TI - The placebo effect in asthma. AB - The placebo effect is a complex phenomenon occurring across a variety of clinical conditions. While much placebo research has been conducted in diseases defined by self-report such as depression, chronic pain, and irritable bowel syndrome (IBS), asthma has been proposed as a useful model because of its easily measured objective outcomes. Studies examining the placebo response in asthma have not only contributed to an understanding of the mechanisms behind the placebo response but also shed an interesting light on the current treatment and diagnosis of asthma. This paper will review current literature on placebos in general and specifically on the placebo response in asthma. It focuses on what we know about the mechanisms behind the placebo effect, whether there is a specific portion of the population who responds to placebos, which patient outcomes are influenced by the placebo effect, and whether the effect can be augmented. PMID- 24951240 TI - His-containing plant metallothioneins: comparative study of divalent metal-ion binding by plant MT3 and MT4 isoforms. AB - Metallothioneins (MTs) are a superfamily of Cys-rich, low-molecular weight metalloproteins that bind heavy metal ions. These cytosolic metallopeptides, which exist in most living organisms, are thought to be involved in metal homeostasis, metal detoxification, and oxidative stress protection. In this work, we characterise the Zn(II)- and Cd(II)-binding abilities of plant type 3 and type 4 MTs identified in soybean and sunflower, both of them being His-containing peptides. The recombinant metal-MT complexes synthesised in Zn(II) or Cd(II) enriched Escherichia coli cultures have been analysed by ESI-MS, and CD, ICP-AES, and UV spectroscopies. His-to-Ala type 3 MT mutants have also been constructed and synthesised for the study of the role of His in divalent metal ion coordination. The results show comparable divalent metal-binding capacities for the MTs of type 3, and suggest, for the first time, the participation of their conserved C-term His residues in metal binding. Interesting features for the Zn(II)-binding abilities of type 4 MTs are also reported, as their variable His content may be considered crucial for their biological performance. PMID- 24951241 TI - Prostate-specific membrane antigen (PSMA) immunoexpression in the neovasculature of colorectal carcinoma in Egyptian patients. AB - In Egypt colorectal carcinoma (CRC) is the most common type of malignancy of the digestive system. Selectively inhibiting neoangiogenesis by targeting tumor associated blood vessels is an important therapeutic strategy. Prostate specific membrane antigen (PSMA) is expressed in the tumor-associated neovasculature of most solid cancers making it an interesting therapeutic target. We thought to study the expression of PSMA in a series of CRCs in order to test for its possible use as a target for antiangiogenic cancer therapy in Egyptian patients. One hundred CRC cases were retrieved. Representative sections from each tumor were subjected to immunohistochemistry using PSMA antibodies and CD31 antibodies as reference marker. Accordingly vascular endothelial cell immunoreactivity was semiquantitatively scored. PSMA immunostaining was positive in the neovasculature of 75% of tumors. A statistically significant relation was found between PSMA immunostaining and distant metastasis as well as vascular invasion. The present findings strengthen the evidence on the potential usefulness of PSMA as a therapeutic vascular target. This study is the first to demonstrate a positive relation between PSMA expression in CRC and distant metastasis as well vascular invasion, suggesting that PSMA may play a significant role in vascular invasion and subsequent metastasis. PMID- 24951242 TI - The changes of stage distribution of seminiferous epithelium cycle and its correlations with Leydig cell stereological parameters in aging men. AB - PURPOSE: To evaluate the changes of stage distribution of seminiferous epithelium cycle and its correlations with Leydig cell stereological parameters in aging men. METHODS: Point counting method was used to analyze the stereological parameters of Leydig cells. The stage number of seminiferous epithelium cycle was calculated in the same testicular tissue samples which were used for Leydig cell stereological analysis. RESULTS: The aging group had shown more severe pathological changes as well as higher pathologic scores than the young group. Compared with the control group, the volume density (VV) and surface density (NA) of Leydig cells in the aging group were increased significantly. The stage number of seminiferous epithelium cycle in the aging group was decreased coincidently compared to the young group. Leydig cell Vv in the young group has a positive relationship with stages I, II, III, V and VI of seminiferous epithelium cycle, and Leydig cell NA and numerical density (NV) were positively related to stage IV. However, only the correlation between NV and stage II was found in the aging group. CONCLUSIONS: The stage number of seminiferous epithelium cycle was decreased in aging testes. Changes in the stage distribution in aging testes were related to the Leydig cell stereological parameters which presented as a sign of morphological changes. PMID- 24951243 TI - Influence of toxoplasmosis on acetylcholinesterase activity, nitric oxide levels and cellular lesion on the brain of mice. AB - The objective of this study was to investigate the activity of acetylcholinesterase (AChE), nitrite/nitrate (NOx) levels, as well as the biomarkers of cellular damage in the brain of mice experimentally infected with Toxoplasma gondii. Sixty mice were divided into two experiments: in experiment I the mice were infected with T. gondii/RH strain, while in experiment II they were infected with T. gondii, strains VEG and ME-49. Our evaluations were carried out on brain homogenized samples, assessing the AChE and glutathione reductase (GR) activities, and NOx, TBARS and AOPP levels in all the infected animals, compared with the control group. In both experiments, I and II, it was observed an increase in the activity of AChE and GR, as well as in the levels of NOx in the brain of infected mice with T. gondii. TBARS levels were increased in mice infected with the three different strains, RH, ME-49, and VEG. AOPP concentration was increased only in mice infected with the RH strain. Animals infected with the strains VEG and ME-49 showed histological lesions, associated with the presence of the parasite in the brain. Therefore, the infection by T. gondii is able to interfere in cholinesterase activity and NO levels, in association with oxidative stress and histological lesion. PMID- 24951244 TI - Balloon cell nevus of the iris. AB - Balloon cell nevus is a rare histopathological lesion characterized by a predominance of large, vesicular and clear cells, called balloon cells. There is only 1 case of balloon cell nevus of the iris reported in the literature. CASE REPORT: A 55 year-old man presented a pigmented elevated lesion in the right iris since the age of 12 years old. The lesion had been growing for the past 2 years and excision was performed. Histopathological examination showed a balloon cell nevus composed of clear and vacuolated cells without atypia. A typical spindle cell nevus of the iris was also observed. The differential diagnosis included xanthomatous lesions, brown adipocyte or other adipocytic lesions, clear cell hidradenoma, metastatic clear cell carcinoma of the kidney and clear cell sarcoma. The tumor was positive for Melan A, S100 protein and HMB45. CONCLUSION: Balloon cell nevus of the iris is rare but should be considered in the differential diagnosis of melanocytic lesions of the iris. PMID- 24951245 TI - Overdentures on primary mandibular implants in patients with oral cancer: a follow-up study over 14 years. AB - We aimed to assess oral functioning, patients' satisfaction, condition of peri implant tissues, and survival of implants up to 14 years after their insertion in patients with oral cancer who had had mandibular overdentures placed over primary implants. Endosseous dental implants were inserted prospectively in the interforaminal region of the mandible during resection of the tumour in 164/180 patients with oral cancer. All 58 patients were evaluated by questionnaires and clinical assessments during a final assessment in 2012. Implant-retained mandibular overdentures were inserted, and prosthetic rehabilitation and oral functioning were not associated with primary site or stage of the tumour, number or type of implants inserted, or the type of reconstruction. Over time the peri implant mucosa was usually free of inflammation. More implants were lost in patients treated by radiotherapy (27/318, 8.5%) than in those not so treated (1/206, 0.5%). Patients who had been treated by irradiation reported more problems in oral functioning and less satisfaction than those who had not. Patients with an implant-retained mandibular overdenture reported fewer problems in oral functioning than patients without an overdenture. Primary insertion of an implant should be routinely incorporated in the surgical planning for patients with oral cancer, as oral functioning in those wearing mandibular overdentures improved considerably and peri-implant health was at least reasonable. PMID- 24951246 TI - [Measuring the quality of intensive care medicine]. PMID- 24951247 TI - [Chronic stress and psychiatric disorders as risk factors in influenza A]. PMID- 24951249 TI - Prey and plastic ingestion of Pacific Northern Fulmars (Fulmarus glacialis rogersii) from Monterey Bay, California. AB - Marine plastic pollution affects seabirds, including Pacific Northern Fulmars (Fulmarus glacialis rodgersii), that feed at the surface and mistake plastic for prey or incidentally ingest it. Direct and indirect health issues can result, including satiety and possibly leading to inefficient foraging. Our objective was to examine fulmar body condition, identify cephalopod diet to species, enumerate and weigh ingested plastic, and determine if prey number and size were correlated with ingested plastics in beach-cast fulmars wintering in Monterey Bay California (2003, n=178: 2007, n=185). Fulmars consumed mostly Gonatus pyros, G. onyx, and G. californiensis of similar size for both years. We found a significant negative correlation between pectoral muscle index and average size of cephalopod beaks per stomach; a significant increase in plastic categories between 2003 and 2007; and no significant correlation between number and mass of plastic compared with number and size of prey for either year. PMID- 24951250 TI - Kelp Gulls (Larus dominicanus) killed and injured by discarded monofilament lines at a marine recreational fishery in northern Patagonia. AB - Among marine debris, monofilament fishing lines often result in negative impacts on marine organisms. We characterized marine debris and incidence of lost and discarded monofilament lines along beaches used by recreational fishers, and report the impact of lines on Kelp Gulls (Larus dominicanus) at the Bahia San Blas protected area, site of one of the main shore-based recreational fisheries of the southwestern Atlantic. Over 55% of the marine debris recorded originated from recreational fishing activities. Balls of tangled monofilament lines were found at a rate of 40.5 items per km. A total of 27 adult Kelp Gulls were found entangled with monofilament. All individuals were tangled to vegetation within colony boundaries. Four of the gulls had a monofilament line protruding from the bill, showing that they may be also killed when trying to obtain bait. Our results indicate that lost or discarded monofilament lines in the Bahia San Blas recreational fishing area result in undesired impacts on coastal wildlife. PMID- 24951248 TI - The emerging era of genomic data integration for analyzing splice isoform function. AB - The vast majority of multi-exon genes in humans undergo alternative splicing, which greatly increases the functional diversity of protein species. Predicting functions at the isoform level is essential to further our understanding of developmental abnormalities and cancers, which frequently exhibit aberrant splicing and dysregulation of isoform expression. However, determination of isoform function is very difficult, and efforts to predict isoform function have been limited in the functional genomics field. Deep sequencing of RNA now provides an unprecedented amount of expression data at the transcript level. We describe here emerging computational approaches that integrate such large-scale whole-transcriptome sequencing (RNA-seq) data for predicting the functions of alternatively spliced isoforms, and we discuss their applications in developmental and cancer biology. We outline future directions for isoform function prediction, emphasizing the need for heterogeneous genomic data integration and tissue-specific, dynamic isoform-level network modeling, which will allow the field to realize its full potential. PMID- 24951251 TI - Novel roles of Pkd2 in male reproductive system development. AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited genetic diseases, caused by mutations in PKD1 and/ or PKD2. Infertility and reproductive tract abnormalities in male ADPKD patients are very common and have higher incidence than in the general population. In this work, we reveal novel roles of Pkd2 for male reproductive system development. Disruption of Pkd2 caused dilation of mesonephric tubules/efferent ducts, failure of epididymal coiling, and defective testicular development. Deletion of Pkd2 in the epithelia alone was sufficient to cause reproductive tract defects seen in Pkd2(-/-) mice, suggesting that epithelial Pkd2 plays a pivotal role for development and maintenance of the male reproductive tract. In the testis, Pkd2 also plays a role in interstitial tissue and testicular cord development. In-depth analysis of epithelial-specific knockout mice revealed that Pkd2 is critical to maintain cellular phenotype and developmental signaling in the male reproductive system. Taken together, our data for the first time reveal novel roles for Pkd2 in male reproductive system development and provide new insights in male reproductive system abnormality and infertility in ADPKD patients. PMID- 24951252 TI - Effects of glucagon like peptide-1 to mediate glycemic effects of weight loss surgery. AB - To date, weight loss surgeries are the most effective treatment for obesity and glycemic control in patients with type 2 diabetes. Roux-en-Y gastric bypass surgery (RYGB) and sleeve gastrectomy (SG), two widely used bariatric procedures for the treatment of obesity, induce diabetes remission independent of weight loss while glucose improvement after adjustable gastric banding (AGB) is proportional to the amount of weight loss. The immediate, weight-loss independent glycemic effect of gastric bypass has been attributed to postprandial hyperinsulinemia and an enhanced incretin effect. The rapid passage of nutrients into the intestine likely accounts for significantly enhanced glucagon like peptide 1 (GLP-1) secretion, and postprandial hyperinsulinemia after GB is typically attributed to the combined effects of elevated glucose and GLP-1. For this review we focus on the beneficial effects of the three most commonly performed bariatric procedures, RYGB, SG, and AGB, on glucose metabolism and diabetes remission. Central to this discussion will be the extent to which the effects of surgery are mediated by GLP-1. Better understanding of these mechanisms could provide insight to development of novel therapeutic strategies for treatment of diabetes as well as refinement of surgical techniques. PMID- 24951253 TI - Cardiac structural abnormalities associated with IgG4-related coronary periarteritis and inflammation revealed by multimodality imaging. AB - A man presented with shortness of breath, and a globular heart was seen on a chest radiograph. An echocardiogram showed masses at the atrioventricular grooves. Computed tomography (CT) coronary angiography and fluorine-18 ((18)F) fluorodeoxyglucose positron emission tomography (FDG-PET)/CT confirmed coronary aneurysms with hypermetabolic perivascular masses at the coronary arteries and right internal iliac artery. Histologic features were highly suspicious for IgG4 related disease (IgG4-RD). IgG4-RD is a recently recognized fibroinflammatory condition, and FDG-PET/CT can provide information about the disease pattern, which may suggest IgG4-RD, as well as the optimal biopsy site. PMID- 24951254 TI - Diagnostic accuracy of electrocardiographic ST-segment depression in patients with rapid atrial fibrillation for the prediction of coronary artery disease. AB - BACKGROUND: We aimed to examine the diagnostic value of ST-segment depression in patients with rapid atrial fibrillation (AF) for the prediction of coronary artery disease (CAD). METHODS: Hemodynamically stable patients with AF, and a heart rate > 80% of their maximum predicted according to their age, were allocated to 2 groups according to their electrocardiographic findings on admission: group A included patients without any ST-segment abnormalities and group B, patients with downward or horizontal ST-segment depression >= 1 mm in 2 or more contiguous leads. Group A patients were subjected to a dobutamine stress echo or Tl-201 myocardial single-photon emission computed tomography, followed by coronary angiography in case of abnormal results and Group B patients to coronary angiography. CAD was defined angiographically as stenosis of >= 50% in any major epicardial coronary vessel. RESULTS: Out of 115 consecutive patients, with a mean age of 65.9 +/- 10.2 years, 42.6% were male, 18.3% smokers, 68.7% hypertensive, 21.7% had diabetes, and 40% had hyperlipidemia. We enrolled 71 and 44 patients in group A and B, respectively. Prevalence of significant CAD among studied patients was 21.7%, 3/71 (4.2%) and 22/44 (50.0%) in group A and B, respectively. Overall ST-segment depression during rapid AF had 88.0% sensitivity (95% confidence interval [CI], 67.7%-96.8%) and 75.6% specificity (95% CI, 65.2%-83.7%) in predicting presence of CAD, and positive and negative predictive value was 50.0% (95% CI, 34.8%-65.2%) and 95.8% (95% CI, 87.3%-98.7%), respectively. CONCLUSIONS: In consecutive patients with rapid AF, the absence of ST-segment depression might indicate absence of CAD. PMID- 24951255 TI - Coping with cognitive impairment and dementia: Rural caregivers' perspectives. AB - Caregiving in a rural context is unique, but the experience of rural caregivers is understudied. This paper describes how rural caregivers cope with caring for a loved one diagnosed with mild cognitive impairment or dementia using qualitative description to generate a low-inference summary of a response to an open-ended question. This approach allowed these rural caregivers to describe their positive experiences in addition to the more commonly explored caregiver experiences related to stress. Analyses of coping revealed use of social support, engaging in relaxing and physical activity, and cognitive reframing. In addition, caregivers reported strong faith and religiosity, and to a lesser frequency behavioral changes, checking in with the person with dementia via telephone, and joint activity. Predominantly, these methods reflect approach-based strategies. The current data suggest that these caregivers manage well and adopt adaptive coping strategies to meet the demands of the caregiving role. PMID- 24951256 TI - Helicobacter pylori infection in gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma: a re-evaluation. PMID- 24951257 TI - A global consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease. AB - OBJECTIVE: To develop a consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease (pCD), based on best available evidence. METHODS: Based on a systematic literature review, statements were formed, discussed and approved in multiple rounds by the 20 working group participants. Consensus was defined as at least 80% agreement among voters. Evidence was assessed using the modified GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. RESULTS: Highest diagnostic accuracy can only be established if a combination of modalities is used. Drainage of sepsis is always first line therapy before initiating immunosuppressive treatment. Mucosal healing is the goal in the presence of proctitis. Whereas antibiotics and thiopurines have a role as adjunctive treatments in pCD, anti-tumour necrosis factor (anti-TNF) is the current gold standard. The efficacy of infliximab is best documented although adalimumab and certolizumab pegol are moderately effective. Oral tacrolimus could be used in patients failing anti-TNF therapy. Definite surgical repair is only of consideration in the absence of luminal inflammation. CONCLUSIONS: Based on a multidisciplinary approach, items relevant for fistula management were identified and algorithms on diagnosis and treatment of pCD were developed. PMID- 24951260 TI - The influence of positioning in urination: an electromyographic and uroflowmetric evaluation. AB - PURPOSE: We conducted a cross-sectional study to evaluate whether the different positions during urination influence the electrical activity of the abdominal and perineal musculature, as well as the uroflowmetric parameters of children with lower urinary tract dysfunction (LUTD). MATERIALS AND METHODS: Ninety-four children between the ages of 3 and 14 years with symptoms of LUTD were evaluated. All underwent uroflowmetry and electromyography tests (abdominal and perineal) in two different positions: oriented position (trunk bent slightly forward and feet flat) and atypical position (standing on toes for boys and buttocks not in contact with the lavatory seat and legs flexed in girls). We excluded nine patients due to suspicions of outside interference or elements complicating the analysis of charts. RESULTS: Among patients evaluated 55 (64.7%) were girls and 30 (35.3%) were boys with an average age of 8.5 years. Children urinating in atypical position showed higher levels of perineal electrical activity than when they were in normal position (p=0.018). However, there was no difference in the pattern of the curve if normal or abnormal when comparing the two groups (p=0.824). When evaluated separately, the boys demonstrated no difference between positions, in relation to perineal electrical activity (p=0.412) or abdominal electrical activity (p=0.202). CONCLUSIONS: The electrical activity of the pelvic floor musculature is decreased in the oriented position when compared to atypical positions in female children. Our data suggest that special attention should be given to adopting an adequate posture during urination for girls with LUTD. PMID- 24951258 TI - CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis. AB - OBJECTIVE: Progastrin is the incompletely cleaved precursor of gastrin that is secreted by G-cells in the gastric antrum. Both gastrin and progastrin bind to the CCK2 receptor (Cckbr or CCK2R) expressed on a subset of gastric epithelial cells. Little is known about how gastrin peptides and CCK2R regulate gastric stem cells and carcinogenesis. Interconversion among progenitors in the intestine is documented, but the mechanisms by which this occurs are poorly defined. DESIGN: We generated CCK2R-CreERT mice and performed inducible lineage tracing experiments. CCK2R+ antral cells and Lgr5+ antral stem cells were cultured in a three-dimensional in vitro system. We crossed progastrin-overexpressing mice with Lgr5-GFP-CreERT mice and examined the role of progastrin and CCK2R in Lgr5+ stem cells during MNU-induced carcinogenesis. RESULTS: Through lineage tracing experiments, we found that CCK2R defines antral stem cells at position +4, which overlapped with an Lgr5(neg or low) cell population but was distinct from typical antral Lgr5(high) stem cells. Treatment with progastrin interconverts Lgr5(neg or low) CCK2R+ cells into Lgr5(high) cells, increases CCK2R+ cell numbers and promotes gland fission and carcinogenesis in response to the chemical carcinogen MNU. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansion and carcinogenesis. CONCLUSIONS: CCK2R labels +4 antral stem cells that can be activated and expanded by progastrin, thus identifying one hormonal trigger for gastric stem cell interconversion and a potential target for gastric cancer chemoprevention and therapy. PMID- 24951259 TI - Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer. AB - BACKGROUND: Characterisation of colorectal cancer (CRC) genomes by next generation sequencing has led to the discovery of novel recurrently mutated genes. Nevertheless, genomic data has not yet been used for CRC prognostication. OBJECTIVE: To identify recurrent somatic mutations with prognostic significance in patients with CRC. METHOD: Exome sequencing was performed to identify somatic mutations in tumour tissues of 22 patients with CRC, followed by validation of 187 recurrent and pathway-related genes using targeted capture sequencing in additional 160 cases. RESULTS: Seven significantly mutated genes, including four reported (APC, TP53, KRAS and SMAD4) and three novel recurrently mutated genes (CDH10, FAT4 and DOCK2), exhibited high mutation prevalence (6-14% for novel cancer genes) and higher-than-expected number of non-silent mutations in our CRC cohort. For prognostication, a five-gene-signature (CDH10, COL6A3, SMAD4, TMEM132D, VCAN) was devised, in which mutation(s) in one or more of these genes was significantly associated with better overall survival independent of tumor node-metastasis (TNM) staging. The median survival time was 80.4 months in the mutant group versus 42.4 months in the wild type group (p=0.0051). The prognostic significance of this signature was successfully verified using the data set from the Cancer Genome Atlas study. CONCLUSIONS: The application of next-generation sequencing has led to the identification of three novel significantly mutated genes in CRC and a mutation signature that predicts survival outcomes for stratifying patients with CRC independent of TNM staging. PMID- 24951261 TI - Age-related differences in presentation and course of inflammatory bowel disease: an update on the population-based literature. AB - Current data indicate a change in the epidemiology of inflammatory bowel diseases. The disease has become more widespread and the rise in the incidence has been reported in all age groups including early childhood and according to recent data also the elderly population. Some earlier studies have suggested that the phenotype and natural history of the disease may be different according to age of onset. Recently the importance of age at onset was reported in two population-based studies from France and Hungary including both paediatric and adult onset inception cohorts. Early onset disease was associated with more frequent disease extension in both Crohn's disease and ulcerative colitis and in most but not all studies with higher frequency of complicated disease behaviour. This is also accompanied by striking differences in the medical management with earlier and more prevalent (2-3-fold) use of immunosuppressives and to some extent biologicals in patients with early compared to elderly-onset disease, especially in Crohn's disease. However, the results of population-based studies on impact of age on surgery rates in Crohn's disease as well as ulcerative colitis are conflicting. Furthermore, published data indicate that relative but not absolute risk of developing cancer and mortality is higher in patients with an early onset disease. Critical reviews that focus on the importance of age at onset in inflammatory bowel disease are rare. Therefore, the aim of this review is to describe the differences in epidemiology, clinical characteristics, and natural history of paediatric and elderly-onset inflammatory bowel disease based on studies performed in general population. PMID- 24951262 TI - [Re: intramuscular lipomas: large and deep benign lumps not to be underestimated. Review of a series of 51 cases]. PMID- 24951263 TI - Operation Catnip: working together to reduce free-roaming cat populations ethically and effectively. PMID- 24951264 TI - Mycoplasmosis and upper respiratory tract disease of tortoises: a review and update. AB - Tortoise mycoplasmosis is one of the most extensively characterized infectious diseases of chelonians. A 1989 outbreak of upper respiratory tract disease (URTD) in free-ranging Agassiz's desert tortoises (Gopherus agassizii) brought together an investigative team of researchers, diagnosticians, pathologists, immunologists and clinicians from multiple institutions and agencies. Electron microscopic studies of affected tortoises revealed a microorganism in close association with the nasal mucosa that subsequently was identified as a new species, Mycoplasma agassizii. Over the next 24 years, a second causative agent, Mycoplasma testudineum, was discovered, the geographic distribution and host range of tortoise mycoplasmosis were expanded, diagnostic tests were developed and refined for antibody and pathogen detection, transmission studies confirmed the pathogenicity of the original M. agassizii isolate, clinical (and subclinical) disease and laboratory abnormalities were characterized, many extrinsic and predisposing factors were found to play a role in morbidity and mortality associated with mycoplasmal infection, and social behavior was implicated in disease transmission. The translation of scientific research into management decisions has sometimes led to undesirable outcomes, such as euthanasia of clinically healthy tortoises. In this article, we review and assess current research on tortoise mycoplasmosis, arguably the most important chronic infectious disease of wild and captive North American and European tortoises, and update the implications for management and conservation of tortoises in the wild. PMID- 24951265 TI - A pig tonsil cell culture model for evaluating oral, low-dose IFN-alpha treatments. AB - Oral, low-dose IFN-alpha treatments proved effective in several models of viral infections and immunopathological conditions. Also, they do not give rise to the serious side effects observed after parenteral inoculation of high doses (10(5)U/kg b.w. and higher). There is convincing evidence that such treatments work through an early, effective interaction with oral lymphoid tissues before the IFN-alpha molecules are rapidly destroyed by gut enzymes. Yet, the paucity of detailed information about these crucial interactions and the lack of recognized in vitro models hamper the development of proper administration protocols. On the basis of a previous study, we developed an in vitro model of interaction between different types of human and porcine IFNs-alpha at low/moderate concentrations and pig tonsil cells. The IFNs-alpha under study showed different properties with respect to three fundamental control actions: (1) IgA release in culture, (2) release of natural antimicrobial compounds, and (3) homeostatic regulation of the inflammatory response. This was checked in pig intestinal epithelial cells (IPEC J2 cell line) treated with supernatants of control and IFN alpha-treated tonsil cell cultures, respectively, in terms of inflammatory cytokine and chemokine responses. Some IFNs-alpha caused a significant inhibition of IL-8 (protein release and gene expression) and beta-defensin 1 (gene expression) probably through second messengers released by IFN alpha-treated tonsil cells. Interestingly, a human lymphoblastoid IFN-alpha under study caused the decrease of polyclonal IgA release by pig tonsil cells and significantly stimulated the in vitro recall antibody response of swine PBMC to Foot-and-Mouth Disease virus. The modulation of IgA and antibacterial compounds was accompanied by an anti inflammatory control action at the same, low to moderate IFN-alpha concentrations (1-100 U/ml). This highlights the very foundation of the homeostatic control actions performed by Type I IFNs: to promote an effective host response to infectious and non-infectious stressors and to turn off noxious inflammatory responses associated with tissue damage and waste of metabolic energy. The described tonsil cell model in vitro can be conducive to a further development of oral cytokine treatments in humans and animals in the "one health" conceptual framework. PMID- 24951266 TI - Monitoring patient-centered outcomes through the progression of breast reconstruction: a multicentered prospective longitudinal evaluation. AB - Studies have shown that having breast reconstruction has a positive influence on patient satisfaction and health-related quality of life (HRQoL) at the conclusion of treatment. However, no study has critically evaluated changes to these patient reported outcomes during the process of undergoing breast reconstruction. This study was to prospectively evaluate changes to patient-centered metrics through the progression of breast reconstruction. An IRB-approved prospective, multi institutional study was performed for all patients undergoing breast reconstruction between 2009 and 2011. The Breast-Q reconstruction questionnaire was used for evaluation of HRQoL and was administered at five intervals in the perioperative period. Longitudinal evaluation was performed to assess changes to HRQoL metrics during this perioperative interval. One hundred and ten patients were enrolled, and 100 patients (91.9 %) completed appropriate follow-up. Preoperative HRQoL scores were higher in patients electing to forgo reconstruction (P < 0.004), while postoperative HRQoL scores consistently deteriorated at multiple time points following mastectomy as compared to reconstructed patients. On subgroup analysis, results indicated lower initial HRQoL scores in delayed reconstruction (P < 0.05) as compared to immediate reconstruction. These scores did, however, merge at approximately 9 months postoperatively. Changes to HRQoL outcomes occur through progression of breast reconstruction. Within the first year of surgery, early decreases are mirrored by significant increases at later time points above baseline levels when evaluating most forms of reconstruction. Choosing against reconstruction will likely result in continued deterioration of HRQoL for patients undergoing cancer surgery, but steady improvements can be expected if delayed reconstruction is chosen. PMID- 24951268 TI - Cardiovascular events, early discontinuation of trastuzumab, and their impact on survival. AB - To evaluate how often trastuzumab therapy is ended early (i.e., early discontinuation) and how cardiovascular events and early discontinuation affect survival among older women with breast cancer. A population-based cohort of female Medicare beneficiaries with stage I-III breast cancer in 2005-2009 who received trastuzumab was assembled and followed through 2011. Completed trastuzumab treatment was defined as >=11 months of continuous trastuzumab treatments with no delay between trastuzumab treatments >45 days. We identified trastuzumab-associated cardiovascular events as those occurring within 45 days before or after the last trastuzumab treatment. Using Cox proportional hazard models, we examined the association between early discontinuation of trastuzumab and cardiovascular events on all-cause mortality. Our cohort consisted of 585 women (mean age: 71.6 years). Approximately 41 % of women discontinued trastuzumab therapy early. Patients with early discontinuation of trastuzumab were more likely to have heart failure /cardiomyopathy, atrial fibrillation, and other cardiovascular events than women who completed trastuzumab. Cardiovascular events were strongly associated with an increased risk of all-cause mortality [adjusted hazard ratio (AHR) 3.54; 95 % confidence interval (CI) 1.87 to 6.68]. Women with early discontinuation of trastuzumab had a non-significant increase in risk of all-cause mortality (AHR: 1.74; 95 % CI 0.94 to 3.23), compared to women who completed trastuzumab. Early trastuzumab discontinuation was common among older patients, and often associated with adverse cardiovascular events. Development of cardiovascular events was associated with a higher mortality risk than early trastuzumab discontinuation, implying that reducing cardiovascular complications from trastuzumab therapy could likely have a substantive impact on overall survival in this population. PMID- 24951269 TI - Differential impact of body mass index on absolute and percent breast density: implications regarding their use as breast cancer risk biomarkers. AB - Percent breast density (PBD), a commonly used biomarker of breast cancer risk (BCR), is confounded by the influence of non-dense breast tissue on its measurement and factors, such as BMI, which have an impact on non-dense tissue. Consequently, BMI, a potent BCR factor, is, paradoxically, negatively correlated with PBD. We propose that absolute breast density (ABD) is a more accurate biomarker of BCR. We used a volumetric method to compare the correlation between PBD and ABD with baseline demographics and dietary and physical activity variables in a group of 169 postmenopausal women enrolled in a clinical trial prior to any intervention. As expected, a strong negative correlation between PBD and BMI was observed (Rho = -0.5, p < 5e(-12)). In contrast, we observed a strong, previously not well established, positive correlation of BMI with ABD (Rho = 0.41, p < 2.5e(-8)), which supports the use of ABD as a more accurate indicator of BCR. Correction of PBD by BMI did not frequently provide the same information as ABD. In addition, because of the strong influence of BMI on ABD, many correlations between dietary variables and ABD did not emerge, until adjustment was made for BMI. ABD corrected by BMI should be the gold standard BD measurement. These findings identify the optimal measurement of BD when testing the influence of an intervention on BD as a biomarker of BCR. PMID- 24951270 TI - [Life-threatening erosive gastritis in a child with varicella-induced thrombocytopenia]. PMID- 24951267 TI - Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. AB - Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80 %. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. We studied 1,504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1,093 women with unilateral breast cancer (controls) in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Three hundred and thirty-one women had used tamoxifen (22 %); of these 84 (25 %) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to 1 year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95 % CI 0.20-0.69; p = 0.001) compared to women with no tamoxifen use. Among women with 1-4 years of tamoxifen use the odds ratio was 0.53 (95 % CI 0.32-0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95 % CI 0.44-1.55; p = 0.55). Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional 5-year course of treatment. PMID- 24951271 TI - Effects of thyroid dysfunction on the severity of coronary artery lesions and its prognosis. AB - BACKGROUND: Abnormal thyroid hormone metabolism influences the occurrence and progress of coronary heart disease (CHD). The aim of the present study was to analyze the severity of coronary artery lesions and the prognosis of thyroid dysfunction patients admitted for coronary angiography (CAG). METHODS: From July 2011 to July 2012, 605 consecutive patients with suspected coronary heart disease admitted for CAG were selected. The patients were divided into three groups, based on their thyroid function prior to CAG: euthyroid group (n=455 patients), low T3 syndrome group (n=96 patients), and hypothyroidism group (n=54 patients). All patients underwent CAG. Then the severity of coronary artery lesions was assessed by Gensini scores. All patients were followed up for major adverse cardiac events. RESULTS: The prevalence of CHD in low T3 syndrome group and hypothyroidism group was significantly higher than that in the euthyroid group (p<0.001 and p=0.004, respectively). Moreover, the severity of coronary artery lesions in low T3 syndrome group and hypothyroidism group was significantly greater than that in the euthyroid group (all p<0.001). Multinomial logistic regression analysis demonstrated that low T3 syndrome was an independent risk factor of coronary artery moderate [odds ratio (OR)=4.268, 95% CI: 3.294-7.450, p=0.016] and severe (OR=4.294, 95% CI: 2.259-9.703, p<0.001) lesions. The mean duration of follow-up was 15.3+/-3.8 months; patients with thyroid dysfunction had a significantly worse prognosis as compared to those in the euthyroid group for the composite end-point (p<0.01). Moreover, the incidence of the composite end-point (all-cause death, non-fatal myocardial infarction, and coronary revascularization) was significantly higher in low T3 syndrome group and hypothyroidism group compared with that of in the euthyroid group (all p<0.001). CONCLUSIONS: The patients with hypothyroidism and low T3 syndrome had a high prevalence of CHD, increased severity of coronary artery lesions and poor prognosis. PMID- 24951272 TI - Genotoxicity and activation of cellular defenses in transplanted zebra mussels Dreissena polymorpha along the Seine river. AB - The aim of the present study was to confirm the relevance of studying DNA adduct formation in a field study. In that context, freshwater mussels Dreissena polymorpha, collected in a reference station, were transplanted in different sites with a pollution gradient. After one and two months, mussels were collected and DNA adduct formation was analyzed using the (32)P post labelling technique on both gills and digestive glands. In addition, the expression of genes involved in the detoxification system (catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase (GST), HSP70, aryl hydrocarbon receptor (AHR), P glycoprotein (PgP), metallothionein (MT)) was assessed by RT-PCR. DNA adducts were observed at amount comparable to data from literature. Increase of DNA adducts after two months of transplantation could be correlated with strong modulation of gene expression implicated in detoxification processes. Indeed, PgP and HSP70 gene expressions were similarly induced in gills and digestive glands while SOD and CAT expressions were down regulated in both tissues. AHR, GST and MT genes were differently regulated depending upon the tissue studied and the level of contamination in the different sites. We demonstrated that mussels transplanted in the different stations with pollution gradient were able to biotransform PAHs, assessed by DNA adduct formation and the high decrease of detoxification genes. Specific DNA adducts pattern obtained after one and two month mussel transplantations demonstrated the relevance of DNA adduct as biomarker of environmental pollution. PMID- 24951274 TI - Total solid content drives hydrogen production through microbial selection during thermophilic fermentation. AB - In this study, the effect of total solid content (TS) on thermophilic hydrogen production from wheat straw was investigated. Six TS contents ranging from wet to dry conditions (10-34%TS) were tested in batch tests. A decrease of H2 yields was observed and three statistical groups were distinguished according to the TS content: wet conditions (10% and 14%TS) with 15.3 +/- 1.6 NmlH2 gTS(-1), intermediate conditions (19%TS) with 6.4 +/- 1.0 NmlH2 gTS(-1) and dry conditions (25-34%TS) with 3.4 +/- 0.8 NmlH2 gTS(-1). Such a decrease in biohydrogen yields was related to a metabolic shift with an accumulation of lactic acid under dry conditions. Concomitantly, a microbial population shift was observed with a dominance of species related to the class Clostridia under wet conditions, and a co-dominance of members of Bacilli, Clostridia classes and Bacteroidetes phylum under dry conditions. PMID- 24951273 TI - Antioxidant responses of Annelids, Brassicaceae and Fabaceae to pollutants: a review. AB - Pollutants, such as Metal Trace Elements (MTEs) and organic compounds (polycyclic aromatic hydrocarbons, pesticides), can impact DNA structure of living organisms and thus generate damage. For instance, cadmium is a well-known genotoxic and mechanisms explaining its clastogenicity are mainly indirect: inhibition of DNA repair mechanisms and/or induction of Reactive Oxygen Species (ROS). Animal or vegetal cells use antioxidant defense systems to protect themselves against ROS produced during oxidative stress. Because tolerance of organisms depends, at least partially, on their ability to cope with ROS, the mechanisms of production and management of ROS were investigated a lot in Ecotoxicology as markers of biotic and abiotic stress. This was mainly done through the measurement of enzyme activities The present Review focuses on 3 test species living in close contact with soil that are often used in soil ecotoxicology: the worm Eisenia fetida, and two plant species, Trifolium repens (white clover) and Brassica oleracea (cabbage). E. fetida is a soil-dwelling organism commonly used for biomonitoring. T. repens is a symbiotic plant species which forms root nodule with soil bacteria, while B. oleracea is a non-symbiotic plant. In literature, some oxidative stress enzyme activities have already been measured in those species but such analyses do not allow distinction between individual enzyme involvements in oxidative stress. Gene expression studies would allow this distinction at the transcriptomic level. A literature review and a data search in molecular database were carried out on the basis of keywords in Scopus, in PubMed and in GenbankTM for each species. Molecular data regarding E. fetida were already available in databases, but a lack of data regarding oxidative stress related genes was observed for T. repens and B. oleracea. By exploiting the conservation observed between species and using molecular biology techniques, we partially cloned missing candidates involved in oxidative stress and in metal detoxification in E. fetida, T. repens and B. oleracea. PMID- 24951275 TI - Evaluation of humic substances during co-composting of food waste, sawdust and Chinese medicinal herbal residues. AB - Humification during co-composting of food waste, sawdust and Chinese medicinal herbal residues (CMHRs) was investigated to reveal its correlation with compost maturity. Food waste, sawdust and CMHRs were mixed at 5:5:1 and 1:1:1 (dry weight basis) while food waste:sawdust at 1:1 (dry wt. basis) served as control. Lime at 2.25% was added to all the treatments to alleviate low pH, and composted for 56 days. Humic acid/fulvic acid (HA/FA) ratio increased to 0.5, 2.0 and 3.6 in the control and treatment at 5:5:1, and 1:1:1 mixing ratio, respectively at the end of composting. The decrease in aliphatic organics in HA demonstrated the degradation of the readily available organics, while an increase in aromatic functional groups indicated the maturity of compost. Disappearance of hemicellulose and weak intensity of lignin in the CMHRs treatments indicated that the lignin provided the nucleus for HA formation; and the CMHRs accelerated the compost maturity. PMID- 24951276 TI - Enhanced laccase production by Trametes versicolor using corn steep liquor as both nitrogen source and inducer. AB - A highly efficient strategy for laccase production by Trametes versicolor was developed using corn steep liquor (CSL) as both a nitrogen source and a laccase inducer. At the optimal CSL concentration of 20 gL(-1), an extracellular laccase activity of 633.3 UL(-1) was produced after a culture period of only 5 days. This represented a 1.96-fold increase relative to control medium lacking CSL. The addition of crude phenolic extracts from CSL improved laccase production to 91.8% greater than the control. Sinapinic acid, present in CSL, caused a reduction in laccase production, vanillic acid and ferulic acid (also present in CSL) synergistically induced laccase production by more than 100% greater than the control medium. Vanillic acid and ferulic acid provided the main contribution to the enhancement of laccase production. This study provides a basis for understanding the induction mechanism of CSL for laccase production. PMID- 24951277 TI - Outcome of culture-negative pyogenic vertebral osteomyelitis: comparison with microbiologically confirmed pyogenic vertebral osteomyelitis. AB - OBJECTIVES: Although pyogenic vertebral osteomyelitis (PVO) with no identified microorganism is treated empirically, the clinical outcome is not well understood. METHODS: We conducted a retrospective review of patients with PVO at a tertiary-care hospital from 2000 through 2012. The study compared clinical features and outcomes of microbiologically confirmed (M-PVO) with clinically diagnosed PVO (C-PVO). RESULTS: Of 151 patients with PVO, 75 (49.7%) had M-PVO. Compared to patients with M-PVO, patients with C-PVO had fewer underlying medical conditions. In addition, they presented less frequently with fever, high acute phase reactants levels, and paraspinal abscess. The rate of treatment failure tended to be lower in the C-PVO group [9.2% (7/76) vs. 17.3% (13/75); p = 0.157]. The overall relapse rate was 6.6% and did not differ significantly between groups; notably this rate was higher in patients who received antibiotics for <= 6 weeks [18.8% (3/16)] and <= 8 weeks [12.1% (4/33)]. The independent risk factors for treatment failure were higher CRP levels [odds ratio (OR) = 1.087; 95% confidence interval (CI): 1.025-1.153; p = 0.005] and fever >= 37.8 degrees C (OR = 8.556; 95% CI: 2.273-32.207; p = 0.002). CONCLUSIONS: Patients with C-PVO had less systemic inflammatory response and a more favorable outcome compared to M-PVO. Prolonged antibiotic therapy, for at least 8 weeks, might be required for C-PVO, as well as for M-PVO until better outcomes are assured. PMID- 24951278 TI - NS19504: a novel BK channel activator with relaxing effect on bladder smooth muscle spontaneous phasic contractions. AB - Large-conductance Ca(2+)-activated K(+) channels (BK, KCa1.1, MaxiK) are important regulators of urinary bladder function and may be an attractive therapeutic target in bladder disorders. In this study, we established a high throughput fluorometric imaging plate reader-based screening assay for BK channel activators and identified a small-molecule positive modulator, NS19504 (5-[(4 bromophenyl)methyl]-1,3-thiazol-2-amine), which activated the BK channel with an EC50 value of 11.0 +/- 1.4 uM. Hit validation was performed using high-throughput electrophysiology (QPatch), and further characterization was achieved in manual whole-cell and inside-out patch-clamp studies in human embryonic kidney 293 cells expressing hBK channels: NS19504 caused distinct activation from a concentration of 0.3 and 10 uM NS19504 left-shifted the voltage activation curve by 60 mV. Furthermore, whole-cell recording showed that NS19504 activated BK channels in native smooth muscle cells from guinea pig urinary bladder. In guinea pig urinary bladder strips, NS19504 (1 uM) reduced spontaneous phasic contractions, an effect that was significantly inhibited by the specific BK channel blocker iberiotoxin. In contrast, NS19504 (1 uM) only modestly inhibited nerve-evoked contractions and had no effect on contractions induced by a high K(+) concentration consistent with a K(+) channel-mediated action. Collectively, these results show that NS19504 is a positive modulator of BK channels and provide support for the role of BK channels in urinary bladder function. The pharmacologic profile of NS19504 indicates that this compound may have the potential to reduce nonvoiding contractions associated with spontaneous bladder overactivity while having a minimal effect on normal voiding. PMID- 24951279 TI - Astragaloside IV ameliorates renal fibrosis via the inhibition of mitogen activated protein kinases and antiapoptosis in vivo and in vitro. AB - Apoptosis of renal tubular cells plays a crucial role in renal fibrosis. Astragaloside IV (AS-IV), a compound extracted from Radix Astragali, has been shown to inhibit renal tubular cell apoptosis induced by high glucose, but its role in preventing chronic renal fibrosis as well as the underlying molecular mechanisms involved still remain obscure. In this study, human kidney tubular epithelial cells induced by transforming growth factor-beta1 (TGF-beta1) were used to investigate the protective role of AS-IV in antifibrosis. As an in vivo model, mice subjected to unilateral ureteral obstruction (UUO) were administered AS-IV (20 mg/kg) by intraperitoneal injection for 7 days. AS-IV significantly alleviated renal mass loss and reduced the expression of alpha-smooth muscle actin, fibronectin, and collagen IV both in vitro and in vivo, suggesting that this compound functions in the inhibition of renal tubulointerstitial fibrosis. Furthermore, transferase-mediated dUTP nick-end labeling assay results both in vivo and in vitro showed that AS-IV significantly attenuated both UUO and TGF beta1-induced cell apoptosis and prevented renal tubular epithelial cell injury in a dose-dependent manner. Western blotting results also revealed that the antiapoptotic effect of AS-IV was reflected in the inhibition of caspase-3 activation, which might be mediated primarily by the downregulation of mitogen activated protein kinase effectors phospho-p38 and phospho-c-Jun N-terminal kinase. These data infer that AS-IV effectively attenuates the progression of renal fibrosis after UUO injury and may have a promising clinical role as a potential antifibrosis treatment in patients with chronic kidney disease. PMID- 24951280 TI - Molecular evolution of the enzymes involved in the sphingolipid metabolism of Leishmania: selection pressure in relation to functional divergence and conservation. AB - BACKGROUND: Selection pressure governs the relative mutability and the conservedness of a protein across the protein family. Biomolecules (DNA, RNA and proteins) continuously evolve under the effect of evolutionary pressure that arises as a consequence of the host parasite interaction. IPCS (Inositol phosphorylceramide synthase), SPL (Sphingosine-1-P lyase) and SPT (Serine palmitoyl transferase) represent three important enzymes involved in the sphingolipid metabolism of Leishmania. These enzymes are responsible for maintaining the viability and infectivity of the parasite and have been classified as druggable targets in the parasite metabolome. RESULTS: The present work relates to the role of selection pressure deciding functional conservedness and divergence of the drug targets. IPCS and SPL protein families appear to diverge from the SPT family. The three protein families were largely under the influence of purifying selection and were moderately conserved baring two residues in the IPCS protein which were under the influence of positive selection. To further explore the selection pressure at the codon level, codon usage bias indices were calculated to analyze genes for their synonymous codon usage pattern. IPCS gene exhibited slightly lower codon bias as compared to SPL and SPT protein families. CONCLUSION: Evolutionary tracing of the proposed drug targets has been done with a viewpoint that the amino-acids lining the drug binding pocket should have a lower evolvability. Sites under positive selection (HIS20 and CYS30 of IPCS) should be avoided during devising strategies for inhibitor design. PMID- 24951281 TI - Feasibility of a nonoperative management strategy for uncomplicated acute appendicitis in children. AB - BACKGROUND: For decades, urgent operation has been considered the only appropriate management of acute appendicitis in children. The purpose of this study was to investigate the feasibility of nonoperative management of uncomplicated acute appendicitis in children. STUDY DESIGN: A prospective nonrandomized clinical trial of children with uncomplicated acute appendicitis comparing nonoperative management with urgent appendectomy was performed. The primary result was 30-day success rate of nonoperative management. Secondary outcomes included comparisons of disability days, missed school days, hospital length of stay, and measures of quality of life and health care satisfaction. RESULTS: Seventy-seven patients were enrolled during October 2012 to October 2013; 30 chose nonoperative management and 47 chose surgery. There were no significant differences in demographic or clinical characteristics. The immediate and 30-day success rates of nonoperative management were 93% (28 of 30) and 90% (27 of 30). There was no evidence of progression of appendicitis to rupture at the time of surgery in the 3 patients for whom nonoperative management failed. Compared with the surgery group, the nonoperative group had fewer disability days (3 vs 17 days; p < 0.0001), returned to school more quickly (3 vs 5 days; p = 0.008), and exhibited higher quality of life scores in both the child (93 vs 88; p = 0.01) and the parent (96 vs 90; p = 0.03), but incurred a longer length of stay (38 vs 20 hours; p < 0.0001). CONCLUSIONS: Nonoperative management of uncomplicated acute appendicitis in children is feasible, with a high 30-day success rate and short-term benefits that include quicker recovery and improved quality of life scores. Additional follow-up will allow for determination of longer-term success rate, safety, and cost effectiveness. PMID- 24951282 TI - Variations in definition and method of retrieval of complications influence outcomes statistics after pancreatoduodenectomy: comparison of NSQIP with non NSQIP methods. AB - BACKGROUND: NSQIP and the Accordion Severity Grading System have recently been used to develop quantitative methods for measuring the burden of postoperative complications. However, other audit methods such as chart reviews and prospective institutional databases are commonly used to gather postoperative complications. The purpose of this study was to evaluate discordance between different audit methods in pancreatoduodenectomy--a common major surgical procedure. The chief aim was to determine how these different methods could affect quantitative evaluations of postoperative complications. STUDY DESIGN: Three common audit methods were compared with NSQIP in 84 patients who underwent pancreatoduodenectomy. The methods were use of a prospective database, a chart review based on discharge summaries only, and a detailed retrospective chart review. The methods were evaluated for discordance with NSQIP and among themselves. Severity grading was performed using the Modified Accordion System. RESULTS: Fifty-three complications were listed by NSQIP and 31 complications were identified that were not listed by NSQIP. There was poor agreement for NSQIP-type complications between NSQIP and the other audit methods for mild and moderate complications (kappa 0.381 to 0.744), but excellent agreement for severe complications (kappa 0.953 to 1.00). Discordance was usually due to variations in definition of the complications in non-NSQIP methods. There was good agreement among non-NSQIP methods for non-NSQIP complications for moderate and severe complications, but not for mild complications. CONCLUSIONS: There are important differences in perceived surgical outcomes based on the method of complication retrieval. The non-NSQIP methods used in this study could not be substituted for NSQIP in a quantitative analysis unless that analysis was limited to severe complications. PMID- 24951284 TI - Updates in diagnostic immunohistochemistry in endometrial carcinoma. AB - Diagnostic difficulty in the morphologic assessment of endometrial carcinomas may arise in pathology practice. Challenges in tumor classification exist especially in the setting of high-grade carcinomas. These include FIGO grade 3 endometrioid, serous, clear cell, and undifferentiated carcinomas, in addition to carcinomas of mixed cell type and those exhibiting ambiguous morphologic features. This comprehensive review details key morphologic and immunophenotypic features of prototypic endometrial carcinomas, including a description of both well established and novel immunohistochemical markers in the evaluation of these tumors. It also provides recommendations regarding prudent use of these ancillary techniques in distinguishing between various histologic subtypes of endometrial carcinoma that frequently result in persistent diagnostic problems. PMID- 24951283 TI - Role of the clinical pathology laboratory in the evaluation of endometrial carcinomas for Lynch syndrome. AB - Molecular diagnostic testing of endometrial carcinomas in the pathology laboratory has recently emerged as a key component of the clinical evaluation of Lynch syndrome in many centers. Testing modalities involve immunohistochemical and PCR-based analyses. This article outlines the routine application of these analyses, provides a practical guide for troubleshooting some of the common technical issues related to their performance, and reviews common pitfalls in their interpretation. Discrepancies between tissue testing and genetic testing results are discussed in the context of the current understanding of endometrial cancer biology. The merits of universal versus targeted tissue testing based on clinical patient history and histological tumor appearance are also addressed. PMID- 24951285 TI - The ICD-10 system: a gift that keeps on taking. AB - The Protecting Access to Medicare Act of 2014 was signed into law on April Fool's Day. Indeed, 2014 saw unprecedented enthusiasm for the possibility of a permanent solution to the sustainable growth rate formula. Congress failed to come together on methods to pay for that fix. Instead, Congress provided another temporary patch on April 1. As part of that law, International Classification of Diseases 10 (ICD-10) adoption was pushed back by at least 1 year until, at the earliest, October 1, 2015. While many physicians support the delay in ICD-10 implementation, there are those that disagree. PMID- 24951286 TI - Urgent off-label use of the pipeline flow diverter stent in selected ischemic cerebrovascular conditions: thrombotic segments and tortuous arteries. AB - OBJECTIVE: Flow diverter stents were originally designed for the endovascular management of certain types of cerebral aneurysms; however, these devices present characteristics that make them more suitable that regular carotid stents or neurostents for the management of selected ischemic cerebrovascular conditions. METHODS: Eight patients with steno-occlusive disease of the internal carotid (ICA) or vertebral (VA) arteries underwent endovascular reconstruction by means of flow diverter stent implant at our center. Five patients presented with ICA steno-occlusive lesions that involved tortuous segments not amenable to regular carotid stent placement and three patients presented with severe and complex proximal VA dissections. RESULTS: In all cases the procedures were considered technically successful. Flow diverter stent implant allowed recanalization of the treated vessels (stenosis of 89+/-10.5% was improved to 26+/-13%) without procedure related complications. At the 3 month clinical and radiological follow up, patients either improved or remained stable, and showed stent patency. One patient presented with asymptomatic occlusion of the revascularized artery at 13 months, emphasizing the need for prolonged antiplatelet therapy. CONCLUSIONS: This preliminary series of patients with high risk steno-occlusive lesions affecting tortuous arterial segments or presenting with heavy thrombotic load managed by the implant of flow diverter stents shows that this approach is feasible, safe, and effective in achieving arterial recanalization. Further studies will elucidate the role of this technique in ischemic cerebrovascular settings. PMID- 24951287 TI - Technical limitations of dual-energy CT in neuroradiology: 30-month institutional experience and review of literature. AB - BACKGROUND: Dual-energy CT (DECT) has been shown to be a useful modality in neuroradiology. OBJECTIVE: To assess failure modes and limitations of DECT in different neuroimaging applications. PATIENTS AND METHODS: Dual-source DECT scans were performed in 72 patients over 30 months to differentiate contrast agent staining or extravasation from intracranial hemorrhage (ICH) (n=40); to differentiate calcium from ICH (n=2); for metal-artifact reduction (n=5); and for angiographic assessment (n=25). A three-material decomposition algorithm was used to obtain virtual non-contrast (VNC) and iodine (or calcium) overlay images. Images were analyzed in consensus by two board-certified radiologists to determine the success of the algorithm and to assess confounding factors. Furthermore, a dilution experiment using cylinders containing defined heparinized swine blood, normal saline, and selected iodine concentrations was conducted to assess other possible confounding factors. RESULTS: Dual-energy analysis was successful in 65 (90.2%) patients. However, the algorithm failed when images were affected by beam hardening (n=3, 4.2%), the presence of a fourth material (parenchymal calcification) (n=3, 4.2%), or motion (n=1, 1.4%). In the dilution experiment, a saturation effect was seen at high iodine concentrations (>=37 mg/ml). VNC and iodine overlay images were not reliable above this concentration, and beam-hardening artifacts were noted. CONCLUSIONS: DECT material decomposition is usually successful in neuroradiology. However, it can only distinguish up to three preselected materials. A fourth material such as parenchymal calcium may confound the analysis. Artifacts such as beam hardening, metallic streak, or saturation effect can also impair material decomposition. PMID- 24951288 TI - Using nonrandom two-liquid model for solvent system selection in counter-current chromatography. AB - Selection of an appropriate solvent system is of great importance for a successful counter-current chromatography separation. In this work, the nonrandom two-liquid (NRTL) model, a thermodynamic method, was used for predicting the partition coefficient based on a few measured partition coefficients. The NRTL method provides quite satisfactory results for model solutes in first correlating measured partition coefficient in a few representative biphasic liquid systems and then successfully predicting partition coefficient in other two-phase liquid systems. According to the predicted partition coefficient, a suitable solvent system can be screened. Assisted with the NRTL method, the solvent system composed of hexane/ethyl acetate/methanol/water (1:4:1:4, v/v) was rapidly screened for the successful separation of two major compounds with high purity from Malus hupehensis leaves. The results demonstrated that the NRTL model can offer a simple and practical strategy to estimate partition coefficients in support of CCC solvent system selection, which will significantly minimize the experimental efforts and cost involved in solvent system selection. PMID- 24951289 TI - Ribonucleic acid purification. AB - Research on RNA has led to many important biological discoveries and improvement of therapeutic technologies. From basic to applied research, many procedures employ pure and intact RNA molecules; however their isolation and purification are critical steps because of the easy degradability of RNA, which can impair chemical stability and biological functionality. The current techniques to isolate and purify RNA molecules still have several limitations and the requirement for new methods able to improve RNA quality to meet regulatory demands is growing. In fact, as basic research improves the understanding of biological roles of RNAs, the biopharmaceutical industry starts to focus on them as a biotherapeutic tools. Chromatographic bioseparation is a high selective unit operation and is the major option in the purification of biological compounds, requiring high purity degree. In addition, its application in biopharmaceutical manufacturing is well established. This paper discusses the importance and the progress of RNA isolation and purification, considering RNA applicability both in research and clinical fields. In particular and in view of the high specificity, affinity chromatography has been recently applied to RNA purification processes. Accordingly, recent chromatographic investigations based on biorecognition phenomena occurring between RNA and amino acids are focused. Histidine and arginine have been used as amino acid ligands, and their ability to isolate different RNA species demonstrated a multipurpose applicability in molecular biology analysis and RNA therapeutics preparation, highlighting the potential contribution of these methods to overcome the challenges of RNA purification. PMID- 24951290 TI - Pressure-assisted electrokinetic injection stacking for verteporfin drug to achieve highly sensitive enantioseparation and detection in artificial urine by capillary electrophoresis. AB - Pressure-assisted electrokinetic injection (PAEKI) was applied for negatively charged verteporfin (VER) overloading and inline stacking, which targeted highly sensitive enantioseparation by CE. The essential step of PAEKI is a constant pressure used to counterbalance the electroosmotic flow (EOF), consequently, the large amount of analyte could be permitted into capillary and concentrated at the motionless boundary of the sample zone and background electrolyte (BGE). Aiming to know the balance, the velocity of the whole BGE in capillary by the impetus of pressure (0.2-2.0psi), and the velocity of EOF depending on the length of sample plug and voltage (5.0-20kV) was investigated, respectively. The velocity of bulk flow in capillary has good linearity with the pressure or applied voltage. Through the pattern of EOF marked peak and analyte peaks (dissolved in pure water), the constant pressure (0.8psi) vs. the added voltage (-10.3kV) during PAEKI was confirmed to immobilize the bulk flow of BGE, thus the sample injection time could sustain 2.0min without compromising separation efficiency. The obtained LOD (S/N=3) of each isomer at UV detection (428nm) was around 10.3MUg/L, which was improved to 116 and 39-fold in comparison with normal hydrodynamic injection (HDI) and electrokinetic injection (EKI). The LOD is far below the reported value with LIF detection of VER. The RSD (n=5) of migration time and peak area was, respectively, around 3.5% and 5.7% for the proposed PAEKI method. Finally, PAEKI was used for the detection of VER in artificial urine to investigate the matrix interference. PMID- 24951291 TI - Clinical characteristics of severe community-acquired pneumonia among younger patients: an analysis of 18 years at a community hospital. AB - Unlike elderly patients with community-acquired pneumonia whose outcomes are markedly affected by their background characteristics, it appears that the severity of the infection itself contributes to outcomes in younger patients with community-acquired pneumonia. In order to identify clinical characteristics of severe community-acquired pneumonia in younger patients under 60 years old, among such cases prospectively collected at our hospital over a period of 18 years, those meeting the criteria for severe community-acquired pneumonia, as defined in the Infectious Diseases Society of America/American Thoracic Society Guidelines for community-acquired pneumonia, were retrospectively examined and compared to elderly patients with severe community-acquired pneumonia. Younger patients with severe pneumonia accounted for 12.9% of younger hospitalized patients. Although the incidence of severe pneumonia in younger patients was lower than that in elderly patients, its severity may be underestimated by severity assessment based on the conventional guidelines. Thus, attention is required. While Streptococcus pneumoniae and Legionella species were important causative pathogens, atypical pathogens and viruses were also frequently detected. There were only 11 deaths over a period of 18 years. Based on multivariate analysis, the risk factors for aggravation of community-acquired pneumonia among younger patients were age 50 years or older, diabetes mellitus, chronic liver disease, and Legionella pneumonia. Although the mortality rate from community-acquired pneumonia is extremely low in previously healthy younger patients, outcomes might be poor for patients with underlying diseases and those with rapid progression. Multimodal treatments including respiratory management may be appropriate. PMID- 24951292 TI - Clinical effectiveness of gene therapy on critical limb ischemia: a meta-analysis of 5 randomized controlled clinical trials. AB - Therapeutic angiogenesis using gene therapy is a novel strategy for the treatment of critical limb ischemia (CLI). We conducted a meta-analysis to evaluate the efficacy and safety of gene therapy for the treatment of CLI with no option of revascularization. Randomized placebo controlled trials of gene therapy on CLI were identified by searching PubMed (from 1990 to October 2013) and EMBASE (from 1990 to October 2013). Five eligible studies were selected for the meta-analysis. Among these studies, a total of 425 patients received gene therapy of either fibroblast growth factor 1 or hepatocyte growth factor, and 365 patients were given placebo. No statistical differences were observed between the 2 groups in major amputation or death at 1 year (risk ratio [RR], 0.83; 95% confidence interval [CI], 0.51-1.39; P = .48) and wound healing at 6 months (RR, 1.55; 95% CI, 0.73-3.28; P = .25). Gene therapy had similar occurrence of serious adverse events as control (RR, 1.05; 95% CI, 0.97-1.14; P = .23). PMID- 24951293 TI - Open versus endovascular repair of thoracic aortic aneurysms: a Nationwide Inpatient Sample study. AB - PURPOSE: Endovascular repair of descending thoracic aortic aneurysms has become an acceptable surgical option over the past decade. We sought to compare the results of open versus endovascular repair of thoracic aortic aneurysms (TEVAR) in the United States. METHODS: The Nationwide Inpatient Sample (NIS) database was queried to identify all patients undergoing elective repair of a thoracic aortic aneurysm from 1998 to 2007 in the United States. Patient demographic data, preoperative comorbidities, and postoperative complications were recorded. Statistical analyses were performed comparing open versus endovascular repair. Multivariate analyses were conducted controlling for preoperative comorbidities including the presence of diabetes mellitus, cardiac, respiratory, and renal comorbidities as well as patient's age, gender, and ethnicity. The primary end point was mortality. Secondary end points were postoperative neurologic, cardiac, and respiratory complications. RESULTS: There were 8967 patients who met the inclusion criteria. Of these patients, 8255 (92%) had an open repair and 712 (8%) had an endovascular repair. The overall mortality was 4.5% (4.6% for open and 3.6% for endovascular). On multivariate analysis, the odds of death were reduced by 46% among patients undergoing endovascular repair when compared to open repair (odds ratio [OR]: 0.54; P = .016). There was also reduced odds of a postoperative neurologic complication (OR: 0.48; P = .015), cardiac complication (OR: 0.24; P < .001), and respiratory complication (OR: 0.38: P = .001) in the endovascular group. CONCLUSIONS: Nationwide data comparing open and TEVAR in the United States reveal decreased postoperative mortality and a decreased incidence of postoperative neurologic, cardiac, and respiratory complications for TEVAR. PMID- 24951294 TI - Considerations: when more is not necessarily better. PMID- 24951295 TI - [Exceptional association of bilateral popliteal aneurysm with an abdominal aortic aneurysm in Marfan syndrome]. AB - Marfan syndrome is an autosomal dominant disorder with rheumatoid, ophthalmological, neurological, cutaneous and cardiovascular manifestations. Aneurysmal lesions affecting both the abdominal aorta and the peripheral arteries are not often described in the literature. We report a case associating a bilateral popliteal aneurysm and an aneurysm of the infra-renal abdominal aorta. PMID- 24951296 TI - Nitrate supplementation and high-intensity performance in competitive cyclists. AB - Consumption of inorganic nitrate (NO3(-)) is known to enhance endurance exercise performance in recreationally trained subjects. Here we report the effect on a high-intensity performance task in national-level cyclists. The performance test consisted of 2 cycle ergometer time trials of 4 min duration with 75 min between trials. In a randomized crossover design, 26 cyclists performed the test under the following 4 conditions (each separated by a 6-day washout): consumption of 70 mL of nitrate-rich beetroot juice at 150 min or 75 min before the first time trial, addition of a 35 mL "top-up dose" following the first time trial in the 150 min condition, and consumption of a placebo. A linear mixed model with adjustments for learning effects and athlete fitness (peak incremental power) was used to estimate effects on mean power, with probabilistic inferences based on a smallest important effect of 1.0%. Peak plasma nitrite (NO2(-)) concentration was greatest when nitrate was taken 75 min before the first time trial. Relative to placebo, the mean effect of all 3 nitrate treatments was unclear in the first time trial (1.3%, 90% confidence limits: +/-1.7%), but possibly harmful in the second time trial (-0.3%, +/-1.6%). Differences between nitrate treatments were unclear, as was the estimate of any consistent individual response to the treatments. Allowing for sampling uncertainty, the effect of nitrate on performance was less than previous studies. Under the conditions of our experiment, nitrate supplementation may be ineffective in facilitating high intensity exercise in competitive athletes. PMID- 24951297 TI - Systematic review: Carbohydrate supplementation on exercise performance or capacity of varying durations. AB - This systematic review examines the efficacy of carbohydrate (CHO) supplementation on exercise performance of varying durations. Included studies utilized an all-out or endurance-based exercise protocol (no team-based performance studies) and featured randomized interventions and placebo (water only) trial for comparison against exclusively CHO trials (no other ingredients). Of the 61 included published performance studies (n = 679 subjects), 82% showed statistically significant performance benefits (n = 50 studies), with 18% showing no change compared with placebo. There was a significant (p = 0.0036) correlative relationship between increasing total exercise time and the subsequent percent increase in performance with CHO intake versus placebo. While not mutually exclusive, the primary mechanism(s) for performance enhancement likely differs depending on the duration of the exercise. In short duration exercise situations (~1 h), oral receptor exposure to CHO, via either mouthwash or oral consumption (with enough oral contact time), which then stimulates the pleasure and reward centers of the brain, provide a central nervous system-based mechanism for enhanced performance. Thus, the type and (or) amount of CHO and its ability to be absorbed and oxidized appear completely irrelevant to enhancing performance in short duration exercise situations. For longer duration exercise (>2 h), where muscle glycogen stores are stressed, the primary mechanism by which carbohydrate supplementation enhances performance is via high rates of CHO delivery (>90 g/h), resulting in high rates of CHO oxidation. Use of multiple transportable carbohydrates (glucose:fructose) are beneficial in prolonged exercise, although individual recommendations for athletes should be tailored according to each athlete's individual tolerance. PMID- 24951298 TI - Macrophage migration inhibitory factor (MIF) -173 polymorphism is associated with clinical erythema nodosum in Lofgren's syndrome. AB - INTRODUCTION: Macrophage migration inhibitory factor (MIF) has been shown to be a key regulator in innate and adaptive immune responses. A single nucleotide polymorphism in the 5' region of the MIF gene, MIF -173*G/C, is associated with increased MIF protein production, in vivo and in vitro. Associations have been shown between the minor MIF -173C allele and sarcoidosis patients with erythema nodosum (EN). Lofgren's syndrome is an acute and usually self-remitting phenotype of sarcoidosis. It is defined as having an acute onset with bilateral hilar lymphadenopathy (BHL), fever, erythema nodosum (EN) and/or arthritis. The aim of this study was to investigate whether MIF -173G/C associates with the susceptibility to and the clinical manifestations, i.e. arthritis or EN, of Lofgren's syndrome. A total of 171 patients with Lofgren's syndrome and 313 controls were genotyped for a single nucleotide polymorphism at position -173 of the MIF gene (SNP rs755622), using a PCR and a restriction enzyme technique. RESULTS: There were no significant differences found in the MIF -173C allele frequencies between patients with Lofgren's syndrome and controls. In patients with Lofgren's syndrome with only EN, a significantly increased frequency of the C minor allele was observed compared to patients with arthritis only (p=0.0095; OR 3.08, CI: 1.28-7.39). Patients with only EN compared to patients with EN and arthritis showed a significantly increased frequency of the minor C allele (p=0.044; OR 1.97, CI: 1.01-3.85). But patients with only arthritis compared to patients with EN and arthritis did not show a significant difference in C allele frequency (p=0.270; OR 0.64, CI: 0.29-1.42). CONCLUSIONS: The MIF -173C allele is associated with erythema nodosum in Lofgren's syndrome, but not with susceptibility to sarcoidosis. This indicates a role for MIF after antigen presenting to the T cell has taken place and the sarcoid inflammatory response has begun. PMID- 24951299 TI - Esophageal varix predictive performance of lower esophageal Doppler signals during the swallowing process. AB - The objective of this study was to assess whether the swallowing action can improve the display of lower esophageal Doppler signals (LEDS) during transabdominal ultrasound (TUS). Eighty-four patients with cirrhosis underwent both TUS and endoscopic examination for esophageal varices (EVs). LEDS were assessed under the esophageal resting state and during the swallowing process. Univariate analysis indicated that spleen diameter, spleen vein diameter, portal vein diameter, LEDS and left gastric vein hepatofugal flow were significantly associated with the presence of EVs. No LEDS were detected in patients without EVs at rest or during swallowing. Of the 69 patients with EVs, LEDS could be detected in 21 cases (30.4%) in the esophageal resting state and in 58 cases (84.1%) during the swallowing process. Compared with the esophageal resting state, the swallowing action can significantly improve display of LEDS during TUS (p = 0.000), which may be beneficial for TUS detection of EVs. PMID- 24951300 TI - [Experience in the management of immunosuppressant treatment with hepatitis C virus protease inhibitors]. AB - INTRODUCTION: Antiviral drugs for the treatment of hepatitis C virus (HCV) infections have a large number of interactions. The aim of this study was to describe the interactions of telaprevir, boceprevir and sofosbuvir with immunosuppressive drugs in liver transplant recipients. METHODS: A retrospective observational study was performed in liver transplant patients with HCV infection who started treatment with telaprevir, boceprevir or sofosbuvir. Dose, regimens and plasma levels of tacrolimus, cyclosporine and sirolimus before and after antiviral treatment initiation were collected. Average variations in dose, dosing interval and immunosuppressive plasma levels after the start of treatment were calculated. RESULTS: Thirty-five patients were included. In patients treated with telaprevir (n = 18), the cyclosporine dose was reduced by an average of 59.1% (SD = 14.6%), yielding an average reduction of 14.6% (18.8%) in plasma levels. The dose of tacrolimus was reduced by 34.3% (31.7%), increasing the dosing interval by a mean of 73.4 (38.2) hours. After this variation, tacrolimus levels were increased by an average of 59.7% (89.6%). In patients treated with boceprevir (n = 4), tacrolimus started with a reduction of 18.1% (9.8%) of the initial dose and an average increase in the dosing interval of 12.0 (16.9) hours, showing a mean reduction in plasma levels of 37.7% (21.8%). Sofosbuvir therapy (n = 13) showed no significant variations in immunosuppressive drug levels. CONCLUSIONS: The interaction of telaprevir and boceprevir with immunosuppressive drugs requires a substantial dose reduction at the beginning of treatment and close monitoring of plasma levels. PMID- 24951301 TI - [Lead-in in triple therapy for hepatitis C virus. Is it necessary or not?]. PMID- 24951302 TI - [Liver diseases in the elderly]. AB - Liver diseases in the elderly have aroused less interest than diseases of other organs, since the liver plays a limited role in aging. There are no specific liver diseases of old age, but age-related anatomical and functional modifications of the liver cause changes in the frequency and clinical behavior of some liver diseases compared with those in younger patients. This review discusses the most important features of liver function in the healthy elderly population, as well as the features of the most prevalent liver diseases in this age group, especially the diagnostic approach to the most common liver problems in the elderly: asymptomatic elevation of serum transaminases and jaundice. PMID- 24951303 TI - [Acute hepatitis A in a previously vaccinated patient]. PMID- 24951304 TI - [Intestinal myeloid sarcoma: an uncommon presentation of an exceptional disease]. PMID- 24951305 TI - Gut microbiome in sudden infant death syndrome (SIDS) differs from that in healthy comparison babies and offers an explanation for the risk factor of prone position. AB - The role of bacteria in the causation of sudden infant death syndrome (SIDS) is gaining acceptance. Mainstream research favouring respiratory compromise has failed to provide a plausible pathogenetic mechanism despite many years of investigation and thousands of research papers. Bacterial colonisation of the colon of the human infant is influenced by many factors including age, mode of delivery, diet, environment, and antibiotic exposure. The gut microbiome influences development of the immune system. The gut microflora could be important in protection against the bacteria and/or their toxins purportedly involved in SIDS pathogenesis. The aim was to perform a preliminary investigation of the gut microflora in sudden infant death syndrome (SIDS) compared with live comparison babies. The intestinal contents from 52 SIDS, and 102 faecal samples from age-matched live comparison infants were screened by PCR to target 16s RNA genes of Clostridium innocuum, Cl. Perfringens, Cl. difficile, Bacteroides thetaiotaomicron and Staphylococcus aureus. Gut colonisation of the babies with these bacteria was analysed in relation to age, gender and type of feeding; and for SIDS babies sleeping position. Cl. difficile, Cl. innocuum and B. thetaiotaomicron were significantly associated with SIDS with 25%, 46% and 30% of cases PCR positive for these respective bacteria compared with only 6%, 23% and 8.8% respectively in the comparison group. SIDS babies had dual colonisation by both Cl. perfringens and Cl. difficile significantly more often than comparison babies and also with triple colonisation by Cl. perfringens, Cl. difficile and Cl. innocuum. SIDS babies were more often colonised by S. aureus than comparison babies. In addition, SIDS babies found prone were significantly more likely to be colonised by S. aureus than for other positions recorded (OR = infinity; CI = 2.04 - infinity). No significant differences between breast and bottle-fed SIDS babies was observed in regard to each clostridial bacterium, or S. aureus, however Cl. innocuum was found to be significantly associated with formula feeding in the comparison cohort. Comparison of breast and formula feeding of SIDS babies with live comparison babies revealed significant differences with regards to some of the clostridial bacteria. Age-specific differences in gut bacterial microbiome were observed in both SIDS and comparison healthy babies. This study gives an insight into differences in the gut bacterial microbiome of SIDS babies compared with healthy babies. These differences could be important in contributing to a baby's susceptibility to infection and therefore to SIDS. The association of S. aureus colonisation with prone sleep position supports the hypothesis that prone sleep position could increase the risk of ingestion/inhalation of bacteria contaminating the sleeping surface and could account for the increased risk of SIDS in babies who are put to sleep prone. The study provides impetus for broader studies into the gut microbiome of babies and could lead to effective approaches to SIDS prevention. PMID- 24951306 TI - The Staphylococcal Cassette Chromosome mec type V from Staphylococcus aureus ST398 is packaged into bacteriophage capsids. AB - The Staphylococcal Cassette Chromosome mec (SCCmec) confers methicillin resistance to Staphylococcus aureus. While SCCmec is generally regarded as a mobile genetic element, the precise mechanisms by which large SCCmec elements are exchanged between staphylococci have remained enigmatic. In the present studies, we observed that the clinical methicillin-resistant S. aureus (MRSA) isolate UMCG M4 with the sequence type 398 contains four prophages belonging to the serological groups A, B and Fa. Previous studies have shown that certain serological group B bacteriophages of S. aureus are capable of generalized transduction. We therefore assessed the transducing capabilities of the phages from strain UMCG-M4. The results show that some of these phages can indeed transduce plasmid pT181 to the recipient S. aureus strain RN4220. Therefore, we also investigated the possible involvement of these transducing phages in the transmission of the large SCCmec type V (5C2&5) element of S. aureus UMCG-M4. While no transduction of the complete SCCmec element was observed, we were able to demonstrate that purified phage particles did contain large parts of the SCCmec element of the donor strain, including the methicillin resistance gene mecA. This shows that staphylococcal phages can encapsulate the resistance determinant mecA of a large SCCmec type V (5C2&5) element, which may lead to its transfer to other staphylococci. PMID- 24951307 TI - Gene cooption in mycobacteria and search for virulence attributes: comparative proteomic analyses of Mycobacterium tuberculosis, Mycobacterium indicus pranii and other mycobacteria. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a leading infectious disease taking one human life every 15s globally. Mycobacterium undergoes reductive evolution; the ancestors have bigger genome size and rich in metabolic pathways. Mycobacterium indicus pranii (MIP) is placed much above Mycobacterium tuberculosis (M.tb) in evolutionary scale and is a non-pathogenic, saprophytic mycobacterium. Our in silico comparative proteomic analyses of virulence factors of M.tb and their homologs in 12 different Mycobacterial species, including MIP, point toward gene cooption as an important mechanism in evolution of mycobacteria. We propose that adaptive changes in niche factors of non-pathogenic mycobacterium, together with novel gene acquisitions, are key players in the evolution of pathogenicity. Antigenic analyses between M.tb and MIP highlighted the importance of PE/PPE family in host immunomodulation, further supporting the likely potential of MIP as an effective vaccine against TB. PMID- 24951308 TI - Low flucloxacillin concentrations in a patient with central nervous system infection: the need for plasma and cerebrospinal fluid drug monitoring in the ICU. AB - OBJECTIVE: To report the difficulty in achieving and maintaining target antibiotic exposure in critically ill patients with deep-seeded infections. CASE SUMMARY: We present a case of a 36-year-old man who was admitted to the intensive care unit with diffuse central nervous system and peripheral methicillin sensitive Staphylococcus aureus infection (minimum inhibitory concentration; MIC, 1 ug/mL). Owing to the complicated nature of the infection, sequential concentrations of free flucloxacillin were measured in plasma and cerebrospinal fluid (CSF) and used to direct antibiotic dosing. Unsurprisingly, the trough plasma concentrations of flucloxacillin were below the MIC (0.2-0.4 ug/mL), and the corresponding CSF concentrations were undetectable (<0.1 ug/mL) with standard intermittent bolus dosing of 2 g every 4 hours. By administering flucloxacillin by continuous infusion (CI) and increasing the dose to 20 g daily, the plasma (2.2-5.7 ug/mL) and CSF (0.1 ug/mL) levels were increased, albeit lower than the predefined targets (plasma, 40 ug/mL; CSF, 4 ug/mL). DISCUSSION: The presence of physiological changes associated with critical illness-namely, hypoalbuminemia and augmented renal clearance-may significantly alter antibiotic pharmacokinetics, and this phenomenon may lead to suboptimal antibiotic exposure if they are not accounted for. This case also highlights the value of applying CI in such patient groups and demonstrates the significance of monitoring plasma and CSF drug concentrations in optimizing antibiotic delivery. CONCLUSIONS: Future research should aim to evaluate the utility of such drug monitoring with regard to patient outcomes and cost-effectiveness. PMID- 24951309 TI - Reconciling Multiple Hypertension Guidelines to Promote Effective Clinical Practice. AB - The new Joint National Committee 8 (JNC-8) blood pressure guidelines were recently published, and there are some major changes from JNC-7. There are also differences between JNC-8 and hypertension guidelines created by major organizations in North America and around the world published from 2013 to the present. In the face of conflicting evidence, it is difficult for practicing clinicians to reconcile these differences and to incorporate new guidance into their practice. This commentary will identify similarities and differences between guidelines, provide some literature context in the areas of differing recommendations, and then provide advice to enhance patient care. PMID- 24951310 TI - Dapagliflozin for the Treatment of Type 2 Diabetes Mellitus. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trials, and adverse effects of dapagliflozin, a sodium glucose co-transporter 2 (SGLT-2) inhibitor. DATA SOURCES: Data were gathered from articles indexed in PubMed, International Pharmaceutical from (2006 to April 2014) was performed using the following terms "dapagliflozin," "SGLT-2 inhibitor," and "Farxiga." Abstracts and manufacturer's package insert were also used as an additional reference. STUDY SELECTION AND DATA EXTRACTION: All English language prospective randomized, double-blinded trials evaluating the efficacy of dapagliflozin for the treatment of type 2 diabetes were identified. DATA SYNTHESIS: We evaluated 9 clinical trials with dapagliflozin as monotherapy or add-on therapy. Results from these studies demonstrated that dapagliflozin to be noninferior to metformin in treatment naive patients for reduction in A1C. Additionally, dapagliflozin was noninferior to glimepiride when added on to metformin. As an add-on therapy to insulin, insulin sensitizers or sitagliptin, dapagliflozin was found to be clinically effective compared to placebo. Finally, in all of the clinical trials increased risk of urinary infection was common in dapagliflozin group. CONCLUSION: As the second SGLT-2 inhibitor approved in the United States, dapagliflozin is safe and effective for treatment of type 2 diabetes mellitus. It appears to have no increased cardiovascular risk and provides a moderate benefit for patients with high blood pressure or those who are overweight. However, dapagliflozin was found to be associated with nasopharyngitis, mycotic infections, and genital or urinary tract infections. This medication may be best used as adjunctive therapy for patients not well-controlled on other antidiabetic agents. However, caution should be taken when used in patients at risk of urinary tract infections and dehydration. PMID- 24951311 TI - Erratum. AB - Kapitein, B, Biesmans, R CG, van der Sijs, H, et al. Propylene Glycol-Related Delirium After Esmolol Infusion. Ann Pharmacother.2014;48(7): 940-942. (Original Doi:10.1177/1060028014529744). PMID- 24951312 TI - Elevated CO2 decreases the Photorespiratory NH3 production but does not decrease the NH3 compensation point in rice leaves. AB - The exchange of gaseous NH3 between the atmosphere and plants plays a pivotal role in controlling the global NH3 cycle. Photorespiration generates NH3 through oxygenation instead of carboxylation by the CO2-fixing enzyme, ribulose-1,5 bisphosphate carboxylase/oxygenase (RuBisCO). The future increase in the atmospheric CO2 concentration, [CO2], is expected to reduce plant NH3 production by suppressing RuBisCO oxygenation (Vo). We measured the net leaf NH3 uptake rate (FNH3) across NH3 concentrations in the air (na) ranging from 0.2 to 1.6 nmol mol(-1) at three [CO2] values (190, 360 and 750 umol mol(-1)) using rice plants. We analyzed leaf NH3 gas exchange using a custom-made whole-leaf chamber system, and determined the NH3 compensation point (gamma), a measure of potential NH3 emission, as the x-intercept of the linear relationship of FNH3 as a function of na. Our gamma values were lower than those reported for other plant species. gamma did not decrease under elevated [CO2], although leaf NH4 (+) content decreased with decreasing Vo at higher [CO2]. This was also the case for gamma estimated from the pH and NH4 (+) concentration of the leaf apoplast solution (gamma'). gamma' of rice plants, grown at elevated [CO2] for months in a free-air CO2 enrichment facility, was also not decreased by elevated [CO2]. These results suggest that suppression of RuBisCO oxygenation by elevated [CO2] does not decrease potential leaf NH3 emission in rice plants. PMID- 24951314 TI - Zinc-catalyzed synthesis of 2-alkenylfurans via cross-coupling of enynones and diazo compounds. AB - Inexpensive, less-toxic ZnCl2 serves as the catalyst for selective cross-coupling of enynones and diazo compounds, an unprecedented reaction pathway for zinc carbenoids. A cascade sequence comprising formal cyclization/cross-coupling leads to a variety of 2-alkenylfurans. PMID- 24951313 TI - Subcellular targeting of bacterial CusF enhances Cu accumulation and alters root to shoot Cu translocation in arabidopsis. AB - Copper (Cu) is an important environmental pollutant that exerts harmful effects on all living organisms when in excess. In an effort to remove this toxin in situ, a bacterial Cu-binding protein gene CusF was engineered to target CusF for secretion to the cell wall and vacuoles and for accumulation in the cytoplasm. Analysis of transgenic Arabidopsis plants showed that CusF was functionally active and that plants expressing cell wall- (CusFcw transgenic lines) or vacuole targeted CusF (CusFvac transgenic lines) were more resistant to Cu excess than untransformed plants and plants with cytoplasmic CusF (CusFcyto transgenic lines). Under short-term (48 h) exposure to Cu excess, CusFcw transgenic lines showed up to 2-fold increased Cu accumulation in roots compared with the untransformed plants; however, CusFcyto lines and the wild-type plants had similar Cu concentrations in both roots and shoots. Under long-term (40 d) exposure to Cu excess, all transgenic lines accumulated more Cu (up to 3-fold) in roots than the untransformed plants, whereas only CusFcyto lines showed a marked increase (~3-fold of the wild-type plants) of Cu accumulation in shoots. In addition, expression of CusF in the cytosol dramatically enhanced Cu transport from roots to shoots when compared with plants with secretory pathway-targeted CusF. Our results demonstrate the feasibility of Cu tolerance and accumulation by engineering Cu-binding proteins targetable to subcellular compartments and provide new insights into the multifaceted mechanisms of Cu partitioning between roots and shoots. PMID- 24951315 TI - Quantitative analysis of the suppressors of cytokine signaling 1 and 3 in peripheral blood leukocytes of patients with multiple sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disease characterized by a triad of inflammation, demyelination and gliosis. Because the suppressors of cytokine signaling (Socs) regulate the immune response, we quantified SOCS1 and SOCS3 transcription in peripheral blood leukocytes of patients with MS. SOCS1 transcription decreased significantly in MS patients compared with neurologically healthy persons (0.08+/-0.02 vs. 1.02+/-0.23; p=0.0001); while SOCS3 transcription increased in MS patients compared with controls (2.76+/-0.66 vs. 1.03+/-0.27; p=0.0008). Our results showed an imbalance of SOCS1 and SOCS3 transcription in MS patients, and a moderated negative correlation between them (Spearman's r=-0.57; p=0.0003). PMID- 24951316 TI - [Pseudotumoral neurobehcet in a patient treated with anti-tumor necrosis factor alpha]. PMID- 24951317 TI - Serum estrogen receptor beta mediated bioactivity correlates with poor outcome in lung cancer patients. AB - OBJECTIVES: The role of estrogen signaling in lung cancer remains unresolved. We investigate the influence of serum estrogenic compounds and estrogen receptor (ERalpha and ERbeta) mediated bioactivity on lung cancer outcomes. MATERIALS AND METHODS: Serum samples were collected from 222 postmenopausal Chinese patients diagnosed with lung cancer in five Singapore hospitals. Levels of the estrogenic compounds estradiol and estrone were measured using liquid chromatography tandem mass spectrometry. Free estradiol levels were calculated based on sex hormone binding globulin levels. ERalpha- and ERbeta-mediated bioactivity in serum samples were analyzed using reporter gene bioassays in human cells. RESULTS AND CONCLUSION: High ERbeta-mediated bioactivity predicted poorer lung cancer survival (p=0.001) on multivariable Cox regression analysis with adjustment for age, stage of tumor, smoking status, body mass index and histology. In comparison, levels of estrogens and ERalpha-mediated bioactivity were not associated with prognosis. Compared to the lowest tertile of ERbeta-mediated bioactivity, patients in the middle and highest tertiles had HR (95%CI) 1.60 (1.10-2.33) and 1.93 (1.32-2.82) (p for trend=0.001) higher risk of death from lung cancer. Using Kaplan-Meier survival curves, patients with high ERbeta mediated bioactivity correlated with poorer overall survival (p=0.033). ERbeta mediated bioactivity did not differ in terms of age, use of hormone replacement therapy, smoking, stage of tumor or histological subtype. High ERbeta-mediated bioactivity levels in patients' serum were associated with poorer prognosis in lung cancer patients. Our findings suggest that that compound(s) other than endogenous estrogens may be exerting this ERbeta bioactivity and studies to identify these compounds or groups of compounds need to be performed. Furthermore, the measurement of ERbeta activity in sera could potentially serve as a prognostic marker to predict lung cancer survival, and selective blockage of ERbeta signaling may have a role in lung cancer therapy. PMID- 24951318 TI - Serum reactive oxygen species modulator 1 (Romo1) as a potential diagnostic biomarker for non-small cell lung cancer. AB - OBJECTIVES: Reactive oxygen species modulator 1 (Romo1) is a novel protein that localizes in the mitochondrial membrane and induces mitochondrial reactive oxygen species (ROS) generation. Romo1 is increased in most cancer cell lines and is related with resistance to chemotherapy in vitro. However, data on its expression in patients with malignancy is very limited. We evaluated the usefulness of serum Romo1 as a potential diagnostic biomarker in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We initially assessed the expression of Romo1 using Western blotting and enzyme-linked immunosorbent assay in paired lung tissue and serum specimen from NSCLC patients who underwent surgical resection. Then we evaluated and compared serum Romo1 level in a healthy population (n=55), patients with benign lung diseases (n=63) and NSCLC patients (n=58). We explored the correlation between Romo1 expression and clinical parameters and assessed diagnostic performance of serum Romo1 for NSCLC using receiver operating characteristic (ROC) curve analysis. RESULTS: Romo1 expression in lung cancer tissues was significantly increased compared with non-tumorous tissues (p<0.001). Romo1 expression in cancer tissues positively correlated with that in serum (r=0.68, p=0.009). Serum Romo1 level in NSCLC patients significantly increased compared with that of healthy population or patients with benign lung diseases (both p<0.001). ROC curve analysis using an optimal cutoff value of 329.7 pg/mL revealed sensitivity and specificity for the diagnosis of NSCLC of 81.9% and 89.8%, respectively, with an area under the curve of 0.847 (95% confidence interval: 0.789-0.892, p<0.001). Serum Romo1 level was not related with age, gender, smoking status, tumor differentiation, histological type or stage. CONCLUSIONS: Serum Romo1 discriminated NSCLC patients from the population without cancer with considerable sensitivity and specificity. Serum Romo1 could be a potential diagnostic biomarker for NSCLC. PMID- 24951319 TI - Gait and gait-related activities of daily living after total hip arthroplasty: a systematic review. AB - BACKGROUND: Differences in the performance of gait and gait-related activities of daily living are known to persist after total hip arthroplasty compared to healthy controls, but the specific underlying deficits (spatiotemporal, kinematics and kinetics) are not completely understood. This review aimed to map the differences between patients and controls, and between the operated and non operated limbs during various activities of daily living. METHODS: A computerized search with broad search terms was performed in the MEDLINE database. Primary inclusion criteria were: primary osteoarthritis as indication, comparison with healthy controls or comparison between the operated and the non-operated limbs, and follow-up period at least six months after surgery. FINDINGS: The literature search yielded 2177 citations, of which 35 articles were included. Compared to controls, reductions were identified in the operated hip in sagittal range of motion, peak extension, sagittal power generation, abduction moment and external rotation moment. During stair ascent, these reductions did not become more apparent, although deficits in hip kinetics in all three planes were found. Walking speed and step length were reduced compared to controls at longer-term follow-up, but not at short-term follow-up. INTERPRETATION: The hip abduction moment deficit was present both in level walking and in stair ascent in total hip arthroplasty patients compared to controls. Reduced sagittal hip power generation and external rotation moment were also found, of which the clinical relevance remains to be established. Due to a low number of studies, many of the longer term effects of THA on gait and gait-related ADL are not yet accurately known. PMID- 24951320 TI - Biomechanical assessment of composite versus metallic intramedullary nailing system in femoral shaft fractures: A finite element study. AB - BACKGROUND: Intramedullary nails are the primary choice for treating long bone fractures. However, complications following nail surgery including non-union, delayed union, and fracture of the bone or the implant still exist. Reducing nail stiffness while still maintaining sufficient stability seems to be the ideal solution to overcome the abovementioned complications. METHODS: In this study, a new hybrid concept for nails made of carbon fibers/flax/epoxy was developed in order to reduce stress shielding. The mechanical performance of this new implant in terms of fracture stability and load sharing was assessed using a comprehensive non-linear FE model. This model considers several mechanical factors in nine fracture configurations at immediately post-operative, and in the healed bone stages. RESULTS: Post-operative results showed that the hybrid composite nail increases the average normal force at the fracture site by 319.23N (P<0.05), and the mean stress in the vicinity of fracture by 2.11MPa (P<0.05) at 45% gait cycle, while only 0.33mm and 0.39mm (P<0.05) increases in the fracture opening and the fragments' shear movement were observed. The healed bone results revealed that implantation of the titanium nail caused 20.2% reduction in bone stiffness, while the composite nail lowered the stiffness by 11.8% as compared to an intact femur. INTERPRETATION: Our results suggest that the composite nail can provide a preferred mechanical environment for healing, particularly in transverse shaft fractures. This may help bioengineers better understand the biomechanics of fracture healing, and aid in the design of effective implants. PMID- 24951321 TI - Toxoplasmosis as a travel risk. AB - Toxoplasma gondii is a protozoan parasite with worldwide distribution that infects more than one third of the global population. Primary infection in immunocompetent individuals is usually asymptomatic; however, different organs can be affected in immunocompromised individuals leading to the development of encephalitis, myocarditis or pneumonitis. The prevalence of infection with Toxoplasma as well as its genetic structure varies geographically and for that reason travel may be considered as a risk factor to acquire the infection. As toxoplasmosis is a foodborne disease, health care providers should give health education on prevention measures to all prospective travelers in order to decrease the risk of infection in endemic areas. This review presents an overview of the infection with T. gondii with some considerations for travelers to and from endemic zones. PMID- 24951322 TI - Editorial comment on "Effect of tumor size on recurrence-free survival of upper tract urothelial carcinoma following surgical resection". PMID- 24951323 TI - Significance of preoperative butyrylcholinesterase as an independent predictor of survival in patients with muscle-invasive bladder cancer treated with radical cystectomy. AB - OBJECTIVES: Butyrylcholinesterase (BChE) is an alpha-glycoprotein found in the nervous system and liver. Its serum level is reduced in many clinical conditions, such as liver damage, inflammation, injury, infection, malnutrition, and malignant disease. In this study, we analyzed the potential prognostic significance of preoperative BChE levels in patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC). METHODS AND MATERIALS: We retrospectively evaluated 327 patients with MIBC who underwent RC from 1996 to 2013 at a single institution. Serum BChE level was routinely measured before operation in all patients. Covariates included age, gender, preoperative laboratory data (anemia, BChE, lactate dehydrogenase, and C-reactive protein), clinical T (cT) and N stage (cN), tumor grade, and RC with/without neoadjuvant chemotherapy. Univariate and multivariate analyses were performed to identify clinical factors associated with overall survival (OS) and disease-free survival (DFS). Univariate analyses were performed using the Kaplan-Meier and log-rank methods, and the multivariate analysis was performed using a Cox proportional hazard model. RESULTS: The median BChE level was 187 U/l (normal range: 168-470 U/l). The median age of the enrolled patients was 69 years, and the median follow up period was 51 months. The 5-year OS and DFS rates were 69.6% and 69.3%, respectively. The 5-year OS rates were 90.1% and 51.3% in the BChE >= 168 and<168 U/l groups, respectively (P<0.001). The 5-year DFS rates were 83.5% and 55.4% in the BChE >= 168 and <=167 U/l groups, respectively (P<0.001). In the univariate analysis, BChE, cT, cN, and RC with/without neoadjuvant chemotherapy were significantly associated with both OS and DFS. Multivariate analysis revealed that BChE was the factor most significantly associated with OS, and BChE, cT, and cN were significantly associated with DFS. CONCLUSIONS: This study validated preoperative serum BChE levels as an independent prognostic factor for MIBC after RC. PMID- 24951324 TI - Pupil shape in the animal kingdom: from the pseudopupil to the vertical pupil. AB - OBJECTIVE: To study the different pupil shapes adopted by the different animal species. MATERIAL AND METHODS: Review of the related literature, using PubMed database. The initial search strategy was pupil shape (limited to animals). The first volume of System of Ophthalmology (Duke-Elder) and Evolution's witness (I. Schwab) were also reviewed. RESULTS: An optic illusion called pseudopupil is usually observed in the compound eyes of insects. The pupil is circular in most vertebrates, however slit vertical pupils are present in cats and in some snake species. Vertical pupils could have a photoprotective function, as it makes a more complete closure possible in photopic conditions, and helps to camouflage the predator. It has also been hypothesized that it could help to correct chromatic aberration. Ruminants are usually endowed with horizontal pupils. This shape could improve the capacity of the eye to detect vertical silhouettes. Some marine animals have crescent-shaped pupils. In these animals, a superior operculum helps to protect the inferior retina from the great amount of light coming from above. CONCLUSION: There is a surprising variability in pupil shape. Through this variability, nature has fitted the eye to different circumstances. The theories proposed to explain this high variability are discussed in detail in the article. PMID- 24951325 TI - [Ophthalmic care in the World War I, 100 years after]. PMID- 24951326 TI - Comparison of stromal corneal nerves between normal and keratoconus patients using confocal microscopy. AB - OBJECTIVE: To evaluate the differences in stromal corneal nerves between normal patients and keratoconus patients. MATERIAL AND METHODS: A total of 140 eyes of 70 normal patients (group A) and 122 eyes of 87 keratoconus patients (group B) were examined with the confocal microscope, with a central scan of the total corneal thickness being taken. The morphology and thickness of the corneal stromal nerves were evaluated by using the Navis v. 3.5.0. software. Nerve thickness was obtained from the mean between the widest and the narrowest portions of each stromal nerve. RESULTS: Corneal stromal nerves were observed as irregular linear hyper-reflective structures with wide and narrow portions in all cases. Mean corneal stromal nerves thickness in group A was 5.7+/-1.7 (range from 3.3 to 10.4 MU), mean corneal stromal nerves thickness in group B was 7.2+/-1.9 (range from 3.5 to 12.0 MU). There was a statistical significant difference (P<.05) in stromal corneal nerves thickness between group A and group B. CONCLUSION: Stromal corneal nerves morphology was similar in both groups, but stromal nerves were thicker in keratoconus patients. PMID- 24951327 TI - [Halos and multifocal intraocular lenses: origin and interpretation]. AB - OBJECTIVE: To present the theoretical and experimental characterization of the halo in multifocal intraocular lenses (MIOL). METHOD: The origin of the halo in a MIOL is the overlaying of 2 or more images. Using geometrical optics, it can be demonstrated that the diameter of each halo depends on the addition of the lens (DeltaP), the base power (P(d)), and the diameter of the IOL that contributes to the "non-focused" focus. In the image plane that corresponds to the distance focus, the halo diameter (deltaH(d)) is given by: deltaH(d)=d(pn) DeltaP/P(d), where d(pn) is the diameter of the IOL that contributes to the near focus. Analogously, in the near image plane the halo diameter (deltaH(n)) is: deltaH(n)=d(pd) DeltaP/P(d), where d(pd) is the diameter of the IOL that contributes to the distance focus. Patients perceive halos when they see bright objects over a relatively dark background. In vitro, the halo can be characterized by analyzing the intensity profile of the image of a pinhole that is focused by each of the foci of a MIOL. RESULTS AND CONCLUSIONS: A comparison has been made between the halos induced by different MIOL of the same base power (20D) in an optical bench. As predicted by theory, the larger the addition of the MIOL, the larger the halo diameter. For large pupils and with MIOL with similar aspheric designs and addition (SN6AD3 vs ZMA00), the apodized MIOL has a smaller halo diameter than a non-apodized one in distance vision, while in near vision the size is very similar, but the relative intensity is higher in the apodized MIOL. When comparing lenses with the same diffractive design, but with different spherical-aspheric base design (SN60D3 vs SN6AD3), the halo in distance vision of the spherical MIOL is larger, while in near vision the spherical IOL induces a smaller halo, but with higher intensity due to the spherical aberration of the distance focus in the near image. In the case of a trifocal-diffractive IOL (AT LISA 839MP) the most noticeable characteristic is the double-halo formation due to the 2 non-focused powers. PMID- 24951328 TI - Effects of conventional anticonvulsant drugs on generalized tonic-clonic seizures in Noda epileptic rats. AB - Noda epileptic rats (NERs) present with clinico-pathological manifestations reminiscent of human generalized tonic-clonic epilepsy. Thus, this strain of rat has been a model of primary, generalized, tonic-clonic epilepsy. However, the infrequency of seizures in these rats makes the assessment of antiepileptic drugs (AEDs) difficult. Therefore, traditional AEDs have only been tested in NERs against audiogenic seizures evoked by weekly acoustic priming from 3 to 22 weeks of age or by using the kindling procedure in adult animals. Adult NERs are susceptible to changes in their environment, such as bedding replacement or unpleasant sensory stimuli. In the present study, traditional AEDs-phenobarbital (PB) and sodium valproate (VPA)-were evaluated against seizures evoked by strong environmental stimuli in mature NERs that had not been previously primed. The number of animals presenting with seizures decreased in a dose-dependent manner following administration of either PB (dose range 1.0-5.0mg/kg) or VPA (50 and 100mg/kg). Consequently, the utility of NERs as a model of generalized tonic clonic epilepsy was confirmed. This type of protocol can be used to further evaluate AEDs and test effects of chronic administration of AEDs. PMID- 24951329 TI - Development of a novel, multifunctional, membrane-interactive pyridinium salt with potent anticancer activity. AB - The synthesis and biological evaluation of a novel pyridinium salt is reported. Initial membrane interaction with isolated phospholipid monolayers was obtained with the pyridinium salt, and two neutral analogues for comparison, and the anticancer effects of the best compound established using a cytotoxicity screening assay against glioma cells using both an established cell line and three short-term cell cultures-one of which has been largely resistant to all chemotherapeutic drugs tested to date. The results indicate that the pyridinium salt exhibits potent anticancer activity (EC50s=9.8-312.5 MUM) on all cell types, including the resistant one, for a continuous treatment of 72 h. Microscopic examination of the treated cells using a trypan blue exclusion assay showed membrane lysis had occurred. Therefore, this letter highlights the potential for a new class of pyridinium salt to be developed as a much needed alternative treatment for glioma chemotherapy. PMID- 24951330 TI - Orally bioavailable factor Xa inhibitors containing alpha-substituted gem dimethyl P4 moieties. AB - In an effort to identify a potential back-up to apixaban (Eliquis(r)), we explored a series of diversified P4 moieties. Several analogs with substituted gem-dimethyl moieties replacing the terminal lactam of apixaban were identified which demonstrated potent FXa binding affinity (FXa Ki), good human plasma anticoagulant activity (PT EC2x), cell permeability, and oral bioavailability. PMID- 24951332 TI - Conformational analysis of an anti-androgenic, (E,E)-8-hydroxygermacrene B, using NOESY and dynamic NMR spectroscopy. AB - (E,E)-8-Hydroxygermacrene B was prepared by ketone reduction of germacrone, a naturally occurring compound from Curcuma aeruginosa Roxb. with NaBH4 at low temperature (4 degrees C). This compound showed remarkable in vitro anti androgenic activity (IC50 0.15+/-0.022 mM) applicable to male baldness treatments. NMR analysis at -50 degrees C indicated that there were four conformational isomers of (E,E)-8-hydroxygermacrene B in a ratio of 48:40:8:4. The major conformers were assigned by (1)H NMR and 2D-NOESY NMR spectroscopy as having methyl groups at C-10 and C-4 in up-down (UD) orientations (48% predominance) and UU (40%). (1)H NMR spectra implied another two minor conformers with these methyls having DU (8%) and DD (4%) orientations. PMID- 24951331 TI - Syntheses, neural protective activities, and inhibition of glycogen synthase kinase-3beta of substituted quinolines. AB - A new series of fifteen 5-, 6-, and 8-appended 4-methylquinolines were synthesized and evaluated for their neural protective activities. Selected compounds were further examined for their inhibition of glycogen synthase kinase 3beta (GSK-3beta) and protein kinase C (PKC). Two most potent analogs, compounds 3 and 10, show nanomolar protective activities in amyloid beta-induced MC65 cells and enzymatic inhibitory activities against GSK-3beta, but poor PKC inhibitory activities. Using normal mouse model, the distribution of the most potent analog 3 in various tissues and possible toxic effects in the locomotors and inhibition of liver transaminases activities were carried out. No apparent decline of locomotor activity and no inhibition of liver transaminases were found. The compound appears to be safe for long-term use in Alzheimer's disease mouse model. PMID- 24951333 TI - One pot three components microwave assisted and conventional synthesis of new 3 (4-chloro-2-hydroxyphenyl)-2-(substituted) thiazolidin-4-one as antimicrobial agents. AB - A one-pot, three-component, microwave assisted and conventional synthesis of new 3-(4-chloro-2-hydroxyphenyl)-2-(substituted) thiazolidin-4-one (4a-n) was carried out by using N,N-dimethylformamide as a solvent with high product yield. Among these synthesized compounds (4f, 4g, 4l and 4m) were found to be a broad spectrum molecule active against all bacterial and fungus strains tested, except fungus Aspergillus niger. Amongst the compounds (4g, 4l and 4m) were found to be more potent than respective standard drugs used in the experiment against Candida albicans, Staphylococcus aureus and Aspergillus flavus, respectively. All synthesized compounds were also tested for their cytotoxic activity against HeLa and MCF-7 cell lines by the sulforhodamine B (SRB) assay. This study shows that all compounds were non-cytotoxic in nature, and confirmed their antimicrobial specificity apart from any general cytotoxicity. PMID- 24951334 TI - Design, synthesis and evaluation of highly selective pyridone-based class II MET inhibitors. AB - The high incidence of MET oncogene activation in human malignancies has prompted researchers to develop MET inhibitors. As part of our efforts to developing effective and safe therapeutic agents against MET-dependent tumors, a pyridone based class II MET inhibitor, namely, 1-(4-((2-amino-3-iodopyridin-4-yl)-oxy)-3 fluorophenyl)-N-(4-fluorobenzyl)-4-methoxy-6-oxo-1,6-dihydropyridine-3 carboxamide (3s), was identified. Knowledge of the binding mode of class II MET inhibitors led to the design of new inhibitors that utilize 2-pyridone to conformationally restrain key pharmacophoric groups within the molecule. Integrated molecular docking and SAR studies resulted in the discovery of a novel class of pyridone MET inhibitors with high potency (IC50 of 0.005 MUM) and efficient selectivity (>5000 fold) to VEGFR-2, c-Kit and RET kinases. PMID- 24951335 TI - The role of radiotherapy and chemoradiation in the management of primary liver tumours. AB - Due to advances in technical radiotherapy delivery over the past two decades there has been a rapid increase in the use of radiotherapy for intrahepatic malignancies. This overview provides a succinct summary of the current evidence for external beam radiotherapy in the management of primary liver tumours, highlighting areas for future research. Internationally, hepatocellular carcinoma is a leading cause of cancer death and UK incidence rates are rising rapidly. The main risk factor is chronic liver disease and, as a result, most patients will be unsuitable for curative surgical modalities of treatment. Conformal radiotherapy may be used in patients with localised disease who are unsuitable for alternative local therapies. It may also be used in patients with portal venous thrombosis or for palliation in advanced disease. Caution should be used in patients with pre existent liver dysfunction (Childs Pugh B or C) due to increased rates of toxicity. Stereotactic body radiotherapy has been used for early stage disease, with promising long-term local control rates and a favourable toxicity profile. Stereotactic body radiotherapy has also been investigated as a 'bridge to transplant'. Charged particle therapy may be used for patients with more advanced liver dysfunction, or as a means of dose escalation, and warrants further investigation in early stage disease. Cholangiocarcinoma is a rare but aggressive primary liver malignancy in which only a minority of patients will be suitable for resection. Conformal radiotherapy and stereotactic body radiotherapy have been used in both the adjuvant and locally advanced settings, although small patient numbers and a lack of prospective trial data limit interpretation of their role. To fully define the role of radiotherapy in the management pathway for primary liver tumours, prospective randomised studies are required. PMID- 24951337 TI - Pulmonary embolism in elderly patients: prognostic impact of the Cumulative Illness Rating Scale (CIRS) on short-term mortality. AB - BACKGROUND: Pulmonary embolism (PE) is associated with high short-term mortality in elderly patients, even when hemodynamically stable. METHODS: One hundred and seventy hemodynamically stable patients with confirmed PE (41<65years and 129>=65years) were prospectively followed for one month in order to assess whether comorbidities can predict short-term mortality in elderly patients. Upon admission, patients' clinical characteristics (including instrumental and laboratory parameters) were evaluated, and two clinical scores were calculated: the Cumulative Illness Rating Scale (CIRS), commonly used to evaluate comorbidities in elderly patients, and the Pulmonary Embolism Severity Index (PESI). RESULTS: Fifteen patients (all elderly) died within one month from their PE diagnosis (mortality rate=8.8%; 95%CI:4.6-13.1%). In these non survivors, arterial partial oxygen pressure (p<0.0001) and saturation (p<0.0001), pH (p=0.001) and systolic blood pressure (p=0.017) at admission were significantly lower than in survivors, whereas their respiratory rate (p<0.0001), white blood cells (p<0.0001), lactate dehydrogenase (p<0.0001), troponin T (p=0.001) and D dimer (p=0.023) were significantly higher. CIRS correlated with PESI (rho=0.54, p<0.0001), and was higher in non-survivors (p=0.002). The age- and sex-adjusted odds ratio of 1-month mortality was 1.91 (95%CI:1.24-2.95) for every 1-point increase in CIRS. The AUC was 0.78 (95%CI:0.67-0.89) for the logistic model containing CIRS, and 0.88 (95%CI:0.79-0.96) for that containing PESI (p=0.059). CONCLUSIONS: In elderly patients with PE, CIRS demonstrated a fairly good performance in predicting short-term mortality. Its easiness and suitability for use in common clinical practice make CIRS a potentially useful prognostic score for short-term mortality in these patients. PMID- 24951336 TI - Evaluation of the GEM(r)PCL Plus point-of-care device for neonatal coagulation assessment: an observational study on cord blood. AB - INTRODUCTION: Point of care devices (POCT) are used for coagulation evaluation in adults. Reduced blood volumes and the direct use of whole blood allow studies when venous puncture is difficult, such as in newborns. Elimination of sample transport is attractive for use in emergencies and intensive care. OBJECTIVE: To prospectively compare neonatal coagulation parameters measured by the GEM(r)PCL POCT versus a central laboratory. MATERIALS AND METHODS: Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT) were performed on whole cord blood (POCT) and plasma (central laboratory) collected from consecutive newborns at Geneva University Hospitals. Agreement was assessed with a Bland & Altman plot and intra-class correlation coefficient (ICC) in 213 newborns cord blood; intra assay variability (repeatability) was assessed using ICC and coefficient of variation (CV). RESULTS: 189 samples were available for the agreement analysis, 24 were excluded for technical problems. The 95% limits of agreements in the Bland & Altman plot ranged from -5.6 to 11.6 and from -39.6 to 11.6seconds for the PT and aPTT, respectively. The ICC between the two methods was 0.28 (CI 95% 0.06 to 0.47) for PT and 0.20 (CI 95% -0.06 to 0.42) for aPTT. Repeatability (ICC) on the 43 eligible samples was 0.46 (CI 95% 0.19 to 0.67) for PT and 0.52 (CI 95% 0.26 to 0.71) for aPTT. The CV was 10.6% and 12% for PT and aPTT, respectively. CONCLUSIONS: In newborn cord blood, PT and aPTT measurements with the GEM(r)PCL POCT had poor agreement with the central laboratory and poor repeatability. PMID- 24951338 TI - Cilostazol and outcome in outpatients with peripheral artery disease. AB - BACKGROUND: Cilostazol increases the walking distance in patients with intermittent claudication, but there is scarce evidence of any effect on the risk for subsequent ischemic events, bleeding or death. PATIENTS AND METHODS: We used data from the FRENA Registry to compare the clinical outcome in stable outpatients with intermittent claudication, according to the use of cilostazol. RESULTS: As of January 2013, 1,317 patients with intermittent claudication were recruited in FRENA, of whom 191 (14.5%) received cilostazol. Over a mean follow up of 18months, 39 patients developed myocardial infarction, 23 ischemic stroke, 20 underwent limb amputation, 15 had major bleeding and 70 died. There were no significant differences in the rate of subsequent ischemic events, major bleeding or death between patients receiving or not receiving cilostazol. On multivariate analysis, the use of cilostazol had no influence on the risk for subsequent myocardial infarction (hazard ratio [HR]: 0.97; 95% CI: 0.33-20.8), ischemic stroke (HR: 1.46; 95% CI: 0.48-4.43), limb amputation (HR: 0.34; 95% CI: 0.04 20.6), major bleeding (HR: 1.52; 95% CI: 0.33-7.09) or death (HR: 0.90; 95% CI: 0.40-20.0). CONCLUSIONS: In stable outpatients with intermittent claudication, the use of cilostazol was not associated with increased rates of subsequent ischemic events, major bleeding or death. PMID- 24951339 TI - Nutritional concepts for the veterinary practitioner. AB - Although veterinary practitioners know that nutrition can make a difference in the health and recovery from disease or illness in dogs and cats, they may feel poorly equipped to provide unbiased information on nutrition. This article provides information about evaluating and recommending diets and interpreting a pet food label to allow for comparisons among pet foods and discussion about how to do a nutritional assessment. It provides an example of how nutritional assessment and recommendation were successfully introduced into a busy private practice. Finally, some of the myths and misperceptions about nutrition are discussed with information provided from evidence-based research. PMID- 24951340 TI - Handling alternative dietary requests from pet owners. AB - The goal of this article was to provide veterinary practitioners with an overview of the types of alternative dietary options available to pet owners and a practical method by which to evaluate the nutritional adequacy of these various options. Our approach to categorizing the alternative dietary options is based on the nutritional adequacy of these dietary options, because patients will be at risk for nutrition-related diseases if fed a nutritionally incomplete or improperly balanced diet long term. PMID- 24951341 TI - Myths and misperceptions about ingredients used in commercial pet foods. AB - Information and misinformation about pet nutrition and pet foods, including ingredients used in pet foods, is widely available through various sources. Often, this "information" raises questions or concerns among pet owners. Many pet owners will turn to their veterinarian for answers to these questions. One of the challenges that veterinarians have is keeping up with the volume of misinformation about pet foods and sorting out fact from fiction. The goal of this article is to provide facts regarding some common myths about ingredients used in commercial pet foods so as to better prepare veterinarians to address their client's questions. PMID- 24951342 TI - Macronutrients in feline health. AB - Dietary macronutrients include protein, fat, and carbohydrates. Current nutritional recommendations establish minimums but not maximums for protein and fat but not for carbohydrates; thus, commercial feline maintenance diets have a wide range of macronutrient distribution depending on manufacturer, ingredients, and processing. There is growing interest and discussion, however, in defining the ideal macronutrient composition of feline diets to maximize longevity and health. Current recommendations should be tailored to each patient based on age, body condition, presence of muscle mass atrophy, and the presence of disease. PMID- 24951343 TI - Nutrition for working and service dogs. AB - Conformation, genetics, and behavioral drive are the major determinants of success in canine athletes, although controllable variables, such as training and nutrition, play an important role. The scope and breadth of canine athletic events has expanded dramatically in the past 30 years, but with limited research on performance nutrition. There are considerable data examining nutritional physiology in endurance dogs and in sprinting dogs; however, nutritional studies for agility, field trial, and detection are rare. This article highlights basic nutritional physiology and interventions for exercise, and reviews newer investigations regarding aging working and service dogs, and canine detection activities. PMID- 24951344 TI - Nutrition of aging dogs. AB - Aging is a normal process characterized by a variety of physiologic changes. Geriatric dogs are also more likely to be afflicted with certain disease conditions. Both normal and abnormal physiologic changes associated with aging in the dog may be amenable to nutritional intervention. Specific alterations in nutrients or in dietary characteristics can be beneficial; however, these are best done in the context of an individualized nutritional assessment and monitoring paradigm. PMID- 24951345 TI - Nutrition of aging cats. AB - At least one-third of cats seen by veterinarians are mature, defined as 7 years of age or older, and approximately 13% of cats are geriatric, defined as 12 years of age or older. The article reviews physiologic differences between these life stages and relates the changes to nutritional needs. Geriatric cats have increased requirements for dietary energy and protein. Feeding management addresses what, when, how, and where food is provided. This article provides an update on diet-sensitive conditions, including cognitive dysfunction, diabetes mellitus, chronic kidney disease, osteoarthritis, and hyperthyroidism. Although guidelines are provided, patients must be evaluated and fed according to their individual needs. PMID- 24951346 TI - Dietary management of feline endocrine disease. AB - When treating cats with endocrine disease, most veterinarians concentrate on medical or surgical treatments that can be used to manage or cure the disease. Dietary issues are frequently ignored or not properly addressed. However, nutritional support can play an integral role in the successful management of feline endocrine diseases. Furthermore, because most cats with endocrine disease are senior or geriatric, they may also have concurrent health conditions that warrant dietary intervention. This article discusses recommendations for nutritional support of the 2 most common endocrine problems of cats seen in clinical practice: hyperthyroidism and diabetes mellitus. PMID- 24951347 TI - Pet obesity management: beyond nutrition. AB - Excess weight has been associated with many clinical and subclinical conditions that put a pet's health at risk. Successful weight management programs extend beyond standard nutritional management and incorporate an understanding of human animal interaction. Understanding the processes and dynamics of human-animal relationships can be a useful tool for practitioners in developing successful treatment plans for their clients. Obesity is a nutritional disorder requiring lifelong management; however, when veterinarians go beyond standard treatment to include an understanding of human-animal interaction, it is also one of the few conditions in veterinary medicine that is completely preventable and curable. PMID- 24951348 TI - Clinical nutrition. PMID- 24951349 TI - Imaging criteria for assessing tumour response: RECIST, mRECIST, Cheson. AB - Most methods define a limited number of "target" lesions to be measured and other "non-target" lesions to be evaluated qualitatively. RECIST criteria are the most widely used although other criteria have been proposed that are derived from them based on size alone, or size and attenuation. Modified RECIST (mRECIST) criteria only concern hepatocellular carcinoma and only take into account the viable portion (enhanced after injection during the arterial phase). Cheson criteria are more complex as target lesions are defined differently depending on the organ (lymph nodes, liver or spleen, other organs), and involve both CT and PET scans, as well as the clinical examination and bone marrow biopsy. PMID- 24951352 TI - Of particular interest on anterior cruciate ligament and hip arthroscopy. PMID- 24951353 TI - Response to the letter entitled "the rotator cuff repair mess" by Dr. Palomo. PMID- 24951354 TI - Authors' reply. PMID- 24951355 TI - Thromboprophylaxis in arthroscopic surgery. PMID- 24951356 TI - Hamstring autograft size can be predicted and is a potential risk factor for anterior cruciate ligament reconstruction failure. AB - PURPOSE: The purposes of this systematic review were (1) to determine whether there is a minimum hamstring autograft size for anterior cruciate ligament (ACL) reconstruction that significantly decreases the risk of failure and (2) to evaluate the methods to accurately and reliably predict the size of hamstring grafts. METHODS: We performed a systematic review of Level III and IV studies using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analyses) guidelines. All studies assessing failure of quadrupled-strand autograft hamstring ACL reconstruction as a function of graft diameter with at least 1 year of follow-up and those that assessed the use of imaging or anthropometric patient-specific factors to predict hamstring autograft size were included. RESULTS: We identified 4 clinical studies that directly compared graft size and failure rate. These correlated with a 6.8 times greater relative risk of failure if the graft diameter was equal to or less than 8 mm (P = .008). All 9 anthropometric-based prediction studies were able to significantly correlate at least 1 parameter with intraoperative graft size. Height was the most common correlation, with r = 0.45 (P < .00001). Five of 6 imaging-based prediction studies showed signification correlation, with r = 0.66 (P < .00001), between cross-sectional area and graft size. The most common method of imaging prediction was magnetic resonance imaging-derived cross-sectional area of both the semitendinosus and gracilis tendons. CONCLUSIONS: On the basis of the available evidence, ACL reconstruction with a quadrupled-strand hamstring autograft with a diameter equal to or larger than 8 mm decreases failure rates. In addition, grafts larger than 8 mm decrease failure rates in patients aged younger than 20 years, a group identified to be at increased risk of failure. Both patient height and magnetic resonance imaging-derived cross-sectional area of the hamstring tendons can be used preoperatively to reliably predict the hamstring autograft diameter. LEVEL OF EVIDENCE: Level IV, systematic review of Level III and IV studies. PMID- 24951358 TI - Death and bereavement in the First World War: the Australian experience. AB - The First World War was a turning point in the cultural history of death and bereavement in Australia. The mass deaths of some 60,000 soldiers overseas led to communal rituals of mourning for the war dead and minimal public expressions of private grief. The mass slaughter of so many young men and the interminable grief of so many families devalued the deaths of civilians at home and helped to create a new cultural model of suppressed and privatised grieving which deeply constrained the next two generations. Emotional and expressive grieving became less common, mourning ritual was minimised and sorrow became a private matter. PMID- 24951357 TI - Effects of oxytocin on high intensity focused ultrasound (HIFU) ablation of adenomysis: a prospective study. AB - OBJECTIVE: To investigate the effects of oxytocin on high-intensity focused ultrasound (HIFU) ablation for the treatment of adenomyosis. MATERIALS AND METHODS: Eighty-six patients with adenomyosis from three hospitals were randomly assigned to the oxytocin group or control group for HIFU treatment. During HIFU treatment, 80 units of oxytocin was added in 500ml of 0.9% normal saline running at the rate of 2ml/min (0.32U/min) in the oxytocin group, while 0.9% normal saline was used in the control group. Both patients and HIFU operators were blinded to oxytocin or saline application. Treatment results, adverse effects were compared. RESULTS: When using oxytocin, the non-perfused volume (NPV) ratio was 80.7+/-11.6%, the energy-efficiency factor (EEF) was 8.1+/-9.9J/mm(3), and the sonication time required to ablate 1cm(3) was 30.0+/-36.0s/cm(3). When not using oxytocin, the non-perfused volume ratio was 70.8+/-16.7%, the EEF was 15.8+/-19.6J/mm(3), and the sonication time required to ablate 1cm(3) was 58.2+/ 72.7S/cm(3). Significant difference in the NPV ratio, EEF, and the sonication time required to ablate 1cm(3) between the two groups was observed. No oxytocin related adverse effects occurred. CONCLUSION: Oxytocin could significantly decrease the energy for ablating adenomyosis with HIFU, safely enhance the treatment efficiency. PMID- 24951359 TI - Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa induced dyskinesias. AB - BACKGROUND: Modulation of metabotropic glutamate receptors may be a novel therapeutic approach to manage L-Dopa-induced dyskinesias in patients with Parkinson's disease. This article reviews the rationale for use of metabotropic glutamate 5-receptor antagonists in experimental and clinical L-Dopa-induced dyskinesias. METHODS: Systematic literature searches were performed (between May 2012-March 2014) for relevant English language articles using PubMed. Additional articles of interest were identified from reference lists of included publications. Relevant clinical abstracts from Movement Disorder Society meetings were included. RESULTS: 16 preclinical studies of metabotropic glutamate 5 receptor antagonists in animal models of L-Dopa-induced dyskinesias and 7 clinical studies in patients with Parkinson's disease and L-Dopa-induced dyskinesias were included. Anti-dyskinetic effects of metabotropic glutamate 5 receptor blockade (MPEP, MTEP, fenobam, or MRZ-8676) were reported in dyskinetic 6-hydroxydopamine-lesioned rats. Studies in MPTP-lesioned non-human primates reported anti-dyskinetic effects of MPEP, MTEP, fenobam and mavoglurant (AFQ056). Three randomized, double-blind clinical trials reported anti-dyskinetic efficacy of mavoglurant, without effects on anti-parkinsonian therapy, with dizziness the most common adverse event. However, two further studies failed to demonstrate significant anti-dyskinetic efficacy. A randomized, double-blind, placebo controlled safety study of dipraglurant (ADX48621) demonstrated tolerability and positive exploratory secondary outcomes of reduced dyskinesia. CONCLUSIONS: Animal model studies provide evidence for anti-dyskinetic efficacy of metabotropic glutamate 5-receptor antagonists. Initial proof-of-concept clinical trials of mavoglurant and dipraglurant showed positive results; anti-dyskinetic efficacy was not supported by two recent mavoglurant trials. Further evaluations of optimal dosage and long-term efficacy and safety of metabotropic glutamate 5 receptor antagonists for management of L-Dopa-induced dyskinesias in Parkinson's disease are required. PMID- 24951360 TI - Re: Giorgio Gandaglia, Alberto Briganti, Graham Jackson, et Al. A systematic review of the association between erectile dysfunction and cardiovascular disease. Eur urol 2014;65:968-78. PMID- 24951361 TI - Positive surgical margins: race or surgeon? PMID- 24951362 TI - Reply to Christopher Chee Kong Ho, Siew Eng Ho, Srijit Das' letter to the editor re: Giorgio Gandaglia, Alberto Briganti, Graham Jackson, et al. A systematic review of the association between erectile dysfunction and cardiovascular disease. Eur Urol 2014;65:968-78. PMID- 24951363 TI - Toward a better follow-up of ovarian recovery in young women after chemotherapy with a hypersensitive antimullerian hormone assay. AB - OBJECTIVE: To evaluate the utility of a hypersensitive assay for measuring low antimullerian hormone (AMH) levels in young cancer patients during the ovarian recovery phase of their chemotherapy. DESIGN: Retrospective study. SETTING: Academic medical center. PATIENT(S): Fifty-eight samples drawn at least 3 months after the end of chemotherapy in 30 women having either breast cancer (n=13) or hematologic malignancies (n=17) were selected to constitute two equally size groups: amenorrhea (n=30 samples) or spontaneous cycle (n=28 samples). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum AMH levels were measured by a conventional AMH ELISA (EIA AMH/MIS) and a hypersensitive ELISA (PicoAMH, AnshLabs) on the same sample. RESULT(S): Using a conventional assay, serum AMH was detectable (>=3 pmol/L) in 6.7% and in 10.7% of the samples corresponding to amenorrheic or cycling patients, respectively (nonsignificant). By contrast, with PicoAMH, serum AMH was detectable (>=0.07 pmol/L) in 71.4% of the samples from cycling women vs. 16.7% of the samples from amenorrheic patients. Multivariate regression analysis showed that among putative contributors, only the menstrual status (r=0.307) and serum FSH level (r=-0.546) were independently correlated to a detectable serum AMH with the picoAMH assay exclusively. CONCLUSION(S): The picoAMH assay, allowing measurement of very low AMH concentrations in human serum, should refine postchemotherapy ovarian follow-up in young women. PMID- 24951364 TI - Efficacy and safety of intrauterine insemination and assisted reproductive technology in populations serodiscordant for human immunodeficiency virus: a systematic review and meta-analysis. AB - OBJECTIVE: To assess procreative outcomes for HIV-positive men and women with seronegative partners. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Twenty-four studies with extractable data for HIV serodiscordant couples undergoing intrauterine insemination (IUI) or in vitro fertilization (IVF). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): PRIMARY OUTCOMES: HIV transmission to a seronegative partner and per cycle fecundability; secondary outcomes: analysis of multiple gestation rates, miscarriage rates, and cancellation rates. RESULT(S): For serodiscordant couples, HIV-positive men or women undergoing IUI and IVF treatment had a 17%, 30%, 14%, and 16% per cycle fecundability, respectively. Multiple gestation rates were 10%, 33%, 14%, and 29%, respectively. Miscarriage rates were 19%, 25%, 13%, and 20%, respectively. No HIV transmission was observed in 8,212 IUI and 1,254 IVF cycles, resulting in 95% confidence that the true rate is 4.5 transmissions per 10,000 IUI cycles or less. CONCLUSION(S): In serodiscordant couples, IUI and IVF seem effective and safe based on the literature. Evidence-based practice and social justice suggest that our field should increase access to care for HIV-serodiscordant couples. PMID- 24951365 TI - Role of assisted hatching in in vitro fertilization: a guideline. AB - There is good evidence that assisted hatching (AH) slightly improves clinical pregnancy rates, particularly in poor prognosis patients, including those with prior failed in vitro fertilization (IVF) cycles. Due to a limited number of studies, there is insufficient evidence to conclude that AH improves live-birth rates. This document replaces the 2008 American Society for Reproductive Medicine and Society for Assisted Reproductive Technology Practice Committees' document titled, "Assisted hatching in in vitro fertilization: a review of the literature. A committee opinion" (Fertil Steril 2008;90[Suppl 5]:S196-8). PMID- 24951367 TI - Psychosocial predictors and HIV-related behaviors of old adults versus late middle-aged and younger adults. AB - OBJECTIVE: We investigated the psychosocial predictors and HIV-related behaviors of old adults versus late middle-aged and younger adults. METHOD: A demographically representative sample of residents in Italy aged 18 to 75 years (n = 2,018) was subdivided into three age groups: (a) younger adults (18-49 years), (b) late middle-aged adults (50-59 years), and (c) old adults (60-75 years). Interviews were conducted using computer-assisted telephone survey methodology. RESULTS: Despite reporting similar levels of sexual risk behaviors, late middle-aged and old adults were less likely to use condoms and to have ever had an HIV test. The levels of HIV/AIDS knowledge, risk perception, perceived behavioral control, and behavioral intentions toward condom use were lower among old adults compared with younger adults. Old adults were less likely to have discussed HIV/AIDS with friends, relatives, or health professionals. DISCUSSION: Old adults should be included in prevention efforts targeting knowledge, perceptions, and intentions toward condom use. Future studies should be cautious when overgeneralizing the results to all individuals aged 50 and older. PMID- 24951366 TI - Cost-effectiveness analysis comparing continuation of assisted reproductive technology with conversion to intrauterine insemination in patients with low follicle numbers. AB - OBJECTIVE: To compare the cost effectiveness of proceeding with oocyte retrieval vs. converting to intrauterine insemination (IUI) in patients with <=4 mature follicles during assisted reproductive technology (ART) cycles. DESIGN: Probabilistic decision analysis. The cost effectiveness of completing ART cycles in poor responders was compared to that for converting the cycles to IUI. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Cost effectiveness analysis. MAIN OUTCOME MEASURE(S): Cost effectiveness, which was defined as the average direct medical costs per ongoing pregnancy. RESULT(S): In patients with 1-3 mature follicles, completing ART was more cost effective if the cost of a single ART cycle was between $10,000 and $25,000. For patients with 4 mature follicles, if an ART cycle cost<$18,025, it was more cost effective to continue with oocyte retrieval than to convert to IUI. CONCLUSION(S): In patients with <=4 mature follicles following ovarian stimulation in ART cycles, it was on average more cost effective to proceed with oocyte retrieval rather than convert to IUI. However, important factors, such as age, prior ART failures, other fertility factors, and medications used in each individual case need to be considered before this analysis model can be adapted by individual practices. PMID- 24951368 TI - Association of self-reported hearing difficulty to objective and perceived participation outside the home in older community-dwelling adults. AB - OBJECTIVE: To investigate whether hearing difficulty is associated with objective and perceived participation in social and leisure activities outside the home in older adults. METHOD: Self-reported hearing difficulty, frequency of participation, perceived participation and Mini-Mental State Examination (MMSE) were obtained from 848 community-dwelling men and women aged 75 to 90. RESULTS: Among persons with MMSE <= 24, hearing was not associated with participation. In persons with MMSE > 24, relative to persons who reported no difficulty hearing, participants with major hearing difficulty had a higher odds ratio [OR] for infrequent participation in group activities (OR 2.1, 95% confidence interval [CI] [1.2, 3.6]) and more restricted perceived participation (OR 2.1, 95% CI [1.2, 3.7]). Participants with and without hearing difficulty did not differ in their frequency of attending non-group activities or meeting (grand)children or acquaintances. DISCUSSION: Hearing difficulty may restrict older adults with normal cognition from participating in social and leisure activities and living their life as they would like to outside the home. PMID- 24951369 TI - Handoffs and Patient Safety: Grasping the Story and Painting a Full Picture. AB - Effective handoff communication is critical for patient safety. Research is needed to understand how information processes occurring intra-shift impact handoff effectiveness. The purpose of this qualitative study was to examine medical-surgical nurses' (n = 21) perspectives about processes that promote and hinder patient safety intra-shift and during handoff. Results indicated that offgoing nurses' ability to grasp the story intra-shift was essential to convey the full picture during handoff. When oncoming nurses understood the picture being conveyed at the handoff, nurses jointly painted a full picture. Arriving and leaving the handoff with this level of information promoted patient safety. However, intra-shift disruptions often impeded nurses in their processes to grasp the story thus posing risks to patient safety. Improvement efforts need to target the different processes involved in grasping the story and painting a full picture. Future research needs to examine handoff practices and outcomes on units with good and poor practice environments. PMID- 24951370 TI - [The challenge of defining advanced stage dementia and the importance of using more adequate decision-making criteria in the prescribing of drugs]. PMID- 24951371 TI - Characteristics of distal radius speed of sound data in Chinese mainland men and women. AB - Quantitative ultrasound (QUS) assessment of bone health status, as a reliable method, is rapidly gaining popularity. Speed of sound (SOS) is one parameter of skeletal status provided by QUS assessment. The objective of the present study was first to determine the normative distal radius SOS data on healthy Chinese mainland men and women and second to investigate the effects of sex, age, and body size on this parameter. A study cohort consisting of 19,980 healthy Chinese women and 8722 men aged 20-89 yr participated in this investigation. They answered a detailed questionnaire on their healthy condition, and their anthropometric measurements were taken. Their distal radius SOS values were evaluated using the Sunlight ultrasound systems. The distal radius SOS values exhibited a characteristic rise-then-fall pattern with increasing age in both sexes. The peak SOS value occurred at the age of 40-49 both in males and females. Age-related differences were both pronounced among males and females. Pearson correlation and regression analysis showed that age was a major determinant of SOS in both sexes. In females, SOS values had a much stronger correlation with age than male subjects. Body weight was also correlated with SOS but not as well as age. The SOS values of distal radius at present study may be used as normal reference data for Chinese mainland population and will be useful for comparing the results of individual studies and determining diagnostic criteria of osteoporosis by QUS. PMID- 24951372 TI - Total endovascular treatment of an aortic arch aneurysm in a patient with a mechanical aortic valve. AB - INTRODUCTION: Endovascular repair of aortic arch aneurysms using an inner branched device is a new treatment option for patients unfit for open surgery. There are many anatomical restrictions, such as the presence of a mechanical aortic valve that can contraindicate this complete endovascular approach. REPORT: A new delivery system to overcome this issue has been developed. This new system was used to treat an aortic arch aneurysm 77 mm in diameter in a 37-year-old patient with Marfan's syndrome. The patient was considered to be at major risk for open surgery because of severe respiratory insufficiency following a second sternotomy. DISCUSSION: Total endovascular arch aneurysm repair is no longer contraindicated in patients with a mechanical aortic valve. PMID- 24951373 TI - Incidence and risk factors for venous reflux in the general population: Edinburgh Vein Study. AB - OBJECTIVE/BACKGROUND: Chronic venous disease (CVD) is common, but the incidence of venous reflux, a precursor to this condition, is unknown. This study measured the incidence of venous reflux and associated risk factors, and examined the association between venous reflux and the incidence of CVD. METHODS: In the Edinburgh Vein Study, a random sample of 1566 men and women aged 18-64 years were examined at baseline. Eight hundred and eighty of these patients were followed up 13 years and underwent an examination comprising clinical classification of CVD and duplex scanning of the deep and superficial systems to measure venous reflux >=0.5 s. RESULTS: The 13-year incidence of reflux was 12.7% (95% confidence interval [CI] 9.2-17.2), equivalent to an annual incidence of 0.9% (95% CI 0.7 1.3). The 13-year incidence of isolated superficial, isolated deep, and combined deep and superficial reflux was 8.8% (95% CI 5.6-12.0), 2.6% (95% CI 1.2-5.0), and 1.3% (95% CI 0.4-3.2), respectively. The highest incidence was in the great saphenous vein in the lower thigh (8.1%, 95% CI 5.4-11.8). There were no age or sex differences (p > .050). The risk of developing reflux was associated with being overweight (odds ratio [OR] 2.1, 95% CI 1.0-4.4) and with history of deep vein thrombosis (OR 11.3, 95% CI 1.0-132.3). Venous reflux at baseline was associated with new varicose veins at follow up (p < .001): the age- and sex adjusted OR was 4.4 (95% CI 1.8-10.8) in those with isolated superficial reflux and 7.3 (95% CI 2.6-22.5) in those with combined deep and superficial reflux. CONCLUSION: For every year of follow-up, around 1% of this adult population developed venous reflux. In two thirds of cases, the superficial system was affected. Venous reflux increased the risk of developing varicose veins, especially when combined deep and superficial reflux was present. PMID- 24951374 TI - Significant savings with a stepped care model for treatment of patients with intermittent claudication. AB - OBJECTIVES: International guidelines recommend supervised exercise therapy (SET) as primary treatment for intermittent claudication (IC). The aim of this study was to calculate treatment costs in patients with IC and to estimate nationwide annual savings if a stepped care model (SCM, primary SET treatment followed by revascularization in case of SET failure) was followed. METHODS: Invoice data of all patients with IC in 2009 were obtained from a Dutch health insurance company (3.4 million members). Patients were divided into three groups based on initial treatment after diagnosis (t0). The SET group received SET initiated at any time between 12 months before and up to 3 months after t0. The intervention group (INT) underwent endovascular or open revascularization between t0 and t+3 months. The third group (REST) received neither SET nor any intervention. All peripheral arterial disease related invoices were recorded during 2 years and average costs per patient were calculated. Savings following use of a SCM were calculated for three scenarios. RESULTS: Data on 4954 patients were analyzed. Initial treatment was SET (n = 701, 14.1%), INT (n = 1363, 27.5%), or REST (n = 2890, 58.3%). Within 2 years from t0, invasive revascularization in the SET group was performed in 45 patients (6.4%). Additional interventions (primary at other location and/or re-interventions) were performed in 480 INT patients (35.2%). Some 431 REST patients received additional SET (n = 299, 10.3%) or an intervention (n = 132, 4.5%). Mean total IC related costs per patient were ?2,191, ?9851 and ?824 for SET, INT, and REST, respectively. Based on a hypothetical worst, moderate, and best case scenario, some 3.8, 20.6, or 33.0 million euros would have been saved per annum if SCM was implemented in the Dutch healthcare system. CONCLUSION: Implementation of a SCM treatment for patients with IC may lead to significant savings of health care resources. PMID- 24951375 TI - Angio-Seal hopes for antegrade puncture require better evidence. PMID- 24951376 TI - Benefits of remote ischaemic preconditioning in vascular surgery. AB - OBJECTIVES: Remote ischaemic preconditioning (RIPC) is a physiological mechanism to protect against ischaemia-reperfusion injury. It is a technique in which short pre-emptive periods of ischaemia and reperfusion are thought to protect against ischaemia-reperfusion injury during procedures requiring longer periods of ischaemia. Discovered in the 1980s, its clinical application has been investigated heavily since the first human study in 2006. The aim of this paper was to provide a review of this rapidly expanding subject. METHODS: This study consists of a narrative review of the literature focusing on previous meta analyses and randomised control trials. RESULTS: Five small randomised trials have been published on the effects of RIPC in vascular surgery. Several randomised trials have been published in cardiac surgery and percutaneous coronary intervention. Meta-analysis shows a significant reduction in troponin levels and biomarkers of renal dysfunction in RIPC patients, but as yet no convincing clinical benefit. The largest powered randomised trial in cardiac surgery showed no benefit to RIPC. CONCLUSIONS: Current trials and therefore meta analyses are generally underpowered. The technique is physiologically sound but remains lacking in clear clinical benefit. PMID- 24951377 TI - Editor's Choice - efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials. AB - OBJECTIVES: The aim was to perform a review of the efficacy and safety of new oral anticoagulants (NOAs) in the management of venous thromboembolism (VTE). METHODS: This was a systematic review and meta-analysis. On March 26, 2014, Medline, Embase, and the Cochrane trial register were searched for randomized controlled trials (RCTs) comparing the NOAs dabigatran, rivaroxaban, apixaban, and edoxaban with vitamin K antagonists (VKAs) in VTE treatment and secondary prevention. Two investigators assessed the methodological quality of the RCTs. The main study outcomes (efficacy, safety and net clinical benefit) were expressed as risk ratios (RR) with 95% confidence interval (CI). RESULTS: Ten RCTs, mostly with low risk of bias, with nearly 38,000 patients, were identified. In six trials of treatment, NOAs were equally effective as VKAs in preventing recurrent symptomatic VTE (RR 0.89, 95% CI 0.75-1.05), but major bleeding occurred less often (1.08% vs. 1.73% for VKAs, RR 0.63, 95% CI 0.51-0.77), leading net clinical benefit to favor NOAs (RR 0.79, 95% CI 0.70-0.90). Fatal bleeding occurred less often with NOAs (0.09% vs. 0.18% for VKAs), a difference that approached statistical significance (RR 0.51, 95% CI 0.26-1.01). In three secondary prevention trials, NOAs reduced VTE recurrence rates to 1.32% (vs. 7.24% with placebo, RR 0.17, 95% CI 0.12-0.24) and fatal pulmonary embolism (PE) (including unexplained deaths) to 0.1% (vs. 0.29% for placebo, RR 0.37, 95% CI 0.10-1.38) at the expense of clinically relevant non-major bleeding (4.3% vs. 1.8% for placebo, RR 2.32, 95% CI 1.65-3.35), but not major bleeding. All-cause mortality rate was reduced to 0.41% with NOAs (vs. 0.86% with placebo, RR 0.38, 95% CI 0.18-0.79). Net clinical benefit favored NOAs (RR 0.21, 95% CI 0.15-0.29), and NNT was 18. CONCLUSIONS: Compared to VKAs, NOAs are not only effective in treating VTE but also safer in terms of bleeding, thereby conferring clinical benefit. Their safety and efficacy was confirmed further in secondary prevention trials. PMID- 24951378 TI - [Impact of serum Anti-Mullerian Hormone levels on the results of assisted reproductive technologies. Single-center retrospective study from 2011 cycles (ICSI and bilateral tubal obstruction excluded)]. AB - OBJECTIVES: In Assisted Reproductive Technologies (ART), impaired ovarian reserve represents a therapeutic challenge. The Anti-Mullerian Hormone (AMH) serum level would be a good marker of ovarian reserve and a predictor of response to stimulation. The objective of this study is to assess into a population of infertile couples where the woman has at least one patent tube and where the man has sperm parameters compatible with insemination, whether AMH level less than 12pmol/L can be used to establish a strategy supporting the couple's infertility by comparing their chances of pregnancy after Intra-uterine insemination (IUI) or in vitro fertilization (IVF). MATERIALS AND METHODS: This single-center retrospective study of 1012 patients over 28months compared the pregnancy rates of 2011 ART attempts (1385 IUI and 626 IVF, ICSI excluded) according to the value of serum AMH, either reduced if<=12pmol/L or non-reduced if greater. RESULTS: In IVF, a low AMH reduced pregnancy rate (18.4% vs. 32.9% in the normal AMH group, P<0.0001). Conversely, the AMH value did not influence the success in IUI cycles (14.2% vs. 14.5%, respectively, NS). In cases with low AMH, the pregnancy rate per initiated cycle in IVF (18.4%) was not significantly greater than in IUI cycles (14.2%). Converting an IVF attempt in IUI did not impair the pregnancy rate (13.5% vs. 14.5% after immediate IUI, NS). CONCLUSION: When the serum AMH level is less than 12pmol/L, IUI may be an interesting option in case of IVF failure. However, its place remains to be defined: converting IVF in IUI, IUI in relay of failed IVF, or even as first line therapy when the chances with IVF appear to be minimal. PMID- 24951379 TI - Surgical management of cervical radiculomedullary arterial aneurysm with subarachnoid haemorrhage: a case report. AB - The aim of this paper was to report an unusual case of a 30-year-old woman admitted to the emergency department for a subarachnoid spinal haemorrhage. Clinical presentation was typical and the initial CT-scan did not show any intracranial lesions. Diagnosis was then confirmed by a full-spinal MRI that revealed a cervical radiculomedullary artery aneurysm. The diagnosis was also confirmed by an arteriography that showed a left C6 radiculomedullary artery aneurysm. Surgical management was performed and included a direct approach of the vascular lesion using an anterolateral cervicotomy and occlusion of the parent vessel. Histological examination confirmed the typical aspect of the aneurysm. The postoperative course was uneventful and the patient was discharged from hospital at day 15. This type of vascular lesion is very uncommon and requires a prompt diagnosis. Initial MRI can confirm the presence of a subarachnoid haemorrhage related to the aneurysm, which can be also visualized by an arteriography. Management of these vascular disorders requires a multidisciplinary specialized spine-team and is commonly performed using a direct surgical approach. PMID- 24951380 TI - [A paraneoplastic Sharp syndrome reversible after resection of a benign schwannoma: a paraneoplastic syndrome?]. AB - Paraneoplastic syndromes commonly occur in malignancies and often precede the first symptoms of the tumor. By definition, paraneoplastic syndromes are only associated with malignancies although some exceptions have been reported, occurring with benign tumors. We report a patient presenting with a clinical and serological Sharp syndrome, followed a few months later by a cervical schwannoma. Curative surgical resection of the mass resulted in a clinical and serological healing from the Sharp syndrome. To our knowledge, this is the first report of a benign schwannoma complicated by a possible paraneoplastic Sharp syndrome. PMID- 24951381 TI - Preface: The puzzle of pineal tumors. PMID- 24951382 TI - [Learning vascular microsurgical techniques on an animal model]. AB - INTRODUCTION: The aim of this study was to assess the progress of an operator, during microsurgical training, on a bilateral carotid revascularization in the rat. MATERIAL AND METHODS: In this prospective study, nine rats underwent bilateral carotid revascularization. An end-to-end graft of the right carotid artery by the facial vein and an end-to-side bypass of left carotid artery by the jugular external vein were performed. Anastomoses were carried out with 10/0 thread, based on the technique of the symmetric bi-angulation. At the end of procedure, a permeability test was performed on each anastomosis. Duration of survival of the animal, permeability of anastomosis, and evolution of the operating periods during the training were collected and respectively analyzed with a Fisher's and Student's t tests. In cases of procedure success, anastomoses were remotely controlled and a brain dissection was performed in order to seek a possible ischemia due to carotid clamping. In the event of failure, the rat was sacrificed and anastomoses were opened in order to establish the cause of thrombosis. RESULTS: Two thirds of the revascularization procedures were successful. A total of 83.3% of the anastomoses were patent. Of the six rats preserved for remote evaluation of anastomoses, three died. Remotely controlled anastomoses remained all permeable. No cerebral ischemia, associated with carotid clamping (approximately 45 minutes), was highlighted by brain dissection. With the growing experience of the operator, an improvement in results in mastery of the technique was objectively observed. Operative durations were reduced between the beginning and the end of the training: -54 minutes (P=0.001). CONCLUSION: Microsurgical laboratory training seems to be essential in order to acquire the dexterity, ease and experience necessary for performing microsurgical procedures in humans. PMID- 24951383 TI - Surgical management of giant lumbar disc herniation: analysis of 154 patients over a decade. AB - BACKGROUND: We describe a decade of our experience in the surgical management of patients with giant lumbar intervertebral disc herniation (GILID). METHODS: This is a case series of patients operated for a GILID between 2000 and 2009. Among 1334 patients eligible for the present study: 154 patients presented with GILID (study group) and 1180 patients without GILID (control group). Clinical symptoms and preoperative imaging results were obtained from medical records. Complications and long-term results were assessed. RESULTS: This retrospective study documents the characteristic features between patients with and without GILID. The difference in the incidence of female patients was statistically significant between the study group and the control group as was the mean duration of symptoms, hyperalgic radicular pain, bilaterality of symptoms, preoperative motor deficit, central location of lumbar disc herniation (LDH), contained herniation and recurrence of LDH. CONCLUSIONS: GILIDs are a distinct entity: they are distinctly uncommon compared with smaller herniations, patients were statistically more likely to be hyperalgic with bilateral radicular pain and often associated with neurological deficits. The majority of patients do not display a cauda equina syndrome (CES). Low lumbar disc sites are mostly affected and disc fragments are more likely to be central-uncontained. The recurrence rate is lower for GILIDs. PMID- 24951384 TI - Self-intermittent catheterization in multiple sclerosis. AB - Clean intermittent self-catheterization (CISC) is considered the method of choice for treating urinary retention as of neurologic origin. Also, in multiple sclerosis (MS) the method is widely applied. Proper application needs sufficient hand function, possibility for proper positioning, sufficient sensation, cognitive function and as always the choice of the optimal material. The overall results are good. Specifically for MS patients more than average attention has to be given to training and follow-up in case of cognitive function impairment. Complications are acceptable with urinary tract infection having the highest incidence. MS being a progressive disease treatment possibly needs to be changed during follow-up. PMID- 24951385 TI - Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine. AB - The large Trp gene family encodes transient receptor potential (TRP) proteins that form novel cation-selective ion channels. In mammals, 28 Trp channel genes have been identified. TRP proteins exhibit diverse permeation and gating properties and are involved in a plethora of physiologic functions with a strong impact on cellular sensing and signaling pathways. Indeed, mutations in human genes encoding TRP channels, the so-called "TRP channelopathies," are responsible for a number of hereditary diseases that affect the musculoskeletal, cardiovascular, genitourinary, and nervous systems. This review gives an overview of the functional properties of mammalian TRP channels, describes their roles in acquired and hereditary diseases, and discusses their potential as drug targets for therapeutic intervention. PMID- 24951386 TI - Evaluating the marginal fit of zirconia copings with digital impressions with an intraoral digital scanner. AB - STATEMENT OF PROBLEM: Digital impression systems have been developed to overcome the disadvantages associated with conventional impression methods. PURPOSE: The purpose of this study was to compare the marginal fit of zirconia copings designed with the use of an iTero digital scanner with those designed by the conventional impression technique. MATERIAL AND METHODS: Thirty identical cast, base-metal dies from 1 maxillary central incisor prepared for a ceramic crown restoration were fabricated. For the conventional impression group (CI), base metal dies (n=10) were replicated as stone dies by means of a conventional impression technique with polyvinyl siloxane material. For the iTero with polyurethane group (iP), base metal dies (n=10) were replicated as polyurethane dies with the iTero digital impression system. For the iTero with no dies group (iNo), base metal dies (n=10) were scanned with the iTero digital impression system, but no dies were fabricated. For each group, 10 zirconia copings were fabricated based on the stone dies (CI group), polyurethane dies (iP group), or stereolithography files (iNo group). The marginal gap of each specimen was measured with a light microscope at *50 magnification. One-way analysis of variance and the Tukey honestly significant difference test were used for statistical analysis (alpha=.05). RESULTS: Statistically significant differences were found between the CI group and iP group (P<.05) and between the CI group and iNo group (P<.05). CONCLUSIONS: The marginal gap between the restoration and definitive cast base metal die was greater in the groups that used the digital impression method than in the group that used the conventional impression method. However, the marginal discrepancies of all of the groups were clinically acceptable. PMID- 24951387 TI - Finite element analysis of an implant-assisted removable partial denture during bilateral loading: occlusal rests position. AB - STATEMENT OF PROBLEM: When implants are incorporated into an existing partial removable dental prosthesis, the acrylic resin base can fracture. It is therefore essential to study the mechanical behavior of partial removable dental prostheses by using stress and deformation analysis. PURPOSE: The purpose of this study was to analyze the effect of the occlusal rest position on the implant-assisted partial removable dental prosthesis by finite element analysis. MATERIAL AND METHODS: A Faro Arm scan was used to extract the geometrical data of a human partially edentulous mandible. A standard plus regular neck (4.8*12 mm) implant and titanium matrix, tooth roots, and periodontal ligaments were modeled by using a combination of reverse engineering in Rapidform XOR2 and solid modeling with the Solid Works CAD program. The model incorporated a partial removable dental prosthesis and was loaded with standard bilateral forces. A uniform pressure was applied on the occlusal surface so as to generate an equivalent net force of 120 N for both the left and right prosthesis. The finite element analysis program ANSYS Workbench was used to analyze the stress and strain distributions in the implant-assisted partial removable dental prosthesis. RESULTS: Maximum stresses were significantly high for the metal framework compared to the acrylic resin surface, and these stresses were different for the mesial and distal arm designs. The maximum stress in the metal framework for the mesial arm design was 614.9 MPa, and it was 796.4 MPa for the distal arm design. The corresponding stresses in the acrylic resin surface were 10.6 and 8.6 MPa. CONCLUSIONS: Within the limitation of this study, it was found that moving the position of the occlusal rest from the mesial to distal side of the abutment teeth improved the stress distribution in the metal framework and acrylic resin denture base structures. PMID- 24951388 TI - Accelerated techniques for a post and core and a crown restoration with intraoral digital scanners and CAD/CAM and rapid prototyping. AB - Fabricating a post-and-core and a crown restoration for an endodontically treated tooth with extensive loss of tooth structure is complicated, difficult, and time consuming. This article describes 2 techniques for fabricating an anatomically correct ceramic core with fewer defects and a crown restoration with appropriate thickness by using intraoral digital scanners and computer-aided design and computer-aided manufacturing and rapid prototyping technologies. PMID- 24951389 TI - An investigation of heat transfer to the implant-bone interface when drilling through a zirconia crown attached to a titanium or zirconia abutment. AB - STATEMENT OF PROBLEM: Thermal injury to the implant-bone interface may lead to bone necrosis and loss of osseointegration. This is a concern during manipulation of the implant throughout the restorative phase of treatment. The risk of heat transfer to the implant-bone interface during abutment preparation or prosthesis removal should be considered. PURPOSE: The purpose of the study was to examine the amount of heat transferred to the implant-bone interface when a zirconia crown is drilled to access the screw channel or section a crown with a high-speed dental handpiece. MATERIAL AND METHODS: Of the 64 ceramic-veneered zirconia crowns fabricated, 32 had a coping thickness of 0.5 mm and 32 had a coping thickness of 1.0 mm. The crowns were cemented on either titanium stock abutments or zirconia stock abutments. Each group was further subdivided to evaluate heat transfer when the screw channel was accessed or the crown was sectioned with a high-speed handpiece with or without irrigation. Temperature change was recorded for each specimen at the cervical and apical aspect of the implant with thermocouples and a logging thermometer. ANOVA was used to assess the statistical significance in temperature change between the test combinations, and nonparametric Mann-Whitney U tests were used to evaluate the findings. RESULTS: The use of irrigation during both crown removal processes yielded an average temperature increase of 3.59 +/-0.35 degrees C. Crown removal in the absence of irrigation yielded an average temperature increase of 18.76 +/-3.09 degrees C. When all parameter combinations in the presence of irrigation were evaluated, the maximum temperature change was below the threshold of thermal injury to bone. The maximum temperature change was above the threshold for thermal injury at the coronal aspect of the implant and below the threshold at the apical aspect in the absence of irrigation. CONCLUSIONS: Within the limitations of this investigation, the use of irrigation with a high-speed dental handpiece to remove a ceramic veneered zirconia crown results in a temperature increase at the implant-bone interface insufficient to cause irreversible damage. Conversely, a lack of irrigation may yield a temperature increase capable of producing irreversible damage at the coronal aspect of the implant. PMID- 24951390 TI - Influence of particle abrasion or hydrofluoric acid etching on lithium disilicate flexural strength. AB - STATEMENT OF PROBLEM: Lithium disilicate is a translucent, glass-containing material used for ceramic restorations. Clinicians frequently use alumina abrading or hydrofluoric acid etching to create micromechanical retention in the intaglio surface before bonding a lithium disilicate restoration to the tooth. Few studies have investigated how the etching or abrasion processes affect the flexural strength of lithium disilicate ceramics. PURPOSE: The purpose of this study was to measure and compare the flexural strength of e.max CAD after alumina abrasion at differing pressures and acid etching at differing concentrations and times. MATERIAL AND METHODS: Bars of e.max CAD (9 groups of 10; 22*2.5*2.5 mm) were prepared, polished sequentially with 180, 320, and 600 abrasive paper, and sintered according to the manufacturer's instructions. Four groups were particle abraded (30-MUm alumina particles from 10 mm at 55, 100, 200, or 300 kPa for 10 seconds). Four groups were etched with either 5% hydrofluoric acid (20 seconds or 120 seconds) or 9.5% hydrofluoric acid (20 seconds or 120 seconds). The control was polished and fired only (no treatment). Specimens were placed onto an Instron (1 mm/min crosshead speed) and loaded to failure in a 3-point flexural test. One way ANOVA and the Dunnett t test determined intergroup differences (alpha=.05). RESULTS: Compared with the control, the 100, 200, and 300 kPa alumina abraded groups produced significantly lower flexural strengths (P<.001); however, the flexural strength of the 55 kPa abraded group was not statistically different from the control (P=.080). The flexural strength of the 5% and the 9.5% hydrofluoric acid-etched groups also were not significantly different from the control (P>.050); however, the 9.5% hydrofluoric acid at 20 seconds group was nearly statistically significant (P=.051). CONCLUSION: Alumina particle abrasion at pressures of 100 kPa and higher significantly reduced flexural strength by creating stress risers in e.max CAD and should not be used. Hydrofluoric acid etching should be used to increase micromechanical retention and clean the intaglio surface of the restoration before bonding. PMID- 24951391 TI - Recent advances in the preparation of hybrid nanoparticles in miniemulsions. AB - In this review, we summarize recent advances in the synthesis of hybrid nanoparticles in miniemulsions since 2009. These hybrid nanoparticles include organic-inorganic, polymeric, and natural macromolecule/synthetic polymer hybrid nanoparticles. They may be prepared through encapsulation of inorganic components or natural macromolecules by miniemulsion (co)polymerization, simultaneous polymerization of vinyl monomers and vinyl-containing inorganic precursors, precipitation of preformed polymers in the presence of inorganic constituents through solvent displacement techniques, and grafting polymerization onto, from or through natural macromolecules. Characterization, properties, and applications of hybrid nanoparticles are also discussed. PMID- 24951392 TI - Biocontrol opportunities to study microevolution in invasive populations. PMID- 24951393 TI - Meat consumption as a key impact on tropical nature: a response to Laurance et al. PMID- 24951394 TI - Better forecasts of range dynamics using genetic data. AB - The spatiotemporal response of species to past global change must be understood for adaptive management and to make useful predictions. Characteristics of past population dynamics are imprinted in genes, yet these molecular 'log books' are just beginning to be used to improve forecasts of biotic responses to climate change. This is despite there now being robust quantitative frameworks to incorporate such information. A tighter integration of genetic data into models of species range dynamics should lead to more robust and validated predictions of the response of demographic and evolutionary processes to large-scale environmental change. The use of these multidisciplinary methods will help conservation scientists to better connect theory to the on-ground design and implementation of effective measures to protect biodiversity. PMID- 24951395 TI - The impact of meat consumption on the tropics: reply to Machovina and Feeley. PMID- 24951396 TI - Why trees and shrubs but rarely trubs? AB - An analysis of the maximum height of woody plant species across the globe reveals that an intermediate size is remarkably rare. We speculate that this may be due to intrinsic suboptimality or to ecosystem bistability with open landscapes favouring shrubs, and closed canopies propelling trees to excessive tallness. PMID- 24951397 TI - Toll-like receptor co-receptors as master regulators of the immune response. AB - Pattern recognition receptors (PRRs) are generally recognized as the initiators of all immune responses. PRRs bind molecular patterns associated with microorganisms or endogenous mediators released by stressed tissues. Upon ligand binding, PRRs induce the activation of an inflammatory process that ultimately leads to pathogen clearance or restoration of tissue homeostasis. PRRs govern these processes, regulating the activation of a complex network of transcription factors able to induce the appropriate immune response to a specific ligand. Toll like-receptors (TLRs) are the first and best characterized PRR family, and for a long period of time they were believed to be autonomous proteins able to recognize and initiate all the immune response to a given stimulus. Recently this view was challenged by the discovery that so-called TLR co-receptors, such as CD14 and CD36, not only favor TLR-dependent signaling but can also transduce their own signal in a TLR-independent manner. Here we will discuss the capacity of TLR co-receptors to bind different microbial and endogenous ligands and to integrate TLR functions inducing specific signaling modules. PMID- 24951398 TI - Unilateral Mobius syndrome: two cases and a review of the literature. AB - IMPORTANCE: The Mobius sequence is a rare condition defined by the combination of congenital non-progressive facial and abducens nerve palsies. The etiology of the sequence is still unknown, but likely encompasses a group of heterogeneous disorders involving genetic maldevelopment of the brainstem, a fetal vascular insult and/or teratogen exposure. The clinical phenotype reported has expanded over the years, and may be associated with more extensive cranial nerve and oropharyngeal involvement, as well as limb defects. OBSERVATIONS: We describe two cases of children presenting with unilateral Mobius syndrome associated with ipsilateral unilateral palatal weakness. Investigations failed to identified a clear underlying etiology, but both cases shared phenotypic features of other more common cranial facial disorders such as craniofacial microsomia and the velocardiofacial syndrome. CONCLUSION AND RELEVANCE: These two cases highlight the clinical heterogeneity of the Mobius sequence. Although asymmetries are not uncommon, cases with strictly unilateral features are extremely rare, and as such these may represent a distinct subgroup that may pertain to a specific etiology. Although in many cases, evidence of an intrauterine vascular insult may be identified, a contributing genetic etiology should be considered, even in cases with strictly unilateral features. As such genes expressed in the developing rhombencephalon and its vasculature represent good candidates for future investigation. PMID- 24951399 TI - Kawasaki disease is associated with sensorineural hearing loss: a systematic review. AB - CONTEXT: Kawasaki Disease (KD), a systemic vasculitis of unknown etiology, has been associated with the development of sensorineural hearing loss (SNHL). KD is primarily a disease of young children, who are the most susceptible to complications from even minimal hearing loss. If there is a connection between KD and the development of SNHL, a better understanding of this relationship may improve our management of this disease and its complications. OBJECTIVE: To perform a systematic review according to a standardized guideline to evaluate the possible association between KD and SNHL. DATA SOURCES: Medline and PubMed online databases were reviewed for appropriate articles. STUDY SELECTION: All studies available in English discussing KD and SNHL were included. DATA EXTRACTION: Studies were assessed primarily for the incidence of SNHL. Where possible, they were assessed for the degree and laterality of the loss, length of follow up and change in hearing over time. RESULTS: 8 studies meeting the criteria were assessed. 3 were case reports, 1 was a case series and the remaining 4 were prospective control trials. 8 patients have been reported as cases, and 240 assessed in PCT. 36% of patients assessed had some degree of SNHL, and overall 14% had evidence of persistent SNHL at follow up. CONCLUSIONS: This systematic review would suggest there is an association between KD and SNHL. It is important for physicians caring for patients with KD to be aware of this complication and consider screening these patients given possible complications of hearing loss in this age group. PMID- 24951400 TI - Prevalence and incidence rates of mental syndromes after occupational exposure to polychlorinated biphenyls. AB - Mental disorders were often reported following hazardous substance exposure. The present study analyses this association in relation to a work-related exposure to PCBs (polychlorinated biphenyls). Specifically, the aim was to investigate (a) the relationship of inner PCB burden and the severity of mental symptoms and (b) the prevalence and incidence of mental syndromes. This study was initiated as part of the occupational medical surveillance program HELPcB (Health Effects in high level exposure to PCB). A total of 136 individuals were included in the analysis. The plasma PCBs were collected via biomonitoring and the psychological syndromes (i.e., somatoform, depressive, anxiety, panic) with a standardized screening instrument. The relationship of PCB and the severity of mental syndromes were analyzed via linear regression. Prevalence rates, the respective odds ratios (OR) and the incidence rates were calculated with logistic regressions. We thereby compared the higher-PCB burdened individuals with those individuals showing PCB levels comparable to the general population. We found especially a significant relationship between PCB burden and depressivity. Within the higher-PCB-exposed group prevalence rates were descriptively higher than for normal-exposed participants, except for anxiety syndrome. Similarly, the higher exposed group had a higher risk for developing a depressive syndrome. The incidence rates were always descriptively higher in higher-exposed group. To summarize, this study supports a relationship between PCB exposure and mental illness. PMID- 24951401 TI - Neural responses during social reflection in relatives of schizophrenia patients: relationship to subclinical delusions. AB - BACKGROUND: Deficits in the capacity to reflect about the self and others ("social reflection" [SR]) have been identified in schizophrenia, as well as in people with a genetic or clinical risk for the disorder. However, the neural underpinnings of these abnormalities are incompletely understood. METHODS: Responses of a network of brain regions known to be involved in self and other processing (e.g., medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), and superior temporal gyrus (STG)) were measured during SR in 16 first degree, non-psychotic relatives (RELS) of schizophrenia patients and 16 healthy controls (CONS). Because of prior evidence linking dysfunction in this network and delusions, associations between SR-related responses of this network and subclinical delusions (measured using the Peters et al. Delusions Inventory) were also examined. RESULTS: Compared with CONS, RELS showed significantly less SR related activity of the right and left PCC and STG. Moreover, response magnitudes were negatively correlated with levels of delusional thinking across both groups. CONCLUSIONS: These findings suggest that aberrant function of the neural circuitry underpinning SR is associated with the genetic liability to schizophrenia and confers vulnerability to delusional beliefs. PMID- 24951402 TI - Long range frontal/posterior phase synchronization during remembered pursuit task is impaired in schizophrenia. AB - Although smooth pursuit eye movement (SPEM) is a reliable endophenotype of schizophrenia, exact underlying cognitive and neural substrates remain unknown. A simple mechanistic model of SPEM assumes an efficient interaction in integrating sensory input from the medial temporal (MT)/medial superior temporal (MST) brain regions and subsequent motor response through the frontal eye field (FEF). Poor functional connectivity between these two regions could explain impaired motion perception and SPEM maintenance in schizophrenia. In the present study, we combined an eye tracking paradigm with electroencephalography (EEG) recordings to investigate the putative functional connectivity among frontal/posterior brain regions in mediating the modulation of SPEM. Twenty four schizophrenic (SZ) and 22 healthy control (HC) participants performed remembered pursuit tasks with EEG recordings. Behaviorally, HC subjects showed significant improvement in SPEM response on repeated presentations of target compared to SZ subjects. Neurophysiologically HC subjects showed higher frontal/posterior phase synchronization in the beta to low gamma range frequency bands during all target presentations. In addition there was a significant increase in phase synchronization in the beta-2 frequency band in HC subjects during late compared to early target presentation. In contrast, higher frontal/posterior phase synchronization in the beta-2 frequency predicted better performance during late target presentation and lower enduring psychosis in SZ subjects. These data suggest a pathologically perturbed connectivity between frontal and posterior cortical regions during SPEM in SZ. The integrative eye tracking-EEG approach used in this study to dissect the endophenotype may reveal novel targets for studying schizophrenia psychopathology. PMID- 24951403 TI - Choosing your network: social preferences in an online health community. AB - A growing number of online health communities offer individuals the opportunity to receive information, advice, and support from peers. Recent studies have demonstrated that these new online contacts can be important informational resources, and can even exert significant influence on individuals' behavior in various contexts. However little is known about how people select their health contacts in these virtual domains. This is because selection preferences in peer networks are notoriously difficult to detect. In existing networks, unobserved pressures on tie formation--such as common organizational memberships, introductions to friends of friends, or limitations on accessibility--may mistakenly be interpreted as individual preferences for interacting/not interacting with others. We address these issues by adopting a social media approach to studying network formation. We study social selection using an in vivo study within an online exercise program, in which anonymous participants have equal opportunities for initiating relationships with other program members. This design allows us to identify individuals' preferences for health contacts, and to evaluate what these preferences imply for members' access to new kinds of health information, and for the kinds of social influences to which they are exposed. The study was conducted within a goal-oriented fitness competition, in which participation was greatest among a small core of active individuals. Our results show that the active participants displayed indifference to the fitness and exercise profiles of others, disregarding information about others' fitness levels, exercise preferences, and workout experiences, instead selecting partners almost entirely on the basis of similarities on gender, age, and BMI. Interestingly, the findings suggest that rather than expanding and diversifying their sources of health information, participants' choices limited the value of their online resources by selecting contacts based on characteristics that are common sources of homophily in offline relationships. In light of our findings, we discuss design principles that may be useful for organizations and policy makers trying to improve the value of participants' social capital within online health programs. PMID- 24951405 TI - Postabortal and postpartum contraception. AB - Healthcare providers often underestimate a woman' need for immediate effective contraception after an abortion or childbirth. Yet, these are times when women may be highly motivated to avoid or delay another pregnancy. In addition, starting the most effective long-acting reversible methods (i.e. the intrauterine device, intrauterine system or implants) at these times, is safe, with low risk of complications. Good evidence shows that women choosing long-acting reversible contraceptives at the time of an abortion are at significantly lower risk of another abortion, compared with counterparts choosing other methods. Uptake of long-acting reversible methods postpartum can also prevent short inter-pregnancy intervals, which have negative consequences for maternal and child health. It is important, therefore, that providers of abortion and maternity care are trained and funded to be able to provide these methods for women immediately after an abortion or childbirth. PMID- 24951404 TI - Leveraging social influence to address overweight and obesity using agent-based models: the role of adolescent social networks. AB - The prevalence of adolescent overweight and obesity (hereafter, simply "overweight") in the US has increased over the past several decades. Individually targeted prevention and treatment strategies targeting individuals have been disappointing, leading some to propose leveraging social networks to improve interventions. We hypothesized that social network dynamics (social marginalization; homophily on body mass index, BMI) and the strength of peer influence would increase or decrease the proportion of network member (agents) becoming overweight over a simulated year, and that peer influence would operate differently in social networks with greater overweight. We built an agent-based model (ABM) using results from R-SIENA. ABMs allow for the exploration of potential interventions using simulated agents. Initial model specifications were drawn from Wave 1 of the National Longitudinal Study of Adolescent Health (Add Health). We focused on a single saturation school with complete network and BMI data over two waves (n = 624). The model was validated against empirical observations at Wave 2. We focused on overall overweight prevalence after a simulated year. Five experiments were conducted: (1) changing attractiveness of high-BMI agents; (2) changing homophily on BMI; (3) changing the strength of peer influence; (4) shifting the overall BMI distribution; and (5) targeting dietary interventions to highly connected individuals. Increasing peer influence showed a dramatic decrease in the prevalence of overweight; making peer influence negative (i.e., doing the opposite of friends) increased overweight. However, the effect of peer influence varied based on the underlying distribution of BMI; when BMI was increased overall, stronger peer influence increased proportion of overweight. Other interventions, including targeted dieting, had little impact. Peer influence may be a viable target in overweight interventions, but the distribution of body size in the population needs to be taken into account. In low-obesity populations, strengthening peer influence may be a useful strategy. PMID- 24951406 TI - Anthropometric aspects of hand morphology in relation to sex and to body mass in a Turkish population sample. AB - The hand is not only one of the principal structures related to motor function but is also essential for tactile sensations. The genetic endowment of an individual plays an important role in the development and differentiation of the hands. Certain features of hands are known to be sexually dimorphic and body morphology may also affect hand morphology. The aim of this study was to evaluate the anthropometric aspects of the hand in terms of its overall morphology and shape in relation to sex. Three hundred and eighty-five healthy individuals (187 males and 198 females), aged 20-41 years, participated in the study. Hand length, hand width, third finger length and palmar length were measured using a digital caliper with a resolution of 0.01 mm. The shape index, digit index, and palmar length/width ratio were also calculated. The body height and weight of the participants were measured and the body mass index (BMI) was calculated. Analysis of covariance was used to evaluate BMI and sex differentiation of continuous dependent variables (indices). BMI caused a significant difference between sexes with respect to the shape index, digit index, and palmar length/width ratio of the right and left hands. Also, a statistically significant difference between sexes was found with respect to the shape index, digit index, and palmar length/width ratio of the right and left hands. The hands of males are coarser than those of females and males tend to have a stronger grasping ability. Also, the hands of females are narrower than those of males. Thus it can be suggested that sexual dimorphism exists regarding hand morphology, which may be a consequence of differential prenatal exposure of males and females to testosterone and estrogen along with genetic endowment. PMID- 24951407 TI - A re-examination of the human fossil specimen from Backi Petrovac (Serbia). AB - A fragmented human calotte was discovered during the early 1950s near Backi Petrovac (Serbia), in association with Palaeolithic stone tools. After its initial publication, the fossil specimen remained largely unknown outside of the Serbian academe and no detailed comparative study has ever been carried out. Since the whereabouts of the fossil itself are currently unknown, and given its potential significance for the Pleistocene human evolution, we re-examine the data published by Zivanovic (1966, 1975). Using the original measurements, mostly taken on the frontal bone, and a wide comparative sample of 68 fossil specimens, the fossil was compared and analyzed by statistical multivariate methods. We also conducted a visual examination of the morphology based on the available photographic material. Our analysis reveals phenetic similarity with Middle Pleistocene archaic Homo from Africa and anatomically modern Homo sapiens. However, the absence of primitive cranial traits in Backi Petrovac indicates a clear modern Homo sapiens designation. Although lost at the moment, there is a chance for the re-discovery of the fossil in the years to come. This would give us an opportunity to acquire absolute dates and to study the specimen in a more detailed manner. PMID- 24951408 TI - Illuminating the Nubian 'Dark Age': a bioarchaeological analysis of dental non metric traits during the Napatan Period. AB - The origins of one of the most powerful sociopolitical entities of the Nile Valley, the Napatan State (850-650BCE), are debated. Some scholars have suggested local development of this influential Nubian State, while others propose foreign involvement. This study uses a bioarchaeological approach to examine the biological affinity of these Ancient Nubians. The focal site of this research, Tombos, is one of few non-central Napatan Period sites that have been excavated and can, therefore, shed light on the broader Napatan populace. Dental non-metric trait frequencies were examined in the Tombos sample as well as in 12 comparative samples to elucidate the biological affinities of these populations. Analyses indicate that Tombos dental non-metric trait frequencies were not significantly different from the majority of Egyptian and Nubian samples examined here. Therefore, we propose that gene flow, encouraged by long-term coexistence and intermarriage in Nubia, created an Egyptian/Nubian transcultural environment. These findings suggest the Napatan population at Tombos included descendants of Egyptians and Nubians. The Napatan Tombos sample was found to significantly differ from the latter Kushite and Meroitic samples; however, these samples are so temporally removed from the Napatan Period, we suspect subsequent episodes of population movement may have contributed to this variation. PMID- 24951410 TI - Elderly woman with tongue swelling. Spontaneous sublingual hematoma. PMID- 24951409 TI - Twins and the paradox of dental-age estimations: a caution for researchers and clinicians. AB - The biological age difference among twins is frequently an issue in studies of genetic influence on various dental features, particularly dental development. The timing of dental development is a crucial issue also for many clinicians and researchers. The aim of this study was therefore to verify within groups of twins how dental development differs, by applying Demirjian's method, Mincer's charts of development of third molars and two of Cameriere's methods for dental age estimation, which are among the most popular methods both in the clinical and the forensic scenario. The sample consisted of 64 twin pairs: 21 monozygotic, 30 dizygotic same-sex and 13 dizygotic opposite-sex with an age range between 5.8 and 22.6 years. Dental age was determined from radiographs using the mentioned methods. Results showed that dental age of monozygotic twins is not identical even if they share all their genes. The mean intra-pair difference of monozygotic pairs was low and similar to the difference in dizygotic same-sex twins; the maximum difference between monozygotic twins, however, was surprisingly large (nearly two years). This should lead to some circumspection in the interpretation of systematic estimations of dental age both in the clinical and forensic scenario. PMID- 24951412 TI - Pet peeve. PMID- 24951413 TI - Is it time to raise the bar? Age-adjusted D-dimer cutoff levels to exclude pulmonary embolism. PMID- 24951414 TI - Global emergency medicine journal club: social media responses to the January 2014 online emergency medicine journal club on subarachnoid hemorrhage. AB - From January 20 to 24, 2014, Annals continued a successful collaboration with an academic Web site, Academic Life in Emergency Medicine (ALiEM), to host another Global Emergency Medicine Journal Club session featuring the 2013 Journal of the American Medical Association article "Clinical Decision Rules to Rule Out Subarachnoid Hemorrhage for Acute Headache" by Perry et al. This online journal club used the power of rapid Twitter conversations, a live videocast with the authors, and more detailed discussions hosted on the ALiEM Web site's comment section. There were more than 1,431 individuals from 501 cities in 59 countries who viewed the blog post. During this 5-day event, 28 comments (average word count 153 words) and 206 tweets were made. This summary article details the community discussion, shared insights, and analytic data generated during this novel, multiplatform approach. PMID- 24951415 TI - Woman with bleeding lesion on her back. Congenital melanocytic nevus. PMID- 24951416 TI - Viscous lidocaine treatment for painful oral infections in children: disappointingly dismissive of pediatric pain. PMID- 24951417 TI - Ambulance diversion by cooperation: a positive experience with a physician directed ambulance diversion policy in Charleston County, South Carolina. PMID- 24951418 TI - In reply. PMID- 24951419 TI - In reply. PMID- 24951420 TI - Emergency physician identification of a cluster of elder abuse in nursing home residents. PMID- 24951421 TI - Death of a child in the emergency department. AB - The American Academy of Pediatrics, American College of Emergency Physicians, and Emergency Nurses Association have collaborated to identify practices and principles to guide the care of children, families, and staff in the challenging and uncommon event of the death of a child in the emergency department in this policy statement and in an accompanying technical report. PMID- 24951422 TI - Death of a child in the emergency department. AB - The death of a child in the emergency department (ED) is one of the most challenging problems facing ED clinicians. This revised technical report and accompanying policy statement reaffirm principles of patient- and family-centered care. Recent literature is examined regarding family presence, termination of resuscitation, bereavement responsibilities of ED clinicians, support of child fatality review efforts, and other issues inherent in caring for the patient, family, and staff when a child dies in the ED. Appendices are provided that offer an approach to bereavement activities in the ED, carrying out forensic responsibilities while providing compassionate care, communicating the news of the death of a child in the acute setting, providing a closing ritual at the time of terminating resuscitation efforts, and managing the child with a terminal condition who presents near death in the ED. PMID- 24951423 TI - Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm. AB - Thrombosis is common in patients suffering from myeloproliferative neoplasm (MPN), whereas bleeding is less frequent. JAK2(V617F), the main mutation involved in MPN, is considered as a risk factor for thrombosis, although the direct link between the mutation and hemostatic disorders is not strictly established. We investigated this question using conditional JAK2(V617F) knock-in mice with constitutive and inducible expression of JAK2(V617F) in hematopoietic cells, which develop a polycythemia vera (PV)-like disorder evolving into myelofibrosis. In vitro, thrombosis was markedly impaired with an 80% decrease in platelet covered surface, when JAK2(V617F) blood was perfused at arterial shear over collagen. JAK2(V617F) platelets presented only a moderate glycoprotein (GP) VI deficiency not responsible for the defective platelet accumulation. In contrast, a decreased proportion of high-molecular-weight von Willebrand factor multimers could reduce platelet adhesion. Accordingly, the tail bleeding time was prolonged. In the FeCl3-induced thrombosis model, platelet aggregates formed rapidly but were highly unstable. Interestingly, vessels were considerably dilated. Thus, mice developing PV secondary to constitutive JAK2(V617F) expression exhibit a bleeding tendency combined with the accelerated formation of unstable clots, reminiscent of observations made in patients. Hemostatic defects were not concomitant with the induction of JAK2(V617F) expression, suggesting they were not directly caused by the mutation but were rather the consequence of perturbations in blood and vessel homeostasis. PMID- 24951424 TI - A systems approach to hemostasis: 1. The interdependence of thrombus architecture and agonist movements in the gaps between platelets. AB - Hemostatic thrombi develop a characteristic architecture in which a core of highly activated platelets is covered by a shell of less-activated platelets. Here we have used a systems biology approach to examine the interrelationship of this architecture with transport rates and agonist distribution in the gaps between platelets. Studies were performed in mice using probes for platelet accumulation, packing density, and activation plus recently developed transport and thrombin activity probes. The results show that intrathrombus transport within the core is much slower than within the shell. The region of slowest transport coincides with the region of greatest packing density and thrombin activity, and appears prior to full platelet activation. Deleting the contact dependent signaling molecule, Sema4D, delays platelet activation, but not the emergence of the low transport region. Collectively, these results suggest a timeline in which initial platelet accumulation and the narrowing gaps between platelets create a region of reduced transport that facilitates local thrombin accumulation and greater platelet activation, whereas faster transport rates within the shell help to limit thrombin accumulation and growth of the core. Thus, from a systems perspective, platelet accumulation produces an altered microenvironment that shapes thrombus architecture, which in turn affects agonist distribution and subsequent thrombus growth. PMID- 24951425 TI - A systems approach to hemostasis: 2. Computational analysis of molecular transport in the thrombus microenvironment. AB - Hemostatic thrombi formed after a penetrating injury have a heterogeneous architecture in which a core of highly activated, densely packed platelets is covered by a shell of less-activated, loosely packed platelets. In the first manuscript in this series, we show that regional differences in intrathrombus protein transport rates emerge early in the hemostatic response and are preserved as the thrombus develops. Here, we use a theoretical approach to investigate this process and its impact on agonist distribution. The results suggest that hindered diffusion, rather than convection, is the dominant mechanism responsible for molecular movement within the thrombus. The analysis also suggests that the thrombus core, as compared with the shell, provides an environment for retaining soluble agonists such as thrombin, affecting the extent of platelet activation by establishing agonist-specific concentration gradients radiating from the site of injury. This analysis accounts for the observed weaker activation and relative instability of platelets in the shell and predicts that a failure to form a tightly packed thrombus core will limit thrombin accumulation, a prediction tested by analysis of data from mice with a defect in clot retraction. PMID- 24951426 TI - A systems approach to hemostasis: 3. Thrombus consolidation regulates intrathrombus solute transport and local thrombin activity. AB - Hemostatic thrombi formed after a penetrating injury have a distinctive structure in which a core of highly activated, closely packed platelets is covered by a shell of less-activated, loosely packed platelets. We have shown that differences in intrathrombus molecular transport emerge in parallel with regional differences in platelet packing density and predicted that these differences affect thrombus growth and stability. Here we test that prediction in a mouse vascular injury model. The studies use a novel method for measuring thrombus contraction in vivo and a previously characterized mouse line with a defect in integrin alphaIIbbeta3 outside-in signaling that affects clot retraction ex vivo. The results show that the mutant mice have a defect in thrombus consolidation following vascular injury, resulting in an increase in intrathrombus transport rates and, as predicted by computational modeling, a decrease in thrombin activity and platelet activation in the thrombus core. Collectively, these data (1) demonstrate that in addition to the activation state of individual platelets, the physical properties of the accumulated mass of adherent platelets is critical in determining intrathrombus agonist distribution and platelet activation and (2) define a novel role for integrin signaling in the regulation of intrathrombus transport rates and localization of thrombin activity. PMID- 24951427 TI - The polycomb repressive complex 2 governs life and death of peripheral T cells. AB - Differentiation of naive CD4(+) T cells into effector (Th1, Th2, and Th17) and induced regulatory (iTreg) T cells requires lineage-specifying transcription factors and epigenetic modifications that allow appropriate repression or activation of gene transcription. The epigenetic silencing of cytokine genes is associated with the repressive H3K27 trimethylation mark, mediated by the Ezh2 or Ezh1 methyltransferase components of the polycomb repressive complex 2 (PRC2). Here we show that silencing of the Ifng, Gata3, and Il10 loci in naive CD4(+) T cells is dependent on Ezh2. Naive CD4(+) T cells lacking Ezh2 were epigenetically primed for overproduction of IFN-gamma in Th2 and iTreg and IL-10 in Th2 cells. In addition, deficiency of Ezh2 accelerated effector Th cell death via death receptor-mediated extrinsic and intrinsic apoptotic pathways, confirmed in vivo for Ezh2-null IFN-gamma-producing CD4(+) and CD8(+) T cells responding to Listeria monocytogenes infection. These findings demonstrate the key role of PRC2/Ezh2 in differentiation and survival of peripheral T cells and reveal potential immunotherapeutic targets. PMID- 24951428 TI - Acquired von Willebrand syndrome: von Willebrand factor propeptide to von Willebrand factor antigen ratio predicts remission status. AB - We investigated a case of acquired von Willebrand syndrome (AVWS) secondary to a nonneutralizing anti-von Willebrand factor (VWF) antibody associated with an autoimmune disorder. At diagnosis, VWF activity (VWF:Act), antigen (VWF:Ag), multimers, and factor VIII coagulant activity were virtually absent. VWF propeptide (VWFpp) was elevated with an infinitely high VWFpp to VWF:Ag ratio (VWFpp:Ag) consistent with rapid VWF clearance. Immunosuppressive treatment resulted in phenotypic remission 1 with normalization of VWF/factor VIII levels and multimer pattern. However, VWFpp:Ag remained elevated (~2* normal), consistent with ongoing VWF clearance by the remaining anti-VWF antibody still present by enzyme-linked immunosorbent assay. This suggests that increased VWF secretion was compensating for the incomplete remission state. Relapse occurred when VWFpp:Ag was again infinitely high, with associated decreased VWFpp but unchanged anti-VWF titers; switching the balance to favor VWF clearance over secretion. Complete remission with undetectable anti-VWF occurred only when VWFpp:Ag was normal. This case of relapsing-remitting AVWS demonstrates the use of VWFpp:Ag for predicting remission status. PMID- 24951429 TI - Fibrinogen gamma' increases the sensitivity to activated protein C in normal and factor V Leiden plasma. AB - Activated protein C (APC) resistance, often associated with the factor V (FV) Leiden mutation, is the most common risk factor for venous thrombosis. We observed increased APC resistance in carriers of fibrinogen gamma gene (FGG) haplotype 2, which is associated with reduced levels of the alternatively spliced fibrinogen gamma' chain. This finding prompted us to study the effects of fibrinogen and its gamma' chain on APC resistance. Fibrinogen, and particularly the gammaA/gamma' isoform, improved the response of plasma to added APC in the thrombin generation-based assay. Similarly, a synthetic peptide mimicking the C terminus of the fibrinogen gamma' chain, which binds thrombin and inhibits its activities, greatly increased the APC sensitivity of normal and FV Leiden plasma, likely due to its ability to inhibit thrombin-mediated activation of FV and FVIII. Although the fibrinogen gamma' peptide also inhibited protein C activation by the thrombin/thrombomodulin complex, it still increased the sensitivity of plasma to endogenously formed APC when thrombin generation was measured in the presence of soluble thrombomodulin. We conclude that fibrinogen, and particularly fibrinogen gamma', increases plasma APC sensitivity. The fibrinogen gamma' peptide might form the basis for pharmacologic interventions to counteract APC resistance. PMID- 24951430 TI - Baboon envelope pseudotyped LVs outperform VSV-G-LVs for gene transfer into early cytokine-stimulated and resting HSCs. AB - Hematopoietic stem cell (HSC)-based gene therapy holds promise for the cure of many diseases. The field is now moving toward the use of lentiviral vectors (LVs) as evidenced by 4 successful clinical trials. These trials used vesicular stomatitis-virus-G protein (VSV-G)-LVs at high doses combined with strong cytokine-cocktail stimulation to obtain therapeutically relevant transduction levels; however, they might compromise the HSC character. Summarizing all these disadvantages, alternatives to VSV-G-LVs are urgently needed. We generated here high-titer LVs pseudotyped with a baboon retroviral envelope glycoprotein (BaEV LVs), resistant to human complement. Under mild cytokine prestimulation to preserve the HSC characteristics, a single BaEV-LV application at a low dose, resulted in up to 90% of hCD34(+) cell transduction. Even more striking was that these new BaEV-LVs allowed, at low doses, efficient transduction of up to 30% of quiescent hCD34(+) cells, whereas high-dose VSV-G-LVs were insufficient. Importantly, reconstitution of NOD/Lt-SCID/gammac(-/-) (NSG) mice with BaEV-LV transduced hCD34(+) cells maintained these high transduction levels in all myeloid and lymphoid lineages, including early progenitors. This transduction pattern was confirmed or even increased in secondary NSG recipient mice. This suggests that BaEV-LVs efficiently transduce true HSCs and could improve HSC based gene therapy, for which high-level HSC correction is needed for life-long cure. PMID- 24951431 TI - Adhesion of Staphylococcus aureus to the vessel wall under flow is mediated by von Willebrand factor-binding protein. AB - Adhesion of Staphylococcus aureus to blood vessels under shear stress requires von Willebrand factor (VWF). Several bacterial factors have been proposed to interact with VWF, including VWF-binding protein (vWbp), a secreted coagulase that activates the host's prothrombin to generate fibrin. We measured the adhesion of S aureus Newman and a vWbp-deficient mutant (vwb) to VWF, collagen, and activated endothelial cells in a microparallel flow chamber. In vivo adhesion of S aureus was evaluated in the mesenteric circulation of wild-type (WT) and VWF deficient mice. We found a shear-dependent increase in adhesion of S aureus to the (sub)endothelium that was dependent on interactions between vWbp and the A1 domain of VWF. Adhesion was further enhanced by coagulase-mediated fibrin formation that clustered bacteria and recruited platelets into bacterial microthrombi. In vivo, deficiency of vWbp or VWF as well as inhibition of coagulase activity reduced S aureus adhesion. We conclude that vWbp contributes to vascular adhesion of S aureus through 2 independent mechanisms: shear-mediated binding to VWF and activation of prothrombin to form S aureus-fibrin-platelet aggregates. PMID- 24951432 TI - Role of phenotypic and genetic testing in managing clopidogrel therapy. AB - The P2Y12 inhibitors, clopidogrel, prasugrel, and ticagrelor, are administered in fixed doses without laboratory monitoring. Randomized trials in acute coronary syndrome have shown that prasugrel and ticagrelor are more effective than standard-dose clopidogrel. Nonetheless, standard-dose clopidogrel remains widely used because it causes less bleeding and is less expensive. Patients treated with standard-dose clopidogrel have substantial variability in platelet inhibition, which is partly explained by genetic polymorphisms encoding CYP2C19, the hepatic enzyme involved in biotransformation of clopidogrel to its active metabolite. Some advocate tailoring P2Y12 inhibitor therapy according to the results of routine laboratory testing. Although there is good evidence for analytic, biological, and clinical validity of several phenotypic and genotypic biomarkers, the benefit of a management strategy that incorporates routine biomarker testing over standard of care without such testing remains unproven. Appropriately designed, adequately powered trials are needed but face the challenges of feasibility, cost, and the progressive switch from clopidogrel to prasugrel or ticagrelor. PMID- 24951433 TI - Correlated measurement error hampers association network inference. AB - Modern chromatography-based metabolomics measurements generate large amounts of data in the form of abundances of metabolites. An increasingly popular way of representing and analyzing such data is by means of association networks. Ideally, such a network can be interpreted in terms of the underlying biology. A property of chromatography-based metabolomics data is that the measurement error structure is complex: apart from the usual (random) instrumental error there is also correlated measurement error. This is intrinsic to the way the samples are prepared and the analyses are performed and cannot be avoided. The impact of correlated measurement errors on (partial) correlation networks can be large and is not always predictable. The interplay between relative amounts of uncorrelated measurement error, correlated measurement error and biological variation defines this impact. Using chromatography-based time-resolved lipidomics data obtained from a human intervention study we show how partial correlation based association networks are influenced by correlated measurement error. We show how the effect of correlated measurement error on partial correlations is different for direct and indirect associations. For direct associations the correlated measurement error usually has no negative effect on the results, while for indirect associations, depending on the relative size of the correlated measurement error, results can become unreliable. The aim of this paper is to generate awareness of the existence of correlated measurement errors and their influence on association networks. Time series lipidomics data is used for this purpose, as it makes it possible to visually distinguish the correlated measurement error from a biological response. Underestimating the phenomenon of correlated measurement error will result in the suggestion of biologically meaningful results that in reality rest solely on complicated error structures. Using proper experimental designs that allow for the quantification of the size of correlated and uncorrelated errors, can help to identify suspicious connections in association networks constructed from (partial) correlations. PMID- 24951434 TI - Knowledge, attitudes, and beliefs that can influence infant feeding practices in American Indian mothers. AB - The promotion of healthy infant feeding is increasingly recognized as an important obesity-prevention strategy. This is relevant for American Indian populations that exhibit high levels of obesity and low compliance with infant feeding guidelines. The literature examining the knowledge, attitudes, and beliefs surrounding infant feeding within the American Indian population is sparse and focuses primarily on breastfeeding, with limited information on the introduction of solid foods and related practices that can be important in an obesity-prevention context. This research presents descriptive findings from a baseline knowledge, attitudes, and beliefs questionnaire on infant feeding and related behaviors administered to mothers (n=438) from five Northwest American Indian tribes that participated in the Prevention of Toddler Overweight and Teeth Health Study (PTOTS). Enrollment occurred during pregnancy or up to 6 months postpartum. The knowledge, attitudes, and beliefs questionnaire focused on themes of breastfeeding/formula feeding and introducing solid foods, with supplemental questions on physical activity. Knowledge questions were multiple choice or true/false. Attitudes and beliefs were assessed on Likert scales. Descriptive statistics included frequencies and percents and means and standard deviations. Most women knew basic breastfeeding recommendations and facts, but fewer recognized the broader health benefits of breastfeeding (eg, reducing diabetes risk) or knew when to introduce solid foods. Women believed breastfeeding to be healthy and perceived their social networks to agree. Attitudes and beliefs about formula feeding and social support were more ambivalent. This work suggests opportunities to increase the perceived value of breastfeeding to include broader health benefits, increase knowledge about solid foods, and strengthen social support. PMID- 24951435 TI - Skin carotenoids: a biomarker of fruit and vegetable intake in children. AB - BACKGROUND: Studies of adult subjects have found a strong correlation between serum carotenoids and skin carotenoids measured by resonance Raman spectroscopy (RRS). No published studies have examined correlations between skin and serum carotenoids among children. OBJECTIVES: We aimed to validate skin RRS methodology against serum carotenoid measurements by high-performance liquid chromatography and to determine whether RRS can be used as a valid biomarker of fruit and vegetable (F/V) intake among children. DESIGN: In our cross-sectional study, participants were 45 healthy children aged 5 to 17 years who provided three blood samples used to assess serum carotenoid concentrations and three RRS skin measurements of the palm within a 4-week period. Dietary intake of F/V was assessed three times within 4 weeks using a 27-item food frequency questionnaire (FFQ) and an automated multiple-pass 24-hour daily recall. Estimates of intake from three FFQs, completed at least 7 days apart, were averaged. Estimates of intake from 24-hour daily recalls were collected on 2 weekdays and 1 weekend day and averaged. RESULTS: Levels of skin and serum carotenoids were highly correlated (R(2)=0.62; P<0.001). A linear regression model, controlling for child's weight and scanner unit, predicted that for every unit increase of total F/V from FFQ and total F/V as assessed by 24-hour daily recall, RRS intensity was predicted to increase by 3,798 (P=0.001) and 3,504 (P=0.001), respectively. Similar results were observed for reported high-carotenoid vegetable intake. Total carotenoid and beta carotene levels from 24-hour daily recalls correlated to total serum carotenoids levels (P<0.01 and P<0.05, respectively). Total carotenoid, alpha carotene, and beta carotene levels from the 24-hour daily recalls correlated to RRS (P<0.01). CONCLUSIONS: Skin carotenoids measured by RRS were strongly correlated with serum carotenoid levels and were positively associated with estimates of intake from FFQ and an automated multiple-pass 24 hour daily recall among children aged 5 to 17 years. Skin carotenoids may be used as valid biomarker of F/V intake among children. PMID- 24951436 TI - Parent-child associations in selected food group and nutrient intakes among overweight and obese adolescents. AB - Few studies have compared parent-child dietary intake among adolescents who are overweight or obese. The purpose of our study was to determine the relationship between parent-teen intake of selected dietary components among this sample. Baseline data from 165 parent and adolescent (aged 11 to 16 years) pairs who presented for a lifestyle behavior modification intervention were collected between 2010 and 2012. Parent and adolescent dietary intake (servings of fruits and vegetables [F/V]; grams of sugar; and percent energy from total fat, saturated fat, dessert/treats, sugar-sweetened beverages, and snacks) was assessed using web-based 24-hour dietary recalls. Multivariable linear and negative binomial regression models identified associations between parent and child dietary intake adjusting for relevant covariates. A large proportion of adolescents and parents did not meet dietary recommendations for F/V, total fat, and saturated fat. Parent-adolescent intake of F/V, total fat, saturated fat, sugar, sugar-sweetened beverages, and snacks were positively associated (r=0.19 to 0.37). No relationship was observed for dessert/treats. In multivariate models, significant interaction effects suggest that the parent-child association in diet was weaker for fat intake among parents with higher educational attainment (b=-.31; P<0.05) and for snacking among adolescent boys (b=-.30; P<.05). Parent intake of several dietary components important for good health, and related to obesity, was associated with adolescent intake. Helping parents improve their diet may promote improvements in their adolescent's diet and is a potential target for interventions designed to increase healthy eating among adolescents. PMID- 24951437 TI - Effect of a physical conditioning versus health promotion intervention in dancers: a randomized controlled trial. AB - Although dancing requires extensive physical exertion, dancers do not often train their physical fitness outside dance classes. Reduced aerobic capacity, lower muscle strength and altered motor control have been suggested as contributing factors for musculoskeletal injuries in dancers. This randomized controlled trial examined whether an intervention program improves aerobic capacity and explosive strength and reduces musculoskeletal injuries in dancers. Forty-four dancers were randomly allocated to a 4-month conditioning (i.e. endurance, strength and motor control training) or health promotion program (educational sessions). Outcome assessment was conducted by blinded assessors. When accounting for differences at baseline, no significant differences were observed between the groups following the intervention, except for the subscale "Pain" of the Short Form 36 Questionnaire (p = 0.03). Injury incidence rate and the proportion of injured dancers were identical in both groups, but dancers following the conditioning program had significant less low back injuries (p = 0.02). Supplementing regular dance training with a 4-month conditioning program does not lead to a significant increase in aerobic capacity or explosive strength in pre-professional dancers compared to a health promotion program without conditioning training, but leads to less reported pain. Further research should explore how additional training may be organized, taking into account the demanding dance schedule of pre professional dancers. The trial is registered at ClinicalTrials.gov, number NCT01440153. PMID- 24951438 TI - Membrane fluidity and temperature sensing are coupled via circuitry comprised of Ole1, Rsp5, and Hsf1 in Candida albicans. AB - Temperature is a ubiquitous environmental variable which can profoundly influence the physiology of living cells as it changes over time and space. When yeast cells are exposed to a sublethal heat shock, normal metabolic functions become repressed and the heat shock transcription factor Hsf1 is activated, inducing heat shock proteins (HSPs). Candida albicans, the most prevalent human fungal pathogen, is an opportunistic pathogen that has evolved as a relatively harmless commensal of healthy individuals. Even though C. albicans occupies thermally buffered niches, it has retained the classic heat shock response, activating Hsf1 during slow thermal transitions such as the increases in temperature suffered by febrile patients. However, the mechanism of temperature sensing in fungal pathogens remains enigmatic. A few studies with Saccharomyces cerevisiae suggest that thermal stress is transduced into a cellular signal at the level of the membrane. In this study, we manipulated the fluidity of C. albicans membrane to dissect mechanisms of temperature sensing. We determined that in response to elevated temperature, levels of OLE1, encoding a fatty acid desaturase, decrease. Subsequently, loss of OLE1 triggers expression of FAS2, encoding a fatty acid synthase. Furthermore, depletion of OLE1 prevents full activation of Hsf1, thereby reducing HSP expression in response to heat shock. This reduction in Hsf1 activation is attributable to the E3 ubiquitin ligase Rsp5, which regulates OLE1 expression. To our knowledge, this is the first study to define a molecular link between fatty acid synthesis and the heat shock response in the fungal kingdom. PMID- 24951440 TI - F-box protein RcyA controls turnover of the kinesin-7 motor KipA in Aspergillus nidulans. AB - Fungal filamentous growth depends on continuous membrane insertion at the tip, the delivery of membrane-bound positional markers, and the secretion of enzymes for cell wall biosynthesis. This is achieved through exocytosis. At the same time, polarized growth requires membrane and protein recycling through endocytosis. Endocytic vesicles are thought to enter the protein degradation pathway or recycle their content to the cell surface. In Saccharomyces cerevisiae, the Rcy1 F-box protein is involved in the recycling process of a v SNARE protein. We identified a Rcy1 orthologue, RcyA, in the filamentous fungus Aspergillus nidulans as a protein interacting with the KipA kinesin-7 motor protein in a yeast two-hybrid screen. The interaction was confirmed through bimolecular fluorescence complementation. RcyA possesses an F-box domain at the N terminus and a prenylation (CaaX) motif at the C terminus. RcyA shows also similarity to Sec10, a component of the exocyst complex. The RcyA protein localized to the hyphal tip and forming septa, likely through transportation on secretory vesicles and partially on early endosomes, but independently of KipA. Deletion of rcyA did not cause severe morphological changes but caused partial defects in the recycling of the SynA v-SNARE protein and the positioning of the cell end markers TeaA and TeaR. In addition, deletion of rcyA led to increased concentrations of the KipA protein, whereas the transcript concentration was unaffected. These results suggest that RcyA probably labels KipA for degradation and thereby controls the protein amount of KipA. PMID- 24951439 TI - How does it kill?: understanding the candidacidal mechanism of salivary histatin 5. AB - Histatins are salivary cationic peptides that provide the first line of defense against oral candidiasis caused by Candida albicans. This minireview presents a critical evaluation of our knowledge of the candidacidal mechanism of histatin 5 (Hst 5). Hst 5 is the most potent among all histatin family members with regard to its antifungal activity. The mode of action of Hst 5 has been a subject of intense debate. Unlike other classical host innate immune proteins, pore formation or membrane lysis by Hst 5 has largely been disproven, and it is now known that all targets of Hst 5 are intracellular. Hst 5 binds C. albicans cell wall proteins (Ssa1/2) and glycans and is taken up by the cells through fungal polyamine transporters in an energy-dependent manner. Once inside the fungal cells, Hst 5 may affect mitochondrial functions and cause oxidative stress; however, the ultimate cause of cell death is by volume dysregulation and ion imbalance triggered by osmotic stress. Besides these diverse targets, a novel mechanism based on the metal binding abilities of Hst 5 is discussed. Finally, translational approaches for Hst 5, based on peptide design and synergy with other known drugs, are considered a step forward for bench-to-bed application of Hst 5. PMID- 24951441 TI - Interplay between Candida albicans and the antimicrobial peptide armory. AB - Antimicrobial peptides (AMPs) are key elements of innate immunity, which can directly kill multiple bacterial, viral, and fungal pathogens. The medically important fungus Candida albicans colonizes different host niches as part of the normal human microbiota. Proliferation of C. albicans is regulated through a complex balance of host immune defense mechanisms and fungal responses. Expression of AMPs against pathogenic fungi is differentially regulated and initiated by interactions of a variety of fungal pathogen-associated molecular patterns (PAMPs) with pattern recognition receptors (PRRs) on human cells. Inflammatory signaling and other environmental stimuli are also essential to control fungal proliferation and to prevent parasitism. To persist in the host, C. albicans has developed a three-phase AMP evasion strategy, including secretion of peptide effectors, AMP efflux pumps, and regulation of signaling pathways. These mechanisms prevent C. albicans from the antifungal activity of the major AMP classes, including cathelicidins, histatins, and defensins leading to a basal resistance. This minireview summarizes human AMP attack and C. albicans resistance mechanisms and current developments in the use of AMPs as antifungal agents. PMID- 24951443 TI - VeA is associated with the response to oxidative stress in the aflatoxin producer Aspergillus flavus. AB - Survival of fungal species depends on the ability of these organisms to respond to environmental stresses. Osmotic stress or high levels of reactive oxygen species (ROS) can cause stress in fungi resulting in growth inhibition. Both eukaryotic and prokaryotic cells have developed numerous mechanisms to counteract and survive the stress in the presence of ROS. In many fungi, the HOG signaling pathway is crucial for the oxidative stress response as well as for osmotic stress response. This study revealed that while the osmotic stress response is only slightly affected by the master regulator veA, this gene, also known to control morphological development and secondary metabolism in numerous fungal species, has a profound effect on the oxidative stress response in the aflatoxin producing fungus Aspergillus flavus. We found that the expression of A. flavus homolog genes involved in the HOG signaling pathway is regulated by veA. Deletion of veA resulted in a reduction in transcription levels of oxidative stress response genes after exposure to hydrogen peroxide. Furthermore, analyses of the effect of VeA on the promoters of cat1 and trxB indicate that the presence of VeA alters DNA-protein complex formation. This is particularly notable in the cat1 promoter, where the absence of VeA results in abnormally stronger complex formation with reduced cat1 expression and more sensitivity to ROS in a veA deletion mutant, suggesting that VeA might prevent binding of negative transcription regulators to the cat1 promoter. Our study also revealed that veA positively influences the expression of the transcription factor gene atfB and that normal formation of DNA-protein complexes in the cat1 promoter is dependent on AtfB. PMID- 24951442 TI - Toxoplasma gondii development of its replicative niche: in its host cell and beyond. AB - Intracellular pathogens can replicate efficiently only after they manipulate and modify their host cells to create an environment conducive to replication. While diverse cellular pathways are targeted by different pathogens, metabolism, membrane and cytoskeletal architecture formation, and cell death are the three primary cellular processes that are modified by infections. Toxoplasma gondii is an obligate intracellular protozoan that infects ~30% of the world's population and causes severe and life-threatening disease in developing fetuses, in immune comprised patients, and in certain otherwise healthy individuals who are primarily found in South America. The high prevalence of Toxoplasma in humans is in large part a result of its ability to modulate these three host cell processes. Here, we highlight recent work defining the mechanisms by which Toxoplasma interacts with these processes. In addition, we hypothesize why some processes are modified not only in the infected host cell but also in neighboring uninfected cells. PMID- 24951444 TI - Aspergillus parasiticus SU-1 genome sequence, predicted chromosome structure, and comparative gene expression under aflatoxin-inducing conditions: evidence that differential expression contributes to species phenotype. AB - The filamentous fungi Aspergillus parasiticus and Aspergillus flavus produce the carcinogenic secondary metabolite aflatoxin on susceptible crops. These species differ in the quantity of aflatoxins B1, B2, G1, and G2 produced in culture, in the ability to produce the mycotoxin cyclopiazonic acid, and in morphology of mycelia and conidiospores. To understand the genetic basis for differences in biochemistry and morphology, we conducted next-generation sequence (NGS) analysis of the A. parasiticus strain SU-1 genome and comparative gene expression (RNA sequence analysis [RNA Seq]) analysis of A. parasiticus SU-1 and A. flavus strain NRRL 3357 (3357) grown under aflatoxin-inducing and -noninducing culture conditions. Although A. parasiticus SU-1 and A. flavus 3357 are highly similar in genome structure and gene organization, we observed differences in the presence of specific mycotoxin gene clusters and differential expression of specific mycotoxin genes and gene clusters that help explain differences in the type and quantity of mycotoxins synthesized. Using computer-aided analysis of secondary metabolite clusters (antiSMASH), we demonstrated that A. parasiticus SU-1 and A. flavus 3357 may carry up to 93 secondary metabolite gene clusters, and surprisingly, up to 10% of the genome appears to be dedicated to secondary metabolite synthesis. The data also suggest that fungus-specific zinc binuclear cluster (C6) transcription factors play an important role in regulation of secondary metabolite cluster expression. Finally, we identified uniquely expressed genes in A. parasiticus SU-1 that encode C6 transcription factors and genes involved in secondary metabolism and stress response/cellular defense. Future work will focus on these differentially expressed A. parasiticus SU-1 loci to reveal their role in determining distinct species characteristics. PMID- 24951445 TI - Superior vena flow quantification in the newborn: reply to a letter by Kluckow and Evans. PMID- 24951448 TI - Giving back: life beyond the echo lab. PMID- 24951447 TI - Creating the future...together. PMID- 24951446 TI - International evidence-based recommendations for focused cardiac ultrasound. AB - BACKGROUND: Focused cardiac ultrasound (FoCUS) is a simplified, clinician performed application of echocardiography that is rapidly expanding in use, especially in emergency and critical care medicine. Performed by appropriately trained clinicians, typically not cardiologists, FoCUS ascertains the essential information needed in critical scenarios for time-sensitive clinical decision making. A need exists for quality evidence-based review and clinical recommendations on its use. METHODS: The World Interactive Network Focused on Critical UltraSound conducted an international, multispecialty, evidence-based, methodologically rigorous consensus process on FoCUS. Thirty-three experts from 16 countries were involved. A systematic multiple-database, double-track literature search (January 1980 to September 2013) was performed. The Grading of Recommendation, Assessment, Development and Evaluation method was used to determine the quality of available evidence and subsequent development of the recommendations. Evidence-based panel judgment and consensus was collected and analyzed by means of the RAND appropriateness method. RESULTS: During four conferences (in New Delhi, Milan, Boston, and Barcelona), 108 statements were elaborated and discussed. Face-to-face debates were held in two rounds using the modified Delphi technique. Disagreement occurred for 10 statements. Weak or conditional recommendations were made for two statements and strong or very strong recommendations for 96. These recommendations delineate the nature, applications, technique, potential benefits, clinical integration, education, and certification principles for FoCUS, both for adults and pediatric patients. CONCLUSIONS: This document presents the results of the first International Conference on FoCUS. For the first time, evidence-based clinical recommendations comprehensively address this branch of point-of-care ultrasound, providing a framework for FoCUS to standardize its application in different clinical settings around the world. PMID- 24951449 TI - Quality in perioperative echocardiography: it's about time. PMID- 24951450 TI - Comparative genotyping of Clostridium thermocellum strains isolated from biogas plants: genetic markers and characterization of cellulolytic potential. AB - Clostridium thermocellum is among the most prevalent of known anaerobic cellulolytic bacteria. In this study, genetic and phenotypic variations among C. thermocellum strains isolated from different biogas plants were determined and different genotyping methods were evaluated on these isolates. At least two C. thermocellum strains were isolated independently from each of nine different biogas plants via enrichment on cellulose. Various DNA-based genotyping methods such as ribotyping, RAPD (Random Amplified Polymorphic DNA) and VNTR (Variable Number of Tandem Repeats) were applied to these isolates. One novel approach - the amplification of unknown target sequences between copies of a previously discovered Random Inserted Mobile Element (RIME) - was also tested. The genotyping method with the highest discriminatory power was found to be the amplification of the sequences between the insertion elements, where isolates from each biogas plant yielded a different band pattern. Cellulolytic potentials, optimal growth conditions and substrate spectra of all isolates were characterized to help identify phenotypic variations. Irrespective of the genotyping method used, the isolates from each individual biogas plant always exhibited identical patterns. This is suggestive of a single C. thermocellum strain exhibiting dominance in each biogas plant. The genotypic groups reflect the results of the physiological characterization of the isolates like substrate diversity and cellulase activity. Conversely, strains isolated across a range of biogas plants differed in their genotyping results and physiological properties. Both strains isolated from one biogas plant had the best specific cellulose degrading properties and might therefore achieve superior substrate utilization yields in biogas fermenters. PMID- 24951451 TI - Photobacterium piscicola sp. nov., isolated from marine fish and spoiled packed cod. AB - Five isolates from marine fish (W3(T), WM, W1S, S2 and S3) and three isolates misclassified as Photobacterium phosphoreum, originating from spoiled modified atmosphere packed stored cod (NCIMB 13482 and NCIMB 13483) and the intestine of skate (NCIMB 192), were subjected to a polyphasic taxonomic study. Phylogenetic analysis of 16S rRNA gene sequences showed that the isolates were members of the genus Photobacterium. Sequence analysis using the gapA, gyrB, pyrH, recA and rpoA loci showed that these isolates formed a distinct branch in the genus Photobacterium, and were most closely related to Photobacterium aquimaris, Photobacterium kishitanii, Photobacterium phosphoreum and Photobacterium iliopiscarium. The luxA gene was present in isolates W3(T), WM, W1S, S2 and S3 but not in NCIMB 13482, NCIMB 13483 and NCIMB 192. AFLP and (GTG)5-PCR fingerprinting indicated that the eight isolates represented at least five distinct genotypes. DNA-DNA hybridizations revealed 89% relatedness between isolate W3(T) and NCIMB 192, and values below 70% with the type strains of the phylogenetically closest species, P. iliopiscarium LMG 19543(T), P. kishitanii LMG 23890(T), P. aquimaris LMG 26951(T) and P. phosphoreum LMG4233(T). The strains of this new taxon could also be distinguished from the latter species by phenotypic characteristics. Therefore, we propose to classify this new taxon as Photobacterium piscicola sp. nov., with W3(T) (=NCCB 100098(T)=LMG 27681(T)) as the type strain. PMID- 24951452 TI - Biomarkers and surrogate endpoints in Duchenne: meeting report. PMID- 24951453 TI - RYR1-related congenital myopathy with fatigable weakness, responding to pyridostigimine. AB - The spectrum of RYR1 mutation associated disease encompasses congenital myopathies, exercise induced rhabdomyolysis, malignant hyperthermia susceptibility and King-Denborough syndrome. We report the clinical phenotype of two siblings who presented in infancy with hypotonia and striking fatigable ptosis. Their response to pyridostigimine was striking, but genetic screening for congenital myasthenic syndromes was negative, prompting further evaluation. Muscle MRI was abnormal with a selective pattern of involvement evocative of RYR1 related myopathy. This directed sequencing of the RYR1 gene, which revealed two heterozygous c.6721C>T (p.Arg2241X) nonsense mutations and novel c.8888T>C (p.Leu2963Pro) mutations in both siblings. These cases broaden the RYR1-related disease spectrum to include a myasthenic-like phenotype, including partial response to pyridostigimine. RYR1-related myopathy should be considered in the presence of fatigable weakness especially if muscle imaging demonstrates structural abnormalities. Single fibre electromyography can also be helpful in cases like this. PMID- 24951454 TI - Intra-articular enzyme replacement therapy with rhIDUA is safe, well-tolerated, and reduces articular GAG storage in the canine model of mucopolysaccharidosis type I. AB - BACKGROUND: Treatment with intravenous enzyme replacement therapy and hematopoietic stem cell transplantation for mucopolysaccharidosis (MPS) type I does not address joint disease, resulting in persistent orthopedic complications and impaired quality of life. A proof-of-concept study was conducted to determine the safety, tolerability, and efficacy of intra-articular recombinant human iduronidase (IA-rhIDUA) enzyme replacement therapy in the canine MPS I model. METHODS: Four MPS I dogs underwent monthly rhIDUA injections (0.58 mg/joint) into the right elbow and knee for 6 months. Contralateral elbows and knees concurrently received normal saline. No intravenous rhIDUA therapy was administered. Monthly blood counts, chemistries, anti-rhIDUA antibody titers, and synovial fluid cell counts were measured. Lysosomal storage of synoviocytes and chondrocytes, synovial macrophages and plasma cells were scored at baseline and 1 month following the final injection. RESULTS: All injections were well-tolerated without adverse reactions. One animal required prednisone for spinal cord compression. There were no clinically significant abnormalities in blood counts or chemistries. Circulating anti-rhIDUA antibody titers gradually increased in all dogs except the prednisone-treated dog; plasma cells, which were absent in all baseline synovial specimens, were predominantly found in synovium of rhIDUA treated joints at study-end. Lysosomal storage in synoviocytes and chondrocytes following 6 months of IA-rhIDUA demonstrated significant reduction compared to tissues at baseline, and saline-treated tissues at study-end. Mean joint synovial GAG levels in IA-rhIDUA joints were 8.62 +/- 5.86 MUg/mg dry weight and 21.6 +/- 10.4 MUg/mg dry weight in control joints (60% reduction). Cartilage heparan sulfate was also reduced in the IA-rhIDUA joints (113 +/- 39.5 ng/g wet weight) compared to saline-treated joints (142 +/- 56.4 ng/g wet weight). Synovial macrophage infiltration, which was present in all joints at baseline, was abolished in rhIDUA-treated joints only. CONCLUSIONS: Intra-articular rhIDUA is well-tolerated and safe in the canine MPS I animal model. Qualitative and quantitative assessments indicate that IA-rhIDUA successfully reduces tissue and cellular GAG storage in synovium and articular cartilage, including cartilage deep to the articular surface, and eliminates inflammatory macrophages from synovial tissue. CLINICAL RELEVANCE: The MPS I canine IA-rhIDUA results suggest that clinical studies should be performed to determine if IA-rhIDUA is a viable approach to ameliorating refractory orthopedic disease in human MPS I. PMID- 24951456 TI - Bias in the evaluation of effects of statins on mortality in patients with heart failure. PMID- 24951457 TI - Large defect-tailored composite scaffolds for in vivo bone regeneration. AB - The discovery of new strategies to repair large segmental bone defects is currently an open challenge for worldwide clinicians. In the treatment of critical-sized bone defects, an alternative strategy to traditional bone grafting is always more frequently the use of tailor-made scaffolds modelled on the final size and shape of the implant site. Here, poly-epsilon-caprolactone-based composite scaffolds including poly-L-lactic acid continuous fibres and hyaluronan derivates (i.e. HYAFF11(r)) have been investigated for the peculiar 3D architecture characterized by interconnected macroporous networks and tunable mechanical properties. Composite scaffolds were immersed in simulated body fluid solution in order to support in vivo tissue in-growth. Scaffolds loaded with autologous cells (bone marrow stromal cells) plus platelet-rich plasma and osteoconductive protein such bone morphogenetic protein-7 were also tested to evaluate eventual enhancement in bone regeneration. The morphological and mechanical properties of poly-L-lactic acid-reinforced composite scaffolds have been studied to identify the optimal scaffold design to match the implant-site requirements of sheep metatarsal defects. Dynamic mechanical tests allowed to underline the viscoelastic response of the scaffold - resulting in elastic moduli from 2.5 to 1.3 MPa, suitable to temporarily support the structural function of damaged bone tissue. In vivo preliminary investigations in a sheep model of metatarsus shaft defect also showed the attitude of the scaffold to promote osteogenesis, preferentially in association with bone marrow stromal cell and platelet-rich plasma, even if the highest amount of mature bone was reached in the case of scaffold loaded with human bone morphogenetic protein-7 released via hydrolytic degradation of HYAFF11(r) phases in the implant site. PMID- 24951458 TI - Fluorescent chitosan functionalized magnetic polymeric nanoparticles: Cytotoxicity and in vitro evaluation of cellular uptake. AB - Nanoparticles possessing magnetic and fluorescent properties were fabricated by the covalent attachment of fluorescein isothiocyanate onto magnetic polymeric nanoparticles functionalized by chitosan. The synthesized magnetic polymeric nanoparticles-chitosan/fluorescein isothiocyanate were successfully used for labeling the living organ and blood-related cancer cells, i.e., HeLa, Hep G2, and K562 cells. The cytotoxicity test of nanoparticles at various incubation times indicated the high cell viability (>90%) without morphological change. The confocal microscopy revealed that they could pass through cell membrane within 2 h for K562 cells and 3 h for HeLa and Hep G2 cells and then confine inside cytoplasm of all types of tested cells for at least 24 h. Therefore, the synthesized magnetic polymeric nanoparticles-chitosan/fluorescein isothiocyanate would potentially be used as cell tracking in theranostic applications. PMID- 24951455 TI - Alzheimer's disease risk genes and mechanisms of disease pathogenesis. AB - We review the genetic risk factors for late-onset Alzheimer's disease (AD) and their role in AD pathogenesis. More recent advances in understanding of the human genome-technologic advances in methods to analyze millions of polymorphisms in thousands of subjects-have revealed new genes associated with AD risk, including ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5 DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4-RIN3, SORL1, and ZCWPW1. Emerging technologies to analyze the entire genome in large data sets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathologic features of AD. Understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date. PMID- 24951459 TI - Modern mammography screening and breast cancer mortality: population study. AB - OBJECTIVE: To evaluate the effectiveness of contemporary mammography screening using individual information about screening history and breast cancer mortality from public screening programmes. DESIGN: Prospective cohort study of Norwegian women who were followed between 1986 and 2009. Within that period (1995-2005), a national mammography screening programme was gradually implemented, with biennial invitations sent to women aged 50-69 years. PARTICIPANTS: All Norwegian women aged 50-79 between 1986 and 2009. MAIN OUTCOME MEASURES: Multiple Poisson regression analysis was used to estimate breast cancer mortality rate ratios comparing women who were invited to screening (intention to screen) with women who were not invited, with a clear distinction between cases of breast cancer diagnosed before (without potential for screening effect) and after (with potential for screening effect) the first invitation for screening. We took competing causes of death into account by censoring women from further follow-up who died from other causes. Based on the observed mortality reduction combined with the all cause and breast cancer specific mortality in Norway in 2009, we used the CISNET (Cancer Intervention and Surveillance Modeling Network) Stanford simulation model to estimate how many women would need to be invited to biennial mammography screening in the age group 50-69 years to prevent one breast cancer death during their lifetime. RESULTS: During 15 193 034 person years of observation (1986-2009), deaths from breast cancer occurred in 1175 women with a diagnosis after being invited to screening and 8996 women who had not been invited before diagnosis. After adjustment for age, birth cohort, county of residence, and national trends in deaths from breast cancer, the mortality rate ratio associated with being invited to mammography screening was 0.72 (95% confidence interval 0.64 to 0.79). To prevent one death from breast cancer, 368 (95% confidence interval 266 to 508) women would need to be invited to screening. CONCLUSION: Invitation to modern mammography screening may reduce deaths from breast cancer by about 28%. PMID- 24951460 TI - Withdrawal of ventilatory support outside the intensive care unit: guidance for practice. AB - OBJECTIVE: To review the work of one tertiary paediatric palliative care service in facilitating planned withdrawal of ventilatory support outside the intensive care setting, with the purpose of developing local guidance for practice. METHODS: Retrospective 10-year (2003-2012) case note review of intensive care patients whose parents elected to withdraw ventilation in another setting. Demographic and clinical data revealed common themes and specific incidents relevant to local guideline development. RESULTS: 18 children (aged 2 weeks to 16 years) were considered. Three died prior to transfer. Transfer locations included home (5), hospice (8) and other (2). Primary pathologies included malignant, neurological, renal and respiratory diseases. Collaborative working was evidenced in the review including multidisciplinary team meetings with the palliative care team prior to discharge. Planning included development of symptom management plans and emergency care plans in the event of longer than anticipated survival. Transfer of children and management of extubations demonstrated the benefits of planning and recognition that unexpected events occur despite detailed planning. We identified the need for local written guidance supporting healthcare professionals planning and undertaking extubation outside the intensive care setting, addressing the following phases: (i) introduction of withdrawal, (ii) preparation pretransfer, (iii) extubation, (iv) care postextubation and (v) care postdeath. CONCLUSIONS: Planned withdrawal of ventilatory support outside the intensive care setting is challenging and resource intensive. The development of local collaborations and guidance can enable parents of children dependent on intensive care to consider a preferred place of death for their child, which may be outside the intensive care unit. PMID- 24951461 TI - Does sexually transmitted infection always mean sexual abuse in young children? PMID- 24951462 TI - Diagnostic accuracy of ultrasonography for hand bony fractures in paediatric patients. AB - OBJECTIVE: Hand fractures are common in childhood, and radiography is the standard diagnostic procedure. US has been used to evaluate bone injuries, mainly in adults for long-bone trauma; there are only a few studies about hand fractures in children. The purpose of this study was to evaluate and confirm the safety and applicability of the US diagnostic procedure in comparison to X-ray diagnosis. STUDY DESIGN: This cross-sectional study involved a convenience sample of young patients (between 2 and 17 years old) who were taken to the emergency department due to hand trauma. After clinical assessment, patients with a suspected hand fracture first underwent X-ray, and subsequently US examination by two different operators; a radiologist experienced in US and a trained emergency physician in "double-blind" fashion. US and radiographic findings were then compared, and sensitivity as well as specificity was calculated. RESULTS: A total of 204 patients were enrolled in the study. Seventy-nine fractures of phalanges or metacarpals were detected by standard radiography. When US imaging was performed by an expert radiologist, 72 fractures were detected with sensitivity and a specificity of 91.1% and 97.6%, respectively. Sensitivity and specificity were found to be (respectively) 91.5% and 96.8% when US was performed by the ED physicians. CONCLUSIONS: US imaging showed excellent sensitivity and specificity results in the diagnosis of hand fractures in children. The study also showed a great agreement between the results of the US carried out by the senior radiologist and those carried out by the paediatric emergency physician, suggesting that US can be performed by an ED physician, allowing a rapid and accurate evaluation in ED and could become the first diagnostic approach whenever a hand fracture is suspected. PMID- 24951463 TI - Epidemiology of paediatric firearm injuries. PMID- 24951464 TI - NFE2 regulates transcription of multiple enzymes in the heme biosynthesis pathway. PMID- 24951465 TI - PDGFRB-rearranged T-lymphoblastic leukemia/lymphoma occurring with myeloid neoplasms: the missing link supporting a stem cell origin. PMID- 24951466 TI - Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction. AB - The NUP98-NSD1 fusion, product of the t(5;11)(q35;p15.5) chromosomal translocation, is one of the most prevalent genetic alterations in cytogenetically normal pediatric acute myeloid leukemias and is associated with poor prognosis. Co-existence of an FLT3-ITD activating mutation has been found in more than 70% of NUP98-NSD1-positive patients. To address functional synergism, we determined the transforming potential of retrovirally expressed NUP98-NSD1 and FLT3-ITD in the mouse. Expression of NUP98-NSD1 provided mouse strain-dependent, aberrant self-renewal potential to bone marrow progenitor cells. Co-expression of FLT3-ITD increased proliferation and maintained self-renewal in vitro. Transplantation of immortalized progenitors co-expressing NUP98-NSD1 and FLT3-ITD into mice resulted in acute myeloid leukemia after a short latency. In contrast, neither NUP98-NSD1 nor FLT3-ITD single transduced cells were able to initiate leukemia. Interestingly, as reported for patients carrying NUP98-NSD1, an increased Flt3-ITD to wild-type Flt3 mRNA expression ratio with increased FLT3 signaling was associated with rapidly induced disease. In contrast, there was no difference in the expression levels of the NUP98-NSD1 fusion or its proposed targets HoxA5, HoxA7, HoxA9 or HoxA10 between animals with different latencies to develop disease. Finally, leukemic cells co-expressing NUP98-NSD1 and FLT3-ITD were very sensitive to a small molecule FLT3 inhibitor, which underlines the significance of aberrant FLT3 signaling for NUP98-NSD1-positive leukemias and suggests new therapeutic approaches that could potentially improve patient outcome. PMID- 24951467 TI - Results from a clofarabine-busulfan-containing, reduced-toxicity conditioning regimen prior to allogeneic stem cell transplantation: the phase 2 prospective CLORIC trial. AB - We prospectively evaluated the safety and efficacy of a clofarabine, intravenous busulfan and antithymocyte globulin-based reduced-toxicity conditioning (CloB2A2) regimen before allogeneic stem cell transplantation. Thirty high-risk patients (median age: 59 years; acute myeloid leukemia n=11, acute lymphoblastic leukemia n=13; myelodysplastic syndrome n=5, bi-phenotypic leukemia n=1) were included in this phase 2 study. At time of their transplant, 20 and seven patients were in first and second complete remission, respectively, while three patients with myelodysplastic syndrome were responding to chemotherapy or who had not been previously treated. The CloB2A2 regimen consisted of clofarabine 30 mg/m(2)/day for 4 days, busulfan 3.2 mg/kg/day for 2 days and antithymocyte globulin 2.5 mg/kg/day for 2 days. The median follow-up was 23 months. Engraftment occurred in all patients. The 1-year overall survival, leukemia-free survival, relapse incidence and non-relapse mortality rates were 63+/-9%, 57+/-9%, 40+/-9%, and 3.3+/-3%, respectively. Comparing patients with acute myeloid leukemia/myelodysplastic syndrome versus those with acute lymphoblastic leukemia/bi-phenotypic leukemia, the 1-year overall and leukemia-free survival rates were 75+/-10% versus 50+/-13%, respectively (P=0.07) and 69+/-12% versus 43+/-13%, respectively (P=0.08), while the 1-year relapse incidence was 25+/-11% versus 57+/-14%, respectively (P=0.05). The CloB2A2 regimen prior to allogeneic stem cell transplantation is feasible, allowing for full engraftment and low toxicity. Disease control appears to be satisfactory, especially in patients with acute myeloid leukemia/myelodysplastic syndrome. The trial was registered at www.clinicaltrials.gov no. NCT00863148. PMID- 24951469 TI - Challenges and promises in modeling dermatologic disorders with bioengineered skin. AB - The tremendous cost of drug development is often attributed to the long time interval between identifying lead compounds in preclinical studies to assessing clinical efficacy in randomized clinical trials. Many candidate molecules show promise in cell culture or animal models, only to fail in late stage in human investigations. There is a need for novel technologies that allow investigators to quickly and reliably predict drug safety and efficacy. The advent of microtechnology has made it possible to integrate multiple microphysiologic organ systems into a single microfabricated chip. This review focuses on three dimensional engineered skin, which has enjoyed a long history of uses both in clinical treatments of refractory ulcers and as a laboratory model. We discuss current biological and engineering challenges in construction of a robust bioengineered skin and provide a blueprint for its potential utility to model dermatologic disorders such as psoriasis or cutaneous drug reactions. PMID- 24951468 TI - Health-related quality of life in children with newly diagnosed immune thrombocytopenia. AB - Despite its generally transient and benign course, childhood immune thrombocytopenia has a large impact on health-related quality of life. Recently published guidelines state that quality of life should be taken into account while making decisions on management in childhood immune thrombocytopenia. We, therefore, assessed health-related quality of life in children with newly diagnosed immune thrombocytopenia in a prospective multicenter study. One hundred and seven children aged 6 months-16 years (mean age 5.57 years) were included. We used Pediatric Quality of Life InventoryTM and Kids' ITP Tools questionnaires at diagnosis and during standardized follow-up. Scores on the Pediatric Quality of Life InventoryTM Core Scales were compared with those of healthy children. Relationships between health-related quality of life scores and treatment modality, bleeding tendency and course of the disease were examined. Kids' ITP Tools proxy reports and parent self-reports showed significant higher health related quality of life scores in children who recovered than in children with persistent immune thrombocytopenia (at 3 months: Kids' ITP Tools parent self report score 80.85 for recovered patients (n=69) versus 58.98 for patients with persistent disease (n=21), P<0.001). No significant differences in health-related quality of life were found between children with mild or moderate bleeding or between children who received intravenous immunoglobulin or children who were carefully observed. In conclusion, health-related quality of life of children with newly diagnosed immune thrombocytopenia is not influenced by treatment modality or bleeding severity, but only by clinical course of the disease. (Dutch Trial Register identifier: NTR TC1563). PMID- 24951472 TI - Caspase-dependent Mcl-1 cleavage and effect of Mcl-1 phosphorylation in ABT-737 induced apoptosis in human acute lymphoblastic leukemia cell lines. AB - ABT-737 is a BH3-mimetic that has a wide spectrum of single-agent activity against acute lymphoblastic leukemia (ALL) cell lines and xenografts. Previously, we reported that in response to ABT-737, ABT-737-resistant ALL cell lines showed an apparent increase in Mcl-1 (an anti-apoptotic Bcl-2 family protein that is not effectively inhibited by ABT-737) while ABT-737-sensitive ALL cell lines showed decreased Mcl-1 levels. Here we explored the mechanism of Mcl-1 cleavage by ABT 737 and the effect of adjacent phosphorylation sites on Mcl-1 cleavage and apoptosis induced by ABT-737 in a human B-lineage ALL cell line. Caspase cleavage sites in Mcl-1 and the effect of mutation in Mcl-1 phosphorylation sites were determined by transducing Mcl-1 variants tagged with the V5 epitope into human ALL cells. Cytotoxicity was by fluorescence-based DIMSCAN, and changes in protein by immunoblotting. ABT-737 induced a caspase-dependent cleavage of Mcl-1. Of the two Mcl-1 caspase cleavage sites (D127 and D157), D157 was the site of ABT-737 induced cleavage in ALL cells. Cells with exogenously expressed Mcl-1 Delta157 fragment showed greater caspase-3 and caspase-9 activation when they were treated with ABT-737 compared with cells expressing wild-type or D157A mutant Mcl-1. Cells with mutated phosphorylation sites on Mcl-1 (S159A and T163A) were less susceptible to Mcl-1 cleavage and apoptosis induced by ABT-737. Our data showed that Mcl-1 is post-translationally regulated in response to ABT-737 treatment, primarily via a caspase-dependent cleavage that generates a pro-apoptotic Mcl-1 fragment. PMID- 24951473 TI - Distinct adipogenic differentiation phenotypes of human umbilical cord mesenchymal cells dependent on adipogenic conditions. AB - The umbilical cord (UC) matrix is a source of multipotent mesenchymal stem cells (MSCs) that have adipogenic potential and thus can be a model to study adipogenesis. However, existing variability in adipocytic differentiation outcomes may be due to discrepancies in methods utilized for adipogenic differentiation. Additionally, functional characterization of UCMSCs as adipocytes has not been described. We tested the potential of three well established adipogenic cocktails containing IBMX, dexamethasone, and insulin (MDI) plus indomethacin (MDI-I) or rosiglitazone (MDI-R) to stimulate adipocyte differentiation in UCMSCs. MDI, MDI-I, and MDI-R treatment significantly increased peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT enhancer binding protein alpha (C/EBPalpha) mRNA and induced lipid droplet formation. However, MDI-I had the greatest impact on mRNA expression of PPARgamma, C/EBPalpha, FABP4, GPD1, PLIN1, PLIN2, and ADIPOQ and lipid accumulation, whereas MDI showed the least. Interestingly, there were no treatment group differences in the amount of PPARgamma protein. However, MDI-I treated cells had significantly more C/EBPalpha protein compared to MDI or MDI-R, suggesting that indomethacin-dependent increased C/EBPalpha may contribute to the adipogenesis-inducing potency of MDI-I. Additionally, bone morphogenetic protein 4 (BMP4) treatment of UCMSCs did not enhance responsiveness to MDI-induced differentiation. Finally to characterize adipocyte function, differentiated UCMSCs were stimulated with insulin and downstream signaling was assessed. Differentiated UCMSCs were responsive to insulin at two weeks but showed decreased sensitivity by five weeks following differentiation, suggesting that long-term differentiation may induce insulin resistance. Together, these data indicate that UCMSCs undergo adipogenesis when differentiated in MDI, MDI-I, and MDI-R, however the presence of indomethacin greatly enhances their adipogenic potential beyond that of rosiglitazone. Furthermore, our results suggest that insulin signaling pathways of differentiated UCMSCs are functionally similar to adipocytes. PMID- 24951471 TI - Using physiologically-based pharmacokinetic-guided "body-on-a-chip" systems to predict mammalian response to drug and chemical exposure. AB - The continued development of in vitro systems that accurately emulate human response to drugs or chemical agents will impact drug development, our understanding of chemical toxicity, and enhance our ability to respond to threats from chemical or biological agents. A promising technology is to build microscale replicas of humans that capture essential elements of physiology, pharmacology, and/or toxicology (microphysiological systems). Here, we review progress on systems for microscale models of mammalian systems that include two or more integrated cellular components. These systems are described as a "body-on-a chip", and utilize the concept of physiologically-based pharmacokinetic (PBPK) modeling in the design. These microscale systems can also be used as model systems to predict whole-body responses to drugs as well as study the mechanism of action of drugs using PBPK analysis. In this review, we provide examples of various approaches to construct such systems with a focus on their physiological usefulness and various approaches to measure responses (e.g. chemical, electrical, or mechanical force and cellular viability and morphology). While the goal is to predict human response, other mammalian cell types can be utilized with the same principle to predict animal response. These systems will be evaluated on their potential to be physiologically accurate, to provide effective and efficient platform for analytics with accessibility to a wide range of users, for ease of incorporation of analytics, functional for weeks to months, and the ability to replicate previously observed human responses. PMID- 24951475 TI - CSF-venous fistula in spontaneous intracranial hypotension. PMID- 24951470 TI - Bile acid dysregulation, gut dysbiosis, and gastrointestinal cancer. AB - Because of increasingly widespread sedentary lifestyles and diets high in fat and sugar, the global diabetes and obesity epidemic continues to grow unabated. A substantial body of evidence has been accumulated which associates diabetes and obesity to dramatically higher risk of cancer development, particularly in the liver and gastrointestinal tract. Additionally, diabetic and obese individuals have been shown to suffer from dysregulation of bile acid (BA) homeostasis and dysbiosis of the intestinal microbiome. Abnormally elevated levels of cytotoxic secondary BAs and a pro-inflammatory shift in gut microbial profile have individually been linked to numerous enterohepatic diseases including cancer. However, recent findings have implicated a detrimental interplay between BA dysregulation and intestinal dysbiosis that promotes carcinogenesis along the gut liver axis. This review seeks to examine the currently investigated interactions between the regulation of BA metabolism and activity of the intestinal microbiota and how these interactions can drive cancer formation in the context of diabesity. The precarcinogenic effects of BA dysregulation and gut dysbiosis including excessive inflammation, heightened oxidative DNA damage, and increased cell proliferation are discussed. Furthermore, by focusing on the mediatory roles of BA nuclear receptor farnesoid x receptor, ileal transporter apical sodium dependent BA transporter, and G-coupled protein receptor TGR5, this review attempts to connect BA dysregulation, gut dysbiosis, and enterohepatic carcinogenesis at a mechanistic level. A better understanding of the intricate interplay between BA homeostasis and gut microbiome can yield novel avenues to combat the impending rise in diabesity-related cancers. PMID- 24951476 TI - Connectivity at a crossroads: what white matter integrity can tell us about cognitive impairment. PMID- 24951474 TI - Neuropsychological changes in asymptomatic persons with Alzheimer disease neuropathology. AB - OBJECTIVE: To determine whether asymptomatic persons with Alzheimer disease (AD) neuropathologic change differ in the trajectory of their cognitive performance compared to asymptomatic persons without AD neuropathologic change. METHODS: Longitudinal performance on standard neuropsychological tests was examined in participants who died within 2 years of their last cognitive assessment and who were never diagnosed with mild cognitive impairment or dementia (Clinical Dementia Rating global score of 0 at all assessments). Using cognitive and neuropathologic data collected between 2005 and 2013 from the 34 National Institute on Aging-sponsored Alzheimer's Disease Centers, cognitive trajectories were compared for persons with and without evidence of AD neuropathologic change. We evaluated rates of decline in 4 domains (episodic memory, language, attention/working memory, executive function). The significance of the differences (beta) in rates of decline was tested using linear regression, adjusting for age, education, sex, and other neuropathologic lesions. RESULTS: Participants who had low to high levels of AD neuropathologic change (n = 131) showed a greater rate of decline on the attention/working memory domain score (beta = -0.11; 95% confidence interval = -0.19, -0.02; p = 0.02) when compared to 80 participants who died without evidence of AD neuropathologic change. CONCLUSIONS: Clinically normal individuals who come to autopsy with AD neuropathologic change exhibit subtle evidence of declining cognitive trajectories for attention/working memory. PMID- 24951478 TI - Predictors for readmissions after video-EEG monitoring. AB - OBJECTIVE: Identification of variables prognosticating 30-day readmission among adult patients admitted for video-EEG (VEEG) monitoring at a major epilepsy center. METHODS: A retrospective cohort study was conducted, examining 865 consecutive admissions to the epilepsy monitoring unit (EMU) from January 2010 to June 2013. Data extracted from chart review included demographics, length of stay (LOS), seizure type(s), number of 30-day readmissions or emergency department (ED) visits and reasons for these, and patient and system/provider factors potentially contributing to the readmission. RESULTS: Of 865 elective admissions for VEEG monitoring, 49 patients accounted for 33 readmissions and 40 ED visits within 30 days of discharge for an overall 30-day encounter rate of 7.0% after excluding those lost to follow-up; 9 patients had more than one ED visit or readmission. Statistically significant risk factors for urgent 30-day encounters included a history of nonepileptic seizures (NES) (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.1-3.4), a dual diagnosis of both epilepsy and NES (OR 5.9, 95% CI 3.0-11.8), an urgent index admission to the EMU (OR 2.5, 95%CI 1.4 4.8), and a shorter LOS of index hospitalization (median 4.0 days vs 5.0 days, p < 0.01). The most common contributing patient factors included active psychiatric symptoms, medically refractory epilepsy, and living alone; the most common hospitalization-related factors included antiepileptic drug (AED) treatment adverse events or AED adjustment. CONCLUSIONS: In addition to the presence of intractable epilepsy and shorter LOS, mental health comorbidities and the presence of NES were important risk factors for 30-day readmissions and ED visits in the epilepsy population. Therefore, proactively addressing mental health comorbidities may decrease urgent health care utilization after VEEG monitoring. PMID- 24951477 TI - Structural network efficiency is associated with cognitive impairment in small vessel disease. AB - OBJECTIVE: To characterize brain network connectivity impairment in cerebral small-vessel disease (SVD) and its relationship with MRI disease markers and cognitive impairment. METHODS: A cross-sectional design applied graph-based efficiency analysis to deterministic diffusion tensor tractography data from 115 patients with lacunar infarction and leukoaraiosis and 50 healthy individuals. Structural connectivity was estimated between 90 cortical and subcortical brain regions and efficiency measures of resulting graphs were analyzed. Networks were compared between SVD and control groups, and associations between efficiency measures, conventional MRI disease markers, and cognitive function were tested. RESULTS: Brain diffusion tensor tractography network connectivity was significantly reduced in SVD: networks were less dense, connection weights were lower, and measures of network efficiency were significantly disrupted. The degree of brain network disruption was associated with MRI measures of disease severity and cognitive function. In multiple regression models controlling for confounding variables, associations with cognition were stronger for network measures than other MRI measures including conventional diffusion tensor imaging measures. A total mediation effect was observed for the association between fractional anisotropy and mean diffusivity measures and executive function and processing speed. CONCLUSIONS: Brain network connectivity in SVD is disturbed, this disturbance is related to disease severity, and within a mediation framework fully or partly explains previously observed associations between MRI measures and SVD-related cognitive dysfunction. These cross-sectional results highlight the importance of network disruption in SVD and provide support for network measures as a disease marker in treatment studies. PMID- 24951479 TI - Proline responding1 Plays a Critical Role in Regulating General Protein Synthesis and the Cell Cycle in Maize. AB - Proline, an important amino acid, accumulates in many plant species. Besides its role in plant cell responses to environmental stresses, the potential biological functions of proline in growth and development are unclear. Here, we report cloning and functional characterization of the maize (Zea mays) classic mutant proline responding1 (pro1) gene. This gene encodes a Delta1-pyrroline-5- carboxylate synthetase that catalyzes the biosynthesis of proline from glutamic acid. Loss of function of Pro1 significantly inhibits proline biosynthesis and decreases its accumulation in the pro1 mutant. Proline deficiency results in an increased level of uncharged tRNApro AGG accumulation and triggers the phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) in the pro1 mutant, leading to a general reduction in protein synthesis in this mutant. Proline deficiency also downregulates major cyclin genes at the transcriptional level, causing cell cycle arrest and suppression of cell proliferation. These processes are reversible when external proline is supplied to the mutant, suggesting that proline plays a regulatory role in the cell cycle transition. Together, the results demonstrate that proline plays an important role in the regulation of general protein synthesis and the cell cycle transition in plants. PMID- 24951482 TI - Former GP is new chair of House of Commons Health Committee. PMID- 24951481 TI - Plasticity in Cell Division Patterns and Auxin Transport Dependency during in Vitro Embryogenesis in Brassica napus. AB - In Arabidopsis thaliana, zygotic embryo divisions are highly regular, but it is not clear how embryo patterning is established in species or culture systems with irregular cell divisions. We investigated this using the Brassica napus microspore embryogenesis system, where the male gametophyte is reprogrammed in vitro to form haploid embryos in the absence of exogenous growth regulators. Microspore embryos are formed via two pathways: a zygotic-like pathway, characterized by initial suspensor formation followed by embryo proper formation from the distal cell of the suspensor, and a pathway characterized by initially unorganized embryos lacking a suspensor. Using embryo fate and auxin markers, we show that the zygotic-like pathway requires polar auxin transport for embryo proper specification from the suspensor, while the suspensorless pathway is polar auxin transport independent and marked by an initial auxin maximum, suggesting early embryo proper establishment in the absence of a basal suspensor. Polarity establishment in this suspensorless pathway was triggered and guided by rupture of the pollen exine. Irregular division patterns did not affect cell fate establishment in either pathway. These results confirm the importance of the suspensor and suspensor-driven auxin transport in patterning, but also uncover a mechanism where cell patterning is less regular and independent of auxin transport. PMID- 24951480 TI - COP1 and phyB Physically Interact with PIL1 to Regulate Its Stability and Photomorphogenic Development in Arabidopsis. AB - In Arabidopsis thaliana, the cryptochrome and phytochrome photoreceptors act together to promote photomorphogenic development. The cryptochrome and phytochrome signaling mechanisms interact directly with CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1), a RING motif-containing E3 ligase that acts to negatively regulate photomorphogenesis. COP1 interacts with and ubiquitinates the transcription factors that promote photomorphogenesis, such as ELONGATED HYPOCOTYL5 and LONG HYPOCOTYL IN FAR-RED1 (HFR1), to inhibit photomorphogenic development. Here, we show that COP1 physically interacts with PIF3-LIKE1 (PIL1) and promotes PIL1 degradation via the 26S proteasome. We further demonstrate that phyB physically interacts with PIL1 and enhances PIL1 protein accumulation upon red light irradiation, probably through suppressing the COP1-PIL1 association. Biochemical and genetic studies indicate that PIL1 and HFR1 form heterodimers and promote photomorphogenesis cooperatively. Moreover, we demonstrate that PIL1 interacts with PIF1, 3, 4, and 5, resulting in the inhibition of the transcription of PIF direct-target genes. Our results reveal that PIL1 stability is regulated by phyB and COP1, likely through physical interactions, and that PIL1 coordinates with HFR1 to inhibit the transcriptional activity of PIFs, suggesting that PIL1, HFR1, and PIFs constitute a subset of antagonistic basic helix-loop-helix factors acting downstream of phyB and COP1 to regulate photomorphogenic development. PMID- 24951483 TI - Minimally invasive reconstruction of the lateral ankle ligaments using semitendinosus autograft or tendon allograft. AB - BACKGROUND: The purpose of the study was to retrospectively compare the therapeutic effect between semitendinosus autograft and tendon allograft for lateral ankle ligaments reconstruction. METHODS: From September 2006 to June 2011, 68 patients (41 males, 27 females) with chronic ankle instability underwent anatomical reconstruction of the lateral ligaments using semitendinosus autograft (autograft group, 32 patients) or tendon allograft (allograft group, 36 patients) via a minimally invasive approach. All patients were followed up for at least 12 months. The American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale score (AOFAS score) and stress tests were used to evaluate the clinical outcomes. Operation time, time to heal and complications were also recorded. RESULTS: Compared with allograft group, the average operation time was significantly increased (85.5 +/- 11.5 minutes vs 58.1 +/- 10.2 minutes, P < .0001), but the mean time to heal was significantly shorter (11.2 +/- 4.1 months vs 13.5 +/- 5.2 months, P = .0458) in the autograft group. Although the mean AOFAS score was significantly increased at the final follow-up in the autograft group (95.1 +/- 7.5 vs 62.3 +/- 8.2, P = .0001) and allograft group (94.8 +/- 5.5 vs 60.2 +/- 8.4, P < .0001), no significant difference in AOFAS was found between these 2 groups. Similarly, there was no significant difference in talar tilt or shift between autograft and allograft groups. In addition, no patients complained of weakness or disability at the donor site in the autograft group, while incisional swelling was observed in 4 patients in the allograft group, which was resolved via dressing change, oral use of indomethacin or dexamethasone. CONCLUSION: Reconstruction of the lateral ankle ligaments using a semitendinosus tendon autograft and a minimally invasive approach was safe and effective for ankle instability with a relatively short time for healing and minimal donor site problems. LEVEL OF EVIDENCE: Level III, comparative case series. PMID- 24951484 TI - Vitamin D deficiency and pregnancy rates in women undergoing single embryo, blastocyst stage, transfer (SET) for IVF/ICSI. AB - STUDY QUESTION: What is the influence of vitamin D deficiency on pregnancy rates among women undergoing IVF/ICSI and Day 5 (blastocyst stage) single embryo transfer (SET)? SUMMARY ANSWER: Vitamin D deficiency results in significantly lower pregnancy rates in women undergoing single blastocyst transfer. WHAT IS KNOWN ALREADY: Preliminary experiments have identified the presence of vitamin D receptors in the female reproductive system. However, results regarding the effect of vitamin D deficiency on clinical outcomes are conflicting. None of the previous studies adopted a SET strategy. STUDY DESIGN, SIZE, DURATION: Serum vitamin D concentration was measured retrospectively in patients who underwent SET on Day 5. Overall 368 consecutive infertile women treated within a period of 15 months were included in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients underwent ovarian stimulation for IVF/ICSI and Day 5 SET. Serum samples were obtained 7 days prior to embryo transfer and stored frozen at -20 degrees C. Samples were collectively analyzed for their 25-OH vitamin D content. Vitamin D deficiency was defined as serum 25-OH vitamin D levels <20 ng/ml in accordance with the Institute of Medicine and the Endocrine Society clinical practice guidelines. MAIN RESULTS AND THE ROLE OF CHANCE: Clinical pregnancy rates were significantly lower in women with vitamin D deficiency compared with those with higher vitamin D values (41 versus 54%, P = 0.015).Logistic regression analysis was performed to identify whether vitamin D deficiency is independently associated with clinical pregnancy rates after controlling for 16 potential confounding factors. According to our results vitamin D deficiency was independently associated with lower clinical pregnancy rates, odds ratios [ORs (95% confidence interval (CI) 0.61 (0.39-0.95)] for vitamin D deficiency (deficient versus non-deficient women), P = 0.030. Finally, even when restricting our analysis to women undergoing elective SET (274 patients), vitamin D deficiency was again independently associated with pregnancy rates [OR (95% CI) 0.56 (0.33-0.93), P = 0.024]. LIMITATIONS, REASONS FOR CAUTION: Our results refer only to patients undergoing Day 5 SET. Although vitamin D deficiency appears to compromise pregnancy rates in this population, no guidance can be provided regarding a potential relationship between vitamin D deficiency and ovarian reserve or response to ovarian stimulation. WIDER IMPLICATIONS OF THE FINDINGS: Vitamin D deficiency impairs pregnancy rates in women undergoing single blastocyst transfer. Future prospective confirmatory studies are needed to validate our results and examine the exact underlying mechanism by which vitamin D levels may impair pregnancy rates in infertile women undergoing IVF/ICSI. STUDY FUNDING/COMPETING INTERESTS: None declared. PMID- 24951485 TI - Brain MRI to personalise atrial fibrillation therapy: current evidence and perspectives. AB - Advances in the access to and in the performance of brain MRI have led to an increased detection of asymptomatic abnormalities in the brain of patients with cardiovascular diseases. These may have prognostic impact and could influence management in the future. In this review, we summarise the main findings of brain MRI in patients with atrial fibrillation (AF) and explore the available evidence to better quantify the risk for intracerebral haemorrhage and (recurrent) ischaemic stroke based on brain MRI findings. Treatment decisions in the majority of patients with AF should still be based on data from established validated risk scores and large randomised trials. Whether brain MRI has the potential to improve the personalised management of patients with AF by guiding the risk and benefit assessment of stroke prevention by oral anticoagulants remains to be established in large prospective studies using standardised brain MRI. However, even today, brain MRI may help to identify subsets of patients with AF at increased risk for (recurrent) intracerebral bleeding. Although present knowledge and MRI-associated costs do not support routine use of brain MRI in asymptomatic patients with AF, as more data emerge MRI may become an increasingly useful way to stratify patients with AF and individualise their treatment. PMID- 24951486 TI - Atrial fibrillation associated with ivabradine treatment: meta-analysis of randomised controlled trials. AB - OBJECTIVE: To quantify any risk of atrial fibrillation (AF) associated with ivabradine treatment by meta-analysis of clinical trial data. METHODS: Medline, Embase, Web of Knowledge and the Cochrane central register of controlled trials were searched for double-blinded randomised controlled trials of ivabradine with a minimum follow-up period of 4 weeks. For studies where AF data were unpublished, safety data were obtained from the European Medicines Agency (EMeA) website and personal communications. Studies were appraised for risk of bias using components recommended by the Cochrane Collaboration. Meta-analyses were performed of relative risk of AF and absolute risk difference of AF per year of treatment. The main outcome measure was incident AF during the follow-up period. RESULTS: AF data were available from 11 studies: one from the published report, six from the EMeA and four from personal communications. Ivabradine treatment was associated with a relative risk of AF of 1.15 (95% CI 1.07 to 1.24, p=0.0027) among 21 571 patients in the meta-analysis. From this we estimated that the number needed to harm for ivabradine would be 208 (95% CI 122 to 667) per year of treatment. CONCLUSIONS: AF is a substantially more common side effect of ivabradine treatment than one patient in 10 000, the risk presently reported in the product literature. The incidence of AF has not routinely been reported in clinical trials of ivabradine. PMID- 24951488 TI - Tribunal suspends doctor for acting as expert witness beyond his competence. PMID- 24951487 TI - Trafficking of Vacuolar Sorting Receptors: New Data and New Problems. PMID- 24951489 TI - The CDC Clear Communication Index is a new evidence-based tool to prepare and review health information. AB - This article presents the Centers for Disease Control and Prevention Clear Communication Index (the Index), a tool that emphasizes the primary audience's needs and provides a set of evidence-based criteria to develop and assess public communication products for diverse audiences. The Index consists of four open ended introductory questions and 20 scored items that affect information clarity and audience comprehension, according to the scientific literature. A research team fielded an online survey to test the Index's validity. Respondents answered 10 questions about either an original health material or one redesigned with the Index. For 9 out of 10 questions, the materials revised using the Index were rated higher than the original materials. Regardless of education level, respondents rated the revised materials more favorably than the original ones. The results indicate that the Index performed as intended and made it more likely that audiences could correctly identify the intended main message and understand the words and numbers in the materials. The results also support the widely held view that audiences are more positive about clearly designed materials. The Index shows that an evidence-based scoring rubric can assess and improve the clarity of health materials. PMID- 24951490 TI - Reproductive choices and outcomes after freezing oocytes for medical reasons: a follow-up study. AB - STUDY QUESTION: What reproductive choices do women make after they have cryopreserved oocytes for medical reasons? SUMMARY ANSWER: Women who had cryopreserved oocytes for medical reasons and tried to become pregnant, either attempted natural conception or resorted to assisted reproduction with fresh oocytes. WHAT IS KNOWN ALREADY: Women confronted with a risk of premature ovarian insufficiency, due to gonadotoxic therapy, ovarian surgery or genetic predisposition, have an indication to cryopreserve oocytes. Many of these women will retain ovarian function, thus will retain the possibility of natural conception. The added value of cryopreserved oocytes to reproductive outcomes is unknown as there is a lack of follow-up of women who have cryopreserved oocytes for medical reasons. STUDY DESIGN, SIZE AND DURATION: This follow-up study included a cohort of 85 women who cryopreserved their oocytes for medical reasons between 2009 and 2012. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Medical data from women who cryopreserved their oocytes at the Centre for Reproductive Medicine in the Academic Medical Centre in Amsterdam were extracted and self report questionnaires were disseminated. The collected data considered demographics, outcomes of ovarian stimulation, fertility-threatening treatments, menstrual cycle changes, pregnancy attempts and outcomes and intended plans for the cryopreserved oocytes. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 68 women, followed up for an average 25.3 months, returned the questionnaire (response rate: 80%). None of the women had used her cryopreserved oocytes although 16 women had tried to conceive. Of these women, eight were trying to conceive naturally, five had conceived naturally within 2 months and three had conceived with assisted reproduction not requiring cryopreserved oocytes (two women with conventional IVF because of tubal pathology and endometriosis and one woman with IUI because of polycystic ovary syndrome). Three out of the eight pregnancies had resulted in live births, two resulted in miscarriages and three were ongoing. Most women (71%) intended to conceive with their cryopreserved oocytes as a last resource option. LIMITATIONS, REASONS FOR CAUTION: Transferability of our findings is challenged by the small sample but positively affected by our high response rate. As the time span between cryopreservation of oocytes and follow-up was short, follow-up of the cohort should be repeated in 2 years. WIDER IMPLICATIONS OF THE FINDINGS: After a mean follow-up of 2 years, none of the women with a medical reason to cryopreserve oocytes had used her oocytes. Women who were trying to conceive during follow-up were doing so without using their stored oocytes. It is unclear whether starting assisted reproduction while having cryopreserved oocytes is the most appropriate clinical decision. Our findings emphasize the relevance of taking the chances of natural conception into account in counselling women about cryopreservation of oocytes. STUDY FUNDING/COMPETING INTERESTS: This study was not externally funded. There are no conflicts of interest to declare. PMID- 24951491 TI - Understanding the importance of relationships: Perspective of children with intellectual disabilities, their parents, and nurses in Canada. AB - Effective and therapeutic relationships between health care providers and clients are important elements for positive health outcomes. Children with intellectual disabilities (IDs) and their parents face unique challenges in establishing relationships with health care providers due to social and institutional stigma and stereotypes associated with children with IDs. In this article, we discuss the theme of building relationships in a hospital setting that emerged from a qualitative feminist poststructuralist study conducted in Canada with 8 children with IDs, 17 mothers, and 12 nurses who cared for them. Our research provides examples of how nurses and mothers worked in and through the system sometimes with frustration but also sometimes with positive excitement to develop supportive relationships. We can learn from these moments of tension and moments of success about how to work together to ensure positive relationships are provided to children with IDs, their parents, and health care professionals. PMID- 24951492 TI - Self-injurious behaviour, non-interventionism and practitioners' needs: Implications for training and managerial support. AB - The aim of the present article is to critically analyse the literature concerning the factors that lead to non-interventionism towards self-injurious behaviour (SIB) in the field of intellectual disability and to make recommendations for the development of practice. It emerges that the limited behaviour analytic skills of practitioners impede the implementation of behavioural interventions and allow SIB to persist. The implications for the development of in-service training and managerial support that would disseminate the implementation of behavioural interventions are briefly discussed. PMID- 24951493 TI - Information gathering and technology use among low-income minority men at risk for prostate cancer. AB - Health communication researchers, public health workers, and health professionals must learn more about the health information-gathering behavior of low-income minority men at risk for prostate cancer in order to share information effectively with the population. In collaboration with the Milwaukee Health Department Men's Health Referral Network, a total of 90 low-income adult men were recruited to complete a survey gauging information sources, seeking behavior, use of technology, as well as prostate cancer awareness and screening behavior. Results indicated participants primarily relied on health professionals, family, and friends for information about general issues of health as well as prostate cancer. The Internet was the least relied on source of information. A hierarchical regression indicated interpersonal information sources such as family or friends to be the only significant predictor enhancing prostate cancer awareness, controlling for other sources of information. Prostate screening behaviors were predicted by reliance on not only medical professionals but also the Internet. Practical implications of the study are discussed. PMID- 24951494 TI - Children's perspectives on how parents protect them from secondhand smoke in their homes and cars in socioeconomically contrasting communities: a qualitative study. AB - INTRODUCTION: Children are particularly vulnerable to the health effects of secondhand smoke (SHS) and are mainly exposed in the home and the car. Reducing children's SHS exposure is a tobacco control goal, yet few studies have explored children's perspectives on SHS. This study examines children's accounts of the strategies family members employ to protect them from SHS and is the first to examine how these may be constrained or facilitated in communities with contrasting smoking prevalence rates. METHODS: Individual, paired, and group interviews using topic guides and visual stimulus methods were conducted with 38 children aged 10-15 years who lived in 2 Scottish communities of contrasting socioeconomic status and had a close family member who smoked. Transcripts were analyzed thematically. RESULTS: Parents were reported to employ spatial and dispersal measures to reduce children's SHS exposure in homes and cars. Smoking was restricted to certain rooms and to times when those considered more vulnerable were absent. Less distance between smokers and children and more smoking in the home were reported in the disadvantaged community, reflecting less space within homes and greater parental smoking. Participants expressed strong negative views about smoking in cars and the perceived ineffectiveness of dispersal measures in this context. CONCLUSIONS: Although there was general awareness that SHS exposure was potentially harmful, SHS in the home was considered safe by some participants if certain conditions were met, particularly by those from the disadvantaged area. The implications of these findings for tobacco control programs and media campaigns, particularly those targeted at disadvantaged groups, are discussed. PMID- 24951495 TI - Early quit days among methadone-maintained smokers in a smoking cessation trial. AB - INTRODUCTION: Methadone maintenance treatment (MMT) patients have an exceedingly high prevalence of tobacco use, and interventions that have been specifically developed for this vulnerable subpopulation have struggled to attain even modest rates of cessation. A significant barrier has been an inability to initiate a quit attempt early in the treatment process and adherence to treatment. METHODS: This study examined the extent to which self-efficacy, medication adherence, and other demographic and smoking variables predicted an early quit day in a sample of MMT smokers (n = 315) enrolled in a smoking cessation pharmacotherapy trial. Using logistic regression, we estimated the association of having an early quit day-24hr without smoking during the first month of treatment. RESULTS: Only 35.2% of participants reported a successful early quit day. The likelihood of an early quit day increased significantly (odds ratio [OR] = 1.39, 95% CI = 1.04-1.86, p < .05) with education level and if a quit attempt was made in the past year (OR = 2.27, 95% CI = 1.33-3.87, p < .01). Compared to the placebo arm, those randomized to either nicotine replacement therapy (OR = 3.25, 95% CI = 1.30-8.10, p < .01) or varenicline (OR = 3.16, 95% CI = 1.26-7.92) were significantly more likely to have an early quit day. The likelihood of an early quit day was also positively associated with adherence to the medication protocol (OR = 2.05, 95% CI = 1.52 2.76). CONCLUSIONS: Difficulty in achieving an early quit attempt may help explain the very low cessation rates found in studies of MMT smokers. PMID- 24951496 TI - Cigarette users' interest in using or switching to electronic nicotine delivery systems for smokeless tobacco for harm reduction, cessation, or novelty: a cross sectional survey of US adults. AB - INTRODUCTION: We examined: (a) current (past 30-day) smokers' interest in using or switching to electronic nicotine delivery systems (ENDS) or smokeless tobacco for various reasons; (b) correlates of interest in these products; and (c) subgroups of current smokers in relation to interest in these products. METHODS: We conducted a cross-sectional survey assessing sociodemographics, tobacco use, interest in ENDS and smokeless tobacco among smokers, and knowledge about ENDS among 2,501 US adults recruited through an online consumer panel. We oversampled tobacco users (36.7% current cigarette smokers), ethnic minorities, and southeastern US state residents. RESULTS: On average, participants were more interested in ENDS than smokeless tobacco across all reasons provided. Additionally, they were less interested in either product because of their potential use in places prohibiting smoking or due to curiosity and more interested in reducing health risk or cigarette consumption or to aid in cessation. We documented high rates (27.9%) of misbeliefs about Food and Drug Administration approval of ENDS for cessation, particularly among current smokers (38.5%). Also, 27.2% of current smokers had talked with a health care provider about ENDS, with 18.0% reporting that their provider endorsed ENDS use for cessation. Furthermore, cluster analyses revealed 3 groups distinct in their interest in the products, sociodemographics, and smoking-related characteristics. CONCLUSIONS: This study highlights higher interest in ENDS versus smokeless tobacco and greater interest in both for harm reduction and cessation than due to novelty or smoking restrictions. Developing educational campaigns and informing practitioners about caveats around ENDS as cessation or harm reduction aids are critical. PMID- 24951497 TI - Intestinal adaptations in chronic kidney disease and the influence of gastric bypass surgery. AB - Studies have shown that compensatory adaptations in gastrointestinal oxalate transport can impact the amount of oxalate excreted by the kidney. Hyperoxaluria is a major risk factor in the formation of kidney stones, and oxalate is derived from both the diet and the liver metabolism of glyoxylate. Although the intestine generally absorbs oxalate from dietary sources and can contribute as much as 50% of urinary oxalate, enteric oxalate elimination plays a significant role when renal function is compromised. While the mechanistic basis for these changes in the direction of intestinal oxalate movements in chronic renal failure involves an upregulation of angiotensin II receptors in the large intestine, enteric secretion/excretion of oxalate can also occur by mechanisms that are independent of angiotensin II. Most notably, the commensal bacterium Oxalobacter sp. interacts with the host enterocyte and promotes the movement of oxalate from the blood into the lumen, resulting in the beneficial effect of significantly lowering urinary oxalate excretion. Changes in the passive permeability of the intestine, such as in steatorrhoea and following gastric bypass, also promote oxalate absorption and hyperoxaluria. In summary, this report highlights the two way physiological signalling between the gut and the kidney, which may help to alleviate the consequences of certain kidney diseases. PMID- 24951498 TI - Neuronal activation by mucosal biopsy supernatants from irritable bowel syndrome patients is linked to visceral sensitivity. AB - Based on the discomfort/pain threshold during rectal distension, irritable bowel syndrome (IBS) patients may be subtyped as normo- or hypersensitive. We previously showed that mucosal biopsy supernatants from IBS patients activated enteric and visceral afferent neurons. We tested the hypothesis that visceral sensitivity is linked to the degree of neuronal activation. Normo- and hypersensitive IBS patients were distinguished by their discomfort/pain threshold to rectal balloon distension with a barostat. Using potentiometric and Ca(2+) dye imaging, we recorded the response of guinea-pig enteric submucous and mouse dorsal root ganglion (DRG) neurons, respectively, to mucosal biopsy supernatants from normosensitive (n = 12 tested in enteric neurons, n = 9 tested in DRG) and hypersensitive IBS patients (n = 9, tested in both types of neurons). In addition, we analysed the association between neuronal activation and individual discomfort/pain pressure thresholds. The IBS supernatants evoked Ca(2+) transients in DRG neurons and spike discharge in submucous neurons. Submucous and DRG neurons showed significantly stronger responses to supernatants from hypersensitive IBS patients as reflected by higher spike frequency or stronger [Ca(2+)]i transients in a larger proportion of neurons. The neuroindex as a product of spike frequency or [Ca(2+)]i transients and proportion of responding neurons correlated significantly with the individual discomfort/pain thresholds of the IBS patients. Supernatants from hypersensitive IBS patients caused stronger activation of enteric and DRG neurons. The level of activation correlated with the individual discomfort/pain threshold pressure values. These findings support our hypothesis that visceral sensitivity is linked to activation of peripheral neurons by biopsy supernatants. PMID- 24951499 TI - Mechanomyogram amplitude correlates with human gastrocnemius medialis muscle and tendon stiffness both before and after acute passive stretching. AB - The study aimed to assess the level of correlation between muscle-tendon unit (MTU) stiffness and mechanomyogram (MMG) signal amplitude of the human gastrocnemius medialis muscle, both before and after acute passive stretching. The passive torque (Tpass), electrically evoked peak torque (pT) and myotendinous junction displacement were determined at different angles of dorsiflexion (0, 10 and 20 deg), while maximum voluntary isometric torque (Tmax) was assessed only at 0 deg. Measurements were repeated after a bout of passive stretching. From the MMG signal, the root mean square (RMS) and peak to peak (p-p) were calculated. The MTU, muscle and tendon stiffness were determined by ultrasound and Tpass measurements. Before stretching, correlations between MMG RMS and MTU, muscle and tendon stiffness were found (R(2) = 0.22-0.46). After stretching, Tpass, Tmax, pT and MTU, muscle and tendon stiffness decreased by 25 +/- 7, 16 +/- 2, 9 +/- 2, 22 +/- 7, 23 +/- 8 and 28 +/- 5%, respectively (P < 0.05). During voluntary and electrically evoked contractions, MMG p-p decreased by 9 +/- 2 and 5 +/- 1%, while MMG RMS increased by 48 +/- 7 and 50 +/- 8%, respectively (P < 0.05). Correlations between MMG RMS and MTU, muscle and tendon stiffness were still present after stretching (R(2) = 0.44-0.60). In conclusion, correlations between MMG RMS and stiffness exist both before and after stretching, suggesting that a slacker MTU leads to larger muscle fibre oscillations. However, care must be taken in using MMG amplitude as an indirect index to estimate stiffness owing to the relatively small R(2) values of the investigated correlations. PMID- 24951500 TI - Rapidly alternating photoperiods disrupt central and peripheral rhythmicity and decrease plasma glucose, but do not affect glucose tolerance or insulin secretion in sheep. AB - Disrupting circadian rhythms in rodents perturbs glucose metabolism and increases adiposity. To determine whether these effects occur in a large diurnal animal, we assessed the impact of circadian rhythm disruption upon metabolic function in sheep. Adult ewes (n = 7) underwent 3 weeks of a control 12 h light-12 h dark photoperiod, followed by 4 weeks of rapidly alternating photoperiods (RAPs) whereby the time of light exposure was reversed twice each week. Measures of central (melatonin secretion and core body temperature) and peripheral rhythmicity (clock and metabolic gene expression in skeletal muscle) were obtained over 24 h in both conditions. Metabolic homeostasis was assessed by glucose tolerance tests and 24 h glucose and insulin profiles. Melatonin and core body temperature rhythms resynchronized within 2 days of the last photoperiod shift. High-amplitude Bmal1, Clock, Nr1d1, Cry2 and Per3 mRNA rhythms were apparent in skeletal muscle, which were phase advanced by up to 3.5 h at 2 days after the last phase shift, whereas Per1 expression was downregulated at this time. Pparalpha, Pgc1alpha and Nampt mRNA were constitutively expressed in both conditions. Nocturnal glucose concentrations were reduced following chronic phase shifts (zeitgeber time 0, -5.5%; zeitgeber time 12, -2.9%; and zeitgeber time 16, -5.7%), whereas plasma insulin, glucose tolerance and glucose-stimulated insulin secretion were not altered. These results demonstrate that clock gene expression within ovine skeletal muscle oscillates over 24 h and responds to changing photoperiods. However, metabolic genes which link circadian and metabolic clocks in rodents were arrhythmic in sheep. Differences may be due to the ruminant versus monogastric digestive organization in each species. Together, these results demonstrate that despite disruptions to central and peripheral rhythmicity following exposure to rapidly alternating photoperiods, there was minimal impact on glucose homeostasis in the sheep. PMID- 24951501 TI - Endoplasmic reticulum stress-mediated autophagy protects against lipopolysaccharide-induced apoptosis in HL-1 cardiomyocytes. AB - Apoptosis of cardiomyocytes limits the contractile efficiency of the heart during sepsis. Prosurvival autophagy has been proposed as a novel mechanism to maintain normal heart function. Here, we demonstrated that autophagy was activated in lipopolysaccharide (LPS)-treated HL-1 cells, and it counteracted the LPS-induced apoptosis. We investigated further the mechanism by which LPS triggered autophagy in HL-1 cells. We discovered that endoplasmic reticulum (ER) stress played an important role in LPS-triggered autophagy. The ER activated a survival pathway through the ER-localized transmembrane protein PERK, which was essential for LPS induced autophagy. Lipopolysaccharide increased expression of GRP78, phosphorylated PERK and phosphorylated eukaryotic initiation factor 2alpha. Similar results were observed after administration of tunicamycin, a well-known ER stressor. Most importantly, we found that 4-phenylbutyrate, an inhibitor of ER stress, suppressed LPS-activated autophagy in the presence of LPS in HL-1 cells. The same results were observed after small interfering RNA-mediated silencing of PERK protein. We also noticed that LPS-induced apoptosis appeared early, at 4 h. Our findings revealed that PERK, one arm of ER stress, facilitated survival of LPS-treated HL-1 cells by promoting autophagy, and could serve as a potential therapeutic strategy to alleviate septic myocardial dysfunction. PMID- 24951502 TI - Using remote biomonitoring to understand heterogeneity in immune-responses and disease-dynamics in small, free-living animals. AB - Despite the ubiquity of parasites and pathogens, behavioral and physiological responses to infection vary widely across individuals. Although such variation can have pronounced effects on population-level processes, including the transmission of infectious disease, the study of individual responses to infection in free-living animals remains a challenge. To fully understand the causes and consequences of heterogeneous responses to infection, research in ecoimmunology and disease-ecology must incorporate minimally invasive techniques to track individual animals in natural settings. Here, we review how several technologies, collectively termed remote biomonitoring, enable the collection of data on behavioral and physiological responses to infection in small, free-living animals. Specifically, we focus on the use of radiotelemetry and radio-frequency identification to study fever, sickness-behaviors (including lethargy and anorexia), and rates of inter-individual contact in the wild, all of which vary widely across individuals and impact the spread of pathogens within populations. In addition, we highlight future avenues for field studies of these topics using emerging technologies such as global positioning system tracking and tri-axial accelerometry. Through the use of such remote biomonitoring techniques, researchers can gain valuable insights into why responses to infection vary so widely and how this variation impacts the spread and evolution of infectious diseases. PMID- 24951503 TI - Ecological immunology mediated by diet in herbivorous insects. AB - A rapidly advancing area of ecological immunology concerns the effects of diet on animals' immunological responses to parasites and pathogens. Here, we focus on diet-mediated ecological immunology in herbivorous insects, in part because these organisms commonly experience nutritional limitations from their diets of plants. Nutritional immunology highlights nutrient-based trade-offs between immunological and other physiological processes as well as trade-offs among distinct immunological processes. This field reveals that nutrition influences the quality and quantity of immunological defense in herbivorous insects, and conversely that nutritional intake by herbivorous insects can be an adaptive response to the specific types of immune-challenge they face in the context of other physiological processes. Because the diets of herbivores challenge them physiologically with plants' secondary metabolites, another area of study analyzes constraints on immunological defense imposed by secondary metabolites of plants in the diets of herbivorous insects. Alternatively, some herbivores can use secondary metabolites as medicine against parasites or pathogens. Animal medication theory makes an important contribution to ecological immunology by distinguishing prophylactic and therapeutic mechanisms of anti-parasite defense. Integrating ideas from animal-medication and nutritional immunology, we outline a conceptual framework in which the immunological role of the diet consists of mechanisms of prophylaxis, therapy, compensation, and combinations thereof. Then, we use this framework to organize findings from our own research on diet-mediated ecological immunology of woolly bear caterpillars. We show evidence that the woolly bear caterpillar, Grammia incorrupta (Hy. Edwards) (Lepidoptera, Erebidae, and Arctiinae), can employ both diet-mediated prophylaxis and therapy. First, increased consumption of carbohydrate-biased food prior to immune-challenge increased its melanization-response. Second, increased consumption of pyrrolizidine alkaloids (PAs) more than 24 h after parasitism by tachinid flies resulted in anti-parasite resistance. Caterpillars reduced feeding on protein biased food within 24 h after immune-challenge, showing evidence of illness induced anorexia. We synthesize our work to generate the hypothesis that a diet mediated defense by the host against parasites acts as a temporally explicit, multi-stage process. PMID- 24951505 TI - What is a non-randomised controlled trial? PMID- 24951504 TI - Developmental stress, condition, and birdsong: a case study in song sparrows. AB - Sexual-selection theory posits that ornaments and displays can reflect a signaler's condition, which in turn is affected both by recent and developmental conditions. Moreover, developmental conditions can induce correlations between sexually selected and other traits if both types of traits exhibit developmental phenotypic plasticity in response to stressors. Thus, sexually selected traits may reflect recent and/or developmental characteristics of signalers. Here, we review data on the relationships between birdsong, a sexually selected trait, and developmental and current condition of birds from a long-term study of a population of song sparrows (Melospiza melodia). Field studies of free-living birds indicate that the complexity of a male's songs, a permanent trait, reflects the size of a song-control region of his brain (HVC), and is correlated with body size and several parameters of immunity, specifically investment in protective proteins. However, the performance of a male's songs, a dynamic trait, is not correlated to immune investment. Complexity of song is correlated with the glucocorticoid stress-response, and in some years response to stress predicts overwinter survival. Experimental manipulations have revealed that stressors in early life impair development of HVC, but that HVC recovers in size by adulthood. These manipulations result in impaired song-complexity and song-learning, but not song-performance. Experimental developmental stressors also affect growth, endocrine physiology, metabolism, and immune-function, often in a sex-specific manner. Combined, these studies suggest that song-complexity provides reliable information about early developmental experience, and about other traits that have critical developmental periods. Birdsong thus provides a multi-faceted sexually selected trait that may be an indicator both of developmental and recent conditions. PMID- 24951506 TI - Anatomic and histological study of the rabbit mandible as an experimental model for wound healing and surgical therapies. AB - The rabbit is one of the most widely used models for studying bone remodeling or dental implant osseointegration but very few data are available about the rabbit's mandible. The aim of this work was to describe the anatomy of the rabbit mandible and to estimate the available bone volume for experimental studies. First, with a dissection, the morphology of the mandible was described and the mental foramen, the position of the main salivary glands and muscular insertions were located. Then, by X-ray imaging, the position of the inferior alveolar canal, the dental root courses and volume and bone density were described. Finally, with frontal sections of the mandible body, the rabbit's dental and alveolar bone histological structure were assessed. Thus, the relevance of the rabbit mandible as an experimental model for wound healing or surgical therapies was discussed. PMID- 24951507 TI - EARLY BUD-BREAK 1 (EBB1) is a regulator of release from seasonal dormancy in poplar trees. AB - Trees from temperate latitudes transition between growth and dormancy to survive dehydration and freezing stress during winter months. We used activation tagging to isolate a dominant mutation affecting release from dormancy and identified the corresponding gene EARLY BUD-BREAK 1 (EBB1). We demonstrate through positioning of the tag, expression analysis, and retransformation experiments that EBB1 encodes a putative APETALA2/Ethylene responsive factor transcription factor. Transgenic up-regulation of the gene caused early bud-flush, whereas down regulation delayed bud-break. Native EBB1 expression was highest in actively growing apices, undetectable during the dormancy period, but rapidly increased before bud-break. The EBB1 transcript was localized in the L1/L2 layers of the shoot meristem and leaf primordia. EBB1-overexpressing transgenic plants displayed enlarged shoot meristems, open and poorly differentiated buds, and a higher rate of cell division in the apex. Transcriptome analyses of the EBB1 transgenics identified 971 differentially expressed genes whose expression correlated with the EBB1 expression changes in the transgenic plants. Promoter analysis among the differentially expressed genes for the presence of a canonical EBB1-binding site identified 65 putative target genes, indicative of a broad regulatory context of EBB1 function. Our results suggest that EBB1 has a major and integrative role in reactivation of meristem activity after winter dormancy. PMID- 24951509 TI - Simulations clarify when supercooled water freezes into glassy structures. PMID- 24951508 TI - OsNAP connects abscisic acid and leaf senescence by fine-tuning abscisic acid biosynthesis and directly targeting senescence-associated genes in rice. AB - It has long been established that premature leaf senescence negatively impacts the yield stability of rice, but the underlying molecular mechanism driving this relationship remains largely unknown. Here, we identified a dominant premature leaf senescence mutant, prematurely senile 1 (ps1-D). PS1 encodes a plant specific NAC (no apical meristem, Arabidopsis ATAF1/2, and cup-shaped cotyledon2) transcriptional activator, Oryza sativa NAC-like, activated by apetala3/pistillata (OsNAP). Overexpression of OsNAP significantly promoted senescence, whereas knockdown of OsNAP produced a marked delay of senescence, confirming the role of this gene in the development of rice senescence. OsNAP expression was tightly linked with the onset of leaf senescence in an age dependent manner. Similarly, ChIP-PCR and yeast one-hybrid assays demonstrated that OsNAP positively regulates leaf senescence by directly targeting genes related to chlorophyll degradation and nutrient transport and other genes associated with senescence, suggesting that OsNAP is an ideal marker of senescence onset in rice. Further analysis determined that OsNAP is induced specifically by abscisic acid (ABA), whereas its expression is repressed in both aba1 and aba2, two ABA biosynthetic mutants. Moreover, ABA content is reduced significantly in ps1-D mutants, indicating a feedback repression of OsNAP on ABA biosynthesis. Our data suggest that OsNAP serves as an important link between ABA and leaf senescence. Additionally, reduced OsNAP expression leads to delayed leaf senescence and an extended grain-filling period, resulting in a 6.3% and 10.3% increase in the grain yield of two independent representative RNAi lines, respectively. Thus, fine-tuning OsNAP expression should be a useful strategy for improving rice yield in the future. PMID- 24951513 TI - Mentorship for newly appointed consultants: what makes it work? AB - BACKGROUND: Mentorship has been identified as a beneficial practice for doctors and may be particularly valuable for newly appointed consultants. It is associated with a number of potential clinical and non-clinical gains, such as enhanced job satisfaction and well-being. Despite strong support, many formalised schemes fail to launch or gain momentum. Research to date has largely focused on the gains associated with mentorship but has lacked study of the factors that facilitate uptake and maintenance of mentoring relationships by physicians. OBJECTIVES: To explore perceptions of mentorship, the extent to which UK doctors appear to value mentorship and factors that may contribute to its successful use. DESIGN: Qualitative, descriptive, multi-centre study. SAMPLE: 30 doctors including registrars, those newly appointed to consultant grade, senior doctors and medical leaders from nine hospitals in the north of England. METHOD: Semistructured individual interviews were undertaken between August and December 2013. RESULTS: Findings revealed a demand for mentorship for new consultants, with widely recognised benefits associated with its use. Several factors were identified as critical to successful mentorship relationships, including consistent understanding and expectations of mentorship between mentee and mentor, positive prior experiences, a suitable match between mentee and mentor, making time for people to act as mentors and the ensuring that mentors can meet a diverse and changing set of needs. CONCLUSIONS: Mentorship for newly appointed consultants is valued, but current models of mentorship may suffer from rigid structures, mismatched expectations of participants and the absence of a culture of mentorship from training into practice. A social network approach, in which doctors have the opportunity to engage with a range of mentors through informal and naturally occurring relationships, may be one way to encourage successful and sustained mentoring relationships among doctors. An organisational culture in which mentorship is permitted and is the norm may enable such approaches to be widely adopted. PMID- 24951511 TI - Towards a measurement instrument for determinants of innovations. AB - OBJECTIVE: To develop a short instrument to measure determinants of innovations that may affect its implementation. DESIGN: We pooled the original data from eight empirical studies of the implementation of evidence-based innovations. The studies used a list of 60 potentially relevant determinants based on a systematic review of empirical studies and a Delphi study among implementation experts. Each study used similar methods to measure both the implementation of the innovation and determinants. Missing values in the final data set were replaced by plausible values using multiple imputation. We assessed which determinants predicted completeness of use of the innovation (% of recommendations applied). In addition, 22 implementation experts were consulted about the results and about implications for designing a short instrument. SETTING: Eight innovations introduced in Preventive Child Health Care or schools in the Netherlands. PARTICIPANTS: Doctors, nurses, doctor's assistants and teachers; 1977 respondents in total. RESULTS: The initial list of 60 determinants could be reduced to 29. Twenty-one determinants were based on the pooled analysis of the eight studies, seven on the theoretical expectations of the experts consulted and one new determinant was added on the basis of the experts' practical experience. CONCLUSIONS: The instrument is promising and should be further validated. We invite researchers to use and explore the instrument in multiple settings. The instrument describes how each determinant should preferably be measured (questions and response scales). It can be used both before and after the introduction of an innovation to gain an understanding of the critical change objectives. PMID- 24951510 TI - Functional interaction with filamin A and intracellular Ca2+ enhance the surface membrane expression of a small-conductance Ca2+-activated K+ (SK2) channel. AB - For an excitable cell to function properly, a precise number of ion channel proteins need to be trafficked to distinct locations on the cell surface membrane, through a network and anchoring activity of cytoskeletal proteins. Not surprisingly, mutations in anchoring proteins have profound effects on membrane excitability. Ca(2+)-activated K(+) channels (KCa2 or SK) have been shown to play critical roles in shaping the cardiac atrial action potential profile. Here, we demonstrate that filamin A, a cytoskeletal protein, augments the trafficking of SK2 channels in cardiac myocytes. The trafficking of SK2 channel is Ca(2+) dependent. Further, the Ca(2+) dependence relies on another channel-interacting protein, alpha-actinin2, revealing a tight, yet intriguing, assembly of cytoskeletal proteins that orchestrate membrane expression of SK2 channels in cardiac myocytes. We assert that changes in SK channel trafficking would significantly alter atrial action potential and consequently atrial excitability. Identification of therapeutic targets to manipulate the subcellular localization of SK channels is likely to be clinically efficacious. The findings here may transcend the area of SK2 channel studies and may have implications not only in cardiac myocytes but in other types of excitable cells. PMID- 24951515 TI - Esophageal intramural pseudodiverticulosis, a rare cause of food impaction: case report and review of the literature. AB - Esophageal intramural pseudodiverticulosis (EIPD) is a rare, benign condition of uncertain etiology and pathogenesis, which usually presents with either progressive or intermittent dysphagia. Acute presentation with food impaction, requiring emergency esophago-gastroduodenoscopy (EGD), is rare. We report a case of EIPD presenting as food bolus impaction in an elderly black female. The patient had no previous history of dysphagia or odynophagia. Currently accepted risk factors, such as diabetes mellitus, chronic alcoholism, and reflux esophagitis, were not present in our patient. Emergency EGD established the diagnosis and also dislodged the food bolus. Histopathological evaluation of the mucosa diagnosed co-existent acute candidal infection. Medical treatment with proton pump inhibitor and azole antifungal led to resolution of her symptoms. Review of the literature revealed that stenosis, strictures, perforation, gastro intestinal bleed, and fistula formation are potential complications of EIPD. Multiple motility abnormalities have been described but are not consistent. Treatment of the underlying inflammatory and or infectious condition is the mainstay of management of this unusual condition. PMID- 24951516 TI - Evidence-Based Practice in Nursing: Here or Gone With the Wind of Disenchantment? PMID- 24951517 TI - Witnessing. AB - The author in this article explores thinking on witnessing or bearing witness from the theoretical perspectives of nursing, philosophy, Christian theology, and journalism. Although there are nuances in the meanings of witnessing and the actions involved in witnessing, all of the identified disciplines discussed the responsibility they have for bearing witness to the other. PMID- 24951514 TI - Hepatobiliary manifestations of ulcerative colitis: an example of gut-liver crosstalk. AB - The interaction between inflammatory bowel disease (IBD) and hepatobiliary manifestations represents a classic example of liver-gut crosstalk. The importance of liver-gut crosstalk in IBD is demonstrated in the pathogenesis and outcome of primary sclerosing cholangitis (PSC) in IBD patients. Immunoglobulin G4-associated cholangitis (IAC), which has recently been described in UC patients, may also illustrate the significance of gut-liver interaction in these patients. Presence of these hepatobiliary manifestations influences the outcome of associated IBD, in particular ulcerative colitis (UC), and vice versa. The pathogenesis of PSC is postulated to be related to gut inflammation in IBD that results in inflammation in the portal tracts (the 'leaky gut'). Enterohepatic circulation of lymphocytes from the gut to the liver is also of potential relevance to PSC pathogenesis and outcomes. The presence of PSC and gut inflammation in IBD influences the course and outcomes of both diseases. Further research is required, to understand the mutual effect of liver-gut crosstalk in the outcomes of UC patients, and highlights the importance of an interdisciplinary approach-involving gastroenterologists, hepatologists, advanced endoscopists and liver transplant surgeons-in the management of these patients. PMID- 24951518 TI - Traditional or Translational Research for Nursing: More PhDs Please. AB - In this column, the authors focus on the need for more PhD-prepared nurses as opposed to nurses receiving the Doctor of Nursing Practice (DNP). This would help to to facilitate an understanding between traditional research and translational research. The idea of a need for collaboration between these two terminal degrees is highlighted. To that end, the history and intent of the research doctorate and the practice doctorate are entertained along with a brief description of the traditional and translational research processes. PMID- 24951519 TI - Straight Thinking and Ethics in Nursing. AB - A desired outcome for members of healthcare disciplines is to have straight thinking regarding human health and quality of life issues. Difficult situations, embedded with a demand for quick, value-laden healthcare decisions, abound in an ever-changing, complex healthcare arena. The author begins a discussion about potential implications for future disciplinary nurse practice as nurse leaders contemplate what it means to have a straight thinking ethos as providers of vital human health services. Reflections and recommendations for future dialogue with interdisciplinary professionals on the topic of nursing ethics is offered. PMID- 24951520 TI - Imagination: The What-if in Thinking. AB - Teaching-learning environments in nursing education encourage students to think and recall hordes of factual information while checking off a skills list too numerous to mention. In efforts to impart all of this information to students, has the use of imagination been ignored? The author in this column presents a discussion on imagination. First, there is a discussion of the literature, followed by a discussion of imagination in light of the humanbecoming school of thought. A glimpse at the presence of imagination in qualitative research methodologies is also highlighted. The author also presents the limits of imagination, and perhaps, its fading existence in current teaching-learning practices. The column concludes with encouragement toward a greater utilization of imaginative thought in nursing pedagogies. PMID- 24951522 TI - Life as a Mentor. AB - The concept of mentorship is personalized in this discussion of Dr. Fawcett's life as she experienced and thrived as a mentor. The authors describe different types of mentorship and how they were experienced by this leader. PMID- 24951521 TI - What Kind of Nurse Are You? AB - Once again the importance of nursing theory in practice comes to the forefront. By examining one's personal and professional beliefs in how one cares for people, it becomes apparent that nursing theory does guide nursing practice. The moral and ethical judgments one makes before or while caring for a person may reveal that personal bias can detract from the quality of care. PMID- 24951523 TI - The Living Experience of Feeling Overwhelmed: A Parse Research Study. AB - Feeling overwhelmed is a universal living experience of living quality. Although feeling overwhelmed frequently occurs in healthcare, studies related to its meaning have never been published. Parse's humanbecoming school of thought was the theoretical framework for this study. The research question for this study was: What is the structure of the living experience of feeling overwhelmed? The purpose was to advance nursing science and enhance the theory of humanbecoming. Parse's phenomenological-hermeneutic research method was the method used. Participants from the general population included nine women and one man ranging in age from 18 to 65. Descriptions were arrived at through dialogical engagement. The major finding of the study is the structure: Feeling overwhelmed is burdening disconcertedness surfacing with divergent engagements as optimistic anticipation arises while structuring endeavors. PMID- 24951524 TI - Construction, Deconstruction, and Reconstruction: The Roots of Successful Aging Theories. AB - The authors' goals are to examine the evolution of the concept of successful aging and its relevance to nursing science and practice. First, the history of positivist construction of aging in light of disengagement and activity theories is presented. Second, an analysis of the postmodern deconstruction of aging is illustrated with the development of the ageism phenomenon. Third, the beginning of the reconstruction of aging is presented and exemplified by Troutman's middle range nursing theory of successful aging, as connected to Roy's model. Finally, ways in which these theories can be made applicable to nursing practice and research are proposed. PMID- 24951525 TI - Psychometric Properties of the Dietary Salt Reduction Self-Care Behavior Scale. AB - Valid, reliable, and culturally-specific scales to measure salt reduction self care behavior in older adults are needed. The purpose of this study was to develop the Dietary Salt Reduction Self-Care Behavior Scale (DSR-SCB) for use in hypertensive older adults with Orem's self-care deficit theory as a base. Exploratory factor analysis, Rasch modeling, and reliability were performed on data from 242 older Thai adults. Nine items loaded on one factor (factor loadings = 0.63 to 0.79) and accounted for 52.28% of the variance (Eigenvalue = 4.71). The Kaiser-Meyer-Olkin method of sampling adequacy was 0.89, and the Bartlett's test showed significance (chi2 (df =36) = 916.48, p < 0.0001). Infit and outfit mean squares ranged from 0.81 to 1.25, while infit and outfit standardized mean squares were located at +/-2. Cronbach's alpha was 0.88. The 9-item DSR-SCB is a short and reliable scale. PMID- 24951526 TI - Toward a Middle-Range Theory of Weight Management. AB - The authors of this paper present the middle-range theory of weight management that focuses on cultural, environmental, and psychosocial factors that influence behaviors needed for weight control. The theory of weight management was developed deductively from Orem's theory of self-care, a constituent theory within the broader self-care deficit nursing theory and from research literature. Linkages between the conceptual and middle-range theory concepts are illustrated using a substruction model. The development of the theory of weight management serves to build nursing science by integrating extant nursing theory and empirical knowledge. This theory may help predict weight management in populations at risk for obesity-related disorders. PMID- 24951527 TI - Weathering the Storm: Nurses' Stories about Hurricane Sandy. AB - Proposed is a hermeneutic humanbecoming study on the reflections of 16 nurses' stories about Hurricane Sandy. The phenomenon of interest is weathering the storm. The research question is "what are the emerging meanings of the living experience of weathering the storm?" The perspective to be used is the humanbecoming school of thought. The participants were nurses who were living and working in New York City (NYC) during and after Hurricane Sandy. The emergent meanings are to enhance knowledge and understanding of the experience of weathering the storm for global health nursing. PMID- 24951528 TI - Affordable Care Act: Overview and Implications for Advancing Nursing. AB - The Affordable Care Act (ACA) confronts nursing with opportunities as well as challenges. The authors provide an overview of the ACA and highlights opportunities for nursing practice, research, and doctoral education. The importance of disciplinary foundations is also addressed as relevant to envisioning the future of practice and education in the context of healthcare reform. PMID- 24951529 TI - Thoughts About Collaboration-Or Is It Capitulation? AB - In this essay, I share my thoughts about collaboration and capitulation. I pose several questions that point to the danger of capitulation when collaborative efforts between nurses and between nurses and other healthcare team members fail to take into account the distinctive perspectives of the discipline of nursing and the distinctions between associate degree and baccalaureate degree entry into nursing practice programs. PMID- 24951530 TI - Mindfulness and Serendipity. PMID- 24951532 TI - Letter to the Editor: It Is Unethical Not to Care. PMID- 24951533 TI - Pharmacokinetics and pharmacodynamics of boosted once-daily darunavir. AB - The ability to dose antiretroviral agents once daily simplifies the often complex therapeutic regimens required for the successful treatment of HIV infection. Thus, once-daily dosing can lead to improved patient adherence to medication and, consequently, sustained virological suppression and reduction in the risk of emergence of drug resistance. Several trials have evaluated once-daily darunavir/ritonavir in combination with other antiretrovirals (ARTEMIS and ODIN trials) or as monotherapy (MONET, MONOI and PROTEA trials) in HIV-1-infected adults. Data from ARTEMIS and ODIN demonstrate non-inferiority of once-daily darunavir/ritonavir against a comparator and, together with pharmacokinetic data, have established the suitability of once-daily darunavir/ritonavir for treatment naive and treatment-experienced patients with no darunavir resistance-associated mutations. The findings of ARTEMIS and ODIN have led to recent updates to treatment guidelines, whereby once-daily darunavir/ritonavir, given with other antiretrovirals, is now a preferred treatment option for antiretroviral-naive adult patients and a simplified treatment option for antiretroviral-experienced adults who have no darunavir resistance-associated mutations. Once-daily dosing with darunavir/ritonavir is an option for treatment-naive and for treatment experienced paediatric patients with no darunavir resistance-associated mutations based on the findings of the DIONE trial and ARIEL substudy. This article reviews the pharmacokinetics, efficacy, safety and tolerability of once-daily boosted darunavir. The feasibility of darunavir/ritonavir monotherapy as a treatment approach for some patients is also discussed. Finally, data on a fixed-dose combination of 800/150 mg of darunavir/cobicistat once daily are presented, showing comparable darunavir bioavailability to that obtained with 800/100 mg of darunavir/ritonavir once daily. PMID- 24951534 TI - In vivo imaging of disseminated murine Candida albicans infection reveals unexpected host sites of fungal persistence during antifungal therapy. AB - OBJECTIVES: Candida albicans is an important fungal pathogen that can cause life threatening disseminated infections. To determine the efficacy of therapy in murine models, a determination of renal fungal burden as cfu is commonly used. However, this approach provides only a snapshot of the current situation in an individual animal and cryptic sites of infection may easily be missed. Thus, we aimed to develop real-time non-invasive imaging to monitor infection in vivo. METHODS: Bioluminescent C. albicans reporter strains were developed based on a bioinformatical approach for codon optimization. The reporter strains were analysed in vitro and in vivo in the murine model of systemic candidiasis. RESULTS: Reporter strains allowed the in vivo monitoring of infection and a determination of fungal burden, with a high correlation between bioluminescence and cfu count. We confirmed the kidney as the main target organ but additionally observed the translocation of C. albicans to the urinary bladder. The treatment of infected mice with caspofungin and fluconazole significantly improved the clinical outcome and clearance of C. albicans from the kidneys; however, unexpectedly, viable fungal cells persisted in the gall bladder. Fungi were secreted with bile and detected in the faeces, implicating the gall bladder as a reservoir for colonization by C. albicans after antifungal therapy. Bile extracts significantly decreased the susceptibility of C. albicans to various antifungals in vitro, thereby probably contributing to its persistence. CONCLUSIONS: Using in vivo imaging, we identified cryptic sites of infection and persistence of C. albicans in the gall bladder during otherwise effective antifungal treatment. Bile appears to directly interfere with antifungal activity. PMID- 24951536 TI - Phentermine interference and high L-methamphetamine concentration problems in GC EI-MS SIM Analyses of R-(-)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride-derivatized amphetamines and methamphetamines?. AB - In order to achieve chromatographic separation, urine samples shown to be initially positive for amphetamines and methamphetamines in US Department of Defense immunoassays are derivatized with R-(-)-alpha-methoxy-alpha (trifluoromethyl)phenylacetyl chloride (R-(-)-MTPA) prior to gas chromatography electron impact-mass spectrometry (GC-EI-MS) analysis. Phentermine, a member of the phenethylamine class of drugs and a common appetite suppressant, interferes with GC-EI-MS assays of R-(-)-MTPA-derivatized d-amphetamine, degrading the chromatography of the internal standard and analyte ions and skewing concentration calculations. Additionally, when specimens with high concentrations of l-methamphetamine are derivatized with R-(-)-MTPA, signal peaks have the potential to be misidentified by integration software as d-methamphetamine. We have found that replacing R-(-) MTPA with (S)-(+)-alpha-methoxy-alpha (trifluoromethyl)phenylacetyl chloride reduces phentermine interference problems related to internal standard chromatography, reduces the possibility of concentrated l-methamphetamine peaks being misidentified by integration software, improves resolution of d-methamphetamine in the presence of high l methamphetamine concentrations, and is a cost-neutral change that can be applied to current amphetamines GC-EI-MS methods without the need for method modification. PMID- 24951535 TI - Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral. AB - OBJECTIVES: T-705, also known as favipiravir, is a small-molecule inhibitor that is currently in clinical development for the treatment of influenza virus infections. This molecule also inhibits the replication of a broad spectrum of other RNA viruses. The objective of this study was to investigate the antiviral effect of favipiravir on chikungunya virus (CHIKV) replication and to contribute to unravelling the molecular mechanism of action against this virus. METHODS: The anti-CHIKV effect of favipiravir was examined in cell culture and in a mouse model of lethal infection. A five-step protocol was used to select for CHIKV variants with reduced susceptibility to favipiravir. The resistant phenotype was confirmed in cell culture and the whole genome was sequenced. The identified mutations were reverse-engineered into an infectious clone to confirm their impact on the antiviral efficacy of favipiravir. RESULTS: Favipiravir inhibits the replication of laboratory strains and clinical isolates of CHIKV, as well as of a panel of other alphaviruses. Several favipiravir-resistant CHIKV variants were independently selected and all of them in particular acquired the unique K291R mutation in the RNA-dependent RNA polymerase (RdRp). Reverse-engineering of this K291R mutation into an infectious clone of CHIKV confirmed the link between the mutant genotype and the resistant phenotype. Interestingly, this particular lysine is also highly conserved in the RdRp of positive-stranded RNA viruses in general. CONCLUSIONS: This study provides an important insight into the precise molecular mechanism by which favipiravir exerts its antiviral activity against (alpha)viruses, which may be of help in designing other potent broad-spectrum antivirals. PMID- 24951537 TI - Acceleration of an aldo-keto reductase by minimal loop engineering. AB - Aldo-keto reductases tighten coenzyme binding by forming a hydrogen bond across the pyrophosphate group of NAD(P)(H). Mutation of the hydrogen bonding anchor Lys24 in Candida tenuis xylose reductase prevents fastening of the "safety belt" around NAD(H). The loosened NAD(H) binding leads to increased turnover numbers (k(cat)) for reductions of bulky-bulky ketones at constant substrate and coenzyme affinities (i.e. K(m Ketone), K(m NADH)). PMID- 24951538 TI - Expression of fibulin-6 in failing hearts and its role for cardiac fibroblast migration. AB - AIMS: The cardiac extracellular matrix (ECM) undergoes a dynamic transition following myocardial infarction. Fibulin-6 is expressed in cell junctions particularly in tissues subjected to significant mechanical stress. Fibulin-6 deficiency results in defective cell migration in nematodes and early embryonic lethality in mice. The role of fibulin-6 in healthy and failing myocardium is unknown. We have examined the expression and distribution pattern of fibulin-6 during myocardial remodelling (MR) and detailed its effect on the migratory function of cardiac fibroblasts (CFs) in response to TGF-beta1. METHODS AND RESULTS: In healthy murine myocardium, fibulin-6 expression is largely confined to larger coronary arteries. It is induced during the early and the late phase of remodelling after infarction in murine hearts predominantly in the scar-muscle junction. Similar results are obtained in human ischaemic cardiomyopathy. Fibulin 6 is mostly expressed in close vicinity to vimentin-positive cells and is also abundantly expressed in vitro in cultured neonatal CF. TGF-beta1 does not induce smooth muscle actin in fibroblasts deficient of fibulin-6, which also compromised their migration. Cells that had migrated expressed more fibulin-6 compared with stationary cells. Plated on fibulin-6-depleted matrix, stress fibre induction in fibroblast in response to TGF-beta1 was impaired. In ex vivo explant cultures from post-infarct myocardium, the number of emigrating fibroblasts was also significantly reduced by fibulin-6 siRNA knockdown. CONCLUSION: Fibulin-6, a fibroblast-released ECM protein, may play an important role during MR by imparting an effect on CF migration in close and complementary interplay with TGF beta1 signalling. PMID- 24951540 TI - Ubiquitin-specific protease-14 reduces cellular aggregates and protects against mutant huntingtin-induced cell degeneration: involvement of the proteasome and ER stress-activated kinase IRE1alpha. AB - Huntington's disease (HD) is an autosomal inherited neurological disease caused by a CAG-repeat expansion in the first exon of huntingtin gene encoding for the huntingtin protein (Htt). In HD, there is an accumulation of intracellular aggregates of mutant Htt that negatively influence cellular functions. The aggregates contain ubiquitin, and part of the HD pathophysiology could result from an imbalance in cellular ubiquitin levels. Deubiquitinating enzymes are important for replenishing the ubiquitin pool, but less is known about their roles in brain diseases. We show here that overexpression of the ubiquitin specific protease-14 (Usp14) reduces cellular aggregates in mutant Htt-expressing cells mainly via the ubiquitin proteasome system. We also observed that the serine-threonine kinase IRE1 involved in endoplasmic reticulum (ER) stress responses is activated in mutant Htt-expressing cells in culture as well as in the striatum of mutant Htt transgenic (BACHD) mice. Usp14 interacted with IRE1 in control cells but less in mutant Htt-expressing cells. Overexpression of Usp14 in turn was able to inhibit phosphorylation of IRE1alpha in mutant Htt overexpressing cells and to protect against cell degeneration and caspase-3 activation. These results show that ER stress-mediated IRE1 activation is part of mutant Htt toxicity and that this is counteracted by Usp14 expression. Usp14 effectively reduced cellular aggregates and counteracted cell degeneration indicating an important role of this protein in mutant Htt-induced cell toxicity. PMID- 24951539 TI - Novel concepts in HDL pharmacology. AB - High-density lipoproteins (HDL) are a target for drug development because of their proposed anti-atherogenic properties. In this review, we will briefly discuss the currently established drugs for increasing HDL-C, namely niacin and fibrates, and some of their limitations. Next, we will focus on novel alternative therapies that are currently being developed for raising HDL-C, such as CETP inhibitors. Finally, we will conclude with a review of novel drugs that are being developed for modulating the function of HDL based on HDL mimetics. Gaps in our knowledge and the challenges that will have to be overcome for these new HDL based therapies will also be discussed. PMID- 24951541 TI - Golgi fragmentation in pmn mice is due to a defective ARF1/TBCE cross-talk that coordinates COPI vesicle formation and tubulin polymerization. AB - Golgi fragmentation is an early hallmark of many neurodegenerative diseases but its pathophysiological relevance and molecular mechanisms are unclear. We here demonstrate severe and progressive Golgi fragmentation in motor neurons of progressive motor neuronopathy (pmn) mice due to loss of the Golgi-localized tubulin-binding cofactor E (TBCE). Loss of TBCE in mutant pmn and TBCE-depleted motor neuron cultures causes defects in Golgi-derived microtubules, as expected, but surprisingly also reduced levels of COPI subunits, decreased recruitment of tethering factors p115/GM130 and impaired Golgi SNARE-mediated vesicle fusion. Conversely, ARF1, which stimulates COPI vesicle formation, enhances the recruitment of TBCE to the Golgi, increases polymerization of Golgi-derived microtubules and rescues TBCE-linked Golgi fragmentation. These data indicate an ARF1/TBCE-mediated cross-talk that coordinates COPI formation and tubulin polymerization at the Golgi. We conclude that interruption of this cross-talk causes Golgi fragmentation in pmn mice and hypothesize that similar mechanisms operate in human amyotrophic lateral sclerosis and spinal muscular atrophy. PMID- 24951542 TI - A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family. AB - Asymmetric cell division is essential for normal human brain development. Mutations in several genes encoding centrosomal proteins that participate in accurate cell division have been reported to cause autosomal recessive primary microcephaly (MCPH). By homozygosity mapping including three affected individuals from a consanguineous MCPH family from Pakistan, we delineated a critical region of 18.53 Mb on Chromosome 1p21.3-1p13.1. This region contains the gene encoding HsSAS-6, a centrosomal protein primordial for seeding the formation of new centrioles during the cell cycle. Both next-generation and Sanger sequencing revealed a homozygous c.185T>C missense mutation in the HsSAS-6 gene, resulting in a p.Ile62Thr substitution within a highly conserved region of the PISA domain of HsSAS-6. This variant is neither present in any single-nucleotide polymorphism or exome sequencing databases nor in a Pakistani control cohort. Experiments in tissue culture cells revealed that the Ile62Thr mutant of HsSAS-6 is substantially less efficient than the wild-type protein in sustaining centriole formation. Together, our findings demonstrate a dramatic impact of the mutation p.Ile62Thr on HsSAS-6 function and add this component to the list of genes mutated in primary microcephaly. PMID- 24951544 TI - Psychosocial outcomes of a summer overnight recreational experience for children with heart disease. AB - Children with chronic heart disease (CHD) are often turned away from recreational summer overnight experiences because of complicated medical histories and medication regimens. The purpose of this qualitative study was to evaluate the psychosocial impact of a five-day overnight recreational experience for children with CHD and their parents. Thirty-six children with CHD between the age of 8 and 15 years and their parents participated in the study. Data were collected from the children using photovoice interviews. Parent data were collected using a post camp survey. Results included the following external outcome themes: inclusion in a peer group and the importance of friendship, fun, and safety. Internal or personal outcome themes included counselor as a role model, increased self confidence, and the realization of life's possibilities. Parent themes included increased child independence, increased child confidence, and child feelings of normalcy related to belonging to a peer group. Findings from this study can be used to encourage families of children with CHD to allow participation in a well supervised overnight recreational experience. Such an experience can foster the child's overall development, provide peer group support, and reduce parent anxiety about overnight separation from the child. PMID- 24951543 TI - Meta-analysis of genome-wide association studies in multiethnic Asians identifies two loci for age-related nuclear cataract. AB - Age-related cataract is a leading cause of blindness worldwide, especially in developing countries where access to cataract surgery remains limited. Previous linkage and candidate gene studies suggested genetic influences on age-related nuclear cataract but few genetic markers have been identified thus far. We conducted genome-wide association studies on 4569 Asians (including 2369 Malays and 2200 Indians), and replicated our analysis in 2481 Chinese from two independent cohorts (1768 Chinese in Singapore and 803 Chinese in Beijing). We confirmed two genome-wide significant loci for nuclear cataract in the combined meta-analysis of four cohorts (n = 7140). The first locus was at chromosome 3q25.31 in KCNAB1 (rs7615568, fixed-effect Pmeta = 2.30 * 10(-8); random-effect Pmeta = 1.08 * 10(-8)). The second locus was at chromosome 21 in the proximity of CRYAA (rs11911275, fixed-effect Pmeta = 2.77 * 10(-8); random-effect Pmeta = 1.98 * 10(-9)), a major protein component of eye lens. The findings were further supported by up-regulation and down-regulation of KCNAB1 and CRYAA in human lens capsule, respectively, as the severity of nuclear cataract increases. The results offer additional insights into the pathogenesis of nuclear cataract in Asians. PMID- 24951545 TI - NATAS: neural activity trace aware saliency. AB - Saliency detection has raised much interest in computer vision recently. Many visual saliency models have been developed for individual images, video clips, and image pairs. However, image sequence, one most general occasion in the real world, is not explored yet. A general image sequence is different from video clips whose temporal continuity is maintained and image pairs where common objects exist. It might contain some similar low-level properties while completely distinct contents. Traditional saliency detection methods will fail on these general sequences. Based on this consideration, this paper investigates the shortcomings of the classical saliency detection methods, which significantly limit their advantages: 1) inability to capture the natural connections among sequential images, 2) over-reliance on motion cues, and 3) restriction to image pairs/videos with common objects. In order to address these problems, we propose a framework that performs the following contributions: 1) construct an image data set as benchmark through a rigorously designed behavioral experiment, 2) propose a neural activity trace aware saliency model to capture the general connections among images, and 3) design a novel measure to handle the low-level clues contained among sequential images. Experimental results demonstrate that the proposed saliency model is associated with a tremendous advancement compared with traditional methods when dealing with the general image sequence. PMID- 24951546 TI - Spectral embedded hashing for scalable image retrieval. AB - We propose a new graph based hashing method called spectral embedded hashing (SEH) for large-scale image retrieval. We first introduce a new regularizer into the objective function of the recent work spectral hashing to control the mismatch between the resultant hamming embedding and the low-dimensional data representation, which is obtained by using a linear regression function. This linear regression function can be employed to effectively handle the out-of sample data, and the introduction of the new regularizer makes SEH better cope with the data sampled from a nonlinear manifold. Considering that SEH cannot efficiently cope with the high dimensional data, we further extend SEH to kernel SEH (KSEH) to improve the efficiency and effectiveness, in which a nonlinear regression function can also be employed to obtain the low dimensional data representation. We also develop a new method to efficiently solve the approximate solution for the eigenvalue decomposition problem in SEH and KSEH. Moreover, we show that some existing hashing methods are special cases of our KSEH. Our comprehensive experiments on CIFAR, Tiny-580K, NUS-WIDE, and Caltech-256 datasets clearly demonstrate the effectiveness of our methods. PMID- 24951547 TI - Robust hashing with local models for approximate similarity search. AB - Similarity search plays an important role in many applications involving high dimensional data. Due to the known dimensionality curse, the performance of most existing indexing structures degrades quickly as the feature dimensionality increases. Hashing methods, such as locality sensitive hashing (LSH) and its variants, have been widely used to achieve fast approximate similarity search by trading search quality for efficiency. However, most existing hashing methods make use of randomized algorithms to generate hash codes without considering the specific structural information in the data. In this paper, we propose a novel hashing method, namely, robust hashing with local models (RHLM), which learns a set of robust hash functions to map the high-dimensional data points into binary hash codes by effectively utilizing local structural information. In RHLM, for each individual data point in the training dataset, a local hashing model is learned and used to predict the hash codes of its neighboring data points. The local models from all the data points are globally aligned so that an optimal hash code can be assigned to each data point. After obtaining the hash codes of all the training data points, we design a robust method by employing l2,1 -norm minimization on the loss function to learn effective hash functions, which are then used to map each database point into its hash code. Given a query data point, the search process first maps it into the query hash code by the hash functions and then explores the buckets, which have similar hash codes to the query hash code. Extensive experimental results conducted on real-life datasets show that the proposed RHLM outperforms the state-of-the-art methods in terms of search quality and efficiency. PMID- 24951548 TI - Is there still a role for composting? PMID- 24951549 TI - Estimating the possible range of recycling rates achieved by dump waste pickers: The case of Bantar Gebang in Indonesia. AB - This article presents informal recycling contributions made by scavengers in the surrounding area of Bantar Gebang final disposal site for municipal solid waste generated in Jakarta. Preliminary fieldwork was conducted through daily conversations with scavengers to identify recycling actors at the site, and then quantitative field surveys were conducted twice. The first survey (n = 504 households) covered 33% of all households in the area, and the second survey (n = 69 households) was conducted to quantify transactions of recyclables among scavengers. Mathematical equations were formulated with assumptions made to estimate the possible range of recycling rates achieved by dump waste pickers. Slightly over 60% of all respondents were involved in informal recycling and over 80% of heads of households were waste pickers, normally referred to as live-in waste pickers and live-out waste pickers at the site. The largest percentage of their spouses were family workers, followed by waste pickers and housewives. Over 95% of all households of respondents had at least one waste picker or one small boss who has a coequal status of a waste picker. Average weight of recyclables collected by waste pickers at the site was estimated to be approximately 100 kg day(-1) per household on the net weight basis. The recycling rate of solid wastes collected by all scavengers at the site was estimated to be in the range of 2.8 7.5% of all solid wastes transported to the site. PMID- 24951550 TI - Life cycle assessment modelling of waste-to-energy incineration in Spain and Portugal. AB - In recent years, waste management systems have been evaluated using a life cycle assessment (LCA) approach. A main shortcoming of prior studies was the focus on a mixture of waste with different characteristics. The estimation of emissions and consumptions associated with each waste fraction in these studies presented allocation problems. Waste-to-energy (WTE) incineration is a clear example in which municipal solid waste (MSW), comprising many types of materials, is processed to produce several outputs. This paper investigates an approach to better understand incineration processes in Spain and Portugal by applying a multi-input/output allocation model. The application of this model enabled predictions of WTE inputs and outputs, including the consumption of ancillary materials and combustibles, air emissions, solid wastes, and the energy produced during the combustion of each waste fraction. PMID- 24951551 TI - Co-production of activated carbon, fuel-gas, and oil from the pyrolysis of corncob mixtures with wet and dried sewage sludge. AB - This study explored the amount and composition of pyrolysis gas and oil derived from wet material or dried material during the preparation of sludge-corncob activated carbon, and evaluated the physicochemical and surface properties of the obtained two types of sludge-corncob-activated carbons. For wet material, owing to the presence of water, the yields of sludge-corncob activated carbon and the oil fraction slightly decreased while the yield of gases increased. The main pyrolysis gas compounds were H2 and CO2, and more H2 was released from wet material than dried material, whereas the opposite holds for CO2 Heterocyclics, nitriles, organic acids, and steroids were the major components of pyrolysis oil. Furthermore, the presence of water in wet material reduced the yield of polycyclic aromatic hydrocarbons from 6.76% to 5.43%. The yield of furfural, one of heterocyclics, increased sharply from 3.51% to 21.4%, which could be explained by the enhanced hydrolysis of corncob. In addition, the surface or chemical properties of the two sludge-corncob activated carbons were almost not affected by the moisture content of the raw material, although their mesopore volume and diameter were different. In addition, the adsorption capacities of the two sludge corncob activated carbons towards Pb and nitrobenzene were nearly identical. PMID- 24951552 TI - Impact on knowledge and behaviour of the general population of two different methods of solid waste management: An explorative cross-sectional study. AB - The objectives of the present study were to evaluate knowledge among general population about the risks factors of waste management, to estimate the feeling of anxiety concerning the waste, and to compare knowledge of two different methods for collecting municipal solid waste (MSW): a street separate collection system and a door-to-door separate collection system. A cross-sectional study was performed, administering an anonymous questionnaire to 180 inhabitants in Aprilia, Latium, Italy. The study sample consisted of 183 citizens: 64 in the intervention group and 119 in the control group. The intervention was represented by a campaign of door-to-door collection. The correct implementation of separate collection of waste was 87.5% in the intervention group and 63% in the control group (p<0.001). For both groups, the favourite type of waste collection was door to-door (p=0.013); a high difference concerning the quality of information was found (p<0.0001): in the intervention group, 84% declared to be satisfied (67% sufficient and 17.2% good), while in the control group, 21% declared to be satisfied (16.8% sufficient and 4.2% good). The advice mainly reported from the control group respondents was to increase the size of the information pack (80.7%, p=0.024). The information campaign seemed to increase people's awareness about the problem, improving the management of waste and household waste. The door-to-door collection was appreciated and preferred by both groups. The adoption of a door-to-door scheme seems to be a winning option mostly because it is supported by an information and education system for the citizens. PMID- 24951553 TI - Pokeweed antiviral protein alters splicing of HIV-1 RNAs, resulting in reduced virus production. AB - Processing of HIV-1 transcripts results in three populations in the cytoplasm of infected cells: full-length RNA, singly spliced, and multiply spliced RNAs. Rev, regulator of virion expression, is an essential regulatory protein of HIV-1 required for transporting unspliced and singly spliced viral transcripts from the nucleus to the cytoplasm. Export allows these RNAs to be translated and the full length RNA to be packaged into virus particles. In our study, we investigate the activity of pokeweed antiviral protein (PAP), a glycosidase isolated from the pokeweed plant Phytolacca americana, on the processing of viral RNAs. We show that coexpression of PAP with a proviral clone alters the splicing ratio of HIV-1 RNAs. Specifically, PAP causes the accumulation of multiply spliced 2-kb RNAs at the expense of full-length 9-kb and singly spliced 4-kb RNAs. The change in splicing ratio is due to a decrease in activity of Rev. We show that PAP depurinates the rev open reading frame and that this damage to the viral RNA inhibits its translation. By decreasing Rev expression, PAP indirectly reduces the availability of full-length 9-kb RNA for packaging and translation of the encoded structural proteins required for synthesis of viral particles. The decline we observe in virus protein expression is not due to cellular toxicity as PAP did not diminish translation rate. Our results describing the reduced activity of a regulatory protein of HIV-1, with resulting change in virus mRNA ratios, provides new insight into the antiviral mechanism of PAP. PMID- 24951554 TI - Characterization of two homologous 2'-O-methyltransferases showing different specificities for their tRNA substrates. AB - The 2'-O-methylation of the nucleoside at position 32 of tRNA is found in organisms belonging to the three domains of life. Unrelated enzymes catalyzing this modification in Bacteria (TrmJ) and Eukarya (Trm7) have already been identified, but until now, no information is available for the archaeal enzyme. In this work we have identified the methyltransferase of the archaeon Sulfolobus acidocaldarius responsible for the 2'-O-methylation at position 32. This enzyme is a homolog of the bacterial TrmJ. Remarkably, both enzymes have different specificities for the nature of the nucleoside at position 32. While the four canonical nucleosides are substrates of the Escherichia coli enzyme, the archaeal TrmJ can only methylate the ribose of a cytidine. Moreover, the two enzymes recognize their tRNA substrates in a different way. We have solved the crystal structure of the catalytic domain of both enzymes to gain better understanding of these differences at a molecular level. PMID- 24951556 TI - Recurrent syncope. PMID- 24951555 TI - Building a stable RNA U-turn with a protonated cytidine. AB - The U-turn is a classical three-dimensional RNA folding motif first identified in the anticodon and T-loops of tRNAs. It also occurs frequently as a building block in other functional RNA structures in many different sequence and structural contexts. U-turns induce sharp changes in the direction of the RNA backbone and often conform to the 3-nt consensus sequence 5'-UNR-3' (N = any nucleotide, R = purine). The canonical U-turn motif is stabilized by a hydrogen bond between the N3 imino group of the U residue and the 3' phosphate group of the R residue as well as a hydrogen bond between the 2'-hydroxyl group of the uridine and the N7 nitrogen of the R residue. Here, we demonstrate that a protonated cytidine can functionally and structurally replace the uridine at the first position of the canonical U-turn motif in the apical loop of the neomycin riboswitch. Using NMR spectroscopy, we directly show that the N3 imino group of the protonated cytidine forms a hydrogen bond with the backbone phosphate 3' from the third nucleotide of the U-turn analogously to the imino group of the uridine in the canonical motif. In addition, we compare the stability of the hydrogen bonds in the mutant U-turn motif to the wild type and describe the NMR signature of the C+-phosphate interaction. Our results have implications for the prediction of RNA structural motifs and suggest simple approaches for the experimental identification of hydrogen bonds between protonated C-imino groups and the phosphate backbone. PMID- 24951557 TI - Biogeographic analysis reveals ancient continental vicariance and recent oceanic dispersal in amphibians. AB - Amphibia comprises over 7000 extant species distributed in almost every ecosystem on every continent except Antarctica. Most species also show high specificity for particular habitats, biomes, or climatic niches, seemingly rendering long distance dispersal unlikely. Indeed, many lineages still seem to show the signature of their Pangaean origin, approximately 300 Ma later. To date, no study has attempted a large-scale historical-biogeographic analysis of the group to understand the distribution of extant lineages. Here, I use an updated chronogram containing 3309 species (~ 45% of extant diversity) to reconstruct their movement between 12 global ecoregions. I find that Pangaean origin and subsequent Laurasian and Gondwanan fragmentation explain a large proportion of patterns in the distribution of extant species. However, dispersal during the Cenozoic, likely across land bridges or short distances across oceans, has also exerted a strong influence. Finally, there are at least three strongly supported instances of long-distance oceanic dispersal between former Gondwanan landmasses during the Cenozoic. Extinction from intervening areas seems to be a strong factor in shaping present-day distributions. Dispersal and extinction from and between ecoregions are apparently tied to the evolution of extraordinarily adaptive expansion-oriented phenotypes that allow lineages to easily colonize new areas and diversify, or conversely, to extremely specialized phenotypes or heavily relictual climatic niches that result in strong geographic localization and limited diversification. PMID- 24951558 TI - Axiomatic opportunities and obstacles for inferring a species tree from gene trees. AB - The reconstruction of a central tendency "species tree" from a large number of conflicting gene trees is a central problem in systematic biology. Moreover, it becomes particularly problematic when taxon coverage is patchy, so that not all taxa are present in every gene tree. Here, we list four apparently desirable properties that a method for estimating a species tree from gene trees could have (the strongest property states that building a species tree from input gene trees and then pruning leaves gives a tree that is the same as, or more resolved than, the tree obtained by first removing the taxa from the input trees and then building the species tree). We show that although it is technically possible to simultaneously satisfy these properties when taxon coverage is complete, they cannot all be satisfied in the more general supertree setting. In part two, we discuss a concordance-based consensus method based on Baum's "plurality clusters", and an extension to concordance supertrees. PMID- 24951560 TI - A trnI_CAU triplication event in the complete chloroplast genome of Paris verticillata M.Bieb. (Melanthiaceae, Liliales). AB - The chloroplast is an essential plant organelle responsible for photosynthesis. Gene duplication, relocation, and loss in the chloroplast genome (cpDNA) are useful for exploring the evolution and phylogeny of plant species. In this study, the complete chloroplast genome of Paris verticillata was sequenced using the 454 sequencing system and Sanger sequencing method to trace the evolutionary pattern in the tribe Parideae of the family Melanthiaceae (Liliales). The circular double stranded cpDNA of P. verticillata (157,379 bp) consists of two inverted repeat regions each of 28,373 bp, a large single copy of 82,726 bp, and a small single copy of 17,907 bp. Gene content and order are generally similar to the previously reported cpDNA sequences within the order Liliales. However, we found that trnI_CAU was triplicated in P. verticillata. In addition, cemA is suspected to be a pseudogene due to the presence of internal stop codons created by poly(A) insertion and single small CA repeats. Such changes were not found in previously examined cpDNAs of the Melanthiaceae or other families of the Liliales, suggesting that such features are unique to the tribe Parideae of Melanthiaceae. The characteristics of P. verticillata cpDNA will provide useful information for uncovering the evolution within Paris and for further research of plastid genome evolution and phylogenetic studies in Liliales. PMID- 24951559 TI - Probabilistic graphical model representation in phylogenetics. AB - Recent years have seen a rapid expansion of the model space explored in statistical phylogenetics, emphasizing the need for new approaches to statistical model representation and software development. Clear communication and representation of the chosen model is crucial for: (i) reproducibility of an analysis, (ii) model development, and (iii) software design. Moreover, a unified, clear and understandable framework for model representation lowers the barrier for beginners and nonspecialists to grasp complex phylogenetic models, including their assumptions and parameter/variable dependencies. Graphical modeling is a unifying framework that has gained in popularity in the statistical literature in recent years. The core idea is to break complex models into conditionally independent distributions. The strength lies in the comprehensibility, flexibility, and adaptability of this formalism, and the large body of computational work based on it. Graphical models are well-suited to teach statistical models, to facilitate communication among phylogeneticists and in the development of generic software for simulation and statistical inference. Here, we provide an introduction to graphical models for phylogeneticists and extend the standard graphical model representation to the realm of phylogenetics. We introduce a new graphical model component, tree plates, to capture the changing structure of the subgraph corresponding to a phylogenetic tree. We describe a range of phylogenetic models using the graphical model framework and introduce modules to simplify the representation of standard components in large and complex models. Phylogenetic model graphs can be readily used in simulation, maximum likelihood inference, and Bayesian inference using, for example, Metropolis-Hastings or Gibbs sampling of the posterior distribution. PMID- 24951563 TI - Composite conserved promoter-terminator motifs (PeSLs) that mediate modular shuffling in the diverse T4-like myoviruses. AB - The diverse T4-like phages (Tquatrovirinae) infect a wide array of gram-negative bacterial hosts. The genome architecture of these phages is generally well conserved, most of the phylogenetically variable genes being grouped together in a series hyperplastic regions (HPRs) that are interspersed among large blocks of conserved core genes. Recent evidence from a pair of closely related T4-like phages has suggested that small, composite terminator/promoter sequences (promoterearly stem loop [PeSLs]) were implicated in mediating the high levels of genetic plasticity by indels occurring within the HPRs. Here, we present the genome sequence analysis of two T4-like phages, PST (168 kb, 272 open reading frames [ORFs]) and nt-1 (248 kb, 405 ORFs). These two phages were chosen for comparative sequence analysis because, although they are closely related to phages that have been previously sequenced (T4 and KVP40, respectively), they have different host ranges. In each case, one member of the pair infects a bacterial strain that is a human pathogen, whereas the other phage's host is a nonpathogen. Despite belonging to phylogenetically distant branches of the T4 likes, these pairs of phage have diverged from each other in part by a mechanism apparently involving PeSL-mediated recombination. This analysis confirms a role of PeSL sequences in the generation of genomic diversity by serving as a point of genetic exchange between otherwise unrelated sequences within the HPRs. Finally, the palette of divergent genes swapped by PeSL-mediated homologous recombination is discussed in the context of the PeSLs' potentially important role in facilitating phage adaption to new hosts and environments. PMID- 24951561 TI - From prediction to function using evolutionary genomics: human-specific ecotypes of Lactobacillus reuteri have diverse probiotic functions. AB - The vertebrate gut symbiont Lactobacillus reuteri has diversified into separate clades reflecting host origin. Strains show evidence of host adaptation, but how host-microbe coevolution influences microbial-derived effects on hosts is poorly understood. Emphasizing human-derived strains of L. reuteri, we combined comparative genomic analyses with functional assays to examine variations in host interaction among genetically distinct ecotypes. Within clade II or VI, the genomes of human-derived L. reuteri strains are highly conserved in gene content and at the nucleotide level. Nevertheless, they share only 70-90% of total gene content, indicating differences in functional capacity. Human-associated lineages are distinguished by genes related to bacteriophages, vitamin biosynthesis, antimicrobial production, and immunomodulation. Differential production of reuterin, histamine, and folate by 23 clade II and VI strains was demonstrated. These strains also differed with respect to their ability to modulate human cytokine production (tumor necrosis factor, monocyte chemoattractant protein-1, interleukin [IL]-1beta, IL-5, IL-7, IL-12, and IL-13) by myeloid cells. Microarray analysis of representative clade II and clade VI strains revealed global regulation of genes within the reuterin, vitamin B12, folate, and arginine catabolism gene clusters by the AraC family transcriptional regulator, PocR. Thus, human-derived L. reuteri clade II and VI strains are genetically distinct and their differences affect their functional repertoires and probiotic features. These findings highlight the biological impact of microbe:host coevolution and illustrate the functional significance of subspecies differences in the human microbiome. Consideration of host origin and functional differences at the subspecies level may have major impacts on probiotic strain selection and considerations of microbial ecology in mammalian species. PMID- 24951565 TI - Family size evolution in Drosophila chemosensory gene families: a comparative analysis with a critical appraisal of methods. AB - Gene turnover rates and the evolution of gene family sizes are important aspects of genome evolution. Here, we use curated sequence data of the major chemosensory gene families from Drosophila-the gustatory receptor, odorant receptor, ionotropic receptor, and odorant-binding protein families-to conduct a comparative analysis among families, exploring different methods to estimate gene birth and death rates, including an ad hoc simulation study. Remarkably, we found that the state-of-the-art methods may produce very different rate estimates, which may lead to disparate conclusions regarding the evolution of chemosensory gene family sizes in Drosophila. Among biological factors, we found that a peculiarity of D. sechellia's gene turnover rates was a major source of bias in global estimates, whereas gene conversion had negligible effects for the families analyzed herein. Turnover rates vary considerably among families, subfamilies, and ortholog groups although all analyzed families were quite dynamic in terms of gene turnover. Computer simulations showed that the methods that use ortholog group information appear to be the most accurate for the Drosophila chemosensory families. Most importantly, these results reveal the potential of rate heterogeneity among lineages to severely bias some turnover rate estimation methods and the need of further evaluating the performance of these methods in a more diverse sampling of gene families and phylogenetic contexts. Using branch specific codon substitution models, we find further evidence of positive selection in recently duplicated genes, which attests to a nonneutral aspect of the gene birth-and-death process. PMID- 24951564 TI - Settling down: the genome of Serratia symbiotica from the aphid Cinara tujafilina zooms in on the process of accommodation to a cooperative intracellular life. AB - Particularly interesting cases of mutualistic endosymbioses come from the establishment of co-obligate associations of more than one species of endosymbiotic bacteria. Throughout symbiotic accommodation from a free-living bacterium, passing through a facultative stage and ending as an obligate intracellular one, the symbiont experiences massive genomic losses and phenotypic adjustments. Here, we scrutinized the changes in the coevolution of Serratia symbiotica and Buchnera aphidicola endosymbionts in aphids, paying particular attention to the transformations undergone by S. symbiotica to become an obligate endosymbiont. Although it is already known that S. symbiotica is facultative in Acyrthosiphon pisum, in Cinara cedri it has established a co-obligate endosymbiotic consortium along with B. aphidicola to fulfill the aphid's nutritional requirements. The state of this association in C. tujafilina, an aphid belonging to the same subfamily (Lachninae) that C. cedri, remained unknown. Here, we report the genome of S. symbiotica strain SCt-VLC from the aphid C. tujafilina. While being phylogenetically and genomically very closely related to the facultative endosymbiont S. symbiotica from the aphid A. pisum, it shows a variety of metabolic, genetic, and architectural features, which point toward this endosymbiont being one step closer to an obligate intracellular one. We also describe in depth the process of genome rearrangements suffered by S. symbiotica and the role mobile elements play in gene inactivations. Finally, we postulate the supply to the host of the essential riboflavin (vitamin B2) as key to the establishment of S. symbiotica as a co-obligate endosymbiont in the aphids belonging to the subfamily Lachninane. PMID- 24951566 TI - Evolution of the vertebrate Pax4/6 class of genes with focus on its novel member, the Pax10 gene. AB - The members of the paired box (Pax) family regulate key developmental pathways in many metazoans as tissue-specific transcription factors. Vertebrate genomes typically possess nine Pax genes (Pax1-9), which are derived from four proto-Pax genes in the vertebrate ancestor that were later expanded through the so-called two-round (2R) whole-genome duplication. A recent study proposed that pax6a genes of a subset of teleost fishes (namely, acanthopterygians) are remnants of a paralog generated in the 2R genome duplication, to be renamed pax6.3, and reported one more group of vertebrate Pax genes (Pax6.2), most closely related to the Pax4/6 class. We propose to designate this new member Pax10 instead and reconstruct the evolutionary history of the Pax4/6/10 class with solid phylogenetic evidence. Our synteny analysis showed that Pax4, -6, and -10 originated in the 2R genome duplications early in vertebrate evolution. The phylogenetic analyses of relationships between teleost pax6a and other Pax4, -6, and -10 genes, however, do not support the proposed hypothesis of an ancient origin of the acanthopterygian pax6a genes in the 2R genome duplication. Instead, we confirmed the traditional scenario that the acanthopterygian pax6a is derived from the more recent teleost-specific genome duplication. Notably, Pax6 is present in all vertebrates surveyed to date, whereas Pax4 and -10 were lost multiple times in independent vertebrate lineages, likely because of their restricted expression patterns: Among Pax6-positive domains, Pax10 has retained expression in the adult retina alone, which we documented through in situ hybridization and quantitative reverse transcription polymerase chain reaction experiments on zebrafish, Xenopus, and anole lizard. PMID- 24951567 TI - Extensive local gene duplication and functional divergence among paralogs in Atlantic salmon. AB - Many organisms can generate alternative phenotypes from the same genome, enabling individuals to exploit diverse and variable environments. A prevailing hypothesis is that such adaptation has been favored by gene duplication events, which generate redundant genomic material that may evolve divergent functions. Vertebrate examples of recent whole-genome duplications are sparse although one example is the salmonids, which have undergone a whole-genome duplication event within the last 100 Myr. The life-cycle of the Atlantic salmon, Salmo salar, depends on the ability to produce alternating phenotypes from the same genome, to facilitate migration and maintain its anadromous life history. Here, we investigate the hypothesis that genome-wide and local gene duplication events have contributed to the salmonid adaptation. We used high-throughput sequencing to characterize the transcriptomes of three key organs involved in regulating migration in S. salar: Brain, pituitary, and olfactory epithelium. We identified over 10,000 undescribed S. salar sequences and designed an analytic workflow to distinguish between paralogs originating from local gene duplication events or from whole-genome duplication events. These data reveal that substantial local gene duplications took place shortly after the whole-genome duplication event. Many of the identified paralog pairs have either diverged in function or become noncoding. Future functional genomics studies will reveal to what extent this rich source of divergence in genetic sequence is likely to have facilitated the evolution of extreme phenotypic plasticity required for an anadromous life-cycle. PMID- 24951569 TI - The Brugada ECG and schizophrenia. PMID- 24951570 TI - The phenomenon of early repolarization: a false alarm? PMID- 24951568 TI - The draft assembly of the radically organized Stylonychia lemnae macronuclear genome. AB - Stylonychia lemnae is a classical model single-celled eukaryote, and a quintessential ciliate typified by dimorphic nuclei: A small, germline micronucleus and a massive, vegetative macronucleus. The genome within Stylonychia's macronucleus has a very unusual architecture, comprised variably and highly amplified "nanochromosomes," each usually encoding a single gene with a minimal amount of surrounding noncoding DNA. As only a tiny fraction of the Stylonychia genes has been sequenced, and to promote research using this organism, we sequenced its macronuclear genome. We report the analysis of the 50.2-Mb draft S. lemnae macronuclear genome assembly, containing in excess of 16,000 complete nanochromosomes, assembled as less than 20,000 contigs. We found considerable conservation of fundamental genomic properties between S. lemnae and its close relative, Oxytricha trifallax, including nanochromosomal gene synteny, alternative fragmentation, and copy number. Protein domain searches in Stylonychia revealed two new telomere-binding protein homologs and the presence of linker histones. Among the diverse histone variants of S. lemnae and O. trifallax, we found divergent, coexpressed variants corresponding to four of the five core nucleosomal proteins (H1.2, H2A.6, H2B.4, and H3.7) suggesting that these ciliates may possess specialized nucleosomes involved in genome processing during nuclear differentiation. The assembly of the S. lemnae macronuclear genome demonstrates that largely complete, well-assembled highly fragmented genomes of similar size and complexity may be produced from one library and lane of Illumina HiSeq 2000 shotgun sequencing. The provision of the S. lemnae macronuclear genome sets the stage for future detailed experimental studies of chromatin-mediated, RNA-guided developmental genome rearrangements. PMID- 24951571 TI - Does cardiac resynchronization therapy benefit patients with right bundle branch block: cardiac resynchronization therapy has a role in patients with right bundle branch block. PMID- 24951572 TI - Does cardiac resynchronization therapy benefit patients with right bundle branch block: left ventricular free wall pacing: seldom right for right bundle branch block. PMID- 24951573 TI - Chasing red herrings: making sense of the colors while mapping. PMID- 24951575 TI - Steam pop during radiofrequency ablation: imaging features on magnetic resonance imaging and multidetector computed tomography. PMID- 24951574 TI - Editor's perspective: Reentry, pseudo-reentry, and pseudo-pseudo-reentry. PMID- 24951576 TI - Prospective 3-dimensional computed tomography segmentation of the pericardiac right phrenic nerve in the setting of atrial fibrillation ablation. PMID- 24951577 TI - Clinical implication of vitamin D threshold. PMID- 24951578 TI - Reply to J Huang et al. PMID- 24951579 TI - Dietary sodium and cardiovascular health strategies. PMID- 24951580 TI - Reply to SN Thornton and P Lacolley. PMID- 24951586 TI - Defining a role for acid sphingomyelinase in the p38/interleukin-6 pathway. AB - Acid sphingomyelinase (ASM) is one of the key enzymes involved in regulating the metabolism of the bioactive sphingolipid ceramide in the sphingolipid salvage pathway, yet defining signaling pathways by which ASM exerts its effects has proven difficult. Previous literature has implicated sphingolipids in the regulation of cytokines such as interleukin-6 (IL-6), but the specific sphingolipid pathways and mechanisms involved in inflammatory signaling need to be further elucidated. In this work, we sought to define the role of ASM in IL-6 production because our previous work showed that a parallel pathway of ceramide metabolism, acid beta-glucosidase 1, negatively regulates IL-6. First, silencing ASM with siRNA abrogated IL-6 production in response to the tumor promoter, 4beta phorbol 12-myristate 13-acetate (PMA), in MCF-7 cells, in distinction to acid beta-glucosidase 1 and acid ceramidase, suggesting specialization of the pathways. Moreover, treating cells with siRNA to ASM or with the indirect pharmacologic inhibitor desipramine resulted in significant inhibition of TNFalpha- and PMA-induced IL-6 production in MDA-MB-231 and HeLa cells. Knockdown of ASM was found to significantly inhibit PMA-dependent IL-6 induction at the mRNA level, probably ruling out mechanisms of translation or secretion of IL-6. Further, ASM knockdown or desipramine blunted p38 MAPK activation in response to TNFalpha, revealing a key role for ASM in activating p38, a signaling pathway known to regulate IL-6 induction. Last, knockdown of ASM dramatically blunted invasion of HeLa and MDA-MB-231 cells through Matrigel. Taken together, these results demonstrate that ASM plays a critical role in p38 signaling and IL-6 synthesis with implications for tumor pathobiology. PMID- 24951587 TI - Excision of uracil from transcribed DNA negatively affects gene expression. AB - Uracil is an unavoidable aberrant base in DNA, the repair of which takes place by a highly efficient base excision repair mechanism. The removal of uracil from the genome requires a succession of intermediate products, including an abasic site and a single strand break, before the original DNA structure can be reconstituted. These repair intermediates are harmful for DNA replication and also interfere with transcription under cell-free conditions. However, their relevance for cellular transcription has not been proved. Here we investigated the influence of uracil incorporated into a reporter vector on gene expression in human cells. The expression constructs contained a single uracil opposite an adenine (to mimic dUTP misincorporation during DNA synthesis) or a guanine (imitating a product of spontaneous cytosine deamination). We found no evidence for a direct transcription arrest by uracil in either of the two settings because the vectors containing the base modification exhibited unaltered levels of enhanced GFP reporter gene expression at early times after delivery to cells. However, the gene expression showed a progressive decline during subsequent hours. In the case of U:A pairs, this effect was retarded significantly by knockdown of UNG1/2 but not by knockdown of SMUG1 or thymine-DNA glycosylase uracil-DNA glycosylases, proving that it is base excision by UNG1/2 that perturbs transcription of the affected gene. By contrast, the decline of expression of the U:G constructs was not influenced by either UNG1/2, SMUG1, or thymine-DNA glycosylase knockdown, strongly suggesting that there are substantial mechanistic or kinetic differences between the processing of U:A and U:G lesions in cells. PMID- 24951588 TI - Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. AB - Exosomes are nanoscale membrane vesicles secreted from many types of cells. Carrying functional molecules, exosomes transfer information between cells and mediate many physiological and pathological processes. In this report, utilizing selective inhibitors, molecular tools, and specific endocytosis markers, the cellular uptake of PC12 cell-derived exosomes was imaged by high-throughput microscopy and statistically analyzed. It was found that the uptake was through clathrin-mediated endocytosis and macropinocytosis. Furthermore, PC12 cell derived exosomes can enter and deliver microRNAs (miRNAs) into bone marrow derived mesenchymal stromal cells (BMSCs), and decrease the expression level of transforming growth factor beta receptor II (TGFbetaRII) and tropomyosin-1 (TPM1) through miR-21. These results show the pathway of exosome internalization and demonstrate that tumor cell-derived exosomes regulate target gene expression in normal cells. PMID- 24951589 TI - Myosin phosphatase target subunit 1 (MYPT1) regulates the contraction and relaxation of vascular smooth muscle and maintains blood pressure. AB - Myosin light chain phosphatase with its regulatory subunit, myosin phosphatase target subunit 1 (MYPT1) modulates Ca(2+)-dependent phosphorylation of myosin light chain by myosin light chain kinase, which is essential for smooth muscle contraction. The role of MYPT1 in vascular smooth muscle was investigated in adult MYPT1 smooth muscle specific knock-out mice. MYPT1 deletion enhanced phosphorylation of myosin regulatory light chain and contractile force in isolated mesenteric arteries treated with KCl and various vascular agonists. The contractile responses of arteries from knock-out mice to norepinephrine were inhibited by Rho-associated kinase (ROCK) and protein kinase C inhibitors and were associated with inhibition of phosphorylation of the myosin light chain phosphatase inhibitor CPI-17. Additionally, stimulation of the NO/cGMP/protein kinase G (PKG) signaling pathway still resulted in relaxation of MYPT1-deficient mesenteric arteries, indicating phosphorylation of MYPT1 by PKG is not a major contributor to the relaxation response. Thus, MYPT1 enhances myosin light chain phosphatase activity sufficient for blood pressure maintenance. Rho-associated kinase phosphorylation of CPI-17 plays a significant role in enhancing vascular contractile responses, whereas phosphorylation of MYPT1 in the NO/cGMP/PKG signaling module is not necessary for relaxation. PMID- 24951590 TI - Dynamic interaction of the sec translocon with the chaperone PpiD. AB - The Sec translocon constitutes a ubiquitous protein transport channel that consists in bacteria of the three core components: SecY, SecE, and SecG. Additional proteins interact with SecYEG during different stages of protein transport. During targeting, SecYEG interacts with SecA, the SRP receptor, or the ribosome. Protein transport into or across the membrane is then facilitated by the interaction of SecYEG with YidC and the SecDFYajC complex. During protein transport, SecYEG is likely to interact also with the protein quality control machinery, but details about this interaction are missing. By in vivo and in vitro site-directed cross-linking, we show here that the periplasmic chaperone PpiD is located in front of the lateral gate of SecY, through which transmembrane domains exit the SecY channel. The strongest contacts were found to helix 2b of SecY. Blue native PAGE analyses verify the presence of a SecYEG-PpiD complex in native Escherichia coli membranes. The PpiD-SecY interaction was not influenced by the addition of SecA and only weakly influenced by binding of nontranslating ribosomes to SecYEG. In contrast, PpiD lost contact to the lateral gate of SecY during membrane protein insertion. These data identify PpiD as an additional and transient subunit of the bacterial SecYEG translocon. The data furthermore demonstrate the highly modular and versatile composition of the Sec translocon, which is probably essential for its ability to transport a wide range of substrates across membranes in bacteria and eukaryotes. PMID- 24951591 TI - Keratinocyte-derived laminin-332 protein promotes melanin synthesis via regulation of tyrosine uptake. AB - Melanocytes, which produce the pigment melanin, are known to be closely regulated by neighboring keratinocytes. However, how keratinocytes regulate melanin production is unclear. Here we report that melanin production in melanoma cells (B16F10 and MNT-1) was increased markedly on a keratinocyte-derived extracellular matrix compared with a melanoma cell-derived extracellular matrix. siRNA-mediated reduction of keratinocyte-derived laminin-332 expression decreased melanin synthesis in melanoma cells, and laminin-332, but not fibronectin, enhanced melanin content and alpha-melanocyte-stimulating hormone-regulated melanin production in melanoma cells. Similar effects were observed in human melanocytes. Interestingly, however, laminin-332 did not affect the expression or activity of tyrosinase. Instead, laminin-332 promoted the uptake of extracellular tyrosine and, subsequently, increased intracellular levels of tyrosine in both melanocytes and melanoma cells. Taken together, these data strongly suggest that keratinocyte derived laminin-332 contributes to melanin production by regulating tyrosine uptake. PMID- 24951592 TI - Replication intermediates of the linear mitochondrial DNA of Candida parapsilosis suggest a common recombination based mechanism for yeast mitochondria. AB - Variation in the topology of mitochondrial DNA (mtDNA) in eukaryotes evokes the question if differently structured DNAs are replicated by a common mechanism. RNA primed DNA synthesis has been established as a mechanism for replicating the circular animal/mammalian mtDNA. In yeasts, circular mtDNA molecules were assumed to be templates for rolling circle DNA-replication. We recently showed that in Candida albicans, which has circular mapping mtDNA, recombination driven replication is a major mechanism for replicating a complex branched mtDNA network. Careful analyses of C. albicans-mtDNA did not reveal detectable amounts of circular DNA molecules. In the present study we addressed the question of how the unit sized linear mtDNA of Candida parapsilosis terminating at both ends with arrays of tandem repeats (mitochondrial telomeres) is replicated. Originally, we expected to find replication intermediates diagnostic of canonical bi-directional replication initiation at the centrally located bi-directional promoter region. However, we found that the linear mtDNA of Candida parapsilosis also employs recombination for replication initiation. The most striking findings were that the mitochondrial telomeres appear to be hot spots for recombination driven replication, and that stable RNA:DNA hybrids, with a potential role in mtDNA replication, are also present in the mtDNA preparations. PMID- 24951595 TI - A rare complication of transitional cell carcinoma of the renal pelvis: parathyroid hormone-related peptide-induced hypercalcaemia. AB - We describe a rare occurrence of parathyroid hormone-related peptide (PTHrp) associated hypercalcaemia with a recurrence of transitional cell carcinoma of the renal pelvis. Our patient presented with serum calcium of 3.9 mmol/L, PTH of 5 ng/L and a PTHrp of 9.8 pmol/L (<2 pmol/L). He had no evidence of metastatic disease. His hypercalcaemia responded to bisphosphonate therapy. He chose to be treated conservatively and died 5 weeks after presentation. This is the seventh such case described in the literature. PTHrp-induced hypercalcaemia is associated with a grave prognosis, with a mean survival of 65 days from presentation. PMID- 24951593 TI - Reconstituted human polyclonal plasma-derived secretory-like IgM and IgA maintain the barrier function of epithelial cells infected with an enteropathogen. AB - Intravenous administration of polyclonal and monoclonal antibodies has proven to be a clinically valid approach in the treatment, or at least relief, of many acute and chronic pathologies, such as infection, immunodeficiency, and a broad range of autoimmune conditions. Plasma-derived IgG or recombinant IgG are most frequently used for intravenous or subcutaneous administration, whereas a few IgM based products are available as well. We have established recently that secretory like IgA and IgM can be produced upon association of plasma-derived polymeric IgA and IgM with a recombinant secretory component. As a next step toward potential future mucosal administration, we sought to unravel the mechanisms by which these secretory Igs protect epithelial cells located at the interface between the environment and the inside of the body. By using polarized epithelial Caco-2 cell monolayers and Shigella flexneri as a model enteropathogen, we found that polyspecific plasma-derived SIgA and SIgM fulfill many protective functions, including dose-dependent recognition of the antigen via formation of aggregated immune complexes, reduction of bacterial infectivity, maintenance of epithelial cell integrity, and inhibition of proinflammatory cytokine/chemokine production by epithelial cells. In this in vitro model devoid of other cellular or molecular interfering partners, IgM and secretory IgM showed stronger bacterial neutralization than secretory IgA. Together, these data suggest that mucosally delivered antibody preparations may be most effective when combining both secretory-like IgA and IgM, which, together, play a crucial role in preserving several levels of epithelial cell integrity. PMID- 24951597 TI - Chronic dacryocystitis secondary to Stenotrophomonas maltophilia and Staphylococcus aureus mixed infection. AB - A 40-year-old woman with a history of recurrent attacks of dacryocystitis for 2 years developed a lacrimal sac abscess. beta-Lactam antibiotics, considered the first-line treatment for dacryocystitis, were ineffective. She underwent dacryocystorhinostomy. Cultures from the lacrimal sac demonstrated the presence of Stenotrophomonas maltophilia and methicillin-sensitive Staphylococcus aureus, both of which are sensitive to trimethoprim-sulfamethoxazole. This rare and antibiotic-resistant bacterial species should be considered in atypical cases of dacryocystitis, and appropriate antibiotics should be started immediately. PMID- 24951596 TI - Transient small bowel intussusception in adults: an overlooked feature of coeliac disease. AB - Coeliac disease is the commonest immunological gastrointestinal disorder in the Western world. The symptoms of coeliac disease in adults are often non-specific, and a high index of suspicion may be required for timely diagnosis. We describe the case of a 46-year-old woman, with known dilated cardiomyopathy and pulmonary hypertension, who presented with non-specific abdominal symptoms, not initially attributed to gastrointestinal disease. Radiological investigations demonstrated transient small bowel intussusception without other abnormality, leading to the suggestion of coeliac disease as a cause, which was subsequently confirmed as the diagnosis. PMID- 24951594 TI - Sin3b interacts with Myc and decreases Myc levels. AB - Myc expression is deregulated in many human cancers. A yeast two-hybrid screen has revealed that the transcriptional repressor Sin3b interacts with Myc protein. Endogenous Myc and Sin3b co-localize and interact in the nuclei of human and rat cells, as assessed by co-immunoprecipitation, immunofluorescence, and proximity ligation assay. The interaction is Max-independent. A conserved Myc region (amino acids 186-203) is required for the interaction with Sin3 proteins. Histone deacetylase 1 is recruited to Myc-Sin3b complexes, and its deacetylase activity is required for the effects of Sin3b on Myc. Myc and Sin3a/b co-occupied many sites on the chromatin of human leukemia cells, although the presence of Sin3 was not associated with gene down-regulation. In leukemia cells and fibroblasts, Sin3b silencing led to Myc up-regulation, whereas Sin3b overexpression induced Myc deacetylation and degradation. An analysis of Sin3b expression in breast tumors revealed an association between low Sin3b expression and disease progression. The data suggest that Sin3b decreases Myc protein levels upon Myc deacetylation. As Sin3b is also required for transcriptional repression by Mxd Max complexes, our results suggest that, at least in some cell types, Sin3b limits Myc activity through two complementary activities: Mxd-dependent gene repression and reduction of Myc levels. PMID- 24951598 TI - Epigastric pain...it's not always alcohol! An unusual presentation of caecal intussusception. AB - Our patient is a 19-year-old man who presented to the emergency department after consuming 50-60 units of alcohol over a weekend. He presented with a 2-day history of right-upper quadrant (RUQ) and epigastric pain radiating to the back. On examination he was haemodynamically stable. His abdomen was soft with minimal tenderness in the RUQ, epigastric and right-iliac fossa areas. Laboratory results showed a slightly raised erythrocyte sedimentation rate. Amylase and white cell count were normal. Ultrasound was performed raising the suspicion of intussusception. A CT scan was recommended and confirmed the presence of an intussusception. Once diagnosis was established, the patient had an emergency laparotomy and right hemicoloectomy, with per-operative findings consistent with the CT findings. This case illustrates the importance of keeping an open approach to all differentials while considering a diagnosis along with the importance of recognising intussusception when it occurs as complications can each represent a cause of mortality on their own. PMID- 24951599 TI - Sore throat in a young man: guess what.... AB - Sore throat is a common complaint in the outpatient and emergency room settings. Typically, little workup is necessary and includes visual inspection with or without swabs for bacterial infection. We present a case that demonstrates an important entity to be excluded by simple history and physical examination in patients presenting with pain in the throat or neck. The most important cause of pneumomediastinum is previous instrumentation. Spontaneous pneumomediastinum is uncommonly seen in young adults. Most cases of spontaneous pneumomediastinum are uncomplicated, as mediastinal pressures rarely mount to dangerous levels. However, when the patient presents with distended neck veins, cyanosis or marked dyspnoea, further action is necessary. Lastly, since pneumomediastinum can be caused by oesophageal rupture and occasionally present with concurrent pneumothorax, these dangerous entities must be excluded. PMID- 24951600 TI - Simple cough as a cause of subcutaneous emphysema. PMID- 24951601 TI - EDTA-induced pseudothrombocytopenia in association with bladder cancer. AB - Pseudothrombocytopenia is the detection of low platelet counts by an autoanalyser despite lack of shortage in platelets. EDTA-induced pseudothrombocytopenia, the most frequently seen form in clinical practice, occurs mainly due to reaction of antiplatelet antibodies. Pseudothrombocytopenia is not only seen in healthy individuals but it is also reported in association with autoimmune, cardiovascular and liver parenchyma diseases and malignancy. We aimed to review approaches to pseudothrombocytopenia by presenting a case in which EDTA-dependent thrombocytopenia in association with bladder tumour was detected during examination for haematuria. PMID- 24951603 TI - Hypotension in the high-dependency unit: a conundrum. PMID- 24951602 TI - The curious case of free-floating pelvic cysts. AB - The case of a healthy 33-year-old woman who underwent an elective caesarean section with incidental finding of small free-floating cysts within the pelvic peritoneum is presented. Gross examination could not identify the specimens. Histopathological investigation was necessary to classify the specimens as benign mesothelial cysts. The patient had no medical or surgical history and no other risk factors. The presented case is particularly interesting as the cysts were non-adherent to any pelvic or abdominal structure, as is commonly described. Similarly, there are few descriptions of mesothelial cyst diagnosis during pregnancy. PMID- 24951604 TI - Using social media to enhance career development opportunities for health promotion professionals. AB - For health promotion professionals, social media offers many ways to engage with a broader range of colleagues; participate in professional development events; promote expertise, products, or services; and learn about career-enhancing opportunities such as funding and fellowships. Previous work has recommended "building networking into what you are already doing." This article provides updated and new social media resources, as well as practical examples and strategies to promote effective use of social media. Social media offers health promotion professionals cost-effective opportunities to enhance their career by building communities of practice, participating in professional development events, and enriching classroom learning. Developing the skills necessary to use social media for networking is important in the public health workforce, especially as social media is increasingly used in academic and practice settings. PMID- 24951606 TI - Measuring the population impact of introducing stereotactic ablative radiotherapy for stage I non-small cell lung cancer in Canada. AB - BACKGROUND: The Cancer Risk Management Model (CRMM) was used to estimate the health and economic impact of introducing stereotactic ablative radiotherapy (SABR) for stage I non-small cell lung cancer (NSCLC) in Canada. METHODS: The CRMM uses Monte Carlo microsimulation representative of all Canadians. Lung cancer outputs were previously validated internally (Statistics Canada) and externally (Canadian Cancer Registry). We updated costs using the Ontario schedule of fees and benefits or the consumer price index to calculate 2013 Canadian dollars, discounted at a 3% rate. The reference model assumed that for stage I NSCLC, 75% of patients undergo surgery (lobectomy, sublobar resection, or pneumonectomy), 12.5% undergo radiotherapy (RT), and 12.5% undergo best supportive care (BSC). SABR was introduced in 2008 as an alternative to sublobar resection, RT, and BSC at rates reflective of the literature. Incremental cost effectiveness ratios (ICERs) were calculated; a willingness-to-pay threshold of $100,000 (all amounts are in Canadian dollars) per quality-adjusted life-year (QALY) was used from the health care payer perspective. RESULTS: The total cost for 25,085 new cases of lung cancer in 2013 was calculated to be $608,002,599. Mean upfront costs for the 4,318 stage I cases were $7,646.98 for RT, $8,815.55 for SABR, $12,161.17 for sublobar resection, $16,266.12 for lobectomy, $22,940.59 for pneumonectomy, and $14,582.87 for BSC. SABR dominated (higher QALY, lower cost) RT, sublobar resection, and BSC. RT had lower initial costs than SABR that were offset by subsequent costs associated with recurrence. Lobectomy was cost effective when compared with SABR, with an ICER of $55,909.06. CONCLUSION: The use of SABR for NSCLC in Canada is projected to result in significant cost savings and survival gains. PMID- 24951607 TI - Breast cancer, BRCA mutations, and attitudes regarding pregnancy and preimplantation genetic diagnosis. AB - BACKGROUND: Women with premenopausal breast cancer may face treatment-related infertility and have a higher likelihood of a BRCA mutation, which may affect their attitudes toward future childbearing. METHODS: Premenopausal women were invited to participate in a questionnaire study administered before and after BRCA genetic testing. We used the Impact of Event Scale (IES) to evaluate the pre and post-testing impact of cancer or carrying a BRCA mutation on attitudes toward future childbearing. The likelihood of pursuing prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD) was also assessed in this setting. Univariate analyses determined factors contributing to attitudes toward future childbearing and likelihood of PND or PGD. RESULTS: One hundred forty-eight pretesting and 114 post-testing questionnaires were completed. Women with a personal history of breast cancer had less change in IES than those with no history of breast cancer (p = .003). The 18 BRCA-positive women had a greater change in IES than the BRCA-negative women (p = .005). After testing, 31% and 24% of women would use PND and PGD, respectively. BRCA results did not significantly affect attitudes toward PND/PGD. CONCLUSION: BRCA results and history of breast cancer affect the psychological impact on future childbearing. Intentions to undergo PND or PGD do not appear to change after disclosure of BRCA results. Additional counseling for patients who have undergone BRCA testing may be warranted to educate patients about available fertility preservation options. PMID- 24951610 TI - Estimates of young breast cancer survivors at risk for infertility in the U.S. AB - BACKGROUND: Standard treatments for breast cancer can impair fertility. It is unknown how many U.S. survivors are at risk for infertility. We estimated the population at risk for infertility secondary to treatment among reproductive-aged breast cancer survivors. METHODS: We combined data from three sources: the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results cancer registry data on incident breast cancers diagnosed in women aged 15-44 years between 2004 and 2006; treatment data from NPCR's 2004 Breast and Prostate Cancer Data Quality and Patterns of Care (PoC) study; and data on women's intentions to have children from the 2006-2010 National Survey of Family Growth (NSFG). RESULTS: In the cancer registry data, an average of 20,308 women with breast cancer aged <45 years were diagnosed annually. Based on estimates from PoC data, almost all of these survivors (97%, 19,416 women) were hormone receptor positive or received chemotherapy and would be at risk for infertility. These women need information about the impact of treatments on fertility. Estimates based on NSFG data suggest approximately half of these survivors (9,569 women) might want children and could benefit from fertility counseling and fertility preservation. CONCLUSION: Nearly all young breast cancer survivors in the U.S. are at risk for infertility. Physicians should discuss the potential impact of treatment on fertility. A smaller but sizeable number of at-risk survivors may be interested in having children. Given the magnitude of potential infertility and its quality-of-life implications, these survivors should have access to and potential coverage for fertility services. PMID- 24951608 TI - FOLFOX-4 chemotherapy for patients with unresectable or relapsed peritoneal pseudomyxoma. AB - PURPOSE: The standard treatment of peritoneal pseudomyxoma is based on cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC). The establishment of newer systemic treatments is an unmet clinical need for unresectable or relapsed peritoneal pseudomyxoma. The aim of our study was to assess the activity of chemotherapy with 5-fluorouracil and oxaliplatin (FOLFOX-4 regimen) in terms of response rate in this subset of patients. MATERIALS AND METHODS: Patients were included in a single-center, observational study and treated with FOLFOX-4 administered every 2 weeks for up to 12 cycles or until progressive disease or unacceptable toxicity. RESULTS: Twenty consecutive patients were reviewed from July 2011 to September 2013. Only partial responses were observed, with an objective response rate of 20%. Median progression-free survival and overall survival were 8 months and 26 months, respectively. Two patients were able to undergo laparotomy with complete cytoreduction and HIPEC in one case. Safety data for FOLFOX-4 were consistent with the literature. By means of a mutant enriched polymerase chain reaction, KRAS mutation was found in 16 of 19 cases (84%), and MGMT promoter methylation was found in 8 (42%, all KRAS mutant). CONCLUSION: FOLFOX-4 chemotherapy is tolerable and active in patients with peritoneal pseudomyxoma when disease is deemed unresectable or relapsed after peritonectomy and HIPEC. The identification of predictive biomarkers, such as KRAS for resistance to anti-epidermal growth factor receptor monoclonal antibodies and MGMT for response to temozolomide, is a priority for the development of evidence-based treatment strategies for peritoneal pseudomyxoma. PMID- 24951611 TI - Cervical cancer in Ethiopia: survival of 1,059 patients who received oncologic therapy. AB - BACKGROUND: Almost 500,000 women are newly diagnosed with cervical cancer (CC) every year, the majority from developing countries. There is little information on the survival of these patients. Our primary objective was to evaluate consecutive CC patients presenting over 4 years at the only radiotherapy center in Ethiopia. METHODS: All patients with CC from September 2008 to September 2012 who received radiotherapy and/or surgery were included (without brachytherapy). Vital status was obtained through telephone contact or patient cards. RESULTS: Of 2,300 CC patients, 1,059 patients with standardized treatment were included. At the end of the study, 249 patients had died; surviving patients had a median follow-up of 16.5 months; the 10% and 90% percentiles were 3.0 and 32.7 months, respectively. Mean age was 49 years (21-91 years). The majority of patients presented with International Federation of Gynecology and Obstetrics stage IIb IIIa (46.7%). Because of progression during the waiting time (median 3.8 months), this proportion declined to 19.3% at the beginning of radiotherapy. The 1- and 2 year overall survival probabilities were 90.4% and 73.6%. If assuming a worst case scenario (i.e., if all patients not available for follow-up after 6 months had died), the 2-year survival probability would be 45.4%. CONCLUSION: This study gives a thorough 4-year overview of treated patients with CC in Ethiopia. Given the limited treatment availability, a relatively high proportion of patients survived 2 years. More prevention and early detection at all levels of the health care system are needed. Increasing the capacity for external-beam radiation as well as options for brachytherapy would facilitate treatment with curative intention. PMID- 24951609 TI - Quality of life in the trastuzumab for gastric cancer trial. AB - BACKGROUND: The Trastuzumab for Gastric Cancer phase III trial demonstrated that combining trastuzumab with chemotherapy significantly improved overall survival compared with chemotherapy alone in HER2-positive advanced gastric or gastroesophageal junction cancer. We report health-related quality of life (HRQoL) and quality-adjusted time without symptoms of disease or toxicity (Q TWiST) results from this trial. PATIENTS AND METHODS: Patients were randomized to receive six cycles of chemotherapy given every 3 weeks (capecitabine or fluorouracil, plus cisplatin) either alone or combined with administration of trastuzumab every 3 weeks until disease progression. At each clinical visit, HRQoL was assessed using two European Organization for Research and Treatment of Cancer quality of life questionnaires, QLQ-C30 and QLQ-STO22. Q-TWiST methodology was applied retrospectively using the clinical data and utility coefficients. RESULTS: Trastuzumab plus chemotherapy prolonged time to 10% definitive deterioration in all QLQ-C30 and QLQ-STO22 scores, including QLQ-C30 global health status versus chemotherapy alone, from 6.4 months to 10.2 months. In addition, trastuzumab plus chemotherapy extended Q-TWiST by 2.42 months compared with chemotherapy alone. CONCLUSION: Compared with chemotherapy alone, trastuzumab plus chemotherapy prolongs time to deterioration of HRQoL and increases quality-adjusted survival in patients with HER2-positive gastric or gastroesophageal junction cancer. PMID- 24951612 TI - A thalassaemia intermedia case with concomitant left atrial thrombus. AB - Although marked improvements have been observed in the life expectancy of patients with thalassaemia by regular blood transfusion and strict iron chelation therapies in recent years, these patients still have to deal with several complications, mainly cardiovascular. One of the life-threatening complications is the chronic hypercoagulable state and thromboembolic events which develop due to haemostatic alterations in patients with thalassaemia, although they are more frequently seen in those with thalassaemia intermedia. Many thromboembolic complications, mainly deep venous thrombosis and cerebral thrombosis, have been reported in thalassaemia. However, intracardiac thrombosis is rarely seen. In this manuscript, we presented a case that underwent splenectomy 6 years ago but not regularly attended the control visits and presented to our clinic with gradually increasing exercise dyspnoea for 2 months. PMID- 24951613 TI - JPEN Journal Club 5. Review articles. PMID- 24951614 TI - Radiologist-performed hand-held ultrasound screening at average risk of breast cancer: results from a single health screening center. AB - BACKGROUND: Ultrasound (US) screening is not currently recommended as a routine screening modality in the general population of average risk. The cancer detection yield and positive predictive value in an average risk general population who undergo breast screening by experienced radiologists is unclear. PURPOSE: To determine the performance of screening breast US in women at an average risk for breast cancer undergoing breast screening by experienced radiologists. MATERIAL AND METHODS: This study received institutional review board approval, and informed consent was waived. A retrospective review of our database revealed 1526 women who underwent prevalence screening US at a single health screening center and had negative findings on digital mammography (MG). The Breast Imaging and Reporting Data System (BI-RADS) final assessments of the breast US were analyzed retrospectively, with the reference standard defined as a combination of pathology and a 12-month follow-up. The cancer detection rate and positive predictive value (PPV2) of the biopsies were calculated according to breast density. RESULTS: The average time to perform a screening US examination was 15-20 min. Of 1526 women, 1095 (71.8%) were classified as BI-RADS category 1 or 2; 340 (22.3%) were classified as category 3; and 91 (6.0%) were classified as category 4. Five malignant lesions were found in women with dense breasts. The overall cancer detection rate was 3.3, and the cancer detection rate for dense breasts was 5.1 per 1000 screens (4.1 per 1000 screens [heterogeneously dense breast], 7.7 per 1000 screens [extremely dense breast]). The PPV2 for biopsies was 5.3%. CONCLUSION: The radiologist-performed screening US offered to women with an average risk and dense breasts can detect additional mammographically occult breast cancers. In screening US, a relatively high rate of BI-RADS category 3 and 4 lesions was observed. PMID- 24951615 TI - Lung transthoracic ultrasound elastography imaging and guided biopsies of subpleural cancer: a preliminary report. AB - BACKGROUND: Despite the usefulness of elastography in assessing the stiffness/elasticity of tissues, and its proven diagnostic accuracy in thyroid, breast, and prostate cancers, among others, it is not yet applied in transthoracic ultrasound (TUS) scans to investigate lung nodules. PURPOSE: To investigate the potential clinical utility of TUS elastography in diagnosing lung cancer proven by fine-needle aspiration biopsy (FNAB). MATERIAL AND METHODS: TUS elastography was performed in 95 consecutive patients (71 men, 24 women; age, 62.84 +/- 7.37 years) with lesions suspected of involving the chest wall or the pleura detected on chest X-ray or computed tomography (CT). Patients with pleural effusions were not enrolled, but were further evaluated by pleural fluid cytology. Patients were excluded from the study if a diagnosis had already been made based on sputum cytology and/or bronchoscopic histology (making TUS biopsy unnecessary) or if their lung lesions could not be visualized under standard US. Under FNAB, 34 consolidations were ascribed to pneumonia and 65 to cancer. Under TUS, tissue stiffness, detected using a convex multifrequency 2-8-mHz probe and a MyLabTMTwice - ElaXto, was scored from 1 (greatest elasticity) to 5 (no elasticity). Subpleural solid masses (2-5 cm) were initially detected by TUS and subsequently assessed by FNAB. RESULTS: Histological diagnoses were: small cell lung cancer (4/61), adenocarcinoma (29/61), squamous cell carcinoma (SCC) (12/61), large cell lung carcinoma (12/61), and lymphomas (4/61). Patients' age and mass sizes (3.06 +/- 0.88 cm) were not significantly associated with any histological type. A significant lower elasticity of SCC (4.67 +/- 0.492) was observed versus other types of lung cancer (P < 0.005), and versus pneumonia (2.35 +/- 0.48). CONCLUSION: Since only squamous cell lung carcinoma displays the feature of significantly reduced elasticity, and since no clear-cut diagnostic key is yet available, the clinical usefulness of TUS elastography is currently limited with a view to characterizing tumors. Nevertheless, it does enable good non-invasive imaging of lung nodules, providing information on their stiffness, and can improve the accuracy and yield of FNAB. PMID- 24951616 TI - Effective factors to raise diagnostic performance of breast MRI for diagnosing pathologic complete response in breast cancer patients after neoadjuvant chemotherapy. AB - BACKGROUND: Although MRI is a highly effective tool in evaluating residual disease after neoadjuvant chemotherapy (NAC), there are many reports of discordance between the response of MRI and pathology. To increase MR accuracy, additional methods, which reflect post-NAC changes, should be considered in diagnosis. PURPOSE: To evaluate effective methods that raise the diagnostic performance of MRI for predicting pathologic complete response (pCR) in breast cancer after neoadjuvant chemotherapy (NAC). MATERIAL AND METHODS: For 98 invasive breast carcinoma patients, chemotherapeutic response to MRI was evaluated for the following parameters: tumor size, tumor distribution pattern, kinetic curve analysis, and background parenchymal enhancement pattern (BPE). BPE was categorized as "minimal", "mild", "moderate", or "marked", according to the ACR BI-RADS criteria. RESULTS: After NAC, the mean size of tumors decreased by 40% in non-pCR and by 59% in pCR groups, respectively. The sensitivity, specificity, false positive rate and false negative rate of MRI were 96% (78/81), 53% (9/17), 47% (8/17), and 4% (3/81), respectively. At pre-NAC MRI, the most common kinetic curve was delayed washout pattern (68%, 67/98); however, at post NAC MRI the persistent pattern (55%, 47/86). Grouped lesion was the most common tumor distribution pattern on pre-NAC MRI (28%, 27/98), while on post-NAC solitary mass (40%, 34/86). The most common BPE at pre- and post-NAC MRI was mild and minimal enhancement, respectively. CONCLUSION: To improve the diagnostic accuracy of MRI, we should consider additional factors including: tumor distribution pattern, BPE, kinetic curve analysis, and tumor size. PMID- 24951617 TI - Supra-aortic low-dose contrast-enhanced time-resolved magnetic resonance (MR) angiography at 3 T: comparison with time-of-flight MR angiography and high resolution contrast-enhanced MR angiography. AB - BACKGROUND: Low-dose, time-resolved, contrast-enhanced, magnetic resonance angiography (TR-CEMRA) has been described previously; however, a comparative study between low dose TR-CEMRA and time-of-flight MRA (TOF-MRA) in the diagnosis of supra-aortic arterial stenosis has not yet been published. PURPOSE: To demonstrate the feasibility and effectiveness of low-dose TR-CEMRA compared with TOF-MRA, using high-resolution contrast-enhanced MRA (HR-CEMRA) as the reference standard. MATERIAL AND METHODS: This prospective study consisted of 30 consecutive patients. All patients underwent TOF-MRA of the neck and circle of Willis and supra-aortic HR-CEMRA, followed by supra-aortic low-dose TR-CEMRA. Gadoterate meglumine (Gd-DOTA, Dotarem((r)), Guerbet, Roissy CdG Cedex, France) was injected at a dose of 0.1 mmol/kg for HR-CEMRA, followed by a 0.03 mmol/kg bolus for low-dose TR-CEMRA. Three readers evaluated the assessibility and image quality, and then two readers classified each stenosis into the following categories: normal (0-30%), mild stenosis (31-50%), moderate (51-70%), severe (71 99%), and occlusion. RESULTS: TR-CEMRA and HR-CEMRA showed a greater number of assessable arterial segments than TOF-MRA (P < 0.01). For TR-CEMRA, 29 cases showed within or better than the diagnostic range, whereas all 30 cases were in the diagnostic range for TOF-MRA and HR-CEMRA. For evaluation of stenosis in a total of 743 arterial segments, both TR-CEMRA and TOF-MRA results agreed with those of HR-CEMRA in 729 segments (98.1%), with excellent inter-observer agreement of TR-CEMRA; stenosis was overestimated in nine segments (1.2%) and underestimated in five segments (0.7%). For diagnosis of stenosis using 30% as the cut-off value on HR-CEMRA, the sensitivity and specificity were 88.2% and 99.3%, respectively, for the TR-CEMRA procedure, versus 94.1% and 99.6%, respectively, for TOF-MRA. CONCLUSION: Low-dose TR-CEMRA is feasible and effective in the diagnosis of supra-aortic arterial stenosis, and could be more useful option than TOF-MRA. PMID- 24951618 TI - Assessment of in vivo skeletal muscle mitochondrial respiratory capacity in humans by near-infrared spectroscopy: a comparison with in situ measurements. AB - The present study aimed to compare in vivo measurements of skeletal muscle mitochondrial respiratory capacity made using near-infrared spectroscopy (NIRS) with the current gold standard, namely in situ measurements of high-resolution respirometry performed in permeabilized muscle fibres prepared from muscle biopsies. Mitochondrial respiratory capacity was determined in 21 healthy adults in vivo using NIRS to measure the recovery kinetics of muscle oxygen consumption following a ~15 s isometric contraction of the vastus lateralis muscle. Maximal ADP-stimulated (State 3) respiration was measured in permeabilized muscle fibres using high-resolution respirometry with sequential titrations of saturating concentrations of metabolic substrates. Overall, the in vivo and in situ measurements were strongly correlated (Pearson's r = 0.61-0.74, all P < 0.01). Bland-Altman plots also showed good agreement with no indication of bias. The results indicate that in vivo NIRS corresponds well with the current gold standard, in situ high-resolution respirometry, for assessing mitochondrial respiratory capacity. PMID- 24951619 TI - The contribution of cardiac myosin binding protein-c Ser282 phosphorylation to the rate of force generation and in vivo cardiac contractility. AB - Cardiac myosin binding protein-C phosphorylation plays an important role in modulating cardiac muscle function and accelerating contraction. It has been proposed that Ser282 phosphorylation may serve as a critical molecular switch that regulates the phosphorylation of neighbouring Ser273 and Ser302 residues, and thereby govern myofilament contractile acceleration in response to protein kinase A (PKA). Therefore, to determine the regulatory roles of Ser282 we generated a transgenic (TG) mouse model expressing cardiac myosin binding protein C with a non-phosphorylatable Ser282 (i.e. serine to alanine substitution, TG(S282A)). Myofibrils isolated from TG(S282A) hearts displayed robust PKA mediated phosphorylation of Ser273 and Ser302, and the increase in phosphorylation was identical to TG wild-type (TG(WT)) controls. No signs of pathological cardiac hypertrophy were detected in TG(S282A) hearts by either histological examination of cardiac sections or echocardiography. Baseline fractional shortening, ejection fraction, isovolumic relaxation time, rate of pressure development and rate of relaxation (tau) were unaltered in TG(S282A) mice. However, the increase in cardiac contractility as well as the acceleration of pressure development observed in response to beta-adrenergic stimulation was attenuated in TG(S282A) mice. In agreement with our in vivo data, in vitro force measurements revealed that PKA-mediated acceleration of cross-bridge kinetics in TG(S282A) myocardium was significantly attenuated compared to TG(WT) myocardium. Taken together, our data suggest that while Ser282 phosphorylation does not regulate the phosphorylation of neighbouring Ser residues and basal cardiac function, full acceleration of cross-bridge kinetics and left ventricular pressure development cannot be achieved in its absence. PMID- 24951620 TI - Hypometabolism and hypothermia in the rat model of endotoxic shock: independence of circulatory hypoxia. AB - We tested the hypothesis that development of hypothermia instead of fever in endotoxic shock is consequential to hypoxia. Endotoxic shock was induced by bacterial lipopolysaccharide (LPS, 500 MUg kg(-1) i.v.) in rats at an ambient temperature of 22 degrees C. A beta3-adrenergic agonist known to activate metabolic heat production, CL316,243, was employed to evaluate whether thermogenic capacity could be impaired by the fall in oxygen delivery (DO2) during endotoxic shock. This possibility was rejected as CL316,243 (0.15 mg kg( 1) i.v.) evoked similar rises in oxygen consumption (VO2) in the presence and absence of endotoxic shock. Next, to investigate whether a less severe form of circulatory hypoxia could be triggering hypothermia, the circulating volume of LPS-injected rats was expanded using 6% hetastarch with the intention of improving tissue perfusion and alleviating hypoxia. This intervention attenuated not only the fall in arterial pressure induced by LPS, but also the associated falls in VO2 and body temperature. These effects, however, occurred independently of hypoxia, as they were not accompanied by any detectable changes in NAD(+)/NADH ratios. Further experimentation revealed that even the earliest drops in cardiac output and DO2 during endotoxic shock did not precede the reduction in VO2 that brings about hypothermia. In fact, DO2 and VO2 fell in such a synchrony that the DO2/VO2 ratio remained unaffected. Only when hypothermia was prevented by exposure to a warm environment (30 degrees C) did an imbalance in the DO2/VO2 ratio become evident, and such an imbalance was associated with reductions in the renal and hypothalamic NAD(+)/NADH ratios. In conclusion, hypometabolism and hypothermia in endotoxic shock are not consequential to hypoxia but serve as a pre-emptive strategy to avoid hypoxia in this model. PMID- 24951621 TI - Mitochondrial reactive oxygen species production and respiratory complex activity in rats with pressure overload-induced heart failure. AB - We investigated the impact of cardiac reactive oxygen species (ROS) during the development of pressure overload-induced heart failure. We used our previously described rat model where transverse aortic constriction (TAC) induces compensated hypertrophy after 2 weeks, heart failure with preserved ejection fraction at 6 and 10 weeks, and heart failure with systolic dysfunction after 20 weeks. We measured mitochondrial ROS production rates, ROS damage and assessed the therapeutic potential of in vivo antioxidant therapies. In compensated hypertrophy (2 weeks of TAC) ROS production rates were normal at both mitochondrial ROS production sites (complexes I and III). Complex I ROS production rates increased with the appearance of diastolic dysfunction (6 weeks of TAC) and remained high thereafter. Surprisingly, maximal ROS production at complex III peaked at 6 weeks of pressure overload. Mitochondrial respiratory capacity (state 3 respiration) was elevated 2 and 6 weeks after TAC, decreased after this point and was significantly impaired at 20 weeks, when contractile function was also impaired and ROS damage was found with increased hydroxynonenal. Treatment with the ROS scavenger alpha-phenyl-N-tert-butyl nitrone or the uncoupling agent dinitrophenol significantly reduced ROS production rates at 6 weeks. Despite the decline in ROS production capacity, no differences in contractile function between treated and untreated animals were observed. Increased ROS production occurs early in the development of heart failure with a peak at the onset of diastolic dysfunction. However, ROS production may not be related to the onset of contractile dysfunction. PMID- 24951622 TI - Spatial organization and coordination of slow waves in the mouse anorectum. AB - The internal anal sphincter (IAS) develops tone and is important for maintaining a high anal pressure while tone in the rectum is less. The mechanisms responsible for tone generation in the IAS are still uncertain. The present study addressed this question by comparing the electrical properties and morphology of the mouse IAS and distal rectum. The amplitude of tone and the frequency of phasic contractions was greater in the IAS than in rectum while membrane potential (Em) was less negative in the IAS than in rectum. Slow waves (SWs) were of greatest amplitude and frequency at the distal end of the IAS, declining in the oral direction. Dual microelectrode recordings revealed that SWs were coordinated over a much greater distance in the circumferential direction than in the oral direction. The circular muscle layer of the IAS was divided into five to eight 'minibundles' separated by connective tissue septa whereas few septa were present in the rectum. The limited coordination of SWs in the oral direction suggests that the activity in adjacent minibundles is not coordinated. Intramuscular interstitial cells of Cajal and platelet-derived growth factor receptor alpha positive cells were present in each minibundle suggesting a role for one or both of these cells in SW generation. In summary, three important properties distinguish the IAS from the distal rectum: (1) a more depolarized Em; (2) larger and higher frequency SWs; and (3) the multiunit configuration of the muscle. All of these characteristics may contribute to greater tone generation in the IAS than in the distal rectum. PMID- 24951623 TI - Asymmetric temporal interactions of sound-evoked excitatory and inhibitory inputs in the mouse auditory midbrain. AB - In the auditory midbrain, synaptic mechanisms responsible for the precise temporal coding of inputs in the brainstem are absent. Instead, in the inferior colliculus (IC), the diverse temporal firing patterns must be coded by other synaptic mechanisms, about which little is known. Here, we demonstrate the temporal characteristics of sound-evoked excitatory and inhibitory postsynaptic currents (seEPSCs and seIPSCs, respectively) in vivo in response to long-duration tones. The seEPSCs and seIPSCs differ in the variability of their temporal properties. The seEPSCs have either early or late current peaks, and the early peaked currents may be either transient or sustained varieties. The seIPSCs have only early-peaked sustained responses but often have offset responses. When measured in a single neuron, the seIPSC peaks usually follow early, transient seEPSCs, but the seIPSCs precede latest-peaking seEPSCs. A model of the firing produced by the integration of asymmetric seEPSCs and seIPSCs showed that the temporal pattern of the early-peaked sustained neurons was easily modified by changing the parameters of the seIPSC. These results suggest that the considerable variability in the peak time and duration of the seEPSCs shapes the overall time course of firing and often precedes or follows the less variable seIPSC. Despite this, the inhibitory currents are potent in modifying the firing patterns, and the inhibitory response to sound offset appears to be one area where the integration of excitatory and inhibitory synaptic currents is lacking. Thus, the integration of sound-evoked activity in the IC often employs the asymmetric temporal interaction of excitatory and inhibitory synaptic currents to shape the firing pattern of the neuron. PMID- 24951626 TI - Nerve Injuries in Aesthetic Breast Surgery: Systematic Review and Treatment Options. AB - BACKGROUND: The risk of nerve injuries in aesthetic breast surgery has not been well explored. OBJECTIVES: The authors conducted a systematic review to provide evidence-based information on the incidence and treatment of nerve injuries resulting from aesthetic breast surgery. METHODS: A broad literature search of Medline, Embase, and the Cochrane Database of Systematic Reviews was undertaken to identify studies in which nerve injury occurred after breast augmentation or mastopexy. Specific inclusion and exclusion criteria were established before the search was performed. RESULTS: The initial 4806 citations were narrowed by topic, title, and abstract to 53 articles. After full-text review, 36 studies were included. The risk of any nerve injury after breast augmentation ranged from 13.57% to 15.44%. Specific nerve injury rates were calculated for the intercostal cutaneous nerves, branches to the nipple-areola complex, intercostobrachial nerve, long thoracic nerve, and brachial plexus. Also calculated were the total estimated risks of chronic pain, hyperesthesia, hypoesthesia, and numbness. The meta-analysis showed no associations between the rates of breast nerve injury or sensation change and implant size, incision type, or implant position in patients who underwent breast augmentation. The data were insufficient to determine rates of nerve injury in mastopexy. CONCLUSIONS: The possibility of nerve injury, sensation change, or chronic pain with breast augmentation is real, and estimating the incidences of these conditions is useful to both patients and surgeons. Optimizing patient outcomes requires timely treatment by a multidisciplinary team and may include peripheral nerve surgery. LEVEL OF EVIDENCE: 3. PMID- 24951624 TI - Mineralocorticoid and AT1 receptors in the paraventricular nucleus contribute to sympathetic hyperactivity and cardiac dysfunction in rats post myocardial infarct. AB - Intracerebroventricular infusion of a mineralocorticoid receptor (MR) or angiotensin II type 1 receptor (AT1R) blocker in rats attenuates sympathetic hyperactivity and progressive left ventricular (LV) dysfunction post myocardial infarction (MI). The present study examined whether knockdown of MRs or AT1Rs specifically in the paraventricular nucleus (PVN) contributes to these effects, and compared cardiac effects with those of systemic treatment with the beta1 adrenergic receptor blocker metoprolol. The PVN of rats was infused with adeno associated virus carrying small interfering RNA against either MR (AAV-MR-siRNA) or AT1R (AAV-AT1R-siRNA), or as control scrambled siRNA. At 4 weeks post MI, AT1R but not MR expression was increased in the PVN, excitatory renal sympathetic nerve activity and pressor responses to air stress were enhanced, and arterial baroreflex function was impaired; LV end-diastolic pressure (LVEDP) was increased and LV peak systolic pressure (LVPSP), ejection fraction (EF) and dP/dtmax decreased. AAV-MR-siRNA and AAV-AT1R-siRNA both normalized AT1R expression in the PVN, similarly ameliorated sympathetic and pressor responses to air stress, largely prevented baroreflex desensitization, and improved LVEDP, EF and dP/dtmax as well as cardiac interstitial (but not perivascular) fibrosis. In a second set of rats, metoprolol at 70 or 250 mg kg(-1) day(-1) in the drinking water for 4 weeks post MI did not improve LV function except for a decrease in LVEDP at the lower dose. These results suggest that in rats MR-dependent upregulation of AT1Rs in the PVN contributes to sympathetic hyperactivity, and LV dysfunction and remodelling post MI. In rats, normalizing MR-AT1R signalling in the PVN is a more effective strategy to improve LV dysfunction post MI than systemic beta1 blockade. PMID- 24951627 TI - Characterisation of debris from laser and mechanical cutting of bone. AB - Laser cutting of bones has been proposed as a technology in orthopaedic surgery. In this short study, the laser-bone interaction was examined using a pulsed erbium-doped yttrium aluminium garnet laser and compared to a conventional cutting technique. Microscopic analysis revealed the nature of waste debris and showed higher proportions of finer particles for conventional sagittal sawing compared to laser cutting. PMID- 24951628 TI - Feasibility of using mixtures of silicone elastomers and silicone oils to model the mechanical behaviour of biological tissues. AB - Mixtures of silicone elastomer and silicone oil were prepared and the values of their Young's moduli, E, determined in compression. The mixtures had volume fractions, [Formula: see text], of silicone oil in the range of 0-0.73. Measurements were made, under displacement control, for strain rates, [Formula: see text], in the range of 0.04-3.85 s(-1). The behaviour of [Formula: see text] as a function of [Formula: see text] and [Formula: see text] was investigated using a response surface model. The effects of the two variables were independent for the silicones used in this investigation. As a result, the dependence of E values (measured in MPa) on [Formula: see text] and [Formula: see text] (s(-1)) could be represented by [Formula: see text]. This means that these silicones can be mixed to give materials with E values in the range of about 0.02-0.57 MPa, which includes E values for many biological tissues. Thus, the mixtures can be used for making models for training health-care professionals and may be useful in some research applications as model tissues that do not exhibit biological variability. PMID- 24951629 TI - Triage in the defence medical services. AB - Triage of patients into categories according to their need for intervention is a core part of military medical practice. This article reviews how triage has evolved in the Defence Medical Services and how it might develop in the context of recent research. In particular, a simple model demonstrates that the ideal sensitivity and specificity of a triage system depends upon the availability of transport and the capacity of the receiving units. As a result, we may need to fundamentally change the way we approach triage in order to optimise outcomes especially if casualty evacuation timelines become longer and smaller medical units more prevalent on future operations. Some pragmatic options for change are discussed. Finally, other areas of current research around triage are highlighted, perhaps showing where triage may go next. PMID- 24951625 TI - Effects of detraining on the temporal expression of positive and negative angioregulatory proteins in skeletal muscle of mice. AB - Temporal expression of positive and negative angiogenic factors in response to detraining is poorly understood. We report the protein expression of anti angiogenic peptides (thrombospondin-1, TSP-1; and endostatin) as well as pro angiogenic factors (vascular endothelial growth factor, VEGF; matrix metalloproteinases-2 and -9), and nucleolin (a nuclear protein involved with synthesis and maturation of ribosomes) in response to detraining in triceps surae muscles of C57BL/6 mice. Male mice were allowed to exercise voluntarily for 21 days, and then basal and acute response to exercise were evaluated at 1, 7, 14 and 28 days detraining (D1, D7, D14, D28, respectively, n = 12/group). As seen in the D1 mice, training resulted in the increased muscle capillary-to-fibre ratio (C/F), increased maximal running time and elevated basal expression of VEGF and matrix metalloproteinase-9 (P < 0.05). After 7 days of detraining (D7), C/F levels were similar to control levels, but both basal VEGF and TSP-1 were elevated (P < 0.05). At D14 and D28, TSP-1 protein was not different compared to baseline levels; however, VEGF was elevated in gastrocnemius (GA), but not the soleus (SOL) or plantaris (PLT) muscles, of D14 mice. Endostatin tended to decrease in D14 and D28 compared to controls. Timing of nucleolin protein expression differed between muscle groups, with increases at D1, D7 and D14 in the PLT, SOL and GA muscles, respectively. The response of VEGF and nucleolin to acute exercise was blunted with training, and remained blunted in the PLT and SOL even after 28 days of detraining, at a time point long after muscle capillarization was observed to be similar to pre-training levels. These data suggest that TSP-1 may be a mediator of capillary regression with detraining, even in the face of elevated VEGF, suggesting that pro-angiogenic regulators may not be able to prevent the regression of skeletal muscle capillaries under physiological conditions. The responses of matrix metalloproteinases, endostatin and nucleolin poorly correlated with detraining-induced capillary regression. PMID- 24951630 TI - Brain. Editorial. PMID- 24951631 TI - Anatomical predictors of aphasia recovery: a tractography study of bilateral perisylvian language networks. AB - Stroke-induced aphasia is associated with adverse effects on quality of life and the ability to return to work. For patients and clinicians the possibility of relying on valid predictors of recovery is an important asset in the clinical management of stroke-related impairment. Age, level of education, type and severity of initial symptoms are established predictors of recovery. However, anatomical predictors are still poorly understood. In this prospective longitudinal study, we intended to assess anatomical predictors of recovery derived from diffusion tractography of the perisylvian language networks. Our study focused on the arcuate fasciculus, a language pathway composed of three segments connecting Wernicke's to Broca's region (i.e. long segment), Wernicke's to Geschwind's region (i.e. posterior segment) and Broca's to Geschwind's region (i.e. anterior segment). In our study we were particularly interested in understanding how lateralization of the arcuate fasciculus impacts on severity of symptoms and their recovery. Sixteen patients (10 males; mean age 60 +/- 17 years, range 28-87 years) underwent post stroke language assessment with the Revised Western Aphasia Battery and neuroimaging scanning within a fortnight from symptoms onset. Language assessment was repeated at 6 months. Backward elimination analysis identified a subset of predictor variables (age, sex, lesion size) to be introduced to further regression analyses. A hierarchical regression was conducted with the longitudinal aphasia severity as the dependent variable. The first model included the subset of variables as previously defined. The second model additionally introduced the left and right arcuate fasciculus (separate analysis for each segment). Lesion size was identified as the only independent predictor of longitudinal aphasia severity in the left hemisphere [beta = -0.630, t(-3.129), P = 0.011]. For the right hemisphere, age [beta = 0.678, t(-3.087), P = 0.010] and volume of the long segment of the arcuate fasciculus [beta = 0.730, t(2.732), P = 0.020] were predictors of longitudinal aphasia severity. Adding the volume of the right long segment to the first-level model increased the overall predictive power of the model from 28% to 57% [F(1,11) = 7.46, P = 0.02]. These findings suggest that different predictors of recovery are at play in the left and right hemisphere. The right hemisphere language network seems to be important in aphasia recovery after left hemispheric stroke. PMID- 24951634 TI - An ambient assisted living approach in designing domiciliary services combined with innovative technologies for patients with Alzheimer's disease: a case study. AB - BACKGROUND: Alzheimer's disease (AD) is one of the most disabling diseases to affect large numbers of elderly people worldwide. Because of the characteristics of this disease, patients with AD require daily assistance from service providers both in nursing homes and at home. Domiciliary assistance has been demonstrated to be cost effective and efficient in the first phase of the disease, helping to slow down the course of the illness, improve the quality of life and care, and extend independence for patients and caregivers. In this context, the aim of this work is to demonstrate the technical effectiveness and acceptability of an innovative domiciliary smart sensor system for providing domiciliary assistance to patients with AD which has been developed with an Ambient Assisted Living (AAL) approach. METHODS: The design, development, testing, and evaluation of the innovative technological solution were performed by a multidisciplinary team. In all, 15 sociomedical operators and 14 patients with AD were directly involved in defining the end-users' needs and requirements, identifying design principles with acceptability and usability features and evaluating the technological solutions before and after the real experimentation. RESULTS: A modular technological system was produced to help caregivers continuously monitor the health status, safety, and daily activities of patients with AD. During the experimentation, the acceptability, utility, usability, and efficacy of this system were evaluated as quite positive. CONCLUSION: The experience described in this article demonstrated that AAL technologies are feasible and effective nowadays and can be actively used in assisting patients with AD in their homes. The extensive involvement of caregivers in the experimentation allowed to assess that there is, through the use of the technological system, a proven improvement in care performance and efficiency of care provision by both formal and informal caregivers and consequently an increase in the quality of life of patients, their relatives, and their caregivers. PMID- 24951633 TI - Effectiveness of the palliative care 'Availability, Current issues and Anticipation' (ACA) communication training programme for general practitioners on patient outcomes: a controlled trial. AB - BACKGROUND: Although communicating effectively with patients receiving palliative care can be difficult, it may contribute to maintaining or enhancing patients' quality of life. Little is known about the effect of training general practitioners in palliative care-specific communication. We hypothesized that palliative care patients of general practitioners exposed to the 'Availability, Current issues and Anticipation' communication training programme would report better outcomes than patients of control general practitioners. AIM: To evaluate the effectiveness of the Availability, Current issues and Anticipation training programme for general practitioners on patient-reported outcomes. DESIGN: In a controlled trial, general practitioners followed the Availability, Current issues and Anticipation programme or were part of the control group. Patients receiving palliative care of participating general practitioners completed the Palliative Care Outcome Scale, the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative, the Rest & Peace Scale, the Patient Satisfaction Questionnaire-III and the Availability, Current issues and Anticipation Scale, at baseline and 12 months follow-up. We analysed differences between groups using linear mixed models. TRIAL REGISTRATION: ISRCTN56722368. SETTING/PARTICIPANTS: General practitioners who attended a 2-year Palliative Care Training Course in the Netherlands. RESULTS: Questionnaire data were available for 145 patients (89 in intervention and 56 in control group). We found no significant differences over time between the intervention and control groups in any of the five outcome measures. Ceiling effects were observed for the Rest & Peace Scale, Patient Satisfaction Questionnaire-III and Availability, Current issues and Anticipation Scale. CONCLUSION: General practitioner participation in the Availability, Current issues and Anticipation training programme did not have a measurable effect on any of the outcomes investigated. Patients reported high levels of satisfaction with general practitioner care, regardless of group assignment. Future research might focus on general practitioners without special interest in palliative care. PMID- 24951635 TI - Effect of APOE and CHRNA7 genotypes on the cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease. AB - The loss of cholinergic transmission is considered to be an important cause of Alzheimer's disease (AD). Treatment with acetyl cholinesterase inhibitors (ChEIs) shows benefits; however, great heterogeneity has been observed in patient responses. We evaluated apolipoprotein E (APOE) and alpha7 nicotinic receptor (CHRNA7) single-nucleotide polymorphisms (SNPs) and associated these SNPs with pharmacological responses to ChEIs in a Brazilian population with AD. We studied 177 outpatients using ChEIs, and they were classified as responders and nonresponders according to variation in Mini-Mental State Examination (MMSE) status. The analysis of APOE genotypes showed that patients with the epsilon4 allele had a worse response than those without the epsilon4 allele. We observed an association between the CHRNA7 T allele and a better response to treatment with ChEIs in patients with mild AD (MMSE >= 20). The SNP rs6494223 of CHRNA7 as well as APOEepsilon4 could be useful for understanding the response to ChEI treatment in patients with AD. PMID- 24951636 TI - Feeling (Mis)Understood and Intergroup Friendships in Interracial Interactions. AB - The present research investigated whether having out-group friends serves as a buffer for feeling misunderstood in interracial interactions. Across three experience sampling studies, we found that among ethnic minorities who have few White friends or are not interacting with White friends, daily interracial interactions are associated with feeling less understood. By contrast, we found that among ethnic minorities who have more White friends or are interacting with White friends, the relationship between daily interracial interactions and feeling understood is not significant. We did not find similar results for Whites; that is, having ethnic minority friends did not play a role in the relationship between daily interracial interactions and feeling understood. Together, these studies demonstrate the beneficial effects of intergroup friendships for ethnic minorities. PMID- 24951637 TI - Rare infection of implantable cardioverter-defibrillator lead with Candida albicans: case report and literature review. AB - Infection of implanted cardiac devices has a low rate of occurrence. Fungal infections of such devices represent an atypical phenomenon, associated with high mortality. Both medical and surgical therapies are recommended for a successful outcome. A 60-year-old woman with past medical history of heart failure with reduced ejection fraction, implantable cardioverter-defibrillator (ICD) placement, sarcoidosis and diabetes presented with fevers and atypical pleuritic chest pain. Transthoracic echocardiogram revealed a highly mobile 2.09 cm by 4.49 cm mass associated with the ICD wire. Blood cultures were positive for Candida albicans. The patient underwent sternotomy for removal. The vegetation was 4 cm by 2 cm by 2 cm in size, attached to the right ventricle without interference with the tricuspid valve. The patient was treated with micafungin for 2 weeks and then fluconazole for 6 weeks. In this case report, we describe the rare infection of an ICD lead with C. albicans, in the form of a fungal ball. This is the 18th reported case of Candida device-related endocarditis and the first reported in a woman. Prior case reports have occurred primarily in pacemaker rather than ICD leads. The vegetation size is also one of the largest that has been reported, measuring 4 cm at its greatest length. As Candida device-related endocarditis is so rare, and as fatality occurs in half of cases, clinical management can only be derived from sporadic case reports. Therefore, the course of this patient's disease care will be a useful adjunct to the current literature for determining treatment and prognosis in similar cases. PMID- 24951638 TI - Widespread grey matter pathology dominates the longitudinal cerebral MRI and clinical landscape of amyotrophic lateral sclerosis. AB - Diagnosis, stratification and monitoring of disease progression in amyotrophic lateral sclerosis currently rely on clinical history and examination. The phenotypic heterogeneity of amyotrophic lateral sclerosis, including extramotor cognitive impairments is now well recognized. Candidate biomarkers have shown variable sensitivity and specificity, and studies have been mainly undertaken only cross-sectionally. Sixty patients with sporadic amyotrophic lateral sclerosis (without a family history of amyotrophic lateral sclerosis or dementia) underwent baseline multimodal magnetic resonance imaging at 3 T. Grey matter pathology was identified through analysis of T1-weighted images using voxel-based morphometry. White matter pathology was assessed using tract-based spatial statistics analysis of indices derived from diffusion tensor imaging. Cross sectional analyses included group comparison with a group of healthy controls (n = 36) and correlations with clinical features, including regional disability, clinical upper motor neuron signs and cognitive impairment. Patients were offered 6-monthly follow-up MRI, and the last available scan was used for a separate longitudinal analysis (n = 27). In cross-sectional study, the core signature of white matter pathology was confirmed within the corticospinal tract and callosal body, and linked strongly to clinical upper motor neuron burden, but also to limb disability subscore and progression rate. Localized grey matter abnormalities were detected in a topographically appropriate region of the left motor cortex in relation to bulbar disability, and in Broca's area and its homologue in relation to verbal fluency. Longitudinal analysis revealed progressive and widespread changes in the grey matter, notably including the basal ganglia. In contrast there was limited white matter pathology progression, in keeping with a previously unrecognized limited change in individual clinical upper motor neuron scores, despite advancing disability. Although a consistent core white matter pathology was found cross-sectionally, grey matter pathology was dominant longitudinally, and included progression in clinically silent areas such as the basal ganglia, believed to reflect their wider cortical connectivity. Such changes were significant across a range of apparently sporadic patients rather than being a genotype-specific effect. It is also suggested that the upper motor neuron lesion in amyotrophic lateral sclerosis may be relatively constant during the established symptomatic period. These findings have implications for the development of effective diagnostic versus therapeutic monitoring magnetic resonance imaging biomarkers. Amyotrophic lateral sclerosis may be characterized initially by a predominantly white matter tract pathological signature, evolving as a widespread cortical network degeneration. PMID- 24951640 TI - Cortical thickness in individuals with non-clinical and clinical psychotic symptoms. AB - Symptoms that are linked to psychosis are also experienced by individuals who are not in need of care. In the present study, cortical thickness was investigated in these individuals. Fifty individuals with non-clinical auditory verbal hallucinations (most of them also experienced other non-clinical psychotic symptoms), 50 patients with a psychotic disorder and auditory verbal hallucinations, and 50 healthy control subjects underwent structural magnetic resonance imaging. Data were analysed using FreeSurfer. Cortical thickness in the pars orbitalis, paracentral lobule, fusiform gyrus and inferior temporal gyrus was lowest in patients, intermediate in the non-clinical hallucinating group, and highest in control subjects. The patients also showed thinning in widespread additional areas compared to the two other groups, whereas both hallucinating groups showed similar levels of thinning in the insula. Ranking the levels of cortical thickness per brain region across groups revealed that for 88% of brain regions, cortical thickness was lowest in patients, intermediate in the non clinical hallucinating group, and highest in controls. These findings show that individuals with non-clinical psychotic symptoms show a similar but less pronounced pattern of cortical thinning as patients with a psychotic disorder, which is suggestive of a similar, but milder underlying pathophysiology in this group compared to the psychosis group. PMID- 24951639 TI - Self-awareness in neurodegenerative disease relies on neural structures mediating reward-driven attention. AB - Accurate self-awareness is essential for adapting one's tasks and goals to one's actual abilities. Patients with neurodegenerative diseases, particularly those with right frontal involvement, often present with poor self-awareness of their functional limitations that may exacerbate their already jeopardized decision making and behaviour. We studied the structural neuroanatomical basis for impaired self-awareness among patients with neurodegenerative disease and healthy older adults. One hundred and twenty-four participants (78 patients with neurodegenerative diseases including Alzheimer's disease, behavioural variant frontotemporal dementia, right-temporal frontotemporal dementia, semantic variant and non-fluent variant primary progressive aphasia, and 46 healthy controls) described themselves on the Patient Competency Rating Scale, rating observable functioning across four domains (daily living activities, cognitive, emotional control, interpersonal). All participants underwent structural magnetic resonance imaging. Informants also described subjects' functioning on the same scale. Self awareness was measured by comparing self and informant ratings. Group differences in discrepancy scores were analysed using general linear models, controlling for age, sex and disease severity. Compared with controls, patients with behavioural variant frontotemporal dementia overestimated their functioning in all domains, patients with Alzheimer's disease overestimated cognitive and emotional functioning, patients with right-temporal frontotemporal dementia overestimated interpersonal functioning, and patients with non-fluent aphasia overestimated emotional and interpersonal functioning. Patients with semantic variant aphasia did not overestimate functioning on any domain. To examine the neuroanatomic correlates of impaired self-awareness, discrepancy scores were correlated with brain volume using voxel-based morphometry. To identify the unique neural correlates of overlooking versus exaggerating deficits, overestimation and underestimation scores were analysed separately, controlling for age, sex, total intracranial volume and extent of actual functional decline. Atrophy related to overestimating one's functioning included bilateral, right greater than left frontal and subcortical regions, including dorsal superior and middle frontal gyri, lateral and medial orbitofrontal gyri, right anterior insula, putamen, thalamus, and caudate, and midbrain and pons. Thus, our patients' tendency to under-represent their functional decline was related to degeneration of domain general dorsal frontal regions involved in attention, as well as orbitofrontal and subcortical regions likely involved in assigning a reward value to self related processing and maintaining accurate self-knowledge. The anatomic correlates of underestimation (right rostral anterior cingulate cortex, uncorrected significance level) were distinct from overestimation and had a substantially smaller effect size. This suggests that underestimation or 'tarnishing' may be influenced by non-structural neurobiological and sociocultural factors, and should not be considered to be on a continuum with overestimation or 'polishing' of functional capacity, which appears to be more directly mediated by neural circuit dysfunction. PMID- 24951641 TI - Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. AB - The clinical associations of glycine receptor antibodies have not yet been described fully. We identified prospectively 52 antibody-positive patients and collated their clinical features, investigations and immunotherapy responses. Serum glycine receptor antibody endpoint titres ranged from 1:20 to 1:60 000. In 11 paired samples, serum levels were higher than (n = 10) or equal to (n = 1) cerebrospinal fluid levels; there was intrathecal synthesis of glycine receptor antibodies in each of the six pairs available for detailed study. Four patients also had high glutamic acid decarboxylase antibodies (>1000 U/ml), and one had high voltage-gated potassium channel-complex antibody (2442 pM). Seven patients with very low titres (<1:50) and unknown or alternative diagnoses were excluded from further study. Three of the remaining 45 patients had newly-identified thymomas and one had a lymphoma. Thirty-three patients were classified as progressive encephalomyelitis with rigidity and myoclonus, and two as stiff person syndrome; five had a limbic encephalitis or epileptic encephalopathy, two had brainstem features mainly, two had demyelinating optic neuropathies and one had an unclear diagnosis. Four patients (9%) died during the acute disease, but most showed marked improvement with immunotherapies. At most recent follow-up, (2 7 years, median 3 years, since first antibody detection), the median modified Rankin scale scores (excluding the four deaths) decreased from 5 at maximal severity to 1 (P < 0.0001), but relapses have occurred in five patients and a proportion are on reducing steroids or other maintenance immunotherapies as well as symptomatic treatments. The glycine receptor antibodies activated complement on glycine receptor-transfected human embryonic kidney cells at room temperature, and caused internalization and lysosomal degradation of the glycine receptors at 37 degrees C. Immunoglobulin G antibodies bound to rodent spinal cord and brainstem co-localizing with monoclonal antibodies to glycine receptor-alpha1. Ten glycine receptor antibody positive samples were also identified in a retrospective cohort of 56 patients with stiff person syndrome and related syndromes. Glycine receptor antibodies are strongly associated with spinal and brainstem disorders, and the majority of patients have progressive encephalomyelitis with rigidity and myoclonus. The antibodies demonstrate in vitro evidence of pathogenicity and the patients respond well to immunotherapies, contrasting with earlier studies of this syndrome, which indicated a poor prognosis. The presence of glycine receptor antibodies should help to identify a disease that responds to immunotherapies, but these treatments may need to be sustained, relapses can occur and maintenance immunosuppression may be required. PMID- 24951643 TI - Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy. AB - Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of rare diseases resulting from impaired neuromuscular transmission. Their clinical hallmark is fatigable muscle weakness associated with a decremental muscle response to repetitive nerve stimulation and frequently related to postsynaptic defects. Distal myopathies form another clinically and genetically heterogeneous group of primary muscle disorders where weakness and atrophy are restricted to distal muscles, at least initially. In both congenital myasthenic syndromes and distal myopathies, a significant number of patients remain genetically undiagnosed. Here, we report five patients from three unrelated families with a strikingly homogenous clinical entity combining congenital myasthenia with distal muscle weakness and atrophy reminiscent of a distal myopathy. MRI and neurophysiological studies were compatible with mild myopathy restricted to distal limb muscles, but decrement (up to 72%) in response to 3 Hz repetitive nerve stimulation pointed towards a neuromuscular transmission defect. Post-exercise increment (up to 285%) was observed in the distal limb muscles in all cases suggesting presynaptic congenital myasthenic syndrome. Immunofluorescence and ultrastructural analyses of muscle end-plate regions showed synaptic remodelling with denervation-reinnervation events. We performed whole-exome sequencing in two kinships and Sanger sequencing in one isolated case and identified five new recessive mutations in the gene encoding agrin. This synaptic proteoglycan with critical function at the neuromuscular junction was previously found mutated in more typical forms of congenital myasthenic syndrome. In our patients, we found two missense mutations residing in the N-terminal agrin domain, which reduced acetylcholine receptors clustering activity of agrin in vitro. Our findings expand the spectrum of congenital myasthenic syndromes due to agrin mutations and show an unexpected correlation between the mutated gene and the associated phenotype. This provides a good rationale for examining patients with apparent distal myopathy for a neuromuscular transmission disorder and agrin mutations. PMID- 24951645 TI - Down-regulation of BRCA2 expression by collagen type I promotes prostate cancer cell proliferation. PMID- 24951644 TI - Regulation of beta1C and beta1A integrin expression in prostate carcinoma cells. PMID- 24951646 TI - Up-regulation of Skp2 after prostate cancer cell adhesion to basement membranes results in BRCA2 degradation and cell proliferation. PMID- 24951642 TI - Grey matter hypometabolism and atrophy in Parkinson's disease with cognitive impairment: a two-step process. AB - The pathophysiological process underlying cognitive decline in Parkinson's disease is not well understood. Cerebral atrophy and hypometabolism have been described in patients with Parkinson's disease and dementia or mild cognitive impairment with respect to control subjects. However, the exact relationships between atrophy and hypometabolism are still unclear. To determine the extension and topographical distribution of hypometabolism and atrophy in the different cognitive states of Parkinson's disease, we examined 46 patients with Parkinson's disease (19 female, 27 male; 71.7 +/- 5.9 years old; 14.6 +/- 4.2 years of disease evolution; modified Hoehn and Yahr mean stage 3.1 +/- 0.7). Cognitive status was diagnosed as normal in 14 patients, as mild cognitive impairment in 17 and as dementia in 15 patients. Nineteen normal subjects (eight female, 11 male; 68.1 +/- 3.2 years old) were included as controls. (18)F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging scans were obtained, co-registered, corrected for partial volume effect and spatially normalized to the Montreal Neurological Institute space in each subject. Smoothing was applied to the positron emission tomography and magnetic resonance imaging scans to equalize their effective smoothness and resolution (10 mm and 12 mm full-width at half-maximum and Gaussian kernel, respectively). Z-score maps for atrophy and for hypometabolism were obtained by comparing individual images to the data set of control subjects. For each group of patients, a paired Student's t-test was performed to statistically compare the two Z-map modalities (P < 0.05 false discovery rate corrected) using the direct voxel-based comparison technique. In patients with mild cognitive impairment, hypometabolism exceeded atrophy in the angular gyrus, occipital, orbital and anterior frontal lobes. In patients with dementia, the hypometabolic areas observed in the group with mild cognitive impairment were replaced by areas of atrophy, which were surrounded by extensive zones of hypometabolism. Areas where atrophy was more extended than hypometabolism were found in the precentral and supplementary motor areas in both patients with mild cognitive impairment and with dementia, and in the hippocampus and temporal lobe in patients with dementia. These findings suggest that there is a gradient of severity in cortical changes associated with the development of cognitive impairment in Parkinson's disease in which hypometabolism and atrophy represent consecutive stages of the same process in most of the cortical regions affected. PMID- 24951648 TI - Homeodomain-interacting protein kinase-2 stabilizes p27kip1 by its phosphorylation at serine 10 and contributes to cell motility. PMID- 24951650 TI - Parathyroid hormone: critical bridge between bone metabolism and cardiovascular disease. PMID- 24951651 TI - Endothelial cell global positioning system for pulmonary arterial hypertension: homing in on vascular repair. PMID- 24951652 TI - New ways to dismantle a ticking time bomb: microRNA 712/205 and abdominal aortic aneurysm development. PMID- 24951656 TI - Skin-heart connection: what can the epidermis tell us about the myocardium in arrhythmogenic cardiomyopathy? PMID- 24951655 TI - Biochemical and bioinformatic methods for elucidating the role of RNA-protein interactions in posttranscriptional regulation. AB - Our understanding of transcriptional gene regulation has dramatically increased over the past decades, and many regulators of gene expression, such as transcription factors, have been analyzed extensively. Additionally, in recent years, deeper insights into the physiological roles of RNA have been obtained. More precisely, splicing, polyadenylation, various modifications, localization and the translation of messenger RNAs (mRNAs) are regulated by their interaction with RNA-binding proteins (RBPs). New technologies now enable the analysis of this regulation at different levels. A technique known as ultraviolet (UV) cross linking and immunoprecipitation (CLIP) allows us to determine physical protein RNA interactions on a genome-wide scale. UV cross-linking introduces covalent bonds between interacting RBPs and RNAs. In combination with immunoprecipitation and deep sequencing techniques, tens of millions of short reads (representing bound RNAs by an RBP of interest) are generated and are used to characterize the regulatory network mediated by an RBP. Other methods, such as mass spectrometry, can also be used for characterization of cross-linked RBPs and RNAs instead of CLIP methods. In this review, we discuss experimental and computational methods for the generation and analysis of CLIP data. The computational methods include short-read alignment, annotation and RNA-binding motif discovery. We describe the challenges of analyzing CLIP data and indicate areas where improvements are needed. PMID- 24951657 TI - Fractal dimension of hypertrophic cardiomyopathy trabeculation: a window to an unpredictable future? PMID- 24951658 TI - Following-up genome-wide association study signals: lessons learned from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. PMID- 24951659 TI - Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. AB - BACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits. METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with >=1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency >=1%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test. CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci. PMID- 24951660 TI - Sequence variation in TMEM18 in association with body mass index: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. AB - BACKGROUND: Genome-wide association studies for body mass index (BMI) previously identified a locus near TMEM18. We conducted targeted sequencing of this region to investigate the role of common, low-frequency, and rare variants influencing BMI. METHODS AND RESULTS: We sequenced TMEM18 and regions downstream of TMEM18 on chromosome 2 in 3976 individuals of European ancestry from 3 community-based cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, and Framingham Heart Study), including 200 adults selected for high BMI. We examined the association between BMI and variants identified in the region from nucleotide position 586 432 to 677 539 (hg18). Rare variants (minor allele frequency, <1%) were analyzed using a burden test and the sequence kernel association test. Results from the 3 cohort studies were meta-analyzed. We estimate that mean BMI is 0.43 kg/m(2) higher for each copy of the G allele of single-nucleotide polymorphism rs7596758 (minor allele frequency, 29%; P=3.46*10(-4)) using a Bonferroni threshold of P<4.6*10(-4). Analyses conditional on previous genome wide association study single-nucleotide polymorphisms associated with BMI in the region led to attenuation of this signal and uncovered another independent (r(2)<0.2), statistically significant association, rs186019316 (P=2.11*10(-4)). Both rs186019316 and rs7596758 or proxies are located in transcription factor binding regions. No significant association with rare variants was found in either the exons of TMEM18 or the 3' genome-wide association study region. CONCLUSIONS: Targeted sequencing around TMEM18 identified 2 novel BMI variants with possible regulatory function. PMID- 24951661 TI - ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. AB - BACKGROUND: The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4. METHODS AND RESULTS: We sequenced ADAM19 and its promoter region along with the ~21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58*10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56*10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region. CONCLUSIONS: Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4. PMID- 24951662 TI - Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. AB - BACKGROUND: Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG). METHODS AND RESULTS: We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency >=1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05). CONCLUSIONS: Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples. PMID- 24951663 TI - Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. AB - BACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction. METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3*10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25*10(-4) and P=5.2*10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82*10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35*10(-7) and P=2.69*10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67*10(-5)). CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction. PMID- 24951666 TI - MicroRNA therapy for the failing heart. PMID- 24951665 TI - Genetics of ischemic stroke in young adults. PMID- 24951664 TI - Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. AB - BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels. METHODS AND RESULTS: Sequencing (mean depth, 38*) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73*10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28*10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity. CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity. PMID- 24951670 TI - Gamete derivation from stem cells: revisiting the concept of genetic parenthood. AB - Genetic parenthood is usually portrayed as a value-neutral concept that can be confirmed or rejected based on objective, scientific tests. However, on inspection, it is exposed as a very complex idea that we might need to consider as something that comes in different shapes and forms and that is open to interpretation rather than being clearly defined and fixed. Different people may therefore also desire different aspects of the general concept of genetic parenthood, which implies that some may not even be satisfied with gametes that have all the properties that their own natural gametes would have, whereas others may be satisfied with a much simpler solution. Encouraging infertility patients to gain insight into what it is exactly that they hope to gain by pursuing genetic parenthood (rather than choosing for donor conception or adoption) may lead them to recognise that the added advantage may be limited and may be acquired in other ways as well. Nevertheless, many people will find it difficult to let go of the desire for genetic parenthood as it is deeply rooted in our genes. Infertility is experienced as a grave medical condition and entails an intense grieving process for many. For that reason alone it is important that the medical and research community develop and apply methods to help people in their quest for genetic parenthood. On the other hand, it is important not to reinforce the dogma that genetic parenthood is 'the best kind of parenthood'. PMID- 24951667 TI - Obesity genetics and epigenetics: dissecting causality. PMID- 24951671 TI - The moral value of induced pluripotent stem cells: a Japanese bioethics perspective on human embryo research. AB - In contemporary Japan, at least in the field of regenerative medicine, human induced pluripotent stem cells (hiPSCs) are given no moral status and are treated in a purely instrumental way. However, some authors have mentioned the potentiality of hiPSCs in that 'tetraploid complementation' would make it possible to create humans directly from human embryonic stem cells (hESCs) and hiPSCs. A blastocyst consists of inner cell mass (ICM) cells and a trophoblast. The tetraploid complementation technique demonstrates that hESCs and hiPSCs both have the same capacity as ICM cells. If ICM cells, hESCs and hiPSCs were all provided with a trophoblast or a substitute with the same function, which would work as a placenta, they would have the same potential to develop into embryos, fetuses and adult human beings. Thus hiPSCs could be regarded as potential humans. However, no authority or guideline in Japan has specifically considered the status and use of hiPSCs. In this paper, I will address the extent to which the existing recommendations apply to hiPSCs and develop a novel Japanese bioethical perspective on the status of hiPSCs and its implications for hiPSC research, based on the reasoning in the report, 'The fundamental way of thinking in treating the human embryo' presented by the Bioethics Committee of the Council for Science and Technology Policy in 2004, and broader consideration of Japanese culture. PMID- 24951673 TI - Genome comparison of three serovar 5 pathogenic strains of Haemophilus parasuis: insights into an evolving swine pathogen. AB - Haemophilus parasuis is the causative agent of Glasser's disease, a systemic disorder characterized by polyarthritis, polyserositis and meningitis in pigs. Although it is well known that H. parasuis serovar 5 is the most prevalent serovar associated with the disease, the genetic differences among strains are only now being discovered. Genomes from two serovar 5 strains, SH0165 and 29755, are already available. Here, we present the draft genome of a third H. parasuis serovar 5 strain, the formal serovar 5 reference strain Nagasaki. An in silico genome subtractive analysis with full-length predicted genes of the three H. parasuis serovar 5 strains detected 95, 127 and 95 strain-specific genes (SSGs) for Nagasaki, SH0165 and 29755, respectively. We found that the genomic diversity within these three strains was high, in part because of a high number of mobile elements. Furthermore, a detailed analysis of large sequence polymorphisms (LSPs), encompassing regions ranging from 2 to 16 kb, revealed LSPs in virulence related elements, such as a Toll-IL receptor, the AcrA multidrug efflux protein, an ATP-binding cassette (ABC) transporter, lipopolysaccharide-synthetizing enzymes and a tripartite ATP-independent periplasmic (TRAP) transporter. The whole-genome codon adaptation index (CAI) was also calculated and revealed values similar to other well-known bacterial pathogens. In addition, whole-genome SNP analysis indicated that nucleotide changes tended to be increased in membrane related genes. This analysis provides further evidence that the genome of H. parasuis has been subjected to multiple lateral gene transfers (LGTs) and to fine tuning of virulence factors, and has the potential for accelerated genome evolution. PMID- 24951672 TI - Complete genome analysis of a rare group A rotavirus, G11P[25], isolated from a child in Mumbai, India, reveals interspecies transmission and reassortment with human rotavirus strains. AB - Hospital-based rotavirus surveillance was carried out in Mumbai during 2005-2009. An isolate (B08299) with a rare genotype combination (G11P[25]) was detected. The present study was undertaken to characterize the complete genome of the isolate. B08299 exhibited a G11-P[25]-I12-R1-C1-M1-A1-N1-T1-E1-H1 genotype constellation. Phylogenetic analysis of the 11 gene segments of B08299 revealed that the VP2 and NSP5 genes of B08299 had a human origin, while the VP6 gene represented an I12 genotype of obscure origin. The remaining six genes formed a lineage distinct from human and porcine rotaviruses within genotype 1. Analysis of the structural and non-structural genes suggested that B08299 has evolved by gene reassortment. Our findings provide further evidence that interspecies transmission is an important mechanism involved in the evolution and genetic diversity of human rotaviruses in nature. PMID- 24951674 TI - Voxel-based dipole orientation constraints for distributed current estimation. AB - Distributed electroencephalography source localization is a highly ill-posed problem. With measurements on the order of 10(2), and unknowns in the range of 10(4)-10(5), the range of feasible solutions is quite large. One approach to reducing ill-posedness is to intelligently reduce the number of unknowns. Restricting solutions to gray matter is one approach. A further step is to use the anatomy of each patient to identify and constrain the orientation of the dipole within each voxel. While dipole orientation constraints for cortical patch based approaches have been proposed, to our knowledge, no solutions for full volumetric localizations have been presented. Patch techniques account for patch surface area, but place dipoles only on the surface, rather than throughout the cortex. Variability in human cortical thickness means that thicker regions of cortex will potentially contribute more to the EEG signal, and should be accounted for in modeling. Additionally, patch models require cortical surface identification techniques, which can separate them from the extensive literature on voxel-based MR image processing, and require additional adaptation to incorporate more complex information. We present a volumetric approach for computing voxel-based distributed estimates of cortical activity with constrained dipole orientations. Using a tissue thickness estimation approach, we obtain estimates of the cortical surface normal at each voxel. These let us constrain the inverse problem, and yield localizations with reduced spatial blurring and better identification of signal magnitude within the cortex. This is demonstrated for a series of simulated and experimental data using patient-specific bioelectric models. PMID- 24951675 TI - Toward microendoscopic electrical impedance tomography for intraoperative surgical margin assessment. AB - No clinical protocols are routinely used to intraoperatively assess surgical margin status during prostate surgery. Instead, margins are evaluated through pathological assessment of the prostate following radical prostatectomy, when it is too late to provide additional surgical intervention. An intraoperative device potentially capable of assessing surgical margin status based on the electrical property contrast between benign and malignant prostate tissue has been developed. Specifically, a microendoscopic electrical impedance tomography (EIT) probe has been constructed to sense and image, at near millimeter resolution, the conductivity contrast within heterogeneous biological tissues with the goal of providing surgeons with real-time assessment of margin pathologies. This device consists of a ring of eight 0.6-mm diameter electrodes embedded in a 5-mm diameter probe tip to enable access through a 12-mm laparoscopic port. Experiments were performed to evaluate the volume of tissue sensed by the probe. The probe was also tested with inclusions in gelatin, as well as on a sample of porcine tissue with clearly defined regions of adipose and muscle. The probe's area of sensitivity consists of a circular area of 9.1 mm(2) and the maximum depth of sensitivity is approximately 1.5 mm. The probe is able to distinguish between high contrast muscle and adipose tissue on a sub-mm scale (~500 MUm). These preliminary results suggest that EIT is possible in a probe designed to fit within a 12-mm laparoscopic access port. PMID- 24951676 TI - Design of a breath analysis system for diabetes screening and blood glucose level prediction. AB - It has been reported that concentrations of several biomarkers in diabetics' breath show significant difference from those in healthy people's breath. Concentrations of some biomarkers are also correlated with the blood glucose levels (BGLs) of diabetics. Therefore, it is possible to screen for diabetes and predict BGLs by analyzing one's breath. In this paper, we describe the design of a novel breath analysis system for this purpose. The system uses carefully selected chemical sensors to detect biomarkers in breath. Common interferential factors, including humidity and the ratio of alveolar air in breath, are compensated or handled in the algorithm. Considering the intersubject variance of the components in breath, we build subject-specific prediction models to improve the accuracy of BGL prediction. A total of 295 breath samples from healthy subjects and 279 samples from diabetic subjects were collected to evaluate the performance of the system. The sensitivity and specificity of diabetes screening are 91.51% and 90.77%, respectively. The mean relative absolute error for BGL prediction is 21.7%. Experiments show that the system is effective and that the strategies adopted in the system can improve its accuracy. The system potentially provides a noninvasive and convenient method for diabetes screening and BGL monitoring as an adjunct to the standard criteria. PMID- 24951677 TI - Microwave-based stroke diagnosis making global prehospital thrombolytic treatment possible. AB - Here, we present two different brain diagnostic devices based on microwave technology and the associated two first proof-of-principle measurements that show that the systems can differentiate hemorrhagic from ischemic stroke in acute stroke patients, as well as differentiate hemorrhagic patients from healthy volunteers. The system was based on microwave scattering measurements with an antenna system worn on the head. Measurement data were analyzed with a machine learning algorithm that is based on training using data from patients with a known condition. Computer tomography images were used as reference. The detection methodology was evaluated with the leave-one-out validation method combined with a Monte Carlo-based bootstrap step. The clinical motivation for this project is that ischemic stroke patients may receive acute thrombolytic treatment at hospitals, dramatically reducing or abolishing symptoms. A microwave system is suitable for prehospital use, and therefore has the potential to allow significantly earlier diagnosis and treatment than today. PMID- 24951678 TI - Fetal heart rate classification using generative models. AB - This paper presents novel methods for classification of fetal heart rate (FHR) signals into categories that are meaningful for clinical implementation. They are based on generative models (GMs) and Bayesian theory. Instead of using scalar features that summarize information obtained from long-duration data, the models allow for explicit use of feature sequences derived from local patterns of FHR evolution. We compare our methods with a deterministic expert system for classification and with a support vector machine approach that relies on system identification and heart rate variability features. We tested the classifiers on 83 retrospectively collected FHR records, with the gold-standard true diagnosis defined using umbilical cord pH values. We found that our methods consistently performed as well as or better than these, suggesting that the use of GMs and the Bayesian paradigm can bring significant improvement to automatic FHR classification approaches. PMID- 24951679 TI - A wavelet-based electrogram onset delineator for automatic ventricular activation mapping. AB - Electroanatomical mapping (EAM) systems are commonly used in clinical practice for guiding catheter ablation treatments of common arrhythmias. In focal tachycardias, the ablation target is defined by locating the earliest activation area determined by the joint analysis of electrogram (EGM) signals at different sites. However, this is currently a manual time-consuming and experience dependent task performed during the intervention and thus prone to stress-related errors. In this paper, we present an automatic delineation strategy that combines electrocardiogram (ECG) information with the wavelet decomposition of the EGM signal envelope to identify the onset of each EGM signal for activation mapping. Fourteen electroanatomical maps corresponding to ten patients suffering from non tolerated premature ventricular contraction (PVC) beats and admitted for ablation procedure were used for evaluation. We compared the results obtained automatically with two types of manual annotations: one during the intervention by an expert technician (on-procedure) and other after the intervention (off procedure), free from time and procedural constraints, by two other technicians. The automatic annotations show a significant correlation (0.95, p 0.01) with the evaluation reference (off-procedure annotation sets combination) and has an error of 2.1 +/- 10.9 ms, around the order of magnitude of the on-procedure annotations error ( - 2.6 +/- 6.8 ms). The results suggest that the proposed methodology could be incorporated into EAM systems to considerably reduce processing time during ablation interventions. PMID- 24951682 TI - Noise reduction in small-animal PET images using a multiresolution transform. AB - In this paper, we address the problem of denoising reconstructed small animal positron emission tomography (PET) images, based on a multiresolution approach which can be implemented with any transform such as contourlet, shearlet, curvelet, and wavelet. The PET images are analyzed and processed in the transform domain by modeling each subband as a set of different regions separated by boundaries. Homogeneous and heterogeneous regions are considered. Each region is independently processed using different filters: a linear estimator for homogeneous regions and a surface polynomial estimator for the heterogeneous region. The boundaries between the different regions are estimated using a modified edge focusing filter. The proposed approach was validated by a series of experiments. Our method achieved an overall reduction of up to 26% in the %STD of the reconstructed image of a small animal NEMA phantom. Additionally, a test on a simulated lesion showed that our method yields better contrast preservation than other state-of-the art techniques used for noise reduction. Thus, the proposed method provides a significant reduction of noise while at the same time preserving contrast and important structures such as lesions. PMID- 24951681 TI - A logarithmic opinion pool based STAPLE algorithm for the fusion of segmentations with associated reliability weights. AB - Pelvic floor dysfunction is common in women after childbirth and precise segmentation of magnetic resonance images (MRI) of the pelvic floor may facilitate diagnosis and treatment of patients. However, because of the complexity of its structures, manual segmentation of the pelvic floor is challenging and suffers from high inter and intra-rater variability of expert raters. Multiple template fusion algorithms are promising segmentation techniques for these types of applications, but they have been limited by imperfections in the alignment of templates to the target, and by template segmentation errors. A number of algorithms sought to improve segmentation performance by combining image intensities and template labels as two independent sources of information, carrying out fusion through local intensity weighted voting schemes. This class of approach is a form of linear opinion pooling, and achieves unsatisfactory performance for this application. We hypothesized that better decision fusion could be achieved by assessing the contribution of each template in comparison to a reference standard segmentation of the target image and developed a novel segmentation algorithm to enable automatic segmentation of MRI of the female pelvic floor. The algorithm achieves high performance by estimating and compensating for both imperfect registration of the templates to the target image and template segmentation inaccuracies. A local image similarity measure is used to infer a local reliability weight, which contributes to the fusion through a novel logarithmic opinion pooling. We evaluated our new algorithm in comparison to nine state-of-the-art segmentation methods and demonstrated our algorithm achieves the highest performance. PMID- 24951680 TI - MRI upsampling using feature-based nonlocal means approach. AB - In magnetic resonance imaging (MRI), spatial resolution is limited by several factors such as acquisition time, short physiological phenomena, and organ motion. The acquired image usually has higher resolution in two dimensions (the acquisition plane) in comparison with the third dimension, resulting in highly anisotropic voxel size. Interpolation of these low resolution (LR) images using standard techniques, such as linear or spline interpolation, results in distorted edges in the planes perpendicular to the acquisition plane. This poses limitation on conducting quantitative analyses of LR images, particularly on their voxel wise analysis and registration. We have proposed a new non-local means feature based technique that uses structural information of a high resolution (HR) image with a different contrast and interpolates the LR image. In this approach, the similarity between voxels is estimated using a feature vector that characterizes the laminar pattern of the brain structures, resulting in a more accurate similarity measure in comparison with conventional patch-based approach. This technique can be applied to LR images with both anisotropic and isotropic voxel sizes. Experimental results conducted on brain MRI scans of patients with brain tumors, multiple sclerosis, epilepsy, as well as schizophrenic patients and normal controls show that the proposed method is more accurate, requires fewer computations, and thus is significantly faster than a previous state-of-the-art patch-based technique. We also show how the proposed method may be used to upsample regions of interest drawn on LR images. PMID- 24951683 TI - Regularized estimation of magnitude and phase of multi-coil b1 field via Bloch Siegert B1 mapping and coil combination optimizations. AB - Parallel excitation requires fast and accurate B1 map estimation. Bloch-Siegert (BS) B1 mapping is very fast and accurate over a large dynamic range. When applied to multi-coil systems, however, this phase-based method may produce low signal-to-noise ratio estimates in low magnitude regions due to localized excitation patterns of parallel excitation systems. Also, the imaging time increases with the number of coils. In this work, we first propose to modify the standard BS B1 mapping sequence so that it avoids the scans required by previous B1 phase estimation methods. A regularized method is then proposed to jointly estimate the magnitude and phase of multi-coil B1 maps from BS B1 mapping data, improving estimation quality by using the prior knowledge of the smoothness of B1 magnitude and phase. Lastly, we use Cramer-Rao lower bound analysis to optimize the coil combinations, to improve the quality of the raw data for B1 estimation. The proposed methods are demonstrated by simulations and phantom experiments. PMID- 24951684 TI - Motion based X-ray imaging modality. AB - A new X-ray imaging method (patent pending) was developed to visualize function related motion information. We modify existing X-ray imaging methods to provide four images without increasing the necessary measurement time or radiation dose. The most important of these images is a new "kinetic" image that represents motions inside the object or living body. The motion-based contrast of the kinetic image can help visualize details that were not accessible before. The broad range of the movements and high sensitivity of the method are illustrated by imaging the mechanics of a working clock and the chest of a living African clawed frog (Xenopus laevis). The heart, valves, aorta, and lungs of the frog are clearly visualized in spite of the low soft tissue contrast of the animal. The new technology also reconstructs a "static" image similar to the existing conventional X-ray image. The static image shows practically the same information as the conventional image. The new technology presents two more images which show the point-wise errors of the static and kinetic images. This technique gives a better estimation of errors than present methods because it is based entirely on measured data. The new technology could be used in imaging cardiopulmonary movements, nondestructive testing, or port security screening. PMID- 24951686 TI - Motion adaptive patch-based low-rank approach for compressed sensing cardiac cine MRI. AB - One of the technical challenges in cine magnetic resonance imaging (MRI) is to reduce the acquisition time to enable the high spatio-temporal resolution imaging of a cardiac volume within a short scan time. Recently, compressed sensing approaches have been investigated extensively for highly accelerated cine MRI by exploiting transform domain sparsity using linear transforms such as wavelets, and Fourier. However, in cardiac cine imaging, the cardiac volume changes significantly between frames, and there often exist abrupt pixel value changes along time. In order to effectively sparsify such temporal variations, it is necessary to exploit temporal redundancy along motion trajectories. This paper introduces a novel patch-based reconstruction method to exploit geometric similarities in the spatio-temporal domain. In particular, we use a low rank constraint for similar patches along motion, based on the observation that rank structures are relatively less sensitive to global intensity changes, but make it easier to capture moving edges. A Nash equilibrium formulation with relaxation is employed to guarantee convergence. Experimental results show that the proposed algorithm clearly reconstructs important anatomical structures in cardiac cine image and provides improved image quality compared to existing state-of-the-art methods such as k-t FOCUSS, k-t SLR, and MASTeR. PMID- 24951687 TI - Adaptive regularization of the NL-means: application to image and video denoising. AB - Image denoising is a central problem in image processing and it is often a necessary step prior to higher level analysis such as segmentation, reconstruction, or super-resolution. The nonlocal means (NL-means) perform denoising by exploiting the natural redundancy of patterns inside an image; they perform a weighted average of pixels whose neighborhoods (patches) are close to each other. This reduces significantly the noise while preserving most of the image content. While it performs well on flat areas and textures, it suffers from two opposite drawbacks: it might over-smooth low-contrasted areas or leave a residual noise around edges and singular structures. Denoising can also be performed by total variation minimization-the Rudin, Osher and Fatemi model-which leads to restore regular images, but it is prone to over-smooth textures, staircasing effects, and contrast losses. We introduce in this paper a variational approach that corrects the over-smoothing and reduces the residual noise of the NL-means by adaptively regularizing nonlocal methods with the total variation. The proposed regularized NL-means algorithm combines these methods and reduces both of their respective defaults by minimizing an adaptive total variation with a nonlocal data fidelity term. Besides, this model adapts to different noise statistics and a fast solution can be obtained in the general case of the exponential family. We develop this model for image denoising and we adapt it to video denoising with 3D patches. PMID- 24951688 TI - Compressive sensing via nonlocal low-rank regularization. AB - Sparsity has been widely exploited for exact reconstruction of a signal from a small number of random measurements. Recent advances have suggested that structured or group sparsity often leads to more powerful signal reconstruction techniques in various compressed sensing (CS) studies. In this paper, we propose a nonlocal low-rank regularization (NLR) approach toward exploiting structured sparsity and explore its application into CS of both photographic and MRI images. We also propose the use of a nonconvex log det ( X) as a smooth surrogate function for the rank instead of the convex nuclear norm and justify the benefit of such a strategy using extensive experiments. To further improve the computational efficiency of the proposed algorithm, we have developed a fast implementation using the alternative direction multiplier method technique. Experimental results have shown that the proposed NLR-CS algorithm can significantly outperform existing state-of-the-art CS techniques for image recovery. PMID- 24951689 TI - Robust face recognition with structurally incoherent low-rank matrix decomposition. AB - For the task of robust face recognition, we particularly focus on the scenario in which training and test image data are corrupted due to occlusion or disguise. Prior standard face recognition methods like Eigenfaces or state-of-the-art approaches such as sparse representation-based classification did not consider possible contamination of data during training, and thus their recognition performance on corrupted test data would be degraded. In this paper, we propose a novel face recognition algorithm based on low-rank matrix decomposition to address the aforementioned problem. Besides the capability of decomposing raw training data into a set of representative bases for better modeling the face images, we introduce a constraint of structural incoherence into the proposed algorithm, which enforces the bases learned for different classes to be as independent as possible. As a result, additional discriminating ability is added to the derived base matrices for improved recognition performance. Experimental results on different face databases with a variety of variations verify the effectiveness and robustness of our proposed method. PMID- 24951690 TI - Efficient semidefinite spectral clustering via lagrange duality. AB - We propose an efficient approach to semidefinite spectral clustering (SSC), which addresses the Frobenius normalization with the positive semidefinite (p.s.d.) constraint for spectral clustering. Compared with the original Frobenius norm approximation-based algorithm, the proposed algorithm can more accurately find the closest doubly stochastic approximation to the affinity matrix by considering the p.s.d. constraint. In this paper, SSC is formulated as a semidefinite programming (SDP) problem. In order to solve the high computational complexity of SDP, we present a dual algorithm based on the Lagrange dual formalization. Two versions of the proposed algorithm are proffered: one with less memory usage and the other with faster convergence rate. The proposed algorithm has much lower time complexity than that of the standard interior-point-based SDP solvers. Experimental results on both the UCI data sets and real-world image data sets demonstrate that: 1) compared with the state-of-the-art spectral clustering methods, the proposed algorithm achieves better clustering performance and 2) our algorithm is much more efficient and can solve larger-scale SSC problems than those standard interior-point SDP solvers. PMID- 24951685 TI - Comparative evaluation of registration algorithms in different brain databases with varying difficulty: results and insights. AB - Evaluating various algorithms for the inter-subject registration of brain magnetic resonance images (MRI) is a necessary topic receiving growing attention. Existing studies evaluated image registration algorithms in specific tasks or using specific databases (e.g., only for skull-stripped images, only for single site images, etc.). Consequently, the choice of registration algorithms seems task- and usage/parameter-dependent. Nevertheless, recent large-scale, often multi-institutional imaging-related studies create the need and raise the question whether some registration algorithms can 1) generally apply to various tasks/databases posing various challenges; 2) perform consistently well, and while doing so, 3) require minimal or ideally no parameter tuning. In seeking answers to this question, we evaluated 12 general-purpose registration algorithms, for their generality, accuracy and robustness. We fixed their parameters at values suggested by algorithm developers as reported in the literature. We tested them in 7 databases/tasks, which present one or more of 4 commonly-encountered challenges: 1) inter-subject anatomical variability in skull stripped images; 2) intensity homogeneity, noise and large structural differences in raw images; 3) imaging protocol and field-of-view (FOV) differences in multi site data; and 4) missing correspondences in pathology-bearing images. Totally 7,562 registrations were performed. Registration accuracies were measured by (multi-)expert-annotated landmarks or regions of interest (ROIs). To ensure reproducibility, we used public software tools, public databases (whenever possible), and we fully disclose the parameter settings. We show evaluation results, and discuss the performances in light of algorithms' similarity metrics, transformation models and optimization strategies. We also discuss future directions for the algorithm development and evaluations. PMID- 24951691 TI - Subspace-based discrete transform encoded local binary patterns representations for robust periocular matching on NIST's face recognition grand challenge. AB - In this paper, we employ several subspace representations (principal component analysis, unsupervised discriminant projection, kernel class-dependence feature analysis, and kernel discriminant analysis) on our proposd discrete transform encoded local binary patterns (DT-LBP) to match periocular region on a large data set such as NIST's face recognition grand challenge (FRGC) ver2 database. We strictly follow FRGC Experiment 4 protocol, which involves 1-to-1 matching of 8014 uncontrolled probe periocular images to 16 028 controlled target periocular images (~128 million pairwise face match comparisons). The performance of the periocular region is compared with that of full face with different illumination preprocessing schemes. The verification results on periocular region show that subspace representation on DT-LBP outperforms LBP significantly and gains a giant leap from traditional subspace representation on raw pixel intensity. Additionally, our proposed approach using only the periocular region is almost as good as full face with only 2.5% reduction in verification rate at 0.1% false accept rate, yet we gain tolerance to expression, occlusion, and capability of matching partial faces in crowds. In addition, we have compared the best standalone DT-LBP descriptor with eight other state-of-the-art descriptors for facial recognition and achieved the best performance. The two general frameworks are our major contribution: 1) a general framework that employs various generative and discriminative subspace modeling techniques for DT-LBP representation and 2) a general framework that encodes discrete transforms with local binary patterns for the creation of robust descriptors. PMID- 24951692 TI - Vision-based pose estimation from points with unknown correspondences. AB - Pose estimation from points with unknown correspondences currently is still a difficult problem in the field of computer vision. To solve this problem, the SoftSI algorithm is proposed, which can simultaneously obtain pose and correspondences. The SoftSI algorithm is based on the combination of the proposed PnP algorithm (the SI algorithm) and two singular value decomposition (SVD)-based shape description theorems. Other main contributions of this paper are: 1) two SVD-based shape description theorems are proposed; 2) by analyzing the calculation process of the SI algorithm, the method to avoid pose ambiguity is proposed; and 3) an acceleration method to quickly eliminate bad initial values for the SoftSI algorithm is proposed. The simulation results show that the SI algorithm is accurate while the SoftSI algorithm is fast, robust to noise, and has large convergence radius. PMID- 24951693 TI - A consensus-driven approach for structure and texture aware depth map upsampling. AB - This paper presents a method for increasing spatial resolution of a depth map using its corresponding high-resolution (HR) color image as a guide. Most of the previous methods rely on the assumption that depth discontinuities are highly correlated with color boundaries, leading to artifacts in the regions where the assumption is broken. To prevent scene texture from being erroneously transferred to reconstructed scene surfaces, we propose a framework for dividing the color image into different regions and applying different methods tailored to each region type. For the region classification, we first segment the low-resolution (LR) depth map into regions of smooth surfaces, and then use them to guide the segmentation of the color image. Using the consensus of multiple image segmentations obtained by different super-pixel generation methods, the color image is divided into continuous and discontinuous regions: in the continuous regions, their HR depth values are interpolated from LR depth samples without exploiting the color information. In the discontinuous regions, their HR depth values are estimated by sequentially applying more complicated depth-histogram based methods. Through experiments, we show that each step of our method improves depth map upsampling both quantitatively and qualitatively. We also show that our method can be extended to handle real data with occluded regions caused by the displacement between color and depth sensors. PMID- 24951694 TI - Hyperspectral image segmentation using a new spectral unmixing-based binary partition tree representation. AB - The binary partition tree (BPT) is a hierarchical region-based representation of an image in a tree structure. The BPT allows users to explore the image at different segmentation scales. Often, the tree is pruned to get a more compact representation and so the remaining nodes conform an optimal partition for some given task. Here, we propose a novel BPT construction approach and pruning strategy for hyperspectral images based on spectral unmixing concepts. Linear spectral unmixing consists of finding the spectral signatures of the materials present in the image (endmembers) and their fractional abundances within each pixel. The proposed methodology exploits the local unmixing of the regions to find the partition achieving a global minimum reconstruction error. Results are presented on real hyperspectral data sets with different contexts and resolutions. PMID- 24951695 TI - Color-guided depth recovery from RGB-D data using an adaptive autoregressive model. AB - This paper proposes an adaptive color-guided autoregressive (AR) model for high quality depth recovery from low quality measurements captured by depth cameras. We observe and verify that the AR model tightly fits depth maps of generic scenes. The depth recovery task is formulated into a minimization of AR prediction errors subject to measurement consistency. The AR predictor for each pixel is constructed according to both the local correlation in the initial depth map and the nonlocal similarity in the accompanied high quality color image. We analyze the stability of our method from a linear system point of view, and design a parameter adaptation scheme to achieve stable and accurate depth recovery. Quantitative and qualitative evaluation compared with ten state-of-the art schemes show the effectiveness and superiority of our method. Being able to handle various types of depth degradations, the proposed method is versatile for mainstream depth sensors, time-of-flight camera, and Kinect, as demonstrated by experiments on real systems. PMID- 24951696 TI - Repairing bad co-segmentation using its quality evaluation and segment propagation. AB - In this paper, we improve co-segmentation performance by repairing bad segments based on their quality evaluation and segment propagation. Starting from co segmentation results of the existing co-segmentation method, we first perform co segmentation quality evaluation to score each segment. Good segments can be filter out based on the scores. Then, a propagation method is designed to transfer good segments to the rest bad ones so as to repair the bad segmentation. In our method, the quality evaluation is implemented by the measurements of foreground consistency and segment completeness. Two propagation methods such as global propagation and local region propagation are then defined to achieve the more accurate propagation. We verify the proposed method using four state-of-the arts co-segmentation methods and two public datasets such as ICoseg dataset and MSRC dataset. The experimental results demonstrate the effectiveness of the proposed quality evaluation method. Furthermore, the proposed method can significantly improve the performance of existing methods with larger intersection-over-union score values. PMID- 24951697 TI - Coupled binary embedding for large-scale image retrieval. AB - Visual matching is a crucial step in image retrieval based on the bag-of-words (BoW) model. In the baseline method, two keypoints are considered as a matching pair if their SIFT descriptors are quantized to the same visual word. However, the SIFT visual word has two limitations. First, it loses most of its discriminative power during quantization. Second, SIFT only describes the local texture feature. Both drawbacks impair the discriminative power of the BoW model and lead to false positive matches. To tackle this problem, this paper proposes to embed multiple binary features at indexing level. To model correlation between features, a multi-IDF scheme is introduced, through which different binary features are coupled into the inverted file. We show that matching verification methods based on binary features, such as Hamming embedding, can be effectively incorporated in our framework. As an extension, we explore the fusion of binary color feature into image retrieval. The joint integration of the SIFT visual word and binary features greatly enhances the precision of visual matching, reducing the impact of false positive matches. Our method is evaluated through extensive experiments on four benchmark datasets (Ukbench, Holidays, DupImage, and MIR Flickr 1M). We show that our method significantly improves the baseline approach. In addition, large-scale experiments indicate that the proposed method requires acceptable memory usage and query time compared with other approaches. Further, when global color feature is integrated, our method yields competitive performance with the state-of-the-arts. PMID- 24951698 TI - Segmentation and estimation of spatially varying illumination. AB - In this paper, we present an unsupervised method for segmenting the illuminant regions and estimating the illumination power spectrum from a single image of a scene lit by multiple light sources. Here, illuminant region segmentation is cast as a probabilistic clustering problem in the image spectral radiance space. We formulate the problem in an optimization setting, which aims to maximize the likelihood of the image radiance with respect to a mixture model while enforcing a spatial smoothness constraint on the illuminant spectrum. We initialize the sample pixel set under each illuminant via a projection of the image radiance spectra onto a low-dimensional subspace spanned by a randomly chosen subset of spectra. Subsequently, we optimize the objective function in a coordinate-ascent manner by updating the weights of the mixture components, sample pixel set under each illuminant, and illuminant posterior probabilities. We then estimate the illuminant power spectrum per pixel making use of these posterior probabilities. We compare our method with a number of alternatives for the tasks of illumination region segmentation, illumination color estimation, and color correction. Our experiments show the effectiveness of our method as applied to one hyperspectral and three trichromatic image data sets. PMID- 24951699 TI - Surface reconstruction from microscopic images in optical lithography. AB - This paper presents a method to reconstruct 3D surfaces of silicon wafers from 2D images of printed circuits taken with a scanning electron microscope. Our reconstruction method combines the physical model of the optical acquisition system with prior knowledge about the shapes of the patterns in the circuit; the result is a shape-from-shading technique with a shape prior. The reconstruction of the surface is formulated as an optimization problem with an objective functional that combines a data-fidelity term on the microscopic image with two prior terms on the surface. The data term models the acquisition system through the irradiance equation characteristic of the microscope; the first prior is a smoothness penalty on the reconstructed surface, and the second prior constrains the shape of the surface to agree with the expected shape of the pattern in the circuit. In order to account for the variability of the manufacturing process, this second prior includes a deformation field that allows a nonlinear elastic deformation between the expected pattern and the reconstructed surface. As a result, the minimization problem has two unknowns, and the reconstruction method provides two outputs: 1) a reconstructed surface and 2) a deformation field. The reconstructed surface is derived from the shading observed in the image and the prior knowledge about the pattern in the circuit, while the deformation field produces a mapping between the expected shape and the reconstructed surface that provides a measure of deviation between the circuit design models and the real manufacturing process. PMID- 24951700 TI - Decomposition and extraction: a new framework for visual classification. AB - In this paper, we present a novel framework for visual classification based on hierarchical image decomposition and hybrid midlevel feature extraction. Unlike most midlevel feature learning methods, which focus on the process of coding or pooling, we emphasize that the mechanism of image composition also strongly influences the feature extraction. To effectively explore the image content for the feature extraction, we model a multiplicity feature representation mechanism through meaningful hierarchical image decomposition followed by a fusion step. In particularly, we first propose a new hierarchical image decomposition approach in which each image is decomposed into a series of hierarchical semantical components, i.e, the structure and texture images. Then, different feature extraction schemes can be adopted to match the decomposed structure and texture processes in a dissociative manner. Here, two schemes are explored to produce property related feature representations. One is based on a single-stage network over hand-crafted features and the other is based on a multistage network, which can learn features from raw pixels automatically. Finally, those multiple midlevel features are incorporated by solving a multiple kernel learning task. Extensive experiments are conducted on several challenging data sets for visual classification, and experimental results demonstrate the effectiveness of the proposed method. PMID- 24951701 TI - USB: ultrashort binary descriptor for fast visual matching and retrieval. AB - Currently, many local descriptors have been proposed to tackle a basic issue in computer vision: duplicate visual content matching. These descriptors either are represented as high-dimensional vectors relatively expensive to extract and compare or are binary codes limited in robustness. Bag-of-visual words (BoWs) model compresses local features into a compact representation that allows for fast matching and scalable indexing. However, the codebook training, high dimensional feature extraction, and quantization significantly degrade the flexibility and efficiency of BoWs model. In this paper, we study an alternative to current local descriptors and BoWs model by extracting the ultrashort binary descriptor (USB) and a compact auxiliary spatial feature from each keypoint detected in images. A typical USB is a 24-bit binary descriptor, hence it directly quantizes visual clues of image keypoints to about 16 million unique IDs. USB allows fast image matching and indexing and avoids the expensive codebook training and feature quantization in BoWs model. The spatial feature complementarily captures the spatial configuration in neighbor region of each keypoint, hence is used to filter mismatched USBs in a cascade verification. In image matching task, USB shows promising accuracy and nearly one-order faster speed than SIFT. We also test USB in retrieval tasks on UKbench, Oxford5K, and 1.2 million distractor images. Comparisons with recent retrieval methods manifest the competitive accuracy, memory consumption, and significantly better efficiency of our approach. PMID- 24951702 TI - Design of multiple axis robotic platform for postural stability analysis. AB - This paper presents the design and implementation of IsiMove, a new dynamic posturography platform. It allows the evaluation of the static and dynamic balance of a human placed on a force plate. IsiMove is a robotic platform open kinematic with four degrees of freedom: anteroposterior tilt, mediolateral tilt, vertical rotation, and horizontal translation. It is capable of measuring the displacement of the center of pressure over time, with a resolution of 0.1 mm for each foot and support a human of about 120 kg. IsiMove can generate various types of balance perturbations based on parameters such as direction, amplitude, frequency and shape. In this paper, we will give a description of the mechanisms that constitute our platform. First, the technical specifications of the hardware and software architecture will be presented. Then, we will provide details related to extensive experimental evaluations of the platform in both static and dynamic condition as well as result of postural stability analysis with healthy subjects and stroke patients. PMID- 24951703 TI - Tensor based singular spectrum analysis for automatic scoring of sleep EEG. AB - A new supervised approach for decomposition of single channel signal mixtures is introduced in this paper. The performance of the traditional singular spectrum analysis algorithm is significantly improved by applying tensor decomposition instead of traditional singular value decomposition. As another contribution to this subspace analysis method, the inherent frequency diversity of the data has been effectively exploited to highlight the subspace of interest. As an important application, sleep electroencephalogram has been analyzed and the stages of sleep for the subjects in normal condition, with sleep restriction, and with sleep extension have been accurately estimated and compared with the results of sleep scoring by clinical experts. PMID- 24951704 TI - Smoothness as a failure mode of Bayesian mixture models in brain-machine interfaces. AB - Various recursive Bayesian filters based on reach state equations (RSE) have been proposed to convert neural signals into reaching movements in brain-machine interfaces. When the target is known, RSE produce exquisitely smooth trajectories relative to the random walk prior in the basic Kalman filter. More realistically, the target is unknown, and gaze analysis or other side information is expected to provide a discrete set of potential targets. In anticipation of this scenario, various groups have implemented RSE-based mixture (hybrid) models, which define a discrete random variable to represent target identity. While principled, this approach sacrifices the smoothness of RSE with known targets. This paper combines empirical spiking data from primary motor cortex and mathematical analysis to explain this loss in performance. We focus on angular velocity as a meaningful and convenient measure of smoothness. Our results demonstrate that angular velocity in the trajectory is approximately proportional to change in target probability. The constant of proportionality equals the difference in heading between parallel filters from the two most probable targets, suggesting a smoothness benefit to more narrowly spaced targets. Simulation confirms that measures to smooth the data likelihood also improve the smoothness of hybrid trajectories, including increased ensemble size and uniformity in preferred directions. We speculate that closed-loop training or neuronal subset selection could be used to shape the user's tuning curves towards this end. PMID- 24951705 TI - Characterizing motor and cognitive effects associated with deep brain stimulation in the GPi of hemi-Parkinsonian rats. AB - The globus pallidus internus (GPi) is the main output nucleus of the basal ganglia, which is associated with a variety of functions including motor performance and cognition. The GPi is one of the primary targets of deep brain stimulation (DBS) in patients with movement disorders. However, the therapeutic mechanism of GPi-DBS is poorly understood and rodent models have not been characterized. Cognitive side effects, such as impulsivity and depression, of DBS treatment for Parkinson's disease are known, but their relationship to the efficacy of the treatment is not well explained. The goal of this study is to illuminate the effects of GPi-DBS on both motor and cognitive function in a hemi Parkinsonian rat model. In this work, we study the motor performance of the rodents in multiple behaviors, as well as of impulsivity and depression, and consider the relationship between these behavioral variables and the stimulation frequency of the DBS signal. For the first time, the connection is directly established between stimulating the GPi, motor performance and cognition is directly established in the hemi-Parkinsonian rodent model. PMID- 24951706 TI - Nanofluid analysis for the intestinal flow in a symmetric channel. AB - This article deals with the influence of heat transfer and nanofluid on the peristaltic flow of a third order fluid. Numerical solutions are evaluated for temperature, nanofluid phenomenon, streamlines and pressure rise. Graphical illustrations investigate the influence of various embedded parameters. It is seen that with high buoyancy forces and Stress relaxation time velocity profile decreases. PMID- 24951707 TI - 1 MUm-thickness ultra-flexible and high electrode-density surface electromyogram measurement sheet with 2 V organic transistors for prosthetic hand control. AB - A 64-channel surface electromyogram (EMG) measurement sheet (SEMS) with 2 V organic transistors on a 1 MUm-thick ultra-flexible polyethylene naphthalate (PEN) film is developed for prosthetic hand control. The surface EMG electrodes must satisfy the following three requirements; high mechanical flexibility, high electrode density and high signal integrity. To achieve high electrode density and high signal integrity, a distributed and shared amplifier (DSA) architecture is proposed, which enables an in-situ amplification of the myoelectric signal with a fourfold increase in EMG electrode density. In addition, a post fabrication select-and-connect (SAC) method is proposed to cope with the large mismatch of organic transistors. The proposed SAC method reduces the area and the power overhead by 96% and 98.2%, respectively, compared with the use of conventional parallel transistors to reduce the transistor mismatch by a factor of 10. PMID- 24951708 TI - An effective ultrasound video communication system using despeckle filtering and HEVC. AB - The recent emergence of the high-efficiency video coding (HEVC) standard promises to deliver significant bitrate savings over current and prior video compression standards, while also supporting higher resolutions that can meet the clinical acquisition spatiotemporal settings. The effective application of HEVC to medical ultrasound necessitates a careful evaluation of strict clinical criteria that guarantee that clinical quality will not be sacrificed in the compression process. Furthermore, the potential use of despeckle filtering prior to compression provides for the possibility of significant additional bitrate savings that have not been previously considered. This paper provides a thorough comparison of the use of MPEG-2, H.263, MPEG-4, H.264/AVC, and HEVC for compressing atherosclerotic plaque ultrasound videos. For the comparisons, we use both subjective and objective criteria based on plaque structure and motion. For comparable clinical video quality, experimental evaluation on ten videos demonstrates that HEVC reduces bitrate requirements by as much as 33.2% compared to H.264/AVC and up to 71% compared to MPEG-2. The use of despeckle filtering prior to compression is also investigated as a method that can reduce bitrate requirements through the removal of higher frequency components without sacrificing clinical quality. Based on the use of three despeckle filtering methods with both H.264/AVC and HEVC, we find that prior filtering can yield additional significant bitrate savings. The best performing despeckle filter (DsFlsmv) achieves bitrate savings of 43.6% and 39.2% compared to standard nonfiltered HEVC and H.264/AVC encoding, respectively. PMID- 24951709 TI - A novel computerized tool to stratify risk in carotid atherosclerosis using kinematic features of the arterial wall. AB - Valid characterization of carotid atherosclerosis (CA) is a crucial public health issue, which would limit the major risks held by CA for both patient safety and state economies. This paper investigated the unexplored potential of kinematic features in assisting the diagnostic decision for CA in the framework of a computer-aided diagnosis (CAD) tool. To this end, 15 CAD schemes were designed and were fed with a wide variety of kinematic features of the atherosclerotic plaque and the arterial wall adjacent to the plaque for 56 patients from two different hospitals. The CAD schemes were benchmarked in terms of their ability to discriminate between symptomatic and asymptomatic patients and the combination of the Fisher discriminant ratio, as a feature-selection strategy, and support vector machines, in the classification module, was revealed as the optimal motion based CAD tool. The particular CAD tool was evaluated with several cross validation strategies and yielded higher than 88% classification accuracy; the texture-based CAD performance in the same dataset was 80%. The incorporation of kinematic features of the arterial wall in CAD seems to have a particularly favorable impact on the performance of image-data-driven diagnosis for CA, which remains to be further elucidated in future prospective studies on large datasets. PMID- 24951710 TI - Improving compliance in remote healthcare systems through smartphone battery optimization. AB - Remote health monitoring (RHM) has emerged as a solution to help reduce the cost burden of unhealthy lifestyles and aging populations. Enhancing compliance to prescribed medical regimens is an essential challenge to many systems, even those using smartphone technology. In this paper, we provide a technique to improve smartphone battery consumption and examine the effects of smartphone battery lifetime on compliance, in an attempt to enhance users' adherence to remote monitoring systems. We deploy WANDA-CVD, an RHM system for patients at risk of cardiovascular disease (CVD), using a wearable smartphone for detection of physical activity. We tested the battery optimization technique in an in-lab pilot study and validated its effects on compliance in the Women's Heart Health Study. The battery optimization technique enhanced the battery lifetime by 192% on average, resulting in a 53% increase in compliance in the study. A system like WANDA-CVD can help increase smartphone battery lifetime for RHM systems monitoring physical activity. PMID- 24951711 TI - The effect of sample age and prediction resolution on myocardial infarction risk prediction. AB - Myocardial infarction (MI) is one of the leading causes of death in many developed countries. Hence, early detection of MI events is critical for effective preventative therapies, potentially reducing avoidable mortality. One approach for early disease prediction is the use of risk prediction models developed using machine learning techniques. One important component of these models is to provide clinicians with the flexibility to customize (e.g., the prediction range) and use the risk prediction model that they deemed most beneficial for their patients. Therefore, in this paper, we develop MI prediction models and investigate the effect of sample age and prediction resolution on the performance of MI risk prediction models. The cardiovascular health study dataset was used in this study. Results indicate that the prediction model developed using SVM algorithm is capable of achieving high sensitivity, specificity, and balanced accuracy of 95.3%, 84.8%, and 90.1%, respectively, over a time span of 6 years. Both sample age and prediction resolution were found not to have a significant impact on the performance of MI risk prediction models developed using subjects aged 65 and above. This implies that risk prediction models developed using different sample age and prediction resolution is a feasible approach. These models can be integrated into a computer aided screening tool which clinicians can use to interpret and predict the MI risk status of the individual patients after performing the necessary clinical assessments (e.g., cognitive function, physical function, electrocardiography, general changes to health/lifestyle, and medications) required by the models. This could offer a means for clinicians to screen the patients at risk of having MI in the near future and prescribe early medical intervention to reduce the risk. PMID- 24951712 TI - Identification of microsatellites in DNA using adaptive S-transform. AB - Microsatellites are tandem repeats of size 1-6 base pairs, associated with various diseases, DNA fingerprinting, and also useful in evolutionary studies. A signal processing algorithm for microsatellite detection, based on adaptive S transform is proposed. The standard deviation of the Gaussian window kernel of the S-transform has been optimized for integer periods of interest by maximizing the concentration measure. The time-frequency plot is generated using optimal standard deviation values. Candidate repeats are marked by comparing the spectrogram values in the time-frequency plot with a threshold. A preprocessing phase followed by a verification phase extracts final results from the candidate repeats. Simulation studies on DNA sequences establish the superiority of this algorithm over other existing methods. Applicability of this algorithm in the analysis of DNA sequences associated with repeat expansion diseases has also been demonstrated. PMID- 24951713 TI - A dynamic multiarmed bandit-gene expression programming hyper-heuristic for combinatorial optimization problems. AB - Hyper-heuristics are search methodologies that aim to provide high-quality solutions across a wide variety of problem domains, rather than developing tailor made methodologies for each problem instance/domain. A traditional hyper heuristic framework has two levels, namely, the high level strategy (heuristic selection mechanism and the acceptance criterion) and low level heuristics (a set of problem specific heuristics). Due to the different landscape structures of different problem instances, the high level strategy plays an important role in the design of a hyper-heuristic framework. In this paper, we propose a new high level strategy for a hyper-heuristic framework. The proposed high-level strategy utilizes a dynamic multiarmed bandit-extreme value-based reward as an online heuristic selection mechanism to select the appropriate heuristic to be applied at each iteration. In addition, we propose a gene expression programming framework to automatically generate the acceptance criterion for each problem instance, instead of using human-designed criteria. Two well-known, and very different, combinatorial optimization problems, one static (exam timetabling) and one dynamic (dynamic vehicle routing) are used to demonstrate the generality of the proposed framework. Compared with state-of-the-art hyper-heuristics and other bespoke methods, empirical results demonstrate that the proposed framework is able to generalize well across both domains. We obtain competitive, if not better results, when compared to the best known results obtained from other methods that have been presented in the scientific literature. We also compare our approach against the recently released hyper-heuristic competition test suite. We again demonstrate the generality of our approach when we compare against other methods that have utilized the same six benchmark datasets from this test suite. PMID- 24951714 TI - Emotional, cognitive and behavioral reactions to paranoid symptoms in clinical and nonclinical populations. AB - Background: Paranoia is a disruptive belief that can vary across a continuum, ranging from persecutory delusions presented in clinical settings to paranoid cognitions that are highly prevalent in the general population. The literature suggests that paranoid thoughts derive from the activation of a paranoid schema or information processing biases that can be sensitive to socially ambiguous stimuli and influence the processing of threatening situations. Method: Four groups (Schizophrenic participants in active psychotic phases, n=6; stable participants in remission, n=30; participants' relatives, n=32; and healthy controls, n=64) were assessed with self-report questionnaires to determine how the reactions to paranoia of clinical patients differ from healthy individuals. Cognitive, emotional and behavioral dimensions of their reactions to these paranoid thoughts were examined. Results: Paranoid individuals were present in all groups. Most participants referred the rejection by others as an important trigger of paranoid ideations, while active psychotic were unable to identify triggering situations to their thoughts and reactions. This may be determinant to the different reactions and the different degree of invalidation caused by paranoid thoughts observed across groups. Conclusion: Clinical and non-clinical expressions of paranoid ideations differ in terms of their cognitive, emotional and behavioral components. It is suggested that, in socially ambiguous situations, paranoid participants (presenting lower thresholds of paranoid schema activation) lose the opportunity to disconfirm their paranoid beliefs by resourcing to more maladaptive coping strategies. Consequently, by dwelling on these thoughts, the amount of time spent thinking about their condition and the disability related to the disease increases. PMID- 24951716 TI - Turner Mosaicism and Schizoaffective Disorder. PMID- 24951715 TI - Bath Salts Abuse Leading to New-Onset Psychosis and Potential for Violence. AB - BACKGROUND: Bath salts have recently emerged as a popular designer drug of abuse causing significant hazardous effects on mental health and physical health, resulting in public health legislation making its usage illegal in the United States. OBJECTIVE: To educate mental health providers on the effects of the new designer drug bath salts, including its potential to cause psychosis and violence in patients. METHOD: This is a case report on a 40-year-old male with no past psychiatric history who presented with new-onset psychosis and increased risk for violence after ingesting bath salts. In addition, a literature review was performed to summarize the documented effects of bath salts abuse and the current U.S. public health legislation on bath salts. RESULTS: The presented case illustrates a new-onset, substance-induced psychotic disorder related to bath salts usage. The literature review explains the sympathomimetic reaction and the potential for psychotic symptoms. DISCUSSION: To discuss the physical and psychological effects of bath salts, treatment options for bath salts abuse and U.S. legislation by Ohio state law to current U.S. federal law that bans production, sale, and possession of main substances found in bath salts. CONCLUSION: It is important for mental health providers to be aware of bath salts, understand the physical and psychiatric effects of bath salts and be familiar with current legislative policy banning its usage. Lastly, bath salts abuse should be in the differential diagnosis where psychosis is new onset or clinically incongruent with known primary presentation of a psychotic disorder. PMID- 24951718 TI - Sustained improvement of negative symptoms in schizophrenia with add-on tDCS: a case report. PMID- 24951721 TI - MALDI-TOF MS for the identification of veterinary non-C. neoformans-C. gattii Cryptococcus spp. isolates from Italy. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) offers an effective alternative to phenotypic and molecular methods for the rapid identification of microorganisms. Our aim in this study was to create an in-house library for a set of strains of nine uncommonly reported human and animal cryptococcal species, including Cryptococcus adeliensis, C. albidosimilis, C. albidus, C. aureus, C. carnescens, C. laurentii, C. magnus, C. victoriae and C. uniguttulatus, and to use this library to make timely and correct identifications using MALDI-TOF MS for use in routine laboratory diagnostics. Protein extracts obtained via the formic acid extraction method of 62 veterinary non-C. neoformans-C. gattii cryptococcal isolates were studied. The obtained mass spectra correctly grouped all 62 studied isolates according to species identification previously obtained by internal transcribe spacer sequence analysis. The in-house database was than exported and successfully uploaded to the Microflex LT (Maldi Biotyper; Bruker Daltonics) instrument at a different diagnostic laboratory in Italy. Scores >2.7 obtained from isolates reanalyzed in the latter laboratory supported the high reproducibility of the method. The possibility of creating and transferring an in-house library adds to the usefulness MALDI-TOF MS an important tool for the rapid and inexpensive identification of pathogenic and saprophytic fungi as required for differential diagnosis of human and animal mycoses. PMID- 24951722 TI - Silver colloidal nanoparticle stability: influence on Candida biofilms formed on denture acrylic. AB - Our aim in this study was to evaluate how the chemical stability of silver nanoparticles (SNs) influences their efficacy against Candida albicans and C. glabrata biofilms. Several parameters of SN stability were tested, namely, temperature (50oC, 70oC, and 100oC), pH (5.0 and 9.0), and time of contact (5 h and 24 h) with biofilms. The control was defined as SNs without temperature treatment, pH 7, and 24 h of contact. These colloidal suspensions at 54 mg/L were used to treat mature Candida biofilms (48 h) formed on acrylic. Their efficacy was determined by total biomass and colony-forming unit quantification. Data were analyzed using analysis of variance and the Bonferroni post hoc test (alpha = 0.05). The temperature and pH variations of SNs did not affect their efficacy against the viable cells of Candida biofilms (P > 0.05). Moreover, the treatment periods were not decisive in terms of the susceptibility of Candida biofilms to SNs. These findings provide an important advantage of SNs that may be useful in the treatment of Candida-associated denture stomatitis. PMID- 24951723 TI - Aspergillus pragensis sp. nov. discovered during molecular reidentification of clinical isolates belonging to Aspergillus section Candidi. AB - The identity of nine clinical isolates recovered from Czech patients and presumptively identified as Aspergillus sp. section Candidi based on colony morphology was revised using sequences of beta-tubulin, calmodulin gene sequence, and internal transcribed spacer rDNA. Six isolates were from suspected and proven onychomycosis, one from otitis externa, and two associated with probable invasive aspergillosis. The results showed that one Aspergillus candidus isolate was the cause of otitis externa, and both isolates obtained from sputa of patients with probable invasive aspergillosis were reidentified as A. carneus (sect. Terrei) and A. flavus (sect. Flavi). Three isolates from nail scrapings were identified as A. tritici, a verified agent of nondermatophyte onychomycosis. One isolate from toenail was determined to be A. candidus and the two isolates belonged to a hitherto undescribed species, Aspergillus pragensis sp. nov. This species is well supported by phylogenetic analysis based on beta-tubulin and calmodulin gene and is distinguishable from other members of sect. Candidi by red-brown reverse on malt extract agar, slow growth on Czapek-Dox agar and inability to grow at 37 degrees C. A secondary metabolite analysis was also provided with comparison of metabolite spectrum to other species. Section Candidi now encompasses five species for which a dichotomous key based on colony characteristics is provided. All clinical isolates were tested for susceptibilities to selected antifungal agents using the Etest and disc diffusion method. Overall sect. Candidi members are highly susceptible to common antifungals. PMID- 24951724 TI - The anorexic effect of Ex4/Fc through GLP-1 receptor activation in high-fat diet fed mice. AB - Exendin-4 (Ex4), a peptide initially found in the saliva of the Gila monster, can activate the signaling pathway of the incretin hormone glucagon-like peptide-1 (GLP-1) through the GLP-1 receptor (GLP-1R). We previously reported that a chimera protein consisting of Ex4 and mouse IgG heavy chain constant regions (Ex4/Fc) can exert biological effects of GLP-1, such as improving glycemic control and ameliorating manifestations in diabetic mice. The aim of this study was to determine whether Ex4/Fc is effective in modulating energy homeostasis in mice. Our results showed that in vivo expression of Ex4/Fc by intramuscular injection of the plasmid encoding Ex4/Fc followed by local electroporation effectively decreased food intake in the mice on high-fat diet (HFD) feeding. In addition, the reduced energy intake was associated with the decreased excrements from the Ex4/Fc-treated HFD mice but not the Fc control mice. Remarkably, the Ex4/Fctreated HFD mice displayed significantly lower triglyceride (TG) levels when compared with the control mice. Interestingly, while the leptin levels were not changed, the circulating ghrelin levels were higher in Ex4/Fc mice than those in the Fc control mice. These results suggested that Ex4/Fc can improve energy metabolism and lipid metabolism through GLP-1R in mice under excessive nutrition conditions. PMID- 24951725 TI - Secondary hypertension due to concomitant aldosterone-producing adenoma and parathyroid adenoma. AB - There is a growing body of evidence supporting a bidirectional relationship between parathyroid hormone (PTH) and aldosterone (Aldo). We report a case of secondary hypertension due to concomitant Aldo-producing adenoma (APA) and parathyroid adenoma (PA) requiring both unilateral adrenalectomy and parathyroidectomy. PMID- 24951726 TI - Expression and gene variation studies deny association of human HSD3B1 gene with aldosterone production or blood pressure. AB - BACKGROUND: Recent evidence suggests that the type I 3beta-hydroxysteroid dehydrogenase, a steroidogenic enzyme encoded by the HSD3B1 gene, could be involved in aldosterone production and that genetic variation in HSD3B1 is associated with blood pressure. These findings challenge the long-standing hypothesis that all adrenocortical steroidogenesis is executed by the type II iso enzyme, encoded by HSD3B2. METHODS: To verify these findings, the adrenal presence of HSD3B1 and its effect on aldosterone synthesis and blood pressure were studied in expression and genetic association analyses, respectively. Expression of HSD3B1 and HSD3B2 was investigated in various adrenocortical tissues (n = 15) and in primary adrenal cell cultures (n = 5) after stimulation with adrenocorticotropin and angiotensin II. Six tagging single nucleotide polymorphisms within the HSD3B1 gene were studied for association with blood pressure and hypertension in a meta-analysis of 4 Dutch cohorts (n = 11,192). RESULTS: HSD3B1 expression was minimal or absent in adrenocortical tissues, including 6 aldosterone-producing adenomas. In contrast with the ubiquitously expressed HSD3B2 mRNA, HSD3B1 levels were not stimulated by adrenocorticotropin or angiotensin II. No variants in the HSD3B1 gene were associated with blood pressure or the occurrence of hypertension. CONCLUSIONS: We found no evidence to support confirmation that HSD3B1 is involved in aldosterone synthesis in the human adrenal cortex or that genetic variation in HSD3B1 affects blood pressure or hypertension, favoring the hypothesis that all adrenocortical steroidogenesis is primarily dependent on the type II 3beta-hydroxysteroid dehydrogenase. PMID- 24951728 TI - Parallel sites implicate functional convergence of the hearing gene prestin among echolocating mammals. AB - Echolocation is a sensory system whereby certain mammals navigate and forage using sound waves, usually in environments where visibility is limited. Curiously, echolocation has evolved independently in bats and whales, which occupy entirely different environments. Based on this phenotypic convergence, recent studies identified several echolocation-related genes with parallel sites at the protein sequence level among different echolocating mammals, and among these, prestin seems the most promising. Although previous studies analyzed the evolutionary mechanism of prestin, the functional roles of the parallel sites in the evolution of mammalian echolocation are not clear. By functional assays, we show that a key parameter of prestin function, 1/alpha, is increased in all echolocating mammals and that the N7T parallel substitution accounted for this functional convergence. Moreover, another parameter, V1/2, was shifted toward the depolarization direction in a toothed whale, the bottlenose dolphin (Tursiops truncatus) and a constant-frequency (CF) bat, the Stoliczka's trident bat (Aselliscus stoliczkanus). The parallel site of I384T between toothed whales and CF bats was responsible for this functional convergence. Furthermore, the two parameters (1/alpha and V1/2) were correlated with mammalian high-frequency hearing, suggesting that the convergent changes of the prestin function in echolocating mammals may play important roles in mammalian echolocation. To our knowledge, these findings present the functional patterns of echolocation-related genes in echolocating mammals for the first time and rigorously demonstrate adaptive parallel evolution at the protein sequence level, paving the way to insights into the molecular mechanism underlying mammalian echolocation. PMID- 24951727 TI - NAD(P)H:quinone oxidoreductase 1 activation reduces blood pressure through regulation of endothelial nitric oxide synthase acetylation in spontaneously hypertensive rats. AB - BACKGROUND: Endothelial nitric oxide synthase (eNOS) is involved in blood pressure (BP) regulation through the production of nitric oxide. Sirtuin I (SIRT1), an NAD-dependent protein deacetylase, promotes vascular relaxation through deacetylation and activation of eNOS. beta-Lapachone (betaL) increases the cellular NAD(+)/NADH ratio by activating NAD(P)H: quinone oxidoreductase 1 (NQO1). In this study, we verified whether activation of NQO1 by betaL modulates BP through regulation of eNOS acetylation in a hypertensive animal model. METHODS: Spontaneously hypertensive rats (SHRs) and an endothelial cell line (bEnd.3 cells) were used to investigate the hypotensive effect of betaL and its mechanism of action. RESULTS: betaL treatment significantly lowered the BP in SHRs, but this hypotensive effect was completely blocked by eNOS inhibition with omega-nitro-l-arginine methyl ester. In vitro studies revealed that betaL activated eNOS, which was accompanied by an increased NAD(+)/NADH ratio. Moreover, betaL significantly decreased acetylation of eNOS; however, this reduced eNOS acetylation was completely precluded by inhibition of SIRT1 in the bEnd.3 cells and in the aorta of the SHRs. Consistent with these effects, betaL induced reduction in BP was also abolished by SIRT1 inhibition in the SHRs. CONCLUSIONS: To the best of our knowledge, this is the first study to demonstrate that eNOS acetylation can be regulated by NQO1 activation in an SIRT1-dependent manner, which is correlated with the relief of hypertension. These findings provide strong evidence that NQO1 might be a new therapeutic target for hypertension. PMID- 24951730 TI - Are Research Publications Original and True? PMID- 24951731 TI - Surgical Site Infection After Arthroplasty: Comparative Effectiveness of Prophylactic Antibiotics: Do Surgical Care Improvement Project Guidelines Need to Be Updated? AB - BACKGROUND: Prophylactic antibiotics decrease surgical site infection (SSI) rates, and their timing, choice, and discontinuation are measured and reported as part of the Surgical Care Improvement Project (SCIP). The aim of this study was to assess the comparative effectiveness of the SCIP-approved antibiotics for SSI prevention. METHODS: This retrospective cohort study utilized national Veterans Affairs (VA) data on patients undergoing elective hip or knee arthroplasty from 2005 to 2009. Data on prophylactic antibiotics were merged with VA Surgical Quality Improvement Program data to identify patient and procedure-related risk factors for SSI. Patients were stratified by documented penicillin allergy. Chi square and Wilcoxon rank-sum tests were used to compare SSI rates among patients receiving SCIP-approved prophylactic antibiotics. RESULTS: A total of 18,830 elective primary arthroplasties (12,823 knee and 6007 hip) were included. Most patients received prophylactic cefazolin as the sole agent (81.9%), followed by vancomycin as the sole agent (8.0%), vancomycin plus cefazolin (5.6%), and clindamycin (4.5%). Documented penicillin allergy accounted for 54.1% of cases involving vancomycin administration compared with 94.6% of cases involving clindamycin. The overall thirty-day SSI rate was 1.4%, and the unadjusted rate was 2.3% with vancomycin only, 1.5% with vancomycin plus cefazolin, 1.3% with cefazolin only, and 1.1% with clindamycin. Unadjusted analysis of penicillin allergic patients revealed an SSI rate of 2.0% with vancomycin only compared with 1.0% with clindamycin (p = 0.18). For patients without penicillin allergy, the SSI rate was 2.6% with vancomycin only compared with 1.6% with vancomycin plus cefazolin (p = 0.17) and 1.3% with cefazolin only (p < 0.01). CONCLUSIONS: Current SCIP guidelines address antibiotic timing but not antibiotic dosage. (The generally accepted recommendation for vancomycin is 15 mg/kg.) Although vancomycin is a narrower-spectrum antibiotic than either cefazolin or clindamycin, our finding of higher SSI rates following prophylaxis with vancomycin only may suggest a failure to use an appropriate dosage rather than an inequality of antibiotic effectiveness. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 24951729 TI - Functional divergence of the miRNA transcriptome at the onset of Drosophila metamorphosis. AB - MicroRNAs (miRNAs) are endogenous RNA molecules that regulate gene expression posttranscriptionally. To date, the emergence of miRNAs and their patterns of sequence evolution have been analyzed in great detail. However, the extent to which miRNA expression levels have evolved over time, the role different evolutionary forces play in shaping these changes, and whether this variation in miRNA expression can reveal the interplay between miRNAs and mRNAs remain poorly understood. This is especially true for miRNA expressed during key developmental transitions. Here, we assayed miRNA expression levels immediately before (>=18BPF [18 h before puparium formation]) and after (PF) the increase in the hormone ecdysone responsible for triggering metamorphosis. We did so in four strains of Drosophila melanogaster and two closely related species. In contrast to their sequence conservation, approximately 25% of miRNAs analyzed showed significant within-species variation in male expression levels at >=18BPF and/or PF. Additionally, approximately 33% showed modifications in their pattern of expression bias between developmental timepoints. A separate analysis of the >=18BPF and PF stages revealed that changes in miRNA abundance accumulate linearly over evolutionary time at PF but not at >=18BPF. Importantly, >=18BPF enriched miRNAs showed the greatest variation in expression levels both within and between species, so are the less likely to evolve under stabilizing selection. Functional attributes, such as expression ubiquity, appeared more tightly associated with lower levels of miRNA expression polymorphism at PF than at >=18BPF. Furthermore, >=18BPF- and PF-enriched miRNAs showed opposite patterns of covariation in expression with mRNAs, which denoted the type of regulatory relationship between miRNAs and mRNAs. Collectively, our results show contrasting patterns of functional divergence associated with miRNA expression levels during Drosophila ontogeny. PMID- 24951732 TI - Predictability of Acetabular Component Angular Change with Postural Shift from Standing to Sitting Position. AB - BACKGROUND: The angles of the acetabular component of a total hip replacement change with body postural changes, and this change can affect stability and wear. We sought to correlate the intraoperative angles of inclination and anteversion of the cup with the changes in these angles when patients moved from standing to sitting and determine if these changes were predictable. METHODS: Eighty-five patients (eighty-five hips) had sagittal (lateral) spinopelvic radiographs made while they were standing and while they were sitting before and after undergoing total hip replacement. The spinosacral tilt and the pelvic tilt were measured on these radiographs. The angles of acetabular inclination and anteversion achieved at surgery changed during sitting. Each patient was classified according to the stiffness of the spine/pelvis as measured by the change in posterior sacral or pelvic tilt between the standing and sitting positions. The magnitude of change of the sagittal cup position (termed ante-inclination) was correlated to the stiffness classification of the pelvis. An experimental phantom model reproduced possible combinations of intraoperative inclination and anteversion and correlated them to sagittal ante-inclination according to pelvic tilt. RESULTS: The pelves with normal stiffness tilted posteriorly 20 degrees to 35 degrees with the postural change from standing to sitting. Ante-inclination of the acetabular cup averaged 29.6 degrees +/- 8.4 degrees (95% confidence interval [CI] = 13.1 degrees to 46 degrees ) with standing and 54.6 degrees +/- 10.2 degrees (95% CI = 44.4 degrees to 64.8 degrees ) with sitting. The stiff pelves had a mean of 4 degrees less tilt than those with normal stiffness and 13 degrees less than the hypermobile pelves with the postoperative sitting position. The phantom model showed ante-inclination could be predicted by measuring the preoperative degrees of change in sacral/pelvic tilt from standing to sitting. CONCLUSIONS: Ante-inclination during sitting results in a more vertical acetabular cup, which can result in hip instability, especially drop-out dislocation, and edge-loading wear. Patients with supine coronal cup inclination of >=50 degrees and anteversion of >=25 degrees and those with a hypermobile pelvis are at risk. It is the pelvic spatial position during postural change that creates the postoperative consequences of the surgical cup placement. PMID- 24951733 TI - Patient-Reported Outcomes, Function, and Gait Mechanics After Fixed and Mobile Bearing Total Ankle Replacement. AB - BACKGROUND: The popularity of total ankle replacement as a treatment for end stage arthritis continues to grow. The purpose of this study was to assess changes in ankle kinetics and kinematics from a preoperative time point through two years postoperatively in patients who had received either a fixed-bearing or a mobile-bearing implant. METHODS: Ninety patients who received a primary total ankle replacement (forty-nine mobile-bearing and forty-one fixed-bearing) were examined. Three-dimensional joint mechanics and ground reaction forces were measured during level walking preoperatively and one and two years postoperatively. Patient-reported and functional outcomes were also collected. Data were analyzed with use of a 3 * 2 repeated-measures analysis of variance (ANOVA) to determine significant differences between implant types and across time (alpha = 0.05). RESULTS: No significant difference was observed in the ankle motion or step time between implant types or across time. However, there was a greater increase in the peak plantar flexion moment and the Short Form-36 (SF-36) total score across time in the fixed-bearing group than in the mobile-bearing group. Conversely, visual analog scale (VAS) pain scores exhibited greater improvement in the mobile-bearing group than in the fixed-bearing group. Independent of implant type, a significant improvement was observed in walking speed, results of the functional tests, spatiotemporal variables, patient reported outcomes, and vertical ground reaction forces. Independent of time, the fixed-bearing group demonstrated a significant increase in both the weight acceptance and the propulsion ground reaction forces compared with the mobile bearing group. The mobile-bearing group completed the Sit-to-Stand test significantly faster. CONCLUSIONS: All of the observed changes suggest improved or maintenance of function following total ankle replacement. In general, the group with a fixed-bearing implant demonstrated improvements in ankle moment and ground reaction forces, while the mobile-bearing-implant group demonstrated improvements in patient-reported pain outcome. There were few significant changes between the two implant types. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 24951734 TI - All-Polyethylene Versus Metal-Backed Tibial Components-An Analysis of 27,733 Cruciate-Retaining Total Knee Replacements from the Swedish Knee Arthroplasty Register. AB - BACKGROUND: Currently, the use of metal-backed tibial components is more common than the use of all-polyethylene components in total knee arthroplasty. However, the available literature indicates that all-polyethylene tibial components are not inferior to the metal-backed design. We hypothesized that there would be no difference in the ten-year survival rate between all-polyethylene and metal backed tibial components of a specific design in a large nationwide cohort. METHODS: In the Swedish Knee Arthroplasty Register, we identified 27,733 cruciate retaining total knee replacements using the press-fit condylar prosthesis with either metal-backed or all-polyethylene tibial components inserted from 1999 to 2011. Unadjusted survival functions were calculated with the end points of revision for any reason, revision due to infection, and revision due to reasons other than infection, and the differences between the groups were investigated with the log-rank test. Cox proportional hazard models were fitted to analyze the influence of various covariates on the adjusted relative risk of revision. RESULTS: The median duration of follow-up was 4.5 years (range, zero to 12.9 years). Of all total knee replacements, 16,896 (60.9%) were in women and 10,837 (39.1%) were in men. Metal-backed components were used in 16,011 total knee arthroplasties (57.7%) and all-polyethylene in 11,722 total knee arthroplasties (42.3%). With revision for any reason as the end point, the all-polyethylene tibial component had slightly superior, unadjusted ten-year survival compared with the metal-backed component: 97.2% (95% confidence interval [CI], 96.7% to 97.7%) compared with 96.6% (95% CI, 96.2% to 96.9%; p = 0.002). Cox multiple regression analysis adjusting for age group, sex, and patellar resurfacing showed that all-polyethylene components had a reduced risk of revision for any reason (relative risk = 0.75; 95% CI, 0.64 to 0.89) and a reduced risk of revision due to infection (relative risk = 0.63; 95% CI, 0.46 to 0.86). Patellar resurfacing and male sex increased the risk of revision due to infection (relative risk = 2.22 [95% CI, 1.37 to 3.62] and 2.21 [95% CI, 1.66 to 2.94], respectively). CONCLUSIONS: These all-polyethylene tibial components were at least as good as or superior to metal-backed tibial components with respect to implant survivorship at ten years in cruciate-retaining total knee replacements. We concluded that these less expensive all-polyethylene tibial components can be safely and effectively used in total knee arthroplasty. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 24951735 TI - Anatomic Alignment and Integrity of the Sustentaculum Tali in Intra-Articular Calcaneal Fractures: Is the Sustentaculum Tali Truly Constant? AB - BACKGROUND: In an intra-articular calcaneal fracture, the sustentaculum tali is generally thought to remain tightly bound to the talus by the interosseous talocalcaneal ligaments, spring ligament, and deltoid ligament, providing a "constant" fragment that remains anatomically aligned. The extensile lateral approach is commonly used for reduction based on this assumption, but because it provides only limited access to the medial aspect of the calcaneus, indirect fracture reduction is required to restore an anatomic relationship of these fragments to the sustentacular fragment. The purpose of this study was to determine the prevalence and displacement of sustentacular fractures in patients with an intra-articular calcaneal fracture, and thus determine whether the sustentacular fragment can be accurately considered as constant and can be consistently relied on to maintain anatomic alignment. METHODS: All patients with an intra-articular calcaneal fracture who presented to two level-I trauma centers from 2006 to 2012 were included in the study if computed tomography scanning was performed. The presence or absence of a sustentacular fracture was documented, along with the displacement and the comminution of any such fracture and the subluxation or dislocation of the sustentaculum tali. RESULTS: Sustentacular fractures were present in ninety-four (44.3%) of the 212 patients who met the inclusion criteria. Seventy-two (76.6%) of the sustentacular fractures were nondisplaced, eleven (11.7%) were displaced, and ten (10.6%) were comminuted. The articulation between the sustentaculum tali and the talus was anatomically aligned in 166 (78.3%) of the calcaneal fractures, subluxated in forty-three (20.3%), and dislocated in two (0.9%). CONCLUSIONS: This study provides a detailed description of the frequency of sustentacular fractures, the displacement of such fractures, and articular subluxation or dislocation associated with intra-articular calcaneal fractures. Fixation by means of a lateral approach may be compromised when the sustentaculum tali is fractured or subluxated. A medial approach or combined medial and lateral approaches may be considered in such circumstances. Special attention should be paid to the integrity and alignment of the sustentacular fragment prior to surgical fixation. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 24951736 TI - Effect of Cigarette Smoking on the Clinical Outcomes of ACL Reconstruction. AB - BACKGROUND: We compared the clinical outcomes of nonsmokers, current smokers, and former smokers following reconstruction of the anterior cruciate ligament (ACL) and investigated the association between the amount of smoking and outcomes following ACL reconstruction. METHODS: We retrospectively reviewed the records of 251 patients who underwent unilateral ACL reconstruction with use of bone patellar tendon-bone autograft between January 2002 and August 2009. Patients were divided into three groups according to smoking history: Group 1, nonsmokers; Group 2, current smokers; and Group 3, former smokers. Preoperative values and twenty-four-month postoperative findings were compared among the groups. The stability of the ACL was evaluated with use of the Lachman test and the pivot shift test, and anterior translation was tested with a KT2000 arthrometer. Functional outcomes were assessed on the basis of the Lysholm score and the International Knee Documentation Committee (IKDC) subjective score and objective grade. RESULTS: The three groups differed significantly in terms of postoperative knee translation, Lysholm score, and IKDC subjective score. The mean side-to-side difference in anterior translation (and standard deviation) was 2.08 +/- 1.08 mm in Group 1 (nonsmokers), 2.65 +/- 1.31 mm in Group 2 (smokers), and 2.15 +/- 1.05 mm in Group 3 (former smokers) (p = 0.003). The mean Lysholm score was 90.5 +/- 6.5 in Group 1, 86.0 +/- 7.1 in Group 2, and 89.8 +/- 6.3 in Group 3 (p < 0.001). The mean IKDC subjective score was 89.3 +/- 5.1 in Group 1, 84.9 +/- 7.5 in Group 2, and 88.5 +/- 4.2 in Group 3 (p < 0.001). However, the difference in the IKDC subjective score among the three groups did not demonstrate a minimal clinically important difference. A dose-dependent association was noted between pack-years of exposure and postoperative anterior translation (estimate, 0.039; p = 0.015) and IKDC objective grade (odds ratio, 1.083; p = 0.002). A comparison of the three subgroups of smokers showed a significant difference in anterior translation (a mean side-to-side difference in anterior translation of 2.31 +/- 1.17 mm for the light smokers, 2.60 +/- 1.14 mm for the moderate smokers, and 3.29 +/- 1.55 mm for the heavy smokers; p = 0.038). The three subgroups also differed significantly in terms of the proportion of cases by IKDC objective grade; among the light smokers, thirteen (42%) were grade A, fifteen (48%) were grade B, two (7%) were grade C, and one (3%) was grade D; among the moderate smokers, seven (35%) were grade A, eight (40%) were grade B, four (20%) were grade C, and one (5%) was grade D; and among the heavy smokers, one (6%) was grade A, eight (44%) were grade B, eight (44%) were grade C, and one (6%) was grade D (p = 0.013). CONCLUSIONS: Cigarette smoking appeared to have a negative effect on subjective and objective outcomes of ACL reconstruction, and heavy smokers showed greater knee instability. Patients who had stopped smoking at least one month prior to ACL reconstruction had no significant difference in outcomes compared with patients who had never smoked. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 24951737 TI - Revision Total Hip Arthroplasty with Retained Acetabular Component. AB - BACKGROUND: Aseptic loosening and osteolysis commonly limit the survivorship of total hip prostheses. Retention of a well-fixed acetabular component, rather than full acetabular revision, has multiple advantages, but questions have lingered regarding the clinical success and prosthetic survivorship following this procedure. We examined the impact of acetabular component position, polyethylene type, liner insertion technique, femoral head size, and simultaneous revision of the entire femoral component (as opposed to head and liner exchange) or bone grafting on mid-term to long-term prosthetic survival following such limited revisions. METHODS: One hundred hips in 100 patients with osteolysis, polyethylene wear, or femoral component loosening underwent revision total hip arthroplasty with retention of the acetabular component. Acetabular component inclination and anteversion were measured on prerevision radiographs and were categorized according to predetermined positional safe zones (inclination of 35 degrees to 55 degrees and anteversion of 5 degrees to 25 degrees ). Operative reports were reviewed for femoral head size, polyethylene liner type (conventional or highly cross-linked), liner insertion technique (use of the existing locking mechanism or cementation), whether the patient had revision of the entire femoral component, and use of bone graft. Outcomes of interest included the Harris hip score, University of California at Los Angeles (UCLA) activity score, episodes of instability, and need for repeat revision. RESULTS: At an average of 6.6 years (range, two to fourteen years) postoperatively, the Harris hip and UCLA activity scores were both significantly improved compared with the preoperative scores (p < 0.0001 and p < 0.01, respectively). Overall, the failure rate was 13%. In addition, 6% of the patients had postoperative instability. Hips in which the acetabular component was outside of the safe zone for inclination had a higher rate of failure (p = 0.048). Use of conventional, rather than highly cross-linked, polyethylene at the time of revision was also associated with an increased rate of repeat revision (p = 0.025). CONCLUSIONS: Revision total hip arthroplasty with retention of the acetabular component is associated with good outcomes in hips with an appropriately positioned, well fixed acetabular component. Acetabular components outside the safe zone for inclination were at a higher risk for failure, as was use of conventional polyethylene. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 24951738 TI - Complete Avulsion of the Proximal Hamstring Insertion: Functional Outcomes After Nonsurgical Treatment. AB - BACKGROUND: Complete proximal hamstring avulsions are an uncommon injury. The purpose of this study was to determine the functional and subjective outcomes following nonsurgical management of complete proximal hamstring avulsions. METHODS: We retrospectively identified nineteen patients (mean age, fifty-nine years; range, forty-four to seventy-three years) at one institution who presented with complete avulsions of the proximal hamstring insertion, confirmed on magnetic resonance imaging, and had nonsurgical treatment. Results on the Lower Extremity Functional Scale (LEFS) and Short Form-12 version 2 (SF-12v2) questionnaires as well as functional and isometric testing (with a handheld dynamometer) were collected. Seventeen patients completed the questionnaires. Ten patients underwent functional testing. The average follow-up period was thirty one months (range, eight to 156 months). RESULTS: The mean score on the LEFS was 70.2 of a maximum of 80 points. The mean SF-12v2 physical and mental component summary scores were 52.5 and 54.1, respectively. Hamstring strength at 45 degrees and 90 degrees of flexion was an average of 62% (p = 0.09) and 66% (p = 0.07), respectively, of that of the uninvolved limb. The single-leg hop test revealed an average decline of 2.2% (p = 0.93) compared with the uninvolved limb. Twelve of the seventeen patients were able to return to their previous sporting activities. CONCLUSIONS: Nonsurgical management after a complete proximal hamstring avulsion yields noticeable subjective and strength deficits. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 24951739 TI - The Influence of Local Bone Density on the Outcome of One Hundred and Fifty Proximal Humeral Fractures Treated with a Locking Plate. AB - BACKGROUND: There is biomechanical evidence that bone density predicts the mechanical failure of implants. The aim of this prospective study was to evaluate the influence of local bone mineral density on the rate of mechanical failure after locking plate fixation of proximal humeral fractures. METHODS: We enrolled 150 patients who were from fifty to ninety years old with a closed, displaced proximal humeral fracture fixed with use of a locking plate from July 2007 to April 2010. There were 118 women and thirty-two men who had a mean age of sixty nine years. Preoperative computed tomography (CT) scans were done to assess bone mineral density of the contralateral humerus, and dual x-ray absorptiometry of the distal end of the radius of the unaffected arm was conducted within the first six weeks postoperatively. At follow-up evaluations at six weeks, three months, and one year postoperatively, pain, shoulder mobility, strength, and multiple functional and quality-of-life outcome measures (Disabilities of the Arm, Shoulder and Hand [DASH] questionnaire; Shoulder Pain and Disability Index [SPADI]; Constant score; and EuroQuol-5D [EQ-5D]) were done and standard radiographs were made. We defined mechanical failure as all complications related to bone quality experienced within one year. RESULTS: After locking plate fixation, fifty-three (35%) of 150 patients had mechanical failure; loss of reduction and secondary screw loosening with perforation were common. CT assessments of local bone mineral density showed no difference between patients with and without mechanical failure (89.82 versus 91.51 mg/cm3, respectively; p = 0.670). One-year DASH, SPADI, and Constant scores were significantly better for patients without mechanical failure (p <= 0.05). CONCLUSIONS: We did not find evidence of an association between bone mineral density and the rate of mechanical failures, which may suggest that patients with normal bone mineral density are less prone to sustain a proximal humeral fracture. Future studies should target other discriminating factors between patients with and without mechanical failure. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 24951740 TI - Acute Rejection of Knee Joint Articular Cartilage in a Rat Composite Tissue Allotransplantation Model. AB - BACKGROUND: Osteochondral allograft transplantation is used to treat severe cartilage injury or chondral defects, with good outcomes in clinical studies. However, allograft chondrocyte death due to apoptosis may occur during storage or as a result of implantation stress. We investigated a third possible cause, chondrocyte apoptosis resulting from an immune response, by means of composite tissue allografting, thus eliminating the role of storage and implantation stresses on osteochondral grafts. METHODS: Vascularized composite tissue allotransplantation (from Fisher 344 to Lewis rat strains) and isotransplantation (from Lewis to Lewis strains) of rat hind limbs were performed. Immunohistochemistry was performed with use of caspase-3 and TUNEL (terminal deoxynucleotidyl transferase mediated dUTP nick end labeling) assays. Analyses were performed immediately after perfusion (day zero) and on postoperative days one, three, seven, twelve, and eighteen (n = 5 for immunohistochemistry). Transmission electron microscopy was used for detection of chondrocyte apoptosis. Laser capture microdissection followed by quantitative real-time polymerase chain reaction assays was used for analysis of postoperative caspase-3 gene expression. RESULTS: Caspase-3 immunochemistry was increasingly positive in allograft chondrocytes from postoperative day seven onward. In contrast, caspase-3 gene expression decreased in all allografts. TUNEL assays showed increasing apoptosis of allograft chondrocytes, and electron microscopy also revealed evidence supporting the development of apoptosis. CONCLUSIONS: Immunorejection of chondrocytes in transplanted cartilage has been thought to be unlikely, but our data reveal that chondrocytes can undergo apoptosis in allotransplantation. This apoptosis involves the caspase-3 cascade and indicates that chondrocytes may induce acute rejection. PMID- 24951741 TI - Metal-Backed Glenoid Components Have a Higher Rate of Failure and Fail by Different Modes in Comparison with All-Polyethylene Components: A Systematic Review. AB - BACKGROUND: Glenoid component failure is a common and serious complication of total shoulder arthroplasty. The purpose of this study was to evaluate published evidence on whether metal backing lessens the rate of glenoid component failure. METHODS: A comprehensive systematic review yielded twenty-one studies on radiolucency, radiographic failure, and revision after arthroplasty with metal backed glenoid components and twenty-three studies with all-polyethylene components. Our analysis included data on 1571 metal-backed and 3035 all polyethylene components. The mean duration of follow-up was 5.8 years in the studies with metal-backed components and 7.3 years with all-polyethylene components. RESULTS: All-polyethylene components had a 42.5% rate of radiolucency compared with 34.9% for metal-backed components (p = 0.0026) and a 21.1% rate of radiographic loosening or failure compared with 16.8% for metal-backed components (p = 0.0005). However, the rate of revision was more than three times higher with metal-backed components (14.0%) than with all-polyethylene components (3.8%, p < 0.0001). Although 77% of the revisions of all-polyethylene components were for loosening, 62% of the revisions of metal-backed components were for other reasons, such as component fracture, screw breakage, component dissociation, polyethylene wear, metal wear, and rotator cuff tear (p < 0.0001). CONCLUSIONS: The published evidence indicates that metal-backed glenoid components require revision at a significantly higher rate and for different reasons in comparison with all-polyethylene components. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 24951742 TI - What's New in Spine Surgery. PMID- 24951743 TI - Normal Health-Related Quality of Life and Ability to Work Twenty-nine Years After in Situ Arthrodesis for High-Grade Isthmic Spondylolisthesis. AB - BACKGROUND: The purpose of this mixed prospective and retrospective case series was to evaluate the long-term health-related quality of life and physical disability after in situ arthrodesis for high-grade isthmic spondylolisthesis. METHODS: Thirty-five of forty consecutive patients who had in situ spinal arthrodesis for high-grade isthmic spondylolisthesis at a mean age of fifteen years (range, nine to twenty-five years) completed validated questionnaires (Short Form-36 [SF-36], EuroQol-5 Dimensions [EQ-5D], Zung depression scale, Oswestry disability index [ODI], Million score, and back and leg pain visual analog scale [VAS]) and underwent physical examination twenty-nine years (range, twenty-three to thirty-five years) after surgery. The mean age at the time of follow-up was forty-three years (range, thirty-seven to fifty-one years). In the absence of a formal control group, the scores on the SF-36 and EQ-5D were compared with Swedish normative data. The proportion of patients at work was compared with an age-matched control group derived from official statistics of Sweden. The Million score at the long-term follow-up was compared with the corresponding results at the mid-term follow-up of the same patients at a mean age of twenty-two years. RESULTS: The scores on the SF-36 and EQ-5D were similar to the scores of the general Swedish population. The mean Zung depression scale score was 30 (range, 20 to 52), the mean ODI score was 10 (range, 0 to 34), the mean back pain VAS score was 13 (range, 0 to 72), and the mean leg pain VAS score was 9 (range, 0 to 60). The Million score averaged 28 (range, 0 to 109) and was slightly worsened compared with the score of 19 (range, 0 to 94) at the mid-term follow-up (p = 0.034). The proportion of patients at work was the same as that for the age-matched general Swedish population. CONCLUSIONS: Our study shows good outcomes in health-related quality of life, disability, pain, and ability to work at up to twenty-nine years after in situ lumbar spine arthrodesis for high-grade isthmic spondylolisthesis. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 24951744 TI - How Frequently Do Four Methods for Mechanically Aligning a Total Knee Arthroplasty Cause Collateral Ligament Imbalance and Change Alignment from Normal in White Patients? AAOS Exhibit Selection. AB - BACKGROUND: Mechanically aligned total knee arthroplasty can create a tight collateral ligament in 0 degrees of extension, instability in a compartment between 0 degrees of extension and 90 degrees of flexion that is uncorrectable by collateral ligament release, and changes in limb and knee alignment from normal. The goal of the present study was to calculate the frequency and range of these undesirable consequences. METHODS: Four methods of mechanically aligned total knee arthroplasty were simulated on fifty normal three-dimensional bone models of the lower extremity from white subjects. Each method resected the distal aspect of the femur and proximal aspect of the tibia perpendicular to their respective mechanical axes. Setting the posterior joint line perpendicular to the anteroposterior axis of the trochlear groove (Method 1), parallel to the transepicondylar axis (Method 2), externally rotated 3 degrees with respect to the posterior condylar axis (Method 3), and parallel to the tibial resection in 90 degrees of flexion with the use of gap-balancing (Method 4) aligned internal external rotation of the femoral component. RESULTS: The proportion of total knee arthroplasties requiring a >=2-mm release of a tight collateral ligament was 34% for the medial collateral ligament and 30% for the lateral collateral ligament. The proportion of total knee arthroplasties with >=2 mm of instability between 0 degrees of extension and 90 degrees of flexion was 56% in the medial compartment and 6% in the lateral compartment for Method 1, 74% and 6% for Method 2, and 42% and 0% for Method 3. Method 4 did not cause ligamentous instability. The proportion of arthroplasties with a >=2 degrees change from normal was 58% for limb alignment and 58% for knee alignment. CONCLUSIONS: Surgeons should be aware that, when using the four methods of mechanically aligning a total knee arthroplasty, they will frequently have to manage a wide range of collateral ligament imbalances that are complex, cumulative, and uncorrectable by collateral ligament release, and a wide range of changes in limb and knee alignment from normal. Patients who perceive these changes in stability, limb alignment, and knee alignment may be dissatisfied and require counseling. PMID- 24951745 TI - Georg Hohmann: A Life Dedicated to Innovation and Academia in Very Difficult Times. PMID- 24951746 TI - What Do the SCIP Guidelines "SKIP"? Commentary on an article by Brent Ponce, MD, et al.: "Surgical Site Infection After Arthroplasty: Comparative Effectiveness of Prophylactic Antibiotics. Do Surgical Care Improvement Project Guidelines Need to Be Updated?" PMID- 24951747 TI - The Challenges of Leaning Forward: Commentary on an article by Vaibhav Kanawade, MD, et al.: "Predictability of Acetabular Component Angular Change with Postural Shift from Standing to Sitting Position". PMID- 24951748 TI - How Much Do We Know About Total Ankle Arthroplasty in 2014? Commentary on an article by Robin M. Queen, PhD, et al.: "Patient-Reported Outcomes, Function, and Gait Mechanics After Fixed and Mobile-Bearing Total Ankle Replacement". PMID- 24951749 TI - Qualitative and Quantitative Anatomic Investigation of the Lateral Ankle Ligaments for Surgical Reconstruction Procedures. AB - BACKGROUND: Lateral ankle sprains are common sports injuries that may require surgery for chronic lateral ankle instability. Anatomic repair or reconstruction is desired, yet there is a scarcity of quantitative information regarding the origins and insertions of the lateral ligaments related to surgically pertinent osseous landmarks. METHODS: Fourteen ankle specimens were dissected to isolate the anterior talofibular ligament, calcaneofibular ligament, posterior talofibular ligament, and cervical ligament. A three-dimensional coordinate measurement device was used to determine the origins, insertions, footprint areas, orientations, and distances from osseous landmarks. RESULTS: A single banded anterior talofibular ligament was identified in seven of the fourteen specimens, and a double-banded anterior talofibular ligament was identified in the remaining seven. The single-banded anterior talofibular ligament originated an average of 13.8 mm (95% confidence interval [CI], 12.3 to 15.3) from the inferior tip of the lateral malleolus at the anterior fibular border and inserted an average of 17.8 mm (95% CI, 16.3 to 19.3) superior to the apex of the lateral talar process along the anterior border of the talar lateral articular facet. The calcaneofibular ligament originated an average of 5.3 mm (95% CI, 4.2 to 6.5) from the inferior tip of the lateral malleolus at the anterior fibular border and inserted an average of 16.3 mm (95% CI, 14.5 to 18.1) from the posterior point of the peroneal tubercle. The posterior talofibular ligament was the largest ligament and originated an average of 4.8 mm (95% CI, 3.7 to 5.9) superior to the inferior tip of the lateral malleolus in the digital fossa to insert an average of 13.2 mm (95% CI, 11.5 to 14.9) from the talar posterolateral tubercle. The cervical ligament originated on the superior part of the calcaneus and inserted at a point that was approximately 50% of the talar neck anteroposterior distance. CONCLUSIONS: Consistent distances from the anterior talofibular ligament, calcaneofibular ligament, posterior talofibular ligament, and cervical ligament footprint centers to osseous landmarks were identified. CLINICAL RELEVANCE: Footprint center distances from surgically relevant osseous landmarks identified in this study can be used during reconstructive surgery of the lateral ankle ligaments and may result in more anatomically accurate placement of the reconstructed ligaments. PMID- 24951750 TI - A Comparison of Various Contemporary Methods to Prevent a Wet Cast. AB - BACKGROUND: Many traditional methods and commercially available products are available to prevent a wet cast, although there is a paucity of literature regarding the optimal strategy. METHODS: Using a synthetic leg model, a short leg cast was applied and six different methods were tested. Group A (Glad Press'n Seal wrap), Group B (plastic bag with rubber band), Group C (plastic bag with duct tape), Group D (double plastic bags with duct tape), Group E (CVS Pharmacy Reusable Cast & Wound Protector), and Group F (Dry Corp Dry Pro Large Half Leg Waterproof Cast Cover). Casts were submerged in water for two minutes and were weighed. Each group had ten individual trials. Effectiveness was measured by calculating the amount of water absorption using cast weights before and after submersion. RESULTS: The percentage of water absorption prevention ranged from 62% to 100%, with Groups A and B being the least effective and Groups D, E, and F being the most effective. There was considerable variation in the simplicity of use. Groups C, D, and E were found to be simple to use, with increasing difficulty in Groups A, B, and F. CONCLUSIONS: Our findings conclude that the six methods tested are effective in preventing the majority of water saturation. Although abstaining from contact with water is the most prudent approach, if a cast cover is to be used, double plastic bags with duct tape (100% prevention, $10) and the CVS cast protector (100% prevention, $13) are the preferred contemporary methods to prevent a wet cast. PMID- 24951751 TI - Variable t-tubule organization and Ca2+ homeostasis across the atria. AB - Although t-tubules have traditionally been thought to be absent in atrial cardiomyocytes, recent studies have suggested that t-tubules exist in the atria of large mammals. However, it is unclear whether regional differences in t-tubule organization exist that define cardiomyocyte function across the atria. We sought to investigate regional t-tubule density in pig and rat atria and the consequences for cardiomyocyte Ca(2+) homeostasis. We observed t-tubules in approximately one-third of rat atrial cardiomyocytes, in both tissue cryosections and isolated cardiomyocytes. In a minority (~10%) of atrial cardiomyocytes, the t tubular network was well organized, with a transverse structure resembling that of ventricular cardiomyocytes. In both rat and pig atrial tissue, we observed higher t-tubule density in the epicardium than in the endocardium. Consistent with high variability in the distribution of t-tubules and Ca(2+) channels among cells, L-type Ca(2+) current amplitude was also highly variable and steeply dependent on capacitance and t-tubule density. Accordingly, Ca(2+) transients showed great variability in Ca(2+) release synchrony. Simultaneous imaging of the cell membrane and Ca(2+) transients confirmed t-tubule functionality. Results from mathematical modeling indicated that a transmural gradient in t-tubule organization and Ca(2+) release kinetics supports synchronization of contraction across the atrial wall and may underlie transmural differences in the refractory period. In conclusion, our results indicate that t-tubule density is highly variable across the atria. We propose that higher t-tubule density in cells localized in the epicardium may promote synchronization of contraction across the atrial wall. PMID- 24951752 TI - Age, aerobic fitness, and cerebral perfusion during exercise: role of carbon dioxide. AB - Middle cerebral artery mean velocity (MCAvmean) is attenuated with increasing age both at rest and during exercise. The aim of this study was to determine the influence of the age-dependent reduction in arterial Pco2 (PaCO2) and physical fitness herein. We administered supplemental CO2 (CO2 trial) or no additional gas (control trial) to the inspired air in a blinded and randomized manner, and assessed middle cerebral artery mean flow velocity during graded exercise in 1) 21 young [Y; age 24 +/- 3 yr (+/-SD)] volunteers of whom 11 were trained (YT) and 10 considered untrained (YUT), and 2) 17 old (O; 66 +/- 4 yr) volunteers of whom 8 and 9 were considered trained (OT) and untrained (OUT), respectively. A resting hypercapnic reactivity test was also performed. MCAvmean and PaCO2 were lower in O [44.9 +/- 3.1 cm/s and 30 +/- 1 mmHg (+/-SE)] compared with Y (59.3 +/- 2.3 cm/s and 34 +/- 1 mmHg, P < 0.01) at rest, independent of aerobic fitness level. The age-related decreases in MCAvmean and PaCO2 persisted during exercise. Supplemental CO2 reduced the age-associated decline in MCAvmean by 50%, suggesting that PaCO2 is a major component in the decline. On the other hand, relative hypercapnic reactivity was neither influenced by age (P = 0.46) nor aerobic fitness (P = 0.36). Although supplemental CO2 attenuated exercise-induced reduction in cerebral oxygenation (near-infrared spectroscopy), this did not influence exercise performance. In conclusion, PaCO2 contributes to the age associated decline in MCAvmean at rest and during exercise; however exercise capacity did not diminish this age effect. PMID- 24951754 TI - Tongxinluo inhibits vascular inflammation and neointimal hyperplasia through blockade of the positive feedback loop between miR-155 and TNF-alpha. AB - Tongxinluo (TXL), a traditional Chinese medicine, has multiple vasoprotective effects, including anti-inflammation. MicroRNA-155 (miR-155) is involved in vascular inflammation and atherosclerosis. However, a direct relationship between TXL and miR-155 in the development of vascular inflammation and remodeling had not yet been shown. The objective of the present study was to investigate whether TXL exerts an inhibitory effect on the vascular inflammatory response and neointimal hyperplasia by regulating miR-155 expression. Using the carotid artery ligation model in mice, we have shown that TXL dose dependently inhibited neointimal formation and reduced the vascular inflammatory response by inhibiting inflammatory cytokine production and macrophage infiltration. miR-155 was induced by carotid artery ligation, and neointimal hyperplasia was strongly reduced in miR-155(-/-) mice. In contrast, miR-155 overexpression partly reversed the inhibitory effect of TXL on neointimal hyperplasia. In bone marrow-derived macrophages, miR-155 and TNF-alpha formed a positive feedback loop to promote the inflammatory response, which could be blocked by TXL. Furthermore, TXL increased Akt1 protein expression and phosphorylation in TNF-alpha-stimulated marrow derived macrophages, and knockdown of Akt1 abrogated the TXL-induced suppression of miR-155. In conclusion, TXL inhibits the vascular inflammatory response and neointimal hyperplasia induced by carotid artery ligation in mice. Suppression of miR-155 expression mediated by Akt1 and blockade of the feedback loop between miR 155 and TNF-alpha are important pathways whereby TXL exerts its vasoprotective effects. PMID- 24951753 TI - Sex differences with aging in nutritive skeletal muscle blood flow: impact of exercise training, nitric oxide, and alpha-adrenergic-mediated mechanisms. AB - The incidence of cardiovascular disease increases progressively with age, but aging may affect men and women differently. Age-associated changes in vascular structure and function may manifest in impaired nutritive blood flow, although the regulation of nutritive blood flow in healthy aging is not well understood. The purpose of this study was to determine if nitric oxide (NO)-mediated or alpha adrenergic-mediated regulation of nutritive skeletal muscle blood flow is impaired with advanced age, and if exercise training improves age-related deficiencies. Nutritive blood flow was monitored in the vastus lateralis of healthy young and aged men and women via the microdialysis-ethanol technique prior to and following seven consecutive days of exercise training. NO-mediated and alpha-adrenergic-mediated regulation of nutritive blood flow was assessed by microdialysis perfusion of acetylcholine, sodium nitroprusside, N(G)-monomethyl-L arginine, norepinephrine, or phentolamine. Pretraining nutritive blood flow was attenuated in aged compared with young women (7.39 +/- 1.5 vs. 15.5 +/- 1.9 ml.100 g(-1).min(-1), P = 0.018), but not aged men (aged 13.5 +/- 3.7 vs. young 9.4 +/- 1.3 ml.100 g(-1).min(-1), P = 0.747). There were no age-associated differences in NO-mediated or alpha-adrenergic-mediated nutritive blood flow. Exercise training increased resting nutritive blood flow only in young men (9.4 +/- 1.3 vs. 19.7 ml.100 g(-1).min(-1), P = 0.005). The vasodilatory effect of phentolamine was significantly reduced following exercise training only in young men (12.3 +/- 6.14 vs. -3.68 +/- 3.26 ml.100 g(-1).min(-1), P = 0.048). In conclusion, the age-associated attenuation of resting nutritive skeletal muscle blood flow was specific to women, while the exercise-induced alleviation of alpha adrenergic mediated vasoconstriction that was specific to young men suggests an age-associated modulation of the sympathetic response to exercise training. PMID- 24951755 TI - PKC-mediated toxicity of elevated glucose concentration on cardiomyocyte function. AB - While it is well established that mortality risk after myocardial infarction (MI) increases in proportion to blood glucose concentration at the time of admission, it is unclear whether there is a direct, causal relationship. We investigated potential mechanisms by which increased blood glucose may exert cardiotoxicity. Using a Wistar rat or guinea-pig isolated cardiomyocyte model, we investigated the effects on cardiomyocyte function and electrical stability of alterations in extracellular glucose concentration. Contractile function studies using electric field stimulation (EFS), patch-clamp recording, and Ca2+ imaging were used to determine the effects of increased extracellular glucose concentration on cardiomyocyte function. Increasing glucose from 5 to 20 mM caused prolongation of the action potential and increased both basal Ca2+ and variability of the Ca2+ transient amplitude. Elevated extracellular glucose concentration also attenuated the protection afforded by ischemic preconditioning (IPC), as assessed using a simulated ischemia and reperfusion model. Inhibition of PKCalpha and beta, using Go6976 or specific inhibitor peptides, attenuated the detrimental effects of glucose and restored the cardioprotected phenotype to IPC cells. Increased glucose concentration did not attenuate the cardioprotective role of PKCepsilon, but rather activation of PKCalpha and beta masked its beneficial effect. Elevated extracellular glucose concentration exerts acute cardiotoxicity mediated via PKCalpha and beta. Inhibition of these PKC isoenzymes abolishes the cardiotoxic effects and restores IPC-mediated cardioprotection. These data support a direct link between hyperglycemia and adverse outcome after MI. Cardiac-specific PKCalpha and beta inhibition may be of clinical benefit in this setting. PMID- 24951756 TI - The atypical structure and function of newborn arterial endothelium is mediated by Rho/Rho kinase signaling. AB - Endothelium of fetal or newborn arteries is atypical, displaying actin stress fibers and reduced nitric oxide (NO)-mediated dilatation. This study tested the hypothesis that Rho/Rho kinase signaling, which promotes endothelial stress fibers and inhibits endothelial dilatation, contributed to this phenotype. Carotid arteries were isolated from newborn [postnatal day 1 (P1)], P7, and P21 mice. Endothelial dilatation to acetylcholine (pressure myograph) was minimal at P1, increased at P7, and further increased at P21. Inhibition of Rho (C3 transferase) or Rho kinase (Y27632, fasudil) significantly increased dilatation to acetylcholine in P1 arteries but had no effect in P7 or P21 arteries. After inhibition of NO synthase (N(G)-nitro-l-arginine methyl ester), Rho kinase inhibition no longer increased acetylcholine responses in P1 arteries. Rho kinase inhibition did not affect dilatation to the NO donor DEA-NONOate. The endothelial actin cytoskeleton was labeled with phalloidin and visualized by laser-scanning microscopy. In P1 arteries, the endothelium had prominent transcytoplasmic stress fibers, whereas in P7 and P21 arteries, the actin fibers had a significantly reduced intensity and were restricted to cell borders. Phosphorylation of myosin light chains, a Rho kinase substrate, was highest in P1 endothelium and significantly reduced in P7 and P21 endothelium (laser-scanning microscopy). In P1 arteries, inhibition of Rho (C3 transferase) or Rho kinase (Y27632) significantly reduced the intensity of actin fibers, which were restricted to cell borders. Similarly, in P1 arteries, Rho inhibition significantly reduced endothelial levels of phosphorylated myosin light chains. These results indicate that the atypical function and morphology of newborn endothelium is mediated by Rho/Rho kinase signaling. PMID- 24951757 TI - MicroRNA-management of lipoprotein homeostasis. PMID- 24951758 TI - Regulating repair: regulatory T cells in myocardial infarction. PMID- 24951761 TI - Pulmonary arterial hypertension: yesterday, today, tomorrow. PMID- 24951759 TI - Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. AB - The clinical syndrome comprising heart failure (HF) symptoms but with a left ventricular ejection fraction (EF) that is not diminished, eg, HF with preserved EF, is increasingly the predominant form of HF in the developed world, and soon to reach epidemic proportions. It remains among the most challenging of clinical syndromes for the practicing clinician and scientist alike, with a multitude of proposed mechanisms involving the heart and other organs and complex interplay with common comorbidities. Importantly, its morbidity and mortality are on par with HF with reduced EF, and as the list of failed treatments continues to grow, HF with preserved EF clearly represents a major unmet medical need. The field is greatly in need of a more unified approach to its definition and view of the syndrome that engages integrative and reserve pathophysiology beyond that related to the heart alone. We need to reflect on prior treatment failures and the message this is providing, and redirect our approaches likely with a paradigm shift in how the disease is viewed. Success will require interactions between clinicians, translational researchers, and basic physiologists. Here, we review recent translational and clinical research into HF with preserved EF and give perspectives on its evolving demographics and epidemiology, the role of multiorgan deficiencies, potential mechanisms that involve the heart and other organs, clinical trials, and future directions. PMID- 24951760 TI - Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium. AB - Age-related diastolic dysfunction is a major factor in the epidemic of heart failure. In patients hospitalized with heart failure, HFpEF is now as common as heart failure with reduced ejection fraction. We now have many successful treatments for heart failure with reduced ejection fraction, while specific treatment options for HFpEF patients remain elusive. The lack of treatments for HFpEF reflects our very incomplete understanding of this constellation of diseases. There are many pathophysiological factors in HFpEF, but aging appears to play an important role. Here, we propose that aging of the myocardium is itself a specific pathophysiological process. New insights into the aging heart, including hormonal controls and specific molecular pathways, such as microRNAs, are pointing to myocardial aging as a potentially reversible process. While the overall process of aging remains mysterious, understanding the molecular pathways of myocardial aging has never been more important. Unraveling these pathways could lead to new therapies for the enormous and growing problem of HFpEF. PMID- 24951762 TI - Pulmonary arterial hypertension: the clinical syndrome. AB - Pulmonary arterial hypertension is a progressive disorder in which endothelial dysfunction and vascular remodeling obstruct small pulmonary arteries, resulting in increased pulmonary vascular resistance and pulmonary pressures. This leads to reduced cardiac output, right heart failure, and ultimately death. In this review, we attempt to answer some important questions commonly asked by patients diagnosed with pulmonary arterial hypertension pertaining to the disease, and aim to provide an explanation in terms of classification, diagnosis, pathophysiology, genetic causes, demographics, and prognostic factors. Furthermore, important molecular pathways that are central to the pathogenesis of pulmonary arterial hypertension are reviewed, including nitric oxide, prostacyclin, endothelin-1, reactive oxygen species, and endothelial and smooth muscle proliferation. PMID- 24951764 TI - The metabolic theory of pulmonary arterial hypertension. AB - Numerous molecular abnormalities have been described in pulmonary arterial hypertension (PAH), complicating the translation of candidate therapies to patients because, typically, 1 treatment addresses only 1 abnormality. The realization that in addition to pulmonary artery vascular cells, other tissues and cells are involved in the syndrome of PAH (eg, immune cells, right ventricular cardiomyocytes, skeletal muscle) further complicates the identification of optimal therapeutic targets. Here, we describe a metabolic theory that proposes that many apparently unrelated molecular abnormalities in PAH do have a common denominator; they either cause or promote a mitochondrial suppression (inhibition of glucose oxidation) in pulmonary vascular cells; in turn, the signaling downstream from this mitochondrial suppression can also explain numerous molecular events previously not connected. This integration of signals upstream and downstream of mitochondria has similarities to cancer and can explain many features of the PAH vascular phenotype, including proliferation and apoptosis resistance. This suppression of glucose oxidation (with secondary upregulation of glycolysis) also underlies the abnormalities in extrapulmonary tissues, suggesting a global metabolic disturbance. The metabolic theory places mitochondria at the center stage for our understanding of PAH pathogenesis and for the development of novel diagnostic and therapeutic tools. Current PAH therapies are each addressing 1 abnormality (eg, upregulation of endothelin-1) and were not developed specifically for PAH but for systemic vascular diseases. Compared with the available therapies, mitochondria-targeting therapies have the advantage of addressing multiple molecular abnormalities simultaneously (thus being potentially more effective) and achieving higher specificity because they address PAH-specific biology. PMID- 24951763 TI - Current clinical management of pulmonary arterial hypertension. AB - During the past 2 decades, there has been a tremendous evolution in the evaluation and care of patients with pulmonary arterial hypertension (PAH). The introduction of targeted PAH therapy consisting of prostacyclin and its analogs, endothelin antagonists, phosphodiesterase-5 inhibitors, and now a soluble guanylate cyclase activator have increased therapeutic options and potentially reduced morbidity and mortality; yet, none of the current therapies have been curative. Current clinical management of PAH has become more complex given the focus on early diagnosis, an increased number of available therapeutics within each mechanistic class, and the emergence of clinically challenging scenarios such as perioperative care. Efforts to standardize the clinical care of patients with PAH have led to the formation of multidisciplinary PAH tertiary care programs that strive to offer medical care based on peer-reviewed evidence-based, and expert consensus guidelines. Furthermore, these tertiary PAH centers often support clinical and basic science research programs to gain novel insights into the pathogenesis of PAH with the goal to improve the clinical management of this devastating disease. In this article, we discuss the clinical approach and management of PAH from the perspective of a single US-based academic institution. We provide an overview of currently available clinical guidelines and offer some insight into how we approach current controversies in clinical management of certain patient subsets. We conclude with an overview of our program structure and a perspective on research and the role of a tertiary PAH center in contributing new knowledge to the field. PMID- 24951768 TI - Letter by Stone et al regarding article, "perspective on the 2013 American Heart Association/American College of Cardiology guideline for the use of statins in primary prevention of low-risk individuals". PMID- 24951765 TI - Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. AB - This review summarizes an expanding body of knowledge indicating that failure to resolve inflammation and altered immune processes underlie the development of pulmonary arterial hypertension. The chemokines and cytokines implicated in pulmonary arterial hypertension that could form a biomarker platform are discussed. Pre-clinical studies that provide the basis for dysregulated immunity in animal models of the disease are reviewed. In addition, we present therapies that target inflammatory/immune mechanisms that are currently enrolling patients, and discuss others in development. We show how genetic and metabolic abnormalities are inextricably linked to dysregulated immunity and adverse remodeling in the pulmonary arteries. PMID- 24951769 TI - Clearance of plasma proprotein convertase subtilisin/kexin 9 by low-density lipoprotein apheresis. PMID- 24951766 TI - The right ventricle in pulmonary arterial hypertension: disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure. AB - The right ventricle (RV) is the major determinant of functional state and prognosis in pulmonary arterial hypertension. RV hypertrophy (RVH) triggered by pressure overload is initially compensatory but often leads to RV failure. Despite similar RV afterload and mass some patients develop adaptive RVH (concentric with retained RV function), while others develop maladaptive RVH, characterized by dilatation, fibrosis, and RV failure. The differentiation of adaptive versus maladaptive RVH is imprecise, but adaptive RVH is associated with better functional capacity and survival. At the molecular level, maladaptive RVH displays greater impairment of angiogenesis, adrenergic signaling, and metabolism than adaptive RVH, and these derangements often involve the left ventricle. Clinically, maladaptive RVH is characterized by increased N-terminal pro-brain natriuretic peptide levels, troponin release, elevated catecholamine levels, RV dilatation, and late gadolinium enhancement on MRI, increased (18)fluorodeoxyglucose uptake on positron emission tomography, and QTc prolongation on the ECG. In maladaptive RVH there is reduced inotrope responsiveness because of G-protein receptor kinase-mediated downregulation, desensitization, and uncoupling of beta-adrenoreceptors. RV ischemia may result from capillary rarefaction or decreased right coronary artery perfusion pressure. Maladaptive RVH shares metabolic abnormalities with cancer including aerobic glycolysis (resulting from a forkhead box protein O1-mediated transcriptional upregulation of pyruvate dehydrogenase kinase), and glutaminolysis (reflecting ischemia-induced cMyc activation). Augmentation of glucose oxidation is beneficial in experimental RVH and can be achieved by inhibition of pyruvate dehydrogenase kinase, fatty acid oxidation, or glutaminolysis. Therapeutic targets in RV failure include chamber-specific abnormalities of metabolism, angiogenesis, adrenergic signaling, and phosphodiesterase-5 expression. The ability to restore RV function in experimental models challenges the dogma that RV failure is irreversible without regression of pulmonary vascular disease. PMID- 24951770 TI - Response to Duell et al. PMID- 24951767 TI - The genetics of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a progressive and fatal disease for which there is an ever-expanding body of genetic and related pathophysiological information on disease pathogenesis. Many germline gene mutations have now been described, including mutations in the gene coding bone morphogenic protein receptor type 2 (BMPR2) and related genes. Recent advanced gene-sequencing methods have facilitated the discovery of additional genes with mutations among those with and those without familial forms of PAH (CAV1, KCNK3, EIF2AK4). The reduced penetrance, variable expressivity, and female predominance of PAH suggest that genetic, genomic, and other factors modify disease expression. These multi faceted variations are an active area of investigation in the field, including but not limited to common genetic variants and epigenetic processes, and may provide novel opportunities for pharmacological intervention in the near future. They also highlight the need for a systems-oriented multi-level approach to incorporate the multitude of biological variations now associated with PAH. Ultimately, an in-depth understanding of the genetic factors relevant to PAH provides the opportunity for improved patient and family counseling about this devastating disease. PMID- 24951773 TI - An integrative analysis of the tumorigenic role of TAZ in human non-small cell lung cancer. AB - PURPOSE: TAZ, also known as WWTR1, has recently been suggested as an oncogene in non-small cell lung cancer (NSCLC). We investigated the clinical relevance of TAZ expression and its functional role in NSCLC tumorigenesis. EXPERIMENTAL DESIGN: We characterized TAZ at the DNA (n=192), mRNA (n=196), and protein levels (n=345) in an NSCLC patient cohort. Gene expression analysis was complemented by a meta analysis of public datasets (n=1,382). The effects of TAZ on cell proliferation and cell cycle were analyzed in cell cultures and on tumor growth in mice. TAZ dependent microarray-based expression profiles in NSCLC cells were combined with molecular profiles in human NSCLC tissues for in silico analysis. RESULTS: Higher TAZ mRNA and protein levels were associated with shorter patient survival. Transduction of TAZ enhanced cell proliferation and tumorigenesis in bronchial epithelial cells, whereas TAZ silencing suppressed cell proliferation and induced cell cycle arrest in NSCLC cells. Microarray and cell culture experiments showed that ErbB ligands (amphiregulin, epiregulin, and neuregulin 1) are downstream targets of TAZ. Our in silico analysis revealed a TAZ signature that substantiated the clinical impact of TAZ and confirmed its relationship to the epidermal growth factor receptor signaling pathway. CONCLUSION: TAZ expression defines a clinically distinct subgroup of patients with NSCLC. ErbB ligands are suggested to mediate the effects of TAZ on lung cancer progression. Our findings emphasize the tumorigenic role of TAZ and may serve as the basis for new treatment strategies. PMID- 24951771 TI - Are hemodynamics surrogate end points in pulmonary arterial hypertension? AB - BACKGROUND: Although frequently assessed in trials and clinical practice, hemodynamic response to therapy has never been validated as a surrogate end point for clinical events in pulmonary arterial hypertension (PAH). METHODS AND RESULTS: We performed a patient-level pooled analysis of 4 randomized, placebo controlled trials to determine whether treatment-induced changes in hemodynamic values at 12 weeks accounted for the relationship between treatment assignment and the probability of early clinical events (death, lung transplantation, atrial septostomy, PAH hospitalization, withdrawal for clinical worsening, or escalation in PAH therapy). We included 1119 subjects with PAH. The median (interquartile range) age was 48 years (37-59 years), and 23% were men. A total of 656 patients (59%) received active therapy (101 [15%] iloprost, 118 [18%] sitaxsentan, 204 [31%] sildenafil, and 233 [36%] subcutaneous treprostinil). Active treatment significantly lowered right atrial pressure, mean pulmonary artery pressure, and pulmonary vascular resistance and increased cardiac output and index (P<0.01 for all). Changes in hemodynamic values (except for right atrial pressure and mean pulmonary artery pressure) were significantly associated with the risk of a clinical event (P<0.02 for all). Although active treatment approximately halved the odds of a clinical event compared with placebo (P<0.001), changes in hemodynamics accounted for only 1.2% to 13.9% of the overall treatment effect. CONCLUSIONS: Treatment-induced changes in hemodynamics at 12 weeks only partially explain the impact of therapy on the probability of early clinical events in PAH. These findings suggest that resting hemodynamics are not valid surrogate end points for short-term events in PAH clinical trials. PMID- 24951772 TI - Dual-contrast molecular imaging allows noninvasive characterization of myocardial ischemia/reperfusion injury after coronary vessel occlusion in mice by magnetic resonance imaging. AB - BACKGROUND: Inflammation and myocardial necrosis play important roles in ischemia/reperfusion injury after coronary artery occlusion and recanalization. The detection of inflammatory activity and the extent of myocardial necrosis itself are of great clinical and prognostic interest. We developed a dual, noninvasive imaging approach using molecular magnetic resonance imaging in an in vivo mouse model of myocardial ischemia and reperfusion. METHODS AND RESULTS: Ischemia/reperfusion injury was induced in 10-week-old C57BL/6N mice by temporary ligation of the left anterior descending coronary artery. Activated platelets were targeted with a contrast agent consisting of microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody directed against a ligand-induced binding site (LIBS) on activated glycoprotein IIb/IIIa (LIBS-MPIOs). After injection and imaging of LIBS-MPIOs, late gadolinium enhancement was used to depict myocardial necrosis; these imaging experiments were also performed in P2Y12 (-/-) mice. All imaging results were correlated to immunohistochemistry findings. Activated platelets were detectable by magnetic resonance imaging via a significant signal effect caused by LIBS-MPIOs in the area of left anterior descending coronary artery occlusion 2 hours after reperfusion. In parallel, late gadolinium enhancement identified the extent of myocardial necrosis. Immunohistochemistry confirmed that LIBS-MPIOs bound significantly to microthrombi in reperfused myocardium. Only background binding was found in P2Y12 (-/-) mice. CONCLUSIONS: Dual molecular imaging of myocardial ischemia/reperfusion injury allows characterization of platelet-driven inflammation by LIBS-MPIOs and myocardial necrosis by late gadolinium enhancement. This noninvasive imaging strategy is of clinical interest for both diagnostic and prognostic purposes and highlights the potential of molecular magnetic resonance imaging for characterizing ischemia/reperfusion injury. PMID- 24951774 TI - Severity of neonatal hyperoxia determines structural and functional changes in developing mouse airway. AB - Wheezing is a major long-term respiratory morbidity in preterm infants with and without bronchopulmonary dysplasia. We hypothesized that mild vs. severe hyperoxic exposure in neonatal mice differentially affects airway smooth muscle hypertrophy and resultant airway reactivity. Newborn mice were exposed to 7 days of mild (40% oxygen) or severe (70% oxygen) hyperoxia vs. room air controls. Respiratory system resistance (Rrs), compliance (Crs), and airway reactivity were measured 14 days after oxygen exposure ended under ketamine/xylazine anesthesia. Baseline Rrs increased and Crs decreased in both treatment groups. Methacholine challenge dose dependently increased Rrs and decreased Crs in 40% oxygen-exposed mice, whereas Rrs and Crs responses were similar between 70% oxygen-exposed and normoxic controls. Airway smooth muscle thickness was increased in 40%- but not 70%-exposed mice, whereas collagen increased and both alveolar number and radial alveolar counts decreased after 40% and 70% oxygen. These data indicate that severity of hyperoxia may differentially affect structural and functional changes in the developing mouse airway that contribute to longer-term hyperreactivity. These findings may be important to our understanding of the complex role of neonatal supplemental oxygen therapy in postnatal development of airway responsiveness. PMID- 24951775 TI - Resveratrol prevents hypoxia-induced arginase II expression and proliferation of human pulmonary artery smooth muscle cells via Akt-dependent signaling. AB - Pulmonary artery smooth muscle cell (PASMC) proliferation plays a fundamental role in the vascular remodeling seen in pulmonary hypertensive diseases associated with hypoxia. Arginase II, an enzyme regulating the first step in polyamine and proline synthesis, has been shown to play a critical role in hypoxia-induced proliferation of human PASMC (hPASMC). In addition, there is evidence that patients with pulmonary hypertension have elevated levels of arginase in the vascular wall. Resveratrol, a natural polyphenol found in red wine and grape skins, has diverse biochemical and physiological actions including antiproliferative properties. Furthermore, resveratrol has been shown to attenuate right ventricular and pulmonary artery remodeling, both pathological components of pulmonary hypertension. The present studies tested the hypothesis that resveratrol would prevent hypoxia-induced pulmonary artery smooth muscle cell proliferation by inhibiting hypoxia-induced arginase II expression. Our data indicate that hypoxia-induced hPASMC proliferation is abrogated following treatment with resveratrol. In addition, the hypoxic induction of arginase II was directly attenuated by resveratrol treatment. Furthermore, we found that the inhibitory effect of resveratrol on arginase II in hPASMC was mediated through the PI3K-Akt signaling pathway. Supporting these in vitro findings, resveratrol normalized right ventricular hypertrophy in an in vivo neonatal rat model of chronic hypoxia-induced pulmonary hypertension. These novel data support the notion that resveratrol may be a potential therapeutic agent in pulmonary hypertension by preventing PASMC arginase II induction and proliferation. PMID- 24951776 TI - Angiotensin II type 2 receptor ligand PD123319 attenuates hyperoxia-induced lung and heart injury at a low dose in newborn rats. AB - Intervening in angiotensin (Ang)-II type 2 receptor (AT2) signaling may have therapeutic potential for bronchopulmonary dysplasia (BPD) by attenuating lung inflammation and preventing arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We first investigated the role of AT2 inhibition with PD123319 (0.5 and 2 mg.kg(-1).day(-1)) on the beneficial effect of AT2 agonist LP2-3 (5 MUg/kg twice a day) on RVH in newborn rats with hyperoxia-induced BPD. Next we determined the cardiopulmonary effects of PD123319 (0.1 mg.kg(-1).day(-1)) in two models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression. Ten days of coadministration of LP2-3 and PD123319 abolished the beneficial effects of LP2-3 on RVH in experimental BPD. In the early treatment model PD123319 attenuated cardiopulmonary injury by reducing alveolar septal thickness, pulmonary influx of inflammatory cells, including macrophages and neutrophils, medial wall thickness of small arterioles, and extravascular collagen III deposition, and by preventing RVH. In the late treatment model PD123319 diminished PAH and RVH, demonstrating that PAH is reversible in the neonatal period. At high concentrations PD123319 blocks the beneficial effects of the AT2-agonist LP2-3 on RVH. At low concentrations PD123319 attenuates cardiopulmonary injury by reducing pulmonary inflammation and fibrosis and preventing PAH-induced RVH but does not affect alveolar and vascular development in newborn rats with experimental BPD. PMID- 24951778 TI - In situ determination of alveolar septal strain, stress and effective Young's modulus: an experimental/computational approach. AB - Alveolar septa, which have often been modeled as linear elements, may distend due to inflation-induced reduction in slack or increase in tissue stretch. The distended septum supports tissue elastic and interfacial forces. An effective Young's modulus, describing the inflation-induced relative displacement of septal end points, has not been determined in situ for lack of a means of determining the forces supported by septa in situ. Here we determine such forces indirectly according to Mead, Takishima, and Leith's classic lung mechanics analysis (J Appl Physiol 28: 596-608, 1970), which demonstrates that septal connections transmit the transpulmonary pressure, PTP, from the pleural surface to interior regions. We combine experimental septal strain determination and computational stress determination, according to Mead et al., to calculate effective Young's modulus. In the isolated, perfused rat lung, we label the perfusate with fluorescence to visualize the alveolar septa. At eight PTP values around a ventilation loop between 4 and 25 cmH2O, and upon total deflation, we image the same region by confocal microscopy. Within an analysis region, we measure septal lengths. Normalizing by unstressed lengths at total deflation, we calculate septal strains for all PTP > 0 cmH2O. For the static imaging conditions, we computationally model application of PTP to the boundary of the analysis region and solve for septal stresses by least squares fit of an overdetermined system. From group septal strain and stress values, we find effective septal Young's modulus to range from 1.2 * 10(5) dyn/cm(2) at low P(TP) to 1.4 * 10(6) dyn/cm(2) at high P(TP). PMID- 24951777 TI - miR-210 promotes IPF fibroblast proliferation in response to hypoxia. AB - Idiopathic pulmonary fibrosis (IPF) is characterized by the relentless spread of fibroblasts from scarred alveoli into adjacent alveolar units, resulting in progressive hypoxia and death by asphyxiation. Although hypoxia is a prominent clinical feature of IPF, the role of hypoxia as a driver of the progressive fibrotic nature of the disease has not been explored. Here, we demonstrate that hypoxia robustly stimulates the proliferation of IPF fibroblasts. We found that miR-210 expression markedly increases in IPF fibroblasts in response to hypoxia and that knockdown of miR-210 decreases hypoxia-induced IPF fibroblast proliferation. Silencing hypoxia-inducible factor (HIF)-2alpha inhibits the hypoxia-mediated increase in miR-210 expression and blocks IPF fibroblast proliferation, indicating that HIF-2alpha is upstream of miR-210. We demonstrate that the miR-210 downstream target MNT is repressed in hypoxic IPF fibroblasts and that knockdown of miR-210 increases MNT expression. Overexpression of MNT inhibits hypoxia-induced IPF fibroblast proliferation. Together, these data indicate that hypoxia potently stimulates miR-210 expression via HIF-2alpha, and high miR-210 expression drives fibroblast proliferation by repressing the c-myc inhibitor, MNT. In situ analysis of IPF lung tissue demonstrates miR-210 expression in a similar distribution with HIF-2alpha and the hypoxic marker carbonic anhydrase-IX in cells within the IPF fibrotic reticulum. Our results raise the possibility that a pathological feed-forward loop exists in the IPF lung, in which hypoxia promotes IPF fibroblast proliferation via stimulation of miR-210 expression, which in turn worsens hypoxia. PMID- 24951780 TI - Abundance and diversity of soybean-nodulating rhizobia in black soil are impacted by land use and crop management. AB - To investigate the effects of land use and crop management on soybean rhizobial communities, 280 nodule isolates were trapped from 7 fields with different land use and culture histories. Besides the known Bradyrhizobium japonicum, three novel genospecies were isolated from these fields. Grassland (GL) maintained a higher diversity of soybean bradyrhizobia than the other cultivation systems. Two genospecies (Bradyrhizobium spp. I and III) were distributed widely in all treatments, while Bradyrhizobium sp. II was found only in GL treatment. Cultivation with soybeans increased the rhizobial abundance and diversity, except for the soybean monoculture (S-S) treatment. In monoculture systems, soybeans favored Bradyrhizobium sp. I, while maize and wheat favored Bradyrhizobium sp. III. Fertilization decreased the rhizobial diversity indexes but did not change the species composition. The organic carbon (OC) and available phosphorus (AP) contents and pH were the main soil parameters positively correlated with the distribution of Bradyrhizobium spp. I and II and Bradyrhizobium japonicum and negatively correlated with Bradyrhizobium sp. III. These results revealed that different land uses and crop management could not only alter the diversity and abundance of soybean rhizobia, but also change interactions between rhizobia and legume or nonlegume plants, which offered novel information about the biogeography of rhizobia. PMID- 24951779 TI - TgaA, a VirB1-like component belonging to a putative type IV secretion system of Bifidobacterium bifidum MIMBb75. AB - Bifidobacterium bifidum MIMBb75 is a human intestinal isolate demonstrated to be interactive with the host and efficacious as a probiotic. However, the molecular biology of this microorganism is yet largely unknown. For this reason, we undertook whole-genome sequencing of B. bifidum MIMBb75 to identify potential genetic factors that would explain the metabolic and probiotic attributes of this bacterium. Comparative genomic analysis revealed a 45-kb chromosomal region that comprises 19 putative genes coding for a potential type IV secretion system (T4SS). Thus, we undertook the initial characterization of this genetic region by studying the putative virB1-like gene, named tgaA. Gene tgaA encodes a peptidoglycan lytic enzyme containing two active domains: lytic murein transglycosylase (LT, cd00254.3) and cysteine- and histidine-dependent amidohydrolase/peptidase (CHAP, pfam05257.4). By means of several in vitro assays, we experimentally confirmed that protein TgaA, consistent with its computationally assigned role, has peptidoglycan lytic activity, which is principally associated to the LT domain. Furthermore, immunofluorescence and immunogold labeling showed that the protein TgaA is abundantly expressed on the cell surface of B. bifidum MIMBb75. According to the literature, the T4SSs, which have not been characterized before in bifidobacteria, can have important implications for bacterial cell-to-cell communication as well as cross talk with host cells, justifying the interest for further studies aimed at the investigation of this genetic region. PMID- 24951781 TI - Optimization of multilocus sequence analysis for identification of species in the genus Vibrio. AB - Multilocus sequence analysis (MLSA) is an important method for identification of taxa that are not well differentiated by 16S rRNA gene sequences alone. In this procedure, concatenated sequences of selected genes are constructed and then analyzed. The effects that the number and the order of genes used in MLSA have on reconstruction of phylogenetic relationships were examined. The recA, rpoA, gapA, 16S rRNA gene, gyrB, and ftsZ sequences from 56 species of the genus Vibrio were used to construct molecular phylogenies, and these were evaluated individually and using various gene combinations. Phylogenies from two-gene sequences employing recA and rpoA in both possible gene orders were different. The addition of the gapA gene sequence, producing all six possible concatenated sequences, reduced the differences in phylogenies to degrees of statistical (bootstrap) support for some nodes. The overall statistical support for the phylogenetic tree, assayed on the basis of a reliability score (calculated from the number of nodes having bootstrap values of >= 80 divided by the total number of nodes) increased with increasing numbers of genes used, up to a maximum of four. No further improvement was observed from addition of the fifth gene sequence (ftsZ), and addition of the sixth gene (gyrB) resulted in lower proportions of strongly supported nodes. Reductions in the numbers of strongly supported nodes were also observed when maximum parsimony was employed for tree construction. Use of a small number of gene sequences in MLSA resulted in accurate identification of Vibrio species. PMID- 24951782 TI - Genetic characterization of plasmid-associated triphenylmethane reductase in Listeria monocytogenes. AB - The enzyme triphenylmethane reductase (TMR) reduces toxic triphenylmethane dyes into colorless, nontoxic derivatives, and TMR-producing microorganisms have been proposed as bioremediation tools. Analysis of the genome of Listeria monocytogenes H7858 (1998-1999 hot dog outbreak) revealed that the plasmid (pLM80) of this strain harboring a gene cassette (bcrABC) conferring resistance to benzalkonium chloride (BC) and other quaternary ammonium disinfectants also harbored a gene (tmr) highly homologous to TMR-encoding genes from diverse Gram negative bacteria. The pLM80-associated tmr was located two genes downstream of bcrABC as part of a putative IS1216 composite transposon. To confirm the role of tmr in triphenylmethane dye detoxification, we introduced various tmr-harboring fragments of pLM80 in a pLM80-cured derivative of strain H7550, from the same outbreak as H7858, and assessed the resistance of the constructs to the triphenylmethane dyes crystal violet (CV) and malachite green. Transcriptional and subcloning data suggest that the regulation of TMR is complex. Constructs harboring fragments spanning bcrABC and tmr were CV resistant, and in such constructs tmr transcription was induced by sublethal levels of either BC or CV. However, constructs harboring only tmr and its upstream intergenic region could also confer resistance to CV, albeit at lower levels. Screening a panel of BC resistant L. monocytogenes strains revealed that all those harboring bcrABC and adjacent pLM80 sequences, including tmr, were resistant to CV and decolorized this dye. The findings suggest a potential role of TMR as a previously unknown adaptive attribute for environmental persistence of L. monocytogenes. PMID- 24951783 TI - Microbial community degradation of widely used quaternary ammonium disinfectants. AB - Benzalkonium chlorides (BACs) are disinfectants widely used in a variety of clinical and environmental settings to prevent microbial infections, and they are frequently detected in nontarget environments, such as aquatic and engineered biological systems, even at toxic levels. Therefore, microbial degradation of BACs has important ramifications for alleviating disinfectant toxicity in nontarget environments as well as compromising disinfectant efficacy in target environments. However, how natural microbial communities respond to BAC exposure and what genes underlie BAC biodegradation remain elusive. Our previous metagenomic analysis of a river sediment microbial community revealed that BAC exposure selected for a low-diversity community, dominated by several members of the Pseudomonas genus that quickly degraded BACs. To elucidate the genetic determinants of BAC degradation, we conducted time-series metatranscriptomic analysis of this microbial community during a complete feeding cycle with BACs as the sole carbon and energy source under aerobic conditions. Metatranscriptomic profiles revealed a candidate gene for BAC dealkylation, the first step in BAC biodegradation that results in a product 500 times less toxic. Subsequent biochemical assays and isolate characterization verified that the putative amine oxidase gene product was functionally capable of initiating BAC degradation. Our analysis also revealed cooperative interactions among community members to alleviate BAC toxicity, such as the further degradation of BAC dealkylation by products by organisms not encoding amine oxidase. Collectively, our results advance the understanding of BAC aerobic biodegradation and provide genetic biomarkers to assess the critical first step of this process in nontarget environments. PMID- 24951784 TI - LacR is a repressor of lacABCD and LacT is an activator of lacTFEG, constituting the lac gene cluster in Streptococcus pneumoniae. AB - Comparison of the transcriptome of Streptococcus pneumoniae strain D39 grown in the presence of either lactose or galactose with that of the strain grown in the presence of glucose revealed the elevated expression of various genes and operons, including the lac gene cluster, which is organized into two operons, i.e., lac operon I (lacABCD) and lac operon II (lacTFEG). Deletion of the DeoR family transcriptional regulator lacR that is present downstream of the lac gene cluster revealed elevated expression of lac operon I even in the absence of lactose. This suggests a function of LacR as a transcriptional repressor of lac operon I, which encodes enzymes involved in the phosphorylated tagatose pathway in the absence of lactose or galactose. Deletion of lacR did not affect the expression of lac operon II, which encodes a lactose-specific phosphotransferase. This finding was further confirmed by beta-galactosidase assays with PlacA-lacZ and PlacT-lacZ in the presence of either lactose or glucose as the sole carbon source in the medium. This suggests the involvement of another transcriptional regulator in the regulation of lac operon II, which is the BglG-family transcriptional antiterminator LacT. We demonstrate the role of LacT as a transcriptional activator of lac operon II in the presence of lactose and CcpA independent regulation of the lac gene cluster in S. pneumoniae. PMID- 24951785 TI - The pH-dependent expression of the urease operon in Streptococcus salivarius is mediated by CodY. AB - Urease gene expression in Streptococcus salivarius 57.I, a strain of one of the major alkali producers in the mouth, is induced by acidic pH and excess amounts of carbohydrate. Expression is controlled primarily at the transcriptional level from a promoter, pureI. Recent sequencing analysis revealed a CodY box located 2 bases 5' to the -35 element of pureI. Using continuous chemostat culture, transcription from pureI was shown to be repressed by CodY, and at pH 7 the repression was more pronounced than that in cells grown at pH 5.5 under both 20 and 100 mM glucose. The direct binding of CodY to pureI was demonstrated by electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) quantitative real-time PCR (qPCR). The result of ChIP-qPCR also confirmed that the regulation of CodY is indeed modulated by pH and the binding of CodY at neutral pH is further enhanced by a limited supply of glucose (20 mM). In the absence of CodY, the C-terminal domain of the RNA polymerase (RNAP) alpha subunit interacted with the AT tracks within the CodY box, indicating that CodY and RNAP compete for the same binding region. Such regulation could ensure optimal urease expression when the enzyme is most required, i.e., at an acidic growth pH with an excess amount of carbon nutrients. PMID- 24951786 TI - Transcriptional regulator LsrB of Sinorhizobium meliloti positively regulates the expression of genes involved in lipopolysaccharide biosynthesis. AB - Rhizobia induce nitrogen-fixing nodules on host legumes, which is important in agriculture and ecology. Lipopolysaccharide (LPS) produced by rhizobia is required for infection or bacteroid survival in host cells. Genes required for LPS biosynthesis have been identified in several Rhizobium species. However, the regulation of their expression is not well understood. Here, Sinorhizobium meliloti LsrB, a member of the LysR family of transcriptional regulators, was found to be involved in LPS biosynthesis by positively regulating the expression of the lrp3-lpsCDE operon. An lsrB in-frame deletion mutant displayed growth deficiency, sensitivity to the detergent sodium dodecyl sulfate, and acidic pH compared to the parent strain. This mutant produced slightly less LPS due to lower expression of the lrp3 operon. Analysis of the transcriptional start sites of the lrp3 and lpsCDE gene suggested that they constitute one operon. The expression of lsrB was positively autoregulated. The promoter region of lrp3 was specifically precipitated by anti-LsrB antibodies in vivo. The promoter DNA fragment containing TN11A motifs was bound by the purified LsrB protein in vitro. These new findings suggest that S. meliloti LsrB is associated with LPS biosynthesis, which is required for symbiotic nitrogen fixation on some ecotypes of alfalfa plants. PMID- 24951787 TI - Trichoderma atroviride transcriptional regulator Xyr1 supports the induction of systemic resistance in plants. AB - As a result of a transcriptome-wide analysis of the ascomycete Trichoderma atroviride, mycoparasitism-related genes were identified; of these, 13 genes were further investigated for differential expression. In silico analysis of the upstream regulatory regions of these genes pointed to xylanase regulator 1 (Xyr1) as a putatively involved regulatory protein. Transcript analysis of the xyr1 gene of T. atroviride in confrontation with other fungi allowed us to determine that xyr1 levels increased during mycoparasitism. To gain knowledge about the precise role of Xyr1 in the mycoparasitic process, the corresponding gene was deleted from the T. atroviride genome. This resulted in strong reductions in the transcript levels of axe1 and swo1, which encode accessory cell wall-degrading enzymes considered relevant for mycoparasitism. We also analyzed the role of Xyr1 in the Trichoderma-Arabidopsis interaction, finding that the plant response elicited by T. atroviride is delayed if Xyr1 is missing in the fungus. PMID- 24951789 TI - Norovirus transmission between hands, gloves, utensils, and fresh produce during simulated food handling. AB - Human noroviruses (HuNoVs), a leading cause of food-borne gastroenteritis worldwide, are easily transferred via ready-to-eat (RTE) foods, often prepared by infected food handlers. In this study, the transmission of HuNoV and murine norovirus (MuNoV) from virus-contaminated hands to latex gloves during gloving, as well as from virus-contaminated donor surfaces to recipient surfaces after simulated preparation of cucumber sandwiches, was inspected. Virus transfer was investigated by swabbing with polyester swabs, followed by nucleic acid extraction from the swabs with a commercial kit and quantitative reverse transcription-PCR. During gloving, transfer of MuNoV dried on the hand was observed 10/12 times. HuNoV, dried on latex gloves, was disseminated to clean pairs of gloves 10/12 times, whereas HuNoV without drying was disseminated 11/12 times. In the sandwich-preparing simulation, both viruses were transferred repeatedly to the first recipient surface (left hand, cucumber, and knife) during the preparation. Both MuNoV and HuNoV were transferred more efficiently from latex gloves to cucumbers (1.2% +/- 0.6% and 1.5% +/- 1.9%) than vice versa (0.7% +/- 0.5% and 0.5% +/- 0.4%). We estimated that transfer of at least one infective HuNoV from contaminated hands to the sandwich prepared was likely to occur if the hands of the food handler contained 3 log10 or more HuNoVs before gloving. Virus contaminated gloves were estimated to transfer HuNoV to the food servings more efficiently than a single contaminated cucumber during handling. Our results indicate that virus-free food ingredients and good hand hygiene are needed to prevent HuNoV contamination of RTE foods. PMID- 24951788 TI - Wastewater irrigation increases the abundance of potentially harmful gammaproteobacteria in soils in Mezquital Valley, Mexico. AB - Wastewater contains large amounts of pharmaceuticals, pathogens, and antimicrobial resistance determinants. Only a little is known about the dissemination of resistance determinants and changes in soil microbial communities affected by wastewater irrigation. Community DNAs from Mezquital Valley soils under irrigation with untreated wastewater for 0 to 100 years were analyzed by quantitative real-time PCR for the presence of sul genes, encoding resistance to sulfonamides. Amplicon sequencing of bacterial 16S rRNA genes from community DNAs from soils irrigated for 0, 8, 10, 85, and 100 years was performed and revealed a 14% increase of the relative abundance of Proteobacteria in rainy season soils and a 26.7% increase in dry season soils for soils irrigated for 100 years with wastewater. In particular, Gammaproteobacteria, including potential pathogens, such as Pseudomonas, Stenotrophomonas, and Acinetobacter spp., were found in wastewater-irrigated fields. 16S rRNA gene sequencing of 96 isolates from soils irrigated with wastewater for 100 years (48 from dry and 48 from rainy season soils) revealed that 46% were affiliated with the Gammaproteobacteria (mainly potentially pathogenic Stenotrophomonas strains) and 50% with the Bacilli, whereas all 96 isolates from rain-fed soils (48 from dry and 48 from rainy season soils) were affiliated with the Bacilli. Up to six types of antibiotic resistance were found in isolates from wastewater-irrigated soils; sulfamethoxazole resistance was the most abundant (33.3% of the isolates), followed by oxacillin resistance (21.9% of the isolates). In summary, we detected an increase of potentially harmful bacteria and a larger incidence of resistance determinants in wastewater-irrigated soils, which might result in health risks for farm workers and consumers of wastewater-irrigated crops. PMID- 24951790 TI - Inhibition of biofilm formation by T7 bacteriophages producing quorum-quenching enzymes. AB - Bacterial growth in biofilms is the major cause of recalcitrant biofouling in industrial processes and of persistent infections in clinical settings. The use of bacteriophage treatment to lyse bacteria in biofilms has attracted growing interest. In particular, many natural or engineered phages produce depolymerases to degrade polysaccharides in the biofilm matrix and allow access to host bacteria. However, the phage-produced depolymerases are highly specific for only the host-derived polysaccharides and may have limited effects on natural multispecies biofilms. In this study, an engineered T7 bacteriophage was constructed to encode a lactonase enzyme with broad-range activity for quenching of quorum sensing, a form of bacterial cell-cell communication via small chemical molecules (acyl homoserine lactones [AHLs]) that is necessary for biofilm formation. Our results demonstrated that the engineered T7 phage expressed the AiiA lactonase to effectively degrade AHLs from many bacteria. Addition of the engineered T7 phage to mixed-species biofilms containing Pseudomonas aeruginosa and Escherichia coli resulted in inhibition of biofilm formation. Such quorum quenching phages that can lyse host bacteria and express quorum-quenching enzymes to affect diverse bacteria in biofilm communities may become novel antifouling and antibiofilm agents in industrial and clinical settings. PMID- 24951791 TI - The functional structure of central carbon metabolism in Pseudomonas putida KT2440. AB - What defines central carbon metabolism? The classic textbook scheme of central metabolism includes the Embden-Meyerhof-Parnas (EMP) pathway of glycolysis, the pentose phosphate pathway, and the citric acid cycle. The prevalence of this definition of central metabolism is, however, equivocal without experimental validation. We address this issue using a general experimental approach that combines the monitoring of transcriptional and metabolic flux changes between steady states on alternative carbon sources. This approach is investigated by using the model bacterium Pseudomonas putida with glucose, fructose, and benzoate as carbon sources. The catabolic reactions involved in the initial uptake and metabolism of these substrates are expected to show a correlated change in gene expressions and metabolic fluxes. However, there was no correlation for the reactions linking the 12 biomass precursor molecules, indicating a regulation mechanism other than mRNA synthesis for central metabolism. This result substantiates evidence for a (re)definition of central carbon metabolism including all reactions that are bound to tight regulation and transcriptional invariance. Contrary to expectations, the canonical Entner-Doudoroff and EMP pathways sensu stricto are not a part of central carbon metabolism in P. putida, as they are not regulated differently from the aromatic degradation pathway. The regulatory analyses presented here provide leads on a qualitative basis to address the use of alternative carbon sources by deregulation and overexpression at the transcriptional level, while rate improvements in central carbon metabolism require careful adjustment of metabolite concentrations, as regulation resides to a large extent in posttranslational and/or metabolic regulation. PMID- 24951792 TI - Elucidation of the molecular basis for arabinoxylan-debranching activity of a thermostable family GH62 alpha-l-arabinofuranosidase from Streptomyces thermoviolaceus. AB - Xylan-debranching enzymes facilitate the complete hydrolysis of xylan and can be used to alter xylan chemistry. Here, the family GH62 alpha-l-arabinofuranosidase from Streptomyces thermoviolaceus (SthAbf62A) was shown to have a half-life of 60 min at 60 degrees C and the ability to cleave alpha-1,3 l-arabinofuranose (l Araf) from singly substituted xylopyranosyl (Xylp) backbone residues in wheat arabinoxylan; low levels of activity on arabinan as well as 4-nitrophenyl alpha-l arabinofuranoside were also detected. After selective removal of alpha-1,3 l-Araf substituents from disubstituted Xylp residues present in wheat arabinoxylan, SthAbf62A could also cleave the remaining alpha-1,2 l-Araf substituents, confirming the ability of SthAbf62A to remove alpha-l-Araf residues that are (1 >2) and (1->3) linked to monosubstituted beta-d-Xylp sugars. Three-dimensional structures of SthAbf62A and its complex with xylotetraose and l-arabinose confirmed a five-bladed beta-propeller fold and revealed a molecular Velcro in blade V between the beta1 and beta21 strands, a disulfide bond between Cys27 and Cys297, and a calcium ion coordinated in the central channel of the fold. The enzyme-arabinose complex structure further revealed a narrow and seemingly rigid l-arabinose binding pocket situated at the center of one side of the beta propeller, which stabilized the arabinofuranosyl substituent through several hydrogen-bonding and hydrophobic interactions. The predicted catalytic amino acids were oriented toward this binding pocket, and the catalytic essentiality of Asp53 and Glu213 was confirmed by site-specific mutagenesis. Complex structures with xylotetraose revealed a shallow cleft for xylan backbone binding that is open at both ends and comprises multiple binding subsites above and flanking the l-arabinose binding pocket. PMID- 24951793 TI - Analysis of strains lacking known osmolyte accumulation mechanisms reveals contributions of osmolytes and transporters to protection against abiotic stress. AB - Osmolyte accumulation and release can protect cells from abiotic stresses. In Escherichia coli, known mechanisms mediate osmotic stress-induced accumulation of K(+) glutamate, trehalose, or zwitterions like glycine betaine. Previous observations suggested that additional osmolyte accumulation mechanisms (OAMs) exist and their impacts may be abiotic stress specific. Derivatives of the uropathogenic strain CFT073 and the laboratory strain MG1655 lacking known OAMs were created. CFT073 grew without osmoprotectants in minimal medium with up to 0.9 M NaCl. CFT073 and its OAM-deficient derivative grew equally well in high- and low-osmolality urine pools. Urine-grown bacteria did not accumulate large amounts of known or novel osmolytes. Thus, CFT073 showed unusual osmotolerance and did not require osmolyte accumulation to grow in urine. Yeast extract and brain heart infusion stimulated growth of the OAM-deficient MG1655 derivative at high salinity. Neither known nor putative osmoprotectants did so. Glutamate and glutamine accumulated after growth with either organic mixture, and no novel osmolytes were detected. MG1655 derivatives retaining individual OAMs were created. Their abilities to mediate osmoprotection were compared at 15 degrees C, 37 degrees C without or with urea, and 42 degrees C. Stress protection was not OAM specific, and variations in osmoprotectant effectiveness were similar under all conditions. Glycine betaine and dimethylsulfoniopropionate (DMSP) were the most effective. Trimethylamine-N-oxide (TMAO) was a weak osmoprotectant and a particularly effective urea protectant. The effectiveness of glycine betaine, TMAO, and proline as osmoprotectants correlated with their preferential exclusion from protein surfaces, not with their propensity to prevent protein denaturation. Thus, their effectiveness as stress protectants correlated with their ability to rehydrate the cytoplasm. PMID- 24951794 TI - Iron triggers lambdaSo prophage induction and release of extracellular DNA in Shewanella oneidensis MR-1 biofilms. AB - Prophages are ubiquitous elements within bacterial chromosomes and affect host physiology and ecology in multiple ways. We have previously demonstrated that phage-induced lysis is required for extracellular DNA (eDNA) release and normal biofilm formation in Shewanella oneidensis MR-1. Here, we investigated the regulatory mechanisms of prophage lambdaSo spatiotemporal induction in biofilms. To this end, we used a functional fluorescence fusion to monitor lambdaSo activation in various mutant backgrounds and in response to different physiological conditions. lambdaSo induction occurred mainly in a subpopulation of filamentous cells in a strictly RecA-dependent manner, implicating oxidative stress-induced DNA damage as the major trigger. Accordingly, mutants affected in the oxidative stress response (DeltaoxyR) or iron homeostasis (Deltafur) displayed drastically increased levels of phage induction and abnormal biofilm formation, while planktonic cells were not or only marginally affected. To further investigate the role of oxidative stress, we performed a mutant screen and identified two independent amino acid substitutions in OxyR (T104N and L197P) that suppress induction of lambdaSo by hydrogen peroxide (H2O2). However, lambdaSo induction was not suppressed in biofilms formed by both mutants, suggesting a minor role of intracellular H2O2 in this process. In contrast, addition of iron to biofilms strongly enhanced lambdaSo induction and eDNA release, while both processes were significantly suppressed at low iron levels, strongly indicating that iron is the limiting factor. We conclude that uptake of iron during biofilm formation triggers lambdaSo-mediated lysis of a subpopulation of cells, likely by an increase in iron-mediated DNA damage sensed by RecA. PMID- 24951795 TI - Effect of microstructure on population growth parameters of Escherichia coli in gelatin-dextran systems. AB - Current literature acknowledges the effect of food structure on bacterial dynamics. Most studies introduce this "structure" factor using a single gelling agent, resulting in a homogeneous environment, whereas in practice most food products are heterogeneous. Therefore, this study focuses on heterogeneous protein-polysaccharide mixtures, based on gelatin and dextran. These mixtures show phase separation, leading to a range of heterogeneous microstructures by adjusting relative concentrations of both gelling agents. Based on confocal microscope observations, the growth of Escherichia coli in gelatin-dextran systems was observed to occur in the dextran phase. To find a relation between microscopic and population behavior, growth experiments were performed in binary and singular gelatin-dextran systems and culture broth at 23.5 degrees C, with or without adding 2.9% (wt/vol) NaCl. The Baranyi and Roberts growth model was fitted to the experimental data and parameter estimates were statistically compared. For salted binary mixtures, a decrease in the population maximum cell density was observed with increasing gelatin concentration. In this series, for one type of microstructure, i.e., a gelatin matrix phase with a disperse dextran phase, the maximum cell density decreased with decreasing percentage of dextran phase. However, this relation no longer held when other types of microstructure were observed. Compared to singular systems, adding a second gelling agent in the presence of NaCl had an effect on population lag phases and maximum cell densities. For unsalted media, the growth parameters of singular and binary mixtures were comparable. Introducing this information into mathematical models leads to more reliable growth predictions and enhanced food safety. PMID- 24951797 TI - UCbase 2.0: ultraconserved sequences database (2014 update). AB - UCbase 2.0 (http://ucbase.unimore.it) is an update, extension and evolution of UCbase, a Web tool dedicated to the analysis of ultraconserved sequences (UCRs). UCRs are 481 sequences >200 bases sharing 100% identity among human, mouse and rat genomes. They are frequently located in genomic regions known to be involved in cancer or differentially expressed in human leukemias and carcinomas. UCbase 2.0 is a platform-independent Web resource that includes the updated version of the human genome annotation (hg19), information linking disorders to chromosomal coordinates based on the Systematized Nomenclature of Medicine classification, a query tool to search for Single Nucleotide Polymorphisms (SNPs) and a new text box to directly interrogate the database using a MySQL interface. To facilitate the interactive visual interpretation of UCR chromosomal positioning, UCbase 2.0 now includes a graph visualization interface directly linked to UCSC genome browser. Database URL: http://ucbase.unimore.it. PMID- 24951796 TI - An analysis of electronic health record-related patient safety concerns. AB - OBJECTIVE: A recent Institute of Medicine report called for attention to safety issues related to electronic health records (EHRs). We analyzed EHR-related safety concerns reported within a large, integrated healthcare system. METHODS: The Informatics Patient Safety Office of the Veterans Health Administration (VA) maintains a non-punitive, voluntary reporting system to collect and investigate EHR-related safety concerns (ie, adverse events, potential events, and near misses). We analyzed completed investigations using an eight-dimension sociotechnical conceptual model that accounted for both technical and non technical dimensions of safety. Using the framework analysis approach to qualitative data, we identified emergent and recurring safety concerns common to multiple reports. RESULTS: We extracted 100 consecutive, unique, closed investigations between August 2009 and May 2013 from 344 reported incidents. Seventy-four involved unsafe technology and 25 involved unsafe use of technology. A majority (70%) involved two or more model dimensions. Most often, non-technical dimensions such as workflow, policies, and personnel interacted in a complex fashion with technical dimensions such as software/hardware, content, and user interface to produce safety concerns. Most (94%) safety concerns related to either unmet data-display needs in the EHR (ie, displayed information available to the end user failed to reduce uncertainty or led to increased potential for patient harm), software upgrades or modifications, data transmission between components of the EHR, or 'hidden dependencies' within the EHR. DISCUSSION: EHR related safety concerns involving both unsafe technology and unsafe use of technology persist long after 'go-live' and despite the sophisticated EHR infrastructure represented in our data source. Currently, few healthcare institutions have reporting and analysis capabilities similar to the VA. CONCLUSIONS: Because EHR-related safety concerns have complex sociotechnical origins, institutions with long-standing as well as recent EHR implementations should build a robust infrastructure to monitor and learn from them. PMID- 24951798 TI - A controlled vocabulary for pathway entities and events. AB - Entities involved in pathways and the events they participate in require descriptive and unambiguous names that are often not available in the literature or elsewhere. Reactome is a manually curated open-source resource of human pathways. It is accessible via a website, available as downloads in standard reusable formats and via Representational State Transfer (REST)-ful and Simple Object Access Protocol (SOAP) application programming interfaces (APIs). We have devised a controlled vocabulary (CV) that creates concise, unambiguous and unique names for reactions (pathway events) and all the molecular entities they involve. The CV could be reapplied in any situation where names are used for pathway entities and events. Adoption of this CV would significantly improve naming consistency and readability, with consequent benefits for searching and data mining within and between databases. Database URL: http://www.reactome.org. PMID- 24951799 TI - Detection of methicillin-resistant coagulase-negative staphylococci by the Vitek 2 system. AB - The accurate performance of the Vitek 2 GP67 card for detecting methicillin resistant coagulase-negative staphylococci (CoNS) is not known. We prospectively determined the ability of the Vitek 2 GP67 card to accurately detect methicillin resistant CoNS, with mecA PCR results used as the gold standard for a 4-month period in 2012. Included in the study were 240 consecutively collected nonduplicate CoNS isolates. Cefoxitin susceptibility by disk diffusion testing was determined for all isolates. We found that the three tested systems, Vitek 2 oxacillin and cefoxitin testing and cefoxitin disk susceptibility testing, lacked specificity and, in some cases, sensitivity for detecting methicillin resistance. The Vitek 2 oxacillin and cefoxitin tests had very major error rates of 4% and 8%, respectively, and major error rates of 38% and 26%, respectively. Disk cefoxitin testing gave the best performance, with very major and major error rates of 2% and 24%, respectively. The test performances were species dependent, with the greatest errors found for Staphylococcus saprophyticus. While the 2014 CLSI guidelines recommend reporting isolates that test resistant by the oxacillin MIC or cefoxitin disk test as oxacillin resistant, following such guidelines produces erroneous results, depending on the test method and bacterial species tested. Vitek 2 cefoxitin testing is not an adequate substitute for cefoxitin disk testing. For critical-source isolates, mecA PCR, rather than Vitek 2 or cefoxitin disk testing, is required for optimal antimicrobial therapy. PMID- 24951800 TI - Practical agar-based disk potentiation test for detection of fosfomycin nonsusceptible Escherichia coli clinical isolates producing glutathione S transferases. AB - The number of reports concerning Escherichia coli clinical isolates that produce glutathione S-transferases responsible for fosfomycin resistance (FR-GSTs) has been increasing. We have developed a disk-based potentiation test in which FR-GST producers expand the growth inhibition zone around a Kirby-Bauer disk containing fosfomycin in combination with sodium phosphonoformate (PPF). PPF, an analog of fosfomycin, is a transition-state inhibitor of FosA(PA), a type of FR-GST from Pseudomonas aeruginosa. Considering its mechanism of action, PPF was expected to inhibit a variety of FR-GSTs. In the presence of PPF, zone enlargement around the disk containing fosfomycin was observed for FosA3-, FosA4-, and FosC2-producing E. coli clinical isolates. Moreover, the growth inhibition zone was remarkably enlarged when the Mueller-Hinton (MH) agar plate contained 25 MUg/ml glucose-6 phosphate (G6P). When we retrospectively tested 12 fosfomycin-resistant (MIC, >=256 MUg/ml) E. coli clinical isolates from our hospital with the potentiation test, 6 FR-GST producers were positive phenotypically by potentiation disk and were positive for FR-GST genes: 5 harbored fosA3 and 1 harbored fosA4. To identify the production of FR-GSTs, we set the provisional cutoff value, 5-mm enlargement, by adding PPF to a fosfomycin disk on the MH agar plates containing G6P. Our disk-based potentiation test reliably identifies FR-GST producers and can be performed easily; therefore, it will be advantageous in epidemiological surveys and infection control of fosfomycin-resistant bacteria in clinical settings. PMID- 24951801 TI - Isolation of West Nile virus from urine samples of patients with acute infection. AB - This study demonstrated that West Nile virus (WNV) excreted in the urine of patients with acute infection can be isolated in cell cultures. In addition, the protocols for WNV isolation from urine samples were standardized, and factors that may affect the efficiency of WNV isolation were identified. PMID- 24951802 TI - Extended characterization of Corynebacterium pyruviciproducens based on clinical strains from Canada and Switzerland. AB - The species Corynebacterium pyruviciproducens was described in 2010 based on the features of a single strain. In this report, we describe the chemotaxonomic and phenotypic characteristics of 11 C. pyruviciproducens clinical strains isolated in Switzerland and Canada in comparison to the strain 06-17730(T). Heterogeneities within the type strain were found in the 16S rRNA gene and in biochemical markers. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) identification of this species could not be achieved since currently this bacterial species is not included in the corresponding database. Reliable identification is obtained only with sequence based identification tools. Results of antimicrobial susceptibility testing of this species with an extended panel of antimicrobials are presented here for the first time. PMID- 24951803 TI - Application of coamplification at lower denaturation temperature-PCR sequencing for early detection of antiviral drug resistance mutations of hepatitis B virus. AB - Nucleoside/nucleotide analogue for the treatment of chronic hepatitis B virus (HBV) infection is hampered by the emergence of drug resistance mutations. Conventional PCR sequencing cannot detect minor variants of <20%. We developed a modified co-amplification at lower denaturation temperature-PCR (COLD-PCR) method for the detection of HBV minority drug resistance mutations. The critical denaturation temperature for COLD-PCR was determined to be 78 degrees C. Sensitivity of COLD-PCR sequencing was determined using serially diluted plasmids containing mixed proportions of HBV reverse transcriptase (rt) wild-type and mutant sequences. Conventional PCR sequencing detected mutations only if they existed in >=25%, whereas COLD-PCR sequencing detected mutations when they existed in 5 to 10% of the viral population. The performance of COLD-PCR was compared to conventional PCR sequencing and a line probe assay (LiPA) using 215 samples obtained from 136 lamivudine- or telbivudine-treated patients with virological breakthrough. Among these 215 samples, drug resistance mutations were detected in 155 (72%), 148 (69%), and 113 samples (53%) by LiPA, COLD-PCR, and conventional PCR sequencing, respectively. Nineteen (9%) samples had mutations detectable by COLD-PCR but not LiPA, while 26 (12%) samples had mutations detectable by LiPA but not COLD-PCR, indicating both methods were comparable (P = 0.371). COLD-PCR was more sensitive than conventional PCR sequencing. Thirty-five (16%) samples had mutations detectable by COLD-PCR but not conventional PCR sequencing, while none had mutations detected by conventional PCR sequencing but not COLD-PCR (P < 0.0001). COLD-PCR sequencing is a simple method which is comparable to LiPA and superior to conventional PCR sequencing in detecting minor lamivudine/telbivudine resistance mutations. PMID- 24951804 TI - Development of two molecular approaches for differentiation of clinically relevant yeast species closely related to Candida guilliermondii and Candida famata. AB - The emerging pathogens Candida palmioleophila, Candida fermentati, and Debaryomyces nepalensis are often misidentified as Candida guilliermondii or Candida famata in the clinical laboratory. Due to the significant differences in antifungal susceptibilities and epidemiologies among these closely related species, a lot of studies have focused on the identification of these emerging yeast species in clinical specimens. Nevertheless, limited tools are currently available for their discrimination. Here, two new molecular approaches were established to distinguish these closely related species. The first approach differentiates these species by use of restriction fragment length polymorphism analysis of partial internal transcribed spacer 2 (ITS2) and large subunit ribosomal DNA with the enzymes BsaHI and XbaI in a double digestion. The second method involves a multiplex PCR based on the intron size differences of RPL18, a gene coding for a protein component of the large (60S) ribosomal subunit, and species-specific amplification. These two methods worked well in differentiation of these closely related yeast species and have the potential to serve as effective molecular tools suitable for laboratory diagnoses and epidemiological studies. PMID- 24951805 TI - First report of blaNDM and blaOXA-58 coexistence in Acinetobacter junii. PMID- 24951806 TI - Improved sensitivity for molecular detection of bacterial and Candida infections in blood. AB - The rapid identification of bacteria and fungi directly from the blood of patients with suspected bloodstream infections aids in diagnosis and guides treatment decisions. The development of an automated, rapid, and sensitive molecular technology capable of detecting the diverse agents of such infections at low titers has been challenging, due in part to the high background of genomic DNA in blood. PCR followed by electrospray ionization mass spectrometry (PCR/ESI MS) allows for the rapid and accurate identification of microorganisms but with a sensitivity of about 50% compared to that of culture when using 1-ml whole-blood specimens. Here, we describe a new integrated specimen preparation technology that substantially improves the sensitivity of PCR/ESI-MS analysis. An efficient lysis method and automated DNA purification system were designed for processing 5 ml of whole blood. In addition, PCR amplification formulations were optimized to tolerate high levels of human DNA. An analysis of 331 specimens collected from patients with suspected bloodstream infections resulted in 35 PCR/ESI-MS-positive specimens (10.6%) compared to 18 positive by culture (5.4%). PCR/ESI-MS was 83% sensitive and 94% specific compared to culture. Replicate PCR/ESI-MS testing from a second aliquot of the PCR/ESI-MS-positive/culture-negative specimens corroborated the initial findings in most cases, resulting in increased sensitivity (91%) and specificity (99%) when confirmed detections were considered true positives. The integrated solution described here has the potential to provide rapid detection and identification of organisms responsible for bloodstream infections. PMID- 24951807 TI - Whole-genome analysis of Exserohilum rostratum from an outbreak of fungal meningitis and other infections. AB - Exserohilum rostratum was the cause of most cases of fungal meningitis and other infections associated with the injection of contaminated methylprednisolone acetate produced by the New England Compounding Center (NECC). Until this outbreak, very few human cases of Exserohilum infection had been reported, and very little was known about this dematiaceous fungus, which usually infects plants. Here, we report using whole-genome sequencing (WGS) for the detection of single nucleotide polymorphisms (SNPs) and phylogenetic analysis to investigate the molecular origin of the outbreak using 22 isolates of E. rostratum retrieved from 19 case patients with meningitis or epidural/spinal abscesses, 6 isolates from contaminated NECC vials, and 7 isolates unrelated to the outbreak. Our analysis indicates that all 28 isolates associated with the outbreak had nearly identical genomes of 33.8 Mb. A total of 8 SNPs were detected among the outbreak genomes, with no more than 2 SNPs separating any 2 of the 28 genomes. The outbreak genomes were separated from the next most closely related control strain by ~136,000 SNPs. We also observed significant genomic variability among strains unrelated to the outbreak, which may suggest the possibility of cryptic speciation in E. rostratum. PMID- 24951808 TI - Use of anidulafungin as a surrogate marker to predict susceptibility and resistance to caspofungin among 4,290 clinical isolates of Candida by using CLSI methods and interpretive criteria. AB - This study addressed the application of anidulafungin as a surrogate marker to predict the susceptibility of Candida to caspofungin due to unacceptably high interlaboratory variation of caspofungin MIC values. CLSI reference broth microdilution methods and species-specific interpretive criteria were used to test 4,290 strains of Candida (eight species), including 71 strains with documented fks mutations. Caspofungin MIC values were compared with those of anidulafungin to determine the percentage of categorical agreement (CA) and very major (VME), major (ME), and minor error rates, as well as the ability to detect fks mutants. For all 4,290 isolates the CA was 97.1% (0.2% VME and ME, 2.5% minor errors) using anidulafungin as the surrogate. Among the 62 isolates of Candida albicans (4 isolates), C. tropicalis (5 isolates), C. krusei (4 isolates), C. kefyr (2 isolates), and C. glabrata (47 isolates) that were nonsusceptible (NS; either intermediate [I] or resistant [R]) to both caspofungin and anidulafungin, 52 (83.8%) contained a mutation in fks1 or fks2. Eight mutants of C. glabrata, two of C. albicans, and one each of C. tropicalis and C. krusei were classified as susceptible (S) to both antifungal agents. The remaining 7 mutants (2 C. albicans and 5 C. glabrata) were susceptible to one of the agents and either intermediate or resistant to the other. Using the epidemiological cutoff value (ECV) of 0.12 MUg/ml for both caspofungin and anidulafungin to differentiate wild type (WT) from non-WT strains of C. glabrata, 42 of the 55 (76.4%) C. glabrata mutants were non-WT and 8 of the 55 (14.5%) were WT for both agents (90.9% concordance). Anidulafungin can accurately serve as a surrogate marker to predict S and R of Candida to caspofungin. PMID- 24951809 TI - Cluster of Escherichia coli isolates producing a plasmid-mediated OXA-48 beta lactamase in a Spanish hospital in 2012. AB - Three unrelated sequence type 131 (ST131), ST58, and ST83 Escherichia coli isolates with low-level resistance to imipenem and resistance to ertapenem were recovered in a Spanish hospital from July to October 2012. They were positive for blaOXA-48 carried by an IncL/M conjugative plasmid, which may have been acquired from Klebsiella pneumoniae. PMID- 24951810 TI - Rothia bacteremia: a 10-year experience at Mayo Clinic, Rochester, Minnesota. AB - Rothia spp. are Gram-positive cocco-bacilli that cause a wide range of serious infections, especially in immunocompromised hosts. Risk factors for Rothia mucilaginosa (previously known as Stomatococcus mucilaginosus) bacteremia include prolonged and profound neutropenia, malignancy, and an indwelling vascular foreign body. Here, we describe 67 adults at the Mayo Clinic in Rochester, MN, from 2002 to 2012 with blood cultures positive for Rothia. Twenty-five of these patients had multiple positive blood cultures, indicating true clinical infection. Among these, 88% (22/25) were neutropenic, and 76% (19/25) had leukemia. Common sources of bacteremia were presumed gut translocation, mucositis, and catheter-related infection. One patient died with Rothia infection. Neutropenic patients were less likely to have a single positive blood culture than were nonneutropenic patients. Antimicrobial susceptibility testing was performed on 21% of the isolates. All of the tested isolates were susceptible to vancomycin and most beta-lactams; however, four of six tested isolates were resistant to oxacillin. There was no difference between the neutropenic and nonneutropenic patients in need of intensive care unit care, mortality, or attributable mortality. PMID- 24951811 TI - Identification of microorganisms by FilmArray and matrix-assisted laser desorption ionization-time of flight mass spectrometry prior to positivity in the blood culture system. AB - In this study, we investigated the performance of the FilmArray and matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) in identifying microorganisms from blood culture (BC) bottles prior to positivity. First, we used simulated BacT/Alert FA Plus BC bottles with five each for Escherichia coli and Staphylococcus aureus isolates. The FilmArray identified all 10 isolates before BC positivity with 9/10 at 5 h and 1 at 7.5 h after incubation in the BC system. MALDI-TOF MS failed to identify the isolates prior to positivity. When the bottles were incubated for 2.5 h at room temperature (RT) before we put them into the BC system, the FilmArray identified 6/10 at 2.5 h and the remaining 4 at 5 h. Finally, we tested simulated BC bottles after incubation at RT. Interestingly, 9/10 isolates were identified with the FilmArray after 8 h of incubation at RT. Second, we studied clinical BC bottles in quadruplicate. When three-fourths of the parallel bottles signaled positive, the FilmArray was run on the fourth nonsignaled bottle and was found to be positive in 14/15 such cases. Third, we analyzed the performance of the FilmArray in the identification of microorganisms from clinical BC bottles before incubation in the system. Two milliliters of broth from 400 BC bottles was collected after arrival at the laboratory and stored at -70 degrees C. Sixteen bottles later signaled positive in the system. When the frozen broth from these bottles was analyzed, the FilmArray identified all the microorganisms in 8/16 bottles prior to incubation in the BC system. This study shows that the FilmArray can identify microorganisms from BC bottles prior to positivity and in some cases even prior to incubation in the BC system. PMID- 24951813 TI - From scientific advances to public health action: the crucial role of science dissemination. PMID- 24951814 TI - Priming of CD8 T cells by adenoviral vectors is critically dependent on B7 and dendritic cells but only partially dependent on CD28 ligation on CD8 T cells. AB - Adenoviral vectors have long been forerunners in the development of effective CD8 T cell-based vaccines; therefore, it is imperative that we understand the factors controlling the induction of robust and long-lasting transgene-specific immune responses by these vectors. In this study, we investigated the organ sites, molecules, and cell subsets that play a critical role in the priming of transgene specific CD8 T cells after vaccination with a replication-deficient adenoviral vector. Using a human adenovirus serotype 5 (Ad5) vector and genetically engineered mice, we found that CD8(+) and/or CD103(+) dendritic cells in the draining lymph node played a critical role in the priming of Ad5-induced CD8 T cell responses. Moreover, we found that CD80/86, but not CD28, was essential for efficient generation of both primary effectors and memory CD8 T cells. Interestingly, the lack of CD28 expression resulted in a delayed primary response, whereas memory CD8 T cells generated in CD28-deficient mice appeared almost normal in terms of both phenotype and effector cytokine profile, but they exhibited a significantly reduced proliferative capacity upon secondary challenge while retaining immediate in vivo effector capabilities: in vivo cytotoxicity and short-term in vivo protective capacity. Overall, our data point to an absolute requirement for professional APCs and the expression of the costimulatory molecules CD80/86 for efficient CD8 T cell priming by adenoviral vectors. Additionally, our results suggest the existence of an alternative receptor for CD80/86, which may substitute, in part, for CD28. PMID- 24951812 TI - Population dynamics of an Acinetobacter baumannii clonal complex during colonization of patients. AB - Acinetobacter baumannii has emerged as one of the leading pathogens causing hospital-acquired infection. The success of A. baumannii as a pathogen has to a large extent been attributed to its capacity to remodel its genome. Several major epidemic clonal complexes of A. baumannii spread across different health care facilities around the world, each of which contains a subset of diversified strains. However, little is known about the population dynamics during colonization of A. baumannii within hosts. Here, whole-genome sequencing was used to analyze population dynamics of A. baumannii strains isolated from a group of patients at different time points as well as from different sites of a particular patient. Seven out of nine of the sampled A. baumannii strains belonged to the international clone II (CC92 clonal complex). While the A. baumannii strains were found to be stable in three patients, there was a change of A. baumannii strains in one patient. Comparative genomic analysis revealed that the accessory genome of these strains contained a large set of virulence-encoding genes and these virulence factors might play a role in determining population dynamics. Microscale genome modification has been revealed by analysis of single nucleotide polymorphisms (SNPs) between A. baumannii strains isolated from the same patient. Parallel evolutionary traits have been observed during genome diversification when A. baumannii colonize in different patients. Our study suggested that both antibiotic usage and host environment might impose selective forces that drive the rapid adaptive evolution in colonizing A. baumannii. PMID- 24951815 TI - 25-hydroxvitamin D3 promotes the long-term effect of specific immunotherapy in a murine allergy model. AB - Calcitriol (1alpha,25-dihydroxyvitamin D3) is the active vitamin D metabolite and mediates immunological functions, which are relevant in allergy. Its therapeutic use is limited by hypercalcaemic toxicity. We have previously shown that the activation of the vitamin D receptor inhibits IgE production and that B cells can synthesize calcitriol from its precursor 25-hydroxyvitamin D3 (inactive precursor) [25(OH)D] upon antigenic stimulation. In this study, we address the impact of 25(OH)D on the development of type I sensitization and determine its role in allergen-specific immunotherapy. BALB/c mice were sensitized to OVA, under 25(OH)D-deficient or sufficient conditions. The humoral immune response over time was measured by ELISA. OVA-specific immunotherapy was established and studied in a murine model of allergic airway inflammation using lung histology, pulmonary cytokine expression analysis, and functional parameters in isolated and perfused mouse lungs. In 25(OH)D-deficient mice, OVA-specific IgE and IgG1 serum concentrations were increased compared with control mice. OVA-specific immunotherapy reduced the humoral immune reaction after OVA recall dose dependently. Coadministration of 25(OH)D in the context of OVA-specific immunotherapy reduced the allergic airway inflammation and responsiveness upon OVA challenge. These findings were paralleled by reduced Th2 cytokine expression in the lungs. In conclusion, 25(OH)D deficiency promotes the development of type I sensitization and correction of its serum concentrations enhances the benefit of specific immunotherapy. PMID- 24951816 TI - Murine spleen tissue regeneration from neonatal spleen capsule requires lymphotoxin priming of stromal cells. AB - Spleen is a tissue with regenerative capacity, which allows autotransplantation of human spleen fragments to counteract the effects of splenectomy. We now reveal in a murine model that transplant of neonatal spleen capsule alone leads to the regeneration of full spleen tissue. This finding indicates that graft-derived spleen stromal cells, but not lymphocytes, are essential components of tissue neogenesis, a finding verified by transplant and regeneration of Rag1KO spleen capsules. We further demonstrate that lymphotoxin and lymphoid tissue inducer cells participate in two key elements of spleen neogenesis, bulk tissue regeneration and white pulp organization, identifying a lymphotoxin-dependent pathway for neonatal spleen regeneration that contrasts with previously defined lymphotoxin-independent embryonic spleen organogenesis. PMID- 24951817 TI - GM-CSF but not IL-17 is critical for the development of severe interstitial lung disease in SKG mice. AB - Interstitial lung disease (ILD) is a common complication and sometimes a prognostic factor of connective tissue diseases (CTDs) in humans. However, suitable animal model of severe CTD-associated ILD (CTD-ILD) has been limited. In this study, we showed that zymosan-treated SKG mice developed not only arthritis but also chronic-progressive ILD with high mortality over several months. The pathological and clinical features of ILD in zymosan-treated SKG mice were similar to that of human severe CTD-ILD. ILD in this mouse was characterized by massive infiltration of Th17 cells, GM-CSF-producing CD4(+) T cells, and CD11b(+) Gr1(+) neutrophils with fibrosis. Naive SKG T cells were skewed to differentiate into GM-CSF-producing cells, and GM-CSF secreted by T cells enhanced IL-6 and IL 1beta production by macrophages, which in turn enhanced differentiation of IL-17A and/or GM-CSF-producing T cells and infiltration of neutrophils into lung. Neutralization of GM-CSF completely blocked the development of this ILD, and the blocking of IL-6 signaling resulted in partial prevention of it, whereas neutralization of IL-17A did not. In contrast, the progression of arthritis was inhibited by the neutralization of GM-CSF and slightly by the neutralization of IL-17A, but not by the blocking of IL-6 signaling. These data suggested zymosan treated SKG mice could be a useful mouse model of severe CTD-ILD, and GM-CSF, rather than IL-17A or IL-6, contributed to the development of ILD in zymosan treated SKG mice, indicating that neutralization of GM-CSF would be a useful therapeutic strategy for severe CTD-ILD. PMID- 24951818 TI - Mode of delivery shapes gut colonization pattern and modulates regulatory immunity in mice. AB - Delivery mode has been associated with long-term changes in gut microbiota composition and more recently also with changes in the immune system. This has further been suggested to link Cesarean section (C-section) with an increased risk for development of immune-mediated diseases such as type 1 diabetes. In this study, we demonstrate that both C-section and cross-fostering with a genetically distinct strain influence the gut microbiota composition and immune key markers in mice. Gut microbiota profiling by denaturing gradient gel electrophoresis and 454/FLX-based 16S rRNA gene amplicon sequencing revealed that mice born by C section had a distinct bacterial profile at weaning characterized by higher abundance of Bacteroides and Lachnospiraceae, and less Rikenellaceae and Ruminococcus. No clustering according to delivery method as determined by principal component analysis of denaturing gradient gel electrophoresis profiles was evident in adult mice. However, the adult C-section-born mice had lower proportions of Foxp3(+) regulatory T cells, tolerogenic CD103(+) dendritic cells, and less Il10 gene expression in mesenteric lymph nodes and spleens. This demonstrates long-term systemic effect on the regulatory immune system that was also evident in NOD mice, a model of type 1 diabetes, born by C-section. However, no effect of delivery mode was seen on diabetes incidence or insulitis development. In conclusion, the first exposure to microorganisms seems to be crucial for the early life gut microbiota and priming of regulatory immune system in mice, and mode of delivery strongly influences this. PMID- 24951819 TI - Klebsiella pneumoniae alleviates influenza-induced acute lung injury via limiting NK cell expansion. AB - A protective effect induced by bacterial preinfection upon a subsequent lethal influenza virus infection has been observed, but the underlying immune mechanisms have not yet been fully elucidated. In this study, we used a mouse model of Klebsiella pneumoniae preinfection to gain insight into how bacterial preinfection influences the subsequent lethal influenza virus infection. We found that K. pneumoniae preinfection significantly attenuated lung immune injury and decreased mortality during influenza virus infection, but K. pneumoniae-specific immunity was not involved in this cross-protection against influenza virus. K. pneumoniae preinfection limited NK cell expansion, which was involved in influenza-induced immune injury and death. Furthermore, K. pneumoniae preinfection could not control NK cell expansion and death during influenza virus infection in Rag1(-/-) mice, but adoptive transfer of T cells from wild-type mice was able to restore this protective effect. Our data suggest that the adaptive immune response activated by bacterial infection limits the excessive innate immune response induced by a subsequent influenza infection, ultimately protecting mice from death. PMID- 24951821 TI - Hunting autoimmune disease genes in NOD: early steps on a long road to somewhere important (hopefully). PMID- 24951820 TI - Nitric oxide regulates BAFF expression and T cell-independent antibody responses. AB - Whereas NO is known to regulate T cell responses, its role in regulating B cell responses remains unclear. Previous studies suggested that inducible NO synthase 2 (NOS2/iNOS) is required for normal IgA Ab responses but inhibits antiviral IgG2a Ab responses. In this study we used NOS2(-/-) mice to determine the role of NO in T cell-dependent and T cell-independent (TI)-2 Ab responses. Whereas T cell dependent Ab responses were only modestly increased in NOS2(-/-) mice, IgM and IgG3 Ab responses as well as marginal zone B cell plasma cell numbers and peritoneal B1b B cells were significantly elevated after immunization with the TI 2 Ag 4-hydroxy-3-nitrophenyl acetyl (NP)-Ficoll. The elevated TI-2 responses in NOS2(-/-) mice were accompanied by significant increases in serum levels of BAFF/BLyS and by increases in BAFF-producing Ly6C(hi) inflammatory monocytes and monocyte-derived dendritic cells (DCs), suggesting that NO normally inhibits BAFF expression. Indeed, we found that NOS2(-/-) DCs produced more BAFF than did wild type DCs, and addition of a NO donor to NOS2(-/-) DCs reduced BAFF production. Bone marrow chimeric mice that lack NOS2 in either nonhematopoietic or hematopoietic cells had intermediate IgM and IgG3 Ab responses after NP-Ficoll immunization, suggesting that NOS2 from both hematopoietic and nonhematopoietic sources regulates TI-2 Ab responses. Similar to NOS2(-/-) mice, depletion of Ly6C(hi) inflammatory monocytes and monocyte-derived DCs enhanced NP-specific IgM and IgG3 responses to NP-Ficoll. Thus, NO produced by inflammatory monocytes and their derivative DC subsets plays an important role in regulating BAFF production and TI-2 Ab responses. PMID- 24951823 TI - The ground state of innate immune responsiveness is determined at the interface of genetic, epigenetic, and environmental influences. AB - Monocytes and macrophages form the major cellular component of the innate immune system, with roles in tissue development, homeostasis, and host defense against infection. Environmental factors were shown to play a significant part in determining innate immune responsiveness, and this included systemic conditions, such as circulating glucose levels, gut microflora, time of year, and even diurnal rhythm, which had a direct impact on innate immune receptor expression. Although the underlying molecular processes are just beginning to emerge, it is clear that environmental factors may alter epigenetic states of peripheral blood monocytes and resident tissue macrophages. We conclude that some measure of cellular ground state must become an essential part of the analysis of myeloid responsiveness or infectious susceptibility. PMID- 24951822 TI - Genetic analysis of autoimmune type 1 diabetes mellitus in mice. 1991. PMID- 24951824 TI - The R292K mutation that confers resistance to neuraminidase inhibitors leads to competitive fitness loss of A/Shanghai/1/2013 (H7N9) influenza virus in ferrets. AB - BACKGROUND: Neuraminidase (NA) inhibitors are the only licensed therapeutic option for human zoonotic H7N9 infections. An NA-R292K mutation that confers broad-spectrum resistance to NA inhibitors has been documented in H7N9 patients after treatment. METHODS: We evaluated the transmission potential of a human influenza A H7N9 isolate with a NA-R292K mutation in the ferret model followed by genotyping assay to monitor its competitive fitness in vivo. RESULTS: Plaque purified A/Shanghai/1/2013 wild-type and NA-R292K viruses transmitted at comparable efficiency to direct or respiratory droplet contact ferrets. In ferrets inoculated with the plaque-purified A/Shanghai/1/2013 NA-R292K virus with dominant K292 (94%), the resistant K292 genotype was outgrown by the wild-type R292 genotype during the course of infection. Transmission of the resistant K292 genotype was detected in 3/4 direct contact and 3/4 respiratory droplet contact ferrets at early time points but was gradually replaced by the wild-type genotype. In the respiratory tissues of inoculated or infected ferrets, the wild type R292 genotype dominated in the nasal turbinate, whereas the resistant K292 genotype was more frequently detected in the lungs. CONCLUSIONS: The NA inhibitor resistant H7N9 virus with the NA-R292K mutation may transmit among ferrets but showed compromised fitness in vivo while in competition with the wild-type virus. PMID- 24951825 TI - ATF3 confers resistance to pneumococcal infection through positive regulation of cytokine production. AB - BACKGROUND: Activating transcription factor-3 (ATF3) is known as a suppressor of cytokine production after exposure to lipopolysaccharide or during gram-negative bacterial infection. However, the mechanism by which ATF3 regulates innate immunity against gram-positive bacterial infection, particularly Streptococcus pneumoniae, remains unknown. METHODS: The wild-type and ATF3 knock-out (KO) mice were infected intranasally (i.n) or intraperitoneally with S. pneumoniae, and bacterial colonization or survival rate was determined. Pneumococcal pneumonia was induced by i.n infection, and ATF3 level was determined by Western blot. ATF3 KO cells or ATF3 siRNA transfection were used to determine expression of ATF3 downstream genes. Enzyme-linked immunosorbent assay was used to examine cytokines levels. RESULTS: ATF3 was highly expressed in various cell lines in vitro and in many organs in vivo. Pneumolysin was a novel inducer of ATF3. Pneumococcal infection induced ATF3, which subsequently stimulated production of cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, and interferon [IFN] gamma). ATF3-mediated cytokine induction protected the host from pneumococcal infection. In the pneumonia infection model, the bacterial clearance of wild-type mice was more efficient than those of ATF3 KO mice. CONCLUSIONS: Taken together, we can conclude that ATF3 regulates innate immunity positively upon pneumococcus infection by enhancing TNF-alpha, IL-1beta, and IFN-gamma expression and modulating bacterial clearance. PMID- 24951826 TI - The potential impact of adding ivermectin to a mass treatment intervention to reduce malaria transmission: a modelling study. AB - BACKGROUND: Ivermectin (IVM), used alongside mass treatment strategies with an artemisinin combination therapy, has been suggested as a possible tool for reducing malaria transmission. Mosquitoes ingesting a bloodmeal containing IVM have increased mortality, reducing the probability that the parasite completes sporogony. METHODS: Human pharmacokinetic data and mortality data for mosquitoes taking bloodmeals containing IVM are used to quantify the mosquitocidal effect of IVM. These are incorporated into a transmission model to estimate the impact of IVM in combination with mass treatment strategies with artemether-lumefantrine on transmission metrics. RESULTS: Adding IVM increases the reductions in parasite prevalence achieved and delays the reemergence of parasites compared to mass treatment alone. This transmission effect is obtained through its effect on vector mortality. IVM effectiveness depends on coverage with the highest impact achieved if given to the whole population rather than only those with existing detectable parasites. Our results suggest that including IVM in a mass treatment strategy can reduce the time taken to interrupt transmission as well as help to achieve transmission interruption in transmission settings in which mass treatment strategies alone would be insufficient. CONCLUSIONS: Including IVM in mass treatment strategies could be a useful adjunct to reduce and interrupt malaria transmission. PMID- 24951827 TI - Superantigens of Staphylococcus aureus from patients with diabetic foot ulcers. AB - BACKGROUND: Diabetic foot ulcer (DFU) infections are challenging. Staphylococcus aureus is the most commonly isolated pathogen in DFUs. Superantigens (SAgs) are causative in many S. aureus infections. We hypothesized both that DFU S. aureus will produce large SAg numbers, consistent with skin infections, and that certain SAgs will be overrepresented. We assessed the SAg and alpha-toxin profile of isolates from patients with DFU, compared with profiles of isolates from other sources. MATERIALS: Twenty-five S. aureus isolates from patients with DFU were characterized. Polymerase chain reaction was used to detect genes for methicillin resistance and SAgs. Some SAgs and the alpha-toxin were quantified. We compared the SAg profile of DFU isolates with SAg profiles of S. aureus isolates from skin lesions of patients with atopic dermatitis and from vaginal mucosa of healthy individuals. RESULTS: Most DFU isolates were methicillin susceptible (64%), with USA100 the most common clonal group. The SAg gene profile of DFU isolates most closely resembled that of isolates from patients with atopic dermatitis, with the highest number of different SAg genes per isolate and a high prevalence of staphylococcal enterotoxin D and the enterotoxin gene cluster. DFU isolates also had a high prevalence of staphylococcal enterotoxin-like X. CONCLUSIONS: Comparison of the SAg profile of DFU isolates to SAg profiles of skin lesion isolates and vaginal mucosa isolates revealed that the SAg profile of DFU isolates was more similar to that of skin lesion isolates. SAgs offer selective advantages in facilitating DFU infections and suggest that therapies to neutralize or reduce SAg production by S. aureus may be beneficial in management of patients with DFU. PMID- 24951828 TI - A novel intramuscular bivalent norovirus virus-like particle vaccine candidate- reactogenicity, safety, and immunogenicity in a phase 1 trial in healthy adults. AB - BACKGROUND: Noroviruses are the most important viral causes of gastroenteritis related morbidity and mortality. A randomized, double-blind, placebo-controlled study evaluated an adjuvanted bivalent intramuscular norovirus virus-like particle (VLP) vaccine. METHODS: Forty-eight adults aged 18-49 years received either 2 doses containing genotype GI.1 VLP and a consensus GII.4 VLP or 2 doses of placebo. Doses (5 ug, 15 ug, 50 ug, or 150 ug of each VLP) were administered 4 weeks apart in the first stage. Subsequently, 54 adults, aged 18-49 (n=16), 50-64 (n=19), and 65-85 (n=19) years, received 2 doses of vaccine containing 50 ug of each VLP. Total and class-specific antibody responses, as well as histoblood group antigen (HBGA) blocking antibody responses, were measured before and after each dose. RESULTS: Local reactions were mainly injection site pain/tenderness, with no reported fever or vaccine-related serious adverse events. One dose of vaccine containing 50 ug of each VLP increased GI.1 geometric mean titers (GMTs) by 118-fold, 83-fold, and 24-fold and increased GII.4 GMTs by 49-fold, 25-fold, and 9-fold in subjects aged 18-49, 50-64, and 65-83 years, respectively. Serum antibody responses peaked at day 7 after the first dose, with no evidence of boosting following a second dose. Most subjects achieved HBGA-blocking antibody titers of >=200. CONCLUSIONS: The vaccine was well tolerated and immunogenic. Rapid immune response to a single dose may be particularly useful in military personnel and travelers and in the control of outbreaks. Clinical Trials Registration. NCT01168401. PMID- 24951829 TI - The oncological outcomes and risk stratification in docetaxel chemotherapy for castration-resistant prostate cancer. AB - OBJECTIVE: To clarify the risk factors and develop a refined risk-stratification model to help in the appropriate selection of docetaxel chemotherapy in patients with castration-resistant prostate cancer. METHODS: This study included 97 Japanese patients with castration-resistant prostate cancer who were treated with 70-75 mg/m(2) docetaxel and 10 mg prednisone every 3 or 4 weeks from 2008 to 2013. The oncological outcomes and prognostic significance of clinicopathological factors were analyzed, and significant prognostic factors were used to develop a risk-stratification model. RESULTS: Prostate-specific antigen decline was observed in 75 patients (77.3%), including 43 (44.3%) who achieved a prostate specific antigen decline of >= 50%. The median progression-free survival and overall survival were 5.1 and 20.8 months, respectively. Univariate analysis identified performance status, alkaline phosphatase value, visceral metastasis, duration from diagnosis, duration from initiation of hormone treatment and prior treatment with estramustine as significant predictors of overall survival. Among these, alkaline phosphatase value, visceral metastasis and duration from initiation of hormone treatment were independent prognostic factors in multivariate analysis. Furthermore, risk classification according to the number of independent risk factors present effectively stratified survival among docetaxel-treated castration-resistant prostate cancer patients. CONCLUSIONS: Oncologic outcomes in Japanese patients with castration-resistant prostate cancer receiving docetaxel chemotherapy were comparable to or slightly better than those in Western populations, and the risk-stratification model developed in this study may help to predict prognosis and contribute to the selection of suitable therapy after castration resistance. PMID- 24951830 TI - Body mass index and risk of gastric cancer: a meta-analysis. AB - OBJECTIVE: Overweight and obesity, indicated as increased body mass index, are associated with the risk of some cancers. We carried out a meta-analysis on published cohort and case-control studies to assess the strength of association between body mass index and gastric cancer. METHODS: Relevant studies were identified through PubMed, Web of Science and Medline electronic databases. Adjusted relative risks (odds ratios) with 95% confidence interval were used to assess the strength of association between body mass index and gastric cancer. RESULTS: Sixteen eligible studies were included in this meta-analysis. Overall, obesity (body mass index >= 30 kg/m(2)) was associated with an increased risk of gastric cancer (odds ratio = 1.13, 95% confidence interval = 1.03-1.24) compared with normal weight (body mass index = 18.5 to <25 kg/m(2)), while overweight (body mass index = 18.5 to <30 kg/m(2)) showed no association (odds ratio = 1.04, 95% confidence interval = 0.96-1.12). Specifically, a stratified analysis showed there were associations between obesity and the increased risk of gastric cancer for males (odds ratio = 1.27, 95% confidence interval = 1.09-1.48), non-Asians (odds ratio = 1.14, 95% confidence interval = 1.02-1.28) and both cohort studies (odds ratio = 1.10, 95% confidence interval = 1.00-1.22) and case-control studies (odds ratio = 1.29, 95% confidence interval = 1.03-1.60). Both overweight (odds ratio = 1.22, 95% confidence interval = 1.05-1.42) and obesity (odds ratio = 1.61, 95% confidence interval = 1.15-2.24) were associated with the increased risk of gastric cardia cancer. CONCLUSIONS: The results indicated that obesity was associated with the risk of gastric cancer, especially for males and among non-Asians. Both overweight and obesity were associated with the risk of gastric cardia cancer. PMID- 24951831 TI - Protein tyrosine phosphatase 1B inhibition protects against podocyte injury and proteinuria. AB - Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed nonreceptor protein-tyrosine phosphatase that regulates various cellular functions, including migration. Recent studies suggest that an increased migratory phenotype of podocytes may be responsible for proteinuria and foot process effacement. The current study addresses the role of PTP1B in podocyte injury and proteinuria. PTP1B was markedly up-regulated in the glomerulus, notably in podocytes, in three rodent models of podocyte injury. Podocyte-specific ablation of the PTP1B gene ameliorated proteinuria induced by lipopolysaccharide and Adriamycin (doxorubicin). The use of a specific PTP1B inhibitor also protected against lipopolysaccharide-induced proteinuria. In contrast, podocyte-specific PTP1B transgenic male mice developed spontaneous proteinuria and foot process effacement. In cultured mouse podocytes, PTP1B knockdown and/or pretreatment with the PTP1B inhibitor blunted lipopolysaccharide-induced cell migration, activation of Src-family kinases (SFKs), and phosphorylation of focal adhesion kinase at Y397 (pFAK(Y397)), the latter being crucial for cell migration. Lipopolysaccharide-injected mice showed increased glomerular expression of active SFKs and pFAK(Y397), both of which were inhibited by podocyte-specific PTP1B knockout and the PTP1B inhibitor. Moreover, podocyte-specific PTP1B transgenic mice showed increased glomerular expression of active SFKs and pFAK(Y397). In summary, PTP1B up-regulation in podocytes induces a migratory response by activating SFKs and FAK, leading to foot process effacement and proteinuria. Pharmacological inhibition of PTP1B may have therapeutic potential in the treatment of proteinuric diseases. PMID- 24951834 TI - Global geographic distribution of Trichinella species and genotypes. AB - Maximum entropy ecological niche modeling was utilized to describe the global geographic distribution of Trichinella species and genotypes and to assess their invasive risk in new areas other than the ones currently known. Also, space-time scan statistic was utilized to identify global spatiotemporal clusters of infection. A database containing 3209 records for 12 species and genotypes identified at the International Trichinella Reference Center (ITRC) as well as climate, elevation, and land cover data extracted from various databases were used. Ecological niche modeling implemented in the Maxent program indicated new potential ranges for T. spiralis (T1), T. nativa (T2), T. britovi (T3), T. pseudospiralis (T4), T. murrelli (T5), T6, T. papuae (T10), and T. zimbabwensis (T11). The area under the curve values for the test data of the models ranged from 0.901 to 0.998, indicating that the models were very good to excellent. The most important bioclimatic factor in modeling the ranges for T. spiralis (T1), T. nativa (T2), T. britovi (T3), T6, and T. zimbabwensis (T11) was temperature, for T. pseudospiralis (T4) and T. papuae (T10) was precipitation, and for T. murrelli (T5) was land cover. T. spiralis (T1), T. britovi (T3), and T. pseudospiralis (T4) had the same primary land cover which was "Grass Crops". The primary land covers were "Conifer Boreal Forest" for T. nativa (T2), "Cool Fields and Woods" for T. murrelli (T5), "Upland Tundra" for T6, "Tropical Rainforest" for T. papuae (T10), and "Crops and Town" for T. zimbabwensis (T11). The scan statistic analyses revealed the presence of significant spatiotemporal clusters (p<0.05) for T. spiralis (T1), T. nativa (T2), T. britovi (T3), T. pseudospiralis (T4), T. murrelli (T5), T6, and T. nelsoni (T7). No significant clusters were found for T. papuae (T10) and T. zimbabwensis (T11). PMID- 24951835 TI - Comparative genomic analysis between typhoidal and non-typhoidal Salmonella serovars reveals typhoid-specific protein families. AB - BACKGROUND: The genus Salmonella contains more than 2600 serovars. While most cause a self-limiting gastroenteritis, four serovars, S. Typhi, S. Paratyphi A, B and C, elicit typhoid, a potentially fatal systemic infection. Because of the prevalence in certain regions, such as South Asia, and the disease severity of typhoidal Salmonella infections, comprehensive studies are needed to elucidate the pathogenesis of diseases caused by these typhoidal serovars. RESULTS: We performed comparative genomic analyses on eight human typhoidal strains and 27 non-human typhoidal Salmonella strains to elucidate their evolutionary relationships and identify the genes specific to the four typhoidal serovars. Our results indicate that Salmonella may have an open pan-genome. A core-genome based phylogeny demonstrated that divergence between S. Paratyphi A and S. Typhi took place not long ago and S. Paratyphi B shared a recent common ancestor with S. Paratyphi C. Of great interest, the divergence between S. Paratyphi B and S. Paratyphi C was shown to be more recent than that between S. Paratyphi A and S. Typhi. Alignment and comparisons of the genomes identified unique complements of protein families to each of the typhoidal serovars. Most of these protein families are phage related and some are candidate virulence factors. Importantly, we found 88 protein families specific to two to three of the four typhoidal serovars. All but two of the 88 genes are present in S. Typhi, with a few in the three paratyphoidal serovars but none in the non-human typhoidal serovars. Most of these genes are predicted to encode hypothetical proteins and some are known to code for virulence factors such as Vi polysaccharide related proteins. CONCLUSIONS: By comprehensive genomic comparisons, we identified protein families specific to the human typhoidal serovars, which will greatly facilitate investigations on typhoid pathogenesis. PMID- 24951832 TI - Rtr1 is a dual specificity phosphatase that dephosphorylates Tyr1 and Ser5 on the RNA polymerase II CTD. AB - The phosphorylation state of heptapeptide repeats within the C-terminal domain (CTD) of the largest subunit of RNA polymerase II (PolII) controls the transcription cycle and is maintained by the competing action of kinases and phosphatases. Rtr1 was recently proposed to be the enzyme responsible for the transition of PolII into the elongation and termination phases of transcription by removing the phosphate marker on serine 5, but this attribution was questioned by the apparent lack of enzymatic activity. Here we demonstrate that Rtr1 is a phosphatase of new structure that is auto-inhibited by its own C-terminus. The enzymatic activity of the protein in vitro is functionally important in vivo as well: a single amino acid mutation that reduces activity leads to the same phenotype in vivo as deletion of the protein-coding gene from yeast. Surprisingly, Rtr1 dephosphorylates not only serine 5 on the CTD but also the newly described anti-termination tyrosine 1 marker, supporting the hypothesis that Rtr1 and its homologs promote the transition from transcription to termination. PMID- 24951836 TI - Approach and avoidant emotion regulation prevent depressive symptoms in children with an Autism Spectrum Disorder. AB - The prevalence of depression is high in children with Autism Spectrum Disorders (ASDs), but its etiology has not yet been studied in this group. Emotion dysregulation is a well-known contributor to the development of depression in typically developing (TD) children, which might also apply to children with ASD. In this study, we examined the longitudinal relationship between three different ways of emotion regulation (approach, avoidance and worry/rumination) and depressive symptoms in children with ASD and a group of TD children which were compatible with the ASD group (age 9-15-years old). Children filled out self report questionnaires at 3 time points (with a 9-month break between each session). To account for missing data multiple imputations were used. A regression model with clustered bootstrapping was used to establish which factors contributed to depression and to identify possible differences between the ASD and TD group. Approach and avoidant strategies prevented the development of depressive symptoms in both respective groups, whereas elevated levels of worry/rumination in turn increased children's depressive symptoms. Besides differences in absolute levels (children with ASD scored higher on symptoms of depression and lower on approach strategies than the TD group), no other differences between the groups emerged. PMID- 24951833 TI - NMR model of PrgI-SipD interaction and its implications in the needle-tip assembly of the Salmonella type III secretion system. AB - Salmonella and other pathogenic bacteria use the type III secretion system (T3SS) to inject virulence proteins into human cells to initiate infections. The structural component of the T3SS contains a needle and a needle tip. The needle is assembled from PrgI needle protomers and the needle tip is capped with several copies of the SipD tip protein. How a tip protein docks on the needle is unclear. A crystal structure of a PrgI-SipD fusion protein docked on the PrgI needle results in steric clash of SipD at the needle tip when modeled on the recent atomic structure of the needle. Thus, there is currently no good model of how SipD is docked on the PrgI needle tip. Previously, we showed by NMR paramagnetic relaxation enhancement (PRE) methods that a specific region in the SipD coiled coil is the binding site for PrgI. Others have hypothesized that a domain of the tip protein-the N-terminal alpha-helical hairpin-has to swing away during the assembly of the needle apparatus. Here, we show by PRE methods that a truncated form of SipD lacking the alpha-helical hairpin domain binds more tightly to PrgI. Further, PRE-based structure calculations revealed multiple PrgI binding sites on the SipD coiled coil. Our PRE results together with the recent NMR-derived atomic structure of the Salmonella needle suggest a possible model of how SipD might dock at the PrgI needle tip. SipD and PrgI are conserved in other bacterial T3SSs; thus, our results have wider implication in understanding other needle-tip complexes. PMID- 24951838 TI - Crystallin alphaB acts as a molecular guard in mouse decidualization: regulation and function during early pregnancy. AB - Although decidualization is crucial for the establishment of successful pregnancy, the molecular mechanism underlying decidualization remains poorly understood. Crystallin alphaB (CryAB), a small heat shock protein (sHSP), is up regulated and phosphorylated in mouse decidua. In mouse primary endometrial stromal cells, CryAB is induced upon progesterone treatment via HIF1alpha. In addition, CryAB is strongly phosphorylated through the p38-MAPK pathway under stress or during in vitro decidualization. Knockdown of CryAB results in the increase of apoptosis of stromal cells and inhibits decidualization under oxidative or inflammatory stress. Our data indicate that CryAB protects decidualization against stress conditions. PMID- 24951839 TI - The centrosome duplication cycle in health and disease. AB - Centrioles function in the assembly of centrosomes and cilia. Structural and numerical centrosome aberrations have long been implicated in cancer, and more recent genetic evidence directly links centrosomal proteins to the etiology of ciliopathies, dwarfism and microcephaly. To better understand these disease connections, it will be important to elucidate the biogenesis of centrioles as well as the controls that govern centriole duplication during the cell cycle. Moreover, it remains to be fully understood how these organelles organize a variety of dynamic microtubule-based structures in response to different physiological conditions. In proliferating cells, centrosomes are crucial for the assembly of microtubule arrays, including mitotic spindles, whereas in quiescent cells centrioles function as basal bodies in the formation of ciliary axonemes. In this short review, we briefly introduce the key gene products required for centriole duplication. Then we discuss recent findings on the centriole duplication factor STIL that point to centrosome amplification as a potential root cause for primary microcephaly in humans. We also present recent data on the role of a disease-related centriole-associated protein complex, Cep164-TTBK2, in ciliogenesis. PMID- 24951841 TI - Cyclic ovarian hormone modulation of supraspinal Delta9-tetrahydrocannabinol induced antinociception and cannabinoid receptor binding in the female rat. AB - Estrous cycle-related fluctuations in delta-9-tetrahydrocannabinol (THC)-induced antinociception have been observed in the rat. The aim of this study was to determine which major ovarian hormone modulates the antinociceptive effects of i.c.v. THC, and whether hormone modulation of THC's behavioral effects could be due to changes in brain cannabinoid receptors (CBr). Vehicle (oil) or hormones (estradiol or progesterone, or both) were administered to female rats on days 3 and 7 post-ovariectomy. On the morning or afternoon of day 8 or day 9, vehicle or THC (100 MUg) was administered i.c.v. Paw pressure, tail withdrawal, locomotor activity and catalepsy tests were conducted over a 3-h period. Estradiol (with and without progesterone) enhanced THC-induced paw pressure antinociception only. Ovarian hormones time-dependently modulated CBr in brain structures that mediate antinociception and locomotor activity, but the changes observed in CBr did not parallel changes in behavior. However, the time course of CBr changes must be further elucidated to determine the functional relationship between receptor changes and antinociceptive sensitivity to THC. PMID- 24951837 TI - Social-cognitive, physiological, and neural mechanisms underlying emotion regulation impairments: understanding anxiety in autism spectrum disorder. AB - Anxiety is one of the most common clinical problems among children, adolescents, and adults with autism spectrum disorder (ASD), yet we know little about its etiology in the context of ASD. We posit that emotion regulation (ER) impairments are a risk factor for anxiety in ASD. Specifically, we propose that one reason why anxiety disorders are so frequently comorbid with ASD is because ER impairments are ubiquitous to ASD, stemming from socio-cognitive, physiological, and neurological processes related to impaired cognitive control, regulatory processes, and arousal. In this review, we offer a developmental model of how ER impairments may arise in ASD, and when (moderating influences) and how (meditational mechanisms) they result in anxiety. PMID- 24951840 TI - Incidence, outcomes, and health services burden of very early onset inflammatory bowel disease. AB - BACKGROUND & AIMS: The Paris pediatric modification of the Montreal classification defines very early onset inflammatory bowel disease (VEO-IBD) as a form of IBD distinct from that of older children. We compared the incidence and outcomes of VEO-IBD with those of IBD in older children. METHODS: We performed a population-based retrospective cohort study of all children diagnosed with IBD in Ontario, Canada, from 1994 through 2009. Trends in standardized incidence were calculated using Poisson regression. We compared outpatient and emergency department visits, hospitalizations, and surgeries among children diagnosed with IBD when they were younger than age 6, ages 6-9.9, and older than age 10 years. Multivariable models were adjusted for income and stratified by sex. RESULTS: The incidence of IBD increased from 9.4 per 100,000 children (95% confidence interval [CI], 8.2-10.8/100,000 children) in 1994 to 13.2 per 100,000 children (95% CI, 11.9-14.6/100,000 children) in 2009 (P < .0001). The incidence increased by 7.4% per year among children younger than 6 years old and 6-9.9 years old, and by 2.2% per year among children >=10 years old. IBD-related outpatient visits were less frequent among children <6 years old than >=10 years old (odds ratio for female patients, 0.67; 95% CI, 0.58-0.78; odds ratio for male patients, 0.86; 95% CI, 0.75-0.98). Hazard ratios [HRs] for hospitalization were lower for children <6 years old (female HR, 0.70; 95% CI, 0.56-0.87; male HR, 1.12; 95% CI, 0.94-1.33) than for older children. HRs for surgery among children <6 years old with Crohn's disease were 0.35 for female patients (95% CI, 0.16-0.78) and 0.59 for male patients (95% CI, 0.34-0.99). HRs for children <6 years old with ulcerative colitis were 0.88 for female patients (95% CI, 0.47-1.63) and 0.42 for male patients (95% CI, 0.21-0.85). There was no difference in hospitalization or surgery rates among children 6-9.9 years old vs those >=10 years old. CONCLUSIONS: Based on a retrospective cohort study, the incidence of VEO-IBD increased from 1994 through 2009. Children diagnosed with IBD before they were 6 years old used fewer health services and had lower rates of surgery than children diagnosed when they were 10 years or older. PMID- 24951842 TI - An improved and reproducible protocol for the extraction of high quality fungal RNA from plant biomass substrates. AB - Isolation of high quantity and quality RNA is a crucial step in the detection of meaningful gene expression data. Obtaining intact fungal RNA from complex lignocellulosic substrates is often difficult, producing low integrity RNA which perform poorly in downstream applications. In this study we developed an RNA extraction method using CsCl centrifugation procedure, modified from previous reports and adapted for isolation of RNA from plant biomass. This method provided high level of integrity and good quantity of RNA which were suitable for reliable analyses of gene expression and produced consistent and reproducible results. PMID- 24951843 TI - Fecal calprotectin-guided dosing of mesalamine in ulcerative colitis: concept proved but more data needed. PMID- 24951845 TI - Intestinal microbiota metabolism of a prebiotic to treat hepatic encephalopathy. PMID- 24951844 TI - Do naps and nocturnal sleep impact gastroesophageal reflux disease differently? PMID- 24951846 TI - A rosebud-like retrograde view of the duodenal bulb. PMID- 24951847 TI - Redux: do little bellyachers grow up to become big bellyachers? PMID- 24951848 TI - Pseudomembranes do not always indicate Clostridium difficile infection. PMID- 24951849 TI - Optimizing outcomes of urethroplasty. PMID- 24951850 TI - To V(CUG) or not to V(CUG) in infants with prenatal hydronephrosis? PMID- 24951851 TI - The legacy of Ernest A. Codman in the 21st century. PMID- 24951852 TI - A new feature extraction framework based on wavelets for breast cancer diagnosis. AB - This paper investigates a pattern recognition framework in order to determine and classify breast cancer cases. Initially, a two-class separation study classifying normal and abnormal (cancerous) breast tissues is achieved. The Histogram of Oriented Gradients (HOG), Dense Scale Invariant Feature Transform (DSIFT), and Local Configuration Pattern (LCP) methods are used to extract the rotation- and scale-invariant features for all tissue patches. A classification is made utilizing Support Vector Machine (SVM), k-Nearest Neighborhood (k-NN), Decision Tree, and Fisher Linear Discriminant Analysis (FLDA) via 10-fold cross validation. Then, a three-class study (normal, benign, and malignant cancerous cases) is carried out using similar procedures in a two-class case; however, the attained classification accuracies are not sufficiently satisfied. Therefore, a new feature extraction framework is proposed. The feature vectors are again extracted with this new framework, and more satisfactory results are obtained. Our new framework achieved a remarkable increase in recognition performance for the three-class study. PMID- 24951853 TI - Occasional spontaneous clearance of chronic hepatitis C virus in HIV-infected individuals. AB - The IL28B genotype has been found to have a strong influence on spontaneous clearance of acute HCV both in HCV mono- and HIV/ the HCV co-infected patients. Spontaneous clearance of chronic HCV without HCV treatment is rare. Here, we report on three chronic HCV cases co-infected with HIV with spontaneous clearance of their HCV infection, all with the IL28B CC genotype. These cases were derived from a surveillance of the total HIV/HCV co-infected cohort in Sweden (n =4 66). The estimated frequency of spontaneous clearance of chronic HCV infection in our cohort was calculated to be 0.6-4.7%. Our cases lend some support to the initiation of ART prior to HCV treatment in HIV/HCV co-infected patients. Furthermore, HCV-RNA testing should be recommended immediately before initiation of HCV treatment, to find the subset of HIV/HCV co-infected patients with IL28B CC that may have cleared their chronic infection spontaneously. PMID- 24951854 TI - Negative allosteric modulation of mGlu5 receptor rescues striatal D2 dopamine receptor dysfunction in rodent models of DYT1 dystonia. AB - Early onset torsion dystonia (DYT1) is an autosomal dominantly inherited disorder caused by deletion in TOR1A gene. Evidence suggests that TOR1A mutation produces dystonia through an aberrant neuronal signalling within the striatum, where D2 dopamine receptors (D2R) produce an abnormal excitatory response in cholinergic interneurons (ChIs) in different models of DYT1 dystonia. The excitability of ChIs may be modulated by group I metabotropic glutamate receptor subtypes (mGlu1 and 5). We performed electrophysiological and calcium imaging recordings from ChIs of both knock-in mice heterozygous for Delta-torsinA (Tor1a(+/Deltagag) mice) and transgenic mice overexpressing human torsinA (hMT1). We demonstrate that the novel negative allosteric modulator (NAM) of metabotropic glutamate 5 (mGlu) receptor, dipraglurant (ADX48621) counteracts the abnormal membrane responses and calcium rise induced either by the D2R agonist quinpirole or by caged dopamine (NPEC-Dopamine) in both models. These inhibitory effects were mimicked by two other well-characterized mGlu5 receptor antagonists, SIB1757 and MPEP, but not by mGlu1 antagonism. D2R and mGlu5 post-receptor signalling may converge on PI3K/Akt pathway. Interestingly, we found that the abnormal D2R response was prevented by the selective PI3K inhibitor, LY294002, whereas PLC and PKC inhibitors were both ineffective. Currently, no satisfactory pharmacological treatment is available for DYT1 dystonia patients. Our data show that negative modulation of mGlu5 receptors may counteract abnormal D2R responses, normalizing cholinergic cell excitability, by modulating the PI3K/Akt post-receptor pathway, thereby representing a novel potential treatment of DYT1 dystonia. PMID- 24951855 TI - The use of stimulant medications for non-core aspects of ADHD and in other disorders. AB - Psychostimulants play a central role in the management of ADHD. Here we review the evidence pertaining to the use of methylphenidate, dexamphetamine and related amphetamine salts, the prodrug lisdexamfetamine and modafinil for the management of comorbid ADHD and non-ADHD indications. There is a growing consensus that stimulant medications are helpful at improving the emotional dysregulation and lability, and oppositional and conduct symptoms that are often associated with ADHD. There is some evidence that psychostimulants may improve outcomes in those with treatment resistant depression, reduce negative symptoms and improve cognitive performance in schizophrenia, and that methylphenidate may reduce binge eating in those with bulimia nervosa. In general medicine, whilst the evidence is at times contradictory, psychostimulants have been shown in some studies to be effective treatments for chronic fatigue and narcolepsy, and to improve outcomes post stroke, post head injury, in dementia and various cancers. It seems likely that these effects often result from a combination of, reduction in fatigue, improvements in concentration and cognitive functioning and a lifting of mood which may be a direct or indirect consequence of the medication. Further studies seem warranted and these should focus on efficacy, effectiveness and long term safety. This article is part of the Special Issue entitled 'CNS Stimulants'. PMID- 24951856 TI - Neural correlates of craving and impulsivity in abstinent former cocaine users: Towards biomarkers of relapse risk. AB - A significant hindrance to effective treatment of addiction is identifying those most likely to relapse. Cocaine addiction is characterized by deficits in inhibitory control and elevated reactivity to cocaine cues, both hypothesized to be integral to development of addiction and propensity to relapse. It follows that reduction of both impulsivity and cue-reactivity following abstinence is protective against relapse, and that persistence of these factors increases vulnerability. Using functional magnetic resonance imaging, we examined neural activation patterns in dorsal and ventral striatum in abstinent cocaine dependent (CD) individuals (N=20) and non-using controls (N=19) as they performed a cocaine craving task. We also examined activations in nodes of the response inhibition circuit (RIC) as they performed an inhibition task. At the between-groups level, no differences in RIC or striatal activation were seen in former users, in contrast to previous investigations in current users, suggesting large-scale functional recovery with abstinence. However, at the individual participant level, abstinent CD individuals displayed an association between cocaine cue related neural activations in the right ventral striatum and compulsive cocaine craving scores. Compulsive craving scores were also negatively correlated with duration of abstinence. Further, there was an association between motor impulsivity scores and inhibition-related activations in the right inferior frontal gyrus and pre-supplementary motor area in abstinent CD individuals. Thus, while former users as a group did not show deficits in inhibitory function or cocaine-cue reactivity, participant-level results pointed to activation patterns in a minority of these individuals that likely contributes to enduring relapse vulnerability. PMID- 24951857 TI - Concurrent and robust regulation of feeding behaviors and metabolism by orexin neurons. AB - Orexin neurons in the hypothalamus regulate energy homeostasis by coordinating various physiological responses. Past studies have shown the role of the orexin peptide itself; however, orexin neurons contain not only orexin but also other neurotransmitters such as glutamate and dynorphin. In this study, we examined the physiological role of orexin neurons in feeding behavior and metabolism by pharmacogenetic activation and chronic ablation. We generated novel orexin-Cre mice and utilized Cre-dependent adeno-associated virus vectors to express Gq coupled modified GPCR, hM3Dq or diphtheria toxin fragment A in orexin neurons. By intraperitoneal injection of clozapine-N oxide in orexin-Cre mice expressing hM3Dq in orexin neurons, we could selectively manipulate the activity of orexin neurons. Pharmacogenetic stimulation of orexin neurons simultaneously increased locomotive activity, food intake, water intake and the respiratory exchange ratio (RER). Elevation of blood glucose levels and RER persisted even after locomotion and feeding behaviors returned to basal levels. Accordantly, 83% ablation of orexin neurons resulted in decreased food and water intake, while 70% ablation had almost no effect on these parameters. Our results indicate that orexin neurons play an integral role in regulation of both feeding behavior and metabolism. This regulation is so robust that greater than 80% of orexin neurons were ablated before significant changes in feeding behavior emerged. PMID- 24951859 TI - Immunization with adenovirus LIGHT-engineered dendritic cells induces potent T cell responses and therapeutic immunity in HBV transgenic mice. AB - LIGHT, a TNF superfamily member (TNFSF14), is a type II transmembrane protein expressed on activated T cells and immature dendritic cells (DCs). However, the expression of LIGHT on mature DCs is down-regulated. Recent studies demonstrated that LIGHT provides potent costimulatory activity for T cells, enhancing proliferation and the production of Th1 cytokines independently of the B7-CD28 pathway. Here, we evaluated the effectiveness of peptide-pulsed DC-mediated antiviral immunity in HBV transgenic mice and the immunoadjuvant effect of LIGHT. The bone marrow-derived DCs were modified in vitro with an adenovirus (Ad) vector expressing mouse LIGHT (Ad-LIGHT), the expression of costimulatory molecules was up-regulated and the secretion of cytokines IL-12 and IFN-gamma increased. LIGHT modified DCs enhanced allostimulation for T cells in mixed lymphocyte reaction (MLR). HBV peptide-pulsed DCs elicited HBV specific CD8+ T cell response and reduced the level of HBsAg and HBV DNA in sera of HBV transgenic mice. Importantly, LIGHT-modified DCs could induce stronger antiviral immunity. These results support the concept that genetic modification of DCs with a recombinant LIGHT adenovirus vector may be a useful strategy for antiviral immunotherapy. PMID- 24951858 TI - Fluorescence cryo-microscopy: current challenges and prospects. AB - Studying biological structures with fine details does not only require a microscope with high resolution, but also a sample preparation process that preserves the structures in a near-native state. Live-cell imaging is restricted mostly to the field of light microscopy. For studies requiring much higher resolution, fast freezing techniques (vitrification) are successfully used to immobilize the sample in a near-native state for imaging with electron and X-ray cryo-microscopy. Fluorescence cryo-microscopy combines imaging of vitrified samples with the advantages of fluorescence labeling of biological structures. Technical considerations as well as the behavior of fluorophores at low temperatures have to be taken into account for developing or adapting super resolution methods under cryo conditions to exploit the full potential of this technique. PMID- 24951860 TI - Detecting and preventing reversion to toxicity for a formaldehyde-treated C. difficile toxin B mutant. AB - The toxicity of Clostridium difficile large clostridial toxin B (TcdB) can be reduced by many orders of magnitude by a combination of targeted point mutations. However, a TcdB mutant with five point mutations (referred to herein as mTcdB) still has residual toxicity that can be detected in cell-based assays and in-vivo mouse toxicity assays. This residual toxicity can be effectively removed by treatment with formaldehyde in solution. Storage of the formaldehyde-treated mTcdB as a liquid can result in reversion over time back to the mTcdB level of toxicity, with the rate of reversion dependent on the storage temperature. We found that for both the "forward" mTcdB detoxification reaction with formaldehyde, and the "reverse" reversion to toxicity reaction, mouse toxicity correlated with several biochemical assays including anion exchange chromatography retention time and appearance on SDS-PAGE. Maintenance of a low concentration of formaldehyde prevents reversion to toxicity in liquid formulations. However, when samples with 0.016% (v/v) formaldehyde were lyophilized and stored at 37 degrees C, formaldehyde continued to react with and modify the mTcdB in the lyophilized state. Lyophilization alone effectively prevented reversion to toxicity for formaldehyde-treated, formaldehyde-removed mTcdB samples stored at 37 degrees C for 6 months. Formaldehyde-treated, formaldehyde-removed lyophilized mTcdB showed no evidence of reversion to toxicity, appeared stable by several assays, and was immunogenic in mice, even after storage for 6 months at 37 degrees C. PMID- 24951862 TI - Professional and ethical responsibilities of health-care workers in regard to vaccinations. PMID- 24951861 TI - Microstructured liposome subunit vaccines reduce lung inflammation and bacterial load after Mycobacterium tuberculosis infection. AB - BACKGROUND: Tuberculosis is a disease affecting millions of people throughout the world. One of the main problems in controlling the disease is the low efficacy of the Bacillus Calmette-Guerin (BCG) vaccine in protecting young adults. The development of new vaccines that induce a long-lasting immune response or that stimulate the immunity induced by BCG may improve the control of tuberculosis. METHODS: The use of microstructured liposomes containing HspX, with or without MPL or CpG DNA adjuvants, as vaccines for tuberculosis was evaluated. The HspX specific humoral and cellular immune responses to the different vaccine formulations were compared. RESULTS: All vaccines containing liposome microparticles and HspX were immunogenic. Vaccines formulated with CpG DNA and HspX induced the strongest humoral and cellular immune responses, mainly by inducing interferon-gamma and tumor necrosis factor-alpha expression by both CD4(+) and CD8(+) T cells. HspX and MPL mainly induced CD8(+) T-cell activation and specific humoral responses. When evaluated the protective efficacy of the formulations against Mycobacterium tuberculosis challenge, the microstructured liposome containing L-HspX and L-HspX-CPG DNA reduced both lung inflammatory lesions and the bacterial load. CONCLUSION: We have thus demonstrated, for the first time, the use of microstructured liposomes as an adjuvant and delivery system for a vaccine formulation against tuberculosis. PMID- 24951863 TI - Comparative performance of public and private sector delivery of BCG vaccination: evidence from Sub-Saharan Africa. AB - BACKGROUND: The private sector is an important source of health care in the developing world. However, there is limited evidence on how private providers compare to public providers, particularly for preventive services such as immunizations. We used data from Sub-Saharan Africa (SSA) to assess public private differences in Bacillus Calmette-Guerin (BCG) vaccine delivery. METHODS AND FINDINGS: We used demographic and health surveys from 102,629 children aged 0 59 months from 29 countries across SSA to measure differences in BCG status for children born at private versus public health facilities (BCG is recommended at birth). We used a probit model to estimate public-private differences in BCG delivery, while controlling for key confounders. Next, we estimated how differences in BCG status evolved over time for children born at private versus public facilities. Finally, we estimated heterogeneity in public-private differences based on wealth and rural-urban residency. We found that children born at a private facility were 7.1 percentage points less likely to receive BCG vaccine in the same month as birth than children born at a public facility (95% CI 6.3-8.0; p<0.001). Most of this difference was driven by for-profit private providers (as opposed to NGOs) where the BCG provision rate was 10.0 percentage points less than public providers (95% CI 9.0-11.2; p<0.001) compared to only 2.4 percentage points for NGOs (95% CI 1.0-3. 8; p<0.01). Moreover, children born at private for-profit facilities remained less likely to be vaccinated up to 59 months after birth. Finally, public-private differences were more pronounced for poorer children and children in rural areas. CONCLUSIONS: The for-profit private sector performed substantially worse than the public sector in providing BCG vaccine to newborns, resulting in a longer duration of vulnerability to tuberculosis. This disparity was greater for poorer children and children in rural areas. PMID- 24951864 TI - Recent progress and concerns regarding the Japanese immunization program: addressing the "vaccine gap". AB - Recent progress in the Japanese immunization program has partially closed the "vaccine gap," i.e., the deficiencies in that program relative to immunization programs in other developed countries. During the last several years, seven new vaccines (12 new products, excluding influenza vaccines) have been introduced in Japan. Five of these new vaccines are produced outside Japan and four are now included as routine vaccines in the National Immunization Program, which is a new development in the licensing and financial support of imported vaccines. However, along with this progress, important concerns have arisen regarding the Japanese immunization program. A rubella epidemic among adults, in 2012-2013, resulted in more than 40 cases of congenital rubella syndrome as of March 2014. In addition, the temporary withdrawal of the active governmental recommendation for human papilloma virus vaccines, in 2013-2014, highlighted challenges in the current Japanese immunization system. Furthermore, some important vaccines - including vaccines for hepatitis B virus, mumps, varicella, and rotavirus - are still not included in the National Immunization Program and have been categorized as voluntary vaccines since their introduction. The possibility of their inclusion in the National Immunization Program remains a matter for discussion. We hope that future initiatives will further address the vaccine gap and protect Japanese children from vaccine-preventable diseases. PMID- 24951865 TI - Prevalence of chronic hepatitis B virus infection before and after implementation of a hepatitis B vaccination program among children in Nepal. AB - BACKGROUND: In Nepal, an estimated 2-4% of the population has chronic hepatitis B virus (HBV) infection. To combat this problem, from 2002 to 2004, a national three dose hepatitis B vaccination program was implemented to decrease infection rates among children. The program does not currently include a birth dose to prevent perinatal HBV transmission. In 2012, to assess the impact of the program, we conducted a serosurvey among children born before and after vaccine introduction. METHODS: In 2012, a cross-sectional nationally representative stratified cluster survey was conducted to estimate hepatitis B surface antigen (HBsAg) prevalence among children born from 2006 to 2007 (post-vaccine cohort) and among children born from 2000 to 2002 (pre-vaccine cohort). Demographic data, as well as written and oral vaccination history were collected. All children were tested for HBsAg; mothers of HBsAg positive children were also tested. Furthermore, we evaluated the field sensitivity and specificity of the SD Bioline HBsAg rapid diagnostic test by comparing results with an enzyme immunoassay. RESULTS: Among 2181 post-vaccination cohort children with vaccination data by either card or recall, 86% (95% confidence interval [CI] 77-95%) received >= 3 hepatitis B vaccine doses. Of 1200 children born in the pre-vaccination cohort, 0.28% (95% CI 0.09-0.85%) were positive for HBsAg; of 2187 children born in the post-vaccination cohort, 0.13% (95% CI 0.04-0.39%) were positive for HBsAg (p=0.39). Of the six children who tested positive for HBsAg, two had mothers who were positive for HBsAg. Finally, we found the SD Bioline HBsAg rapid diagnostic test to have a sensitivity of 100% and a specificity of 100%. CONCLUSIONS: This is the first nationally representative hepatitis B serosurvey conducted in Nepal. Overall, a low burden of chronic HBV infection was found in children born in both the pre and post-vaccination cohorts. Current vaccination strategies should be continued. PMID- 24951866 TI - Evaluation of economic costs of a measles outbreak and outbreak response activities in Keffa Zone, Ethiopia. AB - OBJECTIVE: To estimate the economic impact of a measles outbreak and response activities that occurred in Keffa Zone, Ethiopia with 5257 reported cases during October 1, 2011-April 8, 2012, using the health sector and household perspectives. METHODS: We collected cost input data through interviews and record reviews with government and partner agency staff and through a survey of 100 measles cases-patients and their caretakers. We used cost input data to estimate the financial and opportunity costs of the following outbreak and response activities: investigation, treatment, case management, active surveillance, immunization campaigns, and immunization system strengthening. FINDINGS: The economic cost of the outbreak and response was 758,869 United States dollars (US$), including the opportunity cost of US$327,545 (US$62.31/case) and financial cost of US$431,324 (US$82.05/case). Health sector costs, including the immunization campaign (US$72.29/case), accounted for 80% of the economic cost. Household economic cost was US$29.18/case, equal to 6% of the household median annual income. 92% of financial costs were covered by partner agencies. CONCLUSION: The economic cost of the measles outbreak was substantial when compared to household income and health sector expenditures. Improvement in two dose measles vaccination coverage above 95% would both reduce measles incidence and save considerable outbreak-associated costs to both the health sector and households. PMID- 24951867 TI - AS04-adjuvanted virus-like particles containing multiple M2 extracellular domains of influenza virus confer improved protection. AB - The ectodomain of matrix protein 2 (M2e) of influenza virus is suggested to be a rational target for a universal influenza A vaccine. However, there are some concerns that M2e vaccines might not be highly effective in the general population with diverse genetic backgrounds. Here we examined the immunogenicity and protective efficacy of the baculovirus-derived virus-like particles containing multiple M2e (M2eVLP) with AS04 adjuvant in a C57BL/6 mouse strain (H 2(b)). M2eVLP vaccine induced significant levels of M2e-specific IgG in C57BL/6 mice after vaccination. Furthermore, M2eVLP adjuvanted with AS04 was more effective than M2eVLP alone in conferring protection as well as in inducing recall humoral and T cell responses specific for M2e after lethal influenza virus challenge. A mechanistic study provides evidence that activation of dendritic cells by the toll-like receptor 4 agonist MPL in the AS04 adjuvant was associated with interferon-gamma producing CD4 T cell responses. Our results suggest that AS04 adjuvanted M2eVLP vaccines have the potential to improve cross-protection. PMID- 24951868 TI - Ischemic cardiac events and other adverse events following ACAM2000((r)) smallpox vaccine in the Vaccine Adverse Event Reporting System. AB - BACKGROUND: The Vaccine Adverse Event Reporting System (VAERS) is a passive reporting system, used for monitoring the safety of all US licensed vaccines. In March 2008, ACAM2000((r)) replaced Dryvax((r)) as the only licensed smallpox vaccine and is administered to all persons entering military service and certain civilian researchers. In 2011, routine data mining of VAERS identified a vaccine safety concern resulting in acute ischemic cardiac events (ICE) following ACAM2000((r)). METHODS: During March 1, 2008 through June 30, 2013, we reviewed all serious reports received following ACAM2000((r))and classified them by diagnostic category. We identified possible ICE cases by searching the Medical Dictionary for Regulatory Affairs (MedDRA((r))) terms for "myocardial ischaemia," "acute myocardial infarction," "myocardial infarction," and "ischaemia," and applied standardized surveillance case definitions. RESULTS: VAERS received 1149 reports following ACAM2000((r)) administration; 169 (14.7%) were serious (resulting in permanent disability, hospitalization or prolongation of hospitalization, life-threatening illness or death), including one death. The two most frequent diagnostic categories for serious reports were cardiovascular and other infectious conditions. The MedDRA((r)) search found 31 reports of possible ICE after receipt of ACAM2000((r)) vaccine. Of a total 30 possible ICE cases with demographic information, all but one was male; the age range was 20-45 years (median 32) and median interval to onset of symptoms was 12 days. On clinical review there were 16 cases of myocarditis/pericarditis and 15 ICE cases. CONCLUSIONS: Our review of the data mining signal did not substantiate the concerns about ICE after ACAM2000((r)). Our study also suggests that with current pre-vaccination screening, cardiac morbidity in generally healthy vaccinated populations remains uncommon. PMID- 24951870 TI - Vaccination coverage against hepatitis A and B viruses, Streptococcus pneumoniae, seasonal flu, and A(H1N1)2009 pandemic influenza in HIV-infected patients. AB - BACKGROUND: Several vaccines are recommended in HIV-infected patients due to an increased risk of vaccine-preventable infections, severe forms of the disease, or shared transmission routes. Few data are available regarding vaccination coverage and its determinants in this population. METHODS: A cross-sectional study was performed in HIV-infected patients included in a hospital-based cohort in 2011. Vaccination coverage against hepatitis A virus (HAV), hepatitis B virus (HBV), seasonal and A(H1N1)2009 pandemic influenza, and invasive pneumococcal diseases (IPD) were recorded. Factors associated with vaccination were assessed by multivariate logistic regression. RESULTS: 2467 patients were included (median age: 47 years; male gender 71.5%; men having sex with men (MSM): 43.9%; CDC stage C: 24.3%; HBV and/or hepatitis C virus co-infection: 14.4%). Median duration of HIV infection was 10 years and 93.1% of patients received combination antiretroviral therapy. At baseline, the median CD4 count was 527 cells/mm(3) and HIV viral load was <50 copies/mL in 83.3% of cases. Vaccination coverage for HBV, HAV, seasonal influenza, A(H1N1)2009 pandemic influenza, and IPD were 61.9%, 47.4%, 30.9, 48.3%, and 64.6%, respectively. Factors independently associated with vaccination were a younger (HBV) or an older age (influenza), male gender (HBV, HAV), MSM (HBV), CD4 count >200/mm(3) and HIV-RNA <50 copies/mL (IPD, influenza), longer duration of HIV infection (IPD, influenza), and follow-up by an experienced physician (HBV, IPD). CONCLUSIONS: Vaccination coverage remained insufficient for all vaccine-preventable infections investigated in this study. Determinants for vaccination were largely not evidence-based, and efforts should be focused on improving physicians' knowledge about guidelines. PMID- 24951869 TI - Recombinant measles viruses expressing respiratory syncytial virus proteins induced virus-specific CTL responses in cotton rats. AB - Respiratory syncytial virus (RSV) is a common cause of serious lower respiratory tract illnesses in infants. Natural infections with RSV provide limited protection against reinfection because of inefficient immunological responses that do not induce long-term memory. RSV natural infection has been shown to induce unbalanced immune response. The effective clearance of RSV is known to require the induction of a balanced Th1/Th2 immune response, which involves the induction of cytotoxic T lymphocytes (CTL). In our previous study, recombinant AIK-C measles vaccine strains MVAIK/RSV/F and MVAIK/RSV/G were developed, which expressed the RSV fusion (F) protein or glycoprotein (G). These recombinant viruses elicited antibody responses against RSV in cotton rats, and no infectious virus was recovered, but small amounts of infiltration of inflammatory cells were observed in the lungs following RSV challenge. In the present study, recombinant AIK-C measles vaccine strains MVAIK/RSV/M2-1 and MVAIK/RSV/NP were developed, expressing RSV M2-1 or Nucleoprotein (NP), respectively. These viruses exhibited temperature-sensitivity (ts), which was derived from AIK-C, and expressed respective RSV antigens. The intramuscular inoculation of cotton rats with the recombinant measles virus led to the induction of CD8(+) IFN-gamma(+) cells. No infectious virus was recovered from a lung homogenate following the challenge. A Histological examination of the lungs revealed a significant reduction in inflammatory reactions without alveolar damage. These results support the recombinant measles viruses being effective vaccine candidates against RSV that induce RSV-specific CTL responses with or without the development of an antibody response. PMID- 24951871 TI - Safety and immunogenicity of live-attenuated Japanese encephalitis SA 14-14-2 vaccine co-administered with measles vaccine in 9-month-old infants in Sri Lanka. AB - INTRODUCTION: To facilitate introduction of live attenuated SA 14-14-2 Japanese encephalitis vaccine (LJEV) into the National Immunization Programme of Sri Lanka, we evaluated the safety and immunogenicity of co-administration of LJEV and measles vaccine at 9 months of age. Serum immune responses were evaluated post-vaccination on days 28, 180, and 365 using JE neutralization test and anti measles IgG ELISA. RESULTS: 278 infants received one dose of LJEV and measles vaccine. Of these, 257 were eligible for the per-protocol analysis. On Day 0, 14 infants (5.5%) were seropositive for JE, but none were seropositive for measles. At Day 28, seropositivity rates were 90.7% (95% CI, 86.4-93.9%) for JE and 84.8% (95% CI, 79.8-89.0%) for measles. The geometric mean titer for JE neutralizing antibodies was 111 (95% CI, 90-135), and the geometric mean concentration (GMC) for anti-measles IgG was 375 mI U/mL (95% CI, 351-400 mI U/mL). Over the next year, JE neutralizing antibody responses declined only slightly, with seropositivity at 87.4% (95% CI, 82.6-91.2%) at Day 365. In contrast, measles antibody levels continued to increase over time. Seropositivity for anti-measles IgG reached 97.2% (95% CI, 94.4-98.9%) at Day 365, and the GMC rose to 1202 mI U/mL (95% CI, 1077-1341 mI U/mL). Co-administration of LJEV and measles vaccine was also safe. Most adverse reactions were mild, and no serious adverse events were related to study vaccinations. CONCLUSION: The safety and immunogenicity of LJEV co-administered with measles vaccine in Sri Lankan infants is similar to that seen in other populations, and our results support use of LJEV at 9 months of age. Live SA 14-14-2 vaccine is now prequalified by the WHO for use in infants in Asia, and other countries may wish to introduce LJEV to combat this devastating disease. PMID- 24951872 TI - Okadaic acid: a rapid inducer of lamellar bodies in small intestinal enterocytes. AB - Okadaic acid (OA) is a polyether fatty acid produced by marine dinoflagellates and the causative agent of diarrhetic shellfish poisoning. The effect of OA on apical endocytosis in the small intestine was studied in organ cultured porcine mucosal explants. Within 0.5-1 h of culture, the toxin caused hyper protein phosphorylation, but no detectable loss of cell polarity or cytoskeletal integrity of the enterocytes. Using a fluorescent membrane marker, FM dye, endocytosis from the brush border was affected by the toxin. Although constitutive uptake into subapical terminal web-localized early endosomes (TWEEs) occurred unimpeded in the presence of OA, FM condensed in larger subapical structures by 1 h, implying a perturbed endosomal trafficking/maturation. The fluorescent lysosomotropic agent Lysotracker revealed induction of large lysosomal structures by OA. Endocytosis from the brush border was studied at the electron microscopic level using the membrane-impermeable marker Ruthenium Red (RR). Like FM dye, RR was taken up into TWEEs and multivesicular bodies (MVBs). However, OA induced the formation of a large number of lamellar bodies (LBs), a type of lysosome-related organelles. LBs are the hallmark of phospholipidosis, a pathological condition characterized by lysosomal phospholipid accumulation. Phospholipidosis is observed in acquired lysosomal storage diseases and is induced by a large number of cationic amphiphilic drugs. Unlike the latter, however, OA does not act by accumulating in acidic organelles, implying a different toxic mechanism of action. We propose that rapid induction of LBs, an indicator of phospholipidosis, should be included in the future toxicity profile of OA. PMID- 24951873 TI - First report of microcystin-producing Fischerella sp. (Stigonematales, Cyanobacteria) in tropical Australia. AB - A polyphasic study of four Stigonematales cyanobacteria from tropical Australia (Queensland) revealed production of the hepatotoxins microcystins (MC-LR, MC-LA, MC-LF, MC-FR and demethyl-MC-LR) by Fischerella sp. NQAIF311 isolated from a seasonal creek. Total microcystin content reached 43 MUg g(-1) dry weight. Phylogeny demonstrated high sequence similarities for 16S rRNA (99%), mcyE (97%) and mcyD (95%) genes with microcystin-producing Fischerella sp. CENA161 from Brazil. This is the first report of a cyanotoxin-producing Stigonematal in Australia. PMID- 24951874 TI - Production in Escherichia coli, folding, purification and characterization of notexin with wild type sequence and with N-terminal and catalytic site mutations. AB - Notexin (Ntx) is a group I phospholipase A2 (PLA2) protein, main component of the Australian snake Notechis scutatus scutatus venom. It is both a presynaptic neurotoxin and a myotoxin. In this work, for the first time, a method for the production and folding of recombinant Ntx was developed. Ntx was produced with wild type sequence (rNtx), with an extra peptide (T7-Ntx) or a methionine (M-Ntx) before Asn-1, and with Asn-1 substituted by alanine (Ntx-A1) or by serine (Ntx S1). The proteins were analyzed for their catalytic and toxic activities. rNtx activity resulted to be comparable to that of the venom extracted protein. The Ntx N-terminus was found to have a major influence on both the catalytic and toxic activities of the protein. The first amino acid of snake venom PLA2s is highly conserved: it is an asparagine in about all group I PLA2s, while in most (>70%) of group II PLA2s it is a serine or an asparagine. Interestingly, Ntx-S1 resulted to be, for both enzymatic and toxic activities, the mutant most similar to the wild type protein. The role of the catalytic activity of Ntx in its toxicity was investigated by replacing the aspartic acid 49, involved in the coordination of the cofactor calcium ion, by a lysine. The obtained mutant (Ntx K49) is deprived of catalytic activity but possesses a residual toxicity. PMID- 24951875 TI - Toxicity of scorpion venom in chick embryo and mealworm assay depending on the use of the soluble fraction versus the whole venom. AB - The LD50 is an important metric for venom studies and antivenom development. It has been shown that several variables in the protocol influence the LD50 value obtained, such as venom source, extraction and treatment and administration route. These inconsistencies reduce the utility of the results of these test for comparative studies. In scorpion venom LD50 assays, often only the soluble fraction of the venom is used, whereas other studies use the whole venom. We here tested the toxicity of the soluble fraction in isolation, and of the whole venom in two different systems: chick embryos and mealworms Tenebrio molitor. Ten microliters of venom solutions from Hadrurus arizonensis, Leiurus quinquestriatus, Androctonus australis, Grosphus grandidieri and Heterometrus laoticus were applied to five day old chicken embryos at stage 25-27. Our results showed no significant differences between the LD50 based on the whole venom versus that of only the soluble fraction and in the chicken embryo assay in four of the five scorpion species tested. H. laoticus however, showed a significantly lower LD50 value for the whole venom than the soluble fraction. In assays on mealworms however, this pattern was not seen. Nonetheless, caution may be warranted when using LD50 values obtained from only the soluble fraction. The LD50 values of the five species in this study, based on the chicken embryo assay, showed good correlation with values from the literature based on mouse studies. This suggests that the chick embryo assay may be an economic alternative to rodent assays for scorpion LD50 studies. PMID- 24951876 TI - Antimicrobial peptides from scorpion venoms. AB - The need for new antimicrobial agents is becoming one of the most urgent requirements in modern medicine. The venoms of many different species are rich sources of biologically active components and various therapeutic agents have been characterized including antimicrobial peptides (AMPs). Due to their potent activity, low resistance rates and unique mode of action, AMPs have recently received much attention. This review focuses on AMPs from the venoms of scorpions and examines all classes of AMPs found to date. It gives details of their biological activities with reference to peptide structure. The review examines the mechanism of action of AMPs and with this information, suggests possible mechanisms of action of less well characterised peptides. Finally, the review examines current and future trends of scorpion AMP research, by discussing recent successes obtained through proteomic and transcriptomic approaches. PMID- 24951877 TI - Mechanisms of axon regeneration and its inhibition: roles of sulfated glycans. AB - Axons in the peripheral nervous system can regenerate after injury, whereas axons in the central nervous system (CNS) do not readily regenerate. Intrinsic regenerating capacity and emerging inhibitors could explain these contrasting phenotypes. Among the inhibitors, sulfated sugar chains including chondroitin sulfate and keratan sulfate have recently attracted attention, since these sugar chains strongly inhibit axon regeneration and also induce dystrophic endball formation, a hallmark of injured axons in the adult mammalian CNS. In addition, chondroitin sulfate is a negative regulator of synaptic plasticity. To overcome the inability of CNS axons to regenerate, a comprehensive understanding of both the positive and negative regulations of axon regeneration is required. These may include signaling waves from the injury site to the nucleus, intracellular signals for growth cone formation and axon regeneration, intracellular signals for the inhibition of axon regeneration, and extracellular inhibitory signals and their receptors. This review addresses these issues, with a focus on the roles of chondroitin sulfate and keratan sulfate. PMID- 24951878 TI - CYCP2;1 integrates genetic and nutritional information to promote meristem cell division in Arabidopsis. AB - In higher plants, cell cycle activation in the meristems at germination is essential for the initiation of post-embryonic development. We previously identified the signaling pathways of homeobox transcription factor STIMPY and metabolic sugars as two interacting branches of the regulatory network that is responsible for activating meristematic tissue proliferation in Arabidopsis. In this study, we found that CYCP2;1 is both a direct target of STIMPY transcriptional activation and an early responder to sugar signals. Genetic and molecular studies show that CYCP2;1 physically interacts with three of the five mitotic CDKs in Arabidopsis, and is required for the G2 to M transition during meristem activation. Taken together, our results suggest that CYCP2;1 acts as a permissive control of cell cycle progression during seedling establishment by directly linking genetic control and nutritional cues with the activity of the core cell cycle machinery. PMID- 24951880 TI - Association between the COMT Val158Met polymorphism and fibromyalgia susceptibility and fibromyalgia impact questionnaire score: a meta-analysis. AB - The aim of this study was to explore whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with susceptibility to fibromyalgia and fibromyalgia impact questionnaire (FIQ) score in fibromyalgia patients. We conducted a meta-analysis of the associations of the COMT Val158Met polymorphism with fibromyalgia risk as well as FIQ score in fibromyalgia patients. A total of 993 fibromyalgia patients and 778 controls from 10 studies on the COMT Val158Met polymorphism and 538 fibromyalgia patients from 5 studies on the COMT Val158Met polymorphism and FIQ score were included in this meta-analysis. The meta-analysis revealed an association between fibromyalgia and the COMT Met/Met + Val/Met genotype in all study subjects (odds ratio (OR) 1.635, 95 % confidence interval (CI) 1.029-2.597, p = 0.037). However, stratification by ethnicity indicated no association between the Met/Met + Val/Met genotype and fibromyalgia in the European and Turkish populations (OR 1.202, 95 % CI 0.876-1.649, p = 0.255; OR 2.132, 95 % CI 0.764-5.949, p = 0.148, respectively). Analysis using other genetic models showed no association between the COMT Val158Met polymorphism and fibromyalgia. The meta-analysis also revealed that the FIQ score was significantly higher in individuals with the COMT Met/Met genotype than in those with the Val/Val genotype [weighted mean difference (WMD) = 14.39, 95 % CI 3.316 25.48, p = 0.011] and the Val/Met genotype (WMD = 5.108, 95 % CI 2.212-4.891, p = 0.021). This meta-analysis identified an association between fibromyalgia risk and the COMT Val158Met polymorphism as well as the FIQ score in fibromyalgia patients. PMID- 24951879 TI - Staufen targets coracle mRNA to Drosophila neuromuscular junctions and regulates GluRIIA synaptic accumulation and bouton number. AB - The post-synaptic translation of localised mRNAs has been postulated to underlie several forms of plasticity at vertebrate synapses, but the mechanisms that target mRNAs to these postsynaptic sites are not well understood. Here we show that the evolutionary conserved dsRNA binding protein, Staufen, localises to the postsynaptic side of the Drosophila neuromuscular junction (NMJ), where it is required for the localisation of coracle mRNA and protein. Staufen plays a well characterised role in the localisation of oskar mRNA to the oocyte posterior, where Staufen dsRNA-binding domain 5 is specifically required for its translation. Removal of Staufen dsRNA-binding domain 5, disrupts the postsynaptic accumulation of Coracle protein without affecting the localisation of cora mRNA, suggesting that Staufen similarly regulates Coracle translation. Tropomyosin II, which functions with Staufen in oskar mRNA localisation, is also required for coracle mRNA localisation, suggesting that similar mechanisms target mRNAs to the NMJ and the oocyte posterior. Coracle, the orthologue of vertebrate band 4.1, functions in the anchoring of the glutamate receptor IIA subunit (GluRIIA) at the synapse. Consistent with this, staufen mutant larvae show reduced accumulation of GluRIIA at synapses. The NMJs of staufen mutant larvae have also a reduced number of synaptic boutons. Altogether, this suggests that this novel Staufen-dependent mRNA localisation and local translation pathway may play a role in the developmentally regulated growth of the NMJ. PMID- 24951882 TI - Positive force feedback in development of substrate grip in the stick insect tarsus. AB - The mechanics of substrate adhesion has recently been intensively studied in insects but less is known about the sensorimotor control of substrate engagement. We characterized the responses and motor effects of tarsal campaniform sensilla in stick insects to understand how sensory signals of force could contribute to substrate grip. The tarsi consist of a chain of segments linked by highly flexible articulations. Morphological studies showed that one to four campaniform sensilla are located on the distal end of each segment. Activities of the receptors were recorded neurographically and sensilla were identified by stimulation and ablation of their cuticular caps. Responses were characterized to bending forces and axial loads, muscle contractions and to forces applied to the retractor apodeme (tendon). The tarsal sensilla effectively encoded both the rate and amplitude of loads and muscle forces, but only when movement was resisted. Mechanical stimulation of the receptors produced activation of motor neurons in the retractor unguis and tibial flexor muscles. These findings indicate that campaniform sensilla can provide information about the effectiveness of the leg muscles in generating substrate adherence. They can also produce positive force feedback that could contribute to the development of substrate grip and stabilization of the tarsal chain. PMID- 24951881 TI - Teaching methotrexate self-injection with a web-based video maintains patient care while reducing healthcare resources: a pilot study. AB - The aim of the study was to compare standard nurse-led methotrexate self injection patient education to a web-based methotrexate self-injection education video in conjunction with standard teaching on patient self-confidence for self injection, as well as patient satisfaction, patient knowledge and teaching time. Consecutive rheumatology patients seen for methotrexate self-injection education were enrolled. Prior to education, patient self-confidence for self-injection, age, gender and education were recorded. Patients were randomized 1:1 to standard teaching or the intervention: a 12-min methotrexate self-injection education video followed by further in-person nurse education. Patients recorded their post education confidence for self-injection, satisfaction with the teaching process and answered four specific questions testing knowledge on methotrexate self injection. The time spent providing direct education to the patient was recorded. Twenty-nine patients participated in this study: 15 had standard (C) teaching and 14 were in the intervention group (I). Average age, gender and education level were similar in both groups. Both groups were satisfied with the quality of teaching. There was no difference in pre-confidence (C = 5.5/10 vs. I = 4.7/10, p = 0.44) or post-confidence (C = 8.8, I = 8.8, p = 0.93) between the groups. There was a trend toward improved patient knowledge in the video group versus the standard group (C = 4.7/6, I = 5.5/6, p = 0.15). Nurse teaching time was less in the video group (C = 60 min, I = 44 min, p = 0.012), with men requiring longer education time than women across all groups. An education video may be a good supplement to standard in-person nurse teaching for methotrexate self-injection. It equals the standard teaching practise with regard to patient satisfaction, confidence and knowledge while decreasing teaching time by 25 %. PMID- 24951883 TI - Hydrogen-rich saline controls remifentanil-induced hypernociception and NMDA receptor NR1 subunit membrane trafficking through GSK-3beta in the DRG in rats. AB - BACKGROUND: Although NMDAR trafficking mediated by GSK-3beta involvement in transmission of pronociceptive messages in the spinal cord has been confirmed by our previous studies, whether NMDAR trafficking is implicated in peripheral sensitization remains equivocal. It is demonstrated that inflammation is associated with spinal NMDAR-containing nociceptive neurons activation and the maintenance of opioid induced pain hypersensitivity. However, whether and how hydrogen-rich saline, as an effective anti-inflammatory drug, could prevent hyperalgesia through affecting peripheral sensitization caused by NMDAR activation remains to be explored. METHODS: To test these effects, hydrogen-rich saline (2.5, 5 or 10 ml/kg) was administrated intraperitoneally after remifentanil infusion, NMDAR antagonist MK-801 or GSK-3beta inhibitor TDZD-8 was administrated intravenously before remifentanil infusion in rats. We examined time course of hydrogen concentration in blood after hydrogen-rich saline administration. Mechanical and thermal hyperalgesia were evaluated by measuring PWT and PWL for 48 post-infusion hours, respectively. Western blotting and real time qPCR assay were applied to analyze the NR1 membrane trafficking, GSK-3beta expression and activity in DRG. Inflammatory mediators (TNF-alpha, IL-1beta, and IL-6) expressions in DRG were also analyzed. RESULTS: We found that NR1 membrane trafficking in DRG increased, possibly due to GSK-3beta activation after remifentanil infusion. We also discovered that hydrogen-rich saline not 2.5 ml/kg but 5 and 10 ml/kg could dose-dependently attenuate mechanical and thermal hyperalgesia without affecting baseline nociceptive threshold, reduce expressions of inflammatory mediators (TNF-alpha, IL-1beta, and IL-6) and decrease NR1 trafficking mediated by GSK-3beta, and minimal effective concentration was observed to be higher than 10 MUmol/L, namely peak concentration in arterial blood after administration of HRS 2.5 ml/kg without any influence on hyperalgesia. CONCLUSION: Our results indicated that antihyperalgesic effect of hydrogen-rich saline might depend predominantly on its ability to reverse NR1 trafficking via inhibition of GSK-3beta activity in DRG in a dose-dependent manner. PMID- 24951884 TI - Source of atmospheric heavy metals in winter in Foshan, China. AB - Foshan is a ceramics manufacturing center in the world and the most polluted city in the Pearl River Delta (PRD) in southern China measured by the levels of atmospheric heavy metals. PM2.5 samples were collected in Foshan in winter 2008. Among the 22 elements and ions analyzed, 7 heavy metals (Zn, V, Mn, Cu, As, Cd and Pb) were studied in depth for their levels, spatiotemporal variations and sources. The ambient concentrations of the heavy metals were much higher than the reported average concentrations in China. The levels of Pb (675.7 +/- 378.5 ng/m(3)), As (76.6 +/- 49.1 ng/m(3)) and Cd (42.6 +/- 45.2 ng/m(3)) exceeded the reference values of NAAQS (GB3095-2012) and the health guidelines of the World Health Organization. Generally, the levels of atmospheric heavy metals showed spatial distribution as: downtown site (CC, Chancheng District)>urban sites (NH and SD, Nanhai and Shunde Districts)>rural site (SS, Shanshui District). Two sources of heavy metals, the ceramic and aluminum industries, were identified during the sampling period. The large number of ceramic manufactures was responsible for the high levels of atmospheric Zn, Pb and As in Chancheng District. Transport from an aluminum industry park under light north-west winds contributed high levels of Cd to the SS site (Shanshui District). The average concentration of Cd under north-west wind was 220 ng/m(3), 20.5 times higher than those under other wind directions. The high daily maximum enrichment factors (EFs) of Cd, Pb, Zn, As and Cu at all four sites indicated extremely high contamination by local emissions. Back trajectory analysis showed that the heavy metals were also closely associated with the pathway of air mass. A positive matrix factorization (PMF) method was applied to determine the source apportionment of these heavy metals. Five factors (industry including the ceramic industry and coal combustion, vehicle emissions, dust, transportation and sea salt) were identified and industry was the most important source of atmospheric heavy metals. The present paper suggests a control policy on the four heavy metals Cd, Pb, Zn, and Cu, and suggests the inclusion of As in the ceramic industry emission standard in the future. PMID- 24951885 TI - Anthropogenic loads and biogeochemical role of urea in the Gulf of Trieste. AB - In order to assess the role of urea in the Gulf of Trieste, oceanographic data collected from 2002 to 2011 were analyzed together with ancillary ambient information and compared to past studies. The recent levels of urea found in these coastal waters (median = 1.1 MUM N, maximum value = 19.7 MUM N) are often high and similar to those reported in the early 1980s. A preliminary estimate of the external inputs indicated that this enrichment in urea is mainly due to emissions from urban sewage systems, whereas the contributions of rivers and atmospheric deposition are scarce. As a consequence, urea appears to be a reliable tracer of the diffusion of wastewaters in the coastal marine environment, more specific and sensitive than other nutrients, with a behavior that also reflects the technology of the treatment plants. The stability of urea levels over the last three decades suggests that the upgrade of wastewater treatment technologies was probably balanced by the concomitant increase of the anthropogenic pressure in the area (477,000 to 1,300,000 inhabitant equivalent). Budget estimates on the gulf-wide scale indicate that urea (177-530 t N) is not negligible compared to dissolved inorganic nitrogen (409-919 t N) and that it can constitute up to 56% of the nitrogen available for plankton growth. A large accumulation of urea can occur during summer periods characterized by stable weather conditions and weak circulation, whereas a biologically mediated degradation to ammonium is observed in autumn in concomitance to a strong shift of the marine ecosystem toward heterotrophic conditions. These processes, together with a potential competition between phytoplankton and bacteria for the utilization of this nitrogen form, suggest that the biogeochemical role of urea should be better investigated in mid-latitude coastal zones subjected to highly variable ambient conditions and to overloads of this compound. PMID- 24951886 TI - Prediction of naphthenic acid species degradation by kinetic and surrogate models during the ozonation of oil sands process-affected water. AB - Oil sands process-affected water (OSPW) is a complex mixture of organic and inorganic contaminants, and suspended solids, generated by the oil sands industry during the bitumen extraction process. OSPW contains a large number of structurally diverse organic compounds, and due to variability of the water quality of different OSPW matrices, there is a need to select a group of easily measured surrogate parameters for monitoring and treatment process control. In this study, kinetic and surrogate correlation models were developed to predict the degradation of naphthenic acids (NAs) species during the ozonation of OSPW. Additionally, the speciation and distribution of classical and oxidized NA species in raw and ozonated OSPW were also examined. The structure-reactivity of NA species indicated that the reactivity of individual NA species increased as the carbon and hydrogen deficiency numbers increased. The kinetic parameters obtained in this study allowed calculating the evolution of the concentrations of the acid-extractable fraction (AEF), chemical oxygen demand (COD), and NA distributions for a given ozonation process. High correlations between the AEF and COD and NA species were found, suggesting that AEF and COD can be used as surrogate parameters to predict the degradation of NAs during the ozonation of OSPW. PMID- 24951887 TI - Development and evaluation of antimicrobial activated carbon fiber filters using Sophora flavescens nanoparticles. AB - Activated carbon fiber (ACF) filters have a wide range of applications, including air purification, dehumidification, and water purification, due to their large specific surface area, high adsorption capacity and rate, and specific surface reactivity. However, when airborne microorganisms such as bacteria and fungi adhere to the carbon substrate, ACF filters can become a source of microbial contamination, and their filter efficacy declines. Antimicrobial treatments are a promising means of preventing ACF bio-contamination. In this study, we demonstrate the use of Sophora flavescens in antimicrobial nanoparticles coated onto ACF filters. The particles were prepared using an aerosol process consisting of nebulization-thermal drying and particle deposition. The extract from S. flavescens is an effective, natural antimicrobial agent that exhibits antibacterial activity against various pathogens. The efficiency of Staphylococcus epidermidis inactivation increased with the concentration of S. flavescens nanoparticles in the ACF filter coating. The gas adsorption efficiency of the coated antimicrobial ACF filters was also evaluated using toluene. The toluene-removal capacity of the ACF filters remained unchanged while the antimicrobial activity was over 90% for some nanoparticle concentrations. Our results provide a scientific basis for controlling both bioaerosol and gaseous pollutants using antimicrobial ACF filters coated with S. flavescens nanoparticles. PMID- 24951888 TI - Removal of phenolic endocrine disrupting compounds from waste activated sludge using UV, H2O2, and UV/H2O2 oxidation processes: effects of reaction conditions and sludge matrix. AB - Removal of six phenolic endocrine disrupting compounds (EDCs) (estrone, 17beta estradiol, 17alpha-ethinylestradiol, estriol, bisphenol A, and 4-nonylphenols) from waste activated sludge (WAS) was investigated using ultraviolet light (UV), hydrogen peroxide (H2O2), and the combined UV/H2O2 processes. Effects of initial EDC concentration, H2O2 dosage, and pH value were investigated. Particularly, the effects of 11 metal ions and humic acid (HA) contained in a sludge matrix on EDC degradation were evaluated. A pseudo-first-order kinetic model was used to describe the EDC degradation during UV, H2O2, and UV/H2O2 treatments of WAS. The results showed that the degradation of the 6 EDCs during all the three oxidation processes fitted well with pseudo-first-order kinetics. Compared with the sole UV irradiation or H2O2 oxidation process, UV/H2O2 treatment was much more effective for both EDC degradation and WAS solubilization. Under their optimal conditions, the EDC degradation rate constants during UV/H2O2 oxidation were 45-197 times greater than those during UV irradiation and 11-53 times greater than those during H2O2 oxidation. High dosage of H2O2 and low pH were favorable for the degradation of EDCs. Under the conditions of pH = 3, UV wavelength = 253.7 nm, UV fluence rate = 0.069 mW cm(-2), and H2O2 dosage = 0.5 mol L(-1), the removal efficiencies of E1, E2, EE2, E3, BPA, and NP in 2 min were 97%, 92%, 95%, 94%, 89%, and 67%, respectively. The hydroxyl radical (OH) was proved to take the most important role for the removal of EDCs. Metal ions in sludge could facilitate the removal of EDCs during UV/H2O2 oxidation. Fe, Ag, and Cu ions had more obvious effects compared with other metal ions. The overall role of HA was dependent on the balance between its competition as organics and its catalysis/photosensitization effects. These indicate that the sludge matrix plays an important role in the degradation of EDCs. PMID- 24951889 TI - Platinum-based anticancer drugs in waste waters of a major UK hospital and predicted concentrations in recipient surface waters. AB - Concentrations of the cytotoxic platinum-based anticancer drugs, as total Pt, have been measured over a three week period in one of the main drains and in the effluent of the oncology ward of a major UK hospital (Derriford, Plymouth). Concentrations of Pt were highly variable in both discharges, and ranged from about 0.02 to 140 MUg L(-1) in the oncology effluent and from about 0.03 to 100 MUg L(-1) in the main drain. A comparison of drug administration figures over the study period with an estimate of the quantity of Pt discharged through the drains suggests that about 22% of total Pt is emitted to the environment from the hospital with the remainder being discharged by treated patients in the wider community. Administration figures for the three Pt-based drugs used in the hospital (cisplatin, carboplatin and oxaliplatin) coupled with published measurements on the removal of the drugs by conventional sewage treatment allowed the concentrations of Pt arising from each drug to be predicted in recipient surface waters as a function of water flow rate. For conditions representative of the region under study, concentrations of total Pt between a few tens and in excess of 100 pg L(-1) are predicted, with the principal form of the metal occurring as carboplatin and its metabolites. Although predicted concentrations are below EMEA guidelines warranting further risk assessment, the presence of substances in surface waters that are potentially carcinogenic, mutagenic and teratogenic and yet whose environmental effects are not understood is cause for concern. PMID- 24951890 TI - Energy consumption, greenhouse gas emissions and assessment of sustainability index in corn agroecosystems of Iran. AB - The objectives of this study were to assess the energy flow, greenhouse gas (GHG) emission, global warming potential (GWP) and sustainability of corn production systems in Kermanshah province, western Iran. The data were collected from 70 corn agroecosystems which were selected based on randomly sampled method in the summer of 2011. The results indicated that total input and output energy were 50,485 and 134,946 MJ ha(-1), respectively. The highest share of total input energy in corn production systems was recorded for N fertilizer, electricity power and diesel fuel with 35, 25 and 20%, respectively. Energy use efficiency and energy productivity were 2.67 and 0.18 kg MJ(-1), respectively. Also agrochemical energy ratio was estimated as 40%. Applying chemical inputs produced the following emissions of greenhouse gases: 2994.66 kg CO2, 31.58 kg N2O and 3.82 kg CH4 per hectare. Hence, total GWP was 12,864.84 kg Co2eq ha(-1) in corn production systems. In terms of CO2 equivalents 23% of the GWPs came from CO2, 76% from N2O, and 1% from CH4. In this study input and output C equivalents per total GHG and Biomass production were 3508.59 and 10,696.34 kg Cha(-1). Net carbon and sustainability indexes in corn production systems were 7187.75 kg Cha( 1) and 2.05. Accordingly, efficient use of energy is essential to reduce the greenhouse gas emissions and environmental impact in corn agroecosystems. PMID- 24951891 TI - Contamination of free-range ducks by chlordecone in Martinique (French West Indies): a field study. AB - The former use of chlordecone (CLD) in the French West Indies has resulted in long-term pollution of soils and subsequently of food chains. In contaminated areas, free-range ducks used to control weeds in orchards may be exposed to CLD through polluted soil ingestion. The question arises whether they may be consumed. Muscovy ducks were raised on a guava orchard planted on a soil moderately contaminated (410 MUg CLD/kg dry matter). Ducks were raised indoor up to 6 weeks of age and allowed to range freely outdoors thereafter. Twenty-nine females were sequentially slaughtered by groups of 2 to 5 ducks, after 4, 16, 19, 22 or 26 weeks spent in the orchard or after 16-17 weeks in the orchard followed by 3, 6 or 9 weeks in a closed shelter for depuration. CLD concentration increased from 258 to 1051, 96 to 278, 60 to 169 and 48 to 145 MUg/kg fresh matter (FM) as the exposure through grazing increased from 4 to 22 weeks, in liver, abdominal fat and leg with and without skin, respectively. Eggs collected in the orchard contained up to 1001 MUg CLD/kg FM. All these values exceeded the Maximum Residue Limit (MRL) of 20 MUg/kg FM. CLD concentration in all tissues was divided by around 10 within the 9-week confinement period. Despite this quite rapid decontamination, it is estimated that 12-13 weeks would be required to achieve the MRL in liver and in eggs, and 5-6 weeks in leg muscle. Such durations would be too long in practice. Thus, the consumption of products from free-range ducks should be avoided, even in areas mildly contaminated with CLD. PMID- 24951892 TI - Mercury biomagnification in three geothermally-influenced lakes differing in chemistry and algal biomass. AB - Accumulation of Hg in aquatic organisms is influenced not only by the contaminant load but also by various environmental variables. We compared biomagnification of Hg in aquatic organisms, i.e., the rate at which Hg accumulates with increasing trophic position, in three lakes differing in trophic state. Total Hg (THg) concentrations in food webs were compared in an oligotrophic, a mesotrophic and a eutrophic lake with naturally elevated levels of Hg associated with geothermal water inputs. We explored relationships of physico-chemistry attributes of lakes with Hg concentrations in fish and biomagnification in the food web. Trophic positions of biota and food chain length were distinguished by stable isotope (15)N. As expected, THg in phytoplankton decreased with increasing eutrophication, suggesting the effect of biomass dilution. In contrast, THg biomagnification and THg concentrations in trout were controlled by environmental physico-chemistry and were highest in the eutrophic lake. In the more eutrophic lake frequent anoxia occurred, resulting in favorable conditions for Hg transfer into and up the food chain. The average concentration of THg in the top predator (rainbow trout) exceeded the maximum recommended level for consumption by up to 440%. While there were differences between lakes in food chain length between plankton and trout, THg concentration in trout did not increase with food chain length, suggesting other factors were more important. Differences between the lakes in biomagnification and THg concentration in trout correlated as expected from previous studies with eight physicochemical variables, resulting in enhanced biomagnification of THg in the eutrophic lake. PMID- 24951893 TI - Co-exposure to n-TiO2 and Cd2+ results in interactive effects on biomarker responses but not in increased toxicity in the marine bivalve M. galloprovincialis. AB - The increasing production of nanoparticles (NPs) will lead to their release into the aquatic environment, where they could modify the bioavailability/bioconcentration and consequent biological impact of other contaminants. Interactive effects of n-TiO2, one of the most widespread NP type, and Cd(2+), a common heavy metal pollutant, have been described in freshwater species, whereas no information is available in marine organisms. In this work, the effects of co-exposure to n-TiO2 and Cd(2+) were investigated in the marine bivalve Mytilus galloprovincialis. Experimental conditions (100 MUg/L, 96 h), were chosen in order to induce early but measurable stress responses (biomarkers) without toxicity. Several biomarkers, from molecular to tissue level, were measured in hemolymph and digestive gland; the effects on embryo development were also evaluated. In hemolymph, Cd(2+) abolished the increase in immune parameters induced by n-TiO2 (NO production and lysozyme activity). In the digestive gland, distinct interactive effects of n-TiO2 and Cd(2+) were observed on different lysosomal biomarkers (lysosomal membrane stability, lipid accumulation and lysosome/cytoplasm volume ratio) and transcription of the immune genes lysozyme and toll-like receptor (TLR). However, n-TiO2 did not affect specific metal induced responses (metallothionein induction) and tissue metal accumulation. Cd(2+) alone, but not in combination with n-TiO2, affected embryo development. The interactive effects observed on different biomarkers were not apparently due to differences in bioavailability/bioaccumulation of Cd(2+) in the presence of n TiO2 agglomerates; these effects may result from interactions of either contaminant with both common and distinct targets/mechanisms of action at different levels of biological organization. Overall, the results indicate that co-exposure to n-TiO2 and Cd(2+) did not result in increased adverse effects in M. galloprovincialis. These data underline the need for further knowledge on the potential interactions of NPs with existing contaminants in marine organisms. PMID- 24951894 TI - Hospital wastewater treatment by fungal bioreactor: removal efficiency for pharmaceuticals and endocrine disruptor compounds. AB - Hospital effluents contribute to the occurrence of emerging contaminants in the environment due to their high load of pharmaceutical active compounds (PhACs) and some endocrine disruptor compounds (EDCs). Nowadays, hospital wastewaters are co treated with urban wastewater; however, the dilution factor and the inefficiency of wastewater treatment plants in the removal of PhACs and EDCs make inappropriate the co-treatment of both effluents. In this paper, a new alternative to pre-treat hospital wastewater concerning the removal of PhACs and EDCs is presented. The treatment was carried out in a batch fluidized bed bioreactor under sterile and non-sterile conditions with Trametes versicolor pellets. Results on non-sterile experiments pointed out that 46 out of the 51 detected PhACs and EDCs were partially to completely removed. The total initial PhAC amount into the bioreactor was 8185 MUg in sterile treatment and 8426 MUg in non-sterile treatment, and the overall load elimination was 83.2% and 53.3% in their respective treatments. In addition, the Microtox test showed reduction of wastewater toxicity after the treatment. Hence, the good efficiency of the fungal treatment regarding removal of the wide diversity of PhACs and EDCs detected in hospital effluents is demonstrated. PMID- 24951895 TI - Molecular cloning, characterization and expression of miR-15a-3p and miR-15b-3p in dairy cattle. AB - MicroRNA (miRNA) plays an important role in modulating immune responses. We identified miR-15a-3p and miR-15b-3p which were immune related in bovine. Fourteen potential target genes were predicted. Both miR-15a-3p and miR-15b-3p showed significant differential expression patterns in healthy and mastitis infected cattle (P < 0.01). Expression patterns of the two miRNAs provide important information on the relationships between mastitis and miRNA expression. PMID- 24951896 TI - Double negative (CD19+IgG+IgD-CD27-) B lymphocytes: a new insight from telomerase in healthy elderly, in centenarian offspring and in Alzheimer's disease patients. AB - Immunosenescence is characterized by the impairment of humoral immunity with changes in the memory/naive B cell compartment. In particular we have previously reported the percentage increase of a Memory IgD(-)CD27(-) (Double Negative, DN) B cell population in aged people. In this study, we have further characterized DN B cells with the aim to better understand their contribution to immunosenescence. As DN B cells show a poor ability to proliferate in vitro, we have evaluated the expression of the inhibitory receptors CD307d and CD22 on these cells from young and old individuals. In addition we have evaluated the ability to activate DN B cells by the simultaneous use of innate (CpG) and adaptive (alpha-Ig/CD40) ligands. Our data demonstrate that the refractoriness to proliferate of DN B cells does not depend on the expression of inhibitory receptors, but it is due to the kind of stimulation. Indeed, when DN B cells are stimulated engaging both BCR and TLR9, they become able to proliferate and reactivate the telomerase enzyme. In the present study, we have also compared the telomerase activity in a group of people genetically advantaged for longevity as centenarian offspring (CO) and in a group of moderate-severe Alzheimer's disease (AD) patients, who represent a model of unsuccessful aging. Our study suggests that telomerase reactivation of DN B cells, as well as their number and ability in activating, depend essentially by the biological age of the subjects studied, so the evaluation of DN B cells might allow to gain insight to healthy and unsuccessful aging. PMID- 24951898 TI - Bioelectrochemical sensing of promethazine with bamboo-type multiwalled carbon nanotubes dispersed in calf-thymus double stranded DNA. AB - We report the quantification of promethazine (PMZ) using glassy carbon electrodes (GCE) modified with bamboo-like multi-walled carbon nanotubes (bCNT) dispersed in double stranded calf-thymus DNA (dsDNA) (GCE/bCNT-dsDNA). Cyclic voltammetry measurements demonstrated that PMZ presents a thin film-confined redox behavior at GCE/bCNT-dsDNA, opposite to the irreversibly-adsorbed behavior obtained at GCE modified with bCNT dispersed in ethanol (GCE/bCNT). Differential pulse voltammetry-adsorptive stripping with medium exchange experiments performed with GCE/bCNT-dsDNA and GCE modified with bCNTs dispersed in single-stranded calf thymus DNA (ssDNA) confirmed that the interaction between PMZ and bCNT-dsDNA is mainly hydrophobic. These differences are due to the intercalation of PMZ within the dsDNA that supports the bCNTs, as evidenced from the bathochromic displacement of UV-Vis absorption spectra of PMZ and quantum dynamics calculations at DFTB level. The efficient accumulation of PMZ at GCE/bCNT-dsDNA made possible its sensitive quantification at nanomolar levels (sensitivity: (3.50+/-0.05)*10(8) MUA.cm(-2).M(-1) and detection limit: 23 nM). The biosensor was successfully used for the determination of PMZ in a pharmaceutical product with excellent correlation. PMID- 24951899 TI - [Pharmacological interactions: a professional challenge]. PMID- 24951897 TI - Impact of high dietary lipid intake and related metabolic disorders on the abundance and acyl composition of the unique mitochondrial phospholipid, cardiolipin. AB - Excessive dietary lipid intake, coupled with lack of exercise, are the major causes of the development and progression of metabolic syndrome features e. g. obesity, hepatic steatosis, insulin resistance, type 2 diabetes and cardiovascular diseases. These metabolic diseases are associated with both structural and functional alterations of mitochondria. Cardiolipin (CL) is a unique phospholipid that is almost exclusively localized in the mitochondrial inner membrane. Cardiolipin is at the heart of mitochondrial metabolism playing a key role in several processes of mitochondrial bioenergetics as well as in mitochondrial membrane stability and dynamics, and in many of the mitochondrial dependent steps of apoptosis. Indeed, alterations to CL content and acyl chain profile have been associated with mitochondrial dysfunction in multiple tissues in Barth syndrome and in many other physio-pathological conditions. After a brief overview of the biological roles of CL, we highlight the consequences of lipid overload-related nutritional manipulations as well as related metabolic disorders on both CL content and its fatty acid composition in the major metabolic tissues, the heart, muscle and liver. The goal of this review is to fill a void in the CL literature concerning the effects of CL abundance and form that arise following high lipid supplementation and the related metabolic disorders. PMID- 24951900 TI - [Stability study of oxaliplatin and doxorubicin for intraperitoneal administration with hyperthermia]. AB - OBJECTIVE: To evaluate the in vitro physicochemical stability of oxaliplatin and doxorubicin when the in vivo hyperthermic intraperitoneal conditions are reproduced. METHODS: Three solutions were prepared, A (oxaliplatin 200 mg/L), B(doxorubicin 15 mg/L) and C (oxaliplatin 200 mg/L with doxorubicin 15mg/L) in glucose 5%. The three solutions were subjected to the maximum temperature reached in vivo (49 degrees C) for two hours. Physical stability was focused on visual control of particles or precipitates in solutions, discharge of gases, odor and color. Samples were taken every 15 minutes and the chemical stability was evaluated by determining the concentration of oxaliplatin and doxorubicin remaining in the samples. Oxaliplatin concentrations were determined by atomic absorption graphite chamber while doxorubicin was determined by high performance liquid chromatography.The chemical stability criteria selected was the one described by the American Pharmacopoeia, which sets a permissible variation range between the 90-110% of the initial concentration. RESULTS: During the assay there was no appearance of particles, precipitates in the samples, discharge of gases, nor colour changes in the solutions. The samples showed a remaining concentration of oxaliplatin and doxorubicin within the 90-110% limit. The stability of the samples that follow to two cycles of freeze-thaw after hyperthermia was also found within the specified limits. CONCLUSION: A, B and c solutions in 5% glucose, are physically and chemically stable at 49 degrees C for two hours. Under these conditions, these solutions could be used with guarantees of stability in patients with peritoneal carcinomatosis subsidiary of intraperitoneal hyperthermic chemotherapy based in these antineoplastic agents. PMID- 24951901 TI - [Multidisciplinary approach as a model for detection and monitoring of psychiatric morbidity in patients treated with interferon and ribavirin]. AB - PURPOSE: We aimed to describe the incidence of psychiatric disorders in a cohort of HCV infected patients treated with interferon and ribavirin, and their impact on treatment adherence and viral response rate (SVR). MATERIALS AND METHODS: Retrospective analysis of a cohort of HCV patients visited at an outpatient pharmacy service (OPS). We included all adult patients monoinfected with HCV who had initiated treatment in 2010. Monitoring of psychiatric disorders was assessed at weeks 0, 4, 12, 24, 48, and 72 through the self-administered questionnaires Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire (Goldberg).Adherence to treatment was assessed by counting of drug dispensations and patient reporting and drug exposure with the 80/80/80 rule. Virologic response was determined by the physician according to standard definitions. RESULTS: Among 76 included patients, 19 (25%) had a preexisting psychiatric disorder. The incidence of confirmed psychiatric disorders was 33% (n=25),with a peak of abnormal results in the tests by week 12. Overall, 43% of patients achieved an SVR. There were not significant differences between strict adherence and SVR in patients with or without medically confirmed disorders(96.0% vs 96,8%; p = NS) and SVR (39% vs 52%; p = NS], respectively. CONCLUSIONS: Psychiatric side effects had no effect on adherence to treatment nor on attainment of SVR. Multidisciplinary monitoring provided during the treatment of hepatitis C can contribute to early detection and management of psychiatric disorders and to improve integrated patient care. PMID- 24951902 TI - [Thermolabile drugs stability faced with an accidental interruption in the cold chain]. AB - OBJECTIVE: To develop an updated guide about the stability of thermolabile drugs included in the Pharmacotherapeutic Guide that,according to product information sheet, should be stored under refrigeration or freezing, when are accidentally exposed to temperatures outside the range recommended by the manufacturer. METHODS: It was reviewed the information about storage temperatures recommended in the product information sheet and the available stability data at different temperatures of thermolabile drugs included in the Pharmacotherapeutic Guide of a 400-bed hospital that, according to the manufacturer, should be stored under refrigeration or freezing. Drugs of clinical trials were excluded. Stability data were obtained from the product information sheet, the last two guides published in Spain about thermolabile drugs and through consultations to laboratories(via phone or e-mail). RESULTS: It was created a table with the storage temperatures recommended in the product information sheet and currently available stability data at different temperatures of 209 presentations of several drugs. Stability data were requested to laboratories in 172 cases. CONCLUSIONS: The stability guide is a tool that facilitates decisions of pharmacists when they are faced with an accidental interruption of the cold chain, when it is necessary to know whether the drug can be used and it is not possible to contact the laboratory. PMID- 24951903 TI - [Cost analysis of the use of botulinum toxin type A in Spain]. AB - OBJECTIVE: To estimate treatment costs of blepharospasm, cervical dystonia(CD), upper limb spasticity (ULS) and spasticity in children with cerebral palsy (SCCP) with botulinum neurotoxin type A (BoNT-A) in Spain. METHOD: Annual BoNT-A treatment costs were calculated (2013 ex-factory price (?) applying RDL 8/2010 and RDL 9/2011 deductions), based on initial dose (id), average dose (ad) and maximum dose (md) according to Summary of Product Characteristics of Botox(r) (100U/50U), Dysport(r)(500U) and Xeomin(r) (100U) and considering the use of complete vials.In addition, annual treatment costs were calculated considering the useof vials in more than one patient and also patient population annual treatment costs based on diseases' prevalence. RESULTS: Annual BoNT-A treatment costs per patient were estimated at between ?265 and ?2,120 with savings from 10% to 55% accordingto the selected BoNT-A. CD and ULS treatment provided the greatest cost per patient. Botox(r) provided greater savings in ULS (id/ad), CD(id), and in blepharospasm and SCCP (id/ad/md). Dysport(r) treatment was less costly in CD (md) and ULS (md), while Xeomin(r) was in CD(ad). Based on the estimated treated population in Spain, the annual treatment costs ranged from ?368,392 to ?13,958,836 depending on indication, dose and BoNT-A considered. CONCLUSIONS: The appropriate BoNT-A choice would lead to considerable savings for the National Health System. Botox(r) would generate lower costs per patient than other BoNT-A products in 9 out of 12 scenarios considered. PMID- 24951904 TI - [Design of a risk matrix to assess sterile formulations at health care facilities]. AB - OBJECTIVE: To design a matrix allowing classifying sterile formulations prepared at the hospital with different risk levels. MATERIAL AND METHODS: i) Literature search and critical appraisal of the model proposed by the European Resolution CM/Res Ap(2011)1, ii) Identification of the risk associated to the elaboration process by means of the AMFE methodology (Modal Analysis of Failures and Effects), iii) estimation of the severity associated to the risks detected. After initially trying a model of numeric scoring, the classification matrix was changed to an alphabetical classification, grading each criterion from A to D.Each preparation assessed is given a 6-letter combination with three possible risk levels: low, intermediate, and high. This model was easier for risk assignment, and more reproducible. RESULTS: The final model designed analyzes 6 criteria: formulation process, administration route, the drug's safety profile, amount prepared, distribution, and susceptibility for microbiological contamination.The risk level obtained will condition the requirements of the formulation area, validity time, and storing conditions. CONCLUSIONS: The matrix model proposed may help health care institutions to better assess the risk of sterile formulations prepared,and provides information about the acceptable validity time according to the storing conditions and the manufacturing area. Its use will increase the safety level of this procedure as well as help in resources planning and distribution. PMID- 24951905 TI - [Thermolabile drugs: pharmacist intervention as a guarantee of cold chain maintenance]. AB - OBJECTIVE: To determine whether pharmacist is able to guarantee cold chain maintenance of thermolabile drugs during transport using the available information in the reception process and to compare these results with those obtained in a subsequent intervention phase, in which the manufacturing laboratories were contacted. METHODS: Intervention study, prospective and comparative"before-after". It was analyzed the storage conditions during transport of all thermolabile drugs received in a 400-bed hospital for 3 months, excluding those from clinical trials. RESULTS: The intervention allowed to ensure cold chain maintenance in 76,5% (n = 488) of received drugs, representing an increase of 41,8% (IC 95% 36,7-46,6%; p < 0,001) compared with the percentage obtained before the intervention. CONCLUSIONS: The pharmacist isn't able to ensure the cold chain maintenance of received thermolabile drugs without temperature monitoring device (64,6%). Reports requested from laboratories allowed to increase significantly that percentage. PMID- 24951906 TI - [Clinical decision-making support systems in renal failure]. AB - INTRODUCTION: Support systems in clinical decision-making use individual characteristics of the patient to generate recommendations to the clinician. OBJECTIVE: To assess the impact of a tool for adjusting drug dosing in renal failure asa support system in clinical decision-making regarding the level of acceptance of the interventions as well as the time invested by the pharmacist. METHOD: Non-randomized, prospective and hospital interventional study comparing pre- and post-implementation phases of an automated renal function alert system, carried out at two county hospitals. Forty drugs were monitored before the intervention(2007). The blood work of the patients receiving any of these drugs was reviewed. In case of impaired renal function, an adjustment recommendation was inserted in the medical prescription. If the physician accepted it, it was rated as success. The average time was 1 minute per blood work reviewed and 3 minutes per recommendation. An automated adjustment recommendation system according to renal function with alert pop-ups was implemented in 2008 for 100 drugs. Later (2009), the number of interventions and the success rate for this tool were assessed and compared. RESULTS: Pre-implementation phase. 28,234 electronic medical prescriptions corresponding to a mean number of 205 hospitalized patients/day were validated and 4,035 blood works were reviewed. One hundred and twenty-one pharmaceutical interventions(0.43% of the medical prescriptions) were inserted. A success rate of 33.06% of the interventions was obtained. The time invested by the pharmacist for consulting the bloodworks and making the recommendations was 73.3 hours (67.25 hours corresponding to patients without renal function impairment and in whom no intervention was made).Post implementation phase. 26,584 electronic medical orders corresponding to 193 hospitalized patients/day were validated and 1,737 automated interventions were performed(6.53% of total medical orders), of which 65.69% were accepted (success). CONCLUSIONS: The implementation of clinical decision-making support systems allows extending the number of patients and drugs monitored, optimizing the time invested by the pharmacist. Simultaneous occurrence of an alert during prescription may have contributed to the greater success rate observed. PMID- 24951907 TI - [Analysis of the causes leading to withdrawal of the treatment with triple antiviral therapy for hepatitis C patients]. AB - OBJECTIVE: To assess causes of suspension of hepatitis C treatment in patients receiving triple antiviral therapy (peginterferon+ ribavirin + protease inhibitor). METHODS: Retrospective observational study of patients who received triple antiretroviral therapy against hepatitis C between January 2012 - March 2013 and discontinued their treatment. RESULTS: Of 156 patients who initiated therapy, 41 discontinued treatment: Nineteen due to adverse events, being dermatological events in seven patients ( 36.8 %), intolerance in six(31.6%) and hematologic toxicity in four (15.8%) . Sixteen patients discontinued treatment for being ineffectiveness.Patients with higher inefficacy failure rate were "null responders"(32.3% ) while the group of "relapsers" were the one with the highest rate of toxicity suspensions (15.6%). Two patients died during treatment for pneumonia. CONCLUSIONS: Triple therapy with boceprevir and telaprevir is associated with a significant number of treatment failures due to toxicity and ineffectiveness. PMID- 24951908 TI - [Prevention of medication errors in healthcare transition of patients treated with apomorphine]. AB - The transition of patients between different levels of care process is a particular risk in the production of medication errors. The aim of this paper is to analyze the role of the pharmacist in preventing errors transition care to ensure a safe and cross pharmacotherapy of patients.Transversal, observational and descriptive study in a University Hospital that has a pharmacy service that integrates specialized inpatient care and health centers. Transition of care a patient treated with Apormorfina was analyzed to determine the keypoints of action of the pharmacist. Demographics, disease and medication history, and care transition episodes were collected through the pharmacy program and electronics history.The pharmacist did tasks adapting, reconciliation, management and reporting of medication to the health care team to prevent medication errors in care transition of patients treated with drugs requiring special handling .In conclusion, this work represents perfectly the key role of the pharmacist as coordinator of safe and transverse pharmacotherapy of patients. PMID- 24951910 TI - [Possible denosumab-induced jaw osteonecrosis in the treatment of osteoporosis. A case report]. PMID- 24951909 TI - [New drugs in the treatment of chronic hepatitis C]. AB - OBJECTIVES: To analyze the efficacy and safety of the new direct antiviral agents (DAA) that will become the new therapeutic arsenal for the treatment of hepatitis C. METHODS: We carried out a research in the electronic database with the following criteria: phase II and III clinical trials (CT) published until February 2014. The Mesh term used was "chronic hepatitis C" and "therapy".Studies with boceprevir or telaprevir were excluded. For the analysis of efficacy, we evaluated the rate of Sustained Viral Response(SVR), and for the safety, side effects and safety-related discontinuations were analyzed. RESULTS: We included 24 CT that include associations with ribavirine(RBV) with or without peginterferon (PegINF) and associations of several DAA. The results associated of daclatasvir with PegINF and RBV have not been very successful. On the contrary, sofosbuvir presents activity in all viral genotypes . Sofosbuvir may be administered in free PegINF regimens. Around 90% of naive patients achieve sustained virological response (RVS) and 80% in previously treated. In relation to second wave of NS3/4A protease inhibitors, simeprevir has achieved RVS in 90% of naive patients and close to 80% in previously treated.The main combination of DAA were sofosbuvir and daclatasvir and sofosbuvir and ledipasvir. Both have achieved SVR in 100% of patients who previously had virological failure after receiving a protease inhibitor regimen with boceprevir or telaprevir. CONCLUSIONS: The new generation of AAD for the treatment of hepatitis C will lead to higher response rates in all subtypes of patients with lower complexity regimens and better tolerated. PMID- 24951911 TI - [Toxicity of intravesical gemcitabine in superficial bladder cancer treatment]. PMID- 24951913 TI - [An unexpected and severe infusion reaction induced by trastuzumab]. PMID- 24951912 TI - [Treatment of Stenotrophomonas maltophilia meningoencephalitis with intraventricular colistin]. PMID- 24951914 TI - [Hypersensitivity reaction to etoposide. A case report]. PMID- 24951916 TI - In vivo and in vitro decolorization of synthetic dyes by laccase from solid state fermentation with Trametes sp. SYBC-L4. AB - Synthetic decolorization of dyes through solid cassava residue substrate fermentation with Trametes sp. SYBC-L4 via in vivo and in vitro processes was investigated in this study. Effects of pH and mediator (1-hydroxybenzotriazole, HBT) concentration on dyes decolorization were evaluated. In vitro, decolorization ratios of dyes differed considerably in pH and increased with the increasing of HBT concentration. Crude laccase (50 U/L) derived from Trametes sp. SYBC-L4 decolorized 67.91 +/- 1.25 % Congo red (100 mg/L), 94.58 +/- 1.05 % aniline blue (100 mg/L) and 99.02 +/- 0.54 % indigo carmine (100 mg/L) with 2.5 mM HBT at pH 4.5 in 36 h of incubation. In vivo, decolorization ratios of dyes were not enhanced by usage of the mediator. After 10 days of fermentation, decolorization ratio of Congo red (1,000 mg/kg), aniline blue (1,000 mg/kg) and indigo carmine (1,000 mg/kg) was 57.82 +/- 0.84, 92.53 +/- 1.12 and 97.26 +/- 1.92 % without the usage of mediator at pH 4.5, respectively. Moreover, there was no obvious difference between the in vivo decolorization of aniline blue and indigo carmine in the pH range of 3.0-9.0. Results showed that Trametes sp. SYBC L4 had great potential to be used for dyes decolorization via in vivo and in vitro processes. Moreover, in terms of pH range and mediator, in vivo decolorization with Trametes sp. SYBC-L4 was more advantageous since laccase mediator was needless and the applicable range of pH was broader. PMID- 24951917 TI - Inter-limb coordination and control in boys with and without DCD in ball catching. AB - The purpose of the study was to examine the nature of inter-limb coordination and control, exhibited by ten boys with (M=10.5 years, SD=1.0) and without Developmental Coordination Disorder (DCD), in a ball catching task across different ball speeds. In line with the predictions of coordinated structure theory boys who were typically developing preserved strong and effective temporal relations when catching balls in baseline and fast conditions. Boys with DCD exhibited temporal symmetry in baseline but not in fast attempts, where the decoupling was uniformed across the group, coinciding with failures on >= 50% of the attempts. In terms of stability, no differences in intra-individual variability were observed between the groups. The analysis of spatial and temporal adaptations showed that boys who were typically developing, in essence, covered the same "ground" by decreasing their movement time. The opposite was true for boys with DCD who contacted the ball closer to the body, while failing to adapt the velocity of their hands. Taken together, both groups exhibited strong and stable coordinative relations, in a steady-state but not in a fast condition, where all boys with DCD failed to preserve the desired symmetry. This decoupling also coincided with different and less effective spatio-temporal adaptations at the effector level. Thus, it appears that movement control, hence flexibility of their synergistic relations, represents a movement limiter for boys with DCD who exhibit specific balls skills issues, at inter-limb level of organization. It should be noted, however, that large intra-group variance observed across some variables warrants caution when interpreting the aggregate data. PMID- 24951915 TI - Effectiveness of oral bisphosphonates for primary prevention of osteoporotic fractures: evidence from the AIFA-BEST observational study. AB - PURPOSE: Osteoporosis is a chronic disease of the bone, whose incidence increases progressively with aging. The main consequences of osteoporosis are fragility fractures, which have considerable medical, social, and economic implications. Adequate treatment of osteoporosis must be considered as a compelling public health intervention. Bisphosphonates (BPs) represent the most significant advance in this field in the past decade, and they are widely used in the treatment of osteoporosis. However, evidence for their effectiveness is limited to secondary prevention, whereas their effect in primary prevention is uncertain and needs further investigation. METHODS: Using administrative data collected in the "Biphosphonates Efficacy-Safety Tradeoff" (BEST) study, a nested case-control study was conducted by including 56,058 participants, aged 55 years who were started on oral BPs from 2003 to 2005. Cases were the 1,710 participants who were hospitalized for osteoporotic fractures until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio of fracture associated with categories of treatment duration. RESULTS: Compared with participants assuming BPs for less than 1 year, those who remained on therapy for at least 2 years had a 21% (95% confidence interval (CI) 7 to 33%) fracture risk reduction. CONCLUSION: This study provides evidence that BPs, dispensed for primary prevention of osteoporotic fractures, are associated with a reduced risk of osteoporotic fractures after at least 2 years of treatment. PMID- 24951918 TI - Line-bisectioning and obstacle avoidance: evidence for separate strategies. AB - Previous studies have frequently applied a combination of line-bisection tasks (in which participants indicate the middle of a line) and obstacle avoidance tasks (in which participants move their hand between two obstacles) with the aim of revealing perception-action dissociations in certain neurological disorders, such as visual form agnosia and optic ataxia. However, valid conclusions about the underlying processing pathways can only be drawn if participants apply the same strategy in both tasks (i.e. finding the middle between the obstacles). Yet, this assumption has never been tested directly. In this experiment, we investigated whether participants perform obstacle avoidance and line bisectioning using similar strategies by manipulating the position of the obstacles and the start position of the hand relative to the obstacles. Our results indicate that the lateral hand position during obstacle avoidance does not only vary as a function of obstacle location but also strongly depends on the start position. Moreover, participants showed increased sensitivity to obstacle shifts occurring closer to the hand's start position. In contrast, during line bisectioning the sensitivity to obstacles shifts was unaffected by the hand's start position. The findings suggest that during obstacle-avoidance the need to keep a safe distance from the obstacles is balanced with the requirement to minimise energetic demands. In contrast, the main intention during line bisectioning is to move to the perceived midpoint as accurately as possible. The fact that very different constraints underlie trajectory planning in both tasks implies that caution has to be taken when interpreting differences in performance levels. PMID- 24951919 TI - Development and operation of gold and cobalt oxide nanoparticles containing polypropylene based enzymatic fuel cell for renewable fuels. AB - Newly synthesized gold and cobalt oxide nanoparticle embedded Polypropylene-g Polyethylene glycol was used for a compartment-less enzymatic fuel cell. Glucose oxidase and bilirubin oxidase were selected as anodic and cathodic enzymes, respectively. Electrode fabrication and EFC operation parameters were optimized to achieve high power output. Maximum power density of 23.5 uW cm(-2) was generated at a cell voltage of +560 mV vs Ag/AgCl, in 100mM PBS pH 7.4 with the addition of 20mM of synthetic glucose solution. 20 ug of polymer amount with 185 ug of glucose oxidase and 356 ug of bilirubin oxidase was sufficient to get maximum performance. The working electrodes could harvest glucose, produced during photosynthesis reaction of Carpobrotus Acinaciformis plant, and readily found in real domestic wastewater of Zonguldak City in Turkey. PMID- 24951920 TI - Development of hybrid organic-inorganic surface imprinted Mn-doped ZnS QDs and their application as a sensing material for target proteins. AB - Applying molecular imprinting techniques to the surface of functionalized quantum dots (QDs) allows the preparation of molecularly imprinted polymers (MIPs) with accessible, surface exposed binding sites and excellent optical properties. This paper demonstrates a new strategy for producing such hybrid organic-inorganic imprinted Mn-doped ZnS QDs for specific recognition of bovine hemoglobin. The technique provides surface grafting imprinting in aqueous solutions using amino modified Mn-doped ZnS QDs as supports, acrylamide and methacrylic acid as functional monomers, gamma-methacryloxypropyl trimethoxy silane as the grafting agent, and bovine hemoglobin as a template. The amino propyl functional monomer layer directs the selective occurrence of imprinting polymerization at the QDs surface through copolymerization of grafting agents with functional monomers, but also acts as an assistive monomer to drive the template into the formed polymer shells to create effective recognition sites. Using MIP-QDs composites as a fluorescence sensing material, trace amounts of bovine hemoglobin are signaled with high selectivity by emission intensity changes of Mn-doped ZnS QDs, which is embedded into the imprinted polymers. PMID- 24951921 TI - Quantum dots based molecular beacons for in vitro and in vivo detection of MMP-2 on tumor. AB - Matrix metalloproteinase-2 (MMP-2) is a protease related to tumor invasion and metastasis. It is heavily secreted by malignant tumor cells, allowing the protease to serve as an imaging biomarker of cancer. In this study, a novel sensing system based on fluorescence resonance energy transfer (FRET) from quantum dot (QD, the donor) to organic dye (the acceptor) was constructed for the in vitro and in vivo detection of matrix metalloproteinases-2 via a MMP-2 specific peptide substrate (GPLGVRGKGG). Specifically, 535 nm-emitting CdTe QD were bound to Rhodamine B (RB) through the peptide for in vitro detection of MMP 2, while 720 nm-emitting CdTeS QDs was linked to near infrared dye ICG-Der-02 (MPA) by the peptide for measurement in vivo. When these probes were exposed to MMP-2, the selective cleavage of the peptide resulted in the recovery of fluorescence from QDs. By using the produced 540QD-peptide-RB and 720QD-peptide MPA probes, we successfully examined MMP-2 in live cells and tumor on nude mouse, respectively. Due to the tunable fluorescence of Qds, this nanosensor can be fine tuned for a wide range of applications such as the detection of different biomarkers and early diagnosis of disease. PMID- 24951922 TI - Mesoporous carbon nitride based biosensor for highly sensitive and selective analysis of phenol and catechol in compost bioremediation. AB - Herein, we reported here a promising biosensor by taking advantage of the unique ordered mesoporous carbon nitride material (MCN) to convert the recognition information into a detectable signal with enzyme firstly, which could realize the sensitive, especially, selective detection of catechol and phenol in compost bioremediation samples. The mechanism including the MCN based on electrochemical, biosensor assembly, enzyme immobilization, and enzyme kinetics (elucidating the lower detection limit, different linear range and sensitivity) was discussed in detail. Under optimal conditions, GCE/MCN/Tyr biosensor was evaluated by chronoamperometry measurements and the reduction current of phenol and catechol was proportional to their concentration in the range of 5.00 * 10(-8)-9.50 * 10( 6)M and 5.00 * 10(-8)-1.25 * 10(-5)M with a correlation coefficient of 0.9991 and 0.9881, respectively. The detection limits of catechol and phenol were 10.24 nM and 15.00 nM (S/N=3), respectively. Besides, the data obtained from interference experiments indicated that the biosensor had good specificity. All the results showed that this material is suitable for load enzyme and applied to the biosensor due to the proposed biosensor exhibited improved analytical performances in terms of the detection limit and specificity, provided a powerful tool for rapid, sensitive, especially, selective monitoring of catechol and phenol simultaneously. Moreover, the obtained results may open the way to other MCN-enzyme applications in the environmental field. PMID- 24951923 TI - A robust, state-of-the-art amperometric microbiosensor for glutamate detection. AB - Scientific knowledge of glutamate (GLU) neurobiology is severely hampered by the inadequacy of the available in vivo brain sampling techniques. Due to the crucial role of GLU in central nervous system function and pathology, the development of a reliable sampling device is mandatory. GLU biosensor holds potential to address many of the known issues of in vivo GLU measurement. We report here on the development and test of a labor- and cost-effective microbiosensor, suitable to be applied for measuring brain GLU. A glycerol-based cryopreservation method was also tested. Needle type Pt biosensors were coated with a permselective Nafion Poly(o-phenylenediamine) layer and cross-linked to l-glutamate oxidase with poly(ethylene glycol) diglycidyl ether. Tested in vitro, the device shows high sensitivity and specificity for GLU, while being poorly influenced by common interfering substances such as ascorbate, dopamine and dihydroxyphenylacetic acid. Further, the cryopreservation procedure kept sensitivity unaltered for 30 days and possibly longer. We conclude that a highly efficient GLU biosensor of minimal dimensions can be consistently and affordably constructed with relative ease. Together with the possibility of cryopreservation this shall foster diffusion and exploitation of GLU biosensors technology. PMID- 24951924 TI - Preparation of magnetic TNT-imprinted polymer nanoparticles and their accumulation onto magnetic carbon paste electrode for TNT determination. AB - In this study, the TNT-imprinted polymer shell was created on nano-sized Fe3O4 cores in order to construct the nano-sized magnetic molecularly imprinted polymer (nano-MMIP). For this purpose, the surface of the synthesized magnetic nanoparticles was modified with methacrylic acid. The modified particles were then utilized as the core on which the TNT-imprinted polymeric shell was synthesized. The synthesized materials were then characterized by scanning electron microscopy, FT-IR and thermal gravimetric analysis (TGA). The resulting nano-MMIP particles were suspended in TNT solution and then collected on the surface of a carbon paste electrode via a permanent magnet, situated within the CP electrode. The extracted TNT was analyzed on the CP electrode by applying square wave voltammetry (SWV). It was found that the oxidative signal of TNT is much favorable for TNT detection on the resulting magnetic carbon paste electrode. The electrode with nano-MMIP showed distinctly higher signal to TNT, compared to that containing magnetic non-imprinted polymer (MNIP) nanoparticles. All parameters influencing the method performance including extraction pH, extraction time and sorbent amount were evaluated and optimized. The developed method showed a dynamic linear concentration range of 1.0-130.0 nM for TNT measurement. The detection limit of the method was calculated to be 0.5 nM. The method showed appropriate capability for TNT analysis in real water samples. PMID- 24951925 TI - Breastfeeding interventions in Kansas: a qualitative process evaluation of program goals and objectives. AB - Across the state of Kansas, eighteen public health departments received funding through the 2011 Breastfeeding Grant Initiative to start a breastfeeding intervention. The main objective of this study was to evaluate the progress toward program goals and objectives. This study was a process evaluation. Qualitative data were collected from recipient health departments at two time points during the program year. Structured, open-ended questions were asked through telephone interviews. This study examined: (1) progress toward program goals and objectives, (2) problems encountered during implementation, and (3) evaluation measures employed to assess program impact. All health departments reported making significant progress toward program goals and objectives and reported successful collaboration with other healthcare providers. The use of breast pumps, educational classes, and professional training of staff were reported as providing the best outcome in the promotion of breastfeeding. The majority of respondents did not measure program impact. From a public health perspective, it is important that infants receive breast milk for the first six months of life. It appears that goals and objectives set a priori guided health departments with the administration of their breastfeeding program. Results may be used to enhance and sustain delivery of breastfeeding support programs in Kansas communities. PMID- 24951926 TI - Factors influencing the mechanical stability of alginate beads applicable for immunoisolation of mammalian cells. AB - Transplantation of microencapsulated cells has been proposed as a cure for many types of endocrine disorders. Alginate-based microcapsules have been used in many of the feasibility studied addressing cure of the endocrine disorders, and different cancer types. Despite years of intensive research it is still not completely understood which factors have to be controlled and documented for achieving adequate mechanical stability. Here we studied the strength and elasticity of microcapsules of different composition with and without cell load. We compared strength (force) versus elasticity (time) required to compress individual microcapsule to 60% deformation. It is demonstrated that the alginate viscosity, the size of the beads, the alginate type, the gelling time, the storage solution and the cell load are dominant factors in determining the final strength of alginate-based microcapsules while the type of gelling ion, the polyamino acid incubation time, the type of polyamino acid and the culturing time determines the elasticity of the alginate-based microcapsules. Our data underpin the essence of documenting the above mentioned factors in studies on encapsulated cells as mechanical stability is an essential factor in the success and failure of encapsulated grafts. PMID- 24951928 TI - Improvement of toughness by stereocomplex crystal formation in optically pure polylactides of high molecular weight. AB - A solution casting method followed by thermal homogenization was performed for the preparation of 1:1 blends and non-blended films from poly(d-lactide) (PDLA) and poly(l-lactide) (PLLA) of three different molecular weights, and their thermal and mechanical properties were determined via differential scanning calorimetry (DSC) and tensile tests. According to the literature, when Mw is below 1.0*10(5)g/mol only stereocomplex crystallization takes place, and when it is higher, both homocrystallites and stereocomplex crystallites co-exist. In order to promote crystallization as a homocrystal in neat polylactides and to promote the stereoselective crystallization as stereocomplex in the case of non blended films, and in turn, to achieve different degrees of crystallinity, several thermal treatments of annealing were carried out in this work. Highly stereocomplexed blends were found by the stereospecific thermal treatments. As a consequence, the toughness of 1:1 blends was found significantly enhanced over those of non-blended films, irrespective of molecular weight. For instance, in B2 5050 stereocomplexed blend having poly(l-lactide) and poly(d-lactide) of Mw=1.2*10(5)g/mol, tensile strength increased from 44.0+/-2.1MPa to 65.1+/ 6.1MPa, and the elongation at break from 10.8+/-2.5% to 33.1+/-8.1% with respect to its non-blended poly(l-lactide) counterpart crystallized as homocrystal. This improvement in mechanical properties in stereocomplexed blends is not attributed to the inherent properties of the type of crystal polymorph but to the presence of a higher density of intercrystalline connections through a mobile amorphous phase, i.e. tie chains in the stereocomplexed supramolecular spherulitic entities that provide in the stereocomplexed samples enhanced strength and elongation at break at the same time. PMID- 24951927 TI - Automated AFM force curve analysis for determining elastic modulus of biomaterials and biological samples. AB - The analysis of atomic force microscopy (AFM) force data requires the selection of a contact point (CP) and is often time consuming and subjective due to influence from intermolecular forces and low signal-to-noise ratios (SNR). In this report, we present an automated algorithm for the selection of CPs in AFM force data and the evaluation of elastic moduli. We propose that CP may be algorithmically easier to detect by identifying a linear elastic indentation region of data (high SNR) rather than the contact point itself (low SNR). Utilizing Hertzian mechanics, the data are fitted for the CP. We first detail the algorithm and then evaluate it on sample polymeric and biological materials. As a demonstration of automation, 64 * 64 force maps were analyzed to yield spatially varying topographical and mechanical information of cells. Finally, we compared manually selected CPs to automatically identified CPs and demonstrated that our automated approach is both accurate (< 10nm difference between manual and automatic) and precise for non-interacting polymeric materials. Our data show that the algorithm is useful for analysis of both biomaterials and biological samples. PMID- 24951929 TI - Temporal dynamics of ectomycorrhizal fungi and persistence of Tuber melanosporum in inoculated Quercus robur seedlings in North Europe. AB - Tuber melanosporum is widely cultivated outside its natural habitat in various climatic conditions. This study aims to monitor the persistence of T. melanosporum in inoculated oak seedlings and document temporal changes of native ectomycorrhizal fungi in an Estonian 5-year-old plantation. Sampling of ectomycorrhizal fungi was carried out in June-July 2011-2013 to provide DNA-based identification of the inoculated truffle species and other co-occurring ectomycorrhizal fungi. The mycorrhiza of T. melanosporum proved resistant to cold winters, and the fungus persisted well in the root systems of surviving seedlings albeit slight decline in relative colonization level over 3 years. We identified the genera Hymenogaster and Hebeloma to be the dominant ectomycorrhizal competing fungi in root systems. Good vegetative growth of mycelia and the presence of two compatible mating types suggest that cultivation of T. melanosporum is possible in the Nordic climate. Evaluation of fruit-body production will be a critical next step, because fruiting efficiency allows to determine economic feasibility and ecological sustainability of the Perigord truffle cultivation in northern climate. PMID- 24951930 TI - Laminins 411 and 421 differentially promote tumor cell migration via alpha6beta1 integrin and MCAM (CD146). AB - alpha4-laminins, such as laminins 411 and 421, are mesenchymal laminins expressed by blood and lymphatic vessels and some tumor cells. Laminin-411 promotes migration of leukocytes and endothelial cells, but the effect of this laminin and laminin-421 on tumor cells is poorly understood. In the present study, we demonstrate that laminin-411 and, to a greater extent, laminin-421 significantly promote migration of tumor cells originated from melanomas, gliomas and different carcinomas via alpha6beta1 integrin. In solid-phase binding assays, both laminins similarly bound alpha6beta1 integrin but only laminin-421, among several laminin isoforms, readily bound MCAM (CD146), a cell-surface adhesion molecule strongly associated with tumor progression. Accordingly, a function-blocking mAb to MCAM inhibited tumor cell migration on laminin-421 but not on laminins 411 or 521. In tumor tissues, melanoma cells co-expressed MCAM, laminin alpha4, beta1, beta2 and gamma1 chains, and integrin alpha6 and beta1 chains. The present data highlight the novel role of alpha4-laminins in tumor cell migration and identify laminin 421 as a primary ligand for MCAM and a putative mediator of tumor invasion and metastasis. PMID- 24951931 TI - Incremental utility of iodine-123 meta-iodobenzylguanidine imaging beyond established heart failure risk models. AB - BACKGROUND: Nuclear myocardial imaging with iodine-123 meta-iodobenzylguanidine ((123)I-mIBG) is approved for risk stratification of patients with systolic heart failure (HF). Whether (123)I-mIBG imaging provides incremental prognostic utility beyond established risk models remains unclear. METHODS AND RESULTS: In a multicenter study, 961 patients with moderate systolic HF underwent (123)I-mIBG imaging and were followed for cardiac death, progressive HF, or life-threatening arrhythmias over 2 years. We constructed 4 multivariable models, using variables from each of 4 published HF risk models, and patient-level scores were calculated both before and after adding the heart-to-mediastinum ratio (H/M) from (123)I mIBG imaging. Incremental utility was evaluated by calculating integrated discrimination improvement (IDI), which quantifies the increase in probability of experiencing the primary end point after adding H/M to each model. The composite end point occurred in 25% of patients. After adding H/M, absolute IDI ranged from 2.1% to 3.0%, representing 33%-59% relative improvements in risk stratification. Of note, hazard ratios for H/M were remarkably similar between risk models (0.40 0.44 for predicting the composite end point, 0.10-0.18 for mortality; all P < .001). CONCLUSIONS: Despite notable differences in predictor variables, patient populations, and analytic techniques from which each model was initially derived, adding (123)I-mIBG data to HF risk models consistently identified patients at lower risk of experiencing adverse events. PMID- 24951932 TI - Use of intravenous diuretics on day of discharge in adults hospitalized for heart failure. PMID- 24951933 TI - Exercise ventilatory parameters for the diagnosis of reactive pulmonary hypertension in patients with heart failure. AB - BACKGROUND: Reactive pulmonary hypertension (PH) in left heart disease is associated with poor prognosis. This study aimed to evaluate the diagnostic utility of exercise ventilatory parameters on cardiopulmonary exercise testing for the diagnosis of reactive PH in patients with heart failure (HF) and reduced ejection fraction. METHODS: This was a single-center, retrospective analysis of a prospectively collected database of 131 patients with HF who underwent in hospital assessment for heart transplantation. Pulmonary hemodynamics was assessed by direct cardiac catheterization. Minute ventilation/carbon dioxide production (VE/VCO2) slope, partial pressure of end-tidal carbon dioxide (ETCO2) changes on exercise, oxygen pulse, and exercise oscillatory ventilation were determined from cardiopulmonary exercise testing. RESULTS: Sixty-one of 131 consecutive patients had reactive PH. VE/VCO2 slope (>41), change in ETCO2 on exercise (<1.2 mm Hg) and exercise oscillatory ventilation were independently associated with reactive PH. These 3 parameters in combination produced 3 possible diagnostic scenarios: (1) if all 3 criteria ("if all") were present, (2) if any 2 of the 3 criteria ("2 of 3") were present, and (3) if any of the criteria ("if any") were present. The corresponding positive/negative likelihood ratios for reactive PH if all 3 criteria were present were 3.73/0.83, if 2 of the 3 criteria were present were 2.19/0.45, and if any of the 3 criteria were present were 1.75/0.11. The posttest probability increased from 46% to 76% ("if all" present) and reduced to 9% (if none of the criteria was present). CONCLUSION: Ventilatory parameters on cardiopulmonary exercise test are associated with reactive PH in patients with HF. The absence of abnormalities in these 3 ventilatory parameters can effectively exclude reactive PH in patients with HF and poor ejection fraction. PMID- 24951934 TI - Thirst trajectory and factors associated with persistent thirst in patients with heart failure. AB - BACKGROUND: Thirst is often increased in patients with heart failure (HF) and can cause distress during the course of the condition. The aim of the present study was to describe the trajectory of thirst during an 18-month period and to identify variables associated with persistent thirst in patients with HF. METHODS AND RESULTS: Data were collected from 649 patients with HF with the use of the Revised Heart Failure Compliance Scale at 1, 6, 12, and 18 months after a period of hospital treatment for worsening HF. Thirst trajectory was described for the 4 follow-up visits and logistic regression analysis was used to identify factors independently associated with persistent thirst. In total, 33% (n = 212) of the patients reported thirst on >=1 occasions and 34% (n = 46) continued to have thirst at every follow-up visit. Nineteen percent (n = 121) of the patients had persistent thirst. Patients with persistent thirst were more often younger and male and had more HF symptoms. Higher body mass index and serum urea also increased the risk of persistent thirst. CONCLUSIONS: Patients with HF who were thirsty at the 1-month follow-up were more often also thirsty at subsequent visits. Assessment of thirst is warranted in clinical practice because one-fifth of patients suffer from persistent thirst. PMID- 24951935 TI - Reply to the Article Ben Yaacov A, Sadot E, Ben David M, Wasserberg N, Keidar A. Laparoscopic total gastrectomy with Roux-y esophagojejunostomy for chronic gastric fistula after laparoscopic sleeve gastrectomy. Obes Surg. 2014 Mar;24(3):425-9. PMID- 24951936 TI - Investigation on the high-temperature flow behavior of biomass and coal blended ash. AB - The high-temperature flow behavior of biomass (straw) and coal blended ash was studied. The variation of viscosity and the temperature of critical viscosity with different straw content were investigated. It is found that the straw ash with high viscosity is unsuitable for directly gasification and the 20% straw content sample can effectively decrease the viscosity. The solid phase content and mineral matters variation calculated by FactSage demonstrate the change of viscosity. In addition, the network theory illustrates that the Si-O-Si bond decreases to improve the viscosity of 20% straw content sample. The variation of mineral matters in XRD analysis validates the change of viscosity. Furthermore, the temperature of critical viscosity and lowest operation temperature reach the minimum when the straw content is 20%. Hysteresis between heating and cooling process of the sample with 20% straw content is more obvious than that of the samples with 40% and 80% straw content. PMID- 24951937 TI - Co-pyrolysis of corn cob and waste cooking oil in a fixed bed. AB - Corn cob (CC) and waste cooking oil (WCO) were co-pyrolyzed in a fixed bed. The effects of various temperatures of 500 degrees C, 550 degrees C, 600 degrees C and CC/WCO mass ratios of 1:0, 1:0.1, 1:0.5, 1:1 and 0:1 were investigated, respectively. Results show that co-pyrolysis of CC/WCO produce more liquid and less bio-char than pyrolysis of CC individually. Bio-oil and bio-char yields were found to be largely dependent on temperature and CC/WCO ratios. GC/MS of bio-oil show it consists of different classes and amounts of organic compounds other than that from CC pyrolysis. Temperature of 550 degrees C and CC/WCO ratio of 1:1 seem to be the optimum considering high bio-oil yields (68.6 wt.%) and good bio oil properties (HHV of 32.78 MJ/kg). In this case, bio-char of 24.96 MJ/kg appears attractive as a renewable source, while gas with LHV of 16.06 MJ/Nm(3) can be directly used in boilers as fuel. PMID- 24951939 TI - Effects of nitrogen source and nitrogen supply model on the growth and hydrocarbon accumulation of immobilized biofilm cultivation of B. braunii. AB - The immobilized biofilm cultivation was a promising method to greatly improve the biomass productivity of microalga Botryococcus braunii, which was considered as an feedstock of renewable biofuel. In this research, the effects of different nitrogen sources and supply methods on growth and hydrocarbon production of B. braunii under immobilized biofilm cultivation (attached cultivation) were studied. Of the total 5 different nitrogen sources, NaNO3 was selected as the best one with which the high biomass productivity and hydrocarbon productivity of 6.45 gm(-2)d(-1) and 2.79 gm(-2)d(-1) were obtained respectively. The optimized nitrogen concentration was 0.99 mM for non-circulating medium supply model, while for the circulating model, the optimized nitrogen concentration as well as medium volume was 1.49 mM and 1.2L, respectively. Furthermore, nitrogen inputs based on growth of 1 kg dry algae biomass was only 28.92 g with circulating model. Attached cultivation was high efficient in light, nutrient and water utilization. PMID- 24951938 TI - Fast microwave-assisted pyrolysis of microalgae using microwave absorbent and HZSM-5 catalyst. AB - Fast microwave-assisted pyrolysis (fMAP) in the presence of a microwave absorbent (SiC) and catalyst (HZSM-5) was tested on a Chlorella sp. strain and on a Nannochloropsis strain. The liquid products were characterized, and the effects of temperature and catalyst:biomass ratio were analyzed. For Chlorella sp., a temperature of 550 degrees C, with no catalyst were the optimal conditions, resulting in a maximum bio-oil yield of 57 wt.%. For Nannochloropsis, a temperature of 500 degrees C, with 0.5 of catalyst ratio were shown to be the optimal condition, resulting in a maximum bio-oil yield of 59 wt.%. These results show that the use of microwave absorbents in fMAP increased bio-oil yields and quality, and it is a promising technology to improve the commercial application and economic outlook of microwave pyrolysis technology. Additionally, the use of a different catalyst needs to be considered to improve the bio-oil characteristics. PMID- 24951940 TI - Optimization of glucose formation in karanja biomass hydrolysis using Taguchi robust method. AB - The main objective of the present study is aimed to optimize the process parameters for the production of glucose from karanja seed cake. The Taguchi robust design method with L9 orthogonal array was applied to optimize hydrolysis reaction conditions and maximize sugar yield. Effect of temperature, acid concentration, and acid to cake weight ratio were considered as the main influencing factors which effects the percentage of glucose and amount of glucose formed. The experimental results indicated that acid concentration and liquid to solid ratio had a principal effect on the amount of glucose formed when compared to that of temperature. The maximum glucose formed was 245 g/kg extractive free cake. PMID- 24951941 TI - Physicochemical parameters optimization, and purification of phycobiliproteins from the isolated Nostoc sp. AB - The present study investigated the effects of several physicochemical parameters on the improvement of phycobiliproteins (especially phycocyanin) synthesis in a newly isolated species of Nostoc sp. Standard BG110 medium was modified to enhance the biomass productivity in different photobioreactors. The initial pH of 8, light intensity of 40 MUmol m(-2)s(-1), temperature of 35 degrees C, diurnal cycle of 16:8 h (light:dark regime), 75.48 MUM Na2CO3 and 17.65 mM NaNO3 were found most suitable for the phycobiliproteins synthesis. Cyanobacteria exhibited chromatic adaptation, causing overexpression of phycocyanin in red and phycoerythrin in green light. The maximum phycobiliproteins yield of 0.13 gg(-1) dry cell weight was obtained in green light. Phycocyanin was further purified using thin layer chromatography (TLC), anion exchange chromatography and SDS-PAGE (denaturing gel) electrophoresis. PMID- 24951942 TI - Biodegradation of pyrene by a Pseudomonas aeruginosa strain RS1 isolated from refinery sludge. AB - High molecular weight (HMW) polynuclear aromatic hydrocarbons (PAHs) with more than three rings are inherently difficult to degrade. Degradation of HMW PAHs is primarily reported for actinomycetes, such as, Rhodococcus and Mycobacterium. This study reports pyrene degradation by a Pseudomonas aeruginosa strain isolated from tank bottom sludge in a refinery. High cell surface hydrophobicity induced during growth on pyrene facilitated its utilization as sole carbon source. Specific growth rate (MU) in the range of 0.03-0.085 h(-1) could be achieved over the concentration range 25-500 mg/L. The specific growth rate and specific pyrene utilization rate increased linearly with increase in total pyrene concentration. Although various degradation intermediates were identified in the aqueous phase, accumulation of total organic carbon (TOC) in the aqueous phase was only a small fraction of TOC equivalents of pyrene lost from the cultures. The degradation pathway appears to be similar to that reported for Mycobacterium sp. PYR-I. PMID- 24951943 TI - Variance misperception explains illusions of confidence in simple perceptual decisions. AB - Confidence in a perceptual decision is a judgment about the quality of the sensory evidence. The quality of the evidence depends not only on its strength ('signal') but critically on its reliability ('noise'), but the separate contribution of these quantities to the formation of confidence judgments has not been investigated before in the context of perceptual decisions. We studied subjective confidence reports in a multi-element perceptual task where evidence strength and reliability could be manipulated independently. Our results reveal a confidence paradox: confidence is higher for stimuli of lower reliability that are associated with a lower accuracy. We show that the subjects' overconfidence in trials with unreliable evidence is caused by a reduced sensitivity to stimulus variability. Our results bridge between the investigation of miss-attributions of confidence in behavioral economics and the domain of simple perceptual decisions amenable to neuroscience research. PMID- 24951944 TI - Intragroup contact and anxiety among ethnic minority adolescents: considering ethnic identity and school diversity transitions. AB - Everyday interactions with same-racial/ethnic others may confer positive benefits for adolescents, but the meaning of these interactions are likely influenced by individual differences and larger structural contexts. This study examined the situation-level association between contact with same-ethnic others and anxiety symptoms among a diverse sample of 306 racial/ethnic minority adolescents (Mage = 14 years; 66% female), based on (1) individual differences in ethnic identity centrality and (2) developmental histories of transitions in diversity between elementary, middle, and high school. The results indicated that at the level of the situation, when adolescents interacted with more same-ethnic others, they reported fewer anxiety symptoms. Further, for adolescents who had experienced a transition in school diversity, the positive benefits of contact with same-ethnic others was only conferred for those who felt that their ethnicity was very important to them. The importance of examining individual differences within larger developmental histories to understand the everyday experiences of ethnic minority adolescents are discussed. PMID- 24951945 TI - Pharmacists in pharmacovigilance: can increased diagnostic opportunity in community settings translate to better vigilance? AB - The pharmacy profession has undergone substantial change over the last two to three decades. Whilst medicine supply still remains a central function, pharmacist's roles and responsibilities have become more clinic and patient focused. In the community (primary care), pharmacists have become important providers of healthcare as Western healthcare policy advocates patient self-care. This has resulted in pharmacists taking on greater responsibility in managing minor illness and the delivery of public health interventions. These roles require pharmacists to more fully use their clinical skills, and often involve diagnosis and therapeutic management. Community pharmacists are now, more than ever before, in a position to identify, record and report medication safety incidents. However, current research suggests that diagnostic ability of community pharmacists is questionable and they infrequently report to local or national schemes. The aim of this paper is to highlight current practice and suggest ways in which community pharmacy can more fully contribute to patient safety. PMID- 24951946 TI - RPPApipe: a pipeline for the analysis of reverse-phase protein array data. AB - BACKGROUND AND SCOPE: Today, web-based data analysis pipelines exist for a wide variety of microarray platforms, such as ordinary gene-centered arrays, exon arrays and SNP arrays. However, most of the available software tools provide only limited support for reverse-phase protein arrays (RPPA), as relevant inherent properties of the corresponding datasets are not taken into account. Thus, we developed the web-based data analysis pipeline RPPApipe, which was specifically tailored to suit the characteristics of the RPPA platform and encompasses various tools for data preprocessing, statistical analysis, clustering and pathway analysis. IMPLEMENTATION AND PERFORMANCE: All tools which are part of the RPPApipe software were implemented using R/Bioconductor. The software was embedded into our web-based ZBIT Bioinformatics Toolbox which is a customized instance of the Galaxy platform. AVAILABILITY: RPPApipe is freely available under GNU Public License from http://webservices.cs.uni-tuebingen.de. A full documentation of the tool can be found on the corresponding website http://www.cogsys.cs.uni-tuebingen.de/software/RPPApipe. PMID- 24951947 TI - Are there clinical variables determining antibiotic prophylaxis-susceptible versus resistant infection in open fractures? AB - PURPOSE: In Gustilo grade III open fractures, it remains unknown which demographic or clinical features may be associated with an infection resistant to the administered prophylactic agent, compared to one that is susceptible. METHODS: This was a retrospective case-control study on patients hospitalized from 2004 to 2009. RESULTS: We identified 310 patients with Gustilo-III open fractures, 36 (12%) of which became infected after a median of ten days. In 26 (72%) of the episodes the pathogen was susceptible to the prophylactic antibiotic agent prescribed upon admission, while in the other ten it was resistant. All antibiotic prophylaxis was intravenous; the median duration of treatment was three days and the median delay between trauma and surgery was one day. In multivariate analysis adjusting for case-mix, only Gustilo-grade-IIIc fractures (vascular lesions) showed tendency to be infected with resistant pathogens (odds ratio 10; 95% confidence interval 1.0-10; p = 0.058). There were no significant differences between cases caused by antibiotic resistant and susceptible pathogen cases in patient's sex, presence of immune suppression, duration and choice of antibiotic prophylaxis, choice of surgical technique or materials, time delay until surgery, use of bone reaming, fracture localization, or presence of compartment syndrome. CONCLUSION: We were unable to identify any specific clinical parameters associated with infection with antibiotic resistant pathogens in Gustilo-grade III open fractures, other than the severity of the fracture itself. More research is needed to identify patients who might benefit from a broader-spectrum antibiotic prophylaxis. PMID- 24951949 TI - All-inside anterior cruciate ligament reconstruction. AB - All-inside anterior cruciate ligament (ACL) reconstruction has undergone a series of modifications over the past 20 years. Current techniques offer the advantages of improved cosmesis, less postoperative pain, decreased bone removal, and gracilis preservation. Few all-inside ACL reconstruction outcome studies are available; therefore, additional research is necessary to compare the results to conventional techniques. The purpose of this article is to review the evolution of all-inside ACL reconstruction, the advantages and disadvantages, our preferred technique, and clinical experience to date. PMID- 24951950 TI - Meniscal allograft transplantation: preoperative assessment, surgical considerations, and clinical outcomes. AB - The purpose of this review is to characterize the preoperative assessment of meniscal allograft transplantation (MAT) candidates, to detail MAT surgical techniques, and to evaluate current clinical outcome data on MAT. The MAT candidate is typically less than 50 years old and has a history of knee injury, previous meniscus surgery, and persistent pain. Physical exam generally reveals knee pain with joint line tenderness with normal radiographs and magnetic resonance imaging demonstrating the postmeniscectomized state. There are several common surgical techniques used for transplantation, with fixation achieved through sutures, bony fixation, or a combination of the two. Concomitant procedures such as anterior cruciate ligament reconstruction, osteotomy, and other cartilage procedures are commonly performed. The available short- and long term studies of clinical outcomes of MAT are variable and difficult to effectively compare due to heterogeneity of the study population and available treatment techniques. In addition, there are no published randomized controlled trials. However, recent reviews and cohort studies of clinical outcomes following MAT have shown that whether performed in isolation or performed with concomitant articular cartilage, realignment, or soft tissue reconstruction procedures MAT outcomes have been acceptable with the majority of studies reporting improved clinical outcomes regardless of the scoring system employed. MAT has proven to be a safe and effective technique in reducing knee pain and improving function in the symptomatic meniscal deficient knee. Evaluation of long-term clinical outcomes is necessary as is evaluation of meniscal replacement alternatives. PMID- 24951948 TI - Five-year results of arthroscopic techniques for the treatment of acetabular chondral lesions in femoroacetabular impingement. AB - PURPOSE: This study assesses and compares the clinical outcomes of the arthroscopic matrix-induced autologous chondrocyte implant (MACI) and autologous matrix-induced chondrogenesis (AMIC) techniques for the treatment of acetabular chondral defects between 2 and 4 cm(2) consequent to femoral acetabular impingement. METHODS: Fifty-seven consecutive patients were treated with the MACI (n = 26) or AMIC (n = 31) technique. Patients were assessed pre-operatively and up to five years using the modified Harris Hip Score (mHHS) to compare outcomes. RESULTS: In both the MACI and AMIC groups, significant hip score improvements were measured over baseline levels at six months post-op (81.2 +/- 8.4 for MACI, 80.3 +/- 8.3 for AMIC, both p < 0.001). The mHHS continued to improve up to three years post-op and remained stable over time until the final five year follow-up. Statistically significant differences between the groups were not observed. The mean mHHS improvement at the five year follow-up with respect to preoperative level was 37.8 +/- 5.9 and 39.1 +/- 5.9 in patients who underwent MACI and AMIC, respectively (NS). Subgroup analysis of both MACI and AMIC treatment outcomes for patients with an initial chondral defect larger than 3 cm(2) yielded comparable results at each time point. CONCLUSIONS: This study suggests that both arthroscopic MACI and AMIC are valid procedures to repair medium-sized chondral defects on the acetabular side of the hip found during treatment of femoroacetabular impingement. Due to its high sustainability and minimal invasiveness, the single-stage AMIC procedure can reduce total treatment time and minimise morbidity while providing the same beneficial effects as the two-stage MACI intervention. PMID- 24951951 TI - Disadvantages and advantages of transtibial technique for creating the anterior cruciate ligament femoral socket. AB - Anterior cruciate ligament (ACL) femoral socket techniques have distinct advantages and disadvantages when considering the following techniques: transtibial, anteromedial portal, outside-in, and outside-in retroconstruction. There is no one perfect technique and we have an incomplete understanding of anatomical, biomechanical, isometry, stability, and clinical outcomes. Our primary focus is transtibial technique for creating the ACL femoral socket. Advantages include less invasive, isometric graft placement, stable Lachman exam, and minimal graft impingement with the tunnel and notch. Disadvantages include nonanatomic vertical graft placement that can cause rotational instability and positive pivot shift, interference screw divergence, graft-tunnel length mismatch, femoral socket constraint, posterior cruciate ligament impingement, and a short, oblique tibial tunnel that may undermine the medial plateau in an attempt to achieve anatomic ACL reconstruction. PMID- 24951952 TI - Replication forks reverse at high frequency upon replication stress in Physarum polycephalum. AB - The addition of hydroxyurea after the onset of S phase allows replication to start and permits the successive detecting of replication-dependent joint DNA molecules and chicken foot structures in the synchronous nuclei of Physarum polycephalum. We find evidence for a very high frequency of reversed replication forks upon replication stress. The formation of these reversed forks is dependent on the presence of joint DNA molecules, the impediment of the replication fork progression by hydroxyurea, and likely on the propensity of some replication origins to reinitiate replication to counteract the action of this compound. As hydroxyurea treatment enables us to successively detect the appearance of joint DNA molecules and then of reversed replication forks, we propose that chicken foot structures are formed both from the regression of hydroxyurea-frozen joint DNA molecules and from hydroxyurea-stalled replication forks. These experiments underscore the transient nature of replication fork regression, which becomes detectable due to the hydroxyurea-induced slowing down of replication fork progression. PMID- 24951953 TI - Measuring the quality of mental health care: consensus perspectives from selected industrialized countries. AB - This international initiative sought to develop a consensus framework of mental health quality measures. The 656 quality measures identified via literature review were narrowed to 36 measurement concepts. A modified Delphi process was used to rate these for validity, importance, and feasibility. The highest rated concepts for validity and importance included 7-day follow-up after inpatient discharge, involuntary/compulsory hospitalization, seclusion, death rates, medication adherence, medication errors, and restraint. Importance and validity scores were correlated, with importance scores higher than validity scores. Further work is needed to develop and implement a core set of measures for international comparison of mental health quality. PMID- 24951954 TI - Proportional evaluation of anterior cruciate ligament footprint size and knee bony morphology. AB - PURPOSE: The purpose of this study was to reveal the correlation in size between the native anterior cruciate ligament (ACL) footprint and the femoral intercondylar notch and the tibia plateau, and to calculate the proportion in size between the ACL footprint and knee bony morphology. METHODS: Twenty-six non paired human cadaver knees were used. All soft tissues around the knee were resected except the ACL. The ACL was cut in the middle, and the femoral bone was cut at the most proximal point of the femoral notch. The ACL was carefully dissected, and the periphery of the ACL insertion site was outlined on both the femoral and tibial sides. An accurate lateral view of the femoral condyle and an axial view of the tibial plateau were photographed with a digital camera, and the images were downloaded to a personal computer. The size of the femoral and tibial ACL footprints and the area of the lateral wall of the intercondylar notch and the tibia plateau were measured with Image J software (National Institution of Health). RESULTS: The sizes of the native femoral and tibial ACL footprints were 69.8 +/- 25 and 133.8 +/- 31.3 mm(2), respectively. The areas of the lateral wall of the intercondylar notch and the tibia plateau were 390.5 +/- 70.5 and 2,281.7 +/- 377.3 mm(2), respectively. The femoral ACL footprint area and the area of the lateral wall of the femoral intercondylar notch (Pearson's correlation coefficient = 0.603, p = 0.001), and the tibial ACL footprint area and the area of the tibia plateau (Pearson's correlation coefficient = 0.452, p = 0.02) both showed significant correlation. The femoral ACL footprint was 17.8 +/- 4.9 %, the size of the lateral wall of the femoral intercondylar notch, and the tibial ACL footprint was 5.9 +/- 1.3 %, the size of the tibia plateau. CONCLUSION: For clinical relevance, the femoral ACL footprint is approximately 18 %, the size of the intercondylar notch, and the tibial ACL footprint is approximately 6 %, the size of the tibia plateau. It might be possible to predict the size of the ACL measuring these parameters preoperatively. PMID- 24951955 TI - HoxA10 induces proliferation in human prostate carcinoma PC-3 cell line. AB - The objectives of this study were to examine the expression levels of Homeobox A10 (HoxA10) in prostate cancer cells and to study the molecular mechanism of HoxA10-mediated regulation of prostate cancer cell growth and development. We investigated the effect of HoxA10 on cell proliferation by stably overexpressing or silencing HoxA10 in prostate cancer PC-3 cell line using lentiviral vectors. Quantitative real-time PCR and western blotting analysis were used to compare the expressions of HoxA10 in prostate cancer cell lines and normal prostate epithelium. Cancer cell proliferation was examined by MTT assay and colony formation assay. The levels of HoxA10 expression were significantly increased in prostate cancer cell lines and tissues compared to those in normal prostate epithelium. Overexpression of HoxA10 in PC-3 cells induced significant cancer cell proliferation, whereas silencing of HoxA10 expression by RNAi resulted in decreased proliferation rates. HoxA10 was highly expressed in prostate cancer cells and tissues, suggesting its functional involvement in cancer cell proliferation. We successfully overexpressed or silenced HoxA10 in prostate cancer PC-3 cell line and discovered that the levels of HoxA10 directly correlate with cancer cell proliferation. These findings contribute to a better understanding of the regulatory mechanism of HoxA10 in prostate cancer. PMID- 24951956 TI - Rap2B promotes migration and invasion of human suprarenal epithelioma. AB - The aim of our study was to elucidate the role of Rap2B in the development of human suprarenal epithelioma and to investigate the effect of Rap2B on suprarenal epithelioma cells migration and invasion. We use tissue microarray and immunohistochemistry to evaluate Rap2B staining in 75 suprarenal epithelioma tissues and 75 tumor-adjacent normal renal tissues. And the expression of Rap2B protein in human suprarenal epithelioma cells and tissues was detected by western blot simultaneously. The role of Rap2B in suprarenal epithelioma cells migration and invasion was detected by using wound healing assay, cell migration assay, and matrigel invasion assay. After that, we performed western blot analysis and gelatin zymography to detect MMP-2 protein expression and enzyme activity. Our research showed that Rap2B expression was increased in tumor tissues compared with tumor-adjacent normal renal tissues. But no correlation was found between Rap2B expression and clinicopathological parameters. In addition, we found that Rap2B promoted the cell migration and invasion abilities, and Rap2B increased MMP 2 expression and enzyme activity in suprarenal epithelioma cells. Our data indicated that Rap2B expression is significantly increased in human suprarenal epithelioma and Rap2B can promote the cell migration and invasion abilities, which may provide a new target for the treatment of suprarenal epithelioma. PMID- 24951957 TI - Grb2-associated binder 1 is essential for cardioprotection against ischemia/reperfusion injury. AB - We have shown recently that endothelial Grb-2-associated binder 1 (Gab1), an intracellular scaffolding adaptor, has a protective effect against limb ischemia via mediating angiogenic signaling pathways. However, the role of Gab1 in cardiac ischemia/reperfusion (I/R) injury remains unknown. In this study, we show that Gab1 is required for cardioprotection against I/R injury. I/R injury led to remarkable phosphorylation of Gab1 in cardiomyocytes. Compared with controls, the mice with cardiomyocyte-specific deletion of Gab1 gene (CGKO mice) exhibited an increase in infarct size and a decrease in cardiac function after I/R injury. Consistently, in hearts of CGKO mice subjected to I/R, the activation of caspase 3 and myocardial apoptosis was markedly enhanced whereas the activation of protein kinase B (Akt) and mitogen-activated protein kinase (MAPK), which are critical for cardiomyocyte survival, was attenuated. Oxidative stress is regarded as a major contributor to myocardial I/R injury. To examine the role of Gab1 in oxidative stress directly, isolated adult cardiomyocytes were subject to oxidant hydrogen peroxide and the cardioprotective effects of Gab1 were confirmed. Furthermore, we found that the phosphorylation of Gab1 and Gab1-mediated activation of Akt and MAPK by oxidative stress was suppressed by ErbB receptor and Src kinase inhibitors, accompanied by an increase in apoptotic cell death. In conclusion, our results suggest that Gab1 is essential for cardioprotection against I/R oxidative injury via mediating survival signaling. PMID- 24951958 TI - beta3 adrenergic receptor selective stimulation during ischemia/reperfusion improves cardiac function in translational models through inhibition of mPTP opening in cardiomyocytes. AB - Selective stimulation of beta3 adrenergic-receptor (beta3AR) has been shown to reduce infarct size in a mouse model of myocardial ischemia/reperfusion. However, its functional long-term effect and the cardioprotective mechanisms at the level of cardiomyocytes have not been elucidated, and the impact of beta3AR stimulation has not been evaluated in a more translational large animal model. This study aimed at evaluating pre-perfusion administration of BRL37344 both in small and large animal models of myocardial ischemia/reperfusion. Pre-reperfusion administration of the beta3AR agonist BRL37344 (5 MUg/kg) reduced infarct size at 2-and 24-h reperfusion in wild-type mice. Long-term (12-weeks) left ventricular (LV) function assessed by echocardiography and cardiac magnetic resonance (CMR) was significantly improved in beta3AR agonist-treated mice. Incubation with beta3AR agonist (BRL37344, 7 MUmol/L) significantly reduced cell death in isolated adult mouse cardiomyocytes during hypoxia/reoxygenation and decreased susceptibility to deleterious opening of the mitochondrial permeability transition pore (mPTP), via a mechanism dependent on the Akt-NO signaling pathway. Pre-reperfusion BRL37344 administration had no effect on infarct size in cyclophilin-D KO mice, further implicating mPTP in the mechanism of protection. Large-white pigs underwent percutaneous coronary ischemia/reperfusion and 3-T CMR at 7 and 45 days post-infarction. Pre-perfusion administration of BRL37344 (5 MUg/kg) decreased infarct size and improved long-term LV contractile function. A single-dose administration of beta3AR agonist before reperfusion decreased infarct size and resulted in a consistent and long-term improvement in cardiac function, both in small and large animal models of myocardial ischemia/reperfusion. This protection appears to be executed through inhibition of mPTP opening in cardiomyocytes. PMID- 24951959 TI - Labeled content of two furanocoumarins in dietary supplements correlates with neither actual content nor CYP3A inhibitory activity. AB - Dietary supplements are a multi-billion dollar business, with yearly profit increases. Allegedly safe, these supplements are marketed to a variety of niches, encompassing claims from immune support to weight loss. Six sports nutrition supplements were acquired that were labeled to contain the furanocoumarin(s) bergamottin and/or 6',7'-dihydroxybergamottin (DHB), both of which are potent irreversible inhibitors of the prominent drug metabolizing enzyme cytochrome P450 3A (CYP3A). Both furanocoumarins are typically present in grapefruit juice, which has been shown to inhibit intestinal CYP3A, perpetrating an increase in the systemic exposure of certain concomitant 'victim' drugs. The acquired supplements were analyzed using ultra-performance liquid chromatography coupled to both a photodiode array (PDA) detector and a triple quadrupole mass spectrometer (MS). Contrary to the product labeling, four of the supplements contained no detectable quantities of either furanocoumarin (LOD 0.060MUg/capsule), while two of the supplements contained minimal amounts (one contained 12.13 (+/-0.23) MUg bergamottin and 65.51 (+/-0.64) MUg DHB per capsule; the other contained 2.705 (+/-0.069) MUg bergamottin per capsule and no detectable quantities of DHB). A CYP3A inhibition bioassay was used to assess whether the actual content of the furanocoumarins correlated with CYP3A inhibitory activity. Despite the low amounts of bergamottin and DHB, CYP3A inhibition by the supplements was greater than could be accounted for by the two furanocoumarins. The additional activity suggests the presence of other potent or highly abundant CYP3A inhibitors. PMID- 24951960 TI - Effects of social networks on physical health among people with serious mental illness. AB - This study examined the effects of social network characteristics on physical health among people with serious mental illness using social transactions that are reciprocal, and the combination of objective and subjective health measures. The sample consisted of a probability sample of 231 adults with serious mental illness who resided in permanent supportive housing in Philadelphia, Pennsylvania. Path analyses were conducted to examine the relationships between social network characteristics and two aspects of medical comorbidity, objective health and subjective health. Bivariate statistics showed that individuals with medical comorbidity were more likely to have contact with their network members and had a higher level of reciprocal positive tangible support when compared to those who did not have medical comorbidity. The results of the path analyses revealed that none of the social network characteristics were associated with better physical health. The lack of a significant relationship between social networks and better physical health is contrary to prior research findings. However, this is the first study to include both types of social transactions simultaneously as predictors of better physical health for individuals with serious mental illness. A longitudinal study would provide more insight into the temporal relationship of social networks and physical health conditions of people with serious mental illness. Furthermore, the transactional nature of social relationships, particularly for those with mental health issues, requires greater exploration. PMID- 24951961 TI - Differential cross-sectional associations of work- and leisure-time sitting, with cardiorespiratory and muscular fitness among working adults. AB - OBJECTIVES: Sedentary behavior is increasingly recognized as a risk factor for cardiovascular and metabolic morbidity and mortality. Recent studies suggest that sitting during work and leisure time may affect markers of cardiometabolic health, differently. However, little is known about associations' between sitting time and cardiorespiratory and muscular fitness among adults. The aim of the present study was to examine associations between work- and leisure-time sitting, and key markers of cardiorespiratory and muscular fitness among working adults. METHODS: Working adults (N=2544) aged 18-69 from Health2006, a Danish population based study, were included in this cross-sectional study. Sitting time during work and leisure time along with sociodemographic and behavioral covariates, including physical activity, were self-reported. Participants underwent a health examination with assessment of cardiorespiratory fitness (step test estimated VO 2Max, systolic and diastolic blood pressure) and muscular fitness (handgrip strength, lower limb extension power). Associations were explored by linear regression. Results Leisure-time sitting time was significantly (P<0.05) and inversely associated with VO 2Max, systolic blood pressure and handgrip strength among adults <50 years. There were no significant associations between sitting time at work and any of the markers of cardiorespiratory and muscular fitness. CONCLUSION: Work- and leisure-time sitting were differentially associated with cardiorespiratory and muscular fitness among working adults. This suggests that the domain in which sitting time is accrued should be considered when further investigating the relationship between sedentary behaviors and various healthy outcomes. In particular, caution should be exercised when labeling occupational sitting a danger per se for health. PMID- 24951962 TI - Incidence and risk of depression associated with diabetes in adults: evidence from longitudinal studies. AB - This meta-analysis examined depression as a consequence of diabetes by conducting a meta-analysis, using data from longitudinal studies. Databases were systematically searched for relevant studies. Incidence of depression is presented as cumulative incident proportion (CIP). Pooled effect sizes were calculated using random-effects model. The data were reconstructed to compute relative risk (RR) and CIP. The 16 studies selected for review generated 16 datasets of which 11 studies reporting binary estimates (RR) and 5 studies reporting time-to-event estimates [hazard ratio (HR)]. Both RR and HR were significant at 1.27 (95% CI 1.17-1.38) and 1.23 (95% CI 1.08-1.40) for incident depression associated with diabetes mellitus. Our observations also revealed greater cumulative incidence of depression in diabetes than in non diabetes groups. Our study shows that diabetes is a significant risk factor for the onset of depression. PMID- 24951963 TI - Enhanced freeze tolerance of baker's yeast by overexpressed trehalose-6-phosphate synthase gene (TPS1) and deleted trehalase genes in frozen dough. AB - Several recombinant strains with overexpressed trehalose-6-phosphate synthase gene (TPS1) and/or deleted trehalase genes were obtained to elucidate the relationships between TPS1, trehalase genes, content of intracellular trehalose and freeze tolerance of baker's yeast, as well as improve the fermentation properties of lean dough after freezing. In this study, strain TL301(TPS1) overexpressing TPS1 showed 62.92 % higher trehalose-6-phosphate synthase (Tps1) activity and enhanced the content of intracellular trehalose than the parental strain. Deleting ATH1 exerted a significant effect on trehalase activities and the degradation amount of intracellular trehalose during the first 30 min of prefermentation. This finding indicates that acid trehalase (Ath1) plays a role in intracellular trehalose degradation. NTH2 encodes a functional neutral trehalase (Nth2) that was significantly involved in intracellular trehalose degradation in the absence of the NTH1 and/or ATH1 gene. The survival ratio, freeze-tolerance ratio and relative fermentation ability of strain TL301(TPS1) were approximately twice as high as those of the parental strain (BY6-9alpha). The increase in freeze tolerance of strain TL301(TPS1) was accompanied by relatively low trehalase activity, high Tps1 activity and high residual content of intracellular trehalose. Our results suggest that overexpressing TPS1 and deleting trehalase genes are sufficient to improve the freeze tolerance of baker's yeast in frozen dough. The present study provides guidance for the commercial baking industry as well as the research on the intracellular trehalose mobilization and freeze tolerance of baker's yeast. PMID- 24951964 TI - Assessment of respiratory flow and efforts using upper-body acceleration. AB - In this paper, an innovative method for estimating the respiratory flow and efforts is proposed and evaluated in various postures and flow rates. Three micro electro-mechanical system accelerometers were mounted on the suprasternal notch, thorax and abdomen of subjects in supine, prone and lateral positions to record the upper airway acceleration and the movements of the chest and abdomen wall. The respiratory flow and efforts were estimated from the recorded acceleration signals by applying machine learning methods. To assess the agreement of the estimated signals with the well-established measurement methods, standard error of measurement (SEM) was calculated and rho=1-SEM was estimated for every condition. A significant agreement between the estimated and reference signals was found (rho=0.83, 0.82 and 0.89 for the estimated flow, thorax and abdomen efforts respectively). Additionally, the agreement of the estimated and reference flows was assessed by calculating the ratio of time at the tidal peak inspiration flow to the inspiration time (tPTIF/tI) and the ratio of time at the tidal peak expiration flow to the expiration time (tPTEF/tE). Overall mean and standard deviation of absolute value of differences between tPTIF/tI and tPTEF/tE ratios calculated for every breathing cycle of reference and estimated flow were 0.0035 (0.06) and 0.051 (0.032), respectively. The presented results demonstrate the feasibility of using the upper-body acceleration as a simple solution for long term monitoring of respiratory features. PMID- 24951965 TI - Protection afforded by pre- or post-treatment with 4-phenylbutyrate against liver injury induced by acetaminophen overdose in mice. AB - Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is a widely used analgesic/antipyretic drug with few adverse effects at therapeutic doses; suicidal or unintentional overdose of APAP frequently induces severe hepatotoxicity. To explore a new and effective antidote for APAP hepatotoxicity, this study examined the effects of sodium 4-phenylbutyrate (4-PBA) on liver injury induced by APAP overdose in mice. Liver injury was induced in C57BL/6 male mice by intraperitoneal injection of APAP (400mg/kg). The effects of 4-PBA (100 200mg/kg) treatment at 1h before the APAP injection were evaluated with serum alanine aminotransferase (ALT) and blood ammonia levels, hepatic pathological changes, including histopathology, DNA damage, nitrotyrosine formation, and mRNA or protein expression involved in the development of hepatotoxicity, such as X box binding protein-1 (XBP1), c-Jun N-terminal kinase (JNK), C/EBP homologous protein (CHOP) and B-cell lymphoma 2 interacting mediator of cell death (Bim). In addition, glutathione depletion and CYP2E1 protein expression, which are measures of the metabolic conversion of APAP to a toxic metabolite, were examined. Furthermore, we examined the effects of post-treatment with 4-PBA against APAP induced hepatotoxicity in mice. When administered at 1h before APAP injection, 4 PBA significantly prevented the increase in serum ALT and blood ammonia levels, centrilobular necrosis of hepatocytes, DNA fragmentation, and nitrotyrosine formation induced by APAP in mice. 4-PBA also inhibited hepatic Xbp1 mRNA splicing and JNK phosphorylation induced by APAP, but did not suppress CHOP and Bim mRNA and protein expression. In addition, 4-PBA had little effect on hepatic glutathione depletion and CYP2E1 expression, parameters of toxic APAP metabolite production. Post-treatment with 4-PBA administration at 1 or 2h after APAP injection also attenuated the increase in serum ALT and blood ammonia levels and hepatic pathological changes in APAP-induced hepatotoxicity in mice. Although post-treatment with 4-PBA did not show any effects on hepatic Xbp1 mRNA splicing and JNK phosphorylation, it drastically attenuated the DNA fragmentation induced by APAP. The precise molecular mechanisms of the protection afforded by 4-PBA against APAP hepatotoxicity in mice are unclear, but they seem to involve inhibition of hepatocellular DNA fragmentation. We suggest that 4-PBA is a promising candidate as an antidote against APAP-induced liver injury. PMID- 24951967 TI - Spatial and temporal distribution of chiral pesticides in Calanus spp. from three Arctic fjords. AB - Concentration and enantiomeric fractions (EFs) of chiral chlorinated pesticides (alpha-hexachlorocyclohexane (alpha-HCH), trans-, cis- and oxychlordane) were determined in Arctic zooplankton, mainly Calanus spp. collected in the period 2007-11 from Svalbard fjords and open pack-ice. The temporal and spatial enantiomer distribution varied considerably for all species and chiral pesticides investigated. An overall enantiomeric excess of (+)-oxychlordane (EF 0.53-0.86) were observed. Cis-chlordane was close to racemic (EF 0.46-0.55), while EF for trans-chlordane varied between 0.29 and 0.55, and between 0.38 and 0.59 for alpha HCH. The biodegradation potential for trans-chlordane was higher compared to cis chlordane. The comprehensive statistical evaluation of the data set revealed that the EF distribution of alpha-HCH was affected by ice cover to a higher extent compared to cis-chlordane. Potential impact from benthic processes on EFs in zooplankton is an interesting feature and should be further investigated. Enantiomeric selective analyses may be a suitable tool for investigations of climate change related influences on Arctic ecosystems. PMID- 24951966 TI - Statins upregulate cystathionine gamma-lyase transcription and H2S generation via activating Akt signaling in macrophage. AB - Hydrogen sulfide (H2S), the third gaseous transmitter, is implicated in various pathophysiologic processes. In the cardiovascular system, H2S exerts effects of cardioprotection, vascular tone regulation, and atherogenesis inhibition. Recent studies demonstrated that atorvastatin, the inhibitor of 3-hydroxyl-3-methyl coenzyme A reductase, affected H2S formation in kidney and other organs. However, the underlying mechanisms are not fully understood. In this study, we examined the effects of three different statins (fluvastatin, atorvastatin and pravastatin) on H2S formation in raw264.7 macrophages. There was a remarkable rise in H2S level in fluvastatin- and atorvastatin-stimulated macrophages, while pravastatin failed to show any significant effect on it. Moreover, fluvastatin and atorvastatin enhanced the mRNA and protein expression of cystathionine gamma lyase (CSE) in dose- and time-dependent manners. Fluvastatin also markedly enhanced the CSE activity. However, fluvastatin did not alter the mRNA or protein expression of another H2S-producing enzyme 3-mercaptopyruvate sulfurtransferase. Blockade of CSE with its inhibitor dl-propargylglycine (PAG) or siRNA markedly reduced the H2S level in fluvastatin-stimulated macrophages. In addition, fluvastatin elevated Akt phosphorylation, which occurred as early as 15 min after treatment, peaked at 1h, and lasted at least 3h. Both PI3K inhibitor LY294002 (10 MUM) and Akt inhibitor perifosine (10MUM) were able to reverse the increases of CSE mRNA and H2S production in fluvastatin-stimulated macrophages. Last, we showed that fluvastatin reduced the mRNA levels of pro-inflammatory molecules such as IL-1beta and MCP-1 in LPS-treated macrophages, which were completely reversed by CSE inhibitor PAG. Taken together, the findings demonstrate that statins may up-regulate CSE expression/activity and subsequently elevate H2S generation by activating Akt signaling pathway and also imply that CSE-H2S pathway plays a critical role in the anti-inflammation elicited by statins. PMID- 24951968 TI - Mapping polycyclic aromatic hydrocarbon and total toxicity equivalent soil concentrations by visible and near-infrared spectroscopy. AB - In this study, we used data from spectroscopic models based on visible and near infrared (vis-NIR; 350-2500 nm) diffuse reflectance spectroscopy to develop soil maps of polycyclic aromatic hydrocarbons (PAHs) and total toxicity equivalent concentrations (TTEC) of the PAH mixture. The TTEC maps were then used for hazard assessment of three petroleum release sites in the Niger Delta province of Nigeria (5.317 degrees N, 6.467 degrees E). As the paired t-test revealed, there were non-significant (p > 0.05) differences between soil maps of PAH and TTEC developed with chemically measured and vis-NIR-predicted data. Comparison maps of PAH showed a slight to moderate agreement between measured and predicted data (Kappa coefficient = 0.19-0.56). Using proposed generic assessment criteria, hazard assessment showed that the degree of action for site-specific risk assessment and/or remediation is similar for both measurement methods. This demonstrates that the vis-NIR method may be useful for monitoring hydrocarbon contamination in a petroleum release site. PMID- 24951969 TI - Bacterial diversity in snow on North Pole ice floes. AB - The microbial abundance and diversity in snow on ice floes at three sites near the North Pole was assessed using quantitative PCR and 454 pyrosequencing. Abundance of 16S rRNA genes in the samples ranged between 43 and 248 gene copies per millilitre of melted snow. A total of 291,331 sequences were obtained through 454 pyrosequencing of 16S rRNA genes, resulting in 984 OTUs at 97 % identity. Two sites were dominated by Cyanobacteria (72 and 61 %, respectively), including chloroplasts. The third site differed by consisting of 95 % Proteobacteria. Principal component analysis showed that the three sites clustered together when compared to the underlying environments of sea ice and ocean water. The Shannon indices ranged from 2.226 to 3.758, and the Chao1 indices showed species richness between 293 and 353 for the three samples. The relatively low abundances and diversity found in the samples indicate a lower rate of microbial input to this snow habitat compared to snow in the proximity of terrestrial and anthropogenic sources of microorganisms. The differences in species composition and diversity between the sites show that apparently similar snow habitats contain a large variation in biodiversity, although the differences were smaller than the differences to the underlying environment. The results support the idea that a globally distributed community exists in snow and that the global snow community can in part be attributed to microbial input from the atmosphere. PMID- 24951973 TI - [Salivary cortisol as an indicator of physological stress in children and adults; a systematic review]. AB - Salivary cortisol is a steroid hormone that is produced in the hypothalamic pituitary-adrenal axis and secreted into saliva when persons are under stress. High levels of cortisol in saliva can be produced by many different factors, including obesity and certain psychological disorders. The articles selected for inclusion in this review were identified using Google Scholar and Medline, and this search obtained a total of 57 items. The validity of these studies was established according to the degree of evidence presented, by citations and by their applicability to the healthcare context in Spain. Specifically, this review takes into consideration studies of salivary cortisol and stress in children and adults, and those examining the relation between high levels of salivary cortisol and other disorders such as anxiety, attention-deficit/hyperactivity disorder, social phobia or emotional deprivation. These studies show that salivary cortisol is a clear indicator of stress in both children and adults. High levels of this hormone in saliva are associated with the following main consequences: reduced immune function, affecting healing and thus prolonging recovery time; delayed growth in children; increased blood pressure and heart rate in both children and adults. PMID- 24951974 TI - [Potential dietary interventions for prevention and treatment of infant allergy]. AB - The incidence of atopic diseases such as asthma, atopic dermatitis and food allergies has increased exponentially in recent decades. Although atopic diseases have a clear genetic basis, environmental factors such as the diet, seems to play an important role in its development. This article summarizes main studies exploring whether feeding practices of mothers and infants intervenes in the development of allergic diseases. The potential role of dietary practices of the mother and infants for the prevention and/or management of allergies in infants is discussed. The available evidence was analyzed for: (1) does mothers consumption of essential fatty acids, prebiotics and probiotics modulates the onset of allergic disorders?, (2) Does breastfeeding and artificial formula prevent/trigger the onset of allergy symptoms? (3) Does timing of introduction of solid feeding and the selection of certain common food allergens participate in achieving oral tolerance in infants? Accumulated evidence in recent years suggest that exposure to allergens early in life may promote immune tolerance and contribute to prevent infant food sensitization. PMID- 24951975 TI - [Benefits of strength training for the prevention and treatment of sarcopenia]. AB - Sarcopenia is a syndrome characterized by a gradual loss and generalized skeletal muscle mass and strength at risk for adverse outcomes such as physical disability, poor quality of life and mortality. It has several contributing factors: the aging process throughout life, influences on development in the early stages of life, eating sub optimal, bed rest or sedentary lifestyle, chronic diseases and certain drug treatments. Sarcopenia represents a deterioration of health status with a high personal cost: mobility disorders, increased risk of falls and fractures, impaired ability to perform everyday activities, disability, loss of independence and increased risk of death. The strength training is currently one of the most effective methods for combating sarcopenia by stimulating hypertrophy and increase strength. The strength training programs in older people themselves are probably one of the most effective preventive measures to delay the onset of sarcopenia. In this literature review different factors related sarcopenia and strength training as a preventive method is analyzed. PMID- 24951976 TI - Adherence to Mediterranean diet and bone health. AB - INTRODUCTION: Several studies have concluded that incidences of osteoporosis and osteoporosis-related fractures vary across the European Union, the lowest incidence being reported in the Mediterranean area. The beneficial effect is mainly attributed to a specific eating pattern. The Mediterranean diet contain a complex array of naturally occurring bioactive molecules with antioxidant, anti inflammatory and alkalinising properties that may contribute to the bone-sparing effect of the Mediterranean diet. OBJECTIVE: The purpose of this review is to examine the evidence to date on the effects of Mediterranean diet on bone health. METHODS: The search for articles came from extensive research in the following databases: PubMed, Scopus and Web of Science. We used the search terms "Mediterranean diet", "adherence", "fruit and vegetable", "olive oil", "fish" "legume", "cereal" "alcohol", "bone", "osteoporosis", "fracture", and combinations, such as "Mediterranean diet and bone" or "Mediterranean diet and fracture". RESULTS: A limited number of studies have examined the relationship between Mediterranean Diet and bone health, and they have reported conflicting results. On the one hand, adherence to a traditional MeDi has been associated with higher bone mineral density and lower fracture risk. The results of these studies could be attributed to the combined beneficial effects of individual components of the Mediterranean diet. On the contrary, several studies failed to show any association between adherence to the MeDi and indices of bone mass. CONCLUSIONS: Further large-scale studies are required to clarify the effect of Mediterranean diet on bone health, in order to establish the role of this diet in the prevention of osteoporosis. PMID- 24951970 TI - Causes of death among persons who survive an acute ischemic stroke. AB - Stroke and especially its complications are a leading cause of death. Despite reduced morbidity in some developed countries, mortality in stroke patients is still high worldwide. In the past decades, treatment of acute stroke has focused on early intervention, such as revascularization and cerebral edema prevention. However, long-term clinical observations indicate that poststroke pneumonia, cardiovascular complications, and vascular embolism are the major reasons for the increased death rate after stroke. Few evidence-based data are available currently to guide the management of these complications. Thus, systematic studies of these adverse events are essential and urgent to improve survival after stroke. PMID- 24951977 TI - [Effect of pre and post natal undernutrition on components of metabolic syndrome later in life; systematic review]. AB - BACKGROUND: A fetal environment or postnatal undernutrition, might become risk factors that increase susceptibility for chronic-degenerative diseases later in life. Fetal programming means that during prenatal period adverse environment might increase the susceptibility for metabolic changes later in life. OBJECTIVE: The purpose of this study was to analyze the effect of pre-and postnatal malnutrition in the presentation of obesity and components of metabolic syndrome (MS) later in life. METHODS: A literature electronic search on PubMed and EBSCO was conducted. The following term was searched: "Undernutrition in early life and obesity", from studies published from November 1997 through January 2014. Seven studies were identified, and six more were included from other references. RESULTS: We analyzed thirteen publications form six studies conducted in six countries from Asia, Africa, Europe and Latin America. Ten of the studies were retrospectives and the age ranged from 11 to 70 years old. In all studies an association of pre or postnatal undernutrition with components of MS later in life was observed. CONCLUSION: This review shows a consistent association between prenatal and postnatal undernutrition with one or more MS components later in life. PMID- 24951978 TI - Pilot nutrition and physical activity intervention for preschool children attending daycare centres (JUNJI): primary and secondary outcomes. AB - INTRODUCTION: A pilot intervention was conducted to promote physical activity and nutrition in public preschool education (near half a million children in Chile), in order to prevent obesity. OBJECTIVE: To assess the primary (body fat) and secondary outcomes (physical activity and energy intake) of a nutrition and physical activity pilot intervention for preschool children, attending day care centres. METHODS: A pilot intervention in six day care centres selected at random (n = 530), in 4-5 years old preschool children, Santiago, Chile intending to: provide nutritional and physical activity education to educators and health promotion activities for the family, which in turn, will affect the primary (body fat), and secondary outcomes (physical activity pattern and energy food intake) were measured in a representative subsample of 120 intervened and 145 controls children. RESULTS: In relation to secondary outcomes monitoring, moderate vigorous activity was duplicated in the intervention group (+5.4% and +4.7%, respectively), in both obese and eutrophic children. Energy intake decreased in 11.7% in obese and 7.5% in eutrophic children. Dietary fat intake was reduced ( 11 g in obese and -8.4 g in eutrophic children). Intervened obese children reduced body fat in 1.5%, meanwhile in control obese children, body fat increased 1.3% (p < 0.01). CONCLUSIONS: The pilot intervention demonstrated the feasibility to influence dietary risk factors and physical activity at the day care centres and families. Therefore, the implementation of the validated intervention program will be tested in different weather conditions, to prevent unhealthy habits in preschool children and their families. PMID- 24951979 TI - Super obese behave different from simple and morbid obese patients in the changes of body composition after tailored one anastomosis gastric bypass (BAGUA). AB - INTRODUCTION: Super obese patients behave different from simple and morbid obese patients when they reach final changes of body composition (BC) after bariatric surgery. This has led us to tailor One Anastomosis Gastric Bypass (BAGUA) to achieve better results in this group of patients. PATIENTS AND METHODS: We studied 83 (37 diabetic and 46 nondiabetic BMI 30 and up) patients who completed all evaluation appointment (preoperative, 10 days, 1, 3, 6 and 12 months) after tailored BAGUA for diabesity. We used the Tanita body composition analyzer BC-420 MA by the method of single frequency impedance to analyze the evolution of BC in patients classified by BMI 30 - 34,9, 35 - 50, and >50. RESULTS: While preoperative excess weight presented dramatic decreases after tailored BAGUA in all the groups, super obese have different final BC. Diabetics retained more fat mass and visceral fat, where super obese have double (14 kg) that simple obese patients (6 kg), they lost more muscle mass, and have higher basal metabolism. The final BC is altered in all parameters if diabetes is added. CONCLUSIONS: The reduction of the preoperative excess weight is motivated largely by the tailored effect of BAGUA. Patients BMI 30-50 behaved homogeneous in BC after surgery while patients BMI >50 behave different. Super obese lose less weight, retained more fat mass, visceral fat, bone mass, and total water. This effect should be treated by more aggressive surgery by measuring the entire small intestine to make a proper exclusion (tailored) to achieve homogeneous effects. PMID- 24951980 TI - [Screening for Cushing's syndrome in obese patients; is it really necessary?]. AB - to be more frequent among patients with metabolic syndrome. Previous studies have suggested to perform a routine screening for CS in obese patients; however, more recent reports only recommend a case-finding approach in patients with uncontrolled diabetes and hypertension, despite appropriate treatment. Objective: The aim of this study was to evaluate the prevalence of unsuspected CS in morbidly obese patients in an outpatient's clinic. Patients and methods: Retrospective case-note study. We reviewed the medical records of morbidly obese patients referred to our clinic prior to bariatric surgery between january 2001 and december 2011. All patients had a complete medical history including physical examination, and 399 underwent screening for CS as part of our pre-surgical protocol. As screening for autonomous cortisol secretion, we performed an overnight 1 mg Dexamethasone Suppression Test (DST). Serum cortisol < 1.8 MUg/dl was the cut-off point for normal suppression. Results: 399 patients (308 female; mean age 41.9 +/- 10.5 years; mean BMI 51.5 +/- 8.4 kg/m2). In the retrospective analysis, prediabetes and diabetes mellitus were observed in 10.3% and 27.8% respectively. In 21 of 399 patients, screening was considered to be abnormal. Eight of these 21 patients had subsequent normal 24h Urinary Free Cortisol (UFC) levels (150 MUg/24h). In 13 of 20 patients, we repeated an overnight 1mg DST, on suspicion of failing to take the dexamethasone correctly. Three patients failed to suppress their cortisol levels, two of them were on carbamazepine, which was considered to be a false positive result. The other patient with abnormal UFC levels was diagnosed with CS (0.26%), whose cause was a pituitary microadenoma. Conclusion: A low proportion of patients with morbid obesity were found to have CS. Our findings suggest that morbidly obese patients should not be routinely screened for CS. PMID- 24951981 TI - High-oleic peanuts increase diet-induced thermogenesis in overweight and obese men. AB - BACKGROUND: Evidences suggest that nuts consumption can improve energy metabolism. PURPOSE: This study aimed to compare the effects of acute ingestion of high-oleic and conventional peanuts on appetite, food intake, and energy metabolism in overweight and obese men. METHODS: Seventy one subjects (29.8 +/- 2.4 kg/m2) were assigned to the groups: control (CT, n = 24); conventional peanuts (CVP, n = 23); high-oleic peanuts (HOP, n = 24). Subjects consumed 56 g of peanuts (CVP and HOP) or control biscuits (CT) after overnight fasting. Thereafter, energy metabolism was evaluated over 200 minutes, during which diet induced thermogenesis (DIT) and substrate oxidation were analyzed. Appetite sensation was recorded for 3 hours. Statistical analyses were performed using the SAS software considering 5% as the significance level. RESULTS: Postprandial energy expenditure and DIT were significantly higher in HOP than in CVP. Substrate oxidation did not differ between groups. Only HOP presented score below 100 indicating incomplete compensation. CT and CVP showed a complete caloric compensation (scores > 100). Regarding appetite sensation, CVP group felt less "full" than HOP and CT. After 3 hours, satiety score of CVP returned to baseline, whereas HOP and CT remained significantly higher. Hunger scores returned to baseline in CVP and CT and they were maintained significantly lowered in HOP. CONCLUSION: High-oleic peanuts contributed to higher DIT, higher sensation of fullness and incomplete compensation for energy intake compared to conventional peanuts and may be useful to dietary intervention to reduce body weight. PMID- 24951982 TI - Prevalence of overweight and obesity among a university faculty and staffs from 2004 to 2010 in Wuhu, China. AB - BACKGROUND: Overweight and obesity are epidemic worldwide. Our present study was to examine the prevalence of overweight and obesity in a university faculty and staffs using two references [Working Group on Obesity references in China (2004) and World Health Organization (WHO) criteria 2000 ]. OBJECTIVE: The purpose of this study was to estimate the prevalence of overweight and obesity among university faculty and staffs in China. METHODS: A cross-sectional study was designed to collect the routine health screening data for a university faculty and staffs from 2004 to 2010(2004, 2006, 2008 and 2010); the subjects aged 22-94 years. RESULTS: Depending on the references used (China and WHO, respectively), the overall prevalence of overweight, including obesity of the subjects was 36.1% and 25.5%, the prevalence of obesity was 5.3%, and 1.5%, respectively, the prevalence of overweight, including obesity among the male subjects was 46% and 32.5%, respectively, the prevalence of overweight, including obesity among the female subjects was 21% and 14.1%, respectively, An interesting observation made was that the overall prevalence of overweight was increased with age. CONCLUSIONS: Regarding the harmful of overweight and obesity, it is encourage reducing liberal food environment and increasing physical activity among university faculty and staffs, especially for male faculty. PMID- 24951984 TI - Length of residence and risk of eating disorders in immigrant adolescents living in madrid. The AFINOS study. AB - OBJECTIVES: This study was designed to compare the risk of having an eating disorder (ED) among immigrant and native adolescents living in Madrid and to determine the possible influence of length of residence (LOR) on the risk of the immigrants. METHODS: A cross-sectional survey was conducted from november 2007 to february 2008 in a representative sample of adolescents aged 13 to 17 years (n = 2,077, 1,052 girls) living in the Madrid region. Data were collected using the Spanish version of the SCOFF Eating Disorders Questionnaire. Further factors considered were country of birth, LOR and several biological, sociodemographic, lifestyle and health-related variables. RESULTS: According to the three logistic regression models constructed, female immigrant adolescents on the whole showed a greater ED risk (OR = 1.95; 95% CI 1.29- 2.95; p = 0.001) than native adolescents. Moreover, the likelihood of ED was higher among female immigrants living in Spain for <6 years than for Spanish native females (OR = 2.44; 95% CI 1.42-4.18; p = 0.001), while no significant differences were found when female natives were compared with female immigrants living in this country for >= 6 years. Similarly, no differences were observed in the ED risk recorded for male native and immigrant adolescents, both as a whole and by length of residence in Spain. CONCLUSIONS: The immigrant status and the length of Spanish residence are relevant factors in regard to the ED risk in adolescents living in Madrid. PMID- 24951983 TI - A comparison of dual energy x-ray absorptiometry and two bioelectrical impedance analyzers to measure body fat percentage and fat-free mass index in a group of Mexican young women. AB - INTRODUCTION: Studies of obesity require the estimation of fat mass (FM) and fat free mass (FFM); therefore it is important to validate methods that evaluate these measurements. OBJECTIVE: We sought to compare two different bioelectrical impedance analysis systems (BIAs) to estimate FM and FFM using dual-energy X-ray absorptiometry (DXA) as reference. METHODS: We used a cross-sectional design. We evaluated FM and FFM using DXA and two types of BIA equipment: a foot-foot system (FFS) and a hand-foot system (HFS). We conducted paired analysis (paired ttest). We used Bland-Altman plots to assess the relationships between FM and FFMI, limits of agreement were constructed (CL). RESULTS: A total of 175 female students (22.9 +/- 2.2 years old) participated in the study. The paired analysis showed significant differences between the mean value of body fat percentage (BF%) estimated by BIA equipment compared to DXA (FFS = 28.7%, HFS= 34.4% and DXA= 35.3%). The mean difference between the HFS and DXA of BF% was -0.96, ((CL 5.29, 7.20). For the FFS, the mean difference was -6.69, (CL -0.29, -13.09). The paired analysis revealed significant differences between the estimates of FFMI by BIA compared to DXA (FFS =16.29, HFS =14.95, DXA =14.18). The mean difference between HFS and DXA was 0.78, and (CL -2.27, 0.72) whereas the FFS mean difference was -2.11 (CL -3.73 -0.49). CONCLUSION: A different magnitude of bias was observed between the BIA equipment arrays. The HFS appears to be more reliable than the FFS used, particularly in obtaining FFMI in young women. PMID- 24951985 TI - [Assessing food acceptance in scholar children; qualitative visual record versus food waste analysis]. AB - INTRODUCTION: School canteens have rules of management and supervision of menus, however has not been assessed if they are totally consumed. OBJECTIVE: To assess the acceptance of food by weigh food leftovers and validation of a methodology for visual estimation in school canteens of Murcia. METHODOLOGY: Participated pupils in the second and third cycle of primary education, between 8 and 12 years. The estimate of leftovers was performed by 765 food trays. Visual estimation of 300 trays was based on a categorical scale as follow: 1 (0-25%), 2 (26-50%), 3 (51- 75%), 4 (76-100%) by two dietitians and reliability was assessed with respect to the weighed food. The reliability between both methods was assessed in two samples stratified by presence or absence of school kitchen. RESULTS: The first dishes with leftovers were pasta, rice and vegetable purees and was higher in those schools without kitchen (p < 0.05). Also, the second dishes poultry and fish salads and vegetables garnish. Fruit and the total sum of leftovers was higher in schools without dining menus (p < 0.05). The agreement between evaluators was high in meat dishes and salads, and substantial in vegetables, pre-cooked, omelet, pasta, fish and rice. CONCLUSIONS: The leftlovers are high and there are differences in the acceptance of certain foods according to the type of menu offered. The visual scale is a reliable to measure acceptance indirectly, but training to catering staff is needed. PMID- 24951986 TI - [Tool of nutrition education for allergic to egg and cow's milk protein in pediatric age]. AB - INTRODUCTION: Food allergy affects a large part of the population and their numbers are increasing. Although the knowing of this pathology is growing, allergic patients have really difficulties to lead a normal life, especially with food. Until now,this group hadn t practical tools that would help them in the development of a balanced daily diet, as there are for the general population in the form of pyramids and dietary guidelines . This work has covered this need for two of the most prevalent allergies in early life. AIMS: gather information on the allergy of cow's milk protein and egg, to design a food pyramid for these patients, based on the consensus, recommendations and scientific guidance. RESULTS: After confirming the absence of a similar work, food pyramids allergy to egg and cow's milk protein, adapted to each, and a joint pyramid is designed to both allergies. Besides basic recommendations for healthy eating were included in general and in particular individuals, with special interest for the collective (food hygiene, food additives, cosmetics, medicines, etc). CONCLUSIONS: Due to the importance of nutrition in childhood and acquires the underlying difficulties this group, to properly plan the diet is very important as it can prevent accidents and long-term nutritional deficiencies. Therefore provide graphical tools and practices to this goal, is importance for population and medical and scientific community, and is the result of this work. PMID- 24951987 TI - Women with metabolic syndrome improve antrophometric and biochemical parameters with green banana flour consumption. AB - BACKGROUND: Consumption of green banana flour (GBF) may promote health benefits, such as, decreased appetite, weight loss, glycemic control, intestinal function and lipid profile improvement, aging delay, cancer and heart disease prevention. The aim of this study was to evaluate the effects of green banana flour consumption on anthropometric and biochemical parameters in overweight women. METHODS: The glycemic index of flour in the study was determined. The effects of consumption of 20 g of green banana flour/day on weight, body mass index (BMI), blood pressure, waist and hip circumference, body composition, hemoglobin, lipid profile, glucose, insulin, insulin resistance, liver function and energy intake were evaluated in 25 overweight women for 45 days. RESULTS: The glycemic index of the flour under study was classified as low. Reduction (p < 0.05) in systolic blood pressure, hip circumference and fasting glucose levels were found in women who had metabolic syndrome criteria. CONCLUSIONS: Consumption of green banana flour (20 g/day) for 45 days did not promote weight loss or changes in body composition in overweight women. It was noted, however, decreased hip circumference. Significant health parameter improvements were also noted in individuals with metabolic syndrome, which showed a reduction in systolic blood pressure and fasting glucose. PMID- 24951988 TI - Improved metabolic response after 16 weeks of calorie-restricted low-glycaemic index diet and metformin in impaired glucose tolerance subjects. AB - AIM: This study analyzed the metabolic effects of dietary advice to follow calorie-restricted low-glycaemic index diet with metformin in overweight / obese impaired glucose tolerance subjects. METHODS: Sixteen subjects with body mass index between 27-38 kg/m2 were followed monthly for 16 weeks and treated with metformin (1 g/day) and dietary prescription for low-glycaemic index diet with energy reduction of 25-30% their total energy expenditure. Glucose metabolism, lipid profile, anthropometric and body composition, and food intake parameters were measured before and after the treatment. Paired t-tests/Wilcoxon tests were used to compare differences from baseline, with a statistical significance criterion of p <=?0.05. RESULTS: There were significant reductions in anthropometric and body composition parameters, decrease in HOMA2-%beta?and triglycerides concentrations, and increase in Cederholm index. These results show enhanced peripheral insulin sensitivity and preservation of pan - creatic beta cell function. CONCLUSION: Calorie-restricted low-glycaemic index diet and metformin was benefit to metabolic and anthropometric parameters in overweight/obese subjects with impaired glucose tolerance. PMID- 24951989 TI - Metabolic disorders of liver and iron in diabetic and non-diabetic patients BMI < 35 or > 35 before gastric bypass. AB - INTRODUCTION: The presence of abnormalities in the metabolic pathways of iron and liver functioning can produce insulin resistance or metabolic syndrome. Therefore, it is important to examine those alterations that may lead to the development of diseases. Nutritional status is another important factor that is intimately linked to diabetes and obesity. PATIENTS AND METHODS: We studied 131 patients (78 nondiabetic patients and 53 diabetic), 37 patients BMI <=?35 (3 BMI < 25, 18 BMI 25-29.9, 16 BMI 30-34.9) and 94 patients BMI >=?35 (81 BMI 35-49.9 and 13 BMI >=?50). Subjects underwent to laboratory studies related to liver functioning and iron metabolism. Nutritional status was also determined in our patients. RESULTS: Iron was altered 14% of patients BMI >35 and diabetics reached 3% to 25%. Vitamin B12 was low 4% of non-diabetics BMI > 35, and high in 6% of diabetics BMI < 35. The 6% of diabetics BMI < 35 had hyperbilirubinemia. Transaminases are elevated in patients BMI >35 but exacerbated on diabetics. GGT is raised 41% to 47% in BMI >35. ALP is elevated in 25% of diabetics. Total protein and serum albumin were altered in diabetics causing mild malnutrition. 90% of patients had normal nutrition and 10% mild malnutrition. CONCLUSIONS: The metabolisms Hepatic and iron are closely related to the onset of obesity and diabetes. If there is weight gain, cumulative metabolic risks rise. The presence of diabesity and increased duration of diabetes produce altered metabolism. Nutritional status is altered in obesity but is worse with the addition of diabetes. PMID- 24951990 TI - Glycemic and lipid metabolic disorders in diabetic and non-diabetic patients bmi < 35 or > 35 before gastric bypass. AB - INTRODUCTION: Obesity and diabetes are diseases with high prevalence worldwide. There is currently no effective medical treatment for combat the weight gain. It is precursor of diseases such as diabetes or metabolic syndrome. It is necessary to know if weight gain has cumulative effects on the glycemic and lipid metabolism as precursors of complications or comorbidities. PATIENTS AND METHODS: We studied 131 patients (78 nondiabetic and 53 diabetic), 37 BMI <=?35 (3 BMI < 25, 18 BMI 25-29.9, 16 BMI 30-34.9) and 94 BMI >=?35 (81 BMI 35-49.9 and 13 BMI >=?50).We analyzed BMI, gender, diabetes and the time of evolution. Lipid profile, glucose, HbA1c and C-peptide evaluated after 12-hour fasting. RESULTS: Diabetic and diabese patients showed high triglycerides. Non-diabetics have impaired glucose (58% BMI < 35 and 36% BMI > 35). The 20% of non-diabetics BMI < 35 had high C-peptide, and 19% of BMI > 35 had high levels. The 5% of diabetics BMI < 35 had low Cpeptide and 36% of BMI > 35 had high levels. HbA1c was higher in 40% of non-diabetic patients BMI < 35 compared to 13% BMI > 35. CONCLUSIONS: Glucose and triglycerides increase with age and years of development of T2DM. Age of 51 and more, and men are more affected. The weight increase has cumulative effect by altering the metabolism favoring the onset of diabetes and comorbidities. Despite having intensive control treatment of diabetes, it continues its deleterious effects on patients through the years. PMID- 24951992 TI - Antioxidant responses of damiana (Turnera diffusa Willd) to exposure to artificial ultraviolet (UV) radiation in an in vitro model; part I; UV-C radiation. AB - INTRODUCTION: Ultraviolet type C (UV-C) radiation has higher energy than the UV-B radiation and has been less studied because it is completely absorbed by the ozone layer. However, artificial UV-C radiation can generate diverse modifications in the plants. Given that exposure to UV-C for short periods of time increases the antioxidant content, improving the appearance and shelf-life of products, its potential application in postharvest treatments to modify the antioxidant content of medicinal plants, such as damiana (Turnera diffusa), is novel and relevant. OBJECTIVE: To determine the effects of UV-C radiation on enzymatic and non-enzymatic antioxidant defenses, as well as oxidative damage levels, in damiana (Turnera diffusa) plants in vitro. RESULTS: UV-C radiation decreased superoxide dismutase (SOD, EC 1.15.1.1) and total peroxidases (POX, EC 1.11.1) activities, the concentration of chlorophylls (a and b), carotenes, vitamin C, and total antioxidant capacity. UV-C radiation increased the phenolic compound levels in damiana. Loss of antioxidant defenses was higher in damiana plants exposed to higher UV-C doses and/or for longer periods. This study suggests that UV-C radiation induces oxidative stress, evidenced as increased protein carbonyls and phenolic compound content, in damiana (T. diffusa). CONCLUSION: Low dose, short exposure to UV-C stimulates phenolic compound content in damiana. Thus, controlled UV-C treatments could be used as postharvest treatment to increase phenolic compound content in damiana plants. PMID- 24951991 TI - Hypocaloric diet associated with the consumption of jam enriched with microencapsulated fish oil decreases insulin resistance. AB - BACKGROUND: The metabolic syndrome is related to the increase in cardiovascular diseases. Polyunsaturated fatty acids from fish oil help in reducing cardiovascular risk factors and are natural bindings of PPAR?2. OBJECTIVE: To evaluate the impact of hypocaloric diet associated with microencapsulated fish oil supplementation in women with metabolic syndrome. METHODS: We conducted a randomized, single-blind and placebo-controlled clinical trial with adult women who presented metabolic syndrome (n = 30) for 90 days. The volunteers were divided into two groups: placebo group (n = 15) and microencapsulated fish oil group (n = 15) (3 g/day of microencapsulated fish oil containing 0.41 g/day of eicosapentaenoic acid and decosahexaneoic acid). Anthropometric, body composition, clinical and laboratory parameters were assessed before and after the intervention. Paired t-test was used for comparisons within groups and Student's t-test for comparison between groups. We considered p < 0.05 as significant values. RESULTS: The comparison between groups revealed a significant reduction of blood glucose, insulinemia and the homeostasis model assessment in the microencapsulated fish oil group after 90 days, as opposed to the placebo group. We also observed reduction of the systolic arterial pressure in the microencapsulated fish oil group. CONCLUSION: A hypocaloric diet associated with the consumption of microencapsulated fish oil was effective in reducing blood glucose, insulinemia and insulin resistance in women with MS. PMID- 24951993 TI - Antioxidant responses of damiana (Turnera diffusa Willd) to exposure to artificial ultraviolet (UV) radiation in an in vitro model; part ii; UV-B radiation. AB - INTRODUCTION: Ultraviolet type B (UV-B) radiation effects on medicinal plants have been recently investigated in the context of climate change, but the modifications generated by UV-B radiation might be used to increase the content of antioxidants, including phenolic compounds. OBJECTIVE: To generate information on the effect of exposure to artificial UV-B radiation at different highdoses in the antioxidant content of damiana plants in an in vitro model. METHODS: Damiana plantlets (tissue cultures in Murashige- Skoog medium) were irradiated with artificial UV-B at 3 different doses (1) 0.5 +/- 0.1 mW cm-2 (high) for 2 h daily, (2) 1 +/- 0,1 mW cm-2 (severe) for 2 h daily, or (3) 1 +/- 0.1 mW cm-2 for 4 h daily during 3 weeks. The concentration of photosynthetic pigments (chlorophylls a and b, carotenoids), vitamins (C and E) and total phenolic compounds, the enzymatic activity of superoxide dismutase (SOD, EC 1.15.1.1) and total peroxidases (POX, EC 1.11.1), as well as total antioxidant capacity and lipid peroxidation levels were quantified to assess the effect of high artificial UV-B radiation in the antioxidant content of in vitro damiana plants. RESULTS: Severe and high doses of artificial UV-B radiation modified the antioxidant content by increasing the content of vitamin C and decreased the phenolic compound content, as well as modified the oxidative damage of damiana plants in an in vitro model. CONCLUSION: UV-B radiation modified the antioxidant content in damiana plants in an in vitro model, depending on the intensity and duration of the exposure. PMID- 24951994 TI - [Home parenteral nutrition; satisfaction of patients and their caregivers with nutrition unit and pharmacy service]. AB - INTRODUCTION: Home Parenteral Nutrition (HPN) is a practice in continually growing by the significant advantages involved for the patient and the healthcare system. Today, in the investigation of health outcomes is essential to assess the patient s opinion. Among the measures focused on patients with HPN, several studies about quality of life have been done, but the degree of satisfaction with this treatment modality has not been evaluated. OBJECTIVE: To evaluate the degree of satisfacion of patients and their caregivers receiving HPN with doctors, pharmacists and nurses in a hospital. MATERIAL AND METHODS: An anonymous survey was distributed, which consisted of 48 closed questions to patients and their caregivers receiving HPN who voluntarily answered. With survey responses a database in SPSS with the following variables was created: personal, sociocultural, clinical and related to HPN data and valoration of health personnel involved (nutrition area of the Pharmacy Service and Nursing and Medical Nutrition Units) and hospital facilities related to HPN. Also a section of open response suggestions was included. RESULTS: 24 surveys were distributed, 12 to patients and 12 to caregivers. Response rate was 91.7% in the case of patients and 58.3% in the caregivers. 63.6% of patients and 42.9% of caregivers were women. Mean age was, respectively, 46.1 years (SD: 13.7) and 47.0 years (SD: 3.6). Most of patients (55.6%) and caregivers (60.0%) had secondary studies and were pensoniers (72.7% and 71.4%, respectively). Underlying diseases of patients were: radiation enteritis (27.3%), intestinal obstruction (18.2%), intestinal carcinomatosis (45.5%) and Chron s disease (9.1%). With respect to items assessing satisfaction with physicians, nurses and pharmacists, in general both patients and caregivers were satisfied. Suggestions made were: greater amplitude of delivery schedule of HPN and inclusion of audiovisual information. CONCLUSIONS: The degree of satisfaction of patients receiving HPN and their caregivers with the care given by doctors, pharmacists and nurses is appropriate, but it s possible to make improvements to optimize the quality of the whole process. PMID- 24951995 TI - The role of prenatal nutrition assistance on the prevalence of night blindness in pregnant adults. AB - INTRODUCTION: In developing countries, night blindness is a very common public health problem among pregnant women. OBJECTIVE: Evaluate the effect of the changes occurred on prenatal care concerning prenatal nutritional care on the occurrence of night blindness (XN) in adult pregnant women in public maternity hospital in Rio de Janeiro between 1999-2001 and between 2007-2008. METHODS: Two cross-sectional studies were conducted, been the first one conducted between 1999 2001 and the second one between 2007-2008. Were studied 402 puerperal women, 225 between 1999-2001 (GI) and 177 between 2007-2008 (GII). The gestational XN was investigated during the immediate puerperium (GI) and during the prenatal/puerperium (GII), diagnosed by the World Health Organization. The study collected sociodemographic, clinical, obstetric, anthropometric and prenatal care information. RESULTS: It verified significant reduce of prevalence of gestational XN (GI = 18.7% e GII = 0.6%, p < 0.001). The occurrence of gestational XN was associated to sanitary conditions, education level, more than six prenatal consultations, miscarriage at last pregnancy, higher average number of deliveries, average number of prenatal care consultations and prenatal nutritional (p < 0.05). There was no association between gestational XN and marital status, skin color, pre-gestational nutritional status, adequacy of gain of total gestational weight, gestational anaemia and average number of pregnancies (p > 0.05). CONCLUSION: The inclusion of nutritional care in routine prenatal care may have contributed to the reduction of gestational XN. Studies to assess the nutritional intervention in the prevention and treatment of gestational XN at regions at greatest risk are suggested. PMID- 24951996 TI - Effects of quercetin on polychlorinated biphenyls-induced liver injury in rats. AB - INTRODUCTION: Polychlorinated biphenyls (PCBs), used as pesticides in agriculture, can lead to irreversible injuries in living organisms, particularly in liver. Oxidative stress has been implicated in the liver pathogenesis induced by different molecules, including PCBs. It has been demonstrated that quercetin, an antioxidant flavonoid found in the diet, exhibits a potent antioxidant effect in different liver pathologies. OBJECTIVE: To evaluate oxidative stress caused by PCBs in liver and the antioxidant activity of quercetin. METHODOLOGY: We used male Wistar rats (n = 36), divided in 4 groups: control, quercetin (50 mg/kg/day), PCBs (0.4 ml/kg/day), and rats treated with both PCBs and quercetin. On day 25 blood was collected to assess liver integrity (enzymes AST, ALT and ALP), and liver samples to measure oxidative stress (TBARS), activity of antioxidant enzymes (SOD, CAT, GPx) and DNA damage (micronucleus assay), and histological damage. RESULTS: TBARS concentration and SOD activity were significantly higher in PCBs animals as compared to the PCB group receiving quercetin. CAT and GPx decreased in PCBs and increased when quercetin was added. The histological analysis showed damage to hepatocytes in PCBs, but quercetin was able to afford protection against such damage. The micronucleus test showed there was an increase in the production of microclenucleus compared to control, and quercetin was able to reduce this effect. CONCLUSION: Contamination with PCBs led to increased lipid peroxidation and DNA damage, and the use of antioxidant quercetin was effective in reducing PCBs-induced liver injury. PMID- 24951997 TI - [Introducing a mixed nutritional screening tool (CIPA) in a tertiary hospital]. AB - INTRODUCTION: Malnourishment in hospitalized patients is very prevalent and therefore it is important to implement screening methods. A mixed nutritional screening method (CIPA) has been developed at our center; this method includes four parameters: (a) control of intakes for 72 h; (b) BMI; (c) proteins; and (d) albumin. OBJECTIVES: (1) To know the prevalence of malnourishment at the Internal Medicine Department of our Center; (2) To analyze the variables associated to higher prevalence of malnourishment. MATERIALS AND METHOD: The results of the nutritional screening tests carried out in 305 patients admitted to the Internal Medicine Department in the period of November of 2012-October of 2013 were retrospectively reviewed. The prevalence of hospital malnourishment was analyzed, as well as the association of a positive screening test (at least one positive item) with the following variables: BMI, age, gender, underlying disease, hospital staying, early re-admittance (< 1 month) and hospital mortality. RESULTS: The test yielded a positive result in 23% of the patients. Patients with a positive screening test had lower BMI (24.9 +/- 7.2 vs. 27.8 +/- 6.4 kg/m; p = 0.002). Neoplastic and infectious pathologies were associated with greater positivity (35.3 and 28.9%, respectively; p = 0.006). Gender and age were not associated with a positive screening test. Patients with a positive screening test had longer mean hospital staying (26.7 +/- 25 vs. 19.4 +/- 16.5; p = 0.005), higher early re-admittance rates (18.6 vs. 6.8%; p = 0.003) and higher mortality (30 vs. 10.3%; p < 0.001). CONCLUSIONS: The CIPA screening test can detect malnourished patients and predict worse clinical prognosis (mortality, mean hospital staying and early readmittance). PMID- 24951998 TI - Nutritional status, lipid profile and HOMA-IR in post-liver transplant patients. AB - INTRODUCTION: A high prevalence of overweight, obesity, diabetes and dyslipidemia has been reported following liver transplantation (LT). Although these conditions are known to induce an increased risk for cardiovascular events, which are among the major causes of death in post-LT patients, much debate remains in the literature regarding the applicability of different nutritional assessments methods to this population. OBJECTIVE: To assess the nutritional status, lipid profile, homeostatic model assessment of insulin resistance (HOMA-IR) and dietary intake adequacy in the post-LT period. METHODS: Cross-sectional study of patients after a maximum of 2 years post-LT, involving the assessment of body mass index (BMI), percent weight loss, arm (AC) and arm muscle circumference (AMC), triceps skinfold (TSF), neck (NC) and waist (WC) circumference, lipid profile, HOMA-IR and percent adequacy of dietary intake. RESULTS: In the group of 36 patients, 61.1% were male, mean age 53.2 years (+/- 10.6). Severe weight loss was noted in 66.7% of patients. Most individuals were eutrophic according to BMI, AC and AMC, while TSF showed malnutrition, NC demonstrated overweight and WC showed metabolic risk. Dyslipidemia was diagnosed in 87.5% of patients, and insulin resistance in 57% of the patients. Most patients had adequate dietary intake, although the time since transplant was positively correlated with AC (r = 0.353; p = 0.035) and negatively correlated with vitamin A intake (r = - 0.382; p = 0.022), with the caloric adequacy (r = -0.338; p = 0.044) and vitamin A adequacy (r = -0.382; p = 0.021). CONCLUSION: Although anthropometry provided somewhat variable nutritional diagnoses, when combined with biochemical tests, findings showed the prevalence of cardiovascular risk. As such, patients should be provided with transdisciplinary assistance, and strategies should be developed so as to reduce the risk factors recorded in this population. PMID- 24951999 TI - Fluid intake in Spanish children and adolescents; a cross-sectional study. AB - INTRODUCTION: Some studies demonstrated that dehydration process is prevalent among young populations and subsequently, a cause of concern. However, the evaluation of the fluid consumption pattern of children and adolescent populations has not been widely assessed. OBJECTIVE: To evaluate the total fluid intake from different types of beverages in Spanish children and adolescents. METHODS: A total of 238 children and adolescents aged 3-17 years were randomly recruited from all Spanish regions. The information about the quantity and quality of daily fluid intake from different types of beverages was collected using a 24 h fluid-specific diary over 7 consecutive days. RESULTS: Fluid intake was < 80% of the EFSA recommendations in 87% of the study population. In our sample, water was the main contributor to fluid intake, followed by milk and derivates and sweet regular beverages. No differences in consumption patterns were found according to gender. Consumption of hot beverages as well as sweet regular and sweet light beverages increased with age, while milk and milk derivates consumption decreased. CONCLUSION: The large majority of our young population did not meet the EFSA recommendations for total water intake. Therefore, an increase in plain water consumption in children and adolescents should be promoted in order to fulfill the fluid needs without increasing calorie intake. PMID- 24952000 TI - Fluid intake from beverages in Spanish adults; cross-sectional study. AB - INTRODUCTION: Dietary questionnaires usually only assess the intake of drinks that provide calories, but do not accurately evaluate total fluid or water intake. The evaluation of the fluid consumption pattern of a population has been the main objective of only a very few studies. OBJECTIVE: To evaluate the total fluid intake from different types of beverages in Spanish adults. METHODS: A total of 1,262 adults aged 18-70 years were randomly recruited from all Spanish regions. The information about the quantity and quality of daily fluid intake from different types of beverages was collected using a 24h fluid-specific diary over 7 consecutive days. RESULTS: 50.4% of the study population had a fluid intake < 80% of the EFSA recommendations for total water intake. The odds of meeting the recommendations of total fluid intake were higher in women [OR: 2.48; 95%CI: 1.81-3.40], and in those with higher leisure-time physical activity (3-4 times/week [OR: 1.57; 95%CI: 1.01- 2.46]; 5 times/week or more [OR: 1.97; 95% CI: 1.37-2.83]). Women consumed significantly more hot and sweet light beverages. However, men consumed significantly more sweet regular and alcoholic drinks. A significant higher percentage of young and normal/underweight subjects exceed the WHO recommendations for free sugars (> 10% total energy intake) from beverages alone. CONCLUSION: Half of the adults studied do not meet the EFSA fluid intake recommendations. Water is the main fluid consumed. Differences in the pattern of fluid consumption were observed between ages and genders. A quarter of the population studied consumes from beverages alone already more sugar than recommended from the total diet. PMID- 24952001 TI - Fluid intake in Mexican adults; a cross-sectional study. AB - INTRODUCTION: An adequate hydration is critical for a series of body functions, including proper regulation of core body temperature, elimination of waste metabolites by the kidney and maintenance of normal physical and cognitive functions. Some institutions have set recommendations for adequate intake of water, but these recommendations vary widely. OBJECTIVE: To estimate the usual daily consumption of fluids (water and all other beverages) by a selective sample of Mexican population. METHODS: Cross-sectional sample of 1,492 male and female adults between 18-65 years of age, drawn from 16 cities throughout Mexico. Self reported fluid intake data collected over a 7-day consecutive period, recording intake of water, milk and derivatives, hot beverages, sugar sweetened beverages (SSB), alcoholic beverages and others. RESULTS: We found that 87.5% of adult males and 65.4% of adult females reported drinking below their recommended daily fluid intake (3 L for males and 2 L for females), and in 80% of the population SSB, not including hot beverages or milk and derivatives, accounted for a larger amount and proportion of fluid intake than plain water. Sixty-five percent of adult males and 66% of adult females consumed more than 10% of their estimated daily caloric intake from fluids. Fluid intake did not differ significantly by gender, but showed a declining trend with age. CONCLUSION: Our findings may have important implications for policy recommendations, as part of comprehensive strategies to promote the adoption of healthy life styles, in this case, promoting consumption of plain water while discouraging excessive consumption of caloric beverages. PMID- 24952002 TI - Sweets and fats tasting in patients with anorexia nervosa: the role of the thought-shape fusion cognitive distortion. AB - INTRODUCTION: It has been found that the olfactorygustatory function is altered in patients with eating disorders, with an impairment affecting the perception of olfactory and gustatory stimuli. OBJECTIVE: The aim was to explore the subjective reactivity after the exposure and tasting of foods with different gradient of sweetness and different fats textures. In addition, changes in the thought-shape fusion (TSF) cognitive distortion were assessed after tasting those different presentations as well as the correlations between the initial scores on TSF Questionnaire (TSF-Q) and the different responses after that tasting. METHOD: A total of 15 healthy controls and 23 outpatients with anorexia nervosa underwent two sessions of tasting (sweets with different gradient of sweetness and fats with different textures) and they filled several questionnaires (pre- and post tasting) to measure their responses after tasting. RESULTS: Participants showed less "self-control" after tasting sweets. The score on TSF-Q increased significantly after the sweets tasting in the patients group. Patients had the worst response after tasting presentations with more quantity of glucose (less gradient of sweetness) than after tasting those with more amount of sucrose (much more sweetness). With respect to the fats, patients showed the worst reaction after tasting the most unfamiliar texture. Pre fats tasting TSF-Q scores correlated significantly with all responses in the patients group. DISCUSSION: Both psychological and biological (e.g. genetic) factors could be involved in the reactions of patients with anorexia nervosa after tasting sweets and fats. PMID- 24952003 TI - The posterior surgical treatment for focal kyphosis in upper-middle thoracic spine. AB - PURPOSE: To analyze the clinical characteristics of focal kyphosis in upper thoracic spine, and observe the outcome of the posterior corrective surgical procedures. METHODS: Thirteen patients of focal kyphosis were treated with posterior surgical procedures in our medical center. The kyphosis apex was above T6 in all cases. The surgical procedures performed in this study included pedicle subtraction osteotomy (PSO) in six cases and vertebral column resection (VCR) in seven cases. For each case, the kyphosis angle, curvature of lower thoracic spine, lumbar lordosis angle, cervical lordosis angle, pelvic parameters, and the sagittal plane balance of the spine were compared before and after surgery. Neurological function change was assessed based on Frankel grading system and oswestry disability index (ODI). RESULTS: The average follow-up time of this study was 28.3 months. The average kyphosis angle was reduced from 73.5o before surgery to 32.7o immediately after surgery, and remained at 33.5o at follow-up. The average ODI improved from 22.5 before surgery to 15.5 at follow-up. The neurological function improved after surgery in eight cases. There were two cases of transient neurological deficiency in the lower extremities after VCR procedure, who eventually recovered under postoperative care. One case had recurrent kyphosis due to implant failure after VCR procedure, and recovered after the revision surgery. CONCLUSIONS: Although high risk needs to be warned, the corrective surgery for focal kyphosis in upper thoracic spine still can achieve satisfactory results. Given the comparative surgical results yet less complications, PSO seems to be a preferable procedure over VCR for kyphosis at this region. PMID- 24952005 TI - Spinal balance: the toll of bipedalism or the "French Connection". PMID- 24952004 TI - Letter to the Editor concerning the article "Anterior pedicle screw fixation of C2: an anatomic analysis of axis morphology and simulated surgical fixation" [Zeng-Hui Wu et al. (2014); Eur Spine J 23(2):356-361]. PMID- 24952006 TI - Reply to the Letter to the Editor of J. Padulo et al. concerning "Calculation of corrected body height in idiopathic scoliosis: comparison of four methods" by M. Tyrakowski et al. (Eur Spine J, DOI 10.1007/s00586-014-3275-1). PMID- 24952007 TI - The effect of growing rod lengthening technique on the sagittal spinal and the spinopelvic parameters. AB - PURPOSE: The aim of this retrospective clinical study is to evaluate the effect of growing rod lengthening technique on sagittal balance in relationship with the spinopelvic parameters, in early onset scoliosis (EOS). METHODS: Twenty-three patients (18 female, 5 male), with a mean age of 8.3 years during the operation (range 3.2-12.2), with EOS due to various etiologies were operated using growing rod (8 single, 15 dual) technique, between the years 2007 and 2011. The patients were operated in two different institutions and were evaluated retrospectively via the parameters on the radiographic charts including the mean curve angle, T1 S1 distance, cervical lordosis, thoracic kyphosis, lumbar lordosis, sagittal and coronal balance, pelvic tilt, sacral slope and pelvic incidence. The parameters were measured in the preoperative and the early postoperative periods and during the last follow-up. The data obtained from the measurements were evaluated statistically. Complications were also noted. RESULTS: The mean follow-up period was 34.2 months (range 24-57.6). The mean thoracic kyphosis angle was 53.6 degrees (range 25 degrees -119 degrees ) preoperatively, 39.6 degrees (range 20 degrees -61 degrees ) early postoperatively (p < 0.05) and 39.9 degrees (range 21 degrees -65 degrees ) during the last follow-up (p < 0.05). The mean lumbar lordosis angle was -46.1 degrees (range -67 degrees to -13 degrees ) preoperatively, -41 degrees (range -64 degrees to -11 degrees ) early postoperatively (p > 0.05) and -39.7 degrees (range -62 degrees to -16 degrees ) during the last follow-up (p > 0.05). Average sagittal balance was measured as 0.2 cm (range -7 to 24.7 cm) preoperatively, -0.1 cm (range -6.6 to 8.5 cm) initial postoperatively (p > 0.05) and -0.2 cm (range -7.3 to 13.5 cm) during the last follow-up (p > 0.05). The average pelvic incidence was found as 46.4 degrees (range 27 degrees -83 degrees ) preoperatively, 45.2 degrees (range 28 degrees 78 degrees ) (p > 0.05) early postoperatively and 45.7 degrees (range 28 degrees -82 degrees ) during the last follow-up (p > 0.05). We have encountered complications in 14 patients. These consisted of eight rod fractures, seven screw pull-outs, four hook dislodgements, three proximal junctional kyphosis, two screw nut loosening, one lamina fracture, one skin slough, one superficial wound infection and one deep wound infection. CONCLUSION: Significant improvement was found in the global thoracic kyphosis angle, by comparing the preoperative, the early postoperative and the last follow-up parameters statistically (p < 0.05). There was no statistically significant improvement in the spinopelvic parameters (p > 0.05). We claim that growing rod technique doesn't provide statistically significant improvement, in the sagittal spinal and the spinopelvic parameters, except for the kyphosis, in the treatment of EOS patients. PMID- 24952008 TI - Incidence of traumatic spinal cord injury worldwide: a systematic review. AB - PURPOSE: Traumatic spinal cord injuries (TSCI) are among the most devastating conditions in developed and developing countries, which can be prevented. The situation of TSCI around the world is not well understood which complicates the preventive policy decision making in fight against TSCI. This study was aimed to gather the available information about incidence of TSCI around the world. METHODS: A systematic search strategy was designed and run in Medline and EMBASE, along with extensive grey literature search, personal communications, website searching, and reference checking of related papers. RESULTS: Overall, 133 resources including 101 papers, 17 trauma registries, 6 conference proceedings, 5 books, 2 theses and 2 personal communication data were retrieved. Data were found for 41 individual countries. The incidence of TSCI ranges from 3.6 to 195.4 patients per million around the world. Australia, Canada, US, and high-income European countries have various valuable reports of TSCI, while African and Asian countries lack the appropriate epidemiologic data on TSCI. CONCLUSION: Data of epidemiologic information in TSCI are available for 41 countries of the world, which are mostly European and high-income countries. Researches and efforts should be made to gather information in developing and low-income countries to plan appropriate cost-effective preventive strategies in fight against TSCI. PMID- 24952009 TI - CT screening for pulmonary pathology in common variable immunodeficiency disorders and the correlation with clinical and immunological parameters. AB - BACKGROUND: Pulmonary disease is common in patients with common variable immunodeficiency disorders (CVID) and involves infections, chronic airway disease and interstitial lung disease. Chronic pulmonary disease is associated with excess morbidity and early mortality and therefore early detection and monitoring of progression is essential. METHODS AND PURPOSE: Thin slice CT scan and pulmonary function were used to determine the prevalence and spectrum of chronic (pre-clinical) pulmonary disease in adult CVID patients regardless of symptoms. CT Scans were scored for airway abnormalities (AD) and interstitial lung disease (ILD). Other CVID related complications and B and T lymphocyte subsets were analyzed to identify patients at risk for pulmonary disease. RESULTS: Significant pulmonary abnormalities were detected in 24 of the 47 patients (51%) consisting of AD in 30% and ILD in 34% of cases. In only 7 (29%) of these 24 patients pulmonary function test proved abnormal. The presence of AD was correlated to (recurrent) lower respiratory tract infections despite IgG therapy. The presence of ILD was correlated to autoimmune disease and a reduction in the numbers of CD4 + T cells, naive CD4 + T cells, naive CD8 + T cells and memory B cells and lower IgG through levels over time. CONCLUSION: Preclinical signs of AD and ILD are common in CVID patients despite Ig therapy and do not correlate to pulmonary function testing. Patients at risk for ILD might be identified by the presence of autoimmunity or a deranged T cell pattern. Larger studies are needed to confirm these findings and to determine thresholds for the T lymphocyte subsets. PMID- 24952011 TI - Cryptococcal meningitis in patients with autoimmune hemolytic anemia. AB - To summarize the epidemiology, clinical features, treatment, and outcome of cryptococcal meningitis (CM) in autoimmune hemolytic anemia (AIHA) patients and to provide a reference for the prevention and control of AIHA complicated with CM, we evaluated five cases of CM in patients with AIHA treated in our hospital from 2003 to 2013 and eight related foreign cases. All of the clinical isolates were Cryptococcus neoformans var. grubii and grouped into the VNI genotype and serotype A. The clinical features exhibit significant features. Headache, nausea, and fever are common symptoms of AIHA complicated with CM. The early clinical manifestations lack specificity, which may lead to delayed diagnosis and treatment. Long-term use of prednisone (>=15 mg day(-1)), poor control of anemia, and splenectomy are risk factors for AIHA complicated with cryptococcal infection. The combination of intravenous amphotericin B and oral 5 fluorocytosine remains the preferred treatment for AIHA complicated with CM. PMID- 24952010 TI - Divergence in expression of candidate genes for the smoltification process between juvenile resident rainbow and anadromous steelhead trout. AB - Rainbow and steelhead trout (Oncorhynchus mykiss), among other salmonid fishes, exhibit tremendous life history diversity, foremost of which is variation in migratory propensity. While some individuals possess the ability to undertake an anadromous marine migration, others remain resident in freshwater throughout their life cycle. Those that will migrate undergo tremendous physiological, morphological, and behavioral transformations in a process called smoltification which transitions freshwater-adapted parr to marine-adapted smolts. While the behavior, ecology, and physiology of smoltification are well described, our understanding of the proximate genetic mechanisms that trigger the process are not well known. Quantitative genetic analyses have identified several genomic regions associated with smoltification and migration-related traits within this species. Here we investigate the divergence in gene expression of 18 functional and positional candidate genes for the smoltification process in the brain, gill, and liver tissues of migratory smolts, resident parr, and precocious mature male trout at the developmental stage of out-migration. Our analysis reveals several genes differentially expressed between life history classes and validates the candidate nature of several genes in the parr-smolt transformation including Clock1alpha, FSHbeta, GR, GH2, GHR1, GHR2, NDK7, p53, SC6a7, Taldo1, THRalpha, THRbeta, and Vdac2. PMID- 24952012 TI - Trichosporon inkin: an uncommon agent of scalp white piedra. Report of four cases in Brazilian children. AB - We report four cases of scalp white piedra (SWP) in Brazilian female children. Morphological and physiological approaches gave inconsistent results for identifying Trichosporon to species level, while the sequencing of the intergenic spacer 1 region of ribosomal DNA accurately identified the agent of SWP as T. inkin. These cases emphasize the occurrence of this species causing this type of infection. The molecular identification of the suspected agent is needed for appropriate epidemiological surveillance of superficial mycoses caused by Trichosporon species. PMID- 24952014 TI - Ochroconis humicola coexisting with esthesioneuroblastoma: an incidental coloniser or allergen? AB - Ochroconis humicola, a fish pathogen, is rarely reported to cause disease in human. We report its first isolation from nasal tissue of a human immunodeficiency virus-positive young female patient. Histopathologically, the nasal mass was diagnosed as esthesioneuroblastoma. She presented with right-sided nasal obstruction and bleeding for two and half months. Computed tomography scan showed the nasal mass filling the whole right nasal cavity, maxillary, ethmoid and sphenoid sinuses. The direct microscopy of the nasal tissue and mucin demonstrated the presence of septate hyphae. On culture, O. humicola was isolated from the same tissue and the fungus was identified by morphologic, physiologic and molecular data including sequencing of ITS and 28S rDNA regions. No antifungal was prescribed, and the whole mass was resected out by endoscopic surgery. The patient was treated further by radical radiotherapy. After 1 year of follow-up, patient is stable with no recurrence of tumour. The role of this fungus was not clear, as it may be bystander or producing allergic fungal rhinosinusitis. PMID- 24952013 TI - Epidemiology of invasive fungal infections in patients with acquired immunodeficiency syndrome at a reference hospital for infectious diseases in Brazil. AB - Invasive fungal infections (IFIs) represent one of the main causes of morbimortality in immunocompromised patients. Pneumocystosis, cryptococcosis and histoplasmosis are the most frequently occurring IFIs in patients with acquired immunodeficiency syndrome (AIDS). Fungi, such as Candida spp. and Aspergillus spp., may cause severe diseases during the course of an HIV infection. Following the introduction of highly active anti-retroviral therapy, there has been a marked reduction of opportunistic fungal infections, which today is 20-25 % of the number of infections observed in the mid-1990s. This study is an observational and retrospective study aimed at the characterising IFI incidence and describing the epidemiology, clinical diagnostic and therapeutic features and denouement in HIV/AIDS patients. In HIV/AIDS patients, the IFI incidence is 54.3/1,000 hospitalisation/year, with a lethality of 37.7 %. Cryptococcosis represents the main opportunistic IFI in the population, followed by histoplasmosis. Nosocomial pathogenic yeast infections are caused principally by Candida spp., with a higher candidemia incidence at our institution compared to other Brazilian centres. PMID- 24952015 TI - Isavuconazole and nine comparator antifungal susceptibility profiles for common and uncommon Candida species collected in 2012: application of new CLSI clinical breakpoints and epidemiological cutoff values. AB - The in vitro activity of isavuconazole and nine antifungal comparator agents was assessed using reference broth microdilution methods against 1,421 common and uncommon species of Candida from a 2012 global survey. Isolates were identified using CHROMagar, biochemical methods and sequencing of ITS and/or 28S regions. Candida spp. were classified as either susceptible or resistant and as wild type (WT) or non-WT using CLSI clinical breakpoints or epidemiological cutoff values, respectively, for the antifungal agents. Isolates included 1,421 organisms from 21 different species of Candida. Among Candida spp., resistance to all 10 tested antifungal agents was low (0.0-7.9 %). The vast majority of each species of Candida, with the exception of Candida glabrata, Candida krusei, and Candida guilliermondii (modal MICs of 0.5 ug/ml), were inhibited by <=0.12 ug/ml of isavuconazole (99.0 %; range 94.3 % [Candida tropicalis] to 100.0 % [Candida lusitaniae and Candida dubliniensis]). C. glabrata, C. krusei, and C. guilliermondii were largely inhibited by <=1 ug/ml of isavuconazole (89.7, 96.9 and 92.8 %, respectively). Decreased susceptibility to isavuconazole was most prominent with C. glabrata where the modal MIC for isavuconazole was 0.5 ug/ml for those strains that were SDD to fluconazole or WT to voriconazole, and was 4 ug/ml for those that were either resistant or non-WT to fluconazole or voriconazole, respectively. In conclusion, these data document the activity of isavuconazole and generally the low resistance levels to the available antifungal agents in a large, contemporary (2012), global collection of molecularly characterized species of Candida. PMID- 24952016 TI - Liver-directed treatments for metastatic colorectal cancer. AB - OPINION STATEMENT: When possible, surgical resection remains the "gold standard" for the treatment of hepatic colorectal metastases. Liver resection should be considered when complete removal of all macroscopic disease can be achieved safely. For those patients with unresectable metastases, or when a patient may not be a candidate for liver resection, many choices are available to the clinician in an attempt to achieve locoregional control, including tumor ablation, intra-arterial therapies, and radiation therapy. Whereas with surgical resection, durable local control can be considered potentially curable, other liver-directed approaches currently are mostly palliative. Ongoing trials are being undertaken to evaluate the role of such cytoreductive therapies. During the initial evaluation of any patient who might be a candidate for liver-directed therapy, particularly when the intent may be curative, complete assessment with high-quality imaging should be done before any therapy to determine the full extent of disease. Most importantly, the establishment of a multidisciplinary team upon initial diagnosis can optimize the choice and sequencing of the various systemic and locoregional choices available to the colorectal cancer patient. PMID- 24952017 TI - Does acid etching enhance remineralisation of arrested white spot lesions? AB - AIM: To investigate the effect of acid etching procedure on the remineralisation of white spot lesions (WSL) which had undergone an initial phase of arrest, and to compare between the effect of fluoride and/or CPP-ACP on remineralisation before and after acid etching. STUDY DESIGN: In vitro study. METHODS: WSL were prepared in vitro on 130 human enamel slabs which were allocated into four experimental groups (N = 30) and one control group (N = 10). Changes in mineral content were registered weekly by Quantitative Light Induced Fluorescence QLF. When changes had arrested (after 8 weeks), the enamel surface of 20 slabs in each group were acid etched. The remineralisation process was continued until it slowed down again (after 5 weeks). RESULTS: Mean fluorescence gain was 13.7 +/- 0.9% in the fluoride group, 16.5 +/- 1.1% in the CPP-ACP group, and 11.4 +/- 1.2% in the combination of fluoride and CPP-ACP group. CONCLUSIONS: There was a tendency toward better remineralisation after acid etching but this did not reach a significant level; the effect of etching was more pronounced in the presence of fluoride. Although CPP-ACP seemed to give a steadier rate of remineralisation over time when compared with fluoride, the overall remineralisation in the regimens was similar. In this model, combined treatment of fluoride and CPP-ACP did not have an extra benefit over the fluoride or CPP-ACP alone. PMID- 24952018 TI - Body composition in gene knockouts of sulfur amino acid-metabolizing enzymes. AB - Plasma concentrations of several amino acids are elevated in human obesity and insulin resistance, but there is no conclusive evidence on whether the amino acid alterations are causal. Dietary restriction of the essential SAA methionine (MR) in rats produces a hypermetabolic phenotype, with an integrated set of transcriptional changes in lipid enzymes in liver and adipose tissue. MR also induces an array of changes in methionine metabolites, including elevated plasma homocysteine and decreased cystathionine, cysteine, glutathione, and taurine. Several knockouts of enzymes acting downstream of methionine recapitulate the phenotypic results of MR, suggesting that the MR phenotype may be driven by changes distal to methionine. Here we review the changes in SAA and body composition in seven relevant knockout mouse models. All seven models feature decreased body weight, which in five of these have been further explored and shown to result from predominantly decreased fat mass. Common to several models is increased energy expenditure, enhanced insulin sensitivity, and protection against dietary obesity, as occurs in MR. A decrease in plasma total cysteine concentrations is also seen in most models. The lean phenotype could often be reversed by dietary supplementation of cysteine or choline, but not taurine, betaine or a H2S donor. Importantly, the plasma concentrations of both cysteine and choline are positively associated with fat mass in large populations studies, while taurine, betaine, and H2S are not. Collectively, the emerging data from dietary and knockout models are in harmony with human epidemiologic data, suggesting that the availability of key nutrients in the SAA pathway regulates fat storage pathways. PMID- 24952020 TI - Marginal ectropion induced by conjunctival ingrowth after levator resection surgery. AB - BACKGROUND: Levator resection surgery is commonly performed to correct ptosis, and a large number of postoperative complications are well known. This report presents a previously unreported complication of marginal ectropion after levator resection surgery for congenital ptosis. METHODS: The three patients with upper eyelid marginal ectropion in this observational case series previously had undergone levator resection surgery for congenital ptosis. The patients' medical records and clinical photographs were reviewed retrospectively. The patients underwent reoperations for ectropion correction. Unusual tissues identified during the surgery were excised and processed for histopathologic analysis. RESULTS: The patients presented with upper eyelid marginal ectropion and had a history of levator resection surgery for congenital ptosis on the same eye. Ingrown tissues were observed during the second operations for ectropion correction in all three patients. Histopathologic analysis was performed for two of the patients, confirming that the tissue consisted of mucosa. The ectropions were corrected after surgical removal of the ingrown tissues. CONCLUSIONS: Marginal ectropion can occur after levator resection surgery. In this study, the ectropion was attributed to mucosal ingrowth, a complication not previously reported. To improve the surgical outcomes, surgeons should be aware of this complication. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24952019 TI - Protozoan predation is differentially affected by motility of enteric pathogens in water vs. sediments. AB - Survival of enteric bacteria in aquatic habitats varies depending upon species, strain, and environmental pressures, but the mechanisms governing their fate are poorly understood. Although predation by protozoa is a known, top-down control mechanism on bacterial populations, its influence on the survival of fecal derived pathogens has not been systematically studied. We hypothesized that motility, a variable trait among pathogens, can influence predation rates and bacterial survival. We compared the survival of two motile pathogens of fecal origin by culturing Escherichia coli O157 and Salmonella enterica Typhimurium. Each species had a motile and non-motile counterpart and was cultured in outdoor microcosms with protozoan predators (Tetrahymena pyriformis) present or absent. Motility had a significant, positive effect on S. enterica levels in water and sediment in the presence or absence of predators. In contrast, motility had a significant negative effect on E. coli O157 levels in sediment, but did not affect water column levels. The presence/absence of protozoa consistently accounted for a greater proportion of the variability in bacterial levels (>95 %) than in bacterial motility (<4 %) in the water column. In sediments, however, motility was more important than predation for both bacteria. Calculations of total CFU/microcosm showed decreasing bacterial concentrations over time under all conditions except for S. enterica in the absence of predation, which increased ~0.5-1.0 log over 5 days. These findings underscore the complexity of predicting the survival of enteric microorganisms in aquatic habitats, which has implications for the accuracy of risk assessment and modeling of water quality. PMID- 24952021 TI - What are the Limits of the Surgeon's Responsibility in the Operating Theater? PMID- 24952022 TI - Autoantibodies involved in neuropsychiatric manifestations associated with systemic lupus erythematosus: a systematic review. AB - Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most important manifestations of SLE, and includes a variety of clinical manifestations, classified by the American College of Rheumatology in 19 different neuropsychiatric syndromes. To date, more than 116 antibodies have been reported in SLE and at least 20 of them, including 11 brain-specific and 9 systemic antibodies, have been controversially associated with NPSLE. To systematically review the available evidence, to define the association between the above antibodies and NPSLE as a whole and with the 19 neuropsychiatric syndromes associated with SLE, by strictly applying the American College Rheumatology case definitions. Medline reports published between 1999 and 2013 investigating the association between antibodies and NPSLE were included. Whenever possible, associations between antibodies and both NPSLE as a whole and with the 19 syndromes were analysed. This systematic review is based on available data from more than 8,000 patients and controls from 42 studies analysing antibodies and NPSLE. Nineteen studies analysed the role of antiphospholipid antibodies (aPL), 11 focused on anti-ribosomal-P protein antibodies and 5 on anti N-Methyl-D-Aspartate receptor antibodies. Two studies analysed, respectively, antibodies to aquaporin-4 and VH4-34 encoded antibodies. Given the multitude of clinical manifestations related to NPSLE, a single biomarker failed to be reliably associated with all neuropsychiatric events. Our findings provide evidence that aPL, mainly the lupus anticoagulant, and anti-ribosomal P antibodies are significantly associated with specific manifestations of neuropsychiatric disease attributed to SLE, namely, cerebrovascular events and psychosis, respectively. PMID- 24952024 TI - Could adult female acne be associated with modern life? AB - In recent years, the prevalence of adult female acne has increased, but the reason for this increase remains unclear. Acne is one of the most common skin disorders. It can be triggered or worsened by endogenous and exogenous factors, including genetic predisposition, hormone concentrations, diet, smoke and stress; although the interaction with this last factor is not well understood. Modern life presents many stresses including urban noises, socioeconomic pressures and light stimuli. Women are especially affected by stress during daily routine. The recent insertion in the labor market is added to the duties of the mother and wife. Women also have a higher risk of developing psychiatric disorders such as depression and anxiety. Sleep restriction is added to these factors, with several negative consequences on health, including on hormonal secretion and the immune system. This is further complicated by the natural variation in sleep architecture across the menstrual cycle. Recent studies have brought new data about the mechanisms and possible factors involved. This review aims to establish a connection between stress, sleep deprivation and adult female acne. PMID- 24952023 TI - The Differential Diagnosis of Dry Eyes, Dry Mouth, and Parotidomegaly: A Comprehensive Review. AB - Primary Sjogren's syndrome (pSS) is a frequent autoimmune systemic disease, clinically characterized by eyes and mouth dryness in all patients, salivary gland swelling or extraglandular systemic manifestations in half of the patients, and development of lymphoma in 5 to 10 % of the patients. However, patients presenting with sicca symptoms or salivary gland swelling may have a variety of conditions that may require very different investigations, treatments, or follow up. Eye and/or mouth dryness is a frequent complaint in clinical setting, and its frequency increases with age. When evaluating a patient with suspected pSS, the first step is to rule out its differential diagnoses, before looking for positive arguments for the disease. Knowledge of normal and abnormal lachrymal and salivary gland physiology allows the clinician to prescribe the most adapted procedures for evaluating their function and structure. New tests have been developed in recent years for evaluating these patients, notably new ocular surface staining scores or salivary gland ultrasonography. We describe the different diagnoses performed in our monocentric cohort of 240 patients with suspected pSS. The most frequent diagnoses are pSS, other systemic autoimmune diseases, idiopathic sicca syndrome and drug-induced sicca syndrome. However, other diseases are important to rule out due to their specific management, such as sarcoidosis, granulomatosis with polyangeitis, IgG4-related disease, chronic hepatitis C virus or human immunodeficiency virus infections, graft-versus-host disease, and head and neck radiation therapy. At the light of these data, we propose a core of minimal investigations to be performed when evaluating a patient with suspected pSS. PMID- 24952025 TI - A non-digestible fraction of the common bean (Phaseolus vulgaris L.) induces cell cycle arrest and apoptosis during early carcinogenesis. AB - We have previously demonstrated that the non-digestible fraction (NDF) from common cooked beans (P. vulgaris L., cv Negro 8025) inhibits azoxymethane (AOM) induced colon cancer and influences the expression of genes involved in the induction of apoptosis and cell cycle arrest through the action of butyrate. The objective of this study was to identify cell cycle alterations and morphological changes induced by treatment with AOM and to examine the formation of colonic aberrant crypt foci (ACF) in male Sprague Dawley rats fed with these beans. Rats were fed control diets upon arrival and were randomly placed into four groups after one week of acclimatization: control, NDF (intragastric administration), NDF + AOM and AOM. Rats treated with NDF + AOM exhibited a significantly lower number of total colonic ACF with a notable increase in the number of cells present in the G1 phase (83.14%); a decreased proliferation index was observed in the NDF + AOM group when compared to AOM group. NDF + AOM also displayed a higher number of apoptotic cells compared to AOM group. NDF of cooked common beans inhibited colon carcinogenesis at an early stage by inducing cell cycle arrest of colon cells and morphological changes linked to apoptosis, thus confirming previous results obtained with gene expression studies. PMID- 24952027 TI - [Effective informing of patients by practical year medical students]. PMID- 24952026 TI - Human umbilical cord-derived mesenchymal stem cells differentiate into epidermal like cells using a novel co-culture technique. AB - Human umbilical cord-derived mesenchymal stem cells (hUCMSCs) isolated from human umbilical Wharton's Jelly are a population of primitive and pluripotent cells. In specific conditions, hUCMSCs can differentiate into various cells, including adipocytes, osteoblasts, chondrocytes, neurocytes, and endothelial cells. However, few studies have assessed their differentiation into epidermal cells in vitro. To assess the potential of hUCMSCs to differentiate into epidermal cells, a microporous membrane-based indirect co-culture system was developed in this study. Epidermal stem cells (ESCs) were seeded on the bottom of the microporous membrane, and hUCMSCs were seeded on the top of the microporous membrane. Cell morphology was assessed by phase contrast microscopy, and the expression of early markers of epidermal cell lineage, P63, cytokeratin19 (CK19), and beta1-integrin, was determined by immunofluorescence, Western blot, and quantitative real-time PCR (Q-PCR) analyses. hUCMSC morphology changed from spindle-like to oblate or irregular with indirect co-culture with ESCs; they also expressed greater levels P63, CK19, and beta1-integrin mRNA and protein compared to the controls (p < 0.01). As compared to normal co-cultures, indirect co-culture expressed significantly greater CK19 protein (p < 0.01). Thus, hUCMSCs may have the capability to differentiate into the epidermal lineage in vitro, which may be accomplished through this indirect co-culture model. PMID- 24952028 TI - Estrogen receptor, progesterone receptor, and HER2 status predict lymphovascular invasion and lymph node involvement. AB - BACKGROUND: The ACOSOG Z0011 trial demonstrated that axillary dissection (ALND) is not necessary for local control or survival in women with T1/2cN0 cancer undergoing breast-conserving therapy. There is concern about applying these results to triple-negative (TN) cancers secondary to their high local-recurrence (LR) rate. We examined the frequency of lymphovascular invasion (LVI) and nodal metastases in TN cancers to determine whether ALND can be safely avoided in this subtype. METHODS: Data were obtained from a database of patients with invasive breast cancer treated at Memorial Sloan Kettering Cancer Center from January 1998 to December 2010. A total of 11,596 tumors were classifiable into clinical surrogates for molecular subtype by immunohistochemical analysis: hormone receptor (HR)+/HER2+, HR+/HER2-, HR-/HER2+, and TN (HR-/HER2-). Multivariable logistic regression analysis (MVA) was used to determine associations between clinicopathologic variables and subtype. RESULTS: There were differences in age, tumor size, LVI, grade, and nodal involvement among groups. On MVA controlling for size, grade, and age, ER, PR, and HER2 status were significantly associated with LVI (p < 0.0001). Relative to TN tumors, HR+/HER2-, HR+/HER2+, and HR-/HER2+ tumors had higher odds of demonstrating LVI of 1.8 (odds ratio 1.8; 95 % confidence interval 1.6-2.1), 2.5 (2.5; 2.0-3.0), and 1.7 (1.7; 1.4-2.1), respectively. On MVA adjusting for size, grade, LVI, and age, TN tumors had the lowest odds of having any or high-volume nodal involvement (>=4 nodes, p < 0.0001). CONCLUSIONS: LVI and nodal metastases were least frequent in TN cancers compared with other subtypes, despite the uniformly worse prognosis and increased LR rate in TN tumors. This suggests TN cancers spread via lymphatics less frequently than other subtypes and ALND may be avoided in TN patients meeting Z0011 eligibility criteria. PMID- 24952029 TI - Cumulative prognostic scores based on plasma fibrinogen and serum albumin levels in esophageal cancer patients treated with transthoracic esophagectomy: comparison with the Glasgow prognostic score. AB - PURPOSE: The purpose of this study was to establish a prognostic indicator based on preoperative plasma fibrinogen and serum albumin levels (FA score) in esophageal cancer patients and to compare the correlation with survival to that of the Glasgow prognostic score. METHODS: Patient characteristics, clinicopathological factors, and preoperative biochemical markers (fibrinogen, albumin, and C-reactive protein) were investigated in esophageal cancer patients who underwent transthoracic esophagectomy. Pretreatment fibrinogen and albumin levels were reviewed in patients who received neoadjuvant treatment. Patients with elevated fibrinogen and decreased albumin levels were allocated a score of 2, those with only one of these abnormalities were allocated a score of 1, and those with neither of these abnormalities were allocated a score of 0. The fibrinogen cut-off value was defined as 350 mg/dL according to our previous report, and the albumin cut-off value was defined as the lower quartile. RESULTS: Among 199 consecutive patients, the interquartile range of preoperative albumin was 3.8-4.3 g/dL and the cut-off value was 3.8 g/dL. Thus, 108 (54 %), 68 (34 %), and 23 (12 %) patients had an FA score of 0, 1, and 2. The patients with a high preoperative FA score showed considerably shorter disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that pretreatment stage and preoperative FA score were independently associated with postoperative DFS and OS. CONCLUSIONS: Preoperative FA score was significantly associated with postoperative survival in esophageal cancer patients, and the prognostic value is currently being validated in a prospective multicenter cohort study. PMID- 24952031 TI - Telephone versus office-based management of warfarin: impact on international normalized ratios and outcomes. AB - Studies have concluded that telephone-based management of warfarin is an effective alternative to in-office management. High rates of patient and physician satisfaction have been reported with telephone-based monitoring. Proposed benefits of telephone-based monitoring include time- and cost savings for patients and healthcare providers alike as well as increased access to care for those patients who have difficulty making in-office appointments. This study aimed to evaluate the impact of telephone versus office-based management of warfarin on extreme INR values. A retrospective cohort study was conducted to assess outcomes of patients receiving warfarin managed either by telephone or in office appointments. The primary endpoint of the study was the frequency of extreme INR values, defined as an INR <=1.5 or >=4.5. A total of 110 patients were evaluated; subjects were distributed 2:1 between the in-office and telephone groups. Baseline characteristics were similar between groups. Subjects followed via telephone had a twofold increase in the incidence of extreme INR values compared to the patients followed in-office (15.18 vs. 7.98 %; p < 0.0001). Overall TTR was similar between groups (85.39 vs. 80.38 %, p = 0.1171). There was no difference between the two groups in the incidence of major bleeding events (2.67 vs. 0 %, p = 1.00), thromboembolic events (8 vs. 0 %, p = 0.1740), or hospitalizations related to anticoagulation therapy (6.67 vs. 0 %, p = 0.1758). Patients monitored via telephone had a higher incidence of extreme INR values than patients followed in-office, which may lead to an increased incidence of adverse outcomes in the long-term. Well-designed, prospective studies are needed to confirm such findings. PMID- 24952030 TI - Generation of CD44 gene-deficient mouse derived induced pluripotent stem cells: CD44 gene-deficient iPSCs. AB - Induced pluripotent stem cells (iPSCs) show good promise for the treatment of defects caused by numerous genetic diseases. Herein, we successfully generated CD44 gene-deficient iPSCs using Oct4, Sox2, Klf4, and vitamin C. The generated iPSCs displayed a characteristic morphology similar to the well-characterized embryonic stem cells. Alkaline phosphatase, cell surface (SSEA1, NANOG, and OCT4), and pluripotency markers were expressed at high levels in these cells. The iPSCs formed teratomas in vivo and supported full-term development of constructed porcine embryos by inter-species nuclear transplantation. Importantly, incubation with trichostatin A increased the efficiency of iPSCs generation by increasing the histone acetylation levels. Moreover, more iPSCs colonies appeared following cell passaging during colony picking, thus increasing the effectiveness of iPSCs selection. Thus, our work provides essential stem cell materials for the treatment of genetic diseases and proposes a novel strategy to enhance the efficiency of induced reprogramming. PMID- 24952032 TI - First case report of SAM(r) Junctional tourniquet use in Afghanistan to control inguinal hemorrhage on the battlefield. AB - Junctional hemorrhage, bleeding that occurs at the junction of the trunk and its appendages, is the most common preventable cause of death from compressible hemorrhage on the battlefield. As of January 2014, four types of junctional tourniquets have been developed and cleared by the U.S. Food and Drug Administration (FDA). Successful use of the Abdominal Aortic Tourniquet (AATTM) and Combat Ready Clamp (CRoCTM) has already been reported. We report here the first known prehospital use of the SAM(r) Junctional Tourniquet (SJT) for a battlefield casualty with inguinal junctional hemorrhage. PMID- 24952033 TI - Abdominal aortic and junctional tourniquet controls hemorrhage from a gunshot wound of the left groin. AB - "Junctional hemorrhage" is defined as bleeding from the areas at the junction of the trunk and its appendages. This is an important cause of potentially preventable deaths on the battlefield and a difficult condition to treat in the civilian prehospital setting. Having a solution to definitively treat the condition decreases the mortality and morbidity of these injuries. The Abdominal Aortic and Junctional Tourniquet(tm) is (1) a Food and Drug Administration?cleared device that is currently indicated for pelvic, inguinal, and axillary bleeding; (2) the only junctional tourniquet with an indication for pelvic bleeding; (3) the only junctional tourniquet reported with a successful axillary use; and (4) effective at lower tissue pressures than other junctional tourniquets available. PMID- 24952034 TI - Corneal foreign body management at a role 1 flight line aid station: risks, benefits, and implications for Special Operations medicine. AB - Eye injuries are common in forward areas of operations. Definitive diagnosis and care may be limited not by provider skill but rather by available equipment. The ability to treat simple trauma such as corneal foreign bodies at the Role 1 level has advantages including rapid return to duty, decreased cost of treatment, and, most important, decreased risk of delayed care. We propose the device such as a hand-held portable slit lamp should be made available for appropriate Special Operations Medical Forces (SOFMED) or aviation providers. PMID- 24952035 TI - Preparedness for resuscitation at a geographically isolated army troop medical clinic: lessons from Camp Blanding, Florida. AB - INTRODUCTION: Many Servicemembers rely on nondeployed Role 1 facilities, such as troop medical clinics, as their primary source of healthcare. At geographically isolated military installations, these facilities are the "only game in town" for medical care. Servicemembers may present to these facilities with emergent conditions, regardless of designed intent of the facility or the wishes of staff. The U.S. Army Troop Medical Clinic, Camp Blanding is such a facility. METHODS: The clinic was reorganized with a 5S approach, streamlining supply, equipment, and workflow processes. This was accomplished to allow the facility to not only improve its general delivery of care but also ensure capability to handle at least one medical or trauma resuscitation. Equipment, disposable supplies, documentation, and staff training were addressed. Results/Discussion/Conclusion: Despite facility intention, lack of supplies/equipment, or staff inexperience with emergency care, an acute ill or injured Servicemember must be stabilized at the nondeployed Role 1 facility while awaiting transport to a higher level of care. This expectation is the same as that of deployed Role 1 facilities. A cost savings can also be realized when minor "emergencies" are handled in-house. PMID- 24952036 TI - Safety and Effectiveness Evidence of SAM(r) Junctional Tourniquet to Control Inguinal Hemorrhage in a Perfused Cadaver Model. AB - BACKGROUND: Hemorrhage from the trunk?appendage junctions is a common, preventable cause of death on the battlefield. The recently U.S. Food and Drug Administration (FDA)-cleared SAM? Junctional Tourniquet (SJT) was designed to control out-of-hospital inguinal and axillary hemorrhage. The purpose of the present study was to provide safety and effectiveness data associated with use of the SJT. Such data provided support for regulatory clearance. METHODS: The SJT was tested in a perfused cadaver experiment simulating inguinal or axillary wound hemorrhage. RESULTS: No safety problems or tissue damage occurred, and flow normalized promptly after tourniquet removal. During SJT use, an average of 107 mmHg occluded the distal external iliac artery in an average of 7 seconds of inflation time; manual pressure as a control averaged 139 mmHg. In SJT use, an average of 739 mmHg occluded the axillary artery in an average of 5 seconds of inflation time; manual pressure as a control averaged 1237 mmHg. The control was a referent that achieved results that were similar in one body area but different in the other; both findings indicate the device is as safe as, if not safer than, manual compression. CONCLUSION: The SJT was shown to be safe and effective in hemorrhage control in a cadaver model for both the axillary and inguinal areas. The SJT's Target Compression Devices required pressures approximately equal to or lower than manual pressure to achieve hemostasis in these junctional regions. PMID- 24952037 TI - Warzone stressor exposure, unit support, and emotional distress among U.S. Air force pararescuemen. AB - OBJECTIVES: Combat exposure is associated with increased mental health symptom severity among military personnel, whereas unit support is associated with decreased severity. However, to date no studies have examined these relationships among U.S. Air Force pararescuemen (PJs), who have a unique and specialized career field that serves in both medical and combatant capacities. DESIGN: Cross sectional self-report survey. METHODS: Self-reported survey data regarding depression symptoms, posttraumatic stress disorder (PTSD) symptoms, perceived unit support, and exposure to traditional combat experiences (e.g., firefights) and medical consequences of combat (e.g., injuries and human remains) were collected from 194 PJs in seven rescue squadrons. RESULTS: Levels of combat exposure were compared with previously published findings from combat units, and levels of medical exposure were compared with previously published findings among military medical professionals. Medical exposure intensity showed a stronger relationship with PTSD severity (?=.365, p=.018) than with combat exposure intensity (?=.136, p=.373), but neither combat nor medical exposure was associated with depression severity (?s<.296, ps>.164). Unit support was associated with less severe PTSD (?=?.402, p<.001) and depression (?=?.259, p=.062) symptoms and did not moderate the effects of combat or medical exposure. CONCLUSIONS: Medical stressors contribute more to PTSD among PJs than do traditional combat stressors. Unit support is associated with reduced PTSD and depression severity regardless of intensity of warzone exposure among PJs. PMID- 24952038 TI - Comparison of muscle paralysis after intravenous and intraosseous administration of succinylcholine in Swine. AB - AIM: To compare the onset and duration of intravenous (IV) and intraosseous (IO) administration of succinylcholine in swine. METHODS: Electromyographic (EMG) amplitudes were used to characterize muscle paralysis following administration of succinylcholine via the IV or IO route in four Yorkshire-cross swine. RESULTS: The onset of action of succinylcholine was statistically longer after IO administration (0.97+/-0.40) compared with IV administration (0.55+/-0.26) (p=.048). Duration of action was unaffected by route of administration: IO, 11.4+/-4.2, and IV, 12.9+/-3.8 (p=.65). CONCLUSIONS: Succinylcholine can be effectively administered via the IO route. However, an increased dose may be necessary when administering succinylcholine via the IO route to achieve the same rapid onset as standard IV dosing. PMID- 24952039 TI - An observational study assessing completion time and accuracy of completing the tactical combat casualty care card by combat medic trainees. AB - INTRODUCTION: Prehospital care documentation is crucial to improving battlefield care outcomes. Developed by United States Army Ranger Special Operations Combat Medics (SOCMs), the Tactical Combat Casualty Care (TCCC) is currently fielded to deployed units to record prehospital injury data. This study documents length of time and accuracy of U.S. Army Combat Medic trainees in completing the minimum preestablished required fields on the TCCC card, establishing a baseline for point-of-injury cards. DESIGN AND METHODS: This was a prospective observational study in which U.S. Army combat medic trainees were timed while recording data on the TCCC card in both the classroom and simulated combat environment. We hypothesized that trainees could complete the TCCC card in less than 1 minute with 90% or greater accuracy. RESULTS: We enrolled 728 U.S. Army Combat Medic trainees in the study during May?June 2011 at Fort Sam Houston, TX. We observed an average TCCC card completion time of less than 1 minute with greater than 90% accuracy in the unstressed classroom environment but an increase to nearly 2 minutes on average and a decrease to 85% accuracy in the simulated combat environment. CONCLUSION: RESULTS imply that the TCCC card is well designed to quickly and accurately record prehospital combat injury information. Further investigation and future studies may compare other prehospital data collection methods with the TCCC card in terms of timely and accurate data collection. PMID- 24952040 TI - Evaluation of commercially available traction splints for battlefield use. AB - BACKGROUND: Femoral fracture is a common battlefield injury with grave complications if not properly treated. Traction splinting has been proved to decrease morbidity and mortality in battlefield femur fractures. However, little standardization of equipment and training exists within the United States Armed Forces. Currently, four traction splints that have been awarded NATO Stock Numbers are in use: the CT-6 Leg Splint, the Kendrick Traction Device (KTD), the REEL Splint (RS), and the Slishman Traction Splint (STS). OBJECTIVE: The purpose of this study was to determine the differences between the four commercially available traction devices sold to the U.S. Government. METHODS: After standardized instruction, subjects were timed and evaluated in the application of each of the four listed splints. Participant confidence and preferences were assessed by using Likert-scaled surveys. Free response remarks were collected before and after timed application. RESULTS: Subjects had significantly different application times on the four devices tested (analysis of variance [ANOVA], p<.01). Application time for the STS was faster than that for both the CT-6 (t test, p<.0028) and the RS (p<.0001). Subjects also rated the STS highest in all post-testing subjective survey categories and reported significantly higher confidence that the STS would best treat a femoral fracture (p<.00229). CONCLUSIONS: The STS had the best objective performance during testing and the highest subjective evaluation by participants. Along with its ability to be used in the setting of associated lower extremity amputation or trauma, this splint is the most suitable for battlefield use of the three devices tested. PMID- 24952041 TI - Treatment of sea urchin injuries. AB - Sea urchin injuries can be sustained in a variety of environments in which U.S. Forces are operating, and familiarity with this uncommon injury can be useful. Injuries by sea urchin spines can occur during military activities close to rocky salt aquatic ecosystems via three mechanisms. The author describes these mechanisms and discusses the diagnosis, management, and treatment of sea urchin injuries. PMID- 24952042 TI - Singapore's perspective, little India riot: an impetus to develop tactical medicine among medics in Singapore? AB - This is a report of the first riot in Singapore since 1969 and the subsequent emergency response from the police force and emergency medical services. Lessons learned are discussed, and recommendations for future medical response in incidents of civil unrest are made. PMID- 24952043 TI - Medical operations of the 6th ranger infantry battalion. AB - The author gives a history of the formation of the 6th Ranger Infantry Battalion and varied aspects of Ranger medical operations, including personnel composition of the medical detachment, the work of the battalion?s surgeon during combat and noncombat operations, medical aspects of operational planning, available medical supplies, medical evacuation procedures, and preventive care. PMID- 24952044 TI - Intra-articular Morphine versus Lidocaine for Acute Knee Pain. AB - OBJECTIVE: The authors conducted an unfunded randomized controlled trial approved by the Brooke Army Medical Center (BAMC) Institutional Review Board (IRB) to determine the possible efficacy of intra-articular morphine for pain in acute knee injuries. METHODS: Patients presenting to the emergency department at San Antonio Military Medical Center (SAMMC) from May 2012 to August 2013 with knee pain due to an acute injury were consented and then enrolled based on a convenience sample. Patients were randomized to one of three intervention arms (morphine, lidocaine, or morphine and lidocaine) and were blinded to the intervention. The respective solution was injected into the knee joint using standard techniques. The patients self-reported their levels of knee pain via a standard 100mm visual analogue scale (VAS) at the time of injection and 30 minutes, 60 minutes, 90 minutes, 2 hours, 6 hours, and 24 hours postinjection. At 24 hours, the patients also reported the estimated amount of time they applied ice to the knee and the amount of oral analgesia consumed in the previous 24 hours. RESULTS: The primary outcome was relative pain reduction as measured by the VAS. Secondary outcomes were the total cumulative use of ice and analgesics during the first 24 hours. Although this was a small study, the results showed a possible trend toward better pain control at all time intervals with injections containing morphine compared with lidocaine-only injections. Ice and oral analgesia usage was equivalent between the three intervention arms. CONCLUSION: Further investigation with a larger sample is required to explore whether these results are statistically significant and the possible superiority of intra articular morphine to lidocaine for acute knee pain. PMID- 24952045 TI - Fast-roping: potential consequences of vibrations for sensation and regulation of movement. AB - OBJECTIVES: Short-term exposure (2?30 seconds) to segmental mechanical vibrations with frequencies between 20 and 80 Hz affects proprioception of the central nervous system and manual dexterity and strength of man. It could be supposed that during fast-roping, Soldiers are exposed to hand?arm vibrations caused by the geometry of the rope. After the maneuver, Soldiers are encouraged to operate with high precision (e.g., aiming and shooting) within a few seconds. For safety, disturbances of the sensory system should be strongly avoided. The purpose of the study was to determine the vibrations induced by different rope geometries during fast-roping. METHODS: Eight men of the German Special Forces performed 10 fast roping maneuvers with two different shaped ropes (slightly molded versus deeply molded). Vibration data and frequency spectrum for each trial were measured by using fast Fourier transformation. RESULTS: The analysis of data showed that fast roping with a slightly molded rope produced frequencies of up to 10 Hz, while the frequencies with a deeply molded rope accounted for 18 to 60 Hz. The ropes differed significantly (p<.001) in frequencies between 20 and 50 Hz. The exposure time of vibration lasted between 3 and 5 seconds. CONCLUSION: Considering the negative effects associated with vibrations, prudence is required when using deeply molded ropes due to the increased vibrations of about 20 Hz. PMID- 24952046 TI - Operational stressors on physical performance in special operators and countermeasures to improve performance: a review of the literature. PMID- 24952047 TI - An integrated approach for special operations. AB - The Department of Defense (DoD) faces unprecedented challenges as the Nation confronts balancing a strong military to confront threats with the realities of diminishing financial resources. That each warfighter is a critical resource was underscored the Special Operations principal tenet "humans are more important than hardware." These challenges have popularized the term "human performance optimization" (HPO), which became ingrained in DoD around 2005. This article is the first in a new series relating to HPO, and we define the term and concept of HPO, describe other phrases used (e.g., performance enhancement; performance sustainment, performance restoration; and human performance modification). Last, we introduce an integrated model for HPO. PMID- 24952049 TI - Prevention of foot blisters. AB - Foot blisters are the most common medical problem faced by Soldiers during foot march operations and, if untreated, they can lead to infection. Foot blisters are caused by boots rubbing on the foot (frictional forces), which separates skin layers and allows fluid to seep in. Blisters can be prevented by wearing properly sized boots, conditioning feet through regular road marching, wearing socks that reduce reduce friction and moisture, and possibly applying antiperspirants to the feet. PMID- 24952048 TI - Cholera. AB - Vibrio cholerae is a comma-shaped, gram-negative rod that produces an enterotoxin, which causes an acute-onset diarrheal disease ranging in severity from mild to life threatening. Worldwide, there are an estimated 3?5 million cases per year, with more than 100,000 deaths. The disease remains a significant cause of death and illness in sub-Saharan Africa, southeast Asia (especially Bangladesh and India), and Haiti, and the infection should be recognized by the Special Operations Forces (SOF) medical provider. PMID- 24952050 TI - Clinical encounters in tactical medicine: a mission-specific analysis of the Maryland State Police experience. AB - INTRODUCTION: The Maryland State Police (MSP) Tactical Medical Unit (TMU) provides tactical emergency medical support (TEMS) through the deployment of specially trained state trooper tactical paramedics. The MSP TMU maintains an operational database of all mission related medical activity. This information constitutes a robust dataset derived from real world operational medicine experiences. METHODS: A retrospective analysis of de-identified entries from the MSP TMU operational response database was performed for the 5-year period of 2007?2013. A summative analysis of missions, as well as a subgroup analysis of types of patients encountered, was performed to further characterize patient encounters based on the type of law enforcement tactical mission. RESULTS: Analysis was performed on 1,042 tactical missions, of which there were 367 total patient encounters during the study period. The majority (67%; 246/367) of patients encountered were law enforcement tactical team personnel. The most frequently occurring mission, by type, was high-risk warrant service, accounting for 45% (470/1,042) of all missions in this series. Law enforcement training support missions comprised 25% (259/1,042), and 15% (157/1,042) of all missions in the database were medical standbys for law enforcement operations. The highest number of patient contacts were associated with training activities, resulting in 29% (108/367) of clinical encounters. The next most common mission associated with patient encounters was high-risk warrant service (24%; 88/367). CONCLUSION: The 5-year analysis conducted in this study represents the largest known retrospective assessment of a state police tactical medical program. Training activities resulted in the highest number of patient encounters by this program, with law enforcement/tactical team personnel comprising the majority of patient encounters. The majority of chief complaints encountered were non?life threatening and reinforce the need for expanded scope of practice training and enhanced treatment protocols for tactical medics. PMID- 24952052 TI - Development of a National Consensus for Tactical Emergency Medical Support (TEMS) Training Programs--Operators and Medical Providers. AB - INTRODUCTION: Tactical teams are at high risk of sustaining injuries. Caring for these casualties in the field involves unique requirements beyond what is provided by traditional civilian emergency medical services (EMS) systems. Despite this need, the training objectives and competencies are not uniformly agreed to or taught. METHODS: An expert panel was convened that included members from the Departments of Defense, Homeland Security, Justice, and Health and Human Services, as well as federal, state, and local law-enforcement officers who were recruited through requests to stakeholder agencies and open invitations to individuals involved in Tactical Emergency Medical Services (TEMS) or its oversight. Two face-to-face meetings took place. Using a modified Delphi technique, previously published TEMS competencies were reviewed and updated. RESULTS: The original 17 competency domains were modified and the most significant changes were the addition of Tactical Emergency Casualty Care (TECC), Tactical Familiarization, Legal Aspects of TEMS, and Mass Casualty Triage to the competency domains. Additionally, enabling and terminal learning objectives were developed for each competency domain. CONCLUSION: This project has developed a minimum set of medical competencies and learning objectives for both tactical medical providers and operators. This work should serve as a platform for ensuring minimum knowledge among providers, which will serve enhance team interoperability and improve the health and safety of tactical teams and the public. PMID- 24952053 TI - PCR Innovation Day: connecting the innovation dots. PMID- 24952054 TI - Rewriting the history of vascular closure devices. PMID- 24952055 TI - Renal denervation revisited: comparative appraisal of safety and efficacy. PMID- 24952056 TI - Cost-effectiveness of contemporary vascular closure devices for the prevention of vascular complications after percutaneous coronary interventions in an all-comers PCI population. AB - AIMS: The present observational case-control study assessed the cost effectiveness of contemporary vascular closure devices (VCDs) for the prevention of vascular complications in an all-comers transfemoral percutaneous coronary intervention (PCI) population. METHODS AND RESULTS: A total of 8,292 consecutive PCI patients were enrolled from a single-centre prospective registry from January 2005 to December 2010. VCDs were available from July 2007 and, from that time point, VCDs were implanted in 1,780 of the 5,394 patients (33%). Vascular complications occurred in 221 (2.7%) patients. The use of VCDs was independently associated with a 53% risk reduction (OR 0.47, 95% CI: 0.3-0.7) in vascular complications (3.0% vs. 1.5%) and with a 65% risk reduction (IRR 0.37, 95% CI: 0.32-0.43) in the post-PCI length of hospital stay (LOS) (mean 2.8 vs. 1.5 days). Mainly due to the reduced LOS, the patients with VCDs accrued vascular direct medical costs (VCD, diagnosis and treatment of vascular complications, post-PCI LOS) that were on average 498? less than those accrued by the non-VCD patients. The cost-effectiveness was present across all vascular risk profiles. CONCLUSIONS: In this large, all-comers transfemoral PCI population, the use of VCDs was independently associated with a reduction in the rate of vascular complications and the post-PCI length of hospital stay and proved to be cost saving across all vascular risk profiles. PMID- 24952057 TI - Rationale and design of a randomised clinical trial comparing vascular closure device and manual compression to achieve haemostasis after diagnostic coronary angiography: the Instrumental Sealing of ARterial puncture site - CLOSURE device versus manual compression (ISAR-CLOSURE) trial. AB - AIMS: Vascular closure devices (VCD) have been introduced into clinical practice with the aim of increasing the procedural efficiency and clinical safety of coronary angiography. However, clinical studies comparing VCD and manual compression have yielded mixed results, and large randomised clinical trials comparing the two strategies are missing. Moreover, comparative efficacy studies between different VCD in routine clinical use are lacking. METHODS AND RESULTS: The Instrumental Sealing of ARterial puncture site - CLOSURE device versus manual compression (ISAR-CLOSURE) trial is a prospective, randomised clinical trial designed to compare the outcomes associated with the use of VCD or manual compression to achieve femoral haemostasis. The test hypothesis is that femoral haemostasis after coronary angiography achieved using VCD is not inferior to manual compression in terms of access-site-related vascular complications. Patients undergoing coronary angiography via the common femoral artery will be randomised in a 1:1:1 fashion to receive FemoSeal VCD, EXOSEAL VCD or manual compression. The primary endpoint is the incidence of the composite of arterial access-related complications (haematoma >=5 cm, pseudoaneurysm, arteriovenous fistula, access-site-related bleeding, acute ipsilateral leg ischaemia, the need for vascular surgical/interventional treatment or documented local infection) at 30 days after randomisation. According to power calculations based on non inferiority hypothesis testing, enrolment of 4,500 patients is planned. The trial is registered at www.clinicaltrials.gov (study identifier: NCT01389375). CONCLUSIONS: The safety of VCD as compared to manual compression in patients undergoing transfemoral coronary angiography remains an issue of clinical equipoise. The aim of the ISAR-CLOSURE trial is to assess whether femoral haemostasis achieved through the use of VCD is non-inferior to manual compression in terms of access-site-related vascular complications. PMID- 24952059 TI - Direct TAVI using a balloon-expandable system: a novel technique to eliminate pre deployment balloon aortic valvuloplasty. AB - AIMS: Transcatheter aortic valve implantation (TAVI) is now the therapy of choice for those patients with severe symptomatic aortic stenosis who are considered to be at too high risk for conventional surgery. Balloon aortic valvuloplasty (BAV) is routinely performed to allow placement of the balloon-expandable valve during the procedure. Instrumentation of the valve has been linked to procedural stroke risk, with the associated runs of rapid pacing risking haemodynamic compromise. We outline a novel technique to eliminate BAV prior to transcatheter valve placement. METHODS AND RESULTS: We illustrate a clinical case that outlines the problems encountered in transcatheter valve placement despite a prior BAV. The solution used in this case involved the partial inflation of the distal section of the balloon allowing easy passage of the SAPIEN XT valve from the transaortic route. After bench testing, we report a series of patients who have undergone this "direct TAVI" procedure from both the transaortic and the transfemoral routes. CONCLUSIONS: In a limited series within a single centre, "direct TAVI" has been shown to be effective in allowing accurate placement of a balloon expandable device without the need for prior BAV. PMID- 24952058 TI - Platelet reactivity and cardiovascular events after percutaneous coronary intervention in patients with stable coronary artery disease: the Stent Thrombosis In Belgium (STIB) trial. AB - AIMS: The Stent Thrombosis In Belgium (STIB) trial aimed to determine whether assessing platelet reactivity (PR) in patients with stable coronary artery disease undergoing elective percutaneous coronary intervention (PCI) could predict the risk of ischaemic complications and adverse clinical events up to 30 days post PCI. METHODS AND RESULTS: PR before intervention was determined in 891 patients undergoing PCI for stable angina pectoris. Twelve to 24 hours before PCI, all patients received a 600 mg clopidogrel dose followed by 75 mg daily, and 500 mg of aspirin followed by 80-100 mg daily. Residual PR was assessed by VerifyNow point-of-care aspirin and P2Y12 assay before PCI. "Non-responders" to antiplatelet therapy were defined as aspirin reaction unit (ARU) >550 and as P2Y12 reaction unit (PRU) >230. The endpoint of the study was the composite of periprocedural myonecrosis, stent thrombosis, non-fatal myocardial infarction (MI), stroke and death at 30 days in patients with or without high PR. The endpoint was observed in 180 patients: four deaths, one stroke, 11 Q-wave MI, three non-Q-wave MI and 161 periprocedural myonecroses. At multivariate analysis, the endpoint was predicted by total stent length (OR: 1.020), GFR <60 ml/min (OR: 1.87), history of PCI (OR: 0.58), white blood cell count (OR: 1.95) and diabetes (OR: 1.83). No significant association was found between residual PR and the primary endpoint or any of its components. CONCLUSIONS: PR measured before PCI in stable patients undergoing elective PCI who are preloaded with 500 mg of aspirin and 600 mg of clopidogrel is not predictive of periprocedural myocardial injury or adverse ischaemic complications up to 30 days. PMID- 24952060 TI - Balloon-expandable valves for degenerated mitral xenografts or failing surgical rings. AB - AIMS: Transcatheter mitral valve-in-valve implantation (TMViVI) for the treatment of failing mitral xenografts or recurrent mitral regurgitation after surgical ring implantation is an emerging therapy for patients in need of repeated mitral valve surgery. Despite the fact that these procedures have been shown to be feasible and effective, haemodynamic data after TMViVI are still limited in the literature. METHODS AND RESULTS: Twelve patients (logES: 39.2+/-23.5%) were treated either by transapical (n=7) or transseptal (n=5) TMViVI, as a valve-in valve (ViV, n=8) or valve-in-ring (ViR, n=4) implantation. Left atrial pressures (LAP), transmitral gradients and right heart haemodynamics (Swan-Ganz catheterisation) were studied before and after TMViVI. Procedural success was 100%, mitral regurgitation after TMViVI was mild in one, trace in five and absent in six patients. Thirty-day mortality was 0%. Left atrial pressures decreased significantly after valve implantation (before LAPmean/v-wave: 24.3/44.1 mmHg; after LAP/v-wave 15.9/22.1 mmHg; p<0.001) and cardiac output increased significantly. Transmitral gradients corresponded to mitral surface areas between 1.7 and 3.5 cm2, and were thus very acceptable in terms of the high surgical risk population. CONCLUSIONS: In conclusion, TMViVI with the balloon-expandable SAPIEN XT valve for ViV or ViR implantation is feasible with promising acute transmitral haemodynamic data. Nevertheless, sustained long-term performance remains to be demonstrated in the future. PMID- 24952061 TI - Transfemoral valve-in-ring implantation for a failing mitral homograft in the tricuspid position. PMID- 24952062 TI - Evaluation of lesion and thermodynamic characteristics of Symplicity and EnligHTN renal denervation systems in a phantom renal artery model. AB - AIMS: Radiofrequency renal artery denervation has been used effectively to treat resistant hypertension. However, comparison of lesion and thermodynamic characteristics for different systems has not been previously described. We aimed to assess spatiotemporal lesion growth and ablation characteristics of Symplicity and EnligHTN systems. METHODS AND RESULTS: A total of 39 ablations were performed in a phantom renal artery model using Symplicity (n=17) and EnligHTN (n=22) systems. The phantom model consisted of a hollowed gel block surrounding a thermochromic liquid crystal (TLC) film, exhibiting temperature sensitivity of 50 78 degrees C. Flow was simulated using 37 degrees C normal saline with impedance equal to blood. Radiofrequency ablations with each system were delivered with direct electrode tip contact to the TLC. Lesion size was interpreted from the TLC as the maximum dimensions of the 51 degrees C isotherm. Mean lesion depth was 3.82 mm+/-0.04 versus 3.44 mm+/-0.03 (p<0.001) for Symplicity and EnligHTN, respectively. Mean width was 7.17 mm+/-0.08 versus 6.23 mm+/-0.07 (p<0.001), respectively. With EnligHTN, steady state temperature was achieved 20 sec earlier, and was 15 degrees C higher than Symplicity. CONCLUSIONS: In this phantom model, Symplicity formed larger lesions compared to EnligHTN with lower catheter-tip temperature. The clinical significance of our findings needs to be explored further. PMID- 24952063 TI - Tools & techniques--statistics: Dealing with time-varying covariates in survival analysis--joint models versus Cox models. PMID- 24952064 TI - How should I treat an adult with unoperated complex cyanotic heart disease with severe pulmonary stenosis? PMID- 24952065 TI - Exploring the structural and functional impact of the ALK F1174L mutation using bioinformatics approach. AB - Crizotinib is the most effective and the only drug that has been approved for the treatment of anaplastic lymphoma kinase (ALK)-positive lung cancer. Reports suggest that there is a development of an acquired resistance against crizotinib action due to the emergence of several mutations in the ALK gene and F1174L is one such mutation. In this study, we used molecular docking and molecular dynamics (MD) approach to decipher the effect of F1174L mutation in drug-target binding. Docking results suggest that crizotinib was found to adopt the most promising conformations to the native-type ALK by identifying the M1199 residue as a prospective partner for making a hydrogen bond as compared to the mutant type ALK. MD results showed that the average atom, especially atoms of the native type ALK-crizotinib complex, movements were less, displayed less fluctuation, fast convergence of energy, and changes in geometry. This shows the stable binding of crizotinib with the native-type ALK in comparison to the mutant-type ALK. We believe that this study could be useful for the logical design of stronger, more selective, and more consistent ALK inhibitor against drug resistant F1174L mutation. PMID- 24952066 TI - Binding-competent states for L-arginine in E. coli arginine repressor apoprotein. AB - Arginine repressor of E. coli is a multifunctional hexameric protein that provides feedback regulation of arginine metabolism upon activation by the negatively cooperative binding of L-arginine. Interpretation of this complex system requires an understanding of the protein's conformational landscape. The ~50 kDa hexameric C-terminal domain was studied by 100 ns molecular dynamics simulations in the presence and absence of the six L-arg ligands that bind at the trimer-trimer interface. A rotational shift between trimers followed by rotational oscillation occurs in the production phase of the simulations only when L-arg is absent. Analysis of the system reveals that the degree of rotation is correlated with the number of hydrogen bonds across the trimer interface. The trajectory presents frames with one or more apparently open binding sites into which one L-arg could be docked successfully in three different instances, indicating that a binding-competent state of the system is occasionally sampled. Simulations of the resulting singly-liganded systems reveal for the first time that the binding of one L-arg results in a holoprotein-like conformational distribution. PMID- 24952068 TI - Carvedilol attenuates 6-hydroxydopamine-induced cell death in PC12 cells: involvement of Akt and Nrf2/ARE pathways. AB - Oxidative stress is closely related to the pathogenesis of neurodegenerative disorders such as Parkinson's disease. Carvedilol, a nonselective beta-adrenergic receptor blocker with pleiotropic activity has been shown to exert neuroprotective effect due to its antioxidant property. However, the neuroprotective mechanism of carvedilol is still not fully uncovered. The phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway plays key role in cell survival and the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is the major cellular defense mechanism against oxidative stress. Here we investigated the effects of carvedilol on 6 hydroxydopamine (6-OHDA)-induced cell death as well as the Akt and Nrf2/ARE pathways in PC12 cells. We found that carvedilol significantly increased cell viability and decreased reactive oxygen species in PC12 cells exposed to 6-OHDA. Furthermore, carvedilol activated the Akt and Nrf2/ARE pathways in a concentration-dependent manner, and increased the protein levels of heme oxygenase-1(HO-1) and NAD(P)H quinone oxidoreductase-1(NQO-1), two downstream factors of the Nrf2/ARE pathway. In summary, our results indicate that carvedilol protects PC12 cells against 6-OHDA-induced neurotoxicity possibly through activating the Akt and Nrf2/ARE signaling pathways. PMID- 24952067 TI - Actin filament reorganization in astrocyte networks is a key functional step in neuroinflammation resulting in persistent pain: novel findings on network restoration. AB - In recent years, the importance of glial cell activation in the generation and maintenance of long-term pain has been investigated. One novel mechanism underlying long-lasting pain is injury-induced inflammation in the periphery, followed by microglial activation in the dorsal horn of the spinal cord, which results in local neuroinflammation. An increase in neuronal excitability may follow, with intense signaling along the pain tracts to the thalamus and the parietal cortex along with other cortical regions for the identification and recognition of the injury. If the local neuroinflammation develops into a pathological state, then the astrocytes become activated. Previous studies in which lipopolysaccharide (LPS) was used to induce inflammation have shown that in a dysfunctional astrocyte network, the actin cytoskeleton is reorganized from the normally occurring F-actin stress fibers into the more diffusible, disorganized, ring-form globular G-actin. In addition, Ca(2+) signaling systems are altered, Na(+)- and glutamate transporters are downregulated, and pro-inflammatory cytokines, particularly IL-1beta, are released in dysfunctional astrocyte networks. In a series of experiments, we have demonstrated that these LPS-induced changes in astrocyte function can be restored by stimulation of Gi/o and inhibition of Gs with a combination of a MU-receptor agonist and ultralow concentrations of a MU-receptor antagonist and by inhibition of cytokine release, particularly IL-1beta, by the antiepileptic drug levetiracetam. These findings could be of clinical significance and indicate a novel treatment for long-term pain. PMID- 24952071 TI - Mechanistic studies for monodisperse exenatide-loaded PLGA microspheres prepared by different methods based on SPG membrane emulsification. AB - Poly(DL-lactic-co-glycolic acid) (PLGA) microspheres have been widely prepared by many methods, including solvent evaporation, solvent extraction and the co solvent method. However, very few studies have compared the properties of microspheres fabricated by these methods. This is partly because the broad size distribution of the resultant particles severely complicates the analysis and affects the reliability of the comparison. To this end, uniform-sized PLGA microspheres have been prepared by Shirasu porous glass premix membrane emulsification and used to encapsulate exenatide, a drug for treating Type 2 diabetes. Based on this technique, the influences on the properties of microspheres fabricated by the aforementioned three methods were intensively investigated, including in vitro release, degradation and pharmacology. We found that these microspheres presented totally different release behaviors in vitro and in vivo, but exhibited a similar trend of PLGA degradation. Moreover, the internal structural evolution visually demonstrated these release behaviors. We selected for further examination the microsphere prepared by solvent evaporation because of its constant release rate, and explored its pharmacodynamics, histology, etc., in more detail. This microsphere when injected once showed equivalent efficacy to that of twice-daily injections of exenatide with no inflammatory response. PMID- 24952069 TI - Does family history of depression predict major depression in midlife women? Study of Women's Health Across the Nation Mental Health Study (SWAN MHS). AB - This study aims to determine whether family history of depression predicts major depression in midlife women independent of psychosocial and health profiles at midlife. Participants were 303 African American and Caucasian women (42-52 years at baseline) recruited into the Study of Women's Health Across the Nation (SWAN) and the Women's Mental Health Study (MHS) in Pittsburgh. Major depression was assessed annually with the Structured Clinical Interview for DSM-IV. Family mental health history was collected at the ninth or tenth follow-up. Multivariable logistic regression was used to determine whether family history of depression predicted major depression in midlife, adjusting for covariates. The odds of experiencing major depression during the study were three times greater for those with a family history than for those without a family history (OR = 3.22, 95% CI = 1.95-5.31). Family history predicted depression (OR = 2.67, 95% CI = 1.50-4.78) after adjusting for lifetime history of depression, age, trait anxiety, chronic medical conditions, and stressful life events. In analyses stratified by lifetime history of depression, family history significantly predicted depression only among women with a lifetime history of depression. Family history of depression predicts major depression in midlife women generally, but particularly in those with a lifetime history of depression prior to midlife. PMID- 24952072 TI - Charge-selective fractions of naturally occurring nanoparticles as bioactive nanocarriers for cancer therapy. AB - A carnivorous fungus, Arthrobotrys oligospora, has been shown to secrete nanoparticles. In the present work, the potential of two charge-selective fractions of fungal nanoparticles (FNPs) as bioactive nanocarriers in cancer therapy is explored by investigating their immunostimulatory activities, cytotoxic mechanisms and in vitro immunochemotherapeutic effects. A surface charge-selective fractionation procedure to purify crude FNPs has been established, and two FNP fractions (i.e. FNP1 and FNP2), with different surface charges and similarly reduced diameters of 100-200nm, are obtained. Both FNP fractions enhance the secretion of multiple proinflammatory cytokines and chemokines from macrophages and splenocytes. However, FNP2 has stronger cytotoxicity than FNP1. It is FNP2 not FNP1 that could clearly inhibit cell proliferation by inducing apoptosis and arresting cells at the sub G0/G1 phase. Both the FNP fractions can form pH-responsive nanocomplexes with doxorubicin (DOX) via electrostatic interactions. For direct cytotoxicity, DOX-FNP2 complexes demonstrate higher activity than DOX against multiple tumor cells, while DOX-FNP1 complexes show weaker activity than DOX. Interestingly, in a co-culture experiment where splenocytes are co-cultured with tumor cells, both DOX-FNP complexes demonstrate higher cytotoxicity than DOX. In conclusion, this work proposes a combined therapeutics for cancer treatment using charge-selective fractions of FNPs as bioactive nanocarriers. PMID- 24952070 TI - Depressive symptoms in the second trimester relate to low oxytocin levels in African-American women: a pilot study. AB - Low-income African-American women report elevated prenatal depressive symptoms more often (42 %) than the national average (20 %). In the USA in 2012, 16.5 % of African-American women experienced a premature birth (less than 36 completed gestational weeks) compared to 10.3 % of white women. In addition, 13 % of African-American women had a low-birth weight infant (less than 2,500 g) compared to 7 % of white women. Variation in the neuropeptide, oxytocin has been implicated in perinatal depression, maternal behavior, regulation of stress responses, and may be associated with this health disparity. The purpose of this investigation was to examine factors associated with prenatal depressive symptoms, including plasma oxytocin levels and birth weight, in a sample of urban African-American women. Pregnant African-American women (N = 57) completed surveys and had blood drawn twice during pregnancy at 15-22 weeks and 25-37 weeks. In addition, birth data were collected from medical records. A large number of participants reported elevated prenatal depressive symptoms at the first (n = 20, 35 %) and the second (n = 19, 33 %) data points. Depressive symptoms were higher in multigravidas (t(51) = -2.374, p = 0.02), women with higher anxiety (r(47) = 0.71, p = 0.001), women who delivered their infants at an earlier gestational age (r(51) = -0.285, p = 0.04), and those without the support of the infant's father (F(4, 48) = 2.676, p = 0.04). Depressive symptoms were also higher in women with low oxytocin levels than in women with high oxytocin levels (F(2, 47) = 3.3, p = 0.05). In addition, women who had low oxytocin tended to have infants with lower birth weights (F(2, 47) = 2.9, p = 0.06). Neither prenatal depressive symptoms nor prenatal oxytocin levels were associated with premature birth. Pregnant multigravida African-American women with increased levels of anxiety and lacking the baby's father's support during the pregnancy are at higher risk for prenatal depressive symptoms. Prenatal depressive symptoms are associated with low oxytocin levels and lower infant birth weights. Further research is needed to understand the mechanisms between prenatal depressive symptoms, oxytocin, and birth weight in order to better understand this health disparity. PMID- 24952073 TI - IrOx-carbon nanotube hybrids: a nanostructured material for electrodes with increased charge capacity in neural systems. AB - Nanostructured iridium oxide-carbon nanotube hybrids (IrOx-CNT) deposited as thin films by dynamic electrochemical methods are suggested as novel materials for neural electrodes. Single-walled carbon nanotubes (SWCNT) serve as scaffolds for growing the oxide, yielding a tridimensional structure with improved physical, chemical and electrical properties, in addition to high biocompatibility. In biological environments, SWCNT encapsulation by IrOx makes more resistant electrodes and prevents the nanotube release to the media, preventing cellular toxicity. Chemical, electrochemical, structural and surface characterization of the hybrids has been accomplished. The high performance of the material in electrochemical measurements and the significant increase in cathodal charge storage capacity obtained for the hybrid in comparison with bare IrOx represent a significant advance in electric field application in biosystems, while its cyclability is also an order of magnitude greater than pure IrOx. Moreover, experiments using in vitro neuronal cultures suggest high biocompatibility for IrOx-CNT coatings and full functionality of neurons, validating this material for use in neural electrodes. PMID- 24952074 TI - Development of sustained antimicrobial-release systems using poly(2-hydroxyethyl methacrylate)/trimethylolpropane trimethacrylate hydrogels. AB - Reconstructive materials with sustained antimicrobial effects could be useful for preventing infectious diseases in an environment containing indigenous bacteria or fungi such as the oral cavity. With the objective of applying a non biodegradable hydrogel to resin-based materials as a reservoir for water-soluble antimicrobials, novel hydrogels consisting of 2-hydroxyethyl methacrylate (HEMA) and trimethylolpropane trimethacrylate (TMPT) were fabricated. Cetylpyridinium chloride (CPC) was loaded into five hydrogels comprising different ratios of HEMA/TMPT, and their ability to release as well as to be recharged with CPC was examined in vitro. A polyHEMA/TMPT hydrogel comprising 50% HEMA/50% TMPT could be effectively loaded and recharged with CPC by immersion into a CPC solution, demonstrating the longest release of CPC, above the concentration required to inhibit bacteria and fungi. The binding of CPC to the hydrogels was mainly through hydrophobic interaction. Loading of CPC into a hydrogel by mixing CPC powder with the HEMA/TMPT monomer before polymerization resulted in marked extension of the initial CPC-release period. The CPC-pre-mixed hydrogel was confirmed to exhibit antibacterial activity by agar diffusion tests. It is possible to achieve a sustained release system for antimicrobials by pre-mix loading and recharging CPC into a 50% HEMA/50% TMPT hydrogel. PMID- 24952075 TI - Comparable constitutive expression and activity of cytochrome P450 between the lobes of the porcine liver. AB - Due to limited availability of human liver tissue for the study of cytochrome P450 (CYP450), porcine liver tissue has been suggested as an alternative source to prepare microsomes and hepatocytes. The porcine liver is made by four different lobes. The present study investigated the expression and activity of specific CYP450 isoforms in the four lobes, with the purpose to examine if one lobe of the porcine liver resembles the human more than others. Samples from the four major lobes were taken from female pigs and mRNA expression and activity of CYP1A, 2A, 2C, 2D, 2E and 3A determined. The results showed no differences in specific mRNA expression and activity of any of the investigated CYP450 isoforms. In conclusion, the study shows that all parts of the porcine liver are equally useful as model tissue. PMID- 24952076 TI - Occult risk of broken instruments for endoscopy-assisted surgery. AB - BACKGROUND: The influence of broken sophisticated surgical instruments on the safety of surgery has yet to be determined, in spite of an assumption that breakage of surgical instruments is not associated with critical incidents. The purpose of the present study was to delineate the risk from breakage of surgical instruments used in surgery assisted by endoscopy. METHODS: A retrospective analysis was conducted to determine the frequency of breakage of instruments used in 39,817 operations from 2007 to 2011. Data of breakage were collected using incident/near-incident reports and the request forms for repair of broken instruments. RESULTS: During the study period, 441 instruments were reported to be broken intraoperatively, and 7,541 were found to be broken on inspection. The incidence of breakage adjusted by the number of operations and the number of uses suggested that instruments for endoscopy-assisted surgery are broken more frequently intraoperatively than are any other type of instruments (visceral surgery: 0.039 versus 0.017, P = 0.0002, RR = 2.318; obstetrics/gynecology: 0.023 versus 0.0067, P < 0.0001, RR = 3.461; thoracic surgery: 0.019 versus 0.004, P = 0.0772, RR = 5.212). Inappropriate use and wearing out were two major possible causes of breakage of instruments. The predominant adverse events were suggested to be attributable to parts falling off broken instruments because of inappropriate use. CONCLUSIONS: Our results demonstrated that surgery assisted by endoscopy has its own occult risk, which has not been previously highlighted. Minimally invasive surgery is not necessarily safe with respect to breakage of surgical instruments. Our data provide substantial evidence for higher risk of instrument breakage in endoscopy-assisted surgery, as well as its possible detrimental effect on patient safety. PMID- 24952077 TI - Clinical strategy for the reconstruction of middle hepatic vein tributaries in right liver living donor liver transplantation. AB - BACKGROUND: Venous drainage of the right paramedian sector (segments V and VIII), which is mainly via the middle hepatic vein (MHV), remains the major concern when using a right liver graft in living donor liver transplantation (LDLT). We herein describe our approach to decision making in the reconstruction of MHV tributaries in LDLT using a right liver graft without the MHV trunk. METHODS: A total of 77 consecutive right liver LDLTs were performed between January 2011 and December 2012. The MHV trunk was not taken with the graft, and all MHV tributaries were ligated during donor hepatectomy. The right liver graft was subsequently assessed on the back table for congestion in the right paramedian sector as an indicator for the need to reconstruct MHV tributaries. RESULTS: Based on the algorithm, reconstruction of MHV tributaries was performed in 18 patients (23.4 %). Although a mild degree of congestion in the right paramedian sector was noted in a few liver grafts without venous reconstruction, this congestion was well tolerated by recipients and was not visible afterward. The recipients' outcomes were similar in groups with and without venous reconstruction, and the 1-year survival rates were 83.3 and 86.2 %, respectively. CONCLUSION: A right liver graft without the MHV trunk can be successfully performed in LDLT with a satisfactory outcome. However, these experiences show that this approach might be safely applied as a strategy for determining the necessity of reconstruction of MHV tributaries in a right liver graft without the MHV trunk in LDLT. PMID- 24952078 TI - Is the outcome of a salvage surgery for T4 thoracic esophageal squamous cell carcinoma really poor? AB - BACKGROUND: Among patients with T4 thoracic esophageal squamous cell carcinoma (TESCC), it is unclear whether the outcomes of late responders who undergo high dose chemoradiotherapy (CRT) followed by salvage esophagectomy differs from those of early responders who undergo low-dose CRT followed by esophagectomy. METHODS: A total of 153 patients with T4 TESCC were treated with CRT. The first evaluation was performed after 40 Gy of CRT for downstaging. Of these, 28 patients could be downstaged, and underwent subsequent surgery (early responders). For the remaining patients, additional CRT was administered, and patients were re evaluated after treatment and underwent salvage surgery. In total, 40 patients (early + late responders) were analyzed. RESULTS: The primary tumors exhibited a grade 3 response in six (21.4 %) of the early responders and two (16.7 %) of the late responders (p = 1.000). The rate of residual tumor in the primary tumor was 80 % (32/40 patients). The proportions of resected lymph nodes and positive metastatic nodes were similar between early and late responders (p = 0.406 and p = 0.859, respectively). The 5-year overall survival rates among the early and late responders were 25.9 and 36.5 %, respectively, and the median survival times were 24.8 and 24.3 months (p = 0.925), respectively. The 5-year cause-specific survival rates in the early and late responder groups were 61.5 and 72.9 % (p = 0.425), respectively. CONCLUSION: The outcomes of both early and late responders to CRT were similar, and salvage surgery for T4 TESCC outweighs the risks in patients with T4 TESCC. PMID- 24952080 TI - Quality of Life after Minimally Invasive Versus Open Esophagectomy. PMID- 24952079 TI - Preoperative biliary drainage of severely jaundiced patients increases morbidity of pancreaticoduodenectomy: results of a case-control study. AB - BACKGROUND: Recent studies have indicated that preoperative biliary drainage (PBD) should not be routinely performed in patients suffering from obstructive jaundice before surgery. The severity of jaundice that mandates PBD has yet to be defined. Our aim was to investigate whether PBD is truly justified in severely jaundiced patients before pancreaticoduodenectomy. The parameters evaluated were overall morbidity, length of hospital stay, and total in-hospital mortality. METHODS: From January 2000 to December 2012, a total of 240 patients underwent pancreaticoduodenectomy for periampullary tumors. Group A comprised 76 patients with preoperative serum bilirubin >=15 mg/dl who did not undergo PBD before surgery. Group B comprised another 76 patients, matched for age and tumor localization (papillary vs. pancreatic head) who underwent PBD 2-4 weeks before pancreaticoduodenectomy and were identified from the same database. RESULTS: Less operative time was required in the 'no PBD' group compared with the 'PBD' group (210 vs. 240 min). Total intraoperative blood loss and blood transfusions were also significantly less in the 'no PBD' group. There was no difference detected in the rate of pancreatic fistula or biliary fistula formation. Group A patients demonstrated significantly lower morbidity than group B (24 vs. 36 %, respectively) and therefore required briefer hospitalization (11 vs. 16 days). Mild infectious complications appear to be the main factor that enhanced morbidity in the PBD group. However, total in-hospital mortality was not significantly different between the two groups. CONCLUSIONS: Even severe jaundice should not be considered as an indication for PBD before pancreaticoduodenectomy, as PBD increases infections and postoperative morbidity, therefore delaying definite treatment. PMID- 24952081 TI - Withholding tragic knowledge may lead to a tragic death: a palliative care perspective. PMID- 24952082 TI - Resistance to noise-induced hearing loss in 129S6 and MOLF mice: identification of independent, overlapping, and interacting chromosomal regions. AB - Noise-induced hearing loss (NIHL) is a prevalent health risk. Inbred mouse strains 129S6/SvEvTac (129S6) and MOLF/EiJ (MOLF) show strong NIHL resistance (NR) relative to CBA/CaJ (CBACa). In this study, we developed quantitative trait locus (QTL) maps for NR. We generated F1 animals by intercrossing (129S6 * CBACa) and (MOLF * CBACa). In each intercross, NR was recessive. N2 animals were produced by backcrossing F1s to their respective parental strain. The 232 N2 129S6 and 225 N2-MOLF progenies were evaluated for NR using auditory brainstem response. In 129S6, five QTL were identified on chromosomes (Chr) 17, 18, 14, 11, and 4, referred to as loci nr1, nr2, nr3, nr4, and nr5, respectively. In MOLF, four QTL were found on Chr 4, 17, 6, and 12, referred to as nr7, nr8, nr9, and nr10, respectively. Given that NR QTL were discovered on Chr 4 and 17 in both the N2-129S6 and N2-MOLF cross, we generated two consomic strains by separately transferring 129S6-derived Chr 4 and 17 into an otherwise CBACa background and a double-consomic strain by crossing the two strains. Phenotypic analysis of the consomic strains indicated that whole 129S6 Chr 4 contributes strongly to mid frequency NR, while whole 129S6 Chr 17 contributes markedly to high-frequency NR. Therefore, we anticipated that the double-consomic strain containing Chr 4 and 17 would demonstrate NR across the mid- and high-frequency range. However, whole 129S6 Chr 17 masks the expression of mid-frequency NR from whole 129S6 Chr 4. To further dissect NR on 129S6 Chr 4 and 17, CBACa.129S6 congenic strains were generated for each chromosome. Phenotypic analysis of the Chr 17 CBACa.129S6 congenic strains further defined the NR region on proximal Chr 17, uncovered another NR locus (nr6) on distal Chr 17, and revealed an epistatic interaction between proximal and distal 129S6 Chr 17. PMID- 24952084 TI - Letter to the editor: Editorial: Transition from training to practice--is there a better way? PMID- 24952083 TI - Systemic lipopolysaccharide compromises the blood-labyrinth barrier and increases entry of serum fluorescein into the perilymph. AB - The blood vessels that supply the inner ear form a barrier between the blood and the inner ear fluids to control the exchange of solutes, protein, and water. This barrier, called the blood-labyrinth barrier (BLB) is analogous to the blood-brain barrier (BBB), which plays a critical role in limiting the entry of inflammatory and infectious agents into the central nervous system. We have developed an in vivo method to assess the functional integrity of the BLB by injecting sodium fluorescein into the systemic circulation of mice and measuring the amount of fluorescein that enters perilymph in live animals. In these experiments, perilymph was collected from control and experimental mice in sequential samples taken from the posterior semicircular canal approximately 30 min after systemic fluorescein administration. Perilymph fluorescein concentrations in control mice were compared with perilymph fluorescein concentrations after lipopolysaccharide (LPS) treatment (1 mg/kg IP daily for 2 days). The concentration of perilymphatic fluorescein, normalized to serum fluorescein, was significantly higher in LPS treated mice compared to controls. In order to assess the contributions of perilymph and endolymph in our inner ear fluid samples, sodium ion concentration of the inner ear fluid was measured using ion-selective electrodes. The sampled fluid from the posterior semicircular canal demonstrated an average sodium concentration of 145 mM, consistent with perilymph. These experiments establish a novel technique to assess the functional integrity of the BLB using quantitative methods and to provide a comparison of the BLB to the BBB. PMID- 24952085 TI - Not the last word: The ACGME core competencies are overrated. PMID- 24952086 TI - Herbivore defence compounds occur in pollen and reduce bumblebee colony fitness. AB - Herbivory defence chemicals in plants can affect higher trophic levels such as predators and parasitoids, but the impact on pollinators has been overlooked. We show that defensive plant chemicals can damage pollinator fitness when expressed in pollen. Crop lupins (Lupinus species from Europe and South America) accumulate toxic quinolizidine alkaloids in vegetative tissues, conferring resistance to herbivorous pests such as aphids. We identified the alkaloid lupanine and its derivatives in lupin pollen, and then provided this compound at ecologically relevant concentrations to queenless microcolonies of bumblebees (Bombus terrestris) in their pollen to determine how foraging on these crops may impact bee colony health and fitness. Fewer males were produced by microcolonies provided with lupanine-treated pollen and they were significantly smaller than controls. This impact on males was not linked to preference as workers willingly fed lupanine-treated pollen to larvae, even though it was deleterious to colony health. Agricultural systems comprising large monocultures of crops bred for herbivore resistance can expose generalist pollinators to deleterious levels of plant compounds, and the broader environmental impacts of crop resistance must thus be considered. PMID- 24952087 TI - Effect of dietary supplementation of probiotics and palm fruits extracts on the antioxidant enzyme gene expression in the mucosae of gilthead seabream (Sparus aurata L.). AB - Antioxidant activity is particularly important, since oxidation is an unavoidable reaction in all living bodies. At present, natural antioxidants to be used on food as an alternative to synthetic ones are being sought. Gilthead seabream (Sparus aurata L.) specimens were fed for 4 weeks with diets enriched with bacterial probiotics (Shewanella putrefaciens Pdp11 and Bacillus sp), single or in combination with Tunisian dates palm fruit extracts. The expression of the main antioxidant enzyme genes (superoxide dismutase, catalase and glutathione reductase) in the mucosae (gut, skin and gill) was evaluated after 2 and 4 weeks. Previously, free radical scavenging and several antioxidant assays were developed to know the antioxidant properties present on the palm fruits extracts. The results demonstrated that experimental diets alter the expression of the studied antioxidant genes, primarily in the gill and skin. Furthermore, the tested probiotics and mainly, the aqueous date palm fruits extracts had significant antioxidant properties based on their protective effect against the levels of intracellular reactive oxygen species, especially when administering during 4 weeks. For this reason, probiotics and date palm fruit extracts may serve as good natural antioxidants and could potentially be considered as a functional food ingredient for fish in farms. PMID- 24952088 TI - A galectin with quadruple-domain from red abalone Haliotis rufescens involved in the immune innate response against to Vibrio anguillarum. AB - Galectins are proteins that recognize and bind specifically beta-galactosidase residues, playing important roles in the innate immune response of vertebrates and invertebrates. The cDNA of a tandem repeat galectin from the red abalone Haliotis rufescens cDNA (HrGal) was cloned and characterized using rapid amplification of cDNA end technique. The full-length cDNA of HrGal was 2471 bp, with a 5' terminal untranslated region (UTR) of 131 bp, a 3' UTR of 672 pb, and an open reading frame (ORF) of 1668 bp encoding a polypeptide of 556 amino acid. The ORF contains four domains carbohydrate recognition (CRD) with typical conserved motifs, which are important for carbohydrate recognition, and it appear to posses neither a signal peptide nor a transmembrane domain. The deduced amino acid sequence and the multi-domain organization of HrGal were highly similar to those described for other tandem repeat galectins of invertebrate organisms. Quantitative real time PCR analyses indicated that HrGal mRNA was highly expressed in hemocytes and gills tissues. The temporal expression of HrGal mRNA in hemocytes challenged to Vibrio anguillarum was time-dependent, showing u regulation at 32 h post challenge. The results suggest that HrGal may be involved in the immune innate response against bacterial infection. PMID- 24952089 TI - Synthesis, aggregation and spectroscopic studies of novel water soluble metal free, zinc, copper and magnesium phthalocyanines and investigation of their anti bacterial properties. AB - In this study, novel phthalonitrile derivative (3) was synthesized by the reaction between 4-nitrophthalonitrile (2) and a triazole derivative (1) containing pyridine moiety. Crystal structure of compound (3) was characterized by X-ray diffraction. New metal free and metallo-phthalocyanine complexes (Zn, Cu, and Mg) were synthesized using the phthalonitrile derivative (3). Cationic derivatives of these phthalocyanines (5, 7, 9, and 11) were prepared from the non ionic phthalocyanines (4, 6, 8, and 10). All proposed structures were supported by instrumental methods. The aggregation behaviors of the phthalocyanines (4-11) were investigated in different solvents such as dimethylsulfoxide (DMSO), N,N dimethylformamide (DMF), chloroform and water. Water soluble cationic Pcs (5, 7, 9, and 11) aggregated in water and sodium dodecyl sulfate was used to prevent the aggregation. The second derivatives of the UV-Vis spectra of aggregated Pcs were used for analyzing the Q and B bands of aggregated species. Thermal behaviors of the phthalocyanines were also studied. In addition, anti-bacterial properties of the phthalocyanines were investigated. We used four gram negative and two gram positive bacteria to determine antibacterial activity of these compounds. Compound 7 has the best activity against the all bacteria with 125MUg/mL of MIC value. Compounds 4, 6, and 10 have the similar effect on the bacteria with 250MUg/mL of MIC value. PMID- 24952090 TI - Preparation of manganese(II), chromium(III) and ferric(III) oxides nanoparticles in situ metal citraconate complexes frameworks. AB - The new reactions of some divalent and trivalent transition metal ions (Mn(II), Cr(III), and Fe(III)) with citraconic acid has been studied. The obtained results indicate the formation of citraconic acid compounds with molar ratio of metal to citraconic acid of 2:2 or 2:3 with general formulas Mn2(C5H4O4)2 or M2(C5H4O4)3?nH2O where n=6 for Cr, and Fe(III). The thermal decomposition of the crystalline solid complexes was investigated. The IR spectra of citraconate suggested that the carboxylic groups are bidentatically bridging and chelating. In the course of decomposition the complexes are dehydrated and then decompose either directly to oxides in only one step or with intermediate formation of oxocarbonates. This proposal dealing the preparation of MnO2, Fe2O3 and Cr2O3 nanoparticles. The crystalline structure of oxide products were checked by X-ray powder diffraction (XRD), and the morphology of particles by scanning electron microscopy (SEM). PMID- 24952091 TI - Helminth infections predispose mice to pneumococcal pneumonia but not to other pneumonic pathogens. AB - Pneumonia is the leading killer of children worldwide. Here, we report that helminth-infected mice develop fatal pneumonia when challenged with Streptococcus pneumoniae. Mice were chronically infected with either the flatworm Taenia crassiceps or the roundworm Heligmosomoides polygyrus. Upon challenge with a pneumonic type 3 strain of S. pneumoniae (A66.1), the worm-infected mice developed pneumonia at a rate and to a degree higher than age-matched control mice as measured by bioluminescent imaging and lung titers. This predisposition to pneumonia appears to be specific to S. pneumoniae, as worm-infected mice did not show evidence of increased morbidity when challenged with a lethal dose of influenza virus or sublethal doses of Staphylococcus aureus or Listeria monocytogenes. The defect was also present when worm-infected mice were challenged with a type 2 sepsis-causing strain (D39); an increased rate of pneumonia, decreased survival, and increased lung and blood titers were found. Pneumococcal colonization and immunity against acute otitis media were unaffected. Anti-helminthic treatment in the H. polygyrus model reversed this susceptibility. We conclude that helminth coinfection predisposes mice to fatal pneumococcal pneumonia by promoting increased outgrowth of bacteria in the lungs and blood. These data have broad implications for the prevention and treatment for pneumonia in the developing world, where helminth infections are endemic and pneumococcal pneumonia is common. PMID- 24952093 TI - Differential vulnerability to the punishment of cocaine related behaviours: effects of locus of punishment, cocaine taking history and alternative reinforcer availability. AB - BACKGROUND: The availability of alternative reinforcement has been shown to reduce drug use, but it remains unclear whether it facilitates a reduction or cessation of drug seeking or taking. OBJECTIVES: We compared the effects of punishment of cocaine seeking or taking behaviour after brief or extended cocaine taking histories when behavioural reallocation was facilitated or not by making available an alternative ingestive reinforcer (sucrose). METHODS: In the first experiment, punishment of either seeking or taking responses was introduced immediately after training on the seeking-taking chained schedule. In the second experiment, punishment of cocaine seeking was introduced after 12 additional days of either 1 or 6 h daily access to cocaine self-administration. In both experiments, beginning 1 week before the introduction of punishment, a subset of rats had concurrent nose poke access to sucrose while seeking or taking cocaine. RESULTS: The presence of an alternative source of reinforcement markedly facilitated behavioural reallocation from punished cocaine taking after acquisition. It also facilitated punishment-induced suppression of cocaine seeking after an extensive cocaine self-administration history likely by prompting goal-directed motivational control over drug use. However, a significant proportion of rats were deemed compulsive-maintaining drug use after an extensive cocaine history despite the presence of abstinence-promoting positive and negative incentives. CONCLUSION: Making available an alternative reinforcer facilitates disengagement from punished cocaine use through at least two different processes but remains ineffective in a subpopulation of vulnerable animals, which continued to seek cocaine despite the aversive consequence of punishment and the presence of the alternative positive reinforcer. PMID- 24952095 TI - Electronic cigarettes: the road ahead. AB - Electronic cigarettes (e-cig) are proliferating in the world's lucrative nicotine delivery market at an alarmingly fast pace. E-cig are aggressively marketed as an alternative to conventional tobacco cigarettes, although very little is known about the health consequences of e-cig use. Chemical analysis of e-cig vapor/liquid has shown that many toxicants and carcinogens present in cigarette smoke are also found, albeit generally in lower concentrations, in a wide range of e-cig products. Notwithstanding the presence of toxicants and carcinogens in e cig products, the biological effects of exposure to these contaminants have not been determined in e-cig users. The ongoing research and future investigations on e-cig initiation, use, perceptions, dependence, and toxicity are expected to provide empirical evidence that can be used to inform the general public, scientific community, and regulatory authorities of the health risks/benefits associated with e-cig use. This information will help stimulate scientists in the field of tobacco research, as well as assist the regulatory agencies in making scientifically based decisions on the development and evaluation of regulations on tobacco products to protect the public's health. Finding the scientific underpinnings for the health risks/benefits of e-cig use can impact millions of people who are increasingly turning to e-cig as a replacement for or complement to conventional tobacco cigarettes. PMID- 24952094 TI - Receipt of pertussis vaccine during pregnancy across 7 Vaccine Safety Datalink sites. AB - OBJECTIVE: In response to widespread pertussis outbreaks and infant deaths, in 2010, the California Department of Health (CDPH) and in 2011 the Advisory Committee on Immunization Practices (ACIP) advised that the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine be administered during pregnancy. The goals of this study were to describe Tdap coverage among pregnant women following these recommendations. METHODS: In this observational cohort study, we utilized electronic medical record and claims data from seven Vaccine Safety Datalink sites to identify pregnancies and Tdap administrations. All Tdap doses were classified as pre-pregnancy, during pregnancy or post pregnancy/postpartum. For pregnancies ending in a live birth, we evaluated factors associated with Tdap vaccination. RESULTS: Among 289,141 live births at the California VSD sites, receipt of Tdap during pregnancy increased substantially in the years 2010, 2011, and 2012, when coverage was 15.9, 30.0 and 19.5%, respectively. Among 82,398 women with live births at the Oregon, Washington, Colorado, Wisconsin and Minnesota VSD sites, receipt of Tdap during pregnancy first increased in 2012, at 16.0%. Women receiving early prenatal care and other vaccine(s) during pregnancy had higher Tdap coverage. CONCLUSION: We observed substantial increases in Tdap coverage during pregnancy following CDPH and ACIP recommendations. PMID- 24952092 TI - Sex differences in neurosteroid and hormonal responses to metyrapone in posttraumatic stress disorder. AB - RATIONALE: Mechanisms contributing to sex differences in the regulation of acute stress responsivity and their effect on the increased incidence of posttraumatic stress disorder (PTSD) in women are poorly understood. The reproductive hormone, progesterone, through conversion to allopregnanolone (ALLO), suppresses the hypothalamic pituitary adrenal (HPA) axis and has potent anxiolytic effects. The potential that progesterone and allopregnanolone reactivity modulate HPA axis responses and account for sex differences in PTSD has not been previously examined. OBJECTIVE: The present study examined the effects of sex and PTSD on adrenocorticotropic hormone (ACTH), progesterone, and allopregnanolone responses to metyrapone and whether progesterone and allopregnanolone reactivity could affect the ACTH response in PTSD. METHODS: Healthy medication-free male and premenopausal follicular phase female participants with chronic PTSD (n = 43; 49 % female) and controls (n = 42; 50 % female) completed an overnight metyrapone challenge and ACTH, progesterone, and allopregnanolone were obtained by repeated blood sampling. RESULTS: The increase in ACTH response to metyrapone was higher in PTSD subjects compared to controls and in women compared to men. Contrary to our initial prediction of an inverse relationship, progesterone and allopregnanolone were positively associated with ACTH. Progesterone and allopregnanolone partially mediated the relationship between PTSD and ACTH. CONCLUSIONS: Our findings of increased ACTH to metyrapone in PTSD and in women may reflect heightened hypothalamic CRF hypersecretion. Progesterone and allopregnanolone partially mediated the ACTH response in PTSD. Further characterizing sex differences in these processes will advance our understanding of the pathophysiology of PTSD, and may ultimately lead to better-targeted, more effective treatment. PMID- 24952096 TI - Use of single nucleotide polymorphisms and haplotypes to identify genomic regions associated with protein content and water-soluble protein content in soybean. AB - KEY MESSAGE: Four major SPC-specific loci were identified, and these accounted for 8.5-15.1 % of the phenotypic variation, thus explaining why certain soybean varieties have a high PC but a low SPC. Water-soluble protein content (SPC) is a critical factor in both food quality and the production of isolated soybean proteins. However, few data are available regarding the genetic control and the mechanisms contributing to elevated SPC. In this study, a soybean collection of 192 accessions from a wide geographic range was used to identify genomic regions associated with soybean protein content (PC) and SPC using an association mapping approach employing 1,536 SNP makers and 232 haplotypes. The diverse panel revealed a large genetic variation in PC and SPC. Association mapping was performed using three methods to minimize false-positive associations. This resulted in 4/8 SNPs and 3/6 haplotypes that were significantly associated with soybean PC/SPC in two or more environments based on the mixed model. An SNP that was highly significantly associated with PC, BARC-021267-04016, was localized 0.28 cM away from a published glycinin gene, G7, and was detected across all four environments. Four major SPC-specific loci, BARC-029149-06088, BARC-018023-02499, BARC-041663-08059 and haplotype 15 (hp15), were stably identified on chromosomes five and eight and explained 8.5-15.1 % of the phenotypic variation. Moreover, a glutelin type-B 2-like gene was identified on chromosome eight and may be related to soybean protein solubility. These markers, which are located in previously reported QTL, reconfirmed previous findings and may be important targets for the identification of protein-related genes. These novel SNPs and haplotypes are important for further understanding the genetic basis of PC and SPC. In addition, by comparing the correlation and genetic loci between PC and SPC, we provide new insights into why certain soybean varieties have a high protein content but a low SPC. PMID- 24952098 TI - Red ginseng delays age-related hearing and vestibular dysfunction in C57BL/6 mice. AB - Since Korean red ginseng (KRG) has been proven to protect against gentamicin induced vestibular and hearing dysfunction, the effects of KRG on age-related inner ear disorder in C57BL/6 mice were investigated. While age-related hearing loss was detected at the age of 6months (32kHz) and 9months (16kHz) in the control group, it was significantly delayed (p<0.05) in the 150mg/kg KRG-treated group. Vestibular dysfunction was observed in the tail-hanging and swimming tests, with significantly different severity scores and swimming times detected between the control and 150mg/kg KRG-treated group at the age of 12months (p<0.05). Mice treated with 500mg/kg KRG exhibited irritability and aggravated inner ear dysfunction. Histological observation supported the findings of hearing and vestibular function defects. In conclusion, C57BL/6 mice showed early-onset hearing loss and progressive vestibular dysfunction with aging, which were delayed by treatment with 150mg/kg KRG. However, 500mg/kg KRG treatment may induce aggressive behavior. PMID- 24952099 TI - Ear decomposition of 3-regular polyhedral links with applications. AB - In this paper, we introduce a notion of ear decomposition of 3-regular polyhedral links based on the ear decomposition of the 3-regular polyhedral graphs. As a result, we obtain an upper bound for the braid index of 3-regular polyhedral links. Our results may be used to characterize and analyze the structure and complexity of protein polyhedra and entanglement in biopolymers. PMID- 24952097 TI - Reconceptualizing balance: attributes associated with balance performance. AB - Balance tests are commonly used to screen for impairments that put older adults at risk for falls. The purpose of this study was to determine the attributes that were associated with balance performance as measured by the Frailty and Injuries: Cooperative Studies of Intervention Techniques (FICSIT) balance test. This study was a cross-sectional secondary analysis of baseline data from a longitudinal cohort study, the Boston Rehabilitative Impairment Study of the Elderly (Boston RISE). Boston RISE was performed in an outpatient rehabilitation research center and evaluated Boston area primary care patients aged 65 to 96 (N=364) with self reported difficulty or task-modification climbing a flight of stairs or walking 1/2 of a mile. The outcome measure was standing balance as measured by the FICSIT 4 balance assessment. Other measures included: self-efficacy, pain, depression, executive function, vision, sensory loss, reaction time, kyphosis, leg range of motion, trunk extensor muscle endurance, leg strength and leg velocity at peak power. Participants were 67% female, had an average age of 76.5 (+/-7.0) years, an average of 4.1 (+/-2.0) chronic conditions, and an average FICSIT-4 score of 6.7 (+/-2.2) out of 9. After adjusting for age and gender, attributes significantly associated with balance performance were falls self-efficacy, trunk extensor muscle endurance, sensory loss, and leg velocity at peak power. FICSIT-4 balance performance is associated with a number of behavioral and physiologic attributes, many of which are amenable to rehabilitative treatment. Our findings support a consideration of balance as multidimensional activity as proposed by the current International Classification of Functioning, Disability, and Health (ICF) model. PMID- 24952101 TI - Thermodynamic evaluation of immobilized cellulose tris(3,5 dichlorophenylcarbamate) as a stationary phase for liquid chromatographic separation of darunavir enantiomers. AB - Liquid chromatographic separation of darunavir (DRV) enantiomers was studied on Chiralpak IC column containing immobilized cellulose tris(3,5 dichlorophenylcarbamate) using a variety of mobile phase solvents at different temperatures. The separations were accomplished under normal phase conditions using different compositions of n-hexane, organic modifier (2-propanol, ethanol or 1-propanol) and diethyl amine (0.1%) as mobile phase solvents. The effect of volume and nature of organic modifier and column temperature on retention, separation and resolution were studied. Van't Hoff plots (ln k' vs 1/T) were drawn from the chromatographic retention data to calculate to apparent thermodynamic parameters and explain the interactions between the DRV enantiomers and cellulose tris(3,5-dichlorophenylcarbamate) immobilized on silica. PMID- 24952100 TI - The aggregation of tuna around floating objects: what could be the underlying social mechanisms? AB - Several empirical and theoretical studies have shown how the exploitation of food sources, the choice of resting sites or other types of collective decision-making in heterogeneous environments are facilitated and modulated by social interactions between conspecifics. It is well known that many pelagic fishes live in schools and that this form of gregarious behavior provides advantages in terms of food intake and predator avoidance efficiency. However, the influence of social behavior in the formation of aggregations by tuna under floating objects (FOBs) is poorly understood. In this work, we investigated the collective patterns generated by different theoretical models, which either include or exclude social interactions between conspecifics, in the presence of two aggregation sites. The resulting temporal dynamics and distributions of populations were compared to in situ observations of tuna behavior. Our work suggests that social interactions should be incorporated in aggregative behavior to reproduce the temporal patterns observed in the field at both the individual and the group level, challenging the common vision of tuna aggregations around FOBs. Our study argues for additional data to further demonstrate the role of social behavior in the dynamics of these fish aggregations. Understanding the interplay between environmental and social factors in the associative behavior of fish with FOBs is necessary to assess the consequences of the widespread deployment of artificial FOBs by fishermen. PMID- 24952102 TI - Condition-dependent chemosignals in reproductive behavior of lizards. AB - This article is part of a Special Issue "Chemosignals and Reproduction". Many lizards have diverse glands that produce chemosignals used in intraspecific communication and that can have reproductive consequences. For example, information in chemosignals of male lizards can be used in intrasexual competition to identify and assess the fighting potential or dominance status of rival males either indirectly through territorial scent-marks or during agonistic encounters. Moreover, females of several lizard species "prefer" to establish or spend more time on areas scent-marked by males with compounds signaling a better health or body condition or a higher genetic compatibility, which can have consequences for their mating success and inter-sexual selection processes. We review here recent studies that suggest that the information content of chemosignals of lizards may be reliable because several physiological and endocrine processes would regulate the proportions of chemical compounds available for gland secretions. Because chemosignals are produced by the organism or come from the diet, they should reflect physiological changes, such as different hormonal levels (e.g. testosterone or corticosterone) or different health states (e.g. parasitic infections, immune response), and reflect the quality of the diet of an individual. More importantly, some compounds that may function as chemosignals also have other important functions in the organism (e.g. as antioxidants or regulating the immune system), so there could be trade offs between allocating these compounds to attending physiological needs or to produce costly sexual "chemical ornaments". All these factors may contribute to maintain chemosignals as condition-dependent sexual signals, which can inform conspecifics on the characteristics and state of the sender and allow making behavioral decisions with reproductive consequences. To understand the evolution of chemical secretions of lizards as sexual signals and their relevance in reproduction, future studies should examine what information the signals are carrying, the physiological processes that can maintain the reliability of the message and how diverse behavioral responses to chemosignals may influence reproductive success. PMID- 24952103 TI - Cortisol mediates cleaner wrasse switch from cooperation to cheating and tactical deception. AB - Recent empirical research, mostly done on humans, recognizes that individuals' physiological state affects levels of cooperation. An individual's internal state may affect the payoffs of behavioural alternatives, which in turn could influence the decision to either cooperate or to defect. However, little is known about the physiology underlying condition dependent cooperation. Here, we demonstrate that shifts in cortisol levels affect levels of cooperation in wild cleaner wrasse Labroides dimidiatus. These cleaners cooperate by removing ectoparasites from visiting 'client' reef fishes but prefer to eat client mucus, which constitutes cheating. We exogenously administrated one of three different compounds to adults, that is, (a) cortisol, (b) glucocorticoid receptor antagonist mifepristone RU486 or (c) sham (saline), and observed their cleaning behaviour during the following 45min. The effects of cortisol match an earlier observational study that first described the existence of "cheating" cleaners: such cleaners provide small clients with more tactile stimulation with their pectoral and pelvic fins, a behaviour that attracts larger clients that are then bitten to obtain mucus. Blocking glucocorticoid receptors led to more tactile stimulation to large clients. As energy demands and associated cortisol concentration level shifts affect cleaner wrasse behavioural patterns, cortisol potentially offers a general mechanism for condition dependent cooperation in vertebrates. PMID- 24952105 TI - A mathematical model of a fishery with variable market price: sustainable fishery/over-exploitation. AB - We present a mathematical bioeconomic model of a fishery with a variable price. The model describes the time evolution of the resource, the fishing effort and the price which is assumed to vary with respect to supply and demand. The supply is the instantaneous catch while the demand function is assumed to be a monotone decreasing function of price. We show that a generic market price equation (MPE) can be derived and has to be solved to calculate non trivial equilibria of the model. This MPE can have 1, 2 or 3 equilibria. We perform the analysis of local and global stability of equilibria. The MPE is extended to two cases: an age structured fish population and a fishery with storage of the resource. PMID- 24952104 TI - Hypothalamic Kiss1 and RFRP gene expressions are changed by a high dose of lipopolysaccharide in female rats. AB - Reproductive function is suppressed by several types of stress. Hypothalamic kisspeptin, which is a product of the Kiss1 gene, and GnIH/RFRP have pivotal roles in the regulation of GnRH and gonadotropins through their receptors Kiss1r and GPR147 in many species. However, alterations of these factors under stress conditions have not been fully evaluated. This study investigated the mechanisms of immune stress-induced reproductive dysfunction, especially focusing on the changes of Kiss1 and RFRP gene expression. Serum LH levels and hypothalamic Kiss1 and GnRH mRNA levels were decreased, while hypothalamic RFRP and GPR147 mRNA levels were increased by administration of a high dose of LPS (5mg/kg) in both ovariectomized and gonadal intact female rats. In this condition, Kiss1 and/or RFRP mRNA levels were positively and negatively correlated with GnRH expression, respectively. In contrast, hypothalamic Kiss1, RFRP, and GPR147 mRNA levels were not changed by administration of a moderate dose of LPS (500MUg/kg) in ovariectomized rats. Rats with high-dose LPS injection showed more prolonged fever responses and severe anorexia compared with rats with moderate-dose LPS injection, indicating that more energy was used for the immune response in the former. These results suggest that the underlying mechanisms of dysfunction of gonadotropin secretion are changed according to the severity of immune stress, and that changes of some reserved factors, such as kisspeptin and RFRP, begin to participate in the suppression of GnRH and gonadotropin in severe conditions. As reproduction needs a large amount of energy, dysfunction of gonadotropin secretion under immune stress may be a biophylatic mechanism by which more energy is saved for the immune response. PMID- 24952106 TI - Clinical effectiveness of wireless CROS (contralateral routing of offside signals) hearing aids. AB - This study evaluated the clinical effectiveness of wireless contralateral routing of offside signals hearing aids (CROS) in patients with severe to profound unilateral sensorineural hearing loss (USNHL). Twenty-one patients with USNHL were enrolled in this prospective study. The change of subjective satisfaction was evaluated using three questionnaires (K-HHIE, K-IOI-HA, K-SSQ). Changes in objective measurements were evaluated with sound localization test (SLT) and hearing in noise test (HINT). These tests were performed at pre-CROS fitting, 2 and 4 weeks after use of CROS. Subjects were grouped according to the age: young (<40 years) vs. old (>=40 years) group. The average K-HHIE and K-SSQ scores significantly improved with the use of CROS. SLT result revealed that hit rate and error degree improved in the young group and lateralization ability improved in both groups. In quiet environments, the reception threshold for speech also indicated a significant benefit in the young group. When the noise was presented to the normal ear, HINT revealed benefit of CROS, while loss of performance with CROS use was significant when noise was presented to the impaired ear. Wireless CROS provided increased satisfaction and overall improvement of localization and hearing. Although true binaural hearing cannot be obtained, CROS is a practical option for rehabilitation of USNHL. PMID- 24952107 TI - Genetics of diabetic retinopathy. AB - Diabetic retinopathy (DR) is a polygenic disorder. Twin studies and familial aggregation studies have documented clear familial clustering. Heritability has been estimated to be as high as 27 % for any DR and 52 % for proliferative diabetic retinopathy (PDR), an advanced form of the disease. Linkage analyses, candidate gene association studies and genome-wide association studies (GWAS) performed to date have not identified any widely reproducible risk loci for DR. Combined analysis of the data from multiple GWAS is emerging as an important next step to explain the unaccounted heritability. Key factors to future discovery of the genetic underpinnings of DR are precise DR ascertainment, a focus on the more heritable disease forms such as PDR, stringent selection of control participants with regards to duration of diabetes, and methods that allow combination of existing datasets from different ethnicities to achieve sufficient sample sizes to detect variants with modest effect sizes. PMID- 24952108 TI - Type 1 diabetes and celiac disease: clinical overlap and new insights into disease pathogenesis. AB - Type 1 diabetes (T1D) and celiac disease (CD) are autoimmune diseases with clinical and pathogenic overlap. The mean prevalence of CD in patients with T1D is about 8 %. Classic intestinal symptoms of CD may not be present in T1D leading to the recommendation for active case finding in this higher risk group. Screening is done with sensitive and specific serologies including tissue transglutaminase (tTG) IgA and deaminated gliadin peptide (DGP) IgA and IgG. Positive serologies are confirmed by the presence of villous atrophy and increased intraepithelial lymphocytes on duodenal biopsy. A strict gluten free diet is recommended, although this can pose challenges for T1D patients who already have dietary restrictions. In aggregate, it appears as if the gluten free diet may help T1D management. T1D and CD have overlapping genetic and environmental risk factors. Among these, non-HLA genetic factors and the gut microbiome are among recent developments that will be discussed in this review. PMID- 24952109 TI - The relationships between demographic and clinical characteristics and quality of life during and after radiotherapy: in women with breast cancer. AB - PURPOSE: The purpose of this longitudinal study was to investigate quality of life (QOL) before, during, and after the course of radiotherapy (RT) and to identify risk factors for diminished QOL in women with breast cancer. METHODS: Patients (N = 188) completed the short-form 12 (SF-12), the Karnofsky Performance Status Scale, Memorial Symptom Assessment Scale, and the Self-Administrated Comorbidity Questionnaire 1 week prior to the start of RT. To assess changes in QOL, patients also completed the SF-12 1, 2, 3, and 6 months after the baseline. A random-intercept and slope model (mixed model) for each patient was used to estimate linear trends for the mental component score and physical component score of QOL (five time points for each patient). Descriptive statistics were used to analyze demographic and clinical characteristics. RESULTS: The physical component score (PCS) did not change significantly (p = 0.078) during the course of RT in women with breast cancer. An increase in the number of symptoms and a higher comorbidity profile was negatively related to the PCS. The mental component score (MCS) did not change from the start of RT until the 2-month assessment, but increased significantly after 2 months (p = 0.044). An increase in the number of symptoms was negatively related to the MCS. CONCLUSION: The MCS and PCS of QOL remained stable at a diminished level except for the MCS which improved between 2 and 6 months after the start of RT. The total number of symptoms was the only variable that was negatively associated with both component scores (MCS and PCS) during the 6 months. PMID- 24952110 TI - Physical activity and health-related quality of life: US adults with and without limitations. AB - PURPOSE: The purpose of this study was to examine the dose-response relationship between physical activity (PA) and health-related quality of life (HRQOL) among adults with and without limitations. METHODS: We dichotomized HRQOL as >=14 unhealthy (physical or mental) days (past 30 days), or <14 unhealthy days. By using a moderate-intensity minute equivalent, PA categories were as follows: inactive, 10-60, 61-149, 150-300, and >300 min/week. Persons with limitations reported having problems that limited their activities or required use of special equipment. Age-adjusted prevalence estimates and logistic regression analyses were performed with 2009 Behavioral Risk Factor Surveillance System data (n = 357,665), controlling for demographics, BMI, smoking, and heavy alcohol use. RESULTS: For adults without limitations, the odds of >=14 unhealthy days were lower among adults obtaining any PA (10-60 min/week, AOR = 0.79, 95 % CI 0.70, 0.88), compared with those inactive. A quadratic trend (P < 0.001) indicated enhanced HRQOL with each PA level, but improvements were less marked between lower and upper sufficient PA categories (150-300 and >300 min/week). Because of a significant age interaction, persons with limitations were stratified by age (18-34, 35-64, and 65+ years). Findings for persons aged 35 years or older with limitations were similar to those without limitations. Lower odds of poor HRQOL for persons aged 18-34 years with limitations were associated with recommended levels of PA (150-300 min/week; AOR = 0.61, 95 % CI 0.43, 0.88 and >300 min/week; AOR = 0.58, 95 % CI 0.43, 0.80). CONCLUSIONS: PA is positively associated with HRQOL among persons with and without limitations. PMID- 24952112 TI - The contribution of acetylcholine and dopamine to subprocesses of visual working memory--what patients with amnestic mild cognitive impairment and Parkinson's disease can tell us. AB - Attentional selection, i.e. filtering out of irrelevant sensory input and information storage are two crucial components of working memory (WM). It has been proposed that the two processes are mediated by different neurotransmitters, namely acetylcholine for attentional selection and dopamine for memory storage. However, this hypothesis has been challenged by others, who for example linked a lack in dopamine levels in the brain to filtering deficits. Here we tested the above mentioned hypothesis in two patient cohorts which either served as a proxy for a cholinergic or a dopaminergic deficit. The first group comprised 18 patients with amnestic mild cognitive impairment (aMCI), the second 22 patients with Parkinson's disease (PD). The two groups did not differ regarding their overall cognitive abilities. Both patient groups as well as a control group without neurological deficits (n=25) performed a visuo-spatial working memory task in which both the necessity to filter out irrelevant information and memory load, i.e. the number of items to be held in memory, were manipulated. In accordance with the primary hypothesis, aMCI patients displayed problems with filtering, i.e., were especially impaired when the task required ignoring distracting stimuli. PD patients on the other hand showed difficulties when memory load was increased suggesting that they mainly suffered from a storage deficit. In sum, this study underlines how the investigation of neurologic patients with a presumed neurotransmitter deficit can aid to clarify these neurotransmitters' contribution to specific cognitive functions. PMID- 24952111 TI - Accountability and empathy effects on medical students' clinical judgments in a disability determination context for low back pain. AB - Accountability has been shown to affect clinical judgments among health care providers in several ways. It may increase a provider's motivation for accuracy, leading to more deliberative judgments, or it may enhance biases that evaluators consistently demonstrate with patients with chronic pain. In this study, medical students read a vignette about a hypothetical patient referred for evaluation of severe low back pain by the Office of Vocational Rehabilitation. Accountability to the patient was either weak (consultative 1-time evaluation) or strong (ongoing primary care provision); societal accountability was either weak (evaluation information as secondary source for disability determination) or strong (evaluation information primary to disability determination). Participants then made judgments regarding validity of the patient's presentation, influence of psychosocial factors on the presentation, and patient's level of pain, distress, and disability, and completed an empathy measure. Results showed that empathy had strong associations with symptom validity and severity judgments. With empathy as a covariate, 3 crossover interactions emerged. Judgments of symptom validity were lower when the 2 forms of accountability were inconsistent (ie, one weak and the other strong) than when they were consistent (ie, both weak or both strong). Likewise, judgments of psychosocial factors and pain/distress/disability were higher under consistent accountability conditions than when accountability conditions were inconsistent. This pattern may imply conflict avoidance or self-protection as a motivation for judgments under inconsistent accountability. This study demonstrated that role demands can affect symptom judgments in complex ways, and that empathy may play both direct and moderating roles. Because physicians are the primary gatekeepers regarding disability determination in both consultative and treating roles, accountability may have significant mediating effects on such determinations. PERSPECTIVE: This study demonstrated that medical student judgments of pain-related symptoms were strongly associated with their levels of empathic concern. Student judgments of symptom validity and psychosocial influences on patient adjustment were differentially affected by their level of accountability to the patient and society in a disability determination process. PMID- 24952113 TI - Effects of the human antiepileptic drug carbamazepine on the behavior, biomarkers, and heat shock proteins in the Asian clam Corbicula fluminea. AB - Carbamazepine (CBZ), an anticonvulsant and mood-stabilizing pharmaceutical, is a widespread contaminant in aquatic environments. In this study, the effects of chronic exposure to environmentally relevant CBZ concentrations were investigated in freshwater clams Corbicula fluminea. Adult C. fluminea were exposed to 0.5, 5, and 50 MUg/L of CBZ for 30 days, after which siphoning behavior (filtration rates), biomarker levels, and heat shock protein expression were measured. The filtration rates were significantly decreased (p<0.05) by 50 MUg/L CBZ treatment, indicating a negative impact on C. fluminea health. Superoxide dismutase (SOD) and glutathione reductase (GR) activities were decreased, and catalase (CAT) activity and malondialdehyde (MDA) content were increased in the gills and digestive gland, suggesting that CBZ induced an oxidative effect. The levels of Hsp22, Hsp40, and Hsp70 mRNAs were also markedly induced after 5 or 50 MUg/L CBZ treatment (p<0.05), whereas Hsp60 and Hsp90 mRNAs in gills and Hsp60 mRNA in digestive gland were significantly repressed (p<0.05). Finally, the expression of Hsp70 protein was significantly increased (p<0.05) by 5 and 50 MUg/L exposure. In aggregate, these results confirm that environmentally relevant concentrations of CBZ can exert a negative effect on C. fluminea tissue at the molecular and protein level. PMID- 24952114 TI - Hypothalamic inflammation and the central nervous system control of energy homeostasis. AB - The control of energy homeostasis relies on robust neuronal circuits that regulate food intake and energy expenditure. Although the physiology of these circuits is well understood, the molecular and cellular response of this program to chronic diseases is still largely unclear. Hypothalamic inflammation has emerged as a major driver of energy homeostasis dysfunction in both obesity and anorexia. Importantly, this inflammation disrupts the action of metabolic signals promoting anabolism or supporting catabolism. In this review, we address the evidence that favors hypothalamic inflammation as a factor that resets energy homeostasis in pathological states. PMID- 24952115 TI - Brain as an endocrine source of circulating 5-hydroxytryptamine in ontogenesis in rats. AB - This study was aimed to test the authors' hypothesis stating that the developing brain before the closure of the blood brain barrier (BBB) operates as an endocrine organ that secretes classical neurotransmitters and neuropeptides into the general circulation. 5-Hydroxytryptamine (5-HT) was selected as a marker of brain endocrine activity though it is also secreted by peripheral organs. 5-HT was detected in blood of rats in a biologically active concentration at any studied age, from the 21st embryonic day till the 30th postnatal day. The brain was proven to be a source of circulating 5-HT before the BBB closure by showing that the 5-HT concentration in blood decreased significantly after the inhibition of 5-HT synthesis in the brain of neonates. The 5-HT concentration in blood was not diminished after the BBB closure, apparently due to compensatory increase of 5-HT secretion by peripheral sources. Thus, brain-derived 5-HT is delivered to the general circulation before the BBB closure being potentially capable of providing endocrine regulation of target organs. PMID- 24952116 TI - Small bite, big threat: World Health Day 2014. PMID- 24952117 TI - World Malaria Day 2014: invest in the future. Defeat malaria. PMID- 24952118 TI - Knowledge and perceptions of prescribers regarding adherence to standard treatment guidelines for malaria: a comparative cross-sectional study from Pakistan. AB - Despite the availability of standard treatment guidelines for malaria in Pakistan adherence to protocols by prescribers is poor. This descriptive, cross-sectional study aimed to explore the perceptions and knowledge of prescribers in Islamabad and Rawalpindi cities towards adherence to standard treatment guidelines for malaria. A questionnaire was distributed to a random sample of 360 prescribers; 64.7% were satisfied with the available antimalarial drugs and 41.3% agreed that antimalarial drugs should only be prescribed after diagnostic testing. Only half the prescribers had the guidelines available in their health facility. Almost all the prescribers (97.7%) agreed that there was a need for more educational programmes about the guidelines. Most prescribers were unaware of the correct standard treatment regimen for Plasmodium falciparum and P. vivax malaria. There were no differences in knowledge between males and females, but prescribers having more experience, practising as general practitioners and working in private health-care facilities possessed significantly better knowledge than their counterparts. PMID- 24952119 TI - Laboratory and field evaluation of two formulations of Bacillus thuringiensis M-H 14 against mosquito larvae in the Islamic Republic of Iran, 2012. AB - Due to low efficacy in the field of a local commercial product of Bacillus thuringiensis M-H-14 (Bioflash((r))), a study was designed to assess its efficacy in laboratory, glass standard aquarium, semi-field and field conditions at both target and higher dosages against immature stages of Anopheles spp. and Culex spp. In laboratory conditions, the LC50 values of wettable powder and granule formulations were 227 and 1031 ppm respectively against a susceptible strain of An. stephensi. Following application of wettable powder and granules at 56.1 mg/aquarium, the survival rates of the exposed larvae to the granule formulation were 65.6% and 54.2% on days 6 and 8 respectively. In the artificial ponds, the larval density was reduced to 38.9%, 39.3% and 65.1% at dosages of 2, 4 and 8 g/m(2) respectively. In rice fields, at a dosage of 2 kg/ha, the density of immature larvae were reduced to 33.1% and 28.6% 7-days post-treatment. Further investigations are needed for the reasons for the low efficacy of this larvicide. PMID- 24952120 TI - Study on validity of a rapid diagnostic test kit versus light microscopy for malaria diagnosis in Ahmedabad city, India. AB - Light microscopy of blood smears for diagnosis of malaria in the field has several limitations, notably delays in diagnosis. This study in Ahmedabad in Gujarat State, India, evaluated the diagnostic performance of a rapid diagnostic test for malaria (SD Bioline Malaria Ag P.f/Pan) versus blood smear examination as the gold standard. All fever cases presenting at 13 urban health centres were subjected to rapid diagnostic testing and thick and thin blood smears. A total of 677 cases with fever were examined; 135 (20.0%) tested positive by rapid diagnostic test and 86 (12.7%) by blood smear. The sensitivity of the rapid diagnostic test for malaria was 98.8%, specificity was 91.5%, positive predictive value 63.0% and negative predictive value 99.8%. For detection of Plasmodium falciparum the sensitivity of rapid diagnostic test was 100% and specificity was 97.3%. The results show the acceptability of the rapid test as an alternative to light microscopy in the field setting. PMID- 24952121 TI - Rapid diagnosis of schistosomiasis in Yemen using a simple questionnaire and urine reagent strips. AB - Schistosomiasis ranks second to malaria in terms of socioeconomic and public health importance in Yemen. This study assessed the validity of a morbidity questionnaire and urine reagent strips as a rapid tool for screening schoolchildren for urinary schistosomiasis as compared with the presence of eggs in urine as the gold-standard parasitological diagnosis. The study examined urine samples and interviewed 696 children (mean age 12.5 years) attending a primary preparatory school in south Yemen. Urinary schistosomiasis was confirmed in 126 (18.1%) children. Diagnostic performance was poor for 2 items in the morbidity questionnaire (self-reported history of previous infection and self-reported history of antischistosomal treatment). However, self-reported dysuria, self reported haematuria in the questionnaire and microhaematuria by reagent strips (alone or with macrohaematuria) revealed good diagnostic performance. The results indicated that reagent strips are a valid method for detection of microhaematuria for identifying individuals and communities infected with Schistosoma haematobium. PMID- 24952123 TI - [Causes of death in Tunisia: estimates of years of life lost]. AB - This study estimated the number of years of life lost (YLL) by cause due to premature death in Tunisia for the year 2006. We adopted the methodology (SEYLL) proposed by Murray and Lopez. The crude rate of YLL was 58.1 per 1000 inhabitants. After age-standardization using the world population, we obtained a rate of 57.7 YLL per 1000. Cardiovascular diseases (CVD) (19.3% of total YLL) and cancers (17.8%) dominated the burden of premature mortality, followed by perinatal conditions (13.6%). Excluding extreme age groups where perinatal conditions (0-4 years) and CVD (> 60 years) dominated the YLL's causes, injuries (road traffic crashes, falls, etc.) and cancers were most responsible for YLL. The present study highlights the major contribution of noncommunicable diseases to YLL in Tunisia. The promotion of healthy lifestyle and the reinforcement of secondary prevention in primary health care are the best ways to tackle these diseases. PMID- 24952122 TI - Brucellosis outbreak in Chouf district of Lebanon in 2009: a case-control study. AB - A study was conducted to determine risk factors associated with brucellosis infection in an outbreak in Chouf district of Lebanon during summer 2009. Cases of brucellosis reported to the Ministry of Public Health were identified, and for each case 2 controls were matched by sex, age and residence. Sociodemographic data, exposure to animals and animal products, knowledge about brucellosis, symptoms and history of past brucellosis infections were collected. Consumption of raw cheese was a significant risk factor for contracting brucellosis (matched OR = 29.5), whereas wearing gloves when in contact with animals and animal products and self-preparing dairy products were protective factors (OR = 0.08 and 0.13 respectively). Low and inaccurate knowledge about brucellosis was prevalent among subjects, with a common misconception about human-human transmission. Ensuring animal vaccination, educating people on correct ways of milk pasteurization and handling meat products, and elevating food safety monitoring threshold are key elements in controlling brucellosis. PMID- 24952124 TI - Risk of aggression and criminal behaviour among adolescents living in Alexandria Governorate, Egypt. AB - Adolescent risk-taking and aggressive behaviours are among the most visible forms of violence in society. A study was carried out to identify the prevalence and risk factors for aggression, violence and criminal behaviour among adolescents in Alexandria, Egypt. Using multistage, cluster sampling of families from all health districts in Alexandria, the mothers of 783 adolescents aged 11-19 years answered an Arabic version of the Mentor Research Institute screening questionnaire. Overall 26.9% of adolescents were assessed to be at high risk and 20.2% at extremely high risk of aggression and criminal behaviour. Living in urban/slum areas, male sex, low level of parents' education/occupation, exposure to violence within the family and changes in behaviour of any family member were associated with risk of aggression/violence. In multivariate analysis, the significant independent variables were adolescents' sex, presence of behavioural changes in the family, violence against brothers and sisters and substance abuse by any family member. PMID- 24952125 TI - Detection of methicillin-resistant Staphylococcus aureus directly by loop mediated isothermal amplification and direct cefoxitin disk diffusion tests. AB - We evaluated the utility of 2 methods for detection of methicillin-resistant Staphylococcus aureus (MRSA) directly from signal-positive blood culture bottles: loop-mediated isothermal amplification (LAMP) assay, and direct cefoxitin disk diffusion (DCDD) test using a 30 MUg cefoxitin disk. In parallel, standard microbiological identification and oxacillin susceptibility testing with MecA PCR was performed. Of 60 blood cultures positive for Gram-positive cocci in clusters, LAMP (via detection of the FemA and MecA genes) showed 100% sensitivity and specificity for identification of MRSA/MSSA. When coagulase-negative staphylococci were tested, sensitivity for detection of methicillin resistance was 91.7% and specificity was 100%. DCDD along with direct tube coagulase assay detected only 80.6% of MRSA/MSSA. LAMP showed higher diagnostic accuracy although DCDD was more cost-effective and did not require additional reagents or supplies. PMID- 24952126 TI - Proposal for further study of risk factors and health policy for human brucellosis in Northern Jordan. PMID- 24952128 TI - Physiological strategies contributing to the coexistence of two predatory species of stoneflies: Dinocras cephalotes and Perla bipunctata. AB - Our study focuses on the oxidative state of two aquatic insects of the order Plecoptera belonging to the family Perlidae, namely Dinocras cephalotes (Curtis, 1827) and Perla bipunctata Pictet, 1833. These species are widely distributed throughout the Western Palearctic region and coexist in the stream where individuals for this study come from. We highlight the physiological strategies of these two different predator species of stoneflies, showing a higher accumulation of lipid reserves in P. bipunctata, higher glucose levels in the body tissues of D. cephalotes and a higher capacity of the antioxidant enzymes in P. bipunctata, what provides it a protection against oxidation of lipids, which are greater in this species. This leads to a similar oxidative state in both species. Based on these results is discussed how two close related species developing a very similar ecological role in the same habitat can achieve a similar fitness with differences in their physiological strategies. PMID- 24952127 TI - Lipid-lowering therapies, glucose control and incident diabetes: evidence, mechanisms and clinical implications. AB - Lipid-lowering therapies constitute an essential part in the treatment and prevention of cardiovascular diseases and are consistently shown to reduce adverse cardiovascular outcomes in wide-scale populations. Recently, there is increased awareness of the possibility that lipid-lowering drugs may affect glucose control and insulin resistance. This phenomenon is reported in all classes of lipid-modifying agents, with differential effects of distinct drugs. Since the prevalence of metabolic syndrome and diabetes is rising, and lipid modifying therapies are widely used to reduce the cardiovascular burden in these populations, it is of importance to examine the relationship between lipid lowering drugs, glycemic control and incident diabetes. In the current review we discuss the evidence, ranging from experimental studies to randomized controlled clinical trials and meta-analyses, of how lipid-modifying therapies affect glycemic control and insulin sensitivity. Cumulative data suggest that both statins and niacin are associated with increased risk of impaired glucose control and development of new-onset diabetes, as opposed to bile-acid sequestrants which display concomitant moderate lipid and glucose lowering effects, and fibrates (particularly the pan-PPAR agonist bezafibrate) which may produce beneficial effects on glucose metabolism and insulin sensitivity. Ezetimibe is implied to ameliorate metabolic markers such as hepatic steatosis and insulin resistance, with yet little support from clinical trials, while fish oils which in experimental studies produce favorable effects on insulin sensitivity, although studied extensively, continue to show inconclusive effects on glucose homeostasis in patients with diabetes. Suggested mechanisms of how lipid-modifying agents affect glucose control and their clinical implications in this context, are summarized. PMID- 24952129 TI - mitoSAVE: mitochondrial sequence analysis of variants in Excel. AB - The mitochondrial genome (mtGenome) contains genetic information amenable to numerous applications such as medical research, population and evolutionary studies, and human identity testing. However, inconsistent nomenclature assignment makes haplotype comparison difficult and can lead to false exclusion of potentially useful profiles. Massively Parallel Sequencing (MPS) is a platform for sequencing large datasets and potentially whole populations with relative ease. However, the data generated are not easily parsed and interpreted. With this in mind, mitoSAVE has been developed to enable fast conversion of Variant Call Format (VCF) files. mitoSAVE is an Excel-based workbook that converts data within the VCF into mtDNA haplotypes using phylogenetically-established nomenclature as well as rule-based alignments consistent with current forensic standards. mitoSAVE is formatted for human mitochondrial genome; however, it can easily be adapted to support other reasonably small genomes. PMID- 24952130 TI - Psychophysiological arousal at encoding leads to reduced reactivity but enhanced emotional memory following sleep. AB - While sleep's role in emotional memory processing is gaining increasing support, its effect on emotion regulation remains equivocal. Moreover, little is known about the link between emotional reactivity at the time of encoding and subsequent sleep-based emotional memory consolidation. This study examined whether sleep would potentiate, protect, or depotentiate measures of heart rate and skin conductance in response to scenes containing emotional and neutral objects, and assessed how these measures of reactivity would predict subsequent memory for the objects across delays of sleep and wake. Heart rate deceleration (HRD) and skin conductance response (SCR) data were collected at encoding and recognition. Although HRD and SCR reactivity to objects were depotentiated after a sleep-filled delay, they remained unchanged after a delay containing wakefulness. Moreover, increased arousal responses to negative scenes at encoding as measured by HRD and SCR responses were positively correlated with subsequent memory for the negative objects of scenes, but only in the sleep group. This suggests that larger reactions to negative images at the time of encoding set the stage for the preferential consolidation of these images during a night of sleep. Although arousal responses are often thought to account for emotional enhancement in long-term memory, these findings suggest that both an arousal response at encoding and a subsequent period of sleep are needed to optimize selective emotional memory consolidation. PMID- 24952131 TI - Suppression of prolactin signaling by pyrrolidine dithiocarbamate is alleviated by N-acetylcysteine in mammary epithelial cells. AB - Prolactin is the key hormone to stimulate milk synthesis in mammary epithelial cells. It signals through the Jak2-Stat5 pathway to induce the expression of beta casein, a milk protein which is often used as a marker for mammary differentiation. Here we examined the effect of pyrrolidine dithiocarbamate (PDTC) on prolactin signaling. Our results show that PDTC downregulates prolactin receptor levels, and inhibits prolactin-induced Stat5 tyrosine phosphorylation and beta-casein expression. This is not due to its inhibitory action on NF-kappaB since application of another NF-kappaB inhibitor, BAY 11-7082, and overexpression of I-kappaBalpha super-repressor do not lead to the same results. Instead, the pro-oxidant activity of PDTC is involved as inclusion of the antioxidant N acetylcysteine restores prolactin signaling. PDTC triggers great extents of activation of ERK and JNK in mammary epithelial cells. These do not cause suppression of prolactin signaling but confer serine phosphorylation of insulin receptor substrate-1, thereby perturbing insulin signal propagation. As insulin facilitates optimal beta-casein expression, blocking insulin signaling by PDTC might pose additional impediment to beta-casein expression. Our results thus imply that lactation will be compromised when the cellular redox balance is dysregulated, such as during mastitis. PMID- 24952132 TI - Pharmacological characterisation of alpha6beta4* nicotinic acetylcholine receptors assembled from three chimeric alpha6/alpha3 subunits in tsA201 cells. AB - The distribution and physiological functions of the alpha6 subunit-containing (alpha6*) nicotinic acetylcholine receptors in the central nervous system make them interesting putative therapeutic targets in several disorders. However, investigations into the receptors have been complicated by their inefficient functional expression in vitro. In the present study we have characterized and compared the pharmacological properties displayed by alpha6beta4 and alpha6beta4beta3 nicotinic acetylcholine receptors assembled in tsA201 cells from the classical alpha6/alpha3 chimera (C1) and two novel alpha6/alpha3 chimeras (C6F223L and C16F223L) identified in a recent study (Jensen et al., 2013). Whereas the Bmax values exhibited by [3H]epibatidine at wild-type alpha6beta4, C1beta4, C6F223Lbeta4 and C16F223Lbeta4 receptors differed substantially, the radioligand and seven orthosteric nicotinic agonists exhibited very similar KD and Ki values at the four receptors. In the FLIPRTM Membrane Potential Blue assay, the agonists exhibited the same rank order of potencies [(+/-) epibatidine>sazetidine A>varenicline>(-)-cytisine~(S) nicotine>acetylcholine>carbachol] at the C1beta4, C1beta4beta3, C6F223Lbeta4, C6F223Lbeta4beta3, C16F223Lbeta4 and C16F223Lbeta4beta3 receptors, albeit the absolute EC50 values differed somewhat between the receptors. Furthermore, four reference antagonists displayed the same rank order of inhibitory potencies at the six receptors [alpha-conotoxin PIA>2,2,6,6-tetramethylpiperidin-4-yl heptanoate>mecamylamine>dihydro-beta-erythroidine]. Although all interpretations based on these results should be made keeping the molecular modifications in the alpha6 surrogate subunits in mind, this study sheds light on the pharmacological properties of alpha6beta4* nicotinic acetylcholine receptors and demonstrates the applicability of the C6F223L and C16F223L chimeras for studies of these receptors. PMID- 24952134 TI - Prevalence and risk factors of postpartum posttraumatic stress disorder: a meta analysis. AB - Research has demonstrated that women develop postpartum PTSD. Prevalence of postpartum PTSD has ranged from 1% to 30%, and many risk factors have been identified as predictors of postpartum PTSD. While qualitative reviews have identified patterns of risk, the lack of quantitative reviews prevents the field from identifying specific risk factors and making a single estimate of the prevalence of postpartum PTSD. The current meta-analysis investigated prevalence and risk factors of postpartum PTSD, both due to childbirth and other events, among community and targeted samples. Prevalence of postpartum PTSD in community samples was estimated to be 3.1% and in at-risk samples at 15.7%. Important risk factors in community samples included current depression, labor experiences such as interactions with medical staff, as well as a history of psychopathology. In at-risk samples, impactful risk factors included current depression and infant complications. Further research should investigate how attitudes towards pregnancy and childbirth may interact with women's experiences during delivery. Additionally, studies need to begin to evaluate possible long-term effects that these symptoms may have on women and their families. PMID- 24952133 TI - Lipolytic and antiadipogenic effects of (3,3-dimethylallyl) halfordinol on 3T3-L1 adipocytes and high fat and fructose diet induced obese C57/BL6J mice. AB - Aegle marmelos Correa., (Rutaceae) is a medium sized tree distributed in South East Asia and used traditionally for the management of obestiy and diabetes. In this study the lipolytic and antiadipogenic effects of (3,3-dimethylallyl) halfordinol (Hfn) isolated from leaves of A. marmelos have been investigated. Intracellular lipid accumulation was measured by oil red O staining and glycerol secretion. The expression of genes related to adipocyte differentiation was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). Hfn decreased intracellular triglyceride accumulation and increased glycerol release in a dose dependent manner (5-20 MUg/ml) in differentiated 3T3-L1 adipocytes. In high fat diet fed C57/BL 6J mice, treatment with Hfn for four weeks reduced plasma glucose, insulin and triglyceride levels and showed a significant reduction in total adipose tissue mass by 37.85% and visceral adipose tissue mass by 62.99% at 50mg/kg b.w. concentration. RT-PCR analyses indicated that Hfn decreased the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT enhancer binding protein alpha (CEBPalpha) and increased the expression of sterol regulatory enzyme binding protein (SREBP-1c), peroxisome proliferator-activated receptor alpha (PPARalpha), Adiponectin and Glucose transporter protein 4 (GLUT4) compared to the high fat diet group. These results suggested that Hfn decreased adipocyte differentiation and stimulated lipolysis of adipocytes. This study justifies the folklore medicinal uses and claims about the therapeutic values of this plant for the management of insulin resistance and obesity. PMID- 24952135 TI - RNA-Seq for the identification of novel Mediator transcripts in endothelial progenitor cells. AB - Mediator (MED) complex is a multiprotein playing a key role in the eukaryotic transcription. Alteration of MED function may have enormous pathophysiological consequences and several MED genes have been implicated in human diseases. Here, we have combined computational and experimental approaches to identify and characterize, new transcripts generated by alternative splicing (AS) for all MED genes, through the analysis of our recently published RNA-Sequencing datasets of endothelial progenitor cells (EPCs). This combined strategy allowed us to identify novel transcripts for MED4, MED9, MED11, MED14, MED27 and CDK8 most of them generated by AS. All the newly identified transcripts, except MED11, are predicted to encode novel protein isoforms. The identification of novel MED variants could lead to the finding of other MED complexes with different functions depending on their subunit composition. Finally, the expression profile of all MED genes, together with an extensive gene expression analysis, may be useful to better classify the diverse subsets of cell populations that contribute to neovascularization. PMID- 24952137 TI - Expression of csp genes in E. coli K-12 in defined rich and defined minimal media during normal growth, and after cold-shock. AB - Cold-shock proteins (Csps) are a family of small nucleic acid-binding proteins found in 72% of sequenced bacterial genomes. Where it has been examined, at least one csp gene is required for cell viability. In Escherichia coli K-12, there are nine homologous csp genes named A-I. Regulation studies performed on individual members of this family have suggested that cspA, cspB, cspG, and cspI are cold induced, cspC and cspE are constitutively expressed, cspD is stationary phase induced, and the induction patterns for cspF and cspH have yet to be determined. Aside from microarray studies, transcript levels from all nine csp genes have never been assayed using the same technique or in the same cells. The purpose of this study was to use quantitative RT-PCR to establish csp expression patterns for all nine csp genes at 37 degrees C in defined rich and defined minimal media, and after a shift to 15 degrees C for either 1h or 4h. We found that transcript levels for each of the csp genes changed throughout the growth curve. Transcripts for cspA, -B, and -E were more abundant than those detected for the other csp genes in defined rich medium. cspE mRNA levels in defined minimal medium were drastically higher than mRNA for the other csp genes. Of the nine csp genes, only cspI showed a significant increase in mRNA accumulation after cold-shock in defined rich medium. When mRNA accumulation was compared across the nine csp genes, there were more cspE transcripts in the cell than cspA, -B, -G, or -I transcripts after 1h cold-shock in either defined rich or defined minimal media. In defined minimal medium, transcription of cspA, -B, -G, and -I was induced after cold-shock. PMID- 24952136 TI - Cloning, expression, and functional characterization of the rat Pax6 5a orthologous splicing variant. AB - Pax6 functions as a pleiotropic regulator in eye development and neurogenesis. Its splice variant Pax6 5a has been cloned in many vertebrate species including human and mouse, but never in rat. This study focused on the cloning and characterization of the Pax6 5a orthologous splicing variant in rat. It was cloned from Sprague-Dawley rats 10 days post coitum (E10) by RT-PCR and was sequenced for comparison with Pax6 sequences in the GenBank by BLAST. The rat Pax6 5a was revealed to contain an additional 42 bp insertion at the paired domain. At the nucleotide level, the rat Pax6 5a coding sequence (1,311 bp) had a higher degree of homology to the mouse (96% identical) than to the human (93% identical) sequence. At the amino acid (aa) level, rat PAX6 5a shares 99.8% identity with the mouse sequence and 99.5% with the human sequence. The splice variant is preferentially expressed in the rat E10 embryonic headfolds and not in the trunk of neurula. Its effects on the proliferation of rat mesenchymal stem cells (rMSCs) were preliminarily evaluated by the MTT assay. Both pLEGFP-Pax6 5a transfected cells and pLEGFP-Pax6-transfected cells exhibited a similar growth curve (P>0.05), suggesting that the Pax6 5a has a similar effect on the proliferation of rMSCs as Pax6. PMID- 24952139 TI - Hydrogen peroxide metabolism and sensing in human erythrocytes: a validated kinetic model and reappraisal of the role of peroxiredoxin II. AB - Hydrogen peroxide (H2O2) metabolism in human erythrocytes has been thoroughly investigated, but unclear points persist. By integrating the available data into a mathematical model that accurately represents the current understanding and comparing computational predictions to observations we sought to (a) identify inconsistencies in present knowledge, (b) propose resolutions, and (c) examine their functional implications. The systematic confrontation of computational predictions with experimental observations of the responses of intact erythrocytes highlighted the following important discrepancy. The high rate constant (10(7)-10(8) M(-1) s(-1)) for H2O2 reduction determined for purified peroxiredoxin II (Prx2) and the high abundance of this protein indicate that under physiological conditions it consumes practically all the H2O2. However, this is inconsistent with extensive evidence that Prx2's contribution to H2O2 elimination is comparable to that of catalase. Models modified such that Prx2's effective peroxidase activity is just 10(5) M(-1) s(-1) agree near quantitatively with extensive experimental observations. This low effective activity is probably due to a strong but readily reversible inhibition of Prx2's peroxidatic activity in intact cells, implying that the main role of Prx2 in human erythrocytes is not to eliminate peroxide substrates. Simulations of the responses to physiological H2O2 stimuli highlight that a design combining abundant Prx2 with a low effective peroxidase activity spares NADPH while improving potential signaling properties of the Prx2/thioredoxin/thioredoxin reductase system. PMID- 24952138 TI - Phenethyl isothiocyanate induces DNA damage-associated G2/M arrest and subsequent apoptosis in oral cancer cells with varying p53 mutations. AB - Phenethyl isothiocyanate (PEITC) is a naturally occurring cruciferous vegetable derived compound that inhibits cell growth and induces apoptosis in oral cancer cells. However, the exact mechanism of PEITC action has not been fully elucidated. This study investigated the molecular mechanism and anticancer potential of PEITC in oral squamous cell carcinoma (OSCC) cells with various p53 statuses. PEITC inhibited the growth of OC2, SCC4, and SCC25 cells (functional p53 mutants) in a dose-dependent manner with low toxicity to normal cells. Treatment with PEITC induced reactive oxygen species production, nitric oxide generation, and GSH depletion and triggered DNA damage response as evidenced by flow cytometry, 8-OHdG formation, and comet assay. Furthermore, the subsequent activation of ATM, Chk2, and p53 as well as the increased expression of downstream proteins p21 and Bax resulted in a G2/M phase arrest by inhibiting Cdc25C, Cdc2, and cyclin B1. The PEITC-induced apoptotic cell death, following a diminished mitochondrial transmembrane potential, reduced the expression of Bcl-2 and Mcl-1, released mitochondrial cytochrome c, and activated caspase 3 and PARP cleavage. The p53 inhibitor pifithrin-alpha and the antioxidants N-acetylcysteine and glutathione (GSH) protected the cells from PEITC-mediated apoptosis. However, mito-TEMPO, catalase, apocynin, and L-NAME did not prevent PEITC-induced cell death, suggesting that PEITC induced G2/M phase arrest and apoptosis in oral cancer cells via a GSH redox stress and oxidative DNA damage-induced ATM-Chk2-p53 related pathway. These results provide new insights into the critical roles of both GSH redox stress and p53 in the regulation of PEITC-induced G2/M cell cycle arrest and apoptosis in OSCCs. PMID- 24952140 TI - Editorial. PMID- 24952141 TI - Assessment of occupational health problems and physiological stress among the brick field workers of West Bengal, India. AB - OBJECTIVES: The brick field industry is one of the oldest industries in India, which employs a large number of workers of poor socioeconomic status. The main aim of the present investigation is i) to determine the prevalence of musculoskeletal disorders among brick field workers, ii) to determine the prevalence of respiratory disorders and physiological stress among brick field workers compared to control workers. MATERIAL AND METHODS: For this study, a total of 220 brick field workers and 130 control subjects were selected randomly. The control subjects were mainly involved in hand-intensive jobs. The Modified Nordic Questionnaire was applied to assess the discomfort felt among both groups of workers. Thermal stress was also assessed by measuring the WBGT index. The pulmonary functions were checked using the spirometry. Physiological assessment of the workload was carried out by recording the heart rate and blood pressure of the workers prior to work and just after work in the field. RESULTS: Brick field workers suffered from pain especially in the lower back (98%), hands (93%), knees (86%), wrists (85%), shoulders (76%) and neck (65%). Among the brick-making activities, brick field workers felt discomfort during spading for mud collection (98%), carrying bricks (95%) and molding (87%). The results showed a significantly lower p value < 0.001 in FVC, FEV1, FEV1/FVC ratio and PEFR in brick field workers compared to the control group. The post-activity heart rate of the brick field workers was 148.6 beats/min, whereas the systolic and diastolic blood pressure results were 152.8 and 78.5 mm/Hg, respectively. CONCLUSIONS: This study concludes that health of the brick field workers was highly affected due to working in unhealthy working conditions for a long period of time. PMID- 24952142 TI - Promoting voluntary help-seeking among doctors with mental disorders. AB - OBJECTIVES: To explore if the Barcelona Integral Care Program for Doctors with mental disorders (PAIMM, in Catalan) has achieved its goal of enhancing earlier and voluntary help-seeking amongst sick doctors. MATERIAL AND METHODS: We conducted a retrospective chart review of 1363 medical records of physicians admitted to the inpatient and outpatient units of the PAIMM from February 1st, 1998 until December 31st, 2011. The sample was divided into 3 time periods: 1998 2004, 2005-2007 and 2008-2011 (477, 497, and 389 cases, respectively). RESULTS: The mean age at admission decreased (F = 77.57, p < 0.001) from the first period (x = 54.18; SD = 10.28 years) to the last period (x = 44.81; SD = 10.65 years), while voluntary referrals increased from 81.3% to 91.5% (Chi(2) = 17.85, p < 0.001). Mental disorders other than substance use disorders grew from 71% during the 1998-2003 period, to 87.4% (2004-2007), and 83.9% in the last period (Chi2 = 29.01, p < 0.001). Adjustment disorders increased their prevalence, while inpatient treatment progressively represented less of the overall clinical activity. CONCLUSIONS: Sick doctors may feel encouraged to seek help in non punitive programs specially designed for them and where treatment becomes mandatory only when there is risk or evidence of malpractice. PMID- 24952143 TI - Evaluation of discomfort glare in the 50+ elderly: experimental study. AB - OBJECTIVES: The aim of the study was to analyze discomfort glare sensation in subjects aged 50 years and more in comparison with younger subjects (i.e. younger than 35 years of age). MATERIAL AND METHODS: The experiments were performed on a computer workstation placed in controlled lighting environment where 2 discomfort glare conditions were modeled. Each participant performed for about 1 h specially designed visual tasks, including the tests with Landolt's rings presented on the screen by a computer program. The glare evaluation method consisted of subjective evaluation of discomfort glare on the semantic glare rating scale, tests of mesopic contrast and glare sensitivity, subjective assessment of lighting quality and asthenopic symptoms. The time needed to perform the task and the number of mistakes were also recorded. The subjective evaluation of glare was compared with the Unified Glare Rating (UGR) index calculated by the DIALux simulation program. RESULTS: A higher percentage of the younger group subjects assessed glare after the experimental session as uncomfortable and intolerable than in the 50+ group, who more often assessed glare as acceptable. The assessment of discomfort glare in the younger group corresponded to higher UGR value compared to UGR value calculated by DIALux. In the 50+ group, such correlation was found only for lower discomfort glare (UGR = 19). The results showed that younger participants more frequently suffered from visual fatigue and assessed lighting as less comfortable. However, the mesopic glare sensitivity increased significantly after the experiments only in the 50+ group under both glare conditions. CONCLUSIONS: The obtained results showed that discomfort glare sensation changes with age. The younger population seems to be more sensitive and demanding than the older one in relation to discomfort glare limiting, in spite of the lack of significant objective measures of fatigue. The exposure of the elderly to bigger discomfort glare could adversely affect the objective measures of fatigue like mesopic glare sensitivity and visual performance. PMID- 24952144 TI - Assessment of selected B cells populations in the workers of X-ray departments. AB - OBJECTIVES: Workers of X-ray departments are occupationally exposed to long-term low levels of ionizing radiation (LLIR), which may affect their humoral immunity. The aim of the study was to assess the influence of LLIR on the number and proportion of B cells (CD19+), B1 cells (CD5+CD19+) and memory B cells (CD27+CD19+) in peripheral blood of such workers. MATERIALS AND METHODS: In the study group of 47 X-ray departments workers and the control group consisting of 38 persons, the number and percentage of CD19+, CD5+CD19+, CD27+CD19+ cells as well as CD5+CD19+/CD19+ and CD27+CD19+/CD19+ cell ratios were assessed using flow cytometry. Additionally, the study group was divided into 2 groups by the length of employment below and over 15 years and analysis adjusted for age and smoking habit was performed. RESULTS: The total number of CD19+ cells showed significant increase in the group of workers in comparison with the persons from the control group, whereas the percentage of CD5+CD19+ cells as well as CD27+CD19+/CD19+ and CD5+CD19+/CD19+ cell ratios were lower. Percentage, number of CD5+CD19+ cells and CD5+CD19+/CD19+ cell ratio were significantly lower in the workers with length of employment longer than 15 years in comparison with those employed below 15 years. Moreover, we found positive associations between the number of CD19+ cells and employment as well as smoking habit, whereas the number of CD5+CD19+ cells was positively associated with cigarette smoking alone. Percentage of CD5+CD19+ cells as well as CD5+CD19+/CD19+ and CD27+CD19+/CD19+ cell ratios were negatively correlated with employment. CONCLUSIONS: The study suggests association between the suppressive influence of low level ionizing radiation on circulating in peripheral blood, especially of B1 cells as well as of memory B cells, in workers of X-ray units, which is adverse in relation to microbiological threat. PMID- 24952145 TI - Patterns and correlates of physical activity among middle-aged employees: a population-based, cross-sectional study. AB - OBJECTIVES: The purpose of this study was to determine the level, pattern and correlates (socio-demographic, lifestyle and work-related) of physical activity among middle-aged employees in Croatia. MATERIAL AND METHODS: In this cross sectional study the data were collected using a household interview on a random sample of 766 middle-aged employees (52% female) living in Croatia. The International Physical Activity Questionnaire (IPAQ-long) was used to assess physical activity. An additional questionnaire was used to collect data on socio demographic, lifestyle and work-related correlates. RESULTS: The median (95% CI) total physical activity for the whole sample was 78.7 (69.1-88.3) MET-hours/week. Most physical activity was accumulated in the domain of work (26.4 (20.3-32.5) MET-hours/week) or in domestic activities (19.2(17.8-20.7) MET-hours/week), whilst a significantly lower physical activity was found in the transport (3.3 (2.9-3.7) MET-hours/week) and leisure-time domains (6.5 (5.7-7.3) MET hours/week). The multiple regression analysis showed an inverse relationship between educational level and the size of settlements with the domestic-related and total physical activity (beta range: -0.11 to -0.22; p < 0.01). Among lifestyle correlates, only alcohol consumption was positively related to the total physical activity (beta = 0.12; p < 0.01), while the perceived level of stress outside work was the only one, which was inversely associated with the work-related (beta = -0.09; p < 0.01) and leisure-time physical activity (beta = 0.10; p < 0.01). CONCLUSIONS: Middle-aged employees in Croatia accumulate most of their daily physical activity in the work and domestic domains. Analysis of the relationship between physical activity and potential socio-demographic, lifestyle, and work-related correlates indicated that physical activity promotional activities should be primarily focused on males, employees living in smaller settlements and those with higher educational levels. The correlates of physical activity among middle-aged employees seem to be domain-specific. Therefore, future studies in this area should consider assessing physical activity in each domain separately. PMID- 24952146 TI - Physical activity levels as a quantifier in police officers and cadets. AB - OBJECTIVES: The aim of the present study was to determine the physical activity levels of active duty police officers and police academy cadets in different life domains and intensities. These parameters were treated as potential quantifiers that could be used when assessing individuals preparing for work as future police officers. MATERIAL AND METHODS: The study recruited 153 active police officers and 176 cadets attending a police academy and administered a diagnostic survey, the long-form version of the International Physical Activity Questionnaire, while in the statistical analysis the Student's t-test for independent groups was applied. RESULTS: It was determined that police officers present high physical activity levels within the work domain, which are developed from initial training at a police academy and then throughout their police career. CONCLUSIONS: Such data are important in the light of the role police officers play in public safety as well as the prominence of physical activity within a particular profession and how it can be targeted and tailored to their needs. PMID- 24952147 TI - Prevention of phrenic nerve injury during interventional electrophysiologic procedures. PMID- 24952148 TI - Incidence and prediction of ischemic stroke among atrial fibrillation patients with end-stage renal disease requiring dialysis. AB - BACKGROUND: Renal dysfunction is a significant risk factor for ischemic stroke in atrial fibrillation (AF). However, the incidence of ischemic stroke and how to predict its occurrence among AF patients with end-stage renal disease (ESRD) are unclear. OBJECTIVE: The purpose of this study was to compare the CHADS2 and CHA2DS2-VASc scores for stroke risk stratification in AF patients with ESRD. METHODS: A total of 10,999 AF patients with ESRD undergoing renal replacement therapy who were not receiving oral anticoagulants or antiplatelet agents were identified from Taiwan's National Health Insurance Research Database. The study end-point was occurrence of ischemic stroke. RESULTS: The median (interquartile) CHADS2 and CHA2DS2-VASc scores for the study cohort were 3 (2-5) and 5 (4-7), respectively. During follow-up, 1217 patients (11.7%) experienced ischemic stroke, with an incidence rate of 6.9 per 100 person-years. In Cox regression models, the CHADS2 and CHA2DS2-VASc scores both were significant predictors of ischemic stroke. C-indexes for CHADS2 and CHA2DS2-VASc were 0.608 and 0.682, respectively (P < .001). CHA2DS2-VASc improved the net reclassification index by 4.8% compared with CHADS2 (P < .0001). Among 1409 patients with a CHADS2 score of 0 or 1, the CHA2DS2-VASc score ranged from 1 to 4, with event rates ranging from 2.1 to 4.7 per 100 person-years. CONCLUSION: The CHA2DS2-VASc score was useful in predicting ischemic stroke in AF patients with ESRD undergoing dialysis and was superior to the CHADS2 score. The net clinical benefit balancing stroke reduction against major bleeding with anticoagulation in these high-risk patients remains to be defined. PMID- 24952149 TI - In vitro assessment of induced phrenic nerve cryothermal injury. AB - BACKGROUND: Phrenic nerve injury, both left and right, is considered a significant complication of cryoballoon ablation for treatment of drug-refractory atrial fibrillation, and functional recovery of the phrenic nerve can take anywhere from hours to months. OBJECTIVE: The purpose of this study was to focus on short periods of cooling to determine the minimal amount of cooling that may terminate nerve function related to cryo ablation. METHODS: Left and/or right phrenic nerves were dissected from the pericardium and connective tissue of swine (n = 35 preparations). Nerves were placed in a recording chamber modified with a thermocouple array. This apparatus was placed in a digital water bath to maintain an internal chamber temperature of 37 degrees C. Nerves were stimulated proximally with a 1-V, 0.1-ms square wave. Bipolar compound action potentials were recorded proximal and distal to the site of ablation both before and after ablation, then analyzed to determine changes in latency, amplitude, and duration. Temperatures were recorded at a rate of 5 Hz, and maximum cooling rates were calculated. RESULTS: Phrenic nerves were found to elicit compound action potentials upon stimulation for periods up to 4 hours minimum. Average conduction velocity was 56.7 +/- 14.7 m/s preablation and 49.8 +/- 16.6 m/s postablation (P = .17). Cooling to mild subzero temperatures ceased production of action potentials for >1 hour. CONCLUSION: Taking into account the data presented here, previous publications, and a conservative stance, during cryotherapy applications, cooling of the nerve to below 4 degrees C should be avoided whenever possible. PMID- 24952150 TI - Cloning, functional characterization, and remodeling of K2P3.1 (TASK-1) potassium channels in a porcine model of atrial fibrillation and heart failure. AB - BACKGROUND: Effective treatment of atrial fibrillation (AF) remains an unmet need. Human K2P3.1 (TASK-1) K(+) channels display atrial-specific expression and may serve as novel antiarrhythmic targets. In rodents, inhibition of K2P3.1 causes prolongation of action potentials and QT intervals. We used a porcine model to further elucidate the significance of K2P3.1 in large mammals. OBJECTIVE: The purpose of this study was to study porcine (p)K2P3.1 channel function and cardiac expression and to analyze pK2P3.1 remodeling in AF and heart failure (HF). METHODS: The porcine K2P3.1 ortholog was amplified and characterized using voltage-clamp electrophysiology. K2P3.1 mRNA expression and remodeling were studied in domestic pigs during AF and HF induced by atrial burst pacing. RESULTS: Porcine K2P3.1 cDNA encodes a channel protein with 97% identity to human K2P3.1. K(+) currents recorded from Xenopus oocytes expressing pK2P3.1 were functionally and pharmacologically similar to their human counterparts. In the pig, K2P3.1 mRNA was predominantly expressed in atrial tissue. AF and HF were associated with reduction of K2P3.1 mRNA levels by 85.1% (right atrium) and 77.0% (left atrium) at 21-day follow-up. In contrast, ventricular K2P3.1 expression was low and not significantly affected by AF/HF. CONCLUSION: Porcine K2P3.1 channels exhibit atrial expression and functional properties similar to their human orthologs, supporting a general role as antiarrhythmic drug targets. K2P3.1 down regulation in AF with HF may indicate functional relevance of the channel that remains to be validated in prospective interventional studies. PMID- 24952152 TI - Fluoroquinolone-metal complexes: a route to counteract bacterial resistance? AB - Microbial resistance to antibiotics is one of the biggest public health threats of the modern world. Antibiotic resistance is an area of much clinical relevance and therefore research that has the potential to identify agents that may circumvent it or treat resistant infections is paramount. Solution behavior of various fluoroquinolone (FQ) complexes with copper(II) in the presence and absence of 1,10-phenanthroline (phen) was studied in aqueous solution, by potentiometry and/or spectrophotometry, and are herein described. The results obtained showed that under physiological conditions (micromolar concentration range and pH7.4) only copper(II):FQ:phen ternary complexes are stable. Hence, these complexes were synthesised and characterised by means of UV-visible and IR spectroscopy, elemental analysis and single-crystal X-ray diffraction. In these complexes, the FQ acts as a bidentate ligand that coordinates the metal cation through the carbonyl and carboxyl oxygen atoms and phen coordinates through two N atoms forming the equatorial plane of a distorted square-pyramidal geometry. The fifth position of the penta-coordinated Cu(II) centre is generally occupied axially by an oxygen atom from a water molecule or from a nitrate ion. Minimum inhibitory concentration (MIC) determinations of the complexes and comparison with free FQ in various E. coli strains indicate that the Cu-complexes are as efficient antimicrobials as the free antibiotic. Moreover, results strongly suggest that the cell intake route of both species is different supporting, therefore, the complexes' suitability as candidates for further biological testing in FQ-resistant microorganisms. PMID- 24952151 TI - Lipoprotein(a) level and apolipoprotein(a) phenotype as predictors of long-term cardiovascular outcomes after coronary artery bypass grafting. AB - OBJECTIVE: To evaluate the relationships of lipoprotein(a) (Lp(a)) concentration and apolipoprotein(a) (apo(a)) phenotype to major adverse cardiovascular events after coronary artery bypass grafting (CABG) in long-term follow-up. METHODS: This single-center study included 356 patients with stable coronary heart disease (CHD) who underwent successful CABG. At baseline, we assessed the patient's risk factor profile for atherosclerosis, Lp(a) concentration and apo(a) phenotype. The primary endpoint was the composite of cardiovascular death and non-fatal myocardial infarction (MI). The secondary endpoint also included hospitalization for recurrent or unstable angina and repeat revascularization. RESULTS: Over a mean of 8.5 +/- 3.5 years (range 0.9-15.0 years), the primary and secondary endpoints were registered in 46 (13%) and 107 (30%) patients, respectively. Patients with Lp(a) >=30 mg/dL were at significantly greater risk for the primary endpoint (hazard ratio (HR) 2.98, 95% confidence interval (CI) 1.76-5.03, p < 0.001) and secondary endpoint (HR 3.47, 95% CI 2.48-4.85, p < 0.001) than patients with Lp(a) values <30 mg/dL. The low molecular-weight apo(a) phenotype was also associated with higher risk of both primary and secondary endpoints (3.57 (1.87-6.82) and 3.05 (2.00-4.62), respectively; p < 0.001 for both), regardless of conventional risk factors and statins use. CONCLUSION: In stable CHD patients Lp(a) concentration and low molecular-weight apo(a) phenotype are independently associated with three-fold increase in risk of major adverse cardiovascular events within 15 years after CABG. Lp(a) levels may provide an additional information for postoperative cardiovascular risk assessment. PMID- 24952153 TI - Synthetic cellularity based on non-lipid micro-compartments and protocell models. AB - This review discusses recent advances in the design and construction of protocell models based on the self-assembly or microphase separation of non-lipid building blocks. We focus on strategies involving partially hydrophobic inorganic nanoparticles (colloidosomes), protein-polymer globular nano-conjugates (proteinosomes), amphiphilic block copolymers (polymersomes), and stoichiometric mixtures of oppositely charged biomolecules and polyelectrolytes (coacervates). Developments in the engineering of membrane functionality to produce synthetic protocells with gated responses and control over multi-step reactions are described. New routes to protocells comprising molecularly crowded, cytoskeletal like hydrogel interiors, as well as to the construction of hybrid protocell models are also highlighted. Together, these strategies enable a wide range of biomolecular and synthetic components to be encapsulated, regulated and processed within the micro-compartmentalized volume, and suggest that the development of non-lipid micro-ensembles offers an approach that is complementary to protocell models based on phospholipid or fatty acid vesicles. PMID- 24952154 TI - Spontaneous acute tumour lysis syndrome in gastric adenocarcinoma: a case report and literature review. PMID- 24952155 TI - Atomic resolution structure of the E. coli YajR transporter YAM domain. AB - YajR is an Escherichia coli transporter that belongs to the major facilitator superfamily. Unlike most MFS transporters, YajR contains a carboxyl terminal, cytosolic domain of 67 amino acid residues termed YAM domain. Although it is speculated that the function of this small soluble domain is to regulate the conformational change of the 12-helix transmembrane domain, its precise regulatory role remains unclear. Here, we report the crystal structure of the YAM domain at 1.07-A resolution, along with its structure determined using nuclear magnetic resonance. Detailed analysis of the high resolution structure revealed a symmetrical dimer in which a belt of well-ordered poly-pentagonal water molecules is embedded. A mutagenesis experiment and a thermal stability assay were used to analyze the putative role of this dimerization in response to changes in halogen concentration. PMID- 24952156 TI - A role for carbohydrate recognition in mammalian sperm-egg binding. AB - Mammalian fertilization usually requires three sequential cell-cell interactions: (i) initial binding of sperm to the specialized extracellular matrix coating the egg known as the zona pellucida (ZP); (ii) binding of sperm to the ZP via the inner acrosomal membrane that is exposed following the induction of acrosomal exocytosis; and (iii) adhesion of acrosome-reacted sperm to the plasma membrane of the egg cell, enabling subsequent fusion of these gametes. The focus of this review is on the initial binding of intact sperm to the mammalian ZP. Evidence collected over the past fifty years has confirmed that this interaction relies primarily on the recognition of carbohydrate sequences presented on the ZP by lectin-like egg binding proteins located on the plasma membrane of sperm. There is also evidence that the same carbohydrate sequences that mediate binding also function as ligands for lectins on lymphocytes that can inactivate immune responses, likely protecting the egg and the developing embryo up to the stage of blastocyst hatching. The literature related to initial sperm-ZP binding in the three major mammalian models (human, mouse and pig) is discussed. Historical perspectives and future directions for research related to this aspect of gamete adhesion are also presented. PMID- 24952158 TI - Role of hydrophobic mutations on the binding affinity and stability of blood coagulation factor VIIIa: a computational molecular dynamics and free-energy analysis. AB - Factor VIIIa is a non-covalently bound hetero-trimer among A1, A2 and A3-C1-C2 domains and an essential co-factor for factor IXa enzyme during proteolytic activation of factor X zymogen. The relatively weak interactions between A2 and the interface A1/A3 domains dampen the functional stability of FVIIIa in plasma and results in rapid degradation. We studied the mutational effect of three charged residues (Asp519, Glu665 and Asp666) to several hydrophobic residues by molecular dynamics simulations. Analysis of the binding free energy by MM-PBSA and MM-GBSA methods shows that the mutation of Asp519 and Glu665 residues to either Val or Ala enhance the A2 domain binding affinity in agreement with the experimental site-specific mutagenesis data. Mutation of Asp666 to Val, Tyr, Met and Phe showed largest improvement in the A2-domain binding among the eight hydrophobic mutants studied. Our studies suggest that the enrichment of hydrophobic interactions in the buried surface regions of A2 domain plays crucial role in improving the overall stability of FVIIIa. PMID- 24952159 TI - Post-translational modification and mitochondrial relocalization of histone H3 during apoptosis induced by staurosporine. AB - Post-translational modifications (PTMs) of histones such as phosphorylation, acetylation, and ubiquitination, collectively referred to as the "histone-code", have been known to regulate gene expression and chromatin condensation for over a decade. They are also implicated in processes such as DNA repair and apoptosis. However, the study of the phosphorylation of histones has been mainly focused on chromosome condensation and mitosis. Therefore, the phosphorylation of histones in apoptosis is not fully understood. It was recently demonstrated by Tang et al. that histones are released from nucleosome during apoptosis, an observation that is in agreement with our findings. In addition to the release of histones, the dephosphorylation of histone H3 at Thr-3 and Ser-10 was observed during apoptosis in some cancer cells. Our data suggest that the modification and release of histones could serve markers of apoptosis in human cancer cells. We also suggest that the released histones, especially H3, could be translocated to mitochondria during apoptosis. PMID- 24952157 TI - NMDA-induced accumulation of Shank at the postsynaptic density is mediated by CaMKII. AB - Shank is a specialized scaffold protein present in high abundance at the postsynaptic density (PSD). Using pre-embedding immunogold electron microscopy on cultured hippocampal neurons, we had previously demonstrated further accumulation of Shank at the PSD under excitatory conditions. Here, using the same experimental protocol, we demonstrate that a cell permeable CaMKII inhibitor, tatCN21, blocks NMDA-induced accumulation of Shank at the PSD. Furthermore we show that NMDA application changes the distribution pattern of Shank at the PSD, promoting a 7-10 nm shift in the median distance of Shank labels away from the postsynaptic membrane. Inhibition of CaMKII with tatCN21 also blocks this shift in the distribution of Shank. Altogether these results imply that upon activation of NMDA receptors, CaMKII mediates accumulation of Shank, preferentially at the distal regions of the PSD complex extending toward the cytoplasm. PMID- 24952161 TI - [Frequency of glucose-6-phosphate dehydrogenase deficiency (A-376/202) in three Malian ethnic groups]. AB - Erythrocyte G6PD deficiency is the most common worldwide enzymopathy. The aim of this study was to determine erythrocyte G6PD deficiency in 3 ethnic groups of Mali and to investigate whether erythrocyte G6PD deficiency was associated to the observed protection against malaria seen in Fulani ethnic group. The study was conducted in two different areas of Mali: in the Sahel region of Mopti where Fulani and Dogon live as sympatric ethnic groups and in the Sudanese savannah area where lives mostly the Malinke ethnic group. The study was conducted in 2007 in Koro and in 2008 in Naguilabougou. It included a total 90 Dogon, 42 Fulani and 80 Malinke ethnic groups. Malaria was diagnosed using microscopic examination after Giemsa-staining of thick and thin blood smear. G6PD deficiency (A (376/202)) samples were identified using RFLP (Restriction Fragment Length Polymorphism) assay and analysis of PCR-amplified DNA amplicon. G6PD deficiency (A-(376/202)) rate was 11.1%, 2.4%, and 13.3% in Dogon, Fulani, and Malinke ethnic group respectively. Heterozygous state for G6PD (A-(376/202)) was found in 7.8% in Dogon; 2.4% in Fulani and 9.3% in Malinke ethnic groups while hemizygous state was found at the frequency of 2.2% in Dogon and 4% in Malinke. No homozygous state was found in our study population.We conclude that G6PD deficiency is not differing significantly between the three ethnic groups, Fulani, Dogon and Malinke. PMID- 24952160 TI - Study on dioxygen reduction by mutational modifications of the hydrogen bond network leading from bulk water to the trinuclear copper center in bilirubin oxidase. AB - The hydrogen bond network leading from bulk water to the trinuclear copper center in bilirubin oxidase is constructed with Glu463 and water molecules to transport protons for the four-electron reduction of dioxygen. Substitutions of Glu463 with Gln or Ala were attributed to virtually complete loss or significant reduction in enzymatic activities due to an inhibition of the proton transfer steps to dioxygen. The single turnover reaction of the Glu463Gln mutant afforded the highly magnetically interacted intermediate II (native intermediate) with a broad g=1.96 electron paramagnetic resonance signal detectable at cryogenic temperatures. Reactions of the double mutants, Cys457Ser/Glu463Gln and Cys457Ser/Glu463Ala afforded the intermediate I (peroxide intermediate) because the type I copper center to donate the fourth electron to dioxygen was vacant in addition to the interference of proton transport due to the mutation at Glu463. The intermediate I gave no electron paramagnetic resonance signal, but the type II copper signal became detectable with the decay of the intermediate I. Structural and functional similarities between multicopper oxidases are discussed based on the present mutation at Glu463 in bilirubin oxidase. PMID- 24952163 TI - Protective effect of ellagic acid on healing alveolar bone after tooth extraction in rat--a histological and immunohistochemical study. AB - OBJECTIVE: This study has attempted to evaluate the effects of ellagic acid (EA) on alveolar bone healing after tooth extraction in rats. DESIGN: Twenty-four Sprague Dawley (SD) male rats (200-250g) were selected and were anaesthetised for the extraction of upper left incisor. Then, the rats were divided into two groups, comprising 12 rats each; the first group has been considered as a control group and was given only normal saline, whereas, the second group (treated group) was intragastrically administrated with EA daily once, for 28 days. Then three rats from each group had been selected on 7th, 14th, 21st, and 28th days to dissect their maxilla tissue either for histological observation and homogenisation purposes. The tissues fixed, decalcified and embedded in paraffin. Serial sections of 5MUm thickness were prepared and stained with haematoxylin and eosin (H&E) for the histological study. Similar sections were taken for immunohistochemical analysis to assess osteocalcin (OSC) and osteopontin (OPN). Furthermore, Malondialdehyde (MDA) and superoxide dismutase (SOD) were measured in homogenated gingival maxilla tissue of rat by commercial kit. RESULTS: Based on the histological analysis we have identified that, EA treatment has induced earlier trabecular bone deposition in the treated group, resulting in more organised bone matrix on the 14th, 21st, and 28th days after tooth extraction, as against the control group. In comparison to control group, the positive labelling of OSC and OPN of the treated group have been highly expressed in the alveolar socket on 14th, and 21st days, which has indicated a the possibility of formation of new bone trabeculae at the beginning of the mineralisation process, after tooth extraction. In the EA treatment group, lipid per-oxidation (MDA) was significantly decreased (P<0.05), as opposed to the control group. However, the antioxidant defense enzyme (SOD) was significantly increased in the maxilla tissue treated with EA (P<0.05), compared to control group, which suggests that, after tooth extraction, EA plays an important role in the protection against the induction of lipid per-oxidation, particularly after 28 days of treatment with EA. CONCLUSION: This study has concluded that, EA may accelerated the healing process in teeth socket of rats. Furthermore, the EA treated group showed a stronger positive immunolabelling for OSC and OPN, when compared with the control group. PMID- 24952164 TI - Alkaline and alkaline peroxide pretreatments at mild temperature to enhance enzymatic hydrolysis of rice hulls and straw. AB - The current study explores alkaline and alkaline peroxide pretreatments in order to achieve a method to improve saccharification of agricultural residues for ethanol production. The effects of reagent concentration and pretreatment time at 30 degrees C and atmospheric pressure on biomass dissolution after the pretreatment and enzymatic hydrolysis of the pretreated biomass were investigated. In fact, although all pretreatments tested improved enzymatic hydrolysis of native residues, the best results were not achieved for the highest biomass loss. The maximum conversions to reducing sugars in the hydrolysis stage of 77.5% and 92.6% were obtained for rice hulls and straw pretreated by alkaline peroxide (4%, 24h) and alkaline (1%, 48 h) methods, respectively. For both pretreated residues, the reduction to more than half the recommended enzyme loading allowed obtaining more than 94% the reducing sugars attained with the recommended dose. PMID- 24952165 TI - On the essentials of etiological research for preventive medicine. PMID- 24952167 TI - Status and thoughts of Chinese patent medicines seeking approval in the US market. AB - VeregenTM and Fulyzaq are the first two botanical drug products that were approved by the Food and Drug Administration (FDA) to market in the US in recent years. Additional herbal medicines, including Compound Danshen Dripping Pills, Fuzheng Huayu Tablets, Xuezhikang Capsule, Guizhi Fuling Capsule, Kanglaite Capsule and Kanglaite Injection, have filed the investigational new drug (IND) application to the FDA and are in phase II or phase III clinical development. In order to gain better understanding of the process of botanical drug approval in the US, this article examines the aforementioned drugs by looking at their composition, indication, prior clinical experience and clinical development process, and summarizes key features that enabled IND filing and marketing approval by the FDA. PMID- 24952166 TI - Anemia in the general population: prevalence, clinical correlates and prognostic impact. AB - Low hemoglobin concentration is associated with increased mortality, but there is disagreement with regard to the clinical definition of anemia. We aimed to evaluate the prevalence, clinical correlates and association with total and cause specific long-term mortality across the hemoglobin distribution and for previously proposed definitions of anemia. Blood hemoglobin concentration and mean corpuscular volume was measured in participants of the Malmo diet and cancer study-a prospective cohort study, and related to baseline characteristics and outcomes during follow-up. Primary endpoints were all-cause mortality, cardiovascular mortality and cancer-related mortality. A U-shaped association of hemoglobin with total mortality was observed in spline regression analyses, with nadir at hemoglobin 150 g/L among men and 130 g/L among women. Mortality increased steeply with more strict definitions of anemia, hazard ratio: 1.36, 1.94 and 2.16 for hemoglobin <140/130 (men/women), 132/122 and 130/120 g/L, respectively. Similar trends were seen for both cancer- and cardiovascular mortality. The incidence of coronary disease and cancer did not differ across groups. Erythrocyte volume was an independent predictor of mortality, with the highest mortality observed for macrocytic anemia, which was less prevalent than microcytic and normocytic anemia. Dietary intake of iron and vitamin B12 were significantly lower and use of antithrombotic medications was significantly higher in subjects with anemia. The World Health Organisation definition of anemia was associated with increased mortality (hazard ratio 2.16) but excess mortality was also observed at higher hemoglobin levels. Of morphological subtypes, anemia with macrocytosis was rare but associated with the highest mortality. PMID- 24952168 TI - Underlying mechanisms of Tai-Chi-Chuan training for improving balance ability in the elders. AB - OBJECTIVE: To compare balance ability between elderly individuals who practiced Tai-Chi-Chuan (TCC) for average 9.64 years and elderly individuals who did not practice TCC and its relationship with lower extremity muscle strength and ankle proprioception. METHODS: Twenty-five elderly volunteers were divided into two groups according to their TCC practcing experience. Sixteen were TCC group and the other nine were control population. Subjects completed a static balance test and ankle proprioception test using a custom-designed evaluation system, and concentric and eccentric knee extensor and flexor muscle strength tests. Subjects stood on the plate form to measure the proprioception in functional standing position which was differed from the previous studies. Multiple linear regressions were also used to predict the important factor affecting balance. RESULTS: TCC group performed better than the control group in balance, proprioception, and muscle strength of lower extremity. The proprioception was the most important factor related to balance ability and it can be accounted for explaining 44% of variance in medial-lateral sway direction, and 53% of variance in antero-posterior sway direction. The proprioception may be a more important factor which affecting the balance ability. CONCLUSION: TCC training is recommended to the elders; as it can improve balance ability through better proprioception. PMID- 24952169 TI - Nodule and eminence on frenulum labii superioris: diagnostic markers for metastatic colorectal cancer. AB - OBJECTIVE: To determine whether the nodule and eminence on the frenulum labii superioris, location of Yinjiao (DU28) according to the meridian theory, could be used to prognosticate the recurrence of patients with colorectal cancer. METHODS: The data of 101 patients with colorectal cancer in Tianjin Medical University Cancer Institute and Hospital from May 2011 to November 2011 was analyzed. The photos of all patients' frenulum labii superioris were taken. Nodule and eminence on frenulum labii superioris were the positive standard. Biopsy and pathological testing for the nodule were carried out on one patient with large nodule on frenulum labii superioris. RESULTS: Patients with positive frenulum labii superioris had a higher risk of recurrence and/or metastasis than patients with negative frenulum labii superioris. There were no significant differences in diagnosis of recurrence and/or metastasis between the status of frenulum labii superioris and the traditional diagnostic criteria (P =0.238). The Kappa was 0.606 (P <0.001). The sensitivity was 76.0% and the specificity was 85.4%. The pathological report demonstrated that the nodule on frenulum labii superioris was mucosal excrescence with normal structure. CONCLUSION: Nodule and eminence on frenulum labii superioris are potential diagnostic markers for metastatic colorectal cancer. PMID- 24952170 TI - Effect of modified Zhuye Shigao Decoction and its components on preventing radiation esophagitis of rats. AB - OBJECTIVE: To investigate the effect of Modified Zhuye Shigao Decoction (MZSD) and its components on preventing radiation esophagitis of rats. METHODS: One hundred Wistar rats were randomly divided into 5 groups, including the control group, radiation model group, MZSD group, Zhuye Shigao Decoction (ZSD) group, and added ingredients group, 20 rats in each group. The model of radiation esophagitis of rat was established by once local radiation of 40 Gy (330 Mu/min) with a high energy linear accelerator. The administration of Chinese medicine was continued for 14 days from 7 days before radiation application in the three treatment groups. On the 7th and 14th day, the serum was isolated and the levels of inflammatory cytokines tumor necrosis factor (TNF-alpha), interleukin 1beta (IL-1beta) and IL-8 were tested. The pathological slices of esophagus were obtained, and the pathological changes were observed. During the whole process, weight and food intake were recorded each day. RESULTS: On the 7th day after radiation, the esophagus of rats in the MZSD group was almost intact, and the pathological injury score was significantly lower than that of the radiation model group, ZSD group and added ingredients group (P<0.01). Compared with the control group, the body weight and food intake of rats in the radiation model group were significantly decreased, and the levels of TNF-alpha, IL-1beta and IL 8 were significantly increased (P<0.05 or P<0.01), while the MZSD group showed a significant increase in body weight and food intake, and a significant decrease in the levels of TNF-alpha, IL-1beta and IL-8 compared with the radiation model group, ZSD group and added ingredients group (P <0.05 or P<0.01). CONCLUSION: MZSD prevents the development of radiation esophagitis probably by inhibiting the generation and release of the inflammatory cytokines TNF-alpha, IL-1beta and IL 8. PMID- 24952172 TI - beta-chain of ATP synthase as a lipophorin binding protein and its role in lipid transfer in the midgut of Panstrongylus megistus (Hemiptera: Reduviidae). AB - Lipophorin, the main lipoprotein in the circulation of the insects, cycles among peripheral tissues to exchange its lipid cargo at the plasma membrane of target cells, without synthesis or degradation of its apolipoprotein matrix. Currently, there are few characterized candidates supporting the functioning of the docking mechanism of lipophorin-mediated lipid transfer. In this work we combined ligand blotting assays and tandem mass spectrometry to characterize proteins with the property to bind lipophorin at the midgut membrane of Panstrongylus megistus, a vector of Chagas' disease. We further evaluated the role of lipophorin binding proteins in the transfer of lipids between the midgut and lipophorin. The beta subunit of the ATP synthase complex (beta-ATPase) was identified as a lipophorin binding protein. beta-ATPase was detected in enriched midgut membrane preparations free of mitochondria. It was shown that beta-ATPase partially co localizes with lipophorin at the plasma membrane of isolated enterocytes and in the sub-epithelial region of the midgut tissue. The interaction of endogenous lipophorin and beta-ATPase was also demonstrated by co-immunoprecipitation assays. Blocking of beta-ATPase significantly diminished the binding of lipophorin to the isolated enterocytes and to the midgut tissue. In vivo assays injecting the beta-ATPase antibody significantly reduced the transfer of [(3)H] diacylglycerol from the midgut to the hemolymph in insects fed with [9,10-(3)H] oleic acid, supporting the involvement of lipophorin-beta-ATPase association in the transfer of lipids. In addition, the beta-ATPase antibody partially impaired the transfer of fatty acids from lipophorin to the midgut, a less important route of lipid delivery to this tissue. Taken together, the findings strongly suggest that beta-ATPase plays a role as a docking lipophorin receptor at the midgut of P. megistus. PMID- 24952171 TI - Characterization of a novel Manduca sexta beta-1, 3-glucan recognition protein (betaGRP3) with multiple functions. AB - Recognition of pathogens by insect pattern recognition receptors is critical to mount effective immune responses. In this study, we reported a new member (betaGRP3) of the beta-1, 3-glucan recognition protein (betaGRP) family from the tobacco hornworm Manduca sexta. Unlike other members of the M. sexta betaGRP family proteins, which contain an N-terminal small glucan binding domain and a C terminal large glucanase-like domain, betaGRP3 is 40-45 residues shorter at the N terminus and lacks the small glucan binding domain. The glucanase-like domain of betaGRP3 is most similar to that of M. sexta microbe binding protein (MBP) with 78% identity. betaGRP3 transcript was mainly expressed in the fat body, and both its mRNA and protein levels were not induced by microorganisms in larvae. Recombinant betaGRP3 purified from Drosophila S2 cells could bind to several Gram negative and Gram-positive bacteria and yeast, as well as to laminarin (beta-1, 3 glucan), mannan, lipopolysaccharide (LPS), lipoteichoic acid (LTA), and meso diaminopimelic acid (DAP)-type peptidoglycan (PG), but did not bind to Lysine type PG. Binding of betaGRP3 to laminarin could be competed well by free laminarin, mannan, LPS and LTA, but almost not competed by free PGs. Recombinant betaGRP3 could agglutinate Bacillus cereus and Escherichia coli in a calcium dependent manner and showed antibacterial (bacteriostatic) activity against B. cereus, novel functions that have not been reported for the betaGRP family proteins before. M. sexta betaGRP3 may serve as an immune surveillance receptor with multiple functions. PMID- 24952173 TI - Identification and comparative analysis of G protein-coupled receptors in Pediculus humanus humanus. AB - The body louse has the smallest genome size among the known genome-sequenced insects. Here, 81 GPCRs were identified in Pediculus humanus humanus, 56, 14, 6 and 5 GPCRs for family-A, -B, -C and -D, respectively. These GPCRs constitute the comparable repertoire of GPCRs with other insects. Moreover, it contains a more complete set of neuropeptide and protein hormone receptors not even than Acyrthosiphon pisum but also Drosophila melanogaster, for example, Sulfakinin, Corazonin, Trissin and PTHRL only presented in P. h. humanus but lost either in A. pisum or D. melanogaster. However, it has less duplication among the sub families. Meanwhile, ACP, AVPL, HE6 receptors and Boss were also absent from P. h. humanus. These results indicated that the repertoire of GPCRs in P. h. humanus were not affected by its smallest genome size, and further suggested that P. h. humanus has a relatively original and concise GPCR regulation system. PMID- 24952174 TI - Furosemide diminishes 18F-fluoroethylcholine uptake in prostate cancer in vivo. AB - PURPOSE: (18)F-Fluoroethylcholine ((18)F-FECh) is excreted via the urinary system with high activity accumulation in the urinary bladder. Furosemide and oral hydration can be administered concomitantly to reduce urinary activity to provide better detectability of retroperitoneal and pelvic lesions. Currently it is unknown if there is any effect of furosemide on (18)F-FECh uptake in organs, tissues and tumour lesions and the extent to which image quality along the urinary tract may be improved by furosemide. METHODS: We retrospectively analysed 217 (18)F-FECh PET/CT examinations from 213 patients with known prostate cancer (PCa), performed either with oral hydration (109) or furosemide 20 mg together with oral hydration (108). Maximum (18)F-FECh uptake in different organs, tissues, lymph nodes and osseous metastases was quantified in terms of standardized uptake value (SUV) in a volume of interest and compared between the two groups. To characterize the impact of furosemide on lesion detectability a three-point rating scale was used to assess the presence of focal activity spots in the ureters and of perivesicular artefacts. RESULTS: Patient characteristics and distribution of tumour lesions were well balanced between the two groups. Overall, SUVmax values from normal organs were increased after furosemide compared to the values in patients scanned without furosemide. Significant changes were observed in the salivary glands, liver, spleen, pancreas, kidneys, gluteus muscle and perirenal fat. SUVmax values were significantly decreased after furosemide in lymph node metastases (SUVmax 4.81 +/- 2.68 vs. 6.48 +/- 4.22, p = 0.0006), but not in osseous metastases. Evaluation of image quality along the urinary tract revealed significantly better depiction of the perivesicular space and significantly less focal tracer accumulation in the ureters in patients receiving furosemide, but the number of detected lymph nodes was not significantly different. CONCLUSION: Furosemide administration reduced choline uptake in tumour lesions, especially significant in pelvic lymph node metastases. Although furosemide administration improved image quality, optimal image quality may also be obtained by adequate hydration without the risk of diminishing choline uptake in PCa lesions. Therefore a controlled hydration protocol seems more appropriate than administration of furosemide. PMID- 24952177 TI - MALDI profiling and applications in medicine. AB - Matrix-assisted laser desorption ionisation (MALDI) mass spectrometry allows for the rapid profiling of different biomolecular species from both biofluids and tissues. Whilst originally focussed upon the analysis of intact proteins and peptides, MALDI mass spectrometry has found further applications in lipidomic analysis, genotyping, micro-organism identification, biomarker discovery and metabolomics. The combining of multiple profiles data from differing locations across a sample, furthermore, allows for spatial distribution of biomolecules to be established utilising imaging MALDI analysis. This chapter discusses the MALDI process, its usual applications in the field of protein identification via peptide mass fingerprinting before focusing upon advances in the application of the profiling potential of MALDI mass spectrometry and its various applications in biomedicine. PMID- 24952176 TI - Mass spectrometry for proteomics-based investigation. AB - Within the past years, we have witnessed a great improvement in mass spectrometry (MS) and proteomics approaches in terms of instrumentation, protein fractionation, and bioinformatics. With the current technology, protein identification alone is no longer sufficient. Both scientists and clinicians want not only to identify proteins but also to identify the protein's posttranslational modifications (PTMs), protein isoforms, protein truncation, protein-protein interaction (PPI), and protein quantitation. Here, we describe the principle of MS and proteomics and strategies to identify proteins, protein's PTMs, protein isoforms, protein truncation, PPIs, and protein quantitation. We also discuss the strengths and weaknesses within this field. Finally, in our concluding remarks we assess the role of mass spectrometry and proteomics in scientific and clinical settings in the near future. This chapter provides an introduction and overview for subsequent chapters that will discuss specific MS proteomic methodologies and their application to specific medical conditions. Other chapters will also touch upon areas that expand beyond proteomics, such as lipidomics and metabolomics. PMID- 24952175 TI - A homozygous mutation in the NDUFS1 gene presents with a mild cavitating leukoencephalopathy. AB - We report a case of mild cavitating leukoencephalopathy associated with a homozygous c.755A > G (p.Asp252Gly) NDUFS1 mutation in a 7-year old boy. Biochemical analysis confirmed an isolated reduction in complex I activity. Magnetic resonance imaging of the brain showed a diffuse cystic leukoencephalopathy with the involvement of the corpus callosum and sparing of the gray matter. The clinical course was marked by an acute presentation of neurological deficits at 24 months followed by recurrent episodes of mild neurological deterioration, subsequent remissions, and prolonged periods of stability. This is one of the mildest known clinical presentations of complex I deficiency secondary to mutations in NDUFS1, expanding the clinical spectrum and natural history of this disorder. Consideration of clinical variability needs to be taken into account in patient management and family counseling. PMID- 24952178 TI - Simplifying the proteome: analytical strategies for improving peak capacity. AB - The diversity of biological samples and dynamic range of analytes being analyzed can prove to be an analytical challenge and is particularly prevalent to proteomic studies. Maximizing the peak capacity of the workflow employed can extend the dynamic range and increase identification rates. The focus of this chapter is to present means of achieving this for various analytical techniques such as liquid chromatography, mass spectrometry, and ion mobility. A combination of these methods can be used as part of a data-independent acquisition strategy, thereby limiting issues such as chimericy when analyzing regions of extreme analyte density. PMID- 24952179 TI - Quantitative shotgun proteomics with data-independent acquisition and traveling wave ion mobility spectrometry: a versatile tool in the life sciences. AB - Data-independent acquisition (DIA) implemented in a method called MS(E) can be performed in a massively parallel, time-based schedule rather than by sampling masses sequentially in shotgun proteomics. In MS(E) alternating low and high energy spectra are collected across the full mass range. This approach has been very successful and stimulated the development of variants modeled after the MS(E) protocol, but over narrower mass ranges. The massively parallel MS(E) and other DIA methodologies have enabled effective label-free quantitation methods that have been applied to a wide variety of samples including affinity pulldowns and studies of cells, tissues, and clinical samples. Another complementary technology matches accurate mass and retention times of precursor ions across multiple chromatographic runs. This further enhances the impact of MS(E) in counteracting the stochastic nature of mass spectrometry as applied in proteomics. Otherwise significant amounts of data in typical large-scale protein profiling experiments are missing. A variety of software packages perform this function similar in concept to matching of accurate mass tags. Another enhancement of this method involves a variation of MS(E) coupled with traveling wave ion mobility spectrometry to provide separations of peptides based on cross sectional area and shape in addition to mass/charge (m/z) ratio. Such a two dimensional separation in the gas phase considerably increases protein coverage as well as typically a doubling of the number of proteins detected. These developments along with advances in ultrahigh pressure liquid chromatography have resulted in the evolution of a robust and versatile platform for label-free protein profiling. PMID- 24952180 TI - Stable isotope labeling by amino acids in cell culture (SILAC) for quantitative proteomics. AB - Stable isotope labeling by amino acids in cell culture (SILAC) is a powerful approach for high-throughput quantitative proteomics. SILAC allows highly accurate protein quantitation through metabolic encoding of whole cell proteomes using stable isotope labeled amino acids. Since its introduction in 2002, SILAC has become increasingly popular. In this chapter we review the methodology and application of SILAC, with an emphasis on three research areas: dynamics of posttranslational modifications, protein-protein interactions, and protein turnover. PMID- 24952181 TI - Utility of computational structural biology in mass spectrometry. AB - Recent developments of mass spectrometry (MS) allow us to identify, estimate, and characterize proteins and protein complexes. At the same time, structural biology helps to determine the protein structure and its structure-function relationship. Together, they aid to understand the protein structure, property, function, protein-complex assembly, protein-protein interaction and dynamics. The present chapter is organized with illustrative results to demonstrate how experimental mass spectrometry can be combined with computational structural biology for detailed studies of protein's structures. We have used tumor differentiation factor protein/peptide as ligand and Hsp70/Hsp90 as receptor protein as examples to study ligand-protein interaction. To investigate possible protein conformation we will describe two proteins, lysozyme and myoglobin. PMID- 24952182 TI - Affinity-mass spectrometry approaches for elucidating structures and interactions of protein-ligand complexes. AB - Affinity-based approaches in combination with mass spectrometry for molecular structure identification in biological complexes such as protein-protein, and protein-carbohydrate complexes have become popular in recent years. Affinity-mass spectrometry involves immobilization of a biomolecule on a chemically activated support, affinity binding of ligand(s), dissociation of the complex, and mass spectrometric analysis of the bound fraction. In this chapter the affinity-mass spectrometric methodologies will be presented for (1) identification of the epitope structures in the Abeta amyloid peptide, (2) identification of oxidative modifications in proteins such as nitration of tyrosine, (3) determination of carbohydrate recognition domains, and as (4) development of a biosensor chip based mass spectrometric system for concomitant quantification and identification of protein-ligand complexes. PMID- 24952183 TI - Neurological analyses: focus on gangliosides and mass spectrometry. AB - Gangliosides, sialylated glycosphingolipids, are particularly enriched in mammalian central nervous system where their expression is cell type-specific and changes particularly during brain development, maturation, aging, and diseases. For this reason, gangliosides are important diagnostic markers for various brain ailments, including primary and secondary brain tumors and neurodegenerative diseases. Among all biochemical and biophysical methods employed so far for ganglioside analysis, mass spectrometry (MS) emerged as one of the most reliable due to the sensitivity, accuracy, and speed of analysis as well as the possibility to characterize in details the molecular structure of the identified biomarkers.This chapter presents significant achievements of MS with either electrospray (ESI), chip-based ESI, or matrix-assisted laser desorption/ionization (MALDI) in the analysis of gangliosides in normal and diseased human brain. Specifically, the chapter assesses the MS contribution in determination of topospecificity, filogenetic, and brain development stage dependence of ganglioside composition and structure as well as in discovery of ganglioside markers in neurodegenerative/neurodevelopmental conditions, primary and secondary brain tumors. The highlighted accomplishments in characterization of novel structures associated to severe brain pathologies show that MS has real perspectives to become a routine method for early diagnosis and therapy based on this biomolecule class. PMID- 24952184 TI - Mass spectrometric analysis of post-translational modifications (PTMs) and protein-protein interactions (PPIs). AB - Of the 25,000-30,000 human genes, about 2 % code for proteins. However, there are about one to two million protein entities. This is primarily due to alternative splicing and post-translational modifications (PTMs). Identifying all these modifications in one proteome at a particular time point during development or during the transition from normal to cancerous cells is a great challenge to scientists. In addition, identifying the biological significance of all these modifications, as well as their nature, such as stable versus transient modifications, is an even more challenging. Furthermore, interaction of proteins and protein isoforms that have one or more stable or transient PTMs with other proteins and protein isoforms makes the study of proteins daunting and complex. Here we review some of the strategies to study proteins, protein isoforms, protein PTMs, and protein-protein interactions (PPIs). Our goal is to provide a thorough understanding of these proteins and their isoforms, PTMs and PPIs and to shed light on the biological significance of these factors. PMID- 24952185 TI - Applications for mass spectrometry in the study of ion channel structure and function. AB - Ion channels are intrinsic membrane proteins that form gated ion-permeable pores across biological membranes. Depending on the type, ion channels exhibit sensitivities to a diverse range of stimuli including changes in membrane potential, binding by diffusible ligands, changes in temperature and direct mechanical force. The purpose of these proteins is to facilitate the passive diffusion of ions down their respective electrochemical gradients into and out of the cell, and between intracellular compartments. In doing so, ion channels can affect transmembrane potentials and regulate the intracellular homeostasis of the important second messenger, Ca(2+). The ion channels of the plasma membrane are of particular clinical interest due to their regulation of cell excitability and cytosolic Ca(2+) levels, and the fact that they are most amenable to manipulation by exogenously applied drugs and toxins. A critical step in improving the pharmacopeia of chemicals available that influence the activity of ion channels is understanding how their three-dimensional structure imparts function. Here, progress has been slow relative to that for soluble protein structures in large part due to the limitations of applying conventional structure determination methods, such as X-ray crystallography, nuclear magnetic resonance imaging, and mass spectrometry, to membrane proteins. Although still an underutilized technique in the assessment of membrane protein structure, recent advances have pushed mass spectrometry to the fore as an important complementary approach to studying the structure and function of ion channels. In addition to revealing the subtle conformational changes in ion channel structure that accompany gating and permeation, mass spectrometry is already being used effectively for identifying tissue-specific posttranslational modifications and mRNA splice variants. Furthermore, the use of mass spectrometry for high-throughput proteomics analysis, which has proven so successful for soluble proteins, is already providing valuable insight into the functional interactions of ion channels within the context of the macromolecular-signaling complexes that they inhabit in vivo. In this chapter, the potential for mass spectrometry as a complementary approach to the study of ion channel structure and function will be reviewed with examples of its application. PMID- 24952187 TI - Mass spectrometry-based tissue imaging of small molecules. AB - Mass spectrometry imaging (MSI) of tissue samples is a promising analytical tool that has quickly become associated with biomedical and pharmacokinetic studies. It eliminates several labor-intensive protocols associated with more classical imaging techniques and provides accurate histological data at a rapid pace. Because mass spectrometry is used as the readout, MSI can be applied to almost any molecule, especially those that are biologically relevant. Many examples of its utility in the study of peptides and proteins have been reported; here we discuss its value in the mass range of small molecules. We explore its success and potential in the analysis of lipids, medicinals, and metal-based compounds by featuring representative studies from MSI laboratories around the globe. PMID- 24952189 TI - Analysis of fluorinated proteins by mass spectrometry. AB - (19)F NMR has been used as a probe for investigating bioorganic and biological systems for three decades. Recent reviews have touted this nucleus for its unique characteristics that allow probing in vivo biological systems without endogenous signals. (19)F nucleus is exceptionally sensitive to molecular and microenvironmental changes and thus can be exploited to explore structure, dynamics, and changes in a protein or molecule in the cellular environment. We show how mass spectrometry can be used to assess and characterize the incorporation of fluorine into proteins. This methodology can be applied to a number of systems where (19)F NMR is used. PMID- 24952188 TI - Redox proteomics: from bench to bedside. AB - In general protein posttranslation modifications (PTMs) involve the covalent addition of functional groups or molecules to specific amino acid residues in proteins. These modifications include phosphorylation, glycosylation, S nitrosylation, acetylation, lipidation, among others (Angew Chem Int Ed Engl 44(45):7342-7372, 2005). Although other amino acids can undergo different kinds of oxidative posttranslational modifications (oxPTMs) (Exp Gerontol 36(9):1495 1502, 2001), in this chapter oxPTM will be considered specifically related to Cysteine oxidation, and redox proteomics here is translated as a comprehensive investigation of oxPTMs, in biological systems, using diverse technical approaches. Protein Cysteine residues are not the only amino acid that can be target for oxidative modifications in proteins (Exp Gerontol 36(9):1495-1502, 2001; Biochim Biophys Acta 1814(12):1785-1795, 2011), but certainly it is among the most reactive amino acid (Nature 468(7325):790-795, 2010). Interestingly, it is one of the least abundant amino acid, but it often occurs in the functional sites of proteins (J Mol Biol 404(5):902-916, 2010). In addition, the majority of the Cysteine oxidations are reversible, indicating potential regulatory mechanism of proteins. The global analysis of oxPTMs has been increasingly recognized as an important area of proteomics, because not only maps protein caused by reactive oxygen species (ROS) and reactive nitrogen species (RNS), but also explores protein modulation involving ROS/RNS. Furthermore, the tools and strategies to study this type oxidation are also very abundant and developed, offering high degree of accuracy on the results. As a consequence, the redox proteomics field focuses very much on analyzing Cysteine oxidation in proteins under several experimental conditions and diseases states. Therefore, the identification and localization of oxPTMs within cellular milieu became critical to understand redox regulation of proteins in physiological and pathological conditions, and consequently an important information to develop better strategies for treatment and prevention of diseases associated with oxidative stress.There is a wide range of techniques available to investigate oxPTMs, including gel-based and non-gel based separation approaches to be combined with sophisticated methods of detection, identification, and quantification of these modifications. The strategies and approaches to study oxPTMs and the respective applications related to physiological and pathological conditions will be discussed in more detail in this chapter. PMID- 24952190 TI - Mass spectrometry for proteomics-based investigation using the zebrafish vertebrate model system. AB - The zebrafish (Danio rerio) is frequently being used to investigate the genetics of human diseases as well as resulting pathologies. Ease of both forward and reverse genetic manipulation along with conservation of vertebrate organ systems and disease causing genes has made this system a popular model. Many techniques have been developed to manipulate the genome of zebrafish producing mutants in a vast array of genes. While genetic manipulation of zebrafish has progressed, proteomics have been under-utilized. This review highlights studies that have already been performed using proteomic techniques and as well as our initial proteomic work comparing changes to the proteome between the ascl1a-/- and WT intestine. PMID- 24952186 TI - A mass spectrometry view of stable and transient protein interactions. AB - Through an impressive range of dynamic interactions, proteins succeed to carry out the majority of functions in a cell. These temporally and spatially regulated interactions provide the means through which one single protein can perform diverse functions and modulate different cellular pathways. Understanding the identity and nature of these interactions is therefore critical for defining protein functions and their contribution to health and disease processes. Here, we provide an overview of workflows that incorporate immunoaffinity purifications and quantitative mass spectrometry (frequently abbreviated as IP-MS or AP-MS) for characterizing protein-protein interactions. We discuss experimental aspects that should be considered when optimizing the isolation of a protein complex. As the presence of nonspecific associations is a concern in these experiments, we discuss the common sources of nonspecific interactions and present label-free and metabolic labeling mass spectrometry-based methods that can help determine the specificity of interactions. The effective regulation of cellular pathways and the rapid reaction to various environmental stresses rely on the formation of stable, transient, and fast-exchanging protein-protein interactions. While determining the exact nature of an interaction remains challenging, we review cross-linking and metabolic labeling approaches that can help address this important aspect of characterizing protein interactions and macromolecular assemblies. PMID- 24952191 TI - Mass spectrometry-based biomarkers in drug development. AB - Advances in mass spectrometry, proteomics, protein bioanalytical approaches, and biochemistry have led to a rapid evolution and expansion in the area of mass spectrometry-based biomarker discovery and development. The last decade has also seen significant progress in establishing accepted definitions, guidelines, and criteria for the analytical validation, acceptance, and qualification of biomarkers. These advances have coincided with a decreased return on investment for pharmaceutical research and development and an increasing need for better early decision making tools. Empowering development teams with tools to measure a therapeutic interventions impact on disease state and progression, measure target engagement, and to confirm predicted pharmacodynamic effects is critical to efficient data-driven decision making. Appropriate implementation of a biomarker or a combination of biomarkers can enhance understanding of a drugs mechanism, facilitate effective translation from the preclinical to clinical space, enable early proof of concept and dose selection, and increase the efficiency of drug development. Here we will provide descriptions of the different classes of biomarkers that have utility in the drug development process as well as review specific, protein-centric, mass spectrometry-based approaches for the discovery of biomarkers and development of targeted assays to measure these markers in a selective and analytically precise manner. PMID- 24952192 TI - Detection of biomedically relevant stilbenes from wines by mass spectrometry. AB - Stilbenes represent a class of compounds with a common 1,2-diphenylethylene backbone that have shown extraordinary potential in the biomedical field. As the most well-known example, resveratrol proved to have anti-aging effects and significant potential in the fight against cardiovascular diseases and some types of cancer. Mass spectrometry is an analytical method of critical importance in all studies related to stilbenes that are important in the biomedical field. From the discovery of new natural compounds and mapping the grape metabolome up to advanced investigations of stilbenes' potential for the protection of human health in clinical studies, mass spectrometry has provided critical analytical information. In this review we focus on various approaches related to mass spectrometry for the detection of stilbenes-such as coupling with chromatographic separation methods and direct infusion-with presentation of some illustrative applications. Clearly, the potential of mass spectrometry for assisting in the discovery of new stilbenes of biomedical importance, elucidating their mechanisms of action, and quantifying minute quantities in complex matrices is far from being exhausted. PMID- 24952193 TI - Mass spectrometric DNA adduct quantification by multiple reaction monitoring and its future use for the molecular epidemiology of cancer. AB - The formation of DNA adducts is considered essential for tumor initiation. Quantification of DNA adducts may be achieved by various techniques of which LC MS/MS-based multiple reaction monitoring has become the most prominent in the past decade. Adducts of single nucleosides are analyzed following enzymatic break down of a DNA sample following adduct enrichment usually by solid-phase extraction. LC-MS/MS quantification is carried out using stable isotope-labeled internal reference substances. An upcoming challenge is the use of DNA adducts as biomarkers either for internal exposure to electrophilic genotoxins or for the approximation of cancer risk. Here we review recent studies in which DNA adducts were quantified by LC-MS/MS in DNA samples from human matrices. We outline a possible way for future research to aim at the development of an "adductome" approach for the characterization of DNA adduct spectra in human tissues. The DNA adduct spectrum reflects the inner exposure of an individual's tissue to electrophilic metabolites and, therefore, should replace the conventional and inaccurate external exposure in epidemiological studies in the future. PMID- 24952194 TI - Using breast milk to assess breast cancer risk: the role of mass spectrometry based proteomics. AB - Although mammography and treatment advances have led to declines in breast cancer mortality in the United States, breast cancer remains a major cause of morbidity and mortality. Breast cancer in young women is associated with increased mortality and current methods of detecting breast cancers in this group of women have known limitations. Tools for accurately assessing personal breast cancer risk in young women are needed to identify those women who would benefit the most from earlier intervention. Proteomic analysis of breast milk could identify biomarkers of breast cancer risk and provide a tool for identifying women at increased risk. A preliminary analysis of milk from four women provides a proof of concept for using breast milk to assess breast cancer risk. PMID- 24952195 TI - Cancer secretomes and their place in supplementing other hallmarks of cancer. AB - The secretome includes all macromolecules secreted by cells, in particular conditions at defined times, allowing cell-cell communication. Cancer cell secretomes that are altered compared to normal cells have shown significant potential for elucidating cancer biology. Proteins of secretomes are secreted by various secretory pathways and can be studied using different methods. Cancer secretomes seem to play an important role in known hallmarks of cancers such as excessive proliferation, reduced apoptosis, immune invasion, angioneogenesis, alteration in energy metabolism, and development of resistance against anti cancer therapy [1, 2]. If a significant role of an altered secretome can be identified in cancer cells, using advanced mass spectrometry-based techniques, this may allow researchers to screen and characterize the secretome proteins involved in cancer progression and open up new opportunities to develop new therapies. We aim to elaborate upon recent advances in cancer cell secretome analysis using different proteomics techniques. In this review, we highlight the role of the altered secretome in contributing to already recognized and emerging hallmarks of cancer and we discuss new challenges in the field of secretome analysis. PMID- 24952196 TI - Thiostrepton, a natural compound that triggers heat shock response and apoptosis in human cancer cells: a proteomics investigation. AB - Thiostrepton is a natural antibiotic produced by bacteria of Streptomyces genus. We identified Thiostrepton as a strong hit in a cell-based small molecule screen for DIAP1 stability modulators. It was shown previously that Thiostrepton induces upregulation of several gene products in Streptomyces lividans, including the TipAS and TipAL isoforms, and that it can induce apoptotic cell death in human cancer cells. Furthermore, it was suggested that thiostrepton induces oxidative and proteotoxic stress, as inferred from the transcriptional upregulation of stress-related genes and endoplasmic reticulum (ER) stress genes. We used a combination of biochemical and proteomics approaches to investigate the effect of Thiostrepton and other compounds in human cells. Our mass-spectrometry data and subsequent biochemical validation shows that Thiostrepton (and MG-132 proteasome inhibitor) trigger upregulation of heat shock proteins HspA1A, Hsp70, Hsp90alpha, or Hsp105 in various human cancer cells. We propose a model where Thiostrepton induced proteasome inhibition leads to accumulation of protein aggregates that trigger a heat shock response and apoptosis in human cancer cells. PMID- 24952197 TI - Using proteomics to unravel the mysterious steps of the HBV-life-cycle. AB - Infection with Hepatitis B virus (HBV) is the most common cause of liver disease in the world. Infection becomes chronic in up to 10 % of adults, with severe consequences on liver function, including inflammation, fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCC is a fast progressing disease causing the death of approximately one million patients annually; current treatment has very limited success, mainly due to late-stage diagnosis and poor screening methodologies. Therefore, unraveling the complex HBV-host cell interactions during progression of the disease is of crucial importance, not only to understand the mechanisms underlying carcinogenesis, but importantly, for the development of new biomarkers for prognostic and early diagnosis. This is an area of research strongly influenced by proteomic studies, which have benefited in the last decade from major technical improvements in accuracy of quantification and sensitivity, large-scale analysis of low-abundant proteins, such as those from clinical samples being now possible and widely applied. This work is a critical review of the impact of the proteomic studies on our current understanding of HBV associated pathogenesis, diagnostics, and treatment. PMID- 24952198 TI - Oxidative stress and antibiotic resistance in bacterial pathogens: state of the art, methodologies, and future trends. AB - Despite the significant advances of modern medicine and the availability of a wide variety of antibiotics for the treatment of microbial infections, there is an alarming increase of multiresistant bacterial pathogens. This chapter discusses the status of bacterial resistance mechanisms and the relationship with oxidative stress and provides an overview of the methods used to assess oxidative conditions and their contribution to the antibiotic resistance. PMID- 24952199 TI - Proteomic approaches to dissect neuronal signaling pathways. AB - With an increasing awareness of mental health issues and neurological disorders, "understanding the brain" is one of the biggest current challenges in biological research. This has been recognized by both governments and funding agencies, and includes the need to understand connectivity of brain regions and coordinated network activity, as well as cellular and molecular mechanisms at play. In this chapter, we will describe how we have taken advantage of different proteomic techniques to unravel molecular mechanisms underlying two modulators of neuronal function: Neurotrophins and antipsychotics. PMID- 24952201 TI - Mass spectrometry for the study of autism and neurodevelopmental disorders. AB - Mass spectrometry (MS) has been increasingly used to study central nervous system disorders, including autism spectrum disorders (ASDs). The first studies of ASD using MS focused on the identification of external toxins, but current research is more directed at understanding endogenous protein changes that occur in ASD (ASD proteomics). This chapter focuses on how MS has been used to study ASDs, with particular focus on proteomic analysis. Other neurodevelopmental disorders have been investigated using this technique, including genetic syndromes associated with autism such as fragile X syndrome and Smith-Lemli-Opitz syndrome. PMID- 24952200 TI - Investigating a novel protein using mass spectrometry: the example of tumor differentiation factor (TDF). AB - Better understanding of central nervous system (CNS) molecules can include the identification of new molecules and their receptor systems. Discovery of novel proteins and elucidation of receptor targets can be accomplished using mass spectrometry (MS). We describe a case study of such a molecule, which our lab has studied using MS in combination with other protein identification techniques, such as immunohistochemistry (IHC) and Western blotting. This molecule is known as tumor differentiation factor (TDF), a recently-found protein secreted by the pituitary into the blood. TDF mRNA has been detected in brain; not heart, placenta, lung, liver, skeletal muscle, or pancreas. Currently TDF has an unclear function, and prior to our studies, its localization was only minimally understood, with no understanding of receptor targets. We investigated the distribution of TDF in the rat brain using IHC and immunofluorescence (IF). TDF protein was detected in pituitary and most other brain regions, in specific neurons but not astrocytes. We found TDF immunoreactivity in cultured neuroblastoma, not astrocytoma. These data suggest that TDF is localized to neurons, not to astrocytes. Our group also conducted studies to identify the TDF receptor (TDF-R). Using LC-MS/MS and Western blotting, we identified the members of the Heat Shock 70-kDa family of proteins (HSP70) as potential TDF-R candidates in both MCF7 and BT-549 human breast cancer cells (HBCC) and PC3, DU145, and LNCaP human prostate cancer cells (HPCC), but not in HeLa cells, NG108 neuroblastoma, or HDF-a and BLK CL.4 cell fibroblasts or fibroblast-like cells. These studies have combined directed protein identification techniques with mass spectrometry to increase our understanding of a novel protein that may have distinct actions as a hormone in the body and as a growth factor in the brain. PMID- 24952202 TI - Biomarkers in major depressive disorder: the role of mass spectrometry. AB - Major depressive disorder (MDD) is common. Despite numerous available treatments, many individuals fail to improve clinically. MDD continues to be diagnosed exclusively via behavioral rather than biological methods. Biomarkers-which include measurements of genes, proteins, and patterns of brain activity-may provide an important objective tool for the diagnosis of MDD or in the rational selection of treatments. Proteomic analysis and validation of its results as biomarkers is less explored than other areas of biomarker research in MDD. Mass spectrometry (MS) is a comprehensive, unbiased means of proteomic analysis, which can be complemented by directed protein measurements, such as Western Blotting. Prior studies have focused on MS analysis of several human biomaterials in MDD, including human post-mortem brain, cerebrospinal fluid (CSF), blood components, and urine. Further studies utilizing MS and proteomic analysis in MDD may help solidify and establish biomarkers for use in diagnosis, identification of new treatment targets, and understanding of the disorder. The ultimate goal is the validation of a biomarker or a biomarker signature that facilitates a convenient and inexpensive predictive test for depression treatment response and helps clinicians in the rational selection of next-step treatments. PMID- 24952203 TI - Application of mass spectrometry to characterize localization and efficacy of nanoceria in vivo. AB - In vivo study of nanomaterials is complicated by the physical and chemical changes induced in the nanomaterial by exposure to biological compartments. A diverse array of proteins can bind to the nanomaterial, forming a protein corona which may alter the dispersion, surface charge, distribution, and biological activity of the material. Evidence suggests that unique synthesis and stabilization strategies can greatly affect the composition of the corona, and thus, the in vivo properties of the nanomaterial. Protein and elemental analyses techniques are critical to characterizing the nature of the protein corona in order to best predict the in vivo behavior of the nanomaterial. Further, as described here, inductively coupled mass spectroscopy (ICP-MS) can also be used to quantify nanomaterial deposition in tissues harvested from exposed animals. Elemental analysis of ceria content demonstrated deposition of cerium oxide nanoparticles (CeNPs) in various tissues of healthy mice and in the brains of mice with a model of multiple sclerosis. Thus, ICP-MS analysis of nanomaterial tissue distribution can complement data illustrating the biological, and in this case, therapeutic efficacy of nanoparticles delivered in vivo. PMID- 24952204 TI - Bottlenecks in proteomics. AB - Mass spectrometry (MS) is the core for advanced methods in proteomic experiments. When effectively used, proteomics may provide extensive information about proteins and their post-translational modifications, as well as their interaction partners. However, there are also many problems that one can encounter during a proteomic experiment, including, but not limited to sample preparation, sample fractionation, sample analysis, data analysis & interpretation, and biological significance. Here we discuss some of the problems that researchers should be aware of when performing a proteomic experiment. PMID- 24952206 TI - African origin and europe-mediated global dispersal of the cyanobacterium Microcystis aeruginosa. AB - Microcystis aeruginosa is a bloom-forming cyanobacteria, which currently has a cosmopolitan distribution. Since M. aeruginosa can produce toxic compounds across all continents that it inhabits, it is of major public health relevance to assess its origin and dispersal. Thus, we conducted a worldwide study using 29 isolates representative of all the main continents, and used a concatenated genetic system for phylogenetic analyses consisting of four genetic markers (spanning ca. 3,485 bp). Our results support an early origin of M. aeruginosa in the African continent, with a subsequent dispersal to establish a second genetic pool in the European continent, from where M. aeruginosa then colonized the remaining continental regions. Our findings indicate that the European population has a cosmopolitan distribution, and is genetically closer to populations from Africa and North America. Our study also highlights the utility of using a concatenated dataset for phylogenetic inferences in cyanobacteria. PMID- 24952207 TI - Look where you're going! Perceptual attention constrains the online guidance of action. AB - Action guidance, like perceptual discrimination, requires selective attention. Perception is enhanced at the target of a reaching movement, but it is not known whether selecting an object for perception reciprocally prioritises it for action. Two theoretical frameworks, the premotor theory and the Visual Attention Model, predict that this reciprocal relation should hold. We tested the influence of perceptual attention on the online control of reaching. In Experiment 1, participants attended covertly to a flanker on one or other side of a fixated target, prior to reaching for that target, which occasionally jumped, after reach onset, to the attended or non-attended side. Participants corrected their reaches for almost all target jumps. In Experiment 2, we required covert monitoring of the flanker during reaching. This concurrent perceptual task globally reduced correction behaviour, indicating that perception and action share a common attentional resource. Corrections were especially unlikely toward the attended side. This is explained by assuming that perceptual attention primed an action toward the attended location and that the participant inhibited this primed action. The data thus imply that perceptual selection constrains online action guidance, as predicted by the premotor theory and the VAM. We further argue that the fact that participants can inhibit a location within the action system but simultaneously maintain its prioritisation for perceptual monitoring, is easier to reconcile with the VAM than with the premotor theory. PMID- 24952208 TI - Association between human leukocyte antigen-G 14-bp insertion/deletion polymorphism and cancer risk: a meta-analysis and systematic review. AB - BACKGROUND: Human leukocyte antigen-G (HLA-G) is involved in the development and progression of human cancers, and numerous molecular epidemiological studies have been conducted to explore the potential relationship of HLA-G 14-bp insertion/deletion (ins/del) polymorphism with cancer risk. However, results from published studies were inconclusive. METHODS: Both PUBMED and EMBASE databases were searched comprehensively to identify eligible studies investigating the association of HLA-G 14-bp ins/del polymorphism with cancer risk. Statistical analysis was performed by using STATA 12.0 and Review Manager 5.0. RESULTS: Fourteen eligible studies with 2340 cancer patients and 3967 controls were included and analyzed with odds ratio (OR) and its corresponding 95% confidence interval (CI). Overall, no significant association between HLA-G 14-bp ins/del polymorphism and overall cancer risk was detected in all comparison models. Further subgroup analyses based on ethnicity and cancer types demonstrated the significant association among Asians (ins/del vs. del/del: OR = 0.80, 95% CI, 0.66-0.95; ins/ins+ins/del vs. del/del: OR = 0.80, 95% CI, 0.65-0.97) and for breast cancer (ins allele vs. del allele: OR = 0.76, 95% CI, 0.61-0.96; ins/ins vs. del/del: OR = 0.57, 95% CI, 0.37-0.87; and ins/ins vs. ins/del+del/del: OR = 0.60, 95% CI, 0.42-0.87). CONCLUSION: This study suggested that HLA-G 14-bp ins/del polymorphism might contribute to breast cancer susceptibility and overall cancer risk among Asians. Further well-designed studies with larger sample size are warranted to validate our conclusion. PMID- 24952209 TI - Humoral immunity in hand transplantation: anti-HLA and non-HLA response. AB - Antibodies against donor's HLA antigens and B cell activity are recognized modulators of immune response to allograft. The role of both anti-HLA and non-HLA antibodies is understood in solid organ transplantation, but has not been addressed in composite tissue allografts. AIM: We decided to evaluate the presence and role of anti-HLA and non-HLA antibodies after hand transplantation. METHODS: We assayed anti-HLA and non-HLA antibodies in 5 consecutive hand transplant patients. The presence of anti-HLA antibodies was tested by flow-PRA method (One Lambda). Non-HLA antibodies were defined as anti-endothelial cell (AECA), anti-angiotensin II type 1 receptor (anti-AT1R), anti-endothelin receptor antibodies (anti-ETAR). RESULTS: Anti-HLA antibodies were present in 1 patient in class I and in another one in class II. Both patients developed one episode of acute rejection. AECA were present in only one recipient with borderline activity. Both anti-AT1R and Anti-ETAR were found strongly positive in one patient who repeatedly developed acute rejection episodes. CONCLUSION: The presence of non-HLA antibodies (anti-AT1R and anti-ETAR) and the occurrence of multiple rejection episodes found in one patient here require further investigation into a possible association and role of humoral immunity in composite tissue rejection. PMID- 24952210 TI - Identification of sequence variants in the CCL3 chemokine gene family in the HapMap West African reference population. AB - Gene copy number variation (CNV) of the CC Chemokine ligand 3-Like-1 (CCL3L1) gene located on chromosome 17q12 has been associated with many diseases, including viral infections and autoimmune diseases. High sequence homology between CCL3L1 and three other related genes within the same cluster, CCL3, CCL3L2, and CCL3L3, make it difficult to determine the copy number of each gene as well as distinguishing variants within each gene versus between genes. We identified a total of 50SNPs, 31 known and 19 novel SNPs, in a subset of West Africa Reference (Yoruba individuals from Ibadan, Nigeria (YRI)) samples from HapMap. One of these previously unidentified variations is a non-synonymous change while several other unreported variations are located near potential regulatory sites. The variations identified in these immune-related genes from this study will shed light in the understanding of both structural and nucleotide polymorphisms that can be used in association studies of diseases in populations. PMID- 24952205 TI - Perinatal and early childhood environmental factors influencing allergic asthma immunopathogenesis. AB - BACKGROUND: The prevalence of asthma has increased dramatically over the past several decades. While hereditary factors are highly important, the rapid rise outstrips the pace of genomic variation. Great emphasis has been placed on potential modifiable early life exposures leading to childhood asthma. METHODS: We reviewed the recent medical literature for important studies discussing the role of the perinatal and early childhood exposures and the inception of childhood asthma. RESULTS AND DISCUSSION: Early life exposure to allergens (house dust mite (HDM), furred pets, cockroach, rodent and mold), air pollution (nitrogen dioxide (NO(2)), ozone (O(3)), volatile organic compounds (VOCs), and particulate matter (PM)) and viral respiratory tract infections (Respiratory syncytial virus (RSV) and human rhinovirus (hRV)) has been implicated in the development of asthma in high risk children. Conversely, exposure to microbial diversity in the perinatal period may diminish the development of atopy and asthma symptoms. PMID- 24952211 TI - WITHDRAWN: Associations between polymorphisms of HLA-B gene and postmenopausal osteoporosis in Chinese Han population. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 24952212 TI - Age-dependent association of mannose-binding lectin polymorphisms with the development of pulmonary tuberculosis in Viet Nam. AB - Mannose-binding lectin (MBL) binds to pathogens and induces complement-mediated opsonophagocytosis. Although the association between MBL2 polymorphisms and tuberculosis (TB) has been studied in various populations, the results are controversial. We explored the stages of TB associated with MBL2 polymorphisms. X/Y (rs7096206) and A/B (rs1800450) were genotyped in 765 new patients with active pulmonary TB without HIV infection and 556 controls in Hanoi, Viet Nam. The MBL2 nucleotide sequences were further analyzed, and plasma MBL levels were measured in 109 apparently healthy healthcare workers and 65 patients with TB. Latent TB infection (LTBI) was detected by interferon-gamma release assay (IGRA). The YA/YA diplotype, which exhibited high plasma MBL levels, was associated with protection against active TB in younger patients (mean age = 32)? 45 years old (odds ratio, 0.61; 95% confidence interval, 0.46-0.80). The resistant diplotype was less frequently found in the younger patients at diagnosis (P = 0.0021). MBL2 diplotype frequencies and plasma MBL levels were not significantly different between the IGRA-positive and -negative groups. MBL2 YA/YA exhibited a protective role against the development of TB in younger patients, whereas the MBL2 genotype and MBL levels were not associated with LTBI. High MBL levels may protect against the early development of pulmonary TB after infection. PMID- 24952214 TI - Chemosensory event-related brain potentials (CSERP) after strictly monorhinal stimulation. AB - Using flow-olfactometer for chemosensory event related brain potentials (CSERP) the air escapes the contralateral nostril from the stimulated nostril via the nasopharynx. Theoretically, the escaping odorous airflow is able to stimulate the contralateral chemosensory receptors and might activate the olfactory or the trigeminal brain processes. Testing 18 healthy subjects, we were able to show that it was possible to generate CSERP by strictly monorhinal stimulation with closed contralateral nostril. That means that the rectangular shapes of the brief chemosensory stimuli were not disturbed. The latencies of N1 and P2 and the amplitudes (N1P2) of CSERP (stimulants: H2S and CO2) were not different with either open or closed contralateral nostril. The induced CSERP were independent of stimulated nostril side. Additionally we found that with closed contralateral nostril more than 90% of passive monorhinal chemosensory stimuli were perceived. In further imaging studies the presented paradigm should be applied with strictly monorhinal stimulation to investigate the chemosensory processing pathways with high time resolution (EEG/MEG). PMID- 24952213 TI - Association of STAT6 variants with asthma risk: a systematic review and meta analysis. AB - A large number of studies have reported that the genetic variants in STAT6 gene may be implicated in susceptibility to asthma, but with inconsistent results. Therefore, the aim of this meta-analysis was to determine the likelihood of developing asthma for the individuals with different STAT6 variants. The database including Pubmed, Embase and CNKI (Chinese National Knowledge Infrastructure) were searched to find the relevant papers. Data were extracted by two independent reviewers and the odds radios (ORs) were pooled with 95% confidence intervals (CIs), using random effect or fixed effect models as appropriate, to indicate the risk of asthma for different STAT6 variants. The heterogeneity and bias were tested for each pooled result. Data from 19 studies were pooled that reported associations of rs324015, rs71802646 and rs324011 in STAT6 gene with asthma risk. The results demonstrated that 13GT and short GT in rs71802646 were both associated with increased risk of asthma in overall analysis (OR = 1.26 for 13GT and 1.30 for short GT). Further, subgroup analysis showed an increased risk of asthma in Asian population with 13GT (OR = 1.21), 14GT (OR = 1.97) and short GT (OR = 1.27). Besides, 13GT, 14GT and short GT all contributed to higher risk of atopic asthma, with OR 1.50, 2.21 and 1.65 respectively. However, rs324015 (G>A) appeared to be associated with decreased risk for atopic asthma (with OR = 0.83, 0.68 and 0.79 for A, AA and AA+AG respectively). Both overall and subgroup analyses indicated no effect of rs324011 on asthma risk. In conclusion, our meta analyses suggest that short GT repeats of rs71802646 in STAT6 contribute to higher risk for asthma, while rs324015 may have a protective effect on atopic asthma. PMID- 24952215 TI - The ERP correlates of target checking are dependent upon the defining features of the prospective memory cues. AB - In some contexts, prospective memory (PM) is thought to be dependent upon strategic monitoring of the environment for relevant cues. Behavioral data reveal that strategic monitoring is associated with slowing of response time for ongoing activity trials when a prospective component is added to the task, and functional imaging data reveal that monitoring is associated with recruitment of the anterior prefrontal cortex and other cortical structures. In the current study, event-related brain potentials (ERPs) were used to examine the neural correlates of target checking, one process underlying strategic monitoring. Consistent with previous research the behavioral data revealed a Stimulus Specific Interference Effect, wherein slowing of response time varied depending upon whether PM cues were words or nonwords. The ERP data also revealed that the neural correlates of target checking were sensitive to the defining features of the PM cues (i.e., were a word or nonword). When PM cues were words, the effect of target checking was associated with variation in ERP amplitude beginning around 100ms after stimulus onset. In contrast, when PM cues were nonwords, the effect of target checking on the ERPs did not emerge until around 200ms after stimulus onset. These data provide support for the multi-process view of PM by demonstrating that the pattern of neural recruitment related to target checking is sensitive to the defining characteristics of the PM cues. PMID- 24952219 TI - Characterization of a recently purified thermophilic DNase from a novel thermophilic fungus. AB - A newly isolated thermophilic fungus was found to produce a partially inducible extracellular DNase. This manuscript focuses on the characterization of this novel thermophilic DNase in terms of optimal enzyme conditions, molecular weight, and certain kinetic properties. The DNase was found to be inactivated by the presence of EDTA demonstrating its dependence on metal cofactors for activity. Maximum activity occurred at pH 6.0 with no activity at pH 2.0 or 10.0. The optimal temperature for the purified DNase was 65 degrees C. The thermophilic DNase was found to be an exonuclease with an estimated molecular weight of 56 kDa. PMID- 24952216 TI - Merging molecular mechanism and evolution: theory and computation at the interface of biophysics and evolutionary population genetics. AB - The variation among sequences and structures in nature is both determined by physical laws and by evolutionary history. However, these two factors are traditionally investigated by disciplines with different emphasis and philosophy molecular biophysics on one hand and evolutionary population genetics in another. Here, we review recent theoretical and computational approaches that address the crucial need to integrate these two disciplines. We first articulate the elements of these approaches. Then, we survey their contribution to our mechanistic understanding of molecular evolution, the polymorphisms in coding region, the distribution of fitness effects (DFE) of mutations, the observed folding stability of proteins in nature, and the distribution of protein folds in genomes. PMID- 24952218 TI - Up-to 5-year efficacy of pasireotide in a patient with Cushing's disease and pre existing diabetes: literature review and clinical practice considerations. AB - PURPOSE: Pasireotide is a multi-receptor-targeted somatostatin analogue approved in the EU and in the US for the treatment of adults with Cushing's disease (CD). Pasireotide has a safety profile similar to other somatostatin analogues with the exception of hyperglycemia. In this report and literature review, the current understanding of predicting a positive treatment response to pasireotide in CD and the management of diabetes mellitus (DM) during pasireotide treatment are discussed and analyzed. CASE PRESENTATION: We report a case of a 55-year-old woman with CD and DM who benefitted from long-term pasireotide. The patient, who was enrolled in a phase III trial of the drug, showed early clinical improvements with pasireotide [900 MUg subcutaneously twice daily (bid)] but was classified as a non-responder as urinary free cortisol (UFC) levels, were not normalized. Continuation of pasireotide for 12 months at an increased dose (1,200 MUg bid) normalized UFC levels and restored cortisol rhythm. The initial deterioration in her blood glucose was managed with insulin and metformin; however, after 12 months' treatment with pasireotide her DM was well controlled with oral hypoglycemic agents. Five years later, the patient is still receiving pasireotide (300 MUg bid) with no loss of clinical or biochemical efficacy and with continued glycemic control. CONCLUSIONS: This case presentation indicates that uncontrolled UFC levels during the first few months of pasireotide treatment as well as worsening of glycemic control in patients with CD and DM are not always predictive of the efficacy and tolerability and appears to support the long-term continuation of pasireotide. PMID- 24952217 TI - Resilience of biochemical activity in protein domains in the face of structural divergence. AB - Recent studies point to the prevalence of the evolutionary phenomenon of drastic structural transformation of protein domains while continuing to preserve their basic biochemical function. These transformations span a wide spectrum, including simple domains incorporated into larger structural scaffolds, changes in the structural core, major active site shifts, topological rewiring and extensive structural transmogrifications. Proteins from biological conflict systems, such as toxin-antitoxin, restriction-modification, CRISPR/Cas, polymorphic toxin and secondary metabolism systems commonly display such transformations. These include endoDNases, metal-independent RNases, deaminases, ADP ribosyltransferases, immunity proteins, kinases and E1-like enzymes. In eukaryotes such transformations are seen in domains involved in chromatin-related peptide recognition and protein/DNA-modification. Intense selective pressures from 'arms race'-like situations in conflict and macromolecular modification systems could favor drastic structural divergence while preserving function. PMID- 24952221 TI - Role of aqueous electron and hydroxyl radical in the removal of endosulfan from aqueous solution using gamma irradiation. AB - The removal of endosulfan, an emerging water pollutant, from water was investigated using gamma irradiation based advanced oxidation and reduction processes (AORPs). A significant removal, 97% of initially 1.0 MUM endosulfan was achieved at an absorbed dose of 1020 Gy. The removal of endosulfan by gamma-rays irradiation was influenced by an absorbed dose and significantly increased in the presence of aqueous electron (eaq(-)). However, efficiency of the process was inhibited in the presence of eaq(-) scavengers, such as N2O, NO3(-), acid, and Fe(3+). The observed dose constant decreased while radiation yield (G-value) increased with increasing initial concentrations of the target contaminant and decreasing dose-rate. The removal efficiency of endosulfan II was lower than endosulfan I. The degradation mechanism of endosulfan by the AORPs was proposed showing that reductive pathways involving eaq(-) started at the chlorine attached to the ring while oxidative pathway was initiated due to attack of hydroxyl radical at the SO bond. The mass balance showed 95% loss of chloride from endosulfan at an absorbed dose of 1020 Gy. The formation of chloride and acetate suggest that gamma irradiation based AORPs are potential methods for the removal of endosulfan and its by-products from contaminated water. PMID- 24952220 TI - DuraLith geopolymer waste form for Hanford secondary waste: correlating setting behavior to hydration heat evolution. AB - The binary furnace slag-metakaolin DuraLith geopolymer waste form, which has been considered as one of the candidate waste forms for immobilization of certain Hanford secondary wastes (HSW) from the vitrification of nuclear wastes at the Hanford Site, Washington, was extended to a ternary fly ash-furnace slag metakaolin system to improve workability, reduce hydration heat, and evaluate high HSW waste loading. A concentrated HSW simulant, consisting of more than 20 chemicals with a sodium concentration of 5 mol/L, was employed to prepare the alkaline activating solution. Fly ash was incorporated at up to 60 wt% into the binder materials, whereas metakaolin was kept constant at 26 wt%. The fresh waste form pastes were subjected to isothermal calorimetry and setting time measurement, and the cured samples were further characterized by compressive strength and TCLP leach tests. This study has firstly established quantitative linear relationships between both initial and final setting times and hydration heat, which were never discovered in scientific literature for any cementitious waste form or geopolymeric material. The successful establishment of the correlations between setting times and hydration heat may make it possible to efficiently design and optimize cementitious waste forms and industrial wastes based geopolymers using limited testing results. PMID- 24952222 TI - Determination of hip-joint loading patterns of living and extinct mammals using an inverse Wolff's law approach. AB - It is well known that bone adapts its microstructure in response to loading. Based on this form-follows-function relationship, we previously developed a reverse approach to derive joint loads from bone microstructure as acquired with micro-computed tomography. Here, we challenge this approach by calculating hip joint loading patterns for human and dog, two species exhibiting different locomotion, and comparing them to in vivo measurements. As a proof of concept to use the approach also for extinct taxa, we applied it to a cave lion fossil bone. Calculations were in close agreement with in vivo measurements during walking for extant species, showing distinguished patterns for bipedalism and quadrupedalism. The cave lion calculations clearly revealed its quadrupedal locomotion and suggested a more diverse behaviour compared to the dog, which is in agreement with extant felids. This indicates that our novel approach is potentially useful for making inferences about locomotion in living as well as extinct mammals and to study evolutionary joint development. PMID- 24952223 TI - Endoscopic versus microsurgical resection of colloid cysts: a systematic review and meta-analysis of 1,278 patients. AB - OBJECTIVE: Colloid cysts of the third ventricle have been successfully treated with transcranial microsurgical approaches. However, the endoscopic approach has recently been advocated as a lesser invasive technique. We conducted a systematic review and meta-analysis of published studies to compare the outcomes between the two approaches. METHODS: A PubMED search of contemporary literature (1990-2014) was performed to identify surgical series of open and endoscopic treatment of colloid cysts. Relevant articles were identified and data were extracted concerning surgical treatment, extent of resection, and outcomes. RESULTS: A meta analysis was performed for recurrence rates based on treatment strategy. A total of 583 patients were included in the microsurgical group, and 695 patients in the endoscopic group. The microsurgical approach was found to have a significantly higher gross total resection rate (96.8% vs. 58.2%; P < 0.0001), lower recurrence rate (1.48% vs. 3.91%; P = 0.0003), and lower reoperation rate (0.38% vs. 3.0%; P = 0.0006) compared with the endoscopic group. There was no significant difference in mortality rate (1.4% vs. 0.6%) or shunt dependency (6.2% vs. 3.9%) between the two groups. The overall morbidity rate was lower in the endoscopic group (10.5%) than in the microsurgery group (16.3%). Within the microsurgery group, the transcallosal approach had a lower overall morbidity rate (14.4%) than the transcortical approach (24.5%). CONCLUSIONS: Microsurgical resection of colloid cysts is associated with a higher rate of complete resection, lower rate of recurrence, and fewer reoperations than with endoscopic removal. However, the rate of morbidity is higher with microsurgery than with endoscopy. PMID- 24952224 TI - Focused ultrasound: relevant history and prospects for the addition of mechanical energy to the neurosurgical armamentarium. AB - Although the concept of focused ultrasonography emerged more than 70 years ago, the need for a craniectomy obviated its development as a noninvasive technology. Since then advances in phased array transducers and magnetic resonance imaging technology have resurrected the ultrasound as a noninvasive therapeutic for a plethora of neurological conditions ranging from embolic stroke and intracranial hemorrhage to movement disorders and brain neoplasia. In the same way that stereotactic radiosurgery has fundamentally changed the scope and treatment paradigms of tumor and specifically skull base surgery, focused ultrasound has a similar potential to revolutionize the field of neurological surgery. In addition, focused ultrasound comes without the general complexity or the risks of ionizing radiation that accompany radiosurgery. As the quest for minimally invasive and noninvasive therapeutics continues to define the new neurosurgery, the focused ultrasound evolves to join the neurosurgical armamentarium. PMID- 24952225 TI - Neuro-ophthalmology and intracranial aneurysms. PMID- 24952226 TI - Readjusting lumbar pedicle screws nonparallel to the superior endplate. PMID- 24952227 TI - A phase II study of radiofrequency ablation therapy for thoracic malignancies with evaluation by FDG-PET. AB - PURPOSE: Computed tomography (CT)-guided radiofrequency ablation (RFA) is safe and effective for patients with unresectable primary, recurrent, or metastatic thoracic malignancies. Several studies have shown the benefit of employing 18 fluoro-deoxyglucose positron-emission tomography (FDG-PET) to follow thoracic malignancies treated with RFA. In this prospective study, we show the safety and therapeutic efficacy of RFA and the utility of FDG-PET as tool for early detection of local recurrence. METHODS: Twenty patients were enrolled in this study, and 24 lesions were ablated. Seven lesions were primary lung cancer, and 17 lesions were recurrent tumors or metastases from extrathoracic sites. Tumor size was in the range of 0.4-3.3 cm in diameter (mean: 1.5 cm). CT and FDG-PET scans were scheduled 7-14 days and 3-6 months after RFA treatment. RESULTS: There were 17 adverse events (70.8 %) in 24 ablations included 13 pneumothoraces, two cases of chest pain, and two episodes of fever. With a median follow-up of 35.9 months (range 1-62 months), the overall 2-year survival rate was 84.2 %. Local recurrence occurred at four sites (2-year local control rate was 74.3 %). The FDG PET results 7-14 days after RFA did not predict recurrence, whereas positive findings 3-6 months after RFA significantly correlated with local recurrence (p = 0.0016). CONCLUSIONS: We confirmed the effectiveness of RFA for unresectable primary and secondary thoracic malignancies. FDG-PET analysis 3-6 months after ablation is a useful tool to assess local control. PMID- 24952228 TI - Methods to detect non-compliance and reduce its impact on population PK parameter estimates. AB - This work proposes and evaluates two methods (CM1 and CM2) for detecting non compliance using concentration-time data and for obtaining estimates of population pharmacokinetic model parameters in a population with prevalent non compliance. CM1 estimates individual residual variability (RV) and identifies subjects with higher than average RV as non-compliant. Exclusion of subjects with high RV from the analysis dataset reduces the bias in the estimates of the model parameters. Various methods of identification and exclusion of non-compliant subjects were tested, compared, and shown to reduce or eliminate bias in parameter estimates associated with non-compliance. The tested methods were (i) a pre-defined cutoff value of the random effect on RV, (ii) sequential exclusion of subjects with the highest RV percentiles, and (iii) use of a mixture model for RV. CM2 is applicable for the data with a specific sampling pattern that includes a potentially non-compliant outpatient part with several trough samples followed by a dense profile after the inpatient (compliant) dose. It relies only on the doses known to be administered (e.g., inpatient doses). In this method, all concentration measurements during the outpatient part of the study (except the trough value immediately preceding the inpatient dose) are removed from the dataset and an additional parameter (individual relative bioavailability of the outpatient doses) is introduced. For a number of simulated datasets with various sampling schemes and non-compliance patterns the proposed methods allowed to identify subjects with compliance problems and to reduce or eliminate bias in the estimates of the model parameters. PMID- 24952229 TI - An automatic framework for quantitative validation of voxel based morphometry measures of anatomical brain asymmetry. AB - The study of anatomical brain asymmetries has been a topic of great interest in the neuroimaging community in the past decades. However, the accuracy of brain asymmetry measurements has been rarely investigated. In this study, we propose a fully automatic methodology for the quantitative validation of brain tissue asymmetries as measured by Voxel Based Morphometry (VBM) from structural magnetic resonance (MR) images. Starting from a real MR image, the methodology generates simulated 3D MR images with a known and realistic pattern of inter-hemispheric asymmetry that models the left-occipital right-frontal petalia of a normal brain and the related rightward bending of the inter-hemispheric fissure. As an example, we generated a dataset of 64 simulated MR images and applied this dataset for the quantitative validation of optimized VBM measures of asymmetries in brain tissue composition. Our results suggested that VBM analysis strongly depended on the spatial normalization of the individual brain images, the selected template space, and the amount of spatial smoothing applied. The most accurate asymmetry detections were achieved by 9-degrees of freedom registration to the symmetrical template space with 4 to 8mm spatial smoothing. PMID- 24952230 TI - The integrity of the cholinergic system determines memory performance in healthy elderly. AB - The cholinergic system plays a central role in episodic memory-related processes in health and disease. Cerebral acetylcholinesterase (AChE) activity, a measure of the integrity of the cholinergic system, can be assessed in vivo using positron emission tomography (PET) and [(11)C]N-methyl-4-piperidyl acetate (MP4A). A close relationship between the kinetic constant k3 of MP4A and mnestic functions has been demonstrated for patients suffering from amnestic mild cognitive impairment and Alzheimer's disease. Under the hypothesis that AChE activity and memory are intimately linked in older age, we obtained MP4A-PET and structural magnetic resonance images as well as neuropsychological data from fourteen healthy older adults. Multiple regression analysis revealed that AChE activity in areas previously implicated in mnestic functions predicted episodic memory performance irrespective of cortical atrophy. Data suggest that in older adults the integrity of the cholinergic system underlies inter-individual variability in memory function. PMID- 24952231 TI - Prerequisites for a reliable introduction of in vitro neurotoxicity testing within the REACH framework. PMID- 24952233 TI - A meta-analysis of the evidence on the impact of prenatal and early infancy exposures to mercury on autism and attention deficit/hyperactivity disorder in the childhood. AB - Although a measurable number of epidemiological studies have been conducted to clarify the associations between mercury exposure during embryo or early infancy and later incidences of autism spectrum disorders (ASD) or attention-deficit hyperactivity disorder (ADHD), the conclusion still remains unclear. Meta analysis was conducted for two major exposure sources; i.e., thimerosal vaccines that contain ethylmercury (clinical exposure), and environmental sources, using relevant literature published before April 2014. While thimerosal exposures did not show any material associations with an increased risk of ASD or ADHD (the summary odds ratio (OR) 0.99, 95% confidence interval (CI) 0.80-1.24 for ASD; OR 0.91, 95% CI 0.70-1.13 for ADHD/ADD), significant associations were observed for environmental exposures in both ASD (OR 1.66, 95% CI 1.14-2.17) and ADHD (OR 1.60, 95% CI 1.10-2.33). The summary ORs were similar after excluding studies not adjusted for confounders. Moderate adverse effects were observed only between environmental inorganic or organic mercury exposures and ASD/ADHD. However, these results should be interpreted with caution since the number of epidemiological studies on this issue was limited and still at an early stage. Further studies focused on subjects with genetic vulnerabilities of developmental disorders are warranted for better understanding of the effects of such environmental exposures. PMID- 24952234 TI - Executive function and sleep problems in childhood epilepsy. AB - Pediatric epilepsy has been reported to be associated with both sleep problems and cognitive deficits. In turn, in healthy children, poorer sleep has been associated with deficits in cognitive functioning. We hypothesized that poor sleep in childhood epilepsy may contribute to cognitive deficits. Using actigraphy, we objectively measured the sleep of children with epilepsy alongside that of healthy controls. In contrast to previous reports, we did not find any differences in objectively measured sleep between children with epilepsy and healthy controls. However, significant deficits in cognitive functioning were demonstrated that were not explained by differences in sleep. PMID- 24952232 TI - Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism. AB - Several epidemiological studies have reported an association between arsenic exposure and increased rates of psychiatric disorders, including depression, in exposed populations. We have previously demonstrated that developmental exposure to low amounts of arsenic induces depression in adulthood along with several morphological and molecular aberrations, particularly associated with the hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis. The extent and potential reversibility of this toxin-induced damage has not been characterized to date. In this study, we assessed the effects of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on adult animals exposed to arsenic during development. Perinatal arsenic exposure (PAE) induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after acute exposure to a predator odor (2,4,5-trimethylthiazoline, TMT). Chronic fluoxetine treatment prevented these behaviors in both tasks in arsenic-exposed animals and ameliorated arsenic-induced blunted stress responses, as measured by corticosterone (CORT) levels before and after TMT exposure. Morphologically, chronic fluoxetine treatment reversed deficits in adult hippocampal neurogenesis (AHN) after PAE, specifically differentiation and survival of neural progenitor cells. Protein expression of BDNF, CREB, the glucocorticoid receptor (GR), and HDAC2 was significantly increased in the dentate gyrus of arsenic animals after fluoxetine treatment. This study demonstrates that damage induced by perinatal arsenic exposure is reversible with chronic fluoxetine treatment resulting in restored resiliency to depression via a neurogenic mechanism. PMID- 24952236 TI - Intracerebral cystic rhabdoid papillary meningioma in an 11-year-old patient. AB - INTRODUCTION: Rhabdoid papillary meningioma is a rare meningioma variant categorized as WHO grade III. We report an 11-year-old girl with an intracerebral rhabdoid papillary meningioma. MATERIALS AND METHODS: An 11-year-old girl presented to our hospital with a short history of severe headache and vomiting. MRI revealed a left frontal intracerebral cystic lesion with rim enhancement. The tumor, including the cyst wall, was totally removed. Since the histological diagnosis was rhabdoid papillary meningioma, she was treated with postoperative radiotherapy. She is currently undergoing routine follow-up without any symptoms of recurrence. CONCLUSION: We discuss the clinical picture of this patient with reference to the published literature on this uncommon diagnosis. PMID- 24952235 TI - Asymmetries in attention as revealed by fixations and saccades. AB - Neurologically normal individuals devote more attention to the left side; an asymmetry known as pseudoneglect, which reflects right hemisphere involvement in visuospatial attention. The role of eye movements in attentional asymmetries has received little consideration, particularly in terms of the greyscales task. Stimulus length, elevation, and presentation duration were manipulated, while monitoring eye movements during the greyscales task. Region of interest analyses compared time spent examining each quadrant of the stimulus. Further, saccades were examined in conjunction with fixations to gain an understanding of overall eye movement patterns. Scatterplots combining x-and y-coordinates illustrate mean eye position. Results demonstrated a comparison strategy was used, where the dark portions of each rectangle were fixated. Mean eye position was within the lower left quadrant. The left visual field was inspected most for the baseline condition. Interestingly, the lower visual field was examined most when duration, length, or elevation was manipulated. Eye movement patterns provide a possible explanation for why correlations are y not observed between visuospatial tasks. Different strategies, based on specific-task demands, are likely to be used, which in turn, engage separate aspects of visuospatial attention. PMID- 24952237 TI - Fetal intracranial hemorrhage related to maternal autoimmune thrombocytopenic purpura. AB - BACKGROUND: Maternal autoimmune thrombocytopenic purpura (AITP) can cause fetal intracranial hemorrhage. CASE REPORT: A 19-year-old primigravida was referred to our institution for prenatally detected ventriculomegaly at 30th week of gestation. Her personal and family histories were unremarkable. Her platelet count was 54 * 109/L. Fetal neurosonography showed intraparenchymal hemorrhage. AITP was diagnosed in the mother and platelet count decreased at 34 * 109/L. Patient was treated with methylprednisolone and intravenous immunoglobulin. She delivered a 2,340-g infant at 37 weeks with elective cesarean section. The platelet count of the newborn was 181 * 109/L and coagulation tests were normal. No antiplatelet specific antibodies were detected in cord blood. Postnatal MRI evaluation confirmed grade IV intracranial hemorrhage. The newborn baby has suffered from mild spasticity and seizures. CONCLUSIONS: Clinicians must be vigilant about the catastrophic fetal complications of maternal AITP; a close follow-up with a multidisciplinary cooperation between obstetricians, hematologists, and neonatologists must be warranted. PMID- 24952238 TI - Intuitive presentation of clinical forensic data using anonymous and person specific 3D reference manikins. AB - The increasing use of CT/MR devices in forensic analysis motivates the need to present forensic findings from different sources in an intuitive reference visualization, with the aim of combining 3D volumetric images along with digital photographs of external findings into a 3D computer graphics model. This model allows a comprehensive presentation of forensic findings in court and enables comparative evaluation studies correlating data sources. The goal of this work was to investigate different methods to generate anonymous and patient-specific 3D models which may be used as reference visualizations. The issue of registering 3D volumetric as well as 2D photographic data to such 3D models is addressed to provide an intuitive context for injury documentation from arbitrary modalities. We present an image processing and visualization work-flow, discuss the major parts of this work-flow, compare the different investigated reference models, and show a number of cases studies that underline the suitability of the proposed work-flow for presenting forensically relevant information in 3D visualizations. PMID- 24952239 TI - Redox targeting of DNA anchored to MWCNTs and TiO2 nanoparticles dispersed in poly dialyldimethylammonium chloride and chitosan. AB - A key issue associated with electrochemical DNA-based biosensors is how to enhance DNA immobilization on the substrates. In order to improve the immobilization of DNA and to optimize DNA interaction efficiency, different kinds of strategies have been developed. In this regard, nanomaterials have attracted a great deal of attention in electrode surface modification for DNA biosensor fabrication. In this study, nanostructured films were deposited at the surface of a pencil graphite electrode (PGE) as a working electrode. For the present purpose, common polyelectrolytes are used for surface modification with double stranded DNA. Two positively charged polyelectrolyte, namely poly dialyldimethylammonium chloride (PDDA) and chitosan, are initially compared for DNA immobilization at the surface of MWCNTs and TiO2 nanoparticles (TiO2NPs). In a second step, the basic electrochemical properties of the sensors are investigated using voltammetric methods. The modified electrodes are also characterized by scanning electron microscopy and electrochemical impedance measurements. It will be shown that electrode modification with DNA and the nanostructure that disperses in PDDA leads to an enhanced sensitivity of the DNA voltammetric detection mechanism. In a previous study, a comparison was done between MWCNTs and TiO2NPs for determining the effect of nanoparticle effect on DNA immobilization on the electrode surface. In order to compare the efficiency of the prepared DNA-based biosensors, methylene blue is chosen as an electroactive probe. It will be shown that the stability of the immobilized DNA within several days will be much higher when MWCNTs rather than TiO2NPs are used. PMID- 24952240 TI - Management of germ cell tumors with somatic type malignancy: pathological features, prognostic factors and survival outcomes. AB - PURPOSE: Germ cell tumors with somatic type malignancy are rare, occurring in approximately 2.7% to 8.6% of germ cell tumor cases. Prognostic factors and optimal management remain poorly defined. MATERIALS AND METHODS: The Indiana University testis cancer database was queried from 1979 to 2011 for patients demonstrating germ cell tumor with somatic type malignancy at orchiectomy or subsequent resection. Patients with transformation to primitive neuroectodermal tumor only were excluded from study due to distinct management. Chart review, pathological review and survival analysis were performed. RESULTS: A total of 121 patients met the study inclusion criteria. The most common somatic type malignancy histologies were sarcoma (59), carcinoma (31) and sarcomatoid yolk sac tumor (17). Of these patients 32 demonstrated somatic type malignancy at germ cell tumor diagnosis. For those with delayed identification, median time from germ cell tumor to somatic type malignancy diagnosis was 33 months. This interval was longest for carcinomas (108 months). At a median followup of 71 months, 5 year cancer specific survival was 64%. Predictors of poorer cancer specific survival included somatic type malignancy diagnosed at late relapse (p = 0.017), referral to Indiana University for reoperative retroperitoneal lymph node dissection (p = 0.026) and grade (p = 0.026). None of these factors maintained prognostic significance on multivariate analysis. Somatic type malignancy histology subtype, stage, risk category and number of resections were not predictive of cancer specific survival. CONCLUSIONS: Germ cell tumor with somatic type malignancy is associated with poorer cancer specific survival than traditional germ cell tumor. Established prognostic factors for germ cell tumor lose predictive value in the setting of somatic type malignancy. Aggressive and serial resections are often necessary to optimize cancer specific survival. Tumor grade is an important prognostic factor in sarcomas and sarcomatoid yolk sac tumors. PMID- 24952241 TI - Prompt management of anastomotic leak or acute obstruction after minimally invasive pyeloplasty with percutaneous nephrostomy preserves outcomes. AB - PURPOSE: Urine leak or obstruction in the early postoperative period is a worrisome complication of pyeloplasty. Suboptimal management may risk long-term success. We evaluated percutaneous nephrostomy to manage complications of minimally invasive pyeloplasty. MATERIALS AND METHODS: We retrospectively analyzed the records of 125 patients who underwent minimally invasive pyeloplasty performed by a single surgeon from May 2004 to May 2013. All complications were catalogued and patients with anastomotic urine leakage or postoperative obstruction were identified. Less than 7 days postoperatively percutaneous nephrostomy was done in each case. Surgical success was defined as resolution of flank pain and/or improved half-time (less than 20 minutes) on diuretic renogram. RESULTS: Early percutaneous nephrostomy placement was required in 12 patients (9.6%) for symptomatic obstruction (6) or anastomotic urine leakage (6) a median of 4.5 days (range 2 to 7) postoperatively. Percutaneous nephrostomies remained in place a median of 9.5 days (range 5 to 42). Median followup was 15 months (range 2 to 80). Mean half-time was 36.4 minutes preoperatively and 11.1 minutes postoperatively. Continued postoperative obstruction (half-time greater than 20 minutes) was documented in 1 (8%) and 13 patients (11.5%) who did and did not require percutaneous nephrostomy placement, respectively. There was no statistical difference in radiological and clinical success rates between the percutaneous nephrostomy group and the 113 patients in whom minimally invasive pyeloplasty was uncomplicated (p = 0.74 and 0.28, respectively). CONCLUSIONS: In patients treated with minimally invasive pyeloplasty aggressive management of acute urinary complications with percutaneous nephrostomy placement preserved radiographic and symptomatic outcomes that were comparable to those in patients without complications. PMID- 24952244 TI - Critical assessment of human antibody generation in humanized mouse models. AB - Immunodeficient mice reconstituted with human hematopoietic stem cells provide a small-animal model for the study of development and function of human hematopoietic cells in vivo. However, in the current models, the immune response, and especially the humoral response by the human immune cells is far from optimal. The B cells found in these mice exhibit an immature and abnormal phenotype correlating with a reduced capacity to produce antigen-specific affinity matured antibodies upon infection or immunization. Herein, we review the current state of knowledge of development, function and antibody production of human B cells and discuss the obstacles for the improvement of these models. PMID- 24952242 TI - What about Alice? Peripheral neuropathy from taxane-containing treatment for advanced nonsmall cell lung cancer. AB - PURPOSE: In this review, we discuss the plight of Alice, a patient with advanced nonsmall cell lung cancer (NSCLC) who struggles with taxane-related peripheral neuropathy (PN). Using this unique point of view helps us to appreciate the implications of PN on daily activities as well as the difficulty in decision making regarding continuation of treatment. In addition, published reports of phase 3 trials are reviewed to identify the incidence and severity of chemotherapy-induced PN as well as the assessment tools used in these studies. METHODS: A literature review spanning the years 1998-2012 was performed. Phase 3 studies and a meta-analysis of taxane-based therapy in advanced NSCLC were selected for review for their findings regarding the incidence and severity of chemotherapy-induced PN. RESULTS: In total, 16 phase 3 studies and 1 meta analysis were reviewed. Use of grading scales and PN assessment tools was inconsistent across the studies, and some studies did not report PN at all. CONCLUSIONS: The true incidence and severity of chemotherapy-induced PN in clinical trials may be masked by nonstandardized reporting; thus, a more standardized approach to grading, assessing, and reporting PN in clinical trials is greatly needed to allow for appropriate comparisons across studies. Understanding chemotherapy-induced PN from the patient's perspective as well as the development of PN at the clinical trial level will help health care providers anticipate the development of PN and improve their ability to manage it. PMID- 24952243 TI - Isolation of biologically-active exosomes from human plasma. AB - Effects of exosomes present in human plasma on immune cells have not been examined in detail. Immunological studies with plasma-derived exosomes require their isolation by procedures involving ultracentrifugation. These procedures were largely developed using supernatants of cultured cells. To test biologic activities of plasma-derived exosomes, methods are necessary that ensure adequate recovery of exosome fractions free of contaminating larger vesicles, cell fragments and protein/nucleic acid aggregates. Here, an optimized method for exosome isolation from human plasma/serum specimens of normal controls (NC) or cancer patients and its advantages and pitfalls are described. To remove undesirable plasma-contaminating components, ultrafiltration of differentially centrifuged plasma/serum followed by size-exclusion chromatography prior to ultracentrifugation facilitated the removal of contaminants. Plasma or serum was equally acceptable as a source of exosomes based on the recovered protein levels (in MUg protein/mL plasma) and TEM image quality. Centrifugation on sucrose density gradients led to large exosome losses. Fresh plasma was the best source of morphologically-intact exosomes, while the use of frozen/thawed plasma decreased exosome purity but not their biologic activity. Treatments of frozen plasma with DNAse, RNAse or hyaluronidase did not improve exosome purity and are not recommended. Cancer patients' plasma consistently yielded more isolated exosomes than did NCs' plasma. Cancer patients' exosomes also mediated higher immune suppression as evidenced by decreased CD69 expression on responder CD4+ T effector cells. Thus, the described procedure yields biologically-active, morphologically-intact exosomes that have reasonably good purity without large protein losses and can be used for immunological, biomarker and other studies. PMID- 24952246 TI - An improved flow cytometry assay to monitor phagosome acidification. AB - Phago-lysosome formation is important for cell-autonomous immunity to intracellular pathogens, antigen presentation and metabolism. A hallmark feature of phago-lysosomal compartments is that they undergo progressive luminal acidification controlled by the activation of vacuolar V-ATPase. Acidification is required for many enzymatic processes taking place in phago-lysosomes, like proteolysis, and supports the microbicidal activity of macrophages. Here we present a new quantitative methodology to assess phagosome acidification by flow cytometry based on the use of bi-fluorescent particles. This method relies on the use of UV polystyrene beads labelled with the acid sensor pHrodo-succinimidyl ester (pHrodo(TM) SE red) and enables us to dissociate particle association with phagocytes from their engulfment in acidified compartments. This methodology is well suited to monitor the acidification of phagosomes formed in vivo after fluorescent bead administration. PMID- 24952245 TI - The use of BLT humanized mice to investigate the immune reconstitution of the gastrointestinal tract. AB - The gastrointestinal (GI) track represents an important battlefield where pathogens first try to gain entry into a host. It is also a universe where highly diverse and ever changing inhabitants co-exist in an exceptional equilibrium without parallel in any other organ system of the body. The gut as an organ has its own well-developed and fully functional immune organization that is similar and yet different in many important ways to the rest of the immune system. Both a compromised and an overactive immune system in the gut can have dire and severe consequences to human health. It has therefore been of great interest to develop animal models that recapitulate key aspects of the human condition to better understand the interplay of the host immune system with its friends and its foes. However, reconstitution of the GI tract in humanized mice has been difficult and highly variable in different systems. A better molecular understanding of the development of the gut immune system in mice has provided critical cues that have been recently used to develop novel humanized mouse models that fully recapitulate the genesis and key functions of the gut immune system of humans. Of particular interest is the presence of human gut-associated lymphoid tissue (GALT) aggregates in the gut of NOD/SCID BLT humanized mice that demonstrate the faithful development of bona fide human plasma cells capable of migrating to the lamina propria and producing human IgA1 and IgA2. PMID- 24952247 TI - Active asthma and the prevalence of physician-diagnosed COPD. AB - INTRODUCTION: Despite the considerable overlap of asthma and chronic obstructive pulmonary disease (COPD), the extent to which the two diagnoses are the manifestations of the same disease remains unresolved. We conducted these analyses to evaluate the role of active asthma in the prevalence of physician diagnosed COPD. METHODS: From 2006 through 2010, 74,209 adults aged 18-99 years and with a history of asthma participated in the Behavioral Risk Factor Surveillance System (BRFSS) Asthma Call-back Survey and responded to interview administered questionnaires via telephone. We used publicly available data from 71,639 (97%) participants to identify respondents with and without active manifestations of asthma and self-reported, physician-diagnosed COPD. We generated population-weighted estimates of physician-diagnosed COPD prevalence and conducted linear regression to estimate associations between active asthma status and the prevalence of COPD among current smokers, former smokers, and lifetime nonsmokers separately. RESULTS: Physician-diagnosed COPD was reported in an estimated 29% of the population with any history of asthma, including both active and inactive asthma. Age-specific prevalences of physician-diagnosed COPD were consistently higher among adults with active asthma than adults without active asthma. Compared to inactive asthma, active asthma was associated with an 8.3% [95% confidence interval (CI) 6.1, 10.5] higher prevalence of physician diagnosed COPD among lifetime nonsmokers, a 20.6% (95% CI 18.0, 23.3) higher prevalence among former smokers, and a 26.7% (95% CI 22.5, 30.9) higher prevalence among current smokers. CONCLUSIONS: Among adults with a history of asthma, active manifestations of asthma may play an important role in the epidemiology of COPD. PMID- 24952248 TI - Feasibility of a community intervention for the prevention of suicide and alcohol abuse with Yup'ik Alaska Native youth: the Elluam Tungiinun and Yupiucimta Asvairtuumallerkaa studies. AB - The Elluam Tungiinun and Yupiucimta Asvairtuumallerkaa studies evaluated the feasibility of a community intervention to prevent suicide and alcohol abuse among rural Yup'ik Alaska Native youth in two remote communities. The intervention originated in an Indigenous model of protection, and its development used a community based participatory research process. Feasibility assessment aimed to assess the extent to which (1) the intervention could be implemented in rural Alaska Native communities, and (2) the intervention was capable of producing measurable effects. Scales maximally sensitive to change were derived from earlier measurement work, and the study contrasted implementation process and outcomes across the two communities. In one community, medium dose response effects (d = .30-.50), with dose defined as number of intervention activities attended, were observed in the growth of intermediate protective factors and ultimate variables. In the other community, medium dose effects were observed for one intermediate protective factor variable, and small dose effects were observed in ultimate variables. Differences across communities in resources supporting intervention explain these contrasting outcomes. Results suggest implementation in these rural Alaska settings is feasible when sufficient resources are available to sustain high levels of local commitment. In such cases, measureable effects are sufficient to warrant a prevention trial. PMID- 24952250 TI - Primary mediastinal large B-cell lymphoma. AB - Primary mediastinal B-cell lymphoma (PMBCL) is a relatively rare lymphoma subtype affecting mainly young adults. Its molecular signature and clinical features resemble classical Hodgkin lymphoma. The optimal chemotherapy for this lymphoma subtype has not been established. The addition of rituximab to anthracycline based chemotherapy improved response rates and survival. Many centers use R-CHOP as standard treatment, but the role of the intensified regimens and consolidation radiotherapy has to be clarified. Recent data coming from retrospective analyses and an ongoing prospective study addressing the problem of consolidation radiotherapy will help to better identify risk groups and apply risk-adapted and effective treatment strategies. The latest research has helped to understand molecular mechanisms of PMBCL pathogenesis and indicated targets of directed therapy for the future. PMID- 24952249 TI - A protective factors model for alcohol abuse and suicide prevention among Alaska Native youth. AB - This study provides an empirical test of a culturally grounded theoretical model for prevention of alcohol abuse and suicide risk with Alaska Native youth, using a promising set of culturally appropriate measures for the study of the process of change and outcome. This model is derived from qualitative work that generated an heuristic model of protective factors from alcohol (Allen et al. in J Prev Interv Commun 32:41-59, 2006; Mohatt et al. in Am J Commun Psychol 33:263-273, 2004a; Harm Reduct 1, 2004b). Participants included 413 rural Alaska Native youth ages 12-18 who assisted in testing a predictive model of Reasons for Life and Reflective Processes about alcohol abuse consequences as co-occurring outcomes. Specific individual, family, peer, and community level protective factor variables predicted these outcomes. Results suggest prominent roles for these predictor variables as intermediate prevention strategy target variables in a theoretical model for a multilevel intervention. The model guides understanding of underlying change processes in an intervention to increase the ultimate outcome variables of Reasons for Life and Reflective Processes regarding the consequences of alcohol abuse. PMID- 24952252 TI - Heavy metal pollution in vegetables grown in the vicinity of a multi-metal mining area in Gejiu, China: total concentrations, speciation analysis, and health risk. AB - A field survey was conducted to investigate the present situation and health risk of arsenic (As), lead (Pb), cadmium (Cd), copper (Cu), and zinc (Zn) in soils and vegetables in a multi-metal mining area, Gejiu, China. Furthermore, three vegetables (water spinach, potato, and summer squash) containing high metal concentrations were selected to further analyze metal speciation. The results showed that the average concentrations of five metals in soil exceeded the limiting values, and their bioavailable concentrations were significantly positively correlated to the total ones. Heavy metals in the edible parts of vegetables also exceeded the corresponding standards. The leaves of pakchoi, peppermint, and coriander had a strong metal-accumulative ability and they were not suitable for planting. Except the residue forms, the main forms of metals in the edible parts of three selected vegetables were ethanol-, NaCl-, and HAc extractable fractions for As, Pb, and Cd, respectively; however, Cu was mainly presented as NaCl-extractable and Zn as HAc-extractable fractions. A high proportion of ethanol-extractable As showed that As bioactivity and toxic effects were the highest. Although the total and bioavailable Cd were high in soil, its speciation in vegetables was mainly presented as HAc-extractable fraction, which has a relatively low bioactivity. Lead and arsenic were imposing a serious threat on the local residents via vegetable consumption. PMID- 24952251 TI - Post-acquisition data processing for the screening of transformation products of different organic contaminants. Two-year monitoring of river water using LC-ESI QTOF-MS and GCxGC-EI-TOF-MS. AB - This study describes a comprehensive strategy for detecting and elucidating the chemical structures of expected and unexpected transformation products (TPs) from chemicals found in river water and effluent wastewater samples, using liquid chromatography coupled to electrospray ionization quadrupole-time-of-flight mass spectrometer (LC-ESI-QTOF-MS), with post-acquisition data processing and an automated search using an in-house database. The efficacy of the mass defect filtering (MDF) approach to screen metabolites from common biotransformation pathways was tested, and it was shown to be sufficiently sensitive and applicable for detecting metabolites in environmental samples. Four omeprazole metabolites and two venlafaxine metabolites were identified in river water samples. This paper reports the analytical results obtained during 2 years of monitoring, carried out at eight sampling points along the Henares River (Spain). Multiresidue monitoring, for targeted analysis, includes a group of 122 chemicals, amongst which are pharmaceuticals, personal care products, pesticides and PAHs. For this purpose, two analytical methods were used based on direct injection with a LC-ESI-QTOF-MS system and stir bar sorptive extraction (SBSE) with bi-dimensional gas chromatography coupled with a time-of-flight spectrometer (GCxGC-EI-TOF-MS). PMID- 24952253 TI - Catalytic hydrolysis of urea from wastewater using different aluminas by a fixed bed reactor. AB - In order to find an effective method for treating urea wastewater, the experiments on the hydrolysis of urea in wastewater were conducted in a fixed bed reactor with different aluminas (alpha-Al2O3, gamma-Al2O3, and eta-Al2O3) as catalysts respectively in contrast with inert ceramic particle. The results indicate that the three alumina catalysts show obvious catalytic activity for urea hydrolysis at 125 degrees C. The order of activity is eta-Al2O3 > gamma Al2O3 > alpha-Al2O3, and the activity difference increases with increasing temperature. According to the characterization results, surface acidity has little impact on the activity of catalyst. However, it was found that surface basicity of alumina catalyst plays an important role in catalytic hydrolysis of urea, and the activity of catalyst may be also influenced by the basic strength. With eta-Al2O3 as catalyst, the urea concentration in wastewater is reduced to 4.96 mg/L at a temperature of 165 degrees C. Moreover, the eta-Al2O3 shows a good stability for urea hydrolysis. The hydrolysis of urea over eta-Al2O3 catalyst can evidently reduce the reaction temperature and is promising to replace industrial thermal hydrolysis process. PMID- 24952254 TI - Photocatalysis: new highlights from JEP 2013. PMID- 24952256 TI - Perioperative complications associated with spine surgery in patients with established spinal cord injury. AB - BACKGROUND CONTEXT: Only a small percentage of patients with spinal cord injury (SCI) require consideration for reconstructive surgery after their initial injury. For those who do, perioperative complications can be frequent and significant. There has been very little published literature examining treatment of these patients and essentially nothing to guide the surgeon in perioperative decision making and management. PURPOSE: To identify some of the common challenges associated with surgery in this patient population and review the literature to highlight the perioperative concerns in patients with chronic SCI. STUDY DESIGN: Review article. METHODS: A primary PubMed literature search was performed and reviewed for patients with chronic SCI with emphasis on the complications and difficulties encountered during surgical treatment of patients with chronic SCI. RESULTS: For those who do proceed with surgery in this patient population, preoperative nutrition, bone density, and skin should be evaluated and optimized. Preoperative inferior vena cava filters should be considered. The integrity of the reconstruction will be extensively challenged. In addition, augmented fixation and bracing should be contemplated. CONCLUSIONS: Patients with chronic SCI who require spinal reconstruction provide many unique challenges. Indications for surgery must be strong as perioperative complications can be frequent and long-term outcomes unpredictable. Close monitoring for postoperative complications is essential. PMID- 24952255 TI - Association of postoperative outcomes with preoperative magnetic resonance imaging for patients with concurrent multiple sclerosis and cervical stenosis. AB - BACKGROUND CONTEXT: Differentiating between multiple sclerosis (MS) and cervical stenosis (CS) can be difficult because of their overlapping symptoms. Although studies have shown preoperative imaging criteria that are predictive of outcomes in either MS or CS individually, no studies have investigated these factors in patients that have concurrent MS and CS. PURPOSE: To investigate the associations between preoperative magnetic resonance imaging (MRI) findings and postoperative outcomes in patients with concurrent MS and CS with myelopathy. STUDY DESIGN: A retrospective review. PATIENT SAMPLE: All patients presenting with myelopathy who underwent cervical decompression surgery at a single tertiary-care institution between January 1996 and July 2011, diagnosed with concurrent MS and CS. OUTCOME MEASURES: Pre- and postoperative severity of myelopathy was assessed using the modified Japanese Orthopaedic Association (mJOA) scale. METHODS: Preoperative imaging was assessed for stenosis, lesions, signal intensity (graded low, intermediate, or high), extent of lesion (focal or diffuse), and cord atrophy. Imaging was then correlated with postoperative myelopathy outcomes. RESULTS: Forty-eight patients with MS and CS were reviewed for an average follow-up of 53 months. In the short term after surgery, there were 24 patients (50%) who showed improvement in the mJOA myelopathy score and 24 (50%) who did not improve. Significantly greater percentage of patients in the improvement group had high intensity lesions on preoperative MRI as compared with the no-improvement group (p=.03). At long-term follow-up, there were 18 patients (37.5%) who showed postoperative improvement and 30 patients (62.5%) with no improvement. No significant differences were identified on preoperative imaging between those who improved postoperatively and those who did not. CONCLUSIONS: Although certain characteristic preoperative MRI findings are associated with postoperative outcomes in cohorts of either MS or CS patients, we did not find this to be the case in patients with concurrent MS and CS. Accordingly, the treatment of the MS/CS patient population should be unique as their outcomes may not be as good as those with CS but no MS. PMID- 24952257 TI - A claudin 3 and claudin 4-targeted Clostridium perfringens protoxin is selectively cytotoxic to PSA-producing prostate cancer cells. AB - Prostate cancer is the second leading cause of non-cutaneous cancer-related death in males, and effective strategies for treatment of metastatic disease are currently limited. The tight junction proteins, claudin 3 and claudin 4, serve as cell-surface receptors for the pore-forming Clostridium perfringens enterotoxin [CPE]. Most prostate cancer cells overexpress claudin 3 and claudin 4, and claudins are aberrantly distributed over the plasma membrane, making these cells particularly sensitive to cytolysis by CPE. Prostate cancer cells secrete PSA locally that is proteolytically active; however, circulating PSA is inactivated via binding to protease inhibitors. To overcome systemic toxicity of CPE, a modified protoxin was constructed with a tethered ligand attached to the C terminus connected by a flexible linker containing a PSA-specific protease cleavage site. This engineered protoxin selectively and efficiently lyses PSA producing prostate cancer cells whereas CLDN3 and CLDN4 positive cells that do not express PSA are resistant to cytolysis. PMID- 24952258 TI - Epithelial-mesenchymal transition-associated miRNAs in ovarian carcinoma, with highlight on the miR-200 family: prognostic value and prospective role in ovarian cancer therapeutics. AB - MicroRNAs (miRNAs) are a family of short ribonucleic acids found to play a pivotal role in cancer pathogenesis. MiRNAs are crucial in cellular differentiation, growth, stress response, cell death and other fundamental cellular processes, and their involvement in ovarian cancer has been recently shown. They can repress the expression of important cancer-related genes and they can also function both as oncogenes and tumour suppressor genes. During epithelial-mesenchymal transition (EMT), epithelial cells lose their cell polarity and cell-cell adhesion and gain migratory and invasive properties. In the ovarian surface epithelium, EMT is considered the key regulator of the post ovulatory repair process and it can be triggered by a range of environmental stimuli. The aberrant expression of the miR-200 family (miR-200a, miR-200b, miR 200c, miR-141 and miR-429) in ovarian carcinoma and its involvement in ovarian cancer initiation and progression has been well-demonstrated. The miR-200 family members seem to be strongly associated with a pathologic EMT and to have a metastasis suppressive role. MiRNA signatures can accurately distinguish ovarian cancer from the normal ovary and can be used as diagnostic tools to predict the clinical response to chemotherapy. Recent evidence suggests a growing list of new miRNAs (miR-187, miR-34a, miR-506, miRNA-138, miR-30c, miR-30d, miR-30e-3p, miR 370 and miR-106a, among others) that are also implicated in ovarian carcinoma associated EMT, either enhancing or suppressing it. MiRNA-based gene therapy provides a prospective anti-tumour approach for integrated cancer therapy. The aim of nanotechnology-based delivery approach for miRNA therapy is to overcome challenges in miRNA delivery and to effectively encourage the reprogramming of miRNA networks in cancer cells, which may lead to a clinically translatable miRNA based therapy to benefit ovarian cancer patients. PMID- 24952259 TI - Learning ability in bank voles selected for high aerobic metabolism, predatory behaviour and herbivorous capability. AB - Although great progress has been made in understanding neurological mechanisms of cognitive processes, the questions concerning interrelation between evolution of cognitive abilities and evolution of diverse life histories and adaptive strategies remains largely open. We approached the problem using a unique experimental evolution model system: lines of bank voles selected for high swim induced aerobic metabolism, intensity of predatory behaviour towards crickets, and ability to grow on a low-quality herbivorous diet. To test a hypothesis that selection for these traits resulted in correlated changes in spatial learning and memory, voles from generation 13 of the selected and unselected control lines were examined in Morris water maze. Most of the individuals successfully learned the position of the platform hidden under water surface, but the spatial learning scores did not differ significantly between selection directions. The results are not consistent with either the hypothesis of a functional trade-off between high cognitive abilities and capability to cope with adverse nutritional conditions, or the hypothesis of a positive link between evolution of cognitive abilities and high aerobic exercise performance. PMID- 24952261 TI - ADHD impacted by sulfotransferase (SULT1A) inhibition from artificial food colors and plant-based foods. AB - BACKGROUND: Five recent reviews have analyzed trials on the association between artificial food colors and ADHD; the 50 underlying studies and the reviews in aggregate were inconclusive. Recent work has shown human in vivo SULT1A inhibition leading to incremental catecholamines, and an inverted-U relationship between brain catecholamines and proper functioning of the prefrontal cortex where ADHD behavior can arise. METHOD: This study re-examined the same underlying trials for evidence that SULT1A inhibitors were in the placebos and other inactive foods, that these "inactive" materials were symptomatic, and that ADHD symptoms exhibited an inverted-U response to SULT1A inhibition. RESULTS: Nearly all the underlying diets, and many placebos and delivery vehicles, were found to contain SULT1A inhibitors. Eight publications provided evidence of ADHD symptoms caused by the "inactive" materials containing SULT1A inhibitors. Ten studies showed additional SULT1A inhibitors reducing the symptoms of some subjects. CONCLUSION: SULT1A inhibitors in foods, including natural substances and artificial food colors, have a role in ADHD that can both worsen or improve symptoms. Mechanistically, SULT1A enzymes normally deactivate catecholamines, especially dopamine formed in the intestines; SULT1A inhibition can influence brain catecholamines through the intermediary of plasma tyrosine levels, which are influenced by dopamine inhibition of intestinal tyrosine hydroxylase. Biochemical measurements focused on SULT1A activity and plasma tyrosine concentrations are proposed for future work. PMID- 24952260 TI - Quercetin protects the impairment of memory and anxiogenic-like behavior in rats exposed to cadmium: Possible involvement of the acetylcholinesterase and Na(+),K(+)-ATPase activities. AB - The present study investigated the effects of quercetin in the impairment of memory and anxiogenic-like behavior induced by cadmium (Cd) exposure. We also investigated possible alterations in acetylcholinesterase (AChE), Na(+),K(+) ATPase and delta-aminolevulinate dehydratase (delta-ALA-D) activities as well as in oxidative stress parameters in the CNS. Rats were exposed to Cd (2.5mg/kg) and quercetin (5, 25 or 50mg/kg) by gavage for 45days. Animals were divided into eight groups (n=10-14): saline/control, saline/Querc 5mg/kg, saline/Querc 25mg/kg, saline/Querc 50mg/kg, Cd/ethanol, Cd/Querc 5mg/kg, Cd/Querc 25mg/kg and Cd/Querc 50mg/kg. Results demonstrated that Cd impaired memory has an anxiogenic effect. Quercetin prevented these harmful effects induced by Cd. AChE activity decreased in the cerebral cortex and hippocampus and increased in the hypothalamus of Cd-exposed rats. The Na(+),K(+)-ATPase activity decreased in the cerebral cortex, hippocampus and hypothalamus of Cd-exposed rats. Quercetin prevented these effects in AChE and Na(+),K(+)-ATPase activities. Reactive oxygen species production, thiobarbituric acid reactive substance levels, protein carbonyl content and double-stranded DNA fractions increased in the cerebral cortex, hippocampus and hypothalamus of Cd-exposed rats. Quercetin totally or partially prevents these effects caused by Cd. Total thiols (T-SHs), reduced glutathione (GSH), and reductase glutathione (GR) activities decreased and glutathione S-transferase (GST) activity increased in Cd exposed rats. Co treatment with quercetin prevented reduction in T-SH, GSH, and GR activities and the rise of GST activity. The present findings show that quercetin prevents alterations in oxidative stress parameters as well as AChE and Na(+),K(+)-ATPase activities, consequently preventing memory impairment and anxiogenic-like behavior displayed by Cd exposure. These results may contribute to a better understanding of the neuroprotective role of quercetin, emphasizing the influence of this flavonoid in the diet for human health, possibly preventing brain injury associated with Cd intoxication. PMID- 24952262 TI - The effect of blockade of the central V1 vasopressin receptors on anhedonia in chronically stressed infarcted and non-infarcted rats. AB - Chronic mild stress (CMS) and myocardial infarction (MI) induce anhedonia, which is one of the symptoms of depression. The purpose of this study was to determine the role of the central V1 vasopressin receptors (V1R) in post-CMS and post-MI anhedonia. To this end, we investigated the effect of blockage the central V1R [28days of intracerebroventricular (ICV) infusion of V1 receptors antagonist (V1RANT)] on CMS-induced and the post-infarct anhedonia. The experiments were conducted on conscious MI or sham-operated (SO) rats that were either exposed to CMS for 20days or remained at rest. The sucrose/water intake ratio (S/W) was measured to determine hedonic behavior. Seven days after MI, the S/W was reduced. This effect was no longer present 37days after the infarction and was also absent in the SO rats. Exposure to CMS reduced the S/W in SO rats also. In the CMS exposed MI rats, the S/W was similar to that in the CMS-exposed SO rats. ICV administration of V1RANT abolished reductions in the S/W in the CMS-exposed MI rats, however, it did not influence S/W in the SO rats exposed to CMS and in the MI and SO rats not exposed to CMS. We conclude that: (1) myocardial infarction and chronic stressing cause anhedonia, (2) myocardial infarction-induced anhedonia appears to be transient, (3) myocardial infarction does not potentiate CMS-induced anhedonia, and (4) CMS-induced anhedonia critically depends on the stimulation of the central V1 receptors. PMID- 24952263 TI - The impact of a diphenyl diselenide-supplemented diet and aerobic exercise on memory of middle-aged rats. AB - Selenium is an essential trace element for human health and has received attention for its role as a nutrient. The combination of exercise and nutrients has been proposed to promote health. The aim of this study was to determine the effects of a diet supplemented with diphenyl diselenide (PhSe)2 and swimming exercise on memory of middle-aged rats. Male Wistar rats (12months) received standard diet chow supplemented with 1ppm of (PhSe)2 for 4weeks. Rats were submitted to swimming training (20min per day for 4weeks). After 4weeks, memory was evaluated in the object recognition test (ORT) and in the object location test (OLT). The hippocampal levels of phosphorylated cAMP-response element binding protein (CREB) were determined. The results of the present study demonstrated that the association of (PhSe)2-supplemented diet and swimming exercise improved short-term memory, long-term memory and spatial learning, and this effect was not related to the increase in hippocampal p-CREB levels in middle-age rats. This study also revealed that middle-aged rats in the swimming exercise group had the best performance in short- and long-term memory. In conclusion, we demonstrated that swimming exercise, (PhSe)2-supplemented diet or the association of these factors improved learning and memory functioning. The hippocampal levels of CREB were not directly related to the benefits of swimming exercise and (PhSe)2-supplemented diet association in memory of middle-aged rats. PMID- 24952264 TI - Modified sham feeding of foods with different macronutrient compositions differentially influences cephalic change of insulin, ghrelin, and NMR-based metabolomic profiles. AB - Little is known about the effect of the macronutrient composition of foods on cephalic phase response of gastrointestinal hormones. In addition, the metabolomics of cephalic phase response has not been studied before. The objective of the present study was to assess cephalic phase endocrinological and metabolomic responses following modified sham feeding (MSF) of foods with different macronutrient compositions. Ten healthy males attended four separate test sessions after overnight fasting, for a 3-min MSF of water, high-fat, high carbohydrate or high-protein food, respectively, in a randomized order. Blood samples were collected at baseline and at regular time points for 10min following the completion of MSF and assayed for plasma glucose, insulin, ghrelin and glucose-dependent insulinotropic peptide. (1)H nuclear magnetic resonance was used to acquire metabolomic profiles of the plasma samples. Plasma glucose increased after MSF of all test foods, but there were no differences due to the macronutrient composition of the test foods. MSF of the high-carbohydrate food elicited significantly higher insulin, and the high-protein food resulted in higher ghrelin compared to other test sessions. No significant change in glucose dependent insulinotropic peptide was found. Analysis of plasma metabolomic profiles revealed concentrations of lipids were lower after MSF while plasma glucose increased after MSF. There was also a macronutrient-dependent change in certain amino acids. In conclusion, short-term oral exposure to foods with different macronutrient compositions can induce a macronutrient-specific cephalic change in insulin and ghrelin, as well as metabolomic profiles. PMID- 24952265 TI - Is energy intake altered by a 10-week aerobic exercise intervention in obese adolescents? AB - AIM: To examine energy intake adaptations to a 10-week aerobic exercise program in obese adolescents. METHODS: Twenty-six 12-17year old obese adolescents were asked to cycle twice a week for an hour in a research laboratory. Body composition, aerobic fitness (submaximal fitness test) and energy intake (3-day food record) were assessed before and immediately after the 10-week intervention. RESULTS: The average time spent pedaling per session was 55.3+/-12.1min for a mean energy expenditure of 2196+/-561kJpersession. The intervention produced significant improvements in percentage of body fat (44.5+/-10.6% vs. 43.4+/-9.8%; p<0.05) but no significant weight and fat-free mass change. Peak workload (79.5+/ 20.8W vs. 87.3+/-17.6W; p<0.05) and peak heart rate (174.6+/-18.7bpm vs. 166.2+/ 21.0bpm; p<0.01) were improved. The mean total daily energy intake (in kJ/day) showed a tendency to decrease through the intervention (7440+/-1744 to 6740+/ 2124kJ; p=0.07) but a high inter-individual variability observed in the energy intake response to the intervention may explain the non-significant association between the energy intake response and weight loss. CONCLUSION: A 10-week aerobic exercise program may result in a small decrease in energy intake and an associated decrease in percentage of body fat but no weight loss in obese adolescents. This lack of weight loss could be explained by a decrease in spontaneous energy expenditure outside the intervention sessions. PMID- 24952266 TI - Age-related declines in thirst and salt appetite responses in male Fischer 344*Brown Norway rats. AB - The F344*BN strain is the first generational cross between Fischer 344 (F344) and Brown Norway (BN) rats. The F344*BN strain is widely used in aging studies as it is regarded as a model of "healthy" aging (Sprott, 1991). In the present work, male F344*BN rats aged 4mo (young, n=6) and 20mo (old, n=9) received a series of experimental challenges to body fluid homeostasis to determine their thirst and salt appetite responses. Corresponding urinary responses were measured in some of the studies. Following sodium depletion, old rats ingested less saline solution (0.3M NaCl) than young rats on a body weight basis, but both ages drank enough saline solution to completely repair the accrued sodium deficits. Following intracellular dehydration, old rats drank less water than young rats, again on a body weight basis, and were less able than young rats to drink amounts of water proportionate to the osmotic challenge. Compared with young rats, old rats drank less of both water and saline solution after combined food and fluid restriction, and also were refractory to the stimulatory effects of low doses of captopril on water drinking and sodium ingestion. Age differences in urinary water and sodium excretion could not account for the age differences in accumulated water and sodium balances. These results extend observations of diminished behavioral responses of aging animals to the F344*BN rat strain and support the idea that impairments in behavior contribute more to the waning ability of aging animals to respond to body fluid challenges than do declines in kidney function. In addition, the results suggest that behavioral defense of sodium homeostasis is less diminished with age in the F344*BN strain compared to other strains so far studied. PMID- 24952267 TI - After a cold conditioning swim, UCP2-deficient mice are more able to defend against the cold than wild type mice. AB - Uncoupling protein 2 (UCP2) is widely distributed throughout the body including the brain, adipose tissue and skeletal muscles. In contrast to UCP1, UCP2 does not influence resting body temperature and UCP2-deficient (-/-) mice have normal thermoregulatory responses to a single exposure to cold ambient temperatures. Instead, UCP2-deficient mice are more anxious, exhibit anhedonia and have higher circulating corticosterone than wild type mice. To test the possible role of UCP2 in depressive behavior we exposed UCP2-deficient and wild type mice to a cold (26 degrees C) forced swim and simultaneously measured rectal temperatures during and after the swim. The time that UCP2-deficient mice spent immobile did not differ from wild type mice and all mice floated more on day 2. However, UCP2-deficient mice were more able to defend against the decrease in body temperature during a second daily swim at 26 degrees C than wild type mice (area under the curve for wild type mice: 247.0+/-6.4; for UCP2-deficient mice: 284.4+/-3.8, P<0.0001, Student's t test). The improved thermoregulation of wild type mice during a second swim at 26 degrees C correlated with their greater immobility whereas defense against the warmth during a swim at 41 degrees C correlated better with greater immobility of UCP2-deficient mice. Together these data indicate that while the lack of UCP2 has no acute effect on body temperature, UCP2 may inhibit rapid improvements in defense against cold, in contrast to UCP1, whose main function is to promote thermogenesis. PMID- 24952268 TI - Chronic scream sound exposure alters memory and monoamine levels in female rat brain. AB - Chronic scream sound alters the cognitive performance of male rats and their brain monoamine levels, these stress-induced alterations are sexually dimorphic. To determine the effects of sound stress on female rats, we examined their serum corticosterone levels and their adrenal, splenic, and thymic weights, their cognitive performance and the levels of monoamine neurotransmitters and their metabolites in the brain. Adult female Sprague-Dawley rats, with and without exposure to scream sound (4h/day for 21 day) were tested for spatial learning and memory using a Morris water maze. Stress decreased serum corticosterone levels, as well as splenic and adrenal weight. It also impaired spatial memory but did not affect the learning ability. Monoamines and metabolites were measured in the prefrontal cortex (PFC), striatum, hypothalamus, and hippocampus. The dopamine (DA) levels in the PFC decreased but the homovanillic acid/DA ratio increased. The decreased DA and the increased 5-hydroxyindoleacetic acid (5-HIAA) levels were observed in the striatum. Only the 5-HIAA level increased in the hypothalamus. In the hippocampus, stress did not affect the levels of monoamines and metabolites. The results suggest that scream sound stress influences most physiologic parameters, memory, and the levels of monoamine neurotransmitter and their metabolites in female rats. PMID- 24952269 TI - Galectin-3 expressed on different lung compartments promotes organ specific metastasis by facilitating arrest, extravasation and organ colonization via high affinity ligands on melanoma cells. AB - Interactions between molecules on the surface of tumor cells and those on the target organ endothelium play an important role in their arrest in an organ. Galectin-3 on the lung endothelium and high affinity ligands poly-N acetyllactosamine (polyLacNAc) on N-oligosaccharides on melanoma cells facilitate such interactions. However, to extravasate and colonize an organ the cells must stabilize these interactions by spreading to retract endothelium, degrade exposed basement membrane (BM) and move into parenchyma and proliferate. Here, we show that galectin-3 is expressed on all the major compartments of the lungs and participates in not just promoting adhesion but also in spreading. We for the first time demonstrate that both soluble and immobilized galectin-3 induce secretion of MMP-9 required to breach vascular BM. Further, we show that immobilized galectin-3 is used as traction for the movement of cells. Downregulation of galactosyltransferases-I and -V resulted in significant loss in expression of polyLacNAc and thus reduced binding of galectin-3. This was accompanied with a loss in adhesion, spreading, MMP-9 secretion and motility of the cells on galectin-3 and thus their metastasis to lungs. Metastasis could also be inhibited by blocking surface polyLacNAc by pre-incubating cells with truncated galectin-3 (which lacked oligomerization domain) or by feeding mice with modified citrus pectin in drinking water. Overall, these results unequivocally show that polyLacNAc on melanoma cells and galectin-3 on the lungs play a critical role in arrest and extravasation of cells in the lungs and strategies that target these interactions inhibit lung metastasis. PMID- 24952270 TI - Performance and microbial community profiles in an anaerobic reactor treating with simulated PTA wastewater: from mesophilic to thermophilic temperature. AB - Performance and microbial community profiles in a hybrid anaerobic reactor treating synthetic PTA wastewater (contained the major pollutants terephthalate and benzoate) were studied over 220 days from 33 degrees C to 52 degrees C. Results indicated that PTA treatment process was highly sensitive to temperature variations in terms of COD removal. Operation at 37 degrees C showed the best performance as well as the most diverse microbial community revealed by 16S rRNA gene clone library and T-RFLP (terminal restriction fragment length polymorphism). Finally, the anaerobic process achieved a total COD removal of 77.4%, 91.9%, 87.4% and 66.1% at 33, 37, 43 and 52 degrees C. While the corresponding TA removal were 77.6%, 94.0%, 89.1% and 60.8%, respectively. Sequence analyses revealed acetoclastic Methanosaeta was preponderant at 37 degrees C, while hydrogenotrophic genera including Methanobrevibacter and Methanofollis were more abundant at other temperatures. For bacterial community, 16 classes were identified. The largely existent Syntrophorhabdus members (belonging to delta-Proteobacteria) at 37 degrees C was likely to play an important role in mesophilic anaerobic wastewater treatment system contained terephthalate. Meanwhile, beta-Proteobacteria seemed to be favored in an anaerobic system higher than 43 degrees C. PMID- 24952271 TI - Persistence of fecal indicator bacteria in sediment of an oligotrophic river: comparing large and lab-scale flume systems. AB - In this study, both a lab and a large-scale flume system were used to investigate the survival of fecal indicator bacteria (FIB) in bed sediments of an alpine oligotrophic river. To determine the influence of substratum on persistence, survival within 3-cm-deep substratum cages versus on thin, biofilm-covered ceramic tiles was tested. Moreover, the impact of bed shear stress on survival in bed sediments was explored. It was seen that in the lab-scale flume having a very low bed shear stress (0.3 N m(-2)), E. coli and enterococci survival in 3-cm-deep substratum cages was nearly the same as in a thin biofilm (200 MUm). However, in the large-scale flume system characterized by a bed shear stress of 9 N m(-2), the added protection of the deeper substratum cages promoted considerably longer survival of E. coli and enterococci than the thin biofilm. Additionally, the FIB removal mechanisms in the two flume systems varied. At the lab-scale, enterococci was seen to persist twice as long as E. coli, while in the large-scale flume the two FIB were removed at the same rate. A comparison of qPCR analyses performed in both flumes suggests that bed sediment erosion and the influence of grazers/predators were responsible for FIB removal from the sediments in the large-scale flume, whereas in the lab flume FIB inactivation caused removal. These results indicate that hydraulic parameters such as bed shear stress as well as the presence of macroinvertebrates in a system are both important factors to consider when designing flumes as they can significantly impact FIB persistence in sediments of fast-flowing, alpine streams. PMID- 24952272 TI - Efficacy of biochar to remove Escherichia coli from stormwater under steady and intermittent flow. AB - Biofilters, designed to facilitate the infiltration of stormwater into soil, are generally ineffective in removing bacteria from stormwater, thereby causing pollution of groundwater and receiving surface waters. The bacterial removal capacity of biofilters has been shown to be lower in the presence of natural organic matter (NOM) and during intermittent infiltration of stormwater. To improve the removal of fecal indicator bacteria (Escherichia coli) under these conditions, we amended sand with 5% (by weight) biochar, a carbonaceous geomedia produced by pyrolysis of biomass, and investigated the removal and remobilization of E. coli. Three types of biochar were used to evaluate the role of biochar properties on the removal. Compared to sand, biochar not only retained up to 3 orders of magnitude more E. coli, but also prevented their mobilization during successive intermittent flows. In the presence of NOM, the removal capacity of biochar was lower, but remained higher than sand alone. The improved retention with the biochar amendment is attributed to an increase in the attachment of E. coli at the primary minimum and to an increase in the water-holding capacity of biochar-amended sand, which renders driving forces such as moving air-water interfaces less effective in detaching bacteria from grain surfaces. Biochars with lower volatile matter and polarity appear to be more effective in removing bacteria from stormwater. Overall, our results suggest that a biochar amendment to biofilter media has the potential to effectively remove bacteria from stormwater. PMID- 24952273 TI - Clinical and epidemiological analysis of the first case of human infection with avian influenza A (H7N9) virus in Shenzhen, China. AB - The novel influenza A (H7N9) virus can cause severe illness, including pneumonia and acute respiratory disorder syndrome (ARDS), with high rates of intensive care unit admission and death. We report the first case of human infection with avian influenza A (H7N9) virus in Shenzhen, China. The patient was a 38-year-old man. His infection was eventually confirmed 9 days after illness onset. No symptom was found in his 135 close contacts. The patient recovered 43 days after illness onset. Oseltamivir, anti-infective drugs, methylprednisolone, albumin, and intravenous immunoglobulin were administered. Antiviral therapy in the early stage and sufficient supportive management are key to the treatment of infections with this virus, and proper doses of methylprednisolone and intravenous immunoglobulin are recommended. PMID- 24952274 TI - Clinical results of posterior chamber phakic intraocular lens implantation in eyes with low anterior chamber depth. AB - PURPOSE: To investigate visual outcomes of Visian implantable Collamer lens (ICL) implantation in eyes with a shallow anterior chamber depth (ACD). DESIGN: Retrospective, noncomparative, interventional case series. METHODS: Medical charts of the patients with a low ACD of 2.8 mm or less who underwent implantable Collamer lens implantation were reviewed. To evaluate efficacy and safety, preoperative and postoperative uncorrected visual acuity, manifest refractive spherical equivalent (MRSE), endothelial cell count, intraocular pressure, angle opening distance at 500 MUm from the scleral spur, trabecular-iris angle, and postoperative central vault were analyzed. RESULTS: The mean follow-up period for 18 eyes of 10 patients was 24.67 +/- 15.09 months (range, 10 to 51 months). The preoperative ACD was 2.71 +/- 0.08 mm (range, 2.42 to 2.79 mm). There was no postoperative endothelial cell count reduction to less than 2000 cells/mm(2) or intraocular pressure elevation to more than 21 mm Hg. The differences between preoperative and postoperative angle opening distance at 500 MUm from the scleral spur and trabecular-iris angle were statistically significant (P = .000, both). The mean postoperative central vault was 331.83 +/- 181.28 MUm (range, 174 to 811 MUm), which was significantly less than expected (P = .000). Anterior subcapsular cataract was observed in 2 eyes (11.1%). CONCLUSIONS: Implantable Collamer lens implantation in shallow ACD eyes exhibited good visual outcomes. Severe complications did not develop over relatively long periods. Two cases of anterior subcapsular cataract developed in older aged patients, suggesting the need for thorough preoperative warning about the risk of cataract. In addition, a postoperative vault less than expected should be taken into account when determining implantable Collamer lens size in lower ACD eyes. PMID- 24952276 TI - Clostridial pore-forming toxins: powerful virulence factors. AB - Pore formation is a common mechanism of action for many bacterial toxins. More than one third of clostridial toxins are pore-forming toxins (PFTs) belonging to the beta-PFT class. They are secreted as soluble monomers rich in beta-strands, which recognize a specific receptor on target cells and assemble in oligomers. Then, they undergo a conformational change leading to the formation of a beta barrel, which inserts into the lipid bilayer forming functional pore. According to their structure, clostridial beta-PFTs are divided into several families. Clostridial cholesterol-dependent cytolysins form large pores, which disrupt the plasma membrane integrity. They are potent virulence factors mainly involved in myonecrosis. Clostridial heptameric beta-PFTs (aerolysin family and staphylococcal alpha-hemolysin family) induce small pores which trigger signaling cascades leading to different cell responses according to the cell types and toxins. They are mainly responsible for intestinal diseases, like necrotic enteritis, or systemic diseases/toxic shock from intestinal origin. Clostridial intracellularly active toxins exploit pore formation through the endosomal membrane to translocate the enzymatic component or domain into the cytosol. Single chain protein toxins, like botulinum and tetanus neurotoxins, use hydrophobic alpha-helices to form pores, whereas clostridial binary toxins encompass binding components, which are structurally and functionally related to beta-PFTs, but which have acquired the specific activity to internalize their corresponding enzymatic components. Structural analysis suggests that beta-PFTs and binding components share a common evolutionary origin. PMID- 24952275 TI - Effect of anti-vascular endothelial growth factor therapy on choroidal thickness in diabetic macular edema. AB - PURPOSE: To determine the effect of anti-vascular endothelial growth factor (VEGF) therapy on choroidal thickness in eyes with diabetic macular edema (DME). DESIGN: A retrospective, cohort analysis of 59 eyes from 59 patients with DME without prior anti-VEGF therapy. METHODS: Choroidal thickness was measured using semiautomated segmentation of enhanced depth imaging optical coherence tomography images at 0.5-mm intervals from 2.5 mm nasal to 2.5 mm temporal to the fovea. Changes in choroidal thickness with and without anti-VEGF treatment over 6 months were compared. Best-corrected visual acuity and central foveal thickness were analyzed to evaluate the association of choroidal thickness with functional and anatomic outcomes. RESULTS: Of the 59 eyes with DME, 26 eyes were observed without treatment, whereas 33 underwent intravitreal anti-VEGF therapy (mean number of injections, 2.73) over 6 months. In untreated eyes, there was no significant change in best-corrected visual acuity (P = .098), central foveal thickness (P = .472), or choroidal thickness at all measurements along the macula (P = .057 at the fovea). In eyes treated with anti-VEGF injections, choroidal thickness decreased significantly at the fovea (246.6 to 224.8 MUm; P < .001) and at 0.5 mm nasal (240.9 to 221.9 MUm; P = .002) and 0.5 mm temporal (249.3 to 224.8 MUm; P = .011) to the fovea. The decrease in subfoveal choroidal thickness after anti-VEGF treatment was not associated with the cumulative number of anti VEGF injections (R(2) = 0.031; P = .327) or to changes in best-corrected visual acuity (R(2) = 0.017; P = .470) or central foveal thickness (R(2) = 0.040; P = .263). CONCLUSIONS: Central choroidal thickness decreases after anti-VEGF therapy for DME after 6 months, but may not be associated with functional or anatomic outcomes in eyes with DME. PMID- 24952278 TI - Retinal neuroprotective effects of quercetin in streptozotocin-induced diabetic rats. AB - The aim of the present study was to evaluate the effects of Quercetin (Qctn), a plant based flavonol, on retinal oxidative stress, neuroinflammation and apoptosis in streptozotocin-induced diabetic rats. Qctn treatment (25- and 50 mg/kg body weight) was given orally for six months in diabetic rats. Retinal glutathione (GSH) and antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] were estimated using commercially available assays, and inflammatory cytokines levels [tumor necrosis factor-alpha (TNF-alpha), Interleukin-1beta (IL-1beta)] were estimated by ELISA method. Immunofluorescence and western blot studies were performed for nuclear factor kappa B (NF-kB), caspase-3, glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4) expressions. Structural changes were evaluated by light microscopy. In the present study, retinal GSH levels and antioxidant enzyme (SOD and CAT) activities were significantly decreased in diabetic group as compared to normal group. However, in Qctn-treated rats, retinal GSH levels were restored close to normal levels and positive modulation of antioxidant enzyme activities was observed. Diabetic retinas showed significantly increased expression of pro-inflammatory cytokines (TNF-alpha and IL-1beta) as compared to that in normal retinas, while Qctn-treated retinas showed significantly lower levels of cytokines as compared to diabetic retinas. Light microscopy showed significantly increased number of ganglion cell death and decreased retinal thickness in diabetic group compared to those in normal retina; however, protective effect of Qctn was seen. Increased apoptosis in diabetic retina is proposed to be mediated by overexpression of NF kB and caspase-3. However, Qctn showed inhibitory effects on NF-kB and caspase-3 expression. Microglia showed upregulated GFAP expression, and inflammation of Muller cells resulted in edema in their endfeet and around perivascular space in nerve fiber layer in diabetic retina, as observed through AQP4 expression. However, Qctn treatments inhibited diabetes-induced increases in GFAP and AQP4 expression. Based on these findings, it can be concluded that bioflavonoids, such as Qctn can be effective for protection of diabetes induced retinal neurodegeneration and oxidative stress. PMID- 24952277 TI - N-Acetylcysteine increases corneal endothelial cell survival in a mouse model of Fuchs endothelial corneal dystrophy. AB - The present study evaluated survival effects of N-acetylcysteine (NAC) on cultured corneal endothelial cells exposed to oxidative and endoplasmic reticulum (ER) stress and in a mouse model of early-onset Fuchs endothelial corneal dystrophy (FECD). Cultured bovine corneal endothelial cell viability against oxidative and ER stress was determined by CellTiter-Glo((r)) luminescent reagent. Two-month-old homozygous knock-in Col8a2(L450W/L450W) mutant (L450W) and C57/Bl6 wild-type (WT) animals were divided into two groups of 15 mice. Group I received 7 mg/mL NAC in drinking water and Group II received control water for 7 months. Endothelial cell density and morphology were evaluated with confocal microscopy. Antioxidant gene (iNos) and ER stress/unfolded protein response gene (Grp78 and Chop) mRNA levels and protein expression were measured in corneal endothelium by real time PCR and Western blotting. Cell viability of H2O2 and thapsigargin exposed cells pre-treated with NAC was significantly increased compared to untreated controls (p < 0.01). Corneal endothelial cell density (CD) was higher (p = 0.001) and percent polymegathism was lower (p = 0.04) in NAC treated L450W mice than in untreated L450W mice. NAC treated L450W endothelium showed significant upregulation of iNos, whereas Grp78 and Chop were downregulated compared to untreated L450W endothelium by real time PCR and Western blotting. NAC increases survival in cultured corneal endothelial cells exposed against ER and oxidative stress. Systemic NAC ingestion increases corneal endothelial cell survival which is associated with increased antioxidant and decreased ER stress markers in a mouse model of early-onset FECD. Our study presents in vivo evidence of a novel potential medical treatment for FECD. PMID- 24952280 TI - A cross-cultural analysis of Jammu, Kashmir and Ladakh (India) medicinal plant use. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Jammu & Kashmir (J&K) is a predominantly Himalayan state in the north-western part of India. It has three geographically distinct divisions viz., Jammu, Kashmir and Ladakh, which are immensely rich in their biological and cultural diversity. Medicinal plants are an important element of indigenous medical system of the region. The main goal of the present article is to examine the use of ethnomedicinal plants in three divisions of J&K and to discuss cross-cultural consensus on the use of medicinal plants in these divisions. The article also discusses the gaps in the current state of knowledge on ethnomedicinal plants of the region and gives recommendations for the future studies. MATERIALS AND METHODS: Scientific literature on ethnomedicinal field studies conducted in J&K state of India available in the journals, edited books and other scientific databases viz., CAB international, DOAJ, Google Scholar, PubMed, Science direct, SciFinder, Scopus and Web of Science were searched. Only field based ethnomedicinal surveys from last four decades up to December 2013 reporting first hand information on the medicinal plants used to treat human health related ailments by indigenous communities of J&K were included in this study. Venn diagram was used to analyze the cross-cultural consensus on the use of ethnomedicinal plants in the three divisions of J&K. RESULTS: A total of 948 plant taxa (923 angiosperms, 12 gymnosperms and 13 pteridophytes) belonging to 129 families, 509 genera, 937 species and 11 varieties have so far been reported to have a traditional medicinal use by indigenous communities of J&K. Asteraceae (60 genera, 132 spp.) was the most frequently used family followed by Fabaceae (32 genera, 50 spp.) and Lamiaceae (27 genera, 55 spp.). 514, 415 and 397 medicinal plants were used in Jammu, Kashmir and Ladakh divisions, respectively. Sixty eight plant taxa were used in all the three divisions, whereas 95 plants were common between Ladakh and Jammu, 127 plants between Ladakh and Kashmir, and 216 plants between Jammu and Kashmir. Maximum numbers of plant taxa were used for treating dermatological problems (321), followed by cold, cough and throat related ailments (250), fever (224), joint and muscle related ailments (215), gastrointestinal disorders (210), urogenital ailments (199), respiratory ailments (151), body pain (135) and gynecological disorders (127). CONCLUSIONS: This is the first study from the J&K state, which has examined the medicinal plant use in three divisions of J&K and discussed the promising medicinal plant species with cross-cultural consensus. The analysis of the data suggested that while large numbers of plants are used medicinally in each division, there is a low interregional consensus and high variation between medicinal plants used in these divisions, which is due to both cultural divergence as well as biological distinctness. The issues related to current status of knowledge on medicinal plants used by indigenous communities of J&K have been discussed and some recommendations have been made for future studies on medicinal plants in J&K region. PMID- 24952279 TI - Counteraction of Bothrops snake venoms by Combretum leprosum root extract and arjunolic acid. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Serotherapy against snakebite is often unavailable in some regions over Brazil, where people make use of plants from folk medicine to deal with ophidic accidents. About 10% of Combretum species have some ethnopharmacological use, including treatment of snakebites. MATERIALS AND METHODS: We evaluated the ability of the extract of Combretum leprosum and its component arjunolic acid to reduce some in vivo and in vitro effects of Bothrops jararacussu and Bothrops jararaca venoms. The protocols investigated include phospholipase, proteolytic, collagenase, hyaluronidase, procoagulant, hemorrhagic, edematogenic, myotoxic and lethal activities induced by these venoms in Swiss mice. RESULTS: Oral pre-treatment with arjunolic acid reduced the Bothrops jararacussu lethality in up to 75%, while preincubation prevented the death of all the animals. Hemoconcentration effect of Bothrops jararacussu venom was confirmed two hours after i.p. injection, while preincubation with arjunolic acid preserved the hematocrit levels. Both Combretum leprosum extract and arjunolic acid abolished the myotoxic action of Bothrops jararacussu venom. Preincubation of Bothrops jararacussu venom with the extract or arjunolic acid prevented the increase of plasma creatine kinase activity in mice. The hemorrhagic activity of Bothrops jararaca crude venom was reduced down to about 90% and completely inhibited by preincubation with 10 mg/kg or 100 mg/kg Combretum leprosum extract, respectively, while the preincubation and the pretreatment with 30 mg/kg of arjunolic acid reduced the venom hemorrhagic activity down to about 12% and 58%, respectively. The preincubation of the venom with both extract and 30 mg/kg arjunolic acid significantly reduced the bleeding amount induced by Bothrops jararacussu venom. The extract of Combretum leprosum decreased the edema formation induced by Bothrops jararacussu venom both in preincubation and pretreatment, but not in posttreatment. Similarly, arjunolic acid preincubated with the venom abolished edema formation, while pre- and posttreatment have been partially effective. Some enzymatic activities of Bothrops jararacussu and Bothrops jararaca venoms, i.e. phospholipase A2, collagenase, proteolytic and hyaluronidase activities, were to some extent inhibited by the extract and arjunolic acid in a concentration-dependent manner. CONCLUSIONS: Altogether, our results show that Combretum leprosum extract can inhibit different activities of two important Brazilian snake venoms, giving support for its popular use in folk medicine in the management of venomous snakebites. PMID- 24952281 TI - Multi-level Intervention to increase participation in mammography screening: !Fortaleza Latina! study design. AB - BACKGROUND: Breast cancer is the most common cancer and the leading cause of death among Latinas in the United States. The Multi-level Intervention to Increase Participation in Mammography Screening study (!Fortaleza Latina!) is a partnership among research institutions, a Latino-serving community-based primary care clinic organization, and a cancer treatment center. The study will assess the efficacy of a clinic- and patient-level program to increase breast cancer screening among Latinas in Western Washington. METHODS/DESIGN: The intervention is a multi-level breast cancer screening program in four participating primary care clinics. The study is a parallel randomized controlled trial of 600 Latino women aged 42-74 who are non-compliant with breast cancer screening guidelines. Participants will be randomized within clinic using block randomization to: (1) a control arm (usual care); and (2) a theory-based counseling program consisting of a 'promotora' or community health worker-led home-based intervention to encourage breast cancer screening. At the clinic-level, two clinics will offer additional mammography services provided by a mobile mammography unit operated by the Seattle Cancer Care Alliance. The primary endpoint is the rate of mammography uptake over the 1-year follow-up period. DISCUSSION: This multi-level intervention aims to raise rates of participation in breast cancer screening among Latino women. If effective, the program may improve rates of early detection of breast cancer in Latino women. Clinicaltrials.gov REGISTRATION NUMBER: NCT02010008. PMID- 24952284 TI - The politics of health take centre stage in Geneva. PMID- 24952283 TI - Bacterial sensing of bacteriophages in communities: the search for the Rosetta stone. AB - Billions of years of evolution have resulted in microbial viruses and their hosts communicating in such a way that neither of these antagonists can dominate the other definitively. Studies of the molecular mechanisms underlying this dialog, initially in bacteriophages, rapidly identified several of the ways in which bacteria resist bacteriophage infections and bacteriophages defeat bacterial defenses. From an ecological perspective, recent data have raised many questions about the dynamic interactions between bacteria and bacteriophages, the densities of which, in complex microbial populations, are only beginning to be investigated. The next challenge will be determining how the dialog between microbial viruses and their hosts modulates complex ecosystems, such as those found in healthy humans or infected patients. PMID- 24952282 TI - Adaptation and dissemination of an evidence-based obesity prevention intervention: design of a comparative effectiveness trial. AB - Low-income youth are at increased risk for excess weight gain. Although evidence based prevention programs exist, successful adaptation to provide wide dissemination presents a challenge. Hip-Hop to Health (HH) is a school-based obesity prevention intervention that targets primarily preschool children of low income families. In a large randomized controlled trial, HH was found to be efficacious for prevention of excessive weight gain. The Expanded Food and Nutrition Education Program (EFNEP) and the Supplemental Nutrition Assistance Program-Education (SNAP-Ed) are USDA-funded nutrition education programs offered to low-income families, and may provide an ideal platform for the wide dissemination of evidence-based obesity prevention programs. A research-practice partnership was established in order to conduct formative research to guide the adaptation and implementation of HH through EFNEP and SNAP-Ed. We present the design and method of a comparative effectiveness trial that will determine the efficacy of HH when delivered by peer educators through these programs compared to the standard EFNEP and SNAP-Ed nutrition education (NE) curriculum. Results from this trial will inform larger scale dissemination. The dissemination of HH through government programs has the potential to increase the reach of efficacious obesity prevention programs that target low-income children and families. PMID- 24952285 TI - Risk of polio reintroduction to border regions of Islamic Republic of Iran: seroprevalence study of children with at least 5 doses of oral polio vaccine. AB - Movements of populations from countries where polio has not been eradicated is a concern in the Islamic Republic of Iran. A cross-sectional, community-based study was implemented in 2010 in 2 districts in Sistan-va-Baluchestan Province near the south-east border. The aim was to determine the seroprevalence of antibodies in children aged 20 (+/- 2) months who had received at least 5 doses of trivalent oral polio vaccine. Using cluster sampling, 365 children were enrolled for serological testing. Antibody titres >= 1:10 were considered positive. Seropositive rates for antibody against poliovirus serotypes 1, 2 and 3 were 94.1%, 96.7% and 78.3% respectively. The lowest seropositive rate was for antibody against polio serotype 3 (PV3) among boys (58.3%). Exclusive breastfeeding showed a direct relationship with antibody response to PV3 (OR = 2.0; 95% CI: 1.1-3.6). Improving community protection against PV3 is an urgent programme priority. PMID- 24952286 TI - Surveillance of lymphatic filariasis 5 years after stopping mass drug administration in Menoufiya Governorate, Egypt. AB - The World Health Organization recommends that before lymphatic filariasis elimination in an area can be confirmed, an additional survey should be performed at least 5 years after stopping mass drug administration. The current study aimed to determine the status of lymphatic filariasis 5 years after cessation ofthe mass drug administration in 3 sentinel Egyptian villages in Menoufiya Governorate. The rapid immunochromatographic card test (ICT) and a new commercial antibody detection kit (CELISA(r)) were used. All 1321 primary-school children aged 6-7 years old were ICT negative but 27 children were antibody positive. All households surveyed in one village with the highest antibody prevalence were ICT negative, indicating an absence of lymphatic filariasis. The CELISA antibody kit needs more standardization and development to be useful under field conditions. We conclude that lymphatic filariasis is no longer a public health problem in these villages and other villages with similar epidemiological conditions. PMID- 24952287 TI - Prospects for the sustainability of delivering the Basic Package of Health Services in Afghanistan: a stakeholder analysis. AB - This study explored the readiness of stakeholders in Afghanistan for sustaining delivery of the Basic Package of Health Services (BPHS) without external technical and financial assistance. A stakeholder analysis was applied using qualitative methods. Fifteen stakeholders were purposively drawn from the Afghanistan ministries of public health and finance, political representatives, development partners, nonprofit organizations and public health experts. Data were collected through in-depth interviews with the stakeholders and desk review of pertinent documents. We found that sustainability of the BPHS in Afghanistan is questionable as stakeholders are suboptimally organized to come up with effective alternatives. Uneven ownership and divisive positioning are bottlenecks to the evolution of a realistic continuation plan. Those with the most significant influence are lukewarm, while those who are most supportive have the least influence. Sustainability needs to be tackled at the start in designing the BPHS rather than in the wake of eventual donor withdrawal. PMID- 24952288 TI - Air quality and seasonal variations in consultations for respiratory, allergic, dermatological and gastrointestinal diseases in Bahrain, 2007. AB - Environmental health data in Bahrain are scarce. This study in 4 governorates of Bahrain aimed to establish baseline data on the seasonal prevalence of certain disease groups that are sensitive to climate (respiratory, allergic, dermatological and non-specific gastrointestinal diseases) over a 1-year period and to record local climate and air pollutant data for the same year. A 5% sample of medical records for those who attended primary health-care centres during 2007 was taken. Visit rates for all 4 diseases had peaks, in spring and in autumn, with the lowest rates in the summer season when the average temperatures were highest and average humidity was lower. Respiratory-related visits were highest when the air concentrations of SO2 were highest. An ongoing surveillance system for climate-sensitive diseases should be initiated to monitor and relate health and environmental trends. PMID- 24952289 TI - Use of short message service reminders to improve attendance at an internal medicine outpatient clinic in Saudi Arabia: a randomized controlled trial. AB - Non-attendance at outpatient appointments is a major problem. This study aimed to evaluate the efficacy of sending short message service (SMS) reminders to patients' mobile phones in reducing non-attendance at scheduled appointments. A randomized clinical trial was conducted in 2011 in an internal medicine outpatient clinic at a hospital in Eastern Province, Saudi Arabia. Eligible patients (n = 502) were randomly allocated to receive an SMS reminder of their appointment (intervention group) or no reminder (control group). The non attendance rate was significantly lower in the reminder group (26.3%) than the non-reminder group (39.8%). In multivariate logistic regression, age, sex and nationality did not affect attendance rates but having their first contact with the hospital (OR = 7.40) and not receiving an SMS reminder (OR = 0.56) were significant factors in non-attendance. All patients surveyed about their perceptions of the SMS reminder (n = 76) reported they would like to continue to receive SMS reminders in the future. PMID- 24952290 TI - Utilization of a telephone interactive voice-response tobacco cessation support service in the Islamic Republic of Iran. AB - Telephone smoking cessation counselling is a very cost-effective means of reaching dependent smokers in a population. We investigated the frequency of contacts and the types of topics that people accessed after a national telephone helpline was set up in the Islamic Republic of Iran at the beginning of 2011. From a total of 23 979 calls received over a 24-month period, 26.5% of callers hung up without selecting any menus. The most frequently accessed menu was addresses of smoking cessation support services (23.9%), followed by methods of smoking cessation (14.0%), self-help materials for quitting smoking (11.8%) and nicotine dependence assessment (10.4%). The average number of contacts decreased dramatically after the first month of the service but there was a significant increase in the 2 months preceding the feast of Ramadan. Religious messages provide a good opportunity to engage individuals in smoking cessation and may be useful in the planning of media campaigns. PMID- 24952291 TI - Predictors of transition in smoking stages in Iranian adolescents: latent transition analysis. AB - This study determined the prevalence of smoking stages in adolescents, the probability of transition across stages and the personal and environmental predictors of transition. A school-based study was conducted in 2010-11 using a random sample of 5197 students (mean age 15.7 years) in Tabriz city. The students were evaluated twice, 12-months apart. The latent transition analysis model revealed 9 interpretable statuses for the measurement of smoking stages. Prevalence data showed that at the first and second assessments 75.1% and 66.8% of students respectively were in the committer stage, while 4.8% and 7.1% respectively were daily smokers. Over 12 months, 10.1% of the never smokers became experimenters and 1.7% became regular smokers, while 17.0% of experimenters became regular smokers. The analysis also showed factors associated with transitions in cigarette smoking stages. Although the prevalence of smoking was low in our adolescents, the rate of becoming a smoker over 1 year was high. PMID- 24952292 TI - [Assessment of the methodological quality of theses submitted to the Faculty of Medicine Fez]. AB - A thesis in medicine is a scientific work which allows a medical student to acquire a Doctor of Medicine degree. It is therefore recommended that theses presented by students fulfill essential methodological criteria in order to obtain scientifically credible results and recommendations. The aim of this study was to assess the methodology of thesis presented to the Faculty of Medicine in Fez in 2008. We developed an evaluation table containing questions on the different sections of the IMRAD structure on which these theses were based and we estimated the proportion of theses that conformed to each criterion. There were 160 theses on various specialties presented in 2008. The majority of the theses (79.3%) were case series. Research questions were clearly expressed in 62.0% but the primary objectives were pertinent in only 52.0%. Our study shows that there were important deficiencies in the methodological rigor of the theses and very little representation of the theses in publications. PMID- 24952293 TI - Knowledge, attitudes and practices of health-care personnel towards waste disposal management at Ain Shams University Hospitals, Cairo. AB - This study assessed knowledge, attitudes and practices of health-care providers towards waste management at Ain Shams University Hospitals, Cairo, Egypt. In this cross-sectional study 110 physicians, 151 nurses and 89 housekeepers were interviewed using a pre-designed questionnaire. Housekeepers were significantly more knowledgeable than physicians or nurses about hospital policies and systems for waste disposal, but less so about specific details of disposal. Housekeepers also had the highest overall scores for attitudes to waste disposal among the 3 groups. Significantly more nurses had satisfactory practice scores (84.0%) than did physicians (67.3%) (housekeepers were not assessed). Training and duration of work experience were not significantly associated with knowledge, attitude and practice scores, except for nurses with longer work experience, who were more likely to have satisfactory knowledge about waste disposal than less experienced nurses. PMID- 24952294 TI - Improving the health of people with disabilities: what must we do? PMID- 24952296 TI - The CROWN Initiative: journal editors invite researchers to develop core outcomes in women's health. PMID- 24952295 TI - Histamine H3 receptor antagonism by ABT-239 attenuates kainic acid induced excitotoxicity in mice. AB - The multifaceted pathogenesis of temporal lobe epilepsy (TLE) offers a number of adjunctive therapeutic prospects. One such therapeutic strategy could be targeting H3 receptor (H3R) by selective H3R antagonists which are perceived to have antiepileptic and neuroprotective potential. Kainic acid (KA) induced seizure, a reliable model of TLE, triggers epileptogenic events resulting from initial neuronal death and ensuing recurring seizures. The present study aimed to determine whether pre-treatment with ABT-239, a novel H3R antagonist, and its combinations with sodium valproate (SVP) and TDZD-8 (glycogen synthase kinase 3beta (GSK3beta) inhibitor) can prevent the excitotoxic events in mice exposed to KA (10 mg/kg i.p.). ABT-239 (1 and 3 mg/kg i.p.) significantly attenuated KA mediated behavioural and excitotoxic anomalies and restored altered expression of Bax, cleaved caspase-3, phospho-Akt (Ser473) and cAMP response element binding protein (CREB). Surprisingly, restoration of Bcl2 and phospho-GSK3beta (Ser9) by ABT-239 did not reach the level of statistical significance. Co-administration of ABT-239 (1 and 3 mg/kg) with a sub-effective dose of SVP (150 mg/kg i.p.) yielded improved efficacy than when given alone. Similarly, low and high dose combinations of ABT-239 (1 and 3 mg/kg) with TDZD-8 (5 and 10 mg/kg i.p.) produced greater neuroprotection than any other treatment group. Our findings suggests a neuroprotective potential of ABT-239 and its combinations with SVP and TDZD-8 against KA-induced neurotoxicity, possibly mediated through in part each by modulating Akt/GSK3beta and CREB pathways. The use of H3R antagonists as adjuvant in the treatment of human TLE might find potential utility, and can be pursued further. PMID- 24952297 TI - Severity of demographic and clinical characteristics, revascularization feasibility, major amputation, and mortality rate in diabetic patients admitted to a tertiary diabetic foot center for critical limb ischemia: comparison of 2 cohorts recruited at a 10-year distance. AB - BACKGROUND: To compare demographic and clinical characteristics, revascularization, major amputation, and mortality among patients admitted to a diabetic foot center because of critical limb ischemia (CLI) during 1999-2003 (cohort 1) and 2009 (cohort 2). METHODS: During 1999-2003, 564 diabetic patients with CLI (cohort 1) were admitted to our center, and 344 patients (360 affected limbs) were admitted during 2009 (cohort 2). Data on demographic and clinical characteristics, revascularization by peripheral angioplasty (PTA) or bypass graft (BPG), major amputation, and mortality were recorded. RESULTS: Patients belonging to cohort 2 were older than patients of cohort 1 (P = 0.001). In cohort 2, there were more subjects requiring insulin (P = 0.008) and duration of diabetes was longer (P = 0.001); moreover, there were more patients requiring dialysis (P = 0.001), patients with history of stroke (P = 0.004), or foot ulcer (P = 0.001). No significant difference between the 2 groups was found concerning gender, metabolic control, hypertension, lipid values, neuropathy, and retinopathy. Occlusion was more frequent than stenosis in the posterior tibial (P < 0.001) and peroneal (P = 0.016) arteries. However, the revascularization rate did not differ (P = 0.318) between the 2 groups. Restenosis after PTA was not significantly different (P = 0.627), whereas BPG failure was significantly more frequent (P = 0.010) in cohort 2 (2009). Major amputation (P = 0.222) and mortality rate (P = 0.727) did not differ between the 2 groups. CONCLUSIONS: The severity of either foot lesions or patients comorbidities should be concomitantly assessed and taken into proper consideration when evaluating changes in the amputation rate among different studies or in different temporal settings. PMID- 24952298 TI - The end stage of dialysis access: femoral graft or HeRO vascular access device. AB - BACKGROUND: Maintaining and establishing vascular access in end-stage renal disease (ESRD) patients is complicated when they are poor candidates for traditional upper extremity access. Our objective was to compare our experience with 2 alternative dialysis accesses, the femoral arteriovenous graft (fAVG) and the Hemodialysis Reliable Outflow (HeRO), in patients with limited remaining options. METHODS: A single institution, retrospective review of ESRD patients with fAVG or HeRO placed between May 2009 and February 2013 was performed. Adult patients were selected by reviewing all arteriovenous grafts placed at a single institution. Patient demographics, medical history, access characteristics, and outcomes were recorded from both institutional and dialysis center databases. Data were evaluated using Fisher's exact test, unpaired t-test for continuous variables, log-rank test, and univariate analysis. RESULTS: A total of 56 accesses in 43 unique patients met these criteria: 35 fAVG and 21 HeRO; with 1 HeRO patient lost immediately to follow-up. Clinical variables were similar except the HeRO group had more diabetic patients (60% HeRO, 22.9% fAVG; P = 0.01). The average number of years on hemodialysis was 7.0 +/- 1.0 for fAVG and 5.7 +/- 0.9 for HeRO (P = 0.41). Primary patency was 40.5%, 18.7%, and 14.9% for fAVG and 29.0%, 29.0%, and 0% for HeRO at 6 months, 12 months, and 2 years (P = 0.67), respectively. Assisted primary patency was also similar, with 43.8%, 29.4%, and 13.8% for fAVG and 34.8%, 34.8%, and 17.4% for HeRO at 6 months, 12 months, and 2 years (P = 0.81), respectively. Secondary patency was 62.6%, 50.6%, 19.3% for fAVG and 68.0%, 53.5%, 38.3% for HeRO at 6 months, 12 months, and 2 years (P = 0.69), respectively. Average number of interventions to maintain patency for fAVG was 1.1 +/- 1.47 and 1.65 +/- 2.52 for HeRO (P = 0.35). Infectious complications occurred in 29% of fAVG and 15% of HeRO (P = 0.33). CONCLUSIONS: Patients who received either fAVG or HeRO experience poor access patency. ESRD patients who receive either of these procedures appear to be at the end stage of available access options. PMID- 24952299 TI - Association between co-stimulatory molecule gene polymorphism and acute rejection of allograft. AB - Co-stimulatory molecules play important roles in T cell-mediated immune response and transplantation. Numerous epidemiological studies have evaluated the association between CD28, CTLA-4 gene variant and allograft rejection. However, the results of these studies on the association remain conflicting. The main purpose of this study was to integrate previous results and explore whether the CD28 IVS3 +17T/C variant, CTLA-4, CD86 and PDCD1 gene polymorphisms were associated with allograft rejection susceptibility. PubMed and Embase (before 2014-3-25), were searched for studies on the relationship of CD28, CTLA-4, CD86 and PDCD1 gene polymorphisms and the incidence of allograft rejection susceptibility. Eligible articles were included for data extraction. The main outcome was the frequency of co-stimulate molecule gene polymorphisms between rejection and non-rejection populations. Comparison of the distribution of SNP was mainly performed using Review Manager 5.0. The odds ratio (OR) and its 95% confidence interval (95% CI) were used to assess the strength of association. Significant associations of the CD28 IVS3 +17T/C variant with acute allograft rejection susceptibility were found (CC +CT/TT OR, 1.45; 95% CI, 1.08-1.94; P=0.01). Also we found an association of the CD28 IVS3 +17T/C variant with kidney allograft rejection cases (CC +CT/TT OR, 1.72; 95% CI, 1.19-2.49; P=0.004) and (C allele OR, 1.74; 95% CI, 1.11-2.75; P=0.02), but not established for liver allograft rejection cases (CC +CT/TT OR, 1.19; 95% CI, 0.47-2.98; P=0.72) and (C allele OR, 0.96; 95% CI, 0.67-1.39; P=0.84). And we found an association of the CD86 +1057G/A variant with non-allograft rejection cases (AA +AG/GG OR, 0.35; 95% CI, 0.14-0.85; P=0.02). This meta-analysis demonstrates that the CD28 IVS3 +17T/C variant might increase acute allograft rejection risk in kidney transplant but not in liver transplant, and there was an association between CD86 +1057G/A variant and reduced acute rejection risk. Further studies will be needed to confirm our findings. PMID- 24952300 TI - The feasibility and educational value of Hear My Voice, a chaplain-led spiritual life review process for patients with brain cancers and progressive neurologic conditions. AB - Research continues to establish the importance of spirituality for many persons with medical illnesses. This paper describes a pilot study titled, "Hear My Voice," designed to provide an opportunity for persons with progressive neurologic illnesses, including brain tumors and other neurodegenerative diseases, to review and discuss their spirituality with a board-certified chaplain, and to prepare a spiritual legacy document (SLD). First, we provide background information that underscores the importance of such a project for this patient population that is particularly vulnerable to cognitive impairment and communication difficulties. Second, we provide detailed methodology, including the semi-structured interview format used, the development of the SLD, and an overview of responses from participants and investigators. We also describe the quantitative and qualitative approaches to analysis taken with the aim of developing scientific validation in support of the Hear My Voice project. PMID- 24952301 TI - Transformer 2beta (Tra2beta/SFRS10) positively regulates the progression of NSCLC via promoting cell proliferation. AB - Transformer 2beta (Tra2beta), a member of the serine/arginine-rich-like protein family, is an important RNA-binding protein involved in alternative splice. Deregulation of Tra2beta has been observed in several cancers. However, the detailed role of Tra2beta in non-small cell lung cancer (NSCLC) has not been elucidated. In this study, the contribution of Tra2beta to NSCLC development was investigated. On histological level, the expression of Tra2beta was determined by Western and immunohistochemistry assays. It demonstrated that Tra2beta was expressed higher in NSCLC tumor tissues compared with adjacent non-tumor tissues. In addition to confirm the association of Tra2beta expression with histological differentiation and clinical stage (p < 0.05), we also confirmed significant positive correlation between the expression level of Tra2beta and that of Ki67 (p < 0.05, r = 0.446) by Spearman rank correlation test. Moreover, high expression of Tra2beta predicted poor prognosis by Kaplan-Meier survival analysis. And Tra2beta among with other clinicopathologic variables was an independent prognostic indicator for patients' overall survival by multivariate analysis. On cellular level, Tra2beta expression was demonstrated to promote proliferation of NSCLC cells through a series of assays, including serum starvation and release assay, Western blot assay and flow cytometry analysis. Moreover, knockdown of Tra2beta was confirmed to inhibit proliferation and to induce apoptosis of NSCLC cells through flow cytometry analysis, western analysis, cell counting kit-8 assay and Tunnel assay. Our results indicated that Tra2beta was involved in the tumorigenesis of NSCLC and might be a potential therapeutic target of NSCLC. PMID- 24952303 TI - When more is less: doubt, repetition, memory, metamemory, and compulsive checking in OCD. AB - Memory and metamemory phenomena associated with obsessive-compulsive disorder (OCD) have received much attention in literature dedicated to a better understanding of the doubt and repetition associated with obsessions and compulsions. Following previous work on repeated checking among nonclinical participants, we asked participants to repeatedly turn on, turn off and check a real kitchen stove (n = 30 compulsive checkers diagnosed with OCD and n = 30 non clinical undergraduates), or a real kitchen faucet (n = 30 non-clinical undergraduates) in a standardized, ritualized manner, in two connected experiments. Results indicated that following repeated relevant checking, both clinical and nonclinical participants reported significantly reduced memory confidence, vividness and detail; those who completed repeated irrelevant checking did not. The effects of repeated checking on memory accuracy were also explored. Results are discussed in terms of cognitive-behavioural formulations of OCD and in terms of the effects of repetition on memory and metamemory in association with checking behaviour. PMID- 24952302 TI - Three-dimensional reconstruction of light microscopy image sections: present and future. AB - Three-dimensional (3D) image reconstruction technologies can reveal previously hidden microstructures in human tissue. However, the lack of ideal, non destructive cross-sectional imaging techniques is still a problem. Despite some drawbacks, histological sectioning remains one of the most powerful methods for accurate high-resolution representation of tissue structures. Computer technologies can produce 3D representations of interesting human tissue and organs that have been serial-sectioned, dyed or stained, imaged, and segmented for 3D visualization. 3D reconstruction also has great potential in the fields of tissue engineering and 3D printing. This article outlines the most common methods for 3D tissue section reconstruction. We describe the most important academic concepts in this field, and provide critical explanations and comparisons. We also note key steps in the reconstruction procedures, and highlight recent progress in the development of new reconstruction methods. PMID- 24952304 TI - Identification of specific antigenic epitope at N-terminal segment of enterovirus 71 (EV-71) VP1 protein and characterization of its use in recombinant form for early diagnosis of EV-71 infection. AB - Human enterovirus 71 (EV-71) is the main etiologic agent of hand, foot and mouth disease (HFMD). We sought to identify EV-71 specific antigens and develop serologic assays for acute-phase EV-71 infection. A series of truncated proteins within the N-terminal 100 amino acids (aa) of EV-71 VP1 was expressed in Escherichia coli. Western blot (WB) analysis showed that positions around 11-21 aa contain EV-71-specific antigenic sites, whereas positions 1-5 and 51-100 contain epitopes shared with human coxsackievirus A16 (CV-A16) and human echovirus 6 (E-6). The N-terminal truncated protein of VP1, VP16-43, exhibited good stability and was recognized by anti-EV-71 specific rabbit sera. Alignment analysis showed that VP16-43 is highly conserved among EV-71 strains from different genotypes but was heterologous among other enteroviruses. When the GST VP16-43 fusion protein was incorporated as antibody-capture agent in a WB assay and an ELISA for detecting anti-EV-71 IgM in human sera, sensitivities of 91.7% and 77.8% were achieved, respectively, with 100% specificity for both. The characterized EV-71 VP1 protein truncated to positions 6-43 aa has potential as an antigen for detection of anti-EV-71 IgM for early diagnosis of EV-71 infection in a WB format. PMID- 24952305 TI - Design and synthesis of a new series of modified CH-diarylpyrimidines as drug resistant HIV non-nucleoside reverse transcriptase inhibitors. AB - This article reports the design, synthesis and antiviral evaluation of a new series of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The basic skeleton of these target 18 molecules is diarylpyrimidine featuring a substituted amino group between the pyrimidine scaffold and the aryl wing. All of the new compounds have been characterized by spectra analysis. The entire target molecules were evaluated for their in vitro anti-HIV activity with controlling group of FDA approved drugs. Most of them showed good to potent activities against wild-type (WT) HIV-1 with IC50 values in the range of 0.0175-69.21 MUM. 2 (4-Cyanophenylamino)-4-(2-cyanovinylphenylhydrazonomethyl)pyrimidine (1d) displayed potent anti-HIV-1 activity against WT HIV-1 with a selectivity index (SI) of 106367 and an IC50 value of 1.75 nM, which was 47 fold lower than that of AZT. Compound 1d also showed a broad-spectrum inhibitory activity, with an IC50 value of 5.33 MUM and 5.05 MUM against both HIV-1 double-mutated (K103N/Y181C) strain and HIV-2 strain, respectively. The preliminary structure-activity relationship (SAR) was also investigated. The binding modes with HIV-1 RT for both the wild type and mutant type have also been discussed. PMID- 24952306 TI - The association between single-nucleotide polymorphisms of TRPM7 gene and breast cancer in Han Population of Northeast China. AB - Breast cancer is one of the most common cancer and remains the leading cause of cancer-related deaths in women. There is increasing evidence suggesting that TRPM7 plays a pivotal role in breast cancer progression and metastasis. In this study, a case-control study was carried out to investigate the effects of SNPs in TRPM7 genes in the development of breast cancer in Han Population of Northeast China. A total of six SNPs (rs8042919, rs4775899, rs11635825, rs7173321, rs616256, and rs11070795) were chosen and genotyped. Genotypes were analyzed using a single-base primer extension assay. Chi-square (chi (2)) test was used to analyze statistical difference between control and patient groups in genotype and allele frequencies. The genotype-specific risks and allele frequencies of haplotypes in breast cancer patients and controls were estimated by OR and 95 % confidence intervals. The G allele of rs8042919 was associated with a reduced disease risk. The G allele of rs7173321 and particularly its homozygous GG genotype are associated with an increased breast cancer risk. Two of the TRPM7 SNPs (rs8042919 and rs7173321) are associated with breast cancer patients in Han Population of Northeast China. PMID- 24952307 TI - Immunological response induced by abagovomab as a maintenance therapy in patients with epithelial ovarian cancer: relationship with survival-a substudy of the MIMOSA trial. AB - PURPOSE: To determine whether abagovomab induces protective immune responses in ovarian cancer patients in first clinical remission. The present analysis is a substudy of monoclonal antibody immunotherapy for malignancies of the ovary by subcutaneous abagovomab trial (NCT00418574). METHODS: The study included 129 patients, 91 in the abagovomab arm and 38 in the placebo arm. Circulating CA125 specific cytotoxic T lymphocytes (CTL) were measured by a flow cytometry-based interferon-gamma producing assay. Human antimouse antibody and anti-anti idiotypic (Ab3) were assessed by ELISA. Patients were evaluated before starting the treatment and at different time points during induction and maintenance phases. RESULTS: A similar percentage of patients in both the placebo and abagovomab arms had CA125-specific CTL (26.3 and 31.8 %, respectively; p = 0.673 by Fisher's exact test). Patients with CA125-specific CTL in both arms tended to have an increased relapse-free survival (RFS, log-rank test p = 0.095) compared to patients without. Patients (n = 27) in the abagovomab arm without CA125 specific CTL but that developed Ab3 above the cutoff (defined as median Ab3 level at week 22) had a prolonged RFS compared to patients (n = 24) that did not develop Ab3 above the cutoff (log-rank test p = 0.019). CONCLUSION: Abagovomab does not induce CA125-specific CTL. However, patients with CA125-specific CTL perform better than patients without, irrespective of abagovomab treatment. Abagovomab-induced Ab3 associate with prolonged RFS in patients without CA125 specific CTL. Further studies are needed to confirm these data and to assess the potential utility of these immunological findings as a tool for patient selection in clinical trial. PMID- 24952308 TI - A systematic review into the effectiveness of hand exercise therapy in the treatment of rheumatoid arthritis. AB - Hand exercises are often part of the treatment of hand rheumatoid arthritis; however, it is still unclear whether and what type of exercises is effective in the treatment of this condition. Therefore, a systematic review into the effectiveness of hand exercises in the treatment of hand rheumatoid arthritis has been performed. Studies were identified in the literature databases by predefined search criteria. The eight included studies are peer-reviewed studies published between 2000 and 2014. Hand exercises differed between studies, but always included resistance and/or active range of motion exercises. Grip strength in various grip types (power grip, key pinch, precision pinch and tripod pinch) was found to improve by hand exercise therapy without having adverse effects on pain or disease activity. Adaptations in the range of motion in response to hand exercise therapy were less pronounced. There appears to be some transfer from the improvements on the body functioning level to the level of daily functioning, with the largest improvements found on grip ability. With regard to the intervention content, there was some evidence in favour of a longer therapy duration and a higher therapy intensity. No conclusions could be drawn on the effectiveness of the different types of exercises. Collectively, the studies indicate that hand exercises may have positive effects on strength and some aspects of daily functioning without aggravating disease activity or pain, although caution should be taken for subjects in the exacerbation period. PMID- 24952309 TI - Relationships of common polymorphisms in IL-6, IL-1A, and IL-1B genes with susceptibility to osteoarthritis: a meta-analysis. AB - Observational and experimental studies have arrived at inconsistent conclusions about whether common polymorphisms in IL-6, IL-1A, and IL-1B genes are associated with an increased risk of osteoarthritis (OA). Therefore, we undertook a comprehensive meta-analysis to more systematically summarize the relationships of IL-6, IL-1A, and IL-1B genetic polymorphisms with susceptibility to OA. We screened the PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine (CBM), and China National Knowledge Infrastructure (CNKI) databases up to 31 March 2014. We used STATA software to analyze statistical data. Odds ratios (ORs) and their corresponding 95 % confidence intervals (95 % CIs) were calculated. Seventeen independent case control studies were included in this meta-analysis with a total number of 7,491 subjects, comprised of 3,293 OA patients and 4,729 healthy controls. Our results indicate that IL-6, IL-1A, and IL-1B genetic polymorphisms are statistically correlated with an increased risk of OA under the allele and dominant models. According to a subgroup analysis based on disease, a higher frequency of IL-6 genetic polymorphisms was observed among knee OA and hand OA patients, but not among hip OA and DIP OA patients. A higher frequency of IL-1A genetic polymorphisms were found among hip OA patients, hand OA, hip OA and DIP OA patients. Furthermore, we observed a higher IL-1B polymorphism frequency among knee OA and hip OA patients, but not among hand OA patients. Our findings provide evidence that IL-6, IL-1A, and IL-1B genetic polymorphisms may be correlated with susceptibility to OA. PMID- 24952310 TI - Cytotoxicity induced by ochratoxin A, zearalenone, and alpha-zearalenol: effects of individual and combined treatment. AB - This study investigated the cytotoxicity of combined mycotoxins of ochratoxin A (OTA), zearalenone (ZEA), and/or alpha-zearalenol (alpha-ZOL). The cytotoxicity of two mycotoxin combinations (two two-toxin combinations and one three-toxin combination) on human Hep G2 cells was evaluated using a tetrazolium salt (MTT) assay and isobologram analysis. Our results demonstrated significant cytotoxic effects of the two-toxin combination and the three-toxin combination on Hep G2 cells in a time- and concentration-dependent manner. The combination indexes (CI) were 2.73-7.67 for the OTA+ZEA combination and 1.23-17.82 for the OTA+alpha-ZOL combination after 24 h, 48 h, and 72 h of exposure at all inhibit concentration (IC) levels (IC10-IC90), indicating an antagonism. The CIs of the ZEA+alpha-ZOL combination were 1.29-2.55 after 24 h and 72 h of exposure (IC10-IC90), indicating an antagonism. The CIs of the ZEA+alpha-ZOL combination were 0.74-1.68 after 48 h of exposure, indicating synergism (IC80-IC90), additive effects (IC50 IC70), or antagonism (IC10-IC40). For the OTA+ZEA+alpha-ZOL combination, the CIs were 1.41-14.65 after 24 h, 48 h, and 72 h of exposure (IC10-IC90), indicating an antagonism. PMID- 24952312 TI - Statistical characteristics of trajectories of diamagnetic unicellular organisms in a magnetic field. AB - The statistical model is proposed in this paper for description of orientation of trajectories of unicellular diamagnetic organisms in a magnetic field. The statistical parameter such as the effective energy is calculated on basis of this model. The resulting effective energy is the statistical characteristics of trajectories of diamagnetic microorganisms in a magnetic field connected with their metabolism. The statistical model is applicable for the case when the energy of the thermal motion of bacteria is negligible in comparison with their energy in a magnetic field and the bacteria manifest the significant "active random movement", i.e. there is the randomizing motion of the bacteria of non thermal nature, for example, movement of bacteria by means of flagellum. The energy of the randomizing active self-motion of bacteria is characterized by the new statistical parameter for biological objects. The parameter replaces the energy of the randomizing thermal motion in calculation of the statistical distribution. PMID- 24952311 TI - Nitric oxide induces apoptosis and autophagy; autophagy down-regulates NO synthesis in physalin A-treated A375-S2 human melanoma cells. AB - Physalin A is an active withanolide isolated from Physalis alkekengi var. franchetii, a traditional Chinese herbal medicine named Jindenglong, which has been used for the treatment of sore throat, hepatitis, eczema and tumors in China. Our previous study demonstrated that physalin A induced apoptosis and cyto protective autophagy in A375-S2 human melanoma cells. Induction of reactive oxygen species (ROS) with physalin A triggered apoptosis. In this study, NO generated by physalin A induced apoptosis and autophagy in A375-S2 cells, since physalin A induced the expression of inducible nitric oxide synthase (iNOS) in the cells. Generation of NO partially promoted both apoptosis and autophagy in A375-S2 cells. NO suppressed mTOR expression, which led to autophagy induction. An autophagic inhibitor, 3-methyladenine (3MA) promoted NO production, while acceleration of autophagy with an autophagic agonist rapamycin repressed NO production, suggesting that autophagy and NO production form a negative feedback loop that eventually protects the cells from apoptosis. The results together with the previous study indicate apoptosis and autophagy induced by physalin A in A375 S2 cells; the autophagy, repressing production of reactive nitrogen species (RNS) and ROS, protects the cells from apoptosis. PMID- 24952313 TI - Design and designability of protein-based assemblies. AB - Design of protein-based assemblies is an exciting frontier in molecular engineering. It can be seen as an extension of the protein design problem, but with some added hurdles. In recent years, much of the focus in the field has been on patterning existing protein structural units (proteins, oligomers, or structural motifs) to design diverse assembly geometries, focusing on symmetry to encode both "infinite" lattices and finite-sized supramolecular particles. Despite impressive successes, several key challenges remain. Among these are the specificity problem the need to engineer preference for the intended assembly geometry over all alternatives, and the folding problem--understanding what thermodynamic or kinetic features of assembly subunits and inter-subunit interfaces lead to successfully folding superstructures and how to encode these in the amino-acid sequence. Here we focus on recent results in the context of these two problems, summarizing commonalities in successful approaches. We find that natural designability of assembly elements (i.e., their compatibility with diverse populations of natural amino-acid sequences) may be a unifying property of successful designs. PMID- 24952314 TI - Urine homogentisic acid and tyrosine: simultaneous analysis by liquid chromatography tandem mass spectrometry. AB - Alkaptonuria (AKU) is a rare debilitating autosomal recessive disorder of tyrosine metabolism. Deficiency of homogentisate 1,2-dioxygenase results in increased homogentisic acid (HGA) which although excreted in gram quantities in the urine, is deposited as an ochronotic pigment in connective tissues, especially cartilage. Ochronosis leads to a severe, early-onset form of osteoarthritis, increased renal and prostatic stone formation and hardening of heart vessels. Treatment with the orphan drug, Nitisinone, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase has been shown to reduce urinary excretion of HGA, resulting in accumulation of the upstream pre-cursor, tyrosine. Using reverse phase LC-MS/MS, a method has been developed to simultaneously quantify urinary HGA and tyrosine. Using matrix-matched calibration standards, two product ion transitions were identified for each compound and their appropriate isotopically labelled internal standards. Validation was performed across the AKU and post-treatment concentrations expected. Intrabatch accuracy for acidified urine was 96-109% for tyrosine and 94-107% for HGA; interbatch accuracy (n=20 across ten assays) was 95-110% for tyrosine and 91-109% for HGA. Precision, both intra- and interbatch was <10% for tyrosine and <5% for HGA. Matrix effects observed with acidified urine (12% decrease, CV 5.6%) were normalised by the internal standard. Tyrosine and HGA were proved stable under various storage conditions and no carryover, was observed. Overall the method developed and validated shows good precision, accuracy and linearity appropriate for the monitoring of patients with AKU, pre and post-nitisinone therapy. PMID- 24952315 TI - Value of a statistical life in road safety: a benefit-transfer function with risk analysis guidance based on developing country data. AB - We model a value of statistical life (VSL) transfer function for application to road-safety engineering in developing countries through an income-disaggregated meta-analysis of scope-sensitive stated preference VSL data. The income disaggregated meta-analysis treats developing country and high-income country data separately. Previous transfer functions are based on aggregated datasets that are composed largely of data from high-income countries. Recent evidence, particularly with respect to the income elasticity of VSL, suggests that the aggregate approach is deficient because it does not account for a possible change in income elasticity across income levels. Our dataset (a minor update of the OECD database published in 2012) includes 123 scope-sensitive VSL estimates from developing countries and 185 scope-sensitive estimates from high-income countries. The transfer function for developing countries gives VSL=1.3732E 4*(GDP per capita)(?)2.478, with VSL and GDP per capita expressed in 2005 international dollars (an international dollar being a notional currency with the same purchasing power as the U.S. dollar). The function can be applied for low- and middle-income countries with GDPs per capita above $1268 (with a data gap for very low-income countries), whereas it is not useful above a GDP per capita of about $20,000. The corresponding function built using high-income country data is VSL=8.2474E+3*(GDP per capita)(?).6932; it is valid for high-income countries but over-estimates VSL for low- and middle-income countries. The research finds two principal significant differences between the transfer functions modeled using developing-country and high-income-country data, supporting the disaggregated approach. The first of these differences relates to between-country VSL income elasticity, which is 2.478 for the developing country function and .693 for the high-income function; the difference is significant at p<0.001. This difference was recently postulated but not analyzed by other researchers. The second difference is that the traffic-risk context affects VSL negatively in developing countries and positively in high-income countries. The research quantifies uncertainty in the transfer function using parameters of the non-absolute distribution of relative transfer errors. The low- and middle-income function is unbiased, with a median relative transfer error of -.05 (95% CI: -.15 to .03), a 25th percentile error of -.22 (95% CI: -.29 to -.19), and a 75th percentile error of .20 (95% CI: .14 to .30). The quantified uncertainty characteristics support evidence-based approaches to sensitivity analysis and probabilistic risk analysis of economic performance measures for road-safety investments. PMID- 24952317 TI - Hide and vanish: data sets where the most parsimonious tree is known but hard to find, and their implications for tree search methods. AB - Three different types of data sets, for which the uniquely most parsimonious tree can be known exactly but is hard to find with heuristic tree search methods, are studied. Tree searches are complicated more by the shape of the tree landscape (i.e. the distribution of homoplasy on different trees) than by the sheer abundance of homoplasy or character conflict. Data sets of Type 1 are those constructed by Radel et al. (2013). Data sets of Type 2 present a very rugged landscape, with narrow peaks and valleys, but relatively low amounts of homoplasy. For such a tree landscape, subjecting the trees to TBR and saving suboptimal trees produces much better results when the sequence of clipping for the tree branches is randomized instead of fixed. An unexpected finding for data sets of Types 1 and 2 is that starting a search from a random tree instead of a random addition sequence Wagner tree may increase the probability that the search finds the most parsimonious tree; a small artificial example where these probabilities can be calculated exactly is presented. Data sets of Type 3, the most difficult data sets studied here, comprise only congruent characters, and a single island with only one most parsimonious tree. Even if there is a single island, missing entries create a very flat landscape which is difficult to traverse with tree search algorithms because the number of equally parsimonious trees that need to be saved and swapped to effectively move around the plateaus is too large. Minor modifications of the parameters of tree drifting, ratchet, and sectorial searches allow travelling around these plateaus much more efficiently than saving and swapping large numbers of equally parsimonious trees with TBR. For these data sets, two new related criteria for selecting taxon addition sequences in Wagner trees (the "selected" and "informative" addition sequences) produce much better results than the standard random or closest addition sequences. These new methods for Wagner trees and for moving around plateaus can be useful when analyzing phylogenomic data sets formed by concatenation of genes with uneven taxon representation ("sparse" supermatrices), which are likely to present a tree landscape with extensive plateaus. PMID- 24952316 TI - The genus Atheris (Serpentes: Viperidae) in East Africa: phylogeny and the role of rifting and climate in shaping the current pattern of species diversity. AB - Past climatic and tectonic events are believed to have strongly influenced species diversity in the Eastern Afromontane Biodiversity Hotspot. We investigated the phylogenetic relationships and historical biogeography of the East African genus Atheris (Serpentes: Viperidae), and explored temporal and spatial relationships between Atheris species across Africa, and the impact of palaeoclimatic fluctuations and tectonic movements on cladogenesis of the genus. Using mitochondrial sequence data, the phylogeny of East African species of Atheris shows congruent temporal patterns that link diversification to major tectonic and aridification events within East Africa over the last 15million years (my). Our results are consistent with a scenario of a delayed direct west east colonisation of the Eastern Arc Mountains of Atheris by the formation of the western rift. Based on the phylogenetic patterns, this terrestrial, forest associated genus has dispersed into East Africa across a divided route, on both west-southeasterly and west-northeasterly directions (a C-shaped route). Cladogenesis in the Eastern Arc Mountains and Southern Highlands of Tanzania corresponds to late Miocene and Plio-Pleistocene climatic shifts. Taxonomically, our data confirmed the monophyly of Atheris as currently defined, and reveal four major East African clades, three of which occur in discrete mountain ranges. Possible cryptic taxa are identified in the Atheris rungweensis and A. ceratophora clades. PMID- 24952318 TI - Symbiont shift towards Rhizobium nodulation in a group of phylogenetically related Phaseolus species. AB - Bean plants from the Phaseolus genus are widely consumed and represent a nitrogen source for human nutrition. They provide biological fertilization by establishing root nodule symbiosis with nitrogen-fixing bacteria. To establish a successful interaction, bean plants and their symbiotic bacteria need to synchronize a proper molecular crosstalk. Within the Phaseolus genus, P. vulgaris has been the prominent species to study nodulation with Rhizobium symbionts. However the Phaseolus genus comprises diverse species whose symbionts have not been analyzed. Here we identified and studied nodule bacteria from representative Phaseolus species not previously analyzed and from all the described wild species related to P. vulgaris. We found Bradyrhizobium in nodules from most species representing all Phaseolus clades except in five phylogenetically related species from the P. vulgaris clade. Therefore we propose that Bradyrhizobium nodulation is common in Phaseolus and that there was a symbiont preference shift to Rhizobium nodulation in few related species. This work sets the basis to further study the genetic basis of this symbiont substitution. PMID- 24952319 TI - Polyphyly, gene-duplication and extensive allopolyploidy framed the evolution of the ephemeral Vulpia grasses and other fine-leaved Loliinae (Poaceae). AB - The fine-leaved Loliinae is one of the temperate grass lineages that is richest in number of evolutionary switches from perennial to annual life-cycle, and also shows one of the most complex reticulate patterns involving distinct diploid and allopolyploid lineages. Eight distinct annual lineages, that have traditionally been placed in the genus Vulpia and in other fine-leaved ephemeral genera, have apparently emerged from different perennial Festuca ancestors. The phenotypically similar Vulpia taxa have been reconstructed as polyphyletic, with polyploid lineages showing unclear relationships to their purported diploid relatives. Interspecific and intergeneric hybridization is, however, rampant across different lineages. An evolutionary analysis based on cloned nuclear low-copy GBSSI (Granule-Bound Starch Synthase I) and multicopy ITS (Internal Transcribed Spacer) sequences has been conducted on representatives of most Vulpia species and other fine-leaved lineages, using Bayesian consensus and agreement trees, networking split graphs and species tree-based approaches, to disentangle their phylogenetic relationships and to identify the parental genome donors of the allopolyploids. Both data sets were able to reconstruct a congruent phylogeny in which Vulpia was resolved as polyphyletic from at least three main ancestral diploid lineages. These, in turn, participated in the origin of the derived allopolyploid Vulpia lineages together with other Festuca-like, Psilurus-like and some unknown genome donors. Long-distance dispersal events were inferred to explain the polytopic origin of the Mediterranean and American Vulpia lineages. PMID- 24952320 TI - A time-calibrated phylogeny of the butterfly tribe Melitaeini. AB - The butterfly tribe Melitaeini [Nymphalidae] contains numerous species that have been the subjects of a wide range of biological studies. Despite numerous taxonomic revisions, many of the evolutionary relationships within the tribe remain unresolved. Utilizing mitochondrial and nuclear gene regions, we produced a time-calibrated phylogenetic hypothesis for 222 exemplars comprising at least 178 different species and 21 of the 22 described genera, making this the most complete phylogeny of the tribe to date. Our results suggest that four well supported clades corresponding to the subtribes Euphydryina, Chlosynina, Melitaeina, and Phyciodina exist within the tribe. This analysis is also represents the most complete phylogenetic analysis of the Chlosynina to date, and includes several genera and species that have been previously excluded from published phylogenies of this group. PMID- 24952321 TI - Development of a new computerized prism adaptation procedure for visuo-spatial neglect. AB - BACKGROUND: Prism adaptation (PA) is a promising rehabilitation technique for visuo-spatial neglect. However, PA effects are often inconsistent across studies and the clinical application of this technique has been limited. The purpose of the present studies was to validate an easily standardized, home-friendly, and game-like PA technique (Peg-the-Mole) with healthy participants as a first step toward clinical development. NEW METHOD: In study 1, we used Peg-the-Mole with 32 participants wearing prism or sham goggles to investigate whether this procedure can induce significant after-effects on midline judgment and pointing tasks. In study 2, we compared Peg-the-Mole to a typical PA protocol in 42 participants for after-effects and level of enjoyment and to determine if the after-effects generalize to a throwing task. RESULTS AND COMPARISON WITH EXISTING METHOD: Study 1 showed that Peg-the-Mole induced significant after-effects on all outcome measures. Study 2 demonstrated that after-effects induced by Peg-the-Mole were equivalent to those induced by the typical PA procedure on all outcome measures. Peg-the-Mole was rated as more enjoyable than the typical procedure. CONCLUSIONS: Peg-the-Mole is a new computerized PA procedure that can be easily standardized and successfully used to induce significant after-effects. The present findings demonstrate that alterations can be made to the typical PA procedure to make it easier to use and more enjoyable, factors that could increase treatment availability, adherence and intensity. PMID- 24952322 TI - Validation of an imageable surgical resection animal model of Glioblastoma (GBM). AB - BACKGROUND: Glioblastoma (GBM) is the most common and malignant primary brain tumour having a median survival of just 12-18 months following standard therapy protocols. Local recurrence, post-resection and adjuvant therapy occurs in most cases. NEW METHOD: U87MG-luc2-bearing GBM xenografts underwent 4.5mm craniectomy and tumour resection using microsurgical techniques. The cranial defect was repaired using a novel modified cranial window technique consisting of a circular microscope coverslip held in place with glue. RESULTS: Immediate post-operative bioluminescence imaging (BLI) revealed a gross total resection rate of 75%. At censor point 4 weeks post-resection, Kaplan-Meier survival analysis revealed 100% survival in the surgical group compared to 0% in the non-surgical cohort (p=0.01). No neurological defects or infections in the surgical group were observed. GBM recurrence was reliably imaged using facile non-invasive optical bioluminescence (BLI) imaging with recurrence observed at week 4. COMPARISON WITH EXISTING METHOD(S): For the first time, we have used a novel cranial defect repair method to extend and improve intracranial surgical resection methods for application in translational GBM rodent disease models. Combining BLI and the cranial window technique described herein facilitates non-invasive serial imaging follow-up. CONCLUSION: Within the current context we have developed a robust methodology for establishing a clinically relevant imageable GBM surgical resection model that appropriately mimics GBM recurrence post resection in patients. PMID- 24952324 TI - Turing patterns and long-time behavior in a three-species food-chain model. AB - We consider a spatially explicit three-species food chain model, describing generalist top predator-specialist middle predator-prey dynamics. We investigate the long-time dynamics of the model and show the existence of a finite dimensional global attractor in the product space, L(2)(Omega). We perform linear stability analysis and show that the model exhibits the phenomenon of Turing instability, as well as diffusion induced chaos. Various Turing patterns such as stripe patterns, mesh patterns, spot patterns, labyrinth patterns and weaving patterns are obtained, via numerical simulations in 1d as well as in 2d. The Turing and non-Turing space, in terms of model parameters, is also explored. Finally, we use methods from nonlinear time series analysis to reconstruct a low dimensional chaotic attractor of the model, and estimate its fractal dimension. This provides a lower bound, for the fractal dimension of the attractor, of the spatially explicit model. PMID- 24952323 TI - Automated touch screen device for recording complex rodent behaviors. AB - BACKGROUND: Monitoring mouse behavior is a critical step in the development of modern pharmacotherapies. NEW METHOD: Here we describe the application of a novel method that utilizes a touch display computer (tablet) and software to detect, record, and report fine motor behaviors. A consumer-grade tablet device is placed in the bottom of a specially made acrylic cage allowing the animal to walk on the device (MouseTrapp). We describe its application in open field (for general locomotor studies) which measures step lengths and velocity. The device can perform light-dark (anxiety) tests by illuminating half of the screen and keeping the other half darkened. A divider is built into the lid of the device allowing the animal free access to either side. RESULTS: Treating mice with amphetamine and the delta opioid peptide receptor agonist SNC80 stimulated locomotor activity on the device. Amphetamine increased step velocity but not step length during its peak effect (40-70min after treatment), thus indicating detection of subtle amphetamine-induced effects. Animals showed a preference (74% of time spent) for the darkened half compared to the illuminated side. COMPARISON WITH EXISTING METHOD: Animals were videotaped within the chamber to compare quadrant crosses to detect motion on the device. The slope, duration and magnitude of quadrant crosses tightly correlated with overall locomotor activity as detected by MouseTrapp. CONCLUSIONS: We suggest that modern touch display devices such as MouseTrapp will be an important step toward automation of behavioral analyses for characterizing phenotypes and drug effects. PMID- 24952325 TI - Amino acid and carbohydrate tradeoffs by honey bee nectar foragers and their implications for plant-pollinator interactions. AB - Honey bees are important pollinators, requiring floral pollen and nectar for nutrition. Nectar is rich in sugars, but contains additional nutrients, including amino acids (AAs). We tested the preferences of free-flying foragers between 20 AAs at 0.1% w/w in sucrose solutions in an artificial meadow. We found consistent preferences amongst AAs, with essential AAs preferred over nonessential AAs. The preference of foragers correlated negatively with AA induced deviations in pH values, as compared to the control. Next, we quantified tradeoffs between attractive and deterrent AAs at the expense of carbohydrates in nectar. Bees were attracted by phenylalanine, willing to give up 84units sucrose for 1unit AA. They were deterred by glycine, and adding 100 or more units of sucrose could resolve to offset 1unit AA. In addition, we tested physiological effects of AA nutrition on forager homing performance. In a no-choice context, caged bees showed indifference to 0.1% proline, leucine, glycine or phenylalanine in sucrose solutions. Furthermore, flight tests gave no indication that AA nutrition affected flight capacity directly. In contrast, low carbohydrate nutrition reduced the performance of bees, with important methodological implications for homing studies that evaluate the effect of substances that may affect imbibition of sugar solution. In conclusion, low AA concentrations in nectar relative to pollen suggest a limited role in bee nutrition. Most of the 20 AAs evoked a neutral to a mild deterrent response in bees, thus it seems unlikely that bees respond to AAs in nectar as a cue to assess nutritional quality. Nonetheless, free choice behavior of foraging bees is influenced, for instance by phenylalanine and glycine. Thus, AAs in nectar may affect plant-pollinator interactions and thereby exhibit a selective pressure on the flora in the honey bee habitat. PMID- 24952326 TI - Insulin-like peptide response to nutritional input in honey bee workers. AB - The rise in metabolic disorders in the past decades has heightened focus on achieving a healthy dietary balance in humans. This is also an increasingly important issue in the management of honey bees (Apis mellifera) where poor nutrition has negative effects on health and productivity in agriculture, and nutrition is suggested as a contributing factor in the recent global declines in honey bee populations. As in other organisms, the insulin/insulin-like signaling (IIS) pathway is likely involved in maintaining nutrient homeostasis in honey bees. Honey bees have two insulin-like peptides (Ilps) with differing spatial expression patterns in the fat body suggesting that AmIlp1 potentially functions in lipid metabolism while AmIlp2 is a more general indicator of nutritional status. We fed caged worker bees artificial diets high in carbohydrates, proteins or lipids and measured expression of AmIlp1, AmIlp2, and the insulin receptor substrate (IRS) to test their responses to dietary macronutrients. We also measured lifespan, worker weight and gustatory sensitivity to sugar as measures of individual physical condition. We found that expression of AmIlp1 was affected by diet composition and was highest on a diet high in protein. Expression of AmIlp2 and AmIRS were not affected by diet. Workers lived longest on a diet high in carbohydrates and low in protein and lipids. However, bees fed this diet weighed less than those that received a diet high in protein and low in carbohydrates and lipids. Bees fed the high carbohydrates diet were also more responsive to sugar, potentially indicating greater levels of hunger. These results support a role for AmIlp1 in nutritional homeostasis and provide new insight into how unbalanced diets impact individual honey bee health. PMID- 24952327 TI - The future of valves for percutaneous insertion. PMID- 24952328 TI - Loss of glutamic acid decarboxylase (Gad67) in Gpr88-expressing neurons induces learning and social behavior deficits in mice. AB - GABA is the neurotransmitter of striatal projection neurons, however the contribution of the striatal GABAergic output to behavior is not well understood. We assessed motor function, spatial learning, social behavior, olfactory and object recognition preferences in mice lacking the GABA-synthesizing enzyme glutamic acid decarboxylase, Gad67, in neurons expressing the protein Gpr88, an orphan G-protein-coupled receptor primarily expressed in the striatum. Gad67 deficient mice show no impairments in motor coordination and balance, but exhibit enhanced locomotor activity and stereotypic grooming behavior. Furthermore, Gad67 deficient mice show impairments in spatial learning, social behavior, olfactory preferences, and they prefer a familiar compared to a novel object in the object recognition test. These findings provide original evidence that striatal Gad67 expression is involved in the modulation of learning and social behavior. Some of the behavioral abnormalities observed in Gad67-deficient mice are reminiscent of Autism-spectrum-disorder (ASD) deficits, suggesting that abnormal striatal GABAergic output may contribute to behavioral deficits in ASD. PMID- 24952330 TI - The mirror neuron system and motor dexterity: what happens? AB - The mirror neuron system (MNS) is currently one of the most prominent areas of research in neuroscience. Some of the work has focused on the identification of factors that modulate its activity, but until now, no one has tried to identify the effect of motor ability on the MNS regions. The aim of the present work is to study a possible modulation of hand dexterity on the MNS activity. A blocked fMRI experiment has been designed, consisting of an execution condition, where participants must repeatedly perform a precision grasping pantomime, and an observation condition, where the same motor action is passively observed. A conjunction analysis was performed in order to confirm the existence of mirror activity. Moreover, participants were classified depending on their hand dexterity (measured with the Purdue Pegboard Test) as "High dexterity" or "Low dexterity" and a regression analysis was performed to investigate a possible linear relationship between the degree of dexterity and brain activity in the MNS. The conjunction analysis revealed, as expected, activity in the inferior parietal lobule, a region that constitutes one of the nuclei of the putative MNS and which is consistently activated by intransitive actions. The degree of dexterity only seems to modulate MNS regions during action execution. However, under the observation condition, no linear relationship of hand dexterity in MNS regions was registered in either the comparison between groups, or in the regression analysis. Therefore, the MNS network does not seem to be linearly modulated by the degree of motor dexterity, as occurs with other action-related factors like familiarity. PMID- 24952331 TI - Independent modulation of corticospinal and group I afferents pathways during upright standing. AB - Balance control during upright standing is accompanied by an increased amplitude of motor-evoked potentials (MEP) induced by transcranial magnetic stimulation and a decreased amplitude of the Hoffmann (H) reflex in the soleus muscle. Nonetheless, whether these observations reflect reciprocal adjustments between corticospinal and group I afferents pathways during upright standing remains unknown. To further investigate this question, cathodal transcranial direct current stimulation (c-tDCS) applied over the motor cortex and vibration of Achilles tendons were used to modify the excitability of corticospinal and group I afferent pathways, respectively. MEPs and H reflexes were recorded in the soleus muscle during upright standing with or without bilateral Achilles tendon vibration, these recordings being performed before and after 20 min of c-tDCS (1.5 mA) or sham stimulation applied over the sensorimotor cortex. The results indicate that tendon vibration increased MEP amplitude (+28%) and decrease (-68%) the H-reflex amplitude (p<0.05). After c-tDCS, MEP amplitude was reduced by 13% and 26% without and with tendon vibration (p<0.05), respectively. In contrast, no significant change occurred in H-reflex amplitude after c-tDCS. Regardless of the conditions (c-tDCS and tendon vibration), no significant correlation was observed between changes in MEP and H-reflex amplitudes. The results failed to demonstrate close reciprocal changes in soleus MEP and H-reflex amplitudes during upright standing. These original findings suggest independent adjustments in corticospinal and group I afferents pathways during upright standing. PMID- 24952329 TI - Neuronal degeneration, synaptic defects, and behavioral abnormalities in tau45 230 transgenic mice. AB - The complement of mechanisms underlying tau pathology in neurodegenerative disorders has yet to be elucidated. Among these mechanisms, abnormal tau phosphorylation has received the most attention because neurofibrillary tangles present in Alzheimer's disease (AD) and related disorders known as tauopathies are composed of hyperphosphorylated forms of this microtubule-associated protein. More recently, we showed that calpain-mediated cleavage leading to the generation of the 17kDa tau45-230 fragment is a conserved mechanism in these diseases. To obtain insights into the role of this fragment in neurodegeneration, we generated transgenic mice that express tau45-230 and characterized their phenotype. Our results showed a significant increase in cell death in the hippocampal pyramidal cell layer of transgenic tau45-230 mice when compared to wild-type controls. In addition, significant synapse loss was detected as early as six months after birth in transgenic hippocampal neurons. These synaptic changes were accompanied by alterations in the expression of the N-methyl-d-aspartate glutamate (NMDA) receptor subunits. Furthermore, functional abnormalities were detected in the transgenic mice using Morris Water Maze and fear conditioning tests. These results suggest that the accumulation of tau45-230 is responsible, at least in part, for neuronal degeneration and some behavioral changes in AD and other tauopathies. Collectively, these data provide the first direct evidence of the toxic effects of a tau fragment biologically produced in the context of these diseases in vertebrate neurons that develop in situ. PMID- 24952332 TI - Acetylsalicylic acid enhances the anti-inflammatory effect of fluoxetine through inhibition of NF-kappaB, p38-MAPK and ERK1/2 activation in lipopolysaccharide induced BV-2 microglia cells. AB - The latest advancements in neurobiological research provide increasing evidence that inflammatory and neurodegenerative pathways play an important role in depression. According to the cytokine hypothesis, depression could be due to the increased production of pro-inflammatory cytokines by microglia activation. Thus, using the BV-2 microglial cell line, the aim of the present study was to investigate whether fluoxetine (FLX) or acetylsalicylic acid (ASA) could inhibit this microglia activation and could achieve better results in combination. Our results showed that FLX could attenuate lipopolysaccharide (LPS)-induced production of interleukin-1beta (IL-1beta), the expression of the indoleamine 2,3 dioxygenase (IDO) enzyme and the depletion of 5-HT. Moreover, FLX could inhibit phosphorylation of nuclear factor-kappaB (NF-kappaB) and phosphorylation of p38 mitogen-activated protein kinase (MAPK), and the combined use with ASA could enhance these effects. Notably, the adjunctive agent ASA could also inhibit phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2). Taken together, our results suggest that FLX may have some anti-inflammatory effects by modulating microglia activation and that ASA served as an effective adjunctive agent by enhancing these therapeutic effects. PMID- 24952333 TI - Graded defragmentation of cortical neuronal firing during recovery of consciousness in rats. AB - State-dependent neuronal firing patterns reflect changes in ongoing information processing and cortical function. A disruption of neuronal coordination has been suggested as the neural correlate of anesthesia. Here, we studied the temporal correlation patterns of ongoing spike activity, during a stepwise reduction of the volatile anesthetic desflurane, in the cerebral cortex of freely moving rats. We hypothesized that the recovery of consciousness from general anesthesia is accompanied by specific changes in the spatiotemporal pattern and correlation of neuronal activity. Sixty-four contact microelectrode arrays were chronically implanted in the primary visual cortex (contacts spanning 1.4-mm depth and 1.4-mm width) for recording of extracellular unit activity at four steady-state levels of anesthesia (8-2% desflurane) and wakefulness. Recovery of consciousness was defined as the regaining of the righting reflex (near 4%). High-intensity firing (HI) periods were segmented using a threshold (200-ms) representing the minimum in the neurons' bimodal interspike interval histogram under anesthesia. We found that the HI periods were highly fragmented in deep anesthesia and gradually transformed to a near-continuous firing pattern at wakefulness. As the anesthetic was withdrawn, HI periods became longer and increasingly correlated among the units both locally and across remote recording sites. Paradoxically, in 4 of 8 animals, HI correlation was also high at the deepest level of anesthesia (8%) when local field potentials (LFP) were burst-suppressed. We conclude that recovery from desflurane anesthesia is accompanied by a graded defragmentation of neuronal activity in the cerebral cortex. Hypersynchrony during deep anesthesia is an exception that occurs only with LFP burst suppression. PMID- 24952334 TI - Molybdate partly mimics insulin-promoted metabolic effects in Drosophila melanogaster. AB - Molybdenum-containing salts have been found to attenuate diabetes complications in mammals by affecting processes normally regulated by insulin and thus were believed to mimic insulin activity. In this study, we used a fruit fly model to test sodium molybdate, Na2MoO4, action in relation to insulin-promoted processes and toxicity. We studied how larval food supplementation with sodium molybdate affected levels of body carbohydrates and lipids in two-day old adult Drosophila melanogaster. Molybdate salt, in the concentrations used (0.025, 0.05, 0.5, 5, and 10mM), showed low toxicity to fly larvae and slightly influenced development and the percentage of pupated animals. Additionally, sodium molybdate decreased the level of hemolymph glucose in males by 30%, and increased the level of hemolymph trehalose in flies of both sexes. These changes were accompanied by an increase in whole body trehalose and glycogen of about 30-90%. Although total lipid levels in flies of both sexes were depleted by 25%, an increased amount of triacylglycerides among total lipids was observed. These effects were not related to changes in food intake. Taken together, the present data let us suggest that sodium molybdate may at least partly mimic insulin-related effects in Drosophila. PMID- 24952335 TI - Effects of UV radiation on hatching, lipid peroxidation, and fatty acid composition in the copepod Paracyclopina nana. AB - To evaluate the effects of UV radiation on the reproductive physiology and macromolecules in marine zooplankton, several doses of UV radiation were used to treat the copepod Paracyclopina nana, and we analyzed in vivo endpoints of their life cycle such as mortality and reproductive parameters with in vitro biochemical biomarkers such as reactive oxygen species (ROS), the modulated enzyme activity of glutathione S-transferase (GST) and superoxide dismutase (SOD), and the production of a byproduct of peroxidation (e.g. malonedialdehyde, MDA). After UV radiation, the survival rate of P. nana was significantly reduced. Also, egg sac damage and a reduction in the hatching rate of offspring were observed in UV-irradiated ovigerous females. According to the assessed biochemical parameters, we found dose-dependent increases in ROS levels and high levels of the lipid peroxidation decomposition product by 2 kJ m(-2), implying that P. nana was under off-balanced status by oxidative stress-mediated cellular damage. Antioxidant enzyme activities of GST and SOD increased over different doses of UV radiation. To measure UV-induced lipid peroxidation, we found a slight reduction in the composition of essential fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These findings indicate that UV radiation can induce oxidative stress-triggered lipid peroxidation with modulation of antioxidant enzyme activity, leading to a significant effect on mortality and reproductive physiology (e.g. fecundity). These results demonstrate the involvement of UV radiation on essential fatty acids and its susceptibility to UV radiation in the copepod P. nana compared to other species. PMID- 24952336 TI - In pursuit of the ideal antifungal agent for Candida infections: high-throughput screening of small molecules. AB - Candida infections have created a great burden on the public healthcare sector. The situation is worsened by recent epidemiological changes. Furthermore, the current arsenal of antifungal agents is limited and associated with undesirable drawbacks. Therefore, new antifungal agents that surpass the existing ones are urgently needed. High-throughput screening of small molecule libraries enables rapid hit identification and, possibly, increases hit rate. Moreover, the identified hits could be associated with unrecognized or multiple drug targets, which would provide novel insights into the biological processes of the pathogen. Hence, it is proposed that high-throughput screening of small molecules is particularly important in the pursuit of the ideal antifungal agents for Candida infections. PMID- 24952337 TI - Predicting changes in cardiac myocyte contractility during early drug discovery with in vitro assays. AB - Cardiovascular-related adverse drug effects are a major concern for the pharmaceutical industry. Activity of an investigational drug at the L-type calcium channel could manifest in a number of ways, including changes in cardiac contractility. The aim of this study was to define which of the two assay technologies - radioligand-binding or automated electrophysiology - was most predictive of contractility effects in an in vitro myocyte contractility assay. The activity of reference and proprietary compounds at the L-type calcium channel was measured by radioligand-binding assays, conventional patch-clamp, automated electrophysiology, and by measurement of contractility in canine isolated cardiac myocytes. Activity in the radioligand-binding assay at the L-type Ca channel phenylalkylamine binding site was most predictive of an inotropic effect in the canine cardiac myocyte assay. The sensitivity was 73%, specificity 83% and predictivity 78%. The radioligand-binding assay may be run at a single test concentration and potency estimated. The least predictive assay was automated electrophysiology which showed a significant bias when compared with other assay formats. Given the importance of the L-type calcium channel, not just in cardiac function, but also in other organ systems, a screening strategy emerges whereby single concentration ligand-binding can be performed early in the discovery process with sufficient predictivity, throughput and turnaround time to influence chemical design and address a significant safety-related liability, at relatively low cost. PMID- 24952338 TI - Hexavalent chromium is cytotoxic and genotoxic to hawksbill sea turtle cells. AB - Sea turtles are a charismatic and ancient ocean species and can serve as key indicators for ocean ecosystems, including coral reefs and sea grass beds as well as coastal beaches. Genotoxicity studies in the species are absent, limiting our understanding of the impact of environmental toxicants on sea turtles. Hexavalent chromium (Cr(VI)) is a ubiquitous environmental problem worldwide, and recent studies show it is a global marine pollutant of concern. Thus, we evaluated the cytotoxicity and genotoxicity of soluble and particulate Cr(VI) in hawksbill sea turtle cells. Particulate Cr(VI) was both cytotoxic and genotoxic to sea turtle cells. Concentrations of 0.1, 0.5, 1, and 5MUg/cm(2) lead chromate induced 108, 79, 54, and 7% relative survival, respectively. Additionally, concentrations of 0, 0.1, 0.5, 1, and 5MUg/cm(2) lead chromate induced damage in 4, 10, 15, 26, and 36% of cells and caused 4, 11, 17, 30, and 56 chromosome aberrations in 100 metaphases, respectively. For soluble Cr, concentrations of 0.25, 0.5, 1, 2.5, and 5MUM sodium chromate induced 84, 69, 46, 25, and 3% relative survival, respectively. Sodium chromate induced 3, 9, 9, 14, 21, and 29% of metaphases with damage, and caused 3, 10, 10, 16, 26, and 39 damaged chromosomes in 100 metaphases at concentrations of 0, 0.25, 0.5, 1, 2.5, and 5MUM sodium chromate, respectively. These data suggest that Cr(VI) may be a concern for hawksbill sea turtles and sea turtles in general. PMID- 24952339 TI - Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats. AB - Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20mg/kg body weight, p.o) for 28 days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenic exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20mg/kg body weight, p.o) and curcumin (100mg/kg body weight, p.o) for 28 days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin. PMID- 24952340 TI - Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel subsulfide. AB - OBJECTIVE: To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. METHODS: Gene expression changes were determined in micro dissected lung broncho-alveolar cells from Fischer 344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m(3) (0.03, 0.06, 0.11, and 0.44 mgNi/m(3)) for one and four weeks (6h/day, 5 days/week). RESULTS: Broncho alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1 week to up-regulation at 4 weeks. CONCLUSIONS: These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026 mgNi/m(3), for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64 MUgNi/g lung, for immune/inflammatory signaling. IMPLICATIONS: These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity. PMID- 24952341 TI - The relationship between organisational factors and the effectiveness of environmental management. AB - This paper examines the relationship between specific organisational factors (top management support, training, employee participation, teamwork and the link of performance to rewards) with the effectiveness of environmental management. The effectiveness of environmental management is measured in respect of the effectiveness of environmental management processes and environmental performance. Data were collected by mail survey questionnaire from a random sample of 899 senior financial officers in Australian manufacturing organisations. The findings highlight the significance of the effectiveness of environmental management processes as an antecedent of environmental performance and a mediator of the relationship between organisational factors and environmental performance. The findings provide managers with an insight into the specific organisational factors that they need to focus on to enhance the effectiveness of environmental management. PMID- 24952342 TI - Learning curve analysis of intracorporeal cuff suturing during robotic single site total hysterectomy. AB - STUDY OBJECTIVE: To analyze the learning curve of intracorporeal cuff suturing during robotic single-site total hysterectomy. DESIGN: Retrospective study (Canadian Task Force classification II-1). SETTING: University hospital. PATIENTS: Twenty-four patients with benign indications for hysterectomy. INTERVENTIONS: Twenty-four patients who underwent robotic single-site total hysterectomy to treat benign indications were included in the study. Surgical procedures were performed by a single surgeon with extensive experience in laparoscopy, using the single-site platform of the da Vinci Surgical System. All vaginal cuffs were closed intracorporeally using semi-rigid single-site instruments. MEASUREMENTS AND MAIN RESULTS: An exponential learning curve technique was used to analyze the learning curve. The overall mean (SD) vaginal cuff closure time was 23.2 (7) minutes. Learning curve analysis revealed a decrease in vaginal closure time after 14 procedures. CONCLUSIONS: An experienced robotic surgeon requires approximately 14 procedures to achieve proficiency in intracorporeal cuff suturing during robotic single-site total hysterectomy. Novel instruments that create perfect triangulation are needed to overcome the current challenges of suturing and to shorten operative time. PMID- 24952343 TI - Incidence and risk factors for chronic pelvic pain after hysteroscopic sterilization. AB - STUDY OBJECTIVE: To investigate the incidence of and preoperative risk factors for developing pelvic pain after hysteroscopic sterilization using the Essure microinserts. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: University medical center. PATIENTS: A total of 458 patients who underwent hysteroscopic sterilization using Essure between January 1, 2005, and June 30, 2012. INTERVENTION: Hysteroscopic sterilization using Essure. MEASUREMENTS AND MAIN RESULTS: The incidence of acute pelvic pain after hysteroscopic sterilization was 8.1%, and of persistent pain at 3 months after the procedure was 4.2%. The range of presence of pain was 1 to 469 days (mean, 56 days). Of patients who developed chronic pelvic pain after the procedure, 75% reported it within 130 days of the procedure. Patients with previous diagnoses of any chronic pain (chronic pelvic pain, chronic low back pain, chronic headache, and fibromyalgia) were more likely to report both acute pain (odds ratio, 6.81; 95% confidence interval, 2.95-15.73) and chronic pain (odds ratio, 6.15; 95% confidence interval, 2.10-18.10) after hysteroscopic sterilization. CONCLUSIONS: Pelvic pain may develop after hysteroscopic sterilization. Patients with a diagnosis of preexisting chronic pain may be at increased risk of developing pelvic pain after the procedure. Fifty percent of new pelvic pain after Essure placement will resolve within 3 months. PMID- 24952344 TI - Deoxynivalenol induces apoptosis in mouse thymic epithelial cells through mitochondria-mediated pathway. AB - Deoxynivalenol (DON) is a mycotoxin produced as a secondary metabolite by fungal species. In this report, we investigated the apoptotic effect of DON in mouse thymic epithelial cell line 1 (MTEC1). MTEC1 cell apoptosis induced by DON was confirmed by nuclei morphology change, TUNEL positive staining, annexin V/propidium iodide positive staining and increased protein levels of caspase-3, caspase-8, caspase-9 and poly(ADP-ribose) polymerase (PARP). The effects of DON on reactive oxygen species (ROS) levels and mitochondrial membrane potential were investigated via fluorescence microscope and flow cytometry, respectively. In addition, DON could significantly increase the protein levels of p53 and Bax/Bcl 2 ratio in MTEC1 cells. Taken together, our results suggest that DON causes the activation of p53, increased levels of ROS and the induction of mitochondrial dysfunction, which may contribute to DON-induced apoptosis in MTEC1 cells. PMID- 24952345 TI - Implementation of a demand-side approach to reduce aeration requirements of activated sludge systems: directed acclimation of biomass and its effect at the process level. AB - Conventionally, increased oxygen requirements of biological wastewater treatment systems have been addressed through supply-side approaches that focus on upgrading the oxygen mass transfer capabilities of aeration devices. Such approaches entail high aeration energy penalties for relatively low performance improvements, as well as causing decreased oxygen mass transfer efficiencies. In this study, a nitrifying community acclimated to low dissolved oxygen (DO) conditions has been demonstrated to yield similar treatment performance as a conventional nitrifying process with 20% less aeration requirements and 20% improvement in mass transfer efficiency. Such a demand-side approach has been shown to be successful due to an improvement of the half saturation constant of the acclimated biomass that has, in turn, been linked to the expression of hemoglobin proteins. Directed acclimation of nitrifying communities could help address the operational requirement to carry out ammonia oxidation at consistently low DO conditions in the mainstream anammox and simultaneous nitrification-denitrification processes. PMID- 24952346 TI - Copper removal using a heavy-metal resistant microbial consortium in a fixed-bed reactor. AB - A heavy-metal resistant bacterial consortium was obtained from a contaminated river in Sao Paulo, Brazil and utilized for the design of a fixed-bed column for the removal of copper. Prior to the design of the fixed-bed bioreactor, the copper removal capacity by the live consortium and the effects of copper in the consortium biofilm formation were investigated. The Langmuir model indicated that the sorption capacity of the consortium for copper was 450.0 mg/g dry cells. The biosorption of copper into the microbial biomass was attributed to carboxyl and hydroxyl groups present in the microbial biomass. The effect of copper in planktonic cells to form biofilm under copper rich conditions was investigated with confocal microscopy. The results revealed that biofilm formed after 72 h exposure to copper presented a reduced thickness by 57% when compared to the control; however 84% of the total cells were still alive. The fixed-bed bioreactor was set up by growing the consortium biofilm on granular activated carbon (GAC) and analyzed for copper removal. The biofilm-GAC (BGAC) column retained 45% of the copper mass present in the influent, as opposed to 17% in the control column that contained GAC only. These findings suggest that native microbial communities in sites contaminated with heavy metals can be immobilized in fixed-bed bioreactors and used to treat metal contaminated water. PMID- 24952347 TI - DNMT3L interacts with transcription factors to target DNMT3L/DNMT3B to specific DNA sequences: role of the DNMT3L/DNMT3B/p65-NFkappaB complex in the (de )methylation of TRAF1. AB - DNMT3L i.e. DNA (cytosine-5)-methyltransferase 3-like protein, is devoid of cytosine methyltransferase activity, despite clear homology to DNMT3A and DNMT3B, due to the mutation of key catalytic residues. However, DNMT3L participates in de novo methylation reactions through its direct interaction with DNMT3A and DNMT3B. In the present study, we investigated if DNMT3L interacts also directly with transcription factors (TFs). Using TF arrays, we identified 73 TFs that interacted with DNMT3L, 13 of which (ASH2L, ATF1, ATF3, BLZF1, CDX2, CERM, E2F3, E2F4, GCNF, GTF2I, GTF3C5, NFkB-p65 and RXRalpha) interacted only with DNMT3L, but not with DNMT3A/B. By focusing on the interaction with NFkB-p65, we demonstrate that DNMT3L forms a complex with DNMT3B and NFkB-p65 and that this complex is required for the control of DNA methylation at the TRAF1 promoter in the T98G glioma cell line. In addition, our experiments describe the DNA methylation at TRAF1 as being dynamic with a demethylation phase involving TET3. Thus, our data suggests that DNMT3L can address DNMT3A/B to specific sites by directly interacting with TFs that do not directly interact with DNMT3A/B. In summary, our data provide a new avenue for the direction of site-specific de novo DNA methylation catalyzed by DNMT3A/B. PMID- 24952348 TI - PrP(C) signalling in neurons: from basics to clinical challenges. AB - The cellular prion protein PrP(C) was identified over twenty-five years ago as the normal counterpart of the scrapie prion protein PrP(Sc), itself the main if not the sole component of the infectious agent at the root of Transmissible Spongiform Encephalopathies (TSEs). PrP(C) is a ubiquitous cell surface protein, abundantly expressed in neurons, which constitute the targets of PrP(Sc)-mediated toxicity. Converging evidence have highlighted that neuronal, GPI-anchored PrP(C) is absolutely required for prion-induced neuropathogenesis, which warrants investigating into the normal function exerted by PrP(C) in a neuronal context. It is now well-established that PrP(C) can serve as a cell signalling molecule, able to mobilize transduction cascades in response to interactions with partners. This function endows PrP(C) with the capacity to participate in multiple neuronal processes, ranging from survival to synaptic plasticity. A diverse array of data have allowed to shed light on how this function is corrupted by PrP(Sc). Recently, amyloid Abeta oligomers, whose accumulation is associated with Alzheimer's disease (AD), were shown to similarly instigate toxic events by deviating PrP(C)-mediated signalling. Here, we provide an overview of the various signal transduction cascades ascribed to PrP(C) in neurons, summarize how their subversion by PrP(Sc) or Abeta oligomers contributes to TSE or AD neuropathogenesis and discuss the ensuing clinical implications. PMID- 24952349 TI - A computational microscope focused on the sense of smell. AB - In this article, we review studies of the protagonists of the perception of smell focusing on Odorant-Binding Proteins and Olfactory Receptors. We notably put forward studies performed by means of molecular modeling, generally combined with experimental data. Those works clearly emphasize that computational approaches are now a force to reckon with. In the future, they will certainly be more and more used, notably in the framework of a computational microscope meant to observe how the laws of physics govern the biomolecular systems originating our sense of smell. PMID- 24952350 TI - Pterocarpans induce tumor cell death through persistent mitotic arrest during prometaphase. AB - Pterocarpans, a family of isoflavonoids found in the diverse Fabaceae, display potent cytotoxic activity over a panel of tumor cell lines, and among those tested, 2,3,9- trimethoxypterocarpan displays the most potent activity. This study evaluates the effects of 2,3,9-trimethoxypterocarpan and its related derivatives on cell cycle progression and microtubule function in select breast cancer cell lines (MCF7, T47d and HS578T). The pterocarpans, with the exception of 3,4-dihydroxy-9-methoxipterocarpan, induced increased frequencies of mitotic cells by inducing arrest in prometaphase. While microtubule organization in interphase cells was not modified during treatment, mitotic cells exhibited high frequencies of monastral spindles surrounded by condensed chromosomes. Immunofluorescence staining with an anti-gamma-tubulin antibody showed double-dot labeling in the spindle polar region, suggesting that pterocarpan treatment blocked centrosome segregation. We found that this mitotic arrest was reversible when the cells were treated for up to 24 h followed by recovery in drug-free medium, but not after 48-h treatment followed by incubation in drug-free medium. In that case, treated cells typically underwent cell multinucleation and apoptosis. PMID- 24952351 TI - Indole-3-carbinol, a vegetable phytochemical, inhibits adipogenesis by regulating cell cycle and AMPKalpha signaling. AB - Indole-3-carbinol (I3C) is a phytochemical present mainly in cruciferous vegetables. In this study, we investigated the mechanism by which I3C blocks adipogenesis in 3T3-L1 cells, and evaluated the anti-adipogenic effect of I3C in zebrafish. Our data showed that I3C mainly inhibits early differentiation of adipocyte through cell cycle arrest. Inhibition of early differentiation was reflected by down-regulation of early adipogenic factors such as CCAAT-enhancer binding proteins beta and delta (C/EBPbeta and C/EBPdelta), followed by down regulation of late adipogenic factors such as peroxisome proliferator-activated receptor gamma (PPARgamma) and C/EBPalpha, and regulation of signaling molecules. This result was supported by a reduction in triglyceride (TG) levels and TG synthetic enzymes. I3C activated AMP-activated protein kinase alpha (AMPKalpha) to inhibit fatty acid synthesis. In addition, an anti-adipogenic effect of I3C was found in zebrafish study. Our data suggest that vegetables-derived I3C could reduce lipid accumulation via various molecular mechanisms in cell. PMID- 24952353 TI - ZNF143 is regulated through alternative 3'UTR isoforms. AB - ZNF143 is a ubiquitously expressed transcription factor conserved in all vertebrates, regulating genes involved in primary metabolism and cell growth. It is therefore crucial to tightly maintain the adequate level of this factor in the cell. Although ZNF143 expression is auto-regulated at the transcriptional level, nothing is known about the post-transcriptional events influencing its expression. In this work, performed in mammalian cells, we show that ZNF143 expresses different 3'-untranslated regions (3'-UTR) as a result of alternative polyadenylation. These 3'UTR isoforms have a diverse impact on the ZNF143 transcript fate. Indeed, we show that the longest isoform, unlike the short one, contains a destabilizing AU-Rich element and is targeted by the miRNA 590-3p. Additionally we observed a correlation between ZNF143 downregulation and miR-590 3p up-regulation in retinoic acid treated teratocarcinoma cells. This strongly suggests that ZNF143 post-transcriptional regulation depends on the long 3'UTR isoform during teratocarcinoma cells differentiation. Finally we evidenced that the alternative polyadenylation site usage is independent of the previously identified ZNF143 transcriptional auto-regulation. PMID- 24952352 TI - Development of antileishmanial lipid nanocomplexes. AB - Visceral leishmaniasis is a life-threatening disease that affects nearly a million people every year. The emergence of Leishmania strains resistant to existing drugs complicates its treatment. The purpose of this study was to develop a new lipid formulation based on nanocochleates combining two active drugs: Amphotericin B (AmB) and Miltefosine (HePC). Nanocochleates composed of dioleoylphosphatidylserine (DOPS) and Cholesterol (Cho) and Ca(2+), in which HePC and AmB were incorporated, were prepared. Properties such as particle size, zeta potential, drug payload, in-vitro drug release and storage stability were investigated. Moreover, in-vitro stability in gastrointestinal fluid was performed in view of an oral administration. AmB-HePC-loaded nanocochleates with a mean particle size of 250 +/- 2 nm were obtained. The particles displayed a narrow size distribution and a drug payload of 29.9 +/- 0.5 mg/g for AmB, and 14.0 +/- 0.9 mg/g for HePC. Drug release occurred preferentially in intestinal medium containing bile salts. Therefore, AmB-HePC-loaded nanocochleates could be a promising oral delivery system for the treatment of visceral leishmaniasis. PMID- 24952354 TI - Sulforaphane induces autophagy through ERK activation in neuronal cells. AB - Sulforaphane (SFN), an activator of nuclear factor E2-related factor 2 (Nrf2), has been reported to induce autophagy in several cells. However, little is known about its signaling mechanism of autophagic induction. Here, we provide evidence that SFN induces autophagy with increased levels of LC3-II through extracellular signal-regulated kinase (ERK) activation in neuronal cells. Pretreatment with NAC (N-acetyl-l-cysteine), a well-known antioxidant, completely blocked the SFN induced increase in LC3-II levels and activation of ERK. Knockdown or overexpression of Nrf2 did not affect autophagy. Together, the results suggest that SFN-mediated generation of reactive oxygen species (ROS) induces autophagy via ERK activation, independent of Nrf2 activity in neuronal cells. PMID- 24952355 TI - Phosphoglucomutase1 is necessary for sustained cell growth under repetitive glucose depletion. AB - Phosphoglucomutase (PGM)1 catalyzes the reversible conversion reaction between glucose-1-phosphate (G-1-P) and glucose-6-phosphate (G-6-P). Although both G-1-P and G-6-P are important intermediates for glucose and glycogen metabolism, the biological roles and regulatory mechanisms of PGM1 are largely unknown. In this study we found that T553 is obligatory for PGM1 stability and the last C-terminal residue, T562, is critical for its activity. Interestingly, depletion of PGM1 was associated with declined cellular glycogen content and decreased rates of glycogenolysis and glycogenesis. Furthermore, PGM1 depletion suppressed cell proliferation under long-term repetitive glucose depletion. Our results suggest that PGM1 is required for sustained cell growth during nutritional changes, probably through regulating the balance of G-1-P and G-6-P in order to satisfy the cellular demands during nutritional stress. PMID- 24952356 TI - Emergence of pyridoxal phosphorylation through a promiscuous ancestor during the evolution of hydroxymethyl pyrimidine kinases. AB - In the family of ATP-dependent vitamin kinases, several bifunctional enzymes that phosphorylate hydroxymethyl pyrimidine (HMP) and pyridoxal (PL) have been described besides enzymes specific towards HMP. To determine how bifunctionality emerged, we reconstructed the sequence of three ancestors of HMP kinases, experimentally resurrected, and assayed the enzymatic activity of their last common ancestor. The latter has ~ 8-fold higher specificity for HMP due to a glutamine residue (Gln44) that is a key determinant of the specificity towards HMP, although it is capable of phosphorylating both substrates. These results show how a specific enzyme with catalytic promiscuity gave rise to current bifunctional enzymes. PMID- 24952357 TI - Comparing various techniques to produce micro/nanoparticles for enhancing the dissolution of celecoxib containing PVP. AB - One of the major challenges in pharmaceutical development is the poor dissolution performance of drugs. Celecoxib (CLX) is a poorly water soluble drug with its bioavailability being limited by its poor dissolution. In this study several particle engineering methods were employed on CLX using various ratios of CLX:PVP K30. Micro/nanoparticles of CLX:PVP were prepared by using spray drying (SD), antisolvent crystallization followed by freeze drying (CRS-FD) and spray drying (CRS-SD) techniques. The suspension obtained through antisolvent crystallization was also subjected to high pressure homogenization followed by freeze drying (HPH FD). Particle size measurements, saturation solubility, optical and scanning electron microscopy, DSC, XRPD, FT-IR and dissolution test were performed to characterize the physicochemical and pharmaceutical properties of the samples. The results showed that spray dried samples in the presence of (50%) PVP produced spherical particles and exhibited a high dissolution rate. Interestingly in the antisolvent crystallization technique, spherical nanoparticles of drug-PVP were obtained in the range of 291-442 nm. The average particle size was dependent on the concentration of the PVP used during the crystallization process. Solid state analysis showed that these particles were completely amorphous in nature. Also interesting to note was that at concentration of 5% PVP, when the suspension of nanoparticles was subjected to the high pressure homogenization process, the crystallinity of CLX increased. Despite the partial crystallinity of particles produced, they showed excellent dissolution behavior. It can thus be concluded that the method of preparation of CLX micro/nanoparticles had a big impact on the dissolution rate when the concentration of PVP was low (e.g., 5%). At high PVP concentration (e.g., 50%) all methods used to prepare engineered CLX particles showed better dissolution with no significant differences in their dissolution efficiency. PMID- 24952358 TI - Sequential third-party mesenchymal stromal cell therapy for refractory acute graft-versus-host disease. AB - We evaluated the feasibility, safety, and efficacy of the administration of 4 sequential doses (intravenously administered on days 1, 4, 11, and 18) of cryopreserved bone marrow-derived mesenchymal stromal cells (MSC) expanded with platelet lysate and obtained from third-party donors as a second-line treatment for steroid-refractory acute graft-versus-host (aGVHD) disease in a series of 25 patients. All patients received at least 2 doses of MSC, whereas 21 received 3 doses and 18 received the initially planned 4 doses. Because of the achievement of partial response, 4 patients received additional doses of MSC. Median single cell dose administered was 1.1 * 10(6) MSC/kg of recipient body weight. There were no adverse events related to the MSC infusion in the 99 procedures performed, with the exception of a cardiac ischemic event that occurred twice in a patient with prior history of cardiac ischemia. Response to MSC at 60 days after the first dose was evaluable in 24 patients. Seventeen patients (71%) responded (11 complete and 6 partial responses), with a median time to response of 28 days after the first MSC dose, whereas 7 patients did not respond. In summary, we can conclude that sequential cryopreserved third-party MSC therapy administered on days 1, 4, 11, and 18 is a safe procedure for patients with steroid-refractory aGVHD. This strategy may provide a high rate of overall responses of aGVHD with a low toxicity profile. PMID- 24952360 TI - Identification and characterization of mutant clones with enhanced propagation rates from phage-displayed peptide libraries. AB - A target-unrelated peptide (TUP) can arise in phage display selection experiments as a result of a propagation advantage exhibited by the phage clone displaying the peptide. We previously characterized HAIYPRH, from the M13-based Ph.D.-7 phage display library, as a propagation-related TUP resulting from a G->A mutation in the Shine-Dalgarno sequence of gene II. This mutant was shown to propagate in Escherichia coli at a dramatically faster rate than phage bearing the wild-type Shine-Dalgarno sequence. We now report 27 additional fast propagating clones displaying 24 different peptides and carrying 14 unique mutations. Most of these mutations are found either in or upstream of the gene II Shine-Dalgarno sequence, but still within the mRNA transcript of gene II. All 27 clones propagate at significantly higher rates than normal library phage, most within experimental error of wild-type M13 propagation, suggesting that mutations arise to compensate for the reduced virulence caused by the insertion of a lacZalpha cassette proximal to the replication origin of the phage used to construct the library. We also describe an efficient and convenient assay to diagnose propagation-related TUPS among peptide sequences selected by phage display. PMID- 24952359 TI - Systematic review and meta-analysis of psychological interventions to promote treatment adherence in children, adolescents, and young adults with chronic illness. AB - OBJECTIVE: This meta-analysis examined the effectiveness of recent adherence promoting interventions for youth with chronic health conditions. METHODS: Peer reviewed randomized controlled trials of adherence-promoting interventions for youth with a chronic illness published between 2007 and 2013 (n = 23) were reviewed. Intervention delivery (in-person vs. technology-based) and outcome measurement (e.g., self-report) were examined as potential moderators of treatment effects. RESULTS: Mean effect sizes were small at posttreatment (d = 0.20, 95% confidence interval (CI): 0.08, 0.31, n = 23) and follow-up (d = 0.29, 95% CI: 0.15, 0.43, n = 9). Intervention delivery and outcome measurement did not account for variation in treatment effects (p > .05). CONCLUSIONS: The small treatment effects of recent adherence-promoting intervention (APIs) reflect the methodological limitations of the included studies and the need to reexamine the delivery and mechanisms of adherence-promoting interventions. PMID- 24952361 TI - Systemic hemin therapy attenuates blood-brain barrier disruption after intracerebral hemorrhage. AB - Injury to the blood-brain barrier (BBB) is a key feature of intracerebral hemorrhage (ICH) and may contribute to perihematomal cell injury. Pretreatment with the heme oxygenase (HO)-1 inducer hemin improves barrier function and neurological outcome in experimental models of traumatic and ischemic CNS injury. Since hemin is already in clinical use to treat acute porphyrias, this translational study was designed to test its effect on BBB function when initiated after ICH in two mouse models. At a dose similar to those used in most preconditioning studies (26mg/kg i.p.), post-hemorrhage treatment with hemin reduced parenchymal extravasation of Evans blue by about three-quarters in both the blood injection and collagenase ICH models. Similar efficacy was observed when treatment was begun at 1 or 3h. At the lower dose that is currently in clinical use (4mg/kg beginning at 3h), hemin also improved barrier function in both models, as assessed by both Evans blue and FITC-dextran leakage; however, it was somewhat less potent, reducing Evans blue leakage by about half. This dose was nevertheless sufficient to attenuate striatal cell loss and accelerate neurological recovery. Consistent with prior observations, striatal HO-1 expression was increased by hemin, and was localized to perivascular cells. These results suggest that hemin may be an effective therapy for ICH with a clinically relevant time window. Further study of the repurposing of this old drug seems warranted. PMID- 24952362 TI - The prostaglandin EP1 receptor potentiates kainate receptor activation via a protein kinase C pathway and exacerbates status epilepticus. AB - Prostaglandin E2 (PGE2) regulates membrane excitability, synaptic transmission, plasticity, and neuronal survival. The consequences of PGE2 release following seizures has been the subject of much study. Here we demonstrate that the prostaglandin E2 receptor 1 (EP1, or Ptger1) modulates native kainate receptors, a family of ionotropic glutamate receptors widely expressed throughout the central nervous system. Global ablation of the EP1 gene in mice (EP1-KO) had no effect on seizure threshold after kainate injection but reduced the likelihood to enter status epilepticus. EP1-KO mice that did experience typical status epilepticus had reduced hippocampal neurodegeneration and a blunted inflammatory response. Further studies with native prostanoid and kainate receptors in cultured cortical neurons, as well as with recombinant prostanoid and kainate receptors expressed in Xenopus oocytes, demonstrated that EP1 receptor activation potentiates heteromeric but not homomeric kainate receptors via a second messenger cascade involving phospholipase C, calcium and protein kinase C. Three critical GluK5 C-terminal serines underlie the potentiation of the GluK2/GluK5 receptor by EP1 activation. Taken together, these results indicate that EP1 receptor activation during seizures, through a protein kinase C pathway, increases the probability of kainic acid induced status epilepticus, and independently promotes hippocampal neurodegeneration and a broad inflammatory response. PMID- 24952364 TI - Development of an ELISA for sPSP94 and utility of the sPSP94/sPSA ratio as a diagnostic indicator to differentiate between benign prostatic hyperplasia and prostate cancer. AB - BACKGROUND: The serum PSA (sPSA) test has low specificity for prostate cancer (PCa), since sPSA also rises in benign prostatic hyperplasia (BPH). Serum PSP94 (sPSP94), a major secreted prostate protein, is indicated as a PCa marker. The potential of sPSP94 and sPSA in conjunction with each other to improve specificity of diagnostic test for PCa needs to be evaluated. METHODS: PCa patients (n=33), BPH patients (n=44) and healthy controls (n=50) were recruited. A serum-based sandwich ELISA was developed to measure sPSP94 concentrations. Utility of sPSP94 in improving specificity of sPSA test was evaluated by studying sPSP94/sPSA ratios of study participants. RESULTS: Considerable decrease in overlap among sPSP94/sPSA ratio values of BPH and PCa patients was observed, as compared to sPSP94 or sPSA alone. For differentiating between BPH and PCa patients, this ratio had a maximum area under the curve (AUC) of 0.859 (P=0.0132) and had a comparable sensitivity (90.91%) to sPSA with an increased specificity of 70.45%. Further, decision curve analysis (DCA) showed that sPSP94/sPSA ratio had a superior net benefit in identifying PCa, in patients opting for biopsy. CONCLUSION: The sPSP94/sPSA ratio can be a better differentiating marker between BPH and PCa, than sPSP94 or sPSA alone. PMID- 24952363 TI - Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3beta signaling. AB - Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability, and Rett's syndrome-like features. Since the physiological functions of CDKL5 still need to be elucidated, in the current study we took advantage of a new Cdkl5 knockout (KO) mouse model in order to shed light on the role of this gene in brain development. We mainly focused on the hippocampal dentate gyrus, a region that largely develops postnatally and plays a key role in learning and memory. Looking at the process of neurogenesis, we found a higher proliferation rate of neural precursors in Cdkl5 KO mice in comparison with wild type mice. However, there was an increase in apoptotic cell death of postmitotic granule neuron precursors, with a reduction in total number of granule cells. Looking at dendritic development, we found that in Cdkl5 KO mice the newly-generated granule cells exhibited a severe dendritic hypotrophy. In parallel, these neurodevelopmental defects were associated with impairment of hippocampus dependent memory. Looking at the mechanisms whereby CDKL5 exerts its functions, we identified a central role of the AKT/GSK-3beta signaling pathway. Overall our findings highlight a critical role of CDKL5 in the fundamental processes of brain development, namely neuronal precursor proliferation, survival and maturation. This evidence lays the basis for a better understanding of the neurological phenotype in patients carrying mutations in the CDKL5 gene. PMID- 24952365 TI - beta-Catenin mutations in recurrent FIGO IA grade I endometrioid endometrial cancers. PMID- 24952366 TI - A phase II trial of a surgical protocol to decrease the incidence of wound complications in obese gynecologic oncology patients. AB - OBJECTIVES: Obese women have a high incidence of wound separation after gynecologic surgery. We explored the effect of a prospective care pathway on the incidence of wound complications. METHODS: Women with a body mass index (BMI) >=30 kg/m(2) undergoing a gynecologic procedure by a gynecologic oncologist via a vertical abdominal incision were eligible. The surgical protocol required: skin and subcutaneous tissues to be incised using a scalpel or cutting electrocautery, fascial closure using #1 polydioxanone suture, placement of a 7 mm Jackson-Pratt drain below Camper's fascia, closure of Camper's fascia with 3-0 plain catgut suture and skin closure with staples. Wound complication was defined as the presence of either a wound infection or any separation. Demographic and perioperative data were analyzed using contingency tables. Univariable and multivariable regression models were used to identify predictors of wound complications. Patients were compared using a multivariable model to a historical group of obese patients to assess the efficacy of the care pathway. RESULTS: 105 women were enrolled with a median BMI of 38.1. Overall, 39 (37%) had a wound complication. Women with a BMI of 30-39.9 kg/m(2) had a significantly lower risk of wound complication as compared to those with a BMI >40 kg/m(2) (23% vs 59%, p<0.001). After controlling for factors associated with wound complications the prospective care pathway was associated with a significantly decreased wound complication rate in women with BMI <40 kg/m(2) (OR 0.40, 95% C.I.: 0.18-0.89). CONCLUSION: This surgical protocol leads to a decreased rate of wound complications among women with a BMI of 30-39.9 kg/m(2). PMID- 24952367 TI - Intraperitoneal chemotherapy among women in the Medicare population with epithelial ovarian cancer. AB - BACKGROUND: Intraperitoneal combined with intravenous chemotherapy (IV/IP) for primary treatment of epithelial ovarian cancer results in a substantial survival advantage for women who are optimally debulked surgically, compared with standard IV only therapy (IV). Little is known about the use of this therapy in the Medicare population. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify 4665 women aged 66 and older with epithelial ovarian cancer diagnosed between 2005-2009, with their Medicare claims. We defined receipt of any IV/IP chemotherapy when there was claims evidence of any receipt of such treatment within 12 months of the date of diagnosis. We used descriptive statistics to examine factors associated with treatment and health services use. RESULTS: Among 3561 women with Stage III or IV epithelial ovarian cancer who received any chemotherapy, only 124 (3.5%) received IV/IP chemotherapy. The use of IV/IP chemotherapy did not increase over the period of the study. In this cohort, younger women, those with fewer comorbidities, whites, and those living in Census tracts with higher income were more likely to receive IV/IP chemotherapy. Among women who received any IV/IP chemotherapy, we did not find an increase in acute care services (hospitalizations, emergency department visits, or ICU stays). CONCLUSION: During the period between 2005 and 2009, few women in the Medicare population living within observed SEER areas received IV/IP chemotherapy, and the use of this therapy did not increase. We observed marked racial and sociodemographic differences in access to this therapy. PMID- 24952369 TI - Disulfide-containing parenteral delivery systems and their redox-biological fate. AB - Exploiting the redox-sensitivity of disulfide bonds is an increasingly popular means to trigger drug release at a target location in the body. The bio-reducible linker (containing a disulfide) can be cleaved when the drug delivery system in which it is incorporated passes from the poorly reducing extra-cellular biological environments to the strongly reducing intra-cellular spaces. This phenomenon has been characterized for a variety of drug carriers (e.g. antibody drug conjugates and nucleic acid carriers) and made use of not only for intra cellular drug release, but also to provide a mechanism of biodegradation. However, successful therapeutic application of redox-sensitive drug delivery systems, which are mostly investigated in the treatment of cancer, depends on timely cleavage of the disulfide in the body. As a result, an accurate and detailed understanding of the biological redox stimulus and the properties of the redox-sensitive moiety is of importance. This review introduces a number of currently relevant reducing agents and redox enzymes, and provides an overview of the redox environments a disulfide-containing drug delivery system encounters upon parenteral administration. Furthermore, the current state of knowledge regarding the behavior and responsiveness of disulfides in these redox-biological compartments is discussed. PMID- 24952370 TI - Experimental functional analysis of severe skin-picking behavior in Prader-Willi syndrome. AB - Skin picking is an extremely distressing and treatment resistant behavior commonly shown by individuals with Prader-Willi syndrome (PWS). However, with the exception of a limited number of published single-case and survey studies, little is known about the environmental determinants of skin picking in this population. In this study, functional analyses were conducted with thirteen individuals with PWS, aged 6-23 years, who engaged in severe skin-picking behavior. In addition to the conditions typically employed in a functional analysis (i.e., alone, attention, play, demand), we included an ignore condition to examine potential effects of stimulus control by the presence of an adult. Twelve participants engaged in skin picking during the functional analysis, with the highest levels occurring in the alone and ignore conditions for eight participants, suggesting that skin picking in these participants was maintained by automatic reinforcement. For the remaining four participants, an undifferentiated pattern of low-rate skin picking was observed across conditions. These data confirm previous studies indicating that skin picking in PWS may be maintained most often by automatically produced sensory consequences. There were no associations between demographic characteristics of the participants (e.g., sex, age, IQ or BMI) and levels of skin picking observed in the functional analysis. Additional investigations are needed to identify the nature of the sensory consequences produced during episodes of skin picking in PWS. Behavioral interventions designed to extinguish or compete with the potential sensory consequences arising from skin picking in PWS are also warranted. PMID- 24952368 TI - Conjugation of pH-responsive nanoparticles to neural stem cells improves intratumoral therapy. AB - Intratumoral drug delivery is an inherently appealing approach for concentrating toxic chemotherapies at the site of action. This mode of administration is currently used in a number of clinical treatments such as neoadjuvant, adjuvant, and even standalone therapies when radiation and surgery are not possible. However, even when injected locally, it is difficult to achieve efficient distribution of chemotherapeutics throughout the tumor. This is primarily attributed to the high interstitial pressure which results in gradients that drive fluid away from the tumor center. The stiff extracellular matrix also limits drug penetration throughout the tumor. We have previously shown that neural stem cells can penetrate tumor interstitium, actively migrating even to hypoxic tumor cores. When used to deliver therapeutics, these migratory neural stem cells result in dramatically enhanced tumor coverage relative to conventional delivery approaches. We recently showed that neural stem cells maintain their tumor tropic properties when surface-conjugated to nanoparticles. Here we demonstrate that this hybrid delivery system can be used to improve the efficacy of docetaxel-loaded nanoparticles when administered intratumorally. This was achieved by conjugating drug-loaded nanoparticles to the surface of neural stem cells using a bond that allows the stem cells to efficiently distribute nanoparticles throughout the tumor before releasing the drug for uptake by tumor cells. The modular nature of this system suggests that it could be used to improve the efficacy of many chemotherapy drugs after intratumoral administration. PMID- 24952372 TI - Medical students' attitudes towards people with intellectual disabilities: a literature review. AB - The present paper provides a review of research on medical students' attitudes to people with intellectual disabilities. The attitudes of medical students warrant empirical attention because their future work may determine people with intellectual disabilities' access to healthcare and exposure to health inequalities. An electronic search of Embase, Ovid MEDLINE(R), PsycINFO, Scopus, and Web of Science was completed to identify papers published up to August 2013. Twenty-four studies were identified, most of which evaluated the effects of pedagogical interventions on students' attitudes. Results suggested that medical students' attitudes to people with intellectual disabilities were responsive to interventions. However, the evidence is restricted due to research limitations, including poor measurement, self-selection bias, and the absence of control groups when evaluating interventions. Thus, there is a dearth of high-quality research on this topic, and past findings should be interpreted with caution. Future research directions are provided. PMID- 24952371 TI - Characteristics of international websites with information on developmental disabilities. AB - The Internet often serves as a primary resource for individuals seeking health related information, and a large and growing number of websites contain information related to developmental disabilities. This paper presents the results of an international evaluation of the characteristics and content of the top 10 ranked results (i.e., not including sponsored results - pay-per-click) returned when one of five terms related to developmental disabilities (i.e., ADHD, autism, down syndrome, learning disability, intellectual disability) was entered into one of six country specific Google online search engines (i.e., Australia (https://www.google.com.au), Canada (https://www.google.ca), Ireland (https://www.google.ie), New Zealand (https://www.google.co.nz), the United Kingdom (https://www.google.co.uk), and the United States (https://www.google.com)) on October 22, 2013. Collectively, we found that international consumers of websites related to developmental disabilities will encounter different websites with differing content and terminology, and should be critical consumers to ensure they locate the information they are seeking. PMID- 24952373 TI - Caregiver's concerns-quality of life scale (CC-QoLS): development and evaluation of psychometric properties. AB - We have developed a Caregiver's Concerns-Quality of Life Scale (CC-QoLS) for adults with intellectual disabilities (ID) who exhibit aggressive behaviour. The CC-QoLS is a brief (8 items in each subscale, CC and QoL respectively) proxy measure completed by caregivers. This is a specific health related quality of life instrument (HRQoL) combined with measures of caregiver's concerns for use as an outcome measure to assess clinical and cost effectiveness of interventions for aggression in adults with ID. The CC-QoLS was found to have good face validity and very good test-retest reliability with an ICC of 0.81 for CC (range 0.46-0.83 across items) and 0.80 for QoL (range 0.65-0.81 across items). Similarly, the scale had good inter-rater reliability with an ICC of 0.67 for CC (range 0.31 0.63 across items) and 0.63 for QoL (range 0.31-0.65 across items). Internal consistency for each subscale was also good (Cronbach's alpha was 0.85 for CC and 0.80 for QoL; Split-half Spearman-Brown was 0.81 for CC and 0.70 for QoL). Furthermore, the scale showed good concurrent validity with measures of severity of aggressive behaviour, namely Modified Overt Aggression Scale (MOAS) (CC: r=0.4; p<=0.01 and QoL: r=-0.2; p<=0.05) and Aberrant Behavior Checklist Irritability subscale (ABC-I) (CC: r=0.5; p<=0.01 and QoL: r=-0.02; p<=0.05) as well as Caregiver's Uplift and Burden Scale score (<0.05). We believe that the CC QoLS is a user friendly, easy to complete, first-ever HRQoL measure for adults with ID and aggressive behaviour with very good psychometric properties. PMID- 24952374 TI - Dynamics of uptake and elimination of pyrethroid insecticides in zebrafish (Danio rerio) eleutheroembryos. AB - Synthetic pyrethroids (SPs) are among the most heavily used insecticides for residential and agricultural applications. Their residues have frequently been detected in aquatic ecosystems. Despite their high aquatic toxicity, their toxicokinetics are still unclear. In this study, the kinetics of uptake and depuration of three SPs, permethrin (PM), bifenthrin (BF) and lambda-cyhalothrin (lambda-CH), were determined for the first time using zebrafish eleutheroembryo assays. The diastereoisomer selectivity of PM in eleutheroembryos was further examined. The results indicated that three SPs were quickly taken up by eleutheroembryos. The bioaccumulation factors of the SPs ranged from 125.4 to 708.4. The depuration of SPs in zebrafish eleutheroembryos followed the first order process. The elimination rate constants (k2) of SPs in eleutheroembryos ranged from 0.018 h(-1) to 0.0533 h(-1). The half-lives (t1/2) were in the range 13.0-38.5h. The diastereoisomer fraction (DF) values for PM in the eleutheroembryos estimated at different uptake and depuration times were all significantly greater than the original value (DF=0.43), indicating selective enrichment and elimination of cis-PM relative to trans-PM. These results reveal a high capacity for SP bioconcentration by zebrafish eleutheroembryos, suggesting that SPs possess a highly cumulative risk to fish. PMID- 24952375 TI - CD45RA-Foxp3(low) non-regulatory T cells in the CCR7-CD45RA-CD27+CD28+ effector memory subset are increased in synovial fluid from patients with rheumatoid arthritis. AB - Increased numbers of regulatory T (Treg) cells are found in synovial fluid from patients with rheumatoid arthritis (RASF) compared with peripheral blood. However, Treg cells in RASF have been shown to have a decreased capacity to suppress T cells. Here we phenotypically classified CD4+ T cells in RASF into six subsets based on the expression of CD45RA, CCR7, CD27 and CD28, and demonstrated that the CCR7-CD45RA-CD27+CD28+ TEM subset was significantly increased in synovial fluid compared with peripheral blood. In addition, the proportion of Foxp3+ Treg cells in the CCR7-CD45RA-CD27+CD28+ TEM subset was significantly increased in RASF. Furthermore, most of the Foxp3+ Treg cells in RASF were non suppressive CD45RA-Foxp3(low) non-Treg cells, and the frequency of the non-Treg cells in the CCR7-CD45RA-CD27+CD28+ TEM subset was significantly increased in RASF. Our findings suggest that the pro-inflammatory environment in RA joints may induce the increase of CD45RA-Foxp3(low) non-Treg cells in synovial fluid. PMID- 24952376 TI - 4,5-Di-substituted benzyl-imidazol-2-substituted amines as the structure template for the design and synthesis of reversal agents against P-gp-mediated multidrug resistance breast cancer cells. AB - Over-expression of P-glycoprotein (P-gp), a primary multidrug transporter which is located in plasma membranes, plays a major role in the multidrug resistance (MDR) of cytotoxic chemotherapy. Naamidines are a class of marine imidazole alkaloids isolated from Leucetta and Clathrina sponges, possessing a Y-shaped scaffold. Based on the results previously obtained from the third-generation MDR modulator ONT-093 and other modulators developed in our group, we designed and synthesized a series of novel 4,5-di-substituted benzyl-1-methyl-1H-imidazol-2 substituted amines using the Naamidine scaffold as the structure template. Subsequently, their reversing activity for Taxol resistance has been evaluated in P-gp-mediated multidrug resistance breast cancer cell line MDA435/LCC6MDR. Compounds 12c with a Y-shaped scaffold, and compound 17c which is 'X-shaped' scaffold and possesses a 4-diethylamino group at aryl ring B, turned out to be the most potent P-gp modulators. It appears that compounds 12c and 17c at 1 MUM concentration can sensitize LCC6MDR cells toward Taxol by 26.4 and 24.5 folds, with an EC50 212.5 and 210.5 nM, respectively. These two compounds are about 5-6 folds more potent than verapamil (RF = 4.5). Moreover, compounds 12c and 17c did not exhibit obvious cytotoxicity in either cancer cell lines or normal mouse fibroblast cell lines. This study has demonstrated that the synthetic Naamidine analogues can be potentially employed as effective, safe modulators for the P-gp mediated drug resistance cancer cells. PMID- 24952377 TI - A novel 2-oxoindolinylidene inhibitor of bacterial MurD ligase: Enzyme kinetics, protein-inhibitor binding by NMR and a molecular dynamics study. AB - N-(5-(5-nitro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)4-oxo-2-thioxo-1,3-thiazolidin 3-yl)nicotinamide, a 2-oxoindolinylidene derivative with novel structure scaffold, was evaluated for inhibition potency against the MurD enzyme from Escherichia coli using an enzyme steady-state kinetics study. The compound exerted competitive inhibition with respect to UMA, a MurD substrate, and affected bacterial growth. Furthermore, we isolated and purified (13)C selectively labeled MurD enzyme from E. coli and evaluated the binding interactions of the new compound using the (1)H/(13)C-HSQC 2D NMR method. Molecular dynamics calculations showed stable structure for the MurD-inhibitor complex. The binding mode of novel inhibitor was determined and compared to naphthalene-N-sulfonamide-d-Glu derivatives, transition state mimicking inhibitors, UMA and AMP-PCP, an ATP analog. It binds to the UDP/MurNAc binding region. In contrast to transition state mimicking inhibitors, it does not interact with the enzyme's C-terminal domain, which can be beneficial for ligand binding. A pharmacophore pattern was established for the design of novel drugs having a propensity to inhibit a broad spectrum of Mur enzymes. PMID- 24952378 TI - Clinical perspectives on colorectal cancer screening at Latino-serving federally qualified health centers. AB - PURPOSE: Colorectal cancer is the second most common cause of cancer death in the United States, and rates of screening for colorectal cancer are low. We sought to gather the perceptions of clinic personnel at Latino-serving Federally Qualified Health Centers (operating 17 clinics) about barriers to utilization of screening services for colorectal cancer. METHOD: We conducted one-on-one interviews among 17 clinic personnel at four Latino-serving Federally Qualified Health Center networks in Oregon. All interviews were recorded, transcribed, and coded, and themes were grouped by influences at three levels: the patient, the organization, and the external environment. RESULTS: Estimated proportions of eligible patients who are underscreened for colorectal cancer ranged from 20% to 70%. Underscreening was thought to occur among low-income, underinsured, and undocumented patients and patients having multiple health concerns. Limited funding to pay for follow-up testing in patients with positive screens was cited as the key factor contributing to underscreening. CONCLUSIONS: We identified health care provider perceptions about the underutilization of screening services for colorectal cancer; our findings may inform future efforts to promote guideline-appropriate cancer screening. PMID- 24952379 TI - Adherence of human oral keratinocytes and gingival fibroblasts to nano-structured titanium surfaces. AB - BACKGROUND: A key element for long-term success of dental implants is integration of the implant surface with the surrounding host tissues. Modification of titanium implant surfaces can enhance osteoblast activity but their effects on soft-tissue cells are unclear. Adherence of human keratinocytes and gingival fibroblasts to control commercially pure titanium (CpTi) and two surfaces prepared by anodic oxidation was therefore investigated. Since implant abutments are exposed to a bacteria-rich environment in vivo, the effect of oral bacteria on keratinocyte adhesion was also evaluated. METHODS: The surfaces were characterized using scanning electron microscopy (SEM). The number of adhered cells and binding strength, as well as vitality of fibroblasts and keratinocytes were evaluated using confocal scanning laser microscopy after staining with Live/Dead Baclight. To evaluate the effect of bacteria on adherence and vitality, keratinocytes were co-cultured with a four-species streptococcal consortium. RESULTS: SEM analysis showed the two anodically oxidized surfaces to be nano structured with differing degrees of pore-density. Over 24 hours, both fibroblasts and keratinocytes adhered well to the nano-structured surfaces, although to a somewhat lesser degree than to CpTi (range 42-89% of the levels on CpTi). The strength of keratinocyte adhesion was greater than that of the fibroblasts but no differences in adhesion strength could be observed between the two nano-structured surfaces and the CpTi. The consortium of commensal streptococci markedly reduced keratinocyte adherence on all the surfaces as well as compromising membrane integrity of the adhered cells. CONCLUSION: Both the vitality and level of adherence of soft-tissue cells to the nano-structured surfaces was similar to that on CpTi. Co-culture with streptococci reduced the number of keratinocytes on all the surfaces to approximately the same level and caused cell damage, suggesting that commensal bacteria could affect adherence of soft-tissue cells to abutment surfaces in vivo. PMID- 24952380 TI - Sexual risk behavior among people living with HIV and AIDS on antiretroviral therapy at the regional hospital of Sokode, Togo. AB - BACKGROUND: Several studies on the sexual risk behaviors in sub-Saharan Africa have reported that the initiation of antiretroviral therapy leads to safer sexual behaviors. There is however a persistence of risky sexual behavior which is evidenced by a high prevalence of sexually transmitted infections among people living with HIV and AIDS (PLWHA). We sought to determine the factors associated with risky sex among PLWHA on antiretroviral therapy in Togo. METHODS: An analytical cross-sectional survey was conducted from May to July 2013 at regional hospital of Sokode, Togo, and targeted 291 PLWHA on antiretroviral therapy for at least three months. RESULTS: From May to July 2013, 291 PLWHA on antiretroviral treatment were surveyed. The mean age of PLWHA was 37.3 years and the sex ratio (male/female) was 0.4. Overall, 217 (74.6%) PLWHA were sexually active since initiation of antiretroviral treatment, of which, 74 (34.6%) had risky sexual relations. In multivariate analysis, the factors associated with risky sex were: the duration of antiretroviral treatment (1 to 3 years: aOR = 27.08; p = 0.003; more than 3 years: aOR = 10.87; p = 0.028), adherence of antiretroviral therapy (aOR = 2.56; p = 0.014), alcohol consumption before sex (aOR = 3.59; p = 0.013) and level of education (primary school: aOR = 0.34 p = 0.011; secondary school: aOR = 0.23 p = 0.003; high school: aOR = 0.10; p = 0.006). CONCLUSION: There was a high prevalence of unsafe sex among PLWHA receiving ART at the hospital of Sokode. Factors associated with sexual risk behaviors were: low education level, non-adherence to ART, alcohol consumption before sex and the duration of ART. It is important to strengthen the implementation of secondary prevention strategies among this population group. PMID- 24952382 TI - Nonalcoholic steatohepatitis is associated with an atherogenic lipoprotein subfraction profile. AB - BACKGROUND: Nonalcoholic steatohepatitis (NASH) carries an increased risk of cardiovascular disease (CVD) relative to the general population. We sought to evaluate whether differences in lipoprotein subfractions in obese patients with and without NASH contributes to this difference in CVD risk. FINDINGS: Ion mobility analysis was performed on 78 individuals with obesity undergoing weight loss surgery. All individuals had standard of care liver biopsies performed during surgery. Patients with NASH had significantly smaller peak LDL diameter (P = 0.02, 219.0 A vs. 222.6 A), and levels of IDL2 (P = 0.01, 104. nmol/L vs. 133.4 nmol/L) and HDL2b (P = 0.05, 676.7 nmol/L vs. 880.1 nmol/L) compared to those without NASH. NASH patients had significantly higher LDL-IVb levels than those without NASH (P = 0.02, 49.0 nmol/L vs. 37.1 nmol/L).The inverse association of LDL peak diameter with NASH remained significant after adjustment for diabetes (P = 0.02). HDL2b levels were inversely correlated with hepatocyte ballooning and NASH and these remained significant after adjustment for diabetes (P = 0.0017 and P = 0.007, respectively). IDL2 levels were inversely correlated with NASH, hepatocyte ballooning and fibrosis stage but these were not significant after adjustment for diabetes. CONCLUSIONS: The lipoprotein subfraction profile in subjects with NASH is characterized by small peak LDL diameter, reduced HDL2b levels and elevated LDL-IVb levels. These changes may contribute to the increased CVD seen in patients with NASH. PMID- 24952381 TI - RNA-Seq analysis reveals that multiple phytohormone biosynthesis and signal transduction pathways are reprogrammed in curled-cotyledons mutant of soybean [Glycine max (L.) Merr]. AB - BACKGROUND: Soybean is one of the most economically important crops in the world. The cotyledon is the nutrient storage area in seeds, and it is critical for seed quality and yield. Cotyledon mutants are important for the genetic dissection of embryo patterning and seed development. However, the molecular mechanisms underlying soybean cotyledon development are largely unexplored. RESULTS: In this study, we characterised a soybean curled-cotyledon (cco) mutant. Compared with wild-type (WT), anatomical analysis revealed that the cco cotyledons at the torpedo stage became more slender and grew outward. The entire embryos of cco mutant resembled the "tail of swallow". In addition, cco seeds displayed reduced germination rate and gibberellic acid (GA3) level, whereas the abscisic acid (ABA) and auxin (IAA) levels were increased. RNA-seq identified 1,093 differentially expressed genes (DEGs) between WT and the cco mutant. The KEGG pathway analysis showed many DEGs were mapped to the hormone biosynthesis and signal transduction pathways. Consistent with assays of hormones in seeds, the results of RNA-seq indicated auxin and ABA biosynthesis and signal transduction in cco were more active than in WT, while an early step in GA biosynthesis was blocked, as well as conversion rate of inactive GAs to bioactive GAs in GA signaling. Furthermore, genes participated in other hormone biosynthesis and signalling pathways such as cytokinin (CK), ethylene (ET), brassinosteroid (BR), and jasmonate acid (JA) were also affected in the cco mutant. CONCLUSIONS: Our data suggest that multiple phytohormone biosynthesis and signal transduction pathways are reprogrammed in cco, and changes in these pathways may partially contribute to the cco mutant phenotype, suggesting the involvement of multiple hormones in the coordination of soybean cotyledon development. PMID- 24952383 TI - Moyamoya syndrome and neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is the most prevalent autosomal dominant genetic disorder among humans. NF1 vasculopathy is a significant but underrecognized complication of the disease, affecting both arterial and venous blood vessels of all sizes. Moyamoya syndrome is a cerebral vasculopathy that is only rarely observed in association with NF1, particularly in the pediatric age range. Herein, we report of a 5-year-old female with NF1 and moyamoya syndrome and we briefly review the existing literature. PMID- 24952385 TI - ShrimpGPAT: a gene and protein annotation tool for knowledge sharing and gene discovery in shrimp. AB - BACKGROUND: Although captured and cultivated marine shrimp constitute highly important seafood in terms of both economic value and production quantity, biologists have little knowledge of the shrimp genome and this partly hinders their ability to improve shrimp aquaculture. To help improve this situation, the Shrimp Gene and Protein Annotation Tool (ShrimpGPAT) was conceived as a community based annotation platform for the acquisition and updating of full-length complementary DNAs (cDNAs), Expressed Sequence Tags (ESTs), transcript contigs and protein sequences of penaeid shrimp and their decapod relatives and for in silico functional annotation and sequence analysis. DESCRIPTION: ShrimpGPAT currently holds quality-filtered, molecular sequences of 14 decapod species (~500,000 records for six penaeid shrimp and eight other decapods). The database predominantly comprises transcript sequences derived by both traditional EST Sanger sequencing and more recently by massive-parallel sequencing technologies. The analysis pipeline provides putative functions in terms of sequence homologs, gene ontologies and protein-protein interactions. Data retrieval can be conducted easily either by a keyword text search or by a sequence query via BLAST, and users can save records of interest for later investigation using tools such as multiple sequence alignment and BLAST searches against pre-defined databases. In addition, ShrimpGPAT provides space for community insights by allowing functional annotation with tags and comments on sequences. Community-contributed information will allow for continuous database enrichment, for improvement of functions and for other aspects of sequence analysis. CONCLUSIONS: ShrimpGPAT is a new, free and easily accessed service for the shrimp research community that provides a comprehensive and up-to-date database of quality-filtered decapod gene and protein sequences together with putative functional prediction and sequence analysis tools. An important feature is its community-based functional annotation capability that allows the research community to contribute knowledge and insights about the properties of molecular sequences for better, shared, functional characterization of shrimp genes. Regularly updated and expanded with data on more decapods, ShrimpGPAT is publicly available at http://shrimpgpat.sc.mahidol.ac.th/. PMID- 24952386 TI - Creation of a reference dataset of neck sizes in children: standardizing a potential new tool for prediction of obesity-associated diseases? AB - BACKGROUND: Neck circumference (NC), is an emerging marker of obesity and associated disease risk, but is challenging to use as a screening tool in children, as age and sex standardized cutoffs have not been determined. A population-based sample of NC in Canadian children was collected, and age- and sex-specific reference curves for NC were developed. METHODS: NC, waist circumference (WC), weight and height were measured on participants aged 6-17 years in cycle 2 of the Canadian Health Measures Survey. Quantile regression of NC versus age in males and females was used to obtain NC percentiles. Linear regression was used to examine association between NC, body mass index (BMI) and WC. NC was compared in healthy weight (BMI < 85th percentile) and overweight/obese (BMI > 85th percentile) subjects. RESULTS: The sample included 936 females and 977 males. For all age and sex groups, NC was larger in overweight/obese children (p < 0.0001). For each additional unit of BMI, average NC in males was 0.49 cm higher and in females, 0.43 cm higher. For each additional cm of WC, average NC in males was 0.18 cm higher and in females, 0.17 cm higher. CONCLUSION: This study presents the first reference data on Canadian children's NC. The reference curves may have future clinical applicability in identifying children at risk of central obesity-associated conditions and thresholds associated with disease risk. PMID- 24952384 TI - Glimepiride reduces CD14 expression and cytokine secretion from macrophages. AB - BACKGROUND: Activated microglia are associated with deposits of aggregated proteins within the brains of patients with Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases. Since the cytokines secreted from activated microglia are thought to contribute to the pathogenesis of these neurodegenerative diseases, compounds that suppress cytokine production have been identified as potential therapeutic targets. CD14 is a glycosylphosphatidylinositol (GPI)- anchored protein that is part of a receptor complex that mediates microglial responses to peptides that accumulate in prion disease (PrP82-146), AD (amyloid-beta (Abeta)42) and PD (alpha-synuclein (alphaSN)). As some GPI-anchored proteins are released from cells by treatment with glimepiride, a sulphonylurea used for the treatment of diabetes, the effects of glimepiride upon CD14 expression and cytokine production from cultured macrophages were studied. METHODS: RAW 264 cells and microglial cells were treated with glimepiride or phosphatidylinositol (PI)-phospholipase C (PLC) and the expression of cell receptors was analysed by ELISA and immunoblot. Treated cells were subsequently incubated with Abeta42, alphaSN, PrP82-146 or lipopolysaccharide (LPS) and the amounts of Toll-like receptor (TLR)-4, tumour necrosis factor (TNF), interleukin (IL)-1 and IL-6 measured. RESULTS: Glimepiride released CD14 from RAW 264 cells and microglial cells. Pre-treatment with glimepiride significantly reduced TNF, IL-1 and IL-6 secretion from RAW 264 and microglial cells incubated with LPS, Abeta42, alphaSN and PrP82-146. Glimepiride also reduced the LPS, Abeta42, alphaSN and PrP82-146-induced translocation of TLR 4 into membrane rafts that is associated with cell activation. These effects of glimepiride were also seen after digestion of RAW 264 cells with PI-phospholipase C (PLC). In addition, the effects of glimepiride were blocked by pharmacological inhibition of GPI-PLC. The cytokine production was CD14-dependent; it was reduced in microglia from CD14 knockout mice and was blocked by antiserum to CD14. CONCLUSIONS: RAW 264 and microglial cell responses to Abeta1-42, alphaSN, PrP82 146 and LPS are dependent upon CD14 expression. Glimepiride induced the shedding of CD14 from cells by activation of GPI-PLC and consequently reduced cytokine production in response to Abeta42, alphaSN, PrP82-146 and LPS. These results suggest that glimepiride acts as a novel anti-inflammatory agent that could modify the progression of neurodegenerative diseases. PMID- 24952388 TI - Nitric-oxide coated bioactive titanium stents: safer and more effective than second-generation drug-eluting stents? PMID- 24952389 TI - Substrate ablation of post-infarction ventricular tachycardias. PMID- 24952387 TI - Mobile phone text messaging intervention to improve alertness and reduce sleepiness and fatigue during shiftwork among emergency medicine clinicians: study protocol for the SleepTrackTXT pilot randomized controlled trial. AB - BACKGROUND: Mental and physical fatigue while at work is common among emergency medical services (EMS) shift workers. Extended shifts (for example 24 hours) and excessive amounts of overtime work increase the likelihood of negative safety outcomes and pose a challenge for EMS fatigue-risk management. Text message-based interventions are a potentially high-impact, low-cost platform for sleep and fatigue assessment and distributing information to workers at risk of negative safety outcomes related to sleep behaviors and fatigue. METHODS/DESIGN: We will conduct a pilot randomized trial with a convenience sample of adult EMS workers recruited from across the United States using a single study website. Participants will be allocated to one of two possible arms for a 90-day study period. The intervention arm will involve text message assessments of sleepiness, fatigue, and difficulty with concentration at the beginning, during, and end of scheduled shifts. Intervention subjects reporting high levels of sleepiness or fatigue will receive one of four randomly selected intervention messages promoting behavior change during shiftwork. Control subjects will receive assessment only text messages. We aim to determine the performance characteristics of a text messaging tool for the delivery of a sleep and fatigue intervention. We seek to determine if a text messaging program with tailored intervention messages is effective at reducing perceived sleepiness and/or fatigue among emergency medicine clinician shift workers. Additional aims include testing whether a theory-based behavioral intervention, delivered by text message, changes 'alertness behaviors'. DISCUSSION: The SleepTrackTXT pilot trial could provide evidence of compliance and effectiveness that would support rapid widespread expansion in one of two forms: 1) a stand-alone program in the form of a tailored/individualized sleep monitoring and fatigue reduction support service for EMS workers; or 2) an add-on to a multi-component fatigue risk management program led and maintained by employers or by safety and risk management services. TRIAL REGISTRATION: Clinicaltrials.gov NCT02063737, Registered on 10 January 2014. PMID- 24952390 TI - What cardiologists should know about copeptin. PMID- 24952391 TI - A randomized study to compare bioactive titanium stents and everolimus-eluting stents in diabetic patients (TITANIC XV): 1-year results. AB - INTRODUCTION AND OBJECTIVES: Up to 25% of patients who undergo a percutaneous coronary intervention show some limitation in the use of drug-eluting stents. The aim of this study was to evaluate if titanium-nitride-oxide-coated stents could be a good alternative to everolimus-eluting stents in diabetic patients. METHODS: A total of 173 diabetic patients with lesions at moderate risk of restenosis (exclusion criteria: diameter < 2.5 mm or length > 28 mm in vessels < 3mm, chronic occlusion) were randomized to a titanium group (83 patients) or an everolimus group (90 patients). RESULTS: Baseline characteristics were well balanced; 28.3% of patients were insulin dependent. At 1 year, the incidence of major adverse cardiac events (death, nonfatal myocardial infarction, stroke, or repeat target vessel revascularization) was significantly higher in the titanium group than in the everolimus group (total, 14.5% vs 4.4%; P = .02; noninsulin dependent subgroup, 9.7% vs 3.2%; P = .14; insulin-dependent subgroup, 28.6% vs 7.1%; P = .04). The incidence of death, nonfatal myocardial infarction, stroke, or any revascularization was 16.9% in the titanium group and 7.8% in the everolimus group (P = .06). Target lesion and vessel revascularizations occurred in 8.4% compared with 3.3% (P = .15) and in 13.3% compared with 3.3% (P = .01) in the titanium and everolimus groups, respectively. Angiographic follow-up at 9 months showed significantly less late lumen loss in the everolimus group (in segment, 0.52 [standard deviation, 0.58) mm vs -0.05 [0.32] mm; in-stent, 0.76 [0.54] mm vs 0.13 [0.31] mm; P < .0001). CONCLUSIONS: The everolimus-eluting stent is superior to the titanium stent for clinical and angiographic end points in diabetic patients with lesions at moderate risk of restenosis. PMID- 24952392 TI - Pooled analysis of two randomized trials comparing titanium-nitride-oxide-coated stent versus drug-eluting stent in STEMI. AB - INTRODUCTION AND OBJECTIVES: We performed a pooled analysis based on patient level data from the TITAX-AMI and BASE-ACS trials to evaluate the outcome of titanium-nitride-oxide-coated bioactive stents vs drug-eluting stents in patients with ST-segment elevation myocardial infarction at 2-year follow-up. METHODS: The TITAX-AMI trial compared bioactive stents with paclitaxel-eluting stents in 425 patients with acute myocardial infarction. The BASE-ACS trial compared bioactive stents with everolimus-eluting stents in 827 patients with acute coronary syndrome. The primary endpoint for the pooled analysis was major adverse cardiac events: a composite of cardiac death, recurrent myocardial infarction, or ischemia-driven target lesion revascularization at 2-year follow-up. RESULTS: The pooled analysis included 501 patients; 245 received bioactive stents, and 256 received drug-eluting stents. The pooled bioactive stent group was associated with a risk ratio of 0.85 for major adverse cardiac events (95% confidence interval, 0.53-1.35; P=.49) compared to the pooled drug-eluting stent group. Similarly, the pooled bioactive stent group was associated with a risk ratio of 0.71 for cardiac death (95% confidence interval, 0.26-1.95; P=.51), 0.44 for recurrent myocardial infarction (95% confidence interval, 0.20-0.97; P=.04), and 1.39 for ischemia-driven target lesion revascularization (95% confidence interval, 0.74-2.59; P=.30), compared to the pooled drug-eluting stent group. These results were confirmed by propensity-score adjusted analysis of the combined datasets. CONCLUSIONS: In patients with ST-segment elevation myocardial infarction, bioactive stents were associated with lower rates of recurrent myocardial infarction compared to drug-eluting stents at 2-year follow-up; yet, the rates of cardiac death and ischemia-driven target lesion revascularization were similar. PMID- 24952393 TI - Demographic and clinical characteristics of patients with stable coronary artery disease: results from the CLARIFY registry in Spain. AB - INTRODUCTION AND OBJECTIVES: Coronary artery disease is associated with high morbidity and mortality. The objective of the CLARIFY registry is to study the treatment of outpatients with coronary artery disease in the setting of daily clinical practice. METHODS: The CLARIFY registry is a prospective registry conducted in 41 countries that included outpatients with stable coronary artery disease attending primary care or specialist units between October 2009 and June 2010. The present study describes the baseline characteristics of the Spanish cohort compared with the western European cohorts included in the registry. RESULTS: A total of 33,248 patients were included: 14,726 in western Europe and 2257 in Spain (selected by 192 cardiologists). The majority of the participants in Spain were men (81%) with a mean age of 65 years. There was a higher frequency of diabetes (34% vs 25%; P<.0001), coronary artery disease family history (19% vs 31%; P<.0001), myocardial infarction (64% vs 60%; P<.0001), and stroke (5% vs 3%; P=.0007) in the Spanish cohort than in the western European cohorts. The most common treatments in the Spanish sample were lipid-lowering drugs (96%), acetylsalicylic acid (89%), and beta-blockers (74%). CONCLUSIONS: Patients in the Spanish cohort are similar to those in the western European cohorts and seem to be representative of the Spanish population with coronary artery disease. Therefore, they form a suitable basis for the study of prognostic factors at 5 year follow-up. PMID- 24952394 TI - Cocaine use disorders and acute myocardial infarction, excess length of hospital stay and overexpenditure. AB - INTRODUCTION AND OBJECTIVES: To investigate the relationship between the prevalence of cocaine use disorders and acute myocardial infarction in patients aged >= 18 years and to estimate the influence of cocaine use disorders on mortality, excess length of stay, and overexpenditure among hospitalized patients with acute myocardial infarction. METHODS: Retrospective study of the minimum basic data set of 87 Spanish hospitals from 2008 to 2010. RESULTS: Among 5 575 325 admissions reviewed, there were 24 126 patients with cocaine use disorders and 79 076 cases of acute myocardial infarction. The incidence of acute myocardial infarction among patients with cocaine use disorders increased with age and reached a peak at 55 years to 64 years (P < .0001). Multivariate analysis showed that cocaine use disorders were more prevalent among patients with acute myocardial infarction independently of age, sex, other addictive disorders, and 30 other comorbidities (odds ratio = 3.0). Among patients with acute myocardial infarction, those with cocaine use disorders did not show an increase of in hospital death, but did show excess length of hospital stay (1.5 days) and overexpenditure (382 euros). CONCLUSIONS: Cocaine use disorders are associated with acute myocardial infarction and increase the length of hospital stay and overexpenditure among acute myocardial infarction patients. Cessation of cocaine use among these patients should be one of the primary therapeutic goals after hospital discharge. PMID- 24952395 TI - The PLAU P141L single nucleotide polymorphism is associated with collateral circulation in patients with coronary artery disease. AB - INTRODUCTION AND OBJECTIVES: Urokinase-type plasminogen activator, which is encoded by the PLAU gene, plays a prominent role during collateral arterial growth. We investigated whether the PLAU P141L (C > T) polymorphism, which causes a mutation in the kringle domain of the protein, is associated with coronary collateral circulation in a cohort of 676 patients with coronary artery disease. METHODS: The polymorphism was genotyped in blood samples using a TaqMan-based genotyping assay, and collateral circulation was assessed by the Rentrop method. Multivariate logistic regression models adjusted by clinically relevant variables to estimate odds ratios were used to examine associations of PLAU P141L allelic variants and genotypes with collateral circulation. RESULTS: Patients with poor collateral circulation (Rentrop 0-1; n = 547) showed a higher frequency of the TT genotype than those with good collateral circulation (Rentrop 2-3; n = 129; P = .020). The T allele variant was also more common in patients with poor collateral circulation (P = .006). The odds ratio of having poorly developed collaterals in patients bearing the T allele (adjusted for clinically relevant variables) was statistically significant under the dominant model (odds ratio = 1.83 [95% confidence interval, 1.16-2.90]; P = .010) and the additive model (odds ratio = 1.73 [95% confidence interval, 1.14-2.62]; P = .009). CONCLUSIONS: An association was found between coronary collateral circulation and the PLAU P141L polymorphism. Patients with the 141L variant are at greater risk of developing poor coronary collateral circulation. PMID- 24952396 TI - Cryoballoon ablation in young patients with lone paroxysmal atrial fibrillation. AB - INTRODUCTION AND OBJECTIVES: Long-term efficacy following cryoballoon ablation of lone paroxysmal atrial fibrillation remains unknown. We describe long-term follow up results of the single cryoballoon ablation procedure. METHODS: Pulmonary vein isolation was performed in 103 patients (72 male; median age 52 years) with symptomatic lone paroxysmal atrial fibrillation. The end-point of this observational cohort study was first electrocardiogram-documented recurrence of arrhythmia (atrial fibrillation, atrial tachycardia, or atrial flutter) during the 5-year follow-up, in the absence of anti-arrhythmic treatment. RESULTS: Acute complete pulmonary vein isolation was achieved in 86% of the patients with a single cryoballoon. The 6-month, 1-year, and 5-year success rate after a single procedure was 94%, 91%, and 77%, respectively. Arrhythmia recurrence was observed in 24 cases at a median of 14.8 months [range, 8.0-16.8 months]. Thirteen symptomatic patients were well controlled on beta-blockers only. Seven symptomatic patients had anti-arrhythmic treatment (class IC in 5 patients; dronedarone in 2 patients) introduced during the blanking period. Two of them had early arrhythmia recurrence within the blanking period only; they were arrhythmia free in further follow-up on dronedarone. The rate of complications was relatively low and included a 4.8% incidence of transient phrenic nerve palsy. CONCLUSIONS: A single cryoballoon ablation procedure for lone paroxysmal atrial fibrillation resulted in high rates of acute, medium-term, and long-term efficacy. The rate of complications is relatively low and includes a 4.8% incidence of transient phrenic nerve palsy. PMID- 24952397 TI - Update: acute coronary syndromes (VI): treatment of acute coronary syndromes in the elderly and in patients with comorbidities. AB - Acute coronary syndromes have a wide spectrum of clinical presentations and risk of adverse outcomes. A distinction should be made between treatable (extent of ischemia, severity of coronary disease and acute hemodynamic deterioration) and untreatable risk (advanced age, prior myocardial damage, chronic kidney dysfunction, other comorbidities). Most of the patients with "untreatable" risk have been excluded from the "guideline-generating" clinical trials. In recent years, despite the paucity of specific randomized trials, major advances have been completed in the management of elderly patients and patients with comorbidities: from therapeutic nihilism to careful titration of antithrombotic agents, a shift toward the radial approach to percutaneous coronary interventions, and also to less-invasive cardiac surgery. Further advances should be expected from the development of drug regimens suitable for use in the elderly and in patients with renal dysfunction, from a systematic multidisciplinary approach to the management of patents with diabetes mellitus and anemia, and from the courage to undertake randomized trials involving these high-risk populations. PMID- 24952398 TI - Fluoroscopic integration of the CT scan during transeptal puncture. PMID- 24952399 TI - Electrocardiographic diagnosis of fasciculoventricular accessory pathway. PMID- 24952400 TI - Tachycardiomyopathy induced by nonreentrant nodal tachycardia. PMID- 24952401 TI - Long-term outcome of cryoballoon ablation of atrial fibrillation in a low-volume center. PMID- 24952402 TI - Prognostic value of the INTERHEART-cholesterol risk score in patients hospitalized for chest pain. PMID- 24952403 TI - Mitral regurgitation after MitraClip: impact of mitral regurgitant orifice morphology evaluated by three-dimensional echocardiography. PMID- 24952404 TI - Safety and efficacy of transcatheter aortic valve implantation in nonagenarian patients. PMID- 24952405 TI - Dynamic prognostic stratification in ST-elevation myocardial infarction. PMID- 24952406 TI - Dynamic prognostic stratification in ST-elevation myocardial infarction. Response. PMID- 24952407 TI - Mutations in oncogenes: context matters. PMID- 24952408 TI - Summary of the 2014 MD Anderson International Meeting in Gynecologic Oncology: emerging therapies in gynecologic cancer. PMID- 24952409 TI - Assessment tools for determining appropriateness of admission to acute care of persons transferred from long-term care facilities: a systematic review. AB - BACKGROUND: Residents of long-term care facilities have a high risk of acute care admission. Estimates of the frequency of inappropriate transfers vary substantially throughout the studies and various assessment tools have been used. The purpose of this study is to systematically review and describe the internationally existing assessment tools used for determining appropriateness of hospital admissions among long-term care residents. METHOD: Systematic review of the literature of two databases (PubMed and CINAHL(r)). The search covered seven languages and the period between January 2000 and December 2012. All quantitative studies were included if any assessment tool for appropriateness of hospital and/or emergency department admission of long-term care residents was used. Two pairs of independent researchers extracted the data. RESULTS: Twenty-nine articles were included, covering study periods between 1991 and 2009. The proportion of admissions considered as inappropriate ranged from 2% to 77%. Throughout the studies, 16 different assessment tools were used; all were based on expert opinion to some extent; six also took into account published literature or interpretation of patient data. Variation between tools depended on the concepts studied, format and application, and aspects evaluated. Overall, the assessment tools covered six aspects: specific medical diagnoses (assessed by n = 8 tools), acuteness/severity of symptoms (n = 7), residents' characteristics prior to admission (n = 6), residents' or families' wishes (n = 3), existence of a care plan (n = 1), and availability or requirement of resources (n = 10). Most tools judged appropriateness based on one fulfilled item; five tools judged appropriateness based on a balance of aspects. Five tools covered only one of these aspects and only six considered four or more aspects. Little information was available on the psychometric properties of the tools. CONCLUSIONS: Most assessment tools are not comprehensive and do not take into account residents' individual aspects, such as characteristics of residents prior to admission and wishes of residents or families. The generalizability of the existing tools is unknown. Further research is needed to develop a tool that is evidence-based, comprehensive and generalizable to different regions or countries in order to assess the appropriateness of hospital admissions among long-term care residents. PMID- 24952410 TI - Topic usage of kaolin-impregnated gauze as a hemostatic in tonsillectomy. AB - BACKGROUND: The main postoperative complications after tonsillectomy are due to bleeding, and effective hemostasis may lead to a reduction of overall postoperative morbidity. This study was undertaken to determine the efficacy and safety of a novel kaolin-based hemostatic dressing in tonsillectomy. METHODS: A pilot, single-blind, open label study was performed in patients aged 3-20 y with history of chronic or hypertrophic tonsillitis. Cold dissection tonsillectomy (CDT) + ligature was performed by the same surgeon. Hemostasis on each tonsillar fossa was achieved using kaolin-impregnated gauze (KG; study group) or standard surgical cotton gauze (CG; control). Time to complete hemostasis, operative time, intraoperative blood loss, pain score, analgesic use, and return to normal diet and activity were recorded for all children. RESULTS: A total of 230 patients with a mean age of 8.0 y (138 in the study group and 92 in the control group) were included in the study. Both operative time and intraoperative blood loss were significantly reduced in the KG group (P < 0.0001) versus the CG group. At 5 min, 84.8% patients using the KG successfully achieved complete hemostasis versus 34.8% in the CG group where standard gauze controlled bleeding only partially. Results show significantly less pain for the KG group at 6- and 12-h postoperative when compared with the CG group (P < 0.0001). Also, the KG group required less analgesic medications, returned to normal diet and normal activities faster than the CG group (P < 0.01). CONCLUSIONS: Preliminary findings show that the KG is effective and safe in managing surgical bleeding after tonsillectomy. In addition to rapid bleeding control, the dressing causes minimal inflammation and pain and allows patients to quickly return to normal activities. This novel dressing is a promising tool for ear, nose and throat surgical hemostasis. PMID- 24952411 TI - Comparison of culture and molecular techniques for microbial community characterization in infected necrotizing pancreatitis. AB - BACKGROUND: Infected necrotizing pancreatitis is associated with significant morbidity and mortality. Peripancreatic fluid cultures may fail to identify all the infecting organisms. The aim of this study was to compare the bacterial biome of peripancreatic fluid from infected necrotizing pancreatitis patients using 16S ribosomal RNA (rRNA) DNA deep sequencing and quantitative polymerase chain reaction (qPCR) targeting the 16S rRNA gene versus standard laboratory culture. MATERIALS AND METHODS: Peripancreatic fluid was collected during operative or radiologic intervention and samples sent for culture. In parallel, microbial DNA was extracted, qPCR targeting the 16S rRNA gene and 16S rRNA PCR amplification followed by Illumina deep sequencing were performed. RESULTS: Using culture techniques, the bacterial strains most frequently identified were gram-negative rods (Escherichia coli, Klebsiella pneumoniae) and Enterococcus. Samples in which culture results were negative had copy numbers of the 16S rRNA gene close to background in qPCR analysis. For samples with high bacterial load, sequencing results were in some cases in good agreement with culture data, whereas in others there were disagreements, likely due to differences in taxonomic classification, cultivability, and differing susceptibility to background contamination. Sequencing results appeared generally unreliable in cases of negative culture where little microbial DNA was input into qPCR sequencing reactions. CONCLUSIONS: Both sequencing and culture data display their own sources of bias and potential error. Consideration of data from multiple techniques will yield a more accurate view of bacterial infections than can be achieved by any single technique. PMID- 24952412 TI - Lidocaine attenuates lipopolysaccharide-induced inflammatory responses in microglia. AB - BACKGROUND: Lidocaine has been used as a local anesthetic with anti-inflammatory properties, but its effects on neuroinflammation have not been well defined. In the present study, we investigated the prophylactic effects of lidocaine on lipopolysaccharide (LPS)-activated microglia and explored the underlying mechanisms. MATERIALS AND METHODS: Microglial cells were incubated with or without 1 MUg/mL LPS in the presence or absence of lidocaine, a p38 mitogen activated protein kinase (p38 MAPK) inhibitor (SB203580), a nuclear factor-kappa B (NF-kappaB) inhibitor (pyrrolidine dithiocarbamate), or small interfering RNA. The protein and expression levels of inflammatory mediators, such as monocyte chemotactic protein 1, nitric oxide, prostaglandin E2, interleukin 1beta, and tumor necrosis factor alpha were measured using enzyme-linked immunosorbent assays and real-time polymerase chain reaction. The effect of lidocaine on NF kappaB and p38 MAPK activation was evaluated using enzyme-linked immunosorbent assays, Western blot analysis, and electrophoretic mobility shift assay. RESULTS: Lidocaine (>=2 MUg/mL) significantly inhibited the release and expression of nitric oxide, monocyte chemotactic protein 1, prostaglandin E2, interleukin 1beta, and tumor necrosis factor alpha in LPS-activated microglia. Treatment with lidocaine also significantly inhibited the phosphorylation of p38 MAPK and the nuclear translocation of NF-kappaB p50/p65, increased the protein levels of inhibitor kappa B-alpha. Furthermore, our study shows that the LPS-induced release of inflammatory mediators was suppressed by SB203580, pyrrolidine dithiocarbamate, and small interfering RNA. CONCLUSIONS: Prophylactic treatment with lidocaine inhibits LPS-induced release of inflammatory mediators from microglia, and these effects may be mediated by blockade of p38 MAPK and NF kappaB signaling pathways. PMID- 24952413 TI - Combined remote ischemic perconditioning and local postconditioning on liver ischemia-reperfusion injury. AB - BACKGROUND: Remote ischemic perconditioning (rPER) is the newest technique described to mitigate ischemia and reperfusion (IR) injury. Local postconditioning (POS) is also an effective technique for this purpose. It is uncertain if adding local POS to rPER provides superior liver protection, so we tested this hypothesis. MATERIALS AND METHODS: Twenty five Wistar rats were assigned into five groups: sham, IR, POS, rPER, and rPER + POS. Animals were subjected to liver ischemia for 60 min. POS consisted of four cycles of 5-min liver perfusion followed by 5-min liver ischemia (40 min total) after the major ischemic period. rPER consisted of four cycles of 5-min hindlimb ischemia followed by 5 min hindlimb perfusion contemporaneously to major liver ischemic period, during its last 40 min. After 2 h, median and left lobes were harvested for malondialdehyde and Trolox equivalent antioxidant capacity (TEAC) measurement, and blood for the measurement of serum transaminases. RESULTS: All tissue conditioning techniques were able to reduce transaminases serum levels, having no differences among them. All tissue conditioning techniques were able to reduce hepatic tissue MDA level; however, only rPER + POS had higher values than SHAM. All tissue conditioning techniques also enhanced TEAC; however, only POS had lower TEAC than SHAM. CONCLUSIONS: rPER appears as the most promising technique to avoid IR injury. This technique reduced oxidative stress of cell membranes and lowered transaminases serum level. There was no additive protection when POS and rPER were held together. PMID- 24952414 TI - Hernia repair in the presence of ascites. AB - BACKGROUND: The model for end-stage liver disease (MELD) has been validated as a prediction tool for postoperative mortality, but its role in predicting morbidity has not been well studied. We sought to determine the role of MELD, among other factors, in predicting morbidity and mortality in patients with nonmalignant ascites undergoing hernia repair. METHODS: All patients undergoing hernia repair in the American College of Surgeons National Surgical Quality Improvement database (2009-11) were identified. Those with nonmalignant ascites were compared with patients without ascites. A subset analysis of patients with nonmalignant ascites was performed to evaluate the association between MELD and morbidity and mortality with adjustment for potential confounders. The association of significant factors with the rate of morbidity was displayed using a best-fit polynomial regression. RESULTS: Of 138,366 hernia repairs, 778 (0.56%) were performed on patients with nonmalignant ascites. Thirty-day morbidity (4% versus 19%) and mortality (0.2% versus 5.3%) were significantly more frequent in patients with ascites (P < 0.001). In univariate analysis of the 636 patients with a calculable MELD, MELD was associated with both morbidity and mortality (P < 0.001 each). In multivariate analysis, MELD remained significantly associated with morbidity (odds ratio [OR] = 1.11). Ventral hernia repair (OR = 2.9), dependent functional status (OR = 2.3), alcohol use (OR = 2.3), emergent operation (OR = 2.0) white blood count (OR = 1.1), and age (OR = 1.02) were also significantly associated with morbidity (P < 0.05). CONCLUSIONS: Before hernia repair, the MELD score can be used to risk-stratify patients with nonmalignant ascites not only for mortality but also morbidity. Morbidity rates increase rapidly with MELD above 15, but other factors should additionally be accounted for when counseling patients on their perioperative risk. PMID- 24952417 TI - Coming soon to an app near you. PMID- 24952415 TI - Antibody levels to tetanus, diphtheria, measles and varicella in patients with primary immunodeficiency undergoing intravenous immunoglobulin therapy: a prospective study. AB - BACKGROUND: Patients with antibody deficiencies depend on the presence of a variety of antibody specificities in intravenous immunoglobulin (IVIG) to ensure continued protection against pathogens. Few studies have examined levels of antibodies to specific pathogens in IVIG preparations and little is known about the specific antibody levels in patients under regular IVIG treatment. The current study determined the range of antibodies to tetanus, diphtheria, measles and varicella in IVIG products and the levels of these antibodies in patients undergoing IVIG treatment. METHODS: We selected 21 patients with primary antibody deficiencies who were receiving regular therapy with IVIG. Over a period of one year, we collected four blood samples from each patient (every 3 months), immediately before immunoglobulin infusion. We also collected samples from the IVIG preparation the patients received the month prior to blood collection. Antibody levels to tetanus, diphtheria, measles and varicella virus were measured in plasma and IVIG samples. Total IgG levels were determined in plasma samples. RESULTS: Antibody levels to tetanus, diphtheria, varicella virus and measles showed considerable variation in different IVIG lots, but they were similar when compared between commercial preparations. All patients presented with protective levels of antibodies specific for tetanus, measles and varicella. Some patients had suboptimal diphtheria antibody levels. There was a significant correlation between serum and IVIG antibodies to all pathogens, except tetanus. There was a significant correlation between diphtheria and varicella antibodies with total IgG levels, but there was no significant correlation with antibodies to tetanus or measles. CONCLUSIONS: The study confirmed the variation in specific antibody levels between batches of the same brand of IVIG. Apart from the most common infections to which these patients are susceptible, health care providers must be aware of other vaccine preventable diseases, which still exist globally. PMID- 24952416 TI - The Src homology-2 protein Shb modulates focal adhesion kinase signaling in a BCR ABL myeloproliferative disorder causing accelerated progression of disease. AB - BACKGROUND: The Src homology-2 domain protein B (Shb) is an adapter protein operating downstream of several tyrosine kinase receptors and consequently Shb regulates various cellular responses. Absence of Shb was recently shown to reduce hematopoietic stem cell proliferation through activation of focal adhesion kinase (FAK) and thus we sought to investigate Shb's role in the progression of leukemia. METHODS: Wild type and Shb knockout bone marrow cells were transformed with a retroviral BCR-ABL construct and subsequently transplanted to wild type or Shb knockout recipients. Disease latency, bone marrow and peripheral blood cell characteristics, cytokine expression, signaling characteristics and colony formation were determined by flow cytometry, qPCR, western blotting and methylcellulose colony forming assays. RESULTS: It was observed that Shb knockout BCR-ABL-transformed bone marrow cells produced a disease with death occurring at earlier time points compared with corresponding wild type controls due to elevated proliferation of transformed bone marrow cells. Moreover, significantly elevated interleukin-6 and granulocyte colony-stimulation factor mRNA levels were observed in Shb knockout c-Kit + leukemic bone marrow cells providing a plausible explanation for the concurrent peripheral blood neutrophilia. Shb knockout leukemic bone marrow cells also showed increased ability to form colonies in methylcellulose devoid of cytokines that was dependent on the concomitantly observed increased activity of FAK. Transplanting BCR-ABL-transformed Shb knockout bone marrow cells to Shb knockout recipients revealed decreased disease latency without neutrophilia, thus implicating the importance of niche-derived cues for the increase of blood granulocytes. CONCLUSIONS: Absence of Shb accelerates disease progression by exerting dual roles in BCR-ABL-induced leukemia: increased cell expansion due to elevated FAK activity and neutrophilia in peripheral blood, the latter dependent on the genetic background of the leukemic niche. PMID- 24952419 TI - Convergence between the 1990 and 2010 ACR diagnostic criteria and validation of the Spanish version of the Fibromyalgia Survey Questionnaire (FSQ). AB - (1) To assess the degree of convergence between the 1990 and 2010 American College of Rheumatology (ACR) diagnostic criteria; (2) To evaluate the validity and reliability of the 2010 ACR criteria; (3) To validate the Spanish version of the Fibromyalgia Survey Questionnaire (FSQ); and (4) To assess the utility of the FSQ to differentiate fibromyalgia (FM) subgroups by disease severity. In the first study, agreement between the 1990 and 2010 ACR criteria for FM diagnosis was analyzed in a sample of 80 FM patients and 59 healthy controls. Algometry (mean threshold and tender points count) and the 2010 ACR indices [Symptom Severity Scale (SSS), Widespread Index (WPI) and Polysymptomatic Distress Scale (PSD)] were correlated with the key symptoms of FM and with indices of disease interference and quality of life. In a second study, we evaluated the validity and internal consistency of the Spanish version of the FSQ, as well as its ability to discriminate between groups of FM patients with low and high symptom severity. There is good agreement between the 1990 and 2010 ACR criteria for FM diagnosis. The 2010 ACR indices (SSS, WPI and PSD) demonstrated very adequate construct validity and appeared to be useful in the assessment of disease severity and global impact of FM. The FSQ had good internal consistency and validity and showed 100 % concordance with 2010 ACR criteria applied by a clinician. In addition, the FSQ proved to be useful in differentiating FM severity subgroups. PMID- 24952418 TI - Neuromyelitis optica spectrum disorders associated with other autoimmune diseases. AB - Neuromyelitis optica (NMO) is an inflammatory demyelinating autoimmune disease with severe, tremendously incapacitating, consequences in the patient's health and wellbeing. Until 2004, NMO was considered a restricted type of multiple sclerosis but in the same year an auto-antibody reacting against aquaporin-4 (NMO IgG) was found to be related with NMO and it was considered the main etiologic agent of this disease. Its detection is very sensitive and specific allowing an early diagnosis and a better treatment and prognosis. With this tool, a spectrum of diseases including other autoimmune diseases was found to have NMO-IgG antibodies and a new classification named NMO spectrum disorders was created. In this review, we sum up the developments in this field associated with other autoimmune diseases. We approach the latest discoveries in the diagnosis like the new biomarkers that will possibly be used in the close future or the developments in the neuroimaging techniques. We reviewed the literature and synthesized case reports of NMO patients with concurrent autoimmune diseases and the information from useful larger studies. Finally, we summarize the commonly used treatments in NMO and we try to specify the best treatment for NMO with simultaneous autoimmune disease. This review updates the information about this issue and raises the awareness of rheumatologists for these severe diseases. PMID- 24952420 TI - Methods, fluxes and sources of gas phase alkyl nitrates in the coastal air. AB - The daily and seasonal atmospheric concentrations, deposition fluxes and emission sources of a few C3-C9 gaseous alkyl nitrates (ANs) at the Belgian coast (De Haan) on the Southern North Sea were determined. An adapted sampler design for low- and high-volume air-sampling, optimized sample extraction and clean-up, as well as identification and quantification of ANs in air samples by means of gas chromatography mass spectrometry, are reported. The total concentrations of ANs ranged from 0.03 to 85 pptv and consisted primarily of the nitro-butane and nitro pentane isomers. Air mass backward trajectories were calculated by the Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model to determine the influence of main air masses on AN levels in the air. The shorter chain ANs have been the most abundant in the Atlantic/Channel/UK air masses, while longer chain ANs prevailed in continental air. The overall mean N fluxes of the ANs were slightly higher for summer than those for winter-spring, although their contributions to the total nitrogen flux were low. High correlations between AN and HNO2 levels were observed during winter/spring. During summer, the shorter chain ANs correlated well with precipitation. Source apportionment by means of principal component analysis indicated that most of the gas phase ANs could be attributed to traffic/combustion, secondary photochemical formation and biomass burning, although marine sources may also have been present and a contributing factor. PMID- 24952421 TI - Sources and the distribution of heavy metals in the particle size of soil polluted by gold mining upstream of Miyun Reservoir, Beijing: implications for assessing the potential risks. AB - Mining has been carried out upstream of Miyun Reservoir, Beijing, for several decades, and has caused metal emissions to the environment, threatening human health. We conducted a soil survey to assess metal contamination in this area and to determine distribution of heavy metals in the particle size. We attempted to determine the possible sources of the metals and the significance of metals in the fine particle fractions to soil risk assessments. Thirty-four soil samples were collected, and eight samples were partitioned into seven size fractions. Most of the metal concentrations in the soils were higher than the background levels in Beijing, and the metal concentrations and total organic matter (TOC) contents generally increased as the particle size decreased. Each metal except Hg significantly positively correlated with the TOC. The metals in the coarse grained soils were mainly derived from parent materials, but the metals in the fine fractions were mostly anthropogenic. Statistical analyses showed that there were three metal sources: Cd, Cu, Hg, Pb, and Zn had anthropogenic sources; Co, Cr, Ni, and V had mixed anthropogenic and natural sources; and As and Be had natural sources. The trace metals were primarily in the clay and fine silt fractions, and they might pose health risks through the inhalation of resuspended soil particles (PM10 and PM2.5). The elevated accumulation factors, enrichment factors, and ecological risk indices for the metals in the fine fractions suggest that risk assessments should be based on the fine particle size. PMID- 24952423 TI - Molecular characterization of Indian sheeppox and goatpox viruses based on RPO30 and GPCR genes. AB - Sheeppox and goatpox are economically important diseases of small ruminants caused by sheeppox virus (SPPV) and goatpox virus (GTPV), respectively. Although SPPV and GTPV have host preference, some strains may infect both sheep and goats. As capripox viruses (SPPV, GTPV and LSDV) are antigenically related but genetically distinct, their differentiation requires analysis at molecular level. In the present study, RPO30 and GPCR genes of eight Indian SPPV and GTPV isolates were PCR amplified, cloned and sequences are genetically and phylogenetically analyzed. The RPO30 gene of SPPV and GTPV had lineage-specific signatures, and deletion of 21-nucleotide exclusively present in SPPV. Similarly, GPCR gene also had lineage-specific signatures for SPPV and GTPV. Phylogenetic analysis of capripox viruses based on RPO30 and GPCR genes revealed three distinct lineage specific clusters as per their host origin. Our study supports that both RPO30 and GPCR genes could be used for differentiation of SPPV and GTPV as well as for molecular epidemiological studies. The study also highlights the distinct lineage specificities of the Indian SPPV and GTPV isolates including vaccine strains. PMID- 24952425 TI - Pulmonologist versus radiologist interpretation of cystic fibrosis on CT imaging. PMID- 24952422 TI - Whole-genome analyses of DS-1-like human G2P[4] and G8P[4] rotavirus strains from Eastern, Western and Southern Africa. AB - Group A rotaviruses (RVAs) with distinct G and P genotype combinations have been reported globally. We report the genome composition and possible origin of seven G8P[4] and five G2P[4] human RVA strains based on the genetic evolution of all 11 genome segments at the nucleotide level. Twelve RVA ELISA positive stool samples collected in the representative countries of Eastern, Southern and West Africa during the 2007-2012 surveillance seasons were subjected to sequencing using the Ion Torrent PGM and Illumina MiSeq platforms. A reference-based assembly was performed using CLC Bio's clc_ref_assemble_long program, and full-genome consensus sequences were obtained. With the exception of the neutralising antigen, VP7, all study strains exhibited the DS-1-like genome constellation (P[4]-I2-R2-C2-M2-A2-N2-T2-E2-H2) and clustered phylogenetically with reference strains having a DS-1-like genetic backbone. Comparison of the nucleotide and amino acid sequences with selected global cognate genome segments revealed nucleotide and amino acid sequence identities of 81.7-100 % and 90.6-100 %, respectively, with NSP4 gene segment showing the most diversity among the strains. Bayesian analyses of all gene sequences to estimate the time of divergence of the lineage indicated that divergence times ranged from 16 to 44 years, except for the NSP4 gene where the lineage seemed to arise in the more distant past at an estimated 203 years ago. However, the long-term effects of changes found within the NSP4 genome segment should be further explored, and thus we recommend continued whole-genome analyses from larger sample sets to determine the evolutionary mechanisms of the DS-1-like strains collected in Africa. PMID- 24952424 TI - Does context matter? Examining the mental health among homeless people. AB - While much research has focused on the impact community has on health and wellbeing of domiciled populations, limited research has explored the same for homeless people. Using multivariate models, this research explores what factors are related to depressive symptomatology among homeless people living in two distinctly different communities. Results suggest that context matters, but not for every circumstance examined in these models. While some variables exhibit a consistent relationship with depressive symptoms, the role of social capital is noted as particularly important to lowering symptomatology, yet its impact differs significantly by location. PMID- 24952426 TI - Impact of long-acting bronchodilators and exposure to inhaled corticosteroids on mortality in COPD: a real-life retrospective cohort study. AB - INTRODUCTION: We performed a real-life retrospective analysis to assess the impact of long-acting bronchodilator therapy and associated exposure to inhaled corticosteroids (ICS) on all-cause and cardiovascular mortality in patients with chronic obstructive pulmonary disease (COPD). METHODS: We used record linkage data from patients with a diagnosis of COPD in Tayside, Scotland, between 2001 and 2010. All-cause and cardiovascular mortality were assessed using Cox proportional hazard regression. RESULTS: A total of 4,133 patients were included, mean FEV1 of 59.5%, mean age of 68.9 years and mean follow-up of 4.6 years. There were 623 who were exposed to long-acting bronchodilators only and 3,510 to long acting bronchodilators plus ICS. 1,372 patients (33%) died during the study period. Compared with controls taking only long-acting bronchodilators either alone or in combination, all-cause mortality was reduced in patients taking long acting muscarinic antagonist (LAMA) + ICS as dual therapy: adjusted hazard ratio 0.62 (95% CI 0.45-0.85), but not by long-acting beta-agonist (LABA) + ICS: adjusted hazard ratio 1.02 (95% CI 0.80-1.31). Cardiovascular mortality was not reduced by dual therapy with either LABA or LAMA and concomitant ICS exposure. All-cause and cardiovascular mortality were both reduced in patients taking triple therapy with LABA + LAMA + ICS: adjusted hazard ratio 0.51 (95% CI 0.41 0.64) and 0.56 (95% CI 0.35-0.90), respectively. CONCLUSION: In patients exposed to ICS, concomitant use of LAMA alone as dual therapy or in combination with LABA as triple therapy were associated with reductions in all-cause mortality, while concomitant use of LABA without LAMA conferred no reduction. Moreover, only triple therapy was found to confer benefits on cardiovascular mortality. PMID- 24952427 TI - Repetitive severe hypotension induced by indigo carmine. PMID- 24952429 TI - Inflammasome activation is reactive oxygen species dependent and mediates irinotecan-induced mucositis through IL-1beta and IL-18 in mice. AB - Irinotecan is a useful chemotherapeutic for the treatment of various cancers. Irinotecan treatment is associated with mucositis, which clearly limits the use of the drug. Mechanisms that account for mucositis are only partially known. This study assessed mechanisms and the role of inflammasome activation in irinotecan induced mucositis. Mucositis in mice was induced by irinotecan injection in C57BL/6 wild-type, gp91phox(-/-), il-18(-/-), casp-1(-/-), and asc(-/-) mice once a day for 4 consecutive days. In some experiments, mice received apocynin to inhibit NADPH oxidase (NOX), IL-1 receptor antagonist, or IL-18 binding protein to prevent activation of IL-1 and IL-18 receptors, respectively. Mice were euthanized 7 days after the beginning of irinotecan treatment, and small intestines were collected for analysis. Irinotecan treatment resulted in increased IL-1beta and IL-18 production in ileum and NOX-2-dependent oxidative stress. gp91phox(-/-) and apocynin-treated mice had diminished oxidative stress and less severe mucositis. Furthermore, treatment with apocynin decreased caspase 1 activation and IL-1beta and IL-18 production in the ileum. asc(-/-) and casp-1( /-) mice also had less intestinal injury and decreased IL-1beta and IL-18 production. Finally, both the absence of IL-18 and IL-1beta resulted in reduced inflammatory response and attenuated intestinal injury. NOX-2-derived oxidative stress mediates inflammasome activation and inflammasome-dependent production of IL-1beta and IL-18, which mediate tissue injury during irinotecan-induced mucositis in mice. PMID- 24952428 TI - In vivo RNA interference models of inducible and reversible Sirt1 knockdown in kidney cells. AB - The silent mating type information regulation 2 homolog 1 gene (Sirt1) encodes an NAD-dependent deacetylase that modifies the activity of well-known transcriptional regulators affected in kidney diseases. Sirt1 is expressed in the kidney podocyte, but its function in the podocyte is not clear. Genetically engineered mice with inducible and reversible Sirt1 knockdown in widespread, podocyte-specific, or tubular-specific patterns were generated. We found that mice with 80% knockdown of renal Sirt1 expression have normal glomerular function under the basal condition. When challenged with doxorubicin (Adriamycin), these mice develop marked albuminuria, glomerulosclerosis, mitochondrial injury, and impaired autophagy of damaged mitochondria. Reversal of Sirt1 knockdown during the early phase of Adriamycin-induced nephropathy prevented the progression of glomerular injury and reduced the accumulation of dysmorphic mitochondria in podocytes but did not reverse the progression of albuminuria and glomerulosclerosis. Sirt1 knockdown mice with diabetes mellitus, which is known to cause mitochondrial dysfunction in the kidney, developed more albuminuria and mitochondrial dysfunction compared with diabetic mice without Sirt1 knockdown. In conclusion, these results demonstrate that our RNA interference-mediated Sirt1 knockdown models are valid and versatile tools for characterizing the function of Sirt1 in the kidney; Sirt1 plays a role in homeostatic maintenance of podocytes under the condition of mitochondrial stress/injury. PMID- 24952430 TI - Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo. AB - Obesity and metabolic syndrome are linked to an increased prevalence of breast cancer among postmenopausal women. A common feature of obesity, metabolic syndrome, and a Western diet rich in saturated fat is a high level of circulating cholesterol. Epidemiological reports investigating the relationship between high circulating cholesterol levels, cholesterol-lowering drugs, and breast cancer are conflicting. Here, we modeled this complex condition in a well-controlled, preclinical animal model using innovative isocaloric diets. Female severe combined immunodeficient mice were fed a low-fat/no-cholesterol diet and then randomized to four isocaloric diet groups: low-fat/no-cholesterol diet, with or without ezetimibe (cholesterol-lowering drug), and high-fat/high-cholesterol diet, with or without ezetimibe. Mice were implanted orthotopically with MDA-MB 231 cells. Breast tumors from animals fed the high-fat/high-cholesterol diet exhibited the fastest progression. Significant differences in serum cholesterol level between groups were achieved and maintained throughout the study; however, no differences were observed in intratumoral cholesterol levels. To determine the mechanism of cholesterol-induced tumor progression, we analyzed tumor proliferation, apoptosis, and angiogenesis and found a significantly greater percentage of proliferating cells from mice fed the high-fat/high-cholesterol diet. Tumors from hypercholesterolemic animals displayed significantly less apoptosis compared with the other groups. Tumors from high-fat/high-cholesterol mice had significantly higher microvessel density compared with tumors from the other groups. These results demonstrate that hypercholesterolemia induces angiogenesis and accelerates breast tumor growth in vivo. PMID- 24952432 TI - A polymorphism in JMJD2C alters the cleavage by caspase-3 and the prognosis of human breast cancer. AB - JMJD2C is a candidate oncogene that encodes a histone lysine demethylase with the ability to demethylate the lysine 9 residue of histone H3 (H3K9). The expression levels of JMJD2C are associated with tumor development and clinical outcome. Here we identify JMJD2C as a new substrate for caspase-3. JMJD2C is cleaved by caspase 3 at DEVD396G motif and then loses its demethylase activity. Additionally, we uncover D396N polymorphism (rs2296067) in the cleavage site of JMJD2C and establish its influence on the resistant to the cleavage by caspase-3. Importantly, we determined that D396N polymorphism is significantly associated with the prognosis of human breast cancer. We further found that the basal levels of DSB (double strand DNA break) repair proteins gamma-H2AX (gamma-H2AX) increased when cells were treated with tumor necrosis factor-alpha (TNF-alpha) which activates caspase-3 activity. We also show that knockdown of JMJD2C expression results in up-regulation of basal gamma-H2AX. We propose that D396N polymorphism of JMJD2C affects the prognosis of human breast cancer via altering the cleavage by caspase-3 and the ability of DSB repair which may contribute to therapy resistance. PMID- 24952433 TI - Four-part harmony: from hand crank to hash tags. PMID- 24952435 TI - Discussion. PMID- 24952434 TI - Validating trauma-specific frailty index for geriatric trauma patients: a prospective analysis. AB - BACKGROUND: The Frailty Index has been shown to predict discharge disposition in geriatric patients. The aim of this study was to validate the modified 15 variable Trauma-Specific Frailty Index (TSFI) to predict discharge disposition in geriatric trauma patients. We hypothesized that TSFI can predict discharge disposition in geriatric trauma patients. STUDY DESIGN: We performed a 2-year (2011-2013) prospective analysis of all geriatric trauma patients presenting to our Level I trauma center. Patient discharge disposition was dichotomized into unfavorable (discharge to skilled nursing facility or death) and favorable (discharge to home or rehabilitation center) discharge disposition. Patients were evaluated using the developed 15-variable TSFI. Multivariate logistic regression was performed to identify factors that predict unfavorable discharge disposition. RESULTS: A total of 200 patients were enrolled for validation of TSFI. Mean age was 77 +/- 12.1 years, median Injury Severity Score was 15 (interquartile range [IQR] 9 to 20), median Glasgow Coma Scale score was 14 (IQR 13 to 15), and median Frailty Index score was 0.20 (IQR 0.17 to 0.28); 29.5% (n = 59) patients had unfavorable discharge. After adjusting for age, sex, Injury Severity Score, Head Abbreviated Injury Scale, and vitals on admission, Frailty Index (odds ratio = 1.5; 95% CI, 1.1-2.5) was the only significant predictor for unfavorable discharge disposition. Age (odds ratio = 1.2; 95% CI, 0.9-3.1; p = 0.2) was not predictive of unfavorable discharge disposition. CONCLUSIONS: The 15-variable TSFI is an independent predictor of unfavorable discharge disposition in geriatric trauma patients. The Trauma-Specific Frailty Index is an effective tool that can aid clinicians in planning discharge disposition of geriatric trauma patients. LEVEL OF EVIDENCE: II Prognostic Studies-Investigating the Effect of a Patient Characteristic on the Outcome of Disease. PMID- 24952436 TI - Discussion. PMID- 24952431 TI - Nervous translation, do you get the message? A review of mRNPs, mRNA-protein interactions and translational control within cells of the nervous system. AB - In neurons, translation of a message RNA can occur metres away from its transcriptional origin and in normal cells this is orchestrated with perfection. The life of an mRNA will see it pass through multiple steps of processing in the nucleus and the cytoplasm before it reaches its final destination. Processing of mRNA is determined by a myriad of RNA-binding proteins in multi-protein complexes called messenger ribonucleoproteins; however, incorrect processing and delivery of mRNA can cause several human neurological disorders. This review takes us through the life of mRNA from the nucleus to its point of translation in the cytoplasm. The review looks at the various cis and trans factors that act on the mRNA and discusses their roles in different cells of the nervous system and human disorders. PMID- 24952437 TI - Engagement, workplace satisfaction, and retention of surgical specialists in academic medicine in the United States. AB - BACKGROUND: Academic medical centers strive for clinical excellence with operational efficiency and financial solvency, which requires institutions to retain productive and skillful surgical specialists. Faculty workplace perceptions, overall satisfaction, and intent to leave are relationships that have not been examined previously among US surgeons in academic medicine. We hypothesize that critical factors related to workplace satisfaction and engagement could be identified as important for enhancing institutional retention of academic surgeons. STUDY DESIGN: The 2011-2012 Association of American Medical Colleges Faculty Forward Engagement Survey evaluated demographic variables, physician workplace satisfaction, and overall engagement among faculty subgroups, including comparison of surgical and nonsurgical clinicians. Multiple regression analysis (beta = standard regression coefficient) was performed to identify critical factors most closely related to surgeon satisfaction and intent to leave their institutions. RESULTS: A total of 1,356 of 1,949 (70%) surgeons from 14 medical schools responded across different faculty subgroups, and comparisons were made with 1,105 nonsurgical clinicians. Multiple regression indicated that the strongest predictors of surgeons' overall satisfaction with their department included department governance (beta = 0.36; p < 0.001), collegiality and collaboration (beta = 0.23; p < 0.001), and relationship with supervisor (beta = 0.17; p < 0.001). Although compensation and benefits were important (beta = 0.08; p < 0.001), these did not rank as the most important factors. Promotion equality (odds ratio = 0.62; p < 0.05), collegiality and collaboration (odds ratio = 0 .51; p < 0.05), and nature of their work (odds ratio = 0.52; p < 0.05) were most closely related to intent to leave the medical school within 1 to 2 years. CONCLUSIONS: In the largest survey focusing on workplace factors affecting surgical faculty satisfaction and intent to leave, we conclude that institutional understanding of, and improvement in, specific work environment factors can enhance recruitment and retention of academic surgeons. PMID- 24952438 TI - Discussion. PMID- 24952439 TI - Discussion. PMID- 24952440 TI - Discussion. PMID- 24952442 TI - Discussion. PMID- 24952441 TI - A 20-year experience of hepatic resection for melanoma: is there an expanding role? AB - BACKGROUND: Melanoma liver metastasis is most often fatal, with a 4- to 6-month median overall survival (OS). Over the past 20 years, surgical techniques have improved in parallel with more effective systemic therapies. We reviewed our institutional experience of hepatic melanoma metastases. STUDY DESIGN: Overall and disease-specific survivals were calculated from hepatic metastasis diagnosis. Potential prognostic factors including primary tumor type, depth, medical treatment response, location, and surgical approach were evaluated. RESULTS: Among 1,078 patients with melanoma liver metastases treated at our institution since 1991, 58 (5.4%) received surgical therapy (resection with or without ablation). Median and 5-year OS were 8 months and 6.6 %, respectively, for 1,016 nonsurgical patients vs 24.8 months and 30%, respectively, for surgical patients (p < 0.001). Median OS was similar among patients undergoing ablation (with or without resection) relative to those undergoing surgery alone. On multivariate analysis of surgical patients, completeness of surgical therapy (hazard ratio [HR] 3.4, 95% CI 1.4 to 8.1, p = 0.007) and stabilization of melanoma on therapy before surgery (HR 0.38, 95% CI 0.19 to 0.78, p = 0.008) predicted OS. CONCLUSIONS: In this largest single-institution experience, patients selected for surgical therapy experienced markedly improved survival relative to those receiving only medical therapy. Patients whose disease stabilized on medical therapy enjoyed particularly favorable results, regardless of the number or size of their metastases. The advent of more effective systemic therapy in melanoma may substantially increase the fraction of patients who are eligible for surgical intervention, and this combination of treatment modalities should be considered whenever it is feasible in the context of a multidisciplinary team. PMID- 24952443 TI - Discussion. PMID- 24952444 TI - Direct peritoneal resuscitation improves inflammation, liver blood flow, and pulmonary edema in a rat model of acute brain death. AB - BACKGROUND: Brain death in organ donors alters central hemodynamic performance, impairs physiology, exaggerates inflammation, and causes end-organ microcirculatory dysfunction and hypoxia. A new treatment, direct peritoneal resuscitation (DPR), might improve these derangements in acute brain death (ABD). STUDY DESIGN: We studied a standardized rodent model of brain death with matched controls to assess the efficacy of DPR as a resuscitation strategy after ABD. Anesthetized Sprague-Dawley rats were randomized as follows: ABD (supradural balloon inflation) with minimal IV fluid (IVF; 2 mL/h, n = 12); ABD + adequate IVF (5 mL/h, n = 12); ABD with aggressive IVF (goal: mean arterial pressure [MAP] >80 mmHg, n = 15); or ABD + IVF + DPR (goal: MAP >80 mmHg, n = 12). Ventilation support, IVF, and DPR were started at loss of reflexes, and MAP, heart rate, and effective hepatic blood flow were recorded. RESULTS: High IVF and DPR prevented mortality (0%) compared with low IVF (81.8%) or mid IVF (16.7%). Effective hepatic blood flow was decreased in low and mid IVF (2.8 +/- 0.3 mL/min/g body weight and 4.0 +/- 0.5 mL/min/g body weight, respectively) vs baseline, but was stable in high IVF (6.2 +/- 0.5 mL/min/g body weight; NS) or improved with DPR (8.6 +/- 0.7 mL/min/g body weight). The high-IVF group had significant organ edema, which was prevented in the DPR group. The mid-IVF and low-IVF groups had higher serum markers of organ injury compared with high-IVF or DPR groups. The high-IVF group had elevated inflammatory cytokines compared with the DPR group. CONCLUSIONS: Direct peritoneal resuscitation improved survival and effective hepatic blood flow, required less IVF to stabilize blood pressure, prevented organ edema, and normalized fluid electrolyte balance compared with IVF-alone groups. Direct peritoneal resuscitation in animals reduced inflammatory response after ABD compared with IVF-alone controls. These data suggest a potential role for DPR in organ donors to stabilize donors and possibly increase the number of organs suitable for transplantation per donor. PMID- 24952445 TI - Discussion. PMID- 24952446 TI - Discussion. PMID- 24952447 TI - Discussion. PMID- 24952448 TI - Discussion. PMID- 24952449 TI - Discussion. PMID- 24952450 TI - Discussion. PMID- 24952451 TI - Discussion. PMID- 24952452 TI - Gibbon fulfilled. PMID- 24952453 TI - Do normal clinical signs and laboratory tests exclude anastomotic leakage? PMID- 24952455 TI - Copper bioavailability and toxicity to Mytilus galloprovincialis in Shelter Island Yacht Basin, San Diego, CA. AB - The bioavailability and toxicity of copper (Cu) in Shelter Island Yacht Basin (SIYB), San Diego, CA, USA, was assessed with simultaneous toxicological, chemical, and modeling approaches. Toxicological measurements included laboratory toxicity testing with Mytilus galloprovincialis (Mediterranean mussel) embryos added to both site water (ambient) and site water spiked with multiple Cu concentrations. Chemical assessment of ambient samples included total and dissolved Cu concentrations, and Cu complexation capacity measurements. Modeling was based on chemical speciation and predictions of bioavailability and toxicity using a marine Biotic Ligand Model (BLM). Cumulatively, these methods assessed the natural buffering capacity of Cu in SIYB during singular wet and dry season sampling events. Overall, the three approaches suggested negligible bioavailability, and isolated observed or predicted toxicity, despite an observed gradient of increasing Cu concentration, both horizontally and vertically within the water body, exceeding current water quality criteria for saltwater. PMID- 24952456 TI - Polycyclic aromatic hydrocarbons (PAHs) in the mariculture zones of China's northern Yellow Sea. AB - Polycyclic aromatic hydrocarbons (PAHs) were detected in water and sediment samples collected from three mariculture zones in China's northern Yellow Sea. In these samples, total PAH concentrations ranged from 110.8 ng/L to 997.2 ng/L and 142.2 ng/gdry weight (dw) to 750.2 ng/gdw, respectively. The log KOC values of the various PAH compounds examined in this study increased with the log KOW values, which is consistent with the prediction regarding PAH behavior in the environment. However, these KOC values were lower than the predicted values as a result of the effects of organic matters, which were abundant in the mariculture water. The isomeric ratios of the PAHs in sediment indicated that the source of the PAHs in the mariculture zones were mainly pyrolytic. The TEQ(carc) values of PAHs ranged from 7 ng TEQ/gdw to 92 ng TEQ/gdw, and only a few samples met the safe criterion with respect to individual PAH concentrations. PMID- 24952457 TI - Occurrence of persistent organic pollutants in marine fish from the Natuna Island, South China Sea. AB - Five marine fish species were collected from the Natuna Island, South China Sea to investigate the occurrence of polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane and its metabolites (DDTs). Concentrations of PBDEs, PCBs, and DDTs in marine fish ranged from 2.85 to 7.82, 14.3 to 48.1, and 7.99 to 40.3 ng/g lipid weight, respectively. Higher concentrations of PBDEs, PCBs, and DDTs were observed in Snakefish (Trachinocephalus myops), which might be attributed to their different feeding and living habits. PCBs were the predominant POPs in all marine fish, followed by DDTs and PBDEs. BDE 47 and PCB 153 were the predominant congener of PBDEs and PCBs, respectively. Compositional distribution of DDTs indicated the possible presence of fresh input sources around the Natuna Island. The ratios of o,p'-DDT/p,p'-DDT being less than 1 in fish samples suggested that DDT contributions from dicofol seemed considerably low. New input sources of DDT in South China Sea are worth further research. PMID- 24952459 TI - Road traffic noise and hypertension--accounting for the location of rooms. AB - OBJECTIVE: The association between the exposure to road traffic noise and the prevalence of hypertension was assessed accounting for background air pollution and the location of rooms with respect to the road. METHODS: A cross-sectional study was carried out inviting all subjects aged 35-74 years for participation that lived on 7 major trunk roads in 3-4 storey terraced apartment buildings and in parallel side streets that were completely shielded from noise due to the rows of houses along the major roads. The study was performed on 1770 subjects that did not have a self-reported medical doctor diagnosis of hypertension before they moved into their current residence. Noise levels at the facade of the front and the rear side of the houses were drawn from available noise maps of the area. A large set of covariates were considered to adjust the results for confounding. RESULTS: Significant increases between road traffic noise and hypertension were found with respect to the 24h A-weighted average noise indicator L(DEN). The adjusted odds ratio (OR) per noise level increment of 10 dB(A) was 1.11 (95% confidence interval (CI): 1.00-1.23). Stronger significant estimates of the noise effect were found in subjects with long residence time (OR=1.20, CI=1.05-1.37), and with respect to the exposure of the living room during daytime (OR=1.24, CI=1.08-1.41) compared with the exposure of the bedroom during night-time (OR=0.91, CI=0.78-1.06). CONCLUSION: Chronic exposure to road traffic noise is associated with an increased risk of high blood pressure. Daytime noise exposure of the living room had a stronger impact on the association than night-time exposure of the bedroom. PMID- 24952458 TI - Dissecting the contribution of actin and vimentin intermediate filaments to mechanical phenotype of suspended cells using high-throughput deformability measurements and computational modeling. AB - Mechanical cell properties play an important role in many basic biological functions, including motility, adhesion, proliferation and differentiation. There is a growing body of evidence that the mechanical cell phenotype can be used for detection and, possibly, treatment of various diseases, including cancer. Understanding of pathological mechanisms requires investigation of the relationship between constitutive properties and major structural components of cells, i.e., the nucleus and cytoskeleton. While the contribution of actin und microtubules to cellular rheology has been extensively studied in the past, the role of intermediate filaments has been scarcely investigated up to now. Here, for the first time we compare the effects of drug-induced disruption of actin and vimentin intermediate filaments on mechanical properties of suspended NK cells using high-throughput deformability measurements and computational modeling. Although, molecular mechanisms of actin and vimentin disruption by the applied cytoskeletal drugs, Cytochalasin-D and Withaferin-A, are different, cell softening in both cases can be attributed to reduction of the effective density and stiffness of filament networks. Our experimental data suggest that actin and vimentin deficient cells exhibit, in average, 41% and 20% higher deformability in comparison to untreated control. 3D Finite Element simulation is performed to quantify the contribution of cortical actin and perinuclear vimentin to mechanical phenotype of the whole cell. Our simulation provides quantitative estimates for decreased filament stiffness in drug-treated cells and predicts more than two-fold increase of the strain magnitude in the perinuclear vimentin layer of actin deficient cells relatively to untreated control. Thus, the mechanical function of vimentin becomes particularly essential in motile and proliferating cells that have to dynamically remodel the cortical actin network. These insights add functional cues to frequently observed overexpression of vimentin in diverse types of cancer and underline the role of vimentin targeting drugs, such as Withaferin-A, as a potent cancerostatic supplement. PMID- 24952460 TI - Complete feminization of catfish by feeding Limnodilus, an annelid worm collected in contaminated streams. AB - BACKGROUND: Feminization of animals derived from areas polluted by endocrine disrupting chemicals (EDCs) has been observed in all classes of vertebrates. However, feminization of artificially reared offspring by feeding of specific living organisms has never been reported. METHODS: Different food (including Limnodilus spp collected from the wild) and time treatment were applied to southern catfish. In addition, EDCs in Limnodilus spp., an annelid worm collected from wild contaminated small streams, was detected by LC-MS (Liquid chromatography-mass spectrometry). Serum estradiol-17beta and vitellogenin (VTG) levels and gonadal Sf1, Dmrt1, Foxl2, Cyp19a1a expression levels in the catfish were measured through Estradiol/VTG EIA Kit and real-time PCR. RESULTS: Here we report that feeding of Limnodilus spp. resulted in complete feminization of southern catfish, which has a 1:1 sex ratio in wild conditions. Furthermore, HPLC analysis showed that the extraction of Limnodilus spp. contained EDCs, including bisphenol A (BPA), diethylstilbestrol (DES), 4-tert-octylphenol (4-t-OP) and 4 nonylphenol (4-NP), which were further confirmed by LC-MS. Feeding southern catfish using commercial diets sprayed with EDCs cocktail also resulted in 100% female, whereas the control fish displayed approximate 1:1 sex ratio. Limnodilus spp. fed fish displayed similar serum estradiol-17beta and VTG levels and gonadal Sf1, Dmrt1, Foxl2, Cyp19a1a expression levels to those of female control. CONCLUSION: These results demonstrated that EDCs in Limnodilus spp. cause southern catfish feminization by affecting aromatase expression and endogenous estrogen level. This is the first report showing that feeding of any living organism resulted in complete feminization of a vertebrate. PMID- 24952461 TI - Metals in tissues of migrant semipalmated sandpipers (Calidris pusilla) from Delaware Bay, New Jersey. AB - There is an abundance of field data on levels of metals for feathers in a variety of birds, but relatively few data for tissues, especially for migrant species from one location. In this paper we examine the levels of arsenic, cadmium, chromium, lead, manganese, mercury and selenium in muscle, liver, brain, fat and breast feathers from migrant semipalmated sandpipers (Calidris pusilla) collected from Delaware Bay, New Jersey. Our primary objectives were to (1) examine variation as a function of tissue, (2) determine the relationship of metal levels among tissues, and (3) determine the selenium:mercury molar ratio in different tissues since selenium is thought to protect against mercury toxicity. We were also interested in whether the large physiological changes that occur while shorebirds are on Delaware Bay (e.g. large weight gains in 2-3 weeks) affected metal levels, especially in the brain. There were significant differences among tissues for all metals. The brain had the lowest levels of arsenic and cadmium, and was tied for the lowest levels of all other metals except lead and selenium. Correlations among metals in tissues were varied, with mercury levels being positively correlated for muscle and brain, and for liver and breast feathers. Weights vary among individuals at the Delaware Bay stopover, as they arrive light, and gain weight prior to migration north. Bird weight and levels of arsenic, cadmium, and selenium in the brain were negatively correlated, while they were positively correlated for lead. There was no positive correlation for mercury in the brain as a function of body weight. The selenium:mercury molar ratio varied significantly among tissues, with brain (ratio of 141) and fat having the highest ratios, and liver and breast feathers having the lowest. In all cases, the ratio was above 21, suggesting the potential for amelioration of mercury toxicity. PMID- 24952462 TI - The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression. AB - Aberrant activation of WNT signalling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumour stem cell phenotype and identify the zinc-finger transcription factor GATA6 as a key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells whereas it restricts BMP signalling to differentiated tumour cells. Genetic deletion of Gata6 from mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumour stem cells. In human tumours, GATA6 competes with beta-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been linked to increased susceptibility to development of CRC. Hence, GATA6 creates an environment permissive for CRC initiation by lowering the threshold of BMP signalling required for tumour stem cell expansion. PMID- 24952463 TI - MT5-MMP regulates adult neural stem cell functional quiescence through the cleavage of N-cadherin. AB - The identification of mechanisms that maintain stem cell niche architecture and homeostasis is fundamental to our understanding of tissue renewal and repair. Cell adhesion is a well-characterized mechanism for developmental morphogenetic processes, but its contribution to the dynamic regulation of adult mammalian stem cell niches is still poorly defined. We show that N-cadherin-mediated anchorage of neural stem cells (NSCs) to ependymocytes in the adult murine subependymal zone modulates their quiescence. We further identify MT5-MMP as a membrane-type metalloproteinase responsible for the shedding of the N-cadherin ectodomain in this niche. MT5-MMP is co-expressed with N-cadherin in adult NSCs and ependymocytes and, whereas MT5-MMP-mediated cleavage of N-cadherin is dispensable for the regulation of NSC generation and identity, it is required for proper activation of NSCs under physiological and regenerative conditions. Our results indicate that the proliferative status of stem cells can be dynamically modulated by regulated cleavage of cell adhesion molecules. PMID- 24952465 TI - Current status of extracorporeal ventricular assist devices in Japan. AB - Extracorporeal VADs are less expensive, their prices reimbursable by the health insurance being about one-sixth of those of implantable VADs in Japan. However, a disadvantage is that, in Japan, their use is restricted to hospitals, necessitating prolonged hospitalization, reducing the patients' quality of life. According to the Japanese registry for Mechanically Assisted Circulatory Support, the survival rate does not differ significantly between patients with extracorporeal and implantable VADs. As in Europe and North America, extracorporeal VADs in Japan are commonly used as Bridge to Decision or Bridge to Recovery. Extracorporeal VADs are switched to implantable VADs as a Bridge-to Bridge strategy after stabilization or when cardiac function recovery fails. They are also used as right ventricular assist devices (RVADs) in patients with right heart failure. A special characteristic of extracorporeal VADs in Japan is their frequent use as a Bridge to Candidacy. In Japan, indications for implantable VADs are restricted to patients registered for heart transplantation. Therefore, in patients who cannot be registered for transplantation because of transient renal dysfunction, etc., due to heart failure, extracorporeal VADs are used first, and then replaced by implantable VADs after transplant registry is done. Here, we describe the current status of extracorporeal VADs in Japan, focusing on the environmental backgrounds, along with a review of the relevant literature. PMID- 24952464 TI - The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment. AB - Mammalian Hedgehog (Hh) signal transduction requires a primary cilium, a microtubule-based organelle, and the Gli-Sufu complexes that mediate Hh signalling, which are enriched at cilia tips. Kif7, a kinesin-4 family protein, is a conserved regulator of the Hh signalling pathway and a human ciliopathy protein. Here we show that Kif7 localizes to the cilium tip, the site of microtubule plus ends, where it limits cilium length and controls cilium structure. Purified recombinant Kif7 binds the plus ends of growing microtubules in vitro, where it reduces the rate of microtubule growth and increases the frequency of microtubule catastrophe. Kif7 is not required for normal intraflagellar transport or for trafficking of Hh pathway proteins into cilia. Instead, a central function of Kif7 in the mammalian Hh pathway is to control cilium architecture and to create a single cilium tip compartment, where Gli-Sufu activity can be correctly regulated. PMID- 24952468 TI - Measuring predictability in ultrasonic signals: an application to scattering material characterization. AB - In this paper, we present a novel and completely different approach to the problem of scattering material characterization: measuring the degree of predictability of the time series. Measuring predictability can provide information of the signal strength of the deterministic component of the time series in relation to the whole time series acquired. This relationship can provide information about coherent reflections in material grains with respect to the rest of incoherent noises that typically appear in non-destructive testing using ultrasonics. This is a non-parametric technique commonly used in chaos theory that does not require making any kind of assumptions about attenuation profiles. In highly scattering media (low SNR), it has been shown theoretically that the degree of predictability allows material characterization. The experimental results obtained in this work with 32 cement probes of 4 different porosities demonstrate the ability of this technique to do classification. It has also been shown that, in this particular application, the measurement of predictability can be used as an indicator of the percentages of porosity of the test samples with great accuracy. PMID- 24952466 TI - Isolation of Escherichia coli mannitol permease, EIImtl, trapped in amphipol A8 35 and fluorescein-labeled A8-35. AB - Amphipols (APols) are short amphipathic polymers that keep integral membrane proteins water-soluble while stabilizing them as compared to detergent solutions. In the present work, we have carried out functional and structural studies of a membrane transporter that had not been characterized in APol-trapped form yet, namely EII(mtl), a dimeric mannitol permease from the inner membrane of Escherichia coli. A tryptophan-less and dozens of single-tryptophan (Trp) mutants of this transporter are available, making it possible to study the environment of specific locations in the protein. With few exceptions, the single-Trp mutants show a high mannitol-phosphorylation activity when in membranes, but, as variance with wild-type EII(mtl), some of them lose most of their activity upon solubilization by neutral (PEG- or maltoside-based) detergents. Here, we present a protocol to isolate these detergent-sensitive mutants in active form using APol A8-35. Trapping with A8-35 keeps EII(mtl) soluble and functional in the absence of detergent. The specific phosphorylation activity of an APol-trapped Trp-less EII(mtl) mutant was found to be ~3* higher than the activity of the same protein in dodecylmaltoside. The preparations are suitable both for functional and for fluorescence spectroscopy studies. A fluorescein-labeled version of A8-35 has been synthesized and characterized. Exploratory studies were conducted to examine the environment of specific Trp locations in the transmembrane domain of EII(mtl) using Trp fluorescence quenching by water-soluble quenchers and by the fluorescein-labeled APol. This approach has the potential to provide information on the transmembrane topology of MPs. PMID- 24952469 TI - gamma-Hydroxynitrile glucosides from the seeds of Prinsepia utilis. AB - gamma-Hydroxynitrile glucosides (prinsepicyanosides A-E) were isolated alongside 11 known compounds from seeds of Prinsepia utilis Royle. Their structures were determined by detailed analysis of NMR and MS spectroscopic data. The relative configuration of prinsepicyanoside C was established by Cu-Kalpha X-ray crystallography. Prinsepicyanoside A, osmaronin, and 4-(hydroxylmethyl)-5H-furan 2-one exhibited borderline antibacterial activity against Salmonella gallinarum, Vibrio parahaemolyticus, and Vibrio cholera with MIC values of 30.1, 20.7, and 22.8MUg/mL, respectively. PMID- 24952470 TI - The IUPAC aqueous and non-aqueous experimental pKa data repositories of organic acids and bases. AB - Accurate and well-curated experimental pKa data of organic acids and bases in both aqueous and non-aqueous media are invaluable in many areas of chemical research, including pharmaceutical, agrochemical, specialty chemical and property prediction research. In pharmaceutical research, pKa data are relevant in ligand design, protein binding, absorption, distribution, metabolism, elimination as well as solubility and dissolution rate. The pKa data compilations of the International Union of Pure and Applied Chemistry, originally in book form, have been carefully converted into computer-readable form, with value being added in the process, in the form of ionisation assignments and tautomer enumeration. These compilations offer a broad range of chemistry in both aqueous and non aqueous media and the experimental conditions and original reference for all pKa determinations are supplied. The statistics for these compilations are presented and the utility of the computer-readable form of these compilations is examined in comparison to other pKa compilations. Finally, information is provided about how to access these databases. PMID- 24952471 TI - Design of a colicin E7 based chimeric zinc-finger nuclease. AB - Colicin E7 is a natural bacterial toxin. Its nuclease domain (NColE7) enters the target cell and kills it by digesting the nucleic acids. The HNH-motif as the catalytic centre of NColE7 at the C-terminus requires the positively charged N terminal loop for the nuclease activity-offering opportunities for allosteric control in a NColE7-based artificial nuclease. Accordingly, four novel zinc finger nucleases were designed by computational methods exploiting the special structural features of NColE7. The constructed models were subjected to MD simulations. The comparison of structural stability and functional aspects showed that these models may function as safely controlled artificial nucleases. This study was complemented by random mutagenesis experiments identifying potentially important residues for NColE7 function outside the catalytic region. PMID- 24952472 TI - The effect of an outdoor activities' intervention delivered by older volunteers on the quality of life of older people with severe mobility limitations: a randomized controlled trial. AB - BACKGROUND: Older community-living disabled people often have unmet activity needs and participation restrictions potentially reducing their quality of life (QoL). AIMS: We examined the effects of an individualized out-of-home activity intervention delivered by volunteers on QoL among community-living older people, who have difficulty accessing the outdoors independently. METHODS: Volunteering, Access to Outdoor Activities and Wellbeing in Older People (VOW; ISRCTN56847832) was a two-arm randomized single-blinded, controlled effectiveness trial (RCT) in Jyvaskyla, Finland. The inclusion criteria were: age 65 or over, severe mobility limitation, able to communicate, and agree to participate in a RCT. Each intervention group member was assigned a trained volunteer with whom out-of-home activities were done once a week for 3 months (e.g., running errands or recreational activities). The primary outcome was the environmental subscore of QoL assessed with WHOQOL-BREF. Secondary outcomes were the overall QoL, physical capacity, psychological well-being, and social relationships assessed with WHOQOL_BREF and lower-extremity performance assessed with Short Physical Performance Battery (SPPB). RESULTS: 121 people aged 67-92 years (mean age 81.9 years, SD 5.9, 90 % women) were randomized. No treatment effect on the environmental QoL subscore was observed, but for physical capacity subscore a significant treatment effect was observed (General Linear Model, Group by Time p = 0.001). No effects were observed for the other QoL subscores or for SPPB score. DISCUSSION: This study suggests that individualized out-of-home activity intervention delivered by volunteers may influence the QoL of old severely mobility-limited community-living people in a positive way. CONCLUSION: Further studies are needed to better understand how to improve QoL of older disabled community-living people and potentially buffer them against more severe care needs and institutionalization. PMID- 24952474 TI - Measurement of collective dynamical mass of Dirac fermions in graphene. AB - Individual electrons in graphene behave as massless quasiparticles. Unexpectedly, it is inferred from plasmonic investigations that electrons in graphene must exhibit a non-zero mass when collectively excited. The inertial acceleration of the electron collective mass is essential to explain the behaviour of plasmons in this material, and may be directly measured by accelerating it with a time varying voltage and quantifying the phase delay of the resulting current. This voltage-current phase relation would manifest as a kinetic inductance, representing the reluctance of the collective mass to accelerate. However, at optical (infrared) frequencies, phase measurements of current are generally difficult, and, at microwave frequencies, the inertial phase delay has been buried under electron scattering. Therefore, to date, the collective mass in graphene has defied unequivocal measurement. Here, we directly and precisely measure the kinetic inductance, and therefore the collective mass, by combining device engineering that reduces electron scattering and sensitive microwave phase measurements. Specifically, the encapsulation of graphene between hexagonal boron nitride layers, one-dimensional edge contacts and a proximate top gate configured as microwave ground together enable the inertial phase delay to be resolved from the electron scattering. Beside its fundamental importance, the kinetic inductance is found to be orders of magnitude larger than the magnetic inductance, which may be utilized to miniaturize radiofrequency integrated circuits. Moreover, its bias dependency heralds a solid-state voltage-controlled inductor to complement the prevalent voltage-controlled capacitor. PMID- 24952473 TI - Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells. AB - In non-small-cell lung cancer (NSCLC), one-fifth of patients have KRAS mutations, which are considered a negative predictive factor to first-line therapy. Evidence is emerging that not all KRAS mutations have the same biological activities and possible remodeling of cell metabolism by KRAS activation might complicate the scenario. An open question is whether different KRAS mutations at codon-12 affect cellular metabolism differently with possible implications for different responses to cancer treatments. We applied an explorative mass spectrometry-based untargeted metabolomics strategy to characterize the largest possible number of metabolites that might distinguish isogenic NSCLC cells overexpressing mutated forms of KRAS at codon-12 (G12C, G12D, G12V) and the wild-type. The glutamine deprivation assay and real-time PCR were used to confirm the involvement of some of the metabolic pathways highlighted. Cell clones indicated distinct metabolomic profiles in KRAS wild-type and mutants. Clones harboring different KRAS mutations at codon-12 also had different metabolic remodeling, such as a different redox buffering system and different glutamine-dependency not driven by the transcriptional state of enzymes involved in glutaminolysis. These findings indicate that KRAS mutations at codon-12 are associated with different metabolomic profiles that might affect the responses to cancer treatments. PMID- 24952475 TI - Metamaterial mirrors in optoelectronic devices. AB - The phase reversal that occurs when light is reflected from a metallic mirror produces a standing wave with reduced intensity near the reflective surface. This effect is highly undesirable in optoelectronic devices that use metal films as both electrical contacts and optical mirrors, because it dictates a minimum spacing between the metal and the underlying active semiconductor layers, therefore posing a fundamental limit to the overall thickness of the device. Here, we show that this challenge can be circumvented by using a metamaterial mirror whose reflection phase is tunable from that of a perfect electric mirror (phi = pi) to that of a perfect magnetic mirror (phi = 0). This tunability in reflection phase can also be exploited to optimize the standing wave profile in planar devices to maximize light-matter interaction. Specifically, we show that light absorption and photocurrent generation in a sub-100 nm active semiconductor layer of a model solar cell can be enhanced by ~20% over a broad spectral band. PMID- 24952476 TI - Effect of concentrate level on feeding behavior and rumen and blood parameters in dairy goats: relationships between behavioral and physiological parameters and effect of between-animal variability. AB - This work aimed first to compare 2 diets differing in their percentage of concentrate [low (LO): 30% concentrate vs. High (HI): 60% concentrate] by measuring simultaneously feeding behavior, rumen parameters, blood and plasma parameters, and milk yield and composition in 8 mid-lactation goats. The second aim was to study the interrelationships between these variables and to analyze the between-animal variability to better understand the between-animal differences in acidosis susceptibility. All of the animals received the 2 diets ad libitum as total mixed ration according to a crossover design of two 4-wk periods. Mean daily DMI was similar between the 2 diets but the variability was higher for the HI than for the LO diet. Goats produced more milk when fed the HI diet compared with the LO diet but with a lower fat:protein ratio (0.81 vs. 0.99). They ate more rapidly the HI than the LO diet but stopped eating sooner after the afternoon feed allowance, and spent less time chewing. The increase in concentrate percentage modified rumen parameters: the pH and acetate:propionate ratio decreased and total VFA, ammonia, and soluble carbohydrate concentrations increased. Hematocrit, plasma NEFA, and blood K and Ca concentrations decreased but glycemia and uremia increased. Other parameters were not modified: milk fat content, blood pH, and bicarbonate and Na concentrations. A large between-animal variability was detected for all the measured parameters, especially for feeding behavior, with important consequences on rumen and blood parameters. This work confirmed the effects of a high percentage of concentrate on feeding behavior, rumen and blood parameters, and milk production, and some known relationships such as the positive link between rumen pH and chewing index. It also pointed out other relationships between parameters seldom measured at the same time, such as rumen redox potential or blood pH and chewing index, or the negative link between blood and rumen pH. When the animals spent a lot of time chewing, they probably produced a lot of saliva that buffered the rumen pH and prevented them from suffering from subacute ruminal acidosis. However, they used part of their blood bicarbonates reserve, which might have induced metabolic acidosis, as rumen and blood pH were inversely related. This could explain why some animals suffer from acidosis and others do not in a herd receiving the same diet, and why some animals seem to suffer more from subacute ruminal acidosis and others from metabolic acidosis. PMID- 24952478 TI - Recent advances in the genetics of dystonia. AB - Dystonia, a common and genetically heterogeneous neurological disorder, was recently defined as "a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both." Via the application of whole-exome sequencing, the genetic landscape of dystonia and closely related movement disorders is becoming exposed. In particular, several "novel" genetic causes have been causally associated with dystonia or dystonia-related disorders over the past 2 years. These genes include PRRT2 (DYT10), CIZ1 (DYT23), ANO3 (DYT24), GNAL (DYT25), and TUBB4A (DYT4). Despite these advances, major gaps remain in identifying the genetic origins for most cases of adult-onset isolated dystonia. Furthermore, model systems are needed to study the biology of PRRT2, CIZ1, ANO3, Galphaolf, and TUBB4A in the context of dystonia. This review focuses on these recent additions to the family of dystonia genes, genotype-phenotype correlations, and possible cellular contributions of the encoded proteins to the development of dystonia. PMID- 24952479 TI - Botulinum toxin for symptomatic therapy in multiple sclerosis. AB - Botulinum toxin (BT) is a neurotoxin that paralyzes muscles by inhibiting release of acetylcholine from presynaptic vesicles at the neuromuscular junction. In people with multiple sclerosis (MS), clinical experience and research studies show that local injection of minute quantities of BT can temporarily control skeletal muscle spasticity, bladder detrusor hyperreflexia, and tremor. Specifically, BT injections have been shown to reduce muscle tone and improve passive function, and possibly improve active function, in patients with spasticity. Injection of BT into the bladder wall is a uniquely effective, safe, and durable treatment in patients with neurogenic detrusor hyperreflexia due to MS who have insufficient response or who do not tolerate oral antimuscarinic medications. This procedure has markedly reduced the need for indwelling catheters and bladder surgery. In addition, a recent study suggests BT may be effective for select patients with MS-associated upper extremity tremor. Appropriate use of BT can improve quality of life for many patients with MS. PMID- 24952477 TI - Mammary gland involution as an immunotherapeutic target for postpartum breast cancer. AB - Postpartum mammary gland involution has been identified as tumor-promotional and is proposed to contribute to the increased rates of metastasis and poor survival observed in postpartum breast cancer patients. In rodent models, the involuting mammary gland microenvironment is sufficient to induce enhanced tumor cell growth, local invasion, and metastasis. Postpartum involution shares many attributes with wound healing, including upregulation of genes involved in immune responsiveness and infiltration of tissue by immune cells. In rodent models, treatment with non-steroidal anti-inflammatory drugs (NSAIDs) ameliorates the tumor-promotional effects of involution, consistent with the immune milieu of the involuting gland contributing to tumor promotion. Currently, immunotherapy is being investigated as a means of breast cancer treatment with the purpose of identifying ways to enhance anti-tumor immune responses. Here we review evidence for postpartum mammary gland involution being a uniquely defined 'hot-spot' of pro-tumorigenic immune cell infiltration, and propose that immunotherapy should be explored for prevention and treatment of breast cancers that arise in this environment. PMID- 24952480 TI - Pathology in primary progressive aphasia syndromes. AB - 'Primary progressive aphasia' (PPA) refers to core linguistic disorders caused by neurodegenerative disease. Three main PPA variants are recognized: nonfluent/agrammatic, semantic and logopenic. Correctly classifying patients during life according to the underlying histopathology will become increasingly important as cause-specific treatments become available. This article reviews clinical and histopathological studies of PPA, with particular reference to updated PPA classifications. Currently, one-to-one relationships do not exist within PPA subtypes. The semantic variant has the best correspondence between the clinical syndrome and the underlying pathological cause and the logopenic variant the worst correspondence. The use of future biomarkers should facilitate accurate clinicopathological correlation of patients during life. PMID- 24952481 TI - miR-125a inhibits porcine preadipocytes differentiation by targeting ERRalpha. AB - MicroRNAs are a family of small, non-coding RNAs that regulate gene expression in a sequence-specific manner. Estrogen-related receptor alpha (ERRalpha) is an orphan nuclear receptor which plays an important role in adipocyte differentiation. Our previous Solexa sequencing results indicated a high expression of miR-125a in adult pig backfat. In this study, we predicated and experimentally validated ERRalpha as a target of miR-125a. To explore the role of miR-125a in porcine preadipocytes differentiation, miRNA agomir and antagomir were used to perform miR-125a overexpression or knockdown, respectively. Our results showed that overexpression of miR-125a could dramatically reduce the mRNA expression of adipogenic markers PPARgamma, LPL, and aP2, as well as its target gene ERRalpha. Western blotting showed the protein level of aP2 and ERRalpha was also significantly down-regulated. The overexpression of miR-125a also led to a notable reduction in lipid accumulation which was detected by Oil Red O staining. In contrast, we observed promoted differentiation of porcine preadipocytes upon miR-125a inhibition. In conclusion, we verified miR-125a inhibits porcine preadipocytes differentiation through targeting ERRalpha for the first time, which may provide new insights in pork quality improvement and obesity control. PMID- 24952484 TI - Effect of continuous irradiation with terahertz electromagnetic waves of the NO frequency range on behavioral reactions of male albino rats under stress conditions. AB - We studied the effect of terahertz waves (NO frequency range, 150.176-150.664 GHz) on stress-induced variations in behavioral reactions of male albino rats during hypokinetic stress. THz irradiation was followed by partial or complete normalization of behavioral reactions of male albino rats after hypokinetic stress. The most significant effect was observed after continuous irradiation for 30 min. PMID- 24952483 TI - Identification and validation of suitable reference genes for RT-qPCR analysis in mouse testis development. AB - RT-qPCR is a commonly used method for evaluating gene expression; however, its accuracy and reliability are dependent upon the choice of appropriate reference gene(s), and there is limited information available on suitable reference gene(s) that can be used in mouse testis at different stages. In this study, using the RT qPCR method, we investigated the expression variations of six reference genes representing different functional classes (Actb, Gapdh, Ppia, Tbp, Rps29, Hprt1) in mice testis during embryonic and postnatal development. The expression stabilities of putative reference genes were evaluated using five algorithms: geNorm, NormFinder, Bestkeeper, the comparative delta C(t) method and integrated tool RefFinder. Analysis of the results showed that Ppia, Gapdh and Actb were identified as the most stable genes and the geometric mean of Ppia, Gapdh and Actb constitutes an appropriate normalization factor for gene expression studies. The mRNA expression of AT1 as a test gene of interest varied depending upon which of the reference gene(s) was used as an internal control(s). This study suggested that Ppia, Gapdh and Actb are suitable reference genes among the six genes used for RT-qPCR normalization and provide crucial information for transcriptional analyses in future studies of gene expression in the developing mouse testis. PMID- 24952482 TI - Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells. AB - Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 (EML4)--anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK. PMID- 24952485 TI - Activity of the glutathione antioxidant system and NADPH-generating enzymes in blood serum of rats with type 2 diabetes mellitus after administration of melatonin-correcting drugs. AB - We studied the effects of epifamin and melaxen on serum content of reduced glutathione and activities of glutathione peroxidase, glutathione reductase, and NADPH-generating enzymes (glucose-6-phosphate dehydrogenase and NADP-isocitrate dehydrogenase) in rats with type 2 diabetes mellitus. The concentration of reduced glutathione was decreased in rats with this disease (by 1.8 times), but increased after treatment with epifamin and melaxen (by 1.6 and 1.7 times, respectively). Activities of glutathione peroxidase, glutathione reductase, and NADPH-generating enzymes returned to the control level. Correction of melatonin concentration after treatment with the test drugs was probably followed by inhibition of free radical processes. The observed changes were accompanied by normalization of activity of the glutathione antioxidant system and NADPH generating enzymes required for normal function of this system. PMID- 24952486 TI - Oxidized extracellular DNA suppresses nitric oxide production by endothelial NO synthase (eNOS) in human endothelial cells (HUVEC). AB - Circulating DNA from patients with cardiovascular diseases reduce the synthesis of NO in endothelial cells, which is probably related to oxidative modification of DNA. To test this hypothesis, HUVEC cells were cultured in the presence of DNA containing ~1 (nonoxidized DNA), 700, or 2100 8-oxodG/10(6) nucleosides. Nonoxidized DNA stimulated the synthesis of NO, which was associated with an increase in the expression of endothelial NO synthase. Oxidized NO decreased the amount of mRNA and protein for endothelial NO synthase, but increased the relative content of its low active form. These changes were accompanied by reduction of NO production. These findings suggest that oxidative modification of circulating extracellular DNA contributes to endothelial dysfunction manifested in suppression of NO production. PMID- 24952487 TI - Inhibition of plasma coagulation and platelet aggregation with structural analogs of taurine chloramine. AB - We studied the effects of amide and N-alkyl analogs of taurine chloramine on rabbit plasma coagulation and platelet aggregation. Alkyl analog N-isopropyl-N chlorotaurine produced greater increase in plasma coagulation time after its activation by the contact method or with thrombin than amide analog N-propionyl-N chlorotaurine. In case of coagulation induced by the tissue factor, the test analogs produced similar effect. Inhibition of platelet aggregation in platelet rich plasma under the effect of N-isopropyl-N-chlorotaurine depended on the nature of the agonist. Aggregation was suppressed stronger under conditions of collagen stimulation than in response to ADP agonist. Estimated partial charges of the chlorine atom in amide analogs were 5-fold higher than in N-alkyl analogs. This fact determined the difference in the chemoselective interaction with sulfur containing amino acid residues in targets and the specific features of anticoagulation and antiaggregant effects of two analogs of taurine chloramine. PMID- 24952489 TI - Administration of dopamine to rats disorganizes the rhythm of protein synthesis in hepatocytes. AB - Dopamine was injected intravenously (9 MUg/kg) or intraperitoneally (15 MUg/kg) to Wistar rats (3-4 months, 300-400 g). Hepatocytes were isolated 40 min after dopamine injection. Dense cultures were maintained on collagen-coated glasses. By the 5th hour, the circaholarian rhythm of protein synthesis in hepatocytes cultures was absent in the dopamine group, but was present in cultures from animals receiving physiological saline (NaCl). The rhythm-disorganizing effect of dopamine was reversible. The rhythm was observed in cultures of hepatocytes isolated 1 day after dopamine treatment. The effect of dopamine was abolished by melatonin. The protein synthesis rhythm was revealed in 5-h cultures of hepatocytes from rats receiving melatonin (32 ng/kg) 40 min after intraperitoneal injection of dopamine. The results of our in vitro experiments with addition of dopamine into the medium of cultured hepatocytes [1] suggest that dopamine in vivo produces a direct effect on liver cells. The observed changes are discussed taking into account the biochemical mechanisms for a direct cell-cell interaction and previously unknown properties of catecholamines. PMID- 24952488 TI - Hemorheologic effects of dibornol in a model of myocardial ischemia/reperfusion. AB - We studied the effects of novel sterically hindered phenol, 4-methyl-2,6 diisobornyl phenol (dibornol) on the rheological properties of the blood in the model of myocardial ischemia/reperfusion. Dibornol (100 mg/kg intraperitoneally for 3 days before and 5 days after ischemia/reperfusion) decreased blood viscosity by 9-25% in comparison with that in sham-operatedanimals by modulating cellular (erythrocyte deformability and aggregation) and plasma (plasma viscosity) rheological parameters. Normalization of blood rheology under the influence of dibornol increased the availability of oxygen to tissues at high shear rates by 9-18% after acute ischemia/reperfusion in rats. PMID- 24952490 TI - Involvement of cAMP- and IKK-2-dependent signal pathways in the growth capacity of mesenchymal progenitor cells under the influence of basic fibroblast growth factor. AB - We studied the role of cAMP- and IKK-2-dependent pathways under conditions of functional stimulation of mesenchymal progenitor cells by basic fibroblast growth factor. An adenylate cyclase inhibitor 2',5'-dideoxyadenosine had no effect on functional activity of early (primitive) mesenchymal precursors. This agent produced a stimulatory effect on proliferation of stromal precursor cells. Mitotic activity of mesenchymal progenitor cells was shown to decrease after treatment with a specific blocker of the IKK-2 kinase-inhibitor complex. PMID- 24952491 TI - Effect of cyclopentyladenosine on lipid peroxidation during focal cerebral ischemia. AB - The antioxidant effect of an adenosine A1 receptor agonist cyclopentyladenosine was studied on the model of focal cerebral ischemia. Ischemic injury of the brain was accompanied by changes in LPO processes (in the blood and brain tissue) and failure of some factors for antioxidant protection (peroxidase and catalase) that inactivate reactive metabolites. Changes in the ratio between LPO and antioxidant protection were less pronounced after treatment with cyclopentyladenosine. PMID- 24952492 TI - Hypotensive effect of retabolil correcting the concentration of aldosterone during stress exposures. AB - Male rats were exposed to single or repeated (19 days) cold treatment (4 degrees C) and non-cold stress (60-min shaking on a laboratory shuttle device). Retabolil had a hypotensive effect, which was accompanied by the prevention of a stress induced increase in the concentration of a hypertensive hormone aldosterone. Under conditions of repeated stress, these effects were realized via MU-opioid receptors. Our results suggest that retabolil can be used as a hypotensive and aldosterone-blocking agent, at least during stress exposure in animals (and probably in humans). PMID- 24952493 TI - Semaforin Sema4D in the immune system in multiple sclerosis. AB - The expression of class IV semaforin Sema4D and its CD72 receptor on lymphocytes was studied in patients with multiple sclerosis. The disease was associated with an increase in Sema4D level on intact T lymphocytes and with its more intense shedding from the membrane of activated cell. Multiple sclerosis was also associated with a decrease of CD72 receptor expression by B lymphocytes. Possible contribution of Sema4D to the disease development via the direct effects in the CNS and the immunomodulatory effect, specifically, B cell activity regulation, was discussed. PMID- 24952495 TI - Integrins LFA-1 and Mac-1 and cytokines IL-6 and IL-10 in high-cancer mice under the influence of phytoadaptogen. AB - The expression of leukocyte integrins LFA-1 and Mac-1 and cytokines IL-6 and IL 10 was studied in mice predisposed to spontaneous hepatocarcinomas. The efficacy of a phytoadaptogen in correcting these parameters was evaluated. The role of adhesive interactions between immune cells and target cells in the recovery of antitumor regulatory mechanisms was estimated. PMID- 24952494 TI - Biological effects of individually synthesized TNF-binding domain of variola virus CrmB protein. AB - The biological characteristics of a 17-kDa protein synthesized in bacterial cells, a TNF-binding domain (VARV-TNF-BP) of a 47-kDa variola virus CrmB protein (VARV-CrmB) consisting of TNF-binding and chemokine-binding domains, were studied. Removal of the C-terminal chemokine-binding domain from VARV-CrmB protein was inessential for the efficiency of its inhibition of TNF cytotoxicity towards L929 mouse fibroblast culture and for TNF-induced oxidative metabolic activity of mouse blood leukocytes. The results of this study could form the basis for further studies of VARV-TNF-BP mechanisms of activity for prospective use in practical medicine. PMID- 24952496 TI - Ultrastructural changes in ageing lacrimal gland in Wistar rats. AB - We studied age-related ultrastructural reorganization in acinar cells and intercalary ducts of the lacrimal gland acini in 3-, 15-, and 24-month-old Wistar rats. Ultrastructural changes in the lacrimal gland progressed with age and led to dramatic ultrastructural reconstruction of the lacrimal gland at the age of 24 months. These changes mainly included complete destruction of acinar cells and increase in the number of enlarged branched ducts that filled the greater part of gland volume; these dusts were lined with epithelial cells with altered ultrastructure. Acinar cells in the acini communicate via special connecting intermembrane complexes formed by desmosomes and mitochondria adjacent to them in each contacting cell. It is assumed that association of mitochondria with desmosomes found in the acini is a special functional complex indicating that every single acinus is a functional formation. This assumption is indirectly confirmed by the fact that the destruction never occurred in a single cell, but always involved all cells constituting the acini. The revealed ultrastructural changes reflect age-related deterioration of the secretory function of the lacrimal gland. PMID- 24952497 TI - Early echocardiographic manifestations of primary chronic septic endocarditis. AB - Echocardiographic manifestations of the early stages of primary chronic septic endocarditis are studied in patients with mono-, bi-, and multivalvular valvulitis. The basic morphological substrate of the disease is fibrosis; the main trend is progressive fibrosis of valvular and extravalvular endocardial structures leading in many cases to stenosis of the valvular orifices. The results in some cases do not permit us to regard fibrosis as a result of previous "healed" endocarditis ruling out the presence of an inflammatory process. The basic morphological substrate of the disease corresponds to primary chronic inflammation, intrinsic to this condition. The data on the early manifestations of infectious endocarditis supplement the notions on echocardiographic manifestations this condition. PMID- 24952499 TI - The use of inert gas xenon for cryopreservation of leukocytes. AB - We studied the possibility of cryopreservation of human blood nuclear cells under protection with inert gas xenon. A method for inducing clathrate anabiosis of leukocytes was developed that preserved the cells for practical use in biology and medicine. PMID- 24952498 TI - Morphofunctional characteristics of the glutathione cycle in peripheral blood erythrocytes of pregnant women with a history of cytomegalovirus infection exacerbation during gestation. AB - We studied factors influencing peripheral blood erythrocytes of pregnant women with exacerbation of cytomegalovirus infection during gestation. Cytomegalovirus infection was associated with a decrease in the content of reduced glutathione in erythrocytes and glutathione peroxidase, which leads to H2O2 accumulation in the blood. Exacerbation of cytomegalovirus infection was associated with reduction of glutathione reductase and SOD activities. Erythrocyte antioxidant function and the peripheral blood discocyte count decreased. Accumulation of degenerative erythrocytes is fraught with the risk of anemia in pregnant women. PMID- 24952500 TI - A universal method for measuring functional activity of complement in humans, laboratory, domestic, and agricultural animals, amphibians, and birds. AB - A new universal method for measuring activity of the serum complement system in humans, laboratory, domestic, agricultural animals, birds and amphibians is based on automated evaluation of the mortality of ciliate Tetrahymena pyriformis under the effect of the complement system. In contrast to the hemolytic method, measured activity of the complement shows no erroneously high results caused by reactive lysis in febrile patients. The method can be used for studies of the complement system in humans and animals without species-specific adaptation. PMID- 24952501 TI - Measurement of mitochondrial membrane potential in leukocyte suspension by fluorescent spectroscopy. AB - A method for evaluating mitochondrial membrane potential in isolated leukocyte suspension with the use of sensitive fl uorescent cation-active dye 5,5',6,6' tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine (JC-1) and spectrophotometry is described. JC-1 monomer rapidly penetrates through mitochondrial membrane of living cell and form aggregations characterized by red fl uorescence (lambda = 585 nm). In case of mitochondrial membrane depolarization (early sign of apoptosis), JC-1 is not accumulated in the mitochondria and is present in the cytoplasm as a monomer characterized by green spectral fl uorescence (lambda = 510 nm). The method can be used for evaluation of the function of living cells and mechanisms regulating energy metabolism by evaluating the mitochondrial membrane potential. PMID- 24952502 TI - Mathematical modeling of functioning of the p53-Mdm2 protein system. AB - Mathematical simulation of the time course of p53 and Mdm2 protein concentrations during their interactions was carried out. The system states corresponding to threatened uncontrolled apoptotic cell death accelerating aging processes and to situation with hypersuppression of p53-dependent apoptosis fraught with high risk of cancer were modeled. New data indicate the possibility of description (within the framework of mathematical model used in the study) of the p53 and Mdm2 proteins feedback mechanism, which could guarantee adequate reaction to serious DNA damage. PMID- 24952506 TI - Field-theoretic description of charge regulation interaction. AB - In order to find the exact form of the electrostatic interaction between two proteins with dissociable charge groups in aqueous solution, we have studied a model system composed of two macroscopic surfaces with charge dissociation sites immersed in a counterion-only ionic solution. Field-theoretic representation of the grand canonical partition function is derived and evaluated within the mean field approximation, giving the Poisson-Boltzmann theory with the Ninham Parsegian boundary condition. Gaussian fluctuations around the mean field are then analyzed in the lowest-order correction that we calculate analytically and exactly, using the path integral representation for the partition function of a harmonic oscillator with time-dependent frequency. The first-order (one loop) free-energy correction gives the interaction free energy that reduces to the zero frequency van der Waals form in the appropriate limit but in general gives rise to a monopolar fluctuation term due to charge fluctuation at the dissociation sites. Our formulation opens up the possibility to investigate the Kirkwood Shumaker interaction in more general contexts where their original derivation fails. PMID- 24952503 TI - Diverse intracellular pathogens activate type III interferon expression from peroxisomes. AB - Type I interferon responses are considered the primary means by which viral infections are controlled in mammals. Despite this view, several pathogens activate antiviral responses in the absence of type I interferons. The mechanisms controlling type I interferon-independent responses are undefined. We found that RIG-I like receptors (RLRs) induce type III interferon expression in a variety of human cell types, and identified factors that differentially regulate expression of type I and type III interferons. We identified peroxisomes as a primary site of initiation of type III interferon expression, and revealed that the process of intestinal epithelial cell differentiation upregulates peroxisome biogenesis and promotes robust type III interferon responses in human cells. These findings highlight the importance of different intracellular organelles in specific innate immune responses. PMID- 24952504 TI - The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. AB - Assembly of the NLRP3 inflammasome activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1beta and thereby serves a central role in the inflammatory response and in diverse human diseases. Here we found that upon activation of caspase-1, oligomeric NLRP3 inflammasome particles were released from macrophages. Recombinant oligomeric protein particles composed of the adaptor ASC or the p.D303N mutant form of NLRP3 associated with cryopyrin associated periodic syndromes (CAPS) stimulated further activation of caspase-1 extracellularly, as well as intracellularly after phagocytosis by surrounding macrophages. We found oligomeric ASC particles in the serum of patients with active CAPS but not in that of patients with other inherited autoinflammatory diseases. Our findings support a model whereby the NLRP3 inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response. PMID- 24952507 TI - Scientific integrity in Brazil. AB - This article focuses on scientific integrity and the identification of predisposing factors to scientific misconduct in Brazil. Brazilian scientific production has increased in the last ten years, but the quality of the articles has decreased. Pressure on researchers and students for increasing scientific production may contribute to scientific misconduct. Cases of misconduct in science have been recently denounced in the country. Brazil has important institutions for controlling ethical and safety aspects of human research, but there is a lack of specific offices to investigate suspected cases of misconduct and policies to deal with scientific dishonesty. PMID- 24952508 TI - Procedure. AB - This piece examines the diagnostic procedures for breast cancer from the patient's point of view, trying to establish the importance of communication and reassurance, while showing how the absence of these can lead to greater distress than necessitated. PMID- 24952505 TI - The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. AB - Microbes or danger signals trigger inflammasome sensors, which induce polymerization of the adaptor ASC and the assembly of ASC specks. ASC specks recruit and activate caspase-1, which induces maturation of the cytokine interleukin 1beta (IL-1beta) and pyroptotic cell death. Here we found that after pyroptosis, ASC specks accumulated in the extracellular space, where they promoted further maturation of IL-1beta. In addition, phagocytosis of ASC specks by macrophages induced lysosomal damage and nucleation of soluble ASC, as well as activation of IL-1beta in recipient cells. ASC specks appeared in bodily fluids from inflamed tissues, and autoantibodies to ASC specks developed in patients and mice with autoimmune pathologies. Together these findings reveal extracellular functions of ASC specks and a previously unknown form of cell-to-cell communication. PMID- 24952510 TI - Down-regulation of miR-29c in human bladder cancer and the inhibition of proliferation in T24 cell via PI3K-AKT pathway. AB - The purpose of this study was to explore new tumor suppressor microRNA in bladder cancer and to conduct functional analysis of its suppressive role. To investigate the expression of miR-29c, qRT-PCR was used in 30 pairs of bladder cancer tissues and normal tissues (adjacent bladder tissue samples). The expression of miR-29c was down regulated in bladder cancer tissues compared with normal tissues. Also, the low-level expression of miR-29c was associated with tumor stage (P = 0.002), and ectopic over-expression of miR-29c in T24 cells can significantly inhibit cell proliferation, decrease motility, suppress the G1/S cell cycle transition and induce apoptosis. Furthermore, it could cause a decrease in AKT and GSK-3beta phosphorylation. While LY294002 reduced the protein level of pAKT, the over expression of miR-29c can further decrease its level in T24 cells pretreated with LY294002. Our study also indicated that the proliferation inhibition of T24 may take place via AKT-GSK3beta pathway. Thus, miR-29c could be an active player in disease state of bladder cancer and it may be a promising tumor suppressor in bladder cancer. PMID- 24952511 TI - High-resolution genome-wide analysis identified recurrent genetic alterations in NK/T-cell lymphoma, nasal type, which are associated with disease progression. AB - Extranodal NK/T-cell lymphoma, nasal type, is an aggressive mature NK-cell/T-cell lymphoma. Using array-based comparative genomic hybridization (array CGH) assays, we screened genomic alterations and potential candidate genes implicated in pathogenesis, progression, and prognosis. Our array CGH analysis detected an average of 83 chromosomal aberrations in 13 cases, ranging from 0 to 387. There were 177 recurrent chromosomal gains and 35 recurrent losses. Eleven gains and 14 losses were detected in more than 30 % of the cases, including gains of 3q26.1, 7q34, and 8q24.3 and losses of 15q24.2, 19q13.32, 5p13.2, and 14q21.1. The most common losses were observed in the 15q24.2 and 19q13.32 regions (9 cases, 69.2 %, respectively). Loss of 8p11.23 was associated with significant poor survival (P = 0.024). Five out of six patients with the loss of 8p11.23 died within 8 months after initial diagnosis with a median survival of 6 months. Several candidate genes were identified in the regions with frequent chromosomal aberrations, including ADAM3A (8p11.23) and GSTT1 (22q11.23). In summary, our studies detected recurrent genetic alterations in NK/T-cell lymphoma, some of which are associated with adverse prognosis. Some candidate genes in these regions may be involved in the pathogenesis and disease progression. PMID- 24952509 TI - Serum levels of vitamin D, parathyroid hormone and calcium in relation to survival following breast cancer. AB - PURPOSE: Vitamin D, parathyroid hormone (PTH) and calcium in blood are correlated with each other. Previous studies have suggested vitamin D to have anti proliferative effects on tumor cells, whereas PTH may have carcinogenic effects. A cancer disease may influence calcium levels in blood, but less is known about calcium and its potential effect on cancer risk and survival. The aim of this study was to examine pre-diagnostic levels of vitamin D (25OHD), PTH and calcium in relation to survival after breast cancer. METHODS: The Malmo Diet and Cancer Study enrolled 17,035 women between 1991 and 1996. 672 patients developed incident invasive breast cancer up until 31 December 2006. Serum samples collected at baseline were analyzed for 25OHD, PTH and calcium. All patients were followed until 31 December 2010 using the Swedish Cause of Death Registry. The analytes were divided into tertiles and the risk of death from breast cancer was analyzed using an adjusted Cox proportional hazards analysis, yielding hazard ratios with 95 % confidence intervals. RESULTS: Levels of 25OHD and breast cancer mortality were associated in a u-shaped manner with the highest mortality among patients in the first (2.46: 1.38-4.37) and third tertiles (1.99: 1.14-3.49), as compared to the second. An inverse relation was found between calcium levels and breast cancer mortality, with the lowest mortality in the third tertile, (0.53: 0.30-0.92) as compared to the first. There was no clear association between PTH and breast cancer mortality. CONCLUSIONS: This study shows that pre-diagnostic 25OHD and calcium may affect survival following breast cancer. PMID- 24952513 TI - Unilateral duplication of the parotid duct, its embryological basis and clinical significance: a rare cadaveric case report. AB - The parotid gland is the largest salivary gland in humans, and produces mainly serous secretions. The secretion of this gland reaches the oral cavity through single parotid duct (Stensen's duct). The parotid duct begins at the anterior border of the gland, crosses the masseter, and then pierces the buccinator and open the mouth. The present study reports a rare variation of a unilateral double parotid duct that was observed in the right side of the face of a 75-year-old male cadaver during dissection. The embryological basis of this variation can be explained as follows. A sprout originates from epithelium lining the primitive oral cavity, grows dorsally, and bifurcates. The end parts of these branches invaginate into the adjacent mesenchyme separately, proliferate, and make the parotid gland, while their proximal parts later form communicating ducts (D1 and D2) connecting the gland to the mouth. Furthermore, the clinical importance of this variation was discussed. PMID- 24952514 TI - Communication: direct measurements of nascent O((3)P0,1,2) fine-structure distributions and branching ratios of correlated spin-orbit resolved product channels CO(a(3)Pi; v) + O((3)P0,1,2) and CO(X(1)Sigma(+); v) + O((3)P0,1,2) in VUV photodissociation of CO2. AB - We present a generally applicable experimental method for the direct measurement of nascent spin-orbit state distributions of atomic photofragments based on the detection of vacuum ultraviolet (VUV)-excited autoionizing-Rydberg (VUV-EAR) states. The incorporation of this VUV-EAR method in the application of the newly established VUV-VUV laser velocity-map-imaging-photoion (VMI-PI) apparatus has made possible the branching ratio measurement for correlated spin-orbit state resolved product channels, CO(a(3)Pi; v) + O((3)P0,1,2) and CO(X(1)Sigma(+); v) + O((3)P0,1,2), formed by VUV photoexcitation of CO2 to the 4s(10 (1)) Rydberg state at 97,955.7 cm(-1). The total kinetic energy release (TKER) spectra obtained from the O(+) VMI-PI images of O((3)P0,1,2) reveal the formation of correlated CO(a(3)Pi; v = 0-2) with well-resolved v = 0-2 vibrational bands. This observation shows that the dissociation of CO2 to form the spin-allowed CO(a(3)Pi; v = 0-2) + O((3)P0,1,2) channel has no potential energy barrier. The TKER spectra for the spin-forbidden CO(X(1)Sigma(+); v) + O((3)P0,1,2) channel were found to exhibit broad profiles, indicative of the formation of a broad range of rovibrational states of CO(X(1)Sigma(+)) with significant vibrational populations for v = 18-26. While the VMI-PI images for the CO(a(3)Pi; v = 0-2) + O((3)P0,1,2) channel are anisotropic, indicating that the predissociation of CO2 4s(10 (1)) occurs via a near linear configuration in a time scale shorter than the rotational period, the angular distributions for the CO(X(1)Sigma(+); v) + O((3)P0,1,2) channel are close to isotropic, revealing a slower predissociation process, which possibly occurs on a triplet surface via an intersystem crossing mechanism. PMID- 24952515 TI - Communication: direct comparison between theory and experiment for correlated angular and product-state distributions of the ground-state and stretching excited O((3)P) + CH4 reactions. AB - Motivated by a recent experiment [H. Pan and K. Liu, J. Chem. Phys. 140, 191101 (2014)], we report a quasiclassical trajectory study of the O((3)P) + CH4(vk = 0, 1) -> OH + CH3 [k = 1 and 3] reactions on an ab initio potential energy surface. The computed angular distributions and cross sections correlated to the OH(v = 0, 1) + CH3(v = 0) coincident product states can be directly compared to experiment for O + CH4(v3 = 0, 1). Both theory and experiment show that the ground-state reaction is backward scattered, whereas the angular distributions shift toward sideways and forward directions upon antisymmetric stretching (v3) excitation of the reactant. Theory predicts similar behavior for the O + CH4(v1 = 1) reaction. The simulations show that stretching excitation enhances the reaction up to about 15 kcal/mol collision energy, whereas the O + CH4(vk = 1) reactions produce smaller cross sections for OH(v = 1) + CH3(v = 0) than those of O + CH4(v = 0) -> OH(v = 0) + CH3(v = 0). The former finding agrees with experiment and the latter awaits for confirmation. The computed cold OH rotational distributions of O + CH4(v = 0) are in good agreement with experiment. PMID- 24952512 TI - Genetic polymorphism of metallothionein 2A and risk of laryngeal cancer in a Polish population. AB - Metallothioneins are intracellular regulators of many biological mechanisms including differentiation, proliferation, angiogenesis and invasion, which are crucial processes in carcinogenesis. This study examines the association between three single-nucleotide polymorphisms at loci -5 A/G (rs28366003) and -209 A/G (rs1610216) in the core promoter region and at locus +838 C/G (rs10636) in 3'UTR region of the metallothionein 2A (MT2A) gene with squamous cell laryngeal cancer (SCLC) risk, as well as with tumor invasiveness according to tumor front grading (TFG). Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism technique in 323 genetically unrelated individuals with SCLC and 418 randomly selected healthy volunteers. Only one SNP (rs28366003) was significantly related to laryngeal cancer in the study population. Compared with homozygous common allele carriers, heterozygous and homozygous for the G variant had significantly increased risk of SCLC [adjusted odds ratio (OR) = 2.90, 95 % confidence interval (CI) 1.53-5.21, p dominant < 0.001]. The A/G allele carriers at rs28366003 MT2A were at higher risk of SCLC development (OR = 2.63, 95 % CI 1.41-2.85, p < 0.001]. There was a significant association between the rs28366003 and stage and TFG classification. Most carriers of minor allele had a higher stage (OR = 2.76, 95 % CI 1.11-7.52, p = 0.03), increased cancer aggressiveness, as defined by a higher total TFG score (>18 points) (OR = 3.76, 95 % CI 1.15-12.56, p = 0.03) and diffuse tumor growth (OR = 5.86, 95 % Cl 0.72 44.79, p = 0.08). The results of this study raise a possibility that a genetic variation of MT2A may be implicated in the etiology of laryngeal cancer in a Polish population. PMID- 24952516 TI - Communication: ultrafast homonuclear correlation spectroscopy with diagonal suppression. AB - A novel ultrafast 2D NMR experiment is introduced for homonuclear correlation spectroscopy in solution state, with diagonal peak suppression in each scan of a two scan procedure. This experiment permits clear visualization of cross peaks between spins whose chemical shifts are very close, which could otherwise be masked by diagonal peaks. The present report describes the principles of its design and illustrates actual performance. PMID- 24952517 TI - Inclusion of trial functions in the Langevin equation path integral ground state method: application to parahydrogen clusters and their isotopologues. AB - We developed and studied the implementation of trial wavefunctions in the newly proposed Langevin equation Path Integral Ground State (LePIGS) method [S. Constable, M. Schmidt, C. Ing, T. Zeng, and P.-N. Roy, J. Phys. Chem. A 117, 7461 (2013)]. The LePIGS method is based on the Path Integral Ground State (PIGS) formalism combined with Path Integral Molecular Dynamics sampling using a Langevin equation based sampling of the canonical distribution. This LePIGS method originally incorporated a trivial trial wavefunction, psiT, equal to unity. The present paper assesses the effectiveness of three different trial wavefunctions on three isotopes of hydrogen for cluster sizes N = 4, 8, and 13. The trial wavefunctions of interest are the unity trial wavefunction used in the original LePIGS work, a Jastrow trial wavefunction that includes correlations due to hard-core repulsions, and a normal mode trial wavefunction that includes information on the equilibrium geometry. Based on this analysis, we opt for the Jastrow wavefunction to calculate energetic and structural properties for parahydrogen, orthodeuterium, and paratritium clusters of size N = 4 - 19, 33. Energetic and structural properties are obtained and compared to earlier work based on Monte Carlo PIGS simulations to study the accuracy of the proposed approach. The new results for paratritium clusters will serve as benchmark for future studies. This paper provides a detailed, yet general method for optimizing the necessary parameters required for the study of the ground state of a large variety of systems. PMID- 24952518 TI - An improved DNA force field for ssDNA interactions with gold nanoparticles. AB - The widespread applications of single-stranded DNA (ssDNA) conjugated gold nanoparticles (AuNPs) have spurred an increasing interest in the interactions between ssDNA and AuNPs. Despite extensive studies using the most sophisticated experimental techniques, the detailed molecular mechanisms still remain largely unknown. Large scale molecular dynamics (MD) simulations can thus be used to supplement experiments by providing complementary information about ssDNA-AuNP interactions. However, up to now, all modern force fields for DNA were developed based on the properties of double-stranded DNA (dsDNA) molecules, which have hydrophilic outer backbones "protecting" hydrophobic inner nucleobases from water. Without the double-helix structure of dsDNA and thus the "protection" by the outer backbone, the nucleobases of ssDNA are directly exposed to solvent, and their behavior in water is very different from that of dsDNA, especially at the interface with nanoparticles. In this work, we have improved the force field of ssDNA for use with nanoparticles, such as AuNPs, based on recent experimental results and quantum mechanics calculations. With the new improved force field, we demonstrated that a poly(A) sequence adsorbed on a AuNP surface is much more stable than a poly(T) sequence, which is consistent with recent experimental observations. On the contrary, the current standard force fields, including AMBER03, CHARMM27, and OPLSAA, all gave erroneous results as compared to experiments. The current improved force field is expected to have wide applications in the study of ssDNA with nanomaterials including AuNPs, which might help promote the development of ssDNA-based biosensors and other bionano devices. PMID- 24952519 TI - Configuration interaction wave functions: a seniority number approach. AB - This work deals with the configuration interaction method when an N-electron Hamiltonian is projected on Slater determinants which are classified according to their seniority number values. We study the spin features of the wave functions and the size of the matrices required to formulate states of any spin symmetry within this treatment. Correlation energies associated with the wave functions arising from the seniority-based configuration interaction procedure are determined for three types of molecular orbital basis: canonical molecular orbitals, natural orbitals, and the orbitals resulting from minimizing the expectation value of the N-electron seniority number operator. The performance of these bases is analyzed by means of numerical results obtained from selected N electron systems of several spin symmetries. The comparison of the results highlights the efficiency of the molecular orbital basis which minimizes the mean value of the seniority number for a state, yielding energy values closer to those provided by the full configuration interaction procedure. PMID- 24952520 TI - Maximal entropy random walk improves efficiency of trapping in dendrimers. AB - We use maximal entropy random walk (MERW) to study the trapping problem in dendrimers modeled by Cayley trees with a deep trap fixed at the central node. We derive an explicit expression for the mean first passage time from any node to the trap, as well as an exact formula for the average trapping time (ATT), which is the average of the source-to-trap mean first passage time over all non-trap starting nodes. Based on the obtained closed-form solution for ATT, we further deduce an upper bound for the leading behavior of ATT, which is the fourth power of ln N, where N is the system size. This upper bound is much smaller than the ATT of trapping depicted by unbiased random walk in Cayley trees, the leading scaling of which is a linear function of N. These results show that MERW can substantially enhance the efficiency of trapping performed in dendrimers. PMID- 24952522 TI - Relativistic nuclear magnetic resonance J-coupling with ultrasoft pseudopotentials and the zeroth-order regular approximation. AB - We present a method for the first-principles calculation of nuclear magnetic resonance (NMR) J-coupling in extended systems using state-of-the-art ultrasoft pseudopotentials and including scalar-relativistic effects. The use of ultrasoft pseudopotentials is allowed by extending the projector augmented wave (PAW) method of Joyce et al. [J. Chem. Phys. 127, 204107 (2007)]. We benchmark it against existing local-orbital quantum chemical calculations and experiments for small molecules containing light elements, with good agreement. Scalar relativistic effects are included at the zeroth-order regular approximation level of theory and benchmarked against existing local-orbital quantum chemical calculations and experiments for a number of small molecules containing the heavy row six elements W, Pt, Hg, Tl, and Pb, with good agreement. Finally, (1)J(P-Ag) and (2)J(P-Ag-P) couplings are calculated in some larger molecular crystals and compared against solid-state NMR experiments. Some remarks are also made as to improving the numerical stability of dipole perturbations using PAW. PMID- 24952523 TI - Eckart-Sayvetz conditions revisited. AB - It is shown that vibrational displacements satisfying the Eckart-Sayvetz conditions can be constructed by projection of unconstrained displacements. This result has a number of interesting direct and indirect ramifications: (i) The normal coordinates corresponding to an electronic state or an isotopologue of a molecule are transformed to those of another state or isotopologue by a linear and, in general, non-orthogonal transformation. (ii) Novel interpretation of axis switching. (iii) One may enhance the separation of rotational-large-amplitude internal motions and the vibrational motions beyond that offered by the standard use of the Eckart-Sayvetz conditions. (iv) The rotational-vibrational Hamiltonian given in terms of curvilinear internal coordinates may be derived with elementary mathematical tools while taking into account the Eckart conditions with or without enhancement. PMID- 24952521 TI - Fast and anisotropic flexibility-rigidity index for protein flexibility and fluctuation analysis. AB - Protein structural fluctuation, typically measured by Debye-Waller factors, or B factors, is a manifestation of protein flexibility, which strongly correlates to protein function. The flexibility-rigidity index (FRI) is a newly proposed method for the construction of atomic rigidity functions required in the theory of continuum elasticity with atomic rigidity, which is a new multiscale formalism for describing excessively large biomolecular systems. The FRI method analyzes protein rigidity and flexibility and is capable of predicting protein B-factors without resorting to matrix diagonalization. A fundamental assumption used in the FRI is that protein structures are uniquely determined by various internal and external interactions, while the protein functions, such as stability and flexibility, are solely determined by the structure. As such, one can predict protein flexibility without resorting to the protein interaction Hamiltonian. Consequently, bypassing the matrix diagonalization, the original FRI has a computational complexity of O(N(2)). This work introduces a fast FRI (fFRI) algorithm for the flexibility analysis of large macromolecules. The proposed fFRI further reduces the computational complexity to O(N). Additionally, we propose anisotropic FRI (aFRI) algorithms for the analysis of protein collective dynamics. The aFRI algorithms permit adaptive Hessian matrices, from a completely global 3N * 3N matrix to completely local 3 * 3 matrices. These 3 * 3 matrices, despite being calculated locally, also contain non-local correlation information. Eigenvectors obtained from the proposed aFRI algorithms are able to demonstrate collective motions. Moreover, we investigate the performance of FRI by employing four families of radial basis correlation functions. Both parameter optimized and parameter-free FRI methods are explored. Furthermore, we compare the accuracy and efficiency of FRI with some established approaches to flexibility analysis, namely, normal mode analysis and Gaussian network model (GNM). The accuracy of the FRI method is tested using four sets of proteins, three sets of relatively small-, medium-, and large-sized structures and an extended set of 365 proteins. A fifth set of proteins is used to compare the efficiency of the FRI, fFRI, aFRI, and GNM methods. Intensive validation and comparison indicate that the FRI, particularly the fFRI, is orders of magnitude more efficient and about 10% more accurate overall than some of the most popular methods in the field. The proposed fFRI is able to predict B-factors for alpha-carbons of the HIV virus capsid (313 236 residues) in less than 30 seconds on a single processor using only one core. Finally, we demonstrate the application of FRI and aFRI to protein domain analysis. PMID- 24952524 TI - Correlation correction to configuration interaction singles from coupled cluster perturbation theory. AB - A new state specific correlation correction to configuration interaction singles (CIS) excitation energies is presented using coupled cluster perturbation theory (CCPT). General expressions for CIS-CCPT are derived and expanded explicitly to first-order in the wavefunction and second-order in the energy. By virtue of the nature of CCPT this method is a priori size extensive and incorporates infinite order effects into the wavefunction. This results in a balanced singles space excited state theory that at second-order is an improvement over the ubiquitous CIS(D) method and comparable in quality to equation of motion coupled cluster (EOM-CC). A modest test set composed of the first four excited states from nine small organic molecules was used to quantify the accuracy and consistency of the CIS-CCPT2 excitation energies and density of states. We find that CIS-CCPT2 has a standard deviation error of 0.18 eV for excitation energies and 0.14 eV for density of states compared to EOM-CC, a factor of two better than CIS(D) with a significant reduction in the maximum deviation as well. PMID- 24952525 TI - Modeling time-coincident ultrafast electron transfer and solvation processes at molecule-semiconductor interfaces. AB - Kinetic models based on Fermi's Golden Rule are commonly employed to understand photoinduced electron transfer dynamics at molecule-semiconductor interfaces. Implicit in such second-order perturbative descriptions is the assumption that nuclear relaxation of the photoexcited electron donor is fast compared to electron injection into the semiconductor. This approximation breaks down in systems where electron transfer transitions occur on 100-fs time scale. Here, we present a fourth-order perturbative model that captures the interplay between time-coincident electron transfer and nuclear relaxation processes initiated by light absorption. The model consists of a fairly small number of parameters, which can be derived from standard spectroscopic measurements (e.g., linear absorbance, fluorescence) and/or first-principles electronic structure calculations. Insights provided by the model are illustrated for a two-level donor molecule coupled to both (i) a single acceptor level and (ii) a density of states (DOS) calculated for TiO2 using a first-principles electronic structure theory. These numerical calculations show that second-order kinetic theories fail to capture basic physical effects when the DOS exhibits narrow maxima near the energy of the molecular excited state. Overall, we conclude that the present fourth-order rate formula constitutes a rigorous and intuitive framework for understanding photoinduced electron transfer dynamics that occur on the 100-fs time scale. PMID- 24952526 TI - Calculation of state-to-state differential and integral cross sections for atom diatom reactions with transition-state wave packets. AB - A recently proposed transition-state wave packet method [R. Welsch, F. Huarte Larranaga, and U. Manthe, J. Chem. Phys. 136, 064117 (2012)] provides an efficient and intuitive framework to study reactive quantum scattering at the state-to-state level. It propagates a few transition-state wave packets, defined by the eigenfunctions of the low-rank thermal flux operator located near the transition state, into the asymptotic regions of the reactant and product arrangement channels separately using the corresponding Jacobi coordinates. The entire S-matrix can then be assembled from the corresponding flux-flux cross correlation functions for all arrangement channels. Since the transition-state wave packets can be defined in a relatively small region, its transformation into either the reactant or product Jacobi coordinates is accurate and efficient. Furthermore, the grid/basis for the propagation, including the maximum helicity quantum number K, is much smaller than that required in conventional wave packet treatments of state-to-state reactive scattering. This approach is implemented for atom-diatom reactions using a time-dependent wave packet method and applied to the H + D2 reaction with all partial waves. Excellent agreement with benchmark integral and differential cross sections is achieved. PMID- 24952527 TI - On energetic prerequisites of attracting electrons. AB - The internal reorganization energy and the zero-point vibrational energy (ZPE) of fractionally charged molecules embedded in molecular materials are discussed. The theory for isolated open quantum systems is taken as the starting point. It is shown that for isolated molecules the internal reorganization-energy function and its slope, i.e., the chemical potential of an open molecular system are monotonically decreasing functions with respect to increasing amount of negative excess charge (q) in the range of q = [0, 1]. Calculations of the ZPE for fractionally charged molecules show that the ZPE may have a minimum for fractional occupation. The calculations show that the internal reorganization energy and changes in the ZPE are of the same order of magnitude with different behavior as a function of the excess charge. The sum of the contributions might favor molecules with fractional occupation of the molecular units and partial delocalization of the excess electrons in solid-state materials also when considering Coulomb repulsion between the excess electrons. The fractional electrons are then coherently distributed on many molecules of the solid-state material forming a condensate of attracting electrons, which is crucial for the superconducting state. PMID- 24952528 TI - Extension and evaluation of the multilevel summation method for fast long-range electrostatics calculations. AB - Several extensions and improvements have been made to the multilevel summation method (MSM) of computing long-range electrostatic interactions. These include pressure calculation, an improved error estimator, faster direct part calculation, extension to non-orthogonal (triclinic) systems, and parallelization using the domain decomposition method. MSM also allows fully non-periodic long range electrostatics calculations which are not possible using traditional Ewald based methods. In spite of these significant improvements to the MSM algorithm, the particle-particle particle-mesh (PPPM) method was still found to be faster for the periodic systems we tested on a single processor. However, the fast Fourier transforms (FFTs) that PPPM relies on represent a major scaling bottleneck for the method when running on many cores (because the many-to-many communication pattern of the FFT becomes expensive) and MSM scales better than PPPM when using a large core count for two test problems on Sandia's Redsky machine. This FFT bottleneck can be reduced by running PPPM on only a subset of the total processors. MSM is most competitive for relatively low accuracy calculations. On Sandia's Chama machine, however, PPPM is found to scale better than MSM for all core counts that we tested. These results suggest that PPPM is usually more efficient than MSM for typical problems running on current high performance computers. However, further improvements to MSM algorithm could increase its competitiveness for calculation of long-range electrostatic interactions. PMID- 24952529 TI - Modeling intrinsic defects in LiNbO3 within the Slater-Janak transition state model. AB - Intrinsic point defects in LiNbO3, i.e., isolated Nb antisites and Li as well Nb vacancies, are investigated from first-principles within the Slater-Janak transition state model. Thereby the electronic structure of the investigated defects is calculated with hybrid exchange-correlation functionals. This approach allows for the calculation of charge transition levels without comparing the total energies of differently charged supercells. The obtained results are in agreement with previous hybrid density-functional theory calculations based on total-energy differences. Li and Nb vacancies can be formed in the V(-)(Li) and V(5-)(Nb) charge states only, as long as the host is not strongly p-type or n type, respectively. NbLi antisites may capture one or two electrons, forming the defect states often referred to as small bound polaron and bi-polaron. PMID- 24952530 TI - Dirac cones in the spectrum of bond-decorated graphenes. AB - We present a two-band model based on periodic Huckel theory, which is capable of predicting the existence and position of Dirac cones in the first Brillouin zone of an infinite class of two-dimensional periodic carbon networks, obtained by systematic perturbation of the graphene connectivity by bond decoration, that is by inclusion of arbitrary pi-electron Huckel networks into each of the three carbon-carbon pi-bonds within the graphene unit cell. The bond decoration process can fundamentally modify the graphene unit cell and honeycomb connectivity, representing a simple and general way to describe many cases of graphene chemical functionalization of experimental interest, such as graphyne, janusgraphenes, and chlorographenes. Exact mathematical conditions for the presence of Dirac cones in the spectrum of the resulting two-dimensional pi-networks are formulated in terms of the spectral properties of the decorating graphs. Our method predicts the existence of Dirac cones in experimentally characterized janusgraphenes and chlorographenes, recently speculated on the basis of density functional theory calculations. For these cases, our approach provides a proof of the existence of Dirac cones, and can be carried out at the cost of a back of the envelope calculation, bypassing any diagonalization step, even within Huckel theory. PMID- 24952531 TI - Dynamic density functional theory with hydrodynamic interactions and fluctuations. AB - We derive a closed equation for the empirical concentration of colloidal particles in the presence of both hydrodynamic and direct interactions. The ensemble average of our functional Langevin equation reproduces known deterministic Dynamic Density Functional Theory (DDFT) [M. Rex and H. Lowen, "Dynamical density functional theory with hydrodynamic interactions and colloids in unstable traps," Phys. Rev. Lett. 101(14), 148302 (2008)], and, at the same time, it also describes the microscopic fluctuations around the mean behavior. We suggest separating the ideal (non-interacting) contribution from additional corrections due to pairwise interactions. We find that, for an incompressible fluid and in the absence of direct interactions, the mean concentration follows Fick's law just as for uncorrelated walkers. At the same time, the nature of the stochastic terms in fluctuating DDFT is shown to be distinctly different for hydrodynamically-correlated and uncorrelated walkers. This leads to striking differences in the behavior of the fluctuations around Fick's law, even in the absence of pairwise interactions. We connect our own prior work [A. Donev, T. G. Fai, and E. Vanden-Eijnden, "A reversible mesoscopic model of diffusion in liquids: from giant fluctuations to Fick's law," J. Stat. Mech.: Theory Exp. (2014) P04004] on fluctuating hydrodynamics of diffusion in liquids to the DDFT literature, and demonstrate that the fluid cannot easily be eliminated from consideration if one wants to describe the collective diffusion in colloidal suspensions. PMID- 24952532 TI - How to remove the spurious resonances from ring polymer molecular dynamics. AB - Two of the most successful methods that are presently available for simulating the quantum dynamics of condensed phase systems are centroid molecular dynamics (CMD) and ring polymer molecular dynamics (RPMD). Despite their conceptual differences, practical implementations of these methods differ in just two respects: the choice of the Parrinello-Rahman mass matrix and whether or not a thermostat is applied to the internal modes of the ring polymer during the dynamics. Here, we explore a method which is halfway between the two approximations: we keep the path integral bead masses equal to the physical particle masses but attach a Langevin thermostat to the internal modes of the ring polymer during the dynamics. We justify this by showing analytically that the inclusion of an internal mode thermostat does not affect any of the established features of RPMD: thermostatted RPMD is equally valid with respect to everything that has actually been proven about the method as RPMD itself. In particular, because of the choice of bead masses, the resulting method is still optimum in the short-time limit, and the transition state approximation to its reaction rate theory remains closely related to the semiclassical instanton approximation in the deep quantum tunneling regime. In effect, there is a continuous family of methods with these properties, parameterised by the strength of the Langevin friction. Here, we explore numerically how the approximation to quantum dynamics depends on this friction, with a particular emphasis on vibrational spectroscopy. We find that a broad range of frictions approaching optimal damping give similar results, and that these results are immune to both the resonance problem of RPMD and the curvature problem of CMD. PMID- 24952533 TI - Measuring chirality in NMR in the presence of a time-dependent electric field. AB - Traditional nuclear magnetic resonance (NMR) experiments are "blind" to chirality since the spectra for left and right handed enantiomers are identical in an achiral medium. However, theoretical arguments have suggested that the effective Hamiltonian for spin-1/2 nuclei in the presence of electric and magnetic fields can be different for left and right handed enantiomers, thereby enabling NMR to be used to spectroscopically detect chirality even in an achiral medium. However, most proposals to detect the chiral NMR signature require measuring signals that are equivalent to picomolar concentrations for (1)H nuclei, which are outside current NMR detection limits. In this work, we propose to use an AC electric field that is resonantly modulated at the Larmor frequency, thereby enhancing the effect of the chiral term by four to six orders of magnitude. We predict that a steady-state transverse magnetization, whose direction will be opposite for different enantiomers, will build up during application of an AC electric field. We also propose an experimental setup that uses a solenoid coil with an AC current to generate the necessary periodic electric fields that can be used to generate chiral signals which are equivalent to the signal from a (1)H submicromolar concentration. PMID- 24952534 TI - Electrokinetic detection for X-ray spectra of weakly interacting liquids: n decane and n-nonane. AB - The introduction of liquid microjets into soft X-ray absorption spectroscopy enabled the windowless study of liquids by this powerful atom-selective high vacuum methodology. However, weakly interacting liquids produce large vapor backgrounds that strongly perturb the liquid signal. Consequently, solvents (e.g., hydrocarbons, ethers, ketones, etc.) and solutions of central importance in chemistry and biology have been inaccessible by this technology. Here we describe a new detection method, upstream detection, which greatly reduces the vapor phase contribution to the X-ray absorption signal while retaining important advantages of liquid microjet sample introduction (e.g., minimal radiation damage). The effectiveness of the upstream detection method is demonstrated in this first study of room temperature liquid hydrocarbons: n-nonane and n-decane. Good agreement with first principles' calculations indicates that the eXcited electron and Core Hole theory adequately describes the subtle interactions in these liquids that perturb the electronic structure of the unoccupied states probed in core-level experiments. PMID- 24952535 TI - Global analytical ab initio ground-state potential energy surface for the C((1)D)+H2 reactive system. AB - A new global ab initio potential energy surface (called ZMB-a) for the 1(1)A' state of the C((1)D)+H2 reactive system has been constructed. This is based upon ab initio calculations using the internally contracted multireference configuration interaction approach with the aug-cc-pVQZ basis set, performed at about 6300 symmetry unique geometries. Accurate analytical fits are generated using many-body expansions with the permutationally invariant polynomials, except that the fit of the deep well region is taken from our previous fit. The ZMB-a surface is unique in the accurate description of the regions around conical intersections (CIs) and of van der Waals (vdW) interactions. The CIs between the 1(1)A' and 2(1)A' states cause two kinds of barriers on the ZMB-a surface: one is in the linear H-CH dissociation direction with a barrier height of 9.07 kcal/mol, which is much higher than those on the surfaces reported before; the other is in the C((1)D) collinearly attacking H2 direction with a barrier height of 12.39 kcal/mol. The ZMB-a surface basically reproduces our ab initio calculations in the vdW interaction regions, and supports a linear C-HH vdW complex in the entrance channel, and two vdW complexes in the exit channel, at linear CH-H and HC-H geometries, respectively. PMID- 24952536 TI - Unimolecular thermal decomposition of dimethoxybenzenes. AB - The unimolecular thermal decomposition mechanisms of o-, m-, and p dimethoxybenzene (CH3O-C6H4-OCH3) have been studied using a high temperature, microtubular (MUtubular) SiC reactor with a residence time of 100 MUs. Product detection was carried out using single photon ionization (SPI, 10.487 eV) and resonance enhanced multiphoton ionization (REMPI) time-of-flight mass spectrometry and matrix infrared absorption spectroscopy from 400 K to 1600 K. The initial pyrolytic step for each isomer is methoxy bond homolysis to eliminate methyl radical. Subsequent thermolysis is unique for each isomer. In the case of o-CH3O-C6H4-OCH3, intramolecular H-transfer dominates leading to the formation of o-hydroxybenzaldehyde (o-HO-C6H4-CHO) and phenol (C6H5OH). Para-CH3O-C6H4-OCH3 immediately breaks the second methoxy bond to form p-benzoquinone, which decomposes further to cyclopentadienone (C5H4=O). Finally, the m-CH3O-C6H4-OCH3 isomer will predominantly follow a ring-reduction/CO-elimination mechanism to form C5H4=O. Electronic structure calculations and transition state theory are used to confirm mechanisms and comment on kinetics. Implications for lignin pyrolysis are discussed. PMID- 24952537 TI - Theoretical study of Raman chirped adiabatic passage by X-ray absorption spectroscopy: highly excited electronic states and rotational effects. AB - Raman Chirped Adiabatic Passage (RCAP) is an efficient method to climb the vibrational ladder of molecules. It was shown on the example of fixed-in-space HCl molecule that selective vibrational excitation can thus be achieved by RCAP and that population transfer can be followed by X-ray Photoelectron spectroscopy [S. Engin, N. Sisourat, P. Selles, R. Taieb, and S. Carniato, Chem. Phys. Lett. 535, 192-195 (2012)]. Here, in a more detailed analysis of the process, we investigate the effects of highly excited electronic states and of molecular rotation on the efficiency of RCAP. Furthermore, we propose an alternative spectroscopic way to monitor the transfer by means of X-ray absorption spectra. PMID- 24952538 TI - Investigation of 3-fragment photodissociation of O3 at 193.4 and 157.6 nm by coincident measurements. AB - Photodissociation of the ozone molecule at 193.4 nm (6.41 eV) and 157.6 nm (7.87 eV) is studied by fast-beam translational spectroscopy. Coincident detection of the dissociation products allows direct observation of the 3-fragment channel and determination of its kinematic parameters. The results indicate that at each wavelength, 3-fragment dissociation proceeds through synchronous concerted bond breaking, but the energy partitioning among the fragments is different. The branching fraction of the 3-fragment channel increases from 5.2(6)% at 193.4 nm to 26(4)% at 157.6 nm, in agreement with previous studies. It is shown that vibrational excitation of the symmetric stretch mode in O3 molecules created by photodetachment of O(3)(-) anion enhances the absorption efficiency, especially at 193.4 nm, but does not have a strong effect on the 3-fragment dissociation. PMID- 24952540 TI - Dynamics of heavy-Rydberg ion-pair formation in K(14p,20p)-SF6, CCl4 collisions. AB - The dynamics of formation of heavy-Rydberg ion-pair states through electron transfer in K(np)-SF6, CCl4 collisions is examined by measuring the velocity, angular, and binding energy distributions of the product ion pairs. The results are analyzed with the aid of a Monte Carlo collision code that models both the initial electron capture and the subsequent evolution of the ion pairs. The model simulations are in good agreement with the experimental data and highlight the factors such as Rydberg atom size, the kinetic energy of relative motion of the Rydberg atom and target particle, and (in the case of attaching targets that dissociate) the energetics of dissociation that can be used to control the properties of the product ion-pair states. PMID- 24952539 TI - Soft x-ray ionization induced fragmentation of glycine. AB - X-ray absorption commonly involves dissociative core ionization producing not only momentum correlated charged fragments but also low- and high-energy electrons capable of inducing damage in living tissue. This gives a natural motivation for studying the core ionization induced fragmentation processes in biologically important molecules such as amino acids. Here the fragmentation of amino acid glycine following carbon 1s core ionization has been studied. Using photoelectron-photoion-photoion coincidence technique, a detailed analysis on fragmentation of the sample molecule into pairs of momentum correlated cations has been carried out. The main characteristics of core ionization induced fragmentation of glycine were found to be the rupture of the C-Calpha bond and the presence of the CNH(2)(+) fragment. PMID- 24952542 TI - High resolution measurements supported by electronic structure calculations of two naphthalene derivatives: [1,5]- and [1,6]-naphthyridine--estimation of the zero point inertial defect for planar polycyclic aromatic compounds. AB - Polycyclic aromatic hydrocarbons (PAHs) molecules are suspected to be present in the interstellar medium and to participate to the broad and unresolved emissions features, the so-called unidentified infrared bands. In the laboratory, very few studies report the rotationally resolved structure of such important class of molecules. In the present work, both experimental and theoretical approaches provide the first accurate determination of the rotational energy levels of two diazanaphthalene: [1,5]- and [1,6]-naphthyridine. [1,6]-naphthyridine has been studied at high resolution, in the microwave (MW) region using a Fourier transform microwave spectrometer and in the far-infrared (FIR) region using synchrotron-based Fourier transform spectroscopy. The very accurate set of ground state (GS) constants deduced from the analysis of the MW spectrum allowed the analysis of the most intense modes in the FIR (nu38-GS centered at about 483 cm( 1) and nu34-GS centered at about 842 cm(-1)). In contrast with [1,6] naphthyridine, pure rotation spectroscopy of [1,5]-naphthyridine cannot be performed for symmetry reasons so the combined study of the two intense FIR modes (nu22-GS centered at about 166 cm(-1) and nu18-GS centered at about 818 cm(-1)) provided the GS and the excited states constants. Although the analysis of the very dense rotational patterns for such large molecules remains very challenging, relatively accurate anharmonic density functional theory calculations appeared as a highly relevant supporting tool to the analysis for both molecules. In addition, the good agreement between the experimental and calculated infrared spectrum shows that the present theoretical approach should provide useful data for the astrophysical models. Moreover, inertial defects calculated in the GS (DeltaGS) of both molecules exhibit slightly negative values as previously observed for planar species of this molecular family. We adjusted the semi empirical relations to estimate the zero-point inertial defect (Delta0) of polycyclic aromatic molecules and confirmed the contribution of low frequency out of-plane vibrational modes to the GS inertial defects of PAHs, which is indeed a key parameter to validate the analysis of such large molecules. PMID- 24952541 TI - Structure and tunneling dynamics in a model system of peptide co-solvents: rotational spectroscopy of the 2,2,2-trifluoroethanol?water complex. AB - The hydrogen-bonding topology and tunneling dynamics of the binary adduct, 2,2,2 trifluoroethanol (TFE)?water, were investigated using chirped pulse and cavity based Fourier transform microwave spectroscopy with the aid of high level ab initio calculations. Rotational spectra of the most stable binary TFE?water conformer and five of its deuterium isotopologues were assigned. A strong preference for the insertion binding topology where water is inserted into the existing intramolecular hydrogen-bonded ring of TFE was observed. Tunneling splittings were detected in all of the measured rotational transitions of TFE?water. Based on the relative intensity of the two tunneling components and additional isotopic data, the splitting can be unambiguously attributed to the tunneling motion of the water subunit, i.e., the interchange of the bonded and nonbonded hydrogen atoms of water. The absence of any other splitting in the rotational transitions of all isotopologues observed indicates that the tunneling between g+ and g- TFE is quenched in the TFE?H2O complex. PMID- 24952543 TI - Modified Lennard-Jones model: virial coefficients to the 7th order. AB - The modified Lennard-Jones potential, which simplifies the numerical simulations and maintains the realistic behavior of its parent, is proposed to a role of the standard interaction model for both the experimental and theoretical studies. The virial coefficients of this model up to the seventh order have been calculated for the range of temperatures kT/E = 0.3-70. In the computations, a technique has been used, that combines the quadrature integration and Mayer Sampling Monte Carlo method (MSMC). Unlike the original MSMC, this technique does not require the reference coefficients of another potential and can be used in a wide range of temperatures for various interaction models. PMID- 24952544 TI - Explicit correlation treatment of the potential energy surface of CO2 dimer. AB - We present an extensive study of the four-dimensional potential energy surface (4D-PES) of the carbon dioxide dimer, (CO2)2. This PES is developed over the set of intermolecular coordinates. The electronic computations are carried out at the explicitly correlated coupled cluster method with single, double, and perturbative triple excitations [CCSD(T)-F12] level of theory in connection with the augmented correlation-consistent aug-cc-pVTZ basis set. An analytic representation of the 4D-PES is derived. Our extensive calculations confirm that "Slipped Parallel" is the most stable form and that the T-shaped structure corresponds to a transition state. Later on, this PES is employed for the calculations of the vibrational energy levels of the dimer. Moreover, the temperature dependence of the dimer second virial coefficient and of the first spectral moment of rototranslational collision-induced absorption spectrum is derived. For both quantities, a good agreement is found between our values and the experimental data for a wide range of temperatures. This attests to the high quality of our PES. Generally, our PES and results can be used for modeling CO2 supercritical fluidity and examination of its role in planetary atmospheres. It can be also incorporated into dynamical computations of CO2 capture and sequestration. This allows deep understanding, at the microscopic level, of these processes. PMID- 24952545 TI - Interaction of single quantum emitter and dark plasmon supported by a metal nanoring. AB - We explore the interaction between a quantum emitter and a metal nanoring by numerical solution of coupled Maxwell-Liouville equations. When the quantum emitter and nanoring are subjected to an incident plane wave, coupling between the quantum emitter and a dark plasmon supported by the nanoring gives rise to a similar lineshape to the familiar Fano type. It results from the excitation of a dark plasmon via intermediary participation of the quantum emitter. The dark plasmon is characterized through the width and shift parameters of the emitter peak in the absorption spectrum of the nanoparticle. Our results are obtained with the help of finite-difference time-domain method and a recently proposed symmetry-adapted averaging approach. PMID- 24952546 TI - Non-equilibrium dynamics of glass-forming liquid mixtures. AB - The non-equilibrium self-consistent generalized Langevin equation theory of irreversible processes in glass-forming liquids [P. Ramirez-Gonzalez and M. Medina-Noyola, Phys. Rev. E 82, 061503 (2010)] is extended here to multi component systems. The resulting theory describes the statistical properties of the instantaneous local particle concentration profiles nalpha(r, t) of species alpha in terms of the coupled time-evolution equations for the mean value nalpha(r, t) and for the covariance sigma(alphabeta)(r, r'; t) = deltan(alpha)(r, t)deltan(beta)(r', t) of the fluctuations deltan(alpha)(r, t) = n(alpha)(r, t) - nalpha(r, t). As in the monocomponent case, these two coarse-grained equations involve a local mobility function balpha(r, t) for each species, written in terms of the memory function of the two-time correlation function C(alphabeta)(r, r'; t, t') = deltan(alpha)(r, t)deltan(beta)(r', t'). If the system is constrained to remain spatially uniform and subjected to a non-equilibrium preparation protocol described by a given temperature and composition change program T(t) and nalpha(r, t), these equations predict the irreversible structural relaxation of the partial static structure factors Salphabeta(k; t) and of the (collective and self) intermediate scattering functions Falphabeta(k, tau; t) and F(alphabeta)(S)(k, tau; t). We illustrate the applicability of the resulting theory with two examples involving simple model mixtures subjected to an instantaneous temperature quench: an electroneutral binary mixture of equally sized and oppositely charged hard-spheres, and a binary mixture of soft-spheres of moderate size-asymmetry. PMID- 24952547 TI - Configurational entropy of hydrogen-disordered ice polymorphs. AB - The configurational entropy of several H-disordered ice polymorphs is calculated by means of a thermodynamic integration along a path between a totally H disordered state and one fulfilling the Bernal-Fowler ice rules. A Monte Carlo procedure based on a simple energy model is used, so that the employed thermodynamic path drives the system from high temperatures to the low temperature limit. This method turns out to be precise enough to give reliable values for the configurational entropy sth of different ice phases in the thermodynamic limit (number of molecules N -> infinity). The precision of the method is checked for the ice model on a two-dimensional square lattice. Results for the configurational entropy are given for H-disordered arrangements on several polymorphs, including ices Ih, Ic, II, III, IV, V, VI, and XII. The highest and lowest entropy values correspond to ices VI and XII, respectively, with a difference of 3.3% between them. The dependence of the entropy on the ice structures has been rationalized by comparing it with structural parameters of the various polymorphs, such as the mean ring size. A particularly good correlation has been found between the configurational entropy and the connective constant derived from self-avoiding walks on the ice networks. PMID- 24952548 TI - Hydration dynamics of aqueous glucose probed with polarization-resolved fs-IR spectroscopy. AB - The dynamics of water in aqueous solutions of glucose have been investigated using polarization-resolved femtosecond infrared spectroscopy of the hydroxyl stretch vibrations of water and glucose. Using reference measurements on solutions of glucose in dimethylsulfoxide and a spectral decomposition model, we are able to distinguish the reorientation dynamics of the glucose and water hydroxyl groups. We find that the water reorientation dynamics strongly slow down in the presence of glucose. PMID- 24952549 TI - Thermodynamic of fluids from a general equation of state: the molecular discrete perturbation theory. AB - An extensive generalisation of the discrete perturbation theory for molecular multipolar non-spherical fluids is presented. An analytical expression for the Helmholtz free energy for an equivalent discrete potential is given as a function of density, temperature, and intermolecular parameters with implicit shape and multipolar dependence. By varying the intermolecular parameters through their geometrical and multipolar dependence, a set of molecular fluids are considered and their vapor-liquid phase diagrams are tested against available simulation data. Concretely, multipolar and non-polar Kihara and chainlike fluids are tested and it is found that this theoretical approach is able to reproduce qualitatively and quantitatively well the Monte Carlo data for the selected molecular potentials, except near the critical region. PMID- 24952550 TI - Structural heterogeneities at the origin of acoustic and transport anomalies in glycerol glass-former. AB - By means of large scale molecular dynamics simulations, we explore mesoscopic properties of prototypical glycerol glass-former above and below the glass transition. The model used, in excellent agreement with various experimental techniques, permits to carefully study the structure and the vibrational dynamics. We find that a medium range order is present in glycerol glass-former and arises from hydrogen bond network extension. The characteristic size of the structural heterogeneities is related to the anomalous properties of acoustic vibrations (Rayleigh scattering, "mode softening," and Boson Peak) in the glassy state. Finally the characteristic size of these heterogeneities, nearly constant in temperature, is also connected to the cross-over between structural relaxation and diffusion in liquid glycerol. PMID- 24952551 TI - Curvature induced phase stability of an intensely heated liquid. AB - We use non-equilibrium molecular dynamics simulations to study the heat transfer around intensely heated solid nanoparticles immersed in a model Lennard-Jones fluid. We focus our studies on the role of the nanoparticle curvature on the liquid phase stability under steady-state heating. For small nanoparticles we observe a stable liquid phase near the nanoparticle surface, which can be at a temperature well above the boiling point. Furthermore, for particles with radius smaller than a critical radius of 2 nm we do not observe formation of vapor even above the critical temperature. Instead, we report the existence of a stable fluid region with a density much larger than that of the vapor phase. We explain the stability in terms of the Laplace pressure associated with the formation of a vapor nanocavity and the associated effect on the Gibbs free energy. PMID- 24952552 TI - Striking role of non-bridging oxygen on glass transition temperature of calcium aluminosilicate glass-formers. AB - Molecular dynamics simulations are used to study the structural and dynamic properties of calcium aluminosilicate, (CaO-Al2O3)1-x(SiO2)x, glass formers along three joins, namely, R = 1, 1.57, and 3, in which the silica content x can vary from 0 to 1. For all compositions, we determined the glass-transition temperature, the abundances of the non-bridging oxygen, triclusters, and AlO5 structural units, as well as the fragility from the temperature evolution of the alpha-relaxation times. We clearly evidence the role played by the non-bridging oxygen linked either to Al atoms or Si atoms in the evolution of the glass transition temperature as well as of the fragility as a function of silica content along the three joins. PMID- 24952553 TI - The effect of concentration- and temperature-dependent dielectric constant on the activity coefficient of NaCl electrolyte solutions. AB - Our implicit-solvent model for the estimation of the excess chemical potential (or, equivalently, the activity coefficient) of electrolytes is based on using a dielectric constant that depends on the thermodynamic state, namely, the temperature and concentration of the electrolyte, epsilon(c, T). As a consequence, the excess chemical potential is split into two terms corresponding to ion-ion (II) and ion-water (IW) interactions. The II term is obtained from computer simulation using the Primitive Model of electrolytes, while the IW term is estimated from the Born treatment. In our previous work [J. Vincze, M. Valisko, and D. Boda, "The nonmonotonic concentration dependence of the mean activity coefficient of electrolytes is a result of a balance between solvation and ion-ion correlations," J. Chem. Phys. 133, 154507 (2010)], we showed that the nonmonotonic concentration dependence of the activity coefficient can be reproduced qualitatively with this II+IW model without using any adjustable parameter. The Pauling radii were used in the calculation of the II term, while experimental solvation free energies were used in the calculation of the IW term. In this work, we analyze the effect of the parameters (dielectric constant, ionic radii, solvation free energy) on the concentration and temperature dependence of the mean activity coefficient of NaCl. We conclude that the II+IW model can explain the experimental behavior using a concentration-dependent dielectric constant and that we do not need the artificial concept of "solvated ionic radius" assumed by earlier studies. PMID- 24952554 TI - Electron transport in pure and substituted iron oxyhydroxides by small-polaron migration. AB - Iron oxyhydroxides (FeOOH) are common crystalline forms of iron that play a critical role in technology and the natural environment via a variety of important reduction-oxidation reactions, including electrical semiconduction as an aspect. However, a basic understanding of the electron transport properties of these systems is still lacking. We examine the electron mobility in goethite (alpha-FeOOH), akaganeite (beta-FeOOH), and lepidocrocite (gamma-FeOOH) polymorphs by means of density functional theory based (DFT+U) calculations. We show that room temperature charge transport should be dominated by the small polaron hopping type, and that the attendant mobility should be highest for pure goethite and akaganeite. Hopping pathways through the various lattices are discussed in terms of individual electron exchange steps and rates for each. Given the usual occurrence of compositional impurities in natural iron oxyhydroxides, we also investigate the effect of common stoichiometric defects on the electron hopping activation energies such as Al and Cr substitutional cations in goethite, and Cl anions in the channels of akaganeite. PMID- 24952555 TI - Half-metallicity modulation of hybrid BN-C nanotubes by external electric fields: a first-principles study. AB - On the basis of density functional theory, we systematically investigate the electronic and magnetic properties of hybrid BN-C nanotubes, Cx(BN)y where x + y = 12, with and without an external electric field. The BN-C nanotubes are totally distinct from pristine boron-nitride and carbon nanotubes. The electronic properties of Cx(BN)y change significantly with composition: from the nonmagnetic semiconductors to the half-metals. The half-metallicity is attributed to the competition among the band gap, which is related to the width of C domain, the width of BN domain, and the intrinsic polarization field. Application of the external fields can enhance or counterbalance the polarization fields and change the band gaps. The half-metallicity can be modulated. In BN-rich tubes, such as C2(BN)10, the energy gap can be engineered from 0.50 eV to 0.95 eV and in C3(BN)9, the ground state is converted from the nonmagnetic state into the anti ferro-magnetic one. In other tubes, the half-metallicity can be enhanced or destroyed by different external fields. The modulation indicates that hybrid BN-C nanotubes can work as the components of the spin-filter devices. PMID- 24952556 TI - Pressure effect on elastic anisotropy of crystals from ab initio simulations: the case of silicate garnets. AB - A general methodology has been devised and implemented into the solid-state ab initio quantum-mechanical Crystal program for studying the evolution under geophysical pressure of the elastic anisotropy of crystalline materials. This scheme, which fully exploits both translational and point symmetry of the crystal, is developed within the formal frame of one-electron Hamiltonians and atom-centered basis functions. Six silicate garnet end-members, among the most important rock-forming minerals of the Earth's mantle, are considered, whose elastic anisotropy is fully characterized under high hydrostatic compressions, up to 60 GPa. The pressure dependence of azimuthal anisotropy and shear-wave birefringence of seismic wave velocities for these minerals are accurately simulated and compared with available single-crystal measurements. PMID- 24952557 TI - Effects of discreteness of surface charges on the effective electrostatic interactions. AB - In the present work, we study effects of relative arrangement of discrete surface charges on electrostatic potential of mean force (EPMF) between two surfaces immersed in a primitive model electrolyte solution. To help in exploring and ascertaining the relevant mechanism, different combinations of values for electrostatic parameters (such as ion concentration, diameter, and valence, solution temperature and relative permittivity) are investigated by solving classical density functional theory in three dimensional space, in combination with different discrete surface charge configurations and surface charge homogeneity configuration as the effects may alter along with change of the surface charge arrangement. Our findings include: (i) if counter-ion is univalent, the EPMF of charge homogeneity surface is always more repulsive than those of charge heterogeneity surfaces whether the discrete surface charges are distributed on the two face-face surfaces commensurately or non-commensurately; (ii) in presence of high valence counter-ion well depth of like charge attraction between two charge homogeneity surfaces approximately takes an averaged value of those for various charge heterogeneity surfaces whether the discrete surface charges are distributed on the two face-face surfaces commensurately or non commensurately; (iii) the EPMF becomes ever more attractive or less repulsive with a centralization of the discrete surface charges whether the counter-ion valence is univalent, divalent or trivalent; and (iv) the EPMF in the case of charge heterogeneity surfaces is influenced by bulk electrolyte concentration, salt ion diameter and valence, solution temperature, and relative permittivity in the same manner as in the case of charge homogeneity surfaces. All of these findings can be explained self-consistently by a recently proposed hydrogen bonding style mechanism (for dealing with the EPMF between two charge homogeneity surfaces) reinforced by two new concepts: counter-ion effective adsorption spaces belonging to different localized surface charges and hydrogen bond directivity. PMID- 24952558 TI - Desorption of oxygen from alloyed Ag/Pt(111). AB - We have investigated the interaction of oxygen with the Ag/Pt(111) surface alloy by thermal desorption spectroscopy (TDS). The surface alloy was formed during the deposition of sub-monolayer amounts of silver on Pt(111) at 800 K and subsequent cooling to 300 K. The low-temperature phase of the surface alloy is composed of nanometer-sized silver rich stripes, embedded within platinum-rich domains, which were characterized with spot profile analysis low energy electron diffraction. The TDS measurements show that oxygen adsorption is blocked on Ag sites: the saturation coverage of oxygen decreases with increasing Ag coverage. Also, the activation energy for desorption (Edes) decreases with Ag coverage. The analysis of the desorption spectra from clean Pt(111) shows a linear decay of Edes with oxygen coverage, which indicates repulsive interactions between the adsorbed oxygen atoms. In contrast, adsorption on alloyed Ag/Pt(111) leads to an attractive interaction between adsorbed oxygen atoms. PMID- 24952559 TI - Understanding the amorphous-to-microcrystalline silicon transition in SiF4/H2/Ar gas mixtures. AB - We report on the growth of microcrystalline silicon films from the dissociation of SiF4/H2/Ar gas mixtures. For this growth chemistry, the formation of HF molecules provides a clear signature of the amorphous to microcrystalline growth transition. Depositing films from silicon tetrafluoride requires the removal of F produced by SiF4 dissociation, and this removal is promoted by the addition of H2 which strongly reacts with F to form HF molecules. At low H2 flow rates, the films grow amorphous as all the available hydrogen is consumed to form HF. Above a critical flow rate, corresponding to the full removal of F, microcrystalline films are produced as there is an excess of atomic hydrogen in the plasma. A simple yet accurate phenomenological model is proposed to explain the SiF4/H2 plasma chemistry in accordance with experimental data. This model provides some rules of thumb to achieve high deposition rates for microcrystalline silicon, namely, that increased RF power must be balanced by an increased H2 flow rate. PMID- 24952560 TI - Molecular dynamics simulations of the amino acid-ZnO (10-10) interface: a comparison between density functional theory and density functional tight binding results. AB - We investigate the adsorption behavior of four different amino acids (glutamine, glutamate, serine, cysteine) on the zinc oxide (1010) surface, comparing the geometry and energy associated with a number of different adsorption configurations. In doing this, we highlight the benefits and limits of using density-functional tight-binding (DFTB) with respect to standard density functional theory (DFT). The DFTB method is found to reliably reproduce the DFT adsorption geometries. Analysis of the adsorption configurations emphasizes the fundamental role of the first hydration layer in mediating the interactions between the amino acids and the surface. Direct surface-molecule bonds are found to form predominantly via the carboxylate groups of the studied amino acids. No surface-mediated chemical reactions are observed, with the notable exception of a proton transfer from the thiol group of cysteine to a hydroxyl group of the surface hydration layer. The adsorption energies are found to be dominated both by the formation of direct or indirect surface-molecule hydrogen bonds, but also by the rearrangement of the hydrogen-bond network in surface proximity in a non intuitive way. Energetic comparisons between DFTB and DFT are made difficult on one side by the long time necessary to achieve convergence of potential energy values in MD simulations and on the other side by the necessity of including higher-order corrections to DFTB to obtain a good description of the hydrogen bond energetics. Overall, our results suggest that DFTB is a good reference method to set the correct chemical states and the initial geometries of hybrid biomolecule/ZnO systems to be simulated with non-reactive force fields. PMID- 24952561 TI - Charge transfer from an adsorbed ruthenium-based photosensitizer through an ultra thin aluminium oxide layer and into a metallic substrate. AB - The interaction of the dye molecule N3 (cis-bis(isothiocyanato)bis(2,2-bipyridyl 4,4'-dicarbo-xylato)-ruthenium(II)) with the ultra-thin oxide layer on a AlNi(110) substrate, has been studied using synchrotron radiation based photoelectron spectroscopy, resonant photoemission spectroscopy, and near edge X ray absorption fine structure spectroscopy. Calibrated X-ray absorption and valence band spectra of the monolayer and multilayer coverages reveal that charge transfer is possible from the molecule to the AlNi(110) substrate via tunnelling through the ultra-thin oxide layer and into the conduction band edge of the substrate. This charge transfer mechanism is possible from the LUMO+2 and 3 in the excited state but not from the LUMO, therefore enabling core-hole clock analysis, which gives an upper limit of 6.0 +/- 2.5 fs for the transfer time. This indicates that ultra-thin oxide layers are a viable material for use in dye sensitized solar cells, which may lead to reduced recombination effects and improved efficiencies of future devices. PMID- 24952562 TI - Integral equation theory for atactic polystyrene nanocomposite melts with a multi site model. AB - In this work, a multi-site chain model was incorporated into the polymer reference interaction site model to investigate the structure and properties of atactic polystyrene (aPS) melt and the structural correlations of dilute spherical nanoparticles dissolved in aPS melt. The theoretically calculated X-ray scattering intensities, solubility parameters and intermolecular correlation functions of aPS and its nanocomposites are found to be in agreement with the corresponding molecular simulation and experimental data. The theory was further employed to investigate the distribution functions of different size effects of aPS-nanoparticle system with consideration of the potential of mean force and depletion force. The aggregation of large nanoparticles increases with the increase of the nanoparticle-site size ratio in the infinitely dilute limit. The results show that the present theory can be used to investigate the structure of aPS melt and its nanocomposite, and give a further understanding of the filler dispersion and aggregation. All the observations indicate molecular-level details of the underlying mechanisms, providing useful information for the future design control of new aPS-nanocomposite materials with tailored properties. PMID- 24952563 TI - Dynamics of the reaction between the free end of a tethered self-avoiding polymer and a flat penetrable surface: a renormalization group study. AB - The average time taur for one end of a long, self-avoiding polymer to interact for the first time with a flat penetrable surface to which it is attached at the other end is shown here to scale essentially as the square of the chain's contour length N. This result is obtained within the framework of the Wilemski-Fixman approximation to diffusion-limited reactions, in which the reaction time is expressed as a time correlation function of a "sink" term. In the present work, this sink-sink correlation function is calculated using perturbation expansions in the excluded volume and the polymer-surface interactions, with renormalization group methods being used to resum the expansion into a power law form. The quadratic dependence of taur on N mirrors the behavior of the average time tauc of a free random walk to cyclize, but contrasts with the cyclization time of a free self-avoiding walk (SAW), for which taur ~ N(2.2). A simulation study by Cheng and Makarov [J. Phys. Chem. B 114, 3321 (2010)] of the chain-end reaction time of an SAW on a flat impenetrable surface leads to the same N(2.2) behavior, which is surprising given the reduced conformational space a tethered polymer has to explore in order to react. PMID- 24952564 TI - Dipolar correlations in structured solvents under nanoconfinement. AB - We study electrostatic correlations in structured solvents confined to nanoscale systems. We derive variational equations of Netz-Orland type for a model liquid composed of finite size dipoles. These equations are solved for both dilute solvents and solvents at physiological concentrations in a slit nanopore geometry. Correlation effects are of major importance for the dielectric reduction and anisotropy of the solvent resulting from dipole image interactions and also lead to a reduction of van der Waals attractions between low dielectric bodies. Finally, by comparison with other recently developed self-consistent theories and experiments, we scrutinize the effect of solvent-membrane interactions on the differential capacitance of the charged liquid in contact with low dielectric substrates. The interfacial solvent depletion driven by solvent-image interactions plays the major role in the observed low values of the experimental capacitance data, while non-locality associated with the extended charge structure of solvent molecules only brings a minor contribution. PMID- 24952565 TI - Adsorption-induced changes of the structure of the tethered chain layers in a simple fluid. AB - We use density functional theory to study the influence of fluid adsorption on the structure of grafted chain layer. The chains are modeled as freely jointed spheres. The chain segments and spherical molecules of the fluid interact via the Lennard-Jones potential. The fluid molecules are attracted by the substrate. We calculate the excess adsorption isotherms, the average height of tethered chains, and the force acting on selected segments of the chains. The parameters that were varied include the length of grafted chains, the grafting density, the parameters characterizing fluid-chain and fluid-surface interactions, the bulk fluid density, and temperature. We show that depending on the density of the bulk fluid the height of the bonded layer increases, remains constant, or decreases with increasing temperature. PMID- 24952566 TI - Solute dynamics in block-copolymer reverse micelles: do water content and copolymer concentration alter the microenvironment? AB - Solute dynamics has been explored in reverse micelles formed with the triblock copolymer (EO)13-(PO)30-(EO)13 (L64), where EO and PO represent ethylene oxide and propylene oxide units, respectively, with small amounts of water in p-xylene. To this effect, nonradiative rate constants (knr) and reorientation times (taur) of two carbocyanine derivatives, 3,3'-diethyloxadicarbocyanine iodide (DODCI) and merocyanine 540 (MC 540) have been measured at different mole ratios of water to copolymer (W) and also at three copolymer concentrations. By examining the nonradiative rate constants and the reorientation times of the two solutes, the microenvironment offered by L64/water/p-xylene reverse micellar system has been investigated. It has been observed that there is no variation in the nonradiative rate constants as well as in the reorientation times of both DODCI and MC 540 with an increase in W and [L64]. Since knr represents activated twist motion about the double bonds for these solutes, it is sensitive to the local friction and likewise, taur also provides information about the microenvironment. Thus, the results of this study indicate that DODCI and MC 540 are located in the cores of the L64 reverse micelles that are made up of hydrated ethylene oxide blocks and the hydration levels are not altered despite an increase in the water content and copolymer concentration. In other words, there is no variation in the microenvironment offered by L64/water/p-xylene reverse micellar system upon increasing W and [L64]. PMID- 24952567 TI - Driven polymer transport through a periodically patterned channel. AB - We study the driven transport of polymers in a periodically patterned channel using Langevin dynamics simulations in two dimensions. The channel walls are patterned with periodically alternating patches of attractive and non-attractive particles that act as trapping sites for the polymer. We find that the system shows rich dynamical behavior, observing giant diffusion, negative differential mobility, and several different transition mechanisms between the attractive patches. We also show that the channel can act as an efficient high-pass filter for polymers longer than a threshold length Nthr, which can be tuned by adjusting the length of the attractive patches and the driving force. Our findings suggest the possibility of fabricating polymer filtration devices based on patterned nanochannels. PMID- 24952568 TI - A molecular thermodynamic model for the stability of hepatitis B capsids. AB - Self-assembly of capsid proteins and genome encapsidation are two critical steps in the life cycle of most plant and animal viruses. A theoretical description of such processes from a physiochemical perspective may help better understand viral replication and morphogenesis thus provide fresh insights into the experimental studies of antiviral strategies. In this work, we propose a molecular thermodynamic model for predicting the stability of Hepatitis B virus (HBV) capsids either with or without loading nucleic materials. With the key components represented by coarse-grained thermodynamic models, the theoretical predictions are in excellent agreement with experimental data for the formation free energies of empty T4 capsids over a broad range of temperature and ion concentrations. The theoretical model predicts T3/T4 dimorphism also in good agreement with the capsid formation at in vivo and in vitro conditions. In addition, we have studied the stability of the viral particles in response to physiological cellular conditions with the explicit consideration of the hydrophobic association of capsid subunits, electrostatic interactions, molecular excluded volume effects, entropy of mixing, and conformational changes of the biomolecular species. The course-grained model captures the essential features of the HBV nucleocapsid stability revealed by recent experiments. PMID- 24952569 TI - A nucleotide-level coarse-grained model of RNA. AB - We present a new, nucleotide-level model for RNA, oxRNA, based on the coarse graining methodology recently developed for the oxDNA model of DNA. The model is designed to reproduce structural, mechanical, and thermodynamic properties of RNA, and the coarse-graining level aims to retain the relevant physics for RNA hybridization and the structure of single- and double-stranded RNA. In order to explore its strengths and weaknesses, we test the model in a range of nanotechnological and biological settings. Applications explored include the folding thermodynamics of a pseudoknot, the formation of a kissing loop complex, the structure of a hexagonal RNA nanoring, and the unzipping of a hairpin motif. We argue that the model can be used for efficient simulations of the structure of systems with thousands of base pairs, and for the assembly of systems of up to hundreds of base pairs. The source code implementing the model is released for public use. PMID- 24952570 TI - Flexibility of phospholipids with saturated and unsaturated chains studied by Raman scattering: the effect of cholesterol on dynamical and phase transitions. AB - Raman scattering spectra were obtained at 25-320 K for bilayers prepared from saturated 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and mono-unsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) phospholipids, with and without cholesterol. Raman intensities were measured at modes sensitive to lipid inter-chain interactions and/or intra-chain torsional motion (asymmetric CH2 stretching at 2880 cm(-1)) and to the conformational state of lipids (C-C stretching at 1130 cm(-1)). These intensities decreased with temperature, which could be ascribed to increased lipid flexibility. For cholesterol-free and cholesterol-containing DPPC bilayers, the decrease of Raman intensities observed above ~200 K could be related to the phenomenon of dynamical transition known for biological systems near these temperatures. For a cholesterol-free POPC bilayer, the decrease of intensity for the asymmetric CH2 stretching mode started at a lower temperature, above 100 K, while the addition of cholesterol shifted this starting temperature to a more normal ~200 K value. The low-temperature lipid flexibility in the case of POPC was related to the abundance of free-volume holes, which disappeared in presence of cholesterol. Near gel-fluid phase transitions, Raman intensities for cholesterol-free bilayers dropped sharply, while for cholesterol-containing bilayers, they changed smoothly. PMID- 24952571 TI - Vibrational dynamics of thiocyanate and selenocyanate bound to horse heart myoglobin. AB - The structure and vibrational dynamics of SCN- and SeCN-bound myoglobin have been investigated using polarization-controlled IR pump-probe measurements and quantum chemistry calculations. The complexes are found to be in low and high spin states, with the dominant contribution from the latter. In addition, the Mb:SCN high spin complex exhibits a doublet feature in the thiocyanate stretch IR absorption spectra, indicating two distinct molecular conformations around the heme pocket. The binding mode of the high spin complexes was assigned to occur through the nitrogen atom, contrary to the binding through the sulfur atom that was observed in myoglobin derived from Aplysia Limacina. The vibrational energy relaxation process has been found to occur substantially faster than those of free SCN(-) and SeCN(-) ions and neutral SCN- and SeCN-derivatized molecules reported previously. This supports the N-bound configurations of MbNCS and MbNCSe, because S- and Se-bound configurations are expected to have significantly long lifetimes due to the insulation effect by heavy bridge atom like S and Se in such IR probes. Nonetheless, even though their lifetimes are much shorter than those of corresponding free ions in water, the vibrational lifetimes determined for MbNCS and MbNCSe are still fairly long compared to those of azide and cyanide myoglobin systems studied before. Thus, thiocyanate and selenocyanate can be good local probes of local electrostatic environment in the heme pocket. The globin dependence on binding mode and vibrational dynamics is also discussed. PMID- 24952575 TI - Declines in mobility and changes in performance in the instrumental activities of daily living among mildly disabled community-dwelling older adults. AB - BACKGROUND: Gait speed is as an important predictor of mortality, volume of medical care, hospitalization, onset of activities of daily living (ADL) disability, and nursing home placement. We examined associations between change in gait speed and change in observed performance in the instrumental ADL (IADL) in a sample of mild-to-moderately disabled older adults. METHODS: Participants in the Sources of Independence in the Elderly project (n = 375) were approached to complete a 4-m gait assessment and a performance test of IADL competency at three points over 2 years. IADL competency was assessed by occupational therapists, who rated participants using the Assessment of Motor and Process Skills (AMPS) and who also made a global rating of need for help or supervision. Linear mixed models were developed to assess change in motor AMPS score relative to baseline status and change in gait speed and AMPS process scores. RESULTS: Baseline gait and change in gait were significant correlates of change in the AMPS motor ability measures in models that adjusted for cognitive status and AMPS process ability. Even respondents with gait speeds of 1 m/s at baseline were at risk of declining AMPS motor ability and an occupational therapist rating of IADL disability if gait speed declined. CONCLUSIONS: Slowing in gait speed is an important risk factor for IADL disability in mild to moderately disabled older adults. PMID- 24952572 TI - 2D IR spectroscopy reveals the role of water in the binding of channel-blocking drugs to the influenza M2 channel. AB - Water is an integral part of the homotetrameric M2 proton channel of the influenza A virus, which not only assists proton conduction but could also play an important role in stabilizing channel-blocking drugs. Herein, we employ two dimensional infrared (2D IR) spectroscopy and site-specific IR probes, i.e., the amide I bands arising from isotopically labeled Ala30 and Gly34 residues, to probe how binding of either rimantadine or 7,7-spiran amine affects the water dynamics inside the M2 channel. Our results show, at neutral pH where the channel is non-conducting, that drug binding leads to a significant increase in the mobility of the channel water. A similar trend is also observed at pH 5.0 although the difference becomes smaller. Taken together, these results indicate that the channel water facilitates drug binding by increasing its entropy. Furthermore, the 2D IR spectral signatures obtained for both probes under different conditions collectively support a binding mechanism whereby amantadine like drugs dock in the channel with their ammonium moiety pointing toward the histidine residues and interacting with a nearby water cluster, as predicted by molecular dynamics simulations. We believe these findings have important implications for designing new anti-influenza drugs. PMID- 24952576 TI - A randomized clinical trial to determine the efficacy of manufacturers' recommended doses of omega-3 fatty acids from different sources in facilitating cardiovascular disease risk reduction. AB - BACKGROUND: Omega-3 fatty acids confer beneficial health effects, but North Americans are lacking in their dietary omega-3-rich intake. Supplementation is an alternative to consumption of fish; however, not all omega-3 products are created equal. The trial objective was to compare the increases in blood levels of omega 3 fatty acids after consumption of four different omega-3 supplements, and to assess potential changes in cardiovascular disease risk following supplementation. METHODS: This was an open-label, randomized, cross-over study involving thirty-five healthy subjects. Supplements and daily doses (as recommended on product labels) were:Concentrated Triglyceride (rTG) fish oil: EPA of 650 mg, DHA of 450 mgEthyl Ester (EE) fish oil: EPA of 756 mg, DHA of 228 mgPhospholipid (PL) krill oil: EPA of 150 mg, DHA of 90 mgTriglyceride (TG) salmon oil: EPA of 180 mg, DHA of 220 mg.Subjects were randomly assigned to consume one of four products, in random order, for a 28-day period, followed by a 4-week washout period. Subsequent testing of the remaining three products, followed by 4-week washout periods, continued until each subject had consumed each of the products. Blood samples before and after supplementation were quantified for fatty acid analysis using gas chromatography, and statistically analysed using ANOVA for repeated measures. RESULTS: At the prescribed dosage, the statistical ranking of the four products in terms of increase in whole blood omega-3 fatty acid levels was concentrated rTG fish oil > EE fish oil > triglyceride TG salmon oil > PL krill oil. Whole blood EPA percentage increase in subjects consuming concentrated rTG fish oil was more than four times that of krill and salmon oil. Risk reduction in several elements of cardiovascular disease was achieved to a greater extent by the concentrated rTG fish oil than by any other supplement. Krill oil and (unconcentrated) triglyceride oil were relatively unsuccessful in this aspect of the study. CONCLUSION: For the general population, the form and dose of omega-3 supplements may be immaterial. However, given these results, the form and dose may be important for those interested in reducing their risk of cardiovascular disease. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01960660. PMID- 24952578 TI - The oxygen-independent metabolism of cyclic monoterpenes in Castellaniella defragrans 65Phen. AB - BACKGROUND: The facultatively anaerobic betaproteobacterium Castellaniella defragrans 65Phen utilizes acyclic, monocyclic and bicyclic monoterpenes as sole carbon source under oxic as well as anoxic conditions. A biotransformation pathway of the acyclic beta-myrcene required linalool dehydratase-isomerase as initial enzyme acting on the hydrocarbon. An in-frame deletion mutant did not use myrcene, but was able to grow on monocyclic monoterpenes. The genome sequence and a comparative proteome analysis together with a random transposon mutagenesis were conducted to identify genes involved in the monocyclic monoterpene metabolism. Metabolites accumulating in cultures of transposon and in-frame deletion mutants disclosed the degradation pathway. RESULTS: Castellaniella defragrans 65Phen oxidizes the monocyclic monoterpene limonene at the primary methyl group forming perillyl alcohol. The genome of 3.95 Mb contained a 70 kb genome island coding for over 50 proteins involved in the monoterpene metabolism. This island showed higher homology to genes of another monoterpene-mineralizing betaproteobacterium, Thauera terpenica 58EuT, than to genomes of the family Alcaligenaceae, which harbors the genus Castellaniella. A collection of 72 transposon mutants unable to grow on limonene contained 17 inactivated genes, with 46 mutants located in the two genes ctmAB (cyclic terpene metabolism). CtmA and ctmB were annotated as FAD-dependent oxidoreductases and clustered together with ctmE, a 2Fe-2S ferredoxin gene, and ctmF, coding for a NADH:ferredoxin oxidoreductase. Transposon mutants of ctmA, B or E did not grow aerobically or anaerobically on limonene, but on perillyl alcohol. The next steps in the pathway are catalyzed by the geraniol dehydrogenase GeoA and the geranial dehydrogenase GeoB, yielding perillic acid. Two transposon mutants had inactivated genes of the monoterpene ring cleavage (mrc) pathway. 2-Methylcitrate synthase and 2 methylcitrate dehydratase were also essential for the monoterpene metabolism but not for growth on acetate. CONCLUSIONS: The genome of Castellaniella defragrans 65Phen is related to other genomes of Alcaligenaceae, but contains a genomic island with genes of the monoterpene metabolism. Castellaniella defragrans 65Phen degrades limonene via a limonene dehydrogenase and the oxidation of perillyl alcohol. The initial oxidation at the primary methyl group is independent of molecular oxygen. PMID- 24952579 TI - Bi-level CPAP does not change central blood flow in preterm infants with respiratory distress syndrome. AB - BACKGROUND: Current literature provides limited data on the hemodynamic changes that may occur during bi-level continuous positive airway pressure (CPAP) support in preterm infants. However, the application of a positive end-expiratory pressure may be transmitted to the heart and the great vessels resulting in changes of central blood flow. OBJECTIVE: To assess changes in central blood flow in infants with respiratory distress syndrome (RDS) during bi-level CPAP support. DESIGN: A prospective study was performed in a cohort of 18 Very-Low-Birth-Weight Infants who were put on nasal CPAP support (4-5 cmH2O) because they developed RDS within the first 24-72 hours of life. Each subject was switched to bi-level CPAP support (Phigh 8 cmH2O, Plow 4-5 cmH2O, Thigh 0.5-0.6 seconds, 20 breaths/min) for an hour. An echocardiographic study and a capillary gas analysis were performed before and after the change of respiratory support. RESULTS: No differences between n-CPAP and bi-level CPAP in left ventricular output (LVO, 222.17 +/- 81.4 vs 211.4 +/- 75.3 ml/kg/min), right ventricular output (RVO, 287.8 +/- 96 vs 283.4 +/- 87.4 ml/kg/min) and superior vena cava flow (SVC, 135.38 +/- 47.8 vs 137.48 +/- 46.6 ml/kg/min) were observed. The hemodynamic characteristics of the ductus arteriosus were similar. A significant decrease in pCO2 levels after bi-level CPAP ventilation was observed; pCO2 variations did not correlate with modifications of central blood flow (LVO: rho=0.11, p=0,657; RVO: rho=-0.307, p=0.216; SVC: rho=-0.13, p=0.197). CONCLUSIONS: Central blood flow doesn't change during bi-level CPAP support, which could become a hemodinamically safe tool for the treatment of RDS in preterm infants. PMID- 24952580 TI - What is the real impact of acute kidney injury? AB - BACKGROUND: Acute kidney injury (AKI) is a common clinical problem. Studies have documented the incidence of AKI in a variety of populations but to date we do not believe the real incidence of AKI has been accurately documented in a district general hospital setting.The aim here was to describe the detected incidence of AKI in a typical general hospital setting in an unselected population, and describe associated short and long-term outcomes. METHODS: A retrospective observational database study from secondary care in East Kent (adult catchment population of 582,300). All adult patients (18 years or over) admitted between 1st February 2009 and 31st July 2009, were included. Patients receiving chronic renal replacement therapy (RRT), maternity and day case admissions were excluded. AKI was defined by the acute kidney injury network (AKIN) criteria. A time dependent risk analysis with logistic regression and Cox regression was used for the analysis of in-hospital mortality and survival. RESULTS: The incidence of AKI in the 6 month period was 15,325 pmp/yr (adults) (69% AKIN1, 18% AKIN2 and 13% AKIN3). In-hospital mortality, length of stay and ITU utilisation all increased with severity of AKI. Patients with AKI had an increase in care on discharge and an increase in hospital readmission within 30 days. CONCLUSIONS: This data comes closer to the real incidence and outcomes of AKI managed in-hospital than any study published in the literature to date. Fifteen percent of all admissions sustained an episode of AKI with increased subsequent short and long term morbidity and mortality, even in those with AKIN1. This confers an increased burden and cost to the healthcare economy, which can now be quantified. These results will furnish a baseline for quality improvement projects aimed at early identification, improved management, and where possible prevention, of AKI. PMID- 24952577 TI - Prognostic and predictive markers in recurrent high grade glioma; results from the BR12 randomised trial. AB - We evaluated the prognostic and predictive value of a range of molecular changes in the setting of a randomised trial comparing standard PCV (procarbazine, CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea) and vincristine) chemotherapy with the standard temozolomide (TMZ) 5-day (200 mg/m2/day) schedule and a 21-day (100 mg/m2/day) schedule in chemo-naive, high-grade glioma (non-oligodendroglial tumours; WHO (World Health Organisation) grades III and IV) patients at first progression following radiotherapy.354 samples (79.2%) from the first operation of the 447 randomised patients provided enough tumour DNA for some or all parts of the study. Genome-wide array comparative genomic hybridisation (aCGH), mutation analysis of IDH1/2 and TP53 and methylation analyses of the MGMT CpG island was done.84% of grade III tumours and 17% of grade IV had IDH1 or IDH2 mutations that conferred a better prognosis in both; MGMT methylation (defined as average value across 16 CpGs >= 10%) occurred in 75% of tumours and was also associated with improved survival. Both were of independent prognostic value after accounting for clinical factors and tumour grade. None of the molecular changes investigated gave clear evidence of a predictive benefit of TMZ over PCV or 21-day TMZ over 5-day TMZ although power was limited and a role for MGMT methylation could not be ruled out. Loss of 1p and 19q was seen in only 4 patients although hemizygous loss of 1p36 occurred in 20%.The findings support reports that IDH1/2 mutations and MGMT methylation can be used in addition to tumour grade and clinical factors to predict survival in patients with recurrent high grade gliomas when treated with any of the therapy regimes used. PMID- 24952581 TI - Shoulder function and work disability after decompression surgery for subacromial impingement syndrome: a randomised controlled trial of physiotherapy exercises and occupational medical assistance. AB - BACKGROUND: Surgery for subacromial impingement syndrome is often performed in working age and postoperative physiotherapy exercises are widely used to help restore function. A recent Danish study showed that 10% of a nationwide cohort of patients retired prematurely within two years after surgery. Few studies have compared effects of different postoperative exercise programmes on shoulder function, and no studies have evaluated workplace-oriented interventions to reduce postoperative work disability. This study aims to evaluate the effectiveness of physiotherapy exercises and occupational medical assistance compared with usual care in improving shoulder function and reducing postoperative work disability after arthroscopic subacromial decompression. METHODS/DESIGN: The study is a mainly pragmatic multicentre randomised controlled trial. The trial is embedded in a cohort study of shoulder patients referred to public departments of orthopaedic surgery in Central Denmark Region. Patients aged >=18-<=63 years, who still have shoulder symptoms 8-12 weeks after surgery, constitute the study population. Around 130 participants are allocated to: 1) physiotherapy exercises, 2) occupational medical assistance, 3) physiotherapy exercises and occupational medical assistance, and 4) usual care. Intervention manuals allow individual tailoring. Primary outcome measures include Oxford Shoulder Score and sickness absence due to symptoms from the operated shoulder. Randomisation is computerised with allocation concealment by randomly permuted block sizes. Statistical analyses will primarily be performed according to the intention-to-treat principle. DISCUSSION: The paper presents the rationale, design, methods, and operational aspects of the Shoulder Intervention Project (SIP). SIP evaluates a new rehabilitation approach, where physiotherapy and occupational interventions are provided in continuity of surgical episodes of care. If successful, the project may serve as a model for rehabilitation of surgical shoulder patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN55768749. PMID- 24952584 TI - A cross sectional study on factors associated with harmful traditional practices among children less than 5 years in Axum town, north Ethiopia, 2013. AB - BACKGROUND: Every social grouping in the world has its own cultural practices and beliefs which guide its members on how they should live or behave. Harmful traditional practices that affect children are Female genital mutilation, Milk teeth extraction, Food taboo, Uvula cutting, keeping babies out of exposure to sun, and Feeding fresh butter to new born babies. The objective of this study was to assess factors associated with harmful traditional practices among children less than 5 years of age in Axum town, North Ethiopia. METHODS: Community based cross sectional study was conducted in 752 participants who were selected using multi stage sampling; Simple random sampling method was used to select ketenas from all kebelles of Axum town. After proportional allocation of sample size, systematic random sampling method was used to get the study participants. Data was collected using interviewer administered Tigrigna version questionnaire, it was entered and analyzed using SPSS version 16. Descriptive statistics was calculated and logistic regressions were used to analyze the data. RESULTS: Out of the total sample size 50.7% children were females, the mean age of children was 26.28 months and majority of mothers had no formal education. About 87.8% mothers had performed at least one traditional practice to their children; uvula cutting was practiced on 86.9% children followed by milk teeth extraction 12.5% and eye borrows incision 2.4% children. Fear of swelling, pus and rapture of the uvula was the main reason to perform uvula cutting. CONCLUSION: The factors associated with harmful traditional practices were educational status, occupation, religion of mothers and harmful traditional practices performed on the mothers. PMID- 24952582 TI - Examining the ethical and social issues of health technology design through the public appraisal of prospective scenarios: a study protocol describing a multimedia-based deliberative method. AB - BACKGROUND: The design of health technologies relies on assumptions that affect how they will be implemented, such as intended use, complexity, impact on user autonomy, and appropriateness. Those who design and implement technologies make several ethical and social assumptions on behalf of users and society more broadly, but there are very few tools to examine prospectively whether such assumptions are warranted and how the public define and appraise the desirability of health innovations. This study protocol describes a three-year study that relies on a multimedia-based prospective method to support public deliberations that will enable a critical examination of the social and ethical issues of health technology design. METHODS: The first two steps of our mixed-method study were completed: relying on a literature review and the support of our multidisciplinary expert committee, we developed scenarios depicting social and technical changes that could unfold in three thematic areas within a 25-year timeframe; and for each thematic area, we created video clips to illustrate prospective technologies and short stories to describe their associated dilemmas. Using this multimedia material, we will: conduct four face-to-face deliberative workshops with members of the public (n=40) who will later join additional participants (n=25) through an asynchronous online forum; and analyze and integrate three data sources: observation, group deliberations, and a self administered participant survey. DISCUSSION: This study protocol will be of interest to those who design and assess public involvement initiatives and to those who examine the implementation of health innovations. Our premise is that using user-friendly tools in a deliberative context that foster participants' creativity and reflexivity in pondering potential technoscientific futures will enable our team to analyze a range of normative claims, including some that may prove problematic and others that may shed light over potentially more valuable design options. This research will help fill an important knowledge gap; intervening earlier in technological development could help reduce undesirable effects and inform the design and implementation of more appropriate innovations. PMID- 24952583 TI - Genomic insights into the serine protease gene family and expression profile analysis in the planthopper, Nilaparvata lugens. AB - BACKGROUND: The brown planthopper (Nilaparvata lugens) is one of the most destructive rice plant pests in Asia. N. lugens causes extensive damage to rice by sucking rice phloem sap, which results in hopper burn (complete death of the rice plants). Despite its importance, little is known about the digestion, development and defense mechanisms of this hemimetabolous insect pest. In this study, we aim to identify the serine protease (SP) and serine protease homolog (SPH) genes, which form a large family in eukaryotes, due to the potential for multiple physiological roles. Having a fully sequenced genome for N. lugens allows us to perform in-depth analysis of the gene structures, reveal the evolutionary relationships and predict the physiological functions of SP genes. RESULTS: The genome- and transcriptome-wide analysis identified 90 putative SP (65) and SPH (25) genes in N. lugens. Detailed gene information regarding the exon-intron organization, size, distribution and transcription orientation in the genome revealed that many SP/SPH loci are closely situated on the same scaffold, indicating the frequent occurrence of gene duplications in this large gene family. The gene expression profiles revealed new findings with regard to how SPs/SPHs respond to bacterial infections as well as their tissue-, development- and sex-specific expressions. CONCLUSIONS: Our findings provide comprehensive gene sequence resources and expression profiles of the N. lugens SP and SPH genes, which give insights into clarifying the potentially functional roles of these genes in the biological processes including development, digestion, reproduction and immunity. PMID- 24952585 TI - Suboptimal maternal nutrition during early-to-mid gestation in the sheep enhances pericardial adiposity in the near-term fetus. AB - Manipulation of the maternal diet at defined stages of gestation influences long term health by inducing changes in fetal adipose tissue development, characterised as possessing brown and white adipocytes. We determined whether suboptimal maternal nutrition in early-to-mid gestation, followed by ad libitum feeding until term, increases adiposity in the pericardial depot of the sheep fetus. Pericardial adipose tissue was sampled from near-term (140 days) fetuses delivered to mothers fed either 100% (C) or 60% (i.e. nutrient restricted (NR)) of their total metabolisable requirements from 28 to 80 days gestation and then fed ad libitum. Adipose tissue mass, uncoupling protein (UCP) 1 and gene expression of brown and white adipogenic genes was measured. Total visceral and pericardial adiposity was increased in offspring born to NR mothers. The abundance of UCP1 was increased, together with those genes involved in brown (e.g. BMP7 and C/EBPbeta) and white (e.g. BMP4 and C/EBPalpha) adipogenesis, whereas insulin receptor gene expression was downregulated. In conclusion, suboptimal maternal nutrition between early-to-mid gestation followed by ad libitum feeding enhances pericardial adiposity near to term. A combination of raised UCP1 and adipose tissue mass could improve survival following cold exposure at birth. In the longer term, this enhanced adipogenic potential could predispose to greater pericardial adiposity. PMID- 24952586 TI - Metabolic syndrome among psychiatric outpatients with mood and anxiety disorders. AB - BACKGROUND: Few studies have simultaneously compared the impacts of pharmacotherapy and mental diagnoses on metabolic syndrome (MetS) among psychiatric outpatients with mood and anxiety disorders. This study aimed to investigate the impacts of pharmacotherapy and mental diagnoses on MetS and the prevalence of MetS among these patients. METHODS: Two-hundred and twenty-nine outpatients (men/women = 85/144) were enrolled from 1147 outpatients with mood and anxiety disorders by systematic sampling. Psychiatric disorders and MetS were diagnosed using the Structured Clinical Interview for DSM-IV-TR and the new International Diabetics Federation definition, respectively. The numbers of antipsychotics, mood stabilizers, and antidepressants being taken were recorded. Logistic regression was used to investigate the impacts of pharmacotherapy and psychiatric diagnoses on MetS. RESULTS: Among 229 subjects, 51 (22.3%) fulfilled the criteria for MetS. The prevalence of MetS was highest in the bipolar I disorder (46.7%) patients, followed by bipolar II disorder (25.0%), major depressive disorder (22.0%), anxiety-only disorders (16.7%), and no mood and/or anxiety disorders (14.3%). The percentages of MetS among the five categories were correlated with those of the patients being treated with antipsychotics and mood stabilizers. Use of antipsychotics and/or mood stabilizers independently predicted a higher risk of MetS after controlling for demographic variables and psychiatric diagnoses. When adding body mass index (BMI) as an independent variable in the regression model, BMI became the most significant factor to predict MetS. CONCLUSION: BMI was found to be an important factor related to MetS. Pharmacotherapy might be one of underlying causes of elevated BMI. The interactions among MetS, BMI, pharmacotherapy, and psychiatric diagnoses might need further research. PMID- 24952587 TI - Increasing effect of Tangzhiqing formula on IRS-1-dependent PI3K/AKT signaling in muscle. AB - BACKGROUND: Tangzhiqing fomula (TZQ-F), the mixture of Red Paeony root, Mulberry leaf, Lotus leaf, Danshen root and Hawthorn leaf, regulates the abnormal glucose and lipids in prediabetic patients. In this study, we focus on the mechanism of TZQ-F and its fractions on glucose metabolism. METHODS: After orally administration of TZQ-F for 4 weeks in KK-Ay mice, we dissected out the liver and muscle, and employed PCR and western blotting to screening the PI3K/AKT pathway. The following PI3K/AKT signaling pathway were performed in L-6 myotube and HepG2 cells. RESULTS: In the liver of KK-Ay mice, no significance was observed on PI3K, AKT and their phosphorylation between TZQ-F and controls , while, in the muscle, up-regulation of PI3K, AKT, Glycogen synthase (GYS) and their phosphorylation type, as well as GluT4, was deteced in TZQ-F. In HepG2 cells, TZQ-F increased IRS 2 by 10 folds, without interrupting AKT, IRS-1 and GluT4. In L-6 myotube cells, TZQ-F and its fractions treatment significantly increased IRS-1 and AKT at mRNA level. CONCLUSION: TZQ-F prevents pre-diabetes through increasing effect on IRS-1 dependent PI3K/AKT signaling pathway in muscle. PMID- 24952588 TI - Exercise induction of gut microbiota modifications in obese, non-obese and hypertensive rats. AB - BACKGROUND: Obesity is a multifactor disease associated with cardiovascular disorders such as hypertension. Recently, gut microbiota was linked to obesity pathogenesisand shown to influence the host metabolism. Moreover, several factors such as host-genotype and life-style have been shown to modulate gut microbiota composition. Exercise is a well-known agent used for the treatment of numerous pathologies, such as obesity and hypertension; it has recently been demonstrated to shape gut microbiota consortia. Since exercise-altered microbiota could possibly improve the treatment of diseases related to dysfunctional microbiota, this study aimed to examine the effect of controlled exercise training on gut microbial composition in Obese rats (n = 3), non-obese Wistar rats (n = 3) and Spontaneously Hypertensive rats (n = 3). Pyrosequencing of 16S rRNA genes from fecal samples collected before and after exercise training was used for this purpose. RESULTS: Exercise altered the composition and diversity of gut bacteria at genus level in all rat lineages. Allobaculum (Hypertensive rats), Pseudomonas and Lactobacillus (Obese rats) were shown to be enriched after exercise, while Streptococcus (Wistar rats), Aggregatibacter and Sutturella (Hypertensive rats) were more enhanced before exercise. A significant correlation was seen in the Clostridiaceae and Bacteroidaceae families and Oscillospira and Ruminococcus genera with blood lactate accumulation. Moreover, Wistar and Hypertensive rats were shown to share a similar microbiota composition, as opposed to Obese rats. Finally, Streptococcus alactolyticus, Bifidobacterium animalis, Ruminococcus gnavus, Aggregatibacter pneumotropica and Bifidobacterium pseudolongum were enriched in Obese rats. CONCLUSIONS: These data indicate that non-obese and hypertensive rats harbor a different gut microbiota from obese rats and that exercise training alters gut microbiota from an obese and hypertensive genotype background. PMID- 24952589 TI - Efficient search, mapping, and optimization of multi-protein genetic systems in diverse bacteria. AB - Developing predictive models of multi-protein genetic systems to understand and optimize their behavior remains a combinatorial challenge, particularly when measurement throughput is limited. We developed a computational approach to build predictive models and identify optimal sequences and expression levels, while circumventing combinatorial explosion. Maximally informative genetic system variants were first designed by the RBS Library Calculator, an algorithm to design sequences for efficiently searching a multi-protein expression space across a > 10,000-fold range with tailored search parameters and well-predicted translation rates. We validated the algorithm's predictions by characterizing 646 genetic system variants, encoded in plasmids and genomes, expressed in six gram positive and gram-negative bacterial hosts. We then combined the search algorithm with system-level kinetic modeling, requiring the construction and characterization of 73 variants to build a sequence-expression-activity map (SEAMAP) for a biosynthesis pathway. Using model predictions, we designed and characterized 47 additional pathway variants to navigate its activity space, find optimal expression regions with desired activity response curves, and relieve rate-limiting steps in metabolism. Creating sequence-expression-activity maps accelerates the optimization of many protein systems and allows previous measurements to quantitatively inform future designs. PMID- 24952590 TI - Cell cycle population effects in perturbation studies. AB - Growth condition perturbation or gene function disruption are commonly used strategies to study cellular systems. Although it is widely appreciated that such experiments may involve indirect effects, these frequently remain uncharacterized. Here, analysis of functionally unrelated Saccharyomyces cerevisiae deletion strains reveals a common gene expression signature. One property shared by these strains is slower growth, with increased presence of the signature in more slowly growing strains. The slow growth signature is highly similar to the environmental stress response (ESR), an expression response common to diverse environmental perturbations. Both environmental and genetic perturbations result in growth rate changes. These are accompanied by a change in the distribution of cells over different cell cycle phases. Rather than representing a direct expression response in single cells, both the slow growth signature and ESR mainly reflect a redistribution of cells over different cell cycle phases, primarily characterized by an increase in the G1 population. The findings have implications for any study of perturbation that is accompanied by growth rate changes. Strategies to counter these effects are presented and discussed. PMID- 24952592 TI - HGF/c-Met axis drives cancer aggressiveness in the neo-adjuvant setting of ovarian cancer. AB - Ovarian cancer is the most lethal gynecologic malignancy. Recently, NACT (Neo Adjuvant Chemotherapy) has been tested as alternative approach for the management of ovarian cancer patients. A biological predictor helpful in selecting patients for NACT would be desirable. This study was aimed at identifying actionable mechanisms of resistance to NACT. Expression of a panel of microRNAs was screened in a discovery set of 85 patients. Analysis of the potential targets was conducted in the same RNAs by calculating significant correlations between microRNAs and genes. Quantitative fluorescent immunohistochemistry was employed in a validation set of 109 patients. MiR-193a-5p was significantly overexpressed in the NACT setting. Analysis of its potential targets demonstrated that this microRNA is also significantly correlated with HGF and MET genes. Analysis of protein expression in samples taken before and after NACT demonstrated that both HGF and c-Met are increased after NACT. Patients who relapse shortly after NACT exhibited the highest relative basal expression of both HGF and c-Met, while the opposite phenomenon was observed in the best responders. Mir-193a-5p, HGF and c Met expression may help select eligible patients for this modality of treatment. Moreover, inhibitors of this pathway may improve the efficacy of NACT. PMID- 24952591 TI - Screen for mitochondrial DNA copy number maintenance genes reveals essential role for ATP synthase. AB - The machinery of mitochondrial DNA (mtDNA) maintenance is only partially characterized and is of wide interest due to its involvement in disease. To identify novel components of this machinery, plus other cellular pathways required for mtDNA viability, we implemented a genome-wide RNAi screen in Drosophila S2 cells, assaying for loss of fluorescence of mtDNA nucleoids stained with the DNA-intercalating agent PicoGreen. In addition to previously characterized components of the mtDNA replication and transcription machineries, positives included many proteins of the cytosolic proteasome and ribosome (but not the mitoribosome), three proteins involved in vesicle transport, some other factors involved in mitochondrial biogenesis or nuclear gene expression, > 30 mainly uncharacterized proteins and most subunits of ATP synthase (but no other OXPHOS complex). ATP synthase knockdown precipitated a burst of mitochondrial ROS production, followed by copy number depletion involving increased mitochondrial turnover, not dependent on the canonical autophagy machinery. Our findings will inform future studies of the apparatus and regulation of mtDNA maintenance, and the role of mitochondrial bioenergetics and signaling in modulating mtDNA copy number. PMID- 24952593 TI - Nucleosomal regulation of chromatin composition and nuclear assembly revealed by histone depletion. AB - Nucleosomes are the fundamental unit of chromatin, but analysis of transcription independent nucleosome functions has been complicated by the gene-expression changes resulting from histone manipulation. Here we solve this dilemma by developing Xenopus laevis egg extracts deficient for nucleosome formation and by analyzing the proteomic landscape and behavior of nucleosomal chromatin and nucleosome-free DNA. We show that although nucleosome-free DNA can recruit nuclear-envelope membranes, nucleosomes are required for spindle assembly and for formation of the lamina and of nuclear pore complexes (NPCs). We show that, in addition to the Ran G-nucleotide exchange factor RCC1, ELYS, the initiator of NPC formation, fails to associate with naked DNA but directly binds histone H2A-H2B dimers and nucleosomes. Tethering ELYS and RCC1 to DNA bypasses the requirement for nucleosomes in NPC formation in a synergistic manner. Thus, the minimal essential function of nucleosomes in NPC formation is to recruit RCC1 and ELYS. PMID- 24952594 TI - Structural insights into the stabilization of MALAT1 noncoding RNA by a bipartite triple helix. AB - Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly abundant nuclear long noncoding RNA that promotes malignancy. A 3'-stem-loop structure is predicted to confer stability by engaging a downstream A-rich tract in a triple helix, similar to the expression and nuclear retention element (ENE) from the KSHV polyadenylated nuclear RNA. The 3.1-A-resolution crystal structure of the human MALAT1 ENE and A-rich tract reveals a bipartite triple helix containing stacks of five and four U*A-U triples separated by a C+*G-C triplet and C-G doublet, extended by two A-minor interactions. In vivo decay assays indicate that this blunt-ended triple helix, with the 3' nucleotide in a U*A-U triple, inhibits rapid nuclear RNA decay. Interruption of the triple helix by the C-G doublet induces a 'helical reset' that explains why triple-helical stacks longer than six do not occur in nature. PMID- 24952595 TI - Histone deacetylase 2 and N-Myc reduce p53 protein phosphorylation at serine 46 by repressing gene transcription of tumor protein 53-induced nuclear protein 1. AB - Myc oncoproteins and histone deacetylases (HDACs) exert oncogenic effects by modulating gene transcription. Paradoxically, N-Myc induces p53 gene expression. Tumor protein 53-induced nuclear protein 1 (TP53INP1) phosphorylates p53 protein at serine 46, leading to enhanced p53 activity, transcriptional activation of p53 target genes and programmed cell death. Here we aimed to identify the mechanism through which N-Myc overexpressing p53 wild-type neuroblastoma cells acquired resistance to apoptosis. TP53INP1 was found to be one of the genes most significantly repressed by HDAC2 and N-Myc according to Affymetrix microarray gene expression datasets. HDAC2 and N-Myc reduced TP53INP1 gene expression by direct binding to the TP53INP1 gene promoter, leading to transcriptional repression of TP53INP1, p53 protein de-phosphorylation at serine 46, neuroblastoma cell proliferation and survival. Moreover, low levels of TP53INP1 expression in human neuroblastoma tissues correlated with high levels of N-Myc expression and poor patient outcome, and the BET bromodomain inhibitors JQ1 and I BET151 reduced N-Myc expression and reactivated TP53INP1 expression in neuroblastoma cells. These findings identify TP53INP1 repression as an important co-factor for N-Myc oncogenesis, and provide further evidence for the potential application of BET bromodomain inhibitors in the therapy of N-Myc-induced neuroblastoma. PMID- 24952596 TI - Notch inhibition allows oncogene-independent generation of iPS cells. AB - The reprogramming of somatic cells to pluripotency using defined transcription factors holds great promise for biomedicine. However, human reprogramming remains inefficient and relies either on the use of the potentially dangerous oncogenes KLF4 and CMYC or the genetic inhibition of the tumor suppressor gene p53. We hypothesized that inhibition of signal transduction pathways that promote differentiation of the target somatic cells during development might relieve the requirement for non-core pluripotency factors during induced pluripotent stem cell (iPSC) reprogramming. Here, we show that inhibition of Notch greatly improves the efficiency of iPSC generation from mouse and human keratinocytes by suppressing p21 in a p53-independent manner and thereby enriching for undifferentiated cells capable of long-term self-renewal. Pharmacological inhibition of Notch enabled routine production of human iPSCs without KLF4 and CMYC while leaving p53 activity intact. Thus, restricting the development of somatic cells by altering intercellular communication enables the production of safer human iPSCs. PMID- 24952597 TI - A G-quadruplex-containing RNA activates fluorescence in a GFP-like fluorophore. AB - Spinach is an in vitro-selected RNA aptamer that binds a GFP-like ligand and activates its green fluorescence. Spinach is thus an RNA analog of GFP and has potentially widespread applications for in vivo labeling and imaging. We used antibody-assisted crystallography to determine the structures of Spinach both with and without bound fluorophore at 2.2-A and 2.4-A resolution, respectively. Spinach RNA has an elongated structure containing two helical domains separated by an internal bulge that folds into a G-quadruplex motif of unusual topology. The G-quadruplex motif and adjacent nucleotides comprise a partially preformed binding site for the fluorophore. The fluorophore binds in a planar conformation and makes extensive aromatic stacking and hydrogen bond interactions with the RNA. Our findings provide a foundation for structure-based engineering of new fluorophore-binding RNA aptamers. PMID- 24952598 TI - Flow cytometry-based functional selection of RNA interference triggers for efficient epi-allelic analysis of therapeutic targets. AB - BACKGROUND: The dose-response relationship is a fundamental pharmacological parameter necessary to determine therapeutic thresholds. Epi-allelic hypomorphic analysis using RNA interference (RNAi) can similarly correlate target gene dosage with cellular phenotypes. This however requires a set of RNAi triggers empirically determined to attenuate target gene expression to different levels. RESULTS: In order to improve our ability to incorporate epi-allelic analysis into target validation studies, we developed a novel flow cytometry-based functional screening approach (CellSelectRNAi) to achieve unbiased selection of shRNAs from high-coverage libraries that knockdown target gene expression to predetermined levels. Employing a Gaussian probability model we calculated that knockdown efficiency is inferred from shRNA sequence frequency profiles derived from sorted hypomorphic cell populations. We used this approach to generate a hypomorphic epi allelic cell series of shRNAs to reveal a functional threshold for the tumor suppressor p53 in normal and transformed cells. CONCLUSION: The unbiased CellSelectRNAi flow cytometry-based functional screening approach readily provides an epi-allelic series of shRNAs for graded reduction of target gene expression and improved phenotypic validation. PMID- 24952602 TI - Tissue engineering approaches in skeletal pediatric disorders. AB - The therapeutic use of stem cells is a very promising strategy in the area of regenerative medicine. The stem cell regenerative paradigm has been mostly based on the assumption that progenitor cells play a critical role in tissue repair by their plasticity and differentiation potential. However, recent works suggest that the mechanism underlying the benefits of stem cell transplantation might relate to a paracrine modulatory effect rather than the replacement of affected cells at the site of injury. Preclinical and clinical skeletal studies, conducted in animal and adult series, support the use of mesenchymal stem cells (MSCs) for bone healing in critical clinical situations. These results have led to an increasing number of papers reporting the use of MSCs in adult clinical trials, whereas only few papers reported the use of these cells in pediatric skeletal disorders, probably because of unknown long-term results and long-life consequences of cellular therapy. The exponential growth of knowledge in adult MSCs could be translated and applied to pediatric disorders. Pediatric osteoarticular diseases have an enormous potential to be treated by MSCs, as severe congenital bone or local cartilage defects, not responding to conventional surgery treatment, might be successfully treated by cellular therapy. Translating basic stem cell research into routine therapies is a complex multistep process which entails the managing of the expected therapeutic benefits with the potential risks in correlation within the existing regulations. Here, we reported the state of art on the use of MSC in skeletal pediatric disorders. PMID- 24952599 TI - RAGE mediates S100A4-induced cell motility via MAPK/ERK and hypoxia signaling and is a prognostic biomarker for human colorectal cancer metastasis. AB - Survival of colorectal cancer patients is strongly dependent on development of distant metastases. S100A4 is a prognostic biomarker and inducer for colorectal cancer metastasis. Besides exerting intracellular functions, S100A4 is secreted extracellularly. The receptor for advanced glycation end products (RAGE) is one of its interaction partners. The impact of the S100A4-RAGE interaction for cell motility and metastasis formation in colorectal cancer has not been elucidated so far. Here we demonstrate the RAGE-dependent increase in migratory and invasive capabilities of colorectal cancer cells via binding to extracellular S100A4. We show the direct interaction of S100A4 and RAGE, leading to hyperactivated MAPK/ERK and hypoxia signaling. The S100A4-RAGE axis increased cell migration (P<0.005) and invasion (P<0.005), which was counteracted with recombinant soluble RAGE and RAGE-specific antibodies. In colorectal cancer patients, not distantly metastasized at surgery, high RAGE expression in primary tumors correlated with metachronous metastasis, reduced overall (P=0.022) and metastasis-free survival (P=0.021). In summary, interaction of S100A4-RAGE mediates S100A4-induced colorectal cancer cell motility. RAGE by itself represents a biomarker for prognosis of colorectal cancer. Thus, therapeutic approaches targeting RAGE or intervening in S100A4-RAGE-dependent signaling early in tumor progression might represent alternative strategies restricting S100A4-induced colorectal cancer metastasis. PMID- 24952600 TI - Therapeutic effect of Botulinum toxin-A in 88 patients with trigeminal neuralgia with 14-month follow-up. AB - BACKGROUND: We investigated the long-term effects and safety of botulinum toxin-A (BTX-A) for treating trigeminal neuralgia (TN). We also studied long-term maintenance of this therapeutic effect. METHODS: A visual analog scale (VAS) score, pain attack frequency per day, patient's overall response to treatment and side effects during 14-month follow-up were evaluated in 88 patients with TN receiving BTX-A. The primary endpoints were pain severity (assessed by VAS) and pain attack frequency per day. The secondary endpoint was the patient's overall response to treatment, assessed using the Patient Global Impression of Change. The influence of different doses (<=50, 50-100 and >=100 U) on the therapeutic effect was evaluated. RESULTS: Treatment was deemed "effective" within 1 month in 81 patients and at 2 months in 88 patients (100%). The shortest period of effective treatment was 3 months, and complete control of pain was observed in a maximum of 46 patients. The therapeutic effect decreased gradually after 3 months, and the prevalence of effective treatment at 14 months was 38.6%, with complete control of pain seen in 22 patients (25%). There was no significant difference in the prevalence of effective treatment between different dose groups at identical time points (p > 0.05). Three patients showed swelling at injection sites and 10 patients showed facial asymmetry, both of which disappeared spontaneously without special treatment. CONCLUSION: Local subcutaneous injection of BTX-A for TN treatment has considerable therapeutic effects lasting several months and is safe for this indication. At least one-quarter of patients maintained complete analgesia. The maintenance period of the therapeutic effect may be related to the reduction in the VAS score after the first injection of BTX A. PMID- 24952601 TI - Utility of contrast-enhanced ultrasound with perflubutane for diagnosing the macroscopic type of small nodular hepatocellular carcinomas. AB - OBJECTIVE: To clarify the diagnostic value of contrast-enhanced ultrasound (CEUS) with perflubutane in the macroscopic classification of small nodular hepatocellular carcinomas (HCCs). METHODS: A total of 99 surgically resected nodular HCCs with a maximum diameter of 3 cm or less were analysed. HCCs were macroscopically categorized as simple nodular (SN) and non-SN. CEUS findings were evaluated during the arterial phase (vascularity, level and shape of enhancement), portal phase (presence or absence of washout) and post-vascular phase (echo intensity and shape). RESULTS: Sixty-eight HCCs were categorized as SN and the remaining 31 were categorized as non-SN. For diagnosis of non-SN HCC, the areas under the receiver operating characteristic curve (A z) value for the shape of enhancement in the late arterial phase and the shape of the post vascular image were 0.824 (95 % confidence interval [CI] 0.721-0.895) and 0.878 (95 % CI 0.788-0.933), respectively. The A z value for the combination of the shape of enhancement in the late arterial phase and the shape of the post vascular image for the diagnosis of non-SN HCC was 0.907 (95 % CI 0.815-0.956), corresponding to a high diagnostic value. CONCLUSION: CEUS can provide high quality imaging assessment for determining the macroscopic classification of small nodular HCCs. KEY POINTS: * Non-SN is one of the poor prognostic factors in patients with HCC * Assessment of macroscopic type provides valuable information for the management of HCC * CEUS can provide high-quality imaging assessment for macroscopic classification of HCC * For non-SN HCC diagnosed using CEUS, hepatectomy is preferred as curative treatment. PMID- 24952605 TI - Reflections on 'health care in the information society--a prognosis for the year 2013'. AB - In the year 2000 a talk was given and later published on how health care could look like in the year 2013. The aim was to "identify priorities in medical informatics research and necessary activities by policymakers in order to ensure an efficient, advanced, and yet affordable future health care system" (Haux R, Ammenwerth E, Herzog W, Knaup P. Health care in the information society. A prognosis for the year 2013. Int J Med Inform. 2002; 66: 3-21). In the year 2013 a workshop took place, critically reflecting on the prognoses and theses made for the year 2013. This editorial is reporting on the 2013-workshop and is introducing three papers, in which the workshop results have been summarized. PMID- 24952604 TI - TNF A -308G>A polymorphism in Moroccan patients with type 2 diabetes mellitus: a case-control study and meta-analysis. AB - Type 2 diabetes mellitus (T2DM) is one of causes of mortality and morbidity in Moroccan population. The identification of genes implicated in this disease can help to found a specific treatment and to improve the quality of life for type 2 diabetic patients. In this study we analyze the association between a polymorphism (-308G>A) of TNF A promoter gene and T2DM in Moroccan patients. Five hundred and fifty-one individuals (307 patients with T2DM and 244 controls) were genotyped for this polymorphism by PCR-RFLP. This association was further reconsidered by a meta-analysis on 21 studies including 8,187 cases and 7,811 controls. We found that in Moroccan patients the -308A allele is strongly associated with T2DM (p = 0.000002; odds ratio 1.79, 95 % confidence interval 1.41-2.28). Based on our meta-analysis, there was no significant association detected between the TNF A -308G>A polymorphism and risk for T2DM. Our results suggest that the -308G>A polymorphism is a genetic risk factor for the development of T2DM in Moroccan population. On the other hand the meta analysis results led to controversial conclusions in other ethnicities. PMID- 24952603 TI - Association of interleukin 1 receptor antagonist (IL1RN) gene polymorphism with recurrent pregnancy loss risk in the North Indian Population and a meta-analysis. AB - An appropriate ratio of interleukin 1 beta to interleukin 1 receptor antagonist (IL1Ra) is required for successful pregnancy. Our objective was to study the genetic association between IL1RN variable numbers of tandem repeat (VNTR) polymorphism and recurrent pregnancy loss (RPL). To analyze the association between IL1RN VNTR allele and RPL, we investigated the IL1RN VNTR polymorphism in 136 RPL patients and in 200 healthy control women. Meta-analysis on this polymorphism was conducted to support our findings. PCR based approach was used to analyze IL1RN VNTR polymorphism and it was further confirmed by sequencing. Systematic review and meta-analysis was done using electronic database (Pub-Med, Google Scholar and Ovid) up to February 27, 2013. This meta-analysis was assessed by comprehensive meta-analysis software version 2. For meta-analysis 549 cases and 1,450 controls were included. The frequency of IL1RN genotype 2/2 was significantly higher in RPL compared to control group (AORs 3.10, 95 % CI 1.58 6.11, p = 0.001). The presence of rare allele also increased the risk of RPL significantly (ORs 1.63, 95 % CI 1.16-2.29, p = 0.004). The meta-analysis stratified by ethnicity showed that individuals with allele 2 had increased risk of RPL (OR 1.29, 95 % CI 1.04-1.61, p = 0.01), in Asians population by using fixed model. However the data of the present study clearly suggests that IL1RN VNTR polymorphism is a genetic risk factor for pregnancy loss in the study population. PMID- 24952606 TI - Assessing the prognoses on Health care in the information society 2013--thirteen years after. AB - Health care and information technology in health care is advancing at tremendous speed. We analysed whether the prognoses by Haux et al. - first presented in 2000 and published in 2002 - have been fulfilled in 2013 and which might be the reasons for match or mismatch. Twenty international experts in biomedical and health informatics met in May 2013 in a workshop to discuss match or mismatch of each of the 71 prognoses. After this meeting a web-based survey among workshop participants took place. Thirty-three prognoses were assessed matching; they reflect e.g. that there is good progress in storing patient data electronically in health care institutions. Twenty-three prognoses were assessed mismatching; they reflect e.g. that telemedicine and home monitoring as well as electronic exchange of patient data between institutions is not established as widespread as expected. Fifteen prognoses were assessed neither matching nor mismatching. ICT tools have considerably influenced health care in the last decade, but in many cases not as far as it was expected by Haux et al. in 2002. In most cases this is not a matter of the availability of technical solutions but of organizational and ethical issues. We need innovative and modern information system architectures which support multiple use of data for patient care as well as for research and reporting and which are able to integrate data from home monitoring into a patient centered health record. Since innovative technology is available the efficient and wide-spread use in health care has to be enabled by systematic information management. PMID- 24952607 TI - Past and next 10 years of medical informatics. AB - More than 10 years ago Haux et al. tried to answer the question how health care provision will look like in the year 2013. A follow-up workshop was held in Braunschweig, Germany, for 2 days in May, 2013, with 20 invited international experts in biomedical and health informatics. Among other things it had the objectives to discuss the suggested goals and measures of 2002 and how priorities on MI research in this context should be set from the viewpoint of today. The goals from 2002 are now as up-to-date as they were then. The experts stated that the three goals: "patient-centred recording and use of medical data for cooperative care"; "process-integrated decision support through current medical knowledge" and "comprehensive use of patient data for research and health care reporting" have not been reached yet and are still relevant. A new goal for ICT in health care should be the support of patient centred personalized (individual) medicine. MI as an academic discipline carries out research concerning tools that support health care professionals in their work. This research should be carried out without the pressure that it should lead to systems that are immediately and directly accepted in practice. PMID- 24952608 TI - The risk of suicide mortality in chronic pain patients. AB - Chronic pain has long been considered an important risk factor for suicidal behavior. Less well understood are the factors associated with the increased risk for suicide death within chronic pain populations. The purpose of this review is to examine recent research with regard to rates of and risk factors for suicide mortality in patients with chronic musculoskeletal pain. We conclude that patients with a number of chronic pain states are at increased risk for suicide death, and that this risk appears to be due, at least in part, to other well known correlates of pain such as depression and substance use disorders. However, in all likelihood, there are aspects of chronic pain itself that add uniquely to an individual's suicide risk profile. Lastly, we address a theoretical perspective and offer recommendations for clinical practice. PMID- 24952609 TI - Memantine alleviates brain injury and neurobehavioral deficits after experimental subarachnoid hemorrhage. AB - Subarachnoid hemorrhage (SAH) causes brain injury via glutamate excitotoxicity, which leads to an excessive Ca(2+) influx and this starts an apoptotic cascade. Memantine has been proven to reduce brain injury in several types of brain insults. This study investigated the neuro-protective potential of memantine after SAH and explored the underlying mechanisms. An endovascular perforation rat model of SAH was used and Sprague-Dawley rats were randomized into sham surgery, SAH + vehicle, and SAH + memantine groups. The effects of memantine on SAH were evaluated by assessing the neuro-behavioral functions, blood-brain barrier (BBB) permeability and neuronal cell preservation. The mechanisms of action of memantine, with its N-methyl-D-aspartate (NMDA) antagonistic characteristics on nitric oxide synthase (NOS) expression and peroxynitrite formation, were also investigated. The apoptotic cascade after SAH was suppressed by memantine. Neuronal NOS (nNOS) expression, peroxynitrite formation, and subsequent oxidative/nitrosative stress were also reduced. Memantine effectively preserved BBB integrity, rescued neuronal injury, and improved neurological outcome in experimental SAH. Memantine has neuro-protective potential in experimental SAH and may help combat SAH-induced brain damage in the future. PMID- 24952610 TI - High-dimensional analysis of the aging immune system: verification of age associated differences in immune signaling responses in healthy donors. AB - BACKGROUND: Single-cell network profiling (SCNP) is a multiparametric flow cytometry-based approach that simultaneously measures evoked signaling in multiple cell subsets. Previously, using the SCNP approach, age-associated immune signaling responses were identified in a cohort of 60 healthy donors. METHODS: In the current study, a high-dimensional analysis of intracellular signaling was performed by measuring 24 signaling nodes in 7 distinct immune cell subsets within PBMCs in an independent cohort of 174 healthy donors [144 elderly (>65 yrs); 30 young (25-40 yrs)]. RESULTS: Associations between age and 9 immune signaling responses identified in the previously published 60 donor cohort were confirmed in the current study. Furthermore, within the current study cohort, 48 additional immune signaling responses differed significantly between young and elderly donors. These associations spanned all profiled modulators and immune cell subsets. CONCLUSIONS: These results demonstrate that SCNP, a systems-based approach, can capture the complexity of the cellular mechanisms underlying immunological aging. Further, the confirmation of age associations in an independent donor cohort supports the use of SCNP as a tool for identifying reproducible predictive biomarkers in areas such as vaccine response and response to cancer immunotherapies. PMID- 24952611 TI - Malignant solitary fibrous tumor of the pleura slowly growing over 17 years: case report. AB - Although a solitary fibrous tumor of the pleura (SFTP) is a rare disease, and usually has a benign course, it has a malignant potential. We report a case of malignant SFTP treated surgically. A 75-year-old female was admitted with a chief complaint of hemoptysis of two weeks duration. Computed tomography of the chest imaged a large mass in the right hemithorax, which compressed adjacent organs; however, there was no evidence of invasion. We reviewed the patient's medical records and found that the mass had been presented for 17 years. Complete resection was achieved through a right thoracotomy and histopathologic examination confirmed a malignant SFTP. PMID- 24952613 TI - Perfluorinated compounds in serum and urine samples from children aged 5-13 years in South Korea. AB - Serum and urine samples from 120 children aged 5-13 years from Dae-gu, Korea, were analyzed for 16 perfluorinated compounds (PFCs). The total PFC concentrations in the serum were 4.26-29.70 ng/mL, and perfluorohexanesulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS, which was dominant overall, at 6.58 ng/mL), and perfluoroundecanoic acid (PFUndA) were detected in all serum samples. The total PFC concentrations in the urine ranged from below the detection limit to 14.9 ng/mL, and perfluoropentanoic acid (PFPeA) was predominant. The PFOS (p < 0.005) concentration was higher in the serum of children than that of Korean adults aged 20-29. Some of the PFC concentrations in the serum correlated negatively with body mass index and tended to increase with the duration of breastfeeding. However, there were no gender-specific differences in the PFC concentrations and no correlations between PFC concentrations in serum and urine. PMID- 24952612 TI - Dental caries in primary and permanent molars in 7-8-year-old schoolchildren evaluated with Caries Assessment Spectrum and Treatment (CAST) index. AB - BACKGROUND: No reports on a caries pattern covering the full spectrum of the disease could be found in the literature. The aim of this study was to evaluate caries in primary and first permanent molars of 7-8-year-old Polish children by the Caries Assessment Spectrum and Treatment (CAST) index and to find whether there was any correlation between the caries stages in such teeth. METHODS: The study covered 284 7-8-year-old children from randomly selected schools in the Bialystok District, Poland. The prevalence of CAST categories was evaluated with regard to the first and second primary, and first permanent, molars. The Spearman's rank correlation coefficient was used to explore the correlation of the distribution of CAST codes among the evaluated teeth. The level of statistical significance was established at p < 0.05. The intra-examiner reliability was determined by the unweighted kappa coefficient. RESULTS: With regard to the permanent molars, caries was observed in 14.8% to 17.3% of the molar and most lesions were scored at the non-cavitation level. Caries in primary molars was most often recorded at the stage of cavitated dentine lesion. Teeth with pulpal involvement, sepsis and extracted due to caries were found to be more prevalent in first, and then in second primary molars. A strong correlation was found between the status of teeth from the right and left sides of the oral cavity. The correlation of the status of first and second primary teeth was stronger for the left than for the right side of the mouth, r was 0.627 and 0.472 in maxilla and 0.513 and 0.483 in mandible (p < 0.001), respectively. For the neighbouring primary and permanent molars the correlation was assessed to be weak. With regard to the teeth situated in opposite jaws the study revealed that the correlations were moderate - r between 0.33 and 0.49. The intra-examiner reliability was established at 0.96 for the primary dentition and at 0.878 for permanent molars. CONCLUSION: The strongest correlation found in the evaluated population concerned the distribution of caries in primary molars on the left side of the mouth. The study proved the usefulness of the CAST index in epidemiological surveys. PMID- 24952614 TI - Occupational health of patients with obstructive sleep apnea syndrome: a systematic review. AB - PURPOSE: The aim of this systematic literature review was to assess the impact of obstructive sleep apnea syndrome (OSAS) on patients' occupational health. METHODS: We selected 19 studies that dealt with issues related to job performance and productivity, absenteeism, and psychosocial health of patients with OSAS and assessed the risk of bias in their conclusions. RESULTS: Although methodologically rigorous studies are needed to confirm these findings, the results obtained suggest the existence of multiple relationships between OSAS and work limitations of patients (i.e., difficulties maintaining attention, learning new tasks, or performing monotonous tasks). The studies reviewed reached more scientifically consistent conclusions about such patients' risk of taking more days of sick leave or having work disability, particularly if they reported excessive daytime sleepiness. Very few studies have explored the relationship between OSAS and psychosocial occupational health of patients. Thus, there is a need for research to clarify these aspects of occupational medicine. CONCLUSIONS: OSAS has numerous effects on patients' occupational health, yet, in general, results should be confirmed by studies with sufficiently large samples in which OSAS is diagnosed with reliable methods and occupational variables are assessed with standardized and validated questionnaires. PMID- 24952615 TI - Melamine-cyanurate complexes and oxidative stress markers in trout kidney following melamine and cyanuric acid long-term co-exposure and withdrawal. AB - In 2007, renal failure and death in pets were linked to pet food containing both melamine (MEL) and cyanuric acid (CYA). In mammals and fish, the co administration of MEL and CYA causes renal crystal formation. Moreover, little is known about the process of crystal removal in fish. The aim of this study was to evaluate the formation of MEL-cyanurate crystals in kidney of rainbow trout (Oncorhynchus mykiss) fed combined MEL and CYA diets for 10 weeks at 250, 500 and 1,000 mg/kg in feed (equivalent to 2.5, 5, 10 mg/kg body weight of trout fed 1 % body weight per day). During the exposure trial and throughout a withdrawal period, prooxidant effects of MEL and CYA were evaluated on oxidative stress markers such as catalase, glutathione S-transferase and malondialdehyde. Crystal formation was dose and time dependent, and after six withdrawal weeks, crystals persisted in kidney of trout treated the highest triazine dose. Catalase and glutathione S-transferase activity in kidney of trout exposed to both triazines for 10 weeks indicated that MEL (with or without CYA) can exert a higher prooxidant effect than CYA dispensed singly. Although the enzymes activity increase appears to be reverted after two MEL withdrawal weeks, persistence of crystals may lead to severe damage in renal cells of fish. PMID- 24952616 TI - Patterns of regional gray matter and white matter atrophy in cortical multiple sclerosis. AB - We investigated the patterns of regional distribution of focal lesions, white matter (WM) and gray matter (GM) atrophy in patients with cortical (cort) MS in comparison to classical (c) MS patients. Nine cort-MS, nine c-MS and nine age matched healthy controls (HC) underwent a brain MRI exam, including FLAIR and high-resolution T1-weighted scans. MS patients underwent neurological and neuropsychological assessment. Between-group differences of GM and WM volumes and their correlations with neuropsychological performances were assessed with voxel based morphometry. FLAIR and T1 lesion probability maps (LPMs) were also obtained. Performance at neuropsychological tests was worse in cort-MS than in c MS patients. Compared to HC, MS patients had a distributed pattern of GM and WM atrophy. No GM/WM area was more atrophic in c-MS vs cort-MS patients. Compared to c-MS, cort-MS patients experienced GM atrophy of frontal-temporal-parietal areas and cingulate cortex and WM atrophy of the cingulum bundle, bilateral cerebral peduncles, right inferior longitudinal fasciculus and left superior longitudinal fasciculus. FLAIR and T1 LPMs did not differ between c-MS vs cort-MS patients. A higher susceptibility to neurodegenerative processes in key brain regions known to be related to cognitive functions is likely to underlie the clinical manifestations of cort-MS. PMID- 24952617 TI - Population-based incidence and 5-year survival for hospital-admitted traumatic brain and spinal cord injury, Western Australia, 2003-2008. AB - This study aimed at analysing first-time hospitalisations for traumatic brain injury (TBI) and spinal cord injury (SCI) in Western Australia (WA), in terms of socio-demographic profile, cause of injury, relative risks and survival, using tabular and regression analyses of linked hospital discharge and mortality census files and comparing results with published standardised mortality rates (SMRs) for TBI. Participants were all 9,114 first hospital admissions for TBI or SCI from 7/2003 to 6/2008, linked to mortality census data through 12/2008, and the main outcome measures were number of cases by cause, SMRs in hospital and post discharge by year through year 5. Road crashes accounted for 34 % of hospitalised TBI and 52 % of hospitalised SCI. 8,460 live TBI discharges experienced 580 deaths during 24,494 person-years of follow-up. The life-table expectation of deaths in the cohort was 164. Post-discharge SMRs were 7.66 in year 1, 3.86 in year 2 and averaged 2.31 in years 3 through 5. 317 live SCI discharges experienced 18 deaths during 929 years of follow-up. Post-discharge SMRs were 7.36 in year 1 and a fluctuating average of 2.13 in years 2 through 5. Use of data from model systems does not appear to yield biased SMRs. Similarly no systematic variation was observed between all-age studies and the more numerous studies that focused on those aged 14 to 16 and older. Based on two studies, SMRs for TBI, however, may be higher in year 2 post-discharge in Australia than elsewhere. That possibility and its cause warrant exploration. Expanding public TBI/SCI compensation in WA from road crash to all causes might triple TBI compensation and double SCI compensation. PMID- 24952618 TI - Longitudinal MRI and neuropsychological assessment of patients with clinically isolated syndrome. AB - Cognitive impairment (CI) may occur in clinically isolated syndrome (CIS) patients. While the relationship between CI and magnetic resonance imaging (MRI) has been investigated extensively in multiple sclerosis (MS), MRI correlates of CI in CIS patients are unknown. To investigate the evolution of CI and to determine brain MRI structural correlates associated with CI in CIS patients. This prospective 24-month observational study examined 81 CIS patients treated with 30 ug of intramuscular interferon beta 1a once a week. MRI acquisition and neuropsychological (NP) assessment were performed at baseline, 6, 12 and 24 months. Participants were tested with Czech-validated version of Minimal Assessment of Cognitive Function in MS battery and MRI measures of lesion activity and burden, and global, tissue-specific and regional brain atrophy were performed. Over 24 months, 36 CIS patients developed clinically definite MS (CDMS). CI was observed in 10 (12.3 %) CIS patients at baseline and at the 24 months follow-up. Eight CIS patients changed their CI status over the follow-up (four improved and four worsened). No significant difference in development of CI was detected between stable CIS patients and those who developed CDMS. In multivariate regression and mixed-effect model analyses, no significant relationship was found between NP and MRI parameters. The lack of significant relationship between MRI metrics and cognition in this group of CIS patients could be attributed to several factors including the cognitive reserve, effect of disease-modifying therapy and relatively short follow-up period. PMID- 24952619 TI - Subthalamic deep brain stimulation: clinical and neuropsychological outcomes in mild cognitive impaired parkinsonian patients. AB - This observational study reports the long-term follow-up of 184 Parkinson's disease (PD) patients treated with subthalamic deep brain stimulation (STN-DBS), retrospectively analyzing the outcomes of subjects with pre-surgical mild cognitive impairment (MCI) compared to those of patients with normal cognition. Patients were divided into PD-MCI or normal cognition groups at baseline, and then compared after 1, 3, 5 and >5 years of follow-up. Subjects assessed by outpatient clinical follow-up evaluation, not performing a complete clinical and neuropsychological follow-up assessment, were separately considered and rated according to their functional autonomy in daily living activities. The MCI prevalence at baseline was 23 %, increasing to 34 % at 1 year and over 40 % after 3 years. Dementia progressively affected more than 30 % of subjects after a median time of 6 years in the PD-MCI group and 11 years in the normal cognition group (p: 0.028). The mortality risk was slightly higher in PD-MCI patients. Outpatient clinical evaluations showed a progressive increase of subjects completely dependent in the activities of daily living, which ranged from the 11 % at 3 years to 23 % at 5 years and 31 % at >5 years. MCI can be frequently observed in PD patients, possibly influencing the outcome of surgical therapy. Our findings confirm the sustained long-lasting efficacy of STN-DBS on motor functions in both PD-MCI and normal cognition subjects. PD-MCI patients showed a more precocious cognitive impairment, as expected by natural history studies, but no case of dementia was observed early after surgery. PMID- 24952621 TI - Treatment paradigms in multiple sclerosis: who, when and how to treat? PMID- 24952620 TI - Objective assessment of motor fatigue in multiple sclerosis: the Fatigue index Kliniken Schmieder (FKS). AB - Fatigue is a common and frequently disabling symptom of multiple sclerosis (MS). The aim of this study was to develop the Fatigue index Kliniken Schmieder (FKS) for detecting motor fatigue in patients with MS using kinematic gait analysis. The FKS relies on the chaos theoretical term "attractor", which, if unchanged, is a necessary and sufficient indicator of a stable dynamical system. We measured the acceleration of the feet at the beginning of and shortly before stopping a treadmill walking task in 20 healthy subjects and 40 patients with multiple sclerosis. The attractor and movement variability were calculated. In the absence of muscular exhaustion a significant difference in the attractor and movement variability between the two time points demonstrates altered motor control indicating fatigue. Subjects were classified using the FKS. All healthy subjects had normal FKS and thus no fatigue. 29 patients with MS were classified into a fatigue group and 11 patients into a non-fatigue group. This classification agreed with the physician's observation and video analyses in up to 97 % of cases. The FKS did not correlate significantly with the overall and motor dimensions of the fatigue questionnaire scores in patients with MS and motor fatigue. The common concept of fatigue as overall subjective sensation of exhaustion can be affected by conditions including depression, sleep disorder and others. FKS constitutes a robust and objective measure of changes in motor performance. Therefore, the FKS allows correct identification of motor fatigue even in cases where common comorbidities mask motor fatigue. PMID- 24952622 TI - Emphysema early diagnosis using X-ray diffraction enhanced imaging at synchrotron light source. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide, and emphysema is a common component of COPD. Currently, it is very difficult to detect early stage emphysema using conventional radiographic imaging without contrast agents, because the change in X-ray attenuation is not detectable with absorption-based radiography. Compared with the absorption-based CT, phase contrast imaging has more advantages in soft tissue imaging, because of its high spatial resolution and contrast. METHODS: In this article, we used diffraction enhanced imaging (DEI) method to get the images of early stage emphysematous and healthy samples, then extract X-ray absorption, refraction, and ultra-small-angle X-ray scattering (USAXS) information from DEI images using multiple image radiography (MIR). We combined the absorption image with the USAXS image by a scatter plot. The critical threshold in the scatter plot was calibrated using the linear discriminant function in the pattern recognition. RESULTS: USAXS image was sensitive to the change of tissue micro structure, it could show the lesions which were invisible in the absorption image. Combined with the absorption-based image, the USAXS information enabled better discrimination between healthy and emphysematous lung tissue in a mouse model. The false-color images demonstrated that our method was capable of classifying healthy and emphysematous tissues. CONCLUSION: Here we present USAXS images of early stage emphysematous and healthy samples, where the dependence of the USAXS signal on micro-structures of biomedical samples leads to improved diagnosis of emphysema in lung radiographs. PMID- 24952623 TI - [Can we overcome schistosomiasis? A Senegalese example]. AB - The authors report the results of controlling schistosomiasis in 53 villages from Ninefecha area-(Kedougou District, East Senegal) within Schistosomiasis National Control Program partnership. The four aims were: i) praziquantel treatment of 3324 children 6-14 years old, ii) installation of a laboratory for children prevalence annual monitoring (random draw one in three), iii) health education of the concerned people ("sensitization"), iiii) construction of latrines. 900 latrines are required and 649 have been built. The initial prevalence (2006) of 44% for S. mansoni and 4% for S. haematobium are now respectively 1.9% and 1.4% (2013). The program must be continuous as shown in the Assoni village: a prevalence study in children 0-5 years old, for which praziquantel is not recommended, reveals an infestation rate for S. mansoni of 78% in 2008 and of 47% in 2012. This age group is an important parasite reservoir and health education of parents is absolutely necessary. A permanent and effective center like Ninefescha hospital for distribution of praziquantel, sensitization meetings and latrines control is essential for the success of the program. PMID- 24952624 TI - Bioimaging mass spectrometry of trace elements - recent advance and applications of LA-ICP-MS: A review. AB - Bioimaging using laser ablation inductively coupled plasma mass spectrometry (LA ICP-MS) offers the capability to quantify trace elements and isotopes within tissue sections with a spatial resolution ranging about 10-100 MUm. Distribution analysis adds to clarifying basic questions of biomedical research and enables bioaccumulation and bioavailability studies for ecological and toxicological risk assessment in humans, animals and plants. Major application fields of mass spectrometry imaging (MSI) and metallomics have been in brain and cancer research, animal model validation, drug development and plant science. Here we give an overview of latest achievements in methods and applications. Recent improvements in ablation systems, operation and cell design enabled progressively better spatial resolutions down to 1 MUm. Meanwhile, a body of research has accumulated covering basic principles of the element architecture in animals and plants that could consistently be reproduced by several laboratories such as the distribution of Fe, Cu, Zn in rodent brain. Several studies investigated the distribution and delivery of metallo-drugs in animals. Hyper-accumulating plants and pollution indicator organisms have been the key topics in environmental science. Increasingly, larger series of samples are analyzed, may it be in the frame of comparisons between intervention and control groups, of time kinetics or of three-dimensional atlas approaches. PMID- 24952625 TI - Liquid chromatography with diode array detection and multivariate curve resolution for the selective and sensitive quantification of estrogens in natural waters. AB - Following the green analytical chemistry principles, an efficient strategy involving second-order data provided by liquid chromatography (LC) with diode array detection (DAD) was applied for the simultaneous determination of estriol, 17beta-estradiol, 17alpha-ethinylestradiol and estrone in natural water samples. After a simple pre-concentration step, LC-DAD matrix data were rapidly obtained (in less than 5 min) with a chromatographic system operating isocratically. Applying a second-order calibration algorithm based on multivariate curve resolution with alternating least-squares (MCR-ALS), successful resolution was achieved in the presence of sample constituents that strongly coelute with the analytes. The flexibility of this multivariate model allowed the quantification of the four estrogens in tap, mineral, underground and river water samples. Limits of detection in the range between 3 and 13 ng L(-1), and relative prediction errors from 2 to 11% were achieved. PMID- 24952626 TI - Electrocatalytic oxidation and voltammetric determination of ciprofloxacin employing poly(alizarin red)/graphene composite film in the presence of ascorbic acid, uric acid and dopamine. AB - A glassy carbon electrode modified with poly(alizarin red)/electrodeposited graphene (PAR/EGR) composite film was prepared and applied to detect ciprofloxacin (CPFX) in the presence of ascorbic, uric acid and dopamine. The morphology and interface property of PAR/EGR films were examined by scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS). The electrocatalytic oxidation of CPFX on AR/EGR was investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The linearity ranged from 4 * 10(-8) to 1.2 * 10(-4) M with a detection limit (S/N=3) of 0.01 MUM. The modified electrode could be applied to the individual determination of CPFX as well as the simultaneous determination of CPFX, ascorbic acid, uric acid and dopamine. This method proved to be a simple, selective and rapid way to determine CPFX in pharmaceutical preparation and biological media. PMID- 24952627 TI - Determination of hydrazine in drinking water: Development and multivariate optimization of a rapid and simple solid phase microextraction-gas chromatography triple quadrupole mass spectrometry protocol. AB - In this work, the capabilities of solid phase microextraction were exploited in a fully optimized SPME-GC-QqQ-MS analytical approach for hydrazine assay. A rapid and easy method was obtained by a simple derivatization reaction with propyl chloroformate and pyridine carried out directly in water samples, followed by automated SPME analysis in the same vial without further sample handling. The affinity of the different derivatized compounds obtained towards five commercially available SPME coatings was evaluated, in order to achieve the best extraction efficiency. GC analyses were carried out using a GC-QqQ-MS instrument in selected reaction monitoring (SRM) acquisition mode which has allowed the achievement of high specificity by selecting appropriate precursor-product ion couples improving the capability in analyte identification. The multivariate approach of experimental design was crucial in order to optimize derivatization reaction, SPME process and tandem mass spectrometry parameters. Accuracy of the proposed protocol, tested at 60, 200 and 800 ng L(-1), provided satisfactory values (114.2%, 83.6% and 98.6%, respectively), whereas precision (RSD%) at the same concentration levels were of 10.9%, 7.9% and 7.7% respectively. Limit of detection and quantification of 4.4 and 8.3 ng L(-1) were obtained. The reliable application of the proposed protocol to real drinking water samples confirmed its capability to be used as analytical tool for routine analyses. PMID- 24952628 TI - Simulation of the breakthrough behavior of volatile organic compounds against sorbent tube sampler as a function of concentration level and sampling volume. AB - The breakthrough (BT) properties of Tenax TA sorbent were challenged by gaseous standards containing a suite of 13 volatile organic compounds (VOC): (1) aromatic hydrocarbons: benzene (B), toluene (T), p-xylene (p-X), and styrene (S), (2) aldehydes: acetaldehyde (AA), propionaldehyde (PA), butyraldehyde (BA), isovaleraldehyde (IA), and valeraldehyde (VA), (3) ketones: methyl ethyl ketone (MEK) and methyl isobutyl ketone (MIBK), and (4) two others: isobutyl alcohol (i BuAl) and butyl acetate (BuAc). To this end, 1-3 L of standards (10-50 ppb) were loaded on the two sorbent tubes (ST) connected in series at 100 mL min(-1). The front ST-1 was used for calibration purposes, while the ST-2 for breakthrough (recovery criterion of <1% with p-xylene as the key datum point). Although aromatic hydrocarbons generally met such criterion, benzene was readily distinguishable with the maximum BT. The BT for the aldehydes exhibited ~100% (AA) >= 85% (PA) >= 45% (BA) >= 30% (VA and IVA). There is good correlation between ST-2 recovery vs. carbon number for >CO entity (aldehydes, ester, and ketones). As such, BT is essentially concentration independent and relatively predictable across different functional groups and between the homologues. However, the BT behavior of ppb level VOCs is no longer consistent for certain species (like benzene or MEK) relative their ppm counterparts. This variation is explained by the Langmuir equation in which the 1/BTV is proportional to analyte gas-phase concentration, if the gas-phase/sorbent partition coefficient is large. PMID- 24952629 TI - Durable diagnosis of seminal vesicle and sexual gland diseases using the nano optical sensor thin film Sm-doxycycline complex. AB - A new method in which a nano optical sensor for diagnosis of different diseases of seminal vesicle and sexual gland was prepared. The working principle of the method depends on the determination of the fructose concentration in semen of different patients by using nano optical sensor thin film Sm-doxycycline doped in sol-gel matrix. The assay is based on the quenching of the characteristic emission bands of Sm(3+) present in silica doped Sm-doxycycline nanooptode thin film by different fructose concentrations in acetonitrile at lambdaex = 400 nm. This method was optimized for parameters, such as, solvent effect, operational stability, shelf life and interference parameters. Good and reproducible linearity (1 * 10(-9) - 5.0 * 10(-5) mol L(-1)) with a detection limit of 9.0 * 10(-10) mol L(-1) and quantification limit of detection (LOQ) 2.7 * 10(-9) mol L( 1) were obtained. Seminal fructose determination in different patient samples after appropriate dilutions confirmed the reliability of this technique. The method was successfully applied for routine fructose monitoring in human semen samples of different cases such as; obstructive and non-obstructive azoospermia, inflammation of male accessory glands, atrophy of seminal vesicle, congenital vas deferens and retrograde ejaculation. PMID- 24952632 TI - Quality of life related to swallowing in Parkinson's disease. AB - Swallowing difficulties in Parkinson's disease can result in decreased quality of life. The swallowing quality of life questionnaire (SWAL-QOL) is an instrument for specifically assessing quality of life with respect to swallowing, which has been little explored in patients with Parkinson's disease (PD). The goal of this study was to evaluate the quality of life with respect to swallowing in persons with PD compared to controls and at several stages of the disease using the SWAL QOL. The experimental group was composed of 62 persons with PD at stages 1-4. Forty-one age-matched healthy subjects constituted the control group. The SWAL QOL scores were significantly lower for the patients with PD than for the controls in all SWAL-QOL domains. Eating duration had the largest difference in score between persons with PD and the controls and the lowest mean score, followed by communication, fatigue, fear, sleep, and food selection. The scores of most domains were lower at later stages of the disease. The scores for eating duration, symptom frequency, and sleep were significantly lower at stage 4 than stages 1 and 2. In conclusion, patients with PD have significantly lower scores in all domains of the SWAL-QOL than normal controls. This means swallowing difficulties occurring in patients with PD negatively affect their QOL. Progression of the disease worsens swallowing QOL, more specifically in the domains of eating duration, symptom frequency, and sleep. This occurs mostly at later stages of the disease. PMID- 24952630 TI - Stand-alone ALIF with integrated intracorporeal anchoring plates in the treatment of degenerative lumbar disc disease: a prospective study on 65 cases. AB - PURPOSE: ALIF with cages is expected to restore disc height and stabilize the spine promoting fusion, while avoiding damage attributed to rod-pedicle screw fixation. However, it may be related to an increased risk of fusion failure and subsidence. A prospective study was conducted by five investigators across three centers to confirm performance of a PEEK cage for stand-alone ALIF in the treatment of lumbar degenerative disc disease (DDD). METHODS: Sixty-five patients, with back +/- leg pain, requiring surgery for DDD, were included. Efficacy and safety were evaluated at 6 weeks, 3, 6, and 12 months post operatively. Fusion and subsidence were assessed through CT-images at 12-month follow-up. Disc height was measured. Clinical outcomes included back and leg pain (VAS), disability (Oswestry Disability Index), Quality of Life (Short-Form 36), and adverse events. RESULTS: The fusion and the subsidence rates were 96.3 and 2.0 %, respectively. ALIF surgery restored anterior and posterior disc height compared to baseline. There were no device-related serious adverse events, and no revision surgeries. Clinical outcomes improved significantly through 12-month follow-up. CONCLUSION: Safety and efficacy of this stand-alone cage with integrated intracorporeal plates was confirmed through 12 months for treatment of degenerative conditions. The design of the cage and plates may contribute to the decreased subsidence rate observed. PMID- 24952633 TI - What to do when it is technically impossible to perform laparoscopic sleeve gastrectomy. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is increasingly popular with surgeons because of its apparent technical ease. However, performing LSG safely is sometimes not possible during laparoscopy. The objectives of the present study were to (i) describe the context of LSG failure and (ii) suggest preoperative care options or strategies that enable secondary LSG to be performed safely. METHODS: We studied patients having undergone primary and secondary LSG between January 2008 and July 2013. The primary efficacy criterion was the LSG success rate. The secondary efficacy criteria were preoperative care procedures, the complication rate, the failure rate, and the frequency of conversion to open surgery. RESULTS: During the study period, 954 patients underwent first- or second-line LSG. Laparoscopic sleeve gastrectomy was technically impossible in 12 patients (1.2 %). The cause of failure was a large left liver lobe in seven cases (58.3 %) and a lack of space in five cases. Of these 12 patients, nine underwent secondary LSG. The median preoperative BMI before the first LSG was 51.5 kg/m(2). The median (range) time interval between the two LSG attempts was 6 months (3 37). Prior to secondary LSG, the preoperative weight reduction measure was a diet in seven cases (78 %), an intragastric balloon in one case, and no treatment in one case. The median preoperative excess weight loss (EWL) before the second LSG was 10 % (0-20). Five LSGs were successful, two required conversion to open surgery, and two failed again. There were two postoperative complications (22 %), both of which concerned the two patients with conversion to laparotomy. CONCLUSIONS: In the event of LSG technical failure, preoperative weight loss may enable a second attempt at laparoscopic treatment. A preoperative EWL of at least 10 % appears to be required for the avoidance of conversion to laparotomy. PMID- 24952634 TI - Subclinical left ventricular systolic impairment in steady state young adult patients with sickle-cell anemia. AB - Chronic volume overload in sickle-cell anemia (SCA) is associated with left ventricular (LV) enlargement and hypertrophy. The effect of the disease on LV systolic function remains debated. The aim of our study was to investigate LV systolic function in SCA patients using 2D speckle-tracking imaging. We compared 30 steady state asymptomatic adult SCA patients (17 women, mean age 24.7 +/- 5.1 years) with 30 age and sex-matched healthy subjects (17 women, mean age 25.0 +/- 4.9 years). In addition to conventional echocardiographic parameters including LV ejection fraction (LVEF) and LV mass index (LVMi), global longitudinal strain (GLS) and strain rate (GLSR) were measured. GLS (-17.9 +/- 2.0 vs. -19.7 +/- 2.5 %, p = 0.004) and GLSR (-0.92 +/- 0.09 vs. -1.07 +/- 0.17 s(-1), p < 0.0001) values were lower in SCA patients while LVEF values (60.1 +/- 3.8 vs. 61.7 +/- 4.7 %, p = 0.30) were not different. LVMi was increased in SCA patients (100.7 +/ 23.5 vs. 72.4 +/- 15.2 g/m(2), p = 0.0001) and GLSR was significantly lower in the subgroup of patients with LV hypertrophy (-0.88 +/- 0.09 vs. -0.96 +/- 0.08 s(-1), p = 0.02). In SCA patients LVMi was correlated to GLS (r = 0.58, p = 0.001) and GLSR (r = 0.45, p = 0.015) pleading in favor of a pathological LV remodeling. Asymptomatic SCA patients exhibited a subclinical alteration of LV systolic function. Myocardial dysfunction appears to be linked to the degree of LV hypertrophy. 2D speckle-tracking imaging might be useful for long-term follow up and to study the natural course of LV dysfunction in SCA patients. PMID- 24952635 TI - Thioridazine inhibits angiogenesis and tumor growth by targeting the VEGFR 2/PI3K/mTOR pathway in ovarian cancer xenografts. AB - Thioridazine, a member of the phenothiazine family, is a powerful anti-anxiety and anti-psychotic drug. It can also suppress the growth of several types of tumor in vitro. In the current study, we evaluated the direct anti-tumor and anti angiogenic effects of thioridazine in vivo. The injection of thioridazine into human ovarian tumor xenografts in nude mice significantly inhibited tumor growth by ~fivefold, and also decreased tumor vascularity. In addition, thioridazine inhibited the phosphorylation of the signaling molecules downstream of phosphatidylinositol-3'-kinase (PI3K), including Akt, phosphoinositide-dependent protein kinase 1 (PDK1), and mammalian target of rapamycin (mTOR), during ovarian tumor progression via vascular endothelial growth factor receptor 2 (VEGFR-2). These results provide convincing evidence that thioridazine regulates endothelial cell function and subsequent angiogenesis by inhibiting VEGFR-2/PI3K/mTOR signal transduction. Collectively, these results strongly suggest that thioridazine might be a novel anti-tumor and anti-angiogenic agent for use in ovarian cancer. PMID- 24952636 TI - Health inequalities and historically persistent socioeconomic differences in Venice. PMID- 24952637 TI - Lifespan extension in Caenorhabiditis elegans by several traditional Chinese medicine formulas. AB - There is considerable interest in using traditional Chinese medicine formulas (TCMF) to delay aging or treat age-related diseases. Due to cost and duration, the beneficial effects of TCMF on prolongation are mainly extrapolated from vitro studies or physiological indexes. Little is known about whether TCMF are beneficial in whole level, particularly with respect to lifespan. To address this issue, we selected eight formulas with anti-oxidative activity and examined their effects on the lifespan of Caenorhabditis elegans. The results showed that seven of the eight formulas could prolong lifespan of TK22 mutant significantly and five of the eight formulas could obviously extend lifespan of N2 wild-type. To further characterize the prolongation effects, oxidative stress, thermal stress and reproduction test were assayed. We found that the formulas that extended lifespan of TK22 could also protect it from oxidative stress, without reducing the reproductive capacity. Meanwhile, the formulas that prolonged lifespan of N2 wild-type could also enhance its resistance against thermal stress, with damaging the reproductive fitness. These observations indicate that TCMF used in our experiment could be potential therapeutics for anti-aging. PMID- 24952638 TI - Views of pregnant women and clinicians regarding discussion of exposure to phthalate plasticizers. AB - OBJECTIVE: This study explores the views of pregnant women and clinicians regarding discussion of exposure to phthalate plasticizers during pregnancy, subsequent to the 2011 Health Canada ban of certain phthalates at a concentration greater than 1000 mg/kg in baby toys. This occurred with no regulation of products to which pregnant women are exposed, such as food packaging and cosmetics. METHODS: Pregnant women, physicians and midwives were recruited through posters and pamphlets in prenatal clinics in Southwestern Ontario for a semi-structured interview. All interviews were audiotaped, transcribed, and subjected to rigorous qualitative analysis through a grounded theory approach, supported by NVIVOTM software. Themes emerged from line by line, open, and axial coding in an iterative manner. RESULTS: Theoretical sufficiency was reached after 23 pregnant women and 11 clinicians had been interviewed. The themes (and subthemes from which they arose) were: Theme I-Information Provision (IA-Sources of Information, IB-Standardization, IC-Constraints, ID-Role of Government); Theme II-Risk (IIA-Significant Risk, IIB-Perceived Relevance, IIC-Reconciliation); and Theme III- Factors Influencing Level of Concern (IIIA-Current Knowledge, IIIB Demographic Factors). CONCLUSION: To respond to the increasing media and research attention regarding risk of phthalates to women, and pregnant women in particular, national professional organizations should provide patient information. This could include pamphlets on what a pregnant woman should know about phthalates and how they can be avoided, as well as information to clinicians to facilitate this discussion. PMID- 24952639 TI - Sustained release of methotrexate through liquid-crystalline folate nanoparticles. AB - To make chemotherapy more effective, sustained release of the drug is desirable. By controlling the release rates, constant therapeutic levels can be achieved which can avoid re-administration of drug. This helps to combat tumors more effectively with minimal side effects. The present study reports the control release of methotrexate through liquid-crystalline folate nanoparticles. These nanoparticles are composed of highly ordered folate self-assembly which encapsulate methotrexate molecules. These drug molecules can be released in a controlled manner by disrupting this assembly in the environment of monovalent cations. The ordered structure of folate nanoparticles offers low drug losses of about 4-5%, which is significant in itself. This study reports the size-control method of forming methotrexate encapsulated folate nanoparticles as well as the release of methotrexate through these nanoparticles. It has been demonstrated that methotrexate release rates can be controlled by controlling the size of the nanoparticles, cross-linking cation and cross-linking concentration. The effect of different factors like drug loading, release medium, and pH of the medium on methotrexate release rates was also studied. PMID- 24952640 TI - Nutrition-drug interactions: a Web-based approach to pharmaceutical care in Greece. AB - OBJECTIVES: To evaluate Greek pharmacists' willingness to use a new Web-based software program to detect drug-food interactions, to assess the experience of those pharmacists opting to use the program, and to estimate the public benefit associated with use of the program. PRACTICE INNOVATION AND RESULTS: The Nutrition-Drug Interaction program was developed to enable Greek pharmacists to access an online database of medication-related information, including detailed drug and pharmaceutical company listings, nutritional guidelines for patients, potential drug-food and drug-drug interactions, and reaction alerts. More than 50% of the community pharmacists agreeing to use the program found it "quite useful" or "very useful," with more than 62% saying they were "very satisfied" or "quite satisfied" with the quality of information provided through the program. CONCLUSION: A significant proportion of Greek pharmacists, especially those 50 years of age or younger, found a new Web-based drug-food interaction software program to be both informative and useful. Participating pharmacists reported that use of the new program enhanced their role as health consultants and helped improve the quality of the patient services they provide. PMID- 24952641 TI - Identification of host-microbe interaction factors in the genomes of soft rot associated pathogens Dickeya dadantii 3937 and Pectobacterium carotovorum WPP14 with supervised machine learning. AB - BACKGROUND: A wealth of genome sequences has provided thousands of genes of unknown function, but identification of functions for the large numbers of hypothetical genes in phytopathogens remains a challenge that impacts all research on plant-microbe interactions. Decades of research on the molecular basis of pathogenesis focused on a limited number of factors associated with long known host-microbe interaction systems, providing limited direction into this challenge. Computational approaches to identify virulence genes often rely on two strategies: searching for sequence similarity to known host-microbe interaction factors from other organisms, and identifying islands of genes that discriminate between pathogens of one type and closely related non-pathogens or pathogens of a different type. The former is limited to known genes, excluding vast collections of genes of unknown function found in every genome. The latter lacks specificity, since many genes in genomic islands have little to do with host-interaction. RESULT: In this study, we developed a supervised machine learning approach that was designed to recognize patterns from large and disparate data types, in order to identify candidate host-microbe interaction factors. The soft rot Enterobacteriaceae strains Dickeya dadantii 3937 and Pectobacterium carotovorum WPP14 were used for development of this tool, because these pathogens are important on multiple high value crops in agriculture worldwide and more genomic and functional data is available for the Enterobacteriaceae than any other microbial family. Our approach achieved greater than 90% precision and a recall rate over 80% in 10-fold cross validation tests. CONCLUSION: Application of the learning scheme to the complete genome of these two organisms generated a list of roughly 200 candidates, many of which were previously not implicated in plant microbe interaction and many of which are of completely unknown function. These lists provide new targets for experimental validation and further characterization, and our approach presents a promising pattern-learning scheme that can be generalized to create a resource to study host-microbe interactions in other bacterial phytopathogens. PMID- 24952642 TI - Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling. AB - Ion channels are essential for the regulation of neuronal functions. The significance of plasma membrane, mitochondrial, endoplasmic reticulum and lysosomal ion channels in the regulation of Ca(2+) is well established. In contrast, surprisingly little is known about the function of ion channels on the nuclear envelope (NE). Here we demonstrate the presence of functional large conductance, calcium-activated potassium channels (BK channels) on the NE of rodent hippocampal neurons. Functionally, blockade of nuclear BK channels (nBK channels) induces NE-derived Ca(2+) release, nucleoplasmic Ca(2+) elevation and cyclic AMP response element binding protein (CREB)-dependent transcription. More importantly, blockade of nBK channels regulates nuclear Ca(2+)-sensitive gene expression and promotes dendritic arborization in a nuclear Ca(2+)-dependent manner. These results suggest that the nBK channel functions as a molecular link between neuronal activity and nuclear Ca(2+) to convey signals from synapse to nucleus and is a new modulator, operating at the NE, of synaptic activity dependent neuronal functions. PMID- 24952643 TI - Population coding of affect across stimuli, modalities and individuals. AB - It remains unclear how the brain represents external objective sensory events alongside our internal subjective impressions of them--affect. Representational mapping of population activity evoked by complex scenes and basic tastes in humans revealed a neural code supporting a continuous axis of pleasant-to unpleasant valence. This valence code was distinct from low-level physical and high-level object properties. Although ventral temporal and anterior insular cortices supported valence codes specific to vision and taste, both the medial and lateral orbitofrontal cortices (OFC) maintained a valence code independent of sensory origin. Furthermore, only the OFC code could classify experienced affect across participants. The entire valence spectrum was represented as a collective pattern in regional neural activity as sensory-specific and abstract codes, whereby the subjective quality of affect can be objectively quantified across stimuli, modalities and people. PMID- 24952645 TI - Tracking metabolite dynamics in plants via indirect 13C chemical shift imaging with an interleaved variable density acquisition weighted sampling pattern. AB - OBJECTIVE: Developing and evaluating an improved sampling pattern to track the dynamics of labeled substances in plants using indirect (13)C chemical shift imaging. MATERIALS AND METHODS: An algorithm to split an acquisition weighted sampling pattern into several undersampled sub-images is presented. The sampling patterns are used in CSI moving phantom experiments as well as in in vivo POCE CSI experiments on barley stem and grain. Reconstruction is performed traditionally or by compressed sensing. RESULTS: The moving phantom experiments show that the sampling pattern can reduce motion artifacts at the cost of an increased overall noise. The in vivo experiments demonstrate the feasibility of extracting a time series from a single imaging experiment. CONCLUSION: The sampling pattern is suitable for tracking the uptake of label substances into plant material. The use of compressed sensing allows an increased spatial and temporal resolution. PMID- 24952644 TI - Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine evoked plasticity. AB - Acid-sensing ion channel 1A (ASIC1A) is abundant in the nucleus accumbens (NAc), a region known for its role in addiction. Because ASIC1A has been suggested to promote associative learning, we hypothesized that disrupting ASIC1A in the NAc would reduce drug-associated learning and memory. However, contrary to this hypothesis, we found that disrupting ASIC1A in the mouse NAc increased cocaine conditioned place preference, suggesting an unexpected role for ASIC1A in addiction-related behavior. Moreover, overexpressing ASIC1A in rat NAc reduced cocaine self-administration. Investigating the underlying mechanisms, we identified a previously unknown postsynaptic current during neurotransmission that was mediated by ASIC1A and ASIC2 and thus well positioned to regulate synapse structure and function. Consistent with this possibility, disrupting ASIC1A altered dendritic spine density and glutamate receptor function, and increased cocaine-evoked plasticity, which resemble changes previously associated with cocaine-induced behavior. Together, these data suggest that ASIC1A inhibits the plasticity underlying addiction-related behavior and raise the possibility of developing therapies for drug addiction by targeting ASIC-dependent neurotransmission. PMID- 24952646 TI - Chronic variable stress activates hematopoietic stem cells. AB - Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis. Although incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known cross-talk between the brain and immune system includes the hypothalamic-pituitary-adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic-adrenal medullary axis, which controls stress-induced catecholamine release in support of the fight-or-flight reflex. It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes. We found that chronic stress induced monocytosis and neutrophilia in humans. While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Under conditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline, which signaled bone marrow niche cells to decrease CXCL12 levels through the beta3-adrenergic receptor. Consequently, hematopoietic stem cell proliferation was elevated, leading to an increased output of neutrophils and inflammatory monocytes. When atherosclerosis-prone Apoe(-/-) mice were subjected to chronic stress, accelerated hematopoiesis promoted plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans. PMID- 24952647 TI - Noninvasive two-photon microscopy imaging of mouse retina and retinal pigment epithelium through the pupil of the eye. AB - Two-photon excitation microscopy can image retinal molecular processes in vivo. Intrinsically fluorescent retinyl esters in subcellular structures called retinosomes are an integral part of the visual chromophore regeneration pathway. Fluorescent condensation products of all-trans-retinal accumulate in the eye with age and are also associated with age-related macular degeneration (AMD). Here, we report repetitive, dynamic imaging of these compounds in live mice through the pupil of the eye. By leveraging advanced adaptive optics, we developed a data acquisition algorithm that permitted the identification of retinosomes and condensation products in the retinal pigment epithelium by their characteristic localization, spectral properties and absence in genetically modified or drug treated mice. This imaging approach has the potential to detect early molecular changes in retinoid metabolism that trigger light- and AMD-induced retinal defects and to assess the effectiveness of treatments for these conditions. PMID- 24952650 TI - From the editor. PMID- 24952649 TI - CicArMiSatDB: the chickpea microsatellite database. AB - BACKGROUND: Chickpea (Cicer arietinum) is a widely grown legume crop in tropical, sub-tropical and temperate regions. Molecular breeding approaches seem to be essential for enhancing crop productivity in chickpea. Until recently, limited numbers of molecular markers were available in the case of chickpea for use in molecular breeding. However, the recent advances in genomics facilitated the development of large scale markers especially SSRs (simple sequence repeats), the markers of choice in any breeding program. Availability of genome sequence very recently opens new avenues for accelerating molecular breeding approaches for chickpea improvement. DESCRIPTION: In order to assist genetic studies and breeding applications, we have developed a user friendly relational database named the Chickpea Microsatellite Database (CicArMiSatDB http://cicarmisatdb.icrisat.org). This database provides detailed information on SSRs along with their features in the genome. SSRs have been classified and made accessible through an easy-to-use web interface. CONCLUSIONS: This database is expected to help chickpea community in particular and legume community in general, to select SSRs of particular type or from a specific region in the genome to advance both basic genomics research as well as applied aspects of crop improvement. PMID- 24952651 TI - Population health: ASH and the American health care revolution: leadership message from the American Society of Hypertension. PMID- 24952648 TI - Altered translation of GATA1 in Diamond-Blackfan anemia. AB - Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA), congenital asplenia and T cell leukemia. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type- and tissue-specific defects remains unknown. Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease. PMID- 24952652 TI - Diabetes and age-related demographic differences in risk factor control. AB - Disparate vascular outcomes in diabetes by race and/or ethnicity may reflect differential risk factor control, especially pre-Medicare. Assess concurrent target attainment for glycohemoglobin <7%, non-high density lipoprotein cholesterol <130 mg/dL, and blood pressure <140/<90 mm Hg in white, black, and Hispanic diabetics <65 years and >=65 years of age. The National Health and Nutrition Examination Surveys 1999-2010 data were analyzed on diagnosed and undiagnosed diabetics >=18 years old. Concurrent target attainment was higher in whites (18.7%) than blacks (13.4% [P = .02] and Hispanics [10.3%, P < .001] <65 years but not >=65 years of age; 20.0% vs. 15.9% [P = .13], 19.5% [P = .88]). Disparities in health care insurance among younger whites, blacks, and Hispanics, respectively, (87.4% vs. 81.1%, P < .01; 68.0%, P < .001) and infrequent health care (0-1 visits/y; 14.3% vs. 15.0%, P = not significant; 32.0%, P < .001) declined with age. Cholesterol treatment predicted concurrent control in both age groups (multivariable odds ratio >2, P < .001). Risk factor awareness and treatment were lower in Hispanics than whites. When treated, diabetes and hypertension control were greater in whites than blacks or Hispanics. Concurrent risk factor control is low in all diabetics and could improve with greater statin use. Insuring younger adults, especially Hispanic, could raise risk factor awareness and treatment. Improving treatment effectiveness in younger black and Hispanic diabetics could promote equitable risk factor control. PMID- 24952653 TI - Apparent treatment-resistant hypertension and risk for stroke, coronary heart disease, and all-cause mortality. AB - Apparent treatment-resistant hypertension (aTRH) is defined as uncontrolled hypertension despite the use of three or more antihypertensive medication classes or controlled hypertension while treated with four or more antihypertensive medication classes. We evaluated the association of aTRH with incident stroke, coronary heart disease (CHD), and all-cause mortality. Participants from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) Study treated for hypertension with aTRH (n = 2043) and without aTRH (n = 12,479) were included. aTRH was further categorized as controlled aTRH (>=4 medication classes and controlled hypertension) and uncontrolled aTRH (>=3 medication classes and uncontrolled hypertension). Over a median of 5.9, 4.4, and 6.0 years of follow-up, the multivariable adjusted hazard ratio for stroke, CHD, and all-cause mortality associated with aTRH versus no aTRH was 1.25 (0.94-1.65), 1.69 (1.27-2.24), and 1.29 (1.14-1.46), respectively. Compared with controlled aTRH, uncontrolled aTRH was associated with CHD (hazard ratio, 2.33; 95% confidence interval, 1.21-4.48), but not stroke or mortality. Comparing controlled aTRH with no aTRH, risk of stroke, CHD, and all-cause mortality was not elevated. aTRH was associated with an increased risk for coronary heart disease and all-cause mortality. PMID- 24952654 TI - Arterial stiffness is associated with increase in blood pressure over time in treated hypertensives. AB - Arterial stiffness is associated with incident hypertension. We hypothesized that measures of arterial stiffness would predict increases in systolic (SBP), mean (MAP), and pulse pressure (PP) over time in treated hypertensives. Blood pressure (BP) was measured a mean of 8.5 +/- 0.9 years apart in 414 non-Hispanic white hypertensives (mean age, 60 +/- 8 years; 55% women). The average of three supine right brachial BPs was recorded. Measures of arterial stiffness, including carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (AIx), and central pulse pressure (CPP), were obtained at baseline by applanation tonometry. We performed stepwise multivariable linear regression analyses adjusting for potential confounders to assess the associations of arterial stiffness parameters with BP changes over time. SBP, MAP, and PP increased in 80% of participants. After adjustment for covariates listed, cfPWV (m/s) was associated with increases in SBP (beta +/- standard error [SE], 0.71 +/- 0.31) and PP (beta +/- SE, 1.09 +/ 0.27); AIx (%) was associated with increases in SBP (beta +/- SE, 0.23 +/- 0.10) and MAP (beta +/- SE, 0.27 +/- 0.07); and CPP (mmHg) was associated with increases in SBP (beta +/- SE, 0.44 +/- 0.07), MAP (beta +/- SE, 0.24 +/- 0.05), and PP (beta +/- SE, 0.42 +/- 0.06) over time (P <= .02 for each). In conclusion, arterial stiffness measures were associated with longitudinal increases in SBP, MAP, and PP in treated hypertensives. PMID- 24952655 TI - Top 10 landmark studies in hypertension. AB - The field of hypertension has evolved considerably over the last 70 years, from a belief that elevated blood pressure was an inevitable consequence of aging and beneficial, to maintaining perfusion to overwhelming proof of the cardiovascular morbidity and mortality associated with elevated blood pressure. The authors reviewed the literature on hypertension and selected 10 studies pivotal in changing physicians' attitudes regarding the management, treatment, and outcomes of hypertensive patients. Four studies cover treatment initiation and blood pressure goals, two studies compare pharmacologic antihypertensive agents, and the final four address the approach to blood pressure control in special populations (diabetes mellitus and chronic kidney disease). The authors readily acknowledge the many other contributions to the field of hypertension not profiled here. PMID- 24952656 TI - What interventions are effective on reducing inequalities in maternal and child health in low- and middle-income settings? A systematic review. AB - BACKGROUND: The deadline for achieving Millennium Development Goals 4 and 5 is approaching, but inequalities between disadvantaged and other populations is a significant barrier for progress towards achieving these goals. This systematic review aims to collect evidence about the differential effects of interventions on different sociodemographic groups in order to identify interventions that were effective in reducing maternal or child health inequalities. METHODS: We searched the PubMed, EMBASE and other relevant databases. The reference lists of included reviews were also screened to find more eligible studies. We included experimental or observational studies that assessed the effects of interventions on maternal and child health, but only studies that report quantitative inequality outcomes were finally included for analysis. RESULTS: 22 articles about the effectiveness of interventions on equity in maternal and child health were finally included. These studies covered five kinds of interventions: immunization campaigns, nutrition supplement programs, health care provision improvement interventions, demand side interventions, and mixed interventions. The outcome indicators covered all MDG 4 and three MDG 5 outcomes. None of the included studies looked at equity in maternal mortality, adolescent birth rate and unmet need for family planning. The included studies reported inequalities based on gender, income, education level or comprehensive socioeconomic status. Stronger or moderate evidence showed that all kinds of the included interventions may be more effective in improving maternal or child health for those from disadvantaged groups. CONCLUSION: Studies about the effectiveness of interventions on equity in maternal or child health are limited. The limited evidence showed that the interventions that were effective in reducing inequity included the improvement of health care delivery by outreach methods, using human resources in local areas or provided at the community level nearest to residents and the provision of financial or knowledge support to demand side. PMID- 24952659 TI - A trade off between separation, detection and sustainability in liquid chromatographic fingerprinting. AB - It is now recognized that analytical chemistry must also be a target for green principles, in particular chromatographic methods which typically use relatively large volumes of hazardous organic solvents. More generally, high performance liquid chromatography (HPLC) is employed routinely for quality control of complex mixtures in various industries. Acetonitrile and methanol are the most commonly used organic solvents in HPLC, but they generate an impact on the environment and can have a negative effect on the health of analysts. Ethanol offers an exciting alternative as a less toxic, biodegradable solvent for HPLC. In this work we demonstrate that replacement of acetonitrile with ethanol as the organic modifier for HPLC can be achieved without significantly compromising analytical performance. This general approach is demonstrated through the specific example analysis of a complex plant extract. A benchmark method employing acetonitrile for the analysis of Bidens pilosa extract was statistically optimized using the Green Chromatographic Fingerprinting Response (GCFR) which includes factors relating to separation performance and environmental parameters. Methods employing ethanol at 30 and 80 degrees C were developed and compared with the reference method regarding their performance of separation (GCFR) as well as by a new metric, Comprehensive Metric to Compare Liquid Chromatography Methods (CM). The fingerprint with ethanol at 80 degrees C was similar to or better than that with MeCN according to GCFR and CM. This demonstrates that temperature may be used to replace harmful solvents with greener ones in HPLC, including for solvents with significantly different physiochemical properties and without loss in separation performance. This work offers a general approach for the chromatographic analysis of complex samples without compromising green analytical chemistry principles. PMID- 24952657 TI - Supplemental carnitine affects the microRNA expression profile in skeletal muscle of obese Zucker rats. AB - BACKGROUND: In the past, numerous studies revealed that supplementation with carnitine has multiple effects on performance characteristics and gene expression in livestock and model animals. The molecular mechanisms underlying these observations are still largely unknown. Increasing evidence suggests that microRNAs (miRNAs), a class of small non-coding RNA molecules, play an important role in post-transcriptional regulation of gene expression and thereby influencing several physiological and pathological processes. Based on these findings, the aim of the present study was to investigate the influence of carnitine supplementation on the miRNA expression profile in skeletal muscle of obese Zucker rats using miRNA microarray analysis. RESULTS: Obese Zucker rats supplemented with carnitine had higher concentrations of total carnitine in plasma and muscle than obese control rats (P < 0.05). miRNA expression profiling in skeletal muscle revealed a subset of 152 miRNAs out of the total number of miRNAs analysed (259) were identified to be differentially regulated (adjusted P value < 0.05) by carnitine supplementation. Compared to the obese control group, 111 miRNAs were up-regulated and 41 down-regulated by carnitine supplementation (adjusted P-value < 0.05). 14 of these miRNAs showed a log2 ratio >= 0.5 and 7 miRNAs showed a log2 ratio <= -0.5 (adjusted P-value < 0.05). After confirmation by qRT-PCR, 11 miRNAs were found to be up-regulated and 6 miRNAs were down regulated by carnitine supplementation (P < 0.05). Furthermore, a total of 1,446 target genes within the validated miRNAs were revealed using combined three bioinformatic algorithms. Analysis of Gene Ontology (GO) categories and KEGG pathways of the predicted targets revealed that carnitine supplementation regulates miRNAs that target a large set of genes involved in protein localization and -transport, regulation of transcription and RNA metabolic processes, as well as genes involved in several signal transduction pathways, like ubiquitin-mediated proteolysis and longterm depression, are targeted by the miRNAs regulated by carnitine supplementation. CONCLUSION: The present study shows for the first time that supplementation of carnitine affects a large set of miRNAs in skeletal muscle of obese Zucker rats suggesting a novel mechanism through which carnitine exerts its multiple effects on gene expression, which were observed during the past. PMID- 24952660 TI - [Auricular myxoma]. PMID- 24952661 TI - [Generalized cutaneous pustulosis]. PMID- 24952658 TI - The 2HA line of Medicago truncatula has characteristics of an epigenetic mutant that is weakly ethylene insensitive. AB - BACKGROUND: The Medicago truncatula 2HA seed line is highly embryogenic while the parental line Jemalong rarely produces embryos. The 2HA line was developed from one of the rare Jemalong regenerates and this method for obtaining a highly regenerable genotype in M. truncatula is readily reproducible suggesting an epigenetic mechanism. Microarray transcriptomic analysis showed down regulation of an ETHYLENE INSENSITIVE 3-like gene in 2HA callus which provided an approach to investigating epigenetic regulation of genes related to ethylene signalling and the 2HA phenotype. Ethylene is involved in many developmental processes including somatic embryogenesis (SE) and is associated with stress responses. RESULTS: Microarray transcriptomic analysis showed a significant number of up regulated transcripts in 2HA tissue culture, including nodule and embryo specific genes and transposon-like genes, while only a few genes were down-regulated, including an EIN3-like gene we called MtEIL1. This reduced expression was associated with ethylene insensitivity of 2HA plants that was further investigated. The weak ethylene insensitivity affected root and nodule development. Sequencing of MtEIL1 found no difference between 2HA and wild-type plants. DNA methylation analysis of MtEIL1 revealed significant difference between 2HA and wild-type plants. Tiling arrays demonstrated an elevated level of miRNA in 2HA plants that hybridised to the antisense strand of the MtEIL1 gene. AFLP-like methylation profiling revealed more differences in DNA methylation between 2HA and wild-type. Segregation analysis demonstrated the recessive nature of the eil1 phenotype and the dominant nature of the SE trait. CONCLUSIONS: We have demonstrated that EIL1 of Medicago truncatula (MtEIL1) is epigenetically silenced in the 2HA seed line. The possible cause is an elevated level of miRNA that targets its 3'UTR and is also associated with DNA methylation of MtEIL1. Down regulation of MtEIL1 makes it possible to form nodules in the presence of ethylene and affects root growth under normal conditions. Segregation analysis showed no association between MtEIL1 expression and SE in culture but the role and mechanism of ethylene signalling in the process of plant regeneration through SE requires further investigation. The work also suggests that epigenetic changes to a particular gene induced in culture can be fixed in regenerated plants. PMID- 24952662 TI - [Flagellate erythema]. PMID- 24952663 TI - [Ruxolitinib as a bridge to allogeneic hematopoietic cell transplantation in a patient with idiopathic myelofibrosis]. PMID- 24952664 TI - [Autoimmune hemolytic anemia refractory to medical treatment after chlorine dioxide intake in a patient with idiopathic thrombocytopenic purpura]. PMID- 24952665 TI - [Promotion of public access and share of raw data from scientific research]. PMID- 24952666 TI - [Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease)]. PMID- 24952667 TI - [Endobronchial mass as the first manifestation of an anaplastic T-cell lymphoma]. PMID- 24952668 TI - [Atypical mycobacteria in breast implant. A case report]. PMID- 24952669 TI - XIAP inhibitors induce differentiation and impair clonogenic capacity of acute myeloid leukemia stem cells. AB - Acute myeloid leukemia (AML) is a neoplasia characterized by the rapid expansion of immature myeloid blasts in the bone marrow, and marked by poor prognosis and frequent relapse. As such, new therapeutic approaches are required for remission induction and prevention of relapse. Due to the higher chemotherapy sensitivity and limited life span of more differentiated AML blasts, differentiation-based therapies are a promising therapeutic approach. Based on public available gene expression profiles, a myeloid-specific differentiation-associated gene expression pattern was defined as the therapeutic target. A XIAP inhibitor (Dequalinium chloride, DQA) was identified in an in silico screening searching for small molecules that induce similar gene expression regulation. Treatment with DQA, similarly to Embelin (another XIAP inhibitor), induced cytotoxicity and differentiation in AML. XIAP inhibition differentially impaired cell viability of the most primitive AML blasts and reduced clonogenic capacity of AML cells, sparing healthy mature blood and hematopoietic stem cells. Taken together, these results suggest that XIAP constitutes a potential target for AML treatment and support the evaluation of XIAP inhibitors in clinical trials. PMID- 24952670 TI - Did Neanderthals and Denisovans have our de novo genes? PMID- 24952671 TI - Molecular evolutionary history of Sugarcane yellow leaf virus based on sequence analysis of RNA-dependent RNA polymerase and putative aphid transmission factor coding genes. AB - RNA-dependent RNA polymerase (RdRp) encoded by ORF2 and putative aphid transmission factor (PATF) encoded by ORF5 of Sugarcane yellow leaf virus (SCYLV) were detected in six sugarcane cultivars affected by yellow leaf using RT-PCR and real-time RT-PCR assays. Expression of both genes varied among infected plants, but overall expression of RdRp was higher than expression of PATF. Cultivar H87 4094 from Hawaii yielded the highest transcript levels of RdRp, whereas cultivar C1051-73 from Cuba exhibited the lowest levels. Sequence comparisons among 25 SCYLV isolates from various geographical locations revealed an amino acid similarity of 72.1-99.4 and 84.7-99.8 % for the RdRp and PATF genes, respectively. The 25 SCYLV isolates were separated into three (RdRp) and two (PATF) phylogenetic groups using the MEGA6 program that does not account for genetic recombination. However, the SCYLV genome contained potential recombination signals in the RdRp and PATF coding genes based on the GARD genetic algorithm. Use of this later program resulted in the reconstruction of phylogenies on the left as well as on the right sides of the putative recombination breaking points, and the 25 SCYLV isolates were distributed into three distinct phylogenetic groups based on either RdRp or PATF sequences. As a result, recombination reshuffled the affiliation of the accessions to the different clusters. Analysis of selection pressures exerted on RdRp and PATF encoded proteins revealed that ORF 2 and ORF 5 underwent predominantly purifying selection. However, a few sites were also under positive selection as assessed by various models such as FEL, IFEL, REL, FUBAR, MEME, GA-Branch, and PRIME. PMID- 24952672 TI - Paraneoplastic Isaac's syndrome associated with thymoma and anti-neuronal nuclear antibodies 1. PMID- 24952673 TI - The inhibition of Rho kinase blocks cell migration and accumulation possibly by challenging inflammatory cytokines and chemokines on astrocytes. AB - Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by the immune mediated demyelination and neurodegeneration of the CNS. Our previous studies showed that Rho kinase inhibitor Fasudil can delay onset, and ameliorate severity of EAE, accompanied by the improvement in myelination and the inhibition of inflammatory responses in the CNS. In this study, we found that Fasudil inhibited the migration of T cells indirectly by affecting the production of inflammatory factors and the expression of chemokines in astrocytes functions, indicating that Fasudil treatment reduced inflammatory cytokines such as TNF-alpha and IL-6, reactive oxygen species (NO) and chemokines like MIP-3alpha (CCL-20), RANTES (CCL5), MIP-1alpha (CCL-3) and MCP-1 (CCL2) in vitro, and blocked the chemotaxis of reactive mononuclear cells in EAE mice. Further studies found that Fasudil treatment reduced the infiltration and accumulation of pathogenic T cells into the CNS. Astrocytes expressing GFAP and CCL-20 were inhibited in Fasudil-treated EAE compared with control mice. These results demonstrate that Fasudil alleviates the pathogenesis of EAE possibly by blocking astrocyte-derived chemokine-mediated migration of inflammatory macrophages and pathogenic T cells, and might be used to treat MS. PMID- 24952674 TI - [Correlation between urinary catecholamines dosage and apnea-hypopnea index in a hypertension population: pilot study]. AB - AIMS: Sleep disorders like obstructive sleep apnea in adults are associated with increased sympathetic activity, which induced high blood pressure and could be associated with resistant hypertension. Some studies have demonstrated that high urinary catecholamine levels in obstructive sleep apnea patients may be decreased with continuous positive airway pressure therapy. However, very few studies have demonstrated a correlation between apnea-hypopnea index and urinary catecholamine levels in hypertension patients. METHODS: In this pilot study, 20 hypertensive patients referred for hypertension work-up including night-time polygraphy and 24h urinary catecholamine dosage were included. RESULTS: Mean age was 51+/-11 years (30-76), 68% were males. Diagnosis of obstructive sleep apnea was confirmed in 13 patients at the end of the work-up. Mean apnea-hypopnea index was 14+/-9 (2 32). The only urinary catecholamine parameter significantly increased in patients with obstructive sleep apnea was 24h urinary normetanephrine (1931+/-1285 vs 869+/-293nmol/24h; P<0.05). However, this difference was not significant when this parameter was adjusted to 24h urinary creatinine. We observed a significant positive correlation between AHI and 24h urinary normetanephine (r=0.486; P=0.035). CONCLUSION: This pilot study confirms an isolated elevation of 24h urinary normetanephrine in hypertensive patients with obstructive sleep apnea and shows a significant correlation between sleep disorders expressed by apnea hypopnea index and urinary catecholamines excretion. PMID- 24952675 TI - [Itraconazole: a new drug-related cause of hypertension]. AB - Itraconazole is a triazole agent used in the treatment of fungal infections and in some metastatic cancers. Its use has been associated with cardiovascular adverse events and particularly heart failure with preserved ejection fraction. We report the case of a 68-year-old male patient with a well-controlled hypertension treated with irbesartan 150mg/day since 2007. He developed a pulmonary aspergillosis on post-tuberculosis cavitary lesions treated in July 2011 with itraconazole 200mg/day. Early 2012, his antihypertensive treatment had to be gradually increased to a quadritherapy and his blood pressure was at 157/78mmHg at home. Hypokalemia was observed on several occasions as well as edema of the lower limbs. Plasma renin and plasma and urine aldosterone concentrations on treatment not interfering with the renin angiotensin system were low, associated with normal serum and urine cortisol, ACTH, SDHA and DOC, BNP and creatinine concentrations. Plasma itraconazole values were much above the therapeutic range. Left ventricular ejection fraction was preserved. There were no adrenal or renal artery abnormalities at the CT scan. Three months after stopping itraconazole, hypokalemia and edema disappeared and blood pressure was normalized with less treatment. Plasma renin and aldosterone concentrations were normalized. He had a pulmonary lobectomy for his pulmonary aspergillosis. Itraconazole may induce a resistant hypertension with low renin. The mechanisms of this adverse effect of itraconazole remain unknown. PMID- 24952676 TI - [Left ventricular function in hypertension without left ventricular hypertrophy: echographic study with modelisation of left ventricular-aortic coupling]. AB - Because the functional interaction between the LV and arterial systems, termed ventricular-arterial coupling, is recognized as a key determinant of LV performance, the objective of the present study was to assess the impact of uncomplicated HT without LVH on LV performance using simultaneously echocardiography and carotid tonometry. LV maximal power (PmaxVG), cardiac power output (CPO), LV efficiency (CPO/PmaxVG), input aortic and output LV elastance (Ea and Ees) were assessed in 20 normotensive control subjects (NT) and 10 patients with untreated HT. PmaxVG was calculated according to the integral of the product of LV wall stress with strain rate (as an index of gradient velocity). Cyclic variation of wall thickness and SR were measured by speckel tracking. Ea and Ees were derived and modelized from the pressure-volume curve. No difference in age, BMI and sex ratio was observed between NT and HT. Systolic BP (160+/-18 vs. 119+/-10mmHg), LV mass (99+/-15 vs. 76+/-12g/m(2)), PWV (9.7+/-2 vs. 6.9+/-1m/s) were significantly higher (P<0.01) in HT when compared to NT. In HT increased of CPO and Ea was compensated by an increase of LV (15+/-4 vs. 12+/ 3%, P<0.02) and Ees (5.5+/-2 vs. 4.5+/-1.5mmHg/mL), which are significantly elevated in HT (P<0.05). No difference was observed in Ea/Ees between NT and HT. In conclusion at the early phase of HT, in patients without LVH, LV performance and ventricular-arterial coupling were adapted to post-load elevation. This adaptation may be the result of an increased of LV contractility. PMID- 24952677 TI - [Blood pressure control in patient with chronic kidney disease]. AB - Several epidemiological studies have indicated that high blood pressure is associated with deterioration of renal function in patients with renal disease. Target blood pressures in patients with renal diseases have been defined and proposed to the community in several national and international guidelines. However, some of these targets have been recently changed to take into account results of studies, including randomized clinical trials. The aim of this paper is to put into perspective the history of ideas regarding adequate blood pressure control in patients with renal disease in the light of these results, and explain how these trials have changed our perception, practice and guidelines. PMID- 24952678 TI - [Hypertension, chronic kidney disease and genetics in patients with African ancestry]. AB - The incidence and prevalence of hypertension is markedly elevated in Afro American populations vs Caucasians. The development of end-stage renal disease is also more frequent in Afro-American subjects, independently of blood pressure control. As compared to Caucasians, Afro-American subjects have a higher risk of end-stage renal disease when they are infected with HIV or have lupus. For decades, these data remained mysterious. Within the last 3 years, results from studies in the field of genetics and infectious diseases have transformed our view on this problem. The aim of this paper is to explain how these results have changed our understanding of hypertension and its consequences in Afro-American subjects. PMID- 24952680 TI - Hemophilia A in a Belgian Shepherd Malinois dog: case report. AB - This case report presents a Belgian Shepherd Malinois dog affected by hemophilia A recognized at the age of seven months. The clinical follow-up including all the diagnostic procedures leading to the final diagnosis and the course of this disorder are presented. This is a typical proband case demonstrating the appearance of this genetic disease in a breed never involved by this coagulation disorder so far documented that started an intensive and laborious plan to reduce the incidence of hemophilia A and the further appearance of new cases. PMID- 24952679 TI - Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells. AB - Endoplasmic reticulum stress from unfolded proteins is associated with the proliferation of pancreatic tumor cells, making the many regulatory molecules of this pathway appealing targets for therapy. The objective of our study was to assess potential therapeutic efficacy of inhibitors of unfolded protein response (UPR) in pancreatic cancers focusing on IRE1alpha inhibitors. IRE1alpha-mediated XBP-1 mRNA splicing encodes a transcription factor that enhances transcription of chaperone proteins in order to reverse UPR. Proliferation assays using a panel of 14 pancreatic cancer cell lines showed a dose- and time-dependent growth inhibition by IRE1alpha-specific inhibitors (STF-083010, 2-Hydroxy-1 naphthaldehyde, 3-Ethoxy-5,6-dibromosalicylaldehyde, toyocamycin). Growth inhibition was also noted using a clonogenic growth assay in soft agar, as well as a xenograft in vivo model of pancreatic cancer. Cell cycle analysis showed that these IRE1alpha inhibitors caused growth arrest at either the G1 or G2/M phases (SU8686, MiaPaCa2) and induced apoptosis (Panc0327, Panc0403). Western blot analysis showed cleavage of caspase 3 and PARP, and prominent induction of the apoptotic molecule BIM. In addition, synergistic effects were found between either STF-083010, 2-Hydroxy-1-naphthaldehyde, 3-Ethoxy-5,6 dibromosalicylaldehyde, or toyocamycin and either gemcitabine or bortezomib. Our data suggest that use of an IRE1alpha inhibitor is a novel therapeutic approach for treatment of pancreatic cancers. PMID- 24952682 TI - Superior survival with transcatheter core valve over surgery in high-risk patients with aortic stenosis: good news for the Heart Team. PMID- 24952683 TI - Staying ahead of the curve. PMID- 24952681 TI - Effect of dietary supplementation with flaxseed oil or vitamin E on sheep experimentally infected with Fasciola hepatica. AB - The effects of two diets supplemented with flaxseed oil (FO) or vitamin E (VE) were studied in sheep infected with Fasciola hepatica. The control group (CO), not supplemented, had higher weight gain and faecal egg count (P < 0.05) at the end of the study. At necropsy, the number (71.2 +/- 26.5) and size of flukes were lower in the FO group (P < 0.01), probably due to the higher levels of white blood cells and lymphocytes (P < 0.01). This group also had higher red blood cell and haematocrit values (P < 0.01). The CO group had more severe hypoproteinaemia and hypoalbuminaemia, due to having the highest fluke burden (123.0 +/- 35.2), and also the highest IgG1 titre (P < 0.01). The diet did not affect production or gene expression levels of IFN-gamma and IL-4. On the other hand, the supplementation with VE led to a reduction in adult fluke burden (97.7 +/- 39.9) and lower lipid oxidation in the liver (P < 0.001). PMID- 24952684 TI - Use of emergency medical services expedites in-hospital care processes in patients presenting with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - To determine whether door-to-balloon (DTB) times of patients presenting with ST elevation myocardial infarction (STEMI) were reduced in patients transported by emergency medical services (EMS) compared to those who were self-transported. DTB time is an important measure of hospital care processes in STEMI. Use of EMS may expedite in-hospital processing and reduce DTB times. A total of 309 consecutive STEMI patients who underwent primary percutaneous coronary intervention in our institution were analyzed. Excluded were patients who received fibrinolytics, presented in cardiac arrest, were intubated, or were transferred from another hospital. EMS-transported patients (n=83) were compared to self-transported patients (n=226). The primary outcome measure was DTB time and its component time intervals. Secondary end points included symptom-to-door and symptom-to-balloon times, and correlates for DTB >90 minutes. A higher percentage of EMS-transported patients reached the time goal of DTB <90 minutes compared to self-transported patients (83.1 versus 54.3%; p<0.001). EMS-transported patients had shorter DTB times [median (IQR) minutes, 65 (50-86) versus 85 (61-126); p<0.001] due to a reduction of emergency department processing (door-to-call) time, whereas catheterization laboratory processing (call-to-balloon) times were similar in both groups. EMS-transported patients had shorter symptom-to-door [median (IQR) hours, 1.2 (0.8-3.5) versus 2.3 (1.2-7.5); p<0.001] and symptom-to-balloon [median (IQR) hours, 2.5 (1.9-4.7) versus 4.3 (2.6-9.1); p<0.001]. Independent correlates of DTB times >90 minutes were self-transport (odds ratio 5.32, 95% CI 2.65-10.70; p<0.001) and off-hours presentation (odds ratio 2.89, 95% CI 1.60 5.22; p<0.001). Use of EMS transport in STEMI patients significantly shortens time to reperfusion, primarily by expediting emergency department processes. Community education efforts should focus not only on the importance of recognizing symptoms of myocardial infarction, but also taking early action by calling the EMS. PMID- 24952685 TI - Prognostic benefit of optimum left ventricular lead position in cardiac resynchronization therapy: follow-up of the TARGET Study Cohort (Targeted Left Ventricular Lead Placement to guide Cardiac Resynchronization Therapy). AB - OBJECTIVES: This study was conducted to assess the impact of left ventricular (LV) lead position on longer-term survival after cardiac resynchronization therapy (CRT). BACKGROUND: An optimal LV lead position in CRT is associated with improved clinical outcome. A strategy of speckle-tracking echocardiography can be used to guide the implanter to the site of latest activation and away from segments of low strain amplitude (scar). Long-term, prospective survival data according to LV lead position in CRT are limited. METHODS: Data from a follow-up registry of 250 consecutive patients receiving CRT between June 2008 and July 2010 were studied. The study population comprised patients recruited to the derivation group and the subsequent TARGET (Targeted Left Ventricular Lead Placement to guide Cardiac Resynchronization Therapy) randomized, controlled trial. Final LV lead position was described, in relation to the pacing site determined by pre-procedure speckle-tracking echocardiography, as optimal (concordant/adjacent) or suboptimal (remote). All-cause mortality was recorded at follow-up. RESULTS: An optimal LV lead position (n = 202) conferred LV remodeling response superior to that of a suboptimal lead position (change in LV end systolic volume: -24 +/- 15% vs. -12 +/- 17% [p < 0.001]; change in ejection fraction: +7 +/- 8% vs. +4 +/- 7% [p = 0.02]). During long-term follow-up (median: 39 months; range: <1 to 61 months), an optimal LV lead position was associated with improved survival (log-rank p = 0.003). A suboptimal LV lead placement independently predicted all-cause mortality (hazard ratio: 1.8; p = 0.024). CONCLUSIONS: An optimal LV lead position at the site of latest mechanical activation, avoiding low strain amplitude (scar), was associated with superior CRT response and improved survival that persisted during follow-up. PMID- 24952686 TI - Is heart rate important for patients with heart failure in atrial fibrillation? AB - OBJECTIVES: This study sought to investigate the relationship between resting ventricular rate and mortality in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF) who were in sinus rhythm (SR) or atrial fibrillation (AF). BACKGROUND: Slower heart rates are associated with better survival in patients with CHF in SR, but it is not clear whether this is true for those in AF. METHODS: We assessed 2,039 outpatients with CHF and LVEF <=50% undergoing baseline assessment, of whom 24% (n = 488) were in AF; and 841 outpatients reassessed after attempted treatment optimization at 1 year, of whom 22% (n = 184) were in AF. Cox proportional hazards models were used to assess the relationships between heart rate and survival in patients with CHF and AF or sinus rhythm. We analyzed heart rate and rhythm data recorded at the baseline review and after 1-year follow-up. Proportional hazards assumptions were checked by Schoenfeld and Martingale residuals. RESULTS: The median survival for those in AF was 6.1 years (interquartile range [IQR]: 5.3 to 6.9 years) and 7.3 years (IQR: 6.5 to 8.1 years) for those in SR. In univariable analysis, patients with AF had a worse survival (hazard ratio [HR]: 1.26, 95% confidence interval [CI]: 1.08 to 1.47; p = 0.003) but after covariate adjustment, survival rates were similar. After adjusting Cox regression models, there was no association between heart rate (per 10 beats/min increments) and survival in patients with AF before (HR: 0.94, 95% CI: 0.88 to 1.00, p = 0.07) or after (HR: 1.00, 95% CI: 0.99 to 1.00, p = 0.84) therapy optimization. For patients in SR, higher heart rates were associated with worse survival, both before (HR: 1.10, 95% CI: 1.05 to 1.15, p <0.0001) and after (HR: 1.13, 95% CI: 1.03 to 1.24, p = 0.008) therapy optimization. CONCLUSIONS: In patients with CHF and a reduced LVEF, slower resting ventricular rate is associated with better survival for patients in SR but not for those with AF. PMID- 24952687 TI - The association between atrial fibrillation and sudden cardiac death: the relevance of heart failure. AB - OBJECTIVES: The purpose of this study was to evaluate the role of congestive heart failure (CHF) in the association between atrial fibrillation (AF) and sudden cardiac death (SCD). BACKGROUND: Recent studies have reported the possibility of an independent association between AF and SCD. We hypothesized that a history of CHF is a significant confounder of this association. METHODS: In a prospective case-control analysis from the community (The Oregon-SUDS [Sudden Unexpected Death Study], 2002 to 2012), SCD cases (n = 652) with clinical records available (including electrocardiography and/or echocardiography) were compared with age- and sex-matched control patients with coronary artery disease. The association between AF and SCD was analyzed using multivariable logistic regression and propensity score matching. RESULTS: Cases (age 67.3 +/- 11.7 years, 65% male) were more likely than control patients (age 67.2 +/- 11.4 years, 65% male) to have a history of AF (p = 0.0001), myocardial infarction (p = 0.007), CHF (p < 0.0001), stroke (p < 0.0001), and diabetes (p < 0.0001). In multivariate analysis without considering CHF, AF was a significant predictor of SCD (odds ratio [OR]: 1.6; 95% confidence interval [CI]: 1.2 to 2.0; p = 0.002). However, in a model that included CHF, the AF-SCD association was no longer significant (OR: 1.1; 95% CI: 0.8 to 1.5; p = 0.45), whereas CHF was a significant predictor of SCD (OR: 3.1; 95% CI: 2.4 to 4.1; p < 0.0001). Results on the basis of propensity score matching were consistent. CONCLUSIONS: Our findings suggest that a history of CHF, including both systolic and diastolic symptomatic dysfunction, may partially explain the AF-SCD association. PMID- 24952688 TI - Atrial fibrillation and sudden cardiac death: is heart failure the middleman? PMID- 24952689 TI - Pre-capillary pulmonary hypertension and right ventricular dilation predict clinical outcome in cardiac resynchronization therapy. AB - OBJECTIVES: This study examined the prognostic significance of pre- and post capillary components of pulmonary hypertension (PH) in patients receiving cardiac resynchronization therapy (CRT). BACKGROUND: PH is common in patients with left ventricular systolic dysfunction (LVSD) receiving CRT. The impact of PH subtype on clinical outcome in CRT is unknown. METHODS: The study population consisted of 101 patients (average age 66 +/- 13 years, left ventricular ejection fraction 0.23 +/- 0.07, and New York Heart Association functional class 3.2 +/- 0.4) who underwent right heart catheterization in the 6 months before CRT. PH was defined as a mean pulmonary artery pressure >=25 mm Hg; a significant pre-capillary contribution to elevated mean pulmonary artery pressure was defined as a transpulmonary gradient (TPG) >=12 mm Hg. Clinical endpoints were assessed at 2 years and included all-cause mortality and a composite of death, left ventricular assist device, or cardiac transplantation. RESULTS: Patients with TPG >=12 mm Hg were more likely to experience all-cause mortality (hazard ratio [HR]: 3.2; 95% confidence interval [CI]: 1.3 to 7.4; p = 0.009) and the composite outcome (HR: 3.0; 95% CI: 1.4 to 6.3; p = 0.004) compared with patients with TPG <12 mm Hg. After multivariate adjustment for hemodynamic, clinical, and echocardiographic variables, only TPG >=12 mm Hg and baseline right ventricular (RV) dilation (RV end-diastolic dimension >42 mm) were associated with the composite clinical outcome (p = 0.05 and p = 0.04, respectively). CONCLUSIONS: High TPG PH and RV dilation are independent predictors of adverse outcomes in patients with LVSD who are receiving CRT. RV pulmonary vascular dysfunction may be a therapeutic target in select patients receiving CRT. PMID- 24952691 TI - Fatness, fitness, stiffness, and age: how does it lead to heart failure? PMID- 24952690 TI - Association of cardiorespiratory fitness with left ventricular remodeling and diastolic function: the Cooper Center Longitudinal Study. AB - OBJECTIVES: This study sought to compare the cross-sectional associations between fitness and echocardiographic measures of cardiac structure and function. BACKGROUND: Cardiorespiratory fitness is inversely associated with heart failure risk. However, the mechanism through which fitness lowers heart failure risk is not fully understood. METHODS: We included 1,678 men and 1,247 women from the Cooper Center Longitudinal Study who received an echocardiogram from 1999 to 2011. Fitness was estimated by Balke protocol (in metabolic equivalents) and also categorized into age-specific quartiles, with quartile 1 representing low fitness. Cross-sectional associations between fitness (in metabolic equivalents) and relative wall thickness, left ventricular end-diastolic diameter indexed to body surface area, left atrial volume indexed to body surface area, left ventricular systolic function, and E/e' ratio were determined using multivariable linear regression analysis. RESULTS: Higher levels of mid-life fitness (metabolic equivalents) were associated with larger indexed left atrial volume (men: beta = 0.769, p < 0.0001; women: beta = 0.879, p value <=0.0001) and indexed left ventricular end-diastolic diameter (men: beta = 0.231, p < 0.001; women: beta = 0.264, p < 0.0001). Similarly, a higher level of fitness was associated with a smaller relative wall thickness (men: beta = -0.002, p = 0.04; women: beta = 0.005, p < 0.0001) and E/e' ratio (men: beta = -0.11, p = 0.003; women: beta = 0.13, p = 0.01). However, there was no association between low fitness and left ventricular systolic function (p = NS). CONCLUSIONS: Low fitness is associated with a higher prevalence of concentric remodeling and diastolic dysfunction, suggesting that exercise may lower heart failure risk through its effect on favorable cardiac remodeling and improved diastolic function. PMID- 24952692 TI - Contemporary profile of acute heart failure in Southern Nigeria: data from the Abeokuta Heart Failure Clinical Registry. AB - OBJECTIVES: The aim of this study was to determine the contemporary profile, clinical characteristics, and intrahospital outcomes of acute heart failure (AHF) in an African urban community. BACKGROUND: There are limited data on the current burden and characteristics of AHF in Nigerian Africans. METHODS: Comprehensive and detailed clinical and sociodemographic data were prospectively collected from 452 consecutive patients presenting with AHF to the only tertiary hospital in Abeokuta, Nigeria (population about 1 million) over a 2-year period. RESULTS: The mean age was 56.6 +/- 15.3 years (57.3 +/- 13.4 years for men, 55.7 +/- 17.1 years for women), and 204 patients (45.1%) were women. Overall, 415 subjects (91.8%) presented with de novo AHF. The most common risk factor for heart failure was hypertension (pre-existing in 64.3% of patients). Type 2 diabetes mellitus was present in 41 patients (10.0%). Hypertensive heart failure was the most common etiological cause of heart failure, responsible for 78.5% of cases. Dilated cardiomyopathy (7.5%), cor pulmonale (4.4%), pericardial disease (3.3%), rheumatic heart disease (2.4%), and ischemic heart disease were less common (0.4%) causes. The majority of subjects (71.2%) presented with left ventricular dysfunction (mean left ventricular ejection fraction 43.9 +/- 9.0%), with valvular dysfunction and abnormal left ventricular geometry frequently documented. The mean duration of hospital stay was 11.4 +/- 9.1 days, and intrahospital mortality was 3.8%. CONCLUSIONS: Compared with those in high-income countries, patients presenting with AHF in Abeokuta, Nigeria, are relatively younger and still of working age. It is also more common in men and associated with severe symptoms because of late presentation. Intrahospital mortality is similar to that in other parts of the world. PMID- 24952693 TI - Biomarkers of myocardial stress and fibrosis as predictors of mode of death in patients with chronic heart failure. AB - OBJECTIVES: The aim of this study was to determine whether biomarkers of myocardial stress and fibrosis improve prediction of the mode of death in patients with chronic heart failure. BACKGROUND: The 2 most common modes of death in patients with chronic heart failure are pump failure and sudden cardiac death. Prediction of the mode of death may facilitate treatment decisions. The relationship between amino-terminal pro-brain natriuretic peptide (NT-proBNP), galectin-3, and ST2, biomarkers that reflect different pathogenic pathways in heart failure (myocardial stress and fibrosis), and mode of death is unknown. METHODS: HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) was a randomized controlled trial of exercise training versus usual care in patients with chronic heart failure due to left ventricular systolic dysfunction (left ventricular ejection fraction <=35%). An independent clinical events committee prospectively adjudicated mode of death. NT-proBNP, galectin-3, and ST2 levels were assessed at baseline in 813 subjects. Associations between biomarkers and mode of death were assessed using cause specific Cox proportional hazards modeling, and interaction testing was used to measure differential associations between biomarkers and pump failure versus sudden cardiac death. Discrimination and risk reclassification metrics were used to assess the added value of galectin-3 and ST2 in predicting mode of death risk beyond a clinical model that included NT-proBNP. RESULTS: After a median follow up period of 2.5 years, there were 155 deaths: 49 from pump failure, 42 from sudden cardiac death, and 64 from other causes. Elevations in all biomarkers were associated with increased risk for both pump failure and sudden cardiac death in both adjusted and unadjusted analyses. In each case, increases in the biomarker had a stronger association with pump failure than sudden cardiac death, but this relationship was attenuated after adjustment for clinical risk factors. Clinical variables along with NT-proBNP levels were stronger predictors of pump failure (C statistic: 0.87) than sudden cardiac death (C statistic: 0.73). Addition of ST2 and galectin-3 led to improved net risk classification of 11% for sudden cardiac death, but not pump failure. CONCLUSIONS: Clinical predictors along with NT proBNP levels were strong predictors of pump failure risk, with insignificant incremental contributions of ST2 and galectin-3. Predictability of sudden cardiac death risk was less robust and enhanced by information provided by novel biomarkers. PMID- 24952695 TI - Emergency departments, acute heart failure, and admissions: one size does not fit all. PMID- 24952694 TI - The burden of acute heart failure on U.S. emergency departments. AB - OBJECTIVES: The goal of this study was to examine 2006 to 2010 emergency department (ED) admission rates, hospital procedures, lengths of stay, and costs for acute heart failure (AHF). BACKGROUND: Patients with AHF are often admitted and are associated with high readmissions and cost. METHODS: We utilized Nationwide Emergency Department Sample AHF data from 2006 to 2010 to describe admission proportion, hospital length of stay (LOS), and ED charges as a surrogate for resource utilization. Results were compared across U.S. regions, patient insurance status, and hospital characteristics. RESULTS: There were 958,167 mean yearly ED visits for AHF in the United States. Fifty-one percent of the patients were female, and the median age was 75.1 years (interquartile range [IQR]: 62.5 to 83.7 years). Overall, 83.7% (95% confidence interval: 83.1% to 84.2%) were admitted; the median LOS was 3.4 days (IQR: 1.9 to 5.8 days). Comparing 2006 with 2010, there was a small decrease in median LOS (0.09 days), but the proportion admitted did not change. Odds of admission, adjusting for age, sex, hospital characteristic (academic and safety net status), and insurance (Medicare, Medicaid, private, self-pay/no charge) were highest in the Northeast. Median ED charges were $1,075 (IQR: $679 to $1,665) in 2006 and $1,558 (IQR: $1,018 to $2,335) in 2010. Patients without insurance were more likely to be discharged from the ED, but when admitted, were more likely to receive a major diagnostic or therapeutic procedure. CONCLUSIONS: A very high proportion of ED patients with AHF are admitted nationally, with significant variation in disposition and procedural decisions based on region of the country and type of insurance, even after adjusting for potential confounding. PMID- 24952696 TI - Long-term mortality after cardiac allograft vasculopathy: implications of percutaneous intervention. AB - OBJECTIVES: This study compared the prognosis of patients with proximal cardiac allograft vasculopathy (CAV) treated with percutaneous intervention (PCI) to the prognosis of those with severe CAV not amenable to PCI. BACKGROUND: CAV is a progressive form of arterial narrowing affecting patients with orthotopic heart transplants (OHTs). PCI has been used to treat patients with focal CAV, but its efficacy remains unclear. METHODS: Of 853 patients undergoing OHT and subsequent coronary angiographies at the Cleveland Clinic, all patients with at least moderate CAV (>30%) on any coronary angiogram following OHT were included. Of remaining patients with no/mild CAV, 200 patients were randomly chosen to represent the comparison group. All angiograms of the included patients were reviewed and graded according to the International Society of Heart and Lung Transplantation (ISHLT) nomenclature. RESULTS: Of the 393 included patients, 100 patients underwent definitive intervention for CAV. Of these 100 patients, 90 patients underwent PCI only, 6 patients underwent coronary artery bypass grafting, and 4 patients underwent repeat OHT. We observed a progressive increase in long-term mortality with worsening CAV. Patients with ISHLT grade 3 CAV had the highest long-term mortality compared with other groups. In addition, there was a significant reduction in the risk for mortality at 2-year follow-up (adjusted odds ratio: 0.26; 95% confidence interval [CI]: 0.08 to 0.82) and 5 year follow-up (adjusted odds ratio: 0.28; 95% CI: 0.09 to 0.93) after PCI compared with patients diagnosed with ISHLT grade 3 CAV, who were deemed unsuitable for PCI. Furthermore, statin use was associated with a significant survival benefit in patients with CAV (hazard ratio: 0.21; 95% CI: 0.07 to 0.61). CONCLUSIONS: Worsening severity of CAV was associated with progressively worse long-term survival among heart transplant recipients. Among patients with CAV, long-term survival in those with CAV amenable to PCI was greater than that in those with severe CAV not treatable with PCI. PMID- 24952698 TI - Understanding the heterogeneity in volume overload and fluid distribution in decompensated heart failure is key to optimal volume management: role for blood volume quantitation. AB - OBJECTIVES: This study sought to quantitate total blood volume (TBV) in patients hospitalized for decompensated chronic heart failure (DCHF) and to determine the extent of volume overload, and the magnitude and distribution of blood volume and body water changes following diuretic therapy. BACKGROUND: The accurate assessment and management of volume overload in patients with DCHF remains problematic. METHODS: TBV was measured by a radiolabeled-albumin dilution technique with intravascular volume, pre-to-post-diuretic therapy, evaluated at hospital admission and at discharge. Change in body weight in relation to quantitated TBV was used to determine interstitial volume contribution to total fluid loss. RESULTS: Twenty-six patients were prospectively evaluated. Two patients had normal TBV at admission. Twenty-four patients were hypervolemic with TBV (7.4 +/- 1.6 liters) increased by +39 +/- 22% (range, +9.5% to +107%) above the expected normal volume. With diuresis, TBV decreased marginally (+30 +/- 16%). Body weight declined by 6.9 +/- 5.2 kg, and fluid intake/fluid output was a net negative 8.4 +/- 5.2 liters. Interstitial compartment fluid loss was calculated at 6.2 +/- 4.0 liters, accounting for 85 +/- 15% of the total fluid reduction. CONCLUSIONS: TBV analysis demonstrated a wide range in the extent of intravascular overload. Dismissal measurements revealed marginally reduced intravascular volume post-diuretic therapy despite large reductions in body weight. Mobilization of interstitial fluid to the intravascular compartment with diuresis accounted for this disparity. Intravascular volume, however, remained increased at dismissal. The extent, composition, and distribution of volume overload are highly variable in DCHF, and this variability needs to be taken into account in the approach to individualized therapy. TBV quantitation, particularly serial measurements, can facilitate informed volume management with respect to a goal of treating to euvolemia. PMID- 24952697 TI - Effect of rosuvastatin on repeat heart failure hospitalizations: the CORONA Trial (Controlled Rosuvastatin Multinational Trial in Heart Failure). AB - OBJECTIVES: This study sought to examine the effect of statin therapy hospitalizations for heart failure (HFH) in patients in the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) trial. BACKGROUND: HFH is an important, frequently recurrent event. Conventional time-to-first event analyses do not take account repeat events. We used a number of statistical approaches to examine the effect of treatment on first and repeat HFH in the CORONA trial. METHODS: In the CORONA trial, 5,011 patients >=60 years of age with chronic New York Heart Association functional classes II to IV systolic heart failure resulting from ischemia were randomized to receive rosuvastatin or placebo. Poisson, Andersen-Gill, and negative binomial methods (NB) were used to analyze the effect of rosuvastatin on HFH, and the NB and a parametric joint frailty model (JF) were used to examine this effect while accounting for the competing risk of cardiovascular (CV) death. Rosuvastatin/placebo rate ratios were calculated, both unadjusted and adjusted. RESULTS: A total of 1,291 patients had 1 or more HFH (750 of these had a single HFH only), and there were a total of 2,408 HFHs. The hazard ratio for the conventional time-to-first event analysis for HFH was 0.91 (95% confidence interval [CI]: 0.82 to 1.02, p = 0.105). In contrast, the NB on repeat hospitalizations gave an unadjusted RR (RR) for HFH of 0.86 (95% CI: 0.75 to 0.99, p = 0.030), adjusted 0.82 (95% CI: 0.72 to 0.92, p = 0.001), and after including CV death as the last event, adjusted RR of 0.85 (95% CI: 0.77 to 0.94, p = 0.001). The JF gave an adjusted RR of 0.82 (95% CI: 0.73 to 0.92, p = 0.001). Similar results were found in analyses of all CV hospitalizations and all-cause hospitalizations. CONCLUSIONS: When repeat events were included, rosuvastatin was shown to reduce the risk of HFH by approximately 15% to 20%, equating to approximately 76 fewer admissions per 1,000 patients treated over a median 33 months of follow-up. Including repeat events could increase the ability to detect treatment effects in heart failure trials. PMID- 24952699 TI - In search of euvolemia in heart failure. PMID- 24952700 TI - The effect of multiple micronutrient supplementation on left ventricular ejection fraction in patients with chronic stable heart failure: a randomized, placebo controlled trial. AB - OBJECTIVES: This study sought to investigate the effect of a multiple micronutrient supplement on left ventricular ejection fraction (LVEF) in patients with heart failure. BACKGROUND: Observational studies suggest that patients with heart failure have reduced intake and lower concentrations of a number of micronutrients. However, there have been very few intervention studies investigating the effect of micronutrient supplementation in patients with heart failure. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group study involving 74 patients with chronic stable heart failure that compared multiple micronutrient supplementation taken once daily versus placebo for 12 months. The primary endpoint was LVEF assessed by cardiovascular magnetic resonance imaging or 3-dimensional echocardiography. Secondary endpoints were Minnesota Living With Heart Failure Questionnaire score, 6-min walk test distance, blood concentrations of N-terminal prohormone of brain natriuretic peptide, C-reactive protein, tumor necrosis factor alpha, interleukin-6, interleukin-10, and urinary levels of 8-iso-prostaglandin F2 alpha. RESULTS: Blood concentrations of a number of micronutrients increased significantly in the micronutrient supplement group, indicating excellent compliance with the intervention. There was no significant difference in mean LVEF at 12 months between treatment groups after adjusting for baseline (mean difference: 1.6%, 95% confidence interval: -2.6 to 5.8, p = 0.441). There was also no significant difference in any of the secondary endpoints at 12 months between treatment groups. CONCLUSIONS: This study provides no evidence to support the routine treatment of patients with chronic stable heart failure with a multiple micronutrient supplement. (Micronutrient Supplementation in Patients With Heart Failure [MINT-HF]; NCT01005303). PMID- 24952701 TI - Micronutrients for chronic heart failure: end of the road or path to enlightenment? PMID- 24952706 TI - Evaluation of sampling spacing in pharmacokinetic studies using six sigma method. AB - Key elements of pharmacokinetics (PK) studies include both, the number of sampling points (NSP) as well as the spacing between the sampling points (SSP). Optimization of the SSP is discussed in guidelines of all key regulatory agencies (RA). Those however, provide only very general rules on how to properly distribute the NSPs in proposed PK studies. Here we demonstrate that the six sigma (SX) method can be effectively used to assess the quality of SSPs. We have tested a modified SX method analyzing 466 PK profiles from 16 studies including a total of 368 healthy volunteers. Non-compartmental modeling was used to estimate PK parameters. The arithmetic means of minimum and maximum values of SX obtained for each subject in all studies were 1.97 and 3.83, respectively. The method described here allows comparing quality of studies performed at different centers, even if they cover different chemical entities. We propose that the SX values can be used to assess quality of PK studies, what is consistent with recommendations of the RAs. PMID- 24952705 TI - Bortezomib and dexamethasone for multiple myeloma: higher AST and LDH levels associated with a worse prognosis on overall survival. AB - BACKGROUND: Bortezomib offers a novel approach to the treatment of multiple myeloma producing rapid control. The aim of this study was to investigate the outcomes of bortezomib and dexamethasone-treated patients with multiple myeloma. METHODS: We conducted a retrospective study of 44 consecutively-treated multiple myeloma patients with bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11 of a 21-day cycle or 1.3 mg/m(2) intravenously 1, 8, 15, and 22 of every 35-day cycle) and dexamethasone. RESULTS: The median time to progression, progression free survival time, and overall survival time in the treatment groups was 14.9, 14.9, and 38.3 months, respectively. The present study also suggests the possibility that the prognosis of patients with high levels of AST and LDH might be worse. CONCLUSIONS: Our results indicate that the treatment of multiple myeloma with bortezomib and dexamethasone is feasible. PMID- 24952704 TI - Novel combination of mitochondrial division inhibitor 1 (mdivi-1) and platinum agents produces synergistic pro-apoptotic effect in drug resistant tumor cells. AB - Overcoming platinum drug resistance represents a major clinical challenge in cancer treatment. We discovered a novel drug combination using cisplatin and a class of thioquinazolinone derivatives including mdivi-1 (mitochondrial division inhibitor-1), that induces synergistic apoptosis in platinum resistant tumor cells, including those from cisplatin-refractory endstage ovarian cancer patients. However, through study of the combination effect on Drp1 (the reported target of mdivi-1) knockout MEF cells and the functional analysis of mdivi-1 analogs, we revealed that the synergism between mdivi-1 and cisplatin is Drp1 independent. Mdivi-1 impairs DNA replication and its combination with cisplatin induces a synergistic increase of replication stress and DNA damage, causing a preferential upregulation of a BH3-only protein Noxa. Mdivi-1 also represses mitochondrial respiration independent of Drp1, and the combination of mdivi-1 and cisplatin triggers substantial mitochondrial uncoupling and swelling. Upregulation of Noxa and simultaneous mitochondrial swelling causes synergistic induction of mitochondrial outer membrane permeabilization (MOMP), proceeding robust mitochondrial apoptotic signaling independent of Bax/Bak. Thus, the novel mode of MOMP induction by the combination through the "dual-targeting" potential of mdivi-1 on DNA replication and mitochondrial respiration suggests a novel class of compounds for platinum-based combination option in the treatment of platinum as well as multidrug resistant tumors. PMID- 24952707 TI - Rapid identification of a narcotic plant Papaver bracteatum using flow cytometry. AB - In May 2011, numerous poppy plants closely resembling Papaver bracteatum Lindl., a type of narcotic plant that is illegal in Japan, were distributed directly from several large flower shops or through online shopping throughout Japan, including the Tokyo Metropolitan area. In order to better identify the narcotic plants, the relative nuclear DNA content at the vegetative stage was measured by flow cytometric (FCM) analysis in 3 closely-related species of the genus Papaver section Oxytona, namely P. orientale, P. pseudo-orientale, and P. bracteatum, based on the difference between the chromosome numbers of these species. The results showed that the nuclear DNA content differed between these 3 species, and that most of the commercially distributed plants examined in this study could be identified as P. bracteatum. The remaining plants were P. pseudo-orientale, a non narcotic plant. In addition, the FCM results for the identification of P. bracteatum completely agreed with the results obtained by the morphological analysis, the inter-genic spacer sequence of rpl16-rpl14 (PS-ID sequence) of chloroplast DNA, and the presence of thebaine. These results clearly indicate the usefulness of FCM analysis for the identification of P. bracteatum plants, including when they are in their vegetative stage. PMID- 24952708 TI - Prominent corneal nerves. PMID- 24952709 TI - Child allergic symptoms and mental well-being: the role of maternal anxiety and depression. AB - OBJECTIVE: To determine whether maternal mental health mediates the relationship between eczema or asthma symptoms and mental well-being in children. STUDY DESIGN: Analysis of 7250 children from the Avon Longitudinal Study of Parents and Children. Child mental well-being at 8 years was measured by the Strengths and Difficulties Questionnaire. Binary outcomes were high 'internalizing' (anxious/depressive) and 'externalizing' (oppositional/hyperactive) problems (high was >90th percentile). Child rash and wheeze categories were 'none'; 'early onset transient' (infancy/preschool only); 'persistent' (infancy/preschool and at school age); and 'late onset' (school age only). Maternal anxiety and depression were reported during pregnancy and when child was 8 years old. RESULTS: Persistent wheezing symptoms were associated with high externalizing (OR 1.74, 95% CI, 1.41-2.15) and internalizing (1.67, 1.35-2.06) problems compared with never wheeze. Maternal anxiety and depression, and disrupted child sleep, attenuated these associations. Persistent rash (externalizing: 1.74, 1.40-2.15; internalizing: 1.42, 1.16-1.74) and late onset rash (externalizing: 1.62, 1.17 2.25; internalizing: 1.46, 1.07-1.99) symptoms were associated with poorer mental well-being compared with no rash at any age. Maternal anxiety and depression, particularly when child was aged 8 years rather than during pregnancy, accounted for the association with internalizing symptoms and partly for externalizing symptoms. Sleep disruption did not mediate the association. CONCLUSIONS: Maternal anxiety and depression may mediate the association between child rash and wheeze and child mental well-being. PMID- 24952711 TI - An infant with a rash resembling seborrheic dermatitis and petechiae. PMID- 24952710 TI - Independent and combined influence of the components of physical fitness on academic performance in youth. AB - OBJECTIVE: To examine the independent and combined associations of the components of physical fitness with academic performance among youths. STUDY DESIGN: This cross-sectional study included a total of 2038 youths (989 girls) aged 6-18 years. Cardiorespiratory capacity was measured using the 20-m shuttle run test. Motor ability was assessed with the 4*10-m shuttle run test of speed of movement, agility, and coordination. A muscular strength z-score was computed based on handgrip strength and standing long jump distance. Academic performance was assessed through school records using 4 indicators: Mathematics, Language, an average of Mathematics and Language, and grade point average score. RESULTS: Cardiorespiratory capacity and motor ability were independently associated with all academic variables in youth, even after adjustment for fitness and fatness indicators (all P<=.001), whereas muscular strength was not associated with academic performance independent of the other 2 physical fitness components. In addition, the combined adverse effects of low cardiorespiratory capacity and motor ability on academic performance were observed across the risk groups (P for trend<.001). CONCLUSION: Cardiorespiratory capacity and motor ability, both independently and combined, may have a beneficial influence on academic performance in youth. PMID- 24952715 TI - Identification of fungal pathogens by visible microarray system in combination with isothermal gene amplification. AB - The increasing incidence of infectious diseases caused by fungi in immunocompromised patients has encouraged researchers to develop rapid and accurate diagnosis methods. Identification of the causative fungal species is critical in deciding the appropriate treatment, but it is not easy to get satisfactory results due to the difficulty of fungal cultivation and morphological identification from clinical samples. In this study, we established a microarray system that can identify 42 species from 24 genera of clinically important fungal pathogens by using a chemical color reaction in the detection process. The array uses the internal transcribed spacer region of the rRNA gene for identification of fungal DNA at the species level. The specificity of this array was tested against a total of 355 target and nontarget fungal species. The fungal detection was succeeded directly from 10(3) CFU/ml for whole blood samples, and 50 fg DNA per 1 ml of serum samples indicating that the array system we established is sensitive to identify infecting fungi from clinical sample. Furthermore, we conducted isothermal amplification in place of PCR amplification and labeling. The successful identification with PCR-amplified as well as isothermally amplified target genes demonstrated that our microarray system is an efficient and robust method for identifying a variety of fungal species in a sample. PMID- 24952714 TI - Infliximab therapy for Crohn's-like disease in common variable immunodeficiency complicated by massive intestinal hemorrhage: a case report. AB - BACKGROUND: Common variable immune deficiency is the most frequently encountered immunodeficiency in adults, which is characterized by low levels of serum immunoglobulins. Common variable immune deficiency can present with inflammatory bowel disease-like colitis because of the dysregulated immune system; paradoxically activated T cell receptor pathways are thought to be pivotal in pathogenesis of common variable immune deficiency-related colitis. Treatment for severe complications, such as gastrointestinal bleeding, is not established. We report a case of common variable immune deficiency-related Crohn's-like disease presenting massive melena, which was successfully treated by short course infliximab therapy. CASE PRESENTATION: A 26-year-old Japanese man with history of common variable immune deficiency presented with diarrhea, abdominal pain, and fever. Venous administration of antibiotics did not improve his symptoms. Colonoscopy revealed multiple longitudinal ulcers as well as cobblestone-like change in the ileum end and the ascending colon. Histopathological examination of biopsy specimen showed erosion and infiltration of T lymphocytes with lack of B cells. Intravenous hyperalimentation, mesalazine, and steroid did not improve the symptoms and the patient subsequently presented with massive melena. Colonoscopy revealed a protuberant vessel on one of the ulcers in the ascending colon. Endoscopic clipping was repeatedly performed for hemostasis, which was only temporarily successful. In an attempt to manage the bleeding and colitis, a trial of infliximab was given on week 0, week 2 and week 6. Gastrointestinal hemorrhage from the ulcer halted immediately after the first infliximab injection. Colonoscopy performed after the third infliximab showed remarkable improvement in the ileocolitis. No evidence of increased susceptibility to infections was observed and the patient has been in clinical remission for 3 years. CONCLUSIONS: We present this case together with review of literature to share our experience of encountering common variable immune deficiency complicating severe Crohn's like disease and to support that infliximab is a safe and effective treatment that can promptly manage life-threatening intestinal hemorrhage in common variable immune deficiency-related colitis. PMID- 24952717 TI - Control of Ras-mediated signaling in Aspergillus fumigatus. AB - Pathogenic fungi employ numerous mechanisms to flourish in the stressful environment encountered within their mammalian hosts. Central to this arsenal for filamentous fungi is invasive growth within the host microenvironment, mediated by establishment and maintenance of polarized hyphal morphogenesis. In Aspergillus fumigatus, the RasA signal transduction pathway has emerged as a significant regulator of hyphal morphogenesis and virulence, among other processes. The factors contributing to the regulation of RasA itself are not as thoroughly understood, although proper temporal activation of RasA and spatial localization of RasA to the plasma membrane are known to play major roles. Interference with RasA palmitoylation or prenylation results in mislocalization of RasA and is associated with severe growth deficits. In addition, dysregulation of RasA activation results in severe morphologic aberrancies and growth deficits. This review highlights the relationship between RasA signaling, hyphal morphogenesis, and virulence in A. fumigatus and focuses on potential determinants of spatial and temporal RasA regulation. PMID- 24952718 TI - Comparison of commercial methods and the CLSI broth microdilution to determine the antifungal susceptibility of Candida parapsilosis complex bloodstream isolates from three health institutions in Rio de Janeiro, Brazil. AB - Two commercial methods, the Etest and Vitek 2, were compared with the Clinical and Laboratory Standards Institute broth microdilution method to determine the susceptibility of Candida parapsilosis complex to amphotericin B, caspofungin, fluconazole, voriconazole, and itraconazole. One-hundred bloodstream isolates of C. parapsilosis complex from three hospitals in Rio de Janeiro city, Brazil, between 1998 and 2006 were analyzed. C. parapsilosis sensu stricto (61 %) was the predominant species, followed by C. orthopsilosis (37 %) and C. metapsilosis (2 %). Most isolates were susceptible to the tested drugs. However, one C. parapsilosis sensu stricto isolate was considered resistant for amphotericin B. The essential agreement was 100 % between the methods, except for itraconazole (96.3 %). The categorical agreement varied for fluconazole and itraconazole by Etest and for amphotericin B and fluconazole by Vitek 2. This study reinforces the suitability of the commercial methods in routine clinical microbiology laboratories for antifungal susceptibility testing. PMID- 24952719 TI - The association of depression and angina pectoris across 47 countries: findings from the 2002 World Health Survey. AB - Comorbid depression predicts poor health outcomes in patients with angina pectoris (AP). However, epidemiological data on the depression-AP comorbidity is limited and largely restricted to studies from Western countries, making generalizability to other regions uncertain. We aimed to provide additional epidemiological data for non-Western as well as Western countries. The present study used population-based data gathered in 47 countries from four continents (Africa, Asia, South America, and Europe) included in the cross-sectional 2002 WHO World Health Survey. Self-reported indicators of depression included: (a) its diagnosis, (b) its treatment, and (c) seven symptom items to determine presence of a major depressive episode. Similarly, information on AP comprised (a) a self reported diagnosis, (b) self-reported AP treatment, (c) and a definition according to the WHO Rose questionnaire. In primary analyses, we operationalized depression or AP as positive if any of the respective indicators was present. Associations were estimated by multivariate logistic regression. In the entire sample (n = 213,264), the odds of AP were more than doubled among those with depression [odds ratio (OR) = 2.60, 95% confidence interval = 2.36, 2.87] versus those without depression. These positive associations were replicated across all continents and were observed in both men and women. Likewise, meaningful associations (ORs >= 1.5) were observed in virtually all individual countries (46/47). Application of different operationalizations of depression and AP confirmed the above findings, both in the entire sample and in continent-specific analyses. Our study extends the current evidence accrued in Western populations to non-Western populations. The co-occurrence of AP and depression appears to represent a universal phenomenon. PMID- 24952716 TI - Isolation of dermatophytes and related species from domestic fowl (Gallus gallus domesticus). AB - We investigated 793 bird combs [645 chickens and 148 fighting cocks (Shamo)] to determine the prevalence of dermatophytes and their related fungal species. The targeted fungal species were recovered from 195 of the 793 examined birds (24.6 %). Prevalence ratios were compared in temperate (the mainland) and subtropical (Nansei Islands) areas, genders, strains, breeding scale (individual and farm), and housing system (in cage and free ranging). The frequency of the fungal species in the mainland, males, fighting cocks, breeding scale by individual nursing, and free-range housing system exhibited significantly higher positive ratios than that in the other groups. A total of 224 dermatophytes and related species were isolated, including 101 Arthroderma (Ar.) multifidum, 83 Aphanoascus (Ap.) terreus, five Uncinocarpus queenslandicus, two U. reesii, two Ap. pinarensis, one Amauroascus kuehnii, one Ar. simii, one Gymnoascus petalosporus, one Microsporum gallinae, and 28 Chrysosporium-like (Chrysosporium spp.) isolates, which were identified using internal transcribed spacer regions of ribosomal RNA gene sequences. The predominant fungal species in the mainland was Ap. terreus and that in the Nansei Islands was Ar. multifidum. Pathogenic fungal species to humans and animals were limited to M. gallinae and Ar. simii, which corresponded to 0.025 % of the isolates in this study. PMID- 24952720 TI - Multigenerational outbreeding effects in Chinook salmon (Oncorhynchus tshawytscha). AB - Outbreeding, mating between genetically divergent individuals, may result in negative fitness consequences for offspring via outbreeding depression. Outbreeding effects are of notable concern in salmonid research as outbreeding can have major implications for salmon aquaculture and conservation management. We therefore quantified outbreeding effects in two generations (F1 hybrids and F2 backcrossed hybrids) of Chinook salmon (Oncorhynchus tshawytscha) derived from captively-reared purebred lines that had been selectively bred for differential performance based on disease resistance and growth rate. Parental lines were crossed in 2009 to create purebred and reciprocal hybrid crosses (n = 53 families), and in 2010 parental and hybrid crosses were crossed to create purebred and backcrossed hybrid crosses (n = 66 families). Although we found significant genetic divergence between the parental lines (FST = 0.130), reciprocal F1 hybrids showed no evidence of outbreeding depression (hybrid breakdown) or favorable heterosis for weight, length, condition or survival. The F2 backcrossed hybrids showed no outbreeding depression for a suite of fitness related traits measured from egg to sexually mature adult life stages. Our study contributes to the current knowledge of outbreeding effects in salmonids and supports the need for more research to better comprehend the mechanisms driving outbreeding depression. PMID- 24952712 TI - Factors associated with neurodevelopment for children with single ventricle lesions. AB - OBJECTIVE: To measure neurodevelopment at 3 years of age in children with single right-ventricle anomalies and to assess its relationship to Norwood shunt type, neurodevelopment at 14 months of age, and patient and medical factors. STUDY DESIGN: All subjects in the Single Ventricle Reconstruction Trial who were alive without cardiac transplant were eligible for inclusion. The Ages and Stages Questionnaire (ASQ, n = 203) and other measures of behavior and quality of life were completed at age 3 years. Medical history, including measures of growth, feeding, and complications, was assessed through annual review of the records and phone interviews. The Bayley Scales of Infant Development, Second Edition (BSID II) scores from age 14 months were also evaluated as predictors. RESULTS: Scores on each ASQ domain were significantly lower than normal (P < .001). ASQ domain scores at 3 years of age varied nonlinearly with 14-month BSID-II. More complications, abnormal growth, and evidence of feeding, vision, or hearing problems were independently associated with lower ASQ scores, although models explained <30% of variation. Type of shunt was not associated with any ASQ domain score or with behavior or quality-of-life measures. CONCLUSION: Children with single right-ventricle anomalies have impaired neurodevelopment at 3 years of age. Lower ASQ scores are associated with medical morbidity, and lower BSID-II scores but not with shunt type. Because only a modest percentage of variation in 3-year neurodevelopmental outcome could be predicted from early measures, however, all children with single right-ventricle anomalies should be followed longitudinally to improve recognition of delays. PMID- 24952723 TI - Serrated polyposis syndrome. PMID- 24952721 TI - Applications of RNA interference high-throughput screening technology in cancer biology and virology. AB - RNA interference (RNAi) is an ancient intra-cellular mechanism that regulates gene expression and cell function. Large-scale gene silencing using RNAi high throughput screening (HTS) has opened an exciting frontier to systematically study gene function in mammalian cells. This approach enables researchers to identify gene function in a given biological context and will provide considerable novel insight. Here, we review RNAi HTS strategies and applications using case studies in cancer biology and virology. PMID- 24952722 TI - The PHD1 finger of KDM5B recognizes unmodified H3K4 during the demethylation of histone H3K4me2/3 by KDM5B. AB - KDM5B is a histone H3K4me2/3 demethylase. The PHD1 domain of KDM5B is critical for demethylation, but the mechanism underlying the action of this domain is unclear. In this paper, we observed that PHD1KDM5B interacts with unmethylated H3K4me0. Our NMR structure of PHD1KDM5B in complex with H3K4me0 revealed that the binding mode is slightly different from that of other reported PHD fingers. The disruption of this interaction by double mutations on the residues in the interface (L325A/D328A) decreases the H3K4me2/3 demethylation activity of KDM5B in cells by approximately 50% and increases the transcriptional repression of tumor suppressor genes by approximately twofold. These findings imply that PHD1KDM5B may help maintain KDM5B at target genes to mediate the demethylation activities of KDM5B. PMID- 24952724 TI - Effect of bone material properties on effective region in screw-bone model: an experimental and finite element study. AB - BACKGROUND: There have been numerous studies conducted to investigate the pullout force of pedicle screws in bone with different material properties. However, fewer studies have investigated the region of effect (RoE), stress distribution and contour pattern of the cancellous bone surrounding the pedicle screw. METHODS: Screw pullout experiments were performed from two different foams and the corresponding reaction force was documented for the validation of a computational pedicle screw-foam model based on finite element (FE) methods. After validation, pullout simulations were performed on screw-bone models, with different bone material properties to model three different age groups (<50, 50 75 and >75 years old). At maximum pullout force, the stress distribution and average magnitude of Von Mises stress were documented in the cancellous bone along the distance beyond the outer perimeter pedicle screw. The radius and volume of the RoE were predicted based on the stress distribution. RESULTS: The screw pullout strengths and the load-displacement curves were comparable between the numerical simulation and experimental tests. The stress distribution of the simulated screw-bone vertebral unit showed that the radius and volume of the RoE varied with the bone material properties. The radii were 4.73 mm, 5.06 mm and 5.4 mm for bone properties of ages >75, 75 > ages >50 and ages <50 years old, respectively, and the corresponding volumes of the RoE were 6.67 mm3, 7.35 mm3 and 8.07 mm3, respectively. CONCLUSIONS: This study demonstrated that there existed a circular effective region surrounding the pedicle screw for stabilization and that this region was sensitive to the bone material characteristics of cancellous bone. The proper amount of injection cement for augmentation could be estimated based on the RoE in the treatment of osteoporosis patients to avoid leakage in spine surgery. PMID- 24952725 TI - Treatment of body composition changes in obese and overweight older adults: insight into the phenotype of sarcopenic obesity. AB - In recent years, mounting interest has been directed to sarcopenic obesity (SO), given the parallel increase of life expectancy and prevalence of obesity in Western countries. The phenotype of SO is characterized by the coexistence of excess fat mass and decreased muscle mass, leading to the impairment of physical performance. The aim of the present review was to summarize the impact of different treatment strategies contrasting body composition changes in older obese and overweight subjects, providing insight into the SO phenotype. Revision questions were formulated; relevant articles were identified from Pubmed through a systematic search strategy: definition of the search terms (sarcopenic obesity, diet, nutritional supplements, physical activity, exercise, pharmacological treatment); limits: papers published in the last 10 years; humans; age >= 60 years old; body mass index >25 kg/m(2); language: English. Studies dealing with sarcopenia associated to cancer cachexia or neurological diseases, any malignant disease, inflammatory or autoimmune diseases, corticosteroids for systemic use, bedridden subjects, and syndromic obesity were excluded. 14 articles were identified for inclusion in the present systematic review, and were grouped basing on the type of the main intervention: data assessing body composition changes after combined lifestyle interventions, exercise/physical activity, dietary interventions, and pharmacological treatment. Most of the studies were randomized, controlled. Sample size ranged from 12 to 439 subjects, and study duration varied from 6 weeks to 12 months. Weight loss based on diet combined with exercise seems to be the best strategy to adopt for treatment of phenotypic aspects of SO, improving metabolic consequences related to excess fat, preserving lean mass, and allowing functional recovery. PMID- 24952726 TI - Transvaginal hybrid NOTES cholecystectomy--results of a randomized clinical trial after 6 months. AB - INTRODUCTION: For cholecystectomy (CHE), both the needlescopic three-trocar technique with 2-3-mm instruments (needlescopic cholecystectomy (NC)) and the umbilically assisted transvaginal technique with rigid instruments (transvaginal cholecystectomy (TVC)) have been established for further reduction of the trauma remaining from laparoscopy. METHODS: To compare the further outcome of both techniques for elective CHE in female patients, we analyzed the secondary end points of a prospective randomized single-center trial (needlescopic versus transvaginal cholecystectomy (NATCH) trial; ClinicalTrials.gov Identifier: NCT0168577), in particular, satisfaction with aesthetics, overall satisfaction, abdominal pain, and incidence of trocar hernias postoperatively at both 3 and 6 months. After 3 months, the domains "satisfaction" and "pain" of the German version of the Female Sexual Function Index (FSFI-d) were additionally evaluated to detect respective complications. A gynecological control examination was conducted in all TVC patients after 6 months. RESULTS: Forty patients were equally randomized into the therapy and the control groups between February 2010 and June 2012. No significant differences were found for overall satisfaction with the surgical result, abdominal pain, sexual function, and the rate of trocar hernias. However, aesthetics were rated significantly better by TVC patients both after 3 and after 6 months (P = 0.004 and P < 0.001). There were no postoperative pathological gynecological findings. CONCLUSIONS: Following TVC, there is a significantly better aesthetic result as compared to NC, even at 3 and 6 months after the procedure. No difference was found for sexual function. PMID- 24952727 TI - Efficacy of the designer antimicrobial peptide SHAP1 in wound healing and wound infection. AB - Infected wounds cause delay in wound closure and impose significantly negative effects on patient care and recovery. Antimicrobial peptides (AMPs) with antimicrobial and wound closure activities, along with little opportunity for the development of resistance, represent one of the promising agents for new therapeutic approaches in the infected wound treatment. However, therapeutic applications of these AMPs are limited by their toxicity and low stability in vivo. Previously, we reported that the 19-amino-acid designer peptide SHAP1 possessed salt-resistant antimicrobial activities. Here, we analyzed the wound closure activities of SHAP1 both in vitro and in vivo. SHAP1 did not affect the viability of human erythrocytes and keratinocytes up to 200 MUM, and was not digested by exposure to proteases in the wound fluid, such as human neutrophil elastase and Staphylococcus aureus V8 proteinase for up to 12 h. SHAP1 elicited stronger wound closure activity than human cathelicidin AMP LL-37 in vitro by inducing HaCaT cell migration, which was shown to progress via transactivation of the epidermal growth factor receptor. In vivo analysis revealed that SHAP1 treatment accelerated closure and healing of full-thickness excisional wounds in mice. Moreover, SHAP1 effectively countered S. aureus infection and enhanced wound healing in S. aureus-infected murine wounds. Overall, these results suggest that SHAP1 might be developed as a novel topical agent for the infected wound treatment. PMID- 24952728 TI - Thiophenyl-substituted triazolyl-thione L-alanine: asymmetric synthesis, aggregation and biological properties. AB - In this work, we report the asymmetric synthesis and characterization of an artificial amino acid based on triazolyl-thione L-alanine, which was modified with a thiophenyl-substituted moiety, as well as in vitro studies of its nucleic acid-binding ability. We found, by dynamic light scattering studies, that the synthetic amino acid was able to form supramolecular aggregates having a hydrodynamic diameter higher than 200 nm. Furthermore, we demonstrated, by UV and CD experiments, that the heteroaromatic amino acid, whose enzymatic stability was demonstrated by HPLC analysis also after 24 h of incubation in human serum, was able to bind a RNA complex, which is a feature of biomedical interest in view of innovative antiviral strategies based on modulation of RNA-RNA molecular recognition. PMID- 24952729 TI - Principal sequence pattern analysis of episodes of excess mortality due to heat in the Barcelona metropolitan area. AB - The aim of the study is to classify the synoptic sequences associated with excess mortality during the warm season in the Barcelona metropolitan area. To achieve this purpose, we undertook a principal sequence pattern analysis that incorporates different atmospheric levels, in an attempt at identifying the main features that account for dynamic and thermodynamic atmospheric processes. The sequence length was determined by the short-term displacement between temperature and mortality. To detect this lag, we applied the cross-correlation function to the residuals obtained from the modelling of the daily temperature and mortality series of summer. These residuals were estimated by means of an autoregressive integrated moving average (ARIMA) model. A 7-day sequence emerged as the basic temporal unit for evaluating the synoptic background that triggers the temperature related to excess mortality in the Barcelona metropolitan area. The principal sequence pattern analysis distinguished three main synoptic patterns: two dynamic configurations produced by southern fluxes related to an Atlantic low, which can be associated with heat waves recorded in southern Europe, and a third pattern identified by a stagnation situation associated with the persistence of a blocking anticyclone over Europe, related to heat waves recorded in northern and central western Europe. PMID- 24952731 TI - cDNA microarray assessment of early gene expression profiles in Escherichia coli cells exposed to a mixture of heavy metals. AB - Many contaminated sites are characterized by the presence of different metals, thus increasing the complexity of toxic responses in exposed organisms. Within toxicogenomics, transcriptomics can be approached through the use of microarrays aimed at producing a genetic fingerprint for the response of model organisms to the presence of chemicals. We studied temporal changes in the early gene expression profiles of Escherichia coli cells exposed to three metal doses of a polymetallic solution over three exposure times, through the application of cDNA microarray technology. In the absence of metals, many genes belonging to a variety of cellular functions were up- and down-regulated over time. At the lowest metal dose, an activation of metal-specific transporters (Cus and ZraP proteins) and a mobilization of glutathione transporters involved in metal sequestration and trafficking was observed over time; this metal dose resulted in the generation of ROS capable of stimulating the transcription of Mn-superoxide dismutase, the assembly of Fe-S clusters and the synthesis of cysteine. At the intermediate dose, an overexpression of ROS scavengers (AhpF, KatG, and YaaA) and heat shock proteins (ClpP, HslV, DnaK, and IbpAB) was observed. Finally, at the highest dose, E. coli cells showed a repression of genes related with DNA mutation correctors (MutY glycopeptidases). PMID- 24952730 TI - GIST treatment options after tyrosine kinase inhibitors. AB - OPINION STATEMENT: The management of advanced gastrointestinal stromal tumor (GIST) has been dramatically altered by the development of tyrosine kinase inhibitors. The disease, which had a median overall survival of 12 months for patients with unresectable disease, now has a median survival approaching 5 or more years. The challenge faced clinically is how to care for patients when they have progressed on all approved therapies. Clinical trials evaluating the role of novel combination therapies with investigational agents that target AKT/PI3K pathways are of interest especially given the preclinical rationale available. The addition of an mTOR inhibitor can be tried as these are available, but requires care and monitoring for additional toxicities. With improved understanding of this disease, which we thought of as one biology, personalized therapies are being studied and tested and is particularly relevant for GIST that are less responsive to the standard kinase inhibitors, such as platelet-derived growth factor alpha (PDGFRA) D842V and wild-type/succinate dehydrogenase (SDH) deficient GIST. IGF1R inhibitors as a class are not being developed because of the lack of significant efficacy in many clinical trials and the efficacy in WT GIST has been limited; to date drugs targeting VEGFR, such as sunitinib and regorafenib, appear to be the best agents available for this group of patients. The exciting findings seen with CTLA4 and PD-1/PD-L1 antibodies in melanoma and other solid tumors is exciting, especially because there is a growing body of evidence that such approaches have biologic rationale; clinical trials evaluating these agents are awaited with interest. Last, recent work has shed light on older agents that may have a role in GIST. Moving forward to test these agents alone or in combination with TKIs offers potentially new strategies for treating advanced disease. PMID- 24952734 TI - The tissue selecting technique (TST) versus the Milligan-Morgan hemorrhoidectomy for prolapsing hemorrhoids: a retrospective case-control study. AB - BACKGROUND: Milligan-Morgan hemorrhoidectomy (MMH) is the procedure of choice in the management of hemorrhoidal disease. However, this procedure is associated with significant postoperative pain. Tissue selecting technique (TST) is a segmental stapled hemorrhoidopexy, which aims to reduce the postoperative pain, rectovaginal fistula (RVF) and rectal stenosis. The aim of the present study was to compare the clinical outcomes between TST and MMH. METHODS: A case-control study was undertaken to investigate the difference in clinical characteristics between the patients treated with TST and those treated with MMH. Intraoperative and postoperative parameters in both groups were collected and compared. RESULTS: One hundred and ninety-five eligible patients underwent either TST (n = 121) or MMH (n = 74). The pain score was significantly less in the TST group than that in the MMH group at the first defecation and at 12 h, day 3 and day 7 postoperatively (P = 0.001). Further analysis revealed that, at the time point of 12 h, day 3, day 7 and during first defecation, the pain score in the TST group and TST + STE group was less than that in the MMH group (P = 0.001). No patient in either group developed postoperative rectal stenosis. Furthermore, no case of RVF was identified in the TST group. The 1-year recurrence rate was 3.3 % (4/121) and 2.7 % (2/74), respectively, in TST and MMH groups (P = 1.0). CONCLUSIONS: The 1-year recurrence rate after TST and MMH for the treatment of patients with grade III-IV hemorrhoids is similar. It is encouraging that TST is associated with less postoperative pain and no RVF or rectal stenosis. PMID- 24952735 TI - [About the need for cardiovascular risk factors incidence studies in Mexico. A reality?]. PMID- 24952732 TI - The antihypertension drug doxazosin inhibits tumor growth and angiogenesis by decreasing VEGFR-2/Akt/mTOR signaling and VEGF and HIF-1alpha expression. AB - Doxazosin is an alpha1 adrenergic receptor blocker that also exerts antitumor effects. However, the underlying mechanisms by which it modulates PI3K/Akt intracellular signaling are poorly understood. In this study, we reveal that doxazosin functions as a novel antiangiogenic agent by inhibiting vascular endothelial growth factor (VEGF)-induced cell migration and proliferation. It also inhibited VEGF-induced capillary-like structure tube formation in vitro. Doxazosin inhibited the phosphorylation of VEGF receptor-2 (VEGFR-2) and downstream signaling, including PI3K, Akt, 3-phosphoinositide-dependent protein kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and hypoxia-inducible factor 1 (HIF-1alpha). However, it had no effect on VEGF-induced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Furthermore, doxazosin reduced tumor growth and suppressed tumor vascularization in a xenograft human ovarian cancer model. These results provide evidence that doxazosin functions in the endothelial cell system to modulate angiogenesis by inhibiting Akt and mTOR phosphorylation and interacting with VEGFR-2. PMID- 24952733 TI - A pilot study of chronic pudendal nerve stimulation for faecal incontinence for those who have failed sacral nerve stimulation. AB - BACKGROUND: Sacral nerve stimulation (SNS) is used as a first-line treatment for faecal incontinence when conservative measures have failed. However, one-third of patients fail to benefit from this treatment. We hypothesised that sacral afferent stimulation can be maximised using pudendal nerve stimulation (PNS) and this may be of benefit in this patient group. The aim of this study was to assess chronic PNS for those who failed to improve with SNS. METHODS: Ten patients who had failed SNS were recruited. All underwent percutaneous insertion of a stimulation lead with four-electrode array adjacent to the pudendal nerve. Continuous bipolar stimulation was administered using an external pulse generator over a 3-week period. Those who experienced a >=50% reduction in the frequency of incontinent episodes over this period proceeded to chronic stimulation with an implantable pulse generator. RESULTS: Five patients experienced a >=50% reduction of incontinent episodes during test stimulation and proceeded to chronic stimulation. In these five patients, at a median (range) follow-up of 24 (6-36) months, the median (inter quartile range) frequency of incontinent episodes reduced from 5 (18.25) to 2.5 (3) per week (p = 0.043). Three patients maintained a >=50% improvement in soiling. There was an improvement in the St Mark's continence Score from 19 (15-24) to 16 (13-19), p = 0.042. There were no significant changes in ability to defer defecation or in quality of life scores. CONCLUSIONS: Pudendal nerve stimulation failed to improve the symptoms in the majority of patient who had failed SNS. Only a third experienced any improvement. PMID- 24952737 TI - A nanostructured aluminum oxide-based microfluidic device for enhancing immunoassay's fluorescence and detection sensitivity. AB - A nanostructured aluminum oxide (NAO)-based fluorescence biosensing platform with a programmable sample delivery microfluidic interface is reported. The NAO-based fluorescence sensor can tremendously enhance the fluorescence signals, typically up to 100 * or more, over the glass substrate. The programmable sample delivery microfluidic interface, which is integrated with the NAO-based sensors, can automatically generate and deliver a series of different concentrations of the biological samples to each individual sensor. Hence it can facilitate the fluorescence-based biodetection and analysis for high throughput applications. Using Protein A and fluorophore-labeled Immunoglobulin G (IgG) as models, the binding between them on this platform have been demonstrated. It has been shown that the IgG of programmable concentrations can be delivered to individual sensor using the microfluidic interface and confirmed by the fluorescence images. Using current NAO-based fluorescence sensors without any optimization, the detectable concentration of IgG can be as low as 20 pg/mm(2) using a conventional fluorescence microscope. Due to its inexpensive fabrication process, this technology could provide a disposable technical platform for fluorescence-based sensing and analysis. PMID- 24952736 TI - Determinants of physician empathy during medical education: hypothetical conclusions from an exploratory qualitative survey of practicing physicians. AB - BACKGROUND: Empathy is an outcome-relevant physician characteristic and thus a crucial component of high-quality communication in health care. However, the factors that promote and inhibit the development of empathy during medical education have not been extensively researched. Also, currently there is no explicit research on the perspective of practicing physicians on the subject. Therefore the aim of our study was to explore physicians' views of the positive and negative influences on the development of empathy during their medical education, as well as in their everyday work as physicians. METHOD: We administered a written Qualitative Short Survey to 63 physicians in seven specialties. They were able to respond anonymously. Our open-ended question was: "What educational content in the course of your studies and/or your specialist training had a positive or negative effect on your empathy?" We analyzed the data using thematic content analysis following Mayring's approach. RESULTS: Forty-two physicians took part in our survey. All together, they mentioned 68 specific factors (37 positive, 29 negative, 2 neutral) from which six themes emerged: 1. In general, medical education does not promote the development of empathy. 2. Recognizing the psycho-social dimensions of care fosters empathy. 3. Interactions with patients in medical practice promote empathy. 4. Physicians' active self development through reflective practice helps the development of empathy. 5. Interactions with colleagues can both promote and inhibit empathy through their role modeling of empathic and non-empathic behavior. 6. Stress, time pressure, and adverse working conditions are detrimental to empathy development. CONCLUSIONS: Our results provide an overview of what might influence the development of clinical empathy, as well as hypothetical conclusions about how to promote it. Reflective practice seems to be lacking in current medical curricula and could be incorporated. Raising physicians' awareness of the psycho-social dimension of disease, and of the impact of peer influence and role modeling, seems promising in this regard, too. Stress and well-being seem to be closely related to physician empathy, and their modulation must take into account individual, social, and organizational factors. Further research should investigate whether or how these hypothetical conclusions can deepen our understanding of the determinants of physician empathy in order to help its promotion. PMID- 24952738 TI - Variability in the characterization of total coliforms, fecal coliforms and Escherichia coli in recreational water supplies of north Mississippi, USA. AB - The fecal coliform, Escherichia coli, is a historical organism for the detection of fecal pollution in water supplies. The presence of E. coli indicates a potential contamination of the water supply by other more hazardous human pathogens. In order to accurately determine the presence and degree of fecal contamination, it is important that standard methods approved by the US Environmental Protection Agency are designed to determine the presence of E. coli in a water supply, and distinguish E. coli from other coliform bacteria (e.g. Citrobacter, Klebsiella and Enterobacter). These genera of bacteria are present not only in fecal matter, but also in soil and runoff water and are not good indicators of fecal contamination. There is also ambiguity in determining a positive result for fecal coliforms on M-FC filters by a blue colony. When all variations of blue, including light blue or glossy blue, were examined, confirmation methods agreed with the positive M-FC result less often than when colonies that the technician would merely call "blue", with no descriptors, were examined. Approximately 48 % of M-FC positive colonies were found to be E. coli with 4 methylumbelliferyl-beta-D-glucuronide (MUG), and only 23 % of samples producing a positive result on M-FC media were found to be E. coli using API-20E test strips and current API-20E profiles. The majority of other M-FC blue colonies were found to be Klebsiella or were unidentifiable with current API-20E profiles. Two positive M-FC colonies were found to be Kluyvera with API-20E, both of which cleaved MUG and produced fluorescence under UV light, a characteristic used to differentiate E. coli from other fecal coliforms. PMID- 24952741 TI - The transcriptomic profile of peripheral blood nuclear cells in dogs with heart failure. AB - BACKGROUND: In recent years advances have been made in the investigative methods of molecular background of canine heart disease. Studies have been conducted to identify specific genes which, when pathologically expressed, could lead to the dysfunction of the canine heart or are correlated with heart failure. For this purpose genome wide microarray experiments on tissues from failing hearts have been performed. In the presented study a whole genome microarray analysis was used for the first time to describe the transcription profile of peripheral blood nuclear cells in dogs with heart failure. Dogs with recognized heart disease were classified according the ISACHC (International Small Animal Cardiac Health Council) classification scheme as class 1 (asymptomatic)--13 dogs, class 2 (mild to moderate heart failure)--13 dogs and class 3 (severe heart failure)--12 dogs. The control group consisted of 14 healthy dogs. The clinical picture of the animals included: animal history, clinical examination, echocardiographic examination and where applicable electrocardiographic and radiographic examinations. RESULTS: In the present study we identified four sets of differentially expressed genes, namely heart-failure-specific genes and ISACHC1 specific genes, ISACHC2-sepcific genes and ISACHC-3 specific genes. The most important set consisted of genes differentially expressed in all dogs with heart failure, despite the ISACHC stage. We identified 71 heart-failure-specific genes which were involved in two statistically significant receptor signalling pathways, namely angiotensinR - > CREB/ELK-SRF/TP53 signalling and ephrinR - > actin signalling. The number of ISACHC1-specific genes was 83; ISACHC2-specific genes--1247 and ISACHC3-specific--200. CONCLUSIONS: The transcriptomic profile of peripheral blood nuclear cells in dogs with heart failure seems to reflect the presence of clinical signs of the disease in patients based on the observation that the largest number of differentially expressed genes was identified in ISACHC 2 group of patients. This group consists of dogs just starting to show clinical signs of heart failure. A set of genes was also found to have changed expression in all dogs with heart failure, despite the stage of the disease. PMID- 24952742 TI - Economic analysis of a herpes zoster vaccination program in 19 affiliated supermarket pharmacies. AB - OBJECTIVES: To examine the economic impact of providing herpes zoster vaccine (ZOS) in 19 affiliated supermarket pharmacies in a midwestern metropolitan area from the perspective of the pharmacy and to identify factors associated with greater rates of vaccine delivery and profitability. SETTING: 19 affiliated supermarket pharmacies in the Kansas City metropolitan area. PRACTICE DESCRIPTION: Immunizations with ZOS were expanded from 2 pharmacies to all 19 affiliated pharmacies. Various methods to promote the vaccine were used, including personal selling, store signage, and circular ads. PRACTICE INNOVATION: In addition to a broad perspective pharmacoeconomic model, a localized perspective model is proposed to determine profitability for the service. Factors associated with greater success in vaccine delivery and profitability were identified. MAIN OUTCOMES MEASURE: Net financial gains or losses were calculated for each vaccine administered for each of the 19 pharmacies and for the entire supermarket chain. RESULTS: 662 vaccines were given during the study period, accounting for 6.7% of all eligible patients. The profit per vaccine averaged $9.60 (5.7%) and $28.37 (18.9%) using the broad and localized perspective models, respectively. CONCLUSION: Success of the ZOS program was demonstrated using both models. Certain factors correlated with greater profits when using the localized perspective model. PMID- 24952740 TI - Practice network-based care management for patients with type 2 diabetes and multiple comorbidities (GEDIMAplus): study protocol for a randomized controlled trial. AB - BACKGROUND: Care management interventions in the German health-care system have been evaluated with promising results, but further research is necessary to explore their full potential in the context of multi-morbidity. Our aim in this trial is to assess the efficacy of a primary care practice network-based care management intervention in improving self-care behaviour among patients with type 2 diabetes mellitus and multiple co-occurring chronic conditions. METHODS/DESIGN: The study is designed as a prospective, 18-month, multicentre, investigator blinded, two-arm, open-label, individual-level, randomized parallel-group superiority trial. We will enrol 582 patients with type 2 diabetes mellitus and at least two severe chronic conditions and one informal caregiver per patient. Data will be collected at baseline (T0), at the primary endpoint after 9 months (T1) and at follow-up after 18 months (T2). The primary outcome will be the differences between the intervention and control groups in changes of diabetes related self-care behaviours from baseline to T1 using a German version of the revised Summary of Diabetes Self-Care Activities (SDSCA-G). The secondary outcomes will be the differences between the intervention and control groups in: changes in scores on the SDSCA-G subscales, glycosylated haemoglobin A level, health-related quality of life, self-efficacy, differences in (severe) symptomatic hypoglycaemia, cost-effectiveness and financial family burden. The intervention will be delivered by trained health-care assistants as an add-on to usual care and will consist of three main elements: (1) three home visits, including structured assessment of medical and social needs; (2) 24 structured telephone monitoring contacts; and (3) self-monitoring of blood glucose levels after T1 in 3-month intervals. The control group will receive usual care. The confirmatory primary analysis will be performed following the intention-to-treat (ITT) principle. The efficacy of the intervention will be quantified using two level linear regression stratified by type of medical treatment adjusted for baseline values on the SDSCA-G. Secondary analyses will be performed according to the ITT principle. In health economic evaluations, we will estimate the incremental cost-effectiveness ratios. DISCUSSION: We hope that the results of this study will provide insights into the efficacy of practice network-based care management among patients with complex health-care needs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 83908315 (ISRCTN assigned 25 February 2014). PMID- 24952739 TI - Shared decision-making among caregivers and health care providers of youth with type 1 diabetes. AB - The present study aimed to examine perceptions of shared decision-making (SDM) in caregivers of youth with type 1 diabetes (T1D). Interview, survey data, and HbA1c assays were gathered from caregivers of 439 youth with T1D aged 3-18 years. Caregiver-report indicated high perceived SDM during medical visits. Multivariable linear regression indicated that greater SDM is associated with lower HbA1c, older child age, and having a pediatric endocrinologist provider. Multiple logistic regression found that caregivers who did not perceive having made any healthcare decisions in the past year were more likely to identify a non pediatric endocrinologist provider and to report less optimal diabetes self-care. Findings suggest that youth whose caregivers report greater SDM may show benefits in terms of self-care and glycemic control. Future research should examine the role of youth in SDM and how best to identify youth and families with low SDM in order to improve care. PMID- 24952743 TI - Marinomonas profundimaris sp. nov., isolated from deep-sea sediment sample of the Arctic Ocean. AB - A taxonomic study was carried out on strain D104(T), which was isolated from deep sea subsurface sediment sample from the Arctic Ocean. The bacterium was found to be Gram-negative, oxidase negative and catalase weakly positive, rod shaped, motile by means of polar flagellum. The organism grows between 4 and 37 degrees C (optimum 25-28 degrees C) and 0.5-6 % NaCl (optimum 3 %). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain D104(T) belongs to the genus Marinomonas, with highest sequence similarities of 97.7 % to Marinomonas ushuaiensis DSM 15871(T), followed by M. dokdonensis DSW10-10(T) (96.9 %), M. arenicola KMM 3893(T) (96.7 %), M. arctica 328(T) (96.6 %) and other 18 species of the genus Marinomonas (94.4-96.5 %). The average nucleotide identity and estimated DNA-DNA hybridization values between strain D104(T) and M. ushuaiensis DSM 15871(T) were 84.24 % and 20.80 +/- 2.33 % respectively. The principal fatty acids were C16:0, sum in feature 3 (C16:1 omega7c/C16:1 omega6c), sum in feature 8 (C18:1 omega7c/C18:1 omega6c) and C12:1 3OH. The G + C content of the chromosomal DNA was determined to be 44.8 mol%. The respiratory quinone was found to be Q8 (100 %). Polar lipids include phosphatidylglycerol and phosphatidylethanolamine as major phospholipids and aminolipid and phospholipid as minor components. The results of the genotypic and phenotypic analyses indicate that strain D104(T) represents a novel species of the genus Marinomonas, for which the name Marinomonas profundimaris sp. nov. is proposed, with the type strain D104(T) (=MCCC 1A07573(T) = LMG 27696(T)). PMID- 24952744 TI - Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis. AB - Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n=66) and high-grade dysplasia (HGD; n=43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies. PMID- 24952748 TI - Narrow-band red-emitting Sr[LiAl3N4]:Eu2+ as a next-generation LED-phosphor material. AB - To facilitate the next generation of high-power white-light-emitting diodes (white LEDs), the discovery of more efficient red-emitting phosphor materials is essential. In this regard, the hardly explored compound class of nitridoaluminates affords a new material with superior luminescence properties. Doped with Eu(2+), Sr[LiAl3N4] emerged as a new high-performance narrow-band red emitting phosphor material, which can efficiently be excited by GaN-based blue LEDs. Owing to the highly efficient red emission at lambda(max) ~ 650 nm with a full-width at half-maximum of ~1,180 cm(-1) (~50 nm) that shows only very low thermal quenching (>95% relative to the quantum efficiency at 200 degrees C), a prototype phosphor-converted LED (pc-LED), employing Sr[LiAl3N4]:Eu(2+) as the red-emitting component, already shows an increase of 14% in luminous efficacy compared with a commercially available high colour rendering index (CRI) LED, together with an excellent colour rendition (R(a)8 = 91, R9 = 57). Therefore, we predict great potential for industrial applications in high-power white pc-LEDs. PMID- 24952749 TI - Materials for bioelectronics: organic electronics meets biology. PMID- 24952750 TI - Spin voltage generation through optical excitation of complementary spin populations. AB - By exploiting the spin degree of freedom of carriers inside electronic devices, spintronics has a huge potential for quantum computation and dissipationless interconnects. Pure spin currents in spintronic devices should be driven by a spin voltage generator, able to drive the spin distribution out of equilibrium without inducing charge currents. Ideally, such a generator should operate at room temperature, be highly integrable with existing semiconductor technology, and not interfere with other spintronic building blocks that make use of ferromagnetic materials. Here we demonstrate a device that matches these requirements by realizing the spintronic equivalent of a photovoltaic generator. Whereas a photovoltaic generator spatially separates photoexcited electrons and holes, our device exploits circularly polarized light to produce two spatially well-defined electron populations with opposite in-plane spin projections. This is achieved by modulating the phase and amplitude of the light wavefronts entering a semiconductor (germanium) with a patterned metal overlayer (platinum). The resulting light diffraction pattern features a spatially modulated chirality inside the semiconductor, which locally excites spin-polarized electrons thanks to electric dipole selection rules. PMID- 24952751 TI - The 1000th VAD, the great rivalry, and the grand experiment of the Texas Medical Center. PMID- 24952747 TI - Inferring human population size and separation history from multiple genome sequences. AB - The availability of complete human genome sequences from populations across the world has given rise to new population genetic inference methods that explicitly model ancestral relationships under recombination and mutation. So far, application of these methods to evolutionary history more recent than 20,000 30,000 years ago and to population separations has been limited. Here we present a new method that overcomes these shortcomings. The multiple sequentially Markovian coalescent (MSMC) analyzes the observed pattern of mutations in multiple individuals, focusing on the first coalescence between any two individuals. Results from applying MSMC to genome sequences from nine populations across the world suggest that the genetic separation of non-African ancestors from African Yoruban ancestors started long before 50,000 years ago and give information about human population history as recent as 2,000 years ago, including the bottleneck in the peopling of the Americas and separations within Africa, East Asia and Europe. PMID- 24952746 TI - The genomic landscape of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) has extremely skewed ethnic and geographic distributions, is poorly understood at the genetic level and is in need of effective therapeutic approaches. Here we determined the mutational landscape of 128 cases with NPC using whole-exome and targeted deep sequencing, as well as SNP array analysis. These approaches revealed a distinct mutational signature and nine significantly mutated genes, many of which have not been implicated previously in NPC. Notably, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Further functional studies suggested the biological relevance of these lesions to the NPC malignant phenotype. In addition, we uncovered a number of new druggable candidates because of their genomic alterations. Together our study provides a molecular basis for a comprehensive understanding of, and exploring new therapies for, NPC. PMID- 24952752 TI - Mechanical circulatory assist device development at the Texas Heart Institute: a personal perspective. AB - In December 2013, we performed our 1000th ventricular assist device implantation at the Texas Heart Institute. In my professional career, I have been fortunate to see the development of numerous mechanical circulatory support devices for the treatment of patients with advanced heart failure. In fact, most of the cardiac pumps in wide use today were developed in the Texas Heart Institute research laboratories in cooperation with the National Heart, Lung and Blood Institute or device innovators and manufacturers and implanted clinically at our partner St. Luke's Episcopal Hospital. My early involvement in this field was guided by my mentors, Dr Michael E. DeBakey and, especially, Dr Denton A. Cooley. Also, many of the advances are directly attributable to my ongoing clinical experience. What I learned daily in my surgical practice allowed me to bring insights to the development of this technology that a laboratory researcher alone might not have had. Young academic surgeons interested in this field might be well served to be active not only in laboratory research but also in clinical practice. PMID- 24952753 TI - Integrated surgical residency initiative: implications for cardiothoracic surgery. AB - The history, conceptualization, and implementation of the integrated six year cardiothoracic residency paradigm is discussed. Emphasis is placed of critcal logistical points, as well as the challenges associated with obtaining operative case requirements. Strategies for providing and monitoring didactic and technical skills education are presented. PMID- 24952754 TI - Commentary: integrated surgical residency initiative: implications for cardiothoracic surgery. PMID- 24952755 TI - The state of the art in non-small cell lung cancer immunotherapy. AB - Once considered an ineffective modality in lung cancer, immunotherapy has emerged as one of the most promising therapeutic strategies for this lethal disease. The past few years have seen a plethora of clinical trials evaluating various immunotherapeutic approaches in lung cancer. This article discusses the current status of immunotherapy in non-small cell lung cancer with a review of completed studies and ongoing trials. PMID- 24952756 TI - Minimally invasive surgical treatment of valvular heart disease. AB - Cardiac surgery is in the midst of a practice revolution. Traditionally, surgery for valvular heart disease consisted of valve replacement via conventional sternotomy using cardiopulmonary bypass. However, over the past 20 years, the increasing popularity of less-invasive procedures, accompanied by advancements in imaging, surgical instrumentation, and robotic technology, has motivated and enabled surgeons to develop and perform complex cardiac surgical procedures through small incisions, often eliminating the need for sternotomy or cardiopulmonary bypass. In addition to the benefits of improved cosmesis, minimally invasive mitral valve surgery was pioneered with the intent of reducing morbidity, postoperative pain, blood loss, hospital length of stay, and time to return to normal activity. This article reviews the current state-of-the-art of minimally invasive approaches to the surgical treatment of valvular heart disease. PMID- 24952757 TI - The promise and challenges of cardiac stem cell therapy. AB - After an extensive myocardial infarction, restoration of heart function depends on the ability of the heart to promote regeneration and prevent adverse ventricular remodeling. Preclinical research demonstrated that the transplantation of healthy stem cells restored heart function, but the stem cells obtained from older animals or patients were not as efficacious as those from younger individuals. In this paper, we review the successes and limitations discovered in preclinical studies and clinical trials examining cell therapy for damaged hearts. After the modest successes of the early clinical trials, research is now exploring the benefits of enhanced stem cell therapy. Cell based gene therapy markedly improves the angiogenesis achieved. Rejuvenating aged stems cells prior to transplantation restores the functional benefits attained. Transplanting healthy allogeneic stem cells from young donors into aged individuals can restore function if rejection can be prevented. Finally, modulating the cellular environment in aged individuals permits the full functional benefits of stem cell therapy to be realized. Significant challenges remain, but these approaches show promise that cell therapy may become routine therapy to improve functional recovery of older patients after an extensive myocardial infarction. PMID- 24952758 TI - Current readings: Status of surgical treatment for endocarditis. AB - Valve endocarditis is associated with high morbidity and mortality and requires a thorough evaluation including early surgical consultation to identify patients who may benefit from surgery. We review 5 recent articles that highlight the current debates related to best treatment strategies for valve endocarditis. Recent publications have focused on neurologic risk assessment, timing of surgery, and prognostic factors associated with native and prosthetic valve endocarditis. The initial patient assessment and management is best performed by a multidisciplinary team. Future investigations should focus on identifying surgical candidates early and the outcomes affected by replacement valve choice in both native and prosthetic valve endocarditis. PMID- 24952759 TI - Current readings: management of N2 disease for lung cancer. AB - The optimal management of locally advanced, Stage IIIA NSCLC with N2 level nodal metastases remains challenging and controversial. A number of treatment regimens have been shown safe and effective, but existing clinical trial data frequently falls short of providing guidance to match the right approach with the right patient. We review recent literature in this area and its impact. PMID- 24952760 TI - Current readings: the role of stenting in tracheobronchial disease. AB - Airway stents have gained acceptance for palliation or treatment of tracheobronchial pathologies or both since the second half of the 20th century. However, minimal advances have been made in the last 3 decades with regard to innovations in stent technology. Following a health alert issued by the Food and Drug Administration in 2005, silicone stents are now mainly used for benign pathologies whereas self-expanding metal stents are reserved for use with malignant airway obstruction. In this article, we review 5 articles published between 2010 and 2013 addressing the roles of stents in the management of malignant, benign, and post-lung-transplantation-related tracheobronchial narrowing. We identified what were the largest or most clinically relevant series in each case, but with the understanding that all are retrospective reviews with patient selection bias. PMID- 24952745 TI - Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. AB - The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ~8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. PMID- 24952761 TI - State-of-the-art coronary artery bypass graft. PMID- 24952763 TI - Lessons learned through leadership. PMID- 24952762 TI - Genome sequences characterizing five mutations in RNA polymerase and major capsid of phages phiA318 and phiAs51 of Vibrio alginolyticus with different burst efficiencies. AB - BACKGROUND: The burst size of a phage is important prior to phage therapy and probiotic usage. The efficiency for a phage to burst its host bacterium can result from molecular domino effects of the phage gene expressions which dominate to control host machinery after infection. We found two Podoviridae phages, phiA318 and phiAs51, burst a common host V. alginolyticus with different efficiencies of 72 and 10 PFU/bacterium, respectively. Presumably, the genome sequences can be compared to explain their differences in burst sizes. RESULTS: Among genes in 42.5 kb genomes with a GC content of 43.5%, 16 out of 47 open reading frames (ORFs) were annotated to known functions, including RNA polymerase (RNAP) and phage structure proteins. 11 strong phage promoters and three terminators were found. The consensus sequence for the new vibriophage promoters is AATAAAGTTGCCCTATA, where the AGTTG bases of -8 through -12 are important for the vibriophage specificity, especially a consensus T at -9 position eliminating RNAP of K1E, T7 and SP6 phages to transcribe the genes. phiA318 and phiAs51 RNAP shared their own specific promoters. In comparing phiAs51 with phiA318 genomes, only two nucleotides were deleted in the RNAP gene and three mutating nucleotides were found in the major capsid genes. CONCLUSION: Subtle analyses on the residue alterations uncovered the effects of five nucleotide mutations on the functions of the RNAP and capsid proteins, which account for the host-bursting efficiency. The deletion of two nucleotides in RNAP gene truncates the primary translation due to early stop codon, while a second translational peptide starting from GTG just at deletion point can remediate the polymerase activity. Out of three nucleotide mutations in major capsid gene, H53N mutation weakens the subunit assembly between capsomeres for the phage head; E313K reduces the fold binding between beta-sheet and Spine Helix inside the peptide. PMID- 24952764 TI - Ask the authors. PMID- 24952765 TI - Intradiskal steroids: a viable treatment for low back pain? PMID- 24952766 TI - Parent-reported measures of child health and wellbeing in same-sex parent families: a cross-sectional survey. AB - BACKGROUND: It has been suggested that children with same-sex attracted parents score well in psychosocial aspects of their health, however questions remain about the impact of stigma on these children. Research to date has focused on lesbian parents and has been limited by small sample sizes. This study aims to describe the physical, mental and social wellbeing of Australian children with same-sex attracted parents, and the impact that stigma has on them. METHODS: A cross-sectional survey, the Australian Study of Child Health in Same-Sex Families, was distributed in 2012 to a convenience sample of 390 parents from Australia who self-identified as same-sex attracted and had children aged 0-17 years. Parent-reported, multidimensional measures of child health and wellbeing and the relationship to perceived stigma were measured. RESULTS: 315 parents completed the survey (completion rate = 81%) representing 500 children. 80% of children had a female index parent while 18% had a male index parent. Children in same-sex parent families had higher scores on measures of general behavior, general health and family cohesion compared to population normative data (beta = 2.93, 95% CI = 0.35 to 5.52, P = .03; beta = 5.60, 95% CI = 2.69 to 8.52, P = <.001; and beta = 6.01, 95% CI = 2.84 to 9.17, P = <.001 respectively). There were no significant differences between the two groups for all other scale scores. Physical activity, mental health, and family cohesion were all negatively associated with increased stigma (beta = -3.03, 95% CI = -5.86 to -0.21, P = .04; beta = -10.45, 95% CI = -18.48 to -2.42, P = .01; and beta = -9.82, 95% CI = 17.86 to -1.78, P = .02 respectively) and the presence of emotional symptoms was positively associated with increased stigma (beta =0.94, 95% CI = 0.08 to 1.81, P = .03). CONCLUSIONS: Australian children with same-sex attracted parents score higher than population samples on a number of parent-reported measures of child health. Perceived stigma is negatively associated with mental health. Through improved awareness of stigma these findings play an important role in health policy, improving child health outcomes. PMID- 24952767 TI - Transcriptomics of differential vector competence: West Nile virus infection in two populations of Culex pipiens quinquefasciatus linked to ovary development. AB - BACKGROUND: Understanding mechanisms that contribute to viral dissemination in mosquito vectors will contribute to our ability to interfere with the transmission of viral pathogens that impact public health. The expression of genes in two Culex pipiens quinquefasciatus populations from Florida with known differences in vector competence to West Nile virus (WNV) were compared using high throughput sequencing. RESULTS: A total of 15,176 transcripts were combined for comparison of expression differences between the two populations and 118 transcripts were differentially expressed (p < 0.05). The fold change in expression of the differentially expressed genes ranged from -7.5 - 6.13. The more competent population for WNV (Gainesville) over expressed 77 genes and down regulated 44 genes, compared with the less competent population for WNV (Vero Beach). Also, splicing analysis identified 3 transcripts with significantly different splice forms between the two populations. The functional analysis showed that the largest proportion of transcripts was included in the catalytic activity and transporter activity groups except for those in the unknown group. Interestingly, the up- regulated gene set contained most of the catalytic activity function and the down- regulated gene set had a notable proportion of transcripts with transporter activity function. Immune response category was shown in only the down regulated gene set, although those represent a relatively small portion of the function. Several different vitellogenin genes were expressed differentially. Based on the RNAseq data analysis, ovary development was compared across the populations and following WNV infection. There were significant differences among the compared groups. CONCLUSIONS: This study suggests that ovary development is correlated to vector competence in two Culex populations in Florida. Both populations control energy allocations to reproduction as a response to WNV. This result provides novel insight into the defense mechanism used by Culex spp. mosquitoes against WNV. PMID- 24952768 TI - Endoscopic endonasal approach for the treatment of schwannomas of the pterygopalatine fossa: case report and review of the literature. AB - INTRODUCTION: Pterygopalatine fossa (PPF) schwannomas are rare lesions most often arising from branches of the trigeminal nerve. Symptomatic lesions have been traditionally treated by conventional external approaches. However, the development of an expanded endonasal approach (EEA) enables skull base surgeons to reach these deeply seated lesions via a different route with its own advantages and drawbacks. METHODS: Case report and review of the literature. CASE DESCRIPTION: A 41-year-old woman presented with a 6-year history of right facial pain and numbness. Her symptoms had increased progressively over a year, and she recently had developed right-sided otalgia. MRI revealed a right PPF mass, hypointense on T1 and T2 sequences with homogeneous enhancement following the use of gadolinium. A biopsy, attempted at another institution, was considered non diagnostic. We totally removed the lesion through an endoscopic endonasal transmaxillary approach. Final pathology confirmed the diagnosis of schwannoma. Post-operatively, the patient noted a significant improvement of her facial pain (V2 territory). CONCLUSION: The endonasal endoscopic transmaxillary approach provides adequate access to the PPF, thus enabling safe tumor removal with less morbidity than conventional routes. PMID- 24952769 TI - Effect of flaxseed physical form on digestibility of lactation diets fed to Holstein steers. AB - Four multicannulated (rumen, duodenum, and ileum) Holstein steers (459.7+/-46.4kg of initial body weight) were used in a 4*4 Latin square design to determine the effect of flaxseed processing method on ruminal fermentation and digestibility. Treatments were based on inclusion of (1) 7.5% linseed meal (control), (2) 10% whole flaxseed, (3) 10% rolled flaxseed, or (4) 10% ground flaxseed on a dry matter (DM) basis, and were formulated to mimic typical high-producing dairy cow lactation diets. The control diet contained linseed meal in a proportion to provide crude protein (CP) equal to the amount of CP contributed by the flaxseed in the other treatments. Diets were fed for ad libitum intake and contained 30% corn silage, 17% chopped alfalfa hay, 6% sugar beet pulp, and 47% concentrate (comprising ground corn, supplemental protein, trace minerals and vitamins, and either flaxseed or linseed meal (DM basis). Diets were formulated to contain 17% CP, 34% neutral detergent fiber, 21% acid detergent fiber, and 4% fatty acid (DM basis). Periods were 14 d long and consisted of 7 d of adaptation and 7 d of sample collection. Dry matter intake (as a % of body weight) was similar (2.41+/ 0.17) for all treatments. The inclusion of flaxseed, regardless of processing method, tended to decrease total-tract organic matter digestibility relative to the linseed control, but no differences in CP intake, duodenal CP flow (bacterial, apparent feed, or total), ileal CP flow, fecal CP output, microbial efficiency, or CP digestibility (apparent ruminal, true ruminal, small intestine, large intestine, or total tract) were observed between treatments. Method of processing did not alter ruminal pH, ammonia, or volatile fatty acids production. The ground flaxseed treatment had the fastest rate of in situ DM degradation (11.25%/h), followed by the control (7.46%/h), rolled flaxseed (4.53%/h), and whole flaxseed (0.57%/h) treatments. Degradability of CP and fat followed the same pattern as DM degradability for processed flaxseed. In situ degradation rates of alfalfa hay neutral detergent fiber and acid detergent fiber tended to be fastest for the ground flaxseed treatment. Taken together, the digestibility, fermentation, and in situ data indicate that rolling and grinding are both acceptable methods of processing flaxseed. The in situ data strongly support the need for processing flaxseed before inclusion in lactation diets. PMID- 24952770 TI - Cholesterol metabolism, transport, and hepatic regulation in dairy cows during transition and early lactation. AB - The transition from the nonlactating to the lactating state represents a critical period for dairy cow lipid metabolism because body reserves have to be mobilized to meet the increasing energy requirements for the initiation of milk production. The purpose of this study was to provide a comprehensive overview on cholesterol homeostasis in transition dairy cows by assessing in parallel plasma, milk, and hepatic tissue for key factors of cholesterol metabolism, transport, and regulation. Blood samples and liver biopsies were taken from 50 multiparous Holstein dairy cows in wk 3 antepartum (a.p.), wk 1 postpartum (p.p.), wk 4 p.p., and wk 14 p.p. Milk sampling was performed in wk 1, 4, and 14 p.p. Blood and milk lipid concentrations [triglycerides (TG), cholesterol, and lipoproteins], enzyme activities (phospholipid transfer protein and lecithin:cholesterol acyltransferase) were analyzed using enzymatic assays. Hepatic gene expression patterns of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGC) synthase 1 (HMGCS1) and HMGC reductase (HMGCR), sterol regulatory element-binding factor (SREBF)-1 and 2, microsomal triglyceride transfer protein (MTTP), ATP-binding cassette transporter (ABC) A1 and ABCG1, liver X receptor (LXR) alpha and peroxisome proliferator activated receptor (PPAR) alpha and gamma were measured using quantitative RT-PCR. Plasma TG, cholesterol, and lipoprotein concentrations decreased from wk 3 a.p. to a minimum in wk 1 p.p., and then gradually increased until wk 14 p.p. Compared with wk 4 p.p., phospholipid transfer protein activity was increased in wk 1 p.p., whereas lecithin:cholesterol acyltransferase activity was lowest at this period. Total cholesterol concentration and mass, and cholesterol concentration in the milk fat fraction decreased from wk 1 p.p. to wk 4 p.p. Both total and milk fat cholesterol concentration were decreased in wk 4 p.p. compared with wk 1 and 14 p.p. The mRNA abundance of genes involved in cholesterol synthesis (SREBF-2, HMGCS1, and HMGCR) markedly increased from wk 3 a.p. to wk 1 p.p., whereas SREBF-1 was downregulated. The expression of ABCA1 increased from wk 3 a.p. to wk 1 p.p., whereas ABCG1 was increased in wk 14 p.p. compared with other time points. In conclusion, hepatic expression of genes involved in the biosynthesis of cholesterol as well as the ABCA1 transporter were upregulated at the onset of lactation, whereas plasma concentrations of total cholesterol, phospholipids, lipoprotein-cholesterol, and TG were at a minimum. Thus, at the gene expression level, the liver seems to react to the increased demand for cholesterol after parturition. Whether the low plasma cholesterol and TG levels are due to impaired hepatic export mechanisms or reflect an enhanced transfer of these compounds into the milk to provide essential nutrients for the newborn remains to be elucidated. PMID- 24952771 TI - Influence of feeding a low-phosphorus diet on leucocyte function in dairy cows. AB - Phosphorus depletion and hypophosphatemia have been described to interfere with immune function in rats and humans. In dairy cows, hypophosphatemia has been associated with muscle weakness and recumbency as well as with intravascular hemolysis resulting from increased osmotic fragility of erythrocytes, but so far, the influence of P depletion and hypophosphatemia on immune function has not been studied. Therefore, the aim of this study was to investigate whether P depletion and ensuing hypophosphatemia are associated with impaired granulocyte and lymphocyte function. Eight mid-lactation dairy cows were fed a P-deficient ration (0.2% P/kg of DM) for a period of 4wk. The depletion phase was preceded by a 2-wk acclimatization period and followed by a 2-wk repletion phase, during which the same ration was supplemented with P to meet or exceed daily requirements. Blood samples were collected at the end of the acclimatization period, after 2 and 4wk of P depletion, and at the end of the repletion phase. Plasma phosphate concentrations ([Pi]) were determined and white blood cells were counted and isolated. General immune function was investigated by performing a phagocytosis assay with Staphylococcus aureus and a lymphocyte stimulation test (LST) with concanavalin A and pokeweed mitogen. The plasma [Pi] decreased significantly, with the lowest values (mean 0.7+/-0.2mmol/L) occurring after 2wk of depletion, although depletion was continued for another 2wk. During repletion, plasma [Pi] increased above baseline concentrations. Granulocyte counts changed in parallel with plasma [Pi] over time, decreasing significantly at 2wk after P depletion and increasing again thereafter. Granulocyte survival after phagocytosis was lowest after 4wk of P depletion. Phagocytosis activity of surviving granulocytes determined by mean fluorescence intensity was higher, indicating that phagocytosis was not negatively influenced by P depletion. Lymphocyte stimulation showed a similar trend, with a decreasing stimulation index at the end of P depletion, but differences were not statistically significant. Data presented in this study indicate that hypophosphatemia leads to a decrease in granulocyte counts. Chronic P depletion impairs granulocyte survival during phagocytosis but not phagocytosis activity. Lymphocyte function is not influenced by P depletion. PMID- 24952772 TI - Short communication: effect of pomegranate-residue supplement on Cryptosporidium parvum oocyst shedding in neonatal calves. AB - Cryptosporidium parvum is considered one of the most common enteropathogens, responsible for the high incidence of diarrhea and deleterious implications on immunity and health in neonatal calves. The pomegranate is well known for its health-promoting properties. Two experiments were designed to test the antiparasitical and antidiarrheal effects of concentrated pomegranate extract (CPE) supplement in milk in neonatal Holstein calves. Forty-one calves were randomly divided into control (n=20) and treatment (n=21) groups. For the first experiment, the treatment group was supplemented with 3.75% CPE in the daily milk ration, between 3 and 14 d of age, whereas the control group received only milk. Fecal samples were collected between d 5 and 13 to quantify Cryptosporidium oocysts, and the duration and intensity of diarrhea were evaluated. Reduced fecal oocyst count and diarrhea intensity and duration were revealed in the 3.75% CPE calves. No difference was noted in average daily gain between groups. In a second experiment, which was designed to test the effect of a lower CPE concentration (0.6% of daily milk allocation), no effects on fecal oocyst count and average daily gain were observed. However, compared with control, the lower CPE group was characterized by a shorter duration of diarrhea and higher weight gain among males at 14 d of age. These results suggest that the CPE supplement-to-calf milk ratio may potentially alleviate intestinal morbidity caused by Cryptosporidium. PMID- 24952773 TI - Antigenicity and conformational changes of beta-lactoglobulin by dynamic high pressure microfluidization combining with glycation treatment. AB - The combined effect of previous dynamic high-pressure microfluidization treatment (40, 80, 120, and 160MPa) and subsequent glycation with galacto-oligosaccharides (GOS) on the antigenicity of beta-lactoglobulin (beta-LG) was investigated. The antigenicity of beta-LG-GOS decreased at relatively low pressure (<=120MPa). Surface sulfhydryl group content of beta-LG-GOS increased and surface hydrophobicity of beta-LG-GOS decreased. Additionally, protein unfolding in beta LG-GOS samples was reflected by quenching of fluorescence intensity, the red shift of fluorescence spectra, decreased UV absorption, and circular dichroism analysis, indicating tertiary and secondary structural changes of beta-LG. The conformational changes may contribute to the alteration of antigenicity. PMID- 24952774 TI - Cow characteristics and their association with production performance with different dry period lengths. AB - Shortening or omitting the dry period (DP) has been proposed as a management strategy to improve energy balance of dairy cows in early lactation. Both shortening and complete omission of the DP reduces milk production in the subsequent lactation compared with a conventional DP length of 60d. Some cows have less milk production loss than other cows after applying no DP or a short DP. The aim of this study is to evaluate which cow characteristics are associated with the amount of milk production losses following no DP or a short DP (30d). Daily production information from the lactation before and after the DP was available from 161 dairy cows (54 cows with a 0-d DP, 51 cows with a 30-d DP, and 56 cows with a 60-d DP) from a research herd. Daily production (milk, fat, and protein) until 305d in milk was estimated for all cows. Subsequently, total fat- and protein-corrected milk yield from 60d before the expected calving date until 305d in the following lactation (FPCMtotal) was estimated. A statistical analysis was performed to evaluate which cow characteristics were associated with limited or no production losses following no DP or a short DP, compared with a conventional DP length of 60d. Average FPCMtotal was 9,341, 10,499, and 10,795kg for cows with no DP, a 30-d DP, and a 60-d DP, respectively. The cow characteristics parity, daily milk production at 12wk before the expected calving date, and reduction in daily milk production between 16 and 12wk before the expected calving date were associated with production loss due to a short (30d) or no DP. Compared with 60d DP, multiparous cows had less production loss (987kg) following no DP than primiparous cows (2,132kg). The difference in FPCMtotal between the 3DP groups was largest for cows with a low milk production (e.g., 10kg/d) at 12wk before the expected calving date. The greater the reduction in milk production between 16 and 12wk before the expected calving date, the larger the difference in FPCMtotal between the 3DP groups. The difference in FPCMtotal between cows with no DP and 60d DP at a reduction in milk production between 16 and 12wk of 10% was 665kg, whereas this difference was 1,138kg at a reduction of 70%. The cow characteristics found can be used to select cows for specific DP lengths in a decision-support model to support the farmer on the economic optimal DP length for each individual cow. Output of such a decision-support model can be, for instance, to advise a 30-d DP for multiparous cows with high milk production (e.g., 25kg/d) at 12wk before the expected calving date. PMID- 24952775 TI - Gum arabic microcapsules as protectors of the photoinduced degradation of riboflavin in whole milk. AB - Microcapsules (MC) made with gum arabic (GA) as shell material without and with beta-carotene (betac) as core material were prepared by the spray-drying technique. The effect of these MC on the photodegradation of riboflavin (Rf) in whole milk by fluorescent daylight lamp irradiation was evaluated at a storage temperature of 4 degrees C. The additions of 1.37mg/mL of MC without betac (MC GA) and with 0.54MUg/mL of betac (MC-betac-GA) decreased the apparent first-order rate constant of Rf photodegradation by approximately 26 and 30%, respectively. A systematic kinetic and mechanistic analysis of the results indicates that the global protective effect of the MC is mainly due to the combination of quenching of the electronically excited triplet state of Rf and scavenging of the photogenerated reactive oxygen species, such as singlet molecular oxygen, superoxide radical anion and hydroxyl radical. A minor contribution to the photoprotective effect can be also associated with the inner-filter effect exerted by the MC, which partially blocks the direct excitation of Rf. These results allow us to conclude that photodegradation of Rf in milk can be considerably reduced by the addition of small amounts of MC, avoiding large losses in the nutritional value of milk. PMID- 24952776 TI - Biopreservation of Fior di Latte cheese. AB - In this study a new biopreservation system consisting of an active sodium alginate coating containing Lactobacillus reuteri applied to Fior di Latte cheese was studied. The final aim was to extend cheese shelf life by the in situ production of reuterin. Experimental trials were carried out with and without glycerol. How the fermentation time could improve the production of reuterin, enabling Fior di Latte shelf life, was also assessed. To this aim, the experimental analyses were conducted in 2 different trials, using 2 different production batches of samples. In the first one, Fior di Latte samples were dipped into the active sodium alginate solution prepared on the same day of their production, whereas in the second trial, samples were dipped into the active solution prepared 48h before their production to allow a proper fermentation of the inoculated microorganism. Microbiological and sensory quality indices were monitored to prove the effectiveness of biopreservation on product quality during storage. In the first trial, the combination of the probiotic microorganism with glycerol improved the microbial quality by 1 d compared with the same active solution without glycerol, whereas the 48-h-fermented active alginate solution (second trial) showed a further improved microbial quality. The application of an active coating enriched with L. reuteri and glycerol to Fior di Latte cheese is an optimal and innovative way to preserve the product and at the same time, with a combination of an optimal fermentation time, to prolong its microbial quality and thus its shelf life. PMID- 24952777 TI - Effect of planting density on nutritional quality of green-chopped corn for silage. AB - The objective of this on-farm study was to determine the effect of corn planting density on the nutritional quality of whole-plant corn for silage. This study was performed in a commercial 1,900-cow dairy farm located in Piedritas (Buenos Aires, Argentina). Two commercial hybrids (A and B) were planted in experimental plots within a cornfield destined for corn silage. Hybrids were sown at a theoretical seeding rate of 60,000, 70,000, 80,000, and 90,000 seeds/ha in 4 replicates per hybrid. Plots were eight 50-m-long rows separated by 52cm. Corn was planted with a no-till seeder equipped with a pneumatic dosing machine. Ten plants within each plot were cut by hand at 15cm above ground. Whole plants were chopped, weighed, mixed thoroughly, and frozen until analysis. Nutritional composition was determined by near-infrared reflectance spectroscopy. Harvesting occurred at one-quarter milk-line [31.4% dry matter (DM)] and one-half milk-line (34.5% DM) stages of maturity for hybrids B and A, respectively. No interactions between hybrid and planting density were observed for any of the variables of interest. Planting density did not affect either plant DM weight or DM, crude protein, neutral detergent fiber, acid detergent fiber, or starch concentrations of whole-plant corn. Dry matter yield was significantly increased at higher planting densities. The similar per-plant biomass and nutritional quality among different densities can be explained by the abundant precipitation observed during this growing season (719mm since the beginning of fallow until harvest). In conclusion, greater yields of silage can be obtained by increasing corn planting density without affecting its nutritional composition, although the effect of planting density with limiting resources (e.g., precipitation) still needs to be elucidated. PMID- 24952778 TI - Grape marc reduces methane emissions when fed to dairy cows. AB - Grape marc (the skins, seeds, stalk, and stems remaining after grapes have been pressed to make wine) is currently a by-product used as a feed supplement by the dairy and beef industries. Grape marc contains condensed tannins and has high concentrations of crude fat; both these substances can reduce enteric methane (CH4) production when fed to ruminants. This experiment examined the effects of dietary supplementation with either dried, pelleted grape marc or ensiled grape marc on yield and composition of milk, enteric CH4 emissions, and ruminal microbiota in dairy cows. Thirty-two Holstein dairy cows in late lactation were offered 1 of 3 diets: a control (CON) diet; a diet containing dried, pelleted grape marc (DGM); and a diet containing ensiled grape marc (EGM). The diet offered to cows in the CON group contained 14.0kg of alfalfa hay dry matter (DM)/d and 4.3kg of concentrate mix DM/d. Diets offered to cows in the DGM and EGM groups contained 9.0kg of alfalfa hay DM/d, 4.3kg of concentrate mix DM/d, and 5.0kg of dried or ensiled grape marc DM/d, respectively. These diets were offered individually to cows for 18d. Individual cow feed intake and milk yield were measured daily and milk composition measured on 4d/wk. Individual cow CH4 emissions were measured by the SF6 tracer technique on 2d at the end of the experiment. Ruminal bacterial, archaeal, fungal, and protozoan communities were quantified on the last day of the experiment. Cows offered the CON, DGM, and EGM diets, ate 95, 98, and 96%, respectively, of the DM offered. The mean milk yield of cows fed the EGM diet was 12.8kg/cow per day and was less than that of cows fed either the CON diet (14.6kg/cow per day) or the DGM diet (15.4kg/cow per day). Feeding DGM and EGM diets was associated with decreased milk fat yields, lower concentrations of saturated fatty acids, and enhanced concentrations of mono- and polyunsaturated fatty acids, in particular cis-9,trans-11 linoleic acid. The mean CH4 emissions were 470, 375, and 389g of CH4/cow per day for cows fed the CON, DGM, and EGM diets, respectively. Methane yields were 26.1, 20.2, and 21.5g of CH4/kg of DMI for cows fed the CON, DGM, and EGM diets, respectively. The ruminal bacterial and archaeal communities were altered by dietary supplementation with grape marc, but ruminal fungal and protozoan communities were not. Decreases of approximately 20% in CH4 emissions and CH4 yield indicate that feeding DGM and EGM could play a role in CH4 abatement. PMID- 24952779 TI - Genetic merit for fertility traits in Holstein cows: V. Factors affecting circulating progesterone concentrations. AB - This study investigated the factors affecting circulating progesterone (P4) concentrations in cows with similar genetic merit for milk production traits, but with extremes of good (Fert+) or poor (Fert-) genetic merit for fertility traits. Study 1: 28 cows were enrolled in an ovulation synchronization protocol at 61+/ 13 (+/-standard deviation) days postpartum, and data are presented for 13 Fert+ and 9 Fert- cows that remained in the study. Progesterone concentrations were determined from d 0 to 9 (d 0=estrus) and on d 7, corpus luteum (CL) volume and blood flow area (BFA) were measured by B-mode and Doppler ultrasonography, respectively. Cows were administered PGF2alpha on d 7 in the p.m. and d 8 in the a.m. to regress the CL, and 2 controlled internal drug release devices were inserted per vaginum on d 8 in the a.m. Liver biopsies were collected on d 9 and hepatic mRNA abundance of genes involved in P4 catabolism was determined. On d 10, the controlled internal drug release inserts were removed and frequent blood samples were collected to measure the rate of decline in circulating P4. The Fert+ cows tended to have greater dry matter intake compared with Fert- cows (+0.79kg of dry matter/d), but similar milk production (29.82kg/d). After synchronized ovulation, the rate of increase in circulating P4 concentrations was greater in Fert+ cows compared with Fert- cows. No effect of genotype on CL volume was detected, but BFA was 42% greater in Fert+ cows compared with Fert- cows. The Fert- cows had greater mRNA abundance of cytochrome P450, family 3, subfamily A (CYP3A) compared with Fert+ cows, but the mRNA abundance of aldo-keto reductase family 1, member C1 (AKR1C1), AKR1C3, AKR1C4, and cytochrome P450, family 2, subfamily C (CYP2C) were similar. The half-life and metabolic clearance rate of P4 were similar in Fert+ cows and Fert- cows. Study 2: 23 cows were enrolled in an ovulation synchronization protocol at 55+/-7 (+/-standard deviation) d postpartum, and data are presented for 13 Fert+ and 8 Fert- cows that remained in the study. On d 4, 7, 10, and 13 (d 0=estrus), CL volume and BFA were measured as in study 1. Progesterone concentrations were measured from d 1 to 13. Corpus luteum volume was 41% greater in Fert+ cows compared with Fert- cows but no effect of genotype on BFA was detected. Mean circulating P4 concentrations were 79% greater in Fert+ cows compared with Fert- cows. Milk yield was similar in both genotypes. The results indicate that greater circulating P4 concentrations were primarily due to greater CL P4 synthetic capacity rather than differences in P4 clearance in this lactating cow genetic model of fertility. PMID- 24952780 TI - Efficacy of ampicillin trihydrate or ceftiofur hydrochloride for treatment of metritis and subsequent fertility in dairy cows. AB - Our objectives were to evaluate the efficacy of ampicillin trihydrate for the treatment of metritis in dairy cows compared with ceftiofur hydrochloride and the subsequent effects on pregnancy at first insemination (P/AI). Cows in the first 12 d in milk (DIM) with a uterine discharge score of 5 (watery, reddish or brownish discharge of foul smell) and rectal temperature <39.5 degrees C were diagnosed with metritis based on the fetid discharge, and cows with metritis and rectal temperature >=39.5 degrees C were diagnosed as having puerperal metritis. Cows with metritis (n=528) were blocked by parity and type of metritis as fetid discharge or puerperal metritis and, within each block, assigned randomly to receive 11mg/kg of ampicillin (n=259) or 2.2mg/kg of ceftiofur (n=269) once daily for 5 d. Day of diagnosis of metritis was considered study d 1. A cohort of 268 cows without metritis was selected randomly at 12 DIM. Rectal temperature was measured in cows with metritis on study d 1 to 7, and 12, and vaginal discharge was scored on study d 5, 7, and 12. Metritis cure was characterized by vaginal discharge score of <5 or by vaginal discharge score of <5 and no fever. At 32+/-3 DIM, vaginal discharge was scored for diagnosis of purulent vaginal discharge. At 39+/-3 DIM, endometrial cytology was performed. At 53+/-3 and 67+/-3 DIM, ovaries were scanned to determine estrous cyclicity. Pregnancy was evaluated after the first AI. Cure of metritis based on vaginal discharge <5 was greater for ampicillin than ceftiofur on d 5 (37.1 vs. 25.2%) and 7 (57.2 vs. 46.3%), but not on d 12 (82.0 vs. 85.0%). Cure of metritis based on vaginal discharge <5 and no fever was greater for ampicillin than for ceftiofur only on d 7 (50.4 vs. 37.9%), but not on d 5 (23.1 vs. 17.6%) and 12 (66.1 vs. 67.4%). Cows with puerperal metritis had reduced cure compared with cows with fetid discharge on d 5 (30.5 vs. 12.8%), 7 (55.2 vs. 33.6%), and 12 (72.0 vs. 61.1%). The proportion of cows with fever on any day after therapy started did not differ between treatments. Fifty-three percent of cows with metritis based on fetid discharge developed fever after initiating antimicrobial therapy. Cows receiving ampicillin had less prevalence of purulent vaginal discharge than those treated with ceftiofur (57.7 vs. 67.8%), but they were both greater than cows without metritis (21.9%). Prevalence of cytological endometritis did not differ between ampicillin and ceftiofur (30.0 vs. 25.4%), but they were both greater than cows without metritis (14.5%). The proportion of estrous cyclic cows (75.0%) and P/AI did not differ among treatments (ampicillin=28.0% vs. ceftiofur=28.3% vs. without metritis=30.5%). Clinical cure was faster for ampicillin than for ceftiofur, but on study d 12 both treatments resulted in similar cure. Clinical cure was less for cows with puerperal metritis than for cows with fetid uterine discharge. Despite differences in uterine health, P/AI at the first insemination did not differ among treatments. PMID- 24952782 TI - Calving traits, milk production, body condition, fertility, and survival of Holstein-Friesian and Norwegian Red dairy cattle on commercial dairy farms over 5 lactations. AB - The objective of this study was to compare calving traits, BCS, milk production, fertility, and survival of Holstein-Friesian (HF) and Norwegian Red (NR) dairy cattle in moderate-concentrate input systems. The experiment was conducted on 19 commercial Northern Ireland dairy farms, and involved 221 HF cows and 221 NR cows. Cows completed 5 lactations during the experiment, unless they died or were culled or sold. Norwegian Red cows had a lower calving difficulty score than HF cows when calving for the first and second time, but not for the third and fourth time. At first calving, the incidence of stillbirths for NR cows was 4%, compared with 13% for HF cows, whereas no difference existed between breeds in the proportion of calves born alive when calving for the second time. When calving for the first time, NR cows had a poorer milking temperament than HF cows, whereas milking temperament was unaffected by breed following the second calving. Holstein-Friesian cows had a higher full-lactation milk yield than NR cows, whereas NR cows produced milk with a higher milk fat and protein content. Full lactation fat + protein yield was unaffected by genotype. Norwegian Red cows had a lower somatic cell score than HF cows during all lactations. Although NR cattle had a higher BCS than the HF cows during lactations 1 and 2, no evidence existed that the 2 genotypes either lost or gained body condition at different rates. Conception rates to first artificial insemination were higher with the NR cows during lactations 1 to 4 (57.8 vs. 40.9%, respectively), with 28.5% of HF cows and 11.8% of NR cows culled as infertile before lactation 6. A greater percentage of NR cows calved for a sixth time compared with HF cows (27.2 vs. 16.3%, respectively). In general, NR cows outperformed HF cows in traits that have been historically included in the NR breeding program. PMID- 24952781 TI - Invited review: effect, persistence, and virulence of coagulase-negative Staphylococcus species associated with ruminant udder health. AB - The aim of this review is to assess the effect of coagulase-negative staphylococci (CNS) species on udder health and milk yield in ruminants, and to evaluate the capacity of CNS to cause persistent intramammary infections (IMI). Furthermore, the literature on factors suspected of playing a role in the pathogenicity of IMI-associated CNS, such as biofilm formation and the presence of various putative virulence genes, is discussed. The focus is on the 5 CNS species that have been most frequently identified as causing bovine IMI using reliable molecular identification methods (Staphylococcus chromogenes, Staphylococcus simulans, Staphylococcus haemolyticus, Staphylococcus xylosus, and Staphylococcus epidermidis). Although the effect on somatic cell count and milk production is accepted to be generally limited or nonexistent for CNS as a group, indications are that the typical effects differ between CNS species and perhaps even strains. It has also become clear that many CNS species can cause persistent IMI, contrary to what has long been believed. However, this trait appears to be quite complicated, being partly strain dependent and partly dependent on the host's immunity. Consistent definitions of persistence and more uniform methods for testing this phenomenon will benefit future research. The factors explaining the anticipated differences in pathogenic behavior appear to be more difficult to evaluate. Biofilm formation and the presence of various staphylococcal virulence factors do not seem to (directly) influence the effect of CNS on IMI but the available information is indirect or insufficient to draw consistent conclusions. Future studies on the effect, persistence, and virulence of the different CNS species associated with IMI would benefit from using larger and perhaps even shared strain collections and from adjusting study designs to a common framework, as the large variation currently existing therein is a major problem. Also within species variation should be investigated. PMID- 24952783 TI - Cost structure and profitability of Assaf dairy sheep farms in Spain. AB - Twenty dairy sheep farms of Assaf breed, located in the Spanish autonomous community of Castilla y Leon and included in a group receiving technical support, were used to study their production cost structure and to assess their economic profitability during 2009. On average, farms had 89.2+/-38.0 ha (own, 38%), 592+/ 63 ewes, yielded 185.9+/-21.1*10(3) L/yr (i.e., 316+/-15 L/ewe), and were attended by 2.3+/-0.2 annual working units (family, 72%). Total annual income was ?194.4+/-23.0*10(3)/yr (?1.0=$1.3) from milk (78.6%), lamb (13.2%), culled ewes (0.5%), and other sales (0.8%, wool and manure), and completed with the European Union sheep subsidy (6.9%). Total costs were ?185.9+/-19.0*10(3)/yr to attend to feeding (61.6%), labor (18.2%), equipment maintenance and depreciation (7.6%), finances (3.0%), animal health (2.5%), energy, water and milking supplies (2.2%), milk recording (0.5%), and other costs (4.4%; assurances, shearing, association fees, and so on). Mean dairy sheep farm profit was ?8.5+/-5.8*10(3)/yr (?7.4+/ 8.3/ewe) on average, and varied between -?40.6 and ?81.1/ewe among farms. Only 60% of farms were able to pay all costs, the rest had negative balances. Nevertheless, net margin was ?31.0+/-6.5*10(3)/yr on average, varying between ?0.6 and ?108.4*10(3)/yr among farms. In this case, without including the opportunity costs, all farms had positive balances. Total annual cost (TAC; ?/ewe) and total annual income (TAI; ?/ewe) depended on milk yield (MY; L/ewe) and were TAC=161.6 + 0.502 MY (R(2)=0.50), and TAI=78.13 + 0.790 MY (R(2)=0.88), respectively, with the break-even point being 291 L/ewe. Conversely, farm TAC (?/yr) and farm TAI (?/yr) were also predicted as a function of the number of ewes (NOE) per flock, as TAC=18,401 + 282.8 NOE (R(2)=0.89) and TAI=330.9 NOE (R(2)=0.98), with the break-even point being 383 ewes/flock. Finally, according to the increasing trend expected for agricultural commodity prices, it was calculated that a 10% increase of concentrate price will require 5.2% milk price increase for constant profit. Similarly, a 10% increase of forage price will require 2.0% milk price increase to maintain profitability. Under these scenarios of increasing the commodity prices of key feedstuffs, a change of flock feeding should be expected to compensate the losses in farm profitability. Most Assaf dairy sheep farms studied were economically profitable, with flock size, milk yield, and feeding costs key for their profitability. PMID- 24952784 TI - Study of progesterone and cortisol concentrations in the Italian Friesian claw. AB - The present research was conducted to study progesterone and cortisol concentrations in the claw of cattle and to verify whether the cattle claw could be considered an efficient matrix to provide retrospective information regarding progesterone and cortisol concentrations related to pregnancy and peripartum periods. These 2 steroids are involved in hoof growth. The study was performed on 32 calves and 24 pregnant milking cows of the Holstein breed, which were clinically healthy and lacking any claw disorders. Samples of at least 0.5cm in thickness were taken from the sole. Progesterone and cortisol concentrations were determined by RIA. The cortisol concentration in the horny shoe of calves from 0 to 30 d of age was significantly higher than the concentration at 31 to 60 and 61 to 120 d of age. Conversely, the progesterone concentration showed no statistically significant difference in relation to age. The horn progesterone concentrations recorded in the milking dairy cows at 7 mo of pregnancy showed high variability in the horizontal sections of the sole (the individual coefficient of variation ranged between 0.09 and 1.11). In 6 cows, genuine extreme values (genuine outliers) of the progesterone level were found. Moreover, significant differences existed among the progesterone concentrations of the sole's transverse sections. We detected a significant positive correlation between the weight of the horn samples after freeze-drying and their weight after hydration. The cortisol and progesterone levels in soaked horn samples were found to be significantly lower than in the same dry samples. These results show that cortisol and progesterone can be measured in the cattle claw horn. The claws of mature dairy cows could not be used as a matrix to provide a retrospective measure of cumulative hormone secretion, whereas the analysis of the calves' claw horns showed retrospective hormonal information similar to hair samples. PMID- 24952785 TI - Prepartum stocking density: effects on metabolic, health, reproductive, and productive responses. AB - The objectives of the current experiment were to determine the effects of 2 prepartum stocking densities on milk yield, concentration of metabolites during the peripartum period, and health and reproductive parameters of dairy cows. Jersey cows enrolled in the experiment at 254+/-3 d of gestation were balanced for parity (nulliparous vs. parous) and previous lactation projected 305-d mature equivalent milk yield (parous) and assigned to 1 of 2 treatments: 80% headlock stocking density (80SD; 38 animals/48 headlocks) and 100% headlock stocking density (100SD; 48 animals/48 headlocks). The number of experimental units was 8 (4 replicates and 2 pens/treatment per replicate). In total, 154 nulliparous and 184 parous animals were enrolled in the 80SD treatment and 186 nulliparous and 232 parous animals were enrolled in the 100SD treatment. At the start of each replicate, treatments were switched within pen. Cows were milked thrice daily and monthly milk yield, fat and protein content, and somatic cell count data were recorded up to 155 d postpartum. Plasma nonesterified fatty acid concentration was measured weekly, from -18+/-3 to 17+/-3 d relative to calving, and plasma beta-hydroxybutyrate was measured weekly, from 1+/-2 to 17+/-3 d relative to calving. Cows were examined 1, 4+/-1, 7+/-1, 10+/-1, and 13+/-1 d relative to calving for diagnosis of uterine diseases. Blood was sampled for determination of progesterone concentration and resumption of ovarian cycles 35+/-3 and 45+/-3 d relative to calving. Average headlock (74.1+/-0.4 vs. 94.5+/-0.3%) and stall (80.8+/-0.4 vs. 103.1+/-0.4%) stocking density was lower for the 80SD treatment compared with the 100SD treatment. Treatment did not affect incidence of retained fetal membranes (80SD=5.1, 100SD=7.8%), metritis (80SD=21.2, 100SD=16.7%), acute metritis (80SD=9.9, 100SD=9.4%), and vaginal purulent discharge (80SD=5.8, 100SD=7.9%). Concentrations of nonesterified fatty acids (80SD=251.5+/-6.1, 100SD=245.9+/-5.6MUmol/L) and beta-hydroxybutyrate (80SD=508.2+/-14.3, 100SD=490.9+/-13.6MUmol/L) were not different between treatments. Treatment had no effect on percentage of cows removed from the herd on the first 60 d postpartum (80SD=6.1, 100SD=5.1%) and on rate of removal from the herd up to 305 d postpartum 80SD=referent, 100SD [adjusted hazard ratio (95% confidence interval)]=1.02 (0.75, 1.38). Percentages of cows pregnant to first (80SD=41.9, 100SD=48.4%) and second (80SD=49.3, 100SD=42.0%) postpartum AI were not different between treatments. Finally, treatment did not affect energy-corrected milk yield up to 155 d postpartum (80SD=33.8+/-0.5, 100SD=33.4+/-0.5kg/d). In herds with weekly or twice weekly movement of new cows to the prepartum pen and separate housing of nulliparous and parous animals, a target stocking density of 100% of headlocks on the day of movement is not expected to affect health, metabolic, reproductive, and productive parameters. PMID- 24952786 TI - DNA intercalator BMH-21 inhibits RNA polymerase I independent of DNA damage response. AB - DNA intercalation is a major therapeutic modality for cancer therapeutic drugs. The therapeutic activity comes at a cost of normal tissue toxicity and genotoxicity. We have recently described a planar heterocyclic small molecule DNA intercalator, BMH-21, that binds ribosomal DNA and inhibits RNA polymerase I (Pol I) transcription. Despite DNA intercalation, BMH-21 does not cause phosphorylation of H2AX, a key biomarker activated in DNA damage stress. Here we assessed whether BMH-21 activity towards expression and localization of Pol I marker proteins depends on DNA damage signaling and repair pathways. We show that BMH-21 effects on the nucleolar stress response were independent of major DNA damage associated PI3-kinase pathways, ATM, ATR and DNA-PKcs. However, testing a series of BMH-21 derivatives with alterations in its N,N-dimethylaminocarboxamide arm showed that several derivatives had acquired the property to activate ATM- and DNA-PKcs -dependent damage sensing and repair pathways while their ability to cause nucleolar stress and affect cell viability was greatly reduced. The data show that BMH-21 is a chemically unique DNA intercalator that has high bioactivity towards Pol I inhibition without activation or dependence of DNA damage stress. The findings also show that interference with DNA and DNA metabolic processes can be exploited therapeutically without causing DNA damage. PMID- 24952787 TI - A novel scoring system to predict the development of necrotizing enterocolitis totalis in premature infants. AB - BACKGROUND/PURPOSE: Necrotizing enterocolitis totalis (NEC-totalis) is the severest form of NEC, with mortality rate of almost 100% even in the busiest neonatal centers. Despite such a prognosis, its risk factors remain elusive. We seek to identify clinical and laboratory parameters that differentiate NEC totalis from NEC, and to use these factors to develop a scoring system to identify patients at risk for NEC-totalis upon presentation. METHOD: NEC patients were identified from our electronic medical record using ICD9 code. Diagnosis of NEC-totalis was based on operative and autopsy reports. Patients were divided into 2 groups: NEC-but-no-totalis and NEC-totalis. Clinical/laboratory data were obtained for each group. T-test, multivariate logistic regression and backward stepwise regression analysis were performed to identify risk factors for NEC totalis and these risk factors were formulated into a "Totalis Score." RESULT: Among 157 NEC patients, 13 had NEC-totalis. NEC-totalis patients, compared to NEC alone, had fewer platelets, older age at diagnosis of NEC and greater phosphorus and creatinine levels. A 0-5 point scale "Totalis Score" based on these risk factors had sensitivity of 92% and a specificity of 78% for the diagnosis of NEC totalis. CONCLUSION: Low platelet, high phosphorus, high creatinine and older age at diagnosis of NEC were associated with a greater risk of developing NEC totalis. PMID- 24952788 TI - Glutamine downregulates TLR-2 and TLR-4 expression and protects intestinal tract in preterm neonatal rats with necrotizing enterocolitis. AB - BACKGROUND/PURPOSE: Toll-like receptor (TLR)-4 and TLR-2 play an essential role in the pathogenesis of necrotizing enterocolitis (NEC). In this study, we investigated the protective effect of glutamine (Gln) in an NEC neonatal rat model, and the potential association with TLR-4 and TLR-2 expression in local intestinal tissues. METHODS: Preterm neonatal rats were randomly divided into 3 groups: normal control; NEC model; and NEC plus Gln intervention. NEC was induced by feeding with artificial milk substitutes, plus exposure to hypoxia and cold stress. All preterm rats were sacrificed at 3 days after birth. The intestinal tissues were taken for pathological analysis. Protein and mRNA expression of TLR 2, TLR-4, and caspase-3 was examined by immunohistochemistry and real-time RT PCR, respectively. RESULTS: Compared with the normal control, the NEC neonatal rats showed mucosal injury and upregulated mRNA and protein expression of TLR-2, TLR-4, and caspase-3 in ileum and colon. Gln intervention significantly reduced the mucosal injury and suppressed the upregulated expression of TLR-2, TLR-4, and caspace-3 in the ileum and colon of NEC neonatal rats. CONCLUSIONS: Gln protects the intestinal tract of NEC neonatal rats, which may be associated with the reduction of TLR-2 and TLR-4 expression in intestines. PMID- 24952789 TI - Near infrared spectroscopy: experience on esophageal atresia infants. AB - OBJECTIVE: Near infrared spectroscopy (NIRS) gradually became the gold standard to guide anesthetic conduction during cardiac surgery, and nowadays, it is commonly utilized to monitor cerebral oxygenation during invasive procedures. Preterm babies also benefit from this non-invasive monitoring to prevent neurological sequelae. However, few data are available on NIRS perioperative changes in newborn operated on for major non-cardiac malformations. Aim of the present study is to evaluate the usefulness of NIRS assessment during and after esophageal atresia (EA) correction and its correlation with clinical behavior. PATIENTS AND METHODS: All patients treated for EA from May 2011 were prospectively enrolled in the study. All infants underwent "open" correction of EA and cerebral and splanchnic NIRS was applied up to 48h after surgery. Body temperature, blood pressure, pH, paSO2, paCO2, and urine output, were recorded during NIRS registration. Mann-Whitney test and 1-way ANOVA (Kruskal-Wallis and Dunn's multiple comparison tests) were used as appropriate. RESULTS: Seventeen patients were enrolled into the study and 13 were available for the analysis. Four patients were excluded because of poor NIRS registration. Cerebral and renal NIRS values significantly decreased at 24h post-operatively (p<0.05). Interestingly, all parameters studied as possible confounders in NIRS remained stable during the study period. Urine output significantly decreased. CONCLUSION: Our data confirmed that perioperative monitoring of tissue oxygenation during neonatal esophageal surgery is feasible. Cerebral and renal NIRS evaluation, as for cardiac patients, may guide anesthetic conduction and postoperative care. Out data suggest a newly observed hemodynamic reorganization during esophageal surgery involving renal and, probably, splanchnic blood flow redistribution, demonstrated by the observed subsequent significant post-operative transitory decrease in urinary output. Reducing the decrement in cerebral and renal NIRS values may improve, and ideally eliminate, the well-known late sequelae linked to hemodynamic changes during surgery. More studies are needed to better understand the causes of the NIRS described hemodynamic changes and, therefore, correct them. PMID- 24952790 TI - Comparison of long-term outcomes between open and laparoscopic Thal fundoplication in children. AB - OBJECTIVES: In recent years laparoscopic fundoplication is increasingly performed in pediatric surgery. The aim of this study was to compare the long-term outcomes between open and laparoscopic Thal fundoplication in children. METHODS: This retrospective study includes children who underwent a Thal fundoplication between 3/1997 and 7/2009. The minimum follow-up time to enter the study was 2 years; the overall median follow-up was 77 months (range, 29-176 months). RESULTS: A total of 101 patients were included, of which 47 underwent an open and 54 a laparoscopic Thal. Intraoperative problems, early postoperative complications, time to establish enteral feeds and length of stay did not differ among both groups. The mean duration of surgery was significantly less in the open group (OPG) (108.0 (+/- 7.72) versus 144.1 (+/- 6.36) minutes; p=0.001) and this was mainly attributed to patients with neurological problems. Severe dysphagia requiring endoscopy was observed in 10 patients, but this did not differ significantly between groups (n=2 in the OPG vs. n=8 in the laparoscopic group (LAPG); p=0.10). Overall 12 patients (11.9%) (6 in each group) required a redo fundoplication after a median of 18.7 months (range, 6-36 months). In the whole study group, 80 patients (79.2%) were classified as having surgical results being excellent, good or satisfactory and this did not differ significantly between groups. CONCLUSIONS: In the long-term open and laparoscopic Thal fundoplication have similarly good outcomes. The laparoscopic approach can be considered as an alternative, however there is not a clear superiority compared with the open counterpart. PMID- 24952791 TI - Lung biopsy for chronic pulmonary disease in children. AB - INTRODUCTION AND OBJECTIVES: Lung biopsy is frequently used in the management of children with chronic pulmonary disease to obtain a histological diagnosis. We further evaluate the role of lung biopsy by reviewing our experience of this procedure. METHODS: A retrospective case-note review was carried out of all patients in our regional service under 16 years who underwent a lung biopsy from 1998 to 2011. RESULTS: Thirty-three children (12 boys) (median 5 years 5 months, range 2 months to 16 years) underwent lung biopsy in the period studied. Following the procedure, 17 patients required ventilation on the intensive care unit for a median of two days (range 1-56 days). Complication rate was 30% (10/33); seven simple pneumothoraces, one tension pneumothorax, and one pneumonia (one child experienced more than one complication). The operative mortality was 12% (4/33). Three children (9%) died within 28 days of surgery. Twenty-six (79%) biopsies provided a definitive histological diagnosis. In 16 (48%) children, the working diagnosis and treatment were changed following lung biopsy. CONCLUSION: Lung biopsy has an important role in the management of children with chronic pulmonary disease. However, it carries significant risks which must be considered when assessing the need for histological diagnosis. PMID- 24952792 TI - Congenital pyloric atresia, presentation, management, and outcome: a report of 20 cases. AB - BACKGROUND: Congenital pyloric atresia (CPA) is a very rare anomaly. It is usually seen as an isolated condition with excellent prognosis. Few cases are familial. These are usually associated with other hereditary conditions and have a poor prognosis. This is a review of our experience with 20 patients with CPA outlining aspects of diagnosis, associated anomalies and management. PATIENTS AND METHODS: This is a retrospective analysis of 20 cases seen over a 22 year period (December 1990 to December 2012). Their records reviewed for: age, sex, presentation, prenatal history, associated anomalies, investigations, treatment, operative findings and the outcome. RESULTS: 20 cases (9 Males, 11 Females) were treated. 7 patients were full term and the remaining 13 were prematures. Their mean birth weight was 2.1 kg (1.1 kg to 3.9 kg). Polyhydramnios was seen in 13 patients (65%). Two were brothers and four were members of the same family. Isolated CPA was seen in 7 (35%); 13 had an associated conditions: epidermolysis bullosa (EB) in 8 (40%) and multiple intestinal atresias (MIA) in 5 (25%). Three patients had associated esophageal atresia. All were operated on except two who died early due to unrelenting sepsis. The variety of pyloric atresias encountered were as follows: pyloric diaphragm in 13 including double diaphragms in 2, pyloric atresia with a gap in 4 and pyloric atresia without gap in 3. Ten died postoperatively giving an overall survival of 40%. CONCLUSIONS: CPA is a very rare condition. Isolated CPA carries a good prognosis. Association of CPA with other familial and congenital anomalies like EB and MIA carries a poor prognosis. PMID- 24952793 TI - Risk of incomplete pyloromyotomy and mucosal perforation in open and laparoscopic pyloromyotomy. AB - BACKGROUND: Despite randomized controlled trials and meta-analyses, it remains unclear whether laparoscopic pyloromyotomy (LP) carries a higher risk of incomplete pyloromyotomy and mucosal perforation compared with open pyloromyotomy (OP). METHODS: Multicenter study of all pyloromyotomies (May 2007-December 2010) at nine high-volume institutions. The effect of laparoscopy on the procedure related complications of incomplete pyloromyotomy and mucosal perforation was determined using binomial logistic regression adjusting for differences among centers. RESULTS: Data relating to 2830 pyloromyotomies (1802 [64%] LP) were analyzed. There were 24 cases of incomplete pyloromyotomy; 3 in the open group (0.29%) and 21 in the laparoscopic group (1.16%). There were 18 cases of mucosal perforation; 3 in the open group (0.29%) and 15 in the laparoscopic group (0.83%). The regression model demonstrated that LP was a marginally significant predictor of incomplete pyloromyotomy (adjusted difference 0.87% [95% CI 0.006 4.083]; P=0.046) but not of mucosal perforation (adjusted difference 0.56% [95% CI -0.096 to 3.365]; P=0.153). Trainees performed a similar proportion of each procedure (laparoscopic 82.6% vs. open 80.3%; P=0.2) and grade of primary operator did not affect the rate of either complication. CONCLUSIONS: This is one of the largest series of pyloromyotomy ever reported. Although laparoscopy is associated with a statistically significant increase in the risk of incomplete pyloromyotomy, the effect size is small and of questionable clinical relevance. Both OP and LP are associated with low rates of mucosal perforation and incomplete pyloromyotomy in specialist centers, whether trainee or consultant surgeons perform the procedure. PMID- 24952794 TI - The "weekend effect" in pediatric surgery - increased mortality for children undergoing urgent surgery during the weekend. AB - BACKGROUND: For a number of pediatric and adult conditions, morbidity and mortality are increased when patients present to the hospital on a weekend compared to weekdays. The objective of this study was to compare pediatric surgical outcomes following weekend versus weekday procedures. METHODS: Using the Nationwide Inpatient Sample and the Kids' Inpatient Database, we identified 439,457 pediatric (<18 years old) admissions from 1988 to 2010 that required a selected index surgical procedure (abscess drainage, appendectomy, inguinal hernia repair, open fracture reduction with internal fixation, or placement/revision of ventricular shunt) on the same day of admission. Outcome metrics were compared using logistic regression models that adjusted for patient and hospital characteristics as well as procedure performed. RESULTS: Patient characteristics of those admitted on the weekend (n=112,064) and weekday (n=327,393) were similar, though patients admitted on the weekend were more likely to be coded as emergent (61% versus 53%). After multivariate adjustment and regression, patients undergoing a weekend procedure were more likely to die (OR 1.63, 95% CI 1.21-2.20), receive a blood transfusion despite similar rates of intraoperative hemorrhage (OR 1.15, 95% CI 1.01-1.26), and suffer from procedural complications (OR 1.40, 95% CI 1.14-1.74). CONCLUSION: Pediatric patients undergoing common urgent surgical procedures during a weekend admission have a higher adjusted risk of death, blood transfusion, and procedural complications. While the exact etiology of these findings is not clear, the timing of surgical procedures should be considered in the context of systems-based deficiencies that may be detrimental to pediatric surgical care. PMID- 24952795 TI - Estimating pediatric surgical need in developing countries: a household survey in Rwanda. AB - PURPOSE: Surgical services for children are often absent in resource-limited settings. Identifying the prevalence of surgical disease at the community level is important for developing evidence-based pediatric surgical services and training. We hypothesize that the untreated surgical conditions in the pediatric population are largely uncharacterized and that such burden is significant and poorly understood. Furthermore, no such data exist at the population level to describe this population. METHODS: We conducted a nationwide cross-sectional cluster-based population survey to estimate the magnitude of surgical disease in Rwanda. Conducted as a verbal questionnaire, questions included representative congenital, acquired, malignant and injury-related conditions. Pediatric responses were analyzed using descriptive statistics and univariate analysis. RESULTS: A total of 1626 households (3175 individuals) were sampled with a 99% response rate; 51.1% of all individuals surveyed were younger than age 18. An estimated 50.5% of the total current surgical need occurs in children. Of all Rwandan children, 6.3% (95% CI 5.4%-7.4%), an estimated 341,164 individuals, were identified to have a potentially treatable surgical condition at the time of the interview. The geographic distribution of surgical conditions significantly differed between adults and children (p<0.001). CONCLUSIONS: The results emphasize the magnitude of the pediatric surgery need as well as the need for improved education and resources. This may be useful in developing a collaborative local training program. PMID- 24952796 TI - Congenital malformations of pediatric surgical interest: prevalence, risk factors, and prenatal diagnosis between 2005 and 2012 in the capital city of a developing country. Bogota, Colombia. AB - BACKGROUND: Congenital anomalies (CAs) cause nearly one third of infant deaths worldwide. Various surveillance systems have been established, such as the Bogota Congenital Malformations Surveillance Program (BCMSP). Some CAs are of special interest to pediatric surgeons: omphalocele, gastroschisis, intestinal and esophageal atresia, anorectal malformations, vascular anomalies, diaphragmatic hernias, hypospadias and cryptorchidism. The aim of this study is to determine the prevalence of such CAs, and identify possible risk factors. METHODS: Data from the BCMSP were collected between January 2005 and April 2012. CAs were classified in accordance with the ICD-10 and grouped for analysis purposes. Data on CA frequencies were obtained from the BCMSP. Association analyses were performed using the case-control methodology. RESULTS: 282,523 births were registered. 4682 (1.66%) had one or more CAs at birth. The prevalence of CAs requiring pediatric surgery was 1 in 1000. The most frequent CAs were vascular anomalies, hypospadias, and anorectal malformations. Exposure to external factors was significantly associated with selected CAs. 51% of selected birth defects were not diagnosed in prenatal ultrasound. CONCLUSIONS: This study highlights the importance of evaluating the local prevalence of congenital malformations. We propose the creation of specialized centers in Bogota to manage patients with CAs. PMID- 24952797 TI - Hepatobiliary physiological changes after Roux-en-Y cholecysto-colonic diversion. AB - BACKGROUND: We speculated that Roux-en-Y cholecysto-colonic diversion was as effective for treating children with progressive familial intrahepatic cholestasis (PFIC) as partial biliary diversion. The feasibility of the novel approach in bypassing bile was investigated in rabbits. METHODS: Twenty-four rabbits were randomly divided into three groups: sham operated group (Group1), 30cm limb group (Group 2), and 10 cm limb group (Group 3). Group 2 or 3 underwent a Roux-en-Y cholecystocolonic anastomoses with a 30- or 10-cm-long Roux limb. (99mTc)EHIDA dynamic biligraphy was used to detect alterations of bile flow among the three groups at 1 year postoperatively. TBA levels and histological changes were also evaluated. RESULTS: All animals survived and developed normally without clinical symptoms during 1 year follow-up. Bile was diverted into colon directly after cholecystocolonic anastomosis. In group 3, E20 and E35 values were (77.27 +/- 6.15%) and (90.39 +/- 1.49%) respectively. Gallbladder emptying was accelerated in 10 cm short limb group than in 30 cm long limb group. The ratio of bile shunt was (0.547 +/- 0.182), which was also more than that in group 2 (p<0.05). The activity-time curve for the gallbladder area in group 2 looks like a wave. A significant reduction in TBA level was observed in group 2 and 3 (p<0.05). CONCLUSIONS: Roux-en-Y cholecystocolonic bypass was safe and feasible. Its effectiveness is related to the length of Roux loop. Cholecystocolonic bypass led to a significant loss of bile acids in healthy rabbits and might be considered for bile diversion in pediatric patients with selected cholestatic diseases. PMID- 24952798 TI - Simple formulas to determine optimal subclavian central venous catheter tip placement in infants and children. AB - BACKGROUND/PURPOSE: Optimal central venous catheter (CVC) tip location is necessary to decrease the incidence of complications related to their use. We sought to create a practical method to reliably predict the length of catheter to insert into the subclavian vein during CVC placement in children. METHODS: We performed a retrospective review of 727 chest radiographs of children who underwent either left or right subclavian CVC placement. We measured the distance from the subclavian entry site to the to the right atrium/superior vena cava (RA/SVC) junction, following the catheter's course. We analyzed the relationship between that length and patient characteristics, including: age, gender, height, weight and body surface area (BSA). RESULTS: Two derived formulas using the BSA best correlated with the optimal subclavian CVC length. For the left subclavian vein approach, the optimal catheter length was 6.5 BSA+7 cm, and for the right subclavian vein approach it was 5 BSA+6. The use of these formulas correlated in CVC tip placement in a clinically proper location in 92.9% of smaller children and in 95.7% of larger children. CONCLUSION: The optimal length of central venous catheter to insert into the subclavian vein may be determined through the use of a simple formula using the BSA. PMID- 24952799 TI - Sacrococcygeal malignant germ cell tumor (SC-MGCT) with intraspinal extension. AB - BACKGROUND: Neurological involvement due to intraspinal extension in sacrococcygeal malignant germ cell tumors (SC-MGCTs) has rarely been reported. AIM: To evaluate the incidence, presentation, management and the outcome of patients of SC-MGCT with intraspinal extension. MATERIALS AND METHODS: Case records of all cases of SC-MGCT from 2001 to 2008, were reviewed to identify cases with vertebral involvement and intraspinal extension. They were evaluated in terms of their presentation, response to therapy, extent of surgical resection, recovery of neurological symptoms and outcome. RESULTS: Of the 31 cases of SC-MGCT, 5 (16%) had intraspinal extension. Age ranged from 12 to 84 months (median 24 months). Four patients had Altman type 4 disease (stage 4) and 1 had Altman type 3 (stage 3) disease. The intraspinal extension in all patients was detected on contrast CT scan. Patients presented with neurological symptoms in the form of lower limb paresis (80%), bowel and bladder (20%) incontinence. All the tumors responded to pre-operative chemotherapy. Gross complete local resection could be achieved in 4(80%). Neurological recovery was complete in all except for persisting neurogenic bladder in one. During follow up of 3-32 months, all were alive with no recurrence. CONCLUSIONS: SC-MGCT presenting with neurological deficits due to intraspinal extension is usually advanced disease. These patients respond to chemotherapy and surgical resection and most have complete neurological improvement. PMID- 24952800 TI - Intraluminal appendiceal fluid is a predictive factor for recurrent appendicitis after initial successful non-operative management of uncomplicated appendicitis in pediatric patients. AB - BACKGROUND: The risk factors for recurrent appendicitis in pediatric patients are unclear. This study aimed to identify the predictive factors for recurrent appendicitis in pediatric patients who initially underwent successful non operative management of uncomplicated appendicitis. METHODS: Potential predictive factors for recurrent appendicitis in terms of clinical characteristics, laboratory data, and abdominal ultrasonography and computed tomography findings, were evaluated. RESULTS: This study included 125 patients who underwent initial successful non-operative management of appendicitis. The rate of recurrent appendicitis was 19.2%, and the mean time to recurrence was 12.6 months. Univariate analyses found that rebound tenderness, muscle guarding, appendicoliths, appendiceal diameter >9 mm, and intraluminal appendiceal fluid were associated with recurrent appendicitis. Multivariate analysis identified only intraluminal appendiceal fluid as an independent predictor of recurrent appendicitis. CONCLUSIONS: Intraluminal appendiceal fluid is a predictive factor for recurrent appendicitis after initial non-operative management. The results of this study provide valuable information that may help to determine the appropriate management during the first episode of appendicitis. PMID- 24952801 TI - Bowel symptoms in children with anorectal malformation - a follow-up with a gender and age perspective. AB - BACKGROUND: Gender specific outcome for children with anorectal malformations (ARM) is rarely reported although it is important for medical care and in parent counseling. PURPOSE: To assess bowel function according to the Krickenbeck system in relation to ARM-subtype, gender and age. METHOD: All children born with ARM in 1998-2008 and referred to two centers in two different countries were followed up. The bowel function in 50 girls and 71 boys, median age 8 years, was analyzed. RESULTS: Among those with a perineal fistula, incontinence occurred in 42% of the females and in 10% of the males (p=0.005) whereas constipation occurred in 62% of the females and 35% of the males (p<0.001). No bowel symptoms differed between the females with perineal and vestibular fistulas (p>0.3 for every symptom). Sacral malformations were associated with incontinence only in males with rectourethral fistulas. Constipation among the males differed between the age groups: 58% versus 26% (p=0.013). Bowel symptoms did not change with age among the females. CONCLUSION: Gender differences in outcome for children with ARM must be considered. Males with perineal fistulas had less incontinence and constipation than the females with perineal fistulas. The females with perineal and vestibular fistulas had similar outcomes. PMID- 24952803 TI - Intracorporal suturing--driving license necessary? AB - BACKGROUND: Intracorporeal suturing and knot tying (ICKT) in minimal invasive surgery (MIS) represents a key skill for advanced procedures. Different methods exist for measuring knot quality and performance, but the heterogeneity of these methods makes direct comparisons difficult. The aim of this study is to compare the quality of a laparoscopic knot to one that is performed open. METHODS: To compare open and laparoscopic knot-tying methods we used a surgeon's square knot. For laparoscopic knot tying we used a Pelvitrainer. The 32 participants were divided among 4 groups of different skill levels. Group 1 consisted of 6 senior physicians. Group 2 was made up of 10 first to fourth year interns. Groups 3 and 4 contained 16 medical students who had never performed either laparoscopic procedures or open sutures before. Group 3 participants received a 1-hour hands on training in suturing, whereas group 4 participants received no prior training. Total time, knot quality, suture placement accuracy, and performance defined the parameters for assessment in this study. RESULTS: All participants, irrespective of education level were inferior in ICKT compared to open suturing. Only Group 1 showed no significant difference in knot quality and accuracy between the open and laparoscopic suture performance. CONCLUSION: It is well documented that psychomotor skills need to be developed before more advanced skills can be put into practice. Training centres for minimally invasive surgery should be an integral part of surgical education. The variables in our study are meaningful and easy to implement. They can be used to measure personal progress and as objective parameters in the development of laparoscopic trainee education. PMID- 24952802 TI - Magnetic gastrointestinal anastomosis in pediatric patients. AB - BACKGROUND/PURPOSE: To describe 17 patients who underwent magnetic, non-surgical gastrointestinal (GI) anastomoses. METHODS: Patients with GI obstruction, stenosis, or atresia were treated with image-guided and/or endoscopically placed discoid magnet pairs or catheter-based bullet-shaped magnet pairs. RESULTS: Anastomosis was achieved in 7 days in an 11-year-old with gastric outlet obstruction due to metastatic colon cancer. Anastomosis was achieved in 8 and 10 days in 2 patients (age 2.0 years and 3.4 years) who had rectocolonic stenosis. Re-anastomosis was achieved in an average of 6 days (range 3 to 7 days) in 5 patients (age 6 months to 5.9 years) with severe recurrent postsurgical esophageal stenosis refractory to dilatation. Primary esophageal anastomosis was achieved in an average of 4.2 days (range 3 to 6 days) in 9 patients with esophageal atresia (Type A or Type C surgically converted to Type A) with a gap length of 4 cm or less. The average age of these esophageal atresia patients was 3 months (range 23 days to 5 months). CONCLUSION: Minimally invasive magnet placement was feasible and achieved anastomosis in all patients. PMID- 24952804 TI - Negative pressure dressing assisted healing in pediatric burn patients. AB - BACKGROUND/PURPOSE: Pediatric burn patients traditionally require multiple dressing changes and significant amounts of narcotics. Negative pressure dressings (NPDs) have emerged as an effective wound therapy that may represent an alternative primary dressing for these patients. METHODS: This is a single institution, retrospective study of pediatric burn patients treated with NPDs over a defined 2 year period. Twenty-two patients were identified and their charts reviewed for age, sex, mode of injury, location of injury, degree of burn, length of stay, length of dressing required, number of dressing changes, and narcotic use between dressing changes. RESULTS: The average patient was 3.5 years old (range of 8 months to 10 years old) with partial thickness burns involving 8.5% (range 3-18%) body surface area. The average treatment regimen was 3.5 dressing changes more than 6.6 days, with a mean hospital stay of 9.6 days. The average child received 9.4 total doses of delivered narcotics during their inpatient care. DISCUSSION: The use of NPD in pediatric burn patients does require sedation and narcotics which limits its usefulness in the general pediatric burn population. Yet, they adhere well and stay in place even on active children, they capture and quantify fluid losses, they only require changes every 2-4 days and promote the adherence of split thickness skin grafts making them useful in various clinical situations. CONCLUSIONS: NPDs are a viable option for both partial and full thickness burns in pediatric patients that do not require transfer to a burn unit. NPDs may be advantageous in highly active children, those with extensive fluid losses, those that require sedation for dressing changes and those that will require grafting. PMID- 24952805 TI - Development of the human male urethra: a histochemical study on human embryos. AB - PURPOSE: Controversy persists regarding the formation of human penile urethra. The classic fusion theory for the development of the spongy urethra and ectodermal ingrowth or endodermal transformation theories for the development of the glanular urethra do not explain the wide spectrum of anomalies seen in patients with hypospadias. This histological study was made to clarify the mechanism of urethral development. MATERIALS & METHODS: 15 human male embryos ranging from 6 to 14 weeks were studied. The phalluses were examined microscopically and photographed. Tissues were prepared as serial histological sections and stained with haematoxylin and eosin and with special immuno histochemical stains. RESULTS: 1) The penile urethra: At 6 weeks of gestation, the urethral plate which is solid distally and partially grooved proximally becomes grooved distally and has fused proximally by 8 weeks. At 14 weeks of gestation; the urethral opening migrates only to the middle of the shaft. 2) The glanular urethra: At the 6th week of gestation, a solid epithelial plate reached the tip of the genital tubercle, and a glans cannot be identified. At the 7th week, a central vacuolation appears and the penile urethral groove does not reach the tip of the phallus. At the 8th week; coronal sulcus starts to appear, and a well defined blind central canal was evident in the 13th week. During the 14th week, the floor of the glanular canal degenerated to form a glanular groove. CONCLUSIONS: Our observations suggest that the spongy urethra passes through 3 stages of development: a solid epithelial plate, deep urethral groove, and fused urethra. The glanular urethra passes through 4 developmental stages: a solid epithelial plate, a blind central canal, a deep glanular groove, and the floor from the preputial lamella. There was no evidence of ectodermal ingrowth. These observations raise serious questions to the current theories for human urethra development. Further studies on fresh human embryos are needed. PMID- 24952807 TI - Single incision laparoscopic surgery for pediatric adnexal pathology. AB - PURPOSE: Minimally invasive surgery is commonly used to treat gynecologic disease. Literature in the adult population supports that single incision laparoscopic surgery (SIL) is feasible and safe for the treatment of adnexal disease; however, there is little evidence for SIL in the pediatric population. METHODS: A retrospective review of patients with gynecologic disease who underwent SIL from August 2009 to April 2012 was performed. All demographic data, clinical history, radiologic studies, indications for and type of operation, operative time and complications, and pathology were recorded. RESULTS: Thirty four patients with a mean age of 12.5 years (range 3.6-17.4 years) underwent SIL for adnexal pathology. Operative interventions included cystectomy (56%), salpingo oopherectomy (26.5%), detorsion (8.8%), adnexal biopsy (5.9%), and oophoropexy (2.9%). Forty-four percent of the patients also underwent appendectomy. The mean operative time was 42.8 minutes. There was 1 wound infection (2.9%) and 2 patients (5.9%) required additional ports. CONCLUSIONS: Single incision laparoscopy provides a safe and effective approach to diagnostic laparoscopy with the ability to carry out operative interventions in multiple quadrants without adding additional ports. Single incision laparoscopy may be particularly effective in young women with abdominal pain requiring operative intervention. PMID- 24952806 TI - The value of ultrasonography in boys with a non-palpable testis. AB - BACKGROUND: In patients with a non-palpable testis (NPT) on physical examination, the testis is assumed either to be situated intra-abdominally or to be hypoplastic or absent. Diagnostic laparoscopy in these boys is considered the preferable first step. In this study the diagnostic value of pre-operative ultrasound for NPT is assessed in comparison with laparoscopy. METHODS: All boys aged under the age of 17 years who were diagnosed with an NPT by a pediatric surgeon from 2000 till 2012 were evaluated. All patients of whom clinical, ultrasonographic, and operative findings were available were included. RESULTS: Ninety-six boys with 117 NPTs were included. With ultrasound 67 testes were detected in the inguinal canal, which was confirmed peroperatively for 61 testes. Of the 15 testes with an intra-abdominal position on ultrasound, 10 were found intra-abdominally during surgery. The positive predictive value of the ultrasonography is 91% for inguinally located testes and 67% for intra abdominally located testes. CONCLUSION: Ultrasonography has a high positive predictive value for inguinally located testes. When ultrasound locates a testis in an inguinal location, a primary inguinal exploration can be considered, preventing an unnecessary diagnostic laparoscopy. PMID- 24952808 TI - Inguinal herniotomy with the Mitchell-Banks' technique is safe in older children. AB - PURPOSE: There is a tendency for the majority of surgeons to open the inguinal canal in children over two years old when performing inguinal hernia repair. On the other hand, in small children, most surgeons perform the herniotomy superficially to the external ring, as in Mitchell-Banks' technique (MBT). Our aim was to compare the Ferguson hernioplasty (FH) and Mitchell-Banks' technique in terms of recurrence and complication rates in older children. METHODS: We retrospectively reviewed the office medical records of children who were at least two years old and who underwent a herniotomy procedure for inguinal hernia between 1997 and 2012. RESULTS: The 4520 inguinal herniotomy procedures in boys who were over two years old were included in this study. Of these cases, 1607 cases (40.2%) were operated on by a FH with opening the inguinal canal, and 2388 cases (59.8%) by MBT superficially to the external ring. The median ages were 5.1 years (range, 2.0-16.2) in the FH group and 4.6 years (2.0-14.6) in the MBT group. The total complication rates were 2.3% in the FH group and 2.9% in the MBT group (P>.05). Early complications such as wound infection, scrotal edema, and hematoma were seen in 13 (0.8%), 15 (1%), and 10 (0.6%) in the FH group, and 12 (0.5%), 18 (0.7%), and 15 (0.6%) in the MBT group, respectively (P>.05). Late complications such as recurrence, trapped undescended testis, and testicular atrophy were seen in 2 (0.12%), 1 (0.06%), and 2 (0.12%) in the FH group, and 3 (0.12%), 1 (0.04%), and 2 (0.08%) in the MBT group (P>.05). CONCLUSION: The Mitchell-Banks technique is a simple and safe procedure in older boys. PMID- 24952809 TI - Retrograde intrarenal surgery for the treatment of renal stones in children: factors influencing stone clearance and complications. AB - BACKGROUND: Retrograde intrarenal surgery (RIRS) is a known option for the treatment of upper tract calculi with an excellent success. However, the reports of RIRS in prepubertal children are limited. In this study, we evaluated the factors which affected the success rate and the complications of RIRS at renal stone treatment in childhood. METHODS: We retrospectively reviewed the records of children under 14 years old who underwent RIRS for renal stone disease between January 2009 and December 2012. Patients' age, gender, body mass index (BMI), stone size, stone location, stone number, intraoperative complications, stone free status, postoperative complications were recorded. RESULTS: There were 80 ureterorenoscopic procedures performed in 58 renal units of 47 children (23 males and 24 females). The patients' ages ranged from 8 months to 14 years (mean age 4.7 +/- 3.4 years). There was a difference in the distribution of symptoms in age groups. UTI was higher in the 1-4 years age group, abdominal pain was seen mostly in children aged 5-14 years. Multiple stones (included staghorn stone) were noted in 60.4% of patients. In 27.6% of patients, ureteral stones were accompanied by renal stones in our series. In the infancy group, cystine and staghorn stones were more frequently seen, mostly bilateral. After a single ureteroscopic procedure for intrarenal stones in children, we achieved stone free status in 50.9% of the ureters (n=26). After the repeated sessions, the stone clearance rate reached to 85.1%. CONCLUSION: Retrograde intrarenal surgery can be used as a first line therapy to treat renal stones in children. This is especially important if an associated ureteral stone is present that requires treatment; or in patients with cystinuria, which is not favorably treated with ESWL. Complications were seen more frequently in patients with cystine stones. Extravasation was noted more frequently in patients admitted with UTIs. There was a significant relationship between the conversion to open procedures and the age groups, with most procedures occurring in infancy. The parents should be informed about the probability of multiple procedures to achieve stone free status. PMID- 24952810 TI - The risk factors and clinical significance of acute postoperative complications after unstented pediatric pyeloplasty: a single surgeon's experience. AB - PURPOSE: To analyze the risk factors and clinical significance of postoperative complications after unstented pediatric pyeloplasty. MATERIALS AND METHODS: We analyzed 285 kidney units (KUs) on which unstented pyeloplasty was performed between April 2002 and March 2010. Measures included preoperative factors, postoperative complications, change in postoperative differential renal function (DRF), and failure of pyeloplasty. Risk factors for acute complications requiring additional ureteral stenting and decreased DRF were analyzed. RESULTS: During a median follow-up period of 67.0 months, an additional ureteral stenting was required in 28 KUs (9.8%) due to the development of acute postoperative complications after unstented pyeloplasty. The incidence of complications increased significantly as preoperative DRF increased. DRF of more than 60% was the only independent risk factor for acute complications. Postoperative decrease in DRF was observed in 58 KUs (22.4%) among 259 KUs analyzed. Pyeloplasty failure was observed in 10 KUs (3.5%). The development of acute complications was not a risk factor for a decrease in DRF or pyeloplasty failure. CONCLUSIONS: Urinary diversion during pyeloplasty is not related to a decrease in DRF or pyeloplasty failure. However, in patients with a preoperative DRF of greater than 60%, diversion could be considered due to the high prevalence of complications. PMID- 24952811 TI - Minimally invasive surgery in the management of abdominal tumors in children. AB - The application of minimally invasive surgical techniques to pediatric abdominal tumors is a controversial application towards the surgical management of childhood cancer. Although general pediatric surgeons practice minimally invasive surgery techniques in a vast array of abdominal cases, its role in pediatric oncology is still developing, with no consensus in North America about its use for pediatric solid abdominal tumors. The purposes of this article are to review the current literature about the use of minimally invasive surgery in pediatric abdominal oncology and to examine established indications, procedures and technologic advances. PMID- 24952812 TI - A new surgical approach of temporary ovarian transposition for children undergoing brachytherapy: technical assessment and dose evaluation. AB - PURPOSE: We developed a new technique of temporary ovarian transposition (OT) for prepubertal girls undergoing brachytherapy. The aim of this study was to describe it, assess its feasibility and safety and calculate the dose delivered to the ovary in order to prove its efficacy. METHODS: Sixteen prepubertal patients underwent temporary OT for brachytherapy at our center from March 2001 to December 2012. OT was done either by laparotomy or by laparoscopy. In all patients, the ovaries were grasped with an atraumatic forceps and mobilized above the iliac crest level as high as possible without any dissection or division of the ovarian ligaments or of the fallopian tube. They were sutured to the anterior abdominal wall by a transfixing stitch of non-dissolvable suture knotted on the outside of the patient on a pledget. RESULTS: Median age at surgery was 3 years (range: 2-9 years). The integrity of the fallopian tube was respected and not a single ligament was dissected or divided. None of the patients had intraoperative or postoperative complications. The stitches were retrieved after completion of irradiation and the ovaries in all the patients fell back into the pelvis. The calculated median radiation dose to the ovary was 1.4 Gy (range: 0.4-2.4 Gy). CONCLUSIONS: This surgical technique is simple and safe, either by laparotomy or by laparoscopy. It meets the radiation and physical constraints in prepubertal girls with vaginal or bladder RMS. However, longer follow-up is required to assess the ovarian function. PMID- 24952813 TI - Consecutive purse string suture for mesenteric defect closure after tumor resection in children. PMID- 24952814 TI - Re: Shalaby R. et al. laparoscopic inguinal hernia repair; experience with 874 children. J Pediatr Surg 2014;49:460-4. PMID- 24952815 TI - Letter to the editor. PMID- 24952816 TI - Reply to letter to the editor. PMID- 24952817 TI - Mental health impacts of reproductive coercion among women in Cote d'Ivoire. AB - OBJECTIVE: To assess the independent associations of partner-perpetrated reproductive coercion, intimate partner violence (IPV), in-law reproductive coercion, and in-law abuse with recent probable post-traumatic stress disorder (PTSD), and to test their relationship with PTSD symptoms when controlling for the other types of abuse among partnered women in rural Cote d'Ivoire. METHODS: Cross-sectional analyses were conducted using logistic generalized estimating equations, which accounted for village-level clustering. Data were drawn from baseline data from a randomized controlled trial among 24 villages in rural Cote d'Ivoire (n=953 partnered women). Three adjusted models were used to test associations of reproductive coercion and abuse with probable PTSD. RESULTS: Partner-perpetrated reproductive coercion was experienced by 176 (18.5%) women. In model 3, which accounted for the co-occurrence of abuses, partner-perpetrated reproductive coercion (odds ratio [OR] 2.3; 95% confidence interval [CI], 1.4 3.9) and partner-perpetrated IPV (OR 1.7; 95% CI, 1.1-2.7) were the most significant predictors of past-week probable PTSD (P<0.05). CONCLUSION: Reproductive coercion may be a significant contributor to poor mental health. The mental health impacts of reproductive coercion and IPV should be considered within psychosocial programming for rural Ivorian communities to address the full range of traumatic experiences that may have been experienced by women. PMID- 24952818 TI - Temperature effects on recovery time of bacterial growth after rewetting dry soil. AB - The effect of temperature on the recovery of bacterial growth after rewetting dry soil was measured in a soil that responded with bacterial growth increasing immediately upon rewetting in a linear fashion (type (i) response sensu Meisner et al. (Soil Biol Biochem 66: 188-192, 2013)). The soil was air-dried for 4 days and then rewetted at different temperatures. Bacterial growth over time was then estimated using the leucine incorporation method. At 25 degrees C, the recovery of bacterial growth to levels of a wet control soil was rapid, within 6 h, while at 15 degrees C, recovery time increased to around 60 h, becoming more than a week at 5 degrees C. The temperature dependency of the recovery time was well modeled by a square root function. Thus, temperature will not only directly affect growth rates but also affect length of transition periods, like resuscitation after a drying event. The temperature during the rewetting event thus has to be taken into consideration when analyzing the microbial response dynamics. PMID- 24952819 TI - Endovascular treatment of late coronary-subclavian steal syndrome. AB - OBJECTIVE: Coronary-subclavian steal syndrome (CSSS) is a rare cause of myocardial ischemia subsequent to stenosis or occlusion of the subclavian artery (SA) proximal to internal thoracic artery (ITA) coronary bypass. Only single cases have been reported in published studies to date. We report a significant series of patients with late CSSS treated through an endovascular approach. METHODS: We reviewed a series of consecutive patients treated for CSSS. The clinical, anatomic, and technical characteristics of the procedures were considered. Follow-up was performed through clinical and laboratory (electrocardiography, echocardiography, duplex ultrasonography) evaluations. RESULTS: From January 2005 to March 2013, 10 patients with CSSS were treated; 7 had stable and 3 unstable angina. Of the 10 patients, 8 had left SA stenosis (6 ostial to the origin and 2 in the middle segment), 1 had proximal occlusion of the left SA, and 1 had stenosis in the innominate artery (proximally to a right internal thoracic artery). Arterial access was at the brachial artery through surgical exposure (n=6), or radial artery percutaneously (n=3). In 1 case of proximal occlusion of the left SA, simultaneous femoral and percutaneous radial access was necessary. Predilatation of the stenotic lesion was performed in 6. Balloon expandable stents were used in 7 patients with proximal ostial stenosis or occlusion and self-expandable stents in 2 with nonostial lesions. In 1 other patient with proximal heavy calcified stenosis, cutting-balloon predilatation was performed, resulting in dissection of the SA and occlusion of the ITA graft; blood flow was restored in the left upper arm and myocardium by adjunctive dilatation of the SA and endovascular coronary revascularization. No patients developed angina during the follow-up period (15+/-7 months). CONCLUSIONS: A tailored endovascular approach can be used to treat CSSS. However, the occurrence of potentially lethal complications is possible and needs prompt correction. PMID- 24952820 TI - Outcomes of peripheral perfusion with balloon aortic clamping for totally endoscopic robotic mitral valve repair. AB - OBJECTIVE: Although the technique of totally endoscopic robotic mitral valve repair (TERMR) has been well described, few reports have examined the results of peripheral perfusion with balloon clamping. We analyzed the outcomes of TERMR performed using this strategy. METHODS: A total of 108 consecutive patients underwent TERMR by a 2-surgeon team. The preoperative evaluation included chest computed tomography and abdominal and pelvis computed tomography. Additional procedures included appendage exclusion in 96, patent foramen ovale closure in 29, cryoablation in 16, tricuspid valve repair in 2, and septal myectomy in 2. The mean patient age was 59 years (range, 21-86). Central venous drainage was obtained with a long cannula. Arterial return was achieved with femoral cannulation, when possible. An endoballoon catheter was placed through the femoral artery. Transesophageal echocardiography was used to position all catheters. RESULTS: Femoral artery perfusion was possible in 103 of 108 patients (95.3%). The subclavian artery was used in 5 patients (4.6%) with contraindications to retrograde perfusion. An endoballoon clamp was placed by way of the femoral artery. In 105 of 108 patients (97.2%), endoaortic occlusion was successfully used; the mean crossclamp time was 87.4 minutes. The coronary sinus cardioplegia catheter was placed successfully in 81 of the 108 patients (75%). Postoperatively, no or mild inotropic support was needed in 94 (87%) and moderate support in 14 (13.0%). Of the 108 patients, 55 (50.9%) were extubated in the operating room. No hospital mortality, aortic injury, vascular complications, or wound infections occurred. Complications included 2 strokes (no residual deficit) (1.8%) and atrial fibrillation in 18 (16.7%). The median hospital stay was 4 days. Eighty patients (74.1%) were discharged by postoperative day 5. CONCLUSIONS: A preoperative image-guided perfusion strategy and aortic balloon clamping permit routine TERMR with excellent myocardial preservation and minimal complications. PMID- 24952821 TI - Does the addition of atrial pacing to amiodarone reduce the incidence of postoperative atrial fibrillation: a pilot study. PMID- 24952822 TI - Prognostic factors for aorta remodeling after thoracic endovascular aortic repair of complicated chronic DeBakey IIIb aneurysms. AB - OBJECTIVES: The use of thoracic endovascular aortic repair (TEVAR) for chronic DeBakey III type b (CDIIIb) aneurysms is controversial. We analyzed the potential prognostic factors affecting aorta remodeling after this procedure. METHODS: A total of 20 patients with CDIIIb aneurysms underwent TEVAR, with full coverage of reentry tears at the descending thoracic aorta. The potential factors affecting false lumen (FL) remodeling were analyzed, including reentry tears (communicating channels visible on the computed tomography angiogram), large intimal tears below the stent graft (>= 2 consecutive axial cuts on the computed tomography angiogram), visceral branches arising from the FL, and intercostal arteries (ICAs) arising from the FL. RESULTS: All the patients had uneventful in-hospital courses; 2 patients (10%) required reintervention during the follow-up period. Thirteen patients (65%) had complete thrombosis of the FL at stent graft segment. Compared with the complete thrombosis group, the partial thrombosis group had more reentry tears (1.8 vs 2.3, P = .48), large intimal tears (0.8 vs 1.7, P < .05), visceral branches arising from the FL (1.2 vs 2.3, P < .05), and ICAs arising from the FL (3.8 vs 5.1, P = .35). Reentry tears, visceral branches, and ICAs from the FL were significant negative prognostic factors for FL shrinkage (P < .05). CONCLUSIONS: Although reentry tears above the celiac trunk were fully covered, the visceral branches and ICAs from the FL and all communicating channels below the celiac trunk kept the FL pressurized and were unfavorable prognostic factors for aorta remodeling after TEVAR for CDIIIb aneurysms. PMID- 24952825 TI - [Current role of albumin in critical care]. AB - The use of colloids in fluid therapy has been, and still continues to be a controversial topic, particularly when referring to the critical patient. The choice of the fluid that needs to be administered depends on several factors, many of which are theoretical, and continue being an object of debate. The interest in the clinical use of the albumin has emerged again, immediately after recent publications in the search of the most suitable colloid. It is the most abundant protein in the plasma, being responsible for 80% of the oncotic pressure. It regulates the balance between the intra- and extra-vascular volumes. Recent multicenter studies question the supposed lack of safety that was previously assigned to it. Furthermore, in vitro studies demonstrate other important actions besides oncotic, for example neutralization of free radicals, and exogenous (drugs) and endogenous substances (bile pigments, cholesterol). Being aware of these secondary properties of albumin, and evaluating the pathophysiology of the critical patient (in particular, sepsis), to maintain plasma albumin levels within the normal range, could be of great importance. Based on the most recent publications, the aim of this review is to briefly analyze the pathophysiology of albumin, as well as to discuss its possible indications in the critical patient. PMID- 24952826 TI - [Thoracoscopic thymectomy with carbon dioxide insufflation in the mediastinum]. AB - The case is presented of a 71 year-old male, diagnosed with a thymoma. A thoracoscopic thymectomy was performed using the carbon dioxide insufflation technique in the mediastinum. During the procedure, while performing one-lung ventilation, the patient's respiration worsened. The contralateral lung had collapsed, as carbon dioxide was travelling from the mediastinum to the thorax through the opened pleura. Two-lung ventilation was decided upon, which clearly improved oxygenation in the arterial gases and airway pressures. Both pH and pCO2 stabilized. The surgical approach and the carbon dioxide technique were continued because 2-lung ventilation did not affect the surgical procedure. This technique has many serious complications and it should always be performed using 2-lung ventilation. PMID- 24952827 TI - [Comments on the article "Ultrasound-guided peripheral intravenous catheterisation in a surgical patient"]. PMID- 24952823 TI - Targeted imaging of matrix metalloproteinase activity in the evaluation of remodeling tissue-engineered vascular grafts implanted in a growing lamb model. AB - OBJECTIVES: The clinical translation of tissue-engineered vascular grafts has been demonstrated in children. The remodeling of biodegradable, cell-seeded scaffolds to functional neovessels has been partially attributed to matrix metalloproteinases. Noninvasive assessment of matrix metalloproteinase activity can indicate graft remodeling and elucidate the progression of neovessel formation. Therefore, matrix metalloproteinase activity was evaluated in grafts implanted in lambs using in vivo and ex vivo hybrid imaging. Graft growth and remodeling was quantified using in vivo x-ray computed tomography angiography. METHODS: Cell-seeded and unseeded scaffolds were implanted in 5 lambs as inferior vena cava interposition grafts. At 2 and 6 months after implantation, in vivo angiography was used to assess graft morphology. In vivo and ex vivo single photon emission tomography/computed tomography imaging was performed with a radiolabeled compound targeting matrix metalloproteinase activity at 6 months. The neotissue was examined at 6 months using qualitative histologic and immunohistochemical staining and quantitative biochemical analysis. RESULTS: The seeded grafts demonstrated significant luminal and longitudinal growth from 2 to 6 months. In vivo imaging revealed subjectively greater matrix metalloproteinase activity in grafts versus native tissue. Ex vivo imaging confirmed a quantitative increase in matrix metalloproteinase activity and demonstrated greater activity in unseeded versus seeded grafts. The glycosaminoglycan content was increased in seeded grafts versus unseeded grafts, without significant differences in collagen content. CONCLUSIONS: Matrix metalloproteinase activity remained elevated in tissue-engineered grafts 6 months after implantation and could indicate remodeling. Optimization of in vivo imaging to noninvasively evaluate matrix metalloproteinase activity could assist in the serial assessment of vascular graft remodeling. PMID- 24952828 TI - [High fidelity simulation in Spain: from dreams to reality]. AB - Clinical simulation has emerged as a powerful new tool for the learning and assessment of different skills and attitudes in patient care, by using innovative technology such as high fidelity simulators (HFS). OBJECTIVE: To describe the current state of high fidelity clinical simulation in Spain and its principal characteristics. METHODS: Descriptive observational study that analyzes information on the clinical centers that have HFS in our country. RESULTS: There are currently a total of 80 centers with HFS in our country, mainly distributed in university centers (43), hospital and emergency centers (27), simulation centers and institutes of simulation (5), and the rest (5) associated to entities of diverse ownership. The temporal development of HFS has been slowly progressive, with a significant growth in the last 6 years. The majority (74%) have specific facilities, auxiliary equipment (60%), and professionals with a shared commitment (80%). It is already integrated into the training programs in 56% of university centers with HFS. CONCLUSIONS: The development of HFS has been remarkable in our country, and is mainly related to university undergraduate and postgraduate clinical medical education. It would be useful to design a network of simulation training centers of Health Sciences in Spain, which would be operational, sustainable and recognized, to optimize the use of these facilities. PMID- 24952830 TI - Safety algorithms for ultrasound-guided blocks: the next challenge. PMID- 24952831 TI - Challenges and prospects of proteomics of non-model organisms. PMID- 24952829 TI - [Ultrasound-guided superior laryngeal nerve block for rigid bronchoscopy]. PMID- 24952832 TI - Communication in indigenous healthcare: extending the discourse into the physiotherapy domain. PMID- 24952833 TI - Preoperative intervention reduces postoperative pulmonary complications but not length of stay in cardiac surgical patients: a systematic review. AB - QUESTION: Does preoperative intervention in people undergoing cardiac surgery reduce pulmonary complications, shorten length of stay in the intensive care unit (ICU) or hospital, or improve physical function? DESIGN: Systematic review with meta-analysis of (quasi) randomised trials. PARTICIPANTS: People undergoing coronary artery bypass grafts and/or valvular surgery. INTERVENTION: Any intervention, such as education, inspiratory muscle training, exercise training or relaxation, delivered prior to surgery to prevent/reduce postoperative pulmonary complications or to hasten recovery of function. OUTCOME MEASURES: Time to extubation, length of stay in ICU and hospital (reported in days). Postoperative pulmonary complications and physical function were measured as reported in the included trials. RESULTS: The 17 eligible trials reported data on 2689 participants. Preoperative intervention significantly reduced the time to extubation (MD -0.14 days, 95% CI -0.26 to -0.01) and the relative risk of developing postoperative pulmonary complications (RR 0.39, 95% CI 0.23 to 0.66). However, it did not significantly affect the length of stay in ICU (MD -0.15 days, 95% CI -0.37 to 0.08) or hospital (MD -0.55 days, 95% CI -1.32 to 0.23), except among older participants (MD -1.32 days, 95% CI -2.36 to -0.28). When the preoperative interventions were separately analysed, inspiratory muscle training significantly reduced postoperative pulmonary complications and the length of stay in hospital. Trial quality ranged from good to poor and considerable heterogeneity was present in the study features. Other outcomes did not significantly differ. CONCLUSION: For people undergoing cardiac surgery, preoperative intervention reduces the incidence of postoperative pulmonary complications and, in older patients, the length of stay in hospital. PMID- 24952834 TI - Mechanical diagnosis and therapy has similar effects on pain and disability as 'wait and see' and other approaches in people with neck pain: a systematic review. AB - QUESTIONS: In people with neck pain, does Mechanical Diagnosis and Therapy (MDT) reduce pain and disability more than 'wait and see'? Does MDT reduce pain and disability more than other interventions? Are any differences in effect clinically important? DESIGN: Systematic review of randomised trials with meta analysis. PARTICIPANTS: People with neck pain. INTERVENTION: MDT. OUTCOME MEASURES: Pain intensity and disability due to neck pain in the short (< 3 months), intermediate (< 1 year) and long term (>= 1 year). RESULTS: Five trials were included. Most comparisons demonstrated mean differences in effect that favoured MDT over wait-and-see controls or other interventions, although most were statistically non-significant. For pain, all comparisons had a 95% confidence interval (CI) with lower limits that were less than 20 on a scale of 0 to 100, which suggests that the difference may not be clinically important. For disability, even the upper limits of the 95% CI were below this threshold, confirming that the differences are not clinically important. In all of the trials, some or all of the treating therapists did not have the highest level of MDT training. CONCLUSION: The additional benefit of MDT compared with the wait and-see approach or other therapeutic approaches may not be clinically important in terms of pain intensity and is not clinically important in terms of disability. However, these estimates of the effect of MDT may reflect suboptimal training of the treating therapists. Further research could improve the precision of the estimates and assess whether the extent of training in MDT influences its effect. PMID- 24952836 TI - Kinesio taping to generate skin convolutions is not better than sham taping for people with chronic non-specific low back pain: a randomised trial. AB - QUESTION: For people with chronic low back pain, does Kinesio Taping, applied according to the treatment manual to create skin convolutions, reduce pain and disability more than a simple application without convolutions? DESIGN: Randomised trial with concealed allocation, intention-to-treat analysis and blinded assessment of some outcomes. PARTICIPANTS: 148 participants with chronic non-specific low back pain. INTERVENTION: Experimental group participants received eight sessions (over four weeks) of Kinesio Taping applied according to the Kinesio Taping Method treatment manual (ie, 10 to 15% tension applied in flexion to create skin convolutions in neutral). Control group participants received eight sessions (over four weeks) of Kinesio Taping with no tension, creating no convolutions. OUTCOME MEASURES: The primary outcome measures were pain intensity and disability after the four-week intervention. Secondary outcomes were pain intensity and disability 12 weeks after randomisation, and global perceived effect at both four and 12 weeks after randomisation. RESULTS: Applying Kinesio Tape to create convolutions in the skin did not significantly change its effect on pain (MD-0.4 points, 95% CI-1.3 to 0.4) or disability (MD 0.3 points, 95% CI-1.9 to 1.3) at four weeks. There was a small difference in favour of the experimental group for the secondary outcome of global perceived effect (MD 1.4 points, 95% CI 0.3 to 2.5) at four weeks. No significant between group differences were observed for the other secondary outcomes. CONCLUSION: Kinesio Taping applied with stretch to generate convolutions in the skin was no more effective than simple application of the tape without tension for the outcomes measured. These results challenge the proposed mechanism of action of this therapy. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials, RBR 7ggfkv. PMID- 24952835 TI - Normative scores on the Berg Balance Scale decline after age 70 years in healthy community-dwelling people: a systematic review. AB - QUESTIONS: What is the mean Berg Balance Scale score of healthy elderly people living in the community and how does it vary with age? How much variability in Berg Balance Scale scores is present in groups of healthy elderly people and how does this vary with age? DESIGN: Systematic review with meta-analysis. PARTICIPANTS: Any group of healthy community-dwelling people with a mean age of 70 years or greater that has undergone assessment using the Berg Balance Scale. OUTCOME MEASUREMENT: Mean and standard deviations of Berg Balance Scale scores within cohorts of elderly people of known mean age. RESULTS: The search yielded 17 relevant studies contributing data from a total of 1363 participants. The mean Berg Balance Scale scores ranged from 37 to 55 out of a possible maximum score of 56. The standard deviation of Berg Balance Scale scores varied from 1.0 to 9.2. Although participants aged around 70 years had very close to normal Berg Balance Scale scores, there was a significant decline in balance with age at a rate of 0.7 points on the 56-point Berg Balance Scale per year. There was also a strong association between increasing age and increasing variability in balance (R(2) = 0.56, p < 0.001). CONCLUSION: Healthy community-dwelling elderly people have modest balance deficits, as measured by the Berg Balance Scale, although balance scores deteriorate and become more variable with age. PMID- 24952837 TI - Treadmill training provides greater benefit to the subgroup of community-dwelling people after stroke who walk faster than 0.4m/s: a randomised trial. AB - QUESTION: After stroke, does treadmill training provide greater benefit to the subgroup of community-dwelling people who walk faster than 0.4m/s than those who walk more slowly? DESIGN: Subgroup analysis of a randomised trial: the AMBULATE trial. PARTICIPANTS: 68 people with stroke living in the community. INTERVENTION: The experimental group received 30 minutes of treadmill and overground walking, three times a week for four months; the control group received no intervention. OUTCOME MEASURES: The primary outcome was walking distance covered during the six minute walk test. Other outcomes were comfortable and fast walking speed and health status. RESULTS: At four months, in the subgroup of participants with a baseline comfortable walking speed of > 0.4m/s, treadmill training produced an extra distance of 72m (95% CI 23 to 121) and an increased comfortable speed of 0.16m/s (95% CI 0.00 to 0.32), compared with the subgroup with a speed of <=0.4m/s. There was also a trend towards an extra fast speed of 0.17m/s (95% CI 0.04 to 0.36). There was no extra effect of treadmill training in the faster walkers in terms of EuroQol 5Q-5D. There were no differences between the experimental and control groups between subgroups in the long term. CONCLUSION: Treadmill training is more likely to benefit people who walk at a speed of > 0.4m/s. Clinicians should use comfortable walking speed to predict the potential for improvement and to guide intervention. TRIAL REGISTRATION: ACTRN12607000227493. PMID- 24952839 TI - Commentary to: Surgery for cervical radiculopathy followed by physiotherapy may resolve symptoms faster than physiotherapy alone, but with few differences at two years. PMID- 24952838 TI - Soreness during non-music activities is associated with playing-related musculoskeletal problems: an observational study of 731 child and adolescent instrumentalists. AB - QUESTION: Is exposure to non-music-related activities associated with playing related musculoskeletal problems in young instrumentalists? Is non-music-activity related soreness associated with playing-related musculoskeletal problems in this group of instrumentalists? DESIGN: Observational study using a questionnaire and physical measures. PARTICIPANTS: 859 instrumentalists aged 7 to 17 years from the School of Instrumental Music program. RESULTS: Of the 731 respondents who completed the questionnaire adequately, 412 (56%) experienced instrument-playing problems; 219 (30%) had symptoms severe enough to interfere with normal playing. Children commonly reported moderate exposure to non-music-related activities, such as watching television (61%), vigorous physical activity (57%), writing (51%) and computer use (45%). Greater exposure to any non-music activity was not associated with playing problems, with odds ratios ranging from 1.01 (95% CI 0.7 to 1.5) for watching television to 2.08 (95% CI 0.5 to 3.3) for intensive hand activities. Four hundred and seventy eight (65%) children reported soreness related to non-music activities, such as vigorous physical activity (52%), writing (40%), computer use (28%), intensive hand activities (22%), electronic game use (17%) and watching television (15%). Non-music-activity-related soreness was significantly associated with instrument playing problems, adjusting for gender and age, with odds ratios ranging from 2.6 (95% CI 1.7 to 3.9) for soreness whilst watching television, to 4.3 (95% CI 2.6 to 7.1) for soreness during intensive hand activities. CONCLUSION: Non-music-activity-related soreness co-occurs significantly with playing problems in young instrumentalists. The finding of significant co-occurrence of music and non-music-related soreness in respondents in this study suggests that intervention targets for young instrumentalists could include risk factors previously identified in the general child and adolescent population, as well as music-specific risk factors. This is an important consideration for the assessment and management of the musculoskeletal health of young musicians. PMID- 24952840 TI - Surgery for cervical radiculopathy followed by physiotherapy may resolve symptoms faster than physiotherapy alone, but with few differences at two years. PMID- 24952841 TI - Commentary to: Task-specific and impairment-based training improve walking ability in stroke. PMID- 24952842 TI - Task-specific and impairment-based training improve walking ability in stroke. PMID- 24952843 TI - Commentary to: Balance-specific training embedded within a pulmonary rehabilitation program may reduce falls risk in people with COPD. PMID- 24952844 TI - Balance-specific training embedded within a pulmonary rehabilitation program may reduce falls risk in people with COPD. PMID- 24952845 TI - Diagnostic thoracic ultrasound within critical care. PMID- 24952846 TI - The paediatric version of the steep ramp test. PMID- 24952849 TI - Unfair conclusion in review of exercise methods for incontinence. PMID- 24952850 TI - Author response to Liebergall. PMID- 24952852 TI - Improving outcomes in primary percutaneous coronary intervention: Transradial is worth the time. PMID- 24952853 TI - Trial to Assess Chelation Therapy (TACT) and equipoise: When evidence conflicts with beliefs. PMID- 24952854 TI - A systematic review of statin-induced muscle problems in clinical trials. AB - Statin therapy is associated with muscle problems in approximately 10% to 25% of patients treated in clinical practice, but muscle problems have rarely been reported in controlled clinical trials. We performed a systematic search and review of statin clinical trials to examine how these studies evaluated muscle problems and to determine why there are apparent differences in muscle problems between clinical trials and practice. We initially identified 1,012 reports related to clinical trials of statin therapy, 42 of which qualified for analysis. Fifteen, 4, and 22 trials reported creatine kinase values only >10, 5, and 3 times the upper limits of normal, respectively, in both statin- and placebo treated participants. Four trials reported average creatine kinase values, which increased with statin treatment in 3 instances. Twenty-six trials reported muscle problems, with an average incidence in statin- and placebo-treated participants of 13%, but only one trial specifically queried about muscle problems. Three trials used a run-in period to eliminate participants with statin intolerance and noncompliance. The percentage of muscle problems tended to be higher with statin treatment (12.7%) than with placebo group (12.4%, P = .06). This small difference probably reflects a high background rate of nonspecific muscle problems in both groups that could not be distinguished from statin-associated myalgia because most clinical trials did not use a standard definition for statin myalgia. PMID- 24952855 TI - CYP2C19 genotype-guided antiplatelet therapy in ST-segment elevation myocardial infarction patients-Rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study. AB - RATIONALE: In patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (pPCI), the use of dual antiplatelet therapy is essential to prevent atherothrombotic complications. Therefore, patients are treated with acetylsalicylic acid and clopidogrel, prasugrel, or ticagrelor. Clopidogrel, however, shows a major interindividual variation in antiplatelet effect, which is correlated to an increase in atherothrombotic events in patients with high platelet reactivity. This interindividual variation is partly a result of CYP2C19 genetic variants. Ticagrelor and prasugrel reduce atherothrombotic events but increase bleeding rate and drug costs, as compared with clopidogrel. CYP2C19-based tailoring of antiplatelet therapy might be beneficial to STEMI patients. STUDY DESIGN: POPular Genetics (NCT01761786) is a randomized, open-label, multicenter trial involving 2,700 STEMI patients who undergo pPCI. Patients are randomized to CYP2C19 genotyping or routine ticagrelor or prasugrel treatment. In the genotyping group, *1/*1 (wild-type) patients receive clopidogrel, and patients carrying 1 or 2 *2 or *3 loss-of-function alleles receive ticagrelor or prasugrel. The primary net clinical benefit end point is the composite of death, (recurrent) myocardial infarction, definite stent thrombosis, stroke, and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding at 1 year. Primary safety end point is the composite of (PLATO) major and minor bleeding. Cost-effectiveness and quality of life will be assessed by calculating quality-adjusted life-years, net costs per life-year, and per quality-adjusted life-year gained. CONCLUSION: The POPular Genetics study is the first large-scale trial comparing CYP2C19 genotype-guided antiplatelet therapy to a nontailored strategy in terms of net clinical benefit, safety, and cost-effectiveness. PMID- 24952857 TI - Rationale and design of PRIMA II: A multicenter, randomized clinical trial to study the impact of in-hospital guidance for acute decompensated heart failure treatment by a predefined NT-PRoBNP target on the reduction of readmIssion and Mortality rAtes. AB - BACKGROUND: Hospital admissions for acute decompensated heart failure (ADHF) are frequent and are accompanied by high percentages of mortality and readmissions. Brain natriuretic peptide (BNP) and the inactive N-terminal fragment of its precursor proBNP (NT-proBNP) are currently the best predictors of prognosis in heart failure (HF) patients. In the setting of chronic HF, studies that performed guidance of therapy by NT-proBNP have had only limited success. For patients with ADHF, retrospective studies have shown that a reduction in NT-proBNP of <=30% during admission is a significant predictor of HF readmissions and mortality. These data suggest a role for NT-proBNP guidance in the setting of ADHF admissions. STUDY DESIGN: The PRIMA II is an investigator-initiated, multicenter, randomized, controlled, prospective 2-arm trial that investigates the impact of inhospital guidance for ADHF treatment by a predefined NT-proBNP target (>30% reduction during admission) on the reduction of readmission and mortality rates within 180 days. Consenting ADHF patients with NT-proBNP levels of >1,700 ng/L are eligible. After achieving clinical stability, a total of 340 patients are randomized to either NT-proBNP-guided or conventional treatment (1:1). The primary end point is dual, that is, a composite of all-cause mortality and readmission for HF in 180 days and the number of days alive out of hospital in 180 days. Secondary end points are readmissions and/or mortality in 180 days, cost effectiveness of hospitalization days in 180 days, readmissions and mortality in 90 days, and quality of life. CONCLUSION: The PRIMA II trial aims at providing scientific evidence for the use of NT-proBNP-guided therapy compared with conventional treatment in patients admitted for ADHF. PMID- 24952858 TI - EDTA chelation therapy alone and in combination with oral high-dose multivitamins and minerals for coronary disease: The factorial group results of the Trial to Assess Chelation Therapy. AB - BACKGROUND: Disodium ethylenediaminetetraacetic acid (EDTA) reduced adverse cardiac outcomes in a factorial trial also testing oral vitamins. This report describes the intent-to-treat comparison of the 4 factorial groups overall and in patients with diabetes. METHODS: This was a double-blind, placebo-controlled, 2 * 2 factorial multicenter randomized trial of 1,708 post-myocardial infarction (MI) patients >=50 years of age and with creatinine <=2.0 mg/dL randomized to receive 40 EDTA chelation or placebo infusions plus 6 caplets daily of a 28-component multivitamin-multimineral mixture or placebo. The primary end point was a composite of total mortality, MI, stroke, coronary revascularization, or hospitalization for angina. RESULTS: Median age was 65 years, 18% were female, 94% were Caucasian, 37% were diabetic, 83% had prior coronary revascularization, and 73% were on statins. Five-year Kaplan-Meier estimates for the primary end point was 31.9% in the chelation + high-dose vitamin group, 33.7% in the chelation + placebo vitamin group, 36.6% in the placebo infusion + active vitamin group, and 40.2% in the placebo infusions + placebo vitamin group. The reduction in primary end point by double active treatment compared with double placebo was significant (hazard ratio 0.74, 95% CI 0.57-0.95, P = .016). In patients with diabetes, the primary end point reduction of double active compared with double placebo was more pronounced (hazard ratio 0.49, 95% CI 0.33-0.75, P < .001). CONCLUSIONS: In stable post-MI patients on evidence-based medical therapy, the combination of oral high-dose vitamins and chelation therapy compared with double placebo reduced clinically important cardiovascular events to an extent that was both statistically significant and of potential clinical relevance. PMID- 24952860 TI - Trends in the pharmacologic management of atrial fibrillation: Data from the Veterans Affairs health system. AB - BACKGROUND: Prescribing rate control medications with or without antiarrhythmic drugs is often the first course treatment for atrial fibrillation (AF). Clinical trial data suggest that antiarrhythmic drugs are only marginally effective and have multiple drawbacks, whereas rate control alone is sufficient for most patients with minimally symptomatic AF. This study investigates changes in the use of oral rate and rhythm control therapy for AF during fiscal years 2002 through 2011 in the US Veterans Affairs (VA) health system. METHODS: Patients with new AF episodes were identified in Veterans Health Administration administrative data files, and receipt of oral rate- and rhythm-controlling drugs within 90 days of new AF episodes was determined for each patient. RESULTS: The percentage of patients receiving an oral rate-controlling medication decreased from 74.9% in 2002 through 2003 to 70.9% in 2010 through 2011. The use of digoxin decreased by >50%, whereas the use of beta-blockers metoprolol and carvedilol increased. The proportion of patients receiving any oral antiarrhythmic medication decreased from 13.5% in 2002 through 2003 to 11.6% in 2010 through 2011, and use of the most frequently prescribed oral antiarrhythmic, amiodarone, decreased by 17%. CONCLUSIONS: Rate control remains the dominant strategy for treating new AF. The decrease in the use of oral antiarrhythmics may be due to lack of concrete data suggesting mortality and morbidity benefit as well as increasing use of the ablation approach. BULLET POINTS: The proportion of patients with new AF episodes who were prescribed oral rate or rhythm control medications decreased modestly from 2002 through 2011. The use of digoxin decreased by >50%, and amiodarone decreased by 17%. Rate control remains the dominant strategy for treating new AF. PMID- 24952861 TI - Which risk score best predicts perioperative outcomes in nonvalvular atrial fibrillation patients undergoing noncardiac surgery? AB - BACKGROUND: Patients with nonvalvular atrial fibrillation (NVAF) are at increased risk for adverse events after noncardiac surgery. The Revised Cardiac Index (RCI) is commonly used to predict perioperative events; however, the prognostic utility of NVAF risk scores (CHADS2, CHA2DS2-VASc, and R2CHADS2) has not been evaluated in patients undergoing noncardiac surgery. METHODS: Using a population-based data set of NVAF patients (n = 32,160) who underwent major or minor noncardiac surgery between April 1, 1999, and November 30, 2009, in Alberta, Canada, we examined the incremental prognostic value of the CHADS2, CHA2DS2-VASc, and R2CHADS2 scores over the RCI using continuous net reclassification improvement (NRI). The primary composite outcome was 30-day mortality, stroke, transient ischemic attack, or systemic embolism. RESULTS: The median age was 73 years, 55.1% were male, 6.6% had a previous thromboembolism, 17% of patients underwent major surgery, and the median risk scores were as follows: RCI = 1, CHADS2 = 1, CHA2DS2-VASc = 3, and R2CHADS2 = 2. The incidence of our 30-day composite was 4.2% (mortality 3.3%; stroke, transient ischemic attack, or systemic embolism 1.2%); and c indices were 0.65 for the RCI, 0.67 for the CHADS2 (NRI 14.3%, P < .001), 0.67 for CHA2DS2 VASc (NRI 10.7%, P < .001), and 0.68 for R2CHADS2 (NRI 11.4%, P < .001). The CHADS2, CHA2DS2-VASc, and R2CHADS2 scores were also all significantly better than the RCI for mortality risk prediction (NRI 12.3%, 8.4%, and 13.3%, respectively; all Ps < .01). CONCLUSIONS: In NVAF patients undergoing noncardiac surgery, the CHADS2, CHA2DS2-VASc, and R2CHADS2 scores all improved the prediction of major perioperative events including mortality compared to the RCI. PMID- 24952859 TI - A metabolomic profile is associated with the risk of incident coronary heart disease. AB - BACKGROUND: Metabolomics, defined as the comprehensive identification and quantification of low-molecular-weight metabolites to be found in a biological sample, has been put forward as a potential tool for classifying individuals according to their risk of coronary heart disease (CHD). Here, we investigated whether a single-point blood measurement of the metabolome is associated with and predictive for the risk of CHD. METHODS AND RESULTS: We obtained proton nuclear magnetic resonance spectra in 79 cases who developed CHD during follow-up (median 8.1 years) and in 565 randomly selected individuals. In these spectra, 100 signals representing 36 metabolites were identified. Applying least absolute shrinkage and selection operator regression, we defined a weighted metabolite score consisting of 13 proton nuclear magnetic resonance signals that optimally predicted CHD. This metabolite score, including signals representing a lipid fraction, glucose, valine, ornithine, glutamate, creatinine, glycoproteins, citrate, and 1.5-anhydrosorbitol, was associated with the incidence of CHD independent of traditional risk factors (TRFs) (hazard ratio 1.50, 95% CI 1.12 2.01). Predictive performance of this metabolite score on its own was moderate (C index 0.75, 95% CI 0.70-0.80), but after adding age and sex, the C-index was only modestly lower than that of TRFs (C-index 0.81, 95% CI 0.77-0.85 and C-index 0.82, 95% CI 0.78-0.87, respectively). The metabolite score was also associated with prevalent CHD independent of TRFs (odds ratio 1.59, 95% CI 1.19-2.13). CONCLUSION: A metabolite score derived from a single-point metabolome measurement is associated with CHD, and metabolomics may be a promising tool for refining and improving the prediction of CHD. PMID- 24952856 TI - Rationale for and design of the Acarbose Cardiovascular Evaluation (ACE) trial. AB - Patients with cardiovascular disease and impaired glucose tolerance are at increased risk of cardiovascular events and type 2 diabetes mellitus (T2DM). Lifestyle modification or pharmacological intervention can delay progression to T2DM, but there is no clear evidence that they reduce cardiovascular risk in this population. Acarbose, an alpha-glucosidase inhibitor that lowers postprandial blood glucose, has been shown to reduce T2DM risk by 25%, and possibly cardiovascular risk in impaired glucose tolerance subjects without cardiovascular disease. PMID- 24952862 TI - Extent of coronary artery disease and outcomes after ticagrelor administration in patients with an acute coronary syndrome: Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial. AB - BACKGROUND: Extensive coronary artery disease (CAD) is associated with higher risk. In this substudy of the PLATO trial, we examined the effects of randomized treatment on outcome events and safety in relation to the extent of CAD. METHODS: Patients were classified according to presence of extensive CAD (defined as 3 vessel disease, left main disease, or prior coronary artery bypass graft surgery). The trial's primary and secondary end points were compared using Cox proportional hazards regression. RESULTS: Among 15,388 study patients for whom the extent of CAD was known, 4,646 (30%) had extensive CAD. Patients with extensive CAD had more high-risk characteristics and experienced more clinical events during follow-up. They were less likely to undergo percutaneous coronary intervention (58% vs 79%, P < .001) but more likely to undergo coronary artery bypass graft surgery (16% vs 2%, P < .001). Ticagrelor, compared with clopidogrel, reduced the composite of cardiovascular death, myocardial infarction, and stroke in patients with extensive CAD (14.9% vs 17.6%, hazard ratio [HR] 0.85 [0.73-0.98]) similar to its reduction in those without extensive CAD (6.8% vs 8.0%, HR 0.85 [0.74-0.98], Pinteraction = .99). Major bleeding was similar with ticagrelor vs clopidogrel among patients with (25.7% vs 25.5%, HR 1.02 [0.90-1.15]) and without (7.3% vs 6.4%, HR 1.14 [0.98-1.33], Pinteraction = .24) extensive CAD. CONCLUSIONS: Patients with extensive CAD have higher rates of recurrent cardiovascular events and bleeding. Ticagrelor reduced ischemic events to a similar extent both in patients with and without extensive CAD, with bleeding rates similar to clopidogrel. PMID- 24952863 TI - Impact of smoking status on platelet function and clinical outcomes with prasugrel vs. clopidogrel in patients with acute coronary syndromes managed without revascularization: Insights from the TRILOGY ACS trial. AB - BACKGROUND: To further explore the impact of smoking on antiplatelet activity and treatment response, we evaluated time-dependent relationships between smoking status with on-treatment platelet reactivity and clinical outcomes for prasugrel vs. clopidogrel in patients with acute coronary syndromes managed medically without revascularization. METHODS AND RESULTS: A total of 7062 patients aged <75 years from the primary TRILOGY ACS cohort randomized to prasugrel vs. clopidogrel were evaluated through 30 months by baseline and time-dependent smoking status with adjusted proportional-hazards models. A total of 1994 participants (28%) [corrected] were included in a platelet function sub-study evaluating serial P2Y12 reaction unit (PRU) measurements. Current smokers (n = 1566 [22%]) at baseline had fewer comorbidities compared with non-smokers; nearly half quit smoking during follow-up. Although median on-treatment PRU values were lower with prasugrel vs. clopidogrel, persistent smokers had lower serial PRU values in both treatment groups compared with non-smokers, with no differential interaction of treatment response by smoking status. The frequency of cardiovascular death, myocardial infarction, or stroke in current smokers was significantly lower with prasugrel (11.7%) vs. clopidogrel (18.6%), but there was no difference in non smokers (13.8% vs. 13.7%), with significant interaction between treatment and baseline smoking status (P = .0002). Bleeding events occurred more frequently in prasugrel-treated patients with no significant interaction between treatment and baseline smoking status. CONCLUSIONS: Among medically managed ACS patients <75 years of age, the risk of ischemic outcomes was significantly reduced with prasugrel vs. clopidogrel among smokers vs. non-smokers. No interaction between on-treatment platelet reactivity and smoking status was found. PMID- 24952864 TI - Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial. AB - AIMS: Adipose-derived regenerative cells (ADRCs) can be isolated from liposuction aspirates and prepared as fresh cells for immediate administration in cell therapy. We performed the first randomized, placebo-controlled, double-blind trial to examine the safety and feasibility of the transendocardial injections of ADRCs in no-option patients with ischemic cardiomyopathy. METHODS AND RESULTS: Procedural, postoperative, and follow-up safety end points were monitored up to 36 months. After baseline measurements, efficacy was assessed by echocardiography and single-photon emission computed tomography (6, 12, and 18 months), metabolic equivalents and maximal oxygen consumption (MVO2) (6 and 18 months), and cardiac magnetic resonance imaging (6 months). We enrolled 21 ADRC-treated and 6 control patients. Liposuction was well tolerated, ADRCs were successfully prepared, and transendocardial injections were feasible in all patients. No malignant arrhythmias were seen. Adverse events were similar between groups. Metabolic equivalents and MVO2 values were preserved over time in ADRC-treated patients but declined significantly in the control group. The difference in the change in MVO2 from baseline to 6 and 18 months was significantly better in ADRC-treated patients compared with controls. The ADRC-treated patients showed significant improvements in total left ventricular mass by magnetic resonance imaging and wall motion score index. Single-photon emission computed tomography results suggested a reduction in inducible ischemia in ADRC-treated patients up to 18 months. CONCLUSION: Isolation and transendocardial injection of autologous ADRCs in no-option patients were safe and feasible. Our results suggest that ADRCs may preserve ventricular function, myocardial perfusion, and exercise capacity in these patients. PMID- 24952865 TI - Polymorphism of the cystatin C gene in patients with acute coronary syndromes: Results from the PLATelet inhibition and patient Outcomes study. AB - PURPOSE: Elevated cystatin C concentration is an independent risk factor for cardiovascular (CV) events in patients with acute coronary syndromes. Genetic polymorphisms in CST3 influence cystatin C levels, but their relationship to outcomes is unclear. METHODS: We measured cystatin C concentrations in plasma, obtained within 24 hours of admission, in 16,279 acute coronary syndrome patients from the PLATO trial. In 9,978 patients, we performed a genome-wide association study with up to 2.5 million single nucleotide polymorphisms. Single nucleotide polymorphisms affecting cystatin C levels were evaluated in relation to the first occurrence of myocardial infarction (MI) or CV death within 1 year using Cox regression analysis. RESULTS: Several single nucleotide polymorphisms were associated with cystatin C levels, most significantly rs6048952 (P = 7.82 * 10( 16)) adjacent to CST3. Median cystatin C concentrations per genotype were 0.85 mg/L (A/A), 0.80 mg/L (A/G), and 0.73 mg/L (G/G). Modeled as additive, the allelic effect, multivariable adjusted, was -0.045 mg/L per G allele for rs6048952. The multivariable adjusted c-statistic regarding the combined end point (CV death or MI) was 0.6735. Adding cystatin C or genotype-adjusted cystatin C levels resulted in c-statistics of 0.6761 and 0.6758, respectively. The multivariable adjusted hazard ratios per G allele at rs6048952 in the entire population were 0.94 (95% CI 0.83-1.06) for CV death or MI and 0.88 (95% CI 0.71 1.08) for CV death. CONCLUSIONS: Genetic polymorphisms affect cystatin C concentrations independently of kidney function. However, the polymorphisms were not observed to be associated with outcome, nor did they improve risk prediction or discriminative models. PMID- 24952866 TI - Delay in reperfusion with transradial percutaneous coronary intervention for ST elevation myocardial infarction: Might some delays be acceptable? AB - BACKGROUND: Randomized clinical trials (RCTs) suggest benefits for the transradial approach to percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). However, transradial PCI may delay reperfusion, leading to its avoidance. We sought to quantify the delay in reperfusion from transradial PCI ("transradial delay") that would need to be introduced to offset the potential mortality benefit of transradial PCI, compared with transfemoral, observed in RCTs. METHODS: We developed a decision-analytic model to compare transfemoral and transradial PCI in STEMI. Thirty-day mortality rates were estimated by pooling STEMI patients from 2 RCTs comparing transfemoral and transradial PCI. We projected the impact of transradial delay using estimates of the increase in mortality associated with door-to-balloon time delays. Sensitivity analyses were performed to understand the impact of uncertainty in assumptions. RESULTS: In the base case, a transradial delay of 83.0 minutes was needed to offset the mortality benefit of transradial PCI. When the mortality benefit of transradial PCI was one-quarter that observed in RCTs, the delay associated with equivalent mortality was 20.9 minutes. In probabilistic sensitivity analyses, transradial PCI was preferred over transfemoral PCI in 97.5% of simulations when transradial delay was 30 minutes and in 79.0% of simulations when delay was 60 minutes. CONCLUSIONS: A substantial transradial delay is required to eliminate even a fraction of the mortality benefit observed with transradial PCI in RCTs. Results were robust to changing multiple assumptions and have implications for operators reluctant to transition to transradial PCI in STEMI because of concern for delaying reperfusion. PMID- 24952868 TI - Nocturnal patterns of heart rate and the risk of mortality after acute myocardial infarction. AB - BACKGROUND: The purposes of this study were to identify nocturnal patterns of heart rate (HR) in depressed and nondepressed patients after an acute myocardial infarction (MI) and to determine which patterns, if any, are associated with all cause mortality or recurrent infarction. METHODS: Functional data analysis and model-based clustering methods were used to identify nocturnal HR patterns in 245 depressed and 247 nondepressed patients with a recent MI. All-cause mortality and recurrent infarctions were ascertained over a median follow-up of 24 months. RESULTS: Three HR activity patterns were identified. In the first, HR gradually declined during the nighttime and increased the next morning. The second pattern was similar, but with a higher overall HR during the recording interval. The third showed almost no decrease in HR at night (ie, "nondipping"). All-cause mortality was higher among patients with pattern 3 than pattern 1 (P = .007), and the combined end point of recurrent MI or all-cause mortality was higher in pattern 3 than pattern 2 (P = .05). Patterns 2 and 3 were more common in the depressed than in the nondepressed patients. CONCLUSIONS: The nondipping nocturnal HR independently predicts all-cause mortality and recurrent MI. Future studies should examine the underlying causes of nondipping nocturnal HR and its association with depression and investigate the effects of treatment on survival. PMID- 24952867 TI - Preprocedural statin use in patients undergoing percutaneous coronary intervention. AB - BACKGROUND: Earlier studies suggest that administering statins prior to percutaneous coronary interventions (PCIs) is associated with lower risk of periprocedural myocardial infarction and contrast-induced nephropathy. Current American College of Cardiology/American Heart Association guidelines recommend routine use of statins prior to PCI. It is unclear how commonly this recommendation is followed in clinical practice and what its effect on outcomes is. METHODS: We evaluated the incidence and in-hospital outcomes associated with statin pretreatment among patients undergoing PCI and enrolled in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium PCI registry at 44 hospitals in Michigan between January 2010 and December 2012. Propensity and exact matching were used to adjust for the nonrandom use of statins prior to PCI. Long-term mortality was assessed in a subset of patients who were linked to Medicare data. RESULTS: Our study population was comprised of 80,493 patients of whom 26,547 (33 %) did not receive statins prior to undergoing PCI. When compared to statin receivers, nonreceivers had lower rates of prior cardiovascular disease. In the matched analysis, absence of statin use prior to PCI was associated with a similar rate of in-hospital mortality (0.43% vs 0.42%, odds ratio 1.00, 95% CI 0.70-1.42, P = .98) and periprocedural myocardial infarction (2.34% vs 2.10%, odds ratio 1.13, 95% CI 0.97-1.32, P = .11) compared to statin receivers. Likewise, no difference in the rate of coronary artery bypass grafting, cerebrovascular accident (CVA), or contrast-induced nephropathy was observed. There was no association between pre-PCI use of statins and long-term survival among the subset of included Medicare patients (hazard ratio = 1.0, P = .96). CONCLUSIONS: A significant number of patients undergo PCI without statin pretreatment, but this is not associated with in-hospital major complications or long-term mortality. PMID- 24952870 TI - Letter to the editor concerning the rationale and design of the X-VERT trial by Ezekowitz et al. PMID- 24952869 TI - Dexamethasone for the prevention of postpericardiotomy syndrome: A DExamethasone for Cardiac Surgery substudy. AB - BACKGROUND: The postpericardiotomy syndrome (PPS) is a common complication following cardiac surgery. The pathophysiology remains unclear, although evidence exists that surgical trauma and the use of cardiopulmonary bypass provoke an immune response leading to PPS. We hypothesized that an intraoperative dose of dexamethasone decreases the risk of PPS, by reducing this inflammatory response. METHODS: We performed a subanalysis of the DECS study, which is a multicenter, double-blind, placebo-controlled, randomized trial of 4,494 patients undergoing cardiac surgery with use of cardiopulmonary bypass. The aim of the DECS study was to investigate whether a single intraoperative dose of 1 mg/kg dexamethasone reduced the incidence of a composite of death, myocardial infarction, stroke, renal failure, or respiratory failure, within 30 days of randomization. In this substudy, we retrospectively analyzed the occurrence of PPS in 822 patients who were included in the DECS trial and underwent valvular surgery. Postpericardiotomy syndrome was diagnosed if 2 of 5 listed symptoms were present: unexplained fever, pleuritic chest pain, pericardial or pleural rub, new or worsening pericardial or pleural effusion. All medical charts, x-rays, and echocardiograms were reviewed. Secondary end point was the occurrence of complicated PPS, defined as PPS with need for evacuation of pleural effusion, pericardiocentesis, and tamponade requiring intervention or hospital readmission for PPS. This is a blinded, single-center, post hoc analysis. RESULTS: Postpericardiotomy syndrome occurred in 119 patients (14.5%). The incidence of PPS after dexamethasone compared with placebo was 13.5% vs 15.5% (relative risk 0.88, 95% CI 0.63-1.22). For complicated PPS, the incidence was 3.8% versus 3.2% (relative risk 1.17, 95% CI 0.57-2.41, P = .66), respectively. CONCLUSION: In patients undergoing valvular cardiac surgery, high-dose dexamethasone treatment had no protective effect on the occurrence of PPS or complicated PPS. PMID- 24952871 TI - Prognosis of elderly ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention. PMID- 24952872 TI - Response to the letter to the editor by Ariza-Sole et al. PMID- 24952873 TI - ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer. AB - Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p <= 0.001 in BT474; p <= 0.01 in SKBR3) and in vivo (p <= 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naive and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p <= 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p <= 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p <= 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients. PMID- 24952874 TI - RFX1-dependent activation of SHP-1 induces autophagy by a novel obatoclax derivative in hepatocellular carcinoma cells. AB - Obatoclax is a small molecule which targets the Bcl-2 family, and is to treat leukemia, lymphoma and lung carcinoma. Previously, an obatoclax analogue, SC 2001, was found to disrupt the protein-protein interactions of the Bcl-2 family and also repress Bcl-XL and Mcl-1 expression via STAT3 inactivation. Here, we report a novel mechanism of autophagy induction by SC-2001 in liver cancer cells. The findings indicate that SC-2001 induced the autophagy marker LC3-II in four hepatocellular carcinoma (HCC) cells. Autophagosomes induced by SC-2001-treated cells were confirmed by electron microscopy. SC-2001 activated SHP-1, dephosphorylated STAT3 and Mcl-1, and subsequently released free beclin 1. Overexpression of STAT3 and Mcl-1 in PLC5 cells attenuated the induction of SC 2001 on autophagy. Abolishment of SHP-1 by a specific inhibitor aboragated the autophagic effects induced by SC-2001. In addition, it was further revealed that RFX-1, a transcription factor of SHP-1, is a critical regulator in SC-2001 mediated autophagy. Downregulation of RFX-1 by si-RNA protected cells from SC 2001-induced autophagy. Importantly, Huh7 tumor-bearing nude mice treated with SC 2001 showed downregulation of Mcl-1 and p-STAT3 protein expression and upregulation of SHP-1, LC3II, and RFX-1 protein expression. In summary, our data suggest that SC-2001 induces autophagic cell death in a RFX1/SHP-1/STAT3/Mcl-1 signaling cascade. PMID- 24952876 TI - Neural tube defects in Costa Rica, 1987-2012: origins and development of birth defect surveillance and folic acid fortification. AB - Our aim was to provide a descriptive overview of how the birth defects surveillance and folic acid fortification programs were implemented in Costa Rica through the establishment of the Registry Center for Congenital Anomalies (Centro de Registro de Enfermedades Congenitas-CREC), and fortification legislation mandates. We estimated the overall prevalence of neural tube defects (i.e., spina bifida, anencephaly and encephalocele) before and after fortification captured by CREC. Prevalence was calculated by dividing the total number of infants born with neural tube defects by the total number of live births in the country (1987 2012).A total of 1,170 newborns with neural tube defects were identified from 1987 to 2012 (1992-1995 data excluded); 628 were identified during the baseline pre-fortification period (1987-1991; 1996-1998); 191 during the fortification period (1999-2002); and 351 during the post-fortification time period (2003 2012). The overall prevalence of neural tube defects decreased from 9.8 per 10,000 live-births (95 % CI 9.1-10.5) for the pre-fortification period to 4.8 per 10,000 live births (95 % CI 4.3-5.3) for the post-fortification period. Results indicate a statistically significant (P < 0.05) decrease of 51 % in the prevalence of neural tube defects from the pre-fortification period to the post fortification period. Folic acid fortification via several basic food sources has shown to be a successful public health intervention for Costa Rica. Costa Rica's experience can serve as an example for other countries seeking to develop and strengthen both their birth defects surveillance and fortification programs. PMID- 24952875 TI - FHL1C induces apoptosis in Notch1-dependent T-ALL cells through an interaction with RBP-J. AB - BACKGROUND: Aberrantly activated Notch signaling has been found in more than 50% of patients with T-cell acute lymphoblastic leukemia (T-ALL). Current strategies that employ gamma-secretase inhibitors (GSIs) to target Notch activation have not been successful. Many limitations, such as non-Notch specificity, dose-limiting gastrointestinal toxicity and GSI resistance, have prompted an urgent need for more effective Notch signaling inhibitors for T-ALL treatment. Human four-and-a half LIM domain protein 1C (FHL1C) (KyoT2 in mice) has been demonstrated to suppress Notch activation in vitro, suggesting that FHL1C may be new candidate target in T-ALL therapy. However, the role of FHL1C in T-ALL cells remained unclear. METHODS: Using RT-PCR, we amplified full-length human FHL1C, and constructed full-length and various truncated forms of FHL1C. Using cell transfection, flow cytometry, transmission electron microscope, real-time RT-PCR, and Western blotting, we found that overexpression of FHL1C induced apoptosis of Jurkat cells. By using a reporter assay and Annexin-V staining, the minimal functional sequence of FHL1C inhibiting RBP-J-mediated Notch transactivation and inducing cell apoptosis was identified. Using real-time PCR and Western blotting, we explored the possible molecular mechanism of FHL1C-induced apoptosis. All data were statistically analyzed with the SPSS version 12.0 software. RESULTS: In Jurkat cells derived from a Notch1-associated T-ALL cell line insensitive to GSI treatment, we observed that overexpression of FHL1C, which is down-regulated in T ALL patients, strongly induced apoptosis. Furthermore, we verified that FHL1C induced apoptosis depended on the RBP-J-binding motif at the C-terminus of FHL1C. Using various truncated forms of FHL1C, we found that the RBP-J-binding motif of FHL1C had almost the same effect as full-length FHL1C on the induction of apoptosis, suggesting that the minimal functional sequence in the RBP-J-binding motif of FHL1C might be a new drug candidate for T-ALL treatment. We also explored the molecular mechanism of FHL1C overexpression-induced apoptosis, which suppressed downstream target genes such as Hes1 and c-Myc and key signaling pathways such as PI3K/AKT and NF-kappaB of Notch signaling involved in T-ALL progression. CONCLUSIONS: Our study has revealed that FHL1C overexpression induces Jurkat cell apoptosis. This finding may provide new insights in designing new Notch inhibitors based on FHL1C to treat T-ALL. PMID- 24952877 TI - Evaluation of Immunomagnetic Separation Method for the Recovery of Hepatitis A Virus and GI.1 and GII.4 Norovirus Strains Seeded on Oyster and Mussel. AB - Outbreaks of viral diseases are frequently associated with the consumption of minimally processed shellfish. Among the viruses in these outbreaks, hepatitis A virus (HAV) and human norovirus (NoV) have been increasingly reported as the most common food-borne pathogens. These viruses must be concentrated in tested samples in order to be detected. In this study, a method for the detection of NoV and HAV in shellfish using an immuno-magnetic separation (IMS) procedure combined with reverse transcriptase (RT)-PCR was developed. The IMS/RT-PCR method was applied to investigate the recovery rates of HAV, NoV GI.1, and GII.4 from oyster and mussel. Based on IMS/RT-PCR results, recovery rates for HAV from oyster and mussel test samples were 2.4 and 1.1%, respectively. The NoV GI.1 recovery rates from oyster and mussel samples were 4.9-9.2% (mean 6.9%) and 4.3-8.6% (mean 6.2%), respectively, and the NoV GII.4 recovery rates were 8.8 and 8.5%, respectively. These results verified that HAV, NoV GI.1, and GII.4 can be detected in all the test samples using the IMS/RT-PCR method, although the three inoculated viruses were recovered with low efficiency. In conclusion, the IMS/RT PCR method can be used to efficiently and rapidly detect viruses such as HAV and NoV in shellfish such as oyster and mussel. PMID- 24952880 TI - Imaging techniques for the assessment of suspected acute coronary syndromes in the emergency department. PMID- 24952881 TI - Full mouth rehabilitation of a young patient with partial expressions of ectodermal dysplasia: a clinical report. AB - Ectodermal dysplasia (ED) is a hereditary disorder characterized by the abnormal development of specific tissues and structures of ectodermal origin. This clinical report describes the multidisciplinary approach to the diagnosis and treatment of a 24-year-old patient with partial expression of ED. The treatment plan used dental implants to support fixed prostheses and ceramic restorations to establish acceptable esthetics and provide function. PMID- 24952878 TI - UVC Inactivation of dsDNA and ssRNA Viruses in Water: UV Fluences and a qPCR Based Approach to Evaluate Decay on Viral Infectivity. AB - Disinfection by low-pressure monochromatic ultraviolet (UVC) radiation (253.7 nm) became an important technique to sanitize drinking water and also wastewater in tertiary treatments. In order to prevent the transmission of waterborne viral diseases, the analysis of the disinfection kinetics and the quantification of infectious viral pathogens and indicators are highly relevant and need to be addressed. The families Adenoviridae and Polyomaviridae comprise human and animal pathogenic viruses that have been also proposed as indicators of fecal contamination in water and as Microbial Source Tracking tools. While it has been previously suggested that dsDNA viruses may be highly resistant to UVC radiation compared to other viruses or bacteria, no information is available on the stability of polyomavirus toward UV irradiation. Here, the inactivation of dsDNA (HAdV2 and JCPyV) and ssRNA (MS2 bacteriophage) viruses was analyzed at increasing UVC fluences. A minor decay of 2-logs was achieved for both infectious JC polyomaviruses (JCPyV) and human adenoviruses 2 (HAdV2) exposed to a UVC fluence of 1,400 J/m(2), while a decay of 4-log was observed for MS2 bacteriophages (ssRNA). The present study reveals the high UVC resistance of dsDNA viruses, and the UV fluences needed to efficiently inactivate JCPyV and HAdV2 are predicted. Furthermore, we show that in conjunction with appropriate mathematical models, qPCR data may be used to accurately estimate virus infectivity. PMID- 24952882 TI - Masticatory performance of complete denture wearers after using two adhesives: a crossover randomized clinical trial. AB - STATEMENT OF PROBLEM: Masticatory performance analysis of conventional complete denture wearers who use denture adhesives is scarce in the dental literature. PURPOSE: The purpose of this study was to assess the effect of the use of 2 denture adhesives on the masticatory performance of conventional complete denture wearers by means of a crossover study. MATERIAL AND METHODS: Forty individuals who were edentulous received new maxillary and mandibular complete dentures, and, after an adaptation period, were submitted to masticatory performance analysis without denture adhesive (control). The participants were randomly divided and assigned to 2 protocols: protocol 1, denture adhesive 1 (Ultra Corega cream tasteless) use during the first 15 days, followed by no use of denture adhesive over the next 15 days (washout), and then use of denture adhesive 2 (Ultra Corega powder tasteless) for 15 days; protocol 2, denture adhesive 2 (Ultra Corega powder tasteless) use during the first 15 days, followed by no use of denture adhesive during the next 15 days (washout), and then use of denture adhesive 1 (Ultra Corega cream tasteless) for 15 days. The masticatory performance was assessed immediately after the use of denture adhesive by means of the sieve method, in which participants were instructed to deliberately chew 5 almonds for 20 chewing strokes. Masticatory performance was calculated by the weight of comminuted material that passed through the sieves. Data were analyzed by a 1-way ANOVA for paired samples and the multiple comparison of means by using the Bonferroni test (alpha=.05). RESULTS: A significant increase in masticatory performance was noted after using the Ultra Corega cream (mean, 32.6%) and Ultra Corega powder (mean, 31.2%) when compared with the control group (mean, 19.8%) (P<.001). No significant difference was found between the 2 denture adhesives evaluated. CONCLUSION: The use of denture adhesive improved the masticatory performance of conventional complete denture wearers. No difference was found in masticatory performance with the use of cream or powder denture adhesive. PMID- 24952883 TI - An accelerated technique for a ceramic-pressed-to-metal restoration with CAD/CAM technology. AB - The conventional fabrication of metal ceramic restorations depends on an experienced dental technician and requires a long processing time. However, complete-contour digital waxing and digital cutback with computer-aided design and computer-aided manufacturing (CAD/CAM) technology can overcome these disadvantages and provide a correct metal framework design and space for the ceramic material. PMID- 24952884 TI - miR-146a and miR-196a2 polymorphisms in patients with ischemic stroke in the northern Chinese Han population. AB - MicroRNAs are endogenous non-coding RNAs about 22 nucleotides in length that can repress the expression of proteins by binding to the 3'-untranslated regions of target messenger RNAs. We hypothesized that polymorphisms in miR-146a and miR 196a2 are associated with risk of ischemic stroke in the northern Chinese Han population. In a case-control study of 368 ischemic stroke patients and 381 control subjects that were frequency matched by age and gender, we genotyped two single nucleotide polymorphisms (rs11614913 in miR-196a2 and rs2910164 in miR 146a) using polymerase chain reaction-ligation detection reaction. The frequencies of the rs2910164 CC genotype and C allele within miR-146a were not significantly different in patients with ischemic stroke compared with those in the healthy control group. In subgroup meta-analysis, rs2910164 in miR-146a and large-artery atherosclerosis, rather than small-vessel disease, showed the significant association under the dominant model (CC vs CG+GG, OR 1.694; 95 % CI 1.199-2.395 p = 0.003). After adjusting for confounding risk factors of ischemic stroke by logistic regression analysis, this significant correlation remained. In addition, the distributions of the miR-196a2 genotypes and alleles were not statistically different between ischemic stroke and healthy groups. We also did not find any significant association from stroke subtypes. The CC genotype and C allele of rs2910164 within miR-146a are associated with an increased incidence of large-artery atherosclerotic stroke in the northern Chinese Han population. This study indicates that miR-146a (rs2910164) might contribute to ischemic stroke susceptibility in the northern Chinese Han population. PMID- 24952885 TI - Macrophage subsets and microglia in multiple sclerosis. AB - Along with microglia and monocyte-derived macrophages, macrophages in the perivascular space, choroid plexus, and meninges are the principal effector cells in neuroinflammatory and neurodegenerative disorders. These phagocytes are highly heterogeneous cells displaying spatial- and temporal-dependent identities in the healthy, injured, and inflamed CNS. In the last decade, researchers have debated on whether phagocytes subtypes and phenotypes are pathogenic or protective in CNS pathologies. In the context of this dichotomy, we summarize and discuss the current knowledge on the spatiotemporal physiology of macrophage subsets and microglia in the healthy and diseased CNS, and elaborate on factors regulating their behavior. In addition, the impact of macrophages present in lymphoid organs on CNS pathologies is defined. The prime focus of this review is on multiple sclerosis (MS), which is characterized by inflammation, demyelination, neurodegeneration, and CNS repair, and in which microglia and macrophages have been extensively scrutinized. On one hand, microglia and macrophages promote neuroinflammatory and neurodegenerative events in MS by releasing inflammatory mediators and stimulating leukocyte activity and infiltration into the CNS. On the other hand, microglia and macrophages assist in CNS repair through the production of neurotrophic factors and clearance of inhibitory myelin debris. Finally, we define how microglia and macrophage physiology can be harnessed for new therapeutics aimed at suppressing neuroinflammatory and cytodegenerative events, as well as promoting CNS repair. We conclude that microglia and macrophages are highly dynamic cells displaying disease stage and location specific fates in neurological disorders. Changing the physiology of divergent phagocyte subsets at particular disease stages holds promise for future therapeutics for CNS pathologies. PMID- 24952886 TI - The efficiency of a donor-recipient program using infertile donors' egg cryo banking: a Brazilian reality. AB - PURPOSE: To determine whether Brazilian egg donation treatment outcomes with oocytes donated from infertile couples are equivalent to those obtained worldwide with oocytes donated from fertile egg-donors. METHODS: In this descriptive study, egg-donation cycles from 259 women, performed from January 2009 to July 2013, were evaluated. Oocytes were obtained from patients undergoing ICSI who decided to donate their surplus oocytes. We described the survival, fertilization, blastocyst, implantation and pregnancy rates obtained in our infertile donor recipient program. In addition, we described the results obtained in previous published studies. RESULTS: In our egg-donation program we obtained a fertilization rate of 72.9 %, a blastocyst formation rate of 53.2 %, an implantation rate of 31.1 % and the estimated clinical pregnancy rate per warmed oocyte was 5.4 %. The analyzed studies, performed between 2008 and 2013, included varying numbers of egg-donors (range: 20-600), warmed oocytes (range: 123-3826) and survival rates (range: 85.6-92.5 %). Fertilization rates ranged from 74.2 to 87.0 %, blastocyst formation rate ranged from 41.3 % to 68.0 %, implantation rates ranged from 24.7 % to 55.3 % and the clinical pregnancy rate per warmed oocyte ranged from 3.9 % to 9.8 %. CONCLUSIONS: New and reassuring information derived from our egg-donation program demonstrates outcomes similar to those reported for other egg donation programs. PMID- 24952887 TI - Weight loss using evidence-based strategies in mobile apps. PMID- 24952888 TI - Weight loss using evidence-based strategies in mobile apps. Authors' response. PMID- 24952890 TI - Association between KIF1B rs17401966 polymorphism and hepatocellular carcinoma risk: a meta-analysis involving 17,210 subjects. AB - Some publications have evaluated the correlation between KIF1B rs17401966 polymorphism and hepatocellular carcinoma (HCC) with conflicting results. We performed this meta-analysis to clarify the association of KIF1B rs17401966 polymorphism and HCC risk. We searched PubMed, ISI Web of Knowledge, ScienceDirect, and Google Scholar. The combined odds ratio (OR) with 95 % confidence interval (CI) was calculated to estimate the strength of the association. Heterogeneity and publication bias were also assessed. In total, 15 case-control studies with 7,596 HCC cases and 9,614 controls were included in the meta-analysis. A significant association between KIF1B rs17401966 polymorphism and HCC risk was detected (OR = 0.81, 95 % CI 0.72-0.91, P < 0.001). We also found a significant association between KIF1B rs17401966 polymorphism and HCC risk in Chinese (OR = 0.77, 95 % CI 0.67-0.89, P < 0.001). In the subgroup analysis by gender, KIF1B rs17401966 polymorphism was significantly associated with HCC risk in man (OR = 0.57, 95 % CI 0.51-0.64, P < 0.001). In the subgroup analyses of age, the similar associations were also observed in young patients (OR = 0.50, 95 % CI 0.39-0.66, P < 0.001) and old patients (OR = 0.66, 95 % CI 0.57-0.77, P < 0.001). However, no association was observed in women subgroup (OR = 0.79, 95 % CI 0.59-1.06, P = 0.11). This meta-analysis showed a significant association between KIF1B rs17401966 polymorphism and HCC. PMID- 24952889 TI - Relationships between genetic polymorphisms in inflammation-related factor gene and the pathogenesis of nasopharyngeal cancer. AB - Our study aims to discuss the association between inflammation-related factors such as single nucleotide polymorphisms (SNPs) with susceptibility and recurrence in nasopharyngeal carcinoma. We used Taqman real-time polymerase chain reaction (PCR) to characterize the genetic variation of five SNPs in 194 nasopharyngeal carcinoma patients and 231 healthy subjects. All statistical analysis is performed with statistical product and service solutions v13.0; odds ratio (OR) value and 95 % confidence interval (CI) were calculated. There is no relationship between TGFbeta1 -869 T/C, IL-6 -634C/G, TGFbeta1 -509C/T, IL1 -511C/T and nasopharyngeal carcinoma susceptibility. Both single factor and multiple factors analysis showed that IL1a -889 T/T genotype is significantly associated with nasopharyngeal carcinoma in decreasing the risk of nasopharyngeal carcinoma. A highly significant association was found between IL1a -889 T/T genotype and protective genotype as defined by various pathological types. This is more obvious in the protective genotype of the non-keratin-type squamous carcinoma undifferentiated type. We also discovered that genotype G/G and C/G + G/G of IL6 634 gene are associated with reduced recurrence of nasopharyngeal carcinoma. IL1a -889 gene polymorphism and susceptibility is related to nasopharyngeal carcinoma and can potentially decrease the risk of nasopharyngeal carcinoma in the Han Chinese population in north China. IL1-889 TT genotype is protective genotype for nasopharyngeal carcinoma. We have provided evidence that the GG genotype of the IL6 -634 gene is associated with recurrent risk of nasopharyngeal carcinoma. The G allele is the protective gene of nasopharyngeal carcinoma recurrence. PMID- 24952891 TI - Aberrant promoter methylation of the CHD1 gene may contribute to the pathogenesis of breast cancer: a meta-analysis. AB - Cadherin-1 (CHD1), as an invasion suppressor gene, could suppress tumor cell invasion and metastasis in various tumors, but reduced CHD1 levels, resulting from epigenetic silencing, are common in poorly differentiated, advanced stage carcinomas. This meta-analysis was performed to evaluate the relationships between promoter methylation of CHD1 and breast cancer. Relevant studies were retrieved from the Web of Science (1945 ~ 2013), the Cochrane Library (Issue 12, 2013), PubMed (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013) using a systematic literature search. Results were summarized by meta-analyses, conducted using the STATA software (version 12.0, Stata Corporation, College Station, TX, USA). Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were calculated. In the present meta-analysis, 9 cohort studies with a total of 425 patients with breast cancer were included. Our meta-analysis results demonstrated that the frequency of CHD1 promoter methylation in cancer tissues was significantly higher than that in normal tissues, adjacent tissues, and benign tissues (cancer tissue vs. normal tissue OR = 30.87, 95 % CI = 16.76 ~ 56.86, P < 0.001; cancer tissue vs. adjacent tissue OR = 23.30, 95 % CI = 12.85 ~ 42.26, P < 0.001; cancer tissue vs. benign tissue OR = 2.94, 95 % CI = 1.60 ~ 5.40, P < 0.001; respectively). Ethnicity stratified analysis indicated that aberrant CHD1 promoter methylation was strongly correlated with breast cancer among both Asians and Caucasians in the majority of subgroups. Our results suggest that aberrant promoter methylation of the CHD1 gene may have a high frequency in breast cancer tissues. Thus, CHD1 methylation could be correlated with the pathogenesis of breast cancer. PMID- 24952893 TI - Prion permissive pathways: extracellular matrix genes control susceptibility to prion infection. PMID- 24952892 TI - A standardized [18F]-FDG-PET template for spatial normalization in statistical parametric mapping of dementia. AB - [18F]-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) is a widely used diagnostic tool that can detect and quantify pathophysiology, as assessed through changes in cerebral glucose metabolism. [18F]-FDG PET scans can be analyzed using voxel-based statistical methods such as Statistical Parametric Mapping (SPM) that provide statistical maps of brain abnormalities in single patients. In order to perform SPM, a "spatial normalization" of an individual's PET scan is required to match a reference PET template. The PET template currently used for SPM normalization is based on [15O]-H2O images and does not resemble either the specific metabolic features of [18F]-FDG brain scans or the specific morphological characteristics of individual brains affected by neurodegeneration. Thus, our aim was to create a new [18F]-FDG PET aging and dementia-specific template for spatial normalization, based on images derived from both age-matched controls and patients. We hypothesized that this template would increase spatial normalization accuracy and thereby preserve crucial information for research and diagnostic purposes. We investigated the statistical sensitivity and registration accuracy of normalization procedures based on the standard and new template-at the single-subject and group level-independently for subjects with Mild Cognitive Impairment (MCI), probable Alzheimer's Disease (AD), Frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB). We found a significant statistical effect of the population-specific FDG template based normalisation in key anatomical regions for each dementia subtype, suggesting that spatial normalization with the new template provides more accurate estimates of metabolic abnormalities for single-subject and group analysis, and therefore, a more effective diagnostic measure. PMID- 24952895 TI - Not an inside job: non-coded amino acids compromise the genetic code. PMID- 24952894 TI - Molecular mechanism of ligand recognition by membrane transport protein, Mhp1. AB - The hydantoin transporter Mhp1 is a sodium-coupled secondary active transport protein of the nucleobase-cation-symport family and a member of the widespread 5 helix inverted repeat superfamily of transporters. The structure of Mhp1 was previously solved in three different conformations providing insight into the molecular basis of the alternating access mechanism. Here, we elucidate detailed events of substrate binding, through a combination of crystallography, molecular dynamics, site-directed mutagenesis, biochemical/biophysical assays, and the design and synthesis of novel ligands. We show precisely where 5-substituted hydantoin substrates bind in an extended configuration at the interface of the bundle and hash domains. They are recognised through hydrogen bonds to the hydantoin moiety and the complementarity of the 5-substituent for a hydrophobic pocket in the protein. Furthermore, we describe a novel structure of an intermediate state of the protein with the external thin gate locked open by an inhibitor, 5-(2-naphthylmethyl)-L-hydantoin, which becomes a substrate when leucine 363 is changed to an alanine. We deduce the molecular events that underlie acquisition and transport of a ligand by Mhp1. PMID- 24952897 TI - National total survey of German adolescent suicide in prison. AB - Incarcerated adolescents are a high-risk group for suicidal behaviour, but data on completed suicide are scarce in this population. The present study aimed at calculating relative risks (RR) of suicide in detention and identifying age related risk factors. We compared data of a German national total survey of completed suicide of young detainees (14 to <21 years, N = 79) during the years 2000-2010 with age- and gender-adjusted suicide deaths in non-incarcerated adolescents (N = 3,484) and incarcerated adults (N = 781). Prison suicide accounted for 2.3% of all suicide deaths in adolescents, but only 0.1% of this age group was detained. The RR = 23.0 for adolescent suicide in detention exceeded the RR = 7.7 of adults by far. In adults, suicide rates in pre-trial detention was fivefold higher than in criminal detention; suicide rates were more balanced in adolescent detainees. Our results underline the need for age-specific suicide prevention strategies in detention. PMID- 24952896 TI - Equivalence of BCR-ABL transcript levels with complete cytogenetic remission in patients with chronic myeloid leukemia in chronic phase. AB - PURPOSE: Chronic myeloid leukemia (CML) patients are monitored by both cytogenetic and molecular assessments, although present guidelines appear to switch from cytogenetic to molecular criteria. Due to the increasing use of molecular measurements, it was the aim of this work to identify a BCR-ABL level according to the international scale (BCR-ABL(IS)) as an equivalent substitute for complete cytogenetic remission (CCyR). METHODS: In total, 1,329 paired data from 557 patients of the German CML-Study IV were evaluated. The data set was divided into a learning set and a validation set. The best cutoff was determined applying a minimal p value approach to the Fisher test. RESULTS: In the learning set, we found BCR-ABL(IS) values between 0.2 and 1.1 % were well suited for predicting a CCyR. In the validation set, the cutoff level of 1 % led to a mean concordance rate of 90.1 %. CONCLUSIONS: Our results suggest that there is no one to-one cutoff for BCR-ABL(IS) representing CCyR, but we advise to use the 1 % BCR ABL(IS) in order to avoid misclassification of CCyR patients. PMID- 24952898 TI - Identification of a high-risk group for low-dose aspirin-induced gastropathy by measuring serum pepsinogen in H. pylori-infected subjects. AB - BACKGROUND: We recently demonstrated in humans that the extent of low-dose aspirin (LDA)-induced gastropathy was directly related to the individual gastric acid secretion level. We also established reliable cutoff serum pepsinogen (PG) values to predict gastric acid secretion status. In this study, we investigated the clinical usefulness of measuring the serum pepsinogen values for identifying a high-risk group for gastric mucosal injury among chronic LDA users. METHODS: One hundred long-term LDA users were enrolled in this analysis. Serum from each subject was subjected to determination of H. pylori status and measurement of pepsinogen values. According to our recent report, a PG I value >= 50 ng/mL was defined as estimated hyperchlorhydria in H. pylori-negative subjects, while a PG I/II >= 3.3 was defined as estimated hyperchlorhydria in H. pylori-positive subjects. The grade of gastric mucosal injury was assessed endoscopically, and multiple logistic regression analyses were used to estimate the risk. RESULTS: Estimated hyperchlorhydria was a strong independent risk for intensive gastric mucosal injury with an OR (95% CI): 34.0 (4.5-259) and for gastric ulcer with an OR (95% CI): 10.2 (1.8-58.3) in H. pylori-positive subjects, while it was not a significant risk in H. pylori-negative subjects. The association persisted even after excluding those with conventional risks for LDA-gastropathy such as ulcer histories. CONCLUSION: Using simple serum measurement of H. pylori antibody and pepsinogen concentrations, an extremely high-risk group for LDA-induced gastropathy could be extracted, and these patients should become a therapeutic target for prevention of LDA-induced gastropathy. PMID- 24952899 TI - Catheter ablation guided by real-time MRI. AB - Real-time magnetic resonance imaging (MRI) combines the advantages of excellent soft-tissue characterization in a true 3D anatomical and functional model with the possibility of lesion and gap visualization without the need of any radiation. Therefore, real-time MRI presents a particularly attractive imaging technology to guide electrophysiology studies and catheter ablation procedures. This article aims to provide an overview on current routine clinical application of MRI in the setting of interventional electrophysiology. Furthermore, development of real-time MRI guided electrophysiology studies and first experiences with MRI guided catheter ablation procedures are depicted. In this context advantages, challenges and limitations of real-time MRI guided catheter ablation as well as future perspectives are discussed. PMID- 24952900 TI - Nicorandil suppresses urinary protein excretion and activates eNOS in Dahl salt sensitive hypertensive rats. AB - BACKGROUND: Hypertension is a risk factor common to both chronic kidney disease and cardiovascular disease. Nicorandil is widely used for the treatment of angina. We investigated the benefits of nicorandil with respect to renal dysfunction in Dahl salt-sensitive hypertensive (DS) rats. METHOD: DS rats were fed a high-salt (HS) diet and nicorandil was administered via the drinking water. Blood pressure and renal function were measured for 4 weeks after starting the rats on the HS diet. RESULTS: In rats fed the HS diet, renal dysfunction was manifested by an increase in urinary protein and N-acetyl-beta-D-glucosaminidase excretion. Nicorandil ameliorated renal function with a concomitant reduction in urinary 8-hydroxy-2'-deoxyguanosine and an increase in urinary NOx. Significant upregulation of endothelial nitric oxide synthase (eNOS) expression and an increase in the eNOS dimer/monomer ratio (reduction of eNOS uncoupling) was demonstrated in glomeruli following nicorandil treatment. The blood pressure of DS rats was increased by salt loading; however, no significant change in blood pressure was observed with nicorandil treatment. CONCLUSION: In DS rats fed a HS diet, nicorandil prevented the development of renal dysfunction, which was accompanied by an increase in eNOS expression in the kidneys. PMID- 24952901 TI - Assessing the clinical utility of cancer genomic and proteomic data across tumor types. AB - Molecular profiling of tumors promises to advance the clinical management of cancer, but the benefits of integrating molecular data with traditional clinical variables have not been systematically studied. Here we retrospectively predict patient survival using diverse molecular data (somatic copy-number alteration, DNA methylation and mRNA, microRNA and protein expression) from 953 samples of four cancer types from The Cancer Genome Atlas project. We find that incorporating molecular data with clinical variables yields statistically significantly improved predictions (FDR < 0.05) for three cancers but those quantitative gains were limited (2.2-23.9%). Additional analyses revealed little predictive power across tumor types except for one case. In clinically relevant genes, we identified 10,281 somatic alterations across 12 cancer types in 2,928 of 3,277 patients (89.4%), many of which would not be revealed in single-tumor analyses. Our study provides a starting point and resources, including an open access model evaluation platform, for building reliable prognostic and therapeutic strategies that incorporate molecular data. PMID- 24952903 TI - Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing. AB - Genome sequencing studies have shown that human malignancies often bear mutations in four or more driver genes, but it is difficult to recapitulate this degree of genetic complexity in mouse models using conventional breeding. Here we use the CRISPR-Cas9 system of genome editing to overcome this limitation. By delivering combinations of small guide RNAs (sgRNAs) and Cas9 with a lentiviral vector, we modified up to five genes in a single mouse hematopoietic stem cell (HSC), leading to clonal outgrowth and myeloid malignancy. We thereby generated models of acute myeloid leukemia (AML) with cooperating mutations in genes encoding epigenetic modifiers, transcription factors and mediators of cytokine signaling, recapitulating the combinations of mutations observed in patients. Our results suggest that lentivirus-delivered sgRNA:Cas9 genome editing should be useful to engineer a broad array of in vivo cancer models that better reflect the complexity of human disease. PMID- 24952904 TI - Optimization and validation of a label-free MRM method for the quantification of cytochrome P450 isoforms in biological samples. AB - Cytochromes P450 (CYPs) play critical roles in oxidative metabolism of many endogenous and exogenous compounds. Protein expression levels of CYPs in liver provide relevant information for a better understanding of the importance of CYPs in pharmacology and toxicology. This work aimed at establishing a simple method to quantify six CYPs (CYP3A4, CYP3A5, CYP1A2, CYP2D6, CYP2C9, and CYP2J2) in various biological samples without isotopic labeling. The biological matrix was spiked with the standard peptides prior to the digestion step to realize a label free quantification by mass spectrometry. The method was validated and applied to quantify these six isoforms in both human liver microsomes and mitochondria, but also in recombinant expression systems such as baculosomes and the HepG2 cell line. The results showed intra-assay and interassay accuracy and precision within 16 % and 5 %, respectively, at the low quality control level, and demonstrated the advantages of the method in terms of reproducibility and cost. PMID- 24952905 TI - Lipoprotein(a) determination in human serum using a nitrilotriacetic acid derivative immunosensing scaffold on disposable electrodes. AB - A novel strategy for the construction of a disposable integrated amperometric immunosensor for the sensitive and rapid determination of lipoprotein(a) (Lp(a)), an important predictor of cardiovascular disease risk, in human serum is reported. The approach uses a sandwich format involving the covalent immobilization of selective capture antibodies (antiLp(a)) on the surface of N [Nalpha,Nalpha-bis(carboxymethyl)-lysine]-12-mercaptododecanamide (HS-NTA) modified screen-printed carbon electrodes (SPCEs). After a blocking step with skimmed milk, the modified antiLp(a)-SPCEs were incubated with a mixture solution containing the target analyte and a fixed concentration of a specific biotinylated antibody (biotin-antiLp(a)) and a streptavidin-horseradish peroxidase (HRP) (Strep-HRP) conjugate. The amperometric responses of the resulting immunosensor at -0.10 V (vs an Ag pseudo-reference electrode), upon addition of 3,3',5,5'-tetramethylbenzidine (TMB) as electron transfer mediator and H2O2 as the enzyme substrate, were used to monitor the extent of the immunoreactions. The developed methodology exhibited a wide range of linearity between 0.02 and 10 MUg mL(-1), a low detection limit (LOD) of 8 ng mL(-1), and a great selectivity against other serum components. The usefulness of the Lp(a) immunosensor was demonstrated by analyzing spiked serum samples as well as a reference serum containing a certified Lp(a) content. PMID- 24952906 TI - The impact of isolated tumor cells on loco-regional recurrence in breast cancer patients treated with breast-conserving treatment or mastectomy without post mastectomy radiation therapy. AB - To compare the outcome of patients with invasive breast cancer, who had isolated tumor cells (ITC) in sentinel lymph nodes, pN0(i+), to patients with histologically negative nodes, pN0. We retrospectively studied 1,273 patients diagnosed with T1-T3 breast cancer from 1999 to 2009. Patients were divided into 2 populations: 807 patients treated with breast-conserving surgery (BCS) and radiotherapy (RT), 85(10.5 %) with pN0(i+) and 722(89.5 %) with pN0. And the other population had 466 patients treated with mastectomy without post-mastectomy radiation therapy (PMRT), 80(17.2 %) with pN0(i+),and 386(82.8 %)with pN0. All patients underwent sentinel node biopsy, and the presence of ITC was determined. Patients with axillary dissection only or neoadjuvant chemotherapy were excluded. Among the 1,273 patients studied; 87.3 % received adjuvant systemic therapy. Kaplan-Meier, Cox regression, and log-rank statistical tests were used. Median patient age was 55.7 years. Median follow-up was 69.5 months. The 5- and 10-year cumulative incidence of Loco-regional recurrence (LRR) for patients treated with BCS and RT was 1.6 and 3.5 % for 85 pN0(i+) patients, and 2.4 and 5 % for 722 pN0 patients, respectively. For patients treated with mastectomy without PMRT, 5- and 10-year LRR rates were 2.8 and 2.8 % for 80 pN0(i+) patients, and 1.8 and 3 % for 386 pN0 patients, respectively. There were no statistically significant differences in LRR (p = 0.9), distant recurrence (p = 0.3) ,and overall survival (p = 0.5) among all groups. On multivariate analysis, ITC were not associated with increased risk of LRR, distant recurrence and overall survival. Grade (p = 0.003) and systemic therapy (p = 0.02) were statistically significantly associated with risk of LRR. Sentinel node ITC have no significant impact on LRR, distant recurrence and overall survival in breast cancer patients. Additional treatments such as axillary dissection, chemotherapy, or regional radiation should not be given solely based on the presence of sentinel node ITC. PMID- 24952907 TI - Perceived Level of Relationship Commitment, Sexual Risk Taking and Condom Use Among American Indian Men. AB - This study investigated commitment, sexual risk taking behavior and condom use among heterosexual men. The sample was 120 American Indian men ages 18-24 on the Fort Peck Reservation. Measures included sexual risk taking behaviors, attitude towards the relationship, discordance in perception of attitudes toward the relationship, and condom use. Inconsistent condom users comprised 57 % of the sample. Men with more than one sexual partner as well as men who reported inconsistent condom use reported less favorable attitudes toward their relationship. Discordant attitudes were observed in men who reported that their partner was more committed to the relationship then they were. This influenced having multiple sex partners. Inconsistent condom use decreased as respondents perceived an increasing level of partner's attachment to the relationship in comparison to themselves. Further examination of intimate partner relationship characteristics and how these dynamics influence sexual and reproductive health among American Indians is needed. PMID- 24952908 TI - CEMTDD: Chinese Ethnic Minority Traditional Drug Database. PMID- 24952911 TI - Screening for mental health problems: does it work? PMID- 24952909 TI - Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics. AB - Genome-wide association studies (GWAS) have identified thousands of loci associated with complex traits, but it is challenging to pinpoint causal genes in these loci and to exploit subtle association signals. We used tissue-specific quantitative interaction proteomics to map a network of five genes involved in the Mendelian disorder long QT syndrome (LQTS). We integrated the LQTS network with GWAS loci from the corresponding common complex trait, QT-interval variation, to identify candidate genes that were subsequently confirmed in Xenopus laevis oocytes and zebrafish. We used the LQTS protein network to filter weak GWAS signals by identifying single-nucleotide polymorphisms (SNPs) in proximity to genes in the network supported by strong proteomic evidence. Three SNPs passing this filter reached genome-wide significance after replication genotyping. Overall, we present a general strategy to propose candidates in GWAS loci for functional studies and to systematically filter subtle association signals using tissue-specific quantitative interaction proteomics. PMID- 24952912 TI - What is the restriction on over-the-counter emergency contraception access today? PMID- 24952902 TI - Linking T-cell receptor sequence to functional phenotype at the single-cell level. AB - Although each T lymphocyte expresses a T-cell receptor (TCR) that recognizes cognate antigen and controls T-cell activation, different T cells bearing the same TCR can be functionally distinct. Each TCR is a heterodimer, and both alpha- and beta-chains contribute to determining TCR antigen specificity. Here we present a methodology enabling integration of information about TCR specificity with information about T cell function. This method involves sequencing of TCRalpha and TCRbeta genes, and amplifying functional genes characteristic of different T cell subsets, in single T cells. Because this approach retains information about individual TCRalpha-TCRbeta pairs, TCRs of interest can be expressed and used in functional studies, for antigen discovery, or in therapeutic applications. We apply this approach to study the clonal ancestry and differentiation of T lymphocytes infiltrating a human colorectal carcinoma. PMID- 24952913 TI - The authors reply. PMID- 24952910 TI - All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins. AB - All-optical electrophysiology-spatially resolved simultaneous optical perturbation and measurement of membrane voltage-would open new vistas in neuroscience research. We evolved two archaerhodopsin-based voltage indicators, QuasAr1 and QuasAr2, which show improved brightness and voltage sensitivity, have microsecond response times and produce no photocurrent. We engineered a channelrhodopsin actuator, CheRiff, which shows high light sensitivity and rapid kinetics and is spectrally orthogonal to the QuasArs. A coexpression vector, Optopatch, enabled cross-talk-free genetically targeted all-optical electrophysiology. In cultured rat neurons, we combined Optopatch with patterned optical excitation to probe back-propagating action potentials (APs) in dendritic spines, synaptic transmission, subcellular microsecond-timescale details of AP propagation, and simultaneous firing of many neurons in a network. Optopatch measurements revealed homeostatic tuning of intrinsic excitability in human stem cell-derived neurons. In rat brain slices, Optopatch induced and reported APs and subthreshold events with high signal-to-noise ratios. The Optopatch platform enables high-throughput, spatially resolved electrophysiology without the use of conventional electrodes. PMID- 24952914 TI - The authors reply. PMID- 24952915 TI - Neuropeptides, trophic factors, and other substances providing morphofunctional and metabolic protection in experimental models of diabetic retinopathy. AB - Vision is the most important sensory modality for many species, including humans. Damage to the retina results in vision loss or even blindness. One of the most serious complications of diabetes, a disease that has seen a worldwide increase in prevalence, is diabetic retinopathy. This condition stems from consequences of pathological metabolism and develops in 75% of patients with type 1 and 50% with type 2 diabetes. The development of novel protective drugs is essential. In this review we provide a description of the disease and conclude that type 1 diabetes and type 2 diabetes lead to the same retinopathy. We evaluate existing experimental models and recent developments in finding effective compounds against this disorder. In our opinion, the best models are the long-term streptozotocin-induced diabetes and Otsuka Long-Evans Tokushima Fatty and spontaneously diabetic Torii rats, while the most promising substances are topically administered somatostatin and pigment epithelium-derived factor analogs, antivasculogenic substances, and systemic antioxidants. Future drug development should focus on these. PMID- 24952916 TI - Stereological and allometric studies on neurons and axo-dendritic synapses in superior cervical ganglia. AB - The superior cervical ganglion (SCG) plays an important role in neuropathies including Horner's syndrome, stroke, and epilepsy. While mammalian SCGs seem to share certain organizational features, they display natural differences related to the animal size and side and the complexity and synaptic coverage of their dendritic arborizations. However, apart from the rat SCG, there is little information concerning the number of SCG neurons and synapses, and the nature of relationships between body weight and the numbers and sizes of neurons and synapses remain uncertain. In the recognition of this gap in the literature, in this chapter, we reviewed the current knowledge on the SCG structure and its remodeling during postnatal development across a plethora of large mammalian species, focusing on exotic rodents and domestic animals. Instrumentally, we present stereology as a state-of-the-art 3D technology to assess the SCG 3D structure unbiasedly and suggest future research directions on this topic. PMID- 24952917 TI - New insight into the regulation of floral morphogenesis. AB - The beauty and complexity of flowers have held the fascination of scientists for centuries, from Linnaeus, to Goethe, to Darwin, through to the present. During the past decade, enormous progress has been made in understanding the molecular regulation of flower morphogenesis. It seems likely that there are both highly conserved aspects to flower development in addition to significant differences in developmental patterning that can contribute to the unique morphologies of different species. Furthermore, floral development is attractive in that several key genes regulating fundamental processes have been identified. Crucial functional studies of floral organ identity genes in diverse taxa are allowing the real insight into the conservation of gene function, while findings on the genetic control of organ elaboration open up new avenues for investigation. These fundamentals of floral organ differentiation and growth are therefore an ideal subject for comparative analyses of flower development, which will lead to a better understanding of molecular mechanisms that control flower morphogenesis. PMID- 24952918 TI - New insight into role of myosin motors for activation of RNA polymerases. AB - In the eukaryotic cell nucleus, actin and myosin are emerging as essential regulators of nuclear function. At gene level, they regulate chromatin and modulate RNA polymerase transcription, and at the RNA level, they are involved in the metabolism of ribonucleoprotein complexes. Furthermore, actin and myosin are involved in maintaining the structure of cell nucleus by mediating chromatin movement and by interacting with components of the nuclear lamina. This plethora of functions is now supported by evidence that nuclear actin polymerizes just like the cytoplasmic actin fraction. Based on these considerations, we now hypothesize that the nuclear myosin forms function as actin-based motors. In this chapter, our goal is to start from the knowledge acquired in the cytoplasmic field to explore how nuclear myosin functions in gene transcription. One of the pressing issues discussed here is whether nuclear myosin produces local tension or functions as transporters. Based on two current models reported in the literature, we discuss the topology of the actin-based nuclear myosin 1 motor and how it is believed to facilitate propulsion of the RNA polymerase machinery while maintaining chromatin that is compatible with transcription. These mechanisms will be placed in the context of cell cycle progression. PMID- 24952919 TI - New insights into the metabolic and molecular mechanism of plant response to anaerobiosis. AB - Under anaerobic conditions, plants apply a wide spectrum of precise adaptive strategies responding to several critical challenges. The ability of efficiently sensing the oxygen presence demonstrates the existence of both direct and indirect ways of perception. The subsequent coordinate metabolic reassessment is currently under study. The complex molecular response implicates not only transcriptional and translational regulation of specific genes but also posttranscriptional and posttranslational regulatory mechanisms, each and all integrating the metabolic settings. Furthermore, the accumulation of typical metabolites during low oxygen stress condition is a key factor that suggests some critical topics in the regulation of metabolic pathways. Here, we summarize the main routes for adaptive behavior during oxygen depletion, from oxygen availability perception to recently discovered molecular mechanisms and metabolic adaptations. PMID- 24952920 TI - Beyond expectations: novel insights into epidermal keratin function and regulation. AB - The epidermis is a stratified epithelium that relies on its cytoskeleton and cell junctions to protect the body against mechanical injury, dehydration, and infections. Keratin intermediate filament proteins are involved in many of these functions by forming cell-specific cytoskeletal scaffolds crucial for the maintenance of cell and tissue integrity. In response to various stresses, the expression and organization of keratins are altered at transcriptional and posttranslational levels to restore tissue homeostasis. Failure to restore tissue homeostasis in the presence of keratin gene mutations results in acute and chronic skin disorders for which currently no rational therapies are available. Here, we review the recent progress on the role of keratins in cytoarchitecture, adhesion, signaling, and inflammation. By focusing on epidermal keratins, we illustrate the contribution of keratin isotypes to differentiated epithelial functions. PMID- 24952921 TI - Characean internodal cells as a model system for the study of cell organization. AB - Giant internodal cells of characean green algae have been widely used for studying cellular physiology. This review emphasizes their significance for understanding cytoarchitecture and cytoplasmic reorganization. The cytoarchitecture of internodal cells undergoes pronounced, cytoskeleton-dependent changes during development and in response to environmental cues. Under bright light, internodes develop alternating bands of acid and alkaline pH at their surface that correlate with the differential size and abundance of cortical organelles and, in the genus Chara, with the size and distribution of convoluted plasma membrane domains known as charasomes. Wounding induces responses ranging from chloroplast detachment to deposition of wound walls. These properties and the possibility for mechanical manipulation make the internodal cell ideal for exploring plasma membrane domains, organelle interactions, vesicle trafficking, and local cell wall deposition. The significance of this model system will further increase with the application of molecular biological methods in combination with metabolomics and proteomics. PMID- 24952922 TI - Roles of collateral arterial flow and ischemic preconditioning in protection of acutely ischemic myocardium. AB - The extent and rate at which necrosis develops in experimental acute myocardial infarction in the dog heart is presented together with an analysis of the role played by protective mechanisms in myocyte death. Preconditioning with ischemia delays but does not prevent myocyte death. Arterial collateral flows exceeding 30% of control flow essentially prevent myocyte death, while lesser amounts of collateral flow delay myocyte death to a variable extent. Flows of <0.09mlmin( 1)g(-1) wet exert no protective effect. Cell death occurs as quickly as it does with zero flow. Electrocardiography provides a means of detection of the preconditioned state in the dog heart in that the amount of ST elevation observed during the preconditioning episode is reduced during subsequent episodes of ischemia. Also, marked depression of arterial collateral flow can be detected by an increase in the duration of the QRS segment. PMID- 24952923 TI - Extraosseous Gaucher cell deposition without adjacent bone involvement. AB - Extraosseous Gaucher cell deposits are a rare complication of Gaucher disease that can mimic malignancy. We describe a case of Gaucher cell deposition in the subcutaneous soft tissues overlying the lower thoracic spine in an 18-year-old woman with known type III Gaucher disease. This case is unique in the literature because this subcutaneous Gaucher mass was not associated with extension from underlying bone involvement or clear lymph node origin. It demonstrated no discernible continuity with the adjacent thoracic spinous processes, the cortices of which appeared intact. Although patients with Gaucher disease are at increased risk of malignancy, Gaucher cell deposition should remain a differential consideration for soft tissue masses with or without adjacent bone involvement in patients with known Gaucher disease. PMID- 24952924 TI - [Swallowing in disorders of consciousness]. AB - INTRODUCTION: Interest in studying swallowing disorders in patients with altered consciousness has increased over the past decade. Swallowing deficit is frequently encountered in severe brain-injured patients. STATE OF ART: Results of studies have highlighted different factors such as the delay between the injury and the treatment and the level of consciousness of these patients, as well as the presence or not of tracheotomy, which will determine the feasibility of resuming oral feeding. Nowadays, very few valid and sensitive scales can be used to assess swallowing deficit in patients with disorders of consciousness. The Facial Oral Tract Therapy (FOTT) scale is an inter-professional multidisciplinary approach offering a structured way to evaluate and treat patients with swallowing disorders. In contrast with other scales, patients do not have to follow verbal instructions for the FOTT. PERSPECTIVES: This paper presents a review of existing literature on the assessment and management of swallowing disorders in patients with altered state of consciousness, and a description of the FOTT method. CONCLUSION: The FOTT seems to be an interesting assessment and rehabilitation tool for patients with disorders of consciousness. However, clinical studies are needed to confirm the validity and sensitivity of this technique. PMID- 24952925 TI - It's about time: rhythms as a new dimension of molecular marine research. PMID- 24952926 TI - Platelet response to serotonin in patients with stable coronary heart disease. AB - Patients with heart disease and depression have an increased mortality rate. Both behavioral and biologic factors have been proposed as potential etiologic mechanisms. Given that the pathophysiology of depression is considered to involve disruption in brain serotonergic signaling, we investigated platelet response to serotonin stimulation in patients with stable coronary artery disease (CAD). We enrolled 92 patients with stable CAD. Platelet response to increasing concentrations of serotonin (5-HT), epinephrine-augmented 5-HT, and adenosine diphosphate (ADP) was measured by optical aggregation and flow cytometry. As concentrations of 5-HT and ADP increased, so did the activation and aggregation of the platelets. However, on addition of the highest concentration of 5-HT (30 MUM), a significant decrease in platelet activation (p=0.005) was detected by flow cytometry. This contrasts the increase in platelet activation seen with the addition of the highest concentration of ADP. In conclusion, we found increased platelet activation and aggregation with increased concentrations of ADP; however, when platelets are stimulated with a high concentration of 5-HT (30 MUM), there is decreased platelet activation. The data demonstrate unique patterns of platelet activation by 5-HT in patients with stable CAD. The cause of this phenomenon is unclear. Our study sheds light on the in vitro response of platelet function to serotonin in patients with stable CAD, which may further the mechanistic understanding of heart disease and depression. PMID- 24952927 TI - Temporal trends in percutaneous coronary intervention--associated acute cerebrovascular accident (from the 1998 to 2008 Nationwide Inpatient Sample Database). AB - Acute cerebrovascular accident (CVA) after percutaneous coronary intervention (PCI) for acute coronary syndrome and coronary artery disease is associated with high rates of morbidity and mortality. Nationwide Inpatient Sample from 1998 to 2008 was used to identify 1,552,602 PCIs performed for acute coronary syndrome and coronary artery disease. We assessed temporal trends in the incidence, predictors, and prognostic impact of CVA in a broad range of patients undergoing PCI. The overall incidence of CVA was 0.56% (95% confidence interval [CI] 0.55 to 0.57). The incidence of CVA remained unchanged over the study period (adjusted p for trend=0.2271). The overall mortality rate in the CVA group was 10.76% (95% CI 10.1 to 11.4). The adjusted odds ratio (OR) of CVA for in-hospital mortality was 7.74 (95% CI 7.00 to 8.57, p<0.0001); this remained high but decreased over the study period (adjusted p for trend<0.0001). Independent predictors of CVA included older age (OR 1.03, 95% CI 1.02 to 1.03, p<0.0001), disorder of lipid metabolism (OR 1.31, 95% CI 1.24 to 1.38, p<0.001), history of tobacco use (OR 1.21, 95% CI 1.10 to 1.34, p=0.0002), coronary atherosclerosis (OR 1.56, 95% CI 1.43 to 1.71, p<0.0001), and intra-aortic balloon pump use (OR 1.39, 95% CI 1.09 to 1.77, p=0.0073). A nomogram for predicting the probability of CVA achieved a concordance index of 0.73 and was well calibrated. In conclusion, the incidence of CVA associated with PCI has remained unchanged from 1998 to 2008 in face of improved equipment, techniques, and adjunctive pharmacology. The risk of CVA associated in-hospital mortality is high; however, this risk has decreased over the study period. PMID- 24952928 TI - Reperfusion correlates and clinical outcomes of right ventricular dysfunction in patients with inferior ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. AB - We evaluated the relation between reperfusion indexes and right ventricular (RV) dysfunction in patients with inferior ST-segment elevation myocardial infarction (STEMI). We included patients with inferior STEMI undergoing percutaneous coronary intervention and right coronary artery as infarct-related artery. Myocardial reperfusion was evaluated by Thrombolysis In Myocardial Infarction (TIMI) flow, TIMI frame count, myocardial blush grade, and ST-segment resolution. RV dysfunction was defined as tricuspid annular plane systolic excursion<=16 mm in M-mode imaging. RV dysfunction was present in 58 of 141 patients (41.1%) and was more frequent in patients achieving suboptimal postprocedural TIMI flow grade (66.7% vs 36.7%, grades 0 to 2 vs 3, p=0.01), TIMI frame count (63.2% vs 37.7%, >=40 vs <40 frames, p=0.04), and myocardial blush grade (33.3% vs 56.2%, grade 0 or 1 vs 2 or 3, p=0.001). RV dysfunction rates did not differ according to ST segment resolution. Patients with RV dysfunction had increased rates of cardiac death (13.2% vs 2.6%, p=0.03), reinfarction (24.5% vs 10.3%, p=0.03), and stent thrombosis (22.6% vs 6.4%, p=0.01) at 2-year follow-up. Postprocedural TIMI flow grade 3 (odds ratio 0.25, 95% confidence interval 0.09 to 0.68, p=0.007) was the only reperfusion correlate of RV dysfunction at multivariate analysis. In an independent cohort of 84 patients with STEMI, postprocedural TIMI flow grade 3 had a limited sensitivity (52%), with a high specificity (74.5%) and negative predictive value (71%) for excluding RV dysfunction. In conclusion, in patients with inferior STEMI undergoing coronary revascularization, RV dysfunction is associated with a worse long-term prognosis. Postprocedural TIMI flow grade may be a useful tool to predict RV dysfunction. PMID- 24952931 TI - Biomarkers for differentiating Takotsubo syndrome from acute ST elevation myocardial infarction. PMID- 24952929 TI - Cost analysis of periprocedural imaging in patients undergoing catheter ablation for atrial fibrillation. AB - Cardiovascular imaging is an important part of procedural planning and safety for catheter ablation of atrial fibrillation (AF). However, the costs of imaging surrounding catheter ablation of AF have not been described. Medicare fee-for service data were used to evaluate Medicare expenditures before, during, and after catheter ablation for AF from July 2007 to December 2009. Among 11,525 patients who underwent catheter ablation for AF, the mean overall expenditure on the day of the procedure was $14,455 (SD $7,441). The mean imaging expenditure in the periprocedural period, which included the 30 days before the catheter ablation and the day of the ablation itself, was $884 (SD $455). Periprocedural imaging expenditures varied by the imaging strategy used, ranging from a mean of $557 (SD $269) for patients with electroanatomic mapping only to $1,234 (SD $461) for patients with electroanatomic mapping, transesophageal echocardiogram, and computed tomography or magnetic resonance imaging. Mean patient-level imaging expenditures varied by provider (mean $872, SD $249). Periprocedural imaging expenditures also varied by patient risk, with mean expenditures of $862 (SD $444) for patients with a CHADS2 score of >=2 compared with $907 (SD $466) for CHADS2 score<2 (p<0.001). In conclusion, periprocedural imaging accounts for approximately 6% of mean Medicare expenditures for catheter ablation of AF. The expenditures for periprocedural imaging vary both at the patient and at the provider level and they are inversely related to stroke risk by CHADS2 score. PMID- 24952932 TI - Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation: author reply. PMID- 24952933 TI - Cell-to-cell talk: plasmids and exosomes. PMID- 24952934 TI - Diagnostic and prognostic potential of extracellular vesicles in peripheral blood. AB - PURPOSE: Extracellular vesicles (EVs) are small, membrane-enclosed entities released from cells in many different biological systems. These vesicles play an important role in cellular communication by virtue of their protein, RNA, and lipid content, which can be transferred among cells. The complement of biomolecules reflects the parent cell, and their characterization may provide information about the presence of an aberrant process. Peripheral blood is a rich source of circulating EVs, which are easily accessible through a blood sample. An analysis of EVs in peripheral blood could provide access to unparalleled amounts of biomarkers of great diagnostic and prognostic value. The objectives of this review are to briefly present the current knowledge about EVs and to introduce a toolbox of selected techniques, which can be used to rapidly characterize clinically relevant properties of EVs from peripheral blood. METHODS: Several techniques exist to characterize the different features of EVs, including size, enumeration, RNA cargo, and protein phenotype. Each technique has a number of advantages and pitfalls. However, with the techniques presented in this review, a possible platform for EV characterization in a clinical setting is outlined. FINDINGS: Although EVs have great diagnostic and prognostic potential, a lack of standardization regarding EV analysis hampers the full use of this potential. Nevertheless, the analysis of EVs in peripheral blood has several advantages compared with traditional analyses of many soluble molecules in blood. IMPLICATIONS: Overall, the use of EV analysis as a diagnostic and prognostic tool has prodigious clinical potential. PMID- 24952935 TI - Expression of B-cell surface antigens in subpopulations of exosomes released from B-cell lymphoma cells. AB - PURPOSE: Exosomes are small (30- to 100-nm) vesicles secreted by all cell types in culture and found in most body fluids. A mean of 1 mL of blood serum, derived from healthy donors, contains approximately 10(12) exosomes. Depending on the disease, the number of exosomes can fluctuate. Concentration of exosomes in the bloodstream and all other body fluids is extremely high. Several B-cell surface antigens (CD19, CD20, CD22, CD23, CD24, CD37, CD40, and HLA-DR) and the common leukocyte antigen CD45 are interesting in terms of immunotherapy of hematologic malignant neoplasms. The established standard for exosome isolation is ultracentrifugation. However, this method cannot discriminate between exosome subpopulations and other nanovesicles. The main purpose of this study was to characterize CD81(+) and CD63(+) subpopulations of exosomes in terms of these surface markers after release from various types of B-cell lymphoma cell lines using an easy and reliable method of immunomagnetic separation. METHODS: Western blotting, flow cytometry, and electron microscopy were used to compare the total preenriched extracellular vesicle (EV) pool to each fraction of vesicles after specific isolation, using magnetic beads conjugated with antibodies raised against the exosome markers CD63 and CD81. FINDINGS: Magnetic bead-based isolation is a convenient method to study and compare subpopulations of exosomes released from B-cell lymphoma cells. The data indicated that the specifically isolated vesicles differed from the total preenriched EV pool. CD19, CD20, CD24, CD37, and HLA-DR, but not CD22, CD23, CD40, and CD45, are expressed on exosomes from B-cell lymphoma cell lines with large heterogeneity among the different B cell lymphoma cell lines. Interestingly, these B-cell lymphoma-derived EVs are able to rescue lymphoma cells from rituximab-induced complement-dependent cytotoxicity. IMPLICATIONS: Distribution of exosomes that contain CD19, CD20, CD24, CD37, and HLA-DR may intercept immunotherapy directed against these antigens, which is important to be aware of for optimal treatment. The use of an immunomagnetic separation platform enables easy isolation and characterization of exosome subpopulations for further studies of the exosome biology to understand the potential for therapeutic and diagnostic use. PMID- 24952936 TI - Cortisol response to an experimental stress paradigm prospectively predicts long term distress and resilience trajectories in response to active police service. AB - Heterogeneity in glucocorticoid response to experimental stress conditions has shown to differentiate individuals with healthy from maladaptive real-life stress responses in a number of distinct domains. However, it is not known if this heterogeneity influences the risk for developing stress related disorders or if it is a biological consequence of the stress response itself. Determining if glucocorticoid response to stress induction prospectively predicts psychological vulnerability to significant real life stressors can adjudicate this issue. To test this relationship, salivary cortisol as well as catecholamine responses to a laboratory stressor during academy training were examined as predictors of empirically identified distress trajectories through the subsequent 4 years of active duty among urban police officers routinely exposed to potentially traumatic events and routine life stressors (N = 234). During training, officers were exposed to a video vignette of police officers exposed to real-life trauma. Changes in salivary 3-methoxy-4-hydroxyphenylglycol (MHPG) and cortisol in response to this video challenge were examined as predictors of trajectory membership while controlling for age, gender, and baseline neuroendocrine levels. Officers who followed trajectories of resilience and recovery over 4 years mounted significant increases in cortisol in response to the experimental stressor, while those following a trajectory of chronic increasing distress had no significant cortisol change in response to the challenge. MHPG responses were not associated with distress trajectories. Cortisol response prospectively differentiated trajectories of distress response suggesting that a blunted cortisol response to a laboratory stressor is a risk factor for later vulnerability to distress following significant life stressors. PMID- 24952937 TI - Long-term course of pediatric obsessive-compulsive disorder: 3 years of prospective follow-up. AB - OBJECTIVE: This study assesses the long-term course of treatment-seeking youth with a primary diagnosis of DSM-IV OCD. METHOD: Sixty youth and their parents completed intake interviews and annual follow-up interviews for 3 years using the youth version of the Longitudinal Interval Follow-up Evaluation (Y-LIFE) and Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Remission was defined as no longer meeting DSM-IV criteria for OCD for 8 weeks or more, and recurrence was defined as meeting full criteria for OCD for 4 consecutive weeks after having achieved symptom remission. Remission rates for youth were compared to rates of adults participating in the same study. RESULTS: The probability of achieving partial remission of OCD was 0.53 and the probability of achieving full remission was 0.27. Among the 24 youth participants who achieved remission, 79% stayed in remission throughout the study (mean of 88 weeks of follow-up) and 21% experienced a recurrence of symptoms. Better functioning at intake and a shorter latency to initial OCD treatment were associated with faster onset of remission (P<.001). CONCLUSIONS: Remission is more likely among youth versus adults with OCD. Treatment early in the course of illness and before substantial impact on functioning predicted a better course. PMID- 24952938 TI - Testing comparison models of DASS-12 and its reliability among adolescents in Malaysia. AB - OBJECTIVE: The 21-item Depression, Anxiety and Stress Scale (DASS-21) is frequently used in non-clinical research to measure mental health factors among adults. However, previous studies have concluded that the 21 items are not stable for utilization among the adolescent population. Thus, the aims of this study are to examine the structure of the factors and to report on the reliability of the refined version of the DASS that consists of 12 items. METHOD: A total of 2850 students (aged 13 to 17 years old) from three major ethnic in Malaysia completed the DASS-21. The study was conducted at 10 randomly selected secondary schools in the northern state of Peninsular Malaysia. The study population comprised secondary school students (Forms 1, 2 and 4) from the selected schools. RESULTS: Based on the results of the EFA stage, 12 items were included in a final CFA to test the fit of the model. Using maximum likelihood procedures to estimate the model, the selected fit indices indicated a close model fit (chi(2)=132.94, df=57, p=.000; CFI=.96; RMR=.02; RMSEA=.04). Moreover, significant loadings of all the unstandardized regression weights implied an acceptable convergent validity. Besides the convergent validity of the item, a discriminant validity of the subscales was also evident from the moderate latent factor inter correlations, which ranged from .62 to .75. The subscale reliability was further estimated using Cronbach's alpha and the adequate reliability of the subscales was obtained (Total=76; Depression=.68; Anxiety=.53; Stress=.52). CONCLUSION: The new version of the 12-item DASS for adolescents in Malaysia (DASS-12) is reliable and has a stable factor structure, and thus it is a useful instrument for distinguishing between depression, anxiety and stress. PMID- 24952941 TI - Evolving perspectives for personalised management of patients with atrial fibrillation. PMID- 24952939 TI - Epidermal p65/NF-kappaB signalling is essential for skin carcinogenesis. AB - The nuclear factor kappa B (NF-kappaB) signalling pathway exhibits both tumour promoting and tumour-suppressing functions in different tissues and models of carcinogenesis. In particular in epidermal keratinocytes, NF-kappaB signalling was reported to exert primarily growth inhibitory and tumour-suppressing functions. Here, we show that mice with keratinocyte-restricted p65/RelA deficiency were resistant to 7, 12-dimethylbenz(a)anthracene (DMBA)-/12-O-tetra decanoylphorbol-13 acetate (TPA)-induced skin carcinogenesis. p65 deficiency sensitized epidermal keratinocytes to DNA damage-induced death in vivo and in vitro, suggesting that inhibition of p65-dependent prosurvival functions prevented tumour initiation by facilitating the elimination of cells carrying damaged DNA. In addition, lack of p65 strongly inhibited TPA-induced epidermal hyperplasia and skin inflammation by suppressing the expression of proinflammatory cytokines and chemokines by epidermal keratinocytes. Therefore, p65-dependent NF-kappaB signalling in keratinocytes promotes DMBA-/TPA-induced skin carcinogenesis by protecting keratinocytes from DNA damage-induced death and facilitating the establishment of a tumour-nurturing proinflammatory microenvironment. PMID- 24952942 TI - Less clarity as the fog begins to lift. PMID- 24952943 TI - Short-term effects of air pollution on a range of cardiovascular events in England and Wales: case-crossover analysis of the MINAP database, hospital admissions and mortality. AB - OBJECTIVE: To inform potential pathophysiological mechanisms of air pollution effects on cardiovascular disease (CVD), we investigated short-term associations between ambient air pollution and a range of cardiovascular events from three national databases in England and Wales. METHODS: Using a time-stratified case crossover design, over 400,000 myocardial infarction (MI) events from the Myocardial Ischaemia National Audit Project (MINAP) database, over 2 million CVD emergency hospital admissions and over 600,000 CVD deaths were linked with daily mean concentrations of carbon monoxide (CO), nitrogen dioxide (NO2), particulate matter less than 10 MUm in aerodynamic diameter (PM10), particulate matter less than 2.5 MUm in aerodynamic diameter (PM2.5) and sulfur dioxide (SO2), and daily maximum of 8-hourly running mean of O3 measured at the nearest air pollution monitoring site to the place of residence. Pollutant effects were modelled using lags up to 4 days and adjusted for ambient temperature and day of week. RESULTS: For mortality, no CVD outcome analysed was clearly associated with any pollutant, except for PM2.5 with arrhythmias, atrial fibrillation and pulmonary embolism. With hospital admissions, only NO2 was associated with a raised risk: CVD 1.7% (95% CI 0.9 to 2.6), non-MI CVD 2.0% (1.1 to 2.9), arrhythmias 2.9% (0.6 to 5.2), atrial fibrillation 2.8% (0.3 to 5.4) and heart failure 4.4% (2.0 to 6.8) for a 10th-90th centile increase. With MINAP, only NO2 was associated with an increased risk of MI, which was specific to non-ST-elevation myocardial infarction (non STEMIs): 3.6% (95% CI 0.4 to 6.9). CONCLUSIONS: This study found no clear evidence for pollution effects on STEMIs and stroke, which ultimately represent thrombogenic processes, though it did for pulmonary embolism. The strongest associations with air pollution were observed with selected non-MI outcomes. PMID- 24952946 TI - A Capitol year. PMID- 24952944 TI - Mechanistic heterogeneity in site recognition by the structurally homologous DNA binding domains of the ETS family transcription factors Ets-1 and PU.1. AB - ETS family transcription factors regulate diverse genes through binding at cognate DNA sites that overlap substantially in sequence. The DNA-binding domains of ETS proteins (ETS domains) are highly conserved structurally yet share limited amino acid homology. To define the mechanistic implications of sequence diversity within the ETS family, we characterized the thermodynamics and kinetics of DNA site recognition by the ETS domains of Ets-1 and PU.1, which represent the extremes in amino acid divergence among ETS proteins. Even though the two ETS domains bind their optimal sites with similar affinities under physiologic conditions, their nature of site recognition differs strikingly in terms of the role of hydration and counter ion release. The data suggest two distinct mechanisms wherein Ets-1 follows a "dry" mechanism that rapidly parses sites through electrostatic interactions and direct protein-DNA contacts, whereas PU.1 utilizes hydration to interrogate sequence-specific sites and form a long-lived complex relative to the Ets-1 counterpart. The kinetic persistence of the high affinity PU.1 . DNA complex may be relevant to an emerging role of PU.1, but not Ets-1, as a pioneer transcription factor in vivo. In addition, PU.1 activity is critical to the development and function of macrophages and lymphocytes, which present osmotically variable environments, and hydration-dependent specificity may represent an important regulatory mechanism in vivo, a hypothesis that finds support in gene expression profiles of primary murine macrophages. PMID- 24952945 TI - Synergic role of nucleophosmin three-helix bundle and a flanking unstructured tail in the interaction with G-quadruplex DNA. AB - Nucleophosmin (NPM1) is a nucleocytoplasmic shuttling protein, mainly localized at nucleoli, that plays a number of functions in ribosome biogenesis and export, cell cycle control, and response to stress stimuli. NPM1 is the most frequently mutated gene in acute myeloid leukemia; mutations map to the C-terminal domain of the protein and cause its denaturation and aberrant cytoplasmic translocation. NPM1 C-terminal domain binds G-quadruplex regions at ribosomal DNA and at gene promoters, including the well characterized sequence from the nuclease hypersensitive element III region of the c-MYC promoter. These activities are lost by the leukemic variant. Here we analyze the NPM1/G-quadruplex interaction, focusing on residues belonging to both the NPM1 terminal three-helix bundle and a lysine-rich unstructured tail, which has been shown to be necessary for high affinity recognition. We performed extended site-directed mutagenesis and measured binding rate constants through surface plasmon resonance analysis. These data, supported by molecular dynamics simulations, suggest that the unstructured tail plays a double role in the reaction mechanism. On the one hand, it facilitates the formation of an encounter complex through long range electrostatic interactions; on the other hand, it directly contacts the G quadruplex scaffold through multiple and transient electrostatic interactions, significantly enlarging the contact surface. PMID- 24952947 TI - [Surveillance of health care in Japan to develop a community health support network system for those who need it]. PMID- 24952954 TI - A rare 8q24 single nucleotide polymorphism (SNP) predisposes North American men to prostate cancer and possibly more aggressive disease. AB - OBJECTIVE: To assess the frequency of a novel prostate cancer-associated single nucleotide polymorphism (SNP), rs188140481, in a North American population and to evaluate the clinical significance of this variant including annotated prostatectomy pathology. PATIENTS/SUBJECTS AND METHODS: We examined the frequency of the minor allele at rs188140481 in 4299 North American men including 1979 men with prostate cancer and 2320 healthy volunteers. We compared the clinicopathological features of prostate cancer between carriers and non-carriers of the SNP. RESULTS: The rs188140481[A] SNP was present in 1.6% of the cohort; it was significantly more likely to be carried by men with prostate cancer than healthy controls (odds ratio 3.14; 95% confidence interval [CI] 1.85-5.35). After adjusting for age and PSA levels, carriers were found to be 6.73-fold (95% CI 1.69-26.76) more likely to develop prostate cancer than non-carriers. Age at diagnosis, frequency of a positive family history of prostate cancer, and biochemical recurrence rates were similar between SNP carriers and non-carriers. Patients with the SNP had a proportionately higher frequency of stage >=T2c disease (29.5% vs 20.1%; P = 0.13), Gleason >=8 tumours (13.3% vs 6.5%; P = 0.10), and extracapsular extension (28.9% vs 18.8%; P = 0.12) compared with non carriers. CONCLUSIONS: rs188140481[A] is a rare SNP that confers greater risk of prostate cancer compared with SNPs identified by genome-wide association studies. Because of its low frequency, larger studies are needed to validate the prognostic significance of this locus, and associations with adverse pathology. PMID- 24952955 TI - Endothelin ETA receptor antagonism in cardiovascular disease. AB - Since the discovery of the endothelin system in 1988, it has been implicated in numerous physiological and pathological phenomena. In the cardiovascular system, endothelin-1 (ET-1) acts through intracellular pathways of two endothelin receptors (ETA and ETB) located mainly on smooth muscle and endothelial cells to regulate vascular tone and provoke mitogenic and proinflammatory reactions. The endothelin ETA receptor is believed to play a pivotal role in the pathogenesis of several cardiovascular disease including systemic hypertension, pulmonary arterial hypertension (PAH), dilated cardiomyopathy, and diabetic microvascular dysfunction. Growing evidence from recent experimental and clinical studies indicates that the blockade of endothelin receptors, particularly the ETA subtype, grasps promise in the treatment of major cardiovascular pathologies. The simultaneous blockade of endothelin ETB receptors might not be advantageous, leading possibly to vasoconstriction and salt and water retentions. This review summarizes the role of ET-1 in cardiovascular modulation and the therapeutic potential of endothelin receptor antagonism. PMID- 24952957 TI - Simultaneous inference for model averaging of derived parameters. AB - Model averaging is a useful approach for capturing uncertainty due to model selection. Currently, this uncertainty is often quantified by means of approximations that do not easily extend to simultaneous inference. Moreover, in practice there is a need for both model averaging and simultaneous inference for derived parameters calculated in an after-fitting step. We propose a method for obtaining asymptotically correct standard errors for one or several model averaged estimates of derived parameters and for obtaining simultaneous confidence intervals that asymptotically control the family-wise Type I error rate. The performance of the method in terms of coverage is evaluated using a simulation study and the applicability of the method is demonstrated by means of three concrete examples. PMID- 24952956 TI - Contrasting two models of academic self-efficacy--domain-specific versus cross domain--in children receiving and not receiving special instruction in mathematics. AB - In social cognitive theory, self-efficacy is domain-specific. An alternative model, the cross-domain influence model, would predict that self-efficacy beliefs in one domain might influence performance in other domains. Research has also found that children who receive special instruction are not good at estimating their performance. The aim was to test two models of how self-efficacy beliefs influence achievement, and to contrast children receiving special instruction in mathematics with normally-achieving children. The participants were 73 fifth grade children who receive special instruction and 70 children who do not receive any special instruction. In year four and five, the children's skills in mathematics and reading were assessed by national curriculum tests, and in their fifth year, self-efficacy in mathematics and reading were measured. Structural equation modeling showed that in domains where children do not receive special instruction in mathematics, self-efficacy is a mediating variable between earlier and later achievement in the same domain. Achievement in mathematics was not mediated by self-efficacy in mathematics for children who receive special instruction. For normal achieving children, earlier achievement in the language domain had an influence on later self-efficacy in the mathematics domain, and self-efficacy beliefs in different domains were correlated. Self-efficacy is mostly domain specific, but may play a different role in academic performance depending on whether children receive special instruction. The results of the present study provided some support of the Cross-Domain Influence Model for normal achieving children. PMID- 24952958 TI - Diel changes in trace metal concentration and distribution in coastal waters: Catalina Island as a study case. AB - Understanding biogeochemical cycling of trace metals in the ocean requires information about variability in metal concentrations and distribution over short, e.g., diel, time scales. Such variability and the factors that influence it are poorly characterized. To address this shortcoming, we measured trace metal concentrations in the total dissolved, colloidal, and soluble fractions every 3-4 h for several consecutive days and nights in surface waters from a coastal station. Our results show that both the concentration and the size partitioning of some biologically essential (Fe, Cu, Co, and Cd) and anthropogenic (Pb) metals are subjected to diel variations that may be related to both inorganic and biological processes (e.g., photolysis of high-molecular-weight dissolved organic matter, photoinduced reduction/oxidation of metal(hydrous)oxides, uptake by growing phytoplankton, degradation of organic matter, lysis, and grazing). The largest fluctuations were observed in the soluble and colloidal pools. Soluble Fe varied during the day-night cycle by a factor of 40, and the contribution of colloidal Pb to the total dissolved fraction increased from 6+/-3% during the day to as much as 70-80% during the night. Our results suggest that changes occurring over time scales of hours need to be considered when collecting and interpreting trace metal data from the surface ocean. PMID- 24952959 TI - Harnessing the anti-inflammatory potential of palmitoylethanolamide. AB - Palmitoylethanolamide (PEA) is a peroxisome proliferator-activated receptor alpha (PPAR-alpha) ligand that exerts anti-inflammatory, analgesic and neuroprotective actions. PEA is synthetized from phospholipids through the sequential actions of N-acyltransferase and N-acylphosphatidylethanolamine-preferring phospholipase D (NAPE-PLD), and its actions are terminated by its hydrolysis by two enzymes, fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolysing acid amidase (NAAA). Here, we review the impact of PEA administration in inflammatory and neurodegenerative settings and the differential role of FAAH and NAAA in controlling PEA levels. Recent studies with NAAA inhibitors put forth this enzyme as capable of increasing PEA levels in vivo in inflammatory processes, and identified it as an interesting target for drug discovery research. Thus, PEA hydrolysis inhibitors could constitute potential therapeutic alternatives in chronic inflammatory and neurodegenerative diseases. PMID- 24952964 TI - Geometric morphometric study of the skull shape diversification in Sciuridae (Mammalia, Rodentia). AB - It is generally accepted that the high phenotypic diversity of mammals is a combined result of developmental constraint and ecological adaptation, although the influence of these endogenous and exogenous factors varies in different mammal groups. The rodent family Sciuridae represents an ideal candidate for examining phenotypic diversity in relation to phylogeny and ecological adaptations. In the present study, we investigate the effects of phylogeny and lifestyle on the skull shape in different species of Sciuridae by applying geometric morphometric methods. In addition, we investigate the importance of allometry on sciurid skull shape, because results from geometric morphometrics sometimes dispute those of traditional morphometry. Here, we identify significant associations between patristic distances obtained from molecular phylogeny and shape distances in all 3 views of the cranium and the lateral view of the mandible. Multivariate regression demonstrates that shape differences among lifestyle categories are substantial, especially in the dorsal and ventral structures after the influence of phylogeny is taken into account. Allometry plays an important role in the shape variation, although its importance on different skull structures varies. Our results indicate that complex structures of this highly diverse mammal group, which occupies different niches, are affected by ecological factors and developmental constraint. PMID- 24952960 TI - MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. AB - The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA "fingerprint" of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies. PMID- 24952962 TI - Rheumatological diseases and kidneys: a nephrologist's perspective. AB - Renal involvement is a common occurrence in subjects with rheumatological diseases and can develop either due to the disease itself or secondary to drugs used in the treatment. The prevalence of renal involvement and its severity depends on the underlying disease as well as aggressiveness of the therapy. For most rheumatological diseases, renal involvement heralds a poor prognosis and warrants aggressive immunosuppressive treatment. Thus, it is important to diagnose and manage them at an early stage. On the other hand, patients with primary kidney disease can also develop rheumatological manifestations which need to be differentiated from the former. This article provides the nephrologist's perspective upon various rheumatological disorders and associated renal involvement with the aim of sensitizing the rheumatological community about them, resulting in better management of these subjects. PMID- 24952961 TI - A high-resolution spatiotemporal atlas of gene expression of the developing mouse brain. AB - To provide a temporal framework for the genoarchitecture of brain development, we generated in situ hybridization data for embryonic and postnatal mouse brain at seven developmental stages for ~2,100 genes, which were processed with an automated informatics pipeline and manually annotated. This resource comprises 434,946 images, seven reference atlases, an ontogenetic ontology, and tools to explore coexpression of genes across neurodevelopment. Gene sets coinciding with developmental phenomena were identified. A temporal shift in the principles governing the molecular organization of the brain was detected, with transient neuromeric, plate-based organization of the brain present at E11.5 and E13.5. Finally, these data provided a transcription factor code that discriminates brain structures and identifies the developmental age of a tissue, providing a foundation for eventual genetic manipulation or tracking of specific brain structures over development. The resource is available as the Allen Developing Mouse Brain Atlas (http://developingmouse.brain-map.org). PMID- 24952965 TI - Trait-mediated seed predation, dispersal and survival among frugivore-dispersed plants in a fragmented subtropical forest, Southwest China. AB - By tracking the fate of individual seeds from 6 frugivore-dispersed plants with contrasting seed traits in a fragmented subtropical forest in Southwest China, we explored how rodent seed predation and hoarding were influenced by seed traits such as seed size, seed coat hardness and seed profitability. Post-dispersal seed fates varied significantly among the 6 seed species and 3 patterns were witnessed: large-seeded species with a hard seed coat (i.e. Choerospoadias axillaries and Diospyros kaki var. silvestris) had more seeds removed, cached and then surviving at caches, and they also had fewer seeds predated but a higher proportion of seeds surviving at the source; medium-sized species with higher profitability and thinner seed coat (i.e. Phoebe zhennan and Padus braohypoda) were first harvested and had the lowest probability of seeds surviving either at the source or at caches due to higher predation before or after removal; and small-seeded species with lower profitability (i.e. Elaeocarpus japonicas and Cornus controversa) had the highest probability of seeds surviving at the source but the lowest probability of seeds surviving at caches due to lower predation at the source and lower hoarding at caches. Our study indicates that patterns of seed predation, dispersal and survival among frugivore-dispersed plants are highly determined by seed traits such as seed size, seed defense and seed profitability due to selective predation and hoarding by seed-eating rodents. Therefore, trait-mediated seed predation, dispersal and survival via seed-eating rodents can largely affect population and community dynamics of frugivore dispersed plants in fragmented forests. PMID- 24952966 TI - Vomeronasal organ lesion disrupts social odor recognition, behaviors and fitness in golden hamsters. AB - Most studies support the viewpoint that the vomeronasal organ has a profound effect on conspecific odor recognition, scent marking and mating behavior in the golden hamster (Mesocricetus auratus). However, the role of the vomeronasal organ in social odor recognition, social interaction and fitness is not well understood. Therefore, we conducted a series of behavioral and physiological tests to examine the referred points in golden hamster. We found that male hamsters with vomeronasal organ lesion showed no preference between a predator odor (the anal gland secretion of the Siberian weasels (Mustela sibirica) and putative female pheromone components (myristic acid and palmitic acid), but were still able to discriminate between these 2 kinds of odors. In behavioral tests of anxiety, we found that vomeronasal organ removal causes female hamsters to spend much less time in center grids and to cross fewer center grids and males to make fewer crossings between light and dark boxes than sham-operated controls. This indicates that a chronic vomeronasal organ lesion induced anxious responses in females. In aggressive behavioral tests, we found that a chronic vomeronasal organ lesion decreased agonistic behavior in female hamsters but not in males. The pup growth and litter size show no differences between the 2 groups. All together, our data suggested that vomeronasal organ ablation disrupted the olfactory recognition of social chemosignals in males, and induced anxiety-like and aggressive behavior changes in females. However, a vomeronasal organ lesion did not affect the reproductive capacity and fitness of hamsters. Our studies may have important implications concerning the role of the vomeronasal organ in golden hamsters and also in rodents. PMID- 24952967 TI - Perceived damage and areas of needed research for wildlife pests of California agriculture. AB - Many wildlife species cause extensive damage to a variety of agricultural commodities in California, with estimates of damage in the hundreds of millions annually. Given the limited availability of resources to solve all human-wildlife conflicts, we should focus management efforts on issues that provide the greatest benefit to agricultural commodities in California. This survey provides quantitative data on research needs to better guide future efforts in developing more effective, practical and appropriate methods for managing these species. We found that ground squirrels, pocket gophers, birds, wild pigs, coyotes and voles were the most common agricultural wildlife pest species in California. The damage caused by these species could be quite high, but varied by agricultural commodity. For most species, common forms of damage included loss of crop production and direct death of the plant, although livestock depredation was the greatest concern for coyotes. Control methods used most frequently and those deemed most effective varied by pest species, although greater advancements in control methods were listed as a top research priority for all species. Collectively, the use of toxicants, biocontrol and trapping were the most preferred methods for control, but this varied by species. In general, integrated pest management practices were used to control wildlife pests, with a special preference for those approaches that were efficacious and quick and inexpensive to apply. This information and survey design should be useful in establishing research and management priorities for wildlife pest species in California and other similar regions. PMID- 24952968 TI - Sex differences in the influence of social context, salient social stimulation and amphetamine on ultrasonic vocalizations in prairie voles. AB - Prairie voles (Microtus ochrogaster) are a socially monogamous rodent species and their cooperative behaviors require extensive communication between conspecifics. Rodents use ultrasonic vocalizations (USVs) to communicate and because a prairie vole breeder pair must engage in extensive cooperation for successful reproduction, auditory communication may be critical for this species. Therefore, we sought to characterize USVs in adult male and female prairie voles, and to determine how these calls are influenced by social context, salient social stimuli and the psychostimulant drug of abuse amphetamine (AMPH). Here, we characterize prairie vole USVs by showing the range of frequencies of prairie vole USVs, the proportion of various call types, how these call types compare between males and females, and how they are influenced by social stimulation and AMPH. AMPH caused a robust increase in the number of USVs in both males and females and there was a dramatic sex difference in the complexity of call structures of AMPH-induced USVs, with males emitting more elaborate calls. Moreover, we show that novel (i.e. salient) social cues evoked differential increases in USVs across sex, with males showing a much more robust increase in USV production, both with respect to the frequency and complexity of USV production. Exposure to an estrous female in particular caused an extraordinary increase in USVs in male subjects. These data suggest that USVs may be a useful measure of social motivation in this species, including how social behaviors can be impacted by drugs of abuse. PMID- 24952969 TI - Size and dispersion of urticating setae in three species of processionary moths. AB - Larvae of the processionary moths of the Palaearctic region bear urticating setae that are released against vertebrate predators, especially insectivorous birds. A few species are pests of forest and urban trees and, consequently, may threaten human and animal health during outbreaks, causing dermatitis, conjunctivitis and respiratory distress. Although some studies provide detailed information about the setae, particularly those of the pine processionary moth Thaumetopoea pityocampa, there is little knowledge on the morphological traits of the setae and their release by the larvae. In the present study we identify major traits of the setae of 3 species of processionary moth, T. pityocampa, T. pinivora and T. processionea, which are potentially helpful in the understanding of setae dynamics in the environment: (i) diameter and length of setae and (ii) analysis of dynamical properties of the setae in the airborne state. Setae are highly variable in size, with bimodal distribution in T. pityocampa and T. pinivora; in these 2 species, short and long setae are interspersed within the integument fields where they occur. The difference in the seta size has important consequences in dispersion, as smaller setae can spread 5 times further than their bigger counterparts. This information is relevant for a full understanding of the defensive importance of larval setae against natural enemies of the processionary moths, as well for elucidating the importance of the processionary setae as air pollutants, both close to the infested trees and at longer distances. PMID- 24952970 TI - Helminth parasites of freshwater fishes from Cuatro Cienegas, Coahuila, in the Chihuahuan Desert of Mexico: inventory and biogeographical implications. AB - As part of an ongoing inventory of the helminth parasites of freshwater fishes in Mexico, 570 individual fish were collected between Apr 2008 and Oct 2011 in 26 localities along the Cuatro Cienegas region in Coahuila State, northern Mexico. Seventeen species of hosts, mostly corresponding to Nearctic freshwater elements, were studied. A total of 8324 individual worms were collected during this survey, representing 25 species of helminths, of which 9 were digeneans, 3 monogeneans, 3 acanthocephalans, 9 nematodes and 1 cestode. Most of the records in this checklist represent new host or locality records. The information provided in this checklist may be helpful for our understanding of the biodiversity and historical biogeography of this host-parasite system, because in the Cuatro Cienegas region occur a Nearctic freshwater fish fauna, along with Neotropical and endemic elements, and from a biogeographical point of view, this may represent a transitional area. PMID- 24952972 TI - The Lushan earthquake and the giant panda: impacts and conservation. AB - Earthquakes not only result in a great loss of human life and property, but also have profound effects on the Earth's biodiversity. The Lushan earthquake occurred on 20 Apr 2013, with a magnitude of 7.0 and an intensity of 9.0 degrees. A distance of 17.0 km from its epicenter to the nearest distribution site of giant pandas recorded in the Third National Survey was determined. Making use of research on the Wenchuan earthquake (with a magnitude of 8.0), which occurred approximately 5 years ago, we briefly analyze the impacts of the Lushan earthquake on giant pandas and their habitat. An earthquake may interrupt ongoing behaviors of giant pandas and may also cause injury or death. In addition, an earthquake can damage conservation facilities for pandas, and result in further habitat fragmentation and degradation. However, from a historical point of view, the impacts of human activities on giant pandas and their habitat may, in fact, far outweigh those of natural disasters such as earthquakes. Measures taken to promote habitat restoration and conservation network reconstruction in earthquake affected areas should be based on requirements of giant pandas, not those of humans. PMID- 24952971 TI - Novel human H7N9 influenza virus in China. AB - Outbreaks of H7N9 avian influenza in humans in 5 provinces and 2 municipalities of China have reawakened concern that avian influenza viruses may again cross species barriers to infect the human population and thereby initiate a new influenza pandemic. Evolutionary analysis shows that human H7N9 influenza viruses originated from the H9N2, H7N3 and H11N9 avian viruses, and that it is as a novel reassortment influenza virus. This article reviews current knowledge on 11 subtypes of influenza A virus from human which can cause human infections. PMID- 24952973 TI - Predeployment training for forward medicalisation in a combat zone: the specific policy of the French Military Health Service. AB - INTRODUCTION: To improve the mortality rate on the battlefield, and especially the potentially survivable pre-Medical Treatment Facility deaths, Tactical Combat Casualty Care (TCCC) is now considered as a reference for management of combat casualty from the point of injury to the first medical treatment facility. TCCC comprises of a set of trauma management guidelines designed for use on the battlefield. The French Military Health Service also standardised a dedicated training programme, entitled "Sauvetage au Combat" (SC) ("forward combat casualty care"), with the characteristic of forward medicalisation on the battlefield, the medical team being projected as close as possible to the casualty at the point of injury. The aim of our article is to describe the process and the result of the SC training. MATERIALS AND METHODS: Records from the French Military Health Service Academy - Ecole du Val-de-Grace administration, head of the SC teaching programme, defining its guidelines, and supporting its structure and its execution, were examined and analyzed, since the standardisation of the SC training programme in 2008. The total number of trainees was listed following the different courses (SC1, SC2, SC3). RESULTS: At the end of 2013, every deployed combatant underwent SC1 courses (confidential data), 785 health-qualified combatants were graduated for SC2 courses and 672 Role 1 physician-nurse pairs for SC3 courses. CONCLUSION: The SC concept and programmes were defined in France in 2007 and are now completely integrated into the predeployment training of all combatants but also of French Military Health Service providers. Finally, SC teaching programmes enhance the importance of teamwork in forward combat medicalisation settings. PMID- 24952974 TI - Anastomosis coverage by a subcutaneous periosteal flap in an 11-year-old child undergoing foot replantation: A technical note. PMID- 24952975 TI - Oligomeric nanoparticles functionalized with NIR-emitting CdTe/CdS QDs and folate for tumor-targeted imaging. AB - We report herein the facile surface-functionalization of one type of biocompatible, oligomeric nanoparticles 1-NPs with NIR-emitting CdTe/CdS QDs and folate for tumor-targeted imaging in vivo. The -NH2 and -SH groups of cysteine residues on the 1-NPs were utilized to covalently conjugate CdTe/CdS QDs and Mal FA to prepare the hybrid nanoparticles 1-NPs-QDs-FA. As-prepared 1-NPs-QDs-FA showed NIR-fluorescence emission at 734 nm, selective uptake by FR-overexpressing tumor cells in vitro, and selective FR-overexpressing tumor-targeted imaging in vivo. This first example of oligomeric/inorganic hybrid nanoparticles provides people with new type of biomaterials for tumor-targeted imaging with high selectivity. PMID- 24952976 TI - Bone regeneration in a massive rat femur defect through endochondral ossification achieved with chondrogenically differentiated MSCs in a degradable scaffold. AB - Mesenchymal stem cells (MSCs) are multipotent cells capable of proliferating and differentiating into several lineages. In regenerative medicine, their potential as a resource for tissue-replacement therapy is receiving much attention. However, transplanting MSCs to repair larger bone defects in animal models has so far proved disappointing. Here we report on the healing of both critical-sized (5 mm) and massive (15 mm) full-thickness femur defects in rats by implanting a uniquely fabricated PLGA scaffold seeded with MSCs pre-differentiated in vitro into cartilage-forming chondrocytes (MSC-DCs). This strategy closely mimics endochondral ossification, the process by which long bones develop in nature. It is thought that because the transplanted MSC-DCs induced natural bone formation, the defect size was not critical to the outcome. Crucially, after 8 weeks the mean biomechanical strength of femora with the massive 15 mm implant reached 75% that of a normal rat femur, while in the case of 5 mm implants there was no significant difference. Successful healing was also highly reproducible, with bone union occurring in all treated animals examined radiologically 8 or 16 weeks after surgery. PMID- 24952978 TI - Release behavior and intra-articular biocompatibility of celecoxib-loaded acetyl capped PCLA-PEG-PCLA thermogels. AB - In this study, we investigated the in vitro and in vivo properties and performance of a celecoxib-loaded hydrogel based on a fully acetyl-capped PCLA PEG-PCLA triblock copolymer. Blends of different compositions of celocoxib, a drug used for pain management in osteoarthritis, and the acetyl-capped PCLA-PEG PCLA triblock copolymer were mixed with buffer to yield temperature-responsive gelling systems. These systems containing up to 50 mg celecoxib/g gel, were sols at room temperature and converted into immobile gels at 37 degrees C. In vitro, release of celecoxib started after a ~10-day lag phase followed by a sustained release of ~90 days. The release was proven to be mediated by polymer dissolution from the gels. In vivo (subcutaneous injection in rats) experiments showed an initial celecoxib release of ~30% during the first 3 days followed by a sustained release of celecoxib for 4-8 weeks. The absence of a lag phase and the faster release seen in vivo were likely due to the enhanced celecoxib solubility in biological fluids and active degradation of the gel by macrophages. Finally, intra-articular biocompatibility of the 50 mg/g celecoxib-loaded gel was demonstrated using MUCT-scanning and histology, where no cartilage or bone changes were observed following injection into the knee joints of healthy rats. In conclusion, this study shows that celecoxib-loaded acetyl-capped PCLA-PEG-PCLA hydrogels form a safe drug delivery platform for sustained intra-articular release. PMID- 24952979 TI - Antimicrobial potency and selectivity of simplified symmetric-end peptides. AB - Because antimicrobial peptides (AMPs) are potentially useful for the treatment of multidrug-resistant infections, more attention is being paid to the structural modification and structure-function relationship of both naturally occurring and synthetic AMPs. Previous studies indicated that Protegrin-1 (PG-1), isolated from porcine leukocytes, exhibited considerable antimicrobial activity and cytotoxicity. The beta-turn of PG-1 floated on the surface of bacterial membrane, while its beta-strand inserted into the bacterial membrane and formed pores that were dedicated to producing cytotoxicity. For reducing cytotoxicity and improving cells selectivity, we designed a series of simplified symmetric-end peptides by combining the beta-turn of PG-1 with simple amino acid repeat sequences. The sequence of designed symmetric-end peptides is (XR)nH(RX)n, (n = 1,2; X represents I, F, W and P; H represents CRRRFC). The symmetric-end peptides displayed antimicrobial activity against both gram-positive and gram-negative bacteria. In particular, (XR)2H(RX)2 (X here is I, F and W) showed greater antimicrobial potency than PG-1. Hemolysis activity and cytotoxicity, detected by using human red blood cells (RBCs) and human embryonic lung fibroblasts MRC-5 cells, were observably lower than the native peptide PG-1. (IR)2H(RI)2 (IR2), folded into beta-sheet structures, displayed the highest therapeutic index, suggesting its great cell selectivity. The fluorescence spectroscopy, flow cytometry, and electron microscopy observation indicated that IR2 exhibited great membrane penetration potential by inducing membrane blebbing, disruption and lysis. Collectively, generating symmetric-end beta-sheet peptides is a promising strategy for designing effective AMPs with great antimicrobial activities and cell selectivity. PMID- 24952977 TI - Endothelial retention and phenotype on carbonized cardiovascular implant surfaces. AB - Heart valve disease is an increasing clinical burden for which there is no effective treatment outside of prosthetic replacement. Over the last 20 years, clinicians have increasingly preferred the use of biological prosthetics to mechanical valves despite their superior durability because of the lifelong anticoagulation therapy that is required. Mechanical valve surface engineering has largely focused on being as non-thrombogenic as possible, but despite decades of iteration has had insufficient impact on the anticoagulation burden. In this study, we systematically evaluate the potential for endothelialization of the pyrolytic carbon surface used in mechanical valves. We compared adsorbed adhesion ligand type (collagen I, fibronectin, laminin, and purified adhesion domain fragments GFOGER and FN7-10) and concentration on endothelial adhesion rates and adhesion strength on Medtronic-Hall prosthetic valve surfaces. Regardless of ligand type or concentration, endothelial adhesion strengthening was insufficient for their intended ultra-high shear stress environment. We then hypothesized that microfabricated trenches would reduce shear stress to tolerable levels while maintaining endothelial access to the flow stream, thereby promoting a confluent and anticoagulant endothelial monolayer. Computational fluid dynamics simulations predicted an empirical relationship of channel width, depth, and spacing that would maintain interior surface shear stress within tolerable levels. Endothelial cells seeded to confluence in these channels retained a confluent monolayer when exposed to 600 dyn/cm(2) shear stress for 48 h regardless of applied adhesive ligand. Furthermore, sheared EC expressed a mature anti-coagulant profile, including endothelial nitric oxide synthase (eNOS), VE-cadherin, and significantly downregulated plasminogen activator inhibitor-1 (PAI-1). As a final test, channeled pyrolytic carbon surfaces with confluent EC reduced human platelet adhesion 1000-fold over pyrolytic carbon alone. These results advance a promising biohybrid approach to enable active moderation of local coagulative response in mechanical heart valves, which could significantly extend the utility of this important treatment for heart valve disease. PMID- 24952980 TI - Gene transfection in complex media using PCBMAEE-PCBMA copolymer with both hydrolytic and zwitterionic blocks. AB - Safety and high efficacy of vectors are essential requirements for gene therapy. To address these challenges, poly(carboxy betaine methacrylate ethyl ester) poly(carboxy betaine methacrylate) (PCBMAEE-PCBMA) diblock copolymers were synthesized to form core-shell vector for gene delivery. The hydrophobic PCBMAEE segment, a polyzwitterionic precursor, can condense plasmid DNA (pDNA) into a hydrophobic core, which improves pDNA protection from nuclease attack and maintains the condensed structure against dilution. Moreover, the hydrolysis of PCBMAEE in uptaken gene vectors can enhance the pDNA release and reduce the cytotoxicity caused by the cationic polymer accumulation in the host cells. The PCBMA segment, zwitterionic fouling resistant material, is utilized to stabilize the gene vector in the complex medium and reduce the interference from serum proteins without impeding the endocytosis of DNA vector like PEG protection layer. Results showed that the complex formed by PCBMAEE50-PCBMA14 with luciferase or pEGFP gene exhibit higher transfection efficacy of pDNA than that formed by PEI 25 kDa or Lipofectamine((r)) 2000 in tested cell lines (COS-7, HepG 2, HeLa, and HUVEC), especially, in difficult-to-transfect ones, such as HeLa and HUVEC. The luciferase expression level infected by the vectors of PCBMAEE50 PCBMA14/pGL-4 at N/P = 20/1 is 27 times of the branched PEI 25 kDa in COS-7 cells and 16 times of Lipofectamine((r)) 2000 in HUVEC. Furthermore, the complex formed by PCBMAEE50-PCBMA14 also show advantages in transfection rate, dosage effectiveness and preservation of transfecting activity in serum contained growth medium. The luciferase expression of the vectors of PCBMAEE50-PCBMA14/pGL-4 at N/P = 20/1 is 230 times higher than that of PEI complex at low vector dosage (the 5% standard dosage). And the transfection rate is 25 times higher than that of PEI complex in 10% serum contained growth medium. In short, all these results indicated that the polymeric gene vector, consisted of convertible hydrophobic polyzwitterionic precursor and fixed polyzwitterionic fouling resistant segment, is a promising candidate for high and stable gene transfection in complex growth medium. PMID- 24952983 TI - Non-viral oligonucleotide antimiR-138 delivery to mesenchymal stem cell sheets and the effect on osteogenesis. AB - Cell-sheet technology has already constituted an important part in the regenerative medicine. Nonetheless, oligonucleotide delivery that has been widely performed on isolated stem cells to foster specific function is rarely conducted on the cell sheets. This study is designed with the two-fold aims of verifying the feasibility of non-viral oligonucleotide delivery for the cell sheets and confirming the osteogenesis enhancing effect of antimiR-138 on the cell sheets composed of bone marrow mesenchymal stem cells (BMSCs). The BMSC sheets are fabricated by a vitamin C inducing method, which can be successfully delivered with the oligonucleotides with a high delivery efficiency of nearly 100% by the properly adapted and optimized Lipofactamine2000 based formulation. The antimiR 138 delivery significantly enhances the in vitro osteogenic differentiation of BMSC sheets, indicated by the higher alkaline phosphatase (ALP) production, denser extracellular matrix mineralization and up-regulated osteogenesis related genes including runt-related transcription factor-2 (RUNX2), osterix, ALP, osteocalcin and bone morphogenetic protein-2 at both mRNA and protein levels, compared to controls. Regarding the underlying mechanism, the antimiR-138 delivery down-regulates the endogenous miR-138 levels in the BMSC sheets, consequently activates the extracellular signal regulated kinases 1/2 pathway and enhances the RUNX2 expression. The in vivo results indicate a robust enhancing effect of the antimiR-138 delivery on the bone regeneration ability of BMSC sheets. Massive bone with good vascularization is regenerated by the antimiR-138 delivered BMSC sheets, showing immense clinical significance for bone defect repair/regeneration applications. More importantly, the feasibility of non-viral oligonucleotide delivery system for the cell sheets as verified by our study shall hold a general significance for the cell sheets of various cell type and therapeutic purposes. PMID- 24952982 TI - Excitation propagation in three-dimensional engineered hearts using decellularized extracellular matrix. AB - Engineering of three-dimensional (3D) cardiac tissues using decellularized extracellular matrix could be a new technique to create an "organ-like" structure of the heart. To engineer artificial hearts functionally comparable to native hearts, however, much remain to be solved including stable excitation propagation. To elucidate the points, we examined conduction properties of engineered tissues. We repopulated the decellularized hearts with neonatal rat cardiac cells and then, we observed excitation-propagation of spontaneous beatings using high resolution cameras. We also conducted immunofluorescence staining to examine morphological aspects. Live tissue imaging revealed that GFP labeled-isolated cardiac cells were migrated into interstitial spaces through extravasation from coronary arteries. Engineered hearts repopulated with Ca(2+) indicating protein (GCaMP2)-expressing cardiac cells were subjected to optical imaging experiments. Although the engineered hearts generally showed well organized stable excitation-propagation, the hearts also demonstrated arrhythmogenic propensity such as disorganized propagation. Immunofluorescence study revealed randomly-mixed alignment of cardiomyocytes, endothelial cells and smooth muscle cells. The recellularized hearts also showed disarray of cardiomyocytes and markedly decreased expression of connexin43. In conclusion, we successfully demonstrated that the recellularized hearts showed dynamic excitation-propagation as a "whole organ". Our strategy could provide prerequisite information to construct a 3D-engineered heart, functionally comparable to the native heart. PMID- 24952981 TI - Enhanced enrichment of prostate cancer stem-like cells with miniaturized 3D culture in liquid core-hydrogel shell microcapsules. AB - Cancer stem-like cells (CSCs) are rare subpopulations of cancer cells that are reported to be responsible for cancer resistance and metastasis associated with conventional cancer therapies. Therefore, effective enrichment/culture of CSCs is of importance to both the understanding and treatment of cancer. However, it usually takes approximately 10 days for the widely used conventional approach to enrich CSCs through the formation of CSC-containing aggregates. Here we report the time can be shortened to 2 days while obtaining prostate CSC-containing aggregates with better quality based on the expression of surface receptor markers, dye exclusion, gene and protein expression, and in vivo tumorigenicity. This is achieved by encapsulating and culturing human prostate cancer cells in the miniaturized 3D liquid core of microcapsules with an alginate hydrogel shell. The miniaturized 3D culture in core-shell microcapsules is an effective strategy for enriching/culturing CSCs in vitro to facilitate cancer research and therapy development. PMID- 24952984 TI - Trends in excess mortality in follicular lymphoma at a population level. AB - BACKGROUND: Since the 1990s and since the development of humanised monoclonal antibodies in 1998, the treatment of non-Hodgkin lymphoma has undergone profound changes. Follicular lymphoma (FL) was the first to benefit from this treatment, and several clinical trials have shown a significant improvement in overall survival, but little information is available at a population level. OBJECTIVE: Our objective was to estimate changes in FL-specific mortality at a population level, with an appropriate methodology. METHODS: Two French retrospective population-based studies on FL were conducted, one from 1995 to 2004, in 1477 patients, and one from 1995 to 2010, in 451 patients. Trends in excess mortality rates (EMRs) according to age, sex, Ann Arbor stage and year of diagnosis were evaluated using the flexible model of Remontet et al. RESULTS: Trends in the EMR differed according to age at diagnosis and was higher in advanced stage (III, IV) in patients older than 65 yr. The EMR decreased linearly from 1995 to 2010. This decrease was more marked for advanced stages. CONCLUSION: FL-specific mortality decreased over the years of diagnosis, and the difference according to the lymphoma stage diminished in more recent years. However, progress in the management of FL was not able to erase age-related differences. PMID- 24952985 TI - Characteristics of KPC-2-producing Klebsiella pneumoniae (ST258) clinical isolates from outbreaks in 2 Mexican medical centers. AB - The KPC-producing Klebsiella pneumoniae sequence type 258 (ST258) is an important pathogen widely spread in nosocomial infections. In this study, we identified the KPC-2-producing K. pneumoniae clinical isolates of 2 unrelated outbreaks that corresponded to pandemic strain ST258. The isolates showed high resistance to cephalosporins, carbapenems, quinolones, and colistin. The KPC-2-producing K. pneumoniae isolates were compared to the previously studied KPC-3-producing K. pneumoniae isolates from an outbreak in Mexico; they showed an unrelated pulsed field gel electrophoresis fingerprinting pattern and a different plasmid profile. The KPC-2 carbapenemase gene was identified in two 230- and 270-kb non conjugative plasmids; however, 1 isolate transferred the KPC-2 gene onto an 80-kb plasmid. These findings endorse the need of carrying out a continuous molecular epidemiological surveillance of carbapenem-resistant isolates in hospitals in Mexico. PMID- 24952986 TI - Evaluation of the BD Phoenix system for identification of a wide spectrum of clinically important yeast species: a comparison with Vitek 2-YST. AB - The Phoenix Yeast ID and Vitek 2-YST panels were compared using 351 molecularly identified yeast isolates. The Phoenix showed a comparable rate of correct identification for 4 common (Phoenix, 98%; Vitek, 94%) and 45 uncommon species (Phoenix, 70%; Vitek, 64%) and had a shorter mean identification time (6-7 h). PMID- 24952987 TI - Performance of the Cepheid Xpert(r) SA Nasal Complete PCR assay compared to culture for detection of methicillin-sensitive and methicillin-resistant Staphylococcus aureus colonization. AB - Sensitivity, specificity, positive predictive value, and negative predictive value for the Cepheid Xpert(r) SA Nasal Complete detection (N = 971) of methicillin-sensitive Staphylococcus aureus was 86.5%, 98.5%, 94.6%, and 96.1%; detection of methicillin-resistant S. aureus was 89.3%, 97.9%, 79.8%, and 99.0%, respectively. Our results show that testing on long-term care facility patients had lower sensitivity and specificity compared to acute care patient results. PMID- 24952988 TI - [Reply to "Safety algorithm for ultrasound-guided blocks: The next challenge"]. PMID- 24952989 TI - Descriptive study of the anatomical and ultrasound correlation at the lumbar spine. PMID- 24952990 TI - Is cerebral desaturation during beachchair anaesthesia really an indicator of cerebral injury? PMID- 24952991 TI - A systematic review of CAD/CAM fit restoration evaluations. AB - The evolution and development of CAD/CAM systems have led to the production of prosthetic reconstructions by going beyond the use of traditional techniques. Precision adjustment of prosthetic elements is considered essential to ensure sustainable restoration and dental preparation. The purpose of this article was to summarise the current literature on the fitting quality of fixed prostheses obtained by CAD/CAM technology. PMID- 24952992 TI - A three-dimensional measurement approach for the morphology of the femoral head. AB - The hip joint is one of the most frequent sites of osteoarthritis. Advances in diagnosis and clinical treatment have progressed dramatically in the last few decades; however, there are limitations associated with the lack of reliable measures for quantifying hip joint morphology. Current diagnostic measures of the hip are performed with pre-determined measures, typically lengths and angles, on 2D radiographic planes. The current measurement techniques do not utilize the inherent 3D nature of CT and MR imaging and do not necessarily quantify the relevant clinical pathologies. A valid and reliable measurement modality that measures the surface geometry of the femoral head is necessary for early diagnosis and treatment of hip disease. The purpose of this study was to establish a method to quantify femoral head morphology using a three-dimensional model. A novel measurement approach was applied to 45 cadaveric femurs (23 right; 22 left; nine female, 17 male) and their digitally reconstructed 3D CT models. The mean difference between the cadaveric and digital measures was -2.04 mm with 95% confidence limits (CI) of 13.67 mm and -17.75 mm, respectively. The digital measurement approach was found to have excellent intraobserver reliability (ICC = 0.99, CI 0.98-0.99) and interobserver reliability (ICC = 0.98, CI 0.93-0.99). This valid and reliable novel digital measurement approach enables quantification of the 3D surface geometry of the femoral head and is able to measure individual variations and potentially detect abnormalities. This method may be used to assist future studies to establish valid diagnostic measurements for femoral head and head-neck junction pathologies. PMID- 24952993 TI - Physical activity, fitness, and gray matter volume. AB - In this review, we explore the association among physical activity, cardiorespiratory fitness, and exercise on gray matter volume in older adults. We conclude that higher cardiorespiratory fitness levels are routinely associated with greater gray matter volume in the prefrontal cortex and hippocampus and less consistently in other regions. We also conclude that physical activity is associated with greater gray matter volume in the same regions that are associated with cardiorespiratory fitness including the prefrontal cortex and hippocampus. Some heterogeneity in the literature may be explained by effect moderation by age, stress, or other factors. Finally, we report promising results from randomized exercise interventions that suggest that the volume of the hippocampus and prefrontal cortex remain pliable and responsive to moderate intensity exercise for 6 months-1 year. Physical activity appears to be a propitious method for influencing gray matter volume in late adulthood, but additional well-controlled studies are necessary to inform public policies about the potential protective or therapeutic effects of exercise on brain volume. PMID- 24952996 TI - Damage to enteric neurons occurs in mice that develop fatty liver disease but not diabetes in response to a high-fat diet. AB - BACKGROUND: Disorders of gastrointestinal functions that are controlled by enteric neurons commonly accompany fatty liver disease. Established fatty liver disease is associated with diabetes, which itself induces enteric neuron damage. Here, we investigate the relationship between fatty liver disease and enteric neuropathy, in animals fed a high-fat, high-cholesterol diet in the absence of diabetes. METHODS: Mice were fed a high-fat, high-cholesterol diet (21% fat, 2% cholesterol) or normal chow for 33 weeks. Liver injury was assessed by hematoxylin and eosin, picrosirius red staining, and measurement of plasma alanine aminotransaminase (ALT). Quantitative immunohistochemistry was performed for different types of enteric neurons. KEY RESULTS: The mice developed steatosis, steatohepatitis, fibrosis, and a 10-fold increase in plasma ALT, indicative of liver disease. Oral glucose tolerance was unchanged. Loss and damage to enteric neurons occurred in the myenteric plexus of ileum, cecum, and colon. Total numbers of neurons were reduced by 15-30% and neurons expressing nitric oxide synthase were reduced by 20-40%. The RNA regulating protein, Hu, became more concentrated in the nuclei of enteric neurons after high-fat feeding, which is an indication of stress on the enteric nervous system. There was also disruption of the neuronal cytoskeletal protein, neurofilament medium. CONCLUSIONS & INFERENCES: Enteric neuron loss and damage occurs in animals with fatty liver disease in the absence of glucose intolerance. The enteric neuron damage may contribute to the gastrointestinal complications of fatty liver disease. PMID- 24952995 TI - How cognitive aging affects multisensory integration of navigational cues. AB - Entorhinal grid cells and hippocampal place cells are key systems for mammalian navigation. By combining information from different sensory modalities, they provide abstract representations of space. Given that both structures are among the earliest to undergo age-related neurodegenerative changes, we asked whether age-related navigational impairments are related to deficient integration of navigational cues. Younger and older adults performed a homing task that required using visual landmarks, self-motion information, or a combination of both. Further, a conflict between cues assessed the influence of each sensory domain. Our findings revealed performance impairments in the older adults, suggestive of a higher noise in the underlying spatial representations. In addition, even though both groups integrated visual and self-motion information to become more accurate and precise, older adults did not place as much influence on visual information as would have been optimal. As these findings were unrelated to potential changes in balance or spatial working memory, this study provides the first evidence that increasing noise and a suboptimal weighting of navigational cues might contribute to the common problems with spatial representations experienced by many older adults. These findings are discussed in the context of the known age-related changes in the entorhinal-hippocampal network. PMID- 24952997 TI - Neuroendocrine differentiation in prostate cancer: current and emerging therapy strategies. AB - Neuroendocrine differentiation (NED) secondary to androgen deprivation therapy (ADT) may be frequent in various stages of prostate cancer (PC), particularly in castration-resistant PC (CRPC). NED generally involves more aggressive PC clinical behavior and an unfavorable prognosis. The identification of neuropeptides secreted by NE cells and of different proliferative and anti apoptotic pathways has led to attention being focused on probable diagnostic targets and therapeutic options for a subtype of PC. Emerging evidence suggests that the acquisition of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) phenotype are associated with the development of NED in PC, responsible for a complex interaction between ADT, the onset of CRPC and NED, in which EMT and CSC could play a central role, providing potential therapeutic targets. In this article, we review the pathogenetic, prognostic and predictive significance of NED in human PC, providing an insight into innovative agents capable of treating and perhaps preventing NED occurrence. PMID- 24952994 TI - Cerebrospinal fluid sphingolipids, beta-amyloid, and tau in adults at risk for Alzheimer's disease. AB - Cellular studies suggest sphingolipids may cause or accelerate amyloid-beta (Abeta) and tau pathology but in vivo human studies are lacking. We determined cerebrospinal fluid levels of sphingolipids (ceramides and sphingomyelins), amyloid-beta (Abeta1-42, AbetaX-38, AbetaX-40, and AbetaX-42) and tau (T-tau and p-tau181) in 91 cognitively normal individuals, aged 36-69 years, with a parental history of Alzheimer's disease. The 18-carbon acyl chain length ceramide species was associated with AbetaX-38 (r = 0.312, p = 0.003), AbetaX-40 (r = 0.327, p = 0.002), and T-tau (r = 0.313, p = 0.003) but not with AbetaX-42 (r = 0.171, p = 0.106) or p-tau (r = 0.086, p = 0.418). All sphingomyelin species correlated (most p < 0.001) with all Abeta species and T-tau; many also correlated with p tau. Results remained in regression models after controlling for age and APOE genotype. These results suggest in vivo relationships between cerebrospinal fluid ceramides and sphingomyelins and Abeta and tau levels in cognitively normal individuals at increased risk for Alzheimer's disease, indicating these sphingolipids may be associated with early pathogenesis. PMID- 24952998 TI - Challenges to breastfeeding infants with phenylketonuria. AB - Breastfeeding duration for infants with phenylketonuria (PKU) is less than other full-term infants. However, no study has examined the challenges encountered by mothers' breastfeeding infants with PKU. In 75 mothers of a child with PKU, three categories of breastfeeding challenges were identified: common breastfeeding issues, breastfeeding and PKU, and no challenges. The common breastfeeding issues can be identified in the literature but for these mothers, the issues are heightened due to frequent phenylalanine (Phe) monitoring. Even so, many mothers adapt breastfeeding to maintain desired Phe levels. A few mothers had no issues and were the exception, not the norm. PMID- 24953000 TI - The effect of deep venous stenting on healing of lower limb venous ulcers. AB - OBJECTIVE: To report the outcomes of endovascular interventions on deep veins in patients with venous ulcers (C6). METHODS: This was a retrospective review of a case series. All patients with active venous ulceration who underwent endovascular interventions to the deep venous system from February 2011 to June 2013 were included. Patients with C6 disease who failed a trial of adequate compression therapy or superficial vein interventions were considered for evaluation of the deep veins. Patients with deep vein reflux or without significant venous reflux or with a previous history of deep vein thrombosis underwent computed tomographic venogram or ascending venogram. In the absence of intravenous ultrasound trial ballooning to look for a "waist" to identify subtle lesions was used. Lesions were stented with long Nitinol stents. RESULTS: Thirty eight patients underwent deep vein stenting of 44 limbs with venous ulcers. The lesions were considered to be post-thrombotic in 31 limbs and non-thrombotic iliac vein lesions in 13 limbs. A mean of 1.8 stents were used per patient. There were no significant complications associated with the interventions. At a median follow-up of 15 months, the primary and assisted primary patency rates were 94% and 97%, respectively. Sustained ulcer healing was achieved in 60% of limbs. A further 20% of ulcers had reduced in size. Recurrent ulcers developed in 13% of limbs, and half of these healed with interventions for newly developed incompetence in superficial veins. CONCLUSION: Endovascular interventions to the deep veins appear to be an effective adjunct in achieving the healing of recalcitrant ulcers. PMID- 24952999 TI - Mid-term outcomes and aortic remodelling after thoracic endovascular repair for acute, subacute, and chronic aortic dissection: the VIRTUE Registry. AB - OBJECTIVE: The VIRTUE Registry describes the mid-term clinical and morphological results of thoracic endovascular repair (TEVR) in patients with type B aortic dissection. METHODS: This was a prospective cohort study. The VIRTUE Registry is a prospective, multicentre clinical trial that enrolled patients with complicated acute (<15 days), subacute (15-92 days), and chronic (>92 days) type B aortic dissections treated with the Valiant endograft. One hundred patients were enrolled and the clinical outcomes described at the 3-year follow-up. Analysis of the aortic area and false lumen thrombosis rates defined the morphological response to TEVR in the three clinical groups. RESULTS: Three-year all-cause mortality (18%, 4%, and 24%), dissection related mortality (12%, 4%, and 9%), aortic rupture (2%, 0%, and 4%), retrograde type A dissection (5%, 0%, and 0%), and aortic reintervention rates (20%, 22%, and 39%) were, respectively, defined for patients with acute (n = 50), subacute (n = 24), and chronic (n = 26) dissections. Analysis of aortic morphology observed that patients with subacute dissection demonstrated a similar degree of aortic remodelling to patients with acute dissection. Patients with acute and subacute dissection exhibited greater aortic plasticity than patients with chronic dissection. CONCLUSIONS: The principle clinical findings suggest that TEVR is able to provide good protection from aortic-related death in the mid-term, but with a high rate of aortic reintervention. Analysis of aortic morphology suggested that aortic remodelling in subacute patients is similar to the acute group. Retention of aortic plasticity in the subacute group lengthens the therapeutic window for the treatment of uncomplicated type B dissection. PMID- 24953002 TI - [Update of breast cancer in Primary Care (II/V)]. AB - Breast cancer is a prevalent disease affecting all areas of patients' lives. Therefore, family doctors need to thoroughly understand this disease in order to optimize the health care services for these patients, making the best use of available resources. A series of 5 articles on breast cancer is presented below. It is based on a review of the scientific literature over the last 10 years. The second one deals with population screening and its controversies, screening in high-risk women, and the current recommendations. This summary report aims to provide a current and practical review about this problem, providing answers to family doctors, and helping them to be able to care for their patients for their benefit throughout their illness. PMID- 24953001 TI - [Prognostic value of lipopolysaccharide binding protein and procalcitonin in patients with severe sepsis and septic shock admitted to intensive care]. AB - AIMS: 1) To assess the prognostic value of levels on admission and serial measurements of lipopolysaccharide binding protein (LBP) and procalcitonin (PCT) in relation to in-hospital mortality; and 2) to determine whether the addition of these parameters to severity scores (APACHE II and SOFA) is able to improve prognostic accuracy. DESIGN: A single-center, prospective observational study was carried out. SETTING: Intensive Care unit of a university hospital. PATIENTS: One hundred severe sepsis and septic shock patients were included. DATA COLLECTED: Demographic data, APACHE II and SOFA scores, PCT and LBP levels on admission and after 48 hours, and in-hospital mortality. RESULTS: The best area under the curve for predicting in-hospital mortality corresponded to APACHE II on admission and SOFA after 48 h (AUC ROC: 0.75 for both). PCT and LBP levels on admission and LBP clearance were not statistically different between in-hospital survivors and non survivors. Only PCT clearance was higher among in-hospital survivors than in non survivors (AUC ROC: 0.66). The combination of severity scores and PCT clearance did not result in superior areas under the curve. CONCLUSIONS: LBP and PCT levels on admission and LBP clearance showed no prognostic value in severe sepsis and septic shock patients. Only PCT clearance was predictive of in-hospital mortality. The prognostic accuracy was significantly better for APACHE on admission and SOFA after 48 h than for any of the analyzed biomarkers, and the addition of PCT clearance did not improve their prognostic value. PMID- 24953003 TI - Development of physical fitness in children with intellectual disabilities. AB - BACKGROUND: Few studies examined the development of physical fitness in children and youth with intellectual disabilities (ID), but the developmental patterns of physical fitness are largely unknown. The first aim was to examine physical fitness of primary school children with ID, aged 8-12, and compare the results with typically developing children in order to determine the performance level of children with ID. The second aim was to investigate the developmental trajectory of physical fitness in children with ID and the possible influence of gender and severity of cognitive impairment in a 4-year during longitudinal study. METHOD: Seventy-three children with borderline or mild ID (51 boys, 22 girls; age range 8 11 in the year of enrolment) were measured annually on running speed, aerobic endurance (cardiovascular endurance), explosive strength, handgrip strength and trunk strength. Physical fitness scores of 515 typically developing children (266 boys, 249 girls; age range 8-12) were collected for reference values. RESULTS: The results indicated statistically significant differences (with moderate to large Effect Sizes) between children with ID and typically developing children in all ages, favouring the typically developing children, and showed that the gap remained stable across the ages or decreased with increasing age. Multilevel models showed that the children with ID developed statistically significant on all items of physical fitness between age 8 and age 12. There was no statistically significant effect of gender on physical fitness, and the developmental trajectories were similar for boys and girls. For children with borderline and mild ID the developmental trajectories were parallel, but children with mild ID scored statistically significant worse on running speed, explosive strength and handgrip strength. CONCLUSIONS: Despite statistically significant development of physical fitness in children with ID, their physical fitness levels should be stimulated. This should start already in young children (<8 years) and the children with the most severe cognitive impairments need special attention. PMID- 24953004 TI - Multi-elemental profiling and chemo-metric validation revealed nutritional qualities of Zingiber officinale. AB - Ginger rhizome is a valued food, spice and an important ingredient of traditional systems of medicine of India, China and Japan. An Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) based multi-elemental profiling was performed to assess the quantitative complement of elements, nutritional quality and toxicity of 46 ginger germplasms, collected from the north western Himalayan India. The abundance of eighteen elements quantified in the acid digested rhizomes was observed to be K>Mg>Fe>Ca>Na>Mn>Zn>Ba>Cu>Cr>Ni>Pb>Co>Se>As>Be>Cd. Toxic element, Hg was not detected in any of the investigated samples. Chemometric analyses showed positive correlation among most of the elements. No negative correlation was observed in any of the metals under investigation. UPGMA based clustering analysis of the quantitative data grouped all the 46 samples into three major clusters, displaying 88% similarity in their metal composition, while eighteen metals investigated grouped into two major clusters. Quantitatively, all the elements analyzed were below the permissible limits laid down by World Health Organization. The results were further validated by cluster analysis (CA) and principal component analysis (PCA) to understand the ionome of the ginger rhizome. The study suggested raw ginger to be a good source of beneficial elements/minerals like Mg, Ca, Mn, Fe, Cu and Zn and will provide platform for understanding the functional and physiological status of ginger rhizome. PMID- 24953005 TI - Review on recent developments on pulp and paper mill wastewater treatment. AB - Economic benefits of the pulp and paper industry have led it to be one of the most important industrial sections in the world. Nevertheless, in recent years, pulp and paper mills are facing challenges with the energy efficiency mechanisms and management of the resulting pollutants, considering the environmental feedbacks and ongoing legal requirements. This study reviews and discusses the recent developments of affordable methods dealing with pulp and paper mill wastewaters. To this end, the current state of the various processes used for pulp and paper production from virgin or recovered fibers has been briefly reviewed. Also, the relevant contaminants have been investigated, considering the used raw materials and applied techniques as the subject for further discussion about the relevant suitable wastewater treatment methods. The results of the present study indicated that adopting the integrated methods, alongside a combination of biological (e.g., anaerobic digestion) and physicochemical (e.g., novel Fenton reactions) treatment methods, can be environmentally and economically preferable to minimize environmental contaminants and energy recycling. PMID- 24953006 TI - Pathogenesis of idiopathic pulmonary fibrosis and its clinical implications. AB - Idiopathic pulmonary fibrosis (IPF) is the most common and lethal form of idiopathic interstitial pneumonia. The disease is thought to arise following an aberrant reparative response to recurrent alveolar epithelial cell injury leading to progressive loss of function. The median survival time is 3-5 years from diagnosis. Cigarette smoking, exposure to organic and inorganic dust and genetic factors have been shown to increase the risk of disease, although the cause of IPF remains elusive and its pathogenesis incompletely understood. In the last decade, several clinical trials evaluating novel therapies for IPF have been conducted but the results have been mostly disappointing. Conversely, compounds that target anti-fibrotic and growth factor pathways have been proven effective in slowing functional decline and disease progression. These promising results notwithstanding, truly effective therapeutic strategies will likely require combinations of drugs in order to target the multitude of pathways involved in disease pathogenesis. PMID- 24953007 TI - Reproductive technologies and the porcine embryonic transcriptome. AB - The domestic pig is not only an economically-important livestock species, but also an increasingly recognized biomedical animal model due to its physiological similarities with humans. As a result, there is a strong interest in the factors that affect the efficient production of viable embryos and offspring in the pig using either in vivo or in vitro production methods. The application of assisted reproductive technologies (ART) has the potential to increase reproductive efficiency in livestock. These technologies include, but are not limited to: artificial insemination (AI), fixed-time AI, embryo transfer, cryopreservation of sperm/oocytes/embryos, in vitro fertilization and somatic cell nuclear transfer (cloning). However, the application of ART is much less efficient in the pig than in many other mammalian species such as cattle. Until recently, the underlying causes of these inefficiencies have been difficult to study, but advances in molecular biology techniques for studying gene expression have resulted in the availability of a variety of options for gene expression profiling such as microarrays, and next generation sequencing technologies. Capitalizing on these technologies the effects of various ARTs on the porcine embryonic transcriptome has been determined and the impact on the related biological pathways and functions been evaluated. The implications of these results on the efficiency of ARTs in swine, as well potential consequences for the developing embryo and resulting offspring, are reviewed. PMID- 24953009 TI - Analysis of the interferences in quantitation of a site-specifically PEGylated exendin-4 analog by the Bradford method. AB - Protein modification has been found to affect the estimation of protein concentration in some of the traditional dye-based absorbance measurements. In this work, a distinct reduction in A595 was observed during the quantitation of a PEGylated exendin-4 analogue (Ex4C) by the Bradford method and the PEGylation process was found to interfere with the measurement. Lys(12), Arg(20), and Lys(27) were further proved to be the major amino acids that functioned as dye binding sites. The shielding effect produced by the large polymer was demonstrated to depend on the length of PEG that was used for modification. PMID- 24953008 TI - Apathy as a feature of prodromal Alzheimer's disease: an FDG-PET ADNI study. AB - OBJECTIVE: The goal of this study is to evaluate brain metabolism in mild cognitive impairment (MCI) patients with and without apathy (as determined by the Neuropsychiatric Inventory Questionnaire). METHODS: Baseline data from 65 MCI participants (11 with apathy and 54 without) from the Alzheimer's Disease (AD) Neuroimaging Initiative study were analyzed. All participants underwent a comprehensive cognitive and neuropsychiatric assessment, volumetric MRI and measures of cerebral glucose metabolism applying (18)F-fluorodeoxyglucose positron emission tomography at baseline. The presence of apathy at baseline was determined by the Neuropsychiatric Inventory Questionnaire. RESULTS: There was no difference between apathy and apathy-free MCI patients regarding cognitive assessment and neuropsychiatric measures when apathy-specific items were removed. Cerebrovascular disease load and cerebral atrophy were equivalent in both groups. Compared with the apathy-free MCI patients, MCI patients with apathy had significantly decreased metabolism in the posterior cingulate cortex. CONCLUSION: The presence of apathy in MCI patients is associated with AD-specific pattern of brain metabolic defect. These results could suggest that apathy belongs to the spectrum of prodromal AD symptoms. PMID- 24953010 TI - Combined use of [TBA][L-ASP] and hydroxypropyl-beta-cyclodextrin as selectors for separation of Cinchona alkaloids by capillary electrophoresis. AB - In this paper, a new capillary electrophoresis (CE) separation and detection method was developed for the chiral separation of the four major Cinchona alkaloids (quinine/quinidine and cinchonine/cinchonidine) using hydroxypropyl beta-cyclodextrin (HP-beta-CD) and chiral ionic liquid ([TBA][L-ASP]) as selectors. Separation parameters such as buffer concentrations, pH, HP-beta-CD and chiral ionic liquid concentrations, capillary temperature, and separation voltage were investigated. After optimization of separation conditions, baseline separation of the three analytes (cinchonidine, quinine, cinchonine) was achieved in fewer than 7 min in ammonium acetate background electrolyte (pH 5.0) with the addition of HP-beta-CD in a concentration of 40 mM and [TBA][L-ASP] of 14 mM, while the baseline separation of cinchonine and quinidine was not obtained. Therefore, the first-order derivative electropherogram was applied for resolving overlapping peaks. Regression equations revealed a good linear relationship between peak areas in first-order derivative electropherograms and concentrations of the two diastereomer pairs. The results not only indicated that the first order derivative electropherogram was effective in determination of a low content component and of those not fully separated from adjacent ones, but also showed that the ionic liquid appeared to be a very promising chiral selector in CE. PMID- 24953011 TI - In situ protein microarrays capable of real-time kinetics analysis based on surface plasmon resonance imaging. AB - In recent years, in situ protein synthesis microarray technologies have enabled protein microarrays to be created on demand just before they are needed. In this paper, we utilized the TUS-TER immobilization technology to allow label-free detection with real-time kinetics of protein-protein interactions using surface plasmon resonance imaging (SPRi). We constructed an expression-ready plasmid DNA with a C-terminal TUS fusion tag to directionally immobilize the in situ synthesized recombinant proteins onto the surface of the biosensor. The expression plasmid was immobilized on the polyethylene imine-modified gold surface, which was then coupled with a cell-free expression system on the flow cell of the SPRi instrument. The expressed TUS fusion proteins bind on the surface via the immobilized TER DNA sequence with high affinity (~3-7*10(-13)M). The expression and immobilization of the recombinant in situ expressed proteins were confirmed by probing with specific antibodies. The present study shows a new low cost method for in situ protein expression microarrays that has the potential to study the kinetics of protein-protein interactions. These protein microarrays can be created on demand without the problems of stability associated with protein arrays used in the drug discovery and biomarker discovery fields. PMID- 24953012 TI - Impact of tumour microenvironment and Fc receptors on the activity of immunomodulatory antibodies. AB - Immunomodulatory antibodies influence the direction and magnitude of immune responses against cancer. Significant efficacy has been demonstrated across multiple solid tumour types within clinical trials. Recent preclinical studies indicate that successful outcome relies upon mechanistic activity extending beyond simple receptor stimulation or blockade. In addition to blocking co inhibitory signals in secondary lymphoid organs, cytotoxic T-lymphocyte antigen (CTLA)-4 antibodies mediate depletion of tumour-infiltrating regulatory T cells by antibody-dependent cellular cytotoxicity (ADCC). This mechanism appears to be common to other immunomodulatory antibodies including those targeting OX40 and glucocorticoid-induced TNFR-related protein (GITR). If verified in the human setting, these findings have significant implications for antibody design, biomarker discovery, and the development of synergistic combinatorial therapies. PMID- 24953013 TI - AURKA regulates JAK2-STAT3 activity in human gastric and esophageal cancers. AB - Aurora kinase A is a frequently amplified and overexpressed gene in upper gastrointestinal adenocarcinomas (UGCs). Using in vitro cell models of UGCs, we investigated whether AURKA can regulate Signal Transducer and Activator of Transcription 3 (STAT3). Our data indicate that overexpression of AURKA in FLO-1 and AGS cells increase STAT3 phosphorylation at the Tyr705 site, whereas AURKA genetic depletion by siRNA results in decreased phosphorylation levels of STAT3 in FLO-1 and MKN45 cells. Immunofluorescence analysis showed that AURKA overexpression enhanced STAT3 nuclear translocation while AURKA genetic knockdown reduced the nuclear translocation of STAT3 in AGS and FLO-1 cells, respectively. Using a luciferase reporter assay, we demonstrated that AURKA expression induces transcriptional activity of STAT3. Pharmacological inhibition of AURKA by MLN8237 reduced STAT3 phosphorylation along with down-regulation of STAT3 pro-survival targets, BCL2 and MCL1. Moreover, by using clonogenic cells survival assay, we showed that MLN8237 single dose treatment reduced the ability of FLO-1 and AGS cells to form colonies. Additional experiments utilizing cell models of overexpression and knockdown of AURKA indicated that STAT3 upstream non-receptor tyrosine kinase Janus kinase 2 (JAK2) is mediating the effect of AURKA on STAT3. The inhibition of JAK2 using JAK2-specific inhibitor AZD1480 or siRNA knockdown, in presence of AURKA overexpression, abrogated the AURKA-mediated STAT3 activation. These results confirm that the AURKA-JAK2 axis is the main mechanism by which AURKA regulates STAT3 activity. In conclusion, we report, for the first time, that AURKA promotes STAT3 activity through regulating the expression and phosphorylation levels of JAK2. This highlights the importance of targeting AURKA as a therapeutic approach to treat gastric and esophageal cancers. PMID- 24953015 TI - Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations. AB - The FORWARD study is a randomised, double-blind trial that compares the efficacy and safety of 48 weeks treatment with extrafine beclomethasone dipropionate/formoterol fumarate (BDP/FOR), 100/6 MUg pMDI, 2 inhalations BID, vs. FOR 12 MUg pMDI, 1 inhalation BID, in severe COPD patients with a history of exacerbations. Co-primary endpoints were exacerbation rate over 48 weeks and pre dose morning FEV(1) at 12 weeks. The ITT population included 1186 patients (69% males, mean age 64 years) with severe airflow limitation (mean post bronchodilator FEV(1) 42% predicted). Salbutamol as rescue therapy, theophylline and tiotropium (if stable regimen prior to screening) were allowed. Compared to FOR, BDP/FOR: (1) reduced the exacerbation rate (rate ratio: 0.72 [95% confidence interval 0.62-0.84], p < 0.001); (2) improved pre-dose morning FEV(1) (mean difference: 0.069 L [0.043-0.095] p < 0.001); (3) prolonged the time to first exacerbation; (4) improved the SGRQ total score. The percentage of patients with adverse events was similar (52.1% with BDP/FOR and 49.2% with FOR). Pneumonia incidence was low, slightly higher with BDP/FOR (3.8%) than with FOR (1.8%). No difference for laboratory values, ECG or vital signs. Extrafine BDP/FOR significantly reduces the exacerbation rate and improves lung function of patients with severe COPD and history of exacerbations as compared to FOR alone. PMID- 24953016 TI - Opening Pandora's box: understanding the nature, patterns, and 30-day outcomes of intraoperative adverse events. AB - BACKGROUND: Little evidence exists regarding the characteristics of intraoperative adverse events (iAEs). METHODS: Administrative data, the American College of Surgeons - National Surgical Quality Improvement Project, and systematic review of operative reports were used to confirm iAEs in abdominal surgery patients. Standard American College of Surgeons - National Surgical Quality Improvement Project data were supplemented with variables including injury type/organ, phase of operation, adhesions, repair type, and intraoperative consultations. RESULTS: Two hundred twenty-seven iAEs (187 patients) were confirmed in 9,292 patients. Most common injuries were enterotomies during intestinal surgery (68%) and vessel injuries during hepatopancreaticobiliary surgery (61%); 108 iAEs (48%) specifically occurred during adhesiolysis. A third of the iAEs required organ/tissue resection or complex reconstruction. Because of iAEs, 20 intraoperative consults (11%) were requested and 9 of the 66 (16%) laparoscopic cases were converted to open. Thirty-day mortality and morbidity were 6% and 58%, respectively. The complications included perioperative transfusions (36%), surgical site infection (19%), systemic sepsis (13%), and failure to wean off the ventilator (12%). CONCLUSIONS: iAEs commonly occur in reoperative cases requiring lysis of adhesions and possibly lead to increased patient morbidity. Understanding iAEs is essential to prevent their occurrence and mitigate their adverse effects. PMID- 24953014 TI - Brain metastasis: new opportunities to tackle therapeutic resistance. AB - Brain metastasis is a devastating complication of cancer with unmet therapeutic needs. The incidence of brain metastasis has been rising in cancer patients and its response to treatment is limited due to the singular characteristics of brain metastasis (i.e., blood-brain-barrier, immune system, stroma). Despite improvements in the treatment and control of extracranial disease, the outcomes of patients with brain metastasis remain dismal. The mechanisms that allow tumor cells to promulgate metastases to the brain remain poorly understood. Further work is required to identify the molecular alterations inherent to brain metastasis in order to identify novel therapeutic targets and explicate the mechanisms of resistance to systemic therapeutics. In this article, we review current knowledge of the unique characteristics of brain metastasis, implications in therapeutic resistance, and the possibility of developing biomarkers to rationally guide the use of targeted agents. PMID- 24953018 TI - Isolated clonal cytogenetic abnormalities after high-dose therapy: do they matter? PMID- 24953017 TI - Cytogenetics, donor type, and use of hypomethylating agents in myelodysplastic syndrome with allogeneic stem cell transplantation. AB - We investigated the impact of patient and disease characteristics, including cytogenetics, previous therapy, and depth of response, on the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myelodysplastic syndrome (MDS). We analyzed 256 MDS patients who underwent transplantation from a matched related (n = 133) or matched unrelated (n = 123) donor after 2001. Of the 256, 78 (30.5%) did not receive cytoreductive therapy before HSCT; 40 (15.6%) received chemotherapy, 122 (47.7%) received hypomethylating agents (HMA), and 16 (6.2%) received both (chemo+HMA). Disease status at HSCT defined by International Working Criteria was complete remission in 46 (18%) patients. There were significant differences between therapy groups: there were more therapy-related MDS and higher use of matched related donor in the untreated group. The chemotherapy group had higher serum ferritin levels at HSCT. Patients were older and had more high-risk disease by revised International Prognostic Scoring in the HMA group. Despite those differences, transplantation outcomes were similar in patients who were untreated and who received cytoreductive therapy before HSCT. Three-year event-free survival (EFS) was 44.2%, 30.6%, 34.2%, and 32.8% for untreated, chemotherapy, HMA, and chemo+HMA groups, respectively (P = .50). Multivariate analyses revealed that older age (hazard ratio [HR], 1.3; P = .001); high-risk histologic subtypes, including refractory anemia with excess blasts (HR, 1.5; P = .05) and chronic myelomonocytic leukemia (HR, 2.1; P = .03), high-risk cytogenetics with monosomal karyotype (MK) (HR, 4.0; P < .0001) and high serum ferritin level at HSCT (HR, 1.8; P = .002) were poor prognostic factors for EFS. Bone marrow blast count 5% or higher at HSCT (HR, 1.6; P = .01) and MK (HR, 4.2; P < .0001) were the only prognostic factors for increased relapse incidence after HSCT. Patients with MK represented a poor prognostic group, with 3-year EFS of 11.4% and relapse incidence of 60.9%. In this analysis, various therapy approaches before HSCT did not lead to different transplantation outcomes. Cytogenetics defined by MK was able to identify a very poor prognostic groups that innovative transplantation approaches to improve outcomes are urgently needed. PMID- 24953019 TI - Fibrin glue therapy for severe hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. AB - Hemorrhagic cystitis (HC) occurring after allogeneic transplantation significantly affects quality of life and, in some cases, becomes intractable, increasing the risk of death. To date, its therapy is not established. We used the hemostatic agent fibrin glue (FG) to treat 35 patients with refractory post transplantation HC. Of 322 adult patients undergoing an allogeneic transplantation for hematological malignancy, 35 developed grade >= 2 HC refractory to conventional therapy and were treated with FG, diffusely sprayed on bleeding mucosa by an endoscopic applicator. The cumulative incidence of pain discontinuation and complete remission, defined as regression of all symptoms and absence of hematuria, was 100% at 7 days and 83% +/- 7%, respectively, at 50 days from FG application. The 6-month probability of overall survival for all 35 patients and for the 29 in complete remission was 49% +/- 8% and 59% +/- 9%, respectively. In the matched-pair analysis, the 5-year probability of overall survival for the 35 patients with HC and treated with FG was not statistically different from that of the comparative cohort of 35 patients who did not develop HC (32% +/- 9% versus 37% +/- 11%, P = not significant). FG therapy is a feasible, effective, repeatable, and affordable procedure for treating grade >=2 HC after allogeneic transplantation. PMID- 24953020 TI - Assessment of BAK1 activity in different plant receptor-like kinase complexes by quantitative profiling of phosphorylation patterns. AB - Plant receptor-like kinases (RLKs) constitute a large family of receptors coordinating developmental programs with adaptation to environmental stresses including immune defenses. BRI1-ASSOCIATED KINASE 1 (BAK1), a member of the plant RLK family, forms receptor complexes with multiple RLK proteins including BRI1, FLS2, EFR and BIK1 to regulate responses to growth hormones or PAMPs. RLK activation and signal initiation involve protein complex formation and phosphorylation/dephosphorylation between BAK1 and its interacting partners. To gain new insight into how phosphorylation contributes to BAK1-mediated signaling specificity, we first mapped the phosphorylation patterns of BAK1 associated with different RLK partners (BRI1, FLS2, EFR and BIK1). Quantitative phospho-pattern profiling by label-free mass spectrometry revealed that differential phosphorylation patterns of RLK partners resulted from altered BAK1 phosphorylation status. More interestingly, the study of two BAK1 mutants (T450A and C408Y) both showing severe defect in immune defense yet normal growth phenotype suggested that varied phosphorylation patterns of RLK partners by BAK1 could be the molecular basis for selective regulation of multiple BAK1-dependent pathways. Taken together, this phospho-pattern profiling strategy allowed for explicit assessment of BAK1 kinase activity in different RLK complexes, which would facilitate elucidation of BAK1 diverse functions in plant development, defense, and adaptation. BIOLOGICAL SIGNIFICANCE: BAK1 is a functionally important co-receptor known to interact with different receptor-like kinases (RLKs) to coordinate plant development and immune defenses. Our study first mapped the phosphorylation patterns of BAK1 associated with four RLK partners (BRI1, FLS2, EFR and BIK1), and further revealed that differential phosphorylation patterns of multiple RLK partners resulted from altered BAK1 phosphorylation status. More interestingly, the study of two BAK1 mutants suggested that varied phosphorylation patterns of RLK partners by BAK1 could be the basis for selective regulation of signaling pathways. Taken together, this phospho-pattern profiling strategy allowed for explicit assessment of BAK1 kinase activity in different RLK complexes, which would facilitate elucidation of BAK1 diverse functions in plant development, defense, and adaptation. PMID- 24953021 TI - Multicentre randomised controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding. AB - BACKGROUND & AIMS: Rebleeding after an initial oesophageal variceal haemorrhage remains a significant problem despite therapy with band ligation, non-selective beta-blockers or a combination of these. Carvedilol is a vasodilating non selective beta-blocker with alpha-1 receptor and calcium channel antagonism. A recent study has suggested it is effective in the prevention of a first variceal bleed. Our aim was to compare oral carvedilol with variceal band ligation (VBL) in the prevention of rebleeding following a first variceal bleed. METHODS: Patients who were stable 5 days after presentation with a first oesophageal variceal haemorrhage and had not been taking beta-blockers were randomised to oral carvedilol or VBL. Patients were followed-up after one week, monthly, then every 3 months. The primary end point was variceal rebleeding on intention-to treat analysis. RESULTS: 64 patients were randomised, 33 to carvedilol and 31 to VBL. 58 (90.6%) patients had alcohol related liver disease. Age and Child-Pugh score were similar in both groups at baseline. Median follow-up was 26.3 (interquartile range [IQR] 10.2-46.6)months. Compliance was 68% and 65% for carvedilol and VBL respectively (p=0.993) and serious adverse events between the two groups were similar (p=0.968). Variceal rebleeding occurred during follow-up in 12 (36.4%) and 11 (35.5%) patients in the carvedilol and VBL groups, respectively (p=0.857), with 9 (27.3%) and 16 (51.6%) deaths in each group, respectively (p=0.110). CONCLUSIONS: Carvedilol is not superior to VBL in the prevention of variceal rebleeding. The trend to a survival benefit for patients taking this drug compared with those undergoing banding requires further exploration. PMID- 24953022 TI - Long-term cannabinoid type 2 receptor agonist therapy decreases bacterial translocation in rats with cirrhosis and ascites. AB - BACKGROUND & AIMS: Intestinal hyperpermeability, impaired peritoneal macrophages (PMs) phagocytosis, and bacterial translocation (BT), resulting in increased systemic and local infection/inflammation such as spontaneous bacterial peritonitis (SBP) together with increased tumor necrosis factor-alpha (TNFalpha) levels, are all implicated in the pathogenesis of cirrhosis-related complications. Manipulation of the cannabinoid receptors (CB1R and CB2R), which are expressed on the gut mucosa and PMs, has been reported to modulate intestinal inflammation and systemic inflammatory cytokine release. Our study aims to explore the effects of chronic CB1R/CB2R agonist/antagonist treatments on relevant abnormalities in cirrhotic ascitic rats. METHODS: Vehicle, archidonyl-2 chloroethylamide (ACEA, CB1R agonist), JWH133 (CB2R agonist), and AM630 (CB2R antagonist) were given to thioacetamide (TAA) and common bile duct ligation (BDL) cirrhotic rats with ascites for two weeks and various measurement were performed. RESULTS: Compared to sham rats, CB2Rs were downregulated in cirrhotic rat intestines and PMs. The two-week JWH133 treatment significantly decreased systemic/intestinal oxidative stress, TNFalpha and inflammatory mediators, infection, intestinal mucosal damage and hyperpermeability; the JWH133 treatment also decreased bacterial overgrowth/adhesion, BT and SBP, upregulated intestinal tight junctions and downregulated the PM TNFalpha receptor/NFkappaBp65 protein expression in cirrhotic rats. Acute and chronic JWH133 treatment corrected the TNFalpha-induced suppression of phagocytosis of cirrhotic rat PMs, which then could be reversed by concomitant AM630 treatment. CONCLUSIONS: Our study suggests that CB2R agonists have the potential to treat BT and various relevant abnormalities through inhibition of systemic/intestinal oxidative stress, inflammatory cytokines and TNFalpha release in cirrhosis. Overall, the chronic CB2R agonist treatment affects multiple approach mechanisms, and its direct effect on the hyperdynamic circulation is only minor. PMID- 24953024 TI - Direct-acting antivirals trump interferon-alpha in their capacity to rescue exhausted T cells upon HCV clearance. PMID- 24953023 TI - The Fas/Fas ligand apoptosis pathway underlies immunomodulatory properties of human biliary tree stem/progenitor cells. AB - BACKGROUND & AIMS: Human biliary tree stem/progenitor cells (hBTSCs) are multipotent epithelial stem cells, easily obtained from the biliary tree, with the potential for regenerative medicine in liver, biliary tree, and pancreas diseases. Recent reports indicate that human mesenchymal stem cells are able to modulate the T cell immune response. However, no information exists on the capabilities of hBTSCs to control the allogeneic response. The aims of this study were to evaluate FasL expression in hBTSCs, to study the in vitro interaction between hBTSCs and human lymphocytes, and the role of Fas/FasL modulation in inducing T cell apoptosis in hBTSCs/T cell co-cultures. METHODS: Fas and FasL expression were evaluated in situ and in vitro by immunofluorescence and western blotting. Co-cultures of hBTSCs with human leukocytes were used to analyze the influence of hBTSCs on lymphocytes activation and apoptosis. RESULTS: hBTSCs expressed HLA antigens and FasL in situ and in vitro. Western blot data demonstrated that hBTSCs constitutively expressed high levels of FasL that increased after co-culture with T cells. Confocal microscopy demonstrated that FasL expression was restricted to EpCAM(+)/LGR5(+) cells. FACS analysis of T cells co-cultured with hBTSCs indicated that hBTSCs were able to induce apoptosis in activated CD4(+) and CD8(+) T cell populations. Moreover, the Fas receptor appears to be more expressed in T cells co-cultured with hBTSCs than in resting T cells. CONCLUSIONS: Our data suggest that hBTSCs could modulate the T cell response through the production of FasL, which influences the lymphocyte Fas/FasL pathway by inducing "premature" apoptosis in CD4(+) and CD8(+) T cells. PMID- 24953025 TI - Sensing based on the motion of enzyme-modified nanorods. AB - Asymmetric modification with an enzyme confers nanorods an enhanced diffusive motion that is dependent on the concentration of the enzyme substrate. In turn, such a motion opens the possibility of determining the concentration of the enzyme substrate by measuring the diffusion coefficient of nanorods modified with the appropriate enzyme. Nanorods, with a Pt and a polypyrrole (PPy) segment, were fabricated. The PPy segment of such nanorods was then modified with glucose oxidase (GOx), glutamate oxidase (GluOx), or xanthine oxidase (XOD). Calibration curves, linking the diffusion coefficient of the oxidase-modified nanorods to the concentration of the oxidase substrate, were subsequently built. The oxidase modified nanorods and their calibration curves were finally used to determine substrate concentrations both in simple aqueous solutions and in complex samples such as horse serum and cell culture media. Based on the obtained results we are confident that our motion-based approach to sensing can be developed to the point where different nanorods in a mixture simultaneously report on the concentration of different compounds with good temporal and spatial resolution. PMID- 24953026 TI - QOL in caregivers of Japanese patients with Prader-Willi syndrome with reference to age and genotype. AB - This study aimed to measure quality of life (QOL) of the primary family caregivers for patients with Prader-Willi syndrome (PWS). Comparisons were made between caregivers' QOL in regard to their dependents' genotype and age group. The participants with PWS consisted of 22 children (aged from 6 to 12 years) and 23 adolescents (aged from 13 to 19 years), including 6 children and 7 adolescents with maternal uniparental disomy (mUPD) and 16 children and 16 adolescents with deletion (DEL). The QOL of the primary family caregiver for each patient was assessed using the Japanese version of the WHOQOL-BREF. To examine the effect that age (children vs. adolescents) and genotype (DEL vs. mUPD) have on the QOL of caregivers, a two-way ANOVA was conducted, followed by the Bonferroni procedure to test the simple main effects. The two age groups and the two genotypes of PWS were used as independent variables and the total QOL of caregivers as a dependent variable. The two-way ANOVA (F(1, 41) = 6.98, P < 0.05), followed by the Bonferroni procedure, showed the following: the total QOL of caregivers of DEL adolescents showed little difference from that with DEL children, but the QOL of caregivers for mUPD adolescents was shown to be lower than that with mUPD children along with that of caregivers with DEL adolescents. There is hence a growing tendency for the deterioration in the QOL of caregivers to manifest itself later in the patients' adolescence, found mainly with mUPD patients. PMID- 24953027 TI - Synthesis and anticancer activity of some novel 5,6-fused hybrids of juglone based 1,4-naphthoquinones. AB - Six novel 5,6-fused hybrids such as dihydrobenzofuran-quinone (4a and 4b), benzofuran-quinone (5a and 5b) and chromene-quinone (6a and 6b) of juglone based 1,4-naphthoquinones were synthesized by employing a three step protocol with the cyclisation of o-allyl phenol as the key step. The anticancer activity of the newly synthesized compounds was evaluated in vitro against seven human cancer cell lines including cervix (ME-180 and HeLa), breast (MCF-7, MDA-MB-453 and MDA MB-231), prostate (PC-3) and colon (HT-29) by using MTT assay. The screening results showed that majority of the synthesized compounds exhibited significant anticancer activity. In particular, compounds 6a and 6b showed potent activities than the standard drug etoposide against prostate and breast cancer cell lines respectively. Flow cytometric analysis revealed that compounds 6a and 6b induced apoptosis and arrested the cell cycle at G2/M phase in PC-3 and MDA-MB-453 cells respectively. PMID- 24953028 TI - Antibacterial evaluation of structurally amphipathic, membrane active small cationic peptidomimetics: synthesized by incorporating 3-amino benzoic acid as peptidomimetic element. AB - A new series of small cationic peptidomimetics were synthesized by incorporating 3-amino benzoic acid (3-ABA) in a small structural framework with the objective to mimic essential properties of natural antimicrobial peptides (AMPs). The new design approach resulted into improvement of activity and selectivity in comparison to linear peptides and allowed us to better understand the influence of structural amphipathicity on biological activity. Lead peptidomimetics displayed antibacterial activities against resistant pathogens (MRSA & MRSE). A calcein dye leakage experiment revealed a membranolytic effect of 4g and 4l which was further confirmed by fluorescence microscopy. In addition, proteolytic stability and no sign of resistance development against Staphylococcus aureus and MRSA demonstrate their potential for further development as novel antimicrobial therapeutics. PMID- 24953029 TI - Synthesis and antitumor activities of novel alpha-aminophosphonate derivatives containing an alizarin moiety. AB - A series of novel alpha-aminophosphonate derivatives containing an alizarin moiety (6-7) was designed and synthesized as antitumor agents. MTT (3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) assay results indicated that most compounds exhibited moderate to high inhibitory activity against KB, NCI-H460, HepG 2, A549, MGC-803, Hct-116, CNE and Hela tumor cell lines. The action mechanism of representative compounds 7h, 7j and 7n were investigated by fluorescence staining assays, flow cytometric analysis and real-time polymerase chain reaction (PCR) assays, which indicated that these compounds induced apoptosis and involved G1 phase arrest by increasing the production of intracellular Ca(2+) and reactive oxygen species (ROS) and affecting associated enzymes and genes. The results demonstrated that these compounds may induce apoptosis through a mitochondrion-dependent pathway. PMID- 24953030 TI - Optimization of troglitazone derivatives as potent anti-proliferative agents: towards more active and less toxic compounds. AB - Delta2-Troglitazone derivatives were shown to exhibit anti-proliferative activity in a PPARgamma-independent manner. We prepared various compounds in order to increase their potency and decrease their toxicity towards non-malignant primary cultured hepatocytes. Many compounds induced viabilities less than 20% at 10 MUM on various cancer cell lines. Furthermore, five of them showed hepatocyte viability of 80% or more at 200 MUM. In addition, compounds 17 and 18 exhibited promising maximum tolerated doses on a murine model, enabling future investigations. PMID- 24953031 TI - Synthesis and crystal structure determination of copper(II)-complex: In vitro DNA and HSA binding, pBR322 plasmid cleavage, cell imaging and cytotoxic studies. AB - New Cu(II) complex 1 of indole-3-propionic acid and 1,10-phenanthroline was synthesized and characterized by analytical, spectroscopic and single crystal X ray diffraction. In vitro DNA binding studies of 1 was performed by employing UV vis and fluorescence spectroscopic techniques. The binding affinity towards human serum albumin (HSA) was also investigated to understand the carrier role in body system, as the time dependent HPLC experiment of 1 revealed that bonded drug with protein releases slowly in presence of DNA. Complex 1 exhibited good anti-tumor activity (GI50 values <10 MUg/ml), and to elucidate the mechanism of tumor inhibition, topoisomerase I enzymatic activity was carried out and further validated by cell imaging studies which clearly showed its nuclear localization. PMID- 24953032 TI - Generation of the SCN1A epilepsy mutation in hiPS cells using the TALEN technique. AB - Human induced pluripotent stem cells (iPSC) can be used to understand the pathological mechanisms of human disease. These cells are a promising source for cell-replacement therapy. However, such studies require genetically defined conditions. Such genetic manipulations can be performed using the novel Transcription Activator-Like Effector Nucleases (TALENs), which generate site specific double-strand DNA breaks (DSBs) with high efficiency and precision. Combining the TALEN and iPSC methods, we developed two iPS cell lines by generating the point mutation A5768G in the SCN1A gene, which encodes the voltage gated sodium channel Nav1.1 alpha subunit. The engineered iPSC maintained pluripotency and successfully differentiated into neurons with normal functional characteristics. The two cell lines differ exclusively at the epilepsy susceptibility variant. The ability to robustly introduce disease-causing point mutations in normal hiPS cell lines can be used to generate a human cell model for studying epileptic mechanisms and for drug screening. PMID- 24953033 TI - The protective effect of Smilax glabra extract on advanced glycation end products induced endothelial dysfunction in HUVECs via RAGE-ERK1/2-NF-kappaB pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Smilax glabra Roxb. (SGR) is a traditional Chinese herb that has been used in folk for the treatment of diabetic vascular complications. Advanced glycation end products (AGEs)-induced endothelial dysfunction has been thought to be a major cause of diabetic vascular complications. The present study was conducted to investigate the protective effect of SGR extract on AGEs-induced endothelial dysfunction and its underlying mechanisms. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to 200 MUg/ml AGEs to induce endothelial dysfunction. Acridine orange/ethidium bromide (AO/EB) fluorescence assay and Annexin-V/PI double-staining were performed to determine endothelium apoptosis. Dihydroethidium (DHE) fluorescence probe, SOD and MDA kits were used to evaluate oxidative stress. The effect of SGR extract on AGEs-induced TGF-beta1 expression was determined by immunocytochemistry and western blotting. Attenuations of SGR extract on receptor for AGEs (RAGE) expression, extracellular regulated protein kinases (ERK1/2) activation and NF-kappaB phosphorylation were determined by immunofluorescence assay and western blotting. The blockade assays for RAGE and ERK1/2 were carried out using a specific RAGE-antibody (RAGE-Ab) or a selective ERK1/2 inhibitor PD98059 in immunofluorescence assay. RESULTS: The pretreatment of SGR extract (0.125, 0.25 and 0.5 mg crude drug/ml) significantly attenuated AGEs-induced endothelium apoptosis, and down-regulated TGF-beta1 protein expression in HUVECs. It was also well shown that SGR extract could down-regulate dose-dependently ROS over-generation, MDA content, TGF-beta1 expression, ERK1/2 and NF-kappaB activation whereas increase significantly SOD activity. Furthermore, the AGEs-induced ERK1/2 activation could be attenuated by the blockade of RAGE-Ab (5 MUg/ml) while the NF-kappaB activation was ameliorated by ERK1/2 inhibitor PD98059 (10 MUM). CONCLUSION: These results indicated that SGR extract could attenuate AGEs-induced endothelial dysfunction via RAGE-ERK1/2-NF kappaB pathways. Our findings suggest that SGR extract may be beneficial for attenuating endothelial dysfunction in diabetic vascular complications. PMID- 24953034 TI - Interactions of pharmacokinetic profile of different parts from Ginkgo biloba extract in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Extracts from Ginkgo biloba L. leaves confer their therapeutic effects through the synergistic actions of flavonoid and terpenoid components, but some non-flavonoid and non-terpenoid components also exist in this extract. In the study of this paper, an investigation was carried out to compare the pharmacokinetic parameters of fourteen compounds to clarify the influences of non-flavonoid and non-terpenoid fraction (WEF) on the pharmacokinetics profile of the flavonoid fraction (FF) and the terpene lactone fraction (TLF) from Ginkgo biloba extracts. MATERIALS AND METHODS: A selective and sensitive UPLC-MS/MS method was established to determine the plasma concentrations of the fourteen compounds to compare the pharmacokinetic parameters after orally administration of FF, TLF, FF-WEF, FF-TLF, TLF-WEF and FF TLF-WEF with approximately the same dose. At different time points, the concentration of rutin (1), isoquercitrin (2), quercetin 3-O-[4-O-(-beta-D glucosyl)-alpha-L-rhamnoside] (3), ginkgolide C (4), bilobalide (5), quercitrin (6), ginkgolide B (7), ginkgolide A (8), luteolin (9), quercetin (10), apigenin (11), kaempferol (12), isorhamnetin (13), genkwanin (14) in rat plasma were determined and main pharmacokinetic parameters including T1/2, Tmax, Cmax and AUC were calculated using the DAS 3.2 software package. The statistical analysis was performed using the Student's t-test with P<0.05 as the level of significance. RESULTS: FF and WEF had no effect on the pharmacokinetic behaviors and parameters of the four terpene lactones, but the pharmacokinetic profiles and parameters of flavonoids changed while co-administered with non-flavonoid components. It was found that Cmax and AUC of six flavonoid aglycones in group FF-WEF, FF-TLF and FF TLF-WEF had varying degrees of reduction in comparison with group FF, especially in group FF-TLF-WEF. On the contrary, the values of Cmax, Tmax and AUC of four flavonoid glycosides in group FF-TLF-WEF were significantly increased compared with those in group FF. CONCLUSIONS: These results indicate that non-flavonoid components in Ginkgo biloba extracts could increase the absorption and improve the bioavailability of flavonoid glycosides but decrease the absorption and reduce the bioavailability of flavonoid aglycones. PMID- 24953036 TI - Hydrosilylation of aldehydes and ketones catalyzed by hydrido iron complexes bearing imine ligands. AB - Two new hydrido iron complexes (2 and 4) were synthesized by the reactions of (4 methoxyphenyl)phenylketimine ((4-MeOPh)PhC=NH) with Fe(PMe3)4 or FeMe2(PMe3)4. The molecular structures of complexes 2 and 4 were confirmed by X-ray single crystal diffraction. Using hydrido iron complexes (1-4) as catalysts, the hydrosilylations of aldehydes and ketones were investigated. The four complexes were effective catalysts for this reduction reaction. Complex 1 among them is the best catalyst. PMID- 24953037 TI - Fully roll-to-roll gravure printable wireless (13.56 MHz) sensor-signage tags for smart packaging. AB - Integration of sensing capabilities with an interactive signage through wireless communication is enabling the development of smart packaging wherein wireless (13.56 MHz) power transmission is used to interlock the smart packaging with a wireless (13.56 MHz) reader or a smart phone. Assembly of the necessary componentry for smart packaging on plastic or paper foils is limited by the manufacturing costs involved with Si based technologies. Here, the issue of manufacturing cost for smart packaging has been obviated by materials that allow R2R (roll-to-roll) gravure in combination with R2R coating processes to be employed. R2R gravure was used to print the wireless power transmission device, called rectenna (antenna, diode and capacitor), and humidity sensor on poly(ethylene terephtalate) (PET) films while electrochromic signage units were fabricated by R2R coating. The signage units were laminated with the R2R gravure printed rectenna and sensor to complete the prototype smart packaging. PMID- 24953035 TI - Effects of San-Huang-Xie-Xin-tang, a traditional Chinese prescription for clearing away heat and toxin, on the pacemaker activities of interstitial cells of Cajal from the murine small intestine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: San-Huang-Xie-Xin-Tang (SHXXT) is a traditional Chinese medicinal formula composed of Coptidis rhizoma (Coptis chinesis Franch), Scutellariae radix (Scutellaria baicalensis Georgi), and Rhei rhizoma (Rheum officinale Baill) and is widely used in Eastern Asia, especially to ameliorate the symptoms of gastrointestinal (GI) disorders related to gastritis, gastric bleeding, peptic ulcers, and abnormal GI motility AIM OF THE STUDY: Interstitial cells of Cajal (ICCs) are pacemaker cells in the GI tract that generate rhythmic oscillations in membrane potentials known as slow waves. Because GI disorders, especially abnormal GI motility, are major lifelong problems, the authors investigated the effects of SHXXT on mouse small intestine ICCs, and sought to identify the receptors and the action mechanisms involved. MATERIALS AND METHODS: Enzymatic digestions were used to dissociate ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record potentials generated by cultured ICCs. RESULTS: SHXXT produced membrane depolarization in current-clamp mode, and Y25130 (a 5-HT3 receptor antagonist) and RS39604 (a 5-HT4 receptor antagonist) blocked SHXXT-induced membrane depolarizations, whereas SB269970 (a 5 HT7 receptor antagonist) did not. However, during external Ca2+ free conditions or in the presence of thapsigargin, SHXXT did not exhibit membrane depolarization. Furthermore, the application of flufenamic acid (a nonselective cation channel (NSCC) blocker) or DIDS (a chloride channel blocker) abolished pacemaker potential generation and blocked SHXXT-induced membrane depolarizations. In addition, SHXXT-induced membrane depolarizations, which are dependent on G-protein, in ICCs were blocked by PD 98059 (a p42/44 mitogen activated protein kinase (MAPK) inhibitor), SB203580 (a p38 MAPK inhibitor), and by a c-jun NH2-terminal kinase (JNK) II inhibitor. Regarding the components of SHXXT, Coptidis rhizome and Rhei rhizoma modulated ICC pacemaking activity, whereas Scutellariae radix did not. CONCLUSION: SHXXT modulates pacemaker potentials via 5-HT3 and 5-HT4 receptor-mediated pathways, external Ca2+ influx, and Ca2+ release from internal stores. Furthermore, NSCCs and Cl- channels play important roles in the regulation of pacemaking activity in a MAPK dependent manner in ICCs. The regulation of pacemaking activity by SHXXT may be due to the activity of Coptidis rhizome and Rhei rhizome. The study shows SHXXT can modulate the pacemaking activity of ICCs in the GI tract, and thus, suggests SHXXT has potential pharmacological relevance for the treatment of GI motility disorders. PMID- 24953039 TI - 1,2,4,3-Triazaborole-based neutral oxoborane stabilized by a Lewis acid. AB - The first example of 1,2,4,3-triazaborole-based oxoborane has been synthesized via hydrogen migration upon the coordination of AlCl3 to the corresponding borinic acid. X-ray diffraction analysis and computational study disclosed the partial B[double bond, length as m-dash]O double-bond property. PMID- 24953038 TI - Access to urban green spaces and behavioural problems in children: Results from the GINIplus and LISAplus studies. AB - AIM: We investigated whether objectively measured access to urban green spaces is associated with behavioural problems in 10-year old children living in Munich and its surrounding areas. METHODS: Behavioural problems were assessed in the GINIplus and LISAplus 10-year follow-up between 2006 and 2009 using the Strengths and Difficulties Questionnaire. Access to green spaces was defined using the distance from a child's residence to the nearest urban green space. Associations between access to urban green spaces and behavioural problems were assessed using proportional odds and logistic regression models in 1932 children with complete exposure, outcome and covariate data. RESULTS: The distance between a child's residence and the nearest urban green space was positively associated with the odds of hyperactivity/inattention, especially among children with abnormal values compared to children with borderline or normal values (odds ratio (OR)=1.20 (95% confidence interval (CI)=1.01-1.42) per 500 m increase in distance). When stratified by sex, this association was only statistically significant among males. Children living further than 500 m away from urban green spaces had more overall behavioural problems than those living within 500 m of urban green spaces (proportional OR=1.41 (95% CI=1.06-1.87)). Behavioural problems were not associated with the distance to forests or with residential surrounding greenness. CONCLUSION: Poor access to urban green spaces was associated with behavioural problems in 10-year old children. Results were most consistent with hyperactivity/inattention problems. PMID- 24953040 TI - The acquisition of contextual cueing effects by persons with and without intellectual disability. AB - Two experiments were conducted to compare the acquisition of contextual cueing effects of adolescents and young adults with intellectual disabilities (ID) relative to typically developing children and young adults. Contextual cueing reflects an implicit, memory based attention guidance mechanism that results in faster search for target locations that have been previously experienced in a predictable context. In the study, participants located a target stimulus embedded in a context of numerous distracter stimuli. During a learning phase, the location of the target was predictable from the location of the distracters in the search displays. We then compared response times to locating predictable relative to unpredictable targets presented in a test phase. In Experiment 1, all of the distracters predicted the location of the target. In Experiment 2, half of the distracters predicted the location of the target while the other half varied randomly. The participants with ID exhibited significant contextual facilitation in both experiments, with the magnitude of facilitation being similar to that of the typically developing (TD) children and adults. We concluded that deficiencies in contextual cueing are not necessarily associated with low measured intelligence that results in a classification of ID. PMID- 24953042 TI - Magnetic-field-induced ferroelectric polarization reversal in magnetoelectric composites revealed by piezoresponse force microscopy. AB - Controlling electric polarization (or magnetization) in multiferroic materials with external magnetic fields (or electric fields) is very important for fundamental physics and spintronic devices. Although there has been some progress on magnetic-field-induced polarization reversal in single-phase multiferroics, such behavior has so far never been realized in composites. Here we show that it is possible to reverse ferroelectric polarization using magnetic fields in a bilayer Terfenol-D/PMN-33%PT composite. We realized this by ferroelectric domain imaging using piezoresponse force microscopy (PFM) under applied magnetic field loading. The internal electric field caused by the magnetoelectric (ME) effect in the PMN-PT crystal is considered as the driving force for the 180 degrees polarization switching, and its existence is verified by switching spectroscopy PFM testing under a series of external magnetic fields. A quantitative method is further suggested to estimate the local ME coefficient based on the switching spectroscopy PFM testing results. PMID- 24953041 TI - Prostaglandin E2 induces retinoic acid receptor-beta up-regulation through MSK1. AB - The pharmacological modulation of putative renoprotective factors hypoxia inducible factor-1alpha (HIF-1alpha) and HIF-1alpha-regulated vascular endothelial growth factor-A (VEGF-A) in the kidney has therapeutic interest. In human renal proximal tubular HK2 cells, prostaglandin E2 (PGE2) up-regulates HIF 1alpha and VEGF-A through epidermal growth factor receptor (EGFR)-dependent up regulation of retinoic acid receptor-beta (RARbeta). Here we studied the role of mitogen-activated protein kinases (MAPKs) ERK1/2 and p38 and their target kinase, mitogen- and stress activated kinase-1 (MSK1), in the signaling cascade. Treatment of HK2 cells with PGE2 resulted in increased phosphorylation of EGFR, the three studied kinases and the histone H3 (Ser10) at the RARbeta gene promoter (the latter has been proposed as a molecular signature of the activated RARbeta gene promoter). Prevention of the phosphorylation of EGFR, ERK1/2, p38 MAPK or MSK1 is by incubating, respectively, with AG1478, PD98059, SB203580 or H89 allowed to elucidate the precise phosphorylation order in the signaling cascade triggered by PGE2: first, EGFR; then, ERK1/2 and p38 MAPK and, finally, MSK1. Phosphorylation of MSK1 led to that of Ser10 in histone H3 and to activation of RARbeta gene transcription (and the consequent increase in the expression of HIF 1alpha and VEGF-A), which was suppressed by H89 or by transfecting cells with a vector encoding for a dominant-negative mutant of MSK1. These results highlight the relevance of MSK1 in the up-regulation of RARbeta by PGE2. They also may contribute to new therapeutic approaches based upon the pharmacological control of HIF-1alpha/VEGF-A in the proximal tubule through the modulation of the PGE2/EGFR/MAPK/MSK1/RARbeta pathway. PMID- 24953044 TI - Multistimuli-responsive supramolecular gels: design rationale, recent advances, and perspectives. AB - This manuscript presents a brief overview of recent advances in multistimuli responsive supramolecular gels (MRSGs). The synthesis of MRSGs with faster and smarter responsive abilities to a variety of external stimuli, such as redox reagents, pH changes, ligands, and coupling reagents, is one key issue for the upgrade of current molecular motors, signal sensors, shape memory devices, drug delivery systems, display devices, and other devices. However, the design rules of MRSGs are still not well understood. The lack of information about the relationship between the spatial structure and gelation behavior of existing gelators means that the knowledge required to design new gelators by the addition of functional moieties to well-known gelators is lacking. Insights into the gelation pathway of known gelators may bring inspiration to researchers who want to exploit elegant designs and specific building blocks to obtain their own MRSGs with predictable stimuli-responsive abilities. PMID- 24953043 TI - A computational prospect to aspirin side effects: aspirin and COX-1 interaction analysis based on non-synonymous SNPs. AB - Aspirin (ASA) is a commonly used nonsteroidal anti-inflammatory drug (NSAID), which exerts its therapeutic effects through inhibition of cyclooxygenase (COX) isoform 2 (COX-2), while the inhibition of COX-1 by ASA leads to apparent side effects. In the present study, the relationship between COX-1 non-synonymous single nucleotide polymorphisms (nsSNPs) and aspirin related side effects was investigated. The functional impacts of 37 nsSNPs on aspirin inhibition potency of COX-1 with COX-1/aspirin molecular docking were computationally analyzed, and each SNP was scored based on DOCK Amber score. The data predicted that 22 nsSNPs could reduce COX-1 inhibition, while 15 nsSNPs showed increasing inhibition level in comparison to the regular COX-1 protein. In order to perform a comparing state, the Amber scores for two Arg119 mutants (R119A and R119Q) were also calculated. Moreover, among nsSNP variants, rs117122585 represented the closest Amber score to R119A mutant. A separate docking computation validated the score and represented a new binding position for ASA that acetyl group was located within the distance of 3.86A from Ser529 OH group. This could predict an associated loss of activity of ASA through this nsSNP variant. Our data represent a computational sub-population pattern for aspirin COX-1 related side effects, and provide basis for further research on COX-1/ASA interaction. PMID- 24953045 TI - Allosteric binding of capsaicin by a bis(beta-cyclodextrin)-2,2'-bipyridine receptor. AB - A new beta-cyclodextrin-based receptor that showed allosteric binding behavior towards capsaicin in aqueous solution was prepared. By NMR titration and nonlinear regression, we obtained binding constants, which increased more than fivefold when an effector (Zn(2+)) was bound to a central 2,2'-bipyridine that acts as the allosteric center. PMID- 24953047 TI - Compound heterozygotes for a novel mutation, apo E1 Nagoya (Arg142Ser) and Apo E2 (Arg158Cys), with severe type III hyperlipoproteinemia and familial hypercholesterolemia. AB - AIM: A patient with severe type III hyperlipoproteinemia and familial hypercholesterolemia (FH) was previously reported (Metabolism, 44,1995:460-465). In the current study, the patient's apolipoprotein (apo) E gene was analyzed. METHODS: An apo E isoform analysis was performed using isoelectric focusing and immunoblotting. In addition, after DNA preparation, a restriction fragment length polymorphism analysis and DNA sequence analysis were performed. RESULTS: The patient's apo E phenotype was E2/E1, and the genotype was epsilon2/epsilon2. The sequence analysis of the patient's DNA revealed a new variant of apo E, which involves a single substitution of one serine (AGC) for one arginine (CGC) at position 142, thereby adding one negatively charged unit to apo E2. Therefore, the patient was compound heterozygous for apo E1 (Arg142Ser) and apo E2 (Arg158Cys). CONCLUSIONS: A novel mutation, apo E1 Nagoya (Arg142Ser) in a patient with severe type III hyperlipoproteinemia with heterozygous FH was characterized. Since the presence of arginine at the amino acid residue 142 of apo E is considered to play an important role in binding to LDL receptors, the mutation apo E1 Nagoya (Arg142Ser) likely contributed to the expression of severe type III hyperlipoproteinemia in this patient. PMID- 24953048 TI - Introduction: the effects of psychotherapy on the psychotherapist. PMID- 24953046 TI - Can intensive lipid-lowering therapy improve the carotid intima-media thickness in Japanese subjects under primary prevention for cardiovascular disease?: The JART and JART extension subanalysis. AB - AIM: This subanalysis aimed to clarify whether intensive lipid-lowering therapy with statins slows the progression of atherosclerosis in Japanese subjects under treatment for primary prevention of cardiovascular disease. METHODS: This was a subanalysis of the Justification for Atherosclerosis Regression Treatment (JART) Study. We compared the efficacy of intensive lipid-lowering therapy and conventional therapy with respect to changes in the mean intima-media thickness (IMT) and serum lipid levels. We also evaluated changes in the mean IMT over 24 months of treatment and assessed the relationship between these changes and reductions in the LDL-C levels using a post-hoc analysis. RESULTS: Intensive lipid-lowering therapy with rosuvastatin was associated with significantly smaller changes in the mean IMT and a greater reduction in the serum lipid levels in comparison to conventional therapy with pravastatin. The average net change in the mean IMT was 0.010 mm (n=121) at 12 months and -0.004 mm (n=56) at 24 months. A decrease in LDL-C was found to be associated with a smaller change in the mean IMT (p=0.0009; Jonckheere-Terpstra trend test). A greater reduction in serum LDL C was found to be associated with a smaller change in the mean IMT. Similar associations were observed for the serum TC and non-HDL-C levels and LDL-C/HDL-C ratio. There were no notable differences in the incidence of serious adverse events among the LDL-C quartiles. CONCLUSIONS: Lowering the LDL-C level with intensive lipid-lowering therapy is associated with reduced changes in the IMT among Japanese subjects at moderate to high risk under treatment for primary prevention. Subjects suitable for primary prevention may receive cardiovascular benefits from intensive lipid-lowering therapy, in association with significantly slower IMT progression than that observed with conventional therapy. PMID- 24953050 TI - Recombinant T cell receptor ligand treatment improves neurological outcome in the presence of tissue plasminogen activator in experimental ischemic stroke. AB - RTL1000 is a partial human MHC molecule coupled to a human myelin peptide. We previously demonstrated that RTL1000 was protective against experimental ischemic stroke in HLA-DR2 transgenic (DR2-Tg) mice. Since thrombolysis with recombinant tissue plasminogen activator (t-PA) is a standard therapy for stroke, we determined if RTL1000 efficacy is altered when combined with t-PA in experimental stroke. Male DR2-Tg mice underwent 60 min of intraluminal middle cerebral artery occlusion (MCAO). t-PA or vehicle was infused intravenously followed by either a single or four daily subcutaneous injections of RTL1000 or vehicle. Infarct size was measured by 2, 3, 5-triphenyltetrazolium chloride staining at 24 or 96 h of reperfusion. Our data showed that t-PA alone reduced infarct size when measured at 24 h but not at 96 h after MCAO. RTL1000 alone reduced infarct size both at 24 and 96 h after MCAO. Combining RTL1000 with t-PA did not alter its ability to reduce infarct size at either 24 or 96 h after MCAO and provides additional protection in t-PA treated mice at 24 h after ischemic stroke. Taken together, RTL1000 treatment alone improves outcome and provides additional protection in t PA-treated mice in experimental ischemic stroke. PMID- 24953049 TI - A 3,4-trans-fused cyclic protecting group facilitates alpha-selective catalytic synthesis of 2-deoxyglycosides. AB - A practical approach has been developed to convert glucals and rhamnals into disaccharides or glycoconjugates with high alpha-selectivity and yields (77-97%) using a trans-fused cyclic 3,4-O-disiloxane protecting group and TsOH?H2O (1 mol%) as a catalyst. Control of the anomeric selectivity arises from conformational locking of the intermediate oxacarbenium cation. Glucals outperform rhamnals because the C6 side-chain conformation augments the selectivity. PMID- 24953051 TI - Adverse prognosis of incidentally detected ambulatory atrial fibrillation. A cohort study. AB - It was the aim of this study to determine prognosis of incidentally detected ambulatory atrial fibrillation (IA-AF) and its response to antithrombotic therapy. We performed a cohort study of 5,555 patients with IA-AF (mean age 70.9 +/- 10.1, 38.4% female) and 24,705 age- and gender-matched controls without AF followed three years using UK Clinical Practice Research Datalink. We measured incidence rates of stroke, all-cause mortality, myocardial infarction, major bleeding, and effect of antithrombotic therapy. Patients with IA-AF had mean CHA2DS2VASc score 2.5 +/- 1.5, 73% with score >=2. The stroke incidence rate (IR) was 19.4 (95% confidence interval 17.1 - 21.9)/1,000 person-years vs 8.4 (7.7 - 9.1) in controls (p<0.001), mortality 40.1 (36.8 - 43.6)/1,000 person-years vs 20.9 (19.8 - 22.0) in controls (p<0.001), and myocardial infarction 9.0 (7.5 - 10.8)/1,000 person-years vs 6.5 (5.9 - 7.2) in controls (p<0.001). IRs of all endpoints increased with age. Oral anticoagulant +/- antiplatelet therapy received by 51.0% in year following IA-AF was associated with adjusted hazard ratio (HR) of 0.35 (0.17 - 0.71) for stroke, and 0.56 (0.36 - 0.85) for death compared to no therapy, while antiplatelet treatment was associated with a non significant reduction of HR: 0.81 (0.51 - 1.29) for stroke, and 0.80 (0.55 - 1.15) for death, though both carried a similar small non-significant adjusted excess IR of major bleeding. In conclusion, asymptomatic AF detected incidentally is associated with a significant adverse effect on stroke and death, with reduction in both associated with oral anticoagulant but not antiplatelet treatment. This provides justification to assess cost-effectiveness of community screening to detect unknown AF. PMID- 24953052 TI - Spatial abilities of medical graduates and choice of residency programs. AB - Spatial abilities have been related in previous studies to three-dimensional (3D) anatomy knowledge and the performance in technical skills. The objective of this study was to relate spatial abilities to residency programs with different levels of content of 3D anatomy knowledge and technical skills. The hypothesis was that the choice of residency program is related to spatial abilities. A cohort of 210 medical graduates was enrolled in a prospective study in a 5-year experiment. Spatial abilities were measured with a redrawn Vandenberg and Kuse Mental Rotations Test (MRT) in two (MRTA) and three (MRTC) dimensions. Medical graduates were enrolled in Family Medicine (n = 76, 36.2%), Internal Medicine (64, 30.5%), Surgery (52, 24.8%), and Anesthesia (18, 8.6%). The assumption was that the level of 3D anatomy knowledge and technical skills content was higher in Surgery and Anesthesia compared to Family Medicine and Internal Medicine. Mean MRTA score of 12.4 (+/-SD 4.6), 12.0 (+/-4.3), 14.1 (+/-4.3), and 14.6 (+/-4.0) was obtained in Family Medicine, Internal Medicine, Surgery, and Anesthesia, respectively (P = 0.0176). Similarly, mean MRTC score of 8.0 (+/-4.4), 7.5 (+/-3.6), 8.5 (+/-3.9), and 7.9 (+/-4.1) was obtained (P = 0.5647). Although there was a tendency for lower MRTA score in Family Medicine and Internal Medicine compared to Surgery and Anesthesia, no statistically significant main effect of residency, year, sex, or the interactions were observed for the MRTA and MRTC. Studied sample of medical graduates was not found to choose their residency programs based on their innate spatial abilities. PMID- 24953053 TI - Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation. AB - Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in ~?n10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML). Recent studies have shown that EZH2 mutations are often associated with RUNX1 mutations in MDS patients, although its pathological function remains to be addressed. Here we establish an MDS mouse model by transducing a RUNX1S291fs mutant into hematopoietic stem cells and subsequently deleting Ezh2. Ezh2 loss significantly promotes RUNX1S291fs-induced MDS. Despite their compromised proliferative capacity of RUNX1S291fs/Ezh2-null MDS cells, MDS bone marrow impairs normal hematopoietic cells via selectively activating inflammatory cytokine responses, thereby allowing propagation of MDS clones. In contrast, loss of Ezh2 prevents the transformation of AML via PRC1-mediated repression of Hoxa9. These findings provide a comprehensive picture of how Ezh2 loss collaborates with RUNX1 mutants in the pathogenesis of MDS in both cell autonomous and non-autonomous manners. PMID- 24953054 TI - Association between beta-interferon exposure and hospital events in multiple sclerosis. AB - PURPOSE: A systematic evaluation of hospital events can be an important surrogate measure for drug effectiveness or adverse effects. The purpose of this study was to examine the association between beta-interferon use and hospital events in a large cohort of patients with multiple sclerosis (MS). METHODS: Retrospective cohort study comparing beta-interferon exposed and unexposed patients using clinical data from the British Columbia MS (BCMS) database linked with health administrative databases, 1996-2008. For each patient, the primary outcome was the number of hospital events in each month, analyzed by quasi Poisson regression. Beta-interferon exposure was examined two ways: current and cumulative exposure. Secondary outcomes included whether a hospital event occurred in each month for each specific primary diagnoses, grouped by International Classification of Diseases categories. RESULTS: Current exposure to beta-interferon was not associated with an altered rate of hospital events (adjusted incident rate ratio 1.018; 95% CI 0.803-1.290). Similarly, there was no association with cumulative exposure. Cumulative beta-interferon exposure was associated with a lower odds of respiratory disease-related hospital events compared to those never exposed to beta-interferon. CONCLUSIONS: Exposure to beta interferon for MS was not associated with a change in overall hospital event rates. Preliminary evidence suggests that the beta-interferons may have a protective effect against respiratory diseases requiring hospitalization in MS patients. PMID- 24953055 TI - The low global burden of trichinellosis: evidence and implications. AB - Trichinellosis is a cosmopolitan foodborne disease that may result in severe health disorders and even death. Despite international awareness of the public health risk associated with trichinellosis, current data on its public health impact are still lacking. Therefore we assessed, for the first known time, the global burden of trichinellosis using the Disability-Adjusted Life Year metric. The global number of Disability-Adjusted Life Years due to trichinellosis was estimated to be 76 per billion persons per year (95% credible interval: 38-129). The World Health Organization European Region was the main contributor to this global burden, followed by the WHO region of the Americas and the World Health Organization Western Pacific region. The global burden of trichinellosis is much lower than that of other foodborne parasitic diseases and is in sharp contrast to the high budget allocated to prevent the disease in many industrialised countries. To decrease the uncertainty around the current estimates, more knowledge is needed on the level of underreporting of clinical trichinellosis in different parts of the world. PMID- 24953056 TI - Fatal and non-fatal occupational injuries and diseases among migrant and native workers in South Korea. AB - BACKGROUND: Migrant workers now represent an increasing percentage of workers in Korea, but few studies have evaluated work-related health risks in this population. In this study, we explored the relative risk of occupational injuries and diseases in migrant workers compared with native Korean workers. METHOD: An analysis of work-related injuries and diseases among migrant workers in Korea during 2005-2007 was conducted in each industrial subsector using nationwide data. RESULTS: Risks of fatal and non-fatal occupational injuries for migrant workers were considerably higher than their Korean counterparts. The industry adjusted standard mortality ratios of fatal occupational injuries were 1.89 (1.45 2.47), 2.29 (1.81-2.88), and 1.73 (1.36-2.22) for 2005, 2006, and 2007, respectively. CONCLUSIONS: A greater proportion of migrant workers is exposed to higher risks of occupational safety and health issues than their Korean counterparts, demonstrating that the occupational safety and health of migrant workers requires more attention than that of Korean workers. PMID- 24953058 TI - Bullous pemphigoid occurring under anti-tumor necrosis factor-alpha therapy. PMID- 24953057 TI - How useful is endorectal ultrasound in the management of early rectal carcinoma? AB - INTRODUCTION: Endorectal ultrasonography (EUS) is used to T stage early rectal tumours and select patients to whom transanal endoscopic microsurgery (TEM) could be offered. Published papers have shown that EUS can have good accuracy, but there is little literature on how EUS influences patient management. The study aim is to ascertain the value of EUS in the management of early rectal tumours. METHODS: Patients with adenomas/early rectal carcinoma being considered for TEM were prospectively studied. Each patient underwent EUS. The surgeon recorded the expected T stage, confidence level of the T stage and management plan for each patient on a proforma before and after the ultrasound result was revealed. Comparison was made between the ultrasound stage and final pathological stage where available. RESULTS: Ninety-six patients were referred over 2 years. Nine were out of reach of the rigid probe and were excluded. Proformas were completed on 53/87 patients (age range 28-87 years, mean age 66 years, 30 males/23 females). Forty-eight patients had a pathological report to compare with the EUS T stage. Ultrasound agreed with the pathological T staging in 43 patients (90%). Patient management was changed in five patients. In 30% of (16/53) patients, EUS increased the confidence level for T staging. CONCLUSION: Although EUS has a high accuracy in predicting the T stage of early rectal cancers, it never changes the management plan for lesions thought to be benign. It seldom changes the pre operative selection process when clinical examination is considered with other imaging modalities (MRI/CT). EUS should be reserved for answering specific questions in difficult cases rather than for all patients. PMID- 24953059 TI - Risk factors for delayed bleeding after endoscopic submucosal dissection. PMID- 24953061 TI - EVITEACH: a study exploring ways to optimise the uptake of evidence-based practice to undergraduate nurses. AB - EVITEACH aimed to increase undergraduate nursing student's engagement with evidence-based practice and enhance their knowledge utilisation and translation capabilities. Building students capabilities to apply evidence in professional practice is a fundamental university role. Undergraduate nursing students need to actively engage with knowledge utilisation and translational skill development to narrow the evidence practice gap in the clinical setting. A two phase mixed methods study was undertaken over a three year period (2008-2010, inclusive) utilizing a Plan-Do-Study-Act (PDSA) approach. Three undergraduate nursing cohorts (N = 188) enrolled in a compulsory knowledge translation and utilisation subject at one Australian university participated. Data collection comprised of subject evaluation data and reflective statements. Preliminary investigations identified priority areas related to subject: materials, resources, teaching and workload. These priority areas became the focus of action for two PDSA cycles. PDSA cycle 1 demonstrated significant improvement of the subject overall (p > 0.05), evaluation of the materials used (p > 0.001) and teaching sub-groups (p > 0.05). PDSA cycle 2 continued to sustain improvement of the subject overall (p > 0.05). Furthermore reflective statements collected during PDSA cycle 2 identified four themes: (1) What engages undergraduate nurses in the learning process; (2) The undergraduate nurses learning trajectory; (3) Undergraduate nurses' preconceptions of research and evidenced-based practice; and (4) Appreciating the importance of research and evidence-based practice to nursing. There is little robust evidence to guide the most effective way to build knowledge utilisation and translational skills. Effectively engaging undergraduate nursing students in knowledge translation and utilisation subjects could have immediate and long term benefits for nursing as a profession and patient outcomes. Developing evidence based practice capabilities is important in terms of improving patient outcomes, organisational efficiencies and creating satisfying work environments. PMID- 24953062 TI - Representative tasks that define the essence of the nursing domain: using nursing sensitive indicators for deliberate practice. PMID- 24953063 TI - United States nurse practitioner students' attitudes, perceptions, and beliefs working with the uninsured. AB - To reduce health disparities, nurses are expected to provide compassionate and high quality care to all patients regardless of socioeconomic and insurance status. In the United States (US) nurse practitioner (NP) educators need to expose students to clinical practice settings, such as free clinics, where the vulnerable populations like the non-documented immigrants and uninsured receive care. The purpose of this mixed method study was to provide an immersion experience for (NP) students at free clinics. Then researchers evaluated the impact of a clinical immersion experience on NP students' attitudes, perceptions, and beliefs about the uninsured and determine whether the clinical experience impacted their willingness to consider working with vulnerable populations in the future. Qualitative and quantitative data suggests students challenged their own beliefs and attitudes regarding the vulnerable populations, gained insight into care provided at these free clinics, and expressed their intent to volunteer at these settings. In the era of health care reform both nationally and internationally and the need to improve primary care access globally, educational initiatives are needed to expose NP students to economically vulnerable populations. Future research needs to replicate and extend the findings of this study, focusing on teaching-learning experiences for nurse practitioners and other advanced practice nursing students. PMID- 24953060 TI - Advances in the management of colorectal cancer: from biology to treatment. AB - BACKGROUND: Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide and the fourth leading cause of cancer-related deaths. This article reviews the epidemiology, risk factors, pathogenesis, and prognosis of CRC with special emphasis on advances in the management of CRC over the past decade. METHODS: A review of the published English literature was conducted using the search engines PubMed, Medline, EMBASE, and Google Scholar. A total of 127 relevant publications were identified for further review. RESULTS: Most CRC are sporadic and are due to genetic instability and multiple somatic mutations. Approximately 80% of cancers are diagnosed at the early stage and are curable. The pathologic stage at presentation is the most important predictor of outcome after resection of early stage cancer. Surgery is the primary treatment modality for localized CRC. Advances in (neo)adjuvant chemotherapy and radiation have reduced the disease recurrence and increased survival in high risk diseases. Although recent advancements in combination chemotherapy and target agents have increased the survival of incurable CRC, it is remarkable that only selected patients with advanced CRC can be cured with multimodality therapy. CONCLUSION: Over the past decade, there has seen substantial progress in our understanding of and in the management of CRC. PMID- 24953064 TI - Preconditioned stem cells: a promising strategy for cell-based ischemic stroke therapy. AB - Ischemic stroke is a leading cause of mortality and morbidity worldwide. Numerous therapeutic studies, including stem cell therapy, have been explored in order to find the possible approach treating cerebral ischemia effectively. However, massive grafted-cell death and low survival rate made us pessimistic about the widespread application of stem cell therapy. The approach of preconditioning stem cells became an attractive option due to its high cell viability after transplantation. In this review, we focused on preconditioning stem cells via cytokines, chemical drugs and other factors including interleukin 6 (IL-6), lipopolysaccharide (LPS), minocycline, melatonin and hypoxia to increase grafted stem cell survival, proliferation, migration to ischemic peri-focal area and ultimately improve neurobehavioral outcomes. We explored the underlying therapeutic efficacy of preconditioning stem cells as well as possible mechanisms and potential risks. Finally, we discussed the prospects of the application of cell-based therapy in clinical patients with ischemic stroke. PMID- 24953065 TI - Mitochondrial membrane lipids in life and death and their molecular modulation by diet: tuning the furnace. AB - The traditional view of mitochondria as cell powerhouses is a matter of common knowledge, but the overall view of these extraordinary organelles has been revolutionized in the last years. In fact, a large number of important and diverse processes take place at the mitochondrial level, which clearly surpass the energy production scope, intruding the critical fragile balance between cell life and death. The entangled biochemistry of mitochondrial membranes has been found to be dependent on specific lipid requirements, with cardiolipin holding a great part of the raised functional interest. Mitochondria contain a complex membrane system, based on a variety of lipids and exquisite asymmetries. Mitochondria lipid membrane composition depends on a tight interplay with the endoplasmic reticulum, from which some of the lipids present in the mitochondrial membranes have to be imported, at least in the form of precursors. Here, we review some external interventions resulting in alterations of mitochondrial lipid content, namely dietary interventions and genetic manipulation. Such manipulations of mitochondrial membrane lipid composition should result in physiological impact, given the importance of lipid-protein interactions within the mitochondrial membrane boundaries. We provide arguments for future experiments using the most modern chemical and biophysical approaches as well as computer simulation studies applied to appropriate biological membrane model systems, in order to identify the effects exerted by diet-induced lipid changes on membrane physical properties. PMID- 24953067 TI - Hand carriage of Candida occurs at lesser rates in hospital personnel who use antimicrobial hand disinfectant. AB - BACKGROUND: The hands of hospital personnel are considered to be important for colonization and infection of patients with Candida spp. The aim of this study was to evaluate the effectiveness of different hand disinfectants in reducing the carriage of Candida species on the hands of hospital personnel. METHODS: A controlled study was conducted at Duzce University School of Medicine Hospital. Eighty hospital personnel were included in the trial. Subjects were divided into 4 groups according to hand hygiene procedures: group 1, hand rubbing with alcohol based solution; group 2, hand washing with 4% chlorhexidine gluconate; group 3, hand washing with 7.5% povidone-iodine; group 4, hand washing with plain soap and water. The hands of all participants were tested by culture with the broth wash technique. RESULTS: Hand carriage of Candida spp. was lower in the 4% chlorhexidine gluconate group (10.5%, p = 0.006), in the 7.5% povidone-iodine group (18.7%, p = 0.043), and in the alcohol-based hand rub group (21.1%, p = 0.048) compared to the group washing hands with plain soap and water (50%). CONCLUSIONS: The use of hand disinfectant containing antimicrobial agents is more effective than hand washing with water and soap in reducing carriage of Candida on the hands of hospital personnel. It is recommended that hospital personnel use an antimicrobial hand disinfectant in units where there is a high risk of Candida infection. PMID- 24953068 TI - Creating placebo responders and nonresponders in the laboratory: boons and banes. PMID- 24953066 TI - Loss of histone H4K20 trimethylation predicts poor prognosis in breast cancer and is associated with invasive activity. AB - INTRODUCTION: Loss of histone H4 lysine 20 trimethylation (H4K20me3) is associated with multiple cancers, but its role in breast tumors is unclear. In addition, the pathological effects of global reduction in H4K20me3 remain mostly unknown. Therefore, a major goal of this study was to elucidate the global H4K20me3 level in breast cancer tissue and investigate its pathological functions. METHODS: Levels of H4K20me3 and an associated histone modification, H3 lysine 9 trimethylation (H3K9me3), were evaluated by immunohistochemistry in a series of breast cancer tissues. Univariate and multivariate clinicopathological and survival analyses were performed. We also examined the effect of overexpression or knockdown of the histone H4K20 methyltransferases, SUV420H1 and SUV420H2, on cancer-cell invasion activity in vitro. RESULTS: H4K20me3, but not H3K9me3, was clearly reduced in breast cancer tissue. A reduced level of H4K20me3 was correlated with several aspects of clinicopathological status, including luminal subtypes, but not with HER2 expression. Multivariate analysis showed that reduced levels of H4K20me3 independently associated with lower disease-free survival. Moreover, ectopic expression of SUV420H1 and SUV420H2 in breast cancer cells suppressed cell invasiveness, whereas knockdown of SUV420H2 activated normal mammary epithelial-cell invasion in vitro. CONCLUSIONS: H4K20me3 was reduced in cancerous regions of breast-tumor tissue, as in other types of tumor. Reduced H4K20me3 level can be used as an independent marker of poor prognosis in breast cancer patients. Most importantly, this study suggests that a reduced level of H4K20me3 increases the invasiveness of breast cancer cells in a HER2 independent manner. PMID- 24953071 TI - Pain in hip and knee osteoarthritis. PMID- 24953073 TI - Persistent pain in chronically ill children without detectable disease activity. AB - Children with organic diseases may experience persistent pain in the presence of controlled disease, as evidenced by little or no measurable disease activity or inflammation. Historically, dualistic definitions of pain have informed standard diagnostic approaches to persistent pain; aggressive investigation and treatment targeting underlying disease, even in the absence of evidence indicating disease escalation. Evidence across disease populations, in children with inflammatory bowel disease, sickle cell disease, and juvenile idiopathic arthritis indicates that persistent pain in these conditions may be better conceptualized as functional in nature, potentially resulting from disordered somatosensory processing including central sensitization. Applying a biopsychosocial understanding of persistent pain and multidisciplinary functional pain management strategies may lead to improved health outcomes. PMID- 24953074 TI - Diagnosis and management of neuropathic pain. AB - A recent revision in the definition of neuropathic pain has highlighted this condition as a distinct disease entity. More accurate search for a lesion in the somatosensory nervous system as the pain-generating mechanism will help target the treatment by pharmacological agents. A multidisciplinary approach is recommended, with pharmacotherapy supplemented by psychological therapy and physical rehabilitation, and appropriate interventional treatment for selected refractory cases. PMID- 24953075 TI - The role of screening tools in diagnosing neuropathic pain. AB - Neuropathic pain affects 6-8% of the general adult population. It is reported by 27% of chronic pain patients and 40% of cancer patients, yet there is no standardized diagnostic test for neuropathic pain. A number of screening tools have been developed based on verbal pain descriptors, with or without limited clinical examination, to identify individuals with neuropathic pain. Over the past decade these neuropathic pain screening tools have been validated in a wide range of pain populations, as well as translated into many languages, to discriminate between neuropathic and non-neuropathic pain. We describe here the five most commonly used neuropathic pain screening tools and discuss current assessment guidelines, the use of screening tools in novel clinical contexts and their potential use in personalized therapy. PMID- 24953072 TI - Using TENS for pain control: the state of the evidence. AB - Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacological intervention that activates a complex neuronal network to reduce pain by activating descending inhibitory systems in the central nervous system to reduce hyperalgesia. The evidence for TENS efficacy is conflicting and requires not only description but also critique. Population-specific systemic reviews and meta analyses are emerging, indicating both HF and LF TENS being shown to provide analgesia, specifically when applied at a strong, nonpainful intensity. The purpose of this article is to provide a critical review of the latest basic science and clinical evidence for TENS. Additional research is necessary to determine if TENS has effects specific to mechanical stimuli and/or beyond reduction of pain and will improve activity levels, function and quality of life. PMID- 24953076 TI - The pharmacoeconomic picture in Saudi Arabia. AB - Saudi Arabia is the largest country in the region and it is the largest oil producing country in the world. It is one of the few countries in the world which was not affected significantly by the global economic crisis. Health care spending is led mainly by governmental expenditure. Private sector share of the health care services is supported by the government and increasing. The demands for pharmaceutical products, medical devices and health care services is fueled by the rapidly growing population and the wide spread of chronic diseases. Publications and expertise in the field of pharmacoeconomics is scarce within the country. There is an urgent need to establish a national center for pharmacoeconomics to lead the country efforts in controlling the cost of health care services. Such a center is needed to promote pharmacoeconomics research and train health care professionals in this field. PMID- 24953078 TI - Three-dimensional super-resolution and localization of dense clusters of single molecules. AB - When a single molecule is detected in a wide-field microscope, the image approximates the point spread function of the system. However, as the distribution of molecules becomes denser and their images begin to overlap, existing solutions to determine the number of molecules present and their precise three-dimensional locations can tolerate little to no overlap. We propose a localization scheme that can identify several overlapping molecule images while maintaining high localization precision. A solution to this problem involving matched optical and digital techniques, as here proposed, can substantially increase the allowable labeling density and accelerate the data collection time of single-molecule localization microscopy by more than one order of magnitude. PMID- 24953077 TI - 3'UTR shortening identifies high-risk cancers with targeted dysregulation of the ceRNA network. AB - Competing endogenous RNA (ceRNA) interactions form a multilayered network that regulates gene expression in various biological pathways. Recent studies have demonstrated novel roles of ceRNA interactions in tumorigenesis, but the dynamics of the ceRNA network in cancer remain unexplored. Here, we examine ceRNA network dynamics in prostate cancer from the perspective of alternative cleavage and polyadenylation (APA) and reveal the principles of such changes. Analysis of exon array data revealed that both shortened and lengthened 3'UTRs are abundant. Consensus clustering with APA data stratified cancers into groups with differing risks of biochemical relapse and revealed that a ceRNA subnetwork enriched with cancer genes was specifically dysregulated in high-risk cancers. The novel connection between 3'UTR shortening and ceRNA network dysregulation was supported by the unusually high number of microRNA response elements (MREs) shared by the dysregulated ceRNA interactions and the significantly altered 3'UTRs. The dysregulation followed a fundamental principle in that ceRNA interactions connecting genes that show opposite trends in expression change are preferentially dysregulated. This targeted dysregulation is responsible for the majority of the observed expression changes in genes with significant ceRNA dysregulation and represents a novel mechanism underlying aberrant oncogenic expression. PMID- 24953079 TI - Diagnostic and prognostic values of ADAMTS13 activity measured during daily plasma exchange therapy in patients with acquired thrombotic thrombocytopenic purpura. AB - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) requires immediate treatment with plasma exchange (PE) to prevent disease mortality and/or morbidity. Frequently, PE is initiated before blood sample is collected to confirm ADAMTS13 deficiency. However, the effect of PE treatments on the evaluation of ADAMTS13 is uncertain. Moreover, the pertinence of ADAMTS13 activity during PE therapy to prediction of treatment outcomes is unclear. Thus, clarification of the diagnostic and prognostic values of ADAMTS13 activity obtained during PE treatment is an unmet clinical need. STUDY DESIGN AND METHODS: A total of 212 sequential samples were obtained during the course of daily PE treatment from 19 patients with acquired TTP. ADAMTS13 activity levels were determined in these longitudinal samples for analysis. RESULTS: After the initial three daily PE procedures, the sensitivities of ADAMTS13 activity in diagnosis of TTP (<10%) were 89, 83, and 78%, respectively. To determine prognostic value, patients with (n = 7) and without (n = 12) a recovery of ADAMTS13 activity to more than 10% within seven sessions of daily PE treatment were compared. Recovery of ADAMTS13 activity to more than 10% within 7 days is significantly associated with a timely achievement of clinical response (p < 0.01). In contrast, the patients without more than 10% ADAMTS13 within 1 week appear at risk for worse treatment outcomes manifested as TTP exacerbation, treatment refractoriness, or death. CONCLUSION: The data suggest that ADAMTS13 activities measured during the initial period of PE therapy offer both diagnostic and prognostic values in acquired TTP. PMID- 24953080 TI - Examining public trust in risk-managing organizations after a major disaster. AB - This research investigates the public's trust in risk-managing organizations after suffering serious damage from a major disaster. It is natural for public trust to decrease in organizations responsible for mitigating the damage. However, what about trust in organizations that address hazards not directly related to the disaster? Based on the results of surveys conducted by a national institute, the Japanese government concluded, in a White Paper on Science and Technology, that the public's trust in scientists declined overall after the 2011 Tohoku Earthquake. Because scientists play a key role in risk assessment and risk management in most areas, one could predict that trust in risk-managing organizations overall would decrease after a major disaster. The methodology of that survey, however, had limitations that prevented such conclusions. For this research, two surveys were conducted to measure the public's trust in risk managing organizations regarding various hazards, before and after the Tohoku Earthquake (n = 1,192 in 2008 and n = 1,138 in 2012). The results showed that trust decreased in risk-managing organizations that deal with earthquakes and nuclear accidents, whereas trust levels related to many other hazards, especially in areas not touched by the Tohoku Earthquake, remained steady or even increased. These results reject the assertion that distrust rippled through all risk managing organizations. The implications of this research are discussed, with the observation that this result is not necessarily gratifying for risk managers because high trust sometimes reduces public preparedness for disasters. PMID- 24953081 TI - Editor in Chief: Response to Eyre et al. "ALK-positive anaplastic large cell lymphoma: current and future perspectives in adult and paediatric disease". PMID- 24953083 TI - Association between parents' trust in mental health professionals and disengagement from psychiatric service within the first 6 months of initial treatment of schizophrenia. AB - AIM: To investigate the association between parents' encounter with reliable mental health professionals and disengagement from initial treatment among patients with schizophrenia. METHODS: This study was a part of the Reaching People Early Tokyo Survey. Participants were recruited from groups for family members of people with mental ill-health around Tokyo. Self-report questionnaires completed by 467 parents were analysed. RESULTS: Disengagement rate was 16.2% among patients whose parents met reliable mental health professionals within the initial 6 months, but 33.7% among patients whose parents did not report meeting such professionals. The odds of disengagement was less than half in the first group than in the second group (OR 0.38, 95% CI 0.21-0.67). CONCLUSIONS: Establishing trust with family members might prevent disengagement from initial treatment among patients with schizophrenia. Mental health professionals should spend time to build a trusting relationship with families within the initial period of treatment. PMID- 24953082 TI - Measuring parents' experiences and satisfaction with care during very preterm birth: a questionnaire development study. AB - OBJECTIVE: To develop a questionnaire to assess parents' experiences and satisfaction with care during very preterm birth. DESIGN: Questionnaire development. SETTING: Parents whose babies had been cared for at five tertiary neonatal units in England. POPULATION: A total of 145 women who gave birth before 32 weeks of gestation, and 85 of their partners. METHODS: A 30-item questionnaire was developed on the basis of qualitative interviews with parents of very preterm babies, a literature review and discussion with relevant experts. The questionnaire was posted to a second group of parents, and its reliability and validity were explored. MAIN OUTCOME MEASURES: The Preterm Birth Experience and Satisfaction Scale (P-BESS) was correlated with two global questions measuring satisfaction with care during the birth. Internal consistency was measured using Cronbach's alpha. RESULTS: Parents of 458 babies were invited to take part and 147 (32%) responded. Two women and 22 partners were excluded or ineligible, leaving 145 women and 85 partners. Factor analysis produced three clear dimensions: Staff professionalism and empathy, Information and explanations, and Confidence in staff. The total scale and three subscales showed high reliability. Strong positive correlations were found between the questionnaire scales and the two global questions, indicating convergent validity. For women whose partners were present at the birth, a fourth factor was identified 'Partner Involvement'. CONCLUSIONS: The P-BESS appears to be a valid measure of satisfaction with care during very preterm birth. PMID- 24953084 TI - Folding of fourteen small proteins with a residue-specific force field and replica-exchange molecular dynamics. AB - Ab initio protein folding via physical-based all-atom simulation is still quite challenging. Using a recently developed residue-specific force field (RSFF1) in explicit solvent, we are able to fold a diverse set of 14 model proteins. The obtained structural features of unfolded state are in good agreement with previous observations. The replica-exchange molecular dynamics simulation is found to be efficient, resulting in multiple folding events for each protein. Transition path time is found to be significantly reduced under elevated temperature. PMID- 24953085 TI - Staff assessment of structural empowerment and ability to work according to evidence-based practice in mental health care. AB - AIM: To study associations between staff members' self-rated structural empowerment in mental health care, organisational type, and the ability and willingness to work according to evidence-based practice. METHOD: Questionnaire data were collected from 253 mental health staff members. RESULT: Multivariate logistic regressions analyses revealed that participants who scored higher on opportunity (OR 2.5) and were employed by the county council (OR 1.9) vs. the municipality were more likely to report high evidence-based practice ability. A generalised estimating equation taking into account unknown correlations within units found opportunity and resources to be significant predictors of evidence based practice ability. Regarding evidence-based willingness, increased odds were found for higher scores of opportunity (OR 2.2) and being employed by the county council (OR 2.9). The generalised estimating equation also found resources to be a significant predictor of evidence-based willingness. In both organisations, the values for empowerment were moderate. CONCLUSION: Structural conditions such as access to opportunities and resources are important for creating supporting structures for practice to be evidence-based. IMPLICATIONS FOR NURSING MANAGEMENT: Our results emphasise the managers' essential role in creating empowering structures, and especially access to opportunities and resources, for their staff to carry out evidence-based practice. PMID- 24953086 TI - Novel therapeutic agents in neurogastroenterology: advances in the past year. AB - BACKGROUND: There have been significant advances in understanding the pathophysiological mechanisms in patients with neurogastroenterological disorders including irritable bowel syndrome (IBS) and functional abdominal pain, functional diarrhea, chronic constipation, gastroparesis, and functional dyspepsia. These advances have led to the development of novel pharmacological therapy of neurogastroenterological disorders. PURPOSE: To review peer-reviewed articles or prominent preliminary communications presented in the past year regarding medications in development for functional gastrointestinal disorders or gastroparesis. The medications fall into two main categories: first, established classes of medications within established classes, such as 5-HT3 receptor antagonists and 5-HT4 receptor agonists, and second, new classes of medications such as a combined MU-opioid agonist and delta-antagonist, or a small molecule ghrelin agonist. PMID- 24953087 TI - Assessment of the temperature effect on childhood diarrhea using satellite imagery. AB - A quasi-Poisson generalized linear model combined with a distributed lag non linear model was used to quantify the main effect of temperature on emergency department visits (EDVs) for childhood diarrhea in Brisbane from 2001 to 2010. Residual of the model was checked to examine whether there was an added effect due to heat waves. The change over time in temperature-diarrhea relation was also assessed. Both low and high temperatures had significant impact on childhood diarrhea. Heat waves had an added effect on childhood diarrhea, and this effect increased with intensity and duration of heat waves. There was a decreasing trend in the main effect of heat on childhood diarrhea in Brisbane across the study period. Brisbane children appeared to have gradually adapted to mild heat, but they are still very sensitive to persistent extreme heat. Development of future heat alert systems should take the change in temperature-diarrhea relation over time into account. PMID- 24953088 TI - Trends in parent- and teacher-rated emotional, conduct and ADHD problems and their impact in prepubertal children in Great Britain: 1999-2008. AB - BACKGROUND: Evidence from Western countries indicates marked increases in diagnosis and treatment of childhood psychiatric disorders in recent years. These could reflect changes in prevalence of mental health problems, changes in their impact or increased clinical recognition and help-seeking. Epidemiological cross cohort comparisons are required to test possible changes in prevalence, but are lacking for pre-adolescent children in Great Britain. METHODS: Parent and teacher Strength and Difficulties Questionnaire (SDQ) ratings were used to compare rates of emotional, conduct and hyperactivity problems in 7-year-old children across three nationally representative British samples assessed in 1999 (n = 1033), 2004 (n = 648) and 2008 (n = 13,857). The SDQ impact supplement was used to assess associated distress, social, and educational impairment. Stratified analyses examined trends by gender and socio-economic group. RESULTS: There was a decline in mean problem scores and a fall in the percentages scoring in the 'abnormal' range for all symptom types across the period of study. This decline was observed for all demographic groups, for parent and teacher reports, and was more marked for boys than girls. Both parent- and teacher-rated impact scores differed across the three cohorts for boys. Teacher-rated impact scores differed across cohorts for girls. CONCLUSIONS: The first decade of the 21st Century saw a reduction in perceived levels of emotional and behaviour problems in pre-adolescent children in Great Britain. The threshold at which mental health problems have an impact on children's distress and classroom learning has changed over time. Continued monitoring of child mental health remains a priority. PMID- 24953089 TI - Relationship between overtime work hours and cardio-ankle vascular index (CAVI): a cross-sectional study in Japan. AB - OBJECTIVES: The purpose of this research was to evaluate the relationship between overtime work hours and CAVI, a new index of arterial stiffness. METHODS: We measured CAVI of Japanese workers (3,862 men) aged 26 to 59 years. Simultaneously, we obtained information on their monthly overtime work hours for the past few months using a self-administered questionnaire, with responses divided into five groups: <45, >=45 and <60, >=60 and <80, >=80 and <100 and >=100 hours/month. We calculated the odds ratios of CAVI>=9.0 for each group of overtime work hours. RESULTS: In the full sample, there was no significant association between the average CAVI and overtime work hours. Taking<45 overtime hours/month as the reference category, the odds ratios of CAVI>=9.0 were as follows: OR=1.11, 95% CI=0.73-1.69 (>=45 and <60 hours/month); OR=0.92, 95% CI=0.48-1.76 (>=60 and <80 hours/month); OR=1.50, 95% CI=0.50-4.49 (>=80 and <100 hours/month); and OR=2.65, 95% CI=0.82-8.54 (>=100 hours/month). However, for workers in their 50 s, the odds ratio of CAVI>=9.0 was significantly higher among subjects with>=100 hours/month than among those with<45 hours/month (OR=4.26, 95% CI=1.2-15.1) CONCLUSIONS: The present study suggests that CAVI is more likely to be 9.0 or higher in workers in their 50 s when they work>=100 hours of overtime per month. PMID- 24953090 TI - Assessment of exposure to voices and noise via earphones in manufacturing industry workers in Japan. AB - OBJECTIVES: There is concern that sound via earphones and headphones attached to headsets used in workplaces may be a risk factor for noise-induced hearing loss (NIHL). Although there are some previous studies investigating exposure to noise from headphones, almost none have assessed the risks to workers who use earphones. We assessed exposure to noise among workers who regularly wear earphones in noisy workplaces. METHODS: The subjects of this study were 21 workers who regularly wear earphones in three manufacturing companies in Japan. The sound pressure output from earphones and personal exposure to occupational noise was measured for each worker. A noise-dosimeter was used to measure individual exposure to occupational noise. The sound pressure output from the earphones was measured by recording the electric signal with a data recorder attached to the earphones, and the recording was analyzed by playing it back in the laboratory through a sound analyzer via an ear simulator. RESULTS: The mean scores for personal exposure and earphone output LAeq were 87.9 dB and 87.6 dB, respectively. Earphone output LAeq exceeded 85 dB for two-thirds of the subjects. Nearly all the subjects lacked hearing protection devices (HPDs) on their earphones. CONCLUSIONS: The results suggest that workers who use earphones in noisy workplaces are exposed to the following NIHL risk factors: (1) they are deprived of the opportunity to fit appropriate HPDs, and (2) the sound pressure output from the earphones themselves exceeds the occupational exposure limit. PMID- 24953091 TI - Changes in laboratory test results and diagnostic imaging presentation before the detection of occupational cholangiocarcinoma. AB - OBJECTIVES: A cholangiocarcinoma outbreak among workers of an offset color proof printing department in a printing company was recently reported. It is important to understand the clinical course leading to occupational cholangiocarcinoma development for investigation of the carcinogenesis process and for surveillance and early detection. We evaluated the changes in laboratory test results and diagnostic imaging presentation before the detection of cholangiocarcinoma. METHODS: We investigated the changes in laboratory test results and diagnostic imaging presentation before the detection of cholangiocarcinoma in 2 patients because the data were available. Results The clinical courses observed in the 2 participating patients showed persistent elevation of serum gamma-glutamyl transpeptidase levels with or without elevated serum levels of alanine aminotransferase and/or aspartate aminotransferase before cholangiocarcinoma detection. Dilatation of the bile ducts without tumor-induced stenosis was observed several years before cholangiocarcinoma detection and progressed gradually in both patients. The serum concentration of carbohydrate 19-9 also increased prior to cholangiocarcinoma detection in both patients. Eventually, observation of stenosis of the bile duct and a space-occupying lesion strongly suggested cholangiocarcinoma. Pathological examination of the resected specimens showed chronic bile duct injury and neoplastic lesions, such as "biliary intraepithelial neoplasia" and "intraductal papillary neoplasm of the bile duct" in various sites of the bile ducts, particularly in the dilated bile ducts. CONCLUSIONS: The changes in laboratory test results and diagnostic imaging might be related to the development of cholangiocarcinoma. It is important to monitor diagnostic imaging presentation and laboratory test results in workers with extended exposure to organic solvents. PMID- 24953092 TI - Intention to stay and intention to leave: are they two sides of the same coin? A cross-sectional structural equation modelling study among health and social care workers. AB - OBJECTIVES: "Intention to leave" (ITL) has been used interchangeably with the more positive construct "intention to stay" (ITS). The implicit assumption appears to be that both constructs represent different sides of the same coin. This study challenges this assumption. The objectives were (i) to test whether these constructs were similar measures of the same construct, and (ii) to assess the strength of the relationships between ITL and ITS with work-related outcomes. METHODS: The Workforce Dynamics Questionnaire (WDQ) was administered to 298 staff. The WDQ included two items on ITL and was supplemented with three items on ITS. Structural equation modelling (SEM) was used. RESULTS: The response rate was 43%. The correlation between the two constructs was negative and quite high (r= 0.84), indicating potential issues with discriminant validity. However, the constructs behaved differently in relation to job satisfaction and job integration. ITS was a strong predictor (0.95, p<0.001), whereas ITL was not significantly related (0.34, p=0.195) to JS. The direct effects of JI on ITS was 0.30 and on ITL was -0.42. The indirect effects of JI were more contrasting, being 0.56 for ITS and -0.30 for ITL, via job satisfaction. CONCLUSIONS: This is the first study amongst British health and social care workers that has demonstrated that ITS and ITL are not measuring the same construct. While there is overlap, care should be taken when using these constructs interchangeably, particularly when measuring these concepts in organizations and when developing retention programs, policies, or activities to modify ITS and ITL. PMID- 24953093 TI - Comparison of high-resolution computerized tomography with film-screen radiography for the evaluation of opacity and the recognition of coal workers' pneumoconiosis. AB - OBJECTIVES: Current diagnostic standards of pneumoconiosis, which is the most serious occupational disease in China, are based on film-screen radiography (FSR). However, parenchymal structure overlap limits the sensitivity of FSR in the clinic. High-resolution computerized tomography (HRCT) has the advantage of identifying nodular pulmonary parenchymal changes. In this study, we aimed to compare HRCT and FSR for recognition of the profusion of small opacities, opacity shape and opacity coalescence in coal miners with or without radiographic evidence of coal workers' pneumoconiosis (CWP) and evaluate the possible role of HRCT in CWP diagnosis. METHODS: There were 96 coal miners with radiographic evidence of CWP, 67 coal miners without CWP and 37 healthy controls in this study. FSR and HRCT images for all subjects were interpreted separately by three readers. Crude agreement and Kappa values were calculated to evaluate the agreement between the two methods. RESULTS: The overall agreement for CWP evaluation was good (crude agreement rate=87.1%, kappa=0.72, 95% CI: 0.62-0.83) between FSR and HRCT in all coal miners. The sensitivity of HRCT for CWP diagnosis was 96.9% (93/96). We observed that 18 of the 67 (26.9%) miners negative for CWP by FSR were classified as category 1 by HRCT according to the lung parenchyma profusion category system reported by Bergin et al. The difference in the profusion scores between CWP subjects and healthy controls for HRCT scans were statistically significantly higher than those for FSR. CONCLUSIONS: HRCT was more sensitive than FSR in recognition of the profusion of small opacities among coal miners. More research is needed to evaluate the role of HRCT in early diagnosis of CWP. PMID- 24953094 TI - Studies of the impact of occupational exposure of pharmaceutical workers on the development of antimicrobial drug resistance. AB - OBJECTIVES: Pharmaceutical workers involved with the production of antimicrobial drugs are exposed to various antimicrobial chemicals in different steps of manufacturing such as grinding, sieving, compression, granulation, mixing and filling. These exposures may lead to the development of multidrug resistance (MDR) in bacteria. Scientific reports on the occupational health hazard of pharmaceutical workers involved in manufacturing antibiotics are scarce. The present study aimed to compare the degree of bacterial resistance in pharmaceutical workers in Bangladesh to that of individuals not involved in the pharmaceutical field. METHODS: Twenty male workers from five local pharmaceutical companies and twenty male subjects not involved in the pharmaceutical field (non pharmaceutical subjects) were randomly selected. Nasal fluid, mucus/cough and stool specimens were collected from each subject and were cultured separately at 37 degrees C for 24 hours to obtain bacterial growth. The cultured species were then identified, isolated and subjected to microbial sensitivity testing against 18 different antibiotics from eight different groups by the disk diffusion method. Staphylococcus spp., Pseudomonas spp. and Escherichia coli were identified and isolated from the culture of nasal fluids, mucuses and stools, respectively. RESULTS: All the isolated species of bacteria exhibited significant enhancement of the degree of MDR in pharmaceutical workers compared with non pharmaceutical subjects. Workers with a longer working history had greater degree of antibiotic resistance and vice versa. It can be certainly considered that the exposure of pharmaceutical workers to antibiotic agents resulted in a high incidence of multidrug resistance. CONCLUSIONS: Effective steps should be taken to minimize inherent exposure of pharmaceutical workers to antibiotics during work to prevent antimicrobial drug resistance. PMID- 24953095 TI - FtsZ-independent septal recruitment and function of cell wall remodelling enzymes in chlamydial pathogens. AB - The nature and assembly of the chlamydial division septum is poorly defined due to the paucity of a detectable peptidoglycan (PG)-based cell wall, the inhibition of constriction by penicillin and the presence of coding sequences for cell wall precursor and remodelling enzymes in the reduced chlamydial (pan-)genome. Here we show that the chlamydial amidase (AmiA) is active and remodels PG in Escherichia coli. Moreover, forward genetics using an E. coli amidase mutant as entry point reveals that the chlamydial LysM-domain protein NlpD is active in an E. coli reporter strain for PG endopeptidase activity (DeltanlpI). Immunolocalization unveils NlpD as the first septal (cell-wall-binding) protein in Chlamydiae and we show that its septal sequestration depends on prior cell wall synthesis. Since AmiA assembles into peripheral clusters, trimming of a PG-like polymer or precursors occurs throughout the chlamydial envelope, while NlpD targets PG-like peptide crosslinks at the chlamydial septum during constriction. PMID- 24953098 TI - [3+3] annulation of allylic phosphoryl-stabilized carbanions/phosphorus ylides and vinyl azides: a practice strategy for synthesis of polyfunctionalized anilines. AB - Tandem Michael addition and Witting or Horner-Wadsworth-Emmons olefination initiated [3+3] annulation between vinyl azides and allylic phosphorus ylides or allylic phosphoryl-stabilized carbanions has been developed. This one-pot protocol furnishes highly functionalized anilines in good to excellent yields under mild, room-temperature conditions. A rational mechanism is also proposed. PMID- 24953096 TI - Poly(ADP-ribose)-mediated interplay of XPA and PARP1 leads to reciprocal regulation of protein function. AB - Poly(ADP-ribose) (PAR) is a complex and reversible post-translational modification that controls protein function and localization through covalent modification of, or noncovalent binding to target proteins. Previously, we and others characterized the noncovalent, high-affinity binding of the key nucleotide excision repair (NER) protein XPA to PAR. In the present study, we address the functional relevance of this interaction. First, we confirm that pharmacological inhibition of cellular poly(ADP-ribosyl)ation (PARylation) impairs NER efficacy. Second, we demonstrate that the XPA-PAR interaction is mediated by specific basic amino acids within a highly conserved PAR-binding motif, which overlaps the DNA damage-binding protein 2 (DDB2) and transcription factor II H (TFIIH) interaction domains of XPA. Third, biochemical studies reveal a mutual regulation of PARP1 and XPA functions showing that, on the one hand, the XPA-PAR interaction lowers the DNA binding affinity of XPA, whereas, on the other hand, XPA itself strongly stimulates PARP1 enzymatic activity. Fourth, microirradiation experiments in U2OS cells demonstrate that PARP inhibition alters the recruitment properties of XPA green fluorescent protein to sites of laser-induced DNA damage. In conclusion, our results reveal that XPA and PARP1 regulate each other in a reciprocal and PAR dependent manner, potentially acting as a fine-tuning mechanism for the spatio temporal regulation of the two factors during NER. PMID- 24953099 TI - Attachment styles and symptoms in individuals with psychosis. AB - BACKGROUND: The capacity to manage affects is rooted in early interactions with caregivers, which in adulthood are internalized as different attachment styles. Few studies have explored associations between all four attachment styles and symptoms. AIM: Our aim was to investigate the relations between the four attachment styles and psychological distress in a group of people with psychosis. METHOD: In a cross-sectional study, associations between self-reported attachment style and symptoms in a psychosis group were explored. Attachment styles were measured with the Relationship Questionnaire (RQ) and symptoms were assessed with the revised version of the Symptom Checklist (SCL-90R) RESULTS: The analyses showed a significant positive association between preoccupied attachment and the severity of symptoms. Furthermore, the analyses indicated significant positive associations between preoccupied attachment and the subscales measuring depression, anxiety, interpersonal sensitivity, paranoia and psychoticism. We also found significant positive associations between fearful attachment and both interpersonal sensitivity and psychoticism. CONCLUSION: The associations between attachment styles and symptoms found here are consistent with those of previous studies. It could be important for clinicians to identify patients' attachment styles. Such knowledge would help mental health professionals to understand better the patients' capacity to handle distress and help professionals to address interventions aiming to target each patient's specific needs. PMID- 24953100 TI - Complex symptomatology among young women who present with stress-related problems. AB - INTRODUCTION: In Scandinavia and globally, mental health and stress-related problems among adolescent girls and young women are public health concerns that need attention. The aim of this study was to investigate mental health and somatic symptoms with a special focus on internalised problems, self-image and body-mind aspects of body perception in a group of adolescent girls and young women presenting with stress-related problems at a youth-friendly Swedish health centre, and to compare them with normative and clinical reference groups. METHODS: The participants were 47 adolescent girls and young women, aged 17-25 years. The adult self-report (ASR), social analysis of social behaviour (SASB) and body perception questionnaire (BPQ) were used to measure multiple symptom areas. RESULTS: Compared to reference groups, adolescent girls and young women report complex symptomatology with high levels of internalised problems such as anxiousness, depression and somatic complaints. This manifested in attention problems, negative self-image and perceived bodily discomfort and distrust. CONCLUSION: Adolescent girls and young women emerging into adulthood present complex symptomatology of stress-related problems. This study gathered valuable information about their symptoms when they were seeking help. These young women showed higher symptom frequency than normative groups, and similar or higher symptom frequency than other clinical groups. Our findings of internalised and cognitive problems, including impaired self-image and body perceptions, point to the need for preventive strategies and tailored multidisciplinary interventions involving body-based methods to meet this complexity. Using tenets of stress theory, the complex symptomatology may be understood as logical responses to overwhelming stimuli and demands that exceed their ability to cope and disturb their 'equilibrium'. However, the complex gendered interplays between various external/internal stressors and a broad range of stress responses and health outcomes need further study in a long-term perspective. PMID- 24953097 TI - Constipation severity is associated with productivity losses and healthcare utilization in patients with chronic constipation. AB - OBJECTIVE: We sought to evaluate the association between constipation severity, productivity losses and healthcare utilization in a national sample of Italian patients with chronic non-organic constipation (CC). METHODS: We enrolled 878 outpatients with CC. Clinical and demographic data were collected by physicians during clinical examinations. Patients completed a self-administered questionnaire (Patient Assessment of Constipation-Symptoms, PAC-SYM; Work Productivity and Activity Impairment; healthcare utilization, and Symptoms Checklist 90 Revised - Somatization Scale, SCL-90 R). RESULTS: Mean PAC-SYM score was 1.62 +/- 0.69. Mean weekly sick time due to constipation was 2.7 +/- 8.6 h and productivity losses due to presenteeism was 19.7% +/- 22.3%. Adjusted productivity losses in patients with severe CC (PAC-SYM score 2.3-4.0) compared to patients with mild symptoms (PAC-SYM score 0.0-1.0) was Italian Purchase Power Parity US$ 6160. Constipation severity (PAC-SYM quintiles) was associated with higher healthcare utilization (RRPAC-SYM 4/01.84; p-value for linear trend <0.01). After adjustment for somatization scores, the association of constipation severity with productivity losses and healthcare utilization rates was attenuated yet statistically significant. CONCLUSIONS: We observed a graded increase in productivity losses and healthcare utilization with increasing constipation severity. Further studies should evaluate whether significant savings might be achieved with regimens aimed at reducing the constipation severity. PMID- 24953101 TI - [New spirometric reference equations for healthy Chilean adults]. AB - BACKGROUND: To correctly interpret spirometric results, reference values should come from the same population. Current spirometric reference equations have been under scrutiny due to deficiencies to fit adequately for Chilean population, specially, for those aged over 65 years old. AIM: To develop new spirometric reference values for Chilean adults, based on national studies in which spirometries were performed in healthy non-smoker adults. MATERIAL AND METHODS: A standardized database of spirometric values was developed combining spirometric data collected from five population-based studies, in which healthy nonsmoker adults participated. Spirometries from 448 males aged 19 to 84 years and from 726 females aged 19 to 94 years, obtained according to guidelines from the American Thoracic and European Respiratory Societies, were analyzed. Using multiple regression models, which included height, gender, and age, the theoretical value and inferior limits of normality were calculated for 1st second (FEV1), forced vital capacity (FVC), FEV1/FVC, and forced mid-expiratory flow rate (FEF25-75). RESULTS: Reference values and lower limits of normality (LLN) were constructed for Chilean adults of both genders. The new proposed set of equations had a better fit, when compared with the current reference values used in Chile. CONCLUSIONS: The new spirometric references values derived from this study, fit better than currently used ones. Therefore, they should be used as new references values for Chilean adults. PMID- 24953102 TI - [Adjusted Clinical Groups as a risk assessment model for healthcare resource allocation]. AB - BACKGROUND: There is increasing interest in the study and improvement of health system resource allocation. The Adjusted Clinical Groups (ACG) System measures the morbidity burden of patient populations based on disease patterns, age and gender. This system can be used in primary health care settings. AIM: To report the use of the ACG system as a risk based patient classification system and its potential as a resource allocation mechanism in primary health care. MATERIAL AND METHODS: Patient diagnoses from a sample of primary care establishments were processed using the Johns Hopkins ACG System. Linear regressions were used to measure the ACG System's ability to explain resource use and ambulatory visit rates. RESULTS: The ACG System had a statistically significant capacity to explain primary health care costs with an adjusted R2 of 0.26. These results are significantly better, compared with risk assessment models based on patients' age and sex, whose adjusted R2 is 0.05. CONCLUSIONS: The use of risk adjustment mechanisms will contribute to improve health care resource allocation as well to know the disease profile of the population. PMID- 24953103 TI - [Evaluation of financial status of public hospitals considering the updated costs of their services]. AB - In 2011 the Chilean National Health Fund (FONASA) commissioned a study to assess the costs of the 120 most relevant hospital care services with an established fee, in a large sample of public hospitals. We herein report the cost evaluation results of such study, considering the financial condition of those hospitals in the year of the study. Based on the premise that the expenses derived from the provision of institutional and appraised hospital services should be identical to the billing of hospitals to FONASA, the prices are undervalued, since they cover only 56% of billing, generating a gap between expenses and invoicing. This gap shows an important limitation of tariffs, since their prices do not cover the real costs. However not all hospitals behave in the same way. While the provision of services of some hospitals is even higher than their billing, most hospitals do not completely justify their invoicing. These assumptions would imply that, generally speaking, hospital debts are justified by the costs incurred. However, hospitals have heterogeneous financial situations that need to be analyzed carefully. In particular, nothing can be said about their relative efficiency if cost estimations are not adjusted by the complexity of patients attended and comparison groups are not defined. PMID- 24953104 TI - [Women age as a risk factor for maternal, fetal, neonatal and infant mortality]. AB - BACKGROUND: Adolescent pregnancy and advanced maternal age are associated with increased risk for maternal, perinatal and infant death. However, the maternal age with the lowest reproductive risk has not been established. AIM: To determine the range of maternal age with the lowest reproductive risk. MATERIAL AND METHODS: A population-based study (2005-2010) was performed analyzing raw data from vital statistics yearbooks of the National Institute of Statistics of Chile. The association of maternal, fetal, neonatal and infant mortality with maternal age was analyzed. The latter was stratified in quinquenniums, between ages 10 and 54 years. Maternal, fetal, neonatal and infant mortality rates were calculated for each quinquennium. The lowest rate was selected as a control group for risk analysis, which was estimated according to Odds Ratio with 95% confidence intervals. RESULTS: Women of 20-29, 25-34 and under 30 years, had the lowest rate of fetal, neonatal/infant and maternal death, respectively. Women aged 45-49 years had the higher rate of maternal, fetal, neonatal and infant mortality. The risk of fetal, neonatal and infant mortality doubled from 40-44 years onwards, and maternal mortality from the age of 30-34 years. CONCLUSIONS: Our results suggest that the maternal age range with the lesser general reproductive risk is between 20-29 years. This finding should be considered in future studies of reproductive risk and for an appropriate counseling about conception. PMID- 24953105 TI - [Association between diabetes mellitus and cardiovascular disease in Chilean adults: analysis of the National Health Survey 2009-2010]. AB - BACKGROUND: Diabetes mellitus (DM) is a recognized atherosclerotic cardiovascular disease (ACVD) risk factor. This association has yet to be quantified in the Chilean population. AIM: To compare the frequency of ACVD between diabetic and non-diabetic Chilean subjects. MATERIAL AND METHODS: Data was extracted from the Chile National Health Survey (ENS) performed in 2009-2010. DM diagnosis was made with fasting glucose. ACVD (coronary, cerebral and peripheral vascular disease) was established by self-report. Major cardiovascular risk factors were identified by clinical and laboratory assessment. RESULTS: A total of 5,416 adults (2,200 men and 3,216 women) were surveyed in ENS 2009-2010. Of these, 508 were diabetic and 375 reported ACVD. ACVD frequency was 16.1% and 6.1% in diabetic and non diabetic subjects, respectively. In diabetic men, the frequency of ACVD steadily increased with age, from 5.1% to 22.1%. In diabetic women, the highest frequency of ACVD (17.4%) was found in ages ranging from 45 to 54 years. In people younger than 54 years, the odds ratio for ACVD in diabetic compared to non-diabetic subjects, was 3.59 in men (chi2 = 4.03 p < 0.03) and 5.26 in women (chi2 = 7.7 p < 0.007). Cardiovascular risk factors and metabolic syndrome were significantly more common in diabetic subjects with reported ACVD. CONCLUSIONS: DM is associated with an increased frequency of ACVD and cardiovascular risk factors in Chilean adults. In line with international reports, our findings suggest that DM is also a cardiovascular risk factor in Chile, particularly relevant for women. PMID- 24953106 TI - [Evaluation of an online health promotion Diploma]. AB - BACKGROUND: Health promotion in Chile is essential, considering its current epidemiologic status where chronic diseases are predominant. AIM: To report the evaluation of an on-line Diploma in health promotion for Primary Health Care professionals. MATERIAL AND METHODS: Two hundred sixty four professionals from all regions of the country (40% rural and 60% urban) took the Diploma. It lasted 8 months with 248 academic hours distributed in 5 modules with a total of 15 units. The program was evaluated with four surveys answered by the students (general description of participants, mid-term, final and follow-up). RESULTS: Students were highly satisfied with the program and especially with its interactive methodology which included tutorials, individual and group assignments, online discussions and a final project. The drawbacks were time restrictions and limited internet access. Ninety percent of students completed the course with an overall mean grade of 5.57 (out of a 1-7 scale). The follow-up survey showed that students implemented the new health promotion knowledge acquired, and put in practice their final assignment in their local counties. Also, most students improved their working conditions. CONCLUSIONS: The on-line interactive and participative methodology applied in this Diploma had positive results and the evaluation model can be applied in other health promotion on-line education programs. PMID- 24953107 TI - [Gender influence on health related quality of life among resident physicians working in an emergency department]. AB - BACKGROUND: The high emotional burden of physicians working in emergency departments may affect their quality of life perception. AIM: To evaluate health related quality of life among resident physicians performing shifts at an emergency department. MATERIAL AND METHODS: Seventy one physicians aged 26,3 +/- 1,7 years (47 women), working as residents in an emergency department, answered the short version of the Short-Form Health Survey Questionnaire (SF-36(r)). This questionnaire analyses eight domains: physical function, body pain, general health, vitality, social function, emotional role and mental health. RESULTS: Women had a significantly worse perception than a reference population in four dimensions of the SF-36, especially mental health and social functioning. Men had scores similar to the reference population. Among women, vitality is the best predictor of mental health and social functioning. CONCLUSIONS: Women working as residents in an emergency department have a worse perception of their quality of life than men performing the same job. PMID- 24953108 TI - [Adjuvant chemoradiotherapy in advanced gastric cancer: experience in 168 patients]. AB - BACKGROUND: Gastric cancer is one of the most lethal tumors in the Chilean population. AIM: To report the results of adjuvant chemoradiotherapy in advanced gastric cancer. MATERIAL AND METHODS: Review of medical records of patients with locoregionally advanced gastric cancer, subjected to a curative resection and treated with adjuvant chemoradiotherapy. The treatment was based on the INT 0116/SWOG protocol, which includes 5-fuorouracil as a single agent. Patients were followed for a median of 58 months. RESULTS: the records of 168 patients (99 men) treated between 2004 and 2011, were reviewed. Median survival was 41 months. Median lapses between surgery and onset of chemo and radiotherapy were 12 and 17 weeks, respectively. Overall three and five years survival was 53 and 41%, respectively. On multivariate analysis the factors associated with a lower survival were an antral location of the tumor, presence of signet ring cells and more than 15 involved lymph nodes. CONCLUSIONS: Three and five years survival of gastric cancer patients subjected to adjuvant chemoradiotherapy was 53 and 41% respectively. These results are similar to those reported elsewhere. PMID- 24953110 TI - [The link between obesity and cancer]. AB - While some genetic factors may explain the development of cancer, its main causes are related to environmental exposure to carcinogenic agents as well as to the effect of determined lifestyles and habits. Several epidemiological studies have shown a consistent relation between obesity and cancer. In non smokers, obesity is the most relevant risk factor in the development of malignant tumors. There is a clear association between obesity and endometrial cancer, breast cancer in postmenopausal women, pancreatic, esophageal and colon cancer. Sexual steroids, insulin like growth factor axis and adipokines are the three main models to explain the biological basis for the obesity-cancer relationship. However, these models do not explain all the biological mechanisms that link obesity to cancer. There are other factors in play such as chronic inflammation, hypoxia and oxidative stress. Obesity may hamper the screening, diagnosis and treatment of some tumors, increasing mortality rates. Obesity prevention and management, therefore, may be the most important modifiable factor in reducing both incidence and mortality in cancer. New studies are required to quantify the effect of intentional weight reduction on the incidence and relapse of cancer. Considering the efficacy of bariatric surgery for weight reduction, it is an attractive model to study this link. PMID- 24953109 TI - [Neurobiology of borderline personality disorder]. AB - Borderline personality disorder (BPD) is highly prevalent and associated with significant dysfunctional behavior and suicide risk. The association with psychosocial factors is well established, however its neurobiology is not fully unraveled. According with the revised studies, subjects with BPD have structural and functional brain alterations, particularly in areas involved in affective and cognitive regulation and control of impulses. These alterations allow us to understand the psychopathology of this disorder and partly explain its pathogenesis. PMID- 24953111 TI - [Risk of type 2 diabetes mellitus associated with statin therapy: evidence and possible mechanisms]. AB - In the last decade, an increased number of new cases of type 2 diabetes mellitus (T2DM) among patients who use statins have been reported. The aim of the present review is to compile the most relevant information about the risk of T2DM associated with the use and dose of different statins, especially based on meta analysis considering different studies worldwide. To explain this relationship, several studies have reported the effect of statins on insulin resistance in dyslipidemic non-diabetic patients, reporting different findings according to the types of statins. In addition, some reports -based on culture of beta pancreatic cells- have evaluated the effect of these drugs in certain cellular events that are essential for insulin secretion. Clearly, further studies in humans are needed -applying more robust tests than those used up to date- in order to define more precisely the potential mechanisms explaining the higher incidence of T2DM among statin users. PMID- 24953112 TI - [The discharge process]. AB - Discharge is one of the most important processes that hospitalized patients must endure. This process is complex, requires coordination among several professionals and transfers an overwhelming amount of information to patients. Often, it is limited to the writing of the discharge summary, with a primary emphasis on the drug list. Since the rise of hospitalism in 1996, a greater emphasis has been placed on understanding this process and in developing interventions to make it more effective and safe. In our country, little is known about how this process is taking place. Probably the absence of financial penalties for readmissions has influenced in the lack of study and development of this process. In the USA the knowledge of the discharge process is well advanced, and several strategies have been developed for reducing adverse events, medication errors, and 30-days readmissions. Other interventions have increased patient satisfaction and the degree of knowledge about their conditions. The aim of this paper is to do a comprehensive review of the literature, to provide healthcare teams with various tools that could improve both the discharge process as well as the discharge summary. The final objective is to optimize the safety and satisfaction of our patients and the hospital metrics of quality. PMID- 24953113 TI - [Therapeutic strategies to increase the effectiveness of cough]. AB - Cough is a natural reflex that protects respiratory airways against infections or mucus retention. Cough maintains an adequate cleaning of the airways and is a mainstay of respiratory therapy. It can be triggered voluntarily by the patient or by a specific cough device. Peak cough flow (PCF) is used to assess the effectiveness of the cough. When this value is below 160 L/min, cough is considered inefficient and becomes a risk factor for respiratory problems. Patients with weak cough, especially those with neuromuscular disease, have in common a low tidal volume and a decreased maximum insufflation capacity. Both factors directly affect the inspiratory phase previous to cough, which is considered vital to obtain the optimum flow for a productive cough. Different therapeutic measures may help to increase cough efficiency among patients with cough weakness. These interventions may be performed using manual techniques or by mechanical devices. The aim of this review is to analyze the different techniques available for cough assistance, set a hierarchy of use and establish a scientific basis for their application in clinical practice. PMID- 24953114 TI - [Spontaneous rupture of tricuspid valve papillary muscle in pulmonary hypertension secondary to HIV infection. Report of one case]. AB - Acute primary tricuspid regurgitation (TR) secondary to papillary muscle rupture is an extremely rare clinical situation. We report a 42-year-old male with pulmonary artery hypertension (PAH) secondary to HIV infection, who presented with an acute TR due to spontaneous papillary muscle rupture. He remained in cardiogenic shock despite therapy with inotropic drugs and pulmonary vasodilator therapy. He was subjected to a tricuspid valve replacement. In the postoperative period the patient had severe PAH, which was successfully controlled with inhaled nitric oxide. Tricuspid valve replacement and adjunctive use of pulmonary vasodilator therapy can be a life saving and useful approach in this condition. PMID- 24953115 TI - [Presentation of a pheochromocytoma as an acute coronary syndrome: report of one case]. AB - The typical symptoms of pheochromocytoma are palpitations, sweating, headaches and hypertension. We report a 70-year-old female admitted to the hospital due to a sudden onset of precordial pain with electrocardiographic changes. After admission the patient evolved with recurrent chest pain accompanied by hypertensive paroxysms and a pheochromocytoma was suspected. Measurement of catecholamines and metanephrines confirmed the diagnosis and an abdominal magnetic resonance localized the tumor. The patient underwent surgery with successful removal of the pheochromocytoma and was discharged in good conditions. PMID- 24953116 TI - Massive and painful ascites as a presenting manifestation of systemic lupus erythematosus flare: a case report and literature review. AB - Lupus peritonitis (LP) is extremely rare. Acute LP is characterized by rapid onset of ascites and severe abdominal pain, in addition to other well-recognized clinical features of a general systemic lupus erythematosus (SLE) fare. Ascites associated with acute LP has been rarely reported as the prominent feature of a SLE fare. We report a 39-year-old woman who developed massive, painful ascites as the presenting manifestation of a SLE fare. Diagnostic workup ruled out the possibility of hepatic, cardiovascular, infectious, or malignant diseases, and confirmed the presence of a SLE fare. The patient was treated with methyl prednisolone and hydroxychloroquine resulting in dramatic improvement of her condition. During ambulatory follow up, she has remained asymptomatic up to the moment of this writing. Adrenal steroids and hydrocychloroquine may be useful for the management of SLE fares in patients with massive, painful ascites due to acute LP. PMID- 24953118 TI - [World Kidney Day]. PMID- 24953117 TI - [Cryptogenic organizing non-resolving pneumonia. Report of one case]. AB - Non-resolving pneumonia is a common clinical problem that prolongs morbidity and increases hospitalization costs. We report an 82 year-old non-smoking female who was admitted with chronic diarrhea and later developed nosocomial pneumonia. Lung infiltrates did not resolve despite sequential antibiotic treatments. Infectious causes such as resistant nosocomial pathogens, respiratory viruses, tuberculosis, Legionellosis, cytomegalovirus or agents associated with HIV infection were discarded. Non-infectious causes such as thromboembolic lung disease, neoplasms and rheumatic disorders were also ruled out. An exudative pleural effusion was detected, but the study was unremarkable. Fiberoptic bronchoscopy and a transbronchial biopsy, revealed nonspecific findings. The patient persisted febrile, required non-invasive mechanical ventilation and displayed a migratory pattern of lung infiltrates that motivated a second biopsy, this time by open thoracotomy, showing a cryptogenic organizing pneumonia. The patient's conditions improved after treatment with adrenal steroids. In patients with non-resolving pneumonia, a dedicated and comprehensive study should be done using invasive procedures and considering both infectious and non-infectious causes. Cryptogenic organizing pneumonia is one of the alternatives that is potentially treatable, but often underdiagnosed. PMID- 24953119 TI - [Medical care in emergency units]. PMID- 24953120 TI - [Hybris syndrome: description and treatment]. PMID- 24953121 TI - [The farce of homeopathy]. PMID- 24953123 TI - Immunomodulatory effects of selenium and vitamin E on alterations in T lymphocyte subsets induced by T-2 toxin. AB - Abstract Context: T-2 toxin, a potent mycotoxin, has serious effects on immune system. OBJECTIVE: Here, the effects of a sublethal dose of this toxin on T lymphocyte sub-population levels and the potential protective effects from treatment with selenium or vitamin E were studied. MATERIALS AND METHODS: After having determined the sublethal dose of the T-2 toxin in Balb/c mice hosts, the post-injection kinetics of changes in T lymphocyte sub-population (CD3(+), CD4(+) and CD8(+) cells) profiles were analyzed via flow cytometry. For these studies, the selenium and vitamin E were either provided to the mice before or concurrent with the toxin. RESULTS: The results show that after a sublethal dose of T-2 alone, the number of CD8(+) T-lymphocytes was significantly decreased at 12 h and normalized at 48 h. In contrast, level of CD3(+) and CD4(+) T-lymphocytes were significantly increased at 24 h and returned to normal after 48 h. When selenium was injected into the mice 24 h before or concurrent with the T-2, the effects on CD8(+) cells were mitigated. Oddly, only when the selenium was given with the toxin could the effects on the CD3(+) and CD4(+) cells be altered. Vitamin E, when injected 24 h before or concurrent with the T-2 toxin, was only able to impact upon the CD8(+) lymphocyte alterations induced by the toxin. CONCLUSIONS: Compared with vitamin E, it seems that selenium could assert an important effect against the immunotoxic effects of T-2 toxin against T lymphocytes. PMID- 24953122 TI - Effect of rurality on screening for breast cancer: a systematic review and meta analysis comparing mammography. AB - INTRODUCTION: The lower breast cancer survival rate observed among rural women may be related to differences in screening access and utilization. We evaluated existing evidence for rural and urban differences in mammography service use in adult women. METHODS: A systematic search was conducted on 4 April 2012 and updated on 1 November 2012, which yielded 28 studies for inclusion. RESULTS: The rural population was less likely to have mammographic breast screening, and this difference was consistent in various areas of the USA as well as across a number of other countries. Meta-analyses using random effects models showed that women residing in rural areas were less likely than urban women to have ever had a mammogram (odds ratio (OR)=0.74, 95% confidence interval (CI)=0.62-0.89) or to have an up-to-date mammogram (OR=0.59, 95%CI=0.49-0.70). CONCLUSIONS: Mammography is currently the best tool for the early detection and diagnosis of breast cancer. The rural disadvantage this review has identified may contribute to the lower breast cancer survival among women living outside urban areas. PMID- 24953124 TI - Processing of small volumes in blood salvage devices. AB - BACKGROUND: New technical developments such as a small Latham bowl, a continuous autotransfusion system, and a dynamic disk designed for postoperative autotransfusion raise hopes for a possible application of blood salvage in young children. However, the minimal blood volume for effective processing under clinically relevant conditions has yet to be determined. STUDY DESIGN AND METHODS: Fresh blood from volunteer donations adjusted to a hematocrit (Hct) of 10% was used to test ELECTA (Sorin) equipped with a 55-mL bowl, C.A.T.S (Fresenius) in the pediatric program mode, and OrthoPAT (Haemonetics). Twenty milliliter portions of red blood cells (RBCs) were added and processed under various conditions, including clinically relevant first filling and intermittent emptying. RBC recovery and availability and plasma elimination were calculated from the Hct, free hemoglobin, and total protein. RESULTS: The main impediment to recovery and availability was the first filling. There, RBC recovery was significantly reduced, while it subsequently varied between 93 and 98%. To produce the first 30 mL of RBCs, ELECTA required 42 mL and C.A.T.S and OrthoPAT 62 mL owing to the dead space of the separation chamber or reservoir, respectively. RBC availability was much higher in subsequent processes, with only minimal differences between the three devices. They all consistently provided high plasma elimination rates. CONCLUSION: The continuous system showed no advantage over a small Latham bowl. From the results it can be calculated that the limit for feasible cell salvage at present is an infant of 6 months. All three devices are suitable for the processing of small volumes, but have the scope for further optimization. PMID- 24953125 TI - Pharmacoeconomics in the years of crisis: a solution or just a resolution? A Cyprus perspective. AB - Cyprus is one of the latest countries to apply for a bailout with Troika. Major reforms applied and health sector was massively restructured. Cyprus is currently the single EU country without a Health System and health care spending is primarily driven by out-of-pocket payment. Pharmaceutical sector is divided into private and public sector, which are fragmented and are highly heterogeneously regulated. Although there is a need to introduce economic evaluations for pharmaceuticals, current adverse and unstable economic environment, along with some attributes of the country are not good prognostic factors. We suggest that some forms of economic evaluations could be introduced selectively during recession. Unification of health sector in the form of a National System would enable full scale introduction of economic evaluations. PMID- 24953126 TI - Homology-based prediction of interactions between proteins using Averaged One Dependence Estimators. AB - BACKGROUND: Identification of protein-protein interactions (PPIs) is essential for a better understanding of biological processes, pathways and functions. However, experimental identification of the complete set of PPIs in a cell/organism ("an interactome") is still a difficult task. To circumvent limitations of current high-throughput experimental techniques, it is necessary to develop high-performance computational methods for predicting PPIs. RESULTS: In this article, we propose a new computational method to predict interaction between a given pair of protein sequences using features derived from known homologous PPIs. The proposed method is capable of predicting interaction between two proteins (of unknown structure) using Averaged One-Dependence Estimators (AODE) and three features calculated for the protein pair: (a) sequence similarities to a known interacting protein pair (FSeq), (b) statistical propensities of domain pairs observed in interacting proteins (FDom) and (c) a sum of edge weights along the shortest path between homologous proteins in a PPI network (FNet). Feature vectors were defined to lie in a half-space of the symmetrical high-dimensional feature space to make them independent of the protein order. The predictability of the method was assessed by a 10-fold cross validation on a recently created human PPI dataset with randomly sampled negative data, and the best model achieved an Area Under the Curve of 0.79 (pAUC0.5% = 0.16). In addition, the AODE trained on all three features (named PSOPIA) showed better prediction performance on a separate independent data set than a recently reported homology-based method. CONCLUSIONS: Our results suggest that FNet, a feature representing proximity in a known PPI network between two proteins that are homologous to a target protein pair, contributes to the prediction of whether the target proteins interact or not. PSOPIA will help identify novel PPIs and estimate complete PPI networks. The method proposed in this article is freely available on the web at http://mizuguchilab.org/PSOPIA. PMID- 24953127 TI - Ferrocene analogues of sandwich M(CrB6H6)2: a theoretical investigation. AB - The stability and electronic structures of the new sandwich compounds M(CrB6H6)2 (M = Cr, Mn(+), Fe(2+)) are investigated by density functional theory. All the investigated sandwich complexes are in D(6d) symmetry and all of them are thermodynamically stable according to the large HOMO-LUMO gap, binding energy, vertical ionization potential and vertical electron affinity analyses, as well as Fe(C5H5)2 and Cr(C6H6)2, following the 18-electron principle. The natural bond orbital, detailed molecular orbitals and adaptive natural density partitioning analyses suggest that the spd-pi interaction plays an important role in the sandwich compounds. This work challenges the traditional chemical bonding of the inorganic metal compound, investigates first the bonding style of the d atom orbital interacting with the pi MO which was formed by p-d atomic orbitals, and indicates that the metal-doped borane ring can also be an ideal type pi-electron donor ligand to stabilize the transition metal. PMID- 24953128 TI - Au@Ag/Au nanoparticles assembled with activatable aptamer probes as smart "nano doctors" for image-guided cancer thermotherapy. AB - Although nanomaterial-based theranostics have increased positive expectations from cancer treatment, it remains challenging to develop in vivo "nano-doctors" that provide high-contrast image-guided site-specific therapy. Here we designed an activatable theranostic nanoprobe (ATNP) via self-assembly of activatable aptamer probes (AAPs) on Au@Ag/Au nanoparticles (NPs). As both quenchers and heaters, novel Au@Ag/Au NPs were prepared, showing excellent fluorescence quenching and more effective near-infrared photothermal therapy than Au nanorods. The AAP comprised a thiolated aptamer and a fluorophore-labeled complementary DNA; thus, the ATNP with quenched fluorescence in the free state could realize signal activation through target binding-induced conformational change of the AAP, and then achieve on-demand treatment under image-guided irradiation. By using S6 aptamer as the model, in vitro and in vivo studies of A549 lung cancer verified that the ATNP greatly improved imaging contrast and specific destruction, suggesting a robust and versatile theranostic strategy for personalized medicine in future. PMID- 24953130 TI - Genomic regions repeatedly involved in divergence among plant-specialized pea aphid biotypes. AB - Understanding the genetic bases of biological diversification is a long-standing goal in evolutionary biology. Here, we investigate whether replicated cases of adaptive divergence involve the same genomic regions in the pea aphid, Acyrthosiphon pisum, a large complex of genetically differentiated biotypes, each specialized on different species of legumes. A previous study identified genomic regions putatively involved in host-plant adaptation and/or reproductive isolation by performing a hierarchical genome scan in three biotypes. This led to the identification of 11 F(ST) outliers among 390 polymorphic microsatellite markers. In this study, the outlier status of these 11 loci was assessed in eight biotypes specialized on other host plants. Four of the 11 previously identified outliers showed greater genetic differentiation among these additional biotypes than expected under the null hypothesis of neutral evolution (alpha < 0.01). Whether these hotspots of genomic divergence result from adaptive events, intrinsic barriers or reduced recombination is discussed. PMID- 24953129 TI - Mechanistic insights into the oxidation of substituted phenols via hydrogen atom abstraction by a cupric-superoxo complex. AB - To obtain mechanistic insights into the inherent reactivity patterns for copper(I)-O2 adducts, a new cupric-superoxo complex [(DMM-tmpa)Cu(II)(O2(*-))](+) (2) [DMM-tmpa = tris((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amine] has been synthesized and studied in phenol oxidation-oxygenation reactions. Compound 2 is characterized by UV-vis, resonance Raman, and EPR spectroscopies. Its reactions with a series of para-substituted 2,6-di-tert-butylphenols (p-X-DTBPs) afford 2,6 di-tert-butyl-1,4-benzoquinone (DTBQ) in up to 50% yields. Significant deuterium kinetic isotope effects and a positive correlation of second-order rate constants (k2) compared to rate constants for p-X-DTBPs plus cumylperoxyl radical reactions indicate a mechanism that involves rate-limiting hydrogen atom transfer (HAT). A weak correlation of (k(B)T/e) ln k2 versus E(ox) of p-X-DTBP indicates that the HAT reactions proceed via a partial transfer of charge rather than a complete transfer of charge in the electron transfer/proton transfer pathway. Product analyses, (18)O-labeling experiments, and separate reactivity employing the 2,4,6 tri-tert-butylphenoxyl radical provide further mechanistic insights. After initial HAT, a second molar equiv of 2 couples to the phenoxyl radical initially formed, giving a Cu(II)-OO-(ArO') intermediate, which proceeds in the case of p OR-DTBP substrates via a two-electron oxidation reaction involving hydrolysis steps which liberate H2O2 and the corresponding alcohol. By contrast, four electron oxygenation (O-O cleavage) mainly occurs for p-R-DTBP which gives (18)O labeled DTBQ and elimination of the R group. PMID- 24953131 TI - Genetic factors influencing inhibitor development in a cohort of South African haemophilia A patients. AB - A critical complication of factor VIII (FVIII) replacement therapy in Haemophilia A (HA) treatment is inhibitor development. Known genetic factors predisposing to inhibitor development include FVIII (F8) gene mutations, ethnicity, a family history of inhibitors and FVIII haplotype mismatch. The aim of this study was to characterize and correlate these genetic factors in a cohort of South African HA patients. This was a retrospective study that included 229 patients and involved the analysis of patient files, HA molecular and clinical databases and molecular analysis of the F8 gene haplotype. Of the 229 patients, 51% were of black ethnicity, 49% were white, 5% had mild HA, 4% were moderate and 91% were severe, 36% were int22 positive and 13% were inhibitor positive. Of the inhibitor positive patients, 72% were black patients. Inhibitors were reported in 27% of black int22 positive patients, 13% of black int22 negative patients, 9% of white int22 positive patients and 7% of white int22 negative. The H1 haplotype was more common in whites (75%) and H2 was more common in blacks (74%). H3 and H5 were only found in black patients and had a higher frequency of inhibitor development than H1 and H2. In this small HA cohort, black patients had a significantly higher frequency of inhibitor development and the results were indicative of an association between inhibitor development, ethnicity and haplotype. PMID- 24953132 TI - MIT Food Technology: the major driver for food technology for 50 years. PMID- 24953133 TI - Reliable reference gene selection for Cordyceps militaris gene expression studies under different developmental stages and media. AB - Cordyceps militaris is considered a model organism for the study of Cordyceps species, which are highly prized in traditional Chinese medicine. Gene expression analysis has become more popular and important in studies of this fungus. Reference gene validation under different experimental conditions is crucial for RT-qPCR analysis. In this study, eight candidate reference genes, actin, cox5, gpd, rpb1, tef1, try, tub, and ubi, were selected and their expression stability was evaluated in C. militaris samples using four algorithms, genorm, normfinder, bestkeeper, and the comparative ?Ct method. Three sets of samples, five different developmental stages cultured in wheat medium and pupae, and all the samples pool were included. The results showed that rpb1 was the best reference gene during all developmental stages examined, while the most common reference genes, actin and tub, were not suitable internal controls. Cox5 also performed poorly and was less stable in our analysis. The ranks of ubi and gpd were inconsistent in different sample sets by different methods. Our results provide guidelines for reference gene selection at different developmental stages and also represent a foundation for more accurate and widespread use of RT-qPCR in C. militaris gene expression analysis. PMID- 24953134 TI - Prevalence and associated factors of tinnitus: data from the Korean National Health and Nutrition Examination Survey 2009-2011. AB - BACKGROUND: Tinnitus is a common condition and frequently can be annoying to affected individuals. We investigated the prevalence and associated factors for tinnitus in South Korea using the data from the Korea National Health and Nutrition Examination Surveys (KNHANES) during 2009-2011. METHODS: KNHANES is a cross-sectional survey of the civilian, non-institutionalized population of South Korea (n = 21 893). A field survey team that included an otolaryngologist moved with a mobile examination unit and performed interviews and physical examinations. RESULTS: Among the population over 12 years of age, the prevalence of any tinnitus was 19.7% (95% CI 18.8%-20.6%). Tinnitus was more prevalent in women, and the prevalence rate increased with age (P < 0.001). Among those with any tinnitus, 29.3% (95% CI 27.3%-31.3%) experienced annoying tinnitus that affected daily life. Annoying tinnitus also increased with age (P < 0.001), but no sex difference was demonstrated (P = 0.25). In participants aged 40 years or older, age, quality of life, depressive mood, hearing loss, feeling of dizziness, and rhinitis were associated with any tinnitus (P < 0.05). Age, hearing loss, history of cardiovascular disease, and stress were associated with annoying tinnitus (P < 0.05). CONCLUSIONS: Tinnitus is a common condition, and a large population suffers from annoying tinnitus in South Korea. Public understanding of associated factors might contribute to better management of tinnitus. PMID- 24953135 TI - Involvement of calpain-7 in epidermal growth factor receptor degradation via the endosomal sorting pathway. AB - Calpain-7 (CAPN7) is a unique intracellular cysteine protease that has a tandem repeat of microtubule interacting and trafficking (MIT) domains and lacks a penta EF-hand domain. Although the MIT domains of CAPN7 were previously shown to interact with a subset of endosomal sorting complex required for transport (ESCRT)-III and ESCRT-III-related proteins, including charged multivesicular body protein 1 and increased sodium tolerance (IST)1, knowledge of the involvement of the protease in membrane trafficking has been limited. In the present study, compared with control cells, we found that epidermal growth factor receptor (EGFR) degradation was mildly delayed in CAPN7-knockdown HeLa cells and mouse embryonic fibroblast cells established from CAPN7 knockout (Capn7(-/-) ) mice. Re expression of wild-type CAPN7 but not a protease-inactive mutant of CAPN7 (CAPN7(C290S) ) resulted in a recovery of the rate of EGFR degradation. We found, by immunofluorescence microscopic analysis, that monomeric GFP fused with the protease-inactive mutant of CAPN7 [monomeric green fluorescent protein (mGFP) CAPN7(C290S) ] was mobilized to EGFR-positive endosomes upon epidermal growth factor stimulation in HeLa cells. Although mGFP-CAPN7(C290S) exhibited dominant negative effects on EGFR degradation, a deletion mutant of MIT domains in mGFP CAPN7(C290S) did not have such properties, suggesting that the interaction between the MIT domains and ESCRT proteins is important for the function of CAPN7. Moreover, we found that epidermal growth factor stimulation induces translocation of IST1 from the cytosol to endosomes positive in both EGFR and mGFP-CAPN7(C290S) . When IST1 was knocked down, mGFP-CAPN7(C290S) lost its co localization with EGFR. These results demonstrate for the first time that the proteolytic activity of CAPN7 is important for the acceleration of EGFR degradation via the endosomal sorting pathway utilizing a part of the ESCRT system. STRUCTURED DIGITAL ABSTRACT: EGFR and CAPN7 colocalize by fluorescence microscopy (View interaction) EGFR, CAPN7 and IST1 colocalize by fluorescence microscopy (View interaction) EEA1 and CAPN7 colocalize by fluorescence microscopy (View interaction) CAPN7 and LAMP1 colocalize by fluorescence microscopy (View interaction). PMID- 24953138 TI - Extreme strain rate and temperature dependence of the mechanical properties of nano silicon nitride thin layers in a basal plane under tension: a molecular dynamics study. AB - Molecular dynamics simulations are performed to clarify the extreme strain rate and temperature dependence of the mechanical behaviors of nano silicon nitride thin layers in a basal plane under tension. It is found that fracture stresses show almost no change with increasing strain rate. However, fracture strains decrease gradually due to the appearance of additional N(2c)-Si bond breaking defects in the deformation process. With increasing loading temperature, there is a noticeable drop in fracture stress and fracture strain. In the low temperature range, roughness phases can be observed owing to a combination of factors such as configuration evolution and energy change. PMID- 24953136 TI - Differential requirement of GRP94 and GRP78 in mammary gland development. AB - Glucose Regulated Protein (GRP) 94 and GRP78 are critical molecular chaperones and regulators of signaling. Conditional knockout mouse models have revealed tissue specific requirements for GRP94 and GRP78, including selection for allele retention in specific cell types. Here we report the consequences of mammary targeted knockout of these GRPs. Our studies revealed that MMTV-Cre, Grp94(f/f) mammary glands, despite GRP94 deficiency, exhibited normal proliferation and ductal morphogenesis. Interestingly, MMTV-Cre, Grp78(f/f) mammary glands displayed only slightly reduced GRP78 protein levels, associating with the retention of the non-recombined Grp78 floxed alleles in isolated mammary epithelial cells and displayed phenotypes comparable to wild-type glands. In contrast, transduction of isolated Grp78(f/f) mammary epithelial stem/progenitor cells with adenovirus expressing GFP and Cre-recombinase was successful in GRP78 ablation, and the GFP sorted cells failed to give rise to repopulated mammary glands in de-epithelialized recipient mice. These studies imply GRP78, but not GRP94, is required for mammary gland development. PMID- 24953139 TI - Alzheimer's Disease Disrupts Rich Club Organization in Brain Connectivity Networks. AB - Diffusion imaging and brain connectivity analyses can monitor white matter deterioration, revealing how neural pathways break down in aging and Alzheimer's disease (AD). Here we tested how AD disrupts the 'rich club' effect - a network property found in the normal brain - where high-degree nodes in the connectivity network are more heavily interconnected with each other than expected by chance. We analyzed 3-Tesla whole-brain diffusionweighted images (DWI) from 66 subjects (22 AD/44 normal elderly). We performed whole-brain tractography based on the orientation distribution functions. Connectivity matrices were compiled, representing the proportion of detected fibers interconnecting 68 cortical regions. As expected, AD patients had a lower nodal degree (average number of connections) in cortical regions implicated in the disease. Unexpectedly, the normalized rich club coefficient was higher in AD. AD disrupts cortical networks by removing connections; when these networks are thresholded, organizational properties are disrupted leading to additional new biomarkers of AD. PMID- 24953137 TI - AmiA is a penicillin target enzyme with dual activity in the intracellular pathogen Chlamydia pneumoniae. AB - Intracellular Chlamydiaceae do not need to resist osmotic challenges and a functional cell wall was not detected in these pathogens. Nevertheless, a recent study revealed evidence for circular peptidoglycan-like structures in Chlamydiaceae and penicillin inhibits cytokinesis, a phenomenon known as the chlamydial anomaly. Here, by characterizing a cell wall precursor-processing enzyme, we provide insights into the mechanisms underlying this mystery. We show that AmiA from Chlamydia pneumoniae separates daughter cells in an Escherichia coli amidase mutant. Contrary to homologues from free-living bacteria, chlamydial AmiA uses lipid II as a substrate and has dual activity, acting as an amidase and a carboxypeptidase. The latter function is penicillin sensitive and assigned to a penicillin-binding protein motif. Consistent with the lack of a regulatory domain in AmiA, chlamydial CPn0902, annotated as NlpD, is a carboxypeptidase, rather than an amidase activator, which is the case for E. coli NlpD. Functional conservation of AmiA implicates a role in cytokinesis and host response modulation. PMID- 24953140 TI - Development and validation of Neonatal Satisfaction Survey--NSS-13. AB - AIMS: The purpose of this study was to develop and validate a survey to investigate parents' satisfaction with neonatal wards in a population of parents of children with a gestation age of >=24 weeks to 3 months after full-term birth. METHOD: We explored the literature and conducted three focus groups: two with expert health personnel and one with parents. We tested the survey in a parent population (N = 105) and report the different stages in the validation process along with the full survey, the Neonatal Satisfaction Survey - 13 categories (NSS 13). RESULTS: We found 13 subcategories in the Neonatal Satisfaction Survey. The subcategories measure parents' satisfaction with neonatal units based on staff, admission, nurses, anxiety, siblings (parents' perceptions of caring for the siblings of the newborn), information, timeout, doctors, facilities, nutrition, preparation for discharge, trust and visitors. Each subcategory showed acceptable internal consistency. The full version of the Neonatal Satisfaction Survey presents 69 items, and each subcategory contains two to eleven items. CONCLUSION: The Neonatal Satisfaction Survey seems suitable to measure parents' satisfaction with neonatal units and can be used in full, but it can also measure subcategories. Parents' satisfaction with neonatal units can be used to improve the quality in such wards. We consider this study as the first in a series to validate the NSS-13. The full survey with subcategories is presented in this paper. PMID- 24953141 TI - Newborn health on the line: the potential mHealth applications. PMID- 24953142 TI - Segmental and suprasegmental features in speech perception in Cantonese-speaking second graders: an ERP study. AB - Using a multiple-deviant oddball paradigm, this study examined second graders' brain responses to Cantonese speech. We aimed to address the question of whether a change in a consonant or lexical tone could be automatically detected by children. We measured auditory mismatch responses to place of articulation and voice onset time (VOT), reflecting segmental perception, as well as Cantonese lexical tones including level tone and contour tone, reflecting suprasegmental perception. The data showed that robust mismatch negativities (MMNs) were elicited by all deviants in the time window of 300-500 ms in second graders. Moreover, relative to the standard stimuli, the VOT deviant elicited a robust positive mismatch response, and the level tone deviant elicited a significant MMN in the time window of 150-300 ms. The findings suggest that Hong Kong second graders were sensitive to neural discriminations of speech sounds both at the segmental and suprasegmental levels. PMID- 24953144 TI - [Metabolic syndrome and cardiovascular risk patients under antiretrovirals in a day hospital at Bobo-Dioulasso (Burkina Faso)]. AB - Highly active antiretroviral therapy (HAART) has reduced morbidity and mortality of HIV but has led to an increasing metabolic cardiovascular risk. A cross sectional study was conducted from May to September 2011 in Day Care Hospital for HIV-Patients of Bobo-Dioulasso. We included in this study 400 patients infected by HIVon antiretroviral therapy >= 6 months selected by a random draw. Metabolic syndrome was assessed according to the definitions of the IDF and ATP-III. The high risk of cardiovascular disease in 10 years was defined by a Framingham score >= 20%. The average age of our patients was 41.4 years [20-76]. 17% received an IP. The average duration of PI exposure was 35.5 months and 50.1 months for NNRTI. The prevalence of diabetes was 1.3% (95% CI: 0.5-3) and that of hypertension of 12.0 % (95% CI: 9.3-16). The prevalence of metabolic syndrome according to IDF was 10% (95% CI: 7.3-13.5) and the metabolic syndrome according to ATP-III 12.3% (95% CI: 9.3-16). The body mass index was higher (BMI 25.2 vs. 22.5 kg/m(2), p <10(-3) with ATPIII and BMI 26.6 vs. 22.4 kg/m(2), p <10(-3) with IDF), and duration exposure to ARVs longer in patients with metabolic syndrome regardless of the definition used (58.6 months vs 27.9 months). High cardiovascular risk was present in 1.8% (95% CI: 0.8 to 3.7) of our patients, all male more than half (n=4/7) of them were smoking. The choice of antiretroviral therapy must take into account its potential long-term toxicity. It should also strengthen supervision. PMID- 24953145 TI - Spirituality, culture and health in management. PMID- 24953143 TI - Habitual nutrient intake in HIV-infected youth and associations with HIV-related factors. AB - Few studies have evaluated habitual nutrient intake among HIV-infected youth in the United States, even though diet may influence disease progression and risk of comorbidities. This study determined habitual micronutrient and macronutrient intake in HIV-infected youth. HIV-infected subjects and healthy controls 1-25 years old were prospectively enrolled. Nutrient intake was assessed via 24-h dietary recalls performed every 3 months for 1 year and compared to recommended intake from the U.S. Dietary Reference Intakes (DRIs) and Acceptable Macronutrient Distribution Ranges (AMDRs). Subjects with two or more food recalls were analyzed (175 HIV(+) and 43 healthy controls). Groups were similar in age, race, sex, body mass index, and kilocalorie intake. In both groups, intake of several micronutrients was below the DRI. In addition, HIV(+) subjects had a lower percentage DRI than controls for vitamins A, D, E, pantothenic acid, magnesium, calcium, folate, and potassium. HIV(+) subjects' percentage caloric intake from fat was above the AMDR and was higher than controls. Caloric intake was negatively correlated with current and nadir CD4 count. Zinc, riboflavin, and magnesium percentage DRI were positively associated with current CD4 count. In HIV(+) subjects not on antiretroviral therapy, HIV-1 RNA levels were negatively correlated with protein intake. HIV(+) youth have an inadequate dietary intake of several essential nutrients and poorer dietary intake compared to controls. Intake of some nutrients was associated with important HIV-related factors. Further investigation is warranted to determine the impact of dietary intake of specific nutrients on HIV progression and chronic complication risk in this population. PMID- 24953146 TI - 'I still believe...' Reconstructing spirituality, culture and mental health across cultural divides. AB - Whilst striving to create a balanced and healthy life, individuals experience challenges across their life span. Spirituality can contribute to mental health and well-being, as can cultural constructs. In South Africa, apartheid categories are still vivid, which affect spiritual, cultural and racial mental constructs and impact on the mental health of individuals across cultural groups. This article focuses on the long-term development of spiritual and cultural concepts within a selected individual in Cape Town, South Africa, during 11 years of field work. It also explores the impact of spirituality and culture on the researcher researched relationship. A mixed-method approach was used, including various qualitative methods of data collection as well as content analysis to analyse the data and intersubjective validation to interpret them. Findings show a strong intrapersonal interlinkage of spirituality, culture and mental health and the researcher-researched relationship having a strong impact on spiritual, cultural and mental health constructions. We are not human beings having a spiritual experience. We are spiritual beings having a human experience. (Pierre Teilhard de Chardin, 1976). PMID- 24953147 TI - The role of spirituality in coping with the demands of the hospital culture amongst fourth-year nursing students. AB - The aim of this research was to describe the role of spirituality in coping with the demands of the hospital culture amongst fourth-year nursing students. Qualitative, descriptive, hermeneutic interpretive research was done. A case study of 14 female Canadian nursing students was asked to write an essay on their experiences of the demands of the hospital culture. Content analysis was used and positive psychology served as the interpretive lens. Trustworthiness and ethicality were ensured. The findings indicated that although the nursing students expressed themselves in religious and spiritual words, they did not significantly illustrate the theoretically associated intra-, interpersonal and sacred behaviours to be referred to as being spiritual in their experience as a care giver in the hospital culture. They also did not illustrate behaviours linked to other positive psychology constructs such as sense of coherence, resilience, engagement or emotional intelligence. Rather, the nursing students experienced identity crises. Recommendations for the inclusion of mentoring in the curriculum of nursing students were formulated. PMID- 24953148 TI - Acknowledging others as 'whole beings'. Managers' perceptions of spirituality and health in the South African workplace. AB - This article explores the concept of spirituality within selected South African managerial work contexts. The aim of the study was to determine managers' perceptions of spirituality and health-related aspects in various South African workplaces. A phenomenological research paradigm was used, applying an in-depth qualitative research approach. The sample consisted of 12 senior managers from different organizations, including, for example, an international healthcare provider, an international auditing and consulting firm, a manufacturer of paint supplies and decorations and an ecclesiastical organization. Research methods included semi-structured interviews and observation. Data was analysed through content analysis, identifying themes, categories and codes. The findings indicate that spirituality promotes the development of health-related aspects of individuals, such as self-awareness, inner peace and the management of stress and depression. Managers emphasize that spirituality also has an impact on managing teams and teamwork, engaging in competitive behaviour, encouraging honesty and reducing selfishness. Based on the findings, a conclusion is given and practical as well as scientific recommendations are emphasized. In love lies the seed of our growth. The more we love, the closer we are to the spiritual experience. (Paulo Coelho, 1994). PMID- 24953149 TI - 'Following the word of God': Empirical insights into managerial perceptions on spirituality, culture and health. AB - This article focuses on managers in a selected South African organization and the connections they draw between mental health, culture and spirituality within the workplace. The aim is to gain a deeper understanding of the interrelationships in this complex and growing scientific discourse and to respond to the research question of how mental health, culture and spirituality are interrelated from a managerial perspective. The study follows an inductive single case study approach within the phenomenological paradigm. Qualitative research methods using in-depth interviews and observation were used. The sample comprised 27 managers within the international South African automotive organization. The findings show that not only culture, but also spirituality and religion in particular, influence mental health and well-being of managers at work. Conclusions are drawn and recommendations made. PMID- 24953150 TI - 'And the pain just disappeared into insignificance': The healing response in Lourdes - Performance, psychology and caring. AB - Three academic/practitioners from different disciplines (performance, medicine and psychology) describe the ways in which observing, and importantly, participating in the healing rituals of the French pilgrimage site of Lourdes challenged their ways of thinking about both their discipline's research approaches and their understandings of community, caring and healing. By positioning themselves as both first-person and third-person researchers, they suggest that a new type of 'trans-disciplinary', longitudinal, reflexively sensitive methodology is needed in order to investigate activities involving groups of people and spiritual practices as a whole system in order to better understand how they can positively affect our innate healing response. PMID- 24953151 TI - Extraordinary experiences in its cultural and theoretical context. AB - The growing complexity, opaqueness and specialization of many areas of life and - above all - a booming psychological and esoteric market create the necessity for counselling and advice for individuals who encounter so-called 'paranormal' experiences. These experiences are often interpreted as 'transpersonal' or 'spiritual', depending on the cultural background and religious traditions. The term 'spiritual crisis' has become a fashionable diagnosis with some transpersonal psychotherapists. Paranormal experiences, regardless of their acceptance of academic psychology and psychiatry, are still a taboo subject in society. The Parapsychological Counselling Office in Freiburg is a professional unit with governmental support, which helps individuals to cope with such experiences adequately. The work and responsibilities of the counselling centre are presented. A large collection of cases in the form of letters, which were sent in by individuals wanting to communicate their unusual or extraordinary experiences have been analysed. Some of the results are reported here. Finally, we discuss a special form of 'inexplicable experiences' based on a theoretical model. Its recommendations seem counter-intuitive but are ultimately successful. The model starts from a system-theoretical viewpoint and uses concepts such as complementarity and entanglement of generalized quantum theory (GQT) and the model of pragmatic information (MPI). Since it turned out that individuals who contact the counselling centre also offer their own interpretations and 'explanation', the question arises, how these resources can be used to help clients. PMID- 24953152 TI - Religious and cultural aspects of psychotherapy in Muslim patients from tradition oriented societies. AB - Patients from collective cultures with a tradition-bound Islamic cultural background (e.g. people from the Middle East and some Far-East countries such Pakistan and Indonesia), have a different perception of disease and different conceptions of healing, which up till now have not been sufficiently appreciated in modern multimodal therapeutic approaches and health management. Taking patients' value systems into consideration in a culture-sensitive way, with reference to their notions of magic, healing ceremonies and religious rituals and especially patterns of relations and experience in the treatment of psychological diseases in medical psychotherapeutic work, with due regard to scientific psychotherapeutic standards, can be used as an intercultural resource and lead to establishing partnership-like relationships between patients and therapists. PMID- 24953153 TI - Workplace spirituality as a moderator in relation between stress and health: An exploratory empirical assessment. AB - The present study explores the role of workplace spirituality in moderating the relationship between occupational stress and the health of managerial personnel in India. A sample of 150 managers working in different public and private organizations was used to measure workplace spirituality, occupational stress, and health using the Spirituality at Work scale, the Occupational Stress Index and the 28-item General Health Questionnaire, respectively. The findings reveal that workplace spirituality moderates the negative relationship of stress and health. The study also found that stress has a negative impact on health while workplace spirituality positively correlated with health. The findings also support the practical importance of spirituality in the workplace for improving health conditions by providing a healthy atmosphere and meaningful work for employees. This exploratory study encourages future research to understand the role of spirituality in the workplace. PMID- 24953154 TI - Investigating the interlinkages of alcohol use and misuse, spirituality and culture - Insights from a systematic review. AB - Religious values are part of cultures, but spirituality is an internal dimension which may be present in varying degrees across all nations. As both cultural and spiritual factors are important in determining the pattern of alcohol consumption by individuals, it is important to study the relationships between them. The present systematic review aims to summarize the knowledge on the relationship between alcohol use and misuse, religiousness/spirituality and culture drawn from medical studies. Data from the medical literature to date indicate that for some racial and ethnic minorities a return to the traditional culture linked with concepts of spiritual or religious factors can produce a major degree of support for people trying to maintain abstinence from alcohol. This can be seen even in the worst environments. On the other hand, among the general population, religion and/or spirituality can play a positive role in the maintenance of abstinence, but a local heavy drinking culture is a strong risk factor for relapse. These factors are important and can be used for interventions and prevention strategies. However, possible mediating effects need to be explored further. It is likely that both types of intervention (classical medical treatment plus spiritual-based treatment) may work in individuals. PMID- 24953155 TI - Measuring spirituality in South Africa: Validation of instruments developed in the USA. AB - Spirituality is receiving increased attention in the context of the workplace. Research consistently shows that spirituality is significantly correlated with mental health and well-being. Most of the research on spirituality, particularly in the context of the workplace, is conducted with instruments developed in the USA. However, the inter-cultural measurement of constructs remains a concern, because instruments developed in one culture are not necessarily transferable to another culture. In the current study, the transferability of two spiritual measures developed in the USA, namely the Human Spirituality Scale (HSS) and the Organizational Spirituality Values Scale (OSVS) are considered for a sample from South Africa. The results confirm the construct validity of the HSS and the OSVS, but indicate that the factor structures of the HSS and the OSVS should be analysed and reconfirmed when used, particularly in a South African sample. The study provides evidence that the HSS and the OSVS cannot be transferred indiscriminately to a South African sample. This insight contributes to the quality of future research studies in South Africa, not only on the important aspect of spirituality, but also when applying instruments developed elsewhere in the world. PMID- 24953156 TI - Workplace spirituality and job satisfaction. AB - In order to obtain an improved understanding of behaviour at work, employees should be studied from physical, psychological, and spiritual dimensions. Although the physical and psychological dimensions of individuals at work have been studied extensively, the spiritual dimension has been neglected for many years. The objective of the current research was to determine the relationship between workplace spirituality and a positive attitude related to work, that is, job satisfaction. A cross-sectional study was conducted with a sample of 600 white-collar workers, chosen from two organizations in different industries in South Africa. The research results indicate that there is a positive relationship between workplace spirituality and job satisfaction. These findings deepen the understanding of personal spirituality, organizational spirituality, and job satisfaction. They bring new insights into the significant role which spirituality plays in the context of the workplace. To survive in the 21st century, organizations need to be spiritually based. This, in turn, will lead to workers being satisfied with their entire work experience. PMID- 24953157 TI - Bordetella pertussis and pertactin-deficient clinical isolates: lessons for pertussis vaccines. AB - Bordetella pertussis causes whooping cough in humans, a highly transmissible respiratory disease life threatening for unvaccinated infants. Vaccination strategies were thus introduced worldwide with great success in developed countries reaching high vaccine coverage with efficacious vaccines. In the late 20th/early 21st century, acellular pertussis vaccines replaced whole cell pertussis vaccines but B. pertussis still circulates and evolves in humans, its only known reservoir. The latest transformation of this pathogen, and of its close relative Bordetella parapertussis, is the loss of pertactin production, a virulence factor included in different acellular pertussis vaccines. The real impact of this evolution on acellular pertussis vaccines efficacy and effectiveness should be assessed through standardized surveillance and isolation of B. pertussis and B. parapertussis worldwide. PMID- 24953158 TI - Caveolins redistribute in uterine epithelial cells during early pregnancy in the rat: an epithelial polarisation strategy? AB - At the time of implantation, uterine luminal epithelial cells undergo a dramatic change in all plasma membrane domains. Changes in the basolateral plasma membrane at the time of implantation include progression from smooth to highly tortuous, as well as a loss of integrin-based focal adhesions. Another aspect of the basolateral plasma membrane that has not been studied in uterine epithelial cells are caveolae, which are omega-shaped invaginations of the plasma membrane known to be involved in endocytosis and contribute to membrane curvature. The current study investigated caveolin, a major protein of caveolae, to explore the possible roles that they play in the remodelling of the basolateral plasma membrane of uterine epithelial cells during early pregnancy in the rat. Morphological caveolae were found at the time of implantation and were significantly increased compared to day 1 of pregnancy. Caveolins 1 and 2 were found to shift to the basolateral plasma membrane of uterine epithelial cells at the time of implantation as well as when treated with progesterone alone, and in combination with oestrogen. A statistically significant increase in the amount of caveolin-1 and a decrease in caveolin-2 protein in uterine epithelial cells was observed at the time of implantation. Caveolin-1 also co-immunoprecipitated with integrin beta1 on day 1 of pregnancy, which is a protein that has been reported to be found in integrin-based focal adhesions at the basolateral membrane on day 1 of pregnancy. The localisation and expression of caveolin-1 at the time of implantation is consistent with the presence and increase of morphological caveolae seen at this time. The localisation and expression of caveolins 1 and 2 in luminal uterine epithelium at the time of implantation suggest a role in trafficking proteins and the maintenance of a polarised epithelium. PMID- 24953159 TI - Predicting patients with concurrent noncontiguous spinal epidural abscess lesions. AB - BACKGROUND CONTEXT: Spinal epidural abscess (SEA) is a serious condition that can lead to significant morbidity and mortality if not expeditiously diagnosed and appropriately treated. However, the nonspecific findings that accompany SEAs often make its diagnosis difficult. Concurrent noncontiguous SEAs are even more challenging to diagnose because whole-spine imaging is not routinely performed unless the patient demonstrates neurologic findings that are inconsistent with the identified lesion. Failure to recognize a separate SEA can subject patients to a second operation, continued sepsis, paralysis, or even death. PURPOSE: To formulate a set of clinical and laboratory predictors for identifying patients with concurrent noncontiguous SEAs. STUDY DESIGN: A retrospective, case-control study. PATIENT SAMPLE: Patients aged 18 years or older admitted to our institution during the study period who underwent entire spinal imaging and were diagnosed with one or more SEAs. OUTCOME MEASURES: The presence or absence of concurrent noncontiguous SEAs on magnetic resonance imaging or computed tomography (CT)-myelogram. METHODS: A retrospective review was performed on 233 adults with SEAs who presented to our health-care system from 1993 to 2011 and underwent entire spinal imaging. The clinical and radiographic features of patients with concurrent noncontiguous SEAs, defined as at least two lesions in different anatomical regions of the spine (ie, cervical, thoracic, or lumbar), were compared with those with a single SEA. Multivariate logistic regression identified independent predictors for the presence of a skip SEA, and a prediction algorithm based on these independent predictors was constructed. Institutional review board committee approval was obtained before initiating the study. RESULTS: Univariate and multivariate analyses comparing patients with skip SEA lesions (n=22) with those with single lesions (n=211) demonstrated significant differences in three factors: delay in presentation (defined as symptoms for >=7 days), a concomitant area of infection outside the spine and paraspinal region, and an erythrocyte sedimentation rate of >95 mm/h at presentation. The predicted probability for the presence of a skip lesion was 73% for patients possessing all three predictors, 13% for two, 2% for one, and 0% for zero predictors. Receiver operating characteristic curve analysis, used to evaluate the predictive accuracy of the model, revealed a steep shoulder with an area under the curve of 0.936 (p<.001). CONCLUSIONS: The proposed set of three predictors may be a useful tool in predicting the risk of a skip SEA lesion and, consequently, which patients would benefit from entire spinal imaging. PMID- 24953161 TI - Ethics and Rationing Access to Dialysis in Resource-Limited Settings: The Consequences of Refusing a Renal Transplant in the South African State Sector. AB - Resource constraints in developing countries compel policy makers to ration the provision of healthcare services. This article examines one such set of Guidelines: A patient dialysing in the state sector in South Africa may not refuse renal transplantation when a kidney becomes available. Refusal of transplantation can lead to exclusion from the state-funded dialysis programme. This Guideline is legally acceptable as related to Constitutional stipulations which allow for rationing healthcare resources in South Africa. Evaluating the ethical merit of the Guideline, and exploring the ethical dilemma it poses, proves a more complex task. We examine the actions of healthcare professionals as constrained by the Guideline. From a best interests framework, we argue that in these circumstances directing patient decision making (pressurising a patient to undergo renal transplantation) is not necessarily unethical or unacceptably paternalistic. We then scrutinise the guideline itself through several different ethical 'lenses'. Here, we argue that bioethics does not provide a definitive answer as to the moral merit of rationing dialysis under these circumstances, however it can be considered just in this context. We conclude by examining a potential pitfall of the Guideline: Unwilling transplant recipients may not comply with immunosuppressive medication, which raises questions for policies based on resource management and rationing. PMID- 24953160 TI - Effects of dimethyl sulfoxide on asymmetric division and cytokinesis in mouse oocytes. AB - BACKGROUND: Dimethyl sulfoxide (DMSO) is used extensively as a permeable cryoprotectant and is a common solvent utilized for several water-insoluble substances. DMSO has various biological and pharmacological activities; however, the effect of DMSO on mouse oocyte meiotic maturation remains unknown. RESULTS: In DMSO-treated oocytes, we observed abnormal MII oocytes that contained large polar bodies, including 2-cell-like MII oocytes, during in vitro maturation. Oocyte polarization did not occur, due to the absence of actin cap formation and spindle migration. These features are among the primary causes of abnormal symmetric division; however, analysis of the mRNA expression levels of genes related to asymmetric division revealed no significant difference in the expression of these factors between the 3% DMSO-treated group and the control group. After each "blastomere" of the 2-cell-like MII stage oocytes was injected by one sperm head respectively, the oocytes still possessed the ability to extrude the second polar body from each "blastomere" and to begin cleavage. However, MII oocytes with large polar bodies developed to the blastocyst stage after intracytoplasmic sperm injection (ICSI). Furthermore, other permeable cryoprotectants, such as ethylene glycol and glycerol, also caused asymmetric division failure. CONCLUSION: Permeable cryoprotectants, such as DMSO, ethylene glycol, and glycerol, affect asymmetric division. DMSO disrupts cytokinesis completion by inhibiting cortical reorganization and polarization. Oocytes that undergo symmetric division maintain the ability to begin cleavage after ICSI. PMID- 24953162 TI - Systematic review of placental pathology reported in association with stillbirth. AB - INTRODUCTION: Histopathological examination of the placenta is recommended to determine the cause of stillbirth. Although some reports find causal or contributory placental abnormalities in up to 60% of stillbirths, the significance of such findings in this clinical setting remains uncertain. A systematic review was conducted to i) investigate the likelihood of diagnosing a cause of stillbirth from placental examination and ii) to identify the specific causes of death that can be diagnosed from placental pathology. METHODS: Medline, Embase, Biosis, and Web of Science were searched using the terms "stillbirth", "histopathology", "pathology", and "placenta". Case-reports, narrative review articles and studies that failed to define diagnostic sub-groups were excluded. 473 potential studies were identified. Relevant studies (n = 41) were subdivided into those that investigated causes of stillbirth (n = 13), and those that identified conditions associated with stillbirth (n = 5). The contributory value of placental examination to stillbirth classification was evaluated in 10 studies and the role of specific placental abnormalities in the aetiology of stillbirth in 20 studies. RESULTS: The proportion of stillbirths attributed to a placental cause ranged from 11 to 65%. Classification systems which included multiple placental categories and allowed placental findings to supersede other disorders reported higher rates of placental causes and fewer unexplained stillbirths. Diagnoses were frequently based on qualitative, non-specific terminology. CONCLUSIONS: The utility of histopathological examination of the placenta is affected by the classification system used. International consensus is required for both diagnostic criteria and terminology to describe placental abnormalities and on classification of stillbirths.. PMID- 24953163 TI - The significance of elevated placental PHLDA2 in human growth restricted pregnancies. AB - In utero growth restriction is the failure of a fetus to achieve its genetic growth potential during gestation. Elevated expression of the maternally expressed imprinted gene PHLDA2, has been reported in the human placenta of growth restricted pregnancies. A mouse modelling this alteration has been generated and also displays fetal growth restriction suggesting that increased expression of PHLDA2 is not an effect but rather a cause of growth restriction in human pregnancies. Here we review the current data linking PHLDA2 to growth restriction and the data from human and animal model studies suggesting that placental PHLDA2 expression may be responsive to environmental stimuli such as maternal lifestyle. Further investigation is warranted in larger studies of human placentas with the aim of determining whether placental PHLDA2 expression could be used as a diagnostic tool to identify or sub-classify growth restricted infants and to inform more effective interventions and treatment for IUGR in the future. PMID- 24953164 TI - Extracellular ATP decreases trophoblast invasion, spiral artery remodeling and immune cells in the mesometrial triangle in pregnant rats. AB - INTRODUCTION: Preeclampsia is characterized by deficient trophoblast invasion and spiral artery remodeling, a process governed by inflammatory cells. High levels of the danger signal extracellular adenosine triphosphate (ATP) have been found in women with preeclampsia and infusion of ATP in pregnant rats induced preeclampsia-like symptoms such as albuminuria and placental ischemia. We hypothesized that ATP inhibits trophoblast invasion and spiral artery remodeling and affects macrophages and natural killer (NK) cells present in the rat mesometrial triangle. METHODS: Pregnant rats were infused with ATP or saline (control) on day 14 of pregnancy. Rats were sacrificed on day 15, 17 or 20 of pregnancy and placentas with mesometrial triangle were collected. Sections were stained for trophoblast cells, alpha-smooth muscle actin (spiral artery remodeling), NK cells and various macrophage populations. Expression of various cytokines in the mesometrial triangle was analyzed using real-time RT-PCR. RESULTS: ATP infusion decreased interstitial trophoblast invasion on day 17 and spiral artery remodeling on day 17 and 20, increased activated tartrate resistant acid phosphatase (TRAP)-positive macrophages on day 15, decreased NK cells on day 17 and 20, and decreased inducible nitric oxide synthase (iNOS)-positive and CD206-positive macrophages and TNF-alpha and IL-33 expression at the end of pregnancy (day 20). DISCUSSION: Interstitial trophoblast invasion and spiral artery remodeling in the rat mesometrial triangle were decreased by infusion of ATP. These ATP-induced modifications were preceded by an increase in activated TRAP-positive macrophages and coincided with NK cell numbers, suggesting that they are involved. CONCLUSION: Trophoblast invasion and spiral artery remodeling may be inhibited by ATP-induced activated macrophages and decreased NK cells in the mesometrial triangle in rat pregnancy. PMID- 24953165 TI - Medial sural artery perforator flap aided by preoperative computed tomography angiography mapping for tongue reconstruction. AB - The purpose of this paper is to present an innovative method for tongue reconstruction after cancer ablation using the medial sural artery perforator flap with the aid of preoperative computed tomography angiography (CTA) mapping. We describe the case of one patient treated with this technique and illustrate the anatomy of perforator vessels and the surgical techniques used in flap harvest. CTA was applied preoperatively to assess the number and location of medial sural artery perforators. The result obtained was both aesthetically and functionally satisfactory. The flap presented has the advantage of less donor site morbidity, and being thin, it is a suitable option for tongue reconstruction including that of a hemiglossectomy defect. CTA is an effective means of improving the safety of flap harvest. PMID- 24953166 TI - A prospective, single-centre study on patient outcomes following temporomandibular joint replacement using a custom-made Biomet TMJ prosthesis. AB - This study describes the clinical variables in 61 patients following total alloplastic temporomandibular joint reconstruction (TJR) in which the Biomet Microfixation Patient-Patient-Matched TMJ Implant was used. All patients were classified using the Wilkes classification. The visual analogue scale score for jaw pain intensity, the maximum inter-incisal opening (MIO), and the frequency of adverse events were recorded during follow-up; the mean follow-up was 14.2+/-8.6 months. Significant improvements were found in the MIO (P<0.0005), except at the 3-year follow-up. Additionally, a significant reduction in pain was observed both short and long term (P<0.0005). The incidence of adverse events was low (seven of the 81 alloplastic joints); two joints needed revision. TJR appears to be a relevant treatment option in patients with a broad range of temporomandibular joint disorders in whom none of the joint components are salvageable because of significant disease. Our patients gained an almost normal range of mouth opening and experienced a significant reduction in pain. Our results are promising, however TJR is associated with some side effects. TJR should be considered when less invasive procedures fail and a comprehensive presurgical work-up has been performed. Ongoing prospective studies are needed to consolidate the possible significant treatment outcomes. PMID- 24953167 TI - Postpartum changes in methadone maintenance dose. AB - The optimal approach to postpartum dosing among women treated with methadone maintenance is unclear. We examined doses among 101 methadone-maintained pregnant women 2, 6 and 12 weeks postpartum, and compared the incidence of having doses held for oversedation during pregnancy and postpartum. The average dose at delivery was 83.3mg, and the mean change from delivery to 12 weeks postpartum was -3.7 mg (95% CI -6.3, -1.1). The incidence of oversedation events per 10,000 days was 2.8 among pregnant women and 5.6 for postpartum women (incidence rate ratio [IRR] 2.04, 95% CI 0.66, 6.28). After adjusting for benzodiazepine prescriptions, the IRR of an oversedation event among postpartum women compared to pregnant women was 1.74 (95% CI 0.56, 5.30). In conclusion, postpartum dose changes were small in a methadone clinic using clinical assessments to determine dose. Although the incidence of oversedation events remained low postpartum, the clinically important but not statistically significant increase in events among postpartum women and those prescribed benzodiazepines requires further research. While there are not yet adequate data to support pre-specified postpartum dose reductions, the findings suggest that more frequent clinical assessments continuing as late as 12 weeks postpartum may be warranted. PMID- 24953170 TI - [Botulinum toxin in the management of spasticity in children]. AB - INTRODUCTION: Spasticity is a motor disorder, which can be treated by botulinum toxin (BT). We found no studies describing BT management of spasticity in Tunisian children. The aim of our study was to determine the frequency of spastic children treated with BT in the Tunisian hospital population and to evaluate treatment efficacy. METHODS: We conducted a prospective study over a 5-year period including all children diagnosed with spasticity treated with BT and attending the "Movement Disorders and Botulinum Toxin" outpatient clinic of the National Institute of Neurology of Tunis. RESULTS: Hundred and fifteen patients were included (31% of patients attending the "Movement Disorders and Botulinum Toxin" outpatient clinic). Mean age was 7.6years and M:F sex ratio 1.7. Main clinical features were: spastic quadriplegia (48%), equinus deformity (70.4%) and cerebral palsy (88%). All patients were evaluated with the modified Ashworth score and were treated with BT. Other treatments were associated with BT: baclofene, physiotherapy, ortheses, plaster, and sometimes surgical treatment. The average percentage of improvement after BT was>50%. The Ashworth score was significantly lower for the majority of injected muscles. DISCUSSION AND CONCLUSION: Our study is the first to describe BT management of spasticity in Tunisian children. Treatments of spasticity are numerous and vary according to location and extent of spasticity. BT is the main treatment for focal spasticity. Associated with physical therapy, BT allows optimal management of spastic children. PMID- 24953169 TI - Label-free, in situ SERS monitoring of individual DNA hybridization in microfluidics. AB - We present label-free, in situ monitoring of individual DNA hybridization in microfluidics. By immobilizing molecular sentinel probes on nanoporous gold disks, we demonstrate sensitivity approaching the single-molecule limit via surface-enhanced Raman scattering which provides robust signals without photobleaching for more than an hour. We further demonstrate that a target concentration as low as 20 pM can be detected within 10 min under diffusion limited transport. PMID- 24953168 TI - Emerging adult age status predicts poor buprenorphine treatment retention. AB - Emerging adults (18-25 years old) are often poorly retained in substance use disorder treatment. Office-based buprenorphine often enhances treatment retention among people with opioid dependence. In this study, we examined the records of a collaborative care buprenorphine treatment program to compare the treatment retention rates of emerging adults versus older adults. Subjects were 294 adults, 71 (24%) aged 18-25, followed in treatment with buprenorphine, nurse care management, and an intensive outpatient program followed by weekly psychosocial treatment. Compared to older adults, emerging adults remained in treatment at a significantly lower rate at 3 months (56% versus 78%) and 12 months (17% versus 45%), and were significantly more likely to test positive for illicit opioids, relapse, or drop out of treatment. Further research into factors associated with buprenorphine treatment retention among emerging adults is needed to improve treatment and long-term outcomes in this group. PMID- 24953171 TI - [Epilepsy and reproductive health: Senegalese cohort]. AB - INTRODUCTION: Epilepsy is a public health problem in Senegal and Africa because of its severity and its social importance. It occurs at any age sparing no sex. It can influence sexual life and reciprocally. Our aims were to study the effects of antiepileptic drugs on the sexual lives of women with epilepsy, the influence of these drugs on pregnancy and breastfeeding. METHODS: We conducted a prospective study from 1st March to 31st August 2011 in the neurological department of the Fann-Dakar teaching hospital Senegal. Only women with epilepsy were included. RESULTS: We collected 120 patients aged 16-64years with a mean age of 30.58years, 45% married, 44.16% were uneducated preponderant. All patients were taking antiepileptic drugs, 89.16% was alone. Fifty-five percent of our patients had epilepsy for at least 6years; 45.83% had generalized epilepsy; 44.17% of partial seizures. In our cohort, 64.16% were under phenobarbital, 69.16% had good adherence. As side effects of drugs, 90% had sexual problems. Seventy-five percent enjoyed an active sex life. A decrease in the number of sex per week for the disease [31/55=56.66%] was noted. In addition, 51.17% were using contraception, including 38.7% of oral kind and 64.86% had noticed an increase in seizure frequency during their pregnancies. Of the 74 women who had contracted a pregnancy, 41.89% had premature infants, 16.21% have made abortions and 61.17% had psychosocial life affected. DISCUSSION AND CONCLUSION: People with epilepsy often experience sexual problems that may be caused by epilepsy, antiepileptic and/or reactions of the partner and the other facing the diagnosis of epilepsy. PMID- 24953172 TI - [Economic evaluation of a program of coordination between levels for complex chronic patients' management]. AB - OBJECTIVE: The complex chronic patient program (CCP) of the Alt Penedes aims to improve the coordination of care. The objective was to evaluate the relationship between the costs associated with the program, and its results in the form of avoided admissions. DESIGN: Dost-effectiveness analysis from the perspective of the health System based on a before-after study. LOCATION: Alt Penedes. MAIN MEASUREMENTS: Health services utilisation (hospital [admissions, emergency visits, day-care hospital] and primary care visits). CCP Program results were compared with those prior to its implementation. The cost assigned to each resource corresponded to the hospital CatSalut's concert and ICS fees for primary care. A sensitivity analysis using boot strapping was performed. The intervention was considered cost-effective if the incremental cost-effectiveness ratio (ICER) did not exceed the cost of admission (? 1,742.01). RESULTS: 149 patients were included. Admissions dropped from 212 to 145. The ICER was ?1,416.3 (94,892.9?/67). Sensitivity analysis showed that in 95% of cases the cost might vary between ?70,847.3 and ?121,882.5 and avoided admissions between 30 and 102. In 72.4% of the simulations the program was cost-effective. CONCLUSIONS: Sensitivity analysis showed that in most situations the PCC Program would be cost effective, although in a percentage of cases the program could raise overall cost of care, despite always reducing the number of admissions. PMID- 24953173 TI - [Managerial autonomy in primary care: position of health professionals in Mallorca]. AB - OBJECTIVES: To assess the knowledge, perceptions, expectations and attitudes of Primary Care (PC) professionals in Mallorca on managerial autonomy. DESIGN: Cross sectional study based on an ad hoc, anonymous questionnaire, distributed online, from June-July 2013. LOCATION: PC Mallorca. PARTICIPANTS: PC healthcare professionals (n=1,097). MEASUREMENTS: Knowledge of self-management skills, requirements, and future scenarios of the centers with management autonomy (CMA); impact of self-management, commitment and willingness to take risks, and to become a CMA. RESULTS: Response rate: 49.8% (546/1097), with 10.9% showing a high level of knowledge of self-management. The core competencies of a CMA were internal organizational capacity (87.5%) and selection of staff (81.1%). The CMA future was envisaged with motivated and involved professionals (72.6%), efficient results (66%), better quality of care (59.4%), and better training (52.8%). The benefits of self-management were considered important, for individual practitioners and for the improvement of PC in Mallorca (46.8%). The main requirements of the CMA were to have: trained managers (92.6%), budget allocation systems (87.5%), and appropriate management contracts (86.1%). They preferred that the CMA should depend on the Administration (62.7%), and had a personal interest in becoming a CMA (56.9%), but without taking on excessive commitments (waiving statutory regime, financial risk). CONCLUSIONS: These data provide hitherto unknown information of great importance, which could contribute to a more rational planning and participatory implementation of CMA in our midst. PMID- 24953174 TI - [Differences in the survival after an episode of stroke treated with thrombolytic therapy. Study Ebrictus]. AB - OBJECTIVE: To seek if there is gender survival difference among patients treated with thrombolytic therapy. DESIGN: Cohort study. LOCATION: Community based register. PARTICIPANTS: 91 subjects with an episode of stroke collected since April 2006 up to September 2013 and treated with thrombolytic therapy. INTERVENTIONS: Monitoring of vital status. MEASUREMENTS: We collected baseline characteristics in Framingham, Regicor, CHA2DS2-VASc, Essen, NIHSS, Barthel scales and outcomes according to gender; person-time incidence rate; survival analysis by Kaplan-Meier's curves, bivariate analysis between survivors and deaths, and Cox multivariate. RESULTS: 91 patients with middle age 68.02+/-11.9 years. The men have higher cardiovascular basal risk. The average time of follow up was 2.95+/-2.33 years. Incidence rate ratio (IR) shown higher risk in men than in women IR=3.2 (CI 95% 1.2-8.0). The dead cases were older (P=.032); with higher cardiovascular basal risk (P=.040) and more risk of stroke recurrence (P=<.001), with cardiovascular pathology before the stroke (P=.005); more stroke severity (P=.002); and a major fall in the score Barthel one year after the episode (P=.016). The percentage of deaths is significantly higher when the patient is referred by complications to other centres (P=.006) in relation to those referred to home, but just the gender (HR: 1,12; IC 95%: 1,05-1,20) and secondary cardiovascular prevention (HR: 0,13; IC 95%: 0,06-0,28) were associated with higher risk of mortality. CONCLUSIONS: After stroke episode treated with thrombolytic therapy, men have 12% higher risk of dying than women and don't be treated with secondary cardiovascular prevention rise 7.7 times the mortality risk. PMID- 24953175 TI - Relationships between nutritional screening and functional impairment in institutionalized Spanish older people. AB - OBJECTIVES: An association between functional status and nutritional status has previously been demonstrated and the value of the Mini Nutritional Assessment (MNA) as an indicator of functional status has been investigated. However, experience in nursing homes is still limited. The objectives of this survey were to study the relationships between functional impairment as measured by the Barthel Index (BI) and broad nutritional assessment categories as measured by the MNA. STUDY DESIGN: Cross-sectional study developed with data collected from 895 residents in 34 nursing homes all over the province of Albacete (Spain). MAIN OUTCOME MEASURES: Nutritional and functional statuses were assessed using the MNA and the BI, respectively. Correlations between MNA and BI were evaluated. Analyses of BI against the MNA were utilized to obtain cut-off points for three broad categories of the MNA, "well", "at risk" and "malnourished". Multiple logistic regression analyses were used to assess the association of the MNA items with the BI. RESULTS: MNA and BI were significantly correlated. The BI cut-off point that best determined malnourished versus well or at risk was 40.5. The BI cut-off point that best determined well versus malnourished or at risk was 85.5. The BI was positively associated with the following MNA items: mobility, mode of feeding, self view of health status and mid-arm circumference. CONCLUSIONS: Both tests, MNA and BI, are positively associated. The scores of BI can help determine who may be at risk of poor nutrition. PMID- 24953176 TI - Hormonal changes and their impact on cognition and mental health of ageing men. AB - Demographic changes resulting in ageing of the world's population have major implications for health. As men grow older, circulating levels of the principal androgen or male sex hormone testosterone (T) decline, while the prevalence of ill-health increases. Observational studies in middle-aged and older men have shown associations between lower levels of T and poorer mental health in older men, including worse cognitive performance, dementia and presence of depressive symptoms. The role of T metabolites, the more potent androgen dihydrotestosterone (DHT) and the oestrogen receptor ligand estradiol (E2) in the pathophysiology of cognitive decline are unclear. Studies of men undergoing androgen deprivation therapy in the setting of prostate cancer have shown subtle detrimental effects of reduced T levels on cognitive performance. Randomised trials of T supplementation in older men have been limited in size and produced variable results, with some studies showing improvement in specific tests of cognitive function. Interventional data from trials of T therapy in men with dementia are limited. Lower levels of T have also been associated with depressive symptoms in older men. Some studies have reported an effect of T therapy to improve mood and depressive symptoms in men with low or low-normal T levels. T supplementation should be considered in men with a diagnosis of androgen deficiency. Beyond this clinical indication, further research is needed to establish the benefits of T supplementation in older men at risk of deteriorating cognition and mental health. PMID- 24953178 TI - Special issue "polyphenols and health". PMID- 24953179 TI - Phaseolus vulgaris - recalcitrant potential. AB - Since the ability to genetically engineer plants was established, researchers have modified a great number of plant species to satisfy agricultural, horticultural, industrial, medicinal or veterinary requirements. Almost thirty years after the first approaches to the genetic modification of pulse crops, it is possible to transform many grain legumes. However, one of the most important species for human nutrition, Phaseolus vulgaris, still lacks some practical tools for genomic research, such as routine genetic transformation. Its recalcitrance towards in vitro regeneration and rooting significantly hampers the possibilities of improvement of the common bean that suffers from many biotic and abiotic constraints. Thus, an efficient and reproducible system for regeneration of a whole plant is desired. Although noticeable progress has been made, the rate of recovery of transgenic lines is still low. Here, the current status of tissue culture and recent progress in transformation methodology are presented. Some major challenges and obstacles are discussed and some examples of their solutions are presented. PMID- 24953177 TI - A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas. AB - The proto-oncogene proviral integration site for moloney murine leukemia virus (PIM) kinases (PIM-1, PIM-2, and PIM-3) are serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. PIM kinases act in downstream effector functions as inhibitors of apoptosis and as positive regulators of G1-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, and prostate, gastric, and head and neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma and to assess the role PIM function in disease progression and their potential to serve as molecular targets for therapy. One hundred thirty-seven cases of urothelial carcinoma were included in this study of surgical biopsy and resection specimens. High levels of expression of all three PIM family members were observed in both noninvasive and invasive urothelial carcinomas. The second-generation PIM inhibitor, TP-3654, displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 displays favorable human ether-a-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability. In vivo xenograft studies using a bladder cancer cell line show that PIM kinase inhibition can reduce tumor growth, suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas. PMID- 24953180 TI - Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification. AB - The metabolic state of quiescent hematopoietic stem cells (HSCs) is an important regulator of self-renewal, but it is unclear whether or how metabolic parameters contribute to HSC lineage specification and commitment. Here, we show that the commitment of human and murine HSCs to the erythroid lineage is dependent upon glutamine metabolism. HSCs require the ASCT2 glutamine transporter and active glutamine metabolism for erythroid specification. Blocking this pathway diverts EPO-stimulated HSCs to differentiate into myelomonocytic fates, altering in vivo HSC responses and erythroid commitment under stress conditions such as hemolytic anemia. Mechanistically, erythroid specification of HSCs requires glutamine dependent de novo nucleotide biosynthesis. Exogenous nucleosides rescue erythroid commitment of human HSCs under conditions of limited glutamine catabolism, and glucose-stimulated nucleotide biosynthesis further enhances erythroid specification. Thus, the availability of glutamine and glucose to provide fuel for nucleotide biosynthesis regulates HSC lineage commitment under conditions of metabolic stress. PMID- 24953183 TI - Column study for the evaluation of the transport properties of polyphenol-coated nanoiron. AB - Injection of a nano zero valent iron (nZVI) suspension in the subsurface is a remedial option for obtaining the in situ reduction and immobilization of hexavalent chromium in contaminated aquifers. Prerequisite for the successful implementation of this technology is that the nanoparticles form a stable colloidal suspension with good transport properties when delivered in the subsurface. In this study we produced stable suspensions of polyphenol-coated nZVI (GT-nZVI) and we evaluated their transport behavior through representative porous media. Two types of porous materials were tested: (a) silica sand as a typical inert medium and (b) a mixture of calcareous soil and sand. The transport of GT-nZVI through the sand column was effectively described using a classic 1-D convection-dispersion flow equation (CDE) in combination with the colloid filtration theory (CFT). The calculations indicate that nZVI travel distance will be limited in the range 2.5-25cm for low Darcy velocities (0.1-1m/d) and in the order of 2.5m at higher velocities (10m/d). The mobility of GT-nZVI suspension in the soil-sand column is lower and is directly related to the progress of the neutralization reactions between the acidic GT-nZVI suspension and soil calcite. PMID- 24953181 TI - Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. AB - Studies of the identity and physiological function of mesenchymal stromal cells (MSCs) have been hampered by a lack of markers that permit both prospective identification and fate mapping in vivo. We found that Leptin Receptor (LepR) is a marker that highly enriches bone marrow MSCs. Approximately 0.3% of bone marrow cells were LepR(+), 10% of which were CFU-Fs, accounting for 94% of bone marrow CFU-Fs. LepR(+) cells formed bone, cartilage, and adipocytes in culture and upon transplantation in vivo. LepR(+) cells were Scf-GFP(+), Cxcl12-DsRed(high), and Nestin-GFP(low), markers which also highly enriched CFU-Fs, but negative for Nestin-CreER and NG2-CreER, markers which were unlikely to be found in CFU-Fs. Fate-mapping showed that LepR(+) cells arose postnatally and gave rise to most bone and adipocytes formed in adult bone marrow, including bone regenerated after irradiation or fracture. LepR(+) cells were quiescent, but they proliferated after injury. Therefore, LepR(+) cells are the major source of bone and adipocytes in adult bone marrow. PMID- 24953182 TI - Dynamic changes in intracellular ROS levels regulate airway basal stem cell homeostasis through Nrf2-dependent Notch signaling. AB - Airways are exposed to myriad environmental and damaging agents such as reactive oxygen species (ROS), which also have physiological roles as signaling molecules that regulate stem cell function. However, the functional significance of both steady and dynamically changing ROS levels in different stem cell populations, as well as downstream mechanisms that integrate ROS sensing into decisions regarding stem cell homeostasis, are unclear. Here, we show in mouse and human airway basal stem cells (ABSCs) that intracellular flux from low to moderate ROS levels is required for stem cell self-renewal and proliferation. Changing ROS levels activate Nrf2, which activates the Notch pathway to stimulate ABSC self-renewal and an antioxidant program that scavenges intracellular ROS, returning overall ROS levels to a low state to maintain homeostatic balance. This redox-mediated regulation of lung stem cell function has significant implications for stem cell biology, repair of lung injuries, and diseases such as cancer. PMID- 24953185 TI - B2O3-added lithium aluminium germanium phosphate solid electrolyte for Li-O2 rechargeable batteries. AB - B2O3-added Li(1.5)Al(0.5)Ge(1.5)(PO4)3 (LAGP) glass ceramics showing a room temperature ionic conductivity of 0.67 mS cm(-1) have been synthesized by using a melt-quenching method. The prepared glass ceramics are observed to be stable in tetraethylene glycol dimethyl ether containing lithium bis(trifluoromethane) sulfonamide. The augmented conductivity of the B2O3-added LAGP glass ceramic has improved the plateau potential during discharge. Furthermore, the B2O3-added LAGP glass ceramics are successfully employed as a solid electrolyte in a Li-O2 battery to obtain a stable cycling lifetime of up to 15 cycles with the limited capacity protocol. PMID- 24953184 TI - Scalable, transition-metal-free direct oxime O-arylation: rapid access to O arylhydroxylamines and substituted benzo[b]furans. AB - O-aryloximes, generated from readily available and inexpensive oximes through transition-metal-free O-arylation, can either be hydrolyzed to O arylhydroxylamines or conveniently converted to structurally diverse benzo[b]furans through an environmentally benign, one-pot [3,3]-sigmatropic rearrangement/cyclization sequence. PMID- 24953187 TI - Dynamics of riboswitches: Molecular simulations. AB - Riboswitch RNAs play key roles in bacterial metabolism and represent a promising new class of antibiotic targets for treatment of infectious disease. While many studies of riboswitches have been performed, the exact mechanism of riboswitch operation is still not fully understood at the atomistic level of detail. Molecular dynamics simulations are useful for interpreting existing experimental data and producing predictions for new experiments. Here, a wide range of computational studies on riboswitches is reviewed. By elucidating the key principles of riboswitch operation, computation may aid in the effort to design more specific antibiotics with affinities greater than those of the native ligand. Such a detailed understanding may be required to improve efficacy and reduce side effects. These studies are laying the groundwork for understanding the action mechanism of new compounds that inhibit riboswitch activity. Future directions such as magnesium effects, large-scale conformational changes, expression platforms and co-transcriptional folding are also discussed. This article is part of a Special Issue entitled: Riboswitches. PMID- 24953186 TI - CDX2 can be regulated through the signalling pathways activated by IL-6 in gastric cells. AB - The inflammatory infiltrate of the gastric mucosa associated with Helicobacter pylori infection increases the presence of the pro-inflammatory cytokine IL-6 that activates both the SHP-2/ERK/MAPK and the JAK/STAT signalling pathways. Furthermore, the ectopic expression of CDX2 is detected in pre-neoplasic lesions associated with decreased levels of SOX2, and we found that in gastric adenocarcinomas their expression is inversely correlated. To determine the role of IL-6 in the regulation of CDX2, MKN45 that constitutively expresses p-STAT3, and NUGC-4 gastric cancer cell lines were treated with IL-6, which induced the CDX2 up-regulation and SOX2 down-regulation. ChIP assays determined that in IL-6 treated cells, c-JUN and p-STAT3 bound to CDX2 promoter in MKN45 cells whereas in NUGC-4 cells, p-STAT3 binds to and c-JUN releases from the CDX2 promoter. Specific inhibition of STAT3 and ERK1/2 phosphorylation through AG490 and U0126, respectively, and STAT3 down-regulation using shRNA verified that the SHP 2/ERK/MAPK pathway regulates the expression of CDX2 in basal conditions, and the CDX2 up-regulation by IL-6 is through the JAK/STAT pathway in NUGC-4 cells whereas in MKN45 cells both pathways contribute to the CDX2 up-regulation. In conclusion, the signalling pathways activated by IL-6 have a crucial role in the regulation of CDX2 that is a key factor in the process of gastric carcinogenesis, suggesting that the inflammatory infiltrate in the gastric mucosa is relevant in this process and a potential target for new therapeutic approaches. PMID- 24953188 TI - The unfulfilled gene and nervous system development in Drosophila. AB - The unfulfilled gene of Drosophila encodes a member of the NR2E subfamily of nuclear receptors. Like related members of the NR2E subfamily, UNFULFILLED is anticipated to function as a dimer, binding to DNA response elements and regulating the expression of target genes. The UNFULFILLED protein may be regulated by ligand-binding and may also be post-transcriptionally modified by sumoylation and phosphorylation. unfulfilled mutants display a range of aberrant phenotypes, problems with eclosion and post-eclosion behaviors, compromised fertility, arrhythmicity, and a lack of all adult mushroom body lobes. The locus of the fertility problem has not been determined. The behavioral arrhythmicity is due to the unfulfilled-dependent disruption of gene expression in a set of pacemaker neurons. The eclosion and the mushroom body lobe phenotypes of unfulfilled mutants are the result of developmental problems associated with failures in axon pathfinding or re-extension. Interest in genes that act downstream of unfulfilled has resulted in the identification of a growing number of unfulfilled interacting loci, providing the first glimpse into the composition of unfulfilled-dependent gene networks. This article is part of a Special Issue entitled: Nuclear receptors in animal development. PMID- 24953191 TI - The chemokine receptor-CXCR2 plays a critical role in the invasion and metastases of oral squamous cell carcinoma in vitro and in vivo. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the world with about 50% survival rate over 5 years. OSCC has a highly invasive potency and frequently metastasizes to the cervical lymph nodes, which is the principle reason leading to poor prognosis. CXCR2, the receptor of CXC chemokines, has been reported to be involved in invasion and metastasis in multiple types of malignancy. However, the accurate role of CXCR2 in OSCC has been little noticed. METHODS: In this study, we determined the expression of CXCR2 in OSCC using immunohistochemical staining (IHC) and analyzed the association between the expression of CXCR2 and the biobehavior of OSCC. Then, we established stable OSCC cell lines with interference of CXCR2 and observed the effect of CXCR2 knockdown on cell proliferation, migration, invasion, and morphological changes in vitro and in vivo. RESULTS: CXCR2 was positively expressed in 55.3% of OSCC patients and was statistically associated with the high cervical lymph node metastasis in OSCC. CXCR2 silencing markedly inhibited migration and invasion of OSCC cells in vitro and in vivo. Moreover, CXCR2 silencing led to morphological changes and decreased lamellipodial structures in OSCC cells. However, CXCR2 silencing showed no effect on proliferation of OSCC cells in vitro and in vivo. CONCLUSIONS: CXCR2 plays a critical role in the invasion and metastases of OSCC. And it is probably by regulating actin cytoskeletal remodeling that CXCR2 takes part in the invasion and metastases of OSCC. PMID- 24953192 TI - Effects of supra-zero storage on human ovarian cortex prior to vitrification warming. AB - This study investigated the effects of supra-zero storage on ovarian cortex of 12 premenopausal patients before cryopreservation. Fresh ovarian tissue (control) was either vitrified immediately or stored at 4 degrees C for 24 h or 48 h before vitrification. This study assessed malondialdehyde release during storage and the capacity to synthesize oestradiol in culture, follicle morphology and the proportion of apoptotic follicles subsequent to vitrification-warming. The malondialdehyde concentration in the storage medium increased significantly in a time-dependent manner (P = 0.029). Oestradiol release during tissue culture decreased statistically significantly in both storage groups compared with the immediate vitrification group (P = 0.043). The proportion of high-quality follicles was significantly different between the fresh group and the two storage groups (24 h, P < 0.01; 48 h, P < 0.001). The proportion of apoptotic follicles was significantly different between the fresh and immediate vitrification groups (P < 0.05). The 24-h and 48-h groups were not different compared with the other groups. This study provides evidence that storage at supra-zero conditions has detrimental effects on the human ovarian cortex. Storage duration should therefore be limited to a minimum to prevent potential damage. PMID- 24953190 TI - Steroid receptor coactivators: servants and masters for control of systems metabolism. AB - Coregulator recruitment to nuclear receptors (NRs) and other transcription factors is essential for proper metabolic gene regulation, with coactivators enhancing and corepressors attenuating gene transcription. The steroid receptor coactivator (SRC) family is composed of three homologous members (SRC-1, SRC-2, and SRC-3), which are uniquely important for mediating steroid hormone and mitogenic actions. An accumulating body of work highlights the diverse array of metabolic functions regulated by the SRCs, including systemic metabolite homeostasis, inflammation, and energy regulation. We discuss here the cooperative and unique functions among the SRCs to provide a comprehensive atlas of systemic SRC metabolic regulation. Deciphering the fractional and synergistic contributions of the SRCs to metabolic homeostasis is crucial to understanding fully the networks underlying metabolic transcriptional regulation. PMID- 24953189 TI - A TEAD1/p65 complex regulates the eutherian-conserved MnSOD intronic enhancer, eRNA transcription and the innate immune response. AB - Manganese superoxide dismutase (MnSOD), a critical anti-oxidant enzyme, detoxifies the mitochondrial-derived reactive oxygen species, superoxide, elicited through normal respiration or the inflammatory response. Proinflammatory stimuli induce MnSOD gene expression through a eutherian-conserved, intronic enhancer element. We identified two prototypic enhancer binding proteins, TEAD1 and p65, that when co-expressed induce MnSOD expression comparable to pro inflammatory stimuli. TEAD1 causes the nuclear sequestration of p65 leading to a novel TEAD1/p65 complex that associates with the intronic enhancer and is necessary for cytokine induction of MnSOD. Unlike typical NF-kappaB-responsive genes, the induction of MnSOD does not involve p50. Beyond MnSOD, the TEAD1/p65 complex regulates a subset of genes controlling the innate immune response that were previously viewed as solely NF-kappaB-dependent. We also identified an enhancer-derived RNA (eRNA) that is induced by either proinflammatory stimuli or the TEAD1/p65 complex, potentially linking the intronic enhancer to intra- and interchromosomal gene regulation through the inducible eRNA. PMID- 24953194 TI - Medicine is not science: guessing the future, predicting the past. AB - RATIONALE, AIMS AND OBJECTIVES: Irregularity limits human ability to know, understand and predict. A better understanding of irregularity may improve the reliability of knowledge. METHOD: Irregularity and its consequences for knowledge are considered. RESULTS: Reliable predictive empirical knowledge of the physical world has always been obtained by observation of regularities, without needing science or theory. Prediction from observational knowledge can remain reliable despite some theories based on it proving false. A naive theory of irregularity is outlined. Reducing irregularity and/or increasing regularity can increase the reliability of knowledge. Beyond long experience and specialization, improvements include implementing supporting knowledge systems of libraries of appropriately classified prior cases and clinical histories and education about expertise, intuition and professional judgement. CONCLUSIONS: A consequence of irregularity and complexity is that classical reductionist science cannot provide reliable predictions of the behaviour of complex systems found in nature, including of the human body. Expertise, expert judgement and their exercise appear overarching. Diagnosis involves predicting the past will recur in the current patient applying expertise and intuition from knowledge and experience of previous cases and probabilistic medical theory. Treatment decisions are an educated guess about the future (prognosis). Benefits of the improvements suggested here are likely in fields where paucity of feedback for practitioners limits development of reliable expert diagnostic intuition. Further analysis, definition and classification of irregularity is appropriate. Observing and recording irregularities are initial steps in developing irregularity theory to improve the reliability and extent of knowledge, albeit some forms of irregularity present inherent difficulties. PMID- 24953193 TI - Clinical vignettes improve performance in anatomy practical assessment. AB - Although medical curricula now adopt an integrated teaching approach, this is not adequately reflected in assessment of anatomy knowledge and skills. In this study, we aimed to explore the impact of the addition of clinical vignette to item stems on students' performance in anatomy practical examinations. In this study, 129 undergraduate medical students of Durham University took part in a 30 item anatomy practical test consisting of those with and without clinical stem, in a crossover design. Classical test theory was used to analyze item difficulty, discrimination index, point biserial, and reliability. Student performance on items with clinical stem and the percentage of students who correctly answered each item was significantly improved by the addition of a clinical stem in the Year 2 cohort. Also, items with a clinical stem showed much better discrimination index than non-clinical items in the Year 2 cohort. In contrast, there was no significant difference in item performance, student performance and discrimination index between items with a clinical and non-clinical stem in Year 1 cohort. Over 65% of test items in both year groups were of good quality with point biserial exceeding 0.2. However, Year 1 test reliability for non-clinical items was better than clinical items. The results raise question as to what level to apply this method of assessment in undergraduate education. Although interpreted on the basis of a relatively small item sample, the findings support the need for improving anatomy practical examinations in line with overriding curricula changes. PMID- 24953195 TI - Nutritional quality, labelling and promotion of breakfast cereals on the New Zealand market. AB - Breakfast cereals substantially contribute to daily energy and nutrient intakes among children. In New Zealand, new regulations are being implemented to restrict nutrition and health claims to products that meet certain 'healthy' criteria. This study investigated the difference in nutritional quality, labelling and promotion between 'healthy' and 'less healthy' breakfast cereals, and between breakfast cereals intended for children compared with other breakfast cereals on the New Zealand market. The cross-sectional data collection involved taking pictures of the nutrition information panel (NIP) and front-of pack (FoP) for all breakfast cereals (n = 247) at two major supermarkets in Auckland in 2013. A nutrient profiling tool was used to classify products into 'healthy'/'less healthy'. In total 26% of cereals did not meet the 'healthy' criteria. 'Less healthy' cereals were significantly higher in energy density, sugar and sodium content and lower in protein and fibre content compared with 'healthy' cereals. Significantly more nutrition claims (75%) and health claims (89%) featured on 'healthy' compared with 'less healthy' cereals. On the 'less healthy' cereals, nutrition claims (65%) were more predominant than health claims (17%). Of the 52 products displaying promotional characters, 48% were for 'cereals for kids', and of those, 72% featured on 'less healthy' cereals. In conclusion, most breakfast cereals met the 'healthy' criteria; however, 'cereals for kids' were 'less healthy' and displayed more promotional characters than other cereal categories. Policy recommendations include: food composition targets set or endorsed by government, strengthening and enforcing current regulations on health and nutrition claims, considering the application of nutrient profiling for nutrition claims in addition to health claims, introducing an interpretative FoP labelling system and restricting the use of promotional characters on 'less healthy' breakfast cereals. PMID- 24953196 TI - Reproducibility of subjective appetite ratings and ad libitum test meal energy intake in overweight and obese males. AB - BACKGROUND: To determine whether changes in appetite and energy intake (EI) can be detected and play a role in the effectiveness of interventions, it is necessary to identify their variability under normal conditions. We assessed the reproducibility of subjective appetite ratings and ad libitum test meal EI after a standardised pre-load in overweight and obese males. METHODS: Fifteen overweight and obese males (BMI 30.3 +/- 4.9 kg/m(2), aged 34.9 +/- 10.6 years) completed two identical test days, 7 days apart. Participants were provided with a standardised fixed breakfast (1676 kJ) and 5 h later an ad libitum pasta lunch. An electronic appetite rating system was used to assess subjective ratings before and after the fixed breakfast, and periodically during the postprandial period. EI was assessed at the ad libitum lunch meal. Sample size estimates for paired design studies were calculated. RESULTS: Appetite ratings demonstrated a consistent oscillating pattern between test days, and were more reproducible for mean postprandial than fasting ratings. The correlation between ad libitum EI on the two test days was r = 0.78 (P <0.01). Using a paired design and a power of 0.8, a minimum of 12 participants would be needed to detect a 10 mm change in 5 h postprandial mean ratings and 17 to detect a 500 kJ difference in ad libitum EI. CONCLUSION: Intra-individual variability of appetite and ad libitum test meal EI in overweight and obese males is comparable to previous reports in normal weight adults. Sample size requirements for studies vary depending on the parameter of interest and sensitivity needed. PMID- 24953198 TI - Enhanced phosphorescence emission by incorporating aromatic halides into an entangled coordination framework based on naphthalenediimide. AB - Phosphorescence emission at room temperature is turned on in an entangled porous coordination polymer (PCP) with naphthalenediimide (NDI) as chromophore, by incorporating halogenated guests into the pores. The phosphorescent efficiency is drastically increased by the incorporation of aromatic halide guests in comparison with the incorporation of nonaromatic derivatives. Aromatic halide guests trigger a structural transformation, which allows a strong interaction with the NDI ligand in the framework through charge-transfer complexation, and provides an extra population process of the triplet state. The long-lived photoinduced triplet states, with an emission wavelength in the red region of the visible spectrum, demonstrated by this PCP, may open the door for potential uses, for example, as singlet-oxygen generators or for bio-imaging applications. PMID- 24953197 TI - The significance of sensory appeal for reduced meat consumption. AB - Reducing meat (over-)consumption as a way to help address environmental deterioration will require a range of strategies, and any such strategies will benefit from understanding how individuals might respond to various meat consumption practices. To investigate how New Zealanders perceive such a range of practices, in this instance in vitro meat, eating nose-to-tail, entomophagy and reducing meat consumption, focus groups involving a total of 69 participants were held around the country. While it is the damaging environmental implications of intensive farming practices and the projected continuation of increasing global consumer demand for meat products that has propelled this research, when asked to consider variations on the conventional meat-centric diet common to many New Zealanders, it was the sensory appeal of the areas considered that was deemed most problematic. While an ecological rationale for considering these 'meat' alternatives was recognised and considered important by most, transforming this value into action looks far less promising given the recurrent sensory objections to consuming different protein-based foods or of reducing meat consumption. This article considers the responses of focus group participants in relation to each of the dietary practices outlined, and offers suggestions on ways to encourage a more environmentally viable diet. PMID- 24953200 TI - The beneficial demands of conducting psychotherapy. AB - The practice of psychotherapy requires me to have several qualities: presence, perspective, and self-knowledge. These demands of conducting psychotherapy are discussed from an experiential point of view as primarily beneficial. Practicing psychotherapy also frequently reminds me of important lessons that I need to remember. Case examples are provided to illustrate central concepts, and research findings occasionally are presented to supplement primary clinical ideas. PMID- 24953199 TI - Information theory and signal transduction systems: from molecular information processing to network inference. AB - Sensing and responding to the environment are two essential functions that all biological organisms need to master for survival and successful reproduction. Developmental processes are marshalled by a diverse set of signalling and control systems, ranging from systems with simple chemical inputs and outputs to complex molecular and cellular networks with non-linear dynamics. Information theory provides a powerful and convenient framework in which such systems can be studied; but it also provides the means to reconstruct the structure and dynamics of molecular interaction networks underlying physiological and developmental processes. Here we supply a brief description of its basic concepts and introduce some useful tools for systems and developmental biologists. Along with a brief but thorough theoretical primer, we demonstrate the wide applicability and biological application-specific nuances by way of different illustrative vignettes. In particular, we focus on the characterisation of biological information processing efficiency, examining cell-fate decision making processes, gene regulatory network reconstruction, and efficient signal transduction experimental design. PMID- 24953201 TI - [Planimetric measurement of the regurgitant orifice area using tridimensional transoesophageal echocardiography for aortic regurgitation, reproducibility and feasibility]. AB - BACKGROUND: Aortic regurgitation is mainly evaluated by trans-thoracic echocardiography using multi-parametric qualitative and semi quantitative tools. All those parameters can fail to meet expectations, resulting in an imperfect diagnostic reliability and assessment of aortic regurgitation severity can be challenging. OBJECTIVES: We sought to evaluate feasibility and intra- and inter observer reproducibility of aortic regurgitant orifice area measured by planimetry with tridimensional trans-esophageal echocardiography on patients with at least grade 2/4 aortic regurgitation. PATIENTS AND METHODS: Consecutive patients with at least grade 2/4 aortic regurgitation measured by trans-thoracic echocardiography and referred for trans-esophageal echocardiography for any reason were included. Planimetric reconstructions of regurgitant orifice area were studied and reproducibility indexes between senior and junior observers were calculated. RESULTS: Twenty-three patients were included in this study. Intra- and inter-observer reproducibility were excellent with an ICC of 0.95 [0.88 0.98], P<0.0001 and 0.91 [0.79-0.96], P<0.0001, respectively. Mean length of the measurement was 6.6+/-0.9min [CI95% 6.23-7.01]. CONCLUSION: Planimetric measurement of the aortic regurgitant orifice using tridimensional trans esophageal echocardiography seems to be feasible and has great intra- and inter observer reproducibility. Reconstruction durations were compatible with a daily use. There is a need now to investigate the reliability of this measurement as compared with the reference technique. PMID- 24953202 TI - Sudden severe jaundice with high fever in a young woman. PMID- 24953203 TI - Development and validation of the Mayo Clinic Bowel Prep Tolerability Questionnaire. AB - BACKGROUND: Bowel cleansing is paramount for colonoscopy quality. Unfortunately, an adequate bowel preparation is often limited by side effects and/or patient's intolerance to bowel preparation solutions. Comparisons among different preparations are limited by the lack of validated instruments designed to assess patient's tolerability. AIM: To develop and validate a simple, comprehensive instrument to assess bowel preparation tolerability in patients undergoing colonoscopy. METHODS: Development and validation by phases: Phase I (bibliographic search and questionnaire design); Phase II (assessment of content validity and modification of the questionnaire); Phase III (assessment of reproducibility, final validation, and definitive version of the questionnaire). RESULTS: The initial draft of the questionnaire was generated based on a systematic literature review and feedback from a panel of consultants. Content validity was tested in a focus group of 25 patients undergoing colonoscopy. Patients' suggestions were reviewed by the research team and a second draft of the questionnaire was generated. Final validation and reproducibility were successfully tested (agreement: 86-100%, kappa: 0.77-1.00) in a convenience sample of 100 patients undergoing bowel preparation with different cleansing solutions. CONCLUSION: The Mayo Clinic Bowel Prep Tolerability Questionnaire is a simple, comprehensive instrument suitable to evaluate the tolerability of various types of bowel preparations. PMID- 24953204 TI - Determinants of alanine aminotransferase levels in a large population from Southern Italy: relationship between alanine aminotransferase and age. AB - BACKGROUND: Determinants of alanine aminotransferase levels have never been investigated in real-life settings. The relationship between alanine aminotransferase and age remains controversial. We evaluated epidemiological, anthropometric, and metabolic factors associated with alanine aminotransferase, focusing on the relationship between alanine aminotransferase and age. METHODS: A 5-year retrospective analysis was performed on data recorded by 120 general practitioners from Naples (Italy), caring for 170,000 subjects. Exclusion criteria were age <18 years, diagnosis of chronic liver disease, positive markers for viral hepatitis, alcohol abuse, and alanine aminotransferase >100UI/L. RESULTS: 44,232 subjects were enrolled (42.7% males, mean age 56+/-18 years). Alanine aminotransferase showed independent direct associations with body mass index, glycaemia, cholesterol, and triglycerides (p<0.001), and inverse associations with high-density lipoprotein cholesterol (p<0.001) and creatinine (p<0.01). The relationship between alanine aminotransferase and age was better expressed by polynomial regression (r=0.18, p<0.001), creating an inverted parabola. Mean alanine aminotransferase increased until the third decade in males and the fifth in females, with a subsequent progressive decrease in both genders. The inverse association between alanine aminotransferase and age in older subjects was independent from metabolic factors. CONCLUSIONS: This real-life setting study, supports the concept that dysmetabolism is a strong determinant of liver injury. Based on our data, a reduction of the standard upper limit of normal alanine aminotransferase should be considered for older subjects. PMID- 24953206 TI - Triple antiviral therapy in hepatitis C virus infection with or without mixed cryoglobulinaemia: a prospective, controlled pilot study. AB - BACKGROUND: Mixed cryoglobulinaemia is strongly related to hepatitis C virus infection. Treatment with peg-interferon and ribavirin has been indicated as first-line therapy for mild/moderate hepatitis C virus-related mixed cryoglobulinaemia. AIM: To evaluate the safety and efficacy of triple boceprevir based antiviral therapy in patients with or without mixed cryoglobulinaemia previously treated with peg-interferon and ribavirin, and with advanced liver disease. METHODS: Thirty-five hepatitis C virus-positive patients (17 with asymptomatic mixed cryoglobulinaemia, 5 with symptomatic mixed cryoglobulinaemia, and 11 without mixed cryoglobulinaemia) were treated with triple boceprevir-based antiviral therapy. RESULTS: In 19/22 cryoglobulinaemic subjects (86%), the addition of boceprevir induced cryocrit disappearance. Cryocrit behaviour was related to virological response, with improvement of symptoms upon undetectable viraemia and reappearance after virological breakthrough. The rate of sustained virological response was lower in cryoglobulinaemic patients than in patients without mixed cryoglobulinaemia (23.8% vs 70% respectively, p=0.01). CONCLUSION: Boceprevir-based therapy was safe and effective in cryoglobulinaemic patients. The correlation between direct inhibition of hepatitis C virus replication and clinical improvement in mixed cryoglobulinaemic patients is definitive proof of the key pathogenetic role played by viral replication. Further studies are needed to confirm and clarify the reduced virological response in patients with mixed cryoglobulinaemia. PMID- 24953207 TI - Pulse-wave velocity, the ankle-brachial index, and the visceral fat area are highly associated with colorectal adenoma. AB - BACKGROUND: Although both colorectal neoplasms and atherosclerosis may be induced by visceral fat accumulation, no association between these factors has yet been elucidated. METHODS: Among Japanese participants in our colonoscopic screening and annual surveillance programs, asymptomatic subjects were investigated. Visceral fat area was measured by computed tomography, and the ankle-brachial index and pulse-wave velocity (markers of systemic atherosclerosis) were also estimated. Colorectal findings during screening were investigated in association with these parameters. RESULTS: Nine hundred and seven subjects (males: 71.9%; mean age: 57.3+/-8.7 years) were enrolled. Colorectal adenomas were identified during colorectal screening of 407 subjects (44.9%). The prevalence of all colorectal adenoma and advanced neoplasia increased with an elevated pulse-wave velocity from 32.2% (advanced neoplasia, 2.6) to 62.1% (8.4%) in higher quartiles (p<0.001 and p=0.003). The risk of advanced neoplasia was higher in subjects with an abnormal ankle-brachial index (33% vs. 4.6%, p<0.001). Upon multivariate analysis, visceral fat area and pulse-wave velocity were associated with all adenoma, and the ankle-brachial index with advanced neoplasia. CONCLUSIONS: The risk of colorectal adenoma was strongly associated with visceral fat area and markers of atherosclerosis. Colorectal adenoma and atherosclerosis may share a common pathogenesis and the same populations are at high-risk. PMID- 24953205 TI - A simplified clinical risk score predicts the need for early endoscopy in non variceal upper gastrointestinal bleeding. AB - BACKGROUND: Pre-endoscopic triage of patients who require an early upper endoscopy can improve management of patients with non-variceal upper gastrointestinal bleeding. AIMS: To validate a new simplified clinical score (T score) to assess the need of an early upper endoscopy in non variceal bleeding patients. Secondary outcomes were re-bleeding rate, 30-day bleeding-related mortality. METHODS: In this prospective, multicentre study patients with bleeding who underwent upper endoscopy were enrolled. The accuracy for high risk endoscopic stigmata of the T-score was compared with that of the Glasgow Blatchford risk score. RESULTS: Overall, 602 patients underwent early upper endoscopy, and 472 presented with non-variceal bleeding. High risk endoscopic stigmata were detected in 145 (30.7%) cases. T-score sensitivity and specificity for high risk endoscopic stigmata and bleeding-related mortality was 96% and 30%, and 80% and 71%, respectively. No statistically difference in predicting high risk endoscopic stigmata between T-score and Glasgow Blatchford risk score was observed (ROC curve: 0.72 vs. 0.69, p=0.11). The two scores were also similar in predicting re-bleeding (ROC curve: 0.64 vs. 0.63, p=0.4) and 30-day bleeding related mortality (ROC curve: 0.78 vs. 0.76, p=0.3). CONCLUSIONS: The T-score appeared to predict high risk endoscopic stigmata, re-bleeding and mortality with similar accuracy to Glasgow Blatchford risk score. Such a score may be helpful for the prediction of high-risk patients who need a very early therapeutic endoscopy. PMID- 24953208 TI - Endoplasmic reticulum stress and unfolded protein response are involved in paediatric inflammatory bowel disease. AB - BACKGROUND: Endoplasmic reticulum stress and unfolded protein response have been recently associated with the development of inflammatory bowel diseases in adults. We aimed at assessing the involvement of these pathways also in paediatric inflammatory bowel disease by analysing the expression of the main genes involved in endoplasmic reticulum stress and correlating them with the degree of intestinal inflammation. METHODS: Real-time PCR and Western blot analysis of the expression of the endoplasmic reticulum stress marker HSPA5 and of selected genes representing the three pathways of unfolded protein response (IRE-XBP1, PERK-ATF4, ATF6p90-p50) in inflamed and uninflamed biopsies from 28 inflammatory bowel disease paediatric patients and 10 controls. RESULTS: HSPA5, PDIA4, as well as unspliced and spliced XBP1 mRNAs were significantly increased in patients' inflamed colonic mucosa compared to uninflamed mucosa and controls. HSPA5, PDIA4, ATF6, and phospho-IRE proteins were also upregulated, indicating the activation of the IRE-XBP1 and ATF6p90-p50 branches of unfolded protein response. A positive significant correlation between interleukin-8 levels, as a marker of inflammation, and upregulated genes was found in the inflamed colonic mucosa. CONCLUSION: A deregulation of the genes involved in the endoplasmic reticulum stress and unfolded protein response pathways may be a key component of the inflammatory response in paediatric patients with inflammatory bowel disease. PMID- 24953212 TI - Constructing a macromolecular K(3,3) graph through electrostatic self-assembly and covalent fixation with a dendritic polymer precursor. AB - A triply fused tetracyclic macromolecular K(3,3) graph has been constructed through electrostatic self-assembly of a uniformly sized dendritic polymer precursor having six cyclic ammonium salt end groups carrying two units of a trifunctional carboxylate counteranions, and subsequent covalent conversion by the ring-opening reaction of cyclic ammonium salt groups at an elevated temperature under dilution. The K(3,3) graph product was isolated from the two constitutional isomers by means of a recycling SEC technique, as the hydrodynamic volume of the triply fused tetracyclic K(3,3) product is remarkably contracted in comparison with another isomer having a ladder form in solution. PMID- 24953209 TI - An a priori prediction model of response to peginterferon plus ribavirin dual therapy in naive patients with genotype 1 chronic hepatitis C. AB - BACKGROUND: Aim was to select naive patients with genotype 1 chronic hepatitis C having a high probability of response to Peg-interferon+ribavirin therapy. METHODS: In 1073 patients (derivation cohort), predictors of rapid and sustained virological response were identified by logistic analysis; regression coefficients were used to generate prediction models for sustained virological response. Probabilities at baseline and treatment week 4 were utilized to develop a decision rule to select patients with high likelihood of response. The model was then validated in 423 patients (validation cohort). RESULTS: In the derivation cohort, 257 achieved rapid virological response and 818 did not, with sustained virological response rates of 80.2% and 25.4%, respectively; interleukin-28B polymorphisms, fibrosis staging, gamma-glutamyl transferase, and viral load predicted sustained virological response. Assuming a <30% sustained virological response probability for not recommending Peg-interferon+ribavirin, 100 patients (25.6%) in the validation cohort were predicted a priori to fail this regimen. Assuming a >=80% sustained virological response probability as a threshold to continue with Peg-interferon+ribavirin, 61 patients were predicted to obtain sustained virological response, and 55 of them (90.2%) eventually did. CONCLUSIONS: This model uses easily determined variables for a personalized estimate of the probability of sustained virological response with Peg interferon+ribavirin, allowing to identify patients who may benefit from conventional therapy. PMID- 24953211 TI - Frequency of tetrazepam prescription: estimates for Germany. AB - PURPOSE: Authorisation was suspended on 1 August 2013 for tetrazepam-containing medicines. The aim of the study was to assess relevance and pattern of tetrazepam use by estimating the prevalence of prescribing and to analyse prescribing indications and duration. This information is needed to generate baseline data for further evaluation of prescribing muscle relaxants. METHODS: Claims data analysis (Health Insurance Sample AOK Hesse/KV Hesse, 18.75% random sample of insurants from AOK Hesse, Germany). STUDY POPULATION: 267 787 insurants continuously insured or deceased in 2011. Prevalence estimates were standardised to the German population. To assess the quantity of prescribed tetrazepam, we applied defined daily dose (DDD) methodology with 125 mg of tetrazepam as 1 DDD. The prescribing indications were analysed with a matched case-control design. RESULTS: In 2011, 2.6% of the study population received at least one tetrazepam prescription (men, 2.1%; women, 3.0%). The mean prescribed dosage was 15 DDD and increased by age up to 43 DDD in women and 30 DDD in men >=80 years. The most frequently documented diagnoses were low-back pain (21.3%) and cervicalgia (20.3%). It appeared that the greatest difference in prevalence between tetrazepam recipients and controls was for the diagnosis 'Other specified disorders of muscle' (ICD: M62.8). This diagnosis was five times more prevalent in tetrazepam recipients than in controls. CONCLUSION: Tetrazepam was the most widely prescribed muscle relaxant in Germany, hence physicians may seek an alternative after its market withdrawal. However, according to treatment guidelines, muscle relaxants play only a minor role and a multimodal approach should be preferred. PMID- 24953210 TI - Structural and electronic analysis of the atomic scale nucleation of Ag on alpha Ag2WO4 induced by electron irradiation. AB - In this work, we utilise a combination of theory, computation and experiments to understand the early events related to the nucleation of Ag filaments on alpha Ag2WO4 crystals, which is driven by an accelerated electron beam from an electron microscope under high vacuum. The growth process and the chemical composition and elemental distribution in these filaments were analysed in depth at the nanoscale level using TEM, HAADF, EDS and XPS; the structural and electronic aspects were systematically studied in using first-principles electronic structure theory within QTAIM framework. The Ag nucleation and formation on alpha-Ag2WO4 is a result of the order/disorder effects generated in the crystal by the electron beam irradiation. Both experimental and theoretical results show that this behavior is associated with structural and electronic changes of the [AgO2] and [AgO4] clusters and, to a minor extent, to the [WO6] cluster; these clusters collectively represent the constituent building blocks of alpha-Ag2WO4. PMID- 24953213 TI - Polythioester synthesis in Ralstonia eutropha H16: novel insights into 3,3' thiodipropionic acid and 3,3'-dithiodipropionic acid catabolism. AB - Ralstonia eutropha H16 is capable of utilizing 3,3'-thiodipropionic acid (TDP) and 3,3'-dithiodipropionic acid (DTDP) as precursor substrates for biosynthesis of a polythioester (PTE) heteropolymer consisting of 3-hydroxybutyric acid (3HB) and 3-mercaptopropionic acid (3MP). To elucidate the hitherto unknown catabolic pathways of TDP and DTDP in R. eutropha H16, 19 defined deletion mutants were generated based on extensive functional genome analyses. Deletions of two ABC type transporter clusters (H16_A0357-0359, H16_A3658-3660) resulted in an alteration of poly(3HB-co-3MP) composition with TDP as precursor to only 10.2+/ 1.9mol% 3MP in comparison to 15.1+/-5.5mol% in the wild type. A mutant strain of H16 lacking Bordetella uptake gene-like substrate binding proteins (H16_A2779, H16_A0337) incorporated only 7.4+/-3.8mol% 3MP into PTE heteropolymers with DTDP as precursor in comparison to 24.5+/-14.5mol% in the wild type. Therefore, both gene products are probably involved in transport processes of this compound into the cells. However, the most significant reduction in 3MP contents of the heteropolymers with DTDP as precursor occurred upon the deletion of a gene encoding the putative thiol-disulfide interchange protein DsbD (H16_A3455, 3.9+/ 2.6mol% 3MP). DsbD is proposed to be involved in the reduction of DTDP into two molecules of 3MP, the common cleavage product of TDP and DTDP. PMID- 24953214 TI - Community pharmacy services for drug misuse: attitudes and practices of Finnish pharmacists. PMID- 24953215 TI - Functional assessment of rat complement pathway activities and quantification of soluble C5b-9 in an experimental model of renal ischemia/reperfusion injury. AB - There is a growing interest in the monitoring of complement activation, not only in clinical settings but also in experimental models. However, for rodents only a limited number of tools are available to assess complement activity and activation. Here we describe three ELISAs for the measurement of rat classical (CP), MB-lectin (LP) and alternative (AP) pathway activities in serum and plasma. Moreover, we optimised a soluble C5b-9 (sC5b-9) ELISA for the detection of low level complement activation in rat. We determined the conditions for correct sample handling and showed that the assays had low inter- and intra-assay variation. We applied these assays to monitor complement activation in an experimental rat model of renal ischemia/reperfusion injury. We did not observe major complement consumption following reperfusion in CP or LP, and only minor AP consumption at 24h post reperfusion. However, MBL depletion prior to ischemia/reperfusion using a monoclonal antibody, transiently and specifically inhibited 75% of LP activity and ameliorated the AP consumption at 24h. To further assess complement activation during renal IRI, we monitored serum sC5b-9 and found that it was only significantly increased 72h post-reperfusion, but not when rats were pre-treated with anti-MBL or after sham surgery. In conclusion the described assays enable sensitive, reproducible and comprehensive assessment of complement activation in experimental rat models. PMID- 24953216 TI - Improved flow-based method for HIV/SIV envelope-specific memory B-cell evaluation in rhesus macaques. AB - The ability to elicit potent and long-lasting broadly neutralizing HIV envelope (Env)-specific antibodies has become a key goal for HIV vaccine development. Consequently, the ability to rapidly and efficiently monitor development of memory B cells in pre-clinical and clinical vaccine trails is critical for continued progress in vaccine design. We have developed an improved flow cytometry-based method for the rapid and efficient identification of gp120 specific memory B cells in peripheral blood, bone marrow, and mucosal tissues which allows their direct staining without the need for prior cell sorting or enrichment. We demonstrate staining of both HIV and SIV Env-specific memory B cells in PBMC, bone marrow, and rectal tissue of vaccinated and infected rhesus macaques. Validation of the method is illustrated by statistically significant correlations with memory B cell levels quantified by ELISPOT assay and with serum binding antibody titers determined by ELISA. In addition to quantification, this method will bring the power of flow cytometry to the study of homing and trafficking of Env-specific memory B cells. PMID- 24953218 TI - Evaluation of levobupivacaine passage to breast milk following epidural anesthesia for cesarean delivery. AB - BACKGROUND: Following maternal administration, local anesthetics pass into breast milk. In the present study, we aimed to compare the passage of levobupivacaine and bupivacaine into breast milk following epidural anesthesia for cesarean delivery. METHODS: A total of 20 women undergoing elective cesarean delivery under epidural anesthesia were randomized to receive either 0.5% levobupivacaine or 0.5% racemic bupivacaine via an epidural catheter. Immediately before and 30min, 1h, 2h, 6h, 12h and 24h after administration of epidural local anesthetic, maternal blood and breast milk samples were taken simultaneously. Drug concentrations in plasma and milk were determined via high-performance liquid chromatography. The infant's drug exposure was determined by calculating milk/plasma ratios of levobupivacaine and bupivacaine. RESULTS: Both levobupivacaine and bupivacaine were detected in breast milk 30min after epidural administration. Concentrations of both agents showed constant and similar decreases in milk and plasma and were nearly undetectable at 24h. The milk/plasma ratios were 0.34+/-0.13 for levobupivacaine and 0.37+/-0.14 for bupivacaine. CONCLUSIONS: Both levobupivacaine and bupivacaine pass into breast milk following epidural administration. The concentration of both drugs was approximately three times lower in breast milk than in maternal plasma. PMID- 24953217 TI - The potential of o-bromo-trans-decalinvesamicol as a new PET ligand for vesicular acetylcholine transporter imaging. AB - We investigated the characteristics of the regional rat brain distribution of radio-brominated o-bromo-decalinvesamicol (OBDV) in vivo to evaluate its potential as a PET ligand for vesicular acetylcholine transporter (VAChT). In in vivo biodistribution study, the specific brain regional accumulation of [(77) Br]OBDV was revealed 30 min after intravenous injection. The specific brain regional accumulation of [(77) Br]OBDV was significantly inhibited by co injection of (+/-)-vesamicol. In contrast, no significant inhibition of the uptake of [(77) Br]OBDV in all brain regions was observed with co-injection of (+)-pentazocine (selective sigma-1 receptor agonist) and (+)-3-(3-hydroxyphenyl) N-propylpiperidine, [(+)-3-PPP] (sigma-1 and sigma-2 receptor agonist) with [(77) Br]OBDV. [(77) Br]OBDV accumulation in VAChT-rich brain regions was observed in ex vivo autoradiography. These results showed that [(77) Br]OBDV selectively bound to VAChT with high affinity in rat brain in vivo. Hence, OVBDV radiolabelled with more suitable (76) Br was suggested to be a potent VAChT ligand for PET. PMID- 24953219 TI - Reversible electric-field control of magnetization at oxide interfaces. AB - Electric-field control of magnetism has remained a major challenge which would greatly impact data storage technology. Although progress in this direction has been recently achieved, reversible magnetization switching by an electric field requires the assistance of a bias magnetic field. Here we take advantage of the novel electronic phenomena emerging at interfaces between correlated oxides and demonstrate reversible, voltage-driven magnetization switching without magnetic field. Sandwiching a non-superconducting cuprate between two manganese oxide layers, we find a novel form of magnetoelectric coupling arising from the orbital reconstruction at the interface between interfacial Mn spins and localized states in the CuO2 planes. This results in a ferromagnetic coupling between the manganite layers that can be controlled by a voltage. Consequently, magnetic tunnel junctions can be electrically toggled between two magnetization states, and the corresponding spin-dependent resistance states, in the absence of a magnetic field. PMID- 24953220 TI - A hydro-kinetic scheme for the dynamics of hydrogen bonds in water-like fluids. AB - A hydro-kinetic scheme for water-like fluids, based on a lattice version of the Boltzmann equation, is presented and applied to the popular TIP3P model of liquid water. By proceeding in much larger steps than molecular dynamics, the scheme proves to be very effective in attaining global minima of classical pair potentials with directional and radial interactions, as confirmed by further simulations using the three-dimensional Ben-Naim water potential. The scheme is shown to reproduce the propensity of water to form nearly four hydrogen bonds per molecule, as well as their statistical distribution in the presence of thermal fluctuations, at a linear cost of computational time with the system size. PMID- 24953221 TI - Opsismodysplasia resulting from an insertion mutation in the SH2 domain, which destabilizes INPPL1. PMID- 24953223 TI - Isolation of a non-heteroatom-stabilized gold-carbene complex. AB - Gold-carbene complexes are essential intermediates in many gold-catalyzed organic synthetic transformations. While gold-carbene complexes with direct, vinylogous, or phenylogous heteroatom substitution have been synthesized and characterized, the observation in the condensed phase of electronically non-stabilized gold carbenes has so far remained elusive. The sterically extremely shielded, emerald green complex [IPr**Au=CMes2](+)[NTf2](-) has now been synthesized, isolated, and fully characterized. Its absorption maximum at 642 nm, in contrast to 528 nm of the red-purple carbocation [Mes2CH](+), clearly demonstrates that gold is more than just a "soft proton". PMID- 24953224 TI - Oceanic barriers promote language diversification in the Japanese Islands. AB - Good barriers make good languages. Scholars have long speculated that geographical barriers impede linguistic contact between speech communities and promote language diversification in a manner similar to the process of allopatric speciation. This hypothesis, however, has seldom been tested systematically and quantitatively. Here, we adopt methods from evolutionary biology and attempt to quantify the influence of oceanic barriers on the degree of lexical diversity in the Japanese Islands. Measuring the degree of beta diversity from basic vocabularies, we find that geographical proximity and, more importantly, isolation by surrounding ocean, independently explains a significant proportion of lexical variation across Japonic languages. Further analyses indicate that our results are neither a by-product of using a distance matrix derived from a Bayesian language phylogeny nor an epiphenomenon of accelerated evolutionary rates in languages spoken by small communities. Moreover, we find that the effect of oceanic barriers is reproducible with the Ainu languages, indicating that our analytic approach as well as the results can be generalized beyond Japonic language family. The findings we report here are the first quantitative evidence that physical barriers formed by ocean can influence language diversification and points to an intriguing common mechanism between linguistic and biological evolution. PMID- 24953222 TI - Maternal depression and expressive communication in one-year-old infants. AB - To separate effects of maternal depression on infant cognitive versus language development, 1-year-olds were assessed using the revised Bayley Scales of Infant and Toddler Development (BSID-III). Percentile scores on the Bayley Expressive Communication (EC) subscale were significantly negatively correlated with maternal self-report scores on the Beck Depression Inventory (BDI-II). However, mothers' BDI-II scores did not correlate with infant percentile scores on the general cognitive (COG) or receptive communication (RC) subscales. Boys had significantly lower percentile scores than girls on the RC and EC scales, but did not differ on the Cog scale. Gender and maternal depression did not significantly interact on any of the scales. These findings suggest problems with expressive communication precede, and may at least partially account for, apparent deficits in general cognitive development. PMID- 24953225 TI - Association between MDR1 C3435T polymorphism and refractory epilepsy in the Chinese population: a systematic review and meta-analysis. AB - The association between the C3435T polymorphism in the MDR1 gene and refractory epilepsy remains controversial. The association appears to be influenced by ethnicity and region. We have performed a systematic review and meta-analysis to assess the link between the MDR1 C3435T polymorphism and refractory epilepsy in the Chinese population. We searched the Cochrane Library, MIDLINE, EMBASE, CBM disc, CNKI, VIP, and WANFANG databases for literature published through August 2013 for case-control studies that evaluated the association between the MDR1 C3435T polymorphism and refractory epilepsy. Twenty-one case-control studies involving 4269 patients (1863 cases in the group with drug-resistant epilepsy and 2406 in the group with drug-responsive epilepsy) were included in the systematic review and meta-analysis. The analysis showed that there were significantly more cases with the MDR1 3435 CC genotype in the group with drug-resistant epilepsy than in the group with drug-responsive epilepsy [odds ratio (OR)=1.50, 95% confidence interval (CI)=1.09-2.06, P=0.01]. In a subanalysis of patients from the southern regions of China, the correlation was not significant [odds ratio (OR)=1.2, 95% confidence interval (CI)=0.89-1.64, P=0.24]. The relationship established in a subset of the Chinese population between the MDR1 C3435T polymorphism and refractory epilepsy will guide epilepsy treatment and development of new AEDs. PMID- 24953226 TI - Work-injury absence and compensation among partnered and lone mothers and fathers. AB - BACKGROUND: The purpose of this study is to examine the risk of a work-injury absence and the likelihood of receiving compensation among partnered and lone mothers and fathers. METHODS: This study utilized data from an annual survey of Canadian residents. Logistic regression models examined the association between family status and the receipt of workers' compensation, and absences due to work related injury or illnesses of 7 or more days. RESULTS: Being a lone mother was significantly associated with the risk of work-injury absence. Gender differences were observed for workers' compensation: mothers were half as likely as fathers to receive workers' compensation benefits, which may be attributed to differences in work experiences between men and women. CONCLUSIONS: Findings may help in understanding whether some parental situations are more vulnerable than others and may contribute to identifying policies that could help workers sustain employment or return to work following an injury. PMID- 24953227 TI - Trainee perspectives on usefulness of the Trainee Research Requirement. AB - OBJECTIVE: To determine trainee perspectives of the utility of a trainee research project (TRP) or the coursework pathway (CP) in completing the Trainee Research Requirement of the ACEM. METHODS: A survey based on the ACEM learning objectives for research was sent to all trainees and Fellows who had completed or intending to complete the Trainee Research Requirement between 2010 and 2012. Participants were asked to rate the value of the TRP or CP on a scale of 1 to 10 (1 = 'not useful' and 10 = 'invaluable'). In addition, open-ended questions were asked for qualitative assessment. RESULTS: Survey response was 142/621 (23%). Most participants had undertaken the CP (113/142, 79%). Median scores were better for the CP compared with the TRP, and when results were dichotomised to scores of 1-5 as being not useful and 6-10 as being useful, a significantly higher proportion of participants rated the CP as being useful across all learning objectives (P <= 0.01). There was a bimodal distribution of scores for TRPs, with a minority of trainees reporting a very poor TRP experience. Cost was the most commonly cited negative aspect of the CP, whereas the TRP was perceived as time consuming and being difficult to attain. CONCLUSIONS: More ACEM trainees are undertaking the CP compared with a TRP. The CP was associated with better self-reported fulfilment of the ACEM learning objectives for research. There is scope for the ACEM to improve the experience of trainees wishing to undertake their own research projects. PMID- 24953228 TI - Na, K, Ca, Mg, and U-series in fossil bone and the proposal of a radial diffusion adsorption model of uranium uptake. AB - Fossil bones are often the only materials available for chronological reconstruction of important archeological sites. However, since bone is an open system for uranium, it cannot be dated directly and therefore it is necessary to develop models for the U uptake. Hence, a radial diffusion-adsorption (RDA) model is described. Unlike the classic diffusion-adsorption (D-A) model, RDA uses a cylindrical geometry to describe the U uptake in fossil bones. The model was applied across a transverse section of a tibia of an extinct megamammal Macrauchenia patachonica from the La Paz Local Fauna, Montevideo State, Uruguay. Measurements of spatial distribution of Na, K, Ca, and Mg were also performed by neutron activation analysis (NAA). Gamma-ray spectrometric U-series dating was applied to determine the age of the bone sample. From U concentration profile, it was possible to observe the occurrence of a relatively slow and continuous uranium uptake under constant conditions that had not yet reached equilibrium, since the uranium distribution is a ?-shaped closed-system. Predictions of the RDA model were obtained for a specific geochemical scenario, indicating that the effective diffusion coefficient D/R in this fossil bone is (2.4 +/- 0.6)10(-12) cm(2)s(-1). Mean values of Na, K, Ca, and Mg contents along the radial line of the fossil tibia are consistent with the expected behavior for spatial distributions of these mineral elements across a modern bone section. This result indicates that the fossil tibia may have its mineral structure preserved. PMID- 24953229 TI - Homogenity of geological units with respect to the radon risk in the Walloon region of Belgium. AB - In the process of mapping indoor radon risk, an important step is to define geological units well-correlated with indoor radon. The present paper examines this question for the Walloon region of Belgium, using a database of more than 18,000 indoor radon measurements. With a few exceptions like the Carboniferous (to be divided into Tournaisian, Visean and Namurian-Westphalian) and the Tertiary (in which all Series may be treated together), the Series/Epoch stratigraphic level is found to be the most appropriate geological unit to classify the radon risk. A further division according to the geological massif or region is necessary to define units with a reasonable uniformity of the radon risk. In particular, Paleozoic series from Cambrian to Devonian show strong differences between different massifs. Local hot-spots are also observed in the Brabant massif. Finally, 35 geological units are defined according to their radon risk, 6 of which still present a clear weak homogeneity. In the case of 4 of these units (Jurassic, Middle Devonian of Condroz and of Fagne-Famenne, Ordovician of the Stavelot massif) homogeneity is moderate, but the data are strongly inhomogeneous for Visean in Condroz and in the Brabant massif. The 35 geological units are used in an ANOVA analysis, to evaluate the part of indoor radon variability which can be attributed to geology. The result (15.4-17.7%) agrees with the values observed in the UK. PMID- 24953231 TI - Quantification, microbial contamination, physico-chemical stability of repackaged bevacizumab stored under different conditions. AB - In this work, the stability of Bevacizumab (Avastin((r))) repackaged in individual 1 mL single-use syringes and stored at different conditions was assessed. Bevacizumab repackaged in single-use syringes results from the off label use of the drug as an intravitreal agent in the treatment of retinal diseases. Bevacizumab stability was assessed by assaying the anti-VEGF activity using an indirect ELISA method and a Dynamic Light Scattering study. The thermal stability of the drug was also studied by calorimetric analysis, aimed to evaluate thermodynamic parameters associated to the thermal unfolding process. Furthermore, microbiological and fungal tests on the Bevacizumab syringes were performed. As a result, a significant decrease of the anti-VEGF activity was detected when syringes were exposed to UV light at a temperature of 37 degrees C. Under these conditions, the Dynamic Light Scattering study showed an increase of the average size of Bevacizumab; probably due to aggregation. In conclusion, Bevacizumab stability, when stored under different conditions, was assessed considering three different aspects: anti-VEGF activity, microbial contamination and physico-chemical properties. Bevacizumab was found to be stable, under sterile conditions, for 3 months at 4 degrees C and for 7 days at room temperature, exposed to indirect light sources, while a brief exposure of the drug to direct UV radiation proved detrimental to drug stability. PMID- 24953230 TI - A single pathway targets several health challenges of the elderly. AB - New avenues to modulate the autophagy-lysosomal route of protein clearance have the potential to help treat several disease states to which the elderly are particularly vulnerable. Two recent papers identified distinct ways to tap into the lysosomal degradation pathway of autophagy to reduce age-related protein accumulation events. Shoji-Kawata et al. (Nature 2013;494:201-206) describe a new autophagy-inducing peptide, Tat-Beclin 1, that enhances the clearance of polyglutamine aggregates related to Huntington's disease and, interestingly, suppresses viral and bacterial infections. Savolainen et al. (Neurobiol Dis 2014;68:1-15) describe a prolyl oligopeptidase inhibitor that reduces alpha synuclein species related to Parkinson's disease and other alpha synucleinopathies, and this inhibitor caused a concomitant increase in autophagic activation markers. Previous studies have also linked the autophagy-lysosomal pathway to the protective clearing of the Abeta peptides of Alzheimer's disease and tau species of tauopathies. Enhancing autophagy-lysosomal efficiency may provide a therapeutic avenue for diverse types of proteinopathies, including the most common neurodegenerative disorders of the elderly. PMID- 24953233 TI - Finding alternatives to antibiotics. AB - The spread of antibiotic-resistant pathogens requires new treatments. As the rate of development of new antibiotics has severely declined, alternatives to antibiotics must be considered in both animal agriculture and human medicine. Products for disease prevention are different from those for disease treatment, and examples of both are discussed here. For example, modulating the gut microbial community, either through feed additives or fecal transplantation, could be a promising way to prevent certain diseases; for disease treatment, non antibiotic approaches include phage therapy, phage lysins, bacteriocins, and predatory bacteria. Interestingly, several of these methods augment antibiotic efficacy by improving bacterial killing and decreasing antibiotic resistance selection. Because bacteria can ultimately evolve resistance to almost any therapeutic agent, it is important to continue to use both antibiotics and their alternatives judiciously. PMID- 24953232 TI - Power to the patient: care tracks and empowerment a recipe for improving rehabilitation for hip fracture patients. AB - BACKGROUND/AIM: New surgical procedures, early operation and medical optimisation in patients with hip fracture have shown positive results on length of hospital stay. Our aims were to investigate whether patient empowerment along with an individually designed, postoperative rehabilitation programme could reduce length of hospital stay and whether the patients would have better chances to return to their previous living. DESIGN/METHOD: Patients were recruited during a 12-month period 2009-2010, with an intervention group treated with an individually designed, postoperative rehabilitation programme and a control group treated in a traditional way according to the hospitals routines. Final assessment was performed 4 month after surgery. The postoperative programme for the intervention group consisted of four standardised care tracks adapted individually for the patients. Assessments of Activity of Daily Living, American Society of Anesthesiologists classification of medical disease status and Short Portable Mental Status Questionnaire and living conditions were used to determine which care track was most appropriate. The patients were cared for with focus of empowerment in their rehabilitation. RESULTS: The study involved 503 hip fracture patients, 285 patients in the intervention group and 218 patients in the control group. The mean length of stay was 4 days shorter in the intervention group than in the control group (p = 0.04). Varied only to a small extent between the age groups in the intervention group and was greater between the age groups in the control. Patients in the intervention group returned to their previous living in 90% compared with 80% in the control group (p < 0.05). There were no significant differences between the age groups. CONCLUSION: Patient empowerment administrated by specially trained nursing staff and with specialised, tailor-made rehabilitation programme may be of benefit in helping patients to a shorter hospital stay and to return to their previous living. PMID- 24953234 TI - Myopathic phenotype of familial amyloid polyneuropathy with a rare transthyretin variant: ATTR Ala45Asp. PMID- 24953235 TI - Intra-rater and inter-rater reliability at the item level of the Action Research Arm Test for patients with stroke. AB - OBJECTIVE: To examine the intra- and inter-rater reliability of the Action Research Arm Test (ARAT) at the item level after stroke. DESIGN: An intra-rater and inter-rater reliability study. SUBJECTS: Thirty-five participants (median age 62 years, median time post-stroke 22 months) with impaired upper extremity function after stroke were included in the study. METHODS: Two physiotherapists simultaneously, but independently, assessed the participants' performance in all 19 items of the ARAT twice in 1 day. A rank-based statistical method for paired ordinal data, including calculation of percentage agreement (PA), systematic disagreements (relative position (RP), relative concentration (RC)) and individual variability (relative rank variance (RV)) was used. RESULTS: Satisfactory intra-rater and inter-rater agreement was noted for all items except item 19, which was just below satisfactory level. Within and between raters, small but non-negligible systematic disagreements were found for items 11, 14 and 19 and for items 1, 4, 17 and 19, respectively. There was no disagreement due to random variance within or between raters. CONCLUSION: The ARAT is a highly reliable observational rating scale at the item level after stroke. Awareness regarding the small systematic disagreements demonstrated in some items is, however, recommended when using ARAT. PMID- 24953237 TI - Non-ablative fractionated laser skin resurfacing for the treatment of aged neck skin. AB - BACKGROUND: Aging of the neck skin includes poikiloderma of Civatte, skin laxity and wrinkles. While the vascular alterations of poikiloderma of Civatte can be effectively treated with lasers or intense pulsed light, a successful treatment of dyschromia, skin laxity and wrinkles is still difficult to achieve. OBJECTIVE: To evaluate the safety and efficacy of non-ablative fractional 1540 erbium glass laser for the treatment of aged neck skin, also by means of in vivo reflectance confocal microscopy (RCM). METHODS: A prospective study for neck resurfacing in 18 women with aged neck skin. Six laser treatments were performed in 4-week intervals with a 1540-nm erbium-glass fiber laser. RESULTS: By using a 6-point grading scale, the mean score (+/-SD; range) at baseline was 3.6 (+/-1.5; 1-6) for skin dyschromia, 2.9 (+/-1.4; 1-6) for laxity and 3.3 (+/-1.3; 1-5) for wrinkles. Three months after the last laser session, we found a significant clinical improvement of dyschromia (p = 0.0002; Wilcoxon test), and wrinkles (p = 0.0004; Wilcoxon test), with a mean (+/-SD) reduction of 2.5 (+/-1.0) and 1.9 (+/ 1.1) points in the 6-point grading scale, respectively. No change was observed in laxity. These results were also supported by structural changes documented by RCM. CONCLUSION: Non-ablative fractional 1540 erbium glass laser was both safe and effective for the treatment of dyschromia and wrinkles, but not effective for the laxity of the neck skin. PMID- 24953236 TI - Is religiosity related to attitudes toward clinical trials participation? AB - Research indicates that a low percentage of cancer patients enroll in cancer clinical trials. This is especially true among minority groups such as Hispanic Americans. Considering the importance of religion in the Hispanic American community, it is important to understand its relationship to perceptions of clinical trials. Five hundred and three Latina women completed the Barriers to Clinical Trials Participation Scale and the Duke University Religion Index. For the total sample, higher organizational and intrinsic religiosity was significantly associated with a perceived lack of community support for clinical trials participation. In subgroup analysis, the relationship between organizational religiosity and lack of support was stronger among Latinas who were Spanish language preferred and Latinas who were Catholic. Intrinsic religiosity was associated with mistrust among Spanish language-preferred Latinas, and both organizational and intrinsic religiosities were associated with a lack of familiarity with clinical trials among Christian (non-Catholic) Latinas. These results indicate that religious institutions that serve Latinas may be an effective venue for disseminating clinical trial education programs to improve attitudes toward clinical trials participation. PMID- 24953238 TI - Challenges in first line chemotherapy and targeted therapy in advanced gastric cancer. AB - Chemotherapy prolongs survival in advanced gastric cancer (AGC). The challenges involved in this procedure are providing a framework to aid in determining the best single or combined chemotherapy protocols for targeted agents in front-line therapy for patients in a clinical setting. A review of Phase II-III studies published or referenced in major oncology congress publications from 1970 to 2013 was performed. Cisplatin and fluoropyrimidine remain the reference regimen. Fluoropyrimidine combined with oxaliplatin or irinotecan may also be employed in special situations. There are no comparative studies of the same regimens with or without anthacyclines; thus, the effectiveness of anthacyclines remains under debate. The introduction of trastuzumab in the front-line therapy of HER2 positive patients and ramucirumab in refractory patients ushered in an age of targeted therapy for this disease. PMID- 24953239 TI - Thalamocortical neurons display suppressed burst-firing due to an enhanced Ih current in a genetic model of absence epilepsy. AB - Burst-firing in distinct subsets of thalamic relay (TR) neurons is thought to be a key requirement for the propagation of absence seizures. However, in the well regarded Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model as yet there has been no link described between burst-firing in TR neurons and spike-and-wave discharges (SWDs). GAERS ventrobasal (VB) neurons are a specific subset of TR neurons that do not normally display burst-firing during absence seizures in the GAERS model, and here, we assessed the underlying relationship of VB burst-firing with Ih and T-type calcium currents between GAERS and non-epileptic control (NEC) animals. In response to 200-ms hyperpolarizing current injections, adult epileptic but not pre-epileptic GAERS VB neurons displayed suppressed burst firing compared to NEC. In response to longer duration 1,000-ms hyperpolarizing current injections, both pre-epileptic and epileptic GAERS VB neurons required significantly more hyperpolarizing current injection to burst-fire than those of NEC animals. The current density of the Hyperpolarization and Cyclic Nucleotide activated (HCN) current (Ih) was found to be increased in GAERS VB neurons, and the blockade of Ih relieved the suppressed burst-firing in both pre-epileptic P15 P20 and adult animals. In support, levels of HCN-1 and HCN-3 isoform channel proteins were increased in GAERS VB thalamic tissue. T-type calcium channel whole cell currents were found to be decreased in P7-P9 GAERS VB neurons, and also noted was a decrease in CaV3.1 mRNA and protein levels in adults. Z944, a potent T-type calcium channel blocker with anti-epileptic properties, completely abolished hyperpolarization-induced VB burst-firing in both NEC and GAERS VB neurons. PMID- 24953240 TI - Role of atrial natriuretic peptide in mediating the blood pressure-independent natriuresis elicited by systemic inhibition of nitric oxide. AB - While it is clearly recognized that increased intrarenal nitric oxide (NO) levels elicit natriuresis, confounding data showing that systemic nitric oxide synthase inhibition (NOSi) also increases sodium excretion (UNaV) poses a conundrum. This response has been attributed to the associated increases in arterial pressure (AP); however, the increases in AP and in UNaV are temporally dissociated. The changes in regional renal haemodynamics induced by NOSi could also contribute to the alterations of UNaV. To evaluate the roles of AP and non-AP mechanisms mediating the natriuresis, N omega-nitro-L-arginine methyl ester hydrochloride (L NAME) was infused i.v. at doses ranging from 5 to 50 MUg/kg/min in anaesthetized rats. UNaV, perfusion of the cortex (cortical blood flow, CBF) and medulla (medullary blood flow, MBF) with laser-Doppler flowmetry and glomerular filtration rate (GFR) were measured. UNaV increased from 0.6 +/- 0.2 to 1.6 +/- 0.1 MUmol/kg/min (P < 0.05) with the lower nonpressor doses. With the higher doses, AP increased from 116 +/- 4 to 122 +/- 4 mmHg and UNaV increased from 1.1 +/- 0.3 to 3.3 +/- 0.7 MUmol/min/g (P < 0.002). UNaV increased similarly in a group where renal AP was maintained at baseline levels. The associated reductions in CBF (17 +/- 5 and 38 +/- 5 %) and MBF (27 +/- 6 and 52 +/- 6 %) would be expected to attenuate rather than contribute to the natriuresis. Plasma atrial natriuretic peptide (ANP) concentrations increased significantly following NOSi. Anantin, a natriuretic peptide receptor-A blocker, prevented or reversed the L NAME-induced natriuresis without altering the L-NAME-induced changes in AP or CBF. The results indicate that increased ANP and related natriuretic peptides mediate the AP-independent natriuresis, at least partly, elicited by systemic L NAME infusion and help resolve the conundrum of natriuresis during systemic NOSi. PMID- 24953242 TI - Discovering beaten paths in collaborative ontology-engineering projects using Markov chains. AB - Biomedical taxonomies, thesauri and ontologies in the form of the International Classification of Diseases as a taxonomy or the National Cancer Institute Thesaurus as an OWL-based ontology, play a critical role in acquiring, representing and processing information about human health. With increasing adoption and relevance, biomedical ontologies have also significantly increased in size. For example, the 11th revision of the International Classification of Diseases, which is currently under active development by the World Health Organization contains nearly 50,000 classes representing a vast variety of different diseases and causes of death. This evolution in terms of size was accompanied by an evolution in the way ontologies are engineered. Because no single individual has the expertise to develop such large-scale ontologies, ontology-engineering projects have evolved from small-scale efforts involving just a few domain experts to large-scale projects that require effective collaboration between dozens or even hundreds of experts, practitioners and other stakeholders. Understanding the way these different stakeholders collaborate will enable us to improve editing environments that support such collaborations. In this paper, we uncover how large ontology-engineering projects, such as the International Classification of Diseases in its 11th revision, unfold by analyzing usage logs of five different biomedical ontology-engineering projects of varying sizes and scopes using Markov chains. We discover intriguing interaction patterns (e.g., which properties users frequently change after specific given ones) that suggest that large collaborative ontology-engineering projects are governed by a few general principles that determine and drive development. From our analysis, we identify commonalities and differences between different projects that have implications for project managers, ontology editors, developers and contributors working on collaborative ontology-engineering projects and tools in the biomedical domain. PMID- 24953241 TI - Using computational modeling to assess the impact of clinical decision support on cancer screening improvement strategies within the community health centers. AB - Our conceptual model demonstrates our goal to investigate the impact of clinical decision support (CDS) utilization on cancer screening improvement strategies in the community health care (CHC) setting. We employed a dual modeling technique using both statistical and computational modeling to evaluate impact. Our statistical model used the Spearman's Rho test to evaluate the strength of relationship between our proximal outcome measures (CDS utilization) against our distal outcome measure (provider self-reported cancer screening improvement). Our computational model relied on network evolution theory and made use of a tool called Construct-TM to model the use of CDS measured by the rate of organizational learning. We employed the use of previously collected survey data from community health centers Cancer Health Disparities Collaborative (HDCC). Our intent is to demonstrate the added valued gained by using a computational modeling tool in conjunction with a statistical analysis when evaluating the impact a health information technology, in the form of CDS, on health care quality process outcomes such as facility-level screening improvement. Significant simulated disparities in organizational learning over time were observed between community health centers beginning the simulation with high and low clinical decision support capability. PMID- 24953244 TI - Assessment of cone beam CT registration for prostate radiation therapy: fiducial marker and soft tissue methods. AB - INTRODUCTION: This investigation aimed to assess the consistency and accuracy of radiation therapists (RTs) performing cone beam computed tomography (CBCT) alignment to fiducial markers (FMs) (CBCTFM ) and the soft tissue prostate (CBCTST ). METHODS: Six patients receiving prostate radiation therapy underwent daily CBCTs. Manual alignment of CBCTFM and CBCTST was performed by three RTs. Inter-observer agreement was assessed using a modified Bland-Altman analysis for each alignment method. Clinically acceptable 95% limits of agreement with the mean (LoAmean ) were defined as +/-2.0 mm for CBCTFM and +/-3.0 mm for CBCTST . Differences between CBCTST alignment and the observer-averaged CBCTFM (AvCBCTFM ) alignment were analysed. Clinically acceptable 95% LoA were defined as +/-3.0 mm for the comparison of CBCTST and AvCBCTFM . RESULTS: CBCTFM and CBCTST alignments were performed for 185 images. The CBCTFM 95% LoAmean were within +/-2.0 mm in all planes. CBCTST 95% LoAmean were within +/-3.0 mm in all planes. Comparison of CBCTST with AvCBCTFM resulted in 95% LoA of -4.9 to 2.6, -1.6 to 2.5 and -4.7 to 1.9 mm in the superior-inferior, left-right and anterior-posterior planes, respectively. CONCLUSIONS: Significant differences were found between soft tissue alignment and the predicted FM position. FMs are useful in reducing inter observer variability compared with soft tissue alignment. Consideration needs to be given to margin design when using soft tissue matching due to increased inter observer variability. This study highlights some of the complexities of soft tissue guidance for prostate radiation therapy. PMID- 24953243 TI - Molecular characterization of amikacin, kanamycin and capreomycin resistance in M/XDR-TB strains isolated in Thailand. AB - BACKGROUND: The emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) makes the treatment and control of tuberculosis difficult. Rapid detection of drug-resistant strains is important for the successful treatment of drug-resistant tuberculosis; however, not all resistance mechanisms to the injectable second-line drugs such as amikacin (AK), kanamycin (KM), and capreomycin (CAP) are well understood. This study aims to validate the mechanisms associated with AK, KM, and CAP resistance in M. tuberculosis clinical strains isolated in Thailand. RESULTS: A total of 15,124 M. tuberculosis clinical strains were isolated from 23,693 smear-positive sputum samples sent from 288 hospitals in 46 of 77 provinces of Thailand. Phenotypic analysis identified 1,294 strains as MDR-TB and second-line drugs susceptibility was performed in all MDR-TB strains and revealed 58 XDR-TB strains. Twenty-nine KM-resistant strains (26 XDR-TB and 3 MDR-TB) could be retrieved and their genes associated with AK, KM, and CAP resistance were investigated compared with 27 KM susceptible strains. Mutation of the rrs (A1401G) was found in 21 out of 29 KM resistant strains whereas mutations of eis either at C-14 T or at G-37 T were found in 5 strains. Three remaining KM-resistant strains did not contain any known mutations. Capreomycin resistance was determined in 28 of 29 KM-resistant strains. Analysis of tlyA revealed that the A33G mutation was found in all CAP resistant strains and also in susceptible strains. In contrast, the recently identified tlyA mutation T539G and the novel Ins49GC were found in two and one CAP-resistant strains, respectively. In addition, our finding demonstrated the insertion of cytosine at position 581 of the tap, a putative drug efflux encoding gene, in both KM-resistant and KM-susceptible strains. CONCLUSIONS: Our finding demonstrated that the majority of KM resistance mechanism in Thai M. tuberculosis clinical strains was rrs mutation at A1401G. Mutations of the eis promoter region either at C-14 T or G-37 T was found in 5 of 29 strains whereas three strains did not contain any known mutations. For CAP resistance, 3 of 28 CAP-resistant strains contained either T539G or Ins49GC mutations at tlyA that might be associated with the resistant phenotype. PMID- 24953245 TI - Src family kinase inhibitor PP2 enhances differentiation of acute promyelocytic leukemia cell line induced by combination of all-trans-retinoic acid and arsenic trioxide. AB - An all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combination yields high-quality remission and survival in newly-diagnosed acute promyelocytic leukemia (APL). For subsequent similar data, NCCN guidelines indicate that ATRA plus ATO is one of the recommended regimens for the treatment of patients with APL. We demonstrated SFK (Src family kinase) inhibitor PP2-enhanced APL cell differentiation when combined with either ATRA or ATO with difference in activation of RA-induced genes. In this study, we investigated whether SFK inhibitor PP2 could enhance the differentiation of NB4 APL cells when combined with ATRA and ATO and the changes in the expression of intercellular adhesion molecule-1 (ICAM-1) derived from the retinoic acid receptor (RAR) target gene. Treatment of NB4 cells with 1 MUM of ATRA, 0.5 MUM of ATO, or 10 MUM of PP2 for 72 h induced expression of CD11b-positive cells by 13.01%, 11.53% or 13.28%, respectively. However, the combination of ATRA and ATO and the combination of three agents (ATRA, ATO, and PP2) led to a significantly higher expression of CD11b-positive cells (30.96% and 63.17%, respectively). The synergistic effect of the combination of three agents was more significant than the combination of ATRA and ATO. These results were confirmed with NBT staining. These effects were not related to apoptosis. Annexin-V-fluorescein staining revealed that a combination of ATRA and ATO and combination of the three agents did not induce apoptosis in NB4 cells. The expression of ICAM-1 markedly increased in cells treated with the combination of the three agents. These findings suggest that the SFK inhibitor can enhance differentiation of APL cells combined with ATRA and ATO. FDA approved SFK inhibitors, such as dasatinib and bosutinib, may be beneficial for the treatment of APL with a combination of ATRA and ATO. PMID- 24953246 TI - Impaired beta-cell function attenuates training effects by reducing the increase in heart rate reserve in patients with myocardial infarction. AB - BACKGROUND: Insulin resistance (IR) is characterized as a metabolic disorder syndrome that is upstream of hypertension, dyslipidemia, and diabetes mellitus (DM). This study investigated exercise training effects on the exercise tolerance and heart rate dynamics in patients with IR or pancreatic beta-cell dysfunction. METHODS: Seventy patients (mean age, 60.1 years) with myocardial infarction (MI) participating in a phase II cardiac rehabilitation program were studied. Patients diagnosed with DM were excluded. Homeostasis model-assessment indices were used to divide patients into three groups - A: IR; B: normal; and C: beta-cell dysfunction. A cardiopulmonary exercise test (CPX) was performed and peak oxygen uptake (VO2) was measured. After baseline testing, subjects participated in a supervised, combined aerobic and resistance exercise program. RESULTS: Peak VO2 at baseline was comparable among the three groups, and it improved after training in all groups (p<0.05). However, both the increase and percentage increase in peak VO2 were smaller in Group C than in Group A (p<0.05). Heart rate (HR) reserve (peak HR-rest HR), and HR recovery immediately 1min after exercise during CPX were calculated in 45 patients who were not taking negative chronotropic agents. Group C alone did not show any significant increase in HR reserve. HR reserve at both baseline and after training had significant positive correlations with peak VO2. HR recovery was 1.9 beats/min lower in group C than group A, but this was not significant. HR recovery in group C did not increase after cardiac rehabilitation. CONCLUSION: Impaired HR reserve increase after training in patients with pancreatic beta-cell dysfunction attenuates exercise training effects on functional capacity. Comprehensive treatment including vigorous exercise training will be needed in such prediabetic patients. PMID- 24953247 TI - [Geriatric assessment tools in Spanish Geriatric Departments]. AB - INTRODUCTION: Comprehensive Geriatric Assessment (CGA) is the main measurement tool used by Geriatricians. A 2000 survey demonstrated great variability in the tools used for CGA among Spanish Geriatric Departments. A new survey to detect 13 year trends in the use of CGA tools in our country is presented. MATERIAL AND METHODS: Descriptive study using a structured questionnaire on the use of CGA tools in different levels of care sent to the Heads of 39 Spanish Geriatric Departments or Services (27 with postgraduate teaching in Geriatrics) during the first three months of 2013. RESULTS: The response rate was 97.4%. It was found that 78.4% (29 centers) used different tools depending on the level of care. Barthel and Lawton index were the most used functional assessment tools in all Departments and across all geriatric levels, although gait speed and Tinetti scale were frequently used in Day Hospital and Outpatient clinics. The Mini Mental State Exam and its Spanish version Mini Examen Cognoscitivo were the most used mental scales (97.4%), followed by tools for assessing depression-behavior (86.8%) and severity of cognitive impairment tools (84.2%). CGA tools were used in 43.2% of the emergency departments of the hospitals surveyed, being the most frequent. More than two-thirds (69.4%) of the Departments reported that their affiliated Primary Care centers used CGA tools, with the Barthel and Lawton again being indexes the most used. Most of the responding Departments considered that the main domains of CGA are functional, mental and social status. Nutrition, comorbidity, falls and pressure ulcers are other important domains. CONCLUSIONS: There is still a great variability in the CGA tools being used in Spanish Geriatric Departments, although there is a trend towards a greater use of Barthel index, greater adaptation of tools to each level of care, and increasing assessment of new domains like frailty, nutrition or comorbidity. PMID- 24953248 TI - Strategies for desymmetrising trehalose to synthesise trehalose glycolipids. AB - The desymmetrisation and regioselective protection of trehalose are major challenges in the chemical synthesis of biologically essential trehalose glycolipids. We reviewed the literature on desymmetrising trehalose to synthesise trehalose glycolipids and highlighted an efficient regioselective 6-O phosphorylation method that can be applied to synthesise asymmetric trehalose glycolipids. PMID- 24953249 TI - Efficacy of addition of transcutaneous electrical nerve stimulation to standardized physical therapy in subacute spinal spasticity: a randomized controlled trial. AB - OBJECTIVE: To study the immediate and short-term efficacy of adding transcutaneous electrical nerve stimulation (TENS) to standardized physical therapy on subacute spasticity within 6 months of spinal cord injury. DESIGN: Randomized controlled trial for 3 weeks. SETTING: A university hospital. PARTICIPANTS: Subjects (N=16) with clinically determined spasticity were randomly assigned to either the experimental group (n=8) or the control group (n=8). INTERVENTION: Sixty-minute sessions of TENS over the bilateral common peroneal nerves before 30 minutes of physical therapy for the experimental group and 30 minutes of physical therapy alone for the control group. All patients in both groups had access to standardized rehabilitation care. MAIN OUTCOME MEASURES: The composite spasticity score, which included 3 subscores (ankle jerk, muscle tone, and ankle clonus scores), was used as the primary end point to assess plantar flexor spasticity. These subscores were designated as secondary end points. Serial evaluations were made at baseline before study entry and immediately after the first and last sessions in both groups. RESULTS: On analysis for immediate effects, there was a significant reduction only in the composite spasticity score (mean difference, 1.75; 99% confidence interval [CI], 0.47-3.03; P=.002) in the experimental group, but no significant reduction was observed in all outcome variables in the control group. A significant difference in the composite spasticity score (1.63; 99% CI, 0.14-3.11; P=.006) was observed between the 2 groups. After 15 sessions of treatment, a significant reduction was determined in the composite spasticity score (2.75; 99% CI, 1.31-4.19; P<.001), the muscle tone score (1.75; 99% CI, 0.16-3.34; P=.006), and the ankle clonus score (0.75; 99% CI, 0.18-1.32; P=.003) in the experimental group, whereas none of the outcome variables revealed a significant reduction in the control group. The between group difference was significant only for the composite spasticity score (2.13; 99% CI, 0.59-3.66; P=.001) and the muscle tone score (1.50; 99% CI, 0.15-2.85; P=.005) after 15 intervention sessions. CONCLUSION: Addition of TENS to standardized physical therapy had synergistically antispastic action, providing more effective reduction of clinical spasticity. PMID- 24953250 TI - Determinants of use of a walking device in persons with Parkinson's disease. AB - OBJECTIVE: To identify determinants for the use of a walking device in persons with Parkinson's disease (PD). DESIGN: Cross-sectional study of participants with PD. SETTING: Laboratory. PARTICIPANTS: Persons with PD (N=85; 60 men) were studied. Their mean age was 69.4+/-8.9 years. The average time since diagnosis was 7.9+/-5.3 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Age, sex, disease duration, disease severity, and motor impairment were recorded. Participants were asked whether they usually used any walking device (eg, cane or walker) and were categorized as either an "independent walker" or a "device walker." Clinical balance measures including functional reach, turn duration, 5 meter timed Up and Go (5m-TUG) test, and Activities-specific Balance Confidence (ABC) scale were investigated for their contribution to the prediction of walking with a device. RESULTS: Thirty-one participants (36.5%) reported that they usually used a walking device. Classification and regression tree analysis determined that the 5m-TUG test and the ABC scale were important factors in differentiating participants who used a walking device from those who did not. Critical thresholds included 13 seconds for the 5m-TUG test and a score of 75 for the ABC scale in determining device walking. Using only these 2 determinants, the classification and regression tree model correctly classified 81% of the patients as either independent or needing a walking device. CONCLUSION: The 5m-TUG test and the ABC scale may be useful in clinical assessments of the need for a walking device in persons with PD. PMID- 24953251 TI - Can measures of limb loading and dynamic stability during the squat maneuver provide an index of early functional recovery after unilateral total hip arthroplasty? AB - OBJECTIVE: To investigate limb loading and dynamic stability during squatting in the early functional recovery of patients who had undergone total hip arthroplasty (THA). DESIGN: Cohort study. SETTING: Inpatient rehabilitation clinic. PARTICIPANTS: Of the total participants (N=99), a random sample of patients who had undergone THA (n=61; 34 men and 27 women; mean age, 62+/-9y; weight, 77+/-14kg; height, 174+/-9 cm) was assessed twice, 13.2+/-3.8 days (t1) and 26.6+/-3.3 days postsurgery (t2), and compared with a healthy reference group (n=38; 22 men and 16 women; mean age, 47+/-12y; weight, 78+/-20kg; height, 175+/ 10cm). INTERVENTIONS: Patients who had undergone THA received 2 weeks of standard inpatient rehabilitation. MAIN OUTCOME MEASURES: Interlimb vertical force distribution and dynamic stability during the squat maneuver, as defined by the root mean square of the center of pressure in anteroposterior and mediolateral directions, of operated and nonoperated limbs. Self-reported function was assessed via the Function Assessment Questionnaire Hannover for Osteoarthritis questionnaire. RESULTS: At t1, unloading of the operated limb was 15.8% greater (P<.001; d=1.070) and anteroposterior and mediolateral center of pressure root mean square values were 30% to 34% higher in patients who had undergone THA than in the healthy reference group (P<.05). Unloading was reduced by 12.8% toward a more equal distribution from t1 to t2 (P<.001; d=.874). Although mediolateral stability improved between t1 and t2 (operated limb: 14.8%; P=.024; d=.397; nonoperated limb: 13.1%; P=.015; d=.321), anteroposterior stability was not significantly different. Self-reported physical function improved by 15.8% (P<.001; d=.965). CONCLUSIONS: Patients who had undergone THA unload the operated limb and are dynamically more unstable during squatting in the early rehabilitation phase after THA than are healthy adults. Although loading symmetry and mediolateral stability improved to the level of healthy adults with rehabilitation, anteroposterior stability remained impaired. Measures of dynamic stability and load symmetry during squatting provide quantitative information that can be used to clinically monitor early functional recovery from THA. PMID- 24953252 TI - Characterization of phenotypic and genotypic drug resistance patterns of Mycobacterium tuberculosis isolates from a city in Mexico. AB - INTRODUCTION: The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis strains has become a worldwide health care problem, making treatment of tuberculosis difficult. The aim of this study was to determine phenotypic resistance and gene mutations associated with MDR of clinical isolates of Mycobacterium tuberculosis from Guadalajara, Mexico. METHODS: One hundred and five isolates were subjected to drug susceptibility testing to first line drugs using the proportion and Mycobacteria Growth Indicator Tube (MGIT) methods. Genes associated with isoniazid (inhA, katG, ahpC) and rifampicin (rpoB) resistance were analyzed by either pyrosequencing or PCR-RFLP. RESULTS: Resistance to any drug was detected in 48.6% of isolates, of which 40% were isoniazid-resistant, 20% were rifampicin-resistant and 19% were MDR. Drug-resistant isolates had the following frequency of mutations in rpoB (48%), katG (14%), inhA (26%), ahpC (26%). Susceptible isolates also had a mutation in ahpC (29%). CONCLUSIONS: This is the first analysis of mutations associated with MDR of M. tuberculosis in Guadalajara. Commonly reported mutations worldwide were found in rpoB, katG and inhA genes. Substitution C to T in position -15 of the ahpC gene may possibly be a polymorphism. PMID- 24953253 TI - [GeSIDA/National AIDS Plan: Consensus document on antiretroviral therapy in adults infected by the human immunodeficiency virus (Updated January 2014)]. AB - OBJECTIVE: This consensus document is an update of combined antiretroviral therapy (cART) guidelines for HIV-1 infected adult patients. METHODS: To formulate these recommendations a panel composed of members of the Grupo de Estudio de Sida and the Plan Nacional sobre el Sida reviewed the efficacy and safety advances in clinical trials, cohort and pharmacokinetic studies published in medical journals (PubMed and Embase) or presented in medical scientific meetings. Recommendations strength and the evidence in which they are supported are based on modified criteria of the Infectious Diseases Society of America. RESULTS: In this update, antiretroviral therapy (ART) is recommended for all patients infected by type 1 human immunodeficiency virus (HIV-1). The strength and grade of the recommendation varies with the clinical circumstances: CDC stage B or C disease (A-I), asymptomatic patients (depending on the CD4+ T-lymphocyte count: <350cells/MUL, A-I; 350-500 cells/MUL, A-II, and >500 cells/MUL, B-III), comorbid conditions (HIV nephropathy, chronic hepatitis caused by HBV or HCV, age >55years, high cardiovascular risk, neurocognitive disorders, and cancer, A-II), and prevention of transmission of HIV (mother-to-child or heterosexual, A-I; men who have sex with men, A-III). The objective of ART is to achieve an undetectable plasma viral load. Initial ART should always comprise a combination of 3 drugs, including 2 nucleoside reverse transcriptase inhibitors and a third drug from a different family (non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or integrase inhibitor). Some of the possible initial regimens have been considered alternatives. This update presents the causes and criteria for switching ART in patients with undetectable plasma viral load and in cases of virological failure where rescue ART should comprise 2 or 3 drugs that are fully active against the virus. An update is also provided for the specific criteria for ART in special situations (acute infection, HIV-2 infection, and pregnancy) and with comorbid conditions (tuberculosis or other opportunistic infections, kidney disease, liver disease, and cancer). CONCLUSIONS: These new guidelines updates previous recommendations related to cART (when to begin and what drugs should be used), how to monitor and what to do in case of viral failure or drug adverse reactions. cART specific criteria in comorbid patients and special situations are equally updated. PMID- 24953254 TI - IGFBP-3: a cell fate pivot in cancer and disease. AB - One of the hallmarks in the advancement of cancer cells is an ability to overcome and acquire resistance to adverse conditions. There has been a large amount of cancer research on IGFBP-3 as a pro-apoptotic molecule in vitro. These pro apoptotic properties, however, do not correlate with several studies linking high IGFBP-3 levels in breast cancer tissue to rapid growth and poor prognosis. Evidence is emerging that IGFBP-3 also exhibits pro-survival and growth-promoting properties in vitro. How IGFBP-3 pivots cell fate to either death or survival, it seems, comes down to a complex interplay between cells' microenvironments and the presence of cellular IGFBP-3 binding partners and growth factor receptors. The cytoprotective actions of IGFBP-3 are not restricted to cancer but are also observed in other disease states, such as retinopathy and brain ischaemia. Here we review the literature on this paradoxical nature of IGFBP-3, its pro-apoptotic and growth-inhibitory actions versus its cytoprotective and growth-potentiating properties, and discuss the implications of targeting IGFBP-3 for treatment of disease. PMID- 24953256 TI - Low-dose ethanol aggravates allergic dermatitis in mice. AB - Alcohol injures dendritic cells and suppresses cellular immunity, while some evidence indicates that drinking alcohol aggravates allergic asthma. This study investigated the effect of low doses of ethanol in enhancing allergic reactions in the skin of mice. Liquid food containing alcohol was administered to conventional NC/Nga mice to induce alcoholic hepatic steatosis, and spontaneous dermatitis was evaluated. BALB/c mice were administered approximately 1 g/kg body weight of ethanol by gavage, and contact hypersensitivity (CHS) or active cutaneous anaphylaxis (ACA) was induced. Spleens were collected 24 h after the elicitation of CHS and mRNA expressions of interferon (IFN)-gamma, interleukin (IL)-4, IL-6, IL-10, and IL-18 were measured by quantitative RT-PCR. Alcohol containing diet exaggerated spontaneous dermatitis in conventional NC/Nga mice and contact hypersensitivity in BALB/c mice. Ethanol administered by gavage for 5 days enhanced contact hypersensitivity in BALB/c mice. Ethanol administration with gavage also enhanced ACA of BALB/c mice. Ethanol did not affect mRNA expression of IFN-gamma and IL-4, but did enhance IL-6, IL-10, and IL-18 mRNA expression. Histological evaluation revealed an absence of hepatic steatosis in mice administered ethanol by gavage for 5 days. In ethanol-administered mice, inflamed areas presented as lesions or a local extreme accumulation of mononuclear cells in the epidermis. These findings suggest that ethanol enhances the expression of inflammatory cytokines independently from T helper (Th)1/Th2 cytokine phenotypes, causing abnormalities in the epidermis resulting in exacerbated allergic reactivity. PMID- 24953255 TI - IgE FcER1beta polymorphism and risk of developing chronic spontaneous urticaria: A study in an ethnic Kashmiri population. AB - BACKGROUND: The pathogenesis of chronic spontaneous urticaria involves interplay between the genetic and environmental factors, most of which is still poorly understood. It is well-recognized that 30-40% of chronic spontaneous urticaria is autoimmune in nature. Chronic autoimmune urticaria is caused by anti-FcER1beta and less frequently, by anti-IgE auto antibodies that lead to mast cell and basophil activation, thereby giving rise to the release of histamine and other proinflammatory mediators. We investigated the association between SNP loci in FcER1beta and chronic spontaneous urticaria and to see its relation with serum IgE levels in Kashmiri population. METHODS: The autologous serum skin test was used as a screening test for chronic autoimmune urticaria. PCR-RFLP was used to detect the genotype of the SNP loci. Serum IgE levels were assessed by ELISA kit. RESULTS: No significant difference was found between the study population and control group in genotype distribution (wild and variant) among FcER1beta loci (P value=0.06, odds ratio=0.29). The frequency of FcER1beta (C109T) in autologous serum skin test positive chronic autoimmune urticaria patients with the CT genotype was found to be statistically non-significant when compared with the wild genotype (P=0.35). Carriers of FcER1beta (T allele) had a more significant risk of developing CAU than those with C allele (P=0.01). In our population serum total IgE levels did not find any statistical significance with regard to ASST positive & ASST negative patients (P=0.26). CONCLUSIONS: There is statistically no significant association between FcER1beta gene polymorphism and CSU in Kashmiri population; however, there is a probability of developing CSU in patients carrying FcER1beta T allele. Furthermore, serum total IgE levels had no significant association with the development of CAU. PMID- 24953257 TI - Simultaneous removal of inorganic and organic compounds in wastewater by freshwater green microalgae. AB - Batch experiments were carried out for 7 days to investigate the simultaneous removal of various organic and inorganic contaminants including total nitrogen (TN), total phosphorus (TP), metals, pharmaceuticals and personal care products (PPCPs), endocrine disrupting chemicals (EDCs), and estrogenic activity in wastewater by four freshwater green microalgae species, Chlamydomonas reinhardtii, Scenedesmus obliquus, Chlorella pyrenoidosa and Chlorella vulgaris. After treatment for 7 days, 76.7-92.3% of TN, and 67.5-82.2% of TP were removed by these four algae species. The removal of metals from wastewater by the four algae species varied among the metal species. These four algae species could remove most of the metals efficiently (>40% removal), but showed low efficiencies in removing Pb, Ni and Co. The four algae species were also found to be efficient in removing most of the selected organic compounds with >50% removal, and the estrogenic activity with removal efficiencies ranging from 46.2 to 81.1% from the wastewater. Therefore, algae could be harnessed to simultaneously remove various contaminants in wastewater. PMID- 24953258 TI - Sleep deprivation affects somatosensory cortex excitability as tested through median nerve stimulation. AB - BACKGROUND: Changes of cortical excitability after sleep deprivation (SD) in humans have been investigated mostly in motor cortex, while there is little empirical evidence concerning somatosensory cortex, and its plastic changes across SD. OBJECTIVE: To assess excitability of primary somatosensory cortex (S1) and EEG voltage topographical characteristics associated with somatosensory evoked potentials (SEPs) during SD. METHODS: Across 41 h of SD, 16 healthy subjects participated in 4 experimental sessions (11.00 a.m. and 11.00 p.m. of the 1st and 2nd day) with: a) subjective sleepiness ratings; b) EEG recordings; c) SEPs recordings; d) behavioral vigilance responses. RESULTS: A clear enhancement of cortical excitability after SD was indexed by: (a) an amplitude increase of different SEPs component in S1; (b) higher voltage in occipital (around 35-43 ms) and fronto-central areas (around 47-62 ms). Circadian fluctuations did not affect cortical excitability. Voltage changes in S1 were strongly related with post-SD fluctuations of subjective and behavioral sleepiness. CONCLUSIONS: Sleep may have a role in keeping cortical excitability at optimal (namely below potentially dangerous) levels for the human brain, rebalancing progressive changes in cortical responsiveness to incoming inputs occurred during time spent awake. On the other hand, higher level of cortical responsiveness after sleep loss may be one of the mechanisms accounting for post SD alterations in vigilance and behavior. PMID- 24953259 TI - The psychiatric sequelae of burn injury. AB - OBJECTIVE: To examine factors predicting psychiatric morbidity, taking into account the full range of psychiatric disorders before and after burn injury. METHODS: A cohort of 107 patients consecutively admitted to a Swedish national burn center was examined for lifetime psychiatric morbidity, as well as 94 patients at 1 year postinjury. Sixty-seven individuals, some from that same cohort, were interviewed at 2 to 7years postinjury. The predictive effects of psychiatric history, personality and other risk factors for psychiatric morbidity following burn were evaluated with multiple regression analyses. RESULTS: The prevalence of having a psychiatric disorder preburn was 57%. One year postinjury 19% had minor or major depression and 23% had subsyndromal or full posttraumatic stress disorder. At 2 to 7years, 31% fulfilled the criteria for a psychiatric disorder. The strongest contributing factors were a history of psychiatric morbidity and neuroticism. CONCLUSIONS: Two-thirds of the patients had a lifetime psychiatric disorder, and one-third had a psychiatric diagnosis 2 to 7years postburn. Mental health problems can have a major impact on daily life and functional abilities. Thus, identification and treatment of a range of psychiatric disorders, taking into account preburn psychiatric disorders and personality, is important for optimal adjustment after burn. PMID- 24953260 TI - Orlistat abuse in a case of bulimia nervosa: the changing Indian society. AB - Eating disorders like bulimia nervosa, generally considered to be rare in Asian countries, are currently on the rise among the youth, probably secondary to rapid westernization and globalization of the orient. Clinical manifestations of these disorders, which were previously thought to be different in the oriental countries, are now also often seen to parallel their western counterparts. However, detailed clinical descriptions of such cases from Asian countries, documenting the societal change, are missing. In addition, the possibility of abuse of various anti-obesity drugs as a part of bulimic compensatory behavior is high in this population, given the easy and unsupervised access of these drugs over the counter. We report a case of bulimia nervosa in a female medical graduate from India, presenting with classic bulimic symptomatology and with a compensatory behavior consisting almost exclusively of Orlistat abuse. This case sensitizes health professionals to the abuse liability of new medications like Orlistat and also documents the changing symptomatology of bulimia nervosa in India. PMID- 24953261 TI - Is torso soft tissue motion really an artefact within breast biomechanics research? AB - For rigid body POSE estimation, any relative movement of the tracking markers on a segment is often referred to as an artefact; however this may be an important part of the signal within breast biomechanics. This study aimed to quantify differences in breast range of motion when calculated relative to the torso segment using either direct or segment optimised POSE estimation algorithms. Markers on the torso and right nipple were tracked using infrared cameras (200 Hz) during five running gait cycles in three breast support conditions (no bra, everyday bra and sports bra). Multiplanar breast range of motion was calculated relative to the torso segment using two POSE estimation algorithms. First, the torso segment was defined using direct POSE estimation (direct). Second, while standing stationary in the anatomical position; the positional data of the torso markers were used to construct the torso using segment optimised POSE estimation (optimised). The torso segment length defined using direct POSE estimation changed significantly by 3.4 cm compared to that of the segment optimisation POSE estimation in the no bra condition. Subsequently, superioinferior breast range of motion was significantly greater (p<0.017) when calculated using direct POSE estimation, within each of the three breast support conditions. Segment optimisation POSE estimation is recommended to minimise any differences in breast motion associated with intra segment deformation between physical activity types. However, either algorithm is recommended when evaluating different breast support garments, as a correctly fitted bra does not cause the torso markers to move relative to each other. PMID- 24953262 TI - Neurotrophins: Role in adverse pregnancy outcome. AB - Proper placental development is essential during pregnancy since it forms the interface between the maternal-foetal circulations and is critical for foetal nutrition and oxygenation. Neurotrophins such as nerve growth factor (NGF), brain derived neurotrophin (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) are naturally occurring molecules that regulate development of the placenta and brain. BDNF and NGF also involved in the regulation of angiogenesis. Recent studies suggest that the levels of BDNF and NGF are regulated by docosahexaenoic acid (DHA) which is an important omega-3 fatty acid and is a structural component of the plasma membrane. Oxidative stress during pregnancy may lower the levels of DHA and affecting the fluidity of the membranes leading to the changes in the levels and expression of BDNF and NGF. Therefore altered levels and expression of NGF and BDNF may lead to abnormal foetal growth and brain development that may increase the risk for cardiovascular disease, metabolic syndromes and neurodevelopmental disorders in children born preterm. This review discuss about the neurotrophins and their role in the feto-placental unit during critical period of pregnancy. PMID- 24953264 TI - Prehistoric schistosomiasis parasite found in the Middle East. PMID- 24953263 TI - Retardation of fetal dendritic development induced by gestational hyperglycemia is associated with brain insulin/IGF-I signals. AB - Hyperglycemia is an essential risk factor for mothers and fetuses in gestational diabetes. Clinical observation has indicated that the offspring of mothers with diabetes shows impaired somatosensory function and IQ. However, only a few studies have explored the effects of hyperglycemia on fetal brain development. Neurodevelopment is susceptible to environmental conditions. Thus, this study aims to investigate the effects of maternal hyperglycemia on fetal brain development and to evaluate insulin and insulin-like growth factor-I (IGF-I) signals in fetal brain under hyperglycemia or controlled hyperglycemia. At day 1 of pregnancy, gestational rats were intraperitoneally injected with streptozocin (60 mg/kg). Some of the hyperglycemic gestational rats were injected with insulin (20 IU, two times a day) to control hyperglycemia; the others were injected with saline of equal volume. The gestational rats were sacrificed at days 14, 16, and 18 of embryo development. The dendritic spines of subplate cortex neurons in the fetal brain were detected by Golgi-Cox staining. The mRNA levels of insulin receptors (IRs) and IGF-IR in the fetal brain were measured using qRT-PCR. The protein levels of synaptophysin, IR, and IGF-IR in the fetal brain were detected by western blot. No significant difference in fetal brain formation was observed between the maternal hyperglycemic group and insulin-treated group. By contrast, obvious retardation of dendritic development in the fetus was observed in the maternal hyperglycemic group. Similarly, synaptophysin expression was lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. The mRNA and protein expression levels of IRs in the fetal brain were higher in the hyperglycemic group than in the insulin-treated group. By contrast, the levels of IGF-IR in the brain were lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. These results suggested that maternal hyperglycemia can retard dendritic development in the fetal brain and that these changes partially resulted from abnormal insulin/IGF-I signaling in the fetal brain. PMID- 24953265 TI - A simple algorithm reduces computed tomography use in the diagnosis of appendicitis in children. AB - BACKGROUND: A diagnostic algorithm for appendicitis in children was created to reduce computed tomography (CT) use owing to the risk of cancer from radiation exposure and cost of CT. This study evaluates the impact of the algorithm on CT use and diagnostic accuracy of appendicitis. METHODS: Patients <=18 years who underwent appendectomy for suspected appendicitis after presenting to the emergency department for 2 years before and 3 years after algorithm implementation were identified. Clinical characteristics and outcomes, including use of CT and negative appendectomy rate, were compared between the pre- and post implementation periods. Multivariable analysis was used to determine the impact of CT on negative appendectomy. RESULTS: We identified 331 patients-41% in the pre- and 59% in the post-implementation period. CT utilization decreased from 39% to 18% (P < .001) after implementation. The negative appendectomy rate increased from 9% to 11% (P = .59). Use of CT did not impact the risk of negative appendectomy (P = .64). CONCLUSION: Utilization of CT was significantly reduced after implementation of a diagnostic algorithm for appendicitis without impacting diagnostic accuracy. Given the concern for increased risk of cancer after CT, these results support use of an algorithm in children with suspected appendicitis. PMID- 24953266 TI - A comparison of colorectal cancer in Nigerian and North American patients: is the cancer biology different? AB - BACKGROUND: Of the 24 million people predicted to have cancer by 2050, 70% will live in low- and middle-income countries (LMIC). As a result, cancer care is becoming a priority for health care systems in West Africa. This study compares the presentation and pattern of spread of colorectal cancer (CRC) observed in a hospital in West Africa with that of a North American referral center. METHODS: Data on all adults presenting with CRC at a hospital in Nigerian patients (West Africa; 1990-2011) and all adults with stages III or IV CRC at a specialty hospital in (New York City, New York, North America; 2005-2011) were examined retrospectively. Demographic data, stage of disease, site of metastasis, and survival were compared. RESULTS: There were 160 patients identified in West Africa and 1,947 patients identified in North America. Nigerian patients were younger (52 vs 59 years; P < .01) and presented with a later stage of disease (58% stage IV vs 47%; P < .01). Site of disease presentation was different between West African and North American patients (P < .01); 2.2% of West African patients presented with liver metastases only compared with 48.1% of North American patients. Conversely, 61.3% of patients in West Africa presented with peritoneal metastases only compared with 5.4% in North America. Overall survival stratified by stage at presentation (III/IV) showed worse prognosis for patients in either stage subgroup in Nigeria than North America. CONCLUSION: We found differences in the presentation, metastatic pattern, and outcomes of CRC in Nigerian (West Africa) when compared with New York City (North America). Late detection and differential tumor biology may drive the differences observed between the sites. Future studies on early CRC detection and on tumor biology in LMIC will be critical for understanding and treating CRC in this region. PMID- 24953267 TI - Worse outcomes among uninsured general surgery patients: does the need for an emergency operation explain these disparities? AB - BACKGROUND: We hypothesize that lack of access to care results in propensity toward emergent operative management and may be an important factor in worse outcomes for the uninsured population. The objective of this study is to investigate a possible link to worse outcomes in patients without insurance who undergo an emergent operation. METHODS: A retrospective cross-sectional analysis was performed using the Nationwide Inpatient Sample (NIS) 2005-2011 dataset. Patients who underwent biliary, hernia, and colorectal operations were evaluated. Multivariate analyses were performed to assess the associations between insurance status, urgency of operation, and outcome. Covariates of age, sex, race, and comorbidities were controlled. RESULTS: The uninsured group had greatest odds ratios of undergoing emergent operative management in biliary (OR 2.43), colorectal (3.54), and hernia (3.95) operations, P < .001. Emergent operation was most likely in the 25- to 34-year age bracket, black and Hispanic patients, men, and patients with at least one comorbidity. Postoperative complications in emergencies, however, were appreciated most frequently in the populations with government coverage. CONCLUSION: Although the uninsured more frequently underwent emergent operations, patients with coverage through the government had more complications in most categories investigated. Young patients also carried significant risk of emergent operations with increased complication rates. Patients with government insurance tended toward worse outcomes, suggesting disparity for programs such as Medicaid. Disparity related to payor status implies need for policy revisions for equivalent health care access. PMID- 24953268 TI - Readability of online patient resources for the operative treatment of breast cancer. AB - BACKGROUND: Increasing use of Internet resources for health information is important in promoting patient involvement in medical care and decision-making. The National Institutes of Health and American Medical Association have recommended that patient health information should be written at a sixth-grade reading level. This study evaluates the readability of the most commonly used Internet resources for the operative treatment of breast cancer in the context of average American literacy. METHODS: The top 10 websites for "breast cancer surgery" based on public Internet search engines were identified. Patient directed content was downloaded from all relevant articles on these sites. A total of 104 articles were assessed with the use of 10 established readability analyses. Average readability scores were analyzed for all articles as well as by website. RESULTS: The overall average reading level across all sites was 12.9; this was similar between tests (Coleman-Liau 12.6, Flesch Kincaid 12.3, FORCAST 11.2, Fry 14, Gunning Fog 14.4, New Dale-Chall 12.4, New Fog 11, Raygor 14, and Simple Measure of Gobbledygook 14.3). Comparing readability by website showed disparity in average reading level from 11.2 to 16.5. CONCLUSION: Online patient resources for breast cancer surgery exceed recommended reading levels and are too difficult to be understood by a large portion of the United States population. PMID- 24953269 TI - Hypercoagulability after injury in premenopausal females: a prospective, multicenter study. AB - BACKGROUND: Recent studies suggest there are gender-specific differences in injury response that may be related to coagulation. The objective of this study was to test the hypothesis that rapid thrombelastography (rTEG) coagulation profiles differ by gender. METHODS: Adult trauma patients were prospectively followed at 3 level 1 trauma centers over a 14-month period. rTEG was obtained upon arrival and serially at several time points during the hospital stay. Female patients were stratified into premenopausal (<=50 years) and postmenopausal (>50 years) age groups with age-matched male cohorts. Values were analyzed using a repeated-measures multilevel linear model to evaluate the effect of gender on coagulation. RESULTS: A total of 795 patients had serial rTEG data (24% female and 76% male). Compared with age-matched males, premenopausal females were more hypercoagulable by rTEG on admission (P < .001) and for the first 12 hours after arrival. Gender was an effect modifier for alpha angle (P = .02) and maximum amplitude (P = .04). Controlling for Injury Severity Score and mechanism of injury, age-matched males had a >4-fold increased risk of hypercoagulable complications than premenopausal females (odds ratio, 4.7; P = .038). CONCLUSION: This prospective, multicenter study demonstrates that premenopausal females are relatively hypercoagulable compared with age-matched males early after injury. However, this did not translate into higher thromboembolic complications. PMID- 24953270 TI - Assessing the experience in complex hepatopancreatobiliary surgery among graduating chief residents: is the operative experience enough? AB - INTRODUCTION: Resident operative autonomy and case volume is associated with posttraining confidence and practice plans. Accreditation Council for Graduate Medical Education requirements for graduating general surgery residents are four liver and three pancreas cases. We sought to evaluate trends in resident experience and autonomy for complex hepatopancreatobiliary (HPB) surgery over time. METHODS: We queried the Accreditation Council for Graduate Medical Education General Surgery Case Log (2003-2012) for all cases performed by graduating chief residents (GCR) relating to liver, pancreas, and the biliary tract (HPB); simple cholecystectomy was excluded. Mean (+/-SD), median [10th-90th percentiles] and maximum case volumes were compared from 2003 to 2012 using R(2) for all trends. RESULTS: A total of 252,977 complex HPB cases (36% liver, 43% pancreas, 21% biliary) were performed by 10,288 GCR during the 10-year period examined (Mean = 24.6 per GCR). Of these, 57% were performed during the chief year, whereas 43% were performed as postgraduate year 1-4. Only 52% of liver cases were anatomic resections, whereas 71% of pancreas cases were major resections. Total number of cases increased from 22,516 (mean = 23.0) in 2003 to 27,191 (mean = 24.9) in 2012. During this same time period, the percentage of HPB cases that were performed during the chief year decreased by 7% (liver: 13%, pancreas 8%, biliary 4%). There was an increasing trend in the mean number of operations (mean +/- SD) logged by GCR on the pancreas (9.1 +/- 5.9 to 11.3 +/- 4.3; R(2) = .85) and liver (8.0 +/- 5.9 to 9.4 +/- 3.4; R(2) = .91), whereas those for the biliary tract decreased (5.9 +/- 2.5 to 3.8 +/- 2.1; R(2) = .96). Although the median number of cases [10th:90th percentile] increased slightly for both pancreas (7.0 [4.0:15] to 8.0 [4:20]) and liver (7.0 [4:13] to 8.0 [5:14]), the maximum number of cases preformed by any given GCR remained stable for pancreas (51 to 53; R(2) = .18), but increased for liver (38 to 45; R(2) = .32). The median number of HPB cases that GCR performed as teaching assistants (TAs) remained at zero during this time period. The 90th percentile of cases performed as TA was less than two for both pancreas and liver. CONCLUSION: Roughly one-half of GCR have performed fewer than 10 cases in each of the liver, pancreas, or biliary categories at time of completion of residency. Although the mean number of complex liver and pancreatic operations performed by GCR increased slightly, the median number remained low, and the number of TA cases was virtually zero. Most GCR are unlikely to be prepared to perform complex HPB operations. PMID- 24953271 TI - Regionalization of the surgical care of children: a risk-adjusted comparison of hospital surgical outcomes by geographic areas. AB - BACKGROUND: There is an ongoing debate among pediatric surgeons regarding the need or lack thereof to centralize the surgical care of children to high-volume children's centers. Risk-adjusted comparisons of hospitals performing pediatric surgery are needed. METHODS: Admissions from 2006 to 2010 from two national administrative databases were analyzed. Only nontrauma pediatric patients undergoing a noncardiac surgical procedure were included. Risk-adjustment was performed with a validated International Classification of Diseases, 9th Revision code-based tool. Hospitals were grouped into metropolitan regions using the first three digits of their zip code. Poorly performing outlier hospitals were defined by an odds ratio >1 and P value <.05 for mortality compared with the center with the greatest pediatric operative volume in that same region. RESULTS: Information was obtained from 415,546 pediatric surgical admissions, and 173 hospitals in 55 regions were compared. A total of 18 poor performing hospitals (adjusted odds ratio, range 1.91-35.95) in 15 regions were identified. Mortality in poor performers ranged from 1.11% to 10.19% whereas that in the high-volume reference centers was 0.37-2.41%. A subset analysis in patients <1 year of age showed 37 poor performers in 46 regions. Median number of surgical admissions was 345 (interquartile range 152-907) for nonoutlier and 240 (interquartile range 135 566) for outlier centers (P = .30). CONCLUSION: The present analysis is a novel risk-adjusted assessment of the performance of hospitals delivering pediatric surgical care. By identifying the existence of multiple poor performing outlier hospitals, this study provides valuable data for discussion as health care delivery systems continue to debate optimal resource distribution and regionalization of the surgical care of children. PMID- 24953272 TI - Surgical inpatient satisfaction: what are the real drivers? AB - BACKGROUND: Inpatient satisfaction is a key element of hospital pay-for performance programs. Communication and pain management are known to influence results, but additional factors may affect satisfaction scores. We tested the hypothesis that patient factors and outcome parameters not considered previously are clinically important drivers of inpatient satisfaction. METHODS: Medical records were reviewed for 1,340 surgical patients who returned nationally standardized inpatient satisfaction questionnaires. These patients were managed by 41 surgeons in seven specialties at two academic medical centers. Thirty-two parameters based on the patient, surgeon, outcomes, and survey were measured. Univariate and multivariable analyses were performed. RESULTS: Inpatients rated their overall experience favorably 75.7% of the time. Less-satisfied patients were more likely to be female, younger, less ill, taking outpatient narcotics, and admitted via the emergency department (all P < .02). Less-satisfied patients also were more likely to have unresected cancer (P < .001) or a postoperative complication (P < .001). The most relevant independent predictors of dissatisfaction in multivariable analyses were younger age, admission via the emergency department, preoperative narcotic use, lesser severity of illness, unresected cancer, and postoperative morbidity (all P < .01). CONCLUSION: Several patient factors, expectations of patients with cancer, and postoperative complications are important and clinically relevant drivers of surgical inpatient satisfaction. Programs to manage expectations of cancer patient expectations and decrease postoperative morbidity should improve surgical inpatient satisfaction. Further efforts to risk-adjust patient satisfaction scores should be undertaken. PMID- 24953273 TI - Sorafenib and triptolide as combination therapy for hepatocellular carcinoma. AB - INTRODUCTION: Sorafenib is the only drug approved by the Food and Drug Administration for metastatic hepatocellular carcinoma (HCC). Triptolide, a diterpene triepoxide, exhibits antineoplastic properties in multiple tumor cell types. In this study, we examined the effects of these agents and their combination on HCC in vitro and in vivo models. METHODS: HuH-7 and PLC/PRF/5 cells were treated with triptolide (50 nM), sorafenib (1.25 or 2.5 MUM), or a combination of both. Cell viability assay (CCK-8), caspase 3&7 activation, and nuclear factor kappaB assays were performed. For in vivo studies, 40 mice were implanted with subcutaneous HuH7 tumors and divided into four treatment groups (n = 10); saline control, sorafenib 10 mg/kg PO daily (S), Minnelide (a prodrug of triptolide) 0.21 mg/kg intraperitoneally7 daily (M), and combination of both (C). Tumor volumes were assessed weekly. RESULTS: The combination of triptolide and sorafenib was superior to either drug alone in inducing apoptosis and decreasing viability, whereas triptolide alone was sufficient to decrease nuclear factor kappaB activity. After 2 weeks of treatment, tumor growth inhibition rates were S = 59%, M = 84%, and C = 93%, whereas tumor volumes in control animals increased by 9-fold. When crossed over to combination treatment, control mice tumor growth volumes plateaued over the following 4 weeks. CONCLUSION: The combination of sorafenib and triptolide is superior to single drug treatment in increasing cell death and apoptosis in vitro. Combining sorafenib with Minnelide inhibited tumor growth with greater efficacy than single-agent treatments. Importantly, in vivo combination treatment allowed for using a lesser dose of sorafenib (10 mg/kg), which is less than 10% of currently prescribed dose for HCC patients. Therefore, combination treatment could have translational potential in the management of HCC. PMID- 24953276 TI - The rate of operative success achieved with radioguided occult lesion localization and intraoperative ultrasonography in patients with recurrent papillary thyroid cancer. AB - BACKGROUND: To investigate the rate of operative success in excision of nonpalpable lymph nodes with metastatic disease achieved with radioguided occult lesion localization (ROLL) and intraoperative ultrasonography (IOUS) in patients with papillary thyroid cancer (PTC). METHODS: Twenty consecutive PTC patients with nonpalpable lymph nodes with metastatic disease localized in previously operated fields were randomized to receive ROLL (n = 11) or IOUS (n = 9). Nodes were excised along with adjacent soft tissue to accomplish a compartment-oriented dissection. The duration of operation, rate of postoperative complications, pre- and postoperative serum thyroglobulin (Tg) levels, and the findings of postoperative neck ultrasonography and postablation scan were recorded in all patients. Measures of operative success included a postoperative Tg level <50% of preoperative Tg level and no abnormal lesions on postoperative imaging. RESULTS: Histopathologic examination confirmed the excision of all preoperatively identified metastatic nodes. Additional nodes also were excised (2.3 +/- 3.3 per specimen in the ROLL group and 1.6 +/- 1.8 per specimen in the IOUS group), 23% of which were metastatic. No postoperative complications occurred in either group. The duration of operation was similar in the 2 groups (P = .4). Postoperative imaging confirmed the clearance of suspicious nodes in all patients. The rate of operative success in ROLL and IOUS group were 100% and 89%, respectively. CONCLUSION: In patients with recurrent PTC, a high rate of operative success in excision of nonpalpable metastatic lymph nodes was achieved by both ROLL and IOUS. We recommend compartment-oriented dissection; this approach may maximize the removal of metastatic nodes not identified by preoperative imaging. PMID- 24953274 TI - Simultaneous lung resection via a transdiaphragmatic approach in patients undergoing liver resection for synchronous liver and lung metastases. AB - BACKGROUND: For patients with synchronous liver and lung metastases from colorectal cancer, the invasiveness of adding thoracic to abdominal surgery is an obstacle to concurrent liver and lung metastasectomy. We developed a simple technique to resect lung lesions via a transdiaphragmatic approach without thoracic incision in patients undergoing liver metastasectomy. METHODS: Sixteen patients with synchronous liver and unilateral lung metastases underwent transdiaphragmatic wedge resection of lung lesions simultaneous with liver metastasectomy. Short-term operative outcomes were compared with those in 102 patients treated with conventional unilateral wedge resection for colorectal lung metastases. RESULTS: Twenty peripheral (<3 cm from the pleura) lung lesions from various locations in the lung were resected via transdiaphragmatic approach. No conversions to conventional approach were required. The median tumor number and size were 1 (range, 1-3) and 8 mm (range, 3-30 mm), respectively. Transdiaphragmatic resection reduced median operative blood loss compared with conventional resection (0 mL vs 50 mL [P < .001]) and reduced median duration of hospital stay compared with staged liver and lung resection (6 days vs 11 days [P < .001]). Operative duration and rates of lung-related morbidity and positive surgical margin were similar between the transdiaphragmatic and conventional groups (104 minutes vs 105 minutes [P = .61], 13% vs 4% [P = .15], and 6% vs 5% [P = .73], respectively). CONCLUSION: Simultaneous transdiaphragmatic resection of peripheral lung lesions is safe in patients undergoing liver resection. The low-invasive transdiaphragmatic approach facilitates aggressive operative treatment for synchronous liver and lung metastases. PMID- 24953277 TI - Role of right upper mediastinal lymph node metastasis in patients with esophageal squamous cell carcinoma after tri-incisional esophagectomies. AB - BACKGROUND: Whereas standard (infracarinal) mediastinal lymphadenectomy refers to the clearance of lymph nodes in the middle and lower posterior mediastinum, extension along right side of trachea and upper mediastinum is termed extended lymphadenectomy. The benefit of an extended versus standard lymphadenectomy in esophageal cancer is unclear. METHODS: The clinicopathologic data of 391 patients undergoing tri-incisional esophagectomy (McKeown type) for squamous cell carcinoma between 1995 and 2007 were analyzed retrospectively. There were 136 and 255 patients in the infracarinal and extended mediastinal lymphadenectomy groups, respectively. The outcome of these two groups and the clinical importance of right upper mediastinum lymph node metastases (LNM) were investigated. RESULTS: Both groups were comparable in clinicopathologic characteristics except tumor length (infracarinal vs extended group, 4.6 vs 5.2 cm, P = .023) and lymph node status. The 5-year overall survival rates were 29.7% and 27.3%, in the infracarinal and extended groups, respectively (P = .065). In the extended group, the factors correlated to right upper mediastinal LNM included neck LNM (hazard ratio [HR] 2.621, P = .029), abdominal LNM (HR 2.218, P = .016), and tumor locating in the upper/middle third of esophagus (HR 2.781, P = .014). The independent prognostic factors for overall survival included right upper mediastinal LNM (HR 1.964, P < .001), lower mediastinal LNM (HR 1.391, P = .039), and abdominal LNM (HR 1.538, P = .006). CONCLUSION: The procedure of right upper mediastinum lymphadenectomy is not associated with better survival in patients with esophageal squamous cell carcinoma patients; the presence of upper mediastinum LNM predicted poor prognosis. PMID- 24953275 TI - Normal saline influences coagulation and endothelial function after traumatic brain injury and hemorrhagic shock in pigs. AB - BACKGROUND: Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of trauma-related deaths. These insults disrupt coagulation and endothelial systems. This study investigated whether previously reported differences in lesion size and brain swelling during normal saline (NS), colloids (Hextend [HEX]), and fresh frozen plasma (FFP) resuscitation are associated with differential effects on coagulation and endothelial systems. METHODS: We subjected 15 Yorkshire swine to TBI and HS (40% blood volume), and kept in HS for 2 hours before resuscitation with NS, HEX, or FFP. Markers of endothelial activation (E-selectin, Intercellular adhesion molecule [ICAM]-1), coagulation activation (prothrombin fragment 1 + 2), and natural anticoagulation (activated protein C [aPC]) were determined in serum and brain whole cell lysates. RESULTS: Serum levels of aPC were greater in the NS group (203 +/- 30 pg/mL) compared with HEX (77 +/- 28 pg/mL; P = .02) and FFP (110 +/- 28 pg/mL; P = .09), as was PF 1 + 2 in the brain when compared with FFP (PF 1 + 2, 89 +/- 46 vs 37 +/- 14 ng/mL; P = .035). Brain E-selectin was greater in the NS group compared with FFP (3.36 +/- 0.02 vs 3.31 +/- 0.01 ng/mL; P = .029). Circulating ICAM-1 levels were increased in the NS group (151 +/- 9 ng/mL) compared with the HEX (100 +/- 9 ng/mL; P < .01) and FFP (108 +/- 9 ng/mL; P = .01). CONCLUSION: In this clinically realistic large animal model of TBI + HS, NS resuscitation was associated with an early activation of coagulation, natural anticoagulation, and endothelial systems, compared with HEX and FFP. PMID- 24953278 TI - Treatment planning for peripheral arterial disease based on duplex ultrasonography and computed tomography angiography: consistency, confidence and the value of additional imaging. AB - BACKGROUND: Duplex ultrasonography (DUS) can be used for treatment planning for lower extremity peripheral arterial disease (PAD), but has not replaced contrast enhanced imaging such as computed tomography angiography (CTA). We assessed DUS based treatment planning for consistency, confidence, and the value of additional CTA among multinational surgeons. METHODS: Data from 12 patients with PAD were reviewed by 2 American vascular surgeons individually and 1 Dutch vascular department by consensus. Reviewers selected treatment based on DUS first and based on added CTA second. Agreement and consistency of treatment plans was assessed using kappa statistics (kappa). Imaging quality and therapeutic confidence were scored (1-5) and assessed with t-tests. RESULTS: Of the 36 treatment plans formulated, additional CTA confirmed 27 (75%), changed 6 (17%), and supplemented 3 (8%) plans. The approach never changed when open revascularization was selected based on DUS (14 plans; 39%). Agreement between DUS- and CTA-based treatment planning was substantial, with a mean kappa (MUkappa) of 0.68, but agreement between reviewers was fair (MUkappa DUS, 0.24; MUkappa CTA, 0.23). CTA received greater average scores than DUS for quality (4.36 vs 3.29; P < .0001) and confidence (4.36 vs 3.26; P < .0001). Reviewers often expressed the need for additional imaging after DUS (mean, 63%). CONCLUSION: PAD treatment planning based on CTA was mostly consistent with DUS based treatment plans, although CTA was still felt to be needed to increase confidence. This observation suggests that to promote greater use of less invasive DUS imaging, not only improvement of DUS quality but also improvement of clinician confidence is required. PMID- 24953279 TI - Oncologic results after multivisceral resection of clinical T4 tumors. AB - BACKGROUND: Standard operative management of colorectal cancer (CRC) with adherent adjacent organs is en bloc resection to obtain clear resection margins. We analyzed early and long-term outcomes after multivisceral resection for clinically suspected T4 CRC and identified factors predicting survival. METHODS: All patients operated on for clinically suspected T4 CRC between 2000 and 2010 were identified retrospectively. Data concerning demographics, surgery, pathologic examination and oncologic outcome were analyzed. RESULTS: One hundred fifty-two patients underwent partial or total en bloc resection of >=1 adherent organ. An R0 resection was achieved in 136 patients (89.5%). Malignant invasion of the adherent organ was histologically confirmed in 98 patients (64.5%). Five year overall survival and disease-free survival rates were 77.4% and 58.1%, respectively. On univariate analysis, margin positivity, pT4 stage, and lymph node invasion were predictors of a worse disease-free survival. The presence of liver metastases and concomitant hepatectomy were both factors of poor overall and disease-free survival. On multivariate analysis, resection of >=2 adjacent organs was a predictor of better overall survival. This finding may be explained by the significantly higher rate of tumors with microsatellite instability (MSI) in the group with resection of multiple organs. CONCLUSION: The oncologic outcome of multivisceral resection for clinically suspected colorectal T4 tumors was good, especially in MSI patients and patients without liver metastases. The number of organs requiring resection should not contraindicated radical surgery as in this study it was associated with a good prognosis. PMID- 24953280 TI - Microinjection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens inhibits the cocaine-induced upregulation of dopamine receptors and locomotor sensitization. AB - Repeated exposure to addictive drugs enhances dopamine receptor (DR) signaling and the ultimate phosphorylation of the cyclic adenosine 5'-monophosphate (cAMP) response element-binding protein (CREB)-regulated cocaine- and amphetamine regulated transcript (CART) expression in the nucleus accumbens (NAcc). These effects are known to contribute to the expression of behavioral sensitization. CART peptides are neuropeptides that modulate drug reward and reinforcement. The present experiments investigated the effects of CART 55-102 microinjection into the NAcc on (1) the phosphorylation of CREB, (2) cAMP/protein kinase A (PKA) signaling and (3) extracellular signal-regulated kinase (ERK) phosphorylated kinase signaling. Here, we show that repeated microinjections into the NAcc of CART 55-102 peptides (1.0 or 2.5MUg, 0.5MUl/side) attenuates cocaine-induced enhancements of D1R, D2R and D3R phosphorylation in this sites. Furthermore, the microinjection of CART 55-102 followed by repeated injections of cocaine (15mg/kg) dose-dependently blocked the enhancement of cAMP levels, PKA activity and pERK and pCREB levels on the fifth day of cocaine administration. The cocaine induced locomotor activity and behavioral sensitization in rats were also inhibited by the 5-day-microinjection of CART peptides. These results suggest that the phosphorylation of CREB by cocaine in the NAcc was blocked by the CART 55-102 peptide via the inhibition of D1R and D2R stimulation, D3R phosphorylation, cAMP/PKA signaling and ERK phosphorylated kinase signaling. These effects may have played a compensatory inhibitory role in the behavioral sensitization of rats that received microinjections of CART 55-102. PMID- 24953281 TI - Expression of transcribed ultraconserved regions of genome in rat cerebral cortex. AB - Emerging evidence indicates that 481 regions of the genome (>200 bp) that actively transcribe noncoding RNAs shows 100% homology between humans, rats and mice. These transcribed ultraconserved regions (T-UCRs) are thought to control the essential regulatory functions basic for life in rodents and mammals. Using microarray analysis, we presently show that 107 T-UCRs are actively expressed in adult rat cerebral cortex. They are grouped into intragenic (61) and intergenic (46) based on their genic location. Interestingly, 10 T-UCRs are expressed at unusually high levels in cerebral cortex. Additionally, many T-UCRs also showed cogenic expression. We further analyzed the correlation of intragenic T-UCRs with their host protein coding genes. Surprisingly, most of the expressed intragenic T UCRs (54 out of 61) displayed a negative correlation with their host gene expression. T-UCRs are thought to control the splicing and transcription of the protein-coding genes that host them and flank them. Bioinformatics analysis indicated that the protein products of majority of these genes are nuclear in localization, share protein domains and are involved in the regulation of diverse biological and molecular functions including metabolism, development, cell cycle, binding and transcription factor regulation. In conclusion, this is the first study to shows that many T-UCRs are expressed in rodent brain and they might play a role in physiological brain functions. PMID- 24953282 TI - Hypercalciuria in children with monosymptomatic nocturnal enuresis. AB - OBJECTIVE: The aim of this study was to measure the 24 h urinary calcium content in children with monosymptomatic nocturnal enuresis (MNE) and compare with those in healthy children to investigate whether there is any relation with enuresis and hypercalciuria. MATERIAL AND METHODS: This study included 120 children and adolescents with MNE aged between 7 and 14 years. Eighty age- and sex-matched healthy children served as a control group. To determine urinary calcium excretion, 24 h urine samples were collected. The children with enuresis were divided into two sub-groups as hypercalciuric and normocalciuric groups according to the amount of urinary calcium excretion. RESULTS: Hypercalciuria was found in 27 (23%) of the MNE patients compared with two (4%) of continent children (p<0.001). In addition, the mean 24 h urine calcium/body weight ratio was higher in the enuresis group than in the control group, 2.94+/-2.42 versus 1.59+/-1.72, respectively (p=0.002). When the children with enuresis were divided into two groups as normokalsiuric and hypercalciuric, the hypercalciuric children were younger and the majority of this group were boys.. CONCLUSIONS: Our study showed that hypercalciuria is common in children with MNE, so we suggested measuring urine calcium levels in NE patients. However, further studies are needed to clarify the relationship between hypercalciuria and NE in larger series.. PMID- 24953283 TI - Management of anorectal malformation without ligation of fistula: an approach preventing posterior urethral diverticula. AB - OBJECTIVE: The posterior urethral diverticulum is a common urologic complication requiring reoperations in anorectal malformation cases (ARM). We present a series of 24 cases of male ARM managed without ligation of fistula. MATERIAL AND METHODS: A prospective study was conducted between July 2010 and June 2012 including male neonates with ARM, where rectobladder neck and rectoprostatic fistula were approached by the abdominal route. The fistulous tract was dissected to the distal-most possible length and was excised flush with the urethra without its ligation. A per-urethral catheter was placed in situ. A record was made of any features of urinary leak and a micturating cystourethrogram was performed at the 1-year of follow-up. RESULTS: Twenty-four cases of ARM, 16 with rectobladder neck fistula and eight cases with rectoprostatic fistula were included. Of these, 12 had single-stage primary abdominoperineal pull-through and 10 were managed by primary posterior sagittal anorectoplasty. Two cases with colostomy during the neonatal period were managed by laparoscopic assisted anorectoplasty at 6 months. None of the cases had a urinary leak during the postoperative period. All had a normal micturating cystourethrogram at 1 year. CONCLUSIONS: The approach of dividing fistula without ligation may prevent posterior urethral diverticula, but larger long-term follow-up studies are needed. PMID- 24953286 TI - 7 Themes for guiding situated ergonomic assessments of medical devices: a case study of an inpatient glucometer. AB - There is relatively little guidance on the situated ergonomic assessment of medical devices, and few case studies that detail this type of evaluation. This paper reports results of a detailed case study that focuses on the design and use of a modern blood glucose meter on an oncology ward. We spent approximately 150 h in-situ, over 11 days and 4 nights, performing observations and interviews with users. This was complemented by interviews with two staff with oversight and management responsibility related to the device. We identified 19 issues with the design and use of this device. These issues were grouped into 7 themes which can help guide the situated study of medical devices: usability, knowledge gaps and mental models, workarounds, wider tasks and equipment, the patient, connection between services, and policy. PMID- 24953287 TI - Effectiveness of involving pharmacists in the process of ambulatory health care to improve drug treatment adherence and disease control. AB - RATIONALE, AIMS AND OBJECTIVES: To evaluate the effectiveness of incorporating the pharmacist into the ambulatory health care team to increase the proportion of patients with type 2 diabetes mellitus (T2DM) and/or hypertension who adhere to their drug regimen and to improve disease control. METHODS: A non-randomized clinical trial was carried out in patients with T2DM and/or hypertension from two primary care clinics. Patients from one of the clinics comprised the intervention group (IG) who received 'counselling' from the pharmacist. The control group (CG) was comprised of patients who attended another clinic and received the usual care. Adherence was measured by counting pills; hypertension control was evaluated by blood pressure and diabetes control by blood glucose. Statistical analysis was carried out by intention to treat using generalized linear models. RESULTS: There were 440 patients included. There was no difference in the proportion of IG and CG patients who adhered to treatment according to baseline measurements. An increase in the proportion of adherence at baseline and final determination was observed in both groups (IG 71-80%, P=0.006 and CG 72-87%, P=0.000). Generalized linear models showed a 55% or higher probability of IG patients achieving control of hypertension in comparison with the CG. Patients from the IG with T2DM have 13% more possibility of achieving glycaemic control than those of the CG. CONCLUSION: Counselling offered by the pharmacist proved to be effective for improving drug adherence of diabetic and hypertensive patients in ambulatory health care. PMID- 24953288 TI - Metal-free one-pot synthesis of benzofurans. AB - Ethyl acetohydroxamate was efficiently arylated with diaryliodonium salts at room temperature under transition-metal-free conditions. The obtained O-arylated products were reacted in situ with ketones under acidic conditions to yield substituted benzo[b]furans through oxime formation, [3,3]-rearrangement, and cyclization in a fast and operationally simple one-pot fashion without using excess reagents. Alternatively, the O-arylated products could be isolated or transformed in situ to aryloxyamines or O-arylaldoximes. The methodology was applied to the synthesis of Stemofuran A and the formal syntheses of Coumestan, Eupomatenoid 6, and (+)-machaeriol B. PMID- 24953289 TI - Re: letter: a comparison of short-term surgical outcomes between NHS and private sector abdominoplasty surgery. PMID- 24953290 TI - Management of congenital neck lesions in children. AB - INTRODUCTION: A retrospective clinical trial was conducted to evaluate the clinical features and treatment outcomes and to determine the incidence of complications in children with congenital neck lesions (CNLs) treated at our institution with a special emphasis on thyroglossal duct remnant (TGDR), branchial cleft anomaly (BCA), and dermoid cyst (DC). MATERIALS AND METHODS: This series had 72 patients with CNL. The diagnosis of CNL was made by physical examination, ultrasound (US) in most, and for a potential extension of the mass computed tomography (CT) or magnetic resonance imaging (MRI) in a few patients and confirmed by histopathological examination in all of the children. RESULTS: Of the patients in this series, 39 (54.2%) children had thyroglossal duct remnant (TGDR). The most common surgical procedure (n = 36) in these children was Sistrunk's procedure. Four children (10.3%) with TGDR had associated anomalies including Turner syndrome and Morgagni hernia. During the study period, 25 (34.7%) children with branchial cleft anomaly (BCA) were treated and most of these were second branchial anomalies. There were eight children (11.1%) with dermoid cyst (DC). CONCLUSION: TGDR is the most common CNL and is presented clinically rather late with regard to BCA and DC in this series. Surgical resection is optimal choice of therapy in CNLs not only for aesthetic reasons but also for the recurrent infections and the potential danger of malignancy. Definitive surgery may be associated with high morbidity, especially recurrence. Associated anomalies may be observed, especially in children with TGDR. Although the Sistrunk's procedure is a safe and successful technique, life-threatening complications should also be kept in mind during the management of these lesions and early and adequate surgical treatment is suggested. PMID- 24953291 TI - Warfarin-induced skin necrosis progressing to calciphylaxis. PMID- 24953293 TI - Monitoring Ara h 1, 2 and 3-sIgE and sIgG4 antibodies in peanut allergic children receiving oral rush immunotherapy. AB - BACKGROUND: The aim was to study the clinical efficacy and safety of rush oral immunotherapy (OIT) for severe peanut-allergic children and to measure the antibody responses. METHODS: Eighteen Japanese children were enrolled after a positive double-blind, placebo-controlled food challenge (DBPCFC). The patients ingested peanuts up to 3-5 times a day every 30 min, increasing the dose by 20% every time. The goal dose was 3.5-7 g. IgE, IgG, and IgG4 antibody levels to peanut, and peanut allergen components were measured during up to 3 yr of maintenance treatment. RESULTS: Two children dropped out due to side effects. Sixteen patients (14 boys and two girls, median: 9 yr range: 5-14 yr) achieved the goal dose after a median of 11 days (range: 4-19 days). Their median threshold dose at DBPCFC was 0.20 g (range: 0.015-1.0 g). All were sensitized to Ara h 2. Fourteen of them had a history of previous anaphylaxis. In total, 173 adverse events were observed during the treatment (27% of the total ingestions) of which 74 needed medications. The median IgE, IgG, and IgG4 antibody levels to peanut increased during rush OIT. The IgG4 levels were high during the whole maintenance phase. IgE and IgG4 antibodies to Ara h 2 dominated the serological response during the treatment. CONCLUSIONS: The present rush OIT protocol for children with severe peanut allergy was effective and relatively safe. A sustained Ara h 2-specific IgG4 antibody response characterized the treatment. PMID- 24953295 TI - Asthma with allergic comorbidities in adolescence is associated with bronchial responsiveness and airways inflammation. AB - BACKGROUND: Childhood asthma frequently has allergic comorbidities. However, there is limited knowledge of the longitudinal development of asthma comorbidites and their association to bronchial hyper-responsiveness (BHR) and airway inflammation markers. We therefore aimed to assess the association between childhood asthma with allergic comorbidities and BHR and fractional exhaled nitric oxide (FE(NO)) and the impact of gender on these associations. METHODS: Based on data from 550 adolescents in the prospective birth cohort 'Environment and Childhood Asthma' study, asthma was defined for the three time periods 0-2, 2 10 and 10-16 years of age, using recurrent bronchial obstruction (rBO) 0-2 years of age as a proxy for early asthma. Asthma comorbidities included atopic dermatitis (AD) and allergic rhinitis (AR) from 10 to 16 years. At age 16 years BHR, assessed by metacholine bronchial challenge, and airway inflammation, assessed by FE(NO), were compared between the groups of asthma with or without the two comorbidities, to a reference group with no never asthma, and subsequently stratified by gender. RESULTS: Boys with asthma and AR, regardless of AD had significantly more severe BHR and higher FE(NO) than the other asthma phenotypes. Almost half of the children remained in the asthma and AR category from 10 to 16 years, the entire difference being determined by new incident cases from 10 to 16 years. CONCLUSIONS: Asthma phenotypes characterized by allergic comorbidities and AR in particular appears closely associated with BHR and FE(NO), especially among boys. PMID- 24953294 TI - Immunoglobulin A and immunoglobulin G antibodies against beta-lactoglobulin and gliadin at age 1 associate with immunoglobulin E sensitization at age 6. AB - BACKGROUND: Serum immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies against wheat gliadin and cow's milk beta-lactoglobulin (BLG) are considered markers of gut permeability and inflammation which modulate the development of mucosal tolerance. Living on a farm has been shown to decrease allergies in children. Our aim was to study whether farm environment affected mucosal tolerance, immunoglobulin E (IgE) sensitization, or allergic diseases. METHODS: The PASTURE birth cohort study was conducted in Finland, France, Germany, Austria, and Switzerland. At age 1, we measured serum IgA and IgG against wheat gliadin (N = 636) and cow's milk BLG (N = 639) using ELISA. Serum-specific IgE was measured at ages 1 and 6 (N = 459). Data on environmental factors and allergic diseases were collected by questionnaires. Discrete time hazard and multivariate logistic regression models were used for analyses. RESULTS: Increased IgA or IgG antibodies against BLG at age 1 increased the risk of sensitization to at least one of the measured allergens or food allergens at age 6. Increased IgG against gliadin at age 1 increased the risk of sensitization to any, at least one inhalant, or at least one food allergen at age 6. Early exposure to cow's milk formula associated with increased IgA or IgG against BLG. No association with farming or clinical allergy was found. CONCLUSIONS: Increased IgA or IgG against BLG or gliadin at age 1 was associated with IgE sensitization at age 6. We suggest that an enhanced antibody response to food antigens reflects mucosal tolerance aberrancies, e.g., altered microbiota and/or increased gut permeability, which is later seen as sensitization to allergens. PMID- 24953297 TI - Increased incidence of juvenile-onset systemic lupus erythematosus among children with asthma. AB - BACKGROUND: Children with systemic lupus erythematosus (SLE) have an especially aggressive disease course and poor outcomes. Previous studies demonstrated a possible association between SLE and allergies, but the relationship between these disorders remains unclear. This population-based cohort study aimed to investigate the incidence and risk of juvenile-onset SLE (JSLE) among children with asthma. METHODS: From 2000 to 2003, 120,939 children with newly diagnosed asthma and 483,756 randomly selected non-asthma controls were enrolled. We used a multivariable Cox proportional hazard regression model to measure and compare the incidence rate and risk of JSLE in the asthma and non-asthma cohorts. RESULTS: The overall incidence of JSLE was 2.52 times greater in the asthma cohort than that in the non-asthma cohort [3.49 vs. 1.53 per 100,000 person-years; 95% confidence interval (CI): 1.59-3.99]. The risk of JSLE was greatest among boys [hazard ratio (HR) 3.02, 95% CI: 1.21-7.52] and children aged 6-10 yr (HR 3.50, 95% CI: 1.75-7.02). The HR of JSLE increased with greater frequency of asthma related medical visits from 1.22 (95% CI: 0.67-1.41) for those with <=2 visits/yr to 5.88 (95% CI: 3.43-10.1) for subjects with >2 visits/yr (trend test p < 0.001). However, the risk of JSLE declined over time. CONCLUSION: We found an increased incidence of JSLE among children with asthma. The mechanism of asthma on JSLE development should be elucidated to establish innovative disease intervention programs. PMID- 24953296 TI - Parental hay fever reinforces IgE to pollen as pre-clinical biomarker of hay fever in childhood. AB - BACKGROUND: An early IgE response to grass or birch pollen can anticipate seasonal allergic rhinitis to pollen later in life or remain clinically silent. OBJECTIVE: To identify risk factors early in life that allow discriminating pathogenic from non-pathogenic IgE responses and contribute to the development of seasonal allergic rhinitis to grass pollen. METHODS: The German Multicentre Allergy Study examined a birth cohort born in 1990. A questionnaire was yearly administered and blood samples collected at age 1,2,3,5,6,7,10,13 yr. The definition of the primary outcome grass- and birch-pollen-related seasonal allergic rhinitis (SARg, SARb) was based on nasal symptoms in June/July and April, respectively. Serum IgE antibodies to Phleum pratense and Betula verrucosae extracts were monitored with immune-enzymatic singleplex assays. RESULTS: Of the 820 examined children, 177 and 148 developed SARg and SARb, respectively. Among healthy children aged 3 or more years, IgE to grass pollen was the strongest risk factor of SARg (OR 10.39, 95%CI 6.1-17.6, p < 0.001), while parental hay fever was the only risk factor in early childhood independently associated with future SARg (1 parent: OR 2.56, 95%CI 1.4-4.5, p < 0.001; 2 parents: OR 4.17, 95%CI 1.7-10.1) and SARb (1 parent OR: 5.21, 95%CI 2.20-12.4, p < 0.001; 2 parents: OR 8.02, 95%CI 2.0-32.9, p < 0.001). Parental hay fever was associated with an increase of the concentration of pollen-specific IgE in seropositive subjects, after the age of 6 and was also a hallmark of molecularly more complex specific IgE responses to grass or birch pollen at age 6 or older. CONCLUSIONS: Parental hay fever and specific IgE to grass and/or birch pollen are strong pre-clinical determinants and potentially good predictors of seasonal allergic rhinitis. PMID- 24953298 TI - Th2-like chemokine levels are increased in allergic children and influenced by maternal immunity during pregnancy. AB - BACKGROUND: The influence of the intra-uterine environment on the immunity and allergy development in the offspring is unclear. We aimed to investigate (i) whether the pregnancy magnifies the Th2 immunity in allergic and non-allergic women, (ii) whether the maternal chemokine levels during pregnancy influenced the offspring's chemokine levels during childhood and (iii) the relationship between circulating Th1/Th2-associated chemokines and allergy in mothers and children. METHODS: The Th1-associated chemokines CXCL9, CXCL10, CXCL11, and the Th2 associated chemokines CCL17, CCL18 and CCL22 were quantified by Luminex and ELISA in 20 women with and 36 women without allergic symptoms at gestational week (gw) 10-12, 15-16, 25, 35, 39 and 2 and 12 months post-partum and in their children at birth, 6, 12, 24 months and 6 years of age. Total IgE levels were measured using ImmunoCAP Technology. RESULTS: The levels of the Th2-like chemokines were not magnified by pregnancy. Instead decreased levels were shown during pregnancy (irrespectively of maternal allergy status) as compared to post-partum. In the whole group, the Th1-like chemokine levels were higher at gw 39 than during the first and second trimester and post-partum. Maternal CXCL11, CCL18 and CCL22 levels during and after pregnancy correlated with the corresponding chemokines in the offspring during childhood. Increased CCL22 and decreased CXCL10 levels in the children were associated with sensitisation and increased CCL17 levels with allergic symptoms during childhood. Maternal chemokine levels were not associated with maternal allergic disease. CONCLUSIONS: Allergic symptoms and sensitisation were associated with decreased Th1- and increased Th2-associated chemokine levels during childhood, indicating a Th2 shift in the allergic children, possibly influenced by the maternal immunity during pregnancy. PMID- 24953299 TI - Reply: To PMID 24299565. PMID- 24953300 TI - Sodium-metal halide and sodium-air batteries. AB - Impressive developments have been made in the past a few years toward the establishment of Na-ion batteries as next-generation energy-storage devices and replacements for Li-ion batteries. Na-based cells have attracted increasing attention owing to low production costs due to abundant sodium resources. However, applications of Na-ion batteries are limited to large-scale energy storage systems because of their lower energy density compared to Li-ion batteries and their potential safety problems. Recently, Na-metal cells such as Na-metal halide and Na-air batteries have been considered to be promising for use in electric vehicles owing to good safety and high energy density, although less attention is focused on Na-metal cells than on Na-ion cells. This Minireview provides an overview of the fundamentals and recent progress in the fields of Na metal halide and Na-air batteries, with the aim of providing a better understanding of new electrochemical systems. PMID- 24953301 TI - Reflections on intrapersonal and interpersonal changes in a beginning (psychodynamically-oriented) psychotherapist. AB - Becoming a beginning therapist brings about a multitude of changes, both intrapersonally and interpersonally. In this article, I discuss some of these effects as they have manifested in my first (nearly) 2 years of practicing psychotherapy as a trainee. Along the intrapersonal dimension, I note the ways in which being a beginning therapist has shaped my sense of identity and values, while also heightening my sensitivity to my own wounds. With respect to the interpersonal dimension, I explore how my increased psychological mindedness has affected personal relationships as well as my own therapy. I conclude with a description of a defining case of my early career that integrates my understanding of the changes that I have undergone as a beginning therapist. PMID- 24953302 TI - A de novo NADPH generation pathway for improving lysine production of Corynebacterium glutamicum by rational design of the coenzyme specificity of glyceraldehyde 3-phosphate dehydrogenase. AB - Engineering the cofactor availability is a common strategy of metabolic engineering to improve the production of many industrially important compounds. In this work, a de novo NADPH generation pathway is proposed by altering the coenzyme specificity of a native NAD-dependent glyceraldehyde 3-phosphate dehydrogenase (GAPDH) to NADP, which consequently has the potential to produce additional NADPH in the glycolytic pathway. Specifically, the coenzyme specificity of GAPDH of Corynebacterium glutamicum is systematically manipulated by rational protein design and the effect of the manipulation for cellular metabolism and lysine production is evaluated. By a combinatorial modification of four key residues within the coenzyme binding sites, different GAPDH mutants with varied coenzyme specificity were constructed. While increasing the catalytic efficiency of GAPDH towards NADP enhanced lysine production in all of the tested mutants, the most significant improvement of lysine production (~60%) was achieved with the mutant showing similar preference towards both NAD and NADP. Metabolic flux analysis with (13)C isotope studies confirmed that there was no significant change of flux towards the pentose phosphate pathway and the increased lysine yield was mainly attributed to the NADPH generated by the mutated GAPDH. The present study highlights the importance of protein engineering as a key strategy in de novo pathway design and overproduction of desired products. PMID- 24953303 TI - Stereotactic radiosurgery for recurrent high-grade gliomas. PMID- 24953304 TI - Central nervous system tumor distribution at a tertiary referral center in Uganda. PMID- 24953305 TI - Classification of breast cancer subtypes by combining gene expression and DNA methylation data. AB - Selecting the most promising treatment strategy for breast cancer crucially depends on determining the correct subtype. In recent years, gene expression profiling has been investigated as an alternative to histochemical methods. Since databases like TCGA provide easy and unrestricted access to gene expression data for hundreds of patients, the challenge is to extract a minimal optimal set of genes with good prognostic properties from a large bulk of genes making a moderate contribution to classification. Several studies have successfully applied machine learning algorithms to solve this so-called gene selection problem. However, more diverse data from other OMICS technologies are available, including methylation. We hypothesize that combining methylation and gene expression data could already lead to a largely improved classification model, since the resulting model will reflect differences not only on the transcriptomic, but also on an epigenetic level. We compared so-called random forest derived classification models based on gene expression and methylation data alone, to a model based on the combined features and to a model based on the gold standard PAM50. We obtained bootstrap errors of 10-20% and classification error of 1-50%, depending on breast cancer subtype and model. The gene expression model was clearly superior to the methylation model, which was also reflected in the combined model, which mainly selected features from gene expression data. However, the methylation model was able to identify unique features not considered as relevant by the gene expression model, which might provide deeper insights into breast cancer subtype differentiation on an epigenetic level. PMID- 24953306 TI - A query suggestion workflow for life science IR-systems. AB - Information Retrieval (IR) plays a central role in the exploration and interpretation of integrated biological datasets that represent the heterogeneous ecosystem of life sciences. Here, keyword based query systems are popular user interfaces. In turn, to a large extend, the used query phrases determine the quality of the search result and the effort a scientist has to invest for query refinement. In this context, computer aided query expansion and suggestion is one of the most challenging tasks for life science information systems. Existing query front-ends support aspects like spelling correction, query refinement or query expansion. However, the majority of the front-ends only make limited use of enhanced IR algorithms to implement comprehensive and computer aided query refinement workflows. In this work, we present the design of a multi-stage query suggestion workflow and its implementation in the life science IR system LAILAPS. The presented workflow includes enhanced tokenisation, word breaking, spelling correction, query expansion and query suggestion ranking. A spelling correction benchmark with 5,401 queries and manually selected use cases for query expansion demonstrate the performance of the implemented workflow and its advantages compared with state-of-the-art systems. PMID- 24953307 TI - Lithographically defined three-dimensional pore-patterned carbon with nitrogen doping for high-performance ultrathin supercapacitor applications. AB - Supercapacitors that exhibit long cycle lives and fast charge/discharge rates are a promising energy-storage technology for next-generation mobile or wearable electronic systems. A great challenge facing the fabrication of ultrathin supercapacitor components, specifically their porous electrodes, is whether such components can be integrated with the fabrication of electronic devices, i.e., semiconductor fabrication processes. Here, we introduce the lithographic fabrication of micrometre-thick, submicrometre-pore-patterned carbon for supercapacitor electrodes. The pore patterns designed by multi-beam interference lithography and direct carbonisation of the photoresist pattern produced pore patterned carbon films. A facile doping process was subsequently employed to introduce nitrogen atoms into the carbon, which was intended to further enhance the carbon's capacitive properties. Specifically, during these fabrication steps, we developed an approach that uses a supporting shell on the surface of the pore patterns to maintain their structural integrity. The nitrogen-doped, pore patterned carbon electrodes exhibited an areal specific capacitance of 32.7 mF/cm(2) at 0.5 mA/cm(2) when used as supercapacitor electrodes, which is approximately 20 times greater than that of commercially available MWCNT films measured under the same conditions. PMID- 24953308 TI - Synchronization of memristor-based recurrent neural networks with two delay components based on second-order reciprocally convex approach. AB - We extend the notion of Synchronization of memristor-based recurrent neural networks with two delay components based on second-order reciprocally convex approach. Some sufficient conditions are obtained to guarantee the synchronization of the memristor-based recurrent neural networks via delay dependent output feedback controller in terms of linear matrix inequalities (LMIs). The activation functions are assumed to be of further common descriptions, which take a broad view and recover many of those existing methods. A Lyapunov-Krasovskii functional (LKF) with triple-integral terms is addressed in this paper to condense conservatism in the synchronization of systems with additive time-varying delays. Jensen's inequality is applied in partitioning the double integral terms in the derivation of LMIs and then a new kind of linear combination of positive functions weighted by the inverses of squared convex parameters has emerged. Meanwhile, this paper puts forward a well-organized method to manipulate such a combination by extending the lower bound lemma. The obtained conditions not only have less conservatism but also less decision variables than existing results. Finally, numerical results and its simulations are given to show the effectiveness of the proposed memristor-based synchronization control scheme. PMID- 24953310 TI - Formation of oligonucleotide-gated silica shell-coated Fe3O4-Au core-shell nanotrisoctahedra for magnetically targeted and near-infrared light-responsive theranostic platform. AB - A new multifunctional nanoparticle to perform a near-infrared (NIR)-responsive remote control drug release behavior was designed for applications in the biomedical field. Different from the previous studies in formation of Fe3O4-Au core-shell nanoparticles resulting in a spherical morphology, the heterostructure with polyhedral core and shell was presented with the truncated octahedral Fe3O4 nanoparticle as the core over a layer of trisoctahedral Au shell. The strategy of Fe3O4@polymer@Au was adopted using poly-l-lysine as the mediate layer, followed by the subsequent seeded growth of Au nanoparticles to form a Au trisoctahedral shell. Fe3O4@Au trisoctahedra possess high-index facets of {441}. To combine photothermal and chemotherapy in a remote-control manner, the trisoctahedral core shell Fe3O4@Au nanoparticles were further covered with a mesoporous silica shell, yielding Fe3O4@Au@mSiO2. The bondable oligonucleotides (referred as dsDNA) were used as pore blockers of the mesoporous silica shell that allowed the controlled release, resulting in a NIR-responsive DNA-gated Fe3O4@Au@mSiO2 nanocarrier. Taking advantage of the magnetism, remotely triggered drug release was facilitated by magnetic attraction accompanied by the introduction of NIR radiation. DNA-gated Fe3O4@Au@mSiO2 serves as a drug control and release carrier that features functions of magnetic target, MRI diagnosis, and combination therapy through the manipulation of a magnet and a NIR laser. The results verified the significant therapeutic effects on tumors with the assistance of combination therapy consisting of magnetic guidance and remote NIR control. PMID- 24953309 TI - Baseline and follow-up association of the MAX-PC in Men with newly diagnosed prostate cancer. AB - OBJECTIVE: The objective of this paper is to conduct a prospective, longitudinal study employing the Memorial Anxiety Scale for Prostate Cancer (MAX-PC) to examine the baseline and follow-up association of prostate cancer (PCa)-specific anxiety, health-related quality of life (HRQOL), and PCa aggressiveness in men with newly-diagnosed PCa undergoing prostatectomy at our institution. METHODS: From our prospective PCa registry, we identified a total of 350 men with newly diagnosed PCa who completed the MAX-PC and the Expanded Prostate Cancer Index Composite (EPIC) at baseline and one-year following surgery. Scores on both measures were compared with clinical measure and demographics using the Wilcoxon Rank Sum, Fisher's exact, and Cochran-Armitage Trend tests. Spearman test was used to assess correlation at between the MAX-PC and EPIC at baseline and one year. RESULTS: Baseline overall MAX-PC measures were correlated with measures at one-year (r=0.5479, p<0.001). Those reporting high anxiety at one-year were more likely to have Gleason score>6 (p=0.004), T-Stage >= 2C disease (p=0.004), and a postoperative prostate-specific antigen (PSA)>0.1 (p=0.002); however, this did not apply to all anxious patients. Baseline EPIC sexual function scores were predictive of follow-up EPIC sexual function scores as well (r=0.5790, p<0.001). Depression was noted as a problem in 16% of patients at follow-up. CONCLUSIONS: Our data suggests that the MAX-PC could be used at baseline as a tool to determine who may benefit from psychological intervention pre-PCa and post-PCa treatment. In terms of individualized medicine, behavioral therapy may be the most beneficial in improving HRQOL for younger patients, those with advanced stage disease, and more specifically those whose anxiety outweighs their actual prognosis. PMID- 24953311 TI - [Are lifestyle interventions for overweight and obese pregnant women useful?]. PMID- 24953312 TI - [Which prostheses to use in mesh sacrocolpopexy? Experimental and clinical study]. AB - BACKGROUND: Sacrocolpopexy is the standard surgical treatment of genital prolapse of the upper vaginal wall. Nowadays, the laparotomy approach is progressively supplanted by the laparoscopic procedure for the same anatomical results. About sacrocolpopexy, to date it still remains details of the technique, which differ with surgical teams maintaining controversy. Among them, the choice of the meshes certainly creates debate. OBJECTIVES: To state the basic physicochemical principles which are necessary for surgeons to select the most suitable prosthetic material to obtain the most beneficial anatomic and functional outcomes for patients. MATERIAL AND METHODS: The concepts of prosthetic biocompatibility, strength, shrinkage, deformation and elasticity are discussed. They are illustrated by experimental animal references and also human clinical references. RESULTS: Macroporous polypropylene and polyester prostheses (pore size>1 mm) are properly integrated. Collagen prosthetic coating improves tissue integration. Absorbable and nonabsorbable ultralight prostheses expose patients to a high risk of recurrence. Multifilament polyester wide pore-side prostheses have less retraction and are more flexible than monofilament polypropylene prostheses. DISCUSSION AND CONCLUSION: The prosthetic cut-off weight below which the mesh does not offer any guarantee of strength is not precisely known. Moreover, the benefit of weight reduction is not proved. Currently, heavy weight multifilament polyester prostheses with wide pore size, more than 1mm, appear to be the most appropriate meshes for sacrocolpopexy without vaginal incision. PMID- 24953313 TI - [Sentinel node biopsy in breast cancer using magnetic tracer: preliminary study]. AB - OBJECTIVE: To evaluate the feasibility of the magnetic technique for sentinel node biopsy (SNB) in breast cancer. PATIENTS AND METHODS: A total of 10 consecutives patients with breast cancer scheduled for SNB, who were clinically node negative, were recruited. SNB was undertaken after injection of both magnetic and radio-isotopic tracers. RESULTS: One or more SN were identified among 10 patients (identification rate of 100%). The median number of GS taken was 1.7 (range 1-3). In total, 17 GS were taken. SN were radioactive and ferromagnetic (82.3%), 3 were only radioactive and none was only ferromagnetic. DISCUSSION AND CONCLUSION: The magnetic technique is feasible, but cannot be used alone due to technical constraints. PMID- 24953314 TI - An investigation on the fuel savings potential of hybrid hydraulic refuse collection vehicles. AB - Refuse trucks play an important role in the waste collection process. Due to their typical driving cycle, these vehicles are characterized by large fuel consumption, which strongly affects the overall waste disposal costs. Hybrid hydraulic refuse vehicles offer an interesting alternative to conventional diesel trucks, because they are able to recuperate, store and reuse braking energy. However, the expected fuel savings can vary strongly depending on the driving cycle and the operational mode. Therefore, in order to assess the possible fuel savings, a typical driving cycle was measured in a conventional vehicle run by the waste authority of the City of Stuttgart, and a dynamical model of the considered vehicle was built up. Based on the measured driving cycle and the vehicle model including the hybrid powertrain components, simulations for both the conventional and the hybrid vehicle were performed. Fuel consumption results that indicate savings of about 20% are presented and analyzed in order to evaluate the benefit of hybrid hydraulic vehicles used for refuse collection. PMID- 24953316 TI - [Examination of the shoulder joint using true anterior-posterior photography, employing a body surface index]. AB - Radiographic examination of the anterior part of the shoulder includes routine anterior-posterior imaging that enables easy visualization of traumatic injuries and true anterior-posterior imaging that enables the visualization of intra articular injuries. The X-ray incident angle of true anterior-posterior imaging is affected by physique and posture. However, in many reports, the angle is uniformly determined on the basis of the antero-posterior axis and the horizontal plane. We previously reported that the glenohumeral joint can be visualized with good reproducibility by establishing a reference line on the basis of three points on the body as indicators, namely the posterior view of the under-surface of the acromion, the coracoid process, and the inferior angle of the scapula. However, visualizing the undersurface of the acromion using physical indicators to set the angle for imaging remains problematic. In previous reports, the angle was consistently set at 20 degrees to the horizontal plane, regardless of physique or posture, which resulted in poor reproducibility. After examining the imaging techniques described in previous reports, we describe here an imaging technique using a reference line based on indicators on the surface of the scapula that enables the glenohumeral joint and the undersurface of the acromion to be visualized with good reproducibility. PMID- 24953315 TI - TRPC1 is involved in Ca2+ influx and cytotoxicity following Pb2+ exposure in human embryonic kidney cells. AB - Lead (Pb(2+)) is a divalent heavy metal ion which causes severe damage to almost all life forms and is therefore considered a notorious toxicant. Exposure to Pb(2+) is associated with poor cognitive development in children at relatively low levels that previously were thought to be safe. The mechanism through which Pb(2+) enters cells, however, is unclear. Previous studies have showed that Ca(2+) release-activated Ca(2+) protein 1 (Orai1), a component of store-operated Ca(2+) channels (SOCs), contributes to Pb(2+) cellular entry. Canonical transient receptor potential (TRPC1) channel 1 is a transient receptor potential (TRP) channel which is sometimes referred to as a SOC. The present study was designed to investigate the role of TRPC1 in Pb(2+) entry and toxicity in human embryonic kidney cells (HEK293). Additionally, changes in intracellular Ca(2+) concentration were determined through Fluo-4 and Mag-fluo-4 fluorescent Ca(2+) imaging. Following Pb(2+) exposure, there was a dose-dependent decrease in cell viability. Overexpression of TRPC1 increased Pb(2+)-induced cell death, while knockdown of this channel attenuated cell death. There was increased entry of Pb(2+), as measured by inductively coupled plasma mass spectrometry (ICP-MS), following overexpression of TRPC1. Conversely, knockdown of TRPC1 led to a decrease in Pb(2+) influx. Down-regulation of STIM1 by RNA interference attenuated the Pb(2+) influx, and transfection with a mutant STIM1, which could not gate TRPC1, had a similar effect. Co-transfection of mutant STIM1 and mutant TRPC1, which restore the electrostatic interaction between STIM1 and TRPC1, resumed Pb(2+) entry in HEK293 cells. Down-regulation of TRPC1 by RNA interference decreased Ca(2+) influx whilst its overexpression increased Ca(2+) entry in HEK293 cells. These results suggest that TRPC1 is involved in the cytotoxicity and entry of Pb(2+) through molecular interactions with STIM1 and subsequent Ca(2+) influx in HEK293 cells. PMID- 24953317 TI - [Improvements to an automated method for detecting carotid artery calcifications by adopting a positional feature and feature selection]. AB - The purpose of this study was to improve an automated scheme for detecting carotid artery calcification (CAC) in dental panoramic radiographs (DPRs). Using 100 DPRs, the sensitivity of CAC detection employing our previous method was 90.0% with 5.0 false positives (FPs) per image. This study describes two enhancements. One is the adoption of a new feature for the position of CACs in addition to previous features. The other is feature selection employing the support vector machine using all combinations. Five of 12 features were selected. Using our proposed method, the average sensitivity for the same database proved to be 90.0%, with only 2.5 FPs per image. These results indicate the potential effectiveness of the new positional feature and feature selection. PMID- 24953318 TI - [Image distortion and artifacts caused by the use of a titanium aneurism clip in 1.5 tesla- and 3 tesla-magnetic resonance imaging: effect on 60cobalt stereotactic radiosurgery treatment planning]. AB - In gamma knife stereotactic radiosurgery (GKSRS) treatment planning, 1.5 tesla (T)-magnetic resonance imaging (MRI) is normally used to identify the target lesion. Image artifacts and distortion arise in MRI if a titanium clip is surgically implanted in the brain to treat cerebral aneurysm. 3-T MRI scanners, which are increasingly being adopted, provide imaging of anatomic structures with better clinical usefulness than 1.5-T MRI machines. We investigated signal defects and image distortions both close to and more distant from the titanium clip in 1.5-T and 3-T MRI. Two kinds of phantoms were scanned using 1.5-T and 3-T MRI. Acquisitions with and without the clip were performed under the same scan parameters. No difference was observed between 1.5 T and 3 T in local decrease of signal intensity; however, image distortion was observed at 20 mm from the clip in 3 T. Over the whole region, the distortions caused by the clip were less than 0.3 mm and 1.6 mm under 1.5-T and 3-T MRI, respectively. The geometric accuracy of 1.5-T MRI was better than 3-T MRI and thus better for GKSRS treatment planning. 3-T MRI, however, appears less suitable for use in treatment planning. PMID- 24953320 TI - [A review of the position adopted by patients when acquiring images of the base of the hamate hook]. AB - The hamate bone, one of the carpal (wrist) bones, has a large uncinate process protruding from the palm side. In sports such as golf and tennis, the hamate bone can break if is subjected to a high external force, such as from the handle of a racquet or club. At our hospital we take X-ray images of the hamate bone from two directions: an axial image through the carpal tunnel and an image at the base of the hamate hook (conventional method). While the conventional method makes it easy to create images of the base of the hamate hook, the patient may suffer pain during image-taking because the hamate bone is pulled to cause radial flexion. We therefore investigated a method of imaging that would create three-dimensional computed tomography (3DCT) images of the base of the hamate hook in which the patient would only have to only rotate the wrist externally and elevate the fore arm without any radial flexion. Our results suggest that it is possible to obtain images of the base of the hamate hook as clear as those acquired using the conventional method with the patient in a comfortable and painless position taking images at an external rotation angle of 50.3 degrees and a forearm elevation angle of 20.3 degrees . PMID- 24953319 TI - [Impact of point spread function correction in standardized uptake value quantitation for positron emission tomography images: a study based on phantom experiments and clinical images]. AB - While point spread function (PSF)-based positron emission tomography (PET) reconstruction effectively improves the spatial resolution and image quality of PET, it may damage its quantitative properties by producing edge artifacts, or Gibbs artifacts, which appear to cause overestimation of regional radioactivity concentration. In this report, we investigated how edge artifacts produce negative effects on the quantitative properties of PET. Experiments with a National Electrical Manufacturers Association (NEMA) phantom, containing radioactive spheres of a variety of sizes and background filled with cold air or water, or radioactive solutions, showed that profiles modified by edge artifacts were reproducible regardless of background MU values, and the effects of edge artifacts increased with increasing sphere-to-background radioactivity concentration ratio (S/B ratio). Profiles were also affected by edge artifacts in complex fashion in response to variable combinations of sphere sizes and S/B ratios; and central single-peak overestimation up to 50% was occasionally noted in relatively small spheres with high S/B ratios. Effects of edge artifacts were obscured in spheres with low S/B ratios. In patient images with a variety of focal lesions, areas of higher radioactivity accumulation were generally more enhanced by edge artifacts, but the effects were variable depending on the size of and accumulation in the lesion. PET images generated using PSF-based reconstruction are therefore not appropriate for the evaluation of SUV. PMID- 24953321 TI - [Assessment of overall spatial accuracy in image guided stereotactic body radiotherapy using a spine registration method]. AB - Stereotactic body radiotherapy (SBRT) for lung and liver tumors is always performed under image guidance, a technique used to confirm the accuracy of setup positioning by fusing planning digitally reconstructed radiographs with X-ray, fluoroscopic, or computed tomography (CT) images, using bony structures, tumor shadows, or metallic markers as landmarks. The Japanese SBRT guidelines state that bony spinal structures should be used as the main landmarks for patient setup. In this study, we used the Novalis system as a linear accelerator for SBRT of lung and liver tumors. The current study compared the differences between spine registration and target registration and calculated total spatial accuracy including setup uncertainty derived from our image registration results and the geometric uncertainty of the Novalis system. We were able to evaluate clearly whether overall spatial accuracy is achieved within a setup margin (SM) for planning target volume (PTV) in treatment planning. After being granted approval by the Hospital and University Ethics Committee, we retrospectively analyzed eleven patients with lung tumor and seven patients with liver tumor. The results showed the total spatial accuracy to be within a tolerable range for SM of treatment planning. We therefore regard our method to be suitable for image fusion involving 2-dimensional X-ray images during the treatment planning stage of SBRT for lung and liver tumors. PMID- 24953322 TI - [Summary of a survey on radiation exposure during pediatric computed tomography examinations in Japan, focusing on the computed tomography examination environment]. AB - We carried out a nationwide questionnaire survey of pediatric computed tomography (CT) in 339 facilities. Most facilities operated multi detector-row CT (MDCT), and over half operated 64, 128, 256 and 320-slice MDCT. In 32% of facilities, pediatric CT protocols were set taking image quality and dose into consideration. However, in the other facilities, pediatric CT protocols may not be optimized because there is no clear standard for image quality or dosage for pediatric CT examinations in Japan. To promote the optimization of pediatric CT protocols, we regard it as an urgent task to establish diagnostic reference levels for pediatric CT examinations. PMID- 24953323 TI - [JSRT member "Mr. Yoshihiko Kawamura"]. PMID- 24953324 TI - [Introduction of Monte Carlo simulation to radiological technology. Preface]. PMID- 24953325 TI - [ Principle of Monte Carlo method]. PMID- 24953326 TI - [ Surgical treatment for ischemic heart disease]. PMID- 24953327 TI - [Clinical application 1: properties of computed tomography images reconstructed by filtered back projection algorithm]. PMID- 24953328 TI - [Survey of States of Introduction and Safety Assurance of Medical Systems etc. in the 2013 fiscal year]. PMID- 24953329 TI - [Planning to new horizon]. PMID- 24953330 TI - Diet micronutrient balance matters: How the ratio of dietary sterols/steroids affects development, growth and reproduction in two lepidopteran insects. AB - Insects lack the ability to synthesize sterols de novo so they acquire this essential nutrient from their food. Cholesterol is the dominant sterol found in most insects, but in plant vegetative tissue it makes up only a small fraction of the total sterol profile. Instead, plants mostly contain phytosterols; plant feeding insects generate the majority of their cholesterol by metabolizing phytosterols. However, not all phytosterols are readily converted to cholesterol, and some are even deleterious when ingested above a threshold level. In a recent study we showed that caterpillars reared on tobacco accumulating novel sterols/steroids exhibited reduced performance, even when suitable sterols were present. In the current study we examined how the dominant sterols (cholesterol and stigmasterol) and steroids (cholestanol and cholestanone) typical of the modified tobacco plants affected two insect herbivores (Heliothis virescens and Helicoverpa zea). The sterols/steroids were incorporated into synthetic diets singly, as well as in various combinations, ratios and amounts. For each insect species, a range of performance values was recorded for two generations, with the eggs from the 1st-generation adults as the source of neonates for the 2nd generation. Performance on the novel steroids (cholestanol and cholestanone) was extremely poor compared to suitable sterols (cholesterol and stigmasterol). Additionally, performance tended to decrease as the ratio of the novel dietary steroids increased. We discuss how the balance of different dietary sterols/steroids affected our two caterpillar species, relate this back to recent studies on sterol/steroid metabolism in these two species, and consider the potential application of sterol/steroid modification in crops. PMID- 24953331 TI - Evaluation of the Relationship Between Ischemia-Modified Albumin Levels and Thyroid Hormone Levels. AB - BACKGROUND: A novel ischemia marker named ischemia modified albumin was previously considered as an early marker of myocardial ischemia, however due to recent reports, its contribution was demonstrated in different pathologies such as oxidative stress, diabetes, stroke and cancer. We aimed to investigate the relation between oxidative stress and thyroid dysfunctions determining IMA levels since IMA is closely related with increased oxidative stress. METHODS: A total of 88 individuals were participated in this study: 34 cases in hypothyroid, 27 cases in hyperthyroid and 27 cases in euthyroid group. Ischemia-modified albumin levels were measured by albumin cobalt binding test and thyroid hormone levels were determined with electrochemiluminescent method. RESULTS: Ischemia modified albumin levels were significantly decreased in hypothyroid group compared to hyperthyroid and euthyroid groups (p < 0.001). In hyperthyroid individuals ischemia modified albumin levels were higher compared to euthyroid ones (p < 0.001). Ischemia modified albumin was negatively correlated with TSH levels (r = 0.473, p < 0.001), and positively correlated with FT4 and FT3 levels (r = 0.496, p < 0.001 and r = 0.275, p = 0.010, respectively). CONCLUSION: We suggest that albumin adjusted IMA levels are significantly lower in hypothyroid group than hyperthyroid and euthyroid groups. PMID- 24953334 TI - Preclinical evidence that SSR128129E--a novel small-molecule multi-fibroblast growth factor receptor blocker--radiosensitises human glioblastoma. AB - Resistance of glioblastoma to radiotherapy is mainly due to tumour cell radioresistance, which is partially controlled by growth factors such as fibroblast growth factor (FGF). Because we have previously demonstrated the role of FGF-2 in tumour cell radioresistance, we investigate here whether inhibiting FGF-2 pathways by targeting fibroblast growth factor receptor (FGFR) may represent a new strategy to optimise the efficiency of radiotherapy in glioblastoma. Treating radioresistant U87 and SF763 glioblastoma cells with the FGFR inhibitor, SSR12819E, radiosensitises these cells while the survival after irradiation of the more radiosensitive U251 and SF767 cells was not affected. SSR128129E administration to U87 cells increases the radiation-induced mitotic cell death. It also decreased cell membrane availability of the FGFR-1 mainly expressed in these cells, increased this receptor's ubiquitylation, inhibited radiation-induced RhoB activation and modulated the level of hypoxia inducible factor, HIF-1alpha, a master regulator of hypoxia, thus suggesting a role of FGFR in the regulation of hypoxia pathways. Moreover, treating orthotopically U87 xenografted mice with SSR128129E before two subsequent local 2.5Gy irradiations significantly increased the animals neurological sign free survival (NSFS) compared to the other groups of treatment. These results strongly suggest that targeting FGFR with the FGFR blocker SSR128129E might represent an interesting strategy to improve the efficiency of radiotherapy in glioblastoma. PMID- 24953332 TI - Prevalence of germline MUTYH mutations among Lynch-like syndrome patients. AB - BACKGROUND AND AIMS: Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. METHODS: Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. RESULTS: We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P=0.02) and wildtype patients (P<0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P<0.0001). CONCLUSIONS: A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients. PMID- 24953333 TI - First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: a randomised, phase 3 trial. AB - BACKGROUND: In the Iressa Pan-ASia Study (IPASS), gefitinib claimed improved progression-free survival (PFS) versus carboplatin-paclitaxel in clinically selected lung cancer patients. The primary objective of this study was to assess the PFS of pemetrexed-cisplatin (PC) followed by gefitinib maintenance versus gefitinib monotherapy in an IPASS-like population. METHODS: In this open-label, randomised, phase 3 trial, eligible patients were ?18 years, chemonaive, East Asian, light ex-smokers/never-smokers with advanced non-squamous non-small cell lung cancer, an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and unknown epidermal growth factor receptor (EGFR) mutation status who enrolled at 12 sites in Asia. Patients randomly received (1:1) pemetrexed (500 mg/m(2)) plus cisplatin (75mg/m(2)) for six 21-day cycles, followed by gefitinib maintenance or gefitinib monotherapy (250 mg/day). Patient tissue was retrospectively analysed for EGFR mutations. This study is registered with ClinicalTrials.gov, NCT01017874. FINDINGS: Between 23rd November 2009 and 27th April 2012, 253 patients entered, and 236 patients were randomly assigned to and treated with PC therapy (N=114) and gefitinib monotherapy (N=118). Between-arm baseline characteristics were balanced. PFS was not significantly different between treatment arms (p=0.217). The unadjusted hazard ratio (HR) was 0.85 (95% confidence interval (CI) 0.63-1.13). The HR should be cautiously interpreted as it was not constant. EGFR mutation status was determined for 74 tissue samples; 50 (67.6%) had mutations. In a pre-specified subgroup analysis, only the treatment-by-EGFR mutation interaction was significant (p=0.008) for PFS. For the entire treatment period, a higher proportion of patients in the PC/gefitinib arm versus gefitinib experienced possibly drug-related grade 3-4 treatment-emergent adverse events (39 of 114 [34%] versus 19 of 118 [16%]; p=0.002). INTERPRETATION: In the intention-to-treat (ITT) population, PFS was not significantly different. In the biomarker-assessable population, front-line EGFR tyrosine kinase inhibitor monotherapy was not efficacious in patients with wild-type EGFR. Identification of EGFR mutation status is key in the management of advanced non-squamous non small cell lung cancer. FUNDING: Eli Lilly and Company. PMID- 24953335 TI - BRG1 promotes chemoresistance of pancreatic cancer cells through crosstalking with Akt signalling. AB - Gemcitabine is a standard chemotherapeutic agent for locally advanced and metastatic pancreatic cancer. However, the chemoresistance of pancreatic cancer is the major barrier to efficient chemotherapy. Here, we reported that BRG1, a chromatin modulator, was exclusively overexpressed in human pancreatic ductal adenocarcinoma tissues. BRG1 knockdown inhibited PANC-1 and MIA PaCa-2 cell growth in vitro and in vivo, reduced the phosphorylation/activation of Akt and p21(cip/waf), enhanced intrinsic and gemcitabine induced apoptosis and attenuated gemcitabine-induced downregulation of E-cadherin. Moreover, by establishing acquired chemoresistance of MIA PaCa-2 cells in vitro, we found that BRG1 knockdown effectively reversed the chemoresistance to gemcitabine. Surprisingly, inhibiting Akt phosphorylation resulted in BRG1 suppression in pancreatic cancer cells, indicating BRG1 as a new downstream target of Akt signalling. Taken together, our findings suggest that BRG1 promotes both intrinsic and acquired chemoresistance of pancreatic cancer cells, and BRG1 crosstalks with Akt signalling to form a positive feedback loop to promote pancreatic cancer development. PMID- 24953336 TI - Familial transmission of prostate, breast and colorectal cancer in adoptees is related to cancer in biological but not in adoptive parents: a nationwide family study. AB - AIM: Familial clustering of prostate, breast and colorectal cancer is well established, but the familial risk of these cancers has not been determined among adoptees. The aim was to disentangle the contributions of genetic and environmental factors to the familial transmission of prostate, breast and colorectal cancer. METHODS: The Swedish Multi-Generation Register was used to follow all adoptees born between 1932 and 1969 (n=70,965) for prostate, breast and colorectal cancer from January 1958 up to December 2010. The risk of prostate, breast and colorectal cancer was estimated in adoptees with at least one biological parent with the same cancer type compared with adoptees without a biological parent with the same cancer type. The risk of cancer was also determined in adoptees with at least one adoptive parent with cancer compared with adoptees with an adoptive parent without cancer. RESULTS: Adoptees with at least one biological parent with prostate, breast or colorectal cancer were more likely to have cancer of the same type than adoptees with biological parents not affected by these respective cancer types (standardised incidence ratio=SIR: 1.8 [95% confidence interval 1.2-2.7], 2.0 [1.6-2.5] and 1.9 [1.2-2.9], respectively). In contrast, adoptees with at least one adoptive parent with prostate, breast or colorectal cancer were not at an increased risk of these respective cancer types (SIR=1.2 [0.94-1.6], 0.97 [0.71-1.3], and 1.1 [0.71-1.5], respectively). CONCLUSIONS: The findings of the study support the importance of genetic/biological factors in the familial transmission of prostate, breast and colorectal cancer. PMID- 24953337 TI - A rational study for identification of highly effective siRNAs against hepatitis B virus. AB - RNA interference (RNAi) is a powerful gene knockdown technique used for study gene function. It also potentially provides effective agents for inhibiting infectious and genetic diseases. Most of RNAi studies employ a single siRNA designing program and then require large-scale screening experiments to identify functional siRNAs. In this study, we demonstrate that an assembly of results generated from different siRNA designing programs could provide clusters of predicting sites that aided selection of potent siRNAs. Based on the clusters, three siRNA target sites were selected on a conserved RNA region of hepatitis B virus (HBV), known as HBV post-transcriptional regulatory element (HBV PRE) at nucleotide positions 1317-1337, 1357-1377 and 1644-1664. All three chosen siRNAs driven by H1 promoter were highly effective and could drastically decrease expression of HBV transcripts (core, surface and X) and surface protein without induction of interferon response and cell cytotoxicity in liver cancer cell line (HepG2). Based on prediction of secondary structures, the silencing effects of siRNAs were less effective against a loop sequence of the mRNA target with hairpin structure. In summary, we demonstrate an effectual approach for identification of functional siRNAs. Moreover, highly potent siRNAs identified here may serve as novel agents for development of nucleic acid-based HBV therapy. PMID- 24953338 TI - High-contrast sub-millivolt inelastic X-ray scattering for nano- and mesoscale science. AB - Photon and neutron inelastic scattering spectrometers are microscopes for imaging condensed matter dynamics on very small length and time scales. Inelastic X-ray scattering permitted the first quantitative studies of picosecond nanoscale dynamics in disordered systems almost 20 years ago. However, the nature of the liquid-glass transition still remains one of the great unsolved problems in condensed matter physics. It calls for studies at hitherto inaccessible time and length scales, and therefore for substantial improvements in the spectral and momentum resolution of the inelastic X-ray scattering spectrometers along with a major enhancement in spectral contrast. Here we report a conceptually new spectrometer featuring a spectral resolution function with steep, almost Gaussian tails, sub-meV (?620 MUeV) bandwidth and improved momentum resolution. The spectrometer opens up uncharted space on the dynamics landscape. New results are presented on the dynamics of liquid glycerol, in the regime that has become accessible with the novel spectrometer. PMID- 24953339 TI - pi-Cooperativity effect on the base stacking interactions in DNA: is there a novel stabilization factor coupled with base pairing H-bonds? AB - The results from absolutely localized molecular orbital (ALMO)-energy decomposition analysis (EDA) and ALMO-charge transfer analysis (CTA) at M06-2X/cc pVTZ level reveal that double-proton transfer (DPT) reactions through base pairing H-bonds have nonignorable effects on the stacking energies of dinucleotide steps, which introduces us to a novel stabilization (or destabilization) factor in the DNA duplex. Thus, intra- and inter-strand base stacking interactions are coalesced with each other mediated by H-bridged quasirings between base pairs. Changes in stacking energies of dinucleotide steps depending on the positions of H atoms are due to variations in local aromaticities of individual nucleobases, manifesting pi-cooperativity effects. CT analyses show that dispersion forces in dinucleotide steps can lead to radical changes in the redox properties of nucleobases, in particular those of adenine and guanine stacked dimers in a strand. Besides Watson-Crick rules, novel base pairing rules were propounded by considering CT results. According to these, additional base pairing through pi-stacks of nucleobases in dinucleotide steps does not cause any intrinsic oxidative damage to the associated nucleobases throughout DPT. PMID- 24953340 TI - Evaluation of acridine orange, LysoTracker Red, and quinacrine as fluorescent probes for long-term tracking of acidic vesicles. AB - Acidic vesicles can be imaged and tracked in live cells after staining with several low molecular weight fluorescent probes, or with fluorescently labeled proteins. Three fluorescent dyes, acridine orange, LysoTracker Red DND-99, and quinacrine, were evaluated as acidic vesicle tracers for confocal fluorescence imaging and quantitative analysis. The stability of fluorescent signals, achievable image contrast, and phototoxicity were taken into consideration. The three tested tracers exhibit different advantages and pose different problems in imaging experiments. Acridine orange makes it possible to distinguish acidic vesicles with different internal pH but is fairly phototoxic and can cause spectacular bursts of the dye-loaded vesicles. LysoTracker Red is less phototoxic but its rapid photobleaching limits the range of useful applications considerably. We demonstrate that quinacrine is most suitable for long-term imaging when a high number of frames is required. This capacity made it possible to trace acidic vesicles for several hours, during a process of drug-induced apoptosis. An ability to record the behavior of acidic vesicles over such long periods opens a possibility to study processes like autophagy or long-term effects of drugs on endocytosis and exocytosis. PMID- 24953341 TI - Is climate an important driver of post-European vegetation change in the Eastern United States? AB - Many ecological phenomena combine to direct vegetation trends over time, with climate and disturbance playing prominent roles. To help decipher their relative importance during Euro-American times, we employed a unique approach whereby tree species/genera were partitioned into temperature, shade tolerance, and pyrogenicity classes and applied to comparative tree-census data. Our megadata analysis of 190 datasets determined the relative impacts of climate vs. altered disturbance regimes for various biomes across the eastern United States. As the Euro-American period (ca. 1500 to today) spans two major climatic periods, from Little Ice Age to the Anthropocene, vegetation changes consistent with warming were expected. In most cases, however, European disturbance overrode regional climate, but in a manner that varied across the Tension Zone Line. To the north, intensive and expansive early European disturbance resulted in the ubiquitous loss of conifers and large increases of Acer, Populus, and Quercus in northern hardwoods, whereas to the south, these disturbances perpetuated the dominance of Quercus in central hardwoods. Acer increases and associated mesophication in Quercus-Pinus systems were delayed until mid 20th century fire suppression. This led to significant warm to cool shifts in temperature class where cool-adapted Acer saccharum increased and temperature neutral changes where warm-adapted Acer rubrum increased. In both cases, these shifts were attributed to fire suppression rather than climate change. Because mesophication is ongoing, eastern US forests formed during the catastrophic disturbance era followed by fire suppression will remain in climate disequilibrium into the foreseeable future. Overall, the results of our study suggest that altered disturbance regimes rather than climate had the greatest influence on vegetation composition and dynamics in the eastern United States over multiple centuries. Land-use change often trumped or negated the impacts of warming climate, and needs greater recognition in climate change discussions, scenarios, and model interpretations. PMID- 24953342 TI - Two-coordinate Fe0 and Co0 complexes supported by cyclic (alkyl)(amino)carbenes. AB - The CAAC [CAAC=cyclic (alkyl)(amino)carbene] family of carbene ligands have shown promise in stabilizing unusually low-coordination number transition-metal complexes in low formal oxidation states. Here we extend this narrative by demonstrating their utility in affording access to the first examples of two coordinate formal Fe(0) and Co(0) [(CAAC)2M] complexes, prepared by reduction of their corresponding two-coordinate cationic Fe(I) and Co(I) precursors. The stability of these species arises from the strong sigma-donating and pi-accepting properties of the supporting CAAC ligands, in addition to steric protection. PMID- 24953343 TI - Fear of hypoglycemia in parents of children with type 1 diabetes. AB - AIM: The aim of this study is to determine if parental hypoglycaemia fear is associated with worse glycaemic control and increased resource utilisation and to identify risk factors for increased hypoglycaemia fear. METHODS: Parents of children with diabetes completed a modified Hypoglycaemia Fear Survey. Demographic data, phone contacts and mean glycosylated haemoglobin A1c (HbA1c) were also recorded over a 1 year study period. RESULTS: A total of 106 parents participated. Mean patient age was 11.1 years, and duration of diabetes was 4.8 years. Fifty-two per cent were male, and 48% were on insulin pump therapy. Fear of hypoglycaemia was highest among parents of 6- to 11-year-olds. Parents of children with HbA1c less than 7.5% had less hypoglycaemia fear. Previous seizures and increased frequency of phone calls to the diabetes team were not associated with increased fear. CONCLUSION: Fear of hypoglycaemia is associated with worse glycaemic control. It is highest among parents of 6- to 11-year-olds but is not affected by previous severe hypoglycaemia or associated with increased contact with the diabetes team. PMID- 24953345 TI - Abstracts of the 17th World Congress of Basic and Clinical Pharmacology, 13-18 July, 2014, Cape Town, South Africa. PMID- 24953344 TI - Heat-related illness in Washington State agriculture and forestry sectors. AB - BACKGROUND: We sought to describe heat-related illness (HRI) in agriculture and forestry workers in Washington State. METHODS: Demographic and clinical Washington State Fund workers' compensation agriculture and forestry HRI claims data (1995-2009) and Washington Agriculture Heat Rule citations (2009-2012) were accessed and described. Maximum daily temperature (Tmax) and Heat Index (HImax) were estimated by claim date and location using AgWeatherNet's weather station network. RESULTS: There were 84 Washington State Fund agriculture and forestry HRI claims and 60 Heat Rule citations during the study period. HRI claims and citations were most common in crop production and support subsectors. The mean Tmax (HImax) was 95 degrees F (99 degrees F) for outdoor HRI claims. Potential HRI risk factors and HRI-related injuries were documented for some claims. CONCLUSIONS: Agriculture and forestry HRI cases are characterized by potential work-related, environmental, and personal risk factors. Further work is needed to elucidate the relationship between heat exposure and occupational injuries. PMID- 24953347 TI - Spectroscopic distinctions between two types of Ce(3+) ions in X2-Y2SiO5: a theoretical investigation. AB - The Ce(3+) ions occupying the two crystallographically distinct Y(3+) sites both with C1 point group symmetry in the X2-Y2SiO5 (X2-YSO) crystal are discriminated by their spectroscopic properties calculated with ab initio approaches and phenomenological model analyses. Density functional theory (DFT) calculations with the supercell approach are performed to obtain the local structures of Ce(3+), based on which the wave function-based embedded cluster calculations at the CASSCF/CASPT2 level are carried out to derive the 4f -> 5d transition energies. From the ab initio calculated energy levels and wave functions, the crystal-field parameters (CFPs) and the anisotropic g-factor tensors of Ce(3+) are extracted. The theoretical results agree well with available experimental data. The structural and spectroscopic properties for the two types of Ce(3+) ions in X2-YSO are thus distinguished in terms of the calculated local atomic structures, 4f -> 5d transition energies, and spectral parameters. PMID- 24953346 TI - Exposure to air pollutants and mortality in hypertensive patients according to demography: a 10 year case-crossover study. AB - This study evaluated whether short term exposures to NO2, O3, particulate matter <10 mm in diameter (PM10) were associated with higher risk of mortality. A total of 223,287 hypertensive patients attended public health-care services and newly prescribed at least 1 antihypertensive agent were followed-up for up to 5 years. A time-stratified, bi-directional case-crossover design was adopted. For all cause mortality, significant positive associations were observed for NO2 and PM10 at lag 0-3 days per 10 MUg/m(3) increase in concentration (excess risks 1.187% 2.501%). Significant positive associations were found for O3 at lag 1 and 2 days and the excess risks were 1.654% and 1.207%, respectively. We found similarly positive associations between these pollutants and respiratory disease mortality. These results were significant among those aged >=65 years and in cold seasons only. Older hypertensive patients are susceptible to all-cause and respiratory disease-specific deaths from these air pollutants in cold weather. PMID- 24953348 TI - Realising the ICPD 20 years later: shifting the paradigms for research and education. AB - The extent to which people can enjoy their sexual and reproductive health is invariably intertwined with issues of disadvantage, inequality and human rights. Increased conservatism, lack of political will, outright resistance and the limited incorporation of human rights norms and standards into sexual and reproductive health policies and programmes are central challenges. Building capacity and skills to understand and address the range of issues raised by sexual and reproductive health and rights is of critical importance. Committed to the principles underlying the ICPD agenda and heavily involved in research and education, with a shared desire to bring global attention to the need for gender- and rights-oriented research and training in sexual and reproductive health, a group of us came together to form the Rights-Oriented Research and Education (RORE) Network for Sexual and Reproductive Health at the end of 2012. To generate dialogue, discussion and action, we propose what we mean by a human rights orientation to sexual and reproductive health and what we believe is needed going forward to achieve a human rights orientation to sexual and reproductive health education and research. PMID- 24953350 TI - The tidepool shrimp, Palaemon ritteri Holmes, constitutes a novel host to the white spot syndrome virus. AB - The white spot syndrome virus (WSSV) is a lethal and contagious pathogen for penaeid shrimp and a growing number of other crustacean species. To date, there are no effective prophylactic or therapeutic treatments commercially available to interfere with the occurrence and spread of the disease. In addition, the significance of alternative vectors on the dispersal of this disease has been largely ignored and therefore the ecological dynamics of the WSSV is still poorly understood and difficult to ascertain. Thus, an important issue that should be considered in sanitary programmes and management strategies is the identification of species susceptible to infection by WSSV. The results obtained provide the first direct evidence of ongoing WSSV replication in experimentally infected specimens of the tidepool shrimp Palaemon ritteri. Viral replication was detected using a validated set of primers for the amplification by RT-PCR of a 141 bp fragment of the transcript encoding the viral protein VP28. It is therefore conceivable that this shrimp may play a significant role in the dispersal of WSSV. PMID- 24953349 TI - Women's experiences of Takotsubo cardiomyopathy in a short-term perspective--a qualitative content analysis. AB - BACKGROUND: Takotsubo cardiomyopathy is a reversible condition mimicking acute myocardial infarction. The phenomenon is associated with emotional and physical stressful trigger events. Evidence-based patient counselling should be based on disease-specific knowledge of patient experiences. AIM: The aim of the study was to describe women's experiences of Takotsubo cardiomyopathy in a short-term perspective. DESIGN: The study design was explorative and descriptive. METHOD: Semi-structured interviews were conducted with 14 women diagnosed with Takotsubo cardiomyopathy, 1 day to 9 months after hospitalisation. The transcriptions underwent qualitative content analysis. FINDINGS: The main theme that emerged was Takotsubo cardiomyopathy as a continuous process of making sense and adapting. To begin with, understanding and coping with signs and symptoms were described as having a diversity of signs and symptoms, taking actions towards signs and symptoms, receiving treatment for suspected ST/non ST-elevation myocardial infarction diagnosis and finally being diagnosed with Takotsubo cardiomyopathy. Understanding the context of illness was expressed as getting treated for Takotsubo cardiomyopathy diagnosis and having previous stressful conditions of life. The changing perspective that emanated was a combination of having prospects and expectations and experiencing limitations. Finally, managing to live with Takotsubo cardiomyopathy was manifested as returning home with the illness and receiving follow-up health care. CONCLUSION: Information on regaining prior health status and capacity within a short-term perspective may not be accurate. These women struggle and require education and counselling from healthcare professionals to comprehend and manage having a Takotsubo cardiomyopathy diagnosis. Women experiencing Takotsubo cardiomyopathy may be a target group for holistic and individual health care with a longer duration of follow-up. PMID- 24953352 TI - Maternal serum anti-Mullerian hormone at 11-13 weeks' gestation in the prediction of preeclampsia. AB - OBJECTIVE: To investigate the potential value of maternal serum anti-Mullerian hormone (AMH) at 11-13 weeks' gestation in the prediction of preeclampsia (PE). METHODS: The serum concentration of AMH was measured at 11-13 weeks' gestation in cases of PE (n = 50) and normotensive controls (n = 150). Backward stepwise multiple regression analysis was used to determine which of the factors amongst the maternal characteristics and gestation were significant predictors of the serum AMH in the control group and from the regression model the value in each case and control was expressed as a multiple of the expected median (MoM). RESULTS: In normotensive pregnancies, the maternal serum concentration of AMH is higher in Afro-Caribbean than in Caucasian women and in smokers than in non smokers. In the PE group, the median serum concentration of AMH was significantly higher than in the controls (2.140 ng/L, IQR 1.968-2.273 versus 2.062 ng/L, IQR 1.938-2.181; p = 0.025), but the median MoM value of AMH was not significantly different between the PE group and the controls (1.040, IQR 0.941-1.081 versus 0.995, IQR 0.939-1.065, p = 0.147). CONCLUSIONS: Maternal serum AMH is not an effective early predictor for PE. PMID- 24953353 TI - [Current problems and challenges in the diagnosis and treatment of colorectal cancer in China]. AB - In the past 20 years, researches regarding colorectal cancer have experienced unprecedented boom in China. However, a seris problems have been exposed, including a rapid increase in morbility, the geographical limitations of tumor screening, nonstandard diagnosis and treatment, very limited mechanism researches, and lack of randomized controlled clinical trials with Chinese characteristics. This article puts forward some main emphases of the current work, based on the above problems and challenges, in order to improve the overall level of the diagnosis and treatment of colorectal cancer in China. PMID- 24953351 TI - L-Carnitine supplementation impairs endothelium-dependent relaxation in mesenteric arteries from rats. AB - L-Carnitine (L-Car) is taken as fat burner. The risks of L-Car supplementation for the cardiovascular system are unclear. We evaluated the relaxing responses of the mesenteric and aorta rings from rats after four weeks of L-Car supplementation and/or physical training. Concentration response curves to acetylcholine (ACh) and sodium nitroprusside (SNP), as well as cyclic GMP levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) were evaluated. Physical training decreased body weight gain that was potentiated by L-Car. In mesenteric rings, L-Car impaired endothelium-dependent relaxation whereas endothelium independent relaxation was increased. In aorta, exercise improved endothelium-dependent relaxation; however, it was partially inhibited by L-Car. SNP-induced relaxation was similar in aorta of all groups. Basal cGMP were increased in aorta of exercised rats. SOD activity and MDA levels were unaltered. In conclusion, L-Car and physical exercise promotes body weight loss; however, it impairs endothelium-dependent vaso-relaxation possibly involving alterations in muscarinic receptors/eNOS/NO signalling pathway in mesenteric artery. PMID- 24953354 TI - [Interpretation of guidelines for the diagnosis and comprehensive treatment of colorectal cancer liver metastases in China(v2013)]. AB - In recent years there have been great developments in the diagnosis and comprehensive treatment of colorectal cancer liver metastases (CRLM). Guidelines for the Diagnosis and Comprehensive Treatment of Colorectal Cancer Liver Metastases were compiled to standardize and improve the diagnosis and treatment outcomes in China. This paper summarizes the updated content in the Guideline (V.2013). We should conduct gene testing related to CRLM to guide individual treatment, emphasize the role of the multidisciplinary team, and select molecular targeted drugs reasonably. In addition, we discuss the operative timing of CRLM, minimally invasive operation and regional therapy of liver metastases. PMID- 24953355 TI - [Re-evaluation of the clinical significance of TNM staging of mid-low rectal cancer]. AB - The concept of "diagnosis priority using the normalized methods" is the foundation for individualized treatment. A multidisciplinary team, including colorectal surgeons, radiologists and pathologists, should be established for the patients of mid-low rectal cancer. In order to ensure the scientific treatment strategies, reasonable methods of clinical imaging should be arranged to obtain precise clinical TNM staging of pre-therapy. Preoperative neoadjuvant chemoradiotherapy should be performed for the patients of middle-low rectal cancer, whose cancer staging is cT3-4 or cN1-2. The emphasis of the seventh edition of AJCC TNM staging in rectal cancer is to determine what T3 carcinoma is. The basic principle of normalization of mid-low rectal cancer is to achieve R0 resection according to preoperative staging, and to administer comprehensive adjuvant therapy with the evaluation of pathological staging. PMID- 24953356 TI - [Application of extralevator abdominoperineal excision for low rectal carcinoma]. AB - It has been reported that the conventional abdominoperineal excision has the disadvantages of higher rates of positive circumferential resection margin and intraoperative bowel perforation, which affect the prognosis. The technique of extralevator abdominoperineal excision proposed by Holm et al is used to overcome these disadvantages. But this new concept of abdominoperineal excision causes other new problems, such as increased complexity, major trauma and more complications. With further studies, the advanced knowledge about the indications, modifications and complications of this technique has been obtained by the domestic and overseas surgeons. This article reviews the characteristics of extralevator abdominoperineal excision and its indications, research progress and major associated complications. PMID- 24953357 TI - [Perineal reconstruction after extralevator abdominoperineal excision(ELAPE) for carcinoma at the lower rectum]. AB - Extralevator abdominoperineal excision (ELAPE) has been described to improve the outcomes of advanced low rectal cancer, probably because of more pelvic dissection and less positive circumferential resection margin (CRM). Recent improvements of ELAPE have focused on the reconstruction of the large pelvic defect. Different approaches have been focused on the reconstruction including primary closure, uterus retroversion, omentoplasty, myocutaneous flaps, and biological mesh. The optimal method is still controversial. Recent reviews showed that the perineal wound complications of biological mesh reconstruction were comparable to those of myocutaneous flaps. Moreover reviews suggested the use of biologic materials to close the perineal defect because it offers a significant cost saving mostly attributable to reduction in hospital length of stay. The combination of different techniques may be the best way to reconstruct the pelvic defect following ELAPE. PMID- 24953358 TI - [Effect of transanal excision in the treatment of rectal cancer]. AB - The surgical approach for rectal cancer includes trans-abdominal and transanal excision. Total mesorectal excision(TME) is the golden standard for surgical treatment. In the functional surgery era, more and more evidence shows that under strict indications, traditional abdominal radical surgery and transanal excision can achieve similar survival in patients with early stage cancer. However, the local recurrence rate of local resection was significantly higher compared to TME, suggesting strict patients selection for transanal excision. Preoperative accurate evaluation is critical in clinical practice. PMID- 24953359 TI - [Downstaging correlates the prognosis of rectal cancer after intensified neoadjuvant chemoradiotherapy]. AB - OBJECTIVE: To evaluate the impact of downstaging factors on oncologic outcomes in a cohort of patients with rectal cancer after intensified neoadjuvant chemoradiotherapy. METHODS: Clinical and follow-up data of 135 patients with mid low rectal cancer receiving intensified neoadjuvant chemoradiotherapy in our hospital from 2005 to 2012 were analyzed retrospectively. Tumor stages before chemoradiotherapy (uTNM) and after surgery (ypTNM) were compared. The therapeutic regimen consisted of 25 fractions of totaled 50 Gy radiation and 2-3 cycles of combination chemotherapy with 5-Fu/capecitabine plus oxaliplatin. Association of 3-year disease-free survival (DFS) with T-stage, N-stage and TNM-stage was examined through the comparison of uTNM and ypTNM. RESULTS: The mean follow-up of 135 patients was 37.1 (12 to 87) months. The 3-year DFS was 85.2%. The 3-year DFS of patients with downstaging of T-stage (n=76) was 90.8%, which was significantly better compared to those without downstaging (n=48, 75.0%, P=0.040). The 3-year DFS of patients with downstaging of N-stage (n=54) was 98.1%, which was n=53, better compared to those without downstaging (significantly 77.4%) and those with progressive disease (n=16, 75.0%) (P=0.009). Multivariate analysis showed downstaging in N-stage was a prognostic factor for DFS (HR=0.793, 95%CI:0.626 1.004, P=0.054). CONCLUSIONS: Patients with pathologic downstaging in T-stage, N stage and TNM classification after intensified neoadjuvant chemoradiotherapy may improve patient survival. Downstaging in N-stage may be an independent predictor of survival. PMID- 24953362 TI - [Clinicopathological study of safe resectional margin in mid and low rectal cancer after neoadjuvant chemoradiotherapy]. AB - OBJECTIVES: To investigate the regression pattern of mid and low rectal cancer treated with neoadjuvant chemoradiotherapy and then to provide the pathological proofs for reasonable resectional margin in rectal cancer surgery. METHODS: Forty cases of mid and low rectal cancer patients received concurrent chemoradiotherapy and then underwent radical operation. The whole-mount serial sections of resected rectal cancer specimen were stained with cytokeratin antibody using immunohistochemical techniques to show the residual cancer cells under the mucosa. The microscopic measurement was performed to determine the reverse infiltration of cancer cells in the rectal wall and to describe the cancer cells scatter ways in the cancer mass. The Ki-67 immunohistochemical stain was also performed to show the proliferation activity of residual cancer cells after neoadjuvant chemoradiotherapy. RESULTS: The length of specimen was shrinking continuously during the pathologic section production and the shrink rate was 18%. There were remanent cancer cells which showed positive Ki-67 expression and the chemoradiotherapy decreased the Ki-67 expression significantly. The lower edge of remaining ulcers or scars could be used as the reference point from which the cancer infiltration could be measured. According to our measurement, the average reverse infiltration of cancer cells in the whole-mount section was (6.1+/-4.7) mm, the deepest one was 11.0 mm in the section which could be converted into fresh bowel length of 12.98 mm. The pathology showed that the residual cancer cells scattered in the fibrous tissue of ulcers, scars and manifested a regression of spatial distribution. CONCLUSIONS: The rectal cancers show regression in different degrees after neoadjuvant chemoradiotherapy. The residual cancer cells in the fiber tissues manifest proliferation activity. The distal end of resection should be at least 2 cm away from the lower edge of ulcers or scars of primary tumor in the rectal wall in patients after neoadjuvant chemoradiotherapy. The circumferential resection margin should include all the fibrous scar of the tumor area to ensure the remove of tumor cells completely. PMID- 24953361 TI - [Predictive factors associated with pathologic complete response after neoadjuvant chemoradiotherapy in rectal cancer]. AB - OBJECTIVE: To explore predictive factors associated with pathologic complete response (pCR) after neoadjuvant chemoradiotherapy for rectal cancer. METHODS: Clinicopathological data of 163 patients with locally advanced rectal cancer who were treated with neoadjuvant chemoradiotherapy followed by radical surgical resection from January 2007 to May 2013 were analyzed retrospectively. Univariate analysis and multivariate logistic regression analysis were performed to analyze associated factors of pCR, including age, gender, body mass index (BMI), diabetes, anemia, tumor diameter, distance of the tumor from the anal verge, circumferential extent of the tumor, tumor pathological types, tumor differentiation, pre-chemoradiotherapy T stage, pre-chemoradiotherapy N stage, pre-chemoradiotherapy CEA level, pre-chemoradiotherapy CA199 level, per-operation CEA level, pre-operation CA199 level, radiation dose, chemotherapy modality, time interval from completion of chemoradiotherapy to surgery, etc. RESULTS: Twenty nine patients(17.8%) achieved pCR after neoadjuvant chemoradiotherapy for rectal cancer. Univariate analysis showed circumferential extent of tumor(>=1/2 cycle)(P=0.018), tumor pathological types(adenocarcinoma)(P=0.036), tumor differentiation (moderate or high)(P=0.021) and pre-chemoradiotherapy CEA level(<=2.5 MUg/L)(P=0.007) were significantly correlated with pCR after neoadjuvant chemoradiotherapy for rectal cancer. Logistic regression revealed that circumferential extent of tumor (>=1/2 cycle)(OR=2.901, P=0.020) and pre chemoradiotherapy CEA level (<=2.5 MUg/L)(OR=2.775, P=0.022) were independent predictive factors of pCR after neoadjuvant chemoradiotherapy for rectal cancer. CONCLUSION: Patients with circumferential extent of tumor <=1/2 and pre chemoradiotherapy CEA level <=2.5 MUg/L are more likely to achieve pCR after neoadjuvant chemoradiotherapy for rectal cancer, and these two indices can be used to predict pCR after neoadjuvant chemoradiotherapy for rectal cancer. PMID- 24953360 TI - [Prediction of efficacy of neoadjuvant radiochemotherapy based on depth of invasion in T3 rectal cancer]. AB - OBJECTIVE: To investigate the association of mesorectal invasion depth before neoadjuvant radiochemotherapy with pathological outcome and to provide evidence for individualized treatment in T3 rectal cancer. METHODS: Retrospective analysis was performed on the clinical records of 73 consecutive rectal cancer patients treated with neoadjuvant radiochemotherapy and radical surgery in the Shanghai Cancer Center from January 2010 to December 2012. All the patients underwent high resolution MRI and the depth of mesorectal invasion, lymph node status, tumor length, and mesorectal fascia status were evaluated. The category T3 was subdivided according to the measurement of the maximal tumor invasion beyond the outer border of the muscularis propria: T3a(<5 mm), T3b(5-10 mm) and T3c(>10 mm). The association of mesorectal invasion depth,other MRI and clinical features with short-term efficacy was analyzed,especially with pathological complete response(pCR). RESULTS: T3a, T3b and T3c accounted for 19.2%, 64.4% and 16.4% in 73 rectal cancer patients who underwent high resolution MRI, respectively. There were 42.9% of T3a patients achieved pathological complete response,significantly higher than those of T3b(14.9%)and T3c(0%) (P=0.017). CONCLUSIONS: T3a rectal cancer patients are more likely to achieve pCR than those of T3b and T3c after neoadjuvant radiochemotherapy. The maximal tumor invasion beyond the outer border of the muscularis propria less than 5 mm may act as a predictive factor and guide the follow-up treatment of T3 rectal cancer. PMID- 24953363 TI - [Sensitivity study on preoperative individual concomitant radiochemotherapy for rectal cancer]. AB - OBJECTIVE: To explore the predictive factors of sensitivity to preoperative concomitant radiochemotherapy for the local mid-low advanced rectal cancer in order to guide the individualized therapy. METHODS: Clinicopathologic data of 44 patients with local mid-low advanced rectal cancer receiving preoperational concomitant radiochemotherapy were retrospectively analyzed. Expression of epidemical growth factor receptor (EGFR) in biopsy specimen was detected with SP immunohistochemistry (IHC). Downstaging of tumor TNM stage and tumor regression grade (TRG) after radiochemotherapy were used as the standards of sensitivity to preoperational concomitant radiochemotherapy. Association of EGFR expression and pathological change with clinicopathological data before radiochemotherapy (gender, age, pathological type, tumor TNM stage, serum CEA, CA199, radiation method, etc) was analyzed. RESULTS: Percentage of downstaging of tumor TNM stage and 3-4 TRG in patients with negative or weak positive EGFR expression was significantly higher as compared to those with strong and moderate positive EGFR expression [86.7% (13/15) vs. 30.4% (7/23), P<0.01; 80.0% (12/15) vs. 8.7% (2/23), P<0.01]. Percentage of downstaging of tumor TNM stage and 3-4 TRG in patients with tubular adenocarcinoma was significantly higher as compared to those with mucous adenocarcinoma [61.8% (21/34) vs. 10.0% (1/10), P<0.01; 47.1 (16/34) vs. 0 (0/10), P<0.01]. EGFR expression was not associated with pathological type (P>0.05). Sensitivity to preoperative concomitant radiochemotherapy was not associated with age, gender, tumor stage, tumor differentiation, serum CEA, serum CA199 and radiation method (all P>0.05). CONCLUSIONS: Pathological type and EGFR expression level may be two independent predictive markers of sensitivity to preoperative concomitant radiochemotherapy for patients with rectal cancer. Patients with tubular adenocarcinoma or low EGFR expression in tumor tissue may be more sensitive to concomitant radiochemotherapy. PMID- 24953364 TI - [Anatomical basis and main points of pelvic autonomic nerve preserving in proctectomy]. AB - OBJECTIVE: To elucidate the course of pelvic autonomic nerves and its relationship with pelvic fascia in order to identify the safe plane to reduce the damage of pelvic autonomic nerves in total mesorectum I excision(TME). METHODS: The course and distribution of pelvic autonomic nerves were observed and their relationship with pelvic interfascial space was examined through the anatomy of 12 adult pelvic specimens. RESULTS: The entire course of hypogastric nerves ran within the anterior sacral fascia and the inferior hypogastric plexus ran within parietal fascia. Inferior hypogastric plexus crossed the fusion line of Denonvilliers fascia and parietal fascia in the 10 o'clock and 2 o'clock directions of the rectum, and joined urogenital vessel bundle finally. Laterigrade traffic nerves could be found in Denonvilliers fascia. CONCLUSION: The safe plane should be chosen between rectal proper fascia and anterior sacral fascia near rectal proper fascia in posterior dissection and lateral dissection of rectum. More attention should be paid to protect the neurovascular bundle in the 10 o'clock and 2 o'clock directions of rectum and traffic nerve within Denonvilliers fascia in anterior dissection. PMID- 24953365 TI - [Comparison of short-term outcomes of hand-assisted laparoscopic, laparoscopic, and open surgery in the treatment of rectal cancer]. AB - OBJECTIVE: The aim of this study was to compare the short-term outcomes for hand assisted, laparoscopic, and open resection for rectal cancer. METHODS: Three hundred ninety patients with rectal cancer who underwent curative resection between June 2009 and June 2012 were included. Patients were classified into a hand-assisted group (HALS, n=101), a laparoscopic surgery group (LS, n=157), and an open surgery group (OS, n=132). Patient and disease characteristics, operative parameters, postoperative morbidity, pathological results and length of recovery were compared among three groups. RESULTS: The mean operating time was (173+/-39) min for the HALS group, (231+/-61) min for the LS group, and (173+/-39) min for the OS group (P<0.01). Conversion rates did not differ between HALS and LS groups (2.0% vs 3.2%, P=0.708). The overall complication rates were 11.9%, 11.5%, and 19.7% in the HALS, LS and OS groups respectively (P=0.100). The specimen quality with a specimen length, distal resection margin, harvested lymph nodes, and positive lymph nodes did not differ among the three groups. Patients in the HALS and LS groups recovered significantly faster than those from the OS group. CONCLUSIONS: This comparative study shows that HALS and LS can reproduce the equivalent short-term results of standard OS. HALS retained the minimal invasive advantages of LS, and significantly shorten the operation time. PMID- 24953366 TI - [Risk factors associated with lymph node metastasis and prognosis in 69 patients with rectal neuroendocrine tumors]. AB - OBJECTIVE: To investigate risk factors associated with lymph node metastasis and prognosis of rectal neuroendocrine tumor (NET). METHODS: Clinicopathological data of 69 patients with rectal NET in our department from April 2003 to October 2011 were retrospectively analyzed. Associations of clinicopathological factors with lymph node metastasis and prognosis were examined using univariate and multivariate analysis. RESULTS: Of the 69 patients, 9 cases had lymph node metastasis. The lymph node metastasis was significantly associated with tumor size, T stage and G grade by univariate analysis. Multivariate analysis showed that T stage was the only risk factor associated with lymph node metastasis. The overall 5-year survival rate was 90.3%. Prognosis of rectal NET was significantly associated with tumor size, T stage, N stage, M stage, TNM stage and G grade by univariate analysis. Multivariate analysis showed that M stage was significantly associated with long-term survival in rectal NET patients (P=0.000, HR=2.285, 95%CI:1.484~3.518). There was no significant difference in patients with stage I between local and radical resection, while there were significant differences in those with stage II or higher between the two operations (P=0.046). CONCLUSION: T stage is associated with lymph node metastasis and both TNM stage and M stage can affect the prognosis of patients with NET, which may be used as potential predictive factors for rectal NET. Local resection should be recommended for patients with stage I and radical resection should be recommended for patients with stage II or higher. PMID- 24953367 TI - [Application of preoperative nutritional risk screening in perioperative nutrition support for colorectal cancer patients]. AB - OBJECTIVE: To investigate the guidance role of preoperative nutritional risk screening in perioperative nutrition support for colorectal cancer patients in order to provide evidence for the rational clinical application of nutrition support. METHODS: Nutritional risk screening was carried out in 290 hospitalized colorectal cancer patients from The Fourth People's Hospital of Wuxi City, Tongji Hospital of Tongji University and The Second Hospital of Soochow University with the nutritional risk screening(NSR) 2002 score summary table. Postoperative bowel function recovery and associated nutritional indices were compared between patients who received preoperative nutrition support according to the risk screening results and those who did not. RESULTS: Among 110 patients at nutritional risk, 65 received perioperative nutrition support and had faster recovery of intestinal function [time to first flatus (2.3+/-0.5) d vs. (3.3+/ 0.5) d, time to first defecation (3.5+/-0.5) d vs. (4.6+/-0.6) d, semi-fluid intake (10.1+/-1.2) d vs. (12.4+/-2.2) d], shorter postoperative stay [(15.7+/ 1.1) d vs. (18.8+/-1.4) d], and higher albumin, prealbumin and transferrin [(33.2+/-4.5) g/L vs. (26.0+/-4.0) g/L, (0.28+/-0.05) g/L vs. (0.16+/-0.04) g/L, (1.92+/-0.33) g/L vs. (1.75+/-0.45) g/L] at 7-day postoperatively (all P<0.05) as compared to those without perioperative nutrition support(n=45). While among 180 cases without nutritional risk, there were no significant differences in the above indices between patients who received preoperative nutrition support and those who did not (all P>0.05). CONCLUSION: It is important to evaluate the nutritional risk in hospitalized patients with colorectal cancer, and to carry out nutrition support actively for those at nutritional risk. PMID- 24953368 TI - [Clinical study of tissue-selecting therapy in the treatment of mixed hemorrhoids: a single-blind randomized controlled trail]. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of tissue-selecting therapy (TST) in treatment of mixed hemorrhoids. METHODS: A single-blind randomized study was carried out. A total of 120 patients with mixed hemorrhoids from January to December 2012 were prospectively enrolled in the study and equally divided into two groups, TST group and procedure for prolapse and hemorrhoids(PPH) group. Surgical data, efficacy and postoperative complications were compared between the two groups. RESULTS: As compared to PPH group, patients in TST group had shorter operation time [(15.9+/-5.18) min vs. (22.6+/-7.1) min, P<0.05], lower scores of rectal urgency (0.5+/-0.2 vs. 1.5+/-1.4, P<0.05), and shorter hospital stay [(11.2+/-3.7) d vs. (14.8+/-3.7) d, P<0.05]. No anastomotic stricture case was found in TST group, while 11 cases(18.3%) developed anastomotic stricture in PPH group. There were no significant differences in effective rate and pain score of first defecation between the two groups. CONCLUSION: TST is reliable and safe for mixed hemorrhoids with the advantage of simple, rapid recovery and less complications. PMID- 24953369 TI - [Clinical significance of the detection of serum neutrophil gelatinase-associated lipocalin in human colorectal cancer]. AB - OBJECTIVE: To explore the feasibility and clinical significance of the detection of serum neutrophil gelatinase-associated lipocalin (NGAL) in human colorectal cancer. METHODS: Levels of NGAL in serum samples from 133 healthy people, 125 colorectal polyps patients and 100 colorectal cancer patients respectively were determined by sandwich ELISA assay. Relationship of NGAL level with clinicopathological features of colorectal cancer patients was analyzed. The optimal cut-off value of serum NGAL for diagnosing colorectal cancer was determined by ROC curve and compared with CEA and CA19-9. Univariate and multivariate analyses were performed to examine the relationship of NGAL level with the prognosis of patients with colorectal cancer. RESULTS: The median serum NGAL protein level in 100 colorectal cancer cases was 67.96 (53.30-79.86) MUg/L, significantly higher than that in healthy people and colorectal polyps patients. The differences were statistically significant (all P<0.01). Serum NGAL protein level was significantly associated with tumor diameter, TNM stage, lymph node metastasis and vascular involvement (P<0.05). The optimal cut-off point of serum NGAL protein level for diagnosing colorectal cancer was 49.78 MUg/L, and the sensitivity and specificity were 88% and 81% respectively. As for colorectal cancer patients with stage I, the sensitivity of serum NGAL (78.9%) was significantly higher as compared to CA19-9 (31.6%) and CEA (36.8%); as for those with stage II, the sensitivity of serum NGAL(88.0%) was also significantly higher compared to CA19-9 (48.0%) and CEA (52.0%). Kaplan-Meier analysis showed that patients with positive NGAL (>=49.78 MUg/L) had worse survival than those with negative NGAL (P=0.002). Multivariate analysis showed that NGAL was an independent prognostic factor (HR=2.060, 95%CI:1.023-4.150, P=0.043). CONCLUSIONS: NGAL can be served as the novel malignant biological phenotype marker for human colorectal cancer and can be used for the risk stratification. NGAL may be an independent prognostic factor in colorectal cancer. PMID- 24953374 TI - [Progression in bowel dysfunction after sphincter-preserving operation for rectal cancer]. AB - The progress in the idea and technology of rectal cancer improve the rate of sphincter-preservation, while bowel dysfunction is the major problem puzzling patients after sphincter-preserving operation. Recent researches reveal bowel dysfunction is closely associated with the postoperative change of anatomy, nerve damage and sphincter functional injury based on the mechanism of defecation function change through the analysis of anatomy, physiology and dynamics. This paper summarizes the mechanism and epidemiology of bowel dysfunction after rectal cancer operation, and elucidate the role of such mechanism in treatment and prevention of above bowel dysfunction. PMID- 24953373 TI - [Progress in sphincter-preserving surgery in patients with low rectal cancer]. AB - Rectal cancer is a common malignant tumor. In China, low rectal cancer accounts for more in rectal cancer. Surgery currently remains at the center of any potentially curable case. With the rapid development of surgical techniques and progress of pathology research in low rectal cancer, sphincter-preserving surgery has been widely used in the treatment of low rectal cancer. This review is to summarize the current literatures pertaining to sphincter-preserving surgery, including distal resection margin, neoadjuvant therapy, indications, and postoperative complications. PMID- 24953371 TI - [Association of expression of HGF and its receptor c-Met to primary colorectal cancers with synchronous liver metastasis]. AB - OBJECTIVE: To investigate the association between expression of hepatocyte growth factor(HGF) and its receptor c-Met and primary colorectal cancers with synchronous liver metastases. METHODS: A total of 30 colorectal cancer patients with synchronous liver metastasis underwent radical resection of primary cancer and liver cancer in our hospital from June 2001 to June 2010. According to lymphatic metastasis, patients were divided into group A(T1~T4N1~N2M1, n=21) and group B(T1~T4N0M1, n=9). Twenty-one matched T1~T4N1~N2M0 and 21 T1~T4N0M0 patients were used as the controls of group A. Nine matched T1~T4N0M0 patients were used as the controls of group B. Expressions of HGF and c-Met in tissues of primary loci, liver loci and metastatic loci were detected by immunohistochemistry. RESULTS: In primary loci of group A, the positive rate of HGF was significantly higher than that of T1~T4N1~N2M0 and T1~T4N0M0 controls [71%(15/21) vs. 43%(9/21), 19%(4/21), all P<0.05]. The positive rate of c MET[90%(19/21)] was significantly higher compared to T1~T4N0M0 control[43%(9/21), P<0.05], while not significantly different compared to T1~T4N1~N2M0 control[86%(18/21)]. In primary loci of group B, positive rates of HGF and c-MET were not significantly different as compared to T1~T4N0M0 control[6/9 vs. 5/9, P>0.05; 8/9 vs. 6/9, P>0.05]. Concordance of HGF and c-MET expression in group A among primary loci, lymphatic metastatic loci and hepatic metastatic loci was 81%(17/21) and 76%(16/21). CONCLUSION: HGF-c-Met may play a role in colorectal cancer patients with synchronous liver metastasis who have regional lymphatic metastasis, and may have few effect on colorectal cancer with synchronous liver metastasis without corresponding lymphatic metastasis. PMID- 24953375 TI - Comparison of walking energy cost between an anterior and a posterior ankle-foot orthosis in people with foot drop. AB - OBJECTIVE: To compare walking energy cost between an anterior and a posterior ankle-foot orthosis in people with foot drop. DESIGN: Within-group comparisons. PARTICIPANTS: Twenty-three adults (14 women, 9 men; mean age 56.8 years (standard deviation 15.4)) with foot drop. METHODS: PARTICIPANTS were asked to walk for 5 min at their self-selected walking speed under 3 conditions: (i) with shoes only; (ii) with a posterior ankle-foot orthosis; (iii) with an anterior ankle-foot orthosis. Spatio-temporal gait para-meters (speed, step length and step frequency) and walking energy cost per unit of distance were assessed for each walking condition. A visual analogue scale was used to quantify participants' level of perceived comfort for the 2 orthosis. RESULTS: Gait spatio-temporal parameters were higher with anterior ankle-foot orthoses than with posterior ankle-foot orthoses or shoes only. Walking energy cost per unit of distance was lower with anterior than posterior ankle-foot orthosis or shoes only ((mean +/- standard error) 3.53 +/- 1.00 vs 3.94 +/- 1.27 and 3.98 +/- 1.53 J.kg-1.m-1 respectively; p < 0.05) and level of perceived comfort was higher with anterior ((mean +/- standard error) 8.00 +/- 1.32) than with posterior ankle-foot orthosis ((mean +/- standard error) 4.52 +/- 2.57; p < 0.05). CONCLUSION: In people with foot drop the use of anterior ankle-foot orthoses resulted in lower energy costs of walking and higher levels of perceived comfort compared with posterior ankle foot orthoses. Anterior ankle-foot orthoses may enable people with foot drop to walk further with less physical effort than posterior ankle-foot orthoses. PMID- 24953372 TI - [Role of SIRT1 in the protection of intestinal epithelial barrier under hypoxia and its mechanism]. AB - OBJECTIVE: To observe the effect of SIRT1 on intestinal barrier function of epithelial Caco-2 cells under hypoxia and investigate its mechanism. METHODS: Caco-2 cells were randomly divided into three groups: normoxia group (Nx), hypoxia group (Hx,1%O2 for 6 h) and hypoxia plus 40 MUmol/L Resveratrol (agonist of SIRT1) group (Hx+Res). Transepithelial electrical resistance (TER) was determined. mRNA and protein expressions of SIRT1 and tight junctions (ZO-1, Occludin, Claudin-1) were examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: Both mRNA and protein expressions of SIRT1 were significantly reduced in Hx group as compared with Nx group (0.40+/-0.02 vs. 0.70+/-0.07, P=0.001; 0.37+/-0.03 vs. 0.76+/-0.03, P=0.001). The mRNA and protein expressions of SIRT1 were significantly increased in Hx+Res group as compared with Hx group(0.50+/-0.02 vs. 0.40+/-0.02, P=0.026; 0.54+/-0.02 vs. 0.37+/-0.03, P=0.011). The expression levels of ZO-1, Occludin and Claudin-1 in Hx group were lower than those in Nx group (P<0.05), however, pretreatment with Resveratrol could attenuate the decreased expression of above 3 molecules under hypoxia(P<0.05). TERs of Nx group, Hx group and Hx+Res group were (142+/-7) Ohm/cm(2), (94+/-3) Ohm/cm(2) and (119+/-7) Ohm/cm(2) respectively. Compare with the Nx group, the TER of Hx group was significantly decreased(P<0.05). TER of Hx+Res group was significantly increased compare with Hx group, but it was still significantly lower than that in Nx group(P<0.05). CONCLUSIONS: Expression of SIRT1 is significantly reduced under hypoxia. Activation of SIRT1 can maintain the epithelial barrier function through regulating the expression of tight junctions under hypoxia. PMID- 24953376 TI - Maintenance therapy in epithelial ovarian cancer: from chemotherapy to targeted agents. AB - Over the past years, although no increase in the cure rate for advanced epithelial ovarian cancer patients has been achieved, a slow prolongation in patients survival has been observed, thanks to the introduction of effective second line or salvage therapies. Attempts to disease chronicization seem therefore of value in this setting. A major effort has been pursued to establish the role of maintenance therapies for epithelial ovarian cancer patients. Although chemotherapy does not seem to have an effective role, promising results are coming from trials investigating maintenance targeted treatments, especially with antiangiogenic agents or PARP inhibitors for selected patients. The aim of this article is to review current evidences on maintenance therapy for epithelial ovarian cancer and put the results in perspective. PMID- 24953370 TI - [Expressions of STAT3, p-STAT3 and E-cadherin in colorectal cancer and clinical implications]. AB - OBJECTIVE: To investigate the correlation of expressions of STAT3 and p-STAT3 with epithelial mesenchymal transition(EMT)-associated protein E-cadherin in colorectal cancer, and to examine the association of above expressions with tumor invasion and metastasis of colorectal cancer. METHODS: Immunohistochemistry assay ElivisionTM plus was used to detect the expressions of STAT3, p-STAT3 and E cadherin protein in colorectal cancer tissue samples of 50 cases and their corresponding adjacent non-tumor tissues. Association of these protein expressions with tumor invasion and metastasis was analyzed with chi(2) test. Correlation of STAT3 and p-STAT3 with E-cadherin was analyzed with Spearman method. RESULTS: Positive expression rates of STAT3, p-STAT3 and E-cadherin protein in colorectal cancer tissues were 72%(36/50), 76%(38/50) and 26%(13/50), which were significantly higher compared to adjacent normal intestinal mucosa tissues [24%(12/50), 26%(13/50) and 68%(34/50), all P<0.05]. STAT3, p-STAT3 and E cadherin expressions were associated with tumor differentiation, tumor invasion depth, tumor size, lymph node metastasis, TNM staging (all P<0.05). In colorectal cancer tissues, STAT3 protein expression was positively correlated with p-STAT3 expression. STAT3 and p-STAT3 expressions in colorectal cancer tissues were negatively correlated with E-cadherin expression(P<0.05). CONCLUSION: STAT3 and p STAT3 may be involved in tumor EMT through inhibition of E-cadherin expression, leading to the development of colorectal cancer. PMID- 24953377 TI - Diagnostic and medical strategy for renovascular hypertension: report from a monocentric pediatric cohort. AB - Renovascular hypertension accounts for 5-10 % of hypertension cases in children; there is currently no consensus on treatment. Here, we report on our clinical experience with this disease and outline the different pathways in which to investigate it. We report retrospectively on ten children diagnosed with renovascular hypertension at the University Hospital of Nantes from 2001 to 2012. The main findings were obtained by fortuitous screening of children aged 2 months to 14 years old with neurofibromatosis (n = 2) and fibromuscular dysplasia (n = 8). The hypertension was always severe yet asymptomatic. Lesions were complicated in nine out of ten cases and included bilateral, multiple, mid-aortic syndrome and aneurysm. Doppler ultrasound associated with computed tomography allowed for a precise diagnosis in seven out of ten cases. Where ambiguities persisted, they were highlighted by arteriography, the gold standard investigation. Medical treatment was insufficient, leading to invasive procedures in nine out of ten children: 2 nephrectomies, 2 autotransplantations, and 21 repetitive percutaneous transluminal angioplasties. After invasive procedures, blood pressure control improved in four cases and was resolved in three. CONCLUSION: Arteriography remains to be the gold standard technique for renovascular hypertension in children and can be combined with angioplasty when medical treatment is rendered obsolete. The role of computed tomography is controversial. Despite the heterogeneity of the children studied, we present a general medical and therapeutic management pathway for the treatment of this disease. PMID- 24953378 TI - Preterm infants with severe extrauterine growth retardation (EUGR) are at high risk of growth impairment during childhood. AB - Extrauterine growth retardation (EUGR) seriously affects premature newborns and is related to the impairment of growth during childhood. There are very limited data available concerning the growth outcome of EUGR children. Our aim was to assess the growth outcome in a cohort of children born before 34 weeks of gestation with severe EUGR. This was a retrospective multicenter study, performed in outpatient endocrinology clinic. A total of 103 premature children with weight and/or length below -2 standard deviation score (SDS) of "intrauterine" growth expectation at the time of discharge from hospital (within 42 weeks of postmenstrual age) were included in the study. The study participants underwent a thorough anthropometric assessment at a mean age of 3.9 years +/- 1.7 SD. Of the EUGR children, 12.6 % showed a height below -2 SDS and 7.7 % even below -2.5 SDS. Growth impairment was more common in males than in females (17 vs. 8 %). The prevalence of subnormal weight (below -2 SDS) was 13.6 %, being higher in males than in females (17 vs. 10 %). BMI values below -2 SDS were found in 18.4 % of our study population (22.7 % in males and 12 % in females). The 19.6 % of EUGR children did not catch up in head circumference during early childhood. Length at term was the major predictor of height in childhood (P < 0.001). CONCLUSION: A significant proportion of children born prematurely with severe EUGR show growth retardation in childhood thus suggesting the need for a close clinical follow-up to determine their growth potential and implement effective intervention strategies. PMID- 24953379 TI - Selective late sodium current blockade with GS-458967 markedly reduces ischemia induced atrial and ventricular repolarization alternans and ECG heterogeneity. AB - BACKGROUND: Ischemic heart disease is associated with dual risk for atrial and ventricular arrhythmias. OBJECTIVE: We examined whether selectively targeting late sodium channel current (INa) with GS-458967 (hereafter GS967) can reduce cardiac electrical instability and compared its effects to a clinically relevant dose of flecainide. METHODS: Electrode catheters were positioned on the left atrial appendage and left ventricle of anesthetized pigs to monitor repolarization alternans and electrocardiographic heterogeneity before and during left circumflex coronary artery stenosis (75% flow reduction) before and after GS967 (0.4 mg/kg, intravenously [IV]) or flecainide (1 mg/kg, IV, bolus over 2 minutes followed by 1 mg/(kg.h), IV, for 1 hour) administration. RESULTS: Left circumflex coronary artery stenosis increased atrial repolarization alternans by 520% (from 9.4 +/- 1.2 to 58.3 +/- 11.3 MUV; P = .029) and T-wave alternans by 1038% (from 30.7 +/- 8.2 to 349.3 +/- 103.8 MUV; P = .049). GS967 prevented ischemia-induced increases in alternans in the left atrium (19.3 +/- 5.6 MUV vs 58.3 +/- 11.3 MUV; P = .023) and left ventricle (217.9 +/- 95.8 MUV vs 349.3 +/- 103.8 MUV; P < .001) (n = 7). GS967 reduced ischemia-induced increases in depolarization heterogeneity (atrium: from 45% to 28%; ventricle: from 92% to 51%) and repolarization heterogeneity (atrium: 43% to 23%; ventricle: 137% to 91%). GS967 did not alter heart rate, arterial blood pressure, PR and QT intervals, or QRS duration, but it mildly decreased contractility (left ventricular dP/dt) during ischemia, which was consistent with late INa inhibition. Flecainide (n = 7) amplified ischemia-induced increase in atrial and ventricular repolarization alternans, electrocardiographic heterogeneity, and ventricular fibrillation incidence. CONCLUSION: Selective late INa inhibition with GS967 exerts potent protective effects against ischemia-induced depolarization and repolarization abnormalities in both atria and ventricles. PMID- 24953380 TI - Generator replacement is associated with an increased rate of ICD lead alerts. AB - BACKGROUND: Lead malfunction is an important cause of morbidity and mortality in patients with an implantable cardioverter-defibrillator (ICD). We have shown that the failure of recalled high-voltage leads significantly increases after ICD generator replacement. However, generator replacement has not been recognized as a predictor of lead failure in general. OBJECTIVE: The purpose of this study is to assess the effect of ICD generator exchange on the rate of ICD lead alerts. METHODS: A time-dependent Cox proportional hazards model was used to analyze a database of remotely monitored ICDs. The model assessed the impact of generator exchange on the rate of lead alerts after ICD generator replacement. RESULTS: The analysis included 60,219 patients followed for 37 +/- 19 months. The 5-year lead survival was 99.3% (95% confidence interval 99.2%-99.4%). Of 60,219 patients, 7458 patients (12.9%) underwent ICD generator exchange without lead replacement. After generator replacement, the rate of lead alerts was more than 5-fold higher than in controls with leads of the same age without generator replacement (hazard ratio 5.19; 95% confidence interval 3.45-7.84). A large number of lead alerted within 3 months of generator replacement. Lead alerts were more common in patients with single- vs dual-chamber ICDs and in younger patients. Sex was not associated with lead alerts. CONCLUSION: Routine generator replacement is associated with a 5-fold higher risk of lead alert compared to age-matched leads without generator replacement. This suggests the need for intense surveillance after generator replacement and the development of techniques to minimize the risk of lead damage during generator replacement. PMID- 24953381 TI - Perinatal mortality in pregnancies with omphalocele: data from the Chinese national birth defects monitoring network, 1996-2006. AB - BACKGROUND: Previous studies on the mortality rate of omphalocele are limited. The risk of death of non-isolated omphalocele and that of cases of omphalocele that are diagnosed prenatally by ultrasound are unclear. This study aimed to estimate the perinatal mortality of pregnancies with omphalocele. This study also examined the potential risk of death of non-isolated omphalocele and that of cases that are prenatally diagnosed by ultrasound. METHODS: Data were retrieved from the national birth defects registry in China, for 1996-2006. Multinomial logistic regression was used to calculate the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) between perinatal mortality and selected maternal and fetal characteristics. RESULTS: Among 827 cases of omphalocele, 309 (37.4%) cases resulted in termination of pregnancy and stillbirth, and 124 (15.0%) cases resulted in death in the first 7 days after delivery, yielding a perinatal mortality rate of 52.4% (95% CI: 49.0-55.8%). The late fetal death rate (LFDR) of omphalocele that was diagnosed prenatally by ultrasound was 15.91-fold (AOR: 15.91, 95% CI: 10.18-24.87) higher than that of postnatally diagnosed cases. The LFDR of non-isolated omphalocele was 2.64-fold (AOR: 2.64, 95% CI: 1.62-4.29) higher than that of isolated cases. For the early neonatal death rate, neonates with non-isolated omphalocele had a 2.96-fold (AOR: 2.96, 95% CI: 1.82-4.81) higher risk than isolated cases, but the difference between prenatal ultrasound diagnosis and postnatal diagnosis was not significant. CONCLUSIONS: Selected fetal characteristics are significantly associated with the perinatal risk of death from omphalocele. Our findings suggest that improving pregnancy and delivery care, as well as management for omphalocele are important. PMID- 24953382 TI - The melanoma metastasis X-factor. PMID- 24953383 TI - Child maltreatment rates assessed in a national household survey of caregivers and youth. AB - This paper reports on national estimates for past year child maltreatment from a national household survey conducted in 2011. It also discusses the validity of such estimates in light of other available epidemiology. The Second National Survey of Children Exposed to Violence obtained rates based on 4,503 children and youth from interviews with caregivers about the children ages 0-9 and with the youth themselves for ages 10-17. The past year rates for physical abuse by caregivers were 4.0% for all sample children, emotional abuse by caregivers 5.6%, sexual abuse by caregivers 0.1%, sexual abuse by caregivers and non-caregivers 2.2%, neglect 4.7% and custodial interference 1.2%. Overall, 12.1% of the sample experienced at least one of these forms of maltreatment. Twenty-three percent of the maltreated children or 2.8% of the full sample experienced 2 or more forms of maltreatment. Some authority (teacher, police, medical personnel or counselor) was aware of considerable portions of most maltreatment, which suggests the potential for intervention. Many of the study's estimates were reasonable in light of other child maltreatment epidemiological studies, but comparisons about emotional abuse and neglect were problematic because of ambiguity about definitions. PMID- 24953384 TI - Long-term memory performance after surgical treatment of unilateral temporal lobe epilepsy (TLE). AB - Long-term cognitive and memory performance after surgical treatment of unilateral temporal lobe epilepsy (TLE) was investigated in a series of 98 patients. Neuropsychological evaluation was performed preoperatively and after one and three years postoperatively. Fifty-eight patients (59%) became seizure-free (Engel's class I). Verbal learning and memory declined in long-term follow-up in both left and right TLE groups. Visual memory remained stable. Ongoing postoperative seizures were related to decline in the immediate recall of logical prose, and postoperative seizure-freedom to improvement in verbal fluency in patients with left TLE. There was significant variability in the individual postoperative long-term memory performance. Left side of surgery, better baseline performance and older age at surgery were identified as risk factors for individual decline in delayed verbal memory. Selected patients undergoing surgery for drug-resistant TLE are at risk for significant postoperative memory decline especially after left temporal lobe surgery. Preoperative counseling and long term follow-up of cognitive performance in individual patients is recommended. Additionally, more accurate predictors of individual postoperative memory performance would be needed. PMID- 24953386 TI - Enantioselective synthesis of spiroacetals: the conquest of a long-sought goal in asymmetric catalysis. AB - This perspective article briefly outlines the very few and recent methods reported in the literature on catalytic asymmetric synthesis of spiroacetals from achiral substrates. PMID- 24953385 TI - [Consensus statement on the clinical management of non-AIDS defining malignancies. GeSIDA expert panel]. AB - This consensus document has been prepared by a panel of experts appointed by GeSIDA. This paper reviews the recommendations on the most important non-AIDS defining malignancies that can affect patients living with AIDS. Lung cancer, hepatocellular carcinoma, anal carcinoma and other less frequent malignancies such as breast, prostate, vagina or colon cancers are reviewed. The aim of the recommendations is to make clinicians who attend to this patients aware of how to prevent, diagnose and treat this diseases. The recommendations for the use of antiretroviral therapy when the patient develops a malignancy are also presented. In support of the recommendations we have used the modified criteria of the Infectious Diseases Society of America. PMID- 24953387 TI - Novel data on the pathogenesis of atherosclerosis, treatment targets, and new therapeutic interventions in lipid-related cardiovascular risk factors. PMID- 24953388 TI - Effects of lipid-lowering agents on inflammation, haemostasis and blood pressure. AB - In addition to the modification of the lipid profile, most lipid-lowering agents appear to modulate other atherogenic pathways. We summarize the effects of lipid lowering agents on inflammation, hemostasis and blood pressure. We also discuss the potential contribution of these actions on cardiovascular disease prevention. Most lipid-lowering agents appear to exert anti-inflammatory, antithrombotic and antihypertensive effects. These pleiotropic actions appear to contribute to the reduction in cardiovascular events and deep venous thrombosis during statin treatment. Regarding other lipid-lowering agents, it is unclear whether their effects on inflammation, thrombosis or blood pressure play a role in their antiatherogenic potential. PMID- 24953389 TI - Pathophysiological role and clinical significance of lipoprotein-associated phospholipase A2 (Lp-PLA2) bound to LDL and HDL. AB - Lipoprotein-associated phospholipase A2 (Lp-PLA2), also named as platelet activating factor (PAF)-acetylhydrolase, exhibits a Ca2+-independent phospholipase A2 activity and catalyzes the hydrolysis of the ester bond at the sn-2 position of PAF and oxidized phospholipids (oxPL). These phospholipids are formed under oxidative and inflammatory conditions, and may play important roles in atherogenesis. The vast majority of plasma Lp-PLA2 mass binds to low-density lipoprotein (LDL) while a smaller amount is associated with high-density lipoprotein (HDL). Lp-PLA2 is also bound to lipoprotein (a) [Lp(a)], very low density lipoprotein (VLDL) and remnant lipoproteins. Several lines of evidence suggest that the role of plasma Lp-PLA2 in atherosclerosis may depend on the type of lipoprotein particle with which this enzyme is associated. Data from large Caucasian population studies have supported plasma Lp-PLA2 (primarily LDL associated Lp-PLA2) as a cardiovascular risk marker independent of, and additive to, traditional risk factors. On the contrary, the HDL-associated Lp-PLA2 may express antiatherogenic activities and is also independently associated with lower risk for cardiac death. The present review presents data on the biochemical and enzymatic properties of Lp-PLA2 as well as its structural characteristics that determine the association with LDL and HDL. We also critically discuss the possible pathophysiological and clinical significance of the Lp- PLA2 distribution between LDL and HDL in human plasma, in view of the results of prospective epidemiologic studies on the association of Lp-PLA2 with future cardiovascular events as well the recent studies that evaluate the possible effectiveness of specific Lp-PLA2 inhibitors in reducing residual cardiovascular risk. PMID- 24953390 TI - Medications not intended for treatment of dyslipidemias and with a variable effect on lipids. AB - Many therapeutically active medications have significant side effects, some of which can compromise the intended therapeutic goal. The development of plasma lipid abnormalities or a dyslipidemia as the result of a medication intended for an unrelated effect has been reported. Human immunodeficiency virus (HIV) infection can cause dyslipidemia as can the medications used to treat this infection. Such dyslipidemia can be a significant problem made more relevant by the already increased risk of cardiovascular (CV) disease faced by these patients. Some hypoglycemic medications used to treat diabetes can also be associated with dyslipidemia, most notably rosiglitazone. Antihypertensive medications are intended to decrease CV risk but are not free of dyslipidemia problems with thiazides able to cause hypertriglyceridemia and older beta blockers without an alpha-blocking effect associated with moderate plasma lipid abnormalities and altered glucose metabolism. Estrogen administered orally can be associated with a severe hypertriglyceridemia. Currently-used antipsychotic medications have a significant association with hypertriglyceridemia. Clinicians must be aware of the dyslipidemias caused by these medications and know how to manage them, even treating a secondary dyslipidemia with another medication as in the case of HIV infection rather than trying to switch treatment of the infection in many cases. Mention is also made of lipid lowering effects of medications intended for other purposes (e.g. angiotensin receptor blockers and orlistat). PMID- 24953391 TI - Statin treatment non-adherence and discontinuation: clinical implications and potential solutions. AB - Statins are the most powerful lipid lowering drugs in clinical practice. However, the efficacy of statin therapy, as seen in randomized control trials, is undermined by the documented non-adherence observed in clinical practice. Understanding the clinical consequences of statin non-adherence is an important step in implementing successful interventions aimed at improving adherence. Our previous systematic review included a literature search up to January 2010 on the effects of statin non-adherence or discontinuation on cardiovascular (CV) and cerebrovascular outcomes. We provide an update to this publication and a review of promising interventions that have reported a demonstrated improvement in statin adherence. Through a systematic literature search of PubMed, Ovid Medline, Ovid Embase, CINAHL, Cochrane Library and Web of Science, out of the 3440 initially identified, 13 studies were selected. Non-adherence in a primary prevention population was associated with a graded increase in CV risk. Individuals taking statins for secondary prevention were at particular risk when taking statin with highly variable adherence. Moreover, particular attention is warranted for non-adherence in diabetic and rheumatoid arthritis populations, as non-adherence is significantly associated with CV risk as early as 1 month following discontinuation. Statin adherence, therefore, represents an important modifiable risk factor. Numerous interventions to improve adherence have shown promise, including copayment reduction, automatic reminders, mail-order pharmacies, counseling with a health professional, and fixed-dose combination therapy. Given the complexity of causes underlying statin non-adherence, successful strategies will likely need to be tailored to each patient. PMID- 24953392 TI - Halting arterial aging in patients with cardiovascular disease: hypolipidemic and antihypertensive therapy. AB - Aging is associated with arterial stiffening and subsequent acceleration of pulse wave movement. Traditional cardiovascular risk factors such as hypertension and dyslipidemia are associated with increased arterial stiffness, a 'premature' arterial aging. Antihypertensive drugs exhibit beneficial effects on arterial stiffness, both at the central and peripheral level, and these effects are mainly attributed to blood pressure reduction per se. However, additional benefits of the renin-angiotensin system inhibitors have been recently suggested. Furthermore, a disparity in the effects of beta-blockers on arterial stiffness between conventional and vasodilatory agents has also been suggested. Statin treatment is an essential element of cardiovascular therapy and statins are frequently administered by patients with cardiovascular risk factors or established cardiovascular disease. The effects of statins on arterial stiffness are not yet well established. Moreover, the effects of combining statins with antihypertensive drugs or other strategies to attenuate arterial aging are not adequately studied. The aim of the current review is to present the effects of available therapeutic strategies on arterial stiffness with special emphasis on hypolipidemic and antihypertensive drugs, critically evaluate available information and provide future perspectives in this field. PMID- 24953393 TI - Hypolipidaemic drug treatment: yesterday is not gone yet, today is challenging and tomorrow is coming soon; let us combine them all. AB - Statins remain the cornerstone of hypolipidaemic drug treatment. The recent American College of Cardiology (ACC)/American Heart Association (AHA) lipid guidelines suggest using percent reductions of low density lipoprotein cholesterol (LDL-C), according to cardiovascular disease (CVD) risk, rather than specific LDL-C targets. These guidelines raised concerns and other Societies (US, International, European) have not endorsed them. The implementation of previous guidelines in clinical practice is suboptimal due to attitudes of physicians and restrictions in health care systems. Monoclonal antibodies that inhibit proprotein convertase subtilisin/ kexin type 9 (PCSK9), which degrades the LDL receptor, like alirocumab and evolocumab, are in phase 3 trials. These drugs are suitable for statin intolerant or resistant patients, heterozygous familial hypercholesterolaemia (HeFH) and some forms of homozygous FH (HoFH). Mipomersen (antisense oligonucleotide against apolipoprotein B) and lomitapide (microsomal triglyceride transfer protein blocker) have already been approved for HoFH. Eventually, silencing micro-RNA oligonucleotides may also become available. The repair or silencing of genes implicated in hyperlipidaemia and/or atherosclerosis is also on the horizon. If the new therapeutic options mentioned above prove to be effective and safe then by combining them with statins and/or ezetimibe we should be able to effectively control acquired or hereditary dyslipidaemias and substantially further reduce CVD morbidity and mortality. PMID- 24953395 TI - Alcohol and the cardiovascular system: a double-edged sword. AB - Low to moderate alcohol intake has been associated with beneficial effects on the heart and the vasculature, including improvements in several established and emerging cardiovascular disease (CVD) risk factors as well as reduced risk for several metabolic diseases, CVD morbidity and mortality. Binge and heavy drinking exert the opposite effects, leading to increased risks for all the above conditions. With regard to beverage type, there is some evidence supporting red wine superiority in cardioprotection, although other beverages have also been reported to exert beneficial metabolic and vascular effects when consumed in moderate amounts. In this narrative review we discuss the associations between alcohol consumption and CVD morbidity and mortality. Alcohol-induced effects on established and emerging CVD risk factors are also discussed taking into consideration different drinking patterns. Physicians should screen for excessive alcohol use and advise individuals to limit their alcohol intake to moderate amounts (up to 20-30 g/day for men and 10-20 g/day for women), preferably consumed with meals. The question of whether alcohol intake should be encouraged as a measure to prevent CVD remains unanswered. PMID- 24953394 TI - LDL and HDL subfractions, dysfunctional HDL: treatment options. AB - Low-density lipoproteins (LDL) are considered as important risk factors for cardiovascular diseases (CVD), while highdensity lipoproteins (HDL) are well recognized for their putative role in reverse cholesterol transport and other atheroprotective functions. Both LDL and HDL are heterogeneous in nature, including various subfractions depending on the method of isolation (>= 7 LDL and 10 HDL subspecies, respectively). While it is established that small, dense LDL (sdLDL) have atherogenic potential, the role of different HDL subfractions is still largely unclear. The majority of clinical studies suggest an atheroprotective role of larger HDL particles, although recent work has highlighted the role of dysfunctional HDL within different subfractions. Several therapeutic approaches are able to primarily target cholesterol concentration in LDL or HDL. Certain drugs, such as niacin, statins and fibrates target multiple lipid traits (i.e. pleiotropic drug effects), while cholesterol ester transfer protein (CETP) inhibitors are able to increase plasma HDL cholesterol levels. Statins represent the most used lipid-lowering drugs, but there is a continued interest in the development of novel therapeutic approaches, including those that might affect dysfunctional HDL. Targeting distinct LDL and HDL subfractions may potentially reduce the residual risk seen in clinical endpoint trials. PMID- 24953396 TI - Familial hypercholesterolemia: etiology, diagnosis and new treatment options. AB - Familial hypercholesterolemia (FH) is a common genetic disorder that presents with robust increases in low-density lipoprotein cholesterol (LDL-C) and can lead to premature cardiovascular disease. There are heterozygous and homozygous forms. The diagnosis is usually made based on blood cholesterol levels, clinical signs and family history. Genetic testing can be used to confirm the diagnosis. Effective lowering of LDL-C in FH can prevent cardiovascular morbidity and mortality, however, the disease remains greatly underdiagnosed. The mainstay of pharmacologic therapy in FH patients is high-dose statins, which are often combined with other lipid-lowering agents. The homozygous form is mainly treated with lipid apheresis. Guideline-recommended target levels of LDL-C are often not reached, making new treatment options desirable. Four classes of newer lipid lowering drugs offer promising advances in treating FH, namely the apolipoprotein B synthesis inhibitors (mipomersen), the microsomal transfer protein inhibitors (lomitapide), the cholesterol ester transfer protein inhibitors (anacetrapib, evacetrapib) and the proprotein convertase subtilisin/kexin type 9 inhibitors (evolocumab, alirocumab). In this review, the available evidence regarding the use of these drugs in patients with FH is discussed, with particular focus on their efficacy and safety. PMID- 24953397 TI - HDL genetic defects. AB - High density lipoprotein cholesterol (HDL-C) and its related apolipoproteins form part of the reverse cholesterol transport system that removes excessive cholesterol from the periphery to the liver. Many transport proteins and enzymes that are involved in this process are susceptible to genetic defects that influence plasma HDL-C concentrations and HDL function. The HDL-C concentration in the blood may not be as important as the function of this lipid fraction. The genetic defects affecting plasma HDL-C concentrations do not always show a consistent relationship with atherosclerosis. Familial hypoalphalipoproteinaemia is associated with mutations in genes responsible for the transport proteins or the enzymes involved in the biogenesis of HDL-C. Inheritance of a Milano mutation of apolipoprotein A1 decreases the risk of atherosclerotic disease despite low circulating levels of HDL-C. Tangier disease and Fish Eye disease are caused by mutations in the ATP binding cassette A1 (ABCA1), a transport protein, and lecithin cholesterol acyl transferase (LCAT), an enzyme, involved in the esterification of cholesterol, respectively. Patients with these conditions have very low levels of HDL-C concentration. The association between both these conditions and the risk of cardiovascular disease (CVD) is variable and inconsistent. Understanding the molecular mechanism of HDL biogenesis not only helped in defining the pathophysiology of low and high HDL-C syndromes, but also in developing new treatment options to raise HDL-C levels. PMID- 24953398 TI - Apolipoprotein B and apolipopotein A-I in vascular risk prediction - a review. AB - The concentration of low-density lipoprotein cholesterol has long been generally accepted as one of the strongest, independent risk factors for the development of cardiovascular disease. However, an increasing number of studies suggest that the ratio of apolipoprotein B (apoB) to apolipoprotein A-I (apoA-I) is a better risk predictor. In the present review, we focus on apoB and apoA-I as factors in predicting vascular risk in epidemiological studies only, and not in studies involving pharmaceutical intervention. The majority of studies in the present review show that apoB and the apoB/apoA-I ratio are independently and more strongly associated with vascular risk across varying age-groups and geographic regions than are conventional lipids, lipoproteins and lipid ratios. PMID- 24953399 TI - Hypertriglyceridaemia, postprandial lipaemia and non-HDL cholesterol. AB - Maintaining total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels within healthy limits decreases the risk of atherosclerotic vascular disease (AVD) and cardiovascular (CV) events. The predictive value of elevated TG levels for coronary artery disease (CAD) seen in univariate analysis tends to disappear on multivariate analyses, especially when correction is made for HDL-C. The relationship between TG and HDL-C is complex and not fully understood. Hydrolysis of TG by lipoprotein lipase converts HDL subclass 3 to a larger lipoprotein enriched in both phospholipid and TG. This process occurs in postprandial lipaemia (PPL). An additional factor for the complex relationship between TGs and CV risk is that the lipoproteins which transport plasma TG (chylomicrons, very low density lipoproteins and their remnants) are heterogeneous particles. Therefore, they may differ in their level of atherogenicity. PPL is a physiological process during which plasma lipoproteins and their subclasses undergo variations in concentration and composition following consumption of food, particularly fatty food. "Postprandial hyperlipidaemia" is the quantitative/qualitative alteration of this normal process. These lipoprotein alterations could play a role in the development of CV disease (CVD). However, lipid levels used to evaluate CV risk are usually measured in the fasting state. This review focuses on TG, PPL, postprandial hyperlipidaemia and non-HDL-C, their relationships and potential predictive role in atherogenesis and CVD. PMID- 24953400 TI - Combination of statin plus renin angiotensin system inhibition for the prevention or the treatment of atherosclerotic cardiovascular disease. AB - Statins effectively reduce cardiovascular disease (CVD) morbidity and mortality. However, even after low-density lipoprotein cholesterol goal attainment there is a residual CVD risk. To reduce this risk, combining statins with drugs acting on the renin-angiotensin system (RAS) was investigated. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE), Japanese Coronary Artery Disease (JCAD), Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) and The Assessing the Treatment Effect in Metabolic Syndrome Without Perceptible Diabetes (ATTEMPT) trials suggest that the statin plus RAS inhibition combination reduces CVD events more than a statin alone and considerably more than RAS inhibition alone. This benefit seems to be related to effects on endothelial function, vascular inflammation and the initiation, progression and rupture of atheromatous plaques. These effects are, at least in part, driven by mediators, the microRNAs (miRs), that are implicated in the pathogenesis and clinical manifestations of atherosclerosis (e.g. restoration of endothelial function and attenuation of vascular inflammation). Some miRs are favourably affected by statins and others by RAS inhibition. There is a miR family (miR-146a/b), related to coronary artery plaque destabilization that is beneficially affected by both statins and RAS inhibition. Statins and RAS inhibition combination should be routinely prescribed in high risk patients with CVD, hypertension, obesity, metabolic syndrome, and/or diabetes to maximize clinical benefit. PMID- 24953401 TI - Dyslipidaemia related to insulin resistance and cardiovascular disease in South Asian and West African populations. AB - The global burden of diabetes and cardiovascular disease (CVD) is increasing. Obesity is rapidly increasing worldwide and is associated with dyslipidaemia, metabolic syndrome (MetS) and type 2 diabetes (T2DM). Excess risks of T2DM and CVD are found in migrant Indian Asian and West African populations but with increasing urbanization similar changes are occurring in the original populations and are likely to predispose to a large increase in worldwide burden of CVD. Genetic and environmental factors interacting together play a role in the lipid patterns observed. Dyslipidaemia in the MetS associated with insulin resistance is characterised by an atherogenic lipid profile comprising elevated triglycerides, low high density lipoprotein cholesterol (HDL-C) and increased numbers of small dense low density lipoprotein particles. The pattern of dyslipidaemia varies across different ethnic groups with increases in triglycerides and a reduction in HDL-C being the commonest pattern in non Caucasians. This review surveys the literature on dyslipidaemia in Indian Asian and West African populations and how it relates to CVD risk in those populations. It is important that dyslipidaemia and other conventional risk factors for CVD are adequately addressed and managed especially in high-risk populations. PMID- 24953402 TI - Dynamics of the active site architecture in plant-type ferredoxin-NADP(+) reductases catalytic complexes. AB - Kinetic isotope effects in reactions involving hydride transfer and their temperature dependence are powerful tools to explore dynamics of enzyme catalytic sites. In plant-type ferredoxin-NADP(+) reductases the FAD cofactor exchanges a hydride with the NADP(H) coenzyme. Rates for these processes are considerably faster for the plastidic members (FNR) of the family than for those belonging to the bacterial class (FPR). Hydride transfer (HT) and deuteride transfer (DT) rates for the NADP(+) coenzyme reduction of four plant-type FNRs (two representatives of the plastidic type FNRs and the other two from the bacterial class), and their temperature dependences are here examined applying a full tunnelling model with coupled environmental fluctuations. Parameters for the two plastidic FNRs confirm a tunnelling reaction with active dynamics contributions, but isotope effects on Arrhenius factors indicate a larger contribution for donor acceptor distance (DAD) dynamics in the Pisum sativum FNR reaction than in the Anabaena FNR reaction. On the other hand, parameters for bacterial FPRs are consistent with passive environmental reorganisation movements dominating the HT coordinate and no contribution of DAD sampling or gating fluctuations. This indicates that active sites of FPRs are more organised and rigid than those of FNRs. These differences must be due to adaptation of the active sites and catalytic mechanisms to fulfil their particular metabolic roles, establishing a compromise between protein flexibility and functional optimisation. Analysis of site-directed mutants in plastidic enzymes additionally indicates the requirement of a minimal optimal architecture in the catalytic complex to provide a favourable gating contribution. PMID- 24953406 TI - For the RECORD, we should SWITCH our treatment AXIS before the SUNRISES and TARGET the BEST treatments before INTORSECTing with a GOLD METEOR: a tale of sequences and combinations. PMID- 24953404 TI - A CLN8 nonsense mutation in the whole genome sequence of a mixed breed dog with neuronal ceroid lipofuscinosis and Australian Shepherd ancestry. AB - The neuronal ceroid lipofuscinoses (NCLs) are hereditary neurodegenerative diseases characterized by seizures and progressive cognitive decline, motor impairment, and vision loss accompanied by accumulation of autofluorescent lysosomal storage bodies in the central nervous system and elsewhere in the body. Mutations in at least 14 genes underlie the various forms of NCL. One of these genes, CLN8, encodes an intrinsic membrane protein of unknown function that appears to be localized primarily to the endoplasmic reticulum. Most CLN8 mutations in people result in a form of NCL with a late infantile onset and relatively rapid progression. A mixed breed dog with Australian Shepherd and Blue Heeler ancestry developed neurological signs characteristic of NCL starting at about 8months of age. The signs became progressively worse and the dog was euthanized at 21months of age due to seizures of increasing frequency and severity. Postmortem examination of the brain and retinas identified massive accumulations of intracellular autofluorescent inclusions characteristic of the NCLs. Whole genome sequencing of DNA from this dog identified a CLN8:c.585G>A transition that predicts a CLN8:p.Trp195* nonsense mutation. This mutation appears to be rare in both ancestral breeds. All of our 133 archived DNA samples from Blue Heelers, and 1481 of our 1488 archived Australian Shepherd DNA samples tested homozygous for the reference CLN8:c.585G allele. Four of the Australian Shepherd samples tested heterozygous and 3 tested homozygous for the mutant CLN8:c.585A allele. All 3 dogs homozygous for the A allele exhibited clinical signs of NCL and in 2 of them NCL was confirmed by postmortem evaluation of brain tissue. The occurrence of confirmed NCL in 3 of 4 CLN8:c.585A homozygous dogs, plus the occurrence of clinical signs consistent with NCL in the fourth homozygote strongly suggests that this rare truncating mutation causes NCL. Identification of this NCL-causing mutation provides the opportunity for identifying dogs that can be used to establish a canine model for the CLN8 disease (also known as late infantile variant or late infantile CLN8 disease). PMID- 24953403 TI - Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases. AB - BACKGROUND: Creatine transporter deficiency (CTD) is an X-linked inborn error of creatine metabolism characterized by reduced intra-cerebral creatine, developmental delay/intellectual disability, (ID), behavioral disturbance, seizures, and hypotonia in individuals harboring mutations in the SLC6A8 gene. Treatment for CTD includes supplementation with creatine, either alone or in combination with creatine precursors (arginine or glycine). Unlike other disorders of creatine metabolism, the efficacy of its treatment remains controversial. METHODS: We present our systematic literature review (2001-2013) comprising 7 publications (case series/reports), collectively describing 25 patients who met the inclusion criteria, and 3 additional cases treated at our institution. Definitions were established and extracted data analyzed for cognitive ability, psychiatric and behavioral disturbances, epilepsy, and cerebral proton magnetic resonance spectroscopy measurements at pre- and post treatment. RESULTS: Treatment regimens varied among the 28 cases: 2 patients received creatine-monohydrate supplementation; 7 patients received L-arginine; 2 patients received creatine-monohydrate and L-arginine; and 17 patients received a combination of creatine-monohydrate, L-arginine and glycine. Median treatment duration was 34.6 months (range 3 months-5 years). Level of evidence was IV. A total of 10 patients (36%) demonstrated response to treatment, manifested by either an increase in cerebral creatine, or improved clinical parameters. Seven of the 28 patients had quantified pre- and post-treatment creatine, and it was significantly increased post-treatment. All of the patients with increased cerebral creatine also experienced clinical improvement. In addition, the majority of patients with clinical improvement had detectable cerebral creatine prior to treatment. 90% of the patients who improved were initiated on treatment before nine years of age. CONCLUSIONS: Acknowledging the limitations of this systematic review, we conclude that a proportion of CTD patients show amenability to treatment-particularly milder cases with residual brain creatine, and therefore probable residual protein function. We propose systematic screening for CTD in patients with ID, to allow early initiation of treatment, which currently comprises oral creatine, arginine and/or glycine supplementation. Standardized monitoring for safety and evaluation of treatment effects are required in all patients. This study provides effectiveness on currently available treatment, which can be used to discern effectiveness of future interventions (e.g. cyclocreatine). PMID- 24953407 TI - The Mataro Stroke Registry: a 10-year registry in a community hospital. AB - INTRODUCTION: A prospective stroke registry leads to improved knowledge of the disease. We present data on the Mataro Hospital Registry. METHODS: In February 2002 a prospective stroke registry was initiated in our hospital. It includes sociodemographic data, previous diseases, clinical, topographic, etiological and prognostic data. We have analyzed the results of the first 10 years. RESULTS: A total of 2,165 patients have been included, 54.1% male, mean age 73 years. The most frequent vascular risk factor was hypertension (65.4%). Median NIHSS on admission: 3 (interquartile range, 1-8). Stroke subtype: 79.7% ischemic strokes, 10.9% hemorrhagic, and 9.4% TIA. Among ischemic strokes, the etiology was cardioembolic in 26.5%, large-vessel disease in 23.7%, and small-vessel in 22.9%. The most frequent topography of hemorrhages was lobar (47.4%), and 54.8% were attributed to hypertension. The median hospital stay was 8 days. At discharge, 60.7% of patients were able to return directly to their own home, and 52.7% were independent for their daily life activities. After 3 months these percentages were 76.9% and 62.9%, respectively. Hospital mortality was 6.5%, and after 3 months 10.9%. CONCLUSIONS: Our patient's profile is similar to those of other series, although the severity of strokes was slightly lower. Length of hospital stay, short-term and medium term disability, and mortality rates are good, if we compare them with other series. PMID- 24953405 TI - Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: early treatment rescues bone lesions? AB - We treated mucopolysaccharidosis IVA (MPS IVA) mice to assess the effects of long term enzyme replacement therapy (ERT) initiated at birth, since adult mice treated by ERT showed little improvement in bone pathology [1]. To conduct ERT in newborn mice, we used recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in a CHO cell line. First, to observe the tissue distribution pattern, a dose of 250units/g body weight was administered intravenously in MPS IVA mice at day 2 or 3. The infused enzyme was primarily recovered in the liver and spleen, with detectable activity in the bone and brain. Second, newborn ERT was conducted after a tissue distribution study. The first injection of newborn ERT was performed intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from 5th to 14th weeks were intravenous into the tail vein. MPS IVA mice treated with GALNS showed clearance of lysosomal storage in the liver and spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was organized better than that in adult mice treated with ERT; however, hyaline and fibrous cartilage cells in the femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to the treatment. Levels of serum keratan sulfate were kept normal in newborn ERT mice. In conclusion, the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mice. PMID- 24953408 TI - Complex regional pain syndrome type i. An analysis of 7 cases in children. AB - INTRODUCTION: Complex regional pain syndrome (CRPS) is characterised by the presence of pain accompanied by sensory, autonomic and motor symptoms, usually preceded by a lesion or immobilisation. The clinical course is disproportionate to the initial injury in intensity and in duration. Its distribution is regional, predominantly in limbs. It is classified as type I and type II according to the absence or presence of nerve injury. CASES: We present the cases of seven children, 6 girls and 1 boy, aged 7 to 15 years. Three had a history of previous trauma. In 5 cases, the symptoms were located in the lower limbs. Time to diagnosis was between 4 and 90 days. Three patients had clinical features of anxiety and depression. Imaging and immunological studies were performed to rule out differential diagnoses in all the children. Interdisciplinary treatment was performed with physiotherapy, psychotherapy, and gabapentin or pregabalin. All patients had a good clinical outcome, with no relapses in the follow-up period (between 4 and 30 months). CONCLUSIONS: CRPS is frequently unrecognised in children, leading to family anxiety and unnecessary para-clinical costs. Paediatricians and paediatric neurologists should be aware of this syndrome in order to avoid delay in diagnosis, unnecessary studies, and multiple visits to specialists, with a view to providing effective treatment. PMID- 24953409 TI - Type II facial complex regional pain syndrome with documented trophic changes. PMID- 24953411 TI - Semantic verbal fluency in elderly Mexican adults: Reference values. AB - INTRODUCTION: The semantic verbal fluency test (SVF) is sensitive to detecting cognitive decline. It is fast and easy to use in any cultural context; therefore, it is included in most of the neuropsychological assessment protocols. OBJECTIVE: To estimate normative values for the SVF test (animals), in an elderly population aged 65 years and over. MATERIAL AND METHOD: 1233 subjects who were healthy, cognitively preserved, residents of two areas (rural and urban) of Mexico were assessed. A neurological and neuropsychological exploration battery was applied, including SVF. RESULTS: The age average was 73+6 and schooling was 4.0+3.9 years, with 59% women. The average of the words generated in the SVF test was 14+5, and a correlation of 0.16 of these scores with age, education, and gender was found (p<.001), this allowed the estimation of the percentiles in accordance with these variables. CONCLUSIONS: The most important contribution provided by this study was that the data analysis enabled normative values to be obtained for an elderly Mexican population aged 65 years and over. It was also confirmed, as other neuropsychological assessment studies have done, that the SVF test is influenced by socio-demographic variables, such as age and education, aspects to be considered at the time of obtaining normative values. Finally, it was noted that the average scores obtained were lower than other published reference values, due to the low educational level of our sample. PMID- 24953410 TI - Rapid assessment of transient ischaemic attack in a hospital with no on-call neurologist. AB - BACKGROUND: Risk of stroke soon after a transient ischaemic attack (TIA) is high. Urgent care can reduce this risk. Our aim is to describe and evaluate the efficacy of rapid assessment of TIA patients in a hospital without a neurologist available 24 hours a day. METHODS: In February 2007, we set up a protocol of rapid management of patients with symptoms consistent with acute TIA, with the aim of prioritising urgent care and reducing hospital admissions, without increasing risk of recurrences. We analyse our results since the protocol was implemented with particular focus on the analysis of delay in neurological and neurovascular assessment, percentage and reasons for hospitalisation, and stroke recurrence rates after 3 months. RESULTS: Four hundred and eleven patients were studied, with a final diagnosis of TIA in 282 (68.6%). Among other diagnoses, the most frequent were a vasovagal reaction (5.6%) and confusional syndrome (4.6%). Delay between emergency arrival and neurovascular assessment was <24h in 82% of the cases, and <48 h in 93%. After neurological evaluation, 28.7% of the patients were immediately admitted to hospital (most common causes: severe stenosis of a large artery and crescendo TIA). The incidence of ischaemic stroke in TIA patients was 3.55% after 3 months and 70% of them suffered the recurrence within the first week after the initial TIA. CONCLUSIONS: In a hospital without a neurologist available 24 hours a day, early assessment and management of TIA patients can be carried out in accordance with the guidelines, and may avoid hospitalisation in most cases without increasing recurrence rates. PMID- 24953412 TI - Autoimmune acute motor sensory axonal polyradiculoneuritis in a case of inflammatory bowel disease. PMID- 24953413 TI - Regarding emergency department consultations with neurologists. PMID- 24953415 TI - Straightforward proteomic analysis reveals real dynamics of proteins in cells. AB - To reveal real dynamics of proteins in cells, we have developed a novel type of straightforward proteomic analysis named FD-LC-MS/MS. This technique consists of fluorogenic derivatization (FD) of intact proteins, followed by high performance liquid chromatographic (LC) separation, detection and quantification of the derivatized proteins, isolation of the subject proteins, enzymatic digestion of the isolated proteins, and identification of the proteins using HPLC and MS/MS with a database-searching algorithm. The method is uncomplicated, sensitive, reproducible, and easily quantifies and identifies intact proteins in tissues and cells. Additionally, in contrast to other proteomic approaches, our method does not require any pretreatment steps, such as precipitation and clean-up, except for the derivatization, resulting in high reproducibility and the same or higher detectability than that of other methods. In this article, after a brief review of other types of proteomic analyses, we introduce the development and application of the FD-LC-MS/MS method. We also discuss the features and perspectives of this method. PMID- 24953414 TI - Description of series of 10 patients with hypnic headache: Discussion of the diagnostic criteria. AB - INTRODUCTION: Hypnic headache is a rare primary headache. The diagnostic criteria of the International Headache Classification (IHS) for this condition are discussed, as they have been modified in the new edition of the 2013. PATIENTS AND METHODS: The clinical characteristics, and fulfilment of the criteria of the IHS classification in a series of 10patients diagnosed in our Headaches Clinic, are analyzed. RESULTS: The mean age of onset of symptoms was 52.1years (SD: 13.4; range: 28-69). The pain was reported as oppressive in 60% of the patients, and as sharp in 30%. The headache was described as holocranial in 60% and hemicranial in 40%. They occurred exclusively during night-time sleep in 80% of the patients. The mean duration of headache was 136.5minutes (range: 10-480). The mean number of days per month was 16.4 (range: 3-30), and 50% had less than 15 headache days per month. No patient had autonomic manifestations, 70% had phonophobia, 50% had photophobia, and 50% had both. All of them (100%) had a VAS score equal to or higher than 8. CONCLUSIONS: The criteria for hypnic headache of the new classification are best suited to the characteristics of these patients. Our results show the major changes in the criteria: pain is not always dull, headache frequency may be less than 15days a month, and it can occur in people under age 50. There may be phonophobia or photophobia only, or both. Although it does not form part of the diagnostic criteria, the pain intensity in our series was higher than described. PMID- 24953416 TI - Outcomes after surgical resection of thymic carcinoma: A study from a single tertiary referral centre. AB - AIMS: Thymic carcinoma is a rare and invasive mediastinal tumor, with poor prognosis. The optimal treatment for thymic carcinoma is not well defined currently. METHODS: A single-institution retrospective study of patients operated for thymic carcinoma between 1996 and 2011 was conducted. Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis. RESULTS: Seventy-six patients underwent surgery for thymic carcinoma. Masaoka stage was I in 11 patients, II in 20, III in 32, IVa in 13. A complete resection (R0) was achieved in 59 patients. Adjuvant radio/chemotherapy was offered to 58 patients. The 5-year disease-free survival rate and overall survival rate for all the patients were 59.7% and 66.2%, respectively. Patients with incomplete resection had a significantly worse disease-free survival and overall survival as compared to complete resection with univariate analyses (both p < 0.001). Multivariate analysis revealed that complete resection and Masaoka stage were statistically associated with disease free survival and overall survival (p = 0.005 and 0.013 with complete resection; p = 0.006 and 0.009 with Masaoka stage). CONCLUSIONS: Our result indicated that complete resection and Masaoka stage could impact the disease-free survival and overall survival of patients with thymic carcinoma after surgical resection. PMID- 24953418 TI - Contamination event detection using multiple types of conventional water quality sensors in source water. AB - Early warning systems are often used to detect deliberate and accidental contamination events in a water system. Conventional methods normally detect a contamination event by comparing the predicted and observed water quality values from one sensor. This paper proposes a new method for event detection by exploring the correlative relationships between multiple types of conventional water quality sensors. The performance of the proposed method was evaluated using data from contaminant injection experiments in a laboratory. Results from these experiments demonstrated the correlative responses of multiple types of sensors. It was observed that the proposed method could detect a contamination event 9 minutes after the introduction of lead nitrate solution with a concentration of 0.01 mg L(-1). The proposed method employs three parameters. Their impact on the detection performance was also analyzed. The initial analysis showed that the correlative response is contaminant-specific, which implies that it can be utilized not only for contamination detection, but also for contaminant identification. PMID- 24953417 TI - Sentinel node biopsy for high-risk cutaneous squamous cell carcinoma. AB - AIM: The use of sentinel node biopsy (SNB) has not been established for cutaneous squamous cell carcinoma (SCC), and its clinical significance has not been clarified. We investigated the usefulness of and indication criteria for SNB for cutaneous SCC. MATERIALS AND METHODS: Twenty-six patients with high-risk cutaneous SCC that had undergone SNB were retrospectively reviewed. SNB was performed with either the dye method or a combined dye and radioisotope method. RESULTS: Of the 26 patients, recurrence or metastasis was observed in 5 cases (19.2%). Six cases (23.1%) were sentinel node (SN) metastasis-positive. All cases that were SN metastasis-negative survived, and 4 of 6 SN metastasis-positive (66.7%) cases died of the original disease. The 3-year survival rates of all cases, SN metastasis-negative cases, and SN metastasis-positive cases were 82.2%, 100%, and 20.8%, respectively. Tumour thickness was a significant risk factor for SN metastasis (p = 0.049). Recurrence occurred in 4 of 7 cases involving external genitalia, 3 of which died. The 3-year survival rates of external genitalia and nongenital cases were 47.6% and 94.1%, respectively (p = 0.016). CONCLUSIONS: SNB aided the early discovery and treatment of latent lymph node metastasis and helped predict whether SN metastasis had occurred, and therefore helped predict patient prognosis. These results suggest that thickness of the primary lesion is an indication criterion for the use of SNB in cases of cutaneous SCC. SNB should be considered in cases where tumour thickness is >=2 mm and actively performed in cases >=5 mm. PMID- 24953419 TI - Uveal Melanoma Metastatic to the Liver: The Role of Quantitative Volumetric Contrast-Enhanced MR Imaging in the Assessment of Early Tumor Response after Transarterial Chemoembolization. AB - PURPOSE: To determine whether volumetric changes of enhancement as seen on contrast-enhanced magnetic resonance (MR) imaging can help assess early tumor response and predict survival in patients with metastatic uveal melanoma after one session of transarterial chemoembolization (TACE). MATERIALS AND METHODS: Fifteen patients with 59 lesions who underwent MR imaging before and 3 to 4 weeks after the first TACE were retrospectively included. MR analysis evaluated signal intensities, World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), European Association for the Study of the Liver (EASL), modified RECIST (mRECIST), tumor volume [volumetric RECIST (vRECIST)], and volumetric tumor enhancement [quantitative EASL (qEASL)]. qEASL was expressed in cubic centimeters [qEASL (cm(3))] and as a percentage of the tumor volume [qEASL (%)]. Paired t test with its exact permutation distribution was used to compare measurements before and after TACE. The Kaplan-Meier method with the log-rank test was used to calculate overall survival for responders and non-responders. RESULTS: In target lesions, mean qEASL (%) decreased from 63.9% to 42.6% (P = .016). No significant changes were observed using the other response criteria. In non-target lesions, mean WHO, RECIST, EASL, mRECIST, vRECIST, and qEASL (cm(3)) were significantly increased compared to baseline. qEASL (%) remained stable (P = .214). Median overall survival was 5.6 months. qEASL (cm(3)) was the only parameter that could predict survival based on target lesions (3.6 vs 40.5 months, P < .001) or overall (target and non-target lesions) response (4.4 vs 40.9 months, P = .001). CONCLUSION: Volumetric tumor enhancement may be used as a surrogate biomarker for survival prediction in patients with uveal melanoma after the first TACE. PMID- 24953420 TI - Neurocognitive predictors of social cognition in remitted schizophrenia. AB - Knowledge of how specific neurocognition (NC) abilities predict social cognition (SC) in schizophrenia has potential to guide novel integrated cognitive remediation therapies. The scope of studies conducted in this field is limited as they have not examined a comprehensive set of SC domains and they employ small sample sizes of heterogeneous patient groups. We studied a broad range of NC (sustained attention, processing speed, verbal/visual memory and visual processing/encoding, cognitive flexibility and planning) and SC [different levels of theory of mind (ToM)], attributional bias, emotion recognition and social perception] abilities in 170 remitted schizophrenia patients. Multivariate regression analyses revealed attention and planning as predictors of 1st order ToM. Memory encoding was the strongest predictor of 2nd order ToM. Faux-pas recognition, social perception and emotion recognition were influenced by a combination of cognitive flexibility and memory encoding abilities. Overall, NC predicted anywhere between ~4% and 40% of variance observed in specific SC sub dimensions of attributional bias (4%), 1st order (19%) and 2nd order (12%) theory of mind, faux-pas recognition (28%), social perception (29%) and emotion recognition (39%). Individual SC abilities are predicted by distinctive as well as shared NC abilities. These findings have important implications for integrated cognitive remediation. PMID- 24953421 TI - No evidence for a role of the peroxisome proliferator-activated receptor gamma (PPARG) and adiponectin (ADIPOQ) genes in antipsychotic-induced weight gain. AB - Antipsychotics frequently cause changes in glucose metabolism followed by development of weight gain and/or diabetes. Recent findings from our group indicated an influence of glucose-related genes on this serious side effect. With this study, we aimed to extend previous research and performed a comprehensive study on the peroxisome proliferator-activated receptor gamma (PPARG) and the adiponectin (ADIPOQ) genes. In 216 schizophrenic patients receiving antipsychotics for up to 14 weeks, we investigated single-nucleotide polymorphisms in or near PPARG (N=24) and ADIPOQ (N=18). Statistical analysis was done using ANCOVA in SPSS. Haplotype analysis was performed in UNPHASED 3.1.4 and Haploview 4.2. None of the PPARG or ADIPOQ variants showed significant association with antipsychotic-induced weight gain in our combined sample or in a refined subsample of patients of European ancestry treated with clozapine or olanzapine after correction for multiple testing. Similarly, no haplotype association could withstand multiple test correction. Although we could not find a significant influence of ADIPOQ and PPARG on antipsychotic-induced weight gain, our comprehensive examination of these two genes contributes to understanding the biology of this serious side effect. More research on glucose metabolism genes is warranted to elucidate their role in metabolic changes during antipsychotic treatment. PMID- 24953423 TI - Haplotype-tag single nucleotide polymorphism analysis of the vesicular glutamate transporter (VGLUT) genes in severely alcoholic women. PMID- 24953424 TI - Juicy lemons for measuring basic empathic resonance. AB - Watch or even think of someone biting into a juicy lemon and your saliva will flow. This is a phenomenon of resonance, best described by the Perception-Action Model, where a physiological state in a person is activated through observation of this state in another. Within a broad framework of empathy, including manifold abilities depending on the Perception-Action link, resonance has been proposed as one physiological substrate for empathy. Using 49 healthy subjects, we developed a standardized salivation paradigm to assess empathic resonance at the autonomic level. Our results showed that this physiological resonance correlated positively with self-reported empathic concern. The salivation test, delivered an objective and continuous measure, was simple to implement in terms of setup and instruction, and could not easily be unintentionally biased or intentionally manipulated by participants. Therefore, these advantages make such a test a useful tool for assessing empathy-related abilities in psychiatric populations. PMID- 24953422 TI - Low baseline pCO2 predicts poorer outcome from behavioral treatment: evidence from a mixed anxiety disorders sample. AB - Low levels of end-tidal partial pressure of carbon dioxide (pCO2)-the amount of carbon dioxide measured from expired air-are commonly found in individuals with anxiety disorders but have not been examined as predictors of outcome from anxiety treatment. The current study examined pre-treatment baseline pCO2 as a predictor of outcome from cognitive behavioral therapy (CBT) and acceptance and commitment therapy (ACT) for anxiety disorders. Sixty-one individuals with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) defined principal anxiety disorder diagnosis completed 12 sessions of either CBT or ACT. Baseline pCO2 was measured prior to entering treatment. Self-reported anxiety symptoms and quality of life were assessed at pre-treatment, post-treatment, and 6- and 12 month follow-up from baseline. Low baseline pCO2 was associated with higher anxiety symptoms and lower quality of life across follow-up timepoints, above and beyond baseline symptom severity. These results suggest that low baseline pCO2 predicts poorer outcome from CBT and ACT for anxiety and may warrant treatment that directly addresses respiratory dysregulation. PMID- 24953426 TI - Generic chiral method development in supercritical fluid chromatography and ultra performance supercritical fluid chromatography. AB - The development of chiral separation methods in pharmaceutical industry is often a very tedious, labour intensive and expensive process. A trial-and-error approach remains frequently used, given the unpredictable nature of enantioselectivity. To speed-up this process and to maximize the efficiency of method development, a generic chiral separation strategy for SFC is proposed in this study. To define such strategy, the effect of different chromatographic parameters on the enantioselectivity is investigated and evaluated. Subsequently, optimization steps are defined to improve a chiral separation in terms of resolution, analysis time, etc. or to induce separation when initially not obtained. The defined strategy proved its applicability and efficiency with the successful separation of a novel 20-compound test set. In a second stage, the method transfer from a conventional to an ultra-performance SFC system is investigated for the screening step of the separation strategy. The method transfer proved to be very easy and straightforward. Similar enantioresolution values, but slightly shorter analysis times were obtained on the ultra performance equipment. Nevertheless, even more benefit may be expected in ultra performance SFC when customized sub-2 MUm chiral stationary phases will become available. PMID- 24953425 TI - Stability of alexithymia in late adolescence: results of a 4-year follow-up study. AB - The aim of the present study was to assess the stability of alexithymia in adolescents and the effects of parental factors and social support thereon. The sample comprised 315 late adolescents, of whom 259 were female and 56 male. At baseline, the mean age of the subjects was 19 years (range 17-21 years). The follow-up period was 4 years (2008-2012). The 20-item Toronto Alexithymia Scale (TAS-20) was used for the assessment of alexithymia both at baseline and follow up. The Multidimensional Scale of Perceived Social Support (MSPSS) and the Parental Bonding Instrument (PBI) were used as measures at baseline. Regarding absolute stability, the changes in the TAS-20 total scores and two subscales (DIF and EOT) were statistically significant but the effect sizes for the changes were small (Cohen's d 0.21-0.24). The test-retest correlations for the TAS-20 total and subscale scores were high (rho=0.50-0.64, P<0.001), indicating relative stability. While several parental and social support variables were associated with alexithymia at baseline, low social support from friends was the only to predict higher alexithymia at follow-up. Alexithymia is a stable personality trait also in late adolescence. Low social support from friends is related to alexithymia in young adulthood. PMID- 24953427 TI - The endocannabinoid system modulates stress, emotionality, and inflammation. AB - The physiological and behavioral effects of stress are well characterized. Endocannabinoids are produced on demand and function to attenuate many of the physiological effects of the stress response. The endocannabinoid system is made up of cannabinoid receptors, the fatty acid signaling molecules that bind to and activate these receptors, and the enzymes that synthesize and catabolize these endocannabinoid signaling molecules. Cannabinoid research has recently grown substantially, due in no small part to the development of genetic research models as well as highly selective pharmaceutical tools. The purpose of this minireview is to discuss a subset of the many parallels between cannabinoid and behavioral neuroimmunology research, with specific discussion of interactions between the endocannabinoid system and psychological stress, emotionality, and inflammation. PMID- 24953428 TI - The in vivo and in vitro induction of anterior chamber associated immune deviation to myelin antigens in C57BL/6 mice. AB - Introduction of antigens into the anterior chamber (AC) of the eye generates a specific systemic form of tolerance that is termed AC-associated immune deviation (ACAID). Experimental autoimmune encephalomyelitis (EAE) is an animal model of the human CNS demyelinating diseases, including multiple sclerosis (MS) and acute disseminated encephalomyelitis. We investigated whether the encephalitogenic antigens myelin oligodendrocyte glycoprotein (MOG35-55) or myelin basic protein (MBP) induce ACAID in the EAE-prone C57BL/6 mice. We hypothesized that injection of MOG35-55/MBP induces antigen-specific tolerance whether via the AC route, the adoptive transfer of in vitro-generated MOG35-55-specific/MBP-specific ACAID antigen presenting cells (APCs), or the adoptive transfer of MOG35-55 specific/MBP-specific ACAID T regulatory cells (Tregs). ACAID is characterized by the specific impairment of delayed-type hypersensitivity (DTH) responses. Thus, DTH assays were used to test for ACAID following the AC injection of MOG35 55/MBP, or the intravenous injection of MOG35-55-specific/MBP-specific ACAID APCs. The functional local adoptive transfer (LAT) assays were used to examine the putative regulatory functions of in vitro generated MOG35-55-specific/MBP specific Tregs. This report is the first to demonstrate the in vivo and in vitro induction of MOG35-55-specific/MBP-specific ACAID-mediated tolerance in C57BL/6 mice. These findings highlight the need for novel immunotherapeutic strategies for MS and optic neuritis. PMID- 24953432 TI - Optimization of a universal matchbox on an ultrasonic vibrating system. AB - The main scope of the article is to investigate the effect of ferrite cores gap in a universal matchbox on an ultrasonic vibrating system. A gapped transformer mechanism in a universal matchbox has been thoroughly studied. Characteristics of an ultrasonic vibrating system have been recorded such as mechanical vibrations, inductance, resonant frequencies, current and voltage levels as the gap of ferrite cores gradually increases. In addition, the phase difference between the supplied voltage and the current is also computed and displayed in a Lissajous curve in order to determine the optimal gap between two ferrite cores in the universal matchbox. Explanations supplement the experiment results. PMID- 24953429 TI - Single episode of mild murine malaria induces neuroinflammation, alters microglial profile, impairs adult neurogenesis, and causes deficits in social and anxiety-like behavior. AB - Cerebral malaria is associated with cerebrovascular damage and neurological sequelae. However, the neurological consequences of uncomplicated malaria, the most prevalent form of the disease, remain uninvestigated. Here, using a mild malaria model, we show that a single Plasmodium chabaudi adami infection in adult mice induces neuroinflammation, neurogenic, and behavioral changes in the absence of a blood-brain barrier breach. Using cytokine arrays we show that the infection induces differential serum and brain cytokine profiles, both at peak parasitemia and 15days post-parasite clearance. At the peak of infection, along with the serum, the brain also exhibited a definitive pro-inflammatory cytokine profile, and gene expression analysis revealed that pro-inflammatory cytokines were also produced locally in the hippocampus, an adult neurogenic niche. Hippocampal microglia numbers were enhanced, and we noted a shift to an activated profile at this time point, accompanied by a striking redistribution of the microglia to the subgranular zone adjacent to hippocampal neuronal progenitors. In the hippocampus, a distinct decline in progenitor turnover and survival was observed at peak parasitemia, accompanied by a shift from neuronal to glial fate specification. Studies in transgenic Nestin-GFP reporter mice demonstrated a decline in the Nestin-GFP(+)/GFAP(+) quiescent neural stem cell pool at peak parasitemia. Although these cellular changes reverted to normal 15days post parasite clearance, specific brain cytokines continued to exhibit dysregulation. Behavioral analysis revealed selective deficits in social and anxiety-like behaviors, with no change observed in locomotor, cognitive, and depression-like behaviors, with a return to baseline at recovery. Collectively, these findings indicate that even a single episode of mild malaria results in alterations of the brain cytokine profile, causes specific behavioral dysfunction, is accompanied by hippocampal microglial activation and redistribution, and a definitive, but transient, suppression of adult hippocampal neurogenesis. PMID- 24953431 TI - Elucidation of the metabolites of the novel psychoactive substance 4-methyl-N ethyl-cathinone (4-MEC) in human urine and pooled liver microsomes by GC-MS and LC-HR-MS/MS techniques and of its detectability by GC-MS or LC-MS(n) standard screening approaches. AB - 4-methyl-N-ethcathinone (4-MEC), the N-ethyl homologue of mephedrone, is a novel psychoactive substance of the beta-keto amphetamine (cathinone) group. The aim of the present work was to study the phase I and phase II metabolism of 4-MEC in human urine as well as in pooled human liver microsome (pHLM) incubations. The urine samples were worked up with and without enzymatic cleavage, the pHLM incubations by simple deproteinization. The metabolites were separated and identified by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS). Based on the metabolites identified in urine and/or pHLM, the following metabolic pathways could be proposed: reduction of the keto group, N-deethylation, hydroxylation of the 4-methyl group followed by further oxidation to the corresponding 4-carboxy metabolite, and combinations of these steps. Glucuronidation could only be observed for the hydroxy metabolite. These pathways were similar to those described for the N-methyl homologue mephedrone and other related drugs. In pHLM, all phase I metabolites with the exception of the N-deethyl-dihydro isomers and the 4-carboxy-dihydro metabolite could be confirmed. Glucuronides could not be formed under the applied conditions. Although the taken dose was not clear, an intake of 4-MEC should be detectable in urine by the GC-MS and LC-MS(n) standard urine screening approaches at least after overdose. PMID- 24953430 TI - Chronic pancreatitis and systemic inflammatory response syndrome prevent impact of chemotherapy with gemcitabine in a genetically engineered mouse model of pancreatic cancer. AB - BACKGROUND AND AIMS: BACKGROUND AND AIMSGemcitabine is the standard therapy for patients with pancreatic cancer with metastatic disease. Patients with metastatic pancreatic cancer presenting with increased values of C-reactive protein do not respond to gemcitabine. So far, no studies have evaluated the correlation between chronic pancreatitis, systemic inflammatory response syndrome, and the loss of chemotherapeutic benefit. METHODS: Pdx-1-Cre;LSL-Kras(G12D/+);LSL-Trp53(R172H/+) mice were assigned into four groups: 1) Sixteen animals received a daily intraperitoneal injection of caerulein from their ninth week of life on. 2) Sixteen mice were additionally given gemcitabine. 3) Twelve animals received gemcitabine only. 4) Saline-treated control group. Furthermore, human Paca44 pancreatic ductal adenocarcinoma cells were seeded and cultured in 0.5% FBS containing growth medium plus/minus 1 MUM gemcitabine plus/minus recombinant human interleukin (IL)-6. RESULTS: Induced systemic inflammatory response syndrome and a mild chronic pancreatitis diminished the beneficial effects of gemcitabine upon median overall survival. In median, the monogemcitabine group survived 191 days, whereas the caerulein-mono group survived 114, the control group 121, and the caerulein gemcitabine group 127 days (P < .05). In vitro, the induction of STAT3 phosphorylation by recombinant human IL-6 promoted pancreatic ductal adenocarcinoma cell survival during gemcitabine treatment. CONCLUSION: We could demonstrate for the first time that an improvement in median overall survival with gemcitabine is significantly abolished by a persistent mild chronic pancreatitis and a systemic inflammatory response syndrome. In particular, the inflammation biomarkers C-reactive protein, IL-6, and IL-1alpha could indicate the prognostic benefit of gemcitabine chemotherapy and should now be tested in prospective patient-controlled trials. PMID- 24953437 TI - Pediatric burns in University Clinical Center of Kosovo from 2005-2010. AB - OBJECTIVE: The objective of this study was to determine the incidence and cause of burns in children of our population. METHODS: This was a retrospective study that included 399 patients with burns, younger than 15 years old who were admitted to the Department of Plastic Surgery, University Clinical Center of Kosovo, between 1 January 2005 and 31 December 2010. The patients were categorized into the following three age groups: infants and toddlers (0-2 years), early childhood (3-6 years), and late childhood (7-15 years). Arithmetic median and standard deviation were calculated from statistical parameters for gender and age; the differences between the three age groups were measured with one-way analysis of variance (ANOVA). A p value of <0.05 was considered statistically significant. RESULTS: During the study period 2005-2010, in our population, burns in children were predominant in boys with 257 cases or 64.4%, while 142 patients were girls or 35.5% The difference between the three age groups related to the causes of burns was statistically significant: p<0.000 for electrical burns and p<0.002 for burns caused by pyrotechnic devices. CONCLUSION: A high rate of childhood burns in Kosovo induces hospital admissions and prolonged hospital stays. PMID- 24953436 TI - Research on a novel poly (vinyl alcohol)/lysine/vanillin wound dressing: Biocompatibility, bioactivity and antimicrobial activity. AB - Burn wound dressings have played significant roles in daily clinical practice. An "ideal" burn wound dressing is non-adhesion, absorbency and antimicrobial activity. However, such a dressing is currently not available. A novel composite hydrogel was based on poly (vinyl alcohol) (PVA) containing lysine (Lys) and vanillin (V) using freezing-thawing method. The properties of this hydrogel were characterized by environmental scanning electron microscope (ESEM), attenuated total reflectance fourier transform infrared spectroscopy (ATR-FTIR), tensile testing, differential scanning calorimetry (DSC) and water vapour transmission rate (WVTR). Then the antibacterial activity of PVA/Lys/V composite hydrogel was examined by bacteriolytic plate. In vivo experiment, a burn rat model was used to evaluate the histological analysis of this hydrogel. In results, the Schiff base formed in the three-phase system. It improved the tensile strength and crystallization of the PVA/Lys/V composite hydrogel. Meanwhile, this hydrogel showed excellent bactericidal activities to both gram-negative bacteria (E. coli) and gram-positive bacteria (S. aureus) due to the Schiff base. And the antibacterial activity toward gram-negative bacteria was better than another. On Day 7, 95-100% of the surface areas of PVA/Lys/V composite treated burns were covered with regenerating epidermis. And the new tissue and capillary vessel formed around the wounds after treatment. Therefore, it is suggested that treatment with PVA/Lys/V composite hydrogel will be effective also in patients with burns and other skin wounds. PMID- 24953435 TI - Farm to elementary school programming increases access to fruits and vegetables and increases their consumption among those with low intake. AB - OBJECTIVE: To assess the effectiveness of Wisconsin Farm to School (F2S) programs in increasing students' fruit and vegetable (FV) intake. DESIGN: Quasi experimental baseline and follow-up assessments: knowledge and attitudes survey, food frequency questionnaire (FFQ), and lunch tray photo observation. SETTING: Wisconsin elementary schools: 1 urban and 8 rural. PARTICIPANTS: Children, grades 3-5 (n = 1,117; 53% male, 19% non-Caucasian). INTERVENTION(S): Farm to School programming ranging from Harvest of the Month alone to comprehensive, including school garden, locally sourced produce in school meals, and classroom lessons. MAIN OUTCOME MEASURES: Knowledge, attitudes, exposure, liking, willingness; FFQ derived (total), and photo-derived school lunch FV intake. ANALYSIS: t tests and mixed modeling to assess baseline differences and academic-year change. RESULTS: Higher willingness to try FV (+1%; P < .001) and knowledge of nutrition/agriculture (+1%; P < .001) (n = 888), and lunch FV availability (+6% to 17%; P <= .001) (n = 4,451 trays), both with increasing prior F2S program exposure and across the year. There was no effect on overall dietary patterns (FFQ; n = 305) but FV consumption increased among those with the lowest intakes (FFQ, baseline very low fruit intake, +135%, P < .001; photos: percentage of trays with no FV consumption for continuing programs decreased 3% to 10%, P <= .05). CONCLUSIONS AND IMPLICATIONS: Farm to School programming improved mediators of FV consumption and decreased the proportion of children with unfavorable FV behaviors at school lunch. Longer-term data are needed to further assess F2S programs. PMID- 24953434 TI - IV nicotine self-administration in rats using a consummatory operant licking response: sensitivity to serotonergic, glutaminergic and histaminergic drugs. AB - Tobacco smoking is characterized by repeated self-administration of nicotine by placing the cigarette in the mouth. The repeated hand-to-mouth self administration is essentially a consummatory act. We recently developed a paradigm in which rats lick one of two spouts to trigger intravenous (IV) delivery of nicotine, which combines a consummatory act with rapid delivery of nicotine to model the act of tobacco smoking. We have found that rats will lick hundreds of times per nicotine infusion. In the current study, using the operant licking nicotine self-administration model with young adult Sprague-Dawley rats (0.03mg/kg/infusion of nicotine), we tested the effect of antagonists of H1 histamine receptors pyrilamine, serotonin (5HT) type 2 receptors ketanserin and N methyl-d-aspartate (NMDA) glutamate receptors with d-cycloserine as well as an agonist of 5HT2c receptors lorcaserin, in dose ranges that we have found in previous studies to significantly reduce IV nicotine self-administration with the operant lever press operand. The H1 antagonist pyrilamine significantly reduced operant licking for nicotine self-administration. Pyrilamine caused significant reductions in the operant licking paradigm at lower doses (10 and 20mg/kg) than those we previously observed to affect responding in the operant lever press paradigm. In contrast, the 5HT2A and C antagonist ketanserin did not show an effect of reducing nicotine self-administration in the same dose range we had found in a previous study to significantly reduce operant lever press nicotine self-administration. The 5HT2C agonist lorcaserin significantly decreased nicotine self-administration in the licking paradigm at the same dose threshold as with lever press responding. The NMDA glutamate partial agonist d-cycloserine did not produce any change in nicotine self-administration with the licking operand, in contrast to its effect on the classic lever-pressing task. The rat model incorporating consummatory aspects of tobacco addiction can provide distinct and potentially more relevant information concerning possible new avenues of treatment to combat tobacco addiction. PMID- 24953433 TI - The effects of atomoxetine and methylphenidate on the prepulse inhibition of the acoustic startle response in mice. AB - Atomoxetine (ATM) and methylphenidate (MPD) have been used for the treatment of attention deficit hyperactivity disorder (ADHD). ATM is a selective norepinephrine reuptake inhibitor, whereas MPD is a psychostimulant and acts as a norepinephrine and dopamine reuptake inhibitor. In the present study, we investigated the effects of ATM (1, 3 or 10mg/kg) and MPD (5, 10 or 20mg/kg) on pharmacological mouse models of sensorimotor gating measured by prepulse inhibition (PPI) using the acoustic startle response test. MK-801, a non competitive N-methyl-d-aspartate receptor antagonist, or apomorphine, a non competitive dopamine receptor agonist, was used to induce PPI deficits. ATM (3 or 10mg/kg, s.c.) significantly attenuated the MK-801-, but not apomorphine-, induced PPI deficits. In contrast to ATM, MPD did not reverse the PPI deficits induced by either MK-801 or apomorphine. Immunostaining revealed that the number of c-Fos-immunopositive cells was increased in the nucleus accumbens following MK 801 treatment, and this was reversed by the administration of ATM (3mg/kg), but not MPD (10mg/kg). However, neither ATM nor MPD reversed the increased number of c-Fos-immunopositive cells in the nucleus accumbens following apomorphine treatment. These results suggest that the attenuating effect of ATM on the increased c-Fos immunoreactivity in the nucleus accumbens induced by MK-801 may be attributed to the PPI deficit-ameliorating effects of ATM and that ATM would be useful to treat sensorimotor gating-related disorders by improving the patient's attention span or cognitive function. PMID- 24953438 TI - Interrelations of muscle functional MRI, diffusion-weighted MRI and (31) P-MRS in exercised lower back muscles. AB - Exercise-induced changes of transverse proton relaxation time (T2 ), tissue perfusion and metabolic turnover were investigated in the lower back muscles of volunteers by applying muscle functional MRI (mfMRI) and diffusion-weighted imaging (DWI) before and after as well as dynamic (31) P-MRS during the exercise. Inner (M. multifidus, MF) and outer lower back muscles (M. erector spinae, ES) were examined in 14 healthy young men performing a sustained isometric trunk extension. Significant phosphocreatine (PCr) depletions ranging from 30% (ES) to 34% (MF) and Pi accumulations between 95% (left ES) and 120%-140% (MF muscles and right ES) were observed during the exercise, which were accompanied by significantly decreased pH values in all muscles (?pH ~ -0.05). Baseline T2 values were similar across all investigated muscles (approximately 27 ms at 3 T), but revealed right-left asymmetric increases (T2 ,inc ) after the exercise (right ES/MF: T2 ,inc = 11.8/9.7%; left ES/MF: T2 ,inc = 4.6/8.9%). Analyzed muscles also showed load-induced increases in molecular diffusion D (p = .007) and perfusion fraction f (p = .002). The latter parameter was significantly higher in the MF than in the ES muscles both at rest and post exercise. Changes in PCr (p = .03), diffusion (p < .01) and perfusion (p = .03) were strongly associated with T2,inc , and linear mixed model analysis revealed that changes in PCr and perfusion both affect T2,inc (p < .001). These findings support previous assumptions that T2 changes are not only an intra-cellular phenomenon resulting from metabolic stress but are also affected by increased perfusion in loaded muscles. PMID- 24953439 TI - General practitioners' preferences for interventions to improve guideline adherence. AB - RATIONALE, AIMS AND OBJECTIVES: Interventions aimed at improving guideline adherence should take into account the specific features of the target users; however, it is unclear how general practitioners (GPs) evaluate the different types of interventions. The aim of this paper was to identify GPs' preferences for interventions to improve guideline adherence in practice and whether these differ across key guideline recommendations. METHOD: An electronic survey was conducted among 703 GPs working in the south-western part of the Netherlands. Each survey focused on two of four guidelines: cerebrovascular accident, eye inflammation, thyroid disorders and urinary tract infection. GPs were asked to rate potential interventions in terms of their usefulness in improving guideline adherence in general and for specific key guideline recommendations. RESULTS: 264 GPs (38%) completed the questionnaire. In general, GPs preferred interactive small group meetings (84% rated this as much or very much encouraging), audit and feedback (53%), organizational interventions (50%) and the use of local opinion leaders (50%) as methods for improving guideline adherence. Financial interventions (24%), distribution of educational materials (22%) and big group educational meetings (21%) were of least interest. Some interventions were preferred by GPs irrespective of the specific key recommendations (e.g. audit and feedback), while ratings for other interventions differed across key recommendations (reminders/computer support). CONCLUSIONS: To implement guidelines, interventions need to be identified that are acceptable and appealing to the target group. GPs seem to have general and recommendation-specific preferences regarding interventions, these should be taken into account when developing plans for guideline implementation to encourage the uptake of guidelines in practice. PMID- 24953442 TI - Ab initio MP2 and density functional theory computational study of AcAlaNH2 peptide hydration: a bottom-up approach. AB - AcAlaNH2 ? n H2O (n=1-13) complexes have been proposed as models to account for water solvent effects on the molecular properties of N-acetyl-L-alanine amide. Ab initio computations are planned to evaluate peptide-water interactions and to provide a means for approximating relative effects of the short-range many-body interactions arising in real solution without introducing any external parameters intended to quantify empirical or semiempirical potential-energy functions. The present bottom-up approach reveals the formation of compact ring clusters of water molecules strongly bonded to peptidic polar groups throughout hydrogen bonds. The explicit coordination of water molecules around the peptide renders the fully extended (FE) and polyproline II (PPII) conformers more stable with respect to the 310 helix or gamma turn. The alternance of donor and acceptor groups on both sides of the FE and PPII conformers allows for synergy and extensive H-bonding. PMID- 24953441 TI - Nurses' perceptions of multitasking in the emergency department: effective, fun and unproblematic (at least for me) - a qualitative study. AB - INTRODUCTION: The aim was to understand how multitasking is experienced by registered nurses and how it relates to their everyday practice in the emergency department. METHOD: Interviews with open-ended questions were conducted with registered nurses (n = 9) working in one of two included emergency departments in Sweden. Data were analyzed using Schilling's structured model for qualitative content analysis. RESULTS: Three core concepts related to multitasking emerged from the interviews: 'multitasking - an attractive prerequisite for ED care'; 'multitasking implies efficiency' and 'multitasking is not stressful'. From these core concepts an additional theme emerged: '... and does not cause errors - at least for me', related to patient safety. DISCUSSION: This study shows how the patient load and the unreflected multitasking that follows relate to nurses' perceived efficiency and job satisfaction. It also shows that the relationship between multitasking and errors is perceived to be mediated by whom the actor is, and his or her level of experience. Findings from this study add value to the discourse on multitasking and the emergency department context, as few studies go beyond examining the quantitative aspect of interruptions and multitasking and how it is experienced by the staff in their everyday practice. PMID- 24953440 TI - Witnessing clients' emotional transformation: an emotion-focused therapist's experience of providing therapy. AB - Emotion-focused therapy (EFT) is an integrative-humanistic, research-informed, psychological intervention characterized by sustained focus on the client's emotional pain and its transformation. This article discusses the impacts on the therapist when encountering and transforming the client's vulnerability. It is organized around the different phases of the therapy process: meeting a new client, accessing the client's core emotional pain, transforming the client's emotional pain, and ending the therapeutic work. The article also contains personal experiences of the author and provides illustrations of impactful events from therapy sessions. The work, it is suggested, provides significant learning for the therapist on both a personal and a professional level, leading, for example, to the therapist's maturation, better connection with personal hurts and vulnerabilities, greater courage in regard to sharing such feelings, greater kindness toward others and the self, and greater determination to be braver when facing adversity or injustice. PMID- 24953443 TI - Low knowledge and anecdotal use of unauthorized online HIV self-test kits among attendees at a street-based HIV rapid testing programme in Spain. AB - OBJECTIVES: The objectives of this study were to estimate the percentage of potential users who know that unauthorized HIV self-tests can be purchased online and the percentage of those who have already used them, and to determine socio demographic and behavioural correlates. METHODS: A self-administered questionnaire was employed to collect data from attendees at a street-based HIV testing programme. Logistic regression for rare events was performed. RESULTS: Of the 3340 participants, 5.3% (95% confidence interval (CI) 4.5-6.0%) had knowledge of self-tests being sold online and 7.5% (95% CI 6.6-8.5%) thought they existed but had never seen them; only 0.6% (95% CI 0.3-0.9%) had ever used one. Knowing that self-tests are sold online (odds ratio (OR) 3.6, 95% CI 2.4-5.4) and using them (OR 7.3, 95% CI 2.2-23.8) were associated with having undergone more than two previous HIV tests. Use was also associated with being neither Spanish nor Latin American (OR 3.8, 95% CI 1.2-12.0) and with having a university degree (OR 0.2, 95% CI 0.1-0.7). CONCLUSIONS: At the time of the study, the impact on the population of issues related to the use of unauthorized tests was very low. However, media coverage following the approval of self-testing in the USA might have changed the situation. PMID- 24953444 TI - Botulinum toxin A and lidocaine have an impact on adipose-derived stem cells, fibroblasts, and mature adipocytes in vitro. AB - Lipofilling with autologous fat tissue is widely used in plastic and reconstructive surgery to treat soft-tissue deficiency. Unfortunately, implanted cells disappear gradually and make it difficult to predict the resorption rate. Several adjuvants are used to improve the success of fat tissue grafting. In this study, the effect of botulinum toxin (BoNT) on mature adipocytes, as well as adipose-derived stem cells (ASC) and fibroblasts was evaluated. As lidocaine is the most prevalent drug to anesthetize the donor site as well as the area to be treated with autologous fat, this local anesthetic was examined too. Primary ASCs, fibroblasts, and mature adipocytes were exposed to 1, 10, and 20 IU/ml BoNT A and 1% lidocaine. Cells were tested on proliferation, viability, and LDH release. Adipogenic differentiation potential was evaluated by quantitative real time PCR analyzing the expression of FABP4. BoNT had no significant influence on the proliferation or viability of tested cells. By trend, low concentrations of BoNT improved adipogenic potential of ASCs. Lidocaine had a strong diminishing effect on the proliferation of ASCs and fibroblasts and on the viability of these cells. Mature adipocytes show no significant inferior viability after BoNT or lidocaine treatment. BoNT has no negative effect on ASCs, mature adipocytes, or fibroblasts in vitro. Lidocaine (1%) negatively influences the proliferation and viability of fibroblasts and partly of ASCs but not of mature adipocytes. PMID- 24953451 TI - Genetic characteristics of Haemophilus influenzae and Streptococcus pneumoniae isolated from children with conjunctivitis-otitis media syndrome. AB - Acute conjunctivitis is the most common ocular disorders among children and frequently concomitant with acute otitis media (AOM) as conjunctivitis-otitis syndrome. In this study, we evaluated prevalence of causative pathogens and PCR based genotypes of Haemophilus influenzae and Streptococcus pneumoniae among children with conjunctivitis-otitis media syndrome. Nontypeable H. influenzae (NTHi) is identified most often at 61.8% in conjunctiva exudates followed by S. pneumoniae at 28.2% and Moraxella catarrhalis at 19.1%. Genetic beta-lactamase nonproducing ampicillin resistant (gBLNAR) strains of NTHi and genetic penicillin resistant S. pneumoniae (gPRSP) were identified at 72.1% and at 74.2% among conjunctiva isolates by polymerase chain reaction (PCR), respectively. Pneumococcal strains having either ermB or mefE genes were identified at 93.5% among conjunctiva isolates. The restriction fragment of patterns of 89.7% pairs of H. influenzae isolates and 100% pairs of pneumococcal isolates from conjunctiva exudates, middle ear fluids (MEFs) and nasopharyngeal swabs were identical. In contrast to the previous reports, most prevalent strains from conjunctivitis-otitis media syndrome was BLNAR H. influenzae in this study. The causative pathogen responsible for acute conjunctivitis will be originated from the nasopharynx. In the absence of MEFs one can possibly rely on the nasopharyngeal culture to guide an appropriate treatment. PMID- 24953448 TI - Professional diversity and the productivity of cities. AB - Attempts to understand the relationship between diversity, productivity and scale have remained limited due to the scheme-dependent nature of the taxonomies describing complex systems. We analyze the diversity of US metropolitan areas in terms of profession diversity and employment to show how this frequency distribution takes a universal scale-invariant form, common to all cities, in the limit of infinite resolution of occupational taxonomies. We show that this limit is obtained under general conditions that follow from the analysis of the variation of the occupational frequency across taxonomies at different resolutions in a way analogous to finite-size scaling in statistical physical systems. We propose a theoretical framework that derives the form and parameters of the limiting distribution of professions based on the appearance, in urban social networks, of new occupations as the result of specialization and coordination of labor. By deriving classification scheme-independent measures of functional diversity and modeling cities as social networks embedded in infrastructural space, these results show how standard economic arguments of division and coordination of labor can be articulated in detail in cities and provide a microscopic basis for explaining increasing returns to population scale observed at the level of entire metropolitan areas. PMID- 24953446 TI - The effect of a bacterial contamination on the formation of capsular contracture with polyurethane breast implants in comparison with textured silicone implants: an animal study. AB - INTRODUCTION: One of the most common complications following breast augmentation is capsular contracture. The subclinical infection of the implant is often considered to be one of the main risk factors. It is believed that polyurethane (PU) implants, because of their larger foam-like surface, have lower capsular contracture rates due to better tissue integration. It remains unclear if bacterial contamination and biofilm formation result in higher capsular contracture rates under the condition of the increased surface of PU implants compared to textured silicone-gel implants. The effect of this bacterial contamination was examined in an animal-based study. METHODS: A total of 80 mini implants (40 textured silicone-gel implants and 40 PU implants) were implanted in the dorsum of female Wistar rats. In each group, 20 implants were inoculated before implantation with a standard amount of Staphylococcus epidermidis. Capsules and implants were explanted after 60 days, followed by double-blind histological, immunohistochemical, and microbiological examinations. RESULTS: Macroscopic separation of the total capsule in the textured implant group was possible whereas the growth of surrounding tissue into the foam structure of PU implants made separation in that group difficult. After contamination, a thicker capsule could be observed in both groups without significant differences. Histologically, capsules around PU implants showed significantly lower expression of parallel myofibrils. We were able to describe a significant higher infiltration with inflammatory cells in capsules around PU implants both with and without contamination. Microbiological investigations revealed positive growth of S. epidermidis around one PU implant without related signs of capsular contracture. DISCUSSION: This study demonstrates that aside from the surface of silicone implants, bacterial contamination has major impact on the architecture of capsule formation. In our study, we were able to demonstrate that bacterial contamination leads to a thicker capsule and an increased tissue reaction with a higher amount of inflammatory cells. However, a resulting bacterial infection was only demonstrated in one case and had an insignificant influence on capsule architecture. The observed inflammatory reaction around PU implants was observed as a nonbacterial, granulomatose foreign body reaction. EBM RATING: Level I: Evidence obtained from at least one properly designed randomized controlled trial. PMID- 24953447 TI - Prosthesis use and satisfaction among persons with dysvascular lower limb amputations across postacute care discharge settings. AB - OBJECTIVE: To test the hypotheses that patients undergoing major lower limb amputations who received postacute care at an inpatient rehabilitation facility (IRF) would experience higher prosthesis use and satisfaction and lower prosthesis-related adverse effects than those treated at a skilled nursing facility (SNF) or at home. DESIGN: Population-based, observational, prospective, multicenter study. SETTING: Hospitals and communities in 2 racially and geographically diverse states. PARTICIPANTS: Patients 21 years and older who were identified during the surgical acute care stay as undergoing major lower limb amputations. MAIN OUTCOME MEASURES: Prosthesis use; satisfaction with prosthesis' comfort, appearance, and gait; and the presence of skin irritation, pain, and wounds as a result of prosthesis use. METHODS: Two-stage instrumental variable models applied to data collected from medical records and patient interviews. RESULTS: Only 149 (50.2%) of the 297 study participants had a prosthesis at the 6 month follow-up. Regression-adjusted outcomes indicate that patients treated at IRFs used their prosthesis more hours per week (52.8 versus 36.2 h/wk or 46% higher use), were less likely to experience prosthesis-related pain (16% versus 33.7%) and were significantly more likely to be satisfied with their gait (76.1% versus 59.3%) than were patients treated at SNFs. No significant differences in outcomes were found between patients who received care at an IRF and patients who were discharged home. CONCLUSIONS: These results add to the growing body of literature suggesting a general pattern of better outcomes for persons with vascular-related amputations who receive postacute care at IRFs relative to SNFs. PMID- 24953449 TI - The effect of creative psychological interventions on psychological outcomes for adult cancer patients: a systematic review of randomised controlled trials. AB - OBJECTIVE: This systematic review examined the effectiveness of creative psychological interventions (CPIs) for adult cancer patients. In particular, the findings of randomised controlled trials of art, drama, dance/movement and music therapies on psychological outcomes were examined. METHODS: The review yielded 10 original studies analysing data from a total of 488 patients. Data extraction and quality assessment were conducted by two independent reviewers. RESULTS: Four of the papers focused on the use of art therapy, three studies used music therapy, one paper utilised dance therapy, one study used dance/movement therapy and the remaining paper used creative arts therapies, which was a combination of different art-based therapy approaches. Eight papers focused solely on breast cancer patients, and the remaining studies included mixed cancer sites/stages. The studies reported improvements in anxiety and depression, quality of life, coping, stress, anger and mood. However, few physical benefits of CPIs were reported; there was no significant impact of a CPI on physical aspects of quality of life, vigour-activity or fatigue-inertia or physical functioning. One study was assessed as high quality, seven studies were assessed as satisfactory and two studies were assessed to be of poorer quality. CONCLUSIONS: There is initial evidence that CPIs benefit adult cancer patients with respect to anxiety and depression, quality of life, coping, stress, anger and mood; there was no evidence to suggest that any one type of CPI was especially beneficial. However, more and better quality research needs to be conducted, particularly in the areas of drama and dance/movement therapies. PMID- 24953453 TI - The topology of the growing human interactome data. AB - We have long moved past the one-gene–one-function concept originally proposed by Beadle and Tatum back in 1941; but the full understanding of genotype–phenotype relations still largely relies on the analysis of static, snapshot-like, interaction data sets. Here, we look at what global patterns can be uncovered if we simply trace back the human interactome network over the last decade of protein- protein interaction (PPI) screening. We take a purely topological approach and find that as the human interactome is getting denser, it is not only gaining in structure (in terms of now being better fit by structured network models than before), but also there are patterns in the way in which it is growing: (a) newly added proteins tend to get linked to existing proteins in the interactome that are not know to interact; and (b) new proteins tend to link to already well connected proteins. Moreover, the alignment between human and yeast interactomes spanning over 40% of yeast’s proteins — that are involved in regulation of transcription, RNA splicing and other cellcycle-related processes—suggests the existence of a part of the interactome which remains topologically and functionally unaffected through evolution. Furthermore, we find a small sub-network, specific to the “core” of the human interactome and involved in regulation of transcription and cancer development, whose wiring has not changed within the human interactome over the last 10 years of interacome data acquisition. Finally, we introduce a generalisation of the clustering coefficient of a network as a new measure called the cycle coefficient, and use it to show that PPI networks of human and model organisms are wired in a tight way which forbids the occurrence large cycles. PMID- 24953450 TI - Microemulsion based topical hydrogel of sertaconazole: formulation, characterization and evaluation. AB - A microemulsion (ME) based hydrogel had studied as a topical delivery of sertaconazole (STZL) for effective eradication of cutaneous fungal infection. The existence of microemulsion region was investigated in pseudo-ternary phase diagrams and various ME formulations were prepared using oleic acid, Tween 80, propylene glycol and water. Hydrogel of STZL microemulsions (HSM) were prepared in Carbopol 940 (0.75%, w/w) and characterized. The prepared HSM and commercial cream of STZL were evaluated in vitro and ex vivo. The permeation rate of STZL from optimized formulation (HSM-4), composed with oleic acid (8.75%, w/w), tween 80 (33.35%, w/w), propylene glycol (33.35%, w/w) and water (24.55%, w/w) was observed higher in compare with other HSMs and commercial cream. HSM-4 was stable, had 3 times higher drug retention capacity in skin than commercial cream and did not caused any erythema or edema based on skin sensitivity study on rabbit. The average zone of inhibition of HSM-4 (23.54+/-0.72mm) was higher in compare with commercial cream (16.53+/-0.63mm) against Candida albicans which may be due to permeation enhancing effect of ME and skin retention effect of HSM. It is promising that the concentration of STZL used to treat cutaneous fungal infection could be decreased due to the high permeation and anti-fungal effect of STZL in HSM-4. PMID- 24953445 TI - Mandibular volumetric increase following distraction osteogenesis. AB - INTRODUCTION: Mandibular distraction osteogenesis (MDO) for the treatment of Pierre Robin sequence (PRS) enables mandibular lengthening and improves airway and feeding function. It remains unknown how the post-distracted mandibular volume compares to a normal control population. The aim of this study was to analyze mandibular volume and symmetry following bilateral MDO and compare post distraction measurements to a non-distracted, normal age- and sex-matched control cohort. METHODS: Demographic information and three dimensional-computed tomographic (CT) images were obtained from normal control and distracted PRS patients. Mandibular volume and symmetry indices were calculated and results statistically analyzed. P values <=0.05 were considered statistically significant. RESULTS: 24 CT scans and 48 hemimandibles were analyzed (8 control patients: mean age = 5.6 months, 3 females; 8 distracted patients: mean age pre distraction = 1.8 months, mean age post-distraction = 5.3 months, 3 females). No complications were encountered in the distracted group. The mean pre- and post distraction volume in the MDO group measured 7238.1 mm(3) and 15,360.6 mm(3), respectively (P = 0.0003) and the mean percent increase in mandibular volume following distraction was 113.3%. The mean symmetry index increased after distraction from 0.91 to 0.95 (P = 0.31). Matched normal control mandibles measured 13,488.6 mm(3) versus post-distraction mandibles at 15,360.6 mm(3) (P = 0.40). Normal control and post-distraction symmetry indices were 0.99 and 0.95, respectively (P = 0.68). CONCLUSION: Distraction resulted in a significantly increased mandibular volume and an observed preservation in mandibular symmetry. Post-distraction volume was increased compared to normal controls but remained less symmetrical. PMID- 24953455 TI - Integrating sequence analysis with biophysical modelling for accurate transcription start site prediction. AB - Promoter prediction in bacteria is a classical bioinformatics problem, where available methods for regulatory element detection exhibit a very high number of false positives. We here argue that accurate transcription start site (TSS) prediction is a complex problem, where available methods for sequence motif discovery are not in itself well adopted for solving the problem. We here instead propose that the problem requires integration of quantitative understanding of transcription initiation with careful description of promoter sequence specificity. We review evidence for this viewpoint, and discuss a current progress on these issues on the example of sigma70 transcription start sites in E. coli. PMID- 24953454 TI - VANESA - a software application for the visualization and analysis of networks in system biology applications. AB - VANESA is a modeling software for the automatic reconstruction and analysis of biological networks based on life-science database information. Using VANESA, scientists are able to model any kind of biological processes and systems as biological networks. It is now possible for scientists to automatically reconstruct important molecular systems with information from the databases KEGG, MINT, IntAct, HPRD, and BRENDA. Additionally, experimental results can be expanded with database information to better analyze the investigated elements and processes in an overall context. Users also have the possibility to use graph theoretical approaches in VANESA to identify regulatory structures and significant actors within the modeled systems. These structures can then be further investigated in the Petri net environment of VANESA. It is platform independent, free-of-charge, and available at http://vanesa.sf.net. PMID- 24953456 TI - High feather corticosterone indicates better coccidian infection resistance in greenfinches. AB - Differential exposure or sensitivity to stressors can have substantial effects on the variation in immune responsiveness of animals. However, the questions about the causes and consequences of these processes have remained largely unclear, particularly as regards wild animals and their natural pathogens. Here we ask how a potential marker of stress responses, the feather corticosterone (CORT) content, reflects the resistance to an experimental infection with natural coccidian parasites in wild-caught captive greenfinches (Carduelis chloris). CORT content of tail feathers grown in captivity correlated positively with a behavioural measure of captivity-intolerance, i.e., the amount of damage accrued to tail feathers in captivity that results from flapping against cage bars. This finding is consistent with an idea that feather CORT reflects the amount of stress experienced during feather growth. Experimental infection with heterologous coccidian strains increased feather CORT levels. Birds with highest feather CORT levels appeared most resistant to new infection, assessed on the basis of parasite oocyst shedding at the peak phase of infection. Birds with highest feather CORT levels also cleared the infection faster than the birds with lower feather CORT levels. These findings provide the first evidence about positive covariation between feather CORT and resistance to a natural pathogen in a wild bird species. Assuming that feather CORT levels reflect circulating hormone titres, these findings suggest that parasite-mediated selection may contribute to maintenance of phenotypes with high corticosterone responsiveness to stress, despite potential negative behavioural consequences. PMID- 24953457 TI - Status and prognosis of lymph node metastasis in patients with cardia cancer - a systematic review. AB - BACKGROUND: Adenocarcinoma of the gastroesophageal junction (GEJ) has a poor prognosis and survival rates significantly decreases if lymph node metastasis is present. An extensive lymphadenectomy may increase chances of cure, but may also lead to further postoperative morbidity and mortality. Therefore, the optimal treatment of cardia cancer remains controversial. A systematic review of English publications dealing with adenocarcinoma of the cardia was conducted to elucidate patterns of nodal spread and prognostic implications. METHODS: A systematic literature search based on PRISMA guidelines identifying relevant studies describing lymph node metastasis and the associated prognosis. Lymph node stations were classified according to the Japanese Gastric Cancer Association guidelines. RESULTS: The highest incidence of metastasis is seen in the nearest regional lymph nodes, station no. 1-3 and additionally in no. 7, 9 and 11. Correspondingly the best survival is seen when metastasis remain in the most locoregional nodes and survival equally tends to decrease as the metastasis become more distant. Furthermore, the presence of lymph node metastasis significantly correlates to the TNM-stage. Incidences of metastasis in mediastinal lymph nodes are associated with poor survival. CONCLUSION: The best survival rates is seen when lymph node metastasis remains locoregional and survival rates decreases when distant lymph node metastasis is present. The dissection of locoregional lymph nodes offers significantly therapeutic benefit, but larger and prospective studies are needed to evaluate the effect of dissecting distant and mediastinal lymph nodes. PMID- 24953452 TI - Electrochemical Impedance Spectroscopy (bio)sensing through hydrogen evolution reaction induced by gold nanoparticles. AB - A new gold nanoparticle (AuNP) based detection strategy using Electrochemical Impedance Spectroscopy (EIS) through hydrogen evolution reaction (HER) is proposed. This EIS-HER method is used as an alternative to the conventional EIS based on [Fe(CN)6](3-/4-) or [Ru(NH3)6](3+/2+) indicators. The proposed method is based on the HER induced by AuNPs. EIS measurements for different amounts of AuNP are registered and the charge transfer resistance (Rct) was found to correlate and be useful for their quantification. Moreover the effect of AuNP size on electrical properties of AuNPs for HER using this sensitive technique has been investigated. Different EIS-HER signals generated in the presence of AuNPs of different sizes (2, 5, 10, 15, 20, and 50 nm) are observed, being the corresponding phenomena extendible to other nanoparticles and related catalytic reactions. This EIS-HER sensing technology is applied to a magneto-immunosandwich assay for the detection of a model protein (IgG) achieving improvements of the analytical performance in terms of a wide linear range (2-500 ng mL(-1)) with a good limit of detection (LOD) of 0.31 ng mL(-1) and high sensitivity. Moreover, with this methodology a reduction of one order of magnitude in the LOD for IgG detection, compared with a chroamperometric technique normally used was achieved. PMID- 24953458 TI - Image navigation assisted joint-saving surgery for treatment of bone sarcoma around knee in skeletally immature patients. AB - PURPOSE: It is challenge to perform a native joint preserving resection for skeletally immature patients with bone sarcomas around the knee. We determined whether tumor resection under image-guided navigation make joint-saving surgery possible for juxta-articular sarcomas around knee while adhering oncological principles. METHODS: We performed joint-saving limb salvage surgeries on eight patients with metaphyseal bone sarcomas (6 in proximal tibia, 2 in distal femur). Six tumors extend to and 2 beyond the epiphyseal line. Planned tumor resection under image-guided navigation was employed for obtaining clear surgical margin while maximizing host tissue preservation. All tumors were en bloc removed and intercalary defect were reconstructed by combination of allograft with vascularized fibula flap. All specimens were examined for resection margin. Patients were followed up at average of 40.5 months for evaluating of oncologic and functional outcomes. RESULT: Entire joints were preserved in 5 patients and partial joints were saved in 3 patients. Clear surgical margins were achieved in all patients. The minimum of surgical margin width in bone is 6 mm in this series. No patient experienced local recurrence. Bone union achieved in all cases during the study period. The average MSTS score was 27.1 at final follow-up. CONCLUSIONS: With careful patient selection, image navigation aided bone tumor resection was proved to be an effective way in joint-saving limb salvage procedures for treating skeletally immature patients with juxta-articular bone sarcomas around the knee. PMID- 24953461 TI - Vaccine development and developing countries. PMID- 24953464 TI - The use of a placebo in vaccine trials. PMID- 24953463 TI - World Refugee Day: caring for the forcibly displaced. PMID- 24953460 TI - Immunosenescence and resistance to parasite infection in the honey bee, Apis mellifera. AB - Immunosenescence, the systemic reduction of immune efficiency with age, is increasingly recognised as having important implications for host-parasite dynamics. Changes in the immune response can impact on the ability of an individual to resist or moderate parasite infection, depending on how and when it encounters a parasite challenge. Using the European honey bee Apis mellifera and its microsporidian parasite Nosema ceranae, we investigated the effects of host age on the ability to resist parasite infection and on baseline immunocompetence, assessed by quantifying constitutive (PO) and potential levels (PPO) of the phenoloxidase immune enzyme as general measures of immune function. There was a significant correlation between the level of general immune function and infection intensity, but not with survival, and changes in immune function with age correlated with the ability of individuals to resist parasite infection. Older individuals had better survival when challenged with a parasite than younger individuals, however they also had more intense infections and lower baseline immunocomptence. The ability of older individuals to have high infection intensities yet live longer, has potential consequences for parasite transmission. The results highlight the need to consider age in host-parasite studies and show the importance of choosing the correct measure when assaying invertebrate immunity. PMID- 24953462 TI - Health and health care in Australia at a crossroads. PMID- 24953459 TI - In acute experimental autoimmune encephalomyelitis, infiltrating macrophages are immune activated, whereas microglia remain immune suppressed. AB - Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) characterized by loss of myelin accompanied by infiltration of T-lymphocytes and monocytes. Although it has been shown that these infiltrates are important for the progression of MS, the role of microglia, the resident macrophages of the CNS, remains ambiguous. Therefore, we have compared the phenotypes of microglia and macrophages in a mouse model for MS, experimental autoimmune encephalomyelitis (EAE). In order to properly discriminate between these two cell types, microglia were defined as CD11b(pos) CD45(int) Ly-6C(neg) , and infiltrated macrophages as CD11b(pos) CD45(high) Ly-6C(pos) . During clinical EAE, microglia displayed a weakly immune-activated phenotype, based on the expression of MHCII, co-stimulatory molecules (CD80, CD86, and CD40) and proinflammatory genes [interleukin-1beta (IL-1beta) and tumour necrosis factor- alpha (TNF-alpha)]. In contrast, CD11b(pos) CD45(high) Ly-6C(pos) infiltrated macrophages were strongly activated and could be divided into two populations Ly 6C(int) and Ly-6C(high) , respectively. Ly-6C(high) macrophages contained less myelin than Ly-6C(int) macrophages and expression levels of the proinflammatory cytokines IL-1beta and TNF-alpha were higher in Ly-6C(int) macrophages. Together, our data show that during clinical EAE, microglia are only weakly activated whereas infiltrated macrophages are highly immune reactive. PMID- 24953467 TI - Women's health and empowerment in Yemen. PMID- 24953470 TI - Weight loss intervention for football fans - Authors' reply. PMID- 24953473 TI - Systems thinking for the post-2015 agenda. PMID- 24953468 TI - Weight loss intervention for football fans. PMID- 24953466 TI - Simon Stevens: visionary Chief Executive of NHS England. PMID- 24953469 TI - Hepatitis C: a new direction, but an old story? PMID- 24953475 TI - Adverse drug reaction: pomalidomide-induced liver injury. PMID- 24953474 TI - Nian: when Chinese mythology affects air pollution. PMID- 24953471 TI - Mortality from ruptured abdominal aortic aneurysms - Authors' reply. PMID- 24953472 TI - Mortality from ruptured abdominal aortic aneurysms. PMID- 24953476 TI - A coagulopathic dilemma: snakes or genes. PMID- 24953477 TI - Electrochemical dynamics of nanoscale metallic inclusions in dielectrics. AB - Nanoscale metal inclusions in or on solid-state dielectrics are an integral part of modern electrocatalysis, optoelectronics, capacitors, metamaterials and memory devices. The properties of these composite systems strongly depend on the size, dispersion of the inclusions and their chemical stability, and are usually considered constant. Here we demonstrate that nanoscale inclusions (for example, clusters) in dielectrics dynamically change their shape, size and position upon applied electric field. Through systematic in situ transmission electron microscopy studies, we show that fundamental electrochemical processes can lead to universally observed nucleation and growth of metal clusters, even for inert metals like platinum. The clusters exhibit diverse dynamic behaviours governed by kinetic factors including ion mobility and redox rates, leading to different filament growth modes and structures in memristive devices. These findings reveal the microscopic origin behind resistive switching, and also provide general guidance for the design of novel devices involving electronics and ionics. PMID- 24953478 TI - Highly efficient (In2Te3)x(GeTe)(3-3x) thermoelectric materials: a substitute for TAGS. AB - GeTe is a versatile base compound to produce highly efficient p-type thermoelectric materials such as the TAGS materials (AgSbTe2)1-x(GeTe)x and GeTe PbTe nanocomposites. The pure GeTe composition shows a very high power factor, ~42 MUW cm(-1) K(-2), between 673 K and 823 K, which is among the highest power factors that have ever been reported in this temperature range. However, its relatively high thermal conductivity limits the dimensionless figure of merit ZT to values of only unity. In this paper, we present an efficient approach to reduce the thermal conductivity by preparing (In2Te3)x(GeTe)(3-3x) solid solutions. In spite of a slight degradation of the electronic properties, the drastic reduction of the thermal conductivity due to a synergistic combination of reduced electronic thermal conductivity, strong alloy scattering, and vacancy phonon scattering leads to ZT values as high as 1.35 at 823 K for the x = 0.05 sample. Our results show that (In2Te3)x(GeTe)(3-3x) is a prospective substitute for TAGS as a p-leg element for high-temperature power generation. PMID- 24953479 TI - Gender differences in a cohort of major depressive patients: further evidence for the male depression syndrome hypothesis. AB - BACKGROUND: Previous studies have shown that major depressive patients may differ in several features according to gender, but the existence of a specific male depressive syndrome remains controversial. METHODS: As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 125 (27.7%) were of male gender, whereas 317 (72.3%) were female, after exclusion of bipolar I patients. RESULTS: Compared to women, men were more often married, had more associated mixed features, with more bipolar disorder NOS, more hyperthymic temperaments, and less depressive temperaments. Women had an earlier age at onset of depression, more depressive episodes and suicide attempts. A higher family loading was shown in men for bipolar disorder, alcohol use disorder, impulse control disorders and suicide, whereas their family loading for major depressive disorder was lower. Men displayed more comorbidities with alcohol use, impulse control, and cardiovascular disorders, with lower comorbidities with eating, anxiety and endocrine/metabolic disorders. The following independent variables were associated with male gender: hyperthymic temperament (+), alcohol use disorder (+), impulse control disorders (+), and depressive temperament (-). LIMITATIONS: The retrospective design and the lack of specific tools to assess the male depressive syndrome. CONCLUSION: Study findings may lend support to the male depression syndrome concept and draw attention to the role of hyperthymic temperament, soft bipolarity as well as comorbidities as determinants of this syndrome. The latter could help recognize an entity which is probably underdiagnosed, but conveys a high risk of suicide and cardiovascular morbidity. PMID- 24953481 TI - Do depression treatments reduce suicidal ideation? The effects of CBT, IPT, pharmacotherapy, and placebo on suicidality. AB - BACKGROUND: Many well-researched treatments for depression exist. However, there is not yet enough evidence on whether these therapies, designed for the treatment of depression, are also effective for reducing suicidal ideation. This research provides valuable information for researchers, clinicians, and suicide prevention policy makers. METHODS: Analysis was conducted on the Treatment for Depression Research Collaborative (TDCRP) sample, which included CBT, IPT, medication, and placebo treatment groups. Participants were included in the analysis if they reported suicidal ideation on the HRSD or BDI (score of >=1). RESULTS: Multivariate linear regression indicated that both IPT (b=.41, p<.05) and medication (b =.47, p<.05) yielded a significant reduction in suicide symptoms compared to placebo on the HRSD. Multivariate linear regression indicated that after adjustment for change in depression these treatment effects were no longer significant. Moderate Cohen's d effect sizes from baseline to post-test differences in suicide score by treatment group are reported. LIMITATIONS: These analyses were completed on a single suicide item from each of the measures. Moreover, the TDCRP excluded participants with moderate to severe suicidal ideation. CONCLUSIONS: This study demonstrates the specific effectiveness of IPT and medications in reducing suicidal ideation (relative to placebo), albeit largely as a consequence of their more general effects on depression. This adds to the growing body of evidence that depression treatments, specifically IPT and medication, can also reduce suicidal ideation and serves to further our understanding of the complex relationship between depression and suicide. PMID- 24953483 TI - A horse of a different color. PMID- 24953484 TI - Parents and primary care physicians have different views about copying medical letters to parents after paediatric outpatient visits. AB - AIM: We assessed how satisfied parents were when they received a copy of the letter sent to their primary care physician after their child attended a hospital outpatient clinic and compared their views with those of the primary care physician. METHODS: Anonymised questionnaires were sent to parents, and their primary care physician, after their child had visited a paediatric nephrology unit. RESULTS: We received responses from 112 parents (46%) and 69 primary care physicians (93%). Most parents (97%) were satisfied with the process, 94% thought that the letter was a true reflection of the outpatient consultation and easy to understand, and 55% read it to their child. However, 21% would have preferred a simpler letter. More than a third (37%) of the primary care physicians did not approve of the parents being sent the letter, and 30% felt that the letter was difficult for the parents to understand and should be replaced with a simpler letter. CONCLUSION: Most parents (97%) appreciated receiving a copy of the letter following their child's outpatient clinic visit, and 95% understood its contents. More than half (55%) read the letter to their child. However, 37% of primary care physicians did not approve of the practice. PMID- 24953480 TI - Prevalence and clinical correlates of co-occurring insomnia and hypersomnia symptoms in depression. AB - BACKGROUND: The aim was to examine the prevalence and consequences of co occurring insomnia and hypersomnia symptoms in depressed adults drawn from a representative sample of the U.S. population. METHOD: Data from 687 National Comorbidity Survey Replication (NCS-R) respondents meeting criteria for a major depressive episode (MDE) in the past year were included. Respondents completed clinical interviews that assessed 12-month DSM-IV disorders, impairment, mental health treatment, and depressive symptom severity. Outcomes were compared between respondents who experienced insomnia symptoms-only (N=404), hypersomnia symptoms only (N=44), both insomnia and hypersomnia symptoms (N=184) and no sleep problems (N=55) during an MDE. RESULTS: Insomnia and hypersomnia symptoms co-occurred in 27.7% of respondents with past-year MDEs, most frequently in bipolar spectrum disorders and major depressive disorder with dysthymia. Similar to the insomnia only group, respondents with co-occurring sleep disturbances had more severe depression, and higher rates of past-year impulse control disorders and suicide planning. Similar to the hypersomnia-only group, respondents with co-occurring sleep disturbances had higher rates of past-year drug use disorders and suicide attempts. Compared to the insomnia-only and no sleep problem groups, respondents with both sleep disturbances were more frequently in mental health treatment, seeing a general practitioner, and taking antidepressants. LIMITATIONS: The NCS-R is cross-sectional and did not evaluate sleep disorder diagnoses. CONCLUSIONS: Co occurring insomnia and hypersomnia symptoms were associated with a more severe MDE. Further research is warranted to more fully understand the joint presentation of insomnia and hypersomnia in depression. PMID- 24953482 TI - Relationship between sunlight and the age of onset of bipolar disorder: an international multisite study. AB - BACKGROUND: The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode. METHODS: Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations. RESULTS: There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduced by half if there was no family history. The maximum monthly increase in solar insolation occurred in springtime. The effect was one-third smaller for initial episodes of mania than depression. The largest maximum monthly increase in solar insolation occurred in northern latitudes such as Oslo, Norway, and warm and dry areas such as Los Angeles, California. LIMITATIONS: Recall bias for onset and family history data. CONCLUSIONS: A large springtime increase in sunlight may have an important influence on the onset of bipolar disorder, especially in those with a family history of mood disorders. PMID- 24953485 TI - Estimation of vegetation photosynthetic capacity from space-based measurements of chlorophyll fluorescence for terrestrial biosphere models. AB - Photosynthesis simulations by terrestrial biosphere models are usually based on the Farquhar's model, in which the maximum rate of carboxylation (Vcmax ) is a key control parameter of photosynthetic capacity. Even though Vcmax is known to vary substantially in space and time in response to environmental controls, it is typically parameterized in models with tabulated values associated to plant functional types. Remote sensing can be used to produce a spatially continuous and temporally resolved view on photosynthetic efficiency, but traditional vegetation observations based on spectral reflectance lack a direct link to plant photochemical processes. Alternatively, recent space-borne measurements of sun induced chlorophyll fluorescence (SIF) can offer an observational constraint on photosynthesis simulations. Here, we show that top-of-canopy SIF measurements from space are sensitive to Vcmax at the ecosystem level, and present an approach to invert Vcmax from SIF data. We use the Soil-Canopy Observation of Photosynthesis and Energy (SCOPE) balance model to derive empirical relationships between seasonal Vcmax and SIF which are used to solve the inverse problem. We evaluate our Vcmax estimation method at six agricultural flux tower sites in the midwestern US using spaced-based SIF retrievals. Our Vcmax estimates agree well with literature values for corn and soybean plants (average values of 37 and 101 MUmol m(-2) s(-1) , respectively) and show plausible seasonal patterns. The effect of the updated seasonally varying Vcmax parameterization on simulated gross primary productivity (GPP) is tested by comparing to simulations with fixed Vcmax values. Validation against flux tower observations demonstrate that simulations of GPP and light use efficiency improve significantly when our time resolved Vcmax estimates from SIF are used, with R(2) for GPP comparisons increasing from 0.85 to 0.93, and for light use efficiency from 0.44 to 0.83. Our results support the use of space-based SIF data as a proxy for photosynthetic capacity and suggest the potential for global, time-resolved estimates of Vcmax . PMID- 24953486 TI - Wash your hands after playing with that dragon! PMID- 24953489 TI - Anti-anxiety drugs use and cardiovascular outcomes in patients with myocardial infarction: a national wide assessment. AB - OBJECTIVE: Anti-anxiety medication in patients with anxiety may lessen the stress and thereby lower their risk for myocardial infarction (MI). The aim of current study is to examine an association between the use of anti-anxiety medication and long-term mortality risk in patients following MI. METHODS: A universal national health insurance (NHI) program has been implemented in Taiwan since 1995. We used system sampling database from 1997 to 2008 with a total of 1,000,000 subjects. We included subjects with first episode of MI and were above 30 years old. Sudden death, cardiovascular mortality, and heart failure hospitalization were assessed in all included subjects. Anti-anxiety as well as other medications and risk factors were obtained. Cox regression analysis was used to evaluate the adjusted hazard ratio (HR) for all patients and subgroups. RESULTS: The adjusted HRs of sudden death were significantly associated with increased benzodiazepam (BZD) dosage (HRs = 0.639, 1.003, 1.957 from Q2 to Q4 vs. Q1, p = .019 for trend) during approximately 4.8 years. For cardiac mortality and heart failure hospitalization, there was a J-curve dose-response relationship. The HRs for cardiac mortality were 0.255 (p < .001) and 0.385 (p < .001) for Q2 and Q3 vs. Q1, respectively. For patients receiving higher doses of daily BZDs (>5 mg), protective effects for cardiac mortality and heart failure hospitalization decreased and a J-curve dose-response relationship was seen. CONCLUSION: Anti anxiety medications are independent associated with a decreased risk of cardiac mortality and heart failure hospitalization in patients after a new MI. PMID- 24953490 TI - DJ-1 protein regulates CD3+ T cell migration via overexpression of CXCR4 receptor. AB - OBJECTIVE: DJ-1-a multifunctional protein responding to oxidative stress-is a possible regulator of the inflammatory response that plays an important role in atherosclerosis. Stromal cell-derived factor (SDF)-1 and its receptor, chemokine receptor type 4 (CXCR4), have been implicated in the recruitment of inflammatory cells during atherosclerosis. Here we investigated the hypothesis that DJ-1 protein might participate in CD3+ T cell functions in response to SDF-1 and contribute to the pathogenesis of atherosclerosis. METHODS AND RESULTS: SDF-1 stimulated migration in mouse CD3+ T cells in a dose-dependent manner. SDF-1 also elevated the phosphorylation level of extracellular-regulated kinase (ERK) 1/2 in CD3+ T cells. These SDF-1-induced responses were greater in CD3+ T cells from DJ 1 gene knockout (DJ-1(-/-)) mice than in those from wild type (DJ-1(+/+)) mice and were abolished by treatment with WZ811 and PD98059, inhibitors of CXCR4 and ERK1/2, respectively. Flow cytometry revealed that expression of the CXCR4 receptor was greater in CD3+ T cells from DJ-1(-/-) mice than in those from the controls. Moreover, expression of the CD3 protein was observed in the neointimal plaque from carotid artery-ligated mice and was stronger in DJ-1(-/-) mice compared with controls. The CD3+ T cell subsets, Th1 and Th17, showed increased production of interferon-gamma and interleukin-17 in DJ-1(-/-) compared with DJ 1(+/+) mice. CONCLUSION: DJ-1 protein is involved in the SDF-1-induced CD3+ T cell migration via overexpression of the CXCR4 receptor, and that DJ-1 acts as an inhibitory regulator in vascular remodeling such as neointima formation. PMID- 24953492 TI - Chlamydia pneumoniae negatively regulates ABCA1 expression via TLR2-Nuclear factor-kappa B and miR-33 pathways in THP-1 macrophage-derived foam cells. AB - OBJECTIVES: ATP-binding cassette transporter A1 (ABCA1) is critical in exporting cholesterol from macrophages and plays a protective role in the development of atherosclerosis. This study was to determine the effects and potential mechanisms of Chlamydia pneumoniae (C. pneumoniae) on ABCA1 expression and cellular cholesterol efflux in THP-1 macrophage-derived foam cells. METHODS AND RESULTS: C. pneumoniae significantly decreased the expression of ABCA1 and reduced cholesterol efflux. Furthermore, we found that C. pneumoniae suppressed ABCA1 expression via up-regulation of miR-33s. The inhibition of C. pneumoniae-induced NF-kappaB activation decreased miR-33s expression and enhanced ABCA1 expression. In addition, C. pneumoniae increased Toll-like receptor 2 (TLR2) expressions, inhibition of which by siRNA could also block NF-kappaB activation and miR-33s expression, and promot the expression of ABCA1. CONCLUSION: Taken together, these results reveal that C. pneumoniae may negatively regulate ABCA1 expression via TLR2-NF-kappaB and miR-33 pathways in THP-1 macrophage-derived foam cells, which may provide new insights for understanding the effects of C. pneumoniae on the pathogenesis of atherosclerosis. PMID- 24953497 TI - Redox and anion exchange chemistry of a stibine-nickel complex: writing the L, X, Z ligand alphabet with a single element. AB - According to the covalent bond classification (CBC) method, two-electron donors are defined as L-type ligands, one-electron donors as X-type ligands, and two electron acceptors as Z-type ligands. These three ligand functions are usually associated to the nature of the ligating atom, with phosphine, alkyl, and borane groups being prototypical examples of L-, X- and Z-ligands, respectively. A new SbNi platform is reported in which the ligating Sb atom can assume all three CBC ligand functions. Using both experimental and computational data, it is shown that PhICl2 oxidation of (o-(Ph2P)C6H4)3SbNi(PPh3) (1) into [(o (Ph2P)C6H4)3ClSb]NiCl (2) is accompanied by a conversion of the stibine L-type ligand of 1 into a stiboranyl X-type ligand in 2. Furthermore, the reaction of 2 with the catecholate dianion in the presence of cyclohexyl isocyanide results in the formation of [(o-(Ph2P)C6H4)3(o-O2C6H4Sb)]Ni(CNCy) (4), a complex featuring a nickel atom coordinated by a Lewis acidic, Z-type, stiborane ligand. PMID- 24953491 TI - Effects of single and fractionated low-dose irradiation on vascular endothelial cells. AB - OBJECTIVE: An increasing number of epidemiological studies suggest that chronic low-dose irradiation increases the risk of atherosclerosis. We evaluated and compared the in vitro biological effects of both single and fractionated low doses of X-ray irradiation on endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) were irradiated with X-rays, with single doses of 0.125, 0.25 and 0.5 Gy or fractionated doses of 2 * 0.125 Gy and 2 * 0.25 Gy, with 24 h interfraction interval. Survival, apoptosis, reactive oxygen species (ROS) production, nuclear factor-kappaB (NF-kappaB) activation, intercellular adhesion molecule-1 (ICAM-1) expression, HUVEC adhesiveness and DNA damage were investigated. RESULTS: We did not observe any effect on viability and apoptosis. Both single and fractionated doses induced ROS generation, NF-kappaB activation, ICAM-1 protein expression and HUVEC adhesiveness, but only fractionated doses increase significantly ICAM-1 mRNA. The effects measured after fractionated dose result always higher than those induced by the single dose. Moreover, we observed that DNA double strand break (DSB), visualized with gamma-H2AX foci, is dose dependent and that the kinetics of gamma-H2AX foci is not affected by fractionated doses. CONCLUSIONS: We showed that single and fractionated low-dose irradiations with low energy X-rays do not affect cell viability and DNA repair. Interestingly, the greater increase of ICAM-1 surface exposure and endothelial adhesiveness observed after fractionated irradiation, suggests that fractionated low-doses may accelerate chronic vascular inflammation, from which the atherosclerotic process can arise. PMID- 24953487 TI - Prognosis and disease progression in patients under 50 years old undergoing PCI: the CRAGS (Coronary aRtery diseAse in younG adultS) study. AB - OBJECTIVE: Young patients undergoing percutaneous coronary intervention (PCI) are generally considered at low procedural risk, but the potentially aggressive nature of coronary artery disease and long expectancy of life expose them to a high risk of recurrent coronary events. The extent and determinants of disease progression in this patient subset remain largely unknown. The aim of the present study was to evaluate general risk factors for late outcomes among patients <=50 years old who underwent PCI. METHODS: Coronary aRtery diseAse in younG adults (CRAGS) is a multicenter European retrospective registry that enrolled 1617 patients (age <=50 years) who underwent PCI over the years 2002-2012. The median follow-up was 3.0 years. RESULTS: The majority of patients were smokers who were nevertheless prescribed adequate secondary prevention medication, including statins, aspirin, beta blockers and/or ACE inhibitors/AT blockers. At 5 years, survival was 97.8%, while freedom from major adverse cardiac and cerebrovascular events was 74.1%, from repeat revascularization 77.8% and from myocardial infarction 89.9%. Altogether 13.5% of patients exhibited disease progression that indicated a need for repeat revascularization. Other indications for repeat revascularization were restenosis (7.1%) and stent thrombosis (2.1%) at the 5 year follow-up. Independent post-PCI predictors of disease progression were multivessel disease, diabetes and hypertension. CONCLUSION: PCI is associated with excellent survival in patients <=50 years old. Nevertheless, despite guideline-adherent medication, every eighth patient underwent repeat revascularization due to disease progression diagnosed at the median follow-up of three years, underscoring the need for more effective secondary prevention than currently available. PMID- 24953488 TI - Heritability of cardiovascular risk factors in a Chinese population--Taichung Community Health Study and Family Cohort. AB - BACKGROUND AND AIM: Previous studies reporting on estimates of heritability of cardiovascular risk factors in Chinese are limited. This study aims to estimate the heritability of cardiovascular risk factors in relatives of residents who participated in the Taichung Community Health Study (TCHS) and Family Cohort (TCHS-FC) while controlling as many potential confounders as possible. METHODS: A total of 1564 study subjects from 494 families with members aged 12-91 years were enrolled from a random sample of participants of TCHS and their family members (TCHS-FC) from 2009 to 2012. Anthropometric measurement, body composition, blood pressure, plasma lipids, fasting glucose, insulin, highly sensitive C-reactive protein (hs-CRP), brachial-ankle pulse wave velocity (baPWV), and the ankle brachial index (ABI), as well as a questionnaire interview, were obtained from each participant. RESULTS: Cardiovascular risk factors with estimates of heritability greater than 30% after multivariate adjustment were triglyceride (h(2) = 0.41), HDL-C (h(2) = 0.49), LDL-C (h(2) = 0.47), total cholesterol (h(2) = 0.46), hip circumference (h(2) = 0.44), weight (h(2) = 0.42), insulin (h(2) = 0.39), hs-CRP (h(2) = 0.38), BMI (h(2) = 0.38), and percent body fat mass (h(2) = 0.35). Correlation coefficients for significant sibling varied from 0.10 for weight to 0.47 for LDL-C whereas those for significant parent-offspring varied from 0.09 for fasting plasma glucose to 0.43 for baPWV. CONCLUSIONS: This study demonstrated significant heritability and familial aggregation of cardiovascular risk factors in a random sample of ethnic Chinese population. PMID- 24953498 TI - Professional problems: the burden of producing the "global" Filipino nurse. AB - This paper investigates the challenges faced by nursing schools within migrant sending nations, where teachers and school administrators face the task of producing nurse labor, not only for domestic health needs but employers beyond national borders. I situate my research in the Philippines, one of the leading sources of migrant nurse labor in the world. Based on 58 interviews with nursing school instructors and administrators, conducted from 2010 to 2013, I argue that Philippine nursing schools are embedded within a global nursing care chain, where nations lower down the chain must supply nurse labor to wealthier countries higher up the chain. This paper shows how this process forces Filipino nurse educators to negotiate an overloaded curriculum, the influx of aspiring migrants into nursing programs, and erratic labor demand cycles overseas. These issues create problems in defining the professional knowledge needed by Filipino nurses; instilling professional values and standards; and maintaining proper job security. As such, these findings demonstrate how countries like the Philippines bear the burden of ensuring nurses' employability, where educational institutions constantly adjust curriculum and instruction for the benefit of employers within wealthier societies. My interviews reveal how such adjustments undermine the professional values and standards that define the nursing profession within the country. Such inequality is an outcome of nurse migration that current research has not fully explored. PMID- 24953493 TI - Vulnerable plaques in the contralateral carotid arteries in symptomatic patients: a detailed ultrasound analysis. AB - BACKGROUND AND AIM: Carotid plaques may represent a generalized atherosclerotic syndrome or a localized disease. The aim of this study was to assess the morphological and textural features of carotid plaques located contralateral to the symptomatic side and compare them with the symptomatic side and with plaques from asymptomatic patients. METHODS: We studied 66 arteries in 39 patients (mean age 70 +/- 7 year, 33% females). Arterial plaques were classified as either symptomatic (n = 30), contralateral to symptomatic (n = 25) or asymptomatic (n = 11). We compared several plaque features between these groups including the mean values of the grey scale median (GSM), entropy, juxtaluminal black area (JBA) without visible echogenic cap, GSM of the JBA and surface irregularity. RESULTS: The plaques contralateral to symptomatic arteries had similar morphological and textural features to those in the symptomatic arteries. In contrast, they had more vulnerable morphological and textural features than those in asymptomatic arteries: less smooth plaques (12% vs. 55%) and instead more often mildly irregular (60% vs 36%) or markedly irregular (28% vs. 9%; p = 0.03), lower GSM (26.2 +/- 8 vs. 49.4 +/- 14, p < 0.001) and lower GSM of the JBA (5.0 +/- 3.6 vs. 11.4 +/- 2.1, p = 0.008). The frequency of entropy and plaque calcification was similar in all groups. CONCLUSION: Symptomatic patients with carotid artery disease seem to have similar morphological and textural features of vulnerability in the symptomatic and the contralateral carotid arteries, which are profound compared with asymptomatic carotid arteries. These findings support the concept of generalized carotid atherosclerotic pathology rather than incidental unilateral disease, and also emphasize a need for aggressive measures for plaque stabilization, particularly in symptomatic patients. PMID- 24953494 TI - Difference of ruptured plaque morphology between asymptomatic coronary artery disease and non-ST elevation acute coronary syndrome patients: an optical coherence tomography study. AB - BACKGROUND: Autopsy studies have reported that rupture of a thin-cap fibroatheroma and subsequent thrombus formation is the major mechanism leading to acute coronary syndrome (ACS). However, it is not clear why only some plaque ruptures lead to ACS. Optical coherence tomography (OCT) is a high-resolution imaging modality which is capable of investigating detailed coronary plaque morphology in vivo. The objective of this study was to determine whether ruptured plaque morphology assessed by OCT differs between asymptomatic coronary artery disease (CAD) and non-ST elevation acute coronary syndrome (NSTEACS). METHODS: We examined ruptured plaque morphology using OCT in 80 patients, 33 with asymptomatic CAD and 47 with NSTEACS. RESULTS: The frequency of lipid-rich plaque and intracoronary thrombus was significantly lower in asymptomatic CAD than in NSTEACS (61% vs. 85%, p = 0.013 and 9% vs. 83%, p < 0.001, respectively). Although maximal ruptured cavity cross-sectional area (CSA) was similar in both groups, lumen area at the rupture site and minimal lumen area were significantly larger in asymptomatic CAD than in NSTEACS (3.78 +/- 1.50 mm(2) vs. 2.70 +/- 1.55 mm(2), p = 0.003 and 2.75 +/- 0.99 mm(2) vs. 1.72 +/- 0.90 mm(2), p < 0.001, respectively). CONCLUSIONS: OCT revealed that the morphology of ruptured plaques differs between asymptomatic CAD and NSTEACS in terms of lumen area and the frequency of lipid-rich plaques and thrombi. These morphological features may be associated with the clinical presentation of CAD. PMID- 24953504 TI - Plasmodium falciparum and Plasmodium vivax specific lactate dehydrogenase: genetic polymorphism study from Indian isolates. AB - Control and eradication of malaria is hindered by the acquisition of drug resistance by Plasmodium species. This has necessitated a persistent search for novel drugs and more efficient targets. Plasmodium species specific lactate dehydrogenase is one of the potential therapeutic and diagnostic targets, because of its indispensable role in endoerythrocytic stage of the parasite. A target molecule that is highly conserved in the parasite population can be more effectively used in diagnostics and therapeutics, hence, in the present study polymorphism in PfLDH (Plasmodiumfalciparum specific LDH) and PvLDH (Plasmodiumvivax specific LDH) genes was analyzed using PCR-single strand confirmation polymorphism (PCR-SSCP) and sequencing. Forty-six P. falciparum and thirty-five P. vivax samples were screened from different states of India. Our findings have revealed presence of a single PfLDH genotype and six PvLDH genotypes among the studied samples. Interestingly, along with synonymous substitutions, nonsynonymous substitutions were reported to be present for the first time in the PvLDH genotypes. Further, through amino acid sequence alignment and homology modeling studies we observed that the catalytic residues were conserved in all PvLDH genotypes and the nonsynonymous substitutions have not altered the enzyme structure significantly. Evolutionary genetics studies have confirmed that PfLDH and PvLDH loci are under strong purifying selection. Phylogenetic analysis of the pLDH gene sequences revealed that P. falciparum compared to P. vivax, has recent origin. The study therefore supports PfLDH and PvLDH as suitable therapeutic and diagnostic targets as well as phylogenetic markers to understand the genealogy of malaria species. PMID- 24953500 TI - Determinants of the variations in self-reported health status among recent and more established immigrants in Canada. AB - Studies have shown that immigrants are normally in better health on arrival compared to their Canadian-born counterparts. However, the health conditions of new immigrants deteriorate after a few years of their arrival in Canada. This phenomenon is popularly termed the "healthy immigrant effect" (HIE) in the immigrant health literature. Although different hypotheses have been proposed to understand HIE, the causes are subject to ongoing discussion. Unlike previous studies, this study explored the possible causes behind the variations in the health status of recent and more established immigrants comparing 2001 and 2010 Canadian Community Health Surveys (CCHS). Four different hypotheses - namely lifestyle change, barriers to health care services, poor social determinants of health, and work related stress - were tested to understand variations in health status. The study concludes that there is a statistically significant difference in the socioeconomic characteristics and health outcomes of immigrants having less than and more than 10 years of residency in Canada. Logistic regression models show that the health conditions of immigrants are associated with age, sex, ethnic origin, smoking habit, Body Mass Index (BMI), total household income, number of consultations made with a family doctor per year and work related stress. PMID- 24953495 TI - Quantification of levornidazole and its metabolites in human plasma and urine by ultra-performance liquid chromatography-mass spectrometry. AB - We developed and validated an ultra-performance liquid chromatographic (UPLC) method coupled with atmospheric pressure chemical ionization (APCI) mass spectrometry for simultaneous determination of levornidazole and its first-pass metabolites, l-chloro-3-(2-hydroxymethyl-5-nitro-l-imidazolyl)-2-propanol (Ml), 2 methyl-5-nitroimidazole (M2) and 3-(2-methyl-5-nitro-1-imidazolyl)-1,2 propanediol (M4), in human plasma and urine. The biological samples were pretreated by protein precipitation and liquid-liquid extraction and analyzed using an ACQUITY UPLC CSH C18 column (2.1*50 mm, 1.7 MUm) and a QTRAP mass spectrometer in multiple reaction monitoring mode via APCI. Acetonitrile and 0.1% formic acid in water was used as the mobile phase in gradient elution at a flow rate of 0.6 mL/min. The lower limit of quantification of this method was 0.0100, 0.00500, 0.0200 and 0.00250 MUg/mL for levornidazole, M1, M2 and M4, respectively. The linear calibration curves were obtained for levornidazole, M1, M2, and M4 over the range of 0.0100-5.00, 0.00500-2.50, 0.0200-10.0 and 0.00250 1.25 MUg/mL, respectively. The intra- and inter-batch precision was less than 12.2% in plasma and less than 10.8% in urine. The intra- and inter-batch accuracy was 87.8-105.7% in plasma and 92.8-109.2% in urine. The mean recovery of levornidazole, M1, M2 and M4 was 91.1-105.1%, 95.8-103.8%, 87.8-96.8%, 96.8 100.6% from plasma and 96.0-100.9%, 96.9-107.9%, 95.1-102.7%, 103.7-105.9% from urine respectively. This method was validated under various conditions, including room temperature, freeze-thaw cycles, long-term storage at -40 +/- 5 degrees C, after pretreatment in the autosampler (at 10 degrees C), and 10- and 100-fold dilution. This newly established analytical method was successfully applied in a pharmacokinetic study following single intravenous infusion of levornidazole in 24 healthy Chinese subjects. PMID- 24953501 TI - CD19 differentially regulates BCR signalling through the recruitment of PI3K. AB - CD19 is a co-stimulatory surface protein expressed exclusively on B cells and serves to reduce the threshold for signalling via the B-cell receptor (BCR). Co ligation of CD19 with the BCR synergistically enhances mitogen-activated protein (MAP) kinase activity, calcium release and proliferation. We recently found that these parameters were also enhanced in CD19-null primary murine B cells following BCR ligation, suggesting a regulatory role for CD19 in BCR signalling. In this study, we demonstrate that the enhanced BCR signalling in the absence of CD19 was not dependent on the src kinase Lyn, but linked to phosphoinositide 3-kinase (PI3K) activity. Consistent with this, we detect PI3K associated with CD19 outside the lipid raft in resting B cells. Pre-ligation of CD19 to restrict its translocation with the BCR into lipid rafts attenuated BCR-induced PI3K and MAP kinase activation and subsequent B-cell proliferation. Thus, we propose that CD19 can modulate BCR signalling in both a positive and negative manner depending on the receptor/ligand interaction in vivo. PMID- 24953509 TI - [Resisting behind the computer]. PMID- 24953499 TI - Racial and ethnic stratification in the relationship between homeownership and self-rated health. AB - Social scientists have long demonstrated that socioeconomic resources benefit health. More recently, scholars have begun to examine the potential stratification in the health returns different groups receive for a given resource. Motivated by fundamental cause theory, this paper examines homeownership as a salient health resource with potentially stratified benefits. Homeowners have significantly greater housing quality, wealth, neighborhood quality and integration, and physical and mental health than renters. However, there are compelling theoretical reasons to expect the health advantage of homeownership to be unequally distributed across racial and ethnic groups. Regression analyses of 71,874 household heads in the United States from the 2012 March Current Population Survey initially suggest all homeowners experience a significant health advantage. Further examination finds robust evidence for a homeowner health advantage among Whites, on par with the difference between the married and divorced. The advantage among minority households is considerably smaller, and not significant among Latinos or Asians. Conditioning on a broad array of observable characteristics, White homeowners emerge as exceptionally healthy compared to White renters and all minority groups. This leads to the unexpected finding that racial/ethnic differences in health are concentrated among homeowners. The findings demonstrate the interactive nature of racial/ethnic stratification in health through both access to and returns from socioeconomic resources. PMID- 24953503 TI - Skeletal complications in congenital insensitivity to pain with anhidrosis: a case series of 14 patients and review of articles published in Japanese. AB - BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disorder with various skeletal complications; thus, a compilation of data on affected patients could provide a valuable resource for the management of this disease. The aim of this study was to ascertain and report the frequency, location, age of onset, cause, and management of skeletal complications in Japanese patients with CIPA. METHODS: The medical records of 14 CIPA patients in our institute and information on 77 patients reported in Japanese articles were analyzed. Data regarding skeletal-system complications, including location, symptom, major cause and management of fractures, joint dislocations, infections, and Charcot joints, were extracted. RESULTS: Fractures occurred in 59/91 patients (65%), 91% of them in the lower limbs. Joint dislocations occurred in 27/91 patients (30%), 91% of them in the hip joint. Bone and joint infections occurred in 22 patients (24%) and Charcot joints in 26 patients (29%); 62% of infections and 87% of Charcot joints developed in the lower limbs. Most fractures occurred from 1 to 7 years of age; there was no apparent relationship between age and other complications. The major known causes of bone disorders were minor trauma such as short falls; however, most were of unknown cause. Conservative therapy was used more frequently than surgery to manage fractures, dislocations, and Charcot joints. CONCLUSIONS: These data show that most CIPA patients have skeletal complications, most of which occur in the lower limbs. Fractures are frequent between 1 and 7 years of age, whereas other bone disorders have no apparent age relationship. The major known causes of bone disorders were minor trauma such as short falls. Conservative therapy was more frequently used to manage fractures, dislocations, and Charcot joints. PMID- 24953507 TI - Recent insights into host-pathogen interaction in white spot syndrome virus infected penaeid shrimp. AB - Viral disease outbreaks are a major concern impeding the development of the shrimp aquaculture industry. The viral disease due to white spot syndrome virus (WSSV) observed in early 1990s still continues unabated affecting the shrimp farms and cause huge economic loss to the shrimp aquaculture industry. In the absence of effective therapeutics to control WSSV, it is important to understand viral pathogenesis and shrimp response to WSSV at the molecular level. Identification and molecular characterization of WSSV proteins and receptors may facilitate in designing and development of novel therapeutics and antiviral drugs that may inhibit viral replication. Investigations into host-pathogen interactions might give new insights to viral infectivity, tissue tropism and defence mechanism elicited in response to WSSV infection. However, due to the limited information on WSSV gene function and host immune response, the signalling pathways which are associated in shrimp pathogen interaction have also not been elucidated completely. In the present review, the focus is on those shrimp proteins and receptors that are potentially involved in virus infection or in the defence mechanism against WSSV. In addition, the major signalling pathways involved in the innate immune response and the role of apoptosis in host-pathogen interaction is discussed. PMID- 24953496 TI - Development and validation of a SNP-based assay for inferring the genetic ancestry of rhesus macaques (Macaca mulatta). AB - Rhesus macaques (Macaca mulatta) are an important primate model species in several areas of biomedical research. The wide geographic distribution of this species has led to significant genetic differentiation among local and regional populations. These regional differences can be important factors in the selection of the most appropriate subjects for particular research studies, as animals from different populations can respond differently to the same experimental treatment. Consequently, it is valuable to confirm the ancestry of individual rhesus monkeys from geographically distinct populations. Using DNA samples obtained from rhesus macaques from six National Primate Research Centers, we tested a set of 384 potential ancestry informative single nucleotide polymorphisms (SNPs) and identified a final panel of 91 SNPs that can reliably distinguish Indian-origin from Chinese-origin rhesus monkeys. This genetic test can be used to determine the ancestral origin of animals and to detect individuals that are hybrids between these two regional populations. To demonstrate use of the SNP panel, we investigated the ancestry of 480 animals from the Yerkes NPRC (YNPRC) for which the colony records were insufficient to clearly establish ancestry. Three of the YNPRC animals tested were determined to be hybrids. This SNP ancestry tool will be useful to researchers, colony managers, and others who wish to evaluate the ancestral origin of individual rhesus macaques, and therefore will facilitate more effective and efficient use of these animals in biomedical research. PMID- 24953508 TI - Axing the cancer loop. PMID- 24953506 TI - Increased diversity of zoonotic pathogens and Borrelia burgdorferi strains in established versus incipient Ixodes scapularis populations across the Midwestern United States. AB - The center of origin theory predicts that genetic diversity will be greatest near a specie's geographic origin because of the length of time for evolution. By corollary, diversity will decrease with distance from the origin; furthermore, invasion and colonization are frequently associated with founder effects that reduce genetic variation in incipient populations. The blacklegged tick, Ixodes scapularis, harbors a suite of zoonotic pathogens, and the geographic range of the tick is expanding in the upper Midwestern United States. Therefore, we posited that diversity of I. scapularis-borne pathogens across its Midwestern range should correlate with the rate of the range expansion of this tick as well as subsequent disease emergence. Analysis of 1565 adult I. scapularis ticks from 13 sites across five Midwestern states revealed that tick infection prevalence with multiple microbial agents (Borrelia burgdorferi, Borrelia miyamotoi, Babesia odocoilei, Babesia microti, and Anaplasma phagocytophilum), coinfections, and molecular genetic diversity of B. burgdorferi all were positively correlated with the duration of establishment of tick populations, and therefore generally support the center of origin - pathogen diversity hypothesis. The observed differences across the gradient of establishment, however, were not strong and were nuanced by the high frequency of coinfections in tick populations at both established and recently-invaded tick populations. These results suggest that the invasion of ticks and their associated pathogens likely involve multiple means of pathogen introduction, rather than the conventionally presented scenario whereby infected, invading ticks are solely responsible for introducing pathogens to naive host populations. PMID- 24953512 TI - [Functional MRI for schizophrenia: importance of the type of task being scanned]. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) is an important technique for detecting neural network problems in patients with schizophrenia. Very often, however, the professionals involved are insufficiently aware of the fact that when fMRI scans are used for patients with schizophrenia, it is the type of task that patients are performing or failing to perform which is of vital importance for the correct interpretation of the results. AIM: To demonstrate that in scans of patients with schizophrenia the choice of task can influence neuroimaging results, particularly when the neural problems under study are performance-related. METHOD: We begin by presenting a brief history of functional neuroimaging techniques. This provides a context for the study of the potential role of fMRI in detecting dysfunctional brain networks in schizophrenia. In this way we demonstrate more clearly why the rapidly developing scanning techniques and analysis methods are becoming more and more important for measuring specific differences between psychiatric disorders. Then, we discuss the complex relationship between cognitive deficits in patients with schizophrenia, problems in task performance, and disease-related effects on brain activation measured by fMRI. RESULTS: This is illustrated by our own recent work, in which we demonstrate the complex relationship between cognitive deficits in the task performance of patients with schizophrenia and differences in brain activity measured with fMRI. We stress the importance of task-independent neural networks for the interpretation of results. These networks may play a role similar to that of the potentially confounding effects of task choice. Finally, we consider challenges for the future and comment on how fMRI needs to be developed so that it can be used successfully in clinical practice in order to assist with the diagnosis, prognosis and treatment of schizophrenia. CONCLUSION: It is crucial for neuroimaging research into schizophrenia, and for potential clinical applications, that new types of tasks are developed that avoid the confounding effects on neural activity which are caused by performance differences stemming from aspecific factors such as demotivation or task-disengagement. PMID- 24953505 TI - Complete genome sequence of a natural reassortant H9N2 avian influenza virus found in bean goose (Anser fabalis): direct evidence for virus exchange between Korea and China via wild birds. AB - In 2011, we isolated a natural recombinant H9N2 avian influenza virus from fecal droppings of bean goose (Anser fabalis) in Korea. Phylogenetic analyses showed that the A/bean goose/Korea/220/2011(H9N2) isolate is a reassortant of Eurasian and North American lineages of avian influenza virus. In addition, the complete genome sequence, including all 8 gene segments, was associated with Chinese H9N2 viruses isolated from wild birds in the Hunan East Dongting Lake National Nature Reserve. These data provide direct evidence for the exchange of avian influenza viruses between Korea and China via wild birds. PMID- 24953513 TI - [Contribution to quality of care or caught in a digital labyrinth? Experience with electronic records of patients receiving long-term mental health care]. AB - BACKGROUND: In recent years electronic health records (EHRs) have been introduced on a large scale into mental health care. EHRs have a great number of advantages, one of the main ones being readability. However, very little attention seems to have been paid to the potential disadvantages and risks associated with EHRs. AIM: To point to some of the disadvantages and risks of EHRs, in their present form, particularly in relation to the care of patients with severe mental illness (SMI). METHOD: On the basis of clinical experience and relevant literature, we discuss some of the disadvantages and risks associated with EHRs in their current form. RESULTS: In long-term, multidisciplinary and complex treatments of patients with SMI, EHRs in their current form fail to provide the psychiatrist with an adequate overview of the treatment process. This is largely due to the way they are designed: an ever-increasing quantity of information about complex treatment stored in separate files that can only be accessed individually and that contain free text. In mental health care the introduction of new technology, unlike the introduction of new drugs, seems to occur without structured surveillance of the disadvantages and risks involved. CONCLUSION: EHRs need to be re-designed at the earliest opportunity. PMID- 24953515 TI - [Modern antidepressants and hallucinations]. AB - BACKGROUND: A case-vignette illustrates that hallucinations can be an unusual, but potentially serious side-effect of modern antidepressants. AIM: To examine the frequency with which these hallucinations occur and to describe adequate clinical treatment. METHOD: Information was obtained by searching literature and the database of the Netherlands Pharmacovigilance Centre Lareb. RESULTS: The literature reported only a few case-vignettes about hallucinations associated with treatment with sertraline. The search of the Lareb database revealed that hallucinations can occur in any age-group and with any modern antidepressant. CONCLUSION: Age, the use of co-medication, inherent neurodegenerative or psychiatric disorders are possible risk factors. When patients develop hallucinations, good clinical practise seems to be withdrawal of the prescribed antidepressant. If necessary, a different antidepressant can be tried. PMID- 24953502 TI - Anterior coverage after eccentric rotational acetabular osteotomy for the treatment of developmental dysplasia of the hip. AB - BACKGROUND: In periacetabular osteotomy for the treatment of developmental dysplasia of the hip, impairments in ADL due to limitations in hip flexion can occur when anterior displacement is added to lateral displacement in order to obtain sufficient femoral head coverage. This study was conducted to determine, by the range of motion (ROM) simulation based on CT images, the minimum angle of hip flexion and internal rotation at 90 degrees of flexion that is necessary to avoid ADL impairments after eccentric rotational acetabular osteotomy (ERAO) and to estimate the angles of anterior femoral head coverage on plain radiography that enable the above flexion. METHODS: Of 47 hips treated with ERAO at our hospital from December 2007 to May 2012, 27 hips without progressive osteoarthritis which could be CT scanned were examined and included. The mean age at the time of surgery was 40.7 years (SD 1.8). The postoperative follow-up period was 30.2 months (SD 3.6). Two hips were in male patients and 25 hips were in female patients. The disease stage prior to surgery was pre-osteoarthritis in 5 hips, early in 11 hips, and progressive in 11 hips. We checked whether the patients were capable of activities that require deep hip flexion for the evaluation of postoperative ADL. Radiographic examination was performed before and one year after surgery to calculate LCE angle, Sharp angle, AHI, and VCA angle. The angle at which impingement of the displaced fragment of the bone and the femur appeared was measured using 3D CAD software, and the relationship between this angle and the physical findings, ADL impairment, or radiographic findings, were also examined. RESULTS: 22 out of 27 hips that were capable of 116 degrees or more of flexion or 42 degrees or more of internal rotation at 90 degrees of flexion in ROM simulation showed the absence of ADL impairment and a postoperative VCA angle <=42 degrees , whereas 5 hips with 110 degrees or less of flexion or 40 degrees or less of internal rotation at 90 degrees of flexion in ROM simulation had ADL impairments associated with limitations in hip flexion and a postoperative VCA angle >=46 degrees . CONCLUSIONS: Anterior and lateral coverage requires a postoperative VCA angle of >=20 degrees to achieve anterior structural stability and an LCE angle of >25 degrees to obtain adequate superior lateral coverage of the femoral head. A VCA angle <=42 degrees is required to avoid impingement during deep flexion. A VCA angle >=46 degrees is a probable risk factor for pincer FAI syndrome after ERAO. PMID- 24953510 TI - [The stigmatising of schizophrenia and autism in the Flemish daily papers]. AB - BACKGROUND: A considerable social stigma is attached to many types of psychiatric disorders. However, research also shows that there are differences in the degree of social stigma attached to psychiatric disorders. There is evidence that the portrayal of schizophrenia in the media is particularly negative. AIM: To compare the degree of stigma in reporting of autism and schizophrenia in the Flemish daily newspapers. METHOD: Via the websites of the seven Flemish daily newspapers, we searched for all articles published between 2008 and 2012 containing the keywords autism/autist(ic) and schizophrenia/schizophrenic. The collected articles (n = 4,181) were then graded to their stigmatising content. RESULTS: In the collected articles the coverage of autism was mostly positive, whereas the coverage of schizophrenia was predominantly negative. The contrast between the reporting on autism and on schizophrenia was very substantial (p < 0.0001) and the negative coverage of both disorders increased over time. CONCLUSION: The social stigma attached to schizophrenia is poignantly reflected in the Flemish newspapers. The fact that a disorder such as autism, which has many features in common with schizophrenia, is depicted in a much more favourable way than schizophrenia indicates that a more positive image of schizophrenia is not only desirable but also achievable. PMID- 24953511 TI - [Does routine outcome monitoring have a promising future? An investigation into the use of shared decision-making combined with ROM for patients with a combination of physical and psychiatric symptoms]. AB - BACKGROUND: Although routine outcome monitoring (ROM) has been developed and widely used in the course of patient centered outcome research in the Netherlands, so far the technique has hardly ever been used to improve the treatment of individual patients. AIM: To describe how a rom technique based on the principles of shared decision-making (SDM) was developed and evaluated at the Center for Body, Mind and Health at GGz Breburg, a specialised mental health institution in the Netherlands. METHOD: We have developed a conceptual model for SDM that involves patient participation and the use of evidence-based decision aids with cut-off scores. RESULTS: According to the conceptual model for SDM that we developed, the patient and the health professional involved took 'shared' decisions in three phases; the decisions related to triage, the drawing-up of a treatment plan and a follow-up treatment course. At the end of the 6 month intake phase 7 of the 67 patients who were deemed eligible for ROM/SDM were dropped from the study because they were incapable of performing ROM assessments. Due to diagnostic advice and referral at the end of the intake-phase, 25 patients did not require further treatment. Of the remaining 35 patients, 33 delivered at least one follow-up ROM assessment during the subsequent treatment phases. In these patients somatic and psychiatric symptoms were found to be significantly reduced. CONCLUSION: ROM combined with sdm can be used successfully with patients who have a combination of physical and psychiatric symptoms and the technique can be applied by the professional in charge. Very few patients dropped out of the follow-up measurements and somatic as well as depressive or psychiatric symptoms diminished significantly. These findings indicate that a Randomised Clinical Trial is warranted in order to test the effectiveness of sdm combined with ROM as a decision-making instrument. PMID- 24953514 TI - [Minocycline for schizophrenia: a brief overview]. AB - BACKGROUND: The tetracyclic antibiotic minocycline appears to have positive results when added to the the treatment prescribed for persistent symptoms of schizophrenia. AIM: To provide an overview of the literature on minocycline and schizophrenia. METHOD: PubMed, up to September 2013, was scanned for articles relating to minocycline and schizophrenia. RESULTS: We found seven case reports with regard to the use of minocycline as an additive in the treatment of persistent schizophrenia. Furthermore, an open-label study and two randomised placebo-controlled studies regarding this addition were published. Using minocycline may add to the improvement of negative symptoms and cognition in patients with schizophrenia. CONCLUSION: It is concluded, albeit somewhat cautiously, that minocycline may be helpful in treating negative and cognitive symptoms in schizophrenia. PMID- 24953517 TI - Haematological and genotoxic responses in an urban adapter, the banana bat, foraging at wastewater treatment works. AB - Wastewater Treatment Works (WWTWs) are a ubiquitous feature of the urban landscape. The Banana Bat, Neoromicia nana specifically exploits the high abundance of chironomid midge prey available at WWTWs but these populations also have higher levels of non-essential metals (Cd, Cr and Ni) in their tissues than bats foraging at unpolluted sites. Pollutant exposure may elicit primary physiological responses such as DNA damage and haematological changes. We investigated whether pollutant exposure from foraging at WWTWs impacts haematological and genotoxic parameters in N. nana. We compared four measures of haematological/genotoxic damage between N. nana foraging at three WWTWs and two unpolluted sites located in KwaZulu-Natal, South Africa: DNA damage measured by the Comet assay, total antioxidant capacity as indicated by the FRAP assay, chromosomal aberration indicated by micronuclei formation and blood oxygen capacity based on haematocrits. There was significantly higher DNA damage in N. nana at WWTWs than in bats from unpolluted sites, suggesting inadequate repair to double stranded DNA breaks. In addition, WWTW bats had a significantly lower antioxidant capacity than bats from unpolluted sites. This suggests that bats at WWTWs may have a diminished capacity to cope with the excess reactive oxidative species (ROS) produced from pollutants such as metals. There was no increase in micronucleus frequency in WWTW bats, indicating that cellular functioning has not yet been disrupted by chemical exposure. Haematocrits, however, were significantly higher in WWTW bats, possibly due to erythrocyte production in response to certain pollutants. Thus, effects of pollutant exposure in bats foraging at WWTWs elicit sub-lethal haematological and genotoxic responses which may pose serious long-term risks. This provides evidence that WWTWs, that are aimed to remove pollutants from the environment, can themselves act as a source of contamination and pose a threat to animals exploiting these habitats. PMID- 24953516 TI - New reliability criteria for transient elastography increase the number of accurate measurements for screening of cirrhosis and portal hypertension. AB - BACKGROUND & AIMS: Transient elastography (TE) can non-invasively diagnose cirrhosis and portal hypertension (PHT). New TE reliability criteria suggest classifying measurements as very reliable (IQR/M < 0.1), reliable (IQR<0.3 or >0.3, if TE < 7.1 kPa) and poorly reliable (IQR/M > 0.3, if TE > 7.1 kPa). Compare traditional (reliable: success rate >60% + IQR/M <= 0.30) and new TE quality criteria (accurate: very reliable + reliable) regarding their diagnostic accuracy for cirrhosis and PHT and to identify potential confounders (age, aetiology, necroinflammatory activity, steatosis, siderosis, cholestasis, aminotransferases) of TE performance. METHODS: Patients undergoing simultaneous measurements of TE, portal pressure (hepatic venous pressure gradient, HVPG) and liver biopsy were analysed. RESULTS: Among 226 patients (48.7 +/- 13.1 years, 74.7% male, 75.7% viral aetiology, 57% F3/F4), traditional TE quality criteria identified 71.6% reliable measurements, while new criteria yielded in 83.2% accurate results. Reliable TE values according to both criteria significantly correlated with fibrosis stage (r = 0.648 vs. r = 0.636) and HVPG (r = 0.836 vs. r = 0.846). Diagnostic accuracy for cirrhosis (cut-off >14.5 kPa) was 76.5% (AUC: 0.863) and 75.0% (AUC: 0.852) for traditional and new TE criteria, respectively, while for predicting HVPG >= 10 mmHg (>16.1 kPa), the accuracies were 88.9% (AUC: 0.957) and 89.8% (AUC: 0.962). New TE criteria allowed a better discrimination of reliable and non-reliable results for prediction of fibrosis and CSPH. Only aetiology and aminotransferases were independent confounders of the correlation of TE and fibrosis stage, while no confounder affected the correlation of TE and HVPG. CONCLUSIONS: New reliability criteria for TE measurements increase the number of patients with accurate measurements without affecting diagnostic performance for detecting cirrhosis and portal hypertension. Aetiology of liver disease and aminotransferases should be considered when assessing liver fibrosis by TE. PMID- 24953519 TI - Impact of periodontal therapy on general health: evidence from insurance data for five systemic conditions. AB - BACKGROUND: Treatment of periodontal (gum) disease may lessen the adverse consequences of some chronic systemic conditions. PURPOSE: To estimate the effects of periodontal therapy on medical costs and hospitalizations among individuals with diagnosed type 2 diabetes (T2D); coronary artery disease (CAD); cerebral vascular disease (CVD); rheumatoid arthritis (RA); and pregnancy in a retrospective observational cohort study. METHODS: Insurance claims data from 338,891 individuals with both medical and dental insurance coverage were analyzed in 2011-2013. Inclusion criteria were (1) a diagnosis of at least one of the five specified systemic conditions and (2) evidence of periodontal disease. Subjects were categorized according to whether they had completed treatment for periodontal disease in the baseline year, 2005. Outcomes were (1) total allowed medical costs and (2) number of hospitalizations, per subscriber per year, in 2005-2009. Except in the case of pregnancy, outcomes were aggregated without regard to reported cause. Individuals who were treated and untreated for periodontal disease were compared independently for the two outcomes and five systemic conditions using ANCOVA; age, gender, and T2D status were covariates. RESULTS: Statistically significant reductions in both outcomes (p<0.05) were found for T2D, CVD, CAD, and pregnancy, for which costs were lower by 40.2%, 40.9%, 10.7%, and 73.7%, respectively; results for hospital admissions were comparable. No treatment effect was observed in the RA cohorts. CONCLUSIONS: These cost-based results provide new, independent, and potentially valuable evidence that simple, noninvasive periodontal therapy may improve health outcomes in pregnancy and other systemic conditions. PMID- 24953518 TI - Opting out of cervical cancer screening: physicians who do not perform pap tests. AB - BACKGROUND: Some primary care physicians choose not to provide cervical cancer screening. PURPOSE: To investigate the characteristics and screening beliefs of family practitioners and internists who treat adult women in outpatient settings but perform no routine Pap tests. METHODS: A survey of U.S. primary care physicians (N=892) was conducted and analyzed in 2012. RESULTS: Participants who performed no Pap tests during a typical month (17.2% of family practitioners and 44.3% of internists) generally reported that they referred patients to gynecologists for cervical cancer screening. The most significant predictor of Pap test non-provision was agreement that patients are best served by having Pap tests performed by gynecologists (AOR=8.80, 95% CI=5.58, 13.88, p<0.001). CONCLUSIONS: The perception that patients benefit from cervical cancer screening administered by gynecologists may deter screening in primary care settings, resulting in missed opportunities to offer screening to women who are never or rarely screened. PMID- 24953524 TI - Liver involvement in children with ciliopathies. AB - Abnormalities in primary cilia lead to diseases called ciliopathies. Multiple organ involvement is the norm since primary cilia are present in most cells. When cholangiocyte cilia are abnormal, ductal plate malformation ensues leading to such conditions as congenital hepatic fibrosis, Caroli disease or syndrome, or other fibrocystic disease. PMID- 24953525 TI - ABCB4: Insights from pathobiology into therapy. AB - Adenosine triphosphate (ATP)-binding cassette, sub-family B, member 4 (ABCB4), also called multidrug resistance 3 (MDR3), is a member of the ATP-binding cassette transporter superfamily, which is localized at the canalicular membrane of hepatocytes, and mediates the translocation of phosphatidylcholine into bile. Phosphatidylcholine secretion is crucial to ensure solubilization of cholesterol into mixed micelles and to prevent bile acid toxicity towards hepatobiliary epithelia. Genetic defects of ABCB4 may cause progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare autosomic recessive disease occurring early in childhood that may be lethal in the absence of liver transplantation, and other cholestatic or cholelithiasic diseases in heterozygous adults. Development of therapies for these conditions requires understanding of the biology of this transporter and how gene variations may cause disease. This review focuses on our current knowledge on the regulation of ABCB4 expression, trafficking and function, and presents recent advances in fundamental research with promising therapeutic perspectives. PMID- 24953522 TI - Estimation of leisure time physical activity and sedentary behaviour among school adolescents in Nepal. AB - BACKGROUND: Leisure-time physical activity is essential for healthy and physically active life; however, this domain of physical activity is less common in developing countries. Information on leisure time physical activity and sedentary behaviour among Nepalese population is not available. The study was carried out to assess leisure time physical activity and sedentary behaviour among high school adolescents and identify the associated factors in Nepal. METHODS: A cross-sectional descriptive study was carried out in Banke district, Nepal in 2013 among higher secondary school students using self-administered questionnaire based on International Physical Activity Questionnaire. A sample of 405 students, 178 females and 227 males, of the age-group 15 to 20 years from seven schools were included in the study. Multivariate logistic regression analysis was carried out to identify factors associated with participation in leisure time physical activity and sedentary behaviour. RESULTS: Engagement of female in leisure time physical activity was lower but mean time spent on sitting per day was higher. Students who walked to school and have playground/parks near home, younger females (OR = 3.09, 95% CI: 1.18-8.08), females living in nuclear families (OR: 2.16, 95% CI: 1.01-4.62) and males who cycled to school (OR: 8.09, 95% CI: 2.35-27.80) and have provision of extra-curricular activities (OR: 2.49, 95% CI: 1.04-5.97) were more likely to be engaged in leisure time physical activity. On the other hand, students who did not have playground in school and lived in rural areas were more likely to sit for more than 6 hours a day. Likewise, male students of private school (OR: 6.41, 95% CI: 2.89-14.21), who used vehicle to reach school (OR: 5.90, 95% CI: 1.26-27.75) and have no provision of extra-curricular activities (OR: 2.98, 95% CI: 1.09-8.07) had longer sitting time. CONCLUSION: Difference in leisure time physical activity and sedentary behaviour was found among male and female school adolescents. Interventions are needed not only to promote leisure time physical activity but also to reduce sedentary behaviour among this group. PMID- 24953529 TI - Different methylation profiles between intestinal and diffuse sporadic gastric carcinogenesis. AB - OBJECTIVE: Gastric cancer (GC) is histologically classified into intestinal type and diffuse type, and diffuse type cancer can be further subdivided into poorly differentiated carcinoma (PDC) and signet ring cell carcinoma (SRCC). Recent evidence suggests that early SRCC is an initial, differentiated form of diffuse GC that may evolve into PDC. This study aimed at identifying the molecular features of epigenetic methylation changes in histologic differentiation status of GC. METHODS: Included in this study are 149 samples of paraffin-embedded tissues and 115 fresh endoscopically biopsied tissues. Multiple paraffin tissues involving normal (n=22), dysplasias (GDs, n=39), differentiated cancers (DCs, n=35), PDCs (n=33) and SRCCs (n=20) were included as an experimental group. For the validation group, endoscopically biopsied tissues of DCs (n=50), PDCs (n=31), and SRCs (n=34) were analyzed. DNAs, isolated from each group were analyzed to determine the methylation status of 6 genes (GDNF, RORA, MINT25, KLF7, CDH1, LINE 1) using pyrosequencing. RESULTS: LINE-1 was hypomethylated in GCs compared to normal and GD. GDNF, RORA and MINT25 were more hypermethylated in intestinal type GCs than those of diffuse type GCs, whereas CDH1 showed opposite patterns of methylation. Among diffuse type GCs, SRCCs showed lower level of methylation for GDNF, RORA, MINT25 and KLF7, and higher level for CDH1 compared to PDCs. CONCLUSIONS: In conclusion, intestinal type of GCs shows different epigenetic methylation profiles compared to the diffuse one. Moreover, SRCCs have different methylation profiles compared with PDCs, suggesting a unique molecular pathway in the gastric carcinogenesis. PMID- 24953527 TI - Prognostic role of mean platelet volume in patients with chronic hepatitis C. PMID- 24953523 TI - Effects on pregnancy and breastfeeding on DDT residues warrant further attention. PMID- 24953528 TI - Amoebic hepatic and renal abscesses complicating amoebic colitis. PMID- 24953520 TI - Conducting rapid, relevant research: lessons learned from the My Own Health Report project. AB - The lengthy and uncertain translation of research into clinical practice is well documented. Much of the current "gold standard" clinical research is slow, expensive, and lacks perceived relevance for practitioners and decision makers. In contrast, we summarize experiences conducting the My Own Health Report (MOHR) project to collect and address patient reported measures using principles of rapid, relevant pragmatic research. The methods used for rapid design and fielding of the MOHR project to improve attention to health behaviors and mental health are detailed. Within the multisite, pragmatic, implementation-focused MOHR study, we describe the four phases of the research and the key decisions made and actions taken within each. We provide concrete examples of how relevant research can be conducted transparently to rapidly provide information to practitioners. Data were collected and analyzed in 2013. The multisite (seven research centers partnered with 18 clinics) cluster randomized pragmatic delayed intervention trial was conducted in less than 18 months from receipt of funding applications to completion of data collection. Phases that were especially accelerated included funding and review, and recruitment and implementation. Conducting complex studies rapidly and efficiently is a realistic goal. Key lessons learned for prevention research include use of existing research networks; use of web based assessment/feedback tools that are tailored to fit local needs; engaging relevant stakeholders early on and throughout the process to minimize need for redesign; and making pragmatic decisions that balance internal and external validity concerns rather than waiting for perfect solutions. PMID- 24953521 TI - Organic pollution and its effects in the marine mussel Mytilus galloprovincialis in Eastern Mediterranean coasts. AB - Persistent chemicals and emerging pollutants are continuously detected in marine waters and biota. Out of these, polycyclic aromatic hydrocarbons (PAHs) and organochlorine pesticides (OCs) are significant contaminants with decades of presence in the marine environment. The Mediterranean Sea is an ecosystem directly affected by a variety of anthropogenic activities including industry, municipal, touristic, commercial and agricultural. The Mediterranean mussel (Mytilus galloprovincialis) is a filter feeder, which presents wide distribution. In this regard, the specific organism was used as a biological indicator for the monitoring and evaluation of pollution in the studied areas with focus on the mentioned chemical groups. Pristine Turkish sites with minimum effect from anthropogenic activities, in contrast with Greek sites which were subjected to heavy industrial and shipping activity, were selected. A gas chromatographic tandem mass spectrometric method (GC-MS/MS) was developed and validated to monitor 34 compounds (16 EPA priority PAHs and 18 OCs). Analyses of mussel samples in 2011 from sites with the limited anthropogenic pollution shores have shown the occurrence of 11 pollutants (6 PAHs, 5 OCs), while in the samples from sites with intensive activity and expected pollution, 12 PAHs and 6 OCs were detected. Biochemical and biological responses studied only in mussels samples from the sites with the highest contamination showed a situation that was under strong seasonal influence. The intensity of the response was also influenced by deployment duration. Noteworthy correlations were detected among biochemical/biological effects and between mussel body burden and these effects. Continuous monitoring of priority pollutants of East Mediterranean Sea is vital both for ecological and human risk assessment purposes. PMID- 24953526 TI - Decrease in factor V activity in patients treated with azathioprine or 6 mercaptopurine. AB - BACKGROUND AND OBJECTIVE: A decrease in factor V activity has been reported in some patients treated with azathioprine or 6-mercaptopurine. This may lead to unnecessary treatment discontinuation in otherwise asymptomatic patients. Our aim was to review spontaneously reported cases of decreased factor V activity associated with both drugs and to identify the possible impact on patient care. METHODS: Cases of decrease in prothrombin (PT) or factor V activity involving purine analogs were extracted from the French pharmacovigilance database. Reports with evidence of disseminated intravascular coagulation, signs of acute hepatocellular failure, liver cirrhosis or concomitant vitamin K antagonist treatment were excluded. RESULTS: Twenty-four cases (azathioprine: 13 and 6 mercaptopurine: 11) were retained. Therapeutic indications were inflammatory bowel diseases in 11 patients, acute leukemia in eight, and other autoimmune diseases in five. PT activity before treatment was normal in all nine tested patients. The decrease in PT or factor V activity occurs after a median of 10 weeks of treatment and all patients were asymptomatic. The median PT and factor V activities values were 51.5% and 36.4%, respectively. Other coagulation factors were inconsistently decreased. Full recovery was observed within 3-60 days following purine analogs discontinuation. In four patients, drug rechallenge was associated with recurrence of the coagulation disorders. CONCLUSIONS: Although the mechanism remains unknown, this series that includes cases with positive drug reintroduction strongly suggests the causative role of these drugs. As all patients remained asymptomatic, treatment discontinuation should be carefully considered in patients who clearly benefits from this treatment. PMID- 24953532 TI - Newborn health: everybody's business. AB - Despite advances in issue-attention and in evidence of what works to save newborn lives (e.g., kangaroo mother care, antenatal corticosteroids, immediate and exclusive breastfeeding), we are still falling short on impact. To advance the unfinished newborn survival agenda, newborns must become an integral priority in developing countries where the burden of neonatal mortality is highest. Interventions must be adapted to local contexts and cultures and integrated into packages along the continuum of care delivered through the primary health-care systems that countries have at their disposal. PMID- 24953530 TI - B cell follicle-like structures in multiple sclerosis-with focus on the role of B cell activating factor. AB - B lymphocytes play an important role in the pathogenesis of multiple sclerosis (MS). Follicle-like structures (FLS) have recently been found in the subarachnoid space in the leptomeninges in some patients with secondary progressive MS (SPMS). They contain proliferating B lymphocytes, plasma cells, helper T lymphocytes and a network of follicular dendritic cells. FLS have been shown to correlate with increased cortical demyelination, neuronal loss, meningeal infiltration and central nervous system inflammation, as well as lower age at disease onset and progression to severe disability and death. In this review, we will discuss the role of FLS in MS pathogenesis and disease course and the possible influence by B cell activating factor (BAFF) and C-X-C motif chemokine 13 (CXCL13). PMID- 24953531 TI - Plumbagin suppresses dendritic cell functions and alleviates experimental autoimmune encephalomyelitis. AB - Plumbagin (PL, 5-hydroxy-2-methyl-1,4-naphthoquinone) is a herbal compound derived from medicinal plants of the Droseraceae, Plumbaginaceae, Dioncophyllaceae, and Ancistrocladaceae families. Reports have shown that PL exerts immunomodulatory activity and may be a novel drug candidate for immune related disease therapy. However, its effects on dendritic cells (DCs), the most potent antigen-presenting cells (APCs), remain unclear. In this study, we demonstrate that PL inhibits the differentiation, maturation, and function of human monocyte-derived DCs. PL can also restrict the expression of Th1- and Th17 polarizing cytokines in mDC. In addition, PL suppresses DCs both in vitro and in vivo, as demonstrated by its effects on the mouse DC line DC2.4 and mice with experimental autoimmune encephalomyelitis (EAE), respectively. Notably, PL ameliorated the clinical symptoms of EAE, including central nervous system (CNS) inflammation and demyelination. Our results demonstrate the immune suppressive and anti-inflammatory properties of PL via its effects on DCs and suggest that PL could be a potential treatment for DC-related autoimmune and inflammatory diseases. PMID- 24953533 TI - The effectiveness of computer reminders versus postal reminders for improving quality assessment for point-of-care testing in primary care: a randomized controlled trial. AB - RATIONALE, AIMS AND OBJECTIVES: This study aimed to evaluate the relative effectiveness of electronic and postal reminders for increasing adherence to the quality assurance programme for the international normalized ratio (INR) point-of care testing (POCT) device in primary care. METHODS: All 213 family practices that use the Elective Laboratory of the Capital Region, Denmark, and regularly conduct INR POCT were randomly allocated into two similarly sized groups. During the 4-month intervention, these practices were sent either computer reminders (ComRem) or computer-generated postal reminders (Postal) if they did not perform a split test to check the quality of their INR POCT for each calendar month. The adherence of the practices was tracked during the subsequent 8 months subdivided into two 4-month periods both without intervention. Outcomes were measures of split test procedure adherence. RESULTS: Both interventions were associated with an increase in adherence to the split test procedure - a factor 6.00 [95% confidence interval (CI) 4.46-7.72] and 8.22 [95% CI 5.87-11.52] for ComRem and Postal, respectively - but there is no evidence that one of the interventions was more effective than the other. In the ComRem group, the expected number of split tests (out of four) was 2.54 (95% CI 2.33-2.76) versus 2.44 (95% CI 2.24-2.65) in the Postal group, P = 0.14. There was a slight decrease in adherence over the two follow-ups, but neither intervention was better than the other in achieving a lasting improvement in adherence. CONCLUSION: Computer reminders are as efficient as postal reminders in increasing adherence to a quality assurance programme for the INR POCT device in primary care. PMID- 24953534 TI - Solid phase oxime ligations for the iterative synthesis of polypeptide conjugates. AB - Peptide-based complex biomacromolecules are now optimally assembled by sequential ligation of unprotected peptide segments. However, this approach is still limited by the laborious chromatographic purification and handling steps needed for multiple successive chemoselective couplings, which leads to loss of material. An efficient alternative is solid phase chemical ligation (SPCL) initially developed for native chemical ligation. We report here an extension of this approach to iterative oxime ligation reactions, and describe a streamlined approach for the modular preparation of oxime-containing polypeptides. In particular, we determined optimal conditions to remove the Aloc group in the presence of aminooxy and oxime ether groups, and we extended the applicability of iterative C to-N SPCL through simplification of the access to a C-terminally-grafted, unprotected peptide segment, using solid supported chemical transformations only. The high purity of the crude oxime-containing polypeptides highlights the efficiency of our approach. PMID- 24953535 TI - The role of arachidonic acid in the regulation of nitric oxide synthase isoforms by HIV gp120 protein in astroglial cells. AB - HIV-associated neurocognitive disorder (HAND) is a common cognitive impairment in AIDS that affects 15 to 50% of adults infected with human immunodeficiency virus (HIV). Excessive amounts of nitric oxide (NO), as produced by inducible NO synthase (iNOS) upon exposure of activated microglia and astrocytes to cytokines and/or viral proteins (e.g., HIV tat and gp120), are assumed to contribute to neuronal abnormalities in HAND. Evidence exists supporting the notion that iNOS induction takes place after an early decline in physiological NO levels (i.e., NO released by constitutive NOS). Here, we demonstrate that HIV-1 gp120 is able to inhibit neuronal NOS through a cytosolic phospholipase A2 (cPLA2)-dependent arachidonic acid (AA) production, this response being critical for allowing activation of the transcriptional factor NF-kappaB and subsequent iNOS and interleukin-1beta transcription in astroglial cells. In this context, AA seems to act as an upstream proinflammatory effector. In view of the pathogenic role of cPLA2 in HAND, a deeper insight into the molecular and cellular mechanisms of its modulation may be helpful in finding new drugs to manage cognitive impairment in HIV-1 patients. PMID- 24953536 TI - The economic burden of psoriatic diseases in Taiwan. AB - BACKGROUND: Psoriasis is associated with significant economic burdens. Data regarding costs for psoriasis patients in Taiwan are not available. OBJECTIVE: To estimate the economic burden of psoriasis in Taiwan. METHODS: Psoriasis patients and their controls were identified from the 2006 National Health Insurance (NHI) research database, and differences in annual healthcare utilization and costs between psoriasis cases and controls were predicted by two-part models and generalized linear models. Face-to-face interviews were conducted in five hospital settings to collect information on out-of-pocket payments and productivity losses associated with seeking care. All analyses were stratified by the severity level of psoriasis. RESULTS: From the payer's perspective, the NHI cost associated with moderate to severe psoriasis (sPsO) was NT$41,525 and that with mild psoriasis (mPsO) was NT$14,816. Adding the out-of-pocket payments (NT$13,095 for sPsO and NT$7237 for mPsO) and the loss of productivity (NT$6203 for sPsO and NT$2750 for mPsO), the annual total cost for sPsO was NT$60,823 and that for mPsO was NT$24,803. CONCLUSION: Psoriasis is associated with significant economic burdens in Taiwan. Effective treatment of the disease could produce substantial savings in healthcare resources and gains in productivity. PMID- 24953538 TI - Informing women with breast cancer about endocrine therapy: effects on knowledge and adherence. AB - OBJECTIVE: Adherence to adjuvant endocrine therapy in women with breast cancer is low, and patients are not informed sufficiently. This study analyzes the effects of a structured treatment information on patients' satisfaction, knowledge, and adherence. METHODS: An interventional single cohort study of postoperative women with estrogen-receptor-positive breast cancer was conducted to study the effects of enhanced information about endocrine therapy given additionally to clinical routine information. Knowledge and satisfaction with additional information given 1-3 weeks after surgery were assessed before and after informing patients; adherence and knowledge were measured 3 months after start of treatment. RESULTS: A total of 137 patients were analyzed before and after provision of enhanced treatment information as well as 3 months after start of endocrine therapy. Enhanced information increased satisfaction with information and knowledge. The percentage of patients who knew their estrogen receptor status increased from 50% to 93%. At 3 months follow-up, 60% still had correct knowledge. Patients who learned their receptor status were older, and those who forgot had lower cognitive abilities and lower educational level. Patients with higher satisfaction, better learning, and comprehension directly after enhanced information showed better adherence at 3 months follow-up. CONCLUSION: Patients, especially older ones, can benefit from enhanced treatment information given additionally to routine care. Enhanced information about mode of action and potential side effects of endocrine therapy when included into clinical routine might foster patient autonomy and prevent early disruptions in adherence. PMID- 24953537 TI - Dosimetric shield evaluation with tungsten sheet in 4, 6, and 9MeV electron beams. AB - In electron radiotherapy, shielding material is required to attenuate beam and scatter. A newly introduced shielding material, tungsten functional paper (TFP), has been anticipated to become a very useful device that is lead-free, light, flexible, and easily processed, containing very fine tungsten powder at as much as 80% by weight. The purpose of this study was to investigate the dosimetric changes due to TFP shielding for electron beams. TFP (thickness 0-15mm) was placed on water or a water-equivalent phantom. Percentage depth ionization and transmission were measured for 4, 6, and 9MeV electron beams. Off-center ratio was also measured using film dosimetry at depth of dose maximum under similar conditions. Then, beam profiles and transmission with two shielding materials, TFP and lead, were evaluated. Reductions of 95% by using TFP at 0.5cm depth occurred at 4, 9, and 15mm with 4, 6, and 9MeV electron beams, respectively. It is found that the dose tend to increase at the field edge shaped with TFP, which might be influenced by the thickness. TFP has several unique features and is very promising as a useful tool for radiation protection for electron beams, among others. PMID- 24953539 TI - Efficiency of MY09/11 consensus PCR in the detection of multiple HPV infections. AB - Human papillomavirus (HPV) DNA testing has become an important component of cervical cancer screening programs. In this study, we aimed to evaluate the efficiency of MY09/11 consensus polymerase chain reaction (PCR) for the detection of multiple HPV infections. For this purpose, MY09/11 PCR was compared to an original TaqMan-based type-specific real-time PCR assay, which can detect 20 different HPV types. Of the 654 samples, 34.1% (223/654) were HPV DNA positive according to at least one method. The relative sensitivities of MY09/11 PCR and type-specific PCR were 80.7% (180/223) and 97.8% (218/223), respectively. In all, 352 different HPV isolates (66 low-risk and 286 high-risk or probable high-risk types) were identified in 218 samples, but 5 samples, which were positive by consensus PCR only, could not be genotyped. The distribution of the 286 high-risk or probable high-risk HPVs were as follows: 24.5% HPV-16, 8.4% HPV-52, 7.7% HPV 51, 6.3% HPV-39, 6.3% HPV-82, 5.6% HPV-35, 5.6% HPV-58, 5.6% HPV-66, 5.2% HPV-18, 5.2% HPV-68, and 19.6% the other 8 types. A single HPV type was detected in 57.3% (125/218) of the genotyped samples, and multiple HPV types were found in the remaining 42.7% (93/218). The false-negative rates of MY09/11 PCR were found to be 17.4% in single infections, 23.3% in multiple infections, and 34.6% in multiple infections that contained 3 or more HPV types, with the condition that the low-risk types HPV-6 and HPV-11 be considered as a monotype. These data suggest that broad-range PCR assays may lead to significant data loss and that type-specific PCR assays can provide accurate and reliable results during cervical cancer screening. PMID- 24953540 TI - [Face and limb rash in a 58-year-old woman]. PMID- 24953542 TI - A systematic molecular dynamics simulation study of temperature dependent bilayer structural properties. AB - Although lipid force fields (FFs) used in molecular dynamics (MD) simulations have proved to be accurate, there has not been a systematic study on their accuracy over a range of temperatures. Motivated by the X-ray and neutron scattering measurements of common phosphatidylcholine (PC) bilayers (Kucerka et al. BBA. 1808: 2761, 2011), the CHARMM36 (C36) FF accuracy is tested in this work with MD simulations of six common PC lipid bilayers over a wide range of temperatures. The calculated scattering form factors and deuterium order parameters from the C36 MD simulations agree well with the X-ray, neutron, and NMR experimental data. There is excellent agreement between MD simulations and experimental estimates for the surface area per lipid, bilayer thickness (DB), hydrophobic thickness (DC), and lipid volume (VL). The only minor discrepancy between simulation and experiment is a measure of (DB-DHH)/2 where DHH is the distance between the maxima in the electron density profile along the bilayer normal. Additional MD simulations with pure water and heptane over a range of temperatures provide explanations of possible reasons causing the minor deviation. Overall, the C36 FF is accurate for use with liquid crystalline PC bilayers of varying chain types and over biologically relevant temperatures. PMID- 24953543 TI - Endoscopic correction of primary VUR by using polyacrylate polyalcohol copolymer (Vantris) in young girls: 2-year follow-up. AB - OBJECTIVE: Our aim was to evaluate the efficacy and safety of single endoscopic injection of Vantris in young girls affected by primary vesicoureteral reflux (VUR) at more than 2 years of prospective follow-up. MATERIAL AND METHODS: Over the last 4 years, 73 girls with primary VUR of grades (G) I-IV underwent a single endoscopic injection of Vantris. The mean age was 8.48 (SD=4.8) years. VUR was unilateral in 73 and bilateral in 13 patients, comprising 86 renal refluxing units (RRUs). Pre-operative evaluation consisted of: blood biochemistry, urine analysis and culture, ultrasound scan, voiding cystourethrogram (VCUG), and dimercaptosuccinic acid (DMSA) renal isotope scan. Patients were followed using ultrasound scans at 1 month and every 3 months for the first year and then 2 years after injection. Direct radionuclide cystography with technetium pertechnetate was performed at 3 and 12 months after injection. VCUG was performed only in confirmed cases of failure and downgraded VUR at 3, 12, and 24 months after endoscopic correction. RESULTS: Sixty-nine (95%), 61 (83.4%), and 52 (71%) patients completed 3, 12, and 24 months' follow-up respectively. VUR was corrected and downgraded to G I in 81% and 3.3% of RRUs at 3 months' follow-up. The corrected and downgraded RRUs at 12 and 24 months' follow-up were 77%, 10%, and 77%, 11% respectively. De novo contralateral G I VUR was demonstrated in 8.6% of normal ureters. Contralateral GI VUR with normal DMSA isotope renal scans was resolved in 71% of RRUs. Febrile urinary tract infection decreased to 4.1% in the patients. CONCLUSION: According to our study, a single Vantris injection provides a high level of efficacy and safety in the treatment of primary G I-IV VUR in young girls, at 2 years' prospective follow-up. PMID- 24953541 TI - Implementing a knowledge translation intervention in long-term care: feasibility results from the Vitamin D and Osteoporosis Study (ViDOS). AB - OBJECTIVES: To evaluate the feasibility of implementing an interdisciplinary, multifaceted knowledge translation intervention within long-term care (LTC) and to identify any challenges that should be considered in designing future studies. DESIGN: Cluster randomized controlled trial. SETTING: Forty LTC homes across the province of Ontario, Canada. PARTICIPANTS: LTC teams composed of physicians, nurses, pharmacists, and other staff. MEASUREMENTS: Cluster-level feasibility measures, including recruitment, retention, data completion, and participation in the intervention. A process evaluation was completed by directors of care indicating which process/policy changes had been implemented. RESULTS: Recruitment and retention rates were 22% and 63%, respectively. Good fidelity with the intervention was achieved, including attendance at educational meetings. After ViDOS, 7 process indicators were being newly implemented by more than 50% of active intervention homes. CONCLUSION: Despite recruitment and retention challenges, the multifaceted intervention produced a number of policy/process changes and had good intervention fidelity. This study is registered at ClinicalTrials.gov NCT01398527. PMID- 24953544 TI - Management of obstructive calcular anuria with acute renal failure in children less than 4 years in age: a protocol for initial urinary drainage in relation to planned definitive stone management. AB - OBJECTIVES: To describe and evaluate our protocol for management of children<=4years old with obstructive calcular anuria (OCA) and acute renal failure (ARF) to improve selection of initial urinary drainage (ID) method and to facilitate subsequent definitive stone management (DSM) as studies discussing this special group of patients are still few. PATIENTS AND METHODS: Patients with a contraindication to any method of ID were excluded. Decision (percutaneous nephrostomy (PCN) or double J (JJ) stent) was based on degree of hydronephrosis and planned DSM. We used 4.8-5Fr JJ or 6-8Fr PCN under general anesthesia and fluoroscopic guidance. According to our protocol, JJ is inserted for hydronephrosis<=grade 1. When the hydronephrosis is >grade 1, patients with radiolucent stones were treated by JJ whatever the site of the stone. When the stones were radiopaque, PCN was reserved for stones in a solitary functioning kidney and bilateral ureteric stones prepared for subsequent bilateral ureterolithotomy (or stone prepared for ureterolithotomy in a solitary kidney). After normalization of renal functions, DSM was staged attacking only one side before discharge. Both sides were cleared at the same session in cases with bilateral ureterolithotomy. Renal or ureteric stones suitable for SWL in a solitary kidney were treated with percutaneous nephrolithotripsy (PNL) or ureteroscopy. This was followed also in patients with bilateral stones suitable for SWL by clearing one side using ureteroscopy or PNL before discharge. Open surgery (OS) was reserved for cases with failed ureteroscopy or PNL, for ureteric stones>2.5 cm in size or very large volume complex renal stones. Stone free rate (SFR) was evaluated by CT. Our protocol was evaluated as regard recovery of renal functions, complications, and number of interventions to clear stones. RESULTS: This study included 62 boys and 22 girls presented with anuria for 1-4 days. JJ and PCN were inserted in 105 and 30 ureterorenal units (URU), respectively. Creatinine returns normal within 72 h. JJ insertion formed a part of DSM in 78/159 (49%) URU (stones prepared for extracorporeal shockwave lithotripsy or oral chemolytic dissolution therapy). PCN was the ideal tract for subsequent PNL in 11/159 (6.9%) URU. Accordingly, ID participated by 55.97% in DSM. Both operative and imaging times were slightly longer with PCN than JJ. There was no statistically significant difference in the insertion success or mean period to return to normal chemistry. Complications of both methods were mild and without any significant difference. Endourologic procedures constituted the majority of our interventions. Open surgical and endoscopic interventions for clearance of stones (including ID, treatment conversion and 2ry procedures) were done once for 25 patients, twice for 43 patients while it was needed three times for 16 patients. Total number of interventions was 149 procedures. SFR was 94%. CONCLUSION: Our protocol ensures adequate ID with minimal complications when using our selection criteria in children<=4 years in age with OCA and ARF. It also minimizes number of subsequent procedures to clear stones. Complications and success in insertion and drainage were equivalent in PCN and JJ groups. PMID- 24953545 TI - Normal anatomic relationships in prepubescent female external genitalia. AB - OBJECTIVE: Female congenital abnormalities and concomitant ambiguous genitalia constitute the primary reason for female genital reconstruction, however, objective data describing normal female anatomy is lacking. The aim of this study is to describe the normal anatomical relationships and size of the external genital structures in prepubescent females. MATERIALS AND METHODS: Data were collected prospectively from consecutive Tanner stage 1 females undergoing surgery unrelated to the genitalia. Recorded measurements included: clitoris length and width, length from clitoris to anus, clitoris to urethra, clitoris to posterior labia majora, mucosa behind vagina or posterior fourchette, and radius to labia minora at vagina. Patients were stratified by age into four age groups: <2 years, 2-5 years, 5-11 years and >11 years. RESULTS: Fifty-six patients met inclusion criteria. Clitoral width was similar in all age groups. The regression plots for the remaining measurements modeled on age all show a significant linear growth distribution. CONCLUSIONS: The average clitoral width was 3.8 mm, which remained constant between age groups. Clitoral length, length from clitoris to anus, clitoris to posterior labia majora, clitoris to urethra and posterior fourchette length increased across age groups. This study provides insight into the dimensions of normal external genitalia in tanner stage 1 females. PMID- 24953546 TI - Lower urinary tract dysfunction in children after intravesical ureteric reimplantation surgery under one year of age. AB - OBJECTIVE: To report the results of a study conducted on voiding function in children who have undergone intravesical trans-trigonal Cohen ureteric reimplantation surgery before the age of one year. SUBJECTS: Twenty-eight children (18 males, 10 females) had surgery at a mean age of 4.9 months (range 8 352 days). METHODS: Bladder function was assessed at a mean age of 7.3 years using questionnaires, the dysfunctional voiding scoring system, PinQ quality of life tool, uroflowmetry and post-void residuals. RESULTS: Of the total children, 72% had normal lower urinary tract (LUT) function. Eight children (28%) had evidence of LUT dysfunction, two had urge incontinence, two had giggle incontinence, two had voiding postponement, one had dysfunctional elimination syndrome and one had evidence of dysfunctional voiding. Five of the eight children were managed with continence physiotherapy (urotherapy) and one required ongoing anticholinergic therapy. CONCLUSION: When compared to the published rates of LUT dysfunction in the general paediatric community, no evidence was found to suggest an increased incidence of bladder dysfunction in children undergoing intravesical Cohen ureteric reimplantation surgery under one year of age. PMID- 24953547 TI - Transfer entropy and transient limits of computation. AB - Transfer entropy is a recently introduced information-theoretic measure quantifying directed statistical coherence between spatiotemporal processes, and is widely used in diverse fields ranging from finance to neuroscience. However, its relationships to fundamental limits of computation, such as Landauer's limit, remain unknown. Here we show that in order to increase transfer entropy (predictability) by one bit, heat flow must match or exceed Landauer's limit. Importantly, we generalise Landauer's limit to bi-directional information dynamics for non-equilibrium processes, revealing that the limit applies to prediction, in addition to retrodiction (information erasure). Furthermore, the results are related to negentropy, and to Bremermann's limit and the Bekenstein bound, producing, perhaps surprisingly, lower bounds on the computational deceleration and information loss incurred during an increase in predictability about the process. The identified relationships set new computational limits in terms of fundamental physical quantities, and establish transfer entropy as a central measure connecting information theory, thermodynamics and theory of computation. PMID- 24953548 TI - An exploration of the extent of inclusion of spirituality and spiritual care concepts in core nursing textbooks. AB - BACKGROUND: Holistic care that encompasses a spiritual dimension is an expectation in modern healthcare (Rothman, 2009). Increasing attention is being paid to the role of nurses in providing spiritual care to patients. However nurses lack specific skills and expertise in this area (Lundmark, 2006; Timmins, 2010; RCN, 2011), and the extent to which their undergraduate education prepares them for this role is unclear. There is often an absence of clear direction about what to teach undergraduate nursing students. The extent to which core textbooks direct student studies in this area is not known. There is some evidence that some of these fundamental core textbooks provide insufficient direction (Pesut, 2008), thus gaps in knowledge and care provision in this field could be exacerbated. AIM: The aim of this study is to examine the extent to which spiritual care concepts are addressed in core nursing textbooks. METHODS: Five hundred and forty three books were sampled from the Nursing and Midwifery Core Collection list (UK) (Tomlinsons, 2010) representing 94% of the total (n=580). A survey, the Spirituality Textbook Analysis Tool (STAT), was developed and used to collect data. FINDINGS: One hundred and thirty of the books included content related to spirituality and religion. However there was little consistency in the core nursing textbooks with regard to direction for providing spiritual care. Thirty eight percent of the books defined spiritual care and 36% provided an outline of the role of the nurse in providing this. While some books advocated the assessment of patients' spiritual needs (32%) few referred specifically to assessment tools. DISCUSSION: It is essential that nurses are adequately prepared to address the spiritual needs of patients. While there are numerous spiritual care texts that deal solely with this issue for nurses, there is an argument emerging that core nursing texts used by nursing students ought to encompass spiritual care elements. Lack of specific focus on this field, by these key textbooks might infer that this important element of holistic care is less important than other matters in nursing. True holistic care ought to permeate across textbooks and as such spirituality and spiritual care ought not to be sequestered to specialised texts. Core nursing texts need to be strengthened through consistency of application and inclusion of spirituality and spiritual care where relevant. PMID- 24953549 TI - Super-elastic air/water interfacial films self-assembled from soluble surfactants. AB - We show that water-soluble monosodic salts of F-alkyl phosphates C(n)F(2n+1) (CH2)2OP(O)(OH)2, with n=8 and 10 (F8H2Phos and F10H2Phos) form Gibbs films with exceptionally high dilational viscoelastic modules E that reach ~900 mN m(-1) in the condensed phases. These E values are up to one order of magnitude larger than those recorded for phospholipid, protein and polymer films commonly considered as highly viscoelastic. F8H2Phos.1Na undergoes a transition between a liquid expanded and a liquid-condensed phase. In the case of F10H2Phos.1Na, a transition occurs between a gas phase of surface domains, in which the molecules are densely packed, and a liquid-condensed phase. PMID- 24953550 TI - Structure-toxicity relationship and structure-activity relationship study of 2 phenylaminophenylacetic acid derived compounds. AB - 2-Phenylaminophenylacetic acid is a widely-exploited chemical scaffold whereby notable NSAIDs such as diclofenac and lumiracoxib were derived. Yet, their clinical usage has been associated with toxicities in the liver. While some studies have attributed toxicities to the bioactivation of both drugs to reactive intermediates, the structural predisposition for toxicity, as well as relationship between this toxicity and COX inhibitory activity has not been elucidated. In this study, we aimed to address their intricate link by synthesizing compounds that possess the 2-phenylaminophenylacetic acid backbone with varying alkyl and halogen substituents at three positions critical to the COX inhibitory pharmacophore. These compounds were subjected to cytotoxicity testing on two liver cell lines of contrasting metabolic competencies. We observed higher toxicity in the more metabolically competent cell line, supporting the role of bioactivation as a prerequisite for toxicity. We have also shown that structural changes on the chemical scaffold exerted pronounced effect on liver cytotoxicity. The most lipophilic and brominated compound (24) was identified as the most cytotoxic of all the compounds. A concurrent determination of their pharmacological activity using COX inhibition assays allowed us to derive a safety profile, which showed that selectivity towards COX-2 negatively affected activity and toxicity. PMID- 24953552 TI - The adjuvant effect induced by di-(2-ethylhexyl) phthalate (DEHP) is mediated through oxidative stress in a mouse model of asthma. AB - Di-(2-ethylhexyl) phthalate, as the most commonly used plasticizer, is considered to be related to the asthma prevalence. There are studies affirming that the DEHP has an adjuvant effect in the pathogenesis of allergy asthma. Oxidative stress is one possible pathway for DEHP-adjuvant effect. Thus, this study explored whether DEHP could induce adjuvant effect in mouse asthma model via oxidative stress pathway. Male BALB/c mice were randomly divided into six groups: (1) saline group, (2) DEHP group, (3) ovalbumin (OVA) group, (4) DEHP+OVA group, (5) OVA+vitamin E (Vit E) group, (6) DEHP+OVA+Vit E group. The exposure dose of DEHP was 30 mg/kg body weight (bw)/day. After 18 days of the exposure protocol. Reactive oxygen species (ROS), glutathione (GSH) and malonaldehyde (MDA) levels and biomarkers related to asthma model were measured. Collectively, these data indicated higher ROS and MDA levels and lower GSH contents in DEHP+OVA group than that in OVA group, while Vit E, an antioxidant, could restore ROS, MDA and GSH levels to control levels and attenuate the DEHP and/or OVA effects. Our observations suggested that there was a relationship between oxidative stress and the adjuvant effect induced by DEHP in this mouse asthma model. PMID- 24953551 TI - Synergistic effect of quercetin and quinic acid by alleviating structural degeneration in the liver, kidney and pancreas tissues of STZ-induced diabetic rats: a mechanistic study. AB - The aim of this study was to investigate the synergistic effects of quercetin (QE) and quinic acid (QA) on a STZ-induced diabetic rat model to determine their potential role in alleviating diabetes and its associated complications. In our study design, diabetic rats were treated with single and combined doses of QE and QA for 45days to analyse their effects on liver, kidney and pancreas tissues. The study result showed that QE and QA treated groups down-regulated hyperglycaemia and oxidative stress by up-regulating insulin and C-peptide levels. Moreover, histological observations of the liver, kidney and pancreas of diabetic rats treated with single and combined doses of QE and QA showed a significant improvement in the structural degeneration. Interestingly, the combination dose of QE and QA (50 mg/kg) exhibited maximum inhibition of the pro-apoptotic protein Bax expression and demonstrate enhancement of the anti-apoptotic protein Bcl-2 expression in the kidney tissues, suggesting a protective role in the kidneys of diabetic rats. Taken together, these results indicates the synergistic effects of QE and QA in ameliorating hyperglycaemia, hyperlipidemia and insulin resistance in diabetic rats and therefore, open a new window of research on the combinatorial therapy of flavonoids. PMID- 24953554 TI - From dodo bird to mindfulness: the effect of theoretical orientation on work and self. AB - I discuss my transformation from a confused graduate student with a common factors theoretical orientation to a licensed psychologist focused on humanistic, cognitive, and mindfulness approaches. My theoretical journey was shaped by my work with clients and my own personal development and primarily motivated by a sense of uncertainty that accompanied the lack of a specific theoretical identity. This discussion of trying to find the "right" theoretical approach is set against the well-supported empirical findings that theoretical techniques (i.e., "specific factors") contribute relatively little to clinical outcome, and that no single theoretical approach has distinguished itself as superior to others in the literature. I discuss the effects of my theoretical orientations on my work with colleagues, my relationship with my spouse, and being a parent. PMID- 24953553 TI - Evaluation of global sequence comparison and one-to-one FASTA local alignment in regulatory allergenicity assessment of transgenic proteins in food crops. AB - To address the high false positive rate using >35% identity over 80 amino acids in the regulatory assessment of transgenic proteins for potential allergenicity and the change of E-value with database size, the Needleman-Wunsch global sequence alignment and a one-to-one (1:1) local FASTA search (one protein in the target database at a time) using FASTA were evaluated by comparing proteins randomly selected from Arabidopsis, rice, corn, and soybean with known allergens in a peer-reviewed allergen database (http://www.allergenonline.org/). Compared with the approach of searching >35%/80aa+, the false positive rate measured by specificity rate for identification of true allergens was reduced by a 1:1 global sequence alignment with a cut-off threshold of ?30% identity and a 1:1 FASTA local alignment with a cut-off E-value of ?1.0E-09 while maintaining the same sensitivity. Hence, a 1:1 sequence comparison, especially using the FASTA local alignment tool with a biological relevant E-value of 1.0E-09 as a threshold, is recommended for the regulatory assessment of sequence identities between transgenic proteins in food crops and known allergens. PMID- 24953555 TI - Quality of diabetes care in family medicine practices in eastern Bosnia and Herzegovina. AB - OBJECTIVES: In the present study, the audit of medical files of patients with diabetes, followed in family medicine practices in the eastern region of Bosnia and Herzegovina (BiH), was carried out in order to investigate the frequency of the use of screening tests for early diagnosis of diabetes complications. METHODS: The audit was conducted in 32 family medicine practices from 12 primary health care centers in the eastern part of BiH over one-year period (March 2010 to March 2011). A specially established audit team randomly selected medical files of 20 patients with diabetes from the Diabetes Registry administered by each family medicine team database. Screening tests assessed are selected according to the ADA guidelines. RESULTS: Frequency of the individual screening test varied between 99%, found for at least one blood pressure measurement, and 3.8% for ABI measurement. When the frequency of optimal use of screening was analyzed, only 1% of patients received all recommended screening tests. CONCLUSION: The frequency of the use of screening tests for chronic diabetes complications was found to be low in the eastern part of Bosnia and Herzegovina. Multivariate linear regression analysis showed that longer duration of diabetes and a larger number of diabetics per practice were associated with a smaller number of screening tests, but specialists in family medicine provided a higher number of screening tests compared to other physicians. PMID- 24953556 TI - A portable single-sided magnet system for remote NMR measurements of pulmonary function. AB - In this work, we report initial results from a light-weight, low field magnetic resonance device designed to make relative pulmonary density measurements at the bedside. The development of this device necessarily involves special considerations for the magnet, RF and data acquisition schemes as well as a careful analysis of what is needed to provide useful information in the ICU. A homogeneous field region is created remotely from the surface of the magnet such that when the magnet is placed against the chest, an NMR signal is measured from a small volume in the lung. In order to achieve portability, one must trade off field strength and therefore spatial resolution. We report initial measurements from a ping-pong ball size region in the lung as a function of lung volume. As expected, we measured decreased signal at larger lung volumes since lung density decreases with increasing lung volume. Using a CPMG sequence with DeltaTE=3.5 ms and a 20 echo train, a signal to noise ratio ~1100 was obtained from an 8.8mT planar magnet after signal averaging for 43 s. This is the first demonstration of NMR measurements made on a human lung with a light-weight planar NMR device. We argue that very low spatial resolution measurements of different lobar lung regions will provide useful diagnostic information for clinicians treating Acute Respiratory Distress Syndrome as clinicians want to avoid ventilator pressures that cause either lung over distension (too much pressure) or lung collapse (too little pressure). PMID- 24953557 TI - Inhibition of mitochondrial glycerol-3-phosphate dehydrogenase by alpha tocopheryl succinate. AB - alpha-Tocopheryl succinate (TOS), a redox-silent analogue of vitamin E, suppresses cell growth in a number of clinical and experimental cancers, inhibits mitochondrial succinate dehydrogenase (SDH) and activates reactive oxygen species (ROS) generation. The aim of this study was to test whether TOS also inhibits glycerol-3-phosphate dehydrogenase (mGPDH), another flavoprotein-dependent enzyme of the mitochondrial respiratory chain because there are differences between electron transfer pathway from SDH and mGPDH to coenzyme Q pool. For our experiments brown adipose tissue mitochondria with high expression of mGPDH were used. Our data showed that inhibition of glycerol-3-phosphate (GP)-dependent oxygen consumption by TOS was more pronounced than the succinate (SUC)-dependent one (50% inhibition was reached at 10 MUmol/l TOS vs. 80 MUmol/l TOS, respectively). A comparison of the inhibitory effect of TOS on GP-oxidase, GP cytochrome c oxidoreductase and GP-dehydrogenase activities showed that TOS directly interacts with the dehydrogenase. After TOS application the GP-dependent generation of ROS was highly depressed. It may thus be concluded that TOS-induced inhibition of mGPDH is more pronounced than TOS-induced inhibition of SDH and that the inhibitory effect of TOS for both substrates is exerted at different locations of the particular dehydrogenases. Our data indicate that the inhibition of mGPDH activity could also play a role in TOS-induced growth suppression in neoplastic cells. PMID- 24953558 TI - miR-92a regulates TGF-beta1-induced WISP1 expression in pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is the most common and fatal form of idiopathic interstitial pneumonia. MicroRNAs (miRNAs), short, single-stranded RNAs that regulate protein expression in a post-transcriptional manner, have recently been demonstrated to contribute to IPF pathogenesis. We have previously identified WNT1-inducible signaling pathway protein 1 (WISP1) as a highly expressed pro-fibrotic mediator in IPF, but the underlying mechanisms resulting in increased WISP1 expression, remain elusive. Here, we investigated whether WISP1 is a target of miRNA regulation. We applied a novel supervised machine learning approach, which predicted miR-30a/d and miR-92a target sites in regions of the human WISP1 3'UTR preferentially bound by the miRNA ribonucleoprotein complex. Both miRNAs were decreased in IPF samples, whereas WISP1 protein was increased. We demonstrated further that transforming growth factor (TGF)-beta1 induced WISP1 expression in primary lung fibroblasts in vitro and lung homogenates in vivo. Notably, miR-30a and miR-92a reversed TGF-beta1-induced WISP1 mRNA expression in lung fibroblasts. Moreover, miR-92a inhibition increased WISP1 protein expression in lung fibroblasts. An inverse relationship for WISP1 and miR-92a was found in a TGF-beta1 dependent lung fibrosis model in vivo. Finally, we found significantly increased WISP1 expression in primary IPF fibroblasts, which negatively correlated with miR-92a level ex vivo. Altogether, our findings indicate a regulatory role of miR-92a for WISP1 expression in pulmonary fibrosis. PMID- 24953561 TI - Wortmannin potentiates the combined effect of etoposide and cisplatin in human glioma cells. AB - The combination of etoposide and cisplatin represents a common modality for treating of glioma patients. These drugs directly and indirectly produce the most lethal DNA double-stand breaks (DSB), which are mainly repaired by non-homologous DNA end joining (NHEJ). Drugs that can specifically inhibit the kinase activity of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), the major component of NHEJ, are of special interest in cancer research. These small molecule inhibitors can effectively enhance the efficacy of current cancer treatments that generate DNA damage. In this study, we investigated the effect of DNA-PKcs inhibitor, wortmannin, on the cytotoxic mechanism of etoposide and cisplatin in MO59K and MO59J human glioblastoma cell lines. These cell lines are proficient and deficient in DNA-PKcs, respectively. Wortmannin synergistically increased the cytotoxicity of cisplatin and etoposide, when combined, in NHEJ proficient MO59K cells. Surprisingly, wortmannin sensitizing effect was also observed in DNA-PKcs-deficient MO59J cells. These data suggest that wortmannin sensitization to etoposide and cisplatin in human glioma cells is mediated by inhibition of not only DNA-PKcs activity but other enzymes from PI3-K family, e.g. ATM and ATR. A concentration-dependent increase in etoposide and cisplatin induced DSB levels was potentiated by inhibitor in both cell lines. Moreover, drug-induced accumulation in the G2/M checkpoint and S-phase was increased by wortmannin. Wortmannin significantly inhibited drug-induced DSB repair in MO59 cells and this effect was more pronounced in MO59J cells. We conclude that the mechanism of wortmannin potentiation of etoposide and cisplatin cytotoxicity involves DSBs induction, DSBs repair inhibition, G2/M checkpoint arrest and inhibition of not only DNA-PKcs activity. PMID- 24953560 TI - B4GALNT2 gene expression controls the biosynthesis of Sda and sialyl Lewis X antigens in healthy and cancer human gastrointestinal tract. AB - The histo blood group carbohydrate Sd(a) antigen and its cognate biosynthetic enzyme B4GALNT2 show the highest level of expression in normal colon. Their dramatic down regulation previously observed in colon cancer tissues could play a role in the concomitant elevation of the selectin ligand sLe(x), involved in metastasis. However, down regulation of sLe(x) expression by B4GALNT2 has been so far demonstrated in vitro, but not in tissues. The human B4GALNT2 gene specifies at least two transcripts, diverging in the first exon, never studied in normal and cancer tissues. The long form contains a 253 nt exon 1L; the short form contains a 38 nt exon 1S. Using qPCR, we showed that cell lines and normal or cancerous colon, expressed almost exclusively the short form, while the long form was mainly expressed by the embryonic colon fibroblast cell line CCD112CoN. Immunochemistry approaches using colon cancer cells permanently expressing either B4GALNT2 cDNAs as controls, led to the observation of several protein isoforms in human normal and cancerous colon, and cell lines. We showed that tissues expressing B4GALNT2 protein isoforms were able to induce Sd(a) and to inhibit sLe(x) expression; both of which are expressed mainly on PNGase F-insensitive carbohydrate chains. Concomitant expression of B4GALNT2 and siRNA-mediated inhibition of FUT6, the major fucosyltransferase involved in sLe(x) synthesis in colon, resulted in a cumulative inhibition of sLe(x). In normal colon samples a significant relationship between sLe(x) expression and the ratio between FUT6/B4GALNT2 activities exists, demonstrating for the first time a role for B4GALNT2 in sLe(x) inhibition in vivo. PMID- 24953559 TI - AMPK is involved in mediation of erythropoietin influence on metabolic activity and reactive oxygen species production in white adipocytes. AB - Erythropoietin, discovered for its indispensable role during erythropoiesis, has been used in therapy for selected red blood cell disorders in erythropoietin deficient patients. The biological activities of erythropoietin have been found in animal models to extend to non-erythroid tissues due to the expression of erythropoietin receptor. We previously demonstrated that erythropoietin promotes metabolic activity and white adipocytes browning to increase mitochondrial function and energy expenditure via peroxisome proliferator-activated receptor alpha and Sirtuin1. Here we report that AMP-activated protein kinase was activated by erythropoietin possibly via Ca(2+)/calmodulin-dependent protein kinase kinase in adipocytes as well as in white adipose tissue from diet induced obese mice. Erythropoietin increased cellular nicotinamide adenine dinucleotide via increased AMP-activated protein kinase activity, possibly leading to Sirtuin1 activation. AMP-activated protein kinase knock down reduced erythropoietin mediated increase in cellular oxidative function including the increased oxygen consumption rate, fatty acid utilization and induction of key metabolic genes. Under hypoxia, adipocytes were found to generate more reactive oxygen species, and erythropoietin reduced the reactive oxygen species and increased antioxidant gene expression, suggesting that erythropoietin may provide protection from oxidative stress in adipocytes. Erythropoietin also reversed increased nicotinamide adenine dinucleotide by hypoxia via increased AMP-activated protein kinase. Additionally, AMP-activated protein kinase is found to be involved in erythropoietin stimulated increase in oxygen consumption rate, fatty acid oxidation and mitochondrial gene expression. AMP-activated protein kinase knock down impaired erythropoietin stimulated increases in antioxidant gene expression. Collectively, our findings identify the AMP-activated protein kinase involvement in erythropoietin signaling in regulating adipocyte cellular redox status and metabolic activity. PMID- 24953562 TI - Attenuated migration by green tea extract (-)-epigallocatechin gallate (EGCG): involvement of 67 kDa laminin receptor internalization in macrophagic cells. AB - Excessive activation of the microglia in the brain is involved in the development of several neurodegenerative diseases. Previous studies have indicated that (-) epigallocatechin gallate (EGCG), a major active constituent of green tea, exhibits potent suppressive effects on the activation of microglia. As the 67 kDa laminin receptor (67LR) is a key element in cellular activation and migration, we investigated the effect of EGCG on cell migration and 67LR in lipopolysaccharide (LPS)-activated macrophagic RAW264.7 cells. The presence of EGCG (1-25 MUM) markedly attenuated LPS-induced cell migration in a dose-dependent manner. However, the total amount of 67LR protein in the RAW264.7 cells was unaffected by EGCG, as revealed by Western blot analysis. In addition, confocal immunofluorescence microscopy indicated that EGCG caused a marked membrane translocation of 67LR from the membrane surface towards the cytoplasm. Cell surface biotinylation analysis confirmed that EGCG induced a significant internalization of 67LR by 24-68% in a dose-dependent manner. This study helps to explain the pharmacological action of EGCG on 67LR, suggesting its potential use in the treatment of diseases associated with macrophage/microglia activation, such as neurodegenerative diseases and cancer. PMID- 24953563 TI - Comparison between drug screening by immunoassay and ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry in post mortem urine. AB - Immunoassay is currently the most common approach for urine drug screening. However, the continuous emergence of new psychoactive substances (NPS) and their low urinary concentrations have challenged the scope and sensitivity of immunoassays. Consequently, specialized toxicology laboratories rely more and more on mass spectrometry (MS) based techniques. Ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry (UHPLC-HR-TOF-MS) is an especially attractive technique for comprehensive drug screening. The objective was to compare the performances of immunoassay and UHPLC-HR-TOF-MS in terms of scope, flexibility, sensitivity, and reliability of substance identification. A total of 279 post-mortem urine samples were analyzed using a method representative of each technique. The immunoassay method was an Emit II Plus enzyme immunoassay for the following drug groups: amphetamines, benzodiazepines, buprenorphine, cannabis, and opiates. The UHPLC-HR-TOF-MS method was a recently published method covering hundreds of drugs: conventional drugs of abuse, abused prescription drugs, and NPS of various classes. UHPLC-HR-TOF-MS produced a lower number of false positive (FP) results for the drug groups covered by immunoassay. Many of the false negative (FN, n = 40) and FP (n = 22) immunoassay results were obviously due to the higher cut-off concentrations and interfering matrix, respectively. Moreover, the wider scope of UHPLC-HR-TOF-MS allowed detection of NPS and prescription drugs. UHPLC-HR-TOF-MS gave FP results related to a few particular substances. The future option of adjusting all compound-specific reporting parameters individually would allow the method's sensitivity and specificity to be fully exploited. PMID- 24953564 TI - Primary breast lymphoma. AB - Primary breast lymphoma is a rare form of extranodal lymphoma, defined by the presence of a primary lesion within the breast with or without regional nodal involvement but no other extra-mammary sites of involvement. It comprises diverse histologic subtypes, but diffuse large B-cell lymphoma is the most common. In this review, we describe in detail the clinical features, diagnosis and staging, pathogenesis, risk factors and therapy of primary breast diffuse large B-cell lymphoma. We consider choice and number of cycles of chemotherapy, the indications for radiotherapy and discuss the need for central nervous system prophylaxis. We also provide a brief overview of the less commonly encountered histologic subtypes including marginal zone, follicular, Burkitt and breast implant associated anaplastic large cell lymphoma. We conclude with a suggested treatment approach and potential areas of future research. PMID- 24953565 TI - Radiopharmaceutical therapy in the era of precision medicine. AB - Precision medicine is the selection of a treatment modality that is specifically tailored to the genetic and phenotypic characteristics of a particular patient's disease. In cancer, the objective is to treat with agents that inhibit cell signalling pathways that drive uncontrolled proliferation and dissemination of the disease. To overcome the eventual resistance to pathway inhibition therapy, this treatment modality has been combined with chemotherapy. We propose that pathway inhibition therapy is more rationally combined with radiopharmaceutical therapy (RPT), a cytotoxic treatment that is also targeted. RPT exploits pharmaceuticals that either bind specifically to tumours or accumulate by a broad array of physiological mechanisms indigenous to the neoplastic cells to deliver radiation specifically to these cells. Consistent with pathway inhibition therapy and in contrast to chemotherapy, RPT is well tolerated. However, the potential of RPT has not been fully exploited; for the most part, treatment has been implemented without using the ability to customise RPT by imaging and deriving individual patient tumour and normal organ radiation absorbed doses. These are more closely related to biological response and their determination should enable RPT treatment administration to maximum therapeutic benefit by treating to normal organ tolerance or demonstrating futility via tumour dosimetry. This is the essence of precision medicine. PMID- 24953566 TI - Phase 1 study of nab-paclitaxel, cisplatin and 5-fluorouracil as induction chemotherapy followed by concurrent chemoradiotherapy in locoregionally advanced squamous cell carcinoma of the oropharynx. AB - BACKGROUND: Induction chemotherapy followed by concurrent chemoradiation (CRT) (sequential therapy) has been evaluated in the treatment of locoregionally advanced squamous cell cancer of the head and neck (LA-SCCHN), with docetaxel, cisplatin (P) and 5-flurouracil (F) shown to be superior to PF doublet. Nab paclitaxel (A) is a novel albumin-bound paclitaxel with a superior therapeutic index to docetaxel. METHODS: A phase I trial [Clinical trials.gov identifier NCT00731380] to assess the safety and efficacy of nab-paclitaxel+cisplatin+5 fluorouracil (APF) as induction chemotherapy for three cycles, followed by concurrent carboplatin (area-under-curve (AUC) 1.5 weekly) with radiation therapy (RT) (70 Gy/35 fractions), was conducted using a 3+3 design in patients with previously untreated LA-SCCHN. Dose-limiting toxicities (DLTs) included: standard haematologic and non-haematologic toxicities, treatment delays, inability to complete ?95% of RT and skin/mucosal toxicity related to RT assessed from day 1 of treatment to 8 weeks after completion of CRT. RESULTS: 17 patients with oropharyngeal cancer were enrolled in three dose levels, with 15 patients evaluable for DLT. The median age was 54 years (range, 44-65 years), 14 patients were male, and 11 patients' tumours were p16 positive and four negative. Grade 3/4 adverse events during APF (%total number of cycles) were hyponatraemia (14%) neutropenia (10%), lymphopaenia (4%) and thrombocytopenia (2%) during 49 evaluable APF cycles. Febrile neutropenia occurred during one cycle of treatment. CONCLUSION: The recommended phase 2 dose of APF is nab-paclitaxel 100mg/m(2) days 1 and 8, cisplatin 75 mg/mg(2) day 1 and 5-fluorouracil 1000 mg/m(2)/day*96 h days 1-4, every 3 weeks, for three cycles prior to CRT. PMID- 24953568 TI - The effects of implant angulation on the resonance frequency of a dental implant. AB - Dental implants are ideally placed in an orientation that allows vertical transfer of occlusal forces along their long axis. Nevertheless, optimal situations for implant placement are seldom encountered resulting in implants placement in angulated positions, which may affect their long-term success. The resonance frequency (RF) is an objective tool used to monitor stability of the implant tissue integration; however, little is known of the effect of the implant orientation in bone on the RF and its potential significance. The purpose of this research was to determine the relation between the dental implant orientation and the corresponding RF of implant. Three-dimensional (3D) modelling software was used to construct a 3D model of a pig mandible from computed tomography (CT) images. The RF of the implant was analysed using finite element (FE) modal analysis in software ANSYS (v.12). In addition, a cubical model was also developed in MIMICS to investigate the parameters affecting the relationship between RF and implant orientation in a simplified environment. The orientation angle was increased from 0 to 10 degrees in 1 degree increments and the resulting RF was analysed using correlation analysis and one-way ANOVA. Our analysis illustrated that the RF fluctuation following altering implant orientation was strongly correlated (r=0.97) with the contacting cortical to cancellous bone ratio (CCBR) at the implant interface. The most extreme RF change (from 9.81kHz to 10.07kHz) occurred when the implant was moved 0.5mm in positive z-direction, which resulted in the maximum change of CCBR from 52.9 to 54.8. PMID- 24953567 TI - Use of alcohol before suicide in the United States. AB - PURPOSE: Few studies have compared acute use of alcohol in suicide decedents with that in a nonsuicide group. This study provides the first national analysis of acute use of alcohol before suicide compared with an estimate of acute use of alcohol in a living sample. METHODS: Pooled 2003-2011 National Violent Death Reporting System data were used to estimate the prevalence of postmortem blood alcohol content positivity (blood alcohol content >0.0 g/dL) and intoxication (blood alcohol content >=0.08 g/dL). Population estimates of comparable use of alcohol (within the past 48 hours) were based on the National Epidemiologic Survey on Alcohol and Related Conditions. RESULTS: Compared with the living sample, male and female suicide decedents showed, respectively, a 1.83-fold (95% confidence interval [CI], 1.73-1.93) and 2.40-fold (95% CI, 2.24-2.57) increased risk of alcohol ingestion before their death after age, race/ethnicity, and chronic alcohol problems were controlled. Furthermore, male and female decedents exhibited, respectively, a 6.18-fold (95% CI, 5.57-6.86) and a 10.04-fold (95% CI, 8.67-11.64) increased risk of being intoxicated before their death after confounders were considered. CONCLUSIONS: The findings underscore the crucial need to include among the essential components of suicide prevention policies programs that minimize the use of alcohol, particularly drinking to intoxication. PMID- 24953569 TI - Computational fluid dynamics analysis of balloon-expandable coronary stents: influence of stent and vessel deformation. AB - In many computational fluid dynamics (CFD) studies of stented vessel haemodynamics, the geometry of the stented vessel is described using non-deformed (NDF) geometrical models. These NDF models neglect complex physical features, such as stent and vessel deformation, which may have a major impact on the haemodynamic environment in stented coronary arteries. In this study, CFD analyses were carried out to simulate pulsatile flow conditions in both NDF and realistically-deformed (RDF) models of three stented coronary arteries. While the NDF models were completely idealised, the RDF models were obtained from nonlinear structural analyses and accounted for both stent and vessel deformation. Following the completion of the CFD analyses, major differences were observed in the time-averaged wall shear stress (TAWSS), time-averaged wall shear stress gradient (TAWSSG) and oscillatory shear index (OSI) distributions predicted on the luminal surface of the artery for the NDF and RDF models. Specifically, the inclusion of stent and vessel deformation in the CFD analyses resulted in a 32%, 30% and 31% increase in the area-weighted mean TAWSS, a 3%, 7% and 16% increase in the area-weighted mean TAWSSG and a 21%, 13% and 21% decrease in the area weighted mean OSI for Stents A, B and C, respectively. These results suggest that stent and vessel deformation are likely to have a major impact on the haemodynamic environment in stented coronary arteries. In light of this observation, it is recommended that these features are considered in future CFD studies of stented vessel haemodynamics. PMID- 24953571 TI - "Out of the dangerous wild, but not yet out of woods"--the polio end game strategy. PMID- 24953570 TI - Reliability of a new scale for measurement of spasticity in stroke patients. AB - OBJECTIVES: To evaluate the reliability of a new scale, the Triple Spasticity Scale (TSS), for assessing spasticity in stroke, through measurement of affected elbow flexors and ankle plantar flexors of hemiplegic patients with stroke, and to compare the new scale with commonly used scales. DESIGN: Cross-sectional study. SETTING: Inpatients at a rehabilitation hospital. PATIENTS: Seventy-one inpatients with hemiplegic stroke. MAIN OUTCOME MEASURES: TSS, Modified Ashworth Scale (MAS) and Modified Tardieu Scale (MTS). RESULTS: Test-retest reliability for TSS total score was good (intraclass correlation coefficient (ICC) = 0.905~0.918). Inter- rater reliability for TSS total score was also good (ICC = 0.778~0.885). Spearman's correlation coefficient demonstrated significant correlation between the TSS and MAS, in both elbow flexors and plantar flexors (r = 0.840~0.946, p = 0.000), and between the TSS and MTS, in both elbow flexors and plantar flexors (r = 0.715~0.795, p = 0.000). There were small, but significant, correlations between the scores for increased resistance and dynamic muscle length in these 2 muscles (r = 0.307~0.564, p = 0.000~0.009). CONCLUSION: The TSS has good test-retest reliability and inter-rater reliability in measurement of muscle tone. This new scale provides an alternative for measuring spasticity, which avoids some of the shortcomings of previous scales. PMID- 24953572 TI - Organic foods for children: health or hype. AB - Organic foods are promoted as superior and safer options for today's health conscious consumer. Manufacturers of organic food claim it to be pesticide-free and better in terms of micronutrients. Consumers have to pay heavily for these products--and they are willing to--provided they are assured of the claimed advantages. Scientific data proving the health benefits of organic foods, especially in children, are lacking. Indian Government has developed strict guidelines and certification procedures to keep a check on manufacturers in this financially attractive market. American Academy of Pediatrics, in its recently issued guidelines, did not recommend organic foods over conventional food for children. Indian Academy of Pediatrics has not opined on this issue till date. In this perspective, we present a critical review of production and marketing of organic foods, and scientific evidence pertaining to their merits and demerits, with special reference to pediatric population. PMID- 24953573 TI - INDT-ASD: an autism diagnostic tool for Indian children. Developmental pediatrician's perspective. PMID- 24953574 TI - Challenges in diagnosis of autism and the struggle of using western screening tools in different cultures. Psychiatrist's perspective. PMID- 24953576 TI - Glycerin suppository for promoting feeding tolerance in preterm very low birthweight neonates: a randomized controlled trial. AB - OBJECTIVE: To compare the efficacy of glycerin suppository versus no suppository in preterm very-low-birthweight neonates for improving feeding tolerance. DESIGN: Randomized controlled trial. SETTING: Level III neonatal unit from Mumbai, India. PARTICIPANTS: 50 very-low-birthweight (birth weight between 1000 to 1500 grams)preterm (gestational age between 28 to 32 weeks) neonates randomized to glycerine suppository (n=25) or no intervention (n=26). INTERVENTION: Glycerin suppository (1g) once a day from day-2 to day-14 of life or no suppository, along with intermittent oral feeds and standardized care. PRIMARY OUTCOME: Time required to achieve full enteral feeds (180 mL/kg/d). RESULTS: Baseline characteristics of neonates like gestational age, birthweight, gender and age at the time of introduction of feeds were comparable in both groups. The mean (SD) duration to reach full enteral feed was 11.90 (3.1) days in glycerin suppository group and was not significantly different (P=0.58) from control group, [11.33 (3.57) days]. Glycerin suppository group regained birth weight 2 days earlier than control group but this difference was not significant (P=0.16). There was no significant difference in duration of hospital stay or occurrence of necrotizing enterocolitis amongst the two study groups. CONCLUSIONS: Once daily application of glycerin suppository does not accelerate the achievement of full feeds in preterm very-low-birthweight neonates. PMID- 24953575 TI - INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD): development and validation. AB - OBJECTIVE: To develop and validate INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD). DESIGN: Diagnostic test evaluation by cross sectional design. SETTING: Four tertiary pediatric neurology centers in Delhi and Thiruvanthapuram, India. METHODS: Children aged 2-9 years were enrolled in the study. INDT-ASD and Childhood Autism Rating Scale (CARS) were administered in a randomly decided sequence by trained psychologist, followed by an expert evaluation by DSM-IV TR diagnostic criteria (gold standard). MAIN OUTCOME MEASURES: Psychometric parameters of diagnostic accuracy, validity (construct, criterion and convergent) and internal consistency. RESULTS: 154 children (110 boys, mean age 64.2 mo) were enrolled. The overall diagnostic accuracy (AUC=0.97, 95% CI 0.93, 0.99; P<0.001) and validity (sensitivity 98%, specificity 95%, positive predictive value 91%, negative predictive value 99%) of INDT-ASD for Autism spectrum disorder were high, taking expert diagnosis using DSM-IV-TR as gold standard. The concordance rate between the INDT-ASD and expert diagnosis for 'ASD group' was 82.52% [Cohen's k=0.89; 95% CI (0.82, 0.97); P=0.001]. The internal consistency of INDT-ASD was 0.96. The convergent validity with CARS (r = 0.73, P= 0.001) and divergent validity with Binet-Kamat Test of intelligence (r = -0.37; P=0.004) were significantly high. INDT-ASD has a 4-factor structure explaining 85.3% of the variance. CONCLUSIONS: INDT-ASD has high diagnostic accuracy, adequate content validity, good internal consistency high criterion validity and high to moderate convergent validity and 4-factor construct validity for diagnosis of Autistm spectrum disorder. PMID- 24953578 TI - Zinc supplementation for neonatal hyperbilirubinemia: a randomized controlled trial. AB - OBJECTIVE: To determine the efficacy of oral zinc for treatment of idiopathic neonatal hyperbilirubinemia in near-term and term (35-41 weeks) neonates. DESIGN: Randomized placebo-controlled trial. SETTING: Tertiary-care teaching hospital. PARTICIPANTS: Eighty newborns with idiopathic neonatal hyperbilirubinemia. INTERVENTION: Neonates were randomized to receive either oral zinc sulfate (10 mg/d) or placebo for 7 days. MAIN OUTCOME MEASURES: Primary: total serum bilirubin levels at 48 (+/-12) h, 96 (+/-12) h and 144 (+/-12) h after intervention. Secondary: duration of phototherapy, and serum zinc and copper levels. RESULTS: Baseline mean (SD) total serum bilirubin levels were 14.8 (3.8) and 14.4 (3.5) mg/dL in zinc and placebo groups, respectively. No significant differences were observed in total bilirubin levels between the two groups after the intervention. Mean (SD) total serum bilirubin levels in zinc and placebo groups were 13.9 (2.5) vs. 13.4 (1.9) mg/dL (mean difference 0.566; 95% CI 0.535, 1.668, P=0.038) at 48 h, 13.1 (2.7) vs. 12.8 (2.3) mg/dL (mean difference 0.234; 95% CI -1.011, 1.479, P =0.708) at 96 h and 8.0 (2.0) vs. 8.6 (1.2) mg/dL (mean difference -0.569, 95% CI -1.382, 0.242, P=0.166) at 144 h. Although the mean duration of phototherapy in the zinc group was less by 21.3 h (95% CI 11.6, 30.9, P=0.052), the difference was not significant. Post-intervention, serum zinc levels were significantly higher in the zinc-supplemented group while serum copper levels were comparable between the two groups. CONCLUSIONS: Oral zinc sulfate, in a dose of 10 mg/day, is not effective in the management of idiopathic neonatal hyperbilirubinemia. PMID- 24953577 TI - Efficacy of levamisole in children with frequently relapsing and steroid dependent nephrotic syndrome. AB - OBJECTIVE: To assess the efficacy of levamisole in frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome. STUDY DESIGN: Retrospective analysis of hospital case records. SETTING: Pediatric nephrology department of a tertiary referral pediatric hospital. PARTICIPANTS: 62 children with frequently relapsing nephrotic syndrome and 35 children with steroid-dependent nephrotic syndrome. METHODS: Case records of children who were diagnosed as steroid dependant or frequently-relapsing nephrotic syndrome from June 2004 to June 2011, were reviewed. Levamisole was given daily (2 mg/kg/d) along with tapering doses of alternate day steroids after remission on daily steroids. RESULTS: Levamisole was effective in 77.3% children with a better (80.6%) efficacy in frequently relapsing nephrotic syndrome. A total of 34 children completed 1 year follow-up post levamisole therapy. The cumulative mean (SD) steroid dose 1-year before therapy was 4109(1154) mg/m2 and 1-year post therapy was 661 (11) mg/m2 (P<0.001). The relapses were also less during the period of post-levamisole therapy. CONCLUSION: Levamisole is an effective alternative therapy in frequently relapsing and steroid-dependent nephrotic syndrome. PMID- 24953579 TI - Growing pains: practitioners' dilemma. AB - NEED AND PURPOSE OF REVIEW: Though cases of 'growing pains' are quite common in pediatric practice, very little attention has been given to it, even in the standard text books. The resultant confusion among practitioners regarding diagnosis and management of this condition needs to be addressed. METHODS USED FOR LOCATING, SELECTING, EXTRACTING AND SYNTHESIZING DATA: PubMed search was performed using "growing pains "[All Fields] AND (("child"[MeSH Terms] OR "child"[All Fields] OR "children"[All Fields]) AND ("pediatrics"[MeSH Terms] OR "pediatrics"[All Fields] OR "pediatric"[All Fields])). Types of articles included are Review articles, Systemic Reviews, Randomized Controlled Trials, Practice guidelines and Observational studies. Google Scholar was also searched using the term "Growing pains in children". Relevant articles not included in the PubMed results were selected. Reference lists of selected studies were also screened to identify additional studies. MAIN CONCLUSIONS: A fairly accurate diagnosis of growing pains can be made clinically, if the widely accepted diagnostic criteria are followed . A systematic approach, with due consideration of both inclusion as well as exclusion criteria, can avoid unnecessary (sometimes potentially harmful) investigations and medications. Reassurance remains the main stay in the management of 'growing pains'. PMID- 24953580 TI - Health-related quality of life in children with cerebral palsy and their families. AB - OBJECTIVE: To determine the health-related quality of life in children with cerebral palsy and their families. METHODS: One hundred children (3-10 years of age) receiving regular rehabilitation therapy for cerebral palsy for last 1 year at a Child Development Centrer were enrolled and the Lifestyle assessment questionnaire - cerebral palsy was administered to the parents. RESULTS: 9% had good, 24% had mildly-affected, 37% had moderately-affected and 30% had severely affected health-related quality of life. The physical independence, mobility and social integration dimensions were much more severely affected than the clinical burden, economic burden and schooling dimensions. CONCLUSION: Health-related quality of child is affected in most children with cerebral palsy. PMID- 24953581 TI - Extracardiac birth defects in children with congenital heart defects. AB - OBJECTIVES: To assess the proportion and pattern of extracardiac birth defects in children with congenital heart defects referred to a tertiary care institute. METHODS: Cross-sectional observational study from January 2010 to June 2011. RESULTS: Out of 560 children with congenital heart defects, 98 (17.5%) had extracardiac birth defects. Fifty-six had multiple congenital defects; 36 were syndromic cases and 6 had laterality defects. A total of 386 extracardiac birth defects (103 major and 283 minor) were documented, with craniofacial and skeletal birth defects being the commonest. CONCLUSION: Extracardiac birth defects are common in children with congenital heart defects. PMID- 24953582 TI - Effect of a behaviour-change intervention on hand washing with soap in India (SuperAmma): a cluster-randomised trial: evidence-based-medicine viewpoint. PMID- 24953583 TI - Effect of a behaviour-change intervention on hand washing with soap in India (SuperAmma): a cluster-randomised trial: public health and policy viewpoint. PMID- 24953584 TI - Effect of a behaviour-change intervention on hand washing with soap in India (SuperAmma): a cluster-randomised trial: pediatrician's viewpoint. PMID- 24953585 TI - Langerhans cell histiocytosis presenting as isolated mediastinal mass in an infant. AB - BACKGROUND: Isolated mediastinal involvement in Langerhans cell histiocytosis (LCH) has been rarely reported. CASE CHARACTERISTICS: A 3-month-old boy presented with history of low grade intermittent fever, cough and noisy breathing for 2 weeks. OBSERVATION: A chest X-ray showed massive mediastinal widening. Biopsy of the mass confirmed LCH. OUTCOME: Patient is doing well after one year of treatment with LCH III protocol. MESSAGE: Langerhans cell histiocytosis should be considered in differential diagnosis of mediastinal mass in infants. PMID- 24953586 TI - Phenotypic variability in congenital lipoid adrenal hyperplasia. AB - BACKGROUND: Congenital lipoid adrenal hyperplasia presents with adrenal insufficiency and sex reversal in 46XY genetic males. CASE CHARACTERISTICS: Two patients (46 XY karyotype), one having ambiguous genitalia and other having female external genitalia, presented with adrenal crisis at 6 months and 4 weeks of age, respectively. OBSERVATION: Steroidogenic Acute Regulatory Protein gene sequencing revealed homozygous mutations in both patients. OUTCOME: Treatment with hydrocortisone and fludrocortisone resulted in marked improvement. MESSAGE: Congenital lipoid adrenal hyperplasia should be considered in infants having female or ambiguous genitalia, and presenting with adrenal insufficiency. PMID- 24953587 TI - Multidrug-resistant tubercular liver abscess in beta-thalassemia. AB - BACKGROUND: Liver abscesses in thalassemics are predominantly pyogenic. CASE CHARACTERISTICS: 12-year-old thalassemic boy with abdominal pain and high grade fever for 15 days. OBSERVATION: CT abdomen revealed multiple liver abscesses. Pus culture and sensitivity showed multidrug-resistant mycobacteria. Patient was started on second line anti-tubercular drugs. OUTCOME: He responded well with symptomatic improvement and is doing well after 6 months of follow-up. MESSAGE: Liver abscess in patients with thalassemia rarely can be tubercular. PMID- 24953588 TI - Macrophage activation syndrome presenting with pericardial effusion, hyponatremia and renal involvement. AB - BACKGROUND: Macrophage activation syndrome is a rare and life threatening complication of childhood rheumatic disorders. CASE CHARACTERISTICS: 6-year-old male child with macrophage activation syndrome complicating systemic onset juvenile idiopathic arthritis. OBSERVATION: He developed pericardial effusion, hyponatremia and deranged renal function. OUTCOME: Improvement on intravenous cortico steroids. MESSAGE: High index of suspicion can lead to earlier diagnosis of macrophage activation syndrome. PMID- 24953589 TI - Anti-NMDA receptor encephalitis in an adolescent. AB - BACKGROUND: Anti N-methyl-D-aspartate (NMDA) receptor encephalitis is an immune mediated disorder. CASE CHARACTERISTICS: A previously healthy 14-year-old girl presenting with generalized tonic clonic seizures and altered behavior. OBSERVATION: In view of refractory seizures, hallucinations, psychobehavioral and catalepsy like symptoms, and CSF showing lymphocytic pleocytosis, possibility of autoimmune encephalitis was considered. Serum was positive for anti-NMDA receptor antibodies. OUTCOME: She recovered completely in six months without any sequelae. CONCLUSION: Anti-NMDA receptor encephalitis - a potentially treatable disease - should be considered in differential diagnosis of encephalitis when acute behavioral changes, seizures or dyskinesias are present. PMID- 24953590 TI - The ABCD of pediatric practice. PMID- 24953591 TI - Williams syndrome: a case series. AB - Pediatricians awareness about malformation syndromes can help in their timely diagnosis. Williams syndrome is a microdeletion syndrome associated with characteristic facial features and behavioral phenotype. Diagnosis can be confirmed by fluorescence-in-situ hybridization or multiplex ligation probe amplification. Correct diagnosis can help in diagnosing hypercalcemia and cardiac defects, and providing genetic counseling to the family. PMID- 24953593 TI - Brownie-nose: hyperpigmentation in neonatal chikungunya. PMID- 24953592 TI - Accuracy of mothers' perceptions of their child's weight status. AB - The study examined the accuracy of maternal-perceived child weight. Urban affluent mothers of 111 children aged 2-5 years were recruited. Nearly a quarter of mothers overestimated their underweight child as normal weight and all overweight/obese children were perceived as normal weight. Mothers, therefore, were unable to recognize their child's true weight status. PMID- 24953594 TI - Kerion. PMID- 24953595 TI - Acute febrile neutrophilic dermatosis (Sweet syndrome). PMID- 24953596 TI - Cheilitis glandularis simplex. PMID- 24953597 TI - Infantile acne. PMID- 24953598 TI - Podoimbricatin A, a cytotoxic diterpenoid with an unprecedented 6/6/5/6-fused tetracyclic ring system from the twigs and leaves of Podocarpus imbricatus. AB - Podoimbricatin A (1), a diterpenoid possessing an unprecedented 6/6/5/6-fused tetracyclic ring system, and podoimbricatin B (2), a new abietane-type diterpenoid, together with four previously reported diterpenoids and a cyclic peptide were isolated from the twigs and leaves of Podocarpus imbricatus. Their structures were established on the basis of extensive spectroscopic analyses and the relative configuration of 1 was confirmed by single-crystal X-ray diffraction analysis. A plausible biogenetic pathway involving hetero-Diels-Alder cycloaddition as a key reaction is proposed for 1. Compounds 1, 5, and 7 showed inhibitory effects against the A549 and NCI-H292 cancer cell lines. PMID- 24953599 TI - Targeting the PPM1D phenotype; 2,4-bisarylthiazoles cause highly selective apoptosis in PPM1D amplified cell-lines. AB - The metal-dependent phosphatase PPM1D (WIP1) is an important oncogene in cancer, with over-expression of the protein being associated with significantly worse clinical outcomes. In this communication we describe the discovery and optimization of novel 2,4-bisarylthiazoles that phenocopy the knockdown of PPM1D, without inhibiting its phosphatase activity. These compounds cause growth inhibition at nanomolar concentrations, induce apoptosis, activate p53 and display impressive cell-line selectivity. The results demonstrate the potential for targeting phenotypes in drug discovery when tackling challenging targets or unknown mechanisms. PMID- 24953600 TI - Design, synthesis and docking study of 5-(substituted benzylidene)thiazolidine 2,4-dione derivatives as inhibitors of protein tyrosine phosphatase 1B. AB - A series of novel 5-(substituted benzylidene)thiazolidine-2,4-dione derivatives was designed, and synthesized based on our previous studies. Also their activities were evaluated as competitive inhibitors of protein tyrosine phosphatase 1B (PTP1B). Compounds 6d-6g, 7b, 7c, 7e, 7j, 7k, 7m, 14b and 14e-14f showed potent inhibitory effects against PTP1B, and compound 7e, the most potent among the series, had an IC50 of 4.6 MUM. Also a Surflex-Dock docking model of 7e was studied. Compound 7e showed a negative binding energy of -7.35 kcal/mol and a high affinity to PTP1B residues (Gly220, Ala217, Arg221, Asp181, Ser216, Cys215, Phe182, Gln262 and Ile219) in the active sites, indicating that it may stabilize the open form and generate tighter binding to the catalytic sites of PTP1B. PMID- 24953601 TI - Anti-osteoporotic and antioxidant activities of chemical constituents of the aerial parts of Ducrosia ismaelis. AB - A new pterocarpan glycoside, glycinol-3-O-beta-D-glucopyranoside (1), and a new dihydrochalcone glycoside, ismaeloside A (2), were isolated together with 13 known compounds, including several flavonoids (3-8), lignans (9-11), and phenolic compounds (12-15), from the methanol extract of the aerial parts of Ducrosia ismaelis. The chemical structures of these compounds were elucidated from spectroscopic data and by comparison of these data with previously published results. The anti-osteoporotic and antioxidant activities of the isolated compounds were assessed using tartrate-resistant acid phosphatase (TRAP), oxygen radical absorbance capacity (ORAC), and reducing capacity assays. Compound 15 exhibited a dose-dependent inhibition of osteoclastic TRAP activity with a TRAP value of 86.05+/-6.55% of the control at a concentration of 10 MUM. Compounds 1, 3-5, and 8 showed potent peroxyl radical-scavenging capacities with ORAC values of 22.79+/-0.90, 25.57+/-0.49, 20.41+/-0.63, 26.55+/-0.42, and 24.83+/-0.12 MUM Trolox equivalents (TE) at 10 MUM, respectively. Only compound 9 was able to significantly reduce Cu(I) with 23.44 MUM TE at a concentration of 10 MUM. All of the aforementioned compounds were isolated for the first time from a Ducrosia species. PMID- 24953602 TI - Synthesis of bi-/tricyclic azasugars fused thiazinan-4-one and their HIV-RT inhibitory activity. AB - Novel bi-/tricyclic azasugars fused thiazinan-4-one were conveniently synthesized by the tandem Staudinger/aza-Wittig/cyclization reaction under microwave radiation. The aryl group (phenyl or pyridyl) in mercaptan acid had an important effect on the formation of the diastereomers of the tricyclic hybrids 12b-15b. The new bi/tricyclic azasugars 3a-8a, 4b, 6b, 8b and the known ones 2a, 2b were examined for their HIV reverse transcriptase (RT) inhibitory activities. The result showed that compounds 2a-b, 4a, 4b, 5a, and 6a could effectively inhibit RT activity. Among them, the tricyclic azasugar 5a was the best one with the IC50 value of 0.49 MUM. Structure-activity relationship analysis suggested that the phenyl group in the tricyclic azasugars was benefit for their anti-HIV RT activity. PMID- 24953603 TI - Anatomical eponyms, part 1: to look on the bright side. AB - The use of eponyms in medical sciences generally, and in anatomy specifically, remains controversial. In principle, this discussion should have been concluded as far back as 1895 (publication of the first Nomina anatomica): all eponyms should have been removed from the anatomical vocabulary then. In practice, what was believed to be a mere formality proved much more difficult to apply. Most eponyms remain in current use; moreover, their number goes on increasing. Assuming that there's no smoke without fire, we wondered why it seems impossible to get rid of a specific kind of term. The aim of this article and its successor is to weigh up the pros and cons. PMID- 24953604 TI - Fine characterization of glucosylated human IgG by biochemical and biophysical methods. AB - Nonenzymatic glycosylation of proteins finally generates advanced glycation end products (AGEs). The Schiff's base and Amadori adduct are stages of early glycation. AGE-modified IgG may undergo conformational alterations and the final entity of the process may be involved in the pathogenesis of Rheumatoid Arthritis (RA). In this study, glycation of human IgG was carried out with varying concentrations of glucose. Effect of incubation period on glycation of IgG has also been studied. Amadori adduct was detected by nitroblue tetrazolium (NBT) dye. The glucose mediated structural alterations in IgG were studied by UV, fluorescence, CD, FT-IR, DLS and DSC spectroscopy, and SDS-PAGE. Glycation induced aggregation in AGE-IgG was reported in the form of binding of thioflavin T and congo red. Furthermore, AGE-modified IgG exhibited hyperchromicity, decrease of tryptophan fluorescence accompanied by increase in AGE specific fluorescence, loss of beta-sheet, appearance of new peak in FT-IR, increase in hydrodynamic size and melting temperature. SDS-PAGE results showed decrease in the band intensity of glycosylated-IgG compared to native IgG. Glycation-induced modifications and aggregation of IgG might be important in the pathogenesis of RA. PMID- 24953605 TI - Investigating anticancer properties of the sesquiterpene ferutinin on colon carcinoma cells, in vitro and in vivo. AB - AIMS: In this research, ferutinin was evaluated for its possible cytotoxic and apoptotic inducing effects in vitro and in vivo. MAIN METHODS: To determine IC50 values of ferutinin, CT26, HT29 and NIH/3T3 cells were treated with different concentrations of ferutinin. In addition to morphological changes in cells, the DNA damage was studied using DAPI staining, comet assay and PI staining. Ferutinin was also tested for its in vivo activity. KEY FINDINGS: Analyses of cell survival by MTT assay showed that the IC50 values of ferutinin on CT26 and HT29 cells were 26 and 29 MUg/ml, respectively, while after treating nontumoural mouse cells even with 50 MUg/ml ferutinin, 70% of cells was still surviving. The results of DAPI staining and comet assay revealed that ferutinin significantly induced DNA damage in treated cells. Induction of sub-G1 peak after PI staining was also indicative of apoptotic effects of ferutinin in cancerous cells. In vivo studies showed a significant regression in tumour size in mice treated with ferutinin as compared to control groups. Its antitumour effects were very similar to the cisplatin treated group. Histological studies demonstrated that apoptosis rate in tumour cells was increased in comparison to tumour cells in control mice without ferutinin treatment. Interestingly, haematoxylin and eosin staining showed no damage in the spleen and liver of ferutinin treated mice. SIGNIFICANCE: As ferutinin showed less toxic effects in nontumoural cells, and induced its effects via apoptosis induction, it could be considered as an effective anticancer agent for future preclinical experiments. PMID- 24953607 TI - Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice. AB - AIMS: Non-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associated with cardiovascular disease (CVD). Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood. MAIN METHODS: Testicular feminised (Tfm) mice, which have a non functional androgen receptor (AR) and very low serum testosterone levels, were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis. KEY FINDINGS: Hepatic lipid deposition was increased in Tfm mice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator activated receptor-gamma but FASN and ACACA were not altered. SIGNIFICANCE: An action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosterone may act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis. PMID- 24953606 TI - Glucose modulates Pax6 expression through the JNK/p38 MAP kinase pathway in pancreatic beta-cells. AB - AIM: The paired and homeodomain-containing transcription factor, paired box 6 (Pax6), has shown to play pivotal roles in beta-cell function, including cell survival, insulin biosynthesis and secretion. The present study investigates the signaling events that regulate the modulation of Pax6 expression by glucose and the role of this modulation in cell survival in rat insulinoma-1E (INS-1E) cells. MAIN METHODS: INS-1E cells were incubated on 1mM (low) or 25 mM (high) glucose overnight. To elucidate the signaling pathways that regulate Pax6 expression, we utilized specific inhibitors. The siRNA transfection of Pax6 into INS-1E cells was performed by electroporation. The mRNA and protein levels were determined by real-time PCR and Western blotting, respectively. KEY FINDINGS: We found that the mRNA and protein levels of Pax6 were reduced by approximately 4-fold in high, compared to low, glucose-treated cells. Staurosporine, the c-Jun N-terminal kinase (JNK) inhibitor SP600125 and the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 significantly increased Pax6 levels in high glucose treated INS-1E cells compared to their respective controls. However, neither calcium ionophore nor the extracellular signal-regulated kinase (ERK) inhibitor U0126 resulted in any alteration in Pax6 protein expression. Further, a siRNA mediated knockdown of Pax6 significantly decreased the expression of tumor suppressor phosphatase with tensin homology (PTEN) while increasing cell viability in low glucose-treated INS-1E cells. SIGNIFICANCE: This study addresses the signaling events that regulate the glucose-dependent expression of Pax6 and the role of these events in cell survival in pancreatic beta cells. PMID- 24953609 TI - [Clinical significance of hepatitis B surface antigen quantification in chronic hepatitis B]. AB - Since the discovery of HBsAg in the early 1960s, presence of HBsAg in serum has only served to diagnose hepatitis B. Recent development in the quantitative measurement of serum HBsAg has enabled us to improve our understanding on the management of chronic hepatitis B. The surface antigen (sAg) level is at its highest in immune tolerance phase and decreases to the lowest level in immune control/inactive phase when HBeAg is cleared from the serum. Combination of serum sAg titer less than 1,000 IU/mL and serum HBV DNA less than 2,000 IU/mL can identify true inactive carrier from e antigen (eAg) negative hepatitis with diagnostic accuracy of 95%. During the natural course of chronic hepatitis B, changes or absolute level of sAg less than certain level can predict spontaneous sero-clearance of HBsAg. Although the decline of sAg is very slow in interferon (IFN)/pegylated interferon (PEG-IFN) or oral nucleos(-t)ide treated patients, interferon based therapy results in a greater decrease of sAg level and sAg loss. Lack of any decline in sAg titer during PEG-IFN therapy could identify the group of patients who do not response to IFN/PEG-IFN therapy. With the aid of serum HBV DNA, quantitative measurement of serum HBsAg level can be used to optimize the management of chronic hepatitis B in our daily practice. PMID- 24953608 TI - Effects of selective endothelin (ET)-A receptor antagonist versus dual ET-A/B receptor antagonist on hearts of streptozotocin-treated diabetic rats. AB - AIMS: The aim was to study the differences in the effectiveness of two types of endothelin (ET) receptor antagonists (selective ET-A or dual ET-A/B antagonists) on the hearts of streptozotocin (STZ)-induced diabetic rats (type I diabetes) at functional and biochemical/molecular levels. MAIN METHODS: Citrate saline (vehicle) or STZ was injected into rats. The ET-A/B dual receptor antagonist (SB209670, 1mg/kg/day) and the ET-A receptor antagonist (TA-0201, 1mg/kg/day) were then administered to these rats. One week after injection, the animals were separated into those receiving SB209670, TA-0201 or vehicle by 4-week osmotic mini-pump. KEY FINDINGS: The VEGF level and percent fractional shortening in the diabetic heart were significantly decreased compared to the non-diabetic heart, whereas SB209670 and TA-0201 treatments greatly and comparably prevented this decrease. SB209670 treatment was more effective in reversing decreased expressions of KDR and phosphorylated AKT, downstream of VEGF angiogenic signaling, than TA-0201 treatment. The eNOS levels in hearts were significantly higher in diabetic rats than in healthy rats, and this increase was significantly reduced by TA-0210 but not by SB209670 treatment. SIGNIFICANCE: Improvement of KDR mRNA and pAKT levels by SB209670 but not TA-0201 suggests that dual ET-A/-B blockade may be effective in improving intracellular systems of these components in the diabetic rat heart. However, the present study also showed that TA-0201 or SB209670 improved percent fractional shortening and VEGF levels of the diabetic hearts to a similar extent, suggesting that ET-A blockade and dual ET-A/-B blockade are similarly effective in improving cardiac dysfunction in the diabetic rats. PMID- 24953611 TI - [Prognostic value of preoperative positron emission tomography-computed tomography in surgically resected gastric cancer]. AB - BACKGROUND/AIMS: The diagnostic value of PET-CT, in gastric cancer is well known, but the prognostic value of pretreatment PET-CT has not been adequately evaluated. This study aimed to investigate the preoperative prognostic value of PET-CT in gastric cancer patients. METHODS: A total of 107 patients underwent surgical treatment for gastric cancer from April 2007 to December 2010 at Dong-A University Medical Center after confirming the presence of F-18 fluorodeoxyglucose (FDG) uptake on preoperative PET-CT. Among these patients, the following subjects were excluded: follow-up loss (13), palliative resection (5), neoadjuvant chemotherapy (1), and unrelated death (1). The remaining 87 patients were included in this study and data were collected by retrospectively reviewing the medical records. The median follow-up duration, defined as the period from operation to last imaging study date, was 34.2+/-14.8 months. FDG uptake values were represented by maximal standardized uptake value (SUVmax). In order to assess the correlation between SUVmax and recurrence, Kaplan-Meier's survival analysis with log-rank test and cox proportional hazard model were performed. Receiver operating characteristic (ROC) curve was employed to determine the optimal cutoff value of SUVmax. RESULTS: The result of Kaplan-Meier's survival analysis with log-rank test were significantly different between high SUVmax group and low SUVmax group (p=0.035), the cutoff value of which was 5.6. However, in multivariate analysis with cox proportional hazard model, T-staging, N-staging and SUVmax did not show statistical significance (p=0.190, p=0.307, and p=0.436, respectively). CONCLUSIONS: High SUVmax on PET-CT in gastric cancer can be a useful prognostic factor. PMID- 24953610 TI - Difficult establishment of a chronic nonsteroidal anti-inflammatory drugs induced gastric inflammation rat model due to gastric adaptation and small bowel damage. AB - BACKGROUND/AIMS: The prevalence of peptic ulcer disease has not decreased mainly due to an increase in the use of NSAIDs. This study was conducted in order to determine whether a chronic NSAID-induced gastric inflammation model could be established by repeated administration of NSAID. METHODS: Indomethacin (10 mg/kg) was administered once per week for six weeks in 8- and 26-week rats and animals were sacrificed every week after administration. Gross ulcer index, histologic damage index, myeloperoxidase (MPO) activity, and mucus (glucosamine) levels were measured. Small bowel damage was also evaluated. RESULTS: Gross gastric damage index showed a peak level at three weeks and then decreased slowly in the 26-week indomethacin group. Gastric mucosal glucosamine level increased in both the 8 week (p=0.038) and 26-week groups (p=0.007). In addition, gastric mucosal MPO level decreased in the 8-week group (p=0.018) but did not show a decrease in the 26-week group. Small bowel damage began to occur at three weeks during the schedule and eight of 36 rats (22.2%) died due to perforation or peritonitis of the small bowel in the 8- and 26-week indomethacin groups, respectively. CONCLUSIONS: Due to gastric adaptation and small bowel damage, repeated administration of NSAID to experimental animals may not be an adequate method for establishment of the chronic gastric inflammation model. PMID- 24953613 TI - [Analysis of a blog for gastrointestinal disease in the view point of the big data: a single institutional study]. AB - BACKGROUND/AIMS: With the enormous increase in the amount of data, the concept of big data has emerged and this allows us to gain new insights and appreciate its value. However, analysis related to gastrointestinal diseases in the viewpoint of the big data has not been performed yet in Korea. This study analyzed the data of the blog's visitors as a set of big data to investigate questions they did not mention in the clinical situation. METHODS: We analyzed the blog of a professor whose subspecialty is gastroenterology at Gangnam Severance Hospital. We assessed the changes in the number of visitors, access path of visitors, and the queries from January 2011 to December 2013. RESULTS: A total of 50,084 visitors gained accessed to the blog. An average of 1,535.3 people visited the blog per month and 49.5 people per day. The number of visitors and the cumulative number of registered posts showed a positive correlation. The most utilized access path of visitors to the website was blog.iseverance.com (42.2%), followed by Google (32.8%) and Daum (6.6%). The most searched term by the visitors in the blog was intestinal metaplasia (16.6%), followed by dizziness (8.3%) and gastric submucosal tumor (7.0%). CONCLUSIONS: Personal blog can function as a communication route for patients with digestive diseases. The most frequently searched word necessitating explanation and education was 'intestinal metaplasia'. Identifying and analyzing even unstructured data as a set of big data is expected to provide meaningful information. PMID- 24953612 TI - [Comparison of blood leptin concentration and colonic mucosa leptin expression in colon adenoma patients and healthy control]. AB - BACKGROUND/AIMS: Obesity increases the risk of colorectal cancer and adenomatous polyp, and one of the underlying mechanisms of this increase is considered to be due to the growth promoting effects of adipokines, such as leptin. In order to investigate this finding, leptin expression in the colonic tissue and blood leptin concentration of the colonic adenoma patients were compared to those of the control group. METHODS: Colonic adenoma tissues were obtained by polypectomy (n=60). In these patients, normal colonic mucosa at remote areas from the polyp was also obtained and blood samples were collected as well. Age and sex matched control subjects were selected among those who showed normal colonic mucosa in health screening colonoscopy (n=60). RESULTS: There was no significant difference in serum leptin concentration between the colonic adenoma patients and control subjects. Leptin expression was noted in 43.3% of the colonic adenomas, but only in 6.7% of normal colonic mucosa from the control subjects (p<0.01). There were ten cases of concurrent adenocarcinoma in situ in adenoma patients, eight cases of which expressed leptin (p=0.01). In adenoma group, leptin expression rate was significantly high in larger adenomas and in obese patients (p<0.05). However, there was no statistically significant relationship between leptin expression in colonic mucosa and serum leptin level. CONCLUSIONS: Leptin expression was more frequently observed in colonic adenomas, especially in larger adenomas associated with adenocarcinoma in situ, but blood leptin level was not related to tissue leptin expression. Leptin expression was more frequently observed in obese patients from the adenoma group. Therefore, leptin may play an important role in colonic tumorigenesis and progression, especially in obese patient. PMID- 24953614 TI - Pseudoepitheliomatous hyperplasia mimicking esophageal squamous cell carcinoma in a patient with lye-induced esophageal stricture. AB - Pseudoepitheliomatous hyperplasia is a benign condition that may be caused by prolonged inflammation, chronic infection, and/or neoplastic conditions of the mucous membranes or skin. Due to its histological resemblance to well differentiated squamous cell carcinoma, pseudoepitheliomatous hyperplasia may occasionally be misdiagnosed as squamous cell carcinoma. The importance of pseudoepitheliomatous hyperplasia is that it is a self-limited condition that must be distinguished from squamous cell carcinoma before invasive treatment. We report here on a rare case of esophageal pseudoepitheliomatous hyperplasia in a 67-year-old Korean woman with a lye-induced esophageal stricture. Although esophageal pseudoepitheliomatous hyperplasia is infrequently encountered, pseudoepitheliomatous hyperplasia should be considered in the differential diagnosis of esophageal lesions. PMID- 24953615 TI - A case of lipoma of parietal peritoneum causing abdominal pain. AB - Lipomas are common benign tumors of mature adipose tissue, enclosed by thin fibrous capsules. They can occur on any part of the body; however, peritoneal lipoma is extremely rare. We encountered a case of a 75-year-old man presenting with intermittent abdominal pain, who had undergone right hemicolectomy due to colon cancer. Abdominal computerized tomography showed a well-defined heterogenous fatty mass measuring 4.5 * 3.5 cm in size, suggesting fat necrosis located in the abdominal wall. Laparotomy showed a very large soft mass of peritoneum. Pathologically, the tumor was diagnosed as lipoma containing fat necrosis located in parietal peritoneum not fixed to any organs, but with small bowel adhesion. Due to its rare etiologic origin and obscure cause of development, we report on a case of lipoma of parietal peritoneum causing abdominal pain. PMID- 24953616 TI - [A case of successful endoscopic clipping for iatrogenic colon perforation induced by peritoneal catheter insertion]. AB - Advanced cancer patients with refractory ascites often do not respond to conventional treatments including dietary sodium restriction, diuretics, and repeated large volume paracentesis. In these patients, continuous peritoneal drainage by an indwelling catheter may be an effective option for managing refractory ascites with a relative low complication rate. Peritoneal catheter induced complications include hypotension, hematoma, leakage, cellulitis, peritonitis, and bowel perforation. Although bowel perforation is a very rare complication, it can become disastrous and necessitates emergency surgical treatment. Herein, we report a case of a 57-year-old male with refractory ascites due to advanced liver cancer who experienced iatrogenic colonic perforation after peritoneal drainage catheter insertion and was treated successfully with endoscopic clipping. PMID- 24953617 TI - [Clinical review and case report of ceftriaxone-associated gallbladder pseudolithiasis in adult]. AB - Although ceftriaxone can be used safely in most instances, it can sometimes induce biliary sludge or stone formation. Most of the patients remain asymptomatic and children are more susceptible to develop this condition, but adults can be affected as well. Because sludge or stones disappear after discontinuing ceftriaxone, this condition is referred to as ceftriaxone associated pseudolithiasis. A 54-year-old woman was admitted to a local clinic for management of ileus. During admission, she had received ceftriaxone and metronidazole, and had been on nil per os for the past 6 days. She was then referred to our hospital for cholecystectomy due to persistent right upper quadrant pain. Although imaging studies showed gallbladder sludge, pseudolithiasis was suspected because of ceftriaxone administration history and prolonged fasting. After careful watch-and-wait, the condition resolved spontaneously after ceftriaxone discontinuation. Our clear understanding on ceftriaxone-associated gallbladder pseudolithiasis allowed us to avoid an unnecessary cholecystectomy. Herein, we report the case of a 54-year-old woman with ceftriaxone-associated gallbladder pseudolithiasis that was successfully managed by ceftriaxone discontinuation alone. PMID- 24953618 TI - [Challenges of inflammatory dermatoses]. PMID- 24953619 TI - [Definition and psychopathology of chronic hand dermatitis]. AB - Psychopathology in patients with DCM is as complex as its clinical forms where the factors are numerous and often intricate. It combines psychophysiological, psychopathological factors, behavioral disorders which can be the cause or the consequence of DCM but also the negative impact on quality of life and the simplest daily activities. DCM affects the quality of life of every patient, regardless of the severity. Women are more affected by the DCM that man older age, male sex, atopy and the existence of a contact sensitization are independent risk factors of severity. Depression may affect up to 10 % of patients, should involve greater attention from dermatologists and general practitioners. Health authorities and all health actors should be aware of interactions between secondary cognitive troubles or inherent to DCM and efforts required in terms of preventive measures. Thus, the presence of psychiatric comorbidity is more common in patients with chronic dermatoses. Today it is considered that the emotional environment, built by the mother - child relationship must be optimal, otherwise the mental stability of body image may be compromised. Diminished self-esteem, affects less well managed and somatic expression of emotional content. Recently, a surprising study showed that most patients with refractory occupational dermatitis were not able to recognize the warning sign of flare or the role of psychological factors in the formation and maintenance of the dermatose. In fact, they rejected their personal responsibility in the occurrence of the new flare. To address this public health problem, health authorities, trainers and caregivers should be aware of the cognitive impact of DCM in these patients and interactions with current means of prevention. The role of obsessive-compulsive washing as part of an anxiety disorder or personality disorder is most likely a contributing or maintaining factor systematically underestimated in the pathogenesis of DCM and in the therapeutic management. PMID- 24953620 TI - [Hand eczema : disability and impact]. AB - INTRODUCTION: Hand eczema is a dermatological condition that may lead to physical and psychological disability, with psychological impact on social relationships, daily life activities and work. OBJECTIVES: Review of the literature on the impact of eczema of the hands and resulting disabilities. METHODS: Medline and Embase search from 1990 to 2013. RESULTS: Hand eczema is a disabling disease because of its poor prognosis. It has an impact on quality of life, which has been assessed using generic scales (MOS-SF36 and EQ-5D) and generic dermatological scales (DLQI and the Skindex). There are no quality-of-life scales specific to hand eczema. This dermatosis may also have repercussions on work, resulting in absenteeism and at times requiring occupational retraining. Hand eczema has economic repercussions with several factors to be taken into account such as medical consultations, medical expenses, loss of productivity, work leave, changes in job position, compensation, and the need for occupational retraining. CONCLUSION: Management of hand eczema by a dermatologist requires taking into account the importance of the physical and psychological disability and the consequences on social relations, activities of daily life, and work. In this context, measuring quality of life is important in assessing patients'perception of the disease and their experience. PMID- 24953621 TI - [Skin tests in chronic hand dermatitis]. AB - Chronic hand dermatitis is often multifactorial but allergic causes are frequent and can complicate atopic dermatitis or irritant dermatitis. The management of patients affected by hand dermatitis includes detailed interrogation and a complete examination of the skin. Allergologic tests must be systematically realized if examination is suggestive of contact dermatitis or protein contact dermatitis, if an occupational origin is suspected but also in all patients in which treatment is ineffective. Skin tests include patch tests with the European standard series, specialized or additional series if necessary. Skin tests may also include personal items used by patients on a daily basis. If protein contact dermatitis is suspected skin tests include prick tests. Only complete and definitive eviction of allergens can allow a complete and definitive cure of chronic hand dermatitis. PMID- 24953622 TI - [Therapeutic patient education in chronic hand dermatitis]. AB - Hand dermatitis (HD) is usually due to a combination of various interacting factors. It involves significant impairment of the quality of life with psychological and socioeconomic impact. A therapeutic education program in HD.was elaborated by 19 health professionals (dermatologists, occupational clinical physicians, nurses, psychologists, environmental medical advisor) with experience in therapeutic education or skills in HD, according to the recommendations of Haute Autorite de Sante. The program includes an individual medical consultation to perform educational diagnostic, two collective workshops and a medical evaluation consult. Two group workshops "the disease, irritant factors and its treatments" and "the experiences and feelings" were elaborated with learning objectives and educative tools. Different scores were proposed to evaluate the program and acquired skills. Therapeutic education is an efficient way to help patients to adopt skin protection measures essential to healing. We propose a guideline of therapeutic education in HD including skills and educative tools and intended for health professionals to serve as working basis. PMID- 24953623 TI - [Management of chronic hand eczema]. AB - The management of hand eczema, more readily called chronic hand dermatitis, is complex. This heaviness is related not only to the disease itself by its different clinical forms but also the multiplicity and diversity of etiological factors, triggering / maintaining or aggravating factors. The repeated therapeutic failures are ransom of incorrect information about the disease and its environment, a lack of clarity in the prescription and duration of treatment in general too short. The reference treatment is high potency topical steroids with or without occlusion for 4-8 weeks followed by alitretinoin 30 mg / day for at least 3-6 months with a monthly lipid and liver monitoring and mandatory monthly pregnancy test in women of childbearing. Associated measures and patient education are the cornerstones of successful treatment. Other alternative treatments such as phototherapy, methotrexate, cyclosporin, mycophenolate mofetil etc. can be considered in case of resistance or for clearing followed by topical treatments. PMID- 24953624 TI - Details unfold: the endoplasmic reticulum stress response in intestinal inflammation and cancer. PMID- 24953625 TI - Insights into the molecular pathophysiology of inflammatory bowel disease: ATG16L1 suppresses nod-driven inflammation. PMID- 24953626 TI - Combination of daclatasvir and sofosbuvir for hepatitis C genotypes 1, 2, and 3. PMID- 24953627 TI - The fall and rise of 5-hydroxytryptamine receptor antagonists in irritable bowel syndrome with diarrhea. PMID- 24953628 TI - Single-step microfluidic synthesis of various nonspherical polymer nanoparticles via in situ assembling: dominating role of polyelectrolytes molecules. AB - In this paper, a microfluidic approach has been used for the synthesis of ellipsoidal, dumbbell, rodlike, and necklacelike polymer nanoparticles. High yields of special types of nonspherical nanoparticles have been achieved by the implementation of an emulsion polymerization into microfluidic arrangement with a micro hole-plate reactor for the formation of monomer droplets. Here, in particular, the formation of nonspherical polymer nanoparticles is dependent on the presence of polyelectrolyte surface active molecules such as poly(4 styrenesulfonic acid-co-maleic acid) sodium salt (PSS-co-PM), poly(sodium-p styrenesulfonate) (PSSS), and polyanetholesulfonic acid sodium salt (PAES). The shapes and sizes of the interparticle nanoassemblies are precisely controlled by adjusting the concentration of polyelectrolytes in the aqueous phase, and by choosing suitable flow rate ratios (aqueous to monomer phase), respectively. The formation of polymer nanoparticles with different morphologies can be explained by a spontaneous in situ assembling under partial electrostatic repulsive control in the single step synthesis. The effect of particle charge and the competition between thermal motion of particles and electrostatic repulsion on the spontaneous assembling under the condition of a limited polarizability are discussed here as an important factor for the formation process of nonspherical polymer nanoparticles. PMID- 24953630 TI - Plasmon resonance analysis with configuration interaction. AB - Dipole plasmon resonances are described quantum mechanically using configuration interaction (CI). A fictitious system of three interacting configurations is considered, which yields three excited states. Excited states energies and oscillator strengths are derived from the eigenvalues and eigenvectors of the CI matrix, where the diagonal elements alpha(i) (i = 1, 2, 3) correspond to the interacting one-electron transition energies and the off-diagonal elements beta(ij) correspond to the coupling between these configurations. The plasmonic state is easily identified by its higher energy and much larger oscillator strength. This high oscillator strength is due to a constructive addition of the eigenvectors contributing to this state. The maximum oscillator strength enhancement of the plasmon peak is equal to the number of configurations in the CI matrix (three here), which occurs in the ideal case where all alpha elements are equal and all beta elements are equal. When the transitions involved in the CI have different energies (different alpha values), the oscillator strength of the plasmon peak becomes smaller and its energy is shifted in comparison to the ideal case. Increasing all the coupling values from 0 up to the point where the coupling is similar in magnitude to the difference in alpha values leads to a rapid rise of the plasmon peak oscillator strength whereas its energy slightly blue-shifts. A further increase of the coupling values does not affect the oscillator strength of the plasmon peak, which remains near its maximum enhancement value, but drastically affects its energy, which rapidly rises. The plasmonic behavior of noble metal model systems is successfully described using configuration interaction. PMID- 24953629 TI - SUMO1 modification stabilizes CDK6 protein and drives the cell cycle and glioblastoma progression. AB - Ubiquitination governs oscillation of cyclin-dependent kinase (CDK) activity through a periodic degradation of cyclins for orderly cell cycle progression; however, the mechanism that maintains the constant CDK protein levels throughout the cell cycle remains unclear. Here we show that CDK6 is modified by small ubiquitin-like modifier-1 (SUMO1) in glioblastoma, and that CDK6 SUMOylation stabilizes the protein and drives the cell cycle for the cancer development and progression. CDK6 is also a substrate of ubiquitin; however, CDK6 SUMOylation at Lys 216 blocks its ubiquitination at Lys 147 and inhibits the ubiquitin-mediated CDK6 degradation. Throughout the cell cycle, CDK1 phosphorylates the SUMO specific enzyme, ubiquitin-conjugating enzyme9 (UBC9) that in turn mediates CDK6 SUMOylation during mitosis; CDK6 remains SUMOylated in G1 phase and drives the cell cycle through G1/S transition. Thus, SUMO1-CDK6 conjugation constitutes a mechanism of cell cycle control and inhibition of this SUMOylation pathway may provide a strategy for treatment of glioblastoma. PMID- 24953631 TI - The reciprocal internal/external frame of reference model using grades and test scores. AB - BACKGROUND: The reciprocal I/E model (RI/EM) combines the internal/external frame of reference model (I/EM) with the reciprocal effects model (REM). The RI/EM extends the I/EM longitudinally and the REM across domains. The model predicts that, within domains, mathematics and verbal achievement (VACH) and academic self concept have positive effects on subsequent mathematics and VACH and academic self-concept within domains but have negative effects across domains. AIMS: The main purpose is to validate the RI/EM and extend it using objective achievement indicators and grades. SAMPLE: Two waves of data collection from grade 5 to grade 9 with N = 1,045 secondary school students were used. METHODS: Test scores, grades, and self-concept data were obtained. The main analyses were conducted using hierarchical linear modelling. RESULTS: The positive longitudinal effects of grades and test scores on subsequent grades, test scores and academic self concept within domains and the negative effects of grades and test scores on subsequent academic self-concept across domains supported the RI/EM. The effects of academic self-concept on subsequent grades and test scores across domains were near zero when prior achievement indicators were controlled for. Overall, the results using school grades as achievement measures were replicated using standardized achievement test scores. CONCLUSIONS: The results serve to highlight the importance of the combination of common theories, which are mostly investigated individually, to enhance our understanding of the complexity of within- and across-domain relations between academic self-concepts and achievement using grades as well as test scores. PMID- 24953633 TI - The specifics of allergen recognition by CD4(+) T lymphocytes at the epitope level. PMID- 24953634 TI - Comment on: prenatal exposure to acid-suppressive drugs and the risk of allergic disease in the offspring: a cohort study. PMID- 24953635 TI - Response to the comment on: prenatal exposure to acid-suppressive drugs and the risk of allergic disease in the offspring: a cohort study. PMID- 24953637 TI - Application of flow cytometry for genome size determination in Geosmithia fungi: a comparison of methods. AB - Genome size has played an important role in the evolution of plants and animals because changes in genome size seem to accompany if not facilitate evolutionary adaptation to environmental conditions. Flow cytometry (FCM) is a widespread method for determining genome size thanks to its high accuracy and speed of measurements. Nevertheless, only a few comparative studies of FCM methods exist in the field of mycology, and reviews are absent. In this study, we compared the suitability of several concentrations and RNAse A incubation times, fixatives and buffers for estimating genome size in fungi. We chose the genus Geosmithia as a model filamentous fungus. We also introduced a new standard, Aspergillus fumigatus CEA10, to determine absolute genome size. We found FCM to be an appropriate method for measuring genome size in fungi, but optimization steps showed that incorrect propidium iodide staining of nuclei can overestimate genome size due to cytoplasmic staining. We identified fixation with methanol:glacial acetic acid (3:1 v/v), 10% DMSO, 0.1% Triton-X 100, and 5 mM EDTA in combination with Tris-MgCl2 buffer as the best treatment. PMID- 24953638 TI - Hyponatraemic seizure in a 6-month-old infant due to water intoxication. PMID- 24953641 TI - Are people consistent when trading time for health? AB - The conventional, or standard, time trade-off (TTO) procedure, which is used to elicit the values that people place on health states that are in turn required to calculate quality adjusted life-years (QALYs), asks respondents to trade off fewer life years for better health. It is possible to reverse the procedure to ask respondents to trade off less health for more life years. Theoretically, these two procedures should generate the same TTO values for any given health state. This article reports that for health states defined by differing frequencies of migraine attack, the standard TTO gives health state values that are significantly higher than those given by the reverse TTO. The observed systematic procedural invariance, which substantiates some previous findings reported in the literature and is consistent with a loss aversion effect, challenges the validity of the TTO for generating reliable valuations of health states. PMID- 24953639 TI - Nitrogen deposition contributes to soil acidification in tropical ecosystems. AB - Elevated anthropogenic nitrogen (N) deposition has greatly altered terrestrial ecosystem functioning, threatening ecosystem health via acidification and eutrophication in temperate and boreal forests across the northern hemisphere. However, response of forest soil acidification to N deposition has been less studied in humid tropics compared to other forest types. This study was designed to explore impacts of long-term N deposition on soil acidification processes in tropical forests. We have established a long-term N-deposition experiment in an N rich lowland tropical forest of Southern China since 2002 with N addition as NH4 NO3 of 0, 50, 100 and 150 kg N ha(-1) yr(-1) . We measured soil acidification status and element leaching in soil drainage solution after 6-year N addition. Results showed that our study site has been experiencing serious soil acidification and was quite acid-sensitive showing high acidification (pH(H2O) <4.0), negative water-extracted acid neutralizing capacity (ANC) and low base saturation (BS,< 8%) throughout soil profiles. Long-term N addition significantly accelerated soil acidification, leading to depleted base cations and decreased BS, and further lowered ANC. However, N addition did not alter exchangeable Al(3+) , but increased cation exchange capacity (CEC). Nitrogen addition-induced increase in SOC is suggested to contribute to both higher CEC and lower pH. We further found that increased N addition greatly decreased soil solution pH at 20 cm depth, but not at 40 cm. Furthermore, there was no evidence that Al(3+) was leaching out from the deeper soils. These unique responses in tropical climate likely resulted from: exchangeable H(+) dominating changes of soil cation pool, an exhausted base cation pool, N-addition stimulating SOC production, and N saturation. Our results suggest that long-term N addition can contribute measurably to soil acidification, and that shortage of Ca and Mg should receive more attention than soil exchangeable Al in tropical forests with elevated N deposition in the future. PMID- 24953643 TI - Prebiotic cell membranes that survive extreme environmental pressure conditions. AB - Attractive candidates for compartmentalizing prebiotic cells are membranes comprised of single-chain fatty acids. It is generally believed that life may have originated in the depth of the protoocean, that is, under high hydrostatic pressure conditions, but the structure and physical-chemical properties of prebiotic membranes under such conditions have not yet been explored. We report the temperature- and pressure-dependent properties of membranes composed of prebiotically highly-plausible lipids and demonstrate that prebiotic membranes could not only withstand extreme temperatures, but also serve as robust models of protocells operating in extreme pressure environments. We show that pressure not only increases the stability of vesicular systems but also limits their flexibility and permeability to solutes, while still keeping the membrane in an overall fluid-like and thus functional state. PMID- 24953644 TI - Targeting chemokine (C-X-C motif) receptor 3 in thyroid autoimmunity. AB - The C-X-C chemokine receptor (CXCR)3 and its chemokines (CXCL9, CXCL10, CXCL11) are involved in the pathogenesis of autoimmune thyroiditis (AT), Graves' disease (GD) and Graves' Ophthalmopathy (GO). Under the influence of interferon(IFN)gamma, the IFNgamma-induced protein 10 (IP-10/CXCL10) is secreted by thyrocytes, orbital fibroblasts and preadipocytes. In tissue, Th1 lymphocytes are recruited; hence IFNgamma is enhanced, which stimulates CXCL10 secretion reiterating the autoimmune process. The presence of elevated levels of CXCL10 in peripheral liquids is considered a marker of Th1 orientated immune response. High levels of circulating CXCL10 (sCXCL10) have been shown in patients with AT, overall with hypothyroidism. In GD and GO patients high sCXCL10 have been shown particularly in the active disease. A modulatory role of peroxisome proliferator activated receptor (PPAR)gamma or - alpha agonists on CXCR3 chemokines in AT, GD and GO and the immuno-modulatory effect of methimazole on CXCR3 chemokines in GD have been shown. Further studies are ongoing to explore the use of new molecules that act as antagonists of CXCR3, or block CXCL10, in autoimmune disorders, and many interesting patents have been recently applied. PMID- 24953642 TI - Angiotensin-(1-7) reverses angiogenic dysfunction in corpus cavernosum by acting on the microvasculature and bone marrow-derived cells in diabetes. AB - INTRODUCTION: Angiotensin (Ang)-(1-7) is a recently identified vasoprotective heptapeptide, and it appears to activate the reparative functions of bone marrow derived stem/progenitor cells (BMPCs). AIM: This study evaluated the effect of Ang-(1-7) in the angiogenic function of cavernosum in type 1 diabetes (T1D) and delineated the role of BMPCs in this protective function. METHODS: T1D was induced by streptozotocin in mice, and mice with 20-24 weeks of diabetes were used for the study. Ang-(1-7) was administered subcutaneously by using osmotic pumps. Cavernosa, and BMPCs from peripheral blood and bone marrow were evaluated in different assay systems. MAIN OUTCOME MEASURES: Angiogenic function was determined by endothelial tube formation in matrigel assay. Circulating BMPCs were enumerated by flow cytometry and proliferation was determined by BrdU incorporation. Cell-free supernatant of BMPCs were collected and tested for paracrine angiogenic effect. Expression of angiogenic factors in BMPCs and cavernosa were determined by real-time polymerase chain reaction. RESULTS: Ang-(1 7) (100 nM) stimulated angiogenesis in mouse cavernosum that was partially inhibited by Mas1 receptor antagonist, A779 (10 MUM) (P < 0.05). In cavernosa of T1D, the angiogenic responses to Ang-(1-7) (P < 0.005) and VEGF (100 nM) (P < 0.03) were diminished. Ang-(1-7) treatment for 4 weeks reversed T1D-induced decrease in the VEGF-mediated angiogenesis. Ang-(1-7) treatment increased the circulating number of BMPCs and proliferation that were decreased in T1D (P < 0.02). Paracrine angiogenic function of BMPCs was reduced in diabetic BMPCs, which was reversed by Ang-(1-7). In diabetic BMPCs, SDF and angiopoietin-1 were upregulated by Ang-(1-7), and in cavernosum, VEGFR1, Tie-2, and SDF were upregulated and angiopoietin-2 was down-regulated. CONCLUSIONS: Ang-(1-7) stimulates angiogenic function of cavernosum in diabetes via its stimulating effects on both cavernosal microvasculature and BMPCs. PMID- 24953645 TI - Development of a risk-based prioritisation methodology to inform public health emergency planning and preparedness in case of accidental spill at sea of hazardous and noxious substances (HNS). AB - Hazardous and noxious chemicals are increasingly being transported by sea. Current estimates indicate some 2000 hazardous and noxious substances (HNS) are carried regularly by sea with bulk trade of 165milliontonnes per year worldwide. Over 100 incidents involving HNS have been reported in EU waters. Incidents occurring in a port or coastal area can have potential and actual public health implications. A methodology has been developed for prioritisation of HNS, based upon potential public health risks. The work, undertaken for the Atlantic Region Pollution Response programme (ARCOPOL), aims to provide information for incident planning and preparedness. HNS were assessed using conventional methodology based upon acute toxicity, behaviour and reactivity. Tonnage was used as a proxy for likelihood, although other factors such as shipping frequency and local navigation may also contribute. Analysis of 350 individual HNS identified the highest priority HNS as being those that present an inhalation risk. Limitations were identified around obtaining accurate data on HNS handled on a local and regional level due to a lack of port records and also political and commercial confidentiality issues. To account for this the project also developed a software tool capable of combining chemical data from the study with user defined shipping data to be used by operators to produce area-specific prioritisations. In conclusion a risk prioritisation matrix has been developed to assess the acute risks to public health from the transportation of HNS. Its potential use in emergency planning and preparedness is discussed. PMID- 24953647 TI - Hypertension and obesity: correlates with renin-angiotensin-aldosterone system and uric acid. PMID- 24953646 TI - The emerging role of circulating microRNAs as biomarkers in autoimmune diseases. AB - The highly conserved RNAs known as microRNAs (miRNAs) are a class of small, single-stranded, non-coding RNAs that play a critical role in the regulation of host genome expression at the posttranscriptional level. MiRNA-mediated gene regulation is vital for normal cellular functions, such as the cell differentiation, proliferation and apoptosis, and nearly one-third of human messenger RNAs might be miRNA targets. Increasing evidence has suggested that miRNAs play a critical role in the regulating the immune system and preventing autoimmune disorders. Circulating miRNAs, which can be easily detected by a non invasive methods, have been proven to be able to distinguish diseased individuals from healthy subjects. In addition, these circulating miRNAs have relatively high sensitivity and specificity and thus have been developed as biomarkers for the diagnosis and monitoring of human diseases. To date, nearly 100 circulating miRNAs have been proven to be biomarkers for various diseases, and this number continues to rise. This review aims to summarize the most promising identified circulating miRNAs as potential biomarkers in autoimmune diseases and to discuss current challenges and future directions in the field. PMID- 24953648 TI - In vitro functional studies of rare CYP21A2 mutations and establishment of an activity gradient for nonclassic mutations improve phenotype predictions in congenital adrenal hyperplasia. AB - BACKGROUND: A detailed genotype-phenotype evaluation is presented by studying the enzyme activities of five rare amino acid substitutions (Arg233Gly, Ala265Ser, Arg341Trp, Arg366Cys and Met473Ile) identified in the CYP21A2 gene in patients investigated for Congenital adrenal hyperplasia (CAH). OBJECTIVE: To investigate whether the mutations identified in the CYP21A2 gene are disease causing and to establish a gradient for the degree of enzyme impairment to improve prediction of patient phenotype. DESIGN AND PATIENTS: The CYP21A2 genes of seven patients investigated for CAH were sequenced and five mutations were identified. The mutant proteins were expressed in vitro in COS-1 cells, and the enzyme activities towards the two natural substrates were determined to verify the disease-causing state of the mutations. The in vitro activities of these rare mutations were also compared with the activities of four mutations known to cause nonclassic CAH (Pro30Leu, Val281Leu, Pro453Ser and Pro482Ser) in addition to an in silico structural evaluation of the novel mutants. MAIN OUTCOME MEASURE: To verify the disease-causing state of novel mutations. RESULTS: Five CYP21A2 mutations were identified (Arg233Gly, Ala265Ser, Arg341Trp, Arg366Cys and Met473Ile). All mutant proteins exhibited enzyme activities above 5%, and four mutations were classified as nonclassic and one as a normal variant. By comparing the investigated protein changes with four common mutations causing nonclassic CAH, a gradient for the degree of enzyme impairment could be established. Studying rare mutations in CAH increases our knowledge regarding the molecular mechanisms that render a mutation pathogenic. It also improves phenotype predictions and genetic counselling for future generations. PMID- 24953649 TI - Structure of the VipA/B type VI secretion complex suggests a contraction-state specific recycling mechanism. AB - The bacterial type VI secretion system is a multicomponent molecular machine directed against eukaryotic host cells and competing bacteria. An intracellular contractile tubular structure that bears functional homology with bacteriophage tails is pivotal for ejection of pathogenic effectors. Here, we present the 6 A cryoelectron microscopy structure of the contracted Vibrio cholerae tubule consisting of the proteins VipA and VipB. We localized VipA and VipB in the protomer and identified structural homology between the C-terminal segment of VipB and the tail-sheath protein of T4 phages. We propose that homologous segments in VipB and T4 phages mediate tubule contraction. We show that in type VI secretion, contraction leads to exposure of the ClpV recognition motif, which is embedded in the type VI-specific four-helix-bundle N-domain of VipB. Disaggregation of the tubules by the AAA+ protein ClpV and recycling of the VipA/B subunits are thereby limited to the contracted state. PMID- 24953650 TI - Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer. AB - Squamous cell carcinoma (SCC) of the lung is the second most common subtype of lung cancer. With limited treatment options, the 5-year survival rate of SCC is only 15%. Although genomic alterations in SCC have been characterized, identifying the alterations that drive SCC is critical for improving treatment strategies. Mouse models of SCC are currently limited. Using lentiviral delivery of Sox2 specifically to the mouse lung, we tested the ability of Sox2 to promote tumorigenesis in multiple tumor suppressor backgrounds. Expression of Sox2, frequently amplified in human SCC, specifically cooperates with loss of Lkb1 to promote squamous lung tumors. Mouse tumors exhibit characteristic histopathology and biomarker expression similar to human SCC. They also mimic human SCCs by activation of therapeutically relevant pathways including STAT and mTOR. This model may be utilized to test the contribution of additional driver alterations in SCC, as well as for preclinical drug discovery. PMID- 24953651 TI - MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice. AB - Cell-cycle phase is a critical determinant of the choice between DNA damage repair by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Here, we report that double-strand breaks (DSBs) induce ATM-dependent MOF (a histone H4 acetyl-transferase) phosphorylation (p-T392-MOF) and that phosphorylated MOF colocalizes with gamma-H2AX, ATM, and 53BP1 foci. Mutation of the phosphorylation site (MOF-T392A) impedes DNA repair in S and G2 phase but not G1 phase cells. Expression of MOF-T392A also blocks the reduction in DSB associated 53BP1 seen in wild-type S/G2 phase cells, resulting in enhanced 53BP1 and reduced BRCA1 association. Decreased BRCA1 levels at DSB sites correlates with defective repairosome formation, reduced HR repair, and decreased cell survival following irradiation. These data support a model whereby ATM-mediated MOF-T392 phosphorylation modulates 53BP1 function to facilitate the subsequent recruitment of HR repair proteins, uncovering a regulatory role for MOF in DSB repair pathway choice during S/G2 phase. PMID- 24953652 TI - EZH2-mediated inactivation of IFN-gamma-JAK-STAT1 signaling is an effective therapeutic target in MYC-driven prostate cancer. AB - Although small-molecule targeting of EZH2 appears to be effective in lymphomas carrying EZH2 activating mutations, finding similar approaches to target EZH2 overexpressing epithelial tumors remains challenging. In MYC-driven, but not PI3K driven prostate cancer, we show that interferon-gamma receptor 1 (IFNGR1) is directly repressed by EZH2 in a MYC-dependent manner and is downregulated in a subset of metastatic prostate cancers. EZH2 knockdown restored the expression of IFNGR1 and, when combined with IFN-gamma treatment, led to strong activation of IFN-JAK-STAT1 tumor-suppressor signaling and robust apoptosis. Pharmacologic depletion of EZH2 by the histone-methylation inhibitor DZNep mimicked the effects of EZH2 knockdown on IFNGR1 induction and delivered a remarkable synergistic antitumor effect with IFN-gamma. In contrast, although they efficiently depleted histone Lysine 27 trimethylation, EZH2 catalytic inhibitors failed to mimic EZH2 depletion. Thus, EZH2-inactivated IFN signaling may represent a therapeutic target, and patients with advanced prostate cancer driven by MYC may benefit from the combination of EZH2 and IFN-gamma-targeted therapy. PMID- 24953654 TI - V-ATPase/mTOR signaling regulates megalin-mediated apical endocytosis. AB - mTOR kinase is a master growth regulator that can be stimulated by multiple signals, including amino acids and the lysosomal small GTPase Rheb. Recent studies have proposed an important role for the V-ATPase in the sensing of amino acids in the lysosomal lumen. Using the Drosophila wing as a model epithelium, we show here that the V-ATPase is required for Rheb-dependent epithelial growth. We further uncover a positive feedback loop for the control of apical protein uptake that depends on V-ATPase/mTOR signaling. This feedback loop includes Rheb dependent transcriptional regulation of the multiligand receptor Megalin, which itself is required for Rheb-induced endocytosis. In addition, we provide evidence that long-term mTOR inhibition with rapamycin in mice causes reduction of Megalin levels and proteinuria in the proximal tubular epithelium of the kidney. Thus, our findings unravel a homeostatic mechanism that allows epithelial cells to promote protein uptake under normal conditions and to prevent uptake in lysosomal stress conditions. PMID- 24953653 TI - GPS2/KDM4A pioneering activity regulates promoter-specific recruitment of PPARgamma. AB - Timely and selective recruitment of transcription factors to their appropriate DNA-binding sites represents a critical step in regulating gene activation; however, the regulatory strategies underlying each factor's effective recruitment to specific promoter and/or enhancer regions are not fully understood. Here, we identify an unexpected regulatory mechanism by which promoter-specific binding, and therefore function, of peroxisome proliferator-activator receptor gamma (PPARgamma) in adipocytes requires G protein suppressor 2 (GPS2) to prime the local chromatin environment via inhibition of the ubiquitin ligase RNF8 and stabilization of the H3K9 histone demethylase KDM4A/JMJD2. Integration of genome wide profiling data indicates that the pioneering activity of GPS2/KDM4A is required for PPARgamma-mediated regulation of a specific transcriptional program, including the lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Hence, our findings reveal that GPS2 exerts a biologically important function in adipose tissue lipid mobilization by directly regulating ubiquitin signaling and indirectly modulating chromatin remodeling to prime selected genes for activation. PMID- 24953657 TI - Yb integrates piRNA intermediates and processing factors into perinuclear bodies to enhance piRISC assembly. AB - PIWI-interacting RNAs (piRNAs) direct Piwi to repress transposons and maintain genome integrity in Drosophila ovarian somatic cells. piRNA maturation and association with Piwi occur at perinuclear Yb bodies, the centers of piRNA biogenesis. Here, we show that piRNA intermediates arising from the piRNA cluster flamenco (flam) localize to perinuclear foci adjacent to Yb bodies, termed Flam bodies. RNAi-based screening of piRNA factors revealed that Flam body formation depends on Yb, the core component of Yb bodies, while Piwi and another Yb body component, Armitage, are dispensable for formation. Abolishing the RNA-binding activity of Yb disrupts both Flam bodies and Yb bodies. Yb directly binds flam, but not transcripts from neighboring protein-coding genes. Thus, Yb integrates piRNA intermediates and piRNA processing factors selectively into Flam bodies and Yb bodies, respectively. We suggest that Yb is a key upstream factor in the cytoplasmic phase of the piRNA pathway in ovarian somatic cells. PMID- 24953655 TI - The transcription Factor AHR prevents the differentiation of a stage 3 innate lymphoid cell subset to natural killer cells. AB - Accumulating evidence indicates that human natural killer (NK) cells develop in secondary lymphoid tissue (SLT) through a so-called "stage 3" developmental intermediate minimally characterized by a CD34(-)CD117(+)CD94(-) immunophenotype that lacks mature NK cell function. This stage 3 population is heterogeneous, potentially composed of functionally distinct innate lymphoid cell (ILC) types that include interleukin-1 receptor (IL-1R1)-positive, IL-22-producing ILC3s. Whether human ILC3s are developmentally related to NK cells is a subject of ongoing investigation. Here, we show that antagonism of the aryl hydrocarbon receptor (AHR) or silencing of AHR gene expression promotes the differentiation of tonsillar IL-22-producing IL-1R1(hi) human ILC3s to CD56(bright)CD94(+) interferon (IFN)-gamma-producing cytolytic mature NK cells expressing eomesodermin (EOMES) and T-Box Protein 21 (TBX21 or TBET). Hence, we demonstrate the lineage plasticity of human ILCs by identifying AHR as a transcription factor that prevents IL-1R1(hi) ILC3s from differentiating into NK cells. PMID- 24953659 TI - A comparison between ultrasonographic, surgical and histological assessment of tenosynovits in a cohort of idiopathic carpal tunnel syndrome patients. AB - Carpal tunnel syndrome (CTS) may be caused by subclinical tenosynovitis which may be detected by ultrasonography (US). The objective of this study is to investigate whether ultrasonography has a place in the workup of idiopathic CTS patients. Therefore, we investigated the prevalence of tenosynovitis and its association with the clinical outcome of surgery. A cohort of 31 consecutive idiopathic CTS patients (33 wrists) who were a candidate for carpal tunnel release (CTR) surgery was assessed using greyscale ultrasonography (GSUS) and power Doppler ultrasonography (PDUS). Peroperatively, tenosynovitis was evaluated macroscopically by the surgeon. Tissue samples from areas macroscopically suspected for tenosynovitis were taken for histological evaluation. The clinical outcome of the operation was assessed after 6 months and if applicable alternative diagnoses for the CTS were proposed. US tenosynovitis (OMERACT) was detected preoperatively in 58 % of the wrists. Peroperatively, macroscopic tenosynovitis was detected visually in 88 % of the wrists. Histological evaluation demonstrated a limited influx of lymphocytes indicative of a mild chronic inflammatory response in 19 %. Non-specific reactive changes were observed in 78 % of the cases. Ultrasonographically defined tenosynovitis was associated with an OR of 2.81 (95 % CI 0.61-13) for responding well to surgery. Most cases of ultrasonographic and peroperatively defined tenosynovitis were classified by histology as reactive changes. The presence of ultrasonographic tenosynovitis might be associated with a better clinical outcome of surgery. PMID- 24953656 TI - The Mammalian response to virus infection is independent of small RNA silencing. AB - A successful cellular response to virus infection is essential for evolutionary survival. In plants, arthropods, and nematodes, cellular antiviral defenses rely on RNAi. Interestingly, the mammalian response to virus is predominantly orchestrated through interferon (IFN)-mediated induction of antiviral proteins. Despite the potency of the IFN system, it remains unclear whether mammals also have the capacity to employ antiviral RNAi. Here, we investigated this by disabling IFN function, small RNA function, or both activities in the context of virus infection. We find that loss of small RNAs in the context of an in vivo RNA virus infection lowers titers due to reduced transcriptional repression of the host antiviral response. In contrast, enabling a virus with the capacity to inhibit the IFN system results in increased titers. Taken together, these results indicate that small RNA silencing is not a physiological contributor to the IFN mediated cellular response to virus infection. PMID- 24953661 TI - [Ischemic heart failure making the diagnosis of a Vaquez disease: a rare event]. AB - We present the case of a 46-year-old patient without any past medical history, admitted to our ICU for cardiogenic shock complicating acute coronary syndrome. The blood tests found polycethemia, a polycethemia vera was suspected and confirmed by genetic analysis. Ischemic heart failure as an initial symptom of polycethemia vera and its treatment by arterial bleeding is a rare event that we describe in this article. PMID- 24953658 TI - Diet-induced alterations in gut microflora contribute to lethal pulmonary damage in TLR2/TLR4-deficient mice. AB - Chronic intake of Western diet has driven an epidemic of obesity and metabolic syndrome, but how it induces mortality remains unclear. Here, we show that chronic intake of a high-fat diet (HFD), not a low-fat diet, leads to severe pulmonary damage and mortality in mice deficient in Toll-like receptors 2 and 4 (DKO). Diet-induced pulmonary lesions are blocked by antibiotic treatment and are transmissible to wild-type mice upon either cohousing or fecal transplantation, pointing to the existence of bacterial pathogens. Indeed, diet and innate deficiency exert significant impact on gut microbiota composition. Thus, chronic intake of HFD promotes severe pulmonary damage and mortality in DKO mice in part via gut dysbiosis, a finding that may be important for immunodeficient patients, particularly those on chemotherapy or radiotherapy, where gut-microbiota-caused conditions are often life threatening. PMID- 24953663 TI - [Hypernatremia in head-injured patients: friend or foe?]. AB - Hypernatremia is defined by a serum sodium concentration of more than 145 mmol/L and reflects a disturbance of the regulation between water and sodium. The high incidence of hypernatremia in patients with severe brain injury is due various causes including poor thirst, diabetes insipidus, iatrogenic sodium administration, and primary hyperaldosteronism. Hypernatremia in the intensive care unit is independently associated with increased mortality and complications rates. Because of the rapid brain adaptation to extracellular hypertonicity, sustained hypernatremia exposes the patient to an exacerbation of brain edema during attempt to normalize natremia. Like serum glucose, serum sodium concentration must be tightly monitored in the intensive care unit. PMID- 24953660 TI - The labyrinth of autoinflammatory disorders: a snapshot on the activity of a third-level center in Italy. AB - Autoinflammatory disorders (AIDs) are a novel class of diseases elicited by mutations in genes regulating the homeostasis of innate immune complexes, named inflammasomes, which lead to uncontrolled oversecretion of the proinflammatory cytokine interleukin-1beta. Protean inflammatory symptoms are variably associated with periodic fever, depicting multiple specific conditions. Childhood is usually the lifetime in which most hereditary AIDs start, though still a relevant number of patients may experience a delayed disease onset and receive a definite diagnosis during adulthood. As a major referral laboratory for patients with recurrent fevers, we have tested samples from 787 patients in the period September 2007-March 2014, with a total of 1,328 AID-related genes evaluated and a gene/patient ratio of 1.69. In this report, we describe our experience in the clinical approach to AIDs, highlight the most striking differences between child and adult-onset AIDs, and shed an eye-opening insight into their diagnostic process. PMID- 24953662 TI - [Extensive brain necrosis secondary to acute ethylene glycol poisoning]. PMID- 24953664 TI - Sources of tooth wear variation early in life among known-aged wild ring-tailed lemurs (Lemur catta) at the Beza Mahafaly Special Reserve, Madagascar. AB - Ring-tailed lemurs (Lemur catta) at the Beza Mahafaly Special Reserve (BMSR), Madagascar display a high frequency of individuals with notable and sometimes extreme tooth wear. Adult lemurs display a range of tooth wear even among individuals of the same age, but we do not know at what age this variation first appears. This study's goal was to determine whether wear variation occurs in younger wild lemurs. Based on the decade-long study of ring-tailed lemur feeding and dental ecology at BMSR, we hypothesized that younger, natal lemurs (under 5 years of age), would display variation in their degree of tooth wear that would correspond to microhabitat differences, given differences in food availability in different troops' home ranges. We also hypothesized that wear would differ between sexes at this young age, given differences in feeding between males and females in this population. Hypotheses were tested using dental topographic analyses using dental impressions collected from known-aged lemurs across 10 years at BMSR. Results illustrate significant differences in wear-related tooth topography (i.e., relief and slope, presented here as "occlusal lift") for microhabitat, sex and troop affiliation among lemurs under 5 years of age in this population. Although, all lemurs in this population consume mechanically challenging tamarind fruit, those in more disturbed habitats eat additional introduced foods, some of which are also mechanically challenging. Thus, dietary variation is the likely cause of variation in tooth wear. The wear variation we show at a young age suggests caution when assigning age based on tooth wear in living and fossil primates. These wear-related tooth shape changes early in life, which reflects sex, habitat variation and levels of anthropogenic disturbance, may potentially impact reproductive fitness later in life. PMID- 24953665 TI - Acupuncture for treating acute ankle sprains in adults. AB - BACKGROUND: An acute ankle sprain is a sudden-onset injury of one or more of the ankle ligaments. It is one of the most common musculoskeletal injuries in the general population as well as in athletes. In some countries, such as China and Korea, acupuncture is frequently used in the treatment of ankle sprains, either as a single treatment or a secondary intervention accompanied by standard medical treatment. OBJECTIVES: To assess the effects (benefits and harms) of acupuncture for the treatment of ankle sprains in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (May 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 4), MEDLINE (1948 to May week 2 2013), EMBASE (1980 to May week 2 2013), China National Knowledge Infrastructure databases (1994 to August week 4 2013), the Cumulative Index to Nursing and Allied Health Literature (1937 to May 2013), the Allied and Complementary Medicine Database (1985 to May 2013), Science Links Japan (1996 to August week 4 2013), several Korean medical databases (August week 4 2013), the World Health Organization International Clinical Trials Registry Platform (August week 4 2013), the bibliographic references of included trials and conference proceedings. SELECTION CRITERIA: We included randomised and quasi randomised controlled trials involving adults with acute ankle sprains. We included all types of acupuncture practices, such as needle acupuncture, electroacupuncture, laser acupuncture, pharmacoacupuncture, non-penetrating acupuncture point stimulation (e.g. acupressure and magnets) and moxibustion. Acupuncture could be compared with control (no treatment or placebo) or another standard non-surgical intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed trial eligibility, assessed risk of bias and extracted data from the included trials. We calculated risk ratios (RRs) for dichotomous outcomes and mean differences for continuous outcomes. We conducted meta-analyses using the fixed-effect method or, where appropriate, the random-effects method, and used 95% confidence intervals (CI) throughout. MAIN RESULTS: We included a total of 20 heterogeneous studies (2012 participants with acute ankle sprains); three of which included more than one comparison. Seventeen trials were conducted in China. All of the studies had a high risk of bias due to lack of blinding. The results may also have been affected by selection bias, particularly as five studies were quasi-randomised controlled trials and 12 studies gave no information on their method of randomisation. Of our three prespecified primary outcomes, only cure rate was reported by the majority of studies. No study reported on patient-reported assessment of function and only one reported on adverse events (in which three participants receiving a control intervention experienced skin problems from over the-counter Chinese herbal patches). The other 19 studies did not record or report on adverse events. We assessed the quality of evidence for cure rates as very low for all comparisons, which means we are very uncertain about the reliability of any of the estimates.The single study comparing acupuncture treatment with no treatment found acupuncture to be more effective with regard to cure rate at five days (31/31 versus 1/30; RR 20.34, 95% CI 4.27 to 96.68). Acupuncture plus another standard treatment versus that standard treatment alone was tested in eight studies; with cure rate data available for seven. Most of these studies reported higher cure rates in the acupuncture plus another standard treatment group than in the standard treatment alone group. However, while the results of an exploratory meta-analysis of cure rate data from eight trials testing acupuncture versus no acupuncture tended to favour acupuncture, the results were very inconsistent across the studies and the estimated effect was very imprecise (383/396 versus 272/355; RR 1.32, 95% CI 0.95 to 1.84; P value = 0.1; I(2) = 98%).Fourteen studies compared acupuncture with a variety of other non-surgical treatments, such as Chinese drug patches, hot and cold water, ice packs, oral Chinese herbal medicine and elastic bandage. Some studies found in favour of acupuncture, some in favour of the other treatment and some found a lack of evidence for a difference between the two interventions under test. The results of an exploratory meta-analysis of cure rate data from 11 trials testing acupuncture versus another non-surgical intervention tended to slightly favour acupuncture, but these were not statistically significant and the data were very heterogeneous (404/509 versus 416/497; RR 1.07, 95% CI 0.94 to 1.22; P value = 0.30; I(2) = 92%). AUTHORS' CONCLUSIONS: The currently available evidence from a very heterogeneous group of randomised and quasi-randomised controlled trials evaluating the effects of acupuncture for the treatment of acute ankle sprains does not provide reliable support for either the effectiveness or safety of acupuncture treatments, alone or in combination with other non-surgical interventions; or in comparison with other non-surgical interventions. Future rigorous randomised clinical trials with larger sample sizes will be necessary to establish robust clinical evidence concerning the effectiveness and safety of acupuncture treatment for acute ankle sprains. PMID- 24953666 TI - Development of gene therapy for treatment of age-related macular degeneration. AB - Intraocular neovascular diseases are the leading cause of blindness in the Western world in individuals over the age of 50. Age-related macular degeneration (AMD) is one of these diseases. Exudative AMD, the late-stage form, is characterized by abnormal neovessel development, sprouting from the choroid into the avascular subretinal space, where it can suddenly cause irreversible damage to the vulnerable photoreceptor (PR) cells essential for our high-resolution, central vision. The molecular basis of AMD is not well understood, but several growth factors have been implicated including vascular endothelial growth factor (VEGF), and the advent of anti-VEGF therapy has markedly changed the outcome of treatment. However, common to all current therapies for exudative AMD are the complications of repeated monthly intravitreal injections, which must be continued throughout one's lifetime to maintain visual benefits. Additionally, some patients do not benefit from established treatments. Strategies providing long-term suppression of inappropriate ocular angiogenesis are therefore needed, and gene therapy offers a potential powerful technique. This study aimed to develop a strategy based on RNA interference (RNAi) for the sustained attenuation of VEGF. We designed a panel of anti-VEGF short hairpin RNAs (shRNA), and based on the most potent shRNAs, microRNA (miRNA)-mimicked hairpins were developed. We demonstrated an additive VEGF silencing effect when we combined the miRNAs in a tricistronic miRNA cluster. To meet the requirements for development of medical treatments for AMD with long-term effects, the shRNA/miRNA is expressed from vectors based on adeno-associated virus (AAV) or lentivirus (LV). Both vector systems have been found superior in terms of transduction efficiency and persistence in gene expression in retinal cells. The capacity of AAV-encoded RNAi effector molecules to silence endogenous VEGF gene expression was evaluated in mouse models, including the model of laser-induced choroidal neovascularization (CNV), and we found that subretinal administration of self-complementary (sc) AAV2/8 encoding anti-VEGF shRNAs can impair vessel formation. In parallel, a significant reduction of endogenous VEGF was demonstrated following injection of scAAV2/8 vectors expressing multiple anti-VEGF miRNAs into murine hind limb muscles. Furthermore, in an ongoing project we have designed versatile, multigenic LV vectors with combined expression of multiple miRNAs and proteins, including pigment epithelium-derived factor (PEDF), a multifunctional, secreted protein that has anti-angiogenic and neurotrophic functions. Co-expression of miRNAs and proteins from a single viral vector increases safety by minimizing the viral load necessary to obtain a therapeutic effect and thereby reduces the risk of insertional mutagenesis as well as the immune response against viral proteins. Our results show co-expression of functional anti-VEGF-miRNAs and PEDF in cell studies, and in vivo studies reveal an efficient retinal pigment epithelium (RPE) specific gene expression following the incorporation of the vitelliform macular dystrophy 2 (VMD2) promoter, demonstrating the potential applicability of our multigenic LV vectors in ocular anti-VEGF gene therapy, including combination therapy for treatment of exudative AMD. In conclusion, these highly promising data clearly demonstrate that viral-encoded RNAi effector molecules can be used for the inhibition of neovascularization and will, in combination with the growing interest of applying DNA- or RNA-based technologies in the clinic, undoubtedly contribute to the development of efficacious long-term gene therapy treatment of intraocular neovascular diseases. PMID- 24953668 TI - Digging your own grave: OSL signatures in experimental graves. AB - Excavation of mock graves in sediments of aeolian and fluvial origin were conducted to test the bleaching efficiency of grave digging in materials that commonly host ancient burials in Australia. Grave-size pits were dug into Pleistocene aeolian sediments at Willandra Lakes and younger fluvial sediments on the Lachlan River, backfilled, and re-excavated. Samples for optical dating were taken from sediment infilling the mock graves and from the adjacent, undisturbed substrate, and analysed using the single aliquot-regenerative dose (SAR) protocol applied to single quartz grains. The resulting equivalent dose (De) distributions revealed that <=1% of grains had been fully zeroed in both settings, and an additional 1-6% of poorly bleached grains were apparent in the fluvial sediments. Insufficient and heterogeneous bleaching of sediments during excavation and backfilling produced a decrease in the central dose of between 3 and 6 Gy, and an increase in over-dispersion values of between 5 and 10%. These differences were insufficient to clearly distinguish the disturbance event from the effects of bioturbation, biological mixing, or other sources of De variation. The use of the Minimum Age Model substantially over-estimated the burial age (zero years) in both depositional environments, with the degree of over-estimation increasing with the age of the host sediments. These results suggest that optically stimulated luminescence (OSL) techniques will not produce accurate ages for grave infill in a number of forensic and archaeological settings. Further study of the bleaching susceptibility of grains within grave infills, as well as the effectiveness of grave-digging as a bleaching mechanism is required. In other archaeological and geomorphological applications of OSL dating we recommend routine checks on the effective zeroing of sediments in modern equivalent situations. PMID- 24953667 TI - The vertebral remains of the late Miocene great ape Hispanopithecus laietanus from Can Llobateres 2 (Valles-Penedes Basin, NE Iberian Peninsula). AB - Here we describe the vertebral fragments from the partial skeleton IPS18800 of the fossil great ape Hispanopithecus laietanus (Hominidae: Dryopithecinae) from the late Miocene (9.6 Ma) of Can Llobateres 2 (Valles-Penedes Basin, Catalonia, Spain). The eight specimens (IPS18800.5-IPS18800.12) include a fragment of thoracic vertebral body, three partial bodies and four neural arch fragments of lumbar vertebrae. Despite the retention of primitive features (moderately long lumbar vertebral bodies with slightly concave ventrolateral sides), these specimens display a suite of derived, modern hominoid-like features: thoracic vertebrae with dorsally-situated costal foveae; lumbar vertebrae with non ventrally-oriented transverse processes originating from a robust pedicle, caudally-long laminae with caudally-oriented spinous process, elliptical end plates, and moderately stout bodies reduced in length and with no ventral keel. These features, functionally related to orthograde behaviors, are indicative of a broad and shallow thorax with a moderately short and stiff lumbar region in Hispanopithecus. Despite its large body mass (ca. 39-40 kg), its vertebral morphology is more comparable to that of hylobatids and Ateles than to extant great apes. This is confirmed by our morphometric analyses, also indicating that Hispanopithecus most closely resembles Pierolapithecus and Morotopithecus among Miocene apes, whereas Proconsul and Nacholapithecus resemble pronograde monkeys. Only in a few features (craniocaudally short and transversely wide pedicles, transverse processes situated on the pedicle, and slight ventral wedging), Hispanopithecus is more derived towards the extant great ape condition than other Miocene apes. Overall, the vertebral morphology of Hispanopithecus supports previous inferences of an orthograde body plan with suspensory and climbing adaptations. However, given similarities with Ateles and the retention of a longer and more flexible spine than in extant great apes, the Hispanopithecus morphology is also consistent with some degree of above-branch quadrupedalism, as previously inferred from other anatomical regions. PMID- 24953669 TI - Sub-surface movement of stone artefacts at White Paintings Shelter, Tsodilo Hills, Botswana: implications for the Middle Stone Age chronology of central southern Africa. AB - White Paintings Shelter, Tsodilo Hills, Botswana plays a pivotal role in the archaeological chronology of the Middle Stone Age in the Kalahari. Results of refitting and the application of the chaine operatoire on the Middle Stone Age lithic assemblage from this site suggest that the previously reported relatively undisturbed nature of the lower deposits should be refuted. Potential causes for this admixture include sloping deposits and post-depositional processes. The significant consequences for the Middle Stone Age occupation, dating and transition to the Later Stone Age at White Paintings Shelter are explored. PMID- 24953671 TI - Polarization effects of dielectric nanoparticles in aqueous charge-asymmetric electrolytes. AB - Small nanoparticles, globular proteins, viral capsids, and other nanoscopic biomolecules usually display dielectric properties that are different from those of the medium in which they are dispersed. These dielectric heterogeneities can significantly influence the surrounding ion distribution, which determines the self-assembly and colloidal stability of these nanoparticles in solution. Here, we study the impact of a dielectric discontinuity in the structural and thermodynamic properties of a spherical nanoparticle made of different dielectric materials when it is immersed in a charge-asymmetric 1:z supporting electrolyte. The mean electrostatic potential, integrated charge, and ionic profiles are analyzed as a function of both the salt concentration and the nanoparticle's valence via Monte Carlo simulations and the nonlinear Poisson-Boltzmann theory. We observe that the electrostatic screening and charge neutralization near the surface of a nanoparticle increase when the nanoparticle's dielectric permittivity increases in all instances. For 1:1 salts, this effect is small and the nonlinear Poisson-Boltzmann theory displays a good agreement with simulation results. Nevertheless, significant deviations are displayed by the mean field scheme regarding simulation results in the presence of multivalent ions. In particular, for trivalent counterions we observe that increasing the dielectric permittivity or the valence of the nanoparticle decreases the critical salt concentration at which occurs a sign inversion of the mean electrostatic potential at the Helmholtz plane, which is closely related to the behavior of the zeta potential and the electrophoretic mobility. Moreover, we observe that the phenomenon of surface charge amplification, or the augmenting of the net charge of a nanoparticle by the adsorption of like-charged ions on its surface, can be promoted by polarization effects in weakly charged spherical nanoparticles with low dielectric permittivity. PMID- 24953672 TI - Development of chronic myeloid leukaemia in patients treated with anti-VEGF therapies for clear cell renal cell cancer. AB - Tyrosine kinase inhibitors are novel therapies targeting specific cellular signalling pathways. Sunitinib and sorafenib primarily block tyrosine kinase receptors involved in the progression of many tumours, including clear cell renal cell cancer (ccRCC). Although developed to target selected receptors, it is becoming apparent that they inhibit other kinases; this may result in the development of unexpected side effects. This is potentially dangerous as kinases on noncancerous cells are also inhibited. TKI off-target effects contributing to cardiotoxicity, hypothyroidism, hypertension, fatigue, hair depigmentation, hand foot syndrome and gastrointestinal perforation have been described. We report three patients (3/412) treated with sunitinib and sorafenib who developed chronic myeloid leukaemia (CML) during treatment for ccRCC, proposing a molecular mechanism of tyrosine kinase inhibitors action on bone marrow cells that might be co-responsible for CML development. PMID- 24953674 TI - Myxobolus cerebralis (Hofer) infection risk in native cutthroat trout Oncorhynchus clarkii (Richardson) and its relationships to tributary environments in the Yellowstone Lake Basin. AB - Conservation of native species is challenged by the introduction of non-native pathogens and diseases into aquatic and terrestrial environments worldwide. In the Yellowstone Lake basin, Yellowstone National Park, the invasive parasite causing salmonid whirling disease Myxobolus cerebralis (Hofer) has been identified as one factor contributing to population declines of native Yellowstone cutthroat trout Oncorhynchus clarkii bouvieri (Jordan & Gilbert). In 2002 and 2003, we examined relationships between the stream environment and severity of M. cerebralis infection in native trout. Coefficients of variation of environmental features were calculated to examine variability. Ten years later, we reassessed infection levels at 22 tributaries broadly across the system. Results of principal component analysis (PCA) of physical features (2003) were negatively correlated with infection severity, mostly in lower jaw cartilage of cutthroat trout, and PCA of chemical features (and temperature) correlated with infection severity in cranial cartilage. Pelican Creek, where M. cerebralis prevalence and severity was high 2002-2003, remained high in 2012. We did not find evidence that the parasite had dispersed further within the system. Variable environmental features (physiological stress) across short spatiotemporal scales within a stream or season may possibly predispose salmonids to infection in the wild and facilitate parasite establishment. PMID- 24953670 TI - Exploring the influence of the gut microbiota and probiotics on health: a symposium report. AB - The present report describes the presentations delivered at the 7th International Yakult Symposium, 'The Intestinal Microbiota and Probiotics: Exploiting Their Influence on Health', in London on 22-23 April 2013. The following two themes associated with health risks were covered: (1) the impact of age and diet on the gut microbiota and (2) the gut microbiota's interaction with the host. The strong influence of the maternal gut microbiota on neonatal colonisation was reported, as well as rapid changes in the gut microbiome of older people who move from community living to residential care. The effects of dietary changes on gut metabolism were described and the potential influence of inter-individual microbiota differences was noted, in particular the presence/absence of keystone species involved in butyrate metabolism. Several speakers highlighted the association between certain metabolic disorders and imbalanced or less diverse microbiota. Data from metagenomic analyses and novel techniques (including an ex vivo human mucosa model) provided new insights into the microbiota's influence on coeliac, obesity-related and inflammatory diseases, as well as the potential of probiotics. Akkermansia muciniphila and Faecalibacterium prausnitzii were suggested as targets for intervention. Host-microbiota interactions were explored in the context of gut barrier function, pathogenic bacteria recognition, and the ability of the immune system to induce either tolerogenic or inflammatory responses. There was speculation that the gut microbiota should be considered a separate organ, and whether analysis of an individual's microbiota could be useful in identifying their disease risk and/or therapy; however, more research is needed into specific diseases, different population groups and microbial interventions including probiotics. PMID- 24953673 TI - Piloting a stress management and mindfulness program for undergraduate nursing students: student feedback and lessons learned. AB - BACKGROUND: Widespread reports of high stress levels and mental health problems among university student populations indicate the use of interventions to facilitate stress reduction and support student resilience and wellbeing. There is growing evidence that regular mindfulness practice may confer positive health benefits and reduced stress levels. OBJECTIVES: The aim of this pilot project was to explore the impact of a seven-week stress management and mindfulness program as a learning support and stress reduction method for nursing and midwifery students. SETTING: The program was conducted at a large regional university in Australia. PARTICIPANTS: Fourteen first-year undergraduate nursing and midwifery students agreed to attend the program and to participate in a follow-up focus group. METHOD AND DESIGN: A descriptive qualitative design was utilised to examine the impact of the program. A semi-structured focus group interview was conducted with a thematic analysis undertaken of the transcript and process notes. RESULTS: Ten students completed the research component of this project by participating in the focus group interview. Three main themes capture the participants' experience: attending to self, attending to others and attending to program related challenges. Data indicate a positive impact on sleep, concentration, clarity of thought and a reduction in negative cognitions. Participants also identified challenges related to timetabling, program structure and venue. CONCLUSIONS: Overall, this pilot program enhanced the participants' sense of well-being. Despite the challenges, benefits were identified on a personal and professional level. Valuable feedback was provided that will be used to further develop and expand stress management and mindfulness programs offered to students attending this university. PMID- 24953675 TI - Orexin induces excitation of respiratory neuronal network in isolated brainstem spinal cord of neonatal rat. AB - Endogenous neuropeptides known as orexins (hypocretins) play important roles in the regulation of feeding, drinking, endocrine function, and sleep/wakefulness. Orexin neuron projection sites include the rostral ventrolateral medulla of brainstem, which is related to the control of breathing. Previous studies suggest that orexins modulate the central CO2 ventilatory response during wakefulness in rodent. In the present study, we examined the effects of the orexinergic system on central respiratory control by adding orexin into a superfusion medium in the isolated brainstem-spinal cord of neonatal rat. Exposure to orexin B resulted in dose-dependent increases in C4 burst rate via brainstem, but not spinal cord. These increases in C4 burst rate induced concomitant increases in the depolarizing cycle rate of pre-inspiratory (Pre-I) and inspiratory (Insp) neurons. Tonic discharge was induced on C4 recording, although the rhythmic bursts of Pre-I and Insp neurons were maintained. Expiratory (Exp) neurons were also depolarized on administration of orexin B. Our findings indicate that orexin B activates central respiratory activity, mainly through depolarization and decreases in membrane resistance in Pre-I and Insp neurons, and possibly through early initiation of the expiratory phase induced by depolarization of Exp neurons. PMID- 24953676 TI - Endogenous hydrogen sulfide in the rostral ventrolateral medulla/Botzinger complex downregulates ventilatory responses to hypoxia. AB - Hydrogen sulfide (H2S) is now recognized as a new gaseous transmitter involved in several brain-mediated responses. The rostral ventrolateral medulla (RVLM)/Botzinger complex is a region in the brainstem that is involved in cardiovascular and respiratory functions. Recently, it has been shown that exogenous H2S in the RVLM modulates autonomic function and thus blood pressure. In the present study, we investigated whether H2S, endogenously produced in the RVLM/Botzinger complex, plays a role in the control of hypoxia-induced hyperventilation. Ventilation (VE) was measured before and after bilateral microinjection of Na2S (H2S donor, 0.04, 1 and 2 pmol/100 nl) or aminooxyacetate (AOA, 0.2, 1 and 2 pmol/100 nl, a cystathionine beta-synthase, CBS, inhibitor) into the RVLM/Botzinger complex followed by a 60-min period of hypoxia (7% inspired O2) or normoxia exposure. Control rats received microinjection of vehicle. Microinjection of vehicle, AOA or Na2S did not change VE in normoxic conditions. Exposure to hypoxia evoked a typical increase in VE. Microinjection of Na2S (2 pmol) followed by hypoxia exposure attenuated the hyperventilation. Conversely, microinjection of AOA (2 pmol) into the RVLM/Botzinger complex caused an increase in the hypoxia-induced hyperventilation. Thus, endogenous H2S in the RVLM/Botzinger complex seems to play no role in the maintenance of basal pulmonary ventilation during normoxia whereas during hypoxia H2S has a downmodulatory function. Homogenates of RVLM/Botzinger complex of animals previously exposed to hypoxia for 60 min exhibited a decreased rate of H2S production. Our data are consistent with the notion that the gaseous messenger H2S synthesis is downregulated in the RVLM/Botzinger complex during hypoxia favoring hyperventilation. PMID- 24953678 TI - Characteristics and predictors of home injury hazards among toddlers in Wenzhou, China: a community-based cross-sectional study. AB - BACKGROUND: Home hazards are associated with toddlers receiving unintentional home injuries (UHI). These result in not only physical and psychological difficulties for children, but also economic losses and additional stress for their families. Few researchers pay attention to predictors of home hazards among toddlers in a systematic way. The purpose of this study is firstly to describe the characteristics of homes with hazards and secondly to explore the predicted relationship of children, parents and family factors to home hazards among toddlers aged 24-47 months in Wenzhou, China. METHODS: A random cluster sampling was employed to select 366 parents having children aged 24 - 47 months from 13 kindergartens between March and April of 2012. Four instruments assessed home hazards, demographics, parent's awareness of UHI, as well as family functioning. RESULTS: Descriptive statistics showed that the mean of home hazards was 12.29 (SD = 6.39). The nine kinds of home hazards that were identified in over 50% of households were: plastic bags (74.3%), coin buttons (69.1%), and toys with small components (66.7%) etc. Multivariate linear regression revealed that the predictors of home hazards were the child's age, the child's residential status and family functioning (b = .19, 2.02, -.07, p < .01, < .05 and < .01, respectively). CONCLUSIONS: The results showed that a higher number of home hazards were significantly attributed to older toddlers, migrant toddlers and poorer family functioning. This result suggested that heath care providers should focus on the vulnerable family and help the parents assess home hazards. Further study is needed to find interventions on how to manage home hazards for toddlers in China. PMID- 24953679 TI - Homologous overexpression of alkyl hydroperoxide reductase subunit C (ahpC) protects Bifidobacterium longum strain NCC2705 from oxidative stress. AB - The ability to manage reactive oxygen species (ROS) effectively is crucial for the survival of gut bifidobacteria under conditions of oxidative stress. Alkyl hydroperoxide reductase catalytic subunit C (ahpC) of Bifidobacterium longum responds to various oxidative stresses. In this study, an ahpC-overexpressing transformant of B. longum strain NCC2705 was constructed to investigate the role and function of ahpC in oxidative stresses inflicted by treatments with hydrogen peroxide (H2O2), cumene hydroperoxide, and aerobic oxygen. Results indicated that in B. longum, AhpC is the primary scavenger of endogenous H2O2 generated by aerobic metabolism, but it is unable to detoxify high concentrations of exogenous H2O2. The ahpC-overexpressing B. longum strain showed increased resistance to organic hydroperoxide killing, increased viability under aerobic growth, but decreased resistance to exogenous H2O2 in comparison to the control strain. Analysis of genes from the oxidative stress-defense pathway encoding oxygen independent coproporphyrinogen III oxidase (HemN), NADH oxidase (Nox) and thioredoxin reductase-like protein (TrxB) showed increased transcript levels in the ahpC-overexpressing vs. control strain. These findings suggest that elevated ahpC expression facilitates or activates the different electron donor-dependent ROS-elimination pathways in B. longum's response to oxidative stress. PMID- 24953680 TI - Editorial - The Journal of Medical Engineering and Technology. PMID- 24953681 TI - The significance of requirements engineering for the medical domain. AB - This paper aims to raise awareness of the importance of Requirements Engineering (RE) for the successful and efficient development of high-quality systems and products for the medical domain. It does so by providing an introduction to RE from the viewpoints of project and programme management and systems engineering in general and by illustrating the usefulness of a sound RE approach to the development of a local healthcare system in a deprived region in central Africa. The paper concludes that RE is just as crucial for the development of systems and products in the medical domain, as it is for the development of systems in the aerospace industry or software systems in the consumer electronics industry; while the degree of detail and formality of how RE is used has to be tailored to fit the context in question. PMID- 24953683 TI - Global health diplomacy, 'smart power', and the new world order. AB - Both the theory and practice of foreign policy and diplomacy, including systems of hard and soft power, are undergoing paradigm shifts, with an increasing number of innovative actors and strategies contributing to international relations outcomes in the 'New World Order'. Concurrently, global health programmes continue to ascend the political spectrum in scale, scope and influence. This concatenation of circumstances has demanded a re-examination of the existing and potential effectiveness of global health programmes in the 'smart power' context, based on adherence to a range of design, implementation and assessment criteria, which may simultaneously optimise their humanitarian, foreign policy and diplomatic effectiveness. A synthesis of contemporary characteristics of 'global health diplomacy' and 'global health as foreign policy', grouped by common themes and generated in the context of related field experiences, are presented in the form of 'Top Ten' criteria lists for optimising both diplomatic and foreign policy effectiveness of global health programmes, and criteria are presented in concert with an examination of implications for programme design and delivery. Key criteria for global health programmes that are sensitised to both diplomatic and foreign policy goals include visibility, sustainability, geostrategic considerations, accountability, effectiveness and alignment with broader policy objectives. Though diplomacy is a component of foreign policy, criteria for 'diplomatically-sensitised' versus 'foreign policy-sensitised' global health programmes were not always consistent, and were occasionally in conflict, with each other. The desirability of making diplomatic and foreign policy criteria explicit, rather than implicit, in the context of global health programme design, delivery and evaluation are reflected in the identified implications for (1) international security, (2) programme evaluation, (3) funding and resource allocation decisions, (4) approval systems and (5) training. On this basis, global health programmes are shown to provide a valuable, yet underutilised, tool for diplomacy and foreign policy purposes, including their role in the pursuit of benign international influence. A corresponding alignment of resources between 'hard' and 'smart' power options is encouraged. PMID- 24953684 TI - A new class of high-contrast Fe(II) selective fluorescent probes based on spirocyclized scaffolds for visualization of intracellular labile iron delivered by transferrin. AB - Iron is an essential metal nutrient that plays physiologically and pathologically important roles in biological systems. However, studies on the trafficking, storage, and functions of iron itself in living samples have remained challenging due to the lack of efficient methods for monitoring labile intracellular iron. Herein, we report a new class of Fe(2+)-selective fluorescent probes based on the spirocyclization of hydroxymethylrhodamine and hydroxymethylrhodol scaffolds controlled by using our recently established N-oxide chemistry as a Fe(2+) selective switch of fluorescence response. By suppressing the background signal, the spirocyclization strategy improved the turn-on rate dramatically, and reducing the size of the substituents of the N-oxide group enhanced the reaction rate against Fe(2+), compared with the first generation N-oxide based Fe(2+) probe, RhoNox-1. These new probes showed significant enhancements in the fluorescence signal against not only the exogenously loaded Fe(2+) but also the endogenous Fe(2+) levels. Furthermore, we succeeded in monitoring the accumulation of labile iron in the lysosome induced by transferrin-mediated endocytosis with a turn-on fluorescence response. PMID- 24953685 TI - Source identification and hazardous risk delineation of heavy metal contamination in Yanqi basin, northwest China. AB - A total of 469 surface soil samples were collected from the Yanqi basin in northwest China and evaluated for levels of ten heavy metals. Multivariate statistical analyses were used to study sources of and map the spatial distribution of heavy metals, as well as determine the relationship between land use types and soil source materials. It was found that: (1) the average amounts of ten heavy metals in the Yanqi basin were all below the national soil environmental quality standards of China (GB15618-1998), but the average amount of Cd, Hg, Mn, Ni, Pb, and Zn all exceeded the heavy metal background levels of soil in Xinjiang, China and exhibited accumulation. The ten heavy metals analyzed in this study can be categorized into four principal components as follows: Principal component 1 was Co, Cr, Mn, Ni, and Zn, and principal component 3 was As and Cu. Both of these originated from a natural geological background. Principal component 2 consisted of Cd and Pb and originated from industrial, agricultural and transportation influences. Principal component 4 consisted of Hg and was due to industrial influences. Our study found that Pb and Zn were a large part in the principal components 1 and 3 and were influenced by a combination of geologic background and human activity. (2) Heavy metals Cd and Hg were at high levels in construction land and farmland, while Co, Cr, Cu, Mn, and Ni were significantly higher in lacustrine deposits than in sandy shale from weathered material, coarse crystalline rock weathered material, and diluvial material. The land use types correlated significantly with the accumulation of Cd and Hg, and the soil parent material was the major factor for the accumulation of As, Co, Cr, Cu, Mn, and Ni. (3) The single element, element integration and the corresponding principal component presented similar spatial patterns of hazardous risk. Following comprehensive assessment of all elements, the high risk regions were found to be located in densely-populated urban areas and western parts of the study area. This was attributed to the higher geological background in the western part and strong human influence in the central part. Research shows that Cd, Hg, Pb, and Zn were locally enriched in the basin and this warrants increased attention. PMID- 24953686 TI - Cognitive deficit reversal as shown by changes in the Veterans Affairs Saint Louis University Mental Status (SLUMS) examination scores 7.5 years later. AB - OBJECTIVE: The Veterans Affairs Saint Louis University Mental Status (SLUMS) examination is a screening tool that has the sensitivity to detect mild neurocognitive impairment and dementia. This study explores patients' cognitive impairment trajectories based on the SLUMS examination score changes after 7.5 years. DESIGN: Retrospective chart review. SETTING: The Geriatric Research, Education, and Clinical Center at the Department of Veterans Affairs Medical Center (VAMC), St Louis, MO. PARTICIPANTS: A review of 533 charts indicated that 357 patients who had participated in the SLUMS examination validation study in 2003 were still alive. MEASUREMENT: Charts were screened for indicators of cognitive status in both 2003 and 2010 and interventions after baseline evaluation. RESULTS: The mean age of the 357 individuals in 2003 was 74, all were men, and 73% had a high school education or more. A total of 223 (62%) of the 357 completed the SLUMS examination at baseline and at the 7.5-year follow-up visit; of those, 33 (15%) progressed to mild cognitive deficit, 20 (9%) progressed to severe cognitive deficit, and 53 (24%) improved or reverted back to normal. Further exploration revealed that at least one reversible cause was identified for most (n = 36/53, 68%) of the reversions. The primary interventions that differentiated reversers from nonreversers were correction of visual loss (P = .005) and discontinuation of anticholinergic medications (P = .002). CONCLUSION: Cognitive improvement (reversion) as indicated by the SLUMS examination after 7.5 years was associated with the correction of some reversible causes. This stresses the importance of early detection and exclusion of reversible causes for persons screened for cognitive dysfunction using the SLUMS examination. PMID- 24953687 TI - Effective recruitment of rural breast cancer survivors into a lifestyle intervention. PMID- 24953688 TI - Newborn mice exposed prenatally to bisphenol A show hyperactivity and defective neocortical development. AB - The central nervous system is especially susceptible to toxic insults during development. Prenatal administration of bisphenol A (BPA) induces histologic anomalies in the dorsal telencephalon of the embryo. Whether these anomalies affect the morphogenesis and maturation of neuronal function of the newborn neocortex, however, is unknown. To evaluate the neurodevelopmental and behavioral effects of prenatal BPA exposure at 20 and 200MUg/kg/day in newborn mice, we performed a detailed histologic analysis of the neocortex and tested for the presence of behavioral abnormalities in newborn mice prenatally exposed to BPA using our newly developed behavioral test. Observations of newborn mice prenatally exposed to BPA revealed abnormal neuronal distribution and layer formation, hypoplasia of layer 6b, and abnormal dopaminergic neuronal projections in the neocortex. Further, the newborn mice exhibited hyperactivity. These findings suggest that prenatal BPA exposure induces neurobehavioral toxicity associated with abnormal dopaminergic neuronal projections, and abnormal corticogenesis and lamination. Histologic and behavioral analyses of newborn mice are considered useful for assessing the neurodevelopmental and behavioral toxicity of chemicals. PMID- 24953689 TI - Association of low-level arsenic exposure in drinking water with cardiovascular disease: a systematic review and risk assessment. AB - The U.S. Environmental Protection Agency (EPA) is developing an integrated assessment of non-cancer and cancer risk assessment of inorganic arsenic (iAs). Cardiovascular disease (CVD) in association with iAs exposure has been examined in a number of studies and provides a basis for evaluating a reference dose (RfD) for assessing potential non-cancer health risks of arsenic exposure. In this systematic review of low-level iAs exposure (i.e., <100-150MUg/L arsenic water concentration) and CVD in human populations, 13 cohort and case-control studies from the United States, Taiwan, Bangladesh, and China were identified and critically examined for evidence for derivation of a RfD. Eight cross-sectional and ecological studies from the United States were also examined for additional information. Prospective cohort data from Bangladesh provided the strongest evidence for determining the point of departure in establishing a candidate RfD based on a combined endpoint of mortality from "ischemic heart disease and other heart diseases." This study as well as the overall literature supported a no observed-adverse-effect level of 100MUg/L for arsenic in water, which was equivalent to an iAs dose of 0.009mg/kg-day (based on population-specific water consumption rates and dietary iAs intake). The study population was likely sensitive to arsenic toxicity because of nutritional deficiencies affecting arsenic methylation and one-carbon metabolism, as well as increasing CVD risk. Evidence is less clear on the interaction of CVD risk factors in the United States (e.g., diabetes, obesity, and hypertension) with arsenic at low doses. Potential uncertainty factors up to 3 resulted in a RfD for CVD in the range of 0.003-0.009mg/kg-day. Although caution should be exercised in extrapolating these results to the U.S. general population, these doses allow a margin of exposure that is 10-30 times the current RfD derived by EPA (based on skin lesions in Southwest Taiwan). These findings suggest that the current EPA RfD is protective of CVD. PMID- 24953690 TI - Intracellular calcium levels can regulate Importin-dependent nuclear import. AB - We previously showed that increased intracellular calcium can modulate Importin (Imp)beta1-dependent nuclear import of SRY-related chromatin remodeling proteins. Here we extend this work to show for the first time that high intracellular calcium inhibits Impalpha/beta1- or Impbeta1-dependent nuclear protein import generally. The basis of this relates to the mislocalisation of the transport factors Impbeta1 and Ran, which show significantly higher nuclear localization in contrast to various other factors, and RCC1, which shows altered subnuclear localisation. The results here establish for the first time that intracellular calcium modulates conventional nuclear import through direct effects on the nuclear transport machinery. PMID- 24953691 TI - Effects of celecoxib on proliferation and tenocytic differentiation of tendon derived stem cells. AB - NSAIDs are often ingested to reduce the pain and improve regeneration of tendon after tendon injury. Although the effects of NSAIDs in tendon healing have been reported, the data and conclusions are not consistent. Recently, tendon-derived stem cells (TDSCs) have been isolated from tendon tissues and has been suggested involved in tendon repair. Our study aims to determine the effects of COX-2 inhibitor (celecoxib) on the proliferation and tenocytic differentiation of TDSCs. TDSCs were isolated from mice Achilles tendon and exposed to celecoxib. Cell proliferation rate was investigated at various concentrations (0.1, 1, 10 and 100 MUg/ml) of celecoxib by using hemocytometer. The mRNA expression of tendon associated transcription factors, tendon associated collagens and tendon associated molecules were determined by reverse transcription-polymerase chain reaction. The protein expression of Collagen I, Collagen III, Scleraxis and Tenomodulin were determined by Western blotting. The results showed that celecoxib has no effects on TDSCs cell proliferation in various concentrations (p>0.05). The levels of most tendon associated transcription factors, tendon associated collagens and tendon associated molecules genes expression were significantly decreased in celecoxib (10 MUg/ml) treated group (p<0.05). Collagen I, Collagen III, Scleraxis and Tenomodulin protein expression were also significantly decreased in celecoxib (10 MUg/ml) treated group (p<0.05). In conclusion, celecoxib inhibits tenocytic differentiation of tendon-derived stem cells but has no effects on cell proliferation. PMID- 24953692 TI - Membrane inlet mass spectrometry reveals that Ceriporiopsis subvermispora bicupin oxalate oxidase is inhibited by nitric oxide. AB - Membrane inlet mass spectrometry (MIMS) uses a semipermeable membrane as an inlet to a mass spectrometer for the measurement of the concentration of small uncharged molecules in solution. We report the use of MIMS to characterize the catalytic properties of oxalate oxidase (E.C. 1.2.3.4) from Ceriporiopsis subvermispora (CsOxOx). Oxalate oxidase is a manganese dependent enzyme that catalyzes the oxygen-dependent oxidation of oxalate to carbon dioxide in a reaction that is coupled with the formation of hydrogen peroxide. CsOxOx is the first bicupin enzyme identified that catalyzes this reaction. The MIMS method of measuring OxOx activity involves continuous, real-time direct detection of oxygen consumption and carbon dioxide production from the ion currents of their respective mass peaks. (13)C2-oxalate was used to allow for accurate detection of (13)CO2 (m/z 45) despite the presence of adventitious (12)CO2. Steady-state kinetic constants determined by MIMS are comparable to those obtained by a continuous spectrophotometric assay in which H2O2 production is coupled to the horseradish peroxidase catalyzed oxidation of 2,2'-azinobis-(3 ethylbenzthiazoline-6-sulphonic acid). Furthermore, we used MIMS to determine that NO inhibits the activity of the CsOxOx with a KI of 0.58+/-0.06 MUM. PMID- 24953693 TI - Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta. AB - BACKGROUND: Apolipoprotein E-knockout (ApoE(-/-)) mice is a classic model of atherosclerosis. We have found that ApoE(-/-) mice showed splenomegaly, higher titers of serum anti-nuclear antibody (ANA) and anti-dsDNA antibody compared with C57B6/L (B6) mice. However, whether ApoE(-/-) mice show autoimmune injury remains unclear. METHODS AND RESULTS: Six females and six males in each group, ApoE(-/)( ), Fas(-/-) and B6 mice, were used in this study. The titers of serum ANA, anti dsDNA antibody and creatinine and urine protein were measured by ELISA after 4 months of high-fat diet. The spleen weight and the glomerular area were determined. The expressions of IgG, C3 and macrophage in kidney and atherosclerotic plaque were detected by immunostaining followed by morphometric analysis. Similar to the characteristics of Fas(-/-) mice, a model of systemic lupus erythematosus (SLE), ApoE(-/-) mice, especially female, displayed significant increases of spleen weight and glomerular area when compared to B6 mice. Also, elevated titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein. Moreover, the expressions of IgG, C3 and macrophage in glomeruli and aortic plaques were found in ApoE(-/-) mice. In addition, the IgG and C3 expressions in glomeruli and plaques significantly increased (or a trend of increase) in female ApoE(-/-) mice compared with males. CONCLUSIONS: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta. PMID- 24953694 TI - Induction of the cellular miR-29c by influenza virus inhibits the innate immune response through protection of A20 mRNA. AB - Influenza A viruses (IAVs) are negative-sense, single-stranded, segmented RNA viruses, which primarily targets respiratory epithelial cells and produces clinical outcomes ranging from mild upper respiratory infection to severe pneumonia. MicroRNAs (miRNAs) represent a family of small noncoding RNAs controlling translation and transcription of many genes. The human miR-29 family of miRNAs has three mature members, miR-29a, miR-29b, and miR-29c. Recent studies have revealed that miR-29 is involved in regulation of the innate and adaptive immune responses. However, the function of miR-29 in the immune response to IAV infection remains to be further explored. Our previous study has shown that miR 29 family members are up-regulated during IAV infection, especially miR-29c. Here we report that miR-29c is involved in inhibition of IAV-induced innate immune responses. We found that posttranscriptional regulation was involved in IAV induced A20 expression in A549 cells. Consistent with a previous report, miR-29c functionally protected A20 transcripts in A549 cells. Overexpression of miR-29c with miR-29c mimic enhanced IAV-induced A20 protein expression and conversely that miR-29c inhibitor significantly blocked IAV-induced A20 protein expression in A549 cells. Furthermore, functional results showed that IAV-induced miR-29c expression correlated with decreased NF-kappaB activity and expression of several antiviral and proinflammatory cytokines via up-regulation of A20. Together, the findings indicate a new role of miR-29c in IAV infection and suggest its induction may contribute to counteract the innate immune response. PMID- 24953695 TI - Ethanol affects hepatitis C pathogenesis: humanized SCID Alb-uPA mouse model. AB - Alcohol consumption exacerbates the course of hepatitis C viral (HCV) infection, worsens outcomes and contributes to the development of chronic infection that exhibits low anti-viral treatment efficiency. The lack of suitable in vivo models makes HCV-ethanol studies very difficult. Here, we examine whether chimeric SCID Alb-uPA mice transplanted with human hepatocytes and infected with HCV develop worsening pathology when fed ethanol. After 5 weeks of feeding, such mice fed chow+water (control) or chow+20% ethanol in water (EtOH) diets mice developed oxidative stress, decreased proteasome activity and increased steatosis. Importantly, HCV(+) mice in the control group cleared HCV RNA after 5 weeks, while the infection persisted in EtOH-fed mice at the same or even higher levels compared with pre-feeding HCV RNA. We conclude that in chimeric SCID Alb-uPA mice, EtOH exposure causes the complex biochemical and histological changes typical for alcoholic liver injury. In addition, ethanol feeding delays the clearance of HCV RNA thereby generating persistent infection and promoting liver injury. Overall, this model is appropriate for conducting HCV-ethanol studies. PMID- 24953696 TI - Function of wheat Ta-UnP gene in enhancing salt tolerance in transgenic Arabidopsis and rice. AB - Based on microarray analysis results of the salt tolerant wheat mutant, we identified and cloned an unknown salt-induced gene Ta-UnP (Triticum aestivum unknown protein). Quantitative PCR results revealed that Ta-UnP expression was induced not only by salt but also by polyethylene glycol, abscisic acid, and other environmental stress factors. Under salt stress, transgenic Arabidopsis plants that overexpressed Ta-UnP showed superior physiological properties (content of proline, soluble sugar, MDA, and chlorophyll) compared with the control. Subcellular localization demonstrated that Ta-UnP was mainly localized on the cell membrane. The expressions of nine salt tolerance-related genes of Arabidopsis in Ta-UnP-overexpressed Arabidopsis were analyzed via qPCR, and the results revealed that the expressions of SOS2, SOS3, RD29B, and P5CS were significantly up-regulated, whereas the other five genes only slightly changed. The results of the salt tolerance analysis indicated that Ta-UnP can enhance the salt tolerance of transgenic rice plants, and RNAi transgenic rice plants became highly susceptible to salt stress. The results from this study indicate that this novel Ta-UnP may be useful in improving of plant tolerance to salt stress. PMID- 24953697 TI - Intracellular calcium signaling in the fertilized eggs of Annelida. AB - Fertilization is such a universal and indispensable step in sexual reproduction, but a high degree of variability exists in the way it takes place in the animal kingdom. As discussed in other reviews in this issue, recent works on this subject clarified many points. However, important results on the mechanisms of fertilization are obtained mainly from a few restricted model organisms. In this sense, it is utterly important to collect more information from various phyla. In this review, we have re-introduced Annelida as one of the most suitable models for the analysis of fertilization process. We have briefly reviewed the historical works on the fertilization of Annelida. Then, we have described recent findings on the two independent Ca(2+) increases in the fertilized eggs of Annelida, which arise from two different mechanisms and may have distinct physiological roles toward sperm entry and egg activation. We propose that the Ca(2+) increase in the fertilized eggs reflect the specific needs of the zygote in a given species. PMID- 24953698 TI - The oxidation of sulfur dioxide by single and double oxygen transfer paths. AB - The oxidation of SO2 by nonmetal oxoanions in the gas phase is investigated in an experimental and theoretical study of the structure of the species involved and the reaction kinetics and mechanism. SO3 , SO3(.-) and SO4(.-) are efficiently produced by reaction of On XO(-) anions (X=Cl, Br, and I; n=0 and 1) with SO2 ; XO(-) ions mainly react to give SO3 by oxygen-atom transfer, whereas OXO(-) ions mainly give SO3(.-) by oxygen-anion transfer. On descending the halogen group from chlorine to iodine, the SO3 /SO3(.-) ratio decreases and increases for reactions involving XO(-) and OXO(-) anions, respectively, whereas the formation of SO4(.-) is particularly significant with OIO(-). Kinetic factors play a major role in the reactions of On XO(-), depending on the halogen atom and its oxidation state. PMID- 24953700 TI - Lessons offered, lessons learned: reflections on how doing family therapy can affect therapists. AB - Only in working conjointly with couples and families do therapists literally witness clients struggling to improve their most intimate relationships. In writing this article, we realized that, in true systemic fashion, not only have many of our clients benefited from working with us, but also we have learned some invaluable lessons from them. Indeed, practicing couple and family therapy gives therapists many opportunities to learn about themselves, especially when it is done thoughtfully. In this article, we reflect on myriad ways in which couples and family therapy has affected each of us personally-as individuals, as partners, as parents, as adult children in our families of origin, and as educators. PMID- 24953699 TI - [Update of breast cancer in Primary Care (III/V)]. AB - Breast cancer is a prevalent disease with implications in all aspects of patients life, therefore, family doctors must know this pathology in depth, in order to optimize the health care provided to these patients with the best available resources. This series of five articles on breast cancer is based on a review of the scientific literature of the last ten years. This third article will review the clinical context and the staging and prognostic factors of the disease. This summary report aims to provide a global, current and practical review about this problem, providing answers to family doctors and helping them to be by the patients for their benefit throughout their illness. PMID- 24953701 TI - The value of nerve blocks in the diagnoses and treatment of complex regional pain syndrome type 1: a series of 14 cases. AB - OBJECTIVES: Complex regional pain syndrome type 1 (CRPS-1) can progress to joint stiffness, which may be related to pain and/or capsule-ligament contracture. In this context, it is difficult to distinguish the respective causative roles of pain and contractures. Nerve blocks (NBs) can be used to determine the aetiology of joint stiffness. Subsequent treatment will depend on whether contractures are present or not. The objective of the present study was to evaluate the diagnostic and therapeutic value of the nerve blocks in the management of joint stiffness caused by CRPS-1. DESIGN OF THE STUDY: A retrospective case series. METHODS: Implementation of NBs in subjects with joint stiffness caused by CRPS-1. Primary efficacy criterion: an increase in the range of joint movement. Secondary criteria: pain level, treatment decision, duration of therapeutic NBs, return to work. RESULTS: Fourteen patients with joint stiffness underwent 17 NBs. Ten NBs (59%) were associated with the normalization of the range of joint movement (i.e. the absence of contractures and the presence of an isolated pain component), prompting the implementation of physical therapy during NBs ("therapeutic NBs") in 90% of these cases. Three NBs (18%) were associated with a partial increase in the range of joint movement (i.e. a background of joint stiffness due to a combination of pain and contracture), prompting the implementation of a therapeutic NB in all of these cases. Four NBs (23%) were not associated with any increase in the range of joint movement (i.e. pure contractures), prompting consultation with a surgeon in all of these cases. Forty-three percent of the patients have since returned to work. CONCLUSIONS: Nerve block is a valuable diagnostic and therapeutic option in the management of joint stiffness caused by CRPS-1. PMID- 24953702 TI - OnabotulinumtoxinA and multiple sclerosis. AB - Lower urinary tract dysfunction is present in two of three patients with multiple sclerosis five years after the diagnosis. Most frequent symptoms are related to neurogenic detrusor overactivity, often associated with detrusor-sphincter dyssynergia. From the end of the 1990s, there is growing evidence that neurogenic detrusor overactivity can be effectively managed by intradetrusorial injections of botulinum toxin type A. This treatment has shown, in different randomised placebo-controlled trials, to be safe and effective on clinical and urodynamic parameters with significant improvement in quality of life. The median duration of effect is in mean nine months. The vast majority of studies have been conducted with onabotulinumtoxinA. The dose of onabotulinumtoxinA commonly used to treat neurogenic detrusor overactivity in patients with multiple sclerosis is 200 UI, even if in selected patients lower doses can be preferred. To be considered eligible for treatment, all patients should accept and be instructed to perform clean intermittent self-catheterisation, since the risk of increased post-void residual volume and/or urinary retention after injection is high, especially with 200 UI of onabotulinumtoxinA. However, quality of life and patient satisfaction seem not to be affected by the need of intermittent catheterisation. The risk of urinary infection after the procedure is to be kept in mind, mainly in patients with multiple sclerosis, so that adequate antibiotic prophylaxis is highly recommended. PMID- 24953703 TI - Feasibility of the cognitive assessment scale for stroke patients (CASP) vs. MMSE and MoCA in aphasic left hemispheric stroke patients. AB - INTRODUCTION: Post-stroke aphasia makes it difficult to assess cognitive deficiencies. We thus developed the CASP, which can be administered without using language. Our objective was to compare the feasibility of the CASP, the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in aphasic stroke patients. MATERIAL AND METHODS: All aphasic patients consecutively admitted to seven French rehabilitation units during a 4-month period after a recent first left hemispheric stroke were assessed with CASP, MMSE and MoCA. We determined the proportion of patients in whom it was impossible to administer at least one item from these 3 scales, and compared their administration times. RESULTS: Forty-four patients were included (age 64+/-15, 26 males). The CASP was impossible to administer in eight of them (18%), compared with 16 for the MMSE (36%, P=0.05) and 13 for the MoCA (30%, P=0.21, NS). It was possible to administer the CASP in all of the patients with expressive aphasia, whereas the MMSE and the MoCA could not be administered. Administration times were longer for the CASP (13+/-4min) than for the MMSE (8+/-3min, P<10(-6)) and the MoCA (11+/ 5min, P=0.23, NS). CONCLUSION: The CASP is more feasible than the MMSE and the MoCA in aphasic stroke patients. PMID- 24953705 TI - Photocatalytic decomposition of cortisone acetate in aqueous solution. AB - The photocatalytic decomposition of cortisone 21-acetate (CA), a model compound for the commonly used steroid, cortisone, was studied. CA was photocatalytically decomposed in a slurry reactor with the initial rates between 0.11 and 0.46 mg L( 1)min(-1) at 10 mg L(-1) concentration, using the following heterogeneous photocatalysts in decreasing order of their catalytic activity: ZnO>Evonik TiO2 P25>Hombikat TiO2>WO3. Due to the lack of ZnO stability in aqueous solutions, TiO2 P25 was chosen for further experiments. The decomposition reaction was found to be pseudo-first order and the rate constant decreased as a function of increasing initial CA concentration. Changing the initial pH of the CA solution did not affect the reaction rate significantly. The decomposition reaction in the presence of the oxidizing sacrificial agent sodium persulfate showed an observed decomposition rate constant of 0.004 min(-1), lower than that obtained for TiO2 P25 (0.040 min(-1)). The highest photocatalytic degradation rate constant was obtained combining both TiO2 P25 and S2O8(2-) (0.071 min(-1)) showing a synergistic effect. No reactive intermediates were detected using LC-MS showing fast photocatalytic decomposition kinetics of CA. PMID- 24953704 TI - Convenient, sensitive and high-throughput method for screening botanic origin. AB - In this work, a rapid (within 4-5 h), sensitive and visible new method for assessing botanic origin is developed by combining loop-mediated isothermal amplification with cationic conjugated polymers. The two Chinese medicinal materials (Jin-Yin-Hua and Shan-Yin-Hua) with similar morphology and chemical composition were clearly distinguished by gene SNP genotyping assays. The identification of plant species in Patented Chinese drugs containing Lonicera buds is successfully performed using this detection system. The method is also robust enough to be used in high-throughput screening. This new method is very helpful to identify herbal materials, and is beneficial for detecting safety and quality of botanic products. PMID- 24953706 TI - Ozonation of benzotriazole and methylindole: Kinetic modeling, identification of intermediates and reaction mechanisms. AB - The ozonation of 1H-benzotriazole (BZ) and 3-methylindole (ML), two emerging contaminants that are frequently present in aquatic environments, was investigated. The experiments were performed with the contaminants (1MUM) dissolved in ultrapure water. The kinetic study led to the determination of the apparent rate constants for the ozonation reactions. In the case of 1H benzotriazole, these rate constants varied from 20.1 +/- 0.4M(-1)s(-1) at pH=3 to 2143 +/- 23 M(-1)s(-1) at pH=10. Due to its acidic nature (pKa=8.2), the degree of dissociation of this pollutant was determined at every pH of work, and the specific rate constants of the un-dissociated and dissociated species were evaluated, being the values of these rate constants 20.1 +/- 2.0 and 2.0 +/- 0.3 * 10(3)M(-1)s(-1), respectively. On the contrary, 3-methylindole does not present acidic nature, and therefore, it can be proposed an average value for its rate constant of 4.90 +/- 0.7 * 10(5)M(-1)s(-1) in the whole pH range 3-10. Further experiments were performed to identify the main degradation byproducts (10 mg L( 1) of contaminants, 0.023 gh(-1) of ozone). Up to 8 intermediates formed in the ozonation of 3-methylindole were identified by LC-TOFMS, while 6 intermediates were identified in the ozonation of 1H-benzotriazole. By considering these intermediate compounds, the reaction mechanisms were proposed and discussed. Finally, evaluated rate constants allowed to predict and modeling the oxidation of these micropollutants in general aquatic systems. PMID- 24953707 TI - Manzamine alkaloids: isolation, cytotoxicity, antimalarial activity and SAR studies. AB - The infectious disease Malaria is caused by different species of the genus Plasmodium. Resistance to quinoline antimalarial drugs and decreased susceptibility to artemisinin-based combination therapy have increased the need for novel antimalarial agents. Historically, natural products have been used for the treatment of infectious diseases. Identification of natural products and their semi-synthetic derivatives with potent antimalarial activity is an important method for developing novel antimalarial agents. Manzamine alkaloids are a unique group of beta-carboline alkaloids isolated from various species of marine sponge displaying potent antimalarial activity against drug-sensitive and resistant strains of Plasmodium. In this review, we demonstrate antimalarial potency, cytotoxicity and antimalarial SAR of manzamine alkaloids. PMID- 24953708 TI - Academic drug discovery centres: the economic and organisational sustainability of an emerging model. AB - Academic drug discovery centres (ADDCs) are seen as one of the solutions to fill the innovation gap in early drug discovery, which has proven challenging for previous organisational models. Prior studies of ADDCs have identified the need to analyse them from the angle of their economic and organisational sustainability. We take that angle in an in-depth study of four prominent ADDCs. Our findings indicate that there are clear similarities in the way sustainable centres are organised, managed and financed. We also identify factors in the frameworks of academia and research funding affecting their performance. PMID- 24953709 TI - Translational applications of hyperpolarized 3He and 129Xe. AB - Clinical magnetic resonance imaging of the lung is technologically challenging, yet over the past two decades hyperpolarized noble gas ((3)He and (129)Xe) imaging has demonstrated the ability to measure multiple pulmonary functional biomarkers. There is a growing need for non-ionizing, non-invasive imaging techniques due to increased concern about cancer risk from ionizing radiation, but the translation of hyperpolarized gas imaging to the pulmonary clinic has been stunted by limited access to the technology. New developments may open doors to greater access and more translation to clinical studies. Here we briefly review a few translational applications of hyperpolarized gas MRI in the contexts of ventilation, diffusion, and dissolved-phase imaging, as well as comparing and contrasting (3)He and (129)Xe gases for these applications. Simple static ventilation MRI reveals regions of the lung not participating in normal ventilation, and these defects have been observed in many pulmonary diseases. Biomarkers related to airspace size and connectivity can be quantified by apparent diffusion coefficient measurements of hyperpolarized gas, and have been shown to be more sensitive to small changes in lung morphology than standard clinical pulmonary functional tests and have been validated by quantitative histology. Parameters related to gas uptake and exchange and lung tissue density can be determined using (129)Xe dissolved-phase MRI. In most cases functional biomarkers can be determined via MRI of either gas, but for some applications one gas may be preferred, such as (3)He for long-range diffusion measurements and (129)Xe for dissolved-phase imaging. Greater access to hyperpolarized gas imaging coupled with newly developing therapeutics makes pulmonary medicine poised for a potential revolution, further adding to the prospects of personalized medicine already evidenced by advancements in molecular biology. Hyperpolarized gas researchers have the opportunity to contribute to this revolution, particularly if greater clinical application of hyperpolarized gas imaging is realized. PMID- 24953710 TI - Hydroxytyrosol induces apoptosis in human colon cancer cells through ROS generation. AB - Cancer cells are usually under higher levels of oxidative stress compared to normal cells. We hypothesized that the introduction of additional reactive oxygen species (ROS) or the suppression of antioxidant activity may selectively enhance cancer cell killing by generating oxidative agents through stress overload or stress sensitization. The aim of this work was to test whether hydroxytyrosol (HT), one of the major polyphenolic constituents of extra virgin olive oil, could exert anti-cancer effects on human colon adenocarcinoma cells via its ability to induce apoptosis through ROS generation. HT exhibits preferential anti proliferative effects on human colon cancer cells (DLD1 cells) but not on normal colon epithelial 1807 cells. HT causes oxidative stress, activates the phosphoinositide 3-kinase/Akt pathway, phosphorylates FOXO3a and then downregulates FOXO3a's target genes. Combined with SOD or catalase treatment, there are different responses in HT-treated DLD1 cells. The results support the hypothesis that the two main species of ROS, superoxide and H2O2, play different roles in cancer cell survival. The present work shows that HT induces apoptotic cell death and mitochondrial dysfunction by generating ROS in colon cancer cells. This research presents important evidence on the in vitro chemopreventive effect of HT and shows that the disruption of the intrinsic redox status promotes cancer cell death. PMID- 24953712 TI - Effect of sclerostin antibody treatment in a mouse model of severe osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I production in osteoblasts. Stimulation of bone formation through sclerostin antibody treatment (Sost-ab) has shown promising results in mouse models of relatively mild OI. We assessed the effect of once-weekly intravenous Sost-ab injections for 4weeks in male Col1a1(Jrt)/+mice, a model of severe dominant OI, starting either at 4weeks (growing mice) or at 20weeks (adult mice) of age. Sost-ab had no effect on weight or femur length. In OI mice, no significant treatment-associated differences in serum markers of bone formation (alkaline phosphatase activity, procollagen type I N-propeptide) or resorption (C-telopeptide of collagen type I) were found. Micro-CT analyses at the femur showed that Sost-ab treatment was associated with higher trabecular bone volume and higher cortical thickness in wild type mice at both ages and in growing OI mice, but not in adult OI mice. Three-point bending tests of the femur showed that in wild type but not in OI mice, Sost-ab was associated with higher ultimate load and work to failure. Quantitative backscattered electron imaging of the femur did not show any effect of Sost-ab on CaPeak (the most frequently occurring calcium concentration in the bone mineral density distribution), regardless of genotype, age or measurement location. Thus, Sost-ab had a larger effect in wild type than in Col1a1(Jrt)/+mice. Previous studies had found marked improvements of Sost-ab on bone mass and strength in an OI mouse model with a milder phenotype. Our data therefore suggest that Sost-ab is less effective in a more severely affected OI mouse model. PMID- 24953711 TI - Marrow fat composition in anorexia nervosa. AB - PURPOSE: Women with anorexia nervosa (AN) have increased marrow fat despite severe depletion of body fat. Recent studies have suggested that marrow fat composition may serve as a biomarker for bone quality. The purpose of our study was to investigate marrow fat composition of the femur using proton MR spectroscopy ((1)H MRS), and the relationship between measures of marrow fat composition and BMD and body composition in women with AN and normal-weight controls. MATERIALS AND METHODS: 14 women with AN (29.5+/-1.9years) and 12 age matched normal-weight controls underwent (1)H MRS to determine total marrow fat content and marrow fat composition of the femoral diaphysis and soleus intramyocellular lipids und unsaturated muscle lipids. MRI was performed to quantify abdominal fat, thigh fat and muscle areas. Lumbar spine BMD, fat and lean mass were assessed by DXA. RESULTS: Subjects with AN had higher marrow fat content (p<0.05), but similar marrow fat composition (p>0.05) compared to normal weight controls. There was an inverse association between marrow methylene protons, an estimate of fatty acid (FA) saturated bonds, and lumbar spine BMD (r= 0.52, p=0.008) independent of %ideal body weight (%IBW). Olefinic protons at 5.3ppm, an estimate of FA unsaturated bonds, were inversely associated with body fat depots, independent of %IBW, and positively associated with soleus unsaturation (p<=0.05). CONCLUSION: Women with AN have higher total femoral marrow fat but similar composition compared to normal-weight controls. The degree of marrow FA saturation correlates inversely with BMD, suggesting that saturated lipids may have negative effects on BMD. The degree of marrow FA unsaturation correlates positively with soleus unsaturation, suggesting that marrow fat composition may be influenced by the same factors as ectopic lipid composition in muscle. PMID- 24953714 TI - Effects of the New Prokinetic Agent DA-9701 Formulated With Corydalis Tuber and Pharbitis Seed in Patients With Minimal Change Esophagitis: A Bicenter, Randomized, Double Blind, Placebo-controlled Study. AB - BACKGROUND/AIMS: DA-9701 (Motilitone) is a new prokinetic agent formulated with Corydalis Tuber and Pharbitis Seed. We assessed the efficacy of DA-9701 in symptomatic patients with minimal change esophagitis. METHODS: Patients with minimal change esophagitis presenting with reflux or dyspeptic symptoms were randomly assigned to receive either DA-9701 30 mg or placebo t.i.d. (means 3 times a day). After 4 weeks of treatment, the primary efficacy end point determined by changes of the Nepean dyspepsia index questionnaire-Korean version (NDI-K) symptom scores, was analyzed. RESULTS: Forty-two and 39 patients were assigned to the treatment and control groups, respectively. After 4 weeks, NDI-K symptom scores were reduced from 35.4 to 13.5 (P < 0.001) and from 43.0 to 27.7 (P < 0.001) in the treatment and the control groups, respectively. However, changes in the symptom scores did not differ between the 2 groups (P = 0.741). Although the quality of life scores were significantly improved after 4 weeks in both groups, changes in the quality of life score between the baseline value and that at 4 weeks did not differ between the 2 groups. The reflux symptom score was significantly improved in the treatment group compared to the placebo group in patients aged 65 years or older (P = 0.035). CONCLUSIONS: Although NDI-K symptom scores and quality of life scores were improved after 4 weeks of treatment compared with baseline values in patients with minimal change esophagitis, DA 9701 did not improve the symptom scores or quality of life scores compared with the placebo. PMID- 24953713 TI - Modulatory effects of peroxisome proliferator-activated receptor-gamma on CXCR3 chemokines. AB - An increasing body of evidence shows the importance of the chemokine (C-X-C motif) receptor (CXCR)3 and cognate chemokines (C-X-C motif) ligand (CXCL)9, CXCL10 and CXCL11 in the T helper 1 immune response, and in inflammatory diseases such as bowel inflammatory disorders, allograft rejection, thyroid autoimmune disorders, vascular and renal inflammation, and others. Peroxisome proliferator activated receptor (PPAR)-gamma agonists show a strong inhibitory effect on the expression and production of CXCR3 chemokines in vitro, in various kinds of cells, such as denditric cells, monocytes, macrophages, endothelial and vascular smooth muscle cells, intestinal cells, thyrocytes, fibroblasts, preadypocytes and mesangial cells, and in vivo in animal models. As rosiglitazone has recently been linked to a higher risk of heart failure, stroke, and all-cause mortality in old patients, it has been interrupted from the European market. On the contrary, the safety profile of pioglitazone seems favorable. However, further studies are ongoing to explore the use of new PPAR-gamma agonists in the treatment of the above mentioned inflammatory disorders, and many interesting patents have been recently applied. PMID- 24953715 TI - Pathogenesis of irritable bowel syndrome: is it really in the gene? PMID- 24953716 TI - The gut microbiome. AB - Since the discovery and use of the microscope in the 17(th) century, we know that we host trillions of micro-organisms mostly in the form of bacteria indwelling the "barrier organs" skin, gut, and airways. They exert regulatory functions, are in a continuous dialogue with the intestinal epithelia, influence energy handling, produce nutrients, and may cause diabetes and obesity. The human microbiome has developed by modulating or avoiding inflammatory responses; the host senses bacterial presence through cell surface sensors (the Toll-like receptors) as well as by refining mucous barriers as passive defense mechanisms. The cell density and composition of the microbiome are variable and multifactored. The way of delivery establishes the type of initial flora; use of antibiotics is another factor; diet composition after weaning will shape the adult's microbiome composition, depending on the subject's life-style. Short chain fatty acids participate in the favoring action exerted by microbiome in the pathogenesis of type-2 diabetes and obesity. Clinical observation has pinpointed a sharp rise of various dysimmune conditions in the last decades, including IBD and rheumatoid arthritis, changes that outweigh the input of simple heritability. It is nowadays proposed that the microbiome, incapable to keep up with the changes of our life-style and feeding sources in the past few decades might have contributed to these immune imbalances, finding itself inadequate to handle the changed gut environment. Another pathway to pathology is the rise of directly pathogenic phyla within a given microbiome: growth of adherent E. coli, of C. concisus, and of C. jejuni, might be examples of causes of local enteropathy, whereas the genus Prevotella copri is now suspected to be linked to rise of arthritic disorders. Inflammasomes are required to shape a non colitogenic flora. Treatment of IBD and infectious enteritides by the use of fecal transplant is warranted by this knowledge. PMID- 24953717 TI - The prevalence of the extensor digitorum communis tendon and its insertion variants: a systematic review and meta-analysis. AB - The tendons of the Extensor Digitorum Communis (EDC) are frequently injured in hand trauma. Dislocation and spontaneous rupture can also occur during the course of wrist osteoarthritis and rheumatoid arthritis. The EDC exhibits many variations including splitting of its individual slips to the medial four fingers or their absence. The aim of this systematic review is to assemble evidence about the prevalence of the EDC and its variants on the dorsum of the hand. Twenty-four cadaveric studies met the inclusion criteria, providing data from a total of 2,005 hands. Meta-analysis yielded the following results: (a) for EDC-II (Index), the pooled prevalence estimates (PPEs) were 99.8, 98, 1.8, and 0.2% for the total, single, double, and triple slips, respectively; (b) for EDC-III (Middle), the PPEs were 100, 67.7, 24.2, 6, and 0.42% for the total, single, double, triple, and quadruple slips, respectively; (c) for EDC-IV (Ring), the PPEs were 100, 58.6, 29.1, 7.1, and 1.3% for the total, single, double, triple, and quadruple slips, respectively; (d) for EDC-V (Little), the PPEs were 63.2, 58.5, 10.4, 0.94, and 25% for the total, single, double, triple, and common 4th-5th slips, respectively. There were no significant differences in relation to hand side. Many EDC slip variants demonstrated some interaction with ancestry. A sound knowledge of EDC variants and their prevalences is paramount for assessing and treating hand injuries and disorders. PMID- 24953718 TI - Viral infections in mice with reconstituted human immune system components. AB - Pathogenic viruses are often difficult to study due to their exclusive tropism for humans. The development of mice with human immune system components opens the possibility to study those human pathogens with a tropism for the human hematopoietic lineage in vivo. These include HCMV, EBV, KSHV, HIV, HTLV-1, dengue virus and JC virus. Furthermore, some human pathogens, like HSV-2, adenovirus, HCV, HBV and influenza A virus, with an additional tropism for somatic mouse tissues or for additional transplanted human tissues, mainly liver, have been explored in these models. The cellular tropism of these viruses, their associated diseases and primarily cell-mediated immune responses to these viral infections will be discussed in this review. Already some exciting information has been gained from these novel chimeric in vivo models and future avenues to gain more insights into the pathology, but also potential therapies, will be outlined. Although the respective in vivo models of human immune responses can still be significantly improved, they already provide preclinical systems for in vivo studies of important viral pathogens of humans. PMID- 24953719 TI - The digital thermal hyperemia pattern is associated with the onset of digital ulcerations in systemic sclerosis during 3 years of follow-up. AB - OBJECTIVES: One of the most important skin complications in systemic sclerosis (SSc) is digital ulceration. Local thermal hyperemia (LTH) in the skin is a biphasic response to local heating involving both neurovascular and endothelial responses. Since LTH is abnormal in SSc patients, we aimed at testing whether LTH could be a prognostic tool for the onset of digital ulcers. METHODS: We prospectively enrolled 51 patients with SSc. Nailfold capillaroscopy and LTH were recorded at baseline, and patients were followed for 3 years. RESULTS: No patient with a LTH peak/plateau ratio >=1 (n=19) developed digital ulcerations during the 3 year follow-up (100% negative predictive value), while 6 out of 32 patients with a LTH peak/plateau ratio <1 at enrolment presented with finger pad ulcerations within 3 years (p=0.05). In contrast, when lidocaine/prilocaine was applied to the finger pad, no relationship between thermal hyperemia and digital ulcerations was observed. CONCLUSIONS: A LTH peak/plateau ratio on the finger pad greater than 1, which can easily be determined in routine clinical practice, could be used to reassure patients, whatever the subtype of SSc, about the low probability of future digital ulceration. However, the prognostic value of this parameter should be confirmed in a larger cohort. PMID- 24953720 TI - Iron deficiency and anemia are associated with low retinol levels in children aged 1 to 5 years. AB - OBJECTIVE: To analyze the occurrence of anemia and iron deficiency in children aged 1 to 5 years and the association of these events and retinol deficiency. METHODS: This was an observational analytic cross-sectional study conducted in Vitoria, ES, Brazil, between April and August of 2008, with healthy children aged 1 to 5 years (n=692) that lived in areas covered by primary healthcare services. Sociodemographic and economic conditions, dietary intake (energy, protein, iron, and vitamin A ingestion), anthropometric data (body mass index-for-age and height for-age), and biochemical parameters (ferritin, hemoglobin, and retinol serum) were collected. RESULTS: The prevalence of anemia, iron deficiency, and retinol deficiency was 15.7%, 28.1%, and 24.7%, respectively. Univariate analysis showed a higher prevalence of anemia (PR: 4.62, 95% CI: 3.36, 6.34, p<0.001) and iron deficiency (PR: 4.51, 95% CI: 3.30, 6.17, p<0.001) among children with retinol deficiency. The same results were obtained after adjusting for socioeconomic and demographic conditions, dietary intake, and anthropometric variables. There was a positive association between ferritin vs. retinol serum (r=0.597; p<0.001) and hemoglobin vs. retinol serum (r=0.770; p<0.001). CONCLUSIONS: Anemia and iron deficiency were associated with low levels of serum retinol in children aged 1 to 5 years, and a positive correlation was verified between serum retinol and serum ferritin and hemoglobin levels. These results indicate the importance of initiatives encouraging the development of new treatments and further research regarding retinol deficiency. PMID- 24953721 TI - Vitamin E concentration in human milk and associated factors: a literature review. AB - OBJECTIVE: To systematize information about vitamin E concentration in human milk and the variables associated with this composition in order to find possible causes of deficiency, supporting strategies to prevent it in postpartum women and infants. SOURCE: Studies published between 2004 and 2014 that assayed alpha tocopherol in human milk of healthy women by high performance liquid chromatography were evaluated. The keywords used were "vitamin E", "alpha tocopherol", "milk, human", "lactation", and equivalents in Portuguese, in the BIREME, CAPES, PubMed, SciELO, ISI Web of Knowledge, HighWire Press, Ingenta, and Brazilian Digital Library of Theses and Dissertations databases. SUMMARY OF THE FINDINGS: Of the 41 publications found on the subject, 25 whose full text was available and met the inclusion criteria were selected. The alpha-tocopherol concentrations found in milk were similar in most populations studied. The variable phase of lactation was shown to influence vitamin E content in milk, which is reduced until the mature milk appears. Maternal variables parity, anthropometric nutritional status, socioeconomic status, and habitual dietary intake did not appear to affect the alpha-tocopherol levels in milk. However, the influence of the variables maternal age, gestational age, biochemical nutritional status in alpha-tocopherol, and maternal supplementation with vitamin E had conflicting results in the literature. CONCLUSION: Alpha-tocopherol concentration in milk decreases during lactation, until the mature milk appears. To confirm the influence of some maternal and child variables on milk vitamin E content, further studies with adequate design are needed. PMID- 24953722 TI - Medication use among children 0-14 years old: population baseline study. AB - OBJECTIVE: Determine the prevalence of medication use in children and adolescents in 20 municipalities of Vale do Jequitinhonha, Minas Gerais-Brazil, showing the main groups and variables that may have influenced use. METHODS: Descriptive population-based survey sample of 555 interviews, selected by simple random cluster sampling of 137 census tracts. Inclusion criteria were age <= 14 years, mandatory interview with the legal guardians, and regardless of having received medications. Regarding the usage pattern, participants were divided into two groups: consumption and non-consumption of drugs. A descriptive analysis of the variables and tests of association were performed. RESULTS: The prevalence of drug consumption was 56.57%, and 42.43% showed no consumption. The use of medicinal plants was 72.9% for drug users and 74.3% for non-users. The health conditions for consumption were cough, common cold, flu, nasal congestion or bronchospasm (49.7%), fever (5.4%), headache (5.4%), diarrhea, indigestion, and abdominal colic (6.7%). In cases of self-medication, 30.57% of the drugs were given by the mother, and 69.42% were prescription drugs. Self-medication was prevalent using paracetamol (30.2%), dipyrone (20.8%), and cold medicine (18.8%). There was increased use of analgesics/antipyretics, followed by respiratory medications, systemic antibiotics, histamine H1 antagonists, and vitamins/antianemics. CONCLUSIONS: The prevalence of drugs use in children was high, indicating the need for formulating educational programs aiming at the awareness of caregivers regarding rational use. PMID- 24953724 TI - Early life factors among the many influences of child fruit and vegetable consumption. PMID- 24953723 TI - Viral suppression and adherence among HIV-infected children and adolescents on antiretroviral therapy: results of a multicenter study. AB - OBJECTIVE: To evaluate treatment adherence among perinatally-infected pediatric human immunodeficiency virus (HIV) patients followed in pediatric centers in Brazil. METHODS: This was a cross-sectional multicenter study. Medical records were reviewed and adherence scale, assessment of caregivers' quality of life (WHOQOL-BREF), anxiety, depression, and alcohol/substances use/abuse were assessed. Outcomes included self-reported 100% adherence in the last three days and HIV viral load (VL)<50 copies/mL. Statistical analyses included contingency tables and respective statistics, and multivariable logistic regression. RESULTS: 260 subjects were enrolled: 78% children and 22% adolescents; 93% of caregivers for the children and 77% of adolescents reported 100% adherence; 57% of children and 49% of adolescents had VL<50 copies/mL. In the univariate analyses, HIV diagnosis for screening due to maternal infection, lower caregiver scores for anxiety, and higher scores in physical and psychological domains of WHOQOL-BREF were associated with 100% adherence. Shorter intervals between pharmacy visits were associated with VL<50 copies/mL (p <= 0.01). Multivariable regression demonstrated that caregivers who did not abuse alcohol/other drugs (OR=0.49; 95% CI: 0.27-0.89) and median interval between pharmacy visits<33 days (OR=0.97; 95% CI: 0.95-0.98) were independently associated with VL<50 copies/mL; whereas lower caregiver scores for anxiety (OR=2.57; 95% CI: 1.27-5.19) and children's HIV diagnosis for screening due to maternal infection (OR=2.25; 95% CI: 1.12-4.50) were found to be independently associated with 100% adherence. CONCLUSIONS: Pediatric HIV programs should perform routine assessment of caregivers' quality of life, and anxiety and depression symptoms. In this setting, pharmacy records are essential to help identify less-than-optimal adherence. PMID- 24953725 TI - Interactive effects of elevated CO2 and nitrogen deposition on fatty acid molecular and isotope composition of above- and belowground tree biomass and forest soil fractions. AB - Atmospheric carbon dioxide (CO2) and reactive nitrogen (N) concentrations have been increasing due to human activities and impact the global carbon (C) cycle by affecting plant photosynthesis and decomposition processes in soil. Large amounts of C are stored in plants and soils, but the mechanisms behind the stabilization of plant- and microbial-derived organic matter (OM) in soils are still under debate and it is not clear how N deposition affects soil OM dynamics. Here, we studied the effects of 4 years of elevated (13C-depleted) CO2 and N deposition in forest ecosystems established in open-top chambers on composition and turnover of fatty acids (FAs) in plants and soils. FAs served as biomarkers for plant- and microbial-derived OM in soil density fractions. We analyzed above- and belowground plant biomass of beech and spruce trees as well as soil density fractions for the total organic C and FA molecular and isotope (delta13C) composition. FAs did not accumulate relative to total organic C in fine mineral fractions, showing that FAs are not effectively stabilized by association with soil minerals. The delta13C values of FAs in plant biomass increased under high N deposition. However, the N effect was only apparent under elevated CO2 suggesting a N limitation of the system. In soil fractions, only isotope compositions of short-chain FAs (C16+18) were affected. Fractions of 'new' (experimental-derived) FAs were calculated using isotope depletion in elevated CO2 plots and decreased from free light to fine mineral fractions. 'New' FAs were higher in short-chain compared to long-chain FAs (C20-30), indicating a faster turnover of short-chain compared to long-chain FAs. Increased N deposition did not significantly affect the quantity of 'new' FAs in soil fractions, but showed a tendency of increased amounts of 'old' (pre-experimental) C suggesting that decomposition of 'old' C is retarded by high N inputs. PMID- 24953726 TI - Acute hand ischemia after radial artery cannulation resulting in amputation. AB - Although radial artery cannulation is a common procedure, in rare cases, it can cause thrombosis leading to severe ischemia of the hand and potentially subsequent gangrene resulting in tissue loss. In this case report, a patient who developed a severely ischemic left hand subsequent to radial artery cannulation is presented. Doppler ultrasound studies showed adequate flow in the patient's hand, however complete thrombosis of the radial artery and significant low flow of the ulnar artery were found using arterial angiogram. The ischemia progressed and surgical intervention to revascularize the hand was unsuccessful, which led to the ultimate amputation of the patient's hand. In cases such as these, where Doppler ultrasound findings show flow but the hand ischemia continues to progress, further diagnostic studies and surgical intervention should be performed as soon as possible to minimize the amount of tissue loss. PMID- 24953727 TI - Histological characteristics of the abdominal aortic wall in patients with vascular chronic Q fever. AB - The aim of this study was to describe specific histological findings of the Coxiella burnetii-infected aneurysmal abdominal aortic wall. Tissue samples of the aneurysmal abdominal aortic wall from seven patients with chronic Q fever and 15 patients without evidence of Q fever infection were analysed and compared. Chronic Q fever was diagnosed using serology and tissue PCR analysis. Histological sections were stained using haematoxylin and eosin staining, Elastica van Gieson staining and immunohistochemical staining for macrophages (CD68), T lymphocytes (CD3), T lymphocyte subsets (CD4 and CD8) and B lymphocytes (CD20). Samples were scored by one pathologist, blinded for Q fever status, using a standard score form. Seven tissue samples from patients with chronic Q fever and 15 tissue samples from patients without Q fever were collected. Four of seven chronic Q fever samples showed a necrotizing granulomatous response of the vascular wall, which was characterized by necrotic core of the arteriosclerotic plaque (P = 0.005) and a presence of high numbers of macrophages in the adventitia (P = 0.007) distributed in typical palisading formation (P = 0.005) and surrounded by the presence of high numbers of T lymphocytes located diffusely in media and adventitia. Necrotizing granulomas are a histological finding in the C. burnetii-infected aneurysmal abdominal aortic wall. Chronic Q fever should be included in the list of infectious diseases with necrotizing granulomatous response, such as tuberculosis, cat scratch disease and syphilis. PMID- 24953729 TI - Polarised cell migration: intrinsic and extrinsic drivers. AB - Cell polarity arises out of asymmetry of the distribution and organisation of cell contents. Polarity is an important feature of all living organisms and much energy is devoted to breaking symmetry and establishing polarity. Recent developments in our understanding of how the budding yeast Saccharomyces cerevisiae establishes and maintains polarity for cell division shed light on universal mechanisms that may be relevant to both asymmetric cell division and polarised cell migration in other organisms. Here, we summarise some of the recent developments in our understanding of polarity of the cytoskeleton and associated signalling molecules as it relates to cell migration. Parallels are drawn between planar cell polarity and apical-basal polarity in epithelial tissues and front-back polarity in migrating cells. PMID- 24953728 TI - Energy conversion analysis of microalgal lipid production under different culture modes. AB - Growth and lipid production performance of Scenedesmus sp. under different culture modes were investigated. Under heterotrophic aerobic mode, algal biomass concentration and total lipid content reached 3.42 g L(-1) and 43.0 wt.%, which were much higher than those in autotrophic aerobic mode (0.55 g L(-1)/20.2 wt.%). The applied light exposure of 7.0 Wm(-2) was beneficial to biomass and lipid accumulation. Mixotrophic aerobic mode produced the highest biomass concentration of 3.84 g L(-1). The biomass was rich in lipids (51.3 wt.%) and low in proteins (17.9 wt.%) and carbohydrates (10.3 wt.%). However, lower algal biomass concentration (2.93 g L(-1)) and total lipid content (36.1 wt.%) were obtained in mixotrophic anaerobic mode. Mixotrophic aerobic mode gave the maximum heat value conversion efficiency of 45.7%. These results indicate that mixotrophic aerobic cultivation was a promising culture mode for lipid production by Scenedesmus sp. PMID- 24953730 TI - [Antenatal exposure of several factors and development of allergic diseases in offspring]. PMID- 24953731 TI - [Allergen immunotherapy in pregnancy]. PMID- 24953732 TI - [Guideline for hereditary angioedema (HAE) 2010 by the Japanese Association for Complement Research: points for diagnosis and treatment]. PMID- 24953733 TI - [The mechanism of airway hyperresponsiveness by lipid mediators]. PMID- 24953734 TI - [Therapeutic strategies for atopic dermatitis on skin barrier function]. PMID- 24953735 TI - [How to use Japanese allergic conjunctival disease quality-of-life questionnaire (JACQLQ)]. PMID- 24953737 TI - [Clinical aspects of 41 cases performed challenge test with immediate-type wheat allergy due to hydrolyzed wheat protein (HWP-IWA)]. AB - BACKGROUND: Immediate-type wheat allergy due to hydrolyzed wheat protein (HWP IWA) supplemented soap has been a serious social issue. We investigated the significance of challenge test and other tests not only to diagnose HWP-IWA but to know the symptoms of each patients. METHODS: From January 2010 to June 2012, we performed challenge test in 41 cases with positive prick test of Glupearl 19S(r), a major allergic HWP found in Cha no Shizuku(r). RESULTS: Thirty nine of 41 cases were challenge test positive. In two patients who showed positive skin prick test but negative for challenge test, titer of specific IgE antibody and/or basophil histamine release test against Glupearl 19S(r) revealed positive reaction. CONCLUSION: Challenge test is not included in indispensable examinations for the diagnosis of HWP-IWA in the recommended guidelines. However, challenge test is still a useful tool for assessing actual severity of each patient's symptoms and determining the timing of cessation of wheat avoidance. In addition, combined check-up with several laboratory examination and challenge test may help appropriate diagnosis of HWP-IWA. PMID- 24953736 TI - [Clinical relevance of biomarkers in allergic rhinitis]. PMID- 24953738 TI - [Allergy due to probable contamination of bread used for school meals with milk]. AB - BACKGROUND: In May 2012, two schoolchildren developed allergic symptoms after eating a school meal of fried bread in Osaka, Japan. One specific raw material, milk, should not be present in fried bread. However, we suspected the unintentional mixing of milk in the bread manufacturing process. Our aim was to verify the reason if this was so. METHODS: We first manufactured bread that contained milk as one of its components. We then thoroughly cleaned the manufacturing line except for the dough divider and, as per the revised instruction manual, continuously manufactured bread that did not contain milk. In this manner, we tried to simulate the conditions at the time of the incident. Casein is a major milk protein. We, therefore, determined casein concentration in the milk-free bread, using casein enzyme-linked immunosorbent assay. RESULTS: We observed casein levels higher than 1000 ppm in the initial lots of breads, but lower levels in the later lots. Casein levels also decreased upon frying of bread. CONCLUSION: High casein levels, which were observed in the earlier lots of breads, were lower in the later lots. In the manufacturing line, the remnants of the bread dough that contained milk presumably got mixed with the dough used in the subsequent manufacture of milk-free bread. PMID- 24953739 TI - [Ten-year questionnaire survey on adult asthma patients in Miyazaki Prefecture, Japan]. AB - OBJECTIVES: To decrease the number of asthma deaths occurring in Miyazaki Prefecture in Japan by promoting guideline-based treatment through the bronchial asthma forum. METHODS: A self-completed questionnaire survey of adult asthma patients was conducted in Miyazaki Prefecture during the same season for 10 consecutive years from 1999 to 2008. RESULTS: A total of 7899 responses were collected from medical institutions throughout the prefecture. In the course of 10 years, the doses of the drugs used for long-term management, including inhaled steroids, long-acting inhaled beta2-stimulants, and leukotriene receptor antagonists, increased year after year. Consequently, the frequency of asthma symptoms declined and there was a decrease in the use of short-acting inhaled beta2-stimulants, parenteral aminophylline, and slow-release theophylline preparations in response to this trend. Prescription rate of inhaled steroids and patients satisfaction was higher in the facilities of specialists than non specialists. In patients with rhinitis symptoms, asthma was improved by concurrently treating both rhinitis and asthma in the survey of 2008. CONCLUSIONS: Asthma treatment based on the guideline was increasing in Miyazaki Prefecture, and this may have resulted in the improvement of asthma symptoms, increased patient satisfaction, and more importantly, a decrease in the number of asthma deaths. PMID- 24953740 TI - Ultrafast X-ray Auger probing of photoexcited molecular dynamics. AB - Molecules can efficiently and selectively convert light energy into other degrees of freedom. Disentangling the underlying ultrafast motion of electrons and nuclei of the photoexcited molecule presents a challenge to current spectroscopic approaches. Here we explore the photoexcited dynamics of molecules by an interaction with an ultrafast X-ray pulse creating a highly localized core hole that decays via Auger emission. We discover that the Auger spectrum as a function of photoexcitation--X-ray-probe delay contains valuable information about the nuclear and electronic degrees of freedom from an element-specific point of view. For the nucleobase thymine, the oxygen Auger spectrum shifts towards high kinetic energies, resulting from a particular C-O bond stretch in the pipi* photoexcited state. A subsequent shift of the Auger spectrum towards lower kinetic energies displays the electronic relaxation of the initial photoexcited state within 200 fs. Ab-initio simulations reinforce our interpretation and indicate an electronic decay to the npi* state. PMID- 24953742 TI - Composition dependent intrinsic defect structures in SrTiO3. AB - Intrinsic point defect complexes in SrTiO3 under different chemical conditions are studied using density functional theory. The Schottky defect complex consisting of nominally charged Sr, Ti and O vacancies is predicted to be the most stable defect structure in stoichiometric SrTiO3, with a relatively low formation energy of 1.64 eV per defect. In addition, the mechanisms of defect complex formation in nonstoichiometric SrTiO3 are investigated. Excess SrO leads to the formation of oxygen vacancies and a strontium-titanium antisite defect, while a strontium vacancy together with an oxygen vacancy and a titanium strontium antisite defect are produced in an excess TiO2 environment. Since point defects, such as oxygen vacancies and cation antisite defects, are intimately related to the functionality of SrTiO3, these results provide guidelines for controlling the formation of intrinsic point defects and optimizing the functionality of SrTiO3 by controlling nonstoichiometric chemical compositions of SrO and TiO2 in experiments. PMID- 24953743 TI - Quality of life in Parkinson's disease patients with motor fluctuations and dyskinesias in five European countries. AB - BACKGROUND: Little is known about the relationship between specific subtypes of treatment-associated motor complications and different domains of health-related Quality of Life (QoL) in patients with Parkinson's disease (PD). Larger studies that investigate these aspects within a cross-cultural setting are scarce. OBJECTIVE: To assess QoL and its association with on-off fluctuations, peak-dose dyskinesias, biphasic dyskinesias, and off-dystonias in PD patients from five European countries. METHODS: Data from 817 PD patients were collected cross sectionally in France, Germany, Italy, Spain, and the UK. QoL was measured with the generic EuroQoL 5-Dimension questionnaire (EQ-5D) and the disease-specific Parkinson's Disease Questionnaire-39 (PDQ-39). Multivariable linear regression analyses were performed to test the associations of motor complication subtypes with QoL. RESULTS: Thirty-three percent of the patients (varying from 23% in Italy to 58% in France) suffered from motor complications, either a single subtype or a combination of different subtypes. On-off fluctuations were associated with a 7.1 percentage point decrease in the EQ-5D (p < 0.001) and a 3.6 percentage point deterioration in the PDQ-39 (p = 0.01). Dyskinesias were not seen to affect global QoL scores, but had detrimental effects on the PDQ-39 dimensions activities of daily living, cognitions, stigma, and bodily discomfort. Patients from Spain, Italy, and France had lower global QoL scores in the multivariable analyses than patients from Germany and the UK. CONCLUSION: Motor complications, primarily on-off fluctuations, may impact QoL in PD patients. This substantiates the importance of clinical strategies targeting the prevention, delay of onset, and management of motor complications in PD patients. PMID- 24953741 TI - Integrated regulation of motor-driven organelle transport by scaffolding proteins. AB - Intracellular trafficking pathways, including endocytosis, autophagy, and secretion, rely on directed organelle transport driven by the opposing microtubule motor proteins kinesin and dynein. Precise spatial and temporal targeting of vesicles and organelles requires the integrated regulation of these opposing motors, which are often bound simultaneously to the same cargo. Recent progress demonstrates that organelle-associated scaffolding proteins, including Milton/TRAKs (trafficking kinesin-binding protein), JIP1, JIP3 (JNK-interacting proteins), huntingtin, and Hook1, interact with molecular motors to coordinate activity and sustain unidirectional transport. Scaffolding proteins also bind to upstream regulatory proteins, including kinases and GTPases, to modulate transport in the cell. This integration of regulatory control with motor activity allows for cargo-specific changes in the transport or targeting of organelles in response to cues from the complex cellular environment. PMID- 24953744 TI - Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: an overview. AB - The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been used to describe a syndrome characterized by various obsessions, compulsions, tics, hyperactivity, motor stereotypies, and paroxysmal movement disorders that are correlated with prior infection by group A beta-hemolytic Streptococcus pyogenes (GABHS) infections. Five clinical criteria can be used to diagnose PANDAS: (1) the presence of obsessive-compulsive disorder (OCD) and/or any other tic disorders; (2) prepuberal onset (between 3 years of age and the start of puberty); (3) abrupt onset and relapsing-remitting symptom course; (4) a distinct association with GABHS infection; and (5) association with neurological abnormalities during exacerbations (adventitious movements or motoric hyperactivity). The exact pathogenesis of PANDAS remains unclear, and several theories that focus on multiple etiologic or contributive factors have emerged. PANDAS appears to be a neurobiological disorder that potentially complicates GABHS infections in genetically susceptible individuals. The current standard of care for PANDAS patients remains symptomatic, and cognitive behavioral therapy, such as exposure and response prevention, combined with family counseling and psychoeducation, should be the first approach for treating PANDAS. This review examines current theories of PANDAS pathogenesis, identifies possible treatments for managing this complex condition, and highlights areas for future research. Moving forward, developing more standardized diagnostic criteria and identifying specific laboratory markers to facilitate PANDAS diagnoses are crucial. PMID- 24953745 TI - Influence of oxidative nanopatterning and anodization on the fatigue resistance of commercially pure titanium and Ti-6Al-4V. AB - With an increasingly aging population, a significant challenge in implantology is the creation of biomaterials that actively promote tissue integration and offer excellent mechanical properties. Engineered surfaces with micro- and nanoscale topographies have shown great potential to control and direct biomaterial-host tissue interactions. Two simple yet efficient chemical treatments, oxidative nanopatterning and anodization, have demonstrated the ability to confer exciting new bioactive capacities to commercially pure titanium and Ti-6Al-4V alloy. However, the resulting nanoporous and nanotubular surfaces require careful assessment in regard to potential adverse effects on the fatigue resistance, a factor which may ultimately cause premature failure of biomedical implants. In this work, we have investigated the impact of oxidative nanopatterning and anodization on the fatigue resistance of commercially pure titanium and Ti-6Al 4V. Quantitative (e.g., S-N curves) and qualitative analyses were carried out to precisely characterize the fatigue response of treated metals and compare it to that of polished controls. Scanning electron microscopy (SEM) imaging revealed the effects of cyclic loading on the fracture surface and on the structural integrity of chemically grown nanostructured oxides. Results from this study reinforce the importance of mechanical considerations in the development and optimization of micro- and nanoscale surface treatments for metallic biomedical implants. PMID- 24953746 TI - Are APLS formulae for estimating weight appropriate for use in children admitted to PICU? [Resuscitation 85 (2014) 927 - 31]. PMID- 24953747 TI - Editorial: At the crossroad between inflammation and skin aging. PMID- 24953748 TI - Acute encephalitis in children: Progress and priorities from an Australasian perspective. AB - Encephalitis is a complex neurological syndrome caused by inflammation of the brain that occurs with highest incidence in children. It is challenging to diagnose and manage due to the variety of aetiologies and non-specific clinical presentations. We discuss the recent progress in clinical case definitions; review recent, large, prospective epidemiological studies; and describe aetiologies. We emphasise infectious causes relevant to children in Australasia but also consider emerging immune-mediated syndromes responsive to immune therapies. We identify priorities for future research in children, given the potential for climate change and international travel to influence the emergence of infectious agents in our region. PMID- 24953749 TI - Socio-economic characteristics of patients with generalized retinal dystrophy in Denmark. AB - PURPOSE: To examine socio-economic characteristics of patients with generalized retinal dystrophy in Denmark. METHODS: Cross-sectional population-based study with analysis of socio-economic characteristics including income, education, employment status and civil status in 2285 patients from the Danish Retinitis Pigmentosa Registry and 228,500 control subjects matched by age and gender. Demographic and socio-economic data were retrieved from Statistics Denmark. Differences between cases and controls were estimated using conditional logistic regression. RESULTS: On 1 January 2012, 2285 patients with a Danish civil registration number were registered as having a generalized retinal dystrophy. At the age of 40 years, less patients than controls had a high education (odds ratio (OR), 0.51; 95% confidence interval (CI95), 0.41-0.62), a high income (OR, 0.21; CI95, 0.17-0.26) and were married (OR, 0.39; CI95, 0.33-0.45). More patients than controls were pensioners (OR, 6.04; CI95, 5.23-6.97). CONCLUSIONS: We found that patients with generalized retinal dystrophy differed significantly from a matched control group on several socio-economic characteristics. The differences were more pronounced in patients with systemic involvement and patients with an early age at disease presentation. The socio-economic inequalities of this group of blinding diseases emphasize the importance of rehabilitation and need for a substantial and multidisciplinary support from the healthcare, educational and social systems. PMID- 24953750 TI - Sensitivity and specificity of serological tests, histopathology and immunohistochemistry for detection of Toxoplasma gondii infection in domestic chickens. AB - Since free-range chickens are important for the epidemiology of toxoplasmosis, this study evaluated the sensitivity and specificity of different laboratory techniques for the diagnosis of Toxoplasma gondii in these animals. Serum samples from 135 adult domestic chickens were tested for anti-T. gondii antibodies by the indirect fluorescent antibody test (IFAT), enzyme-linked immunosorbent assay (ELISA), modified agglutination test (MAT), and indirect hemagglutination test (IHAT). Tissue samples from all animals were analyzed by histopathology, immunohistochemistry and mouse bioassay (gold standard). Fifty-four chickens were positive for T. gondii in the bioassay. The sensitivity and specificity of the different tests were, respectively, 85% and 56% for ELISA; 80% and 52% for IFAT; 76% and 68% for MAT; 61% and 80% for IHAT; 7% and 98% for immunohistochemistry, and 6% and 98% for histopathology. The MAT was the most effective method for the diagnosis of T. gondii infection in chickens, followed by ELISA. Histopathology and immunohistochemistry are useful tools for the diagnosis of T. gondii infection in chickens due to their specificity. PMID- 24953751 TI - The infection of questing Dermacentor reticulatus ticks with Babesia canis and Anaplasma phagocytophilum in the Chernobyl exclusion zone. AB - Tick occurrence was studied in the Chernobyl exclusion zone (CEZ) during the August-October 2009-2012. Dermacentor reticulatus ticks were collected using the flagging method and then screened for infection with Anaplasma phagocytophilum and Babesia canis by a PCR method incorporating specific primers and sequence analysis. The prevalence of infection with B. canis canis and A. phagocytophilum was found to be 3.41% and 25.36%, respectively. The results present the first evidence of B. canis canis and A. phagocytophilum in questing D. reticulatus ticks from the Chernobyl exclusion zone. They also reveal the presence of tick borne disease foci in areas with no human activity, and confirm that they can be maintained in areas after a nuclear disaster with radioactive contamination. PMID- 24953752 TI - Assessing the speed of kill of hookworms, Ancylostoma caninum, by Advantage Multi (r) for Dogs using endoscopic methods. AB - Endoscopic capsules and endoscopy were used to assess the speed of kill and the clearance of hookworms in dogs experimentally infected with Ancylostoma caninum. A total of four adult dogs were inoculated in two separate cohorts comprised of two 4-year-old females and two 7-year-old males. Dogs were treated topically with Advantage Multi((r)) for Dogs 13 days (Cohort 1) or 16 days (Cohort 2) after infection. Endoscopic imaging of the small intestine was carried out both pre- and post-treatment. Examination of the first cohort revealed that the worms had been cleared and the hookworm-induced lacerations were markedly diminished within 48 h of treatment. In the second cohort, endoscopic capsules were given the day of, the day after, and two days after treatment; within 24h of product administration, the worms had been removed with a concurrent reduction in observed lesions. Topical application of Advantage Multi((r)) for Dogs rapidly removed worms from the small intestine of the dogs in this study as early as 24h post-treatment, with a marked reduction in the number of mucosal lesions seen. PMID- 24953753 TI - Outcome of a heartworm treatment protocol in dogs presenting to Louisiana State University from 2008 to 2011: 50 cases. AB - Since 2008, the American Heartworm Society has recommended using a three-dose melarsomine protocol (a single intramuscular injection of melarsomine dihydrochloride at 2.5mg/kg, followed approximately 1 month later with two doses administered 24h apart) for all heartworm-positive dogs, with doxycycline given at 10mg/kg twice daily for 4 weeks prior to administration of melarsomine. To report the efficacy and side effects of this standard heartworm treatment protocol in 50 dogs presenting to our hospital from 2008 to 2011, information on the history, clinical, laboratory, and diagnostic imaging findings and treatment was obtained from medical records. When possible, additional follow-up information was obtained through telephone interviews with referring veterinarians and owners. Twenty-six dogs (52%) experienced minor complications, such as injection site reactions, gastrointestinal signs (vomiting, diarrhea, inappetance), and behavioral changes (lethargy, depression) during or after heartworm treatment. Twenty-seven dogs (54%) experienced respiratory signs (coughing, dyspnea) and heart failure attributed to progressive heartworm disease and worm death. Seven dogs (14%) died within the treatment period. Owners frequently reported behavioral changes, such as depression and lethargy, suspected to be secondary to pain. Fifty percent of owners surveyed indicated that, prior to the diagnosis, they either were not currently administering heartworm preventative, or they had recently adopted the dog from a shelter that did not administer preventatives. After treatment, 100% were administering heartworm preventatives to their pet. Eighteen dogs (36%) received a heartworm antigen test 6 months after adulticide therapy, 12 of which tested negative and six tested positive. Four of the dogs with a positive test at 6 months had negative tests 1 month later with no additional treatment. Adverse effects were common with the recommended protocol, but the majority of these were mild. Dogs in Class 1 (i.e., heartworm positive but otherwise largely lacking clinical evidence of disease) did not experience any major adverse effects or death. PMID- 24953754 TI - Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment. AB - OBJECTIVE: We examined the interrelationships of pituitary thyrotropin (TSH) with circulating thyroid hormones to determine whether they were expressed either invariably or conditionally and distinctively related to influences such as levothyroxine (L-T4) treatment. DESIGN AND METHODS: This prospective study employing 1912 consecutive patients analyses the interacting equilibria of TSH and free triiodothyronine (FT3) and free thyroxine (FT4) in the circulation. RESULTS: The complex interrelations between FT3, FT4 and TSH were modulated by age, body mass, thyroid volume, antibody status and L-T4 treatment. By group comparison and confirmation by more individual TSH-related regression, FT3 levels were significantly lower in L-T4-treated vs untreated nonhypothyroid autoimmune thyroiditis (median 4.6 vs 4.9 pm, P < 0.001), despite lower TSH (1.49 vs 2.93 mU/l, P < 0.001) and higher FT4 levels (16.8 vs 13.8 pm, P < 0.001) in the treated group. Compared with disease-free controls, the FT3-TSH relationship was significantly displaced in treated patients with carcinoma, with median TSH of 0.21 vs 1.63 (P < 0.001) at a comparable FT3 of 5.0 pm in the groups. Disparities were reflected by calculated deiodinase activity and remained significant even after accounting for confounding influences in a multivariable model. CONCLUSIONS: TSH, FT4 and FT3 each have their individual, but also interlocking roles to play in defining the overall patterns of thyroidal expression, regulation and metabolic activity. Equilibria typical of the healthy state are not invariant, but profoundly altered, for example, by L-T4 treatment. Consequently, this suggests the revisitation of strategies for treatment optimization. PMID- 24953755 TI - Effect of surface treatment and type of cement on push-out bond strength of zirconium oxide posts. AB - STATEMENT OF PROBLEM: The effect of the surface treatment of zirconium oxide posts on their push-out bond strength is controversial. PURPOSE: The purpose of this study was to compare the effects of 2 surface treatments on the bond strength of zirconium oxide posts cemented with different cements and to assess the failure mode. MATERIAL AND METHODS: Seventy extracted human teeth were divided into 7 groups (n=10). Custom zirconium oxide posts (Cercon; Degudent) were fabricated for 6 groups. Posts in 3 groups were airborne-particle abraded (A). Posts in the other 3 groups were tribochemical silica coated (T). Three cements were used. Zinc phosphate cement was used to cement the zirconium oxide posts in groups AZ and TZ, RelyX ARC cement was used in groups ARA and TRA, and RelyX Unicem cement was used in groups ARU and TRU. Group C contained custom metal posts cemented with zinc phosphate cement. Specimens were horizontally sectioned into 3 sections and subjected to a push-out test. A mixed model analysis of variance, 1-way ANOVA, and the Tukey multiple comparison tests were used for statistical analysis. RESULTS: The highest push-out bond strength was recorded for Group ARU (21.03 MPa), and the lowest was recorded for Group ARA (7.57 MPa). No significant difference in push-out bond strength was found among the different surface treatments and root regions (P>.05). The type of cement had a significant effect on the push-out bond strength of zirconium oxide posts (P=.049). RelyX Unicem cement recorded (19.57 +/-8.83 MPa) significantly higher push-out bond strength compared with zinc phosphate (9.95 +/-6.31 MPa) and RelyX ARC cements (9.39 +/-5.45 MPa). Adhesive failure at the post-cement interface was recorded for 75% of the posts cemented with zinc phosphate and RelyX ARC cements, while mixed failure was recorded for 75% of the posts cemented with RelyX Unicem cement. CONCLUSIONS: The type of cement used resulted in a statistically significant difference in the push-out bond strength of zirconium oxide posts, while both the surface treatment and root region resulted in no statistically significant effect after artificial aging. RelyX Unicem cement had significantly higher push-out bond strength than did zinc phosphate and RelyX ARC cements. PMID- 24953757 TI - Subchronic treatment with phencyclidine in adolescence leads to impaired exploratory behavior in adult rats without altering social interaction or N methyl-D-aspartate receptor binding levels. AB - Although both the onset of schizophrenia and human phencyclidine (PCP) abuse typically present within the interval from adolescence to early adulthood, the majority of preclinical research employing the PCP model of schizophrenia has been conducted on neonatal or adult animals. The present study was designed to evaluate the behavioral and neurochemical sequelae of subchronic exposure to PCP in adolescence. Male 35-42-day-old Sprague Dawley rats were subcutaneously administered either saline (10 ml . kg(-1) ) or PCP hydrochloride (10 mg . kg(-1) ) once daily for a period of 14 days (n = 6/group). The animals were allowed to withdraw from treatment for 2 weeks, and their social and exploratory behaviors were subsequently assessed in adulthood by using the social interaction test. To examine the effects of adolescent PCP administration on the regulation of N methyl-D-aspartate receptors (NMDARs), quantitative autoradiography was performed on brain sections of adult, control and PCP-withdrawn rats by using 20 nM (3) H MK-801. Prior subchronic exposure to PCP in adolescence had no enduring effects on the reciprocal contact and noncontact social behavior of adult rats. Spontaneous rearing in response to the novel testing arena and time spent investigating its walls and floor were reduced in PCP-withdrawn animals compared with control. The long-term behavioral effects of PCP occurred in the absence of persistent deficits in spontaneous locomotion or self-grooming activity and were not mediated by altered NMDAR density. Our results document differential effects of adolescent PCP administration on the social and exploratory behaviors of adult rats, suggesting that distinct neurobiological mechanisms are involved in mediating these behaviors. PMID- 24953756 TI - Mercury in the marine environment of the Canadian Arctic: review of recent findings. AB - This review summarizes data and information which have been generated on mercury (Hg) in the marine environment of the Canadian Arctic since the previous Canadian Arctic Contaminants Assessment Report (CACAR) was released in 2003. Much new information has been collected on Hg concentrations in marine water, snow and ice in the Canadian Arctic. The first measurements of methylation rates in Arctic seawater indicate that the water column is an important site for Hg methylation. Arctic marine waters were also found to be a substantial source of gaseous Hg to the atmosphere during the ice-free season. High Hg concentrations have been found in marine snow as a result of deposition following atmospheric mercury depletion events, although much of this Hg is photoreduced and re-emitted back to the atmosphere. The most extensive sampling of marine sediments in the Canadian Arctic was carried out in Hudson Bay where sediment total Hg (THg) concentrations were low compared with other marine regions in the circumpolar Arctic. Mass balance models have been developed to provide quantitative estimates of THg fluxes into and out of the Arctic Ocean and Hudson Bay. Several recent studies on Hg biomagnification have improved our understanding of trophic transfer of Hg through marine food webs. Over the past several decades, Hg concentrations have increased in some marine biota, while other populations showed no temporal change. Marine biota also exhibited considerable geographic variation in Hg concentrations with ringed seals, beluga and polar bears from the Beaufort Sea region having higher Hg concentrations compared with other parts of the Canadian Arctic. The drivers of these variable patterns of Hg bioaccumulation, both regionally and temporally, within the Canadian Arctic remain unclear. Further research is needed to identify the underlying processes including the interplay between biogeochemical and food web processes and climate change. PMID- 24953758 TI - Nutrient media optimization for simultaneous enhancement of the laccase and peroxidases production by coculture of Dichomitus squalens and Ceriporiopsis subvermispora. AB - Coculturing of two white-rot fungi, Dichomitus squalens and Ceriporiopsis subvermispora, was explored for the optimization of cultivation media for simultaneous augmentation of laccase and peroxidase activities by response surface methodology (RSM). Nutrient parameters chosen from our previous studies with the monocultures of D. squalens and C. subvermispora were used to design the experiments for the cocultivation study. Glucose, arabinose, sodium nitrate, casein, copper sulfate (CuSO4 ), and manganese sulfate (MnSO4 ) were combined according to central composite design and used as the incubation medium for the cocultivation. The interaction of glucose and sodium nitrate resulted in laccase and peroxidase activities of approximately 800 U/g protein. The addition of either glucose or sodium nitrate to the medium also modifies the impact of other nutrients on the ligninolytic activity. Both enzyme activities were cross regulated by arabinose, casein, CuSO4 , and MnSO4 as a function of concentrations. Based on RSM, the optimum nutrient levels are 1% glucose, 0.1% arabinose, 20 mM sodium nitrate, 0.27% casein, 0.31 mM CuSO4 , and 0.07 mM MnSO4 . Cocultivation resulted in the production of laccase of 1,378 U/g protein and peroxidase of 1,372 U/g protein. Lignin (16.9%) in wheat straw was degraded by the optimized enzyme mixture. PMID- 24953759 TI - Multicenter study on the long-term (3-year) efficacy of lanthanum carbonate in dialysis patients. AB - We previously conducted a multicenter study enrolling 101 dialysis patients with hyperphosphatemia in which lanthanum carbonate (LC) was administered for 2 years. In this study, the administration has been continued for an additional year, and we have evaluated the long-term (a total of 3 years) effects of LC. The average serum phosphorus (P) level was 6.05 mg/dL at the start and decreased to 5.84 mg/dL after 3 years, but no significant differences were observed at both points. The average serum corrected calcium (Ca) level significantly reduced after 3 years (P < 0.001). As results of evaluating the achievement rates with the management target values of serum P, Ca and intact parathyroid hormone (PTH) stated in the Japanese guideline, the achievement rates increased after 3 years. From these results, LC is considered to be a useful P binder that can be used for long-term treatment of hyperphosphatemia, without causing a Ca load. PMID- 24953760 TI - Clinical effects of long-term (36-month) lanthanum carbonate administration in hemodialysis patients in Japan. AB - In this study, we investigated the clinical effects of long-term administration of the phosphorus (P) binder lanthanum carbonate (LC), which was launched in Japan in 2009. The subjects were 58 dialysis patients who began receiving LC, and we evaluated the clinical effects for up to 36 months after treatment initiation. The average serum P concentration remained low during the 36-month study period, with a significant reduction from 6.25 mg/dL at the start of the study to 4.94 mg/dL after 36 months (P < 0.001). A significant reduction was also observed in the average serum calcium concentration after 36 months (P < 0.05), but not in the serum intact parathyroid hormone concentration. Significant reductions were also observed in the average serum total protein, albumin and potassium concentrations (P < 0.05). The dosages of LC increased by approximately 1.9-fold after 36 months, in contrast, the dosages of concomitantly used sevelamer hydrochloride and Ca carbonate preparations decreased. These results indicate that LC could be used to treat hyperphosphatemia without causing hypercalcemia, and would be useful for long-term treatment with hemodialysis patients. PMID- 24953761 TI - Increase in the dosage amount of vitamin D3 preparations by switching from calcium carbonate to lanthanum carbonate. AB - It is widely known that dialysis patients who are administered vitamin D preparations have a better prognosis than patients who are not. In this study, of 22 patients on maintenance dialysis who had been administered calcium (Ca) carbonate in our hospital, we investigated the dosage amount of vitamin D3 preparations after the phosphorus (P) binder was switched from Ca carbonate to the newly developed lanthanum carbonate (LC). After completely switching to LC, the dosage amount of oral vitamin D3 preparation (alfacalcidol equivalent) was significantly increased from 0.094 MUg/day to 0.375 MUg/day (P = 0.0090). No significant changes were observed in the values of serum corrected Ca, alkaline phosphatase, intact parathyroid hormone and P after switching. The administration of LC enabled complete cessation of the administration of Ca carbonate preparations, and increased the dosage amount of vitamin D3 preparations. Therefore, LC may be a useful P binder to improve patient prognosis. PMID- 24953762 TI - Effects of change in the formulation of lanthanum carbonate on laboratory parameters. AB - Lanthanum carbonate (LC) is available in the two formulations of chewable tablets and granules. In this study, we changed the formulation of LC from chewable tablet to granules, and compared the laboratory parameters for 3 months before and after changing formulation in 58 hemodialysis (HD) patients. We also surveyed patients about their preferences for the two formulations. The mean serum phosphorus (P) levels decreased significantly (P < 0.01) from 6.7 mg/dL to 6.4 mg/dL after the change. The levels for serum albumin and geriatric nutritional risk index increased significantly (P < 0.01). Serum calcium levels also increased significantly (P < 0.01), while serum intact parathyroid hormone levels decreased significantly (P < 0.01). In the survey, approximately half of the patients responded that the granules were easier to take than the chewable tablets. These findings suggest that changing the formulation of LC to granules may reduce serum P levels of the HD patients in clinical practices. PMID- 24953763 TI - Is granular formulation of lanthanum carbonate more effective than chewable tablets? AB - Maintenance dialysis patients at our hospital who had been receiving lanthanum carbonate (LC) chewable tablets were switched to the same dosage of the granules, and the differences in serum phosphorus (P) levels were compared, together with stratifying patients at the baseline characteristics. Compared to average serum P level of 5.48 mg/dL for 2 months prior to switching, the average level for 2 months after switching was 4.99 mg/dL (P = 0.049). For patients who were under 60, serum P levels were significantly improved after switching (P = 0.016), and for patients who were concomitantly taking many kinds of medications, a correlation to high reductions of serum P level after switching was shown (R = 0.635, P = 0.015). In order to maximize pharmaceutical potential of LC, we think that it is not only necessary to provide patients with how to take the medication, but it is also important to take into consideration the patients' baseline characteristics. PMID- 24953764 TI - Questionnaire survey and serum phosphorus levels in maintenance hemodialysis patients switching lanthanum carbonate formulation from chewable tablets to granules. AB - We conducted a questionnaire survey of 79 maintenance hemodialysis patients switching lanthanum carbonate (LC) formulation from chewable tablets to granules, to investigate the compliance and patient preferences of these two formulations. For the number of times chewed when taking chewable tablets, the ratio of patients who responded 10 times or more was 54.4%, who responded four to nine times was 24.1% and who responded three times or less was 8.9%. Thirty-seven patients (46.8%) responded "Granules are easier to take", 22 patients (27.8%) responded "Chewable tablets are easier to take", and 20 patients (25.3%) responded "No difference between formulations." Changes in serum phosphorus (P) levels were also measured for 4 weeks after switching formulation, but no significant differences were observed before and after switching. We think that these questionnaire survey results show the compliance status and the patient needs for LC in the clinical practices. PMID- 24953765 TI - Cutaneous infection with Dermocystidium salmonis in cardinal tetra, Paracheirodon axelrodi (Schultz, 1956). PMID- 24953767 TI - Adult development and the transformative powers of psychotherapy. AB - This article explores the ways in which receiving, providing, and teaching others to do psychotherapy have influenced my adult development. In my 70s, I arrived at the conviction that at every stage of adulthood, practicing psychotherapy has had a direct and causal influence on my efforts to fill my personal life with meaning, virtue, and maturity. The first section of this article focuses on the ways in which learning to be a particular kind of psychoanalytic therapist facilitated my transition into early adulthood. The middle sections describe how I have used the professional practice of psychotherapy to integrate or dissolve the boundaries between work and play, and science and art, in the everyday conduct of my life. My psychobiographical analysis concludes with some reflections on a professional failure and the compensations of being an aging therapist. PMID- 24953766 TI - In a double-blind, randomized and placebo-controlled trial, adjuvant allopurinol improved symptoms of mania in in-patients suffering from bipolar disorder. AB - Allopurinol is a drug used primarily to treat hyperuricemia. In patients suffering from acute mania, increased levels of uric acid are observed, and symptom improvements are associated with decreased levels of uric acid. Accordingly, a purinergic dysfunction is plausibly a causative factor in the pathophysiology of mania. The aim of the present study was therefore to investigating whether allopurinol has benefits for patients treated with sodium valproate during acute mania. (Background) A double-blind, placebo-controlled study lasting 4 weeks was performed. The intention-to-treatment population included 57 patients; 50 concluded the study per protocol. Patients suffering from BPD and during acute mania were randomly assigned either to a treatment (sodium valproate 15-20 mg/kg+300 mg allopurinol twice a day) or to a control condition (sodium valproate 15-20 mg/kg+placebo). Experts rated illness severity and illness improvements (Clinical Global impression), and extent of mania via the Young Mania Rating scale. Uric acid levels were assessed at the beginning and end of the study. (Experimental procedures) Compared to the control group, symptoms of mania decreased significantly over time in the treatment group. Uric acid levels declined significantly in the treatment as compared to the control group. Probability of remission after 4 weeks was 23 times higher in the treatment than the control group. Lower uric acid levels after 4 weeks were associated with symptom improvements. (Results) The pattern of results from this double-blind, randomized and placebo-controlled study indicates that adjuvant allopurinol leads to significant improvements in patients suffering from acute mania (Conclusion). PMID- 24953768 TI - A randomized trial comparing Tai Chi with and without cognitive-behavioral intervention (CBI) to reduce fear of falling in community-dwelling elderly people. AB - The aim of this randomized trial was to compare the effects of Tai Chi with and without CBI on a primary outcome of reducing the fear of falling, and on secondary outcomes including encouraging better social engagement, improving self perceived personal wellbeing, and achieving better mobility among elderly people with fear of falling. One hundred and twenty-two community-dwelling elderly people aged >= 65 were randomly assigned to either a Tai Chi or a Tai Chi plus CBI group. Participants' level of fear of falling, physical mobility, self perceived personal wellbeing and social participation were compared before and after completing the 8-week intervention and then at a 2-month follow-up. The findings showed that Tai Chi both with and without CBI had a similar effect on reducing elderly people's fear of falling, but only Tai Chi plus CBI had a positive effect on participants' self-perceived personal wellbeing. Tai Chi both with and without CBI had no effect on participants' self-perceived social participation and mobility. Apart from a slight improvement in participants' self perceived personal wellbeing, other outcome effects were similar for Tai Chi with and without CBI. This finding raises a question about the additive effects of combined intervention over Tai Chi alone in reducing elderly people's fear of falling. In view of the higher demand for resources and manpower to implement a combined intervention, further study is still required to confirm the potential additional benefits of this combined intervention prior to recommending it to community services. PMID- 24953770 TI - Vitamin D status and risk of metabolic syndrome among non-diabetic young adults. AB - BACKGROUND AND AIMS: Low vitamin D status has been linked to obesity, insulin resistance, and metabolic syndrome. In the present study, we aimed to explore the nature and strength of the relationship between vitamin D and metabolic syndrome among non-diabetic young adults. METHODS: This was a campus-based cross-sectional study of 355 non-diabetic young adult graduate students (233 males and 132 females; mean age, 23.5 +/- 2.4 years) in Northern Taiwan. We measured and tested the association of serum 25-hydroxyvitamin D levels with metabolic syndrome and cardio-metabolic parameters. RESULTS: A total of 24 (6.8%) recruited young adults had metabolic syndrome. There were decreasing trends of body mass index (BMI), Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR) and prevalence of metabolic syndrome across increasing tertiles of vitamin D levels irrespective of age and sex (P for trend <0.05). Without adjusting for BMI or HOMA-IR, the odds of having metabolic syndrome decreased across increasing tertiles of vitamin D levels (P for trend 0.021). The odds ratio of having metabolic syndrome was 0.26 (95% confidence interval: 0.08-0.85, P = 0.025) for the highest vs. the lowest tertile of vitamin D levels. However, further adjustments for BMI and HOMA-IR largely removed the inverse association of vitamin D status with metabolic syndrome and its individual components. CONCLUSION: Among non-diabetic young adults, the potential inverse relationship between vitamin D status and metabolic syndrome may be attributable to the conjunctive effects of individual obesity and insulin resistance. PMID- 24953769 TI - Conformational dynamics of human FXR-LBD ligand interactions studied by hydrogen/deuterium exchange mass spectrometry: insights into the antagonism of the hypolipidemic agent Z-guggulsterone. AB - Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of transcription factors that plays a key role in the regulation of bile acids, lipid and glucose metabolisms. The regulative function of FXR is governed by conformational changes of the ligand binding domain (LBD) upon ligand binding. Although FXR is a highly researched potential therapeutic target, only a limited number of FXR-agonist complexes have been successfully crystallized and subsequently yielded high resolution structures. There is currently no structural information of any FXR-antagonist complexes publically available. We therefore explored the use of amide hydrogen/deuterium exchange (HDX) coupled with mass spectrometry for characterizing conformational changes in the FXR-LBD upon ligand binding. Ligand-specific deuterium incorporation profiles were obtained for three FXR ligand chemotypes: GW4064, a synthetic non-steroidal high affinity agonist; the bile acid chenodeoxycholic acid (CDCA), the endogenous low affinity agonist of FXR; and Z-guggulsterone (GG), an in vitro antagonist of the steroid chemotype. A comparison of the HDX profiles of their ligand-bound FXR-LBD complexes revealed a unique mode of interaction for GG. The conformational features of the FXR-LBD-antagonist interaction are discussed. PMID- 24953772 TI - A prospective study on the radiation therapy associated changes in body weight and bioelectrical standardized phase angle. AB - BACKGROUND & AIMS: Standardized phase angle (SPA) is a value derived from bioelectrical impedance phase angle analysis and has been recognized as marker of nutritional risk and clinical status of cancer patients. This study aimed to evaluate the changes in SPA during radiation therapy of cancer patients and identify possible nutritional and clinical determinants of these changes. METHODS: Nutritional assessment was performed before the initiation and at the end of the radiotherapy. It included anthropometrics and bioelectrical impedance analysis. A generalized linear mixed model was used to evaluate the effects of selected independent variables on the changes in standardized phase angle. RESULTS: A total of 104 patients entered the study and those with complete information were included in the analysis (n = 62). Most patients (61%) were at clinical stage I and II, the most prevalent irradiation site was the pelvis (39%) and 98% were well nourished or overweight. According to the regression analysis, changes in body weight and irradiation at head and neck/upper abdomen and thorax were associated with standardized phase angle modifications during radiotherapy. Clinical stage and radiation dose were not associated with changes in standardized phase angle. Compared to baseline values, for every 1 kg weight reduction during the radiation therapy, the standardized phase angle also decreased by 0.107 (p < 0.0001). CONCLUSIONS: In well nourished or overweight patients, weight loss during radiation therapy is closely associated with decrease in standard phase angle. PMID- 24953771 TI - Toward a chronobiological characterization of obesity and metabolic syndrome in clinical practice. AB - BACKGROUND & AIMS: To test several circadian rhythm variables in a female population to identify the best tool to assess chronodisruption in obesity and metabolic syndrome (MetS) to define a score to be used for chronodisruption characterization in clinical practice. METHODS: Anthropometric measurements and markers of circadian rhythms, such as sleep and feeding diary, Horne-Ostberg questionnaire, melatonin and cortisol measurements, and wrist temperature measurements, were determined. MetS variables were also analyzed. Study was conducted in 70 women. Data were subjected to factor analysis. Receiver operating characteristic curves were used as predictors of chronodisruption risk, and a score was calculated to classify the subjects of risk. RESULTS: Factor analysis showed that the first-factor grouped variables were related to the skin temperature measurement. Second factor consisted of variables related to salivary cortisol levels and obesity-related measurements. Third factor included variables related to sleep-wake cycle. Fourth factor referred to peripheral temperature variables and included the classification of subjects according to the Horne Ostberg questionnaire. To obtain a final punctuation we performed the weighted mean of the first four factors. The final range was from 27 to 57, mean value of 42. Punctuation was defined as the "chronodisruption score." Women displaying higher chronodisruption scores had higher MetS risk. CONCLUSION: The study demonstrates that wrist temperature recordings, together with two questions of sleep onset and offset, and one morning salivary cortisol determination could be enough to characterize the chronobiology of obesity and MetS, a new chronodisruption score was developed. PMID- 24953773 TI - Forecasting the student-professor matches that result in unusually effective teaching. AB - BACKGROUND: Two important influences on students' evaluations of teaching are relationship and professor effects. Relationship effects reflect unique matches between students and professors such that some professors are unusually effective for some students, but not for others. Professor effects reflect inter-rater agreement that some professors are more effective than others, on average across students. AIMS: We attempted to forecast students' evaluations of live lectures from brief, video-recorded teaching trailers. SAMPLE: Participants were 145 college students (74% female) enrolled in introductory psychology courses at a public university in the Great Lakes region of the United States. METHODS: Students viewed trailers early in the semester and attended live lectures months later. Because subgroups of students viewed the same professors, statistical analyses could isolate professor and relationship effects. RESULTS: Evaluations were influenced strongly by relationship and professor effects, and students' evaluations of live lectures could be forecasted from students' evaluations of teaching trailers. That is, we could forecast the individual students who would respond unusually well to a specific professor (relationship effects). We could also forecast which professors elicited better evaluations in live lectures, on average across students (professor effects). Professors who elicited unusually good evaluations in some students also elicited better memory for lectures in those students. CONCLUSIONS: It appears possible to forecast relationship and professor effects on teaching evaluations by presenting brief teaching trailers to students. Thus, it might be possible to develop online recommender systems to help match students and professors so that unusually effective teaching emerges. PMID- 24953775 TI - 2013 President's Plenary International Psycho-oncology Society: embracing the IPOS standards as a means of enhancing comprehensive cancer care. AB - BACKGROUND: The second President's Plenary at the 2013 International Psycho oncology Society's World Congress in Rotterdam, the Netherlands aimed to progress and, where needed, initiate changes to achieve comprehensive cancer care. Recent initiatives have been driven by the need to see psychosocial care as an integrated part of holistic multidisciplinary quality cancer care. The President's Plenary session covered the need for the following: An internationally agreed standard of quality cancer care, which includes psychosocial care for patients and their families and caregivers. An endorsement to assess distress as the 6th vital sign. Psycho-oncology professionals to integrate into a federation promoting better national and international outcomes. CONCLUSION: This overview highlights progress in terms of enhanced communication between and within different professionals groups supporting the implementation of a model of comprehensive patient care that is inclusive of psychosocial support and screening for distress. Tasks and challenges for the future are set out but the primary message is of the importance of collaboration in order to achieve recognition that psychosocial care is integrated into comprehensive cancer care; in this way, patient, family and carer needs can be more appropriately met. PMID- 24953774 TI - Variants of autophagy-related gene 5 are associated with neuromyelitis optica in the Southern Han Chinese population. AB - Neuromyelitis optica (NMO) and multiple sclerosis (MS) are autoimmune demyelinating diseases of the central nervous system. The discovery of NMO immunoglobulin G (NMO-IgG) antibody has improved the clinical definition of NMO. Recently, the autophagy-related genes (ATGs) have been proved to be associated with several autoimmune and inflammation diseases. Increased T cell expression of ATG5 may be correlated with the pathogenesis of inflammatory demyelination in MS. However, the association of ATG5 variants with MS and NMO patients has not been well studied. In this study, five ATG5 variants were genotyped in 144 MS patients, 109 NMO patients and 288 controls in the Han Chinese population. In the cohort of NMO patients, we observed that the CC genotype of rs548234 increased susceptibility to NMO (p = 0.016), while the allele T of rs548234 (p = 0.003) and the allele A of rs6937876 (p = 0.009) acted as protective factors for NMO-IgG positive NMO patients. However, no association was found between ATG5 variants and MS patients. These results indicated that ATG5 variants are associated with NMO but not MS patients, which may provide a clue for further clarifying the autoimmune mechanisms of autophagy-related pathogenesis in NMO. PMID- 24953776 TI - Structure of dimeric axonemal dynein in cilia suggests an alternative mechanism of force generation. AB - The mechanism by which the two different heads of the ciliary outer dynein arm produce force to translocate the microtubule during beating is still unknown. In this report we use cryo-electron tomography and image processing to analyze the conformational changes and the relative abundance of each conformation of the two dynein heads from mouse respiratory cilia. In the absence of nucleotides the majority of dynein dimers are in the apo form and both heads are tightly packed, whereas they are dissociated and move independently in the presence of nucleotides. The head of the external outer arm dynein heavy chain has a diagonal shift toward both the neighboring B-tubule and the proximal end of the axoneme, while the head of the internal heavy chain shifts only longitudinally toward the proximal end. In the presence of nucleotides a significant number of the dynein dimers have two heads overlapped in the proximal shifting form or overlapped in the apo form. During ciliary bending axonemal dynein translocates microtubules by moving with short steps and two heads stay at the same position longer than cytoplasmic dynein. This demonstrates that the step of the outer arm dynein dimer is not dominated by the hand-over-hand motion, but also indicates the difference between axonemal dynein and cytoplasmic dynein. PMID- 24953777 TI - Total synthesis of gonytolides C and G, lachnone C, and formal synthesis of blennolide C and diversonol. AB - The first stereoselective total synthesis of gonytolide C, which is a monomeric unit of an innate immune promoter gonytolide A, has been accomplished from the aldol reaction between acetophenone derived from orcinol and butyrolactone containing alpha-keto ester followed by the excellent diastereoselective intramolecular cyclization. The first total synthesis of gonytolide G has been achieved by the oxidation of benzylic methyl in gonytolide C. Additionally, total synthesis of lachnone C and a formal synthesis of blennolide C and diversonol have been achieved by this synthetic method. PMID- 24953779 TI - Membrane organization determines barrier properties of endothelial cells and short-chain sphingolipid-facilitated doxorubicin influx. AB - The endothelial lining and its outer lipid membrane are the first major barriers drug molecules encounter upon intravenous administration. Our previous work identified lipid analogs that counteract plasma membrane barrier function for a series of amphiphilic drugs. For example, short-chain sphingolipids (SCS), like N octanoyl-glucosylceramide, effectively elevated doxorubicin accumulation in tumor cells, both in vitro and in vivo, and in endothelial cells, whereas other (normal) cells remained unaffected. We hypothesize here that local membrane lipid composition and the degree of lipid ordering define SCS efficacy in individual cells. To this end, we study the differential effect of SCS on bovine aortic endothelial cells (BAEC) in its confluent versus proliferative state, as a model system. While their (plasma membrane) lipidome stays remarkably unaltered when BAECs reach confluency, their lipids segregate to form apical and basolateral domains. Using probe NR12S, we reveal that lipids in the apical membrane are more condensed/liquid-ordered. SCS preferentially attenuate the barrier posed by these condensed membranes and facilitate doxorubicin influx in these particular membrane regions. We confirm these findings in MDCK cells and artificial membranes. In conclusion, SCS-facilitated drug traversal acts on condensed membrane domains, elicited by confluency in resting endothelium. PMID- 24953778 TI - Intrinsic differences in BRITE adipogenesis of primary adipocytes from two different mouse strains. AB - BRITE (brown-in-white) cells are brown adipocyte-like cells found in white adipose tissue (WAT) of rodents and/or humans. The recruitment of BRITE adipocytes, referred to as the browning of WAT, is hallmarked by the expression of UCP1 and exerts beneficial metabolic effects. Here we address whether beyond systemic cues depot- and strain-specific variation in BRITE recruitment is determined by a cellular program intrinsic to progenitors. Therefore we compared the browning capacity of serum and investigated brown and BRITE adipogenesis in primary cultures of stromal-vascular cells isolated from interscapular brown adipose tissue (iBAT), inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) in two inbred mouse strains C57BL/6J (B6, a strain with low browning propensity) and 129/S6SvEv (129, a strain with high browning propensity). Paradoxically, serum collected from B6 mice was more potent in the promotion of browning than serum collected from 129 mice. Nevertheless, we demonstrate that depot- and strain-specific differences observed in vivo are pheno-copied in primary cultures in vitro, as judged by UCP1 expression and by functional analysis. Notably, primary adipocytes from 129 mice had a higher capacity for isoproterenol-induced uncoupled respiration than B6. We conclude that cues intrinsic to the progenitor cells contribute to differential BRITE adipogenesis. Further analyses demonstrate that these cues are independent of autocrine/paracrine mechanisms, BRITE progenitor abundance and genetic variation in the gene regulatory region of Ucp1 but rather depend on trans-acting factors. These results provide new insights on the molecular basis of strain and depot specific differences in BRITE adipogenesis. PMID- 24953780 TI - Characterization of the interaction of diacylglycerol acyltransferase-2 with the endoplasmic reticulum and lipid droplets. AB - Acyl CoA:diacylglycerol acyltransferase-2 (DGAT2) is an integral membrane protein that catalyzes the synthesis of triacylglycerol (TG). DGAT2 is present in the endoplasmic reticulum (ER) and also localizes to lipid droplets when cells are stimulated with oleate. Previous studies have shown that DGAT2 can interact with membranes and lipid droplets independently of its two transmembrane domains, suggesting the presence of an additional membrane binding domain. In order to identify additional membrane binding regions, we confirmed that DGAT2 has only two transmembrane domains and demonstrated that the loop connecting them is present in the ER lumen. Increasing the length of this short loop from 5 to 27 amino acids impaired the ability of DGAT2 to localize to lipid droplets. Using a mutagenesis approach, we were able to identify a stretch of amino acids that appears to have a role in binding DGAT2 to the ER membrane. Our results confirm that murine DGAT2 has only two transmembrane domains but also can interact with membranes via a previously unidentified helical domain containing its active site. PMID- 24953782 TI - Reduction of sympathetic nervous activity with device-guided breathing. PMID- 24953781 TI - DHA-mediated enhancement of TRAIL-induced apoptosis in colon cancer cells is associated with engagement of mitochondria and specific alterations in sphingolipid metabolism. AB - Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid present in fish oil, may exert cytotoxic and/or cytostatic effects on colon cancer cells when applied individually or in combination with some anticancer drugs. Here we demonstrate a selective ability of subtoxic doses of DHA to enhance antiproliferative and apoptotic effects of clinically useful cytokine TRAIL (tumor necrosis factor-related apoptosis inducing ligand) in cancer but not normal human colon cells. DHA-mediated stimulation of TRAIL-induced apoptosis was associated with extensive engagement of mitochondrial pathway (Bax/Bak activation, drop of mitochondrial membrane potential, cytochrome c release), activation of endoplasmic reticulum stress response (CHOP upregulation, changes in PERK level), decrease of cellular inhibitor of apoptosis protein (XIAP, cIAP1) levels and significant changes in sphingolipid metabolism (intracellular levels of ceramides, hexosyl ceramides, sphingomyelines, sphingosines; HPLC/MS/MS). Interestingly, we found significant differences in representation of various classes of ceramides (especially C16:0, C24:1) between the cancer and normal colon cells treated with DHA and TRAIL, and suggested their potential role in the regulation of the cell response to the drug combination. These study outcomes highlight the potential of DHA for a new combination therapy with TRAIL for selective elimination of colon cancer cells via simultaneous targeting of multiple steps in apoptotic pathways. PMID- 24953783 TI - Stable isotope-labeled collagen: a novel and versatile tool for quantitative collagen analyses using mass spectrometry. AB - Collagens are the most abundant proteins in animals and are involved in many physiological/pathological events. Although various methods have been used to quantify collagen and its post-translational modifications (PTMs) over the years, it is still difficult to accurately quantify type-specific collagen and minor collagen PTMs. We report a novel quantitative method targeting collagen using stable isotope-labeled collagen named "SI-collagen", which was labeled with isotopically heavy lysine, arginine, and proline in fibroblasts culture. We prepared highly labeled and purified SI-collagen for use as an internal standard in mass spectrometric analysis, particularly for a new approach using amino acid hydrolysis. Our method enabled accurate collagen analyses, including quantification of (1) type-specific collagen (types I and III in this paper), (2) total collagen, and (3) collagen PTMs by LC-MS with high sensitivity. SI-collagen is also applicable to other diverse analyses of collagen and can be a powerful tool for various studies, such as detailed investigation of collagen-related disorders. PMID- 24953784 TI - Removal of bicortical screws and other osteosynthesis material that caused symptoms after bilateral sagittal split osteotomy: a retrospective study of 251 patients, and review of published papers. AB - Rigid fixation with either bicortical screws or miniplates is the current standard way to stabilise the mandibular segments after bilateral sagittal split osteotomy (BSSO). Both techniques are widely used and the superiority of one or other method is still debatable. One complication of rigid fixation is the need to remove the osteosynthesis material because of associated complaints. The main aim of this retrospective study was to analyse how often we needed to remove bicortical screws because they caused symptoms after BSSO in our clinic. Review of other published papers also enabled us to investigate the reported rates of removal of screws and miniplates at other centres. The mean (SD) duration of follow-up of 251 patients (502 sites) was 432 (172) days, and the number of bicortical screws removed in our clinic was 14/486 sites (3%). Other methods of fixation were used at 16 sites. We found no significant association between removal of bicortical screws and age, sex, presence of third molars, or bad splits. Published rates of removal of bicortical screws and miniplates are 3.1% 7.2% and 6.6%-22.2% per site, respectively. These findings show that fixation with bicortical screws after BSSO is associated with a low rate of removal of osteosynthesis material. Reported incidences imply a lower rate of removal for screws than for miniplates. PMID- 24953786 TI - Primary intra-renal desmoplastic small round cell tumor: expanding the histologic spectrum, with special emphasis on the differential diagnostic considerations. AB - Intra-abdominal desmoplastic small round cell tumor (DSRCT) is a rare, aggressive tumor affecting adolescent and young males. DSRCT presenting as a primary renal mass in the absence of visceral or serosal involvement is extremely rare. Herein, we present the pathologic and molecular findings in the case of a young man who presented with a large renal mass without any visceral or serosal involvement. Noticeably, the tumor lacked prominent desmoplastic stroma and only focally expressed cytokeratin, both of which are considered characteristic histologic features for this tumor. Fluorescence in situ hybridization studies using an EWSR1 break-apart probe confirmed the presence of a rearrangement involving the EWSR1 locus and RT-PCR demonstrated the presence of an EWSR1-WT1 fusion transcript associated with the t(11;22) rearrangement, which supported a diagnosis of DSRCT. We also discuss the differential diagnostic considerations faced by the pathologist in the workup of small round cell neoplasms of the kidney. PMID- 24953785 TI - Reduction of angiotensin A and alamandine vasoactivity in the rabbit model of atherogenesis: differential effects of alamandine and Ang(1-7). AB - Novel treatments are necessary to reduce the burden of cardiovascular disease (CVD). Alamandine binds to MrgD and is reported to induce vasodilation via stimulation of endothelial nitric oxide synthase (eNOS), but its role in atherogenic blood vessels is yet to be determined. To determine the vasoactive role of alamandine and its precursor AngA in diseased aorta, New Zealand White rabbits were fed a diet containing 1% methionine + 0.5% cholesterol + 5% peanut oil for 4 weeks (MC, n = 5) or control (n = 6). In abdominal aorta, alamandine (1 MUM) was added 30 min before a dose-response curve to angiotensin II or AngA (1 nM-1 MUM), and immunohistochemistry was used to identify MrgD receptors and eNOS. The thoracic aorta, renal, carotid and iliac arteries were mounted in organ baths. Rings were precontracted with phenylephrine, then a bolus dose of alamandine (1 MUM) was added 10 min before a dose-response curve to acetylcholine (0.01 MUM-10 MUM). The MrgD receptor was localized to normal and diseased aorta and colocalized with eNOS. In control but not diseased blood vessels, alamandine enhanced acetylcholine-mediated vasodilation in the thoracic aorta and the iliac artery (P < 0.05) and reduced it in the renal artery (P < 0.05). In control abdominal aorta, AngA evoked less desensitization than AngII (P < 0.05) and alamandine reduced AngA-mediated vasoconstriction (P < 0.05). In MC, AngA constriction was markedly reduced vs. control (P < 0.05). The vasoactivity of alamandine and AngA are reduced in atherogenesis. Its role in the prevention of CVD remains to be validated. PMID- 24953787 TI - Death or revascularization among nonadmitted ED patients with low-positive vs negative troponin T results. AB - STUDY OBJECTIVE: Compare outcomes among emergency department (ED) patients with low-positive (0.01-0.02 ng/mL) vs negative troponin T. METHODS: Retrospective cohort study of nonadmitted ED patients with troponin testing at a tertiary-care hospital. Trained research assistants used a structured tool to review charts from all nonadmitted ED patients with troponin testing, 12/1/2009 to 11/30/2010. Outcomes of death and coronary revascularization were assessed at 30 days and 6 months via medical record review, Social Security Death Index searches, and patient contact. RESULTS: There were 57596 ED visits; with 33388 (58%) discharged immediately, 6410 (11%) assigned to the observation unit, and 17798 (31%) admitted or other. Troponin was measured in 2684 (6.7%) of the nonadmitted cases. Troponin was negative in 2523 (94.0%), low positive in 78 (2.9%), and positive (>=0.03 ng/mL) in 83 (3.1%). Of troponin-negative cases, 0.8% (95% CI, 0.4-1.1%) died or were revascularized by 30 days, vs 2.8% (95% CI, 0.0-6.7%) of low positive cases (risk difference [RD], 2.0%; 95% CI, -1.8 to 5.9%). At 6 months, the rates were 1.7% (95% CI, 1.1-2.2%) and 12.9% (95% CI, 5.0-20.7%) (RD, 11%; 95% CI, 3.3-19.1%). Death alone at 30 days occurred in 0.4% (95% CI, 0.1-0.6%) vs 1.3% (95% CI, 0.0-3.8%) (RD, 0.9%; 95% CI, -1.6 to 3.4%). Death at 6 months occurred in 1.2% (95% CI, 0.8-1.6%) vs 11.7% (95% CI, 4.5-18.9%) (RD, 10%; 95% CI, 3.3-17.7%). CONCLUSION: Among patients not initially admitted, rates of death and coronary revascularization differed insignificantly at 30 days but significantly at 6 months. Detailed inspection of our results reveals that the bulk of the added risk at 6 months was due to non-cardiac mortality. PMID- 24953788 TI - Using discrete event computer simulation to improve patient flow in a Ghanaian acute care hospital. AB - OBJECTIVES: Crowding and limited resources have increased the strain on acute care facilities and emergency departments worldwide. These problems are particularly prevalent in developing countries. Discrete event simulation is a computer-based tool that can be used to estimate how changes to complex health care delivery systems such as emergency departments will affect operational performance. Using this modality, our objective was to identify operational interventions that could potentially improve patient throughput of one acute care setting in a developing country. METHODS: We developed a simulation model of acute care at a district level hospital in Ghana to test the effects of resource neutral (eg, modified staff start times and roles) and resource-additional (eg, increased staff) operational interventions on patient throughput. Previously captured deidentified time-and-motion data from 487 acute care patients were used to develop and test the model. The primary outcome was the modeled effect of interventions on patient length of stay (LOS). RESULTS: The base-case (no change) scenario had a mean LOS of 292 minutes (95% confidence interval [CI], 291-293). In isolation, adding staffing, changing staff roles, and varying shift times did not affect overall patient LOS. Specifically, adding 2 registration workers, history takers, and physicians resulted in a 23.8-minute (95% CI, 22.3-25.3) LOS decrease. However, when shift start times were coordinated with patient arrival patterns, potential mean LOS was decreased by 96 minutes (95% CI, 94-98), and with the simultaneous combination of staff roles (registration and history taking), there was an overall mean LOS reduction of 152 minutes (95% CI, 150 154). CONCLUSIONS: Resource-neutral interventions identified through discrete event simulation modeling have the potential to improve acute care throughput in this Ghanaian municipal hospital. Discrete event simulation offers another approach to identifying potentially effective interventions to improve patient flow in emergency and acute care in resource-limited settings. PMID- 24953789 TI - Parent readiness to change differs for overweight child dietary and physical activity behaviors. AB - Parent involvement is important to help overweight children lose weight. However, parent readiness to make changes around child eating and physical activity (PA) behaviors can differ across domains. Using a cross-sectional design, our aim was to examine which factors were associated with parents being in the Action/Maintenance stage of change in each domain. From November 2008 to August 2009, parents of overweight/obese children (n=202) attending a tertiary care obesity clinic in Providence, RI, answered questions assessing their stage of change, beliefs about child health and weight, and provider behaviors. Separate multivariate logistic regression models were created to determine which factors were associated with parent readiness to make changes for child dietary and PA behaviors. Almost 62% of parents were in the Action stage of change for child dietary behaviors, but only 41% were in the Action stage of change for PA behaviors. Parents who believed their own weight was a health problem were less likely to be ready to make changes to their child's dietary behaviors. Physician discussion of strategies was related to readiness to make changes for child dietary behaviors, but not PA behaviors. In the PA domain, parents of younger children were more likely to be ready to make changes. Training health care providers to address PA readiness and be aware of factors influencing dietary and PA readiness may result in more effective conversations with parents and improve behavior change efforts for pediatric weight loss. PMID- 24953790 TI - Iron deficiency is associated with food insecurity in pregnant females in the United States: National Health and Nutrition Examination Survey 1999-2010. AB - Food-insecure pregnant females may be at greater risk of iron deficiency (ID) because nutrition needs increase and more resources are needed to secure food during pregnancy. This may result in a higher risk of infant low birth weight and possibly cognitive impairment in the neonate. The relationships of food insecurity and poverty income ratio (PIR) with iron intake and ID among pregnant females in the United States were investigated using National Health and Nutrition Examination Survey 1999-2010 data (n=1,045). Food security status was classified using the US Food Security Survey Module. One 24-hour dietary recall and a 30-day supplement recall were used to assess iron intake. Ferritin, soluble transferrin receptor, or total body iron classified ID. Difference of supplement intake prevalence, difference in mean iron intake, and association of ID and food security status or PIR were assessed using chi(2) analysis, Student t test, and logistic regression analysis (adjusted for age, race, survey year, PIR/food security status, education, parity, trimester, smoking, C-reactive protein level, and health insurance coverage), respectively. Mean dietary iron intake was similar among groups. Mean supplemental and total iron intake were lower, whereas odds of ID, classified by ferritin status, were 2.90 times higher for food insecure pregnant females compared with food-secure pregnant females. Other indicators of ID were not associated with food security status. PIR was not associated with iron intake or ID. Food insecurity status may be a better indicator compared with income status to identify populations at whom to direct interventions aimed at improving access and education regarding iron-rich foods and supplements. PMID- 24953791 TI - The neovascular age-related macular degeneration database: report 2: incidence, management, and visual outcomes of second treated eyes. AB - PURPOSE: To study the characteristics of second treated eyes in patients with neovascular age-related macular degeneration (nAMD) treated with ranibizumab in the United Kingdom National Health Service. DESIGN: Multicenter national nAMD database study. PARTICIPANTS: Twelve thousand nine hundred fifty-one treatment naive eyes of 11,135 patients receiving 92,976 ranibizumab injections. METHODS: Up to 5 years of routinely collected, anonymized data within electronic medical record systems were extracted remotely from 14 centers. Participating centers exclusively used ranibizumab to treat nAMD (loading phase of 3 monthly injections followed by monthly visits and pro re nata re-treatment). The minimum data set included: age, logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) at baseline and at all subsequent visits, and injection episodes. MAIN OUTCOME MEASURES: Baseline, change and actual VA over 3 years, and number of treatments and clinic visits. RESULTS: During the study, 1816 (16.3%) of the 11 135 patients received treatment to the fellow eye. Mean baseline and final VA were 0.66 (standard deviation, 0.32) and 0.65 (0.40) for first treated eyes and 0.41 (0.34) and 0.56 (0.40) for second treated eyes. The rate of VA loss after the loading phase was similar in first and second treated eyes (0.03 and 0.05 logMAR units/year). When fellow eyes with baseline VA worse than 20/200 were excluded to restrict analyses to eyes at risk of nAMD, the rate of second-eye involvement was 14.0% per year (42%/3 years). Mean number of injections/visits in years 1, 2, and 3 were similar for first and second treated eyes (5.6/8.2, 3.9/8.0, 3.8/8.2 and 5.5/8.7, 3.6/9.4, and 3.8/9.1, respectively). CONCLUSIONS: Second treated eyes with nAMD commence treatment with better baseline VA, do not show significant vision gain but maintain better VA than first treated eyes at all time points for at least 3 years, making them the more important eye functionally. These data highlight the high burden of second eye involvement, with almost half of all eyes at risk requiring bilateral treatment by 3 years, and the need for regular monitoring of fellow eyes for best visual outcomes which theoretically may reduce the benefits of extended monitoring regimens. PMID- 24953792 TI - Cigarette smoking and the natural history of age-related macular degeneration: the Beaver Dam Eye Study. AB - PURPOSE: To examine the association of current cigarette smoking and pack-years smoked with the incidence and progression of age-related macular degeneration (AMD) and to examine the interactions of current smoking and pack-years smoked with complement factor H (CFH, rs1061170) and age-related maculopathy susceptibility 2 (ARMS2, rs10490924) genotype. DESIGN: A longitudinal population based study of AMD in a representative American community. Examinations were performed every 5 years over a 20-year period. PARTICIPANTS: A total of 4439 participants in the population-based Beaver Dam Eye Study (BDES). METHODS: Age related macular degeneration status was determined from grading retinal photographs. Multi-state models were used to model the relationship of current smoking and pack-years smoked and interactions with CFH and ARMS2 with the incidence and progression of AMD over the entire age range. MAIN OUTCOME MEASURES: Incidence and progression of AMD over a 20-year period and interactions between current smoking and pack-years smoked with CFH and ARMS2 genotype. RESULTS: The incidence of early AMD over the 20-year period was 24.4%, and the incidence of late AMD was 4.5%. Current smoking was associated with an increased risk of transitioning from minimal to moderate early AMD. A greater number of pack-years smoked was associated with an increased risk of transitioning from no AMD to minimal early AMD and from severe early AMD to late AMD. Current smoking and a greater number of pack-years smoked were associated with an increased risk of death. There were no statistically significant multiplicative interactions between current smoking or pack-years smoked and CFH or ARMS2 genotype. CONCLUSIONS: Current smoking and a greater number of pack-years smoked increase the risk of the progression of AMD. This has important health care implications because smoking is a modifiable behavior. PMID- 24953793 TI - Risk factors associated with developing branch retinal vein occlusion among enrollees in a United States managed care plan. AB - PURPOSE: To determine risk factors associated with development of a branch retinal vein occlusion (BRVO) among a large group of managed-care plan beneficiaries in the United States. DESIGN: Retrospective, longitudinal cohort study. PARTICIPANTS: All beneficiaries age >=55 years continuously enrolled for >=2 years in a managed care network from 2001-2009 who had >=2 visits to an eye care provider. METHODS: Multivariable Cox regression analyses identified sociodemographic factors, ocular and nonocular conditions associated with incident BRVO. MAIN OUTCOME MEASURES: Hazard of incident BRVO with 95% confidence interval (CI). RESULTS: Of the 492,488 enrollees who met inclusion criteria, 2283 (0.5%) developed incident BRVO. After adjustment for confounding factors, blacks (adjusted hazard ratio [aHR], 1.43; CI, 1.19-1.73; P = 0.0001) had a 43% increased hazard of BRVO relative to non-Hispanic whites. Enrollees with hypertension (HTN) alone (aHR, 1.78; CI, 1.36-2.32; P < 0.0001) or HTN along with other metabolic syndrome components (diabetes mellitus [DM] and hyperlipidemia; aHR, 1.44; CI, 1.12-1.84; P = 0.005) had an increased hazard of developing a BRVO compared with those with none of these conditions. Disease severity was important; enrollees with end-organ damage caused by HTN had a 107% increased hazard of developing BRVO compared with enrollees without HTN (aHR, 2.07; CI, 1.75-2.45; P < 0.0001). Although there was no association between DM without end organ damage and BRVO (aHR, 0.92; CI, 0.81-1.04; P = 0.2), individuals with end organ damage from DM had a 36% increased hazard of BRVO (aHR, 1.36; CI, 1.18 1.57; P < 0.0001) compared with those without DM. Although cerebrovascular accident was associated with an increased hazard of developing BRVO (aHR, 1.34; CI, 1.19-1.52; P < 0.0001), other diseases of the vascular system (deep venous thrombosis/pulmonary embolism, peripheral vascular disease, hypercoagulable state, myocardial infarction) or anticoagulant use did not increase the risk of BRVO (P > 0.10 for all comparisons). CONCLUSIONS: Both HTN and end-organ damage from DM contribute to arteriosclerosis, atherosclerosis, and endothelial dysfunction, which seem to be major risk factors for BRVO. Ophthalmologists should emphasize to patients and their primary physicians the importance of effectively managing systemic medical conditions associated with BRVO. PMID- 24953794 TI - Rituximab therapy for refractory scleritis: results of a phase I/II dose-ranging, randomized, clinical trial. AB - OBJECTIVE: To determine whether rituximab, a monoclonal antibody against the B lymphocyte antigen CD20, is effective in the treatment of refractory noninfectious scleritis. DESIGN: Prospective, dose-ranging, randomized, double masked phase I/II clinical trial. PARTICIPANTS: Twelve patients with noninfectious scleritis refractory to systemic corticosteroid and >=1 other systemic immunosuppressive agent were enrolled from January 2007 to March 2010. INTERVENTION: Subjects were randomly assigned to 500 (n = 5) or 1000 mg (n = 7) dosing arms of rituximab intravenous infusions (500 or 1000 mg), given at study days 1 and 15. Initial responders with breakthrough inflammation after study week 24 were offered treatment with an additional cycle of 2 open-label rituximab 1000 mg infusions. MAIN OUTCOME MEASURES: Primary outcomes were reduction of inflammation, as measured with a validated scleritis disease grading scale (SGS) and reduction in corticosteroid dose by >=50%. Patients were characterized as responders to study therapy if >=1 of these endpoints showed improvement and neither showed evidence of worsening. Secondary outcomes were improvement in visual acuity, reduction in pain, and improvement in patient and physician reported global health assessment. RESULTS: Of 12 enrolled patients, 9 met the SGS endpoint at or before week 24, and 4 additionally were able to reduce corticosteroid dose by >=50%. With regard to secondary outcome measures, 11 and 9 patients showed improvement in patient and physician global health scores, respectively, and 7 patients had reduction in pain. Of 9 initial responders, 7 experienced breakthrough inflammation after 24 weeks and were treated with a second cycle of rituximab infusions. Four patients had significant objective or subjective worsening within 8 weeks of receiving rituximab; this event was averted in subsequent patients by treatment with peri-infusional oral corticosteroid. No other significant adverse events were noted. No differences in efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms. CONCLUSIONS: Rituximab was effective treatment for 9 of 12 enrolled patients with refractory, noninfectious scleritis at 24 weeks, although 7 required reinfusion with rituximab to maintain inflammatory control. The treatment was well-tolerated, and peri-infusional inflammatory exacerbations were managed successfully with oral corticosteroids. Further long-term studies are warranted to determine the safety and efficacy of rituximab in treating noninfectious scleritis and other ocular inflammatory diseases. PMID- 24953795 TI - Effect of ST3GAL 4 and FUT 7 on sialyl Lewis X synthesis and multidrug resistance in human acute myeloid leukemia. AB - Sialyl Lewis X (sLe X, CD15s) is a key antigen produced on tumor cell surfaces during multidrug resistance (MDR) development. The present study investigated the effect of alpha1, 3 fucosyltransferase VII (FucT VII) and alpha2, 3 sialyltransferase IV (ST3Gal IV) on sLe X oligosaccharides synthesis as well as their impact on MDR development in acute myeloid leukemia cells (AML). FUT7 and ST3GAL4 were overexpressed in three AML MDR cells and bone marrow mononuclear cells (BMMC) of AML patients with MDR by real-time polymerase chain reaction (PCR). A close association was found between the expression levels of FUT7 and ST3GAL4 and the amount of sLe X oligosaccharides, as well as the phenotypic variation of MDR of HL60 and HL60/ADR cells both in vitro and in vivo. Manipulation of these two genes' expression modulated the activity of phosphoinositide-3 kinase (PI3K)/Akt signaling pathway, thereby regulating the proportionally mutative expression of P-glycoprotein (P-gp) and multidrug resistance related protein 1 (MRP1), both of which are known to be involved in MDR. Blocking the PI3K/Akt pathway by its specific inhibitor LY294002 or Akt short hairpin RNA (shRNA) resulted in the reduced MDR of HL60/ADR cells. This study indicated that sLe X involved in the development of MDR of AML cells probably through FUT7 and ST3GAL4 regulating the activity of PI3K/Akt signaling pathway and the expression of P-gp and MRP1. PMID- 24953796 TI - Inhibition of the recombinant cattle tick Rhipicephalus (Boophilus) annulatus glutathione S-transferase. AB - Rhipicephalus (Boophilus) annulatus is a bloodsucking ectoparasite that causes severe production losses in the cattle industry. This study aims to evaluate the in vitro effects of tannic acid, hematin (GST inhibitors) and different plant extracts (rich in tannic acid) on the activity of the recombinant glutathione S transferase enzyme of the Egyptian cattle tick R. annulatus (rRaGST), in order to confirm their ability to inhibit the parasitic essential detoxification enzyme glutathione S-transferase. Extraction with 70% ethanol of Hibiscus cannabinus (kenaf flowers), Punica granatum (red and white pomegranate peel), Musa acuminata (banana peel) (Musaceae), Medicago sativa (alfalfa seeds), Tamarindus indicus (seed) and Cuminum cyminum (cumin seed) were used to assess: (i) inhibitory capacities of rRaGST and (ii) their phenolic and flavonoid contents. Ethanol extraction of red pomegranate peel contained the highest content of phenolic compounds (29.95mg gallic acid/g dry tissue) compared to the other studied plant extracts. The highest inhibition activities of rRaGST were obtained with kenaf and red pomegranate peel (P. granatum) extracts with IC50 values of 0.123 and 0.136mg dry tissue/ml, respectively. Tannic acid was the more effective inhibitor of rRaGST with an IC50 value equal to 4.57MUM compared to delphinidine-HCl (IC50=14.9+/-3.1MUM). Gossypol had a weak inhibitory effect (IC50=43.7MUM), and caffeic acid had almost no effect on tick GST activity. The IC50 values qualify ethacrynic acid as a potent inhibitor of rRaGST activity (IC50=0.034MUM). Cibacron blue and hematin showed a considerable inhibition effect on rRaGST activity, and their IC50 values were 0.13MUM and 7.5MUM, respectively. The activity of rRaGST was highest for CDNB (30.2MUmol/min/mg protein). The enzyme had also a peroxidatic activity (the specific activity equals 26.5MUmol/min/mg protein). Both tannic acid and hematin inhibited rRaGST activity non competitively with respect to GSH and competitively with respect to CDNB. While red pomegranate extracts inhibited rRaGST activity competitively with respect to GSH, uncompetitive inhibition was observed with respect to CDNB. PMID- 24953797 TI - A novel AP92-like Crimean-Congo hemorrhagic fever virus strain, Greece. AB - Ticks were collected from various regions of northern Greece and tested for the presence of Crimean-Congo hemorrhagic fever virus (CCHFV) RNA. Human and animal sera were collected in the regions where CCHFV-positive ticks were detected, and they were tested for the presence of IgG antibodies against the virus. A CCHFV strain was detected in Rhipicephalus bursa ticks collected from sheep in Kastoria regional unit, differing by 9.7% at the nucleotide level from the AP92 strain, which was isolated in 1975 in another region of Greece. Up to date, CCHF cases have not been reported in these regions. The human seroprevalence in the area was estimated at 6%, while IgG-positive sheep was detected in two of the four neighboring farms tested. The circulation of this specific CCHFV lineage in Greece, especially in a region where the seroprevalence is high, together with the lack of human CCHF cases, suggests a probable antigenic, but non- or low pathogenic character of this lineage. Further studies on these strains will increase our knowledge about the role of AP92-like strains in the CCHF epidemiology, which might be useful for drug and vaccine design. PMID- 24953800 TI - Editorial. AB - In much of the industrialized world, the worst recession since the 1930s seems determined to plague us for a while longer. In that grim context, many of us are particularly interested in healthcare delivery and administrative solutions involving innovations that do not cost the earth - and that might even save some money. In this issue of Healthcare Quarterly, you'll find many examples of both. PMID- 24953798 TI - Rapid generation of mouse models with defined point mutations by the CRISPR/Cas9 system. AB - Introducing a point mutation is a fundamental method used to demonstrate the roles of particular nucleotides or amino acids in the genetic elements or proteins, and is widely used in in vitro experiments based on cultured cells and exogenously provided DNA. However, the in vivo application of this approach by modifying genomic loci is uncommon, partly due to its technical and temporal demands. This leaves many in vitro findings un-validated under in vivo conditions. We herein applied the CRISPR/Cas9 system to generate mice with point mutations in their genomes, which led to single amino acid substitutions in proteins of interest. By microinjecting gRNA, hCas9 mRNA and single-stranded donor oligonucleotides (ssODN) into mouse zygotes, we introduced defined genomic modifications in their genome with a low cost and in a short time. Both single gRNA/WT hCas9 and double nicking set-ups were effective. We also found that the distance between the modification site and gRNA target site was a significant parameter affecting the efficiency of the substitution. We believe that this is a powerful technique that can be used to examine the relevance of in vitro findings, as well as the mutations found in patients with genetic disorders, in an in vivo system. PMID- 24953801 TI - Perhaps I am one of the lucky ones. AB - I recently participated in the Ontario Hospital Association (OHA) webinar on quality and safety, in which I was asked to address the topic of engaging physicians in performance measurement, quality and safety. I am not a physician, but much of my work in healthcare has involved working with clinical leaders in these areas. At St. Joseph's Healthcare Hamilton, we started our quality and safety journey by creating a medical quality scorecard specifically designed for physicians. The card, written in physician-friendly versus business language, enabled physicians to drop the traditional business quadrants of finance and human resources and select four quadrants focused on clinical process and outcome indicators that matched their daily practice. Quality improvement initiatives resulting from the scorecard included the launch of a sepsis-management campaign in the emergency room and a new approach to neonatal safety. PMID- 24953799 TI - Urinary tract involvement in systemic lupus erythematosus: coexistence with lupus mesenteric vasculitis or intestinal pseudo-obstruction? PMID- 24953802 TI - Effective governance: helping boards acquire, adapt and apply evidence to improve quality and patient safety. AB - They don't spend a lot of time treating patients. And they're seldom included on grand rounds. But health services boards of directors still have a significant role to play in quality and patient safety. Their responsibilities for quality go beyond those of boards in many other settings and so, therefore, does their need for specialized education and training. As Maura Davies, chief executive officer (CEO) of Saskatoon Health Region, has pointed out, "There is increasing awareness that health services boards cannot abdicate their responsibilities for ensuring quality and safety and need to take specific actions to address these duties" (Davies 2010: 37). PMID- 24953804 TI - Recent advances in stroke outcomes research: contributions from Canada. AB - Stroke is a devastating disease for patients, families and the healthcare system. Outcomes research can contribute with the analysis, evaluation and dissemination of the result of specific treatment, processes of care or medical procedures to improve patient outcomes. According to the Agency for Healthcare Research and Quality (2000), outcomes research "seeks to understand the end results of specific health care practices and interventions." By linking the care people get to the outcomes they experience, outcomes research can become the key to developing better ways to monitor and improve the quality of care. PMID- 24953803 TI - Improving measures of hip fracture wait times: a focus on ontario. AB - In 2009-2010, a "time of surgery" data element was added to CIHI's Discharge Abstract Database enabling a more precise calculation of patient wait times for hip fracture repair, measured in hours rather than days. Using an Ontario sample, we explored this more precise calculation for the first three quarters of 2009 2010 (April to December), and the impact of adding wait times in the emergency department (ED) to the total wait. When we linked emergency department and in patient care wait times, the percent of patients meeting the benchmark of 48 hours dropped from 78% (when the start time was admission to an acute care bed) to 71%. PMID- 24953805 TI - By the numbers: measuring for quality care. AB - Saskatchewan's Health Quality Council (HQC) was launched in 2003 with a mandate to not only measure and report on healthcare but also work with a range of partners to improve the province's health system. In late 2007, HQC's board decided it was time for Saskatchewan to reinvent its healthcare system, using the highest-performing systems in the world as its model. And in 2008, HQC launched Accelerating Excellence, a multi-level program to rethink, redesign and renew healthcare. To help maintain momentum and show other provinces whether high performing healthcare can be achieved in Canada, HQC is documenting its journey toward high-performing healthcare. This fourth article in the series discusses using measurements to improve quality in healthcare. PMID- 24953806 TI - 2010 longwoods scholar dr. Davy C.h. Cheng. AB - Launched in 2010 in conjunction with the University of Toronto's Rotman School of Management, the Longwoods Scholar program honours leaders in Canada's healthcare sector who are at the forefront of research, practice and policy. PMID- 24953807 TI - ICONS: Managing Care and Costs: The Sustained Cost Impact of Reduced Hospitalizations in a Partnership-Measurement Model of Disease Management. AB - Improving Cardiovascular Outcomes in Nova Scotia (ICONS) was a multidisciplinary partnership, measurement-driven disease management project designed to improve the care and outcomes of patients with acute and chronic heart diseases in Nova Scotia. Previous analyses demonstrated beneficial clinical and macroeconomic end points at the population and system levels, including heightened awareness of the value of team care, increased use of proven therapies, decreased re hospitalizations and a positive dollar return on investment for the economies of Nova Scotia and Canada. This article analyzes the additional cost-reduction benefits resulting from the reduced re-hospitalizations that occurred among patient populations with heart attacks and heart failure. Over the five-year course of ICONS, one-year readmissions and readmission rates fell continuously for both index disease states. Despite a general inflationary rise in real hospital costs, the per-event cost of readmissions expressed in constant 2002 dollars also decreased: from $10,377 in 1997 to $9,022 in 2002 for the heart attack patient population; and from $9,020 to $8,697 for patients with heart failure. Total real yearly costs for heart attack readmissions fell from $7.4 million in 1997 to $6.4 million in 2002, a 14% decrease; for heart failure, yearly costs decreased by 26%, from $9.2 million to $6.8 million. These microeconomic data supplement the previously reported improvements in patient care and the positive macroeconomic impact of ICONS. Overall, ICONS demonstrated that quality and cost of healthcare could be simultaneously and successfully managed over a sustained period of time for whole patient populations in a real world setting. ICONS offers strong evidence of the value of the partnership measurement model of disease management and prevention as a reproducible and desirable template for next-generation healthcare in Canada. PMID- 24953808 TI - Evaluation of healthcare services: asking the right questions to develop new policy and program-relevant knowledge for decision-making. AB - This article presents a framework for thinking about the key questions that need to be answered to develop new policy and program-relevant knowledge that can be used to make more informed decisions. It is a primer for administrators, policy makers and others about how to identify the knowledge they need to make decisions regarding new or existing programs. The article covers three related dimensions in evaluation: types of evaluations, key domains of inquiry and generic research questions. While the questions are generic, they can be readily adapted to any new and/or existing healthcare program evaluation. Examples of how the generic questions can be adapted to primary healthcare clinics and home care are presented. PMID- 24953809 TI - Optimizing resource allocation and patient flow: process analysis and reorganization in three chemotherapy outpatient clinics. AB - Optimizing human and physical resources is a major concern for cancer care decision-makers and practitioners. This issue is particularly acute in the context of ambulatory out patient chemotherapy clinics, especially when - as is the case almost everywhere in the industrialized world - the number of people requiring systemic therapy is increasing while budgets, staffing and physical space remain static. Recent initiatives at three hospital-based chemotherapy units - in Halifax, Toronto and Kingston - shed light on the value of process analysis and reorganization for using existing human and physical resources to their full potential, improving patient flow and enhancing patient satisfaction. The steps taken in these settings are broadly applicable to other healthcare settings and would likely result in similar benefits in those environments. PMID- 24953810 TI - Rapid access to cardiology expertise: an innovative program to provide telephone support for family physicians. AB - The increasing incidence of chronic diseases in the Canadian population represents one of the biggest challenges to Canada's healthcare system and its patient population. In 2005, more than one-third of Canadians were burdened with one or more chronic diseases (Broemeling et al. 2008). Moreover, it is estimated that, between 2005 and 2015, two million Canadians will die of causes related to a chronic disease at a cost of more than $9 billion (World Health Organization 2005). An aging population and improvements in the acute care of many diseases predicts that chronic diseases will continue to rise in the foreseeable future. This is a concern as those with a chronic disease use twice the amount of healthcare resources compared to the average adult and have hospital stays that are four times longer than those with acute conditions (Broemeling et al. 2005). PMID- 24953811 TI - Clinical governance: the need for new directions in Canada: [includes principles to guide changes and evaluation]. AB - As greater attention is paid to various facets of quality and safety within the Canadian healthcare system, it is important to understand the current state of clinical governance and clinical quality processes in Canada. Significant advances have been made internationally in understanding the important role of clinical governance in achieving quality and safety. It is clear, however, from various reports that major developments in clinical governance are needed if the quality and safety missions of governing boards of health authorities and other provincial and national bodies are to be achieved. In this paper, several key elements of an effective clinical governance system will be reviewed, some issues that characterize clinical governance in Canada will be raised and some principles that might help in evaluation and moving forward will be identified. PMID- 24953813 TI - Successful Advance Directives through Quality Disease Management. AB - Recently there has been talk about the benefit of advance care planning. This is an issue which resurfaces from time to time, as is evident in recent New England Journal of Medicine articles and editorials (April 2010). It has also resurfaced in Canada in a recent document titled Advance Care Planning in Canada: National Framework for Consultation (Health Canada 2010). This document acknowledges that many of us believe in the value of advance directives, finding "that most of the general public (60-90%) is supportive of advance care planning. However, only 10 20% of the public in the US, Canada and Australia have completed an advance care plan of any kind" (Health Canada 2010: 6). In Muriel R. Gillick's editorial in the New England Journal Medicine, she strongly makes the point that few people complete advance directives and further states that "directives have been a resounding failure" (Gillick 2010: 1239). These statements, although not exhaustive on the subject, show that we have a problem translating the support for advance directives into actual plans. PMID- 24953812 TI - Informed consent: exploring surgical residents' beliefs, attitudes and practices. AB - Patients rely on the knowledge and skill of the physician proposing treatment to relay information and inform their decision-making. In academic medical centres (AMCs), surgical trainees frequently request consent on behalf of an attending surgeon. There is a paucity of knowledge regarding the frequency of this practice and any associated impacts on surgical trainees. This study poses the following queries: (1) Are surgical residents requesting informed consent (IC) while perceiving themselves to possess insufficient knowledge to facilitate the IC process? (2) If yes, what motivates a resident to request IC with inadequate knowledge? (3) Do residents experience an emotional response? (4) What, if any, support mechanisms are sought? Surgical residents in a Canadian urban AMC (n = 38) completed a survey designed to assess how surgical trainees complete the process of IC as well as probe beliefs and attitudes associated with its execution. This study finds that surgical residents frequently seek consent from patients while perceiving themselves insufficiently informed to discuss the risks and benefits of proposed procedures. The majority of participants (82%) indicated that they had personally requested consent while believing themselves inadequately aware of relevant surgical risks. Surgical trainees see this as a significant issue, feel motivated to complete the IC process due to perceived pressures, experience emotional distress and commonly seek collegial support. A cohort of residents from various surgical departments reported requesting IC while possessing inadequate knowledge to inform patient decision-making. Management of this reality could better ensure that the surgical environment both safeguards patients and enhances trainee education. PMID- 24953814 TI - Healthcare integration: the study of the toronto central regional hospice palliative care "system" and its integration challenges. AB - The Ontario Ministry of Health and Long-Term Care's End-of-Life strategy did not result in integrated hospice palliative care (HPC) systems. Consequently, HPC has evolved differently across the 14 local health integration networks. In the Toronto Central Local Health Integration Network, the HPC sector lacks foundational systems integration elements: infrastructure and tools that can ensure optimal access and delivery; centralized data capture and management resources to support delivery and planning; and central planning and performance authority that will further improvements in systems delivery, planning and accountability. The sector has been able to function because of inter organizational initiatives and system linkage tools. PMID- 24953816 TI - Person-centred dementia care: a case study at the lodge at broadmead. AB - Dementia care best practice is achievable through a multi-faceted program, including a familiar, home-like environment for residents; an interdisciplinary team approach; a clear clinical program document; continual education/training for staff in all roles; and constant participatory evaluation. With such a comprehensive approach, staff will likely increase their focus on residents as individuals rather than tasks; familiarity, communication and collaboration within the team; and knowledge and understanding of dementias and dementia care. This claim is based on five years of continual evaluation of the Dementia Care Program at the Lodge at Broadmead in Victoria, British Columbia. PMID- 24953815 TI - Moving toward an organized approach to patient education in canadian hospitals. PMID- 24953817 TI - A robotic needle-positioning and guidance system for CT-guided puncture: Ex vivo results. AB - PURPOSE: To test the feasibility of a robotic needle-guidance platform during CT guided puncture ex vivo. MATERIAL AND METHODS: Thin copper wires inserted into a torso phantom served as targets. The phantom was placed on a carbon plate and the robot-positioning unit (RPU) of the guidance platform (iSYS Medizintechnik GmbH, Kitzbuehel, Austria) was attached. Following CT imaging and automatic registration a double oblique trajectory was planned and the RPU was remotely moved into appropriate position and angulation. A 17G-puncture needle was then manually inserted until the preplanned depth, permanently guided by the RPU. The CT scan was repeated and the distance between the actual needle tip and the target was evaluated. RESULTS: Automatic registration was successful in ten experiments and the median duration of an experiment was 9.6 (6.4-46.0) minutes. The angulation of the needle path in x-y and z-axis was within 15.6 degrees to 32.6 degrees , and -32.8 degrees to 3.2 degrees , respectively and the needle insertion depth was 92.8 +/- 14.4 mm. The Euclidean distance between the actual needle tip and the target was 2.3 +/- 0.8 (range, 0.9-3.7) mm. CONCLUSION: Automatic registration and accurate needle placement close to small targets was demonstrated. Study settings and torso phantom were very close to the clinical reality. PMID- 24953819 TI - Development of novel azabenzofuran TRPA1 antagonists as in vivo tools. AB - The transient receptor potential ankyrin 1 (TRPA1) channel is activated by noxious stimuli including chemical irritants and endogenous inflammatory mediators. Antagonists of this channel are currently being investigated for use as therapeutic agents for treating pain, airway disorders, and itch. A novel azabenzofuran series was developed that demonstrated in vitro inhibition of allyl isothiocyanate (AITC)-induced (45)Ca(2+) uptake with nanomolar potencies against both human and rat TRPA1. From this series, compound 10 demonstrated in vivo target coverage in an AITC-induced flinching model in rats while providing unbound plasma concentrations up to 16-fold higher than the TRPA1 rat IC50. PMID- 24953818 TI - Presynaptic GABAB autoreceptor regulation of nicotinic acetylcholine receptor mediated [(3)H]-GABA release from mouse synaptosomes. AB - Activation of nicotinic acetylcholine receptors (nAChRs) can elicit neurotransmitter release from presynaptic nerve terminals. Mechanisms contributing to cell-and-terminal specific regulation of nAChR-mediated neurotransmitter exocytosis are not fully understood. The experiments discussed here examine how activation of GABAB auto- and hetero-receptors suppress nAChR mediated release of [(3)H]-GABA and [(3)H]-dopamine ((3)H-DA) from mouse striatal synaptosomes. Activation of presynaptic GABAB receptors with (R)-baclofen decreased both [(3)H]-GABA and [(3)H]-DA release evoked by potassium depolarization. However, when nAChRs were activated with ACh to evoke neurotransmitter release, (R)-baclofen had no effect on [(3)H]-DA release, but potently inhibited ACh-evoked [(3)H]-GABA release. Inhibition of nAChR-evoked [(3)H]-GABA release by (R)-baclofen was time sensitive and the effect was lost after prolonged exposure to the GABAB agonist. The early inhibitory effect of GABAB activation on ACh-evoked [(3)H]-GABA release was partially attenuated by antagonists of the phosphatase, calcineurin. Furthermore, antagonists of protein kinase C (PKC) prevented the time-dependent loss of the inhibitory (R)-baclofen effect on [(3)H]-GABA release. These results suggest that alpha4beta2*-nAChRs present on GABAergic nerve terminals in the striatum are subject to functional regulation by GABAB autoreceptors that is apparently cell-type specific, since it is absent from DAergic striatal nerve terminals. In addition, the functional modulation of alpha4beta2*-type nAChRs on striatal GABAergic nerve terminals by GABAB autoreceptor activation is time-sensitive and appears to involve opposing actions of calcineurin and PKC. PMID- 24953820 TI - Novologues containing a benzamide side chain manifest anti-proliferative activity against two breast cancer cell lines. AB - Hsp90 represents a promising target for the development of both anti-cancer and neuroprotective agents. Structure-activity relationship studies on novobiocin and novobiocin analogues, led to the development of KU-32 and recently, KU-596, as lead compounds for the potential treatment of neurodegenerative diseases. Similar to KU-32, we have demonstrated that upon replacement of the acetamide side chain present in KU-32 with a benzamide, this neuroprotective agent was transformed into a scaffold that manifests anti-proliferative activity. To assess structure activity relationships for this new scaffold, a library of benzamide-containing novologues was prepared and evaluated against two breast cancer cell lines. Compound 14a manifested the most potent anti-proliferative activity from these studies and induced Hsp90-dependent client protein degradation in a concentration dependent manner. PMID- 24953821 TI - Synthesis and biological evaluation of 4-aza-2,3-dihydropyridophenanthrolines as tubulin polymerization inhibitors. AB - A series of novel 4-aza-2,3-dihydropyridophenanthrolines 12(a-t) were synthesized by a one-step three component condensation of 1,10-phenanthroline amine, tetronic acid and various aromatic aldehydes. These were evaluated for their antiproliferative activity against three human cancer cell lines (MIAPACA, MCF-7 and HeLa) using SRB assay. Majority of the tested compounds exhibited significant anticancer activity on these cell lines and interestingly compounds 12h and 12i were more potent than etoposide and podophyllotoxin against all three tested cancer cell lines with GI50 values in the range of 0.01-0.5 MUM. Furthermore, these compounds showed significant inhibition of tubulin polymerization which is comparable to that of podophyllotoxin and disrupted microtubule network by accumulating tubulin in the soluble fraction. The flow cytometry analysis confirmed that the synthesized compounds led to cell cycle arrest at the G2/M phase. Moreover, the structure activity relationship studies in this series are also discussed. PMID- 24953822 TI - Progesterone and synthetic progestin, dienogest, induce apoptosis of human primary cultures of adenomyotic stromal cells. AB - OBJECTIVES: To investigate the direct effects of progesterone receptor (PR) agonists on proliferation and apoptosis of human adenomyotic cells. STUDY DESIGN: Human primary cultures of adenomyotic stromal cells (ASCs) from 24 patients with adenomyosis were co-treated with estradiol (E2) plus the PR agonists, endogenous progesterone (P) or the synthetic progestin dienogest (DNG), which is used to treat endometriosis. In ASCs, anti-proliferative effects and induction of apoptosis were evaluated in the presence or absence of P (10(-8)-10(-6)M) or DNG (10(-8)-10(-6)M) in culture medium containing E2. Cellular proliferation was analyzed with bromodeoxyuridine incorporation and flow cytometry. Apoptosis was detected with annexin V/7-amino-actinomycin D (7-AAD) staining with flow cytometry and cellular caspase 3/7 activity. RESULTS: P and DNG significantly decreased the proportion of cells in the S phase. In addition, both P and DNG increased apoptosis as measured by annexin V-positive/7-AAD -negative cells and caspase 3/7 activity. CONCLUSIONS: Both endogenous P and synthetic progestin directly inhibited cellular proliferation and induced apoptosis in human ASCs. These pharmacological features of progestational compounds provide insight into the therapeutic strategy for the treatment of adenomyosis. PMID- 24953823 TI - A model for predicting wear rates in tooth enamel. AB - It is hypothesized that wear of enamel is sensitive to the presence of sharp particulates in oral fluids and masticated foods. To this end, a generic model for predicting wear rates in brittle materials is developed, with specific application to tooth enamel. Wear is assumed to result from an accumulation of elastic-plastic micro-asperity events. Integration over all such events leads to a wear rate relation analogous to Archard's law, but with allowance for variation in asperity angle and compliance. The coefficient K in this relation quantifies the wear severity, with an arbitrary distinction between 'mild' wear (low K) and 'severe' wear (high K). Data from the literature and in-house wear-test experiments on enamel specimens in lubricant media (water, oil) with and without sharp third-body particulates (silica, diamond) are used to validate the model. Measured wear rates can vary over several orders of magnitude, depending on contact asperity conditions, accounting for the occurrence of severe enamel removal in some human patients (bruxing). Expressions for the depth removal rate and number of cycles to wear down occlusal enamel in the low-crowned tooth forms of some mammals are derived, with tooth size and enamel thickness as key variables. The role of 'hard' versus 'soft' food diets in determining evolutionary paths in different hominin species is briefly considered. A feature of the model is that it does not require recourse to specific material removal mechanisms, although processes involving microplastic extrusion and microcrack coalescence are indicated. PMID- 24953824 TI - Linear and nonlinear optical properties of V-shaped D-pi-A-pi-D chromophores: effects of the incorporation of aromatic rings in the polyenic pi-bridges of open chain ketocyanines. AB - Following previous studies on alpha and beta polarizabilities of ketocyanines, a subgroup of D-pi-A-pi-D quadrupolar chromophores with moderately V-shaped structure, the present work analyses the effects of modifying the pi-bridges connecting the D (NMe2) and A (CO) groups. This aim is pursued through a detailed comparison between the previously studied ketocyanines (KC2, KC3) and a Michler's ketone analogue (KM1) bearing styrenic (in the place of polyenic) pi-bridges. First, we report a spectroscopic study, including absorption and fluorescence anisotropy spectra, aimed to probe the electronic peculiarities of KM1 as well as to derive consistent three-state model (TSM) parameters for the three compounds. The paper goes on with an extensive theoretical study, carried out in the framework of the density functional theory (DFT), encompassing the structure, the electronic spectrum, alpha and beta polarizabilities and two-photon absorption (TPA) cross-sections (sigmaTP). Calculations performed according to the sum-over states (SOS) approach are discussed with reference to the performances of few state descriptions, it is shown that such descriptions (including TSM), which have been proved to be quite reliable in the case of KC2 and KC3, lose their effectiveness with KM1 because of the electronic characteristics related to the styrenic pi-bridges. As to the TPA cross-sections, the results of TSM and SOS approaches concerning the TSM g -> c and g -> e transitions are supplemented by those obtained using the quadratic response theory. A common qualitative conclusion, traceable to the degree of bending of the V-shaped structure, is that in the case of KM1 the allowed (g -> e) and the "forbidden" (g -> c) transitions both should be observable in the TPA spectrum, as confirmed by experiment. PMID- 24953826 TI - Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for preserving residual kidney function in peritoneal dialysis patients. AB - BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are widely used in peritoneal dialysis (PD) patients, yet controversy exists about their impact on residual kidney function. OBJECTIVES: This review aimed to evaluate the benefits and harms of ACEis and ARBs for preserving residual kidney function in PD patients. SEARCH METHODS: The Cochrane Renal Group's specialised register, Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE (OvidSP interface), Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI) and other resources were searched by applying a prespecified comprehensive search strategy. Date of last search: 01 May 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing ACEis or ARBs with placebo, other antihypertensive drugs or each other in PD patients were included. DATA COLLECTION AND ANALYSIS: Screening, selection, data extraction and quality assessments for each retrieved article were carried out by two authors using standardised forms. Authors were contacted when published data were incomplete. Statistical analyses were performed using the random effects model and results expressed as risk ratio (RR) with 95% confidence intervals (CI). Heterogeneity among studies was explored using the Cochran Q statistic and the I2 test, subgroup analyses and random effects meta-regression. MAIN RESULTS: Six open label studies (257 patients) were identified. One study compared ACEi with other antihypertensive drugs, three compared ARBs with other antihypertensive drugs, and two studies compared an ARB with an ACEi. Long-term use (>= 12 months) of an ARB showed significantly benefit of preserving residual kidney function in continuous ambulatory PD (CAPD) patients (MD 1.11 mL/min/1.73 m2, 95% CI 0.38 to 1.83), although there was no significant benefit when an ARB were used short-term (<= six months). One study showed that compared with other antihypertensive drugs, long-term use (12 months) of the ACEi ramipril showed a significant reduction in the decline of residual kidney function in patients on CAPD (MD 0.93 mL/min/1.73m2, 95% CI -0.75 to -0.11), and delayed the progression to complete anuria (RR 0.64, 95% CI 0.41 to 0.99). There was no significant difference in serum potassium, urinary protein excretion, Kt/V, weekly creatinine clearance and blood pressure for ARBs versus other antihypertensive drugs. Compared with other antihypertensive drugs, ramipril showed no difference in mortality and cardiovascular events. Compared with an ACEi, ARBs did not show any difference in residual kidney function.The selection bias assessment was low in four studies and unclear in two. Five studies were open-label; however the primary outcome (residual kidney function) was obtained objectively from laboratory tests, and were not likely to be influenced by the lack of blinding. Reporting bias was unclear in all six studies. AUTHORS' CONCLUSIONS: Compared with other antihypertensive drugs, long-term use (>= 12 months) of ACEis or ARBs showed additional benefits of preserving residual kidney function in CAPD patients. There was no significant difference on residual kidney function preservation between ARBs and ACEis. However, limited by the small number of RCTs enrolling small number of participants, there is currently insufficient evidence to support the use of an ACEi or an ARB as first line antihypertensive therapy in PD patients. PMID- 24953825 TI - Reversal of warfarin associated coagulopathy with 4-factor prothrombin complex concentrate in traumatic brain injury and intracranial hemorrhage. AB - Warfarin-associated intracranial hemorrhage is associated with a high mortality rate. Ongoing coagulopathy increases the likelihood of hematoma expansion and can result in catastrophic hemorrhage if surgery is performed without reversal. The current standard of care for emergency reversal of warfarin is with fresh frozen plasma (FFP). In April 2013, the USA Food and Drug Administration approved a new reversal agent, 4-factor prothrombin complex concentrate (PCC), which has the potential to more rapidly correct coagulopathy. We sought to determine the feasibility and outcomes of using PCC for neurosurgical patients. A prospective, observational study of all patients undergoing coagulopathy reversal for intracranial hemorrhage from April 2013 to December 2013 at a single, tertiary care center was undertaken. Thirty three patients underwent emergent reversal of coagulopathy using either FFP or PCC at the discretion of the treating physician. Intracranial hemorrhage included subdural hematoma, intraparenchymal hematoma, and subarachnoid hemorrhage. FFP was used in 28 patients and PCC was used in five patients. International normalized ratio at presentation was similar between groups (FFP 2.9, PCC 3.1, p=0.89). The time to reversal was significantly shorter in the PCC group (FFP 256 minutes, PCC 65 minutes, p<0.05). When operations were performed, the time delay to perform operations was also significantly shorter in the PCC group (FFP 307 minutes, PCC 159 minutes, p<0.05). In this preliminary experience, PCC appears to provide a rapid reversal of coagulopathy. Normalization of coagulation parameters may prevent further intracranial hematoma expansion and facilitate rapid surgical evacuation, thereby improving neurological outcomes. PMID- 24953827 TI - Individually addressable arrays of replica microbial cultures enabled by splitting SlipChips. AB - Isolating microbes carrying genes of interest from environmental samples is important for applications in biology and medicine. However, this involves the use of genetic assays that often require lysis of microbial cells, which is not compatible with the goal of obtaining live cells for isolation and culture. This paper describes the design, fabrication, biological validation, and underlying physics of a microfluidic SlipChip device that addresses this challenge. The device is composed of two conjoined plates containing 1000 microcompartments, each comprising two juxtaposed wells, one on each opposing plate. Single microbial cells are stochastically confined and subsequently cultured within the microcompartments. Then, we split each microcompartment into two replica droplets, both containing microbial culture, and then controllably separate the two plates while retaining each droplet within each well. We experimentally describe the droplet retention as a function of capillary pressure, viscous pressure, and viscosity of the aqueous phase. Within each pair of replicas, one can be used for genetic analysis, and the other preserves live cells for growth. This microfluidic approach provides a facile way to cultivate anaerobes from complex communities. We validate this method by targeting, isolating, and culturing Bacteroides vulgatus, a core gut anaerobe, from a clinical sample. To date, this methodology has enabled isolation of a novel microbial taxon, representing a new genus. This approach could also be extended to the study of other microorganisms and even mammalian systems, and may enable targeted retrieval of solutions in applications including digital PCR, sequencing, single cell analysis, and protein crystallization. PMID- 24953830 TI - Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine. AB - The long held view is cocaine's pharmacological effects are mediated by monoamine reuptake inhibition. However, drugs with rapid brain penetration like sibutramine, bupropion, mazindol and tesofensine, which are equal to or more potent than cocaine as dopamine reuptake inhibitors, produce no discernable subjective effects such as drug "highs" or euphoria in drug-experienced human volunteers. Moreover they are dysphoric and aversive when given at high doses. In vivo experiments in animals demonstrate that cocaine's monoaminergic pharmacology is profoundly different from that of other prescribed monoamine reuptake inhibitors, with the exception of methylphenidate. These findings led us to conclude that the highly unusual stimulant profile of cocaine and related compounds, eg methylphenidate, is not mediated by monoamine reuptake inhibition alone. We describe the experimental findings which suggest cocaine serves as a negative allosteric modulator to alter the function of the dopamine reuptake transporter (DAT) and reverse its direction of transport. This results in a firing-dependent, retro-transport of dopamine into the synaptic cleft. The proposed mechanism of cocaine is, therefore, different from other small molecule negative allostereric modulators of the monoamine reuptake transporters, eg SoRI 6238, which merely reduce the rate of inward transport. Because the physiological role of DAT is to remove dopamine from the synapse and the action of cocaine is the opposite of this, we have postulated that cocaine's effect is analogous to an inverse agonist. If this hypothesis is validated then cocaine is the prototypical compound that exemplifies a new class of monoaminergic drugs; DAT "inverse agonists". This article is part of the Special Issue entitled 'CNS Stimulants'. PMID- 24953828 TI - A novel multi-target ligand (JM-20) protects mitochondrial integrity, inhibits brain excitatory amino acid release and reduces cerebral ischemia injury in vitro and in vivo. AB - We previously showed that JM-20, a novel 1,5-benzodiazepine fused to a dihydropyridine moiety, possessed an anxiolytic profile similar to diazepam and strong neuroprotective activity in different cell models relevant to cerebral ischemia. Here, we investigated whether JM-20 protects against ischemic neuronal damage in vitro and in vivo. The effects of JM-20 were evaluated on hippocampal slices subjected to oxygen and glucose deprivation (OGD). For in vivo studies, Wistar rats were subjected 90 min of middle cerebral artery occlusion (MCAo) and oral administration of JM-20 at 2, 4 and 8 mg/kg 1 h following reperfusion. Twenty-four hours after cerebral blood flow restoration, neurological deficits were scored, and the infarct volume, histopathological changes in cortex, number of hippocampal and striatal neurons, and glutamate/aspartate concentrations in the cerebrospinal fluid were measured. Susceptibility to brain mitochondrial swelling, membrane potential dissipation, H2O2 generation, cytochrome c release, Ca2+ accumulation, and morphological changes in the organelles were assessed 24 h post-ischemia. In vitro, JM-20 (1 and 10 MUM) administered during reperfusion significantly reduced cell death in hippocampal slices subjected to OGD. In vivo, JM-20 treatment (4 and 8 mg/kg) significantly decreased neurological deficit scores, edema formation, total infarct volumes and histological alterations in different brain regions. JM-20 treatment also protected brain mitochondria from ischemic damage, most likely by preventing Ca2+ accumulation in organelles. Moreover, an 8-mg/kg JM-20 dose reduced glutamate and aspartate concentrations in cerebrospinal fluid and the deleterious effects of MCAo even when delivered 8 h after blood flow restoration. These results suggest that in rats, JM-20 is a robust neuroprotective agent against ischemia/reperfusion injury with a wide therapeutic window. Our findings support the further examination of potential clinical JM-20 use to treat acute ischemic stroke. PMID- 24953829 TI - Functional consequences of cocaine re-exposure after discontinuation of cocaine availability. AB - Cocaine users exhibit a wide range of behavioral impairments accompanied by brain structural, neurochemical and functional abnormalities. Metabolic mapping studies in cocaine users and animal models have shown extensive functional alterations throughout the striatum, limbic system, and cortex. Few studies, however, have evaluated the persistence of these effects following cessation of cocaine availability. The purpose of this study, therefore, was to assess the functional effects of re-exposure to cocaine in nonhuman primates after the discontinuation of cocaine self-administration for 30 or 90 days, using the quantitative autoradiographic 2-[14C]deoxyglucose (2DG) method. Rhesus monkeys self administered cocaine (fixed interval 3-min schedule, 30 infusions per session, 0.3 mg/kg/infusion) for 100 sessions followed by 30 (n=4) or 90 days (n=3) during which experimental sessions were not conducted. Food-reinforced control animals (n=5) underwent identical schedules of reinforcement. Animals were then re exposed to cocaine or food for one final session and the 2DG method applied immediately after session completion. Compared to controls, re-exposure to cocaine after 30 or 90 day drug-free periods resulted in lower rates of glucose utilization in ventral and dorsal striatum, prefrontal and temporal cortex, limbic system, thalamus, and midbrain. These data demonstrate that vulnerability to the effects of cocaine persists for as long as 90 days after cessation of drug use. While there was some evidence for recovery (fewer brain areas were affected by cocaine re-exposure at 90 days as compared to 30 days), this was not uniform across regions, thus suggesting that recovery occurs at different rates in different brain systems. PMID- 24953831 TI - Delayed treatment with NSC23766 in streptozotocin-induced diabetic rats ameliorates post-ischemic neuronal apoptosis through suppression of mitochondrial p53 translocation. AB - NSC23766, a specific inhibitor of Rac1, has recently been shown to protect against cerebral ischemic injury, although the effects of NSC23766 in a diabetic model have not been examined. Therefore, the aim of our study was to investigate if NSC23766 provided neuroprotection in streptozotocin-induced diabetic rats and to determine the potential mechanism through which NSC23766 works. Diabetic Sprague-Dawley rats were subjected to right middle cerebral artery occlusion (MCAO) for 90 min. NSC23766 (10 or 30 mg kg(-1)) or isotonic saline were administered intraperitoneally twice daily starting 24 h after cerebral ischemia, for three consecutive days. Cerebral infarct volume, neurological deficit scores, neuronal apoptosis, and the release of cytochrome c, as well as the generation of ROS and mitochondrial integrity, were evaluated 96 h after reperfusion. In addition, the mitochondrial translocation of p53 and the expression of p53 upregulated modulator of apoptosis (PUMA) in the mitochondria of the cerebral ischemic cortex were determined by western blotting. NSC23766 not only ameliorated post-ischemic neuronal apoptosis but also decreased cerebral ischemia induced mitochondrial p53 translocation and the expression of PUMA in mitochondria in diabetic rats. Thus, our data indicate that NSC23766 has therapeutic potential against cerebral ischemic reperfusion injury and that NSC23766 significantly ameliorates neuronal apoptosis by suppressing mitochondrial p53 translocation in streptozotocin-induced diabetic rats. PMID- 24953832 TI - Long non-coding RNA HOTAIR, a c-Myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer. AB - BACKGROUND: Protein coding genes account for only about 2% of the human genome, whereas the vast majority of transcripts are non-coding RNAs including long non coding RNAs. A growing volume of literature has proposed that lncRNAs are important players in cancer. HOTAIR was previously shown to be an oncogene and negative prognostic factor in a variety of cancers. However, the factors that contribute to its upregulation and the interaction between HOTAIR and miRNAs are largely unknown. METHODS: A computational screen of HOTAIR promoter was conducted to search for transcription-factor-binding sites. HOTAIR promoter activities were examined by luciferase reporter assay. The function of the c-Myc binding site in the HOTAIR promoter region was tested by a promoter assay with nucleotide substitutions in the putative E-box. The association of c-Myc with the HOTAIR promoter in vivo was confirmed by chromatin immunoprecipitation assay and Electrophoretic mobility shift assay. A search for miRNAs with complementary base paring with HOTAIR was performed utilizing online software program. Gain and loss of function approaches were employed to investigate the expression changes of HOTAIR or miRNA-130a. The expression levels of HOTAIR, c-Myc and miRNA-130a were examined in 65 matched pairs of gallbladder cancer tissues. The effects of HOTAIR and miRNA-130a on gallbladder cancer cell invasion and proliferation was tested using in vitro cell invasion and flow cytometric assays. RESULTS: We demonstrate that HOTAIR is a direct target of c-Myc through interaction with putative c-Myc target response element (RE) in the upstream region of HOTAIR in gallbladder cancer cells. A positive correlation between c-Myc and HOTAIR mRNA levels was observed in gallbladder cancer tissues. We predicted that HOTAIR harbors a miRNA 130a binding site. Our data showed that this binding site is vital for the regulation of miRNA-130a by HOTAIR. Moreover, a negative correlation between HOTAIR and miRNA-130a was observed in gallbladder cancer tissues. Finally, we demonstrate that the oncogenic activity of HOTAIR is in part through its negative regulation of miRNA-130a. CONCLUSION: Together, these results suggest that HOTAIR is a c-Myc-activated driver of malignancy, which acts in part through repression of miRNA-130a. PMID- 24953834 TI - Forensic relevance of post-mortem CT imaging of the haemopericardium in determining the cause of death. AB - The post-mortem diagnosis of pericardial tamponade is associated with several medical legal problems. Thus, we explored whether post-mortem computed tomography might provide useful and reliable information for the diagnosis of this relevant disease in combination with autopsy data. We retrospectively reviewed the post mortem computed tomography and autopsy reports of 15 autopsy cases with haemopericardium detected at the Institute of Forensic Medicine in Berne from July 2005 to February 2010. Two computer tomography findings were examined in combination with autopsy results. The first was the "hyperdense armoured heart," which has been previously described as post-mortem evidence of heart beating for a time after the initiation of intrapericardial bleeding. The second was the "flattening of the anterior surface" of the heart which has been previously observed in vivo as a sign of the compression effect of the haemopericardium on the heart. Our retrospective analysis showed the combined presence of both of these findings in all cases of autopsy evidence of pericardial tamponade with the exception of one case. In contrast, the concomitance of both of them was never observed in cases of autopsy death due to haemorrhage in which neither the flattening of the anterior surface of the heart was detected except for one case. In conclusion, these results should be considered a first step toward the potentially using post-mortem computed tomography in combination with autopsy data in the diagnosis of pericardial tamponade especially considering the possibility to detect sign as the flattened heart signal which cannot be assessed after opening the pericardium at autopsy. PMID- 24953833 TI - Strong antenna-enhanced fluorescence of a single light-harvesting complex shows photon antibunching. AB - The nature of the highly efficient energy transfer in photosynthetic light harvesting complexes is a subject of intense research. Unfortunately, the low fluorescence efficiency and limited photostability hampers the study of individual light-harvesting complexes at ambient conditions. Here we demonstrate an over 500-fold fluorescence enhancement of light-harvesting complex 2 (LH2) at the single-molecule level by coupling to a gold nanoantenna. The resonant antenna produces an excitation enhancement of circa 100 times and a fluorescence lifetime shortening to ~20 ps. The radiative rate enhancement results in a 5.5-fold improved fluorescence quantum efficiency. Exploiting the unique brightness, we have recorded the first photon antibunching of a single light-harvesting complex under ambient conditions, showing that the 27 bacteriochlorophylls coordinated by LH2 act as a non-classical single-photon emitter. The presented bright antenna enhanced LH2 emission is a highly promising system to study energy transfer and the role of quantum coherence at the level of single complexes. PMID- 24953835 TI - Coral-algal phase shifts alter fish communities and reduce fisheries production. AB - Anthropogenic stress has been shown to reduce coral coverage in ecosystems all over the world. A phase shift towards an algae-dominated system may accompany coral loss. In this case, the composition of the reef-associated fish assemblage will change and human communities relying on reef fisheries for income and food security may be negatively impacted. We present a case study based on the Raja Ampat Archipelago in Eastern Indonesia. Using a dynamic food web model, we simulate the loss of coral reefs with accompanied transition towards an algae dominated state and quantify the likely change in fish populations and fisheries productivity. One set of simulations represents extreme scenarios, including 100% loss of coral. In this experiment, ecosystem changes are driven by coral loss itself and a degree of habitat dependency by reef fish is assumed. An alternative simulation is presented without assumed habitat dependency, where changes to the ecosystem are driven by historical observations of reef fish communities when coral is lost. The coral-algal phase shift results in reduced biodiversity and ecosystem maturity. Relative increases in the biomass of small-bodied fish species mean higher productivity on reefs overall, but much reduced landings of traditionally targeted species. PMID- 24953837 TI - The node, a hub for mineral nutrient distribution in graminaceous plants. AB - Mineral elements, including both essential and toxic elements, are delivered to different tissues after they are taken up from the roots, but the mechanism (or mechanisms) underlying the distribution remains poorly understood. In graminaceous plants, this distribution occurs in nodes, which have a complex, well-organized vascular system. A transfer of mineral elements between different vascular bundles is required, especially for preferential distribution to developing tissues that have low transpiration but high nutrient requirements. This intervascular transfer is mediated by various transporters localized at different cells in the node. In this opinion article, we propose four modes of distribution for different mineral elements: xylem-switch, phloem-tropic, phloem kickback, and minimum-shift, based on specific molecular transport processes identified in the nodes mainly of rice (Oryza sativa). We also discuss the prospects for future studies on mineral nutrient distribution in the nodes. PMID- 24953840 TI - In-situ DNA hybridization detection with a reflective microfiber grating biosensor. AB - A label-free fiber-optic biosensor with a reflective microfiber Bragg grating (mFBG) configuration for in-situ DNA hybridization detection has been proposed and experimentally demonstrated. A single straight Bragg grating inscribed in the silica microfiber provides two well-defined resonances in reflection, which show different response to external medium refractive index (RI) and present the same temperature sensitivity. By monitoring the wavelength separation between these two resonances, temperature-compensated RI measurement has been achieved. The label-free bio-recognition scheme used demonstrates that the sensor relies on the surface functionalization of a monolayer of poly-l-lysine (PLL), synthetic DNA sequences that bind with high specificity to a given target. In addition to monitoring the surface functionalization of the fiber in real-time, the results also show how the fiber biosensor can detect the presence of the DNA hybridization with high specificity, in various concentration of target DNA solutions, with lowest detectable concentration of 0.5 uM. PMID- 24953836 TI - Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn's disease: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND AND AIMS: Bile acid malabsorption (BAM)-associated diarrhea is an important clinical issue in patients with Crohn's disease (CD). We analyzed the efficacy and safety of the bile acid sequestrant colesevelam for treatment of BAM associated diarrhea in CD patients in a randomized, double-blind, placebo controlled study. METHODS: The primary endpoint was the proportion of patients with >30% reduction of liquid stools/day from baseline to termination visit at week 4. Secondary endpoints were reduction of the number of liquid stools/day, improvement of stool consistency and quality of life. RESULTS: 26 patients were analyzed in the intention-to-treat (ITT) analysis. The primary endpoint was reached by 10 patients (69.7%) in the colesevelam group compared to 3 patients (27.3%) in the placebo group (risk difference RD=.394, 95%CI:[-0.012; 0.706]; P=.0566). In the per-protocol analysis (n=22), the risk difference was statistically significant (RD=.470, 95%CI:[0.018; 0.788], P(H0: RD=0)=0.0364; 95% CI:[1.3;54.7]). Regarding secondary endpoints, in the ITT population colesevelam treated patients had a significant reduction of liquid stools/day at week 4 (median 5.0 to 2.0; P=0.01), while patients treated with placebo had no significant reduction (median 4.0 to 3.0; P=0.42). Significantly more patients in the colesevelam group had improvement of stool consistency of at least one level in the Bristol stool chart, as compared to the placebo group (P=0.003). CONCLUSIONS: We found significant differences in favor for colesevelam treatment compared to placebo treatment for CD patients with BAM regarding the reduction of the number of liquid stools/day and stool consistency. ClinicalTrials.gov number: NCT01203254. PMID- 24953841 TI - Covalent functionalization of gold nanoparticles as electronic bridges and signal amplifiers towards an electrochemical immunosensor for botulinum neurotoxin type A. AB - This work introduced an efficient approach for modification of AuNPs with multicomponents by diazonium salt couplings. The multifunctionalized AuNPs with protruding functional groups that allow simple bioconjugation to large amounts of biomolecules have been successfully used as electronic bridges and signal amplifiers for an electrochemical immunosensor towards the detection of BoNT/A. The one-step anchoring AuNPs strategy has greatly increased the efficiency for attachment of biomolecules and subsequently increased the sensitivity. Sensitivity was further amplified by preparation of bioconjugates particles containing horseradish peroxidase (HRP) labels along with detection antibodies (AbL) attached to AuNPs. The immunosensor can be used for the detection of BoNT/A over the range of 4-35 pg mL(-1) with the lowest detection limit of 1 pg mL(-1) and assay time of 10 min. The herein sensing strategy is rapid, robust, selective, sensitive, and is promising for future fabrication of point-of-care devices. PMID- 24953842 TI - Selective nonenzymatic bilirubin detection in blood samples using a Nafion/Mn-Cu sensor. AB - The specific detection of biological organics without the use of an enzyme is challenging, and it is crucial for analytical and clinical chemistry. We report specific nonenzymatic bilirubin detection through the catalytic oxidation of bilirubin molecule on the Nafion/Mn-Cu surface. The catalytic ability, true surface area, morphology, crystallinity, composition, and oxidation state of the sensor surface were assessed using voltammetry, coulometry, XPS, XRD, Brunauer Emmett-Teller (BET), SEM, EDXS, and TOF-SIMS experiments. The results showed that the surface was composed of microporous Mn-Cu bimetallic crystal in flake shape with a large BET surface area (3.635 m(2)g(-1)), where the surface area and crystallinity mainly affected the sensor performance. Product analysis of the catalytic reaction on the sensor probe revealed a specific two-electron oxidation of dipyrromethane moiety to dipyrromethene in the bilirubin molecule. Experimental variables affecting the analysis of bilirubin were optimized in terms of probe composition, temperature, pH, and potential. At the optimized condition, the dynamic range was between 1.2 MUM and 0.42 mM, which yielded the equation of DeltaI (MUA)=(1.03 +/- 0.72)+(457.0 +/- 4.03) [C] (mM) with 0.999 of correlation coefficient, and the detection limit was 25.0 +/- 1.8 nM (n=5, k=3). The stability test, interference effects, and analysis of real clinical samples, human whole blood and certified serum samples were demonstrated to confirm the reliability of the proposed bilirubin sensor. PMID- 24953843 TI - Chitosan coated copper and cadmium hexacyanocobaltate nanocubes as immunosensing probes for the construction of multiple analytes platform. AB - In this work, Cd3[Co(CN)6]2 and Cu3[Co(CN)6]2 (CdNCs and CuNCs) nanocubes were synthesized simply by a one-step process at room temperature in the presence of chitosan (CS). It was found that CdNCs and CuNCs produced obviously distinctive anodic peak currents at -0.7 V and -0.1 V (vs. Ag/AgCl), whose separation enabled differentiation between two analytes. They were used as novel electrochemical probes in multiplex electrochemical detection for carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) in a single run. The good performance of the new electrochemical probes was obtained. The linearity range was from 0.025 to 250 ng mL(-1) for both CEA and AFP. The detection limit of CEA was 0.0175 ng mL(-1) and that of AFP was 0.0109 ng mL(-1) at a signal-to-noise of 3. Analysis of clinical serum samples using this immunosensor was well consistent with the data determined by the enzyme-linked immunosorbent assay (ELISA). The novel electrochemical probes could be generally used in multiplex protein detections. PMID- 24953844 TI - Enzyme orientation for direct electron transfer in an enzymatic fuel cell with alcohol oxidase and laccase electrodes. AB - A new full enzymatic fuel cell was built and characterized. Both enzymatic electrodes were molecularly oriented to enhance the direct electron transfer between the enzyme active site and the electrode surface. The anode consisted in immobilized alcohol oxidase on functionalized carbon nanotubes with 4 azidoaniline, which acts as active-site ligand to orientate the enzyme molecule. The cathode consisted of immobilized laccase on functionalized graphite electrode with 4-(2-aminoethyl) benzoic acid. The enzymatic fuel cell reaches 0.5 V at open circuit voltage with both, ethanol and methanol, while in short circuit the highest current intensity of 250 MUA cm(-2) was obtained with methanol. Concerning the power density, the methanol was the best substrate reaching 60 MUW cm(-2), while with ethanol 40 MUW cm(-2) was obtained. PMID- 24953845 TI - Carbon nanotubes functionalized electrospun nanofibers formed 3D electrode enables highly strong ECL of peroxydisulfate and its application in immunoassay. AB - A new biosensing platform based on electrospun carbon nanotubes nanofibers (CNTs@PNFs) composite, which enabled strong electrochemiluminescent emission of peroxydisulfate, was firstly developed for immunoassay with favorable analytical performances, and then was utilized to evaluate the interaction between antibody and antigen in vitro. Moreover, the obvious ECL image of peroxydisulfate on the prepared sensing platform was firstly recorded in this report. In order to expand the application of peroxydisulfate ECL, the specific recognization biomolecules, alpha-fetoprotein (AFP) antibody was bound to the functionalized film via electrostatic interaction for fabricating label-free ECL immunosensor to detect alpha-AFP. Based on the ECL change resulting from the specific immunoreaction between antigen and antibody, the quantitative analysis for AFP with wide dynamic response in the range from 0.1 pg mL(-1) to 160 ng mL(-1) was realized. And the limit of detection was estimated to be 0.09 pg mL(-1). Therefore, the flexible sensing platform not only acted as the sensitized sensing element, but also offered a suitable carrier for immobilization of biological recognition elements with low-toxicity and eco-friendliness, which opened a promising approach to developing further electrospun nanofiber based amplified ECL biosensor with favorable analytical performances. PMID- 24953846 TI - Engineering a reagentless biosensor for single-stranded DNA to measure real-time helicase activity in Bacillus. AB - Single-stranded DNA-binding protein (SSB) is a well characterized ubiquitous and essential bacterial protein involved in almost all aspects of DNA metabolism. Using the Bacillus subtilis SSB we have generated a reagentless SSB biosensor that can be used as a helicase probe in B. subtilis and closely related gram positive bacteria. We have demonstrated the utility of the probe in a DNA unwinding reaction using a helicase from Bacillus and for the first time, characterized the B. subtilis SSB's DNA binding mode switching and stoichiometry. The importance of SSB in DNA metabolism is not limited to simply binding and protecting ssDNA during DNA replication, as previously thought. It interacts with an array of partner proteins to coordinate many different aspects of DNA metabolism. In most cases its interactions with partner proteins is species specific and for this reason, knowing how to produce and use cognate reagentless SSB biosensors in different bacteria is critical. Here we explain how to produce a B. subtilis SSB probe that exhibits 9-fold fluorescence increase upon binding to single stranded DNA and can be used in all related gram positive firmicutes which employ drastically different DNA replication and repair systems than the widely studied Escherichia coli. The materials to produce the B. subtilis SSB probe are commercially available, so the methodology described here is widely available unlike previously published methods for the E. coli SSB. PMID- 24953847 TI - Relapse and its remission in Japanese patients with idiopathic membranous nephropathy. AB - BACKGROUND: The prognosis in patients with idiopathic membranous nephropathy (IMN) is diverse. However, the prognosis after relapse and factors affecting relapse remain unclear. METHODS: A total of 146 Japanese patients with IMN who had been followed up for at least 3 years, or until end-stage renal failure or death were enrolled in this retrospective study. The initial clinicopathological factors were examined between the patients with and without relapse. The patients were assigned to two groups based on the electron microscopic findings: homogeneous type with synchronous electron-dense deposits and heterogeneous type with various phases of dense deposits. RESULTS: A total of 105 of the 146 patients (72 %) achieved complete remission (CR) or incomplete remission (ICR) I after initial treatment. Twenty-six of the 105 patients relapsed after CR or ICR I (25 %). There were no differences in initial clinical findings or data between the patients with and without relapse, except for the higher degree of proteinuria at onset in patients with relapse. The relapse rate of the heterogeneous group (43 %) was higher than that in the homogeneous group (20 %). There were no significant associations between relapse rate and immunosuppressive therapy at onset. Eleven of 26 patients showing relapse (42 %) achieved CR or ICR I, which was lower than the rate for patients with initial remission. CONCLUSION: Our results suggest that patients with relapse achieved CR or ICR I and that electron microscopic findings demonstrating heterogeneous type indicated susceptibility to relapse. PMID- 24953849 TI - Physicochemical properties and in vitro mineralization of porous polymethylmethacrylate cement loaded with calcium phosphate particles. AB - The main goal of this study was to evaluate the effects of incorporation of calcium phosphate (CaP) particles on the physicochemical properties and mineralization capacity of cements in vitro. Herein, two different types of CaP particles were loaded into polymethylmethacrylate (PMMA) cements exhibiting an interconnected porosity created by mixing with carboxymethylcellulose. The incorporation of CaP particles did not influence the maximum polymerization temperature of the porous PMMA, but reduced the porosity and the average pore size. Small CaP particles formed agglomerations within the PMMA pores, whereas big CaP particles were partially embedded in the PMMA matrix and partially exposed to the pores. Both types of CaP particles enhanced the mineralization capacity of PMMA cement without compromising their mechanical properties. The data presented herein suggest that porous PMMA/CaP cements hold strong promise for surgical application in bone reconstruction. PMID- 24953850 TI - Hydrogen abstraction/acetylene addition revealed. AB - For almost half a century, polycyclic aromatic hydrocarbons (PAHs) have been proposed to play a key role in the astrochemical evolution of the interstellar medium (ISM) and in the chemistry of combustion systems. However, even the most fundamental reaction mechanism assumed to lead to the simplest PAH naphthalene- the hydrogen abstraction-acetylene addition (HACA) mechanism--has eluded experimental observation. Here, by probing the phenylacetylene (C8 H6 ) intermediate together with naphthalene (C10 H8 ) under combustion-like conditions by photo-ionization mass spectrometry, the very first direct experimental evidence for the validity of the HACA mechanism which so far had only been speculated theoretically is reported. PMID- 24953848 TI - Incidence of malignant neoplasia after heart transplantation--a comparison between cyclosporine a and tacrolimus. AB - BACKGROUND: Heart transplant recipients are at increased risk of developing malignant neoplasms. Administration of the calcineurin inhibitors cyclosporine A (CSA) or tacrolimus (TAC) may contribute to this risk. MATERIAL AND METHODS: We compared tumor incidence in heart transplant recipients receiving either CSA (n=25) or TAC (n=120) as maintenance immunosuppressive therapy. Exclusion criteria were therapy with mammalian target of rapamycin-inhibitors, death within the first postoperative year, re-transplantation, and age less than 18 years. RESULTS: The 2 study groups were comparable with respect to sex, primary and concomitant diagnoses, and mean follow-up (60.7 +/- 19.3 months in the CSA group vs. 59.8 +/- 18.1 months in the TAC group; P=0.81). The CSA group was, however, significantly older compared with the TAC group (58.8 +/- 11.4 years vs. 49.1 +/- 13.0 years, P=0.001), as was the donor age of the CSA group (43.2 +/- 11.2 years vs. 37.0 +/- 11.7 years, P=0.02). In the CSA group, 5 patients (20%) developed malignant neoplasms compared with 10 patients (8.3%) in the TAC group (P=0.14). Covariate-adjusted 5-year tumor-free survival was comparable between groups (relative risk for the CSA group =1.162 [95% CI: 0.378-3.572; P=0.794]). Moreover, covariate-adjusted 5-year overall survival did not differ between the 2 groups (relative risk for the CSA group =1.95 [95% CI: 0.53-7.19; P=0.36). The incidence of infection, acute rejection, graft vasculopathy, renal failure, and neurological complications was also comparable between the 2 groups. CONCLUSIONS: Our data indicate that tumor incidence does not significantly differ in patients receiving CSA or TAC as maintenance therapy. PMID- 24953851 TI - A rapid phenol toxicity test based on photosynthesis and movement of the freshwater flagellate, Euglena agilis Carter. AB - Phenol, a monosubstituted aromatic hydrocarbon with various commercial uses, is a major organic constituent in industrial wastewaters. The ecotoxic action of phenol for aquatic environment is well known. In this study, rapid phenol toxicity tests (1h) were developed based on chlorophyll a (Chl a) fluorescence and the movement parameters of the freshwater flagellate, Euglena agilis Carter. Phenol significantly reduced the maximum quantum yield (Fv/Fm) of photosystem II (PS II) and the maximum photosynthetic electron transport rate (rETRmax) with median effective concentration (EC50) values of 8.94 and 4.67 mM, respectively. Phenol reduced the motility and triggered change in the swimming velocity of the test organism. Among the parameters tested, velocity was the most sensitive biomarker with an EC50 of 3.17 mM. The EC50 values for Fv/Fm, motility, and velocity appear to overlap the permitted levels of phenol. In conclusion, the photosynthesis and movement of E. agilis can be fast and sensitive risk assessment parameters for the evaluation of phenol toxicity in municipal and industrial effluents. PMID- 24953852 TI - Social support and prolonged cardiovascular reactivity: the moderating influence of relationship quality and type of support. AB - The present study investigated the moderating influence of relationship quality on the cardiovascular effects of social support during anticipation of, performance of, and recovery from an evaluative speaking task. Additionally, the generalizability of effects across different types of support was addressed. Sixty normotensive female students were assigned to one of the five support conditions: active verbal support provided by either a supportive or ambivalent friend, mental activation of either a supportive or ambivalent friend, no support. Active support by an ambivalent friend was found to elicit higher magnitude increases in systolic blood pressure (SBP) across all stressor phases. A detrimental influence of mental activation of ambivalent ties on SBP reactivity was observed during speech performance, only. Effects of ambivalence did not extend to experienced emotions and cognitive appraisals. The present findings extend previous research by indicating that interactions with ambivalent ties might be an important determinant of sustained cardiovascular activity. PMID- 24953853 TI - Hemeoxygenase 1 partly mediates the anti-inflammatory effect of dieckol in lipopolysaccharide stimulated murine macrophages. AB - Eisenia bicyclis is edible brown algae recognized as a rich source of bioactive derivatives mainly phlorotannins reported for their anti-oxidant properties. Of all phlorotannins identified so far, dieckol has shown the most potent effect in anti-inflammatory, radical scavenging and neuroprotective functions. However, whether dieckol up-regulates hemeoxygenase 1 (HO-1) and this mediates its anti inflammatory effect in murine macrophages remains poorly understood. Dieckol (12.5-50 MUM) inhibited nitric oxide production and attenuated inducible nitric oxide synthase, phospho (p)-PI-3K, p-Akt, p-IKK-alpha/beta, p-IkappaB-alpha and nuclear p-NF-kappaBp65 protein expressions, and NF-kappaB transcriptional activity in LPS (0.1 MUg/ml) stimulated murine macrophages. On the other hand, dieckol up-regulated HO-1 which partly mediated its anti-inflammatory effect in murine macrophages. Thus, dieckol appeared to be a potential therapeutic agent against inflammation through HO-1 up-regulation. PMID- 24953854 TI - Dexamethasone inhibits in vivo tumor growth by the alteration of bone marrow CD11b+ myeloid cells. AB - Inflammation is closely associated with tumor growth, which is mediated by the activation of bone marrow-derived CD11b(+) cells. Here, we investigated whether anti-inflammatory dexamethasone (Dex), a synthetic glucocorticoid (GC), could regulate tumor growth and CD11b(+) myeloid bone marrow cells (BMCs) in lymphocyte (R1), monocyte (R2) and granulocyte (R3) regions of FSC-SSC dot plot. The growth of B16F10 mouse melanoma tumor was inhibited in Dex-injected group. Lung metastasis was decreased and the lifespan was elongated in Dex-injected mice with tumor resection. Intravenous injection of B16F10 cells increased the percentage of CD11b(+) myeloid BMCs in R1 and R2 regions from 3h to 72h. In contrast, little changes in the percentage of CD11b(+) myeloid BMCs were detected in R3 region. Among CD11b(+) myeloid BMCs, the percentage of CD11b(+)Gr-1(+) cells was increased in R1, R2 and R3 regions. Absolute number of CD11b(+) and CD11b(+)Gr 1(+) cells was enhanced in R1 region from 3h to 72 h. B16F10 tumor growth was significantly increased by intravenous injection of CD11b(+) BMCs. Tumor-bearing mice showed an increase in the percentage of CD11b(+) myeloid BMCs in R2 region and CD11b(+)Gr-1(+) cells in R2 and R3 regions, which are reduced by intravenous injection with Dex. Absolute number of CD11b(+)Gr-1(+) cells was enhanced in R2 and R3 regions. Tumor growth was significantly inhibited by intravenous injection of BMCs collected from Dex-treated tumor-bearing mice. Taken together, data demonstrate that tumor regression by Dex was resulted from the alteration of CD11b(+) myeloid BMCs and their inhibitory function to tumor growth. It suggests that CD11b(+) myeloid BMCs could regulate antitumor efficacy of GCs such as Dex. PMID- 24953855 TI - p21WAF1 mediates the IL-15-induced migration and invasion of human bladder cancer 5637 cells via the ERK1/2/NF-kappaB/MMP-9 pathway. AB - Interleukin-15 (IL-15) functions as a key regulator for the proliferation, differentiation, and activation of lymphocytes. However, the role of IL-15 in cancer biology is not yet understood. In the present study, IL-15 treatment stimulated the wound-healing migration and invasion of bladder cancer 5637 cells, without altering the proliferation of the cells. Treatment of 5637 cells with IL 15 resulted in the promotion of the MMP-9 expression and the activation of NF kappaB binding, which is a functional transcription factor that activates MMP-9 expression. In addition, IL-15 induced the activation of ERK1/2. ERK inhibitor U0126 suppressed the migration, invasion, MMP-9 expression, and NF-kappaB binding activity in IL-15-treated 5637 cells. In addition, the cell-cycle inhibitor p21WAF1 was induced by the addition of IL-15. Finally, the siRNA-mediated knockdown of p21WAF1 attenuated the IL-15-induced stimulation of migration, invasion, ERK1/2 activation, MMP-9 expression, and NF-kappaB binding activation in 5637 cells. Our results suggest that p21WAF1 regulated NF-kappaB-mediated MMP 9 expression via the activation of ERK1/2, which resulted in the migration and invasion of 5637 cells treated with IL-15. These unexpected results suggest a potential role for IL-15 with respect to the progression of bladder cancer. PMID- 24953856 TI - Effect of trabeculectomy and canaloplasty on intra-ocular pressure modifications after postural changes in open-angle glaucoma. PMID- 24953857 TI - The prevalence of the oral allergy syndrome and pollen-food syndrome in an atopic paediatric population in south-west Sydney. AB - AIM: Oral allergy syndrome (OAS) and pollen-food syndrome (PFS) are regarded as uncommon manifestations of paediatric atopic disease. However, little Australian data exist. The aim of this study was to examine the prevalence of OAS in an atopic, paediatric population. METHODS: This cross-sectional study assessed 163 patients aged 4-17 years from the Paediatric Allergy & Immunology Clinic at Campbelltown Hospital, which serves a population base >250,000 with approximately 28% under the age of 18 years. A questionnaire was administered and skin prick tests (SPTs) were performed utilising commercial extracts and fresh and frozen fruit samples. Frozen samples were created by reducing fresh fruit to a semi solid state and storing at -20 degrees Celsius for up to 6 months. RESULTS: Within the studied population, the prevalence of OAS was 14.7%, PFS 4.9%, PFS in those with allergic rhinitis 6.25% and PFS in those with allergic rhinitis and pollen sensitisation 12.1%. All PFS-implicated fruits were tropical fruits with watermelon the most common. The prevalence of OAS caused by food allergy was 13.6%, implicating peanut most frequently. The most common cause of OAS was immunoglobulin E-mediated food allergy (57.9%). Only frozen samples of watermelon, pineapple and rockmelon produced results consistent with the 'gold standard' of fresh fruit SPT. CONCLUSION: This study suggests the prevalence of OAS and PFS are more common in paediatric populations than previously described, with tropical fruits predominantly implicated in PFS. Further research is required to determine whether frozen fruits are a reliable alternative to fresh fruit in SPT. PMID- 24953858 TI - The hand held Doppler device for the detection of perforators in reconstructive surgery: what you hear is not always what you get. AB - BACKGROUND: Perforator-based flaps have become indispensable in the treatment of burn scars. Pre-operative perforator mapping is often performed by use of the hand held Doppler device, partly due to its convenience and the low costs. We expected to find sufficient evidence in literature to support the use of the device, however available literature showed a distinct lack of clinimetric studies that adequately tested the reliability. METHODS: To assess reliability, perforator locations were mapped independently by two clinicians using an 8MHz Doppler device. In healthy volunteers the elbow region or the peri-umbilical region were randomly chosen to be the measurement areas of predefined squares (7cm*7cm). Subsequently, the perforators within the area were mapped with Duplex to establish the validity by means of the positive predictive value. RESULTS: 20 volunteers were included. The hand held Doppler technique showed moderate reliability with a mean Dice coefficient of 0.56. Also, poor validity was found expressed by a mean positive predictive value of 55%. CONCLUSIONS: Surprisingly, this study has shown that performance of the hand held Doppler device was moderate. The Doppler should not be used alone for the detection of perforators. PMID- 24953859 TI - A comparison of low-dose ACTH, glucagon stimulation and insulin tolerance test in patients with pituitary disorders. AB - CONTEXT: Diagnosis of secondary adrenal insufficiency and GH deficiency requires evaluation by dynamic stimulation tests in most cases. Although insulin tolerance test (ITT) is accepted as the gold-standard test for the evaluation of both hypothalamo-pituitary-adrenal (HPA) and (GH)-IGF-1 axes, the test is cumbersome. In clinical practice, low-dose adrenocorticotrophic hormone (ACTH) stimulation test is a sensitive, safe and easily applicable alternative to ITT. Although it takes more time, glucagon stimulation test (GST) is also a good alternative to ITT and can evaluate both axes. OBJECTIVE: The primary aim of this study was to compare the ITT, low-dose ACTH and GSTs in the evaluation of HPA and GH-IGF-1 axes in patients with pituitary disorders and to evaluate the repeatability of all three tests. DESIGN: ITT, low-dose ACTH and GSTs were performed in all 129 patients, and the tests were repeated in 66 of these patients. SETTING: Erciyes University Medical School, Department of Endocrinology. PATIENTS OR OTHER PARTICIPANTS: One hundred and twenty-nine adult patients (76 women, 53 men) with pituitary disorder were included in the study. MAIN OUTCOME MEASURE(S): The cortisol and GH responses of patients to dynamic tests. RESULTS: Peak cortisol levels obtained during ITT were significantly lower than the values obtained during both low-dose ACTH and GSTs. Peak cortisol levels obtained during the GST were lower than those found during the low dose ACTH stimulation test. Peak GH responses were found to be higher in GST than in ITT. All three tests had good reproducibility. CONCLUSIONS: Any of 3 tests can be used in the evaluation of the HPA axis and either GST or the ITT can be used in the evaluation of the GH-IGF-1 axis but cut-off levels for the insufficiency of HPA or GH-IGF-1 axis should be individualized for each test. PMID- 24953862 TI - Hodgkin lymphoma: 2014 update on diagnosis, risk-stratification, and management. AB - DISEASE OVERVIEW: Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 9,200 new patients annually and representing approximately 11.5% of all lymphomas in the United States. DIAGNOSIS: HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte-predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL. RISK STRATIFICATION: An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography scan, are used to optimize therapy. RISK-ADAPTED THERAPY: Initial therapy for HL patients is based on the histology of the disease, the anatomical stage, and the presence of poor prognostic features. Patients with early stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. Management of relapsed/refractory disease: High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, palliative chemotherapy, nonmyeloablative allogeneic transplant, or participation in a clinical trial should be considered. PMID- 24953861 TI - An algorithm recommendation for the management of knee osteoarthritis in Europe and internationally: a report from a task force of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). AB - OBJECTIVES: Existing practice guidelines for osteoarthritis (OA) analyze the evidence behind each proposed treatment but do not prioritize the interventions in a given sequence. The objective was to develop a treatment algorithm recommendation that is easier to interpret for the prescribing physician based on the available evidence and that is applicable in Europe and internationally. The knee was used as the model OA joint. METHODS: ESCEO assembled a task force of 13 international experts (rheumatologists, clinical epidemiologists, and clinical scientists). Existing guidelines were reviewed; all interventions listed and recent evidence were retrieved using established databases. A first schematic flow chart with treatment prioritization was discussed in a 1-day meeting and shaped to the treatment algorithm. Fine-tuning occurred by electronic communication and three consultation rounds until consensus. RESULTS: Basic principles consist of the need for a combined pharmacological and non pharmacological treatment with a core set of initial measures, including information access/education, weight loss if overweight, and an appropriate exercise program. Four multimodal steps are then established. Step 1 consists of background therapy, either non-pharmacological (referral to a physical therapist for re-alignment treatment if needed and sequential introduction of further physical interventions initially and at any time thereafter) or pharmacological. The latter consists of chronic Symptomatic Slow-Acting Drugs for OA (e.g., prescription glucosamine sulfate and/or chondroitin sulfate) with paracetamol at need; topical NSAIDs are added in the still symptomatic patient. Step 2 consists of the advanced pharmacological management in the persistent symptomatic patient and is centered on the use of oral COX-2 selective or non-selective NSAIDs, chosen based on concomitant risk factors, with intra-articular corticosteroids or hyaluronate for further symptom relief if insufficient. In Step 3, the last pharmacological attempts before surgery are represented by weak opioids and other central analgesics. Finally, Step 4 consists of end-stage disease management and surgery, with classical opioids as a difficult-to-manage alternative when surgery is contraindicated. CONCLUSIONS: The proposed treatment algorithm may represent a new framework for the development of future guidelines for the management of OA, more easily accessible to physicians. PMID- 24953860 TI - Dietary intake and plasma metabolomic analysis of polyunsaturated fatty acids in bipolar subjects reveal dysregulation of linoleic acid metabolism. AB - Polyunsaturated fatty acids (PUFA) profiles associate with risk for mood disorders. This poses the hypothesis of metabolic differences between patients and unaffected healthy controls that relate to the primary illness or are secondary to medication use or dietary intake. However, dietary manipulation or supplementation studies show equivocal results improving mental health outcomes. This study investigates dietary patterns and metabolic profiles relevant to PUFA metabolism, in bipolar I individuals compared to non-psychiatric controls. We collected seven-day diet records and performed metabolomic analysis of fasted plasma collected immediately after diet recording. Regression analyses adjusted for age, gender and energy intake found that bipolar individuals had significantly lower intake of selenium and PUFAs, including eicosapentaenoic acid (EPA) (n-3), docosahexaenoic acid (DHA) (n-3), arachidonic acid (AA) (n-6) and docosapentaenoic acid (DPA) (n-3/n-6 mix); and significantly increased intake of the saturated fats, eicosanoic and docosanoic acid. Regression analysis of metabolomic data derived from plasma samples, correcting for age, gender, BMI, psychiatric medication use and dietary PUFA intake, revealed that bipolar individuals had reduced 13S-HpODE, a major peroxidation product of the n-6, linoleic acid (LA), reduced eicosadienoic acid (EDA), an elongation product of LA; reduced prostaglandins G2, F2 alpha and E1, synthesized from n-6 PUFA; and reduced EPA. These observations remained significant or near significant after Bonferroni correction and are consistent with metabolic variances between bipolar and control individuals with regard to PUFA metabolism. These findings suggest that specific dietary interventions aimed towards correcting these metabolic disparities may impact health outcomes for individuals with bipolar disorder. PMID- 24953864 TI - Thermoluminescence of mercaptoethanol-capped ZnS:Mn nanoparticles. AB - The thermoluminescence (TL) of nanoparticles has become a matter of keen interest in recent times but is rarely reported. This article reports the synthesis of ZnS:Mn nanocrystals using a chemical route, with mercaptoethanol (ME) as the capping agent. The particle sizes for the nanocrystals were measured by X-ray diffraction (XRD) and also by studying transmission electron microscopy (TEM) patterns. The particle sizes of the synthesized samples were found to be between 1 and 3 nm. For samples with different concentrations of the capping agent, it was found that the TL intensity of the ZnS:Mn nanoparticles increased as the particle size decreased. A shift in the peak position of the TL glow curve was also seen with decreasing particle size. The TL intensity was found to be maximal for samples with 1.2% of Mn. A change in the peak position was not found for samples with different concentrations of Mn. The half-width glow peak curve method was used to determine the trap-depth. The frequency factor of the synthesized samples was also calculated. The stability of the charge carriers in the traps increases with decreasing nanoparticle size. The higher stability may be attributed to the higher surface/volume ratio and also to the increase in the trap-depth with decreasing particle size. PMID- 24953863 TI - New strategy for expression of recombinant hydroxylated human collagen alpha1(III) chains in Pichia pastoris GS115. AB - Type III collagen is one of the most abundant proteins in the human body, which forms collagen fibrils and provides the stiff, resilient characteristics of many tissues. In this paper, a new method for secretory expression of recombinant hydroxylated human collagen alpha1(III) chain in Pichia pastoris GS115 was applied. The gene encoding for full-length human collagen alpha1(III) chain (COL3A1) without N-terminal propeptide and C-terminal propeptide was cloned in the pPIC9K expression vector. The prolyl 4-hydroxylase (P4H, EC 1.14.11.2) alpha subunit (P4Halpha) and beta-subunit (P4Hbeta) genes were cloned in the same expression vector, pPICZB. Fluorogenic quantitative PCR indicates that COL3A1 and P4H genes have been expressed in mRNA level. SDS-PAGE shows that secretory expression of recombinant human collagen alpha1(III) chain was successfully achieved in P. pastoris GS115. In addition, the result of amino acids composition analysis shows that the recombinant human collagen alpha1(III) chain contains hydroxyproline by coexpression with the P4H. Furthermore, liquid chromatography coupled with tandem mass spectrometry analysis demonstrates that proline residues of the recombinant human collagen alpha1(III) chain were hydroxylated in the X or Y positions of Gly-X-Y triplets. PMID- 24953865 TI - Interactions between clinical factors, p16, and cyclin-D1 expression and survival outcomes in oropharyngeal and hypopharyngeal squamous cell carcinoma. AB - BACKGROUND: P16 and cyclin-D1 are cell cycle proteins commonly dysregulated in head and neck carcinoma. We assessed their expression, clinicopathological variables, and overall survival (OS) in oropharyngeal and hypopharyngeal squamous cell carcinoma (SCC). METHODS: Clinical characteristics and p16 and cyclin-D1 expression were evaluated in 101 patients with oropharyngeal SCC and 75 patients with hypopharyngeal SCC. Associations with OS were assessed using Cox regression and Kaplan-Meier analysis. RESULTS: Compared to oropharyngeal SCC, patients with hypopharyngeal SCC were older, men, ever-smokers with higher mean Charlson Comorbidity Index (CCI), lower p16 expression, and poorer median OS (24.8 vs 62.3 months; p < .01). In oropharyngeal SCC, CCI (p < .001), cyclin-D1 (hazard ratio [HR] = 3.55; p = .007), current smoking (HR = 5.72; p = .004), and former smoking (HR = 4.12; p = .035) were independently associated with OS. In hypopharyngeal SCC, only nodal and Eastern Cooperative Oncology Group status were associated with OS. CONCLUSION: In oropharyngeal SCC, cyclin-D1 expression is correlated with survival, whereas smoking status and CCI may allow further stratification of outcome. PMID- 24953866 TI - Human pharyngeal microbiome may play a protective role in respiratory tract infections. AB - The human pharyngeal microbiome, which resides at the juncture of digestive and respiratory tracts, may have an active role in the prevention of respiratory tract infections, similar to the actions of the intestinal microbiome against enteric infections. Recent studies have demonstrated that the pharyngeal microbiome comprises an abundance of bacterial species that interacts with the local epithelial and immune cells, and together, they form a unique micro ecological system. Most of the microbial species in microbiomes are obligate symbionts constantly adapting to their unique surroundings. Indigenous commensal species are capable of both maintaining dominance and evoking host immune responses to eliminate invading species. Temporary damage to the pharyngeal microbiome due to the impaired local epithelia is also considered an important predisposing risk factor for infections. Therefore, reinforcement of microbiome homeostasis to prevent invasion of infection-prone species would provide a novel treatment strategy in addition to antibiotic treatment and vaccination. Hence continued research efforts on evaluating probiotic treatment and developing appropriate procedures are necessary to both prevent and treat respiratory infections. PMID- 24953868 TI - Left ventricular global function index: Relation with infarct characteristics and left ventricular ejection fraction after STEMI. PMID- 24953867 TI - Adolescent mouse takes on an active transcriptomic expression during postnatal cerebral development. AB - Postnatal cerebral development is a complicated biological process precisely controlled by multiple genes. To understand the molecular mechanism of cerebral development, we compared dynamics of mouse cerebrum transcriptome through three developmental stages using high-throughput RNA-seq technique. Three libraries were generated from the mouse cerebrum at infancy, adolescence and adulthood, respectively. Consequently, 44,557,729 (infancy), 59,257,530 (adolescence) and 72,729,636 (adulthood) reads were produced, which were assembled into 15,344, 16,048 and 15,775 genes, respectively. We found that the overall gene expression level increased from infancy to adolescence and decreased later on upon reaching adulthood. The adolescence cerebrum has the most active gene expression, with expression of a large number of regulatory genes up-regulated and some crucial pathways activated. Transcription factor (TF) analysis suggested the similar dynamics as expression profiling, especially those TFs functioning in neurogenesis differentiation, oligodendrocyte lineage determination and circadian rhythm regulation. Moreover, our data revealed a drastic increase in myelin basic protein (MBP)-coding gene expression in adolescence and adulthood, suggesting that the brain myelin may be generated since mouse adolescence. In addition, differential gene expression analysis indicated the activation of rhythmic pathway, suggesting the function of rhythmic movement since adolescence; Furthermore, during infancy and adolescence periods, gene expression related to axonrepulsion and attraction showed the opposite trends, indicating that axon repulsion was activated after birth, while axon attraction might be activated at the embryonic stage and declined during the postnatal development. Our results from the present study may shed light on the molecular mechanism underlying the postnatal development of the mammalian cerebrum. PMID- 24953869 TI - Pulse pressure affects the relationship between flow-mediated dilatation and cardiovascular risk. PMID- 24953870 TI - Equine-related treatments for mental disorders lack empirical support: a systematic review of empirical investigations. AB - CONTEXT: Equine-related treatments (ERT) for mental disorders are becoming increasingly popular for a variety of diagnoses; however, they have been subjected only to limited systematic investigation. OBJECTIVE: To examine the quality of and results from peer-reviewed research on ERT for mental disorders and related outcomes. METHOD: Peer-reviewed studies (k = 14) examining treatments for mental disorders or closely related outcomes were identified from databases and article reference sections. RESULTS: All studies were compromised by a substantial number of threats to validity, calling into question the meaning and clinical significance of their findings. Additionally, studies failed to provide consistent evidence that ERT is superior to the mere passage of time in the treatment of any mental disorder. CONCLUSION: The current evidence base does not justify the marketing and utilization of ERT for mental disorders. Such services should not be offered to the public unless and until well-designed studies provide evidence that justify different conclusions. PMID- 24953871 TI - Determination of starch lysophospholipids in rice using liquid chromatography mass spectrometry (LC-MS). AB - Acquiring a complete understanding of rice starch lysophospholipids (LPLs), their biosynthetic pathways and genetic diversity, and the influence of genotype by environment interactions has been hampered by the lack of efficient high throughput extraction and analysis methods. It was hypothesized a single-step aqueous n-propanol extraction combined with liquid chromatography-mass spectrometry (LC-MS) could be employed to analyze starch LPLs in white rice. The investigation found different grinding methods showed little effect on the final LPL detected, and a simple single-step extraction with 75% n-propanol (8 mL/0.15 g) heated at 100 degrees C for 2 h was as effective as an onerous multistep extraction method. A LC-MS method was optimized to simultaneously quantify 10 major LPLs in rice starch within 15 min. This method enables total and individual starch LPL analysis of a large number of rice samples at little cost. This approach could be applied to starch LPLs in other cereals. PMID- 24953872 TI - Hoarding disorder in older adulthood. AB - OBJECTIVE: Hoarding disorder (HD) is a chronic condition associated with moderate to severe impairment in health and functioning. HD has been primarily studied in midlife adults, and there is limited research on HD in late life. METHODS: In this review, we summarize research on the presentation and characteristics of HD and hoarding symptoms in older adults, including evidence for associated impairment in daily functioning, physical health, and cognitive function. Finally, we review the evidence available for intervention outcomes for treating HD in older adults. RESULTS: Geriatric HD is characterized by severe functional impairment, medical and psychiatric comorbidities, and cognitive dysfunction. CONCLUSION: There is a lack of randomized controlled trials investigating evidence-based treatments for geriatric HD. PMID- 24953873 TI - Depression and synaptic zinc regulation in Alzheimer disease, dementia with lewy bodies, and Parkinson disease dementia. AB - OBJECTIVE: Depression is a common symptom in dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and Alzheimer disease (AD), yet its molecular basis remains unclear and current antidepressants do not appear to be effective. Cerebral zinc has been implicated in depression and synaptic dysfunction. We investigated the relationship between synaptic zinc regulation (for which zinc transporter 3 [ZnT3] is responsible) and depression in a large clinicopathologic study. METHODS: We examined brains from people with PDD (N = 29), DLB (N = 27), and AD (N = 15) and comparison subjects without depression or dementia (N = 24). Individuals were categorized according to the presence and severity of depression (on a scale of 0-3) based on standardized assessments during life (principally Neuropsychiatric Inventory). Western blotting was used to determine ZnT3 levels in Brodmann area 9 (BA9), and regression analysis was used to determine the relationship between ZnT3 and depression. RESULTS: Reductions in ZnT3 in BA9 were significantly associated with elevated depression scores in the study cohort (beta = -0.351, df = 93, t = -3.318 p = 0.0004). This association remained when only individuals with DLB, PDD, and no dementia or depression were examined (beta = -0.347, df = 78, t = -3.271, p = 0.002) or only individuals with AD and no dementia or depression were examined (beta = -0.433, df = 37, t = -2.924, p = 0.006). CONCLUSION: Although decreased zinc levels have been implicated in the genesis of depression in animal models and in major depressive disorder in humans, this study provides the first evidence of a role for zinc in depression in people with dementia and highlights zinc metabolism as a therapeutic target. PMID- 24953874 TI - Simultaneously occurring meningioma and contralateral glioblastoma multiforme. PMID- 24953875 TI - Termination of ongoing spike-wave discharges investigated by cortico-thalamic network analyses. AB - PURPOSE: While decades of research were devoted to study generation mechanisms of spontaneous spike and wave discharges (SWD), little attention has been paid to network mechanisms associated with the spontaneous termination of SWD. In the current study coupling-dynamics at the onset and termination of SWD were studied in an extended part of the cortico-thalamo-cortical system of freely moving, genetic absence epileptic WAG/Rij rats. METHODS: Local-field potential recordings of 16 male WAG/Rij rats, equipped with multiple electrodes targeting layer 4 to 6 of the somatosensory-cortex (ctx4, ctx5, ctx6), rostral and caudal reticular thalamic nucleus (rRTN & cRTN), ventral postero medial (VPM), anterior- (ATN) and posterior (Po) thalamic nucleus, were obtained. Six seconds lasting pre-SWD->SWD, SWD->post SWD and control periods were analyzed with time-frequency methods, and between-region interactions were quantified with frequency-resolved Granger Causality (GC) analysis. RESULTS: Most channel pairs showed increases in GC lasting from onset to offset of the SWD. While for most thalamo-thalamic pairs a dominant coupling direction was found during the complete SWD, most cortico thalamic pairs only showed a dominant directional drive (always from cortex to thalamus) during the first 500ms of SWD. Channel pair ctx4-rRTN showed a longer lasting dominant cortical drive, which stopped 1.5sec prior to SWD offset. This early decrease in directional coupling was followed by an increase in directional coupling from cRTN to rRTN 1sec prior to SWD offset. For channel pairs ctx5-Po and ctx6-Po the heightened cortex->thalamus coupling remained until 1.5sec following SWD offset, while the thalamus->cortex coupling for these pairs stopped at SWD offset. CONCLUSION: The high directional coupling from somatosensory cortex to the thalamus at SWD onset is in good agreement with the idea of a cortical epileptic focus that initiates and entrains other brain structures into seizure activity. The decrease of cortex to rRTN coupling as well as the increased coupling from cRTN to rRTN preceding SWD termination demonstrates that SWD termination is a gradual process that involves both cortico-thalamic as well as intrathalamic processes. The rostral RTN seems to be an important resonator for SWD and relevant for maintenance, while the cRTN might inhibit this oscillation. The somatosensory cortex seems to attempt to reinitiate SWD following its offset via its strong coupling to the posterior thalamus. PMID- 24953877 TI - Photophysical and calorimetric investigation on the structural reorganization of poly(A) by phenothiazinium dyes azure A and azure B. AB - Poly(A) has significant relevance to mRNA stability, protein synthesis and cancer biology. The ability of two phenothiazinium dyes azure A (AA) and azure B (AB) to bind single-stranded poly(A) was studied by spectroscopic and calorimetric techniques. Strong binding of the dyes and the higher affinity of AA over AB were ascertained from absorbance and fluorescence experiments. Significant perturbation of the circular dichroism spectrum of poly(A) in the presence of these molecules with formation of induced CD bands in the 300-700 nm region was observed. Strong emission polarization of the bound dyes and strong energy transfer from the adenine base pairs of poly(A) suggested intercalative binding to poly(A). Intercalative binding was confirmed from fluorescence quenching experiments and was predominantly entropy driven as evidenced from isothermal titration calorimetry data. The negative values of heat capacity indicated involvement of hydrophobic forces and enthalpy-entropy compensation suggested noncovalent interactions in the complexation for both the dyes. Poly(A) formed a self-assembled structure on the binding of both the dyes that was more favored under higher salt conditions. New insights in terms of spectroscopic and thermodynamic aspects into the self-structure formation of poly(A) by two new phenothiazinium dyes that may lead to structural and functional damage of mRNA are revealed from these studies. PMID- 24953876 TI - Computational analysis of the effectiveness of blood flushing with saline injection from an intravascular diagnostic catheter. AB - Optical techniques including fluorescence lifetime spectroscopy have demonstrated potential as a tool for study and diagnosis of arterial vessel pathologies. However, their application in the intravascular diagnostic procedures has been hampered by the presence of blood hemoglobin that affects the light delivery to and the collection from the vessel wall. We report a computational fluid dynamics model that allows for the optimization of blood flushing parameters in a manner that minimizes the amount of saline needed to clear the optical field of view and reduces any adverse effects caused by the external saline jet. A 3D turbulence (k - omega) model was employed for Eulerian-Eulerian two-phase flow to simulate the flow inside and around a side-viewing fiber-optic catheter. Current analysis demonstrates the effects of various parameters including infusion and blood flow rates, vessel diameters, and pulsatile nature of blood flow on the flow structure around the catheter tip. The results from this study can be utilized in determining the optimal flushing rate for given vessel diameter, blood flow rate, and maximum wall shear stress that the vessel wall can sustain and subsequently in optimizing the design parameters of optical-based intravascular catheters. PMID- 24953878 TI - The link between noise perception and quality of life in South Australia. AB - Environmental noise is a significant risk factor for a range of short- and long term adverse health outcomes such as annoyance, cognitive development impairment, sleep disturbance, cardiovascular effects, and psychiatric problems. The aim of this study was to gather standardized quality of life (QOL) data hitherto rarely correlated with noise annoyance by source category. To provide an evidence-base for environmental noise policy development, a representative state-based survey was undertaken in South Australia (SA). A total of 3015 face-to-face interviews were conducted, using a questionnaire addressing noise sources, distances to busy roads and standardized measures of perceived annoyance and QOL. Population weighted descriptive survey and regression analysis. The most common sources of noise annoyances were road transport (27.7%, using a Likert scale, aggregating "little" to "extreme" annoyance), neighbors (22.0%), construction noise (10.0%), air conditioner noise (5.8%), rail transport noise (4.7%), and industry (3.9%). Using the QOL instrument, all eight health dimensions were significantly decreased for those reporting high noise annoyance ("very much" to "extreme") in relation to road transport and neighbors compared to those reporting low annoyance ("none" to "moderate") from these sources. Noise annoyance is common in the SA general population, and the evidence for a strong association with QOL reinforces the need for environmental noise management at a population basis. PMID- 24953879 TI - Personal noise dosimeters: accuracy and reliability in varied settings. AB - This study investigated the accuracy, reliability, and characteristics of three brands of personal noise dosimeters (N = 7 units) in both pink noise (PN) environments and natural environments (NEs) through the acquisition of decibel readings, Leq readings and noise doses. Acquisition periods included repeated PN conditions, choir room rehearsals and participant (N = 3) Leq and noise dosages procured during a day in the life of a music student. Among primary results: (a) All dosimeters exhibited very strong positive correlations for PN measurements across all instruments; (b) all dosimeters were within the recommended American National Standard Institute (ANSI) SI.25-1991 standard of +/-2 dB (A) of a reference measurement; and (c) all dosimeters were within the recommended ANSI SI.25-1991 standard of +/-2 dB (A) when compared with each other. Results were discussed in terms of using personal noise dosimeters within hearing conservation and research contexts and recommendations for future research. Personal noise dosimeters were studied within the contexts of PN environments and NEs (choral classroom and the day in the life of collegiate music students). This quantitative study was a non-experimental correlation design. Three brands of personal noise dosimeters (Cirrus doseBadge, Quest Edge Eg5 and Etymotic ER200D) were tested in two environments, a PN setting and a natural setting. There were two conditions within each environment. In the PN environment condition one, each dosimeter was tested individually in comparison with two reference measuring devices (Ivie and Easera) while PN was generated by a Whites Instrument PN Tube. In condition two, the PN procedures were replicated for longer periods while all dosimeters measured the sound levels simultaneously. In the NE condition one, all dosimeters were placed side by side on a music stand and recorded sound levels of choir rehearsals over a 7-h rehearsal period. In NE, condition two noise levels were measured during a day in the life of college music students. Three participants each wore two types of dosimeters for an 8-h period during a normal school day. Descriptive statistical analyzes including means, standard deviation and Pearson product-moment correlation. The primary finding is that the dosimeters in this study recorded results within +/-2 dB of either a reference measurement or within dosimeters in all four conditions examined. All dosimeters studied measured steady noise source accurately and consistently, with strong positive correlations across all instruments. Measurements acquired during choral rehearsals indicated a maximum of 1.5 dB difference across dosimeters. The Etymotic research personal noise dosimeters (ER200D) could provide individuals and schools of music with a relatively inexpensive tool to monitor sound doses. Findings from this study suggest that the three brands of dosimeters tested will provide reliable Leq levels and hearing dosages in both PN and natural settings. PMID- 24953880 TI - Protective effect of unilateral and bilateral ear plugs on noise-induced hearing loss: functional and morphological evaluation in animal model. AB - The aim of the following study is to evaluate immediate protective effect of ear plug from noise morphologically and functionally. An 1-month aged 29 male C57BL/6 mice. Subjects were divided into four groups as normal control(G1), bilaterally plugged group (G2), unilaterally plugged group (G3) and noise control group (G4) and later 3 groups were exposed to 110 sound pressure level white noise for 60 min. Immediately after noise exposure, audiologic tests were performed and cochlear morphology and expression levels of a-synuclein in the cochlea were investigated. There were no functional changes in G2 and plugged ears of G3 after noise exposure, whereas unplugged ears of G3 and G4 showed significant hearing loss. In morphological study, there were a significant degeneration of the organ of Corti and mean number and diameter of efferent buttons, in unplugged ears of G3 and G4. Plugged ears of G3 also showed mild changes in morphological study. Reduction of a-synuclein was observed at the efferent terminals or cochlear extracts after noise exposure. The protective effect of ear plug on noise exposure was proven morphologically and functionally in the animal model of noise induced hearing loss. Further study on cellular or ultrastructural level with ear plug will be needed to reveal more precise mechanism. PMID- 24953881 TI - Urban green spaces' effectiveness as a psychological buffer for the negative health impact of noise pollution: a systematic review. AB - Noise pollution is one of the four major pollutions in the world. Little evidence exists about the actual preventive benefits of psychological noise attenuation by urban green spaces, especially from the perspective of environmental medicine and, to the best of our knowledge, there is not a systematic analysis on this topic. The aim of this review was to systematically evaluate whether there is conclusive scientific evidence for the effectiveness of urban green spaces as a psychological buffer for the negative impact of noise pollution on human health and to promote an evidence-based approach toward this still growing environmental hazard. MEDLINE and EMBASE databases were searched for experimental and epidemiological studies published before June 04, 2013 in English and Spanish. Data was independently extracted in two step process by the authors. Due to the heterogeneity of the included studies qualitative assessment was performed. We found moderate evidence that the presence of vegetation can generally reduce the negative perception of noise (supported with an electroencephalogram test in one of the experimental studies; consistent with the data from two epidemiological studies; one experiment found no effect and one was inconclusive about the positive effect). This review fills a gap in the literature and could help researchers further clarify the proper implementation of urban green spaces as a psychological buffer in areas with population exposed to chronic noise pollution. PMID- 24953883 TI - Assessment of the noise annoyance among subway train conductors in Tehran, Iran. AB - Subway transportation system is a new phenomenon in Iran. Noise annoyance interferes with the individual's task performance, and the required alertness in the driving of subway trains. This is the first study conducted to measure the level of noise and noise annoyance among conductors of subway organization in Tehran, Iran. This cross sectional study was conducted among 167 randomly selected train conductors. Information related to noise annoyance was collected by using a self-administered questionnaire. The dosimetry and sound metering was done for the conductors and inside the cabins. There were 41 sound metering measuring samples inside the conductors' cabin, and there were 12 samples of conductors' noise exposure. The results of sound level meter showed that the mean Leq was 73.0 dBA +/- 8.7 dBA and the dosimetry mean measured Leq was 82.1 dBA +/- 6.8 dBA. 80% of conductors were very annoyed/annoyed by noise in their work place. 53.9% of conductors reported that noise affected their work performance and 63.5% reported that noise causes that they lose their concentration. The noise related to movement of train wheels on rail was reported as the worst by 83.2% followed by the noise of brakes (74.3%) and the ventilation noise (71.9%). 56.9% of conductors reported that they are suffering from sleeplessness, 40.1% from tinnitus and 80.2% feeling fatigue and sleepy. The study results showed the high level of noise and noise annoyance among train conductors and the poor health outcome of their exposure to this level of noise. PMID- 24953882 TI - Understanding noise stress-induced cognitive impairment in healthy adults and its implications for schizophrenia. AB - Noise stress (NS) is detrimental to many aspects of human health and behavior. Understanding the effect of noise stressors on human cognitive function is a growing area of research and is crucial to helping clinical populations, such as those with schizophrenia, which are particularly sensitive to stressors. A review of electronic databases for studies assessing the effect of acute NS on cognitive functions in healthy adults revealed 31 relevant studies. The review revealed (1) NS exerts a clear negative effect on attention, working memory and episodic recall, and (2) personality characteristics, in particular neuroticism, and sleep influence the impact of noise stressors on performance in interaction with task complexity. Previous findings of consistent impairment in NS-relevant cognitive domains, heightened sensitivity to stressors, elevated neuroticism and sleep disturbances in schizophrenia, taken together with the findings of this review, highlight the need for empirical studies to elucidate whether NS, a common aspect of urban environments, exacerbates cognitive deficits and other symptoms in schizophrenia and related clinical populations. PMID- 24953884 TI - Occupational hearing loss of market mill workers in the city of Accra, Ghana. AB - Noise induced hearing loss (NIHL) is an irreversible sensorineural hearing loss associated with exposure to high levels of excessive noise. Prevention measures are not well established in developing countries. This comparative cross sectional study aims to determine the prevalence of hearing loss in both a group of high risk workers and a control group and to assess their knowledge of the effects of noise on hearing health. A total of 101 market mill workers and 103 controls employed within markets in the city of Accra, Ghana, were evaluated using a structured questionnaire and pure tone audiometry. The questionnaire assessed factors including self-reported hearing loss, tinnitus, knowledge on the effects of noise on hearing health and the use of hearing protective devices. Pure tone audiometric testing was conducted for both mill workers and controls. Noise levels at the work premises of the mill workers and controls were measured. Symptoms of hearing loss were reported by 24 (23.76%) and 8 (7.7%) mill workers and controls respectively. Fifty-five (54.5%) and fifty-four (52.37%) mill workers and controls exhibited knowledge of the effects of noise on hearing health. Five (5.0%) mill workers used hearing protective devices. There was significant sensorineural hearing loss and the presence of a 4 kHz audiometric notch among mill workers when compared with controls for the mean thresholds of 2 kHz, 3 kHz and 4 kHz (P = 0. 001). The prevalence of hearing loss in the better hearing ears of the mill workers and controls was 24.8% and 4.8% respectively (P < 0.5). The prevalence of hearing loss, which may be characteristic of NIHL in the better hearing ears of the mill workers and controls was 24.8% and 4.8% respectively. The majority of mill workers did not use hearing protection. PMID- 24953885 TI - Hearing and hearing conservation practices among Australia's professional orchestral musicians. AB - Orchestral musicians are an at-risk population for noise-induced hearing loss. Following strategic approaches to mitigate exposure, many must use earplugs to safeguard their hearing, although reported usage rates are poor. Australia has progressive hearing conservation programs within many of its orchestras, yet little is known of earplug usage rates, abilities with earplugs or self-perceived hearing loss in this population. To help direct and inform future approaches to hearing conservation in Australia's orchestras a questionnaire assessing hearing conservation behaviors and the prevalence of self-perceived hearing loss was distributed. A total of 580 musicians across eight professional orchestras were surveyed, with 367 completed surveys (63%) returned. Eighty percent of respondents reported a risk of hearing damage in the orchestra, 64% used earplugs of some type at least some of the time and 83% found this use difficult/impossible. Forty-three percent reported a hearing loss, including 54% in pit orchestras and 46% of those <=50 years of age. Brass players were least likely to use earplugs, most likely to report usage difficulties and most likely of those <=50 years of age to report a hearing loss. While earplug usage rates in Australia are encouraging and may be linked to hearing conservation measures in the orchestras, the widespread difficulty reported with the use of these earplugs, the prevalence of self-reported hearing loss and the continued vulnerability of those most at-risk indicate improvements in both earplug design and further education for musicians are required to progress hearing conservation options for this population. PMID- 24953886 TI - Partners' empathy increases pain ratings: effects of perceived empathy and attachment style on pain report and display. AB - Pain can be influenced by its social context. We aimed to examine under controlled experimental conditions how empathy from a partner and personal attachment style affect pain report, tolerance, and facial expressions of pain. Fifty-four participants, divided into secure, anxious, and avoidant attachment style groups, underwent a cold pressor task with their partners present. We manipulated how much empathy the participants perceived that their partners had for them. We observed a significant main effect of perceived empathy on pain report, with greater pain reported in the high perceived empathy condition. No such effects were found for pain tolerance or facial display. We also found a significant interaction of empathy with attachment style group, with the avoidant group reporting and displaying less pain than the secure and the anxious groups in the high perceived empathy condition. No such findings were observed in the low empathy condition. These results suggest that empathy from one's partner may influence pain report beyond behavioral reactions. In addition, the amount of pain report and expression that people show in high empathy conditions depends on their attachment style. PERSPECTIVE: Believing that one's partner feels high empathy for one's pain may lead individuals to rate the intensity of pain as higher. Individual differences in attachment style moderate this empathy effect. PMID- 24953887 TI - The economic costs of chronic pain among a cohort of treatment-seeking adolescents in the United States. AB - The aim of this study was to assess the economic cost of chronic pain among adolescents receiving interdisciplinary pain treatment. Information was gathered from 149 adolescents (ages 10-17) presenting for evaluation and treatment at interdisciplinary pain clinics in the United States. Parents completed a validated measure of family economic attributes, the Client Service Receipt Inventory, to report on health service use and productivity losses due to their child's chronic pain retrospectively over 12 months. Health care costs were calculated by multiplying reported utilization estimates by unit visit costs from the 2010 Medical Expenditure Panel Survey. The estimated mean and median costs per participant were $11,787 and $6,770, respectively. Costs were concentrated in a small group of participants; the top 5% of those patients incurring the highest costs accounted for 30% of total costs, whereas the lower 75% of participants accounted for only 34% of costs. Total costs to society for adolescents with moderate to severe chronic pain were extrapolated to $19.5 billion annually in the United States. The cost of adolescent chronic pain presents a substantial economic burden to families and society. Future research should focus on predictors of increased health services use and costs in adolescents with chronic pain. PERSPECTIVE: This cost of illness study comprehensively estimates the economic costs of chronic pain in a cohort of treatment-seeking adolescents. The primary driver of costs was direct medical costs followed by productivity losses. Because of its economic impact, policy makers should invest resources in the prevention, diagnosis, and treatment of chronic pediatric pain. PMID- 24953888 TI - Dietary salt intake and coronary atherosclerosis in patients with prehypertension. AB - High dietary salt intake is known to contribute to hypertension and cardiovascular and cerebrovascular diseases. The authors investigated the association between dietary salt intake and development of hypertension or cardiovascular disease (CVD) in 243 patients with prehypertension. After a median follow-up of 4.53 years (range, 3.1-8.7), 123 (50.6%) patients developed hypertension and 71 (29.2%) experienced cardiovascular events, including fatal and nonfatal myocardial infarctions. Adjusted hazard ratios for patients with a high salt diet (>=6 g/d) were 1.57 (95% confidence interval [CI], 1.17-3.31; P=.018) for hypertension and 1.97 (95% CI, 1.08-2.27; P=.011) for CVD. Multivariable-adjusted analyses of subgroups showed a significant association between salt intake and CVD, but no such association was found in patients younger than 60 years, women, or patients with normal weight or normal cholesterol level. These results provide further research of prevention of hypertension and CVD in prehypertension. PMID- 24953889 TI - Remodeling of cortical and corticocancellous fresh-frozen allogeneic block bone grafts--a radiographic and histomorphometric comparison to autologous bone grafts. AB - OBJECTIVES: To compare cortical (AL-C) and corticocancellous (AL-CC) fresh-frozen block bone allografts to cortical block bone autografts (AT) used for lateral ridge augmentation in terms of radiographic dimensional maintenance and histomorphometrical graft remodeling. MATERIALS AND METHODS: Twenty-four patients, requiring ridge augmentation in the anterior maxilla prior to implant placement, were treated with AT, AL-C or AL-CC bone blocks (eight patients per graft type). Patients were examined with CBCT prior to, 14 days, and 6-8 months after grafting. Amount of augmentation and dimensional block graft maintenance over time was evaluated by comparing planimetric measurements of the alveolar ridge made on CBCT sections of the augmentation area. During implant installation surgery, 6-8 months after grafting, cylindrical biopsies were harvested perpendicularly to the lateral aspect of the augmented alveolar ridge. The relative volumes of vital and necrotic bone and soft tissues were histomorphometrically estimated. Comparisons among groups and observation times were performed using Friedman test followed by Dunn's post-hoc test. RESULTS: Radiographic evaluation showed that the three types of grafts resulted in a significant increase in alveolar ridge width, with no significant differences among the groups in terms of ridge dimensions at the various observation times. However, significant graft resorption (P = 0.03) was observed in the AL-CC group over time (-8.3 +/- 7.1%) compared with the AT and AL-C groups, where a slight increase was observed, on average (1.5 +/- 20.6% and 1.3 +/- 14.9%, respectively). Histomorphometrical analysis showed that larger amounts of vital bone were found in the biopsies from the AT augmented sites (25.1 +/- 11.2%) compared with AL-CC and AL-C augmented sites (9.3 +/- 3.8% and 3.9 +/- 4.6%, respectively; P <= 0.01). AL-CC and AT biopsies had the smallest amount of necrotic bone (38.2 +/- 12.1% and 56.7 +/- 26.0, respectively) compared with AL-C (83.7 +/- 10.8%, P < 0.01) biopsies. AL-CC biopsies showed the largest amount of soft tissues (52.5 +/- 11.7%) compared with those from AT (18.1 +/- 17.1%, P = 0.03) and AL-C (12.3 +/- 8.5%, P < 0.01) sites. CONCLUSIONS: AL block bone graft architecture influences significantly its dimensional incorporation and remodeling. Compared with AT bone graft, a small portion of the AL block consists of vital bone 6-8 months after grafting. Cortical AL blocks seem to show the least amounts of vital bone, while corticocancellous AL blocks seem to undergo more resorption over time. PMID- 24953890 TI - Serum bicarbonate concentrations and kidney disease progression in community living elders: the Health, Aging, and Body Composition (Health ABC) Study. AB - BACKGROUND: In populations with prevalent chronic kidney disease (CKD), lower serum bicarbonate levels are associated with more rapid CKD progression, but whether lower bicarbonate levels also are associated with risk of incident estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) and CKD progression among community-living persons with predominantly preserved kidney function is unknown. STUDY DESIGN: Longitudinal observational cohort study. SETTING & PARTICIPANTS: Well-functioning community-living elders aged 70-79 years at inception. PREDICTOR: Serum bicarbonate level measured at the time of collection by arterialized venous blood sample using an arterial blood gas analyzer. OUTCOMES: Change in eGFR over 7 years, and new eGFR < 60 mL/min/1.73 m(2) with a rate of loss of at least 1 mL/min/1.73 m(2) per year. MEASUREMENTS: Linear and logistic regressions were used to evaluate associations of baseline serum bicarbonate level with change in eGFR and incident eGFR < 60 mL/min/1.73 m(2). RESULTS: At baseline, mean eGFR was 84 +/- 16 (SD)mL/min/1.73 m(2), and serum bicarbonate level was 25.2 +/- 1.9 mmol/L. Compared with participants with higher bicarbonate concentrations (23.0-28.0 mmol/L), those with bicarbonate concentrations < 23 mmol/L (n = 85 [8%]) lost eGFR0.55 (95% CI, 0.13-0.97) mL/min/1.73 m(2) per year faster in models adjusted for demographics, CKD risk factors, baseline eGFR, and urine albumin-creatinine ratio. Among the 989 (92%) participants with baseline eGFRs > 60 mL/min/1.73 m(2), 252 (25%) developed incident eGFRs < 60 mL/min/1.73 m(2) at follow-up. Adjusting for the same covariates, participants with bicarbonate concentrations < 23 mmol/L had nearly 2 fold greater odds of incident eGFRs < 60 mL/min/1.73 m(2) (OR, 1.72; 95% CI, 0.97 3.07) compared with those with higher bicarbonate concentrations. LIMITATIONS: Only 2 measurements of kidney function separated by 7 years and loss to follow-up due to intervening mortality in this elderly population. CONCLUSIONS: Lower serum bicarbonate concentrations are associated independently with decline in eGFR and incident eGFR < 60 mL/min/1.73 m(2) in community-living older persons. If confirmed, serum bicarbonate levels may give insight into kidney tubule health in persons with preserved eGFRs and suggest a possible new target for intervention to prevent CKD development. PMID- 24953892 TI - Bile acid nephropathy in a bodybuilder abusing an anabolic androgenic steroid. AB - Bile acid nephropathy, also known as cholemic nephrosis or nephropathy, is an entity that can be seen in patients with severe cholestatic liver disease. It typically is associated with acute kidney injury (AKI) with various forms of hepatic disease. Most often, patients with severe obstructive jaundice develop this lesion, which is thought to occur due to direct bile acid injury to tubular cells, as well as obstructing bile acid casts. Patients with end-stage liver disease also can develop AKI, in which case a more heterogeneous lesion occurs that includes hepatorenal syndrome and acute tubular injury/necrosis. In this circumstance, acute tubular injury develops from a combination of hemodynamic changes with some contribution from direct bile acid-related tubular toxicity and obstructive bile casts. We present a case of AKI due to bile acid nephropathy in a bodybuilder who developed severe cholestatic liver disease in the setting of anabolic androgenic steroid use. PMID- 24953893 TI - Is VIP1 important for Agrobacterium-mediated transformation? AB - Agrobacterium genetically transforms plants by transferring and integrating T (transferred) DNA into the host genome. This process requires both Agrobacterium and host proteins. VirE2 interacting protein 1 (VIP1), an Arabidopsis bZIP protein, has been suggested to mediate transformation through interaction with and targeting of VirE2 to nuclei. We examined the susceptibility of Arabidopsis vip1 mutant and VIP1 overexpressing plants to transformation by numerous Agrobacterium strains. In no instance could we detect altered transformation susceptibility. We also used confocal microscopy to examine the subcellular localization of Venus-tagged VirE2 or Venus-tagged VIP1, in the presence or absence of the other untagged protein, in different plant cell systems. We found that VIP1-Venus localized in both the cytoplasm and the nucleus of Arabidopsis roots, agroinfiltrated Nicotiana benthamiana leaves, Arabidopsis mesophyll protoplasts and tobacco BY-2 protoplasts, regardless of whether VirE2 was co expressed. VirE2 localized exclusively to the cytoplasm of tobacco and Arabidopsis protoplasts, whether in the absence or presence of VIP1 overexpression. In transgenic Arabidopsis plants and agroinfiltrated N. benthamina leaves we could occasionally detect small aggregates of the Venus signal in nuclei, but these were likely to be imagining artifacts. The vast majority of VirE2 remained in the cytoplasm. We conclude that VIP1 is not important for Agrobacterium-mediated transformation or VirE2 subcellular localization. PMID- 24953894 TI - Small fragment locking plate as provisional internal fixation in severe open both bone forearm fractures. AB - A technique using a locking small fragment plate as a temporary internal external fixator for severe open both-bone forearm fractures is described, along with case examples. PMID- 24953891 TI - Low serum bicarbonate and kidney function decline: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Among populations with established chronic kidney disease (CKD), metabolic acidosis is associated with more rapid progression of kidney disease. The association of serum bicarbonate concentrations with early declines in kidney function is less clear. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 5,810 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with a baseline estimated glomerular filtration rate (eGFR) > 60mL/min/1.73 m(2) using the CKD-EPI (CKD Epidemiology Collaboration) creatinine cystatin C equation. PREDICTORS: Serum bicarbonate concentrations. OUTCOMES: Rapid kidney function decline (eGFR decline > 5% per year) and incident reduced eGFR (eGFR < 60mL/min/1.73 m(2) with minimum rate of eGFR loss of 1 mL/min/1.73 m(2) per year). RESULTS: Average bicarbonate concentration was 23.2 +/- 1.8mEq/L. 1,730 (33%) participants had rapid kidney function decline, and 487 had incident reduced eGFR during follow-up. Each 1-SD lower baseline bicarbonate concentration was associated with 12% higher adjusted odds of rapid kidney function decline (95% CI, 6%-20%) and higher risk of incident reduced eGFR (adjusted incidence rate ratio, 1.11; 95% CI, 1.03-1.20) in models adjusting for demographics, baseline eGFR, albuminuria, and CKD risk factors. The OR for the associations of bicarbonate level < 21 mEq/L relative to 23-24 mEq/L was 1.35 (95% CI, 1.05-1.73) for rapid kidney function decline, and the incidence rate ratio was 1.16 (95% CI, 0.83-1.62) for incident reduced eGFR. LIMITATIONS: Cause of metabolic acidosis cannot be determined in this study. CONCLUSIONS: Lower serum bicarbonate concentrations are associated independently with rapid kidney function decline independent of eGFR or albuminuria in community-living persons with baseline eGFR > 60 mL/min/1.73 m(2). If confirmed, our findings suggest that metabolic acidosis may indicate either early kidney disease that is not captured by eGFR or albuminuria or may have a causal role in the development of eGFR < 60 mL/min/1.73 m(2). PMID- 24953895 TI - Clinical correlates of red blood cell omega-3 fatty acid content in male veterans with peripheral arterial disease. AB - OBJECTIVE: Despite available medical therapies, patients with peripheral arterial disease (PAD) remain at high risk for cardiovascular events. The n-3 polyunsaturated fatty acids (PUFA), derived from marine sources, have been shown to improve cardiovascular mortality. The Omega-3 Index (O3I), a proportion of the n-3 PUFA eicosapentaenoic acid and docosahexaenoic acid in the red blood cell membrane, correlates with cardiovascular risk. Previous investigations have found that n-3 PUFA supplementation, fish consumption, older age, and smoking history affect the O3I in different patient populations, although similar correlations have never been explored in PAD. We hypothesized that in our PAD cohort, blood content of omega-3 fatty acids would directly and positively correlate with a history of fish oil supplementation and older age and inversely correlate with a smoking history and obesity. METHODS: This cross-sectional study included 111 patients who had an ankle-brachial index of <0.9 associated with claudication symptoms. We used linear regression to determine the association between clinical factors and the O3I. RESULTS: The mean age of the cohort was 69 +/- 8 years; 37% had diabetes mellitus (hemoglobin A1c, 7% +/- 1%), and 94% reported current smoking or a history of smoking. The mean O3I was 5% +/- 2%. In multivariate linear regression analysis, the O3I was associated with older age, increasing body mass index, and a history of smoking and fish oil intake. CONCLUSIONS: This is the first report of the relation between blood content of omega-3 fatty acids and clinical factors in a PAD population. In patients with PAD, older age, elevated body mass index, and prior fish oil supplementation predicted a higher O3I. A history of smoking correlated with a lower O3I. These results demonstrate that the O3I is a reliable measure of dietary n-3 PUFA intake and that clinical factors related to the O3I in PAD are similar to those observed in other populations. PMID- 24953896 TI - Time and flow-dependent changes in the p27(kip1) gene network drive maladaptive vascular remodeling. AB - OBJECTIVE: Although clinical studies have identified that a single nucleotide polymorphism in the p27(kip1) gene is associated with success or failure after vein bypass grafting, the underlying mechanisms for this difference are not well defined. Using a high-throughput approach in a flow-dependent vein graft model, we explored the differences in p27(kip1)-related genes that drive the enhanced hyperplastic response under low-flow conditions. METHODS: Bilateral rabbit carotid artery interposition grafts with jugular vein were placed with a unilateral distal outflow branch ligation to create differential flow states. Grafts were harvested at 2 hours and at 1, 3, 7, 14, and 28 days after implantation, measured for neointimal area, and assayed for cell proliferation. Whole-vessel messenger RNA was isolated and analyzed using an Affymetrix (Santa Clara, Calif) gene array platform. Ingenuity Pathway Analysis (Ingenuity, Redwood City, Calif) was used to identify the gene networks surrounding p27(kip1). This gene set was then analyzed for temporal expression changes after graft placement and for differential expression in the alternate flow conditions. RESULTS: Outflow branch ligation resulted in an eightfold difference in mean flow rates throughout the 28-day perfusion period (P < .001). Flow reduction led to a robust hyperplastic response, resulting in a significant increase in intimal area by 7 days (0.13 +/- 0.04 mm(2) vs 0.014 +/- 0.006 mm(2); P < .005) and progressive growth to 28 days (1.37 +/- 0.05 mm(2) vs 0.39 +/- 0.06 mm(2); P < .001). At 7 days, low-flow grafts demonstrated a burst of actively dividing intimal cells (36.4 +/- 9.4 cells/mm(2) vs 11.5 +/- 1.9 cells/mm(2); P = .04). Sixty-five unique genes within the microarray were identified as components of the p27(kip1) network. At a false discovery rate of 0.05, 26 genes demonstrated significant temporal changes, and two dominant patterns of expression were identified. Class comparison analysis identified differential expression of 11 genes at 2 hours and seven genes and 14 days between the high-flow and low-flow grafts (P < .05). At 2 hours, oncostatin M and cadherin 1 were the most differentially expressed. Cadherin 1 and protein kinase B exhibited the greatest differential expression at 14 days. CONCLUSIONS: Alterations in flow and shear stress result in divergent patterns of vein graft remodeling. Associated with the dramatic increase in neointimal expansion observed in low-flow vs high-flow grafts is a subset of differentially expressed p27(kip1)-associated genes that correlate with critical stages in the adaptive response. These represent potential biologic targets whose activity may be altered to augment maladaptive vascular remodeling. PMID- 24953897 TI - Race and gender affect outcomes of lower extremity bypass. AB - BACKGROUND: Race and gender have individually been associated with affecting outcomes in vascular interventions. We hypothesized that race and gender stratification would identify variations in outcomes of lower extremity bypass (LEB) procedures. METHODS: LEB procedures were identified using Current Procedural Terminology (American Medical Association, Chicago, Ill) codes from the 2011 American College of Surgeons National Surgical Quality Improvement Program database. Individuals of races other than black or white were excluded because of small sample size. Preoperative variables, such as age, demographics, medical comorbidities, and laboratory values, were evaluated across race and gender groups using chi(2), the Student t-test, and least square means testing. Significant predictors were entered into a multivariate logistic regression model. Six primary outcomes were evaluated: major complications, minor complications, 30-day mortality, early graft failure, readmission, and length of stay (LOS). RESULTS: There were 4518 LEB procedures performed on black (n = 839; male [BM], 56.5%; female [BF], 43.5%) or white (n = 3679; male [WM], 66.4%; female [WF], 33.6%) patients. Black patients were more likely to be younger, diabetic, smokers, functionally dependent, dialysis dependent, and have hypertension, critical limb ischemia, higher creatinine, lower hematocrits, and higher platelet counts. Multivariate analysis revealed no statistically significant gender differences within the white cohort with respect to complications, death, graft failure, or readmission rates. WF and BM had longer LOS than WM (reference group; 4.7 +/- 1.9 days and 5.4 +/- 2.0 days vs 4.3 +/- 2.0 days, respectively; P < .006 and P < .0001) after LEB procedures, but outcomes among these groups did not differ significantly. BF had a longer LOS than WM (5.8 +/- 2.0 days vs 4.3 +/- 2.0 days; P < .0001) and trended toward higher readmission rates (odds ratio, 1.28; 95% confidence interval, 0.97-1.70; P = .08). BF had a higher risk of early graft failure than WM (odds ratio, 2.90; 95% confidence interval, 1.52-5.49; P = .001). CONCLUSIONS: BF had higher early graft failure and LOS compared with WM. WF and BM also had increased LOS compared with WM. Race-gender stratification may predict outcomes in patients undergoing LEB procedures that may not be predicted by gender or race alone. Further studies using this stratification methodology may provide better insight into optimal therapeutic strategies and preventative measures for these patient subgroups. Investigation into causes of increased LOS in black patients and increased graft failure in BF may help improve outcomes. PMID- 24953898 TI - Factors associated with surgical site infection after lower extremity bypass in the Society for Vascular Surgery (SVS) Vascular Quality Initiative (VQI). AB - BACKGROUND: Surgical site infection (SSI) is a major source of morbidity after infrainguinal lower extremity bypass (LEB). This study examines processes of care associated with in-hospital SSI after LEB and identifies factors that could potentially be modified to improve outcomes. METHODS: The Society for Vascular Surgery (SVS) Vascular Quality Initiative (VQI) registry (2003 to 2012) was queried to identify in-hospital SSI after 7908 consecutive LEB procedures performed by 365 surgeons at 91 academic and community hospitals in 45 states. Variables associated with SSI were identified using multivariable logistic regression and hierarchical clustering. Expected and observed SSI rates were calculated for each hospital. RESULTS: The overall in-hospital SSI rate after LEB was 4.8%. Univariate analysis showed that obesity, dialysis, tissue loss, preoperative ankle-brachial index <0.35, distal target, vein graft conduit, continuous incision for vein harvest, transfusion >2 units of packed red blood cells, procedure time >220 minutes, and estimated blood loss >100 mL were associated with higher SSI rates, whereas chlorhexidine (compared with iodine) skin preparation was protective. Multivariable analysis showed independent predictors of SSI included ankle-brachial index <0.35 (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.03-2.30, P < .04), transfusion >2 units (OR, 3.30; 95% CI, 2.17-5.02; P < .001), and procedure time >220 minutes (OR, 2.11; 95% CI, 1.05-4.23; P < .04). Chlorhexidine was protective against SSI (OR, 0.53; 95% CI, 0.35-0.79; P = .002). Stratified analyses based on the presence of tissue loss yielded similar results. Across VQI hospitals, observed SSI rates ranged from 0% to 30%, whereas expected SSI rates adjusted by the four independent predictors ranged from 0% to 7.2%. CONCLUSIONS: In-hospital SSI after LEB varies substantially across VQI hospitals. Three modifiable processes of care (transfusion rate, procedure time, and type of skin preparation) were identified and may be used by hospitals to reduce SSI rates. This study demonstrates the value of the SVS VQI detailed shared clinical registry to identify improvement opportunities directly pertinent to providers that are not available in typical administrative data sets. PMID- 24953899 TI - Outcomes of carotid endarterectomy versus stenting in comparable medical risk patients. AB - OBJECTIVE: In medically high-risk patients the choice between carotid artery stenting (CAS) and carotid endarterectomy (CEA) can be difficult. The purpose of this study was to compare risk-stratified outcomes of CAS and CEA. METHODS: Patients who underwent isolated primary CEA (n = 11,336) or primary CAS (n = 544) at 29 centers in the Vascular Study Group of New England were analyzed (2003 2013); patients with previous ipsilateral CEA or CAS, or concomitant coronary artery bypass graft were excluded. A medical risk score based on predicted 5-year mortality was developed for each patient using a Cox proportional hazards model. Patients in the highest risk score quartile were termed high-risk (vs normal-risk for the other three quartiles). Medically high-risk patients had a 5-year survival of 65% and comprised 23% of CEA and 25% of CAS patients. Risk-stratified outcomes were compared within neurologically symptomatic and asymptomatic patients. RESULTS: Among asymptomatic patients, rates of in-hospital stroke and/or death were not different between CAS and CEA in normal and high-risk cohorts, ranging from 0.7% in normal-risk CEA patients to 1.6% in high-risk CAS patients. In symptomatic patients, significantly worse outcomes were seen with CAS compared with CEA in normal-risk and high-risk patients. Normal-risk symptomatic patients had a stroke or death rate of 1.3% with CEA, but 5.2% with CAS (P < .01). In high-risk symptomatic patients, the stroke or death rate was 1.5% with CEA and 9.3% with CAS (P < .01). No significant differences were seen between asymptomatic CEA and CAS within risk strata across secondary outcome measures of stroke, death, or myocardial infarction, and ipsilateral stroke, major stroke, or death. However, symptomatic high-risk CAS patients had significantly greater rates of all secondary outcomes compared with CEA except death, and symptomatic normal-risk CAS patients had only significantly greater rates of death and stroke, death, or myocardial infarction. CONCLUSIONS: In the Vascular Study Group of New England, asymptomatic normal- and high-risk patients do equally well after CEA or CAS. However, normal- and high-risk symptomatic patients have substantially worse outcomes with CAS compared with CEA. High medical risk alone might be an insufficient indication for CAS in symptomatic patients. PMID- 24953900 TI - Volume of new-onset thrombus is associated with the development of postimplantation syndrome after endovascular aneurysm repair. AB - OBJECTIVE: The objective of this study was to evaluate the impact of contrast medium volume, inferior mesenteric artery (IMA) patency, and pre-existing as well as new-onset thrombus on the inflammatory response after elective endovascular aneurysm repair (EVAR). METHODS: The study included 87 patients undergoing elective endovascular repair of asymptomatic infrarenal aneurysms between January 2011 and November 2011. The patency of the IMA was determined by preoperative computed tomography angiography; the volume of the contrast medium used during the procedure was measured, and the volumes of chronic mural as well as new-onset thrombus were calculated from the preoperative and postoperative computed tomography angiograms with dedicated imaging software. The results were correlated to the occurrence of postimplantation syndrome (PIS) as well as to the main clinical and laboratory components of PIS: fever; increased white blood cell (WBC) count and C-reactive protein (CRP) level; decreased platelet count; and increased interleukin (IL)-6, IL-8, and IL-10 levels. RESULTS: Postoperatively, a statistically significant increase was recorded in the mean values of body temperature, WBCs, CRP, IL-6, IL-8, and IL-10, and a statistically significant decrease was recorded in the number of platelets. After adjustment for endograft type, the volume of new-onset thrombus was found to be significantly correlated with the peak postoperative temperature (beta = .307; P < .05) and the increase in WBC count (beta = .271; P < .05), CRP level (beta = .484; P < .001), and IL-6 level (beta = .288; P < .05). On the contrary, the volume of chronic mural thrombus, the patency of the IMA, and the volume of contrast medium were not found to significantly affect any parameter of the PIS. PIS occurred in 34 patients (39%). Multiple logistic regression analysis showed that both the volume of new-onset thrombus and the type of endograft were independently associated with the development of PIS. CONCLUSIONS: The volume of new-onset thrombus is associated with the development of PIS after EVAR, whereas chronic mural thrombus appears to be an inert material. IMA patency and contrast medium volume are irrelevant to the inflammatory response after EVAR. PMID- 24953901 TI - Discussion. PMID- 24953903 TI - Do young people with comorbid mental and alcohol disorders experience worse behavioural problems? AB - This article examines whether young individuals in the general population with comorbid alcohol use and mental health disorders experience worse internalizing and externalizing behaviour problems than those with single disorders. A large cohort of women at the Mater Misericordiae Hospital in Brisbane, Australia, was enroled during pregnancy in a longitudinal study. Mother/offspring dyads were followed over 21 years. At age 21, offspring behaviour problems were examined using the Young Adult Self Report, alcohol and mental health disorders with the Composite International Diagnostic Interview. Associations between comorbidity and behaviour problems were assessed using multinomial logistic regression, accounting for life-course factors. Twelve per cent of young adults had alcohol/mental health DSM-IV disorders with significant temporal overlap. A further 16% had alcohol disorders only and 23% mental health disorders only. The comorbid group scored significantly higher on total and externalizing behaviour problems but not internalizing behaviour problems. Stronger associations of aggression/delinquency with comorbidity were not fully accounted for by factors known to influence separate development of mental health and alcohol disorders. Young adults with comorbid alcohol/mental health disorders experience more, and more severe, behavioural problems than those with single disorder types, indicating an increased burden from comorbidity, with implications for treatment and public order. PMID- 24953904 TI - Inhibition mechanism of hydroxypropyl methylcellulose acetate succinate on drug crystallization in gastrointestinal fluid and drug permeability from a supersaturated solution. AB - The effects of drug-crystallization inhibitor in bile acid/lipid micelles solution on drug permeation was evaluated during the drug crystallization process. Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was used as a drug-crystallization inhibitor, which efficiently suppressed dexamethasone (DEX) crystallization in a gastrointestinal fluid model containing sodium taurocholate (NaTC) and egg-phosphatidylcholine (egg-PC). Changes of molecular state of supersaturated DEX during the DEX crystallization process was monitored in real time using proton nuclear magnetic resonance (1H NMR). It revealed that DEX distribution to bulk water and micellar phases formed by NaTC and egg-PC was not changed during the DEX crystallization process even in the presence of HPMC-AS. DEX permeation during DEX crystallization was evaluated using dissolution/permeability system. The combination of crystallization inhibition by HPMC-AS and micellar encapsulation by NaTC and egg-PC led to considerably higher DEX concentrations and improvement of DEX permeation at the beginning of the DEX crystallization process. Crystallization inhibition by HPMC-AS can efficiently work even in the micellar solution, where NaTC/egg-PC micelles encapsulates some DEX. It was concluded that a crystallization inhibitor contributed to improvement of permeation of a poorly water-soluble drug in gastrointestinal fluid. PMID- 24953902 TI - Cold hypersensitivity increases with age in mice with sickle cell disease. AB - Sickle cell disease (SCD) is associated with acute vaso-occlusive crises that trigger painful episodes and frequently involves ongoing, chronic pain. In addition, both humans and mice with SCD experience heightened cold sensitivity. However, studies have not addressed the mechanism(s) underlying the cold sensitization or its progression with age. Here we measured thermotaxis behavior in young and aged mice with severe SCD. Sickle mice had a marked increase in cold sensitivity measured by a cold preference test. Furthermore, cold hypersensitivity worsened with advanced age. We assessed whether enhanced peripheral input contributes to the chronic cold pain behavior by recording from C fibers, many of which are cold sensitive, in skin-nerve preparations. We observed that C fibers from sickle mice displayed a shift to warmer (more sensitive) cold detection thresholds. To address mechanisms underlying the cold sensitization in primary afferent neurons, we quantified mRNA expression levels for ion channels thought to be involved in cold detection. These included the transient receptor potential melastatin 8 (Trpm8) and transient receptor potential ankyrin 1 (Trpa1) channels, as well as the 2-pore domain potassium channels, TREK-1 (Kcnk2), TREK-2 (Kcnk10), and TRAAK (Kcnk4). Surprisingly, transcript expression levels of all of these channels were comparable between sickle and control mice. We further examined transcript expression of 83 additional pain-related genes, and found increased mRNA levels for endothelin 1 and tachykinin receptor 1. These factors may contribute to hypersensitivity in sickle mice at both the afferent and behavioral levels. PMID- 24953905 TI - Green strategy from waste to value-added-chemical production: efficient biosynthesis of 6-hydroxy-3-succinoyl-pyridine by an engineered biocatalyst. AB - Value-added intermediates produced by microorganisms during the catabolism of N heterocycles are potential building blocks for agrochemical synthesis and pharmaceutical production. 6-Hydroxy-3-succinoyl-pyridine (HSP), an intermediate in nicotine degradation, is an important precursor for the synthesis of drugs and compounds with biological activities. In the present study, we show that an engineered biocatalyst, Pseudomonas putida P-HSP, efficiently produced HSP from the renewable raw material of tobacco-waste that contains a high concentration of nicotine. The genetically constructed strain P-HSP realized a high accumulation of HSP, and HSP production was 3.7-fold higher than the non-engineered strain S16. Under optimal conditions, HSP was produced at high concentrations of 6.8 g l(-1) and 16.3 g l(-1) from tobacco-waste and nicotine, respectively. This work demonstrates a green strategy to block the catabolic pathway of N-heterocycles, which is a promising approach for the mutasynthesis of valuable compounds. PMID- 24953906 TI - Vanilloid-like agents inhibit aggregation of human platelets. AB - INTRODUCTION: Plant-derived and endogenous vanilloid-like agents exert their effects on cells through transient receptor potential vanilloid-1 (TRPV1). Little is known about the effects of these agents on platelet aggregation. We investigated the effect of various vanilloid-like agents on in-vitro platelet aggregation and tested whether this action is mediated through TRPV1. Understanding the mechanism of action of these compounds in platelets is important in that these compounds may be developed as novel anti-platelet agents. MATERIALS AND METHODS: The effects of plant-derived (capsaicin; dihydrocapsaicin, DHC) and endogenous vanilloid-like agents (N-oleoyldopamine, OLDA; N-arachidonoyl dopamine, NADA) on platelet aggregation were investigated using ADP (5, 10MUM), collagen (4, 8MUg/mL) and arachidonic acid (AA, 300, 400MUg/mL) as agonists. The direct effects of these agents on platelet viability were also determined using an LDH release assay. RESULTS: Capsaicin, OLDA and NADA inhibited ADP-induced platelet aggregation in a concentration-dependent manner. OLDA and NADA, but not capsaicin and DHC, inhibited collagen-induced aggregation, whereas AA-induced aggregation was inhibited by capsaicin, DHC and NADA, but not OLDA. Inhibition of aggregation was not due to direct toxicity of these agents towards platelets. The TRPV1 antagonist, SB-452533, did not affect inhibition of ADP-induced platelet aggregation by capsaicin and OLDA. CONCLUSIONS: These results demonstrate that the endovanilloids, OLDA and NADA, and plant-derived vanilloid, capsaicin, inhibit ADP-induced platelet aggregation. Collagen-induced aggregation was inhibited only by endovanilloids, whereas AA-induced aggregation was inhibited by capsaicin, DHC and NADA. This inhibition was not due to direct toxic effects of these agents, nor was inhibition of ADP-induced aggregation TRPV1 mediated. PMID- 24953908 TI - Vascular surgery in Pakistan: critical issues. PMID- 24953907 TI - Feasibility of event-related potential methodology to evaluate changes in cortical processing after rehabilitation in children with cerebral palsy: a pilot study. AB - This study examined the feasibility of using event-related potentials (ERPs) to measure changes in cortical processing following an established rehabilitative intervention (constraint-induced movement therapy, CIMT) for children with cerebral palsy (CP). Sixteen participants with a diagnosis of hemiparetic CP, with a median age of 6 years, were assessed pre and immediately post CIMT and at 6-month follow-up, using a picture-word match/mismatch discrimination task and standard neurobehavioral measures. Intervention effects were evident in improved performance on behavioral tests of sensory and motor function and the increased mean ERP amplitude of the N400 match/mismatch response on the side ipsilateral to the lesion. These effects were maintained 6 months after the intervention. No such changes were observed on the side contralateral to the lesion. This research suggests that ERPs can measure rehabilitation-induced changes in neural function in children with CP. PMID- 24953909 TI - Postoperative sensitivity of self etch versus total etch adhesive. AB - OBJECTIVE: To compare postoperative sensitivity following composite restoration placed in supra gingival class-V cavities using self etch adhesive and total etch adhesive. STUDY DESIGN: A randomized clinical trial. PLACE AND DURATION OF STUDY: Operative Dentistry Department of Armed Forces Institute of Dentistry, Rawalpindi, from July to December 2009. METHODOLOGY: A total of 70 patients having class-V supra gingival carious lesions were divided into two groups. Classes-V cavities not exceeding 3 mm were prepared. One treatment group was treated with self etch adhesive (adhe SE one Ivoclar) and the control group was treated with total-etch adhesive (Eco-Etch Ivoclar) after acid etching with 37% phosphoric acid. Light cured composite (Te-Econom Ivoclar) restoration was placed for both groups and evaluated for postoperative sensitivity immediately after restoration, after 24 hours and after one week. Data was recorded on visual analogue scale. RESULTS: Comparison of sensitivity between the two treatment groups on application cold stimulus after 24 hours of restoration showed significant difference; however, no statistically significant difference was observed at baseline, immediately after restoration and at 1 week follow-up with cold stimulus or compressed air application. CONCLUSION: Less postoperative sensitivity was observed at postoperative 24 hours assessment in restoration placed using SE adhesives compared to TE adhesives. Thus, the use of SE adhesives may be helpful in reducing postoperative sensitivity during 24 hours after restoration placement. PMID- 24953910 TI - Relationship of high sensitivity C-reactive protein with cardiac biomarkers in patients presenting with acute coronary syndrome. AB - OBJECTIVE: To determine high sensitivity C-reactive protein (hsCRP) levels in patients with acute myocardial infarction (AMI) and its correlation with classical enzyme markers of myocardial damage. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Emergency Medicine at King Khalid University Hospital, King Saud University, Riyadh and Department of Physiology, from August 2010 to December 2011. METHODOLOGY: Consecutive eligible patients with either ST elevation myocardial infarction (STEMI) or non-ST elevation myocardial infarction (NSTEMI) who were admitted to the Emergency Department of King Khalid University Hospital were recruited. A total of 71 subjects were finally selected for the study. The hsCRP, Troponin I (Trop I), creatine kinase myocardial bound (CK-MB), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) concentrations of all patients with an acute myocardial infarction (AMI) were measured. RESULTS: Among all patients 34 (47.9%) patients had diabetes mellitus, 21 (29.6%) were hypertensive, and 16 (22.5%) had no associated illness. Patients with STEMI had significantly higher levels of CKMB (p=0.0348), LDH (p=0.0471) and hsCRP (p=0.0231) compared to NSTEMI patients. While the differences were non-significant for Trop I (p=0.7022), AST (p=0.9729) and Lp(a) (p=0.5985). Spearman's correlations revealed that CRP correlated significantly with Trop I, CK-MB and LDH. There was a significant predictive relationship of hsCRP with Trop I, LDH and CK-MB while with AST it was nonsignificant. CONCLUSION: High sensitivity CRP levels is a significant predictor of standard markers for myocardial damage and it may be a useful prognostic marker in acute coronary syndromes. PMID- 24953911 TI - Effect of hepatitis B vaccination in patients with chronic hepatitis C. AB - OBJECTIVE: To assess the effects of hepatitis B vaccination on the antibody titer in patients with chronic hepatitis C and to compare it with response in normal healthy subjects. STUDY DESIGN: Interventional study. PLACE AND DURATION OF STUDY: Shifa International Hospital, Islamabad, Pakistan, from January 2007 to January 2012. METHODOLOGY: Hepatitis vaccination (Heberbiovac-HB 20) was given intramuscularly to the patients of chronic hepatitis C (HCV group) and normal healthy subjects (control group) at 0, 1 and 6 months intervals. Anti-HBs titer was determined after second and third injection to assess the antibody response. RESULTS: There were 46 patients in the HCV group and 45 patients in the control group. Mean age was 40.9 +/- 9.8 years in the HCV group and 33.18 +/- 8.35 years in the control group. Weight was 67.04 +/- 13.5 kg in the HCV group and 71.78 +/- 14.63 kg in the control group. Height was 162.45 +/- 9.06 cm in the HCV group and 167.03 +/- 7.83 cm in the control group. Anti-HBs antibody levels after the second injection were 253.89 +/- 76.76 mlU/mL in the HCV group and 245.81 +/- 72.65 mlU/mL in the control group (p=0.172). After third injection, the antibody levels were slightly higher in both groups. CONCLUSION: In patients with chronic hepatitis C and normal healthy subjects, Heberbiovac HB in standard dosage gave sero-protective levels in both groups and antibody titers were not significantly different in control and HCV group. PMID- 24953912 TI - Age-related frequency of triple negative breast cancer in women. AB - OBJECTIVE: To determine frequency of triple negative breast cancer (TNBC) in Pakistani women with respect to age. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Armed Forces Institute of Pathology (AFIP), Rawalpindi, from July 2005 to July 2010. METHODOLOGY: Pathological records of all specimens of breast cancer were reviewed and data was obtained for estrogen receptor (ER), progesterone receptor (PR) and HER-2 neu receptor proteins. Specimens having complete record of all three proteins were included for analysis. TNBC was defined as those who were ER, PR and HER-2 neu negative. Overall frequency as well as frequency with respect to age was calculated. Descriptive and categorical variables were analyzed using SPSS version 17. RESULTS: Eight hundred and fifteen patients out of 4715 (17.28%) were found to be TNBC. Mean age of diagnosis of TNBC was found to be 46.26 +/- 12.22 years of age while other breast cancers had a mean age 52.90 +/- 9.78 years (p < 0.001). In the TNBC group, 537 patients (65.88%) were aged < 50 years while 278 patients (34.11%) were aged > 50 years while majority of patients with other breast cancers were elderly females (p < 0.001). CONCLUSION: TNBC comprised 17.28% of the breast cancers in Pakistani women diagnosed at the studied centre. A higher frequency of TNBC was noted in significantly younger patients. PMID- 24953913 TI - The impact of pterygium excision on corneal astigmatism. AB - OBJECTIVE: To compare the corneal astigmatism before and after the excision of pterygium and also to determine the correlation of pterygium size with the postoperative corneal astigmatism. STUDY DESIGN: Cross-sectional interventional study. PLACE AND DURATION OF STUDY: Eye Department, Combined Military Hospital, Abbottabad, from May 2011 to March 2012. METHODOLOGY: Thirty patients underwent pterygium excision. Pre-operatively Snellen visual acuity, manifest refraction and slit lamp examination was done. The size of the pterygium was recorded in mm by projecting a horizontal slit lamp beam from the limbus to the apex. All the pterygium were equal to or greater than 2.5 mm. Keratometry was performed with an automated keratometer. Keratometric data was recorded pre-operatively and at 28 days postoperatively. Wilcoxon signed rank test was used for comparing the pre operative and the postoperative corneal astigmatism. Spearman's rank order was calculated to observe correlation of pterygium size with the postoperative astigmatism. RESULTS: The median (mean rank) pre-operative astigmatism of 2.25 (15.50) reduced to a median (mean rank) postoperative astigmatism of 1.30 (14.96). This decrease in the postoperative astigmatism was statistically significant (p < 0.001). There was a statistically non-significant correlation between the postoperative astigmatism and the pterygium size (rs = -0.29, p = 0.12). CONCLUSION: Pterygium excision caused significant reduction in corneal astigmatism. PMID- 24953914 TI - Effectiveness of nebulized N-acetylcysteine solution in children with acute bronchiolitis. AB - OBJECTIVE: To evaluate the effectiveness of nebulized mucolytic therapy (N acetylcysteine) in treatment of children with acute bronchiolitis. STUDY DESIGN: Prospective randomized, controlled study. PLACE AND DURATION OF STUDY: Paediatric Medical Unit of the Children's Hospital and the Institute of Child Health, Lahore, from November 2011 to April 2012. METHODOLOGY: All the patients aged 2 months to 24 months, with the diagnosis of acute viral bronchiolitis were enrolled in the study. A predesigned proforma was completed after taking parental consent. All eligible patients were randomly assigned to one of the two groups: group-1 received N-acetylcysteine in nebulized form, and group-2 received salbutamol as a nebulized aerosol. Both groups were then compared regarding their clinical improvement and duration of stay in the hospital. The data obtained was analyzed on the statistical software SPSS version 16. Descriptive statistics were obtained by frequencies and percentages. Chi-square test was applied to find p value. RESULTS: A total of 100 patients met the inclusion criteria. The mean age was 3 months. On the first day of treatment, the mean clinical severity score at baseline were 5.38 +/- 2.62 in group-1 and 4.68 +/- 2.2 in group-2. At day 3 and 5, it was 2.9 +/- 1.48 and 3.30 +/- 1.77 in group-1 and 0.88 +/- 1.08 and 1.90 +/ 1.32 in group-2 respectively. The clinical severity score after N-acetylcysteine inhalation therapy was better in group-1 on the third but more so on fifth day after hospital admission. The mean duration of hospitalization was 4.67 +/- 2.2 days for the whole population and it differed between the 2 groups: 4.36 +/- 1.66 days in group-1 versus 4.98 +/- 2.6 days in group-2. CONCLUSION: On the basis of improvement in clinical severity score and early discharge from the hospital, N acetylcysteine was found to be an effective therapy in acute bronchiolitis. PMID- 24953916 TI - Comparison of bupivacaine moistened dressing and conventional dressing for pain relief on skin graft donor sites. AB - OBJECTIVE: To compare the effectiveness of bupivacaine moistened dressing and conventional dressing in patients requiring split thickness skin graft for reconstruction of various defects. STUDY DESIGN: Randomized controlled trial. PLACE AND DURATION OF STUDY: Department of Plastic Surgery and Burns Unit, Mayo Hospital, King Edward Medical University, Lahore, from January 2011 to January 2013. METHODOLOGY: One hundred and fifty patients requiring split thickness skin grafting for various soft tissue defects were divided into two groups A and B, with 75 patients in each group. In Group A, skin graft donor site dressing was kept moist with 12 mL/100 cm2 of 0.25% bupivacaine solution and in Group B, dressing was moistened with same amount of normal saline. Outcome was measured by calculating rescue analgesia requirements in the two groups after 24 hours. Significance was determined by comparing analgesia sparing effect of each dressing using chi-square test. RESULTS: In Group A, 5 out of 75 (6.7%) patients required rescue analgesia. In Group B, 72 out of 75 (96%) patients required rescue analgesia (p < 0.0001). There was 93.3% effectiveness of bupivacaine soaked dressing while only 4% effectiveness of conventional dressing. CONCLUSION: Bupivacaine soaked dressing is much more effective in pain relief and in reducing the requirement of rescue analgesia, in early postoperative period, at split thickness skin graft donor site compared to the conventional dressing. PMID- 24953915 TI - The outcome of microvascular free flap surgery with or without the use of postoperative heparin. AB - OBJECTIVE: To determine the outcome of microvascular free tissue transfer with or without use of postoperative heparin in terms of flap viability and postoperative complications. STUDY DESIGN: Quasi-experimental study. PLACE AND DURATION OF STUDY: Department of Plastic Surgery, King Edward Medical University, Lahore, from July 2010 to July 2012. METHODOLOGY: Thirty eight patients requiring elective or emergency microvascular free tissue transfer were selected. Those with poly-trauma, previous failed free flap and re-anastomosis of vessels were excluded from the study. All anastomoses were performed by trained microvascular surgeons. Per operatively, Aucland test was performed to ensure anastomotic patency. Thereafter, patients were divided into two groups: in group A, heparin was not given postoperatively and in group B, heparin was given postoperatively. The flaps were monitored for signs of vascular compromise, viability or non viability and complications of the procedure. Chi-square test was used to compare the distribution of qualitative variable in two groups. P-value less than 0.05 was considered significant. RESULTS: In group A, the number of viable flaps was 13 (81%) and non-viable flaps were 3 (19%). In group B the number of viable flaps was 11 (73%) and non-viable flaps were 04 (23%) [p = 0.68]. There was no significant difference regarding postoperative complications between the two groups (p > 0.05). CONCLUSION: Postoperative heparin does not appear to have an influence on the viability or complications of free flaps. PMID- 24953917 TI - Sputum neutrophilia in severe persistent asthmatics. AB - OBJECTIVE: To determine the frequency of sputum neutrophilia in patients with severe persistent bronchial asthma. STUDY DESIGN: A cross-sectional study. PLACE AND DURATION OF STUDY: Department of Medicine, Military Hospital, Rawalpindi, from November 2009 to November 2010. METHODOLOGY: Cases of severe persistent bronchial asthma, aged between 12 and 40 years, were included. Sputum samples were collected by induction with hypertonic saline (4.5%). All samples were centrifuged and differential neutrophil count was calculated. Data was analyzed using SPSS 11. RESULTS: Out of 195 patients, there were 129 (66.2%) males and 66 (33.8%) females. The mean age was 27.01 +/- 6.92 years. Mean sputum neutrophilic count was 126.47 +/- 16.52 x 106/ml and the mean neutrophilic percentage was 63.187 +/- 8.3363. Sputum neutrophilia was present in 84 patients (43.1%), out of whom, 56 were males and 28 females. In patients with sputum neutrophilia, mean neutrophilic count was 142.40 +/- 8.49 x 106/ml and the mean neutrophilic percentage was 71.2024 +/- 4.2441%. CONCLUSION: Sputum neutrophilia is a frequent finding in cases with severe persistent bronchial asthma. Presence of sputum neutrophilia in such cases can lessen the inappropriate use of corticosteroids with their associated long-term side effects. PMID- 24953918 TI - Fibromyalgia complicating disease management in rheumatoid arthritis. AB - OBJECTIVE: To evaluate frequency of fibromyalgia in rheumatoid arthritis and its effect on disease activity score. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: The Indus Hospital, Karachi, from December 2010 to May 2011. METHODOLOGY: All adult patients of either gender diagnosed as rheumatoid arthritis on the basis of clinical, laboratory and X-ray criteria were included in the study. The sample data was separated into two groups depending on presence or absence of fibromyalgia and 28 joint disease activity score (DAS-28) value was evaluated. RESULTS: There were 31 (25.83%) patients with rheumatoid arthritis and fibromyalgia (RAFM) out of the total 120. The median (IQR) age of patients was 40 (32 - 51) years. All were females. The overall female frequency was 79 (88.8%). The median (IQR) DAS-28 score in RA group was 4.9 (3.66 - 5.71), while the median (IQR) DAS-28 score in RAFM was 7.04 (6.62 - 7.64) [p < 0.0001]. The number of patient getting combination therapy of DMARD in RAFM group was 61.3% while in RA group was 42.7%. CONCLUSION: DAS-28 was found to be significantly higher in RAFM patients probably because of higher perception of pain. PMID- 24953919 TI - Missed vascular injuries: presentation and outcome. AB - OBJECTIVE: To describe the different presentation, diagnostic evaluation, management and outcome of complications of missed vascular injuries. STUDY DESIGN: A case series. PLACE AND DURATION OF STUDY: Combined Military Hospital, Rawalpindi and Combined Military Hospital, Kharian Cantt, from June 2009 to June 2012. METHODOLOGY: All the patients with vascular injuries missed at the time of causative trauma who reported during this study period were included. Patients presented with acute vascular injuries and iatrogenic aneurysm at the vascular anastomosis site were excluded. All cases were evaluated with either CT or conventional angiography and managed with various open vascular surgical techniques and their results were assessed. RESULTS: Twenty eight patients with missed vascular injury underwent various vascular repairs. Age of patients ranged from 16 to 78 years (mean = 33.7 +/- 15.4 years). Male to female ratio was 6:1. Twelve (42.8%) patients presented with pseudoaneurysm alone, 10 (35.7%) with traumatic arteriovenous fistulae, 4 (14.3%) with post-traumatic thrombosis and occlusion and 2 (7.1%) with pseudoaneurysm and hemorrhage. Penetrating injuries were the commonest cause in 19 (67.8%). The time interval between injury and presentation in hospital ranged from 2 to 1300 weeks (mean 228 weeks). Lower limb vessels were affected in 20 (71.4%), the upper limb in 5 (17.8%) and neck vessels in 3 (10.7%). Superficial femoral artery was the most frequently involved artery in 9 (32.1%) cases. Interposition reverse autogenous saphenous vein graft was most common type of repair in all types of missed vascular injuries. One (3.5%) patient had amputation after secondary hemorrhage. CONCLUSION: Low velocity penetrating trauma was the common cause of missed vascular injury. Pseudoaneurysm was the most common presentation. PMID- 24953920 TI - Systemic aspects of soft tissue rheumatic disorders (STRDs). AB - OBJECTIVE: To determine the markers of systemic inflammation in soft tissue rheumatic disorders (STRDs). STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Rheumatology Clinic, Yazd, Iran, from November 2010 to December 2011. METHODOLOGY: Patients aged 20 years or above with known diagnosis of STRD according to clinical criteria and/ or paraclinical investigations for at least 3 weeks duration were longitudinally followed. Patients with diagnosis of rheumatoid arthritis, hypothyroidism, or any other known systemic conditions (other than diabetes mellitus) were excluded. After careful and detailed history taking, laboratory tests indicating systemic inflammation including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and routine screening rheumatologic tests were assessed. RESULTS: Of the 90 patients, 75% were female and 25% were male and 28 (31.1%) of patients had diabetes mellitus. Fifty six (62%) and 49 (54%) of all studies cases had some degrees of morning stiffness and remarkable fatigue respectively. Twenty two (24%) had elevated CRP and 5 (5.5%) had abnormal ESR. Rheumatoid factor (RF) and anti-CCP was positive in 5 (5.5%) and 12 (13.3%) of patients accordingly. Three (3.3%) patients suffered from anemia of chronic disease. Mean ESR was 48 +/- 7.34 (hl) and mean CRP was 10.06 +/- 1.96 mg/dl. Mean RF was 10.8 +/- 1.64 U/ml and mean anti- CCP was 18.5 +/- 2.71 U/ml. Mean hemoglobin was between 10.4 +/- 1.01 g/dl. CONCLUSION: Features of subtle systemic inflammation are positive in some cases of soft tissue rheumatism. PMID- 24953921 TI - Emergency surgery for spontaneous hemopneumothorax. AB - Emergency management of spontaneous hemopneumothorax patients was retrospectively analysed in this study. From November 2009 to August 2012, 221 patients with spontaneous pneumothorax were treated in the thoracic surgery clinic. Among them, 9 (4.07%) were diagnosed with spontaneous hemopneumothorax. Chest X-ray and computed tomography were the diagnostic tools. Emergency thoracotomy was performed for 7 of 9 patients because of massive hemothorax and continuous bleeding from the chest tube. Massive hematoma was documented in 2 of 7 patients at tomography. Bridging veins and torn pleural adhesion between parietal and visceral pleura were the source of bleeding determined at thoracotomy. Hematoma evacuation, resection of bullae, ligation of pleural adhesions and apical pleurectomy were performed. Spontaneous hemopneumothorax is an emergency due to massive hemorrhage and hematoma formation. Early surgical treatment is recommended for patients with spontaneous hemopneumothorax. PMID- 24953922 TI - Giant intraabdominal endometrial cyst. AB - Endometriosis is the condition where endometrium gets implanted and flourishes outside the uterine cavity, most commonly in ovary and on the peritoneum which lines the abdominal cavity and viscera. Endometrial cells in areas outside the uterus are influenced by hormonal changes and respond in a way similar to the endometrium inside the uterus. Symptoms often worsen with the menstrual cycle. We present a case of 50 years old female who presented with gross abdominal distension and abdominal pain over years. CT scan showed a huge intraabdominal cyst of unknown origin which was compressing adjacent structures. Patient underwent a high risk operation and whole cyst weighing 214 kg (471 lbs) was removed along with both ovaries and uterus. Histopathologically, it was reported as endometrial cyst. PMID- 24953923 TI - Atrial septal defect coexistent with Sjogren's syndrome. AB - Pulmonary hypertension is frequently associated with atrial septal defect and various connective tissue disorders. This case describes a 74-year-old woman who presented with symptoms of heart failure and concomitant involvement of salivary glands and keratoconjunctivitis. An echocardiogram demonstrated ostium secundum atrial septal defect with left to right shunt and severe pulmonary hypertension. Laboratory investigations confirmed the diagnosis of Sjogren's syndrome (SS) with positive anti-nuclear factor and centromere SS-A/Ro pattern. Anti-Ro (SS-A) was found positive. Atrial septal defect was closed through transcatheter route with significant improvement in clinical outcome. This case report suggests a possible association of atrial septal defect with primary Sjogren's syndrome in an adult patient. PMID- 24953924 TI - Transitory inferior dislocation of shoulder in a child after humerus fracture. AB - A case of transitory inferior shoulder dislocation in 12 years old boy is reported. He fell from bicycle and injured his left shoulder region. X-ray revealed mildly displaced fracture of the surgical neck of left humerus. Arm sling was applied on fractured side and analgesics were prescribed for pain. As routine follow-up, X-rays were repeated after one week, alignment of fracture was good but humeral head was dislocated inferior to glenoid. This dislocation was not in immediate post-injury radiograph. Transitory inferiorly dislocation of shoulder is very rare in children. PMID- 24953925 TI - Proportion of exposure of passive smoking in teenage group and symptoms precipitated after exposure to second hand smoke. AB - Exposure of passive smoking and second hand smoke (SHS) exposure in teenage group results in precipitation of several symptoms. Five hundred teenagers between ages of 13 - 19 studying in Army Public School and College Westridge, Rawalpindi, were selected for descriptive cross-sectional study from September 2012 till February 2013. Out of the total 500, 279 (55.8%) were exposed to passive smoking while 221 (44.2%) were not exposed to passive smoking. Out of the exposed 279 (55.8%) students, males were 132 (47.3%) and females were 147 (52.7%) with mean age of 15.06 +/- 1.805 years. After exposure to SHS, multiple responses were observed. Statistical significant association was found between symptoms precipitation and exposure to SHS. Nose irritation was present in 84, while 195 did not complain of it (p = 0.002). Allergic symptoms were precipitated with SHS in 42, while not in 21 students (p < 0.001). Asthma attack was precipitated in 38, while 241 did not experience precipitation of asthma attack (p < 0.001). More cough was present in 168, while not in 111 students (p = 0.037). Nausea was present in 41, while not in 238 (p < 0.001). Nose irritation was seen in 84 and not in 195 students (p = 0.002). More than half of the teenagers had exposure to passive smoking. Statistical significant association was found between passive smoking exposure and precipitation of symptoms. PMID- 24953926 TI - Retrograde intubation in a patient with stridor: an old technique revisited. PMID- 24953927 TI - Pathological features of appendectomy specimens histologically negative for acute inflammation. PMID- 24953928 TI - Septic arthritis of the shoulder joint in a child: an uncommon presentation. PMID- 24953929 TI - Bacteriologic profile and antibiogram of blood culture isolates from a children's hospital in Kabul. AB - OBJECTIVE: To identify the bacterial pathogens causing paediatric septicaemia in Kabul and to determine their antibiogram to improve empirical antibiotic therapy. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Microbiology Laboratory of FMIC, Kabul, Afghanistan, from January 2010 to June 2012. METHODOLOGY: Blood cultures from suspected cases of sepsis were processed in BD (Becton Dickinson, USA) for culture BACTECTM 9240 Blood Culture System. Positive growths were examined and isolates were identified by conventional biochemical tests. Bacteria were identified to the species level using various Analytical Profile Index (API) identification strips. Antibiotic susceptibility testing was performed by modified Kirby-Bauer disk diffusion method. Drug resistant strains were studied for extended spectrum beta lactamase (ESBL) production by combination disk method and for methicillin resistant Staphylococcus aureus (MRSA) by Cefoxitin disk diffusion method. RESULTS: Out of a total 3360 blood cultures received from in-patients, 410 yielded monomicrobial growth; hence the frequency of positive blood culture was 12.2%. Out of a total 410 isolates, 212 (51.71%) were gram-negative bacilli and 184 (44.88%) were gram-positive cocci. In addition, 14 (3.41%) Candida species were also isolated. The frequently isolated species of gram-negative bacteria belonged to Enterobacteriaceae and included 66 Klebsiella (16.1%), 42 Enterobacter (10.2%), 35 Escherichia (E.) coli (8.5%) and 16 Serratia (3.9%) species. In addition, 21 (5.12%) Pseudomonas species were also isolated. Correspondingly, amongst gram-positive cocci, the most frequently isolated species were 108 coagulase-negative Staphylococci (26.34%) followed by 49 Staphylococcus aureus (11.95%) and 21 Streptococcus species (5.12%). Among gram-negative isolates, those that produced ESBL i.e., 110 out of 212 (51.9%) were found to be multidrug-resistant and showed high resistance to commonly used antibiotics namely Ampicillin, Gentamicin, 3rd generation Cephalosporins, Fluoroquinolones and Co-trimoxazole. Most of the isolates were susceptible to Imipenem (200/212, 94.3%), Amikacin (172/212, 81.1%) and Fosfomycin (166/212, 78.3%). Amongst gram-positive cocci, majority were resistant to Penicillin, Gentamicin, 3rd generation Cephalosporins, Fluoroquinolones and Cotrimoxazole. However, most were sensitive to Vancomycin (183/184) Pristinamycin (161/184, 87.5%) and Fosfomycin (134/184, 72.8%). All Staphylococci were resistant to Penicillin and 80/157 (51%) were MRSA. CONCLUSION: Klebsiella, E. coli, Enterobacter and Staphylococci remain the principal organisms responsible for blood stream infection in a paediatrics tertiary care setting in Kabul. The most sensitive among the tested antibiotics for gram-negative organisms were Imipenem, Amikacin, and Fosfomycin and for gram-positive organisms were Vancomycin, Pristinamycin and Fosfomycin. PMID- 24953930 TI - Mitochondrial DNA depletion in single fibers in a patient with novel TK2 mutations. AB - The mitochondrial DNA (mtDNA) depletion syndrome is a genetically heterogeneous group of diseases caused by nuclear gene mutations and secondary reduction in mtDNA copy number. We describe a patient with progressive muscle weakness and increased creatine kinase and lactate levels. Muscle weakness was first noted at age 1.5 years and he died of respiratory failure and bronchopneumonia at age 3.5 years. The muscle biopsy showed dystrophic features with ragged red fibers and numerous cytochrome c oxidase (COX)-negative fibers. qPCR analysis demonstrated depletion of mtDNA and sequence analysis of the mitochondrial thymidine kinase 2 (TK2) gene revealed two novel heterozygous variants, c.332C > T, p.(T111I) and c.156 + 5G > C. Quantitative analysis of mtDNA in single muscle fibers demonstrated that COX-deficient fibers showed more pronounced depletion of mtDNA when compared with fibers with residual COX activity (P < 0.01, n = 25). There was no evidence of manifestations from other organs than skeletal muscle although there was an apparent reduction of mtDNA copy number also in liver. The patient showed a pronounced, albeit transient, improvement in muscle strength after onset of treatment with coenzyme Q10, asparaginase, and increased energy intake, suggesting that nutritional modulation may be a therapeutic option in myopathic mtDNA depletion syndrome. PMID- 24953931 TI - Distal myosin heavy chain-7 myopathy due to the novel transition c.5566G>A (p.E1856K) with high interfamilial cardiac variability and putative anticipation. AB - Myosin-heavy-chain 7 (MYH7)-myopathy manifests clinically with a distal, scapuloperoneal, limb-girdle (proximal), or axial distribution and may involve the respiratory muscles. Cardiac involvement is frequent, ranging from relaxation impairment to severe dilative cardiomyopathy. Progression and earlier onset of cardiac disease in successive generations with MYH7-myopathy is unreported. In a five-generation family MYH7-myopathy due to the novel c.5566G > A (p.E1856K) mutation manifested with late-onset, distal > proximal myopathy and variable degree of cardiac involvement. The index patient developed distal myopathy since age 49 y and anginal chest pain. Her mother had distal myopathy and impaired myocardial relaxation. The daughter of the index patient had discrete myopathy but left ventricular hypertrabeculation/noncompaction and ventricular arrhythmias requiring an implantable cardioverter defibrillator. The granddaughter of the index patient had infantile dilated cardiomyopathy without overt myopathy. Cardiac involvement may be present in MYH7-myopathy and may be progressive between the generations, ranging from relaxation abnormality to noncompaction, ventricular arrhythmias, and dilated cardiomyopathy. PMID- 24953932 TI - Radiation-induced endothelial cell loss and reduction of the relative magnitude of the blood flow in the rat spinal cord. AB - The main purpose of the present study was to examine the time-dependent alterations in the endothelial cell density that occur in the first 180 days after irradiation of the spinal cord and the functional role of these alterations in the spinal cord blood flow. An irradiated cervical spinal cord rat model (C2 T2 segment) was generated using a (60)Co irradiator to deliver 30 Gy. A significant loss of forelimb motor function was observed 180 days post irradiation. The number of neurons in the anterior horn of the spinal cord began to decrease significantly 3 days post-irradiation compared with normal controls, reaching the lowest number at 90 days post-irradiation. A significant reduction in the endothelial cell density was observed from 14 days post-irradiation in the white matter and from 3 days post-irradiation in the gray matter. The lowest endothelial cell density was reached at 30 days post-irradiation in the white matter and at 60 days post-irradiation in the gray matter. A significant reduction in the microvessel density was observed from 3 days post-irradiation in both the white matter and the gray matter. The lowest microvessel density was reached at 90 days post-irradiation in both the white matter and the gray matter. A significant reduction in the relative magnitude of spinal cord blood flow was observed from 21 days post-irradiation. The lowest relative magnitude of spinal cord blood flow was reached at 90 days post-irradiation. We did not find any evidence of demyelination. The results revealed that a single 30-Gy irradiation dose resulted in impaired forelimb motor function, a decreased number of neurons, and reduced endothelial cell density, microvessel density and relative magnitude of spinal cord blood flow. However, a 30-Gy single-dose irradiation was not sufficient to induce demyelination in the rat spinal cord. PMID- 24953933 TI - Transgenic increase of Wnt7b in neural progenitor cells decreases expression of T domain transcription factors and impairs neuronal differentiation. AB - Wnt/beta-catenin signaling plays an important role in neural development, instructing both progenitor cell division and differentiation. During early corticogenesis, Wnt7b is expressed in a restricted expression pattern in the ventricular zone progenitor cells. However, its influence on progenitor cell behavior has not been fully studied. We report that transgenic overexpression of Wnt7b in neural progenitor cells impairs neuronal differentiation and the development of forebrain structures at embryonic day 10.5 (E10.5). This was accompanied by a decreased expression of T-domain transcription factors Tbr1 and Tbr2, in both progenitor cells and post-mitotic neurons. However, proliferation, apoptosis and the overall proportion of pax6(+) neural progenitor cells were similar to wild-type litter mates. These results suggest that Wnt signaling may affect early neural progenitor differentiation by regulating the expression of pro-neural transcription factors. PMID- 24953934 TI - Systematic control of the excited-state dynamics and carrier-transport properties of functionalized benzo[ghi]perylene and coronene derivatives. AB - A series of benzo[ghi]perylene (Bp) and coronene (Cor) derivatives substituted with electron-withdrawing methoxycarbonyl (COOMe) or electron-donating methoxyl (MeO) groups was synthesized. The electrochemical, spectroscopic, and photophysical properties of these compounds were investigated by cyclic voltammetry, steady-state and time-resolved spectroscopy, and quantum-yield measurements. Introduction of suitable substituents onto the aromatic rings enabled control of electrochemical and spectroscopic behavior. Examination of excited-state dynamics revealed that fluorescence quantum yields increased with increasing number of COOMe groups in both Bp and Cor derivatives, consistent with the findings of DFT calculations. Single-crystal analysis allowed the performance of field-effect transistors containing single crystals of the derivatives to be rationalized. PMID- 24953935 TI - Anglesite and silver recovery from jarosite residues through roasting and sulfidization-flotation in zinc hydrometallurgy. AB - Hazardous jarosite residues contain abundant valuable minerals that are difficult to be recovered by traditional flotation process. This study presents a new route, roasting combined with sulfidization-flotation, for the recovery of anglesite and silver from jarosite residues of zinc hydrometallurgy. Surface appearance and elemental distribution of jarosite residues was examined by scanning electron microscopy and energy dispersive X-ray spectrometry analysis, respectively. Decomposition and transformation mechanisms of jarosite residues were illustrated by differential thermal analysis. Results showed that after roasting combined with flotation, the grade and recovery of lead were 43.89% and 66.86%, respectively, and those of silver were 1.3 kg/t and 81.60%, respectively. At 600-700 degrees C, jarosite was decomposed to release encapsulated valuable minerals such as anglesite (PbSO4) and silver mineral; silver jarosite decomposed into silver sulfate (Ag2SO4); and zinc ferrite (ZnO . Fe2O3) decomposed into zinc sulfate (ZnSO4) and hematite (Fe2O3). Bared anglesite and silver minerals were modified by sodium sulfide and easily collected by flotation collectors. This study demonstrates that the combination of roasting and sulfidization-flotation provides a promising process for the recovery of zinc, lead, and silver from jarosite residues of zinc hydrometallurgy. PMID- 24953936 TI - In vitro and in silico investigations of the binding interactions between chlorophenols and trypsin. AB - Being the first-degree toxic pollutants, chlorophenols (CP) have potential carcinogenic and mutagenic activity and toxicity. Since there still lacks studies on molecular interactions of chlorophenols with trypsin, one major binding target of many exogenous environmental pollutants, the binding interactions between five chlorophenols, 2-CP, 2,6-DCP, 2,4,6-TCP, 2,4,6-TCP, 2,3,4,6-TCP and PCP and trypsin were characterized by the combination of multispectroscopic techniques and molecular modeling. The chlorophenols bind at the one main site of trypsin and the binding induces the changes of microenvironment and global conformations of trypsin. Different number of chloride atoms significantly affects the binding and the binding constants KA ranks as KA (2-CP) < KA (2,6-DCP) ~ KA (2,4,6-TCP) < KA (2,3,4,6-TCP) < KA (PCP). These chlorophenols interacts with trypsin mainly through hydrophobic interactions and via hydrogen bonding interactions and aromatic-aromatic pi-pi stacking interaction. Our results offer insights into the binding mechanism of chlorophenols with trypsin and provide important information for possible toxicity risk of chlorophenols to human health. PMID- 24953937 TI - Robust electrochemical analysis of As(III) integrating with interference tests: a case study in groundwater. AB - In Togtoh region of Inner Mongolia, northern China, groundwater encountered high concentrations As contamination (greater than 50 MUg L(-1)) causes an increasing concern. This work demonstrates an electrochemical protocol for robust (efficient and accurate) determination of As(III) in Togtoh water samples using Au microwire electrode without the need of pretreatment or clean-up steps. Considering the complicated conditions of Togtoh water, the efficiency of Au microwire electrode was systematically evaluated by a series of interference tests, stability and reproducibility measurements. No obvious interference on the determination of As(III) was observed. Especially, the influence of humic acid (HA) was intensively investigated. Electrode stability was also observed with long-term measurements (70 days) in Togtoh water solution and under different temperatures (0-35 degrees C). Excellent reproducibility (RSD:1.28%) was observed from different batches of Au microwire electrodes. The results obtained at Au microwire electrode were comparable to that obtained by inductively coupled plasma atomic emission spectroscopy (ICP-AES), indicating a good accuracy. These evaluations (efficiency, robustness, and accuracy) demonstrated that the Au microwire electrode was able to determine As(III) in application to real environmental samples. PMID- 24953938 TI - Analysis of an explosion accident of nitrogen trichloride in a waste liquid containing ammonium ion and platinum black. AB - Five liters of sodium hypochlorite aqueous solution (12 mass%) was poured into 300 L of liquid waste containing ammonium ion of about 1.8 mol/L in a 500 L tank in a plant area; then, two minutes later the solution exploded with a flash on March 30th, 2005. The tank cover, the fluorescent lamp and the air duct were broken by the blast wave. Thus, we have conducted 40 runs of laboratory-scale explosion tests under various conditions (solution concentrations of (NH4)2SO4 and NaClO, temperatures, Pt catalysts, pH, etc.) to investigate the causes for such an explosion. When solutions of ammonium sulfate and sodium hypochlorite are mixed in the presence of platinum black, explosions result. This is ascribable to the formation of explosive nitrogen trichloride (NCl3). In the case where it is necessary to mix these 2 solutions (ammonium sulfate and sodium hypochlorite) in the presence of platinum black, the following conditions would reduce a probability of explosion; the initial concentration of NH4(+) should be less than 3 mol/L and the pH should be higher than 6. The hypochlorite solution (in 1/10 in volume) to be added at room temperature is recommended to be less than 0.6 mol/L. PMID- 24953939 TI - Oxidative leaching process with cupric ion in hydrochloric acid media for recovery of Pd and Rh from spent catalytic converters. AB - The recycling of platinum-group metals from wastes such as autocatalytic converters is getting growing attention due to the scarcity of these precious metals and the market pressure originated by increase of demand in current and emerging applications. Hydrometallurgical treatment of such wastes is an alternative way to the most usual pyrometallurgical processes based on smelter operations. This paper focuses on the development of a leaching process using cupric chloride as oxidising agent, in HCl media, for recovery of palladium and rhodium from a spent catalyst. The chloride media allows the adequate conditions for oxidising and solubilising the metals, as demonstrated by equilibrium calculations based on thermodynamic data. The experimental study of the leaching process revealed that Pd solubilisation is clearly easier than that of Rh. The factors temperature, time, and HCl and Cu(2+) concentrations were significant regarding Pd and Rh leaching, the latter requiring higher factor values to achieve the same results. Leaching yields of 95% Pd and 86% Rh were achieved under optimised conditions (T = 80 degrees C, t = 4h, [HCl] = 6M, [Cu(2+)] = 0.3M). PMID- 24953940 TI - Sustainable synthesis of metals-doped ZnO nanoparticles from zinc-bearing dust for photodegradation of phenol. AB - A novel strategy of waste-cleaning-waste is proposed in the present work. A metals-doped ZnO (M-ZnO, M = Fe, Mg, Ca and Al) nanomaterial has been prepared from a metallurgical zinc-containing solid waste "fabric filter dust" by combining sulfolysis and co-precipitation processes, and is found to be a favorable photocatalyst for photodegradation of organic substances in wastewater under visible light irradiation. All the zinc and dopants (Fe, Mg, Ca and Al) for preparing M-ZnO are recovered from the fabric filter dust, without any addition of chemical as elemental source. The dust-derived M-ZnO samples deliver single phase indexed as the hexagonal ZnO crystal, with controllable dopants species. The photocatalytic activity of the dust-derived M-ZnO samples is characterized by photodegradation of phenol aqueous solution under visible light irradiation, giving more prominent photocatalytic behaviors than undoped ZnO. Such enhancements may be attributed to incorporation of the dust-derived metal elements (Fe, Mg, Ca and Al) into ZnO structure, which lead to the modification of band gap and refinement of grain size. The results show a feasibility to utilize the industrial waste as a resource of photodegradating organic substances in wastewater treatments. PMID- 24953941 TI - Biodegradation of 2-hydroxyquinoxaline (2-HQ) by Bacillus sp. AB - An aerobic Gram +ve bacterial strain capable of utilizing 2-Hydroxyquinoxaline (2 HQ) as sole source of carbon and energy was isolated from Chrysanthemum indicum Indian agricultural soil and named as HQ2. On the basis of morphology, physico biochemical characteristics and 16S rRNA sequence analysis, strain HQ2 was identified as Bacillus sp. The generation time of Bacillus sp. in log phase during growth on 2-HQ is 0.79 h or 47.4 min. The optimal conditions for 2-HQ degradation by Bacillus sp. were inoculum density of 1.0 OD, pH of 6-8, temperature of 37-45 degrees C and 2-HQ concentration of 500 ppm. Among the additional carbon and nitrogen sources, carbon sources did not influence the degradation rate of 2-HQ, but nitrogen sources-yeast extract marginally enhanced the rate of degradation of 2-HQ. GC-MS analysis of the culture Bacillus sp. grown on 2-HQ indicated the formation of dimers from 2 molecules of 2 hydroxyquinoxaline. The formation of dimer for degradation of 2-HQ by the culture appears to be the first report to our scientific knowledge. PMID- 24953942 TI - Sol-hydrothermal synthesis of inorganic-framework molecularly imprinted TiO2/SiO2 nanocomposite and its preferential photocatalytic degradation towards target contaminant. AB - Inorganic-framework molecularly imprinted TiO2/SiO2 nanocomposite (MIP-TiO2/SiO2) was successfully prepared by sol-hydrothermal method using 4-nitrophenol as template. The morphology, structure, optical property, zeta-potential and photocurrent of MIP-TiO2/SiO2 were characterized. The adsorption performance and photocatalytic selectivity were also studied. MIP-TiO2/SiO2 shows higher adsorption capacity and selectivity than the non-imprinted TiO2/SiO2 (NIP TiO2/SiO2). Kinetics results show that the adsorption equilibrium of 4 nitrophenol on MIP-TiO2/SiO2 is established within 20 min, and the adsorption process obeys the pseudo-second-order model. Moreover, MIP-TiO2/SiO2 can completely degrade 4-nitrophenol within 30 min, while NIP-TiO2/SiO2 takes 110 min. It was found that the MIP-TiO2/SiO2 photocatalyst shows molecular recognition ability, leading to selective adsorption and molecular recognitive photocatalytic degradation of 4-nitrophenol. Furthermore, because of its inorganic framework, MIP-TiO2/SiO2 shows excellent reusability. PMID- 24953943 TI - PCDD/F emissions from light-duty diesel vehicles operated under highway conditions and a diesel-engine based power generator. AB - PCDD/F emissions from three light-duty diesel vehicles--two vans and a passenger car--have been measured in on-road conditions. We propose a new methodology for small vehicles: a sample of exhaust gas is collected by means of equipment based on United States Environmental Protection Agency (U.S. EPA) method 23 A for stationary stack emissions. The concentrations of O2, CO, CO2, NO, NO2 and SO2 have also been measured. Six tests were carried out at 90-100 km/h on a route 100 km long. Two additional tests were done during the first 10 min and the following 60 min of the run to assess the effect of the engine temperature on PCDD/F emissions. The emission factors obtained for the vans varied from 1800 to 8400 pg I-TEQ/Nm(3) for a 2004 model year van and 490-580 pg I-TEQ/Nm(3) for a 2006 model year van. Regarding the passenger car, one run was done in the presence of a catalyst and another without, obtaining emission factors (330-880 pg I-TEQ/Nm(3)) comparable to those of the modern van. Two other tests were carried out on a power generator leading to emission factors ranging from 31 to 78 pg I-TEQ/Nm(3). All the results are discussed and compared with literature. PMID- 24953944 TI - Evaluation of passenger health risk assessment of sustainable indoor air quality monitoring in metro systems based on a non-Gaussian dynamic sensor validation method. AB - Sensor faults in metro systems provide incorrect information to indoor air quality (IAQ) ventilation systems, resulting in the miss-operation of ventilation systems and adverse effects on passenger health. In this study, a new sensor validation method is proposed to (1) detect, identify and repair sensor faults and (2) evaluate the influence of sensor reliability on passenger health risk. To address the dynamic non-Gaussianity problem of IAQ data, dynamic independent component analysis (DICA) is used. To detect and identify sensor faults, the DICA based squared prediction error and sensor validity index are used, respectively. To restore the faults to normal measurements, a DICA-based iterative reconstruction algorithm is proposed. The comprehensive indoor air-quality index (CIAI) that evaluates the influence of the current IAQ on passenger health is then compared using the faulty and reconstructed IAQ data sets. Experimental results from a metro station showed that the DICA-based method can produce an improved IAQ level in the metro station and reduce passenger health risk since it more accurately validates sensor faults than do conventional methods. PMID- 24953946 TI - Is bilateral total knee arthroplasty staged at a one-week interval safe? A matched case control study. AB - Controversy surrounds the safety of bilateral total knee arthroplasty (TKA) and whether staging the procedures one week apart represents a safer option. A consecutive series of 234 patients underwent either a simultaneous (103 patients) or staged bilateral TKA (131 patients) from 2007 to 2012 and were compared to a matched control group of unilateral TKA (131 patients). Staged patients had no difference in one-year complication rate when compared to simultaneous bilateral TKA and the matched unilateral TKA control group (15% vs. 19% vs. 15%, P=0.512). There was also no difference in perioperative complications (10% vs. 14% vs. 7%, P=0.231) or 90-day readmissions (8% vs. 4% vs. 4%, P=0.295). In selected patients with bilateral knee OA, TKA staged at a one-week interval is a safe alternative. PMID- 24953947 TI - Dual descriptor and molecular electrostatic potential: complementary tools for the study of the coordination chemistry of ambiphilic ligands. AB - In this paper, we show that the ambiphilic properties of some organic ligands in organometallic complexes may be retrieved readily from simple calculations in the framework of conceptual density functional theory (C-DFT): namely, the dual descriptor (DD) and the molecular electrostatic potential (MEP) of the ligands afford a rather straightforward interpretation of experimental trends such as the bonding geometry and the electronic properties of complexes in terms of sigma-, pi- and back-bonding. The studied ligands were chosen to be representative of the wide variety organometallic chemistry offers, ranging from neutral to charged systems and from diatomic to polyatomic molecules. The present approach is general since all relevant parameters are retrieved from the electron density, obtained either from a DFT or post-Hartree-Fock calculation. It is believed to be helpful for organometallic chemists, since it allows a deep understanding and may be used as a predictive tool of the coordinating properties of ligands. PMID- 24953945 TI - Large prostate gland size is not a contraindication to low-dose-rate brachytherapy for prostate adenocarcinoma. AB - PURPOSE: Prostate volume greater than 50cc is traditionally a relative contraindication to prostate seed implantation (PSI), but there is little consensus regarding prostate size and clinical outcomes. We report biochemical control and toxicity after low-dose-rate PSI and compare outcomes according to the prostate size. METHODS AND MATERIALS: A total of 429 men who underwent low dose-rate PSI between 1998 and 2009 were evaluated. Median followup was 38.7 months. Patients were classified by prostate volume into small, medium, and large subgroups. Differences were analyzed using the Mann-Whitney and Pearson's chi(2) tests for continuous and categorical variables, respectively. Cox proportional hazards regression models were used to evaluate effect of prostate size on outcomes. RESULTS: Patient pretreatment factors were balanced between groups except for age (p=0.001). The 10-year actuarial freedom from biochemical failure for all patients treated with PSI was 96.3% with no statistically significant difference between large vs. small/medium prostate size (90% vs. 96.6%, p=0.47). In a multivariate analysis, plan type (hazard ratio [HR]=0.25, p=0.03), dose to 90% of the gland (D90: HR=0.98, p=0.02), volume receiving 200Gy (V200: HR=0.98, p=0.026), and biologic effective dose (HR=0.99, p=0.045), but not prostate size (HR=2.27, p=0.17) were significantly associated with freedom from biochemical failure. Prostate size was not significantly associated with time to maximum American Urologic Association score. CONCLUSION: In men with large prostates, the PSI provides biochemical control and temporal changes in genitourinary toxicity that are comparable with men having smaller glands. Accurate dose optimization and delivery of PSI provides the best clinical outcomes regardless of gland size. PMID- 24953949 TI - Tetrahedron DNA dendrimers and their encapsulation of gold nanoparticles. AB - DNA dendrimers have achieved increasing attention recently. Previously reported DNA dendrimers used Y-DNA as monomers. Tetrahedron DNA is a rigid tetrahedral cage made of DNA. Herein, we use tetrahedron DNA as monomers to prepare tetrahedron DNA dendrimers. The prepared tetrahedron DNA dendrimers have larger size compared with those made of Y-DNA. In addition, thanks to the central cavity of tetrahedron DNA monomers, some nanoscale structures (e.g., gold nanoparticles) can be encapsulated within tetrahedron DNA monomers. Tetrahedron DNA encapsulated with gold nanoparticles can be further assembled into dendrimers, guiding gold nanoparticles into clusters. PMID- 24953948 TI - Identification and development of 2-methylimidazo[1,2-a]pyridine-3-carboxamides as Mycobacterium tuberculosis pantothenate synthetase inhibitors. AB - In the present study, we used crystal structure of mycobacterial pantothenate synthetase (PS) bound with 2-(2-(benzofuran-2-ylsulfonylcarbamoyl)-5-methoxy-1H indol-1-yl) acetic acid inhibitor for virtual screening of antitubercular compound database to identify new scaffolds. One of the identified lead was modified synthetically to obtain thirty novel analogues. These synthesized compounds were evaluated for Mycobacterium tuberculosis (MTB) PS inhibition study, in vitro antimycobacterial activities and cytotoxicity against RAW 264.7 cell line. Among the compounds tested, N'-(1-naphthoyl)-2-methylimidazo[1,2 a]pyridine-3-carbohydrazide (5b) was found to be the most active compound with IC50 of 1.90 +/- 0.12 MUM against MTB PS, MIC of 4.53 MUM against MTB with no cytotoxicity at 50 MUM. The binding affinity of the most potent inhibitor 5b was further confirmed biophysically through differential scanning fluorimetry. PMID- 24953950 TI - Benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives as multiple inhibitors of bacterial Mur ligases (MurC-MurF). AB - Enzymes catalyzing the biosynthesis of bacterial peptidoglycan represent traditionally a collection of highly selective targets for novel antibacterial drug design. Four members of the bacterial Mur ligase family-MurC, MurD, MurE and MurF-are involved in the intracellular steps of peptidoglycan biosynthesis, catalyzing the synthesis of the peptide moiety of the Park's nucleotide. In our previous virtual screening campaign, a chemical class of benzene-1,3-dicarboxylic acid 2,5-dimethylpyrrole derivatives exhibiting dual MurD/MurE inhibition properties was discovered. In the present study we further investigated this class of compounds by performing inhibition assays on all four Mur ligases (MurC MurF). Furthermore, molecular dynamics (MD) simulation studies of one of the initially discovered compound 1 were performed to explore its geometry as well as its energetic behavior based on the Linear Interaction Energy (LIE) method. Further in silico virtual screening (VS) experiments based on the parent active compound 1 were conducted to optimize the discovered series. Selected hits were assayed against all Escherichia coli MurC-MurF enzymes in biochemical inhibition assays and molecules 10-14 containing benzene-1,3-dicarboxylic acid 2,5 dimethylpyrrole coupled with five member-ring rhodanine moiety were found to be multiple inhibitors of the whole MurC-MurF cascade of bacterial enzymes in the micromolar range. Steady-state kinetics studies suggested this class to act as competitive inhibitors of the MurD enzyme towards d-Glu. These compounds represent novel valuable starting point in the development of novel antibacterial agents. PMID- 24953951 TI - Enzymatic incorporation and fluorescent labelling of cyclooctyne-modified deoxyuridine triphosphates in DNA. AB - The amino group of 5-aminopropargyl-2'-deoxyuridine-5'-triphosphate was labelled with dibenzocyclooctyne (DIBO) and two derivatives of bicyclo [6.1.0] non-4-yne (BCN) with short and long linkers to produce three different cycloalkyne-modified deoxyuridine triphosphates. BCN was successfully incorporated into DNA at multiple sites by enzyme-mediated primer extension and the polymerase chain reaction (PCR). Efficient fluorescent labelling of the BCN-DNA and DIBO-DNA with Cy3-azide was demonstrated. PMID- 24953952 TI - Triazolopyridyl ketones as a novel class of antileishmanial agents. DNA binding and BSA interaction. AB - A new series of triazolopyridyl pyridyl ketones has been synthetized by regioselective lithiation of the corresponding [1,2,3]triazolo[1,5-a]pyridine at 7 position followed by reaction with different electrophiles. The in vitro antileishmanial activity of these compounds was evaluated against Leishmaniainfantum, Leishmaniabraziliensis, Leishmaniaguyanensis and Leishmaniaamazonensis. Compounds 6 and 7 were found to be the most active leishmanicidal agents. Both of them showed activities at micromolar concentration against cultured promastigotes of Leishmania spp. (IC50=99.8-26.8 MUM), without cytotoxicity on J774 macrophage cells. These two compounds were also tested in vivo in a murine model of acute infection by L. infantum. The triazolopyridine derivative 6 was effective against both spleen and liver parasites forms, while 7 was inactive against liver parasites. Mechanistic aspects of the antileishmanial activity were investigated by means of DNA binding studies (UV-titration and viscosimetry). Results have revealed that these active ligands are able to interact strongly with DNA [Kb=1.14 * 10(5)M(-1) (6) and 3.26 * 10(5)M(-1) (7)]. Moreover, a DNA groove binding has been proposed for both 6 and 7. To provide more insight on the mode of action of compounds 6 and 7 under biological conditions, their interaction with bovine serum albumin (BSA) was monitored by fluorescence titrations and UV-visible spectroscopy. The quenching constants and binding parameters were determined. Triazolopyridine ketones 6 and 7 have exhibited significant affinity towards BSA [Kb=2.5 * 10(4)M(-1) (6) and 1.9 * 10(4)M(-1) (7)]. Finally, to identify the binding location of compounds 6 and 7 on the BSA, competitive binding experiments were carried out, using warfarin, a characteristic marker for site I, and ibuprofen as one for site II. Results derived from these studies have indicated that both compounds interact at BSA site I and, to a lesser extent, at site II. PMID- 24953954 TI - Molecular mechanism of Symplectoteuthis bioluminescence--part 4: chromophore exchange and oxidation of the cysteine residue. AB - Symplectin is one of the few photoproteins, which forms covalent bonds with the dehydro-coelenterazine (DCL) at the binding sites and the active site. This binding takes place through the SH's of the cysteine residues via conjugate addition reaction. This photoprotein contains the chromophore molecules at the binding cites first, and then moves to the active cite Cys-390 for the luminescence. The current study focuses on these dynamic aspects of the chromophore using the natural photoprotein by analyzing the fluorescence changing of the DCL chromophores analogs with 8-(4'-methoxyphenyl)- or 8-(2'-naphthyl) group and 2-(2',4'-difluorophenyl)-group. Exchanges of these chromophores were monitored the fluorescence at slightly acidic media and also from the luminescence function observed at the optimum pH 7.8. The non-fluorescent naphthyl analogs was even proven to make the covalent bond formation at pH 6.0 and evidently to obtain the corresponding luminescent product amide by liquid chromatographic detection from the spent solutions. PMID- 24953953 TI - Synthesis and biological activity of new salicylanilide N,N-disubstituted carbamates and thiocarbamates. AB - The development of novel antimicrobial drugs represents a cutting edge research topic. In this study, 20 salicylanilide N,N-disubstituted carbamates and thiocarbamates were designed, synthesised and characterised by IR, (1)H NMR and (13)C NMR. The compounds were evaluated in vitro as potential antimicrobial agents against Mycobacterium tuberculosis and nontuberculous mycobacteria (Mycobacterium avium and Mycobacterium kansasii) as well as against eight bacterial and fungal strains. Additionally, we investigated the inhibitory effect of these compounds on mycobacterial isocitrate lyase and cellular toxicity. The minimum inhibitory concentrations (MICs) against mycobacteria were from 4 MUM for thiocarbamates and from 16 MUM for carbamates. Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, were inhibited with MICs from 0.49 MUM by thiocarbamates, whilst Gram-negative bacteria and most of the fungi did not display any significant susceptibility. All (thio)carbamates mildly inhibited isocitrate lyase (up to 22%) at a concentration of 10 MUM. The (thio)carbamoylation of the parent salicylanilides led to considerably decreased cytotoxicity and thus improved the selectivity indices (up to 175). These values indicate that some derivatives are attractive candidates for future research. PMID- 24953956 TI - Contributors to emerging investigators 2014. PMID- 24953955 TI - Vitamin D supplementation for prevention of cancer in adults. AB - BACKGROUND: The evidence on whether vitamin D supplementation is effective in decreasing cancers is contradictory. OBJECTIVES: To assess the beneficial and harmful effects of vitamin D supplementation for prevention of cancer in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, Science Citation Index Expanded, and the Conference Proceedings Citation Index-Science to February 2014. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. SELECTION CRITERIA: We included randomised trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults who were healthy or were recruited among the general population, or diagnosed with a specific disease. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1alpha-hydroxyvitamin D (alfacalcidol), or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. We conducted random-effects and fixed-effect model meta-analyses. For dichotomous outcomes, we calculated the risk ratios (RRs). We considered risk of bias in order to assess the risk of systematic errors. We conducted trial sequential analyses to assess the risk of random errors. MAIN RESULTS: Eighteen randomised trials with 50,623 participants provided data for the analyses. All trials came from high-income countries. Most of the trials had a high risk of bias, mainly for-profit bias. Most trials included elderly community-dwelling women (aged 47 to 97 years). Vitamin D was administered for a weighted mean of six years. Fourteen trials tested vitamin D3, one trial tested vitamin D2, and three trials tested calcitriol supplementation. Cancer occurrence was observed in 1927/25,275 (7.6%) recipients of vitamin D versus 1943/25,348 (7.7%) recipients of control interventions (RR 1.00 (95% confidence interval (CI) 0.94 to 1.06); P = 0.88; I2 = 0%; 18 trials; 50,623 participants; moderate quality evidence according to the GRADE instrument). Trial sequential analysis (TSA) of the 18 vitamin D trials shows that the futility area is reached after the 10th trial, allowing us to conclude that a possible intervention effect, if any, is lower than a 5% relative risk reduction. We did not observe substantial differences in the effect of vitamin D on cancer in subgroup analyses of trials at low risk of bias compared to trials at high risk of bias; of trials with no risk of for profit bias compared to trials with risk of for-profit bias; of trials assessing primary prevention compared to trials assessing secondary prevention; of trials including participants with vitamin D levels below 20 ng/mL at entry compared to trials including participants with vitamin D levels of 20 ng/mL or more at entry; or of trials using concomitant calcium supplementation compared to trials without calcium. Vitamin D decreased all-cause mortality (1854/24,846 (7.5%) versus 2007/25,020 (8.0%); RR 0.93 (95% CI 0.88 to 0.98); P = 0.009; I2 = 0%; 15 trials; 49,866 participants; moderate quality evidence), but TSA indicates that this finding could be due to random errors. Cancer occurrence was observed in 1918/24,908 (7.7%) recipients of vitamin D3 versus 1933/24,983 (7.7%) in recipients of control interventions (RR 1.00 (95% CI 0.94 to 1.06); P = 0.88; I2 = 0%; 14 trials; 49,891 participants; moderate quality evidence). TSA of the vitamin D3 trials shows that the futility area is reached after the 10th trial, allowing us to conclude that a possible intervention effect, if any, is lower than a 5% relative risk reduction. Vitamin D3 decreased cancer mortality (558/22,286 (2.5%) versus 634/22,206 (2.8%); RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I2 = 0%; 4 trials; 44,492 participants; low quality evidence), but TSA indicates that this finding could be due to random errors. Vitamin D3 combined with calcium increased nephrolithiasis (RR 1.17 (95% CI 1.03 to 1.34); P = 0.02; I2 = 0%; 3 trials; 42,753 participants; moderate quality evidence). TSA, however, indicates that this finding could be due to random errors. We did not find any data on health-related quality of life or health economics in the randomised trials included in this review. AUTHORS' CONCLUSIONS: There is currently no firm evidence that vitamin D supplementation decreases or increases cancer occurrence in predominantly elderly community-dwelling women. Vitamin D3 supplementation decreased cancer mortality and vitamin D supplementation decreased all-cause mortality, but these estimates are at risk of type I errors due to the fact that too few participants were examined, and to risks of attrition bias originating from substantial dropout of participants. Combined vitamin D3 and calcium supplements increased nephrolithiasis, whereas it remains unclear from the included trials whether vitamin D3, calcium, or both were responsible for this effect. We need more trials on vitamin D supplementation, assessing the benefits and harms among younger participants, men, and people with low vitamin D status, and assessing longer duration of treatments as well as higher dosages of vitamin D. Follow-up of all participants is necessary to reduce attrition bias. PMID- 24953959 TI - Sentence processing and verbal working memory in a white-matter-disconnection patient. AB - The Arcuate Fasciculus/Superior Longitudinal Fasciculus (AF/SLF) is the white matter bundle that connects posterior superior temporal and inferior frontal cortex. Its causal functional role in sentence processing and verbal working memory is currently under debate. While impairments of sentence processing and verbal working memory often co-occur in patients suffering from AF/SLF damage, it is unclear whether these impairments result from shared white-matter damage to the verbal-working-memory network. The present study sought to specify the behavioral consequences of focal AF/SLF damage for sentence processing and verbal working memory, which were assessed in a single patient suffering from a cleft like lesion spanning the deep left superior temporal gyrus, sparing most surrounding gray matter. While tractography suggests that the ventral fronto temporal white-matter bundle is intact in this patient, the AF/SLF was not visible to tractography. In line with the hypothesis that the AF/SLF is causally involved in sentence processing, the patient's performance was selectively impaired on sentences that jointly involve both complex word orders and long word storage intervals. However, the patient was unimpaired on sentences that only involved long word-storage intervals without involving complex word orders. On the contrary, the patient performed generally worse than a control group across standard verbal-working-memory tests. We conclude that the AF/SLF not only plays a causal role in sentence processing, linking regions of the left dorsal inferior frontal gyrus to the temporo-parietal region, but moreover plays a crucial role in verbal working memory, linking regions of the left ventral inferior frontal gyrus to the left temporo-parietal region. Together, the specific sentence processing impairment and the more general verbal-working-memory impairment may imply that the AF/SLF subserves both sentence processing and verbal working memory, possibly pointing to the AF and SLF respectively supporting each. PMID- 24953958 TI - Predictability, plausibility, and two late ERP positivities during written sentence comprehension. AB - Van Petten and Luka's (2012, International Journal of Psychophysiology, 83(2), 176-190) literature survey of late positive ERP components elicited by more or less predictable words during sentence processing led them to propose two topographically and functionally distinct positivities: a parietal one associated with semantically incongruent words related to semantic reanalysis and a frontal one with unknown significance associated with congruent but lexically unpredicted words. With the goal of testing this hypothesis within a single set of experimental materials and participants, we report results from two ERP studies: Experiment 1, a post-hoc analysis of a dataset that varied on dimensions of both cloze probability (predictability) and plausibility, and Experiment 2, a follow up study in which these factors were manipulated in a controlled fashion. In both studies, we observed distinct post-N400 positivities: a more anterior one to plausible, but not anomalous, low cloze probability sentence medial words, and a more posterior one to semantically anomalous sentence continuations. Taken together with an observed canonical cloze-modulated N400, these dual positivities indicate a dissociation between brain processes relating to written words' sentential predictability versus plausibility, clearly an important distinction for any viable neural or psycholinguistic model of written sentence processing. PMID- 24953957 TI - Functional neuroanatomical evidence for the double-deficit hypothesis of developmental dyslexia. AB - The double-deficit hypothesis of dyslexia posits that both rapid naming and phonological impairments can cause reading difficulties, and that individuals who have both of these deficits show greater reading impairments compared to those with a single deficit. Despite extensive behavioral research, the brain basis of poor reading with a double-deficit has never been investigated. The goal of the study was to evaluate the double-deficit hypothesis using functional MRI. Activation patterns during a printed word rhyme judgment task in 90 children with a wide range of reading abilities showed dissociation between brain regions that were sensitive to phonological awareness (left inferior frontal and inferior parietal regions) and rapid naming (right cerebellar lobule VI). More specifically, the double-deficit group showed less activation in the fronto parietal reading network compared to children with only a deficit in phonological awareness, who in turn showed less activation than the typically-reading group. On the other hand, the double-deficit group showed less cerebellar activation compared to children with only a rapid naming deficit, who in turn showed less activation than the typically-reading children. Functional connectivity analyses revealed that bilateral prefrontal regions were key for linking brain regions associated with phonological awareness and rapid naming, with the double-deficit group being the most aberrant in their connectivity. Our study provides the first functional neuroanatomical evidence for the double-deficit hypothesis of developmental dyslexia. PMID- 24953960 TI - Medial temporal and neocortical contributions to remote memory for semantic narratives: evidence from amnesia. AB - Studies of remote memory for semantic facts and concepts suggest that hippocampal lesions lead to a temporally graded impairment that extends no more than ten years prior to the onset of amnesia. Such findings have led to the notion that once consolidated, semantic memories are represented neocortically and are no longer dependent on the hippocampus. Here, we examined the fate of well established semantic narratives following medial temporal lobe (MTL) lesions. Seven amnesic patients, five with lesions restricted to the MTL and two with lesions extending into lateral temporal cortex (MTL+), were asked to recount fairy tales and bible stories that they rated as familiar. Narratives were scored for number and type of details, number of main thematic elements, and order in which the main thematic elements were recounted. In comparison to controls, patients with MTL lesions produced fewer details, but the number and order of main thematic elements generated was intact. By contrast, patients with MTL+ lesions showed a pervasive impairment, affecting not only the generation of details, but also the generation and ordering of main steps. These findings challenge the notion that, once consolidated, semantic memories are no longer dependent on the hippocampus for retrieval. Possible hippocampal contributions to the retrieval of detailed semantic narratives are discussed. PMID- 24953962 TI - Sound field measurement in a double layer cavitation cluster by rugged miniature needle hydrophones. AB - During multi-bubble cavitation the bubbles tend to organize themselves into clusters and thus the understanding of properties and dynamics of clustering is essential for controlling technical applications of cavitation. Sound field measurements are a potential technique to provide valuable experimental information about the status of cavitation clouds. Using purpose-made, rugged, wide band, and small-sized needle hydrophones, sound field measurements in bubble clusters were performed and time-dependent sound pressure waveforms were acquired and analyzed in the frequency domain up to 20 MHz. The cavitation clusters were synchronously observed by an electron multiplying charge-coupled device (EMCCD) camera and the relation between the sound field measurements and cluster behaviour was investigated. Depending on the driving power, three ranges could be identified and characteristic properties were assigned. At low power settings no transient and no or very low stable cavitation activity can be observed. The medium range is characterized by strong pressure peaks and various bubble cluster forms. At high power a stable double layer was observed which grew with further increasing power and became quite dynamic. The sound field was irregular and the fundamental at driving frequency decreased. Between the bubble clouds completely different sound field properties were found in comparison to those in the cloud where the cavitation activity is high. In between the sound field pressure amplitude was quite small and no collapses were detected. PMID- 24953963 TI - Two-dimensional superconductivity at the interface of a Bi2Te3/FeTe heterostructure. AB - The realization of superconductivity at the interface between a topological insulator and an iron-chalcogenide compound is highly attractive for exploring several recent theoretical predictions involving these two new classes of materials. Here we report transport measurements on a Bi2Te3/FeTe heterostructure fabricated via van der Waals epitaxy, which demonstrate superconductivity at the interface, which is induced by the Bi2Te3 epilayer with thickness even down to one quintuple layer, though there is no clear-cut evidence that the observed superconductivity is induced by the topological surface states. The two dimensional nature of the observed superconductivity with the highest transition temperature around 12 K was verified by the existence of a Berezinsky-Kosterlitz Thouless transition and the diverging ratio of in-plane to out-plane upper critical field on approaching the superconducting transition temperature. With the combination of interface superconductivity and Dirac surface states of Bi2Te3, the heterostructure studied in this work provides a novel platform for realizing Majorana fermions. PMID- 24953961 TI - Effects of palmitate on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets. AB - BACKGROUND: Circulating free fatty acids are often elevated in patients with type 2 diabetes (T2D) and obese individuals. Chronic exposure to high levels of saturated fatty acids has detrimental effects on islet function and insulin secretion. Altered gene expression and epigenetics may contribute to T2D and obesity. However, there is limited information on whether fatty acids alter the genome-wide transcriptome profile in conjunction with DNA methylation patterns in human pancreatic islets. To dissect the molecular mechanisms linking lipotoxicity to impaired insulin secretion, we investigated the effects of a 48 h palmitate treatment in vitro on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets. METHODS: Genome-wide mRNA expression was analyzed using Affymetrix GeneChip((r)) Human Gene 1.0 ST whole transcript-based array (n = 13) and genome-wide DNA methylation was analyzed using Infinium HumanMethylation450K BeadChip (n = 13) in human pancreatic islets exposed to palmitate or control media for 48 h. A non-parametric paired Wilcoxon statistical test was used to analyze mRNA expression. Apoptosis was measured using Apo-ONE((r)) Homogeneous Caspase-3/7 Assay (n = 4). RESULTS: While glucose-stimulated insulin secretion was decreased, there was no significant effect on apoptosis in human islets exposed to palmitate. We identified 1,860 differentially expressed genes in palmitate-treated human islets. These include candidate genes for T2D, such as TCF7L2, GLIS3, HNF1B and SLC30A8. Additionally, genes in glycolysis/gluconeogenesis, pyruvate metabolism, fatty acid metabolism, glutathione metabolism and one carbon pool by folate were differentially expressed in palmitate-treated human islets. Palmitate treatment altered the global DNA methylation level and DNA methylation levels of CpG island shelves and shores, 5'UTR, 3'UTR and gene body regions in human islets. Moreover, 290 genes with differential expression had a corresponding change in DNA methylation, for example, TCF7L2 and GLIS3. Importantly, out of the genes differentially expressed due to palmitate treatment in human islets, 67 were also associated with BMI and 37 were differentially expressed in islets from T2D patients. CONCLUSION: Our study demonstrates that palmitate treatment of human pancreatic islets gives rise to epigenetic modifications that together with altered gene expression may contribute to impaired insulin secretion and T2D. PMID- 24953965 TI - Iron deficiency anemia in predominantly breastfed young children. AB - BACKGROUND: Due to the increase of breastfeeding in infants, iron deficiency anemia (IDA) related to prolonged, predominant breastfeeding should be of concern. Mostly, the manifestation of IDA is indistinguishable and the enthusiastic advocacy of breastfeeding without concomitant education of complementary food may lead to ignorance of breast milk-related IDA, which may result in impaired psychomotor development of the baby. This retrospective study was conducted to re-emphasize this easily ignored but still prevalent illness. METHODS: This retrospective study involved 15 breastfeeding babies who were diagnosed with IDA between January 2007 and December 2010 at age 6-18 months. The clinical presentation, age at diagnosis, initial hemoglobin level and mean corpuscular volume, growth percentile, and duration of treatment were recorded and analyzed. RESULTS: None of the babies was suspected to have anemia by caregivers. Pallor was noticed by physicians in nine patients; one patient had seizure, one patient had pica, and, for the remaining four patients, IDA was diagnosed incidentally due to other medical events. Oral iron supplementation for an average of 3.6 months improved both hemoglobin level (from 8.0 g/dL to 11.5 g/dL) and mean corpuscular volume (from 57.5 fL to 73.9 fL). Most babies had appropriate growth and normal neurological development; two babies had both IDA and thalassemia. CONCLUSION: Although the association of IDA with prolonged, predominant breastfeeding is well known, its presentation is so subtle that its detection relies mainly on alert medical personnel. PMID- 24953966 TI - Recent advances of zwitterionic carboxybetaine materials and their derivatives. AB - Zwitterionic polycarboxybetaine (pCB)-based materials have drawn special attention due to their outstanding properties of resisting proteins adsorption, biofilm formation and cell attachment on a variety of substrates and surfaces, reducing the uptake of pCB-coated nanosized materials, as well as providing the capability of further functionalization. Zwitterionic pCBs have been proven to be excellent choices for many applications, not only limited to the field of antifouling. This review will summarize the recent progress on the development of pCB materials and the understanding of the structure-function-property relationships of carboxybetaine materials. PMID- 24953967 TI - Detoxification of acid pretreated spruce hydrolysates with ferrous sulfate and hydrogen peroxide improves enzymatic hydrolysis and fermentation. AB - The aim of the present work was to investigate whether a detoxification method already in use during waste water treatment could be functional also for ethanol production based on lignocellulosic substrates. Chemical conditioning of spruce hydrolysate with hydrogen peroxide (H2O2) and ferrous sulfate (FeSO4) was shown to be an efficient strategy to remove significant amounts of inhibitory compounds and, simultaneously, to enhance the enzymatic hydrolysis and fermentability of the substrates. Without treatment, the hydrolysates were hardly fermentable with maximum ethanol concentration below 0.4 g/l. In contrast, treatment by 2.5 mM FeSO4 and 150 mM H2O2 yielded a maximum ethanol concentration of 8.3 g/l. PMID- 24953964 TI - Attention as an effect not a cause. AB - Attention is commonly thought to be important for managing the limited resources available in sensory areas of the neocortex. Here we present an alternative view that attention arises as a byproduct of circuits centered on the basal ganglia involved in value-based decision making. The central idea is that decision making depends on properly estimating the current state of the animal and its environment and that the weighted inputs to the currently prevailing estimate give rise to the filter-like properties of attention. After outlining this new framework, we describe findings from physiological, anatomical, computational, and clinical work that support this point of view. We conclude that the brain mechanisms responsible for attention employ a conserved circuit motif that predates the emergence of the neocortex. PMID- 24953968 TI - Algal biocathode for in situ terminal electron acceptor (TEA) production: synergetic association of bacteria-microalgae metabolism for the functioning of biofuel cell. AB - Replacement of energy intensive mechanical aeration with sustainable oxygenic photosynthesis by microalgae at cathode was studied in dual-chambered microbial fuel cell (MFC). The synergistic association between bacterial fermentation at anode and the oxygenic photosynthesis of microalgae at cathode facilitated good power output as well as treatment efficiency. However, MFC operation during spring showed higher bioelectrogenic activity (57.0 mW/m(2)) over summer (1.1 mW/m(2)) due to the higher oxygenic photosynthetic activity of microalgae and respective dissolved oxygen (DO) levels. This can be attributed to RuBisCO inactivation under high temperatures and light intensity of summer, which prevented rich algal biomass growth as well as their photosynthetic activity. Unlike abiotic cathode, the algal cathode potential increased with operation time due to the algal biomass growth during spring but was negligible during summer. The catalytic currents on voltammetric signatures and the bioprocess parameters also corroborated well with the observed power output. PMID- 24953969 TI - Optical coherence tomography for the evaluation of asymmetric cardiac allograft vasculopathy in a child. AB - We present an unusual case of CAV in a child with isolated disease in the LAD coronary artery. Initial progression of the disease appeared to have been halted by the use of sirolimus, but the assessment of disease in other vessels (particularly the RCA) was of particular importance in deciding whether or not to relist this patient for transplantation. Due to the known limitations of coronary angiography, we used OCT to assess for angiographically silent CAV. The normal intravascular appearance of the RCA by OCT was reassuring, and the child was not relisted for transplantation. OCT offers multiple advantages for the assessment of CAV in children. PMID- 24953972 TI - Giant-cell tumor of the patella in a skeletally immature girl. AB - BACKGROUND: We reported on a case of a giant-cell tumor of the patella which occurred in a skeletally immature patient. This combination of unusual age of presentation and atypical location made our case clinically and radiologically unique. CASE REPORT: A 13-year-old girl presented with complains of knee pain and swelling. After radiological investigations and percutaneous needle biopsy a diagnosis of giant-cell tumor of the patella was made, for which the patient underwent patellectomy with en bloc resection of the lesion and the diagnosis was confirmed by histopathological examination. CONCLUSIONS: It was concluded that early diagnosis may be difficult in such cases and hence, GCT should be considered in the differential diagnosis of a destructive lesion of the patella, regardless of the age of presentation. PMID- 24953970 TI - Hemocompatibility and cytocompatibility of the hirudin-modified silk fibroin. AB - Hirudin (Hir), a thrombin direct inhibitor, was used to modify a polyethylene glycol diglycidyl ether (PEG-DE) crosslinked regenerated silk fibroin (SF) material to improve hemocompatibility. Hemolysis characteristics, platelet adhesion, platelet activity, and plasma recalcification time were investigated using absorption spectrometry, scanning electron microscopy, MTT analysis, and the time counting method. Hirudin could be grafted evenly to the silk fibroin, and the modified material was resistant to hemolysis at ratios of less than 0.5%. Scanning electron microscopy and MTT results showed that platelet adhesion and aggregation activity decreased after modificaton with trace amounts of hirudin, compared with PEG-DE crosslinked and ethanol-treated silk fibroin film. Plasma recalcification of PEG-DE crosslinked silk fibroin film was slower than with ethanol-treated material, and this increased slightly after hirudin modification. Furthermore, L929, HAVSMC, and HUVEC cells adhered to the modified material, grew well, and possessed high proliferation activity on SF/Hir blend films. This study suggests that hirudin could improve the anticoagulation properties of regenerated silk fibroin materials. PMID- 24953971 TI - DNA nanoarchitectures: steps towards biological applications. AB - DNA's remarkable molecular recognition properties, flexibility, and structural features make it one of the most promising scaffolds to design a variety of nanostructures. During recent decades, two major methods have been developed for the construction of DNA nanomaterials in a programmable way; both generate nanostructures in one, two, and three dimensions. The tile-based assembly process is a useful tool to construct large and simple structures; the DNA origami method is suitable for the production of smaller, more sophisticated and well-defined structures. Proteins, nanoparticles and other functional elements have been specifically positioned into designed patterns on these structures. They can also act as templates to study chemical reactions, help in the structural determination of proteins, and be used as platform for genomic and drug delivery applications. In this review we examine recent progresses towards the potential use of DNA nanostructures in molecular and cellular biology. PMID- 24953974 TI - Glabridin induces glucose uptake via the AMP-activated protein kinase pathway in muscle cells. AB - The present study demonstrates that glabridin, a prenylated isoflavone in licorice, stimulates glucose uptake through the adenosine monophosphate-activated protein kinase (AMPK) pathway in L6 myotubes. Treatment with glabridin for 4h induced glucose uptake in a dose-dependent manner accompanied by the translocation of glucose transporter type 4 (GLUT4) to the plasma membrane. Glabridin needed at least 4h to increase glucose uptake, while it significantly decreased glycogen and increased lactic acid within 15 min. Pharmacological inhibition of AMPK by Compound C suppressed the glabridin-induced glucose uptake, whereas phosphoinositide 3-kinase and Akt inhibition by LY294002 and Akt1/2 inhibitor, respectively, did not. Furthermore, glabridin induced AMPK phosphorylation, and siRNA for AMPK completely abolished glabridin-induced glucose uptake. We confirmed that glabridin-rich licorice extract prevent glucose intolerance accompanied by the AMPK-dependent GLUT4 translocation in the plasma membrane of mice skeletal muscle. These results indicate that glabridin may possess a therapeutic effect on metabolic disorders, such as diabetes and hyperglycemia, by modulating glucose metabolism through AMPK in skeletal muscle cells. PMID- 24953973 TI - Triazole GHS-R1a antagonists JMV4208 and JMV3002 attenuate food intake, body weight, and adipose tissue mass in mice. AB - The only peripherally released orexigenic hormone, ghrelin, plays a key role in food intake and body weight regulation. Antagonizing the ghrelin receptor, GHS R1a, represents a promising approach for anti-obesity therapy. In our study, two novel GHS-R1a antagonists JMV4208 and JMV3002, which are trisubstituted 1,2,4 triazoles, decreased food intake in fasted lean mice in a dose-dependent manner, with ED50 values of 5.25 and 2.05 mg/kg, respectively. Both compounds were stable in mouse blood, with half-lives of 90 min (JMV4208) and 60 min (JMV3002), and disappeared from the blood 8h after administration. Fourteen days of treatment with the ghrelin antagonists (20 mg/kg twice a day) decreased food intake, body weight and adipose tissue mass in mice with diet-induced obesity (DIO). These results are likely attributable to an impact on food intake reduction and an attenuated expression of the lipogenesis-promoting enzymes (acetyl-CoA carboxylase 1 in subcutaneous fat and fatty acid synthase in subcutaneous and intraperitoneal fat). The decrease in fat mass negatively impacted circulating leptin levels. These data suggest that JMV4208 and JMV3002 could be useful therapeutic agents for the treatment of obesity. PMID- 24953976 TI - Electrochemical observation of single collision events: fullerene nanoparticles. AB - Individual fullerene nanoparticles are detected and sized in a non-aqueous solution via cathodic particle coulometry where the direct, quantitative reduction of single nanoparticles is achieved upon collision with a potentiostated gold electrode. This is the first time that the nanoparticle impact technique has been shown to work in a non-aqueous electrolyte and utilized to coulometrically size carbonaceous nanoparticles. Contrast is drawn between single-nanoparticle electrochemistry and that seen using nanoparticle ensembles via modified electrodes. PMID- 24953975 TI - A systematic review of BNP and NT-proBNP in the management of heart failure: overview and methods. AB - B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) levels are increased in persons with heart failure (HF); low levels of these peptides rule out HF. We systematically reviewed the literature to assess the use of BNP and NT proBNP in the diagnosis, prognosis, and treatment for HF. We also examined the biological variation of these peptides in persons with and without HF. We searched Medline, Embase, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL for English-language studies published between January 1989 and June 2012. Supplemental searches involved the gray literature and the reference lists of included studies. Trained reviewers used standardized forms to screen articles for inclusion in the review and to extract data from included papers. We examined the risk of bias with QUADAS-2 for diagnosis studies, the Hayden criteria for prognosis studies, and the Jadad scale for treatment studies. We assessed the strength of evidence in four domains (risk of bias, consistency, directness, and precision) for the diagnosis and treatment studies. Results were reported as narrative syntheses. Additional meta-analyses were conducted for the diagnosis studies. Three hundred ten articles passed through screening and were included in the review. One hundred four articles applied to diagnostic accuracy, 190 papers pertained to prognosis, and nine articles addressed BNP- or NT-proBNP-guided treatment. Each individual paper in this series reports, summarizes, and discusses the evidence regarding diagnosis, prognosis, or treatment. PMID- 24953977 TI - A noncontrolled trial of anti-TNF-alpha chimeric monoclonal antibody (infliximab, Remicade((r))) in exudative age-related macular degeneration. PMID- 24953978 TI - Comparison of Centers for Disease Control and Prevention and World Health Organization references/standards for height in contemporary Australian children: analyses of the Raine Study and Australian National Children's Nutrition and Physical Activity cohorts. AB - AIM: (i) To compare the Centers for Disease Control and Prevention (CDC) reference and World Health Organization (WHO) standard/reference for height, particularly with respect to short stature and eligibility for growth hormone (GH) treatment by applying them to contemporary Australian children; (ii) To examine the implications for identifying short stature and eligibility for GH treatment. METHODS: Children from the longitudinal Raine Study were serially measured for height from 1991 to 2005 (2-15-year-old girls (660) and boys (702) from Western Australia). In the cross-sectional Australian National Children's Nutrition and Physical Activity survey (2-16-year-old boys (2415) and girls (2379) from all states), height was measured in 2007. Heights were converted to standard deviation scores (SDSs) based on CDC and WHO. RESULTS: Means and standard deviations of height-SDS varied between CDC and WHO definitions and with age and gender within each definition. However, both identified similar frequencies of short stature (<1st centile for GH eligibility), although these were very significantly less than the anticipated 1% (0.1-0.7%) of the Australian cohorts. Mean heights in the Australian cohorts were greater than both the WHO and CDC means. CONCLUSIONS: Neither CDC nor WHO height standardisations accurately reflect the contemporary Australian child population. Australian children are taller than the CDC or WHO height means, and significantly less than 1% of Australian children are defined as being short using either CDC or WHO. This study suggests there may be a case for an Australian-specific standard/reference for height. PMID- 24953979 TI - Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors. AB - INTRODUCTION: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long lasting responses, resistance to EGFR TKIs invariably occurs. AREAS COVERED: This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal-epithelial transition factor (MET) amplification, epithelial mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation. CONCLUSION: Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC. PMID- 24953980 TI - Fertility preservation in cancer patients: the global framework. AB - Cancer treatment is the most frequent cause of reduced fertility in cancer patients, with up to 80% of survivors affected. None of the established or experimental fertility preservation methods can assure parenthood, rather they may provide a future opportunity to overcome treatment induced sterility. Around 70-75% of young cancer survivors are interested in parenthood but the numbers of patients who access fertility preservation techniques prior treatment are significantly lower. Moreover, despite existing guidelines, healthcare professionals do not address fertility preservation issues adequately. Lack of time and knowledge about existing options, delay in potentially useful treatment, patient's age, partnership status, existing children, sexual orientation and socioeconomic situation are the main barriers to effective fertility preservation. Patient's fears, expectations and priorities shaped by personal values have to be addressed in the framework of medical necessities, realistic survival probabilities, socio-cultural environment and resources availability. We call for a need of patient centred fertility counselling within a framework that should include patients understanding of medical aspects of their cancer, realistic fertility preservation options, preferences based on personal values and goals. Optional support services could also include legal guidance, psychological and spiritual support and financial counselling. PMID- 24953981 TI - Higher ferritin levels, but not serum iron or transferrin saturation, are associated with Type 2 diabetes mellitus in adult men and women free of genetic haemochromatosis. AB - CONTEXT: Iron overload predisposes to diabetes and higher ferritin levels have been associated with diabetes. However, it is unclear whether ferritin reflects differences in iron-related parameters between diabetic and nondiabetic persons. We examined associations of serum ferritin, iron and transferrin saturation with Type 2 diabetes in adults without genetic predisposition to iron overload. DESIGN, PARTICIPANTS AND MEASUREMENTS: Cross-sectional analysis of community dwelling men and women aged 17-97 years from the Busselton Health Survey, Western Australia. Men and women carrying genotypes associated with haemochromatosis (C282Y/C282Y or C282Y/H63D) were excluded. Serum ferritin, iron and transferrin saturation were assayed. RESULTS: There were 1834 men (122 with diabetes, 6.6%) and 2351 women (141 with diabetes, 6%). In men, higher serum ferritin was associated with diabetes after adjusting for age, smoking, alcohol, cardiovascular history, body mass index (BMI), waist, blood pressure, lipids, C reactive protein (CRP), adiponectin, alanine transaminase (ALT) and gamma glutamyl transpeptidase (GGT) [odds ratio (OR): 1.29 per 1 unit increase log ferritin, 95% confidence interval (CI) = 1.01-1.65, P = 0.043]. In women, higher serum ferritin was associated with diabetes [fully adjusted OR: 1.31 per 1 unit increase log ferritin, 95% CI = 1.04-1.63, P = 0.020; 1.84 for tertile (T) 3 vs T1, 95% CI = 1.09-3.11]. Neither iron levels nor transferrin saturation were associated with diabetes risk in men or women. Higher ferritin was not associated with insulin resistance in nondiabetic adults. CONCLUSIONS: In adults, higher ferritin levels are independently associated with prevalent diabetes while iron and transferrin saturation are not. Ferritin is a robust biomarker for diabetes risk, but further investigation is needed to clarify whether this relationship is mediated via iron metabolism. PMID- 24953983 TI - Relative value units poorly correlate with measures of surgical effort and complexity. AB - BACKGROUND: The relationship between procedural relative value units (RVUs) for surgical procedures and other measures of surgeon effort are poorly characterized. We hypothesized that RVUs would poorly correlate with quantifiable metrics of surgeon effort. METHODS: Using the 2010 American College of Surgeons - National Surgical Quality Improvement Program (NSQIP) database, we selected 11 primary current procedural terminology codes associated with high volume surgical procedures. We then identified all patients with a single reported procedural RVU who underwent nonemergent, inpatient general surgical operations. We used linear regression to correlate length of stay (LOS), operative time, overall morbidity, frequency of serious adverse events (SAEs), and mortality with RVUs. We used multivariable logistic regression using all preoperative NSQIP variables to determine other significant predictors of our outcome measures. RESULTS: Among 14,481 patients, RVUs poorly correlated with individual LOS (R(2) = 0.05), operative time (R(2) = 0.10), and mortality (R(2) = 0.35). There was a moderate correlation between RVUs and SAEs (R(2) = 0.79) and RVUs and overall morbidity (R(2) = 0.75). However, among low- to mid-level RVU procedures (11-35) there was a poor correlation between SAEs (R(2) = 0.15), overall morbidity (R(2) = 0.05), and RVUs. On multivariable analysis, RVUs were significant predictors of operative time, LOS, and SAEs (odds ratio 1.06, 95% confidence interval: 1.05 1.07), but RVUs were not a significant predictor of mortality (odds ratio 1.02, 95% confidence interval: 0.99-1.05). CONCLUSIONS: For common, index general surgery procedures, the current RVU assignments poorly correlate with certain metrics of surgeon work, while moderately correlating with others. Given the increasing emphasis on measuring and tracking surgeon productivity, more objective measures of surgeon work and productivity should be developed. PMID- 24953982 TI - Risk factors for hospital-sssociated venous thromboembolism in the neonatal intensive care unit. AB - OBJECTIVE: To determine hospital-associated venous thromboembolism (HA-VTE) risk factors in critically ill neonates. METHODS: We conducted a case-control study in the neonatal intensive care unit (NICU) of All Children's Hospital Johns Hopkins Medicine (St. Petersburg, FL), from January 1, 2006 - April 10, 2013. We identified HA-VTE cases using electronic health record. Four NICU controls were randomly selected for each HA-VTE case. Associations between putative risk factors and HA-VTE were estimated using odds ratios (ORs) and ninety-five percent confidence intervals (95%CIs) from univariate and multivariate regression analyses. RESULTS: Twenty-three HA-VTE cases and 92 controls were included. The annual HA-VTE incidence was approximately 1.4 HA-VTE cases per 1,000 NICU admissions. In univariate analyses, mechanical ventilation (OR=7.27, 95%CI=2.02 26.17, P=0.002), central venous catheter (CVC; OR=52.95, 95%CI=6.80-412.71, P<0.001), infection (OR=7.24, 95%CI=2.66-19.72, P<0.001), major surgery (OR=5.60, 95%CI=1.82-17.22, P=0.003) and length of stay >=15days (OR=6.67, 95%CI=1.85 23.99, P=0.004) were associated with HA-VTE. Only CVC (OR=29.04, 95%CI=3.18 265.26, P=0.003) remained an independent risk factor in the multivariate analysis. Based on this result, the estimated risk of HA-VTE in NICU patients with a CVC was 0.9%. CONCLUSION: This study identifies CVC as an independent risk factor for HA-VTE in critically ill neonates. However, the level of risk associated with CVC is below the conventional threshold for primary anticoagulation thromboprophylaxis. Larger studies are needed to substantiate these findings and identify novel putative risk factors to further distinguish NICU patients at highest HA-VTE risk. PMID- 24953984 TI - The impact of Aldehyde dehydrogenase 1 expression on prognosis for metastatic colon cancer. AB - BACKGROUND: Cancer stem cells may be associated with tumor progression and prognosis for colon cancer. We hypothesized that expression of Aldehyde dehydrogenase 1 (ALDH1) would increase with tumor progression and be associated with survival. METHODS: Tissue was obtained from resection specimens for isolation of cancer stem cells. In addition, paraffin blocks from resected colon cancers with normal colon, primary tumor, and lymph node and liver metastasis from 2000 to 2010 were identified and stained with ALDH1. RESULTS: In in vitro models (adherent and tumor spheres) ALHD1+ cells grew more efficiently than ALDH1 cells. ALDH1 expression was highest in peritumoral crypt cells (0.137 MUm(2), 95% confidence interval [CI] 0.125-0.356) and normal crypts (median 0.091 MUm(2), 95% CI 0.064-0.299) followed by lymph node metastasis (median 0.025 MUm(2), 95% CI 0-0.131) and the primary cancers (median 0.014 MUm(2), 95% CI 0.0123-0.154). Samples were divided into high and low ALDH1 expression. Survival was associated with expression in the primary tumor (9 versus 23 mo, P = 0.0016) expression but not peritumoral tissue (21 versus 20.5 mo, P = 0.32), normal colon (19 versus 27 mo, P = 0.289), or lymph node metastasis (23 versus 21 mo, P = 0.69). On univariate analysis, ALDH1 expression and grade were associated with survival but ages, number of lymph node metastasis, race, or grade were not associated. On multivariate analysis, only ALDH1 status continued to be associated with survival, odds ratio 4.4, and P = 0.011. CONCLUSIONS: ALDH1 is indicative of stemness and is a biomarker marker in colon cancer. Expression did not increase with progression from normal colon to primary tumors and metastasis. PMID- 24953985 TI - Donor management parameters and organ yield: single center results. AB - BACKGROUND: Management of organ donors in the intensive care unit is an emerging subject in critical care and transplantation. This study evaluates organ yield outcomes for a large number of patients managed by the Indiana Organ Procurement Organization. MATERIALS AND METHODS: This is a retrospective review of intensive care unit records from 2008-2012. Donor demographic information and seven donor management parameters (DMP) were recorded at admission, consent, 12 h after consent, and before procurement. Three study groups were created: donors meeting 0-3, 4, or 5-7 DMP. Active donor Organ Procurement Organization management began at consent; so, data analysis focuses on the 12-h postconsent time point. Outcomes included organs transplanted per donor (OTPD) and transplantation of individual solid organs. RESULTS: Complete records for 499 patients were reviewed. Organ yield was 1415 organs of 3992 possible (35%). At 12 h, donors meeting more DMP had more OTPD: 2.2 (0-3) versus 3.0 (4) versus 3.5 (5-7) (P < 0.01). Aggregate DMP met was significantly associated with transplantation of every organ except intestine. Oxygen tension, vasopressor use, and central venous pressure were the most frequent independent predictors of organ usage. There were significantly more organs transplanted for donors meeting all three of these parameters (4.5 versus 2.7, P < 0.01). CONCLUSIONS: Initial DMP met does not appear to be a significant prognostic factor for OTPD. Aggregate DMP is associated with transplantation rates for most organs, with analysis of individual parameters suggesting that appropriate management of oxygenation, volume status, and vasopressor use could lead to more organs procured per donor. PMID- 24953986 TI - Pivotal role of mast cell carboxypeptidase A in mediating protection against small intestinal ischemia-reperfusion injury in rats after ischemic preconditioning. AB - AIM OF THE STUDY: Mast cell (MC) degranulation contributes to the protection mediated by ischemic preconditioning (IPC); however, the precise mechanisms underlying this protection remain largely unknown. Mast cell carboxypeptidase A (MC-CPA) is released solely from MCs and plays a critical role in degrading toxins and endothelin 1 (ET-1). The present study sought to explore whether MC CPA is involved in the process of IPC in a rodent model of small intestinal ischemia reperfusion (IIR) injury. MATERIALS AND METHODS: IIR injuries were induced in Sprague-Dawley rats by clamping the superior mesenteric artery for 60 min followed by reperfusion for 2 h. One cycle of 10 min intestinal ischemia and 10 min of reperfusion was used in the IPC group, and the MC stabilizer cromolyn sodium and MC potato carboxypeptidase inhibitor were administered before the start of IPC. At the end of experiment, intestine tissue was obtained for assays of the MC-CPA3, tumor necrosis factor-alpha, interleukin-6, and ET-1 contents and myeloperoxidase activities. Intestinal histologic injury scores and MC degranulation were assessed. Apoptosis indices and cleaved caspase- 3 protein expressions were quantified. RESULTS: IIR resulted in severe injury, as evidenced by significant increases in injury scores and MC-CPA3, tumor necrosis factor alpha, interleukin-6, and ET-1 contents that were accompanied with concomitant elevations in cleaved caspase 3 expression, apoptosis indices, and myeloperoxidase activities. IPC induced a significant increase in MC-CPA3, induced MC degranulation, and attenuated IIR injury by downregulating IIR-induced biochemical changes, whereas cromolyn sodium and potato carboxypeptidase inhibitor abolished the IPC-mediated changes. CONCLUSIONS: These data suggest that IPC protected against IIR injury via the MC degranulation-mediated release of MC-CPA. PMID- 24953987 TI - Upregulation of let-7a inhibits vascular smooth muscle cell proliferation in vitro and in vein graft intimal hyperplasia in rats. AB - BACKGROUND: Proliferation of vascular smooth muscle cells (VSMCs) is a crucial event in the pathogenesis of intimal hyperplasia, which is the main cause of restenosis after vascular reconstruction. In this study, we assessed the impact of let-7a microRNA (miRNA) on the proliferation of VSMCs. METHODS: Using miRNA microarrays analysis for miRNA expression in the vein graft model. Lentiviral vector-mediated let-7a was transfected into the vein grafts. In situ hybridization was performed to detect let-7a. Cultured rat VSMCs were transfected with let-7a mimics for different periods of time. Cell proliferation, migration and cell cycle activity were monitored following transfection of the let-7a mimics. Immunohistochemical and Western blotting analysis the expression levels of c-myc and K-ras. RESULTS: We found that let-7a was the most downregulated miRNA in the vein graft model. In vivo proliferation of VSMCs was assessed in a rat model of venous graft intimal hyperplasia. Let-7a was found to localize mainly to the VSMCs. Let-7a miRNA expression was increased in VSMCs in the neointima of the let-7a treated group. Intimal hyperplasia was suppressed by upregulation of let-7a via lentiviral vector-mediated mimics. In cultured VSMCs, the expression of let-7a increased upon starving, and the upregulation of let-7a miRNA significantly decreased cell proliferation and migration. Immunohistochemical and Western blotting analysis demonstrated that treatment with let-7a mimics resulted in decreased expression levels of c-myc and K-ras. CONCLUSIONS: The results indicate that let-7a miRNA is a novel regulator of VSMC proliferation in intimal hyperplasia. These findings suggest that let-7a miRNA is a promising therapeutic target for the prevention of intimal hyperplasia. PMID- 24953988 TI - Node-extranodal soft tissue stage based on extranodal metastasis is associated with poor prognosis of patients with gastric cancer. AB - BACKGROUND: The purpose of this study was to evaluate the effect of Node Extranodal soft tissue (pNE) stage based on Extranodal Metastasis (EM) on recurrence and survival in patients with gastric cancer (GC). MATERIALS AND METHODS: A total of 642 patients were divided into two groups according to statue of EM. Clinicopathologic features were compared among the two groups, the log rank test was used to assess statistical differences between the groups. Independent prognostic factors were identified by the Cox proportional hazards regression model. According to the number of EMs, EM was incorporated into the pN stage of gastric carcinoma. The 5-y overall survival (OS) and disease free survival (DFS) rates were 48.1% and 17.4%, 44.5% and 14.3% between the two groups. Patients with EM had a deeper tumor invasion and more number of lymph node metastases. Peritoneal dissemination and distant metastasis were more frequent with EM. EM is an independent risk factor for distance recurrence (odds ratio = 1.605), and it is the highest risk factor for peritoneal recurrence (odds ratio = 2.448). Multivariate analysis showed that depth of tumor invasion (P = 0.025), lymph node metastasis (P <0.001), and EM (P = 0.006) were independent factors associated with OS. Furthermore, EM (P = 0.0039) was also an independent prognostic factor for DFS. The differences in prognostic prediction between the seventh edition of the pN classification and the pNE classification were directly compared. We found the pNE classification (hazard ratio = 1.730, P <0.001) was more appropriate for predicting the OS of GC patients after curative surgery, and the -2 loglikehood of the pNE staging (4533.991) is smaller than the value of pN. CONCLUSIONS: EM was closely associated with cancer aggressiveness and the presence of EM was a significant independent predictor of reduced DFS and OS in GC patients. EM is an independent risk factor for distance recurrence, especially for peritoneal recurrence, the selection of postoperative adjuvant therapy in systemic (intravenous or intra-arterial) and regional (intraperitoneal) based on EM may be a reasonable approach. The lymph node imaging techniques such as injecting nanocarbon during surgery should be applied. As an important prognostic factor, EM should be incorporated into N stage according to its number retrieved in postoperative samples. PMID- 24953989 TI - A novel in situ model of liver cold ischemia-reperfusion in rats. AB - BACKGROUND: Orthotopic liver transplantation (OLT) is being used for studying cold ischemia reperfusion (I/R)-induced injury in experimental animals, but the technique is complicated and it does not accurately reflect the pathophysiology. Here, we report a novel model, termed "in situ liver cold ischemia (ISLCI)", in Wistar rats. METHODS: ISLCI was achieved in rats by establishing a portal-jugular shunt and a cannula shunt in inferior vena cava, and the liver was continuously perfused with lactate Ringer's solution at a speed of 150 mL/h through the portal vein for 60 min. Portal venous pressure, serum levels of total bilirubin, alkaline phosphatase, alanine aminotransferase and gamma-glutamyl transpeptidase (GGT), and hepatic histopathology were examined, and compared with rats undergoing OLT, in which the donor liver was subjected to a 60 min cold ischemia. RESULTS: Livers from ISLCI and OLT rats showed histopathologic changes characteristic of I/R-induced injury when examined on days 1 and 7, with complete recovery 14 d after reperfusion. Compared with OLT rats, ISLCI rats had significantly lower levels of portal venous pressure 1 and 10 min after porta hepatis clamping. They suffered a milder degree of I/R-induced hepatic injury, reflected by significantly lower levels of GGT, alanine aminotransferase, and alkaline phosphatase on day 1, and a significant lower level of GGT and a lower histopathologic score on day 7 after reperfusion. CONCLUSIONS: Our preliminary results indicate that the ISLCI model is reliable and technically easier, and is superior to OLT for studying cold I/R injury. PMID- 24953990 TI - Risk factors for retained surgical items: a meta-analysis and proposed risk stratification system. AB - BACKGROUND: Retained surgical items (RSI) are designated as completely preventable "never events". Despite numerous case reports, clinical series, and expert opinions few studies provide quantitative insight into RSI risk factors and their relative contributions to the overall RSI risk profile. Existing case control studies lack the ability to reliably detect clinically important differences within the long list of proposed risks. This meta-analysis examines the best available data for RSI risk factors, seeking to provide a clinically relevant risk stratification system. METHODS: Nineteen candidate studies were considered for this meta-analysis. Three retrospective, case-control studies of RSI-related risk factors contained suitable group comparisons between patients with and without RSI, thus qualifying for further analysis. Comprehensive Meta Analysis 2.0 (BioStat, Inc, Englewood, NJ) software was used to analyze the following "common factor" variables compiled from the above studies: body-mass index, emergency procedure, estimated operative blood loss >500 mL, incorrect surgical count, lack of surgical count, >1 subprocedure, >1 surgical team, nursing staff shift change, operation "afterhours" (i.e., between 5 PM and 7 AM), operative time, trainee presence, and unexpected intraoperative factors. We further stratified resulting RSI risk factors into low, intermediate, and high risk. RESULTS: Despite the fact that only between three and six risk factors were associated with increased RSI risk across the three studies, our analysis of pooled data demonstrates that seven risk factors are significantly associated with increased RSI risk. Variables found to elevate the RSI risk include intraoperative blood loss >500 mL (odds ratio [OR] 1.6); duration of operation (OR 1.7); >1 subprocedure (OR 2.1); lack of surgical counts (OR 2.5); >1 surgical team (OR 3.0); unexpected intraoperative factors (OR 3.4); and incorrect surgical count (OR 6.1). Changes in nursing staff, emergency surgery, body-mass index, and operation "afterhours" were not significantly associated with increased RSI risk. CONCLUSIONS: Among the "common risk factors" reported by all three case-control studies, seven synergistically show elevated RSI risk across the pooled data. Based on these results, we propose a risk stratification scheme and issue a call to arms for large, prospective, and multicenter studies evaluating effects of specific changes at the institutional level (i.e., universal surgical counts, radiographic verification of the absence of RSI, and radiofrequency labeling of surgical instruments and sponges) on the risk of RSI. Overall, our findings provide a meaningful foundation for future patient safety initiatives and clinical studies of RSI occurrence and prevention. PMID- 24953992 TI - Optical properties and energy transfer of Eu2+/Ce3+ co-activated Na3Ca6(PO4)5 phosphor. AB - Ce(3+) /Eu(2+) co-doped Na3 Ca6 (PO4 )5 phosphors were prepared using a combustion-assisted synthesis method. X-Ray powder diffraction (XRD) analysis confirmed the formation of a Na3 Ca6 (PO4 )5 crystal phase. Na3 Ca6 (PO4 )5 :Eu(2+) phosphors have an efficient bluish-green emission band that peaks at 489 nm, whereas Ce(3+) -doped Na3 Ca6 (PO4 )5 showed a bright emission band at 391 nm. Analysis of the experimental results suggests that enhancement of the Eu(2+) emission intensity in co-doped Na3 Ca6 (PO4 )5 :Eu(2+) ,Ce(3+) phosphors is due to a resonance-type energy transfer from Ce(3+) to Eu(2+) ions, which is predominantly governed by an exchange interaction mechanism. These results indicate that Ce(3+) /Eu(2+) co-doped Na3 Ca6 (PO4 )5 is potentially useful as a highly efficient, bluish-green emitting, UV-convertible phosphor for white-light emitting diodes. PMID- 24953993 TI - Acid-coated Textiles (pH 5.5-6.5)--a New Therapeutic Strategy for Atopic Eczema? AB - Increased transepidermal water loss (TEWL) and decreased skin capacitance are characteristic features of the disturbed epidermal barrier in atopic eczema (AE). The "acid mantle", which is a slightly acidic film on the surface of the skin has led to the development of acidic emollients for skin care. In this context, the effect of citric acid-coated textiles on atopic skin has not been examined to date. A textile carrier composed of cellulose fibres was coated with a citric acid surface layer by esterification, ensuring a constant pH of 5.5-6.5. Twenty patients with AE or atopic diathesis were enrolled in the study. In a double blind, half-side experiment, patients had to wear these textiles for 12 h a day for 14 days. On day 0 (baseline), 7 and 14, tolerability (erythema, pruritus, eczema, wearing comfort) and efficacy on skin barrier were assessed by TEWL skin hydration (corneometry/capacitance), pH and clinical scoring of eczema (SCORAD). Citric acid-coated textiles were well tolerated and improved eczema and objective parameters of skin physiology, including barrier function and a reduced skin surface pH, with potential lower pathogenic microbial colonisation. PMID- 24953991 TI - Functional anatomy of subthalamic nucleus stimulation in Parkinson disease. AB - OBJECTIVE: We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3-dimensional brain region and to assign statistical significance after stringent type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS. METHODS: Fifty-one PD participants with STN DBS were evaluated off medication, with DBS off and during unilateral STN DBS with clinically optimized settings. Dependent variables included DBS-induced changes in Unified Parkinson Disease Rating Scale (UPDRS) subscores, kinematic measures of bradykinesia and rigidity, working memory, response inhibition, mood, anxiety, and akathisia. Weighted t tests at each voxel produced p images showing where DBS most significantly affected each dependent variable based on outcomes of participants with nearby DBS. Finally, a permutation test computed the probability that this p image indicated significantly different responses based on stimulation site. RESULTS: Most motor variables improved with DBS anywhere in the STN region, but several motor, cognitive, and affective responses significantly depended on precise location stimulated, with peak p values in superior STN/zona incerta (quantified bradykinesia), dorsal STN (mood, anxiety), and inferior STN/substantia nigra (UPDRS tremor, working memory). INTERPRETATION: Our method identified DBS-induced behavioral changes that depended significantly on DBS site. These results do not support complete functional segregation within STN, because movement improved with DBS throughout, and mood improved with dorsal STN DBS. Rather, findings support functional convergence of motor, cognitive, and limbic information in STN. PMID- 24953995 TI - Primary granulocytic sarcoma of larynx. AB - BACKGROUND: Granulocytic sarcoma is an extramedullary tumor of myeloblasts. The purpose of this report was to present a case of a primary laryngeal granulocytic sarcoma and review of the literature. METHODS: A literature review was performed using Medline and PubMed databases to search for cases of all primary and secondary myelogenous tumors of the larynx. RESULTS: A 36-year-old man presented with a mass involving the preepiglottic space that was histologically confirmed as an extramedullary acute myeloid leukemia, or granulocytic sarcoma. Our review found 18 cases of secondary involvement of the larynx by myelogenous tumors, and only 1 previously reported case of primary laryngeal granulocytic sarcoma. CONCLUSION: The detection of granulocytic sarcoma is difficult given its rarity and nonspecific presentation. To our knowledge, this is the second reported case of primary granulocytic sarcoma of the larynx reported in the literature. PMID- 24953994 TI - Oxygen availability and distance to surface environments determine community composition and abundance of ammonia-oxidizing prokaroytes in two superimposed pristine limestone aquifers in the Hainich region, Germany. AB - We followed the abundance and compared the diversity of ammonia-oxidizing archaea (AOA) and bacteria (AOB) in the groundwater of two superimposed pristine limestone aquifers located in the Hainich region (Thuringia, Germany) over 22 months. Groundwater obtained from the upper aquifer (12 m depth) was characterized by low oxygen saturation (0-20%) and low nitrate concentrations (0 20 MUM), contrasting with 50-80% oxygen saturation and 40-200 MUM nitrate in the lower aquifer (48 m and 88 m depth). Quantitative PCR targeting bacterial and archaeal amoA and 16S rRNA genes suggested a much higher ammonia oxidizer fraction in the lower aquifer (0.4-7.8%) compared with the upper aquifer (0.01 0.29%). In both aquifers, AOB communities were dominated by one phylotype related to Nitrosomonas ureae, while AOA communities were more diverse. Multivariate analysis of amoA DGGE profiles revealed a stronger temporal variation of AOA and AOB community composition in the upper aquifer, pointing to a stronger influence of surface environments. Parallel fluctuations of AOA, AOB, and total microbial abundance suggested that hydrological factors (heavy rain falls, snow melt) rather than specific physicochemical parameters were responsible for the observed community dynamics. PMID- 24953996 TI - Genomic sequence of the rare HLA-A*02:95 allele identified by sequence-based typing and cloning. AB - Genomic sequence of HLA-A*02:95 identified in an Anthony Nolan volunteer donor. PMID- 24953997 TI - The Neurospora crassa CPS-1 polysaccharide synthase functions in cell wall biosynthesis. AB - The Neurospora crassa cps-1 gene encodes a polysaccharide synthase with homology to the Cryptococcus neoformans hyaluronic acid synthase Cps1p. Homologs of the cps-1 gene are found in the genomes of many fungi. Loss of CPS-1 results in a cell wall defect that affects all stages of the N. crassa life cycle, including vegetative growth, protoperithecia (female mating structure) development, and conidia (asexual spore) development. The cell wall of cps-1 deletion mutants is sensitive to cell wall perturbation reagents. Our results demonstrate that CPS-1 is required for the incorporation of cell wall proteins into the cell wall and plays a critical role in cell wall biogenesis. We found that the N. crassa cell wall is devoid of hyaluronic acid, and conclude that the polysaccharide produced by the CPS-1 is not hyaluronic acid. PMID- 24953998 TI - No significant brain volume decreases or increases in adults with high functioning autism spectrum disorder and above average intelligence: a voxel based morphometric study. AB - Autism spectrum disorder (ASD) is increasingly being recognized as an important issue in adult psychiatry and psychotherapy. High intelligence indicates overall good brain functioning and might thus present a particularly good opportunity to study possible cerebral correlates of core autistic features in terms of impaired social cognition, communication skills, the need for routines, and circumscribed interests. Anatomical MRI data sets for 30 highly intelligent patients with high functioning autism and 30 pairwise-matched control subjects were acquired and analyzed with voxel-based morphometry. The gray matter volume of the pairwise matched patients and the controls did not differ significantly. When correcting for total brain volume influences, the patients with ASD exhibited smaller left superior frontal volumes on a trend level. Heterogeneous volumetric findings in earlier studies might partly be explained by study samples biased by a high inclusion rate of secondary forms of ASD, which often go along with neuronal abnormalities. Including only patients with high IQ scores might have decreased the influence of secondary forms of ASD and might explain the absence of significant volumetric differences between the patients and the controls in this study. PMID- 24954000 TI - Commercialization of microfluidic devices. AB - Microfluidic devices offer automation and high-throughput screening, and operate at low volumes of consumables. Although microfluidics has the potential to reduce turnaround times and costs for analytical devices, particularly in medical, veterinary, and environmental sciences, this enabling technology has had limited diffusion into consumer products. This article analyzes the microfluidics market, identifies issues, and highlights successful commercialization strategies. Addressing niche markets and establishing compatibility with existing workflows will accelerate market penetration. PMID- 24953999 TI - Brain activity in predominantly-inattentive subtype attention deficit/hyperactivity disorder during an auditory oddball attention task. AB - Previous functional neuroimaging studies have found brain activity abnormalities in attention-deficit/hyperactivity disorder (ADHD) on numerous cognitive tasks. However, little is known about brain dysfunction unique to the predominantly inattentive subtype of ADHD (ADHD-I), despite debate as to whether DSM-IV-defined ADHD subtypes differ in etiology. This study compared brain activity of 18 ADHD-I adolescents (ages 12-18) and 20 non-psychiatric age-matched control participants on a functional magnetic resonance image (fMRI) auditory oddball attention task. ADHD-I participants had significant activation deficits to infrequent target stimuli in bilateral superior temporal gyri, bilateral insula, several midline cingulate/medial frontal gyrus regions, right posterior parietal cortex, thalamus, cerebellum, and brainstem. To novel stimuli, ADHD-I participants had reduced activation in bilateral lateral temporal lobe structures. There were no brain regions where ADHD-I participants had greater hemodynamic activity to targets or novels than controls. Brain activity deficits in ADHD-I participants were found in several regions important to attentional orienting and working memory-related cognitive processes involved in target identification. These results differ from those in previously studied adolescents with combined-subtype ADHD, who had a lesser magnitude of activation abnormalities in frontoparietal regions and relatively more discrete regional deficits to novel stimuli. The divergent findings suggest different etiological factors might underlie attention deficits in different DSM-IV-defined ADHD subtypes, and they have important implications for the DSM-V reconceptualization of subtypes as varying clinical presentations of the same core disorder. PMID- 24954003 TI - Phenolic profile and in vitro antioxidant capacity of insoluble dietary fiber powders from citrus (Citrus junos Sieb. ex Tanaka) pomace as affected by ultrafine grinding. AB - The effects of mechanical and jet grindings on the proximate composition, phenolics, and antioxidant capacity of insoluble antioxidant dietary fiber powder from citrus pomace (IADFP-CP) were investigated in comparison with ordinary grinding. IADFP-CP from jet grinding showed higher levels of crude fat, total sugar, and free phenolics and lower levels of crude protein and bound phenolics than that from ordinary grinding. Totally, 14 phenolics (9 free, 1 bound, and 4 free/bound) in IADFP-CP were identified by RP-HPLC-DAD/ESI-Q-TOF-MS/MS. Hesperidin accounted for >57% of total phenolics in IADFP-CP. Among IADFP-CPs, the jet-ground presented the highest free phenolics but the lowest bound phenolics. The IADFP-CP from jet grinding presented the highest antioxidant capacity of free phenolics (by DPPH and FRAP assays), followed by the ones from mechanical and then ordinary grinding. The present study suggests that jet grinding could improve the extraction of phenolic compounds from IADFP-CP and increase the antioxidant capacities of free phenolics and the resultant powder. PMID- 24954001 TI - Oxidized alginate hydrogels for bone morphogenetic protein-2 delivery in long bone defects. AB - Autograft treatment of large bone defects and fracture non-unions is complicated by limited tissue availability and donor site morbidity. Polymeric biomaterials such as alginate hydrogels provide an attractive tissue engineering alternative due to their biocompatibility, injectability, and tunable degradation rates. Irradiated RGD-alginate hydrogels have been used to deliver proteins such as bone morphogenetic protein-2 (BMP-2), to promote bone regeneration and restoration of function in a critically sized rat femoral defect model. However, slow degradation of irradiated alginate hydrogels may impede integration and remodeling of the regenerated bone to its native architecture. Oxidation of alginate has been used to promote degradation of alginate matrices. The objective of this study was to evaluate the effects of alginate oxidation on BMP-2 release and bone regeneration. We hypothesized that oxidized-irradiated alginate hydrogels would elicit an accelerated release of BMP-2, but degrade faster in vivo, facilitating the formation of higher quality, more mature bone compared to irradiated alginate. Indeed, oxidation of irradiated alginate did accelerate in vitro BMP-2 release. Notably, the BMP-2 retained within both constructs was bioactive at 26days, as observed by induction of alkaline phosphatase activity and positive Alizarin Red S staining of MC3T3-E1 cells. From the in vivo study, robust bone regeneration was observed in both groups through 12weeks by radiography, micro-computed tomography analyses, and biomechanical testing. Bone mineral density was significantly greater for the oxidized-irradiated alginate group at 8weeks. Histological analyses of bone defects revealed enhanced degradation of oxidized-irradiated alginate and suggested the presence of more mature bone after 12weeks of healing. PMID- 24954002 TI - Distribution and innervation of putative arterial chemoreceptors in the bullfrog (Rana catesbeiana). AB - Peripheral arterial chemoreceptors have been located previously in the carotid labyrinth, the aortic arch, and the pulmocutaneous artery of frogs. In the present study we used cholera toxin B neuronal tract tracing and immunohistochemical markers for cholinergic cells (vesicular acetylcholine transporter [VAChT]), tyrosine hydroxylase (TH), and serotonin (5HT) to identify putative O2-sensing cells in Rana catesbeiana. We found potential O2-sensing cells in all three vascular areas innervated by branches of the vagus nerve, whereas only cells in the carotid labyrinth were innervated by the glossopharyngeal nerve. Cells containing either 5HT or TH were found in all three sites, whereas cells containing both neurotransmitters were found only in the carotid labyrinth. Cell bodies containing VAChT were not found at any site. The morphology and innervation of putative O2-sensing cells were similar to those of glomus cells found in other vertebrates. The presence of 5HT- and TH immunoreactive cells in the aorta, pulmocutaneous artery, and carotid labyrinth appears to reflect a phylogenetic transition between the major neurotransmitter seen in the putative O2-sensing cells of fish (5HT) and those found in the glomus cells of mammals (acetylcholine, adenosine, and catecholamines). PMID- 24954004 TI - Environmental radionuclide monitoring of Canadian harbours: a decade of analyses in support of due diligence activities by the Royal Canadian Navy. AB - The Royal Canadian Navy has conducted a comprehensive programme of safety, security and environmental monitoring since the first visits of nuclear powered and nuclear capable vessels (NPV/NCVs) to Canadian harbours in the late 1960s. The outcomes of baseline monitoring and vessel visit sampling for the period 2003 2012 are described for vessel visits to Halifax (NS), Esquimalt (BC) and Nanoose (BC). Data were obtained by gamma-ray spectroscopy using high purity germanium detectors. No evidence was found for the release of radioactive fission or activation products by NCV/NPVs during the study period, although anthropogenically produced radionuclides were observed as part of the study's baseline monitoring. Background activities of Cs-137 can be observed in sediments from all three locations which are derived from well-documented radioactivity releases. The detection of I-131 in aquatic plants is consistently observed in Halifax at activities as high as 15,000 Bq kg(-1) dry weight. These data are tentatively assigned to the release of medical I-131, followed by bioaccumulation from seawater. I-131 was also observed in aquatic plants samples from Esquimalt (33 Bq kg(-1)) and Nanoose (20 Bq kg(-1)) for a single sampling following the Fukushima Daiichi accident. PMID- 24954005 TI - Screening for autism spectrum disorders in children with epilepsy: where to begin... and where to go? PMID- 24954006 TI - Metabolic profiling reveals PAFAH1B3 as a critical driver of breast cancer pathogenicity. AB - Many studies have identified metabolic pathways that underlie cellular transformation, but the metabolic drivers of cancer progression remain less well understood. The Hippo transducer pathway has been shown to confer malignant traits on breast cancer cells. In this study, we used metabolic mapping platforms to identify biochemical drivers of cellular transformation and malignant progression driven through RAS and the Hippo pathway in breast cancer and identified platelet-activating factor acetylhydrolase 1B3 (PAFAH1B3) as a key metabolic driver of breast cancer pathogenicity that is upregulated in primary human breast tumors and correlated with poor prognosis. Metabolomic profiling suggests that PAFAH1B3 inactivation attenuates cancer pathogenicity through enhancing tumor-suppressing signaling lipids. Our studies provide a map of altered metabolism that underlies breast cancer progression and put forth PAFAH1B3 as a critical metabolic node in breast cancer. PMID- 24954008 TI - Folate pathway disruption leads to critical disruption of methionine derivatives in Mycobacterium tuberculosis. AB - In this study, we identified antifolates with potent, targeted activity against whole-cell Mycobacterium tuberculosis (MTB). Liquid chromatography-mass spectrometry analysis of antifolate-treated cultures revealed metabolic disruption, including decreased pools of methionine and S-adenosylmethionine. Transcriptomic analysis highlighted altered regulation of genes involved in the biosynthesis and utilization of these two compounds. Supplementation with amino acids or S-adenosylmethionine was sufficient to rescue cultures from antifolate treatment. Instead of the "thymineless death" that characterizes folate pathway inhibition in a wide variety of organisms, these data suggest that MTB is vulnerable to a critical disruption of the reactions centered around S adenosylmethionione, the activated methyl cycle. PMID- 24954007 TI - Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression. AB - Lysine acetylation regulates gene expression through modulating protein-protein interactions in chromatin. Chemical inhibition of acetyl-lysine binding bromodomains of the major chromatin regulators BET (bromodomain and extraterminal domain) proteins has been shown to effectively block cell proliferation in cancer and inflammation. However, whether selective inhibition of individual BET bromodomains has distinctive functional consequences remains only partially understood. In this study, we show that selective chemical inhibition of the first bromodomain of BET proteins using our small-molecule inhibitor, Olinone, accelerated the progression of mouse primary oligodendrocyte progenitors toward differentiation, whereas inhibition of both bromodomains of BET proteins hindered differentiation. This effect was target specific, as it was not detected in cells treated with inactive analogs and independent of any effect on proliferation. Therefore, selective chemical modulation of individual bromodomains, rather than use of broad-based inhibitors, may enhance regenerative strategies in disorders characterized by myelin loss such as aging and neurodegeneration. PMID- 24954009 TI - Visual scanning behavior during processing of emotional faces in older adults with major depression. AB - OBJECTIVES: Although several reported studies have suggested that younger adults with depression display depression-related biases during the processing of emotional faces, there remains a lack of data concerning these biases in older adults. The aim of our study was to assess scanning behavior during the processing of emotional faces in depressed older adults. METHOD: Older adults with and without depression viewed happy, neutral or sad portraits during an eye movement recording. RESULTS: Depressed older adults spent less time with fewer fixations on emotional features than healthy older adults, but only for sad and neutral portraits, with no significant difference for happy portraits. CONCLUSION: These results suggest disengagement from sad and neutral faces in depressed older adults, which is not consistent with standard theoretical proposals on congruence biases in depression. Also, aging and associated emotional regulation change may explain the expression of depression-related biases. Our preliminary results suggest that information processing in depression consists of a more complex phenomenon than merely a general searching for mood congruent stimuli or general disengagement from all kinds of stimuli. These findings underline that care must be used when evaluating potential variables, such as aging, which interact with depression and selectively influence the choice of relevant stimulus dimensions. PMID- 24954010 TI - Crosstalk between DNA repair and cancer stem cell (CSC) associated intracellular pathways. AB - DNA damaging agents (ionizing radiation and chemotherapeutics) are considered as most effective in cancer treatment. However, there is a subpopulation of carcinoma cells within the tumour demonstrating resistance to DNA damaging treatment approaches. It is suggested that limited tumour response to this kind of therapy can be associated with specific molecular properties of carcinoma stem cells (CSCs) representing the most refractory cell subpopulation. This review article presents novel data about molecular features of CSCs underlying DNA damage response and related intracellular signalling. PMID- 24954012 TI - Impedance boundary conditions for general transient hemodynamics. AB - We discuss the implementation and calibration of a new generalized structured tree boundary condition for hemodynamics. The main idea is to approximate the impedance corresponding to the vessels downstream from a specific outlet. Unlike previous impedance conditions, the one considered here is applicable to general transient flows as opposed to periodic ones only. The physiological character of the approach significantly simplifies calibration. We also describe a novel way to incorporate autoregulation mechanisms in structured arterial trees at minimal computational cost. The strength of the approach is illustrated and validated on several examples through comparison with clinical data. PMID- 24954014 TI - Synthesis and evaluation of 5-(3-(pyrazin-2-yl)benzylidene)thiazolidine-2,4-dione derivatives as pan-pim kinases inhibitors. AB - Pim kinases play a key role in the regulation of signaling pathways including proliferation, migration, and metabolism and are a potential target for cancer therapy. A series of 5-benzylidenethiazolidine-2,4-diones were synthesized as pim kinase inhibitors. The structure-activity relationships (SAR) of the analogues in inhibiting in vitro pim kinase activity as well as the proliferation of leukemia cell lines were examined. SAR studies indicated that a hydroxyl group at the 2 position of the benzene ring of 5-benzylidenethiazolidine-2,4-dione plays an important role in the inhibitory activity against all three pim kinases and replacement with a pyrazinyl group at the 5-position of the benzene ring of 5 benzylidenethiazolidine-2,4-dione improved activity significantly. The compounds exerted anti-proliferative activity against the three leukemia cell lines we tested. The most potent compound, 5i, had an EC50 value of 0.8 uM in the MV4-11 cell line. The result of kinase profiling indicated that compound 5i was highly selective for pim-kinases. PMID- 24954013 TI - Real-time luminescence microspectroscopy monitoring of singlet oxygen in individual cells. AB - A new setup for direct microspectroscopic monitoring of singlet oxygen ((1)O2) has been developed in our laboratory using a novel near-infrared sensitive InGaAs 2D-array detector. An imaging spectrograph has been inserted in front of the 2D array detector, which allows us to acquire spectral images where one dimension is spatial and the other is spectral. The work presents a detailed examination of sensitivity and noise characteristics of the setup and its ability to detect (1)O2. The (1)O2 phosphorescence-based images and near-infrared luminescence spectral images recorded from single TMPyP-containing fibroblast cells reflecting spectral changes during irradiation are demonstrated. The introduction of spectral images addresses the issue of a potential spectral overlap of (1)O2 phosphorescence with near-infrared-extended luminescence of the photosensitizer and provides a powerful tool for distinguishing and separating them, which can be applied to any photosensitizer manifesting near-infrared luminescence. PMID- 24954011 TI - Snail nuclear transport: the gateways regulating epithelial-to-mesenchymal transition? AB - Epithelial-to-mesenchymal transition (EMT) and the reverse process (MET) play central role in organ developmental biology. It is a fine tuned process that when disturbed leads to pathological conditions especially cancers with aggressive and metastatic behavior. Snail is an oncogene that has been well established to be a promoter of EMT through direct repression of epithelial morphology promoter E cadherin. It can function in the nucleus, in the cytosol and as discovered recently, extracellularly through secretory vesicular structures. The intracellular transport of snail has for long been shown to be regulated by the nuclear pore complex. One of the Karyopherins, importin alpha, mediates snail import, while exportin 1 (Xpo1) also known as chromosome maintenance region 1 (CRM1) is its major nuclear exporter. A number of additional biological regulators are emerging that directly modulate Snail stability by altering its subcellular localization. These observations indicate that targeting the nuclear transport machinery could be an important and as of yet, unexplored avenue for therapeutic intervention against the EMT processes in cancer. In parallel, a number of novel agents that disrupt nuclear transport have recently been discovered and are being explored for their anti-cancer effects in the early clinical settings. Through this review we provide insights on the mechanisms regulating snail subcellular localization and how this impacts EMT. We discuss strategies on how the nuclear transport function can be harnessed to rein in EMT through modulation of snail signaling. PMID- 24954016 TI - Comparison of High-voltage- with Standard-voltage Pulsed Radiofrequency of Gasserian Ganglion in the Treatment of Idiopathic Trigeminal Neuralgia. AB - Although pulsed radiofrequency treatment (PRFT) has been used to treat trigeminal neuralgia (TN) safely, satisfactory improvement is lacking. Recently, much attention has been paid to the PRFT dose and intra-operative parameters. It has been reported that high-voltage PRFT could significantly reduce discogenic pain. However, there is no study investigating the effects of high-voltage PRFT on TN. The aim of this prospective, randomized, double-blinded study was to evaluate the efficacy and safety of high-voltage PRFT in comparison with standard-voltage PRFT for idiopathic TN. Sixty severe TN patients were randomly assigned to 2 groups treated with CT-guided standard- or high-voltage-pulsed radiofrequency (RF) of Gasserian ganglion, respectively, between January 2012 and July 2012. Numeric Rating Scales (NRS), carbamazepine dose, and side effects were evaluated at day 1, weeks 1 and 2, months 1, 3, and 6, and 1 year postoperative. There were 27 patients in the standard-voltage group and 26 patients in the high-voltage group who completed the 1-year follow-up study. The effective rates in the standard voltage and high-voltage PRFT groups were 41% and 69%, respectively, at 1, 3, and 6 months postoperative (P = 0.037). The effective rate in the standard-voltage group decreased to 19% at 1-year postoperative, while in the high-voltage group remained at 69% (P = 0.000). No significant side effects were detected in both groups. In conclusion, CT-guided high-voltage PRFT is an effective and safe interventional therapeutic choice for idiopathic TN patients. PMID- 24954015 TI - Reducing systematic review workload through certainty-based screening. AB - In systematic reviews, the growing number of published studies imposes a significant screening workload on reviewers. Active learning is a promising approach to reduce the workload by automating some of the screening decisions, but it has been evaluated for a limited number of disciplines. The suitability of applying active learning to complex topics in disciplines such as social science has not been studied, and the selection of useful criteria and enhancements to address the data imbalance problem in systematic reviews remains an open problem. We applied active learning with two criteria (certainty and uncertainty) and several enhancements in both clinical medicine and social science (specifically, public health) areas, and compared the results in both. The results show that the certainty criterion is useful for finding relevant documents, and weighting positive instances is promising to overcome the data imbalance problem in both data sets. Latent dirichlet allocation (LDA) is also shown to be promising when little manually-assigned information is available. Active learning is effective in complex topics, although its efficiency is limited due to the difficulties in text classification. The most promising criterion and weighting method are the same regardless of the review topic, and unsupervised techniques like LDA have a possibility to boost the performance of active learning without manual annotation. PMID- 24954017 TI - Comparison of two dental implant surface modifications on implants with same macrodesign: an experimental study in the pelvic sheep model. AB - OBJECTIVES: The aim of this study was to compare two different surfaces of one uniform macro-implant design in order to focus exclusively on the osseointegration properties after 2, 4 and 8 weeks and to discuss the animal model chosen. MATERIAL AND METHODS: In six mature sheep, n = 36 implants with a highly crystalline and phosphate-enriched anodized titanium oxide surface (TiU) and n = 36 implants with a hydrophilic, sandblasted, large grit and acid-etched surface (SLA) were placed in the pelvic bone. TiU implants were custom-made to match the SLA implant design. The implant stability and bone-to-implant contact (BIC) were assessed by resonance frequency (ISQ), backscatter scanning electron microscopy (B-SEM), light microscopy (LM), micro-CT and intravital fluorochrome staining. Biomechanical removal torque testing was performed. RESULTS: Overall, no statistically significant differences in BIC total (trabecular + cortical) between TiU and SLA were found via LM and B-SEM. BIC values (B-SEM; LM) in both groups revealed a steady rise in trabecular bone attachment to the implant surface after 2, 4 and 8 weeks. In the 2- to 4-week time interval in the TiU group (P = 0.005) as well as in the SLA group (P = 0.01), a statistically significant increase in BIC trabecular could be observed via LM. B-SEM values confirmed the statistically significant increase for TiU (P = 0.001). In both groups, BIC trabecular values after 8 weeks were significantly higher (P <= 0.05) than after 2 weeks (B-SEM; LM). Biomechanical data confirmed the histological data. CONCLUSION: The two surfaces proved comparable osseointegration in this sheep model. PMID- 24954018 TI - Safety of medication use in primary care. AB - BACKGROUND: Medication errors are one of the leading causes of harmin health care. Review and analysis of errors have often emphasized their preventable nature and potential for reoccurrence. Of the few error studies conducted in primary care to date, most have focused on evaluating individual parts of the medicines management system. Studying individual parts of the system does not provide a complete perspective and may further weaken the evidence and undermine interventions. AIM AND OBJECTIVES: The aim of this review is to estimate the scale of medication errors as a problem across the medicines management system in primary care. Objectives were: To review studies addressing the rates of medication errors, and To identify studies on interventions to prevent medication errors in primary care. METHODS: A systematic search of the literature was performed in PubMed (MEDLINE), International Pharmaceutical Abstracts (IPA), Embase, PsycINFO, PASCAL, Science Direct, Scopus, Web of Knowledge, and CINAHL PLUS from 1999 to November, 2012. Bibliographies of relevant publications were searched for additional studies. KEY FINDINGS: Thirty-three studies estimating the incidence of medication errors and thirty-six studies evaluating the impact of error-prevention interventions in primary care were reviewed. This review demonstrated that medication errors are common, with error rates between <1% and >90%, depending on the part of the system studied, and the definitions and methods used. The prescribing stage is the most susceptible, and that the elderly (over 65 years), and children (under 18 years) are more likely to experience significant errors. Individual interventions demonstrated marginal improvements in medication safety when implemented on their own. CONCLUSION: Targeting the more susceptible population groups and the most dangerous aspects of the system may be a more effective approach to error management and prevention. Co implementation of existing interventions at points within the system may offer time- and cost-effective options to improving medication safety in primary care. PMID- 24954019 TI - An effective haplotype assembly algorithm based on hypergraph partitioning. AB - The haplotype assembly problem has been proven to be complex. Heuristic algorithms are the main methods that are used to solve the problem. These algorithms perform well when the SNP fragments are error-free, but they are less accurate when the error rate increases. The complex relationships caused by fragment errors present a major barrier to assembling accurate haplotypes. Therefore, modeling the complex relationships is the key to solve the problem. In this study, we model the haplotype assembly problem using hypergraph partitioning formulations and propose a novel method termed HGHap (Hypergraph-based Haplotype assembly method). HGHap approaches the haplotype assembly problem in two phases. In the first phase, a hypergraph is constructed in which each vertex corresponds to a fragment and vertices are multiply connected to form hyperedges. In the second phase, a hypergraph partitioning algorithm is employed to obtain two groups of fragments to construct the haplotypes. The hyperedges capture higher order relationships among fragments that facilitate the subsequent partitioning. Our results demonstrate that the method performs better than other methods in most cases, especially in cases with a high error rate. PMID- 24954020 TI - Smooth pursuit eye movements and schizophrenia: literature review. AB - OBJECTIVE: To review the scientific literature about the relationship between impairment on smooth pursuit eye movements and schizophrenia. METHODS: Narrative review that includes historical articles, reports about basic and clinical investigation, systematic reviews, and meta-analysis on the topic. RESULTS: Up to 80% of schizophrenic patients have impairment of smooth pursuit eye movements. Despite the diversity of test protocols, 65% of patients and controls are correctly classified by their overall performance during this pursuit. The smooth pursuit eye movements depend on the ability to anticipate the target's velocity and the visual feedback, as well as on learning and attention. The neuroanatomy implicated in smooth pursuit overlaps to some extent with certain frontal cortex zones associated with some clinical and neuropsychological characteristics of the schizophrenia, therefore some specific components of smooth pursuit anomalies could serve as biomarkers of the disease. Due to their sedative effect, antipsychotics have a deleterious effect on smooth pursuit eye movements, thus these movements cannot be used to evaluate the efficacy of the currently available treatments. CONCLUSION: Standardized evaluation of smooth pursuit eye movements on schizophrenia will allow to use specific aspects of that pursuit as biomarkers for the study of its genetics, psychopathology, or neuropsychology. PMID- 24954021 TI - Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems. AB - Existing nanoscale chemical delivery systems target diseased cells over long, sustained periods of time, typically through one-time, destructive triggering. Future directions lie in the development of fast and robust techniques capable of reproducing the pulsatile chemical activity of living organisms, thereby allowing us to mimic biofunctionality. Here, we demonstrate that by applying programmed femtosecond laser pulses to robust, nanoscale liposome structures containing dopamine, we achieve sub-second, controlled release of dopamine--a key neurotransmitter of the central nervous system--thereby replicating its release profile in the brain. The fast delivery system provides a powerful new interface with neural circuits, and to the larger range of biological functions that operate on this short timescale. PMID- 24954022 TI - Effects of the novel cannabinoid CB1 receptor antagonist PF 514273 on the acquisition and expression of ethanol conditioned place preference. AB - The centrally expressed cannabinoid receptor (CB1) has been considered a potential therapeutic target in treating alcoholism. Though CB1 receptors have been shown to modulate primary and conditioned ethanol reward, much of this research employed animal models that require ethanol ingestion or oral routes of administration. This is problematic considering CB1 antagonist drugs have high anorectic liability and have been used clinically in the treatment of obesity. Therefore, the present study examined CB1 antagonism in DBA/2J mice using an unbiased ethanol-induced conditioned place preference (CPP) procedure, a paradigm that does not require ethanol ingestion. To evaluate the role of CB1 receptors in primary ethanol reward, the highly potent and selective novel CB1 antagonist 2-(2 chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)-6,7-dihydro-2H pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (PF 514273) was administered 30 min before place preference conditioning with a fixed dose of ethanol (acquisition). To evaluate the role of CB1 receptors in ethanol-conditioned reward, PF 514273 was administered 30 min before place preference testing (expression). Although PF 514273 reduced ethanol-stimulated and basal locomotor activity, it did not perturb the acquisition or expression of ethanol-induced CPP. Results from the present study appear inconsistent with other studies that have demonstrated a role for CB1 antagonism in ethanol reward using oral administration paradigms. Our findings suggest that CB1 antagonism may have greater involvement in consummatory behavior than ethanol reward. PMID- 24954023 TI - Prenatal alcohol exposure alters expression of neurogenesis-related genes in an ex vivo cell culture model. AB - Prenatal alcohol exposure can lead to long-lasting changes in functional and genetic programs of the brain, which may underlie behavioral alterations seen in Fetal Alcohol Spectrum Disorder (FASD). Aberrant fetal programming during gestational alcohol exposure is a possible mechanism by which alcohol imparts teratogenic effects on the brain; however, current methods used to investigate the effects of alcohol on development often rely on either direct application of alcohol in vitro or acute high doses in vivo. In this study, we used our established moderate prenatal alcohol exposure (PAE) model, resulting in maternal blood alcohol content of approximately 20 mM, and subsequent ex vivo cell culture to assess expression of genes related to neurogenesis. Proliferating and differentiating neural progenitor cell culture conditions were established from telencephalic tissue derived from embryonic day (E) 15-17 tissue exposed to alcohol via maternal drinking throughout pregnancy. Gene expression analysis on mRNA derived in vitro was performed using a microarray, and quantitative PCR was conducted for genes to validate the microarray. Student's t tests were performed for statistical comparison of each exposure under each culture condition using a 95% confidence interval. Eleven percent of genes on the array had significantly altered mRNA expression in the prenatal alcohol-exposed neural progenitor culture under proliferating conditions. These include reduced expression of Adora2a, Cxcl1, Dlg4, Hes1, Nptx1, and Vegfa and increased expression of Fgf13, Ndn, and Sox3; bioinformatics analysis indicated that these genes are involved in cell growth and proliferation. Decreased levels of Dnmt1 and Dnmt3a were also found under proliferating conditions. Under differentiating conditions, 7.3% of genes had decreased mRNA expression; these include Cdk5rap3, Gdnf, Hey2, Heyl, Pard6b, and Ptn, which are associated with survival and differentiation as indicated by bioinformatics analysis. This study is the first to use chronic low to moderate PAE, to more accurately reflect maternal alcohol consumption, and subsequent neural progenitor cell culture to demonstrate that PAE throughout gestation alters expression of genes involved in neural development and embryonic neurogenesis. PMID- 24954024 TI - Distinct chemokine signaling regulates integrin ligand specificity to dictate tissue-specific lymphocyte homing. AB - Immune surveillance and host defense depend on the precisely regulated trafficking of lymphocytes. Integrin alpha4beta7 mediates lymphocyte homing to the gut through its interaction with mucosal vascular address in cell adhesion molecule-1 (MAdCAM-1). alpha4beta7 also binds vascular cell adhesion molecule-1 (VCAM-1), which is expressed in other tissues. To maintain the tissue specificity of lymphocyte homing, alpha4beta7 must distinguish one ligand from the other. Here, we demonstrate that alpha4beta7 is activated by different chemokines in a ligand-specific manner. CCL25 stimulation promotes alpha4beta7-mediated lymphocyte adhesion to MAdCAM-1 but suppresses adhesion to VCAM-1, whereas CXCL10 stimulation has the opposite effect. Using separate pathways, CCL25 and CXCL10 stimulate differential phosphorylation states of the beta7 tail and distinct talin and kindlin-3 binding patterns, resulting in different binding affinities of MAdCAM-1 and VCAM-1 to alpha4beta7. Thus, our findings provide a mechanism for lymphocyte traffic control through the unique ligand-specific regulation of integrin adhesion by different chemokines. PMID- 24954025 TI - Independent genomic control of neuronal number across retinal cell types. AB - The sizes of different neuronal populations within the CNS are precisely controlled, but whether neuronal number is coordinated between cell types is unknown. We examined the covariance structure of 12 different retinal cell types across 30 genetically distinct lines of mice, finding minimal covariation when comparing synaptically connected or developmentally related cell types. Variation mapped to one or more genomic loci for each cell type, but rarely were these shared, indicating minimal genetic coregulation of final number. Multiple genes, therefore, participate in the specification of the size of every population of retinal neuron, yet genetic variants work largely independent of one another during development to modulate those numbers, yielding substantial variability in the convergence ratios between pre- and postsynaptic populations. Density dependent cellular interactions in the outer plexiform layer overcome this variability to ensure the formation of neuronal circuits that maintain constant retinal coverage and complete afferent sampling. PMID- 24954028 TI - Distribution of PCP4 protein in the forebrain of adult mice. AB - Purkinje-cell protein 4 (PCP4) is a small calmodulin (CaM)-binding protein that has been discovered to be selectively expressed by cerebellar Purkinje cells in the adult rodent brain. In addition, expression of PCP4 mRNA has been detected in the hippocampus and in the cortex. In order to determine the expression of PCP4 protein in the brain, we performed an immunohistochemical analysis using adult mice. We could demonstrate that PCP4 is expressed in neocortical structures, especially in the deep layers, as well as in other cortical structures and parts of the hippocampal formation. Moreover, PCP4 protein is highly expressed in the olfactory bulb and caudate putamen. PCP4 positive cells were also detected in specific areas of the amygdala, thalamus (especially dorsal lateral geniculate nucleus) and hypothalamus. By performing double-labeling experiments together with NeuN (a neuronal marker), we could demonstrate that PCP4 expressing cells in the brain are of neuronal origin. PMID- 24954026 TI - Experimental predictions drawn from a computational model of sign-trackers and goal-trackers. AB - Gaining a better understanding of the biological mechanisms underlying the individual variation observed in response to rewards and reward cues could help to identify and treat individuals more prone to disorders of impulsive control, such as addiction. Variation in response to reward cues is captured in rats undergoing autoshaping experiments where the appearance of a lever precedes food delivery. Although no response is required for food to be delivered, some rats (goal-trackers) learn to approach and avidly engage the magazine until food delivery, whereas other rats (sign-trackers) come to approach and engage avidly the lever. The impulsive and often maladaptive characteristics of the latter response are reminiscent of addictive behaviour in humans. In a previous article, we developed a computational model accounting for a set of experimental data regarding sign-trackers and goal-trackers. Here we show new simulations of the model to draw experimental predictions that could help further validate or refute the model. In particular, we apply the model to new experimental protocols such as injecting flupentixol locally into the core of the nucleus accumbens rather than systemically, and lesioning of the core of the nucleus accumbens before or after conditioning. In addition, we discuss the possibility of removing the food magazine during the inter-trial interval. The predictions from this revised model will help us better understand the role of different brain regions in the behaviours expressed by sign-trackers and goal-trackers. PMID- 24954029 TI - The role of ionic liquids in hydrogen storage. AB - Ionic liquid (IL) based H2 storage for H2 generation from NH3BH3 derivatives is shown. These systems promote H2 generation at low temperature, with good reaction rates and high total H2 yields. The effects of ILs and the H2 yield in correlation with the basicity, the cations of the ILs, and the role of carbenes are discussed. Furthermore, mechanistic findings on the dehydrogenation are described. IL material blends are competitive with conventional H2 storage materials with experimental efficiencies of at least 6.5 wt % H2. PMID- 24954027 TI - Economic risk coding by single neurons in the orbitofrontal cortex. AB - Risk is a ubiquitous feature of the environment for all organisms. Very few things in life are achieved with absolute certainty. Therefore, it is essential that organisms process risky information efficiently to promote adaptive behaviour and enhance survival. Here we outline a clear definition of economic risk derived from economic theory and focus on two experiments in which we have shown subpopulations of single neurons in the orbitofrontal cortex of rhesus macaques that code either economic risk per se or an error-related risk signal, namely a risk prediction error. These biological risk signals are essential for processing and updating risky information in the environment to contribute to efficient decision making and adaptive behaviour. PMID- 24954030 TI - Cerebellar infarction presenting as inner ear decompression sickness following scuba diving: a case report. AB - INTRODUCTION: Inner ear decompression sickness following scuba diving is not uncommon and the characteristic features of this disorder are acute peripheral vestibular syndrome, sometimes associated with cochlear signs, requiring urgent hyperbaric oxygen therapy. Cerebellar infarction can also mimic isolated peripheral vestibulopathy. CASE REPORT: The authors report the case of a 47-year old man in good general health admitted with acute left vestibular dysfunction suggestive of inner ear decompression sickness 6 hours after scuba diving. Normal videonystagmography and delayed onset of occipital headache finally led to brain MRI that confirmed the presence of recent ischaemic infarction in the territory of the medial branch of the posterior inferior cerebellar artery. Complementary investigations revealed the presence of a patent foramen ovale with atrial septal aneurysm. No underlying atherosclerotic disease or clotting abnormalities were observed. DISCUSSION/CONCLUSION: Cerebellar infarction can present clinically with features of inner ear decompression sickness following scuba diving. An underlying air embolism mechanism cannot be excluded, particularly in patients with a large right-to-left circulatory shunt and no other cardiovascular risk factors. PMID- 24954031 TI - Hellebrigenin induces cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells through inhibition of Akt. AB - Hellebrigenin, one of bufadienolides belonging to cardioactive steroids, was found in skin secretions of toads and plants of Helleborus and Kalanchoe genera. In searching for natural constituents with anti-hepatoma activities, we found that hellebrigenin, isolated from traditional Chinese medicine Venenum Bufonis, potently reduced the viability and colony formation of human hepatocellular carcinoma cells HepG2, and went on to explore the underlying molecular mechanisms. Our results demonstrated that hellebrigenin triggered DNA damage through DNA double-stranded breaks and subsequently induced cell cycle G2/M arrest associated with up-regulation of p-ATM (Ser(1981)), p-Chk2 (Tyr(68)), p CDK1 (Tyr(15)) and Cyclin B1, and down-regulation of p-CDC25C (Ser(216)). It was also found that hellebrigenin induced mitochondrial apoptosis, characterized by Bax translocation to mitochondria, disruption of mitochondrial membrane potential, release of cytochrome c into cytosol and sequential activation of caspases and PARP. In addition, Akt expression and phosphorylation were inhibited by hellebrigenin, whereas Akt silencing with siRNA significantly blocked cell cycle arrest but enhanced apoptosis induced by hellebrigenin. Activation of Akt by human insulin-like growth factor I (hIGF-I) could obviously attenuate hellebrigenin-induced cell death. In summary, our study is the first to report the efficacy of hellebrigenin against HepG2 and elucidated its molecular mechanisms including DNA damage, mitochondria collapse, cell cycle arrest and apoptosis, which will contribute to the development of hellebrigenin into a chemotherapeutic agent in the treatment of liver cancer. PMID- 24954032 TI - PCB153, TCDD and estradiol compromise the benzo[a]pyrene-induced p53-response via FoxO3a. AB - TCDD, polychlorinated biphenyls (PCB) and polycyclic aromatic hydrocarbons (PAH) coexist in the environment. However, there are few studies on combined effects of these compounds. We have studied the effect of TCDD, PCB153 and estradiol on p53 signaling induced by PAHs. We show that all three compounds amplified the accumulation of nuclear p53, elicited by benzo[a]pyrene (BaP) or dibenzo[al]pyrene (DBP). This effect was associated with an attenuated PAH induced apoptosis and with decreased levels of phosphorylated FoxO3a Thr32. Thr32 phosphorylation of FoxO3a may promote a translocation of FoxO3a-p53 complex from nucleus to the cytoplasm, and the role of FoxO3a dephosphorylation was further studied. We found that inhibition of PP2A phosphatase restored levels of phosphorylated FoxO3a, led to cytosolic translocation of p53, and activated BaP induced p53-mediated apoptosis. These results were confirmed by silencing FoxO3a with siRNA or by inhibiting 14-3-3 protein; also these treatments trapped BaP induced p53 in the nucleus. Our data indicate interplay between p53, FoxO3a and 14-3-3 leading to an attenuated BaP induced apoptosis in cells co-exposed to TCDD, PCB 153 or estradiol. PMID- 24954033 TI - Resistance to daunorubicin, imatinib, or nilotinib depends on expression levels of ABCB1 and ABCG2 in human leukemia cells. AB - The effect of ABCB1 (P-gp, (P-glycoprotein), MDR1) and ABCG2 (BCRP1, (breast cancer resistance protein 1)) expressions on cell resistance to daunorubicin (DRN), imatinib, and nilotinib was studied in human leukemia cells. We used a set of cells derived from a parental K562 cell line, expressing various levels of ABCB1 and ABCG2, respectively. The function of ABCB1 and ABCG2 was confirmed using calcein AM and pheophorbide A accumulation assays, respectively. These assays indicated distinct differences in activities of ABCB1 and ABCG2 which corresponded to their expression levels. We observed that the resistance to DRN and imatinib was proportional to the expression level of ABCB1. Similarly, the resistance to nilotinib and imatinib was proportional to the expression level of ABCG2. Importantly, K562/DoxDR05 and K562/ABCG2-Z cells with the lowest expressions of ABCB1 and ABCG2, respectively, failed to reduce the intracellular levels of imatinib to provide a significant resistance to this drug. However, the K562/DoxDR05 and K562/ABCG2-Z cells significantly decreased the intracellular levels of DRN and nilotinib, respectively, thereby mediating significant resistances to these drugs. Only cells which expression of ABCB1 or ABCG2 exceeded a certain level exhibited a significantly decreased intracellular level of imatinib, and this effect was accompanied by a significantly increased resistance to this drug. Our results clearly indicated that resistance to anticancer drugs mediated by main ABC transporters, ABCB1 and ABCG2, strongly depends on their expressions at protein levels. Importantly, resistance for one drug might be maintained while resistance for other ones might become undetectable at low transporter expression levels. PMID- 24954034 TI - Formylchromone exhibits salubrious effects against nitrosodiethylamine mediated early hepatocellular carcinogenesis in rats. AB - The salubrious effects of 3-Formylchromone (3-FC) against nitrosodiethylamine (NDEA) mediated early hepatocellular carcinogenesis was investigated in vivo by this study. Male Wistar rats were administered three interspersed intraperitoneal injections of NDEA (200 mg/kg body weight) until sixth week, followed by, thrice a week oral dose of 3-FC (25 mg/kg body weight) from the seventh week to eleventh week. Oral supplementation of Wistar rats with 3-FC prevented the increase in serum marker enzymes (AST, ALT, LDH) and serum pre-neoplastic marker (gamma-GT) induced by NDEA. Biochemical observations were found to be further correlated with histological studies, indicating the potential of 3-FC to mediate suppression of hepatic damage/pre-neoplastic lesions. Argyrophilic nucleolar organizer region (AgNOR) staining was done in histology sections to confirm the anti-proliferative potential of 3-FC against NDEA-induced early hepatocellular carcinogenesis. RT-PCR and immunoblot analysis was done to find the modulations in the gene transcript/protein level expression of pre-neoplastic marker (GST pi), proliferation marker (PCNA), apoptotic mediators (PPARgamma, NFkappaB-p65 and p53). 3-FC was found to favorably modulate the expressions of GST-pi, PCNA, PPARgamma, NFkappaB-p65, p53 clearly confirming the anti-proliferative and apoptotic potential of 3-FC. Further, the apoptotic effect of 3-FC against NDEA induced early hepatocellular carcinogenesis was confirmed by caspase-3 activity assay and DNA fragmentation analysis. Based on these findings, it is concluded that 3-FC possesses hepatoprotective, anti-pre-neoplastic, anti-proliferative and apoptosis inducing capability against NDEA-induced early hepatocellular carcinogenesis. PMID- 24954036 TI - Effect of dietary supplementation of dates in Alzheimer's disease APPsw/2576 transgenic mice on oxidative stress and antioxidant status. AB - Oxidative stress may play a key role in Alzheimer's disease (AD) neuropathology. Changes in the oxidative stress, antioxidants, and membrane-bound enzymes were investigated in the cerebral cortex and hippocampus of AD transgenic mice model after long-term dietary supplementation of date palm fruits from Oman. The 4 month-old mice with double Swedish APP mutation (APPsw/Tg2576) were purchased from Taconic Farm, NY, USA; mice were fed two different doses of dates (such as 4 and 2%) or control diet for 15 months and then assessed for the influence of diet on oxidative stress. Significant increase in oxidative stress in terms of enhanced levels of lipid peroxidation (LPO) and protein carbonyls and parallel decrease in the activity of antioxidant enzymes were observed in control diet treated Tg2576 AD mice. Dates (4 and 2%) treated APPsw/Tg2576 AD mice exhibited significantly attenuated oxidative damage, evidenced by decreased LPO and protein carbonyl levels and restoration in the activities of the antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione, and glutathione reductase). The activities of membrane-bound enzymes (Na(+), K(+) ATPase and acetyl cholinesterase) were altered in control diet-treated APPsw/Tg2576 AD mice brain regions. Meanwhile, both the percentages of date supplementation were able to restore the activity of enzymes to comparable values observed in controls. In summary, we have shown that chronic dietary supplementation of date palm fruits grown in Oman showed possible beneficial effects concomitant with oxidative stress reduction and increased antioxidant enzymes in AD transgenic mice model. These results warrant further exploration of how anti-reactive oxygen species properties of dates offer such beneficial effects on the AD-like brain. PMID- 24954035 TI - Hesperidin blunts streptozotocin-isoproternol induced myocardial toxicity in rats by altering of PPAR-gamma receptor. AB - Hesperidin has been shown to possess cardioprotective and anti-diabetic potential. Hitherto, its molecular mechanism on isoproterenol (ISO)-induced myocardial dysfunction in diabetes is still not explored. Hence, for the first time we sought to investigate whether hesperidin exerts any beneficial effect on the pathophysiology of myocardial infarction (MI) in diabetes through the PPAR gamma pathway by assessing a variety of indices e.g., apoptosis, hemodynamic, biochemical and histoarchitectural changes. Diabetes was induced by a single dose of STZ (50 mg/kg IP). Diabetic rats received either hesperidin (100 mg/kg/day orally), the PPAR-gamma antagonist GW9662 (1 mg/kg/day IP), or both for 14 days with concurrent administration of ISO (85 mg/kg SC) on days 13 and 14. ISO-STZ rats resulted in severe myocardial dysfunction (decreased +/-LVdP/dt and increased LVEDP). In addition, augmented myocardial thiobarbituric acid-reactive substances and serum troponin-I with a concomitant decrease in level of glutathione and activities of catalase, superoxide dismutase antioxidants with cardiac injury biomarkers creatine kinase-MB isoenzyme, lactate dehydrogenase were seen. Morphological studies of the ISO-STZ challenged myocardium exhibited severe necrosis, edema and inflammatory changes. In Western blot analysis, Bcl-2 and PPAR-gamma expression were decreased where as Bax expression was significantly increased, suggesting role of apoptosis in myocardial dysfunction. Interestingly, hesperidin treatment positively modulated these parameters as validated by improved hemodynamic and left ventricular functions, fortified endogenous anti-oxidant defence system and improved structural integrity of the myocardium. However, significant effects were lowered in animals treated with hesperidin plus GW9662. Moreover, down-regulated PPAR-gamma and Bcl-2 expressions in myocardial infarcted diabetic hearts were increased by hesperidin treatment. Hence, for the first time the present study suggests that, hesperidin reduces oxidative stress, apoptosis and improves cardiac function via the PPAR-gamma pathway. PMID- 24954037 TI - Hearing loss in singers: a preliminary study. AB - OBJECTIVE: Singers need good hearing; however, they may be exposed to loud noises during their musical activities. The objectives of this study were to describe the incidence and type of hearing loss (HL) in singers. STUDY DESIGN: Retrospective case cohort. METHODS: Billing records identified patients who had undergone videostroboscopy and audiogram during the same visit over a 3 year period. A singer was defined as anyone who self-identified as a singer (professional or avocational). Age and gender matched nonsingers were used as controls. Patients with otologic diagnoses, surgery, or complaints were excluded. Retrospective chart review was conducted for the presence of HL, type of HL, and pure tones audiogram results. Statistical analysis included descriptive statistics, Students t test, chi-square test, and Fisher exact test. RESULTS: Of 172 singers (44.7 years, 37.8% male), 31 (17.5%) had HL. Pure tone thresholds for the singers with HL subgroup at 3, 4, and 6 kHz were 21.0, 26.5, and 34.4 dB in the right, and 22.8, 30.3, and 38.8 dB in the left ear, respectively. Older age (P = 0.000000000000001), male gender (P < 0.001), longer number of years of singing (P = 0.0000000003), and baritone voice (P < 0.001) were associated with HL. There was no association with genre of music. When compared with controls, the incidence of HL (19.8%) was not significantly different (chi2 = 0.300, P = 0.58). Pure tones at 3, 4, and 6 kHz were not significantly different than controls with HL. Most common type of HL in singers was bilateral sensorineural (83.9%), which was significantly higher than controls (39.0%, chi2 = 14.6, P < 0.001). CONCLUSIONS: The incidence of HL in singers was 17.5%, which was not significantly different from controls. Bilateral sensorineural HL was most common. PMID- 24954038 TI - Cepstral analysis of voice in children with velopharyngeal insufficiency after cleft palate surgery. AB - OBJECTIVES: The purpose of this study is to survey the cepstral peak prominence (CPP) of vowel sounds and to compare objective data obtained from patients with velopharyngeal insufficiency after cleft palate surgery with objective data of those with normal healthy controls using acoustic analyzer. METHODS: Participants were divided into a clinical group and a control group. Every participant was recorded phonating the sustained vowel /a/. Each participant in the clinical group was recorded before surgery, before and after speech therapy. All samples were subjected to acoustic analysis using Praat software. The vowels were analyzed acoustically by the measurement of smoothed cepstral peak prominence (CPPs). RESULTS: The results reveal lower values of CPPs in speakers with velopharyngeal insufficiency before and after the operation. And, the results also reveal that there is no significant difference across the control and the clinical groups after speech therapy. CONCLUSIONS: The results reveal lower values of CPPs in the clinical group before surgery and before speech therapy in comparison with the control group, which could be explained because of the body's compensation for the lack of normal intraoral pressure and habit of articulation. PMID- 24954039 TI - Relationship of laryngeal botulinum toxin dosage to patient age, vitality, and socioeconomic issues. AB - OBJECTIVE: Chemical denervation with botulinum toxin A is the current standard of treatment for spasmodic dysphonia, but dosage is determined individually after a titration period that can take months to years. The objective of this study was to determine if age, body mass index (BMI), overall health, and socioeconomic factors were associated with a patient's optimal dose of botulinum toxin. STUDY DESIGN AND METHODS: This retrospective chart review looked at 32 patients with stabilized doses of botulinum toxin. Age and BMI were obtained from patient charts, and overall health was assessed by the Short-Form 36 survey. RESULTS: Analysis showed that BMI was positively correlated with botulinum toxin dose (r = 0.42, P = 0.02). Overall health showed a positive but nonsignificant association with dose, but subgroup analysis found that adductor spasmodic dysphonia (ADSD) patients without tremor had a significant positive correlation between overall health and dose (r = 0.50, P = 0.04), whereas tremor-only and mixed dystonia showed a negative nonsignificant correlation. Age was found to have no significant association with dose. Although socioeconomic factors were found to impact the number and frequency of injections, they had no significant impact on the ultimate dosage. CONCLUSION: BMI and overall health are positively correlated with higher effective dose and may be useful in guiding clinicians during the titration period. PMID- 24954040 TI - Effect of weight loss on voice after bariatric surgery. AB - OBJECTIVE: To investigate the effect of weight loss on voice. STUDY DESIGN: Prospective study. SUBJECTS: A total of 15 subjects undergoing bariatric surgery were investigated. Six subjects were lost to follow-up, and nine subjects were evaluated preoperatively and 3-6 months postoperatively. The evaluation included a questionnaire on voice quality filled by the patient, laryngeal examination, perceptual evaluation, and acoustic analysis. The questionnaire consisted of four questions: change in vocal pitch, change in vocal loudness, increase or decrease in phonatory effort, and the presence or absence of vocal fatigue. For the perceptual evaluation, a simplified version of the Grade, Roughness, Breathiness, Asthenia, Strain scale classification was used. These parameters were rated using a score ranging from zero to three where zero stands for none and three for severe. For the acoustic analysis, the following variables were measured: fundamental frequency, habitual pitch, jitter, shimmer, noise-to-harmonics ratio, voice turbulence index, and maximum phonation time. RESULTS: The mean age was 35.56 +/- 9.93 years. The mean weight preoperatively and postoperatively was 112.17 and 83.61 kg, respectively. The body mass index dropped by eight points from 38.06 to 30.83. Only three of the nine patients have reported change in voice quality. The latter was described as an increase in vocal pitch in the three cases, reduced loudness and increased phonatory effort in two, and the presence of vocal fatigue in one. There was no significant difference in the mean score of any of the perceptual parameters in patients preoperatively versus postoperatively. There was also no significant difference in any of the acoustic parameters or in the laryngeal findings before and after surgery. CONCLUSION: One third of the patients with weight loss reported change in voice quality that was not documented acoustically. The laryngeal examination is nonrevealing. PMID- 24954041 TI - Intrarater and interrater reliability of sagittal head posture: a novel technique performed by a physiotherapist and a speech and language pathologist. AB - INTRODUCTION: Different professionals such as speech and language pathologists and voice scientists are involved in the evaluation of head and neck posture. Therefore, a reliable, time-efficient, and precise method of posture assessment is essential for use in clinical and research settings. Photogrammetry is one of the most commonly used methods to assess head and neck posture. The objectives of this study were to evaluate the intrarater reliability of the method with a large sample size and the interrater reliability by two different specialists (a physiotherapist and a speech and language pathologist). METHOD: A total of three hundred four subjects (144 males and 160 females) aged between 18 and 28 years participated in the study. During the test session, a photograph was taken of the left-side profile of each subject in their ordinary and comfortable position. The head posture angle of each picture was calculated by two raters. The whole procedure was repeated in a retest session, 24 hours later. A total number of eight analyses were performed for each subject. The reliability was evaluated at several stages hierarchically and after confirming the reliability in each step, the next step was investigated. Paired t tests on the differences of scores obtained at all the aforementioned stages were used to ensure the absence of any systematic bias. To assess the reliability, intraclass correlation coefficients (ICCs) and the standard error of measurements (SEMs) were calculated. RESULTS: There was no significant difference between the mean values of the test and the retest angles at any stage of calculating the head posture angle in both pictures by both examiners (P > 0.05). The ICC and SEM values calculated for all stages were between 0.86-0.97 and 0.52-1.53, respectively. CONCLUSION: Systematic bias has not occurred at any stage. The ICC and SEM values calculated have demonstrated that there were appropriate relative and absolute reliabilities in all stages. This method is suggested to be used simply in research and clinical areas by different specialists. PMID- 24954042 TI - Hyoid bone tenderness as a clinical indicator of laryngeal pathology. AB - OBJECTIVES: Hyoid bone tenderness is an underemphasized clinical abnormality and is described as discomfort or pain on gentle palpation of the greater cornu. The primary outcome of this study is to assess if there is any association between hyoid tenderness and laryngeal pathology. STUDY DESIGN: This is a retrospective case-control study. METHODS: Ninety-four subjects were identified. These were divided into two groups, those with hyoid tenderness and those without hyoid tenderness. Presenting complaints and findings on nasal laryngoscopy were compared to identify any association between hyoid tenderness and laryngeal pathology. RESULTS: There were a total of 76 (80.9%) female and 18 (19.1%) male patients in the study. Analysis of presenting complaints showed that dysphonia (P < 0.001, odds ratio = 4.82) and neck pain (P = 0.015, odds ratio = 10.9) were significantly associated with hyoid tenderness, more with these symptoms had hyoid tenderness than expected by chance. Findings on nasal laryngoscopy showed a significant association between hyoid tenderness and vocal fold nodules (P < 0.001). Nasopharyngitis (P = 0.065) and tense anterior neck muscles (P = 0.056) were almost significantly associated with hyoid tenderness. CONCLUSION: Hyoid tenderness has previously been reported as an early sign in acute epiglottitis. These results indicate that hyoid bone tenderness may be a useful clinical indicator of various other laryngeal pathologies or dysfunctions. PMID- 24954043 TI - Acoustic parameters and salivary IL-6 levels in overweight and obese teachers. AB - OBJECTIVE: Either obesity or vocal loading task leads to elevation of proinflammatory cytokines such as interleukin 6 (IL-6). However, it is unknown whether vocal parameters after vocal loading are correlated with body mass index (BMI) or IL-6. We hypothesize that vocal loading induces an elevation of acoustic parameters of voice and salivary IL-6 in overweight and obese people. METHODS: A total of 33 schoolteachers without any self-reported voice alterations were invited to participate in this study. Participants were classified according to BMI into normal, overweight, and obese groups. The vocal loading task consisted of loud speech (60-90 minutes) in their classroom. Salivary and voice samples were taken before and after vocal loading. Perceptual and self-reported voice alterations and objective voice analyses were investigated. The relative concentration of salivary IL-6 was estimated by a colorimetric assay. RESULTS: Obese teachers showed a significant elevation in fundamental frequency value after vocal loading. In addition, reduction in harmonics-to-noise ratio (HNR) was observed in teachers with normal weight after vocal loading but not in overweight or obese groups. No significant correlation was observed between BMI and any of the acoustic parameters analyzed or salivary IL-6 levels. Furthermore, teachers who were overweight showed a significant increase in the salivary IL-6 levels after vocal loading. Interestingly, salivary IL-6 levels were positively correlated with HNR value in the overweight group after vocal loading. CONCLUSION: Excessive body weight is related to alterations in fundamental frequency and HNR. In addition, HNR, but not BMI, is associated with salivary IL 6 levels in overweight teachers. PMID- 24954044 TI - Molecular mechanisms that restrict yeast centrosome duplication to one event per cell cycle. AB - BACKGROUND: The spindle pole body (SPB) of budding yeast is the functional equivalent of the mammalian centrosome. Like the centrosome, the SPB duplicates once per cell cycle. The new SPB assembles adjacent to the mother SPB at a substructure called the bridge. The half-bridge, the bridge precursor, is a one sided extension of the SPB central plaque layered on both sides of the nuclear envelope. Parallel Sfi1 molecules longitudinally span the half-bridge with their N termini embedded in the SPB central plaque, whereas their C termini mark the half-bridge distal end. In early G1, half-bridge elongation by antiparallel C-to C dimerization of Sfi1 exposes free N-Sfi1 where the new SPB assembles. After SPB duplication, the dimerized Sfi1 is severed to allow spindle formation and SPB reduplication. RESULTS: We show that Sfi1 C-terminal domain harbors phosphorylation sites for Cdk1 and the polo-like kinase Cdc5. Cdk1 and, to a lesser extent, Cdc5 inhibit SPB duplication as phosphomimetic sfi1 mutations lead to metaphase cells with a single SPB. In contrast, phosphoinhibitory sfi1 mutations in Cdk1 sites are lethal because cells fail to sever the bridge after SPB duplication. Moreover, Cdc14 dephosphorylates C-Sfi1 to prepare it for a new round of duplication, and the kinase Mps1 promotes Sfi1 extension in G1. CONCLUSIONS: Positive (Cdc14) and negative (Cdk1 and Cdc5) SPB duplication signals are integrated at the level of the half-bridge component Sfi1. In addition, Mps1 activates Sfi1 duplication. Fluctuating activities of these regulators ensure one SPB duplication event per cell cycle. PMID- 24954046 TI - Sharing social touch in the primary somatosensory cortex. AB - Touch has an emotional and communicative meaning, and it plays a crucial role in social perception and empathy. The intuitive link between others' somatosensations and our sense of touch becomes ostensible in mirror-touch synesthesia, a condition in which the view of a touch on another person's body elicits conscious tactile sensations on the observer's own body [1]. This peculiar phenomenon may implicate normal social mirror mechanisms [2]. Here, we show that mirror-touch interference effects, synesthesia-like sensations, and even phantom touches can be induced in nonsynesthetes by priming the primary somatosensory cortex (SI) directly or indirectly via the posterior parietal cortex. These results were obtained by means of facilitatory paired-pulse transcranial magnetic stimulation (ppTMS) contingent upon the observation of touch. For these vicarious effects, the SI is engaged at 150 ms from the onset of the visual touch. Intriguingly, individual differences in empathic abilities, assessed with the Interpersonal Reactivity Index [3], drive the activity of the SI when nonsynesthetes witness others' tactile sensations. This evidence implies that, under normal conditions, touch observation activates the SI below the threshold for perceptual awareness [4]; through the visual-dependent tuning of SI activity by ppTMS, what is seen becomes felt, namely, mirror-touch synesthesia. On a broader perspective, the visual responsivity of the SI may allow an automatic and unconscious transference of the sensation that another person is experiencing onto oneself, and, in turn, the empathic sharing of somatosensations [2]. PMID- 24954047 TI - Strategy change in vibrissal active sensing during rat locomotion. AB - During exploration, rats and other small mammals make rhythmic back-and-forth sweeps of their long facial whiskers (macrovibrissae) [1-3]. These "whisking" movements are modulated by head movement [4] and by vibrissal sensory input [5, 6] and hence are often considered "active" in the Gibsonian sense of being purposive and information seeking [7, 8]. An important hallmark of active sensing is the modification of the control strategy according to context [9]. Using a task in which rats were trained to run circuits for food, we tested the hypothesis that whisker control, as measured by high-speed videography, changes with contextual variables such as environment familiarity, risk of collision, and availability of visual cues. In novel environments, functionally blind rats moved at slow speeds and performed broad whisker sweeps. With greater familiarity, however, they moved more rapidly, protracted their whiskers further, and showed decreased whisking amplitude. These findings indicate a strategy change from using the vibrissae to explore nearby surfaces to using them primarily for "look ahead." In environments with increased risk of collision, functionally blind animals moved more slowly but protracted their whiskers further. Sighted animals also showed changes in whisker control strategy with increased familiarity, but these changes were different to those of the functionally blind strain. Sighted animals also changed their vibrissal behavior when visual cues were subsequently removed (by being placed in darkness). These contextual influences provide strong evidence of active control and demonstrate that the vibrissal system provides an accessible model of purposive behavior in mammals. PMID- 24954045 TI - Transcriptional regulation of LUX by CBF1 mediates cold input to the circadian clock in Arabidopsis. AB - Circadian clocks allow organisms to anticipate daily changes in the environment to enhance overall fitness. Transcription factors (TFs) play a prominent role in the molecular mechanism but are incompletely described possibly due to functional redundancy, gene family proliferation, and/or lack of context-specific assays. To overcome these, we performed a high-throughput yeast one-hybrid screen using the LUX ARRYHTHMO (LUX) gene promoter as bait against an Arabidopsis TF library. LUX is a unique gene because its mutation causes severe clock defects and transcript maintains high-amplitude cycling in the cold. We report the well-characterized cold-inducible C-repeat (CRT)/drought-responsive element (DRE) binding factor CBF1/DREB1b is a transcriptional regulator of LUX. We show that CBF1 binds the CRT in the LUX promoter, and both genes overlap in temporal and spatial expression. CBF1 overexpression causes upregulation of LUX and also alters other clock gene transcripts. LUX promoter regions including the CRT and Evening Element (EE) are sufficient for high-amplitude transcriptional cycling in the cold, and cold-acclimated lux seedlings are sensitive to freezing stress. Our data show cold signaling is integrated into the clock by CBF-mediated regulation of LUX expression, thereby defining a new transcriptional mechanism for temperature input to the circadian clock. PMID- 24954048 TI - The centriolar protein Bld10/Cep135 is required to establish centrosome asymmetry in Drosophila neuroblasts. AB - Centrosome asymmetry has been implicated in stem cell fate maintenance in both flies and vertebrates [1, 2]. Drosophila neuroblasts, the neural precursors of the fly's central nervous system [3], contain molecularly and physically asymmetric centrosomes, established through differences in pericentriolar matrix (PCM) retention [4-7]. For instance, the daughter centriole maintains PCM and thus microtubule-organizing center (MTOC) activity through Polo-mediated phosphorylation of Centrobin (Cnb) [7, 8]. The mother centriole, however, quickly downregulates PCM and moves away from the apical cortex, randomly migrating through the cytoplasm until maturation sets in at prophase [4-6, 8]. How PCM downregulation is molecularly controlled is currently unknown, but it involves Pericentrin (PCNT)-like protein (PLP) to prevent premature Polo localization and thus MTOC activity [9]. Here, we report that the centriolar protein Bld10, the fly ortholog of Cep135, is required to establish centrosome asymmetry in Drosophila neuroblasts through shedding of Polo from the mother centrosome. bld10 mutants fail to downregulate Polo and PCM, generating two active, improperly positioned MTOCs. Failure to shed Polo and PCM causes spindle alignment and centrosome segregation defects, resulting in neuroblasts incorrectly retaining the older mother centrosome. Since Cep135 is implicated in primary microcephaly, we speculate that perturbed centrosome asymmetry could contribute to this rare neurodevelopmental disease. PMID- 24954049 TI - Deep proteomics of the Xenopus laevis egg using an mRNA-derived reference database. AB - BACKGROUND: Mass spectrometry-based proteomics enables the global identification and quantification of proteins and their posttranslational modifications in complex biological samples. However, proteomic analysis requires a complete and accurate reference set of proteins and is therefore largely restricted to model organisms with sequenced genomes. RESULTS: Here, we demonstrate the feasibility of deep genome-free proteomics by using a reference proteome derived from heterogeneous mRNA data. We identify more than 11,000 proteins with 99% confidence from the unfertilized Xenopus laevis egg and estimate protein abundance with approximately 2-fold precision. Our reference database outperforms the provisional gene models based on genomic DNA sequencing and references generated by other methods. Surprisingly, we find that many proteins in the egg lack mRNA support and that many of these proteins are found in blood or liver, suggesting that they are taken up from the blood plasma, together with yolk, during oocyte growth and maturation, potentially contributing to early embryogenesis. CONCLUSION: To facilitate proteomics in nonmodel organisms, we make our platform available as an online resource that converts heterogeneous mRNA data into a protein reference set. Thus, we demonstrate the feasibility and power of genome-free proteomics while shedding new light on embryogenesis in vertebrates. PMID- 24954050 TI - Dynamics of neural population responses in prefrontal cortex indicate changes of mind on single trials. AB - Decision making is a complex process in which different sources of information are combined into a decision variable (DV) that guides action [1, 2]. Neurophysiological studies have typically sought insight into the dynamics of the decision-making process and its neural mechanisms through statistical analysis of large numbers of trials from sequentially recorded single neurons or small groups of neurons [3-6]. However, detecting and analyzing the DV on individual trials has been challenging [7]. Here we show that by recording simultaneously from hundreds of units in prearcuate gyrus of macaque monkeys performing a direction discrimination task, we can predict the monkey's choices with high accuracy and decode DV dynamically as the decision unfolds on individual trials. This advance enabled us to study changes of mind (CoMs) that occasionally happen before the final commitment to a decision [8-10]. On individual trials, the decoded DV varied significantly over time and occasionally changed its sign, identifying a potential CoM. Interrogating the system by random stopping of the decision-making process during the delay period after stimulus presentation confirmed the validity of identified CoMs. Importantly, the properties of the candidate CoMs also conformed to expectations based on prior theoretical and behavioral studies [8]: they were more likely to go from an incorrect to a correct choice, they were more likely for weak and intermediate stimuli than for strong stimuli, and they were more likely earlier in the trial. We suggest that simultaneous recording of large neural populations provides a good estimate of DV and explains idiosyncratic aspects of the decision-making process that were inaccessible before. PMID- 24954051 TI - Novel cell types, neurosecretory cells, and body plan of the early-diverging metazoan Trichoplax adhaerens. AB - BACKGROUND: Trichoplax adhaerens is the best-known member of the phylum Placozoa, one of the earliest-diverging metazoan phyla. It is a small disk-shaped animal that glides on surfaces in warm oceans to feed on algae. Prior anatomical studies of Trichoplax revealed that it has a simple three-layered organization with four somatic cell types. RESULTS: We reinvestigate the cellular organization of Trichoplax using advanced freezing and microscopy techniques to identify localize and count cells. Six somatic cell types are deployed in stereotyped positions. A thick ventral plate, comprising the majority of the cells, includes ciliated epithelial cells, newly identified lipophil cells packed with large lipid granules, and gland cells. Lipophils project deep into the interior, where they alternate with regularly spaced fiber cells whose branches contact all other cell types, including cells of the dorsal and ventral epithelium. Crystal cells, each containing a birefringent crystal, are arrayed around the rim. Gland cells express several proteins typical of neurosecretory cells, and a subset of them, around the rim, also expresses an FMRFamide-like neuropeptide. CONCLUSIONS: Structural analysis of Trichoplax with significantly improved techniques provides an advance in understanding its cell types and their distributions. We find two previously undetected cell types, lipohil and crystal cells, and an organized body plan in which different cell types are arranged in distinct patterns. The composition of gland cells suggests that they are neurosecretory cells and could control locomotor and feeding behavior. PMID- 24954052 TI - Formins determine the functional properties of actin filaments in yeast. AB - The actin cytoskeleton executes a broad range of essential functions within a living cell. The dynamic nature of the actin polymer is modulated to facilitate specific cellular processes at discrete locations by actin-binding proteins (ABPs), including the formins and tropomyosins (Tms). Formins nucleate actin polymers, while Tms are conserved dimeric proteins that form polymers along the length of actin filaments. Cells possess different Tm isoforms, each capable of differentially regulating the dynamic and functional properties of the actin polymer. However, the mechanism by which a particular Tm localizes to a specific actin polymer is unknown. Here we show that specific formin family members dictate which Tm isoform will associate with a particular actin filament to modulate its dynamic and functional properties at specific cellular locations. Exchanging the localization of the fission yeast formins For3 and Cdc12 results in an exchange in localizations of Tm forms on actin polymers. This nucleator driven switch in filament composition is reflected in a switch in actin dynamics, together with a corresponding change in the filament's ability to regulate ABPs and myosin motor activity. These data establish a role for formins in dictating which specific Tm variant will associate with a growing actin filament and therefore specify the functional capacity of the actin filaments that they create. PMID- 24954053 TI - Oral health status in Navajo Nation Head Start children. AB - OBJECTIVE: This study assessed oral health status for preschool-aged children in the Navajo Nation to obtain data on baseline decayed, missing, and filled tooth surfaces (dmfs) and dental caries patterns, describe sociodemographic correlates of children's baseline dmfs measures, and compare the children's dmfs measures with previous dental survey data for the Navajo Nation from the Indian Health Service and the National Health and Nutrition Examination Survey (NHANES). METHODS: The analyzed study sample included 981 child/caregiver dyads residing in the Navajo Nation who completed baseline dmfs assessments for an ongoing randomized clinical trial involving Navajo Nation Head Start Centers. Calibrated dental hygienists collected baseline dmfs data from child participants ages 3-5 years (488 males and 493 females), and caregivers completed a basic research factors questionnaire. RESULTS: Mean dmfs for the study population was 21.33 (SD=19.99) and not appreciably different from the 1999 Indian Health Service survey of Navajo Nation preschool-aged children (mean=19.02, SD=16.59, P=0.08). However, only 69.5 percent of children in the current study had untreated decay compared with 82.9 percent in the 1999 Indian Health Service survey (P<0.0001). Study results were considerably higher than the 16.0 percent reported for 2-4 year-old children in the whites-only group from the 1999-2004 NHANES data. Age had the strongest association with dmfs, followed by child gender, then caregiver income and education. CONCLUSION: Dental caries in preschool-aged Navajo children is extremely high compared with other US population segments, and dmfs has not appreciably changed for more than a decade. PMID- 24954054 TI - The solvatochromic, spectral, and geometrical properties of nifenazone: a DFT/TD DFT and experimental study. AB - The solvatochromic, spectral, and geometrical properties of nifenazone (NIF), a pyrazole-nicotinamide drug, were experimentally and computationally investigated in several neat solvents and in hydro-organic binary systems such as water acetonitrile and water-dioxane systems. The bathochromic spectral shift observed in NIF absorption spectra when reducing the polarity of the solvent was correlated with the orientation polarizability (Deltaf). Unlike aprotic solvents, a satisfactory correlation between lambda(max) and Deltaf was determined (linear correlation of regression coefficient, R, equal to 0.93) for polar protic solvents. In addition, the medium-dependent spectral properties were correlated with the Kamlet-Taft solvatochromic parameters (alpha, beta, and pi*) by applying a multiple linear regression analysis (MLRA). The results obtained from this analysis were then employed to establish MLRA relationships for NIF in order to estimate the spectral shift in different solvents, which in turn exhibited excellent correlation (R > 0.99) with the experimental values of nu(max). Density functional theory (DFT) and time-dependent DFT theory calculations coupled with the integral equation formalism-polarizable continuum model (IEF-PCM) were performed to investigate the solvent-dependent spectral and geometrical properties of NIF. The calculations showed good and poor agreements with the experimental results using the CAM-B3LYP and B3LYP functionals, respectively. Experimental and theoretical results confirmed that the chemical properties of NIF are strongly dependent on the polarity of the chosen medium and its hydrogen bonding capability. This in turn supports the hypothesis of the delocalization of the electron density within the pyrazole ring of NIF. PMID- 24954055 TI - Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: the CHARGE study. AB - BACKGROUND: Gestational exposure to several common agricultural pesticides can induce developmental neurotoxicity in humans, and has been associated with developmental delay and autism. OBJECTIVES: We evaluated whether residential proximity to agricultural pesticides during pregnancy is associated with autism spectrum disorders (ASD) or developmental delay (DD) in the Childhood Autism Risks from Genetics and Environment (CHARGE) study. METHODS: The CHARGE study is a population-based case-control study of ASD, DD, and typical development. For 970 participants, commercial pesticide application data from the California Pesticide Use Report (1997-2008) were linked to the addresses during pregnancy. Pounds of active ingredient applied for organophophates, organochlorines, pyrethroids, and carbamates were aggregated within 1.25-km, 1.5-km, and 1.75-km buffer distances from the home. Multinomial logistic regression was used to estimate the odds ratio (OR) of exposure comparing confirmed cases of ASD (n = 486) or DD (n = 168) with typically developing referents (n = 316). RESULTS: Approximately one-third of CHARGE study mothers lived, during pregnancy, within 1.5 km (just under 1 mile) of an agricultural pesticide application. Proximity to organophosphates at some point during gestation was associated with a 60% increased risk for ASD, higher for third-trimester exposures (OR = 2.0; 95% CI: 1.1, 3.6), and second-trimester chlorpyrifos applications (OR = 3.3; 95% CI: 1.5, 7.4). Children of mothers residing near pyrethroid insecticide applications just before conception or during third trimester were at greater risk for both ASD and DD, with ORs ranging from 1.7 to 2.3. Risk for DD was increased in those near carbamate applications, but no specific vulnerable period was identified. CONCLUSIONS: This study of ASD strengthens the evidence linking neurodevelopmental disorders with gestational pesticide exposures, particularly organophosphates, and provides novel results of ASD and DD associations with, respectively, pyrethroids and carbamates. PMID- 24954056 TI - Dental arcade arteriovenous fistulas: from diagnosis to treatment with emphasis on the role of endovascular or percutaneous treatment: single centre experience. AB - OBJECTIVE: Dental arcade arteriovenous fistula (DA-AVF) are rare. The purpose of this study was to understand the angioarchitecture of these lesions, changing strategies of endovascular treatment and to analyse the best therapeutic option which will allow normal skeletal development especially in children. MATERIALS AND METHODS: Retrospective study of all the patients of DA-AVF managed at our centre over the last 16 years. Detailed analysis of the clinical features, the imaging findings, endovascular treatment and angiographic outcomes was done. RESULTS: Total of six patients were treated. 5 were in the mandible and one in the maxilla. Transarterial glue embolization was done in 3 patients and direct puncture of the intraosseous venous pouch in 2. Transarterial Onyx was used in 2 patients through dual lumen balloon catheter. Overall cure was achieved in 5 out of 6 patients (83%). CONCLUSION: High index of suspicion is required to diagnose it on panoramic radiographs. CT/MR/CTA can lead to early diagnosis. Transarterial Onyx embolization using dual lumen balloon catheter is a promising technique & allows excellent penetration of Onyx into the intraosseous venous pouch. PMID- 24954057 TI - Vaccines for post-exposure prophylaxis against varicella (chickenpox) in children and adults. AB - BACKGROUND: The prevention of varicella (chickenpox) using live attenuated varicella vaccines has been demonstrated both in randomised controlled trials (RCTs) and in population-based immunisation programmes in countries such as the United States and Australia. Many countries do not routinely immunise children against varicella and exposures continue to occur. Although the disease is often mild, complications such as secondary bacterial infection, pneumonitis and encephalitis occur in about 1% of cases, usually leading to hospitalisation. The use of varicella vaccine in persons who have recently been exposed to the varicella zoster virus has been studied as a form of post-exposure prophylaxis (PEP). OBJECTIVES: To assess the efficacy and safety of vaccines for use as PEP for the prevention of varicella in children and adults. SEARCH METHODS: We searched CENTRAL (2014, Issue 1), MEDLINE (1966 to March week 1, 2014), EMBASE (January 1990 to March 2014) and LILACS (1982 to March 2014). We searched for unpublished trials registered on the clinicaltrials.gov and WHO ICTRP websites. SELECTION CRITERIA: RCTs and quasi-RCTs of varicella vaccine for PEP compared with placebo or no intervention. The outcome measures were efficacy in prevention of clinical cases and/or laboratory-confirmed clinical cases and adverse events following vaccination. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and analysed data using Review Manager software. MAIN RESULTS: We identified three trials involving 110 healthy children who were siblings of household contacts. The included trials varied in study quality, vaccine used, length of follow-up and outcomes measured and, as such, were not suitable for meta-analysis. We identified high or unclear risk of bias in two of the three included studies. Overall, 13 out of 56 vaccine recipients (23%) developed varicella compared with 42 out of 54 placebo (or no vaccine) recipients (78%). Of the vaccine recipients who developed varicella, the majority only had mild disease (with fewer than 50 skin lesions). In the three trials, most participants received PEP within three days following exposure; too few participants were vaccinated four to five days post-exposure to ascertain the efficacy of vaccine given more than three days after exposure. No included trial reported on adverse events following immunisation. AUTHORS' CONCLUSIONS: These small trials suggest varicella vaccine administered within three days to children following household contact with a varicella case reduces infection rates and severity of cases. We identified no RCTs for adolescents or adults. Safety was not adequately addressed. PMID- 24954058 TI - Emerging investigators: new challenges spawn new innovations. PMID- 24954059 TI - Novel approach to the preparation of hemisuccinates of steroids bearing tertiary alcohol group. AB - 17beta-O-Hemisuccinates of typical representatives of Anabolic-Androgenic Steroids, 17beta-hydroxy-17-methylandrostan-4-en-3-one, 17beta-hydroxy-17-methyl 2-oxa-5alpha-androstan-3-one, 17beta-hydroxy-17-methyl-5alpha-androstano-[3,2 c]pyrazole, were prepared. Several methods for the hemisuccinate preparation were tested. The indirect method using 1-ethyl-3-(dimethylaminopropyl)carbodiimide coupling reagent to form an ester bond of steroid with 2-(trimethylsilyl)ethyl hydrogen butanedioate was finally applied. Using the selectively removable protecting group, the desired hemisuccinates of steroids bearing tertiary alcohol group were obtained. PMID- 24954060 TI - Psychiatric disturbances in patients with progressive supranuclear palsy: a case control study. AB - OBJECTIVES: To investigate the frequency and the different types of psychiatric disturbances in PSP patients using validated psychiatric instruments. METHODS: We conducted a case-control study using the Structured Clinical Interview (SCID-I) for DSM-IV to investigate psychiatric disorders in 28 PSP patients and 28 age and gender matched healthy controls. PSP severity was scored using the PSP rating scale; cognitive functions were assessed using the Montreal Cognitive Assessment scale and the Frontal Assessment Battery scale. RESULTS: SCID-I disclosed that psychiatric disturbances were more frequent in PSP patients (53%) than in healthy controls (17.8%) (p = 0.005). Psychiatric disorders in PSP patients were characterized by mood disorders. Depression due to PSP was the most frequent diagnosis and was found in 8 of the 15 patients with depressive disorders. None of the PSP patients had a diagnosis of other SCID-I disorders. No clinical or demographic differences were found when comparing PSP patients with and without psychiatric disturbances. CONCLUSIONS: Psychiatric disturbances, namely depressive disorders, were more frequent in PSP patients than in controls. A thorough evaluation of psychiatric disorders is important to insure appropriate treatment of PSP patients.. PMID- 24954061 TI - Transient blepharospasm, apraxia of eyelid opening, and hemidyskinesia following a right parietotemporal infarct. PMID- 24954062 TI - The role of whole brain radiation therapy in the management of melanoma brain metastases. AB - BACKGROUND: Brain metastases are common in patients with melanoma, and optimal management is not well defined. As melanoma has traditionally been thought of as "radioresistant," the role of whole brain radiation therapy (WBRT) in particular is unclear. We conducted this retrospective study to identify prognostic factors for patients treated with stereotactic radiosurgery (SRS) for melanoma brain metastases and to investigate the role of additional up-front treatment with whole brain radiation therapy (WBRT). METHODS: We reviewed records of 147 patients who received SRS as part of initial management of their melanoma brain metastases from January 2000 through June 2010. Overall survival (OS) and time to distant intracranial progression were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. RESULTS: WBRT was employed with SRS in 27% of patients and as salvage in an additional 22%. Age at SRS > 60 years (hazard ratio [HR] 0.64, p = 0.05), multiple brain metastases (HR 1.90, p = 0.008), and omission of up-front WBRT (HR 2.24, p = 0.005) were associated with distant intracranial progression on multivariate analysis. Extensive extracranial metastases (HR 1.86, p = 0.0006), Karnofsky Performance Status (KPS) <= 80% (HR 1.58, p = 0.01), and multiple brain metastases (HR 1.40, p = 0.06) were associated with worse OS on univariate analysis. Extensive extracranial metastases (HR 1.78, p = 0.001) and KPS (HR 1.52, p = 0.02) remained significantly associated with OS on multivariate analysis. In patients with absent or stable extracranial disease, multiple brain metastases were associated with worse OS (multivariate HR 5.89, p = 0.004), and there was a trend toward an association with worse OS when up-front WBRT was omitted (multivariate HR 2.56, p = 0.08). CONCLUSIONS: Multiple brain metastases and omission of up-front WBRT (particularly in combination) are associated with distant intracranial progression. Improvement in intracranial disease control may be especially important in the subset of patients with absent or stable extracranial disease, where the competing risk of death from extracranial disease is low. These results are hypothesis generating and require confirmation from ongoing randomized trials. PMID- 24954064 TI - Patient-reported symptom questionnaires in laryngeal cancer: voice, speech and swallowing. AB - OBJECTIVES: To validate questionnaires on voice, speech, and swallowing among laryngeal cancer patients, to assess the need for and use of rehabilitation services, and to determine the association between voice, speech, and swallowing problems, and quality of life and distress. MATERIALS AND METHODS: Laryngeal cancer patients at least three months post-treatment completed the VHI (voice), SHI (speech), SWAL-QOL (swallowing), EORTC QLQ-C30, QLQ-HN35, HADS, and study specific questions on rehabilitation. RESULTS: Eighty-eight patients and 110 healthy controls participated. Cut off scores of 15, 6, and 14 were defined for the VHI, SHI, and SWAL-QOL (sensitivity > 90%; specificity > 80%). Based on these scores, 56% of the patients reported voice, 63% speech, and 54% swallowing problems. VHI, SHI, and SWAL-QOL scores were associated significantly with quality of life (EORTC QLQ-C30 global quality of life scale) (r = .43 (VHI and SHI) and r = .46 (SWAL-QOL)) and distress (r = .50 (VHI and SHI) and r = .58 (SWAL-QOL)). In retrospect, 32% of the patients indicated the need for rehabilitation at time of treatment, and 81% of these patients availed themselves of such services. Post-treatment, 8% of the patients expressed a need for rehabilitation, and 20% of these patients actually made use of such services. CONCLUSION: Psychometric characteristics of the VHI, SHI, and SWAL-QOL in laryngeal cancer patients are good. The prevalence of voice, speech, and swallowing problems is high, and clearly related to quality of life and distress. Although higher during than after treatment, the perceived need for and use of rehabilitation services is limited. PMID- 24954063 TI - Effects of dopamine D2/D3 blockade on human sensory and sensorimotor gating in initially antipsychotic-naive, first-episode schizophrenia patients. AB - It has been suggested that psychophysiological measures of sensory and sensorimotor gating, P50 gating and prepulse inhibition of the startle reflex (PPI), underlie core features of schizophrenia and are linked to dopaminergic pathways in the striatum and prefrontal cortex. In the present study, the effects of a potent D2/D3 receptor antagonist, amisulpride, were investigated on PPI and P50 gating in a large sample of antipsychotic-naive, first-episode patients with schizophrenia. A total of 52 initially antipsychotic-naive, first-episode schizophrenia patients were assessed for their P50 gating, PPI, and habituation/sensitization abilities at baseline and after 2 and 6 weeks of treatment with flexible doses of amisulpride. In addition, 47 matched healthy controls were assessed at baseline and after 6 weeks. At baseline, the patients showed significantly reduced PPI, yet normal levels of P50 gating, habituation, and sensitization. Treatment with amisulpride showed no effects on these measures, either at 2 or 6 weeks of follow-up. This is the first study investigating the effects of monotherapy with a relatively selective dopamine D2/D3 receptor antagonist (amisulpride) on sensory and sensorimotor gating deficits in a longitudinal study of a large group of initially antipsychotic naive, first-episode patients with schizophrenia. Our finding that amisulpride effectively reduced symptom severity in our patients without reducing their PPI deficits indicates that increased activity of dopamine D2 receptors may be involved in symptomatology of patients with schizophrenia, but not in their sensorimotor gating deficits. PMID- 24954066 TI - Syntheses and properties of elastic copoly(ester-urethane)s containing a phospholipid moiety and the fabrication of nanosheets. AB - In these years, we have investigated the syntheses of novel diamine and diol monomers containing phosphorylcholine (PC) group to obtain biocompatible polymers, the backbone components of which were thermally stable and mechanically strong. In this study, the preparations of elastic copoly(ester-urethane)s containing PC group and polycarbonate segment were carried out by polycondensation and polyaddition using a diol monomer containing PC group and polycarbonate diol. It was found that the obtained polymers exhibited the high thermal stability up to 200 degrees C and the elasticity derived from the soft segment. The introduction of PC group was effective to improve the resistance to the adhesions of proteins and platelets on the polymer films, which was the result of surface properties derived from the PC moiety. In addition, we tried to prepare ultra-thin polymer films composed of copoly(ester-urethane)s, so-called nanosheets. As a result, the desired nanosheets were successfully fabricated and the obtained nanosheets exhibited the high adhesive strength, indicating that the nanosheets could conform closely to the desired surfaces due to their exquisite flexibility and low roughness. PMID- 24954065 TI - Phase II multicenter trial of Caphosol for the reduction of mucositis in patients receiving radiation therapy for head and neck cancer. AB - PURPOSE: We conducted a phase II multicenter study evaluating Caphosol in patients receiving head and neck radiation (H/N RT) +/- chemotherapy or biologic sensitizer. MATERIALS/METHODS: The primary endpoint of the study tested the rate of functional mucositis (WHO grade > or equal to 2) with the hypothesis that <75% of patients would develop > or equal to 2 mucositis with Caphosol compared with a historical rate of >90%. New methods were applied with higher than historic rigor. 5 Institutions were included in this study: Moffitt Cancer Center (MCC), MD Anderson Cancer Center (MDACC), Duke University Cancer Center (DUCC), University of Florida (UF) and Temple University Cancer Center (TUCC). Caphosol was taken by patients at least 4 times a day and up to 10 times per day commencing with day 1 of RT and for a total duration of 8 weeks after completion of RT. Detailed questionnaires were completed weekly by patients and a unique algorithm was used to generate the WHO grade of mucositis. RESULTS: 98 Patients were enrolled in the study. 59/98 (60%) patients were evaluable for the primary endpoint giving us 80% power. All evaluable patients experienced WHO grade > or equal to 2 mucositis and the trial failed to reject the null hypothesis. > or equal to 2 mucositis rates at weeks 2, 4, 6, 11 and 15 were as follows: 45%, 90%, 98%, 71%, 50%. CONCLUSION: We were unable to demonstrate that Caphosol significantly reduced WHO grade 2 or higher mucositis below a 90% historic rate. We are not surprised with this finding given our rigorous methodology in grading. PMID- 24954067 TI - Lost in a haystack: the importance of physical re-examination. AB - We report an unusual case of varicella zoster in a 19-year-old, who presented with persisting fever even after her lesions began forming scabs. Fever workup for secondary complications was negative. A re-examination revealed an axillary eschar. She recovered completely with doxycycline. This report suggests the importance of keeping in mind, epidemiological data of common diseases in the locality, as well as the significance of a thorough physical examination in patients with fever. PMID- 24954068 TI - Ultrasound-guided core biopsy in the diagnostic work-up of tuberculous lymphadenitis in Saudi Arabia, refining the diagnostic approach. Case series and review of literature. AB - OBJECTIVE: Tuberculous cervical lymphadenitis is the most common presentation of extrapulmonary tuberculosis (TB) in Saudi Arabia and worldwide. Obtaining a tissue biopsy for culture and histopathology is frequently needed to establish the diagnosis. The available diagnostic tools include excisional surgical biopsy, fine needle aspiration (FNA) and ultrasound-guided core lymph node biopsy. We present a single center experience of the use of ultrasound-guided core lymph node biopsy as a diagnostic tool for tuberculous lymphadenitis. METHODS: A retrospective review of the interventional radiology database for all of the patients with cervical lymphadenopathy undergoing ultrasound-guided core biopsy at King Abdulaziz Medical City-Riyadh, Saudi Arabia from January 1 2008 to December 30 2011. The data were the patient demographics, clinical characteristics, biopsy method and pathological and clinical diagnoses. RESULTS: Five cases underwent ultrasound-guided cervical lymph node biopsy during the study period. A total of 55 cases underwent excisional cervical lymph node biopsy in the same period. The age of the patients who underwent the core biopsy ranged from 18 to 76 years old. All of the biopsies were performed as one-day surgery, and all of the patients were discharged on the same day with no complications. The final diagnosis was confirmed in all of the cases (100%); with tuberculosis being the diagnosis in four of the five cases (80%), and one case being diagnosed as lymphoma. CONCLUSION: Ultrasound-guided core biopsy is an underutilized procedure in our hospital and could be a very valuable asset in the diagnostic algorithm of tuberculous lymphadenitis in Saudi Arabia. The widespread use of the procedure would positively affect patient care, providing earlier diagnosis and treatment. PMID- 24954069 TI - Degradation behavior of biodegradable Fe35Mn alloy stents. AB - This article reports a degradation study that was done on stent prototypes made of biodegradable Fe35Mn alloy in a simulated human coronary arterial condition. The stent degradation was observed for a short-term period from 0.5 to 168 h, which simulates the early period of stenting procedure. Potentiodynamic polarization and electrochemical impedance spectroscopy were used to quantify degradation rate and surface property of the stents. Results showed that signs of degradation were visible on both crimped and expanded stents after 1 h of test, mostly located on the stent's curvatures. The degradation rate of stent was higher compared to that of the original alloy, indicating the surface altering effect of stent fabrication processing to degradation. A single oxide layer was formed and detected as a porous structure with capacitive behavior. Expanded stents exhibited lower polarization resistance compared to the nonexpanded ones, indicating the cold work effect of expansion procedure to degradation. PMID- 24954070 TI - Identification of caleosin and two oleosin isoforms in oil bodies of pine megagametophytes. AB - Numerous oil bodies of 0.2-2 MUm occupied approximately 80% of intracellular space in mature pine (Pinus massoniana) megagametophytes. They were stably isolated and found to comprise mostly triacylglycerols as examined by thin layer chromatography analysis and confirmed by both Nile red and BODIPY stainings. Fatty acids released from the triacylglycerols of pine oil bodies were mainly unsaturated, including linoleic acid (60%), adrenic acid (12.3%) and vaccenic acid (9.7%). Proteins extracted from pine oil bodies were subjected to immunological cross-recognition, and the results showed that three proteins of 28, 16 and 14 kDa were detected by antibodies against sesame seed caleosin, sesame oleosin-L and lily pollen oleosin-P, respectively. Complete cDNA fragments encoding these three pine oil-body proteins, tentatively named caleosin, oleosin L and oleosin-G, were obtained by PCR cloning and further confirmed by mass spectrometric analysis. Consistently, phylogenetic tree analyses showed that pine caleosin was closely-related to the caleosin of cycad megagametophyte among known caleosin sequences. While pine oleosin-L was found clustered with seed oleosin isoforms of angiosperm species, oleosin-G was distinctively grouped with the oleosin-P of lily pollen. The oleosin-G identified in pine megagametophytes seems to represent a new class of seed oleosin isoform evolutionarily close to the pollen oleosin-P. PMID- 24954071 TI - Hormonal dynamics during recovery from drought in two Eucalyptus globulus genotypes: from root to leaf. AB - Drought is a limiting environmental stress that represents a growing constraint to the forestry sector. Eucalyptus globulus is a widely planted coppice species, which capacity to cope with water deficit has already been described. However, the capacity of this species to recover is still poorly understood. In this study, we aimed to investigate the changes in abscisic acid (ABA), ABA-glucose ester (ABA-GE) and jasmonic acid (JA) content in leaves, xylem sap and roots of two genotypes (AL-10 and AL-18) during rewatering (2 h, 4 h, 24 h, and 168 h), after a drought stress period (0 h). We wished to clarify the role of these hormones in the recovery from drought and to determine whether these hormonal relations were related to specific genotype metabolisms. Our results showed that drought caused an increased in ABA and ABA-GE levels in all analysed plant parts, while JA content decreased in leaves, increased in xylem sap and did not change in roots. Some of these responses were genotype specific. During rewatering, ABA and ABA-GE content decreased in both genotypes and all plant parts, but at different time scales, and JA levels did not greatly change. Again, the genotypes responded differently. Altogether, our results characterised the response pattern of clone AL-10 as more responsive and defended that leaf should be used in preliminary screening methods of stress tolerance. The hormonal dynamics were related to the previously documented responses of these genotypes and sustain further physiological and molecular studies of water stress in this and other tree species. PMID- 24954073 TI - Sequence elements distal to the ligand binding pocket modulate the efficiency of a synthetic riboswitch. AB - Synthetic riboswitches can serve as sophisticated genetic control devices in synthetic biology, regulating gene expression through direct RNA-ligand interactions. We analyzed a synthetic neomycin riboswitch, which folds into a stem loop structure with an internal loop important for ligand binding and regulation. It is closed by a terminal hexaloop containing a U-turn and a looped out adenine. We investigated the relationship between sequence, structure, and biological activity in the terminal loop by saturating mutagenesis, ITC, and NMR. Mutants corresponding to the canonical U-turn fold retained biological activity. An improvement of stacking interactions in the U-turn led to an RNA element with slightly enhanced regulatory activity. For the first position of the U-turn motif and the looped out base, sequence-activity relationships that could not initially be explained on the basis of the structure of the aptamer-ligand complex were observed. However, NMR studies of these mutants revealed subtle relationships between structure and dynamics of the aptamer in its free or bound state and biological activity. PMID- 24954072 TI - von Willebrand factor in iris vasculature of glaucoma patients. AB - BACKGROUND: Previous reports have indicated the role of endothelium disturbances, as expressed by von Willebrand factor (vWF) release, in pathophysiology of glaucoma. The objective of this study was to investigate the vWF expression in iris vasculature of patients with primary open-angle glaucoma (POAG). MATERIAL AND METHODS: Immunohistochemistry of vWF expression was performed on cryostat sections of samples collected at the time of peripheral iridectomy and controls collected from dead donors. RESULTS: Twenty-seven Caucasians age 66.6+/-3.7 with 5.8+/-3.7-year history of treated PAOG and 10 controls age 62.2+/-1.92 with no history of glaucoma. The percentage of patients who presented normal and up regulation of vWF phenotype expression differed statistically between examined and control groups: 48% versus 100% (p=0.035, chi-square test with Yates' correction). Sex, age, glaucoma duration, and visual field quantitative indices had no impact on vWF expression. A significant correlation between mean pre surgery intraocular pressure and vWF expression was found (Spearman r=0.42, p=0.03). CONCLUSIONS: Considering the results, it may be suggested that vWF is actively involved in the pathophysiology of glaucoma. PMID- 24954074 TI - Neonatal domoic acid abolishes latent inhibition in male but not female rats and has differential interactions with social isolation. AB - Deficits in attention have long been identified as a core feature in schizophrenia and related neuropsychiatric disorders. We have investigated the combined effects of neonatal treatment with domoic acid (DOM) and social isolation rearing (both putative animal models of schizophrenia) on latent inhibition (LI), a measure of attentional processing. Daily subcutaneous injections of 20 MUg/kg DOM or saline were administered to rat pups from postnatal days (PND) 8-14. After weaning, rats were housed either alone or in groups of 4 until LI was assessed at PND 110 using a lick-suppression conditional emotional response paradigm. Neonatal treatment with DOM abolished LI behaviour in adult male rats regardless of housing condition when tested 48 h after conditioning, but this effect was not observed in female rats. Social isolation rearing also reduced LI in male rats, but not to the same extent as DOM. When tested again one week later, single-housed males treated with DOM displayed significant LI whereas saline treated or group-housed DOM males did not. No significant differences were found with females 1 week later. We conclude that neonatal DOM and social isolation both impair attentional processing in young adult male, but not female, rats although the mechanisms by which this occurs appear to be different. PMID- 24954075 TI - The effects of a 5-HT7 receptor agonist and antagonist on morphine withdrawal syndrome in mice. AB - Withdrawal from opioids leads to the expression of aversion behaviors. Previous studies have shown that the serotonergic system has an important role in morphine withdrawal syndrome. The 5-HT7 receptor is a recently discovered member of the 5 HT receptor family that has been shown to be involved in these behaviors. The aim of the present study was to test the role of the 5-HT7 receptor in withdrawal syndrome in morphine-dependent mice with AS19 and SB269970, a selective agonist and antagonist of this receptor, respectively. Dependence was induced by the repeated administration of morphine for five consecutive days. The morphine dependent mice received AS19 (3, 5, or 10mg/kg, intraperitoneal) or SB269970 (1, 3, or 10mg/kg, intraperitoneal) 15 min prior to the precipitation of morphine withdrawal syndromes by naloxone (3mg/kg, subcutaneous). Withdrawal symptoms, including percent weight loss, jumping, teeth chattering, writhing, body and face grooming, sniffing, standing, and head and limb shaking, were recorded for 30 min after the naloxone injection. The morphine-dependent mice had significantly more withdrawal symptoms than naive control mice. The administration of AS19 reduced most of the morphine withdrawal symptoms. However, SB2699 increased some of the withdrawal symptoms, including teeth chattering, face grooming, jumping, and head and limb shaking. These findings suggest that the 5-HT7 receptor is involved in morphine withdrawal. Its activation decreased and its inactivation increased the morphine withdrawal syndrome. Further studies are recommended to better understand the role of the 5-HT7 receptor in morphine dependence and withdrawal. PMID- 24954078 TI - A universal, rapid method for clean transfer of nanostructures onto various substrates. AB - Transfer and integration of nanostructures onto target substrates is the prerequisite for their fundamental studies and practical applications. Conventional transfer techniques that involve stamping, lift-off, and/or striping suffer from the process-specific drawbacks, such as the requirement for chemical etchant or high-temperature annealing and the introduction of surface discontinuities and/or contaminations that can greatly hinder the properties and functions of the transferred materials. Herein, we report a universal and rapid transfer method implementable at mild conditions. Nanostructures with various dimensionalities (i.e., nanoparticles, nanowires, and nanosheets) and surface properties (i.e., hydrophilic and hydrophobic) can be easily transferred to diverse substrates including hydrophilic, hydrophobic, and flexible surfaces with good fidelity. Importantly, our method ensures the rapid and clean transfer of two-dimensional materials and allows for the facile fabrication of vertical heterostructures with various compositions used for electronic devices. We believe that our method can facilitate the development of nanoelectronics by accelerating the clean transfer and integration of low-dimensional materials into multidimensional structures. PMID- 24954077 TI - Do stimulant medications improve educational and behavioral outcomes for children with ADHD? AB - We examine the effects of a policy change in the province of Quebec, Canada which greatly expanded insurance coverage for prescription medications. We show that the change was associated with a sharp increase in the use of stimulant medications commonly prescribed for ADHD in Quebec relative to the rest of Canada. We ask whether this increase in medication use was associated with improvements in emotional functioning or academic outcomes among children with ADHD. We find little evidence of improvement in either the medium or the long run. Our results are silent on the effects on optimal use of medication for ADHD, but suggest that expanding medication in a community setting had little positive benefit and may have had harmful effects given the average way these drugs are used in the community. PMID- 24954076 TI - Expression of androgen receptor in the brain of a sub-oscine bird with an elaborate courtship display. AB - Sex steroids control vertebrate behavior by modulating neural circuits specialized for sex steroid sensitivity. In birds, receptors for androgens (AR) and estrogens (ERalpha) show conserved expression in neural circuits controlling copulatory and vocal behaviors. Male golden-collared manakins have become a model for evaluating hormonal control of complex physical courtship displays. These birds perform visually and acoustically elaborate displays involving considerable neuromuscular coordination. Androgens activate manakin courtship and AR are expressed widely in spinal circuits and peripheral muscles utilized in courtship. Using in situ hybridization, we report here the distributions of AR and ERalpha mRNA in the brains of golden-collared manakins. Overall patterns of AR and ERalpha mRNA expression resemble what has been observed in non-vocal learning species. Notably, however, we detected a large area of AR expression in the arcopallium, a forebrain region that contains a crucial premotor song nucleus in vocal learning species. These results support the idea that AR signaling both centrally and peripherally is responsible for the activation of male manakin courtship, and the arcopallium is likely a premotor site for AR-mediated displays. PMID- 24954079 TI - Improvement of ischaemic macular oedema after intravitreal injection of autologous bone marrow-derived haematopoietic stem cells. PMID- 24954080 TI - New uses for rehabilitation protocol for oral sinus communications in ARONJ patients. AB - This report presents a new use for rehabilitation protocol for oral sinus communications in patients with antiresorptive agent-induced osteonecrosis of the jaw. The treatment plan consisted of constructing an atraumatic complete denture with rounded edges, made with nontoxic resin, to prevent any injury to the mucosa and recurrence of the disease. The patient was followed up for 4 years, without any complications, and was socially reintegrated by resuming the normal life he experienced before tooth loss. PMID- 24954081 TI - Paraneoplastic neuromyelitis optica spectrum disorder associated with stomach carcinoid tumor. AB - Neuromyelitis optica (NMO), or Devic's syndrome, is an autoimmune central nervous system demyelinating disorder primarily affecting the spinal cord and the optic nerves. It is characterized by the presence of NMO antibodies, alongside clinical and radiological findings. NMO and NMO-spectrum disorders (NMO-SD) have been reported in autoimmune disorders, and are infrequently described as a paraneoplastic syndrome with cancers of lung, breast, and carcinoid tumors of the thyroid. We report a patient who presented with severe vomiting, blurring of vision, vertigo, diplopia, left hemiparesis and hemisensory loss and ataxia. She was found to have a longitudinally-extensive demyelinating lesion extending from the medulla to the upper cervical spinal cord on MRI. Her gastric endoscopy revealed carcinoid tumor of the stomach, and classic paraneoplastic antibodies in the serum were negative. She had extremely high serum gastrin level and high titer of NMO IgG autoantibody. The patient made an excellent recovery with tumor resection and immunotherapy, with both clinical and radiological improvement. On rare instances, NMO or NMO-SD may present as a paraneoplastic neurological syndrome associated with carcinoid tumor of the stomach. PMID- 24954082 TI - Promoting meaning-making to help our patients grieve: an exemplar for genetic counselors and other health care professionals. AB - Genetic counselors and other health professionals frequently meet with patients who are grieving a loss. It is thus helpful for medical professionals to be familiar with approaches to bereavement counseling. Grief theory has evolved over the last few decades, from primarily stage theories of grief such as Kubler Ross's "five stages of grief" to frameworks that promote more complex and long term ways to cope with a loss. Herein I present one recent grief theory - meaning making - and describe how it can be applied to help parents of children with disabilities grieve the loss of the child that they expected. In particular, I describe a scenario that many genetic counselors face - meeting with the parents of a child with Down syndrome. I outline the research done on the reactions, grief and coping experienced by parents in this circumstance, and I present suggestions for encouraging healthy coping and adjustment for parents, based on the meaning-making perspective. The meaning-making theory can also be applied to many of the other losses faced by genetic counseling patients. PMID- 24954083 TI - Genetic counseling in direct-to-consumer exome sequencing: a case report. PMID- 24954084 TI - Testing for germline mutations in sporadic pheochromocytoma/paraganglioma: a systematic review. AB - BACKGROUND: The presence of germline mutations in sporadic pheochromocytomas and paragangliomas (SPPs) may change the clinical management of both index patients and their family members. However, the frequency of germline mutations in SPPs is unknown. OBJECTIVE: To describe the frequency of germline mutations in SPPs and to determine the value of testing index patients and their family members for these mutations. METHODS: We searched databases through June 2012 for observational studies of patients with SPPs who underwent germline genetic testing. The criteria used to define sporadic tumours were (i) the absence of a family history of PCC/PG, (ii) the absence of syndromic features, (iii) the absence of bilateral disease and (iv) the absence of metastatic disease. RESULTS: We included 31 studies including 5031 patients (mean age 44). These patients received tests for any of these ten mutations: SDHAF2, RET, SDHD, SDHB, SDHC, VHL, TMEM127, MAX, Isocitrate Dehydrogenase Mutation (IDH) and NF1. The overall frequency of germline mutation in SPP was 551 of 5031 or 11%; when studies with patients fulfilling four criteria for sporadic tumours were used, the frequency was 171 of 1332 or 13%. The most common germline mutation was SDHB 167 of 3611 (4.6%). Little outcome data were available to assess the benefits of genetic testing in index cases and family members. CONCLUSIONS: The frequency of germline mutations in SPPs is approximately 11-13% and the most common mutations affect less than 1 in 20 patients. The value of testing for germline mutations in patients with SPPs and their family members is unknown, as the balance of potential benefits and harms remains unclear. PMID- 24954087 TI - Pharyngeal mis-sequencing in dysphagia: characteristics, rehabilitative response, and etiological speculation. AB - OBJECTIVE: Clinical data are submitted as documentation of a pathophysiologic feature of dysphagia termed pharyngeal mis-sequencing and to encourage clinicians and researchers to adopt more critical approaches to diagnosis and treatment planning. BACKGROUND: Recent clinical experience has identified a cohort of patients who present with an atypical dysphagia not specifically described in the literature: mis-sequenced constriction of the pharynx when swallowing. As a result, they are unable to coordinate streamlined bolus transfer from the pharynx into the esophagus. This mis-sequencing contributes to nasal redirection, aspiration, and, for some, the inability to safely tolerate an oral diet. METHOD: Sixteen patients (8 females, 8 males), with a mean age of 44 years (range=25-78), had an average time post-onset of 23 months (range=2-72) at initiation of intensive rehabilitation. A 3-channel manometric catheter was used to measure pharyngeal pressure. RESULTS: The average peak-to-peak latency between nadir pressures at sensor-1 and sensor-2 was 15 ms (95% CI, -2 to 33 ms), compared to normative mean latency of 239 ms (95% CI, 215 to 263 ms). Rehabilitative responses are summarized, along with a single detailed case report. CONCLUSION: It is unclear from these data if pharyngeal mis-sequencing is (i) a pathological feature of impaired motor planning from brainstem damage or (ii) a maladaptive compensation developed in response to chronic dysphagia. Future investigation is needed to provide a full report of pharyngeal mis-sequencing, and the implications on our understanding of underlying neural control of swallowing. PMID- 24954086 TI - CLIPPERS among patients diagnosed with non-specific CNS neuroinflammatory diseases. AB - Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is an inflammatory CNS disorder characterized by 1) subacute onset of cerebellar and brainstem symptoms, 2) peripontine contrast enhancing perivascular lesions with a "salt-and-pepper" appearance on MRI, and 3) angiocentric, predominantly T-lymphocytic infiltration as revealed by brain biopsy. Inflammatory diseases including neuroinfections, CNS lymphoma and neurosarcoidosis must be excluded. Since CLIPPERS was described in 2010, many patients might have been misdiagnosed in the past. We therefore searched medical records from a large tertiary neurological center, the Department of Neurology at Rigshospitalet, Copenhagen University Hospital, for patients discharged between 1999 and 2013 with a diagnosis of "sarcoidosis with other localization", "other acute disseminating demyelination", "other demyelinating disease in the CNS" or "encephalitis, myelitis or encephalomyelitis". Of 206 identified patients, 24 had been examined by brain biopsy and were included for further evaluation. Following clinical, neuroradiological and neuropathological review, 3 patients (12.5%) were reclassified as having CLIPPERS. Median long-term follow-up was 75 months. The present results suggest that clinical re-evaluation of patients previously diagnosed with unspecified inflammatory demyelinating CNS disease or atypical neurosarcoidosis may increase the detection rate of CLIPPERS. Further, potentially severe neurological deficits and progressive parenchymal atrophy on MRI may suggest neurodegenerative features, which emphasizes the need for early immunomodulatory treatment. PMID- 24954088 TI - The King-Devick (K-D) test of rapid eye movements: a bedside correlate of disability and quality of life in MS. AB - OBJECTIVE: We investigated the King-Devick (K-D) test of rapid number naming as a visual performance measure in a cohort of patients with multiple sclerosis (MS). METHODS: In this cross-sectional study, 81 patients with MS and 20 disease-free controls from an ongoing study of visual outcomes underwent K-D testing. A test of rapid number naming, K-D requires saccadic eye movements as well as intact vision, attention and concentration. To perform the K-D test, participants are asked to read numbers aloud as quickly as possible from three test cards; the sum of the three test card times in seconds constitutes the summary score. High contrast visual acuity (VA), low-contrast letter acuity (1.25% and 2.5% levels), retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT), MS Functional Composite (MSFC) and vision-specific quality of life (QOL) measures (25-Item NEI Visual Functioning Questionnaire [NEI-VFQ-25] and 10-Item Neuro Ophthalmic Supplement) were also assessed. RESULTS: K-D time scores in the MS cohort (total time to read the three test cards) were significantly higher (worse) compared to those for disease-free controls (P=0.003, linear regression, accounting for age). Within the MS cohort, higher K-D scores were associated with worse scores for the NEI-VFQ-25 composite (P<0.001), 10-Item Neuro-Ophthalmic Supplement (P<0.001), binocular low-contrast acuity (2.5%, 1.25%, P<0.001, and high-contrast VA (P=0.003). Monocular low-contrast vision scores (P=0.001-0.009) and RNFL thickness (P=0.001) were also reduced in eyes of patients with worse K-D scores (GEE models accounting for age and within-patient, inter-eye correlations). Patients with a history of optic neuritis (ON) had increased (worse) K-D scores. Patients who classified their work disability status as disabled (receiving disability pension) did worse on K-D testing compared to those working full-time (P=0.001, accounting for age). CONCLUSIONS: The K-D test, a <2 minute bedside test of rapid number naming, is associated with visual dysfunction, neurologic impairment, and reduced vision-specific QOL in patients with MS. Scores reflect work disability as well as structural changes as measured by OCT imaging. History of ON and abnormal binocular acuities were associated with worse K-D scores, suggesting that abnormalities detected by K-D may go along with afferent dysfunction in MS patients. A brief test that requires saccadic eye movements, K-D should be considered for future MS trials as a rapid visual performance measure. PMID- 24954085 TI - Novel genetic variants modify the effect of smoking on carotid plaque burden in Hispanics. AB - BACKGROUND AND PURPOSE: Smoking greatly increases the risk of atherosclerotic plaque and the effect may vary from individual to individual. A genome-wide scan was performed for smoking*single nucleotide polymorphism (SNP) interactions on carotid plaque burden (CPB) to identify the potential genetic moderators in Hispanics. METHODS: Carotid B-mode ultrasonography and genotyping by the Affymetrix 6.0 chip were performed in a discovery sample of 665 Caribbean Hispanics, followed by replication analyses in 264 Caribbean Hispanics. CPB was expressed as the sum of plaque areas over the segments in common and internal carotid arteries and bifurcation. Smoking was classified as 0, <20, and >=20 cigarette pack-years. Assuming an additive genetic model, regression analysis was conducted to test for smoking*SNP interaction on the cube root transformed CPB while controlling for age, sex, and the top 3 principal components of ancestry. RESULTS: Two SNPs showed a significant interaction with smoking on CPB with the similar effects in both discovery (P<1.0E-5) and replication (P<0.05) populations. Specifically, for SNP rs10205487 within MXD1, more smoking was significantly associated with greater CPB in A allele carriers (beta+/-SE: 0.24+/ 0.08, P=0.005 in AG carriers; beta+/-SE: 0.48+/-0.12, P=0.0002 in AA carriers) but not in GG (P=0.06). For SNP rs7001413 within LY96 and JPH1, more smoking was significantly associated with greater CPB in GG carriers (beta+/-SE: 0.24+/-0.06, P=6.8E-5) but not in T carriers (P=0.06). CONCLUSIONS: Our study suggests that genetic variants may modulate the effect of smoking on CPB and highlights several genes for further investigation of their role in atherosclerosis, especially in smoking population. PMID- 24954089 TI - FK506-loaded chitosan conduit promotes the regeneration of injured sciatic nerves in the rat through the upregulation of brain-derived neurotrophic factor and TrkB. AB - FK506 has been shown to exert neurotrophic and neuroprotective effects, but its long-term application for nerve regeneration is limited. This study evaluated the potential application of a novel FK506-loaded chitosan conduit for peripheral nerve repair, and explored the underlying mechanism. A sciatic nerve injury model was created in male Wistar rats, which were then randomly divided into three treatment groups (n=40, each): chitosan-only, chitosan+FK506 injection, and FK506 loaded chitosan. We found significant recovery of normal morphology of sciatic nerves and higher density of myelinated nerve fibers in rats treated with FK506 loaded chitosan. Similarly, the total number of myelinated nerve fibers, myelin sheath thickness, and axon diameters were significantly higher in this group compared with the others, and the compound muscle action potentials and motor nerve conduction velocity values of sciatic nerves were significantly higher. BDNF and TrkB levels in motor neurons were highest in rats treated with FK506 loaded chitosan. In conclusion, FK506-loaded chitosan promoted peripheral nerve repair and regeneration in a rat model of sciatic nerve injury. These effects are correlated with increased BDNF and TrkB expression in motor neurons. PMID- 24954090 TI - Discovery, optimization, and pharmacophore modeling of oleanolic acid and analogues as breast cancer cell migration and invasion inhibitors through targeting Brk/Paxillin/Rac1 axis. AB - Bioassay-guided fractionation of Terminalia bentzoe L. leaves methanol extract identified the known triterpene oleanolic acid (1) as its major breast cancer cell migration inhibitor. Further chemical optimization afforded five new (9-12 and 15) and seven known (4-8, 13, and 14) semisynthetic analogues. All compounds were tested for their ability to inhibit human breast cancer MDA-MB-231 cells migration, proliferation, and invasion. The results revealed that 3-O-[N-(3' chlorobenzenesulfonyl)-carbamoyl]-oleanolic acid (11) and 3-O-[N-(5' fluorobenzenesulfonyl)-carbamoyl]-oleanolic acid (12) were the most active hits at low MUM concentration. Western blot analysis indicated the activity of 1, 11, and 12 might be related, at least in part, to the suppression of Brk/Paxillin/Rac1 signaling pathway. Pharmacophore modeling study was conducted to better understand the common structural binding epitopes important for the antimigratory activity. The sulfonyl carbamoyl moiety with an optimal bulkiness electron-deficient phenyl ring is associated with improved activity. This study is the first to discover the antimigratory and anti-invasive activities of oleanolic acid and analogues through targeting the Brk/Paxillin/Rac1 axis. PMID- 24954091 TI - Design, synthesis and luminescence properties of Ba2 YB2 O6 Cl- and Ba2 YB2 O6 F based phosphors. AB - Using a high-temperature solid-state reaction, the chlorine in Ba2 YB2 O6 Cl is gradually replaced by F, and a new compound with the nominal chemical formula Ba2 YB2 O6 F and two phosphors doped with Ce(3+) and Eu(3+) , respectively, are obtained. X-Ray diffraction and photoluminescence spectroscopy are used to characterize the as-synthesized samples. The as-synthesized Ba2 YB2 O6 Cl exhibits bright blue emission in the spectral range ~ 330-410 nm with a maximum around 363 nm under X-ray or UV excitation. Ba2 YB2 O6 F:0.01Ce(3+) exhibits blue emission in the range ~ 340-570 nm with a maximum around 383 nm. Ba2 YB2 O6 F:0.01Eu(3+) exhibits a predominantly (5) D0 -(7) F2 emission (~610 nm) and the relative intensities of the (5) D0 -(7) F0,1,2 emissions are tunable under different wavelength UV excitation. The luminescence behaviors of the two phosphors are explained simply in terms of the host composition and site occupancy probability of Ce(3+) and Eu(3+) , respectively. The results indicate that these phosphors have potential application as a blue phosphor or as a red phosphor. PMID- 24954092 TI - Nickel exposure when working out in the gym. PMID- 24954093 TI - Children's responses to social atypicality among group members - advantages of a contextualized social developmental account. AB - Abrams, Rutland, Palmer, Ferrell, and Pelletier (2014) showed that better second order mental state understanding facilitates 6-7-year-olds' ability to link a partially disloyal child's atypicality to inclusive or exclusive reactions by in group or outgroup members. This finding is interpreted in terms of predictions from the developmental subjective group dynamics model. We respond to thoughtful commentaries by Rhodes and Chalik, Patterson, and Rakoczy. Children face a significant developmental challenge in becoming able to recognize and interpret social atypicality in intergroup contexts. Researching that ability to contextualize judgements raises new questions about the nature of peer inclusion and exclusion, about children's social cognition, and about the way that social cognitive development and social experience combine. Rather than individual focused cognition taking priority over category-based cognition, we argue the two become more systematically integrated during development. We note that loyalty is but one example of typicality, and we also consider the role of more advanced perspective taking among older children, and the role of multiple classification skill among younger children, as well as potential implications for intervention to reduce peer victimization and prejudice. PMID- 24954095 TI - Genomic full-length sequence of two HLA-A*11 alleles, identified by cloning and sequencing. AB - Genomic full length sequences of HLA-A*11:01:01 and A*11:02:01 were identified by cloning and sequencing from two different Chinese donors. PMID- 24954096 TI - Evaluating time-reminder strategies before amber: common signal, green flashing and green countdown. AB - The safety level of signalized intersection depends greatly on drivers' decision making behaviors, which are significantly influenced by the time-reminder strategy before amber of the signal device. However, previous related studies are mainly based on the statistical results from the field data rather than explore the influence mechanism of the signal device on the signalized intersection's safety level. Therefore, this study aims to find out how these three typical signal devices with various time-reminder strategies, i.e., common signal device (CSD), green signal flashing device (GSFD), and green signal countdown device (GSCD), affect drivers' decision-making processes during the period from the end of the green phase to the onset of the red phase (i.e., G2R) and then evaluate their safety performance from the aspect of RLR violations. Firstly, an overall decision-making framework during G2R is presented to describe the driver-signal interaction and encloses four decision-making processes, which can be analyzed and modeled based on the field data collected from six signalized intersections in Changsha, China. Empirical analyses show that the time point of decision making before amber under GSCD is the earliest and that under CSD is the latest, which can also be modeled and reproduced by back propagation neural network (BPNN). After that, five binary logistic regression models are developed to determine the safety effect during other various processes and results show that red-light-running (RLR) violations are not only dependent on the range of dilemma zones (DZ) but also substantially on stop and go decisions of those vehicles in DZ, both of which are the potential cause and direct factors to RLR violations and found to be significantly affected by the time-reminder strategy of the green signal device. Finally, although GSCD stimulates the drivers in DZ to choose to cross the intersection during amber, which produces a higher RLR risk compared with CSD and GSFD, the intersection with GSCD is verified to own the lowest RLR violations due to its greatly positive effect in cutting down the range of DZ. PMID- 24954094 TI - Irradiation for locoregionally recurrent, never-irradiated oral cavity cancers. AB - BACKGROUND: The purpose of this study was to report the clinical outcomes and related prognostic factors of patients who underwent radiotherapy (RT) for the treatment of recurrent, never-irradiated oral cavity cancer (recurrent OCC). METHODS: The records of consecutive patients with nonmetastatic recurrent OCC who presented to and were treated with RT at our institution between 1989 and 2011 were reviewed. The Kaplan-Meier method was used to calculate overall survival (OS). The cumulative incidences of disease-specific death, local failure, regional failure, and distant metastasis were calculated with death as a competing risk. RESULTS: One hundred twenty-three patients were identified. Median follow-up for living patients was 54 months and 16 months for all patients. Ninety-one patients had salvage surgery followed by adjuvant RT. Definitive RT was utilized in the remaining 32 patients. The 5-year OS was 40%. The 5-year cumulative incidence of disease-specific death, local failure, regional failure, and distant metastasis was 55%, 34%, 22%, and 20%, respectively. Recurrent T classification and lack of salvage surgery were independently associated with worse disease-specific death and decreased OS, respectively. Subset analysis of patients who underwent salvage surgery demonstrated that age, recurrent T classification, and perineural invasion (PNI) were independently associated with decreased OS; recurrent T classification and thicker tumors were independently associated with worse disease-specific death; and positive/close margins and primary T classification were independently associated with increased local failure. CONCLUSION: In this group of patients with recurrent OCC, clinical outcomes were similar or improved when compared with other recurrent OCC-specific reports. In the salvage surgery subset, tumor thickness and PNI are recurrent pathologic features associated with outcomes that were only previously demonstrated in studies of primary disease. Because of the relatively worse outcomes in patients receiving definitive or adjuvant RT for recurrent OCC, we advocate for the appropriate use of postoperative RT in the initial management of oral cavity cancers. PMID- 24954097 TI - Applied neuroscience: functional enhancement, prevention, characterisation and methodology. (Hosting the Society of Applied Neuroscience). PMID- 24954099 TI - Proteomic analysis reveals protein expression differences in Escherichia coli strains associated with persistent versus transient mastitis. AB - Escherichia coli is a leading cause of bacterial mastitis in dairy cattle. Typically this infection is transient in nature, causing an infection that lasts 2-3days. However, in a minority of cases, E. coli has been shown to cause a persistent infection. The mechanisms that allow for a persistent E. coli infection are not fully understood. The goal of this work was to determine protein expression differences between E. coli strains isolated from dairy cattle with transient and persistent mastitis infections. Three persistent and three transient mastitis-derived strains of E. coli were compared using iTRAQ in a shotgun proteomics experiment. Expression data for 1127 proteins were determined. Of these, 28 proteins were associated with expression changes correlated with a difference in disease phenotype. Of particular interest were proteins that have been shown to be essential for bacterial swimming and swarming. Bacterial swimming and swarming assays showed that the strains from the persistent mastitis cases were significantly better in these motility assays than the strains from the transient cases. This work identifies important protein expression differences between E. coli strains that cause a persistent versus a transient infection as well as demonstrates a corresponding difference in the associated bacterial motility phenotypes. BIOLOGICAL SIGNIFICANCE: The significance of this study is that proteins associated with bacterial swimming and swarming are more highly expressed in the E. coli strains that cause persistent mastitis infections. These findings point to swimming and swarming as important mechanisms involved in how a pathogen establishes a persistent infection in the mammary gland. The role of swimming and swarming in clinical mastitis clearly requires further experimentation. PMID- 24954100 TI - Use of antidepressants and statins and short-term risk of new-onset diabetes among high risk adults. AB - AIMS: We evaluated the association of combined use of antidepressants and statins and the risk of new-onset diabetes among high-risk adults. METHODS: We used a retrospective, observational, longitudinal design among adults (age >= 22 years) who were diabetes free at baseline and had reported hypertension or hyperlipidemia or heart disease. We used data were from 2004 to 2009 Medical Expenditure Panel Survey and identified from self-reported diabetes or insulin use. We categorized antidepressants and statins use into four groups: antidepressants only, statins only, combined use of antidepressants and statins (antidepressants-statins), and neither antidepressant nor statins. We conducted chi-square and multivariable logistic regressions to examine the association between use of antidepressants-statins and new-onset diabetes after controlling for demographic and economic characteristics, health-status, access to care, presence of depression, and lifestyle risk factors. RESULTS: In our study sample, 9.3% used antidepressants only, 10.7% used statins only and 2.4% adults reported use of antidepressants-statins. Nearly 2% of the study sample reported new-onset diabetes. In unadjusted analyses, significantly higher proportion of adults using antidepressants-statins (3.2%) reported new-onset diabetes compared to those using neither antidepressants nor statins (1.1%). However, after controlling for all other variables in multivariable regression we did not observe a statistically significant association between use of antidepressants-statins and new-onset diabetes. CONCLUSIONS: Our study results do not suggest that use of antidepressants-statins may increase the risk of new-onset diabetes. Future research needs to examine this relationship with specific combinations of these drug classes and using longer follow up periods. PMID- 24954101 TI - Longitudinal changes in transtibial amputee gait characteristics when negotiating a change in surface height during continuous gait. AB - BACKGROUND: Negotiating a raised surface during continuous gait is an important activity of daily living and is a potentially hazardous task with regards to trips, falls and fall-related injury. However, it is not known how recent transtibial amputees adapt to performing stepping gait tasks in the 6-month period following discharge from rehabilitation. METHODS: Recent transtibial amputees performed continuous gait trials, stepping onto and from a raised surface walkway representing the height of a street kerb, whilst kinematic and kinetic data were recorded at one, three and six months post-discharge from rehabilitation. FINDINGS: Walking speed increased when stepping down (p=0.04) and was invariant across the study period when stepping up. At one month post discharge, participants displayed an affected lead limb preference (90.8%) when stepping down and an intact lead limb preference (70.0%) when stepping up, although these lead limb preferences diminished over time. Participants spent more time in stance on the intact limb compared to the affected limb in both stepping down (trail limb) (p=0.01) and stepping up (lead and trail limbs) (p=0.05). Participants displayed significantly greater joint mobility and power bursts in the intact trail limb when stepping down and in the intact lead limb when stepping up. INTERPRETATION: Transtibial amputees prefer to exploit intact limb function to a greater extent, although over time, the means by which this occurs changes which affects the initial lead limb preferences. The results from the current study enable future evidence-based therapeutic and prosthetic interventions to be designed that improve transtibial amputee stepping gait. PMID- 24954098 TI - Sex differences in the acute in vivo effects of different human SP-A variants on the mouse alveolar macrophage proteome. AB - Surfactant protein A (SP-A) is involved in lung innate immunity. Humans have two SP-A genes, SFTPA1 and SFTPA2, each with several variants. We examined the in vivo effects of treatment with specific SP-A variants on the alveolar macrophage (AM) proteome from SP-A knockout (KO) mice. KO mice received either SP-A1, SP-A2, or both. AM were collected and their proteomes examined with 2D-DIGE. We identified 90 proteins and categorized them as related to actin/cytoskeleton, oxidative stress, protease balance/chaperones, regulation of inflammation, and regulatory/developmental processes. SP-A1 and SP-A2 had different effects on the AM proteome and these effects differed between sexes. In males more changes occurred in the oxidative stress, protease/chaperones, and inflammation groups with SP-A2 treatment than with SP-A1. In females most SP-A1-induced changes were in the actin/cytoskeletal and oxidative stress groups. We conclude that after acute SP-A1 and SP-A2 treatment, sex-specific differences were observed in the AM proteomes from KO mice, and that these sex differences differ in response to SP A1 and SP-A2. Females are more responsive to SP-A1, whereas the gene-specific differences in males were minimal. These observations not only demonstrate the therapeutic potential of exogenous SP-A, but also illustrate sex- and gene specific differences in the response to it. BIOLOGICAL SIGNIFICANCE: This study shows that changes occur in the alveolar macrophage proteome in response to a single in vivo treatment with exogenous SP-A1 and/or SP-A2. We demonstrate that SP-A1 and SP-A2 have different effects on the AM proteome and that sex differences exist in the response to each SP-A1 and SP-A2 gene product. This study illustrates the potential of exogenous SP-A1 and SP-A2 treatment for the manipulation of macrophage function and indicates that the specific SP-A variant used for treatment may vary with sex and with the cellular functions being modified. The observed changes may contribute to sex differences in the incidence of some lung diseases. PMID- 24954102 TI - Diurnal variation of gait in patients with rheumatoid arthritis: The DIVIGN study. AB - BACKGROUND: Circadian variation of joint stiffness (morning stiffness) and its impact on functional ability are widely recognised in rheumatoid arthritis. Subsequent within-day variation of walking ability is important due to the increased availability of instrumented gait analysis. This study aimed to quantify diurnal variation of gait in patients with rheumatoid arthritis, and explore associations with disease characteristics. METHODS: Thirty one inpatients with rheumatoid arthritis walked at a self-selected speed along a GAITRite instrumented walkway 5 times during a single day. FINDINGS: Participants showed marked diurnal variation in gait, leading to a systematic variation throughout the day (F=19.56, P=<0.001). Gait velocity and stride length both increased, whereas the proportion of each gait cycle spent in stance phase or double support decreased, consistent with improving function throughout the day. Although absolute gait velocity correlated with disease characteristics, the magnitude of diurnal variation appeared to be independent of disease activity (rho=0.26, P=0.15), disease duration (rho=-0.19, P=0.324), and underlying functional ability (rho=0.09, P=0.65). INTERPRETATION: Although morning stiffness is well recognised in rheumatoid arthritis, this is the first time that its effect on gait has been quantified. Patients with rheumatoid arthritis exhibited a systematic change in walking ability throughout the day, which was independent of disease characteristics. These findings have important implications for the interpretation of existing data and the design of future studies. Repeat measures should be conducted at the same time of day to exclude the effects of diurnal variation. PMID- 24954104 TI - Production of fatty acid butyl esters using the low cost naturally immobilized Carica papaya lipase. AB - In this work, the low cost naturally immobilized Carica papaya lipase (CPL) was investigated for production of fatty acid butyl esters (FABE) to fulfill the aim of reducing the lipase cost in the enzymatic butyl-biodiesel process. The CPL showed specificities to different alcohol acyl acceptors. Alcohols with more than three carbon atoms did not have negative effects on the CPL activity. The CPL catalyzed butanolysis for FABE production was systematically investigated. The reaction solvent, alcohol/oil molar ratio, enzyme amount, reaction temperature, and water activity all affected the butanolysis process. Under the optimized conditions, the highest conversion of 96% could be attained in 24 h. These optimal conditions were further applied to CPL catalyzed butanolysis of other vegetable oils. All of them showed very high conversion. The CPL packed-bed reactor was further developed, and could be operated continuously for more than 150 h. All of these results showed that the low cost Carica papaya lipase can be used as a promising lipase for biodiesel production. PMID- 24954105 TI - A cross-sectional study examining computer task completion by adolescents with cerebral palsy across the Manual Ability Classification System levels. AB - AIM: The aim of this study was to analyze the cursor trajectories of adolescents with cerebral palsy (CP) when using a mouse for point-and-click computer tasks. By identifying some of the factors limiting cursor movement and gaining a better understanding of human movement, it will be possible to design more accessible computer interfaces. METHOD: This study evaluated cursor trajectories of 29 individuals with bilateral CP who had different levels of upper limb function as measured by the Manual Ability Classification System, and compared the results with those of 12 adolescents with typical development. RESULTS: Among adolescents with typical development, movement time increases linearly as the index of difficulty increases (Fitts' law); however, this linearity was not apparent in adolescents with bilateral CP. INTERPRETATION: Interfaces for members of the population are designed around Fitts' law, with low precision requirements at indices of difficulty lower than 4. We found that interactive displays for adolescents with CP should be limited to an index of difficulty of 2. PMID- 24954106 TI - Demographic characteristics and food choices of participants in the Special Diabetes Program for American Indians Diabetes Prevention Demonstration Project. AB - OBJECTIVE: American Indians and Alaska Natives (AI/ANs) suffer a disproportionate burden of diabetes. Identifying food choices of AI/ANs at risk of type 2 diabetes, living in both rural and urban settings, is critical to the development of culturally relevant, evidence-based education strategies designed to reduce morbidity and mortality in this population. DESIGN: At baseline, 3135 AI/AN adults participating in the Special Diabetes Program for American Indians Diabetes Prevention Demonstration Project (SDPI-DP) completed a socio-demographic survey and a 27-item food frequency questionnaire (FFQ). The primary dietary behavior goal of SDPI-DP education sessions and lifestyle coaching is changes in food choices, i.e., increased fruits, vegetables and whole grains, decreased high sugar beverages, red meat, and processed foods. Subsequently, program assessment focuses on changes in food types. Foods were delineated using a 'healthy' and 'unhealthy' classification as defined by the educators advising participants. Urban and rural differences were examined using chi(2) tests and two sample t tests. Multiple linear regressions and linear mixed models were used to assess the association between socio-demographic factors and food choice. RESULTS: Retired participants, those living in urban areas and with high income and education selected healthy foods most frequently. Young males, those with low income and education consumed unhealthy foods most frequently. Selection of unhealthy foods did not differ by urban and rural setting. CONCLUSIONS: The ubiquitous nature of unhealthy food choices makes them hard to avoid. Food choice differences by gender, age, income, and setting suggest that nutrition education should more effectively target and meets the needs of young AI/AN males. PMID- 24954107 TI - miR-145 inhibits invasion of bladder cancer cells by targeting PAK1. AB - OBJECTIVES: MicroRNAs play important roles in cancer. In many cancers, miR-145 acts as a tumor suppressor, and it is down-regulated in bladder cancer. In the present study, we explored the modulation of oncogenic gene PAK1 by miR-145 in bladder cancer. MATERIAL AND METHODS: Expression of miR-145 was detected in bladder cancer tissues and cell lines by quantitative real-time polymerase chain reaction. Through the bioinformatics approach, PAK1 has been predicted to be a direct target of miR-145 and was confirmed by the PAK1 messenger RNA 3' untranslated region luciferase activity assay. To investigate whether miR-145 regulates PAK1 expression, it was overexpressed in J82 and T24 bladder cancer cells. In 10 paired bladder normal and tumor tissues, we determined the relationship between miR-145 and PAK1 through quantitative real-time polymerase chain reaction and western blot. By using transwell invasion assay and western blotting analysis, we investigated the effects of miR-145 and PAK1 on bladder cancer cell invasion and expression of invasion marker genes. RESULTS: The level of miR-145 decreases and PAK1 protein expression up-regulates in bladder cancer tissue, as compared with the paired normal bladder tissue. Moreover, miR-145 directly targets PAK1 in bladder cancer cells. The level of miR-145 negatively correlates with PAK1 protein expression in bladder cancer. In addition, PAK1 promotes invasion and enhances the expression and activity of MMP-9, whereas miR 145 inhibits bladder cancer cell invasion and expressions of PAK1 and MMP-9. CONCLUSIONS: Our results indicate that miR-145 inhibits bladder cancer cell invasion, at least partly through targeting PAK1. Restoration or replacement of miR-145 could be an efficient approach to inhibit PAK1 and bladder cancer development in the tumor therapy. PMID- 24954108 TI - Presence of lymphovascular invasion in urothelial bladder cancer specimens after transurethral resections correlates with risk of upstaging and survival: a systematic review and meta-analysis. AB - OBJECTIVES: This study aimed to elucidate the relationship between lymphovascular invasion (LVI) at transurethral resection of bladder tumor (TURBT) and the risk of pathologic upstaging as well as the clinical outcomes. MATERIALS AND METHODS: PubMed, Scopus, Web of Science, and Cochrane Library databases were searched from the respective dates of inception until November 11, 2013. RESULTS: A total of 16 articles met the eligibility criteria for this systematic review, which included a total of 3,905 patients. LVI was detected in 18.6% of TURBT specimens. A significant association was found between LVI at TURBT and pathologic upstaging of bladder cancer (odds ratio = 2.21, 95% CI: 1.44-3.39) without heterogeneity (I(2) = 45%, P = 0.14). The pooled hazard ratio (HR) was statistically significant for recurrence-free survival (HR = 1.47, 95% CI: 1.24-1.74), progression-free survival (HR = 2.28, 95% CI: 1.45-3.58), and disease-specific survival (HR = 1.35, 95% CI: 1.01-1.81), but not for overall survival (HR = 1.55, 95% CI: 0.90-2.67). Tests of inconsistency for disease-specific survival (I(2) = 66%, P = 0.007) and overall survival (I(2) = 72%, P = 0.03) could not exclude a significant heterogeneity. The results of the Begg and the Egger tests showed that there was evidence of publication bias on pathologic upstaging and progression-free survival. CONCLUSIONS: The data obtained in this meta-analysis indicate that the presence of LVI at TURBT portends the increased risk of pathologic upstaging and may provide additional prognostic information. However, a large, well-designed, prospective study is needed to investigate potential treatment options for bladder cancer with LVI. PMID- 24954109 TI - Effect of post-solubilization conditions on the yield and efficiency of recombinant streptokinase purification at large-scale. AB - Streptokinase, a plasminogen activator which converts plasminogen to plasmin and consequently promotes fibrinolysis, is the leading drug for treating acute myocardial infarction in developing countries and its production is industrially demanded. In this work, the substantial influence of inclusion body (IB) post solubilization condition on the performance of a sequential chromatography method for large-scale purification of recombinant streptokinase was demonstrated. In the preliminary experiments, various post-solubilization pH conditions were studied, and it was shown that the pH value of solubilized inclusion bodies (i.e., in 4M urea) had a marked impact on the purity of streptokinase obtained at the end of post-solubilization process. When the pH value of the solution containing solubilized IBs was decreased from 7.5 to 6.5 and 6.0, the greatest increases (10% and 27%, respectively) in streptokinase purity occurred. The influence of different post-solubilization pH conditions on the efficiency and yield of large-scale chromatographic purification methods was next investigated. When the solubilized IBs solution with pH adjusted to 6.0 was utilized for subsequent sequential chromatography process, the complete elution peak with high overall yield (91.3%) and purity (98%) was achieved. In comparison to this, while the sequential chromatography procedure was instigated by using the solubilized IBs solution with pH 4.2, four elution fractions (EF1 to EF4) with disparate target protein purities (i.e., 57%, 77.3%, 91.4% and 86.7%, respectively) were attained, the process was incompletely effective, and the highest recovery and purity figures (81.8% and 91.4%, respectively, belonging to EF3) were much lower than those for the earlier process. PMID- 24954110 TI - Effects of aerobic training, resistance training, or combined resistance-aerobic training on the left ventricular myocardium in a rat model. AB - This study follows the left ventricular (LV) hypertrophy in rats undergoing aerobic training alone (A), resistance training alone (R), or combined resistance and aerobic training (RA) (usually referred as concurrent training) program. A sedentary control group (C) was included. LV remodeling was evaluated using electron and light microscopy. The LV weight to body weight (LVW: BW) increased 11.4% in A group, 35% in the R group, and 18% in the RA group compared to the C group. The LV thickness increased 6% in the A group, 17% in the R group, and 10% in the RA group. The LV internal diameter increased 19% in the A group, 3% in the R group, and 8% in the RA group compared with the C group. The cross-sectional area of cardiomyocyte increased by 1% with the A group, 27% with R group, and 12% with RA training. The capillary density increased by 5.4% with A training, 11.0% with R training, and 7.7% with RA training compared with the C group. The volume fraction of interstitial collagen increased by 0.4% with training A, increased by 2.8% with R training, and 0.9% with RA training. In conclusion, except for the LV internal diameter, which increased more in the A group, the cardiac parameters increased more in the R group than in the other groups and in RA group than in A group. Collagen density increased from 5.4 +/- 0.8% in the C group to 5.8 +/- 0.6% in the A group (n. s.) (P > 0.05), to 8.2 +/- 0.7% in the R group (P < 0.05), and to 6.3 +/- 0.4% in the RA group (P < 0.05). These results demonstrate a significant increase for collagen content in the LV with R and RA exercise, but the increase was higher with R training alone than with RA training. PMID- 24954111 TI - Chromosomes rein back the spindle pole body during horsetail movement in fission yeast meiosis. AB - In meiosis, pairing and recombination of homologous chromosomes are crucial for the correct segregation of chromosomes, and substantial movements of chromosomes are required to achieve homolog pairing. During this process, it is known that telomeres cluster to form a bouquet arrangement of chromosomes. The fission yeast Schizosaccharomyces pombe provides a striking example of bouquet formation, after which the entire nucleus oscillates between the cell poles (these oscillations are generally called horsetail nuclear movements) while the telomeres remain clustered to the spindle pole body (SPB; a centrosome-equivalent structure in fungi) at the leading edge of the moving nucleus. S. pombe mutants defective in telomere clustering frequently form aberrant spindles, such as monopolar or nonpolar spindles, leading to missegregation of the chromosomes at the subsequent meiotic divisions. Here we demonstrate that such defects in meiotic spindle formation caused by loss of meiotic telomere clustering are rescued when nuclear movement is prevented. On the other hand, stopping nuclear movement does not rescue defects in telomere clustering, nor chromosome missgregation even in cells that have formed a bipolar spindle. These results suggest that movement of the SPB without attachment of telomeres leads to the formation of aberrant spindles, but that recovering bipolar spindles is not sufficient for rescue of chromosome missegregation in mutants lacking telomere clustering. PMID- 24954112 TI - Equation of state and adsorption dynamics of soft microgel particles at an air water interface. AB - Understanding the adsorption dynamics of soft microgel particles is a key step in designing such particles for potential applications as stimuli-responsive Pickering stabilizers for foams or emulsions. In this study we experimentally determine an equation of state (EOS) for poly (N-isopropylacrylamide) (PNIPAM) microgel particles adsorbed onto an air-water interface using a Langmuir film balance. We detect a finite surface pressure at very low surface concentration of particles, for which standard theories based on hard disk models predict negligible pressures, implying that the particles must deform strongly upon adsorption to the interface. Furthermore, we study the evolution of the surface pressure due to the adsorption of PNIPAM particles as a function of time using pendant drop tensiometry. The equation of state determined in the equilibrium measurements allows us to extract the adsorbed amount as a function of time. We find a mixed-kinetic adsorption that is initially controlled by the diffusion of particles towards the interface. At later stages, a slow exponential relaxation indicates the presence of a coverage-dependent adsorption barrier related to crowding of particles at the interface. PMID- 24954113 TI - No increased systemic fibrinolysis in women with heavy menstrual bleeding. AB - BACKGROUND: Bleeding disorders have been recognized as important etiologic or contributory factors in women with heavy menstrual bleeding. Fibrinolysis in the endometrium plays a role in heavy menstrual bleeding. It is unknown whether increased systemic fibrinolysis might also increase the risk of heavy menstrual bleeding. OBJECTIVE: To investigate fibrinolytic parameters, including clot lysis time, in women with heavy menstrual bleeding. METHODS: We included 102 patients referred for heavy menstrual bleeding (Pictorial Bleeding Assessment Chart score of > 100) in our cohort. Patients and controls (28 healthy volunteers without heavy menstrual bleeding) underwent hemostatic testing in the first week after menstruation. For 79 patients and all controls, fibrinolytic parameters (thrombin activatable fibrinolysis inhibitor activity, and plasminogen activator inhibitor 1, tissue-type plasminogen activator and plasmin inhibitor levels) and clot lysis time were available. RESULTS: Fibrinolytic parameters were similar between patients and controls, except for thrombin-activatable fibrinolysis inhibitor (89.4% vs. 82.5%) and plasmin inhibitor (106% vs. 96%), the levels of which which were significantly higher in patients. In women with menorrhagia without gynecologic abnormalities, we found lower thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 levels than in women with gynecologic abnormalities (thrombin-activatable fibrinolysis inhibitor, 85.4% vs. 94.8%; plasminogen activator inhibitor-1, 16.0 MUg L(-1) vs. 24.5 MUg L(-1) ). CONCLUSION: Systemic fibrinolytic capacity is not increased in women with heavy menstrual bleeding. Overall, levels of the fibrinolytic inhibitors thrombin activatable fibrinolysis inhibitor and plasmin inhibitor were even higher in patients than in controls. However, in a subgroup of women without gynecologic abnormalities, relatively lower levels of inhibitors may contribute to the heavy menstrual bleeding. PMID- 24954114 TI - Infliximab vs adalimumab for Crohn's disease. PMID- 24954115 TI - Lessons learned in Andrology: keep your options open and do not hesitate to follow leads and change directions! PMID- 24954117 TI - Tools to study lipid functions. Preface. PMID- 24954116 TI - Treatment by testicular sperm extraction and intracytoplasmic sperm injection of 65 azoospermic patients with non-mosaic Klinefelter syndrome with birth of 17 healthy children. AB - The aim of this work was to present the clinical and embryological outcomes of 65 azoospermic patients with non-mosaic Klinefelter syndrome (KS), treated by testicular sperm extraction (TESE), followed by intracytoplasmic sperm injection (ICSI), either with fresh or cryopreserved testicular spermatozoa. In total, spermatozoa were recovered in 25/65 (38.5%) of the cases. Of the 48 patients who choose to perform TESE followed by ICSI using fresh testicular spermatozoa (treatment TESE), spermatozoa was recovered in 19 patients (40%), with birth of 12 newborn. Of the 17 patients who choose to perform TESE followed by testicular sperm cryopreservation, spermatozoa were recovered in six patients (35%), with birth of one child. Of the patients who performed treatment TESE, nine went for a new cycle using cryopreserved spermatozoa. Of these, five patients had a previous failed treatment cycle (two patients, three newborn) and four with a previous success went for a new cycle (one patient, one newborn). Overall, the embryological and clinical rates were as follows: 52% of fertilization, 41% of blastocyst, 27% of implantation, 39% of live birth delivery and 47% of newborn. Of the 16 clinical pregnancies, 14 had a successful delivery (12 girls and 5 boys). The 17 newborns had a mean gestation time of 37.2 weeks (35.3% pre-term) and a mean newborn weight of 2781.3 g (37.5% low weight). Comparisons between cycles with fresh and frozen-thaw spermatozoa revealed higher fertilization and clinical pregnancy rates with fresh spermatozoa, with no differences regarding implantation or newborn rates. Of the 17 newborns, no abnormal karyotypes (n = 3) or numerical abnormalities in chromosomes 13, 18, 21, X and Y (n = 14) as evaluated by Multiplex Ligation-dependent Probe Amplification were observed. In conclusion, this study presents further data that reassures that men with KS have no increased risk of transmitting their genetic problem to the offspring. PMID- 24954118 TI - Avanti lipid tools: connecting lipids, technology, and cell biology. AB - Lipid research is challenging owing to the complexity and diversity of the lipidome. Here we review a set of experimental tools developed for the seasoned lipid researcher, as well as, those who are new to the field of lipid research. Novel tools for probing protein-lipid interactions, applications for lipid binding antibodies, enhanced systems for the cellular delivery of lipids, improved visualization of lipid membranes using gold-labeled lipids, and advances in mass spectrometric analysis techniques will be discussed. Because lipid mediators are known to participate in a host of signal transduction and trafficking pathways within the cell, a comprehensive lipid toolbox that aids the science of lipidomics research is essential to better understand the molecular mechanisms of interactions between cellular components. This article is part of a Special Issue entitled Tools to study lipid functions. PMID- 24954119 TI - Impact of anticholinergic load of medications on the length of stay of cancer patients in hospice care. AB - OBJECTIVES: An important goal of hospice care is to relieve pain and suffering of terminal cancer patients. Anticholinergic medications are effective in the symptom palliation among terminal cancer patients. However, use of these medications has been associated with increased risk of side effects, which might lead to premature mortality. Short lengths of stay in hospice care leave patients with a higher level of unmet needs. The study was conducted to examine the effect of increasing anticholinergic load on the length of stay of cancer patients in hospice care in the USA. METHODS: The National Home and Hospice Care Survey 2007 was used as the data source. The Cox proportional hazards model was used to investigate the risk of death among users of moderate and high anticholinergic load compared with users of low anticholinergic load in presence of other prognostic factors. KEY FINDINGS: Cancer patients on a moderate anticholinergic load had a 12.7% lower hazard of death (P = 0.0244), while those on a high anticholinergic load had a 15.6% lower hazard of death (P = 0.0071) as compared with those patients on a low anticholinergic load. Among other prognostic factors, non-elderly age group, male gender, white race, metropolitan hospice agency, non-profit hospice agency, severe activities of daily living dependency and cognitive impairment were significantly associated with a higher probability of death. CONCLUSIONS: These results provide no evidence for increasing anticholinergic load increasing mortality in cancer patients using hospice care. Thus, high anticholinergic load might have conferred a protective effect on the patients because of better symptom control. PMID- 24954120 TI - Comparative maxillary bone-defect healing by calcium-sulphate or deproteinized bovine bone particles and extra cellular matrix membranes in a guided bone regeneration setting: an experimental study in rabbits. AB - OBJECTIVES: The aim of this study was to histologically compare the dynamics of bone healing response between calcium sulphate (CaS) and deproteinized bovine bone mineral (DBBM) particles in guided bone regeneration utilizing an extracellular matrix membrane (ECM) as barrier. MATERIALS AND METHODS: Eighteen rabbits were used in thisstudy. 5 * 5 mm defects were created in the edentulous space between the incisors and molars in the maxilla. The CaS and DBBM particles were placed in the defects, with or without the placement of a membrane by means of random selection. Healing was evaluated at 2, 4 and 8 weeks by histology. RESULTS: A total resorption of the CaS material was seen already at 2 weeks. Only minor resorption could be seen of the DBBM particles. The CaS group showed significantly more bone regeneration at all three healing periods compared to the DBBM group. The addition of an ECM membrane demonstrated significant additional effect on bone regeneration. The CaS group showed significant increased amounts of blood vessels compared to the DBBM group. CONCLUSIONS: Thisstudy showed that CaS in combination with an ECM membrane provided synergistic effects on bone regeneration, seemingly due to stimulating angiogenesis in the early healing process. PMID- 24954122 TI - [Fourth annual series of workshops of the SFGM-TC to harmonize practices in allogeneic stem cell transplantation]. PMID- 24954121 TI - [Allogeneic stem cell transplantation from an HLA-haploidentical related donor: SFGM-TC recommendations (part 2)]. AB - Haploidentical allogeneic stem cell transplantation (CST) has globally taken off in the past decade. It appears to be a valid alternative to other sources of stem cells; however, further research is necessary to validate the use of this approach in standard patient care. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. This is part two of the recommendations regarding allogeneic stem cell transplantation from an HLA haploidentical related donor. PMID- 24954123 TI - Fast multipoint immobilized MOF bioreactor. AB - An enzyme-NBD@MOF bioreactor with exemplary proteolytic performance, even after successive reuse and storage, was produced through a novel, rapid and simple multipoint immobilization technique without chemical modification of the solid support. Enzyme loading and distribution could be directly monitored from the fluorescence emission of the bioreactor. The dye molecular dimension plays a role in its overall performance. PMID- 24954125 TI - [MP Veran's report on hospital interim work: an incomplete and biased assessment (or how to miscount people and deny their professionalism)]. PMID- 24954124 TI - [Intravenous lipid emulsion and local anesthetic-induced systemic toxicity: mechanisms and limits]. AB - OBJECTIVES: Intravenous lipid emulsions (ILE) are recommended today in cases of local anesthetic-induced systemic toxicity (LAST). The objectives of this review consists in describing mechanisms involved in the interaction between ILE and local anesthetic (LA) factors influencing this interaction and the limits associated with the use of ILE. DATA SOURCES: References were obtained from Pubmed data bank (http://www.ncbi.nlm.nih.gov/pubmed) using the following keywords: Intralipid((r)), local anesthetic, toxicity, intravenous lipid emulsion. DATA SYNTHESIS: Effects of the association between ILE-LA are based on droplet formations as well as changes in cell metabolism involving survival cell pathway, on functional properties and on direct hemodynamic parameters. Hypoxia, acidosis and high doses of epinephrine modified the effects of ILE-LA association. CONCLUSION: Prescription of ILE is recommended by published guidelines on LAST resuscitation. ILE cannot substitute to the standard resuscitation protocol. It should be added to that protocol. Experimental studies as well as a case report registry will allow understanding further the effects induced by the ILE-LA association. PMID- 24954126 TI - [Cerebral oedema: new therapeutic ways]. AB - Cerebral oedema (CO) after brain injury can occur from different ways. The vasogenic and cytotoxic oedema are usually described but osmotic and hydrostatic CO, respectively secondary to plasmatic hypotonia or increase in blood pressure, can also be encountered. Addition of these several mechanisms can worsen injuries. Consequences are major, leading quickly to death secondary to intracerebral hypertension and later to neuropsychic sequelae. So therapeutic care to control this phenomenon is essential and osmotherapy is actually the only way. A better understanding of physiopathological disorders, particularly energetic ways (lactate), aquaporine function, inflammation lead to new therapeutic hopes. The promising experimental results need now to be confirmed by clinical data. PMID- 24954127 TI - [Communication between general practitioners and intensivists: evaluation study of an improvement strategy]. PMID- 24954128 TI - Adsorption structures of non-aromatic hydrocarbons on silicalite-1 using the single-crystal X-ray diffraction method. AB - The actual adsorption structures of non-aromatic hydrocarbons on the MFI-type zeolites have not yet been determined. This is due to the presence of twinning, which makes crystallographic analysis difficult. We recently overcame this problem, and now report the various adsorption structures of n-butane, n-pentane, n-hexane, 1-butene, cis and trans-2-butene, 2-butyne and isopentane on silicalite 1 (MFI-type zeolite) as determined via single-crystal X-ray diffraction. The structures were elucidated for both low and high loadings of each guest molecule in order to clarify the adsorption process. The low-loaded structures provide valuable insight into guest-framework interactions and initial adsorption behavior. The n-alkanes are initially adsorbed in the sinusoidal channel, while 2 butyne is adsorbed in the straight channel. In the case of the normal hydrocarbons, the molecular configuration (bent or linear) of the compound determines which channel is the preferred adsorption site. Bent molecules prefer the sinusoidal channel and linear molecules prefer the straight channel. In contrast, isopentane is initially adsorbed at the intersection, since the channels are too narrow to maintain the preferred distance between the framework and the bulky isopentane molecule. In the high-loaded structures, the guest molecules occupy additional sites, such that the normal hydrocarbons are located in both channels and isopentane is found at the intersection and the sinusoidal channel. PMID- 24954129 TI - Demographic transitions and migration in prehistoric East/Southeast Asia through the lens of nonmetric dental traits. AB - The aim of this study is to examine and assess the nonmetric dental trait evidence for the population history of East and Southeast Asia and, more specifically, to test the two-layer hypothesis for the peopling of Southeast Asia. Using a battery of 21 nonmetric dental traits we examine 7,247 individuals representing 58 samples drawn from East and Southeast Asian populations inhabiting the region from the late Pleistocene, through the Neolithic, Bronze Age, Iron Age, and into the historic and modern periods. The chief data reduction technique is a neighbor-joining tree generated from the triangular matrix of mean measure of divergence values. Principal findings indicated a major dichotomization of the dataset into (1) an early Southeast Asian sample with close affinities to modern Australian and Melanesian populations and (2) a very distinct grouping of ancient and modern Northeast Asians. Distinct patterns of clinal variation among Neolithic and post-Neolithic Mainland Southeast Asian samples suggest a center to periphery spread of genes into the region from Northeast Asia. This pattern is consistent with archaeological and linguistic evidence for demic diffusion that accompanied agriculturally driven population expansion in the Neolithic. Later Metal Age affinities between Island and Mainland coastal populations with Northeast Asian series is likely a consequence of a South China Sea interaction sphere operating from at least 500 BCE, if not from the Neolithic. Such results provide extensive support for the two-layer hypothesis to account for the population history of the region. PMID- 24954130 TI - Mimicking filtration and transport of rotavirus and adenovirus in sand media using DNA-labeled, protein-coated silica nanoparticles. AB - Rotavirus (RoV) and adenovirus (AdV) are important viral pathogens for the risk analysis of drinking water. Despite this, little is known about their retention and transport behaviors in porous media due to a lack of representative surrogates. We developed RoV and AdV surrogates by covalently coupling 70-nm sized silica nanoparticles with specific proteins and a DNA marker for sensitive detection. Filtration experiments using beach sand columns demonstrated the similarity of the surrogates' concentrations, filtration efficiencies and attachment kinetics to those of the target viruses. The surrogates showed the same magnitude of concentration reduction as the viruses. Conversely, MS2 phage (a traditional virus model) over-predicted concentrations of AdV and RoV by 1- and 2-orders of magnitude respectively. The surrogates remained stable in size, surface charge and DNA concentration for at least one year. They can be easily and rapidly detected down to a single particle. Preliminary tests suggest that they were readily detectable in a number of environmental waters and treated effluent. With up-scaling validation in pilot trials, the surrogates developed here could be a cost-effective new tool for studying virus retention and transport in porous media. Examples include assessing filter efficacy in water and wastewater treatment, tracking virus migration in groundwater after effluent land disposal, and establishing safe setback distances for groundwater protection. PMID- 24954131 TI - Two new flavonols from Cudrania cochinchinensis. AB - Two new flavonols, 6-p-hydroxybenzyl kaempferol (1) and 6-p-hydroxybenzyl quercetin (2), together with six known compounds were isolated from the roots of Cudrania cochinchinensis and their structures elucidated on the basis of spectroscopic methods. Their antioxidant capacities were evaluated by 1,1 diphenyl-2-picryl-hydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical-scavenging assays. The results suggested that compounds 2, 4, and 7 showed significant radical-scavenging activities. PMID- 24954132 TI - Remodeling of channel-forming ORAI proteins determines an oncogenic switch in prostate cancer. AB - ORAI family channels have emerged as important players in malignant transformation, yet the way in which they reprogram cancer cells remains elusive. Here we show that the relative expression levels of ORAI proteins in prostate cancer are different from that in noncancerous tissue. By mimicking ORAI protein remodeling observed in primary tumors, we demonstrate in in vitro models that enhanced ORAI3 expression favors heteromerization with ORAI1 to form a novel channel. These channels support store-independent Ca(2+) entry, thereby promoting cell proliferation and a smaller number of functional homomeric ORAI1-based store operated channels, which are important in supporting susceptibility to apoptosis. Thus, our findings highlight disrupted dynamic equilibrium of channel-forming proteins as an oncogenic mechanism. PMID- 24954135 TI - Determining the thickness of atomically thin MoS2 and WS2 in the TEM. AB - Multislice simulations were used to analyze the reliability of annular dark field scanning transmission electron microscopy (ADF-STEM) imaging and selected-area electron diffraction (SAED) for determining the thicknesses of MoS2 and WS2 specimens in the aberration-corrected TEM. Samples of 1 to 4 layers in thickness for both 2H and 1T polymorphs were studied and tilts up to 500mrad off of the [0001] zone axis were considered. All thicknesses including the monolayer showed distortions and intensity variations in their ADF-STEM images and SAED patterns as a result of tilt. Both techniques proved to be applicable to distinguish monolayers from multilayers using tilt. Without tilt, neither technique allows unambiguous thickness determination solely by comparing relative intensities of atomic columns in ADF-STEM images or diffraction patterns oriented along at [0001] zone axis, with the exception of monolayer 2H WS2. However, differentiation is possible using absolute intensities in ADF-STEM images. The analysis of ADF-STEM images and SAED patterns also allows identification of the 2H and 1T polymorphs of MoS2 and WS2. PMID- 24954134 TI - Effectiveness of green tea mouthwash in comparison to chlorhexidine mouthwash in patients with acute pericoronitis: a randomized clinical trial. AB - The objective of this study was to evaluate the effectiveness of green tea mouthwash in controlling the pain and trismus associated with acute pericoronitis in comparison to chlorhexidine (CHX) mouthwash. Ninety-seven patients with acute pericoronitis underwent debridement and received 5% green tea mouthwash (study group) or 0.12% CHX mouth rinse (control group). Pain (visual analogue scale; VAS), number of analgesics, maximum mouth opening (MMO), and number of patients with trismus were determined. There were no significant differences in demographic variables (P>0.05), or baseline VAS (P>0.006), MMO (P>0.017) or number of patients with trismus (P>0.017) between the two groups. The mean VAS score of the study group was statistically lower than that of the control group between post-treatment days 3 and 5 (P<0.006). A significantly lower number of analgesics were taken by the study group (P<0.05). Although the MMO of the study group was significantly lower on day 3 (P<0.017), no significant difference was observed on day 7 (P>0.017). Fewer of the patients rinsing with green tea had trismus on days 3 and 7, but the difference was non-significant (P>0.017). Hence, green tea mouth rinse could be an appropriate and effective choice for the control of pain and trismus in acute pericoronitis. PMID- 24954136 TI - The experimental electron mean-free-path in Si under typical (S)TEM conditions. AB - The electron mean-free-path in Si was measured by EELS using the test structure with the certified dimensions as a calibration standard. In a good agreement with the previous CBED measurements, the mean-free-path is 150nm for 200keV and 179nm for 300keV energy of primary electrons at large collection angles. These values are accurately predicted by the model of Iakoubovskii et al. while the model of Malis et al. incorporated in common microscopy software underestimates the mean free-path by 15% at least. Correspondingly, the thickness of TEM samples reported in many studies of the Si-based materials last decades might be noticeably underestimated. PMID- 24954133 TI - Quiescent sox2(+) cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma. AB - Functional heterogeneity within tumors presents a significant therapeutic challenge. Here we show that quiescent, therapy-resistant Sox2(+) cells propagate sonic hedgehog subgroup medulloblastoma by a mechanism that mirrors a neurogenic program. Rare Sox2(+) cells produce rapidly cycling doublecortin(+) progenitors that, together with their postmitotic progeny expressing NeuN, comprise tumor bulk. Sox2(+) cells are enriched following anti-mitotic chemotherapy and Smoothened inhibition, creating a reservoir for tumor regrowth. Lineage traces from Sox2(+) cells increase following treatment, suggesting that this population is responsible for relapse. Targeting Sox2(+) cells with the antineoplastic mithramycin abrogated tumor growth. Addressing functional heterogeneity and eliminating Sox2(+) cells presents a promising therapeutic paradigm for treatment of sonic hedgehog subgroup medulloblastoma. PMID- 24954137 TI - Controllability and observability analysis for vertex domination centrality in directed networks. AB - Topological centrality is a significant measure for characterising the relative importance of a node in a complex network. For directed networks that model dynamic processes, however, it is of more practical importance to quantify a vertex's ability to dominate (control or observe) the state of other vertices. In this paper, based on the determination of controllable and observable subspaces under the global minimum-cost condition, we introduce a novel direction-specific index, domination centrality, to assess the intervention capabilities of vertices in a directed network. Statistical studies demonstrate that the domination centrality is, to a great extent, encoded by the underlying network's degree distribution and that most network positions through which one can intervene in a system are vertices with high domination centrality rather than network hubs. To analyse the interaction and functional dependence between vertices when they are used to dominate a network, we define the domination similarity and detect significant functional modules in glossary and metabolic networks through clustering analysis. The experimental results provide strong evidence that our indices are effective and practical in accurately depicting the structure of directed networks. PMID- 24954138 TI - Effect of magnetic field and iron content on NMR proton relaxation of liver, spleen and brain tissues. AB - Iron accumulation is observed in liver and spleen during hemochromatosis and important neurodegenerative diseases involve iron overload in brain. Storage of iron is ensured by ferritin, which contains a magnetic core. It causes a darkening on T2 -weighted MR images. This work aims at improving the understanding of the NMR relaxation of iron-loaded human tissues, which is necessary to develop protocols of iron content measurements by MRI. Relaxation times measurements on brain, liver and spleen samples were realized at different magnetic fields. Iron content was determined by atomic emission spectroscopy. For all samples, the longitudinal relaxation rate (1/T1 ) of tissue protons decreases with the magnetic field up to 1 T, independently of iron content, while their transverse relaxation rate (1/T2 ) strongly increases with the field, either linearly or quadratically, or a combination thereof. The extent of the inter-echo time dependence of 1/T2 also varies according to the sample. A combination of theoretical models is necessary to describe the relaxation of iron-containing tissues. This can be due to the presence, inside tissues, of ferritin clusters of different sizes and densities. When considering all samples, a correlation (r(2) = 0.6) between 1/T1 and iron concentration is observed at 7.0 T. In contrast the correlation between 1/T2 and iron content is poor, even at high field (r(2) = 0.14 at 7.0 T). Our results show that MRI methods based on T1 or T2 measurements will easily detect an iron overloading at high magnetic field, but will not provide an accurate quantification of tissue iron content at low iron concentrations. PMID- 24954139 TI - Pattern of TGFbeta receptor 1 expression differs between kras-mutated keratoacanthomas and squamous cell carcinomas of the skin. AB - PURPOSE: Increasing evidence indicates that TGFbeta- and EGFR-signaling is involved in the pathogenesis of keratoacanthoma (KA) and squamous cell carcinoma (SCC) of the skin. We analyzed the expression pattern of TGFbeta-signaling components and screened for mutations in tgfbetaR1, egfr, kras and braf in KAs and SCCs. METHODS: Immunohistochemical analysis of TGFbeta1, TGFbetaR1, TGFbetaR2 and phospho-SMAD2/3 was performed on skin tumors (29 KAs, 30 well and 31 moderately differentiated SCCs). Mutation screening in hotspot regions of tgfbetaR1, egfr, kras and braf was performed through pyrosequencing of tumor DNA. FINDINGS: Expression of TGFbeta1, TGFbetaR1 and p-SMAD2/3 was increased in tumors as compared to surrounding skin. In KAs characteristic strong discontinuous membranous TGFbetaR1 expression pattern frequently associated with kras mutation was noted. SCCs showed continuous TGFbetaR1 expression, stronger p-SMAD2/3 expression and less frequent kras mutations. In tumors at sun-exposed sites stronger TGFbetaR1 expression was noted. One SCC showed tgfbetaR1 mutation, but no other mutations were found. CONCLUSION: Although tgfbetaR1 germline mutations cause inherited KAs and our finding of strong discontinuous membranous expression in KAs suggests accumulation of functionally altered protein, we found no tgfbetaR1 mutations or influence on TGFbeta-signaling, but frequent kras mutations in this subgroup of KAs. Characteristic TGFbetaR1 expression pattern in KA can facilitate histopathologic distinction from SCC. PMID- 24954141 TI - Studying dynamic events in the developing myocardium. AB - Differentiation and conduction properties of the cardiomyocytes are critically dependent on physical conditioning both in vitro and in vivo. Historically, various techniques were introduced to study dynamic events such as electrical currents and changes in ionic concentrations in live cells, multicellular preparations, or entire hearts. Here we review this technological progress demonstrating how each improvement in spatial or temporal resolution provided answers to old and provoked new questions. We further demonstrate how high-speed optical mapping of voltage and calcium can uncover pacemaking potential within the outflow tract myocardium, providing a developmental explanation of ectopic beats originating from this region in the clinical settings. PMID- 24954140 TI - [Occipital-cervical instability in Morquio disease: a presentation of 2 cases and a review of the literature]. AB - INTRODUCTION: Morquio syndrome is caused by an inherited autosomal recessive enzyme deficiency. It presents with numerous musculoskeletal anomalies, among which atlantoaxial instability is highlighted, due it being life-threatening. Occipital-cervical arthrodesis surgery (and decompression) is indicated in these cases. OBJECTIVE: The cases of 2 patients with Morquio syndrome that required this type of surgery are presented, along with a review of the literature. PATIENTS AND METHODS: Two patients: one boy and one girl, with Morquio syndrome and high cervical instability, with neurological signs and symptoms, who were subjected to surgery using decompression and instrumented occipital-cervical arthrodesis and followed up for 6 months and one year, respectively. RESULTS: The neurological problems of both patients improved, and are currently having a normal life for their age. CONCLUSION: Occipital-cervical arthrodesis with decompression provides a safe biomechanical environment that prevents neurological involvement. It should be indicated before the appearance of symptoms or mechanical instability. PMID- 24954142 TI - [Plant hormones, plant growth regulators]. AB - Plants seem to be rather defenceless, they are unable to do motion, have no nervous system or immune system unlike animals. Besides this, plants do have hormones, though these substances are produced not in glands. In view of their complexity they lagged behind animals, however, plant organisms show large scale integration in their structure and function. In higher plants, such as in animals, the intercellular communication is fulfilled through chemical messengers. These specific compounds in plants are called phytohormones, or in a wide sense, bioregulators. Even a small quantity of these endogenous organic compounds are able to regulate the operation, growth and development of higher plants, and keep the connection between cells, tissues and synergy between organs. Since they do not have nervous and immume systems, phytohormones play essential role in plants' life. PMID- 24954143 TI - [The diagnosis of hepatitis C virus infection]. AB - The successful therapy of hepatitis C viral infection requires that the illness is diagnosed before the development of structural changes of the liver. Testing is stepwise consisting of screening, diagnosis, and anti-viral therapy follow-up. For these steps there are different biochemical, serological, histological and molecular biological methods available. For screening, alanine aminotransferase and anti-HCV tests are used. The diagnosis of infection is confirmed using real time polymerase chain reaction of the viral nucleic acid. Before initiation of the therapy liver biopsy is recommended to determine the level of structural changes in the liver. Alternatively, transient elastography or blood biomarkers may be also used for this purpose. Differential diagnosis should exclude the co existence of other viral infections and chronic hepatitis due to other origin, with special attention to the presence of autoantibodies. The outcome of the antiviral therapy and the length of treatment are mainly determined by the viral genotype. In Hungary, most patients are infected with genotype 1, subtype b. The polymorphism type that occurs in the single nucleotide located next to the interleukin 28B region in chromosome 19 and the viral polymorphism type Q80K for infection with HCV 1a serve as predictive therapeutic markers. The follow-up of therapy is based on the quantitative determination of viral nucleic acid according to national and international protocols and should use the same method and laboratory throughout the treatment of an individual patient. PMID- 24954145 TI - [Anti-NXP2-positive dermatomyositis associated with ulcerative colitis and celiac disease]. AB - The authors discuss a rare case of a 25-year-old female patient having dermatomyositis associated with celiac disease and ulcerative colitis. The idiopathic inflammatory myopathies are systemic, chronic, immune-mediated diseases characterized by proximal, symmetrical muscle weakness. Many examples from the literature refer that celiac disease occurs more often in patients with myositis than in the general population, but its association with ulcerative colitis is a real rarity in the international literature. PMID- 24954146 TI - [The history of the chapel of the (New) St. John's Hospital in Budapest]. PMID- 24954144 TI - [Psychosocial status of Hungarian cancer patients. A descriptive study]. AB - INTRODUCTION: Psychosocial status of cancer patients is still understudied in Hungary. AIM: The aim of the authors was to obtain current information on the mental and social status of this patient group. METHOD: Altogether, 1070 cancer patients with a wide range of cancer types were included in the study (30.0% male; age: 55.9 +/- 11.0 years). RESULTS: A large part of the patients had serious financial difficulties and 41.3% of them were struggling with at least one more comorbid chronic disease. Further, 52.2% of the patients reported at least moderate anxiety or depression, while the occurrence of suicidal thoughts was almost three times higher among them than in the Hungarian normal population (13.0% vs. 4.6%). Level of perceived social support was also lower than the population standards and 61.6% of the patients reported willingness to benefit from professional psychological support. Quality of social life of the patients deteriorated with time after cancer diagnosis. A positive phenomenon, however, was that the primary coping style reported was active problem solving. CONCLUSIONS: The authors conclude that it is necessary to screen cancer patients for psychosocial difficulties and to establish conditions for their adequate mental and social care in Hungary. PMID- 24954148 TI - Quantifying stair gait stability in young and older adults, with modifications to insole hardness. AB - Stair gait falls are prevalent in older adults aged 65 years and older. Extrinsic variables such as changes to insole hardness are important factors that can compromise the balance control system and increase the incidence of falls, especially since age-related decline in the cutaneous sensation is common. Balance measurements such as the minimum center of mass/base of support (COM-BOS, termed 'stability margin') and COM-BOS medial/lateral range provide information about stability during stair gait. This study was conducted to investigate stair gait stability of young and older adults, with modifications to insole hardness. Twenty healthy adults (10 young adults, 10 older adults) were recruited (mean age = 23.1, SD 2.1; mean age = 73.2, SD 5.5) and instructed to descend a 4 step staircase, for a total of 40 trials. All participants wore similar canvas shoes of varying sizes, and corresponding insole hardnesses (barefoot, soft, medium, hard). Kinematic equipment utilized 12 infrared markers anteriorly placed on the individual to record COM motion and BOS location. The findings from the study demonstrated that older adults were less stable during stair descent. Consequently, insole conditions revealed that the barefoot condition may increase the likelihood of falls, as opposed to the other insole hardnesses (soft, medium and hard). These results suggest that older adults while barefoot are putting themselves at a great risk of falling during stair descent. Since age-related changes are inevitable and the preferred footwear of choice inside the home is bare feet, this is a crucial issue that should be addressed. PMID- 24954149 TI - Characteristics of non-motor symptoms in patients with Parkinson's disease exhibiting camptocormia. AB - OBJECTIVE: This study aims to investigate the differences in the prevalence and severity of NMS between patients with Parkinson's disease (PD) who manifest camptocormia and those who do not manifest camptocormia. METHODS: A total of 50 PD patients with camptocormia and 50 gender and disease duration 1:1 matched patients with PD but without camptocormia were included in this case-control study. The severity of motor symptoms was assessed with the Unified PD Rating Scale (UPDRS) part III and Hoehn and Yahr (H&Y) staging. The prevalence and severity of NMS were assessed with non-motor symptom scale (NMSS). RESULTS: Patients with PD exhibiting camptocormia showed significantly higher scores in UPDRS part III and H&Y staging than those who do not exhibit camptocormia (P < 0.05). The frequency of the cardiovascular domain with the item of "light headedness/dizziness", the gastrointestinal domain with the item of "dribbling saliva", and the miscellaneous domain with the items of "taste or smell change", "weight change", and "excessive sweating" was significantly higher in PD patients with camptocormia compared with those without camptocormia (P < 0.05). The mean scores of sleep/fatigue and perceptual problems/hallucinations domains, the mood/apathy domain with the item of "feelings of nervousness" in PD patients with camptocormia were higher than in those without camptocormia (P < 0.05). CONCLUSIONS: PD patients manifesting camptocormia are likely subjected to NMS than patients without camptocormia, especially autonomic and miscellaneous symptoms. These patients also suffered from more severe neuropsychiatric symptoms and sleep disorders. PMID- 24954150 TI - Micelle dynamic simulation and physicochemical characterization of biorelevant media to reflect gastrointestinal environment in fasted and fed states. AB - The characterization of biorelevant media simulating the upper part of the gastrointestinal tract in the fasted and fed states was investigated by classical determination of physicochemical parameters such as pH, osmolality, surface tension and results were compared to in vivo physiological data. Incorporation of fatty material, in order to better simulate the influence of high fat meal was also performed. Stability and characterization of this medium was studied and compared to classical FeSSIF. Micelle characterization and computer dynamic simulation were performed in order to understand the interaction between lecithin and taurocholate and possible interactions between mixed micelle and drugs. The addition of NaTc, lecithin, and/or fatty materials has no influence on pH and osmolality, whereas the presence of fatty material modifies the surface tension. Values of FaSSIF and FeSSIF are in accordance with in vivo parameters and the presence of micelles can simulate the gastrointestinal environment. Modelization of micelles by computer simulation led to a model of mixed micelles in which structures of NaTc interact either by their hydrophilic or hydrophobic phase to give a bilayer stable model in which the lecithin molecule can insert its long carbon chain. The micelle structure is stable and can enhance dissolution of hydrophobic molecules by hydrophobic interaction with the numerous hydrophobic spaces available in the multilayer hydrophilic/hydrophobic layer. PMID- 24954151 TI - The emergence of human population genetics and narratives about the formation of the Brazilian nation (1950-1960). AB - This paper discusses the emergence of human population genetics in Brazil in the decades following World War II, and pays particular attention to narratives about the formation of the Brazilian nation. We analyze the institutionalization of this branch of genetics in the 1950s and 1960s, and look at research on the characteristics of the population of Brazil, which made use of new explanatory models of evolutionary dynamics. These developments were greatly influenced by the activities of the Rockefeller Foundation and by the presence of North American geneticists in Brazil, especially Theodosius Dobzhansky. One of the main points of this paper is to show that explanations of Brazilian human genetic diversity constructed in the mid-twentieth century closely followed interpretations that had been produced since the end of the nineteenth century, in which notions of 'racial mixing' played a central role. Even as population genetics was conditioned by nationalist concerns that had long marked Brazilian history, we argue that its emergence and institutionalization was closely associated with global, post-World War II socio-political contexts, especially with regards to modernization projects and growing scientific internationalization. PMID- 24954152 TI - Molecular origin of pH-dependent fibril formation of a functional amyloid. AB - Fibrils derived from Pmel17 are functional amyloids upon which melanin is deposited. Fibrils of the repeat domain (RPT) of Pmel17 form under strict melanosomal pH (4.5-5.5) and completely dissolve at pH>=6. To determine which Glu residue is responsible for this reversibility, aggregation of single, double, and quadruple Ala and Gln mutants were examined by intrinsic Trp fluorescence, circular dichroism spectroscopy, and transmission electron microscopy. Charge neutralization of E404, E422, E425, or E430, which are located in the putative amyloid-forming region, modulated aggregation kinetics. Remarkably, the removal of a single negative charge at E422, one of 16 carboxylic acids, shifted the pH dependence by a full pH unit. Mutation at E404, E425, or E430 had little to no effect. We suggest that protonation at E422 is essential for initiating amyloid formation and that the other Glu residues play an allosteric role in fibril stability. PMID- 24954153 TI - Estimating urban roadside emissions with an atmospheric dispersion model based on in-field measurements. AB - Urban vehicle emission models have been utilized to calculate pollutant concentrations at both microscopic and macroscopic levels based on vehicle emission rates which few researches have been able to validate. The objective of our research is to estimate urban roadside emissions and calibrate it with in field measurement data. We calculated the vehicle emissions based on localized emission rates, and used an atmospheric dispersion model to estimate roadside emissions. A non-linear regression model was applied to calibrate the localized emission rates using in-field measurement data. With the calibrated emission rates, emissions on urban roadside can be estimated with a high accuracy. PMID- 24954154 TI - The fat-like cadherin CDH-4 acts cell-non-autonomously in anterior-posterior neuroblast migration. AB - Directed migration of neurons is critical in the normal and pathological development of the brain and central nervous system. In Caenorhabditis elegans, the bilateral Q neuroblasts, QR on the right and QL on the left, migrate anteriorly and posteriorly, respectively. Initial protrusion and migration of the Q neuroblasts is autonomously controlled by the transmembrane proteins UNC 40/DCC, PTP-3/LAR, and MIG-21. As QL migrates posteriorly, it encounters and EGL 20/Wnt signal that induces MAB-5/Hox expression that drives QL descendant posterior migration. QR migrates anteriorly away from EGL-20/Wnt and does not activate MAB-5/Hox, resulting in anterior QR descendant migration. A forward genetic screen for new mutations affecting initial Q migrations identified alleles of cdh-4, which caused defects in both QL and QR directional migration similar to unc-40, ptp-3, and mig-21. Previous studies showed that in QL, PTP 3/LAR and MIG-21 act in a pathway in parallel to UNC-40/DCC to drive posterior QL migration. Here we show genetic evidence that CDH-4 acts in the PTP-3/MIG-21 pathway in parallel to UNC-40/DCC to direct posterior QL migration. In QR, the PTP-3/MIG-21 and UNC-40/DCC pathways mutually inhibit each other, allowing anterior QR migration. We report here that CDH-4 acts in both the PTP-3/MIG-21 and UNC-40/DCC pathways in mutual inhibition in QR, and that CDH-4 acts cell-non autonomously. Interaction of CDH-4 with UNC-40/DCC in QR but not QL represents an inherent left-right asymmetry in the Q cells, the nature of which is not understood. We conclude that CDH-4 might act as a permissive signal for each Q neuroblast to respond differently to anterior-posterior guidance information based upon inherent left-right asymmetries in the Q neuroblasts. PMID- 24954155 TI - Identification of a transient Sox5 expressing progenitor population in the neonatal ventral forebrain by a novel cis-regulatory element. AB - Precise control of lineage-specific gene expression in the neural stem/progenitor cells is crucial for generation of the diversity of neuronal and glial cell types in the central nervous system (CNS). The mechanism underlying such gene regulation, however, is not fully elucidated. Here, we report that a 377 bp evolutionarily conserved DNA fragment (CR5), located approximately 32 kbp upstream of Olig2 transcription start site, acts as a cis-regulator for gene expression in the development of the neonatal forebrain. CR5 is active in a time specific and brain region-restricted manner. CR5 activity is not detected in the embryonic stage, but it is exclusively in a subset of Sox5+ cells in the neonatal ventral forebrain. Furthermore, we show that Sox5 binding motif in CR5 is important for this cell-specific gene regulatory activity; mutation of Sox5 binding motif in CR5 alters reporter gene expression with different cellular composition. Together, our study provides new insights into the regulation of cell-specific gene expression during CNS development. PMID- 24954156 TI - Quality of life in major depressive disorder before/after multiple steps of treatment and one-year follow-up. AB - OBJECTIVE: This study examines the impact of major depressive disorder (MDD) and its treatment on quality of life (QOL). METHOD: From the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, we analyzed complete data of 2280 adult MDD out-patients at entry/exit of each level of antidepressant treatments and after 12 months of entry to follow-up. QOL was measured using the QOL Enjoyment and Satisfaction Questionnaire (Q-LES-Q). The proportions of patients scoring 'within-normal' QOL (within 10% of Q-LES-Q community norms) and those with 'severely impaired' QOL (>2 SD below Q-LES-Q community norms) were analyzed. RESULTS: Before treatment, no more than 3% of MDD patients experienced 'within-normal' QOL. Following treatment, statistically significant improvements were detected; however, the proportion of patients achieving 'within-normal' QOL did not exceed 30%, with >50% of patients experiencing 'severely impaired' QOL. Although remitted patients had greater improvements compared with non-remitters, 32-60% continued to experience reduced QOL. 12-month follow-up data revealed that the proportion of patients experiencing 'within-normal' QOL show a statistically significant decrease in non-remitters. CONCLUSION: Symptom-focused treatments of MDD may leave a misleading impression that patients have recovered when, in fact, they may be experiencing ongoing QOL deficits. These findings point to the need for investigating specific interventions to ameliorate QOL in MDD. PMID- 24954158 TI - Characteristics of pilomatrixoma in children: a review of 137 patients. AB - OBJECTIVE: To describe our institutional experience with pilomatrixoma in the pediatric population, specifically examining its clinical presentation, associated conditions, surgical treatment and future implications. METHODS: This is a retrospective review of a single tertiary care center. Subjects included 137 patients with diagnosis of pilomatrixoma between the years of 2000 and 2013 up to the age of 19. Patient gender, age at excision, number of tumors, tumor size, tumor location, preoperative diagnosis, recurrence, patient race and zip code, along with associated medical conditions were assessed. RESULTS: There were a total of 174 tumors in 137 patients. The median age at excision was 7.1 years old, with the youngest patient at 6 months and the oldest at 19 years. Head and neck tumors predominated with 70% (n=122) of all pilomatrixomas, followed by the upper extremity with 22% (38). Other locations included the hair-bearing back, chest and lower extremities. A male to female ration of 1:1.2 was observed. Tumor diameter size ranged from 0.2 to 5.2 cm with an average diameter of 1.4 cm. There were no cases of recurrence. Associated diagnoses included Turner syndrome and Sticker syndrome. CONCLUSIONS: Pilomatrixoma, previously thought to be a rare lesion, is one of the most common causes of superficial head and neck masses in children. This study demonstrates clinical presentations that should help guide differential diagnoses. We demonstrate associations that are consistent with the proposed pathophysiology of pilomatrixoma. Surgical excision is curative. PMID- 24954157 TI - Maize Elongin C interacts with the viral genome-linked protein, VPg, of Sugarcane mosaic virus and facilitates virus infection. AB - The viral genome-linked protein, VPg, of potyviruses is involved in viral genome replication and translation. To determine host proteins that interact with Sugarcane mosaic virus (SCMV) VPg, a yeast two-hybrid screen was used and a maize (Zea mays) Elongin C (ZmElc) protein was identified. ZmELC transcript was observed in all maize organs, but most highly in leaves and pistil extracts, and ZmElc was present in the cytoplasm and nucleus of maize cells in the presence or absence of SCMV. ZmELC expression was increased in maize tissue at 4 and 6 d post SCMV inoculation. When ZmELC was transiently overexpressed in maize protoplasts the accumulation of SCMV RNA was approximately doubled compared with the amount of virus in control protoplasts. Silencing ZmELC expression using a Brome mosaic virus-based gene silencing vector (virus-induced gene silencing) did not influence maize plant growth and development, but did decrease RNA accumulation of two isolates of SCMV and host transcript encoding ZmeIF4E during SCMV infection. Interestingly, Maize chlorotic mottle virus, from outside the Potyviridae, was increased in accumulation after silencing ZmELC expression. Our results describe both the location of ZmElc expression in maize and a new activity associated with an Elc: support of potyvirus accumulation. PMID- 24954160 TI - An analysis of pancreas transplantation outcomes based on age groupings--an update of the UNOS database. AB - INTRODUCTION: Previously, increasing age has been a part of the exclusion criteria used when determining eligibility for a pancreas transplant. However, the analysis of pancreas transplantation outcomes based on age groupings has largely been based on single-center reports. METHODS: A UNOS database review of all adult pancreas and kidney-pancreas transplants between 1996 and 2012 was performed. Patients were divided into groups based on age categories: 18-29 (n = 1823), 30-39 (n = 7624), 40-49 (n = 7967), 50-59 (n = 3160), and >=60 (n = 280). We compared survival outcomes and demographic variables between each age grouping. RESULTS: Of the 20 854 pancreas transplants, 3440 of the recipients were 50 yr of age or above. Graft survival was consistently the greatest in adults 40-49 yr of age. Graft survival was least in adults age 18-29 at one-, three-, and five-yr intervals. At 10- and 15-yr intervals, graft survival was the poorest in adults >60 yr old. Patient survival and age were found to be inversely proportional; as the patient population's age increased, survival decreased. CONCLUSION: Pancreas transplants performed in patients of increasing age demonstrate decreased patient and graft survival when compared to pancreas transplants in patients <50 yr of age. PMID- 24954159 TI - Facile fabrication of a near-infrared responsive nanocarrier for spatiotemporally controlled chemo-photothermal synergistic cancer therapy. AB - Remote-controlled nanocarriers for drug delivery are of great promise to provide timely, sensitive and spatiotemporally selective treatments for cancer therapy. Due to convenient and precise manipulation, deep penetration through tissues and excellent biocompatibility, near-infrared (NIR) irradiation is a preferred external stimulus for triggering the release of loaded drugs. In this work, for spatiotemporally controlled chemo-photothermal synergistic cancer therapy, a NIR responsive nanocarrier was fabricated using reduced graphene oxide nanosheets (rNGO) decorated with mesoporous silica shell and the subsequent functionalization of the thermoresponsive polymer brushes (pNIPAM-co-pAAm) at the outlet of the silica pore channels. rNGO, which combined with the mesoporous silica shell provide a high loading capacity for anticancer drugs (doxorubicin, DOX), was assigned to sense NIR irradiation for the manipulation of pNIPAM-co pAAm valve to control the diffusion of loaded DOX. Under NIR irradiation, rNGO would generate heat, which could not only elevate the surrounding temperature over the low critical solution temperature (LCST) of pNIPAM-co-pAAm to open the thermoresponsive polymer valve and promote the diffusion of DOX, but also kill the cancer cells through the hypothermia effect. By manipulating NIR irradiation, the nanocarrier exhibited efficiently controlled release of loaded DOX both in the buffer and in living HeLa cells (the model cancer cells), providing powerful and site-targeted treatments, which can be attributed to synergistic effects of chemo-photothermal therapy. To sum up, this novel nanocarrier is an excellent drug delivery platform in remote-controlled chemo-photothermal synergistic cancer therapy via NIR irradiation. PMID- 24954161 TI - Regenerative therapy in experimental parkinsonism: mixed population of differentiated mouse embryonic stem cells, rather than magnetically sorted and enriched dopaminergic cells provide neuroprotection. AB - AIM: The objective of the study was to develop regenerative therapy by transplanting varied populations of dopaminergic neurons, differentiated from mouse embryonic stem cells (mES) in the striatum for correcting experimental parkinsonism in rats. METHODS: mES differentiated by default for 7 days in serum free media (7D), or by enhanced differentiation of 7D in retinoic acid (7R), or dopaminergic neurons enriched by manual magnetic sorting from 7D (SSEA-) were characterized and transplanted in the ipsilateral striatum of 6-hydroxydopamine induced hemiparkinsonian rats. Neurochemical, neuronal, glial and neurobehavioral recoveries were examined. RESULTS: 7R and SSEA- contained significantly reduced NANOG and high MAP2 mRNA and protein levels as revealed, respectively, by reverse transcriptase-PCR and immunocytochemistry, compared with 7D. Striatal engraftment of 7D resulted in a significantly better behavioral and neurochemical recovery, as compared to the animals that received either 7R or SSEA-. The 7R transplanted animals showed improvement neither in behavior nor in striatal dopamine level. The grafted striatum revealed increased GFAP staining intensity in 7D and SSEA-, but not in 7R cells transplanted group, suggesting a vital role played by glial cells in the recovery. Substantia nigra ipsilateral to the side of the striatum, which received transplants showed more tyrosine hydroxylase immunostained neurons, as compared to 6-hydroxydopamine-infused animals. CONCLUSION: These results demonstrate that default differentiated mixed population of cells are better than sorted, enriched dopaminergic cells, or cells containing more mature neurons for transplantation recovery in hemiparkinsonian rats. PMID- 24954162 TI - Docosahexanoic acid diet supplementation attenuates the peripheral mononuclear cell inflammatory response to exercise following LPS activation. AB - Exercise induces changes in circulating pro- and anti-inflammatory cytokines. The aim was to investigate the effect of docosahexaenoic acid (DHA) diet supplementation on the plasma cytokine levels and on the peripheral mononuclear (PBMCs) cells cytokine production after a training season or an acute bout of exercise. Fifteen male soccer players were randomly assigned to a placebo or an experimental group. The experimental group consumed an almond-based beverage enriched with DHA, whereas the placebo group consumed the same beverage without DHA. Three blood samples were taken: in basal conditions at the beginning of the nutritional intervention and after eight weeks of training season in basal and post-exercise conditions. The DHA content increased in erythrocytes after 8weeks of training and supplementation. Neither diet supplementation with DHA nor training season altered the basal plasma cytokines and growth factors. Only acute exercise significantly increased plasma IL6 in experimental and placebo groups. Lipopolysaccharide (LPS) activation induced the inflammatory response in PBMCs, with a significant production rate of TNFalpha, IL6 and IL8 mainly after acute exercise. DHA supplementation significantly reduced the rate of TNFalpha and IL6 production by stimulated PBMCs. Acute exercise increased the Toll-like receptor 4 (TLR4) protein levels in PBMCs, although the increase was only statistically significant in the placebo group. In conclusion, a training season does not induce significant changes in the circulating cytokine profile in well-trained soccer players. Exercise increases the PBMCs cell capabilities to produce cytokines after TLR4 stimulation with LPS and this rate of cytokine production is attenuated by diet DHA supplementation. PMID- 24954163 TI - Intrahepatic landscape of regulatory T-cell subsets in chronically HCV-infected patients with cirrhosis and HCC. PMID- 24954164 TI - Nonsteroidal anti-inflammatory drugs (NSAIDs) in older people: prescribing patterns according to pain prevalence and adherence to clinical guidelines. AB - The evidence on the patterns of nonsteroidal anti-inflammatory drug (NSAID) use according to pain prevalence and clinical guidelines in older people is sparse. This cross-sectional study examined the patterns of NSAID use according to pain prevalence and concordance with clinical guideline recommendations for safe NSAID use in older people, in relation to duration of use, patterns of use, concomitant use of proton pump inhibitors (PPIs), and prevalence of specific drug interactions. Community-dwelling men (n=1696) age >= 70 years living in Sydney were studied. 8.2% (n=139) of participants reported regular NSAID use compared with 2.9% (n=50) reporting as-needed use. The mean treatment duration for regular NSAID use was 4.9 years, suggesting long-term rather than short-term use as recommended by the guidelines. Although guidelines recommend use of PPIs together with an NSAID, only 25.2% of regular NSAID users reported PPI use. Regular NSAID users were significantly more likely to report use of opioid analgesics (P<.0001) compared with nonregular users. In relation to pain prevalence, regular NSAID users were significantly more likely to report chronic pain (P<.0001), recent pain (P=.0001), and chronic intrusive pain (P<.0001) compared with nonregular users. The findings of this study indicate that NSAID prescribing practices do not align with clinical guidelines for safe use in older people. This difference between the guideline recommendations and what is happening in the real world should be explored further. PMID- 24954165 TI - Differential changes in functional disability and pain intensity over the course of psychological treatment for children with chronic pain. AB - Patients presenting for treatment of chronic pain often believe that pain reduction must be achieved before returning to normal functioning. However, treatment programs for chronic pain typically take a rehabilitative approach, emphasizing decreasing pain-related disability first with the expectation that pain reduction will follow. This information is routinely provided to patients, yet no studies have systematically examined the actual trajectories of pain and disability in a clinical care setting. In this study of youth with chronic pain (N=94, 8 to 18 years), it was hypothesized that 1) functional disability and pain would decrease over the course of psychological treatment for chronic pain and 2) functional disability would decrease more quickly than pain intensity. Participants received cognitive behavioral therapy (CBT) for pain management (M=5.6 sessions) plus standard medical care. The Functional Disability Inventory and a Numeric Rating Scale of average pain intensity were completed by the child at every CBT session. Hierarchical linear modeling was conducted to examine the longitudinal trajectories of disability and pain. Standardized estimates of the slopes of change were obtained to test differences in rates of change between pain and disability. Results showed an overall significant decline in functional disability over time. Although pain scores reduced slightly from pretreatment to posttreatment, the longitudinal decline over treatment was not statistically significant. As expected, the rate of change of disability was significantly more rapid than pain. Evidence for variability in treatment response was noted, suggesting the need for additional research into individual trajectories of change in pediatric pain treatment. PMID- 24954166 TI - Biased agonism of the MU-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers. AB - Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating MU opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5mg), placebo, or morphine (10mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5mg) elicited higher peak analgesia (105, 116 seconds latency vs 75 seconds for morphine, P<.02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180 seconds) with TRV130 (3, 4.5mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (-15.9 for morphine versus -7.3, -7.6, and 9.4 h*L/min, P<.05). More subjects experienced severe nausea after morphine (n=7) than TRV130 1.5 or 3mg (n=0, 1), but not 4.5mg (n=9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy. PMID- 24954167 TI - Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis. AB - Extracellular high mobility group box-1 protein (HMGB1) plays important roles in the pathogenesis of nerve injury- and cancer-induced pain. However, the involvement of spinal HMGB1 in arthritis-induced pain has not been examined previously and is the focus of this study. Immunohistochemistry showed that HMGB1 is expressed in neurons and glial cells in the spinal cord. Subsequent to induction of collagen antibody-induced arthritis (CAIA), Hmgb1 mRNA and extranuclear protein levels were significantly increased in the lumbar spinal cord. Intrathecal (i.t.) injection of a neutralizing anti-HMGB1 monoclonal antibody or recombinant HMGB1 box A peptide (Abox), which each prevent extracellular HMGB1 activities, reversed CAIA-induced mechanical hypersensitivity. This occurred during ongoing joint inflammation as well as during the postinflammatory phase, indicating that spinal HMGB1 has an important function in nociception persisting beyond episodes of joint inflammation. Importantly, only HMGB1 in its partially oxidized isoform (disulfide HMGB1), which activates toll-like receptor 4 (TLR4), but not in its fully reduced or fully oxidized isoforms, evoked mechanical hypersensitivity upon i.t. injection. Interestingly, although both male and female mice developed mechanical hypersensitivity in response to i.t. HMGB1, female mice recovered faster. Furthermore, the pro-nociceptive effect of i.t. injection of HMGB1 persisted in Tlr2- and Rage-, but was absent in Tlr4-deficient mice. The same pattern was observed for HMGB1-induced spinal microglia and astrocyte activation and cytokine induction. These results demonstrate that spinal HMGB1 contributes to nociceptive signal transmission via activation of TLR4 and point to disulfide HMGB1 inhibition as a potential therapeutic strategy in treatment of chronic inflammatory pain. PMID- 24954168 TI - Drug co-loading and pH-sensitive release core-shell nanoparticles via layer-by layer assembly. AB - Multifunctional core-shell nanoparticles are widely used for biomedical and catalytic applications. In this work, bilayers of chitosan (Cs) and phosphorylated polyvinyl alcohol (PPVA) were sequentially deposited on 3 Aminopropyltri-ethoxysilane-modified SiO2 nanoparticles via layer-by-layer electrostatic self-assembly. The good spherical shape and size distribution were observed by DLS and transmission electron microscope analysis. 7-Hydroxycoumarin (7-HC) and rhodamine B (RhB) as model drugs were loaded in the core and shell of the nanoparticles separately. Confocal laser scanning microscopy shows the core shell structure of HC-SiO2(PPVA/Cs)n-RhB nanoparticles and the embedded location of 7-HC and RhB. The pH-sensitive release investigation of RhB indicates that the release profiles of RhB from HC-SiO2(PPVA/Cs)3PPVA-RhB core-shell nanoparticles are totally different at pH values of 2.0, 7.4, and 9.2. These results predict that the multifunctional nanoparticle SiO2(PPVA/Cs)n has a great potential for drug delivery. PMID- 24954169 TI - The economic impact of Marfan syndrome: a non-experimental, retrospective, population-based matched cohort study. AB - BACKGROUND: Marfan syndrome is a rare disease of the connective tissues, affecting multiple organ systems. Elevated morbidity and mortality in these patients raises the issue of costs for sickness funds and society. To date, there has been no study analysing the costs of Marfan syndrome from a sickness fund and societal perspective. OBJECTIVE: To estimate excess health resource utilisation, direct (non-)medical and indirect costs attributable to Marfan syndrome from a healthcare payer and a societal perspective in Germany in 2008. METHODS: A retrospective matched cohort study design is applied, using claims data. For isolating the causal effect of Marfan syndrome on excess costs, a genetic matching algorithm was used to reduce differences in observable characteristics between Marfan syndrome patients and the control group. 892 patients diagnosed with Marfan syndrome (ICD-10 Q87.4) were matched from a pool of 26,645 control individuals. After matching, we compared health resource utilisation and costs. RESULTS: From the sickness fund perspective, an average Marfan syndrome patient generates excess annual costs of ?2496 compared with a control individual. From the societal perspective, excess annual costs amount to ?15,728. For the sickness fund, the strongest cost drivers are inpatient treatment and care by non physicians. From the sickness fund perspective, the third (25-41 years) and first (0-16 years) age quartiles reveal the greatest surplus in total costs. Marfan syndrome patients have 39% more physician contacts, a 153% longer average length of hospital stay, 119% more inpatient stays, 33% more prescriptions, 236% more medical imaging and 20% higher average prescription costs than control individuals. Depending on the prevalence, the economic impact from the sickness fund perspective ranges between ?24.0 million and ?61.4 million, whereas the societal economic impact extends from ?151.3 million to ?386.9 million. CONCLUSIONS: Relative to its low frequency, Marfan syndrome requires high healthcare expenditure. Not only the high costs of Marfan syndrome but also its burden on patients' lives call for more awareness from policy-makers, physicians and clinical researchers. Consequently, the diagnosis and treatment of Marfan syndrome should begin as soon as possible in order to prevent disease complications, early mortality and substantial healthcare expenditure. PMID- 24954170 TI - Uptake of human papillomavirus vaccine among adolescent males and females: Immunization Information System sentinel sites, 2009-2012. AB - OBJECTIVE: The Advisory Committee on Immunization Practices (ACIP) has recommended routine human papillomavirus (HPV) vaccination at age 11 or 12 years for girls since 2006 and for boys since 2011. We sought to describe adolescent HPV vaccination coverage, doses administered from 2009 to 2012, and age at first vaccination by sex. METHODS: Aggregate data were analyzed from 8 Immunization Information System sentinel sites on HPV vaccinations in children and adolescents aged 11 to 12 years, 13 to 15 years, and 16 to 18 years. Vaccination coverage by age group was reported for 2009 to 2012, and weekly doses administered were determined. Age at first HPV vaccination was calculated for girls in 2007 and 2011 and for boys in 2011. RESULTS: This analysis included data on 2.9 million adolescents aged 11 to 18 years. There were small increases in coverage for girls, with receipt of >=1 dose of HPV vaccine reaching 27.1% of ages 11 to 12, 47.9% of ages 13 to 15, and 57.1% of ages 16 to 18 by December 31, 2012. Uptake of >=1 dose in boys reached ~18% for all age groups. Doses administered showed seasonal variation, with highest uptake before back to school among girls and steady increases in boys after the 2009 ACIP recommendation for permissive use. Doses administered to boys surpassed those administered to girls by September 2012. Among vaccinated girls, more received vaccine at the recommended age of 11 to 12 years in 2011 (74.2%) compared to 2007 (9.9%). In 2011, 27.3% of vaccinated boys received their first dose at age 11 to 12 years. CONCLUSIONS: HPV vaccination coverage increased among adolescents between 2009 and 2012. However, increases among girls were small, and coverage for boys and girls remained below target levels. PMID- 24954172 TI - [Diagnosis and management of alcohol-use disorders]. AB - With the publication of the DSM-5, the alcoholic disease becomes Alcohol-use disorders taking into account dependence and damages according to a gradient of severity. This conceptual evolution should improve the screening of people affected by this chronic and progressive disease associated with a heavy impact on morbidity and mortality. This identification is provided by the clinical interview and examination. Its sensitivity can be improved by questionnaires and biological markers. Damage and related pathologies have to be systematically revealed. In this context, the MoCA test allows the early detection of cognitive disorders. Care management aims for a change in consumption and consists in supporting the patient in his/her approach. Care management should be personalized, appropriated to the patient's informed choice and graded according to disorders' severity. This includes a psychosocial intervention which can be associated with drugs. Abstinence is no longer the only alternative: decreasing consumption with the aim of regulation has been shown interesting in the reduction of harmful consumption. When therapeutic withdrawal turns out to be necessary, use of a treatment should not be systematic. If necessary, benzodiazepines remain the first-line treatment with a limited duration of prescription. According to his/her profile, the patient can receive a long-term treatment to help to maintain abstinence, prevent relapse or reduce consumption. There is evidence that identifying and involving patients in their care significantly improve their health. Effective treatments are available for treating alcohol-use disorders. However, only a relatively small number of patients receive specific management appropriated to their needs and according to concrete goals. PMID- 24954171 TI - Toward rapid, high-sensitivity, volume-constrained biomarker quantification and validation using backscattering interferometry. AB - Realizing personalized medicine, which promises to enable early disease detection, efficient diagnostic staging, and therapeutic efficacy monitoring, hinges on biomarker quantification in patient samples. Yet, the lack of a sensitive technology and assay methodology to rapidly validate biomarker candidates continues to be a bottleneck for clinical translation. In our first direct and quantitative comparison of backscattering interferometry (BSI) to fluorescence sensing by ELISA, we show that BSI could aid in overcoming this limitation. The analytical validation study was performed against ELISA for two biomarkers for lung cancer detection: Cyfra 21-1 and Galectin-7. Spiked serum was used for calibration and comparison of analytical figures of merit, followed by analysis of blinded patient samples. Using the ELISA antibody as the probe chemistry in a mix-and-read assay, BSI provided significantly lower detection limits for spiked serum samples with each of the biomarkers. The limit of quantification (LOQ) for Cyrfa-21-1 was measured to be 230 pg/mL for BSI versus 4000 pg/mL for ELISA, and for Galectin-7, it was 13 pg/mL versus 500 pg/mL. The coefficient of variation for 5 day, triplicate determinations was <15% for BSI and <10% for ELISA. The two techniques correlated well, ranging from 3-29% difference for Cyfra 21-1 in a blinded patient sample analysis. The label-free and free-solution operation of BSI allowed for a significant improvement in analysis speed, with greater ease, improved LOQ values, and excellent day-to-day reproducibility. In this unoptimized format, BSI required 5.5-fold less sample quantity needed for ELISA (a 10 point calibration curve measured in triplicate required 36 MUL of serum for BSI vs 200 MUL for ELISA). The results indicate that the BSI platform can enable rapid, sensitive analytical validation of serum biomarkers and should significantly impact the validation bottleneck of biomarkers. PMID- 24954173 TI - Relationship between personality traits and choosing a medical specialty. AB - BACKGROUND/PURPOSE: The recent imbalance in the labor market structure of medical specialists can cause problems in access to care, and result in lower quality and increased costs of medical care. The labor market structure of medical specialists requires discussion in relation to specialty selection and personality traits. This study examined the relationship between personality traits and specialist selection among medical students. METHODS: This study used the Edwards Personal Preference Schedule and a customized questionnaire. The participants were 358 medical students of the College of Medicine at Chang Gung University. RESULTS: Medical students scored the highest in Intraception and the lowest in Deference. Women scored significantly higher compared to men for Intraception, Succorance, and Change, whereas men scored significantly higher than women for Dominance and Heterosexuality. Medical students who have family or friends who are also physicians scored higher in Affiliation and lower in Deference than other medical students. Medical students who did not participate in extracurricular activities scored higher in Aggression than those who did. Fourth-year medical students scored significantly higher in Succorance than 7(th) year medical students. A significant difference was found among medical students of different specialties regarding Exhibition, Autonomy, Intraception, Succorance, and Nurturance. Surgery students scored significantly higher in Exhibition than general medicine students. Students who chose a specialty scored higher in Autonomy than general medicine students. General medicine students scored higher in Intraception and Succorance than surgery students. CONCLUSION: The results of this study can be used as a frame of reference in the field of medical education or in the formulation of governmental policies regarding physician human resource management. PMID- 24954174 TI - Aortic valve reconstruction using autologous pericardium for patients aged less than 60 years. AB - OBJECTIVE: We have performed an original aortic valve reconstruction using autologous pericardium. The feasibility for patients aged less than 60 years is reviewed. METHODS: From April 2007 to April 2013, aortic valve reconstruction was performed in 108 patients aged less than 60 years. A total of 51 patients had aortic stenosis, 7 patients had annuloaortic ectasia, 7 patients had infective endocarditis, and 43 patients had aortic regurgitation. Fifty-seven patients had bicuspid valves, and 11 patients had unicuspid valves. There were 75 male and 33 female patients, with a mean age of 47.8 +/- 11.2 years. Preoperative echocardiography showed an average peak pressure gradient of 86.1 +/- 35.1 mm Hg with aortic stenosis. The surgical procedure is based on the independent tricuspid replacement using autologous pericardium. First, the distance between the commissures is measured using an original sizing apparatus, and then the pericardial cusp is trimmed using an original template and sutured to the annulus. RESULTS: There was no conversion to prosthetic valve replacement. There were no in-hospital mortalities. Postoperative echocardiography showed an average peak pressure gradient of 14.8 +/- 7.8 mm Hg 1 week after surgery and 12.8 +/- 3.1 mm Hg 4 years after surgery. One patient required reoperation because of infective endocarditis. The other 107 patients showed less than mild aortic regurgitation. No thromboembolic events were recorded. The mean follow-up period was 34.2 +/- 15.7 months. Freedom from reoperation was 98.9% with 76 months of follow-up. CONCLUSIONS: Original aortic valve reconstruction was feasible for patients aged less than 60 years. Long-term data will be disclosed in the future. PMID- 24954175 TI - Early and intermediate outcome after aortic valve replacement with a sutureless bioprosthesis: Results of a multicenter study. AB - OBJECTIVE: The aim of this study was to evaluate the outcome of aortic valve replacement with the sutureless Perceval S aortic valve bioprosthesis (Sorin Biomedica Cardio Srl, Saluggia, Italy). METHODS: This is a retrospective analysis of 314 patients (mean age, 77.9 +/- 5.0 years, mean European System for Cardiac Operative Risk Evaluation II, 9.0% +/- 7.6%) who underwent aortic valve replacement with the Perceval S valve with (94 patients) or without (220 patients) concomitant coronary artery bypass surgery at 5 European centers. RESULTS: The Perceval S valve was successfully implanted in all but 1 patient (99.7%). The mean aortic crossclamping time was 43 +/- 20 minutes (isolated procedure, 39 +/- 15 minutes; concomitant coronary surgery, 52 +/- 26 minutes). Severe paravalvular leak occurred in 2 patients (0.6%). In-hospital mortality was 3.2% (1.4% after isolated procedure and 7.4% after concomitant coronary surgery). In-hospital mortality was 2.8% and 4.0% among patients with a European System for Cardiac Operative Risk Evaluation II less than 10% and 10% or greater, respectively (P = .558). Octogenarians had slightly higher in-hospital mortality (5.2% vs 2.0%, P = .125; after isolated procedure: 2.7% vs 0.7%, P = .223; after concomitant coronary surgery: 9.5% vs 5.8%, P = .491) compared with younger patients. Full sternotomy did not increase the in-hospital mortality risk compared with ministernotomy or minithoracotomy access (1.3% vs 1.4%, when adjusted for baseline covariates: P = .921; odds ratio, 0.886; 95% confidence interval, 0.064-12.346). One-year survival was 90.5%. Freedom from valve-related mortality, stroke, endocarditis, and reoperation was 99.0%, 98.1%, 99.2%, and 98.3%, respectively. CONCLUSIONS: The sutureless Perceval S valve is associated with excellent early survival in high-risk patients, particularly among those undergoing an isolated procedure. Further studies are needed to prove the durability of this bioprosthesis. PMID- 24954177 TI - Diabetic hearts have lower basal urocortin levels that fail to increase after cardioplegic arrest: association with increased apoptosis and postsurgical cardiac dysfunction. AB - OBJECTIVES: The present study investigated the cardioprotective role of urocortin (Ucn) and its relationship with protein kinase C (PKC)epsilon and PKCdelta in patients with (DMPs) and without (NDMPs) diabetes mellitus after on-pump cardiac surgery (OPCS). The molecular mechanisms responsible for the reported worse outcomes of DMP after OPCS remain unknown. METHODS: Two sequential biopsy specimens were obtained from the right atrium of 27 DMPs and 22 NDMPs before and after cardiopulmonary bypass. RESULTS: Postcardioplegic induction of Ucn in NDMPs (P<.01) was not observed in the DMPs, whose precardioplegic Ucn levels were 50% lower than those in the NDMPs (P<.05). In the NDMPs, cardioplegic arrest increased PKCepsilon mRNA and protein (P<.05); overexpression of PKCdelta was not seen. In contrast, DMPs showed increased PKCdelta expression (P<.01), with no change in PKCepsilon. Apoptosis was more than twofold greater in the postcardioplegic samples from the DMPs than in those from the NDMPs. The apoptotic myocytes were Ucn negative and exhibited nuclear relocation of PKCdelta. Enhanced PKCepsilon/mitochondrial co-localization was observed in viable, Ucn-positive, myocytes. The leakage of troponin I documented in the DMPs was greater than that in the NDMPs, although the difference was not statistically significant (P=.06). Furthermore, despite a similar incidence of perioperative acute myocardial infarction, the DMPs did not show postoperative improvement of systolic or diastolic function, although that was seen in the NDMPs (P<.05). CONCLUSIONS: Cardioplegic arrest failed to induce in DMPs myocyte overexpression of Ucn or PKCepsilon but was associated with induction and mitochondrial relocation of PKCdelta, resulting in apoptosis. Failure to overexpress Ucn in the DMPs was associated with apoptosis and cardiac dysfunction and, thus, might contribute to worse postoperative outcomes. PMID- 24954178 TI - Should clopidogrel be discontinued before coronary artery bypass grafting for patients with acute coronary syndrome? A systematic review and meta-analysis. AB - OBJECTIVE: Patients presenting with acute coronary syndrome (ACS) are treated with dual antiplatelet agents, including aspirin and clopidogrel, to prevent mortality and recurrent ischemia. However, those who require coronary artery bypass grafting (CABG) could have increased postoperative bleeding and bleeding related adverse outcomes. The current guidelines on clinical management differ significantly. The present meta-analysis examined the evidence for clopidogrel in the treatment of patients presenting with ACS requiring CABG, with a focus on the timing of medication cessation before surgery. METHODS: A systematic review of 9 electronic databases was performed to identify all relevant studies with comparable outcomes for patients with ACS treated with clopidogrel before CABG. The endpoints included reoperation, major bleeding, mortality, and a composite endpoint of mortality and recurrent myocardial infarction. RESULTS: Five relevant studies were identified according to the predefined selection criteria. Patients who had received clopidogrel had a significantly lower incidence of composite endpoints than those who had not. However, patients who underwent CABG < 5 days after the last dose of clopidogrel had a significantly greater incidence of reoperation, major bleeding, and combined adverse outcomes than those who had had a washout period >5 days. CONCLUSIONS: The results from the present meta-analysis suggest that patients who present with ACS should be treated with dual antiplatelet therapy, including clopidogrel. However, for patients subsequently referred for CABG, a minimum washout period of 5 days should be observed to minimize perioperative bleeding and bleeding-related complications, unless emergency indications exist. These results differ from those of previous studies and guidelines. PMID- 24954182 TI - To associate editors, editorial advisory board and editorial board members of CYTOKINE, a letter from the founding Editors-in-Chief, Scott Durum and Gordon Duff. PMID- 24954179 TI - Estrogen receptor signaling during vertebrate development. AB - Estrogen receptors are expressed and their cognate ligands produced in all vertebrates, indicative of important and conserved functions. Through evolution estrogen has been involved in controlling reproduction, affecting both the development of reproductive organs and reproductive behavior. This review broadly describes the synthesis of estrogens and the expression patterns of aromatase and the estrogen receptors, in relation to estrogen functions in the developing fetus and child. We focus on the role of estrogens for the development of reproductive tissues, as well as non-reproductive effects on the developing brain. We collate data from human, rodent, bird and fish studies and highlight common and species specific effects of estrogen signaling on fetal development. Morphological malformations originating from perturbed estrogen signaling in estrogen receptor and aromatase knockout mice are discussed, as well as the clinical manifestations of rare estrogen receptor alpha and aromatase gene mutations in humans. This article is part of a Special Issue entitled: Nuclear receptors in animal development. PMID- 24954183 TI - Genome typing of nonhuman primate models: implications for biomedical research. AB - The success of personalized medicine rests on understanding the genetic variation between individuals. Thus, as medical practice evolves and variation among individuals becomes a fundamental aspect of clinical medicine, a thorough consideration of the genetic and genomic information concerning the animals used as models in biomedical research also becomes critical. In particular, nonhuman primates (NHPs) offer great promise as models for many aspects of human health and disease. These are outbred species exhibiting substantial levels of genetic variation; however, understanding of the contribution of this variation to phenotypes is lagging behind in NHP species. Thus, there is a pivotal need to address this gap and define strategies for characterizing both genomic content and variability within primate models of human disease. Here, we discuss the current state of genomics of NHP models and offer guidelines for future work to ensure continued improvement and utility of this line of biomedical research. PMID- 24954180 TI - An interactive network of long non-coding RNAs facilitates the Drosophila sex determination decision. AB - Genome analysis in several eukaryotes shows a surprising number of transcripts which do not encode conventional messenger RNAs. Once considered noise, these non coding RNAs (ncRNAs) appear capable of controlling gene expression by various means. We find that Drosophila sex determination, specifically the master-switch gene Sex-lethal (Sxl), is regulated by long ncRNAs (>200nt). The lncRNAs influence the dose sensitive establishment promoter of Sxl, SxlPe, which must be activated to specify female sex. They are primarily from two regions, R1 and R2, upstream of SxlPe and show a dynamic developmental profile. Of the four lncRNA strands only one, R2 antisense, has its peak coincident with SxlPe transcription, suggesting that it may promote activation. Indeed, its expression is regulated by the X chromosome counting genes, whose dose determines whether SxlPe is transcribed. Transgenic lines which ectopically express each of the lncRNAs show they can act in trans, not only impacting the process of sex determination but also altering the levels of the other lncRNAs. Generally, expression of R1 is negative whereas R2 is positive to females. This ectopic expression also results in a change in the local chromatin marks, affecting the timing and strength of SxlPe transcription. The chromatin marks are those deposited by the Polycomb and trithorax groups of chromatin modifying proteins, which we find bind to the lncRNAs. We suggest that the increasing numbers of non-coding transcripts being identified are a harbinger of interacting networks similar to the one we describe. PMID- 24954184 TI - The quality of written instructions for dental prostheses in China. AB - PURPOSE: To investigate the quality of written instructions for dental prostheses in China, including metal-ceramic fixed restorations and removable partial dentures (RPDs). MATERIALS AND METHODS: A total of 1600 prepiloted questionnaires were distributed to five major commercial dental laboratories in different regions in China. The opinions of dental technicians on the written instructions provided by dentists were investigated. In addition, this study also revealed the technicians' responses to poorly written instructions. RESULTS: Seven percent of the written instructions clarified the disinfection status of the impressions or casts, while 32% of the instructions provided general patient information (e.g., gender and age). In cases of metal-ceramic fixed restorations, percentages of written instructions specifying shade, ceramic veneering area, and margin design were 72%, 20%, and 9%, respectively. In fixed partial denture cases, 60% of written instructions provided the number of pontics, while 22% specified the pontic design. In the case of RPDs, 90% of instructions showed the type and position of clasps, 88% provided connector design, while 68% mentioned information regarding the artificial teeth. Dental technicians claimed that 78% of the written instructions involved were inadequately prescribed to some extent, but only about one-third of them would contact dentists for clarification. CONCLUSIONS: Written instructions are not well prescribed in many cases. This situation may jeopardize the quality of prosthodontic treatment. It is necessary to shape responsible policy and mandatory professional guidelines for prosthodontic treatment procedures including dental laboratory services. PMID- 24954185 TI - Perceptions of pharmacists' integration into patient-centered medical home teams. AB - BACKGROUND: Patient-centered medical homes (PCMHs) are a newer paradigm of health care service delivery. Team-based care that includes pharmacists has been implemented in several countries. Subsequently studies have successfully identified challenges and barriers with team-based care. Research on pharmacists' integration into PCMH is warranted to help bridge knowledge from earlier studies exploring team-based care. In 2010, the Department of Veteran Affairs (VA) began a national PCMH implementation, operationalized as "Patient-Aligned Care Teams" (PACTs). The VA's national PACT implementation presents an opportunity to describe other persistent barriers to effective coordination between primary care and pharmacy providers. OBJECTIVE: To identify perceived barriers and facilitators to pharmacist integration into VA PACTs from the perspective of non pharmacist team members. METHODS: Semi-structured interviews were conducted as part of a formative evaluation of PCMH implementation. Participants were from VA medical centers and community-based outpatient clinics in the Midwestern United States and included physicians, nurses, associated health care professionals, and health system administrators. RESULTS: In working toward pharmacy service integration, role clarity and work activities were influenced by team member attitudes toward and previous experiences with pharmacists. Interviewees reported that coordination with pharmacists was hindered if communication placed extra burdens on other team members. Interviewees reported collaboration was easier when pharmacists were onsite, but that technology helped facilitate off-site access to pharmacy services. Finally, some team members characterized pharmacist integration as essential while others failed to integrate pharmacists at all. CONCLUSION: Non-pharmacist members of PACT teams reported some reluctance in pharmacists' integration. They attributed this reluctance to knowledge deficits, limited participation in PACT training by pharmacists, an imbalance in effort expended for pharmacists' integration, and coordination or communication challenges. While there may be unique opportunities for pharmacists to improve patient care through participation in PCMHs, work remains to improve other health professionals' knowledge of and attitudes toward pharmacists' roles on health care teams. PMID- 24954181 TI - Regulation of histone methylation by noncoding RNAs. AB - Cells can adapt to their environment and develop distinct identities by rewiring their transcriptional networks to regulate the output of key biological pathways without concomitant mutations to the underlying genes. These alterations, called epigenetic changes, persist stably through mitotic or, in some instances, meiotic cell divisions. In eukaryotes, heritable changes to chromatin structure are a prominent, but not exclusive, mechanism by which epigenetic changes are mediated. These changes are initiated by sequence-specific events, which trigger a cascade of molecular interactions resulting in feedback mechanisms, alterations in chromatin structure, histone posttranslational modifications (PTMs), and ultimately establishment of distinct transcriptional states. In recent years, advances in next generation sequencing have led to the discovery of several novel classes of noncoding RNAs (ncRNAs). In addition to their well-established cytoplasmic roles in posttranscriptional regulation of gene expression, ncRNAs have emerged as key regulators of epigenetic changes via chromatin-dependent mechanisms in organisms ranging from yeast to man. They function by affecting chromatin structure, histone PTMs, and the recruitment of transcriptional activating or repressing complexes. Among histone PTMs, lysine methylation serves as the binding substrate for the recruitment of key protein complexes involved in the regulation of genome architecture, stability, and gene expression. In this review, we will outline the known mechanisms by which ncRNAs of different origins regulate histone methylation, and in doing so contribute to a variety of genome regulatory functions in eukaryotes. PMID- 24954186 TI - Impact of patients' religious and spiritual beliefs in pharmacy: from the perspective of the pharmacist. AB - BACKGROUND: Socio-cultural perspectives including religious and spiritual beliefs affect medicine use and adherence. Increasingly communities that pharmacists serve are diverse and pharmacists need to counsel medicine use issues with ethical and cultural sensitivity as well as pharmaceutical competence. There is very little research in this social aspect of pharmacy practice, and certainly none conducted in Australia, an increasingly multicultural, diverse population. OBJECTIVES: The purpose of this study was to explore, from a pharmacy practitioner's viewpoint, the frequency and nature of cases where patients' articulated religious/spiritual belief affect medicine use; and pharmacist perspectives on handling these issues. METHODS: Qualitative method employing semi structured interviews with pharmacy practitioners, constructed around an interview guide. Pharmacist participants were recruited purposively from areas of linguistic diversity in Sydney, New South Wales, Australia. Verbatim transcription and thematic analyses were performed on the data. RESULTS: Thematic analyses of 21 semi-structured interviews depicted that scenarios where religious and spiritual belief and medication use intersect were frequently encountered by pharmacists. Patient concerns with excipients of animal origin and medication use while observing religious fasts were the main issues reported. Participants displayed scientific competence; however, aspects of ethical sensitivity in handling such issues could be improved. This novel study highlights the urgent need for more research, training and resource development for practitioners serving patients in multi-faith areas. PMID- 24954189 TI - Metabolic profiling approach to explore compounds related to the umami intensity of soy sauce. AB - A metabolic profiling approach was employed to explore the compounds that affect the intensity of umami taste in soy sauce. Twenty-five kinds of soy sauces were analyzed using GC-MS and LC-MS, wherein measurement data for 427 compounds were obtained. The umami taste intensity of each soy sauce sample was also quantitated by sensory evaluation and a projection to latent structure (PLS) regression analysis was conducted using the compounds' measurements and umami taste intensity data. Variable importance for the projection (VIP) value obtained via PLS was used for the estimation of the relevance for umami taste intensity. N-(1 Deoxyfructos-1-yl)glutamic acid (Fru-Glu) had the highest VIP value, and addition of Fru-Glu to soy sauce increased umami taste intensity better than glutamic acid at the same concentration as confirmed by sensory evaluation. This study showed that the combination of metabolic profiling approach and sensory evaluation can be used effectively to determine compounds related to taste. PMID- 24954187 TI - Computer-aided drug discovery approach finds calcium sensitizer of cardiac troponin. AB - In the fight against heart failure, therapeutics that have the ability to increase the contractile power of the heart are urgently needed. One possible route of action to improve heart contractile power is increasing the calcium sensitivity of the thin filament. From a pharmaceutical standpoint, calcium sensitizers have the distinct advantage of not altering cardiomyocyte calcium levels and thus have lower potential for side-effects. Small chemical molecules have been shown to bind to the interface between cTnC and the cTnI switch peptide and exhibit calcium-sensitizing properties, possibly by stabilizing cTnC in an open conformation. Building on existing structural data of a known calcium sensitizer bound to cardiac troponin, we combined computational structure-based virtual screening drug discovery methods and solution NMR titration assays to identify a novel calcium sensitizer 4-(4-(2,5-dimethylphenyl)-1-piperazinyl)-3 pyridinamine (NSC147866) which binds to cTnC and the cTnC-cTnI147-163 complex. Its presence increases the affinity of switch peptide to cTnC by approximately a factor of two. This action is comparable to that of known levosimendan analogues. PMID- 24954190 TI - Determination of beta-N-oxalyl-L-alpha,beta-diaminopropionic acid and homoarginine in Lathyrus sativus and Lathyrus cicera by capillary zone electrophoresis. AB - BACKGROUND: Lathyrus species as legumes represent an alternative protein source for human and animal nutrition. Heavy consumption of these species can lead to lathyrism, caused by the non-protein amino acid beta-N-oxalyl-l-alpha,beta diaminopropionic acid (beta-ODAP). Currently, there is no well-defined level below which beta-ODAP is considered non-toxic. In this work, the beta-ODAP content was determined in L. sativus and L. cicera samples to assess their potential toxicity. Homoarginine is another non-protein amino acid found in Lathyrus spp. with interesting implications for human and animal nutrition. RESULTS: The level of beta-ODAP found in these two species ranged from 0.79 to 5.05 mg g(-1). The homoarginine content of the samples ranged from 7.49 to 12.44 mg g(-1). CONCLUSION: This paper describes an accurate, fast and sensitive method of simultaneous detection and quantification of beta-ODAP and homoarginine by capillary zone electrophoresis in L. cicera and L. sativus seeds. Moreover, several methods of extraction were compared to determine the highest performance. PMID- 24954191 TI - Can young adolescents with cochlear implants perceive different timbral cues? AB - OBJECTIVE: This study aimed to compare the timbre recognition and preferences of young adolescents with cochlear implants (CIs) to that of adolescents with normal hearing (NH). METHODS: Nine Korean adolescents with CIs and 25 adolescents with NH participated in this study. After listening to each of four Western instruments and five traditional Korean instruments, participants were asked to identify presented instruments and rate how much they liked the timbres. RESULTS: The results showed that the CI group recognized instruments significantly less often than the NH group. They also tended to show a relatively higher recognition of the instruments bearing a rapid and strong attack time. With regard to timbre preferences, no significant differences were found between the groups. DISCUSSION: Young adolescents with CIs show potential for detecting salient features in sound information, especially instrumental timbre. This study indicates what can be considered to incorporate more sounds with varying origins and tone qualities into music perception and education for this population. PMID- 24954192 TI - Photostimulated luminescence properties of Eu2+ -doped barium aluminate phosphor. AB - An intense green photostimulated luminescence in BaAl2 O4 :Eu(2+) phosphor was prepared. The thermoluminescence results indicate that there are at least three types of traps (T1 , T2 , T3 ) with different trap depths in BaAl2 O4 :Eu(2+) phosphor according to the bands located at 327, 361 and 555 K, respectively, which are closely associated with the phosphor's long persistent luminescence and photostimulated luminescence properties. In addition, as a novel optical read-out form, a photostimulated persistent luminescence signal can be repeatedly obtained in BaAl2 O4 :Eu(2+) phosphor. This shows that re-trapping of the electron released from a deep trap plays an important role in photostimulated persistent luminescence. PMID- 24954188 TI - Clinical, genomic, and metagenomic characterization of oral tongue squamous cell carcinoma in patients who do not smoke. AB - BACKGROUND: Evidence suggests the incidence of oral tongue squamous cell carcinoma is increasing in young patients, many who have no history of tobacco use. METHODS: We clinically reviewed 89 patients with oral tongue cancer. Exomic sequencing of tumor DNA from 6 nonsmokers was performed and compared to previously sequenced cases. RNA from 20 tumors was evaluated by massively parallel sequencing to search for potentially oncogenic viruses. RESULTS: Non smokers (53 of 89) were younger than smokers (36 of 89; mean, 50.4 vs 61.9 years; p < .001), and seemed more likely to be women (58.5% vs 38.9%; p = .069). Nonsmokers had fewer TP53 mutations (p = .02) than smokers. No tumor-associated viruses were detected. CONCLUSION: The young age of nonsmoking patients with oral tongue cancer and fewer TP53 mutations suggest a viral role in this disease. Our efforts to identify such a virus were unsuccessful. Further studies are warranted to elucidate the drivers of carcinogenesis in these patients. PMID- 24954194 TI - Pneumonia, thrombosis and vascular disease. AB - SUMMARY: An enhanced risk of cardiovascular mortality has been observed after pneumonia. Epidemiological studies have shown that respiratory tract infections are associated with an increased risk of thrombotic-related vascular disease such as myocardial infarction, ischemic stroke and venous thrombosis. Myocardial infarction and stroke have been detected essentially in the early phase of the disease (i.e. within 48 h from hospital admission), with an incidence ranging from as low as 1% to as high as 11%. Age, previous cardiovascular events and high pneumonia severity index were independent predictors of myocardial infarction; clinical predictors of stroke were not identified. Deep venous thrombosis and pulmonary embolism may also occur after pneumonia but incidence and clinical predictors must be defined. The biological plausibility of such an association may be deduced by experimental and clinical studies, showing that lung infection is complicated by platelet aggregation and clotting system activation, as documented by up-regulation of tissue factor and down-regulation of activated protein C. The effect of antithrombotic drugs has been examined in experimental and clinical studies but results are still inconclusive. PMID- 24954195 TI - Evaluation of the causality of the low-density lipoprotein receptor gene (LDLR) for serum lipids in pigs. AB - A significant quantitative trait locus (QTL) for low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) was identified around the LDLR gene on chromosome 2 (SSC2) in a White Duroc * Erhualian F2 resource population and Sutai pigs in our previous study. However, in previous reports, the causality of LDLR with serum lipids is controversial in pigs. To systematically assess the causality of LDLR with serum lipids, association analyses were successively performed in three populations: Sutai pigs, a White Duroc * Erhualian F2 resource population and a Duroc * (Landrace * Large White) population. We first performed a haplotype-based association study with 60K SNP genotyping data and evidenced the significant association with LDL-C and TC around the LDLR gene region. We also found that there is more than one QTL for LDL-C and TC on SSC2. Then, we evaluated the causalities of two missense mutations, c.1812C>T and c.1520A>G, with LDL-C and TC. We revealed that the c.1812C>T SNP showed the strongest association with LDL-C (P = 5.40 * 10(-11) ) and TC (P = 3.64 * 10(-8) ) and explained all the QTL effect in Sutai pigs. Haplotype analysis found that two missense SNPs locate within a 1.93-Mb haplotype block. One major haplotype showed the strongest significant association with LDL-C (P = 4.62 * 10(-18) ) and TC (P = 1.06 * 10(-9) ). However, the c.1812C>T SNP was not identified in the White Duroc * Erhualian intercross, and the association of c.1520A>G with both LDL-C and TC did not achieve significance in this F2 population, suggesting population heterogeneity. Both missense mutations were identified in the Duroc * (Landrace * Large White) population and showed significant associations with LDL-C and TC. Our data give evidence that the LDLR gene should be a candidate causative gene for LDL-C and TC in pigs, but heterogeneity exists in different populations. PMID- 24954193 TI - Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. AB - In rodents, brown adipose tissue (BAT) regulates cold- and diet-induced thermogenesis (CIT; DIT). Whether BAT recruitment is reversible and how it impacts on energy metabolism have not been investigated in humans. We examined the effects of temperature acclimation on BAT, energy balance, and substrate metabolism in a prospective crossover study of 4-month duration, consisting of four consecutive blocks of 1-month overnight temperature acclimation (24 degrees C [month 1] -> 19 degrees C [month 2] -> 24 degrees C [month 3] -> 27 degrees C [month 4]) of five healthy men in a temperature-controlled research facility. Sequential monthly acclimation modulated BAT reversibly, boosting and suppressing its abundance and activity in mild cold and warm conditions (P < 0.05), respectively, independent of seasonal fluctuations (P < 0.01). BAT acclimation did not alter CIT but was accompanied by DIT (P < 0.05) and postprandial insulin sensitivity enhancement (P < 0.05), evident only after cold acclimation. Circulating and adipose tissue, but not skeletal muscle, expression levels of leptin and adiponectin displayed reciprocal changes concordant with cold acclimated insulin sensitization. These results suggest regulatory links between BAT thermal plasticity and glucose metabolism in humans, opening avenues to harnessing BAT for metabolic benefits. PMID- 24954196 TI - Implementing an emergency medical services system in Kathmandu, Nepal: a model for "white coat diplomacy". AB - Wilderness medicine providers often visit foreign lands, where they come in contact with medical situations that are representative of the prevailing healthcare issues in the host countries. The standards of care for matters of acute and chronic care, public health, and crisis intervention are often below those we consider to be modern and essential. Emergency medical services (EMS) is an essential public medical service that is often found to be underdeveloped. We describe our efforts to support development of an EMS system in the Kathmandu Valley of Nepal, including training the first-ever class of emergency medical technicians in that country. The purpose of this description is to assist others who might attempt similar efforts in other countries and to support the notion that an effective approach to improving foreign relations is assistance such as this, which may be considered a form of "white coat diplomacy." PMID- 24954197 TI - Extreme altitude: words from on high. AB - Medical science has its own objective language for describing the effects of high altitude. Mountaineers' words and metaphors tell the story with subjectivity and feeling. This essay will include only limited physiology about lowlanders and high altitude. Instead, the focus will be literary, using the quotations of 20th century mountaineers and mountaineer physicians to provide color commentary about the hardship. These are Words From on High. PMID- 24954201 TI - Stem cells: keeping alert. PMID- 24954202 TI - Gene expression: beta-globin transcription activation: LDB1 looping it all together. PMID- 24954211 TI - The regulations about eligibility for women with hyperandrogenism to compete in women's category are well founded. A rebuttal to the conclusions by Healy et al. PMID- 24954212 TI - Cognitive-behavioral therapy for hypochondriasis/health anxiety: a meta-analysis of treatment outcome and moderators. AB - The present investigation employed meta-analysis to examine the efficacy of cognitive-behavioral therapy (CBT) for hypochondriasis/health anxiety as well as potential moderators that may be associated with outcome. A literature search revealed 15 comparisons among 13 randomized-controlled trials (RCTs) with a total sample size of 1081 participants that met inclusion criteria. Results indicated that CBT outperformed control conditions on primary outcome measures at post treatment (Hedges's g = 0.95) and at follow-up (Hedges's g = 0.34). CBT also outperformed control conditions on measures of depression at post-treatment (Hedges's g = 0.64) and at follow-up (Hedges's g = 0.35). Moderator analyses revealed that higher pre-treatment severity of hypochondriasis/health anxiety was associated with greater effect sizes at follow-up visits and depression symptom severity was significantly associated with a lower in effect sizes at post treatment. Although effect size did not vary as a function of blind assessment, smaller effect sizes were observed for CBT vs. treatment as usual control conditions than for CBT vs. waitlist control. A dose response relationship was also observed, such that a greater number of CBT sessions was associated with larger effect sizes at post-treatment. This review indicates that CBT is efficacious in the treatment of hypochondriasis/health anxiety and identifies potential moderators that are associated with outcome. The implications of these findings for further delineating prognostic and prescriptive indicators of CBT for hypochondriasis/health anxiety are discussed. PMID- 24954208 TI - Polo-like kinases: structural variations lead to multiple functions. AB - Members of the polo-like kinase (PLK) family are crucial regulators of cell cycle progression, centriole duplication, mitosis, cytokinesis and the DNA damage response. PLKs undergo major changes in abundance, activity, localization and structure at different stages of the cell cycle. They interact with other proteins in a tightly controlled spatiotemporal manner as part of a network that coordinates key cell cycle events. Their essential roles are highlighted by the fact that alterations in PLK function are associated with cancers and other diseases. Recent knowledge gained from PLK crystal structures, evolution and interacting molecules offers important insights into the mechanisms that underlie their regulation and activity, and suggests novel functions unrelated to cell cycle control for this family of kinases. PMID- 24954209 TI - Understanding nucleotide excision repair and its roles in cancer and ageing. AB - Nucleotide excision repair (NER) eliminates various structurally unrelated DNA lesions by a multiwise 'cut and patch'-type reaction. The global genome NER (GG NER) subpathway prevents mutagenesis by probing the genome for helix-distorting lesions, whereas transcription-coupled NER (TC-NER) removes transcription blocking lesions to permit unperturbed gene expression, thereby preventing cell death. Consequently, defects in GG-NER result in cancer predisposition, whereas defects in TC-NER cause a variety of diseases ranging from ultraviolet radiation sensitive syndrome to severe premature ageing conditions such as Cockayne syndrome. Recent studies have uncovered new aspects of DNA-damage detection by NER, how NER is regulated by extensive post-translational modifications, and the dynamic chromatin interactions that control its efficiency. Based on these findings, a mechanistic model is proposed that explains the complex genotype phenotype correlations of transcription-coupled repair disorders. PMID- 24954213 TI - George Armelagos, 1936-2014. PMID- 24954214 TI - Looking inside the black box: Mechanisms linking social behavior to health and fitness. PMID- 24954215 TI - Anthropology stampede in Calgary. PMID- 24954216 TI - Do we understand the genetic basis of evolution?: Most traits look polygenic, but that may not be how they evolve. PMID- 24954210 TI - Cellular senescence: from physiology to pathology. AB - Recent discoveries are redefining our view of cellular senescence as a trigger of tissue remodelling that acts during normal embryonic development and upon tissue damage. To achieve this, senescent cells arrest their own proliferation, recruit phagocytic immune cells and promote tissue renewal. This sequence of events - senescence, followed by clearance and then regeneration - may not be efficiently completed in aged tissues or in pathological contexts, thereby resulting in the accumulation of senescent cells. Increasing evidence indicates that both pro senescent therapies and antisenescent therapies can be beneficial. In cancer and during active tissue repair, pro-senescent therapies contribute to minimize the damage by limiting proliferation and fibrosis, respectively. Conversely, antisenescent therapies may help to eliminate accumulated senescent cells and to recover tissue function. PMID- 24954217 TI - Genes, development, and evolvability in primate evolution. AB - Development is the process whereby a fertilized cell becomes a mature individual. In metazoans, this complex process involves the differentiation of somatic cells into committed cell and tissue types; the organization and migration of cells, tissues, and anatomical structures relative to one another; and growth. Development matters to evolution in two ways. First, development carries out heritable genetic instructions contained in zygotes to produce functioning yet phenotypically varied individuals. At the population level, this variation in form and function among individuals provides the "raw material" for evolution. Second, the mechanisms of development influence the magnitude, direction, and interdependence of heritable phenotypic variation among traits. Together with phenomena such as genetic drift, organismal development determines the raw material available to selection and thus influences the rate and direction of phenotypic evolution. PMID- 24954218 TI - What does feeding system morphology tell us about feeding? AB - Feeding is the set of behaviors whereby organisms acquire and process the energy required for survival and reproduction. Thus, feeding system morphology is presumably subject to selection to maintain or improve feeding performance. Relationships among feeding system morphology, feeding behavior, and diet not only explain the morphological diversity of extant primates, but can also be used to reconstruct feeding behavior and diet in fossil taxa. Dental morphology has long been known to reflect aspects of feeding behavior and diet but strong relationships of craniomandibular morphology to feeding behavior and diet have yet to be defined. PMID- 24954220 TI - Functional analysis of the nuclear localization signal of the POU transcription factor Skn-1a in epidermal keratinocytes. AB - POU domain proteins are a family of critical regulators of development and differentiation due to their transcriptional activity in the nucleus. Skn-1a, a member of the POU domain protein family, appears to be expressed predominantly in epidermal keratinocytes and is thought to play a critical role in keratinocyte differentiation and proliferation. In this study, we examined the mechanisms involved in the nuclear localization of Skn-1a. We transiently expressed enhanced green fluorescent protein (EGFP) reporter constructs encoding EGFP fusions with Skn-1a deletion and mutation proteins in normal human epidermal keratinocytes (NHEKs). The experiments clearly demonstrated that Skn-1a contained a functional nuclear localization signal (NLS) domain, and that the smallest domain necessary for Skn-1a nuclear transport was the GRKRKKR sequence located within amino acids 279-285. Previous studies have shown that the phosphorylation of specific amino acids neighboring the NLS may regulate nuclear transport and that the amino acid residues threonine (Thr) and serine (Ser) have the potential to undergo phosphorylation. We examined whether the amino acids Thr286 and Ser287, which reside adjacent to the NLS at the carboxy-terminal side, play a role in Skn-1a nuclear localization. For this purpose, we generated three EGFP-Skn-1a mutation constructs, in which Thr286, Ser287, or both Thr286 and Ser287 residues were replaced with alanine, respectively. The results showed that the Thr286 and Ser287 residues were involved in the regulation of nuclear localization as well as epidermal differentiation. These results suggested that the epidermal differentiation signaling pathway, involving kinase and phosphatase activation, may regulate the NLS activity of Skn-1a in keratinocytes. Collectively, these data contribute to understanding the mechanisms of nuclear translocation of POU domain proteins and epidermal differentiation. PMID- 24954222 TI - Testicular defense systems: immune privilege and innate immunity. AB - The mammalian testis possesses a special immunological environment because of its properties of remarkable immune privilege and effective local innate immunity. Testicular immune privilege protects immunogenic germ cells from systemic immune attack, and local innate immunity is important in preventing testicular microbial infections. The breakdown of local testicular immune homeostasis may lead to orchitis, an etiological factor of male infertility. The mechanisms underlying testicular immune privilege have been investigated for a long time. Increasing evidence shows that both a local immunosuppressive milieu and systemic immune tolerance are involved in maintaining testicular immune privilege status. The mechanisms underlying testicular innate immunity are emerging based on the investigation of the pattern recognition receptor-mediated innate immune response in testicular cells. This review summarizes our current understanding of testicular defense mechanisms and identifies topics that merit further investigation. PMID- 24954221 TI - Immune cells in term and preterm labor. AB - Labor resembles an inflammatory response that includes secretion of cytokines/chemokines by resident and infiltrating immune cells into reproductive tissues and the maternal/fetal interface. Untimely activation of these inflammatory pathways leads to preterm labor, which can result in preterm birth. Preterm birth is a major determinant of neonatal mortality and morbidity; therefore, the elucidation of the process of labor at a cellular and molecular level is essential for understanding the pathophysiology of preterm labor. Here, we summarize the role of innate and adaptive immune cells in the physiological or pathological activation of labor. We review published literature regarding the role of innate and adaptive immune cells in the cervix, myometrium, fetal membranes, decidua and the fetus in late pregnancy and labor at term and preterm. Accumulating evidence suggests that innate immune cells (neutrophils, macrophages and mast cells) mediate the process of labor by releasing pro-inflammatory factors such as cytokines, chemokines and matrix metalloproteinases. Adaptive immune cells (T-cell subsets and B cells) participate in the maintenance of fetomaternal tolerance during pregnancy, and an alteration in their function or abundance may lead to labor at term or preterm. Also, immune cells that bridge the innate and adaptive immune systems (natural killer T (NKT) cells and dendritic cells (DCs)) seem to participate in the pathophysiology of preterm labor. In conclusion, a balance between innate and adaptive immune cells is required in order to sustain pregnancy; an alteration of this balance will lead to labor at term or preterm. PMID- 24954223 TI - Ly49 receptors activate angiogenic mouse DBA+ uterine natural killer cells. AB - In humans, specific patterns of killer immunoglobulin-like receptors (KIRs) expressed by uterine natural killer (uNK) cells are linked through HLA-C with pregnancy complications (infertility, recurrent spontaneous abortion, intrauterine growth restriction and preeclampsia). To identify mechanisms underpinning the associations between NK cell activation and pregnancy success, pregnancies were studied in mice with genetic knockdown (KD) of the MHC-activated Ly49 receptor gene family. B6.Ly49(KD) pregnancies were compared to normal control B6.Ly49(129) and C57BL/6 (B6) pregnancies. At mid-pregnancy (gestation day (gd9.5)), overall uNK cell (TCRbeta(-)CD122(+)DBA(+)DX5(-) (DBA(+)DX5(-))) and TCRbeta(-)CD122(+)DBA(-)DX5(+) (DBA(-)DX5(+))) frequencies in pregnant uterus were similar between genotypes. Ly49(KD) lowered the normal frequencies of Ly49(+) uNK cells from 90.3% to 47.8% in DBA(-)DX5(+) and 78.8% to 6.3% in DBA(+)DX5(-) uNK cell subtypes. B6.Ly49(KD) matings frequently resulted in expanded blastocysts that did not implant (subfertility). B6.Ly49(KD) mice that established pregnancy had gestational lengths and litter sizes similar to controls. B6.Ly49(KD) neonates, however, were heavier than controls. B6.Ly49(KD) implantation sites lagged in early (gd6.5) decidual angiogenesis and were deficient in mid-pregnancy (gd10.5) spiral arterial remodelling. Ultrastructural analyses revealed that B6.Ly49(KD) uNK cells had impaired granulogenesis, while immunocytochemistry revealed deficient vascular endothelial cell growth factor (VEGFA) production. Perforin and IFNG expression were normal in B6.Ly49(KD) uNK cells. Thus, in normal mouse pregnancies, Ly49 receptor signaling must promote implantation, early decidual angiogenesis and mid-pregnancy vascular remodelling. Disturbances in these functions may underlie the reported genetic associations between human pregnancy complications and the inability of specific conceptus MHCs to engage activating KIR on uNK cells. PMID- 24954224 TI - Liaison between natural killer cells and dendritic cells in human gestation. AB - A successful pregnancy relies on immunological adaptations that allow the fetus to grow and develop in the uterus, despite being recognized by maternal immune cells. Among several immunocompetent cell types present within the human maternal/fetal interface, DC-SIGN(+) dendritic cells (DCs) and CD56(+) natural killer (NK) cells are of major importance for early pregnancy maintenance, not only generating maternal immunological tolerance but also regulating stromal cell differentiation. Previous reports show the presence of NK-DC cell conjugates in first trimester human decidua, suggesting that these cells may play a role in the modulation of the local immune response within the uterus. While effective immunity is necessary to protect the mother from harmful pathogens, some form of tolerance must be activated to avoid an immune response against fetal antigens. This review article discusses current evidence concerning the functions of DC and NK cells in pregnancy and their liaison in human decidua. PMID- 24954227 TI - Brain metastases in non-small-cell lung cancer. AB - Up to 50% of patients with advanced non-small-cell lung cancer will develop brain metastases at some point during their illness. These metastases cause a substantial burden in morbidity and mortality, which has motivated research and technological innovation over the past 2 decades. Surgery, radiotherapy, and systemic therapies have each played a role in management, with the greatest changes associated with the popularization of stereotactic radiosurgery. In this review, the evidence behind each modality used in the management of brain metastases for non-small-cell lung cancer patients is examined, and recommendations regarding the current standards of care and areas of future research focus are provided. PMID- 24954225 TI - MicroRNAs, immune cells and pregnancy. AB - MicroRNAs (miRNAs) are a recently discovered class of non-coding RNAs that are expressed in many cell types, where they regulate the expression of complementary RNAs, thus modulating the stability and translation of mRNAs. miRNAs are predicted to regulate the expression of ~50% of all protein coding genes in mammals. Therefore, they participate in virtually all cellular processes investigated so far. Altered miRNAs expressions are associated with both physiological (pregnancy) and pathological processes (cancer). As the dynamic maternal-fetal interface plays a critical role in the maintenance of successful pregnancy, it is not surprising that the miRNAs that are unique to reproductive tissues are abundantly expressed. Research in this field has demonstrated the presence and dysregulation of a distinct set of pregnancy-associated miRNAs; however, most studies have centered on localizing various miRNAs in reproductive microdomains associated with normal or complicated pregnancies. Although several independent miRNA regulatory mechanisms associated with endometrial receptivity, immune cells, angiogenesis and placental development have been studied, miRNA mediated regulation of pregnancy remains poorly understood. This review provides a summary of the current data on miRNA regulation as well as functional profiles of miRNAs that are found in the uterus, in immune cells associated with maternal tolerance to the fetus, and those involved in angiogenesis and placental development. PMID- 24954229 TI - Fractionated scheme of oral vinorelbine as single-agent therapy or in combination with cisplatin concomitantly with thoracic radiotherapy in stage III non-small cell lung cancer: dose-escalation phase I trial. AB - INTRODUCTION: A dose-determination study was conducted in untreated stage III non small-cell lung cancer to assess continuous exposure to fractionated oral vinorelbine (NVBo), a radiosensitizer, during the radiotherapy period, either alone (first cohort) or in combination with cisplatin (second cohort). PATIENTS AND METHODS: Three patients with stage IIIAN2/IIIB were expected at each dose level, with 3 additional patients in case of dose-limiting toxicity (DLT). Concomitantly with a 60-Gy total dose of radiotherapy, NVBo was given from 60 mg up to 180 mg total dose per week split on days 1, 3, and 5. Once the maximum tolerated dose (MTD), defined as 2 DLTs in a dose level, was determined and the recommended dose of NVBo alone was established, the trial assessed its recommended dose in combination with cisplatin 80 mg/m(2) every 3 weeks. RESULTS: In the first cohort, 26 patients were enrolled. MTD was 160 mg/wk; there were 3 cases of grade 3 esophagitis and 1 of grade 3 pneumonia as DLT out of 5 patients in this dose level. In the recommended dose level (150 mg/wk), only 1 of 6 patients experienced a DLT. In the second cohort, 11 patients received NVBo weekly doses from 130 mg to 150 mg with cisplatin. Only 2 patients received 150 mg/wk NVBo; the trial closed before MTD was determined. The confirmed response rates were 42% and 55% in the first and second cohort, respectively. CONCLUSION: The recommended dose of this fractionated NVBo scheme as single-agent therapy concomitantly with radiotherapy for 6 weeks is 50 mg on days 1, 3, and 5 (150 mg/wk); combined with cisplatin 80 mg/m(2) every 3 weeks, the dose should be 140 to 150 mg/wk adapted on hematology. The response rate is promising. PMID- 24954228 TI - Oral vinorelbine plus cisplatin as first-line chemotherapy in nonsquamous non small-cell lung cancer: final results of an International randomized phase II study (NAVotrial 01). AB - BACKGROUND: The combination of oral vinorelbine plus cisplatin has been studied in numerous trials as first-line treatment of patients with non-small cell lung cancer (NSCLC) regardless of histologic subtype. NAVoTrial 01 is the first study that explores this combination specifically in nonsquamous (NS) NSCLC by assessing the feasibility of this doublet (ratio 1:2) in an investigational approach. A reference arm with pemetrexed plus cisplatin was included. Maintenance therapy with single-agent therapy after 4 cycles of combination therapy was included in the study schedules because it reflected a trend in first line treatment of NSCLC. PATIENTS AND METHODS: Stage IIIB/IV untreated/relapsed patients with NS NSCLC received a 3-week cycle of pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) on day 1 (arm A) or oral vinorelbine 80 mg/m(2) on days 1 and 8 (first cycle 60 mg/m(2)) and cisplatin 80 mg/m(2) on day 1 (arm B). After 4 cycles, patients without disease progression received single-agent maintenance treatment with pemetrexed or oral vinorelbine. RESULTS: Overall, 153 patients were randomized (arm A/arm B: 51/102). Disease control rate (%) for arm A was 76.5 (95% confidence interval [CI], 62.5-87.2) and for arm B it was 75.0 (95% CI, 65.3-83.1), Response rates for arm A were 31.4% (95% CI, 19.1-45.9) and for arm B were 24.0% (95% CI, 16.0-33.6). Median progression-free survival for arm A was 4.3 months (95% CI, 3.8-5.6) and for arm B it was 4.2 months (95% CI, 3.6-4.7). Median survival for arm A was 10.8 months (95% CI, 7.0-16.4) and for arm B it was 10.2 months (95% CI, 7.8-11.9). Main grade 3/4 hematologic toxicities were neutropenia 18.3% (arm A) and 44.0% (arm B), whereas febrile neutropenia was reported in 2% of patients in each arm. CONCLUSION: Oral vinorelbine and cisplatin had an efficacy in line with that achieved with a standard treatment such as pemetrexed and cisplatin, coupled with an acceptable safety profile. PMID- 24954226 TI - Extracellular vesicles and reproduction-promotion of successful pregnancy. AB - Extracellular vesicles (EVs) are membrane-bound complexes secreted from cells under both physiological and pathological conditions. They contain proteins, nucleic acids and lipids and act as messengers for cell-cell communication and signalling, particularly between immune cells. EV research is a rapidly evolving and expanding field, and it appears that all biological fluids contain very large numbers of EVs; they are produced from all cells that have been studied to date, and are known to have roles in several reproductive processes. This review analyses the evidence for the role of EVs throughout human reproduction, starting with the paternal and maternal gametes, followed by the establishment and continuation of successful pregnancies, with specific focus, where possible, on the interaction of EVs with the maternal immune system. Importantly, variations within the EV populations are identified in various reproductive disorders, such as pre-term labour and pre-eclampsia. PMID- 24954230 TI - Complications from computed tomography-guided core needle biopsy for patients receiving stereotactic body radiation therapy for early-stage lesions of the lung. AB - BACKGROUND: Obtaining a tissue diagnosis has traditionally been standard practice before initiating therapy for early-stage non-small-cell lung cancer (NSCLC). In several recent studies from Europe and Asia, a substantial proportion of patients have received stereotactic body radiation therapy (SBRT) based only on the imaging characteristics of the suspicious lesion. The underlying assumption is that the risk of percutaneous needle biopsy may outweigh the benefits in a population that generally has underlying pulmonary dysfunction and other medical comorbidity. Nevertheless, there is limited information regarding biopsy-related complication rates in high-risk patients with early-stage NSCLC who are treated with SBRT. MATERIALS AND METHODS: This was a retrospective review of outcomes after biopsy in patients treated with SBRT. Complications of percutaneous core needle biopsy were analyzed in relation to patient and tumor characteristics. Each biopsy event was analyzed independently for patients with multiple biopsies. RESULTS: A total of 112 percutaneous biopsies were performed in 103 patients. Pneumothorax of any degree was observed in 40 patients (35%) (95% CI, 27%-45%), and 12 patients (10.7%) had a clinically significant pneumothorax requiring chest tube placement (95% CI, 6%-18%). The time to first fraction of SBRT was not different in patients who had a pneumothorax or placement of a chest tube. On multivariate analysis, age, performance status, smoking history, pack-years of smoking, chronic obstructive pulmonary disease history, and forced expiratory volume in the first second of expiration were not statistically significantly associated with chest tube placement. CONCLUSION: Computed tomography-guided needle biopsy in a primarily medically inoperable patient population is safe, with an acceptable degree of complications. PMID- 24954231 TI - management of nonhematologic toxicities associated with different EGFR-TKIs in advanced NSCLC: a comparison analysis. AB - INTRODUCTION: Nonhematologic toxicities are frequently observed in patients receiving epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: For the 2010-2013 period, the authors evaluated 158 patients diagnosed with advanced or metastatic NSCLC treated in first-, second-, or third-line with the EGFR-TKIs afatinib, erlotinib, or gefitinib. The study assessed the incidence of cutaneous rash, diarrhea, and mucositis/stomatitis by grade at initial assessment (< 30 days) compared with last assessment after correct management, and the authors developed a proposal for a new modality of evaluation and management of adverse events. RESULTS: The incidence of adverse events (cutaneous rash, diarrhea, and mucositis/stomatitis), classified by grade at the initial assessment and the reevaluation after management, demonstrated a reduction of about 95% from the starting toxicity grade for diarrhea, 65% for cutaneous rash, and approximately 70% for mucositis/stomatitis. CONCLUSION: These results suggest that the safety profiles regarding cutaneous rash, diarrhea, and mucositis after afatinib, erlotinib, or gefitinib treatment become similar after prompt and correct management. This analysis suggests that immediate therapeutic approaches and continuous management are required to ensure treatments without severe adverse events that could adversely affect survival and the quality of life. PMID- 24954232 TI - Containing infectious disease. PMID- 24954233 TI - Absence of subependymal nodules in patients with tubers suggests possible neuroectodermal mosaicism in tuberous sclerosis complex. AB - AIM: Patients with tuberous sclerosis complex (TSC) with brain involvement usually have both tubers and subependymal nodules (SENs) and the occurrence of one lesion without the other seems to be rare. The aim of this study was to assess the specific clinical manifestations and genotype of patients with one type of lesion or the other but not both. METHOD: The magnetic resonance images of 220 patients with TSC were reviewed, and patients with either tubers or SENs, but not both, were identified. RESULTS: Out of a total of 220 patients (95 males, 125 females; mean age 22y 9mo, range 9mo-81y), six (3%) had tubers without SENs (two males; four females; mean age 34y 10mo, range 11-48y); however, no patients with SENs and without tubers were identified. No mutation was identified (NMI) in any of the six patients who underwent mutational analysis of TSC1 and TSC2. Five of the six patients had three or fewer tubers. INTERPRETATION: We found no patients with SENs but without tubers among our cohort. In all patients with tubers but without SENs, mutational studies of TSC1/TSC2 were negative, and the majority of these had three or fewer tubers. A possible mechanism for patients with NMI and an absence of SENs is a mosaicism with a first postzygotic mutation in the neuroectoderm. PMID- 24954236 TI - The coexisting phase behavior of thermo-responsive copolymer solutions. AB - Using a molecular theory for dilute PEO-b-PNIPAm solutions, we first take the formation of hydrogen bonds between copolymer monomers and water molecules into account, which enables us to study the impact of temperature on PEO-b-PNIPAm self assembly effectively by quantitatively describing the different changes in water affinities of two blocks. With the increase of temperature, hydrogen bonds between PNIPAm and water break down dramatically, resulting in the hydrophobic character of PNIPAm while PEO remains hydrophilic. Amphiphilic copolymers in the aqueous surrounding can aggregate into various structures: micelles and vesicles. According to the equilibrium criterion of the excess grand potential under the conditions of the grand canonical ensemble, we find that both structures are stable and can coexist. Theoretically calculated potentials of mean force of aggregates further verify the coexistence of micelles and vesicles, although the low critical solution temperatures of different aggregates are different under these conditions. A phase diagram as functions of temperature and the weight fraction of PEO (fPEO) is obtained, which shows different regions of micelles, vesicles and their coexistence. It implies the appearance of two types of micelle vesicle transition: spontaneous and temperature-induced. Since PEO-b-PNIPAm as a thermoresponsive material has a broad range of applications, a systematic investigation of the phase behavior is very useful not only for the scientific interest but also for the practical applications. PMID- 24954235 TI - A molecular survey of febrile cases in malaria-endemic areas along China-Myanmar border in Yunnan province, People's Republic of China. AB - BACKGROUND: Imported malaria is a major threat to neighboring malaria-eliminating countries such as P.R. China and is difficult to monitor. A molecular survey of febrile patients with a history of traveling abroad along the Myanmar-China endemic border areas from January 2008 to August 2012 was carried out. The rates of infection with species of Plasmodium and compliance of microscopy diagnosis with nested PCR (Polymerase Chain Reaction) results were calculated. RESULTS: Plasmodium genus-specific nested PCR confirmed that 384 cases were positive. Further species-specific nested PCR showed that the rate of Plasmodium vivax infection was 55% (213/384); that of Plasmodium falciparum was 21% (81/384) and 17% (67/384) of cases were co-infection cases of P. vivax and P. falciparum; the remaining 6% (23/384) of cases were caused by other species, such as Plasmodium ovale, P. malaria, P. knowlesi or mixed infections of Plasmodium. In total there was 13% (50/384) false microscopy diagnosis including 6% (22/384) error in species diagnosis and 7% (28/384) undiagnosed cases in co-infection or low parasitemia malaria cases. CONCLUSIONS: This study indicates that there are considerable numbers of malaria cases in the China-Myanmar endemic border areas that remain undiagnosed or misdiagnosed by microscopy, especially in low-level and/or complex co-infection cases. It is urgent to develop accurate rapid diagnostic tests and apply PCR confirmation for efficient surveillance. PMID- 24954234 TI - Phospholipid transport via mitochondria. AB - In eukaryotic cells, complex membrane structures called organelles are highly developed to exert specialized functions. Mitochondria are one of such organelles consisting of the outer and inner membranes (OM and IM) with characteristic protein and phospholipid compositions. Maintaining proper phospholipid compositions of the membranes is crucial for mitochondrial integrity, thereby contributing to normal cell activities. As cellular locations for phospholipid synthesis are restricted to specific compartments such as the endoplasmic reticulum (ER) membrane and the mitochondrial inner membrane, newly synthesized phospholipids have to be transported and distributed properly from the ER or mitochondria to other cellular membranes. Although understanding of molecular mechanisms of phospholipid transport are much behind those of protein transport, recent studies using yeast as a model system began to provide intriguing insights into phospholipid exchange between the ER and mitochondria as well as between the mitochondrial OM and IM. In this review, we summarize the latest findings of phospholipid transport via mitochondria and discuss the implicated molecular mechanisms. PMID- 24954237 TI - Effects of oleuropein in rats with simultaneous type 2 diabetes and renal hypertension: a study of antihypertensive mechanisms. AB - The mechanism of oleuropein's antihypertensive effects was examined in rat model of simultaneous type 2 diabetes and renal hypertension (diabetic hypertensive). Five groups of male Sprague-Dawley rats including a control, a diabetic hypertensive group receiving vehicle, and three diabetic-hypertensive groups receiving oleuropein at 20, 40, or 60 mg/kg/day were used. The duration of diabetes was 10 weeks; during the last 4 weeks of which, animals were hypertensive and received vehicle or oleuropein. Systolic blood pressure, glucose and malondialdehyde, heart rate, and maximal response to phenylephrine (PE) in the absence of nitro-L-arginine methyl ester (L-NAME) of oleuropein-treated groups were significantly lower than those of vehicle-treated group. Erythrocyte superoxide dismutase, maximal response to PE in the presence of L-NAME, and maximal response to acetylcholine (Ach) of oleuropein-treated groups were significantly higher than those of vehicle-treated group. The findings indicate that antihypertensive effects of oleuropein might be partly mediated by improving the release of nitric oxide, and antioxidant and sympathoplegic activities. PMID- 24954238 TI - Tumor necrosis factor-alpha predicts response to cardiac resynchronization therapy in patients with chronic heart failure. AB - BACKGROUND: Pro-inflammatory cytokines contribute to the pathophysiology of heart failure (HF) and are up-regulated in affected patients. We investigated whether pro-inflammatory cytokines might predict the response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 were assessed in 91 patients before CRT. Response to CRT was defined as a decrease >=15% in left ventricular end-systolic volume (LVESV) at 6 months. Baseline TNF-alpha did correlate with LVESV reduction (P=0.001) after CRT. The subject group was divided according to tertiles of TNF-alpha. From the lower to the upper tertile LVESV (-31+/-28%, 17+/-17%, -9+/-22%) and LV end-diastolic volume (-23+/-25%, -14+/-16%, -4+/-18%) were progressively less reduced after CRT (P<0.001). The proportion of responders to CRT was 70%, 42% and 33%, according to the lower, intermediate and upper tertile of TNF-alpha distribution (P=0.01). Serious cardiac events (cardiac death, HF hospitalization or urgent heart transplantation) occurred in 63% of patients in the upper tertile vs. 32% and 17% in the intermediate and lower tertiles, respectively, during a median follow-up of 47 months (P<0.001). CONCLUSIONS: Circulating TNF-alpha predicts the degree of LV reverse remodeling after CRT and may contribute to the early identification of those patients at higher risk of events after device implantation. PMID- 24954240 TI - Switchable friction using contacts of stimulus-responsive and nonresponding swollen polymer brushes. AB - Stimulus-responsive (SR), solvated polymers can switch between an expanded state and a collapsed state via external stimuli. Using molecular dynamics simulations, I show that such SR polymers can be employed to control the frictional response between two opposing polymer brushes in relative sliding motion. By using a brush composed of SR polymers in contact with a nonresponding solvated polymer brush, the presence of capillaries and the overlap between molecules of the opposing brushes can be switched. When both brushes are solvated, a capillary is formed and polymers of the opposing brushes interdigitate. Interdigitation dominates friction upon shearing flat brush-bearing surfaces, while the breaking and formation of capillaries dominate friction in the low-velocity limit between rough brush-bearing surfaces. Thus, when either rough or flat polymer-bearing surfaces are sheared, friction between two swollen brushes can be high. In contrast, when the SR brush is collapsed, the solvent absorbs only in the brush that does not respond to the external stimulus. The latter circumvents the presence of capillaries and interdigitation of the brushes, which results in a low friction force upon shearing. PMID- 24954239 TI - Increased urine aquaporin-2 relative to plasma arginine vasopressin is a novel marker of response to tolvaptan in patients with decompensated heart failure. AB - BACKGROUND: Preserved function of the renal collecting duct may be essential for response to the vasopressin V2receptor antagonist, tolvaptan (TLV), but the predictors of response to TLV are unknown. METHODS AND RESULTS: Sixty consecutive patients with stage D decompensated heart failure (HF) who had received TLV on a de novo basis were retrospectively enrolled (TLV(+) group). Among them, 41 patients were responders defined according to urine volume (UV) increase after TLV initiation. In the UV-defined responders, plasma arginine vasopressin (P-AVP) had a close correlation with urine aquaporin-2 (U-AQP2; 5.42+/-3.54 ng/ml; r=0.843, P<0.001). In contrast, 19 were UV-defined non-responders, and they had extremely low U-AQP2 (0.76+/-0.59 ng/ml, P<0.001 vs. responders) regardless of P AVP level. On receiver operating characteristic analysis, U-AQP2/P-AVP >=0.5*10(3)clearly separated the UV-defined responders from the non-responders. We then identified AQP-defined responders as having U-AQP2/P-AVP >=0.5*10(3). Sixty propensity score-matched HF patients without TLV treatment were examined, and exactly the same number of patients as that of the AQP-defined responders (n=41) was selected. These patients had a poorer survival without TLV than the TLV-treated responders during a 2-year observation period (73.8% vs. 94.8%, P=0.034). CONCLUSIONS: U-AQP2/P-AVP is a novel predictor of response to TLV in patients with decompensated HF. AQP-defined responders may have a better prognosis on TLV treatment. PMID- 24954241 TI - Radiofrequency catheter ablation of idiopathic left anterior fascicular ventricular tachycardia in children. AB - BACKGROUND: Idiopathic ventricular tachycardia of left anterior fascicular origin (IVT-LAF) is a rare condition, and radiofrequency catheter ablation (RFCA) therapy has not been reported in children. OBJECTIVE: This study aimed to evaluate the procedures and outcomes of RFCA for pediatric IVT-LAF. METHODS: Pediatric IVT-LAF cases for which RFCA was performed between June 2006 and May 2012 at our hospital were reviewed. RESULTS: Of 537 pediatric cases of RFCA, 6 had IVT-LAF; 4 had anterior fascicular involvement only, while 2 had both anterior and posterior fascicular involvement. All 6 of them underwent RFCA at the median age of 8.8 years (range 4.3-14.3 years). RFCA was successful in all patients, but 4 had recurrence and underwent 1-3 additional sessions of RFCA. In a total of 10 RFCA sessions, the overall recurrence rate was 50%. The site of RFCA was determined on the basis of detection of diastolic potential during ventricular tachycardia (7 sessions) or isolated delayed potential during sinus rhythm (1) or by pace mapping (2). During the median follow-up period of 33 months, no further recurrence was reported except for 1 patient, who had a recurrence and was scheduled for additional session at the time of this report. Major complications included 1 case of complete atrioventricular block and 1 case of complete left bundle branch block. CONCLUSION: Despite a high recurrence rate and a few complications, RFCA of the site of isolated delayed potential or diastolic potential, if applied cautiously, is a possible treatment of choice for pediatric IVT-LAF. PMID- 24954243 TI - Primary intracranial germ cell tumours: experience of a single South-East Asian institution. AB - Primary intracranial germ cell tumours (ICGCT) are a rare group of brain tumours arising predominantly in the paediatric and pre-adult population, accounting for up to 9.5% of paediatric brain tumours in East Asia. The National Cancer Centre Singapore (NCCS) is a tertiary referral centre for patients from all over South East Asia. Our study aims to describe the characteristics of ICGCT patients in South-East Asia. Data on all patients with ICGCT who were seen at the Therapeutic Radiology Department of NCCS from 2000 to 2013 were collected retrospectively. Patient demographics, disease characteristics and treatment outcomes were analysed. Characteristics and survival of our patients were similar to other centres. Pure germinomas demonstrated 5 year overall survival (OS) and disease free survival (DFS) rates of 89.2% (95% confidence interval [CI] 60.2-97.5) and 85.2% (95%CI 60.8-95.0) respectively. Secreting germinomas, non-germinomatous germ cell tumours and mixed germ cell tumours were evaluated together and demonstrated 5 year OS of 70.6% (95%CI 41.0-87.3) and DFS of 61.4% (95%CI 31.9 81.3). Patients ? 12 years had marginally better 5 year OS than their older counterparts (81.0% [95%CI 49.5-93.9] versus 77.9% [95%CI 47.3-92.0], respectively). Patients who underwent extended field radiotherapy had longer OS and DFS than those who received local field irradiation. Treatment outcomes of our ICGCT patients are comparable with those in other Asian and Western centres. Extended field radiotherapy is a pivotal component of ICGCT treatment. Adding chemotherapy confers no extra survival benefit in treating germinomas. Treatment of mixed germ cell tumours and non-germinomatous germ cell tumours involves a multidisciplinary approach that varies for each histological subtype. PMID- 24954242 TI - How do sex hormones modify arrhythmogenesis in long QT syndrome? Sex hormone effects on arrhythmogenic substrate and triggered activity. AB - Gender differences in cardiac repolarization and the arrhythmogenic risk of patients with inherited and acquired long QT syndromes are well appreciated clinically. Enhancing our knowledge of the mechanisms underlying these differences is critical to improve our therapeutic strategies for preventing sudden cardiac death in such patients. This review summarizes the effects of sex hormones on the expression and function of ion channels that control cardiac cell excitation and repolarization as well as key proteins that regulate Ca(2+) dynamics at the cellular level. Moreover, it examines the role of sex hormones in modifying the dynamic spatiotemporal (regional and transmural) heterogeneities in action potential duration (eg, the arrhythmogenic substrate) and the susceptibility to (sympathetic) triggered activity at the tissue, organ, and whole animal levels. Finally, it explores the implications of these effects on the management of patients with LQTS. PMID- 24954244 TI - Anaplastic pilocytic astrocytoma. AB - This clinical series examines the presentation of three adult patients who were found to have de novo anaplastic pilocytic astrocytoma. Initial imaging demonstrated an intracranial mass with histological analysis diagnostic of pilocytic astrocytoma with anaplastic features including necrosis, marked nuclear pleomorphism and a very high mitotic rate leading to the diagnosis of anaplastic pilocytic astrocytoma. We discuss the clinical pitfalls, treatment and implications when managing this condition. PMID- 24954245 TI - Preparation of a sulfo-group-containing rod-like polysilsesquioxane with a hexagonally stacked structure and its proton conductivity. AB - A sulfo-group-containing rod-like polysilsesquioxane with a hexagonally stacked structure (PSQ-SO3H) was successfully prepared by oxidation and hydrolytic polycondensation of 3-mercaptopropyltrimethoxysilane (MPTMS) in a mixed aqueous solution of NaOH and H2O2. The X-ray diffraction pattern of the PSQ-SO3H film exhibited three diffraction peaks with a d-value ratio of 1:1/?3:1/2, indicating the formation of a hexagonally stacked structure. In addition, the transmission electron microscopy image of PSQ-SO3H exhibited a striped pattern, indicating that the rod-like PSQs were stacked in a parallel fashion. The presence of ionic side-chains composed of the sulfonate anions and sodium cations during the hydrolytic polycondensation of MPTMS was found to be essential for the formation of this regularly structured PSQ. Finally, the proton conductivity of the PSQ SO3H film, determined by using complex impedance spectroscopy, was relatively high (>10(-2) S cm(-1)) at 80 degrees C and 30-90 % relative humidity. PMID- 24954246 TI - Remote ischemic preconditioning for prevention of acute kidney injury: a meta analysis of randomized controlled trials. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) to prevent acute kidney injury (AKI) following cardiac and vascular interventions is a controversial practice. STUDY DESIGN: We conducted a systematic review and meta-analysis using the MEDLINE database (1966 through November 2013), EMBASE (1988 through November 2013), and Cochrane Library database. SETTING & POPULATION: Patients undergoing cardiac and vascular interventions. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials comparing patient outcome with or without RIPC for prevention of AKI following cardiac and vascular interventions. INTERVENTION: RIPC using an inflatable tourniquet around the limb or cross-clamping the iliac arteries versus non-RIPC. OUTCOMES: AKI, need for renal replacement therapy, postoperative kidney biomarkers, in-hospital mortality, and length of intensive care unit and hospital stay. RESULTS: 13 trials (1,334 participants) were included. RIPC decreased the risk of AKI for patients undergoing cardiac and vascular interventions compared with the control group (11 trials; 1,216 participants; risk ratio [RR], 0.70; 95% CI, 0.48-1.02; P = 0.06; I(2) = 45%) with marginal statistical significance. There were no differences in levels of postoperative kidney biomarkers (serum creatinine and glomerular filtration rate), incidence of renal replacement therapy, in-hospital mortality, hospital stay, or intensive care unit stay between the 2 groups. Metaregression analysis indicated that contrast intervention was not a covariate contributing significantly to heterogeneity on the risk estimate for AKI incidence; also, there was no dose effect of RIPC using tourniquet cuff around the limb on AKI prevention based on different ischemia duration. LIMITATIONS: Different AKI definitions adopted in the trials included. CONCLUSIONS: RIPC might be beneficial for the prevention of AKI following cardiac and vascular interventions, but the current evidence is not robust enough to make a recommendation. Adequately powered trials are needed to provide more evidence in the future. PMID- 24954247 TI - Hantavirus infection with severe proteinuria and podocyte foot-process effacement. AB - Nephropathia epidemica, a zoonosis caused by Hantavirus infection (most commonly subtype Puumala) is associated with flu-like symptoms and acute kidney failure. Kidney manifestations are characterized predominantly by tubulointerstitial nephritis, hemorrhage into medullary tissues, interstitial edema, and tubular cell necrosis. Kidney failure is accompanied by proteinuria, and in some cases, nephrotic-range proteinuria may occur. However, the cellular mechanisms of proteinuria remain to be elucidated. We describe a Hantavirus (Puumala) infection in a 27-year-old man with acute kidney failure and severe and rapidly reversible proteinuria. Light microscopy of a kidney biopsy specimen showed only minor changes of glomeruli. However, transmission electron microscopy revealed podocyte foot-process effacement. Immunofluorescence staining of the slit diaphragm protein podocin and the tight junction protein ZO-1 revealed a partial mislocalization of these proteins. Together, these findings highlight that Hantavirus infection may perturb podocyte integrity, resulting in glomerular proteinuria. These alterations of podocytes and consequently the glomerular filtration barrier may be transient and resolve within weeks. PMID- 24954248 TI - Cochlear implantation at 12 months: Limitations and benefits for vocabulary production. AB - OBJECTIVE: The purpose of this investigation was to learn the degree to which cochlear implantation at 12 months of age could reduce gaps in performance between hearing age and chronological age - that is, whether infants with access to cochlear implants at 12 months of age would be 12 months delayed, or less, in vocabulary production one year later. METHOD: Baseline vocabulary production was measured by parent interview and direct observation approximately 4 months post cochlear implant (CI) activation, and again 12 months after CI activation using the MacArthur-Bates Communicative Development Inventory: Words and Sentences. RESULTS: Infants produced few if any words shortly after CI activation. Word production increased significantly during the 12 months following CI activation but scores were still significantly below age-level expectations based on chronological age. Vocabulary scores were, however, significantly better than expected based on hearing age, or duration of implant use. CONCLUSION: Word production was delayed at both time points; however, access to cochlear implants at 12 months of age decreased the size of anticipated delays one year later, narrowing the expected gap between hearing age and chronological age. PMID- 24954249 TI - Multiplex genome engineering in human cells using all-in-one CRISPR/Cas9 vector system. AB - CRISPR/Cas9-mediated genome editing is a next-generation strategy for genetic modifications, not only for single gene targeting, but also for multiple targeted mutagenesis. To make the most of the multiplexity of CRISPR/Cas9, we established a system for constructing all-in-one expression vectors containing multiple guide RNA expression cassettes and a Cas9 nuclease/nickase expression cassette. We further demonstrated successful examples of multiple targeting including chromosomal deletions in human cells using the all-in-one CRISPR/Cas9 vectors constructed with our novel system. Our system provides an efficient targeting strategy for multiplex genome/epigenome editing, simultaneous activation/repression of multiple genes, and beyond. PMID- 24954250 TI - Substance use in adulthood following adolescent self-harm: a population-based cohort study. AB - OBJECTIVE: To determine whether adolescents who self-harm are at increased risk of heavy and dependent substance use in adulthood. METHOD: Fifteen-year prospective cohort study of a random sample of 1943 adolescents recruited from secondary schools across the state of Victoria, Australia. Data pertaining to self-harm and substance use was obtained at seven waves of follow-up, from mean age 15.9 years to mean age 29.1 years. RESULTS: Substance use and self-harm were strongly associated during the adolescent years (odds ratio (OR): 3.3, 95% CI 2.1 5.0). Moreover, adolescent self-harmers were at increased risk of substance use and dependence syndromes in young adulthood. Self-harm predicted a four-fold increase in the odds of multiple dependence syndromes (sex- and wave-adjusted OR: 4.2, 95% CI: 2.7-6.6). Adjustment for adolescent anxiety/depression attenuated but did not eliminate most associations. Adolescent substance use confounded all associations, with the exception of multiple dependence syndromes, which remained robustly associated with adolescent self-harm (fully adjusted odds ratio: 2.0, 95% CI: 1.2-3.2). CONCLUSION: Adolescent self-harm is an independent risk factor for multiple dependence syndromes in adulthood. This level of substance misuse is likely to contribute substantially to the premature mortality and disease burden experienced by individuals who self-harm. PMID- 24954251 TI - Accurate craniopharyngioma topography for patient outcome improvement. PMID- 24954252 TI - Accuracy of pedicle screw placement in the thoracic and lumbosacral spine using a conventional intraoperative fluoroscopy-guided technique: a national neurosurgical education and training center analysis of 1236 consecutive screws. AB - OBJECTIVE: Pedicle screw placement is a very common procedure used to stabilize all three columns of the thoracic and lumbar spine. The purpose of this study is to evaluate the incidence of screw misplacement and related complications in patients who underwent fluoroscopy-guided transpedicular screw fixation at a neurosurgical teaching institution. METHODS: We retrospectively reviewed consecutive patients who underwent fluoroscopy-guided transpedicular screw fixation from January 2007 to May 2011 in the Department of Neurosurgery, Kantonsspital Aarau, a certified Swiss National Neurosurgical Education and Training Center. The accuracy of the pedicle screw trajectory was assessed using reconstructed postoperative axial, sagittal, and coronal computed tomography images. The displacement was classified as minor (<= 2 mm), moderate (2.1-4 mm), and severe (>4 mm). RESULTS: A total of 1236 pedicle screws were placed in 273 consecutive patients in the thoracic and lumbosacral spine. All surgeries were performed under the supervision of 7 board-certified neurosurgeons and faculty members. A total of 17 surgeons, including trainees, participated in all procedures. A total of 247 (20%) screws breaching the pedicle were identified, with 135 (10.9%) minor violations, 65 (5.3%) moderate violations, and 47 (3.8%) severe violations. Sixteen (5.9%) patients developed postoperative radiculopathy. All of these patients belonged to the subgroup of severe screw displacement. CONCLUSIONS: The data presented confirm that for a training and education center, transpedicular fluoroscopy-guided screw fixation remains a technically demanding procedure. As defined in this study, neurological symptoms are likely associated only with severe screw misplacement. PMID- 24954253 TI - Current treatment strategies for cavernous internal carotid artery aneurysms. PMID- 24954254 TI - Can we more wisely choose residents? PMID- 24954256 TI - Endoscopic-assisted techniques at the craniovertebral junction: understanding indications and limitations. PMID- 24954255 TI - Attitudes toward neurosciences in medical students in Wuhan, China: a survey study. AB - BACKGROUND: Neurophobia is a well-described phenomenon among medical students in many countries. Little is reported concerning the perceptions of neurosciences among medical students in China. METHODS: We surveyed senior medical students in Wuhan, China, on their perceptions of neuroscience. RESULTS: Students' self assessments of knowledge in various specialties ranked neurology low, but not the lowest. Students' confidence in diagnosing neurological patients and managing neurological patients demonstrated significant correlation. A positive correlation was noted between confidence in these clinical parameters and the likelihood of specializing in neurology. Students reported bedside teaching and small group sessions as having the greatest value in learning neurology. CONCLUSIONS: The low, but not the lowest ranking of self-perceived knowledge in neurology by medical students in Wuhan, China, differs from findings reported in other countries. In this exploratory study the investigators hypothesize that the well-described phenomenon of neurophobia may exhibit a less pronounced influence in Wuhan, China. PMID- 24954257 TI - The three-dimensional endoscopic far-lateral approach: many dimensions to the craniocervical junction with a far-from-average operation. PMID- 24954258 TI - Thyrotropin pituitary adenomas. PMID- 24954259 TI - Cavernous carotid aneurysms: you can but should you? PMID- 24954260 TI - Medical complications after aneurysmal subarachnoid hemorrhage: an emerging contributor to poor outcome. PMID- 24954261 TI - Histamine receptor 2 is a key influence in immune responses to intestinal histamine-secreting microbes. PMID- 24954264 TI - Maintaining distances with the engineer: patterns of coexistence in plant communities beyond the patch-bare dichotomy. AB - Two-phase plant communities with an engineer conforming conspicuous patches and affecting the performance and patterns of coexisting species are the norm under stressful conditions. To unveil the mechanisms governing coexistence in these communities at multiple spatial scales, we have developed a new point-raster approach of spatial pattern analysis, which was applied to a Mediterranean high mountain grassland to show how Festuca curvifolia patches affect the local distribution of coexisting species. We recorded 22 111 individuals of 17 plant perennial species. Most coexisting species were negatively associated with F. curvifolia clumps. Nevertheless, bivariate nearest-neighbor analyses revealed that the majority of coexisting species were confined at relatively short distances from F. curvifolia borders (between 0-2 cm and up to 8 cm in some cases). Our study suggests the existence of a fine-scale effect of F. curvifolia for most species promoting coexistence through a mechanism we call 'facilitation in the halo'. Most coexisting species are displaced to an interphase area between patches, where two opposite forces reach equilibrium: attenuated severe conditions by proximity to the F. curvifolia canopy (nutrient-rich islands) and competitive exclusion mitigated by avoiding direct contact with F. curvifolia. PMID- 24954262 TI - TNF-alpha/IL-17 synergy inhibits IL-13 bioactivity via IL-13Ralpha2 induction. PMID- 24954263 TI - Predictors for the development of progressive severity in new-onset adult asthma. AB - BACKGROUND: A proportion of patients with adult-onset asthma have severe disease. Risk factors for an increase in asthma severity are poorly known. OBJECTIVE: We sought to identify predictors for the development of severe asthma in adults. METHODS: A cohort of 200 adults with new-onset asthma was prospectively followed for 2 years. At baseline, patients underwent a comprehensive assessment of clinical, functional, and inflammatory parameters. After 2 years, change in asthma severity was assessed by using the Global Initiative for Asthma score (range, 1-4), which is based on asthma control (Asthma Control Questionnaire), lung function (FEV1), and inhaled corticosteroid requirement. ANOVA and multiple regression equations were used in the analysis. RESULTS: One hundred twenty-eight patients completed 2 years of follow-up. Seventeen (13.3%) patients had an increase in asthma severity, whereas 53 (41.4%) patients had a decrease. A lower postbronchodilator FEV1/forced vital capacity ratio and a higher number of cigarette pack years smoked at baseline were significantly associated with an increase in asthma severity at follow-up. Multiple regression equations showed that only the number of cigarette pack years smoked was independently associated with an increase in asthma severity, with an odds ratio of 1.4 (95% CI, 1.02 1.91) for every 10 pack years smoked. CONCLUSION: A history of cigarette smoking in patients with new-onset adult asthma predicts an increase in asthma severity during the first 2 years of the disease in a dose-dependent manner. PMID- 24954265 TI - Treatment of chronically FIV-infected cats with suberoylanilide hydroxamic acid. AB - Feline immunodeficiency virus (FIV) is a naturally-occurring, large animal model of lentiviral-induced immunodeficiency syndrome, and has been used as a model of HIV pathogenesis and therapeutic interventions. HIV reservoirs in the form of latent virus remain the primary roadblock to viral eradication and cure, and FIV has been previously established an animal model of lentiviral latency. The goal of this study was to determine whether administration of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) to aviremic, chronically FIV-infected cats would induce latent viral reactivation in vivo. A proof-of concept experiment in a Transwell co-culture system demonstrated the ability of SAHA to reactivate latent virus which was replication competent and able to infect naive cells. Oral SAHA (250mg/m(2)) was administered with food to four asymptomatic, experimentally FIV-infected cats and one uninfected control cat, and a limited pharmacokinetic and pharmacodynamic analysis was performed. A statistically significant increase in cell-associated FIV RNA was detected in the cat with the greatest serum SAHA exposure, and cell-free viral RNA was detected at one time point in the three cats that achieved the highest levels of SAHA in serum. Interestingly, there was a significant decrease in viral DNA burden at 2h post drug administration in the same three cats. Though the sample size is small and the drug response was modest, this study provides evidence that in vivo treatment of FIV-infected cats with the HDACi SAHA can induce viral transcriptional reactivation, which may be dependent upon the concentration of SAHA achieved in blood. Importantly, alternative putative antilatency therapy drugs, and multimodal drug combinations, could be studied in this in vivo system. The FIV/cat model provides a unique opportunity to test novel therapeutic interventions aimed at eradicating latent virus in vivo. PMID- 24954266 TI - Factors influencing the aroma composition of Chardonnay wines. AB - Chardonnay is one of the oldest and most widely distributed wine grape cultivars and is of commercial importance for the world's wine-producing nations. It is an extremely flexible variety that has adapted to different regions with varied weather and soil characteristics. Somewhat uniquely among white wines, Chardonnay lends itself to a wide variety of production styles, which can be tailored to the target market. Techniques such as skin maceration, barrel and stainless steel fermentation, use of selected or indigenous yeasts, malolactic fermentation, and aging in barrels with or without lees are all applicable and lead to different compositional outcomes. A number of research papers have been published with a view to understanding Chardonnay composition and quality as well as the impact of different enological techniques on the final product. This review summarizes current knowledge, explaining the influence of viticultural and production techniques on aroma composition, and poses directions for further research into Chardonnay wines. PMID- 24954267 TI - Sonographic appearance of the placenta. AB - The placenta forms the interface between the mother and the fetus and is essential to fetal growth and development. In addition to the exchange of gases and nutrients, it serves immunologic and endocrine functions that protect the fetus and support physiological changes in pregnancy. Although often largely ignored during routine obstetric ultrasound and discarded after delivery, careful sonographic evaluation of the placenta can identify abnormalities that have profound implications for pregnancy outcomes and management. After describing the normal sonographic appearance of the placenta and normal anatomical variations, we review pathologic placental conditions, emphasize ultrasound findings, and highlight implications for pregnancy management and outcomes. PMID- 24954268 TI - Letter from the guest editor. PMID- 24954269 TI - Preparation and characterization of kefiran electrospun nanofibers. AB - In this study, we report the first successful production of kefiran nanofibers through electrospinning process using distilled water as solvent. For this purpose, kefiran was extracted from cultured kefir grains, and homogenous kefiran solutions with different concentrations were prepared and then electrospun to obtain uniform nanofibers. The effect of main process parameters, including applied voltage, tip-to-collector distance, and feeding rate, on diameter and morphology of produced nanofibers, was studied. Scanning electron microscopy (SEM) and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy were used to characterize electrospun mats. Rheological behavior of the kefiran solution was evaluated via a cone and plate rheometer too. The results exhibited that diameter of kefiran nanofibers increased with increasing polymer concentration, applied voltage, and polymer feeding rate, while tip-to collector distance did not have significant effect on nanofiber diameter. ATR FTIR spectra showed that kefiran has maintained its molecular structure during electrospinning process. Flow curves also demonstrated shear thinning behavior for kefiran solutions. PMID- 24954270 TI - The antitumor activity of a red alga polysaccharide complexes carrying 5 fluorouracil. AB - Porphyran is a sulfated galactan isolated from red algae Porphyra haitanensis, and have been reported to have many kinds of biological activities such as antitumor activity. In order to provide a water-soluble macromolecule prodrug of 5-Fu showing slow release of 5-Fu and reducing side-effect, we carried out fixation of 5-Fu to porphyran at 6-position. In this study, the antitumor and immunomodulation activities of low MW porphyran carrying 5-Fu on transplanted S180 tumor mice were studied. Weight of immune organ, proliferation ratio of lymphocyte concentration of TNF-alpha and NO from the transplanted S180 tumor mice were also determined. Results indicated that the conjugate could enhance antitumor activity of 5-Fu and improve immunocompetence damaged by 5-Fu. PMID- 24954271 TI - Controlled drug delivery attributes of co-polymer micelles and xanthan-O carboxymethyl hydrogel particles. AB - Herein, C16 alkyl chain-grafted-xanthan copolymer was synthesized and characterized. The copolymer self-assembled into nanometer-size spherical micellar structures in water and incorporated ~100% glibenclamide into its deeper lipophilic confines. The micellar dispersion exhibited negative zeta potential value (-27.6 mV). The copolymer micelles controlled the drug release rate in phosphate buffer solution (pH 6.8) for an extended period. Further incorporation of drug-loaded copolymer micelles into O-carboxymethyl xanthan hydrogel particles slowed the drug release rate in HCl solution (pH 1.2) as well as in phosphate buffered solution (pH 6.8) (releasing only ~8% drug in 2 h). The drug release data correlated well with the degree of swelling of the hydrogel particles in different drug release media. Scanning electron microscopy revealed spherical shape of the hydrogel particles (600 MUm). X-ray diffraction and Fourier transform infrared (FTIR) spectroscopy analyses suggested amorphous encapsulation of the drug and its chemical compatibility with the polymers, respectively. Pharmacodynamic evaluation suggested that the formulations had an immense potential in controlling blood glucose level in animal model over a longer duration. In summary, it was pointed out that the copolymer micelles of glibenclamide, a poor water-soluble anti-diabetic, and their subsequent entrapment into hydrogel particles could be a promising approach in the controlled and effective management of diabetes. PMID- 24954272 TI - Fabrication of doxorubicin and heparin co-loaded microcapsules for synergistic cancer therapy. AB - In this study, a layer-by-layer (LbL) assembly (HEP/CHI)5 microcapsule with doxorubicin hydrochloride (DOX) encapsulating inside was fabricated via alternatively depositing heparin (HEP) and chitosan (CHI) onto DOX-loaded CaCO3 templates. The microcapsules were of stable architecture and had good dispersity in aqueous medium. Fluorescence observation showed that DOX distributed both in the wall and in the cavity of microcapsules, while HEP presented in the capsule wall. The release rate of DOX increased at acidic pH as compared with that at basic pH, suggesting a pH-responsive drug release behavior. The microcapsules with positively charged CHI lying on the outer layer could protect HEP from heparanase degradation and achieve intracellular co-delivery of both DOX and HEP. Thus, the DOX-loaded microcapsules could have improved inhibition activity against A549 cells by combining pharmacological actions of DOX and HEP. PMID- 24954274 TI - Benefits of understanding allergen thresholds. PMID- 24954273 TI - Niche divergence promotes rapid diversification of East African sky island white eyes (Aves: Zosteropidae). AB - The Eastern Afromontane biodiversity hotspot composed of highly fragmented forested highlands (sky islands) harbours exceptional diversity and endemicity, particularly within birds. To explain their elevated diversity within this region, models founded on niche conservatism have been offered, although detailed phylogeographic studies are limited to a few avian lineages. Here, we focus on the recent songbird genus Zosterops, represented by montane and lowland members, to test the roles of niche conservatism versus niche divergence in the diversification and colonization of East Africa's sky islands. The species-rich white-eyes are a typically homogeneous family with an exceptional colonizing ability, but in contrast to their diversity on oceanic islands, continental diversity is considered depauperate and has been largely neglected. Molecular phylogenetic analysis of ~140 taxa reveals extensive polyphyly among different montane populations of Z. poliogastrus. These larger endemic birds are shown to be more closely related to taxa with divergent habitat types, altitudinal distributions and dispersal abilities than they are to populations of restricted endemics that occur in neighbouring montane forest fragments. This repeated transition between lowland and highland habitats over time demonstrate that diversification of the focal group is explained by niche divergence. Our results also highlight an underestimation of diversity compared to morphological studies that has implications for their taxonomy and conservation. Molecular dating suggests that the spatially extensive African radiation arose exceptionally rapidly (1-2.5 Ma) during the fluctuating Plio-Pleistocene climate, which may have provided the primary driver for lineage diversification. PMID- 24954275 TI - Winter birth in inner-city asthmatic children is associated with increased food allergen sensitization risk. PMID- 24954276 TI - Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria. AB - BACKGROUND: Wheal reactions to intradermally injected neuropeptides, such as substance P (SP) and vasoactive intestinal peptide, are significantly larger and longer lasting in patients with chronic urticaria (CU) than in nonatopic control (NC) subjects. Mas-related gene X2 (MrgX2) has been identified as a receptor for basic neuropeptides, such as SP and vasoactive intestinal peptide. Mast cell (MC) responsiveness to eosinophil mediators contributes to the late-phase reaction of allergy. OBJECTIVE: We sought to compare the frequency of MrgX2 expression in skin MCs from patients with CU and NC subjects and to identify the receptor for basic eosinophil granule proteins on human skin MCs. METHODS: MrgX2 expression was investigated by using immunofluorescence in skin tissues from NC subjects and patients with severe CU and on skin-derived cultured MCs. MrgX2 expression in human MCs was reduced by using a lentiviral small hairpin RNA silencing technique. Ca(2+) influx was measured in CHO cells transfected with MrgX2 in response to eosinophil granule proteins. Histamine and prostaglandin D2 levels were measured by using enzyme immunoassays. RESULTS: The number of MrgX2(+) skin MCs and the percentage of MrgX2(+) MCs in all MCs in patients with CU were significantly greater than those in NC subjects. Eosinophil infiltration in urticarial lesions was observed in 7 of 9 patients with CU. SP, major basic protein, and eosinophil peroxidase, but not eosinophil-derived neurotoxin, induced histamine release from human skin MCs through MrgX2. CONCLUSION: MrgX2 might be a new target molecule for the treatment of wheal reactions in patients with severe CU. PMID- 24954279 TI - Comparing voxel-based iterative sensitivity and voxel-based morphometry to detect abnormalities in T2-weighted MRI. AB - This study aimed to test the superiority proposed by Abbott et al. (2011) of their Voxel based iterative sensitivity (VBIS) method over Voxel Based Morphometry using T2-weighted images (T2-VBM), in detecting intensity changes in Alzheimer's disease (AD). A comparison was made first in simulated intensity lesions and then in AD patients. Intensity changes were evaluated in the whole brain with VBIS and with a simple intensity-based approach and in specific tissue classes with the conventional VBM method of using tissue probability segments. Results showed that VBIS performed well in the simulated environment though it showed no superiority in detecting the lesion compared to the much simpler VBM approach. The VBIS method, however, failed to detect any meaningful signal intensity reduction in AD patient data. Moreover, its whole brain approach was contaminated by the excess cerebrospinal fluid signal (very bright on T2-weighted scans) in areas of maximal measurable atrophy (mesial temporal lobes); this gave rise to spurious signal intensity increases in these regions in AD. The same artefact was observed for both intensity-based methods but not with the conventional VBM approach of performing statistics on grey matter segments. In conclusion, no evidence was found to indicate that VBIS offers benefits over T2 VBM in AD, nor in simulation intensity lesions. The study highlights the necessity of empirically testing voxel-based analysis techniques rather than merely claiming superiority of one method over another on theoretical grounds. PMID- 24954277 TI - The relationship of early-life antibiotic use with asthma in at-risk children. PMID- 24954278 TI - Molecular cloning and characterization of the putative Halloween gene Phantom from the small brown planthopper Laodelphax striatellus. AB - Ecdysteroid hormone 20-hydroxyecdysone plays fundamental roles in insect postembryonic development and reproduction. Several cytochrome P450 mono oxygenases (CYPs), encoded by the Halloween genes, have been documented to be involved in ecdysteroidogenesis in representative insects in Diptera, Lepidoptera and Orthoptera. Here the putative Halloween gene Phantom (Phm, cyp306a1) from a hemipteran insect species, the small brown planthopper Laodelphax striatellus, was cloned. LsPHM shows five insect conserved P450 motifs, that is, Helix-C, Helix-I, Helix-K, PERF and heme-binding motifs. Temporal and spatial expression patterns of LsPhm were evaluated by quantitative polymerase chain reaction. Through the fourth-instar and the early fifth-instar stages, LsPhm showed two expression peaks in day 2 and days 4-5 fourth-instar nymphs, and three troughs in day 1 and 3 fourth instars and day 1 fifth instars. On day 5 of the fourth-instar nymphs, LsPhm clearly had a high transcript level in the thorax where the prothoracic glands were located. Dietary introduction of double-stranded RNA (dsRNA) of LsPhm at the nymph stage successfully knocked down the target gene, decreased expression level of ecdysone receptor (LsEcR) gene and caused a higher nymphal mortality rate and delayed development. Ingestion of 20-hydroxyecdysone on LsPhm-dsRNA-exposed nymphs did not increase LsPhm expression level, but almost completely rescued the LsEcR mRNA level, and relieved the negative effects on survival and development. Thus, our data suggest that the putative LsPhm encodes a functional 25-hydroxylase that catalyzes the biosynthesis of ecdysteroids in L. striatellus. PMID- 24954280 TI - A 4D neonatal head model for diffuse optical imaging of pre-term to term infants. AB - Diffuse optical tomography is most accurate when an individual's MRI data can be used as a spatial prior for image reconstruction and for visualization of the resulting images of changes in oxy- and deoxy-hemoglobin concentration. As this necessitates an MRI scan to be performed for each study, which undermines many of the advantages of diffuse optical methods, the use of registered atlases to model the individual's anatomy is becoming commonplace. Infant studies require carefully age-matched atlases because of the rapid growth and maturation of the infant brain. In this paper, we present a 4D neonatal head model which, for each week from 29 to 44 weeks post-menstrual age, includes: 1) a multi-layered tissue mask which identifies extra-cerebral layers, cerebrospinal fluid, gray matter, white matter, cerebellum and brainstem, 2) a high-density tetrahedral head mesh, 3) surface meshes for the scalp, gray-matter and white matter layers and 4) cranial landmarks and 10-5 locations on the scalp surface. This package, freely available online at www.ucl.ac.uk/medphys/research/4dneonatalmodel can be applied by users of near-infrared spectroscopy and diffuse optical tomography to optimize probe locations, optimize image reconstruction, register data to cortical locations and ultimately improve the accuracy and interpretation of diffuse optical techniques in newborn populations. PMID- 24954281 TI - Applications of multivariate modeling to neuroimaging group analysis: a comprehensive alternative to univariate general linear model. AB - All neuroimaging packages can handle group analysis with t-tests or general linear modeling (GLM). However, they are quite hamstrung when there are multiple within-subject factors or when quantitative covariates are involved in the presence of a within-subject factor. In addition, sphericity is typically assumed for the variance-covariance structure when there are more than two levels in a within-subject factor. To overcome such limitations in the traditional AN(C)OVA and GLM, we adopt a multivariate modeling (MVM) approach to analyzing neuroimaging data at the group level with the following advantages: a) there is no limit on the number of factors as long as sample sizes are deemed appropriate; b) quantitative covariates can be analyzed together with within-subject factors; c) when a within-subject factor is involved, three testing methodologies are provided: traditional univariate testing (UVT) with sphericity assumption (UVT UC) and with correction when the assumption is violated (UVT-SC), and within subject multivariate testing (MVT-WS); d) to correct for sphericity violation at the voxel level, we propose a hybrid testing (HT) approach that achieves equal or higher power via combining traditional sphericity correction methods (Greenhouse Geisser and Huynh-Feldt) with MVT-WS. To validate the MVM methodology, we performed simulations to assess the controllability for false positives and power achievement. A real FMRI dataset was analyzed to demonstrate the capability of the MVM approach. The methodology has been implemented into an open source program 3dMVM in AFNI, and all the statistical tests can be performed through symbolic coding with variable names instead of the tedious process of dummy coding. Our data indicates that the severity of sphericity violation varies substantially across brain regions. The differences among various modeling methodologies were addressed through direct comparisons between the MVM approach and some of the GLM implementations in the field, and the following two issues were raised: a) the improper formulation of test statistics in some univariate GLM implementations when a within-subject factor is involved in a data structure with two or more factors, and b) the unjustified presumption of uniform sphericity violation and the practice of estimating the variance-covariance structure through pooling across brain regions. PMID- 24954282 TI - A functional network estimation method of resting-state fMRI using a hierarchical Markov random field. AB - We propose a hierarchical Markov random field model for estimating both group and subject functional networks simultaneously. The model takes into account the within-subject spatial coherence as well as the between-subject consistency of the network label maps. The statistical dependency between group and subject networks acts as a regularization, which helps the network estimation on both layers. We use Gibbs sampling to approximate the posterior density of the network labels and Monte Carlo expectation maximization to estimate the model parameters. We compare our method with two alternative segmentation methods based on K-Means and normalized cuts, using synthetic and real fMRI data. The experimental results show that our proposed model is able to identify both group and subject functional networks with higher accuracy on synthetic data, more robustness, and inter-session consistency on the real data. PMID- 24954283 TI - Dosimetric analysis of the brachial plexus using Monte Carlo-based intensity modulated radiotherapy for head and neck cancer. PMID- 24954284 TI - Curative therapy for bladder cancer in routine clinical practice: a population based outcomes study. AB - AIMS: Definitive therapy of bladder cancer involves cystectomy or radiotherapy; controversy exists regarding optimal management. Here we describe the management and outcomes of patients treated in routine practice. MATERIALS AND METHODS: Treatment records were linked to the Ontario Cancer Registry to identify all cases of bladder cancer in Ontario treated with cystectomy or radiotherapy in 1994-2008. Practice patterns are described in three study periods: 1994-1998, 1999-2003, 2004-2008. Logistic regression, Cox model and propensity score analyses were used to evaluate factors associated with treatment choice and survival. RESULTS: In total, 3879 cases (74%) underwent cystectomy and 1380 (26%) were treated with primary radiotherapy. Cystectomy use increased over time (66, 75, 78%), whereas radiotherapy decreased (34, 25, 22%), P < 0.001. There was substantial regional variation in the proportion of cases undergoing radiotherapy (range 16-51%). Five year cancer-specific survival (CSS) and overall survival were 40 and 36% for surgical cases and 35 and 26% for radiotherapy cases (P < 0.001). In multivariate Cox model and propensity score analyses, there was no significant difference in CSS between surgery and radiotherapy (hazard ratio 0.99, 95% confidence interval 0.91-1.08); radiotherapy was associated with slightly inferior overall survival (hazard ratio 1.08, 95% confidence interval 1.00-1.16). CONCLUSION: Utilisation of cystectomy for bladder cancer in routine practice has increased over time with no evidence of a significant difference in CSS between radiotherapy and cystectomy. PMID- 24954285 TI - Fixed restorations supported by Morse-taper connection implants: a retrospective clinical study with 10-20 years of follow-up. AB - OBJECTIVES: Rehabilitation with implant-supported fixed prostheses is a predictable modality to restore lost function and esthetics; however, fixed restorations are subject to biological and prosthetic complications, which may represent a problem in the long-term. The aim of this study was to evaluate the long-term survival and complication rates of fixed restorations supported by Morse-taper connection implants. MATERIALS AND METHODS: Between January 1992 and December 2002, 49 patients (age range 22-70 years), were included in this study. The restorations involved 58 fixed reconstructions (15 single crowns [SCS], 29 partial prostheses, 14 full-arches), supported by 178 Morse-taper connection implants with a follow-up ranging from 10 to 20 years. Outcomes such as implant survival, marginal bone loss, frequency of biological and prosthetic complications as well as "complication-free" survival of restorations were investigated. RESULTS: The 20-year overall cumulative implant survival was 97.2%. A few biological (3.4%) and prosthetic (10.3%) complications were reported. The "complication-free" survival rate of restorations was 85.5%. No statistically significant differences were observed among patients' gender, age, smoking or parafunctional habits, prosthesis site and type. CONCLUSIONS: Satisfactory "complication-free" survival rates can be achieved after 20 years for fixed restorations supported by Morse-taper connection implants, with minimal marginal bone loss and complications. PMID- 24954286 TI - Can aortic atherosclerosis or epicardial adipose tissue volume be used as a marker for predicting coronary artery disease? AB - PURPOSE: To investigate whether aortic atherosclerosis or epicardial adipose tissue (EAT) volume on multidetector computed tomography (CT) can predict the presence of significant coronary artery disease (CAD). MATERIALS AND METHODS: Coronary CT angiography was performed in 202 cases of CAD that were known or based on suspicion. Based on coronary CT angiography results, the patients with significant stenosis (>=50%) and without significant stenosis (<50%) were compared in terms of demographic characteristics, traditional cardiovascular risk factors, aortic atherosclerosis, and EAT volume. RESULTS: Significant coronary artery stenosis was detected in 92 cases (45.5%). Although EAT volume was higher in the patients with significant stenosis, the difference between the two groups was not statistically significant. The presence of calcification in the descending aorta was significantly higher in the patients with significant stenosis than the patients without significant stenosis (50.4% and 15.4%, respectively, p=0.0001). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy rates of the presence of calcification in the descending aorta in predicting the presence of significant coronary artery stenosis were respectively found as 53.8%, 84.4%, 74.6%, 68.1%, and 70.3%. The sensitivity, specificity, PPV, NPV, and accuracy rates of the >=2.45mm wall thickness of the descending aorta in predicting the presence of significant coronary artery stenosis were respectively found as 75.3%, 74.3%, 71.4%, 77.9%, and 74.8%. CONCLUSION: There is a strong relationship between thoracic aortic atherosclerosis and CAD. However, the relationship between EAT volume and CAD is not significant. The presence of aortic atherosclerosis can be used as an additional marker together with traditional cardiovascular risk factors for predicting CAD. PMID- 24954287 TI - Slope in preload recruitable stroke work relationship predicts survival after left ventriculoplasty and mitral repair in patients with idiopathic cardiomyopathy. AB - BACKGROUND: Left ventriculoplasty (LVP) and mitral valve plasty (MVP) are sometimes effective for patients with idiopathic dilated cardiomyopathy (DCM) who are not eligible for heart transplantation. Strict patient selection is warranted for these controversial procedures. METHODS AND RESULTS: The subjects were 18 patients with idiopathic DCM and mitral regurgitation who had not been indicated for heart transplantation due to either older age or patient refusal, and who underwent LVP and MVP. Their mean age was 57+/-14 years and 50% were dependent on catecholamine infusion. The preload recruitable stroke work (PRSW) relationship and its slope (Mw) were estimated by a single-beat technique using transthoracic echocardiography. There were one 30-day mortality and six (33%) hospital deaths due to heart failure. The one-year survival rate was 50%. Left ventricular end diastolic dimension (LVDd) decreased from 77+/-11 to 68+/-11mm (p=0.001) whereas the ejection fraction did not change. Preoperative Mw was significantly higher in one-year survivors than that in non-survivors (54+/-17ergcm(-3)10(3) vs. 31+/ 10ergcm(-3)10(3), p=0.005). Preoperative LVDd was not different between the groups. The cut-off value of 42ergcm(-3)10(3) for Mw predicted one-year survival with high sensitivity (100%) and specificity (77%). CONCLUSIONS: Mw, the slope in the PRSW relationship, may predict survival after LVP and MVP in patients with idiopathic DCM. PMID- 24954288 TI - Analysis of factors associated with portal vein thrombosis in pediatric living donor liver transplant recipients. AB - The technique of vascular reconstruction plays a major role in the outcome of living donor liver transplantation (LDLT). An increased use of vascular grafts (VGs) as replacements for sclerotic portal veins has become a standard technique for our group. The aim of this study was to analyze the factors associated with portal vein thrombosis (PVT) in pediatric LDLT. We performed a retrospective analysis of 486 primary pediatric LDLT procedures performed between October 1995 and May 2013. VGs used for portal reconstruction included living donor inferior mesenteric veins, living donor ovarian veins, recipient internal jugular veins, deceased donor iliac arteries, and deceased donor iliac veins. Thirty-four patients (7.0%) developed PVT. The incidence of PVT dropped from 10.1% to 2%; the overall utilization of VGs increased from 3.5% to 37.1%. In a multivariate analysis, only the use of VGs remained an independent risk factor for the occurrence of PVT (hazard ratio = 7.2, 95% confidence interval = 2.8-18.7, P < 0.001). There was no difference in survival rates between patients with PVT and patients without PVT. No patient with PVT underwent retransplantation. In conclusion, the use of VGs was independently associated with the development of PVT. Over time, there was a reduction in the incidence of early PVT in this cohort, and there was a trend toward a reduction in total PVT. The occurrence of isolated PVT in this study was not associated with decreased patient or graft survival. PMID- 24954289 TI - An accessory nipple revealed during pregnancy. PMID- 24954290 TI - [Effects of chocolate consumption on physiology and cardiovascular diseases]. AB - Cocoa has a high content in polyphenols, especially flavonols. Flavonols exert a favourable effect on endothelium-derived vasodilation via the stimulation of nitric oxide-synthase (NOS), the increased availability of l-arginine (NO donor) and the decreased degradation of NO. Cocoa may also have a beneficial effect via the decreased platelet aggregation, the decreased lipid oxidation and insulin resistance. These effects are associated with a modest decrease of blood pressure and a favourable trend towards a reduction in cardiovascular events and strokes. PMID- 24954292 TI - Diagnostic of cystic fibrosis in adult. PMID- 24954291 TI - Advance directives: Better than nothing at all. PMID- 24954293 TI - Erythema gyratum repens: Not always a paraneoplastic disease. PMID- 24954294 TI - Mycotic abdominal aortic aneurysm from Listeria monocytogenes. PMID- 24954295 TI - Hemophagocytic lymphohistiocytosis: A serious challenge for every physician. PMID- 24954296 TI - Cushings syndrome and avascular hip necrosis: Presentation of two patients. PMID- 24954298 TI - Synthesis and biological evaluation of 2-oxo-pyrazine-3-carboxamide-yl nucleoside analogues and their epimers as inhibitors of influenza A viruses. AB - Novel 2-oxo-pyrazine-3-carboxamide-yl nucleoside analogues and their epimers were designed, synthesized and evaluated for their activities against influenza A viruses H1N1 and H3N2 in Madin-Darby canine kidney cells. All the compounds showed low cytotoxicities in these anti-influenza tests. One of the epimers, 4 [(1S, 3R, 4R, 7R)-7-hydroxy-1-(hydroxymethyl)-2,5-dioxabicyclo[2.2.1]heptan-3-yl] 3-oxo-3,4-dihydropyrazine-2-carboxamide 8a, with high antiviral activities (IC50 = 7.41, 5.63 MUm for H3N2 and H1N1, respectively) and remarkable low cytotoxicity (TC50 > 200 MUm), has great potential for further development as a novel anti influenza A agent. Molecular docking of compound 8a with RNA-dependent RNA polymerase was performed to understand the binding mode between these inhibitors and the active site of RdRp and to rationalize some SARs. PMID- 24954297 TI - Regio-selective chemical-enzymatic synthesis of pyrimidine nucleotides facilitates RNA structure and dynamics studies. AB - Isotope labeling has revolutionized NMR studies of small nucleic acids, but to extend this technology to larger RNAs, site-specific labeling tools to expedite NMR structural and dynamics studies are required. Using enzymes from the pentose phosphate pathway, we coupled chemically synthesized uracil nucleobase with specifically (13) C-labeled ribose to synthesize both UTP and CTP in nearly quantitative yields. This chemoenzymatic method affords a cost-effective preparation of labels that are unattainable by current methods. The methodology generates versatile (13) C and (15) N labeling patterns which, when employed with relaxation-optimized NMR spectroscopy, effectively mitigate problems of rapid relaxation that result in low resolution and sensitivity. The methodology is demonstrated with RNAs of various sizes, complexity, and function: the exon splicing silencer 3 (27 nt), iron responsive element (29 nt), Pro-tRNA (76 nt), and HIV-1 core encapsidation signal (155 nt). PMID- 24954299 TI - Exploring bis(cyclometalated) ruthenium(II) complexes as active catalyst precursors: room-temperature alkene-alkyne coupling for 1,3-diene synthesis. AB - Described is the development of a new class of bis(cyclometalated) ruthenium(II) catalyst precursors for C-C coupling reactions between alkene and alkyne substrates. The complex [(cod)Ru(3-methallyl)2] reacts with benzophenone imine or benzophenone in a 1:2 ratio to form bis(cyclometalated) ruthenium(II) complexes (1). The imine-ligated complex 1 a promoted room-temperature coupling between acrylic esters and amides with internal alkynes to form 1,3-diene products. A proposed catalytic cycle involves C-C bond formation by oxidative cyclization, beta-hydride elimination, and C-H bond reductive elimination. This Ru(II)/Ru(IV) pathway is consistent with the observed catalytic reactivity of 1 a for mild tail to-tail methyl acrylate dimerization and for cyclobutene formation by [2+2] norbornene/alkyne cycloaddition. PMID- 24954300 TI - Unusual ultrasonographic findings after nerve trauma explained by Martin-Gruber anastomosis. PMID- 24954301 TI - Pathway-based toxicity: history, current approaches and liver fibrosis and steatosis as prototypes. AB - The Human Toxicology Project Consortium (HTPC) was created to accelerate implementation of the science and policies required to achieve a pathway-based foundation for toxicology as articulated in the 2007 National Research Council report, Toxicity Testing in the 21st Century: a Vision and a Strategy. The HTPC held a workshop, "Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action," in January, 2013, in Baltimore, MD, to further the science of pathway-based approaches to liver toxicity. This review was initiated as a thought-starter for this workshop and has since been updated to include insights from the workshop and other activities occurring in 2013. The report of the workshop has been published elsewhere in this journal (Willett et al., 2014). PMID- 24954305 TI - Morphology-tunable synthesis of ZnO nanoforest and its photoelectrochemical performance. AB - Understanding and manipulating synthesis reactions and crystal growth mechanisms are keys to designing and constructing the morphology and functional properties of advanced materials. Herein, the morphology-controlled synthesis of three dimensional (3D) ZnO nanoforests is reported via a facile hydrothermal route. Specifically, the respective and synergistic influence of polyethylenimine (PEI) and ammonia on tuning the architecture of ZnO nanoforests is systematically studied. An in-depth understanding of the mechanism of hydrothermal growth is vital for advancing this facile approach and incorporating special 3D nanostructures into versatile nanomanufacturing. More importantly, its unique architectural characteristics endow the willow-like ZnO nanoforest with prominent photoelectrochemical water splitting performance, including small charge transfer resistance, long photoelectron lifetime, a high photocurrent density of 0.919 mA cm(-2) at +1.2 V (vs. Ag/AgCl), and more important, a high photoconversion efficiency of 0.299% at 0.89 V (vs. RHE), which leads the realm of homogeneous ZnO nanostructures. In all, it is expected that this work will open up an unprecedented avenue to govern desirable 3D ZnO nanostructures and broaden the application potentials of 3D nanotechnology. PMID- 24954303 TI - Changes in circulating leptin levels during acute stress and associations with craving in abstinent smokers: a preliminary investigation. AB - Recent research suggests a role for the appetite hormone leptin in cigarette smoking. This study examined patterns of change in leptin in response to stress and associations with craving during the initial phase of a quit attempt. Thirty six smokers (average age+/-SEM, 33.4+/-2.4) interested in smoking cessation set a quit day and were required to be abstinent for 24h. After, they completed a laboratory session including public speaking and cognitive challenges, and attended 4 weekly post-cessation assessments. Blood samples and self-report measures were collected throughout the laboratory session. The results indicated that leptin levels significantly increased following exposure to acute stress. We also found positive correlations between leptin and craving for cigarettes. No differences were observed in leptin levels between smokers who maintained abstinence for 4 weeks and those who relapsed during this period. These findings suggest that leptin levels may change in response to stress and that leptin could be a useful marker of craving for smoking. PMID- 24954302 TI - Population variation in neuroendocrine activity is associated with behavioral inhibition and hemispheric brain structure in young rhesus monkeys. AB - Population variation in hypothalamic-pituitary-adrenal (HPA) activity and reactivity was assessed in a healthy sample of 48 juvenile rhesus monkeys. Cluster analysis of the HPA profiles revealed four distinct neuroendocrine phenotypes based on six indices of HPA functioning. Behavioral reactivity was also evaluated in response to novel stimuli, and revealed marked differences between animals in the highest- and lowest-cortisol clusters. Specifically, animals in the high-cortisol cluster showed larger stress-induced cortisol responses and blunted feedback sensitivity to dexamethasone. They were also emotionally reactive, displayed more aggressive behaviors, and were less likely to approach novel objects. In contrast, monkeys in the low-cortisol cluster were more likely to approach and explore novel objects. Representative animals with high or low cortisol profiles were scanned with Magnetic Resonance Imaging to evaluate structural differences in global and regional gray matter (GM) and white matter (WM) volumes. Monkeys with higher cortisol reactivity evinced less hemispheric brain asymmetry, due to decreased GM in the right hemisphere. Stress reactivity was inversely related to global GM and positively related to total cerebrospinal fluid volume. This inverse relationship was also observed in several stress-sensitive regions, including prefrontal and frontal cortices. Our study demonstrates that population variation in pituitary-adrenal activity is related to behavioral disposition and cerebral structure in this nonhuman primate species. PMID- 24954306 TI - Diversity of endophytic bacteria in Lolium perenne and their potential to degrade petroleum hydrocarbons and promote plant growth. AB - The aim of this study was to assess the ability of twenty-nine endophytic bacteria isolated from the tissues of ryegrass (Lolium perenne L.) to promote plant growth and the degradation of hydrocarbon. Most of the isolates belonged to the genus Pseudomonas and showed multiple plant growth-promoting abilities. All of the bacteria that were tested exhibited the ability to produce indole-3-acetic acid and were sensitive to streptomycin. These strains were capable of phosphate solubilization (62%), cellulolytic enzyme production (62%), a capacity for motility (55%) as well as for the production of siderophore (45%), ammonium (41%) and hydrogen cyanide (38%). Only five endophytes had the emulsification ability that results from the production of biosurfactants. The 1-aminocyclopropane-1 carboxylate deaminase (ACCD) gene (acdS) was found in ten strains. These bacteria exhibited ACCD activities in the range from 1.8 to 56.6 MUmol of alpha ketobutyrate mg(-1)h(-1), which suggests that these strains may be able to modulate ethylene levels and enhance plant growth. The potential for hydrocarbon degradation was assessed by PCR amplification on the following genes: alkH, alkB, C23O, P450 and pah. The thirteen strains that were tested had the P450 gene but the alkH and pah genes were found only in the Rhodococcus fascians strain (L11). Four endophytic bacteria belonging to Microbacterium sp. and Rhodococcus sp. (L7, S12, S23, S25) showed positive results for the alkB gene. PMID- 24954304 TI - Serum free thyroxine levels are positively associated with arterial stiffness in the SardiNIA study. AB - OBJECTIVE: Thyroid dysfunction may accelerate atherosclerosis. Aortic pulse wave velocity (PWV) is an early index of arterial stiffness and an important risk factor for cardiovascular disease and might therefore be linked to changes in thyroid activity. We investigated the relationship between thyroid function and carotid-femoral PWV, as an index of arterial stiffness. DESIGN: Cross-sectional cohort study. PATIENTS: Participants from the SardiNIA study. Those being treated for thyroid diseases were excluded, yielding a sample of 5875 aged 14-102. MEASUREMENTS: Clinical parameters, blood tests including serum TSH and serum FT4, and carotid-femoral PWV were measured. RESULTS: After adjusting for confounders, a direct and linear association between FT4 and PWV was shown (multiple regression analysis). The model containing age, mean blood pressure, body mass index, heart rate, FT4, hypertension, diabetes and dyslipidaemia accounted for 55% of the variation in PWV. CONCLUSIONS: Like several other known risk factors, serum FT4 levels are associated with carotid-femoral PWV, suggesting that high FT4 levels have a detrimental effect on aortic stiffness and may contribute to ageing process of the vascular system. This finding may help to understand the pathogenesis of cardiovascular disease and contribute to improve prevention therapy. PMID- 24954307 TI - The effect of celastrol, a triterpene with antitumorigenic activity, on conformational and functional aspects of the human 90kDa heat shock protein Hsp90alpha, a chaperone implicated in the stabilization of the tumor phenotype. AB - BACKGROUND: Hsp90 is a molecular chaperone essential for cell viability in eukaryotes that is associated with the maturation of proteins involved in important cell functions and implicated in the stabilization of the tumor phenotype of various cancers, making this chaperone a notably interesting therapeutic target. Celastrol is a plant-derived pentacyclic triterpenoid compound with potent antioxidant, anti-inflammatory and anticancer activities; however, celastrol's action mode is still elusive. RESULTS: In this work, we investigated the effect of celastrol on the conformational and functional aspects of Hsp90alpha. Interestingly, celastrol appeared to target Hsp90alpha directly as the compound induced the oligomerization of the chaperone via the C-terminal domain as demonstrated by experiments using a deletion mutant. The nature of the oligomers was investigated by biophysical tools demonstrating that a two-fold excess of celastrol induced the formation of a decameric Hsp90alpha bound throughout the C-terminal domain. When bound, celastrol destabilized the C terminal domain. Surprisingly, standard chaperone functional investigations demonstrated that neither the in vitro chaperone activity of protecting against aggregation nor the ability to bind a TPR co-chaperone, which binds to the C terminus of Hsp90alpha, were affected by celastrol. CONCLUSION: Celastrol interferes with specific biological functions of Hsp90alpha. Our results suggest a model in which celastrol binds directly to the C-terminal domain of Hsp90alpha causing oligomerization. However, the ability to protect against protein aggregation (supported by our results) and to bind to TPR co-chaperones are not affected by celastrol. Therefore celastrol may act primarily by inducing specific oligomerization that affects some, but not all, of the functions of Hsp90alpha. GENERAL SIGNIFICANCE: To the best of our knowledge, this study is the first work to use multiple probes to investigate the effect that celastrol has on the stability and oligomerization of Hsp90alpha and on the binding of this chaperone to Tom70. This work provides a novel mechanism by which celastrol binds Hsp90alpha. PMID- 24954308 TI - Picosecond dynamics in haemoglobin from different species: a quasielastic neutron scattering study. AB - BACKGROUND: Dynamics in haemoglobin from platypus (Ornithorhynchus anatinus), chicken (Gallus gallus domesticus) and saltwater crocodile (Crocodylus porosus) were measured to investigate response of conformational motions on the picosecond time scale to naturally occurring variations in the amino acid sequence of structurally identical proteins. METHODS: Protein dynamics was measured using incoherent quasielastic neutron scattering. The quasielastic broadening was interpreted first with a simple single Lorentzian approach and then by using the Kneller-Volino Brownian dynamics model. RESULTS: Mean square displacements of conformational motions, diffusion coefficients of internal dynamics and residence times for jump-diffusion between sites and corresponding effective force constants (resilience) and activation energies were determined from the data. CONCLUSIONS: Modifications of the physicochemical properties caused by mutations of the amino acids were found to have a significant impact on protein dynamics. Activation energies of local side chain dynamics were found to be similar between the different proteins being close to the energy, which is required for the rupture of single hydrogen bond in a protein. GENERAL SIGNIFICANCE: The measured dynamic quantities showed significant and systematic variations between the investigated species, suggesting that they are the signature of an evolutionary adaptation process stimulated by the different physiological environments of the respective protein. PMID- 24954309 TI - Are root letters compulsory for lexical access in Semitic languages? The case of masked form-priming in Arabic. AB - Do Semitic and Indo-European languages differ at a qualitative level? Recently, it has been claimed that lexical space in Semitic languages (e.g., Hebrew, Arabic) is mainly determined by morphological constraints, while lexical space in Indo-European languages is mainly determined by orthographic constraints (Frost, Kugler, Deutsch, & Forster, 2005). One of the key findings supporting the qualitative difference between Semitic and Indo-European languages is the absence of masked form priming in Hebrew/Arabic with productive words. Here we examined whether masked form priming occurs in Arabic words when one of the letters from the productive root is replaced in the prime stimulus by another letter. Results showed a significant masked form priming effect with the lexical decision task in three experiments (including yes/no, go/no-go, and sandwich priming), to a similar degree to that reported in previous research with Indo-European languages. These data support the view that the processing of word forms in Semitic vs. Indo-European languages differs more at a quantitative than at a qualitative level. PMID- 24954310 TI - Molecular approach to allergy diagnosis and therapy. AB - Presently, allergy diagnosis and therapy procedures are undergoing a transition phase in which allergen extracts are being step-by-step replaced by molecule based products. The new developments will allow clinicians to obtain detailed information on sensitization patterns, more accurate interpretation of allergic symptoms, and thus improved patients' management. In this respect, recombinant technology has been applied to develop this new generation of molecule-based allergy products. The use of recombinant allergens allows full validation of identity, quantity, homogeneity, structure, aggregation, solubility, stability, IgE-binding and the biologic potency of the products. In contrast, such parameters are extremely difficult to assay and standardize for extract-based products. In addition to the possibility of bulk production of wild type molecules for diagnostic purposes, recombinant technology opened the possibility of developing safer and more efficacious products for allergy therapy. A number of molecule-based hypoallergenic preparations have already been successfully evaluated in clinical trials, bringing forward the next generation of allergy vaccines. In this contribution, we review the latest developments in allergen characterization, molecule-based allergy diagnosis, and the application of recombinant allergens in therapeutic setups. A comprehensive overview of clinical trials using recombinant allergens as well as synthetic peptides is presented. PMID- 24954311 TI - Development and application of chronic disease risk prediction models. AB - Currently, non-communicable chronic diseases are a major cause of morbidity and mortality worldwide, and a large proportion of chronic diseases are preventable through risk factor management. However, the prevention efficacy at the individual level is not yet satisfactory. Chronic disease prediction models have been developed to assist physicians and individuals in clinical decision-making. A chronic disease prediction model assesses multiple risk factors together and estimates an absolute disease risk for the individual. Accurate prediction of an individual's future risk for a certain disease enables the comparison of benefits and risks of treatment, the costs of alternative prevention strategies, and selection of the most efficient strategy for the individual. A large number of chronic disease prediction models, especially targeting cardiovascular diseases and cancers, have been suggested, and some of them have been adopted in the clinical practice guidelines and recommendations of many countries. Although few chronic disease prediction tools have been suggested in the Korean population, their clinical utility is not as high as expected. This article reviews methodologies that are commonly used for developing and evaluating a chronic disease prediction model and discusses the current status of chronic disease prediction in Korea. PMID- 24954313 TI - Can ultrasound be as a surrogate marker for diagnosing a papillary thyroid cancer? Comparison with BRAF mutation analysis. AB - PURPOSE: We investigated the merit of ultrasound (US) features and BRAF(V600E) mutation as an additional study of cytology and compared the diagnostic performances of cytology alone, cytology with US correlation, cytology with BRAFV600E mutation, and a combination of cytology, US, and BRAFV600E mutation all together. MATERIALS AND METHODS: This study included 185 patients (mean age, 48.4 years; range 20-77 years) with 191 thyroid nodules who underwent US-guided fine needle aspiration (FNA) with an additional BRAFV600E mutation test. Three radiologists highly experienced in thyroid imaging retrospectively reviewed US images and classified each nodule into two categories (positive for malignancy or negative for malignancy). Interobserver variability (IOV) of US assessment between the three readers was estimated using the generalized kappa statistic of Landis and Koch. We also calculated the diagnostic performances of these studies. RESULTS: There were 131 cases of malignancy (131/191, 68.6%) and 60 cases of benign nodules (60/191, 31.4%). In terms of IOV of US assessment, the generalized kappa value was 0.242, indicating fair agreement was reached. The combination of cytology with BRAFV600E showed higher specificity (100%) and positive predictive value (PPV) (100%) compared to the combination of cytology, BRAFV600E, and US (specificity 28.3%, 66.7%, 68.3%; PPV 74.6%, 86.6%, 86.8%, respectively; p<0.001). However, cytology with BRAFV600E showed lower sensitivity (84.7%) than cytology with BRAFV600E and US (96.2%, 98.5%, 95.4%, respectively; p<0.001). CONCLUSION: Considering the diagnostic performance and low reproducibility of US, the combination of FNA with BRAFV600E is the most reliable and objective method for diagnosing thyroid malignancy. PMID- 24954312 TI - Insulin receptor expression in clear cell renal cell carcinoma and its relation to prognosis. AB - PURPOSE: Both insulin and insulin-like growth factor (IGF)-1 signaling are key regulators of energy metabolism, cellular growth, proliferation, and survival. The IGF-1 receptor (IGF-1R) is overexpressed in most types of human cancers including renal cell carcinoma (RCC) with poor prognosis. Insulin receptor (IR) shares downstream effectors with IGF-1R; however, the expression and function of IR in the tumorigenesis of renal cancer remains elusive. Therefore, we examined the expression of IR and its prognostic significance in clear cell RCC (CCRCC). MATERIALS AND METHODS: Immunohistochemical staining for IR was performed on 126 formalin-fixed paraffin-embedded CCRCC tissue samples. Eight of these cases were utilized for western blot analysis. The results were compared with various clinico-pathologic parameters of CCRCC and patient survival. RESULTS: IR was expressed in the nuclei of CCRCC tumor cells in 109 cases (87.9%). Higher IR expression was significantly correlated with the presence of cystic change, lower Fuhrman nuclear grade, lower pathologic T stage, and lower TNM stage, although it wasn't significantly related to diabetes status and patient survival. Western blot analyses supported the results of the immunohistochemistry studies. CONCLUSION: IR expression in CCRCC may be associated with favorable prognostic factors. PMID- 24954314 TI - Pathologic spectrum of lymphocytic infiltration and recurrence of papillary thyroid carcinoma. AB - PURPOSE: The aim of this study was to investigate the prognosis of papillary thyroid carcinoma (PTC) patients according to different pathologic grades of lymphocytic thyroiditis (LT). MATERIALS AND METHODS: This study included 144 PTC patients who underwent total thyroidectomy with radioactive iodine remnant ablation therapy. Pathologic grades of LT were separated at two points, chronic lymphocytic thyroiditis (CLT) and Hashimoto thyroiditis (HT). Patients were divided into two groupings according to the presence of the diseases (Grouping 1; patients with CLT or HT and without CLT or HT, Grouping 2; patients with HT and without HT). The groupings were compared according to recurrence, clinicopathologic and ultrasound (US) characteristics, and disease free survival. RESULTS: Of 144 patients, 41 had CLT and 19 had HT. There were 10 patients (6.9%) with tumor recurrence. In both groupings, the presence of calcification was more frequently associated with patients with LT (p=0.041 and 0.047, respectively). In Grouping 2, the mean age at diagnosis was older in patients without HT compared to patients with HT (p=0.032). On multivariate analysis, the presence of LT was not an independent predictor of recurrence in both groupings. For both groupings, pathologic tumor size and taller than wide shape on US were independent predictors of recurrence. The presence of LT in PTC patients did not affect recurrence. CONCLUSION: There was no relationship between PTC prognosis and different grades of LT. Pathologic tumor size and taller than wide shape on ultrasound were independent predictors of PTC recurrence regardless of concurrent LT. PMID- 24954316 TI - The effect of ablation for paroxysmal atrial fibrillation on left atrial volume and function: a one-year follow-up study. AB - PURPOSE: The effect of radiofrequency catheter ablation (RFCA) on left atrial (LA) volume and function in patients with paroxysmal atrial fibrillation (PAF) has not been extensively studied. The aim of this study was to evaluate the long term impact of RFCA on LA volume and function in patients with PAF. MATERIALS AND METHODS: A total of 90 patients with drug-refractory PAF who had sinus rhythm on the initial echocardiogram were examined at baseline, 3 months and 1 year after ablation. We measured LA volume index, LA ejection fraction (LAEF; maximal minimal LA volume/maximal LA volume), and LA active emptying fraction (LAAEF; mid diastolic-minimal LA volume/mid-diastolic LA volume). RESULTS: After 12+/-1 months, 78 patients returned, and 61 patients (78%) had sinus rhythm. After 3 months, the LA maximal volume indices decreased (from 33+/-13 to 28+/-12 mL/m2; p<0.001). But, LAEF and LAAEF also decreased (from 48+/-13 to 39+/-12; p<0.001, from 27+/-13 to 19+/-11; p<0.001). After 1 year, LA volumes, LAEF, and LAAEF remained similar at 3 months. In patients without atrial fibrillation (AF) recurrence, LAEF and LAAEF decreased after 3 months (from 50+/-12 to 40+/-11; p<0.001, from 29+/-13 to 22+/-11; p<0.001) and did not change after 1 year. However, in patients with AF recurrence, those who did not have decreased levels after 3 months had significantly decreased after 1 year (from 43+/-14 to 34+/-11; p=0.026, from 22+/-12 to 15+/-10; p=0.012). CONCLUSION: Successful RFCA of PAF decreased LA volume and function at 3 months. At one year, LA volume and function was remained unchanged in successfully ablated patients whereas LA function in patients with AF recurrence worsened. PMID- 24954315 TI - A novel synthetic compound 3-amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione (KR22332) exerts a radioprotective effect via the inhibition of mitochondrial dysfunction and generation of reactive oxygen species. AB - PURPOSE: Acute side effects of radiation such as oral mucositis are observed in most patients. Although several potential radioprotective agents have been proposed, no effective agent has yet been identified. In this study, we investigated the effectiveness of synthetic compound 3-amino-3-(4-fluoro-phenyl) 1H-quinoline-2,4-dione (KR22332) as a radioprotective agent. MATERIALS AND METHODS: Cell viability, apoptosis, the generation of reactive oxygen species (ROS), mitochondrial membrane potential changes, and changes in apoptosis-related signaling were examined in human keratinocyte (HaCaT). RESULTS: KR22332 inhibited irradiation-induced apoptosis and intracellular ROS generation, and it markedly attenuated the changes in mitochondrial membrane potential in primary human keratinocytes. Moreover, KR22332 significantly reduced the protein expression levels of ataxia telangiectasia mutated protein, p53, and tumor necrosis factor (TNF)-alpha compared to significant increases observed after radiation treatment. CONCLUSION: KR22332 significantly inhibited radiation-induced apoptosis in human keratinocytes in vitro, indicating that it might be a safe and effective treatment for the prevention of radiation-induced mucositis. PMID- 24954317 TI - Coronary flow reserve in the remote myocardium predicts left ventricular remodeling following acute myocardial infarction. AB - PURPOSE: Coronary flow reserve (CFR) in the non-infarcted myocardium is often impaired following acute myocardial infarction (AMI). However, the clinical significance of CFR in the non-infarcted myocardium is not fully understood. The objective of the present study was to assess whether a relationship exists between CFR and left ventricular remodeling following AMI. MATERIALS AND METHODS: We enrolled 18 consecutive patients undergoing coronary intervention. Heart function was analyzed using real-time myocardial contrast echocardiography at one week and six months after coronary angioplasty. Ten subjects were enrolled as the control group and were examined using the same method at the same time to assess CFR. Cardiac troponin I (cTnI) levels were routinely analyzed to estimate peak concentration. RESULTS: CFR was 1.55+/-0.11 in the infarcted zone and 2.05+/-0.31 in the remote zone (p<0.01) at one week following AMI. According to CFR values in the remote zone, all patients were divided into two groups: Group I (CFR <2.05) and Group II (CFR >2.05). The levels of cTnI were higher in Group I compared to Group II on admission (36.40 vs. 21.38, p<0.05). Furthermore, left ventricular end diastolic volume was higher in Group I compared to Group II at six months following coronary angioplasty. CONCLUSION: Microvascular dysfunction is commonly observed in the remote myocardium. The CFR value accurately predicts adverse ventricular remodeling following AMI. PMID- 24954318 TI - Increased serum cathepsin K in patients with coronary artery disease. AB - PURPOSE: Cathepsin K is a potent collagenase implicated in human and animal atherosclerosis-based vascular remodeling. This study examined the hypothesis that serum CatK is associated with the prevalence of coronary artery disease (CAD). MATERIALS AND METHODS: Between January 2011 and December 2012, 256 consecutive subjects were enrolled from among patients who underwent coronary angiography and percutaneous coronary intervention treatment. A total of 129 age matched subjects served as controls. RESULTS: The subjects' serum cathepsin K and high sensitive C-reactive protein (hs-CRP) and high-density lipoprotein cholesterol were measured. The patients with CAD had significantly higher serum cathepsin K levels compared to the controls (130.8+/-25.5 ng/mL vs. 86.9+/-25.5 ng/mL, p<0.001), and the patients with acute coronary syndrome had significantly higher serum cathepsin K levels compared to those with stable angina pectoris (137.1+/-26.9 ng/mL vs. 102.6+/-12.9 ng/mL, p<0.001). A linear regression analysis showed that overall, the cathepsin K levels were inversely correlated with the high-density lipoprotein levels (r=-0.29, p<0.01) and positively with hs CRP levels (r=0.32, p<0.01). Multiple logistic regression analyses shows that cathepsin K levels were independent predictors of CAD (odds ratio, 1.76; 95% confidence interval, 1.12 to 1.56; p<0.01). CONCLUSION: These data indicated that elevated levels of cathepsin K are closely associated with the presence of CAD and that circulating cathepsin K serves a useful biomarker for CAD. PMID- 24954320 TI - Early repolarization and myocardial scar predict poorest prognosis in patients with coronary artery disease. AB - PURPOSE: Recent studies show positive association of early repolarization (ER) with the risk of life-threatening arrhythmias in patients with coronary artery disease (CAD). This study was to investigate the relationships of ER with myocardial scarring and prognosis in patients with CAD. MATERIALS AND METHODS: Of 570 consecutive CAD patients, patients with and without ER were assigned to ER group (n=139) and no ER group (n=431), respectively. Myocardial scar was evaluated using cardiac single-photon emission computed tomography. RESULTS: ER group had previous history of myocardial infarction (33% vs. 15%, p<0.001) and lower left ventricular ejection fraction (57+/-13% vs. 62+/-13%, p<0.001) more frequently than no-ER group. While 74 (53%) patients in ER group had myocardial scar, only 121 (28%) patients had in no-ER group (p<0.001). During follow up, 9 (7%) and 4 (0.9%) patients had cardiac events in ER and no-ER group, respectively (p=0.001). All patients with cardiac events had ER in inferior leads and horizontal/descending ST-segment. Patients with both ER in inferior leads and horizontal/descending ST variant and scar had an increased adjusted hazard ratio of cardiac events (hazard ratio 16.0; 95% confidence interval: 4.1 to 55.8; p<0.001). CONCLUSION: ER in inferior leads with a horizontal/descending ST variant was associated with increased risk of cardiac events. These findings suggest that ER in patients with CAD may be related to myocardial scar rather than pure ion channel problem. PMID- 24954321 TI - Safety and cost-effectiveness of bridge therapies for invasive dental procedures in patients with mechanical heart valves. AB - PURPOSE: Bridge anticoagulation therapy is mostly utilized in patients with mechanical heart valves (MHV) receiving warfarin therapy during invasive dental procedures because of the risk of excessive bleeding related to highly vascular supporting dental structures. Bridge therapy using low molecular weight heparin may be an attractive option for invasive dental procedures; however, its safety and cost-effectiveness compared with unfractionated heparin (UFH) is uncertain. MATERIALS AND METHODS: This study investigated the safety and cost-effectiveness of enoxaparin in comparison to UFH for bridge therapy in 165 consecutive patients (57+/-11 years, 35% men) with MHV who underwent invasive dental procedures. RESULTS: This study included 75 patients treated with UFH-based bridge therapy (45%) and 90 patients treated with enoxaparin-based bridge therapy (55%). The bleeding risk of dental procedures and the incidence of clinical adverse outcomes were not significantly different between the UFH group and the enoxaparin group. However, total medical costs were significantly lower in the enoxaparin group than in the UFH group (p<0.001). After multivariate adjustment, old age (>=65 years) was significantly associated with an increased risk of total bleeding independent of bridging methods (odds ratio, 2.51; 95% confidence interval, 1.15 5.48; p=0.022). Enoxaparin-based bridge therapy (beta=-0.694, p<0.001) and major bleeding (beta=0.296, p=0.045) were significantly associated with the medical costs within 30 days after dental procedures. CONCLUSION: Considering the benefit of enoxaparin in cost-effectiveness, enoxaparin may be more efficient than UFH for bridge therapy in patients with MHV who required invasive dental procedures. PMID- 24954319 TI - Clinical outcomes of patients with acute myocardial infarction complicated by severe refractory cardiogenic shock assisted with percutaneous cardiopulmonary support. AB - PURPOSE: Limited data are available on the role of percutaneous cardiopulmonary support (PCPS) for the treatment of acute myocardial infarction (AMI) patients with cardiogenic shock. We investigated the clinical outcomes and predictors of in-hospital mortality after PCPS in patients with AMI complicated by severe refractory cardiogenic shock. MATERIALS AND METHODS: From January 2004 to December 2011, we analyzed data from 96 consecutive AMI patients with cardiogenic shock assisted by a PCPS system. The primary outcome was in-hospital mortality. The predictors of in-hospital mortality were determined by a Cox proportional hazards model. RESULTS: In-hospital mortality occurred in 51 (53.1%) patients and 58 (60.4%) patients were able to be weaned from PCPS. Cardiopulmonary resuscitation (CPR) was performed in 61 (63.5%) patients before PCPS initiation. On multivariate analysis, age>=67 years [adjusted hazard ratio (HR), 4.74; 95% confidence interval (CI), 2.27-9.93; p<0.001], CPR (adjusted HR, 2.32; 95% CI, 1.11-4.85; p=0.03), lactate clearance for 48 hours<70% (adjusted HR, 2.50; 95% CI, 1.04-6.05; p=0.041), and unsuccessful revascularization (adjusted HR, 3.57; 95% CI, 1.85-6.90; p=0.002) were independent predictors of in-hospital mortality after PCPS in patients with AMI complicated by cardiogenic shock. CONCLUSION: In spite of PCPS management, AMI patients complicated by severe refractory cardiogenic shock demonstrated high mortality. Older age, CPR, lower lactate clearance for 48 hours, and unsuccessful revascularization were independent predictors of in-hospital mortality. PMID- 24954322 TI - Optical coherence tomographic observation of morphological features of neointimal tissue after drug-eluting stent implantation. AB - PURPOSE: The impacts of different time courses and the degree of neointimal growth on neointimal morphology have not yet been sufficiently investigated. Therefore, we evaluated the morphological features of neointimal tissue after drug-eluting stent (DES) implantation using optical coherence tomography (OCT). MATERIALS AND METHODS: The morphological features of neointimal tissue in stented segments with a maximal percentage of cross-sectional area (CSA) stenosis of neointima were evaluated in 507 DES-treated lesions with >100 MUm mean neointimal thickness on follow-up OCT. Neointimal tissue was categorized as homogeneous, heterogeneous, layered, or neoatherosclerotic. RESULTS: In lesions with <50% of neointimal CSA stenosis, homogeneous neointima (68.2%) was predominant, followed by heterogeneous neointima (14.1%) and layered neointima (14.1%). In lesions with >=50% of neointimal CSA stenosis, layered neointima was most frequently observed (68.3%), followed by neoatherosclerotic neointima (25.2%). In subgroup analysis of lesions with >=50% of neointimal CSA stenosis, 89.5% of the lesions with a stent age<30 months were layered neointima, while 62.3% of the lesions with a stent age>=30 months were neoatherosclerotic neointima. CONCLUSION: This study suggests that the OCT-detected morphology of DES neointimal tissue was different according to the follow-up time course and degree of neointimal hyperplasia. PMID- 24954323 TI - Prognostic indicators for acute liver failure development and mortality in patients with hepatitis A: consecutive case analysis. AB - PURPOSE: Due to the seroepidemiological shift in hepatitis A (HA), its severity, mortality, and complications have increased in recent years. Thus, the aim of this study was to identify predictive factors associated with poor prognosis among patients with HA. MATERIALS AND METHODS: A total of 304 patients with HA admitted to our institution between July 2009 and June 2011 were enrolled consecutively. Patients with complications defined as acute liver failure (ALF) were evaluated, and mortality was defined as death or liver transplantation. RESULTS: The mean age of patients (204 males, 100 females) was 32 years. Eighteen (5.9%) patients had progressed to ALF. Of the patients with ALF, 10 patients (3.3%) showed spontaneous survival while 8 (2.6%) died or underwent liver transplantation. Multivariate regression analysis showed that Model for End-Stage Liver Disease (MELD) and systemic inflammatory response syndrome (SIRS) scores were significant predictive factors of ALF. Based on receiver operating characteristics (ROC) analysis, a MELD>=23.5 was significantly more predictive than a SIRS score>=3 (area under the ROC: 0.940 vs. 0.742, respectively). In addition, of patients with a MELD score>=23.5, King's College Hospital criteria (KCC) and SIRS scores were predictive factors associated with death/transplantation in multivariate analysis. CONCLUSION: MELD and SIRS scores>=23.5 and >=3, respectively, appeared to be related to ALF development. In addition, KCC and SIRS scores>=3 were valuable in predicting mortality of patients with a MELD>=23.5. PMID- 24954325 TI - Comparison of methicillin-resistant Staphylococcus aureus community-acquired and healthcare-associated pneumonia. AB - PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) is recognized as an important cause of not only healthcare-associated pneumonia (HCAP) but also community-acquired pneumonia (CAP). We determined the impact of MRSA on differences in clinical characteristics, courses, and outcomes between CAP and HCAP. MATERIALS AND METHODS: We conducted a retrospective observational study on 78 adult patients admitted with MRSA pneumonia at a university-affiliated tertiary hospital between January 2008 and December 2011. We compared baseline characteristics, chest radiographs, treatment outcomes, and drug resistance patterns between the CAP and HCAP groups. RESULTS: Of the 78 patients with MRSA pneumonia, 57 (73.1%) were HCAP and 21 (26.9%) were CAP. MRSA infection history in the previous year (29.8% vs. 14.3%, p=0.244) tended to be more common in HCAP than in CAP. Despite similar Pneumonia Severity Index scores (151 in CAP vs. 142 in HCAP), intubation rates (38.1% vs. 17.5%; p=0.072) and intensive care unit admission (42.9% vs. 22.8%; p=0.095) tended to be higher in the CAP group, while 28-day mortality was higher in the HCAP group (14.3% vs. 26.3%; p=0.368), although without statistical significance. All patients showed sensitivity to vancomycin and linezolid; meanwhile, HCAP patients showed greater resistance to gentamicin than CAP patients (58.3% vs. 16.6%; p=0.037). The median total hospital charges were 6899 American dollars for CAP and 5715 American dollars for HCAP (p=0.161). CONCLUSION: MRSA pneumonia showed significantly differences in baseline characteristics, chest radiographs, treatment outcomes, and medical expenses between HCAP and CAP groups. PMID- 24954324 TI - Correlation between soluble triggering receptor expressed on myeloid cells-1 and endoscopic activity in intestinal Behcet's disease. AB - PURPOSE: The serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) have recently been shown to be correlated highly with disease activity in patients with intestinal Behcet's disease (BD). However, it remains unclear whether sTREM-1 levels reflect endoscopic activity in intestinal BD. This study aimed to evaluate the correlation of sTREM-1 levels with endoscopic activity in intestinal BD. MATERIALS AND METHODS: A total of 84 patients with intestinal BD were enrolled. Endoscopic activity was compared with sTREM-1 levels as well as other laboratory findings, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). RESULTS: sTREM-1 levels were significantly increased in intestinal BD patients compared with controls (37.98+/-27.09 pg/mL vs. 16.65+/-7.76 pg/mL, p=0.002), however, there was no difference between endoscopically quiescent and active diseases (43.53+/-24.95 pg/mL vs. 42.22+/ 32.68 pg/mL, p=0.819). Moreover, serum sTREM-1 levels did not differ in terms of number, shape, depth, size, margin, or type of ulcer in patients with intestinal BD. However, mean ESR and CRP levels in patients with active disease were significantly higher than those in patients with quiescent disease (p=0.001, p<0.001, respectively). In addition, endoscopic activity scores for intestinal BD were correlated significantly with both CRP levels (gamma=0.329) and ESR (gamma=0.298), but not with sTREM-1 levels (gamma=0.166). CONCLUSION: Unlike CRP levels and ESR, serum sTREM-1 levels were not correlated with endoscopic activity in patients with intestinal BD. PMID- 24954326 TI - Usefulness of the endotoxin activity assay to evaluate the degree of lung injury. AB - PURPOSE: It has been reported that the Pulse Contour Cardiac Output (PiCCO) is very useful mainly in the field of intensive care and treatment to grasp the pathophysiological conditions of pulmonary edema because of its capability of obtaining data such as Pulmonary Vascular Permeability Index (PVPI) and Extra Vascular Lung Water (EVLW). Furthermore, a high degree of usability of various markers has been reported for better understanding of the pathological conditions in cases with septicemia. MATERIALS AND METHODS: The correlation between the cardiorespiratory status based upon the PiCCO monitor (EVLW and PVPI) and inflammatory markers including C reactive protein, procalcitonin (PC), and Endotoxin Activity Assay (EAA) were evaluated in 11 severe cases that required treatment with a respirator in an intensive care unit. RESULTS: The EAA values were significantly higher in patients with abnormal EVLW at 0.46+/-0.20 compared to the normal EVLW group at 0.21+/-0.19 (p=0.0064). In a similar fashion, patients with abnormal PVPI values tended to have higher PC levels at 18.9+/-21.8 compared to normal PVPI cases at 2.4+/-2.2 (p=0.0676). On the other hand, PVPI was significantly higher in the abnormal EAA group at 3.55+/-0.48 in comparison with the normal EAA group at 1.99+/-0.68 (p=0.0029). The abnormal EAA group tended to have higher PVPI values than the normal EAA group. CONCLUSION: The EAA is a measurement method designed to estimate the activity of endotoxins in the whole blood. Our results suggest that the EAA value, which had the greatest correlation with lung disorders diagnosed by the PiCCO monitoring, reflects inflammatory reactions predominantly in the lungs. PMID- 24954327 TI - Clinical characteristics of asthma combined with COPD feature. AB - PURPOSE: In clinical practice, some patients with asthma show incompletely reversible airflow obstruction, resembling chronic obstructive pulmonary disease (COPD). The aim of this study was to analyze this overlap phenotype of asthma with COPD feature. MATERIALS AND METHODS: A total of 256 patients, over the age of 40 years or more with a diagnosis of asthma, based on either 1) positive response to bronchodilator: >200 mL forced expiratory volume in 1 s (FEV1) and >12% baseline or 2) positive methacholine or mannitol provocation test, were enrolled. Among the asthma patients, we defined the overlap group with incompletely reversible airflow obstruction [postbronchodilator FEV1/forced vital capacity (FVC)<70] at the initial time of admission and continuing airflow obstruction after at least 3 months follow up. We evaluated clinical features, serum eosinophil counts, serum total immunoglobulin (Ig) E with allergy skin prick test, spirometry, methacholine or mannitol provocation challenges and bronchodilator responses, based on their retrospective medical record data. All of the tests mentioned above were performed within one week. RESULTS: The study population was divided into two groups: asthma only (62%, n=159, postbronchodilator FEV1/FVC>=70) and overlap group (38%, n=97, postbronchodilator FEV1/FVC<70). The overlap group was older, and contained more males and a higher percentage of current or ex-smokers than the asthma only group. Significantly lower FEV1 and higher total lung capacity, functional residual capacity, and residual volume were observed in the overlap group. Finally, significantly lower serum eosinophil count and higher IgE were seen in the overlap group. CONCLUSION: Our results showed that the overlap phenotype was older, male asthmatic patients who have a higher lifetime smoking intensity, more atopy and generally worse lung function. PMID- 24954328 TI - Clinical factors associated with acquisition of resistance to levofloxacin in Stenotrophomonas maltophilia. AB - PURPOSE: Fluoroquinolones, rapidly gaining prominence in treatment of Stenotrophomonas maltophilia (SMP), are noted for their potency and tolerability. However, SMP may rapidly acquire resistance to fluoroquinolones. We evaluated associations of clinical factors with acquisition of levofloxacin resistance (LFr) in SMP. MATERIALS AND METHODS: Our retrospective cohort study was based on patient data collected between January 2008 and June 2010. Through screening of 1275 patients, we identified 122 patients with data for SMP antibiotic susceptibility testing in >=3 serial SMP isolates. RESULTS: We assigned the 122 patients to either the SS group (n=54) in which levofloxacin susceptibility was maintained or the SR group (n=31) in which susceptible SMP acquired resistance. In multivariate regression analysis, exposure to levofloxacin for more than 3 weeks [odds ratio (OR) 15.39, 95% confidential interval (CI) 3.08-76.93, p=0.001] and co-infection or co-colonization with Klebsiella pneumoniae resistant to levofloxacin (OR 4.85, 95% CI 1.16-20.24, p=0.030) were independently associated with LFr acquisition in SMP. CONCLUSION: Acquisition of LFr during serial sampling of SMP was related to the levofloxacin exposure. PMID- 24954329 TI - Evaluation of a chromogenic culture medium for the detection of Clostridium difficile. AB - PURPOSE: Clostridium difficile (C. difficile) is an important cause of nosocomial diarrhea. Diagnostic methods for detection of C. difficile infection (CDI) are shifting to molecular techniques, which are faster and more sensitive than conventional methods. Although recent advances in these methods have been made in terms of their cost-benefit, ease of use, and turnaround time, anaerobic culture remains an important method for detection of CDI. MATERIALS AND METHODS: In efforts to evaluate a novel chromogenic medium for the detection of C. difficile (chromID CD agar), 289 fecal specimens were analyzed using two other culture media of blood agar and cycloserine-cefoxitin-fructose-egg yolk agar while enzyme immunosorbent assay and polymerase chain reaction-based assay were used for toxin detection. RESULTS: ChromID showed the highest detection rate among the three culture media. Both positive rate and sensitivity were higher from chromID than other culture media. ChromID was better at detecting toxin producing C. difficile at 24 h and showed the highest detection rate at both 24 h and 48 h. CONCLUSION: Simultaneous use of toxin assay and anaerobic culture has been considered as the most accurate and sensitive diagnostic approach of CDI. Utilization of a more rapid and sensitive chromogenic medium will aid in the dianogsis of CDI. PMID- 24954331 TI - Resolution of ambiguous HLA genotyping in korean by multi-group-specific sequence based typing. AB - PURPOSE: To evaluate a multi-group-specific sequence-based typing (SBT) method for resolving ambiguous results from human leukocyte antigen (HLA) genotyping. MATERIALS AND METHODS: A total of 50 samples that showed ambiguous genotypes for at least two HLA loci from HLA-A, -B, -C and -DRB1 by the conventional SBT assay were evaluated using a new SBT test, the AVITA plus assay. The most likely HLA genotypes for the respective samples considering allele frequencies in Korean were concordant between the AVITA and conventional SBT assays. RESULTS: An average of 3.3 loci among the HLA-A, -B, -C and -DRB1 loci per sample gave results with two or more possible allele combinations with the conventional SBT, and 48 (96.0%) out of 50 showed reduced numbers of possible genotypes for at least one HLA locus with the AVITA. A total of 41, 43, 42, and 38 cases among the 50 samples showed ambiguous results for HLA-A, -B, -C, and -DRB1 typing by the conventional SBT, respectively. The average numbers of possible allele combinations for the respective four HLA loci were 8.2, 6.7, 5.9, and 3.2, and they were reduced to 1.5, 2.2, 4.4, and 1.8, respectively, by the AVITA. Ambiguity was resolved by the AVITA in 33 (80.5%), 31 (72.1%), 17 (40.5%) and 28 (73.7%) samples among the ambiguous cases from the conventional SBT for HLA-A, B, -C, and -DRB1 typing, respectively. CONCLUSION: The multi-group-specific SBT method considerably reduced the number of ambiguous results, and thus may be useful for accurate HLA typing in clinical laboratories. PMID- 24954330 TI - Production of egg yolk antibodies specific to house dust mite proteins. AB - PURPOSE: House dust mites (HDMs) are an important source of indoor allergens associated with asthma, rhinitis and atopic dermatitis. Chicken immunoglobulin (Ig) Y is known to be a good alternative to mice and rabbit antibody production. In this study, we produced IgYs specific to HDMs and investigated their IgE immunoreactivities. MATERIALS AND METHODS: Total IgYs were isolated from the yolks of White Leghorn hens immunized with either Dermatophagoides pteronyssinus or D. farinae protein extract. Control antibodies were separated from the yolks of immunized hens with phosphate buffered saline. IgYs specific to HDMs were analyzed using enzyme-linked immunosorbent assay and Western blotting analysis. RESULTS: The concentration of egg IgY specific to D. farinae in an immunized hen increased and the highest achieved was 661.3 ug/mg (per an egg) on day 47, compared with 760 ug/mg IgY specific to D. pteronyssinus on day 16. The D. pteronyssinus or D. farinae-specific IgY was detected by binding of each mite proteins, and their immunoreactivities were elevated dependent of the specific IgY concentration. CONCLUSION: IgY specific to HDMs may be a promising antibody for immunological diagnosis as well as identification of possible resistance relating to HDM allergy. PMID- 24954332 TI - Identification of pancreatic cancer-associated tumor antigen from HSP-enriched tumor lysate-pulsed human dendritic cells. AB - PURPOSE: Vaccine strategies utilizing dendritic cells (DCs) to elicit anti-tumor immunity are the subject of intense research. Although we have shown that DCs pulsed with heat-treated tumor lysate (HTL) induced more potent anti-tumor immunity than DCs pulsed with conventional tumor lysate (TL), the underlying molecular mechanism is unclear. In order to explore the molecular basis of this approach and to identify potential antigenic peptides from pancreatic cancer, we analyzed and compared the major histocompatibility complex (MHC) ligands derived from TL- and HTL-pulsed dendritic cells by mass spectrophotometry. MATERIALS AND METHODS: Human monocyte-derived dendritic cells were pulsed with TL or HTL prior to maturation induction. To delineate differences of MHC-bound peptide repertoire eluted from DCs pulsed with TL or HTL, nanoflow liquid chromatography electrospray ionization-tandem mass spectrometry (nLC-ESI-MS-MS) was employed. RESULTS: HTL, but not TL, significantly induced DC function, assessed by phenotypic maturation, allostimulation capacity and IFN-gamma secretion by stimulated allogeneic T cells. DCs pulsed with TL or HTL displayed pancreas or pancreatic cancer-related peptides in context of MHC class I and II molecules. Some of the identified peptides had not been previously reported as expressed in pancreatic cancer or cancer of other tissue types. CONCLUSION: Our partial lists of MHC-associated peptides revealed the differences between peptide profiles eluted from HTL-and TL-loaded DCs, implying that induced heat shock proteins in HTL chaperone tumor-derived peptides enhanced their delivery to DCs and promoted cross-presentation by DC. These findings may aid in identifying novel tumor antigens or biomarkers and in designing future vaccination strategies. PMID- 24954333 TI - Comparison of the body adiposity index to body mass index in Korean women. AB - PURPOSE: Obesity is a major public health issue and is associated with many metabolic abnormalities. Consequently, the assessment of obesity is very important. A new measurement, the body adiposity index (BAI), has recently been proposed to provide valid estimates of body fat percentages. The objective of this study was to compare the BAI and body mass index (BMI) as measurements of body adiposity and metabolic risk. MATERIALS AND METHODS: This was a cross sectional analysis performed on Korean women. The weight, height, and hip circumferences of 2950 women (mean age 25+/-5 years old, 18-39 years) were measured, and their BMI and BAI [hip circumference (cm)/height (m)1.5-18] values were calculated. Bioelectric impedance analysis was used to evaluate body fat content. Glucose tolerance status was assessed with a 75-g oral glucose tolerance test, and insulin sensitivity was estimated with the insulin sensitivity index. RESULTS: BMI was more significantly correlated with fat mass and fat percentage. Additionally, BMI was also more significantly associated with metabolic parameters, including fasting glucose, post-load 2-h glucose, fasting insulin, post-load 2-h insulin, triglycerides, and high density lipoprotein cholesterol than BAI. Receiver operating characteristic curve analysis revealed that BMI was a better tool for predicting body fat percentage than BAI. Insulin sensitivity and metabolic syndrome were more significantly associated with BMI than with BAI. CONCLUSION: In Korean women, the current BMI-based classifications for obesity might be superior to BAI-based measurements for determining obesity and predicting metabolic risk. PMID- 24954334 TI - Association between serum 25-hydroxyvitamin D level and insulin resistance in a rural population. AB - PURPOSE: A low serum 25-hydroxyvitamin D [25(OH)D] level in the blood has been correlated with an increased risk of diabetes mellitus; however, the association between serum 25(OH)D level and insulin resistance has not been established in a Korean rural population. The aim of this study was to investigate the independent association between serum 25(OH)D level and insulin resistance in rural Korean adults. MATERIALS AND METHODS: This study used data from the Korean Genome Epidemiology Study-Kangwha Study. In the 2011 study, 1200 adults completed health examinations. In an ancillary study, serum 25(OH)D level was measured in a subsample (n=813). After excluding those taking vitamin D supplements, a cross sectional analysis was carried out on 807 participants (324 men and 483 women) aged 40 to 89 years old. Measured from overnight fasting blood samples, glucose and insulin levels were used to calculate the homeostasis model assessment for insulin resistance (HOMA-IR). Measures of glucose, insulin, and HOMA-IR were log transformed for parametric tests. RESULTS: Serum 25(OH)D level was inversely associated with HOMA-IR (beta=-0.003, p=0.039) in a univariate analysis. However, the association was not significant after adjustment for sex and age (beta= 0.002, p=0.123) or after adjustment for sex, age, body mass index, smoking status, alcohol intake, and regular exercise (beta=-0.003, p=0.247). CONCLUSION: Our findings suggest that vitamin D is not independently associated with insulin resistance in Korean men and women. PMID- 24954337 TI - Knowledge on osteoporosis of prescriber according to level of medical institute. AB - PURPOSE: There are gaps between the treatment guideline and clinical practice of osteoporosis showing low compliance. Although attitude and knowledge of prescriber have been known to be associated with the low compliance in real clinical practice, no study has assessed the knowledge of prescriber regarding osteoporosis in accordance to the level of medical institution. We compared the knowledge on osteoporosis of general practitioners with that of practitioners in a tertiary referral hospital. MATERIALS AND METHODS: In May 2012, 40 general practitioners and 40 practitioners in a tertiary referral hospital were evaluated using a modified Facts on Osteoporosis Quiz. RESULTS: The level of knowledge of general practitioners was similar with that of practitioners in a tertiary referral hospital (p=0.386). And, both groups were lack of knowledge of effect of physical exercise. CONCLUSION: The level of knowledge on osteoporosis was not associated with the level of medical institute, and the effect of physical exercise should be stressed in an educational program on osteoporosis for practitioners. PMID- 24954335 TI - Efficacy and safety of sustained-release recombinant human growth hormone in Korean adults with growth hormone deficiency. AB - PURPOSE: The administration of recombinant human growth hormone in adults with growth hormone deficiency has been known to improve metabolic impairment and quality of life. Patients, however, have to tolerate daily injections of growth hormone. The efficacy, safety, and compliance of weekly administered sustained release recombinant human growth hormone (SR-rhGH, DeclageTM) supplement in patients with growth hormone deficiency were evaluated. MATERIALS AND METHODS: This trial is 12-week prospective, single-arm, open-label trial. Men and women aged >=20 years with diagnosed growth hormone deficiency (caused by pituitary tumor, trauma and other pituitary diseases) were eligible for this study. Each subject was given 2 mg (6 IU) of SR-rhGH once a week, subcutaneously for 12 weeks. Efficacy and safety at baseline and within 30 days after the 12th injection were assessed and compared. Score of Assessment of Growth Hormone Deficiency in Adults (AGHDA score) for quality of life and serum IGF-1 level. RESULTS: The IGF-1 level of 108.67+/-74.03 ng/mL was increased to 129.01+/-68.37 ng/mL (p=0.0111) and the AGHDA QoL score was decreased from 9.80+/-6.51 to 7.55+/ 5.76 (p<0.0001) at week 12 compared with those at baseline. Adverse events included pain, swelling, erythema, and warmth sensation at the administration site, but many adverse events gradually disappeared during the investigation. CONCLUSION: Weekly administered SR-rhGH for 12 weeks effectively increased IGF-1 level and improved the quality of life in patients with GH deficiency without serious adverse events. PMID- 24954336 TI - Prevalence of osteoporosis in the Korean population based on Korea National Health and Nutrition Examination Survey (KNHANES), 2008-2011. AB - PURPOSE: We analyzed age-related changes of bone mineral density (BMD) and compared with those of U.S and Japanese participants to investigate the prevalence of osteoporosis in Korea. MATERIALS AND METHODS: The data were collected in the 2008-2011 in Korea National Health and Nutrition Examination Survey (KNHANES) IV and V to select a representative sample of civilian, noninstitutionalized South Korean population. Bone mineral measurements were obtained from 8332 men and 9766 women aged 10 years and older. RESULTS: BMD in men continued to decline from 3rd decade, however, in women, BMD remained nearly constant until the 4th decade and declined at rapid rate from the 5th decade. The prevalence of osteoporosis in Korea is 7.3% in males and 38.0% in females aged 50 years and older. The prevalence of osteopenia in Korea is 46.5% in males and 48.7% in females, aged 50 years and older. The lumbar spine and femur BMD in Korean females 20 to 49 years of ages was lower than in U.S. and Japan participants. CONCLUSION: There was obvious gender, and age differences in the BMD based on the 2008-2011 KNHANES IV and V, a nationwide, cross-sectional survey conducted in a South Korean population. We expect to be able to estimate reference data through ongoing KNHANES efforts in near future. PMID- 24954338 TI - Combined muscle motor and somatosensory evoked potentials for intramedullary spinal cord tumour surgery. AB - PURPOSE: To evaluate whether intraoperative neurophysiologic monitoring (IONM) with combined muscle motor evoked potentials (mMEPs) and somatosensory evoked potentials is useful for more aggressive and safe resection in intramedullary spinal cord tumour (IMSCT) surgery. MATERIALS AND METHODS: We reviewed data from consecutive patients who underwent surgery for IMSCT between 1998 and April 2012. The patients were divided into two groups based on whether or not IONM was applied. In the monitored group, the procedures were performed under IONM using 75% muscle amplitude decline weaning criteria. The control group was comprised of patients who underwent IMSCT surgery without IONM. The primary outcome was the rate of gross total excision of the tumour on magnetic resonance imaging at one week after surgery. The secondary outcome was the neurologic outcome based on the McCormick Grade scale. RESULTS: The two groups had similar demographics. The total gross removal tended to increase when intraoperative neurophysiologic monitoring was used, but this tendency did not reach statistical significance (76% versus 58%; univariate analysis, p=0.049; multivariate regression model, p=0.119). The serial McCormick scale score was similar between the two groups (based on repeated measure ANOVA). CONCLUSION: Our study evaluated combined IONM of trans-cranial electrical (Tce)-mMEPs and SEPs for IMSCT. During IMSCT surgery, combined Tce-mMEPs and SEPs using 75% muscle amplitude weaning criteria did not result in significant improvement in the rate of gross total excision of the tumour or neurologic outcome. PMID- 24954339 TI - Cervical arthroplasty for moderate to severe disc degeneration: clinical and radiological assessments after a minimum follow-up of 18 months--Pfirrmann grade and cervical arthroplasty. AB - PURPOSE: Clinical outcomes and radiologic results after cervical arthroplasty have been reported in many articles, yet relatively few studies after cervical arthroplasty have been conducted in severe degenerative cervical disc disease. MATERIALS AND METHODS: Sixty patients who underwent cervical arthroplasty (Mobi C(r)) between April 2006 and November 2011 with a minimum follow-up of 18 months were enrolled in this study. Patients were divided into two groups according to Pfirrmann classification on preoperative cervical MR images: group A (Pfirrmann disc grade III, n=38) and group B (Pfirrmann disc grades IV or V, n=22). Visual analogue scale (VAS) scores of neck and arm pain, modified Oswestry Disability Index (mODI) score, and radiological results including cervical range of motion (ROM) were assessed before and after surgery. RESULTS: VAS and mean mODI scores decreased after surgery from 5.1 and 57.6 to 2.7 and 31.5 in group A and from 6.1 and 59.9 to 3.7 and 38.4 in group B, respectively. In both groups, VAS and mODI scores significantly improved postoperatively (p<0.001), although no significant intergroup differences were found. Also, cervical dynamic ROM was preserved or gradually improved up to 18 months after cervical arthroplasty in both groups. Global, segmental and adjacent ROM was similar for both groups during follow-up. No cases of device subsidence or extrusion were recorded. CONCLUSION: Clinical and radiological results following cervical arthroplasty in patients with severe degenerative cervical disc disease were no different from those in patients with mild degenerative cervical disc disease after 18 months of follow-up. PMID- 24954340 TI - Prognostic factors after intra-articular hyaluronic acid injection in ankle osteoarthritis. AB - PURPOSE: The goal of this study was to identify baseline prognostic factors of outcome in ankle osteoarthritis patients after intra-articular hyaluronic acid injection. MATERIALS AND METHODS: Patients with ankle osteoarthritis who received hyaluronic acid injection therapy were retrospectively reviewed. Each patient received weekly intra-articular hyaluronic acid injections (2 mL) for 3 weeks. Six predictors including gender, age, symptom duration, radiographic osteoarthritis stage, radiographic subchondral cyst, and fracture history were evaluated. Visual analogue scale (VAS) and patient satisfaction were evaluated as outcome measures. These predictors and outcome measurements were included in a logistic regression model for statistical analysis. RESULTS: Total of 40 consecutive patients (21 male, 19 female) were included in this study. Mean age was 60.6. Average follow up period was 13 months. The mean VAS recorded 3, 6, and 12 months after the first injection was 3.6 (SD 2.54, p<0.001), 4.33 (SD 2.9, p<0.001), and 5.3 (SD 2.7, p=0.0071), respectively, when compared to baseline VAS. Early stage disease was identified as an independent predictor associated with 'positive VAS outcome' at 3 and 6 months. Early stage disease and duration of pain less than 1 year were independent predictors associated with higher satisfaction. CONCLUSION: While hyaluronic acid injection for ankle osteoarthritis is a safe and effective treatment, careful selection of patients should be made according to the above prognostic predictors. PMID- 24954341 TI - Mid-term follow up results of subtalar distraction arthrodesis using a double bone-block for calcaneal malunion. AB - PURPOSE: This study was designed to evaluate the mid-term results and efficacy of subtalar distraction double bone-block arthrodesis for calcaneal malunion. MATERIALS AND METHODS: From January 2004 to June 2007, we operated on 6 patients (10 cases). There were 5 males (9 cases) and 1 female (1 case), four of which presented with bilateral calcaneal malunion. Seven cases were operated on initially. The period between initial injury and arthrodesis was 23 months, and the average follow up period was 58 months. In operation, we applied an extensile lateral approach and arthrodesis was performed through a tricortical double bone block and cannulated screws. The American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot scale was used for clinical evaluation. In radiologic analysis, plain X-ray and CT were examined to assess union and various parameters. RESULTS: The mean age of the patients was 41 years. All cases achieved radiologic union at the final follow-up. The mean AOFAS Ankle-Hindfoot scale (maximum of 94 points) increased from 43.3 points preoperatively to 85.4 points at the final follow-up. The radiologic analysis of the pre- and postoperative standing lateral radiographs showed improvements of 5.6 mm in talo calcaneal height, 1.8 degrees in talocalcaneal angle, 5.1 degrees in talar declination angle and 5.3 degrees in talo-first metatarsal angle. CONCLUSION: Subtalar distraction two bone-block arthrodesis provides overall good results not only in the short term but also the mid-term with significant improvement in clinical and radiologic outcomes. This procedure warrants consideration for managing calcaneal malunion with loss of height and subtalar arthritis. PMID- 24954342 TI - Concentration of non-steroidal anti-inflammatory drugs in the pelvic floor muscles: an experimental comparative rat model. AB - PURPOSE: The aim of this study is to explore non-steroid anti-inflammation drugs (NSAIDs) potency for pelvic floor muscle pain by measuring local concentration in a rat model. MATERIALS AND METHODS: We used nine NSAIDs, including nabumetone, naproxen, ibuprofen, meloxicam, piroxicam, diclofenac potassium, etodolac, indomethacin, and sulindac, and 9 groups of female Wister rats. Each group of rats was fed with one kind of NSAID (2 mg/mL) for three consecutive days. Thereafter, one mL of blood and one gram of pelvic floor muscle were taken to measure drug pharmacokinetics, including partition coefficient, lipophilicity, elimination of half-life (T1/2) and muscle/plasma converting ratio (Css, muscle/Css, plasma). RESULTS: Diclofenac potassium had the lowest T1/2 and the highest mean Css, muscle/Css, plasma (1.9 hours and 0.85+/-0.53, respectively). The mean Css, muscle/Css, plasma of sulindac, naproxen and ibuprofen were lower than other experimental NSAIDs. CONCLUSION: Diclofenac potassium had the highest disposition in pelvic floor muscle in a rat model. The finding implies that diclofenac potassium might be the choice for pain relief in pelvic muscle. PMID- 24954343 TI - Perioperative psychological and music interventions in elderly patients undergoing spinal anesthesia: effect on anxiety, heart rate variability, and postoperative pain. AB - PURPOSE: The aim of this study was to evaluate the effects of perioperative psychological and music interventions in elderly patients undergoing elective surgery on anxiety, post-operative pain, and changes in heart rate variability (HRV) to ascertain if perioperative psychological and music interventions can affect overall anxiety levels. MATERIALS AND METHODS: Fourty elderly patients undergoing elective surgery were randomized to two groups; one group received psychological and music intervention, and the other was the control. The intervention group underwent psychological intervention and listening to music for 30 min before surgery. RESULTS: The mean change in HRV as determined by low frequency (LF) power measurements. After the intervention, the ratio of mean LF to high frequency (HF) power decreased significantly in the intervention group compared to before the intervention (p<0.05). In the control group, mean LF measurements and the ratio of LF:HF did not change significantly. In the intervention group, mean HF power was significantly higher after the procedure than before (p<0.01). Moreover, the mean self-rating anxiety score of the intervention group decreased after the procedure compared to before (p<0.05). The mean visual analogue score of the intervention group 6 hours after surgery was significantly lower than that of the control group (p<0.01). CONCLUSION: Perioperative psychological and music interventions can reduce anxiety and postoperative pain in elderly patients. PMID- 24954344 TI - Efficacy of intrathecal morphine combined with intravenous analgesia versus thoracic epidural analgesia after gastrectomy. AB - PURPOSE: Epidural analgesia has been the preferred analgesic technique after major abdominal surgery. On the other hand, the combined use of intrathecal morphine (ITM) and intravenous patient controlled analgesia (IVPCA) has been shown to be a viable alternative approach for analgesia. We hypothesized that ITM combined with IVPCA is as effective as patient controlled thoracic epidural analgesia (PCTEA) with respect to postoperative pain control after conventional open gastrectomy. MATERIALS AND METHODS: Sixty-four patients undergoing conventional open gastrectomy due to gastric cancer were randomly allocated into the intrathecal morphine combined with intravenous patient-controlled analgesia (IT) group or patient-controlled thoracic epidural analgesia (EP) group. The IT group received preoperative 0.3 mg of ITM, followed by postoperative IVPCA. The EP group preoperatively underwent epidural catheterization, followed by postoperative PCTEA. Visual analog scale (VAS) scores were assessed until 48 hrs after surgery. Adverse effects related to analgesia, profiles associated with recovery from surgery, and postoperative complications within 30 days after surgery were also evaluated. RESULTS: This study failed to demonstrate the non inferiority of ITM-IVPCA (n=29) to PCTEA (n=30) with respect to VAS 24 hrs after surgery. Furthermore, the IT group consumed more fentanyl than the EP group did (1247.2+/-263.7 MUg vs. 1048.9+/-71.7 MUg, p<0.001). The IT group took a longer time to ambulate than the EP group (p=0.021) and had higher incidences of postoperative ileus (p=0.012) and pulmonary complications (p=0.05) compared with the EP group. CONCLUSION: ITM-IVPCA is not as effective as PCTEA in patients undergoing gastrectomy, with respect to pain control, ambulation, postoperative ileus and pulmonary complications. PMID- 24954345 TI - Estimation of gastrocnemius muscle volume using ultrasonography in children with spastic cerebral palsy. AB - PURPOSE: This study aimed to investigate useful parameters for estimating gastrocnemius (GCM) muscle volume (MV) using ultrasonography (US) and anthropometry in children with spastic cerebral palsy (CP). MATERIALS AND METHODS: Eighteen legs from nine children with spastic CP aged 2 to 6 years were investigated in this study. Tibial length (TL) of each leg was measured and muscle thickness (MT) and anatomical cross-sectional area (aCSA) of GCM muscles were assessed using US. The volume of the GCM was measured by magnetic resonance imaging (MRI) scans. The relationship of TL, MT, and aCSA with MV measured by MRI was investigated. Simple and multiple regression analyses were performed to establish muscle volume prediction equations. RESULTS: Resting MT, aCSA, and TL were highly related to MV of both medial and lateral head of GCM determined by MRI. The MV prediction equation based on simple regression analysis resulted in r2 values ranging from 0.591 to 0.832 (p<0.05). The r2 values were higher using aCSA as independent variable than using MT. The MV prediction equation based on multiple regression analysis resulted in r2 values ranging from 0.779 to 0.903 (p<0.05). However, the relatively high standard error of the estimate values ranged from 18.0-33.6% on simple regression and 15.5-25.6% on multiple regression. The contribution of aCSA was higher than that of MT for predicting MV of GCM. CONCLUSION: Our study demonstrated the suitability of US assessment of aCSA and MT combined with TL for estimating MV of GCM in children with spastic CP and showed that aCSA is more useful parameter than MT. PMID- 24954346 TI - Change of distribution and timing of bite force after botulinum toxin type A injection evaluated by a computerized occlusion analysis system. AB - PURPOSE: The aim of this study was to determine the force distribution and pattern of mastication after injection of botulinum toxin type A (BTX-A) into both masseter muscles. The hypothesis to be tested was that the difference between right and left balance of occlusal force diminishes over time following BTX-A injection. MATERIALS AND METHODS: Fifteen patients were submitted to BTX-A injection therapy for subjective masseter hypertrophy. A total of 25 U of BTX-A (50 U in total) was injected into two points located 1 cm apart at the center of the lower one-third of both masseter muscles. All patients were examined using the T-Scan occlusion analysis system before and 4, 8, 12, and 24 weeks after BTX A injection. RESULTS: A significant change in force balance was found between the right and left sides over time and the difference between the two sides decreased with the time post-injection, reaching a minimum at 12 weeks. Comparison of the force balance between the anterior and posterior occlusions revealed no significant difference at any of the time points. The occlusion and disclusion times (right and left sides) did not differ significantly with time since BTX-A injection. CONCLUSION: A decline in the difference in the clenching force between the left and right sides was found with increasing time up to 12 weeks following BTX-A injection. PMID- 24954347 TI - Effects of transplantation with marrow-derived mesenchymal stem cells modified with survivin on renal ischemia-reperfusion injury in mice. AB - PURPOSE: To determine whether renal injury induced by ischemia-reperfusion (I/R) could be further improved by mesenchymal stem cells (MSCs) modified with survivin. MATERIALS AND METHODS: Lentiviral vectors were used to introduce the survivin gene into MSCs and the MSCs modified with survivin were transplanted into established mice models of renal I/R injury. Seven days later, serum creatinine (Scr) and blood urea nitrogen (BUN) were measured and the survival of MSCs was determined. Hematoxylin and eosin staining was used to assess renal pathological change. The expressions of hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) in kidney tissue were detected by western blot. RESULTS: Mice transplanted with survivin-modified MSCs demonstrated good renal function recovery with Scr and BUN decline close to normal levels and improvement of renal I/R injury repair. Additionally, the survival of transplanted MSCs modified with survivin was enhanced and the expression of HGF and bFGF in kidney tissue was increased. CONCLUSION: Our results demonstrated that MSCs engineered to over-express survivin could enhance their therapeutic effect on renal I/R injury in mice, probably via the improved survival ability of MSCs and increased production of protective cytokines in ischemic tissue. PMID- 24954348 TI - Dietary restraint is non-genetically associated with change in body mass index: the Healthy Twin Study. AB - PURPOSE: We aimed to examine if past and more recent body mass index (BMI) changes are associated with eating behavior (EB) traits and whether these associations are due to non-genetic factors. MATERIALS AND METHODS: In 1321 Korean twins and family members, recent and past BMI change groups were defined using quartiles of BMI change between first and second visits over 2.4+/-0.9 years and BMI change between 20 years old and second visit, respectively. We applied linear mixed analysis for relationships of past or recent BMI change groups and each EB (restrained, external, and emotional EB using the Dutch Eating Behavior Questionnaire) assessed at second visit after adjusting for household effect and covariates (age, gender, education, medical history of diabetes, hypertension, and dyslipidemia, alcohol use, physical activity, smoking habit, and calorie intake). In monozygotic twin pairs, paired t-test for within-pair comparison and conditional logistic regression analysis were conducted regarding EB. RESULTS: Greater past BMI change was associated with higher restrained eating scores (P for trend=0.031), whereas greater recent BMI change was associated with higher external eating scores (P for trend=0.046). In co-twin-control analysis, twins with greater past BMI change were more likely to have higher restrained eating scores as compared with their co-twins with lower past BMI change (odds ratio 1.80; 95% confidence interval 1.13-2.87), whereas there were no associations between recent BMI change and external eating scores. CONCLUSION: Greater BMI change since 20 years old is associated with higher dietary restraint, and non-genetic factors explain this relationship. PMID- 24954349 TI - Different location of triaxial accelerometer and different energy expenditures. AB - PURPOSE: We performed a study to determine the best appropriate wearing site of a triaxial accelerometer at different exercise speeds. MATERIALS AND METHODS: We conducted an observational study with 66 healthy Korean adults (26 men and 40 women). Resting metabolic rate (RMR) before exercise, physical activity-related energy expenditure (PAEE) by cardiorespiratory gas analyzer and Signal Vector Magnitude (SVM) were measured while wearing four triaxial accelerometers on four different sites (wrist, waist, upper arm, and ankle) at exercise speeds from 2-10 km/h. RESULTS: The mean RMR was 4.03 mL/kg/min and Actual METs (oxygen consumption at different exercise speeds divided by individual RMR) compared with the calculated METs (oxygen consumption divided by 3.5 mL/kg/min) showed relatively low value. The overall correlation between PAEE and SVM was highest when the accelerometer was worn on the wrist at low exercise speed (r=0.751, p<0.001), waist at a moderate speed (r=0.821, p<0.001), and ankle at a high speed (r=0.559, p<0.001). Using regression analysis, it was shown that the ankle at a low speed (R2=0.564, p<0.001), high speed (R2=0.559, p<0.001), and the waist at a moderate speed (R2=0.821, p<0.001) were the best appropriate sites. CONCLUSION: When measuring the PAEE and SVM at different exercise speeds, the ankle in low and high exercise speed, and waist in moderate speed are the most appropriate sites for an accelerometer. PMID- 24954350 TI - Hydrogen peroxide as an effective disinfectant for Pasteurella multocida. AB - Pasteurella multocida (P. multocida) infections vary widely, from local infections resulting from animal bites and scratches to general infections. As of yet, no vaccine against P. multocida has been developed, and the most effective way to prevent pathogenic transmission is to clean the host environment using disinfectants. In this study, we identified which disinfectants most effectively inhibited environmental isolates of P. multocida. Three readily available disinfectants were compared: 3% hydrogen peroxide (HP), 70% isopropyl alcohol, and synthetic phenol. In suspension tests and zone inhibition tests, 3% HP was the most promising disinfectant against P. multocida. PMID- 24954352 TI - Suicide: affected by the internet. PMID- 24954351 TI - Isolated cerebellar variant of adrenoleukodystrophy with a de novo adenosine triphosphate-binding cassette D1 (ABCD1) gene mutation. AB - X-linked adrenoleukodystrophy (X-ALD) shows a wide range of phenotypic expression, but clinical presentation as an isolated lesion of the cerebellar white matter and dentate nuclei has not been reported. We report an unusual presentation of X-ALD only with an isolated lesion of the cerebellar white matter and dentate nuclei. The proband, a 37-year-old man presented with bladder incontinence, slurred speech, dysmetria in all limbs, difficulties in balancing, and gait ataxia. Brain magnetic resonance imaging showed an isolated signal change of white matter around the dentate nucleus in cerebellum. With high level of very long chain fatty acid, gene study showed a de novo mutation in exon 1 at nucleotide position c.277_296dup20 (p.Ala100Cysfs*10) of the adenosine triphosphate-binding cassette D1 gene. It is advised to consider X-ALD as a differential diagnosis in patients with isolated cerebellar degeneration symptoms. PMID- 24954357 TI - Gefitinib-Integrated Regimen versus Chemotherapy Alone in Heavily Pretreated Patients with Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma: A Case-Control Study. AB - BACKGROUND: The study aimed to compare the tolerability and efficacy of gefitinib combined with chemotherapy agents versus chemotherapy alone for the treatment of epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma in heavily pretreated patients. METHODS: The study was designed as a matched-pair case control investigation to minimize intergroup heterogeneity. Patients were stratified into gefitinib plus chemotherapy and chemotherapy alone groups with matching for sex, age, ECOG performance status, progress-free survival (PFS) from previous EGFR tyrosine kinase inhibitor treatment, EGFR mutation types, and tumor metastasis status. RESULTS: Sixty-six patients were selected from our database using the matched-pair method. The median age was 61 years (95% confidence interval, 57-65 years). During a follow-up period of 14.5 months on average, the overall response rates of the gefitinib-integrated and chemotherapy alone groups were 9.1% and 6.5%, respectively (P > .05), whereas the corresponding disease control rates were 39.4% and 30.3%, respectively (P > .05). No statistically significant differences in PFS (median, 4.2 vs 3.3 months; P = .06) and overall survival (median, 10.4 vs 7.9 months; P = .44) were observed between two groups. The 6-month survival rates of the gefitinib-integrated and chemotherapy alone groups were 21.2% and 12.1%, respectively (P < .05). Side effects were mild, and all treatments were well tolerated. CONCLUSIONS: Our results indicated that gefitinib-integrated therapy offered a trend to better PFS and an improved 6 month survival rate in heavily pretreated patients with metastatic EGFR-mutated lung adenocarcinoma. All treatments were well tolerated. Future prospective studies are warranted to confirm our findings. PMID- 24954356 TI - Claudin-1 Expression Is Elevated in Colorectal Cancer Precursor Lesions Harboring the BRAF V600E Mutation. AB - BACKGROUND: Sessile serrated adenomas/polyps (SSA/P) are now recognised precursors of colorectal cancer (CRC) including cancers harbouring somatic BRAF (V600E) mutations. While the morphological diagnostic criteria of SSA/P have been established, distinguishing between small/early SSA/P and microvesicular hyperplastic polyps (MVHP) is challenging and may not be possible in routine practice. METHODS: Gene expression profiling of MVHP (n=5, all BRAF V600E wild type) and SSA/P (n=5, all BRAF V600E mutant) samples was performed. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical analysis was performed to verify the expression of claudin 1 (CLDN1) in MVHP and SSA/P. RESULTS: Gene expression profiling studies conducted between MVHP and SSA/P identified CLDN1 as the most statistically significant differentially expressed gene (p<0.05). Validation with qRT-PCR confirmed an up-regulation of CLDN1 in BRAF V600E mutant polyps regardless of polyp type (p<0.0005). Immunohistochemical analysis of CLDN1 expression in BRAF V600E mutant SSA/Ps (n=53) and MVHPs (n=111) and BRAF wild-type MVHPs (n=58), demonstrated a strong correlation between CLDN1 expression and the BRAF V600E mutation in both SSA/P and MVHP samples when compared to wild-type polyps (p<0.0001). CONCLUSION: This study demonstrates an up regulation of CLDN1 protein in serrated colorectal polyps including MVHP harbouring the BRAF V600E mutation. Our results demonstrated an apparent heterogeneity on the molecular level within the MVHP group and suggest that MVHP with somatic BRAF V600E mutation and up-regulated expression of CLDN1 are closely related to SSA/P and may in fact represent a continuous spectrum of the same neoplastic process within the serrated pathway of colorectal carcinogenesis. PMID- 24954358 TI - A novel role for interferon regulatory factor 1 (IRF1) in regulation of bone metabolism. AB - Increased risk of bone fractures is observed in patients with chronic inflammatory conditions, such as inflammatory bowel disease and rheumatoid arthritis. Members of the Interferon Response Factor family of transcriptional regulators, IRF1 and IRF8, have been identified as genetic risk factors for several chronic inflammatory and autoimmune diseases. We have investigated a potential role for the Irf1 gene in bone metabolism. Here, we report that Irf1(-/ ) mutant mice show altered bone morphology in association with altered trabecular bone architecture and increased cortical thickness and cellularity. Ex vivo studies on cells derived from bone marrow stimulated with Rank ligand revealed an increase in size and resorptive activity of tartrate-resistant acid-positive cells from Irf1(-/-) mutant mice compared with wild-type control mice. Irf1 deficiency was also associated with decreased proliferation of bone marrow derived osteoblast precursors ex vivo, concomitant with increased mineralization activity compared with control cells. We show that Irf1 plays a role in bone metabolism and suggest that Irf1 regulates the maturation and activity of osteoclasts and osteoblasts. The altered bone phenotype of Irf1(-/-) mutants is strikingly similar to that of Stat1(-/-) mice, suggesting that the two interacting proteins play a critical enabling role in the common regulation of these two cell lineages. PMID- 24954359 TI - The presence of extrathoracic metastasis is more prognostic of survival than Masaoka stage (IVa/IVb) in metastatic thymic epithelial tumor: a retrospective cohort study. AB - PURPOSE: Our aim in this study was to identify independent prognostic factors for overall survival (OS) in order to explain the heterogeneity of OS in patients with metastatic thymic epithelial tumor (TET). METHODS: Sixty-one consecutive patients with histologic diagnosis of Masaoka stage IV TET between January 1980 and March 2009 were analyzed at a single institution. Masaoka stage IVa was defined as pleural or pericardial dissemination, and IVb as lymphogenous or hematogenous metastasis. Metastasis outside the thoracic cage was defined as extrathoracic metastasis. To identify prognostic factors, relationships between clinicopathologic factors and outcomes were analyzed. RESULTS: Of the 61 patients, 30 (49.2%) had thymoma, 28 (45.9%) had thymic carcinoma, and the remaining 3 (4.9%) had an unclear histologic subtype. The Masaoka stage was IVa in 27 patients (44.3%) and IVb in 34 patients (55.7%). Significant independent adverse prognostic factors for OS were histologic subtype and extrathoracic metastasis (hazard ratio [HR]=3.09 and 6.03, 95% CI: 1.41-6.74 and 1.89-19.30, p=0.005 and 0.002, respectively). The presence of extrathoracic metastasis was also an independent prognostic factor for decreased progression-free survival time (PFS) (HR=6.62, 95% CI: 1.19-24.17, p=0.004). The only significant criterion for prognostic discrimination was the presence of extrathoracic metastasis in metastatic TET. CONCLUSIONS: Significant independent prognostic factors for lower OS were the histologic subtype of thymic carcinoma and the presence of extrathoracic metastasis. A new concept of extrathoracic metastasis might provide additional information for the understanding of metastatic TET. PMID- 24954360 TI - Synthesis of atypical bile acids for use as investigative tools for the genetic defect of 3beta-hydroxy-Delta(5)-C27-steroid oxidoreductase deficiency. AB - Deficiency of 3beta-hydroxy-Delta(5)-C27-steroid oxidoreductase (HSD3B7), an enzyme catalyzing the second step in the pathway for bile acid synthesis, leads to a complete lack of the primary bile acids, cholic and chenodeoxycholic acids, and the accumulation of 3beta,7alpha-dihydroxy- and 3beta,7alpha,12alpha trihydroxy-Delta(5)-cholenoic acids. Patients affected by this autosomal recessive genetic defect develop cholestatic liver disease that is clinically responsive to primary bile acid therapy. Reference standards of these compounds are needed to facilitate diagnosis and to accurately quantify biochemical responses to therapy. Described are a novel synthesis of atypical bile acids that characterize the HSD3B7 deficiency and their effect on bile acid-activated nuclear receptors, target genes and cytochromes involved in bile acid homeostasis and detoxification. The failure of 3beta-hydroxy-Delta(5)-cholenoic acids to function as FXR, PXR and CAR agonists and to exert hepatoprotective actions explains the mechanism for progressive cholestatic liver disease in patients with HSD3B7 deficiency. PMID- 24954361 TI - Critical adsorption of polyelectrolytes onto charged Janus nanospheres. AB - Based on extensive Monte Carlo simulations and analytical considerations we study the electrostatically driven adsorption of flexible polyelectrolyte chains onto charged Janus nanospheres. These net-neutral colloids are composed of two equally but oppositely charged hemispheres. The critical binding conditions for polyelectrolyte chains are analysed as function of the radius of the Janus particle and its surface charge density, as well as the salt concentration in the ambient solution. Specifically for the adsorption of finite-length polyelectrolyte chains onto Janus nanoparticles, we demonstrate that the critical adsorption conditions drastically differ when the size of the Janus particle or the screening length of the electrolyte are varied. We compare the scaling laws obtained for the adsorption-desorption threshold to the known results for uniformly charged spherical particles, observing significant disparities. We also contrast the changes to the polyelectrolyte chain conformations close to the surface of the Janus nanoparticles as compared to those for simple spherical particles. Finally, we discuss experimentally relevant physico-chemical systems for which our simulations results may become important. In particular, we observe similar trends with polyelectrolyte complexation with oppositely but heterogeneously charged proteins. PMID- 24954362 TI - Scaling up: human genetics as a Cold War network. AB - In this commentary I explore how the papers here illuminate the processes of collection that have been so central to the history of human genetics since 1945. The development of human population genetics in the Cold War period produced databases and biobanks that have endured into the present, and that continue to be used and debated. In the decades after the bomb, scientists collected and transferred human biological materials and information from populations of interest, and as they moved these biological resources or biosocial resources acquired new meanings and uses. The papers here collate these practices and map their desires and ironies. They explore how a large international network of geneticists, biological anthropologists, virologists and other physicians and scientists interacted with local informants, research subjects and public officials. They also track the networks and standards that mobilized the transfer of information, genealogies, tissue and blood samples. As Joanna Radin suggests here, the massive collections of human biological materials and data were often understood to be resources for an "as-yet-unknown" future. The stories told here contain elements of surveillance, extraction, salvage and eschatology. PMID- 24954363 TI - Chromosome surveys of human populations: between epidemiology and anthropology. AB - It is commonly held that after 1945 human genetics turned medical and focussed on the individual rather than on the study of human populations that had become discredited. However, a closer look at the research practices at the time quickly reveals that human population studies, using old and new tools, prospered in this period. The essay focuses on the rise of chromosome analysis as a new tool for the study of human populations. It reviews a broad array of population studies ranging from newborn screening programmes to studies of isolated or 'primitive' people. Throughout, it highlights the continuing role of concerns and opportunities raised by the propagation of atomic energy for civilian and military uses, the collection of large data bases and computers, and the role of international organisations like the World Health Organisation and the International Biological Programme in shaping research agendas and carving out a space for human heredity in the postwar era. PMID- 24954364 TI - Intraoperative electromyography as an adjunct to sacral neuromodulation for chronic pelvic pain. AB - OBJECTIVE: Sacral neuromodulation is an established technique for the treatment of chronic intractable pelvic and anorectal pain. Stimulation of sacral roots S2 4 is typically associated with therapeutic paresthesia, while stimulation of the S1 nerve root causes unwanted leg paresthesia. Here we describe and evaluate the use of intraoperative electromyography (EMG) of the gastrocnemius, foot intrinsic muscles, and anal sphincter as an adjunct to epidural stimulator placement. MATERIALS AND METHODS: Two female patients with intractable pelvic pain underwent implantation of sacral epidural paddles with intraoperative EMG. These cases were retrospectively reviewed to evaluate intraoperative EMG activation and therapeutic paresthesia. RESULTS: We found cephalad-to-caudal transitions in EMG activation with stimulation: medial gastrocnemius to foot intrinsics to anal sphincter. Coactivation of foot intrinsic muscles with anal sphincter and absence of medial gastrocnemius stimulation correlated with therapeutic perineal paresthesia. CONCLUSIONS: Intraoperative EMG of the gastrocnemius, foot intrinsics, and anal sphincter may be a useful adjunct to sacral stimulation for pelvic pain. PMID- 24954365 TI - Standing the test of time: outcomes of a decade of prioritizing patients with hepatocellular carcinoma, results of the UNOS natural geographic experiment. AB - Priority is given to patients with hepatocellular carcinoma (HCC) to receive liver transplants, potentially causing significant regional disparities in organ access and possibly outcomes in this population. Our aim was to assess these disparities by comparing outcomes in long waiting time regions (LWTR, regions 5 and 9) and short waiting time regions (SWTR regions 3 and 10) by analyzing the United Network for Organ Sharing (UNOS) database. We analyzed 6,160 HCC patients who received exception points in regions 3, 5, 9, and 10 from 2002 to 2012. Data from regions 5 and 9 were combined and compared to data from regions 3 and 10. Survival was studied in three patient cohorts: an intent-to-treat cohort, a posttransplant cohort, and a cohort examining overall survival in transplanted patients only (survival from listing to last posttransplant follow-up). Multivariate analysis and log-rank testing were used to analyze the data. Median time on the list in the LWTR was 7.6 months compared to 1.6 months for SWTR, with a significantly higher incidence of death on the waiting list in LWTR than in SWTR (8.4% versus 1.6%, P < 0.0001). Patients in the LWTR were more likely to receive loco-regional therapy, to have T3 tumors at listing, and to receive expanded-criteria donor (ECD) or donation after cardiac death (DCD) grafts than patients in the SWTR (P < 0.0001 for all). Survival was significantly better in the LWTR compared to the SWTR in all three cohorts (P < 0.0001 for all three survival points). Being listed/transplanted in an SWTR was an independent predictor of poor patient survival on multivariate analysis (P < 0.0001, hazard ratio = 1.545, 95% confidence interval 1.375-1.736). CONCLUSION: This study provides evidence that expediting patients with HCC to transplant at too fast a rate may adversely affect patient outcomes. PMID- 24954366 TI - Acta Oncologica and a new generation of scientists in oncology. PMID- 24954367 TI - Arterial ligation in anterior resection for rectal cancer: A validation study of the Swedish Colorectal Cancer Registry. AB - BACKGROUND: The level of arterial ligation has been a variable of the Swedish Colorectal Cancer Registry since 2007. The aim of this study is to evaluate the accuracy of this registry variable in relation to anterior resection for rectal cancer. METHODS: The operative charts of all cardiovascularly compromised patients who underwent anterior resection during the period 2007-2010 in Sweden were retrieved and compared to the registry. We selected the study population to reflect the common assumption that these patients would be more sensitive to a compromised visceral blood flow. Levels of vascular ligation were defined, both oncologically and functionally, and their sensitivity, specificity, positive and negative predictive values, level of agreement and Cohen's kappa were calculated. RESULTS: Some 744 (94.5%) patients were eligible for analysis. Functional high tie level showed a sensitivity of 80.2% and a specificity of 90.1%. Positive and negative predictive values were 87.7 and 83.8%, respectively. Level of agreement was 85.5% and Cohen's kappa 0.70. The corresponding calculations for oncologic tie level yielded similar results. CONCLUSION: The suboptimal validity of the Swedish Colorectal Cancer Registry regarding the level of vascular ligation might be problematic. For analyses with rare positive outcomes, such bowel ischaemia, or with minor expected differences in outcomes, it would be beneficial to collect data directly from the operative charts of the medical records in order to increase the chance of identifying clinically relevant differences. PMID- 24954368 TI - Multiscale analysis of anterior cruciate ruptures: Prospective study of 49 cases. AB - INTRODUCTION: Partial anterior cruciate ligament (ACL) ruptures are common. The ability to distinguish between various types of ACL ruptures preoperatively would allow surgeons to choose the most appropriate surgical treatment. HYPOTHESIS: A partial ACL rupture can be diagnosed preoperatively. MATERIAL AND METHODS: The goal of this single-center, prospective study was to establish correlations between various macroscopic types of ACL ruptures determined by arthroscopy with data from clinical examination, knee laxity measurements (GnRB((r))) and magnetic resonance imaging (MRI). The 49 patients included over a six-month period had a diagnosis of ACL rupture based on the clinical examination. Four arthroscopy categories were defined based on the French Arthroscopy Society (SFA) classification. Each patient had their knee laxity measured, a preoperative MRI performed and a clinical exam done in the operating room before the procedure. RESULTS: During arthroscopy, the ACL was described as "Complete tear" in 23 of 49 patients, "Healed onto PCL" in 12, "Posterolateral bundle preserved" in 14 and "Healed into notch" in none of the patients. The clinical exam alone could not discriminate between the various types of ruptures (P>0.05). With MRI, the sensitivity was 84% and the specificity was 92% for partial ACL rupture. There was a strong correlation between MRI and the various arthroscopy groups (P<0.05). There was a significant difference (P<0.05) between partial and complete ruptures in terms of knee laxity. CONCLUSION: This study helped define the relationships between arthroscopy findings, MRI findings and knee laxity measurements. It is feasible to make a preoperative diagnosis of partial ACL rupture. LEVEL OF EVIDENCE: Level IV, prospective cohort study. PMID- 24954369 TI - Reply to Letter to the Editor regarding transoral laser microsurgery. PMID- 24954370 TI - Effect of diagnostic criteria on prevalence of frontotemporal dementia in the elderly. AB - BACKGROUND: Frontotemporal dementia (FTD) is believed to be rare in the elderly, and the influence of different criteria on the prevalence of FTD is unclear. METHODS: Population-based samples of 70- to 95-year-olds (n = 2462) in Gothenburg, Sweden, underwent neuropsychiatric examinations. Behavioral variant FTD (bvFTD) was diagnosed according to the International Behavioural Variant FTD Criteria Consortium (FTDC), the Frontotemporal Lobe Degeneration Consensus criteria, and the Lund-Manchester Research Criteria. A subset (n = 1074) underwent computerized tomography (CT) of the brain. RESULTS: The prevalence of bvFTD varied between 0.2% and 0.5% at age 70 to 79 years, between 2.5% and 3.6% at age 80 to 89 years, and between 1.7% and 2.2% at age 90 to 95 years. The agreement between different criteria was low to moderate (kappa = 0.20-0.42). Among those with bvFTD according to FTDC, 93.3% had frontal and/or temporal lobar atrophy on CT, compared with 12.6% of those without bvFTD (P < .001). CONCLUSIONS: The prevalence of bvFTD was higher than expected in this population. To a large extent, different criteria captured different individuals. PMID- 24954372 TI - Effects of probiotics for the treatment of atopic dermatitis: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The effects of probiotics on the treatment of atopic dermatitis (AD) are inconclusive. OBJECTIVE: To determine the clinical effect of probiotics in the management of AD overall and in different age groups. METHODS: A comprehensive search of databases through December 2013 was performed. For this meta-analysis, randomized controlled trials measuring the treatment effects of probiotics or synbiotics in patients diagnosed with AD were included. The primary outcome was a difference in Scoring of Atopic Dermatitis (SCORAD) values between the treatment and placebo groups overall and in different age populations. RESULTS: Twenty-five randomized controlled trials (n = 1,599) were available for this meta-analysis. Significant differences in SCORAD values favoring probiotics over the control were observed overall (mean -4.51, 95% confidence interval -6.78 to -2.24), in children 1 to 18 years old (-5.74, 95% confidence interval -7.27 to -4.20), and in adults (-8.26, 95% confidence interval -13.28 to -3.25). However, the effectiveness of probiotics in infants (<1 year old) with AD was not proved. The effect of synbiotic use was not significantly different from that of probiotic use. Treatment with a mixture of different bacterial species or of Lactobacillus species showed greater benefit than did treatment with Bifidobacterium species alone. CONCLUSION: The overall result of this meta analysis suggests that probiotics could be an option for the treatment of AD, especially for moderate to severe AD in children and adults. However, no evidence was found supporting the beneficial role of probiotics in infants. PMID- 24954373 TI - The chitinase-like protein YKL-40 is not a useful biomarker for severe persistent asthma in children. AB - BACKGROUND: The chitinase-like protein YKL-40 is thought to play a role in inflammation and tissue remodeling. In adults with severe asthma, YKL-40 is expressed in the airway and YKL-40 levels are elevated in the serum. OBJECTIVE: To compare YKL-40 levels in children with severe persistent asthma with those in adults with severe persistent asthma and to determine whether YKL-40 levels correlate with increasing asthma severity in childhood asthma. METHODS: In this prospective, cross-sectional study, 23 adults and 19 children with severe persistent asthma, 23 children with moderate persistent asthma, and 19 children with mild persistent asthma were enrolled. The following data were collected on each patient: spirometry, exhaled nitric oxide, percutaneous skin testing results to aeroallergens, peripheral eosinophils, serum IgE levels, and serum YKL-40 levels. RESULTS: Compared with adults, children with severe persistent asthma had significantly lower YKL-40 levels, higher values for forced vital capacity and forced expiration volume in 1 second, higher serum IgE levels, and higher exhaled nitric oxide levels. YKL-40 levels did not correlate with increasing asthma severity in the pediatric cohort. CONCLUSION: Severe persistent asthma in childhood is not associated with elevated YKL-40 levels, unlike in adults with severe persistent asthma. YKL-40 is not a useful biomarker for asthma severity in childhood asthma. PMID- 24954371 TI - Association of fish oil supplement use with preservation of brain volume and cognitive function. AB - OBJECTIVE: The aim of this study was to investigate whether the use of fish oil supplements (FOSs) is associated with concomitant reduction in cognitive decline and brain atrophy in older adults. METHODS: We conducted a retrospective cohort study to examine the relationship between FOS use during the Alzheimer's Disease Neuroimaging Initiative and indicators of cognitive decline. Older adults (229 cognitively normal individuals, 397 patients with mild cognitive impairment, and 193 patients with Alzheimer's disease) were assessed with neuropsychological tests and brain magnetic resonance imaging every 6 months. Primary outcomes included (1) global cognitive status and (2) cerebral cortex gray matter and hippocampus and ventricular volumes. RESULTS: FOS use during follow-up was associated with significantly lower mean cognitive subscale of the Alzheimer's Disease Assessment Scale and higher Mini-Mental State Examination scores among those with normal cognition. Associations between FOS use and the outcomes were observed only in APOE epsilon4-negative participants. FOS use during the study was also associated with less atrophy in one or more brain regions of interest. PMID- 24954374 TI - IgE-binding properties of a recombinant lipid transfer protein from Cannabis sativa. PMID- 24954375 TI - The single nucleotide polymorphism rs2208454 confers an increased risk for ischemic stroke: a case-control study. AB - AIM: A recent genome-wide association study identified a strong association of covert magnetic resonance imaging infarcts with the single nucleotide polymorphism (SNP) rs2208454. The aim of this study was to determine whether the rs2208454 polymorphism is associated with an increased risk for ischemic stroke (IS). METHODS: Ischemic stroke patients (n = 712) and control subjects (n = 774) from a southern Chinese Han population were included. The snapshot technique was used for genotype analysis. RESULTS: Compared with the GT+GG or GG genotype, the frequency of the TT genotype was significantly higher in IS than in controls. After adjusting for age, gender, family history of IS, hypertension history, and history of diabetes mellitus, a significant correlation between the TT genotype and IS persisted (TT vs. GT+GG: adjusted OR = 1.79, 95% CI: 1.16-2.77; TT vs. GG: adjusted OR = 1.88, 95% CI: 1.20-2.94). In subgroup analyses, SNP rs2208454 was significantly associated with large artery atherosclerosis (LAA) (TT vs. GG: adjusted OR = 2.16, 95% CI: 1.19-3.93), but failed to show significant association with small-artery occlusion or cardioembolism IS subtypes. CONCLUSIONS: Single nucleotide polymorphism rs2208454 confers an increased risk for IS in a southern Chinese Han population. When the IS subtype was examined, the effect of the SNP was restricted to LAA. PMID- 24954376 TI - When can scientific studies promote consensus among conflicting stakeholders? AB - While scientific studies may help conflicting stakeholders come to agreement on a best management option or policy, often they do not. We review the factors affecting trust in the efficacy and objectivity of scientific studies in an analytical-deliberative process where conflict is present, and show how they may be incorporated in an extension to the traditional Bayesian decision model. The extended framework considers stakeholders who differ in their prior beliefs regarding the probability of possible outcomes (in particular, whether a proposed technology is hazardous), differ in their valuations of these outcomes, and differ in their assessment of the ability of a proposed study to resolve the uncertainty in the outcomes and their hazards--as measured by their perceived false positive and false negative rates for the study. The Bayesian model predicts stakeholder-specific preposterior probabilities of consensus, as well as pathways for increasing these probabilities, providing important insights into the value of scientific information in an analytic-deliberative decision process where agreement is sought. It also helps to identify the interactions among perceived risk and benefit allocations, scientific beliefs, and trust in proposed scientific studies when determining whether a consensus can be achieved. The article provides examples to illustrate the method, including an adaptation of a recent decision analysis for managing the health risks of electromagnetic fields from high voltage transmission lines. PMID- 24954377 TI - C-21 steroidal glycosides from Dregea sinensis. AB - Two new C-21 steroidal glycosides, dregeosides D (1) and E (2), were isolated from the roots of Dregea sinensis. The structures of the isolated compounds were elucidated on the basis of 1D and 2D NMR spectra and HR-ESI-MS analysis. Finally, the inhibited effects of the isolated compounds on interleukin 2 receptor were evaluated by enzyme-linked immunosorbent assay. PMID- 24954378 TI - Myeloid cell dysfunction and the pathogenesis of the diabetic chronic wound. AB - Diabetes can promote a state of chronic inflammation associated with serious complications that are difficult to treat, including ulceration of the lower extremities and chronic wounds. Chronic wounds are often incurable and contribute to both a reduced quality of life for patients and an enormous burden for healthcare services. In diabetes, the inflammatory response early in wound healing is inappropriately amplified and prolonged, leading to the persistent presence in the wound of vastly elevated numbers of dysfunctional, hyperpolarised macrophages that fail to transition to a pro-healing phenotype. Recent evidence suggests that systemic chronic inflammation induces intrinsic defects in monocytes via chromatin modifications that may pre-programme monocytes to a pro inflammatory phenotype, while the local wound environment inhibits differentiation to a pro-healing phenotype. Current understanding remains incomplete, and careful dissection of how local and systemic inflammation combine to negatively influence myeloid cell development will be key to developing effective therapies aimed at healing the diabetic wound. PMID- 24954379 TI - Viral pathogenesis: Neural receptor for reovirus revealed. PMID- 24954381 TI - A procedure for the sensory evaluation of Salama da sugo, a typical fermented sausage produced in the Emilia Romagna Region, Italy. AB - BACKGROUND: Salama da sugo is a fermented sausage from the Ferrara tradition (Italy, Emilia-Romagna region), subjected to a long ripening period (4-6 months) and characterised by a high content of wine and spices in the mixture. It can be consumed after cooking and it is served with its sugo, i.e. the liquid extracted by cooking process. The aim of this work was to set up a method for the sensory profile of Salama da sugo as a request for Protected Geographical Indication (PGI) has been made to the European Commission. RESULTS: A system of sample preparation that provides for the precooking in an autoclave and cooking in boiling water was set up. A specific sheet for sensory evaluation of Salama da sugo has been created and reports 23 descriptors identified during the lexicon development. The differences in sensory profile of four samples were evaluated and principal component analysis highlighted the more discriminant parameters, i.e. odour intensity, wine odour, spicy aroma, fat/lean connection, sweet, bitter, juiciness, chewiness and pricking. CONCLUSIONS: The proposed method allows the standardisation of sensory profiling of Salama da sugo, and is also to verify compliance with the specification PGI. PMID- 24954380 TI - Tracking cerebral blood flow in BOLD fMRI using recursively generated regressors. AB - BOLD functional MRI (fMRI) data are dominated by low frequency signals, many of them of unclear origin. We have recently shown that some portions of the low frequency oscillations found in BOLD fMRI are systemic signals closely related to the blood circulation (Tong et al. [2013]: NeuroImage 76:202-215). They are commonly treated as physiological noise in fMRI studies. In this study, we propose and test a novel data-driven analytical method that uses these systemic low frequency oscillations in the BOLD signal as a tracer to follow cerebral blood flow dynamically. Our findings demonstrate that: (1) systemic oscillations pervade the BOLD signal; (2) the temporal traces evolve as the blood propagates though the brain; and, (3) they can be effectively extracted via a recursive procedure and used to derive the cerebral circulation map. Moreover, this method is independent from functional analyses, and thus allows simultaneous and independent assessment of information about cerebral blood flow to be conducted in parallel with the functional studies. In this study, the method was applied to data from the resting state scans, acquired using a multiband EPI sequence (fMRI scan with much shorter TRs), of seven healthy participants. Dynamic maps with consistent features resembling cerebral blood circulation were derived, confirming the robustness and repeatability of the method. PMID- 24954382 TI - Kidney-selective gene transfection using anionic bubble lipopolyplexes with renal ultrasound irradiation in mice. AB - This study assessed the ability of a new ultrasound (US) responsive gene delivery carrier, bubble lipopolyplexes, to deliver genes to the kidneys. The bubble lipopolyplexes showed highly selective gene expression in kidney tubules, but only after renal irradiation with US. These bubble lipopolyplexes, however, did not increase the expression of biomarkers of kidney injury, including blood urea nitrogen, serum creatinine, kidney injury molecule-1 mRNA, and clusterin mRNA, or induce any histopathological abnormalities in the kidney. Furthermore, pDNA containing CMV early enhancer/chicken beta-actin promoter prolonged gene expression by the bubble lipopolyplexes in the kidney for 42 days. This novel renal gene delivery method, in which transfection of bubble lipopolyplexes was followed by US irradiation of the kidneys, resulting in cell-selective, high, and long-term gene expression without renal injury in mice, may have future applications in patient treatment. FROM THE CLINICAL EDITOR: This study demonstrates a novel gene delivery method to the kidneys, utilizing bubble resulting in highly selective gene expression in renal tubules after ultrasound irradiation. In the studied rodent model, there was no evidence for renal damage using this novel delivery system. PMID- 24954383 TI - Sensor arrays based on nanoparticles for early detection of kidney injury by breath samples. AB - The outcomes of acute kidney injury (AKI) could be severe and even lethal, if not diagnosed in its early stages and treated appropriately. Blood and urine biomarkers, currently in use as indicators for kidney function, are either inaccurate in various cases or not timely. We report on dramatic changes in exhaled breath composition, associated with kidney dysfunction after ischemic insult in rat models. Gas chromatography linked mass spectrometry examination of breath samples indicated significant elevations in the concentration of three exhaled volatile organic compounds, two to six hours after AKI was surgically induced. Relying on these findings, we introduce an array of sensors, based on organic-layer capped gold nanoparticles, sensitive to odor changes. The ability of the array to detect AKI via breath testing was examined and scored a sensitivity of 96%, only one hour after disease induction. FROM THE CLINICAL EDITOR: In this study, organic-layer capped gold nanoparticle-based biosensors are used to analyse breath samples in an acute kidney injury model, capitalizing on the observation that specific volatile organic compounds are present in breath samples in that condition. The authors report excellent sensitivity in as little as one hour after acute kidney injury. This method, if commercialized, may replace the current blood and urine sample analysis-based tests with a more convenient, rapid and accurate nanotechnology-based method. PMID- 24954384 TI - A simple way to track single gold-loaded alginate microcapsules using x-ray CT in small animal longitudinal studies. AB - The use of alginate based microcapsules to deliver drugs and cells with a minimal host interaction is increasingly being proposed. A proficient method to track the position of the microcapsules during such therapies, particularly if they are amenable to commonly used instrumentation, would greatly help the development of such treatments. Here we propose to label the microcapsules with gold nanoparticles to provide a bright contrast on small animal x-ray micro-CT systems enabling single microcapsule detection. The microcapsules preparation is based on a simple protocol using inexpensive compounds. This, combined with the widespread availability of micro-CT apparatus, renders our method more accessible compared with other methods. Our labeled microcapsules showed good mechanical stability and low cytotoxicity in-vitro. Our post-mortem rodent model data strongly suggest that the high signal intensity generated by the labeled microcapsules permits the use of a reduced radiation dose yielding a method fully compatible with longitudinal in-vivo studies. FROM THE CLINICAL EDITOR: The authors of this study report the development of a micro-CT based tracking method of alginate-based microcapsules by incorporating gold nanoparticles in the microcapsules. They demonstrate the feasibility of this system in rodent models, where due to the high signal intensity, even reduced radiation dose is sufficient to track these particles, providing a simple and effective method to track these commonly used microcapsules and allowing longitudinal studies. PMID- 24954385 TI - NMR diffusion-ordered spectroscopy can explain differences in skin penetration enhancement between microemulsion formulations. AB - Changing the formulation variables of microemulsion systems has a significant influence on the resulting transdermal enhancement effect. NMR diffusion-ordered spectroscopy (DOSY) can offer an extremely valuable tool to interpret the differences in the obtained fluxes based on variations in self-diffusions between the drug and its locus domain. From the clinical editor: Microemulsion systems are often used as vehicles for transdermal drug delivery. In this communication authors interpret quantitative differences between microemulsion formulations based on studying the self-diffusion of testosterone relative to the diffusion of its residing oil phase based on DOSY spectroscopy. PMID- 24954386 TI - Temporal variations of mobile carbohydrates in Abies fargesii at the upper tree limits. AB - Low temperatures are associated high-altitude treelines, but the functional mechanism of treeline formation remains controversial. The relative contributions of carbon limitation (source activity) and growth limitation (sink activity) require more tests across taxa and regions. We examined temporal variations of mobile carbon supply in different tissues of Abies fargesii across treeline ecotones on north- and south-facing slopes of the Qinling Mountains, China. Non structural carbohydrate (NSC) concentrations in tissues along the altitudinal gradient on both slopes changed significantly in the early and late growing season, but not in the mid-growing season, indicating the season-dependent carbon supply status. Late in the growing season on both slopes, trees at the upper limits had the highest NSC concentrations and total soluble sugars and lowest starch concentrations compared to trees at the lower elevations. NSC concentrations tended to increase in needles and branches throughout the growing season with increasing elevation on both slopes, but declined in roots and stems. NSC concentrations across sampling dates also indicated increases in needles and branches, and decreases in roots and stem with increasing elevation. Overall altitudinal trends of NSC in A. fargesii revealed no depletion of mobile carbon reserves at upper elevation limits, suggesting limitation of sink activity dominates tree life across treeline ecotones in both north- and south-facing slopes. Carbon reserves in storage tissues (especially roots) in the late growing season might also play an important role in winter survival and early growth in spring at upper elevations on both slopes, which define the uppermost limit of A. fargesii. PMID- 24954388 TI - Universal Design and disability: an interdisciplinary perspective. AB - PURPOSE: To discuss Universal Design (UD) as an interdisciplinary topic with relevance for rehabilitation professions and planning and building professions. Significant for this topic is to discuss to what model of disability UD strategies correlates. The paper argues that the UN Convention on the Rights for Persons with Disabilities (CRPD) pre-supposes a relational model of disability. METHOD: This is a theoretical paper on the understanding of UD and the significance of UD as a subject of interdisciplinary research and teaching. The paper is based on literature and focuses on how to understand UD in interdisciplinary contexts. Both impairment effects and disabling barriers are important for understanding UD. Rehabilitation professions together with user representatives provide knowledge on impairments as an aspect of human diversity; planning professionals provide knowledge on architecture and spatial planning. As an emerging field of knowledge, UD involves different knowledge; however, these differences may also lead to difficulties in communication. RESULTS: Both theoretically and practically UD must correspond to an understanding of disability as relational, involving person, interaction and barriers. Implementing UD strategies ought to be linked to a concept of person that clearly includes impairments as a dimension of human plurality. CONCLUSION: In conclusion, the paper suggests that a common knowledge platform can prove productive for interdisciplinary work with UD. Implications for Rehabilitation Universal Design is a strategy to improve equal access for people with disabilities. A concept of the person and of disability is of importance for implementing Universal Design strategies. The interdisciplinary involvement in Universal Design must involve rehabilitation professions to attend to the individual dimension in Universal Design. PMID- 24954389 TI - Universally design social policy: when disability disappears? AB - PURPOSE: The aim of this paper is to review and evaluate the legal and policy feasibility of applying the principles of Universal Design (UD) to create a "universalised disability policy" that targets the needs and circumstances of persons with disabilities in light of universal human rights, conscious of individual differences. METHODS: Applying modified versions of the principles of UD to disability social policy and using core interpretative strategies for human rights implementation (used in the United Nations' Convention on the Rights of Persons with Disabilities) to illuminate, by analogy, ways to resolve the dilemma between seeking equality and respecting difference. RESULTS: The aspirations of UD in architecture and planning - namely to design buildings and cities to accommodate the needs of the widest spectrum of abilities as possible - can successfully be applied to social policy that focuses on the needs and circumstances of persons with disabilities, and which underwrites a blueprint for reform in the delivery of social services. CONCLUSIONS: "Universal social policy", and UD, are feasible and desirable approaches to their respective domains, if we adopt a strategy derived from the legal interpretation of human rights implementation. The consequence, however, may be a policy that begins a process of social disappearance of disability. Implications for Rehabilitation The well-recognised principles of Universal Design (UD) have analogs for social policy that focuses on the needs of persons with disabilities. Universal social policy is consistent with the rights and aspirations of the UN Convention on the Rights of Persons with Disabilities. Universalising social policy may lead eventually to the disappearance of "disability" as a policy category. PMID- 24954390 TI - Fatigue in patients with chronic widespread pain participating in multidisciplinary rehabilitation treatment: a prospective cohort study. AB - PURPOSE: To explore the associations between (improvement in) fatigue and (improvement in) clinical and cognitive factors in patients with chronic widespread pain (CWP), participating in multidisciplinary rehabilitation treatment. METHODS: Data were used from baseline, 6 and 18 months of follow-up during a prospective cohort study of 120 CWP patients who completed multidisciplinary rehabilitation treatment. Cross-sectional and longitudinal relationships were analyzed between fatigue, clinical (i.e. pain, interference of pain and depression) and pain related cognitive factors (i.e. negative emotional cognitions, active cognitive coping, and control and chronicity beliefs). RESULTS: Higher levels of pain, interference of pain, depression, negative emotional cognitions, and negative control and chronicity beliefs were associated with a higher level of fatigue. Improvement in depression was related to improvement in fatigue. CONCLUSIONS: In CWP patients, worse clinical status, and dysfunctional pain-related cognitions are associated with a higher level of fatigue. Our results suggest that improvement in depression might be a mechanism of improvement in fatigue. Furthermore, improvement in fatigue seems to be independent of improvement in pain related cognitions. Targeting fatigue in multidisciplinary pain treatment may need specific strategies. IMPLICATIONS FOR REHABILITATION: Improvement in depression may be a mechanism of change to improve the level of fatigue in CWP. Improvement in dysfunctional (pain related) cognitions seems to be independent of improvement in fatigue. Targeting fatigue in multidisciplinary treatment may need specific strategies (e.g. additional interventions focusing on reducing fatigue and specific attention to improvement of sleep). PMID- 24954391 TI - A study of shear strength properties of municipal solid waste in Chongqing landfill, China. AB - The aim of this study is to analyze the effect of biodegradation on the shear strength of municipal solid waste (MSW), leachate, and biogas production. The direct shear (DS) test shows that the shear strength of waste in the initial stages is mainly depended on its composition and inter-structure. After the waste has been in a landfill for 30 days, the waste's increased biodegradation exhibited a great influence on the waste's shear strength. The increase of moisture content in the waste mass might cause a decrease of its shear strength. Tri-axial tests under consolidation-drained (CD) condition show that the shear strength of the cohesion and friction angle for degraded samples increased when the defined axial strain increased from 5 to 20 %. The cohesion varied from 35.90 to 66.42 kPa and the drained friction angle ranged between 29 degrees and 38 degrees . The measurements of shear strength properties are utilized to assess the slope stability of landfills. PMID- 24954387 TI - 'Black sheep' that don't leave the double-stranded RNA-binding domain fold. AB - The canonical double-stranded RNA (dsRNA)-binding domain (dsRBD) is composed of an alpha1-beta1-beta2-beta3-alpha2 secondary structure that folds in three dimensions to recognize dsRNA. Recently, structural and functional studies of divergent dsRBDs revealed adaptations that include intra- and/or intermolecular protein interactions, sometimes in the absence of detectable dsRNA-binding ability. We describe here how discrete dsRBD components can accommodate pronounced amino-acid sequence changes while maintaining the core fold. We exemplify the growing importance of divergent dsRBDs in mRNA decay by discussing Dicer, Staufen (STAU)1 and 2, trans-activation responsive RNA-binding protein (TARBP)2, protein activator of protein kinase RNA-activated (PKR) (PACT), DiGeorge syndrome critical region (DGCR)8, DEAH box helicase proteins (DHX) 9 and 30, and dsRBD-like fold-containing proteins that have ribosome-related functions. We also elaborate on the computational limitations to discovering yet-to-be identified divergent dsRBDs. PMID- 24954392 TI - Isotherm studies for the determination of Cd (II) ions removal capacity in living biomass of a microalga with high tolerance to cadmium toxicity. AB - The biosorption characteristics of Cd (II) ions using the living biomass of the marine diatom Phaeodactylum tricornutum were investigated. This microalga is a highly tolerant species to cadmium toxicity; for this reason, it is interesting to know its potential for use in the removal of this metal. The use of living biomass offers better possibilities than that of dead biomass since cadmium can also be bioaccumulated inside the cells. For this purpose, tolerant species are necessary. P. tricornutum is within this category with an EC50,96h of 19.1 +/- 3.5 mg Cd (II)/L, and in the present manuscript, it is demonstrated that this microalga has a very good potential for bioremediation of Cd (II) ions in saline habitats. Cadmium removed by the cells was divided into three fractions: total, intracellular and bioadsorbed. The experiments were conducted for 96 h in natural seawater with a concentration range of 1-100 mg Cd (II)/L. Each fraction was characterized every 24 h by sorption isotherms. The experimental isotherm data were analyzed using the Langmuir, Freundlich, Dubinin-Radushkevich and Temkin equations. The biosorption was well described by Langmuir isotherm followed by Freundlich. The worst model was Temkin. The biosorption capacity of this microalga for Cd (II) ions was found to be 67.1 +/- 3.2 mg/g after 96 h with approximately 40 % of this capacity in the intracellular fraction. The bioconcentration factor determined was 2,204.7 after 96 h and with an initial Cd (II) concentration of 1 mg/L. PMID- 24954393 TI - Pathophysiology of takotsubo syndrome: temporal phases of cardiovascular responses to extreme stress. AB - Takotsubo syndrome (TTS), also known as takotsubo cardiomyopathy, is an acute heart failure syndrome that typically occurs after a period of great emotional stress. The archetypal patient is a postmenopausal woman who presents with chest pain, ST-segment elevation and acute hypokinesia of the apical and middle segment of the left ventricle that extends beyond the territory of a single coronary artery, coupled with hyperkinesia of the basal myocardium. Recent preclinical and clinical studies have shown the importance of high catecholamine levels in precipitating TTS. We propose that this is caused by activation of beta adrenoceptors and the subsequent activation of a negatively-inotropic pathway, perhaps to protect the heart from catecholamine overload. We explore the pathophysiology of TTS according to its "phases", both preclinically and clinically. This will show that the condition is not one of static apical hypokinesia that simply improves, but rather a dynamic condition that changes as the disease progresses. We hope that further exploration of TTS using its "phases" will aid in its characterization, diagnosis and treatment. PMID- 24954395 TI - Critical Casimir interactions around the consolute point of a binary solvent. AB - Spatial confinement of a near-critical medium changes its fluctuation spectrum and modifies the corresponding order parameter distribution, resulting in effective, so-called critical Casimir forces (CCFs) acting on the confining surfaces. These forces are attractive for like boundary conditions of the order parameter at the opposing surfaces of the confinement. For colloidal particles dissolved in a binary liquid mixture acting as a solvent close to its critical point of demixing, one thus expects the emergence of phase segregation into equilibrium colloidal liquid and gas phases. We analyze how such phenomena occur asymmetrically in the whole thermodynamic neighborhood of the consolute point of the binary solvent. By applying field-theoretical methods within mean-field approximation and the semi-empirical de Gennes-Fisher functional, we study the CCFs acting between planar parallel walls as well as between two spherical colloids and their dependence on temperature and on the composition of the near critical binary mixture. We find that for compositions slightly poor in the molecules preferentially adsorbed at the surfaces, the CCFs are significantly stronger than at the critical composition, thus leading to pronounced colloidal segregation. The segregation phase diagram of the colloid solution following from the calculated effective pair potential between the colloids agrees surprisingly well with experiments and simulations. PMID- 24954397 TI - Triggered dynamics in a model of different fault creep regimes. AB - The study is focused on the effect of transient external force induced by a passing seismic wave on fault motion in different creep regimes. Displacement along the fault is represented by the movement of a spring-block model, whereby the uniform and oscillatory motion correspond to the fault dynamics in post seismic and inter-seismic creep regime, respectively. The effect of the external force is introduced as a change of block acceleration in the form of a sine wave scaled by an exponential pulse. Model dynamics is examined for variable parameters of the induced acceleration changes in reference to periodic oscillations of the unperturbed system above the supercritical Hopf bifurcation curve. The analysis indicates the occurrence of weak irregular oscillations if external force acts in the post-seismic creep regime. When fault motion is exposed to external force in the inter-seismic creep regime, one finds the transition to quasiperiodic- or chaos-like motion, which we attribute to the precursory creep regime and seismic motion, respectively. If the triggered acceleration changes are of longer duration, a reverse transition from inter seismic to post-seismic creep regime is detected on a larger time scale. PMID- 24954399 TI - First pass intestinal and liver metabolism of paracetamol in a microfluidic platform coupled with a mathematical modeling as a means of evaluating ADME processes in humans. AB - We developed a microfluidic platform to investigate paracetamol intestinal and liver first pass metabolism. This approach was coupled with a mathematical model to estimate intrinsic in vitro parameters and to predict in vivo processes. The kinetic modeling estimated the paracetamol and paracetamol sulfate permeabilities, the sulfate and glucuronide effluxes in the intestine compartment. Based on a gut model, we estimated intrinsic intestinal clearance of between 26 and 77 L/h for paracetamol in humans, a permeability of 10 L/h, and a gut availability between 0.17 and 0.53 (compared to 0.95-1 in vivo). The role played by the liver in paracetamol metabolism was estimated via in vitro intrinsic clearances of 7.6, 13.6, and 11.5 uL/min/10(6) cells for HepG2/C3a, rat primary hepatocytes, and human primary hepatocytes, respectively. Based on a parallel tube model to describe the liver, the paracetamol hepatic clearance, and the paracetamol hepatic availability in humans were estimated at 6.5 mL/min/kg of bodyweight (BDW) and 0.7, respectively (when compared to 5 mL/min/kg of BDW and 0.77 to 0.88 for in vivo values, respectively). The drug availability was predicted ranging between 0.24 and 0.41 (0.88 in vivo). The overall approach provided a first step in an integrated strategy combining in silico/in vitro methods based on microfluidic for evaluating drug absorption, distribution and metabolism processes. PMID- 24954394 TI - Metabolomics of ApcMin/+ mice genetically susceptible to intestinal cancer. AB - BACKGROUND: To determine how diets high in saturated fat could increase polyp formation in the mouse model of intestinal neoplasia, ApcMin/+, we conducted large-scale metabolome analysis and association study of colon and small intestine polyp formation from plasma and liver samples of ApcMin/+ vs. wild-type littermates, kept on low vs. high-fat diet. Label-free mass spectrometry was used to quantify untargeted plasma and acyl-CoA liver compounds, respectively. Differences in contrasts of interest were analyzed statistically by unsupervised and supervised modeling approaches, namely Principal Component Analysis and Linear Model of analysis of variance. Correlation between plasma metabolite concentrations and polyp numbers was analyzed with a zero-inflated Generalized Linear Model. RESULTS: Plasma metabolome in parallel to promotion of tumor development comprises a clearly distinct profile in ApcMin/+ mice vs. wild type littermates, which is further altered by high-fat diet. Further, functional metabolomics pathway and network analyses in ApcMin/+ mice on high-fat diet revealed associations between polyp formation and plasma metabolic compounds including those involved in amino-acids metabolism as well as nicotinamide and hippuric acid metabolic pathways. Finally, we also show changes in liver acyl-CoA profiles, which may result from a combination of ApcMin/+-mediated tumor progression and high fat diet. The biological significance of these findings is discussed in the context of intestinal cancer progression. CONCLUSIONS: These studies show that high-throughput metabolomics combined with appropriate statistical modeling and large scale functional approaches can be used to monitor and infer changes and interactions in the metabolome and genome of the host under controlled experimental conditions. Further these studies demonstrate the impact of diet on metabolic pathways and its relation to intestinal cancer progression. Based on our results, metabolic signatures and metabolic pathways of polyposis and intestinal carcinoma have been identified, which may serve as useful targets for the development of therapeutic interventions. PMID- 24954396 TI - Correlating atomic structure and transport in suspended graphene nanoribbons. AB - Graphene nanoribbons (GNRs) are promising candidates for next generation integrated circuit (IC) components; this fact motivates exploration of the relationship between crystallographic structure and transport of graphene patterned at IC-relevant length scales (<10 nm). We report on the controlled fabrication of pristine, freestanding GNRs with widths as small as 0.7 nm, paired with simultaneous lattice-resolution imaging and electrical transport characterization, all conducted within an aberration-corrected transmission electron microscope. Few-layer GNRs very frequently formed bonded-bilayers and were remarkably robust, sustaining currents in excess of 1.5 MUA per carbon bond across a 5 atom-wide ribbon. We found that the intrinsic conductance of a sub-10 nm bonded bilayer GNR scaled with width as GBL(w) ~ 3/4(e(2)/h)w, where w is the width in nanometers, while a monolayer GNR was roughly five times less conductive. Nanosculpted, crystalline monolayer GNRs exhibited armchair terminated edges after current annealing, presenting a pathway for the controlled fabrication of semiconducting GNRs with known edge geometry. Finally, we report on simulations of quantum transport in GNRs that are in qualitative agreement with the observations. PMID- 24954401 TI - Sonographic appearance of the iliocapsularis muscle of the hip. PMID- 24954400 TI - Dural herniation of the spinal cord: a rare cause of myelopathy with unique imaging features. PMID- 24954402 TI - Monitoring daily function in persons with transfemoral amputations using a commercial activity monitor: a feasibility study. AB - OBJECTIVE: To assess in a feasibility study the mobility of persons with transfemoral amputations using data collected from a popular, consumer-oriented activity monitor (Fitbit). DESIGN: Observational cohort study. SETTING: Research hospital outpatient evaluation. PARTICIPANTS: Nine subjects with transfemoral amputations (4 women and 5 men, ages 21-64 years) and Medicare functional assessments (K level) of K3 (n = 7), K2 (n = 1), and K4 (n = 1). METHODS: One week monitoring of physical activity using the Fitbit One activity monitor. MAIN OUTCOME MEASURES: Daily estimates of step counts, distance walked, floors/stairs climbed, calories burned, and proprietary Fitbit activity scores. For each day, the amount of time in each of the following levels of activity was also reported: sedentary, lightly active, fairly active, and highly active. RESULTS: The percentage of movement time above the fairly active level had a predictable relationship to the designated K level. The average activity measures show decreased levels of activity for obese subjects (body mass index >30). Estimated step counts were highly predictive/redundant with estimated miles walked without setting individual stride lengths. Using linear regression prediction models, calorie estimates were found to be highly dependent on subject age, height, and weight, whereas the proprietary activity score was independent of all 3 demographic factors. CONCLUSIONS: This feasibility study demonstrates that the Fitbit activity monitor estimates the activity of subjects with transfemoral amputations, producing results that correlate with their K-level functional activity classifications. The Fitbit activity score is independent of individual variations in age, weight, and height compared with estimated calories for this small sample size. These tools may provide useful insights into prosthetic use in an at-home environment. PMID- 24954404 TI - Sortagging: a robust and efficient chemoenzymatic ligation strategy. AB - Bioorthogonal, chemoselective ligation methods are an essential part of the tools utilized to investigate biochemical pathways. Specifically enzymatic approaches are valuable methods in this context due to the inherent specificity of the deployed enzymes and the mild conditions of the modification reactions. One of the most common strategies is based on the transpeptidation catalyzed by sortase A derived from Staphylococcus aureus. The procedure is well established and a wide variety of applications have been published to date. Here, implementations of sortase A, which range from protein labeling using fluorescence dyes and the preparation of cyclic proteins to the modification of entire cells, are summarized. Furthermore, there is a focus on the optimization approaches established to solve the drawbacks of sortase-mediated transpeptidation. PMID- 24954403 TI - Detection of brucellosis and leptospirosis in feral pigs in New South Wales. AB - OBJECTIVE: To determine the presence and estimate the prevalence of Brucella suis, Leptospira interrogans serovar Pomona (hereafter L. pomona) and Leptospira borgpetersenii serovar Hardjo (hereafter L. hardjo) in feral pigs culled in New South Wales (NSW), Australia. METHODS: During 2012 and 2013, 239 serum samples were collected from feral pigs killed as pests or game in NSW. All sera were subjected to the rose-bengal test for B. suis, with positives subjected to the complement fixation test (CFT). Attempts were made to detect B. suis by culture and PCR on CFT-positive samples. All sera were tested separately for the presence of L. pomona and L. hardjo antibodies using the microscopic agglutination test. RESULTS: Of 238 samples tested, 7 were positive (4 with CFT titres >= 32) for B. suis antibodies (3% seroprevalence). However, B. suis was not cultured or detected by PCR. Of 239 sera tested for L. pomona antibodies, 126 samples were positive (53%) and 9 (4%) were positive for L. hardjo. CONCLUSIONS: The findings are the first tangible evidence that feral pigs in northern NSW harbour B. suis, providing a plausible explanation for recent human and canine cases of brucellosis related to pig hunting. The increased seroprevalence of L. pomona occurred in years preceded by flooding and rodent plagues, suggesting a potential for zoonotic infection much greater than previously realised. Advice to the community should focus on encouraging the adoption of improved hygiene practices during pig hunting and consideration of vaccinating livestock against leptospirosis. PMID- 24954405 TI - Modelling the root system architecture of Poaceae. Can we simulate integrated traits from morphological parameters of growth and branching? AB - Our objective was to calibrate a model of the root system architecture on several Poaceae species and to assess its value to simulate several 'integrated' traits measured at the root system level: specific root length (SRL), maximum root depth and root mass. We used the model ArchiSimple, made up of sub-models that represent and combine the basic developmental processes, and an experiment on 13 perennial grassland Poaceae species grown in 1.5-m-deep containers and sampled at two different dates after planting (80 and 120 d). Model parameters were estimated almost independently using small samples of the root systems taken at both dates. The relationships obtained for calibration validated the sub-models, and showed species effects on the parameter values. The simulations of integrated traits were relatively correct for SRL and were good for root depth and root mass at the two dates. We obtained some systematic discrepancies that were related to the slight decline of root growth in the last period of the experiment. Because the model allowed correct predictions on a large set of Poaceae species without global fitting, we consider that it is a suitable tool for linking root traits at different organisation levels. PMID- 24954406 TI - Lid closure mechanism of Yarrowia lipolytica lipase in methanol investigated by molecular dynamics simulation. AB - In nonaqueous organic solvents, lipases can catalyze esterification reactions, which increase their application value. Yarrowia lipolytica Lipase (Lip2) possesses potential values in medicine and industrial production. In order to investigate its lid closure mechanism in methanol we performed molecular dynamics (MD) simulations of the open conformation of Lip2 in methanol and hexane, respectively. Simulation results indicated that Lip2 undergoes a greater conformational change in methanol. Principle component analysis showed Lip2 has "double-domain" and "torsion" motion modes in hexane and methanol. By analyzing B factor and dynamical cross-correlation, region Ser274-Asn288, region Thr106 His126, and region Asp61-Asp67 were found to interact with the lid region (Thr88 Leu105). Furthermore, local restricted MD simulations showed that closure mechanism of Lip2 is "double-lid movement" which is also observed in Pseudomonas aeruginosa Lipase (PAL), and we detected two interaction propagation pathways in Lip2 driven by the interaction between Ser274-Asn288 and methanol. PMID- 24954407 TI - A mammary repopulating cell population characterized in mammary anlagen reveals essential mammary stroma for morphogenesis. AB - The cells with mammary repopulating capability can achieve mammary gland morphogenesis in a suitable cellular microenvironment. Using cell surface markers of CD24, CD29 and CD49f, mouse mammary repopulating unit (MRU) has been identified in adult mammary epithelium and late embryonic mammary bud epithelium. However, embryonic MRU remains to be fully characterized at earlier mammary anlagen stage. Here we isolated discrete populations of E14.5 mouse mammary anlagen cells. Only Lin(-)CD24(med)CD29(+) cell population was predicted as E14.5 MRU by examining their capacities of forming mammosphere and repopulating cleared mammary fat pad in vivo. However, when we characterized gene expressions of this E14.5 cell population by comparing with adult mouse MRU (Lin(-)CD24(+)CD29(hi)), the gene profiling of these two cell populations exhibited great differences. Real-time PCR and immunostaining assays uncovered that E14.5 Lin( )CD24(med)CD29(+) cell population was a heterogeneous stroma-enriched cell population. Then, limiting dilutions and single-cell assays also confirmed that E14.5 Lin(-)CD24(med)CD29(+) cell population possessed low proportion of stem cells. In summary, heterogeneous Lin(-)CD24(med)CD29(+) cell population exhibited mammary repopulating ability in E14.5 mammary anlagen, implying that only suitable mammary stroma could enable mammary gland morphogenesis, which relied on the interaction between rare stem cells and microenvironment. PMID- 24954408 TI - Tonsil-derived mesenchymal stem cells alleviate concanavalin A-induced acute liver injury. AB - Acute liver failure, the fatal deterioration of liver function, is the most common indication for emergency liver transplantation, and drug-induced liver injury and viral hepatitis are frequent in young adults. Stem cell therapy has come into the limelight as a potential therapeutic approach for various diseases, including liver failure and cirrhosis. In this study, we investigated therapeutic effects of tonsil-derived mesenchymal stem cells (T-MSCs) in concanavalin A (ConA)- and acetaminophen-induced acute liver injury. ConA-induced hepatitis resembles viral and immune-mediated hepatic injury, and acetaminophen overdose is the most frequent cause of acute liver failure in the United States and Europe. Intravenous administration of T-MSCs significantly reduced ConA-induced hepatic toxicity, but not acetaminophen-induced liver injury, affirming the immunoregulatory capacity of T-MSCs. T-MSCs were successfully recruited to damaged liver and suppressed inflammatory cytokine secretion. T-MSCs expressed high levels of galectin-1 and -3, and galectin-1 knockdown which partially diminished interleukin-2 and tumor necrosis factor alpha secretion from cultured T-cells. Galectin-1 knockdown in T-MSCs also reversed the protective effect of T MSCs on ConA-induced hepatitis. These results suggest that galectin-1 plays an important role in immunoregulation of T-MSCs, which contributes to their protective effect in immune-mediated hepatitis. Further, suppression of T-cell activation by frozen and thawed T-MSCs implies great potential of T-MSC banking for clinical utilization in immune-mediated disease. PMID- 24954409 TI - B-plexins control microtubule dynamics and dendrite morphology of hippocampal neurons. AB - Semaphorins and their receptors plexins are implicated in various processes in the nervous system, but how B-plexins regulate the growth of dendrites remains poorly characterized. We had previously observed that Plexin-B1 and B3 interact with microtubule end-binding proteins (EBs) that are central adapters at growing microtubule tips, and this interaction is involved in neurite growth. Therefore, we hypothesized that plexins regulate microtubule dynamics and through that also dendritogenesis. The role of all three B-plexins was systematically examined in these processes. B-plexins and their ligand Semaphorin-4D influence the dynamics of microtubule tips both EB-dependently and independendently. EB3 as well as Plexin-B1, B2 and B3 turned out to have a significant role in the development of dendritic arbor of rat hippocampal neurons. Our results clearly indicate that semaphorin-plexin-EB pathway is one molecular mechanism how extracellular guidance cues are translated into intracellular mechanics. Taken together, Semaphorin-4D and B-plexins modulate the dynamic behavior of microtubule tips, and are therefore important in neurite growth. PMID- 24954412 TI - [Snow-blindness in the splendor of Antiquity]. PMID- 24954410 TI - Pulmonary administration of integrin-nanoparticles regenerates collapsed alveoli. AB - Chronic obstructive pulmonary disease (COPD) is an intractable pulmonary disease, causes widespread and irreversible alveoli collapse. In search of a treatment target molecule, which is able to regenerate collapsed alveoli, we sought to identify a factor that induces differentiation in human alveolar epithelial stem cells using all-trans retinoic acid (ATRA), whose alveolar repair capacity has been reported in animal experiments. When human alveolar epithelial stem cells were exposed to ATRA at a concentration of 10MUM for over seven days, approximately 20% of the cells differentiated into each of the type-I and type-II alveolar epithelial cells that constitute the alveoli. In a microarray analysis, integrin-alpha1 and integrin-beta3 showed the largest variation in the ATRA treated group compared with the controls. Furthermore, the effect of the induction of differentiation in human alveolar epithelial stem cells using ATRA was suppressed by approximately one-fourth by siRNA treatments with integrin alpha1 and integrin beta3. These results suggested that integrin alpha1 and beta3 are factors responsible for the induction of differentiation in human alveolar epithelial stem cells. We accordingly investigated whether integrin nanoparticles also had a regenerative effect in vivo. Elastase-induced COPD model mouse was produced, and the alveolar repair effect of pulmonary administration using nanoparticles of integrin protein was evaluated by X-ray CT scanning. Improvement in the CT value in comparison with an untreated group indicated that there was an alveolar repair effect. In this study, it was shown that the differentiation inducing effect on human alveolar epithelial stem cells by ATRA was induced by increased expression of integrin, and that the induced integrin enhanced phosphorylation signaling of AKT, resulting in inducing differentiations. Furthermore, the study demonstrated that lung administration of nanoparticles with increased solubility and stability of integrin repaired the alveolus of an Elastase-induced COPD model mouse. Those results show that those integrin nanoparticles are effective as novel COPD treatment target compounds. PMID- 24954411 TI - Infantile postnatal exposure to lead (Pb) enhances tau expression in the cerebral cortex of aged mice: relevance to AD. AB - The sporadic nature in over 90% of Alzheimer's disease (AD) cases, the differential susceptibility and course of illness, and latent onset of the disease suggest involvement of an environmental component in the etiology of late onset AD (LOAD). Recent reports from our lab have demonstrated that molecular alterations favor abundant tau phosphorylation and immunoreactivity in the frontal cortex of aged primates with infantile lead (Pb) exposure (Bihaqi and Zawia, 2013). Here we report that developmental Pb exposure results in elevation of protein and mRNA levels of tau in aged mice. Western blot analysis revealed aberrant site-specific tau hyperphosphorylation accompanied by elevated cyclin dependent kinase 5 (CDK5) levels in aged mice with prior Pb exposure. Mice with developmental Pb exposure also displayed altered protein ratio of p35/p25 with more Serine/Threonine phosphatase activity at old age. These changes favored increase in tau phosphorylation, thus providing evidence that neurodegenerative diseases may be in part due to environmental influences that occur during development. PMID- 24954413 TI - Peripheral yttrium aluminium garnet (YAG) iridotomy versus phacoemulsification in primary angle closure: prospective comparative study. AB - PURPOSE: A study was designed to determine and describe the changes induced in the anterior segment of the eye and the intraocular pressure (IOP) after laser peripheral iridotomy (LPI) versus phacoemulsification in primary angle closure suspects (PACS) and primary angle closure (PAC). METHODS: Forty-seven eyes (47 patients) with Shaffer gonioscopy 0-II were included and split into 2 groups: cataract surgery (n=29) or LPI (n=18), depending on the lens sclerosis and visual acuity. Tonometry, gonioscopy, funduscopy, and automated measurements of the anterior chamber by Pentacam were performed before the intervention, and one and 3 months after the technique. RESULTS: Phacoemulsification reduces IOP after one and 3 months (P<.01). LPI reduces IOP after 3 months (P<.04), and after one month (P<.38). IOP was 16.2mmHg (SD: 3.59) in the phacoemulsification group vs. 16.83mmHg (SD: 2.36) in the LPI group after one month (P=.4), and 15.52 (SD: 2.95) vs. 16.05 (SD: 2.46) in the third month (P=.5). There were no significant differences in the antiglaucoma drugs. Shaffer gonioscopy grading was greater in the phacoemulsification group vs. in the LPI group one and 3 months after the intervention (P=.01). The highest difference between both techniques was found in the superior quadrant. The anterior chamber depth, angle and volume by Pentacam were wider in the phacoemulsification group after one and 3 months (P<.01). CONCLUSIONS: Although phacoemulsification and LPI could both be effective techniques in the prevention of pupillary block in PAC, faster and greater amplitude of the angle and the anterior chamber can be obtained after phacoemulsification than after LPI. PMID- 24954414 TI - Relationship between contrast sensitivity test and disease severity in multiple sclerosis patients. AB - OBJECTIVE: To assess the importance of the Pelli-Robson contrast sensitivity test in multiple sclerosis patients according to the Expanded Disability Status Scale (EDSS). MATERIAL AND METHODS: A total of 62 patients with multiple sclerosis were included in a retrospective study. Patients were enrolled from the Neurology Department to Neuroophthalmology at Virgen de la Victoria Hospital. Patients were classified into 3 groups according to EDSS: group A) lower than 1.5, group B) between 1.5 and 3.5 and group C) greater than 3.5. Visual acuity and monocular and binocular contrast sensitivity were performed with Snellen and Pelli-Robson tests respectively. Twelve disease-free control participants were also recruited. Correlations between parameter changes were analyzed. RESULTS: The mean duration of the disease was 81.54+/-35.32 months. Monocular and binocular Pelli-Robson mean values in the control group were 1.82+/-0.10 and 1.93+/-0.43 respectively, and 1.61+/-0.29 and 1.83+/-0.19 in multiple sclerosis patients. There were statistically significant differences in the monocular analysis for a level of significance P<.05. Mean monocular and binocular Pelli-Robson values in relation to gravity level were, in group A: 1.66+/-0.24 and 1.90+/-0.98, group B: 1.64+/ 0.21 and 1.82+/-0.16, and group C: 1.47+/-0.45 and 1.73+/-0.32 respectively. Group differences were statistically significant in both tests: P=.05 and P=.027. CONCLUSIONS: Monocular and binocular contrast discrimination analyzed using the Pelli-Robson test was found to be significantly lower when the severity level, according EDSS, increases in multiple sclerosis patients. PMID- 24954415 TI - Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2. AB - Hepatic insulin resistance is a key contributor to the pathogenesis of obesity and type 2 diabetes (T2D). Paradoxically, the development of insulin resistance in the liver is not universal, but pathway selective, such that insulin fails to suppress gluconeogenesis but promotes lipogenesis, contributing to the hyperglycemia, steatosis, and hypertriglyceridemia that underpin the deteriorating glucose control and microvascular complications in T2D. The molecular basis for the pathway-specific insulin resistance remains unknown. Here we report that oxidative stress accompanying obesity inactivates protein-tyrosine phosphatases (PTPs) in the liver to activate select signaling pathways that exacerbate disease progression. In obese mice, hepatic PTPN2 (TCPTP) inactivation promoted lipogenesis and steatosis and insulin-STAT-5 signaling. The enhanced STAT-5 signaling increased hepatic IGF-1 production, which suppressed central growth hormone release and exacerbated the development of obesity and T2D. Our studies define a mechanism for the development of selective insulin resistance with wide-ranging implications for diseases characterized by oxidative stress. PMID- 24954416 TI - SDHAF4 promotes mitochondrial succinate dehydrogenase activity and prevents neurodegeneration. AB - Succinate dehydrogenase (SDH) occupies a central place in cellular energy production, linking the tricarboxylic cycle with the electron transport chain. As a result, a subset of cancers and neuromuscular disorders result from mutations affecting any of the four SDH structural subunits or either of two known SDH assembly factors. Herein we characterize an evolutionarily conserved SDH assembly factor designated Sdh8/SDHAF4, using yeast, Drosophila, and mammalian cells. Sdh8 interacts specifically with the catalytic Sdh1 subunit in the mitochondrial matrix, facilitating its association with Sdh2 and the subsequent assembly of the SDH holocomplex. These roles for Sdh8 are critical for preventing motility defects and neurodegeneration in Drosophila as well as the excess ROS generated by free Sdh1. These studies provide insights into the mechanisms by which SDH is assembled and raise the possibility that some forms of neuromuscular disease may be associated with mutations that affect this SDH assembly factor. PMID- 24954417 TI - The LYR factors SDHAF1 and SDHAF3 mediate maturation of the iron-sulfur subunit of succinate dehydrogenase. AB - Disorders arising from impaired assembly of succinate dehydrogenase (SDH) result in a myriad of pathologies, consistent with its unique role in linking the citric acid cycle and electron transport chain. In spite of this critical function, however, only a few factors are known to be required for SDH assembly and function. We show here that two factors, Sdh6 (SDHAF1) and Sdh7 (SDHAF3), mediate maturation of the FeS cluster SDH subunit (Sdh2/SDHB). Yeast and Drosophila lacking SDHAF3 are impaired in SDH activity with reduced levels of Sdh2. Drosophila lacking the Sdh7 ortholog SDHAF3 are hypersensitive to oxidative stress and exhibit muscular and neuronal dysfunction. Yeast studies revealed that Sdh6 and Sdh7 act together to promote Sdh2 maturation by binding to a Sdh1/Sdh2 intermediate, protecting it from the deleterious effects of oxidants. These studies in yeast and Drosophila raise the possibility that SDHAF3 mutations may be associated with idiopathic SDH-associated diseases. PMID- 24954419 TI - Interglacial genetic diversification of Moussonia deppeana (Gesneriaceae), a hummingbird-pollinated, cloud forest shrub in northern Mesoamerica. AB - Recent empirical work on cloud forest-adapted species supports the role of both old divergences across major geographical areas and more recent divergences attributed to Pleistocene climate changes. The shrub Moussonia deppeana is distributed in northern Mesoamerica, with geographically disjunct populations. Based on sampling throughout the species range and employing plastid and nuclear markers, we (i) test whether the fragmented distribution is correlated with main evolutionary lineages, (ii) reconstruct its phylogeographical history to infer the history of cloud forest in northern Mesoamerica and (iii) evaluate a set of refugia/vicariance scenarios for the region and demographic patterns of the populations whose ranges expanded and tracked cloud forest conditions during the Last Glacial Maximum. We found a deep evolutionary split in M. deppeana about 6-3 Ma, which could be consistent with a Pliocene divergence. Comparison of variation in plastid and nuclear markers revealed several lineages mostly congruent with their isolated geographical distribution and restricted gene flow among groups. Results of species distribution modelling and coalescent simulations fit a model of multiple refugia diverging during interglacial cycles. The demographic history of M. deppeana is not consistent with an expanding-contracting cloud forest archipelago model during the Last Glacial Maximum. Instead, our data suggest that populations persisted across the geographical range throughout the glacial cycles, and experienced isolation and divergence during interglacial periods. PMID- 24954420 TI - Impact of porcine circovirus type 2 (PCV2) vaccination on boar semen quality and quantity using two different vaccines. AB - Porcine circovirus type-2 (PCV2) is widespread in domestic pig populations. It can be shed with boar semen, but the role boars have in epidemiology is still unclear. Vaccinating boars against PCV2 can reduce disease and virus load in semen, but may have unwanted side effects, that is, impairment of spermatogenesis. Therefore, the aim of this study was to investigate the effect and impact of two different PCV2 vaccines on boar semen quality and quantity. Healthy normospermic Large White boars in three groups of 12 each were vaccinated with either Circovac, Ingelvac CircoFLEX, or received NaCl. Eight ejaculates were collected starting 1 week after vaccination and assessed for quantitative traits. In general, sperm quantity and quality parameters did not change due to the vaccination (P > 0.05). Only DNA integrity between the Circovac and control group was P < 0.05 but remained at a low level (<2%). One boar showed clinical signs with body temperature up to 39.9 degrees C and went off feed. For this animal, a clear relation between vaccination, fever period, and impaired sperm quality could be observed. The results indicate that both vaccines did not have a major impact on sperm quality or quantity. Therefore, vaccination of boars against PCV2 seems to be feasible. However, one boar treated with the oil-based vaccine showed a temporarily impaired semen quality after elevated body temperature after vaccination. Thus, possible systemic reactions and the subsequent impact on sperm quality should be taken into account when choosing a PCV2 vaccine for boars. PMID- 24954422 TI - Shifts in population dietary patterns and physical inactivity as determinants of global trends in the prevalence of diabetes: an ecological analysis. AB - BACKGROUND AND AIMS: The worldwide epidemiology of diabetes is rapidly changing as a result of the spreading of westernised nutritional and lifestyle habits. We conducted an ecological analysis to identify dietary, lifestyle and socio economic factors associated with global diabetes prevalence. METHODS AND RESULTS: Country-specific estimates of diabetes prevalence were obtained. Data were then matched to year- and country-specific food and energy availability for consumption, and to year-specific information on obesity, physical inactivity, urbanisation, gross domestic product (GDP), and smoking. Data were obtained from publicly available databases compiled by the Food Agricultural Organisation (FAO), World Health Organisation (WHO) and World Bank. Cluster analysis was used to derive dietary patterns of global food consumption. The association with diabetes prevalence was evaluated. Stepwise multiple regression analysis was conducted to identify predictors associated with worldwide diabetes prevalence. 96 countries were eligible for inclusion in the analysis. The average diabetes prevalence was 7.0% and the highest rate was observed in the Middle-Eastern region (13.1%). The worldwide prevalence of obesity and physical inactivity was 15.1% and 36.1%, respectively. Diabetes prevalence was associated with age and physical inactivity prevalence in a fully adjusted multiple regression model. Three dietary patterns (agricultural, transitional and westernised) were identified by the cluster analysis. Diabetes prevalence showed a direct dose response association with the degree of exposure to a westernised dietary pattern. CONCLUSIONS: The adoption of sedentary lifestyle and westernised dietary patterns appears to be closely linked to the global rise in diabetes prevalence. PMID- 24954418 TI - The cholesterol metabolite 27-hydroxycholesterol promotes atherosclerosis via proinflammatory processes mediated by estrogen receptor alpha. AB - Oxysterols are cholesterol metabolites that serve multiple functions in lipid metabolism, including as liver X receptor (LXR) ligands. 27-hydroxycholesterol (27HC) is an abundant oxysterol metabolized by CYP7B1. How 27HC impacts vascular health is unknown. We show that elevations in 27HC via cyp7b1 deletion promote atherosclerosis in apoe(-/-) mice without altering lipid status; furthermore, estrogen-related atheroprotection is attenuated. In wild-type mice, leukocyte endothelial cell adhesion is increased by 27HC via estrogen receptor (ER) dependent processes. In monocytes/macrophages, 27HC upregulates proinflammatory genes and increases adhesion via ERalpha. In endothelial cells, 27HC is also proadhesive via ERalpha, and in contrast to estrogen, which blunts NF-kappaB activation, 27HC stimulates NF-kappaB activation via Erk1,2 and JNK-dependent IkappaBalpha degradation. Whereas 27HC administration to apoe(-/-) mice increases atherosclerosis, apoe(-/-);eralpha(-/-) are unaffected. Thus, 27HC promotes atherosclerosis via proinflammatory processes mediated by ERalpha, and it attenuates estrogen-related atheroprotection. Strategies to lower 27HC may complement approaches targeting cholesterol to prevent vascular disease. PMID- 24954421 TI - High density lipoprotein metabolism in low density lipoprotein receptor-deficient mice. AB - The LDL receptor (LDLR) and scavenger receptor class B type I (SR-BI) play physiological roles in LDL and HDL metabolism in vivo. In this study, we explored HDL metabolism in LDLR-deficient mice in comparison with WT littermates. Murine HDL was radiolabeled in the protein ((125)I) and in the cholesteryl ester (CE) moiety ([(3)H]). The metabolism of (125)I-/[(3)H]HDL was investigated in plasma and in tissues of mice and in murine hepatocytes. In WT mice, liver and adrenals selectively take up HDL-associated CE ([(3)H]). In contrast, in LDLR(-/-) mice, selective HDL CE uptake is significantly reduced in liver and adrenals. In hepatocytes isolated from LDLR(-/-) mice, selective HDL CE uptake is substantially diminished compared with WT liver cells. Hepatic and adrenal protein expression of lipoprotein receptors SR-BI, cluster of differentiation 36 (CD36), and LDL receptor-related protein 1 (LRP1) was analyzed by immunoblots. The respective protein levels were identical both in hepatic and adrenal membranes prepared from WT or from LDLR(-/-) mice. In summary, an LDLR deficiency substantially decreases selective HDL CE uptake by liver and adrenals. This decrease is independent from regulation of receptor proteins like SR-BI, CD36, and LRP1. Thus, LDLR expression has a substantial impact on both HDL and LDL metabolism in mice. PMID- 24954423 TI - Is a specific drinking pattern a consistent feature of the Mediterranean diet in Spain in the XXI century? AB - BACKGROUND AND AIM: Over the last 50 years, people in Spain have increasingly been eating their main meal away from home and are shifting from the typical Mediterranean diet (MD). In addition, wine consumption has decreased whereas beer intake has risen. Consequently, it is uncertain if the Mediterranean drinking pattern (MDP; moderate alcohol intake mainly from wine and during meals) is a habitual feature of the MD today. METHODS AND RESULTS: Cross-sectional study conducted from 2008 to 2010 among 8894 individuals representative of the Spanish population aged 18-64 years. Consumption of alcoholic beverages and food was collected with a validated diet history. Accordance with the MD was defined as a score >=8 on the Mediterranean Diet Adherence Screener (MEDAS) or >=5 in the Trichopoulou index (after excluding alcohol intake from both indices). Among individuals with MEDAS-based MD accordance, only 17.1% had a MDP. After adjustment for potential confounders, this drinking pattern showed a weak association with higher MD accordance (odds ratio (OR) 1.32; 95% confidence interval (CI) 1.12-1.57). Only 14.7% of those with Trichopoulou-based MD accordance had a MDP; this pattern showed an even weaker association with higher MD accordance (OR 1.17; 95% CI 1.01-1.36). Similar results were obtained when this drinking pattern was redefined to include persons who drank wine with or outside of meals, as well as those who were primarily beer drinkers. CONCLUSIONS: The MDP is not a habitual feature of the MD in the early XXI century in Spain. PMID- 24954424 TI - Therapeutic strategies for metabolic diseases: Small-molecule diacylglycerol acyltransferase (DGAT) inhibitors. AB - Metabolic diseases such as atherogenic dyslipidemia, hepatic steatosis, obesity, and type II diabetes are emerging as major global health problems. Acyl CoA:diacylglycerol acyltransferase (DGAT) is responsible for catalyzing the final reaction in the glycerol phosphate pathway of triglycerol synthesis. It has two isoforms, DGAT-1 and DGAT-2, which are widely expressed and present in white adipose tissue. DGAT-1 is most highly expressed in the small intestine, whereas DGAT-2 is primarily expressed in the liver. Therefore, the selective inhibition of DGAT-1 has become an attractive target with growing potential for the treatment of obesity and type II diabetes. Furthermore, DGAT-2 has been suggested as a new target for the treatment of DGAT-2-related liver diseases including hepatic steatosis, hepatic injury, and fibrosis. In view the discovery of drugs that target DGAT, herein we attempt to provide insight into the scope and further reasons for optimization of DGAT inhibitors. PMID- 24954425 TI - Midurethral autologous fascial sling surgery with reconstruction of the lower abdominal wall using the tensor fascia lata muscle flap for post-hemipelvectomy stress urinary incontinence. AB - Hemipelvectomy is surgery for pelvic bone neoplasms. In the case of pubic bone osteosarcoma, the distal end of the rectus abdominis muscle is severed from the pubic and ischium bones, and the pelvic floor muscles are resected en bloc with the bone, which leads to stress urinary incontinence. Cancer control is prioritized over complications, and stress urinary incontinence is generally disregarded. A 25-year-old woman presented with stress urinary incontinence. She had undergone a hemipelvectomy for left pubic bone osteosarcoma, and stress urinary incontinence appeared and persisted since the surgery. We carried out a reconstruction of the tissue deficit of the rectus abdominis using the tensor fascia lata muscle flap simultaneously with a midurethral autologous fascial sling anchoring to the tensor fascia lata flap. Stress incontinence was successfully improved without morbidity. This is the first reported case of midurethral suspension with reconstruction of the lower abdominal wall with the tensor fascia lata flap for post-hemipelvectomy stress urinary incontinence. PMID- 24954426 TI - Are peripherally inserted central catheters associated with increased risk of adverse events in status 1B patients awaiting transplantation on continuous intravenous milrinone? AB - BACKGROUND: Peripherally inserted central catheters (PICCs) are used to deliver continuous intravenous (IV) milrinone in stage D heart failure (HF) patients awaiting heart transplantation (HT). METHODS: We retrospectively analyzed PICC adverse events (AEs) and associated cost in 129 status 1B patients from 2005 to 2012. End points were HT, left ventricular assist device (LVAD), and death. Regression analysis was used to identify AE risk factors. RESULTS: Fifty-three PICC AEs occurred in 35 patients (27%), consisting of 48 infections, 4 thromboses, and 1 bleeding event. Median duration of PICC support was 63 (interquartile range [IQR] 34-131) days, and median time to first PICC infection was 44 (IQR 14-76) days. Among PICC infections, 9% required defibrillator removal and 30% were inactivated on the HT list for a mean of 23 +/- 17 days. Rate of HT, LVAD, or death was similar between groups (P > .05). Regression analysis found that a double lumen PICC was associated with a shorter time to first PICC infection (hazard ratio 7.59, 95% CI 1.97-29.23; P = .003). Median cost per PICC infection was $10,704 (IQR $7,401-$26,083). CONCLUSIONS: PICC infections were the most frequent AEs. PICCs with >1 lumen were associated with increased risk of infection. PICC AEs accounted for increased intensive care unit admissions, HT list inactivations, and overall cost. PMID- 24954427 TI - Predictors of memory performance among Taiwanese postmenopausal women with heart failure. AB - BACKGROUND: There are no studies describing the nature of memory deficits among women with heart failure (HF). OBJECTIVES: The aims of this study were to examine memory performance among Taiwanese women with HF compared with age- and education matched healthy women, and to evaluate factors that explain memory performance in women with HF. METHODS AND RESULTS: Seventy-six women with HF and 64 healthy women were recruited in Taiwan. Women completed working, verbal, and visual memory tests; HF severity was collected from the medical records. Women with HF performed significantly worse than healthy women on tests of working memory and verbal memory. Among women with HF, older age explained poorer working memory, and older age, higher HF severity, more comorbidities, and systolic HF explained poorer verbal memory. Menopausal symptoms were not associated with memory performance. CONCLUSIONS: Results of the study validate findings of memory loss in HF patients from the United States and Europe in a culturally different sample of women. Working memory and verbal memory were worse in Taiwanese women with HF compared with healthy participants. Studies are needed to determine mechanisms of memory deficits in these women and develop interventions to improve memory. PMID- 24954428 TI - Cognitive dysfunction in older adults hospitalized for acute heart failure. AB - BACKGROUND: Few studies have measured cognitive dysfunction in older adults during acute exacerbations of heart failure (HF), even though 25% of patients are readmitted within 30 days. The aims of this study were to examine cognitive dysfunction and acute HF symptoms in older adults hospitalized for HF and to evaluate the relationship between cognitive dysfunction and 30-day rehospitalization rates for acute HF. METHODS AND RESULTS: A cross-sectional descriptive design was used to characterize cognitive function in 53 older adults hospitalized for acute HF with the use of Cogstate computerized neuropsychologic tests. Demographic characteristics, HF symptoms (dyspnea, fatigue, pain, and depressed mood), comorbidity, and 30-day readmission HF rates were also measured. Dyspnea was measured with the use of the Parshall Brief Clinical Dyspnea Rating Questionnaire while fatigue was measured with the use of the Chalder et al Brief Fatigue Scale. We measured pain with the use of the Short-Form McGill Pain Questionnaire and depressed mood with the use of the depression subscale of the Hospital Anxiety and Depression Scale. Comorbid conditions were measured with the use of the Charlson comorbidity index. With the use of linear regression, dyspnea (beta = -.281; P = .030), pain (beta = .323; P = .011), and depressed mood (beta = .406, P = .003) were associated with reduced attention and working memory speed, and pain (beta = -.372; P = .005) and fatigue (beta = -.275; P = .033) were associated with reduced accuracy of attention and working memory. Ten patients were readmitted within 30 days for HF. According to Mann-Whitney U analysis, cognitive dysfunction measures (P = .090-.803) failed to show differences in HF readmission. CONCLUSIONS: Participants with more and worse symptoms had decreased speed and decreased accuracy in the cognitive domains tested. Cognitive dysfunction measures did not differentiate participants who were readmitted versus those who were not readmitted within 30 days for acute HF. PMID- 24954429 TI - A pilot study of cognitive training in clinical high risk for psychosis: initial evidence of cognitive benefit. PMID- 24954431 TI - Septal perforator size may play a key role in alcohol septal ablation success. PMID- 24954430 TI - First report of hypersensitivity to ticagrelor. PMID- 24954432 TI - Micro-computed tomography assessment of vertebral column defects in retinoic acid induced rat model of myelomeningocele. AB - BACKGROUND: Myelomeningocele (MMC) is a common congenital malformation and the most severe form of spina bifida characterized by the protrusion of spinal cord and meninges through the spinal defect. Our objective was to improve the assessment of congenital vertebral defects in animal models of MMC using three dimensional high resolution micro-computed tomography (micro-CT) imaging and quantitative digital analyses methods. METHODS: Lumbosacral MMC was induced in fetal rats by exposure of pregnant mothers at embryonic day 10 (E10) to all-trans retinoic acid, and rats were examined at term (embryonic day 22). The axial skeleton was examined in an MMC model for the first time using ex vivo micro-CT at 10 MUm voxel resolution to allow high resolution two-dimensional and three dimensional characterization of anomalies in lumbosacral vertebrae, and quantitative assessment of distances between dorsal vertebral arches in lumbosacral regions in MMC rats, compared with normal controls. RESULTS: We observed, in detail, skeletal defects in lumbosacral vertebra of MMC rats, including in the morphology of individual dorsal vertebral arches. Use of high resolution micro-CT has also enabled us to identify the delayed (nonfused) or absent ossification in vertebral bodies, increased fusion of adjacent lateral vertebral elements, and quantify the extent of dorsal arch widening. Distances between dorsal vertebral arches showed statistically significant increases from L5 through S4 in MMC rats, compared with normal controls. CONCLUSION: High resolution micro-CT combined with digital quantification methods is a powerful technique ideally suited for precise assessment of complex congenital skeletal abnormalities such as examined in this rodent model of MMC. PMID- 24954437 TI - From molecules to materials: computational design of N-containing porous aromatic frameworks for CO2 capture. AB - Porous aromatic frameworks (PAFs) are novel materials with diamond topology. With the aim of enhancing their CO(2) capture and storage capacity and investigating the effect of nitrogen and/or -COOH decorations on CO(2) adsorption in PAFs, a series of N-containing PAFs were designed based on ab initio results. The interaction energies (E(int)) between CO(2) and each six-membered ring were calculated at the B2PLYP-D2/def2-TZVPP level, then the six-membered rings with high CO(2) -binding affinity were selected and used in the PAFs. To explore the performance of the designed PAFs, the CO(2) uptake, selectivity of CO(2) over CH(4), H(2), and N(2), and the E(int) value of CO(2) in PAFs were investigated by using grand canonical Monte Carlo (GCMC) simulations and ab initio calculations. This work shows that pyridine with one nitrogen atom can provide a strong physisorption site for CO(2), whereas more nitrogen atoms in heterocycles will reduce the interaction, especially at relatively low pressure. PAFs with -COOH groups show high CO(2) capacity. Our work provides an efficient way to understand the adsorption mechanism and a supplemental approach to experimental work. PMID- 24954438 TI - Synthesis and evaluation of salicylanilide derivatives as potential epidermal growth factor receptor inhibitors. AB - Two series of novel salicylanilide were synthesized as potential epidermal growth factor receptor (EGFR) inhibitors. The enzyme inhibitory activity against EGFR of all compounds was carried out, and their antiproliferative activities against the A549 and A431 cell lines were also evaluated. Of the compounds studied, majority of them exhibited high antiproliferative activities compared with gefitinib; especially, 12a and 12b exhibited stronger inhibitory activity against EGFR with IC50 values of 10.4 +/- 2.25 and 15.4 +/- 2.33 nm, respectively, which were comparable to the positive control of gefitinib (IC50 = 12.1 +/- 2.21 nm). Compound 12b also showed outstanding inhibitory activity against A431 and A549 cell lines with the IC50 values of 0.42 +/- 0.43 MUm and 0.57 +/- 0.43 MUm, which was better than the positive controls. In the molecular modeling study, compound 12b was bound into the active pocket of EGFR with two hydrogen bond and with minimum binding free energy ?Gb = -25.1125 kcal/mol. The result also suggested that compound 12b could bind the EGFR kinase well. PMID- 24954442 TI - Linguistic validation of the sleep disturbance scale for children (SDSC) in Iranian children with Persian language. AB - OBJECTIVE: The aim of this study was to have a linguistic validation of the Sleep Disturbance Scale for Children (SDSC) in Iranian children with Persian language. METHODS: The study included a randomly selected sample of children, aged 6-15 years, from three primary and secondary schools located in Isfahan City, Iran. Following the forward-backward translation method, parents completed the SDSC as well as the Pediatric Quality of Life Inventory (PedsQL). Reliability (Cronbach's alpha) and convergent validity (item-subscale and subscale-total correlations) were assessed. The association of SDSC scores with PedsQL scores was evaluated for construct validity. RESULTS: One hundred children were studied; mean age, 9.36+/-2.58 years, 68 girls. Scale Cronbach's alpha was 0.82, ranging from 0.40 for 'disorder of arousal' to 0.86 for 'sleep hyperhidrosis' subscales. Convergent validity was acceptable according to the corrected item-subscale correlations (r = 0.22-0.76) and corrected subscale-total correlations (r = 0.30-0.50). The SDSC total score as well as its subscales, except the 'disorder of arousal', were associated with the total PedsQL score and its factors (r = -0.20 to -0.64). CONCLUSION: The overall psychometric properties of the Persian version of the SDSC seem to be appropriate in Iranian children. PMID- 24954444 TI - A Rasch analysis of the harm reduction self-efficacy questionnaire in Portugal. AB - INTRODUCTION: A high degree of self-efficacy is required from drug users if they are to adopt long-term abstinence-maintaining or harm-reducing behaviors. Our objective was to analyze the psychometric quality of the Harm Reduction Self Efficacy Questionnaire (HRSEQ) with the Rating Scale Model (RSM), an extension of the Rasch Model for polytomous items. METHODS: Participants were 419 drug dependents from both harm reduction low threshold methadone program and therapeutic community programs in Portugal (84.5% male). RESULTS: Indicate that the original 11-category response system did not work adequately in any of the HRSEQ situations (Withdrawal, Negative emotions and Social pressure). There was no gender-related or group-related DIF and thus the findings of neither group nor gender-related difference in harm reduction self-efficacy cannot be plausibly attributed to that technical problem. CONCLUSIONS: After recoding the rating scales by collapsing the eleven categories into four, the HRSEQ scores show good model fit and psychometric adequacy. PMID- 24954443 TI - Substrate-guided front-face reaction revealed by combined structural snapshots and metadynamics for the polypeptide N-acetylgalactosaminyltransferase 2. AB - The retaining glycosyltransferase GalNAc-T2 is a member of a large family of human polypeptide GalNAc-transferases that is responsible for the post translational modification of many cell-surface proteins. By the use of combined structural and computational approaches, we provide the first set of structural snapshots of the enzyme during the catalytic cycle and combine these with quantum mechanics/molecular-mechanics (QM/MM) metadynamics to unravel the catalytic mechanism of this retaining enzyme at the atomic-electronic level of detail. Our study provides a detailed structural rationale for an ordered bi-bi kinetic mechanism and reveals critical aspects of substrate recognition, which dictate the specificity for acceptor Thr versus Ser residues and enforce a front-face SN i-type reaction in which the substrate N-acetyl sugar substituent coordinates efficient glycosyl transfer. PMID- 24954445 TI - Circadian cycle-dependent EEG biomarkers of pathogenicity in adult mice following prenatal exposure to in utero inflammation. AB - Intrauterine infection or inflammation in preterm neonates is a known risk for adverse neurological outcomes, including cognitive, motor and behavioral disabilities. Our previous data suggest that there is acute fetal brain inflammation in a mouse model of intrauterine exposure to lipopolysaccharides (LPS). We hypothesized that the in utero inflammation induced by LPS produces long-term electroencephalogram (EEG) biomarkers of neurodegeneration in the exposed mice that could be determined by using continuous quantitative video/EEG/electromyogram (EMG) analyses. A single LPS injection at E17 was performed in pregnant CD1 dams. Control dams were injected with same volumes of saline (LPS n=10, Control n=8). At postnatal age of P90-100, 24-h synchronous video/EEG/EMG recordings were done using a tethered recording system and implanted subdural electrodes. Behavioral state scoring was performed blind to treatment group, on each 10s EEG epoch using synchronous video, EMG and EEG trace signatures to generate individual hypnograms. Automated EEG power spectrums were analyzed for delta and theta-beta power ratios during wake vs. sleep cycles. Both control and LPS hypnograms showed an ultradian wake/sleep cycling. Since rodents are nocturnal animals, control mice showed the expected diurnal variation with significantly longer time spent in wake states during the dark cycle phase. In contrast, the LPS-treated mice lost this circadian rhythm. Sleep microstructure also showed significant alteration in the LPS mice specifically during the dark cycle, caused by significantly longer average non-rapid eye movement (NREM) cycle durations. No significance was found between treatment groups for the delta power data; however, significant activity-dependent changes in theta-beta power ratios seen in controls were absent in the LPS-exposed mice. In conclusion, exposure to in utero inflammation in CD1 mice resulted in significantly altered sleep architecture as adults that were circadian cycle and activity state dependent. PMID- 24954447 TI - Use of X-rays to treat shoulder tendonitis/bursitis: a historical assessment. AB - This article assesses the therapeutic efficacy of ionizing radiation for the treatment of shoulder tendonitis/bursitis in the USA over the period of its use (human 1936-1961; veterinary 1954-1974). Results from ~3,500 human cases were reported in the clinical case studies over 30 articles, and indicated a high treatment efficacy (>90 %) for patients. Radiotherapy was effective with a single treatment. The duration of treatment effectiveness was prolonged, usually lasting until the duration of the follow-up period (i.e., 1-5 years). Therapeutic effectiveness was reduced for conditions characterized as chronic. Similar findings were reported with race horses in the veterinary literature. These historical findings are consistent with clinical studies over the past several decades in Germany, which have used more rigorous study designs and a broader range of clinical evaluation parameters. Radiotherapy treatment was widely used in the mid twentieth century in the USA, but was abandoned following the discovery of anti-inflammatory drugs and the fear of radiation-induced cancer. That X-ray treatment could be an effective means of treating shoulder tendonitis/bursitis, as a treatment option, and is essentially unknown by the current medical community. This paper is the first comprehensive synthesis of the historical use of X-rays to treat shoulder tendonitis/bursitis and its efficacy in the USA. PMID- 24954446 TI - Real-time analysis of diaquat dibromide monohydrate in water with a SERS-based integrated microdroplet sensor. AB - We report the fast and sensitive trace analysis of diaquat dibromide monohydrate (DQ) in water using a surface-enhanced Raman scattering (SERS)-based microdroplet sensor. This sensor is composed of two compartments: the first one is for droplet generation for fresh silver nanoparticle (AgNP) synthesis and the second for droplet merging for SERS detection. Silver ions were nucleated and grown to large size AgNPs in droplets, and then each droplet was synchronously merged with another droplet containing DQ for SERS detection. This two-phase liquid-liquid segmented flow system prevented memory effects caused by the precipitation of nanoparticle aggregates on channel walls because the aqueous droplets were isolated by a continuous oil phase. The limit of detection (LOD) of DQ in water was determined to be below 5 nM, which satisfies the maximum contaminant level defined by the United States EPA. This method was also validated successfully in DQ-spiked tap water. The SERS-based integrated sensing system is expected to be useful as an in-the-field sensing platform for fast and reproducible trace analysis of environmental pollutants in water. PMID- 24954448 TI - Association between malocclusion and headache among 12- to 15-year-old adolescents: a population-based study. AB - OBJECTIVES: Headaches are a common problem among adolescents, and malocclusion is a possible risk factor. The purpose of this study was to investigate the association between malocclusion and headache among Japanese adolescents aged 12 15 years using a population-based sample. METHODS: A total of 938 adolescents (94.7% of the target population in Koshu City) participated. A modified version of the Index of Orthodontic Treatment Need (IOTN) was used by orthodontists to evaluate occlusal characteristics, and the frequency of headaches (none, rarely, sometimes) was assessed via questionnaire (N = 938). Ordered logistic regression analyses were used to analyze the association between malocclusion and headache. RESULTS: The prevalence of malocclusion diagnosed using the modified version of the IOTN was 44.9%. Multiple ordered logistic regression analyses showed that the odds ratio (OR) of having malocclusion for headache was 1.38 (95% confidence interval [CI]: 1.06-1.80), after adjustment for demographics, lifestyle, and dental status including orthodontic treatment history and tooth size. Moreover, among occlusal traits, lower crowding was independently associated with headache (OR: 1.64, 95% CI: 1.07-2.51). CONCLUSIONS: We found that malocclusion, especially lower crowding, was associated with headache in a population-based sample of adolescents aged 12-15 years in Japan. Further study is needed to elucidate the mechanisms by which malocclusion affects headache. PMID- 24954450 TI - Conscious awareness of action potentiates sensorimotor learning. AB - Many everyday skills are unconsciously learned through repetitions of the same behaviour by binding independent motor acts into unified sets of actions. However, our ability to be consciously aware of producing newly and highly trained motor skills raises the question of the role played by conscious awareness of action upon skill acquisition. In this study we strengthened conscious awareness of self-produced sequential finger movements by way of asking participants to judge their performance in terms of maximal fluency after each trial. Control conditions in which participants did not make any judgment or performance-unrelated judgments were also included. Findings indicate that conscious awareness of action, enhanced via subjective appraisal of motor efficiency, potentiates sensorimotor learning and skilful motor production in optimising the processing and sequencing of action units, as compared to the control groups. The current work lends support to the claim that the learning and skilful expression of sensorimotor behaviours might be grounded upon our ability to be consciously aware of our own motor capability and efficiency. PMID- 24954449 TI - Italian ryegrass for the phytoremediation of solutions polluted with terbuthylazine. AB - The phytoextraction capacity of Italian ryegrass (Lolium multiflorum L.) to remove terbuthylazine (TBA) from aqueous solution has been assessed using a plant based biotest (RHIZOtest). Three TBA concentrations (0.5, 1.0 and 2.0 mg L(-1)) were chosen to evaluate the tolerance capacity of the ryegrass. Even though the treatments negatively affected plants, they were able to remove up to 30-40% of TBA. In addition, some enzymatic activities involved in the response to TBA induced stress were determined. Glutathione S-transferase (GST) has been activated with a TBA-dose dependent trend; ascorbate peroxidase (APX) activities have been induced within the first hours after the treatments, followed by decreases or disappearance in plants exposed to two higher dosages. In conclusion, this case-study highlights that the combination of ryegrass and RHIZOtest resulted to be effective in the remediation of aqueous solutions polluted by TBA. PMID- 24954451 TI - The persistence of chronic lead nephropathy. PMID- 24954452 TI - Do implantable defibrillators help patients with CKD? PMID- 24954453 TI - Dialysis recovery time: more than just another serum albumin. PMID- 24954454 TI - IgG4-restricted anti-glomerular basement membrane autoantibodies targeting quaternary epitopes of native alpha345(IV) collagen. PMID- 24954455 TI - Dialysis vintage could confound survival trends in ESRD patients. PMID- 24954456 TI - In reply to 'dialysis vintage could confound survival trends in ESRD patients'. PMID- 24954457 TI - Effects of age, sex, and estrogen on serum phosphorus: role for growth hormone and klotho? PMID- 24954458 TI - In Reply to 'IgG4-Restricted Anti-Glomerular Basement Membrane Autoantibodies Targeting Quaternary Epitopes of Native alpha345(IV) Collagen'. PMID- 24954459 TI - Quiz page JULY 2014: bilateral abdominal masses in an infant. Diagnosis: Bilateral cystic nephroma. PMID- 24954460 TI - Pre-load stress echocardiography for predicting the prognosis in mild heart failure. AB - OBJECTIVES: This study sought to introduce and confirm the efficacy of pre-load stress echocardiography with leg-positive pressure (LPP) for improving risk stratification of patients with mild stable heart failure. BACKGROUND: Heart failure patients with mild symptoms and a poor prognosis should be identified and treated aggressively to improve clinical outcome. METHODS: We performed transthoracic echocardiography with LPP in 202 patients with chronic cardiac disease. Twenty-two of these patients also underwent cardiac catheterization, and left ventricular pressure was measured during LPP along with simultaneous Doppler recordings. Patients were classified into 3 groups on the basis of their left ventricular (LV) diastolic dysfunction as assessed by transmitral flow velocity: restrictive or pseudonormal (PN) at rest, impaired relaxation (IR) at rest and during LPP (stable IR), and IR at rest and PN during LPP (unstable IR). Clinical outcome was compared among these groups. RESULTS: The LPP increased LV end diastolic pressure from 15.8 +/- 4.7 mm Hg to 20.5 +/- 5.0 mm Hg in the unstable IR group and from 10.5 +/- 2.6 mm Hg to 14.7 +/- 3.8 mm Hg in the stable IR group (both p < 0.001). During an average follow-up of 548 +/- 407 days, 5 patients had cardiac death, 37 had acute heart failure, 4 had an acute myocardial infarction, and 7 had a stroke. The all-cause cardiac event rate in unstable IR was higher than in stable IR (p < 0.001), and was similar in the PN group (p = 0.81). Event free survival was significantly lower in unstable IR than in stable IR (p = 0.003). In a Cox proportional hazards model, unstable IR was an independent predictor of all-cause cardiac events (hazard ratio: 8.0; p < 0.001). CONCLUSIONS: The left LV end-diastolic pressure-volume relationship can be estimated by changes in transmitral flow velocity during LPP. Thus, pre-load stress echocardiography using LPP provides additional prognostic information in mild heart failure beyond that provided by conventional Doppler echocardiography at rest. PMID- 24954461 TI - Coronary artery calcification and family history of myocardial infarction in the Dallas heart study. AB - OBJECTIVES: This study aimed to investigate the independent and joint associations between family history of myocardial infarction (FH) and coronary artery calcification (CAC) with incident coronary heart disease (CHD). BACKGROUND: FH and CAC are associated with each other and with incident CHD. It is not known whether FH retains its predictive value after CAC results are accounted for. METHODS: Among 2,390 participants without cardiovascular disease enrolled in the Dallas Heart Study, we assessed FH (myocardial infarction in a first-degree relative) and prevalent CAC by electron-beam computed tomography. The primary outcome, a composite of CHD-related death, myocardial infarction, and percutaneous or surgical coronary revascularization, was assessed over a mean follow-up of 8.0 +/- 1.2 years. The individual and joint associations with the CHD composite outcome were determined for FH and CAC. RESULTS: The mean age of the population was 44 +/- 9 years; 32% had FH and 47% had a CAC score of 0. In multivariate models adjusted for traditional risk factors, FH was independently associated with CHD (adjusted hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2; p < 0.001). Further adjustment for prevalent CAC did not diminish this association (adjusted hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2; p < 0.001). FH and CAC were additive: CHD event rates in those with both FH and CAC were 8.8% vs. 3.3% in those with prevalent CAC alone (p < 0.001). CHD rates were 1.9% in those with FH alone compared with 0.4% in those with neither FH nor CAC (p < 0.017). Among subjects without CAC, FH characterized a group with a more unfavorable cardiometabolic profile. CONCLUSIONS: FH provided prognostic information that was independent of and additive to CAC. Among those with CAC, FH identified subjects at particularly high short-term risk, and, among those without it, selected a group with an adverse risk-factor profile. PMID- 24954462 TI - CMR in patients with severe myocarditis: diagnostic value of quantitative tissue markers including extracellular volume imaging. AB - OBJECTIVES: This study evaluated the accuracy of T2, T1, and extracellular volume (ECV) quantification as novel quantitative tissue markers in comparison with standard "Lake-Louise" cardiac magnetic resonance (CMR) criteria to diagnose myocarditis. BACKGROUND: Novel approaches using T2 and T1 mapping may overcome the limitations of signal intensity-based parameters, which would potentially result in a better diagnostic accuracy compared with standard CMR techniques in suspected myocarditis. METHODS: CMR was performed in 104 patients with myocarditis and 21 control subjects at 1.5-T. Patients with myocarditis underwent CMR 2 weeks (interquartile range: 1 to 7 weeks) after presentation with new-onset heart failure (n = 66) or acute chest pain (n = 38). T2 and T1 mapping were implemented into a standard protocol including T2-weighted (T2w), early gadolinium enhancement (EGE) CMR, and late gadolinium enhancement (LGE) CMR. T2 quantification was performed using a free-breathing, navigator-gated multiecho sequence. T1 quantification was performed using the modified Look-Locker inversion recovery sequence before and after administration of 0.075 mmol/kg gadobenate dimeglumine. T2, T1, and ECV maps were generated using a plug-in for the OsiriX software (Pixmeo, Bernex, Switzerland) to calculate mean global myocardial T2, T1, and ECV values. RESULTS: The diagnostic accuracies of conventional CMR were 70% (95% confidence interval [CI]: 61% to 77%) for T2w CMR, 59% (95% CI: 56% to 73%) for EGE, and 67% (95% CI: 59% to 75%) for LGE. The diagnostic accuracies of mapping techniques were 63% (95% CI: 53% to 73%) for myocardial T2, 69% (95% CI: 60% to 76%) for native myocardial T1, and 76% (95% CI: 68% to 82%) for global myocardial ECV. The diagnostic accuracy of CMR was significantly improved to 90% (95% CI: 84% to 95%) by a stepwise approach, using the presence of LGE and myocardial ECV >=27% as diagnostic criteria, compared with 79% (95% CI: 71% to 85%; p = 0.0043) for the Lake-Louise criteria. CONCLUSIONS: In patients with clinical evidence for subacute, severe myocarditis, ECV quantification with LGE imaging significantly improved the diagnostic accuracy of CMR compared with standard Lake-Louise criteria. PMID- 24954464 TI - Nationalizing paired donation. PMID- 24954463 TI - Hospital-level variation in use of cardiovascular testing for adults with incident heart failure: findings from the cardiovascular research network heart failure study. AB - OBJECTIVES: This study aimed to characterize the use of cardiovascular testing for patients with incident heart failure (HF) hospitalization who participated in the National Heart, Lung, and Blood Institute sponsored Cardiovascular Research Network (CVRN) Heart Failure study. BACKGROUND: HF is a common cause of hospitalization, and testing and treatment patterns may differ substantially between providers. Testing choices have important implications for the cost and quality of care. METHODS: Crude and adjusted cardiovascular testing rates were calculated for each participating hospital. Cox proportional hazards regression models were used to examine hospital testing rates after adjustment for hospital level patient case mix. RESULTS: Of the 37,099 patients in the CVRN Heart Failure study, 5,878 patients were hospitalized with incident HF between 2005 and 2008. Of these, evidence of cardiovascular testing was available for 4,650 (79.1%) patients between 14 days before the incident HF admission and ending 6 months after the incident discharge. We compared crude and adjusted cardiovascular testing rates at the hospital level because the majority of testing occurred during the incident HF hospitalization. Of patients who underwent testing, 4,085 (87.9%) had an echocardiogram, 4,345 (93.4%) had a systolic function assessment, and 1,714 (36.9%) had a coronary artery disease assessment. Crude and adjusted testing rates varied markedly across the profiled hospitals, for individual testing modalities (e.g., echocardiography, stress echocardiography, nuclear stress testing, and left heart catheterization) and for specific clinical indications (e.g., systolic function assessment and coronary artery disease assessment). CONCLUSIONS: For patients with newly diagnosed HF, we did not observe widespread overuse of cardiovascular testing in the 6 months following incident HF hospitalization relative to existing HF guidelines. Variations in testing were greatest for assessment of ischemia, in which testing guidelines are less certain. PMID- 24954467 TI - Emesis following laparoscopic left donor nephrectomy. PMID- 24954468 TI - From membranes to organelles: emerging roles for dynamin-like proteins in diverse cellular processes. AB - Dynamin is a GTPase mechanoenzyme most noted for its role in vesicle scission during endocytosis, and belongs to the dynamin family proteins. The dynamin family consists of classical dynamins and dynamin-like proteins (DLPs). Due to structural and functional similarities DLPs are thought to carry out membrane tubulation and scission in a similar manner to dynamin. Here, we discuss the newly emerging roles for DLPs, which include vacuole fission and fusion, peroxisome maintenance, endocytosis and intracellular trafficking. Specific focus is given to the role of DLPs in the budding yeast Saccharomyces cerevisiae because the diverse function of DLPs has been well characterized in this organism. Recent insights into DLPs may provide a better understanding of mammalian dynamin and its associated diseases. PMID- 24954470 TI - Heteroatom-doped graphene materials: syntheses, properties and applications. AB - Heteroatom doping can endow graphene with various new or improved electromagnetic, physicochemical, optical, and structural properties. This greatly extends the arsenal of graphene materials and their potential for a spectrum of applications. Considering the latest developments, we comprehensively and critically discuss the syntheses, properties and emerging applications of the growing family of heteroatom-doped graphene materials. The advantages, disadvantages, and preferential doping features of current synthesis approaches are compared, aiming to provide clues for developing new and controllable synthetic routes. We emphasize the distinct properties resulting from various dopants, different doping levels and configurations, and synergistic effects from co-dopants, hoping to assist a better understanding of doped graphene materials. The mechanisms underlying their advantageous uses for energy storage, energy conversion, sensing, and gas storage are highlighted, aiming to stimulate more competent applications. PMID- 24954469 TI - PARP-1 activation causes neuronal death in the hippocampal CA1 region by increasing the expression of Ca(2+)-permeable AMPA receptors. AB - An excessive activation of poly(ADP-ribose) polymerases (PARPs) may trigger a form of neuronal death similar to that occurring in neurodegenerative disorders. To investigate this process, we exposed organotypic hippocampal slices to N methyl-N'-nitro-N'-nitrosoguanidine (MNNG, 100MUM for 5min), an alkylating agent widely used to activate PARP-1. MNNG induced a pattern of degeneration of the CA1 pyramidal cells morphologically similar to that observed after a brief period of oxygen and glucose deprivation (OGD). MNNG exposure was also associated with a dramatic increase in PARP-activity and a robust decrease in NAD(+) and ATP content. These effects were prevented by PARP-1 but not PARP-2 inhibitors. In our experimental conditions, cell death was not mediated by AIF translocation (parthanatos) or caspase-dependent apoptotic processes. Furthermore, we found that PARP activation was followed by a significant deterioration of neuronal membrane properties. Using electrophysiological recordings we firstly investigated the suggested ability of ADP-ribose to open TRPM2 channels in MNNG induced cells death, but the results we obtained showed that TRPM2 channels are not involved. We then studied the involvement of glutamate receptor-ion channel complex and we found that NBQX, a selective AMPA receptor antagonist, was able to effectively prevent CA1 neuronal loss while MK801, a NMDA antagonist, was not active. Moreover, we observed that MNNG treatment increased the ratio of GluA1/GluA2 AMPAR subunit expression, which was associated with an inward rectification of the IV relationship of AMPA sEPSCs in the CA1 but not in the CA3 subfield. Accordingly, 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca(2+)-permeable GluA2-lacking AMPA receptors, reduced MNNG-induced CA1 pyramidal cell death. In conclusion, our results show that activation of the nuclear enzyme PARP-1 may change the expression of membrane proteins and Ca(2+) permeability of AMPA channels, thus affecting the function and survival of CA1 pyramidal cells. PMID- 24954471 TI - Response to Al-Husayni and Hassoun. PMID- 24954472 TI - Non-polio enterovirus association with persistent diarrhea in children as revealed by a follow-up study of an Indian cohort during the first two years of life. AB - BACKGROUND: We recently reported significant association of non-polio enteroviruses (NPEVs) with acute diarrhea in children. Persistent diarrhea (PD) remains a major cause of morbidity and mortality in infants below two years of age in developing countries. Understanding age-dependent frequency and duration of NPEV infections is important to determine their association with persistent diarrhea and disease burden. OBJECTIVES: A cohort of 140 infants was followed for 6 months to 2 years of age to determine the frequency, duration, and association with PD of NPEV infections in comparison with rotavirus and other agents. STUDY DESIGN: Stool samples were collected every 14 days, and diarrheal episodes and their duration were recorded. Enteroviruses were characterized by RT-PCR and VP1 gene sequence analysis, rotavirus by electropherotyping, and other agents by PCR. RESULTS: Of 4545 samples, negative for oral polio vaccine strains, 3907 (85.96%) and 638 (14.04%) were NPEV-negative and NPEV-positive, respectively, representing 403 (8.87%) infection episodes. About 68% of NPEV infections occurred during the first year with every child having at least one episode lasting between four days and four months. Approximately 38% and 22% of total diarrheal episodes were positive for NPEV and RV, respectively. While about 18% of NPEV infection episodes were associated with diarrhea, 6% being persistent, 13% of total diarrheal episodes were persistent involving infections by monotype NPEV strains or sequential infections by multiple strains and other agents. CONCLUSIONS: This is the first report revealing NPEVs as the single most frequently and persistently detected viral pathogen in every PD episode. PMID- 24954473 TI - Liver-specific transcriptional modules identified by genome-wide in silico analysis enable efficient gene therapy in mice and non-human primates. AB - The robustness and safety of liver-directed gene therapy can be substantially improved by enhancing expression of the therapeutic transgene in the liver. To achieve this, we developed a new approach of rational in silico vector design. This approach relies on a genome-wide bio-informatics strategy to identify cis acting regulatory modules (CRMs) containing evolutionary conserved clusters of transcription factor binding site motifs that determine high tissue-specific gene expression. Incorporation of these CRMs into adeno-associated viral (AAV) and non viral vectors enhanced gene expression in mice liver 10 to 100-fold, depending on the promoter used. Furthermore, these CRMs resulted in robust and sustained liver specific expression of coagulation factor IX (FIX), validating their immediate therapeutic and translational relevance. Subsequent translational studies indicated that therapeutic FIX expression levels could be attained reaching 20 35% of normal levels after AAV-based liver-directed gene therapy in cynomolgus macaques. This study underscores the potential of rational vector design using computational approaches to improve their robustness and therefore allows for the use of lower and thus safer vector doses for gene therapy, while maximizing therapeutic efficacy. PMID- 24954474 TI - MicroRNA-103-1 selectively downregulates brain NCX1 and its inhibition by anti miRNA ameliorates stroke damage and neurological deficits. AB - Na(+)/Ca2+ exchanger (NCX) is a plasma membrane transporter that, by regulating Ca2+ and Na(+) homeostasis, contributes to brain stroke damage. The objectives of this study were to investigate whether there might be miRNAs in the brain able to regulate NCX1 expression and, thereafter, to set up a valid therapeutic strategy able to reduce stroke-induced brain damage by regulating NCX1 expression. Thus, we tested whether miR-103-1, a microRNA belonging to the miR-103/107 family that on the basis of sequence analysis might be a potential NCX1 regulator, could control NCX1 expression. The role of miR-103-1 was assessed in a rat model of transient cerebral ischemia by evaluating the effect of the correspondent antimiRNA on both brain infarct volume and neurological deficits. NCX1 expression was dramatically reduced when cortical neurons were exposed to miR-103-1. This alleged tight regulation of NCX1 by miR-103-1 was further corroborated by luciferase assay. Notably, antimiR-103-1 prevented NCX1 protein downregulation induced by the increase in miR-103-1 after brain ischemia, thereby reducing brain damage and neurological deficits. Overall, the identification of a microRNA able to selectively regulate NCX1 in the brain clarifies a new important molecular mechanism of NCX1 regulation in the brain and offers the opportunity to develop a new therapeutic strategy for stroke. PMID- 24954475 TI - Anti-microRNA-378a enhances wound healing process by upregulating integrin beta-3 and vimentin. AB - Delayed or impaired wound healing is a major public health issue worldwide, especially in patients with diabetes mellitus and vascular atherosclerosis. MicroRNAs have been identified as key regulators of wound healing. Here, we show that miR-Pirate378a transgenic mice (and thus have inhibited miR-378a-5p function) display enhanced wound healing. Expression of vimentin and beta3 integrin, two important modulators of wound healing, is markedly elevated in the transgenic mice. MiR-Pirate378a-transfected cells display greater mobility during migration assays, which was hypothesized to be due to the upregulation of vimentin and beta3 integrin. Both molecules were confirmed to be targets of miR 378a, and thus their expression could be rescued by miR-Pirate378a. Overexpression of vimentin also contributed to fibroblast differentiation, and upregulation of beta3 integrin was responsible for increased angiogenesis. Mice treatment with miR-Pirate378a-conjugated nanoparticles displayed enhanced wound healing. Thus, we have demonstrated that knockdown of miR-378a increased the expression of its target proteins, vimentin, and beta3 integrin, which accelerated fibroblast migration and differentiation in vitro and enhanced wound healing in vivo. PMID- 24954477 TI - Shaping the future of nursing: developing an appraisal framework for public engagement with nursing policy reports. AB - It is accepted that research should be systematically examined to judge its trustworthiness and value in a particular context. No such appraisal is required of reports published by organizations that have possibly even greater influence on policy that affects the public. This paper explores a philosophical framework for appraising reports. It gives the reasons why informed engagement is important, drawing on Popper's concept of the open society, and it suggests a method for appraisal. Gadamer's concept of the two horizons and Jauss's reception theory offer a methodological framework to enable the individual citizen, whether professional or lay, to engage in debate about policy that affects him or her. By way of a worked example, the framework is applied to two international reports on nursing. Conclusions suggest that nursing policy should be subjected to robust interrogatory appraisal by both profession and public for a democratic debate and creative discourse. Although this analysis is related to international nursing policy, it has a wider relevance and application beyond nursing. PMID- 24954476 TI - Targeted inhibition of prostate cancer metastases with an RNA aptamer to prostate specific membrane antigen. AB - Cell-targeted therapies (smart drugs), which selectively control cancer cell progression with limited toxicity to normal cells, have been developed to effectively treat some cancers. However, many cancers such as metastatic prostate cancer (PC) have yet to be treated with current smart drug technology. Here, we describe the thorough preclinical characterization of an RNA aptamer (A9g) that functions as a smart drug for PC by inhibiting the enzymatic activity of prostate specific membrane antigen (PSMA). Treatment of PC cells with A9g results in reduced cell migration/invasion in culture and metastatic disease in vivo. Importantly, A9g is safe in vivo and is not immunogenic in human cells. Pharmacokinetic and biodistribution studies in mice confirm target specificity and absence of non-specific on/off-target effects. In conclusion, these studies provide new and important insights into the role of PSMA in driving carcinogenesis and demonstrate critical endpoints for the translation of a novel RNA smart drug for advanced stage PC. PMID- 24954478 TI - Amelioration of salmonellosis in pre-weaned dairy calves fed Saccharomyces cerevisiae fermentation products in feed and milk replacer. AB - Salmonellosis is an insidious and potentially epidemic problem in pre-weaned dairy calves. Managing this disease, or any other diarrheal disease, is a financial burden to producers. Calf mortalities and medicinal treatments are overt costs of salmonellosis, while hidden costs include hampered weight gains and persistent intestinal colonization of the pathogen. In this study, we examined the anti-Salmonella effects of Saccharomyces cerevisiae fermentation products (SCFP) incorporated into both the milk replacer and the starter grain. In a blinded study, 2-8 day-old calves were fed SCFP (n=20 calves) or an SCFP free Control (n=20 calves) for two weeks before and three weeks after experimental challenge with Salmonella enterica serotype Typhimurium. Following the challenge, calves were monitored for clinical signs and parameters associated with salmonellosis. Calves were then euthanized and examined for rumen development and intestinal Salmonella colonization. When compared to calves that received milk replacer and feed lacking SCFP, calves fed SCFP had fewer bouts of diarrhea and fever. Rumens from these calves were more developed, as measured by the length of papillae, which is consistent with the enhanced weight gain observed in this treatment group. Additionally, Salmonella intestinal colonization was reduced in SCFP-fed calves and Salmonella fecal shedding disappeared at an earlier stage in these calves. This study revealed that the combination of two proprietary S. cerevisiae fermentation products provide marked benefit for preventing the negative effects of salmonellosis in pre-weaned dairy calves, while also boosting productivity. The mechanism of action needs to be clarified, but it may be related to the observed decrease in colonization by the pathogen and increase in rumen development. PMID- 24954479 TI - Characterization of tilapia (Oreochromis niloticus) gonadotropins by modeling and immunoneutralization. AB - In fish, both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) play important roles in reproduction. Here we explored the structure and differential specificity of tilapia (t) gonadotropins (GTHs) to delineate their physiological relevance and the nature of their regulation. We generated structural models of tGTHs and GTH receptors (R) that enabled us to better understand the hormone-receptor interacting region. In tilapia, FSH release is under the control of the hypothalamic decapeptide GnRH, an effect that was abolished by specific bioneutralizing antisera [anti-recombinant (r) tFSHbeta]. These antisera also reduced the basal secretion and delayed GnRH-stimulated production of 11-ketotestosterone (11KT), and dramatically reduced LH levels. Immunoneutralization of tLH using anti-rtLHbeta significantly reduced its GnRH stimulated levels. Basal 11KT and FSH levels were also reduced. Taken together, these results suggest a feedback mechanism between FSH and LH release in tilapia. PMID- 24954480 TI - Reduced expression of transcriptional intermediary factor 1 gamma promotes metastasis and indicates poor prognosis of hepatocellular carcinoma. AB - Transcriptional intermediary factor 1 gamma (TIF1gamma) may play either a potential tumor-suppressor or -promoter role in cancer. Here we report on a critical role of TIF1gamma in the progression of hepatocellular carcinoma (HCC). Reduced expression of TIF1gamma was detected in HCC, especially in advanced HCC tissues, compared to adjacent noncancerous tissues. HCC patients with low TIF1gamma expression had shorter overall survival times and higher recurrence rates than those with high TIF1gamma expression. Reduced TIF1gamma expression was an independent and significant risk factor for recurrence and survival after curative resection. In HCC cells, TIF1gamma played a dual role: It promoted tumor growth in early-stage HCC, but not in advanced-stage HCC, whereas it inhibited invasion and metastasis in both early- and advanced-stage HCC. Mechanistically, we confirmed that TIF1gamma inhibited transforming growth factor-beta/ Drosophila mothers against decapentaplegic protein (TGF-beta/Smad) signaling through monoubiquitination of Smad4 and suppressed the formation of Smad2/3/4 complex in HCC cells. TGF-beta-inducing cytostasis and metastasis were both inhibited by TIF1gamma in HCC. We further proved that TIF1gamma suppressed cyotstasis-related TGF-beta/Smad downstream c-myc down-regulation, as well as p21/cip1 and p15/ink4b up-regulation in early-stage HCC. Meanwhile, TGF-beta inducible epithelial mesenchymal transition and TGF-beta/Smad downstream metastatic cascades, including phosphatase and tensin homolog deleted on chromosome ten down regulation, chemokine (CXC motif) receptor 4 and matrix metalloproteinase 1 induction, and epidermal growth factor receptor- and protein kinase B-signaling transactivation, were inhibited by TIF1gamma. In addition, we found that the down regulation of TIF1gamma in HCC was caused by hypermethylation of CpG islands in the TIF1gamma promoter, and demonstrated that the combination of TIF1gamma and phosphorylated Smad2 was a more powerful predictor of poor prognosis. CONCLUSION: TIF1gamma regulates tumor growth and metastasis through inhibition of TGF beta/Smad signaling and may serve as a novel prognostic biomarker in HCC. PMID- 24954481 TI - Pharmacokinetics and disposition of dalcetrapib in rats and monkeys. AB - 1. The pharmacokinetics and metabolism of dalcetrapib (JTT-705/RO4607381), a novel cholesteryl ester transfer protein inhibitor, were investigated in rats and monkeys. 2. In in vitro stability studies, dalcetrapib was extremely unstable in plasma, liver S9 and small intestinal mucosa, and the pharmacologically active form (dalcetrapib thiol) was detected as major component. Most of the active form in plasma was covalently bound to plasma proteins via mixed disulfide bond formation. 3. Following oral administration of (14)C-dalcetrapib to rats and monkeys, active form was detected in plasma. The active form was mainly metabolized to the glucuronide conjugate and the methyl conjugate at the thiol group. Several minor metabolites including mono- and di-oxidized forms of the glucuronide are also detected in the plasma and urine. 4. The administered radioactivity was widely distributed to all tissues and mainly excreted into the feces (85.7 and 62.7% of the dose in rats and monkeys, respectively). Most of the radioactivity was recovered by 168 h. Although the absorbed dalcetrapib was hydrolyzed to the active form and was bound to endogenous thiol via formation of disulfide bond, it was relatively rapidly eliminated from the body and was not retained. PMID- 24954482 TI - Anterior knee pain following total knee replacement correlates with the OARSI score of the cartilage of the patella. AB - BACKGROUND: Attempts to relate patellar cartilage involvement to anterior knee pain (AKP) have yielded conflicting results. We determined whether the condition of the cartilage of the patella at the time of knee replacement, as assessed by the OARSI score, correlates with postsurgical AKP. PATIENTS AND METHODS: We prospectively studied 100 patients undergoing knee arthroplasty. At surgery, we photographed and biopsied the articular surface of the patella, leaving the patella unresurfaced. Following determination of the microscopic grade of the patellar cartilage lesion and the stage by analyzing the intraoperative photographs, we calculated the OARSI score. We interviewed the patients 1 year after knee arthroplasty using the HSS patella score for diagnosis of AKP. RESULTS: 57 of 95 patients examined had AKP. The average OARSI score of painless patients was 13 (6-20) and that of patients with AKP was 15 (6-20) (p = 0.04). Patients with OARSI scores of 13-24 had 50% higher risk of AKP (prevalence ratio = 1.5, 95% CI: 1.0-2.3) than patients with OARSI scores of 0-12. INTERPRETATION: The depth and extent of the cartilage lesion of the knee-cap should be considered when deciding between the various options for treatment of the patella during knee replacement. PMID- 24954483 TI - Women in Charnley class C fail to improve in mobility to a higher degree after total hip replacement. AB - BACKGROUND: The Charnley comorbidity classification organizes patients into 3 classes: (A) 1 hip involved, (B) 2 hips involved, and (C) other severe comorbidities. Although this simple classification is a known predictor of health related quality of life (HRQoL) after total hip replacement (THR), interactions between Charnley class, sex, and age have not been investigated and there is uncertainty regarding whether A and B should be grouped together. METHODS: We selected a nationwide cohort of patients from the Swedish Hip Arthroplasty Register operated with THR due to primary osteoarthritis between 2008 and 2010. For estimation of HRQoL, we used the generic health outcome questionnaire EQ-5D of the EuroQol group. This consists of 2 parts: the EQ-5D index and the EQ VAS estimates. We modeled the EQ-5D index and the EQ VAS against the self administered Charnley classification. Confounding was controlled for using preoperative HRQoL values, pain, and previous contralateral hip surgery. RESULTS: We found that women in class C had a poorer EQ-5D outcome than men. This effect was mostly due to the fact that women failed to improve in the mobility dimension; only 40% improved, while about 50% of men improved. Age did not interact with Charnley class. We also found that the classification performed best without splitting or aggregating classes. INTERPRETATION: Our results suggests that the self-administered Charnley classification should be used in its full capacity and that it may be interesting to devote special attention to women in Charnley class C. PMID- 24954484 TI - The influence of hip rotation on femoral offset in plain radiographs. AB - BACKGROUND AND PURPOSE: Adequate restoration of femoral offset (FO) is critical for successful outcome after hip arthroplasty or fixation of hip fracture. Previous studies have identified that hip rotation influences the projected femoral offset (FOP) on plain anteroposterior (AP) radiographs, but the precise effect of rotation is unknown. PATIENTS AND METHODS: We developed a novel method of assessing rotation-corrected femoral offset (FORC), tested its clinical application in 222 AP hip radiographs following proximal femoral nailing, and validated it in 25 cases with corresponding computed tomography (CT) scans. RESULTS: The mean FORC was 57 (29-93) mm, which differed significantly (p < 0.001) from the mean FOP 49 (22-65) mm and from the mean femoral offset determined by the standard method: 49 (23-66) mm. FORC correlated closely with femoral offset assessed by CT (FOCT); the Spearman correlation coefficient was 0.94 (95% CI: 0.88-0.97). The intraclass correlation coefficient for the assessment of FORC by AP hip radiographs correlating the repeated measurements of 1 observer and of 2 independent blinded observers was 1.0 and 1.0, respectively. INTERPRETATION: Hip rotation affects the FOP on plain AP radiographs of the hip in a predictable way and should be adequately accounted for. PMID- 24954485 TI - Comparison of extracapsular pseudotumors seen in magnetic resonance imaging and in revision surgery of 167 failed metal-on-metal hip replacements. AB - BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) is important for detecting extracapsular pseudotumors, but there is little information on the accuracy of MRI and appropriate intervals for repeated imaging. We evaluated the sensitivity and specificity of MRI for detecting pseudotumors in 155 patients (167 hips) with metal-on-metal (MoM) hip arthroplasties that failed due to adverse reactions to metal debris (ARMD). METHODS: Preoperative MRIs were performed with two 1.5 T MRI scanners and graded by a senior musculoskeletal radiologist using a previously described MRI pseudotumor grading system. Revision findings were retrieved from surgical notes, and pseudotumors were retrospectively graded as fluid-filled, mixed-type, or solid. RESULTS: The sensitivity of MRI was 71% and the specificity was 87% for detecting extracapsular pseudotumors. The sensitivity was 88% (95% CI: 70-96) when MRI was performed less than 3 months before the revision surgery. Interestingly, when the time that elapsed between MRI and revision was more than 1 year, the sensitivity calculated was only 29% (95% CI: 14-56). Comparison between MRI and revision classifications gave moderate agreement (Cohen's kappa = 0.4). INTERPRETATION: A recent MRI predicts the presence of a pseudotumor well, but there is more discrepancy when the MRI examination is over a year old, most likely due to the formation of new pseudotumors. 1 year could be a justifiable limit for considering a new MRI if development of ARMD is suspected. MRI images over a year old should not be used in decision making or in planning of revision surgery for MoM hips. PMID- 24954486 TI - The acetabulum in Perthes' disease: inter-observer agreement and reliability of radiographic measurements. AB - BACKGROUND AND PURPOSE: Perthes' disease leads to radiographic changes in both the femoral head and the acetabulum. We investigated the inter-observer agreement and reliability of 4 radiographic measurements assessing the acetabular changes. PATIENTS AND METHODS: We included 123 children with unilateral involvement, femoral head necrosis of more than 50%, and age at diagnosis of 6 years or older. Radiographs were taken at onset, and 1 year and 5 years after diagnosis. Sharp's angle, acetabular depth-width ratio (ADR), lateral acetabular inclination (LAI), and acetabular retroversion (ischial spine sign, ISS) were measured by 3 observers. Before measuring, 2 of the observers had a consensus meeting. RESULTS: We found good agreement and moderate to excellent reliability for Sharp's angle for all observers (intra-class correlation coefficient (ICC) > 0.80 with consensus, ICC = 0.46-0.57 without consensus). There was good agreement and substantial reliability for ADR between the observers who had had a consensus meeting (ICC = 0.62-0.89). Low levels of agreement and poor reliability were found for observers who had not had a consensus meeting. LAI showed fair agreement throughout the course of the disease (kappa = 0.28-0.52). The agreement between observations for ISS ranged from fair to good (kappa = 0.20-0.76). INTERPRETATION: Sharp's angle showed the highest reliability and agreement throughout the course of the disease. ADR was only reliable and showed good agreement between the observers when landmarks were clarified before measuring the radiographs. Thus, we recommend both parameters in clinical practice, provided a consensus is established for ADR. The observations for LAI had only fair agreement and ISS showed inconclusive agreement in our study. Thus, LAI and ISS can hardly be recommended in clinical practice. PMID- 24954487 TI - Faster recovery without the use of a tourniquet in total knee arthroplasty. AB - BACKGROUND AND PURPOSE: Tourniquet application is still a common practice in total knee arthroplasty (TKA) surgery despite being associated with several adverse effects. We evaluated the effects of tourniquet use on functional and clinical outcome and on knee range of motion (ROM). PATIENTS AND METHODS: 70 patients who underwent TKA were randomized into a tourniquet group (n = 35) and a non-tourniquet group (n = 35). All operations were performed by the same surgeon and follow-up was for 1 year. Primary outcomes were functional and clinical outcomes, as evaluated by KOOS and knee ROM. Secondary outcomes were intraoperative blood loss, surgical time and visibility, postoperative pain, analgesic consumption, and transfusion requirements. RESULTS: Patients in the non tourniquet group showed a better outcome in all KOOS subscores and better early knee ROM from surgery to week 8. No difference was detected at the 6- and 12 month follow-ups. Postoperative pain and analgesic consumption were less when a tourniquet was not used. Surgical time and visibility were similar between groups. Intraoperative blood loss was greater when not using a tourniquet, but no postoperative transfusions were required. INTERPRETATION: This study shows that TKA without the use of a tourniquet results in faster recovery in terms of better functional outcome and improved knee ROM. Furthermore, reduced pain and analgesic use were registered and no intraoperative difficulties were encountered. PMID- 24954488 TI - No clinical benefit of gender-specific total knee arthroplasty. AB - BACKGROUND AND PURPOSE: There is no consensus regarding the clinical relevance of gender-specific prostheses in total knee arthroplasty (TKA). We summarize the current best evidence in a comparison of clinical and radiographic outcomes between gender-specific prostheses and standard unisex prostheses in female patients. METHODS: We used the PubMed, Embase, Cochrane, Science Citation Index, and Scopus databases. We included randomized controlled trials published up to January 2013 that compared gender-specific prostheses with standard unisex prostheses in female patients who underwent primary TKAs. RESULTS: 6 trials involving 423 patients with 846 knee joints met the inclusion criteria. No statistically significant differences were observed between the 2 designs regarding pain, range of motion (ROM), knee scores, satisfaction, preference, complications, and radiographic results. The gender-specific design (Gender Solutions; Zimmer Inc, Warsaw, Indiana) reduced the prevalence of overhang. However, it had less overall coverage of the femoral condyles compared to the unisex group. In fact, the femoral prosthesis in the standard unisex group matched better than that in the gender-specific group. INTERPRETATION: Gender specific prostheses do not appear to confer any benefit in terms of clinician- and patient-reported outcomes for the female knee. PMID- 24954490 TI - Good stability but high periprosthetic bone mineral loss and late-occurring periprosthetic fractures with use of uncemented tapered femoral stems in patients with a femoral neck fracture. AB - BACKGROUND AND PURPOSE: We previously evaluated a new uncemented femoral stem designed for elderly patients with a femoral neck fracture and found stable implant fixation and good clinical results up to 2 years postoperatively, despite substantial periprosthetic bone mineral loss. We now present the medium-term follow-up results from this study. PATIENTS AND METHODS: In this observational prospective cohort study, we included 50 patients (mean age 81 (70-92) years) with a femoral neck fracture. All patients underwent surgery with a cemented cup and an uncemented stem specifically designed for fracture treatment. Outcome variables were migration of the stem measured with radiostereometry (RSA) and periprosthetic change in bone mineral density (BMD), measured with dual-energy X ray absorptiometry (DXA). Hip function and health-related quality of life were assessed using the Harris hip score (HHS) and the EuroQol-5D (EQ-5D). DXA and RSA data were collected at regular intervals up to 4 years, and data concerning reoperations and hip-related complications were collected during a mean follow-up time of 5 (0.2-7.5) years. RESULTS: At 5 years, 19 patients had either passed away or were unavailable for further participation and 31 could be followed up. Of the original 50 patients, 6 patients had suffered a periprosthetic fracture, all of them sustained after the 2-year follow-up. In 19 patients, we obtained complete RSA and DXA data and no component had migrated after the 2-year follow up. We also found a continuous total periprosthetic bone loss amounting to a median of -19% (-39 to 2). No changes in HHS or EQ-5D were observed during the follow-up period. INTERPRETATION: In this medium-term follow-up, the stem remained firmly fixed in bone despite considerable periprosthetic bone mineral loss. However, this bone loss might explain the high number of late-occurring periprosthetic fractures. Based on these results, we would not recommend uncemented femoral stems for the treatment of femoral neck fractures in the elderly. PMID- 24954492 TI - Poor intermediate-term survival of the uncemented Optan anatomically adapted femoral component. AB - PURPOSE: We evaluated the 5-year survival of the uncemented Optan anatomically adapted femoral stem, with revision for aseptic loosening as the endpoint. METHODS: Between January 2004 and March 2007, 432 total hip arthroplasties (THAs) were performed in 432 patients. After follow-up for a mean time of 5 years, the patients were evaluated using the WOMAC questionnaire and plain radiography. Patients who were unable to attend the follow-up visit were contacted by telephone to determine whether they had had any revision surgery of their THA. RESULTS: Within 5 years, 39 patients (9%) had died of unrelated causes and 63 patients (15%) had been lost to follow-up. Of the remaining cohort, 224 patients (68%) had full follow-up while 88 patients (27%) were evaluated with WOMAC only and 18 patients (5%) were evaluated with radiography only. The mean WOMAC score of all evaluated patients was 21 (10-100). At 5-year follow-up, there were 26 stem revisions reported (6%), 14 hips (3%) showed aseptic loosening, and 12 hips (3%) had had a periprosthetic femoral fracture. The 5-year survival to revision for any reason was 94%. Worst-case analysis yielded a 5-year survival of 79%. INTERPRETATION: The 5-year survival for aseptic loosening of the Optan anatomically adapted femoral component was disappointing. Radiographic evaluation showed evidence of proximal radiolucencies and distal cortical bone hypertrophy, which we attribute to insufficient proximal bone in-growth and increased load transfer at the tip of the stem. We do not recommend the use of the Optan femoral stem. PMID- 24954491 TI - Role of preoperative pain, muscle function, and activity level in discharge readiness after fast-track hip and knee arthroplasty. AB - BACKGROUND AND PURPOSE: The concept of fast-track surgery has led to a decline in length of stay after total hip arthroplasty (THA) and total knee arthroplasty (TKA) to about 2-4 days. However, it has been questioned whether this is only achievable in selected patients-or in all patients. We therefore investigated the role of preoperative pain and functional characteristics in discharge readiness and actual LOS in fast-track THA and TKA. METHODS: Before surgery, hip pain (THA) or knee pain (TKA), lower-extremity muscle power, functional performance, and physical activity were assessed in a sample of 153 [corrected] patients and used as independent variables to predict the outcome (dependent variable) - readiness for hospital discharge - for each type of surgery. Discharge readiness was assessed twice daily by blinded assessors RESULTS: Median discharge readiness and actual length of stay until discharge were both 2 days. Univariate linear regression followed by multiple linear regression revealed that age was the only independent predictor of discharge readiness in THA and TKA, but the standardized coefficients were small (<= 0.03). INTERPRETATION: These results support the idea that fast-track THA and TKA with a length of stay of about 2-4 days can be achieved for most patients independently of preoperative functional characteristics. PMID- 24954489 TI - Adherence of hip and knee arthroplasty studies to RSA standardization guidelines. A systematic review. AB - BACKGROUND AND PURPOSE: Guidelines for standardization of radiostereometry (RSA) of implants were published in 2005 to facilitate comparison of outcomes between various research groups. In this systematic review, we determined how well studies have adhered to these guidelines. METHODS: We carried out a literature search to identify all articles published between January 2000 and December 2011 that used RSA in the evaluation of hip or knee prosthesis migration. 2 investigators independently evaluated each of the studies for adherence to the 13 individual guideline items. Since some of the 13 points included more than 1 criterion, studies were assessed on whether each point was fully met, partially met, or not met. RESULTS: 153 studies that met our inclusion criteria were identified. 61 of these were published before the guidelines were introduced (2000-2005) and 92 after the guidelines were introduced (2006-2011). The methodological quality of RSA studies clearly improved from 2000 to 2011. None of the studies fully met all 13 guidelines. Nearly half (43) of the studies published after the guidelines demonstrated a high methodological quality and adhered at least partially to 10 of the 13 guidelines, whereas less than one fifth (11) of the studies published before the guidelines had the same methodological quality. Commonly unaddressed guideline items were related to imaging methodology, determination of precision from double examinations, and also mean error of rigid-body fitting and condition number cutoff levels. INTERPRETATION: The guidelines have improved methodological reporting in RSA studies, but adherence to these guidelines is still relatively low. There is a need to update and clarify the guidelines for clinical hip and knee arthroplasty RSA studies. PMID- 24954493 TI - Body mass index and risk of perioperative cardiovascular adverse events and mortality in 34,744 Danish patients undergoing hip or knee replacement. AB - BACKGROUND AND PURPOSE: Obesity is a risk factor for osteoarthritis in the lower limb, yet the cardiovascular risks associated with obesity in hip or knee replacement surgery are unknown. We examined associations between body mass index (BMI) and the risk of a major adverse cardiovascular event (MACE: ischemic stroke, acute myocardial infarction, or cardiovascular death) or the risk of all cause mortality in a nationwide Danish cohort of patients who underwent primary hip or knee replacement surgery. METHODS: Using Danish nationwide registries, we identified 34,744 patients aged >= 20 years who underwent elective primary hip or knee replacement surgery between 2005 and 2011. We used multivariable Cox regression models to calculate the 30-day risks of MACE and mortality associated with 5 BMI groups (underweight (BMI < 18.5 kg/m(2)), normal weight (18.5-24 kg/m(2)), overweight (25-29 kg/m(2)), obese 1 (30-34 kg/m(2)), and obese 2 (>= 35 kg/m(2))). RESULTS: In total, 232 patients (0.7%) had a MACE and 111 (0.3%) died. Compared with overweight, adjusted hazard ratios (HRs) were 1.2 (95% CI: 0.4 3.3), 1.3 (0.95-1.8), 1.6 (1.1-2.2), and 1.0 (0.6-1.9) for underweight, normal weight, obese 1, and obese 2 regarding MACE. Regarding mortality, the corresponding HRs were 7.0 (2.8-15), 2.0 (1.2-3.2), 1.5 (0.9-2.7), and 1.9 (0.9 4.2). Cubic splines suggested a significant U-shaped relationship between BMI and risks with nadir around 27-28. INTERPRETATION: In an unselected cohort of patients undergoing elective primary hip or knee replacement surgery, U-shaped risks of perioperative MACE and mortality were found in relation to BMI. Patients within the extreme ranges of BMI may warrant further attention. PMID- 24954495 TI - Incomplete periacetabular acetabuloplasty. PMID- 24954494 TI - Worse patient-reported outcome after lateral approach than after anterior and posterolateral approach in primary hip arthroplasty. A cross-sectional questionnaire study of 1,476 patients 1-3 years after surgery. AB - BACKGROUND: The surgical approach in total hip arthroplasty (THA) is often based on surgeon preference and local traditions. The anterior muscle-sparing approach has recently gained popularity in Europe. We tested the hypothesis that patient satisfaction, pain, function, and health-related quality of life (HRQoL) after THA is not related to the surgical approach. PATIENTS: 1,476 patients identified through the Norwegian Arthroplasty Register were sent questionnaires 1-3 years after undergoing THA in the period from January 2008 to June 2010. Patient reported outcome measures (PROMs) included the hip disability osteoarthritis outcome score (HOOS), the Western Ontario and McMaster Universities osteoarthritis index (WOMAC), health-related quality of life (EQ-5D-3L), visual analog scales (VAS) addressing pain and satisfaction, and questions about complications. 1,273 patients completed the questionnaires and were included in the analysis. RESULTS: Adjusted HOOS scores for pain, other symptoms, activities of daily living (ADL), sport/recreation, and quality of life were significantly worse (p < 0.001 to p = 0.03) for the lateral approach than for the anterior approach and the posterolateral approach (mean differences: 3.2-5.0). These results were related to more patient-reported limping with the lateral approach than with the anterior and posterolateral approaches (25% vs. 12% and 13%, respectively; p < 0.001). INTERPRETATION: Patients operated with the lateral approach reported worse outcomes 1-3 years after THA surgery. Self-reported limping occurred twice as often in patients who underwent THA with a lateral approach than in those who underwent THA with an anterior or posterolateral approach. There were no significant differences in patient-reported outcomes after THA between those who underwent THA with a posterolateral approach and those who underwent THA with an anterior approach. PMID- 24954496 TI - Current and future drugs for treatment of MS-associated bladder dysfunction. AB - A majority of patients diagnosed with multiple sclerosis (MS) will develop lower urinary tract symptoms (LUTS) during the course of the disease. Even if antimuscarinic (anticholinergic) treatment is currently the mainstay of conservative treatment of neurogenic detrusor overactivity (NDO), including MS induced NDO, extensive data regarding their effectiveness and safeness are lacking. When antimuscarinic medications fail to prove efficacious, a further option is intradetrusor injections of onabotulinumtoxin A. In several studies, more than half (and up 76%) of the patients treated with onabotulinumtoxin A experienced significant improvement in symptoms or even achieved complete continence. Cannabis extracts have shown some promise but has still not gained wide acceptance as an effective treatment. Over the last few years many new disease-modifying drugs that have been approved and introduced for treatment of MS. These drugs may have effects not only on the MS disease process, but also on the disease symptoms, including LUTS. However, MS is not primarily a bladder disease and treatment of the underlying pathophysiology should be the main goal of treatment. Since most of the urology drugs are targeting LUTS, these drugs should be regarded as "adds on" to treatments modifying the underlying disorder. Considering that most of these drugs have not been studied specifically with respect to efficacy on LUTS, and since they are not without significant side effects, it seems important that if and when they are going to be used for treatment of bladder symptoms should be a joint decision between the neurologist and urologist taking care of the patient. PMID- 24954497 TI - Urinary disorders, behavioral and cognitive therapy and functional disorder. PMID- 24954498 TI - Place of perineal electrophysiologic testing in multiple sclerosis patients. AB - At present, apart from visual evoked potential testing, clinical neurophysiological testing is rarely used in multiple sclerosis (MS) patients at all. In MS patients with lower urinary tract, bowel and/or sexual dysfunction, which are highly prevalent in MS, clinical neurophysiological tests of the sacral nervous system have been introduced in the past and reported as abnormal. Their usefulness is--in selected patients--to substantiate the suspicion of the neurogenic nature of the pelvic organ dysfunction, but there is no specific recommendation for MS patients. Concentric needle EMG of the perineal muscles, bulbocavernosus reflex latency measurement and pudendal SEP may be particularly useful in those rare patients in whom MS may affect the conus medullaris, to demonstrate "directly" this lesion of the lower sacral segments. Clinical neurophysiological testing retains the potential to further clarify interesting research questions of correlation of nervous system function and pelvic organ dysfunction, particularly relevant for application of sophisticated new rehabilitative methods including electrical stimulation of the nervous system. PMID- 24954499 TI - Letter to the Editor regarding transoral laser microsurgery followed by radiotherapy in advanced oropharyngeal cancer. PMID- 24954500 TI - Anticoagulation therapy is harmful to large-sized cerebellar infarction. AB - AIM: Anticoagulants are commonly used to treat ischemic stroke. Its impact on cerebellar infarction has not been fully understood. METHODS: In the clinical study, we reviewed a consecutive series of patients with large-sized cerebellar infarction (diameter > 3 cm, n = 30) treated with or without anticoagulation. In animal study, cerebellar infarction operation was performed in 12 Cynomolgus monkeys. Then the animals were administrated with low molecular weight heparin (LMWH) or vehicle for 14 days. RESULTS: Six patients died during the following treatment. All the subjects that died received anticoagulation therapy, while nobody in the survival group received such a therapy. Compared with sham-operated animals, all monkeys with cerebellar infarction have obvious neurological deficits. The number and size of the Purkinje cells in the cerebellar area were also reduced. Two animals in the LMWH group (33%) died, while all animals in the vehicle control group survived. Compared with the vehicle group, the neurological score in the LMWH group was significantly increased (P < 0.05). The water content in the cerebella was also significantly higher (P < 0.05). Edema, hemorrhage, and subarachnoid hemorrhage occurred in the cerebella as well as brainstem of all the LMWH treated animals. CONCLUSIONS: These results indicated the harmful effects of anticoagulation therapy on large-sized cerebellar infarction. PMID- 24954502 TI - Oct4 is a critical regulator of stemness in head and neck squamous carcinoma cells. AB - Cancer stem cells (CSCs) have been suggested as responsible for the initiation and progression of cancers. Octamer-binding transcription factor 4 (Oct4) is an important regulator of embryonic stem cell fate. Here, we investigated whether Oct4 regulates stemness of head and neck squamous carcinoma (HNSC) CSCs. Our study showed that ectopic expression of Oct4 promotes tumor growth through cyclin E activation, increases chemoresistance through ABCC6 expression and enhances tumor invasion through slug expression. Also, Oct4 dedifferentiates differentiated HNSC cells to CSC-like cells. Furthermore, Oct4(high) HNSC CSCs have more stem cell-like traits compared with Oct4(low) cells, such as self renewal, stem cell markers' expression, chemoresistance, invasion capacity and xenograft tumorigeneity in vitro and in vivo. In addition, knockdown of Oct4 led to markedly lower HNSC CSC stemness. Finally, there was a significant correlation between Oct4 expression and survival of 119 HNSC patients. Collectively, these data suggest that Oct4 may be a critical regulator of HNSC CSCs and its targeting may be potentially valuable in the treatment of HNSC CSCs. PMID- 24954503 TI - BTK inhibitors in chronic lymphocytic leukemia: a glimpse to the future. AB - The treatment of chronic lymphocytic leukemia (CLL) with inhibitors targeting B cell receptor signaling and other survival mechanisms holds great promise. Especially the early clinical success of Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK), has received widespread attention. In this review we will focus on the fundamental and clinical aspects of BTK inhibitors in CLL, with emphasis on Ibrutinib as the best studied of this class of drugs. Furthermore, we summarize recent laboratory as well as clinical findings relating to the first cases of Ibrutinib resistance. Finally, we address combination strategies with Ibrutinib, and attempt to extrapolate its current status to the near future in the clinic. PMID- 24954501 TI - Evaluating weight of evidence in the mystery of Balkan endemic nephropathy. AB - Balkan endemic nephropathy (BEN) is a chronic, progressive wasting disease of the kidneys, endemic in certain rural regions of the Balkan nations Croatia, Serbia, Bulgaria, and Romania. It is irreversible and ultimately fatal. Though this disease was first described in the 1950s, its causes have been a mystery and a source of much academic and clinical contention. Possible etiologic agents that have been explored include exposure to metals and metalloids, viruses and bacteria, and the dietary toxins aristolochic acid (AA) and ochratoxin A (OTA). AA is a toxin produced by weeds of the genus Aristolochia, common in Balkan wheat fields. Aristolochia seeds may intermingle with harvested grains and thus inadvertently enter human diets. OTA is a mycotoxin (fungal toxin) common in many foods, including cereal grains. In this study, we analyzed the weight of evidence for each of the suspected causes of BEN using the Bradford Hill criteria (BHC): nine conditions that determine weight of evidence for a causal relationship between an agent and a disease. Each agent postulated to cause BEN was evaluated using the nine criteria, and for each criterion was given a rating based on the strength of the association between exposure to the substance and BEN. From the overall available scientific evidence for each of these suspected risk factors, AA is the agent with the greatest weight of evidence in causing BEN. We describe other methods for testing causality from epidemiological studies, which support this conclusion of AA causing BEN. PMID- 24954504 TI - MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma. AB - Glioblastomas are aggressive adult brain tumors, characterized by inadequately organized vasculature and consequent nutrient and oxygen (O2)-depleted areas. Adaptation to low nutrients and hypoxia supports glioblastoma cell survival, progression and therapeutic resistance. However, specific mechanisms promoting cellular survival under nutrient and O2 deprivation remain incompletely understood. Here, we show that miR-124 expression is negatively correlated with a hypoxic gene signature in glioblastoma patient samples, suggesting that low miR 124 levels contribute to pro-survival adaptive pathways in this disease. As miR 124 expression is repressed in various cancer types (including glioblastoma), we quantified miR-124 abundance in normoxic and hypoxic regions in glioblastoma patient tissue, and investigated whether ectopic miR-124 expression compromises cell survival during tumor ischemia. Our results indicate that miR-124 levels are further diminished in hypoxic/ischemic regions within individual glioblastoma patient samples, compared with regions replete in O2 and nutrients. Importantly, we also show that increased miR-124 expression affects the ability of tumor cells to survive under O2 and/or nutrient deprivation. Moreover, miR-124 re-expression increases cell death in vivo and enhances the survival of mice bearing intracranial xenograft tumors. miR-124 exerts this phenotype in part by directly regulating TEAD1, MAPK14/p38alpha and SERP1, factors involved in cell proliferation and survival under stress. Simultaneous suppression of these miR 124 targets results in similar levels of cell death as caused by miR-124 restoration. Importantly, we further demonstrate that SERP1 reintroduction reverses the hypoxic cell death elicited by miR-124, indicating the importance of SERP1 in promoting tumor cell survival. In support of our experimental data, we observed a significant correlation between high SERP1 levels and poor patient outcome in glioblastoma patients. Collectively, among the many pro-tumorigeneic properties of miR-124 repression in glioblastoma, we delineated a novel role in promoting tumor cell survival under stressful microenvironments, thereby supporting tumor progression. PMID- 24954505 TI - The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers. AB - Disease progression and recurrence are major barriers to survival for breast cancer patients. Understanding the etiology of recurrent or metastatic breast cancer and underlying mechanisms is critical for the development of new treatments and improved survival. Here, we report that two commonly overexpressed breast cancer oncogenes, Ron (Recepteur d'Origine Nantaise) and DEK, cooperate to promote advanced disease through multipronged effects on beta-catenin signaling. The Ron receptor is commonly activated in breast cancers, and Ron overexpression in human disease stimulates beta-catenin nuclear translocation and is an independent predictor of metastatic dissemination. Dek is a chromatin-associated oncogene whose expression has been linked to cancer through multiple mechanisms, including beta-catenin activity. We demonstrate here that Dek is a downstream target of Ron receptor activation in murine and human models. The absence of Dek in the MMTV-Ron mouse model led to a significant delay in tumor development, characterized by decreased cell proliferation, diminished metastasis and fewer cells expressing mammary cancer stem cell markers. Dek complementation of cell lines established from this model was sufficient to promote cellular growth and invasion. Mechanistically, Dek expression stimulated the production and secretion of Wnt ligands to sustain an autocrine/paracrine canonical beta-catenin signaling loop. Finally, we show that Dek overexpression promotes tumorigenic phenotypes in immortalized human mammary epithelial MCF10A cells and, in the context of Ron receptor activation, correlates with disease recurrence and metastasis in patients. Overall, our studies demonstrate that DEK overexpression, due in part to Ron receptor activation, drives breast cancer progression through the induction of Wnt/beta-catenin signaling. PMID- 24954506 TI - The PI3K/Akt signal hyperactivates Eya1 via the SUMOylation pathway. AB - Eyes absent 1 (Eya1) is a conserved critical regulator of organ-specific stem cells. Ectopic Eya1 activities, however, promote transformation of mammary epithelial cells. Signals that instigate Eya1 oncogenic activities remain to be determined. Here, we show that Akt1 kinase physically interacts with Eya1 and phosphorylates a conserved consensus site of the Akt kinase. PI3K/Akt signaling enhances Eya1 transcription activity, which largely attributes to the phosphorylation-induced reduction of Eya1 SUMOylation. Indeed, SUMOylation inhibits Eya1 transcription activity; and pharmacologic and genetic activation of PI3K/Akt robustly reduces Eya1 SUMOylation. Wild-type but not Akt phosphorylation site mutant Eya1 variant rescues the cell migratory phenotype of EYA1-silenced breast cancer cells, highlighting the importance of Eya1 phosphorylation. Furthermore, knockdown EYA1 sensitizes breast cancer cells to the PI3K/Akt1 inhibitor and irradiation treatments. Thus, the PI3K/Akt signal pathway activates Eya1. These findings further suggest that regulation of SUMOylation by PI3K/Akt signaling is likely an important aspect of tumorigenesis. PMID- 24954507 TI - PHLDA1 expression is controlled by an estrogen receptor-NFkappaB-miR-181 regulatory loop and is essential for formation of ER+ mammospheres. AB - Crosstalk between estrogen receptor (ER) and the inflammatory nuclear factor kappaB (NFkappaB) pathway in ER+ breast cancers may contribute to a more aggressive phenotype. Pleckstrin Homology-Like Domain, Family A, member 1 (PHLDA1), a target gene of ER-NFkappaB crosstalk, has been implicated in cell survival and stem cell properties. 17beta-estradiol (E2), acting through ERalpha, and pro-inflammatory cytokines, acting through NFkappaB, increase the nascent transcript and PHLDA1 messenger RNA stability, indicating both transcriptional and post-transcriptional control of PHLDA1 expression. We show that PHLDA1 is a direct target of miR-181 and that mature miR-181a and b, as well as their host gene, are synergistically downregulated by E2 and tumor necrosis factor alpha, also in an ER- and NFkappaB-dependent manner. Thus, ER and NFkappaB work together to upregulate PHLDA1 directly through enhanced transcription and indirectly through repression of miR-181a and b. Previous studies have suggested that PHLDA1 may be a stem cell marker in the human intestine that contributes to tumorigenesis. Our findings that PHLDA1 is upregulated in mammospheres (MS) of ER+ breast cancer cells and that PHLDA1 knockdown impairs both MS formation and the expansion of aldehyde dehydrogenase (ALDH)-positive population, suggest that PHLDA1 may play a similar role in breast cancer cells. Upregulation of PHLDA1 in MS is largely dependent on the NFkappaB pathway, with downregulated miR-181 expression a contributing factor. Over-expression of miR-181 phenocopied PHLDA1 knockdown and significantly impaired MS formation, which was reversed, in part, by protection of the PHLDA1 3' untranslated region (UTR) or overexpression of PHLDA1 lacking the 3'UTR. Furthermore, we find that elevated PHLDA1 expression is associated with a higher risk of distant metastasis in ER+ breast cancer patients. Altogether, these data suggest that high PHLDA1 expression is controlled through an ER-NFkappaB-miR-181 regulatory axis and may contribute to a poor clinical outcome in patients with ER+ breast tumors by enhancing stem-like properties in these tumors. PMID- 24954508 TI - beta-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids. AB - Cancer cells form three-dimensional (3D) multicellular aggregates (or spheroids) under non-adherent culture conditions. In ovarian cancer (OC), spheroids serve as a vehicle for cancer cell dissemination in the peritoneal cavity, protecting cells from environmental stress-induced anoikis. To identify new targetable molecules in OC spheroids, we investigated gene expression profiles and networks upregulated in 3D vs traditional monolayer culture conditions. We identified ALDH1A1, a cancer stem cell marker as being overexpressed in OC spheroids and directly connected to key elements of the beta-catenin pathway. beta-Catenin function and ALDH1A1 expression were increased in OC spheroids vs monolayers and in successive spheroid generations, suggesting that 3D aggregates are enriched in cells with stem cell characteristics. beta-Catenin knockdown decreased ALDH1A1 expression levels and beta-catenin co-immunoprecipitated with the ALDH1A1 promoter, suggesting that ALDH1A1 is a direct beta-catenin target. Both short interfering RNA-mediated beta-catenin knockdown and A37 ((ethyl-2-((4-oxo-3-(3 (pryrrolidin-1-yl)propyl)-3,4-dihydrobenzo [4,5]thioeno [3,2-d]pyrimidin-2 yl)thio)acetate)), a novel ALDH1A1 small-molecule enzymatic inhibitor described here for the first time, disrupted OC spheroid formation and cell viability (P<0.001). beta-Catenin knockdown blocked tumor growth and peritoneal metastasis in an OC xenograft model. These data strongly support the role of beta-catenin regulated ALDH1A1 in the maintenance of OC spheroids and propose new ALDH1A1 inhibitors targeting this cell population. PMID- 24954512 TI - Flexible establishment of functional brain networks supports attentional modulation of unconscious cognition. AB - In classical theories of attention, unconscious automatic processes are thought to be independent of higher-level attentional influences. Here, we propose that unconscious processing depends on attentional enhancement of task-congruent processing pathways implemented by a dynamic modulation of the functional communication between brain regions. Using functional magnetic resonance imaging, we tested our model with a subliminally primed lexical decision task preceded by an induction task preparing either a semantic or a perceptual task set. Subliminal semantic priming was significantly greater after semantic compared to perceptual induction in ventral occipito-temporal (vOT) and inferior frontal cortex, brain areas known to be involved in semantic processing. The functional connectivity pattern of vOT varied depending on the induction task and successfully predicted the magnitude of behavioral and neural priming. Together, these findings support the proposal that dynamic establishment of functional networks by task sets is an important mechanism in the attentional control of unconscious processing. PMID- 24954510 TI - Synuclein gamma protects Akt and mTOR and renders tumor resistance to Hsp90 disruption. AB - Heat shock protein (Hsp)90 regulates many key pathways in oncogenesis, including Akt and mammalian target of rapamycin (mTOR). The strengths of disruption of Hsp90 in cancer therapy include their versatility in inhibiting a wide range of oncogenic pathways. The present study demonstrated that synuclein gamma (SNCG) protects the functions of Akt and mTOR in the condition when the function of Hsp90 is blocked. Disruption of Hsp90 abolished Akt activity and mTOR signaling. However, expression of SNCG restored Akt activity and mTOR signaling. SNCG bound to Akt and mTOR in the presence and absence of Hsp90. Specifically, the C terminal (Gln106-Asp127) of SNCG bound to the loop connecting alphaC helix and beta4 sheet of the kinase domain of Akt. SNCG renders resistance to 17-AAG induced apoptosis both in vitro and in tumor xenograft. A clinical follow-up study indicates that patients with an SNCG-positive breast cancer have a significantly shorter disease-free survival and overall survival than patients with SNCG-negative tumors. The present study indicates that SNCG protects Hsp90 client proteins of Akt and mTOR, and renders drug resistance to Hsp90 disruption. PMID- 24954509 TI - HSF1 regulation of beta-catenin in mammary cancer cells through control of HuR/elavL1 expression. AB - There is now compelling evidence to indicate a place for heat shock factor 1 (HSF1) in mammary carcinogenesis, tumour progression and metastasis. Here we have investigated a role for HSF1 in regulating the expression of the stem cell renewal factor beta-catenin in immortalized human mammary epithelial and carcinoma cells. We found HSF1 to be involved in regulating the translation of beta-catenin, by investigating effects of gain and loss of HSF1 on this protein. Interestingly, although HSF1 is a potent transcription factor, it was not directly involved in regulating levels of beta-catenin mRNA. Instead, our data suggest a complex role in translational regulation. HSF1 was shown to regulate levels of the RNA-binding protein HuR that controlled beta-catenin translation. An extra complexity was added to this scenario when it was shown that the long non-coding RNA molecule lincRNA-p21, known to be involved in beta-catenin mRNA (CTNNB1) translational regulation, was controlled by HSF1 repression. We have shown previously that HSF1 was positively regulated through phosphorylation by mammalian target of rapamycin (mTOR) kinase on a key residue, serine 326, essential for transcriptional activity. In this study, we found that mTOR knockdown not only decreased HSF1-S326 phosphorylation in mammary cells, but also decreased beta-catenin expression through a mechanism requiring HuR. Our data point to a complex role for HSF1 in the regulation of HuR and beta-catenin expression that may be significant in mammary carcinogenesis. PMID- 24954511 TI - Effect of a low dose combined oral contraceptive pill on the hormonal profile and cycle outcome following COS with a GnRH antagonist protocol in women over 35 years old. AB - This prospective study examines if pre-treatment with two different doses of an oral contraceptive pill (OCP) modifies significantly the hormonal profile and/or the IVF/ICSI outcome following COS with a GnRH antagonist protocol. Infertile patients were allocated to receive either OCP containing 0.03 mg of ethinylestradiol and 3 mg of drospirenone, or OCP containing 0.02 mg of ethinylestradiol and 3 mg of drospirenone prior to initiation of controlled ovarian stimulation (COS) with recombinant gonadotropins on a variable multi-dose antagonist protocol (Ganirelix), while the control group underwent COS without OCP pretreatment. Lower dose OCP was associated with recovery of FSH on day 3 instead of day 5, but the synchronization of the follicular cohort, the number of retrieved oocytes and the clinical pregnancy rate were similar to higher dose OCP. PMID- 24954513 TI - Heteronuclear refocusing by nonlinear phase and amplitude modulation on a single transmitter channel. AB - The application of low magnetic fields to heteronuclear NMR has expanded recently alongside the emergence of methods for achieving near unity polarization of spin ensembles, independent of magnetic field strength. The parahydrogen induced hyperpolarization methods in particular, often use a hybrid arrangement where a high field spectrometer is used to detect or image polarized molecules that have been conjured on a separate, dedicated polarizer instrument operating at fields in the mT regime where yields are higher. For controlling polarizer chemistry, spare TTL channels of portable NMR spectrometers can be used to pulse program reaction timings in synchrony with heteronuclear RF transformations. The use of a spectrometer as a portable polarizer control module has the advantage of allowing detection in situ, simplifying the process of optimizing polarization yields prior to in vivo experimental trials. Suitable heteronuclear spectrometers compatible with this application are becoming more common, but are still sparsely available in comparison to a large existing infrastructure of single channel NMR consoles. With the goal of expanding the range of these systems to multinuclear applications, the feasibility of rotating a pair of heteronuclear spins ((13)C and (1)H) at 12mT was investigated in this study. Nonlinear phase and amplitude modulated waveforms designed to simultaneously refocus magnetization at 128kHz ((13)C) and 510kHz ((1)H) were generated numerically with optimal control. Although precise quantitative comparisons were not attempted due to limitations of the experimental setup, signals refocused at heteronuclear frequencies with this PANORAMIC approach (Precession And Nutation for Observing Rotation At Multiple Intervals about the Carrier) yielded amplitudes comparable to signals which were refocused using traditional block pulses on heteronuclear channels. Using this PANORAMIC approach to heteronuclear NMR at low field would reduce expense as well as hardware complexity and bulk, weighed against the caveat that elaborate pulses are required. More work will be necessary to test this method on the targeted application of parahydrogen induced hyperpolarization as well as to quantify efficiency, but upon further development we anticipate that this method may offer a viable 'software' approach to heteronuclear manipulations of spins at low magnetic fields. PMID- 24954514 TI - Comparative genome analysis and molecular epidemiology of the reemerging porcine epidemic diarrhea virus strains isolated in Korea. AB - Porcine epidemic diarrhea virus (PEDV), a member of the Coronaviridae family, is an enveloped, positive-sense, single-stranded RNA virus, which causes severe diarrhea and dehydration in suckling pigs. We detected three PEDV strains from ten small intestine samples from piglets with acute diarrhea and we determined the complete genome sequences of the reemerging Korean PEDV field isolates, except for the noncoding regions from both ends. The complete genome sequences of the strains were identical or almost identical (one synonymous single-nucleotide polymorphism (SNP) in the ORF1a/1b genomic sequence). Interestingly, comparative genome analysis of recent Korean PEDV isolates and other strains revealed that the complete genome sequences of recent Korean strains were almost identical (99.9%) to those of the US PEDV strains isolated in 2013. These results suggest that the three reemerging Korean strains are distinct from previous endemic Korean PEDV strains and has been recently introduced into Korea from oversea with high likelihood. PMID- 24954515 TI - Rational design of urea-based glutamate carboxypeptidase II (GCPII) inhibitors as versatile tools for specific drug targeting and delivery. AB - Glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane antigen (PSMA), is an established prostate cancer marker and is considered a promising target for specific anticancer drug delivery. Low-molecular-weight inhibitors of GCPII are advantageous specific ligands for this purpose. However, they must be modified with a linker to enable connection of the ligand with an imaging molecule, anticancer drug, and/or nanocarrier. Here, we describe a structure-activity relationship (SAR) study of GCPII inhibitors with linkers suitable for imaging and drug delivery. Structure-assisted inhibitor design and targeting of a specific GCPII exosite resulted in a 7-fold improvement in Ki value compared to the parent structure. X-ray structural analysis of the inhibitor series led to the identification of several inhibitor binding modes. We also optimized the length of the inhibitor linker for effective attachment to a biotin-binding molecule and showed that the optimized inhibitor could be used to target nanoparticles to cells expressing GCPII. PMID- 24954517 TI - Conception rate and litter size in multiparous sows after intrauterine insemination using frozen-thawed boar semen in a commercial swine herd in Thailand. AB - The aim of the present study was to determine the conception rate and litter size in sows after fixed time intra-uterine insemination using frozen-thawed boar semen in a commercial swine herd in Thailand. Sixty-nine Landrace multiparous sows were randomly allocated into two groups, including control (n=36) and treatment (n=33). The control sows were inseminated with extended fresh semen (3 * 10(9) motile sperm/dose, 100 ml) at 24, 36 and 48 hr after the onset of estrus. The treatment sows were inseminated with frozen-thawed semen (2 * 10(9) motile sperm/dose, 20 ml) at 24 and 36 hr after induction of ovulation by human chorionic gonadotropin. All inseminations were carried out by using an intra uterine insemination technique. The time of ovulation was determined by using transrectal real-time B-mode ultrasonography. The conception rate, farrowing rate, total number of piglets born/litter (TB) and number of piglets born alive/litter (BA) were evaluated. The sows inseminated with extended fresh semen yield a higher TB (10.8 versus 9.0 piglets/l, P=0.015) and tended to have a higher conception rate (88.9% versus 75.8%, P=0.150) than sows inseminated with frozen-thawed semen. In conclusion, insemination using frozen-thawed boar semen can be practiced with convinced fertility under field conditions by fixed-time intrauterine insemination with 2 * 10(9) sperm/ dose of 20 ml at 24 and 36 hr after the onset of estrus. PMID- 24954516 TI - Biomarkers for risk prediction in acute decompensated heart failure. AB - Risk prediction in patients admitted with acute decompensated heart failure (ADHF) remains a challenge. Biomarkers may improve risk prediction, which in turn may help to better inform patients regarding short-term and long-term prognosis, therapy and care. Most data on biomarkers have been derived from patient cohorts with chronic heart failure. In ADHF, currently, risk tools largely rely on common clinical and biochemical parameters. However, ADHF is not a single disease. It presents in various manners and different etiologies may underlie ADHF, which are reflected by different biomarkers. In the last decade, many studies have reported the prognostic value of these biomarkers. These studies have attempted to describe a value for statistical modeling, e.g., reclassification indices, in an effort to report incremental value over a clinical model or the "gold standard". However, the overall incremental predictive value of biomarkers has been modest compared to already existing clinical models. Natriuretic peptides, e.g., (NTpro )BNP, are the benchmark, but head-to-head comparisons show that there are novel biomarkers with comparable prognostic value. Multimarker strategies may provide superior risk stratification. Future studies should elucidate cost-effectiveness of single or combined biomarker testing. The purpose of this review was to provide an update on current biomarkers and to identify new promising biomarkers than can be used in prognostication of acute heart failure. PMID- 24954520 TI - The drugs don't sell: DIY heart health and the over-the-counter statin experience. AB - This paper draws on a study of over-the-counter statins to provide a critical account of the figure of the 'pharmaceutical consumer' as a key actor in the pharmaceuticalisation literature. A low dose statin, promising to reduce cardiovascular risk, was reclassified to allow sale in pharmacies in the UK in 2004. We analysed professional and policy debates about the new product, promotional and sales information, and interviews with consumers and potential consumers conducted between 2008 and 2011, to consider the different consumer identities invoked by these diverse actors. While policymakers constructed an image of 'the citizen-consumer' who would take responsibility for heart health through exercising the choice to purchase a drug that was effectively rationed on the NHS and medical professionals raised concerns about 'a flawed consumer' who was likely to misuse the product, both these groups assumed that there would be a market for the drug. By contrast, those who bought the product or potentially fell within its target market might appear as 'health consumers', seeking out and paying for different food and lifestyle products and services, including those targeting high cholesterol. However, they were reluctant 'pharmaceutical consumers' who either preferred to take medication on the advice of a doctor, or sought to minimize medicine use. In comparison to previous studies, our analysis builds understanding of individual consumers in a market, rather than collective action for access to drugs (or, less commonly, compensation for adverse effects). Where some theories of pharmaceuticalisation have presented consumers as creating pressure for expanding markets, our data suggests that sociologists should be cautious about assuming there will be demand for new pharmaceutical products, especially those aimed at prevention or asymptomatic conditions, even in burgeoning health markets. PMID- 24954519 TI - Is trust really social capital? Commentary on Carpiano and Fitterer (2014). PMID- 24954521 TI - Everyday suffering outside prison walls: a legacy of community justice in post genocide Rwanda. AB - Twenty years after the 1994 genocide, Rwanda shows all indications of moving quickly towards socio-economic prosperity. Rwanda's community justice system, Gacaca, was to complement this prosperity by establishing peace and stability through justice, reconciliation and healing. Evaluations of the Gacaca courts' achievements from 2002 to 2012 have had widely differing conclusions. This article adds to previous evaluations by drawing attention to specific forms of relatively neglected suffering (in literature and public space) that have emerged from the Gacaca courts or were amplified by these courts and jeopardize Gacaca's objectives. The ethnographic study that informs the article was conducted in southeastern Rwanda from September 2008-December 2012 among 19 ex-prisoners and 24 women with husbands in prison including their family members, friends and neighbors. Study findings suggest that large scale imprisonment of genocide suspects coupled with Gacaca court proceedings have tainted the suffering of ex prisoners and women with imprisoned husbands in unique ways, which makes their plight unparalleled in other countries. We argue that the nature and scale of this suffering and the potentially detrimental impact on families and communities require humanitarian action. However, in Rwanda's post-genocide reality, the suffering of these two groups is overwhelmed by that of other vulnerable groups, such as genocide survivors and orphaned children; hence it is rarely acknowledged. PMID- 24954522 TI - Hydrodynamic interactions slow down crystallization of soft colloids. AB - Colloidal suspensions are often argued to be an ideal model for studying phase transitions such as crystallization, as they have the advantage of tunable interactions and experimentally tractable time and length scales. Because crystallization is assumed to be unaffected by details of particle transport other than the bulk diffusion coefficient, findings are frequently argued to be transferable to pure melts without solvent. In this article, we present molecular dynamics simulations of crystallization in a suspension of colloids with Yukawa interactions which challenge this assumption. In order to investigate the role of hydrodynamic interactions mediated by the solvent, we model the solvent both implicitly and explicitly, using Langevin dynamics and the fluctuating lattice Boltzmann method, respectively. Our simulations show a significant reduction of the crystal growth velocity due to hydrodynamic interactions even at moderate hydrodynamic coupling. This slowdown is accompanied by a reduction of the width of the layering region in front of the growing crystal. Thus the dynamics of a colloidal suspension differ strongly from that of a melt, making it less useful as a model for solvent-free melts than previously thought. PMID- 24954518 TI - Selection of competent blastocysts for transfer by combining time-lapse monitoring and array CGH testing for patients undergoing preimplantation genetic screening: a prospective study with sibling oocytes. AB - BACKGROUND: Recent advances in time-lapse monitoring in IVF treatment have provided new morphokinetic markers for embryonic competence. However, there is still very limited information about the relationship between morphokinetic parameters, chromosomal compositions and implantation potential. Accordingly, this study aimed at investigating the effects of selecting competent blastocysts for transfer by combining time-lapse monitoring and array CGH testing on pregnancy and implantation outcomes for patients undergoing preimplantation genetic screening (PGS). METHODS: A total of 1163 metaphase II (MII) oocytes were retrieved from 138 PGS patients at a mean age of 36.6 +/- 2.4 years. These sibling MII oocytes were then randomized into two groups after ICSI: 1) Group A, oocytes (n = 582) were cultured in the time-lapse system and 2) Group B, oocytes (n = 581) were cultured in the conventional incubator. For both groups, whole genomic amplification and array CGH testing were performed after trophectoderm biopsy on day 5. One to two euploid blastocysts within the most predictive morphokinetic parameters (Group A) or with the best morphological grade available (Group B) were selected for transfer to individual patients on day 6. Ongoing pregnancy and implantation rates were compared between the two groups. RESULTS: There were significant differences in clinical pregnancy rates between Group A and Group B (71.1% vs. 45.9%, respectively, p = 0.037). The observed implantation rate per embryo transfer significantly increased in Group A compared to Group B (66.2% vs. 42.4%, respectively, p = 0.011). Moreover, a significant increase in ongoing pregnancy rates was also observed in Group A compared to Group B (68.9% vs. 40.5%. respectively, p = 0.019). However, there was no significant difference in miscarriage rate between the time-lapse system and the conventional incubator (3.1% vs. 11.8%, respectively, p = 0.273). CONCLUSIONS: This is the first prospective investigation using sibling oocytes to evaluate the efficiency of selecting competent blastocysts for transfer by combining time-lapse monitoring and array CGH testing for PGS patients. Our data clearly demonstrate that the combination of these two advanced technologies to select competent blastocysts for transfer results in improved implantation and ongoing pregnancy rates for PGS patients. PMID- 24954523 TI - Rational tailoring of substrate and inhibitor affinity via ATRP polymer-based protein engineering. AB - Atom transfer radical polymerization (ATRP)-based protein engineering of chymotrypsin with a cationic polymer was used to tune the substrate specificity and inhibitor binding. Poly(quaternary ammonium) was grown from the surface of the enzyme using ATRP after covalent attachment of a protein reactive, water soluble ATRP-initiator. This "grafting from" conjugation approach generated a high density of cationic ammonium ions around the biocatalytic core. Modification increased the surface area of the protein over 40-fold, and the density of modification on the protein surface was approximately one chain per 4 nm(2). After modification, bioactivity was increased at low pH relative to the activity of the native enzyme. In addition, the affinity of the enzyme for a peptide substrate was increased over a wide pH range. The massively cationic chymotrypsin, which included up to 2000 additional positive charges per molecule of enzyme, was also more stable at extremes of temperature and pH. Most interestingly, we were able to rationally control the binding of two oppositely charged polypeptide protease inhibitors, aprotinin and the Bowman-Birk trypsin chymotrypsin inhibitor from Glycine max, to the cationic derivative of chymotrypsin. This study expands upon our efforts to use polymer-based protein engineering to predictably engineer enzyme properties without the need for molecular biology. PMID- 24954525 TI - Contrasting biogeochemical characteristics of the Oubangui River and tributaries (Congo River basin). AB - The Oubangui is a major tributary of the Congo River. We describe the biogeochemistry of contrasting tributaries within its central catchment, with watershed vegetation ranging from wooded savannahs to humid rainforest. Compared to a 2-year monitoring record on the mainstem Oubangui, these tributaries show a wide range of biogeochemical signatures, from highly diluted blackwaters (low turbidity, pH, conductivity, and total alkalinity) in rainforests to those more typical for savannah systems. Spectral analyses of chromophoric dissolved organic matter showed wide temporal variations in the Oubangui compared to spatio temporal variations in the tributaries, and confirm that different pools of dissolved organic carbon are mobilized during different hydrological stages. delta(13)C of dissolved inorganic carbon ranged between -28.10/00 and -5.80/00, and was strongly correlated to both partial pressure of CO2 and to the estimated contribution of carbonate weathering to total alkalinity, suggesting an important control of the weathering regime on CO2 fluxes. All tributaries were oversaturated in dissolved greenhouse gases (CH4, N2O, CO2), with highest levels in rivers draining rainforest. The high diversity observed underscores the importance of sampling that covers the variability in subcatchment characteristics, to improve our understanding of biogeochemical cycling in the Congo Basin. PMID- 24954524 TI - Enzymatic glycosylation of vancomycin aglycon: completion of a total synthesis of vancomycin and N- and C-terminus substituent effects of the aglycon substrate. AB - Studies on the further development of the sequential glycosylations of the vancomycin aglycon catalyzed by the glycosyltransferases GtfE and GtfD and the observation of unusual, perhaps unexpected, aglycon substrate substituent effects on the rate and efficiency of the initial glycosylation reaction are reported. PMID- 24954526 TI - The development of a financial toxicity patient-reported outcome in cancer: The COST measure. AB - BACKGROUND: Considering patients' experience is essential for optimal decision making. However, despite increasing recognition of the impact of costs on oncology care, there is no patient-reported outcome measure (PROM) that specifically describes the financial distress experienced by patients. METHODS: The content for a comprehensive score for financial toxicity (COST) was developed with a stepwise approach: step 1) a literature review and semistructured, qualitative interviews with patients for content generation; step 2) patients' assessment of the items for importance to their quality of life; step 3) pilot testing assessing interitem (IIC) and item-total (ITC) correlations to identify redundancy (Spearman rho, > 0.7) and statistically unrelated content (P > .05); and step 4) exploratory factor analysis. Sociodemographic data were collected. RESULTS: In total, 155 patients with advanced cancer who were receiving treatment (20 patients in step 1, 35 patients in step 2, and 100 patients in steps 3 and 4) participated in the PROM development. In step 1, the literature was reviewed, and 20 patients generated 147 items, which were reduced to 58 items because of redundancy. In step 2, 35 patients rated the 58 items on importance, and 30 items were retained. In step 3, 46 patients assessed the 30 items, 14 items were excluded because of high IIC, and 3 were excluded because of nonsignificant ITC. In step 4, 2 items were discarded because of poor loadings in a factor analysis of 100 patients, resulting in an 11-item PROM. CONCLUSIONS: The content for a financial toxicity PROM was developed in 155 patients. The provisional COST measure demonstrated face and content validity as well as internal consistency and should be validated in larger samples. PMID- 24954527 TI - Toxic effects of Microgramma vacciniifolia rhizome lectin on Artemia salina, human cells, and the schistosomiasis vector Biomphalaria glabrata. AB - The present study evaluated the toxicity of Microgramma vacciniifolia rhizome lectin (MvRL) to Artemia salina, human tumour cell lines (larynx epidermoid carcinoma Hep-2, NCI-H292 lung mucoepidermoid carcinoma, and chronic myelocytic leukaemia K562), and normal peripheral blood mononuclear cells (PBMCs), as well as to Biomphalaria glabrata embryos and adults. MvRL was toxic to A. salina (LC50=159.9 MUg/mL), and exerted cytotoxic effects on NCI-H292 cells (IC50=25.23 MUg/mL). The lectin (1-100 MUg/mL) did not affect the viability of K562 and Hep-2 tumour cells, as well as of PBMCs. MvRL concentration of 1, 10, and 100 MUg/mL promoted malformations (mainly exogastrulation) in 7.8%, 22.5%, and 27.7% of embryos, respectively, as well as delayed embryo development in 42.0%, 69.5%, and 54.7% of embryos, respectively. MvRL at a concentration of 100 MUg/mL killed B. glabrata embryos (17.7%) and adults (25%). Further, MvRL damaged B. glabrata reproductive processes, which was evidenced by observations that snails exposed to the lectin (100 MUg/mL) deposited fewer eggs than those in the control group, and approximately 40% of the deposited eggs exhibited malformations. Comparison of these results with that from A. salina assay indicates that MvRL is adulticidal at the concentration range which is toxic to environment. In conclusion, the cytotoxicity of MvRL on tumour cell and absence of toxicity to normal cell indicate its potential as chemotherapeutic drug. Also, the study revealed that the lectin is able to promote deleterious effects on B. glabrata embryos at environmentally safe concentrations. PMID- 24954529 TI - Relapse of skeletal class III with anterior open bite after bimaxillary orthognathic surgery depending on maxillary posterior impaction and mandibular counterclockwise rotation. AB - The goal of this study is to evaluate relapse after orthognathic surgery of skeletal class III with anterior open bite depending on the posterior impaction and mandibular counterclockwise rotation. Patients (n = 29) were divided into two groups according to the change of mandibular occlusal plane angle (MnOP): Group A had a clockwise change of MnOP > 0 degrees (n = 11) and Group B had a counterclockwise change of MnOP < -2 degrees (n = 18). Lateral cephalograms were analyzed preoperatively, and at immediate stage, six weeks, six months, and one year after surgery. One year after surgery, the stability of the maxilla was good in both groups. Upward movement of the mandible was observed six weeks after surgery due to mandibular autorotation. The amount of mean relapse was small, although a significant difference was observed horizontally between groups. Group B demonstrated more forward movement of B point, pogonion, and menton than Group A (p < 0.05). SNB angle increased in both groups (p < 0.05). At one year follow up, good occlusal stability was observed in both groups with positive overbite. Our study suggested that bimaxillary procedures with clockwise and counterclockwise rotation of mandibular occlusal planes for correction of mandibular prognathism with anterior open bite appeared to be relatively stable procedures. PMID- 24954528 TI - A comparison study of different facial soft tissue analysis methods. AB - OBJECTIVES: The purpose of this study was to evaluate several different facial soft tissue measurement methods. MATERIALS AND METHODS: After marking 15 landmarks in the facial area of 12 mannequin heads of different sizes and shapes, facial soft tissue measurements were performed by the following 5 methods: Direct anthropometry, Digitizer, 3D CT, 3D scanner, and DI3D system. With these measurement methods, 10 measurement values representing the facial width, height, and depth were determined twice with a one week interval by one examiner. These data were analyzed with the SPSS program. RESULTS: The position created based on multi-dimensional scaling showed that direct anthropometry, 3D CT, digitizer, 3D scanner demonstrated relatively similar values, while the DI3D system showed slightly different values. All 5 methods demonstrated good accuracy and had a high coefficient of reliability (>0.92) and a low technical error (<0.9 mm). The measured value of the distance between the right and left medial canthus obtained by using the DI3D system was statistically significantly different from that obtained by using the digital caliper, digitizer and laser scanner (p < 0.05), but the other measured values were not significantly different. On evaluating the reproducibility of measurement methods, two measurement values (Ls-Li, G-Pg) obtained by using direct anthropometry, one measurement value (N'-Prn) obtained by using the digitizer, and four measurement values (EnRt-EnLt, AlaRt-AlaLt, ChRt ChLt, Sn-Pg) obtained by using the DI3D system, were statistically significantly different. However, the mean measurement error in every measurement method was low (<0.7 mm). All measurement values obtained by using the 3D CT and 3D scanner did not show any statistically significant difference. CONCLUSION: The results of this study show that all 3D facial soft tissue analysis methods demonstrate favorable accuracy and reproducibility, and hence they can be used in clinical practice and research studies. PMID- 24954530 TI - Number, causes and destinations of horses leaving the Australian Thoroughbred and Standardbred racing industries. AB - OBJECTIVE: Significant proportions of horses leave the Australian Thoroughbred and Standardbred racing industries, which has ramifications for both the economic sustainability and the public perception of racing. The aim of this study was to quantify potential horse wastage, describe the destinations of exiting horses and identify risk factors for horses going to these destinations. METHODS: Questionnaires were sent to 1258 selected Thoroughbred and 981 Standardbred trainers, with response rates of 30% and 32%, respectively. The survey investigated the role of various risk factors for wastage, including horse age, sex and number of years in training. The destination of departing horses was also examined in relation to these risk factors. RESULTS: Total horse exit rates for the 2002-03 official race year were 39.7% and 38.7% for the Thoroughbred and Standardbred racing industries, respectively. Reasons for leaving included 'poor performance/slow' (36.5% Thoroughbreds, 35.2% Standardbreds), 'illness/injury' (31.0%, 27.1%), 'to breed' (9.4%, 10.1%), 'unsuitable temperament/behaviour' (6.4%, 6.4%) and 'other' (16.8%, 21.2%). Statistically significant (P < 0.001) risk factors influencing the destinations of both Thoroughbred and Standardbred racing horses included whether the trainer owned the horses, sex, age and reasons for leaving. In addition, some factors were specific to one breed or the other. CONCLUSIONS: Improved behaviour training and early identification of the causes of poor performance could assist in reducing wastage. PMID- 24954531 TI - Synthesis and surface-spectroscopic characterization of photoisomerizable glyco SAMs on Au(111). AB - Photoisomerizable glyco-SAMs (self-assembled monolayers), utilizing synthetic azobenzene glycoside derivatives were fabricated. The ultimate goal of this project is to assay the influence of the 3D arrangement of sugar ligands on cell adhesion, and eventually make cell adhesion photoswitchable. However, it is a prerequisite for any biological study on the spatial conditions of carbohydrate recognition, that photoisomerization of the surface molecules can be verified. Here, we employed IRRAS and XPS to spectroscopically characterize glyco-SAMs. In particular and unprecedented to date, we prove reversible E->Z->E isomerization of azobenzene glycoside-terminated SAMs. PMID- 24954532 TI - Ectopic over-expression of peroxisomal ascorbate peroxidase (SbpAPX) gene confers salt stress tolerance in transgenic peanut (Arachis hypogaea). AB - Peroxisomal ascorbate peroxidase gene (SbpAPX) of an extreme halophyte Salicornia brachiata imparts abiotic stress endurance and plays a key role in the protection against oxidative stress. The cloned SbpAPX gene was transformed to local variety of peanut and about 100 transgenic plants were developed using optimized in vitro regeneration and Agrobacterium mediated genetic transformation method. The T0 transgenic plants were confirmed for the gene integration; grown under controlled condition in containment green house facility; seeds were harvested and T1 plants were raised. Transgenic plants (T1) were further confirmed by PCR using gene specific primers and histochemical GUS assay. About 40 transgenic plants (T1) were selected randomly and subjected for salt stress tolerance study. Transgenic plants remained green however non-transgenic plants showed bleaching and yellowish leaves under salt stress conditions. Under stress condition, transgenic plants continued normal growth and completed their life cycle. Transgenic peanut plants exhibited adequate tolerance under salt stress condition and thus could be explored for the cultivation in salt affected areas for the sustainable agriculture. PMID- 24954533 TI - A new mutation in the gene ROR2 causes brachydactyly type B1. AB - Brachydactyly type B, an autosomal dominant disorder that is characterized by hypoplasia of the distal phalanges and nails, can be divided into brachydactyly type B1 (BDB1) and brachydactyly type B2 (BDB2). BDB1 is caused by mutations in the receptor tyrosine kinase gene ROR2, which maps to chromosome 9q22, whereas BDB2 is caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Here, we report a three-generation Chinese family with dominant inheritance of the BDB1 limb phenotype. Sequence analysis identified a novel heterozygous base deletion (c.1396-1398delAA) in the gene ROR2 in all affected family members. This new deletion is expected to produce a truncated Ror2 protein with a new polypeptide of 57 amino acids at the C-terminal. PMID- 24954534 TI - Global analysis of population structure, spatial and temporal dynamics of genetic diversity, and evolutionary lineages of Iris yellow spot virus (Tospovirus: Bunyaviridae). AB - Thrips-transmitted Iris yellow spot virus is an economically important viral pathogen of Allium crops worldwide. A global analysis of known IYSV nucleocapsid gene (N gene) sequences was carried out to determine the comparative population structure, spatial and temporal dynamics with reference to its genetic diversity and evolution. A total of 98 complete N gene sequences (including 8 sequences reported in this study) available in GenBank and reported from 23 countries were characterized by in-silico RFLP analysis. Based on RFLP, 94% of the isolates could be grouped into NL or BR types while the rest belonged to neither group. The relative proportion of NL and BR types was 46% and 48%, respectively. A temporal shift in the IYSV genotypes with a greater incremental incidence of IYSVBR was found over IYSVNL before 2005 compared to after 2005. The virus population had at least one evolutionarily significant recombination event, involving IYSVBR and IYSVNL. Codon substitution studies did not identify any significant differences among the genotypes of IYSV. However, N gene codons were minimally positively selected, moderately negatively selected denoting the action of purifying selection, thus rejecting the theory of neutral mutation in IYSV population. However, one codon position (139) was found to be positively selected in all the genotypes. Population selection statistics in the IYSVBR, IYSVNL genotypes and in the population as a whole also revealed the action of purifying selection or population expansion, whereas IYSVother displayed a decrease in population size. Genetic differentiation studies showed inherent differentiation and infrequent gene flow between IYSVBR and IYSVNL genotypes corroborating the geographical confinement of these genotypes. Taken together the study suggests that the observed diversity in IYSV population and temporal shift in IYSVBR genotype is attributable to genetic recombination, abundance of purifying selection, insignificant positive selection and population expansion. Restricted gene flow between the two major IYSV genotypes further emphasizes the role of genetic drift in modeling the population architecture, evolutionary lineage and epidemiology of IYSV. PMID- 24954537 TI - Enzyme replacement therapy delays pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis. AB - Late-infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a hereditary neurological disorder characterized by progressive retinal degeneration and vision loss, cognitive and motor decline, seizures, and pronounced brain atrophy. This fatal pediatric disease is caused by mutations in the CLN2 gene which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Utilizing a TPP1-/- Dachshund model of CLN2 disease, studies were conducted to assess the effects of TPP1 enzyme replacement administered directly to the CNS on disease progression. Recombinant human TPP1 (rhTPP1) or artificial cerebrospinal fluid vehicle was administered to CLN2-affected dogs via infusion into the CSF. Untreated and vehicle treated affected dogs exhibited progressive declines in pupillary light reflexes (PLRs) and electroretinographic (ERG) responses to light stimuli. Studies were undertaken to determine whether CSF administration of rhTPP1 alters progression of the PLR and ERG deficits in the canine model. rhTPP1 administration did not inhibit the decline in ERG responses, as rhTPP1 treated, vehicle treated, and untreated dogs all exhibited similar progressive and profound declines in ERG amplitudes. However, in some of the dogs treated with rhTPP1 there were substantial delays in the appearance and progression of PLR deficits compared with untreated or vehicle treated affected dogs. These findings indicate that CSF administration of TPP1 can attenuate functional impairment of neural pathways involved in mediating the PLR but does not prevent loss of retinal responses detectable with ERG. PMID- 24954538 TI - Dysregulation of neurotrophic and inflammatory systems accompanied by decreased CREB signaling in ischemic rat retina. AB - Although permanent bilateral common carotid artery occlusion (2VO) has been demonstrated to induce retinal injury, there is still a lack of systematic research on the complex processing of retinal degeneration. In the present study, time-dependent (at three, 14, 60 days after 2VO surgery) changes of neurotrophic and inflammatory systems, as well as cAMP-responsive element binding protein (CREB) signaling, which has been previously reported to effectively regulate these two systems, were evaluated. First, a morphological study confirmed that 2VO surgery progressively induced severe inner retinal degeneration and down regulation of synaptic proteins, PSD95 and synaptophysin. The mRNA or protein levels of neurotrophic factors (NGF, BDNF, NT-3 and GDNF) and their receptors (TrkA, TrkB and TrkC) showed marked and persistent down-regulation in the rat retina since three days after 2VO surgery, whereas the gene transcription levels of CNTF were increased and p75(NTR) mRNA levels remained unchanged. In contrast to inner retinal degeneration, retinal Muller cells displayed rapid and prolonged activation since three days after 2VO lesion, whereas the microglia cell number, and TNF-alpha and IL-1beta levels showed a robust increase with a maximal effect at three days and returned to levels that were slightly over baseline at 14 and 60 days after 2VO lesion. Interestingly, the gene expression levels of iNOS significantly decreased in the rat retina at both three and 14 days after 2VO surgery. Finally, as we hypothesized, remarkable reduction of CREB and extracellular signal-regulated kinase (ERK) phosphorylation levels were observed in the rat retina at three days after 2VO surgery. Thus, for the first time, our study demonstrated that chronic ischemia induced long-term aberrant CREB signaling and time-dependent progressive dysregulation of neurotrophic and inflammatory systems in the retina, which may provide important clues for a better understanding of the pathogenesis of retinal ischemic damage. PMID- 24954536 TI - KRAS and YAP1 converge to regulate EMT and tumor survival. AB - Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival upon KRAS suppression. In particular, the transcriptional coactivator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling. PMID- 24954535 TI - Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. AB - Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible Kras(G12D)-driven mouse model of PDAC has established a critical role for sustained Kras(G12D) expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of Kras(G12D)-independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras(G12D)-independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC. PMID- 24954539 TI - Ocular and cardiac artifact rejection for real-time analysis in MEG. AB - BACKGROUND: Recently, magnetoencephalography (MEG) based real-time brain computing interfaces (BCI) have been developed to enable novel and promising methods for neuroscience research. It is well known that artifact rejection prior to source localization largely enhances the localization accuracy. However, many BCI approaches neglect real-time artifact removal due to its time consuming process. NEW METHOD: The method (referred to as ocular and cardiac artifact rejection for real-time analysis, OCARTA) is based on constrained independent component analysis (cICA), where a priori information of the underlying source signals is used to optimize and accelerate signal decomposition. Thereby, prior information is incorporated by using the subject's individual cardiac and ocular activity. The algorithm automatically uses different separation strategies depending on the underlying source activity. RESULTS: OCARTA was tested and applied to data from three different but most commonly used MEG systems (4D Neuroimaging, VSM MedTech Inc. and Elekta Neuromag). Ocular and cardiac artifacts were effectively reduced within one iteration at a time delay of 1ms performed on a standard PC (Intel Core i5-2410M). COMPARISON WITH EXISTING METHODS: The artifact rejection results achieved with OCARTA are in line with the results reported for offline ICA-based artifact rejection methods. CONCLUSION: Due to the fast and subject-specific signal decomposition the new approach introduced here is capable of real-time ocular and cardiac artifact rejection. PMID- 24954540 TI - Localising and classifying neurons from high density MEA recordings. AB - Neuronal microcircuits are formed of a myriad of spatially and functionally specific cell classes. Despite the importance of the spatial component in the characterisation of neural circuits, it has not received the attention it deserves. While multi-electrodes are widely used in the study of microcircuits, the spatial information available from them remains largely unexploited for analysis beyond spike sorting. Here we show how the spatial pattern of the extracellular signal is determined by both the electrophysiology and morphology of neurons. Starting from known current source models for the generation of the extracellular potential, we use the spatial pattern observed across a multi electrode array to localise and classify neurons into putative morphological classes. We evaluated the localisation and classification models with low fitting errors in simulated data. When applying them to recorded data we found correspondence between localisation statistics and expected recording radius and found evidence to support the separation into putative morphological classes. While existing localisation methods do not hold for the recording distances expected on multi-electrode recordings (under 60MUm), classification methods have been limited to the temporal component by either characterising spike shape or firing patterns. We show here how the information available from extracellular recordings can be used to localise and classify neurons based on the spatial pattern seen by multi-electrode arrays. Together they can improve current characterisation and classification of neurons based on complementary criteria such us firing pattern and functional characterisation. PMID- 24954541 TI - [Biomarkers for liver fibrosis: advances, advantages and disadvantages]. AB - Liver cirrhosis in Mexico is one of the most important causes of death in persons between the ages of 25 and 50 years. One of the reasons for therapeutic failure is the lack of knowledge about the molecular mechanisms that cause liver disorder and make it irreversible. One of its prevalent anatomical characteristics is an excessive deposition of fibrous tissue that takes different forms depending on etiology and disease stage. Liver biopsy, traditionally regarded as the gold standard of fibrosis staging, has been brought into question over the past decade, resulting in the proposal for developing non-invasive technologies based on different, but complementary, approaches: a biological one that takes the serum levels of products arising from the fibrosis into account, and a more physical one that evaluates scarring of the liver by methods such as ultrasound and magnetic resonance elastography; some of the methods were originally studied and validated in patients with hepatitis C. There is great interest in determining non-invasive markers for the diagnosis of liver fibrosis, since at present there is no panel or parameter efficient and reliable enough for diagnostic use. In this paper, we describe the biomarkers that are currently being used for studying liver fibrosis in humans, their advantages and disadvantages, as well as the implementation of new-generation technologies and the evaluation of their possible use in the diagnosis of fibrosis. PMID- 24954543 TI - Site-directed RNA editing with antagomir deaminases--a tool to study protein and RNA function. AB - RNA-guided machineries perfectly satisfy the demand for rationally programmable tools that manipulate gene function inside the cell. Over the last ten years, various natural machineries have been harnessed, with RNA interference being among the most prominent examples. It is now time to tackle the engineering of novel RNA-guided tools not provided by nature. In this respect, we highlight RNA guided site-directed RNA editing as a new concept for the manipulation of RNA and protein function. In contrast to currently available techniques, RNA editing allows for the introduction of selected point mutations into the transcriptome without the need for genomic manipulation. In particular, the approach described using chemically stabilized, antagomir-like guideRNAs may offer advantages over others, such as specificity and circumvention of immunogenicity. These new tools have significant potential for the advancement of both basic science and medicinal application, especially in the treatment of genetic diseases. PMID- 24954542 TI - Intellectual disability and bariatric surgery: a case study on optimization and outcome. PMID- 24954544 TI - Editorial comment to effect of propiverine hydrochloride on stress urinary incontinence. PMID- 24954545 TI - Non-invasive ventilation in the treatment of sleep-related breathing disorders: A review and update. AB - Non-invasive mechanical ventilation (NIV) was originally used in patients with acute respiratory compromises or exacerbations of chronic respiratory diseases as an alternative to intubation. Over the last thirty years NIV has been used during the night in patients with stable chronic lung diseases such as obstructive sleep apnea, the overlap syndrome (COPD and obstructive sleep apnea), neuromuscular disorders, obesity-hypoventilation syndrome and in other conditions such as sleep disorders associated with congestive heart failure. In this review we discuss the different types of NIV, the specific conditions in which they can be used as well as the indications, recommendations, and evidence supporting the efficacy of NIV. PMID- 24954546 TI - Wilms' tumor gene 1 transcript levels in leukapheresis of peripheral blood hematopoietic cells predict relapse risk in patients autografted for acute myeloid leukemia. AB - Autologous hematopoietic stem cell transplantation (ASCT) is a curative option alternative to allogeneic transplantation for patients with acute myeloid leukemia (AML). Relapse after ASCT can be due to contamination with leukemic blasts of autologous peripheral blood stem cells (PBSCs) collected by leukapheresis (LK). Identification and quantification of a minimal residual disease (MRD) marker in PBSCs could be relevant in determining the relapse risk after ASCT. High levels of the WT1 gene transcript in bone marrow of AML patients after treatment completion predict disease relapse. We evaluated WT1 transcript levels in autologous PBSC from LK used for ASCT in 30 consecutive AML patients in complete remission (CR) and established a correlation with clinical outcome. At diagnosis, all patients had WT1 overexpression. All patients were in morphological and genetic CR at the time of PBSC collection and before ASCT. Real time quantitative PCR of WT1 was performed in samples of each LK, using TaqMan technology on RNA from mononucleated cells. The median WT1 transcript level in the PBSC graft (WT1-LK) of patients who relapsed was significantly higher than of those who did not relapse after transplantation (P <.0001). We defined a cut-off level of 80 WT1-LK copies/ABL 10e4 copies to discriminate between positive and negative PBSC grafts. The cut-off level was strongly associated with disease recurrence, DFS and OS. Our study represents the largest series of patients evaluating WT1 as a marker of MRD in PBSC LK products using a completely standardized real-time WT1-reverse transcriptase-PCR based assay. These data, if confirmed by prospective study, will help to determine an individual patient's adapted postremission allocation strategy. PMID- 24954548 TI - The evaluation of statins as potential inhibitors of the LEDGF/p75-HIV-1 integrase interaction. AB - Lovastatin was identified through virtual screening as a potential inhibitor of the LEDGF/p75-HIV-1 integrase interaction. In an AlphaScreen assay, lovastatin inhibited the purified recombinant protein-protein interaction (IC50 = 1.97 +/- 0.45 MUm) more effectively than seven other tested statins. None of the eight statins, however, yielded antiviral activity in vitro, while only pravastatin lactone yielded detectable inhibition of HIV-1 integrase strand transfer activity (31.65% at 100 MUm). A correlation between lipophilicity and increased cellular toxicity of the statins was observed. PMID- 24954549 TI - Experimental and theoretical investigation of the first-order hyperpolarizability of octupolar merocyanine dyes. AB - Hyper-Rayleigh scattering experiments and quantum chemical calculations are combined to investigate the second-order nonlinear optical responses of a series of three-arm merocyanine derivatives. They exhibit an octupolar hyperpolarizability response with lower amplitude than crystal violet due to a lower extent of the photoinduced charge transfer and reduced bond length alternation. Strong effects on the second-order optical response measured close to the two-photon absorption level are clearly evidenced; for example, the effective measured polarization ratio deviates below the ideal octupolar value of 3/2 even at very low excitation power. These effects are attributed to two-photon absorption resonance, which we believe modifies dynamically the population of the ground state versus that of the excited state. PMID- 24954547 TI - Parametric response mapping as an indicator of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. AB - The management of bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation presents many challenges, both diagnostically and therapeutically. We developed a computed tomography (CT) voxel-wise methodology termed parametric response mapping (PRM) that quantifies normal parenchyma, functional small airway disease (PRM(fSAD)), emphysema, and parenchymal disease as relative lung volumes. We now investigate the use of PRM as an imaging biomarker in the diagnosis of BOS. PRM was applied to CT data from 4 patient cohorts: acute infection (n = 11), BOS at onset (n = 34), BOS plus infection (n = 9), and age-matched, nontransplant control subjects (n = 23). Pulmonary function tests and bronchoalveolar lavage were used for group classification. Mean values for PRM(fSAD) were significantly greater in patients with BOS (38% +/- 2%) when compared with those with infection alone (17% +/- 4%, P < .0001) and age-matched control subjects (8.4% +/- 1%, P < .0001). Patients with BOS had similar PRM(fSAD) profiles, whether a concurrent infection was present or not. An optimal cut-point for PRM(fSAD) of 28% of the total lung volume was identified, with values >28% highly indicative of BOS occurrence. PRM may provide a major advance in our ability to identify the small airway obstruction that characterizes BOS, even in the presence of concurrent infection. PMID- 24954551 TI - Highly enantioselective construction of tricyclic derivatives by the desymmetrization of cyclohexadienones. AB - The asymmetric synthesis of tricyclic compounds by the desymmetrization of cyclohexadienones is presented. The reaction tolerated a large variety of substituents at different positions of the cyclohexadienone, and heterocyclic rings of different sizes were accessible. Density functional theory calculations showed that the reaction proceeds through an asynchronous [4+2] cycloaddition. PMID- 24954552 TI - Do predator cues influence turn alternation behavior in terrestrial isopods Porcellio laevis Latreille and Armadillidium vulgare Latreille? AB - Terrestrial isopods (Crustacea: Oniscidea) make more alternating maze turns in response to negative stimuli, a navigational behavior that corrects divergence from a straight line. The present study investigates this behavioral pattern in two species, Porcellio laevis Latreille and Armadillidium vulgare Latreille, in response to short-term vs. long-term exposure to indirect cues from predatory ants. Neither isopod species increased the number of alternating turns in response to short-term indirect exposure to ants, but both species made significantly more alternating turns following continuous indirect exposure to ants for a period of one-week. These results are surprising given differences in behavioral and morphological predator defenses between these species (the Armadillidiidae curl into defensive postures when attacked, whereas the Porcellionidae flee). The marked similarity in alternating turn behavior of the two families suggests evolutionary conservation of antipredator navigation mechanisms. PMID- 24954553 TI - Evidence of a relational spatial strategy in learning the centre of enclosures in human children (Homo sapiens). AB - Three- to five-year-old children were trained to localize a sensor hidden underneath the floor, in the centre of a square-shaped enclosure (1.5m*1.5m). Walking over the sensor caused a pleasant music to be played in the environment, thus engaging children in a playful spatial search. Children easily learned to find the centre of the training environment starting from random positions. After training, children were tested in enclosures of different size and/or shape: a larger square-shaped enclosure (3m*3m), a rectangle-shaped enclosure (1.5m*3m), an equilateral triangle-shaped enclosure (side 3m) and an isosceles triangle shaped enclosure (base 1.5m; sides 3m). Children searched in the central region of the enclosures, their precision varying as a function of the similarity of the testing enclosure's shape to the shape of the training enclosure. This suggests that a relational spatial strategy was used, and that it depended on the encoding of geometrical shape. This result highlights a distinctive role of the geometric centre of enclosed spaces in place learning in children, as already observed in nonhuman species. PMID- 24954554 TI - Effects of binders combined with glucono-delta-lactone on the quality characteristics of pressure-induced cold-set restructured pork. AB - This study investigated the effects of binders and glucono-delta-lactone (GdL) on characteristics of pressure-induced (450MPA for 3min) cold-set restructured pork. Isolated soy protein (SP), wheat flour (WF), and kappa-carrageenan (CG) were adopted as binders. The addition of binders improved water-binding properties of restructured pork, and the binders diminished the decrease in water binding properties caused by GdL-induced acidification. Pressure-induced restructured pork prepared with binders showed less harder and more cohesive texture than those of the thermal-treated control (TC). The results indicate that pressure induced cold-set meat restructuring could be achieved when binders and GdL were used in the formulation. PMID- 24954555 TI - Single crystalline wurtzite ZnO/zinc blende ZnS coaxial heterojunctions and hollow zinc blende ZnS nanotubes: synthesis, structural characterization and optical properties. AB - Synthesis of ZnO/ZnS heterostructures under thermodynamic conditions generally results in the wurtzite (WZ) structure of the ZnS component because its WZ phase is thermodynamically more stable than its zinc blende (ZB) phase. In this report, we demonstrate for the first time the preparation of ZnO/ZnS coaxial nanocables composed of single crystalline ZB structured ZnS epitaxially grown on WZ ZnO via a two-step thermal evaporation method. The deposition temperature is believed to play a crucial role in determining the crystalline phase of ZnS. Through a systematic structural analysis, the ZnO core and the ZnS shell are found to have an orientation relationship of (0002)ZnO(WZ)//(002)ZnS(ZB) and [01-10]ZnO(WZ)//[2 20]ZnS(ZB). Observation of the coaxial nanocables in cross-section reveals the formation of voids between the ZnO core and the ZnS shell during the coating process, which is probably associated with the nanoscale Kirkendall effect known to result in porosity. Furthermore, by immersing the ZnO/ZnS nanocable heterojunctions in an acetic acid solution to etch away the inner ZnO cores, single crystalline ZnS nanotubes orientated along the [001] direction of the ZB structure were also achieved for the first time. Finally, optical properties of the hollow ZnS tubes were investigated and discussed in detail. We believe that our study could provide some insights into the controlled fabrication of one dimensional (1D) semiconductors with desired morphology, structure and composition at the nanoscale, and the synthesized WZ ZnO/ZB ZnS nanocables as well as ZB ZnS nanotubes could be ideal candidates for the study of optoelectronics based on II-VI semiconductors. PMID- 24954556 TI - Effects of overshadowing on conditioned and unconditioned nausea in a rotation paradigm with humans. AB - We examine whether overshadowing by salient stimuli is effective in reducing the ability of a certain environment (the putative conditioned stimulus) to evoke conditioned nausea in healthy humans that experience nausea-evoking rotation (as the unconditioned stimulus, US) in that environment. Twenty-four rotation susceptible subjects (12 males, 12 females) were randomly assigned to receive either overshadowing by salient tasting beverages (OS+), or a control treatment (a familiar beverage, water; OS-) prior to rotation on three consecutive days (acquisition). To control for taste experiences, the alternative beverage was consumed 12 h later in the home environment (OS+: water, OS-: salient beverage). At Day 4 (test), all subjects drank the familiar beverage (water) prior to rotation (US). Rotation was standardized as 2 * 1-min rotation/day. Nausea was determined by a 7-item symptom scale measuring symptom number (SN) prior to (anticipatory), immediately after, and 15 and 30 min after rotation and by the Nausea Profile (NP) questionnaire immediately after rotation. Cortisol and tumour necrosis factor (TNF)-alpha in saliva were sampled at the same time-points. SN and cortisol were also measured at home. Overshadowing reduced anticipatory (conditioned) SN. Post-rotation nausea (i.e. the unconditioned response) measured by the NP decreased within the OS+ group only. Anticipatory cortisol and TNF alpha were not affected by overshadowing. Treatment * gender interactions manifested for post-rotation cortisol and TNF-alpha. Groups did not differ in SN and cortisol at home. Overshadowing is effective in reducing symptoms of anticipatory nausea and rotation-induced unconditioned nausea; its effect on endocrine and immunological parameters is gender specific. Its application in alleviation of anticipatory nausea in cancer patients is considered. PMID- 24954557 TI - Asymmetric balance control between legs for quiet but not for perturbed stance. AB - Interlateral performance asymmetry in upright balance control was evaluated in this investigation by comparing unipedal stance on the right versus the left leg. Participants were healthy young adults, hand-foot congruent preference for the right body side. Balance performance was evaluated in unperturbed quiet stance and in the recovery of balance stability following a mechanical perturbation induced by unexpected load release. Evaluation was made under availability of full sensory information, and under deprivation of vision combined with distortion of sensory inputs from the feet soles. Results from perturbed posture revealed that muscular response latency and postural sway were symmetric between the legs. Unipedal stance was more stable when the body was supported on the right as compared with the left leg. No interaction was found between leg and sensory condition. Our findings are interpreted as resulting from specialization of the sensorimotor system controlling the right leg for continuous low-magnitude postural adjustments, while corrections to large-scale stance sway are symmetrically controlled between body sides. PMID- 24954558 TI - Dental attendance among adult Finns after a major oral health care reform. AB - OBJECTIVES: Between 2001 and 2002, all age limits restricting the availability of subsidized private dental care and Public Dental Services (PDS) were abolished in Finland. In addition, the reform aimed to address income- and residence-related disparities in access to subsidized oral health care services. The aim of this study was to analyse how dental attendance and factors associated with it changed after the reform. METHODS: We carried out three consecutive surveys on the use of oral health care services and perceived oral health. The surveys were conducted in 2001 (n = 2837), in 2004 (n = 2420) and in 2007 (n = 2296), and the study population comprised Finnish adults born in 1970 or earlier. Logistic regression analyses were used to examine factors associated with the use of the services. RESULTS: The percentage of respondents who attended dental care regularly or had used oral health care services over the past 12 months rose between 2001 and 2007. In particular, there was an increase in the proportion of subjects who used PDS. The average number of visits to a private dentist decreased between 2001 and 2007. In the regression analyses, the use of services was associated with older age, perceived lack of need for care, perceived toothache during the past 12 months, perceived good oral health, lower number of missing teeth and regular dental visiting habits. The use of private dental care services was associated with perceived good oral health and perceived lack of need for care, higher household income and older age in all three study years while the use of PDS was associated with younger age, perceived good oral health and perceived lack of need for care only in 2001. CONCLUSIONS: The use of oral health care services rose and age did not seem to be a barrier to the use of oral health care services after the reform, as was the aim of the reform. No change in the association of household income with the use of oral health care services was seen after the OHCR. PMID- 24954559 TI - Males exceed females in PCB concentrations of cisco (Coregonus artedi) from Lake Superior. AB - We determined whole-fish polychlorinated biphenyl (PCB) concentrations of 25 male and 25 female age-7 ciscoes (Coregonus artedi) captured from a spawning aggregation in Thunder Bay, Lake Superior, during November 2010. We also determined PCB concentrations in the ovaries and somatic tissue of five additional female ciscoes (ages 5-22). All 55 of these ciscoes were in ripe or nearly ripe condition. Bioenergetics modeling was used to determine the contribution of the growth dilution effect toward a difference in PCB concentrations between the sexes, as females grew substantially faster than males. Results showed that the PCB concentration of males (mean = 141 ng/g) was 43% greater than that of females (mean = 98 ng/g), and this difference was highly significant (P<0.0001). Mean PCB concentrations in the ovaries and the somatic tissue of the five females were 135 and 100 ng/g, respectively. Based on these PCB determinations for the ovaries and somatic tissue, we concluded that release of eggs by females at previous spawnings was not a contributing factor to the observed difference in PCB concentrations between the sexes. Bioenergetics modeling results indicated that the growth dilution effect could explain males being higher than females in PCB concentration by only 3-7%. We concluded that the higher PCB concentration in males was most likely due to higher rate of energy expenditure, originating from greater activity and a higher resting metabolic rate. Mean PCB concentration in the cisco eggs was well below the U. S. Food and Drug Administration and Ontario Ministry of Environment guidelines of 2000 and 844 ng/g, respectively, and this finding may have implications for the cisco roe fishery currently operating in Lake Superior. PMID- 24954560 TI - Evaluation of process conditions triggering emissions of green-house gases from a biological wastewater treatment system. AB - In this study, methane (CH4) and nitrous oxide (N2O) emission dynamics of a plug flow bioreactor located in a municipal full-scale wastewater treatment plant were monitored during a period of 10 weeks. In general, CH4 and N2O gas emissions from the bioreactor accounted for 0.016% of the influent chemical oxygen demand (COD) and 0.116% of the influent total Kjeldahl nitrogen (TKN) respectively. In order to identify the emission patterns in the different zones, the bioreactor was divided in six different sampling sites and the gas collection hood was placed for a period of 2-3 days in each of these sites. This sampling strategy also allowed the identification of different process perturbations leading to CH4 or N2O peak emissions. CH4 emissions mainly occurred in the first aerated site, and were mostly related with the influent and reject wastewater flows entering the bioreactor. On the other hand, N2O emissions were given along all the aerated parts of the bioreactor and were strongly dependant on the occurrence of process disturbances such as periods of no aeration or nitrification instability. Dissolved CH4 and N2O concentrations were monitored in the bioreactor and in other parts of the plant, as a contribution for the better understanding of the transport of these greenhouse gases across the different stages of the treatment system. PMID- 24954561 TI - PBDE levels in franciscana dolphin (Pontoporia blainvillei): temporal trend and geographical comparison. AB - Total PBDE concentrations determined in archived blubber samples from franciscana dolphins (Pontoporia blainvillei) unintentionally captured in the Brazilian coastal region off Rio Grande do Sul State (FMA III) between 1994 and 2004 (n = 73) ranged from 7.9 to 65 ng g(-1) lipid weight in mature males, with an increase over the ten-year period. Total PBDE concentrations in blubber samples collected from the FAM II (n = 41) between 2002 and 2005 were higher (67.8 to 763.7 ng g( 1)lw) than those from FMA III. This is possibly due to the proximity to important industrial development sites in the state of Sao Paulo. Despite the differences in total concentrations, PBDE profiles were comparable and the PBDE concentrations decreased in the following order BDE 47>BDE99>BDE 100 for both FMA and for males and females as well as adults, juveniles and pups. PMID- 24954562 TI - The role of humic and fulvic acids in the phototransformation of phenolic compounds in seawater. AB - Humic substances (HS) are known to act as photosensitizers toward the transformation of pollutants in the surface layer of natural waters. This study focused on the role played by HS toward the transformation of xenobiotics in seawater, with the purpose of assessing the prevailing degradation routes. Phenol was chosen as model xenobiotic and its transformation was investigated under simulated sunlight in the presence of terrestrial or marine humic and fulvic acids, in pure water at pH8, artificial seawater (ASW) or natural seawater (NSW). The following parameters were determined: (1) the phenol degradation rate; (2) the variation in HS concentration with irradiation time; (3) the production of transformation products; (4) the influence of iron species on the transformation process. Faster transformation of phenol was observed with humic acids (HA) compared to fulvic acids (SRFA), and transformation induced by both HA and SRFA was faster in ASW than that in pure water. These observations can be explained by assuming an interplay between different competing and sometimes opposite processes, including the competition between chloride, bromide and dissolved oxygen for reaction with HS triplet states. The analysis of intermediates formed in the different matrices under study showed the formation of several hydroxylated (hydroquinone, 1,4-benzoquinone, resorcinol) and condensed compounds (2,2'-bisphenol, 4,4'-bisphenol, 4-phenoxyphenol). Although 1,4-benzoquinone was the main transformation product, formation of condensed molecules was significant with both HA and SRFA. Experiments on natural seawater spiked with HS confirmed the favored formation of condensed products, suggesting a key role of humic matter in dimerization reactions occurring in saline water. PMID- 24954563 TI - Identification of sensitive parameters in the modeling of SVOC reemission processes from soil to atmosphere. AB - Semi-volatile organic compounds (SVOCs) are subject to Long-Range Atmospheric Transport because of transport-deposition-reemission successive processes. Several experimental data available in the literature suggest that soil is a non negligible contributor of SVOCs to atmosphere. Then coupling soil and atmosphere in integrated coupled models and simulating reemission processes can be essential for estimating atmospheric concentration of several pollutants. However, the sources of uncertainty and variability are multiple (soil properties, meteorological conditions, chemical-specific parameters) and can significantly influence the determination of reemissions. In order to identify the key parameters in reemission modeling and their effect on global modeling uncertainty, we conducted a sensitivity analysis targeted on the 'reemission' output variable. Different parameters were tested, including soil properties, partition coefficients and meteorological conditions. We performed EFAST sensitivity analysis for four chemicals (benzo-a-pyrene, hexachlorobenzene, PCB 28 and lindane) and different spatial scenari (regional and continental scales). Partition coefficients between air, solid and water phases are influent, depending on the precision of data and global behavior of the chemical. Reemissions showed a lower variability to soil parameters (soil organic matter and water contents at field capacity and wilting point). A mapping of these parameters at a regional scale is sufficient to correctly estimate reemissions when compared to other sources of uncertainty. PMID- 24954564 TI - Impact of pond aquaculture effluents on seagrass performance in NE Hainan, tropical China. AB - The impact of pond aquaculture effluents on the distribution and performance of seagrasses was examined in NE Hainan, tropical China. Samples were taken along transects in three back-reef areas with different extent of aquaculture production in their hinterland. High delta(15)N in seagrass leaves and epiphytes (6-90/00) similar to values in pond effluents documented aquaculture as dominant nitrogen source in the back-reefs with decreasing impact with distance from shore. Seagrass species abundance, shoot density and biomass were lower and concentrations of nutrients, chlorophyll and suspended matter were higher at nearshore sites with high and moderate pond abundance than at the control site. High epiphyte loads and low delta(34)S in seagrass leaves suggest temporal shading and sulphide poisoning of the nearshore seagrasses. Observed gradients in environmental parameters and seagrass performance indicate that the distance from the pond outlets and size of the adjacent pond agglomeration are major determinants of seagrass degradation. PMID- 24954566 TI - Hyperbolic Dirac Nets for medical decision support. Theory, methods, and comparison with Bayes Nets. AB - We recently introduced the concept of a Hyperbolic Dirac Net (HDN) for medical inference on the grounds that, while the traditional Bayes Net (BN) is popular in medicine, it is not suited to that domain: there are many interdependencies such that any "node" can be ultimately conditional upon itself. A traditional BN is a directed acyclic graph by definition, while the HDN is a bidirectional general graph closer to a diffuse "field" of influence. Cycles require bidirectionality; the HDN uses a particular type of imaginary number from Dirac's quantum mechanics to encode it. Comparison with the BN is made alongside a set of recipes for converting a given BN to an HDN, also adding cycles that do not usually require reiterative methods. This conversion is called the P-method. Conversion to cycles can sometimes be difficult, but more troubling was that the original BN had probabilities needing adjustment to satisfy realism alongside the important property called "coherence". The more general and simpler K-method, not dependent on the BN, is usually (but not necessarily) derived by data mining, and is therefore also introduced. As discussed, BN developments may converge to an HDN like concept, so it is reasonable to consider the HDN as a BN extension. PMID- 24954565 TI - The use of cholinesterase as potential biomarker: In vitro characterization in the polychaete Capitella teleta. AB - The ecological relevance of polychaetes coupled with their easy culture and maintenance in the laboratory, has led them to become increasingly used in marine ecotoxicological studies, raising the need to validate frequently applied monitoring tools at various biological levels. The present study was aimed to characterize the cholinesterases (ChE) activity in the polychaete Capitella teleta, using three substrates (acetylthiocholine iodide, propionylthiocholine iodide, and S-butyrylthiocholine iodide) and four known inhibitors (eserine hemisulfate, BW284c51, iso-OMPA and chlorpyrifos-oxon). Results showed that most of the measured cholinesterase activity was acetylcholinesterase (AChE). Inhibition of enzyme kinetic experiments denoted that sensitivity of C. teleta's ChE to the organophosphorous metabolite chlorpyrifos-oxon (IC50=60.72 nM) was analogous to some fish species. This study highlights the relevance of ChE characterization before its use as a biomarker in ecotoxicology and biomonitoring studies. PMID- 24954567 TI - Catheter-based edge-to-edge mitral valve repair after percutaneous mitral valve annuloplasty failure. PMID- 24954568 TI - Stent deformation in bifurcation stenting with final kissing balloon inflation: in vivo demonstration with enhanced cine fluoroscopic imaging. PMID- 24954569 TI - Percutaneous valve-in-valve transcatheter tricuspid valve replacement with simultaneous paravalvular leak closure in a patient with refractory right heart failure. PMID- 24954570 TI - Successful treatment of spontaneous coronary artery dissection with cutting balloon angioplasty as evaluated with optical coherence tomography. PMID- 24954572 TI - Transcatheter aortic valve implantation in a patient with severe bicuspid aortic valve stenosis and ascending aortic aneurysm. PMID- 24954571 TI - Futility, benefit, and transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) is a transformative innovation that provides treatment for high or prohibitive surgical risk patients with symptomatic severe aortic stenosis who either were previously not referred for or were denied operative intervention. Trials have demonstrated improvements in survival and symptoms after TAVR versus medical therapy; however, there remains a sizable group of patients who die or lack improvement in quality of life soon after TAVR. This raises important questions about the need to identify and acknowledge the possibility of futility in some patients considered for TAVR. In this very elderly population, a number of factors in addition to traditional risk stratification need to be considered including multimorbidity, disability, frailty, and cognition in order to assess the anticipated benefit of TAVR. Consideration by a multidisciplinary heart valve team with broad areas of expertise is critical for assessing likely benefit from TAVR. Moreover, these complicated decisions should take place with clear communication around desired health outcomes on behalf of the patient and provider. The decision that treatment with TAVR is futile should include alternative plans to optimize the patient's health state or, in some cases, discussions related to end-of-life care. We review issues to be considered when making and communicating these difficult decisions. PMID- 24954573 TI - Operator radiation exposure and physical discomfort during a right versus left radial approach for coronary interventions: a randomized evaluation. AB - OBJECTIVES: This study sought to assess radiation exposure and operator discomfort when using left radial approach (LRA) versus right radial approach (RRA) for coronary diagnostic and percutaneous interventions. BACKGROUND: The transradial approach is increasingly being adopted as the preferred vascular access for coronary interventions. Currently, most are performed using an RRA. This is in part due to the perceived increased operator physical discomforts as well increased radiation exposure with an LRA. METHODS: One hundred patients were randomized to an LRA or RRA. Each operator (n = 5) had an independent randomization process, and patients were stratified according to obesity status. Operator radiation was measured using separate sets of radiation dosimeter badges placed externally on the head and thyroid and internally on the sternum. Operator physical discomfort was surveyed at 2 time points: during vascular access and at the end of the procedure. Moderate to severe physical discomfort was defined as a score of >4. RESULTS: There were no significant differences in baseline and procedural variables between groups. There was a significant increase in external radiation exposure using the RRA versus LRA (head: median: 6.12 [interquartile range (IQR): 2.6 to 16.6] mRems vs. median: 12.0 [IQR: 6.4 to 22.0] mRems, p = 0.02; thyroid: median: 10.10 [IQR: 4.3 to 25] mRems vs. median: 18.70 [IQR: 11.0 to 38] mRems, p = 0.001). More discomfort was reported with the LRA during access (LRA: 22% vs. RRA: 4%; p = 0.017), but not during the procedure (LRA: 10.0% vs. RRA: 4.0%, p = 0.43). This difference was almost entirely noted in obese patients (LRA: 30.0% vs. RRA: 3.7%, p = 0.005). CONCLUSIONS: LRA is as effective as RRA, showing a safer profile with decreased radiation exposure to the operator, at the expense of more operator discomfort only during vascular access and limited to obese patients. PMID- 24954574 TI - CoreValve degeneration with severe transvalvular aortic regurgitation treated with valve-in-valve implantation. PMID- 24954575 TI - Treatment of a failing St. Jude Medical Trifecta by Medtronic Corevalve Evolut valve-in-valve implantation. PMID- 24954577 TI - Is dexamethasone as effective as prednisone or prednisolone in the management of pediatric asthma exacerbations? PMID- 24954576 TI - Transcriptional profiling of belatacept and calcineurin inhibitor therapy in renal allograft recipients. AB - Calcineurin inhibitor (CNI) use may lead to allograft injury and compromised renal function. Gene expression profiles of 12-month kidney biopsies from a Phase 3 study of belatacept and a CNI comparator, cyclosporine (CsA), were compared with expression profiles of a set of historical, demographically matched, preimplantation control biopsies. Gene set enrichment analysis was used to test each set of differentially expressed genes (DEGs) for the enrichment of an in vitro-derived CNI toxicity (CNIT) gene set and published gene sets associated with chronic allograft injury (CAI), immune modulation and tissue remodeling. The unique set of genes differentially expressed in CNI biopsies compared with preimplantation controls was enriched for genes associated with fibrosis, early tubulointerstitial damage and in vitro CNIT. The DEGs from belatacept biopsies were not enriched for the CNIT genes but, instead, exhibited enrichment for gene sets associated with immune response and tissue remodeling. A combined analysis of DEGs across both treatment groups identified select solute transporter and cellular differentiation genes whose expression at 12 months correlated with renal function at 36 months. These results provide mechanistic insights into the reduced CAI and higher renal function observed in belatacept- versus CsA-treated patients. PMID- 24954578 TI - The flex track: flexible partitioning between low- and high-acuity areas of an emergency department. AB - STUDY OBJECTIVE: Emergency departments (EDs) with both low- and high-acuity treatment areas often have fixed allocation of resources, regardless of demand. We demonstrate the utility of discrete-event simulation to evaluate flexible partitioning between low- and high-acuity ED areas to identify the best operational strategy for subsequent implementation. METHODS: A discrete-event simulation was used to model patient flow through a 50-bed, urban, teaching ED that handles 85,000 patient visits annually. The ED has historically allocated 10 beds to a fast track for low-acuity patients. We estimated the effect of a flex track policy, which involved switching up to 5 of these fast track beds to serving both low- and high-acuity patients, on patient waiting times. When the high-acuity beds were not at capacity, low-acuity patients were given priority access to flexible beds. Otherwise, high-acuity patients were given priority access to flexible beds. Wait times were estimated for patients by disposition and Emergency Severity Index score. RESULTS: A flex track policy using 3 flexible beds produced the lowest mean patient waiting time of 30.9 minutes (95% confidence interval [CI] 30.6 to 31.2 minutes). The typical fast track approach of rigidly separating high- and low-acuity beds produced a mean patient wait time of 40.6 minutes (95% CI 40.2 to 50.0 minutes), 31% higher than that of the 3-bed flex track. A completely flexible ED, in which all beds can accommodate any patient, produced mean wait times of 35.1 minutes (95% CI 34.8 to 35.4 minutes). The results from the 3-bed flex track scenario were robust, performing well across a range of scenarios involving higher and lower patient volumes and care durations. CONCLUSION: Using discrete-event simulation, we have shown that adding some flexibility into bed allocation between low and high acuity can provide substantial reductions in overall patient waiting and a more efficient ED. PMID- 24954579 TI - Are antifibrinolytic agents effective in the treatment of aneurysmal subarachnoid hemorrhage? PMID- 24954580 TI - Statins in neurological disorders: an overview and update. AB - Statins have, at present, the potential to provide a new therapeutic target for various neurological diseases. It is well established that statins reduce cholesterol levels and prevent coronary heart disease. Moreover, evidence suggest that statins have additional properties such as endothelial protection via action on the nitric oxide synthase system as well as antioxidant, anti-inflammatory and anti-platelet effects. These properties might have potential therapeutic implication not only in stroke but also in neurological disorders such as Alzheimer disease, Parkinson's disease, multiple sclerosis and primary brain tumors. In addition to their potent anti-atherosclerotic and cardio-protective effects, compelling clinical and preclinical studies delineate the neuro protective efficacy of statins in all these neurological disorders. It is apparent from these studies that most patients with central nervous system disorders probably benefit to some extent from lipid-lowering therapy. But data are not univocal, and we must also consider the adverse effects due to the administration of lipid-lowering therapy. Thus, in these scenarios the effectiveness of statins in treating stroke, Alzheimer's disease, Parkinson disease, multiple sclerosis, and primary brain tumors have to be conclusively proven in vivo and/or in adequate clinical trials. PMID- 24954581 TI - Exposing synonymous mutations. AB - Synonymous codon changes, which do not alter protein sequence, were previously thought to have no functional consequence. Although this concept has been overturned in recent years, there is no unique mechanism by which these changes exert biological effects. A large repertoire of both experimental and bioinformatic methods has been developed to understand the effects of synonymous variants. Results from this body of work have provided global insights into how biological systems exploit the degeneracy of the genetic code to control gene expression, protein folding efficiency, and the coordinated expression of functionally related gene families. Although it is now clear that synonymous variants are important in a variety of contexts, from human disease to the safety and efficacy of therapeutic proteins, there is no clear consensus on the approaches to identify and validate these changes. Here, we review the diverse methods to understand the effects of synonymous mutations. PMID- 24954582 TI - BR2BodPR2: highly fluorescent alternatives to PPh3 and PhPCy2. AB - The syntheses of highly fluorescent analogues of PPh3 and PhPCy2 based on the Bodipy chromophore are described. The ligands have been incorporated into two- to four-coordinate group 11 metal complexes. The synthesis, characterisation and photophysical properties of the novel ligands and their metal complexes are reported; many of these compounds have also been characterised by single-crystal X-ray diffraction. Incorporation of the phosphino group and complexation to the group 11 metal centre has little effect on the absorption and emission profiles; high molar extinction coefficients and fluorescence quantum yields were still obtained. In particular, incorporation of the dicyclohexylphosphino substituent significantly increases the quantum yields relative to the parent dyes. PMID- 24954584 TI - Factors affecting self-care in elderly patients with hypertension in Korea. AB - The objective of this study was to test nine variables which derived from the model of self-care in chronic illness and previous studies on elderly patients with hypertension. A descriptive research design was employed in this study. Totally, 306 elderly patients diagnosed with hypertension were selected from three public health centres for the study. The stepwise regression analysis was conducted by analysing predictors of self-care in elderly patients with hypertension. Statistical analyses, including correlation analysis, t-test and analysis of variance tests were conducted for seven variables. The results indicated that only four variables were significant, and the model explained 57% of the variance in self-care. Among these predictors, empowerment was the strongest predictor, followed by social support, depression and perceived severity. These findings demonstrate the significance of assessing predictors of self-care behaviour when examining patients' health behaviours and planning intervention strategies. PMID- 24954585 TI - Programming of the preimplantation embryo by the embryokine colony stimulating factor 2. AB - Events in the preimplantation period can have long-term consequences that affect embryo competence to establish and maintain pregnancy and which can extend into fetal and postnatal life. One of the molecules responsible for maternal modulation of embryonic development during this time is colony stimulating factor 2, also termed granulocyte-macrophage colony stimulating factor. This cytokine is produced by the oviduct and endometrium and can act on the preimplantation embryo to improve competence of the embryo to establish pregnancy and develop to term. Actions of CSF2 on the embryo include changes in gene expression (particularly for genes related to apoptosis and differentiation), inhibition of apoptosis, and an increase in numbers of cells in the inner cell mass. Female embryos respond to CSF2 differently than male embryos. Alterations in maternal environment during the preimplantation period can affect subsequent development in a sex-specific manner and CSF2 may be one of the maternal signals responsible for this phenomenon. PMID- 24954586 TI - Ultrastructure of spermatogenesis, spermatozoon and processes of testicular regression and recrudescence in Eptesicus furinalis (Chiroptera: Vespertilionidae). AB - Studies have shown that the annual reproductive cycle of Eptesicus furinalis includes at least one period of total testicular regression. Thus, this study aimed to evaluate their reproductive cycle ultrastructurally. The annual reproductive cycle was divided into four periods: active, regressing, regressed and recrudescence. The active period was similar to that of other bats, including the completion of spermatogenesis with three main types of spermatogonia (Ad, Ap and B) and 12 steps in the process of spermatid differentiation. However, its spermatozoa differed in that outer dense fibers 1, 5, 6 and 9 are larger than the others and due to the presence of what is likely a probably genera-specific bulging in the anterior portion. In the regressing period, Sertoli cell nuclei migrate to the basal compartment with the nuclei close to the basal lamina. The basal compartment had a more compact appearance than the adluminal compartment, with relaxed cellular connections. In the regressed period, spermatogenesis ceased; the seminiferous epithelium was composed only of Sertoli cells and three types of spermatogonia: types Ad, 1 and 2. In the recrudescence period, spermatogenesis restarted, with the process of reactivation divided into three phases: early, medial and late recrudescence. In conclusion, our study described the process of spermatogenesis and the ultrastructure of the spermatozoa and confirmed the presence of a process of total testicular regression in the annual cycle of E. furinalis. We characterize distinct morphologic variations in the ultrastructure of the testicular cells during the four different periods of the annual reproductive cycle. PMID- 24954583 TI - Ancestral repeats have shaped epigenome and genome composition for millions of years in Arabidopsis thaliana. AB - Little is known about the evolution of repeated sequences over long periods of time. Using two independent approaches, we show that the majority of the repeats found in the Arabidopsis thaliana genome are ancient and likely to derive from the retention of fragments deposited during ancestral bursts that occurred early in the Brassicaceae evolution. We determine that the majority of young repeats are found in pericentromeric domains, while older copies are frequent in the gene rich regions. Our results further suggest that the DNA methylation of repeats through small RNA-mediated pathways can last over prolonged periods of time. We also illustrate the way repeated sequences are composted by mutations towards genomic dark matter over time, probably driven by the deamination of methylcytosines, which also have an impact on epigenomic landscapes. Overall, we show that the ancient proliferation of repeat families has long-term consequences on A. thaliana biology and genome composition. PMID- 24954587 TI - Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation. AB - Farnesoid X receptor (FXR) is the master regulator of bile acid (BA) homeostasis because it controls BA synthesis, influx, efflux, and detoxification in the gut/liver axis. Deregulation of BA homeostasis has been linked to hepatocellular carcinoma (HCC), and spontaneous hepatocarcinogenesis has been observed in FXR null mice. This dreaded liver neoplasm has been associated with both FXR gene deletion and BA-mediated metabolic abnormalities after inactivation of FXR transcriptional activity. In the present study, we addressed the hypothesis that intestinal selective FXR reactivation would be sufficient to restore the fibroblast growth factor 15 (FGF15)/cholesterol-7alpha-hydroxylase (Cyp7a1) enterohepatic axis and eventually provide protection against HCC. To this end, we generated FXR-null mice with re-expression of constitutively active FXR in enterocytes (FXR(-/-)iVP16FXR) and corresponding control mice (FXR(-/-)iVP16). In FXR-null mice, intestinal selective FXR reactivation normalized BA enterohepatic circulation along with up-regulation of intestinal FXR transcriptome and reduction of hepatic BA synthesis. At 16 months of age, intestinal FXR reactivation protected FXR-null mice from spontaneous HCC development that occurred in otherwise FXR-null mice. Activation of intestinal FXR conferred hepatoprotection by restoring hepatic homeostasis, limiting cellular proliferation through reduced cyclinD1 expression, decreasing hepatic inflammation and fibrosis (decreased signal transducer and activator of transcription 3 activation and curtailed collagen deposition). CONCLUSION: Intestinal FXR is sufficient to restore BA homeostasis through the FGF15 axis and prevent progression of liver damage to HCC even in the absence of hepatic FXR. Intestinal-selective FXR modulators could stand as potential therapeutic intervention to prevent this devastating hepatic malignancy, even if carrying a somatic FXR mutation. PMID- 24954588 TI - Cancer research: a hurdle race. AB - Cancer research has shifted in recent years from studying intracellular processes (identification of damaged genes and signaling pathways) to extracellular (hierarchy of tumor cells, cell transitions, clone competition) and tissue (interactions of a tumor with its environment) research. But then the next step seems to be logical: studying biochemistry of tumor-bearing organisms (namely, cancer-induced changes in cellular and tissue metabolism leading to the organism's death). These data can help to develop new methods of cancer treatment. This article discusses some of the challenges of contemporary oncology and possible ways to overcome them. PMID- 24954589 TI - Role of zinc and copper ions in the pathogenetic mechanisms of Alzheimer's and Parkinson's diseases. AB - Disbalance of zinc (Zn2+) and copper (Cu2+) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as multisystem atrophy, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Wilson-Konovalov disease, Alzheimer's disease, and Parkinson's disease. Among these, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent age-related neurodegenerative pathologies with disorders in Zn2+ and Cu2+ homeostasis playing a pivotal role in the mechanisms of pathogenesis. In this review we generalized and systematized current literature data concerning this problem. The interactions of Zn2+ and Cu2+ with amyloid precursor protein (APP), beta-amyloid (Abeta), tau-protein, metallothioneins, and GSK3beta are considered, as well as the role of these interactions in the generation of free radicals in AD and PD. Analysis of the literature suggests that the main factors of AD and PD pathogenesis (oxidative stress, structural disorders and aggregation of proteins, mitochondrial dysfunction, energy deficiency) that initiate a cascade of events resulting finally in the dysfunction of neuronal networks are mediated by the disbalance of Zn2+ and Cu2+. PMID- 24954590 TI - Dynorphins in regulation of immune system functions. AB - Dynorphins constitute a family of opioid peptides manifesting the highest affinity for kappa-opiate receptors. Immune system cells are known to express a kappa-receptor similar to that in the central nervous system, and as a consequence dynorphins are involved in the interaction between cells of the nervous and immune systems. In this review, data on dynorphin structure are analyzed and generalized, the kappa-opiate receptor is characterized, and data on the regulation by dynorphins of functioning of the innate and adaptive immunity cells are summarized. PMID- 24954591 TI - The role of cytochrome b5 structural domains in interaction with cytochromes P450. AB - To understand the role of the structural elements of cytochrome b5 in its interaction with cytochrome P450 and the catalysis performed by this heme protein, we carried out comparative structural and functional analysis of the two major mammalian forms of membrane-bound cytochrome b5 - microsomal and mitochondrial, designed chimeric forms of the heme proteins in which the hydrophilic domain of one heme protein is replaced by the hydrophilic domain of another one, and investigated the effect of the highly purified native and chimeric heme proteins on the enzymatic activity of recombinant cytochromes P4503A4 and P45017A1 (CYP3A4 and CYP17A1). We show that the presence of a hydrophobic domain in the structure of cytochrome b5 is necessary for its effective interaction with its redox partners, while the nature of the hydrophobic domain has no significant effect on the ability of cytochrome b5 to stimulate the activity of cytochrome P450-catalyzed reactions. Thus, the functional properties of cytochrome b5 are mainly determined by the structure of the heme-binding domain. PMID- 24954592 TI - Calix[4]arene C-90 selectively inhibits Ca2+,Mg2+-ATPase of myometrium cell plasma membrane. AB - The supramolecular compound calix[4]arene C-90 (5,11,17,23 tetra(trifluoro)methyl(phenylsulfonylimino)-methylamino-25,26,27,28 tetrapropoxycalix[4]arene) is shown to efficiently inhibit the ATP hydrolase activity of Ca2+,Mg2+-ATPase in the myometrium cell plasma membrane fraction and also in a preparation of the purified enzyme solubilized from this subcellular fraction. The inhibition coefficient I0.5 values were 20.2 +/- 0.5 and 58.5 +/- 6.4 uM for the membrane fraction and the solubilized enzyme, respectively. The inhibitory effect of calix[4]arene C-90 was selective comparatively to other ATPases localized in the plasma membrane: calix[4]arene C-90 did not influence the activities of Na+,K+-ATPase and "basal" Mg2+-ATPase. The inhibitory effect of calix[4]arene C-90 on the Ca2+,Mg2+-ATPase activity was associated with the cooperative action of four trifluoromethylphenylsulfonylimine (sulfonylamidine) groups oriented similarly on the upper rim of the calix[4]arene macrocycle (the calix[4]arene "bowl"). The experimental findings seem to be of importance for studies, using calix[4]arene C-90, of membrane mechanisms of regulation of calcium homeostasis in smooth muscle cells and also for investigation of the participation of the plasma membrane Ca2+-pump in control of electro- and pharmacomechanical coupling in myocytes. PMID- 24954593 TI - Mechanisms of generation of local DeltapH in mitochondria and bacteria. AB - The concepts of global and local coupling between proton generators, the enzymes of the respiratory chain, and the consumer, the ATP synthase, coexist in the theory of oxidative phosphorylation. Global coupling is trivial proton transport via the aqueous medium, whereas local coupling implies that the protons pumped are consumed before they escape to the bulk phase. In this work, the conditions for the occurrence of local coupling are explored. It is supposed that the membrane retains protons near its surface and that the proton current generated by the proton pumps rapidly decreases with increasing proton motive force (pmf). It is shown that the competition between the processes of proton translocation across the membrane and their dissipation from the surface to the bulk can result in transient generation of a local DeltapH in reply to a sharp change in pmf; the appearance of local DeltapH, in turn, leads to rapid recovery of the pmf, and hence, it provides for stabilization of the potential at the membrane. Two mechanisms of such kind are discussed: 1) pH changes in the surface area due to proton pumping develop faster than those due to proton escape to the bulk; 2) the former does not take place, but the protons leaving the surface do not equilibrate with the bulk immediately; rather, they give rise to a non equilibrium concentration near the surface and, as a result, to a back proton flow to the surface. The first mechanism is more efficient, but it does not occur in mitochondria and neutrophilic bacteria, whereas the second can produce DeltapH on the order of unity. In the absence of proton retardation at the surface, local DeltapH does not arise, whereas the formation of global DeltapH is possible only at buffer concentration of less than 10 mM. The role of the mechanisms proposed in transitions between States 3 and 4 of the respiratory chain is discussed. The main conclusion is that surface protons, under conditions where they play a role, support stabilization of the membrane pmf and rapid communication between proton generators and consumers, while their contribution to the energetics is not significant. PMID- 24954594 TI - Arachidonic acid activates release of calcium ions from reticulum via ryanodine receptor channels in C2C12 skeletal myotubes. AB - Arachidonic acid causes an increase in free cytoplasmic calcium concentration ([Ca2+]i) in differentiated skeletal multinucleated myotubes C2C12 and does not induce calcium response in C2C12 myoblasts. The same reaction of myotubes to arachidonic acid is observed in Ca2+-free medium. This indicates that arachidonic acid induces release of calcium ions from intracellular stores. The blocker of ryanodine receptor channels of sarcoplasmic reticulum dantrolene (20 uM) inhibits this effect by 68.7 +/- 6.3% (p < 0.001). The inhibitor of two-pore calcium channels of endolysosomal vesicles trans-NED19 (10 uM) decreases the response to arachidonic acid by 35.8 +/- 5.4% (p < 0.05). The phospholipase C inhibitor U73122 (10 uM) has no effect. These data indicate the involvement of ryanodine receptor calcium channels of sarcoplasmic reticulum in [Ca2+]i elevation in skeletal myotubes caused by arachidonic acid and possible participation of two pore calcium channels from endolysosomal vesicles in this process. PMID- 24954595 TI - Identification and characterization of SlVKOR, a disulfide bond formation protein from Solanum lycopersicum, and bioinformatic analysis of plant VKORs. AB - Homologs of vitamin K epoxide reductase (VKOR) exist widely in plants. However, only VKOR of Arabidopsis thaliana has been the subject of many studies to date. In the present study, the coding region of a VKOR from Solanum lycopersicum (JF951971 in GenBank) was cloned; it contained a membrane domain (VKOR domain) and an additional soluble thioredoxin-like (Trx-like) domain. Bioinformatic analysis showed that the first 47 amino acids in the N-terminus should act as a transit peptide targeting the protein to the chloroplast. Western blot demonstrated that the protein is localized in thylakoid membrane with the Trx like domain facing the lumen. Modeling of three-dimensional structure showed that SlVKOR has a similar conformation with Arabidopsis and cyanobacterial VKORs, with five transmembrane segments in the VKOR domain and a typical Trx-like domain in the lumen. Functional assay showed that the full-length of SlVKOR with Trx-like domain without the transit peptide could catalyze the formation of disulfide bonds. Similar transit peptides at the N-terminus commonly exist in plant VKORs, most of them targeting to chloroplast according to prediction. Comparison of sequences and structures from different plants indicated that all plant VKORs possess two domains, a transmembrane VKOR domain and a soluble Trx-like domain, each having four conservative cysteines. The cysteines were predicted to be related to the function of catalyzing the formation of disulfide bonds. PMID- 24954596 TI - Ozone ameliorates age-related oxidative stress changes in rat liver and kidney: effects of pre- and post-ageing administration. AB - The ageing process is known to be accompanied by increased oxidative stress and compromised antioxidant defenses. Controlled ozone administration has been shown to be effective in various pathophysiological conditions with an underlying oxidative burden. However, its effect on the biochemical alterations associated with the ageing process has been rarely studied. Therefore, the present work was carried out to study the role of ozone in counteracting the state of oxidative stress associated with ageing in rat liver and kidneys using two experimental models. In the pre-ageing model, ozone was administered prior to the onset of ageing at adulthood and continued after the start of the ageing process (3-month old rats until the age of 15 months). While in the post-ageing model, ozone was administered after ageing has begun and lasted for one month (14-month-old rats until the age of 15 months). The pre-ageing ozone administration effectively reduced lipid and protein oxidation markers, namely, malondialdehyde and protein carbonyl levels and decreased lipofuscin pigment deposition in rat liver and kidneys. Moreover, it significantly restored hepatic and renal reduced glutathione (GSH) contents and normalized cytosolic hepatic glutathione peroxidase activity. Similar but less pronounced effects were observed in the post-ageing ozone-treated group. Nevertheless, in the latter model ozone administration failed to significantly affect liver and kidney lipofuscin levels, as well as kidney GSH contents. These data provide evidences for potentially positive effects of pre-ageing ozone therapy in neutralizing chronic oxidative stress associated with ageing in rat liver and kidneys. PMID- 24954597 TI - Interaction of linear cationic peptides with phospholipid membranes and polymers of sialic acid. AB - Polysialic acid (PSA) is a natural anionic polymer typically occurring on the outer surface of cell membranes. PSA is involved in cell signaling and intermolecular interactions with proteins and peptides. The antimicrobial potential of peptides is usually evaluated in model membranes consisting of lipid bilayers but devoid of either PSA or its analogs. The goal of this work was to investigate the possible effect of PSA on the structure of melittin (Mlt) and latarcins Ltc1K, Ltc2a, and the activity of these peptides with respect to model membranes. These peptides are linear cationic ones derived from the venom of bee (Mlt) and spider (both latarcins). The length of each of the peptides is 26 amino acid residues, and they all have antimicrobial activity. However, they differ with respect to conformational mobility, hydrophobic characteristics, and overall charge. In this work, using circular dichroism spectroscopy, we show that the peptides adopt an alpha-helical conformation upon interaction with either PSA or phospholipid liposomes formed of either zwitterionic or anionic phospholipids or their mixtures. The extent of helicity depends on the amino acid sequence and properties of the medium. Based on small angle X-ray scattering data and the analysis of the fluorescence spectrum of the Trp residue in Mlt, we conclude that the peptide forms an oligomeric complex consisting of alpha-helical Mlt and several PSA molecules. Both latarcins, unlike Mlt, the most hydrophobic of the peptides, interact weakly with zwitterionic liposomes. However, they bind anionic liposomes or those composed of anionic/zwitterionic lipid mixtures. Latarcin Ltc1K forms associates on liposomes composed of zwitterionic/anionic lipid mixture. The structure of the peptide associates is either disordered or of beta sheet conformation. In all other cases the studied peptides adopt predominately alpha-helical conformation. In addition, we demonstrate that PSA inhibits membranolytic activity of Mlt and latarcin Ltc1K. These data suggest that the peptides, due to their high conformational lability, can vary structural and amphiphilic properties in the presence of PSA. As a result, various scenarios of the interaction of the peptides with membranes, whose surface is abundant with anionic polysaccharides, can take place. This can account for difficulties in understanding the structure-functional relationships in interactions of linear cationic peptides with biological membranes. PMID- 24954599 TI - Polyphosphates as an energy source for growth of Saccharomyces cerevisiae. AB - Cells of the yeast Saccharomyces cerevisiae with a low content of polyphosphates (polyP) are characterized by disturbance of growth in medium with 0.5% glucose. The parent strain with polyP level reduced by phosphate starvation had a longer lag phase. The growth rate of strains with genetically determined low content of polyP due to their enhanced hydrolysis (CRN/pMB1_PPN1 Sc is a superproducer of exopolyphosphatase PPN1) or reduced synthesis (the BY4741 vma2Delta mutant with impaired vacuolar membrane energization) was lower in the exponential phase. The growth of cells with high content of polyP was accompanied by polyP consumption. In cells of strains with low content of polyP, CRN/pMB1_PPN1 Sc and BY4741 vma2Delta, their consumption was insignificant. These findings provide more evidence indicating the use of polyP as an extra energy source for maintaining high growth rate. PMID- 24954598 TI - Effect of conserved intersubunit amino acid substitutions on Hfq protein structure and stability. AB - Hfq is a thermostable RNA-binding bacterial protein that forms a uniquely shaped homohexamer. Based on sequence and structural similarity, Hfq belongs to the like Sm (LSm) protein family. In spite of a rather high degree of homology between archaeal and eukaryotic LSm proteins, their quaternary structure is different, usually consisting of five to eight monomers. In this work, the importance of conserved intersubunit hydrogen bonds for the Hfq spatial organization was tested. The structures and stabilities for the Gln8Ala, Asn28Ala, Asp40Ala, and Tyr55Ala Hfq mutants were determined. All these proteins have the same hexamer organization, but their stability is different. Elimination of a single intersubunit hydrogen bond due to Gln8Ala, Asp40Ala, and Tyr55Ala substitutions results in decreased stability of the Hfq hexamer. Tyr55Ala Hfq as well as the earlier studied His57Ala Hfq has reduced protein thermostability, which seems to correspond to an opening of the protein hydrophobic core. PMID- 24954600 TI - Towards a genomics approach to tick (Acari: Ixodidae) control in cattle: a review. AB - Ticks and tick-borne disease (TBD) are major challenges to cattle production in the tropics and subtropics. Economic losses associated with ticks amount to billions of dollars annually. Although efforts to eradicate ticks and TBD using chemical control strategies have been implemented in many developing countries for decades, these acaricides are costly, and cattle susceptibility to ticks remains unchanged. Traditional breeding methods, where the farmer selected animals using records to improve the host genetic resistance to ticks (HGRT), are less than fully effective and time consuming. The HGRT has been reported in literature. To date, solutions to fight ticks and TBD are still unclear. Development of single-nucleotide polymorphism (SNP) technologies has created an opportunity to estimate breeding values of animals from DNA samples. The use of SNP technology for genomic selection allows information retrieval from the genotype even before the gene is expressed; thus potentially giving farmers the ability to make selection decisions on HGRT at an earlier age. This review discusses factors that affect HGRT, breeding selection, immunology, and genomic approaches and their application to improve HGRT in order to enhance livestock production. PMID- 24954601 TI - Preface: global metabolic profiling. PMID- 24954602 TI - Treatment outcome and prognostic factors of head and neck hemangiopericytoma: meta-analysis. AB - BACKGROUND: Head and neck hemangiopericytoma (HNHPC) is rare. Treatment outcome and specific prognostic factors were unexplored. METHODS: A case meta-analysis, in which treatment and outcome data were available, was performed. RESULTS: A total of 116 primary HNHPC cases were analyzed. Poor pathologic differentiation was associated with increased risk of tumor recurrence (odds ratio [OR] = 2.378; p = .005), metastasis (OR = 3.634; p = .011), and mortality (OR = 4.563; p = .002), whereas surgery was associated with decreased risk of tumor recurrence (OR = 0.109; p = .004). The tumor size >5.0 cm in diameter (hazard ratio [HR] = 6.391; p = .002), nonsurgical treatment (HR = 7.648; p = .000), and poor pathologic differentiation (HR = 1.705; p = .012) were the independent unfavorable prognostic factors for disease-free survival. Moreover, nonsurgical treatment (HR = 8.097; p = .002) and deep tumor location (HR = 4.074; p = .013) were independent adverse prognostic factors for overall survival (OS). CONCLUSION: These results suggest a management emphasizing the surgical removal of the tumor as first-line treatment. Tumor size >5.0 cm, poor pathologic differentiation, deep tumor location, and nonsurgical treatment were independent adverse prognostic factors. PMID- 24954603 TI - Methamphetamine induces dynamic changes of histone deacetylases in different phases of behavioral sensitization. PMID- 24954604 TI - Managing the Fukushima challenge. AB - The Fukushima Daiichi accident raises a fundamental question: Can science and technology prevent the inevitability of serious accidents, especially those with low probabilities and high consequences? This question reminds us of a longstanding challenge with the trans-sciences, originally addressed by Alvin Weinberg well before the Three Mile Island and Chernobyl accidents. This article, revisiting Weinberg's issue, aims at gaining insights from the accident with a special emphasis on the sociotechnical or human behavioral aspects lying behind the accident's causes. In particular, an innovative method for managing the challenge is explored referring to behavioral science approaches to a decision making process on risk management; such as managing human behavioral risks with information asymmetry, seeking a rational consensus with communicative action, and pursuing procedural rationality through interactions with the outer environment. In short, this article describes the emerging need for Japan to transform its national safety management institutions so that these might be based on interactive communication with parties inside and outside Japan. PMID- 24954605 TI - Nickel hypersensitivity in patients with inferior vena cava filters: case report and literature and MAUDE database review. AB - Placement of a prophylactic retrievable inferior vena cava (IVC) filter was requested in a 73-year-old woman with nickel hypersensitivity resulting in a clinical dilemma. Given that all retrievable filters contain nickel, the published literature and the Manufacturer and User Facility Device Experience (MAUDE) database were reviewed; no documented case of IVC filter placement in a patient with nickel hypersensitivity or reported hypersensitivity reaction in a patient after IVC filter placement could be identified. This article presents the uneventful course of the case described and a review of the literature and recommendations on use of nickel-containing devices in patients with nickel hypersensitivity. PMID- 24954606 TI - Predictive value of pattern classification 24 hours after radiofrequency ablation of liver metastases on CT and positron emission tomography/CT. AB - PURPOSE: To assess a classification scheme for predicting local tumor progression (LTP) after radiofrequency (RF) ablation of liver metastases, using predefined patterns on contrast-enhanced computed tomography (CT) and positron emission tomography (PET) combined with CT (PET/CT) acquired 24 hours after RF ablation. MATERIALS AND METHODS: There were 45 metastases in 20 patients treated. After 24 hours, imaging of the ablation zones was performed with contrast-enhanced PET/CT. Three independent radiologists prospectively assessed contrast-enhanced CT and combined PET/CT images to identify three patterns: pattern I, no tissue enhancement or fluorodeoxyglucose uptake between the ablation zone and the liver parenchyma; pattern II, a rimlike pattern; and pattern III, a peripheral nodule. PET/CT images obtained after 8-10 weeks were evaluated for LTP. The patterns were analyzed for their sensitivity, specificity, positive predictive value, and negative predictive value for predicting LTP. RESULTS: Pattern I was most frequently observed (81% for contrast-enhanced CT and 61% for PET/CT) as well as for ablation zones that showed LTP (52% and 37%, respectively). Conversely, pattern II was observed for tumors that were completely ablated (6% and 29%, respectively). Patterns II and III together had the highest sensitivity for predicting LTP (48% and 63%, respectively); pattern III had the highest specificity (94% and 95%, respectively). For nodular patterns, test characteristics were better for PET/CT compared with contrast-enhanced CT, but the difference was not significant. Nodular patterns > 1 cm achieved high positive predictive value (both 100%). CONCLUSIONS: Inflammation and hyperemia can hinder interpretation on imaging 24 hours after RF ablation, especially on PET/CT. Nodular patterns around the ablation zone on early contrast-enhanced CT and PET/CT have a high predictive value for LTP and should be taken into account for disease management. PMID- 24954609 TI - Fabrication of full-color InGaN-based light-emitting diodes on amorphous substrates by pulsed sputtering. AB - InGaN-based light-emitting diodes (LEDs) have been widely accepted as highly efficient light sources capable of replacing incandescent bulbs. However, applications of InGaN LEDs are limited to small devices because their fabrication process involves expensive epitaxial growth of InGaN by metalorganic vapor phase epitaxy on single-crystal wafers. If we can utilize a low-cost epitaxial growth process, such as sputtering on large-area substrates, we can fabricate large-area InGaN light-emitting displays. Here, we report the growth of GaN (0001) and InGaN (0001) films on amorphous SiO2 by pulsed sputtering deposition. We found that using multilayer graphene buffer layers allows the growth of highly c-axis oriented GaN films even on amorphous substrates. We fabricated red, green, and blue InGaN LEDs and confirmed their successful operation. This successful fabrication of full-color InGaN LEDs on amorphous substrates by sputtering indicates that the technique is quite promising for future large-area light emitting displays on amorphous substrates. PMID- 24954607 TI - Comparison of sonographically guided percutaneous sodium tetradecyl sulfate injection with ethanol injection in the treatment of benign nonfunctioning thyroid nodules. AB - PURPOSE: To compare the efficacy of percutaneous sodium tetradecyl sulfate (STS) injection with ethanol injection in the treatment of benign nonfunctioning thyroid nodules. MATERIALS AND METHODS: This prospective study included 47 patients with 50 benign thyroid nodules. The lesions were randomly assigned into two groups: 20 in the ethanol arm and 30 in the STS arm. The mean lesion volume was 25.6 mL +/- 28.5 (range, 4-122.1 mL) in the ethanol arm and 25.4 mL +/- 27 (range, 0.72-129 mL) in the STS arm. One sitting of sclerosant injection was done in 20 lesions, and two injections, three injections, four injections, five injections, six injections, seven injections, and eight sittings of injections were done in 9 lesions, 4 lesions, 8 lesions, 4 lesions, 2 lesions, 2 lesions, and 1 lesion. The mean volumes of the instilled ethanol and STS were 5.3 mL and 7.8 mL, respectively, per sitting. Follow-up sonography was performed at 1, 3, 6, and 12 months after the procedure. RESULTS: The final 12-month follow-up lesion volumes were 4.1 mL +/- 3.7 (range, 0.3-15.2 mL) in the ethanol group and 4.4 mL +/- 5.8 (range, 0.01-29.6 mL) in the STS group (P = .85). The mean volume reduction was 84% and 82.8% in the two groups. No significant adverse effects were seen in either of the two groups. CONCLUSIONS: Sonographically guided percutaneous ethanol and STS injections are not significantly different from each other in terms of the volume reduction achieved in benign nonfunctioning thyroid nodules. PMID- 24954610 TI - Parenting styles and hormone levels as predictors of physical and indirect aggression in boys and girls. AB - This study examines the relationship between parenting style, androgen levels, and measures of physical and indirect aggression. Peer ratings of aggression were obtained from 159 eight-year-old children (89 boys and 70 girls). Parenting styles (authoritative, authoritarian or permissive) were assessed using the Parenting Styles and Dimensions Questionnaire (PSDQ).Saliva samples were obtained from children and assayed for testosterone and androstenedione concentrations. A regression analysis revealed that high testosterone levels were associated with a higher level of physical aggression in boys with authoritarian mothers. Testosterone was also found to moderate the relationship between father's authoritarian parenting and physical aggression in girls, with both moderate and high levels being significant. In relation to indirect aggression, moderate and high levels of testosterone were associated with higher levels of this type of aggression in girls with permissive mothers. Our results highlight the importance of taking into account the interaction of biological and psychosocial variables when investigating aggressive behavior. PMID- 24954611 TI - The dorsal medial frontal cortex mediates automatic motor inhibition in uncertain contexts: evidence from combined fMRI and EEG studies. AB - Response inhibition is commonly thought to rely on voluntary, reactive, selective, and relatively slow prefrontal mechanisms. In contrast, we suggest here that response inhibition is achieved automatically, nonselectively, within very short delays in uncertain environments. We modified a classical go/nogo protocol to probe context-dependent inhibitory mechanisms. Because no single neuroimaging method can definitely disentangle neural excitation and inhibition, we combined fMRI and EEG recordings in healthy humans. Any stimulus (go or nogo) presented in an uncertain context requiring action restraint was found to evoke activity changes in the supplementary motor complex (SMC) with respect to a control condition in which no response inhibition was required. These changes included: (1) An increase in event-related BOLD activity, (2) an attenuation of the early (170 ms) event related potential generated by a single, consistent source isolated by advanced blind source separation, and (3) an increase in the evoked-EEG Alpha power of this source. Considered together, these results suggest that the BOLD signal evoked by any stimulus in the SMC when the situation is unpredictable can be driven by automatic, nonselective, context-dependent inhibitory activities. This finding reveals the paradoxical mechanisms by which voluntary control of action may be achieved. The ability to provide controlled responses in unpredictable environments would require setting-up the automatic self-inhibitory circuitry within the SMC. Conversely, enabling automatic behavior when the environment becomes predictable would require top-down control to deactivate anticipatorily and temporarily the inhibitory set. PMID- 24954612 TI - "That land means everything to us as Anishinaabe....": Environmental dispossession and resilience on the North Shore of Lake Superior. AB - This article shares results of a community-based (CBR) study that qualitatively examined the perceived health impacts of environmental dispossession among Elders in two Anishinaabe communities in Ontario, Canada. Through in-depth interviews, Elders (n=46) recounted changes in health and well-being, specifically that related to reduced access to traditional foods and decreased capacity to participate in, and share knowledge of, land-based practices. Elders discussed the ways in which they have remained resilient to these changes in their ways of living. With a greater purpose of proposing solutions that will improve contemporary patterns of Indigenous health, this research underscores the importance of engaging theoretically in concepts of environmental dispossession and resilience. PMID- 24954613 TI - Neighborhood socioeconomic deprivation characteristics in child (0-18 years) health studies: a review. AB - BACKGROUND: Growing up in socioeconomically deprived neighborhoods has been shown to have negative health effects on children. However, the most recent review on which measures are used to investigate the association between neighborhood characteristics and child (0-18 year) health included studies only until 2004. Insight into more recent research is needed for the further development of these measures. OBJECTIVES: To review neighborhood socioeconomic deprivation characteristics used in recent studies investigating the relationship between neighborhood socioeconomic deprivation and child health. METHODS: Sensitive search in MEDLINE, Embase, PsycINFO, Sociological Abstracts databases (2004 2013). RESULTS: Ultimately, 19 studies were included. We found ten neighborhood socioeconomic deprivation constructs, of which income/wealth, employment, and education were most frequently used. The choice for neighborhood characteristics seemed independent of the health outcome and in most cases was not based on a specific theoretical background or earlier work. CONCLUSION: Studies vary regarding study designs, measures and outcomes. Researchers should clearly specify their choice of neighborhood socioeconomic deprivation characteristics; preferably, these should be theory-based and used consistently. PMID- 24954614 TI - The toilet tripod: understanding successful sanitation in rural India. AB - Building toilets and getting people to use them is critical for public health. We deployed a political ecology approach specifically to identify the multi-scalar political, economic, and environmental factors influencing toilet adoption in rural India. The research used ethnographic and technical methods in rural villages of West Bengal and Himachal Pradesh over the period September 2012 to May 2013. The elements of successful sanitation adoption depended on three factors (i.e., toilet tripod): (1) multi-scalar political will on the part of both government and NGOs over the long term; (2) proximate social pressure, i.e., person-to-person contact between rural inhabitants and toilets; (3) political ecology, i.e., assured access to water, compatible soil type, and changing land use. This research contributes to studies of sustainable development and global public health by developing a theory and framework for successful sanitation. PMID- 24954615 TI - Mitochondrial ROS and involvement of Bcl-2 as a mitochondrial ROS regulator. AB - Mitochondria are the major intracellular source of reactive oxygen species (ROS). While excessive mitochondrial ROS (mitoROS) production induces cell injury and death, there is accumulating evidence that non-toxic low levels of mitoROS could serve as important signaling molecules. Therefore, maintenance of mitoROS at physiological levels is crucial for cell homeostasis as well as for survival and proliferation. This review describes the various mechanisms that keep mitoROS in check, with particular focus on the role of the onco-protein Bcl-2 in redox regulation. In addition to its canonical anti-apoptotic activity, Bcl-2 has been implicated in mitoROS regulation by its effect on mitochondrial complex IV activity, facilitating the mitochondrial incorporation of GSH and interaction with the small GTPase-Rac1 at the mitochondria. We also discuss some of the plausible mechanism(s) which allows Bcl-2 to sense and respond to the fluctuations in mitoROS. PMID- 24954616 TI - Structure-based characterization of multiprotein complexes. AB - Multiprotein complexes govern virtually all cellular processes. Their 3D structures provide important clues to their biological roles, especially through structural correlations among protein molecules and complexes. The detection of such correlations generally requires comprehensive searches in databases of known protein structures by means of appropriate structure-matching techniques. Here, we present a high-speed structure search engine capable of instantly matching large protein oligomers against the complete and up-to-date database of biologically functional assemblies of protein molecules. We use this tool to reveal unseen structural correlations on the level of protein quaternary structure and demonstrate its general usefulness for efficiently exploring complex structural relationships among known protein assemblies. PMID- 24954617 TI - Elongated structure of the outer-membrane activator of peptidoglycan synthesis LpoA: implications for PBP1A stimulation. AB - The bacterial cell envelope contains the stress-bearing peptidoglycan layer, which is enlarged during cell growth and division by membrane-anchored synthases guided by cytoskeletal elements. In Escherichia coli, the major peptidoglycan synthase PBP1A requires stimulation by the outer-membrane-anchored lipoprotein LpoA. Whereas the C-terminal domain of LpoA interacts with PBP1A to stimulate its peptide crosslinking activity, little is known about the role of the N-terminal domain. Herein we report its NMR structure, which adopts an all-alpha-helical fold comprising a series of helix-turn-helix tetratricopeptide-repeat (TPR)-like motifs. NMR spectroscopy of full-length LpoA revealed two extended flexible regions in the C-terminal domain and limited, if any, flexibility between the N- and C-terminal domains. Analytical ultracentrifugation and small-angle X-ray scattering results are consistent with LpoA adopting an elongated shape, with dimensions sufficient to span from the outer membrane through the periplasm to interact with the peptidoglycan synthase PBP1A. PMID- 24954618 TI - The LxVP and PxIxIT NFAT motifs bind jointly to overlapping epitopes on calcineurin's catalytic domain distant to the regulatory domain. AB - The serine/threonine phosphatase calcineurin (Cn) targets the nuclear factors of activated T cells (NFATs) that activate cytokine genes. Calcium influx activates Cn to dephosphorylate multiple serine residues within the ~200 residue NFAT regulatory domain, which triggers joint nuclear translocation of NFAT and Cn. The dephosphorylation process relies on the interaction between Cn and the conserved motifs PxIxIT and LxVP, which are located N- and C-terminal to the phosphorylation sites in NFAT's regulatory domain. Here, we show that an NFATc1 derived 15-residue peptide segment containing the conserved LxVP motif binds to an epitope on Cn's catalytic domain (CnA), which overlaps with the previously established PxIxIT binding site on CnA and is distant to the regulatory domain (CnB). Both NFAT motifs partially compete for binding but do not fully displace each other on the CnA epitope, revealing that both segments bind simultaneously to the same epitope on the catalytic domain. PMID- 24954620 TI - [Dynamic reconstruction of Achilles tendon by free composite perforator flap with functional assessment]. AB - INTRODUCTION, DEFECTS: Achilles tendon are common in patients after immobilization, therefore the reconstruction of a ruptured Achilles tendon with defects remains a surgical challenge. The ideal characteristics are a thin layer of skin, a strong tendon component, combined with a reliable blood supply and minimal morbidity at the donor site. We present a reconstructive technique using a composite anterolateral thigh perforator free flap, meeting these criteria, for the treatment of rupture of Achilles tendon with cutaneous and tendon defect. METHODS: A 34-year-old patient presenting a third rupture of his left Achilles tendon with 4cm composite defect was reconstructed with a contralateral anterolateral thigh perforator flap with part of the fasciae latae. The latter was raised by dissecting one intramuscular perforating artery from a descending branch of the lateral circumflex femoral artery. The postoperative observation period was one year. The functional outcome was determined by clinical scores (IKDC, OAK and Lysholm-Tegner). RESULTS: The healing time was 21 days. At six months, the aesthetic and functional result was satisfactory without delayed healing or secondary rupture. The aesthetic discomfort at the donor site was considered negligible by the patient. At one year, there is a continuing stability with no recurrence. The functional result was considered good with a clinical score of 75/100. CONCLUSION: Therefore, this method seems to be a good option for complex reconstruction of Achilles meeting the requirements of reconstruction with good stability at a distance. PMID- 24954619 TI - Constructing tailored isoprenoid products by structure-guided modification of geranylgeranyl reductase. AB - The archaeal enzyme geranylgeranyl reductase (GGR) catalyzes hydrogenation of carbon-carbon double bonds to produce the saturated alkyl chains of the organism's unusual isoprenoid-derived cell membrane. Enzymatic reduction of isoprenoid double bonds is of considerable interest both to natural products researchers and to synthetic biologists interested in the microbial production of isoprenoid drug or biofuel molecules. Here we present crystal structures of GGR from Sulfolobus acidocaldarius, including the structure of GGR bound to geranylgeranyl pyrophosphate (GGPP). The structures are presented alongside activity data that depict the sequential reduction of GGPP to H6GGPP via the intermediates H2GGPP and H4GGPP. We then modified the enzyme to generate sequence variants that display increased rates of H6GGPP production or are able to halt the extent of reduction at H2GGPP and H4GGPP. Crystal structures of these variants not only reveal the structural bases for their altered activities; they also shed light onto the catalytic mechanism employed. PMID- 24954621 TI - Blood pressure and urinary sodium excretion in relation to 16 genetic polymorphisms in the natriuretic peptide system in Chinese. AB - We systematically investigated the association between single nucleotide polymorphisms (SNPs) in the natriuretic peptide system (NPPA, NPPB, NPPC, NPRA, NPRC, and Corin genes) and blood pressure in a Chinese population. The study population was recruited from a mountainous area 500 km south of Shanghai from 2003 to 2009. Using the ABI SNapShot method, we first genotyped 951 subjects enrolled in 2005 for 16 SNPs and then the remaining 1355 subjects as validation for 5 SNPs selected from the primary study. Overall, the association of the studied genetic polymorphisms with blood pressure and urinary excretion of cations was weak or non-significant. However, in the primary study, there was significant (Pint = 0.003) interaction between the rs198358 polymorphism and age in relation to diastolic blood pressure. After adjustment for covariates, diastolic blood pressure was significantly higher in the G allele carriers than AA homozygotes in 176 subjects aged 60 years or older (77.8 +/- 1.72 vs 73.9 +/- 1.54 mmHg, P = 0.001). In the primary combined with validation studies, this interaction remained statistically significant (Pint = 0.02). The odds ratio of hypertension for carrying the G allele versus AA homozygotes was 1.25 (95% CI: 1.03-1.52; P = 0.03) in all subjects, and 0.85 (0.51-1.41; P = 0.53), 1.30 (0.98 1.73; P = 0.06), and 1.45 (0.95-2.22; P = 0.08) in the subjects younger than 40 years, 40-59 years, and 60 years or older, respectively. Some of the genetic polymorphisms in the natriuretic peptide system might be associated with blood pressure. However, not only the size, but also the direction of the association may change with age. PMID- 24954622 TI - MR imaging for rectal cancer: the role in staging the primary and response to neoadjuvant therapy. AB - Pre-operative staging is an essential aspect of modern rectal cancer management and radiological assessment is central to this process. An ideal radiological assessment should provide sufficient information to reliably guide pre-operative decision-making. Technical advances allow high-resolution imaging to not only provide prognostic information but to define the anatomy, helping the surgeon to anticipate potential pitfalls during the operation. The main imaging modality for local staging of rectal cancer is Magnetic Resonance Imaging (MRI), as it defines the tumour and relevant anatomy providing the most detail on the important prognostic factors that influence treatment choice. In addition, there is an emerging role for MRI in the assessment of the response to neoadjuvant therapy. This article is an evidence-based review of rectal cancer staging focusing on post-treatment assessment of response using MRI. The discussion extends into the implications for reliably assessing response and how this may influence future rectal cancer management. PMID- 24954625 TI - Idiopathic desquamative interstitial pneumonia in a child: a case report. AB - BACKGROUND: Desquamative interstitial pneumonia is a rare form of interstitial lung disease in children. Respiratory symptoms appear progressively, are often subtle, and diagnosis is often delayed by a mean of 6 months after onset. High resolution chest computed tomography is the most sensitive imaging technique for demonstrating and identifying interstitial pneumonia. The typical histologic pattern of desquamative interstitial pneumonia, with prominent clustered alveolar macrophages, diffuse reactive alveolar epithelial hyperplasia and globular proteinaceous material, is diagnostic. Desquamative interstitial pneumonia in children can be idiopathic, though it is mostly related to an inborn error of surfactant metabolism. CASE PRESENTATION: We present the complex clinical course and pathologic findings of a 30-months-old Mauritian and Senegalese girl with idiopathic desquamative interstitial pneumonia and multiple extrapulmonary manifestations. To our knowledge, this is the first case report of desquamative interstitial pneumonia to occur as part of a syndrome with multiple organ involvement. CONCLUSION: We believe that desquamative interstitial pneumonia is not always associated with mutations of the surfactant proteins, and can still be idiopathic, especially when occurring as part of a syndrome with multiple organ involvement, as described in other interstitial lung diseases. PMID- 24954626 TI - Disclination lines at homogeneous and heterogeneous colloids immersed in a chiral liquid crystal. AB - In the present work we perform Monte Carlo simulations in the isothermal-isobaric ensemble to study defect topologies formed in a cholesteric liquid crystal due to the presence of a spherical colloidal particle. Topological defects arise because of the competition between anchoring at the colloidal surface and the local director. We consider homogeneous colloids with either local homeotropic or planar anchoring to validate our model by comparison with earlier lattice Boltzmann studies. Furthermore, we perform simulations of a colloid in a twisted nematic cell and discuss the difference between induced and intrinsic chirality on the formation of topological defects. We present a simple geometrical argument capable of describing the complex three-dimensional topology of disclination lines evolving near the surface of the colloid. The presence of a Janus colloid in a cholesteric host fluid reveals a rich variety of defect structures. Using the Frank free energy we analyze these defects quantitatively indicating a preferred orientation of the Janus colloid relative to the cholesteric helix. PMID- 24954624 TI - Diabetic neuropathy: mechanisms, emerging treatments, and subtypes. AB - Diabetic neuropathies (DNs) differ in clinical course, distribution, fiber involvement (type and size), and pathophysiology, the most typical type being a length-dependent distal symmetric polyneuropathy (DSP) with differing degrees of autonomic involvement. The pathogenesis of diabetic DSP is multifactorial, including increased mitochondrial production of free radicals due to hyperglycemia-induced oxidative stress. Mechanisms that impact neuronal activity, mitochondrial function, membrane permeability, and endothelial function include formation of advanced glycosylation end products, activation of polyol aldose reductase signaling, activation of poly(ADP ribose) polymerase, and altered function of the Na(+)/K(+)-ATPase pump. Hyperglycemia-induced endoplasmic reticulum stress triggers several neuronal apoptotic processes. Additional mechanisms include impaired nerve perfusion, dyslipidemia, altered redox status, low-grade inflammation, and perturbation of calcium balance. Successful therapies require an integrated approach targeting these mechanisms. Intensive glycemic control is essential but is insufficient to prevent onset or progression of DSP, and disease-modifying treatments for DSP have been disappointing. Atypical forms of DN include subacute-onset sensory (symmetric) or motor (asymmetric) predominant conditions that are frequently painful but generally self-limited. DNs are a major cause of disability, associated with reduced quality of life and increased mortality. PMID- 24954623 TI - The diagnosis and treatment of pediatric narcolepsy. AB - Narcolepsy in children is a serious disorder marked by a chronic course and lifelong handicap in school performance and choice of employment, by free time activity limitation, and by behavior and personality changes, all of which constitute a major influence on the quality of life. Increased daytime sleepiness may be the only sign at the disease onset, with attacks of sleep becoming longer and lasting up to hours. Also present may be confusional arousals with features of sleep drunkenness. Paradoxically, preschool and young children may show inattentiveness, emotional lability, and hyperactive behavior. Cataplexy may develop after onset of sleepiness and affect mainly muscles of the face. Hypnagogic hallucinations and sleep paralysis are seldom present. Multiple Sleep Latency Test criteria are not available for children younger than 6 years. The haplotype (HLA-DQB1:0602) can be associated with the disorder; however, the best predictor of narcolepsy-cataplexy is hypocretin deficiency. The treatment generally used in adults is regarded as off-label in childhood, which is why the management of pediatric narcolepsy is difficult. PMID- 24954627 TI - Network based analyses of gene expression profile of LCN2 overexpression in esophageal squamous cell carcinoma. AB - LCN2 (lipocalin 2) is a member of the lipocalin family of proteins that transport small, hydrophobic ligands. LCN2 is elevated in various cancers including esophageal squamous cell carcinoma (ESCC). In this study, LCN2 was overexpressed in the EC109 ESCC cell line and we applied integrated analyses of the gene expression data to identify protein-protein interactions (PPI) network to enhance our understanding of the role of LCN2 in ESCC. Through further mining of PPI sub networks, hundreds of differentially expressed genes (DEGs) were identified to interact with thousands of other proteins. Subcellular localization analyses found the DEGs and their directly or indirectly interacting proteins distributed in multiple layers, which was applied to analyze the possible paths between two DEGs. Gene Ontology annotation generated a functional annotation map and found hundreds of significant terms, especially those associated with the known and potential roles of LCN2 protein. The algorithm of Random Walk with Restart was applied to prioritize the DEGs and identified several cancer-related DEGs ranked closest to LCN2 protein. These analyses based on PPI network have greatly expanded our understanding of the mRNA expression profile of LCN2 overexpression for future examination of the roles and mechanisms of LCN2. PMID- 24954630 TI - Leucocyte adhesion deficiency III in a mixed-breed dog. AB - BACKGROUND: Leucocyte adhesion deficiencies are inherited disorders characterised by immunodeficiency leading to recurrent infections and a marked leucocytosis. We describe the clinical characteristics, diagnosis and management of an Australian mixed- breed dog with leucocyte adhesion deficiency III. CASE REPORT: A 16-month old male, neutered, German Shepherd * Rottweiler dog was investigated for pyrexia, persistent leucocytosis, marked periodontal disease, lameness, increased mucosal haemorrhages and poor wound healing. Numerous diagnostics were performed including a leucocyte adhesion deficiency III PCR test, which was positive. The patient was managed with topical pressure at bleeding sites, antibiotics, analgesics and dental prophylaxis when required. DISCUSSION: Leucocyte adhesion deficiency III is a rare disorder that manifests because of impaired activation of beta integrins. This results in an absence of neutrophil chemotaxis and adhesion, and platelet dysfunction. Mutations within the KINDLIN3 gene resulting in the absence of the kindlin-3 protein have been identified as the cause of this disease. Leucocyte adhesion deficiency III has previously been reported in humans and a German Shepherd dog. This report describes the first reported case of leucocyte adhesion deficiency III in Australia and the first reported case in a mixed-breed dog worldwide. PMID- 24954628 TI - The effect of care setting in the delivery of high-value colon cancer care. AB - BACKGROUND: The effect of care setting on value of colon cancer care is unknown. METHODS: A Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort study of 6544 patients aged >= 66 years with stage IV colon cancer (based on the American Joint Committee on Cancer staging system) who were diagnosed between 1996 and 2005 was performed. All patients were followed through December 31, 2007. Using outpatient and carrier claims, patients were assigned to a treating hospital based on the hospital affiliation of the primary oncologist. Hospitals were classified academic or nonacademic using the SEER-Medicare National Cancer Institute Hospital File. RESULTS: Of the 6544 patients, 1605 (25%) received care from providers affiliated with academic medical centers. The unadjusted median cancer-specific survival was 16.0 months at academic medical centers versus 13.9 months at nonacademic medical centers (P < .001). After adjustment, treatment at academic hospitals remained significantly associated with a reduced risk of death from cancer (hazard ratio, 0.87; 95% confidence interval [95% CI], 0.82-0.93 [P < .001]). Adjusted mean 12-month Medicare spending was $8571 higher at academic medical centers (95% CI, $2340-$14,802; P = .007). The adjusted median cost was $1559 higher at academic medical centers; this difference was not found to be statistically significant (95% CI, -$5239 to $2122; P = .41). A small percentage of patients who received very expensive care skewed the difference in mean cost; the only statistically significant difference in adjusted costs in quantile regressions was at the 99.9th percentile of costs (P < .001). CONCLUSIONS: Among Medicare beneficiaries with stage IV colon cancer, treatment by a provider affiliated with an academic medical center was associated with a 2 month improvement in overall survival. Except for patients in the 99.9th percentile of the cost distribution, costs at academic medical centers were not found to be significantly different from those at nonacademic medical centers. PMID- 24954631 TI - Uranium release from sediment to groundwater: influence of water chemistry and insights into release mechanisms. AB - Uranium (U) contamination in groundwater often results from natural geochemical processes such as mineral dissolution and desorption of adsorbed U from mineral surface. Although U adsorption and U mineral dissolution have been extensively studied, current knowledge of minerals and water chemistry conditions that control U release in uncontaminated soil and aquifers is still limited. Identification of these minerals and the knowledge of how water chemistry conditions influence U release is critical to better understand, predict, and manage geogenic U contamination in soil and groundwater. The objective of this study is to determine the extent and mechanisms of U release from a heterogeneous natural sediment under water chemistry conditions relevant to natural soil water and groundwater. A sediment sample was collected and characterized by XRD, SEM EDX and extraction methods, and examined using laboratory leaching experiments. Our results show that Fe-Mn (oxy)hydroxides and silicate minerals are the major U hosting minerals, and a substantial fraction of U exists as adsorbed ions on minerals. We also found that U release is controlled by a number of interactive processes including dissolution of U-bearing minerals, U desorption from mineral surface, formation of aqueous U complexes, and reductive precipitation of U. Results from this study shed light on the important geochemical reactions that need be considered for developing a conceptual model that predicts U contamination in subsurface environment. PMID- 24954629 TI - Cationic PAMAM dendrimers as pore-blocking binary toxin inhibitors. AB - Dendrimers are unique highly branched macromolecules with numerous groundbreaking biomedical applications under development. Here we identified poly(amido amine) (PAMAM) dendrimers as novel blockers for the pore-forming B components of the binary anthrax toxin (PA63) and Clostridium botulinum C2 toxin (C2IIa). These pores are essential for delivery of the enzymatic A components of the internalized toxins from endosomes into the cytosol of target cells. We demonstrate that at low MUM concentrations cationic PAMAM dendrimers block PA63 and C2IIa to inhibit channel-mediated transport of the A components, thereby protecting HeLa and Vero cells from intoxication. By channel reconstitution and high-resolution current recording, we show that the PAMAM dendrimers obstruct transmembrane PA63 and C2IIa pores in planar lipid bilayers at nM concentrations. These findings suggest a new potential role for the PAMAM dendrimers as effective polyvalent channel-blocking inhibitors, which can protect human target cells from intoxication with binary toxins from pathogenic bacteria. PMID- 24954633 TI - Elucidating the structure-property relationships of donor-pi-acceptor dyes for dye-sensitized solar cells (DSSCs) through rapid library synthesis by a one-pot procedure. AB - The creation of organic dyes with excellent high power conversion efficiency (PCE) is important for the further improvement of dye-sensitized solar cells. We wish to describe the rapid synthesis of a 112-membered donor-pi-acceptor dye library by a one-pot procedure, evaluation of PCEs, and elucidation of structure property relationships. No obvious correlations between epsilon, and the eta were observed, whereas the HOMO and LUMO levels of the dyes were critical for eta. The dyes with a more positive E(HOMO), and with an E(LUMO)<-0.80 V, exerted higher PCEs. The proper driving forces were crucial for a high J(sc), and it was the most important parameter for a high eta. The above criteria of E(HOMO) and E(LUMO) should be useful for creating high PCE dyes; nevertheless, that was not sufficient for identifying the best combination of donor, pi, and acceptor blocks. Combinatorial synthesis and evaluation was important for identifying the best dye. PMID- 24954632 TI - Zoledronic acid in osteoporosis secondary to mastocytosis. AB - BACKGROUND: Osteoporosis is the prevalent manifestation of bone involvement in patients with systemic mastocytosis. Mastocytosis-related osteoporosis is characterized by both absolute and relative prevalence of osteoclastic activity, consistent with the positive results reported in small series of patients with antiresorptive drugs, such as bisphosphonates. The aim of this study is to investigate the efficacy of zoledronic acid in patients with mastocytosis-related osteoporosis. METHODS: Twenty-five patients with osteoporosis secondary to indolent systemic mastocytosis were given a single intravenous infusion of 5 mg zoledronic acid dissolved in 100 mL of 0.9% saline over 60 minutes. RESULTS: After 1 year, the mean increase in bone mineral density was 6.0% +/- 4.4% at the spine and 2.4% +/- 3.2% at the total hip. Serum levels of bone turnover markers decreased versus baseline: bone alkaline phosphatase -34% and -35%, and C terminal telopeptide -68% and -56% at 6 and 12 months, respectively. None of the patients reported new fractures during the year of follow-up. In all the first 20 treated patients, a transitory acute phase response was observed, but this was prevented in 4 of 5 subsequent patients in whom acetaminophen was given systematically during the 3 days post-infusion. CONCLUSIONS: A single 5 mg zoledronic acid intravenous infusion in patients with osteoporosis secondary to indolent systemic mastocytosis is associated with significant increases in spine and hip bone mineral density and decreases of bone turnover markers over at least 1 year. Yearly zoledronic acid might represent a therapeutic option for indolent systemic mastocytosis-associated osteoporosis. PMID- 24954636 TI - Tailored functionalization of polyphenol-based molecular platforms. AB - General and efficient methods for selective modification of macrocyclic oligomers are rare, mostly because restricting a reaction to a defined number of identical functional groups is difficult to achieve. This work describes a unique, general, and rational methodology for the iteroselective functionalization of polyphenolic platforms by N-tert-butylaminocarbonyl (Bac) groups. The methodology consists of reacting the oligomeric platform with t-BuNCO and an inorganic base in an apolar solvent. This very simple one-step procedure has been applied to various calix[4, 5, 6, and 8]arenes, and in all cases, calixarenes with a single leftover phenolic moiety were isolated in high yields (>90%). Interestingly, this so-called "all but-one" methodology gives a straightforward access to calixarenes displaying inherent chirality. It is also shown that the Bac group can be used as a protective group. Thus, the all-but-one methodology has been used for the efficient monofunctionalization of a key precursor platform, illustrating its huge potential for the tailored synthesis of sophisticated macrocyclic oligomers. PMID- 24954634 TI - Fluoride exposure regulates the elongation phase of protein synthesis in cultured Bergmann glia cells. AB - Fluoride is an environmental pollutant present in dental products, food, pesticides and water. The latter, is the greatest source of exposure to this contaminant. Structural and functional damages to the central nervous system are present in exposed population. An established consequence of the neuronal is the release of a substantial amount of glutamate to the extracellular space, leading to an excitotoxic insult. Glutamate exerts its actions through the activation of specific plasma membrane receptors and transporters present in neurons and in glia cells and it is the over-activation of glutamate receptors and transporters, the biochemical hallmark of neuronal and oligodendrocyte cell death. In this context, taking into consideration that fluoride leads to degeneration of cerebellar cells, we took the advantage of the well-established model of cerebellar Bergmann glia cultures to gain insight into the molecular mechanisms inherent to fluoride neurotoxicity that might be triggered in glia cells. We could establish that fluoride decreases [(35)S]-methionine incorporation into newly synthesized polypeptides, in a time-dependent manner, and that this halt in protein synthesis is the result of a decrease in the elongation phase of translation, mediated by an augmentation of eukaryotic elongation factor 2 phosphorylation. These results favor the notion of glial cells as targets of fluoride toxicity and strengthen the idea of a critical involvement of glia cells in the function and dysfunction of the brain. PMID- 24954635 TI - Expression profile and role of prostacyclin receptor (PTGIR) in peri-implantation porcine conceptuses. AB - Prostacyclin (prostaglandin I2 [PGI2]) signaling system not only plays a pivotal role in vascular function in many species but is also important during early pregnancy in rodents and ruminants. Recently, abundant concentrations of PGI2 were found in the endometrium and uterine lumen of gilts at the time of implantation. In the present study, conceptuses collected on Days 10, 12, 14, 16, and 18 of pregnancy were examined for the expression of PGI2 receptors, PTGIR. Moreover, the effect of iloprost (a PGI2 analogue) on attachment, proliferation, and apoptosis in conceptus trophoblast (Tr) cells was investigated in vitro. Increased PTGIR mRNA expression was observed in Day 16 trophoblasts compared with Days 10, 12, and 14 conceptuses (P < 0.001) and Day 18 trophoblast tissue (P < 0.01). Embryos from Day 18 of gestation revealed greater PTGIR mRNA expression compared with Day 16 embryos (P < 0.01). In contrast to mRNA, PTGIR protein level in conceptus and trophoblast tissue was high on Days 12 and 14, followed by a decrease observed on Day 16. On Day 18 of pregnancy, PTGIR protein was detected in both trophoblast and embryonic tissue. Iloprost stimulated attachment and proliferation of Tr cells, but this effect was abolished by the addition of the PTGIR-specific antagonist, CAY10441, into culture medium. Addition of iloprost neither did affect the ratio of BAX/BCL-2 gene expression in cultured Tr cells nor did protect these cells from staurosporine-induced apoptosis. In summary, PTGIR is expressed in porcine conceptuses, and PGI2 acting through this receptor may promote the attachment and proliferation of Tr cells, thereby facilitating conceptus implantation. PMID- 24954637 TI - Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms. AB - Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurological disorders characterized by pathophysiologic hallmark of length-dependent distal axonal degeneration of the corticospinal tracts. The prominent features of this pathological condition are progressive spasticity and weakness of the lower limbs. To date, 72 spastic gait disease-loci and 55 spastic paraplegia genes (SPGs) have been identified. All modes of inheritance (autosomal dominant, autosomal recessive, and X-linked) have been described. Recently, a late onset spastic gait disorder with maternal trait of inheritance has been reported, as well as mutations in genes not yet classified as spastic gait disease. Several cellular processes are involved in its pathogenesis, such as membrane and axonal transport, endoplasmic reticulum membrane modeling and shaping, mitochondrial function, DNA repair, autophagy, and abnormalities in lipid metabolism and myelination processes. Moreover, recent evidences have been found about the impairment of endosome membrane trafficking in vesicle formation and about the involvement of oxidative stress and mtDNA polymorphisms in the onset of the disease. Interactome networks have been postulated by bioinformatics and biological analyses of spastic paraplegia genes, which would contribute to the development of new therapeutic approaches. PMID- 24954638 TI - Signals from activation of B-cell receptor with anti-IgD can override the stimulatory effects of excess BAFF on mature B cells in vivo. AB - The selection and maturation of B-cell clones are critically determined by tonic signals from activated B cell receptors (BCR) and survival signals from BAFF cytokine. These finely tuned and coordinated signals provide a net positive signal that can promote the selection, maturation, proliferation and differentiation of a developing B cell. Stimulation with an anti-IgD antibody can also activate BCR but can lead to depletion and an arrest of mature B-cell development in vivo. It is not known whether survival signals from excess BAFF can override the suppressive effects of treatment with anti-IgD on mature B cells in vivo. Herein, we examined the effects of co-treatment of BAFF and anti-IgD on the mature B-cell compartment and antibody production in vivo by treating mice with either 1mg/kg BAFF or anti-IgD alone or in combination for 3 consecutive days. We found that co-treatment with anti-IgD significantly abrogated these stimulatory effects of BAFF treatment on splenic CD19+ B cells as well as mature CD19+IgD(hi)IgM+ B cells in vivo. Anti-IgD down-regulated the expression of the BCR complex (mIgM, mIgD and CD19) and the BAFF receptor TACI without regard to the presence of BAFF. Anti-IgD treatment also significantly negated BAFF-induced IgM production in vivo. Both BAFF and anti-IgD could individually stimulate IL-10 synthesis in B cells but did not affect one another. Taken together, our data suggest that activation of BCR with an anti-IgD antibody can override the stimulatory effects from excess BAFF on B cell proliferation and antibody production by down-regulating the expression of BCR complex and BAFF receptors. PMID- 24954639 TI - Allergen-specific regulation of allergic rhinitis in mice by intranasal exposure to IgG1 monoclonal antibody Fab fragments against pathogenic allergen. AB - Fab fragments (Fabs) have the ability to bind to specific antigens but lack the Fc portion for binding to receptors on immune and inflammatory cells that play a critical role in allergic diseases. In the present study, we investigated whether Fabs of an allergen-specific IgG1 monoclonal antibody (mAb) inhibited allergic rhinitis in mice. BALB/c mice sensitized by intraperitoneal injections of ovalbumin (OVA) plus alum on days 0 and 14 were intranasally challenged with OVA on days 28-30, and 35. Fabs prepared by the digestion of an anti-OVA IgG1 mAb (O1 10) with papain were also intranasally administered 15min before each OVA challenge. The results showed that treatment with O1-10 Fabs significantly suppressed the sneezing frequency, associated with decrease of OVA-specific IgE in the serum and infiltration by mast cells in the nasal mucosa seen following the fourth antigenic challenge; additionally, the level of mouse mast cell protease-1, a marker of mast cell activation, in serum was decreased. Furthermore, infiltration of eosinophils and goblet cell hyperplasia in the nasal mucosa at the fourth challenge were inhibited by treatment with O1-10 Fabs. In conclusion, these results suggest that intranasal exposure to Fabs of a pathogenic antigen-specific IgG1 mAb may be effective in regulating allergic rhinitis through allergen capture by Fabs in the nasal mucosa before the interaction of the intact antibody and allergen. PMID- 24954641 TI - A role for migration-linked genes and genomic islands in divergence of a songbird. AB - Next-generation sequencing has made it possible to begin asking questions about the process of divergence at the level of the genome. For example, recently, there has been a debate around the role of 'genomic islands of divergence' (i.e. blocks of outlier loci) in facilitating the process of speciation-with-gene-flow. The Swainson's thrush, Catharus ustulatus, is a migratory songbird with two genetically distinct subspecies that differ in a number of traits known to be involved in reproductive isolation in birds (plumage coloration, song and migratory behaviour), despite contemporary gene flow along a secondary contact zone. Here, we use RAD-PE sequencing to test emerging hypotheses about the process of divergence at the level of the genome and identify genes and gene regions involved in differentiation in this migratory songbird. Our analyses revealed distinct genomic islands on 15 of the 23 chromosomes and an accelerated rate of divergence on the Z chromosome, one of the avian sex chromosomes. Further, an analysis of loci linked to traits known to be involved in reproductive isolation in songbirds showed that genes linked to migration are significantly more differentiated than expected by chance, but that these genes lie primarily outside the genomic islands. Overall, our analysis supports the idea that genes linked to migration play an important role in divergence in migratory songbirds, but we find no compelling evidence that the observed genomic islands are facilitating adaptive divergence in migratory behaviour. PMID- 24954642 TI - The effect of three different head-neck positions on the average EMG activity of three important neck muscles in the horse. AB - The Knowledge of muscle activity in common head-neck positions (HNPs) is a necessary precondition for making judgements on HNPs. The aim of the study was to record the surface electromyography activities of important muscles of the horse's neck in various HNPs. The electrical activities of the m. splenius, brachiocephalicus and trapezius were recorded on both sides. Five horses, both with and without a rider, were examined in all three gaits on both hands in three different HNPs: a 'free' position, a 'gathered' (head higher, neck more flexed) position with the noseline in front of the vertical and a 'hyperflexed' position. Averages of ten consecutive gait cycles in each HNP were evaluated and compared by standard statistical methods. No difference between ridden and unridden horses could be detected. The m. brachiocephalicus was in the hyperflexed position in all gaits significantly (p < 0.01) more active than in the gathered and free position, which were not significantly different. By contrast, the m. splenius was in the hyperflexed position less active than in the free position (p < 0.02), in which it always showed the highest activity. In walking, the muscle activities in the free and gathered positions deviated significantly (p < 0.01). The m. trapezius was in the hyperflexed posture during walking significantly less active than in the free (p < 0.01) and gathered (p < 0.01) positions with the strongest activities in the free position. Again, the free and gathered positions differed significantly (p < 0.01). In trot, the same pattern occured, although the gathered and hyperflexed positions did not differ significantly. In the canter, the activities of the m. trapezius showed no differences between HNPs. In HNPs with the noseline in front of the vertical, the muscles of the topline (m. splenius, m. trapezius) are activated and trained. In the hyperflexed position, however, a major muscle of the lower topline (m. brachiocephalicus) is activated and trained. PMID- 24954643 TI - Timing of developmental events in the early mouse embryo. AB - The timing of developmental events during early mouse development has been investigated in embryos that have been subject to experimental manipulation of cell number and tissue mass. These phenomenological studies revealed that the timing of preimplantation events, such as compaction, formation of blastocyst cavity and lineage allocation is correlated with the rounds of cleavage division or DNA replication of the blastomeres. Timing of postimplantation processes, such as formation of proamniotic cavity and onset of gastrulation is sensitive to cell number and probably the tissue mass, which may be measured by a mechanosensory signaling mechanism. Developmental changes in these two physical attributes are correlated with the cell proliferative activity and the growth trajectory of the whole embryo prior to the transit to organogenesis. During organogenesis, timing of morphogenesis appears to be regulated by individual devices that could be uncoupled during compensatory growth. Insights of the timing mechanism may be gleaned from the analysis of genomic activity associated with the transition through developmental milestones. PMID- 24954640 TI - Data compatibility in the addiction sciences: an examination of measure commonality. AB - The need for comprehensive analysis to compare and combine data across multiple studies in order to validate and extend results is widely recognized. This paper aims to assess the extent of data compatibility in the substance abuse and addiction (SAA) sciences through an examination of measure commonality, defined as the use of similar measures, across grants funded by the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Data were extracted from applications of funded, active grants involving human-subjects research in four scientific areas (epidemiology, prevention, services, and treatment) and six frequently assessed scientific domains. A total of 548 distinct measures were cited across 141 randomly sampled applications. Commonality, as assessed by density (range of 0-1) of shared measurement, was examined. Results showed that commonality was low and varied by domain/area. Commonality was most prominent for (1) diagnostic interviews (structured and semi structured) for substance use disorders and psychopathology (density of 0.88), followed by (2) scales to assess dimensions of substance use problems and disorders (0.70), (3) scales to assess dimensions of affect and psychopathology (0.69), (4) measures of substance use quantity and frequency (0.62), (5) measures of personality traits (0.40), and (6) assessments of cognitive/neurologic ability (0.22). The areas of prevention (density of 0.41) and treatment (0.42) had greater commonality than epidemiology (0.36) and services (0.32). To address the lack of measure commonality, NIDA and its scientific partners recommend and provide common measures for SAA researchers within the PhenX Toolkit. PMID- 24954646 TI - Preparation and characterization of bioactive composites and fibers for dental applications. AB - OBJECTIVES: The present study was carried out to create composites and fibers using polyurethane (PU) with hydroxyapatite (HA) that could be used for dental applications. METHODS: Composites with varying HA concentration were prepared by solution casting technique. Similarly, PU-HA fibers with varying PU hard and soft segments and fixed HA concentration were also prepared. Various characterization techniques, such as, X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy and Fourier transform infrared spectroscopy in conjunction with photo-acoustic sampling cell were employed to study the composites and fibers for changes in their physicochemical properties before and after immersion in artificial saliva at 37 degrees C for up to 5 days. RESULTS: The results indicated formation of amorphous apatite layers with maximum amorphicity in composites containing highest amount of HA with 5 days of immersion in artificial saliva. Similarly, fibers with more PU hard segment resulted in better transformation of crystalline HA to its amorphous state with increasing immersion time thus confirming the bioactive nature of the HA-PU fibers. SIGNIFICANCE: Concentrations of HA and PU hard segment along with the duration of immersion in artificial saliva are two major factors involved in the modification of solid-state properties of HA. The amorphous apatite layer on the surface is known to have tendency to bind with living tissues and hence the use of optimum amount of HA and PU hard segment in composites and fibers, respectively could help in the development of novel dental filling material. PMID- 24954648 TI - Novel tracer method to measure isotopic labeled gas-phase nitrous acid (HO15NO) in biogeochemical studies. AB - Gaseous nitrous acid (HONO), the protonated form of nitrite, contributes up to ~60% to the primary formation of hydroxyl radical (OH), which is a key oxidant in the degradation of most air pollutants. Field measurements and modeling studies indicate a large unknown source of HONO during daytime. Here, we developed a new tracer method based on gas-phase stripping-derivatization coupled to liquid chromatography-mass spectrometry (LC-MS) to measure the 15N relative exceedance, psi(15N), of HONO in the gas-phase. Gaseous HONO is quantitatively collected and transferred to an azo dye, purified by solid phase extraction (SPE), and analyzed using high performance liquid chromatography coupled to mass spectrometry (HPLC MS). In the optimal working range of psi(15N)=0.2-0.5, the relative standard deviation of psi(15N) is <4%. The optimum pH and solvents for extraction by SPE and potential interferences are discussed. The method was applied to measure HO15NO emissions from soil in a dynamic chamber with and without spiking 15) labeled urea. The identification of HO15NO from soil with 15N urea addition confirmed biogenic emissions of HONO from soil. The method enables a new approach of studying the formation pathways of HONO and its role for atmospheric chemistry (e.g., ozone formation) and environmental tracer studies on the formation and conversion of gaseous HONO or aqueous NO2- as part of the biogeochemical nitrogen cycle, e.g., in the investigation of fertilization effects on soil HONO emissions and microbiological conversion of NO2- in the hydrosphere. PMID- 24954647 TI - Antibacterial activity and ion release of bonding agent containing amorphous calcium phosphate nanoparticles. AB - OBJECTIVE: Recurrent caries at the margins is a primary reason for restoration failure. The objectives of this study were to develop bonding agent with the double benefits of antibacterial and remineralizing capabilities, to investigate the effects of NACP filler level and solution pH on Ca and P ion release from adhesive, and to examine the antibacterial and dentin bond properties. METHODS: Nanoparticles of amorphous calcium phosphate (NACP) and a quaternary ammonium monomer (dimethylaminododecyl methacrylate, DMADDM) were synthesized. Scotchbond Multi-Purpose (SBMP) primer and adhesive served as control. DMADDM was incorporated into primer and adhesive at 5% by mass. NACP was incorporated into adhesive at filler mass fractions of 10%, 20%, 30% and 40%. A dental plaque microcosm biofilm model was used to test the antibacterial bonding agents. Calcium (Ca) and phosphate (P) ion releases from the cured adhesive samples were measured vs. filler level and solution pH of 7, 5.5 and 4. RESULTS: Adding 5% DMADDM and 10-40% NACP into bonding agent, and water-aging for 28 days, did not affect dentin bond strength, compared to SBMP control at 1 day (p>0.1). Adding DMADDM into bonding agent substantially decreased the biofilm metabolic activity and lactic acid production. Total microorganisms, total streptococci, and mutans streptococci were greatly reduced for bonding agents containing DMADDM. Increasing NACP filler level from 10% to 40% in adhesive increased the Ca and P ion release by an order of magnitude. Decreasing solution pH from 7 to 4 increased the ion release from adhesive by 6-10 folds. SIGNIFICANCE: Bonding agents containing antibacterial DMADDM and remineralizer NACP were formulated to have Ca and P ion release, which increased with NACP filler level from 10% to 40% in adhesive. NACP adhesive was "smart" and dramatically increased the ion release at cariogenic pH 4, when these ions would be most-needed to inhibit caries. Therefore, bonding agent containing DMADDM and NACP may be promising to inhibit biofilms and remineralize tooth lesions thereby increasing the restoration longevity. PMID- 24954649 TI - Microfluidic-based, live-cell analysis allows assessment of NK-cell migration in response to crosstalk with dendritic cells. AB - Migration and localization of NK cells into peripheral tissues are tightly regulated under normal and pathological conditions. The physiological importance of NK cell-DC crosstalk has been well documented. However, the ways in which DCs regulate the migratory properties of NK cells (such as chemotaxis, chemokinesis, chemo-repulsion) are not fully defined in vitro. Here, we employed a microfluidic platform to examine, at the single-cell level, C57BL/6 NK-cell migrations in a stable chemical gradient. We observed that soluble factors released by the immature and LPS-activated mature DCs induced a high level of chemotactic movement of IL-2-activated NK cells in vitro. We confirmed these findings in a standard trans-well migration assay, and identified CXCR3 as a key receptor on the NK cells that mediated the migration. More interestingly, we revealed a novel function of granulocyte macrophage colony-stimulating factor in repulsing NK-cell migrations. The future uses of such microfluidic device in the systematic evaluations of NK-cell migratory responses in NK cell-DC crosstalk will provide new insights into the development of DC-based NK-cell therapies against tumor and infections. PMID- 24954650 TI - A possible protective role of Nrf2 in preeclampsia. AB - Excess release of reactive oxygen species (ROS) is a major cause of oxidative stress. This disturbance has been implicated as a cause of preeclampsia, a pregnancy-related disorder characterized by hypertension and proteinuria. Increased oxidative stress leads to trophoblast apoptosis/necrosis and alters the balance between pro- and anti-angiogenic factors, resulting in generalized maternal endothelial dysfunction. Trials using antioxidants have significantly failed to improve the condition of, or in any way protect, the mother from the life-threatening complications of this syndrome. Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a potent transcription activator that regulates the expression of a multitude of genes that encode detoxification enzymes and anti oxidative proteins. Recent discussion on evidence of a link between Nrf2 and vascular angiogenic balance has focussed on the downstream target protein, heme oxygenase-1 (HO-1). HO-1 metabolizes heme to biliverdin, iron and carbon monoxide (CO). HO-1/CO protects against hypertensive cardiovascular disease and contributes to the sustained health of the vascular system. In one animal model, sFlt-1 (soluble fms-like tyrosine kinase-1) has induced blood pressure elevation, but the induction of HO-1 attenuated the hypertensive response in the pregnant animals. The special conditions under which Nrf2 participates in the pathogenesis of preeclampsia are still unclear, as is whether Nrf2 attenuates or stimulates the processes involved in this syndrome. In this review, we summarize recent theories about how Nrf2 is involved in the pathogenesis of preeclampsia and present the reasons for considering Nrf2 as a therapeutic target for the treatment of preeclampsia. PMID- 24954651 TI - Salicylato titanocene complexes as cooperative organometallic Lewis acid and Bronsted acid catalysts for three-component mannich reactions. AB - A binary acid system has been developed that features an air-stable organometallic precursor, titanocene dichloride, and simple organic cooperative Bronsted acids, which allowed for mild and highly efficient Mannich reactions of both aryl and alkyl ketones with excellent yields and satisfactory diastereoselectivity. Mechanistic studies, including (1) H NMR titration, X-ray structure analyses as well as isolation of catalytically active species, elucidated the dramatic synergistic effects of this new binary acid system. PMID- 24954652 TI - Uptake of noninvasive prenatal testing at a large academic referral center. AB - OBJECTIVE: Noninvasive prenatal testing (NIPT) is a recently developed risk assessment technique with high sensitivity and specificity for fetal aneuploidy. The effect NIPT has had on traditional screening and diagnostic testing has not been clearly demonstrated. In this study, NIPT uptake and subsequent changes in the utilization of first-trimester screen (FTS), chorionic villus sampling (CVS), and amniocentesis in a single referral center is reported. STUDY DESIGN: Monthly numbers of NIPT (in high-risk patients), FTS, CVS, and amniocentesis were compared between a 35-month baseline period (April 2009 through February 2012) before introduction of NIPT, and the initial 16 months following NIPT introduction divided in 4-month quarters beginning in March 2012 through June 2013. RESULTS: A total of 1265 NIPT, 6637 FTS, 251 CVS, and 1134 amniocentesis were recorded over the 51-month study period in singleton pregnancies of women who desired prenatal screening and diagnostic testing. NIPT became the predominant FTS method by the second quarter following its introduction, increasing by 55.0% over the course of the study period. Total first-trimester risk assessments (NIPT+FTS) were not statistically different following NIPT (P = .312), but average monthly FTS procedures significantly decreased following NIPT introduction, decreasing by 48.7% over the course of the study period. Average monthly CVS and amniocentesis procedures significantly decreased following NIPT introduction, representing a 77.2% and 52.5% decrease in testing, respectively. Screening and testing per 100 morphological ultrasounds followed a similar trend. CONCLUSION: NIPT was quickly adopted by our high-risk patient population, and significantly decreased alternate prenatal screening and diagnostic testing in a short period of time. PMID- 24954654 TI - Prediction of birthweight from third-trimester ultrasound in morbidly obese women. AB - OBJECTIVE: The gestation-adjusted projection method (GAP method) uses third trimester ultrasound fetal weight to predict birthweight. Our study sought to assess if the accuracy of the GAP method in morbidly obese women depended on (1) ultrasound timing or (2) extreme elevations in maternal body mass index (BMI). STUDY DESIGN: We conducted a diagnostic accuracy study from 2007 to 2012 of all singleton pregnancies with BMI >40 kg/m(2) at the time of delivery that had fetal growth assessment between 30+0 and 35+0 weeks (EARLY) and greater than 35+0 weeks (LATE). Next, a 'reference' BMI group (30-35) was compared with subcategories of women with BMI >=40. Paired t tests, chi(2) tests and analysis of variance were used to determine significance. RESULTS: A total of 235 pregnancies for the first objective and 430 for the second objective were included. The mean absolute percent error was comparable between the 2 periods (EARLY 7.9 +/- 6.7%, LATE 7.4 +/- 5.6%; P = .33) and across BMI categories (30-35: 7.6 +/- 6.3%, 40-50: 7.2 +/- 5.7%, >50: 7.8 +/- 6.0%; P = .79). The sensitivity and specificity of the GAP method to predict macrosomia during the EARLY time period was 46% (95% confidence interval 28-66) and 97% (94-99) and in the 40-50 BMI subcategory was 72% (47-90) and 96% (90-99), respectively. CONCLUSION: Prediction of birthweight using the GAP method in obese women does not appear to be influenced by timing of ultrasound or extreme BMI. In a population where clinical estimated fetal weight is difficult, the GAP method may aid in delivery planning. PMID- 24954653 TI - Maternal obesity and gestational diabetes are associated with placental leptin DNA methylation. AB - OBJECTIVE: In this study, we aimed to investigate relationships between maternal prepregnancy obesity and gestational diabetes mellitus and placental leptin DNA methylation. STUDY DESIGN: This study comprises data on 535 mother-infant dyads enrolled in the Rhode Island Child Health Study, a prospective cohort study of healthy term pregnancies. Prepregnancy body mass index was calculated from self reported anthropometric measures and gestational diabetes mellitus diagnoses gathered from inpatient medical records. DNA methylation of the leptin promoter region was assessed in placental tissue collected at birth using quantitative bisulfite pyrosequencing. RESULTS: In a multivariable regression analysis adjusted for confounders, infants exposed to gestational diabetes mellitus had higher placental leptin methylation (beta = 1.89, P = .04), as did those demonstrating prepregnancy obesity (beta = 1.17, P = .06). Using a structural equations model, we observed that gestational diabetes mellitus is a mediator of the effects of prepregnancy obesity on placental leptin DNA methylation (beta = 0.81, 95% confidence interval, 0.27-2.71). CONCLUSION: Our results suggest that the maternal metabolic status before and during pregnancy can alter placental DNA methylation profile at birth and potentially contribute to metabolic programming of obesity and related conditions. PMID- 24954655 TI - The influence of comorbid conditions on racial disparities in endometrial cancer survival. AB - OBJECTIVE: There are known disparities in endometrial cancer survival with black women who experience a greater risk of death compared with white women. The purpose of this investigation was to evaluate the role of comorbid conditions as modifiers of endometrial cancer survival by race. STUDY DESIGN: Two hundred seventy-one black women and 356 white women who had been diagnosed with endometrial cancer from 1990-2005 were identified from a large urban integrated health center. A retrospective chart review was conducted to gather information on comorbid conditions and other known demographic and clinical predictors of survival. RESULTS: Black women experienced a higher hazard of death from any cause (hazard ratio [HR] 1.51; 95% confidence interval [CI], 1.22-1.87) and from endometrial cancer (HR, 2.42; 95% CI, 1.63-3.60). After adjustment for known clinical prognostic factors and comorbid conditions, the hazard of death for black women was elevated but no longer statistically significant for overall survival (HR, 1.22; 95% CI, 0.94-1.57), and the hazard of death from endometrial cancer remained significantly increased (HR, 2.27; 95% CI, 1.39-3.68). Both black and white women with a history of hypertension experienced a lower hazard of death from endometrial cancer (HR, 0.47; 95% CI, 0.23-0.98; and HR, 0.35; 95% CI, 0.19-0.67, respectively). CONCLUSION: The higher prevalence of comorbid conditions among black women does not explain fully the racial disparities that are seen in endometrial cancer survival. The association between hypertension and a lower hazard of death from endometrial cancer is intriguing, and further investigation into the underlying mechanism is needed. PMID- 24954656 TI - Prognostic role and predictors of complete pathologic response to neoadjuvant chemotherapy in primary unresectable ovarian cancer. AB - OBJECTIVE: The objective of the study was to analyze in a large series of unresectable advanced ovarian cancer (AOC) patients the prognostic role of pathological response to neoadjuvant chemotherapy (NACT). STUDY DESIGN: We retrospectively evaluated 322 unresectable AOC patients treated with NACT followed by interval debulking surgery (IDS). Pathological response was classified as follows: complete (cPR) in the absence of residual disease, microscopic (microPR) in the presence of microscopic tumor foci (maximum diameter <=3 mm), and macroscopic (macroPR) when macroscopic residual disease was detected. RESULTS: cPR was observed in 21 (6.5%), microPR in 104 (32.3%), and macroPR in 197 (61.2%) patients. No differences were observed in the distribution of baseline clinicopathological characteristics between the groups. Median progression-free survival was 36 months in cPR, 16 in microPR, and 13 in macroPR (P = .001). Median overall survival was 72 months in cPR, 38 in microPR, and 29 in macroPR (P = .018). The survival differences between microPR and macroPR patients were not confirmed when the analysis included only cases resected to no gross residual disease at IDS. cPR retained the independent prognostic role in the multivariate analysis. International Federation of Gynecology and Obstetrics stage IV was the only negative independent predictor of cPR (chi(2) = 5.362, P = .021). CONCLUSION: cPR is an uncommon event in AOC patients receiving NACT and is associated with a longer progression-free survival and overall survival compared with women showing no cPR, even in patients receiving IDS with no gross residual disease. The proposed classification of pathological response may serve in the next future as an easily assessable and highly valuable prognostic tool in this clinical setting. PMID- 24954657 TI - Reply: To PMID 24679944. PMID- 24954658 TI - Vancomycin dosage for group B streptococcus prophylaxis. PMID- 24954661 TI - Development and evaluation of a real-time fluorogenic loop-mediated isothermal amplification assay integrated on a microfluidic disc chip (on-chip LAMP) for rapid and simultaneous detection of ten pathogenic bacteria in aquatic animals. AB - Rapid, low-cost, and user-friendly strategies are urgently needed for early disease diagnosis and timely treatment, particularly for on-site screening of pathogens in aquaculture. In this study, we successfully developed a real-time fluorogenic loop-mediated isothermal amplification assay integrated on a microfluidic disc chip (on-chip LAMP), which was capable of simultaneously detecting 10 pathogenic bacteria in aquatic animals, i.e., Nocardia seriolae, Pseudomonas putida, Streptococcus iniae, Vibrio alginolyticus, Vibrio anguillarum, Vibrio fluvialis, Vibrio harveyi, Vibrio parahaemolyticus, Vibrio rotiferianus, and Vibrio vulnificus. The assay provided a nearly-automated approach, with only a single pipetting step per chip for sample dispensing. This technique could achieve limits of detection (LOD) ranging from 0.40 to 6.42pg per 1.414MUL reaction in less than 30 min. The robust reproducibility was demonstrated by a little variation among duplications for each bacterium with the coefficient of variation (CV) for time to positive (Tp) value less than 0.10. The clinical sensitivity and specificity of this on-chip LAMP assay in detecting field samples were 96.2% and 93.8% by comparison with conventional microbiological methods. Compared with other well-known techniques, on-chip LAMP assay provides low sample and reagent consumption, ease-of-use, accelerated analysis, multiple bacteria and on-site detection, and high reproducibility, indicating that such a technique would be applicable for on-site detection and routine monitoring of multiple pathogens in aquaculture. PMID- 24954660 TI - Retarded photooxidation of cyamemazine in biomimetic microenvironments. AB - Cyamemazine (CMZ) is a neuroleptic drug that mediates cutaneous phototoxicity in humans. Here, the photobehavior of CMZ has been examined within alpha1 -acid glycoproteins, beta- and gamma-cyclodextrins and SDS micelles. In all these microenvironments, CMZ emission was enhanced and blue-shifted, and its lifetime was longer. Irradiation of the entrapped drug at 355 nm, under air; led to the N,S-dioxide. Within glycoproteins or SDS micelles the reaction was clearly slower than in phosphate buffered solution (PBS); protection by cyclodextrins was less marked. Transient absorption spectroscopy in PBS revealed formation of the triplet state ((3)CMZ*) and the radical cation (CMZ(+*)). Upon addition of glycoprotein, the contribution of CMZ(+*) became negligible, whereas (3)CMZ* dominated the spectra; in addition, the triplet lifetime became considerably longer. In cyclodextrins, this occurred to a lower extent. In all microheterogeneous systems, quenching by oxygen was slower than in solution; this was most remarkable inside glycoproteins. The highest protection from photooxidation was achieved inside SDS micelles. The results are consistent with photooxidation of CMZ through photoionization and subsequent trapping of the resulting radical cation by oxygen. This reaction is extremely sensitive to the medium and constitutes an appropriate probe for localization of the drug within a variety of biological compartments. PMID- 24954663 TI - Oral delivery of paclitaxel nanocrystal (PNC) with a dual Pgp-CYP3A4 inhibitor: preparation, characterization and antitumor activity. AB - Several molecular inheritances have severely restrained the peroral delivery of taxanes. The main objective of the present investigation was to develop a paclitaxel (PTX) formulation which can circumvent the hurdles of its extremely poor solubility and permeability, Pgp efflux and high pre-systemic metabolism. Positively charged PTX nanocrystals of 209 nm were prepared by sonoprecipitation with high pressure homogenization technique, wherein an arginine based surfactant was explored as a stabilizer. The BET surface area analysis revealed that the surface area of PNC was 8.53 m(2)/gm, reflecting significant rise in surface area with nanonization of PTX. The DSC and XRD pattern suggested that the PTX is in the form of the most stable dihydrate crystal. The PNC showed very rapid dissolution profile compared to plain PTX in both sinks and non-sink conditions. Clarithromycin (CLM) was evaluated as a better alternative to cyclosporin A in improving PTX permeability. The PNC-CLM showed remarkable enhancement of 453% in relative bioavailability along with maintaining the therapeutic concentration of PTX for 8h. Efficacy data in B16 F10 melanoma tumor bearing mice showed substantial reduction in tumor volume and improvement in percentage survival compared to the control group. PMID- 24954662 TI - Hybrid liposomal PEGylated calix[4]arene systems as drug delivery platforms for curcumin. AB - The tremendous therapeutic potential of curcumin as a chemopreventive, antineoplastic and chemosensitizing agent has failed to progress towards clinical development and commercialization due to its unfavorable physicochemical properties, low aqueous solubility, chemical instability, and pharmacokinetics. The present contribution is focused on the feasibility of using PEGylated calixarene, in particular polyoxyethylene-derivatized tert-butylcalix[4]arene, to prepare various platforms for delivery of curcumin such as inclusion complex, supramolecular aggregates, and hybrid liposomal systems. The inclusion complex is characterized by UV-vis and FT-IR spectroscopy as well as thermal gravimetrical analysis and differential scanning calorimetry. At concentrations exceeding the critical micellization concentration of PEGylated calixarene, the tremendous solubility enhancement of curcumin is attributed to additional solubilization and hydrophobic non-covalent interactions of the drug with supramolecular aggregates. A hybrid liposomal system is created via encapsulation of the inclusion complex in dipalmitoylphosphatidylcholine:cholesterol liposomes. Bare and liposomal curcumin:BEC-X inclusion complexes, as well as free curcumin were additionally investigated for cytotoxicity and apoptogenic activity against human tumor cell lines. PMID- 24954664 TI - Apical vesicle trafficking takes center stage in neonatal enteropathies. PMID- 24954665 TI - Entrustable professional activities for gastroenterology fellowship training. PMID- 24954659 TI - Maternal serum serpin B7 is associated with early spontaneous preterm birth. AB - OBJECTIVE: We sought to identify serum biomarkers of early spontaneous preterm birth (SPTB) using semiquantitative proteomic analyses. STUDY DESIGN: This was a nested case-control study of pregnant women with previous SPTB. Maternal serum was collected at 19-24 and 28-32 weeks' gestation, and analyzed by liquid chromatography-multiple reaction monitoring/mass spectrometry. Targeted and shotgun proteomics identified 31 candidate proteins that were differentially expressed in pooled serum samples from spontaneous preterm (cases [<34 weeks]) and term (controls) deliveries. Candidate protein expression was compared in individual serum samples between cases and controls matched by age and race groups, and clinical site. Protein expression was verified by Western blot in the placenta and fetal membranes from cases and controls. RESULTS: Serum samples were available for 35 cases and 35 controls at 19-24 weeks, and 16 cases and 16 controls at 28-32 weeks. One protein, serpin B7, yielded serum concentrations that differed between cases and controls. The mean concentration of serpin B7 at 28-32 weeks was 1.5-fold higher in women with subsequent preterm deliveries compared to controls; there was no difference at 19-24 weeks. Higher levels of serpin B7 at both gestational age windows were associated with a shorter interval to delivery, and higher levels of serpin B7 in samples from 28-32 weeks were associated with a lower gestational age at delivery. Western blotting identified serpin B7 protein in placenta, amnion, and chorion from cases and controls. CONCLUSION: Targeted and shotgun serum proteomics analyses associated 1 protein, serpin B7, with early SPTB. Our results require validation in other cohorts and analysis of the possible mechanistic role of serpin B7 in parturition. PMID- 24954666 TI - Hydrophilicity of dentin bonding systems influences in vitro Streptococcus mutans biofilm formation. AB - OBJECTIVE: To evaluate in vitro Streptococcus mutans (S. mutans) biofilm formation on the surface of five light-curing experimental dental bonding systems (DBS) with increasing hydrophilicity. The null hypothesis tested was that resin chemical composition and hydrophilicity does not affect S. mutans biofilm formation. METHODS: Five light-curing versions of experimental resin blends with increasing hydrophilicity were investigated (R1, R2, R3, R4 and R5). R1 and R2 contained ethoxylated BisGMA/TEGDMA or BisGMA/TEGDMA, respectively, and were very hydrophobic, were representative of pit-and-fissure bonding agents. R3 was representative of a typical two-step etch-and-rinse adhesive, while R4 and R5 were very hydrophilic resins analogous to self-etching adhesives. Twenty-eight disks were prepared for each resin blend. After a 24h-incubation at 37 degrees C, a multilayer monospecific biofilm of S. mutans was obtained on the surface of each disk. The adherent biomass was determined using the MTT assay and evaluated morphologically with confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). RESULTS: R2 and R3 surfaces showed the highest biofilm formation while R1 and R4 showed a similar intermediate biofilm formation. R5 was more hydrophilic and acidic and was significantly less colonized than all the other resins. A significant quadratic relationship between biofilm formation and hydrophilicity of the resin blends was found. CLSM and SEM evaluation confirmed MTT assay results. CONCLUSIONS: The null hypothesis was rejected since S. mutans biofilm formation was influenced by hydrophilicity, surface acidity and chemical composition of the experimental resins. Further studies using a bioreactor are needed to confirm the results and clarify the role of the single factors. PMID- 24954668 TI - Utilization behavior after lesions restricted to the frontal cortex. AB - Utilization behavior, which refers to the tendency of patients to use objects presented to them out of context and in the absence of instructions to use them, has been ascribed to dysfunction of the frontal cortex. However, careful examination of the reports of patients presenting utilization behavior shows that these patients had sustained widespread cerebral lesions extending beyond the frontal cortex and often involving massive subcortical damage. The present study examined whether utilization behavior can be observed in patients with lesions restricted to the prefrontal cortex and no more than the immediately subjacent white matter. All patients had surgical excisions, except for three patients in the frontal group who had sustained a cerebrovascular accident. A group of patients with excisions in the temporal lobe and a group of healthy participants were also studied for comparison. The investigation of utilization behavior took place in the context of a broader neuropsychological examination. There was no difference in the presence of utilization behavior in patients with lesions restricted to the prefrontal cortex in comparison with patients with temporal lobe lesions and carefully matched neurologically intact individuals. The results suggest that, in previous studies, the exhibition of utilization behavior by patients with extensive damage to the anterior part of the brain may have been due to damage to subcortical structures or to the prefrontal cortex in conjunction with subcortical damage. PMID- 24954667 TI - Effects of microRNA-30a on migration, invasion and prognosis of hepatocellular carcinoma. AB - The role of microRNA-30a (miR-30a) deregulation in tumor progression and its downstream signaling pathways remain unknown. Here we confirmed significant downregulation of miR-30a in hepatocellular carcinoma (HCC) tissues and cell lines compared with non-tumor counterparts. MiR-30a downregulation was significantly associated with worse disease-free survival (DFS) of HCC patients. Gain- and loss-of-function studies revealed that downregulation of miR-30a facilitated tumor cell migration, invasion and epithelial-mesenchymal transition (EMT). We identified SNAI1 as a direct target of miR-30a and demonstrated miR-30a as a novel regulator of EMT by targeting SNAI1, indicating its potential therapeutic value for reducing invasion and metastasis of HCC. PMID- 24954669 TI - Critical review of NGS analyses for de novo genotyping multigene families. AB - The genotyping of highly polymorphic multigene families across many individuals used to be a particularly challenging task because of methodological limitations associated with traditional approaches. Next-generation sequencing (NGS) can overcome most of these limitations, and it is increasingly being applied in population genetic studies of multigene families. Here, we critically review NGS bioinformatic approaches that have been used to genotype the major histocompatibility complex (MHC) immune genes, and we discuss how the significant advances made in this field are applicable to population genetic studies of gene families. Increasingly, approaches are introduced that apply thresholds of sequencing depth and sequence similarity to separate alleles from methodological artefacts. We explain why these approaches are particularly sensitive to methodological biases by violating fundamental genotyping assumptions. An alternative strategy that utilizes ultra-deep sequencing (hundreds to thousands of sequences per amplicon) to reconstruct genotypes and applies statistical methods on the sequencing depth to separate alleles from artefacts appears to be more robust. Importantly, the 'degree of change' (DOC) method avoids using arbitrary cut-off thresholds by looking for statistical boundaries between the sequencing depth for alleles and artefacts, and hence, it is entirely repeatable across studies. Although the advances made in generating NGS data are still far ahead of our ability to perform reliable processing, analysis and interpretation, the community is developing statistically rigorous protocols that will allow us to address novel questions in evolution, ecology and genetics of multigene families. Future developments in third-generation single molecule sequencing may potentially help overcome problems that still persist in de novo multigene amplicon genotyping when using current second-generation sequencing approaches. PMID- 24954670 TI - Periconceptional undernutrition increases quantity and quality of oocyte population, but not cognitive or emotional response of 60-day-old lambs. AB - Maternal periconceptional undernutrition is associated with altered development and increased risks of adverse outcomes in the offspring. The aim of this work was to determine the effect of periconceptional undernutrition on behavioural and reproductive aspects of the offspring. Fifty ewes were synchronized in oestrus (day 0) and allocated to two groups (n = 25) to be fed diets that provided 1.5 (C) or 0.5 (L) times the requirements for maintenance until day 15. Ewes were mated and fed the control diet from day 16 until lambing. Two months after lambing, 26 lambs were exposed to tests to determine their cognitive/emotional responses. Six ewe lambs were euthanized and in vitro oocyte maturation and fertilization procedures performed. The experimental diets produced no changes of mean live weight (LW) of C ewes, L ewes presenting a reduction in their initial LW with significant differences at day 15, in comparison with C ewes (p < 0.05). L ewes experienced a significant reduction in their body condition (BC) in comparison with C ewes (p < 0.05). Fourteen days after the onset of the experimental diets, mean LW and BC of L ewes was significantly lower than those of C ewes (p < 0.05). Undernourished ewes presented a trend to a reduction of prolificacy and fecundity (p < 0.10) in comparison with C ewes. Emotional and cognitive test revealed a similar response between groups. Ewe lambs from the undernourished ewes presented a population of oocytes 1.7 times higher than ovaries from control ewe lambs (66.0 +/- 0.73 vs. 113.7 +/- 15.6 oocytes; p < 0.05) and had more oocytes in the 'good' (p < 0.05) and 'healthy' (p < 0.05) categories. In conclusion, a low plane of nutrition around conception significantly increases quantity and quality of the oocyte population of 60-day old female descendants. Modifications of the cognitive and emotional responses of the progeny have not been evidenced. PMID- 24954671 TI - Respiratory response to combined heat and hypoxia in the marine bivalves Pecten maximus and Mytilus spp. AB - Coastal ecosystems are increasingly disturbed by the increase of mean sea surface temperature and expansion of hypoxic areas. The objectives of the present work were to describe and compare the respiratory responses to combined heat and hypoxia in two bivalve species (Pecten maximus and Mytilus spp.) living in two contrasted coastal habitats (subtidal and intertidal, respectively). Results were consistent with the vertical zonation of both species. Mytilus spp. seemed to cope better with a temperature increase than P. maximus, which was found to be outside of its optimal thermal window at 25 degrees C. Concerning respiratory responses to hypoxia at a given temperature, P. maximus displayed greater oxyregulation capacity that was maintained over a larger range of O2 levels, as compared to Mytilus spp. When acclimation temperatures increased, both species showed a decrease in their oxyregulation capacities alongside a reduction in aerobic performance, especially in P. maximus. The comparison between species suggests that subtidal species, such as P. maximus, might be more vulnerable to a combination of heat and hypoxia than intertidal species, such as Mytilus spp. Lastly, this study highlighted the utility of segmented linear models to estimate PcO2 and regulation percentages in marine organisms exposed to hypoxia. PMID- 24954672 TI - Monitoring structural dynamics of in situ spray-deposited zinc oxide films for application in dye-sensitized solar cells. AB - The spray-deposition technique is an effective and scalable method to deposit zinc oxide nanostructures, which are used as active layers for dye-sensitized solar cells (DSSCs) in the present study. The dynamics of structural evolution are studied with grazing incidence small-angle X-ray scattering during in situ spraying. Nanostructured films obtained through multiple spray shots provide suitable structural length scales, morphologies, and film thicknesses; this leads to reasonable performance in a DSSC with the highest short-circuit current density reported so far. PMID- 24954673 TI - Imaging insights into basal ganglia function, Parkinson's disease, and dystonia. AB - Recent advances in structural and functional imaging have greatly improved our ability to assess normal functions of the basal ganglia, diagnose parkinsonian syndromes, understand the pathophysiology of parkinsonism and other movement disorders, and detect and monitor disease progression. Radionuclide imaging is the best way to detect and monitor dopamine deficiency, and will probably continue to be the best biomarker for assessment of the effects of disease modifying therapies. However, advances in magnetic resonance enable the separation of patients with Parkinson's disease from healthy controls, and show great promise for differentiation between Parkinson's disease and other akinetic rigid syndromes. Radionuclide imaging is useful to show the dopaminergic basis for both motor and behavioural complications of Parkinson's disease and its treatment, and alterations in non-dopaminergic systems. Both PET and MRI can be used to study patterns of functional connectivity in the brain, which is disrupted in Parkinson's disease and in association with its complications, and in other basal-ganglia disorders such as dystonia, in which an anatomical substrate is not otherwise apparent. Functional imaging is increasingly used to assess underlying pathological processes such as neuroinflammation and abnormal protein deposition. This imaging is another promising approach to assess the effects of treatments designed to slow disease progression. PMID- 24954674 TI - The expanding universe of disorders of the basal ganglia. AB - The basal ganglia were originally thought to be associated purely with motor control. However, dysfunction and pathology of different regions and circuits are now known to give rise to many clinical manifestations beyond the association of basal ganglia dysfunction with movement disorders. Moreover, disorders that were thought to be caused by dysfunction of the basal ganglia only, such as Parkinson's disease and Huntington's disease, have diverse abnormalities distributed not only in the brain but also in the peripheral and autonomic nervous systems; this knowledge poses new questions and challenges. We discuss advances and the unanswered questions, and ways in which progress might be made. PMID- 24954675 TI - Hepatitis B virus infection. AB - Hepatitis B virus infection is a major public health problem worldwide; roughly 30% of the world's population show serological evidence of current or past infection. Hepatitis B virus is a partly double-stranded DNA virus with several serological markers: HBsAg and anti-HBs, HBeAg and anti-HBe, and anti-HBc IgM and IgG. It is transmitted through contact with infected blood and semen. A safe and effective vaccine has been available since 1981, and, although variable, the implementation of universal vaccination in infants has resulted in a sharp decline in prevalence. Hepatitis B virus is not cytopathic; both liver damage and viral control--and therefore clinical outcome--depend on the complex interplay between virus replication and host immune response. Overall, as much as 40% of men and 15% of women with perinatally acquired hepatitis B virus infection will die of liver cirrhosis or hepatocellular carcinoma. In addition to decreasing hepatic inflammation, long-term antiviral treatment can reverse cirrhosis and reduce hepatocellular carcinoma. Development of new therapies that can improve HBsAg clearance and virological cure is warranted. PMID- 24954676 TI - Slowing of neurodegeneration in Parkinson's disease and Huntington's disease: future therapeutic perspectives. AB - Several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease and Huntington's disease. These advances have been informed by both direct analysis of the post mortem brain and by study of the biological consequences of the genetic causes of these diseases. Some of the pathways that have been implicated so far include mitochondrial dysfunction, oxidative stress, kinase pathways, calcium dysregulation, inflammation, protein handling, and prion-like processes. Intriguingly, these pathways seem to be important in the pathogenesis of both diseases and have led to the identification of molecular targets for candidate interventions designed to slow or reverse their course. We review some recent advances that underlie putative therapies for neuroprotection in Parkinson's disease and Huntington's disease, and potential targets that might be exploited in the future. Although we will need to overcome important hurdles, especially in terms of clinical trial design, we propose several target pathways that merit further study. In Parkinson's disease, these targets include agents that might improve mitochondrial function or increase degradation of defective mitochondria, kinase inhibitors, calcium channel blockers, and approaches that interfere with the misfolding, templating, and transmission of alpha-synuclein. In Huntington's disease, strategies might also be directed at mitochondrial bioenergetics and turnover, the prevention of protein dysregulation, disruption of the interaction between huntingtin and p53 or huntingtin-interacting protein 1 to reduce apoptosis, and interference with expression of mutant huntingtin at both the nucleic acid and protein levels. PMID- 24954679 TI - Silicon meets cyclotron: muon spin resonance of organosilicon radicals. AB - Muons, generated at a high-powered cyclotron, can capture electrons to form muonium atoms. Muon spin resonance spectra can be recorded for organosilyl radicals obtained by addition of muonium atoms to silylenes and silenes. We present a brief summary of progress in this new area since the first such experiments were reported in 2008. PMID- 24954677 TI - Effectiveness of (PhSe)2 in protect against the HgCl2 toxicity. AB - This work investigated the preventive effect of diphenyl diselenide [(PhSe)2] on renal and hepatic toxicity biomarkers and oxidative parameters in adult mice exposed to mercury chloride (HgCl2). Selenium (Se) and mercury (Hg) determination was also carried out. Mice received a daily oral dose of (PhSe)2 (5.0mg/kg/day) or canola oil for five consecutive days. During the following five days, the animals were treated with a daily subcutaneous dose of HgCl2 (5.0mg/kg/day) or saline (0.9%). Twenty-four hours after the last HgCl2 administration, the animals were sacrificed and biological material was obtained. Concerning toxicity biomarkers, Hg exposure inhibited blood delta-aminolevulinic acid dehydratase (delta-ALA-D), serum alanine aminotransferase (ALT) activity and also increased serum creatinine levels. (PhSe)2 partially prevented blood delta-ALA-D inhibition and totally prevented the serum creatinine increase. Regarding the oxidative parameters, Hg decreased kidney TBARS levels and increased kidney non-protein thiol levels, while (PhSe)2 pre-treatment partially protected the kidney thiol levels increase. Animals exposed to HgCl2 presented Hg content accumulation in blood, kidney and liver. The (PhSe)2 pre-treatment increased Hg accumulation in kidney and decreased in blood. These results show that (PhSe)2 can be efficient in protecting against these toxic effects presented by this Hg exposure model. PMID- 24954678 TI - Protective effects of selenium against cadmium induced hematological disturbances, immunosuppressive, oxidative stress and hepatorenal damage in rats. AB - Cadmium is a non-essential toxic metal used in industrial process, causes severe risk to human health. Selenium (Se) is an essential trace mineral of fundamental importance for human health. Selenium has antioxidant enzymes roles and is needed for the proper function of the immune system. In this study, the protective effects of selenium against cadmium intoxication in rats have been investigated by monitoring some selective cytokines (IL-1beta, TNF alpha, IL-6, IL-10 and IFN gamma), antioxidant enzymes reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and lipid peroxidation malondialdehyde (MDA) as well as some selective biochemical markers of liver and kidney functions. Thirty-two rats were divided into four equal groups; the first group was used as a control. Groups 2-4 were treated with selenium (Se; 0.1mg/kg BW), cadmium (Cd; 40mg/L drinking water) and selenium plus cadmium, respectively. Rats were orally administered their relevant doses daily for 30 days. Blood samples were collected from heart puncture at the end of the experiment (30 days) for complete blood picture (CBC) and serum was separated to evaluate the different immunological parameters and biochemical parameters, as well as liver specimens for Cd and Se estimation. Rats in the Cd treated group have a significantly higher hepatic concentration of Cd than in other treated groups. Results revealed that cadmium significantly increased IL-1beta, TNF alpha, IL-6 and IL-10, beside peripheral neutrophils count, while the IFN-gamma and lymphocytes were decreased in rat sera. In addition, GSH level, CAT, SOD and GPx activities were significantly decreased while lipid peroxidation (MDA) was increased. Regarding, liver and renal markers, they were significantly increased in the activities of aminotransferases (AST, ALT), urea and creatinine, while total plasma proteins and albumin were significantly decreased. On the other hand, selenium treated group, showed significantly increased IFN-gamma, GSH level, CAT, and GPx activities, as well as lymphocyte count while IL-10 was decreased. Selenium in combination with cadmium, significantly improved the elevation of serum IL-1beta, IL-6, TNF alpha, IL-10 and malondialdehyde in addition to enhancing the antioxidant enzyme activities of GSH, CAT, GPx and SOD. Moreover, selenium has ameliorated the cadmium-induced liver and kidney damage by improving hepatic and renal markers. The results of this investigation demonstrated that selenium has the potential to countermeasure the immunosuppressive as well as hepatic and renal oxidative damage induced by cadmium in rats; selenium has shown promising effects against Cd toxicity. PMID- 24954680 TI - Surgical correction of childhood intermittent exotropia and the risk of developing mental illness. AB - PURPOSE: To assess whether successful surgical intervention for intermittent exotropia, or the timing of intervention, has any effect on the development of mental illness. DESIGN: Retrospective, observational case series. METHODS: All patients (<19 years of age) diagnosed with intermittent exotropia in Olmsted County, Minnesota, from January 1, 1975, through December 31, 1994, were reviewed retrospectively. Potential cases were identified using the resources of the Rochester Epidemiology Project, a medical records database designed to capture data on any patient-physician encounter in Olmsted County, Minnesota. The main outcome measures were the occurrence and severity of mental illness among those who underwent strabismus surgery compared with those who did not. RESULTS: Ninety six (52%) of the 184 children identified were diagnosed with a mental illness at a mean age of 23.3 years (range, 6 to 41 years). Thirty-five (36%) of the 96 children in whom mental illness developed underwent strabismus surgery. Success at surgery (<10 prism diopters) was not associated with a decreased occurrence of mental illness (P = .30). Of the 88 patients in whom mental illness did not develop, strabismus surgery was not more commonly performed (P = .54), nor was it performed at a younger age (P = 1.0), when compared with the 96 patients in whom mental illness developed later. CONCLUSIONS: Strabismus surgery for children with intermittent exotropia, regardless of success or age at surgery, did not alter the development of mental illness by early adulthood. PMID- 24954681 TI - Psychopathy and the ability to read the "language of the eyes": divergence in the psychopathy construct. AB - The capacity to interpret others people's behavior and mental states is a vital part of human social communication. This ability, also called mentalizing or Theory of Mind (ToM), may also serve as a protective factor against aggression and antisocial behavior. This study investigates the relationship between two measures of psychopathy (clinical assessment and self-report) and the ability to identify mental states from photographs of the eye region. The participants in the study were 92 male inmates at Bergen prison, Norway. The results showed some discrepancy in connection to assessment methodology. For the self-report (SRP III), we found an overall negative association between mental state discrimination and psychopathy, while for the clinical instrument (PCL-R) the results were more mixed. For Factor 1 psychopathic traits (interpersonal and affective), we found positive associations with discrimination of neutral mental states, but not with the positive or negative mental states. Factor 2 traits (antisocial lifestyle) were found to be negatively associated with discrimination of mental states. The results from this study demonstrate a heterogeneity in the psychopathic construct where psychopathic traits related to an antisocial and impulsive lifestyle are associated with lower ability to recognize others' mental states, while interpersonal and affective psychopathic traits are associated with a somewhat enhanced ability to recognize others' emotional states. PMID- 24954682 TI - A rapid and enhanced DNA detection method for crop cultivar discrimination. AB - In many crops species, the development of a rapid and precise cultivar discrimination system has been required for plant breeding and patent protection of plant cultivars and agricultural products. Here, we successfully evaluated strawberry cultivars via a novel method, namely, the single tag hybridization (STH) chromatographic printed array strip (PAS) using the PCR products of eight genomic regions. In a previous study, we showed that genotyping of eight genomic regions derived from FaRE1 retrotransposon insertion site enabled to discriminate 32 strawberry cultivars precisely, however, this method required agarose/acrylamide gel electrophoresis, thus has the difficulty for practical application. In contrast, novel DNA detection method in this study has some great advantages over standard DNA detection methods, including agarose/acrylamide gel electrophoresis, because it produces signals for DNA detection with dramatically higher sensitivity in a shorter time without any preparation or staining of a gel. Moreover, this method enables the visualization of multiplex signals simultaneously in a single reaction using several independent amplification products. We expect that this novel method will become a rapid and convenient cultivar screening assay for practical purposes, and will be widely applied to various situations, including laboratory research, and on-site inspection of plant cultivars and agricultural products. PMID- 24954684 TI - Shale gas regulation in the UK and health implications of fracking. PMID- 24954683 TI - Poppers maculopathy. PMID- 24954685 TI - Can current models of accommodation and vergence predict accommodative behavior in myopic children? AB - Investigations into the progression of myopia in children have long considered the role of accommodation as a cause and solution. Myopic children show high levels of accommodative adaptation, coupled with accommodative lag and high response AC/A (accommodative convergence per diopter of accommodation). This pattern differs from that predicted by current models of interaction between accommodation and vergence, where weakened reflex responses and a high AC/A would be associated with a low not high levels of accommodative adaptation. However, studies of young myopes were limited to only part of the accommodative vergence synkinesis and the reciprocal components of vergence adaptation and convergence accommodation were not studied in tandem. Accordingly, we test the hypothesis that the accommodative behavior of myopic children is not predicted by current models and whether that departure is explained by differences in the accommodative plant of the myopic child. Responses to incongruent stimuli (-2D, +2D adds, 10 prism diopter base-out prism) were investigated in 28 myopic and 25 non-myopic children aged 7-15 years. Subjects were divided into phoria groups - exo, ortho and eso based upon their near phoria. The school aged myopes showed high levels of accommodative adaptation but with reduced accommodation and high AC/A. This pattern is not explained by current adult models and could reflect a sluggish gain of the accommodative plant (ciliary muscle and lens), changes in near triad innervation or both. Further, vergence adaptation showed a predictable reciprocal relationship with the high accommodative adaptation, suggesting that departures from adult models were limited to accommodation not vergence behavior. PMID- 24954686 TI - Exogenous application of estradiol to eggs unexpectedly induces male development in two turtle species with temperature-dependent sex determination. AB - Steroid hormones affect sex determination in a variety of vertebrates. The feminizing effects of exposure to estradiol and the masculinizing effects of aromatase inhibition during development are well established in a broad range of vertebrate taxa, but paradoxical findings are occasionally reported. Four independent experiments were conducted on two turtle species with temperature dependent sex determination (Chrysemys picta and Chelydra serpentina) to quantify the effects of egg incubation temperature, estradiol, and an aromatase inhibitor on offspring sex ratios. As expected, the warmer incubation temperatures induced female development and the cooler temperatures produced primarily males. However, application of an aromatase inhibitor had no effect on offspring sex ratios, and exogenous applications of estradiol to eggs produced male offspring across all incubation temperatures. These unexpected results were remarkably consistent across all four experiments and both study species. Elevated concentrations of estradiol could interact with androgen receptors or inhibit aromatase expression, which might result in relatively high testosterone concentrations that lead to testis development. These findings add to a short list of studies that report paradoxical effects of steroid hormones, which addresses the need for a more comprehensive understanding of the role of sex steroids in sexual development. PMID- 24954687 TI - Reprint of "Current perspectives on the androgen 5 alpha-dihydrotestosterone (DHT) and 5 alpha-reductases in teleost fishes and amphibians". AB - The androgen 5 alpha-dihydrotestosterone (DHT) is a steroidogenic metabolite that has received little attention in non-mammalian species. DHT is produced by the reduction of the double-bond of testosterone by a group of enzymes called 5 alpha reductases of which there can be multiple isoforms (i.e., srd5a1, srd5a2, and srd5a3). Data from amphibians suggest that the expression of the srd5a genes occurs in early development, and continues until adulthood; however insufficient data exist in fish species, where DHT is thought to be relatively biologically inactive. Here, we demonstrate that fathead minnow (FHM; Pimephales promelas) developing embryos and adults express srd5a enzyme isoforms. During FHM embryogenesis, both srd5a1 and srd5a3 mRNA levels were significantly correlated in expression levels while srd5a2 showed a more unique pattern of expression. In adult FHMs, males had significantly higher levels of srd5a2 in the liver and gonad compared to females. In the male and female liver, transcript levels for srd5a2 were more abundant compared to srd5a1 and srd5a3, suggesting a prominent role for srd5a2 in this tissue. Interestingly, the ovary expressed higher mRNA levels of srd5a3 than the testis. Thus, data suggest that srd5a isoforms can show sexually dimorphic expression patterns in fish. We also conducted a literature review of the biological effects observed in embryonic and adult fish and amphibians after treatments with DHT and DHT-related compounds. Treatments with DHT in teleost fishes and amphibians have resulted in unexpected biological responses that are characteristic of both androgens and anti-androgens. For example, in fish DHT can induce vitellogenin in vitro from male and female hepatocytes and can increase 17beta-estradiol production from the teleost ovary. We propose, that to generate further understanding of the roles of DHT in non mammals, studies are needed that (1) address how DHT is synthesized within tissues of fish and amphibians; (2) examine the full range of biological responses to endogenous DHT, and its interactions with other signaling pathways; and (3) investigate how DHT production varies with reproductive stage. Lastly, we suggest that the Srd5a enzymes can be targets of endocrine disruptors in fish and frogs, which may result in disruptions in the estrogen:androgen balance in aquatic organisms. PMID- 24954689 TI - Accuracy-rate tradeoffs: how do enzymes meet demands of selectivity and catalytic efficiency? AB - I discuss some physico-chemical and evolutionary aspects of enzyme accuracy (selectivity, specificity) and speed (turnover rate, processivity). Accuracy can be a beneficial side-product of active-sites being refined to proficiently convert a given substrate into one product. However, exclusion of undesirable, non-cognate substrates is also an explicitly evolved trait that may come with a cost. I define two schematic mechanisms. Ground-state discrimination applies to enzymes where selectivity is achieved primarily at the level of substrate binding. Exemplified by DNA methyltransferases and the ribosome, ground-state discrimination imposes strong accuracy-rate tradeoffs. Alternatively, transition state discrimination, applies to relatively small substrates where substrate binding and chemistry are efficiently coupled, and evokes weaker tradeoffs. Overall, the mechanistic, structural and evolutionary basis of enzymatic accuracy rate tradeoffs merits deeper understanding. PMID- 24954688 TI - Inhibition of human drug-metabolising cytochrome P450 and UDP glucuronosyltransferase enzyme activities in vitro by uremic toxins. AB - OBJECTIVE: To investigate the potential inhibitory effects of uremic toxins on the major human hepatic drug-metabolising cytochrome P450 (CYP) and UDP glucuronosyltransferase (UGT) enzymes in vitro. METHODS: Benzyl alcohol, p cresol, indoxyl sulfate, hippuric acid and a combination of the four uremic toxins were co-incubated with human liver microsomes and selective probe substrates for the major human drug-metabolising CYP and UGT enzymes. The percentage of enzyme inhibition was calculated by measuring the rates of probe metabolite formation in the absence and presence of the uremic toxins. Kinetics studies were conducted to evaluate the K i values and mechanism(s) of the inhibition of CYP2E1, CYP3A4, UGT1A1 and UGT1A9 by p-cresol. RESULTS: The individual uremic toxins inhibited CYP and UGT enzymes to a variable extent. p Cresol was the most potent individual inhibitor, producing >50% inhibition of CYP2E1, CYP3A4, UGT1A1, UGT1A9 and UGT2B7 at a concentration of 100 MUM. The greatest inhibition was observed with UGT1A9. p-Cresol was shown to be an uncompetitive inhibitor of UGT1A9, with unbound K i values of 9.1 and 2.5 MUM in the absence and presence of bovine serum albumin (BSA), respectively. K i values for p-cresol inhibition of human liver microsomal CYP2E1, CYP3A4 and UGT1A1 ranged from 43 to 89 MUM. A combination of the four uremic toxins produced >50% decreases in the activities of CYP1A2, CYP2C9, CYP2E1, CYP3A4, UGT1A1, UGT1A9 and UGT2B7. CONCLUSIONS: Uremic toxins may contribute to decreases in drug hepatic clearance in individuals with kidney disease by inhibition of hepatic drug metabolising enzymes. PMID- 24954691 TI - Estrogen receptors regulate the estrous behavior induced by progestins, peptides, and prostaglandin E2. AB - The role of classical estrogen receptors (ERs) in priming female reproductive behavior has been studied previously; however, the participation of this receptor during activation of estrous behavior has not been extensively studied. The purpose of this work was to test the possibility that the facilitation of lordosis behavior in estrogen-primed rats by progesterone (P) and its 5alpha- and 5beta-reduced metabolites, gonadotropin-releasing hormone (GnRH), leptin, prostaglandin E2 (PGE2) and vagino-cervical stimulation (VCS) involves interactions with classical ERs by using the selective ER modulator, tamoxifen. To further assess the role of ERs, we also explored the effects of the pure ER antagonist, ICI182780 (ICI), on estrous behavior induced by P and GnRH. Ovariectomized, estrogen-primed rats (5MUg estradiol benzoate 40h earlier) were injected intraventricularly with the above-mentioned compounds, or they received VCS. All compounds and VCS effectively facilitated estrous behavior when tested at 60, 120 or 240min after infusion or application of VCS. Intraventricular infusion of tamoxifen (5MUg), 30min before, significantly attenuated estrous behaviors induced in estradiol-primed rats by P, most of its 5alpha- and 5beta reduced metabolites, GnRH, and PGE2, but not by VCS. Although there was a trend for reduction, tamoxifen did not significantly decrease lordosis in females treated with 5beta-pregnan-3,20-dione. ICI also inhibited lordosis behavior induced by P and GnRH at some testing intervals. These results suggest that activation of classical ERs participates in the triggering effects on estrous behavior induced by agents with different chemical structures that do not bind directly to ERs. PMID- 24954690 TI - Sexual activity, endogenous reproductive hormones and ovulation in premenopausal women. AB - We investigated whether sexual activity was associated with reproductive function in the BioCycle Study, a prospective cohort study that followed 259 regularly menstruating women aged 18 to 44years for one (n=9) or two (n=250) menstrual cycles in 2005-2007. Women were not attempting pregnancy nor using hormonal contraceptives. History of ever having been sexually active was assessed at baseline and frequency of sexual activity, defined as vaginal-penile intercourse, was self-reported daily throughout the study. Serum concentrations of estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, and testosterone were measured up to 8times/cycle. Sporadic anovulation was identified using peak progesterone concentration. Linear mixed models were used to estimate associations between sexual activity and reproductive hormone concentrations and generalized linear models were used to estimate associations with sporadic anovulation. Models were adjusted for age, race, body mass index, perceived stress, and alcohol consumption and accounted for repeated measures within women. Elevated concentrations of estrogen (+14.6%, P<.01), luteal progesterone (+41.0%, P<.01) and mid-cycle LH (+23.4%, P<.01), but not FSH (P=.33) or testosterone (P=.37), were observed in sexually active women compared with sexually inactive women (no prior and no study-period sexual activity); sexually active women had lower odds of sporadic anovulation (adjusted odds ratio=0.34, 95% confidence interval: 0.16-0.73). Among sexually active women, frequency of sexual activity was not associated with hormones or sporadic anovulation (all P>.23). Findings from our study suggest that ever having been sexually active is associated with improved reproductive function, even after controlling for factors such as age. PMID- 24954692 TI - Prostate cancer biomarker annexin A3 detected in urines obtained following digital rectal examination presents antigenic variability. AB - OBJECTIVES: Annexin A3 (ANXA3) is a potential marker for prostate cancer (PCa). We aimed to develop robust immunoassays suitable for quantifying ANXA3 in urine samples obtained following digital rectal examination (DRE) in order to facilitate the diagnostic performance evaluation of this marker. DESIGN AND METHODS: Anti-ANXA3 monoclonal antibodies were generated and their epitopes mapped. Two different ANXA3 assay prototypes were established on the VIDAS(r) automated immunoanalyser and analytical validation was carried out using post-DRE urine samples obtained from patients with PCa (n=23) or benign prostate hyperplasia (n=31). RESULTS: The assays had the same capture antibody (TGC44) but different detection antibodies (13A12 or 5C5), recognizing novel distinct epitopes. Both had a lower limit of quantification <1ng/mL and were highly specific for ANXA3, not cross-reacting with other annexins. Interassay imprecision was <=11% and <=15% for 13A12 and 5C5 assays, respectively. Surprisingly, a total lack of correlation was observed between ANXA3 levels measured by these two assays in post-DRE urines, indicating detection of distinct antigenic variants. Two freeze-thaw cycles did not affect analyte stability in either assay, whereas a lack of stability of antigenic variants was observed when samples were stored at -80 degrees C for 1month. CONCLUSIONS: Two different antigenic variants of ANXA3 are present in post-DRE urines and their clinical significance for diagnosis of prostate cancer should be further investigated. These variants are not stable over time in samples preserved at -80 degrees C. Until this issue is resolved, ANXA3 should only be measured in freshly collected samples. PMID- 24954694 TI - The impact of providing therapy on the therapist: a student's reflection. AB - Providing psychotherapy changes the therapist in a variety of ways. This article discusses one doctoral student's perceptions of these changes, such as increasing her patience, gratitude, and reliance on faith; stretching her ability to tolerate ambiguity; and influencing her interpersonal relationships. PMID- 24954693 TI - Insights into pathophysiology of dystropy through the analysis of gene networks: an example of bronchial asthma and tuberculosis. AB - Co-existence of bronchial asthma (BA) and tuberculosis (TB) is extremely uncommon (dystropic). We assume that this is caused by the interplay between genes involved into specific pathophysiological pathways that arrest simultaneous manifestation of BA and TB. Identification of common and specific genes may be important to determine the molecular genetic mechanisms leading to rare co occurrence of these diseases and may contribute to the identification of susceptibility genes for each of these dystropic diseases. To address the issue, we propose a new methodological strategy that is based on reconstruction of associative networks that represent molecular relationships between proteins/genes associated with BA and TB, thus facilitating a better understanding of the biological context of antagonistic relationships between the diseases. The results of our study revealed a number of proteins/genes important for the development of both BA and TB. PMID- 24954696 TI - Summary of knowledge gaps related to quality and efficacy of current influenza vaccines. AB - Influenza viruses are a public health threat, as they are pathogenic, highly transmissible and prone to genetic changes. For decades vaccination strategies have been based on trivalent inactivated vaccines, which are regulated by specific guidelines. The progress in scientific knowledge and the lessons learned from the A(H1N1)2009 pandemic have highlighted further the need to improve current guidelines, including the immunogenicity criteria set by the CHMP in 1997, and to promote the discussion on the shortcomings encountered, e.g. the evaluation of vaccine efficacy in the paediatric and elderly populations, the measurement of the naivety of a population, the impact of prior immunity on subsequent vaccinations, and the technical issues with the serological assays for detection of immunity and immunogenicity. The authors attempted to summarise and tackle key gaps in the existing evidence concerning quality and efficacy of influenza vaccines, aiming at favouring a common understanding and a coordinated approach across stakeholders. PMID- 24954697 TI - Response to "Letter to the editor: Angiogenesis factors in cord blood and post natal growth failure: a biochemical evaluation". PMID- 24954695 TI - Pyriproxyfen for mosquito control: female sterilization or horizontal transfer to oviposition substrates by Anopheles gambiae sensu stricto and Culex quinquefasciatus. AB - BACKGROUND: The use of gravid mosquitoes as vehicles to auto-disseminate larvicides was recently demonstrated for the transfer of pyriproxyfen (PPF) by container-breeding Aedes mosquitoes and presents an appealing idea to explore for other disease vectors. The success of this approach depends on the female's behaviour, the time of exposure and the amount of PPF that can be carried by an individual. We explore the effect of PPF exposure at seven time points around blood feeding on individual Anopheles gambiae sensu stricto and Culex quinquefasciatus fecundity and ability to transfer in laboratory assays. METHOD: Mosquitoes were exposed to 2.6 mg PPF per m2 at 48, 24 and 0.5 hours before and after a blood meal and on the day of egg-laying. The proportion of exposed females (N=80-100) laying eggs, the number of eggs laid and hatched was studied. Transfer of PPF to oviposition cups was assessed by introducing 10 late instar insectary-reared An. gambiae s.s. larvae into all the cups and monitored for adult emergence inhibition. RESULTS: Exposure to PPF between 24 hours before and after a blood meal had significant sterilizing effects: females of both species were 6 times less likely (Odds ratio (OR) 0.16, 95% confidence interval (CI) 0.10 0.26) to lay eggs than unexposed females. Of the few eggs laid, the odds of an egg hatching was reduced 17 times (OR 0.06, 95% CI 0.04-0.08) in Anopheles but only 1.2 times (OR 0.82, 95% CI 0.73-0.93) in Culex. Adult emergence inhibition from larvae introduced in the oviposition cups was observed only from cups in which eggs were laid. When females were exposed to PPF close to egg laying they transferred enough PPF to reduce emergence by 65-71% (95% CI 62-74%). CONCLUSION: PPF exposure within a day before and after blood feeding affects egg-development in An. gambiae s.s. and Cx. quinquefasciatus and presents a promising opportunity for integrated control of vectors and nuisance mosquitoes. However, sterilized females are unlikely to visit an oviposition site and therefore do not transfer lethal concentrations of PPF to aquatic habitats. This suggests that for successful auto-dissemination the optimum contamination time is close to oviposition. PMID- 24954698 TI - Angiogenesis factors in cord blood and post-natal growth failure: a biochemical evaluation. PMID- 24954699 TI - Carotid intima-media thickness and calcification in relation to bone mineral density in postmenopausal women-the OSTPRE-BBA study. AB - OBJECTIVES: Atherosclerosis (AS) and osteoporosis are common diseases in elderly people and may be metabolically related. The aim of this cross-sectional population-based study was to explore the association between common carotid artery intima-media thickness (cIMT), carotid artery calcification (CAC), and BMD in postmenopausal women. In addition, the association of postmenopausal hormone therapy (HT) and selected diseases with cIMT and carotid calcification was studied. STUDY DESIGN: The 290 women (mean age 73.6 years) included in this Bone Brain Atherosclerosis study (OSTPRE-BBA) were randomly selected from the population-based Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study cohort, Finland. MAIN OUTCOME MEASURES: For this cross-sectional study, cIMT was measured with B-mode ultrasound; femoral neck and total body BMD were measured with dual-energy X-ray absorptiometry. RESULTS: There were no statistically significant associations between mean cIMT and femoral neck T-score (p>0.05). However, an increased maximum cIMT was significantly associated with low femoral neck T-score. In the osteoporotic group (T-score <-2.5, n=20), the maximum cIMT was 2.51+/-0.88mm (mean+/-SD); in the normal BMD group (T-score >-1, n=122), it was 1.93+/-0.64mm (p=0.001). The odds of having CAC were approximately four-fold higher in the osteoporotic group compared with the group with a normal femoral neck T-score (odds ratio [OR]=4.2, p=0.038). The maximum cIMT was smaller in HT users (1.98+/-0.56mm, n=190) than in non-users (2.16+/-0.74mm, n=156, p=0.036). CONCLUSIONS: The results of our population-based study suggest that BMD is related to AS, at least in carotid arteries. They indirectly support the hypothesis of partially shared pathophysiological mechanisms between these two disorders. PMID- 24954701 TI - Migraine and perimenopause. AB - Perimenopause and migraine are closely linked. The hormonal instability during the perimenopausal period not only causes vasomotor symptoms and mood disturbances, but also increases migraine incidence. Women do report new onset migraine during this period, but the increased incidence is reported by women with menstrually related migraine (MRM). The hormonal fluctuations can be stabilized with hormone replacement therapy (HRT), while simultaneously improving the migraine in some patients. The increased stroke risk in women with migraine with aura (MA) should be taken into consideration when intending to treat perimenopausal women with migraine with HRT. PMID- 24954702 TI - A healthy body habitus is more than just a normal BMI: implications of sarcopenia and sarcopenic obesity. PMID- 24954700 TI - Sex and gender differences in the causes of dementia: a narrative review. AB - This is a narrative review of new ideas and concepts related to differences between men and women in their risk of developing dementia or Alzheimer's disease (AD). We introduce the concept of dimorphic neurology and the distinction between sex and gender. We then provide three examples of risk factors related to sex and gender from the literature. Apolipoprotein E genotype is equally common in men and women but has a stronger effect in women. Apolipoprotein E genotype is a biological factor that cannot be modified but interacts with sex or gender related factors that can be modified. Low education has a similar harmful effect in men and women but has been historically more common in women. Education is a social factor related to gender that can be modified. Finally, bilateral oophorectomy is a factor restricted to women. Bilateral oophorectomy is a surgical practice related to sex that can be modified. Consideration of risk and protective factors in men and women separately may accelerate etiologic research for neurological diseases in general, and for dementia and AD in particular. Similarly, future preventive interventions for dementia should be tailored to men and women separately. PMID- 24954703 TI - Increased ventilation by fish leads to a higher risk of parasitism. AB - BACKGROUND: Fish are common intermediate hosts of trematode cercariae and their gills can potentially serve as important sites of penetration by these larval stages. We experimentally tested the hypothesis that volume of ventilation flow across the gills contributes to acquisition of these parasites by fish. We manipulated the intensity of ventilation by using different oxygen concentrations. METHODS: Juvenile Oncorhynchus mykiss were individually exposed for 10 minutes to a standard dose of Diplostomum pseudospathaceum cercariae at three levels of oxygen concentration, 30, 60 and 90%. Ventilation amplitude (measured as a distance between left and right operculum), operculum beat rate, and the number of cercariae established in the eyes of fish were recorded. RESULTS: Fish reacted to low oxygen concentration with wider expansion of opercula (but not with increasing beat rate), leading to an increase in ventilation volume. As expected, the intensity of infection increased with decreasing oxygen saturation-probably due to a higher exposure to cercariae caused by increased ventilation under low oxygen concentrations. The number of cercariae acquired by an individual fish was positively correlated with ventilation amplitude and with ventilation volume, but not with operculum beat rate. However, even though the infection rate increased under these circumstances, the proportion of larval trematodes successfully establishing in fish eyes decreased with increasing ventilation volume, suggesting that the high flow velocity, although increasing host exposure to cercarial parasites, may interfere with the ability of these parasites to penetrate their hosts. There was no difference in the behaviour of trematode cercariae exposed to low and high oxygen concentrations. CONCLUSION: A reduction in oxygen saturation resulted in an increase in ventilation volume across the gills and in doing so an increase in the exposure of fish to cercariae. A significant correlation between ventilation volume and parasitism represents the first experimental evidence that this physiological mechanism generates variation in transmission of parasites to fish hosts. Other factors that modify ventilation flow, e.g. physiological or social stressors, are expected to produce similar effects on the transmission success of the parasites penetrating fish hosts using the gills. PMID- 24954704 TI - Clinical characteristics and prognostic significance of changes in platelet count in an internal medicine ward. AB - BACKGROUND: The clinical characteristics and prognostic significance of changes in platelet count (PC) during hospitalization in internal medicine wards have not been well investigated. METHODS: Demographic, clinical and laboratory data were collected from 345 patients admitted to an internal medicine ward. Following discharge, all-cause mortality was recorded. These data were compared, according to deltaPC (PC on discharge minus PC on admission): group 1 (drop in PC, deltaPC 50*10(9)/l), group 2 (no significant PC changes, deltaPC up to 50*10(9)/l) and group 3 (rise in PC, deltaPC +50*10(9)/l). RESULTS: Groups 1, 2 and 3 comprised 64 (18.5%), 200 (58%) and 81 (23.5%) patients, respectively. Patients from group 3 were younger, more likely admitted for infection and less likely for cardiovascular disorder, and less often presenting with coronary artery disease, complex nursing care and thrombocytosis on admission or thrombocytopenia on discharge than patients from groups 1 and 2. Mean platelet volume was higher in group 2 on admission and lower in group 3 on discharge. During a median follow-up of 25 months, 146 (42.3%) of 345 patients died. The survival rate was higher for group 3 (65.4%) than for groups 1 (45.3%) and 2 (58.5%), p=0.003. In the entire cohort, each 100*10(9)/l increment of deltaPC was a powerful predictor of lower mortality (p=0.03, relative risk=0.83, 95% confidence interval=0.71-0.98). CONCLUSIONS: Increased PC throughout hospitalization was associated with better prognosis than a drop or blunted rise in PC. The assessment of PC changes in an internal medicine ward may provide useful prognostic information. PMID- 24954706 TI - Production of colourful pigments consisting of amorphous arrays of silica particles. AB - It is desirable to produce colourful pigments that have anti-fading properties and are environmentally friendly. In this Concept, we describe recently developed pigments that exhibit such characteristics. The pigments consist of amorphous arrays of submicron silica particles, and they exhibit saturated and angle independent structural colours. Variously coloured pigments can be produced by changing the size of the particles, and the saturation of the colour can be controlled by incorporating small amounts of black particles. We review a simple analysis that is useful for interpreting the angular independence of the structural colours and discuss the remaining tasks that must be accomplished for the realistic application of these pigments. PMID- 24954705 TI - Infective endocarditis due to multidrug resistant gram-negative bacilli: single centre experience over 5 years. AB - BACKGROUND: Infective endocarditis (IE) due to gram-negative (GN) bacilli is uncommon. Although multi- and extensively-drug resistant (MDR/XDR) GN infections are emerging, very few data are available on IE due to these microrganisms. METHODS: In this study, we describe the clinical characteristics, course and outcome of five contemporary, definite, MDR/XDR GNIE cases seen at our centre. RESULTS: All patients had been admitted to a hospital during the 6months before IE onset, 2 were on hemodialysis and 3 on intravenous medications. Three of the 5 cases were hospital-acquired. Intracardiac prosthetic devices were present in all cases (3 central venous lines, 2 prosthetic heart valves, 2 pacemakers). Mean Charlson comorbidity index was 5.8. Causative pathogens were XDR Pseudomonas aeruginosa (2 cases), XDR Acinetobacter baumannii, MDR Burkolderia cepacia and MDR Escherichia coli (1 case each). Concomitant pathogens with a MDR/XDR phenotype were isolated in 4 patients. Both valves and intracardiac devices and left and right sides of the heart were involved. The rate of complications was high. Antibiotic treatment hinged on the use of colistin, a carbapenem or both. Cardiovascular surgical procedures were performed in 3 patients. Despite aggressive therapeutic regimens, outcomes were poor. Clearance of bacteremia was obtained in 3 patients, in-hospital death occurred in 3 patients, only 1 patient survived during follow up. CONCLUSIONS: MDR/XDR GN are emerging as a cause of IE in carriers of intracardiac prostheses with extensive healthcare contacts and multiple comorbidities. Resistant GNIE has a complicated course and shows a dismal prognosis. PMID- 24954707 TI - Palladium/Carbon dioxide cooperative catalysis for the production of diketone derivatives from carbohydrates. AB - The one-pot production of industrially valuable diketone derivatives from carbohydrates is achieved through a bifunctional catalytic process. In particular, Pd/C-catalyzed hydrogenation of HMF in water and under CO2 affords 1 hydroxypentane-2,5-dione with up to 77% yield. The process is also eligible starting from fructose and inulin, affording 1-hydroxyhexane-2,5-dione with 36% and 15% yield, respectively. The key of the process is reversible in situ formation of carbonic acid, which is capable of assisting Pd/C during the hydrogenation reaction by promoting the dehydration of carbohydrates and the ring opening of furanic intermediates. Interestingly, by changing the reaction medium from H2 O to a H2 O/THF mixture (1:9), it is possible to switch the selectivity of the reaction and to produce 2,5-hexanadione with 83% yield. Within the framework of sustainable chemistry, reactions presented in this report show 100% carbon economy, involve CO2 to generate acidity, require water as a solvent, and are conducted under rather low hydrogen pressures (10 bar). PMID- 24954708 TI - Extracorporeal membrane oxygenation for very high-risk transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) can cause profound haemodynamic perturbation in the peri-operative period. Veno-arterial extracorporeal membrane oxygenation (ECMO) can be used to provide cardiorespiratory support during this time, either prophylactically or emergently. METHOD: 100 TAVI procedures were performed between 2009 and 2013 in our institution. ECMO was used in 11 patients, including eight prophylactic and three rescue cases. Rescue ECMO was required for ventricular fibrillation after valvuloplasty, and aortic annulus rupture. The criteria for prophylactic ECMO included heart failure requiring stabilisation pre-TAVI, haemodynamic instability with balloon aortic valvuloplasty performed to improve heart function pre-TAVI, moderate or severe left and/or right ventricular failure, or borderline haemodynamics at procedure. Differences in preoperative characteristics and postoperative outcomes between ECMO and non-ECMO TAVI patients were compared, and significant results were further assessed controlling for EuroSCORE. RESULTS: Compared to TAVI patients who did not require ECMO, ECMO patients had significantly higher mean EuroSCORE (51 vs. 30%, p<.05). Postoperative outcomes, however, were largely comparable between the two groups. All-cause mortality occurred in nil prophylactic ECMO patients, one rescue ECMO patient, and two non ECMO patients. The difference in mortality between ECMO and non-ECMO patients was not significantly different (9 vs. 2%; p>.05). ECMO patients were more likely to develop acute renal failure than non-ECMO patients (36 vs. 8%, p<.05), which was most likely due to haemodynamic collapse and end-organ dysfunction in patients that required ECMO rescue. CONCLUSIONS: Instituting prophylactic ECMO in selected very high-risk patients may help avoid consequences of intra-operative complications and the need for emergent rescue ECMO. PMID- 24954710 TI - Conservative management of a prosthetic valve thrombosis--report of a successful case. AB - Prosthetic valve thrombosis (PVT) refers to the presence of non infective material in valvular apparatus, interfering with its function. It is a potentially fatal complication of valvular replacement surgery. Treatment options include surgery, fibrinolysis and anticoagulation optimisation. The authors present the case of a young man, carrier of an aortic prosthetic mechanical valve, who didn't take his anticoagulant medicine, admitted for an acute obstructive PVT, with evidence of a large thrombotic mass on the aortic valve (> 1cm(2)). The patient refused surgical treatment and eventually presented a complete resolution of the acute PVT with anticoagulation optimisation. PMID- 24954709 TI - Use of pressure-volume conductance catheters in real-time cardiovascular experimentation. AB - BACKGROUND: Most applications of pressure-volume conductance catheter measurements assess cardiovascular function at a single point in time after genetic, pharmacologic, infectious, nutritional, or toxicologic manipulation. Use of these catheters as a continuous monitor, however, is fraught with complexities and limitations. METHODS: Examples of the limitations and optimal use of conductance catheters as a continuous, real-time monitor of cardiovascular function are demonstrated during inotropic drug infusion in anesthetised rats. RESULTS: Inotropic drug infusion may alter ventricular dimensions causing relative movement of a well-positioned catheter, generating artifacts, including an abrupt pressure rise at end-systole that leads to over estimation of indices of contractility (max dP/dt) and loss of stroke volume signal. Simple rotation of the catheter, echocardiography-guided placement to the centre of the ventricle, or ventricular expansion through crystalloid infusion may correct for these artifacts. Fluid administration, however, alters left ventricular end-diastolic pressure and volume and therefore stroke volume, thereby obscuring continuous real-time haemodynamic measurements. CONCLUSIONS: Pressure-volume artifacts during inotropic infusion are caused by physical contact of the catheter with endocardium. Repeated correction of catheter position may be required to use pressure volume catheters as a continuous real-time monitor during manipulations that alter ventricular dimensions, such as inotropic therapy. PMID- 24954712 TI - [Primary prevention of cardiovascular diseases with statins in patients with diabetes]. PMID- 24954711 TI - Dynamic and quantitative control of the DNA-mediated growth of gold plasmonic nanostructures. AB - Reproducible and controllable growth of nanostructures with well-defined physical and chemical properties is a longstanding problem in nanoscience. A key step to address this issue is to understand their underlying growth mechanism, which is often entangled in the complexity of growth environments and obscured by rapid reaction speeds. Herein, we demonstrate that the evolution of size, surface morphology, and the optical properties of gold plasmonic nanostructures could be quantitatively intercepted by dynamic and stoichiometric control of the DNA mediated growth. By combining synchrotron-based small-angle X-ray scattering (SAXS) with transmission electron microscopy (TEM), we reliably obtained quantitative structural parameters for these fine nanostructures that correlate well with their optical properties as identified by UV/Vis absorption and dark field scattering spectroscopy. Through this comprehensive study, we report a growth mechanism for gold plasmonic nanostructures, and the first semiquantitative revelation of the remarkable interplay between their morphology and unique plasmonic properties. PMID- 24954714 TI - The Italian primary school-size distribution and the city-size: a complex nexus. AB - We characterize the statistical law according to which Italian primary school size distributes. We find that the school-size can be approximated by a log normal distribution, with a fat lower tail that collects a large number of very small schools. The upper tail of the school-size distribution decreases exponentially and the growth rates are distributed with a Laplace PDF. These distributions are similar to those observed for firms and are consistent with a Bose-Einstein preferential attachment process. The body of the distribution features a bimodal shape suggesting some source of heterogeneity in the school organization that we uncover by an in-depth analysis of the relation between schools-size and city-size. We propose a novel cluster methodology and a new spatial interaction approach among schools which outline the variety of policies implemented in Italy. Different regional policies are also discussed shedding lights on the relation between policy and geographical features. PMID- 24954715 TI - Correlations between Berg balance scale and gait speed in individuals with stroke wearing ankle-foot orthoses - a pilot study. AB - PURPOSE: The Berg balance scale (BBS) is commonly used to assess balancing ability in patients with stroke. The BBS may be a good candidate for clinical assessment prior to orthotic intervention, if it correlates well with outcome measures such as gait speed. The purpose of this study was to investigate the correlation between the BBS measured prior to walking with an ankle-foot orthosis (AFO) and specific temporal-spatial parameters of gait when walking with an AFO donned. METHODS: Eight individuals with chronic stroke participated in this study. Balancing ability was assessed using the BBS, while temporal-spatial parameters of gait (gait speed, bilateral step length, stride length and step width) were measured using a three-dimensional motion analysis system. The correlations between the BBS and gait parameters were investigated using a non parametric Kendall's Tau (tau) correlation analysis. RESULTS: The BBS showed correlations with gait speed (tau = 0.64, p < 0.05), the step length of the affected side (tau = 0.74, p < 0.05), and the stride length (tau = 0.64, p < 0.05). CONCLUSIONS: Assessment of the BBS prior to AFO prescription may potentially help clinicians to estimate the gait speed achievable following orthotic intervention in patients with stroke. Implications for Rehabilitation Assessment of the BBS prior to AFO prescription may help orthotists to estimate the gait speed following an orthotic intervention in patients with stroke. Assessment of the BBS prior to AFO prescription may help orthotists to understand overall balance and postural control abilities in patients with stroke. A larger scale multifactorial analysis is warranted to confirm the results of this pilot study. PMID- 24954713 TI - Prefrontal cortical recordings with biomorphic MEAs reveal complex columnar laminar microcircuits for BCI/BMI implementation. AB - The mammalian prefrontal cortex known as the seat of high brain functions uses a six layer distribution of minicolumnar neurons to coordinate the integration of sensory information and the selection of relevant signals for goal driven behavior. To reveal the complex functionality of these columnar microcircuits we employed simultaneous recordings with several configurations of biomorphic microelectrode arrays (MEAs) within cortical layers in adjacent minicolumns, in four nohuman primates (NHPs) performing a delayed match-to-sample (DMS) visual discrimination task. We examined: (1) the functionality of inter-laminar, and inter-columnar interactions between pairs of cells in the same or different minicolumns by use of normalized cross-correlation histograms (CCH), (2) the modulation of glutamate concentration in layer 2/3, and (3) the potential interactions within these microcircuits. The results demonstrate that neurons in both infra-granular and supra-granular layers interact through inter-laminar loops, as well as through intra-laminar to produce behavioral response signals. These results provide new insights into the manner in which prefrontal cortical microcircuitry integrates sensory stimuli used to provide behaviorally relevant signals that may be implemented in brain computer/machine interfaces (BCI/BMIs) during performance of the task. PMID- 24954716 TI - Speech outcome in complete unilateral cleft lip and palate - a comparison of three methods of the hard palate closure. AB - The aim of this study was to compare the speech in subjects with cleft lip and palate, in whom three methods of the hard palate closure were used. One hundred and thirty-seven children (96 boys, 41 girls; mean age = 12 years, SD = 1.2) with complete unilateral cleft lip and palate (CUCLP) operated by a single surgeon with a one-stage method were evaluated. The management of the cleft lip and soft palate was comparable in all subjects; for hard palate repair, three different methods were used: bilateral von Langenbeck closure (b-vL group, n = 39), unilateral von Langenbeck closure (u-vL group, n = 56) and vomerplasty (v-p group, n = 42). Speech was assessed: (i) perceptually for the presence of a) hypernasality, b) compensatory articulations (CAs), c) audible nasal air emissions (ANE) and d) speech intelligibility; (ii) for the presence of compensatory facial grimacing, (iii) with clinical intra-oral evaluation and (iv) with videonasendoscopy. A total rate of hypernasality requiring pharyngoplasty was 5.1%; total incidence post-oral compensatory articulations (CAs) was 2.2%. The overall speech intelligibility was good in 84.7% of cases. Oronasal fistulas (ONFs) occurred in 15.7% b-vL subjects, 7.1% u-vL subjects and 50% v-p subjects (P < 0.001). No statistically significant intergroup differences for hypernasality, CAs and intelligibility were found (P > 0.1). In conclusion, the speech after early one-stage repair of CUCLP was satisfactory. The method of hard palate repair affected the incidence of ONFs, which, however, caused relatively mild and inconsistent speech errors. PMID- 24954717 TI - Differential responses to thermal variation between fitness metrics. AB - Temperature is a major factor affecting population abundance and individual performance. Net reproductive rate (R0) and intrinsic rate of increase (r) differ in their response to different temperature regimes, and much of the difference is mediated by generation time (Tg). Here, we evaluate the effects of thermal mean and variability on R0, r and Tg, at four population densities in Drosophila melanogaster. The results show that R0, r and Tg present differential responses to thermal variation. Although temperature effects on R0 and Tg are non-linear, r response was negligible. R0 and Tg comprise a generational time scale, while r is at a chronological time scale. Thus, we argue that individuals growing under different thermal environments perform similarly on a chronological scale, but differently on a generational scale. PMID- 24954718 TI - How to promote the use of biological monitoring. PMID- 24954719 TI - Myoclonic axial jerks for diagnosing atypical evolution of ataxia telangiectasia. AB - BACKGROUND: Ataxia telangiectasia (A-T) is a common inherited cause of early childhood-onset ataxia, distinguished by progressive cerebellum malfunction, capillary vessel extension, and immunodeficiency. The diagnosis of A-T is sometimes difficult to establish in patients with atypical clinical evolution. CASE REPORT: We experienced a pediatric 12-years-old female patient, who was finally diagnosed with classic A-T, demonstrating progressive dystonic-myoclonic axial jerks with ataxia as a predominant clinical feature. Oculocutaneous telangiectasias and immune status were unremarkable. Her myoclonic jerks were spontaneous or stimulus-sensitive, and partially ameliorated by levodopa treatment, but the ataxia was slowly progressive. A laboratory examination showed moderate atrophy of the vermis and cerebellum on brain magnetic resonance imaging, elevated serum alpha fetoprotein (AFP) levels, and total absence of A-T mutated (ATM) protein activity. We subsequently confirmed compound heterozygous truncating mutations of the ATM gene in this patient. CONCLUSION: Our findings highlight the importance of recognizing dystonic-myoclonic jerks as one of the extrapyramidal signs of classic A-T. Measurement of AFP levels should be considered in patients with unexplained myoclonic jerk movements with ataxia in whom definitive diagnoses are not identified. Physicians should be aware that there are cases where typical findings of A-T may not be fulfilled. PMID- 24954720 TI - Reliability of immunostaining using pan-melanoma cocktail, SOX10, and microphthalmia transcription factor in confirming a diagnosis of melanoma on fine needle aspiration smears. AB - BACKGROUND: Accurate fine-needle aspiration (FNA) diagnosis of metastatic melanoma is of therapeutic and prognostic significance and often requires ancillary studies. To the authors' knowledge, the reliability of immunostaining using a pan-melanoma cocktail, Sry-related HMG-BOX gene 10 (SOX10), and microphthalmia transcription factor (MITF) in confirming a diagnosis of melanoma on FNA smears has not been studied to date. METHODS: This retrospective study included 50 FNA cases with a definitive diagnosis of melanoma. Twenty-nine cases were epithelioid type (group 1), and 21 cases were predominantly spindle cell type with or without an epithelioid component (group 2). Each case was immunostained using pan-melanoma cocktail, SOX10, and MITF. Staining intensity and the percentage of positive cells were recorded. RESULTS: The pan-melanoma cocktail was positive in 43 cases (86%), SOX10 was positive in 50 cases (100%), and MITF in 45 cases (90%). SOX10 and MITF demonstrated nuclear staining with stronger and more diffuse staining with less or no background staining compared with pan-melanoma cocktail, which displayed cytoplasmic staining. For pan melanoma cocktail and SOX10, the detection rates were identical in groups 1 and 2 (86% with pan-melanoma cocktail and 100% with SOX10). For MITF, the detection rate was higher in group 1 compared with Group 2 (93% vs 86%). CONCLUSIONS: In the current study, SOX10 was found to have the highest overall detection rate, followed by MITF and pan-melanoma cocktail. The pan-melanoma cocktail and SOX10 performed equally well for groups 1 and 2, and MITF had a higher detection rate in group 1. Overall, SOX10 and MITF appeared to be superior to the pan-melanoma cocktail and SOX10 seemed better than MITF in confirming a diagnosis of melanoma on FNA smears. PMID- 24954721 TI - Ce3+ sensitized GdPO4:Tb3+ with iron oxide nanoparticles: a potential biphasic system for cancer theranostics. AB - We report a biphasic system (BPS) consisting of PEGylated Tb(3+)-doped GdPO4 nanorice sensitized with Ce(3+) (PEG-NRs) and glutamic acid coated iron oxide nanoparticles (IONPs) with multifunctional capabilities. The mesoporous PEG-NRs exhibit green light luminescence properties and a high degree of aqueous stability. Their drug loading and release capacities were investigated for anti cancer chemo doxorubicin (DOX). Their mesoporous nature and availability of plenty of negatively charged functional groups (-COO(-)) on the surface of PEG NRs facilitate approximately 94 wt% DOX loading. In vitro studies carried out for PEG-NRs and their biphasic integrated system with iron oxide using HeLa and MCF-7 cell lines demonstrated their cell killing efficacy. The green luminescence observed under confocal laser scanning microscopy (CLSM) confirms the cellular uptake of PEG-NRs by HeLa cell lines and their accumulation in the cytoplasm. Approximately 50-55% of HeLa and MCF-7 cell death was observed after 24 h of incubation with DOX loaded BPS (2 mg IONPs and 0.25 mg PEG-NRs + DOX), which further increased to about 90% when exposed to an AC magnetic field (ACMF) for 25 min. Our findings demonstrate that the therapeutic efficacy of BPS loaded with DOX could be a powerful multimodal system for imaging and synergistic chemo thermal cancer therapy. PMID- 24954723 TI - Statistically designed nonionic surfactant vesicles for dermal delivery of itraconazole: characterization and in vivo evaluation using a standardized Tinea pedis infection model. AB - The study aims to statistically develop a hydrogel of itraconazole loaded nonionic surfactant vesicles (NSVs) for circumventing the shortcomings and adverse effects of currently used therapies. Influential factors were screened using first-order Taguchi design, thereafter, optimization was performed via D optimal design involving screened factors (surfactant type, content and molar ratio of cholesterol: surfactant). Response variables investigated were percent drug entrapment, vesicle size, drug skin retention and permeation in 6h. Suspensions of NSVs were gelled to improve topical applicability. Characterization of formulations was performed using vesicle shape, size, surface charge, texture analysis and rheology behavior. Ex vivo studies in rat skin depicted that optimized formulation augmented drug skin retention and permeation in 6h than conventional cream and oily solution of itraconazole. Standardized Tinea pedis model in Wistar rats exhibited in vivo antifungal efficacy of optimized formulation, observed in terms of physical manifestations, fungal burden score and histopathological profiles. Also, a unique investigation involving studying local oxidative stress of infected paw skins as an indicator of fungal infection was performed. Rapid alleviation of infection in animals treated with optimized hydrogel was observed in comparison to commonly prescribed therapies. Therefore, the optimized NSVs may be a promising and efficient alternative to available antifungal therapies. PMID- 24954722 TI - Identification of promiscuous ene-reductase activity by mining structural databases using active site constellations. AB - The exploitation of catalytic promiscuity and the application of de novo design have recently opened the access to novel, non-natural enzymatic activities. Here we describe a structural bioinformatic method for predicting catalytic activities of enzymes based on three-dimensional constellations of functional groups in active sites ('catalophores'). As a proof-of-concept we identify two enzymes with predicted promiscuous ene-reductase activity (reduction of activated C-C double bonds) and compare them with known ene-reductases, that is, members of the Old Yellow Enzyme family. Despite completely different amino acid sequences, overall structures and protein folds, high-resolution crystal structures reveal equivalent binding modes of typical Old Yellow Enzyme substrates and ligands. Biochemical and biocatalytic data show that the two enzymes indeed possess ene reductase activity and reveal an inverted stereopreference compared with Old Yellow Enzymes for some substrates. This method could thus be a tool for the identification of viable starting points for the development and engineering of novel biocatalysts. PMID- 24954724 TI - Microfluidic conceived drug loaded Janus particles in side-by-side capillaries device. AB - A side-by-side capillaries microfluidic device was developed to fabricate drug loaded poly(acrylamide)/poly(methyl acrylate) Janus particles in the range of 59 240 MUm by UV-assisted free radical polymerization. This system was characterized in terms of continuous and dispersed phases flow rates (Qc/Qd), monomer composition of the two compartments, surfactant nature and concentration, outlet tube diameter and UV intensity. These factors were adequately controlled to get different particle shapes ranging from core-shell to bi-compartmental particles. For the latter, a low surfactant concentration (0.75 wt.%) was necessary when the two dispersed phases were pumped at equal flow rate, while at high surfactant concentration, dispersed phases flow rates have to be changed. FTIR analysis suggested complete polymerization of monomers and cytotoxicity test showed these particles were biocompatible having LD 50 of 9 mg/mL. Both ketoprofen and sodium fluorescein were released in sustained release manner at pH 6.8 by following a diffusion type release mechanism. Drug release was faster for bigger particles and found to result from the irregular distribution of the two phases and indentation on bigger particles as revealed by SEM analysis. In comparison, sodium fluorescein release was slower which was attributed to low encapsulation but could be modified by decreasing crosslinker concentration. PMID- 24954725 TI - Effect of liquid crystals with cyclodextrin on the bioavailability of a poorly water-soluble compound, diosgenin, after its oral administration to rats. AB - Diosgenin, found in wild yam (Dioscorea villosa), has been shown to ameliorate diabetes and hyperlipidemia, increase cell proliferation in a human 3D skin model, and inhibits melanin production in B16 melanoma cells. It is also an active element in cosmeceutical and dietary supplements. Although the bioavailability of diosgenin is low due to its poor solubility and intestinal permeability, it was subsequently improved using a beta-cyclodextrin (beta-CD) inclusion complex. Recently liquid crystals (LCs) were shown to enhance the bioavailability of poorly water-soluble drugs. The purpose in the present study was to prepare diosgenin LCs and investigate the interaction between LC and beta CD in order to improve its bioavailability of diosgenin. Crystallinity and particle diameters of LCs in water were determined by small angle X-ray scattering (SAXS) and Zetasizer. Pharmacokinetic parameters were calculated using the plasma content of diosgenin after its oral administration to Wistar rats. Regarding the formation of glyceryl monooleate (GMO) and phytantriol (PHY) LC, SAXS patterns showed the hexagonal and cubic phases, respectively. Bioavailability was significantly enhanced after oral administration of LCs prepared by GMO than after diosgenin alone. The bioavailability was further improved with the combination of LC and beta-CD than LC and water. PMID- 24954726 TI - Near infrared spectroscopic (NIRS) analysis of drug-loading rate and particle size of risperidone microspheres by improved chemometric model. AB - Microspheres have been developed as drug carriers in controlled drug delivery systems for years. In our present study, near infrared spectroscopy (NIRS) is applied to analyze the particle size and drug loading rate in risperidone poly(d,l-lactide-co-glycolide) (PLGA) microspheres. Various batches of risperidone PLGA microspheres were designed and prepared successfully. The particle size and drug-loading rate of all the samples were determined by a laser diffraction particle size analyzer and high performance liquid chromatography (HPLC) system. Monte Carlo algorithm combined with partial least squares (MCPLS) method was applied to identify the outliers and choose the numbers of calibration set. Furthermore, a series of preprocessing methods were performed to remove signal noise in NIR spectra. Moving window PLS and radical basis function neural network (RBFNN) methods were employed to establish calibration model. Our data demonstrated that PLS-developed model was only suitable for drug loading analysis in risperidone PLGA microspheres. Comparatively, RBFNN-based predictive models possess better fitting quality, predictive effect, and stability for both drug loading rate and particle size analysis. The correlation coefficients of calibration set (Rc(2)) were 0.935 and 0.880, respectively. The performance of optimum RBFNN models was confirmed by independent verification test with 15 samples. Collectively, our method is successfully performed to monitor drug loading rate and particle size during risperidone PLGA microspheres preparation. PMID- 24954727 TI - Enantioselective organocatalytic Michael/aldol sequence: anticancer natural product (+)-trans-dihydrolycoricidine. AB - A total synthesis of the anticancer natural product (+)-trans-dihydrolycoricidine is reported from alpha-azidoacetone and cinnamaldehyde precursors. Key elements include an asymmetric organocatalytic sequence proceeding by a regiospecific secondary-amine-catalyzed syn Michael addition followed by an intramolecular aldol reaction. The sequence results in the formation of an advanced intermediate, containing three stereogenic centers, in one step which and was converted into the title compound in eight steps. PMID- 24954728 TI - Silica-encapsulated Gd3+-aggregated gold nanoclusters for in vitro and in vivo multimodal cancer imaging. AB - Gd(3+)-aggregated gold nanoclusters (AuNCs) encapsulated by silica shell (Gd(3+) A-AuNCs@SiO2NPs) were strategically designed and prepared. The as-prepared nanoparticles exhibit aggregation-enhanced fluorescence (AEF), with an intensity that is up to 3.8 times that of discrete AuNCs. The clusters served as novel nanoprobes for in vitro and in vivo multimodal (fluorescence, magnetic resonance, and computed X-ray tomography) cancer imaging. PMID- 24954729 TI - Representations, approximations, and limitations within a computational framework for cognitive science. Comment on "Toward a computational framework for cognitive biology: Unifying approaches from cognitive neuroscience and comparative cognition" by W. Tecumseh Fitch. PMID- 24954730 TI - Why network neuroscience? Compelling evidence and current frontiers. Comment on "Understanding brain networks and brain organization" by Luiz Pessoa. PMID- 24954731 TI - Pest control: a modelling approach. Comment on "Multiscale approach to pest insect monitoring: random walks, pattern formation, synchronization, and networks" by S. Petrovskii, N. Petrovskaya and D. Bearup. PMID- 24954732 TI - Aptamer-functionalized superporous hydrogels for sequestration and release of growth factors regulated via molecular recognition. AB - While the discovery of highly potent biologics has led to the development of promising therapies for various human diseases, biologics can cause severe toxicity if delivered inappropriately. Thus, great efforts have been made to synthesize polymeric systems for safe and efficient delivery of biologics. However, the application of polymeric delivery systems is often limited by problems such as harsh reaction conditions, low drug sequestration efficiency, and difficult drug release regulation. This study was aimed at developing a superporous material system with a hydrogel and an aptamer to overcome these challenges. The results have shown that the superporous hydrogel is capable of instantaneously and fully sequestering a large amount of growth factors, owing to the presence of superporous architectures and aptamers. Moreover, the sequestering and loading procedure does not involve any harsh conditions. The release kinetics of growth factors can be molecularly modulated by either changing the binding affinity of the aptamer or by using a triggering effector. Therefore, this study presents a promising superporous material for the delivery of highly potent biologics such as growth factors for clinical applications. PMID- 24954733 TI - Poly (gamma-glutamic acid) based combination of water-insoluble paclitaxel and TLR7 agonist for chemo-immunotherapy. AB - Advanced anti-cancer regimens are being introduced for more effective cancer treatment with improved life expectancy. In this research, immuno-stimulating agent toll-like receptor-7 (TLR-7) agonist-imiquimod and low dose chemotherapeutic agent-paclitaxel were synergized to demonstrate tumor therapy along with anti-tumor memory effect. Both therapeutic agents being water insoluble were dispersed in water with the help of water soluble polymer: poly (gamma-glutamic acid) (gamma-PGA) using a co-solvent systems leading to formation of micro-dispersions of drugs. Paclitaxel and imiquimod formed crystalline microstructures in the size range of 2-3 MUm and were stably dispersed in gamma PGA matrix for more than 6 months. Paclitaxel and combination of paclitaxel and imiquimod had significant tumor killing effect in-vitro on various tumor cell lines, while antigen presenting cells (dendritic cells-DCs) treated with the same concentration of imiquimod along with the combination led to enhanced proliferation (250%). In DCs, enhanced secretion of pro-inflammatory and Th1 cytokines was observed in cells co-treated with paclitaxel and imiquimod dispersed in gamma-PGA. When administered by intra-tumoral injection in mouse melanoma tumor model, the treatment with combination exemplified drastic inhibition of tumor growth leading to 70% survival as compared to individual components with 0% survival at day 41. The anti-tumor response generated was also found to have systemic memory response since the vaccinated mice significantly deferred secondary tumor development at distant site 6 weeks after treatment. The relative number and activation status of DCs in-vivo was found to be dramatically increased in case of mice treated with combination. The dramatic inhibition of tumor treated with combination is expected to be mediated by both chemotherapeutic killing of tumor cells followed by uptake of released antigen by the DCs and due to enhanced proliferation and activation of the DCs. PMID- 24954735 TI - Brothers with Smith-Lemli-Opitz syndrome. AB - Abnormal cholesterol metabolism is the cause of SLOS, with low cholesterol levels and elevated levels of cholesterol precursors thought to contribute to the clinical findings in this syndrome. Management of SLOS involves early intervention with appropriate therapies for identified disabilities, genetic counseling for families, nutritional consultations, educational interventions, and behavioral management. Although no randomized dietary studies have been conducted, cholesterol supplementation continues to be a common recommendation for persons with SLOS, because it may result in clinical improvement and has few adverse effects (Nowaczyk, 2013). Even with early detection and treatment (e.g., sibling B in this case report), persons with SLOS often have significant behavioral issues and cognitive and developmental delays that require a team approach by parents, educators, specialists, and primary care providers. PMID- 24954734 TI - Extending neurites sense the depth of the underlying topography during neuronal differentiation and contact guidance. AB - The topography of the extracellular microenvironment influences cell morphology, provides conduct guidance and directs cell differentiation. Aspect ratio and dimension of topography have been shown to affect cell behaviours, but the ability and mechanism of depth-sensing is not clearly understood. We showed that murine neural progenitor cells (mNPCs) can sense the depth of the micro-gratings. Neurite elongation, alignment and neuronal differentiation were observed to increase with grating depth. We proposed a mechanism for depth-sensing by growing neurites: filopodial adhesion in the growth cones favour elongation but the bending rigidity of the neurite cytoskeleton resists it. Thus, perpendicular extension on deeper grooves is unfavourable as neurites need to bend over a larger angle. A quantitative model was developed and its prediction of neurite growth on gratings fit well with the experimental data. The results indicated that mNPC fate can be directed by appropriately designed patterned surfaces. PMID- 24954736 TI - A cochlear-bone wave can yield a hearing sensation as well as otoacoustic emission. AB - A hearing sensation arises when the elastic basilar membrane inside the cochlea vibrates. The basilar membrane is typically set into motion through airborne sound that displaces the middle ear and induces a pressure difference across the membrane. A second, alternative pathway exists, however: stimulation of the cochlear bone vibrates the basilar membrane as well. This pathway, referred to as bone conduction, is increasingly used in headphones that bypass the ear canal and the middle ear. Furthermore, otoacoustic emissions, sounds generated inside the cochlea and emitted therefrom, may not involve the usual wave on the basilar membrane, suggesting that additional cochlear structures are involved in their propagation. Here we describe a novel propagation mode within the cochlea that emerges through deformation of the cochlear bone. Through a mathematical and computational approach we demonstrate that this propagation mode can explain bone conduction as well as numerous properties of otoacoustic emissions. PMID- 24954738 TI - Re: Response to Magos et al. PMID- 24954739 TI - Opportunities for certificate of completion of training. PMID- 24954740 TI - para-Nitroblebbistatin, the non-cytotoxic and photostable myosin II inhibitor. AB - Blebbistatin, the best characterized myosin II-inhibitor, is commonly used to study the biological roles of various myosin II isoforms. Despite its popularity, the use of blebbistatin is greatly hindered by its blue-light sensitivity, resulting in phototoxicity and photoconversion of the molecule. Additionally, blebbistatin has serious cytotoxic side effects even in the absence of irradiation, which may easily lead to the misinterpretation of experimental results since the cytotoxicity-derived phenotype could be attributed to the inhibition of the myosin II function. Here we report the synthesis as well as the in vitro and in vivo characterization of a photostable, C15 nitro derivative of blebbistatin with unaffected myosin II inhibitory properties. Importantly, para nitroblebbistatin is neither phototoxic nor cytotoxic, as shown by cellular and animal tests; therefore it can serve as an unrestricted and complete replacement of blebbistatin both in vitro and in vivo. PMID- 24954741 TI - Latent class analysis was accurate but sensitive in data simulations. AB - OBJECTIVES: Latent class methods are increasingly being used in analysis of developmental trajectories. A recent simulation study by Twisk and Hoekstra (2012) suggested caution in use of these methods because they failed to accurately identify developmental patterns that had been artificially imposed on a real data set. This article tests whether existing developmental patterns within the data set used might have obscured the imposed patterns. STUDY DESIGN AND SETTING: Data were simulated to match the latent class pattern in the previous article, but with varying levels of randomly generated variance, rather than variance carried over from a real data set. Latent class analysis (LCA) was then used to see if the latent class structure could be accurately identified. RESULTS: LCA performed very well at identifying the simulated latent class structure, even when the level of variance was similar to that reported in the previous study, although misclassification began to be more problematic with considerably higher levels of variance. CONCLUSION: The failure of LCA to replicate the imposed patterns in the previous study may have been because it was sensitive enough to detect residual patterns of population heterogeneity within the altered data. LCA performs well at classifying developmental trajectories. PMID- 24954742 TI - A facile green antisolvent approach to Cu2+-doped ZnO nanocrystals with visible light-responsive photoactivities. AB - An environmentally benign antisolvent method has been developed to prepare Cu(2+) doped ZnO nanocrystals with controllable dopant concentrations. A room temperature ionic liquid, known as a deep eutectic solvent (DES), was used as the solvent to dissolve ZnO powders. Upon the introduction of the ZnO-containing DES into a bad solvent which shows no solvation to ZnO, ZnO was precipitated and grown due to the dramatic decrease of solubility. By adding Cu(2+) ions to the bad solvent, the growth of ZnO from the antisolvent process was accompanied by Cu(2+) introduction, resulting in the formation of Cu(2+)-doped ZnO nanocrystals. The as-prepared Cu(2+)-doped ZnO showed an additional absorption band in the visible range (400-800 nm), which conduced to an improvement in the overall photon harvesting efficiency. Time-resolved photoluminescence spectra, together with the photovoltage information, suggested that the doped Cu(2+) may otherwise trap photoexcited electrons during the charge transfer process, inevitably depressing the photoconversion efficiency. The photoactivity of Cu(2+)-doped ZnO nanocrystals for photoelectrochemical water oxidation was effectively enhanced in the visible region, which achieved the highest at 2.0 at% of Cu(2+). A further increase in the Cu(2+) concentration however led to a decrease in the photocatalytic performance, which was ascribed to the significant carrier trapping caused by the increased states given by excessive Cu(2+). The photocurrent action spectra illustrated that the enhanced photoactivity of the Cu(2+)-doped ZnO nanocrystals was mainly due to the improved visible photon harvesting achieved by Cu(2+) doping. These results may facilitate the use of transition metal ion-doped ZnO in other photoconversion applications, such as ZnO based dye-sensitized solar cells and magnetism-assisted photocatalytic systems. PMID- 24954744 TI - Assessing environmental support for better health: active living opportunity audits in rural communities in the southern United States. AB - OBJECTIVE: Leisure-time physical activity in the United States is lower rural areas and the South and has been linked to socioeconomic and environmental aspects of where people live. The purpose of this study is to assess the built environment and policies for physical activity in rural communities. METHODS: Eight rural communities in Alabama and Mississippi were assessed in 2011 using the Rural Active Living Assessment (RALA) street segment (SSA), town-wide (TWA), and town program and policies (PPA) assessment tools. Community Health Advisors Trained as Research Partners (CHARPS) and local staff conducted the assessments. The TWA and PPA were scored by domain and total scores. Data were analyzed using descriptive and nonparametric statistics. RESULTS: 117 segments were assessed in 22 towns in 8 counties. Built environmental barriers existed in all communities. Sidewalks were available in only 10-40% of the segments. TWA identified parks and playgrounds as the most available community feature. PPA scores indicated few policies for physical activity outside of school settings with mean scores higher in Mississippi compared to Alabama (61 vs. 49, respectively). CONCLUSIONS: Multiple components of rural communities can be successfully assessed by CHARPs using RALA tools, providing information about resources and barriers for physical activity. PMID- 24954747 TI - Nanosized LiFePO4-decorated emulsion-templated carbon foam for 3D micro batteries: a study of structure and electrochemical performance. AB - In this article, we report a novel 3D composite cathode fabricated from LiFePO4 nanoparticles deposited conformally on emulsion-templated carbon foam by a sol gel method. The carbon foam is synthesized via a facile and scalable method which involves the carbonization of a high internal phase emulsion (polyHIPE) polymer template. Various techniques (XRD, SEM, TEM and electrochemical methods) are used to fully characterize the porous electrode and confirm the distribution and morphology of the cathode active material. The major benefits of the carbon foam used in our work are closely connected with its high surface area and the plenty of space suitable for sequential coating with battery components. After coating with a cathode material (LiFePO4 nanoparticles), the 3D electrode presents a hierarchically structured electrode in which a porous layer of the cathode material is deposited on the rigid and bicontinuous carbon foam. The composite electrodes exhibit impressive cyclability and rate performance at different current densities affirming their importance as viable power sources in miniature devices. Footprint area capacities of 1.72 mA h cm(-2) at 0.1 mA cm(-2) (lowest rate) and 1.1 mA h cm(-2) at 6 mA cm(-2) (highest rate) are obtained when the cells are cycled in the range 2.8 to 4.0 V vs. lithium. PMID- 24954745 TI - Phase II study of bevacizumab in combination with docetaxel and radiation in locally advanced squamous cell carcinoma of the head and neck. AB - BACKGROUND: The purpose of this study was to establish the efficacy and toxicities of concurrent bevacizumab and docetaxel with radiation for locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Patients with previously untreated HNSCC received standard daily radiotherapy (RT) with concurrent weekly docetaxel (20 mg/m(2) ) and biweekly bevacizumab (5 mg/kg). Biweekly bevacizumab was then continued for up to 1 year after RT. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS), patterns of failure, and toxicities of treatment. RESULTS: Thirty patients were recruited. With median follow-up of 38 months, the 3-year PFS, OS, locoregional recurrence-free survival, and distant metastasis-free survival was 61.7%, 68.2%, 84.5%, and 80.5%, respectively. The most common local toxicities were mucositis and dermatitis. Two patients developed hemorrhage. There was no grade 5 toxicity. CONCLUSION: The combination of bevacizumab, docetaxel, and RT is tolerable and effective in HNSCC. This regimen is worthy of further study in appropriate subset of patients receiving chemoradiation therapy. PMID- 24954748 TI - High-resolution habitat mapping on mud fields: new approach to quantitative mapping of Ocean quahog. AB - During 2009-2012 stocks of the bivalve Arctica islandica (Linnaeus, 1767) (Ocean quahog) in Kandalaksha Bay (the White Sea) has been assessed using a side-scan sonar, grab sampling and underwater photo imaging. Structurally uniform localities were highlighted on the basis of side-scan signal. Each type of a signal reflects combination of sediment type, microtopography and structural characteristics of benthic community. The distribution of A. islandica was the predominant factor in determining community structure. Seabed attributes considered most significant were defined for each type of substrate type. Relations of sonar signal and sediment type were used for landscape mapping based on sonar data. Community characteristics at known localities were reliably interpolated to the area of survey using statistical processing of geophysical data. A method of integrated sonar and sampling data interpretation for high resolution mapping of A. islandica by biomass groups, benthic faunal groups and associated habitats was developed. PMID- 24954746 TI - Dynamic protein conformations preferentially drive energy transfer along the active chain of the photosystem II reaction centre. AB - One longstanding puzzle concerning photosystem II, a core component of photosynthesis, is that only one of the two symmetric branches in its reaction centre is active in electron transfer. To investigate the effect of the photosystem II environment on the preferential selection of the energy transfer pathway (a prerequisite for electron transfer), we have constructed an exciton model via extensive molecular dynamics simulations and quantum mechanics/molecular mechanics calculations based on a recent X-ray structure. Our results suggest that it is essential to take into account an ensemble of protein conformations to accurately compute the site energies. We identify the cofactor CLA606 of active chain as the most probable site for the energy excitation. We further pinpoint a number of charged protein residues that collectively lower the CLA606 site energy. Our work provides insights into the understanding of molecular mechanisms of the core machinery of the green-plant photosynthesis. PMID- 24954751 TI - A comparative study of structural patterns and luminescent properties of silver DAFO complexes with carborane- versus "classical"-diphosphanes. AB - New complexes with the DAFO (4,5-diazafluoren-9-one) ligand of stoichiometry [Ag(DAFO)(P-P)]OTf [P-P = dppe, 1,2-bis(diphenylphosphane)ethane; dppp, 1,3 bis(diphenylphosphane)propane; dppph, ortho-bis(diphenylphosphane)benzene; dppcc, 1,2-bis(diphenylphosphane)-1,2-dicarba-closo-dodecaborane; dipcc, 1,2 bis(diisopropylphosphane)-1,2-dicarba-nido-dodecaborane], [Ag(DAFO)(P-P*)] [P-P* = dppnc, 7,8-bis(diphenylphosphane)-7,8-dicarba-nido-undecaborate(-1); dipnc, 7,8 bis(diisopropylphosphane)-7,8-dicarba-closo-undecaborate(-1)] and [Ag(DAFO)(OTf)L] [L = PPh3; dpccMe, 1-diphenylphosphane-2-methyl-1,2-dicarba closo-dodecaborane] are reported. The structures of the complexes depend on the skeleton of the diphosphane. Most of these compounds are luminescent and their emissions seem to have originated from IL (DAFO) transitions, modified upon coordination to silver. PMID- 24954752 TI - Bromocriptine-induced coronary spasm in postpartum. PMID- 24954753 TI - Spectroscopic detection of etoposide binding to chromatin components: the role of histone proteins. AB - Chromatin has been introduced as a main target for most anticancer drugs. Etoposide is known as a topoisomerase II inhibitor, but its effect on chromatin components is unknown. This report, for the first time, describes the effect of etoposide on DNA, histones and DNA-histones complex in the structure of nucleosomes employing thermal denaturation, fluorescence, UV absorbance and circular dichroism spectroscopy techniques. The results showed that the binding of etoposide decreased UV absorbance and fluorescence emission intensity, altered secondary structure of chromatin and hypochromicity was occurred in thermal denaturation profiles. The drug exhibited higher affinity to chromatin compared to DNA. Quenching of drug chromophores with tyrosine residues of histones indicated that globular domain of histones is the site of etoposide binding. Moreover, the binding of etoposide to histones altered their secondary structure accompanied with hypochromicity revealing compaction of histones in the presence of the drug. From the results it is concludes that apart from topoisomerase II, chromatin components especially its protein moiety can be introduced as a new site of etoposide binding and histone proteins especially H1 play a fundamental role in this process and anticancer activity of etoposide. PMID- 24954754 TI - Comparative study between univariate spectrophotometry and multivariate calibration as analytical tools for simultaneous quantitation of Moexipril and Hydrochlorothiazide. AB - Three simple, accurate, reproducible, and selective methods have been developed and subsequently validated for the simultaneous determination of Moexipril (MOX) and Hydrochlorothiazide (HCTZ) in pharmaceutical dosage form. The first method is the new extended ratio subtraction method (EXRSM) coupled to ratio subtraction method (RSM) for determination of both drugs in commercial dosage form. The second and third methods are multivariate calibration which include Principal Component Regression (PCR) and Partial Least Squares (PLSs). A detailed validation of the methods was performed following the ICH guidelines and the standard curves were found to be linear in the range of 10-60 and 2-30 for MOX and HCTZ in EXRSM method, respectively, with well accepted mean correlation coefficient for each analyte. The intra-day and inter-day precision and accuracy results were well within the acceptable limits. PMID- 24954755 TI - Structural investigation of a self-assembled monolayer material 5-[(3 methylphenyl) (phenyl) amino] isophthalic acid for organic light-emitting devices. AB - The molecular structure and vibrations of 5-[(3-methylphenyl) (phenyl) amino] isophthalic acid (MePIFA) were investigated by infrared and Raman spectroscopies, UV-Vis, (1)H and (13)C NMR spectroscopic techniques and NBO analysis. FT-IR, FT Raman and dispersive Raman spectra were recorded in the solid phase. (1)H and (13)C NMR spectra and UV-Vis spectrum were recorded in DMSO solution. HOMO-LUMO analysis and molecular electrostatic potential (MEP) analysis were performed. The theoretical calculations for the molecular structure and spectroscopies were performed with DFT (B3LYP) and 6-311G(d,p) basis set calculations using the Gaussian 09 program. After the geometry of the molecule was optimized, vibration wavenumbers and fundamental vibration wavenumbers were assigned on the basis of the potential energy distribution (PED) of the vibrational modes calculated with VEDA 4 program. The total (TDOS), partial (PDOS) density of state and overlap population density of state (OPDOS) diagrams analysis were made using GaussSum 2.2 program. The results of theoretical calculations for the spectra of the title compound were compared with the observed spectra. PMID- 24954756 TI - Al2O3 influence on structural, elastic, thermal properties of Yb(3+) doped Ba-La tellurite glass: evidence of reduction in self-radiation trapping at 1MUm emission. AB - Ba-La-tellurite glasses doped with Yb(3+) ions have been prepared through melt quenching technique by modifying their composition with the inclusion of varied concentration of Al2O3 to elucidate its effects on glass structural, elastic, thermal properties and Yb(3+) ion NIR luminescence performance. The FTIR spectral analysis indicates Al2O3 addition is promoting the conversion of BOs from NBOs which have been generated during the process of depolymerisation of main glass forming TeO4 units. The elastic properties of the glass revealed an improved rigidity of the glass network on addition of Al2O3. In concurrence to this, differential thermal analysis showed an increase in glass transition temperature with improved thermal stability factor. Also, Yb(3+) fluorescence dynamics demonstrated that, Al2O3 inclusion helps in restraining the detrimental radiation trapping of ~1MUm emission. PMID- 24954757 TI - Overexpression of caspase-1 in aorta of patients with coronary atherosclerosis. AB - OBJECTIVES: Plenty of studies on animals suggest the involvement of caspase-1 in the development of atherosclerosis. The aim of this study was to investigate the changes of caspase-1 in the aorta of patients with coronary atherosclerosis and its association with atherosclerotic risk factors. METHODS: We collected button sized aortic tissues from patients (n = 48) undergoing coronary artery bypass graft (CABG) surgery. Renal arterial tissues from 18 kidney donors without atherosclerosis were taken as control. The expression of caspase-1 was determined by immunohistochemistry, and Gensini score was used to evaluate the severity of coronary atherosclerosis. RESULTS: Caspase-1 was strongly expressed in aortas from CABG patients. Spearman correlation revealed that the aortic caspase-1 expression was significantly correlated with coronary severity scores (r = 0.656, P < 0.05). The relative level of aortic caspase-1 expression was elevated in patients who were smokers or with hypertension or diabetes. The caspase-1 expression was positively correlated with total cholesterol, low density lipoprotein cholesterol, and lipoprotein(a) (P < 0.05); but negatively correlated with high density lipoprotein cholesterol (P < 0.05). CONCLUSIONS: Our findings demonstrate a highly expressed caspase-1 in aortas from patients with coronary atherosclerosis, and that modulation of caspase-1 could be a potential target for prevention and treatment of atherosclerosis. PMID- 24954758 TI - Effects of lipophilic statins for heart failure: a meta-analysis of 13 randomised controlled trials. AB - BACKGROUND: The effects of lipophilic statins in heart failure (HF) were controversial. The goal of the present study was to systematically review all randomised controlled trials evaluating the effects of lipophilic statins in patients with HF. METHODS: We performed a comprehensive literature search to identify eligible trials that prospectively randomised patients with HF to lipophilic statins or control. Primary end points were all-cause mortality, cardiovascular mortality, hospitalisation for worsening HF, left ventricular ejection fraction (LVEF), and low-density lipoprotein cholesterol. Risk ratios (RRs) and Weighted mean differences (WMDs) were calculated using fixed-effects models or random-effects models. RESULTS: A total of 13 randomised trials with 1,532 subjects were included in this analysis. Ten trials randomised patients to atorvastatin, two to simvastatin, and one to pitavastatin. Overall, lipophilic statins significantly decreased all-cause mortality (RR 0.53, P<0.001), cardiovascular mortality (RR 0.66, P=0.04), and hospitalisation for worsening HF (RR 0.60, P<0.001). Subgroup analyses showed that the effects of lipophilic statins in HF were not modified by age, baseline LVEF, and cause of HF. In addition, patients randomised to lipophilic statins had a significant increase in LVEF (WMD 3.91%, P<0.001) and decrease in low-density lipoprotein cholesterol (WMD 0.90 mmol/L, P<0.001). CONCLUSIONS: It appears that further studies are needed to determine if lipophilic statins are beneficial for HF patients. PMID- 24954759 TI - Gold nanoparticle-packed microdisks for multiplex Raman labelling of cells. AB - Micro/nanoparticles containing densely packed gold nanoparticles (AuNPs) possess unique properties potentially useful for various biomedical applications. The micro/nanoparticles are conventionally produced by the bottom-up methods, which have limited capability for controlling the particle size, shape and structure. This article reports development of a top-down method that integrates layer-by layer assembly and microcontact printing to fabricate disk-shaped microparticles named microdisks composed of densely packed AuNPs. This method allows precise control of not only the size, shape and structure of the microdisks but also the amount of the AuNPs in the microdisks. The microdisks can be loaded with different Raman reporters to generate characteristic surface-enhanced Raman scattering spectra under the near infrared excitation over a centimetre-scale lens-sample distance. Moreover, the microdisks can be attached to single live cells. This microdisk platform holds potential for multiplex Raman labelling of therapeutic cells for in vivo tracking of the cells. PMID- 24954760 TI - Verification of the usability of a navigation method in dental implant surgery: in vitro comparison with the stereolithographic surgical guide template method. AB - OBJECTIVE: This study investigates the usefulness of a navigation method using a reference frame directly fixed to the mandible compared to the stereolithographic (STL) surgical guide template method in dental implant surgery. MATERIALS AND METHODS: Twenty rapid prototyping (RP) mandibular models were divided into two groups. Simulation surgery was performed using SimPlant software for both groups. The actual dental implants were placed in the RP models using a real-time navigation system or the surgical guide template, which was fabricated based on STL data by a 3-dimensional printer. Positional implantation errors were measured by comparing the simulation surgery implant positions to the actual postoperative implant positions. RESULTS: The vertical distance error of the top surface area in the first molar region was not significantly different between groups. Otherwise, the implantation method using real-time navigation showed greater errors except for the horizontal and vertical errors in the apical area of the canine region. CONCLUSION: The STL surgical guide template was associated with fewer errors than the real-time navigation method in dental implant surgery. PMID- 24954761 TI - Is prophylactic decompression of the optic canal necessary in surgical correction of fronto-orbital fibrous dysplasia?: a review of 11 consecutive cases. AB - Fronto-orbital fibrous dysplasia is a disease characterized by frontal bossing and orbital dystopia. Simultaneous, prophylactic optic canal decompression remains controversial in the surgical correction of this condition. The authors review a series of 11 patients with fronto-orbital fibrous dysplasia. All patients underwent intracranial malformation excision. Concomitant optic canal decompression was carried out in 6 of 11 cases. Simultaneous reconstruction was carried out using autologous bone in all cases except for 1. Esthetic morphological satisfaction was obtained in all 11 cases. In 2 of 6 cases with optic canal decompression, 1 exhibited half-blindness, and the other exhibited quarter-blindness postoperatively. In 5 cases without decompression, there have been no changes in visual acuity through follow-up ranging from 5 to 22 years. Although therapeutic decompression is well accepted, prophylactic decompression is controversial and the efficacy of prophylactic decompression is questionable. Current strategies should focus on esthetic improvement, with careful observation carried out to assess for optic canal encroachment without prophylactic decompression. PMID- 24954762 TI - Comparison of the effects of mandibular protruding devices on obstructive sleep apnoea patients and healthy volunteers. AB - PURPOSE: To evaluate upper airway diameter differences before and after placement of custom made mandible protruding devices (MPD) in OSAS group and to compare with control group using computerized tomography. METHODS: The OSAS group was composed of 15 patients aged from 25 to 45 years with mild-moderate OSAS and the control group included 15 healthy volunteers, aged from 25 years to 44 years. On coronal and sagittal reformated CT images, anteroposterior (AP) and lateral (LAT) diameters at three levels (passing through soft palate [level 1], 5 mm above uvula [level 2] and 1 cm above the tip of epiglottis [level 3]) were measured before and after MPD placement in both groups. RESULTS: LAT diameters at level 1, level 2 and AP diameter at level 2 in OSAS group were significantly lower than in control group before MPD placement. Only LAT diameters at level 2 in OSAS group were significantly lower than in control group after MPD placement. When we compared upper airway diameters before and after placement of the MPD within each group, statistically significant increase in diameters at all levels were observed. CONCLUSION: MPD is a cheap, easily usable device providing increase in upper airway diameters. PMID- 24954763 TI - Load transfer in Christensen((r)) TMJ in alloplastic total joint replacement for two different mouth apertures. AB - This study analyses load transfer in the fossa component based on two numerical models of total temporomandibular joint (TMJ) implants for two mouth openings. The TMJ articulation is a very complex system with muscles, ligaments and cartilage. Until now, studies of TMJ implants have analysed only condylar behaviour. The finite element models were constructed based on CT scans of a cadaveric mandible and cranium, considering the bone geometry and position. The influence of five principal muscle actions was simulated for two mouth positions, 5 mm and 15 mm openings at the incisive tooth support. Strain distributions into the surrounding bone tissue were analysed in both models in the condyle and fossa components. The results demonstrate that in Christensen((r)) TJR of the temporomandibular joint the fossa component is the more critical part, presenting more stress near the screw holes and contact regions with the cranium. The most critical region is around the first two screws and the least critical is in the condyle component. For the mandible condyle reconstructed with a Christensen((r)) prosthesis, the 15 mm mouth opening was more critical, as compression was increased, but for the fossa component the most critical situation occurred with the 5 mm opening. The micromovements observed suggest that the number of screws could be reduced to increase osteointegration of screws in the mandible condyle. PMID- 24954764 TI - Microsurgical reconstruction of the head and neck--current concepts of maxillofacial surgery in Europe. AB - INTRODUCTION: Microvascular surgery following tumour resection has become an important field of oral maxillofacial surgery (OMFS). This paper aims to evaluate current microsurgical practice in Europe. METHODS: The questionnaire of the DOESAK collaborative group for Microsurgical Reconstruction was translated into English, transformed into an online based survey and distributed to 200 OMFS units with the aid of the European Association for Cranio-Maxillo-Facial Surgery (EACMFS). RESULTS: 65 complete and 72 incomplete questionnaires were returned. Hospitals from the United Kingdom, France, Italy, the Netherlands, Spain, Belgium, Greece, Slovenia and Lithuania participated. 71% of contributing centres were university hospitals, 87% out of these perform microvascular tumour surgery at least on a two-weekly base. Overall complication rate was at around five percent. Most frequently used transplants were the radial forearm flap and the fibular flap. The perioperative management varied widely. Success factors for flap survival, however, were uniformly rated, with the surgical skill being the most important factor, followed by the quality of postoperative management. Medication seems to play a less important role. CONCLUSION: Within Europe microvascular surgery is a common and safe procedure for maxillofacial reconstructive surgery in the field of OMFS. While there is a major accordance for the surgical procedure itself and the most frequently used flaps, perioperative management shows a wide variety of protocols with low presumed impact on surgical outcome. PMID- 24954766 TI - Polymorphisms in the heparanase gene in multiple myeloma association with bone morbidity and survival. AB - OBJECTIVES: In multiple myeloma, heparanase (HSPE) is involved in myeloma cell growth, angiogenesis, osteoclastogenesis and shedding of syndecan-1, a key player in myeloma pathophysiology. Different single nucleotide polymorphisms (SNPs) in the HSPE gene with effect on gene function have been described, and some are associated with haematological malignancies. METHODS: In this study, we evaluated four SNPs rs11099592, rs4364254, rs4693608 and rs6535455 in the HSPE gene in 348 newly diagnosed multiple myeloma patients with focus on bone morbidity (lytic bone disease and vertebral fractures) and outcome after high-dose chemotherapy with stem cell support (HDT). RESULTS: We observed that homozygous carriers of the rs4693608 wild-type A-allele had a higher frequency of vertebral fractures compared to carriers of the variant G-allele, P = 0.02. In multivariate analysis, homozygous carriers of the rs6535455 variant T-allele had a longer survival than homo- and heterozygous carriers of the wild-type C-allele, hazard ratio 0.3 (95% CI 0.1-0.7, P = 0.002). CONCLUSION: The SNPs rs4693608 and rs6535455 in the HSPE gene may influence bone morbidity and outcome in multiple myeloma. Our results are an interesting observation but can be chance findings and need confirmation in studies exploring the functional role of SNPs in the HSPE gene in multiple myeloma. PMID- 24954765 TI - Head and neck teratoma: from diagnosis to treatment. AB - INTRODUCTION: Head and neck teratoma is a rare entity. Its prognosis mostly depends on the risk of neonatal respiratory distress, its extension and potential malignancy. Surgical management must be as complete as possible to avoid recurrences and malignant transformation. The authors present a retrospective analysis of 6 cervicofacial teratomas and a review of the literature. The aim of the study was to analyse prenatal, neonatal and postnatal management of teratoma. MATERIALS AND METHODS: Charts of children presenting with a head and neck teratoma, managed by our maxillofacial and plastic surgery unit, were analysed and antenatal, clinical, biological, radiological and pathological characteristics were collected. Surgical treatment, recurrences and surgical outcomes were analysed. RESULTS: Six patients were included: 2 with a cervical teratoma, 2 with a facial teratoma and 2 with intraoral teratomas. In 2 cases, the lesions were diagnosed antenatally and both patients required neonatal resuscitation. All the patients underwent early surgery, and 3 with complete excisions. All patients with an initial incomplete excision eventually presented a recurrence and therefore second look surgery. No malignant transformation was noted. CONCLUSION: Early prenatal diagnosis is crucial to neonatal care. Early surgery and meticulous follow-up are critical in the long-term favourable outcome. PMID- 24954767 TI - Exploring the influence of Traditional Chinese Medicine on self-care among Chinese cancer patients. AB - PURPOSE: The aim of this study was to explore the influence of traditional Chinese medicine (TCM) on self-care among Chinese cancer patients. METHODS: This was an exploratory qualitative study. A purposive sample of thirty cancer patients who were currently undergoing either chemotherapy or radiotherapy was interviewed. Qualitative content analysis was conducted for data analysis. RESULTS: Two core categories were emerged from their accounts of experiences with practising TCM-supported self-care activities: perceived beneficial effects and concerns about undesirable effects. The perceived beneficial effects of these self-care activities were mainly stemmed from the traditional beliefs in TCM, which included: strengthening the "origin", removing toxins, and mind-soothing. Concerns about undesirable effects of these self-care activities were raised due to lack of knowledge and unpleasant experience with these self-care activities. CONCLUSION: The findings revealed that the philosophy of TCM had been deeply integrated by Chinese cancer patients into their self-care. While Western medicine is the mainstream cancer treatment, Chinese cancer patients also practised various TCM-supported self-care activities. However, they were perplexed about the effects of these self-care activities. They could not ascertain whether the perceived benefits were just due to their own belief in the TCM philosophy, and their lack of knowledge in this aspect and unpleasant experience further confused them. Nurses have to be proactive in identifying the unique health-deviation self-care requisites of their clients in a culturally sensitive manner, explore how their self-care experience affects their wellbeing and treatment compliance, and be prepared to clarify misconceptions about their conditions and progress. PMID- 24954768 TI - Validation of the G8 screening tool in older patients with aggressive haematological malignancies. AB - BACKGROUND: Incidence rates of haematological malignancies increase with age. In these older cancer patients, important information may be missed without a Comprehensive Geriatric Assessment (CGA). A validated screening instrument is needed to identify those patients for whom a CGA would be beneficial. The G8 has recently been validated as a screening tool for older cancer patients in need of a CGA. OBJECTIVES: To test the performance of the G8 screening tool in older patients with aggressive haematological malignancies to identify those who would benefit from a CGA. METHODS: Cross-sectional study of patients >=70 years with a recently diagnosed haematological malignancy. G8, CGA (including six questionnaires) and Cumulative Illness Rating Scale for Geriatrics (CIRS-G) were completed in each patient. The CGA was considered abnormal when at least one questionnaire showed an impaired score. RESULTS: Fifty patients with median age of 76 years were included; 88% (N = 44) had an abnormal CGA. ROC curve analyses revealed a G8 score <=14 obtained a sensitivity of 89% (95% CI 75-96) and a specificity of 100% (95% CI 54-100), suggesting an optimal cut-off point. AUC +/- SE was 0.949 +/- 0.030. Inclusion of comorbidity in the CGA did not change the performance of the G8 (0.943 +/- 0.034; P = 0.895). CONCLUSION: The G8 can be used as a valid screening tool in older patients with aggressive haematological malignancies to identify those patients who would benefit from a CGA. Comorbidity should be assessed routinely and independently of the G8. PMID- 24954769 TI - Prospective analysis of the risk factors for falls in lymphoma patients. AB - PURPOSE: To explore the risk factors for falls in lymphoma patients receiving chemotherapy. METHODS: Lymphoma patients (203) who received chemotherapy were prospectively recruited and analyzed. Eligible participants were followed up by weekly telephone contact for 6 months or until the time of a fall or death. Risk factors for falling in lymphoma patients were identified using univariate regression analysis and multivariate binary logistic regression analysis. RESULTS: Of the 203 cases, 13.3% (27 cases) had a fall during follow-up. Univariate regression analysis showed the following risk factors for falls in lymphoma patients: gender (P = 0.023), Eastern Cooperative Oncology Group (ECOG) performance status score (P < 0.0001), cancer stage (P < 0.0001), extranodal involvement (P = 0.041), serum lactate dehydrogenase (LDH) level (P < 0.0001), revised International Prognostic Index (R-IPI) (P < 0.0001), history of falls (P < 0.0001), gait (P < 0.0001), cognitive condition (P = 0.029) and intravenous catheter placement (P < 0.0001). Multivariate binary logistic regression analysis found four independent factors significantly associated with the risk of falling in lymphoma patients: female gender (P = 0.042), later stage (P = 0.021), R-IPI (P = 0.030), and intravenous catheter placement (P = 0.001). CONCLUSIONS: Gender, stage, R-IPI, and intravenous catheter placement were independent risk factors for falls in patients with lymphoma. Lymphoma patients with these four risk factors should receive particular attention and fall prevention education to reduce the incidence of falls. The R-IPI may be a new predictor of falling in lymphoma patients and may aid in the management of falls. PMID- 24954770 TI - Patients' perceptions of how healthcare providers communicate with them and their families following a diagnosis of colorectal cancer and undergoing chemotherapy treatment. AB - PURPOSE: Chemotherapy can result in many unpredictable and often debilitating side-effects hence patients undergoing chemotherapy treatment may have to rely on their loved ones to support them through this most challenging period. In view of this possibility then good communication skills between patients, healthcare providers and family members is of paramount importance for effective patient outcomes. The aim of this study therefore, was to explore patients' perceptions of how healthcare providers communicate with them and their family members whilst undergoing chemotherapy treatment for cancer. METHODS: Using a qualitative methodology and a descriptive design, data were collected using unstructured interviews with patients undergoing chemotherapy (n = 14) and analysed by content analysis. RESULTS: Participants expressed that both they and their family members were treated with compassion, kindness, empathy and understanding. They appreciated the time given to them and their family members to listen and answer their questions before, during and/or after treatment. In addition they commented positively on the warm and cheerful environment and the selective use of appropriate humour by oncology healthcare providers in the chemotherapy units. CONCLUSION: The data highlights in particular the positive communication encounters between patients with cancer and their healthcare providers and family members. Oncology nurses were identified as being particularly supportive to both patients and their family members. Despite chemotherapy units being a difficult place to be a part of, this study highlights that healthcare providers can help make this a less daunting place for patients and their family members through their appropriate use of professional communication. PMID- 24954771 TI - Salting-out-assisted liquid-liquid extraction with acetonitrile for the determination of trimetazidine in rat plasma using liquid chromatography-mass spectrometry. AB - A high-throughout bioanalytical method based on salting-out-assisted liquid/liquid extraction (SALLE) method with acetonitrile and mass spectrometry compatible salts followed by LC-MS/MS analysis of trimetazidine in rat plasma is presented. It required only 50 MUL of plasma and allows the use of minimal volumes of organic solvents. The seamless interface of SALLE and LC-MS eliminated the drying-down step and the extract was diluted and injected into an LC-MS/MS system with a cycle time of 2.5 min/sample. The retention times of trimetazidine and IS were approximately 1.1 and 1.7 min, respectively. Calibration curves were linear over the concentration range of 0.1-100 ng/mL, which can be extended to 500 ng/mL by dilution. The intra- and inter-batch precision, accuracy and the relative standard deviation were all <15%. This method was successfully applied to determine trimetazidine concentrations in rat plasma. PMID- 24954772 TI - Using zebrafish to uncover the genetic and neural basis of aggression, a frequent comorbid symptom of psychiatric disorders. AB - Aggression is an important adaptive behavior that can be used to monopolize resources such as mates or food, acquire and defend territory and establish dominant hierarchies in social groups. It is also a symptom of several psychiatric disorders including attention-deficit/hyperactivity disorder and schizophrenia. The frequent comorbidity of aggression and psychiatric diseases suggests that common genes and neural circuits may link these disorders. Research using animal models has the potential to uncover these genes and neural circuits despite the difficulty of fully modeling human behavioral disorders. In this review we propose that zebrafish may be a suitable model organism for aggression research with the potential to shed light upon the aggressive symptoms of human diseases. PMID- 24954773 TI - Introduction: circadian rhythm and its disruption: impact on reproductive function. AB - Almost all forms of life have predictable daily or circadian rhythms in molecular, endocrine, and behavioral functions. In mammals, a central pacemaker located in the suprachiasmatic nuclei coordinates the timing of these rhythms. Daily light exposure that affects the retina of the eye directly influences this area, which is required to align endogenous processes to the appropriate time of day. The present "Views and Reviews" articles discuss the influence of circadian rhythms, especially nightly secretion of melatonin, on reproductive function and parturition. In addition, an examination is made of problems that arise from recurrent circadian rhythm disruption associated with changes in light exposure patterns common to modern day society. Finally, a possible solution to prevent disruptions in circadian phase markers by filtering out short wavelengths from nocturnal light is reviewed. PMID- 24954774 TI - Who will benefit from uterus-sparing surgery in adenomyosis-associated subfertility? AB - OBJECTIVE: To analyze the determinants of successful pregnancy following laparoscopic adenomyomectomy. DESIGN: Retrospective cohort study. SETTING: A general hospital. PATIENT(S): A total of 102 women who had a desire for pregnancy underwent laparoscopic adenomyomectomy from 2007 to 2012. INTERVENTION(S): Surgical excision of the uterine adenomyosis; statistical analysis for fertility outcomes. MAIN OUTCOME MEASURE(S): Pregnancy rates and the results of univariable and multivariable analyses. RESULT(S): When the women were divided into <=39 years and >=40 years age groups, clinical pregnancy rates were 41.3% and 3.7%, respectively. Factors associated with clinical pregnancy were: history of IVF treatments, posterior wall involvements, and age, with odds ratios of 6.22, 0.18, and 0.77, respectively. In the younger group, 60.8% of women with history of IVF failure showed successful pregnancy after surgery. We experienced 2 cases of placenta accreta in far advanced cases. CONCLUSION(S): This study demonstrated age as a determinant in fertility outcomes. Surgery could be a beneficial treatment for women who experienced IVF treatment failures, especially at ages of <=39 years. We could not show a clear benefit of the surgery on fertility outcomes of the group aged >=40 years. Extremely severe adenomyosis affecting a broad range of the uterine subendomerial myometrium should be treated carefully on a pregnancy course. PMID- 24954775 TI - Revised minimum standards for practices offering assisted reproductive technologies: a committee opinion. AB - This document is designed to assist assisted reproductive technology (ART) programs in establishing and maintaining a successful clinical practice and set criteria that meet or exceed the requirements suggested by the Centers for Disease Control and Prevention (CDC) for certification of ART laboratories. This document replaces the document of the same name last published in 2008 (Fertil Steril 2008;90:S165-8). PMID- 24954776 TI - Maternal and neonatal outcomes after gonadotropin-releasing hormone agonist trigger for final oocyte maturation in patients undergoing in vitro fertilization. AB - OBJECTIVE: To compare the rate of congenital anomalies, obstetrical complications, and neonatal complications in antagonist cycles where either GnRH agonist (GnRHa) or hCG was used for final oocyte maturation. DESIGN: Retrospective cohort study. SETTING: University-based tertiary fertility center. PATIENT(S): Three hundred ninety-two women under 40 years of age who underwent controlled ovarian stimulation using a GnRH antagonist protocol and who had final oocyte maturation triggered with either a GnRHa or hCG that resulted in pregnancy and delivery after 16 weeks' gestation. INTERVENTION(S): GnRHa versus hCG trigger of final oocyte maturation. MAIN OUTCOME MEASURE(S): Congenital anomaly rates, obstetrical complications, and neonatal complications. RESULT(S): There were no significant differences in the rate of congenital anomalies between GnRHa and hCG trigger (6.6 vs. 9.2%). There were also no differences in the maternal complications (27.6 vs. 20.8%) or neonatal complications (19.7 vs. 20.0%) between the GnRHa trigger and hCG trigger groups. CONCLUSION(S): GnRHa trigger does not affect the rate of congenital anomalies or obstetrical or neonatal complications and remains a viable option in the prevention of ovarian hyperstimulation syndrome. PMID- 24954777 TI - Sir John Gurdon: father of nuclear reprogramming. AB - Sir John Gurdon founded the field of nuclear reprogramming. His work set the stage for the ever burgeoning area of stem cell biology and regenerative medicine. Here I provide personal reflections on times I shared with John Gurdon and professional reflections of the impact of his ground-breaking research on my own development as a scientist and on the field in general. His paradigm-shifting experiments will continue to provoke scientists to think outside the box for many years to come. PMID- 24954779 TI - Chemoimmunotherapy: still waiting for the magic to happen. PMID- 24954780 TI - How safe is a standard-risk child with ALL? PMID- 24954778 TI - Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort. AB - BACKGROUND: Treatment of patients with paediatric acute lymphoblastic leukaemia has evolved such that the risk of late effects in survivors treated in accordance with contemporary protocols could be different from that noted in those treated decades ago. We aimed to estimate the risk of late effects in children with standard-risk acute lymphoblastic leukaemia treated with contemporary protocols. METHODS: We used data from similarly treated members of the Childhood Cancer Survivor Study cohort. The Childhood Cancer Survivor Study is a multicentre, North American study of 5-year survivors of childhood cancer diagnosed between 1970 and 1986. We included cohort members if they were aged 1.0-9.9 years at the time of diagnosis of acute lymphoblastic leukaemia and had received treatment consistent with contemporary standard-risk protocols for acute lymphoblastic leukaemia. We calculated mortality rates and standardised mortality ratios, stratified by sex and survival time, after diagnosis of acute lymphoblastic leukaemia. We calculated standardised incidence ratios and absolute excess risk for subsequent neoplasms with age-specific, sex-specific, and calendar-year specific rates from the Surveillance, Epidemiology and End Results Program. Outcomes were compared with a sibling cohort and the general US population. FINDINGS: We included 556 (13%) of 4329 cohort members treated for acute lymphoblastic leukaemia. Median follow-up of the survivors from 5 years after diagnosis was 18.4 years (range 0.0-33.0). 28 (5%) of 556 participants had died (standardised mortality ratio 3.5, 95% CI 2.3-5.0). 16 (57%) deaths were due to causes other than recurrence of acute lymphoblastic leukaemia. Six (1%) survivors developed a subsequent malignant neoplasm (standardised incidence ratio 2.6, 95% CI 1.0-5.7). 107 participants (95% CI 81-193) in each group would need to be followed-up for 1 year to observe one extra chronic health disorder in the survivor group compared with the sibling group. 415 participants (376-939) in each group would need to be followed-up for 1 year to observe one extra severe, life-threatening, or fatal disorder in the group of survivors. Survivors did not differ from siblings in their educational attainment, rate of marriage, or independent living. INTERPRETATION: The prevalence of adverse long-term outcomes in children treated for standard risk acute lymphoblastic leukaemia according to contemporary protocols is low, but regular care from a knowledgeable primary-care practitioner is warranted. FUNDING: National Cancer Institute, American Lebanese Syrian Associated Charities, Swiss Cancer Research. PMID- 24954782 TI - Environmental-confinement-induced stability enhancement of chiral molecules. AB - We computationally study the transition process of a chiral difluorobenzo[c]phenanthrene (DFBcPh) molecule within non-polar fullerene C(260) to explore the confinement effect. We find blue-shifts in the infrared and Raman spectra of the molecule inside the fullerene relative to those of isolated systems. Six types of spectrum features of the molecule appear in the 0-60 cm(-1) band. Interestingly, the energy barrier of the chiral transformation of the molecule is elevated by 15.88 kcal mol(-1) upon the confinement by the fullerene, indicating improvement in the stability of the enantiomers. The protection by C(260) lowers the highest occupied molecular orbital energy level and lifts the lowest unoccupied molecular orbital energy level of the chiral molecule such that the chiral molecule is further chemically stabilized. We concluded that the confinement environment has an impact at the nanoscale on the enantiomer transformation process of the chiral molecule. PMID- 24954781 TI - Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open label, randomised, phase 3 trial. AB - BACKGROUND: We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. METHODS: TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m(2), 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m(2) orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte macrophage colony-stimulating factor (GM-CSF; 75 MUg) and GV1001 (0.56 mg; days 1, 3, and 5, once on weeks 2-4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. FINDINGS: The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6.0 months (IQR 2.4-12.2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7.9 months [95% CI 7.1-8.8] vs 6.9 months [6.4-7.6]; hazard ratio [HR] 1.19, 98.25% CI 0.97-1.48, p=0.05), or in the concurrent chemoimmunotherapy group (8.4 months [95% CI 7.3-9.7], HR 1.05, 98.25% CI 0.85-1.29, p=0.64; overall log-rank of chi(2)2df=4.3; p=0.11). The commonest grade 3-4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). INTERPRETATION: Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. FUNDING: Cancer Research UK and KAEL-GemVax. PMID- 24954784 TI - Engineering E. coli for the biosynthesis of 3-hydroxy-gamma-butyrolactone (3HBL) and 3,4-dihydroxybutyric acid (3,4-DHBA) as value-added chemicals from glucose as a sole carbon source. AB - 3-hydroxy-gamma-butyrolactone (3HBL) is a versatile chiral synthon, deemed a top value-added chemical from biomass by the DOE. We recently reported the first biosynthetic pathway towards 3HBL and its hydrolyzed form, 3,4-dihydroxybutyric acid (3,4-DHBA) in recombinant Escherichia coli using glucose and glycolic acid as feedstocks and briefly described their synthesis solely from glucose. Synthesis from glucose requires integration of the endogenous glyoxylate shunt with the 3,4-DHBA/3HBL pathway and co-overexpression of seven genes, posing challenges with respect to expression, repression of the glyoxylate shunt and optimal carbon distribution between the two pathways. Here we discuss engineering this integration. While appropriate media and over-expression of glyoxylate shunt enzymes helped overcome repression, two orthogonal expression systems were employed to address the expression and carbon distribution challenge. Synthesis of up to 0.3g/L of 3HBL and 0.7g/L of 3,4-DHBA solely from glucose was demonstrated, amounting to 24% of the theoretical maximum. PMID- 24954783 TI - Manufacturing of highly functional and specific T cells for adoptive immunotherapy against virus from granulocyte colony-stimulating factor-mobilized donors. AB - BACKGROUND AIMS: Cytomegalovirus (CMV) reactivation remains an important risk after hematopoietic stem cell transplantation, which can be effectively controlled through adoptive transfer of donor-derived CMV-specific T cells (CMV T). CMV-T are usually obtained from donor peripheral blood mononuclear cells (PBMCs) collected before G-CSF mobilization. Despite previous studies that showed impaired T-cell function after granulocyte colony-stimulating factor (G-CSF) mobilization, recent publications suggest that G-CSF-primed PBMCs retain anti viral function and are a suitable starting material for CMV-T manufacturing. The objective of this study was to assess the feasibility of generating CMV-T from G CSF-mobilized donors by use of the activation marker CD137 in comparison with conventional non-primed PBMCs. METHODS: CMV-T were isolated from G-CSF-mobilized and non-mobilized donor PBMCs on the basis of CMVpp65 activation-induced CD137 expression and expanded during 3 weeks. Functional assays were performed to assess antigen-specific activation, cytokine release, cytotoxic activity and proliferation after anti-genic re-stimulation. RESULTS: We successfully manufactured highly specific, functional and cytotoxic CMV-T from G-CSF-mobilized donor PBMCs. Their anti-viral function was equivalent to non-mobilized CMV-T, and memory phenotype would suggest their long-term maintenance after adoptive transfer. CONCLUSIONS: We confirm that the use of an aliquot from G-CSF-mobilized donor samples is suitable for the manufacturing of CMV cellular therapies and thereby abrogates the need for successive donations and ensures the availability for patients with unrelated donors. PMID- 24954785 TI - [Mosquito allergy]. AB - Althought serious illnesses can be transmitted by mosquitoes, the most frequent manifestations are due to the contact with saliva of mosquitoes during the blood meal. Culex and Aedes are meeting in countries with moderate climates. Clinical signs vary according to the immunoallergical response, from simple pruritic wheals to immediate and/or delayed allergic reactions. Some reactions can provoke confusion with an infectious cellulitis and an inappropriate antibiotherapy. The natural history of insect bite reactions in an individual tends to progress through 5 stages until immunizing tolerance settles down. Skin prick testing or Serum specific IgE of whole body extracts are lacking sensibility and specificity. Actually, they must be reserved for the most invalidating or severe cases. The recombinant allergens of the saliva of mosquitoes should allow to improve diagnosis and to envisage immunotherapy. PMID- 24954786 TI - Hepcidin in tumor-related iron deficiency anemia and tumor-related anemia of chronic disease: pathogenic mechanisms and diagnosis. AB - OBJECTIVES: Anemia is a common hematological abnormality in patients with cancer. Iron deficiency anemia (IDA) and anemia of chronic disease (ACD) are the most prevalent, both characterized by hypochromic microcytic anemia and low serum iron (SI). Their differential diagnosis is difficult in clinical practice, hampering their treatment. Our objective was to evaluate the use of hepcidin to discriminate tumor-related IDA and ACD and to investigate the mechanism of action of hepcidin in these anemias. METHODS: Blood samples were collected at Jiangsu Cancer Hospital. Patients were divided into IDA and ACD groups by Prussian blue staining of bone marrow smears. Serum hepcidin was measured by enzyme-linked immunosorbent assay. SI, total iron-binding capacity (TIBC), transferrin saturation (TSAT), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF alpha) also determined in this study. RESULTS: Areas under the curve on receiver operating characteristic analysis indicated the diagnostic sensitivity and specificity of hepcidin to be better than those of SI, TIBC, and TSAT. In ACD, hepcidin was correlated positively with IL-6 (r = 0.81, P < 0.01) and negatively with SI (r = -0.78, P < 0.01). In IDA, no significant relationship between IL-6 and hepcidin was found (r = -0.20, P = 0.17), but hepcidin decreased with decreasing quartiles of SI (r = 0.89, P < 0.01). SI was positively correlated with hemoglobin (r = 0.89, P < 0.01; r = 0.84, P < 0.01) in both groups. CONCLUSIONS: Hepcidin is a promising serological marker for the differential diagnosis of tumor-related ACD and IDA, clarifying the pathogenesis of these anemias and guiding corrective treatment. PMID- 24954788 TI - Phylogeny and population dynamics of respiratory syncytial virus (Rsv) A and B. AB - Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants and young children. RSV is characterised by high variability, especially in the G glycoprotein, which may play a significant role in RSV pathogenicity by allowing immune evasion. To reconstruct the origin and phylodynamic history of RSV, we evaluated the genetic diversity and evolutionary dynamics of RSV A and RSV B isolated from children under 3 years old infected in Italy from 2006 to 2012. Phylogenetic analysis revealed that most of the RSV A sequences clustered with the NA1 genotype, and RSV B sequences were included in the Buenos Aires genotype. The mean evolutionary rates for RSV A and RSV B were estimated to be 2.1 * 10(-3) substitutions (subs)/site/year and 3.03 * 10(-3) subs/site/year, respectively. The time of most recent common ancestor for the tree root went back to the 1940s (95% highest posterior density-HPD: 1927-1951) for RSV A and the 1950s (95%HPD: 1951-1960) for RSV B. The RSV A Bayesian skyline plot (BSP) showed a decrease in transmission events ending in about 2005, when a sharp growth restored the original viral population size. RSV B BSP showed a similar trend. Site-specific selection analysis identified 10 codons under positive selection in RSV A sequences and only one site in RSV B sequences. Although RSV remains difficult to control due to its antigenic diversity, it is important to monitor changes in its coding sequences, to permit the identification of future epidemic strains and to implement vaccine and therapy strategies. PMID- 24954789 TI - Genomic evidence of homologous recombination in spring viremia of carp virus: a negatively single stranded RNA virus. AB - A new strain of spring viraemia of carp virus, denominated SVCV-265, was isolated from an ornamental common carp (Cyprinus carpio) in Shanghai, China, 2013. The isolate could produce obvious cytopathic effects on EPC cells, while was shown to be of low virulence for juvenile koi. Complete genome sequencing revealed the genome of the SVCV-265 strain is 11,029 nucleotides in length and phylogenetic analysis showed the isolate was clustered within Asia clade but was divergent from Chinese A1, A2 and BJ0505-2 strains. Previous report indicated that the G and P gene of SVCV shared similar topologies of evolutionary trees. In this study, phylogenetic analysis based on the P gene sequences showed the SVCV-265 was clustered into Iai subgroup and divergent from Chinese isolates A1, A2 and BJ0505-2, which were clustered into Iaii group. However, sequence alignment of the G gene showed the SVCV-265 has a close relationship with A1, A2 and BJ0505-2 isolates. Recombination analysis of all the whole sequences of SVCV available revealed isolates A2 and BJ0505-2 were likely the homologous recombination descendants of the A1 and SVCV-265. The crossover regions were located between 3845-6387nt for A2 and 3573-6444 nt for BJ0505-2, respectively. Phylogenetic analysis of the crossover region further confirmed these findings. This current study describes the molecular characterization of the new isolate SVCV-265 from China and is the first report of homologous recombination in SVCV. PMID- 24954787 TI - Selection of fully processed HIV-1 nucleocapsid protein is required for optimal nucleic acid chaperone activity in reverse transcription. AB - The mature HIV-1 nucleocapsid protein (NCp7) is generated by sequential proteolytic cleavage of precursor proteins containing additional C-terminal peptides: NCp15 (NCp7-spacer peptide 2 (SP2)-p6); and NCp9 (NCp7-SP2). Here, we compare the nucleic acid chaperone activities of the three proteins, using reconstituted systems that model the annealing and elongation steps in tRNA(Lys3) primed (-) strong-stop DNA synthesis and subsequent minus-strand transfer. The maximum levels of annealing are similar for all of the proteins, but there are important differences in their ability to facilitate reverse transcriptase (RT) catalyzed DNA extension. Thus, at low concentrations, NCp9 has the greatest activity, but with increasing concentrations, DNA synthesis is significantly reduced. This finding reflects NCp9's strong nucleic acid binding affinity (associated with the highly basic SP2 domain) as well as its slow dissociation kinetics, which together limit the ability of RT to traverse the nucleic acid template. NCp15 has the poorest activity of the three proteins due to its acidic p6 domain. Indeed, mutants with alanine substitutions for the acidic residues in p6 have improved chaperone function. Collectively, these data can be correlated with the known biological properties of NCp9 and NCp15 mutant virions and help to explain why mature NC has evolved as the critical cofactor for efficient virus replication and long-term viral fitness. PMID- 24954790 TI - Mini-retroperitoneoscopic clampless partial nephrectomy for "low-complexity" renal tumours (PADUA score <=8). AB - An alternative to conventional laparoscopy when looking for virtually scarless surgery is mini-laparoscopy, a reproducible technique that preserves the triangulation concept. A drawback of this approach is the poor image quality provided by mini-scopes. The introduction of the SPIEs technology, a novel endoscopic camera allowing for better visualisation of anatomic details even with 3-mm optics, has boosted the use of a mini-laparoscopic approach in our centre for laparoscopic partial nephrectomy (LPN) to treat low-complexity renal masses. Allowing for inclusion criteria, 10 consecutive patients who satisfied inclusion criteria were enrolled in our prospective study undergoing clampless mini retroperitoneoscopic LPN performed by a single surgeon with laparoscopic expertise. Preliminary data show that the approach seems to be safe and effective, with comparable outcomes to conventional LPN. Larger sample size and comparative studies are needed to confirm these findings. The evaluation of cosmetic results will be the focus of further studies. PMID- 24954791 TI - Degarelix as an intermittent androgen deprivation therapy for one or more treatment cycles in patients with prostate cancer. AB - BACKGROUND: Guidelines for prostate cancer treatment suggest that intermittent androgen deprivation (IAD) can be considered for certain patients. OBJECTIVE: To evaluate the efficacy and safety of degarelix as IAD for one or more treatment cycle(s) in prostate cancer patients requiring androgen deprivation. DESIGN, SETTING, AND PARTICIPANTS: This open-label uncontrolled multicenter study included patients with prostate-specific antigen (PSA) >4 to 50 ng/ml or PSA doubling time <24 mo. Induction included 7-mo treatment. Off-treatment period started when PSA was <=4 ng/ml and lasted up to 24 mo based on PSA and testosterone levels. Treatment was reinitiated when PSA was >4 ng/ml. INTERVENTION: Each induction period included a starting dose of degarelix 240mg, and thereafter 80mg once a month for 6 mo, followed by off-treatment periods. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was time to PSA >4 ng/ml. Secondary end points were subgroup analysis of the primary end point, time to testosterone >0.5 and >2.2 ng/ml, quality of life (QoL), and sexual function during the first off-treatment period. RESULTS AND LIMITATIONS: Of 213 patients in the first induction period, 191 entered the first off treatment period, 35 patients entered the second induction, and 30 entered the second off-treatment period. Only two patients entered the third cycle. Median time to PSA >4 ng/ml and duration of first off-treatment period was 392 d each. Significant differences in time to PSA >4 ng/ml were observed between subgroups stratified by prognostic factors (previous curative treatment, cancer stage, PSA levels, and Gleason scores). Time to testosterone >0.5 and >2.2 ng/ml was 112 and 168 d, respectively. Change in QoL remained nonsignificant, and sexual function gradually improved during the off-treatment period. Adverse events were fewer during the off-treatment period and subsequent treatment cycles. CONCLUSIONS: IAD with degarelix resulted in an improvement in sexual function commensurate with increased testosterone levels while PSA remained suppressed. The treatment for one treatment cycle or more was well tolerated. PATIENT SUMMARY: Guidelines for prostate cancer treatment suggest that intermittent androgen deprivation (IAD) can be considered for certain patients. IAD with degarelix resulted in improved sexual function commensurate with increased testosterone levels while prostate specific antigen remained suppressed. The treatment for one treatment cycle or more was well tolerated. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00801242. PMID- 24954792 TI - Standardized reporting of resection technique during nephron-sparing surgery: the surface-intermediate-base margin score. AB - A standardized reporting system of nephron-sparing surgery resection techniques is lacking. The surface-intermediate-base scoring system represents a formal reporting instrument to assist in interpretation of reported data and to facilitate comparisons in the urologic literature. PMID- 24954793 TI - Obesity is associated with risk of progression for low-risk prostate cancers managed expectantly. AB - BACKGROUND: Active surveillance (AS) is an expectant management strategy for prostate cancer (PCa). The impact of obesity on progression is not well characterized in this population. OBJECTIVE: To determine if obesity is associated with progression in men on AS for low-risk PCa. DESIGN, SETTING, AND PARTICIPANTS: Men undergoing AS for low-risk PCa (no Gleason pattern >=4, three or fewer cores involved or one-third or less of the total number of cores involved, and no core with >50% cancer involvement) were identified at our institution. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcomes were pathologic progression (defined as no longer meeting low-risk criteria on follow up biopsy) and therapeutic progression (defined as intent to initiate active treatment). Kaplan-Meier curves and multivariable logistic regression and Cox proportional hazards models were used, with separate models for reclassification at confirmatory biopsy (first biopsy after diagnostic biopsy) and progression beyond confirmatory biopsy. RESULTS AND LIMITATIONS: In this cohort of 565 men (median follow-up: 48 mo), 124 (22%) were obese (body mass index [BMI] >=30kg/m(2)). Pathologic and therapeutic progression occurred in 168 men (30%) and 172 men (30%), respectively. No association was noted between obesity and risk of progression at the confirmatory biopsy. However, beyond confirmatory biopsy, obesity was associated with a greater probability of pathologic progression (p=0.007) and therapeutic progression (p=0.007) in Kaplan-Meier analyses. In adjusted Cox models, each 5-unit increase in BMI was associated with an increased risk of pathologic progression (hazard ratio [HR]: 1.5; 95% confidence interval [CI], 1.1-2.1; p=0.02) and therapeutic progression (HR: 1.4; 95% CI, 1.0-1.9; p=0.05). The main limitation is the retrospective design, limiting the ability to assess BMI changes over time. CONCLUSIONS: Obesity was associated with a significantly increased risk of progression beyond the confirmatory biopsy. This suggests an increased risk of long-term biologic progression rather than solely misclassification. PATIENT SUMMARY: As opposed to immediate active treatment (surgery or radiation), active surveillance (AS) involves closely monitoring low-risk prostate cancers and only using active treatment if there are signs of progression. Our study is the first to suggest that obesity is associated with a higher risk of cancer progression while on AS. Further research is needed to determine if diet and exercise can decrease the risk of cancer progression while on AS. PMID- 24954796 TI - Rapid and sensitive determination of levofloxacin in microsamples of human plasma by high-performance liquid chromatography and its application in a pharmacokinetic study. AB - A rapid, sensitive and simple high-performance liquid chromatographic assay with ultraviolet detection was developed for the quantification of levofloxacin in microsamples (100 MUL) of human plasma. The extraction procedure included a protein precipitation technique and a short chromatographic running time (4.5 min). Analyses were carried out on a Symmetry C18 column using a mixture of acetonitrile and 0.01 m potassium dihydrogen aqueous solution (pH 3.4; 14:86 v/v) as mobile phase. The method provided specificity and was linear (r >= 0.9992) over the concentration range 0.1-12 ug/mL. The average absolute recovery was 93.59%. The intra- and inter-day coefficients of variation were <6%. Additionally, levofloxacin was stable in all evaluations. The usefulness of this method was demonstrated in a pharmacokinetic study of levofloxacin in healthy adult volunteers. The present method offers two main advantages: (a) the use of microsamples reduces the total volume of blood to be collected from patients; and (b) it provides a good cost-effectiveness ratio. It is concluded that the method is rapid, simple, sensitive, economical and suitable for the determination of levofloxacin in human plasma using a small volume of sample. PMID- 24954798 TI - Absolute and relative endocranial size in Neandertals and later Pleistocene Homo. AB - Eurasian Neandertals encompass the entire observed range of recent and fossil Homo sapiens in absolute, but not relative endocranial volume, and Neandertals attest an average EQ significantly lower than their Upper Pleistocene successors. While the cognitive, social, and evolutionary implications of this phenomenon have been emphasised, the statistical basis of a mean inference of EQ in the Neandertal hypodigm has not been appropriately demonstrated. A demonstrable male bias in the available postcranial, not cranial, series has skewed perceptions of Neandertal brain-to-body size scaling towards a rejection of the null hypothesis. A simple resolution to this problem is a concise assessment of paired associated covariates against a suitable recent human comparator series. Permutations of Fisher's z and Student's t statistics are valid metrics in tests of significance in single datum hypotheses. Bootstrapped single observation tests determined significance in body size, absolute and relative endocranial volume in Pleistocene archaic, early modern, and late Pleistocene H. sapiens. With respect to absolute ECV, all current Middle-Upper Pleistocene crania fall within the substantial recent Homo range. Nevertheless, simple indices derived from raw and modified data in normal and logarithmic space reveal that Western European Neandertal males approach the lower extremes of our observed size range in relative ECV, yet none exceed statistical significance. Results confirm that relative ECV/brain size in Neandertals was not significantly depressed relative to recent and fossil H. sapiens and this is consistent with a substantial body of data from living humans dismissing any simple correspondence of relative brain size with intelligence and, by extension, evolutionary success. PMID- 24954794 TI - The immunological, environmental, and phylogenetic perpetrators of metastatic leishmaniasis. AB - Cutaneous leishmaniases have persisted for centuries as chronically disfiguring parasitic infections affecting millions of people across the subtropics. Symptoms range from the more prevalent single, self-healing cutaneous lesion to a persistent, metastatic disease, where ulcerations and granulomatous nodules can affect multiple secondary sites of the skin and delicate facial mucosa, even sometimes diffusing throughout the cutaneous system as a papular rash. The basis for such diverse pathologies is multifactorial, ranging from parasite phylogeny to host immunocompetence and various environmental factors. Although complex, these pathologies often prey on weaknesses in the innate immune system and its pattern recognition receptors. This review explores the observed and potential associations among the multifactorial perpetrators of infectious metastasis and components of the innate immune system. PMID- 24954795 TI - Acylation in trypanosomatids: an essential process and potential drug target. AB - Fatty acylation--the addition of fatty acid moieties such as myristate and palmitate to proteins--is essential for the survival, growth, and infectivity of the trypanosomatids: Trypanosoma brucei, Trypanosoma cruzi, and Leishmania. Myristoylation and palmitoylation are critical for parasite growth, targeting and localization, and the intrinsic function of some proteins. The trypanosomatids possess a single N-myristoyltransferase (NMT) and multiple palmitoyl acyltransferases, and these enzymes and their protein targets are only now being characterized. Global inhibition of either process leads to cell death in trypanosomatids, and genetic ablation of NMT compromises virulence. Moreover, NMT inhibitors effectively cure T. brucei infection in rodents. Thus, protein acylation represents an attractive target for the development of new trypanocidal drugs. PMID- 24954797 TI - International scientists' priorities for research on pharmaceutical and personal care products in the environment. AB - Pharmaceuticals and personal care products (PPCPs) are widely discharged into the environment via diverse pathways. The effects of PPCPs in the environment have potentially important human and ecosystem health implications, so credible, salient, and legitimate scientific evidence is needed to inform regulatory and policy responses that address potential risks. A recent "big questions" exercise with participants largely from North America identified 22 important research questions around the risks of PPCP in the environment that would help address the most pressing knowledge gaps over the next decade. To expand that analysis, we developed a survey that was completed by 535 environmental scientists from 57 countries, of whom 49% identified environmental or analytical chemistry as their primary disciplinary background. They ranked the 22 original research questions and submitted 171 additional candidate research questions they felt were also of high priority. Of the original questions, the 3 perceived to be of highest importance related to: 1) the effects of long-term exposure to low concentrations of PPCP mixtures on nontarget organisms, 2) effluent treatment methods that can reduce the effects of PPCPs in the environment while not increasing the toxicity of whole effluents, and 3) the assessment of the environmental risks of metabolites and environmental transformation products of PPCPs. A question regarding the role of cultural perspectives in PPCP risk assessment was ranked as the lowest priority. There were significant differences in research orientation between scientists who completed English and Chinese language versions of the survey. We found that the Chinese respondents were strongly orientated to issues of managing risk profiles, effluent treatment, residue bioavailability, and regional assessment. Among English language respondents, further differences in research orientation were associated with respondents' level of consistency when ranking the survey's 15 comparisons. There was increasing emphasis on the role of various other stressors relative to PPCPs and on risk prioritization as internal decision making consistency increased. Respondents' consistency in their ranking choices was significantly and positively correlated with SETAC membership, authors' number of publications, and longer survey completion times. Our research highlighted international scientists' research priorities and should help inform decisions about the type of hazard and risk-based research needed to best inform decisions regarding PPCPs in the environment. Disciplinary training of a scientist or engineer appears to strongly influence preferences for research priorities to understand PPCPs in the environment. Selection of participants and the depth and breadth of research prioritization efforts thus have potential effects on the outcomes of research prioritization exercises. Further elucidation of how patterns of research priority vary between academic and government scientists and between scientists and other government and stakeholders would be useful in the future and provide information that helps focus scientific effort on socially relevant challenges relating to PPCPs in the environment. It also suggests the potential for future collaborative research between industry, government, and academia on environmental contaminants beyond PPCPs. PMID- 24954799 TI - Utility of urinary ethyl glucuronide analysis in post-mortem toxicology when investigating alcohol-related deaths. AB - Use and abuse of alcohol are common findings when unnatural deaths are investigated as evidenced by high blood- and urine- alcohol concentrations (BAC and UAC) at autopsy. Because ethanol is metabolized in the liver until the time of death, the autopsy BAC or UAC might be negative even though the deceased had consumed alcohol in the immediate ante-mortem period. Analysis of the non oxidative metabolite of ethanol [ethyl glucuronide (EtG)] offers a more sensitive test of recent drinking. In this paper, we determined the concentrations of ethanol and EtG in urine samples from 972 consecutive forensic autopsies. In 425 cases (44%) both EtG and ethanol were positive, which supports ante-mortem drinking. In 342 cases (35%), both EtG and ethanol was negative, which speaks against any consumption of alcohol just before death. In 181 cases, ethanol was negative in urine (<0.2 g/kg), whereas EtG was positive (>0.5 mg/L), which points towards ingestion of alcohol some time before death. In these cases, mean and median concentrations of EtG were 53.2 mg/L and 23.7 mg/L, respectively, although there was no mention of alcohol on 131 of the death certificates. Alcohol was mentioned on death certificates as an underlying or immediate cause of death or a contributing factor in 435 (45%) cases, which rose to 566 (58%) cases when positive EtG results were included. This article demonstrates the usefulness of EtG analysis in routine post-mortem toxicology when ante-mortem drinking and alcohol-related deaths are investigated. PMID- 24954800 TI - Singlet molecular oxygen generated by biological hydroperoxides. AB - The chemistry behind the phenomenon of ultra-weak photon emission has been subject of considerable interest for decades. Great progress has been made on the understanding of the chemical generation of electronically excited states that are involved in these processes. Proposed mechanisms implicated the production of excited carbonyl species and singlet molecular oxygen in the mechanism of generation of chemiluminescence in biological system. In particular, attention has been focused on the potential generation of singlet molecular oxygen in the recombination reaction of peroxyl radicals by the Russell mechanism. In the last ten years, our group has demonstrated the generation of singlet molecular oxygen from reactions involving the decomposition of biologically relevant hydroperoxides, especially from lipid hydroperoxides in the presence of metal ions, peroxynitrite, HOCl and cytochrome c. In this review we will discuss details on the chemical aspects related to the mechanism of singlet molecular oxygen generation from different biological hydroperoxides. PMID- 24954802 TI - New editorial policies for the International Journal of Infectious Diseases: good or bad news for developing countries. PMID- 24954801 TI - The neurotoxicity of iron, copper and manganese in Parkinson's and Wilson's diseases. AB - Impaired cellular homeostasis of metals, particularly of Cu, Fe and Mn may trigger neurodegeneration through various mechanisms, notably induction of oxidative stress, promotion of alpha-synuclein aggregation and fibril formation, activation of microglial cells leading to inflammation and impaired production of metalloproteins. In this article we review available studies concerning Fe, Cu and Mn in Parkinson's disease and Wilson's disease. In Parkinson's disease local dysregulation of iron metabolism in the substantia nigra (SN) seems to be related to neurodegeneration with an increase in SN iron concentration, accompanied by decreased SN Cu and ceruloplasmin concentrations and increased free Cu concentrations and decreased ferroxidase activity in the cerebrospinal fluid. Available data in Wilson's disease suggest that substantial increases in CNS Cu concentrations persist for a long time during chelating treatment and that local accumulation of Fe in certain brain nuclei may occur during the course of the disease. Consequences for chelating treatment strategies are discussed. PMID- 24954803 TI - A density-based adaptive quantum mechanical/molecular mechanical method. AB - We present a density-based adaptive quantum mechanical/molecular mechanical (DBA QM/MM) method, whereby molecules can switch layers from the QM to the MM region and vice versa. The adaptive partitioning of the molecular system ensures that the layer assignment can change during the optimization procedure, that is, on the fly. The switch from a QM molecule to a MM molecule is determined if there is an absence of noncovalent interactions to any atom of the QM core region. The presence/absence of noncovalent interactions is determined by analysis of the reduced density gradient. Therefore, the location of the QM/MM boundary is based on physical arguments, and this neatly removes some empiricism inherent in previous adaptive QM/MM partitioning schemes. The DBA-QM/MM method is validated by using a water-in-water setup and an explicitly solvated L-alanyl-L-alanine dipeptide. PMID- 24954804 TI - Adjuvant treatment for gastric cancer: too much is not enough. PMID- 24954807 TI - Duplication of 20qter and deletion of 20pter due to paternal pericentric inversion: patient report and review of 20qter duplications. AB - Duplications of the terminal long arm of chromosome 20 are rare chromosomal anomalies. We report a male infant found on array comparative genomic hybridization analysis to have a 19.5 Mb duplication of chromosome 20q13.12 13.33, as well as an 886 kb deletion of 20p13 at 18,580-904,299 bp. This anomaly occurred as the recombinant product of a paternal pericentric inversion. There have been 23 reported clinical cases involving 20qter duplications; however, to our knowledge this is only the second reported patient with a paternal pericentric inversion resulting in 46,XY,rec(20)dup(20q). This patient shares many characteristics with previously described patients with 20qter duplications, including microphthalmia, anteverted nares, long ears, cleft palate, small chin, dimpled chin, cardiac malformations, and normal intrauterine growth. While there is variable morbidity in patients with terminal duplications of 20q, a review of previously reported patients and comparison to our patient's findings shows significant phenotypic similarity. PMID- 24954806 TI - Goal setting, using goal attainment scaling, as a method to identify patient selected items for measuring arm function. AB - OBJECTIVE: Following stroke or brain injury, goals for rehabilitation of the hemiparetic upper limb include restoring active function if there is return of motor control or, if none is possible, improving passive function, and facilitating care for the limb. To inform development of a new patient reported outcome measure (PROM) of active and passive function in the hemiparetic upper limb, the Arm Activity measure, we examined functional goals for the upper limb, identified during goal setting for spasticity intervention (physical therapy and concomitant botulinum toxin A interventions). DESIGN: Using secondary analysis of a prospective observational cohort study, functional goals determined between patients, their carers and the clinical team were assigned into categories by two raters. Goal category identification, followed by assignment of goals to a category, was undertaken and then confirmed by a second reviewer. PARTICIPANTS: Participants comprised nine males and seven females of mean (SD) age 54.5 (15.7) years and their carers. Fifteen had sustained a stroke and one a traumatic brain injury. RESULTS: Goals were used to identify five categories: passive function, active function, symptoms, cosmesis and impairment. Two passive function items not previously identified by a previous systematic review were identified. CONCLUSIONS: Analysis of goals important to patients and carers revealed items for inclusion in a new measure of arm function and provide a useful alternative method to involve patients and carers in standardised measure development. PMID- 24954808 TI - A novel adaptive switching function on fault tolerable sliding mode control for uncertain stochastic systems. AB - A novel switching function based on an optimization strategy for the sliding mode control (SMC) method has been provided for uncertain stochastic systems subject to actuator degradation such that the closed-loop system is globally asymptotically stable with probability one. In the previous researches the focus on sliding surface has been on proportional or proportional-integral function of states. In this research, from a degree of freedom that depends on designer choice is used to meet certain objectives. In the design of the switching function, there is a parameter which the designer can regulate for specified objectives. A sliding-mode controller is synthesized to ensure the reachability of the specified switching surface, despite actuator degradation and uncertainties. Finally, the simulation results demonstrate the effectiveness of the proposed method. PMID- 24954805 TI - Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S 1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. AB - BACKGROUND: The prognosis for locally advanced gastric cancer is poor despite advances in adjuvant chemotherapy. We did the Stomach cancer Adjuvant Multi Institutional group Trial (SAMIT) to assess the superiority of sequential treatment (paclitaxel then tegafur and uracil [UFT] or paclitaxel then S-1) compared with monotherapy (UFT or S-1) and also the non-inferiority of UFT compared with S-1. METHODS: We did this randomised phase 3 trial with a two-by two factorial design at 230 hospitals in Japan. We enrolled patients aged 20-80 years with T4a or T4b gastric cancer, who had had D2 dissection and a ECOG performance score of 0-1. Patients were randomly assigned to one of four treatment groups with minimisation for tumour size, lymph node metastasis, and study site. Patients received UFT only (267 mg/m(2) per day), S-1 only (80 mg/m(2) per day) for 14 days, with a 7-day rest period or three courses of intermittent weekly paclitaxel (80 mg/m(2)) followed by either UFT, or S-1. Treatment lasted 48 weeks in monotherapy groups and 49 weeks in the sequential treatment groups. The primary endpoint was disease-free survival assessed by intention to treat. We assessed whether UFT was non-inferior to S-1 with a non inferiority margin of 1.33. This trial was registered at UMIN Clinical Trials Registry, number C000000082. FINDINGS: We randomly assigned 1495 patients between Aug 3, 2004, and Sept 29, 2009. 374 patients were assigned to receive UFT alone, 374 to receive S-1 alone, 374 to received paclitaxel then UFT, and 373 to receive paclitaxel then S-1. We included 1433 patients in the primary analysis after at least 3 years of follow-up (359, 364, 355, and 355 in each group respectively). Protocol treatment was completed by 215 (60%) patients in the UFT group, 224 (62%) in the S-1 group, 242 (68%) in the paclitaxel then UFT group, and 250 (70%) in the paclitaxel then S-1 group. 3-year disease-free survival for monotherapy was 54.0% (95% CI 50.2-57.6) and that of sequential treatment was 57.2% (53.4 60.8; hazard ratio [HR] 0.92, 95% CI 0.80-1.07, p=0.273). 3-year disease-free survival for the UFT group was 53.0% (95% CI 49.2-56.6) and that of the S-1 group was 58.2% (54.4-61.8; HR 0.81, 95% CI 0.70-0.93, p=0.0048; pnon inferiority=0.151). The most common grade 3-4 haematological adverse event was neutropenia (41 [11%] of 359 patients in the UFT group, 48 [13%] of 363 in the S 1 group, 46 [13%] of 355 in the paclitaxel then UFT group, and 83 [23%] of 356 in the paclitaxel then S-1 group). The most common grade 3-4 non-haematological adverse event was anorexia (21 [6%], 24 [7%], seven [2%], and 18 [5%], respectively). INTERPRETATION: Sequential treatment did not improve disease-free survival, and UFT was not non-inferior to S-1 (and S-1 was superior to UFT), therefore S-1 monotherapy should remain the standard treatment for locally advanced gastric cancer in Japan. FUNDING: Epidemiological and Clinical Research Information Network. PMID- 24954809 TI - Finite element based model predictive control for active vibration suppression of a one-link flexible manipulator. AB - This paper presents a unique approach for active vibration control of a one-link flexible manipulator. The method combines a finite element model of the manipulator and an advanced model predictive controller to suppress vibration at its tip. This hybrid methodology improves significantly over the standard application of a predictive controller for vibration control. The finite element model used in place of standard modelling in the control algorithm provides a more accurate prediction of dynamic behavior, resulting in enhanced control. Closed loop control experiments were performed using the flexible manipulator, instrumented with strain gauges and piezoelectric actuators. In all instances, experimental and simulation results demonstrate that the finite element based predictive controller provides improved active vibration suppression in comparison with using a standard predictive control strategy. PMID- 24954810 TI - Centralized PI control for high dimensional multivariable systems based on equivalent transfer function. AB - This article presents a new scheme to design full matrix controller for high dimensional multivariable processes based on equivalent transfer function (ETF). Differing from existing ETF method, the proposed ETF is derived directly by exploiting the relationship between the equivalent closed-loop transfer function and the inverse of open-loop transfer function. Based on the obtained ETF, the full matrix controller is designed utilizing the existing PI tuning rules. The new proposed ETF model can more accurately represent the original processes. Furthermore, the full matrix centralized controller design method proposed in this paper is applicable to high dimensional multivariable systems with satisfactory performance. Comparison with other multivariable controllers shows that the designed ETF based controller is superior with respect to design complexity and obtained performance. PMID- 24954811 TI - Advances in diagnostic modalities to detect occult lymph node metastases in head and neck squamous cell carcinoma. AB - Regional metastasis is a prominent feature of head and neck squamous cell carcinoma (HNSCC) and is an important prognostic factor. The currently available imaging techniques for assessment of the neck have limitations in accuracy; thus, elective neck dissection has remained the usual choice of management of the clinically N0 neck (cN0) for tumors with significant (>=20%) incidence of occult regional metastasis. As a consequence, the majority of patients without regional metastasis will undergo unnecessary treatment. The purpose of this review was to discuss new developments in techniques that potentially improve the accuracy of the assessment of the neck in patients with HNSCC. Although imaging has improved in the last decades, a limitation common to all imaging techniques is a lack of sensitivity for small tumor deposits. Therefore, complementary to improvements in imaging techniques, developments in more invasive diagnostic procedures, such as sentinel node biopsy (SNB) will add to the accuracy of diagnostic algorithms for the staging of the neck. PMID- 24954812 TI - BODIPY-bridged push-pull chromophores for nonlinear optical applications. AB - A set of linear and dissymmetric BODIPY-bridged push-pull dyes are synthesized. The electron-donating substituents are anisole and dialkylanilino groups. The strongly electron-accepting moiety, a 1,1,4,4-tetracyanobuta-1,3-diene (TCBD) group, is obtained by insertion of an electron-rich ethyne into tetracyanoethylene. A nonlinear push-pull system is developed with a donor at the 5-position of the BODIPY core and the acceptor at the 2-position. All dyes are fully characterized and their electrochemical, linear and nonlinear optical properties are discussed. The linear optical properties of dialkylamino compounds show strong solvatochromic behavior and undergo drastic changes upon protonation. The strong push-pull systems are non-fluorescent and the TCBD-BODIPY dyes show diverse photochemistry and electrochemistry, with several reversible reduction waves for the tetracyanobutadiene moiety. The hyperpolarizability MUbeta of selected compounds is evaluated using the electric-field-induced second-harmonic generation technique. Two of the TCBD-BODIPY dyes show particularly high MUbeta (1.907 MUm) values of 2050 * 10(-48) and 5900 * 10(-48) esu. In addition, one of these dyes shows a high NLO contrast upon protonation-deprotonation of the donor residue. PMID- 24954813 TI - The faulty statistics of complementary alternative medicine (CAM). AB - The authors illustrate the difficulties involved in obtaining a valid statistical significance in clinical studies especially when the prior probability of the hypothesis under scrutiny is low. Since the prior probability of a research hypothesis is directly related to its scientific plausibility, the commonly used frequentist statistics, which does not take into account this probability, is particularly unsuitable for studies exploring matters in various degree disconnected from science such as complementary alternative medicine (CAM) interventions. Any statistical significance obtained in this field should be considered with great caution and may be better applied to more plausible hypotheses (like placebo effect) than that examined - which usually is the specific efficacy of the intervention. Since achieving meaningful statistical significance is an essential step in the validation of medical interventions, CAM practices, producing only outcomes inherently resistant to statistical validation, appear not to belong to modern evidence-based medicine. PMID- 24954814 TI - Improved operative efficiency of free fibula flap mandible reconstruction with patient-specific, computer-guided preoperative planning. AB - BACKGROUND: Free fibula osteocutaneous flaps are the primary option for reconstruction after segmental mandibulectomies. This study evaluates the impact of CT-guided preoperative planning on operative outcomes after free fibula mandible reconstruction. METHODS: We conducted a retrospective review of all patients undergoing free fibula reconstruction of the mandible from 2002 to 2011. RESULTS: Fifty-seven patients underwent free fibula osteocutaneous flap reconstruction for head and neck cancers involving the mandible. Twelve patients had shaping of the neomandible performed on the back table while 20 patients underwent shaping in situ without the use of any adjunctive technology. The remaining 25 patients underwent preoperative CT imaging, which significantly decreased operative time (707 minutes vs 534 minutes; p < .0003) as well as overall costs ($24,532.50 vs $20,950.48). There were no significant differences in outcomes or complications. CONCLUSION: Preoperative, patient-specific CT modeling, and cutting guide fabrication outweigh the costs associated with the additional technology without jeopardizing overall outcomes or increasing complication rates. PMID- 24954815 TI - An energy investigation into 1D/2D oriented-attachment assemblies of 1D Ag nanocrystals. AB - In the field of oriented-attachment crystal growth, one-dimensional nanocrystals are frequently employed as building blocks to synthesize two-dimensional or large aspect-ratio one-dimensional nanocrystals. Despite recent extensive experimental advances, the underlying inter-particle interaction in the synthesis still remains elusive. In this report, using Ag as a platform, we investigate the van der Waals interactions associated with the side-by-side and end-to-end assemblies of one-dimensional nanorods. The size, aspect ratio, and inter-particle separation of the Ag precursor nanorods are found to have dramatically different impacts on the van der Waals interactions in the two types of assemblies. Our work facilitates the fundamental understanding of the oriented-attachment assembling mechanism based on one-dimensional nanocrystals. PMID- 24954816 TI - Post-Soviet Central Asia: a summary of the drug situation. AB - BACKGROUND: The paper aims to provide a snapshot of the drug situation in Kazakhstan, Kyrgyzstan, Tajikistan, and Uzbekistan using the EU methodology of "harmonised indicators of drug epidemiology." METHODS: Most of the data reported here were gathered and analysed within the framework of the EU-funded CADAP project in 2012. Together with members of CADAP national teams, we conducted extraction from the databases of national institutions in the field of (public) health and law enforcement, issued formal requests for the provision of specific information to national governmental authorities, and obtained national grey literature in Russian. In specific cases, we leaned on the expert opinions of the national experts, gathered by means of simple online questionnaires or focus group. In the rather scarce cases where peer-reviewed sources on the specific topics exist, it is used for comparisons and discussion. RESULTS: All the post Soviet Central Asian countries lack information on drug use in the general population. School surveys are relatively well developed in Kazakhstan, and Kyrgyzstan benefited from an international survey project on health in schools organised by private donors in 2009. For Tajikistan and Uzbekistan, the most recent available data on drug use in the school population are from 2006 and as such are of little relevance. Problem drug use is widespread in Central Asia and estimates of its prevalence are available for all four countries. All the post Soviet Central Asian countries use a rather outdated system of narcological registers as the only source of data on drug users who are treated (and those investigated by the police), which was inherited from Soviet times. The availability of treatment is very low in all the countries reported on here except Kyrgyzstan; opioid substitution treatment (OST) was introduced first in Kyrgyzstan; Kazakhstan and Tajikistan are piloting their OST programmes but the coverage is extremely low, and in Uzbekistan the OST pilot programme has been abolished. HIV and hepatitis C virus (HCV) infections are concentrated in injecting drug users (IDUs) in Central Asia, with the situation in Kazakhstan having stabilised; HIV is on the increase among Kyrgyz IDUs. The sharp decrease in HIV and VHC seroprevalence among IDUs in Uzbekistan and Tajikistan still awaits an explanation. The system for monitoring of fatal drug overdoses needs substantial improvement in all the countries reported on here. Overall mortality studies of drug users registered in the narcological registers were performed in Uzbekistan, Kazakhstan, and Tajikistan; the highest excess mortality among registered drug users was found in Uzbekistan, and in all three countries, it was substantially higher for women than men. The seizures of illegal drugs are by far the highest in Kazakhstan; however, wild-growing cannabis represents 90% of these seizures. Uzbekistan was the country with the highest number of drug arrests. In Kazakhstan, after the decriminalisation of drug use in 2011, the number of reported drug-related offences dropped to below 50% of the figure for the previous year. CONCLUSION: The drug situation monitoring system in the four post Soviet countries of Central Asia still needs substantial improvement. However, in its current state it is already able to generate evidence that is useful for the planning of effective national and regional drug policies, which would be of the utmost importance in the forthcoming years of the withdrawal of the International Security Assistance Force from Afghanistan. PMID- 24954817 TI - Here/In this issue and there/abstract thinking: "80 billion dollars, every year". PMID- 24954818 TI - To text or not to text: applying clinical and professionalism principles to decisions about text messaging with patients. PMID- 24954819 TI - Pediatric psychopharmacology: food and drug administration approval through the evidence lens. PMID- 24954820 TI - Inflammatory depressive bowel diseases: the new era. PMID- 24954821 TI - How evidence on the developmental nature of attention-deficit/hyperactivity disorder can increase the validity and utility of diagnostic criteria. PMID- 24954823 TI - Impact of the DSM-5 attention-deficit/hyperactivity disorder age-of-onset criterion in the US adolescent population. AB - OBJECTIVE: The present study aims to compare the prevalence and clinical correlates of DSM-IV versus DSM-5-defined attention-deficit/hyperactivity disorder (ADHD) and subtypes in a nationally representative sample of US youth based on the age-of-onset criterion. METHOD: The sample includes 1,894 participants 12 to 15 years of age from cross-sectional National Health and Nutrition Examination Survey (NHANES) surveys conducted from 2001 to 2004. Data on DSM-IV and DSM-5 criteria for ADHD were derived from administration of the parental ADHD module of the National Institute of Mental Health (NIMH) Diagnostic Interview Schedule for Children, Version IV (DISC-IV). RESULTS: Extension of the age-of-onset criterion from 7 to 12 years led to an increase in the prevalence rate of ADHD from 7.38% (DSM-IV) to 10.84% (DSM-5). Youth with later age of onset did not differ from those with earlier age of onset in terms of severity and patterns of comorbidity. However, the group with later age of onset was more likely to be from lower income and ethnic minority families. CONCLUSION: The comparability of the clinical significance of the early and later age-of-onset groups supports the DSM-5 extension of the age-of-onset criterion in ADHD. PMID- 24954822 TI - Randomized efficacy trial of two psychotherapies for depression in youth with inflammatory bowel disease. AB - OBJECTIVE: Pediatric inflammatory bowel disease (IBD) is associated with high rates of depression. This study compared the efficacy of cognitive behavioral therapy (CBT) to supportive nondirective therapy (SNDT) in treating youth with comorbid IBD and depression. METHOD: Youth (51% female and 49% male; age 9-17 years, mean age 14.3 years) with depression and Crohn's disease (n = 161) or ulcerative colitis (n = 56) were randomly assigned to a 3-month course of CBT or SNDT. The primary outcome was comparative reduction in depressive symptom severity; secondary outcomes were depression remission, increase in depression response, and improved health-related adjustment and IBD activity. RESULTS: A total of 178 participants (82%) completed the 3-month intervention. Both psychotherapies resulted in significant reductions in total Children's Depression Rating Scale Revised score (37.3% for CBT and 31.9% for SNDT), but the difference between the 2 treatments was not significant (p = .16). There were large pre-post effect sizes for each treatment (d = 1.31 for CBT and d = 1.30 for SNDT). More than 65% of youth had a complete remission of depression at 3 months, with no difference between CBT and SNDT (67.8% and 63.2%, respectively). Compared to SNDT, CBT was associated with a greater reduction in IBD activity (p = .04) but no greater improvement on the Clinical Global Assessment Scale (p = .06) and health-related quality of life (IMPACT-III scale) (p = .07). CONCLUSION: This is the first randomized controlled study to suggest improvements in depression severity, global functioning, quality of life, and disease activity in a physically ill pediatric cohort treated with psychotherapy. Clinical trial registration information-Reducing Depressive Symptoms in Physically Ill Youth; http://clinical trials.gov; NCT00534911. PMID- 24954824 TI - Three-year latent class trajectories of attention-deficit/hyperactivity disorder (ADHD) symptoms in a clinical sample not selected for ADHD. AB - OBJECTIVE: This study aims to examine trajectories of attention deficit/hyperactivity disorder (ADHD) symptoms in the Longitudinal Assessment of Manic Symptoms (LAMS) sample. METHOD: The LAMS study assessed 684 children aged 6 to 12 years with the Kiddie-Schedule for Affective Disorders and Schizophrenia (K SADS) and rating scales semi-annually for 3 years. Although they were selected for elevated manic symptoms, 526 children had baseline ADHD diagnoses. With growth mixture modeling (GMM), we separately analyzed inattentive and hyperactive/impulsive symptoms, covarying baseline age. Multiple standard methods determined optimal fit. The chi(2) and Kruskal-Wallis analysis of variance compared resulting latent classes/trajectories on clinical characteristics and medication. RESULTS: Three latent class trajectories best described inattentive symptoms, and 4 classes best described hyperactive/impulsive symptoms. Inattentive trajectories maintained their relative position over time. Hyperactive/impulsive symptoms had 2 consistent trajectories (least and most severe). A third trajectory (4.5%) started mild, then escalated; and a fourth (14%) started severe but improved dramatically. The improving trajectory was associated with the highest rate of ADHD and lowest rate of bipolar diagnoses. Three-fourths of the mildest inattention class were also in the mildest hyperactive/impulsive class; 72% of the severest inattentive class were in the severest hyperactive/impulsive class, but the severest inattention class also included 62% of the improving hyperactive-impulsive class. CONCLUSION: An ADHD rather than bipolar diagnosis prognosticates a better course of hyperactive/impulsive, but not inattentive, symptoms. High overlap of relative severity between inattention and hyperactivity/impulsivity confirms the link between these symptom clusters. Hyperactive/impulsive symptoms wane more over time. Group means are insufficient to understand individual ADHD prognosis. A small subgroup deteriorates over time in hyperactivity/impulsivity and needs better treatments than currently provided. PMID- 24954825 TI - Biological overlap of attention-deficit/hyperactivity disorder and autism spectrum disorder: evidence from copy number variants. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur and share genetic risks. The aim of this analysis was to determine more broadly whether ADHD and ASD share biological underpinnings. METHOD: We compared copy number variant (CNV) data from 727 children with ADHD and 5,081 population controls to data from 996 individuals with ASD and an independent set of 1,287 controls. Using pathway analyses, we investigated whether CNVs observed in individuals with ADHD have an impact on genes in the same biological pathways as on those observed in individuals with ASD. RESULTS: The results suggest that the biological pathways affected by CNVs in ADHD overlap with those affected by CNVs in ASD more than would be expected by chance. Moreover, this was true even when specific CNV regions common to both disorders were excluded from the analysis. After correction for multiple testing, genes involved in 3 biological processes (nicotinic acetylcholine receptor signalling pathway, cell division, and response to drug) showed significant enrichment for case CNV hits in the combined ADHD and ASD sample. CONCLUSION: The results of this study indicate the presence of significant overlap of shared biological processes disrupted by large rare CNVs in children with these 2 neurodevelopmental conditions. PMID- 24954826 TI - Risk and protective factors associated with substance use disorders in adolescents with first-episode mania. AB - OBJECTIVE: Adolescents with bipolar disorder (BD) are more likely to develop substance use disorders (SUDs) than adolescents without psychiatric disorders; however, to our knowledge, specific risk factors underlying this relationship have not been prospectively examined. The purpose of this study was to identify predictors of developing SUDs after a first manic episode. METHOD: Participants aged 12 to 20 years and hospitalized with their first manic episode associated with bipolar I disorder (BP-I) were recruited as part of the University of Cincinnati First-Episode Mania Study and prospectively evaluated for patterns of substance use. Follow-up ranged between 17 and 283 weeks (mean = 113 weeks, SD = 71.9 weeks). Demographic and clinical variables were compared between adolescents with and without SUDs. RESULTS: Of the 103 adolescents with BD, 49 (48%) either had a SUD at baseline or developed one during follow-up. Of the 71 participants who did not have a SUD at study entry, 17 (24%) developed one during follow-up (median = 40 weeks). Later onset of BD, manic (versus mixed) mood episode, and comorbid disruptive behavior disorders were associated with an increased risk of developing a SUD in univariate analyses. Adolescents treated with psychostimulant treatment before their first manic episode were significantly less likely to develop a SUD independent of attention-deficit/hyperactivity disorder (ADHD) diagnosis. Comorbid posttraumatic stress disorder (PTSD) and psychotic symptoms were the strongest predictors of SUD development. CONCLUSION: Our results confirm high rates of SUD in adolescents with BD. In addition, our findings identify potential risk factors associated with SUDs in adolescents with BD. These data are preliminary in nature and should be explored further in future studies. PMID- 24954827 TI - Mapping the development of the basal ganglia in children with attention deficit/hyperactivity disorder. AB - OBJECTIVE: The basal ganglia are implicated in the pathophysiology of attention deficit/hyperactivity disorder (ADHD), but little is known of their development in the disorder. Here, we mapped basal ganglia development from childhood into late adolescence using methods that define surface morphology with an exquisite level of spatial resolution. METHOD: Surface morphology of the basal ganglia was defined from neuroanatomic magnetic resonance images acquired in 270 youth with DSM-IV-defined ADHD and 270 age- and sex-matched typically developing controls; 220 individuals were scanned at least twice. Using linear mixed model regression, we mapped developmental trajectories from age 4 through 19 years at approximately 7,500 surface vertices in the striatum and globus pallidus. RESULTS: In the ventral striatal surfaces, there was a diagnostic difference in developmental trajectories (t = 5.6, p < .0001). Here, the typically developing group showed surface area expansion with age (estimated rate of increase of 0.54 mm(2) per year, standard error [SE] 0.29 mm(2) per year), whereas the ADHD group showed progressive contraction (decrease of 1.75 mm(2) per year, SE 0.28 mm(2) per year). The ADHD group also showed significant, fixed surface area reductions in dorsal striatal regions, which were detected in childhood at study entry and persisted into adolescence. There was no significant association between history of psychostimulant treatment and developmental trajectories. CONCLUSIONS: Progressive, atypical contraction of the ventral striatal surfaces characterizes ADHD, localizing to regions pivotal in reward processing. This contrasts with fixed, nonprogressive contraction of dorsal striatal surfaces in regions that support executive function and motor planning. PMID- 24954828 TI - Different mechanisms of white matter abnormalities in attention deficit/hyperactivity disorder: a diffusion tensor imaging study. AB - OBJECTIVE: Literature regarding white matter (WM) abnormalities in attention deficit/hyperactivity disorder (ADHD) is sparse and inconsistent. In this article, we shed more light on WM microstructure in ADHD, its association with symptom count, and the familiality of WM abnormalities in ADHD. METHOD: Diffusion tensor imaging (DTI) was performed in a large sample of individuals with ADHD (n = 170), their unaffected siblings (n = 80), and healthy controls (n = 107), aged 8 to 30 years. Extensive categorical as well as dimensional data regarding ADHD status and symptom count were collected. A whole-brain voxelwise approach was used to investigate associations between ADHD status and symptom count and WM microstructure, as measured by fractional anisotropy (FA) and mean diffusivity (MD). RESULTS: Individuals with ADHD showed decreased FA and decreased MD in several widespread, non-overlapping brain regions. In contrast, higher ADHD symptom count was consistently associated with increased FA and decreased MD in the ADHD group. Unaffected siblings resembled individuals in the ADHD group with regard to decreased FA but had MD similar to that in healthy controls. Results were not confounded by socioeconomic status, the presence of comorbidities, or a history of medication use. CONCLUSIONS: Our results indicate widespread disturbances in WM microstructure in ADHD, which seem to be driven by 2 different mechanisms. Decreased FA in ADHD may be due to a familial vulnerability to the disorder, whereas a second mechanism may drive the association between ADHD symptom count and both higher FA and lower MD. Such different mechanisms may play an important role in the inconsistencies found in the current literature. PMID- 24954831 TI - Norepinephrine provides short-term neuroprotection against Abeta1-42 by reducing oxidative stress independent of Nrf2 activation. AB - Pathophysiological evidence correlating locus ceruleus neuron loss with increased Alzheimer's disease pathology suggests that norepinephrine (NE) is neuroprotective. Here, we evaluated the effects of NE on amyloid-beta (Abeta)1-42 induced neurotoxicity and determined how NE exerts its actions in human SK-N-SH neurons. NE protected SK-N-SH cells against Abeta1-42-induced neurotoxicity only after a 4-hour treatment. The ability of NE to reduce Abeta1-42-induced neurotoxicity was independent of the adrenoceptor signaling pathway. Notably, NE downregulated Abeta1-42-mediated increases in intracellular reactive oxygen species (ROS) production. However, NE did not affect Abeta1-42-induced activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) redox signaling pathway, known to be involved in oxidative stress. Among the antioxidants tested, N-acetyl cysteine and glutathione, which are not only ROS scavengers but also thiol-reducing agents, mimicked the protective effects of NE. Consistently, Kelch like ECH-associating protein 1 inhibitors, which activated the Nrf2 pathway, failed to decrease Abeta1-42-induced ROS generation and elicited no protection against Abeta1-42. Taken together, these findings suggest that NE could exert neuroprotective function against Abeta1-42 via redox cycling and reduction of intracellular oxidative stress regardless of downstream activation of the Nrf2 pathway. PMID- 24954829 TI - Early life stress and trauma and enhanced limbic activation to emotionally valenced faces in depressed and healthy children. AB - OBJECTIVE: Previous studies have examined the relationships between structural brain characteristics and early life stress in adults. However, there is limited evidence for functional brain variation associated with early life stress in children. We hypothesized that early life stress and trauma would be associated with increased functional brain activation response to negative emotional faces in children with and without a history of depression. METHOD: Psychiatric diagnosis and life events in children (starting at age 3-5 years) were assessed in a longitudinal study. A follow-up magnetic resonance imaging (MRI) study acquired data (N = 115 at ages 7-12, 51% girls) on functional brain response to fearful, sad, and happy faces relative to neutral faces. We used a region-of interest mask within cortico-limbic areas and conducted regression analyses and repeated-measures analysis of covariance. RESULTS: Greater activation responses to fearful, sad, and happy faces in the amygdala and its neighboring regions were found in children with greater life stress. Moreover, an association between life stress and left hippocampal and globus pallidus activity depended on children's diagnostic status. Finally, all children with greater life trauma showed greater bilateral amygdala and cingulate activity specific to sad faces but not the other emotional faces, although right amygdala activity was moderated by psychiatric status. CONCLUSIONS: These findings suggest that limbic hyperactivity may be a biomarker of early life stress and trauma in children and may have implications in the risk trajectory for depression and other stress-related disorders. However, this pattern varied based on emotion type and history of psychopathology. PMID- 24954833 TI - Suicide in elderly South Tyroleans in various residential settings at the time of death: a psychological autopsy study. AB - BACKGROUND: Completed suicide is more frequent among older adults than any other age group. Data on suicide in nursing homes and other residential facilities are inconsistent. This work aims to describe the characteristics of elderly suicide victims in different residential settings compared to young suicide victims. METHODS: Data on people who died by suicide in the South Tyrol (Alto Adige) region of Italy between 2000 and 2009 were gathered from the local Provincial Mortality Register. Further detailed information was collected via questionnaires to mental health departments and psychological services, family physicians and relatives of the deceased. RESULTS: A total of 525 cases of suicide were recorded, with a linearly decreasing trend during the study period. About one third of the suicides occurred in those aged 60 years and over. Suicide in the elderly was associated with low education level (odds ratio (OR) = 7.1, P < 0.001), living in a one-person household (OR = 2.4, P < 0.01), not having economic troubles (OR = 6.1, P < 0.01), having seen a doctor in the past month (OR = 2.4, P < 0.01) and living in a residential facility (OR = 2.6, P < 0.05). Twenty-four (17.9%) suicide victims aged 60 years and over were in a residential facility/hospital at the time of the death. They were more likely to be women, not married, and to die by jumping from a height. CONCLUSIONS: The suicide risk should be carefully assessed in the elderly who live alone or are institutionalized or hospitalized. Efforts are warranted to reduce seniors' access to high places in hospitals and facilities. PMID- 24954832 TI - Is sense of coherence helpful in coping with caregiver burden for dementia? AB - BACKGROUND: Sense of coherence (SOC) is associated with a reduced risk of various health problems and is thought to be a major factor related to the ability to cope with stress. In the present study, we examined the association between caregiver burden and SOC among caregivers to persons with dementia. METHODS: Participants included 274 caregivers or family members of community-dwelling elderly dementia patients. To assess the cognitive function of patients, neuropsychological tests (e.g. Mini-Mental State Examination, Clinical Dementia Rating) were conducted by a clinical psychologist who was well trained in interviewing participants; the tests used a semi-structured interview protocol. Senior neurologists and psychiatrists also independently evaluated the dementia status of patients. To assess the SOC and caregiver burden, a social welfare counsellor asked questions from a 13-item version of the SOC scale and the short, eight-item Japanese version of the Zarit Caregiver Burden Interview (ZBI). RESULTS: Among 78 caregivers of elderly subjects with cognitive impairment due to dementia, the ZBI score was significantly associated with SOC (r = -0.38, P = 0.001). Multiple regression analyses revealed that SOC scores (beta = -0.42, P < 0.001) and Mini-Mental State Examination scores (beta = -0.28, P = 0.009) were significantly associated with ZBI scores (F(2, 76) = 10.51, P < 0.001). SOC was closely associated with personal strain in the ZBI (beta = -0.41, P < 0.001; F(3, 75) = 8.53, P < 0.001). CONCLUSION: Caregivers with a strong SOC may be less prone to experiencing personal strain from their burden. These results suggest that reinforcement of SOC would contribute to reducing the personal strain. PMID- 24954834 TI - Imaging discrepancies between magnetic resonance imaging and brain perfusion single-photon emission computed tomography in the diagnosis of Alzheimer's disease, and verification with amyloid positron emission tomography. AB - BACKGROUND: In the diagnosis of Alzheimer's disease (AD), discrepancies are often observed between magnetic resonance imaging (MRI) and brain perfusion single photon emission computed tomography (SPECT) findings. MRI, brain perfusion SPECT, and amyloid positron emission tomography (PET) findings were compared in patients with mild cognitive impairment or early AD to clarify the discrepancies between imaging modalities. METHODS: Several imaging markers were investigated, including the cortical average standardized uptake value ratio on amyloid PET, the Z-score of a voxel-based specific regional analysis system for AD on MRI, periventricular hyperintensity grade, deep white matter hyperintense signal grade, number of microbleeds, and three indicators of the easy Z-score imaging system for a specific SPECT volume-of-interest analysis. Based on the results of the regional analysis and the three indicators, we classified patients into four groups and then compared the results of amyloid PET, periventricular hyperintensity grade, deep white matter hyperintense signal grade, and the numbers of microbleeds among the groups. RESULTS: The amyloid deposition was the highest in the group that presented typical AD findings on both the regional analysis and the three indicators. The two groups that showed an imaging discrepancy between the regional analysis and the three indicators demonstrated intermediate amyloid deposition findings compared with the typical and atypical groups. The patients who showed hippocampal atrophy on the regional analysis and atypical AD findings using the three indicators were approximately 60% amyloid-negative. The mean periventricular hyperintensity grade was highest in the typical group. CONCLUSIONS: Patients showing discrepancies between MRI and SPECT demonstrated intermediate amyloid deposition findings compared with patients who showed typical or atypical findings. Strong white matter signal abnormalities on MRI in patients who presented typical AD findings provided further evidence for the involvement of vascular factors in AD. PMID- 24954835 TI - Do depressive symptoms on hospital admission impact early functional outcome in elderly patients with hip fracture? AB - BACKGROUND: Depression is the most common mood disorder in elderly people and one of the most prevalent comorbidities in older people with hip fracture. While several authors have confirmed that depressive symptoms assessed at a later stage after hip fracture impact functional outcome and mortality, the role of depressive symptoms identified at an earlier stage after hip fracture remains understudied. The aim of the present study was to determine if depressive symptoms assessed on hospital admission impact early functional outcome after hip fracture surgery. METHODS: We studied 112 patients who underwent surgery for hip fracture during a 6-month period. Depressive symptoms were assessed using the 30 item Geriatric Depression Scale on admission to the acute setting. Multidimensional assessment included sociodemographic characteristics, general health status, cognitive status, functional status prior to injury, and perioperative variables. The primary outcome measure was motor Functional Independence Measure at discharge. RESULTS: Adjusted multivariate regression analysis revealed that the presence of moderate to severe depressive symptoms (Geriatric Depression Scale >= 20), older age, and female gender were independently related to motor Functional Independence Measure at discharge. CONCLUSION: Increasing levels of depressive symptoms in elderly hip fracture patients influence short-term functional outcome. We strongly support the introduction of routine assessment of this baseline comorbidity, especially in female patients. Failure to identify such patients is a missed opportunity for possible improvement of early functional outcome after hip fracture in elderly. PMID- 24954836 TI - Predictors of length of hospital stay for patients with late-onset depression in Japan. AB - BACKGROUND: The length of hospital stay (LOHS) for elderly patients tends to be long. We aimed to identify factors related to long hospitalization periods for elderly Japanese patients with late-onset depression. METHODS: We retrospectively examined 133 patients with late-onset depression. Univariate and multivariate analyses were performed to confirm the relationship between each clinical feature and the duration of hospital stay. RESULTS: The mean LOHS was 83.9 +/- 55.6 days. On the basis of univariate analysis, we found that living as a housewife, death of a close relative or friend, recurrent depression, melancholic features, and treatment with electroconvulsive therapy, tricyclic or tetracyclic antidepressants or mood stabilizer were associated with a longer LOHS. Multivariate analysis showed that treatment with tricyclic or tetracyclic antidepressants, atypical antipsychotics were associated with prolonged LOHS. CONCLUSIONS: These results suggest that job status, changes in household circumstances and the failure of initial treatment is responsible for the long LOHS in Japan. PMID- 24954837 TI - Immune response and disease resistance of carotenoids supplementation diet in Cyprinus carpio against Aeromonas hydrophila. AB - The effect of carotenoid-supplementation diet on immune response and disease resistance in common carp, Cyprinus carpio against Aeromonas hydrophila at weeks 1, 2, and 4 is reported. The cumulative mortality was 10% when fish were fed with 50 or 100 mg kg(-1) supplementation diets while the un-supplementation diet treated group suffered 90% mortality against the pathogen. The phagocytic activity and complement activity significantly increased with 50 and 100 mg kg( 1) diet groups from weeks 2 and 4 but not in other groups. The reactive oxygen species (ROS) production was significantly enhanced with 50 and 100 mg kg(-1) diets from weeks 1 to 4 while the production of reactive nitrogen species (RNS) enhanced on weeks 2 and 4. The lysozyme activity significantly increased when fed with 50 and 100 mg kg(-1) diets on weeks 2 and all supplementation diets on week 4. These results suggest that diet enriched with carotenoid pigment positively enhance the immune status and protects C. carpio from A. hydrophila infection. PMID- 24954838 TI - Lipopolysaccharides isolated from Aeromonas salmonicida and Vibrio anguillarum show quantitative but not qualitative differences in inflammatory outcome in Sparus aurata (Gilthead seabream). AB - In fish, the defence system recognises pathogenic microorganisms via pathogen recognition receptors (PRRs) that sense particular structures of the pathogens; the so-called pathogen associated molecular patterns (PAMPs) such as bacterial lipopolysaccharides (LPSs). The result of the PAMP-PRR interactions leads to complex and orchestrated immune responses. In this study, Sparus aurata (Gilthead seabream) were intraperitoneally injected with purified lipopolysaccharide (LPS) from Aeromonas salmonicida (As)- and Vibrio anguillarum (Va) (1 mg*Kgfish(-1)), both Gram negative bacteria responsible for vibriosis and furunculosis respectively, therefore causing an impact upon marine fish cultures. Head-kidney, intestine, spleen, liver and blood samples were collected at 3, 6, 12 and 24 h post-injection. Plasma levels of cortisol, prostaglandins and lactate were measured and were significantly increased after As-LPS and Va-LPS treatment. Furthermore, tissue-specific differences of the gene regulatory patterns were evident for each LPS. When monocyte/macrophage cell cultures were challenged with As-LPS and Va-LPS, the pro-inflammatory cytokine mRNA abundances present a similar pattern of response. However, As-LPS always triggered a stronger response concerning TNFalpha, IL1beta and cyclooxygenase-2 (COX2) mRNA abundance as well as PGE2 levels in the supernatant. Overall, the results indicate that specific LPSs do not activate different pro-inflammatory responses and that the observed gene expression pattern is tissue and concentration dependent. PMID- 24954839 TI - Deoxycholic acid induced changes in electrophysiological parameters and macromolecular permeability in murine small intestine with and without functional enteric nervous system plexuses. AB - BACKGROUND: We have previously shown in mice that the fecal proportion and concentration of the hydrophobic bile acid deoxycholic acid (DCA) is elevated with high-fat feeding and that these changes are able to disrupt the intestinal barrier function. The aim of this study was to investigate whether these changes are mediated by the enteric nervous system (ENS). METHODS: The function of the ENS in the small intestinal tissues of mice was compromised by two different methods: by removing the seromuscular layer and by incubating the intact tissues with tetrodotoxin (TTX), a neural conduction blocker, before DCA treatment. Tissues with or without functional plexuses were mounted into a Ussing chamber system and treated with 3 mM DCA for 20 min. After DCA treatment, the intestinal permeability to fluorescein was assessed. Short-circuit current (Isc ) and transepithelial resistance (TER) were recorded throughout the experiment. KEY RESULTS: DCA increased intestinal fluorescein permeability only in tissues where the seromuscular layer was removed. In tissues with intact seromuscular layer, DCA induced a significant increase in TER, which was attenuated by blocking of the neural function by TTX. CONCLUSIONS & INFERENCES: The results of this study suggest that the DCA-induced increase observed in fluorescein permeability is not mediated through neural pathways, but more due to a direct effect on the epithelium. However, as TTX was able to attenuate the DCA-induced increase in TER, it can be speculated that DCA is also able to elicit responses through neural pathways. PMID- 24954841 TI - AZF gene microdeletions: case series and literature review. AB - OBJECTIVE: Aproximately 10% of patients with non-obstructive azoospermia and 5% with non-obstructive severe oligozoospermia carry AZF region microdeletions (AZoospermic Factor) in the Y chromosome. The aim of this study is to analize the clinical and pathological findings in this group of patients and compare them with the previous evidence. MATERIAL AND METHODS: Retrospective study of 11 patients with diagnosis of azoospermia or oligozoospermia and the presence of AZFa, AZFb, AZFc microdeletions or any combination of them. RESULTS: Microdeletions of AZFc region were found in 45% of cases, AZFa in 33% and a 10% showed a deletion of the three regions (a,b and c). 91% of them demonstrated azoospermia with low testicular volume in 62,5% cases. CONCLUSION: Microdeletions of AZF regions are associated with azoospermia and a low expectation of sperm retrieval in testicular biopsy. On the other hand, they seem not related with significative modifications on the hormone profile. PMID- 24954842 TI - Bacterial characteristics and clinical significance of ureteral double-J stents in children. AB - OBJECTIVE: To determine the incidence of urinary tract infection in those patients that we have used an ureteral double-J stent as internal diversion after urological procedures. MATERIAL AND METHODS: We reviewed all the medical records of patients who had a ureteral double-J stent after a urological procedure from August 2007 to May 2013. We have analyzed the following data: age, gender, type of prophylaxis, incidence of urinary tract infection (UTI), days of internal diversion with double-J stent, surgical procedure, bacterial characteristics, bacterial sensibility to antibiotics and UTI treatment. RESULTS: We have used 73 double-J stents as ureteral internal diversion in 67 patients with a mean age of 44.73+/-57.23. Surgical procedures were 50 laparoscopic Anderson-Hynes pyeloplasties in 49 patients, and 20 high-pressure balloon dilatation of the ureterovesical junction to treat primary obstructive megaureter in 15 patients; and 3 patients with ureterovesical obstruction after endoscopic treatment of vesicoureteral reflux. Forty three stents showed a bacterial colonization in cultures. Pseudomona aeruginosa was present in 9 (20.9%) stents. Only in 12 stents, bacterial colonization was sensible to antibiotic prophylaxis. Stent colonization was higher in boys and younger patients. Four patients had a febrile UTI. Incidence of UTI in younger patients that underwent HBPD of UVJ is higher. CONCLUSION: Bacterial colonization is frequent in double-J stents but the incidence of UTI is low. Double-J colonization is higher in younger patients. Patients that underwent HPBD have a higher risk of UTI related with ureteral double J stent. PMID- 24954844 TI - Impaired off-line motor skills consolidation in young primary insomniacs. AB - Compelling evidence indicates that sleep can facilitate the off-line consolidation of declarative, perceptual, emotional and procedural memories. Here we assessed the sleep-related off-line consolidation of motor skills in 13 young primary insomniacs (23.31+/-2.5 yrs) compared to 13 healthy sleepers (24.31+/-1.6 yrs) using the sequential finger tapping task. During a training session insomniacs performed less correct sequences than controls. However, both groups exhibited similar on-line motor learning in the pre-sleep evening session. After a night of sleep, healthy controls improved their performance, indicating an overnight effect of sleep on motor skills consolidation. In contrast, insomniacs failed to exhibit a sleep-related enhancement in memory performance indicating impairment in the off-line motor skills consolidation process. Our results suggest that young adults with insomnia experience impaired off-line memory consolidation which seems not to be associated with reduced ability to acquire new motor information. PMID- 24954848 TI - The unsung heroes in science. PMID- 24954840 TI - Cross-validation of serial optical coherence scanning and diffusion tensor imaging: a study on neural fiber maps in human medulla oblongata. AB - We established a strategy to perform cross-validation of serial optical coherence scanner imaging (SOCS) and diffusion tensor imaging (DTI) on a postmortem human medulla. Following DTI, the sample was serially scanned by SOCS, which integrates a vibratome slicer and a multi-contrast optical coherence tomography rig for large-scale three-dimensional imaging at microscopic resolution. The DTI dataset was registered to the SOCS space. An average correlation coefficient of 0.9 was found between the co-registered fiber maps constructed by fractional anisotropy and retardance contrasts. Pixelwise comparison of fiber orientations demonstrated good agreement between the DTI and SOCS measures. Details of the comparison were studied in regions exhibiting a variety of fiber organizations. DTI estimated the preferential orientation of small fiber tracts; however, it didn't capture their complex patterns as SOCS did. In terms of resolution and imaging depth, SOCS and DTI complement each other, and open new avenues for cross-modality investigations of the brain. PMID- 24954843 TI - Differential effects of acute cortisol administration on deep and shallow episodic memory traces: a study on healthy males. AB - We aimed at investigating rapid effects of plasma cortisol elevations on the episodic memory phase of encoding or retrieval, and on the strength of the memory trace. Participants were asked either to select a word containing the letter "e" (shallow encoding task) or to judge if a word referred to a living entity (deep encoding task). We intravenously administered a bolus of 20mg of cortisol either 5 min before encoding or 5 min before retrieval, in a between-subjects design. The study included only male participants tested in the late afternoon, and neutral words as stimuli. When cortisol administration occurred prior to retrieval, a main effect of group emerged. Recognition accuracy was higher for individuals who received cortisol compared to placebo. The higher discrimination accuracy for the cortisol group was significant for words encoded during deep but not shallow task. Cortisol administration before encoding did not affect subsequent retrieval performance (either for deep or shallow stimuli) despite a facilitatory trend. Because genomic mechanisms take some time to develop, such a mechanism cannot apply to our findings where the memory task was performed shortly after the enhancement of glucocorticoid levels. Therefore, glucocorticoids, through non-genomic fast effects, determine an enhancement in episodic memory if administered immediately prior to retrieval. This effect is more evident if the memory trace is laid down through deep encoding operations involving the recruitment of specific neural networks. PMID- 24954845 TI - Characterization of the fecal microbiome in different swine groups by high throughput sequencing. AB - Swine have a complex microbial community within their gastrointestinal tract that plays a critical role in both health and disease. High-throughput 16S rRNA gene based pyrosequencing was used to identify the possible core microorganisms in the gut of swine groups that differ in meat quality and weight grades (level 1 as higher meat quality and level 2 as lower meat quality). Samples were taken from the rectum and/or stool from ten animals, DNA was extracted, and the V1-V3 regions of the 16S rRNA gene were amplified. Two bacterial populations (Bacteroidetes and Firmicutes) dominated and were shared between the two groups. Significant differences between the groups were found at the genus level. The genera Lactobacillus and Oscillibacter were found in slightly higher proportions in the level 2 group (12.6 and 12.4% of the classified reads, respectively) than those of level 1 (9.6 and 7.7%, respectively). By contrast, the proportion of reads assigned to the genus Roseburia in the level 1 group (13.0%) was higher than that of level 2 (4.8%). The largest differences were related to the genera Clostridium, Oscillibacter, and Roseburia as core microorganisms. Moreover, two genera, Roseburia and Clostridium, related to level 1 produced linoleic acid or short chain fatty acids that might contribute to swine health and development. In conclusion, the presence of core bacteria in the swine gut is associated with meat quality with reduced body fat in swine. PMID- 24954854 TI - Implicit learning is better at subjectively defined non-optimal time of day. AB - Individual preferences in morningness-eveningness rhythms modulate temporal fluctuations of cognitive performance over a normal day. Besides enhanced cognitive performance at individual's peak time as derived from morningness eveningness questionnaires, a few studies have shown increased implicit memory abilities at a non-optimal (NOP) time of day. Various subjective factors might also determine the clock time for high or low cognitive efficiency. Using an artificial grammar learning (AGL) task, we show enhanced implicit learning of high-order information at NOP [vs optimal (OP)] time of day as subjectively defined by participants, irrespective of morningness-eveningness scores. Our results suggest that subjectively defined efficiency periods are a modulating factor in the testing of cognitive functions. PMID- 24954855 TI - Methyl CpG binding domain ultra-sequencing: a novel method for identifying inter individual and cell-type-specific variation in DNA methylation. AB - Experience-dependent changes in DNA methylation can exert profound effects on neuronal function and behaviour. A single learning event can induce a variety of DNA modifications within the neuronal genome, some of which may be common to all individuals experiencing the event, whereas others may occur in a subset of individuals. Variations in experience-induced DNA methylation may subsequently confer increased vulnerability or resilience to the development of neuropsychiatric disorders. However, the detection of experience-dependent changes in DNA methylation in the brain has been hindered by the interrogation of heterogeneous cell populations, regional differences in epigenetic states and the use of pooled tissue obtained from multiple individuals. Methyl CpG Binding Domain Ultra-Sequencing (MBD Ultra-Seq) overcomes current limitations on genome wide epigenetic profiling by incorporating fluorescence-activated cell sorting and sample-specific barcoding to examine cell-type-specific CpG methylation in discrete brain regions of individuals. We demonstrate the value of this method by characterizing differences in 5-methylcytosine (5mC) in neurons and non-neurons of the ventromedial prefrontal cortex of individual adult C57BL/6 mice, using as little as 50 ng of genomic DNA per sample. We find that the neuronal methylome is characterized by greater CpG methylation as well as the enrichment of 5mC within intergenic loci. In conclusion, MBD Ultra-Seq is a robust method for detecting DNA methylation in neurons derived from discrete brain regions of individual animals. This protocol will facilitate the detection of experience-dependent changes in DNA methylation in a variety of behavioural paradigms and help identify aberrant experience-induced DNA methylation that may underlie risk and resiliency to neuropsychiatric disease. PMID- 24954856 TI - Histone deacetylase inhibitor-mediated cell death is distinct from its global effect on chromatin. AB - Romidepsin and vorinostat are histone deacetylase inhibitors (HDACis) that have activity in T-cell lymphomas, but have not gained traction in solid tumors. To gain deeper insight into mechanisms of HDACi efficacy, we systematically surveyed 19 cell lines with different molecular phenotypes, comparing romidepsin and vorinostat at equipotent doses. Acetylation at H3K9 and H4K8 along with 22 other histone lysine acetylation and methylation modifications were measured by reverse phase proteomics array (RPPA), and compared with growth inhibition (IC50), and cell cycle arrest. These assays typically used to assess HDACi effect showed that acetylation and methylation of specific lysine residues in response to HDACis were consistent across cell lines, and not related to drug sensitivity. Using a treatment duration more reflective of the clinical exposure, cell death detected by annexin staining following a 6 h drug exposure identified a subset of cell lines, including the T-cell lymphoma line, that was markedly more sensitive to HDAC inhibition. Kinetic parameters (Km values) were determined for lysine acetylation and for cell cycle data and were themselves correlated following HDACi exposure, but neither parameter correlated with cell death. The impact on cell survival signaling varied with the molecular phenotype. This study suggests that cellular response to HDACis can be viewed as two distinct effects: a chromatin effect and a cell death effect. All cells undergo acetylation, which is necessary but not sufficient for cell death. Cells not primed for apoptosis will not respond with cell death to the impact of altered histone acetylation. The divergent apoptotic responses observed reflect the variable clinical outcome of HDACi treatment. These observations should change our approach to the development of therapeutic strategies that exploit the dual activities of HDACis. PMID- 24954857 TI - Interleukin-6 drives melanoma cell motility through p38alpha-MAPK-dependent up regulation of WNT5A expression. AB - Extensive research has demonstrated a tumor-promoting role of increased WNT5A expression in malignant melanoma. However, very little light has been shed upon how WNT5A expression is up-regulated in melanoma. A potential regulator of WNT5A expression is the pro-inflammatory cytokine Interleukin (IL)-6, which shares the ability of WNT5A to increase melanoma cell invasion. Here, we investigate whether IL-6 can promote melanoma cell motility through an increased expression of WNT5A. We clearly demonstrate that the WNT5A-antagonistic peptide Box5 could inhibit IL 6-induced melanoma cell migration and invasion. Furthermore, IL-6 stimulation of the human melanoma cell lines HTB63 and A375 increased the expression of WNT5A in a dose-dependent manner. To identify the signaling mechanism responsible for this up-regulation, we explored the involvement of the three main signals induced by IL-6; STAT3, Akt and ERK 1/2. Of these, only STAT3 was activated by IL-6 in the melanoma cell lines tested. However, the STAT3 inhibitor S3I-201 failed to inhibit IL-6-induced WNT5A up-regulation in HTB63 and A375 cells. Nor did STAT3 siRNA silencing affect the expression of WNT5A. In search of an alternative signaling mechanism, we detected IL-6-induced activation of p38-MAPK in HTB63 and A375 cells. The p38-MAPK inhibitor SB203580 abolished the IL-6-induced WNT5A up regulation and blocked IL-6-induced melanoma cell invasion. The latter effect could be rescued by the addition of recombinant WNT5A. Notably, immunoprecipitation analysis revealed that only the p38alpha-MAPK isoform was activated by IL-6, and subsequent siRNA silencing of p38alpha-MAPK abolished the IL-6-induced up-regulation of WNT5A. Taken together, we demonstrate a novel link between the two melanoma pro-metastatic agents IL-6 and WNT5A explaining how IL-6 can increase melanoma cell invasion and thus promote the metastatic process. This finding provides a basis for future therapeutic intervention of melanoma progression. PMID- 24954859 TI - Differential role of apoptosis and autophagy associated with anticancer effect of lupulone (hop beta-acid) derivatives on prostate cancer cells. AB - Lupulone, a beta-acid derived from hop extracts has been shown to exhibit cytotoxic activity against cancer cells. In this study we investigated the functional role of different modes of cell death that mediate anticancer effect of lupulone derivatives in prostate cancer cells. ELISA, immunoblotting and siRNA approaches were utilised to study cell death, expression of proteins of interest and their functional activities. We found that the anticancer effect of lupulone derivatives on prostate cancer cells is associated with induction of apoptosis and autophagy as determined by increases of DNA fragmentation and LC3I/ LC3II conversion respectively. Inhibition of apoptosis using a pan-caspase inhibitor resulted in increased levels of autophagy. Following screening of proteins associated with autophagy we found that Atg4beta expression was increased in prostate cancer cells after treatment with lupulone. Transfection of cells with siRNA against Atg4beta resulted in increased levels of apoptosis in prostate cancer cells. Treatment of prostate cancer cells with lupulone derivatives initiated two modes of cell death: apoptosis as a killing pathway and autophagy as a protection against cell death. Further studies are required to investigate the regulation of Atg4beta activity in lupulone derivatives-induced negative crosstalk between apoptosis and autophagy. PMID- 24954861 TI - Medicinal chemistry. Editorial. PMID- 24954858 TI - Long noncoding RNA profiles identify five distinct molecular subtypes of colorectal cancer with clinical relevance. AB - Colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behavior and response to therapy. Increasing evidence suggests that long noncoding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, and some of them have been implicated in CRC biogenesis and prognosis. Using an lncRNA-mining approach, we constructed lncRNAs expression profiles in approximately 888 CRC samples. By applying unsupervised consensus clustering to LncRNA expression profiles, we identified five distinct molecular subtypes of CRC with different biological pathways and phenotypically distinct in their clinical outcome in both univariate and multivariate analysis. The prognostic significance of the lncRNA-based classifier was confirmed in independent patient cohorts. Further analysis revealed that most of the signature lncRNAs positively correlated with somatic copy number alterations (SCNAs). This lncRNAs-based classification schema thus provides a molecular classification applicable to individual tumors that has implications to influence treatment decisions. PMID- 24954860 TI - Dinuclear berenil-platinum (II) complexes as modulators of apoptosis in human MCF 7 and MDA-MB231 breast cancer cells. AB - The metabolism of alkylating agents is accompanied by the generation of reactive oxygen species. The aim of this study was to treat estrogen receptor-positive and estrogen receptor-negative human breast cancer cells, MCF-7 and MDA-MB-231, respectively, with cisplatin and five different berenil-platinum (II) complexes, and then to investigate the oxidative modifications of DNA, lipid and protein, and to compare them with the profile of various pro- and antiapoptotic proteins. Changes in the levels of 8-hydroxy-2'-deoxyguanosine, 4-hydroxynonenal, carbonyl groups, dityrosine, active caspases 3, 8 and 9, as well as the expression of Bcl 2, Bax, cytochrome c, and p53 were subsequently examined. Activities of superoxide dismutase, catalase and glutathione, vitamin C levels were also investigated. Cellular reactions to cisplatin and the berenil-platinum (II) derivatives were more pronounced in MCF-7 cells as compared with the MDA-MB231 cells. Furthermore, the berenil-platinum (II) derivatives were found to be more effective than cisplatin. All of the complexes reduced the activity of superoxide dismutase and catalase, and also lowered the levels of non-enzymatic antioxidants. Increased level of lipid, protein as well as DNA damage markers was also observed after berenil-platinum (II) derivatives treatment. Similarly, the increase in the levels of the proapoptotic factors, were detected in MCF-7 and MDA-MB231 cells. Incubation of examined cells with the berenil-platinum (II) complexes also led to the increase in the levels of active caspases 3, 8 and 9. In conclusion, the results of the present study demonstrated that berenil platinum (II) complexes more efficiently mediate cellular oxidative modifications and proapoptotic metabolism, particularly in MCF-7 cells, compared to cisplatin. Pt2(isopropylamine)4berenil2 and Pt2(piperidine)4(berenil)2 notably affected the cellular metabolism of estrogen-positive breast cancer cells. Thus, these complexes may be valuable for the design of additional anticancer drugs. PMID- 24954862 TI - [Cochlear microphonic latency]. AB - INTRODUCTION AND OBJECTIVE: By using appropriate instrumentation, we have found that cochlear microphonics (CM) advance or delay their appearance, depending on the sound pressure that generates them. This time variation is on the order of microseconds. We have not found any reference to this behaviour, which is why we make the finding known. MATERIAL AND METHOD: We used the standard instrumentation specified for the study of CM. The method was based on the phase shift function of the CM according to the intensity of the stimulus. RESULTS: Latency was observed in CM, and we determined that latency time diminishes as the intensity of the stimulus increases. CONCLUSIONS: From the sound stimulus to the bioelectric potential transduction, there is a time period of microseconds, the shorter the more powerful the stimulus. This suggests that electromechanical transduction is not a simple mechanical process. PMID- 24954863 TI - Drill-induced noise level during cochleostomy. AB - CONCLUSIONS: Noise induced by drilling during cochleostomy is of high level and can cause acoustic trauma to the inner ear, particularly after the membranous labyrinth has been exposed. Our method utilizes non-invasive noise measurement and the equipment that is connected to the operative area can be sterilized, thus it can be applied to intraoperative recordings. OBJECTIVES: To investigate the noise level generated by otological electrical drills during the cochleostomy procedure and to further explore the feasibility of noise monitoring in vivo. METHODS: Acoustic measurements during drilling on the promontory of cochleae were carried out on 16 human cadavers (19 ears) using an ER7C probe microphone system. RESULTS: The peak noise level generated during cochleostomy differed obviously from specimen to specimen and ranged from 85.9 to 131.5 dB SPL. We found three cases in which the peak noise level exceeded 130 dB SPL when the running burr touched the endosteal membrane. PMID- 24954864 TI - Biodiversity differentials between the numerically-dominant macrobenthos of seagrass and adjacent unvegetated sediment in the absence of sandflat bioturbation. AB - Species composition, abundance and biodiversity of the South African estuarine invertebrate fauna are known to show marked differentials between seagrass beds and adjacent unvegetated sands in enclosed estuarine/marine bays. Such differentials were investigated at four disparate localities in a bay lacking the callianassid bioturbation of other local sites. Here there were no such marked or consistent differences: <50% of differentials were statistically significant, with seagrass showing the lower, not higher, level in half of those. Overall, faunal abundance was lower in seagrass in the ratio of 0.64 : 1, whilst species density was higher but only by 1.13 to 1. Seagrass assemblages at a given locality were more similar to those of the adjacent bare sand than they were to seagrass assemblages at other localities, and likewise in respect of those in the bare sand. This suggests that marked differentials, where they occur, may result not from any supposed favourability of seagrass as a habitat but from the operation of processes within the unvegetated-sediment compartment of the system. PMID- 24954866 TI - Long-term consequences of bile duct injury after cholecystectomy. AB - Late complications arising after bile duct injury (BDI) include biliary strictures, hepatic atrophy, cholangitis and intra-hepatic lithiasis. Later, fibrosis or even secondary biliary cirrhosis and portal hypertension can develop, enhanced by prolonged biliary obstruction associated with recurrent cholangitis. Secondary biliary cirrhosis resulting in associated hepatic failure or digestive tract bleeding due to portal hypertension is a substantial risk factor for morbidity and mortality after bile duct repair. Parameters that determine the management of late complications of BDI include the type of biliary injury, associated vascular injury, hepatic atrophy, the presence of intra-hepatic strictures or lithiasis, repetitive infectious complications, the quality of underlying parenchyma (fibrosis, secondary biliary cirrhosis) and the presence of portal hypertension. Endoscopic drainage is indicated for patients with uncontrolled acute sepsis, patients at high operative risk, patients with cirrhosis who are not eligible for liver transplantation and patients who have previously undergone several attempts at repair. Roux-en-Y hepaticojejunostomy, whether de novo or as an iterative repair, is the technique of reference for post cholecystectomy BDI. Hepatic resection is indicated in only rare instances, mainly in case of extended hilar stricture, multiple stone retention in one sector of the liver or in patients for whom the repair is deemed technically difficult. Liver transplantation is indicated only in exceptional circumstances, when secondary biliary cirrhosis is associated with liver failure and portal hypertension. PMID- 24954867 TI - Excision of thymic remnants via cervicotomy. PMID- 24954865 TI - A cell-surface beta-hydroxylase is a biomarker and therapeutic target for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) has a poor prognosis as a result of widespread intra- and extrahepatic metastases. There is an urgent need to understand signaling cascades that promote disease progression. Aspartyl-(asparaginyl)-beta hydroxylase (ASPH) is a cell-surface enzyme that generates enhanced cell motility, migration, invasion, and metastatic spread in HCC. We hypothesize that inhibition of its enzymatic activity could have antitumor effects. Small molecule inhibitors (SMIs) were developed based on the crystal structure of the ASPH catalytic site followed by computer-assisted drug design. Candidate compounds were tested for inhibition of beta-hydroxylase activity and selected for their capability to modulate cell proliferation, migration, invasion, and colony formation in vitro and to inhibit HCC tumor growth in vivo using orthotopic and subcutaneous murine models. The biological effects of SMIs on the Notch signaling cascade were evaluated. The SMI inhibitor, MO-I-1100, was selected because it reduced ASPH enzymatic activity by 80% and suppressed HCC cell migration, invasion, and anchorage-independent growth. Furthermore, substantial inhibition of HCC tumor growth and progression was observed in both animal models. The mechanism(s) for this antitumor effect was associated with reduced activation of Notch signaling both in vitro and in vivo. CONCLUSIONS: These studies suggest that the enzymatic activity of ASPH is important for hepatic oncogenesis. Reduced beta-hydroxylase activity generated by the SMI MO-I-1100 leads to antitumor effects through inhibiting Notch signaling cascade in HCC. ASPH promotes the generation of an HCC malignant phenotype and represents an attractive molecular target for therapy of this fatal disease. PMID- 24954868 TI - Epidemiology and control of bovine herpesvirus 1 infection in Europe. AB - Bovine herpesvirus 1 (BHV-1) causes infectious bovine rhinotracheitis (IBR), infectious pustular vulvovaginitis, abortion and balanoposthitis, as well as neurological and systemic disease in cattle. The virus is endemic in cattle populations worldwide although in Europe six countries and several regions in other countries have achieved 'IBR-free' status by implementing control measures. According to European Union (EU) directives, all member states must comply with specific requirements related to BHV-1 infection status in semen and embryos. The requirement that 'IBR-free' states restrict the importation of cattle from endemically infected regions has motivated several European countries to instigate disease eradication programmes. Despite such control measures within the EU, outbreaks of IBR persist in 'IBR-free' states contiguous with infected countries. This review presents a summary of recent research on the epidemiology of BHV-1, highlights the control measures and surveillance systems in place, and discusses the challenges facing eradication schemes. PMID- 24954869 TI - Dose-dependent effect of experimental Schmallenberg virus infection in sheep. AB - Schmallenberg virus (SBV) is an orthobunyavirus affecting European domestic ruminants. In this study, the dose-dependent effect of experimental infection of sheep with SBV was evaluated. Four groups of three ewes were each inoculated subcutaneously with 1 mL of successive 10-fold dilutions of an SBV infectious serum. The ewes were monitored for 10 days, but no clinical signs were observed. The number of productively infected animals within each group, as evidenced by viraemia, seroconversion and viral RNA in the organs, depended on the inoculated dose, indicating that a critical dose has to be administered to obtain a homogeneous response in infected animals under experimental conditions. In the productively infected animals, no statistical differences between the different inoculation doses were found in the duration or quantity of viral RNA circulating in blood, nor in the amount of viral RNA present in virus positive lymphoid organs. PMID- 24954870 TI - Longitudinal prevalence and faecal shedding of Chlamydia pecorum in sheep. AB - The prevalence and faecal shedding of Chlamydia spp. in sheep in Australia has not been well described. Two species-specific quantitative PCRs (qPCRs) targeting the chlamydial outer membrane protein cell surface antigen gene (ompA) were validated and used to determine the prevalence and faecal shedding of C. abortus and C. pecorum from faecal samples of lambs at three sampling times (weaning, post-weaning and pre-slaughter) from eight farms in South Australia, New South Wales, Victoria and Western Australia. A total of 3412 faecal samples were collected and screened from approximately 1189 lambs across the four states. C. abortus was not detected in any of the samples screened. The overall prevalence of C. pecorum was 1027/3412 (30.1%) and median bacterial concentrations at weaning, post-weaning and pre-slaughter were 1.8 * 10(7), 1.2 * 10(7) and 9.6 * 10(5)/g faeces, respectively. A subset of C. pecorum positive samples from each farm, (n = 48) was sequenced to confirm their identity. The present study demonstrates that C. pecorum is prevalent in Australian sheep, highlighting a need for further research on the impact of this bacterium on production. PMID- 24954871 TI - CIP2A mediates erlotinib-induced apoptosis in non-small cell lung cancer cells without EGFR mutation. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors show favorable clinical response in some patients with non-small cell lung cancer (NSCLC) who have no EGFR mutation, indicating alternative mechanisms for their tumoricidal effects. We previously showed erlotinib, a selective EGFR antagonist, inhibited the growth of sensitive hepatocellular carcinoma cells by inhibiting the cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway. The aim of this study was to determine if erlotinib can also inhibit the growth of NSCLC cells by inactivating the CIP2A-dependent signaling pathway. METHODS: Four NSCLC cell lines (H358 H441 H460 and A549) were treated with erlotinib to determine their sensitivity to erlotinib-induced cell death and apoptosis. Expression of CIP2A and the downstream AKT were analyzed. The effects of CIP2A on erlotinib-induced apoptosis were confirmed by overexpression of CIP2A and knockdown of CIP2A gene expression in the sensitive cells and resistant cells, respectively. In vivo efficacy of erlotinib against H358 xenograft tumor was also determined in nude mice. RESULTS: Erlotinib induced significant cell death and apoptosis in H358 and H441 cells, as evidenced by increased caspase 3 activity and cleavage of pro caspase 9 and PARP, but not in H460 or A549 cells. The apoptotic effect of erlotinib in the sensitive H358 cells was associated with downregulation of CIP2A, increase in PP2A activity and decrease in AKT phosphorylation. Overexpression of CIP2A and AKT protected the sensitive H358 cells from erlotinib induced apoptosis. Knockdown of CIP2A gene expression by siRNA enhanced the erlotinib-induced apoptotic in the resistant H460 cells that resembled the sensitive H358 cells. Erlotinib also inhibited the growth of H358 tumors in nude mice. CONCLUSIONS: The CIP2A-dependent pathway mediates the tumoricidal effects of erlotinib on NSCLC cells without EGFR mutations in vitro and in vivo. CIP2A may be a novel molecular target against NSCLC for future drug development. PMID- 24954872 TI - Oligogenic germline mutations identified in early non-smokers lung adenocarcinoma patients. AB - OBJECTIVES: A polygenic model is commonly assumed for the predisposition to common cancers. With respect to lung cancer, Genome Wide Association Studies (GWAS) have identified three loci at 15q25, 5p15.33, and 6p21. However, the relative risks associated with alleles at these loci are low; in addition, the data are limited to smokers, and have not been quite reproducible. MATERIALS AND METHODS: In order to investigate genetic susceptibility we have adopted an entirely novel patient selection strategy. First, we have selected for adenocarcinoma (ADCA) histology only; second, we have selected non-smokers; third we have selected patients who developed ADCA of lung before the age of 60 and who had an older unaffected sib: we have identified 31 such sib-pairs. Among them, we selected two patients with very early age at disease onset (37- and 49-years old), and having a healthy sibling available for genome comparison older than at least 7 years. RESULTS: On germline DNA samples of four subjects of two such pairs we have carried out whole exome sequencing. Truncating mutations were detected in 8 'cancer genes' in one affected, and in 5 cancer genes in the other affected subject: but none in the two healthy sibs (p=0.0026). Some of these mutant genes (such as BAG6, SPEN and WISP3) are recognized as major cancer players in lung tumors; others have been previously identified in other human cancers (JAK2, TCEB3C, NELFE, TAF1B, EBLN2), in mouse models (GON4L, NOP58, and RBMX) or in genome-wide association studies (KIAA2018, ZNF311). CONCLUSIONS: This study identifies for the first time in non-smokers with lung adenocarcinoma specific sets of germline mutations that, together, may predispose to this tumor. PMID- 24954873 TI - Successful video-assisted thoracoscopic lobectomy in a pregnant woman with lung cancer. AB - A 38-year-old non-smoking female patient was evaluated at our hospital for an increasing mass in the right lower lung field at 24 weeks of gestation. Computed tomography revealed an approximately 7.5-cm diameter mass in the right lower lung lobe. After assessing the benefits to the patient and risks to the fetus, we performed a lobectomy with mediastinal lymph node dissection using video-assisted thoracoscopy. Three months postoperatively, the patient delivered a healthy male baby. The patient is alive 10 months following the lobectomy, and no evidence of recurrence and distant metastasis is noted. The 6-month-old infant is also doing well postpartum. PMID- 24954874 TI - Genetics and treatment options for recurrent acute and chronic pancreatitis. AB - OPINION STATEMENT: Worldwide research efforts demonstrate a major role of gene environment interactions for the risk, development, and progression of most pancreatic diseases, including recurrent acute and chronic pancreatitis. New findings of pancreas disease-associated risk variants have been reported in the CPA1, GGT1, CLDN2, MMP1, MTHFR, and other genes. These risk genes and their regulatory regions must be added to the known pathogenic variants in the PRSS1, SPINK1, CFTR, CTRC, CASR, UBR1, SBDS, CEL, and CTSB genes. This new knowledge promises to improve disease management and prevention through personalized medicine. At the same time, however, knowledge of an increasing number of pathogenic variants, and their complicated effects when present in combination, results in increasing difficulty in interpretation and development of recommendations. Direct-to-consumer marketing of genetic testing results also adds complexity to disease management paradigms, especially without interpretation and, in many cases, proven accuracy. While improvements in the ability to rapidly and accurately interpret complex genetic tests are clearly needed, some results, such as pathogenic CFTR variants, including a new class of bicarbonate-defective mutations, and PRSS1 variants have immediate implications that direct management. In addition, discovery of pancreatitis-associated genetic variants in patients with glucose intolerance may suggest underlying type 3c diabetes, which also has implications for treatment and disease management. PMID- 24954875 TI - Role of individual's T-cell immunome in controlling HIV-1 progression. AB - Viral and host factors can influence HIV-1 progression, among them human leucocyte antigen (HLA) has shown the strongest effect. However, studies on the functional contribution of HLA in controlling HIV progression toward AIDS are limited by multiple issues, including the viral strain variability within the study subjects. In this study, in a cohort of children infected with a monophyletic strain (CRF02_AG) during an outbreak, we evaluated the HIV-1 Gag, Vif, Vpr, Tat and hepatitis C virus E1/E2 (as control) proteins circulating in a cohort for the capability to be presented by the HLA molecules in the same population. A total of 70 Non-progressors and 37 Progressors to AIDS were evaluated. In the presence of a constant capability of HIV-1 to mutate in the region containing epitopes of Gag protein, the number of epitopes recognized in silico by the combination of the HLA alleles along the Gag consensus sequence is significantly higher in the Non-progressors compared with Progressors (HLA-A: Non progressors = 1.532 +/- 1.211, Progressors = 0.7714 +/- 1.031, P = 0.0016; HLA-B: Non-progressors = 1.556 +/- 1.298, Progressors = 1.000 +/- 0.817, P = 0.0319; HLA DR: Non-progressors = 13.30 +/- 9.488, Progressors = 7.294 +/- 6.952, P = 0.0006). Similar results were obtained for the other HIV-1 proteins Vif and Vpr, whereas no differences were obtained in the number of epitopes for the hepatitis C virus E1/E2 protein sequence or for the scrambled HIV-1 sequence. Finally, the results were confirmed also in a subgroup of subjects where both HLA typing and Gag sequence were available. In conclusion, in the absence of bias due to viral strain diversity, it is the overall fitting of the HLA molecules that are capable of better binding HIV-1 proteins in determining the major role in the control of HIV-1 replication and progression to AIDS. PMID- 24954876 TI - Sensations and regional brain responses evoked by tussive stimulation of the airways. AB - Stimuli that evoke cough in humans also elicit a sensation described as the urge to-cough. This sensation is perceived at levels of stimulation below the threshold for coughing and increases in intensity in response to higher levels of stimulation. Cough in humans can be consciously modified in intensity or suppressed altogether, and the urge-to-cough is likely to contribute to discretionary responses to tussive stimulation. Converging evidence from animal and human experiments have identified a widely distributed network of brain regions that are implicated in the representation of urge-to-cough and the control of coughing. This network incorporates regions that show responses associated with urge-to-cough ratings, such as limbic and somatosensory cortices, as well as paralimbic and premotor regions implicated in response inhibition that activate in association with efforts to suppress cough. The urge-to-cough can be influenced by psychological factors and preliminary findings suggest that these effects could be mediated by top-down influences. There is considerable impetus to understand circuits involved in the modulation of urge-to-cough because it may be possible to antagonise the troubling sensation while preserving the critical cough reflex. PMID- 24954877 TI - Adalimumab in the treatment of refractory adult-onset Still's disease. PMID- 24954878 TI - Adsorption of polyelectrolytes and polyelectrolytes-surfactant mixtures at surfaces: a physico-chemical approach to a cosmetic challenge. AB - The use of polymer and polymer - surfactant mixtures for designing and developing textile and personal care cosmetic formulations is associated with various physico-chemical aspects, e.g. detergency and conditioning in the case of hair or wool, that determine their correct performances in preserving and improving the appearance and properties of the surface where they are applied. In this work, special attention is paid to the systems combining polycations and negatively charged surfactants. The paper introduces the hair surface and presents a comprehensive review of the adsorption properties of these systems at solid-water interfaces mimicking the negative charge and surface energy of hair. These model surfaces include mixtures of thiols that confer various charge densities to the surface. The kinetics and factors that govern the adsorption are discussed from the angle of those used in shampoos and conditioners developed by the cosmetic industry. Finally, systems able to adsorb onto negatively charged surfaces regardless of the anionic character are presented, opening new ways of depositing conditioning polymers onto keratin substrates such as hair. PMID- 24954879 TI - Epidemic of avian influenza A (H7N9) virus in China. PMID- 24954880 TI - Poor-quality medicines: from knowledge to control and prevention. PMID- 24954881 TI - Piloting the EHR4CR feasibility platform across Europe. AB - BACKGROUND: Pharmaceutical clinical trials are primarily conducted across many countries, yet recruitment numbers are frequently not met in time. Electronic health records store large amounts of potentially useful data that could aid in this process. The EHR4CR project aims at re-using EHR data for clinical research purposes. OBJECTIVE: To evaluate whether the protocol feasibility platform produced by the Electronic Health Records for Clinical Research (EHR4CR) project can be installed and set up in accordance with local technical and governance requirements to execute protocol feasibility queries uniformly across national borders. METHODS: We installed specifically engineered software and warehouses at local sites. Approvals for data access and usage of the platform were acquired and terminology mapping of local site codes to central platform codes were performed. A test data set, or real EHR data where approvals were in place, were loaded into data warehouses. Test feasibility queries were created on a central component of the platform and sent to the local components at eleven university hospitals. RESULTS: To use real, de-identified EHR data we obtained permissions and approvals from 'data controllers' and ethics committees. Through the platform we were able to create feasibility queries, distribute them to eleven university hospitals and retrieve aggregated patient counts of both test data and de identified EHR data. CONCLUSION: It is possible to install a uniform piece of software in different university hospitals in five European countries and configure it to the requirements of the local networks, while complying with local data protection regulations. We were also able set up ETL processes and data warehouses, to re-use EHR data for feasibility queries distributed over the EHR4CR platform. PMID- 24954882 TI - Pre-transplant donor HLA-specific antibodies: characteristics causing detrimental effects on survival after lung transplantation. AB - BACKGROUND: The impact of Luminex-detected HLA antibodies on outcomes after lung transplantation is unclear. Herein we have undertaken a retrospective study of pre-transplant sera from 425 lung transplants performed between 1991 and 2003. METHODS: Pre-transplant sera, originally screened by complement-dependent cytotoxicity (CDC) assays, were retrospectively tested for the presence of HLA specific antibodies using HLA-coated Luminex beads and C4d deposition on Luminex beads. The results were correlated with graft survival at 1 year. RESULTS: Twenty seven patients were retrospectively identified as having been transplanted against donor-specific HLA antibodies (DSA) and 36 patients against non-donor specific HLA antibodies (NDSA). DSA-positive patients had 1-year survival of 51.9% compared with 77.8% for NDSA and 71.8% for antibody-negative patients (p = 0.029). One-year survival of patients with complement-fixing DSA was 12.5% compared with 62.5% for non-complement-fixing DSA, 75.8% for non-complement fixing NDSA and 71.8% for antibody-negative patients (p < 0.0001). DSA-positive patients with mean fluorescence intensity (MFI) >5,000 had 1-year survival of 33.3% compared with 71.4% for MFI 2,000 to 5000 and 62.5% for MFI <2,000 (p = 0.0046). Multivariable analysis revealed DSA to be an independent predictor of poor patient survival within 1 year (p = 0.0010, hazard ratio [HR] = 3.569) as well as complement-fixing DSA (p < 0.0001, HR = 11.083) and DSA with MFI >5,000 (p = 0.0001, HR = 5.512). CONCLUSIONS: Pre-formed DSA, particularly complement fixing DSA, and high MFI are associated with poor survival within the first year after lung transplantation. Risk stratification according to complement fixation or MFI levels may allow for increased transplantation in sensitized patients. PMID- 24954883 TI - C3d plasma levels and CD21 expressing B-cells in children after ABO-incompatible heart transplantation: Alterations associated with blood group tolerance. AB - BACKGROUND: Most children transplanted with ABO-incompatible (ABOi) hearts develop selective tolerance to donor A/B antigens, whereas anti-A/B antibodies typically re-accumulate in adults after ABOi kidney transplantation. Deficiency of essential factors linking innate and adaptive immunity in early childhood may promote development of tolerance, specifically interactions between complement split product C3d and its ligand CD21 on B cells, considering their role in augmenting "T-independent" B-cell activation. METHODS: Blood and clinical data were analyzed from children after ABOi or ABO-compatible (ABOc) heart transplantation (HTx). Plasma C3d levels were quantified by enzyme-linked immunoassay. Peripheral blood mononuclear cells (PBMC) were phenotyped by flow cytometry; expression of B-cell co-receptor components CD21 and CD81 was quantified. RESULTS: Fifty-five samples from pediatric HTx recipients (median age at transplant: 4.2 [range 0.03 to 20.4] months; age at sample collection: 14.6 [0.04 to 51.3] months; 53% ABOi) and 21 controls were studied. CD21-expressing B cells increased in trend with age (p = 0.079); longitudinal measures in individual patients showed a strong correlation with age. CD21 expression intensity in B-cells was not age-dependent. Plasma C3d levels did not correlate with age. Comparing ABOc vs ABOi HTx, CD21-expressing cell proportions were similar; however, serum C3d levels were significantly lower after ABOi HTx (p < 0.05). CONCLUSIONS: In children, including HTx patients, CD21-expressing B-cells show a trend to increase with age, corresponding with improved responsiveness to polysaccharide antigens. This does not differ in patients with ABOi grafts developing tolerance to donor ABO antigens. C3d levels are not age-dependent, but reduced C3d levels after ABOi HTx suggest altered complement metabolism contributing to ABO tolerance. PMID- 24954884 TI - A contemporary review of adult heart transplantation: 2012 to 2013. AB - Important developments have occurred during the past 2 years in the field of heart transplantation. These include refinements in donor management, preservation, and allocation, and evaluation of immunosuppression strategies for rejection and for allograft vascular disease. Finally, long-term outcomes addressing areas of significant morbidity for patients, including renal dysfunction and cancer, have seen important advances. This contemporary review will highlight the key articles for 2012 to 2013. PMID- 24954885 TI - Urea for management of the syndrome of inappropriate secretion of ADH: A systematic review. AB - Urea has been recently proposed for the management of hyponatremia linked to the syndrome of inappropriate secretion of ADH (SIADH). The objective of the study was to review the levels of evidence for treatment of hyponatremia associated with SIADH with urea. We performed a: systematic review of experimental trials and grading according to SIGN. No clinical trials were found. The 6 studies analysed had methodological limitations and were prone to biases. In conclusion, there is no evidence to support the efficacy of urea for the treatment of hyponatremia following SIADH. PMID- 24954887 TI - How I treat ovarian cancer in older women. AB - Advancing age in patients with epithelial ovarian cancer is a risk factor for decreased survival. The exact cause is unknown but part of this may be due to less than adequate therapy for these patients. To optimize treatment, this paper presents the available data for therapy and my own approach in the management of this disease. For optimal outcomes, there also needs to be a close collaboration between subspecialists (gynecologic oncology, medical oncology, pathology) in all aspects of treatment planning. Progression-free and overall survival can be prolonged and patients' quality of life can be maintained with appropriate management. PMID- 24954888 TI - Cancer incidence in California farm workers, 1988-2010. AB - BACKGROUND: Farmers and farm workers have previously been found to experience decreased risk of some causes of death but elevated risks of certain types of cancer. A previous report on cancer incidence in a farm worker labor union between 1987 and 1997 found increased leukemia, brain, stomach, and uterine cervix cancer rates in this working population. METHODS: A roster of farm workers was created and electronically linked to the database of the California Cancer Registry. Proportionate cancer incidence (PCIR), stage, and age at diagnosis and histological subtypes of cancer were compared between the United Farm Workers (UFW) members and the Hispanic population of California as well as to the non Hispanic whites (NHW). RESULTS: In this population of 139,000 farm workers in California, more than 3,600 cancer diagnoses were recorded between 1988 and 2010. Proportionately more cancer was noted in the UFW than among California NHW for kidney and renal pelvis cancer (PCIR = 1.60), liver (PCIR = 4.24), prostate (PCIR = 1.13), and uterine cervix cancer (PCIR = 2.08). Proportionately less breast (PCIR = 0.85), lung (PCIR = 0.75), skin melanoma (PCIR = 0.18), and urinary bladder cancer (PCIR = 0.59) was found. Stage at diagnosis was more advanced in the farm workers for several cancer sites, although, not for colorectal cancer. CONCLUSIONS: These farm workers experience proportionally more prostate, kidney and renal pelvis, brain, liver, stomach, cervix and leukemia and less breast, melanoma, and colorectal cancer than reference populations. For many sites, cancer is not diagnosed as early in the farm workers as in the comparison groups, except for colorectal cancer in females and melanoma in males. PMID- 24954886 TI - Imaging mouse lung allograft rejection with (1)H MRI. AB - PURPOSE: To demonstrate that longitudinal, noninvasive monitoring via MRI can characterize acute cellular rejection in mouse orthotopic lung allografts. METHODS: Nineteen Balb/c donor to C57BL/6 recipient orthotopic left lung transplants were performed, further divided into control-Ig versus anti-CD4/anti CD8 treated groups. A two-dimensional multislice gradient-echo pulse sequence synchronized with ventilation was used on a small-animal MR scanner to acquire proton images of lung at postoperative days 3, 7, and 14, just before sacrifice. Lung volume and parenchymal signal were measured, and lung compliance was calculated as volume change per pressure difference between high and low pressures. RESULTS: Normalized parenchymal signal in the control-Ig allograft increased over time, with statistical significance between day 14 and day 3 posttransplantation (0.046->0.789; P < 0.05), despite large intermouse variations; this was consistent with histopathologic evidence of rejection. Compliance of the control-Ig allograft decreased significantly over time (0.013 >0.003; P < 0.05), but remained constant in mice treated with anti-CD4/anti-CD8 antibodies. CONCLUSION: Lung allograft rejection in individual mice can be monitored by lung parenchymal signal changes and by lung compliance through MRI. Longitudinal imaging can help us better understand the time course of individual lung allograft rejection and response to treatment. PMID- 24954889 TI - The economic burden of disease by industry: Differences in quality-adjusted life years and associated costs. AB - BACKGROUND: This study compares differences in quality-adjusted life expectancy across the eight original National Occupational Research Agenda (NORA) industry sectors. METHODS: Data from the 1997 to 2012 National Health Interview Survey (NHIS) were used to estimate quality-adjusted life years (QALYs) for all workers and by NORA sector. Differences in QALYs were calculated and translated into economic values using estimates of the societal willingness-to-pay per QALY. RESULTS: Mean QALYs across workers was 29.17 years. Among NORA sectors, wholesale, and retail trade workers had the highest average QALYs remaining (35.88), while mining workers had the lowest QALYs (31.4). The economic value of this difference ranges from $604,843 to $1,155,287 per worker depending on the societal willingness-to-pay per QALY. CONCLUSION: The value of life lost within some industries is very high relative to others. Additional investments in occupational safety, benefits, and health promotion initiatives may reduce these losses, but experimental research is needed to assess the effectiveness of such programs. PMID- 24954890 TI - Multidimensional outcome measure of selective dorsal rhizotomy in spastic cerebral palsy. AB - BACKGROUND: One of the treatment option to reduce spasticity in cerebral palsy children is selective dorsal rhizotomy. Several studies have demonstrated short and long term improvements in gait and other activities after rhizotomy but this surgery still remains a controversial procedure and patient outcome indicators measures are not uniform. AIMS: To describe our assessment and outcome evaluation protocol and to verify by this protocol short term results of rhizotomy. METHODS: We recruited 9 cerebral palsy children (mean age 7.9 years +/- 3.2) affected by mild to moderate spastic diplegia and operated by rhizotomy. Patients were studied preoperatively and at 12 months after surgery by the following clinical and instrumental measures correlated to the International Classification of Functioning: modified Ashworth Scale, passive Range of Motion, Medical Research Council Scale, Selective Motor Control Scale, 3D-motion analysis and energy cost of locomotion measurements (indicators of "body functions"); Gross Motor Functional Measure and Motor Functional Independence Measure (indicators of "activities and participation"). RESULTS: Our data showed, after rhizotomy, reduction of spasticity specially in plantarflexors muscles (p < 0.01), increase of strength of knee flexors/extensors and foot plantar/dorsiflexion muscles (p < 0.01), improvement of selective motor control (p < 0.05), more similar spatio temporal parameters of gait analysis to healthy subjects, reduced equinus foot and knees hyperflexion as energy cost. CONCLUSION: The complementary use of multiple indicators may improve the evaluation of the results of dorsal rhizotomy. A beneficial outcome measured by these indicators has been found in our spastic diplegic children one year after rhizotomy. PMID- 24954891 TI - Spleen-derived macrophages are readily polarized into classically activated (M1) or alternatively activated (M2) states. AB - Bone marrow derived macrophages (BM-MPhi) that differentiate from precursor cells can be polarized into classically activated pro-inflammatory (M1) or alternatively activated (M2) states depending upon the cytokine microenvironment. We questioned whether tissue MPhi, such as spleen-derived MPhi (Sp-MPhi), have the ability to differentiate into M1 or M2 cells. We show in response to activation with IFN-gamma (IFN-gamma) and lipopolysaccharide (LPS), that the Sp MPhi readily acquired an M1 status indicated by up-regulation of iNOS mRNA, nitric oxide (NO) production, and the co-stimulatory molecule CD86. Conversely, Sp-MPhi exposed to IL-4 exhibited increased levels of mannose receptor (CD 206), arginase-1 (Arg)-1 mRNA expression, and significant urea production typical of M2 cells. At this stage of differentiation, the M2 Sp-MPhi were more efficient at phagocytosis of cell-associated antigens than their M1 counterparts. This polarization was not indefinite as the cells could revert back to their original state upon the removal of stimuli and exhibited flexibility to convert from M2 to M1. Remarkably, both M1 and M2 Sp-MPhi induced more CD4 expression on their cells surface after stimulation. We also demonstrate that adherent macrophages cultured for a short term in IL-4 enhances ARG-1 and YM-1 mRNA along with increasing urea producing capacity: traits indicative of an M2 phenotype. Moreover, in response to in vivo virus infection, the adherent macrophages obtained from spleens rapidly express iNOS. These results provide new evidence for the polarization capabilities of Sp-MPhi when exposed to pro-inflammatory or anti-inflammatory cytokines. PMID- 24954892 TI - Zinc supplementation in acute diarrhea. AB - OBJECTIVE: To determine the effect of zinc supplementation on the duration of acute diarrhea in children. METHODS: A search was conducted in PubMed, the Cochrane Library database, China Biology Medicine (CBM), CNKI, VIP, and Wanfang Data to find studies on zinc supplementation for children with acute diarrhea from the date of establishment of the respective databases to June 2013. Clinical trials were included, and reviews or other types of studies were excluded. Considering the inclusion criteria, articles were evaluated by two individual investigators. The Cochrane Handbook 5.0.2 was used to evaluate the methodological quality. RevMan 5.2 software was used for meta-analysis. Heterogeneity of the included studies was tested to select a proper effect model. Measurement data were expressed as standard mean difference (SMD), weighted mean difference (WMD), and 95 % confidence interval (CI). RESULTS: A total of 860 relevant articles were found, and 8 randomized control trials that met the inclusion criteria were included. Meta-analysis showed a significant difference in the duration of acute diarrhea between treatment and control groups, with a WMD of -14.47 (95 % CI: -25.06 to -3.89; P = 0.007). However, significant heterogeneity was found among the studies. Sensitivity analysis and subgroup analyses based on admission condition, sample size and age group were also performed, for which heterogeneity cannot be completely eliminated. CONCLUSIONS: Zinc supplementation can decrease the duration of acute diarrhea in children, but future studies should carry out a more thorough analysis in less heterogeneous subjects for a more definitive conclusion. PMID- 24954894 TI - Next-generation optimized biotherapeutics - A review and preclinical study. AB - Biotherapeutics have been clinically used since the 1990s. Recently, next generation optimized biotherapeutics, which are expected to act on the same molecular target as their predecessors with further properties by antibody-drug conjugation, radiolabeling, PEGylation and glycoconjugation, are on the market. This article reviews recent next-generation optimized biotherapeutics. Moreover, since trials of protein engineering for biotherapeutics have been conducted, these preclinical approaches are also described. This article is part of a Special Issue entitled: Recent advances in molecular engineering of antibody. PMID- 24954893 TI - Interleukin-2-mediated inhibition of dendritic cell development correlates with decreased CD135 expression and increased monocyte/macrophage precursors. AB - We have previously shown that interleukin-2 (IL-2) inhibits dendritic cell (DC) development from mouse bone marrow (BM) precursors stimulated with the ligand for FMS-like tyrosine kinase 3 receptor (Flt3L), and have provided evidence that this inhibition occurs at the monocyte DC precursor stage of DC development. Here, we explored the mechanism of IL-2-mediated inhibition of DC development. First, we showed that these in vitro cultures accurately model DCs that develop in vivo by comparing gene and protein expression of the three main Flt3L-induced DC subsets from the BM, CD11b(+) and CD24(+) conventional DCs (cDCs) and plasmacytoid DCs (pDCs) with their respective ex vivo spleen DC subsets (CD11b(+), CD8(+) and pDCs). Next, gene expression changes were quantified in Flt3L DC subsets that developed in the presence of IL-2. These changes included increased expression of Bcl2l11, which encodes the apoptosis-inducing protein Bim, and decreased expression of Flt3 (CD135), the receptor that initiates DC development. Interleukin-2 also significantly reduced Flt3 protein expression on all three Flt3L DC subsets, and attenuated Flt3L-induced STAT3 phosphorylation in DCs. Based on these data, we hypothesized that decreased Flt3 signalling may divert BM precursors down monocyte and macrophage lineages. Indeed, addition of IL-2 led to increases in Flt3(-) cells, including cKit(+) Ly6C(+) CD11b(-) populations consistent with the recently identified committed monocyte/macrophage progenitor. Therefore, IL-2 can inhibit DC development via decreased signalling through Flt3 and increased monocyte/macrophage development. PMID- 24954896 TI - Clinical data integration model. Core interoperability ontology for research using primary care data. AB - INTRODUCTION: This article is part of the Focus Theme of METHODS of Information in Medicine on "Managing Interoperability and Complexity in Health Systems". BACKGROUND: Primary care data is the single richest source of routine health care data. However its use, both in research and clinical work, often requires data from multiple clinical sites, clinical trials databases and registries. Data integration and interoperability are therefore of utmost importance. OBJECTIVES: TRANSFoRm's general approach relies on a unified interoperability framework, described in a previous paper. We developed a core ontology for an interoperability framework based on data mediation. This article presents how such an ontology, the Clinical Data Integration Model (CDIM), can be designed to support, in conjunction with appropriate terminologies, biomedical data federation within TRANSFoRm, an EU FP7 project that aims to develop the digital infrastructure for a learning healthcare system in European Primary Care. METHODS: TRANSFoRm utilizes a unified structural / terminological interoperability framework, based on the local-as-view mediation paradigm. Such an approach mandates the global information model to describe the domain of interest independently of the data sources to be explored. Following a requirement analysis process, no ontology focusing on primary care research was identified and, thus we designed a realist ontology based on Basic Formal Ontology to support our framework in collaboration with various terminologies used in primary care. RESULTS: The resulting ontology has 549 classes and 82 object properties and is used to support data integration for TRANSFoRm's use cases. Concepts identified by researchers were successfully expressed in queries using CDIM and pertinent terminologies. As an example, we illustrate how, in TRANSFoRm, the Query Formulation Workbench can capture eligibility criteria in a computable representation, which is based on CDIM. CONCLUSION: A unified mediation approach to semantic interoperability provides a flexible and extensible framework for all types of interaction between health record systems and research systems. CDIM, as core ontology of such an approach, enables simplicity and consistency of design across the heterogeneous software landscape and can support the specific needs of EHR-driven phenotyping research using primary care data. PMID- 24954897 TI - Panayiotopoulos syndrome with convulsive status epilepticus at the onset: a long term study. AB - PURPOSE: To better define the convulsive status epilepticus (CSE) as a possible manifestation at the onset of Panayiotopoulos syndrome (PS) and to assess its prognostic value in these children. METHODS: Children with CSE and diagnostic criteria of PS were identified, followed clinically and compared with a group of patients with PS without CSE from 1993 to 2012. RESULTS: We identified 37 patients with CSE at the onset of PS. During the same period we identified 72 children with autonomic symptoms of PS without CSE. The first episode of CSE occurred at a mean age of 6.5 years. Generalized clonic seizures were the most common ictal event and one-third of the patients required admission to Intensive Care Units. Interictal EEGs showed occipital spike activity in 31 (83.7%) subjects. Only 14 (37.8%) patients were treated with valproic acid and for two of them (5.40%) it was necessary to administer other drugs. There were no intractable cases. The overall prognosis was excellent. After the first event, 15 subjects (40.54%) experienced at least another typical PS seizure, but all patients were seizure free at the last follow-up. CONCLUSION: CSE is not uncommon in PS and it may occur at the onset of benign childhood epilepsy, without leading to a poor prognosis. PMID- 24954898 TI - Investigating white matter perfusion using optimal sampling strategy arterial spin labeling at 7 Tesla. AB - PURPOSE: Cerebral blood flow (CBF) is an informative physiological marker for tissue health. Arterial spin labeling (ASL) is a noninvasive MRI method of measuring this parameter, but it has proven difficult to measure white matter (WM) CBF due to low intrinsic contrast-to-noise ratio compared with gray matter (GM). Here we combine ultra-high field and optimal sampling strategy (OSS) ASL to investigate WM CBF in reasonable scan times. METHODS: A FAIR-based ASL sequence at 7T was combined with a real-time-feedback OSS technique, to iteratively improve post-label image acquisition times (TIs) on a tissue- and subject specific basis to obtain WM CBF quantification. RESULTS: It was found 77% of WM voxels gave a reasonable CBF fit. Averaged WM CBF for these voxels was found to be 16.3 +/- 1.5 mL/100 g/min (discarding partial-volumed voxels). The generated TI schedule was also significantly different when altering the OSS weighted tissue-mask, favoring longer TIs in WM. CONCLUSION: WM CBF could be reasonably quantified in over 75% of identified voxels, from a total preparation and scan time of 15 min. OSS results suggest longer TIs should be used versus general GM ASL settings; this may become more important in WM disease studies. PMID- 24954899 TI - Canal wall up tympanoplasty for cholesteatoma with intact stapes. Comparison of hearing results between cartilage and PORP on stapes and impact of malleus removal and total reinforcement of the tympanic membrane by cartilage. AB - OBJECTIVES: To compare the results obtained with canal wall up (CWU) tympanoplasty for cholesteatoma using cartilage or an hydroxyapatite (HA) PORP positioned on the head of the stapes and to analyse the impact of malleus removal and total reinforcement of the tympanic membrane with cartilage. MATERIALS AND METHODS: Retrospective study of 128 cases (99 adults, 29 children) operated between 2003 and 2012 for cholesteatoma by CWU tympanoplasty with use of a cartilage graft (90 cases) or a PORP (38 cases) on the head of the stapes. Audiometric results were analysed according to the International Bureau for Audiophonology (BIAP) criteria and were submitted to statistical analysis. All ossiculoplasties were performed during the first operation and only 39% of patients required surgical revision. The malleus was preserved in 79 cases and sacrificed in 49 cases. RESULTS: With a follow-up of 2 years, the residual mean air-bone gap was 16.8 dB in the cartilage group (gain of 7.6 dB; P = 0.001) and 15.8 dB in the PORP group (gain of 8.5 dB; P = 0.002). The air-bone gap was less than 20 dB in 67.6% of cases in the cartilage group and 70.4% of cases in the PORP group. No significant difference was observed between the 2 techniques and no significant difference was observed according to whether or not the malleus was preserved in either the cartilage group or the PORP group. CONCLUSION: These results confirm the value of cartilage graft placed on the head of the stapes as ossiculoplasty technique in cholesteatoma operated by CWU tympanoplasty, giving comparable results to those obtained with a PORP. Malleus removal did not induce any reduction of the quality of hearing obtained. Total reinforcement of the tympanic membrane with cartilage appeared to decrease the cholesteatoma recurrence rate (8.5%). PMID- 24954900 TI - The changing patterns of psychosocial exposures at work in the south of Europe: Spain as a labor market laboratory. AB - AIMS: To examine the pattern of psychosocial risk exposures at work among wage earners in Spain in 2005 and 2010, and to analyze changes in exposure inequalities by gender and job category. METHODS: Psychosocial exposures were compared using the COPSOQ-ISTAS21 method, based on two surveys representative of the Spanish wage-earning population (2005 and 2010). Statistical analysis was conducted using correspondence analysis. RESULTS: There was an increase in exposure to high Double Presence, low Social Support, high Work Pace, and high Insecurity about finding a job; and reduction in exposure to high Insecurity about losing a job, and to high Insecurity over worsening of employment conditions. A gender- and occupation-related gradient was maintained. CONCLUSION: Although this study analyzes wage-earner "survivors" after the outbreak of the current economic crisis, it shows a worsening of harmful exposures to some psychosocial risks. In a context of job destruction, concerns about worsening working conditions appear to be subordinate to insecurity about job loss. PMID- 24954901 TI - Chromatin reader Brd4 functions in Ig class switching as a repair complex adaptor of nonhomologous end-joining. AB - Class switch recombination (CSR) is a B cell-specific genomic alteration induced by activation-induced cytidine deaminase (AID)-dependent DNA break at the immunoglobulin heavy-chain locus, followed by repair. Although chromatin associated factors in promoting AID-induced DNA break have been widely reported, the involvement of chromatin adaptors at the repair phase of CSR remains unknown. Here, we show that the acetylated histone reader Brd4 is critical for nonhomologous end-joining (NHEJ) repair of AID- and I-SceI-induced DNA breaks. Brd4 was recruited to the DNA break regions, and its depletion from the chromatin caused CSR impairment without affecting the DNA break generation. Inhibition of Brd4 suppressed the accumulation of 53BP1 and uracil DNA glycosylase at the switch regions, perturbed the switch junctional microhomology, and reduced Igh/c myc translocation. We conclude that Brd4 serves as a chromatin platform required for the recruitment of repair components during CSR and general DNA damage. PMID- 24954895 TI - Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia. AB - Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p <= 5 * 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 * 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations. PMID- 24954903 TI - Direct evaluation of tRNA aminoacylation status by the T-box riboswitch using tRNA-mRNA stacking and steric readout. AB - T-boxes are gene-regulatory mRNA elements with which Gram-positive bacteria sense amino acid availability. T-boxes have two functional domains. Stem I recognizes the overall shape and anticodon of tRNA, while a 3' domain evaluates its aminoacylation status, overcoming an otherwise stable transcriptional terminator if the bound tRNA is uncharged. Although T-boxes are believed to evaluate tRNA charge status without using any proteins, this has not been demonstrated experimentally because of the instability of aminoacyl-tRNA. Using a simple method to prepare homogeneous aminoacyl-tRNA, we show that the Bacillus subtilis glyQS T-box functions independently of any tRNA-binding protein. Comparison of aminoacyl-tRNA analogs demonstrates that the T-box detects the molecular volume of tRNA 3'-substituents. Calorimetry and fluorescence lifetime analysis of labeled RNAs shows that the tRNA acceptor end coaxially stacks on a helix in the T-box 3' domain. This intimate intermolecular association, selective for uncharged tRNA, stabilizes the antiterminator conformation of the T-box. PMID- 24954902 TI - Co-opting the Fanconi anemia genomic stability pathway enables herpesvirus DNA synthesis and productive growth. AB - DNA damage associated with viral DNA synthesis can result in double-strand breaks that threaten genome integrity and must be repaired. Here, we establish that the cellular Fanconi anemia (FA) genomic stability pathway is exploited by herpes simplex virus 1 (HSV-1) to promote viral DNA synthesis and enable its productive growth. Potent FA pathway activation in HSV-1-infected cells resulted in monoubiquitination of FA effector proteins FANCI and FANCD2 (FANCI-D2) and required the viral DNA polymerase. FANCD2 relocalized to viral replication compartments, and FANCI-D2 interacted with a multisubunit complex containing the virus-encoded single-stranded DNA-binding protein ICP8. Significantly, whereas HSV-1 productive growth was impaired in monoubiquitination-defective FA cells, this restriction was partially surmounted by antagonizing the DNA-dependent protein kinase (DNA-PK), a critical enzyme required for nonhomologous end-joining (NHEJ). This identifies the FA-pathway as a cellular factor required for herpesvirus productive growth and suggests that FA-mediated suppression of NHEJ is a fundamental step in the viral life cycle. PMID- 24954904 TI - WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. AB - Mammalian cell homeostasis during starvation depends on initiation of autophagy by endoplasmic reticulum-localized phosphatidylinositol 3-phosphate (PtdIns(3)P) synthesis. Formation of double-membrane autophagosomes that engulf cytosolic components requires the LC3-conjugating Atg12-5-16L1 complex. The molecular mechanisms of Atg12-5-16L1 recruitment and significance of PtdIns(3)P synthesis at autophagosome formation sites are unknown. By identifying interacting partners of WIPIs, WD-repeat PtdIns(3)P effector proteins, we found that Atg16L1 directly binds WIPI2b. Mutation experiments and ectopic localization of WIPI2b to plasma membrane show that WIPI2b is a PtdIns(3)P effector upstream of Atg16L1 and is required for LC3 conjugation and starvation-induced autophagy through recruitment of the Atg12-5-16L1 complex. Atg16L1 mutants, which do not bind WIPI2b but bind FIP200, cannot rescue starvation-induced autophagy in Atg16L1-deficient MEFs. WIPI2b is also required for autophagic clearance of pathogenic bacteria. WIPI2b binds the membrane surrounding Salmonella and recruits the Atg12-5-16L1 complex, initiating LC3 conjugation, autophagosomal membrane formation, and engulfment of Salmonella. PMID- 24954906 TI - Direct binding of Ataxin-2 to distinct elements in 3' UTRs promotes mRNA stability and protein expression. AB - It has been proposed that Ataxin-2, a member of the like-Sm (LSm) protein family, participates in the regulation of RNA metabolism through interaction with PABPC1. However, the exact biological mechanism and in vivo targets remain unknown. Here, we report that Ataxin-2 binds directly to RNAs in a PABPC1-independent manner. High-throughput sequencing of Ataxin-2-bound RNAs prepared by PAR-CLIP revealed that Ataxin-2 binds predominantly to uridine-rich elements, including well characterized cis-regulatory AU-rich elements, in the 3' UTRs of target mRNAs. Gene expression analysis after Ataxin-2 depletion or overexpression revealed that Ataxin-2 stabilizes target mRNAs and increases the abundance of the corresponding proteins. A tethering assay demonstrated that Ataxin-2 elicits this effect by direct interaction with mRNAs. We also found that disease-associated polyglutamine expansion downregulates the physiological activity of Ataxin-2. These findings suggest that Ataxin-2 is an RNA-binding protein that targets cis regulatory elements in 3' UTRs to stabilize a subset of mRNAs and increase protein expression. PMID- 24954905 TI - Cellular noise suppression by the regulator of G protein signaling Sst2. AB - G proteins and their associated receptors process information from a variety of environmental stimuli to induce appropriate cellular responses. Generally speaking, each cell in a population responds within defined limits, despite large variation in the expression of protein signaling components. Therefore, we postulated that noise suppression is encoded within the signaling system. Using the yeast mating pathway as a model, we evaluated the ability of a regulator of G protein signaling (RGS) protein to suppress noise. We found that the RGS protein Sst2 limits variability in transcription and morphogenesis in response to pheromone stimulation. While signal suppression is a result of both the GAP (GTPase accelerating) and receptor binding functions of Sst2, noise suppression requires only the GAP activity. Taken together, our findings reveal a hitherto overlooked role of RGS proteins as noise suppressors and demonstrate an ability to uncouple signal and noise in a prototypical stimulus-response pathway. PMID- 24954908 TI - CO2-assisted synthesis of silk fibroin hydrogels and aerogels. AB - Biocompatible and biodegradable porous materials based on silk fibroin (SF), a natural protein derived from the Bombyx mori silkworm, are being extensively investigated for use in biomedical applications including mammalian cell bioprocessing, tissue engineering and drug delivery applications. In this work, low-pressure, gaseous CO2 is used as an acidifying agent to fabricate SF hydrogels. This low-pressure CO2 acidification method is compared to an acidification method using high-pressure CO2 to demonstrate the effect of CO2 mass transfer and pressure on SF sol-gel kinetics. The effect of SF molecular weight on the sol-gel kinetics is determined using the low-pressure CO2 method. The results from these studies demonstrate that low-pressure CO2 processing proves to be a facile method for synthesizing 3-D SF hydrogels. PMID- 24954907 TI - Omalizumab therapy for bullous pemphigoid. AB - BACKGROUND: Bullous pemphigoid (BP) responds to a variety of immunosuppressive agents and usually controls, but does not cure, the disease. Omalizumab, Food and Drug Administration-approved for asthma, selectively suppresses the activity of IgE, an important immunoglobulin in the pathogenesis of BP. OBJECTIVE: We wished to determine if systemic omalizumab would have a therapeutic effect in patients with BP. METHODS: We treated 6 patients with BP using omalizumab and followed up their disease for up to 42 months. RESULTS: Although variable, 5 of the 6 patients with BP received therapeutic benefit from systemic omalizumab (the sixth terminated treatment because of intercurrent illness) with less use of other immunosuppressants, inhibition of new bullae, less pruritus, and dramatic decreases in eosinophil counts. None of the patients had untoward side effects from omalizumab. LIMITATIONS: This was an open, uncontrolled study. CONCLUSIONS: Omalizumab neutralizes the activity of IgE in patients with BP and improves the control of their disease activity. PMID- 24954910 TI - In situ regeneration of skeletal muscle tissue through host cell recruitment. AB - Standard reconstructive procedures for restoring normal function after skeletal muscle defects involve the use of existing host tissues such as muscular flaps. In many instances, this approach is not feasible and delays the rehabilitation process and restoration of tissue function. Currently, cell-based tissue engineering strategies have been used for reconstruction; however, donor tissue biopsy and ex vivo cell manipulation are required prior to implantation. The present study aimed to overcome these limitations by demonstrating mobilization of muscle cells into a target-specific site for in situ muscle regeneration. First, we investigated whether host muscle cells could be mobilized into an implanted scaffold. Poly(l-lactic acid) (PLLA) scaffolds were implanted in the tibialis anterior (TA) muscle of rats, and the retrieved scaffolds were characterized by examining host cell infiltration in the scaffolds. The host cell infiltrates, including Pax7+ cells, gradually increased with time. Second, we demonstrated that host muscle cells could be enriched by a myogenic factor released from the scaffolds. Gelatin-based scaffolds containing a myogenic factor were implanted in the TA muscle of rats, and the Pax7+ cell infiltration and newly formed muscle fibers were examined. By the second week after implantation, the Pax7+ cell infiltrates and muscle formation were significantly accelerated within the scaffolds containing insulin-like growth factor 1 (IGF-1). Our data suggest an ability of host stem cells to be recruited into the scaffolds with the capability of differentiating to muscle cells. In addition, the myogenic factor effectively promoted host cell recruitment, which resulted in accelerating muscle regeneration in situ. PMID- 24954909 TI - Advances in synthesis of calcium phosphate crystals with controlled size and shape. AB - Calcium phosphate (CaP) materials have a wide range of applications, including biomaterials, adsorbents, chemical engineering materials, catalysts and catalyst supports and mechanical reinforcements. The size and shape of CaP crystals and aggregates play critical roles in their applications. The main inorganic building blocks of human bones and teeth are nanocrystalline CaPs; recently, much progress has been made in the application of CaP nanocrystals and their composites for clinical repair of damaged bone and tooth. For example, CaPs with special micro- and nanostructures can better imitate the biomimetic features of human bone and tooth, and this offers significantly enhanced biological performances. Therefore, the design of CaP nano-/microcrystals, and the shape and hierarchical structures of CaPs, have great potential to revolutionize the field of hard tissue engineering, starting from bone/tooth repair and augmentation to controlled drug delivery devices. Previously, a number of reviews have reported the synthesis and properties of CaP materials, especially for hydroxyapatite (HAp). However, most of them mainly focused on the characterizations and physicochemical and biological properties of HAp particles. There are few reviews about the control of particle size and size distribution of CaPs, and in particular the control of nano-/microstructures on bulk CaP ceramic surfaces, which is a big challenge technically and may have great potential in tissue engineering applications. This review summarizes the current state of the art for the synthesis of CaP crystals with controlled sizes from the nano- to the macroscale, and the diverse shapes including the zero-dimensional shapes of particles and spheres, the one dimensional shapes of rods, fibers, wires and whiskers, the two-dimensional shapes of sheets, disks, plates, belts, ribbons and flakes and the three dimensional (3-D) shapes of porous, hollow, and biomimetic structures similar to biological bone and tooth. In addition, this review will also summarize studies on the controlled formation of nano-/microstructures on the surface of bulk ceramics, and the preparation of macroscopical bone grafts with 3-D architecture nano-/microstructured surfaces. Moreover, the possible directions of future research and development in this field, such as the detailed mechanisms behind the size and shape control in various strategies, the importance of theoretical simulation, self-assembly, biomineralization and sacrificial precursor strategies in the fabrication of biomimetic bone-like and enamel-like CaP materials are proposed. PMID- 24954911 TI - Static axial stretching enhances the mechanical properties and cellular responses of fibrin microthreads. AB - Fibrin microthreads are a platform technology that can be used for a variety of applications, and therefore the mechanical requirements of these microthreads differ for each tissue or device application. To develop biopolymer microthreads with tunable mechanical properties, we analyzed fibrin microthread processing conditions to strengthen the scaffold materials without the use of exogenous crosslinking agents. Fibrin microthreads were extruded, dried, rehydrated and static axially stretched 0-200% of their original lengths; then the mechanical and structural properties of the microthreads were assessed. Stretching significantly increased the tensile strength of microthreads 3-fold, yielding scaffolds with tensile strengths and stiffnesses that equaled or exceeded values reported previously for carbodiimide crosslinked threads without affecting intrinsic material properties such as strain hardening or Poisson's ratio. Interestingly, these stretching conditions did not affect the rate of proteolytic degradation of the threads. The swelling ratios of stretched microthreads decreased, and scanning electron micrographs showed increases in grooved topography with increased stretch, suggesting that stretching may increase the fibrillar alignment of fibrin fibrils. The average cell alignment with respect to the longitudinal axis of the microthreads increased 2-fold with increased stretch, further supporting the hypothesis that stretching microthreads increases the alignment of fibrin fibrils on the surfaces of the scaffolds. Together, these data suggest that stretching fibrin microthreads generates stronger materials without affecting their proteolytic stability, making stretched microthreads ideal for implantable scaffolds that require short degradation times and large initial loading properties. Further modifications to stretched microthreads, such as carbodiimide crosslinking, could generate microthreads to direct cell orientation and align tissue deposition, with additional resistance to degradation for use as a long-term scaffold for tissue regeneration. PMID- 24954912 TI - Carbon nanotube-collagen three-dimensional culture of mesenchymal stem cells promotes expression of neural phenotypes and secretion of neurotrophic factors. AB - Microenvironments provided by three-dimensional (3-D) hydrogels mimic native tissue conditions, supplying appropriate physical cues for regulating stem cell behaviors. Here, we focused on carbon nanotubes (CNTs) dispersed within collagen hydrogels to provide 3-D microenvironmental conditions for mesenchymal stem cells (MSCs) in stimulating biological functions for neural regeneration. Small concentrations of CNTs (0.1-1wt.%) did not induce toxicity to MSCs, and even improved the proliferative potential of the cells. MSCs cultured within the CNT collagen hydrogel expressed considerable levels of neural markers, including GAP43 and betaIII tubulin proteins by immunostaining as well as GAP43 and synapse I genes by reverse transcriptase polymerase chain reaction (RT-PCR). Of note was that neurotrophic factors, particularly nerve growth factor and brain derived neurotrophic factor, were significantly promoted by the incorporation of CNTs as confirmed by RT-PCR and Western blot analysis. A model experiment involving neuritogenesis of PC12 cells influenced by those releasing neurotrophic factors from MSCs cultured within the CNT-collagen hydrogel demonstrated the significant enhancement in neurite outgrowth behaviors. Taken together, collagen hydrogel provides excellent 3-D conditions for MSC growth, and a small incorporation of CNTs within the hydrogel significantly stimulates MSC expression of neural markers and secretion of neurotrophic factors. PMID- 24954913 TI - [Limp: looking beyond transient synovitis]. PMID- 24954914 TI - [Acute gallbladder hydrops associated with rotavirus infection]. PMID- 24954915 TI - [Cerebellar cognitive affective syndrome secondary to a cerebellar tumour]. AB - Cerebellar cognitive affective syndrome is characterized by disturbances of executive function, impaired spatial cognition, linguistic difficulties, and personality change. The case of an 11 year old boy is presented, with behavior problems, learning difficulties and social interaction problems. In the physical examination he had poor visual contact, immature behavior, reduced expressive language and global motor disability with gait dyspraxia, with no defined cerebellar motor signs. In the neuropsychological evaluation he has a full scale overall intellectual quotient of 84, with signs of cerebellar cognitive affective syndrome. A tumour affecting inferior cerebellar vermis was observed in the magnetic resonance imaging, which had not significantly grown during 5 years of follow up. The cerebellum participates in controlling cognitive and affective functions. Cerebellar pathology must be considered in the differential diagnosis of children with cognitive or learning disorder with associated behavioral and emotional components. PMID- 24954916 TI - Tropical infection after a case of total hip arthroplasty. AB - In non-endemic areas, malaria is mainly an imported disease. This article reports a case of transfusion-related Plasmodium falciparum malaria in a non-endemic area. Despite initial clinical signs consistent with malaria, the diagnosis was not elicited because of the absence of any identified epidemiological risk factors. The case indicates that transfusion-transmitted malaria still occurs in non-endemic countries. The role of laboratory testing to prevent and diagnose transfusion-transmitted malaria in non-endemic malaria countries is crucial. PMID- 24954917 TI - Cardiac stress test is normal in pre-motor Parkinson's disease. AB - Cardiac sympathetic denervation is an early nonmotor feature of Parkinson's disease (PD). The aim of the current study was to trace evidence for cardiac dysfunction abnormalities in the premotor phase of PD. We retrospectively reviewed treadmill ergometric tests of a large cohort (n = 16,841) between 2000 and 2012, that attended the Executive Screening Survey (ESS) at Sheba Medical Center. Heart rate and blood pressure profiles as well as exercise capacity were compared between subjects who later developed PD and age- and sex-matched subjects (ratio 1:2) who did not. We identified 28 subjects (24 males) who developed PD at follow-up. The PD group was older than the group of subjects who did not develop PD on first ergometric test (64.82 +/- 8.82 vs. 48.91 +/- 10.60 years, P < 0.001). The time between the first ergometric test and motor symptoms onset was 4.64 +/- 2.86 years. Patients who later developed PD had lower maximal heart rate (P < 0.001) and lower heart rate reserve than healthy controls (P < 0.001); however, compared with age- and sex-matched subjects, subjects who developed PD had similar exercise capacity and heart rate profile during rest, exercise, and recovery, even 1 year before diagnosis. In this study, we did not detect significant signs of sympathetic dysfunction during the premotor phase of PD. PMID- 24954918 TI - [Answer to: "re: intramuscular lipomas: large and deep benign lumps not to be underestimated. Review of a series of 51 cases"]. PMID- 24954919 TI - Mechanical comparison of cortical screw fixation versus locking plate fixation in first metatarsal base osteotomy. AB - The oblique closing base wedge osteotomy has been used for surgical treatment of moderate to severe hallux valgus deformities with an intermetatarsal angle typically greater than 15 degrees . Several postoperative complications have been identified that relate to failure of the fixation construct used to fixate the osteotomy, especially when that construct has been subjected to a vertical load. We performed a mechanical analysis comparing 2 constructs used to fixate oblique osteotomies of the first metatarsal using composite first metatarsals. An oblique base osteotomy was uniformly performed on 40 composite first metatarsals. Of the 40 specimens, 20 were fixated with a locking plate construct and 18 with a cortical screw construct, consisting of an anchor and compression screw (2 specimens from the latter group were excluded because of hinge fracture). Each specimen was loaded in a materials testing machine to measure the maximum load at construct failure when a vertical force was applied to the plantar aspect of the metatarsal head. The mean load to failure for the locking plate construct was significantly greater than the cortical screw construct (190.0 +/- 70 N versus 110.3 +/- 20.3 N, p < .001). Our study results have demonstrated that the locking plate construct was able to withstand a significantly greater vertical load before failure than was the 2-cortical screw construct in oblique osteotomies performed at the base of composite first metatarsals. PMID- 24954920 TI - Pain Management for Elective Foot and Ankle Surgery: A Systematic Review of Randomized Controlled Trials. AB - Pain after foot and ankle surgery can significantly affect the postoperative outcomes. We performed a systematic review of randomized controlled trials assessing postoperative pain after foot and ankle surgery, because the surgery will lead to moderate-to-severe postoperative pain, but the optimal pain therapy has been controversial. A systematic review of randomized controlled trials in English reporting on pain after foot and ankle surgery in adults published from January 1946 to February 2013 was performed. The primary outcome measure was the postoperative pain scores. The secondary outcome measures included supplemental analgesic requirements and other recovery outcomes. With 953 studies identified, 45 met the inclusion criteria. The approaches improving pain relief (reduced pain scores or opioid requirements) included peripheral nerve blocks, wound infiltration, intravenous dexamethasone, acetaminophen, nonsteroidal anti inflammatory drugs, cyclooxygenase-2 selective inhibitors, and opioids. Wound instillation, intra-articular injection, and intravenous regional analgesia had variable analgesia. The lack of homogeneous study design precluded quantitative analyses. Optimal pain management strategies included locoregional analgesic techniques plus acetaminophen and nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 selective inhibitors, with opioids used for "rescue," and 1 intraoperative dose of parenteral dexamethasone. Popliteal sciatic nerve blocks would be appropriate when expecting severe postoperative pain (extensive surgical procedure), and ankle blocks and surgical incision infiltration would be appropriate when expecting moderate postoperative pain (less extensive and minimally invasive surgical procedures). Additional studies are needed to assess multimodal analgesia techniques. PMID- 24954922 TI - A new pencil beam model for photon dose calculations in heterogeneous media. AB - The pencil beam method is commonly used for dose calculations in intensity modulated radiation therapy (IMRT). In this study, we have proposed a novel pencil model for calculating photon dose distributions in heterogeneous media. To avoid any oblique kernel-related bias and reduce computation time, dose distributions were computed in a spherical coordinate system based on the pencil kernels of different distances from source to surface (DSS). We employed two different dose calculation methods: the superposition method and the fast Fourier transform convolution (FFTC) method. In order to render the superposition method more accurate, we scaled the depth-directed component by moving the position of the entry point and altering the DSS value for a given beamlet. The lateral components were thus directly corrected by the density scaling method along the spherical shell without taking the densities from the previous layers into account. Significant computation time could be saved by performing the FFTC calculations on each spherical shell, disregarding density changes in the lateral direction. The proposed methods were tested on several phantoms, including lung- and bone-type heterogeneities. We compared them with Monte Carlo (MC) simulation for several field sizes with 6 MV photon beams. Our results revealed mean absolute deviations <1% for the proposed superposition method. Compared to the AAA algorithm, this method improved dose calculation accuracy by at least 0.3% in heterogeneous phantoms. The FFTC method was approximately 40 times faster than the superposition method. However, compared with MC, mean absolute deviations were <3% for the FFTC method. PMID- 24954923 TI - European Federation of Organisations for Medical Physics (EFOMP) policy statement 12.1: Recommendations on medical physics education and training in Europe 2014. AB - In 2010, EFOMP issued Policy Statement No. 12: "The present status of Medical Physics Education and Training in Europe. New perspectives and EFOMP recommendations" to be applied to education and training in Medical Physics within the context of the developments in the European Higher Education Area arising from the Bologna Declaration and with a view to facilitate the free movement of Medical Physics professionals within Europe. Concurrently, new recommendations regarding qualifications frameworks were published by the European Parliament and Council which introduced new terminology and a new qualifications framework - the European Qualifications Framework (EQF) for lifelong learning. In addition, a new European directive involving the medical use of ionizing radiations and set to replace previous directives in this area was in the process of development. This has now been realized as Council Directive 2013/59/Euratom of 5 December 2013 which has repealed directive 97/43/Euratom. In this regard, a new document was developed in the context of the EC financed project "European Guidelines on the Medical Physics Expert" and published as RP174. Among other items, these guidelines refer to the mission statement, key activities, qualification framework and curricula for the specialty areas of Medical Physics relating to radiological devices and protection from ionizing radiation. These developments have made necessary an update of PS12; this policy statement provides the necessary update. PMID- 24954921 TI - Hypersensitivity pneumonitis in workers exposed to metalworking fluids. AB - BACKGROUND: This study used data from a large UK outbreak investigation, to develop and validate a new case definition for hypersensitivity pneumonitis due to metalworking fluid exposure (MWF-HP). METHODS: The clinical data from all workers with suspected MWF-HP were reviewed by an experienced panel of clinicians. A new MWF-HP Score was then developed to match the "gold standard" clinical opinion as closely as possible, using standard diagnostic criteria that were relatively weighted by their positive predictive value. RESULTS: The new case definition was reproducible, and agreed with expert panel opinion in 30/37 cases. This level of agreement was greater than with any of the three previously utilized case definitions (agreement in 16-24 cases). Where it was possible to calculate, the MWF-HP Score also performed well when applied to 50 unrelated MWF HP cases. CONCLUSIONS: The MWF-HP Score offers a new case definition for use in future outbreaks. PMID- 24954924 TI - Occurrence of the antidiabetic drug Metformin and its ultimate transformation product Guanylurea in several compartments of the aquatic cycle. AB - In 2030, the World Health Organization estimates that more than 350 million people will be diagnosed with diabetes. Consequently, Metformin - the biguanide drug of choice orally administered for diabetes type II - is anticipated to see a spike in production. Unlike many pharmaceutical drugs, Metformin (Met) is not metabolized by humans but passes through the body unchanged. Entering aquatic compartments, such as in sewage, it can be bacterially transformed to the ultimate transformation product Guanylurea (Gua). Sampling over one week (n=5) from a Southern German sewage treatment plant revealed very high average (AV) concentrations in influent (AVMet=111,800ng/L, AVGua=1300ng/L) and effluent samples (AVMet=4800ng/L, AVGua=44,000ng/L). To provide a more complete picture of the distribution and potential persistence of these compounds in the German water cycle, a new, efficient and highly sensitive liquid chromatography mass spectrometric method with direct injection was used for the measurement of Metformin and Guanylurea in drinking, surface, sewage and seawater. Limits of quantification (LOQ) ranging from 2-10ng/L allowed the detection of Metformin and Guanylurea in different locations such as: Lake Constance (n=11: AVMet=102ng/L, AVGua=16ng/L), river Elbe (n=12: AVMet=472ng/L, AVGua=9ng/L), river Weser (n=6: AVMet=349ng/L, AVGua=137ng/L) and for the first time in marine North Sea water (n=14: AVMet=13ng/L, AVGua=11ng/L). Based on daily water discharges, Metformin loads of 15.2kg/d (Elbe) and 6.4kg/d (Weser) into the North Sea were calculated. Lake Constance is used to abstract potable water which is further purified to be used as drinking water. A first screening of two tap water samples contained 2ng/L and 61ng/L of Metformin, respectively. The results of this study suggest that Metformin and Guanylurea could be distributed over a large fraction of the world's potable water sources and oceans. With no natural degradation processes, these compounds can be easily reintroduced to humans as they enter the food chain. PMID- 24954925 TI - Plasmacytoid variant urothelial bladder cancer: is it time to update the treatment paradigm? AB - OBJECTIVES: Plasmacytoid variant (PCV) urothelial cancer (UC) of the bladder is rare, with poor clinical outcomes. We sought to identify factors that may better inform expectations of tumor behavior and improve management options in patients with PCV UC. MATERIALS AND METHODS: A retrospective analysis of the Indiana University Bladder Cancer Database between January 2008 and June 2013 was performed comparing 30 patients with PCV UC at cystectomy to 278 patients with nonvariant (NV) UC at cystectomy who underwent surgery for muscle-invasive disease. Multivariable logistic regression was used to assess precystectomy variables associated with non-organ-confined disease at cystectomy and Cox regression analysis to assess variables associated with mortality. RESULTS: Patients with PCV UC who were diagnosed with a higher stage at cystectomy (73% pT3-4 vs. 40%, P = 0.001) were more likely to have lymph node involvement (70% vs. 25%, P<0.001), and positive surgical margins were found in 40% of patients with PCV UC vs. 10% of patients with NV UC (P<0.001). Median overall survival and disease-specific survival were 19 and 22 months for PCV, respectively. Median overall survival and disease-specific survival had not been reached for NV at 68 months (P<0.001). Presence of PCV UC on transurethral resection of bladder tumor was associated with non-organ-confined disease (odds ratio = 4.02; 95% CI: 1.06 15.22; P = 0.040), and PCV at cystectomy was associated with increased adjusted risk of mortality (hazard ratio = 2.1; 95% CI: 1.2-3.8; P = 0.016). CONCLUSIONS: PCV is an aggressive UC variant, predicting non-organ-confined disease and poor survival. Differentiating between non-muscle- and muscle-invasive disease in patients with PCV UC seems less important than the aggressive nature of this disease. Instead, any evidence of PCV on transurethral resection of bladder tumor may warrant aggressive therapy. PMID- 24954927 TI - Reproductive failure in moose (Alces alces) due to embryonic mortality and unfertilized oocytes. AB - Knowledge on reproductive success is vital for successful management of large ungulates and is often measured by means of observing surviving offspring. In harvested ungulates, postmortem investigations of reproductive organs are used to estimate reproductive potential by obtaining ovulation rates and fetus numbers. However, there are differences in numbers of offspring observed, fetal/embryo counts, and ovulation rates. We hypothesize that the discrepancy between estimated reproductive potential and reproductive outcome in large ungulates is not only due to ova loss but also due to embryonic mortality. We investigated reproductive status in early pregnancy by sampling hunter-harvested moose (Alces alces) in southern Sweden from 2007 to 2011. In all, 213 reproductive organs were examined postmortem, and in confirmed pregnant moose (n = 53), 25 % (19 of 76) embryos were nonviable and 6 % of ova was unfertilized. The discrepancy between the ovulation rate of all pregnant moose (1.49) and the number of expected offspring per pregnant female, when embryonic mortality and unfertilized oocytes were accounted for (1.08), was 27.5 %. An association between inflammation of the inner mucous membrane (endometritis) of the moose's uterus and embryonic mortality was observed. This is the first comprehensive report of embryonic mortality and endometritis in moose. The observed discrepancy between ovulation rates and early embryonic development/survival shows that ovulation rates are indicative but not accurate estimates of moose reproductive rate. The use of ovulation rates as a sole estimator of future offspring rates may lead to an overharvest of a managed moose population. PMID- 24954928 TI - "Reversed" intraguild predation: red fox cubs killed by pine marten. AB - Camera traps deployed at a badger Meles meles set in mixed pine forest in north eastern Poland recorded interspecific killing of red fox Vulpes vulpes cubs by pine marten Martes martes. The vixen and her cubs settled in the set at the beginning of May 2013, and it was abandoned by the badgers shortly afterwards. Five fox cubs were recorded playing in front of the den each night. Ten days after the first recording of the foxes, a pine marten was filmed at the set; it arrived in the morning, made a reconnaissance and returned at night when the vixen was away from the set. The pine marten entered the den several times and killed at least two fox cubs. It was active at the set for about 2 h. This observation proves that red foxes are not completely safe from predation by smaller carnivores, even those considered to be subordinate species in interspecific competition. PMID- 24954926 TI - The influence of habitat structure on genetic differentiation in red fox populations in north-eastern Poland. AB - The red fox (Vulpes vulpes) has the widest global distribution among terrestrial carnivore species, occupying most of the Northern Hemisphere in its native range. Because it carries diseases that can be transmitted to humans and domestic animals, it is important to gather information about their movements and dispersal in their natural habitat but it is difficult to do so at a broad scale with trapping and telemetry. In this study, we have described the genetic diversity and structure of red fox populations in six areas of north-eastern Poland, based on samples collected from 2002-2003. We tested 22 microsatellite loci isolated from the dog and the red fox genome to select a panel of nine polymorphic loci suitable for this study. Genetic differentiation between the six studied populations was low to moderate and analysis in Structure revealed a panmictic population in the region. Spatial autocorrelation among all individuals showed a pattern of decreasing relatedness with increasing distance and this was not significantly negative until 93 km, indicating a pattern of isolation-by distance over a large area. However, there was no correlation between genetic distance and either Euclidean distance or least-cost path distance at the population level. There was a significant relationship between genetic distance and the proportion of large forests and water along the Euclidean distances. These types of habitats may influence dispersal paths taken by red foxes, which is useful information in terms of wildlife disease management. PMID- 24954929 TI - Thank you, editor DiPiro, for your enthusiasm and dedication to AJPE. PMID- 24954930 TI - Impact of pharmacy student interventions in an urban family medicine clinic. AB - OBJECTIVES: To determine the number of interventions made by pharmacy students at an urban family medicine clinic and the acceptance rate of these recommendations by the healthcare providers. The secondary objective was to investigate the cost avoidance value of the interventions. METHODS: A prospective, unblinded study was conducted to determine the number and cost avoidance value of clinical interventions made by pharmacy students completing advanced pharmacy practice experiences (APPEs) in an urban family medicine clinic. RESULTS: Eighteen students completed this experience in the 8 months studied. Of the 718 interventions performed, 77% were accepted by physicians, including 58% of the 200 interventions that required immediate action. Projected avoidance was estimated at $61,855. CONCLUSION: The clinical interventions by pharmacy students were generally well received by healthcare providers and resulted in significant cost savings. Pharmacy students can play an important role in a family medicine clinic. PMID- 24954931 TI - Qualitative analysis of common definitions for core advanced pharmacy practice experiences. AB - OBJECTIVE: To determine how colleges and schools of pharmacy interpreted the Accreditation Council for Pharmacy Education's (ACPE's) Standards 2007 definitions for core advanced pharmacy practice experiences (APPEs), and how they differentiated community and institutional practice activities for introductory pharmacy practice experiences (IPPEs) and APPEs. METHODS: A cross-sectional, qualitative, thematic analysis was done of survey data obtained from experiential education directors in US colleges and schools of pharmacy. Open-ended responses to invited descriptions of the 4 core APPEs were analyzed using grounded theory to determine common themes. Type of college or school of pharmacy (private vs public) and size of program were compared. RESULTS: Seventy-one schools (72%) with active APPE programs at the time of the survey responded. Lack of strong frequent themes describing specific activities for the acute care/general medicine core APPE indicated that most respondents agreed on the setting (hospital or inpatient) but the student experience remained highly variable. Themes were relatively consistent between public and private institutions, but there were differences across programs of varying size. CONCLUSION: Inconsistencies existed in how colleges and schools of pharmacy defined the core APPEs as required by ACPE. More specific descriptions of core APPEs would help to standardize the core practice experiences across institutions and provide an opportunity for quality benchmarking. PMID- 24954932 TI - Education, training, and academic experience of newly hired, first-time pharmacy faculty members. AB - Objective. To describe the education, training, and academic experiences of newly hired faculty members at US colleges and schools of pharmacy during the 2012-2013 academic year. Methods. A survey regarding education, training, and academic experiences was conducted of all first-time faculty members at US colleges and schools of pharmacy hired during the 2012-2013 academic year. Results. Pharmacy practice faculty members accounted for the majority (68.2%) of new hires. Ambulatory care was the most common pharmacy specialty position (29.8%). Most new faculty members had a doctor of pharmacy (PharmD) as their terminal degree (74.8%), and 88.3% of pharmacy practice faculty members completed a residency. Of new faculty members who responded to the survey, 102 (67.5%) had at least 3 prior academic teaching, precepting, or research experiences. Conclusion. New faculty members were hired most frequently for clinical faculty positions at the assistant professor level and most frequently in the specialty of ambulatory care. Prior academic experience included precepting pharmacy students, facilitating small discussions, and guest lecturing. PMID- 24954933 TI - Modification of a pharmacokinetics course design to improve student performance. AB - OBJECTIVE: To determine if the addition of weekly quizzes or reducing the number of faculty members teaching improved third-year (P3) pharmacy students' final grades in a clinical pharmacokinetics course. DESIGN: Four sections of a pharmacokinetics and pharmacodynamics course were divided according to the number of faculty members teaching the course and the administration of weekly quizzes. Two sections were taught by 6 faculty members and 2 were taught by 3 faculty members. Also, 1 section in each group received weekly quizzes, creating a 2-by-2 design. ASSESSMENT: The performance of the 201 P3 students enrolled in the course was assessed by comparing the average of 3 examination grades while excluding quiz grades. The mean final grade of classes in which quizzes were not administered was lower than that for classes in which quizzes were administered (p=0.019). The mean final grade in classes taught by 3 faculty members vs 6 faculty members was higher, but not significantly. A positive significant correlation existed between performance in a prerequisite biopharmaceutics class and this advanced class. CONCLUSION: Making minor modifications to the delivery of a course, such as number of quizzes administered and number of faculty members teaching the course, had a positive impact on student performance. Grades in a prerequisite course may enable earlier identification of students at risk of poor performance in advanced courses. PMID- 24954934 TI - Interprofessional education among student health professionals using human patient simulation. AB - OBJECTIVE: To describe the planning, implementation, and outcomes of an interprofessional education clinical laboratory facilitated through human patient simulation. DESIGN: An interprofessional education clinical laboratory was developed with a patient-care scenario of acute exacerbation of heart failure that incorporated the use of a high-fidelity patient simulator. Pharmacy and nursing students assumed clinical roles in this realistic scenario and collaborated to diagnose and treat the patient. ASSESSMENT: Student attitudes toward and readiness to participate in interprofessional education improved following participation in the laboratory. Students reported that the greatest benefit of the experience was in their communication skills. CONCLUSION: Students' ability to participate in interprofessional education experiences and their attitudes toward them improved following participation in this curricular initiative. Further evaluation of the impact of interprofessional education on student learning outcomes and changes in practice is warranted. PMID- 24954935 TI - Student knowledge and confidence in an elective clinical toxicology course using active-learning techniques. AB - OBJECTIVE: To measure changes in students' knowledge and confidence scores after completing an elective clinical toxicology course in an accelerated doctor of pharmacy (PharmD) program. DESIGN: Various active-learning techniques were used to create a learner-centered environment. Approximately two-thirds of the course used student-led presentations. Some of those not presenting were assigned to be evaluators, responsible for asking the presenter a question or writing quiz questions based on the presented material. Other learner-centered activities included weekly quizzes and discussions at the conclusion of each presented topic. ASSESSMENT: A test instrument designed to measure students' knowledge and associated level of confidence on each item was administered at the beginning and end of the course. Students' knowledge and confidence scores increased significantly from pretest to posttest. CONCLUSIONS: Students' increased confidence and knowledge scores were well correlated after course completion, indicating students were better able to self-assess these areas. These findings suggest that confidence could be an additional measure of students' metacognitive skill development. PMID- 24954936 TI - Comparison of online versus classroom delivery of an immunization elective course. AB - OBJECTIVE: To compare performance and preferences of students who were randomly allocated to classroom or online sections of an elective course on immunization. METHODS: Students were randomly assigned to either the classroom or online section. All course activities (lectures, quizzes, case discussions, vaccine administration, and final examination) were the same for both sections, except for the delivery of lecture material. ASSESSMENT: Students were surveyed on their preferences at the beginning and end of the semester. At the end of the semester, the majority of students in the classroom group preferred classroom or blended delivery while the majority of students in the online group preferred blended or online delivery (p<0.01). Student performance was compared at the end of the semester. There was no significant difference for any of the grades in the course between the 2 sections. CONCLUSION: There was no difference in student performance between the classroom and online sections, suggesting that online delivery is an effective way to teach students about immunization. PMID- 24954937 TI - Faculty development: who, what, why, where, when, and how? PMID- 24954939 TI - Faculty development program models to advance teaching and learning within health science programs. AB - Within health science programs there has been a call for more faculty development, particularly for teaching and learning. The primary objectives of this review were to describe the current landscape for faculty development programs for teaching and learning and make recommendations for the implementation of new faculty development programs. A thorough search of the pertinent health science databases was conducted, including the Education Resource Information Center (ERIC), MEDLINE, and EMBASE, and faculty development books and relevant information found were reviewed in order to provide recommendations for best practices. Faculty development for teaching and learning comes in a variety of forms, from individuals charged to initiate activities to committees and centers. Faculty development has been effective in improving faculty perceptions on the value of teaching, increasing motivation and enthusiasm for teaching, increasing knowledge and behaviors, and disseminating skills. Several models exist that can be implemented to support faculty teaching development. Institutions need to make informed decisions about which plan could be most successfully implemented in their college or school. PMID- 24954938 TI - A checklist for the development of faculty mentorship programs. AB - Mentoring of junior faculty members continues to be a widespread need in academic pharmacy in both new programs and established schools. The American Association of Colleges of Pharmacy (AACP) Joint Council Task Force on Mentoring was charged with gathering information from member colleges and schools and from the literature to determine best practices that could be shared with the academy. The task force summarized their findings regarding the needs and responsibilities for mentors and proteges at all faculty levels; what mentoring pieces are in existence, which need improvement, and which need to be created; and how effective mentoring is defined and could be measured. Based on these findings, the task force developed several recommendations as well as the PAIRS Faculty Mentorship Checklist. Academic institutions can benefit from the checklist whether they are planning to implement a faculty mentorship program or are interested in modifying existing programs. PMID- 24954941 TI - Engaging external senior faculty members as faculty mentors. AB - A small nonprofit private college with limited resources and a high proportion of junior faculty developed a nontraditional external faculty mentor program in the summer of 2011 in response to the American Association of Colleges of Pharmacy (AACP) faculty survey data regarding the professional development needs of pharmacy faculty members. Experienced faculty members with national reputations from other colleges and schools of pharmacy were hired as consultants to serve as mentors for assigned faculty members. Program goals were to provide directed, individual mentorship for pharmacy practice and basic science faculty members, expand peer review of faculty teaching prowess, and enhance monthly faculty development programming. The latter was based upon the specific needs assessment of the faculty. Program outcomes reported will include faculty satisfaction (AACP faculty survey data) changes over time, achievement of board certification for clinical faculty members and other credentialing, and other benchmarks, eg, publications, grant funding, service engagement (site development, professional organizations), after the implementation of the nontraditional faculty-mentoring program. PMID- 24954940 TI - A formal mentorship program for faculty development. AB - OBJECTIVE: To describe the development, implementation, and evaluation of a formal mentorship program at a college of pharmacy. METHODS: After extensive review of the mentorship literature within the health sciences, a formal mentorship program was developed between 2006 and 2008 to support and facilitate faculty development. The voluntary program was implemented after mentors received training, and mentors and proteges were matched and received an orientation. Evaluation consisted of conducting annual surveys and focus groups with mentors and proteges. RESULTS: Fifty-one mentor-protege pairs were formed from 2009 to 2012. A large majority of the mentors (82.8%-96.9%) were satisfied with the mentorship program and its procedures. The majority of the proteges (>=70%) were satisfied with the mentorship program, mentor-protege relationship, and program logistics. Both mentors and proteges reported that the proteges most needed guidance on time management, prioritization, and work-life balance. While there were no significant improvements in the proteges' number of grant submissions, retention rates, or success in promotion/tenure, the total number of peer reviewed publications by junior faculty members was significantly higher after program implementation (mean of 7 per year vs 21 per year, p=0.03) in the college's pharmacy practice and administration department. CONCLUSIONS: A formal mentorship program was successful as measured by self-reported assessments of mentors and proteges. PMID- 24954942 TI - A collaboration among health sciences schools to enhance faculty development in teaching. AB - Those involved in providing faculty development may be among only a few individuals for whom faculty development is an interest and priority within their work setting. Furthermore, funding to support faculty development is limited. In 2010, an interprofessional, self-formed, faculty learning community on faculty development in teaching was established to promote collaboration on faculty development initiatives that have transference to faculty members across disciplines and to share expertise and resources for wider impact. The organic structure and processes of the faculty learning community created an environment that has not only resulted in an increased offering of faculty development opportunities and resources across the health science campus, but has created a rich environment that combines the knowledge, innovation, and experience to promote collaborative efforts that benefit all. The background, structure, processes, successes, and lessons learned of the interprofessional faculty learning community on faculty development in teaching are described. PMID- 24954944 TI - A primer for objective structured teaching exercises. AB - The objective structured teaching exercise (OSTE) is a high-fidelity training method for advancing the teaching and interpersonal communication skills of faculty members and preceptors. This paper is a primer for implementation of OSTEs as part of a comprehensive faculty development program. This primer addresses teaching and precepting skills that can be most effectively enhanced and assessed by the OSTE method. Development of case scenarios, recruitment and training of standardized students, OSTE session implementation processes, and OSTE evaluation methods are discussed. The experience of the authors as well as recommendations from a review of the literature and discussions with educators with OSTE experience are included. PMID- 24954943 TI - A reflective teaching challenge to motivate educational innovation. AB - OBJECTIVE: To describe a teaching challenge intended to increase faculty use of evidence-based and student-centered instructional strategies in the demanding school of pharmacy context with technology-savvy students. DESIGN: A teaching challenge was created that required faculty members to incorporate a "new-to-you" innovative teaching method in a class, course, or experiential activity. The method was linked to at least 1 of 7 evidence-based principles for effective teaching. Faculty members were exposed to colleagues' teaching strategies via brief voluntary presentations at department meetings. ASSESSMENT: A post challenge survey provided assessment data about the challenge. Responses to a baseline survey provided additional information about what faculty members were already doing (52% response rate). Eighty-one percent of faculty respondents completed the challenge. A wide array of new strategies (13 categories such as flipped classrooms and social media) was implemented and 75% included the use of technology. Nearly all respondents (96%) thought that participation in the challenge was worth the effort and planned to participate again the following year. All faculty members intended to continue using their new strategy and 56% planned additional modifications with future implementations. The challenge demonstrated how multiple goals of curricular improvement, faculty development, and student-centered instruction could be achieved together. CONCLUSION: The teaching challenge motivated most of the faculty members to try something new to them. Links between evidence-based principles and day-to-day activities were strengthened. The new-to-you design placed the challenge within reach of faculty members regardless of their background, subject, or experience. PMID- 24954945 TI - A nontraditional faculty development initiative using a social media platform. AB - OBJECTIVE: To assess the outcomes from an 11-year nontraditional professional development activity implemented by female faculty members at several colleges and schools of pharmacy. DESIGN: Within the context of an online fantasy football league, faculty members practiced community-based faculty development strategies, including peer mentoring, skills development, constructive feedback and other supportive behaviors. ASSESSMENT: Data were extracted from curriculum vitae to characterize the academic progress of participants and to quantify scholarly work collaborations among league members. Analyses were limited to members who had participated in the league for 10 or more consecutive years. Seventy-one collaborative scholarly works occurred among team managers, including presentation of 20 posters and 2 oral presentations at national or international meetings, publication of 29 peer-reviewed articles and 15 book chapters, and funding of 5 research projects. CONCLUSION: Social media platforms can foster nontraditional faculty development and mentoring by enhancing connectivity between pharmacy educators who share similar interests. PMID- 24954946 TI - Orientating nonpharmacist faculty members to pharmacy practice. AB - OBJECTIVE: To design, implement, and evaluate a faculty development program intended to orient nonpharmacist faculty members to pharmacy practice. DESIGN: A multifaceted program was implemented in 2012 that included 4 shadowing experiences in which faculty members visited acute care, ambulatory care, hospital, and community pharmacy settings under the guidance of licensed preceptors. Itineraries for each visit were based on objective lists of anticipated practice experiences that define the role of the pharmacist in each setting. ASSESSMENT: The 4 shadowing experiences culminated with reflection and completion of a survey to assess the impact of the program. All of the faculty participants agreed that the experience improved their conceptual understanding of contemporary pharmacy practice and the role of the pharmacist in the healthcare setting. The experience also improved faculty comfort with creating practice-relevant classroom activities. CONCLUSIONS: A shadowing experience is an effective way of orienting nonpharmacist faculty members to the practice of pharmacy. This program inspired the creation of an experience to introduce pharmacy practice faculty to pharmaceutical science faculty research initiatives. PMID- 24954947 TI - A faculty member on Match Day. PMID- 24954948 TI - The need to cover generic medications and generic substitution practice in the curricula of pharmacy colleges in Saudi Arabia. PMID- 24954949 TI - Discussion of "The Need for More Emphasis on Prediction: A 'Nondenominational' Model-Based Approach" PMID- 24954951 TI - Developmental Relations between Reading and Writing at the Word, Sentence and Text Levels: A Latent Change Score Analysis. AB - Relations between reading and writing have been studied extensively but the less is known about the developmental nature of their interrelations. This study applied latent change score modeling to investigate longitudinal relations between reading and writing skills at the word, sentence and text levels. Latent change score models were used to compare unidirectional pathways (reading-to writing and writing-to-reading) and bidirectional pathways in a test of nested models. Participants included 316 boys and girls who were assessed annually in grades 1 through 4. Measures of reading included pseudo-word decoding, sentence reading efficiency, oral reading fluency and passage comprehension. Measures of writing included spelling, a sentence combining task and writing prompts. Findings suggest that a reading-to-writing model better described the data for the word and text levels of language, but a bidirectional model best fit the data at the sentence level. PMID- 24954950 TI - Genomics: moving behavioural ecology beyond the phenotypic gambit. AB - Researchers studying the adaptive significance of behaviour typically assume that genetic mechanisms will not inhibit evolutionary trajectories, an assumption commonly known as the 'phenotypic gambit'. Although the phenotypic gambit continues to be a useful heuristic for behavioural ecology, here we discuss how genomic methods provide new tools and conceptual approaches that are relevant to behavioural ecology. We first describe how the concept of a genetic toolkit for behaviour can allow behavioural ecologists to synthesize both genomic and ecological information when assessing behavioural adaptation. Then we show how gene expression profiles can be viewed as complex phenotypic measurements, used to (1) predict behaviour, (2) evaluate phenotypic plasticity and (3) devise methods to manipulate behaviour in order to test adaptive hypotheses. We propose that advances in genomics and bioinformatics may allow researchers to overcome some of the logistical obstacles that motivated the inception of the phenotypic gambit. Behavioural ecology and genomics are mutually informative, providing potential synergy that could lead to powerful advances in the field of animal behaviour. PMID- 24954952 TI - Tests of Mediation: Paradoxical Decline in Statistical Power as a Function of Mediator Collinearity. AB - Increasing the correlation between the independent variable and the mediator (a coefficient) increases the effect size (ab) for mediation analysis; however, increasing a by definition increases collinearity in mediation models. As a result, the standard error of product tests increase. The variance inflation due to increases in a at some point outweighs the increase of the effect size (ab) and results in a loss of statistical power. This phenomenon also occurs with nonparametric bootstrapping approaches because the variance of the bootstrap distribution of ab approximates the variance expected from normal theory. Both variances increase dramatically when a exceeds the b coefficient, thus explaining the power decline with increases in a. Implications for statistical analysis and applied researchers are discussed. PMID- 24954953 TI - THE RELATIONSHIPS AMONG VIGILANT COPING STYLE, RACE, AND DEPRESSION. AB - Although Black-white differences in depression are well documented, vigilant coping style as an explanation for the observed inequalities in depression is less understood. Using data from 718 adults in the Exploring Health Disparities in Integrated Communities (EHDIC) Study, we estimated logistic regression models to examine the cross sectional relationship between race, vigilant coping style, and depression. After controlling for demographic variables, white adults were more likely to report depression than Black adults. Moreover, when accounting for coping style, the Black-white difference in depression widened. This association persisted even with the addition of the covariates. While high rates of depression among whites compared with Blacks are well documented, the degree of the differences appears to be greater than previously reported once vigilance is accounted for. This finding suggests that if it were not for the high prevalence of vigilant coping in blacks, the well-documented black advantage regarding depression compared to whites would likely be even greater. PMID- 24954954 TI - Dual-Emissive Difluoroboron Naphthyl-Phenyl beta-Diketonate Polylactide Materials: Effects of Heavy Atom Placement and Polymer Molecular Weight. AB - Luminescent materials are important for imaging and sensing. Aromatic difluoroboron beta-diketonate complexes (BF2bdks) are classic fluorescent molecules that have been explored as photochemical reagents, two-photon dyes, and oxygen sensors. A series of BF2bdks with naphthyl and phenyl groups was synthesized, and photophysical properties were investigated in both methylene chloride and poly(lactic acid) (PLA). Polymer molecular weight and dye attachment site along with bromide heavy atom placement were varied to tune optical properties of dye-PLA materials. Systems without heavy atoms have long phosphorescence lifetimes, which is useful for lifetime-based oxygen sensing. Bromine substitution on the naphthyl ring resulted in intense, clearly distinguishable fluorescence and phosphorescence peaks important for ratiometric oxygen sensing and imaging. PMID- 24954955 TI - mtsslSuite: In silico spin labelling, trilateration and distance-constrained rigid body docking in PyMOL. AB - Nanometer distance measurements based on electron paramagnetic resonance methods in combination with site-directed spin labelling are powerful tools for the structural analysis of macromolecules. The software package mtsslSuite provides scientists with a set of tools for the translation of experimental distance distributions into structural information. The package is based on the previously published mtsslWizard software for in silico spin labelling. The mtsslSuite includes a new version of MtsslWizard that has improved performance and now includes additional types of spin labels. Moreover, it contains applications for the trilateration of paramagnetic centres in biomolecules and for rigid-body docking of subdomains of macromolecular complexes. The mtsslSuite is tested on a number of challenging test cases and its strengths and weaknesses are evaluated. PMID- 24954956 TI - PELDOR in rotationally symmetric homo-oligomers. AB - Nanometre distance measurements by pulsed electron-electron double resonance (PELDOR) spectroscopy have become an increasingly important tool in structural biology. The theoretical underpinning of the experiment is well defined for systems containing two nitroxide spin-labels (spin pairs); however, recently experiments have been reported on homo-oligomeric membrane proteins consisting of up to eight spin-labelled monomers. We have explored the theory behind these systems by examining model systems based on multiple spins arranged in rotationally symmetric polygons. The results demonstrate that with a rising number of spins within the test molecule, increasingly strong distortions appear in distance distributions obtained from an analysis based on the simple spin pair approach. These distortions are significant over a range of system sizes and remain so even when random errors are introduced into the symmetry of the model. We present an alternative approach to the extraction of distances on such systems based on a minimisation that properly treats multi-spin correlations. We demonstrate the utility of this approach on a spin-labelled mutant of the heptameric Mechanosensitive Channel of Small Conductance of E. coli. PMID- 24954958 TI - Inequality and City Size. AB - Between 1979 and 2007 a strong positive monotonic relationship between wage inequality and city size has developed. This paper investigates the links between this emergent city size inequality premium and the contemporaneous nationwide increase in wage inequality. After controlling for the skill composition of the workforce across cities of different sizes, we show that at least 23 percent of the overall increase in the variance of log hourly wages in the United States from 1979 to 2007 is explained by the more rapid growth in the variance of log wages in larger locations relative to smaller locations. This influence occurred throughout the wage distribution and was most prevalent during the 1990s. More rapid growth in within skill group inequality in larger cities has been by far the most important force driving these city size specific patterns in the data. Differences in the industrial composition of cities of different sizes explain up to one-third of this city size effect. These results suggest an important role for agglomeration economies in generating changes in the wage structure during the study period. PMID- 24954957 TI - Investigating the structure of the factor B vWF-A domain/CD55 protein-protein complex using DEER spectroscopy: successes and pitfalls. AB - The electron paramagnetic resonance technique of double electron-electron resonance (DEER) was used to measure nanometre-scale distances between nitroxide spin labels attached to the complement regulatory protein CD55 (also known as decay accelerating factor) and the von Willebrand factor A (vWF-A) domain of factor B. Following a thorough assessment of the quality of the data, distances obtained from good-quality measurements are compared to predicted distances from a previously hypothesised model for the complex and are found to be incompatible. The success of using these distances as restraints in multi-body docking routines is presented critically. PMID- 24954959 TI - Preparation of orthogonally protected (2S, 3R)-2-amino-3-methyl-4 phosphonobutyric acid (Pmab) as a phosphatase-stable phosphothreonine mimetic and its use in the synthesis of Polo-box domain-binding peptides. AB - Reported herein is the first stereoselective synthesis of (2S,3R)-4-[bis-(tert butyloxy)phosphinyl]-2-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-3-methylbutanoic acid [(N-Fmoc, O,O-(bis-(tert-butyl))-Pmab, 4] as a hydrolytically-stable phosphothreonine mimetic bearing orthogonal protection compatible with standard solid-phase protocols. The synthetic approach used employs Evans' oxazolidinone for chiral induction. Also presented is the application of 4 in the solid-phase synthesis of polo-like kinase 1 (Plk1) polo box domain (PBD)-binding peptides. These Pmab-containing peptides retain PBD binding efficacy similar to a parent pThr containing peptide. Reagent 4 should be a highly useful reagent for the preparation of signal transduction-directed peptides. PMID- 24954960 TI - Exploiting the Divalent Nature of Isonitriles: a novel Pictet-Spengler Amidination process. AB - An isocyanide-based multicomponent reaction (IMCR) utilized for the rapid assembly of novel, biologically relevant dihydropyrrolo[1,2-a]quinoxalines amidines is herein presented. Starting from 1-(2-aminophenyl)pyrroles, aldehydes, and isonitriles, the target heterocyclic scaffold is assembled in a one-pot, operationally friendly process. With three points of diversity and formation of three chemical bonds in one step, this strategy proves to be very general. Novel, mild methodology for the generation of amidines from secondary amine anilines and isonitriles is also introduced. PMID- 24954961 TI - What Makes Annuitization More Appealing? AB - We conduct and analyze two large surveys of hypothetical annuitization choices. We find that allowing individuals to annuitize a fraction of their wealth increases annuitization relative to a situation where annuitization is an "all or nothing" decision. Very few respondents choose declining real payout streams over flat or increasing real payout streams of equivalent expected present value. Highlighting the effects of inflation increases demand for cost of living adjustments. Frames that highlight flexibility, control, and investment significantly reduce annuitization. A majority of respondents prefer to receive an extra "bonus" payment during one month of the year that is funded by slightly lower payments in the remaining months. Concerns about later-life income, spending flexibility, and counterparty risk are the most important self-reported motives that influence the annuitization decision. PMID- 24954962 TI - Leaving A Legacy: Parental Migration and School Outcomes Among Young Children in the Philippines. AB - This article examines the link between parental migration and young children's education using data from the Philippine country study of the Child Health and Migrant Parents in South-East Asia (CHAMPSEA) Project. The key research question probed here is: what difference does parental migration make to the school outcomes of young children? Specifically, it looks at factors that explain children's school progression (school pacing) and academic performance (school achievement) using multiple regression analysis. These questions are explored using CHAMPSEA data gathered from a survey of children under 12 years of age and their households in Laguna and Batangas (n=487). The concern that parental absence due to migration can negatively affect the school performance of children is not supported by the study. If parental migration affects school outcomes, it is associated with positive outcomes, or with outcomes which show that children in transnational households are not doing worse than children living with both parents. Positive school outcomes are best associated with a migrant-carer arrangement where fathers work abroad and mothers stay home as carers -children in these households fare very well when it comes to school pacing and school achievement. The study concludes that families and households need to provide both economic and psychological support to enhance the chances that children are at pace with their schooling and are doing well at school. PMID- 24954963 TI - The Subjective Well-Being of Children in Transnational and Non-Migrant Households: Evidence from Thailand. AB - To date, research that includes children's views on parental migration has been insufficient. Based on the children's assessment of well-being, we use a case study of Thailand to ask whether children of overseas migrant parents are less or more resilient compared to children of non-migrant parents. We make use of data from the Child Health and Migrant Parents in South-East Asia (CHAMPSEA) Project, one of the few studies that provide space for children, both of migrant and non migrant parents, to voice their views. Our sample includes 496 children aged 9 to 11 years old. The outcome variable captures children's subjective well-being as an indicator of whether they are a resilient child. Our multivariate analysis controls for other potential contributing factors, including the children's individual attributes, carer's mental health, parents' education, family functioning as reported by the children, and household economic status in order to investigate the effects of parental migration. Qualitative information from in depth interviews with selected carers and group interviews with community leaders are also used to explain the results. Our findings highlight the importance of taking into account children's own perceptions. Compared to children of non migrant parents, those of migrant parents are more likely to give a positive assessment of their own well-being. The other contributing factors include whether the child sees their family as functioning well. In Thailand, international migration is predominantly undertaken by fathers while childcare remains the responsibility of mothers, and public attitudes towards overseas migration, especially paternal migration, is generally favorable. This may help explain the positive perception of children of migrants towards themselves. PMID- 24954964 TI - Alcohol Use among Very Early Adolescents in Vietnam: What Difference Does Parental Migration Make? AB - Little is known about the patterns of alcohol use among adolescents and the transmission of alcohol use behaviors from parents to children, including the passage into responsible and problem drinking, in the developing world. The following paper uses primary data from the Child Health and Migrant Parents in South-East Asia (CHAMPSEA) Project for older children aged 9, 10 and 11 to examine the prevalence (16.2 percent) and correlates of alcohol use initiation including parental migration status, caregiving arrangements and exposure to environmental alcohol use (family and friends) in Vietnam. Contrary to expectations, there is no observed migrant 'deficit.' There is some indication that early adolescents in the care of their grandparents are less likely to have a history of experimentation with alcohol use, although it is fully attenuated after controlling for other factors. Peer use is the most powerful explanatory measure of early adolescent drinking, with early adolescents more than five times as likely to have ever drunk alcohol if their friends drink also, and as expected, there is a strong child gender difference with girls much less likely to have a history of alcohol use. "A man without alcohol is like a flag without wind"- Popular Vietnamese saying. PMID- 24954965 TI - Securing a Better Living Environment for Left-Behind Children: Implications and Challenges for Policies. AB - Migration is an increasingly significant driver of transformations in family configurations and caregiving practices as well as living arrangements. The sustainability of geographically-split family formations is dependent on several factors, including the presence and strength of care support networks among migrants and their left-behind families, access to communication infrastructure and the stability of the families' financial resources. Drawing on both a selective review of relevant academic literature as well as key findings from the CHAMPSEA Project, the article first examines the effects of these three factors on the well-being of migrants' left-behind family members, especially children. The article also considers major implications of the project's findings, as well as possible challenges for migration and development policies. One area of concern for migration and development policy arising from our research findings is the need to provide better support for left-behind caregivers or carers who are substituting for the absent migrant in childcare and domestic work but who may also need care and support themselves. Another area relates to the need to improve communication infrastructure to help migrants and their families maintain their relationships across transnational spaces; while a third lies with the importance of minimizing migrant families' economic stress stemming from the cycle of debts resulting from exorbitant broker fees and the mismanagement of remittances. By acknowledging both the social and economic costs of international labor migration on families, governments of labor-sending countries can create a more effective legal and institutional framework as well as design suitable supporting mechanisms for left-behind families. There is then a stronger possibility that migration can become a sustainable development strategy for transnational families in South-East Asia. PMID- 24954966 TI - Never Seem to Find the Time: Evaluating the Physiological Time Course of Visual Word Recognition with Regression Analysis of Single Item ERPs. AB - Visual word recognition is a process that, both hierarchically and in parallel, draws on different types of information ranging from perceptual to orthographic to semantic. A central question concerns when and how these different types of information come online and interact after a word form is initially perceived. Numerous studies addressing aspects of this question have been conducted with a variety of techniques (e.g., behavior, eye-tracking, ERPs), and divergent theoretical models, suggesting different overall speeds of word processing, have coalesced around clusters of mostly method-specific results. Here, we examine the time course of influence of variables ranging from relatively perceptual (e.g., bigram frequency) to relatively semantic (e.g., number of lexical associates) on ERP responses, analyzed at the single item level. Our results, in combination with a critical review of the literature, suggest methodological, analytic, and theoretical factors that may have led to inconsistency in results of past studies; we will argue that consideration of these factors may lead to a reconciliation between divergent views of the speed of word recognition. PMID- 24954967 TI - Family Relationships and Adolescents' Health Attitudes and Weight: The Understudied Role of Sibling Relationships. AB - Family relationships are important predictors of adolescents' diet, physical activity, and health issues including obesity. Despite their prominence in the family, siblings have received little attention on how they may influence these health-related behaviors. Addressing this gap, the present study examined associations between sibling relationship qualities and adolescents' health attitudes, exercise behaviors, and weight controlling for other family relationship qualities. Participants included one parent and two adolescent siblings (ages 12 to 19) from 326 families. Multilevel models indicated that net of parent-adolescent relationship qualities and adolescents' personal characteristics, sibling intimacy was related to healthy attitudes and greater exercise behaviors, whereas sibling conflict was associated with increased risk of being overweight. Links between sibling conflict and weight status, however, were further qualified by gender composition of the sibling dyad. Results highlight the significance of sibling relationships in adolescents' everyday health attitudes and behaviors and implications for intervention efforts are discussed. PMID- 24954968 TI - Functionalization of Complexed N2O in Bis(pentamethylcyclopentadienyl) Systems of Zirconium and Titanium. AB - Methyl triflate reacts with the metastable azoxymetallacyclopentene complex Cp*2Zr(N(O)NCPhCPh), generated in situ from nitrous oxide insertion into the Zr-C bond of Cp*2Zr(eta2-PhCCPh) at -78 degrees C, to afford the salt [Cp*2Zr(N(O)N(Me)CPhCPh)][O3SCF3] (1) in 48% isolated yield. A single-crystal X ray structure of 1 features a planar azoxymetallacycle with methyl alkylation taking place only at the beta-nitrogen position of the former Zr(N(O)NCPhCPh) scaffold. In addition to 1, the methoxy-triflato complex Cp*2Zr(OMe)(O3SCF3) (2) was also isolated from the reaction mixture in 26% yield and fully characterized, including its independent synthesis from the alkylation of Cp*2Zr=O(NC5H5) with MeO3SCF3. Complex 2 could also be observed, spectroscopically, from the thermolysis of 1 (80 degrees C, 2 days). In contrast to Cp*2Zr(N(O)NPhCCPh), the more stable titanium N2O-inserted analogue, Cp*2Ti(N(O)NCPhCPh), reacts with MeO3SCF3 to afford a 1:1 mixture of regioisomeric salts, [Cp*2Ti(N(O)N(Me)CPhCPh)][O3SCF3] (3) and [Cp*2Ti(N(OMe)NCPhCPh)][O3SCF3] (4), in a combined 65% isolated yield. Single-crystal X-ray diffraction studies of a cocrystal of 3 and 4 show a 1:1 mixture of azoxymetallacyle salts resulting from methyl alkylation at both the beta-nitrogen and the beta-oxygen of the former Ti(N(O)NCPhCPh ring. As opposed to alkylation reactions, the one-electron reduction of Cp*2Ti(N(O)NCPhCPh) with KC8, followed by encapsulation with the cryptand 2,2,2-Kryptofix, resulted in the isolation of the discrete radical anion [K(2,2,2-Kryptofix)][Cp*2Ti(N(O)NCPhCPh)] (5) in 68% yield. Complex 5 was studied by single-crystal X-ray diffraction, and its solution X-band EPR spectrum suggested a nonbonding sigma-type wedge hybrid orbital on titanium, d(z2)/d(x2 y2), houses the unpaired electron, without perturbing the azoxymetallacycle core in Cp*2Ti(N(O)NCPhCPh). Theoretical studies of Ti and the Zr analogue are also presented and discussed. PMID- 24954969 TI - Conducting Research on Adolescent Suicide Attempters: Dilemmas and Decisions. AB - Research on effective treatments for adolescent suicide attempters is urgently needed. However, there has been a lack of research in this area. This is likely a result of the multiple challenges faced by investigators working with individuals at high risk of suicide. Based on our experiences conducting a large, randomized clinical trial with adolescent suicide attempters, in this article, we review ways to address these challenges in order to facilitate needed research on suicide prevention in adolescents. PMID- 24954970 TI - Optimal Retirement with Increasing Longevity. AB - We develop an optimizing life-cycle model of retirement with perfect capital markets. We show that longer healthy life expectancy usually leads to later retirement, but with an elasticity less than unity. We calibrate our model using data from the US and find that, over the last century, the effect of rising incomes, which promote early retirement, has dominated the effect of rising lifespans. Our model predicts continuing declines in the optimal retirement age, despite rising life expectancy, provided the rate of real wage growth remains as high as in the last century. PMID- 24954971 TI - More Than "Getting Us Through:" A Case Study in Cultural Capital Enrichment of Underrepresented Minority Undergraduates. AB - Minority students continue to be underrepresented among those who seek graduate and professional degrees in the sciences. Much previous research has focused on academic preparation. Equally important, however, are the psychological-social barriers and lack of institutional support encountered by many minority students. We present a case study of a university-sponsored intervention program for minority science majors that addresses not only academics, but also socialization into the academic community, networking, and the ability to practice newfound skills and dispositions through undergraduate research. In examining this case, we suggest that concerted, formal efforts toward expanding habitus and thereby augmenting cultural and social capital may have positive effects for underrepresented minority (URM) college students' academic and career prospects. Moreover, we argue that these differences complement the gains program participants make in academic preparedness, showing that attention to academics alone may be insufficient for addressing longstanding inequities in science career attainment among URM students. PMID- 24954972 TI - Modeling-error robustness of a viral-load preconditioning strategy for HIV treatment switching. AB - In previous work, we have developed optimal-control based approaches that seek to minimize the risk of subsequent virological failure by "pre-conditioning" the viral load during therapy switches. In this paper, we use Monte-Carlo methods to evaluate the sensitivity of an open-loop implementation of these approaches to modeling errors. To account for hidden parameter dependencies, we use parameter distributions obtained from the convergence of Bayesian parameter estimation techniques applied to sets of clinical data obtained during serial therapy interruptions as the distribution from which the Monte-Carlo method samples. PMID- 24954973 TI - Prevalence of Personality Disorders at Midlife in a Community Sample: Disorders and Symptoms Reflected in Interview, Self, and Informant Reports. AB - This report is concerned with the prevalence of symptoms of specific personality disorders in a representative community sample and draws attention to the importance of different sources of diagnostic information. We recruited a sample of 1,630 people between the ages of 55 and 64 to participate in a study regarding personality and health. Using careful recruitment methods, our participation rate was 43 %. Participants completed the SIDP-IV interview as well as a questionnaire (self-report MAPP). Informants completed the same questionnaire (informant MAPP), describing the participant's maladaptive personality characteristics. According to the diagnostic interview, 7 % of participants met criteria for exactly one PD, 1 % met criteria for 2 or 3 PDs, and 2 % met criteria for PD NOS (defined as 10 or more miscellaneous criteria). Avoidant and obsessive compulsive PDs were the most common types. Correlations between the three sources of information indicated significant agreement among these measurement methods, but they are not redundant. In comparison to interview and self-report data, informants reported more symptoms of personality pathology (except for avoidant PD). Symptoms of personality pathology are continuously distributed, and subthreshold features may have an important impact on health and social adjustment. In this community sample, rates of co-morbidity among PDs and the proportion of PDNOS diagnoses are substantially lower than reported from clinical samples. Future research must evaluate the validity of diagnostic thresholds and competing sources of diagnostic information in relation to important life outcomes. PMID- 24954974 TI - Reactive Functionalized Membranes for Polychlorinated Biphenyl Degradation. AB - Membranes have been widely used in water remediation (e.g. desalination and heavy metal removal) because of the ability to control membrane pore size and surface charge. The incorporation of nanomaterials into the membranes provides added benefits through increased reactivity with different functionality. In this study, we report the dechlorination of 2-chlorobiphenyl in the aqueous phase by a reactive membrane system. Fe/Pd bimetallic nanoparticles (NPs) were synthesized (in-situ) within polyacrylic acid (PAA) functionalized polyvinylidene fluoride (PVDF) membranes for degradation of polychlorinated biphenyls (PCBs). Biphenyl formed in the reduction was further oxidized into hydroxylated biphenyls and benzoic acid by an iron-catalyzed hydroxyl radical (OH*) reaction. The formation of magnetite on Fe surface was observed. This combined pathway (reductive/oxidative) could reduce the toxicity of PCBs effectively while eliminating the formation of chlorinated degradation byproducts. The successful manufacturing of full-scale functionalized membranes demonstrates the possibility of applying reactive membranes in practical water treatment. PMID- 24954975 TI - Iron-Based Redox Polymerization of Acrylic Acid for Direct Synthesis of Hydrogel/Membranes, and Metal Nanoparticles for Water Treatment. AB - Functionalized polymer materials with ion exchange groups and integration of nano structured materials is an emerging area for catalytic and water pollution control applications. The polymerization of materials such as acrylic acid often requires persulfate initiator and a high temperature start. However, is generally known that metal ions accelerate such polymerizations starting from room temperature. If the metal is properly selected, it can be used in environmental applications adding two advantages simultaneously. This paper deals with this by polymerizing acrylic acid using iron as accelerant and its subsequent use for nanoparticle synthesis in hydrogel and PVDF membranes. Characterizations of hydrogel, membranes and nanoparticles were carried out with different techniques. Nanoparticles sizes of 30-60 nm were synthesized. Permeability and swelling measurements demonstrate an inverse relationship between hydrogel mesh size (6.30 to 8.34 nm) and membrane pores (222 to 110 nm). Quantitative reduction of trichloroethylene/chloride generation by Fe/Pd nanoparticles in hydrogel/membrane platforms was also performed. PMID- 24954976 TI - False-positive reduction in mammography using multiscale spatial Weber law descriptor and support vector machines. AB - In a CAD system for the detection of masses, segmentation of mammograms yields regions of interest (ROIs), which are not only true masses but also suspicious normal tissues that result in false positives. We introduce a new method for false-positive reduction in this paper. The key idea of our approach is to exploit the textural properties of mammograms and for texture description, to use Weber law descriptor (WLD), which outperforms state-of-the-art best texture descriptors. The basic WLD is a holistic descriptor by its construction because it integrates the local information content into a single histogram, which does not take into account the spatial locality of micropatterns. We extend it into a multiscale spatial WLD (MSWLD) that better characterizes the texture micro structures of masses by incorporating the spatial locality and scale of microstructures. The dimension of the feature space generated by MSWLD becomes high; it is reduced by selecting features based on their significance. Finally, support vector machines are employed to classify ROIs as true masses or normal parenchyma. The proposed approach is evaluated using 1024 ROIs taken from digital database for screening mammography and an accuracy of Az = 0.99 +/- 0.003 (area under receiver operating characteristic curve) is obtained. A comparison reveals that the proposed method has significant improvement over the state-of-the-art best methods for false-positive reduction problem. PMID- 24954978 TI - Improved appreciation of the functioning and importance of biological soil crusts in Europe: the Soil Crust International Project (SCIN). AB - Here we report details of the European research initiative "Soil Crust International" (SCIN) focusing on the biodiversity of biological soil crusts (BSC, composed of bacteria, algae, lichens, and bryophytes) and on functional aspects in their specific environment. Known as the so-called "colored soil lichen community" (Bunte Erdflechtengesellschaft), these BSCs occur all over Europe, extending into subtropical and arid regions. Our goal is to study the uniqueness of these BSCs on the regional scale and investigate how this community can cope with large macroclimatic differences. One of the major aims of this project is to develop biodiversity conservation and sustainable management strategies for European BSCs. To achieve this, we established a latitudinal transect from the Great Alvar of Oland, Sweden in the north over Gossenheim, Central Germany and Hochtor in the Hohe Tauern National Park, Austria down to the badlands of Tabernas, Spain in the south. The transect stretches over 20 degrees latitude and 2,300 m in altitude, including natural (Hochtor, Tabernas) and semi natural sites that require maintenance such as by grazing activities (Oland, Gossenheim). At all four sites BSC coverage exceeded 30 % of the referring landscape, with the alpine site (Hochtor) reaching the highest cyanobacterial cover and the two semi-natural sites (Oland, Gossenheim) the highest bryophyte cover. Although BSCs of the four European sites share a common set of bacteria, algae (including cyanobacteria) lichens and bryophytes, first results indicate not only climate specific additions of species, but also genetic/phenotypic uniqueness of species between the four sites. While macroclimatic conditions are rather different, microclimatic conditions and partly soil properties seem fairly homogeneous between the four sites, with the exception of water availability. Continuous activity monitoring of photosystem II revealed the BSCs of the Spanish site as the least active in terms of photosynthetic active periods. PMID- 24954977 TI - Multi-modal molecular diffuse optical tomography system for small animal imaging. AB - A multi-modal optical imaging system for quantitative 3D bioluminescence and functional diffuse imaging is presented, which has no moving parts and uses mirrors to provide multi-view tomographic data for image reconstruction. It is demonstrated that through the use of trans-illuminated spectral near infrared measurements and spectrally constrained tomographic reconstruction, recovered concentrations of absorbing agents can be used as prior knowledge for bioluminescence imaging within the visible spectrum. Additionally, the first use of a recently developed multi-view optical surface capture technique is shown and its application to model-based image reconstruction and free-space light modelling is demonstrated. The benefits of model-based tomographic image recovery as compared to 2D planar imaging are highlighted in a number of scenarios where the internal luminescence source is not visible or is confounding in 2D images. The results presented show that the luminescence tomographic imaging method produces 3D reconstructions of individual light sources within a mouse-sized solid phantom that are accurately localised to within 1.5mm for a range of target locations and depths indicating sensitivity and accurate imaging throughout the phantom volume. Additionally the total reconstructed luminescence source intensity is consistent to within 15% which is a dramatic improvement upon standard bioluminescence imaging. Finally, results from a heterogeneous phantom with an absorbing anomaly are presented demonstrating the use and benefits of a multi-view, spectrally constrained coupled imaging system that provides accurate 3D luminescence images. PMID- 24954979 TI - High photobiont diversity in the common European soil crust lichen Psora decipiens. AB - The genetic diversity of green algal photobionts (chlorobionts) in soil crust forming lichens was studied as part of the SCIN-project (Soil Crust InterNational). A total of 64 lichen samples were collected from four different sites along latitudinal and altitudinal gradients in Europe (Tabernas/Spain; Hochtor-Grobetaglockner/Austria; Gynge Alvar/Sweden; Ruine Homburg/Germany). The dominant lichen species at all four sites was Psora decipiens, often occurring with Buellia elegans, Fulgensia bracteata, F. fulgens and Peltigera rufescens. Genetic identification of chlorobionts was carried out using the nuclear marker (nrITS) and a chloroplast marker (psbL-J). We found P. decipiens to be associated with several different species of Trebouxia and Asterochloris, although previously described to only have Asterochloris sp. The phylogenetic analyses revealed a high chlorobiont diversity with 12 well supported clades, including Trebouxia asymmetrica, T. jamesii, T. impressa and other, as yet taxonomically unidentified clades (Trebouxia sp. URa1-4, T. sp. URa6, T. sp. URa7-13). Additionally, five clades of Asterochloris were identified (A. magna, A. sp. URa14 -17). Most of the chlorobiont species appeared to be cosmopolitan, but five clades were unevenly distributed between the sampling sites with only Trebouxia being found in the warm and dry Spanish habitats and combinations of Trebouxia and Asterochloris in the cooler and more humid habitats. The wide range of chlorobiont species might contribute to the observed domination of P. decipiens at all four research sites of the SCIN project which range from a desert in Spain to an alpine site in the Alps of Austria. PMID- 24954980 TI - Green algae in alpine biological soil crust communities: acclimation strategies against ultraviolet radiation and dehydration. AB - Green algae are major components of biological soil crusts in alpine habitats. Together with cyanobacteria, fungi and lichens, green algae form a pioneer community important for the organisms that will succeed them. In their high altitudinal habitat these algae are exposed to harsh and strongly fluctuating environmental conditions, mainly intense irradiation, including ultraviolet radiation, and lack of water leading to desiccation. Therefore, green algae surviving in these environments must have evolved with either avoidance or protective strategies, as well as repair mechanisms for damage. In this review we have highlighted these mechanisms, which include photoprotection, photochemical quenching, and high osmotic values to avoid water loss, and in some groups flexibility of secondary cell walls to maintain turgor pressure even in water limited situations. These highly specialized green algae will serve as good model organisms to study desiccation tolerance or photoprotective mechanisms, due to their natural capacity to withstand unfavorable conditions. We point out the urgent need for modern phylogenetic approaches in characterizing these organisms, and molecular methods for analyzing the metabolic changes involved in their adaptive strategies. PMID- 24954981 TI - The factors influencing car use in a cycle-friendly city: the case of Cambridge. AB - Encouraging people out of their cars and into other modes of transport, which has major advantages for health, the environment and urban development, has proved difficult. Greater understanding of the influences that lead people to use the car, particularly for shorter journeys, may help to achieve this. This paper examines the predictors of car use compared with the bicycle to explore how it may be possible to persuade more people to use the bicycle instead of the car. Multivariable logistic regression was used to examine the socio-demographic, transport and health-related correlates of mode choice for work, shopping and leisure trips in Cambridge, a city with high levels of cycling by UK standards. The key findings are that commuting distance and free workplace parking were strongly associated with use of the car for work trips, and car availability and lower levels of education were associated with car use for leisure, shopping and short-distanced commuting trips. The case of Cambridge shows that more policies could be adopted, particularly a reduction in free car parking, to increase cycling and reduce the use of the car, especially over short distances. PMID- 24954982 TI - Key challenges in providing services to people who use drugs: The perspectives of people working in emergency departments and shelters in Atlantic Canada. AB - AIMS: Many people who use drugs (PWUD) have multiple health and social needs, and research suggests that this population is increasingly accessing emergency departments (EDs) and shelters for health care and housing. This qualitative study explored the practices of those working in EDs and shelters when providing services to PWUD, with a particular focus on key challenges in service provision. METHODS: EDs and shelters were conceptualized as 'micro environments' with various components (i.e. social, physical and resource). One-on-one interviews were conducted with 57 individuals working in EDs and shelters in Atlantic Canada. FINDINGS: The social, physical and resource environments within some EDs and shelters are key forces in shaping the challenges facing those providing services. For example, the social environments within these settings are focused on acute health care in the case of EDs, and housing in the case of shelters. These mandates do not encompass the complex needs of many PWUD. Resource issues within the wider community (e.g. limited drug treatment spaces) further contribute to the challenges. CONCLUSIONS: Structural issues, internal and external to EDs and shelters need to be addressed to reduce the challenges facing many who work in these settings when providing services to PWUD. PMID- 24954983 TI - A Healthy New World: Emergent Opportunities for Clinical Psychologists in the Patient Protection and Affordable Care Act. AB - The Patient Protection and Affordable Care Act (ACA) is radically transforming the health and mental health care landscape. Emergent opportunities exist for clinical psychologists to redefine their role in healthcare. We reflect on the Chor and colleagues article (this issue) elucidating key issues for psychologists, and present additional recommendations for consideration. Specifically, we highlight three points: (1) moving beyond just training and hoping; (2) recovery, not just symptom reduction; and (3) it's a healthy new world. Under each of these points, we suggest tactics for how to achieve these goals. PMID- 24954984 TI - Comparison between intra-venous versus intra-arterial heparin during transradial coronary artery catheterization. AB - BACKGROUND: Trans-radial coronary artery catheterization is gaining popularity, heparin has been proven to reduce the rate of radial artery occlusion, intra venous or intra-arterial heparin have no effect on the radial artery occlusion, we investigate the effect of route of heparin administration on different procedure related parameters. METHODS: We randomized 150 consecutive patients to receive intra-venous (75 patients) or intra-arterial (75 patients) heparin; the two groups were compared regarding different procedure related parameters. RESULTS: The success rate was over 99% and rate of radial artery spasm was about 5%. There was no statistically significant difference between the two groups regarding the parameters tested. CONCLUSION: The trans-radial angiography can be performed successfully in the Saudi population, Studies with larger sample size are needed to show a significant difference between intra-arterial and intra venous heparin administration. PMID- 24954985 TI - Outcome of low body weight (<2.2 kg) infants undergoing cardiac surgery. AB - INTRODUCTION: Infants with low body weight (LBW) following cardiac surgery are a major challenge for the post cardiac surgery care unit. It has been observed that post surgery outcome for LBW infants is worse compared to the outcome of normal body weight infants. A study was conducted to compare post operative course and outcome of infants with body weight of 2.2 kg or less against infants with normal body weight who underwent similar cardiac surgeries. METHODS: A retrospective review was performed for all infants below 2.2 kg who underwent cardiac operations at King Abdulaziz Cardiac Center from January 2001 to October 2011. Cases with LBW (Group A) were compared with matching group (Group B) of normal body weight infants who had similar cardiac surgeries and matching surgical risk category. The demographic, ICU parameters, complications, and short-term outcome of both groups were analyzed. RESULTS: Two groups were formed, with 37 patients in Group A, and 39 patients in Group B. Except for weight (2.13 +/- 0.08 kg in Group A vs 3.17 +/- 0.2 kg in Group B), there was no statistical difference in demographic data between both groups. Cardiac procedures included coarctation repair, arterial switch, ventricular septal defect (VSD) repair, tetralogy of Fallot repair, systemic to pulmonary shunt and Norwood procedures. Patients in Group A had statistically significant difference from Group B in terms of bypass time (p = 0.01), duration of inotropes (p = 0.01), duration of mechanical ventilation (p = 0.004), number of re-intubations (p = 0.015), PCICU length of stay (p = 0.007), and hospital mortality: 13.5% in Group A vs 0% in Group B (p value 0.02). CONCLUSION: Patients with LBW (<2.2 kg) underwent cardiac surgery with overall satisfactory results, but with increased risk of ICU morbidity and mortality. PMID- 24954986 TI - Procedural and clinical utility of transulnar approach for coronary procedures following failure of radial route: Single centre experience. AB - OBJECTIVES: To assess the feasibility and safety of transulnar approach whenever transradial access fails. BACKGROUND: Radial access for coronary procedures has gained sound recognition. However, the method is not always successful. METHODS: Between January 2010 and June 2013, diagnostic with or without percutaneous coronary intervention (PCI) was attempted in 2804 patients via the radial approach. Transradial approach was unsuccessful in 173 patients (6.2%) requiring crossover to either femoral (128 patients, 4.6%) or ulnar approach (45 patients, 1.6%). Patients who had undergone ulnar approach constituted our study population. Selective forearm angiography was performed after ulnar sheath placement. We documented procedural characteristics and major adverse cardio cerebrovascular events. RESULTS: Radial artery spasm was the most common cause of crossover to the ulnar approach (64.4%) followed by failure to puncture the radial artery (33.4%). Out of 45 patients (82.2%), 37 underwent successful ulnar approach. The eight failed cases (17.8%) were mainly due to absent or weak ulnar pulse (75%). PCI was performed in 17 cases (37.8%), of which 8 patients underwent emergency interventions. Complications included transient numbness, non significant hematoma, ulnar artery perforation, and minor stroke in 15.5%, 13.3%, 2.2% and 2.2%, respectively. No major cardiac-cerebrovascular events or hand ischemia were noted. CONCLUSION: Ulnar approach for coronary diagnostic or intervention procedures is a feasible alternative whenever radial route fails. It circumvents crossover to the femoral approach. Our study confirms satisfactory success rate of ulnar access in the presence of adequate ulnar pulse intensity and within acceptable rates of complications. PMID- 24954987 TI - Impact of metabolic syndrome on global left ventricular function: As evaluated by the myocardial performance index. AB - BACKGROUND: Metabolic syndrome is associated with the development of diabetes mellitus and cardiovascular disease. The impact of metabolic syndrome on the progression of atherosclerosis has been well documented. This study was designed to evaluate the impact of metabolic syndrome on global left ventricular function by using left ventricular myocardial performance index (LVMPI). METHODS: The diagnosis of metabolic syndrome was made as per the criteria of the International Diabetes Federation. Echocardiography was performed with a Philips IE33 machine using a 1-5 MHz transthoracic probe. LVMPI was calculated by adding isovolumic contraction time with isovolumic relaxation time and dividing it by ejection time. RESULTS: The mean LVMPI value in metabolic syndrome was 0.64 +/- 0.09, while that in controls was 0.48 +/- 0.06 (p < 0.001). Metabolic syndrome was seen to have more significant influence on LVMPI. CONCLUSIONS: Metabolic syndrome is a strong predictor of sub-clinical myocardial dysfunction in subjects free of clinically apparent heart disease. PMID- 24954989 TI - Late stent fracture - A potential role of left ventricular dilatation. AB - BACKGROUND: Coronary stent fracture is an under-recognized event but one that has been reported frequently in the drug-eluting stent era. Most reported cases of stent fracture occurred within days to two years after implantation, and are related to stent thrombosis and restenosis. CASE REPORT: Presentation of a 69 year-old male with a history of arterial hypertension and previous percutaneous coronary intervention (PCI), and with implantation of three overlapping drug eluting stents (DES) on proximal-to-middle left anterior descending artery (LAD). At five-year outpatient evaluation, the patient was found to have a new left bundle branch block associated with mild elevation in Troponin-I value and severe left ventricular dysfunction. The patient recovered as non ST-segment elevation myocardial infarction (NSTEMI) and consequently a new coronary angiography showed total occlusion of proximal LAD with multiple stent fracture. Here we discuss the role of left ventricular dilatation as a contributing factor to late drug-eluting stent fracture. CONCLUSION: Different anatomical coronary settings have been described as predisposing factors to stent fracture. Consequently, the remodeling of the left ventricle, together with the rise in diastolic pressure, may have affected the shear stress of LAD stents by increasing mechanical forces produced in the diastolic phase on the epicardial vessel. In addition, left ventricular enlargement could have increased the elongation forces on the stent frames by altering the curvature of the stent. All predisposing factors of stent fracture, including coronary and left ventricular issues, need to be considered before stent implantation to avoid stent fracture and clinical sequelae. PMID- 24954988 TI - "Open" approach to aortic arch aneurysm repair. AB - Aortic arch aneurysm is a relatively rare entity in cardiac surgery. Repair of such aneurysms, either in isolation or combined with other cardiac procedures, remains a challenging task. The need to produce a relatively bloodless surgical field with circulatory arrest, while at the same time protecting the brain, is the hallmark of this challenge. However, a clear understanding of the topic allows a better and less morbid approach to such a complex surgery. Literature has shown the advantage of selective cerebral perfusion techniques in comparison with only circulatory arrest. Ability to perfuse the brain has allowed circulatory arrest temperatures at moderate hypothermia without the need for deep hypothermia. Even though cannulation site selection appears to be a minor issue, literature has shown that the subclavian/axillary route has the best outcomes and that femoral cannulation should only be reserved for no access patients. Although different techniques for arch anastomosis have been described, we routinely perform the distal first technique as we find it to be less cumbersome and easiest to reproduce. In this review our aim is to outline a systematic approach to aortic arch surgery. Starting with indications for intervention and proceeding with approaches on site of cannulation, approaches to brain protection with hypothermia and selective cerebral perfusion and finally surgical steps in performing the distal and arch vessels anastomosis. PMID- 24954990 TI - Atrial myxoma related myocardial infarction: Case report and review of the literature. AB - Atrial myxomas are the commonest primary cardiac tumors and usually affect the left atrium. Patients with atrial myxomas present with intracardiac obstruction, embolization to the pulmonary and systemic circulation, or constitutional symptoms. The coronary arteries' involvement in myxomatous embolization, although rare, has been described to cause acute myocardial infarction (AMI). We report a case of atrial myxoma associated MI and present the clinical and echocardiographic features of this presentation followed by review of the English literature for the association of atrial myxomas and acute myocardial infarctions (AMI). PMID- 24954991 TI - Ebstein cardiac anomaly, functional pulmonary atresia and isovaleric acidemia: A case report. AB - In this report, we present a rare association between Ebstein anomaly (EA) and isovaleric acidemia (IVA) in a newborn who was admitted to our cardiac center. He underwent for PDA stenting to maintain adequate pulmonary blood flow, later he developed recurrent metabolic acidosis, prominent sweaty feet odor, neutropenia and thrombocytopenia. His organic acids profile in the urine confirmed the diagnosis of IVA. To the best of our knowledge, there is no association between these two rare diseases. We are presenting this case report to highlight this rare association. PMID- 24954992 TI - A large Right atrial mass in a patient with hepatocellular carcinoma: Case report and literature review. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignancy and the most frequent sites of metastasis include lungs, bone, lymphatic, and brain, however, Intra-cardiac involvement rarely develops in patients with HCC and it has poor prognosis. The clinical course may be complicated by many fatal cardiovascular complications. Absence of cardiac symptoms, however, is an unusual condition. CASE REPORT: We reported a rare case of hepatocellular carcinoma with large invasion into the right atrium and no cardiac symptoms. CONCLUSION: Cardiac metastases occur in 10% of all cancer patients. Heart involvement should be suspected in all patients. PMID- 24954993 TI - Arterio-venous fistulae: A possible complication of transradial approach with a possible non invasive management. AB - Arteriovenous fistulae is rarely reported as a complication of percutaneous coronary interventions with trans-radial approach. We report herein a case of radial arteriovenous fistulae that was treated conservatively by applying manual compression and avoiding surgical intervention. PMID- 24954994 TI - Modification of Microbial Polymalic Acid With Hydrophobic Amino Acids for Drug Releasing Nanoparticles. AB - Microbial poly(beta, l-malic acid) was modified with either l-leucine ethyl ester (L) or l-phenylalanine methyl ester (F) to produce amphiphylic copolymers. The degradation of these copolymers in aqueous buffer took place under physiological conditions in a few weeks by hydrolysis of the side chain ester group followed by cleavage of the main chain. Spherical nanoparticles with diameters ranging between 70 and 230 nm were prepared from these copolymers by the dialysis precipitation method. No alteration of the cell viability was observed after incubation of these nanoparticles in different cell lines. Anticancer drugs temozolomide and doxorubicin were encapsulated in the nanoparticles. Temozolomide was released within several hours whereas doxorubicin took several weeks to be completely liberated. PMID- 24954995 TI - Phonetic Category Learning and Its Influence on Speech Production. AB - One of the hallmarks of any flexible system of perception and motor control is the ability to adjust to changes induced by dialect, development, fatigue, disease, or aging. Phonetic categories are an essential component of language that enables listeners and speakers to communicate effectively. Four studies are reviewed that illustrate how adults and infants adjust their phonetic categories rapidly and efficiently to maintain a tight coupling between speech perception and speech production. Although this process of adaptive plasticity takes place at the level of phonetic categories, it is also constrained by the lexicon. Words that share similar sounds or similar vocal-articulatory gestures impede the process of adaptation. PMID- 24954996 TI - Planning an Action: A Developmental Progression in Tool Use. AB - How children pick up a tool reveals their ability to plan an action with the end goal in mind. When presented with a spoon whose handle points away from their dominant hand, children between infancy and 8 years of age progress from using an awkward ulnar grip that causes food to spill from the spoon to consistently using a radial grip. At 4 years of age children's grip strategies are highly variable, including the awkward grips of infancy and use of the non-dominant hand, but they also employ adult-like grips never seen in infancy. By 8 years of age the infantile ulnar grip has completely disappeared and is replaced by more mature and effective grips that indicates better planning for the end goal. PMID- 24954997 TI - Affordances as Probabilistic Functions: Implications for Development, Perception, and Decisions for Action. AB - We propose a new way to describe affordances for action. Previous characterizations of affordances treat action possibilities as binary categories either possible or impossible-separated by a critical point. Here, we show that affordances are probabilistic functions, thus accounting for variability in motor performance. By measuring an affordance function, researchers can describe the likelihood of success for every unit of the environment. We demonstrate how to fit an affordance function to performance data using established psychophysical procedures and illustrate how the threshold and variability parameters describe different possibilities for action. Finally, we discuss the implications of probabilistic affordances for development, perception, and decision-making. PMID- 24954998 TI - Reference value sensitivity of measures of unfair health inequality. AB - Most politicians and ethical observers are not interested in pure health inequalities, as they want to distinguish between different causes of health differences. Measures of "unfair" inequality - direct unfairness and the fairness gap, but also the popular standardized concentration index - therefore neutralize the effects of what are considered to be "legitimate" causes of inequality. This neutralization is performed by putting a subset of the explanatory variables at reference values, e.g. their means. We analyze how the inequality ranking of different policies depends on the specific choice of reference values. We show with mortality data from the Netherlands that the problem is empirically relevant and we suggest a statistical method for fixing the reference values. PMID- 24954999 TI - Serious Delinquency and Gang Participation: Combining and Specializing in Drug Selling, Theft and Violence. AB - Using Pittsburgh Youth Study data, we examined the extent to which over 600 gang members and non-gang involved young men specialized in drug selling, serious theft, or serious violence or engaged simultaneously in these serious delinquent behaviors, throughout the 1990s. We found that the increase in delinquency associated with gang membership was concentrated in two combinations: serious violence and drug selling; serious violence, drug selling, and serious theft. Several covariates were similarly associated with multi-type serious delinquency and gang membership (age, historical time, Black race, and residential mobility), suggesting that these behaviors may share common developmental, familial, and contextual risks. We encourage future research to further examine the association of gang membership with engagement in particular configurations of serious delinquency. PMID- 24955000 TI - An improved protocol for carrot haploid and doubled haploid plant production using induced parthenogenesis and ovule excision in vitro. AB - In this work, we describe an improved protocol for induced parthenogenesis and ovule culture of carrot (Daucus carota L.). The effects of pollination with parsley pollen and/or 2,4-dichlorophenoxyacetic acid (2,4-D) treatment on the stimulation of parthenogenesis were studied using heterozygous donor plants of 30 varieties and breeding populations of carrots. Isolated ovules, cultured in vitro, enlarged and developed embryos or calli. The application of 2,4-D on pollinated flowers stimulated callus development but did not increase the frequency of embryo development from ovules and, thus, was not useful for increasing the frequency of haploid plant recovery. The efficiency of embryo development was accession-dependent and varied from 0 to 24.29%. In optimized conditions, most accessions responded by embryo development exclusively. The highest frequency of embryo development was observed from ovules excised from ovaries 20-22 d after pollination with parsley pollen. Among several media used for ovule culture, 1/2-strength Murashige and Skoog medium with 0.06 MUM indole-3 acetic acid (IAA) was the best. It allowed the production of embryos at a similar frequency as on the media supplemented with kinetin, gibberellic acid, putrescine, or thidiazuron, but restricted callus development. Most plants obtained were haploids and diploids derived from parthenogenesis, as evidenced by homozygosity at three independent loci based on isozyme and PCR analyses. In total, considering haploids and embryo-derived homozygous diploids together, 72.6% of regenerated plants were of gametic origin. PMID- 24955001 TI - Two-Dimensional Solution Surface for Weighted Support Vector Machines. AB - The support vector machine (SVM) is a popular learning method for binary classification. Standard SVMs treat all the data points equally, but in some practical problems it is more natural to assign different weights to observations from different classes. This leads to a broader class of learning, the so-called weighted SVMs (WSVMs), and one of their important applications is to estimate class probabilities besides learning the classification boundary. There are two parameters associated with the WSVM optimization problem: one is the regularization parameter and the other is the weight parameter. In this paper we first establish that the WSVM solutions are jointly piecewise-linear with respect to both the regularization and weight parameter. We then develop a state-of-the art algorithm that can compute the entire trajectory of the WSVM solutions for every pair of the regularization parameter and the weight parameter, at a feasible computational cost. The derived two-dimensional solution surface provides theoretical insight on the behavior of the WSVM solutions. Numerically, the algorithm can greatly facilitate the implementation of the WSVM and automate the selection process of the optimal regularization parameter. We illustrate the new algorithm on various examples. PMID- 24955002 TI - Automated Factor Slice Sampling. AB - Markov chain Monte Carlo (MCMC) algorithms offer a very general approach for sampling from arbitrary distributions. However, designing and tuning MCMC algorithms for each new distribution, can be challenging and time consuming. It is particularly difficult to create an efficient sampler when there is strong dependence among the variables in a multivariate distribution. We describe a two pronged approach for constructing efficient, automated MCMC algorithms: (1) we propose the "factor slice sampler", a generalization of the univariate slice sampler where we treat the selection of a coordinate basis (factors) as an additional tuning parameter, and (2) we develop an approach for automatically selecting tuning parameters in order to construct an efficient factor slice sampler. In addition to automating the factor slice sampler, our tuning approach also applies to the standard univariate slice samplers. We demonstrate the efficiency and general applicability of our automated MCMC algorithm with a number of illustrative examples. PMID- 24955003 TI - Collaborative Staffing Model for Multiple Sites: Reducing the challenges of study coordination in complex, multi-site clinical trials. AB - The implementation of complex, multi-site clinical trials presents challenges that make recruitment efforts, participant follow-up, and organization of staff critical to the success of the overall outcome. This article describes a unique staffing model utilized by the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) study, an NIH (National Institutes of Health) sponsored trial designed to explore treatment options for type 2 diabetes in youth. At each study center, the program coordinator (PC) and diabetes educator (DE) work together to implement the study protocol. A staffing model that provides this type of mutual support for two key members of the study team may decrease the burden customarily encountered solely by the PC in complex trials, and furthermore allows for cross-coverage and flexibility. To determine the degree of overlap and task sharing between the PC and DE across study sites, a self administered survey was distributed to all PCs and DEs. Survey results as well as specific examples demonstrating an effective collaborative approach by front-line study personnel in managing various challenges encountered in study implementation are included. PMID- 24955004 TI - Research on the Influence of the Type of Surfactant and Concentrator in Aqueous Dispersion of Pigments. AB - This work reports tests performed to evaluate the stability of aqueous dispersions of inorganic oxide pigments with different specific surface areas, with the use of anionic and non-ionic surfactants and concentrators. Color mixtures of oxide compounds of blue, green, olive and brown with the unit cell spinel structure were used as pigments. The sodium salt of sulfosuccinic acid monoester, oxyethylenated nonylphenol and ethoxylated derivatives of lauryl alcohol, fatty alcohol and fatty amine were used as surfactants. The concentrators used were: poly(vinyl alcohol), the sodium salt of carboxymethyl cellulose as well as a water-based polyurethane oligomer. The highest dispersion efficiency was found for dispersed systems in which surfactant and concentrator were incorporated in the formula. The one containing the sodium salt of carboxymethyl cellulose or polyurethane oligomer with ethoxylated saturated fatty alcohol or fatty amine was found to be the most efficient. It was discovered that a higher dispersion efficiency corresponds to pigments with larger specific surface. The efficiency is also found to improve when the concentrator is an acrylic polymer or copolymer made up of two acrylic species. In this case, the concentrator interaction with the surfactant is more effective if the value of its boundary viscosity number is higher. This observation confirms the existence of interactions between macro-chains of the concentrator and surfactant molecules forming micelles with the pigment particles. PMID- 24955005 TI - Washing and filtering of cell-salvaged blood - does it make autotransfusion safer? PMID- 24955006 TI - Insights into the molecular mechanism of glucose metabolism regulation under stress in chicken skeletal muscle tissues. AB - As substantial progress has been achieved in modern poultry production with large scale and intensive feeding and farming in recent years, stress becomes a vital factor affecting chicken growth, development, and production yield, especially the quality and quantity of skeletal muscle mass. The review was aimed to outline and understand the stress-related genetic regulatory mechanism, which significantly affects glucose metabolism regulation in chicken skeletal muscle tissues. Progress in current studies was summarized relevant to the molecular mechanism and regulatory pathways of glucose metabolism regulation under stress in chicken skeletal muscle tissues. Particularly, the elucidation of those concerned pathways promoted by insulin and insulin receptors would give key clues to the understanding of biological processes of stress response and glucose metabolism regulation under stress, as well as their later effects on chicken muscle development. PMID- 24955008 TI - Ovarian surface epithelium receptors during pregnancy and estrus cycle of rats with emphasis on steroids and gonadotropin fluctuation. AB - The present study is designed to demonstrate the ovarian surface epithelial cells' (OSE) estrogen receptor alpha (ERalpha) and progesterone receptor (PR) during pregnancy and estrous cycle in rat. Moreover, determination of the levels of plasma progesterone, estradiol, FSH and LH was also made. The levels of plasma progesterone, estradiol, FSH and LH concentrations were determined on days 7 (n = 5), 14 (n = 5), and 21 (n = 5) of pregnancy in three groups of rats and during the estrous cycle (n = 5) using an ELISA kit. Immunohistochemical method for PR and ERalpha expressions was also made on the ovary. During pregnancy, FSH and LH remained low except at term when LH levels began to increase from 16 ng/ml to 47 ng/ml. Progesterone levels significantly exceeded estradiol values in all pregnant rats with a peak value of 202 ng/ml on day 14. Elevated progesterone levels were associated negatively with LH and estradiol levels during pregnancy. The levels of estradiol surged significantly on day 21. Immunohistochemistry of the ovary showed low levels of OSE cells staining positive for ERalpha expression. ERalpha positive cells were absent on day 7 and 14 of pregnancy, only day 21 recorded a very low percentage of immunostaining (0.5%) within the nuclei of OSE cells. On the contrary, immunostaining of PR was not observed within the nuclei of OSE cells in all groups of study. In conclusion, these results may suggest that the progesterone effect during pregnancy seems to be overriding the positive effect of estrogens on OSE cells. High progesterone levels may have a direct negative effect on gonadotropin production and thereby it might inhibit events leading to both follicular development and OSE proliferation. Understanding the factors affecting OSE proliferation may help elucidating the mechanism(s) of assisted diseases such as ovarian cancer. PMID- 24955010 TI - Cilioprotists as biological indicators for estimating the efficiency of using Gravel Bed Hydroponics System in domestic wastewater treatment. AB - Interest has increased over the last several years in using different methods for treating sewage. The rapid population growth in developing countries (Egypt, for example, with a population of more than 87 millions) has created significant sewage disposal problems. There is therefore a growing need for sewage treatment solutions with low energy requirements and using indigenous materials and skills. Gravel Bed Hydroponics (GBH) as a constructed wetland system for sewage treatment has been proved effective for sewage treatment in several Egyptian villages. The system provided an excellent environment for a wide range of species of ciliates (23 species) and these organisms were potentially very useful as biological indicators for various saprobic conditions. Moreover, the ciliates provided excellent means for estimating the efficiency of the system for sewage purification. Results affirmed the ability of this system to produce high quality effluent with sufficient microbial reduction to enable the production of irrigation quality water. PMID- 24955009 TI - Status of breeding seabirds on the Northern Islands of the Red Sea, Saudi Arabia. AB - We undertook breeding surveys between 2010 and 2011 to assess the status of breeding birds on 16 islands in the northern Saudi Arabia. Sixteen bird species were found breeding at three different seasons; i.e. winter (Osprey), spring (Caspian and Saunder's Terns), and summer (Lesser Crested, White-cheeked, Bridled Terns). It is postulated that food availability is an important factor influencing the breeding of seabirds in the northern Saudi Arabian Red Sea. Several species laid eggs earlier in northern parts of the Red Sea than in southern parts. The predicted increases in temperatures (Ta ) could have a negative effect on species survival in the future, especially on those whose nests that are in the open. Finally, disturbance, predation and egg collection were probably the main immediate threats affecting the breeding seabird species in the northern Red Sea. PMID- 24955011 TI - Performance evaluation of indigenous and exotic honey bee (Apis mellifera L.) races in Assir region, southwestern Saudi Arabia. AB - This study was conducted in the Assir region of southwestern Saudi Arabia to compare the activities of honeybee colonies of indigenous Apis mellifera jemenitica (AMJ) and imported Apis mellifera carnica (AMC) during the late summer and autumn of 2009 and 2010. The results showed that the workers of the two races exhibited relatively similar forage timings throughout the period of study (August-November). The highest numbers of foraged workers were recorded at 6:00 am, 10:00 am and 6:00 pm, while the lowest numbers were recorded at 8:00 am, 12:00 pm and 4:00 pm. Although foraging activity was negatively affected by decreased temperature, AMJ was more resistant to cold than AMC. In the first season, the smallest amount of worker brood rearing was recorded in August, and the highest amount of rearing occurred in November in both races. In the second season, the smallest amount of brood was observed in October, and the largest amount of brood was observed in November. Brood rearing and pollen collecting was significantly (P < 0.05) higher in AMJ compared with AMC, while AMC stored significantly (P < 0.05) more honey than AMJ during the tested periods. In AMJ colonies, a positive significant correlation was observed between the area of the sealed worker brood and stored pollen, while a negative but nonsignificant correlation was observed between the area of the sealed worker brood and surplus honey. In the AMC colonies, a positive significant correlation was observed between the area of the sealed brood and the stored pollen and surplus honey. PMID- 24955013 TI - Functional compounds from the integument of adult red palm weevil Rhynchophorus ferrugineus. AB - This study deals with the analysis of the integument of the red palm weevil Rhynchophorus ferrugineus of both sexes using the GC-MS technique. The results of the study revealed many promising compounds. These include aspidofractinine-3 methanol (kopsinyl alcohol) which was found in the acetone extract of the sternum of females, and 3-buten-2-ol (32-B) which was found in the extracts of sternum and tergum of males. This compound the aggregation pheromone was secreted by males. Additionally, compounds with methoxy groups were found. These may be responsible for insects' resistance. This study, through separation and identification of these compounds, aims to open a new possibility for their future medical and therapeutic usage. PMID- 24955014 TI - Soft cheese supplemented with black cumin oil: Impact on food borne pathogens and quality during storage. AB - Black cumin seed oil (BCSO) was tested for its inhibitory effect against some pathogenic bacteria (Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 8739, Listeria monocytogenes Scott A and Salmonella enteritidis PT4) in Domiati cheese during cold storage. Physical, chemical and sensorial changes in cheese during storage were recorded. Pasteurized milk was inoculated before renneting with a mixed culture of bacteria at ca. 4 log CFU mL(-1). In vitro and in situ supplementation with BCSO showed antimicrobial impact on the growth of S. aureus, E. coli, L. monocytogenes and S. enteritidis inoculated into media and cheese samples. Supplementing of cheese with BCSO (0.1% or 0.2%, w/w) significantly reduced the counts of the inoculated pathogens by ca. 1.3 log and 1.5 log CFU g( 1) after 21 days of storage. In addition, BCSO controlled the development of titratable acidity, limited the changes in ripening indices, flavor components and kept considerable physicochemical and sensorial properties of cheese. PMID- 24955012 TI - Potential impact of silymarin in combination with chlorogenic acid and/or melatonin in combating cardiomyopathy induced by carbon tetrachloride. AB - The aim of this study was to investigate the effective role of silymarin either alone or in combination with chlorogenic acid and/or melatonin against the toxic impact of carbon tetrachloride (CCl4) induced cardiac infarction. CCl4 (l.2 ml/kg body weight) was administered as a single dose intraperitoneally. The results revealed that the administration of silymarin alone or in combination with chlorogenic acid (CGA) and/or melatonin for 21 consecutive days, 24 h after CCl4 injection to rats, markedly ameliorated the increases in serum markers of cardiac infarction, including troponin T and creatine kinase-MB (CK-MB), as well as increases in the pro-inflammatory biomarkers, including interleukin-6 (IL-6), interferon-gamma (IFN-gamma) in serum and tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein in cardiac tissue compared to CCl4 intoxicated rats. The used agents also successfully modulated the alteration in vascular endothelial growth factor (VEGF) in serum and the oxidative DNA damage and the increase in the apoptosis marker caspase 3 in cardiac tissue in response to CCl4 toxicity. The present biochemical results are supported by histo-pathological examination. The current results proved that treatment with silymarin in combination with CGA and melatonin was the most effective one in ameliorating the toxicity of CCl4 induced cardiac damage and this may support the use of this combination as an effective drug to treat cardiac damage induced by toxic agents. PMID- 24955007 TI - The changing epitome of species identification - DNA barcoding. AB - The discipline taxonomy (the science of naming and classifying organisms, the original bioinformatics and a basis for all biology) is fundamentally important in ensuring the quality of life of future human generation on the earth; yet over the past few decades, the teaching and research funding in taxonomy have declined because of its classical way of practice which lead the discipline many a times to a subject of opinion, and this ultimately gave birth to several problems and challenges, and therefore the taxonomist became an endangered race in the era of genomics. Now taxonomy suddenly became fashionable again due to revolutionary approaches in taxonomy called DNA barcoding (a novel technology to provide rapid, accurate, and automated species identifications using short orthologous DNA sequences). In DNA barcoding, complete data set can be obtained from a single specimen irrespective to morphological or life stage characters. The core idea of DNA barcoding is based on the fact that the highly conserved stretches of DNA, either coding or non coding regions, vary at very minor degree during the evolution within the species. Sequences suggested to be useful in DNA barcoding include cytoplasmic mitochondrial DNA (e.g. cox1) and chloroplast DNA (e.g. rbcL, trnL-F, matK, ndhF, and atpB rbcL), and nuclear DNA (ITS, and house keeping genes e.g. gapdh). The plant DNA barcoding is now transitioning the epitome of species identification; and thus, ultimately helping in the molecularization of taxonomy, a need of the hour. The 'DNA barcodes' show promise in providing a practical, standardized, species-level identification tool that can be used for biodiversity assessment, life history and ecological studies, forensic analysis, and many more. PMID- 24955016 TI - Asymptotics of nonparametric L-1 regression models with dependent data. AB - We investigate asymptotic properties of least-absolute-deviation or median quantile estimates of the location and scale functions in nonparametric regression models with dependent data from multiple subjects. Under a general dependence structure that allows for longitudinal data and some spatially correlated data, we establish uniform Bahadur representations for the proposed median quantile estimates. The obtained Bahadur representations provide deep insights into the asymptotic behavior of the estimates. Our main theoretical development is based on studying the modulus of continuity of kernel weighted empirical process through a coupling argument. Progesterone data is used for an illustration. PMID- 24955017 TI - Spatiotemporal Distribution of Airborne Particulate Metals and Metalloids in a Populated Arid Region. AB - A statistical analysis of data from the Interagency Monitoring of Protected Visual Environments (IMPROVE) network of aerosol samplers has been used to study the spatial and temporal concentration trends in airborne particulate metals and metalloids for southern Arizona. The study region is a rapidly growing area in southwestern North America characterized by high fine soil concentrations (among the highest in the United States), anthropogenic emissions from an area within the fastest growing region in the United States, and a high density of active and abandoned mining sites. Crustal tracers in the region are most abundant in the summer (April - June) followed by fall (October - November) as a result of dry meteorological conditions which favor dust emissions from natural and anthropogenic activity. A distinct day-of-week cycle is evident for crustal tracer mass concentrations, with the greatest amplitude evident in urban areas. There have been significant reductions since 1988 in the concentrations of toxic species that are typically associated with smelting and mining. Periods with high fine soil concentrations coincide with higher concentrations of metals and metalloids in the atmosphere, with the enhancement being higher at urban sites. PMID- 24955015 TI - Impact of energy loss index on left ventricular mass regression after aortic valve replacement. AB - BACKGROUND: Recently, the energy loss index (ELI) has been proposed as a new functional index to assess the severity of aortic stenosis (AS). The aim of this study was to investigate the impact of the ELI on left ventricular mass (LVM) regression in patients after aortic valve replacement (AVR) with mechanical valves. METHODS: A total of 30 patients with severe AS who underwent AVR with mechanical valves was studied. Echocardiography was performed to measure the LVM before AVR (pre-LVM) (n = 30) and repeated 12 months later (post-LVM) (n = 19). The ELI was calculated as [effective orifice area (EOA) * aortic cross sectional area]/(aortic cross sectional area - EOA) divided by the body surface area. The LVM regression rate (%) was calculated as 100 * (post-LVM - pre-LVM)/(pre-LVM). A cardiac event was defined as a composite of cardiac death and heart failure requiring hospitalization. RESULTS: LVM regressed significantly (245.1 +/- 84.3 to 173.4 +/- 62.6 g, P < 0.01) at 12 months after AVR. The LVM regression rate negatively correlated with the ELI (R = -0.67, P < 0.01). By receiver operating characteristic (ROC) curve analysis, ELI <1.12 cm(2)/m(2) predicted smaller (< 30.0 %) LVM regression rates (area under the curve = 0.825; P = 0.030). Patients with ELI <1.12 cm(2)/m(2) had significantly lower cardiac event-free survival. CONCLUSION: The ELI as well as the EOA index (EOAI) could predict LVM regression after AVR with mechanical valves. Whether the ELI is a stronger predictor of clinical events than EOAI is still unclear, and further large-scale study is necessary to elucidate the clinical impact of the ELI in patients with AVR. PMID- 24955018 TI - Role of intraoperative pathology consultation in skeletal tumors and tumor-like lesions. AB - Early and accurate detection of bone tumors and their staging are important since some of them are highly malignant. Intraoperative pathological consultation in bone tumors and tumor-like conditions is quite complex; however, it allows improvement in prognosis and limb salvage. Present study was conducted on 52 patients who underwent surgical procedure after clinical and radiological diagnosis of bone tumors/tumor-like conditions. Fresh unfixed tissue was quickly inspected grossly, followed by preparation of imprint smears and frozen section which were evaluated by two pathologists separately and compared subsequently with reports of paraffin-embedded sections. Clinical reasons for intraoperative consultation were to make diagnosis in 65.4% of cases and to determine resection margin status in 21.1% while in 13.5% of cases, it was for both indications. Diagnostic yield of imprint smears was 87.8% (13 malignant, 22 benign, and 1 tumor-like) and of frozen section was 90.2% (16 malignant, 19 benign, and 2 nonneoplastic) while paraffin sections could diagnose specific tumors in 95.1% (18 malignant, 18 benign, and 3 nonneoplastic). Although frozen section had better sensitivity (88.2%), it had less specificity (94.7%) as compared to imprint smears (76.5% and 100%, resp.). Imprint cytology and frozen section together provide a quick, safe, and reliable intraoperative provisional tissue diagnosis in skeletal tumors and tumor-like conditions. PMID- 24955020 TI - Transition into first sex among adolescents in slum and non-slum communities in Nairobi, Kenya. AB - While early sexual experiences are a key marker of the transition from childhood to adulthood, it is widely acknowledged that precocious initiation of sexual activity predisposes adolescents to negative health and psychological outcomes. Extant studies investigating adolescent sexuality in sub-Saharan Africa often rely on cross-sectional data lacking information on the social-psychological underpinnings of adolescent behavior. Through the theoretical lens of the protection-risk conceptual framework, this paper draws on two waves of longitudinal data collected from 2,134 adolescents to examine sociodemographic, psychosocial and behavioral predictors of transition to first sex among adolescents living in slum and non-slum settlements in urban Kenya. We employ logistic regression models to examine the effect of antecedent sociodemographic and risk and protective factors measured during the first wave of data collection on transition to first sex by the second wave. We observe that transition to first sex is influenced by age, slum residence, perceived parental monitoring, and peer behavior. We also find evidence for coupling of risk behaviors. Study findings underscore the need to focus on very young adolescents and those growing up in resource poor settings as these young people may be highly vulnerable to negative health outcomes stemming from precocious sexual activity. PMID- 24955019 TI - Inorganic Nanoparticles for Therapeutic Delivery: Trials, Tribulations and Promise. AB - Inorganic nanomaterials have a wide array of physical and structural properties that make them attractive candidates for imaging and therapeutic delivery. Nanoparticle platforms have been intensely studied for these applications, and examples are starting to enter the clinic. This review looks at why inorganic particles provide promising platforms for biomedicine, and what issues need to be addressed for them to reach their potential. PMID- 24955022 TI - "Molecular profiling and ways towards personalized medicine in advanced differentiated thyroid cancer". PMID- 24955021 TI - Teacher Involvement as a Protective Factor from the Association between Race Based Bullying and Smoking Initiation. AB - Experiencing bullying as a victim is associated with negative health and health behavior outcomes, including substance use, among adolescents. However, understandings of protective factors - factors that enhance adolescents' resilience to the negative consequences of bullying - remain limited. The current study investigates whether teacher involvement protects adolescent students from the association between being bullied due to race and smoking initiation. Students were recruited from 12 Kindergarten through 8th grade schools in an urban school district in the Northeast United States. The analytic sample included 769 students who responded to surveys in 5th or 6th grade (2009), and two years later in 7th or 8th grade (2011). Students primarily identified as Latino and/or Black, and 90% were eligible for free or reduced lunch. Fifty-four (7%) students initiated smoking between survey time points. Among students reporting lower teacher involvement, race-based bullying was associated with higher likelihood of smoking initiation (OR = 1.69, p = .03). In contrast, among students reporting higher teacher involvement, racebased bullying was not associated with higher likelihood of smoking initiation (OR = 0.95, p = .81). Results suggest that teacher involvement may protect students from the association between race-based bullying and smoking initiation. Enhancing teacher involvement among students experiencing race-based bullying in schools may limit smoking initiation. PMID- 24955024 TI - Molecular diagnostics of fine needle aspiration for the presurgical screening of thyroid nodules. AB - "The incidence of thyroid cancer, the most common endocrine malignancy, is rising. The two most common types of thyroid cancer are papillary and follicular" thyroid carcinomas. "Fine-needle aspiration (FNA) of thyroid nodules" can permit to detect many genetic mutations and other molecular alterations, including RAS and BRAF point mutations, PAX8/peroxisome proliferator-activated receptor (PPAR)gamma and "RET/PTC rearrangements, occurring in thyroid papillary and follicular carcinomas" (more than 70% of cases), which can be used successfully to improve the diagnosis "and the management of patients with thyroid nodules". The most extensive experience has been accumulated with "the diagnostic use of BRAF mutation", which is highly specific for malignancy. "Testing FNA samples for a panel of mutations" that typically includes RAS, BRAF, PAX8/PPARgamma and RET/PTC could permit to achieve the biggest diagnostic impact. "The accuracy of cancer diagnosis in thyroid nodules could be improved significantly using these and other emerging molecular markers". PMID- 24955023 TI - Molecular pathways associated with aggressiveness of papillary thyroid cancer. AB - The most common thyroid malignancy is papillary thyroid cancer (PTC). Mortality rates from PTC mainly depend on its aggressiveness. Geno- and phenotyping of aggressive PTC has advanced our understanding of treatment failures and of potential future therapies. Unraveling molecular signaling pathways of PTC including its aggressive forms will hopefully pave the road to reduce mortality but also morbidity from this cancer. The mitogen-activated protein kinase and the phosphatidylinositol 3-kinase signaling pathway as well as the family of RAS oncogenes and BRAF as a member of the RAF protein family and the aberrant expression of microRNAs miR-221, miR-222, and miR-146b all play major roles in tumor initiation and progression of aggressive PTC. Small molecule tyrosine kinase inhibitors targeting BRAF-mediated events, vascular endothelial growth factor receptors, RET/PTC rearrangements, and other molecular targets, show promising results to improve treatment of radioiodine resistant, recurrent, and aggressive PTC. PMID- 24955025 TI - Proteomics, and metabolomics: magnetic resonance spectroscopy for the presurgical screening of thyroid nodules. AB - We review the progress and state-of-the-art applications of studies in Magnetic Resonance Spectroscopy (MRS) and Imaging as an aid for diagnosis of thyroid lesions of different nature, especially focusing our attention to those lesions that are cytologically undetermined. It appears that the high-resolution of High Resolution Magic-Angle-Spinning (HRMAS) MRS improves the overall accuracy of the analysis of thyroid lesions to a point that a significant improvement in the diagnosis of cytologically undetermined lesions can be expected. This analysis, in the meantime, allows a more precise comprehension of the alterations in the metabolic pathways induced by the development of the different tumors. Although these results are promising, at the moment, a clinical application of the method to the common workup of thyroid nodules cannot be used, due to both the limitation in the availability of this technology and the wide range of techniques, that are not uniformly used. The coming future will certainly see a wider application of these methods to the clinical practice in patients affected with thyroid nodules and various other neoplastic diseases. PMID- 24955026 TI - Application of molecular diagnostics to the evaluation of the surgical approach to thyroid cancer. AB - Recent important studies that include long-term follow-up have shown that BRAF and RAS mutations can have negative implications for disease recurrence and survival. BRAF positivity has been shown to be associated with decreased survival and is an independent predictor of poor prognosis. Reliable pre-operative identification of high-risk papillary thyroid cancer (PTC) patients may productively guide initial surgical management since reoperative neck surgery is associated with increased morbidity. However, it is probably too early to conclude that at present it is possible to tailor surgical therapy patient by patient only on the basis of their mutational status. Other important parameters, not including molecular testing, represented by some specific morphological aspects, still play an important role, probably still more significant than molecular diagnostics, such as neck ultrasonography. Pre-operative knowledge of BRAF-positive PTC could alter the initial surgical treatment for at least 20% of patients and can potentially prevent the increased morbidity associated with reoperative neck exploration. However, additional multi-institutional and randomized studies will be needed to further define the role of the pre-operative identification of BRAF positivity to guide not only the initial extent of total thyroidectomy (TT) but also the need for and extent of lymphadenectomy. PMID- 24955027 TI - Personalization of targeted therapy in advanced thyroid cancer. AB - Although generally the prognosis of differentiated thyroid carcinoma (DTC) is good, approximately 5% of people are likely to develop metastases which fail to respond to radioactive iodine, and other traditional therapies, exhibiting a more aggressive behavior. Nowadays, therapy is chosen and implemented on a watch-and wait basis for most DTC patients. Which regimen is likely to work best is decided on the basis of an individual's clinical information, but only data referring to outcomes of groups of patients are employed. To predict the best course of therapy, an individual patient's biologic data is rarely employed in a systematic way. Anyway, the use of not expensive individual genomic analysis could lead us to a new era of patient-specific and personalized care. Recently, key targets that are now being evaluated in the clinical setting have been evidenced in the pathogenesis of these diseases. Some of the known genetic alterations playing a crucial role in the development of thyroid cancer include B-Raf gene mutations, rearranged during transfection/ papillary thyroid carcinoma gene rearrangements, and vascular endothelial growth factor receptor-2 angiogenesis pathways. The development of targeted novel compounds able to induce clinical responses and stabilization of disease has overcome the lack of effective therapies for DTC, which are resistant to radioiodine and thyroid stimulating hormone-suppressive therapy. Interestingly, the best responses have been demonstrated in patients treated with anti-angiogenic inhibitors such as vandetanib and XL184 in medullary thyroid cancer, and sorafenib in papillary and follicular DTC. PMID- 24955028 TI - Increasing the Coding Potential of Genomes Through Alternative Splicing: The Case of PARK2 Gene. AB - The completion of the Human Genome Project aroused renewed interest in alternative splicing, an efficient and widespread mechanism that generates multiple protein isoforms from individual genes. Although our knowledge about alternative splicing is growing exponentially, its real impact on cellular life is still to be clarified. Connecting all splicing features (genes, splice transcripts, isoforms, and relative functions) may be useful to resolve this tangle. Herein, we will start from the case of a single gene, Parkinson protein 2, E3 ubiquitin protein ligase (PARK2), one of the largest in our genome. This gene is implicated in the pathogenesis of autosomal recessive juvenile Parkinsonism and it has been recently linked to cancer, leprosy, autism, type 2 diabetes mellitus and Alzheimer's disease. PARK2 primary transcript undergoes an extensive alternative splicing, which enhances transcriptomic diversification and protein diversity in tissues and cells. This review will provide an update of all human PARK2 alternative splice transcripts and isoforms presently known, and correlate them to those in rat and mouse, two common animal models for studying human disease genes. Alternative splicing relies upon a complex process that could be easily altered by both cis and trans-acting mutations. Although the contribution of PARK2 splicing in human disease remains to be fully explored, some evidences show disruption of this versatile form of genetic regulation may have pathological consequences. PMID- 24955031 TI - A computational algorithm for functional clustering of proteome dynamics during development. AB - Phenotypic traits, such as seed development, are a consequence of complex biochemical interactions among genes, proteins and metabolites, but the underlying mechanisms that operate in a coordinated and sequential manner remain elusive. Here, we address this issue by developing a computational algorithm to monitor proteome changes during the course of trait development. The algorithm is built within the mixture-model framework in which each mixture component is modeled by a specific group of proteins that display a similar temporal pattern of expression in trait development. A nonparametric approach based on Legendre orthogonal polynomials was used to fit dynamic changes of protein expression, increasing the power and flexibility of protein clustering. By analyzing a dataset of proteomic dynamics during early embryogenesis of the Chinese fir, the algorithm has successfully identified several distinct types of proteins that coordinate with each other to determine seed development in this forest tree commercially and environmentally important to China. The algorithm will find its immediate applications for the characterization of mechanistic underpinnings for any other biological processes in which protein abundance plays a key role. PMID- 24955030 TI - Why adult stem cell functionality declines with age? Studies from the fruit fly Drosophila melanogaster model organism. AB - Highly regenerative adult tissues are supported by rare populations of stem cells that continuously divide to self-renew and generate differentiated progeny. This process is tightly regulated by signals emanating from surrounding cells to fulfill the dynamic demands of the tissue. One of the hallmarks of aging is slow and aberrant tissue regeneration due to deteriorated function of stem and supporting cells. Several Drosophila regenerative tissues are unique in that they provide exact identification of stem and neighboring cells in whole-tissue anatomy. This allows for precise tracking of age-related changes as well as their targeted manipulation within the tissue. In this review we present the stem cell niche of Drosophila testis, ovary and intestine and describe the major changes and phenotypes that occur in the course of aging. Specifically we discuss changes in both intrinsic properties of stem cells and their microenvironment that contribute to the decline in tissue functionality. Understanding these mechanisms in adult Drosophila tissues will likely provide new paradigms in the field of aging. PMID- 24955029 TI - Life-history Constraints on the Mechanisms that Control the Rate of ROS Production. AB - The quest to understand why and how we age has led to numerous lines of investigation that have gradually converged to consider mitochondrial metabolism as a major player. During mitochondrial respiration a small and variable amount of the consumed oxygen is converted to reactive species of oxygen (ROS). For many years, these ROS have been perceived as harmful by-products of respiration. However, evidence from recent years indicates that ROS fulfill important roles as cellular messengers. Results obtained using model organisms suggest that ROS dependent signalling may even activate beneficial cellular stress responses, which eventually may lead to increased lifespan. Nevertheless, when an overload of ROS cannot be properly disposed of, its accumulation generates oxidative stress, which plays a major part in the ageing process. Comparative studies about the rates of ROS production and oxidative damage accumulation, have led to the idea that the lower rate of mitochondrial oxygen radical generation of long-lived animals with respect to that of their short-lived counterpart, could be a primary cause of their slow ageing rate. A hitherto largely under-appreciated alternative view is that such lower rate of ROS production, rather than a cause may be a consequence of the metabolic constraints imposed for the large body sizes that accompany high lifespans. To help understanding the logical underpinning of this rather heterodox view, herein I review the current literature regarding the mechanisms of ROS formation, with particular emphasis on evolutionary aspects. PMID- 24955032 TI - Can a Happy Relationship Predict a Happy Life? A Population-Based Study of Maternal Well-Being During the Life Transition of Pregnancy, Infancy, and Toddlerhood. AB - The association between overall life satisfaction (LS) and relationship satisfaction (RS) was investigated longitudinally among mothers (N=67,355), using data from the Norwegian Mother and Child Cohort Study (MoBa), conducted by the Norwegian Institute of Public Health. Data were collected twice during pregnancy, and at 6 and 36 months postpartum. Satisfaction increased during pregnancy, with RS decreasing immediately following birth and LS showing an initial increase followed by a decrease postpartum. The results showed that LS and RS levels were quite stable over time (.46-.75), as was their cross-sectional associations (.42 .59). Structural equation modeling using a cross-lagged longitudinal model evidenced cross-concept cross-time effects for both LS and RS. The strengths of the cross-effects were asymmetrical and life-phase specific, with RS predicting change in LS more than LS predicted changes in RS during pregnancy and infancy. Having a satisfying romantic relationship is important for retaining and increasing future life satisfaction. PMID- 24955034 TI - Caveolin-1 induces lamellipodia formation via an Akt-dependent pathway. AB - BACKGROUND: The enhancement of migration is critical for facilitating cancer cell metastasis. METHOD: Lung cancer H23 cells were transfected with either a caveolin 1 (Cav-1) overexpression or shCav-1 plasmid and further subjected to cell migration assays and lamellipodia characterization. The regulation of Cav-1 via an ATP-dependent tyrosine kinase (Akt) pathway was further examined by Akt knockdown in Cav-1 overexpressing cells and migratory behavior investigations. RESULTS: Here, we demonstrate for the first time that overexpression of Cav-1 in human lung cancer H23 cells significantly increased the formation of lamellipodia, whereas the suppression of Cav-1 using shRNA transfection had the opposite effect. Consistent with an increase in lamellipodia, Cav-1 overexpressing cells exhibited increased migratory activity in comparison to their parental, control-transfected, H23 cells. The induction of lamellipodia was demonstrated to occur via the Akt pathway because the addition of the Akt inhibitor LY294002 inhibited lamellipodia in both Cav-1-overexpressing and H23 cells. Additionally, transient transfection with Akt-siRNA significantly inhibited the formation of lamellipodia and the migration of Cav-1-overexpressing H23 cells. In addition, Cav-1 levels and the migratory action of other lung cancer cells, namely, H460 and A549, were assessed, and the migration of these cells was found to be correlated with the basal Cav-1 level. CONCLUSION: These data showed that Cav-1 enhances cancer cell migration through Akt-mediated lamellipodia formation. Our results provide novel insights regarding the molecular mechanism controlling cancer cell migration, leading to a better understanding of cancer cell biology. PMID- 24955033 TI - Sleepiness and Safety: Where Biology Needs Technology. AB - Maintaining human alertness and behavioral capability under conditions of sleep loss and circadian misalignment requires fatigue management technologies due to: (1) dynamic nonlinear modulation of performance capability by the interaction of sleep homeostatic drive and circadian regulation; (2) large differences among people in neurobehavioral vulnerability to sleep loss; (3) error in subjective estimates of fatigue on performance; and (4) to inform people of the need for recovery sleep. Two promising areas of technology have emerged for managing fatigue risk in safety-sensitive occupations. The first involves preventing fatigue by optimizing work schedules using biomathematical models of performance changes associated with sleep homeostatic and circadian dynamics. Increasingly these mathematical models account for individual differences to achieve a more accurate estimate of the timing and magnitude of fatigue effects on individuals. The second area involves technologies for detecting transient fatigue from drowsiness. The Psychomotor Vigilance Test (PVT), which has been extensively validated to be sensitive to deficits in attention from sleep loss and circadian misalignment, is an example in this category. Two shorter-duration versions of the PVT recently have been developed for evaluating whether operators have sufficient behavioral alertness prior to or during work. Another example is online tracking the percent of slow eyelid closures (PERCLOS), which has been shown to reflect momentary fluctuations of vigilance. Technologies for predicting and detecting sleepiness/fatigue have the potential to predict and prevent operator errors and accidents in safety-sensitive occupations, as well as physiological and mental diseases due to inadequate sleep and circadian misalignment. PMID- 24955035 TI - Change over Time: Conducting Longitudinal Studies of Children's Cognitive Development. AB - Developmental scientists have argued that the implementation of longitudinal methods is necessary for obtaining an accurate picture of the nature and sources of developmental change (Magnusson & Cairns, 1996; Morrison & Ornstein, 1996; Magnusson & Stattin, 2006). Developmentalists studying cognition have been relatively slow to embrace longitudinal research, and thus few exemplar studies have tracked individual children's cognitive performance over time and even fewer have examined contexts that are associated with this growth. In this article we first outline some of the benefits of implementing longitudinal designs. Using illustrations from existing studies of children's basic cognitive development and of their school-based academic performance, we discuss when it may be appropriate to employ longitudinal (versus other) methods. We then outline methods for integrating longitudinal data into one's research portfolio, contrasting the leveraging of existing longitudinal data sets with the launching of new longitudinal studies in order to address specific questions concerning cognitive development. Finally, for those who are interested in conducting longitudinal investigations of their own, we provide practical on-the-ground guidelines for designing and carrying out such studies of cognitive development. PMID- 24955036 TI - Born to observe. PMID- 24955037 TI - Editorial commentary. PMID- 24955038 TI - Waiting. PMID- 24955040 TI - Slope of the anterior mitral valve leaflet: a new measurement of left ventricular unloading for left ventricular assist devices and systolic dysfunction. AB - Left ventricular assist device (LVAD)-supported patients are evaluated routinely with use of transthoracic echocardiography. Values of left ventricular unloading in this unique patient population are needed to evaluate LVAD function and assist in patient follow-up. We introduce a new M-mode measurement, the slope of the anterior mitral valve leaflet (SLAM), and compare its efficacy with that of other standard echocardiographically evaluated values for left ventricular loading, including E/e' and pulmonary artery systolic pressures. Average SLAM values were determined retrospectively for cohorts of random, non-LVAD patients with moderately to severely impaired left ventricular ejection fraction (LVEF) (<0.35, n=60). In addition, pre- and post-LVAD implantation echocardiographic images of 81 patients were reviewed. The average SLAM in patients with an LVEF <0.35 was 11.6 cm/s (95% confidence interval, 10.4-12.8); SLAM had a moderately strong correlation with E/e' in these patients. Implantation of LVADs significantly increased the SLAM from 7.3 +/- 2.44 to 14.7 +/- 5.01 cm/s (n=42, P <0.0001). The LVAD-supported patients readmitted for exacerbation of congestive heart failure exhibited decreased SLAM from 12 +/- 3.93 to 7.3 +/- 3.5 cm/s (n=6, P=0.041). In addition, a cutpoint of 10 cm/s distinguished random patients with LVEF <0.35 from those in end-stage congestive heart failure (pre-LVAD) with an 88% sensitivity and a 55% specificity. Evaluating ventricular unloading in LVAD patients remains challenging. Our novel M-mode value correlates with echocardiographic values of left ventricular filling in patients with moderate-to severe systolic function and dynamically improves with the ventricular unloading of an LVAD. PMID- 24955039 TI - Outpatient management of heart failure in the United States, 2006-2008. AB - Better outpatient management of heart failure might improve outcomes and reduce the number of rehospitalizations. This study describes recent outpatient heart failure management in the United States. We analyzed data from the National Ambulatory Medical Care Survey of 2006-2008, a multistage random sampling of non Federal physician offices and hospital outpatient departments. Annually, 1.7% of all outpatient visits were for heart failure (51% females and 77% non-Hispanic whites; mean age, 73 +/- 0.5 yr). Typical comorbidities were hypertension (62%), hyperlipidemia (36%), diabetes mellitus (35%), and ischemic heart disease (29%). Body weight and blood pressure were recorded in about 80% of visits, and health education was given in about 40%. The percentage of patients taking beta-blockers was 38%; the percentage taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs) was 32%. Medication usage did not differ significantly by race or sex. In multivariate-adjusted logistic regression models, a visit to a cardiologist, hypertension, heart failure as a primary reason for the visit, and a visit duration longer than 15 minutes were positively associated with ACEI/ARB use; and a visit to a cardiologist, heart failure as a primary reason for the visit, the presence of ischemic heart disease, and visit duration longer than 15 minutes were positively associated with beta-blocker use. Chronic obstructive pulmonary disease was negatively associated with beta-blocker use. Approximately 1% of heart-failure visits resulted in hospitalization. In outpatient heart-failure management, gaps that might warrant attention include suboptimal health education and low usage rates of medications, specifically ACEI/ARBs and beta-blockers. PMID- 24955041 TI - Natural progression of low-gradient severe aortic stenosis with preserved ejection fraction. AB - Because the natural progression of low-gradient aortic stenosis (LGAS) has not been well defined, we performed a retrospective study of 116 consecutive patients with aortic stenosis who had undergone follow-up echocardiography at a median interval of 698 days (range, 371-1,020 d). All patients had preserved left ventricular ejection fraction (>0.50) during and after follow-up. At baseline, patients were classified by aortic valve area (AVA) as having mild stenosis (>=1.5 cm(2)), moderate stenosis (>=1 to <1.5 cm(2)), or severe stenosis (<1 cm(2)). Severe aortic stenosis was further classified by mean gradient (LGAS, mean <40 mmHg; high-gradient aortic stenosis [HGAS], mean >=40 mmHg). We compared baseline and follow-up values among 4 groups: patients with mild stenosis, moderate stenosis, LGAS, and HGAS. At baseline, 30 patients had mild stenosis, 54 had moderate stenosis, 24 had LGAS, and 8 had HGAS. Compared with the moderate group, the LGAS group had lower AVA but similar mean gradient. Yet the actuarial curves for progressing to HGAS were significantly different: 25% of patients in LGAS reached HGAS status significantly earlier than did 25% of patients in the moderate-AS group (713 vs 881 d; P=0.035). Because LGAS has a high propensity to progress to HGAS, we propose that low-gradient aortic stenosis patients be closely monitored as a distinct subgroup that warrants more frequent echocardiographic follow-up. PMID- 24955042 TI - Role of isoproterenol in predicting the success of catheter ablation in patients with reproducibly inducible atrioventricular nodal reentrant tachycardia. AB - Noninducibility of the arrhythmia is the widely accepted endpoint of successful ablation of atrioventricular nodal reentrant tachycardia (AVNRT). However, to rely upon that as the only endpoint, the arrhythmia must also be inducible before ablation. Despite the fact that AVNRT is not reproducibly inducible in a significant number of cases, the role of reproducible arrhythmia induction and its relationship with the infusion of isoproterenol after successful ablation of AVNRT has not been well defined. We studied 175 consecutive patients who all underwent successful radiofrequency ablation after showing that they had reproducibly inducible AVNRT without use of isoproterenol. In Group 1 (n=90), isoproterenol was used for arrhythmia reinduction after ablation, whereas in Group 2 (n=85) it was not. The procedural and follow-up data of both groups were recorded, and the results of appropriate statistical tests were analyzed. During a mean follow-up time of 18.7 +/- 4.5 months, 4 patients in Group 1 and 3 patients in Group 2 experienced recurrences. Regardless of elimination or modification of slow-pathway conduction, no significant difference was seen in the recurrence rates of AVNRT between the 2 groups (P=0.72). We conclude that, when the original arrhythmia in patients with AVNRT is reproducibly inducible in the basal state, the use of isoproterenol after ablation in order to confirm the noninducibility of AVNRT does not appear to alter the recurrence rates and can be omitted. PMID- 24955043 TI - Sex-specific biatrial volumetric measurements obtained with use of multidetector computed tomography in subjects with and without coronary artery disease. AB - Atrial volumetric measurement has proven clinical implications. Advances in cardiac imaging, notably the precision enabled by multidetector computed tomography (MDCT), herald the need for new criteria of what constitutes normal volumetric measurements. With use of 64-slice MDCT, we compared the atrial volumes in healthy individuals with those in individuals with coronary artery disease. By means of manual segmentation, we measured biatrial volume in 686 participants who underwent retrospective electrocardiographic-gated MDCT angiographic evaluation. The study population included a control group of 203 persons with no cardiac abnormalities, and a study group of 483 patients with obstructive coronary artery disease. All variables were compared between men and women and between the groups. We found a significant difference in left atrial end-systolic and end-diastolic volumes between men and women in the control group (P <0.05); however, right atrial volumes were similar. In comparison with the entire control group, the coronary artery disease group had significantly higher left atrial volume, significantly lower right atrial stroke volume, and significantly lower biatrial ejection fraction, except for left atrial ejection fraction in men. Right atrial volume and left atrial stroke volume were not significantly different. The results imply that a sex-specific reference value is necessary for left atrial volumetric evaluation, and that left atrial volume and biatrial ejection fraction (excluding left atrial ejection fraction in men) might be useful during diagnosis and prognosis in patients who have coronary artery disease. PMID- 24955045 TI - Spontaneous coronary artery dissection (SCAD): new insights into this not-so-rare condition. PMID- 24955046 TI - Takotsubo cardiomyopathy. PMID- 24955047 TI - What is new in the 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic risk in adults? PMID- 24955049 TI - Socioeconomic status and smoking cessation: neighborhood context as an underlying mechanism. PMID- 24955048 TI - Patent foramen ovale. PMID- 24955051 TI - Transventricular mitral valve repair in patients with acute forms of ischemic mitral regurgitation. AB - Transventricular mitral valve surgery combined with left ventricular restoration avoids atriotomy and provides a larger operative field. We describe a series of 5 patients in whom we performed transventricular mitral valve repair by various techniques, such as band annuloplasty, papillary muscle reattachment, chordal cutting, and edge-to-edge repair. The more acute forms of ischemic mitral regurgitation, as found in our patients, can coexist with post-myocardial infarction contained rupture or post-myocardial infarction ventricular septal rupture. Because these patients already have an indication for ventriculotomy, concomitant transventricular repair of the mitral valve can render a separate atriotomy unnecessary and thereby shorten the duration of cardiopulmonary bypass. Moreover, in patients with acute presentations, the absence of atrial dilation (this last associated with chronic cases) might make transventricular repair a better choice than the more difficult atrial approach. PMID- 24955052 TI - Exertional dyspnea as a symptom of infrarenal aortic occlusive disease. AB - Advanced atherosclerosis of the aorta can cause severe ischemia in the kidneys, refractory hypertension, and claudication. However, no previous reports have clearly associated infrarenal aortic stenosis with shortness of breath. A 77-year old woman with hypertension and hyperlipidemia presented with exertional dyspnea. Despite extensive testing and observation, no apparent cause for this patient's dyspnea was found. Images revealed severe infrarenal aortic stenosis. After the patient underwent stenting of the aortic occlusion, she had immediate symptomatic improvement and complete resolution of her dyspnea within one month. Twelve months after vascular intervention, the patient remained asymptomatic. In view of the distinct and lasting elimination of dyspnea after angioplasty and stenting of a nearly occluded infrarenal aortic lesion, we hypothesize that infrarenal aortic stenosis might be a treatable cause of exertional dyspnea. Clinicians should consider infrarenal aortic stenosis as a possible cause of dyspnea. Treatment of the stenosis might relieve symptoms. PMID- 24955053 TI - Cardiac sarcoidosis presenting as constrictive pericarditis. AB - In patients with cardiac sarcoidosis, the sarcoid granulomas usually involve the myocardium or endocardium. The disease typically presents as heart failure with ventricular arrhythmias, conduction disturbances, or both. Constrictive pericarditis has rarely been described in patients with sarcoidosis: we found only 2 reports of this association. We report the case of a 57-year-old man who presented with clinical and hemodynamic features of constrictive pericarditis, of unclear cause. He was admitted for treatment of recurrent pleural effusion. After a complicated hospital course, he underwent pericardiectomy. His clinical and hemodynamic conditions improved substantially, and he was discharged from the hospital in good condition. The pathologic findings, the patient's clinical course, and his response to pericardiectomy led to our diagnosis of cardiac sarcoidosis presenting as constrictive pericarditis. In addition to the patient's case, we discuss the nature and diagnostic challenges of cardiac sarcoidosis. Increased awareness of this disease is necessary for its early detection, appropriate management, and potential cure. PMID- 24955054 TI - Intracardiac abscess with cutaneous fistula secondary to ventricular septal defect repair simulating sternal wound infection. AB - Cutaneous fistula as a clinical presentation of intracardiac abscess of the right side is such an unusual occurrence that it has not until now been reported in the English-language medical literature. We present a rare case of right-sided infective endocarditis caused by Achromobacter xylosoxidans in which recurrent infection presented as sternal wound discharge. The infection was found to have an intracardiac origin and was successfully managed by radical debridement on cardiopulmonary bypass. PMID- 24955055 TI - Aortic perforation by active-fixation atrial pacing lead: an unusual but serious complication. AB - Perforation of a cardiac chamber is an infrequent but serious sequela of pacemaker lead implantation. An even rarer event is the perforation of the aorta by a protruding right atrial wire. We present here the first case in the medical literature of aortic perforation as a sequela to the implantation of a cardiac resynchronization therapy defibrillator. The patient was a 54-year-old man with idiopathic dilated cardiomyopathy who underwent the implantation of a defibrillator, with no apparent sequelae. Six hours after the procedure, he experienced cardiac tamponade and required urgent open-chest surgery. The pericardial effusion was found to be caused by mechanical friction of a protruding right atrial wire on the aortic root. The aortic root and the atrial wall were both repaired with Prolene suture, which achieved complete control of the bleeding. There was no need to reposition the atrial wire. The patient had a good postoperative recovery. PMID- 24955056 TI - Cardioverter-defibrillator implantation to treat cardiac fibroma-induced ventricular tachycardia in a 70-year-old woman. AB - Benign cardiac fibroma is rarely reported in adults. Its clinical symptoms are related to outflow obstruction or dysrhythmias. We present the case of a 70-year old woman who had a syncopal episode from ventricular tachycardia caused by cardiac fibroma. Because of unfavorable tumor anatomy, the patient was not a candidate for surgical excision, and she declined orthotopic heart transplantation. To prevent sudden cardiac death, we placed an implantable cardioverter-defibrillator, and the patient remained well throughout the 2-year follow-up period. To our knowledge, this is the first report of implantable cardioverter-defibrillator therapy to treat an adult patient's unresectable cardiac fibroma. PMID- 24955057 TI - Asymptomatic young man with Danon disease. AB - Danon disease is a rare, codominant X-linked genetic disorder characterized by the triad of left ventricular hypertrophy, mental retardation, and peripheral myopathy. This disease is caused by mutations in the gene that encodes lysosomal associated membrane protein 2 (LAMP2), a deficiency of which results in the accumulation of autophagic granular debris within the vacuoles of muscle cells. This is a report of an asymptomatic 19-year-old man with Danon disease in the absence of mental retardation or clinically significant skeletal myopathy. This case underscores the importance of accurate diagnosis of unexplained left ventricular hypertrophy, in order to establish an appropriate treatment plan and to advise genetic counseling. PMID- 24955058 TI - Acute anterior ST-elevation myocardial infarction and electrical storm secondary to nondominant right coronary artery occlusion. AB - A 42-year-old man emergently presented with chest pain and anterior ST elevation. Refractory ventricular arrhythmias and shock developed rapidly. A coronary angiogram revealed the acute occlusion of a nondominant right coronary artery. After percutaneous coronary intervention, the anterior ST elevation and ventricular arrhythmias resolved. The electrocardiographic pattern was a result of isolated right ventricular infarction that in turn caused profound electrical and hemodynamic instability. We discuss the cause and pathophysiology of this patient's case, and we recommend that interventional and general cardiologists be aware that anterior ST elevation can be caused by the occlusion of a nondominant right coronary artery. PMID- 24955059 TI - Multidetector computed tomographic imaging of Erdheim-Chester disease. AB - Erdheim-Chester disease is a rarely reported disease that can affect nearly every organ and chiefly infiltrates the connective, perivascular, and adipose tissue. The disease is a form of non-Langerhans-cell histiocytosis characterized by the proliferation of foamy histiocytes; its cardiovascular complications carry a severe prognosis. We present the case of a 29-year-old woman who was admitted for analysis of her angina. Our evaluation with use of cardiac multidetector computed tomographic angiography revealed large mediastinal soft tissue that compressed the patient's left anterior descending coronary artery. To our knowledge, this is the first report of the use of low-dose, dual-source, 256-slice multidetector computed tomography to characterize Erdheim-Chester disease that exclusively caused angina and stenosis of a coronary artery in a young adult. PMID- 24955060 TI - Frozen elephant trunk repair for descending thoracic aortic dissection in a man with a hostile left pleural cavity. AB - The frozen elephant trunk procedure is a hybrid, single-staged alternative to conventional surgery for repairing diffuse pathologic conditions of the thoracic aorta. This approach is particularly advantageous in patients who have pathologic conditions of the left side of the chest, because the descending thoracic aorta can be repaired without entering a hostile pleural cavity. We present the case of a 67-year-old man who had undergone repair of acute type A aortic dissection. He presented with aneurysmal dilation of the descending thoracic aorta secondary to chronic dissection, a large acute dissection of the proximal ascending aorta, and a large paraesophageal hernia that made him a poor candidate for conventional, 2 staged open aortic repair. We describe the hybrid frozen elephant trunk technique that we used to repair the aorta, and its broader advantages. PMID- 24955061 TI - Isolated spontaneous celiac artery dissection in a 47-year-old man with von Willebrand disease. AB - Isolated spontaneous dissection of the celiac artery is rare, and its occurrence without aortic dissection is even rarer. The typical symptom of this dissection is acute-onset abdominal pain. Complications of the condition include aneurysm formation, rupture, and abdominal-organ ischemia or infarction, especially in the liver or spleen. We report the case of a 47-year-old man with von Willebrand disease who had an isolated spontaneous dissection of the celiac artery. We used computed tomography and computed tomographic angiography in the diagnosis and characterization of the dissection. To our knowledge, this is the first report of celiac artery dissection in a patient with von Willebrand disease. PMID- 24955062 TI - Left ventricular "pseudo-pseudoaneurysm": an unusual case of focal left ventricular noncompaction. PMID- 24955063 TI - Cardiovascular magnetic resonance depiction of quadricuspid pulmonary valve with associated pulmonary regurgitation and pulmonary artery aneurysm. PMID- 24955065 TI - Cor triatriatum sinister: histopathologic remarks. PMID- 24955064 TI - Comprehensive evaluation of culture-negative endocarditis with use of cardiac and 4-dimensional-flow magnetic resonance imaging. PMID- 24955066 TI - Lehardyia alleithoros, sp. nov. (Turbellaria, Kalyptorhynchia) from the Coast of North Carolina, USA. AB - As with other high-energy beaches, those of North Carolina harbor a diverse fauna of kalyptorhynch turbellarians, and most appear to be new to science. Here, we describe Lehardyia alleithoros, a new kalyptorhynch turbellarian of the Karkinorhynchidae, from 3 high-energy beach sites in North Carolina. We also report an apparent range extension for Carcharodorhynchus flavidusBrunet, 1967. These observations bring the total number of kalyptorhynch turbellarians reported from the marine interstitial environment of North Carolina to five. PMID- 24955068 TI - Epilepsy and inflammation in the brain: overview and pathophysiology. AB - The possibility that inflammatory processes in the brain contribute to the etiopathogenesis of seizures and the establishment of a chronic epileptic focus is increasingly recognized as a result of supportive evidence in experimental models and in the clinical setting. Prototypical inflammatory cytokines (such as IL-1beta) and "danger signals" (such as HMGB1 and S100beta) are overexpressed in human and experimental epileptogenic tissue, prominently by glia. Neurons and endothelial cells of the blood-brain barrier contribute to inflammatory processes. All these cell types also express receptors for inflammatory mediators, suggesting that inflammatory molecules in the brain exert both autocrine and paracrine activation of intracellular signaling cascades; thus, they may act as soluble mediators of cell communication in diseased tissue. In experimental models, seizures also trigger brain inflammation in the absence of cell loss; in human epileptogenic tissue, the type of neuropathology associated with chronic seizures contributes to determine the type of cells expressing the inflammatory mediators, and the extent to which inflammation occurs. Inflammatory molecules, such as IL-1beta and HMGB1, have proconvulsant activity in various seizure models, most likely by decreasing seizure threshold via functional interactions with classical neurotransmitter systems. These findings reveal novel glioneuronal communications in epileptic tissue that highlight potential new targets for therapeutic intervention. PMID- 24955067 TI - Polymorphic Protein Crystal Growth: Influence of Hydration and Ions in Glucose Isomerase. AB - Crystal polymorphs of glucose isomerase were examined to characterize the properties and to quantify the energetics of protein crystal growth. Transitions of polymorph stability were measured in poly(ethylene glycol)/NaCl solutions, and one transition point was singled out for more detailed quantitative analysis. Single crystal x-ray diffraction was used to confirm space groups and identify complementary crystal structures. Crystal polymorph stability was found to depend on the NaCl concentration, with stability transitions requiring > 1 M NaCl combined with a low concentration of PEG. Both salting-in and salting-out behavior was observed and was found to differ for the two polymorphs. For NaCl concentrations above the observed polymorph transition, the increase in solubility of the less stable polymorph together with an increase in the osmotic second virial coefficient suggests that changes in protein hydration upon addition of salt may explain the experimental trends. A combination of atomistic and continuum models was employed to dissect this behavior. Molecular dynamics simulations of the solvent environment were interpreted using quasi-chemical theory to understand changes in protein hydration as a function of NaCl concentration. The results suggest that protein surface hydration and Na+ binding may introduce steric barriers to contact formation, resulting in polymorph selection. PMID- 24955069 TI - Timing of surgery in rasmussen syndrome: is patience a virtue? AB - Rasmussen syndrome affects previously normal people and forever changes their lives and the lives of their families. Although understood as a probable autoimmune condition, medical treatment remains limited and surgery remains the only cure, although with inevitable functional consequences. Difficulties remain in deciding on the optimal timing of surgery. Here, we review data available to aid clinicians faced with making the decision of when to recommend hemispherectomy. Not all patients have rapidly progressive disease, however, and such patients may benefit from immunomodulatory treatment. Thus, a patient's clinical course requires careful evaluation in order to identify those who would benefit most from early surgery. PMID- 24955070 TI - 15-year-old patient with encephalopathy and seizures after vaccination. PMID- 24955071 TI - Inflammatory processes, febrile seizures, and subsequent epileptogenesis. AB - Febrile seizures (FS) are the most common type of seizures in infants and preschool children. Inflammatory mediators, which are known triggers of fever, have also been implicated as contributors to the onset of these seizures. Evidence that inflammation is present following FS and during established epilepsy suggests that it could also influence epileptogenesis. However, the potential involvement of inflammatory mediators to the epileptogenic process that may follow prolonged FS has yet to be fully determined. This article reviews the current state of our knowledge and major gaps that remain by focusing on four questions: Does inflammation contribute to the generation of FS? Does prolonged FS or febrile status epilepticus (SE) cause temporal lobe epilepsy in the absence of predisposing factors? Does inflammation contribute to the process by which febrile SE causes limbic epilepsy? And finally, can inflammation be a foundation for biomarkers and therapy for FS-induced epileptogenesis? PMID- 24955072 TI - Neurocysticercosis and epilepsy. PMID- 24955073 TI - Parasitic Diseases that Cause Seizures. AB - The propensity of parasites to invade the brain, cause disease, and give rise to seizures and epilepsy varies greatly. This reflects the wide diversity of parasites that differ in fundamental ways. This manuscript reviews parasites that invade the brain or its vasculature and give rise to seizures. PMID- 24955074 TI - Epilepsy and viral infections. PMID- 24955075 TI - Status epilepticus in the setting of acute encephalitis. AB - Ms. Q, a 29-year-old woman, began to behave strangely, claiming to see and hear imaginary people. The following day, she was confused and somnolent in the morning. In the late morning, she had a generalized tonic-clonic seizure and was transported to the hospital. Her past medical and developmental histories were unremarkable. She took a daily oral contraceptive and had no drug allergies. She worked as a teacher and had been married for one year. On initial examination, blood pressure was 129/82, pulse 88, respiratory rate 16, temperature 37.5 degrees C. She was stuporous, moving her arms appropriately in response to a painful stimulus. Pupils were 2 mm and reactive. There was no gaze preference, and the rest of the examination was nonfocal. About 30 minutes after her first seizure, she had a second GTCS and was given 4 mg lorazepam intravenously. She had a third GTCS 6 min after her second seizure and received a second dose of lorazepam. Initial blood tests-including complete blood count, comprehensive metabolic panel, urinalysis, and toxic screen-were normal. Head CT was normal. She remained stuporous. EEG demonstrated waxing and waning electrographic ictal activity, and she was loaded with fosphenytoin. Intermittent electrographic seizure activity persisted, and a continuous infusion of intravenous propofol was administered. After 24 hr, propofol was weaned, but electrographic seizures recurred and it was restarted. PMID- 24955077 TI - Takayasu Arteritis in the pediatric population: a contemporary United States based single center cohort. AB - BACKGROUND: Takayasu Arteritis is an idiopathic, chronic, large vessel vasculitis involving the aorta and its primary branches. Few studies have been done in pediatric patients to date with the largest case series of US patients published in 2003 consisting of only 6 patients. METHODS: A retrospective chart review was performed on all patients seen at Cleveland Clinic Children's up until 2012 who met EULAR/PRINTO/PRES classification criteria for childhood Takayasu Arteritis. RESULTS: Twenty-one patients with a mean follow up of 2.3 years were studied. Weight loss, fatigue, and anorexia were the most common presenting complaints. 57.1% of patients were hypertensive at first visit. The most common examintation finding was diminished pulses (61.9%), followed by bruits, and then murmurs. Thoracic aorta stenosis was the most common vascular abnormality. Seven of twenty one patients responded well to methotrexate and prednisone alone. Ten of twenty one patients required an additional medication for symptom and disease control (infliximab most commonly). About two-thirds of patients required at least one anti-hypertensive medication. Eight of the twenty-one patients required surgical intervention for severe disease refractory to medications (renal artery stenosis being the most common indication). Almost all patients reported symptomatic improvement after surgical intervention. Two of the eight patients required a second surgery for return of symptoms. Disease sequelae included arterial aneurysms, resolved heart failure, and hypertensive emergencies. CONCLUSION: Our study emphasizes that constitutional symptoms coupled with objective findings of diminished pulses, bruits, and hypertension should raise clinical suspicion for Takayasu Arteritis in pediatric patients. Pharmacologic therapy alone can be successful in controlling disease progression, however surgery was successful in minimizing symptoms when medical therapies failed. PMID- 24955078 TI - Molecular Dynamics Simulation of Nitrobenzene Dioxygenase Using AMBER Force Field. AB - Molecular dynamics simulation of the oxygenase component of nitrobenzene dioxygenase (NBDO) system, a member of the naphthalene family of Rieske nonheme iron dioxygenases, has been carried out using the AMBER force field combined with a new set of parameters for the description of the mononuclear nonheme iron center and iron-sulfur Rieske cluster. Simulation results provide information on the structure and dynamics of nitrobenzene dioxygenase in an aqueous environment and shed light on specific interactions that occur in its catalytic center. The results suggest that the architecture of the active site is stabilized by key hydrogen bonds, and Asn258 positions the substrate for oxidation. Analysis of protein-water interactions reveal the presence of a network of solvent molecules at the entrance to the active site, which could be of potential catalytic importance. PMID- 24955076 TI - Auxin biosynthesis. AB - lndole-3-acetic acid (IAA), the most important natural auxin in plants, is mainly synthesized from the amino acid tryptophan (Trp). Recent genetic and biochemical studies in Arabidopsis have unambiguously established the first complete Trp dependent auxin biosynthesis pathway. The first chemical step of auxin biosynthesis is the removal of the amino group from Trp by the TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS (TAA) family of transaminases to generate indole 3-pyruvate (IPA). IPA then undergoes oxidative decarboxylation catalyzed by the YUCCA (YUC) family of flavin monooxygenases to produce IAA. This two-step auxin biosynthesis pathway is highly conserved throughout the plant kingdom and is essential for almost all of the major developmental processes. The successful elucidation of a complete auxin biosynthesis pathway provides the necessary tools for effectively modulating auxin concentrations in plants with temporal and spatial precision. The progress in auxin biosynthesis also lays a foundation for understanding polar auxin transport and for dissecting auxin signaling mechanisms during plant development. PMID- 24955079 TI - Universal Grammar and Biological Variation: An EvoDevo Agenda for Comparative Biolinguistics. AB - Recent advances in genetics and neurobiology have greatly increased the degree of variation that one finds in what is taken to provide the biological foundations of our species-specific linguistic capacities. In particular, this variation seems to cast doubt on the purportedly homogeneous nature of the language faculty traditionally captured by the concept of "Universal Grammar." In this article we discuss what this new source of diversity reveals about the biological reality underlying Universal Grammar. Our discussion leads us to support (1) certain hypotheses advanced in evolutionary developmental biology that argue for the existence of robust biological mechanisms capable of canalizing variation at different levels, and (2) a bottom-up perspective on comparative cognition. We conclude by sketching future directions for what we call "comparative biolinguistics," specifying which experimental directions may help us succeed in this new research avenue. PMID- 24955080 TI - In Psychiatric Clinics of North America. PMID- 24955081 TI - Synthetic Studies of Glycosylphosphatidylinositol (GPI) Anchors and GPI-Anchored Peptides, Glycopeptides, and Proteins. AB - Glycosylphosphatidylinositol (GPI) anchorage of proteins and glycoproteins onto the cell surface is ubiquitous in eukaryotes, and GPI-anchored proteins and glycoproteins play an important role in many biological processes. To study GPI anchorage and explore the functions of GPIs and GPI-anchored proteins and glycoproteins, it is essential to have access to these molecules in homogeneous and structurally defined forms. This review is focused on the progress that our laboratory has made towards the chemical and chemoenzymatic synthesis of structurally defined GPI anchors and GPI-anchored peptides, glycopeptides, and proteins. Briefly, highly convergent strategies were developed for GPI synthesis and were employed to successfully synthesize a number of GPIs, including those carrying unsaturated lipids and other useful functionalities such as the azido and alkynyl groups. The latter enabled further site-specific modification of GPIs by click chemistry. GPI-linked peptides, glycopeptides, and proteins were prepared by regioselective chemical coupling of properly protected GPIs and peptides/glycopeptides or through site-specific ligation of synthetic GPIs and peptides/glycopeptides/proteins under the influence of sortase A. The investigation of interactions between GPI anchors and pore-forming bacterial toxins by means of synthetic GPI anchors and GPI analogs is also discussed. PMID- 24955083 TI - Alcohol in the life narratives of women: Commonalities and differences by sexual orientation. AB - AIM: The aim of this study was to explore social representations of alcohol use among women, with a focus on possible differences between sexual minority and heterosexual women. METHODS: This qualitative study was part of a larger study examining mediators of heavier drinking among sexual minority women (lesbian identified, bisexual identified, and heterosexual identified with same sex partners) compared to heterosexual women based on the National Alcohol Survey. Qualitative in-depth life history interviews were conducted over the telephone with 48 women who had participated in the 2009-2010 National Alcohol Survey, including respondents representing different sexual orientation groups. Questions explored the lives and experiences of women, and how use of alcohol may connect to those experiences. FINDINGS: Representations about normative and risky use included social use, use in relation to community connection, addictive use and self-medication. Other representations common across groups included articulation of boundaries that were defined by negative exemplars, marked by indicators of loss of control, and maintained through selective engagement of social networks. Although representations across groups were similar, some representations, such as alcohol use in fostering community connection, appeared to be more salient for sexual minority women. The findings of the study underscore the importance of considering both commonalities and potential differences among women by sexual orientation in meanings and perceived risks associated with alcohol use in future research and intervention efforts. PMID- 24955084 TI - Parental Warmth and Risks of Substance Use in Children with Attention Deficit/Hyperactivity Disorder: Findings from a 10-12 Year Longitudinal Investigation. AB - OBJECTIVE: The study examined factors in the risk trajectory for Substance Use Disorder (SUD) over a 10-12 year period in children with ADHD. METHOD: N=145 children between the ages of 7 and 16 with ADHD and healthy controls were assessed every 2 years for 10-12 years as part of a larger, longitudinal investigation. Onset of substance use disorder was examined using Cox proportional hazards modeling, and included child and parent psychopathology, and parental warmth as well as other key factors. RESULTS: Low paternal warmth and maternal SUD were predictors of SUD in n=59 ADHD participants after adjusting for gender, child ODD, paternal SUD, maternal/paternal ADHD, maternal/paternal major depressive disorder (MDD), maternal/paternal anxiety, and low maternal warmth in the Cox model. CONCLUSIONS: Longitudinal study findings suggest that in addition to the established risk of ADHD and maternal SUD in development of child SUD, low paternal warmth is also associated with onset of SUD. This was evident after controlling for pertinent parent and child psychopathology. These findings suggest that paternal warmth warrants further investigation as a key target for novel interventions to prevent SUD in children with ADHD. More focused investigations examining paternal parenting factors in addition to parent and child psychopathology in the risk trajectory from ADHD to SUD are now warranted. PMID- 24955086 TI - Investigating Epigenetic Effects of Prenatal Exposure to Toxic Metals in Newborns: Challenges and Benefits. AB - Increasing evidence suggest that epigenetic alterations can greatly impact human health, and that epigenetic mechanisms (DNA methylation, histone modifications, and microRNAs) may be particularly relevant in responding to environmental toxicant exposure early in life. The epigenome plays a vital role in embryonic development, tissue differentiation and disease development by controlling gene expression. In this review we discuss what is currently known about epigenetic alterations in response to prenatal exposure to inorganic arsenic (iAs) and lead (Pb), focusing specifically on their effects on DNA methylation. We then describe how epigenetic alterations are being studied in newborns as potential biomarkers of in utero environmental toxicant exposure, and the benefits and challenges of this approach. In summary, the studies highlighted herein indicate how epigenetic mechanisms are impacted by early life exposure to iAs and Pb, and the research that is being done to move towards understanding the relationships between toxicant-induced epigenetic alterations and disease development. Although much remains unknown, several groups are working to understand the correlative and causal effects of early life toxic metal exposure on epigenetic changes and how these changes may result in later development of disease. PMID- 24955087 TI - Robust estimation for partially linear models with large-dimensional covariates. AB - We are concerned with robust estimation procedures to estimate the parameters in partially linear models with large-dimensional covariates. To enhance the interpretability, we suggest implementing a noncon-cave regularization method in the robust estimation procedure to select important covariates from the linear component. We establish the consistency for both the linear and the nonlinear components when the covariate dimension diverges at the rate of [Formula: see text], where n is the sample size. We show that the robust estimate of linear component performs asymptotically as well as its oracle counterpart which assumes the baseline function and the unimportant covariates were known a priori. With a consistent estimator of the linear component, we estimate the nonparametric component by a robust local linear regression. It is proved that the robust estimate of nonlinear component performs asymptotically as well as if the linear component were known in advance. Comprehensive simulation studies are carried out and an application is presented to examine the finite-sample performance of the proposed procedures. PMID- 24955082 TI - Associations between thyroid hormones and serum metabolite profiles in an euthyroid population. AB - The aim was to characterise associations between circulating thyroid hormones free thyroxine (FT4) and thyrotropin (TSH)-and the metabolite profiles in serum samples from participants of the German population-based KORA F4 study. Analyses were based on the metabolite profile of 1463 euthyroid subjects. In serum samples, obtained after overnight fasting (>=8), 151 different metabolites were quantified in a targeted approach including amino acids, acylcarnitines (ACs), and phosphatidylcholines (PCs). Associations between metabolites and thyroid hormone concentrations were analysed using adjusted linear regression models. To draw conclusions on thyroid hormone related pathways, intra-class metabolite ratios were additionally explored. We discovered 154 significant associations (Bonferroni p < 1.75 * 10-04) between FT4 and various metabolites and metabolite ratios belonging to AC and PC groups. Significant associations with TSH were lacking. High FT4 levels were associated with increased concentrations of many ACs and various sums of ACs of different chain length, and the ratio of C2 by C0. The inverse associations observed between FT4 and many serum PCs reflected the general decrease in PC concentrations. Similar results were found in subgroup analyses, e.g., in weight-stable subjects or in obese subjects. Further, results were independent of different parameters for liver or kidney function, or inflammation, which supports the notion of an independent FT4 effect. In fasting euthyroid adults, higher serum FT4 levels are associated with increased serum AC concentrations and an increased ratio of C2 by C0 which is indicative of an overall enhanced fatty acyl mitochondrial transport and beta-oxidation of fatty acids. PMID- 24955085 TI - Beyond the "Pain Matrix," inter-run synchronization during mechanical nociceptive stimulation. AB - Pain is a complex experience that is thought to emerge from the activity of multiple brain areas, some of which are inconsistently detected using traditional fMRI analysis. One hypothesis is that the traditional analysis of pain-related cerebral responses, by relying on the correlation of a predictor and the canonical hemodynamic response function (HRF)- the general linear model (GLM)- may under-detect the activity of those areas involved in stimulus processing that do not present a canonical HRF. In this study, we employed an innovative data driven processing approach- an inter-run synchronization (IRS) analysis- that has the advantage of not establishing any pre-determined predictor definition. With this method we were able to evidence the involvement of several brain regions that are not usually found when using predictor-based analysis. These areas are synchronized during the administration of mechanical punctate stimuli and are characterized by a BOLD response different from the canonical HRF. This finding opens to new approaches in the study of pain imaging. PMID- 24955088 TI - In vitro antibacterial effect of wasp (Vespa orientalis) venom. AB - BACKGROUND: The emergence of antibacterial resistance against several classes of antibiotics is an inevitable consequence of drug overuse. As antimicrobial resistance spreads throughout the globe, new substances will always be necessary to fight against multidrug-resistant microorganisms. Venoms of many animals have recently gained attention in the search for new antimicrobials to treat infectious diseases. Thefore, the present study aimed to study the antibacterial effects of wasp (Vespa orientalis) crude venom. Two gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two gram-negative ones (Escherichia coli and Klesiella pneumonia) were compared for their sensitivity to the venom by determining the inhibition zone (Kirby-Bauer method) and minimum inhibitory concentration (MIC). A microbroth kinetic system based on continuous monitoring of changes in the optical density of bacterial growth was also used for determination of antimicrobial activity. RESULTS: The venom exhibited a well recognized antimicrobial property against the tested bacterial strains. The inhibition zones were determined to be 12.6, 22.7, 22.4 and 10.2 mm for S. aureus, B. subtilis, E. coli and K. pneumonia, respectively. The corresponding MIC values were determined to be 64, 8, 64 and 128 MUg/mL, respectively. The MIC50 and MIC90 values of the venom were respectively determined to be 63.6 and 107 MUg/mL for S. aureus, 4.3 and 7.0 MUg/mL for B. subtilis, 45.3 and 65.7 MUg/mL for E. coli and 74.4 and 119.2 MUg/mL for K. pneumonia. Gram-positive bacteria were generally more sensitive to the venom than gram-negative ones. CONCLUSIONS: Results revealed that the venom markedly inhibits the growth of both gram-positive and gram-negative bacteria and could be considered a potential source for developing new antibacterial drugs. PMID- 24955089 TI - Peroxisome Proliferator-Activated Receptor gamma Regulates the Expression of Lipid Phosphate Phosphohydrolase 1 in Human Vascular Endothelial Cells. AB - Lipid phosphate phosphohydrolase 1 (LPP1), a membrane ectophosphohydrolase regulating the availability of bioactive lipid phosphates, plays important roles in cellular signaling and physiological processes such as angiogenesis and endothelial migration. However, the regulated expression of LPP1 remains largely unknown. Here, we aimed to examine a role of peroxisome proliferator-activated receptor gamma (PPAR gamma ) in the transcriptional control of LPP1 gene expression. In human umbilical vein endothelial cells (HUVECs), quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) demonstrated that activation of PPAR gamma increased the mRNA level of LPP1. Chromatin immunoprecipitation assay showed that PPAR gamma binds to the putative PPAR responsive elements (PPREs) within the 5'-flanking region of the human LPP1 gene. Genomic fragment containing 1.7-kilobase of the promoter region was cloned by using PCR. The luciferase reporter assays demonstrated that overexpression of PPAR gamma and rosiglitazone, a specific ligand for PPAR gamma , could significantly upregulate the reporter activity. However, site-directed mutagenesis of the PPRE motif abolished the induction. In conclusion, our results demonstrated that PPAR gamma transcriptionally activated the expression of LPP1 gene in ECs, suggesting a potential role of PPAR gamma in the metabolism of phospholipids. PMID- 24955090 TI - Breast Cancer Survival Defined by the ER/PR/HER2 Subtypes and a Surrogate Classification according to Tumor Grade and Immunohistochemical Biomarkers. AB - Introduction. ER, PR, and HER2 are routinely available in breast cancer specimens. The purpose of this study is to contrast breast cancer-specific survival for the eight ER/PR/HER2 subtypes with survival of an immunohistochemical surrogate for the molecular subtype based on the ER/PR/HER2 subtypes and tumor grade. Methods. We identified 123,780 cases of stages 1-3 primary female invasive breast cancer from California Cancer Registry. The surrogate classification was derived using ER/PR/HER2 and tumor grade. Kaplan Meier survival analysis and Cox proportional hazards modeling were used to assess differences in survival and risk of mortality for the ER/PR/HER2 subtypes and surrogate classification within each stage. Results. The luminal B/HER2- surrogate classification had a higher risk of mortality than the luminal B/HER2+ for all stages of disease. There was no difference in risk of mortality between the ER+/PR+/HER2- and ER+/PR+/HER2+ in stage 3. With one exception in stage 3, the ER-negative subtypes all had an increased risk of mortality when compared with the ER-positive subtypes. Conclusions. Assessment of survival using ER/PR/HER2 illustrates the heterogeneity of HER2+ subtypes. The surrogate classification provides clear separation in survival and adjusted mortality but underestimates the wide variability within the subtypes that make up the classification. PMID- 24955091 TI - Molecular Typing of Methicillin Resistant Staphylococcus aureus Clinical Isolates on the Basis of Protein A and Coagulase Gene Polymorphisms. AB - Increased frequency of methicillin-resistant Staphylococcus aureus (MRSA) in hospitalized patients requires rapid and reliable characterization of isolates for control of MRSA spread in hospitals. This study evaluated polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) as a molecular typing technique for MRSA strains on the basis of protein A (spa) and coagulase (coa) gene polymorphisms to verify their ability in assessing the relatedness of isolates. Seventy-five MRSA isolates, from different ICUs of Alexandria University Main Hospital, were characterized using antibiotyping and PCR-RFLP analysis of coa and spa genes. Thirty-two antibiotypes were identified. coa gene PCR generated 3 types and 10 subtypes of band patterns. HaeIII restriction digestion of amplified coa gene products produced 5 major banding patterns and 12 subtypes. spa gene PCR products generated 4 major and 11 minor types, and their HaeII restriction digestion showed 5 major and 12 minor banding patterns. The combined coa and spa RFLP patterns generated 22 combined R types. Typing using coa PCR and PCR-RFLP had the same discriminatory index (DI) value (0.64), which was comparable to that of both spa PCR and PCR-RFLP techniques (0.68). The combined grouping increased the DI value to 0.836. The current study revealed that testing for multiple gene polymorphisms is more useful for local epidemiologic purposes. PMID- 24955092 TI - Microbiological Quality of Salads Served along with Street Foods of Hyderabad, India. AB - A study has been done to analyse the microbiological quality of salads served along with street foods of Hyderabad. A total of 163 salad samples, 53 of carrot and 110 of onion samples, were collected from four different zones of Hyderabad. About 74% and 56% had Staphylococcus aureus in carrots and onions, respectively. Fifty-eight percent of carrots and forty-five percent of onions samples contained Salmonella, 68% of carrots and 24% of onions had Yersinia. HACCP study was carried out with 6 street food vendors to identify the source of Salmonella contamination in salads. Food handlers were found to be responsible for Salmonella contamination in salads. The present study revealed the potential hazards of street vended salad vegetables, considering the handling practice usually carried out by vendors. Ninety-eight percent of the vendors did not wash the vegetables before processing and serving while about 56.6% of the vendors did not peel the vegetables. Majority of street vendors' nails were uncut. A significant difference (P < 0.01) was observed in Yersinia spp. and Salmonella spp. in wet-dirty chopping board when compared to clean-dry chopping board. A significant difference (P < 0.05) of Staphylococcus spp. was observed when the status of cleaning cloth was neat/untidy. PMID- 24955093 TI - Photodynamic therapy for diffuse choroidal hemangioma in sturge-weber syndrome. AB - Purpose. To report the treatment outcome of photodynamic therapy with verteporfin (PDT) for exudative retinal detachment (RD) associated with diffuse choroidal hemangioma in Sturge-Weber syndrome (SWS). Methods. An interventional case report of a 10-year-old girl with SWS who developed an exudative RD (visual acuity hand motions) that was treated with PDT. She was treated with a first session of multispot PDT. Posteriorly, a choroidotomy for drainage of subretinal fluid was created, combined with an intravitreal injection of gas (SF6) and cryoapplication. Finally, a second session of PDT was applied. Results. Subretinal fluid resolved over a period of one year and visual acuity increased to 20/125. Conclusions. PDT is an effective therapeutic option for exudative RD associated with diffuse choroidal hemangioma. PMID- 24955094 TI - A proposed quantitative index for assessing the potential contribution of reprogramming to cancer stem cell kinetics. AB - Enrichment of cancer stem cells (CSCs) is thought to be responsible for glioblastoma multiforme (GBM) recurrence after radiation therapy. Simulation results from our agent-based cellular automata model reveal that the enrichment of CSCs may result either from an increased symmetric self-renewal division rate of CSCs or a reprogramming of non-stem cancer cells (CCs) to a stem cell state. Based on plateau-to-peak ratio of the CSC fraction in the tumor following radiation, a downward trend from peak to subsequent plateau (i.e., a plateau-to peak ratio exceeding 1.0) was found to be inconsistent with increased symmetric division alone and favors instead a strong reprogramming component. The two contributions together are seen to be the product of a dynamic equilibrium between CSCs and CCs that is highly regulated by the kinetics of single cells, including the potential for CCs to reacquire a stem cell state and confer phenotypic plasticity to the population as a whole. We conclude that tumor malignancy can be gauged by a degree of cancer cell plasticity. PMID- 24955096 TI - Evaluation of the In Vitro and In Vivo Antioxidant Potentials of Aframomum melegueta Methanolic Seed Extract. AB - Aframomum melegueta Schum (Zingiberaceae) is a perennial herb widely cultivated for its valuable seeds in the tropical region of Africa. The present study evaluated the antioxidant effects of methanolic seed extract of A. melegueta. The antioxidant effects were evaluated using in vitro, 2, 2-diphenylpicrylhydrazine photometric assay and in vivo serum catalase, superoxide dismutase and thiobarbituric acid reactive substance assay method. The extract (25-400 MU g/mL concentration) produced concentration dependent increase in antioxidant activity in 2, 2-diphenylpicrylhydrazine photometric assay. The extract (400 mg/kg) showed a significant (P < 0.05) increase in serum catalase and superoxide dismutase activity when compared with the control group. The extract (400 mg/kg) showed a significant (P < 0.05) decrease in the serum level of thiobarbituric acid reactive substance when compared with the control group. These findings suggest that the seed of A. melegueta has potent antioxidant activity which may be responsible for some of its reported pharmacological activities and can be used as antioxidant supplement. PMID- 24955095 TI - Early Treatment with Intranasal Neostigmine Reduces Mortality in a Mouse Model of Naja naja (Indian Cobra) Envenomation. AB - Objective. Most snakebite deaths occur prior to hospital arrival; yet inexpensive, effective, and easy to administer out-of-hospital treatments do not exist. Acetylcholinesterase inhibitors can be therapeutic in neurotoxic envenomations when administered intravenously, but nasally delivered drugs could facilitate prehospital therapy for these patients. We tested the feasibility of this idea in experimentally envenomed mice. Methods. Mice received intraperitoneal injections of Naja naja venom 2.5 to 10 times the estimated LD50 and then received 5 MU L neostigmine (0.5 mg/mL) or 5 MU L normal saline by nasal administration. Animals were observed up to 12 hours and survivors were euthanized. Results. 100% of control mice died. Untreated mice injected with 2.5* LD50 Naja naja died at average 193 minutes after injection, while 10 of 15 (67%) of treated mice survived and were behaviorally normal by 6 hours (P < 0.02). In the 5* LD50 group, survival was prolonged from 45 minutes to 196 minutes (P = 0.01) and for 10* LD50 mice, survival increased from 30 to 175 minutes (P < 0.02). Conclusion. This pilot suggests that intranasal drugs can improve survival and is the first direct demonstration that such an approach is plausible, suggesting means by which treatment could be initiated before reaching the hospital. Further investigation of this approach to neurotoxic and other types of envenomation is warranted. PMID- 24955097 TI - Association between low vitamin D levels and the diagnosis of asthma in children: a systematic review of cohort studies. AB - BACKGROUND: There is conflicting evidence about the association between low vitamin D levels in children and development of asthma in later life. The objective of this study was to systematically review the evidence for an epidemiological association between low serum levels of vitamin D and the diagnosis of asthma in children. METHODS: We used the Cochrane methodology for conducting systematic reviews. The search strategy included an electronic search of MEDLINE and EMBASE in February 2013. Two reviewers completed, in duplicate and independently, study selection, data abstraction, and assessment of risk of bias. RESULTS: Of 1081 identified citations, three cohort studies met eligibility criteria. Two studies found that low serum vitamin D level is associated with an increased risk of developing asthma late in childhood, while the third study found no association with either vitamin D2 or vitamin D3 levels. All three studies suffer from major methodological shortcomings that limit our confidence in their results. CONCLUSIONS: Available epidemiological evidence suggests a potential association between low serum levels of vitamin D and the diagnosis of asthma in children. High quality studies are needed to reliably answer the question of interest. PMID- 24955098 TI - Genetics patients' perspectives on clinical genomic testing. AB - AIMS: Advances in next-generation sequencing technologies make it possible to envisage multiple contexts in which genomic tools might be used to enhance patient care. We describe how genetics patients and their caregivers view the promises and perils of clinical genomic testing. PATIENTS & METHODS: Fifty-one interviews with patients and parents of pediatric patients seeking genetic evaluation at an academic medical center. RESULTS: Themes from interviews include participants' enthusiasm for clinical genomic testing for diagnostic purposes, medical benefits and concerns about emotional and psychosocial burdens resulting from clinical genomic testing. CONCLUSION: By clarifying these patients' and caregivers' views of clinical genomic testing, the findings we report can help to anticipate other patients' reactions to new forms of personalized medicine enabled by genomic technologies. PMID- 24955099 TI - The contractual genome: how direct-to-consumer genomic services may help patients take ownership of their DNA. AB - The sequencing and genotyping of personal genomes by commercial services outside traditional clinical settings may help to shape the expectations of research subjects and patients regarding control of and responsibility for the information contained in their DNA. A greater sense of individual ownership of personal genomic information could replace overly complex and paternalistic institutional proxies for the protection of personal genotype and sequence data, and also could encourage research participants and patients to become better educated regarding genetic contributors to disease. PMID- 24955100 TI - Safety of Intravenous Application of Mistletoe (Viscum album L.) Preparations in Oncology: An Observational Study. AB - Background. Traditional mistletoe therapy in cancer patients involves subcutaneous applications of Viscum album L. preparations, with doses slowly increasing based on patient responses. Intravenous infusion of high doses may improve therapeutic outcomes and is becoming more common. Little is known about the safety of this "off-label" application of mistletoe. Methods. An observational study was performed within the Network Oncology. Treatment with intravenous mistletoe applications is described. The frequency of adverse drug reactions (ADRs) to intravenous mistletoe applications was calculated and compared to ADR data from a study on subcutaneous applications. Results. Of 475 cancer patients who received intravenous infusions of Helixor, Abnoba viscum, or Iscador mistletoe preparations, 22 patients (4.6%) reported 32 ADRs of mild (59.4%) or moderate severity (40.6%). No serious ADRs occurred. ADRs were more frequently reported to i.v. mistletoe administered alone (4.3%), versus prior to chemotherapy (1.6%). ADR frequency differed with respect to preparation type, with Iscador preparations showing a higher relative frequency, compared to Abnoba viscum and Helixor. Overall, patients were almost two times less likely to experience an ADR to intravenous compared to subcutaneous application of mistletoe. Conclusion. Intravenous mistletoe therapy was found to be safe and prospective studies for efficacy are recommended. PMID- 24955102 TI - Auraptene in the Peels of Citrus kawachiensis (Kawachi Bankan) Ameliorates Lipopolysaccharide-Induced Inflammation in the Mouse Brain. AB - Examination of the dried peel powder of Citrus kawachiensis, one of the citrus products of Ehime, Japan, showed that it contained naringin (NGIN; 44.02 +/- 0.491 mg/g), narirutin (NRTN; 4.46 +/- 0.0563 mg/g), auraptene (AUR; 4.07 +/- 0.033 mg/g), and 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF; 0.27 +/- 0.0039 mg/g). When this dried peel powder was orally preadministered at the dose of 1.2 or 2.4 g/kg/day for 7 days into lipopolysaccharide- (LPS-) injected mice, an animal model of systemic inflammation, it suppressed (1) LPS-induced loss of body weight and abnormal behavior in the open field, (2) LPS-induced activation of microglia and astrocytes in the hippocampus, and (3) LPS-induced expression of cyclooxygenase (COX)-2, which were coexpressed in astrocytes of these mice. When NGIN or AUR was preadministered to LPS-injected mice at an amount similar to that in the peel powder, AUR, but not NGIN, had the ability to suppress the LPS induced inflammation in the brain of these model mice. The dried powder of flavedo tissue (the outer colored layer of the mesocarp of a citrus fruit) and juice, which contained sufficient amounts of AUR, also had anti-inflammatory effect. These results suggest that AUR was the main ingredient responsible for the anti-inflammatory property of the dried peels of C. kawachiensis. PMID- 24955103 TI - Guanxinkang Decoction Exerts Its Antiatherosclerotic Effect Partly through Inhibiting the Endoplasmic Reticulum Stress. AB - Purpose. To investigate the antiatherosclerotic effect of Guanxinkang (GXK) decoction on the apoptosis, mitochondrial membrane potential (MMP), and endoplasmic reticulum stress (ERS) of human umbilical vein endothelial cells (HUVEC) pretreated with homocysteinemia (HCY). Materials and Methods. HUVEC were randomly divided into 5 groups: (1) blank control group (control), (2) model control group (model), (3) GXK low dose group, (4) GXK medium dose group, and (5) GXK high dose group. For the three GXK groups, HCY was given to reach the concentration of 3.0 mmol/L after HUVEC had been incubated with rabbit serum containing GXK for two hours. At 3, 6, 12, and 24 h after HCY had been incubated with the cells, the HUVEC were collected for test of the apoptosis rate, MMP, and GRP78 protein (reflecting ERS). Results. In the model control group, the apoptosis rate and GRP 78 protein expression of HUVEC significantly increased (P < 0.05), while MMP significantly decreased (P < 0.05) compared with the blank control group. After GXK treatment of medium and high doses, the apoptosis rate and the GRP 78 protein expression significantly (P < 0.05) decreased, while MMP significantly increased (P < 0.05) in a time-dependent manner compared with the model control group. Conclusion. GXK can antagonize the injury of HUVEC caused by HCY and the antagonism effect increases with the concentration and treatment duration of GXK, with the possible mechanism of GXK antagonism being through inhibiting ERS caused by HCY. PMID- 24955104 TI - A Randomized Trial of Chinese Diaoshi Jifa on Treatment of Dizziness in Meniere's Disease. AB - Background. Meniere's disease is characterized by refractory dizziness and hearing disturbance. We aimed to investigate the efficacy and tolerance of Diaoshi Jifa, a Chinese hand skill for treating dizziness in Meniere's disease. Methods. An open-labeled, randomized, controlled intervention trial was conducted. Twenty-seven patients diagnosed with Meniere's disease were randomly allocated to control group or experimental group. Both groups were assessed by DHI (dizziness handicap inventory (DHI)) questionnaire score before and within 24 hours of receiving treatment, respectively. Results. Twenty-six participants completed the study, and no adverse event was reported due to Diaoshi Jifa treatment. The difference in the DHI scores between baseline and posttreatment reached significant difference in both groups (63.88 +/- 19.94 versus 10.25 +/- 9.77 and 54.36 +/- 17.97 versus 49.6 +/- 20.50). Significant difference in DHI scores was observed between the two groups after treatment (10.25 +/- 9.77 versus 49.6 +/- 20.50). Further investigation of DHI subscales in the experimental group revealed significant improvement posttreatment in the physical domain, functional domain, and emotional domain. Although higher rate of improvement in the emotional domain compared to physical or functional domains was found, the difference was not statistically significant. Conclusions. Diaoshi Jifa might be a fast, effective, and well-tolerated method for alleviating dizziness in Meniere's disease. PMID- 24955105 TI - Identification of SNP barcode biomarkers for genes associated with facial emotion perception using particle swarm optimization algorithm. AB - BACKGROUND: Facial emotion perception (FEP) can affect social function. We previously reported that parts of five tested single-nucleotide polymorphisms (SNPs) in the MET and AKT1 genes may individually affect FEP performance. However, the effects of SNP-SNP interactions on FEP performance remain unclear. METHODS: This study compared patients with high and low FEP performances (n = 89 and 93, respectively). A particle swarm optimization (PSO) algorithm was used to identify the best SNP barcodes (i.e., the SNP combinations and genotypes that revealed the largest differences between the high and low FEP groups). RESULTS: The analyses of individual SNPs showed no significant differences between the high and low FEP groups. However, comparisons of multiple SNP-SNP interactions involving different combinations of two to five SNPs showed that the best PSO generated SNP barcodes were significantly associated with high FEP score. The analyses of the joint effects of the best SNP barcodes for two to five interacting SNPs also showed that the best SNP barcodes had significantly higher odds ratios (2.119 to 3.138; P < 0.05) compared to other SNP barcodes. In conclusion, the proposed PSO algorithm effectively identifies the best SNP barcodes that have the strongest associations with FEP performance. CONCLUSIONS: This study also proposes a computational methodology for analyzing complex SNP SNP interactions in social cognition domains such as recognition of facial emotion. PMID- 24955106 TI - Clostridium difficile infection in older adults. AB - Clostridium difficile infection, the most frequent cause of nosocomial diarrhea, disproportionately affects older adults. The two most important risk factors for developing C. difficile infection are antimicrobial exposure and age >65 years old. Risk factors specific to older adults are frequent interactions with healthcare systems and age-related changes in physiology, including immune senescence and changes to the gut microbiome. Metronidazole and oral vancomcyin are the mainstays of conventional treatment for C. difficile infection. Alternative therapies include fidaxomicin, a narrow-spectrum macrocyclic antibiotic, and fectal bacteriotherapy, which offers an excellent therapeutic outcome. Strategies to prevent C. difficile infections include enhanced infection control measures and reducing inappropriate antimicrobial use through stewardship. PMID- 24955108 TI - Protocol: a beginner's guide to the analysis of RNA-directed DNA methylation in plants. AB - BACKGROUND: DNA methylation is a conserved epigenetic mark that controls genome stability, development and environmental responses in many eukaryotes. DNA methylation can be guided by non-coding RNAs that include small interfering RNAs and scaffold RNAs. Although measurement of DNA methylation and regulatory non coding RNAs is desirable for many biologists who are interested in exploring epigenetic regulation in their areas, conventional methods have limitations and are technically challenging. For instance, traditional siRNA detection through RNA hybridization requires relatively large amount of small RNAs and involves radioactive isotopes. An alternative approach is RT-qPCR that employs stem loop primers during reverse transcription; however, it requires a prerequisite that the exact sequences of siRNAs should be known. RESULTS: By using the model organism Arabidopsis thaliana, we developed an easy-to-follow, integrative procedure for time-efficient, quantitative measurement of DNA methylation, small interfering RNAs, and scaffold RNAs. Starting with simplified nucleic acid manipulation, we examined DNA methylation levels by using Chop PCR (methylation sensitive enzyme digestion followed by PCR), which allowed for fast screening for DNA methylation mutants without the need of transgenic reporters. We deployed a simple bioinformatics method for mining published small RNA databases, in order to obtain the nucleotide (nt) sequences of individual 24nt siRNAs within the regions of interest. The protocol of commercial TaqMan Small RNA Assay was subsequently optimized for reliable quantitative detection of individual siRNAs. We used nested qPCR to quantify scaffold RNAs that are of low abundance and without Poly-A tails. In addition, nuclei fraction enables separation of chromatin-associated scaffold RNAs from their cognate non-scaffold transcripts that have been released from chromatin. CONCLUSIONS: We have developed a procedure for quantitative investigations on nucleic acids that are core components of RNA-directed DNA methylation. Our results not only demonstrated the efficacy of this procedure, but also provide lists of methylation-sensitive restriction enzymes, novel DNA methylation marker loci, and related siRNA sequences, all of which can be valuable for future epigenetic studies. Importantly, step-by-step protocols are provided in details such that the approaches can be easily followed by biologists with little experience in epigenetics. PMID- 24955107 TI - The inflammasome as a target of modulation by DNA viruses. AB - The cellular innate immune response represents the initial reaction of a host against infecting pathogens. Host cells detect incoming microbes by way of a large and expanding array of receptors that react with evolutionarily conserved molecular patterns exhibited by microbial intruders. These receptors are responsible for initiating signaling that leads to both transcriptional activation of immunologically important genes as well as protease-dependent processing of cellular proteins. The inflammasome refers to a protein complex that functions as an activation platform for the cysteine protease caspase-1, which then processes inflammatory molecules such as IL-1beta and IL-18 into functional forms. Assembly of this complex is triggered following receptor mediated detection of pathogen-associated molecules. Receptors have been identified that are essential to inflammasome activation in response to numerous molecular patterns including virus-associated molecules such as DNA. In fact, the importance of cytoplasmic DNA as an immune stimulus is exemplified by the existence of at least nine distinct cellular receptors capable of initiating innate reactivity in response to this molecule. Viruses that employ DNA as genomic material include herpesviruses, poxviruses and adenoviruses. Each has been described as capable of inducing inflammasome-mediated activity. Interestingly, however, the cellular molecules responsible for these responses appear to vary according to host species, cell type and even viral strain. Secretion of IL-1beta and IL-18 are important components of antimicrobial immunity and, as a result, pathogens have evolved factors to evade or counteract this response. This includes DNA-based viruses, many of which encode multiple redundant counteractive molecules. However, it is clear that such phenotypes are only beginning to be uncovered. The purpose of this review is to describe what is known regarding the activation of inflammasome-mediated processes in response to infection with well-examined families of DNA viruses and to discuss characterized mechanisms of manipulation and neutralization of inflammasome-dependent activity. This review aims to shed light on the biologically important phenomena regarding this virus-host interaction and to highlight key areas where important information is lacking. PMID- 24955109 TI - Software for pre-processing Illumina next-generation sequencing short read sequences. AB - BACKGROUND: When compared to Sanger sequencing technology, next-generation sequencing (NGS) technologies are hindered by shorter sequence read length, higher base-call error rate, non-uniform coverage, and platform-specific sequencing artifacts. These characteristics lower the quality of their downstream analyses, e.g. de novo and reference-based assembly, by introducing sequencing artifacts and errors that may contribute to incorrect interpretation of data. Although many tools have been developed for quality control and pre-processing of NGS data, none of them provide flexible and comprehensive trimming options in conjunction with parallel processing to expedite pre-processing of large NGS datasets. METHODS: We developed ngsShoRT (next-generation sequencing Short Reads Trimmer), a flexible and comprehensive open-source software package written in Perl that provides a set of algorithms commonly used for pre-processing NGS short read sequences. We compared the features and performance of ngsShoRT with existing tools: CutAdapt, NGS QC Toolkit and Trimmomatic. We also compared the effects of using pre-processed short read sequences generated by different algorithms on de novo and reference-based assembly for three different genomes: Caenorhabditis elegans, Saccharomyces cerevisiae S288c, and Escherichia coli O157 H7. RESULTS: Several combinations of ngsShoRT algorithms were tested on publicly available Illumina GA II, HiSeq 2000, and MiSeq eukaryotic and bacteria genomic short read sequences with the focus on removing sequencing artifacts and low quality reads and/or bases. Our results show that across three organisms and three sequencing platforms, trimming improved the mean quality scores of trimmed sequences. Using trimmed sequences for de novo and reference-based assembly improved assembly quality as well as assembler performance. In general, ngsShoRT outperformed comparable trimming tools in terms of trimming speed and improvement of de novo and reference-based assembly as measured by assembly contiguity and correctness. CONCLUSIONS: Trimming of short read sequences can improve the quality of de novo and reference-based assembly and assembler performance. The parallel processing capability of ngsShoRT reduces trimming time and improves the memory efficiency when dealing with large datasets. We recommend combining sequencing artifacts removal, and quality score based read filtering and base trimming as the most consistent method for improving sequence quality and downstream assemblies. ngsShoRT source code, user guide and tutorial are available at http://research.bioinformatics.udel.edu/genomics/ngsShoRT/. ngsShoRT can be incorporated as a pre-processing step in genome and transcriptome assembly projects. PMID- 24955110 TI - BatTool: an R package with GUI for assessing the effect of White-nose syndrome and other take events on Myotis spp. of bats. AB - BACKGROUND: Myotis species of bats such as the Indiana Bat and Little Brown Bat are facing population declines because of White-nose syndrome (WNS). These species also face threats from anthropogenic activities such as wind energy development. Population models may be used to provide insights into threats facing these species. We developed a population model, BatTool, as an R package to help decision makers and natural resource managers examine factors influencing the dynamics of these species. The R package includes two components: 1) a deterministic and stochastic model that are accessible from the command line and 2) a graphical user interface (GUI). RESULTS: BatTool is an R package allowing natural resource managers and decision makers to understand Myotis spp. population dynamics. Through the use of a GUI, the model allows users to understand how WNS and other take events may affect the population. The results are saved both graphically and as data files. Additionally, R-savvy users may access the population functions through the command line and reuse the code as part of future research. This R package could also be used as part of a population dynamics or wildlife management course. CONCLUSIONS: BatTool provides access to a Myotis spp. population model. This tool can help natural resource managers and decision makers with the Endangered Species Act deliberations for these species and with issuing take permits as part of regulatory decision making. The tool is available online as part of this publication. PMID- 24955111 TI - Trauma surgery associations and societies: which organizations match your goals? AB - This focused summary is a multi-institutional, multi-national, and multi generational project designed to briefly summarize current academic trauma societies for both trainees and faculty alike. The co-authorship is composed of former and/or current presidents from most major trauma organizations. It has particular relevance to trainees and/or recent graduates attempting to navigate the multitude of available trauma organizations. PMID- 24955113 TI - Metataxonomic profiling and prediction of functional behaviour of wheat straw degrading microbial consortia. AB - BACKGROUND: Mixed microbial cultures, in which bacteria and fungi interact, have been proposed as an efficient way to deconstruct plant waste. The characterization of specific microbial consortia could be the starting point for novel biotechnological applications related to the efficient conversion of lignocellulose to cello-oligosaccharides, plastics and/or biofuels. Here, the diversity, composition and predicted functional profiles of novel bacterial fungal consortia are reported, on the basis of replicated aerobic wheat straw enrichment cultures. RESULTS: In order to set up biodegradative microcosms, microbial communities were retrieved from a forest soil and introduced into a mineral salt medium containing 1% of (un)treated wheat straw. Following each incubation step, sequential transfers were carried out using 1 to 1,000 dilutions. The microbial source next to three sequential batch cultures (transfers 1, 3 and 10) were analyzed by bacterial 16S rRNA gene and fungal ITS1 pyrosequencing. Faith's phylogenetic diversity values became progressively smaller from the inoculum to the sequential batch cultures. Moreover, increases in the relative abundances of Enterobacteriales, Pseudomonadales, Flavobacteriales and Sphingobacteriales were noted along the enrichment process. Operational taxonomic units affiliated with Acinetobacter johnsonii, Pseudomonas putida and Sphingobacterium faecium were abundant and the underlying strains were successfully isolated. Interestingly, Klebsiella variicola (OTU1062) was found to dominate in both consortia, whereas K. variicola-affiliated strains retrieved from untreated wheat straw consortia showed endoglucanase/xylanase activities. Among the fungal players with high biotechnological relevance, we recovered members of the genera Penicillium, Acremonium, Coniochaeta and Trichosporon. Remarkably, the presence of peroxidases, alpha-L-fucosidases, beta-xylosidases, beta-mannases and beta-glucosidases, involved in lignocellulose degradation, was indicated by predictive bacterial metagenome reconstruction. Reassuringly, tests for specific (hemi)cellulolytic enzymatic activities, performed on the consortial secretomes, confirmed the presence of such gene functions. CONCLUSION: In an in depth characterization of two wheat straw degrading microbial consortia, we revealed the enrichment and selection of specific bacterial and fungal taxa that were presumably involved in (hemi) cellulose degradation. Interestingly, the microbial community composition was strongly influenced by the wheat straw pretreatment. Finally, the functional bacterial-metagenome prediction and the evaluation of enzymatic activities (at the consortial secretomes) revealed the presence and enrichment of proteins involved in the deconstruction of plant biomass. PMID- 24955112 TI - The contribution of cellulosomal scaffoldins to cellulose hydrolysis by Clostridium thermocellum analyzed by using thermotargetrons. AB - BACKGROUND: Clostridium thermocellum is a thermophilic anaerobic bacterium that degrades cellulose by using a highly effective cellulosome, a macromolecular complex consisting of multiple cellulose degrading enzymes organized and attached to the cell surface by non-catalytic scaffoldins. However, due largely to lack of efficient methods for genetic manipulation of C. thermocellum, it is still unclear how the different scaffoldins and their functional modules contribute to cellulose hydrolysis. RESULTS: We constructed C. thermocellum mutants with the primary scaffoldin CipA (cellulosome-integrating protein A) truncated at different positions or lacking four different secondary scaffoldins by using a newly developed thermotargetron system, and we analyzed cellulose hydrolysis, cellulosome formation, and cellulose binding of the mutants. A CipA truncation that deletes six type I cohesin modules, which bind cellulolytic enzymes, decreased cellulose hydrolysis rates by 46%, and slightly longer truncations that also delete the carbohydrate binding module decreased rates by 89 to 92%, indicating strong cellulosome-substrate synergy. By contrast, a small CipA truncation that deletes only the C-terminal type II dockerin (XDocII) module detached cellulosomes from the cells, but decreased cellulose hydrolysis rates by only 9%, suggesting a relatively small contribution of cellulosome-cell synergy. Disruptants lacking any of four different secondary scaffoldins (OlpB, 7CohII, Orf2p, or SdbA) showed moderately decreased cellulose hydrolysis rates, suggesting additive contributions. Surprisingly, the CipA-DeltaXDocII mutant, which lacks cell-associated polycellulosomes, adheres to cellulose almost as strongly as wild-type cells, revealing an alternate, previously unknown cellulose binding mechanism. CONCLUSIONS: Our results emphasize the important role of cellulosome-substrate synergy in cellulose degradation, demonstrate a contribution of secondary scaffoldins, and suggest a previously unknown, non cellulosomal system for binding insoluble cellulose. Our findings provide new insights into cellulosome function and impact genetic engineering of microorganisms to enhance bioconversions of cellulose substrates. PMID- 24955116 TI - Screening for proteinuria in 'at-risk' patients with spinal cord injuries: lessons learnt from failure. AB - Spinal cord injury patients may develop proteinuria as a result of glomerulosclerosis due to urosepsis, hydronephrosis, vesicoureteric reflux, and renal calculi. Proteinuria in turn contributes to progression of kidney disease. We report one paraplegic and two tetraplegic patients, who developed recurrent urine infections, urinary calculi, and hydronephrosis. These patients required several urological procedures (nephrostomy, cystoscopy and ureteric stenting, ureteroscopy and lithotripsy, extracorporeal shock wave lithotripsy). These patients had not received antimuscarinic drugs nor had they undergone video urodynamics. Proteinuria was detected only at a late stage, as testing for proteinuria was not performed during follow-up visits. Urine electrophoresis showed no monoclonal bands in any; Serum glomerular basement membrane antibody screen was negative. Serum neutrophil cytoplasmic antibodies screen by fluorescence was negative. All patients were prescribed Ramipril 2.5 mg daily and there was no further deterioration of renal function. Spinal cord injury patients, who did not receive antimuscarinic drugs to reduce intravesical pressure, are at high risk for developing reflux nephropathy. When such patients develop glomerulosclerosis due to recurrent urosepsis, renal calculi, or hydronephrosis, risk of proteinuria is increased further. TAKE HOME MESSAGE: (1) Screening for proteinuria should be performed regularly in the 'at-risk' patients. (2) In the absence of other renal diseases causing proteinuria, spinal cord injury patients with significant proteinuria may be prescribed angiotensin converting enzyme inhibitor or angiotensin-II receptor antagonist to slow progression of chronic renal disease and reduce the risk of cardiovascular mortality. PMID- 24955114 TI - High-throughput prediction of eucalypt lignin syringyl/guaiacyl content using multivariate analysis: a comparison between mid-infrared, near-infrared, and Raman spectroscopies for model development. AB - BACKGROUND: In order to rapidly and efficiently screen potential biofuel feedstock candidates for quintessential traits, robust high-throughput analytical techniques must be developed and honed. The traditional methods of measuring lignin syringyl/guaiacyl (S/G) ratio can be laborious, involve hazardous reagents, and/or be destructive. Vibrational spectroscopy can furnish high throughput instrumentation without the limitations of the traditional techniques. Spectral data from mid-infrared, near-infrared, and Raman spectroscopies was combined with S/G ratios, obtained using pyrolysis molecular beam mass spectrometry, from 245 different eucalypt and Acacia trees across 17 species. Iterations of spectral processing allowed the assembly of robust predictive models using partial least squares (PLS). RESULTS: The PLS models were rigorously evaluated using three different randomly generated calibration and validation sets for each spectral processing approach. Root mean standard errors of prediction for validation sets were lowest for models comprised of Raman (0.13 to 0.16) and mid-infrared (0.13 to 0.15) spectral data, while near-infrared spectroscopy led to more erroneous predictions (0.18 to 0.21). Correlation coefficients (r) for the validation sets followed a similar pattern: Raman (0.89 to 0.91), mid-infrared (0.87 to 0.91), and near-infrared (0.79 to 0.82). These statistics signify that Raman and mid-infrared spectroscopy led to the most accurate predictions of S/G ratio in a diverse consortium of feedstocks. CONCLUSION: Eucalypts present an attractive option for biofuel and biochemical production. Given the assortment of over 900 different species of Eucalyptus and Corymbia, in addition to various species of Acacia, it is necessary to isolate those possessing ideal biofuel traits. This research has demonstrated the validity of vibrational spectroscopy to efficiently partition different potential biofuel feedstocks according to lignin S/G ratio, significantly reducing experiment and analysis time and expense while providing non-destructive, accurate, global, predictive models encompassing a diverse array of feedstocks. PMID- 24955118 TI - Non-invasive prenatal testing (NIPT): a better option for patients. PMID- 24955117 TI - Non-invasive prenatal diagnosis using massively parallel sequencing - first experience in Germany. PMID- 24955115 TI - Incidence and root causes of cancellations for elective orthopaedic procedures: a single center experience of 17,625 consecutive cases. AB - BACKGROUND: The purpose of the Swedish public health-care system is to provide care on equal terms for all citizens. In this, as in most other systems where taxes and/or insurances pay for most of the care, normal market forces are set aside at least in part. At times, this has, for example, resulted in long waiting lists, particularly in terms of elective orthopaedic surgery, with several negative consequences, such as cancellations of planned surgery. METHODS: The main purpose of this retrospective observational single center study was to evaluate and describe the number and reasons for cancellations in elective orthopaedic surgery. Studied were all the elective patients scheduled for joint replacement, arthroscopy and foot & ankle surgery, January 1, 2007 to December 31, 2011, whose procedure was cancelled at least once. RESULTS: Of all 17,625 patients scheduled for elective surgery 6,911 (39%) received at least one, some several cancellations. The most common reason for cancelling a planned surgery was different patient-related factors 3,293 (33%). Cancellations due to treatment guarantee legislation reached 2,885 (29%) and 1,181 (12%) of the cancellations were related to incomplete pre-operative preparation of the patients. Organisational reasons were the cause of approximately 869 (9%) of the cancellations. CONCLUSIONS: In this study of patients waiting for elective orthopaedic surgery 6,911(39%) had their surgical procedure cancelled at least once, some several times. It appears that it should be possible to eliminate many of these cancellations, while others are unavoidable or caused by factors outside the responsibility of the individual clinic or even hospital. One possible way of influencing the high rate of cancellations might be to change the view of the patients and involve them in the overall planning of the care process. PMID- 24955119 TI - Birth defects: etiology to prevention. PMID- 24955120 TI - Enzyme replacement therapy for lysosomal storage disorders in India. PMID- 24955121 TI - Clinical utility and dilemmas of SNP microarray testing. PMID- 24955122 TI - Current status of sickle cell disease in India: how can you attenuate? PMID- 24955123 TI - Chromosomal instability and molecular mutations in multi spectrum disease of Fanconi anemia. PMID- 24955124 TI - Unlocking the chemistry of bile acids for cancer therapeutics. PMID- 24955125 TI - Challenges in prenatal and pre-implantation genetic diagnosis studies. PMID- 24955126 TI - STR Markers in clinics: a rapid prenatal diagnosis by quantitative fluorescent pcr for aneuploidies. PMID- 24955127 TI - An empirical assay for assessing genomic sensitivity and for improving cancer diagnostics. PMID- 24955128 TI - Maximum toe flexor muscle strength and quantitative analysis of human plantar intrinsic and extrinsic muscles by a magnetic resonance imaging technique. AB - BACKGROUND: The aims of this study were to investigate the relationships between the maximum isometric toe flexor muscle strength (TFS) and cross-sectional area (CSA) of the plantar intrinsic and extrinsic muscles and to identify the major determinant of maximum TFS among CSA of the plantar intrinsic and extrinsic muscles. METHODS: Twenty six young healthy participants (14 men, 12 women; age, 20.4 +/- 1.6 years) volunteered for the study. TFS was measured by a specific designed dynamometer, and CSA of plantar intrinsic and extrinsic muscles were measured using magnetic resonance imaging (MRI). To measure TFS, seated participants optimally gripped the bar with their toes and exerted maximum force on the dynamometer. For each participant, the highest force produced among three trials was used for further analysis. To measure CSA, serial T1-weighted images were acquired. RESULTS: TFS was significantly correlated with CSA of the plantar intrinsic and extrinsic muscles. Stepwise multiple linear regression analyses identified that the major determinant of TFS was CSA of medial parts of plantar intrinsic muscles (flexor hallucis brevis, flexor digitorum brevis, quadratus plantae, lumbricals and abductor hallucis). There was no significant difference between men and women in TFS/CSA. CONCLUSIONS: CSA of the plantar intrinsic and extrinsic muscles is one of important factors for determining the maximum TFS in humans. PMID- 24955129 TI - The effect of foot orthoses and in-shoe wedges during cycling: a systematic review. AB - BACKGROUND: The use of foot orthoses and in-shoe wedges in cycling are largely based on theoretical benefits and anecdotal evidence. This review aimed to systematically collect all published research on this topic, critically evaluate the methods and summarise the findings. METHODS: STUDY INCLUSION CRITERIA WERE: all empirical studies that evaluated the effects of foot orthoses or in-shoe wedges on cycling; outcome measures that investigated physiological parameters, kinematics and kinetics of the lower limb, and power; and, published in English. Studies were located by data-base searching (Medline, CINAHL, Embase and SPORTDiscus) and hand-searching in February 2014. Selected studies were assessed for methodological quality using a modified Quality Index. Data were synthesised descriptively. Meta-analysis was not performed as the included studies were not sufficiently homogeneous to provide a meaningful summary. RESULTS: Six studies were identified as meeting the eligibility criteria. All studies were laboratory based and used a repeated measures design. The quality of the studies varied, with Quality Index scores ranging from 7 to 10 out of 14. Five studies investigated foot orthoses and one studied in-shoe wedges. Foot orthoses were found to increase contact area in the midfoot, peak pressures under the hallux and were perceived to provide better arch support, compared to a control. With respect to physiological parameters, contrasting findings have been reported regarding the effect foot orthoses have on oxygen consumption. Further, foot orthoses have been shown to not provide effects on lower limb kinematics and perceived comfort. Both foot orthoses and in-shoe wedges have been shown to provide no effect on power. CONCLUSION: In general, there is limited high-quality research on the effects foot orthoses and in-shoe wedges provide during cycling. At present, there is some evidence that during cycling foot orthoses: increase contact area under the foot and increase plantar pressures under the hallux, but provide no gains in power. Based on available evidence, no definitive conclusions can be made about the effects foot orthoses have on lower limb kinematics and oxygen consumption, and the effect in-shoe wedges have on power during cycling. Future well-designed studies on this topic are warranted. PMID- 24955130 TI - Changes in granulosa cells gene expression associated with growth, plateau and atretic phases in medium bovine follicles. AB - BACKGROUND: The objective of this study was to build the transcriptomic profile of granulosa cells originating from follicles 6 to 9 mm in diameter in dairy cattle using microarrays. METHODS: Granulosa cells originating from three different phases of antral follicle growth were compared: growing (G), plateau (P) and atresia (A), as categorized by flow cytometry profiles of DNA. The growing and atretic conditions were each hybridized against the plateau condition as a reference in order to understand the specific biological mechanisms modulated in this class of follicles. RESULTS: 2,942 genes were differentially expressed (P < 0.05) in P vs. G and 1,974 in A vs. P. A clear segregation of the 3 phases was confirmed by between group analysis (BGA). The first characteristic of the plateau phase is the activation of the upstream regulators TP53 and PTEN which participate in the reduction of cell growth through MYC, FOS and E2F1-2-3. We also observed the down-regulation of steroidogenesis genes: CYP11A1 and CYP19A1, in the granulosa cells of the plateau phase relative to the growth phase. On the other hand, the A vs. P contrast showed up-regulation of multiple transcripts associated to apoptosis: CCT2, DAB2, DSG2 and TGM2. CONCLUSIONS: This study offers multiple candidate genes to be further studied in order to elucidate their role in the modulation of follicular development and, ultimately, of oocyte quality. PMID- 24955131 TI - Evaluation of the ovarian reserve function in patients with metabolic syndrome in relation to healthy controls and different age groups. AB - OBJECTIVE: To evaluate the ovarian reserve function in female patients with metabolic syndrome (MetS). METHODS: This study evaluated 136 subjects, 67 with MetS and 69 controls. Subjects were divided into three age groups. Group I included 49 subjects aged 20-29 years, 22 with MetS and 27 controls; group II included 45 subjects aged 30-39 years, 22 with MetS and 23 controls; and group III included 42 subjects aged 40-49 years, 23 with MetS and 19 controls. Demographic characteristics, anthropometrics, blood biochemistry, and gonadotrophic hormones were compared as total ovarian volume and antral follicle count on ovarian transvaginal ultrasonography. RESULTS: Serum levels of FSH, LH, E2 and progesterone were similar in the MetS and control groups, while testosterone levels were significantly higher in MetS patients than controls, both in the overall population (p = 0.024) and in those aged 20-29 years (p = 0.018). Total ovarian volume was significantly lower in MetS patients than controls, in both the overall population (p = 0.003) and those aged 20-29 years (p = 0.018), while antral follicle counts were similar. Ovarian volume correlated positively with antral follicle count (AFC) (r = 0.37; p < 0.001) and negatively with age (r = 0.34; p < 0.001) and FSH concentration (r = 0.21; p = 0.013). AFC was negatively correlated with age (r = 0.36; p < 0.001). CONCLUSION: Ovarian reserve function is significantly lower in MetS patients than in healthy control subjects, particularly in women aged 20-29 years. PMID- 24955132 TI - New construction of an animal model for the orthotopic transplantation of an ovarian tumor. AB - A new technique has successfully established the non-obese diabetic/severely combined immunodeficiency (NOD/SCID) mouse model of ovarian cancer. Under 4% chloral hydrate (0.1 mL/g dose) anesthesia, female mice were inoculated with tumor-cell suspension. The expression rate of OVCAR3 to CA125 was assessed using flow cytometry. The inoculated site was hand palpated and the signs and symptoms related to tumor growth were observed with the naked eye. The allophycocyanin (APC) indirectly labeled mouse-antihuman CA125 and fluorescein isothiocyanate (FITC)-labeled anti-mouse MHC Class I molecule (H-2K(d)/H-2D(d)) were observed using a confocal laser scanning microscope. The animal model of ovarian cancer constructed using this method can more directly reflect the characteristics of cancer cells. It provides reliable experimental results and presents a technical platform for the research of ovarian cancer stem cells. PMID- 24955135 TI - Efficient enumeration of monocyclic chemical graphs with given path frequencies. AB - BACKGROUND: The enumeration of chemical graphs (molecular graphs) satisfying given constraints is one of the fundamental problems in chemoinformatics and bioinformatics because it leads to a variety of useful applications including structure determination and development of novel chemical compounds. RESULTS: We consider the problem of enumerating chemical graphs with monocyclic structure (a graph structure that contains exactly one cycle) from a given set of feature vectors, where a feature vector represents the frequency of the prescribed paths in a chemical compound to be constructed and the set is specified by a pair of upper and lower feature vectors. To enumerate all tree-like (acyclic) chemical graphs from a given set of feature vectors, Shimizu et al. and Suzuki et al. proposed efficient branch-and-bound algorithms based on a fast tree enumeration algorithm. In this study, we devise a novel method for extending these algorithms to enumeration of chemical graphs with monocyclic structure by designing a fast algorithm for testing uniqueness. The results of computational experiments reveal that the computational efficiency of the new algorithm is as good as those for enumeration of tree-like chemical compounds. CONCLUSIONS: We succeed in expanding the class of chemical graphs that are able to be enumerated efficiently. PMID- 24955133 TI - Arrested human embryos are more likely to have abnormal chromosomes than developing embryos from women of advanced maternal age. AB - BACKGROUND: Aneuploidy is one of the major factors that result in low efficiency in human infertility treatment by in vitro fertilization (IVF). The development of DNA microarray technology allows for aneuploidy screening by analyzing all 23 pairs of chromosomes in human embryos. All chromosome screening for aneuploidy is more accurate than partial chromosome screening, as errors can occur in any chromosome. Currently, chromosome screening for aneuploidy is performed in developing embryos, mainly blastocysts. It has not been performed in arrested embryos and/or compared between developing embryos and arrested embryos from the same IVF cycle. METHODS: The present study was designed to examine all chromosomes in blastocysts and arrested embryos from the same cycle in patients of advanced maternal ages. Embryos were produced by routine IVF procedures. A total of 90 embryos (45 blastocysts and 45 arrested embryos) from 17 patients were biopsied and analyzed by the Agilent DNA array platform. RESULTS: It was found that 50% of the embryos developed to blastocyst stage; however, only 15.6% of the embryos (both blastocyst and arrested) were euploid, and most (84.4%) of the embryos had chromosomal abnormalities. Further analysis indicated that 28.9% of blastocysts were euploid and 71.1% were aneuploid. By contrast, only one (2.2%) arrested embryo was euploid while others (97.8%) were aneuploid. The prevalence of multiple chromosomal abnormalities in the aneuploid embryos was also higher in the arrested embryos than in the blastocysts. CONCLUSIONS: These results indicate that high proportions of human embryos from patients of advanced maternal age are aneuploid, and the arrested embryos are more likely to have abnormal chromosomes than developing embryos. PMID- 24955134 TI - iDrug: a web-accessible and interactive drug discovery and design platform. AB - BACKGROUND: The progress in computer-aided drug design (CADD) approaches over the past decades accelerated the early-stage pharmaceutical research. Many powerful standalone tools for CADD have been developed in academia. As programs are developed by various research groups, a consistent user-friendly online graphical working environment, combining computational techniques such as pharmacophore mapping, similarity calculation, scoring, and target identification is needed. RESULTS: We presented a versatile, user-friendly, and efficient online tool for computer-aided drug design based on pharmacophore and 3D molecular similarity searching. The web interface enables binding sites detection, virtual screening hits identification, and drug targets prediction in an interactive manner through a seamless interface to all adapted packages (e.g., Cavity, PocketV.2, PharmMapper, SHAFTS). Several commercially available compound databases for hit identification and a well-annotated pharmacophore database for drug targets prediction were integrated in iDrug as well. The web interface provides tools for real-time molecular building/editing, converting, displaying, and analyzing. All the customized configurations of the functional modules can be accessed through featured session files provided, which can be saved to the local disk and uploaded to resume or update the history work. CONCLUSIONS: iDrug is easy to use, and provides a novel, fast and reliable tool for conducting drug design experiments. By using iDrug, various molecular design processing tasks can be submitted and visualized simply in one browser without installing locally any standalone modeling softwares. iDrug is accessible free of charge at http://lilab.ecust.edu.cn/idrug. PMID- 24955137 TI - Measurement of DCF fluorescence as a measure of reactive oxygen species in murine islets of Langerhans. AB - In islets of Langerhans, oxidative stress induced by reactive oxygen species (ROS) is thought to be critically involved in beta-cell dysfunction during the development of diabetes. However, ROS have also been hypothesized to play a role in cellular signalling. To aid in delineating the effects of ROS in living islets of Langerhans, the endocrine portion of the pancreas that contain beta-cells, we sought to develop a robust and reproducible protocol to measure these species using the fluorescent dye, 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA). The protocol that was developed minimized photobleaching and leakage of H2DCF from murineislets and utilized a normalization procedure to further reduce experimental variability. The method allowed for ~25 min of DCF measurement in living islets. We used the developed protocol to compare DCF fluorescence from batches of islets incubated in varying glucose concentrations and observed ~1.5 fold higher fluorescence signals in 3 vs. 20 mM glucose. The effects of diazoxide, which clamps open K+ATP channels reducing intracellular [Ca2+] ([Ca2+]i) without affecting glucose metabolism, were also investigated. The presence of diazoxide increased DCF fluorescence at all glucose concentrations tested while addition of 30 mM K+ to increase [Ca2+]i reduced the fluorescence by ~15%. With the developed protocol, all experimental methods tested to increase [Ca2+]i resulted in a decrease in DCF fluorescence, potentially indicating involvement of ROS in intracellular signalling cascades. PMID- 24955136 TI - Precocious markers of cardiovascular risk and vascular damage in apparently healthy women with previous gestational diabetes. AB - Previous gestational diabetes mellitus (pGDM) indicates future risk for type 2 diabetes (T2DM). Insulin resistance (IR) may precede T2DM in many years and is associated with an increased risk for cardiovascular diseases. AIM: This study aims to identify endothelial dysfunction and cardiovascular risk factors in women with pGDM. METHODS: This cross-sectional analysis included 45 non diabetic women, 20 pGDM and 25 controls, at least one year after delivery. Body mass index (BMI), abdominal circumference (AC), blood pressure, serum lipids, liver enzymes, uric acid, nonesterified fatty acids, C-reactive protein and plasma glucose, insulin, fibrinogen and plasminogen activator inhibitor 1 were measured. HOMA IR and beta were calculated. Pre and post induced ischemia videocapillaroscopy was performed in hand nailfold to evaluate microvascular morphologic aspect and functional response. RESULTS: AC and fasting glucose were significantly higher in pGDM (p = 0.01 and p = 0.002 respectively). Women with pGDM and BMI < 25 kg/m(2) had significantly higher levels of fasting insulin and HOMA IR than controls (p = 0.008 and 0.05 respectively). Abnormal morphologic findings were more frequent and papillae rectification were 3.3 times more prevalent in pGDM (p = 0.003). Other microvascular parameters did not differ between groups. CONCLUSION: Cardiovascular risk factors and a microcirculation abnormality (papillae rectification) were significantly increased in young non-diabetic women with pGDM. PMID- 24955138 TI - (64)Cu labeled sarcophagine exendin-4 for microPET imaging of glucagon like peptide-1 receptor expression. AB - The Glucagon-like peptide 1 receptor (GLP-1R) has become an important target for imaging due to its elevated expression profile in pancreatic islets, insulinoma, and the cardiovascular system. Because native GLP-1 is degraded rapidly by dipeptidyl peptidase-IV (DPP-IV), several studies have conjugated different chelators to a more stable analog of GLP-1 (such as exendin-4) as PET or SPECT imaging agents with various advantages and disadvantages. Based on the recently developed Sarcophagin chelator, here, we describe the construction of GLP-1R targeted PET probes containing monomeric and dimeric exendin-4 subunit. The in vitro binding affinity of BarMalSar-exendin-4 and Mal2Sar-(exendin-4)2 was evaluated in INS-1 cells, which over-express GLP-1R. Mal2Sar-(exendin-4)2 demonstrated around 3 times higher binding affinity compared with BaMalSar exendin-4. After (64)Cu labeling, microPET imaging of (64)Cu-BaMalSar-exendin-4 and (64)Cu-Mal2Sar-(exendin-4)2 were performed on subcutaneous INS-1 tumors, which were clearly visualized with both probes. The tumor uptake of (64)Cu Mal2Sar-(exendin-4)2 was significantly higher than that of (64)Cu-BaMaSarl exendin-4, which could be caused by polyvalency effect. The receptor specificity of these probes was confirmed by effective blocking of the uptake in both tumor and normal positive organs with 20-fold excess of unlabeled exendin-4. In conclusion, sarcophagine cage conjugated exendin-4 demonstrated persistent and specific uptake in INS-1 insulinoma model. Dimerization of exendin-4 could successfully lead to increased tumor uptake in vivo. Both (64)Cu-BaMalSar-exendin 4 and (64)Cu-Mal2Sar-(exendin-4)2 hold a great potential for GLP-1R targeted imaging. PMID- 24955139 TI - Application of (68)Ga-PRGD2 PET/CT for alphavbeta3-integrin imaging of myocardial infarction and stroke. AB - PURPOSE: Ischemic vascular diseases, including myocardial infarction (MI) and stroke, have been found to be associated with elevated expression of alphavbeta3 integrin, which provides a promising target for semi-quantitative monitoring of the disease. For the first time, we employed (68)Ga-S-2-(isothiocyanatobenzyl) 1,4,7-triazacyclononane-1,4,7-triacetic acid-PEG3-E[c(RGDyK)]2 ((68)Ga-PRGD2) to evaluate the alphavbeta3-integrin-related repair in post-MI and post-stroke patients via positron emission tomography/computed tomography (PET/CT). METHODS: With Institutional Review Board approval, 23 MI patients (3 days-2 years post-MI) and 16 stroke patients (3 days-13 years post-stroke) were recruited. After giving informed consent, each patient underwent a cardiac or brain PET/CT scan 30 min after the intravenous injection of (68)Ga-PRGD2 in a dose of approximately 1.85 MBq (0.05 mCi) per kilogram body weight. Two stroke patients underwent repeat scans three months after the event. RESULTS: Patchy (68)Ga-PRGD2 uptake occurred in or around the ischemic regions in 20/23 MI patients and punctate multifocal uptake occurred in 8/16 stroke patients. The peak standardized uptake values (pSUVs) in MI were 1.94 +/- 0.48 (mean +/- SD; range, 0.62-2.69), significantly higher than those in stroke (mean +/- SD, 0.46 +/- 0.29; range, 0.15-0.93; P < 0.001). Higher (68)Ga-PRGD2 uptake was observed in the patients 1-3 weeks after the initial onset of the MI/stroke event. The uptake levels were significantly correlated with the diameter of the diseases (r = 0.748, P = 0.001 for MI and r = 0.835, P = 0.003 for stroke). Smaller or older lesions displayed no uptake. CONCLUSIONS: (68)Ga-PRGD2 uptake was observed around the ischemic region in both MI and stroke patients, which was correlated with the disease phase and severity. The different image patterns and uptake levels in MI and stroke patients warrant further investigations. PMID- 24955140 TI - Image-guided pro-angiogenic therapy in diabetic stroke mouse models using a multi modal nanoprobe. AB - PURPOSE: The efficacy of pro-angiogenic therapy is difficult to evaluate with current diagnostic modalities. The objectives were to develop a non-invasive imaging strategy to define the temporal characteristics of angiogenesis and to evaluate the response to pro-angiogenic therapy in diabetic stroke mouse models. METHODS: A home-made alphanubeta3 integrin-targeted multi-modal nanoprobe was intravenously injected into mouse models at set time points after photothrombotic stroke. Magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging were carried out at 24 h post-injection. Bone marrow-derived endothelial progenitor cells (EPCs) were infused into the mouse models of ischemic stroke to stimulate angiogenesis. RESULTS: The peak signal intensity in the ischemic angiogenic area of diabetic and wild-type mouse models was achieved on day 10, with significantly lower signal enhancement observed in the diabetic models. Although the signal intensity was significantly higher after EPC treatment in both models, the enhancement was less pronounced in the diabetic animals compared with the wild-type controls. Histological analysis revealed that the microvessel density and expression of beta3 integrin were correlated with the signal intensity assessed with MRI and NIRF imaging. CONCLUSIONS: The non-invasive imaging method could be used for early and accurate evaluation of the response to pro-angiogenic therapy in diabetic stroke models. PMID- 24955141 TI - Enhanced plasmonic resonance energy transfer in mesoporous silica-encased gold nanorod for two-photon-activated photodynamic therapy. AB - The unique optical properties of gold nanorods (GNRs) have recently drawn considerable interest from those working in in vivo biomolecular sensing and bioimaging. Especially appealing in these applications is the plasmon-enhanced photoluminescence of GNRs induced by two-photon excitation at infrared wavelengths, owing to the significant penetration depth of infrared light in tissue. Unfortunately, many studies have also shown that often the intensity of pulsed coherent irradiation of GNRs needed results in irreversible deformation of GNRs, greatly reducing their two-photon luminescence (TPL) emission intensity. In this work we report the design, synthesis, and evaluation of mesoporous silica encased gold nanorods (MS-GNRs) that incorporate photosensitizers (PSs) for two photon-activated photodynamic therapy (TPA-PDT). The PSs, doped into the nano channels of the mesoporous silica shell, can be efficiently excited via intra particle plasmonic resonance energy transfer from the encased two-photon excited gold nanorod and further generates cytotoxic singlet oxygen for cancer eradication. In addition, due to the mechanical support provided by encapsulating mesoporous silica matrix against thermal deformation, the two-photon luminescence stability of GNRs was significantly improved; after 100 seconds of 800 nm repetitive laser pulse with the 30 times higher than average power for imaging acquisition, MS-GNR luminescence intensity exhibited ~260% better resistance to deformation than that of the uncoated gold nanorods. These results strongly suggest that MS-GNRs with embedded PSs might provide a promising photodynamic therapy for the treatment of deeply situated cancers via plasmonic resonance energy transfer. PMID- 24955144 TI - Magnetically responsive smart nanoparticles for cancer treatment with a combination of magnetic hyperthermia and remote-control drug release. AB - We report the synthesis of smart nanoparticles (NPs) that generate heat in response to an alternating current magnetic field (ACMF) and that sequentially release an anticancer drug (doxorubicin, DOX). We further study the in vivo therapeutic efficacy of the combination of magnetic hyperthermia (MHT) and chemotherapy using the smart NPs for the treatment of multiple myeloma. The smart NPs are composed of a polymer with a glass-transition temperature (T g) of 44 degrees C, which contains clustered Fe3O4 NPs and DOX. The clustered Fe3O4 NPs produce heat when the ACMF is applied and rise above 44 degrees C, which softens the polymer phase and leads to the release of DOX. The combination of MHT and chemotherapy using the smart NPs destroys cancer cells in the entire tumor and achieves a complete cure in one treatment without the recurrence of malignancy. Furthermore, the smart NPs have no significant toxicity. PMID- 24955145 TI - MRI of breast tumor initiating cells using the extra domain-B of fibronectin targeting nanoparticles. AB - The identification of breast tumor initiating cells (BTICs) is important for the diagnosis and therapy of breast cancers. This study was undertaken to evaluate whether the extra domain-B of fibronectin (EDB-FN) could be used as a new biomarker for BTICs and whether EDB-FN targeting superparamagnetic iron oxide nanoparticles (SPIONs) could be used as a magnetic resonance imaging (MRI) contrast agent for BTIC imaging in vitro and in vivo. BTICs (NDY-1) exhibited high EDB-FN expression, whereas non-BTICs (MCF-7, BT-474, SUM-225, MDA-MB-231) did not exhibit EDB-FN expression. Furthermore, Cy3.3-labeled EDB-FN specific peptides (APTEDB) showed preferential binding to the targeted NDY-1 cells. To construct an EDB-FN targeted imaging probe, APTEDB was covalently attached to a thermally cross-linked SPION (TCL-SPION) to yield APTEDB-TCL-SPION. In the in vitro MRI of cell phantoms, selective binding of APTEDB-TCL-SPION to NDY-1 cells was evident, but little binding was observed in MCF-7 cells. After the intravenous injection of APTEDB-TCL-SPION into the NDY-1 mouse tumor xenograft model, a significant decrease in the signal within the tumor was observed in the T2*-weighted images; however, there was only a marginal change in the signal of non-targeting SPIONs such as APTscramble-TCL-SPION or TCL-SPION. Taken together, we report for the first time that EDB-FN was abundantly expressed in BTICs and may therefore be useful as a new biomarker for identifying BTICs. Our study also suggests that APTEDB-TCL-SPION could be used as an MRI contrast agent for BTIC imaging. PMID- 24955143 TI - Prototype nerve-specific near-infrared fluorophores. AB - Nerve preservation is an important issue during most surgery because accidental transection or injury results in significant morbidity, including numbness, pain, weakness, or paralysis. Currently, nerves are still identified only by gross appearance and anatomical location during surgery, without intraoperative image guidance. Near-infrared (NIR) fluorescent light, in the wavelength range of 650 900 nm, has the potential to provide high-resolution, high-sensitivity, and real time avoidance of nerve damage, but only if nerve-specific NIR fluorophores can be developed. In this study, we evaluated a series of Oxazine derivatives to highlight various peripheral nerve structures in small and large animals. Among the targeted fluorophores, Oxazine 4 has peak emission near into the NIR, which provided nerve-targeted signal in the brachial plexus and sciatic nerve for up to 12 h after a single intravenous injection. In addition, recurrent laryngeal nerves were successfully identified and highlighted in real time in swine, which could be preserved during the course of thyroid resection. Although optical properties of these agents are not yet optimal, chemical structure analysis provides a basis for improving these prototype nerve-specific NIR fluorophores even further. PMID- 24955142 TI - Exploration of panviral proteome: high-throughput cloning and functional implications in virus-host interactions. AB - Throughout the long history of virus-host co-evolution, viruses have developed delicate strategies to facilitate their invasion and replication of their genome, while silencing the host immune responses through various mechanisms. The systematic characterization of viral protein-host interactions would yield invaluable information in the understanding of viral invasion/evasion, diagnosis and therapeutic treatment of a viral infection, and mechanisms of host biology. With more than 2,000 viral genomes sequenced, only a small percent of them are well investigated. The access of these viral open reading frames (ORFs) in a flexible cloning format would greatly facilitate both in vitro and in vivo virus host interaction studies. However, the overall progress of viral ORF cloning has been slow. To facilitate viral studies, we are releasing the initiation of our panviral proteome collection of 2,035 ORF clones from 830 viral genes in the Gateway(r) recombinational cloning system. Here, we demonstrate several uses of our viral collection including highly efficient production of viral proteins using human cell-free expression system in vitro, global identification of host targets for rubella virus using Nucleic Acid Programmable Protein Arrays (NAPPA) containing 10,000 unique human proteins, and detection of host serological responses using micro-fluidic multiplexed immunoassays. The studies presented here begin to elucidate host-viral protein interactions with our systemic utilization of viral ORFs, high-throughput cloning, and proteomic technologies. These valuable plasmid resources will be available to the research community to enable continued viral functional studies. PMID- 24955147 TI - The importance of establishing reliability and validity of assessment instruments for mental health problems: An example from Somali children and adolescents living in three refugee camps in Ethiopia. AB - Assessing mental health problems cross-culturally for children exposed to war and violence presents a number of unique challenges. One of the most important issues is the lack of validated symptom measures to assess these problems. The present study sought to evaluate the psychometric properties of two measures to assess mental health problems: the Achenbach Youth Self-Report and the Child Posttraumatic Stress Disorder Symptom Scale. We conducted a validity study in three refugee camps in Eastern Ethiopia in the outskirts of Jijiga, the capital of the Somali region. A total of 147 child and caregiver pairs were assessed, and scores obtained were submitted to rigorous psychometric evaluation. Excellent internal consistency reliability was obtained for symptom measures for children and their caregivers. Validation of study instruments based on local case definitions was obtained for the caregivers but not consistently for the children. Sensitivity and specificity of study measures were generally low, indicating that these scales would not perform adequately as screening instruments. Combined test-retest and inter-rater reliability was low for all scales. This study illustrates the need for validation and testing of existing measures cross-culturally. Methodological implications for future cross-cultural research studies in low- and middle-income countries are discussed. PMID- 24955146 TI - Expanding the genetic basis of copy number variation in familial breast cancer. AB - INTRODUCTION: Familial breast cancer (fBC) is generally associated with an early age of diagnosis and a higher frequency of disease among family members. Over the past two decades a number of genes have been identified that are unequivocally associated with breast cancer (BC) risk but there remain a significant proportion of families that cannot be accounted for by these genes. Copy number variants (CNVs) are a form of genetic variation yet to be fully explored for their contribution to fBC. CNVs exert their effects by either being associated with whole or partial gene deletions or duplications and by interrupting epigenetic patterning thereby contributing to disease development. CNV analysis can also be used to identify new genes and loci which may be associated with disease risk. METHODS: The Affymetrix Cytogenetic Whole Genome 2.7 M (Cyto2.7 M) arrays were used to detect regions of genomic re-arrangement in a cohort of 129 fBC BRCA1/BRCA2 mutation negative patients with a young age of diagnosis (<50 years) compared to 40 unaffected healthy controls (>55 years of age). RESULTS: CNV analysis revealed the presence of 275 unique rearrangements that were not present in the control population suggestive of their involvement in BC risk. Several CNVs were found that have been previously reported as BC susceptibility genes. This included CNVs in RPA3, NBN (NBS1), MRE11A and CYP19A1 in five unrelated fBC patients suggesting that these genes are involved in BC initiation and/or progression. Of special interest was the identification of WWOX and FHIT rearrangements in three unrelated fBC patients. CONCLUSIONS: This study has identified a number of CNVs that potentially contribute to BC initiation and/or progression. The identification of CNVs that are associated with known tumour suppressor genes is of special interest that warrants further larger studies to understand their precise role in fBC. PMID- 24955148 TI - Therapeutics role of olive fruits/oil in the prevention of diseases via modulation of anti-oxidant, anti-tumour and genetic activity. AB - The current mode of treatment for various diseases is based on synthetic drugs are effective but they show adverse effect and also alter the genetic and metabolic activity. Moreover, some drugs prepared from plants and their constituents show potentiality with more efficacy than synthetic agents used in clinical therapy. Earlier report has shown that regular consumption of fruits and vegetables is strongly related with reduced risk of developing various diseases. Several epidemiological studies has shown that, the incidence heart disease and cancers is lowest in the Mediterranean basin as compared to the part of the world because of their diet rich in olives and olive products. Olives are commonly consumed in Mediterranean and Arabian Peninsula and also have been documented in Holy Quran and modern scientific literatures. Earlier studies have shown that, the constituents from olive such as oleuropein, squalene and hydroxytyrosol modulate the genes functions and other activities. In this review, the medicinal value of olives and their constituents are summarized in terms of therapeutic approach in the diseases management through regulation of various activities. PMID- 24955149 TI - Role of Interleukin-17 in defense against pseudomonas aeruginosa infection in lungs. AB - BACKGROUND: Pseudomonas aeruginosa may cause severe or even fatal infection in hosts with immunodeficiency. Interleukin-17 (IL-17) is a newly discovered pro inflammatory cytokine, which promotes the recruitment and activation of neutrophils in the respiratory tract by inducing release of chemokine C-X-C. OBJECTIVE: This study was conducted to explore the role of IL-17 in host defense against acute pseudomonas aeruginosa infection in lungs. METHODS: The expression of IL-17 and its downstream effectors (IL-1beta, MIP-2 and G-CSF) were detected in mouse lungs with acute pseudomonas aeruginosa infection; 48 h after intratracheal administration of justice plasmid, mice were infected with pseudomonas aeruginosa again, and the bacterial clearance rate and the expression of downstream effectors of IL-17, as well as the mice death rate, were determined 6 h later. RESULTS: The expression of IL-17 and its downstream effectors (IL 1beta, MIP-2 and G-CSF) significantly increased in mouse lungs with acute pseudomonas aeruginosa infection. After intratracheal administration of justice plasmid expressing IL-17, the expression of IL-17 and its downstream effectors significantly increased, accompanied by increase in neutrophil count. The justice plasmid expressing IL-17 was intratracheally administered before acute pseudomonas aeruginosa lung infection, which significantly increased the expression of IL-17 and its downstream effectors (IL-1beta, MIP-2 and G-CSF) in the respiratory tract, leading to increasing clearance rate of bacteria and survival rate. CONCLUSION: IL-17 may recruit neutrophil to the infected areas in the early phase of pseudomonas aeruginosa lung infection. PMID- 24955150 TI - FEM evaluation of cemented-retained versus screw-retained dental implant single tooth crown prosthesis. AB - Prosthetic rehabilitation of partial or total edentulous patients is today a challenge for clinicians and dental practitioners. The application of dental implants in order to recover areas of missing teeth is going to be a predictable technique, however some important points about the implant angulation, the stress distribution over the bone tissue and prosthetic components should be well investigated for having final long term clinical results. Two different system of the prosthesis fixation are commonly used. The screw retained crown and the cemented retained one. All of the two restoration techniques give to the clinicians several advantages and some disadvantages. Aim of this work is to evaluate all the mechanical features of each system, through engineering systems of investigations like FEM and Von Mises analyses. The FEM is today a useful tool for the prediction of stress effect upon material and biomaterial under load or strengths. Specifically three different area has been evaluated through this study: the dental crown with the bone interface; the passant screw connection area; the occlusal surface of the two different type of crown. The elastic features of the materials used in the study have been taken from recent literature data. Results revealed an adequate response for both type of prostheses, although cemented retained one showed better results over the occlusal area. PMID- 24955151 TI - Pre-emptive small dose of fentanyl suppresses fentanyl-induced cough: a meta analysis of randomized controlled trials. AB - Fentanyl-induced cough (FIC) should be effectively prevented in patients requiring stable induction of general anesthesia. We reviewed available randomized-controlled trials (RCTs) that focused on the pre-emptive fentanyl to prevent FIC, and preformed this meta-analysis to clarify the efficacy and to recommend a specific application. The PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and Chinese BioMedical Literature Database were searched for relevant RCTs without restriction on the year or language of the publications. All of the published RCTs that assessed the efficacy of pre-emptive fentanyl on preventing FIC were selected. A total of seven studies were identified for inclusion. Meta-analysis showed that a priming fentanyl dose of 0.5 MUg/kg decreased the FIC incidence (RR = 0.29, 95% CI: 0.17-0.49) and severity (WMD = -0.46, 95% CI -0.70 - -0.23) of FIC; however, a priming fentanyl dose of 1.0 MUg/kg (RR = 0.26, 95% CI 0.04-1.70; WMD = -0.60, 95% CI -1.33-0.14) or 1.5 MUg/kg (RR = 0.94; 95% CI: 0.77-1.15; WMD = -0.08, 95% CI -0.33-0.17) had no effect on FIC. Our meta-analysis demonstrated that pre-emptive low dose of fentanyl could effectively prevent FIC, and the dose of 0.5 MUg/kg was recommended. PMID- 24955152 TI - Effects of intralipid and caffeic acid phenethyl ester on neurotoxicity, oxidative stress, and acetylcholinesterase activity in acute chlorpyriphos intoxication. AB - Chlorpyriphos is one of the most widely used organophosphate (OP) insecticide in agriculture with potential toxicity. Current post-exposure treatments consist of anti-cholinergic drugs and oxime compounds. We studied the effects of intralipid and caffeic acid phenethyl ester (CAPE) on chlorpyriphos toxicity to compose an alternative or supportive treatment for OP poisoning. METHODS: Forty-nine rats were randomly divided into seven groups. Chlorpyriphos was administered for toxicity. Intralipid (IL) and CAPE administered immediately after chlorpyriphos. Serum acetylcholinesterase (AChE) level, total oxidant status (TOS), total antioxidant response (TAR), and histologic examination of cerebellum and brain tissue with Hematoxylin-Eosin and immunohistochemical dyes were examined. RESULTS: Serum enzym levels showed that chlorpyriphos and CAPE inhibited AChE while IL alone had no effect, chlorpyriphos and CAPE intensifies the inhibition effect. Significant difference at AChE levels between the chlorpyriphos+IL and chlorpyriphos+CAPE verified that IL has a protective effect on AChE inhibition. TAR levels were significantly increased in all groups except chlorpyriphos group, TOS levels revealed that CAPE and IL decrease the amount of oxidative stress. Histologic examination revealed that neuronal degeneration was slightly decreased at chlorpyriphos+IL group, but CAPE had a significant effect on protection of neuronal degeneration. CONCLUSION: The results of this study gave us three key points. 1) AChE activity is important for diagnosis of OP intoxication but it has no value for determining the neuro-degeneration. 2) CAPE inhibits AChE activity and may increase the muscarinic-nicotinic hyperactivation. Therefore it should not be used for treatment of OP intoxication. 3) IL decreases the severity of neurodegeneration and symptoms of OP intoxication and it can be used as a supportive agent. PMID- 24955153 TI - miR-18a downregulates DICER1 and promotes proliferation and metastasis of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma, common in Southeast Asia and the southern provinces of China, often has metastasized by the time of diagnosis; thus there exists the need for improved diagnosis and treatment. Accumulating evidence indicates that microRNAs (miRNAs), which post-transcriptionally regulate protein expression, contribute to the processes of tumorigenesis, including metastasis and cellular invasion. Here, we studied the effect of one miRNA, miR-18a-which is believed to target the miRNA-processing enzyme DICERl-on nasopharyngeal carcinoma. In situ hybridization revealed that miR-18a was more highly expressed in nasopharyngeal carcinoma tissues than in control tissues (P < 0.05), and the overexpression correlated with clinical stage and lymph node metastasis (P < 0.05), but not with age and gender (P > 0.05). In vitro analysis of HK1 nasopharyngeal carcinoma cells transfected with miR-18a exhibited significantly decreased expression of DICER1 mRNA and protein but significantly increased proliferation and invasion properties compared to control cells (P < 0.05). Finally, nude mice injected with miR-18a transfected-HK1 cells displayed significantly increased tumor growth and lung metastasis in vivo (P < 0.05). These findings suggest that miR-18a expression can promote proliferation and metastasis of nasopharyngeal carcinoma cells and that these activities may occur through its regulation of DICER1. PMID- 24955154 TI - Correlation between serum IGF-1 and blood lead level in short stature children and adolescent with growth hormone deficiency. AB - This study aimed to investigate correlation between serum insulin-like growth factor-1 (IGF-1) and blood lead level in short stature children with growth hormone deficiency (GHD), and IGF-1 signal molecules were investigated in lead exposed rats. Our findings may provide evidence for clarifying pathogenesis of lead induced short stature in children. METHODS: 880 short stature children were recruited from clinics and divided into GHD group and idiopathic short stature (ISS) group according to the GH peak in growth hormone stimulation test. The height, body weight, serum IGF-1 level and blood lead level were determined. A rat model of lead poisoning was used to establish and western blot assay was employed to detect the phosphorylation of signaling molecules (MAPK and PI3K/Akt) related to IGF-1 signaling pathway. RESULTS: In GHD group, the height, body weight and serum IGF-1 level were significantly lower, but the blood lead level was significantly higher than those in ISS group (P<0.05). Western blot assay confirmed that the protein expression of phosphorylated ERK1/2, JNK, p38, Akt473 and Akt308 increased significantly (P<0.01) in lead exposure rats. CONCLUSION: Our study suggesting that reduction in IGF-1 in children with GHD is associated with blood lead level. Lead exposure may induce expression of phosphorylated MAPK and Akt signaling molecules. The activation of these molecules may influence binding of IGF-1 and tyrosine kinase receptor IGFIR to regulate cell growth via the MAPK and Akt signaling pathways, which then interfere with growth-promoting effect of IGF-1 in short children. PMID- 24955155 TI - Transforming growth factor-beta1 regulates epithelial-mesenchymal transition in association with cancer stem-like cells in a breast cancer cell line. AB - Epithelial-mesenchymal transition (EMT) is associated with altered connection and junctions between cells and changes in abilities of invasion and migration. In this study, we investigated whether SK-BR-3 breast cancer cells induced to undergo EMT exhibit changes in morphological and invasion abilities after Transforming growth factor beta1 (TGF-beta1) treatment. Serum-deprived SK-BR-3 cells were treated with TGF-beta1 (0, 10 ng/mL) for 24 h. The cells morphological changes were observed and imaged using inverted phase contrast microscope. Scratch experiment and invasion experiment were employed to detect changes of invasion ability, cell-flow experiment was used to assess cell cycle, immunohistochemistry technique was used to detect epithelial and mesenchymal markers after the crawling cells were fixed. Our research reveal that SK-BR-3 cells become larger and more messy, the elongated cells extend pseudopodia, the link of the cells became more loosely and cell gap widened after TGF-beta1 treatment. SK-BR-3 cells showed faster growing and improved invasion abilities after TGF-beta1 treatment, and reduced G1 phase cells proportion in the total number of cells after the conversion, in contrast the S phase cells accounted for the proportion of the total number of cells increased. These findings indicate that TGF-beta1-induced EMT in breast cancer cells may be associated with major alterations in morphological and invasion abilities. PMID- 24955156 TI - Prognostic value of circulating microRNA-21 in digestive system cancers: a meta analysis. AB - Circulating microRNAs show aberrant expression in patients with cancer. The aim of this study was to investigate the prognostic value of circulating microRNA-21 (miR-21) in digestive system cancers. METHODS: All the eligible studies were searched by Medline and EMBASE. The hazard ratios (HRs) for overall survival (OS), which compared the expression levels of circulating miR-21 in patients with digestive cancer was extracted and estimated. Pooled HRs and 95% confidence intervals (CI) were calculated. Then a meta-analysis was performed to clarify the prognostic value of the miR-21. RESULTS: A total of seven studies involving 907 subjects were included. The results suggested that higher circulating miR-21 could predict worse OS outcome with the pooled HR of 2.19 (95% CI 1.01-4.75, P = 0.05) in digestive system cancers. Subgroup analysis by ethnicity indicated circulating miR-21 was associated with OS in patients with digestive cancer among Asians with the pooled HR of 2.90 (95% CI 1.30-6.45, P = 0.009). However, subgroup analysis by digestive system site revealed that there is no associated with OS in patients with colorectal cancer with the pooled HR of 1.34 (95% CI 0.45-4.00, P = 0.60). CONCLUSION: The present findings suggest that circulating miR-21 is associated with poor survival in patients with digestive cancer and could be a prognostic biomarker for those patients. PMID- 24955157 TI - Olecular mechanism underlying the myeloperoxidase induced apoptosis of HUVEC-12 cells. AB - OBJECTIVE: This study aimed to investigate the molecular mechanism underlying the myeloperoxidase (MPO) induced apoptosis of human umbilical vein endothelial cells (HUVECs). METHODS: HUVEC-12 cells were treated with myeloperoxidase at different concentrations (0.1 MU/ml, 0.2 MU/ml, 0.4 MU/ml and 0.6 MU/ml) and apoptotic cells were detected by flow cytometry. Then, cells were harvested for the detection of mRNA and protein expression of caspase-3 and Bax by reverse transcription PCR and Western blot assay, respectively. RESULTS: When compared with negative control group, the apoptosis index in 0.2 MU/ml MPO group, 0.4 MU/ml MPO group and 0.6 MU/ml MPO group increased markedly (P<0.05). When compared with negative control group, the mRNA expression of caspase-3 in 0.6 MU/ml MPO group and positive control group increased dramatically (P<0.05). When compared with negative control group, the protein expression of pre-caspase-3 and activated caspase-3 elevated significantly in 0.4 MU/ml MPO group, 0.6 MU/ml MPO group and positive control group (P<0.05). When compared with negative control group, the mRNA and protein expression of Bax elevated dramatically in 0.4 MU/ml MPO group, 0.6 MU/ml MPO group and positive control group (P<0.05). CONCLUSION: MPO at certain extents may induce the apoptosis of HUVEC-12. The MPO induced apoptosis of HUVEC-12 may be dependent on capase-3 signaling pathway, and Bax is also involved in the MPO induced apoptosis of HUVEC-12. PMID- 24955158 TI - Immunoregulation effect of crude extract of C. elegans on allergic asthma. AB - To explore effects of natural crude extract of C. elegans on treatment of asthma. METHOD: Obtain crude extract of C. elegans from synchronically incubated C. elegans via centrifugation, washing and ultrasonic emulsification, etc.; measure C. elegans's protein molecular weight via SDS-polyacrylamide gel electrophoresis (SDS-PAG electrophoresis); construct animal models of asthma with 6-8-week-old BALB/c female mice sensitized by chicken ovalbumin (OVA); conduct immunotherapy on animals with asthma with different doses of mixture of C. elegans and OVA (COM) respectively; take PBS buffer group and OVA group as control groups; conduct inspection of cell factors and differential count of cells in serum IgE, IgG1 and IgG2a antibodies and bronchoalveolar lavage fluid (BALF) via enzyme linked immunosorbent assay (ELISA); and incise lung tissue for pathology observation. RESULT: C. elegans's protein molecular weight is about 50 kd. In bronchoalveolar lavage fluid (BALF) of OVA group, cell factors IL-5 and IL-13 are more than those in PBS buffer group, but IL-2 and IFN-gamma are less than those in PBS buffer group; these differences are of statistical significance (P<0.05). Total cellular score and number of eosinophile granulocyte in BALF of OVA group are more than those in PBS buffer group (P<0.05), and the difference in serum IgE, IgG1 and IgG2a between these two groups is of statistical significance (P<0.05). For groups treatment by different doses of COM, cell factors IL-5 and IL-13 in bronchoalveolar lavage fluid (BALF) are less than those in OVA group, but IL-2 and IFN-gamma are more than those in OVA group; these differences are of statistical significance (P<0.05). Total cellular score and number of eosinophile granulocyte in BALF of COM treatment groups are less than those in OVA group (P<0.05); serum IgE and IgG1 less than those in OVA group, but IgG2a is more than that in OVA group; these differences are of statistical significance (P<0.05). CONCLUSION: The natural crude extract of C. elegans has immunoregulation to animals with asthma. PMID- 24955159 TI - MiR-222 overexpression promotes proliferation of human hepatocellular carcinoma HepG2 cells by downregulating p27. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related death worldwide. Increasing evidence suggests that microRNAs, a novel class of non-coding RNAs that function as endogenous suppressors of gene expression, are deregulated in HCC. Although microRNA-222 (miR-222) overexpression has been described in HCC, the role of miR-222 and its target genes in the proliferation of hepatocellular carcinoma cells remain poorly elucidated. METHODS: HepG2 cells were transfected with miR-222 mimic, inhibitor or their negative controls. Cell proliferation was assessed by Cell Counting Kit 8 (CCK-8) and EdU incorporation assay. Flow cytometry was performed to assess the effects of miR-222 on HepG2 cell cycle progression. MiR-222 and putative targets genes (p27 and p57) expression levels were determined using qRT-PCR and/or Western blot. RESULTS: MiR-222 overexpression induced an enhancement of HepG2 cell proliferation in vitro, paralleling with an altered cell cycle progression via increased cell population in S phase. P27 expression, other than p57, was negatively regulated by miR-222 overexpression at post-transcriptional level in HepG2 cells. Transfection of either small interfering RNA (siRNA) for p27 or miR 222 mimic increased HepG2 cell proliferation rate, whereas co-transfection of p27 siRNA and miR-222 mimic did not further enhance HepG2 cell proliferation in comparison with the cells transfected with p27 siRNA or miR-222 mimic alone, validating that p27 is a target gene of miR-222 during HepG2 cell proliferation. CONCLUSION: This study suggests that miR-222 overexpression promotes HepG2 cell proliferation by downregulating p27. PMID- 24955161 TI - Effects of matrine on the proliferation and apoptosis of human medulloblastoma cell line D341. AB - Matrine, one of the Chinese herbal medicine, has anti-tumor activity in a variety of tumor cells. However, its anti-tumor activity in human medulloblastoma remains unclear. The aim of this study was to investigate the presence and mechanism of matrine-induced proliferation and apoptosis in human medulloblastoma D341 cells. D341 cells were divided into experimental groups in which matrine were added at different concentrations and a control group under the same conditions without matrine applied. D341 cell proliferation was analyzed using a cell counting kit-8 assay, apoptosis was detected by annexin-V FITC/PI double-staining, and the expression of Bax, Bcl-2, caspase-3 and caspase-9 was detected by Western blotting. Results showed that matrine significantly inhibited the proliferation of D341 cells. The cells displayed more and larger cytoplasmic vacuoles, and formed apoptotic bodies after matrine treatment. Western blotting analysis showed that expressions of Bax, caspase-3 and caspase-9 increased, while that of Bcl-2 decreased as the drug concentration gradually increased. The study suggests that matrine could induce human medulloblastoma D341 cells apoptosis and inhibit the cells proliferation in vitro by activating Bax, caspase-3 and caspase-9 and reducing Bcl-2 expression. PMID- 24955160 TI - Isoflurane anesthesia aggravates cognitive impairment in streptozotocin-induced diabetic rats. AB - Several lines of evidence demonstrate that isoflurane anesthesia would be a great risk factor for the patients undergoing surgeries to suffer from postoperative cognitive dysfunction (POCD). Additionally, diabetes is also an important pathogenic factor for the emergence of cognitive dysfunction. If patient is suffering from diabetes, the incidence of cognitive dysfunction greatly increased. We therefore aimed to investigate the effects of isoflurane anesthesia on cognitive dysfunction in a diabetic rat model induced by a single injection of streptozotocin (STZ). Wistar rats received 2 h of 2% isoflurane or oxygen exposure 1 month after a single intraperitoneal injection of 60 mg/kg of STZ or the vehicle. The results showed that isoflurane anesthesia significantly aggravates STZ-induced an increase of the latency to the platform and a decrease of the proportion of time spent in the target quadrant of rats in Morris water maze test. In addition to the expression of amyloid-beta (Abeta), superoxide dismutase (SOD), malonyldialdehyde (MDA), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), isoflurane anesthesia significantly increased as compared with a single injection of STZ. However, isoflurane anesthesia had no effect on the blood glucose and leptin. In conclusion, our results suggested that isoflurane anesthesia aggravating cognitive impairment induced by STZ is probably related to the activation of oxidative stress and inflammatory response in rat hippocampus. PMID- 24955162 TI - A novel fluid resuscitation protocol: provide more protection on acute kidney injury during septic shock in rats. AB - OBJECTIVE: To investigate the therapeutic effects of a novel fluid resuscitation protocol (early fluid resuscitation plus 2% hydrogen inhalation) on acute kidney injury during septic shock induced by lipopolysaccharide in rats. METHODS: Sixty male Wistar rats were randomly divided into four groups (n = 15 per group): control group (C), septic shock group (S), septic shock with early fluid resuscitation group (R), and septic shock with early fluid resuscitation plus 2% hydrogen inhalation group (R+R+H2). The rats were ventilated, and a 2% hydrogen mixture was used in Group R+H2. Lipopolysaccharide (10 mg/kg) was administered to establish the septic shock model in rats and fluid resuscitation was performed in Groups R and R+R+H2. RESULTS: Fluid resuscitation with 2% hydrogen inhalation decreased serum creatinine, blood urea nitrogen, and neutrophil gelatinase associated lipocalin. It also reduced oxidative stress injury and decreased renal tumor necrosis factor-alpha and interleukin-6 levels compared with fluid resuscitation alone. CONCLUSION: Early fluid resuscitation plus 2% hydrogen inhalation provided more protection against AKI during septic shock. PMID- 24955163 TI - Safety and/or effectiveness of methylene blue-guided pilonidal sinus surgery. AB - The effectiveness of methylene blue-guided sacrococcygeal pilonidal sinus disease (SPSD) surgery for the prevention of incomplete excision was evaluated. METHOD: It was a prospective randomized clinical trial that included 33 patients diagnosed with SPSD. Before the excision, methylene blue was injected into the opening of each sinus. At the first excision, all areas that were stained with methylene blue were resected along with the opening of the sinus (Group 1). At the discretion of the surgeon, all areas with granulation tissue were macroscopically re-excised as a single specimen (Group 2). Specimens were evaluated based on five microscopic assessment parameters. RESULTS: All microscopic assessment parameters for SPSD were positive in both the groups. No significant differences were observed between the groups in terms of the positivity of all parameters, except hair shaft (parameter 4) positivity (p > 0.05). Intensities of positivity in Group 1 for all parameters were higher to a statistically significantly degree compared with those of Group 2 (p < 0.05). DISCUSSION: The application of methylene blue for guidance in SPSD surgery may cause inadequate excision of the diseased area. In clinical practice, this condition may manifest itself by recurrence and poor wound healing. PMID- 24955164 TI - Screening of surface markers on rat intestinal mucosa microfold cells by using laser capture microdissection combined with protein chip technology. AB - OBJECTIVE: The objective of this research was to investigate the possibility of screening surface markers on rat intestinal mucosa microfold cells (M cells) by using laser capture microdissection (LCM) combined with protein chip technology. METHODS: We labeled rat intestinal mucosa microfold cells with Ulex europaeus agglutinin (UEA)-1 antibody and visualized these by immunofluorescence staining. Using the Proteome Profiler rat protein chip, we analyzed the protein expression profiles of LCM M-cells compared to lymph follicle-associated epithelial (FAE) cells, and we identified potential differences to screen for marker proteins. RESULTS: M cells can be clearly distinguished from lymphoid FAE cells under the fluorescence microscope. We successfully cut, isolated, and obtained microfold and lymph FAE cells with more than 95% homogeneity. Six differentially expressed proteins were identified through comparison of the protein chip profiles of these 2 cell types. Among these, VEGF, LIX, CNTF, and IL-1alpha/IL-1F1 were found to be at significantly lower levels in M cells, IL-1ra/IL-1F3 and MIG/CXCL9 appeared in significantly higher levels in M cells (P < 0.05). CONCLUSION: The results presented here clearly demonstrate that the combined use of LCM and protein chip technology is effective in the screening of M cell surface markers with high sensitivity and specificity. This will facilitate isolation, identification, and establishment of M cell lines, allowing further characterization of their functional properties. PMID- 24955165 TI - Prophylactic and therapeutic effects of oral budesonide for acute radiation induced enteritis and colitis in rats. AB - No satisfactory means has been found to control the symptoms of diarrhea and weight loss caused by radiation-induced enteritis and colitis. As a glucocorticoid, budesonide has multiple effects, and this study aimed to test whether it could be effective in treating these symptoms. Twenty-eight male Wistar albino rats were randomly allocated into 4 groups. Group I received 0.1 mg/kg/day budesonide at 8-h intervals for 5 days and did not undergo radiation. Group II received 0.1 mg/kg/day budesonide at 8-h intervals for 1 day before radiation treatment and 4 days after irradiation. Group III received 0.1 mg/kg/day budesonide at 8-h intervals for 4 days after irradiation. Group IV received only radiation treatment. On the fifth day after radiation treatment, the rats underwent laparotomy. The rats were weighed before irradiation and before laparotomy. Because of diarrhea, all rats lost weight except group I, which showed weight gain. Weight loss was statistically significant only in group IV. Group I rats exhibited a normal jejunum, ileum, and colon. The other groups showed varying degrees of damage. We conclude that, particularly when given before irradiation, budesonide decreased the side effects of radiation-induced enteritis and colitis both clinically and morphologically. Future pathophysiological and clinical studies will be needed to support this result. PMID- 24955166 TI - Cardiac ablation of Rheb1 reduces sodium currents in infant mice. AB - OBJECTIVE: The Ras homolog enriched in brain gene (Rheb) is a center player within the insulin/Rheb/Mammalian Target of Rapamycin (mTOR) pathway, and plays a critical role in regulating cellular growth. Rheb-/- embryos have been reported to die around midgestation, due to the defects of the development of the cardiovascular system. Recent studies from ours and another group consistently showed that Rheb1 was indispensable for the cardiac hypertrophic growth after early postnatal period. Besides that, we also found that Rheb1 a-MHC-Cre (cKO) mice exhibited ventricular tachycardia. However, the precise mechanism by which Rheb1 knockout causes ventricular arrhythmia in these mice is still unclear. METHODS: Mouse cardiomyocytes were isolated using 10 days suckling Rheb1 cKO and wide type mice using Collagenase Type II. Sodium currents and L-type calcium currents were recorded using the whole-cell patch clamping technique. RESULTS: The sodium current density of ventricular cardiomyocytes from Rheb1 cKO mice was decreased by about 60%. Significant left shift but no slope altered was observed in activation curve with V1/2 values of -35.35 +/- 1.12 mV for Rheb1 cKO group and -40.72 +/- 1.18 mV for the controls. In addition, the area of window current, which refers the overlap of normalized activation and inactivation, was larger in Rheb1 cKO mice. Moreover, the sodium current, in general, was recovered much slower in Rheb1 cKO mice than that of the controls. However, L-type calcium currents were preserved in Rheb1 cKO mice. CONCLUSION: Sodium currents are decreased in Rheb1 cKO mice, which might be responsible for the phenotype of arrhythima in Rheb1 cKO mice. Understanding the molecular composition of sodium ion channel complexes in the heart of these Rheb1 cKO mice will be critical to develop innovative and effective therapies for the treatment of cardiac arrhythmia. PMID- 24955168 TI - Management of periorbital hemangioma by intralesional glucocorticoids and systemic propranolol: a single-center retrospective study. AB - Periorbital hemangioma may lead to the vision impairment so effective treatment should be adopted in time. In this study, we made a retrospective analysis of intralesional glucocorticoids and systemic propranolol in the management of periorbital hemangioma. From Jan. 2006 to Dec. 2013, twenty-five children with periorbital hemangioma were enrolled into this study. Among them, sixteen children accepted intralesional injection of compound betamethasone preparation. Eight children accepted systemic propranolol. One child accepted both of the two treatments. The follow-up period ranged from 6 months to 60 months. The results showed that in the patients with intralesional compound betamethasone preparation, 13/16 patients' tumors involuted completely. 3/16 patients' tumors didn't involute completely at the end of follow-up. In the patients with systemic propranolol, 8/8 patients' tumors involuted almost completely. One patient didn't respond to intralesional glucocorticoids, and so switched to systemic propranolol, which lead to the involution of tumor finally. The adverse effects in the patients with intralesional glucocorticoids included local soft tissue atrophy, local ulcer, and Cushing-like manifestations, which occurred in three patients respectively. In the patients with systemic propranolol, mild diarrhoea occurred in one child. According to our observation, both of intralesional glucocorticoids and systemic propranolol achieved good results in the management of periorbital hemangioma. Systemic propranolol showed superiority in efficacy and safety. We recommend systemic propranolol as the first-line therapy. However, for the children who can't tolerate systemic propranolol, intralesional glucocorticoids still is a feasible choice. PMID- 24955167 TI - Evaluation of mean platelet volume in patients with type 2 diabetes mellitus and blood glucose regulation: a marker for atherosclerosis? AB - OBJECTIVE: Platelets have an important role in atherosclerosis and arterial thrombosis. Cardiovascular complication prevalence of type 2 diabetes mellitus (type 2 DM) may be associated with glycosylated hemoglobin (HbA1c) and mean platelet volume (MPV). The aim of the study was to investigate if platelets were activated in diabetes and its associated vascular complications by measuring the MPV in the diabetics compared to the non-diabetics, and to determine the correlation of MPV with fasting serum glucose (FSG), HbA1c and duration of diabetes in the diabetic patients, respectively. MATERIALS AND METHODS: The study carried out in 65 patients with type 2 DM and 40 non-diabetic subjects. In addition to non-diabetic patients, all diabetic patients were divided into two groups according to their HbA1c levels: group A consisted of patients with HbA1c levels <=7% and group B consisted of patients with HbA1c levels >7%. RESULTS: MPV was significantly higher in Group B as compared to both non-diabetics and Group A. MPV had a high positive correlation with HbA1c and FSG, as with diabetes duration. It is found that MPV was increased in type 2 DM. CONCLUSION: Our findings suggested an association between MPV and HbA1c. Therefore, MPV would be a beneficial prognostic marker of cardio-vascular complications in patients with type 2 DM. PMID- 24955169 TI - Bone marrow mesenchymal stem cell transplantation for treatment of emphysemic rats. AB - OBJECTIVE: To study the efficacy of bone marrow mesenchymal stem cell (MSC) transplantation to treat pulmonary emphysema in rats. METHODS: Sixty rats were randomly divided into control, model and transplantation groups. Each group contained 20 rats. Rat models of emphysema were established via intratracheal instillation of lipopolysaccharide and exposure of model and transplantation groups to smoke. Then, cultured bone marrow MSCs were injected into rats in the transplantation group via the tail vein. Pathological changes of the lung in rats were observed. RESULTS: Emphysemic pathological changes were found in model and transplantation groups, but changes were significantly attenuated after transplantation, compared with that of the model group. The mean alveoli number (MAN) and pulmonary alveolar area (PAA) showed statistically significant differences among the three groups (P < 0.001). The MAN in the transplantation group was higher than that in the model group, but still lower than that in the control group. The PAA in the transplantation group was lower than that in the model group, but higher than that in the control group (P < 0.05). After transplantation, Brdu-positive cells were observed and CK was expressed in a small number of Brdu-positive cells. Brdu- and CK-positive cells were not found in control and model groups. CONCLUSION: Transplantation of bone marrow MSCs can significantly attenuate lung inflammation and pathological changes in emphysemic rats, which may be associated with MSC differentiation into alveolar epithelial cells in recipient lung tissues. PMID- 24955170 TI - Ataxin-3 expression correlates with the clinicopathologic features of gastric cancer. AB - To investigate the expression of Ataxin-3 in human gastric cancer tissues and cell lines, and explore its clinical pathologic significance. METHODS: The expression of Ataxin-3 in gastric cancer (n=536) and noncancerous gastric mucosa (n=312) was determined by immunohistochemistry and correlated to clinicopathologic features such as histologic differentiation and tumor size. The expression of Ataxin-3 protein in the human gastric cancer cell lines MKN45, SGC7901 and in normal human gastric epithelial cells (GES-1) was also evaluated by Western blot analysis. Quantitative real-time PCR was used to determine Ataxin 3 mRNA expression in human gastric cancer cell lines and tissues. RESULTS: The expression of Ataxin-3 protein was decreased in the gastric cancer compared to noncancerous gastric tissue, and correlated with tumor size, Lauren classification, histologic differentiation, and mutant p53 protein (P < 0.05). Similarly, Ataxin-3 mRNA expression was decreased in the gastric cancers compared to the noncancerous gastric tissue. Ataxin-3 protein and mRNA expression was lower in MKN45, SGC7901 cells than in the normal GES-1 cells. CONCLUSION: Decreased expression of Ataxin-3 may play an important role in gastric carcinogenesis and development of gastric cancer. PMID- 24955171 TI - Tempol protects human lymphocytes from genotoxicity induced by cisplatin. AB - The use of cisplatin in treatments of human malignancies is limited by its side effects that include DNA damage and the subsequent risk of developing secondary cancer. In this study, we examined the possible protective effect of Tempol against DNA damage induced by cisplatin in human lymphocytes using chromosomal aberrations (CAs) and sister chromatid exchanges (SCEs) assays. Cisplatin induced significant elevation in the frequencies of CAs and SCEs in cultured human lymphocytes (P < 0.01). Treatment of lymphocytes with Tempol significantly lowered CAs and SCEs induced by cisplatin. Tempol alone did not affect spontaneous levels of SCEs and CAs observed in the control group (P > 0.05). In conclusion, Tempol protects human lymphocytes against genotoxicity induced by the anticancer drug cisplatin. PMID- 24955172 TI - Protective effects of citicoline on TNBS-induced experimental colitis in rats. AB - The aim of this study was to investigate the effects of citicoline on the development of colitis and antioxidant parameters in rats subjected to tribenzene sulfonic acid (TNBS)-induced colitis. Twenty four Wistar Albino female rats were divided into four subgroups (n=6) (control, colitis control, colitis + 50 mg/kg citicoline, colitis + 250 mg/kg citicoline). Colitis was induced using an enema of TNBS and ethanol; following which citicoline was administrated for 3 days and effects of citicoline was subsequently evaluated. Based on microscopic damage scores, there was no difference between rats of the TNBS-colitis and 50 mg/kg citicoline treated groups, whereas treatment with 250 mg/kg citicoline, caused significant reduction in colon injury compared to that observed in rats of TNBS colitis group. In terms of the biochemical analyses, myeloperoxidase (MPO), malondialdehyde (MDA), reduced glutathione (GSH), and IL-6 levels in rats from 250 mg/kg citicoline group were significantly different from that TNBS-colitis group. The levels of MPO, MDA, GSH and IL-6 in control rats were also significantly different those of rats in the TNBS-colitis group. Citicoline may have a positive protective effect on the inflammatory bowel disease treatment process and could, therefore, be used as an adjunct therapy in colitis. These effects of citicoline may exist through anti-inflammatory and antioxidant mechanism. PMID- 24955173 TI - Expansion of myeloid-derived suppressor cells from peripheral blood decreases after 4-week antiviral treatment in patients with chronic hepatitis C. AB - Myeloid-derived suppressor cells (MDSCs) are one of the most important regulators of anti-tumor T-cell responses in cancers. This study aimed to investigate MDSCs in the peripheral blood of patients with chronic hepatitis C (CHC) before and after 4-week treatment with pegylated interferon (PEG-IFN) and ribavirin, and to evaluate their correlation with CD4(+)CD25(high) regulatory T cells (Tregs) and clinical parameters. A total of 80 patients with CHC were enrolled into this study, 37 of whom were treated with PEG-IFN and ribavirin. Compared with healthy controls (0.462% [range 0.257%-0.634%]), the proportion of MDSCs in the peripheral blood of 80 CHC patients (0.601% [range 0.333%-1.027%]) increased significantly before therapy (P=0.011). For 37 HCV patients, the proportion of circulating MDSCs (0 w: 0.597% [range 0.296%-1.021%], 4 w: 0.126% [0.066% 0.239%], P<0.01) and Tregs (0 w: 2.467+/-0.927%, 4 w: 2.074+/-0.840%, P=0.047) decreased significantly after 4-week antiviral treatment. No significant correlation was found between MDSCs and Tregs. These findings suggest that MDSCs expand in the peripheral blood of CHC patients, but decrease after 4-week antiviral treatment. PMID- 24955174 TI - Comparison of the chronic effects of ribavirin and caffeic acid phenethyl ester (CAPE) on pancreatic damage and hepatotoxicity. AB - This study was aimed to comparison of the effects of the chronic use of the Ribavirin and caffeic acid phenethyl ester (CAPE) on the pancreatic damage and hepatotoxicity in rats. METHODS: The rats were given orally 30 mg/kg/day doses of Ribavirin for 30 days, and intraperitoneally 10 MUmol/kg doses of CAPE. The 37 rats were divided into 4 groups: (I) Control (n=7), (II) Ribavirin (R) (n=10), (III) CAPE (n=10), and (IV) R+CAPE (n=10). RESULTS: Ribavirin and CAPE yielded similar results in terms of Serum, total antioxidant status (TAS), total oxidant status (TOS), amylase, lipase, and insulin compared to the control group. However, while Ribavirin provided similar results with the control group in terms of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes, the CAPE group had elevated AST and ALT levels compared to the control group. Histopathologic evaluations revealed that CAPE or Ribavirin had no degenerative effects on both the pancreas and liver tissues. In this way, the biochemical results were confirmed by the histopathologic results. CONCLUSION: It can be concluded that Ribavirin does not lead to any pancreatic damage and hepatotoxicity, and has more beneficial effects than CAPE on especially liver tissue. PMID- 24955175 TI - Quantitative analysis of real-time tissue elastography for evaluation of liver fibrosis. AB - The present study aimed to investigate the feasibility of quantitative analysis of liver fibrosis using real-time tissue elastography (RTE) and its pathological and molecule biological basis. METHODS: Fifty-four New Zealand rabbits were subcutaneously injected with thioacetamide (TAA) to induce liver fibrosis as the model group, and another eight New Zealand rabbits served as the normal control group. Four rabbits were randomly taken every two weeks for real-time tissue elastography (RTE) and quantitative analysis of tissue diffusion. The obtained twelve characteristic quantities included relative mean value (MEAN), standard deviation (SD), blue area % (% AREA), complexity (COMP), kurtosis (KURT), skewness (SKEW), contrast (CONT), entropy (ENT), inverse different moment (IDM), angular secon moment (ASM), correlation (CORR) and liver fibrosis index (LF Index). Rabbits were executed and liver tissues were taken for pathological staging of liver fibrosis (grouped by pathological stage into S0 group, S1 group, S2 group, S3 group and S4 group). In addition, the collagen I (Col I) and collagen III (Col III) expression levels in liver tissue were detected by Western blot. RESULTS: Except for KURT, there were significant differences among the other eleven characteristic quantities (P < 0.05). LF Index, Col I and Col III expression levels showed a rising trend with increased pathological staging of liver fibrosis, presenting a positive correlation with the pathological staging of liver fibrosis (r = 0.718, r = 0.693, r = 0.611, P < 0.05). CONCLUSION: RTE quantitative analysis is expected for noninvasive evaluation of the pathological staging of liver fibrosis. PMID- 24955176 TI - Synthesis and effects of new caffeic acid derivatives on nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages. AB - In this study, 20 new derivatives of caffeic acid esters were synthesized and their inhibitory activities against the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages were determined. Compounds 3l, 3r, 3s and 3t were found to decrease nitrite levels in a dose-dependent manner in LPS induced cells and showed potent inhibitory activities against the NO production in RAW264.7 macrophages with IC50 values of 7.4, 5.9, 3.3 and 2.2 MUM, respectively. They could be selected as compromising compounds for the later pharmacological study. PMID- 24955177 TI - Clinical impact of SPECT-CT in the diagnosis and surgical management of hyper parathyroidism. AB - Hyper-functioning parathyroid glands with autonomous overproduction of PTH is the most frequent cause of hypercalcemia in outpatient populations with primary hyper parathyroidism. It is generally caused by a solitary adenoma in 80%-90% of patients. Despite the various methodologies that are available for preoperative localization of parathyroid lesions, there is still no certain preoperative imaging algorithm to guide a surgical approach prior to the management of primary hyper-parathyroidism (P-HPT). Minimally invasive surgery has replaced the traditional bilateral neck exploration (BNE) as the initial approach in parathyroidectomy at many referral hospitals worldwide. In our study, we investigated diagnostic contributions of SPECT-CT combined with conventional planar scintigraphy in the detection of hyper-functioning parathyroid gland localization, since planar imaging has limitations. We also evaluated the efficacy of preoperative USG in adding to initial diagnostic imaging algorithms to localize a parathyroid adenoma. METHODS: A total of 256 consecutive surgically naive patients with hyper-parathyroidism diagnosis were included in the following preoperative localization study. The study consisted of 256 consecutive patients with HPT, with a selected 154 patients who had neck surgery with definitive histology reports. All patients had 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) double-phase scintigraphy. The SPECT-CT procedure, combined with standard 99mTc MIBI planar parathyroid scintigraphy with a pinhole and parallel-hole collimator to evaluate whether the SPECT-CT procedure was able to provide additional information in the localization of the pathology, caused hyper-parathyroidism in both P-HPT and S-HPT. RESULTS: In the 154 P-HPT patients, 168 lesions (142 adenomas including 2 intrathyroidal and 2 double adenoma, 2 carcinoma, and 22 hyperplastic glands (four patients had MEN I, each with four hyperplastic glands)), were found at surgery. SPECT-CT detected more lesions than planar imaging in P-HPT (97.8% vs. 87.6%). SPECT-CT detected all adenomas and increased sensitivity, particularly in small lesions. Regardless of their size, the number of detected hyperplastic glands by SPECT-CT was remarkably higher than planar imaging. PMID- 24955178 TI - Monosymptomatic nocturnal enuresis caused by seasonal temperature changes. AB - BACKGROUND: Primary nocturnal enuresis is the most frequent urologic complaint among pediatric patients. Enuresis is believed to have a complex etiology involving genetic, somatic, and behavioral factors. We study the relationship between seasonal temperature changes effect and monosymptomatic nocturnal enuresis (MNE). METHODS: Between 2011 and 2012, a total of 75 children with primary MNE selected from urology and pediatry clinics were included in this study. All of the children underwent physical examinations, urine analyses, urinary ultrasounds, and direct urinary graphs. We evaluated the enuresis ratio for the summer (the hot season from June to September) and winter (the cold season from December to March) months in nightly, weekly, and monthly intervals via prepared questionnaires. RESULTS: Of the 75 study participants, 45 were boys (60%) and 30 were girls (40%). The age range was 6-16 years (mean 10.3+/-2.0 years). We observed a difference in the ratio of enuresis data between the summer and winter months in 29 males and 19 females, which totals 48 of the 75 MNE patients evaluated in this study. There was a statistically significant difference noted in monthly enuresis ratio in the summer and winter (p<0.0001). We observed a significant difference in quality of life, and this difference caused considerable emotional discomfort for the patients. CONCLUSION: In the winter months, the nightly, weekly, and monthly ratios are higher in children with MNE. This increase causes a decrease in the quality of life of these children. PMID- 24955179 TI - Relationship between mastication and cognitive function in elderly in L'Aquila. AB - Patients with cognitive deficit have poor oral health and fewer teeth than cognitive normal elderly. The aim of the study was to investigate potential differences in masticatory function between elderly with dementia and those with normal cognitive function. Fifty-five patients (age >61; 82.05 +/- 3.53) were enrolled in the study. Twenty-five subjects cognitively normal (10 females/15 males; 81.04 +/- 4.89 years), were randomly selected and were assigned to Control Group. Thirty subjects (15 females/15 males; 83.16 +/- 6.017 with cognitive impairments were randomly selected from hospitalized patients (Medically Assisted Residences RSA) and were assigned to Test Group. MMSE test, B-ADL and number of teeth were evaluated for each subject. The number of teeth in relation to levels of schooling is not resulted significative. In the cognitively impaired group 26 subjects had fewer than 20 teeth (86.6%); in the cognitively normal group 9 subjects had fewer than 20 teeth (36%). The correlation between number of teeth and age in both groups is significative (p<0.05). There is also a significative correlation between subjects with renal diseases and type II diabetes and number of teeth (p<0.05). Finally a significative correlation is present between number of teeth and sex of the patients (p<0.05) (Table 1). The results of the Wilcoxon's test revealed a significative correlation between MMSE in the two groups (p<0.01). There is also a significative correlation between the two groups and the educational background (p<0.01). The results of the study shows a clear correlation between tooth loss and cognitive function in elderly of L'Aquila. PMID- 24955180 TI - The use of fibrin glue without surgery in the treatment of pilonidal sinus disease. AB - Pilonidal sinus disease is a common disabling condition affecting the natal clefts of the buttocks. We analyze the role of fibrin glue in the treatment of selected patients with pilonidal sinus disease. Forty patients diagnosed with pilonidal sinus disease at Vakif Gureba Training and Research Hospital were treated between December 2007 and December 2011. Recurrence was noted in four patients (10%). Ninety percent of patients had no recurrence one year later (95% confidence interval: 0.85-0.95). This procedure is suggested as a first line of treatment for patients with no prior history of infection and who have only one sinus orifice. PMID- 24955181 TI - Abnormal nail fold capillaroscopic findings in patients with coronary slow flow phenomenon. AB - The coronary slow flow phenomenon (CSFP) is the delayed opacification of coronary arteries in the absence of significant stenosis. The pathogenesis of CSFP has not been completely understood yet. There are several proposed mechanisms such as the structural and functional abnormalities in coronary microcirculation. Nail fold capillaroscopy is a simple, noninvasive examination of the microvasculature and suggested to be a useful technique for analysis in various inflammatory and autoimmune diseases. In this study; we hypothesized that; CSFP is a part of systemic vascular entity rather than a problem confined to coronary vasculature and our aim was to investigate the nail fold capillaries of the patients with CSFP and compare to those with normal coronary flow (NCF). The study was designed as a case-control study and total 25 patients (10 male, mean age 55 +/- 9 years) with documented CSFP, and 24 patients (15 male, mean age 55 +/- 11 years) with NCF were recruited. Nail fold capillaroscopy examinations were performed by video dermatoscopy in all patients and results were compared between two groups. The demographic and clinical characteristics were similar between patients of CSFP and NCF groups. Nail fold capillary abnormalities including dilatation, tortuosity and microhemorrhage were present in 15 (60%) patients in CSFP group and 5 (21%) patients in NCF group (p < 0.05 OR: 5.7 95% C.I 1.602-20.279). In this study, we found that the abnormalities in nail fold capillaries suggesting the presence of inflammation and anatomical changes were significantly higher in patients with CSFP. PMID- 24955182 TI - Serum levels of thrombotic markers in patients with acute myocardial infarction. AB - Tissue plasminogen activator (TPA) and plasminogen activator inhibitor-1 (PAI-1) have pro- and anti-fibrinolytic activities respectively. The net fibrinolytic activity is mainly determined by the balance between TPA and PAI-1 levels. Considering the important role of these markers in thrombotic pathway, we determined the levels of TPA and PAI-1 in sera of 50 AMI patients, 100 patients with associated risk factors (dyslipidemia and high blood pressure) and 100 healthy controls. The findings showed significantly high levels of TPA and PAI-1 in AMI patients as compared to control subjects. Both these markers were only non significantly increased in the risk group. There was no correlation between body mass index and these markers however TPA and PAI-1 were significantly correlated with age and systolic blood pressure, respectively. In conclusion, a combination of these markers could provide a useful tool to assess the prognosis of AMI. PMID- 24955184 TI - Association between gene polymorphisms in TIM1, TSLP, IL18R1 and childhood asthma in Turkish population. AB - Many immunologic and inflammatory mechanisms play a role in asthma etiology. The aim of this study was to investigate the susceptibility of asthma patients in the Turkish population with demonstrating genes for polymorphisms in TIM1, TSLP and IL18R1. All of the genomic DNA samples were isolated from blood samples according to a standard salting-out protocol. DNA samples were stored at -20 degrees C until the genotype analysis was performed. rs3806933 (TSLP -847 C > T) and TIM1 416G > C were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The rs3806933 (TSLP -847 C > T) was genotyped by PCR using our new primers and HphI restriction enzyme digestion. rs2287033 (IL18R1 c. 1270+150 A > G), rs3213733 (IL18R1 c. 626-196 G > T), and rs3771166 (IL18R1- c. 302+1694 C > T) were genotyped using SYBR green dye based real time PCR assay. RESULTS: The allele frequencies of 5 SNPs in TSLP, TIM-1, and IL18R1 genes were determined in 139 asthmatic patients and 126 healthy controls of in Turkish population. The investigated SNPs are as follows; rs3806933 (TSLP -847 C > T), TIM1 -416G > C, rs2287033 (IL18R1 c. 1270+150 A > G), rs3213733 (IL18R1 c. 626 196 G > T), and rs3771166 (IL18R1- c. 302+1694 C > T). Results suggest that IL18R1 c. 626-196 G > T (rs3213733) and TIM1 -416G > C are significantly associated with asthma in patients in Turkish population. Patients with AA genotypes of rs2287033 (IL18R1 c. 1270+150 A > G), have significantly less total serum IgE levels when compared with patients having GG or GA genotypes (p < 0.012; 381.77+/-239.46 vs 557.52+/-549.96, respectively). CONCLUSION: This study showed that IL18R1 c. 626 -196 G > T (rs3213733) and TIM1 -416G > C are significantly associated with asthma patients in Turkish population. PMID- 24955183 TI - Impact of initial platelet count on baseline angiographic finding and end-points in ST-elevation myocardial infarction referred for primary percutaneous coronary intervention. AB - The baseline platelet count (BPC) in patients with acute ST elevation myocardial infarction (STEMI) may reflect the baseline anjiografic finding and may also predic long-term outcomes after primary percutaneous coronary intervention (PPCI). Available data for the value of BPC in patients with STEMI treated with PPCI are still questionable. Therefore, we sought to determine the prognostic value of BPC for baseline angiographic finding and the impact of BPC on clinical outcomes of patients treating with PPCI. Blood sample for BPC was obtained on admission in 140 consecutive patients undergoing PPCI. Patients were divided 2 groups that group-1 (104 patients): TIMI flow-grade 0 and group-2 (36 patients): TIMI flow-grade 1-3. Follow-up was performed at 1-9 months. Baseline demographics were comparable, but, BPC was significantly higher in group-1 comparing 2 (293.7+/-59.8x10(9)/L vs. 237.7+/-50.9x10(9)/L, p<0.0001), pre-procedural lesion length longer in group-1 comparing 2 (13.6+/-3.6 mm vs. 11.4+/-3.9 mm, p:0.003). Distal embolization (19.0% vs. 0.0%, p:0.001), slow-flow (15.2% vs. 2.9%, p:0.033) were more common in group-1 and mean maximum troponin-I level (9.1+/-4.2 MUg/L vs. 5.1+/-3.9 MUg/L, p<0.0001) and mean maximum creatinin kinase (2077.6+/ 1378.4 U/L vs. 1163.4+/-869.7 U/L, p:<0.0001) were higher in group-1. In-hospital and 30-days major cardiac adverse events (MACEs) (16.5% vs. 5.7%), p:0.14) were similarly in both groups, but, at 6-months target vessel revascularization (13.9% vs. 0.0%, p:0.017) and MACEs significantly higher in the group-1 (24.1% vs. 2.9%, p:0.013). CONCLUSION: A higher BPC without any antithrombotic agent is a strongly predictor of total occlusion of IRA in STEMI treated with PPCI. And a higher BPC associated with poor clinical outcomes at 9-months. Apart from prognostic value, measuring of a BPC on admission may also provide further practical and therapeutic profits. PMID- 24955185 TI - CA 125 and other tumor markers in uterine leiomyomas and their association with lesion characteristics. AB - The aim of this study was to investigate the factors associated with serum levels of several tumor markers in a group of patients operated for uterine myoma. One hundred thirty-seven female patients operated for uterine myoma were included. Serum samples were examined for CA 125, CA 19-9, CA 15-3, carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) levels as part of routine workup. Pathological and morphological characteristics of the patients were retrieved from medical records. The mean age was 46.7 +/- 8.8 years (range, 22-85 y). Abnormally high levels of CA 125, CA 19-9, CA 15-3, CEA, and AFP were found in 19.7%, 6.6%, 5.1%, 3.7%, and 1.5% of the patients, respectively. Patients with additional adenomyosis and patients with at least one large myoma (>= 5 cm diameter) had significantly higher levels of CA 125. Multivariate analysis identified coexistence of adenomyosis (OR 7.7 [95% CI, 2.6-23.0], p < 0.001) and presence of at least one large myoma (OR 5.6 [1.4-22.8], p = 0.016) as independent predictors of abnormally high CA 125 levels. CA 125 levels are affected by the tumor size and coexistence of adenomyosis in uterine leiomyomas. Indirect mechanisms caused by large myoma size such as peritoneal irritation may be responsible for CA 125 elevations. PMID- 24955186 TI - Comparison of the performance of TK system with LJ and MGIT methods in the diagnosis of tuberculosis. AB - Tuberculosis is a common infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis (TB). Various liquid or solid media are used for the diagnosis of tuberculosis. TK Rapid Mycobacterial Culture System has been developed recently. In our study, we aimed to compare TK Rapid Mycobacterial Culture System with LJ and MGIT systems in the diagnosis of tuberculosis. 200 clinical specimens (152 sputum, 41 Bronchoalveolar lavage fluid (BAL), 4 gastric aspirations, 2 urine and 1 wound) obtained from 192 patients from different clinics were included for the diagnosis of TB. All specimens were decontaminated by using the same-common procedure in all the methods. The obtained sediment was used for inoculation for the BACTEC MGIT 960, TK and LJ. Additionally, smears were prepared from the residual suspension for Ehrlich-Ziehl Neelsen (EZN) staining for microscopic examination. Contamination was observed in 23 sputum and 4 BAL samples. Contamination rates for TK, LJ, and BACTEC MGIT 960 systems were determined as 3 (1.5%), 13 (6.5%), and 18 (9%) respectively. Mycobacterium tuberculosis growth was determined as 15 (7.5%), 14 (7%) and 13 (6.5%) by TK culture system, MGIT and LJ, respectively. In our study, the total mean detection times of Mycobacterium tuberculosis by the LJ, TK, and MGIT method were 20.1, 17.1, and 8.3 days, respectively. TK system showed a dramatically lower contamination rate than the others. There was no difference in growth rates for each of the three methods. We concluded that the TK culture system is disadvantageous in terms of turnaround time. PMID- 24955187 TI - Evaluation of total antioxidant status, total oxidant status and oxidative stress index in patients with alopecia areata. AB - OBJECTIVES: In this study, we aimed to evaluate total oxidative stress and total antioxidant capacity in serum samples from patients with Alopesia Areata (AA) in our laboratory conditions. METHODS: In this study, 46 subjects with AA (26 females, 20 males) and the control subjects of 36 (20 females, 16 males) age- and sex-matched healthy volunteers from our hospital staffs were enrolled (the mean age was 23.7 +/- 11.0 years). Blood samples were obtained following an overnight fasting state, and were collected on ice at 4 degrees C. The serum samples were separated from the cells by centrifugation at 3000 rpm for 15 min and were stored at -80 degrees C and used for the analysis of the Total Antioxidant Status (TAS) and Total Oxidant Status (TOS). RESULTS: Total Antioxidant Status (TAS) and Total Oxidant Status (TOS), Oxidative Stress Index (OSI) (TOS/TAS) levels of AA patients were 1.4777 +/- 0.1986; 9.7490 +/- 6.0445; 0.6593 +/- 0.4069 respectively. TAS; TOS; OSI (TOS/TAS) levels of controls were 1.4028 +/- 0.1687; 9.4627 +/- 4.2781; 0.6875 +/- 0.3232 respectively. TAS, TOS and OSI levels showed no significant difference between the control and AA group (p > 0.05). CONCLUSION: Future studies about AA pathogenesis should be based not only on oxidant/antioxidant balance but also on several other factors. Because it was observed that the disease showed recurrence in different situations. Since the selection criteria of patients is affected from disease severity and environmental and genetical factors, multicentric studies with better sampled patient population and higher patient number is required. PMID- 24955188 TI - Applications of pressure control ventilation volume guaranteed during one-lung ventilation in thoracic surgery. AB - OBJECTIVE: To explore the effects of ventilatory mode "pressure controlled ventilation-volume guaranteed" (PCV-VG) on the inspiratory pressures, oxygenation parameters and hemodynamics of patients during one lung ventilation (OLV) for thoracic surgery, compared with volume controlled ventilation (VCV). METHODS: Twenty participants were recruited and equally assigned into two groups in a controlled, randomized, crossover design. Group A: VCV was performed initially and changed into PCV-VG after 30 min; Group B: In the reverse order. Blood gas analysis, peak inspiratory pressure (Ppeak), mean inspiratory pressure (Pmean), plateau inspiratory pressure (Plateau) were measured at four different time points: (1) 30 min after total lung ventilation (TLV); (2) 30 min after one lung ventilation (VCV or PCV-VG); (3) 30 min after shifting to the other ventilatory mode, and (4) 30 min after reconstruction of TLV. RESULTS: The Ppeak, Plateau, and Pmean were significantly lower in PCV-VG compared with VCV. There was significant increase in arterial partial pressure of oxygen under PCV-VG. CONCLUSION: In patients undergoing thoracic surgery with OLV, pressure controlled volume guaranteed mode of ventilation may have better effects by decreasing inspiratory pressure parameters and improving arterial oxygenation than volume controlled ventilation. PMID- 24955189 TI - Value of amplitude-integrated electroencephalograph in early diagnosis and prognosis prediction of neonatal hypoxic-ischemic encephalopathy. AB - To investigate value of amplitude-integrated electroencephalograph (aEEG) in early diagnosis and prediction of long-term prognosis of neonatal hypoxic ischemic encephalopathy (HIE), 120 HIE Children were randomly assigned into aEEG group and control group (n = 60 per group). Children in each group were sub divided into mild, moderate and severe HIE groups (n = 20 per group). 1, 3, 14 and 28 days after birth, aEEG was performed in aEEG group; 3, 14 and 28 days after birth, neonatal behavioral neurological assessment (NBNA) was done in both groups. Children who discharged were followed up at adjusted gestational age of 12 months with Denver Developmental Screening Test (DDST) and prognosis evaluation. RESULTS: aEEG manifestation was positively related to clinical severityb of HIE (r = 0.843, P < 0.01). On day 3 and 14, NBNA score was comparable between two groups (P > 0.05), but significant difference in NBNA score was noted on day 28 (P < 0.05). On day 3, 14 and 28, aEEG manifestation was positively associated with prognosis at adjusted gestational age of 12 months (r = 0.832, 0.857, 0.778, 0.743, P < 0.01). In aEEG group, disability rate was 13.8%, which was significantly lower than that in control group (23.2%); cure rate in aEEG group (60%) was significantly higher than that in control group (40%). Moreover, long-term prognosis was also dramatically different between aEEG group and control group (chi(2) = 4.107, P < 0.05). CONCLUSION: aEEG manifestation is significantly associated with clinical severity of HIE and may be helpful for early diagnosis of HIE. aEEG may be used to predict long term prognosis of HIE children. PMID- 24955190 TI - Are there any psychological factors in male patients with primary spontaneous pneumothorax? AB - BACKGROUND: Primary spontaneous pneumothorax (PSP) is usually seen in young male smokers. Pathophysiology of PSP remains unclear, and studies concerning emotional status are scarce. The aim of this study is to investigate psychological factors associated with primary spontaneous pneumothorax. METHODS: The Beck Depression Inventory, Beck Anxiety Inventory, State-Trait Anger Expression Inventory, and State-Trait Anxiety Inventory were administered. RESULTS: A total of 40 patients and 40 healthy controls were included in this study. The mean age in the patient group was 24.60 years, while that in the control group was 26.45 years. The difference was not significant. The weight and body mass index of the patient group were significantly lower compared to those of the control group. The mean Beck Anxiety Inventory scores in the patient and control groups were 10.37 +/- 11.34 and 8.25 +/- 10.60, respectively. Anxiety levels did not differ between the groups (p = 0.389). The mean Beck Depression Inventory scores of the patient and control groups were 8.20 +/- 8.37 and 6.80 +/- 7.57, respectively, but the difference was not significant (p = 0.435). When the anger structures of the groups were compared, no difference was found in any sub-scale. Trait anxiety scores were higher in the patient group compared to those in the control group, but the difference was not significant (p = 0.369). CONCLUSIONS: This study's findings indicated that anger, anxiety, and depression levels did not differ between the primary spontaneous pneumothorax and healthy groups. PMID- 24955191 TI - Study on the executive function of attention in depression patients based on SPECT technology. AB - OBJECTIVE: To investigate event-related potential in executive function of attention and characteristics of cerebral perfusion by 99mTc-ECD single-photon emission computed tomography (SPECT) in depression patients receiving the Oddball task. METHODS: A total of 30 depression patients and 30 normal control subjects were selected to carry out the Oddball task. Event-related potential (ERP) technology combined with SPECT imaging technology was used to compare the reaction time, ERP-P300 latency and amplitude, and cerebral perfusion characteristics on sites of brain. RESULTS: Compared with normal control group, when the Oddball task was performed, the reaction time or ERP-P300 latency was not significantly different in depression patients (P > 0.05), but P300 amplitude on F3 and F7 sites increased significantly (t = 2.241, 2.245, respectively; each P < 0.05). SPECT showed cerebral hypoperfusion in the right basal ganglia, left frontal lobe and temporal lobe of depression patients. CONCLUSION: During the Oddball task, the P300 amplitude on F3 and F7 sites increased significantly in depression patients, who also showed cerebral hypoperfusion in the right basal ganglia, left frontal lobe and temporal lobe. The result suggests that depression patients have brain region functional abnormalities involving attention execution and implicit memory processing during auditory channel information processing. PMID- 24955192 TI - Breast cancer molecular subtypes of Uygur and Han in Xinjiang of China. AB - PURPOSE: To compare the difference between Uygur and Han patients with breast cancer in molecular subtype. METHODS: 4 immunohistochemical (IHC) markers (ER, PR, HER-2 and KI-67) were used to divide Uygur and Han breast cancer patients into 4 subtypes (Luminal A, Luminal B, HER-2 over expression and Basal-like), respectively. statistical analysis were used to evaluate difference in molecular subtype characteristics by race, tumor size, age of onset, menstruation and birth status, histological grade and lymph node metastasis. RESULTS: There is no statistical difference on the molecular subtypes between Han and Uygur. But some characteristics about four subtypes between Han and Uygur have statistical difference like age onset of the Her-2 overexpression cases, subtypes of age less than 35 years, menarche age of the Basal-like cases and tumor size of the Luminal A cases. Between Han and Uygur there is statistical difference on the menarche age, number of childbirths, and tumor size. The HER-2 overexpression and Basal like subtypes were more likely to be grade III tumors both of Han and Uygur. Between 4 molecular subtypes of Han there have statistical difference in number of metastasis lymph nodes. CONCLUSIONS: Our result shows that there are some significant differences between Uygur and Han in the pathological features as well as molecular subtypes. Correct understanding the difference of breast cancer between Uygur and Han can provide guidance for clinical practice. PMID- 24955193 TI - Relationship of osteopontin and renal function with severity of coronary artery lesions. AB - AIM: To explore the relationship of plasma osteopontin (OPN) level and renal function with severity of coronary artery lesions. METHODS: OPN level and renal function were detected and compared in 210 patients with coronary heart disease (CHD group) and 134 patients without coronary heart disease (control group) to analyze the relationship of osteopontin and renal function with severity of coronary artery lesions. RESULTS: Plasma OPN and creatinine level were significantly higher in CHD group than those in control group (P<0.01), and estimated glomerular filtration rate (eGFR) was lower in CHD group than that in control group (P<0.01). The proportions of multi-vessel lesion and moderate to severe decreased renal function were higher in patients with high osteopontin than those in patients with low osteopontin (P<0.05), and the proportion of multi vessel lesion was higher in patients with moderate to severe decreased renal function than that in normal renal function (P<0.05). Osteopontin and renal failure were the independent risk factors for coronary heart disease. CONCLUSIONS: Plasma OPN level is associated with renal failure, both of which are correlated with the severity of coronary artery lesions. PMID- 24955194 TI - Comparison of different ovarian hyperstimulation protocols efficacy in poor ovarian responders according to the Bologna criteria. AB - Many protocols have been proposed to improve IVF outcomes for poor ovarian responders. The aim of this study was to explore the relationship between age, ovarian hyperstimulation protocol and IVF/ICSI outcomes in poor ovarian responder (POR) according to the Bologna criteria, and to compare the efficacy of different protocols used in PORs undergoing IVF/ICSI. We retrospectively analyzed clinical data of 4875 IVF/ICSI cycles, including 592 cycles of women diagnosed with POR according to Bologna criteria. We explored the association of age, different types of ovarian hyperstimulation protocols and prevalence of POR, IVF/ICSI outcomes. Age, basic FSH, AFC, and as well as ovarian hyperstimulation protocols, were all associated with POR. Irrespective of age, PORs in different ovarian hyperstimulation protocol groups had similar AFC, basic sex hormones, number of retrieved oocyte, implantation rate and clinical pregnancy rate as well. However, PORs treated with mild stimulation protocol used least doses of gonadotropins and shortest days of stimulation compared with those treated with other protocols (P<.05). The current study has shown that age, basic FSH, AFC and ovarian stimulation protocols patients used are all significantly associated with POR according to the Bologna criteria. It seems that there is no difference in clinical outcomes such as clinical pregnancy rate, implantation rate and spontaneous abortion rate between different protocols. PMID- 24955195 TI - Thymectomy in central lymph node dissection for papillary thyroid cancer. AB - BACKGROUND: Central lymph node dissection (CND) has been proposed in the treatment of patients affected by papillary thyroid cancer (PTC) with clinically negative neck lymph nodes. The procedure allows pathologic staging of lymph nodes of the central compartment and treatment of the micrometastases. By comparing bilateral and unilateral thymectomy during total thyroidectomy with central lymph node dissection for postoperative complications in sonographically node-negative papillary thyroid carcinomas, we aimed to determine the optimal extent of prophylactic central lymph node dissection. METHODS: Patients were divided into two study groups: Group 1, total thyroidectomy plus unilateral thymectomy during the CND; Group 2, total thyroidectomy associated with bilateral thymectomy (both upper poles) during the CND. Primary endpoints of the study were evaluated by comparing the postoperative complications between the two groups. RESULTS: The only significant result found when comparing the two groups was the rate of transient hypocalcemia. (Group 1: 13.7%, Group 2: 52.4%, p<0.01). A total of five cases of papillary thymic metastases were found in this study. And final pathology confirmed that all cases of thymic metastases were lymph node micrometastases of PTC, only situated in the ipsilateral thymus upper pole. CONCLUSIONS: Bilateral thymectomy during the CND did not provide a better carcinologic resection, as no contralateral thymic metastases were found. The unilateral thymectomy with total thyroidectomy during the CND may represent an effective strategy for reducing the rate of postoperative hypocalcemia. PMID- 24955196 TI - A descriptive study of the oral status in subjects with Sjogren's syndrome. AB - Sjogren's Syndrome (SS) is an autoimmune pathology of varying prevalence. Its involvement in exocrine glands requires that greater attention be paid to patients' oral health. A cross-sectional study was designed to assess the oral health of subjects with SS in constant medical follow-ups. Variables such as the presence of periodontal infections, decay and alterations in the oral mucosa were analyzed, and the individual's salivary flow was measured. The data were analyzed descriptively and with the chi-squared test, considering p<0.05 as statistically significant. 35 subjects of both sexes were studied, aged between 25 and 82 years, with an age average of 53.9 years; they presented on average 7.9 years after the initial diagnosis. The subjects reported a dental check-up every 6 months in only 9% of cases, whereas the rest had one every 1 or 2 years. All the subjects recounted presenting with dry mouth and associated significantly the ingestion of fluids and teeth brushing to improve the sensation of dryness. The salivary flow was objectively seen to be compromised, showing a significant reduction in those with more time since diagnosis of the disease; more than 90% of subjects exhibited periodontal inflammation and a high level of caries. The mucosa presented a low level of pathology. In conclusion, education in oral health is imperative for subjects with this pathology and more frequent check-ups may be useful in decreasing the levels of oral pathology. PMID- 24955197 TI - Total osteocalcin in serum predicts testosterone level in male type 2 diabetes mellitus. AB - OBJECTIVE: To investigate the relationship between total osteocalcin (total OC) and testosterone level in the serum of male patients with type 2 diabetes mellitus (T2DM). METHODS: 98 male T2DM were recruited in our cross-section study. Their anthropometric parameters were measured and body mass index (BMI) was calculated. Serum markers including glucose, insulin, HbA1c, testosterone, total OC and other bone metabolic markers were examined. Simple Pearson correlation and multiple regression analysis were performed. RESULTS: Poor level of glucose control was found in the patients (HbA1c 9.19+/-2.53 and FPG 8.20+/-2.98). In simple Pearson correlation, total OC was positively related with testosterone (r=0.236, P=0.019), and this relation still existed after considering all the parameters of the patients (Model 1, 2 and 3). CONCLUSION: In male patients with T2DM, total OC was positively correlated with testosterone, so total OC might predict the testosterone level in the serum. PMID- 24955198 TI - Unusual cases of pigmented villonodular synovitis after arthroplasty. AB - Pigmented Villonodular Synovitis (PVNS) is a relatively rare, benign proliferation lesion of the synovium of large joints. The etiology is varied and unclear. We had report a 79-year-old woman had PVNS after 14 years right hip arthroplasty with metal prosthesis. Here we report another 4 patients had PVNS after arthroplasty. The second one had PVNS in the 2(th) year after hip arthroplasty with bone cement prosthesis. The specimen was brown and like usual PVNS in tissue. The third case had PVNS in the 8(th) after arthroplasty with human bone prosthesis because of the recurrence of PVNS. The proliferated synovium became black from brown. There was brown and many groups black pigment in the tissue. The fourth one had PVNS in the 4(th) year after knee arthroplasty with polyethylene prosthesis. The specimen was yellow. There was no pigment in the tissue but multinucleated giant cells with unstained foreign body. The fifth patient had PVNS in the 10(th) month after the left hip arthroplasty with metal prosthesis. The macroscopy was yellow. There were hemosiderin particles in the tissue but black metal particles. This indicates that arthroplasty with prosthesis could cause some new disease or PVNS had new etiology with different pathological show. PMID- 24955199 TI - Multiple idiopathic cervical root resorptions: report of one case with 8 teeth involved successively. AB - Multiple idiopathic cervical root resorptions is a rare condition which is usually detected as an incidental radiographic finding. It involves more than 3 teeth in the same patient and the etiology remains elusive. Diagnosis and treatment of the defect is still challenging. The present report describes a case with progressive multiple external cervical resorption involving 8 teeth, including the history, clinical and radiographic findings. Treatment included surgical intervention and restoration of the defect. A 3-month reevaluation of the case confirmed a stable, uneventful clinical recovery. PMID- 24955200 TI - Rigid occlusive titanium barriers for alveolar bone augmentation: two reports with 24-month follow-up. AB - Titanium barriers have been used for guided bone regeneration in preclinical and preliminary clinical reports as a possible alternative to bone grafting. In two cases with lateral bone defects, rigid titanium barriers were used to provide a secluded space in conjunction with bone substitutes. Sufficient lateral bone volume was generated for implant placement, and no complications were observed during 2 years of follow up. In conclusion, space-making stiff titanium barriers may be applied successfully for lateral alveolar crest augmentation. PMID- 24955201 TI - Ultrasonographic features of adenomyoepithelial adenosis: a case report and literature review. AB - Adenomyoepithelial adenosis of the breast is extremely rare. We treated a 35-year old woman with two small painless hard lumps in her breasts. On ultrasonography, the lesion in the right breast (upper inner quadrant) showed heterogeneous echogenicity and irregular, well-defined, uniformly hypoechoic nodules separated by funiform hyperechoic areas. The entire lesion had unclear boundaries. Excisional biopsy showed adenomyoepithelial adenosis. The mass in the left breast was a fibroadenoma. Adenomyoepithelial adenosis can show local recurrence and malignant degeneration, therefore, preoperative ultrasonographic diagnosis is important for surgical planning. The differential diagnosis includes common adenosis, fibroadenoma, adenomyoepithelioma and adenomyoepithelial carcinoma. PMID- 24955202 TI - Completely resorption of autologous skull flap after orthotopic transplantation: a case report. AB - Autologous skull flaps were frequently used in craniotomy, and after craniotomy, autologous skull flaps need to be replanted in situ at most of the time, and complications such as infection and resorption may occur. Ultimately, resorption may result in dislocation of the autologous skull flaps. Here we describe a case of completely resorption of autologous skull flap shortly after orthotopic transplantation which required an extra cranioplasty and potential causes were discussed. Improper processing procedure such as peeling periosteum excessively before replantation, and postoperative subdural effusion and the use of bone wax were considered to be responsible for the rapid complete resorption of the skull flap. PMID- 24955203 TI - A rare case of postmenopausal immature teratoma with a recurrent grave course. AB - Immature teratoma is quite uncommon older women, particular in postmenopausal period. Only a few cases of postmenopausal immature teratoma of the genital tract have been reported. This report describes a postmenopausal aggressive pelvic immature teratoma case with a grave course despite treatment. A 67-year-old woman being in menopause for the past 16 years was diagnosed with immature teratoma in the pelvic cavity. The mass was removed completely and hysterectomy plus bilateral salpingo-oophorectomy was done. Histopathological diagnosis was grade 2 immature teratoma. The patient had a grave course with recurrences despite therapy and died within one year after initial diagnosis. In teratomas diagnosed over 45 years of age, the possibility of malignant teratoma should also be borne in mind. PMID- 24955204 TI - Tissue micro arrays for immunohistochemical detection of inflammatory infiltrates in renal cell carcinoma. PMID- 24955205 TI - Letter to the editor in response to the article "Does adrenal spraying over thyroidectomy area reduce bleeding?" by Ersoy et al. Int J Clin Exp Med 2014;7(1):274-9. PMID- 24955206 TI - Effects of aquatic physiotherapy on the improvement of balance and corporal symmetry in stroke survivors. AB - INTRODUCTION: One of the main problems associate with hemiparesis after stroke is the decrease in balance during static and dynamic postures which can highly affect daily life activities. OBJECTIVE: To assess the effects of aquatic physiotherapy on the balance and quality of life (SS-QoL) of people with pos stroke. METHODS: Chronic stroke participants received at total 18 individual sessions of aquatic physiotherapy using the principle of Halliwick (2x of 40 minutes per week). The outcomes measured were: Berg Balance scale, Timed up & go test (TUG), Stroke Specific Quality of Life Scale (SS-QoL) and baropodometric analysis. These assessment were performed before and one week after intervention. RESULTS: Fifteen participants were included in this study. The mean age was 58.5 and 54% was male. After intervention, participants had a significant improvement on their static balance measured by Berg Balance scale and TUG. Dynamic balance had a significant trend of improvement in mediolateral domain with eyes closed and during sit-to-stand. The mobility domain of the SS-QoL questionnaire was significant higher after intervention. CONCLUSIONS: Our results suggest that aquatic physiotherapy using the method of Halliwick can be a useful tool during stroke rehabilitation to improve balance. However, this improvement may not have significant impact of their quality of life. PMID- 24955207 TI - Sequential left internal mammary artery usage for complex left anterior descending coronary artery revascularization. PMID- 24955208 TI - Identification of adipophilin as a potential diagnostic tumor marker for lung adenocarcinoma. AB - In our previous study, the upregulation of adipophilin in lung adenocarcinoma were identified compared with normal lung tissues by quantitative proteomics. In this study, our aim was to verify the result from quantitative proteomics, further investigate the relationship between adipophilin expression and clinicopathologic factors of lung cancer patients. The expression levels of adipophilin were examined in 10 pairs of lung adenocarcinoma and normal lung tissues using western blotting and the expression and cellular distribution of adipophilin were determined by IHC in 62 formalin-fixed and paraffin embedded primary lung cancer specimens. Adipophilin expression was significantly higher in lung adenocarcinoma specimens than in normal tissues and lung squamous cell carcinomas (P<0.05). There were no significant difference of adipophilin expression between lung squamous cell carcinomas and normal lung tissues. The expression of adipophilin in lung cancer did not correlate with any clinicopathologic factors such as lymph node metastasis, patients' age, gender, tumor size, grade, and TNM stage. In Conclusion, Adipophilin was upregulated in lung adenocarcinoma, suggesting that adipophilin play an important role in tumorigenesis of lung adenocarcinoma and may serve as a potential marker for lung adenocarcinoma. PMID- 24955209 TI - Caenorhabditis elegans: A useful model for studying metabolic disorders in which oxidative stress is a contributing factor. AB - Caenorhabditis elegans is a powerful model organism that is invaluable for experimental research because it can be used to recapitulate most human diseases at either the metabolic or genomic level in vivo. This organism contains many key components related to metabolic and oxidative stress networks that could conceivably allow us to increase and integrate information to understand the causes and mechanisms of complex diseases. Oxidative stress is an etiological factor that influences numerous human diseases, including diabetes. C. elegans displays remarkably similar molecular bases and cellular pathways to those of mammals. Defects in the insulin/insulin-like growth factor-1 signaling pathway or increased ROS levels induce the conserved phase II detoxification response via the SKN-1 pathway to fight against oxidative stress. However, it is noteworthy that, aside from the detrimental effects of ROS, they have been proposed as second messengers that trigger the mitohormetic response to attenuate the adverse effects of oxidative stress. Herein, we briefly describe the importance of C. elegans as an experimental model system for studying metabolic disorders related to oxidative stress and the molecular mechanisms that underlie their pathophysiology. PMID- 24955210 TI - Metabolic syndrome: an important risk factor for Parkinson's disease. AB - Metabolic syndrome is becoming commoner due to a rise in obesity rates among adults. Generally speaking, a person with metabolic syndrome is twice as likely to develop cardiovascular disease and five times as likely to develop diabetes as someone without metabolic syndrome. Increasing oxidative stress in metabolic syndrome and Parkinson's disease is mentioned in the comprehensive articles; however, the system review about clear relation between metabolic syndrome and Parkinson's disease is deficient. In this review, we will focus on the analysis that the metabolic syndrome may be a risk factor for Parkinson's disease and the preventions that reduce the incident of Parkinson's disease by regulating the oxidative stress. PMID- 24955211 TI - Taurine rescues cisplatin-induced muscle atrophy in vitro: a morphological study. AB - Cisplatin (CisPt) is a widely used chemotherapeutic drug whose side effects include muscle weakness and cachexia. Here we analysed CisPt-induced atrophy in C2C12 myotubes by a multidisciplinary morphological approach, focusing on the onset and progression of autophagy, a protective cellular process that, when excessively activated, may trigger protein hypercatabolism and atrophy in skeletal muscle. To visualize autophagy we used confocal and transmission electron microscopy at different times of treatment and doses of CisPt. Moreover we evaluated the effects of taurine, a cytoprotective beta-amino acid able to counteract oxidative stress, apoptosis, and endoplasmic reticulum stress in different tissues and organs. Our microscopic results indicate that autophagy occurs very early in 50 MUM CisPt challenged myotubes (4 h-8 h) before overt atrophy but it persists even at 24 h, when several autophagic vesicles, damaged mitochondria, and sarcoplasmic blebbings engulf the sarcoplasm. Differently, 25 mM taurine pretreatment rescues the majority of myotubes size upon 50 MUM CisPt at 24 h. Taurine appears to counteract atrophy by restoring regular microtubular apparatus and mitochondria and reducing the overload and the localization of autophagolysosomes. Such a promising taurine action in preventing atrophy needs further molecular and biochemical studies to best define its impact on muscle homeostasis and the maintenance of an adequate skeletal mass in vivo. PMID- 24955212 TI - Panaxatriol saponins attenuated oxygen-glucose deprivation injury in PC12 cells via activation of PI3K/Akt and Nrf2 signaling pathway. AB - Panaxatriol saponins (PTS), the main components extracted from Panax notoginseng, have been shown to be efficacious in the prevention and treatment of cerebrovascular diseases in China. NF-E2-related factor 2 (Nrf2), a transcription factor regulating antioxidant and cytoprotective responses to oxidative stress, has received particular attention as a molecular target for pharmacological intervention of ischemic diseases. The aim of this study was to characterize the effect of PTS on the activation of Nrf2 signaling pathway and the potential role in its protective effect. We found that PTS induced heme oxygenase-1 (HO-1) expression in PC12 cells via activating Nrf2 signaling pathway. Phosphatidylinositol 3-kinase (PI3K)/Akt kinase was involved in the upstream of this PTS activated pathway. Moreover, combination of the main components in PTS significantly enhanced the expression of Nrf2 mediated phase II enzymes. Importantly, the protective effect of PTS against oxygen-glucose deprivation reperfusion (OGD-Rep) induced cell death was significantly attenuated by PI3K inhibitor and antioxidant response element (ARE) decoy oligonucleotides, suggesting that both PI3K/Akt and Nrf2 signaling pathway are essential during this protective process. Taken together, our results suggest that PTS may activate endogenous cytoprotective mechanism against OGD-Rep induced oxidative injury via the activation of PI3K/Akt and Nrf2 signaling pathway. PMID- 24955214 TI - SOD1, an unexpected novel target for cancer therapy. AB - Cancer cells have elevated levels of reactive oxygen species (ROS), which are generated in majority by the mitochondria. In the mitochondrial matrix, the manganese dismutase SOD2 acts as a major anti-oxidant enzyme. The deacetylase SIRT3 regulates the activity of SOD2. Recently, SIRT3 was reported to be decreased in 87% of breast cancers, resulting therefore in a decrease in the activity of SOD2 and an elevation in ROS. In addition to SIRT3, we recently reported that SOD2 itself is down-regulated in breast cancer cell lines upon activation of oncogenes, such as Ras. Since in absence of SOD2, superoxide levels are elevated and may cause irreversible damage, mechanisms must exist to retain superoxide below a critical threshold and maintain viability of cancer cells. The copper/zinc dismutase SOD1 localizes in the cytoplasm, the inter-membrane space of the mitochondria and the nucleus. Emerging evidences from several groups now indicate that SOD1 is overexpressed in cancers and that the activity of SOD1 may be essential to maintain cellular ROS under this critical threshold. This review summarizes the studies reporting important roles of SOD1 in cancer and addresses the potential cross-talk between the overexpression of SOD1 and the regulation of the mitochondrial unfolded protein response (UPR(mt)). While mutations in SOD1 is the cause of 20% of cases of familial amyotrophic lateral sclerosis (fALS), a devastating neurodegenerative disease, these new studies expand the role of SOD1 to cancer. PMID- 24955215 TI - The normal function of the cancer kinase Mirk/dyrk1B is to reduce reactive oxygen species. AB - Mirk kinase is a gene upregulated and sometimes amplified in pancreatic cancers and in ovarian cancers, but expressed at very low levels in most normal diploid cells except for skeletal muscle. The muscle cell function of Mirk kinase selected for by cancer cells is unknown. It is now shown that Mirk protein is expressed at low levels and is largely nuclear in cycling skeletal muscle C2C12 myoblasts, but is translocated to the cytoplasm and upregulated when myoblasts initiate differentiation, as shown by immunofluorescence staining and by cell fractionation. Either Mirk depletion or Mirk kinase inhibition increased ROS levels in cycling C2C12 myoblasts. However, Mirk protein is localized in the cytoplasm of mature muscle fibers, specifically in the fast twitch fibers of human skeletal muscle where toxic ROS levels are generated by muscle contraction. C2C12 myoblasts at high density in differentiation media fuse to form differentiated postmitotic myotubes that can contract. A Mirk kinase inhibitor induced a dose-dependent increase in ROS in this model for fast twitch fibers of human skeletal muscle. Efficient Mirk depletion in SU86.86 pancreatic cancer cells by an inducible shRNA decreased expression of eight antioxidant genes. Thus both cancer cells and differentiated myotubes utilize Mirk kinase to relieve oxidative stress. PMID- 24955213 TI - ALK-rearrangements and testing methods in non-small cell lung cancer: a review. AB - The anaplastic lymphoma tyrosine kinase (ALK) gene was first described as a driver mutation in anaplastic non-Hodgkin's lymphoma. Dysregulated ALK expression is now an identified driver mutation in nearly twenty different human malignancies, including 4-9% of non-small cell lung cancers (NSCLC). The tyrosine kinase inhibitor crizotinib is more effective than standard chemotherapeutic agents in treating ALK positive NSCLC, making molecular diagnostic testing for dysregulated ALK expression a necessary step in identifying optimal treatment modalities. Here we review ALKmediated signal transduction pathways and compare the molecular protocols used to identify dysregulated ALK expression in NSCLC. We also discuss the use of crizotinib and second generation ALK tyrosine kinase inhibitors in the treatment of ALK positive NSCLC, and the known mechanisms of crizotinib resistance in NSCLC. PMID- 24955217 TI - IKK is a therapeutic target in KRAS-Induced lung cancer with disrupted p53 activity. AB - Activating mutations in KRAS are prevalent in cancer, but therapies targeted to oncogenic RAS have been ineffective to date. These results argue that targeting downstream effectors of RAS will be an alternative route for blocking RAS-driven oncogenic pathways. We and others have shown that oncogenic RAS activates the NF kappaB transcription factor pathway and that KRAS-induced lung tumorigenesis is suppressed by expression of a degradation-resistant form of the IkappaBalpha inhibitor or by genetic deletion of IKKbeta or the RELA/p65 subunit of NF-kappaB. Here, genetic and pharmacological approaches were utilized to inactivate IKK in human primary lung epithelial cells transformed by KRAS, as well as KRAS mutant lung cancer cell lines. Administration of the highly specific IKKbeta inhibitor Compound A (CmpdA) led to NF-kappaB inhibition in different KRAS mutant lung cells and siRNA-mediated knockdown of IKKalpha or IKKbeta reduced activity of the NF-kappaB canonical pathway. Next, we determined that both IKKalpha and IKKbeta contribute to oncogenic properties of KRAS mutant lung cells, particularly when p53 activity is disrupted. Based on these results, CmpdA was tested for potential therapeutic intervention in the Kras-induced lung cancer mouse model (LSL-Kras (G12D)) combined with loss of p53 (LSL-Kras (G12D)/p53 (fl/fl)). CmpdA treatment was well tolerated and mice treated with this IKKbeta inhibitor presented smaller and lower grade tumors than mice treated with placebo. Additionally, IKKbeta inhibition reduced inflammation and angiogenesis. These results support the concept of targeting IKK as a therapeutic approach for oncogenic RAS-driven tumors with altered p53 activity. PMID- 24955216 TI - CtBP2 proteome: Role of CtBP in E2F7-mediated repression and cell proliferation. AB - C-terminal binding protein (CtBP) family transcriptional corepressors include CtBP1 and CtBP2. While CtBP1 and CtBP2 share significant amino acid sequence homology, CtBP2 possesses a unique N-terminal domain that is modified by acetylation and contributes to exclusive nuclear localization. Although CtBP1 and CtBP2 are functionally redundant for certain activities during vertebrate development, they also perform unique functions. Previous studies have identified several CtBP1-interacting proteins that included other transcriptional corepressors, DNA-binding repressors and histone modifying enzymatic components such as the histone deacetylases and the histone demethylase LSD-1. Here, we carried out an unbiased proteomic analysis of CtBP2-associated proteins and discovered the association of several components of the CtBP1 proteome as well as novel interactions. The CtBP2 proteome contained components of the NuRD complex and the E2F family member E2F7. E2F7 interacted with the hydrophobic cleft region of CtBP1 and CtBP2 through a prototypical CtBP binding motif, PIDLS. E2F7 repressed E2F1 transcription, inhibited cell proliferation in a CtBP-dependent fashion. Our study identified CtBP as a corepressor of E2F7 and as a regulator of DNA damage response. PMID- 24955218 TI - Upregulation of the miR-17-92 cluster and its two paraloga in osteosarcoma - reasons and consequences. AB - Osteosarcomas (OS) are aggressive bone tumors characterized by complex karyotypes with highly variable structural and numerical chromosomal aberrations. Although several genes and pathways commonly altered in malignant tumors have also been identified in OS, the molecular pathogenesis and driving genetic events eventually leading to tumor development are still poorly understood. The microRNA (miRNA) cluster 17-92 and its two paraloga 106a-363 and 106b-25 are known to have diverse oncogenic properties and have been shown to be constantly upregulated in several established OS cell lines. In this study we analyzed a series of 75 well characterized pretherapeutic OS samples for their expression of cluster-related miRNAs and correlated our findings with clinico-pathological parameters including prognosis, metastases and response to neoadjuvant therapy. Interestingly, higher expression levels of specific miRNAs were significantly associated with an adverse outcome of patients and were also higher in patients with systemic spread. We could furthermore show a direct correlation between the expression of cluster activators (MYC, E2F1-3), inhibitors (TP53), individual miRNAs, and pro apoptotic targets (FAS, BIM). Our findings therefore underline a critical role of the miR-17-92 cluster and its two paraloga in OS biology with pathogenetic and prognostic impact. PMID- 24955219 TI - Trigeminal neuralgia treatment outcomes following Gamma Knife radiosurgery with a minimum 3-year follow-up. AB - OBJECTIVE: Effective short-term outcomes have been well documented for trigeminal neuralgia (TN) patients treated with Gamma Knife radiosurgery (GKRS) with reported success rates of 70-90 % with median follow-up intervals of 19-75 months. Fewer series, however, have described uniform long-term follow-up data. In this study, we report our long-term institutional outcomes in patients treated with GKRS after a minimum follow-up of 36 months. METHODS: Thirty-six consecutive patients with medically intractable TN received a median radiation dose of 45 Gy applied with a single 4-mm isocenter to the affected trigeminal nerve. Follow-up data were obtained by clinical examination and telephone questionnaire. Outcome results were categorized based on the Barrow Neurological Institute (BNI) pain scale with BNI I-III considered to be good outcomes and BNI IV-V considered as treatment failure. BNI facial numbness score was used to assess treatment complications. RESULTS: The incidence of early pain relief was high (80.5 %) and relief was noted in an average of 1.6 months after treatment. At minimum follow up of 3 years, 67 % were pain free (BNI I) and 75 % had good treatment outcome. At a mean last follow-up of 69 months, 32 % were free from any pain and 63 % were free from severe pain. Bothersome posttreatment facial numbness was reported in 11 % of the patients. A statistically significant correlation was found between age and recurrence of any pain with age >70 predicting a more favorable outcome after radiosurgery. CONCLUSION: The success rate of GKRS for treatment of medically intractable TN declines over time with 32 % reporting ideal outcome and 63 % reporting good outcome. Patients older than age 70 are good candidates for radiosurgery. This data should help in setting realistic expectations for weighing the various available treatment options. PMID- 24955221 TI - Robot-assisted laparoendoscopic single-site partial nephrectomy with the novel da vinci single-site platform: initial experience. AB - PURPOSE: To report our initial clinical cases of robotic laparoendoscopic single site (R-LESS) partial nephrectomy (PN) performed with the use of the novel Da Vinci R-LESS platform. MATERIALS AND METHODS: Three patients underwent R-LESS PN from November 2013 through February 2014. Perioperative and postoperative outcomes were collected and intraoperative difficulties were noted. RESULTS: Operative time and estimated blood loss volume ranged between 100 and 110 minutes and between 50 and 500 mL, respectively. None of the patients was transfused. All cases were completed with the off-clamp technique, whereas one case required conversion to the conventional (multiport) approach because of difficulty in creating the appropriate scope for safe tumor resection. No major postoperative complications occurred, and all tumors were resected in safe margins. Length of hospital stay ranged between 3 and 7 days. The lack of EndoWrist movements, the external collisions, and the bed assistant's limited working space were noticed to be the main drawbacks of this surgical method. CONCLUSIONS: Our initial experience with R-LESS PN with the novel Da Vinci platform shows that even though the procedure is feasible, it should be applied in only appropriately selected patients. However, further improvement is needed to overcome the existing limitations. PMID- 24955222 TI - Impact of histopathological variant on the outcome of patients treated by radical cystectomy. AB - PURPOSE: It is well established that muscle-invasive urothelial carcinoma (UC) has a marked propensity for divergent differentiation, a fact that has significant diagnostic, prognostic, and therapeutic implications. This work is designed to assess the impact of different histopathologic variants of bladder cancer on morbidity and mortality in patients undergoing radical cystectomy (RC) as compared to the impact in patients with conventional UC. MATERIALS AND METHODS: We reviewed records of 201 patients treated with RC and pelvic lymph node dissections. Demographics as well as clinico-pathologic parameters, including histopathological variant, tumor stage, and nodal status, were reviewed. Multivariate analyses were used to evaluate these parameters for overall survival (OS). Kaplan-Meier curves for overall and cancer-specific survival were plotted. RESULTS: The majority of patients were male (84%), and the mean age was 61+/-13.1 years (range, 27-87 years). The mean follow-up was 67 months (range, 6-132 months). A histological variant of UC tumor was found in 19 patients (11%). The OS was 55%, and the cancer-specific survival was 35%. The histopathologic variance showed significant impact on morbidity and mortality (p=0.02 and p=0.05, respectively). Patients with divergent histopathology of bladder tumor have poorer survival than do those with UC in a multivariate analysis. CONCLUSIONS: The pathologic stages at RC and lymph node involvement are predictors for OS. Because of its aggressive nature, histopathologic variance is an independent risk factor determining the outcome in terms of both morbidity and mortality. PMID- 24955220 TI - The dark side of 5alpha-reductase inhibitors' therapy: sexual dysfunction, high Gleason grade prostate cancer and depression. AB - With aging, abnormal benign growth of the prostate results in benign prostate hyperplasia (BPH) with concomitant lower urinary tract symptoms (LUTS). Because the prostate is an androgen target tissue, and transforms testosterone into 5alpha-dihydrotestosterone (5alpha-DHT), a potent androgen, via 5alpha-reductase (5alpha-R) activity, inhibiting this key metabolic reaction was identified as a target for drug development to treat symptoms of BPH. Two drugs, namely finasteride and dutasteride were developed as specific 5alpha-reductase inhibitors (5alpha-RIs) and were approved by the U.S. Food and Drug Administration for the treatment of BPH symptoms. These agents have proven useful in the reducing urinary retention and minimizing surgical intervention in patients with BPH symptoms and considerable literature exists describing the benefits of these agents. In this review we highlight the adverse side effects of 5alpha-RIs on sexual function, high grade prostate cancer incidence, central nervous system function and on depression. 5alpha-Rs isoforms (types 1-3) are widely distributed in many tissues including the central nervous system and inhibition of these enzymes results in blockade of synthesis of several key hormones and neuro-active steroids leading to a host of adverse effects, including loss of or reduced libido, erectile dysfunction, orgasmic dysfunction, increased high Gleason grade prostate cancer, observed heart failure and cardiovascular events in clinical trials, and depression. Considerable evidence exists from preclinical and clinical studies, which point to significant and serious adverse effects of 5alpha-RIs, finasteride and dutasteride, on sexual health, vascular health, psychological health and the overall quality of life. Physicians need to be aware of such potential adverse effects and communicate such information to their patients prior to commencing 5alpha-RIs therapy. PMID- 24955223 TI - A Comparison Between ThinPrep Monolayer and Cytospin Cytology for the Detection of Bladder Cancer. AB - PURPOSE: The sensitivity of urine cytology is higher for carcinoma in situ and poorly differentiated tumors in bladder cancer, while being fairly low for low grade or well-differentiated tumors. Development of a sensitive diagnostic test to detect bladder carcinoma would significantly facilitate patient management and allow earlier treatment of this disease. This study compared ThinPrep urine cytology (Cytyc Co.) and conventional Cytospin urine cytology (Shandon Scientific Ltd.) in the diagnosis of bladder cancer. MATERIALS AND METHODS: From January 2002 to December 2010, ThinPrep cytology and conventional urine Cytospin cytologic examination of bladder washings were performed in 3,085 subjects suspected of having bladder cancer and in 379 patients with follow-up after transurethral resection of bladder tumor (TUR-BT). The sensitivity and specificity of the urine ThinPrep test was compared with that of conventional Cytospin cytology according to tumor number, size, pathological stage, grade, and recurrence. RESULTS: Of 3,085 subjects, bladder cancer was confirmed by TUR-BT in 379 subjects. The overall sensitivity of ThinPrep and Cytospin cytology was 60.9% and 59.9% in patients suspected of having bladder cancer, respectively. The overall specificity of ThinPrep and Cytospin cytology was 94.8% and 95.3% in patients suspected of having bladder cancer, respectively. The sensitivity of ThinPrep and Cytospin cytology was increased with increasing number, size, pathological stage, and grade, but there was no significant difference between the two tests. CONCLUSIONS: These results suggest that ThinPrep cytology has no advantage in the diagnosis of bladder cancer of a low grade or low stage. PMID- 24955224 TI - Does the time from biopsy to radical prostatectomy affect Gleason score upgrading in patients with clinical t1c prostate cancer? AB - PURPOSE: It is debated whether treatment delay worsens oncologic results in localized prostate cancer (PCa). Few studies have focused on the role of a delay between the time of biopsy and the time of surgery. Thus, we aimed to investigate the effect of the time period between biopsy and surgery on Gleason score upgrading (GSU). MATERIALS AND METHODS: A total of 290 patients who underwent radical retropubic prostatectomy in Ankara Training and Research Hospital were included in the study. The biopsy Gleason score, age, total prostate-specific antigen (PSA) value, prostate volumes, and PSA density (PSAD) were analyzed in all patients. The patients were divided into two groups: patients with GSU (group 1) and patients without GSU (group 2). Variables having a p-value of <=0.05 in the univariate analysis were selected and then evaluated by use of multivariate logistic regression models. Results were considered significant at p<0.05. RESULTS: GSU occurred in 121 of 290 patients (41.7%). The mean age of the patients was 66.0+/-7.2 years in group 1 and 65.05+/-5.60 years in group 2 (p=0.18). The mean PSA values of groups 1 and 2 were 8.6+/-4.1 and 8.8+/-4.3 ng/dL, respectively. The mean prostate volumes of groups 1 and 2 were 43.8+/-14.1 and 59.5+/-29.8 mL, respectively. The PSAD of group 1 was significantly higher than that of group 2 (0.20 vs. 0.17, p=0.003). The mean time to surgery was shorter in group 2 (group 1, 52.2+/-22.6 days; group 2, 45.3+/-15.5 days; p=0.004). According to the logistic regression, time from biopsy to surgery is important in the prediction of GSU. CONCLUSIONS: We suggest that the time period between biopsy and surgery is a significant factor that affects GSU in patients with clinically localized PCa. PMID- 24955225 TI - The changes of voiding pattern after midurethral sling between pure stress urinary incontinence and stress urinary incontinence with overactive bladder group. AB - PURPOSE: The purpose of this study is to compare changes in voiding pattern after midurethral sling surgery (MUS) between the stress urinary incontinence (SUI) group and the overactive bladder (OAB)+SUI group. MATERIALS AND METHODS: From January 2008 to February 2011, a retrospective survey was conducted of 225 female patients who had been diagnosed with SUI and undergone MUS. The subjects were divided into the SUI group and the OAB+SUI group. Changes in the overactive bladder symptom score (OABSS) and American Urological Association-Symptom Index (AUA-SI) before and three months after the MUS were compared. RESULTS: Of the 225 patients, 165 patients (73.3%) were classified as SUI group, and 60 patients (26.7%) were classified as OAB+SUI group. The mean age of the subjects was 54.7 years (range, 31-80 years), and the mean age of patients was 53.9 years (range, 34-80 years), and 56.8 years (range, 31-78 years) in the SUI group and OAB+SUI group. In SUI group, voiding symptom and storage symptom among the AUA-SI were significantly increased (p<0.05). OABSS were slight increased, but was statistically insignificant (p=0.847). In OAB+SUI group, voiding symptom score and OABSS showed a significant increase (p<0.05), but storage symptom score showed an insignificant increase (p=0.790). CONCLUSIONS: OAB may occur in approximately 18% of SUI patients who undergo MUS surgery, and voiding dysfunctions with deteriorated voiding symptom and storage symptom may also occur. The deteriorated OAB was shown in 45% of SUI patients with OAB after the surgery. PMID- 24955226 TI - A population-based study of factors associated with nocturia in reproductive-aged Turkish women. AB - PURPOSE: This study aimed to investigate the prevalence of nocturia according to the International Continence Society (ICS) definition in Turkish women and to determine the associated risk factors and the correlation of other voiding symptoms with nocturia. MATERIALS AND METHODS: A prospective epidemiological study was carried out by use of self-reported questionnaires in 4,250 reproductive-aged women from January 2013 to May 2013. The International Consultation on Incontinence Questionnaire-Short Form and a questionnaire developed by the researchers according to the ICS were administered to define nocturia and other lower urinary tract symptoms. Other physical, reproductive, and health characteristics were also recorded concurrently. RESULTS: Overall, 1,636 women were included in the final analyses. The women had an average age of 34.4+/-5.26 years. The overall prevalence of nocturia was 34.7% (567 of 1,636 women). Women with nocturia were older (p<0.001), had a higher body mass index (p=0.026), and had more children (p<0.001). Nocturia occurred more frequently in women with a history of nocturnal enuresis (p<0.001). Three or more pregnancies, 3 or more deliveries, and age >40 years were significant risk factors for nocturia. We also found that other lower urinary tract symptoms correlated significantly (p<0.001) with nocturia. CONCLUSIONS: Although the prevalence of nocturia is higher with increasing age, younger adults are also affected. Nocturia may cause sleep disorders, mood disturbances, reduced quality of life, and distractibility. Thus, even if one void nightly causes a patient to experience bother, nocturia should be queried about and should be treated if necessary according to the cause of the disease. PMID- 24955227 TI - Effect of potassium magnesium citrate and vitamin B-6 prophylaxis for recurrent and multiple calcium oxalate and phosphate urolithiasis. AB - PURPOSE: To study the effects of long-term treatment with potassium magnesium citrate and vitamin B-6 prophylaxis (Urikind-KM6; 1,100-mg potassium citrate, 375 mg magnesium citrate, and 20-mg pyridoxine hydrochloride/5 mL) every 8 hours over 3 years. MATERIALS AND METHODS: A total of 247 patients with recurrent idiopathic hypocitraturia with or without hyperuricosuria and randomized controls were studied prospectively for 3 years. The total patients were divided into three groups. Control group 1 consisted of 61 patients (24.7%) who had moderate to severe hypocitraturia with or without hyperuricosuria and were recurrent stone formers but discontinued prophylaxis because of drug intolerance within 1 month of therapy. Control group 2 constituted 53 patients (21.5%) who were first-time stone formers and who had mild hypocitraturia with or without hyperuricosuria and were not put on prophylactic therapy and were followed for 3.16+/-0.08 years. Control group 3 constituted 133 patients (54.8%) who were recurrent stone formers who had moderate to severe hypocitraturia with or without hyperuricosuria and were put on prophylaxis therapy and were followed for 3.16+/-0.08 years. All patients were followed up at 6-month intervals. RESULTS: Potassium magnesium citrate prophylaxis produced a sustained increase in 24-hour urinary citrate excretion from initially low values (221.79+/-13.39 mg/dL) to within normal to high limits (604.04+/-5.00 mg/dL) at the 6-month follow-up. Urinary pH rose significantly from 5.62+/-0.2 to 6.87+/-0.01 and was maintained at 6.87+/-0.01. The stone recurrence rate declined from 3.23+/-1.04 per patient per year to 0.35+/-0.47 per patient per year. CONCLUSIONS: Potassium magnesium citrate prophylaxis was effective in reducing the recurrence of calcium oxalate and phosphate urolithiasis. PMID- 24955229 TI - Glued angiocatheter: a rare complication of intrarenal pseudoaneurysm glue angioembolization. AB - Endovascular management of intraparenchymal renal artery pseudoaneurysms is a reasonable and effective therapeutic technique. Endovascular management preserves the maximum amount of renal tissue and reduces the potential risk of nephrectomy. We present the case of an angiocatheter that became stuck in the renal artery following the injection of cyanoacrylate glue for angioembolization of an intrarenal pseudoaneurysm. PMID- 24955228 TI - Beta-Defensin 124 Is Required for Efficient Innate Immune Responses in Prostate Epithelial RWPE-1 Cells. AB - PURPOSE: The present study aimed to determine the role played by beta-defensin 124 (DEFB124) in the innate immunity of prostate epithelial RWPE-1 cells during bacterial infection. MATERIALS AND METHODS: The expression of DEFB124 was examined by quantitative real-time polymerase chain reaction (PCR), Western blotting, and immunocytochemistry. Enzyme-linked immunosorbent assays and quantitative real-time PCR were performed to determine the production of cytokines and chemokines. Western blotting and chromatin immunoprecipitation studies were performed to assess the interaction between DEFB124 and nuclear factor-kappa B (NF-kappaB) in peptidoglycan (PGN)-stimulated RWPE-1 cells. By chemotaxis assay, we assessed the effect of DEFB124 on the migration of monocytes. RESULTS: Exposure to PGN induced DEFB124 upregulation and NF-kappaB activation through IkappaBalpha phosphorylation and IkappaBalpha degradation. Bay11-7082, an NF-kappaB inhibitor, blocked PGN-induced DEFB124 production. Also, NF-kappaB was shown to be a direct regulator and to directly bind to the -3.14 kb site of the DEFB124 promoter in PGN-treated human prostate epithelial RWPE-1 cells. When DEFB124 was overexpressed in RWPE-1 cells, interestingly, the production of cytokines (interleukin [IL] 6 and IL-12) and chemokines (CCL5, CCL22, and CXCL8) was significantly increased. These DEFB124-upregulated RWPE-1 cells markedly induced chemotactic activity for THP-1 monocytes. CONCLUSIONS: Taken together, these results provide strong evidence for the first time that increased DEFB124 expression via NF-kappaB activation in PGN-exposed RWPE-1 cells enhances the production of cytokines and chemokines, which may contribute to an efficient innate immune defense. PMID- 24955230 TI - Urothelial Tumors of the Urinary Bladder in Two Adolescent Patients: Emphasis on Follow-up Methods. AB - Here we describe two cases of papillary urothelial neoplasm of low malignant potential in adolescent boys. One case was a 16-year-old boy with a polypoid mass beside the right ureteral orifice and the other case was a 13-year-old boy with a papillary mass beside the left ureteral orifice. The initial presentation was hematuria in both cases and the bladder mass was detected by ultrasonography. Complete resection of the bladder tumor was performed by using an 11-Fr pediatric resectoscope. Follow-up has been performed with urine analysis, urine cytology, and bladder ultrasonography or cystoscopy every 3 months with no evidence of recurrence. PMID- 24955232 TI - Default mode network in young male adults with autism spectrum disorder: relationship with autism spectrum traits. AB - BACKGROUND: Autism spectrum traits are postulated to lie on a continuum that extends between individuals with autism and individuals with typical development (TD). Social cognition properties that are deeply associated with autism spectrum traits have been linked to functional connectivity between regions within the brain's default mode network (DMN). Previous studies have shown that the resting state functional connectivities (rs-FCs) of DMN are low and show negative correlation with the level of autism spectrum traits in individuals with autism spectrum disorder (ASD). However, it is unclear whether individual differences of autism spectrum traits are associated with the strength of rs-FCs of DMN in participants including the general population. METHODS: Using the seed-based approach, we investigated the rs-FCs of DMN, particularly including the following two core regions of DMN: the anterior medial prefrontal cortex (aMPFC) and posterior cingulate cortex (PCC) in 19 young male adults with high-functioning ASD (mean age = 25.3 +/- 6.9 years; autism-spectrum quotient (AQ) = 33.4 +/- 4.2; full scale IQ (F-IQ) = 109.7 +/- 12.4) compared with 21 age- and IQ-matched young male adults from the TD group (mean age = 24.8 +/- 4.3 years; AQ = 18.6 +/- 5.7; F-IQ = 109.5 +/- 8.7). We also analyzed the correlation between the strength of rs-FCs and autism spectrum traits measured using AQ score. RESULTS: The strengths of rs-FCs from core regions of DMN were significantly lower in ASD participants than TD participants. Under multiple regression analysis, the strengths of rs-FCs in brain areas from aMPFC seed showed negative correlation with AQ scores in ASD participants and TD participants. CONCLUSIONS: Our findings suggest that the strength of rs-FCs in DMN is associated with autism spectrum traits in the TD population as well as patients with ASD, supporting the continuum view. The rs FCs of DMN may be useful biomarkers for the objective identification of autism spectrum traits, regardless of ASD diagnosis. PMID- 24955233 TI - Metal-catalyzed uncaging of DNA-binding agents in living cells. AB - Attachment of alloc protecting groups to the amidine units of fluorogenic DNA binding bisbenzamidines or to the amino groups of ethidium bromide leads to a significant reduction of their DNA affinity. More importantly, the active DNA binding species can be readily regenerated by treatment with ruthenium catalysts in aqueous conditions, even in cell cultures. The catalytic chemical uncaging can be easily monitored by fluorescence microscopy, because the protected products display both different emission properties and cell distribution to the parent compounds. PMID- 24955235 TI - Allergen specific immunotherapy has no influence on standard chemistry and hematology laboratory parameters in clinical studies. AB - BACKGROUND: A set of standard clinical chemistry and hematology parameters are usually measured during clinical studies. The major outcome of these standard tests is to control that the drug investigated does not lead to pathophysiological changes in respective organs or blood. In some cases based on scientific rationale such tests may not be needed. In this paper we report on a standard set of clinical chemistry and hematology laboratory parameters measured before and after treatment in three different immunotherapy studies, representing different routes of administration and different formulations. METHODS: Thirteen hematological laboratory parameters and eight clinical chemistry parameters were evaluated from three double-blind, placebo-controlled, randomized, multi-centre, phase III studies. The three studies include one with sublingual immunotherapy (n = 185), one subcutaneous immunotherapy trial with an aluminium hydroxide-adsorbed recombinant hypoallergenic Bet v1-FV (n = 211) and one with pre-seasonal subcutaneous immunotherapy with a 6-grass pollen allergoid (n = 154). RESULTS: Allergen specific immunotherapy with both administration forms and formulations respectively did not show any influence on any of the 21 laboratory parameters analyzed. Few patients had a change in laboratory parameters from within normal range at baseline to either below or above at end-of-treatment. No differences between active and placebo were seen with respect to number of patients with such a change. CONCLUSIONS: This study with different preparations and routes of application indicates that the value of repeated measurements of standard clinical chemistry and hematology parameters during allergen immunotherapy should be discussed further. PMID- 24955236 TI - Cerebrospinal fluid absorption block at the vertex in chronic hydrocephalus: obstructed arachnoid granulations or elevated venous pressure? AB - BACKGROUND: The lack of absorption of CSF at the vertex in chronic hydrocephalus has been ascribed to an elevation in the arachnoid granulation outflow resistance (Rout). The CSF infusion studies measuring Rout are dependent on venous sinus pressure but little is known about the changes in pressure which occur throughout life or with the development of hydrocephalus. METHODS: Twenty patients with chronic hydrocephalus underwent MR venography and MR flow quantification techniques. The venous outflow pressure was estimated from the sinus blood flow and the cross-sectional area of the transverse sinuses. Adult controls as well as a normal young cohort were selected to estimate the change in sinus pressure which occurs throughout life and following the development of hydrocephalus. Significance was tested with a Student's t-test. RESULTS: The size of the transverse sinuses was unchanged from the 1(st) to the 5(th) decade of life, indicating a stable outflow resistance. However, the blood flow was reduced by 42%, indicating a likely similar reduction in pressure gradient across the sinuses. The sinuses of hydrocephalus patients were 38% smaller than matched controls, indicating a 2.5 times increase in resistance. Despite the 24% reduction in blood flow, a significant increase in sinus pressure is suggested. CONCLUSIONS: The size of the venous sinuses normally does not change over the age range investigated but sinus pressure is reduced proportional to an age-related blood flow reduction. Hydrocephalus is associated with much smaller sinuses than normal and an elevation in venous pressure may explain the lack of CSF absorption into the arachnoid granulations in chronic hydrocephalus. PMID- 24955237 TI - Epigenetic Manipulation of a Filamentous Fungus by the Proteasome-Inhibitor Bortezomib Induces the Production of an Additional Secondary Metabolite. AB - The use of epigenetic modifiers, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, has been explored increasingly as a technique to induce the production of additional microbial secondary metabolites. The application of such molecules to microbial cultures has been shown to upregulate otherwise suppressed genes, and in several cases has led to the production of new molecular structures. In this study, the proteasome inhibitor bortezomib was used to induce the production of an additional metabolite from a filamentous fungus (Pleosporales). The induced metabolite was previously isolated from a plant, but the configuration was not assigned until now; in addition, an analogue was isolated from a degraded sample, yielding a new compound. Proteasome inhibitors have not previously been used in this application and offer an additional tool for microbial genome mining. PMID- 24955234 TI - Diabetic macular edema: new concepts in patho-physiology and treatment. AB - Diabetic macular edema (DME), a serious eye complication caused primarily by hyperglycemia, is one of the major causes of blindness. DME, which is characterized by cystic retinal thickening or lipid deposition, is prone to relapse after successful treatment. DME is a complex pathological process caused by multiple factors, including breakdown of the inner and outer blood-retinal barriers, oxidative stress, and elevated levels of vascular endothelial growth factor which have been demonstrated in both preclinical and clinical studies. Starling's law theory explains many of the features of DME. Early detection and treatment of DME can prevent vision loss. Current effective interventions for DME include treatment of systemic risk factors, such as elevated blood glucose, blood pressure and dyslipidemia. Ophthalmic treatments include laser photocoagulation, surgery and intraocular pharmacotherapy. New drugs, which are given by intraocular injection, have emerged in recent years to become first line treatment for DME that affects the central macula with loss of vision. Laser photocoagulation is still the gold standard of treatment for DME which does not involve the central macular. This review outlines these new treatments with particular emphasis on the optimal timing of how they are given. PMID- 24955238 TI - Interactions of marine mammals and birds with offshore membrane enclosures for growing algae (OMEGA). AB - BACKGROUND: OMEGA is an integrated aquatic system to produce biofuels, treat and recycle wastewater, capture CO2, and expand aquaculture production. This system includes floating photobioreactors (PBRs) that will cover hundreds of hectares in marine bays. To assess the interactions of marine mammals and birds with PBRs, 9 * 1.3 m flat panel and 9.5 * 0.2 m tubular PBRs were deployed in a harbor and monitored day and night from October 10, 2011 to Janurary 22, 2012 using infrared video. To observe interactions with pinnipeds, two trained sea lions (Zalophus californianus) and one trained harbor seal (Phoca vitulina richardii) were observed and directed to interact with PBRs in tanks. To determine the forces required to puncture PBR plastic and the effects of weathering, Instron measurements were made with a sea otter (Enhydra lutris) tooth and bird beaks. RESULTS: A total of 1,445 interactions of marine mammals and birds with PBRs were observed in the 2,424 hours of video recorded. The 95 marine mammal interactions, 94 by sea otters and one by a sea lion had average durations of three minutes (max 44 min) and represented about 1% of total recording time. The 1,350 bird interactions, primarily coots (Fulica americana) and gulls (Larus occidentalis and L. californicus) had average durations of six minutes (max. 170) and represented 5% of recording time. Interactive behaviors were characterized as passive (feeding, walking, resting, grooming, and social activity) or proactive (biting, pecking, investigating, and unspecified manipulating). Mammal interactions were predominantly proactive, whereas birds were passive. All interactions occurred primarily during the day. Ninety-six percent of otter interactions occurred in winter, whereas 73% of bird interactions in fall, correlating to their abundance in the harbor. Trained pinnipeds followed most commands to bite, drag, and haul-out onto PBRs, made no overt undirected interactions with the PBRs, but showed avoidance behavior to PBR tethers. Instron measurements indicated that sea-otter teeth and gull beaks can penetrate weathered plastic more easily than new plastic. CONCLUSIONS: Otter and bird interactions with experimental PBRs were benign. Large-scale OMEGA systems are predicted to have both positive and negative environmental consequences. PMID- 24955240 TI - Knowledge of, attitudes towards, and practice relating to schistosomiasis in two subtypes of a mountainous region of the People's Republic of China. AB - BACKGROUND: Schistosomiasis japonica is still endemic in the People's Republic of China (P.R. China) in five provinces of lake and marshland regions and in two provinces of mountainous regions. Studies elucidated that individual and community perception, attitudes towards schistosomiasis, and hygiene behaviors were crucial factors for preventing schistosomiasis. This study sought to assess the knowledge of, attitudes towards, and practices (KAP) relating to schistosomiasis in two subtypes of a mountainous region in Eryuan County, Yunnan Province, P.R. China. The study's aim is to make suggestions for establishing more specific and effective control measures for disease transmission and interruption in two subtypes of a mountainous region with low-level infection rates. METHODS: A cross-sectional study of 3,000 inhabitants was carried out in the Yongle (plateau basin) and Xinzhuang (plateau canyon) communities of Eryuan County, Yunnan Province in November and December 2011. Stratified cluster random sampling was undertaken using a uniform set of quantitative questionnaires administered by trained assistants. This was further supported with qualitative data from in-depth interviews (IDIs) conducted with ten farmers and ten students. All participants were examined for schistosomiasis using both a serological test (indirect hemagglutination assay [IHA]) and a stool examination (Kato-Katz). RESULTS: The total schistosomiasis knowledge rate in Yongle (83.4%) was significantly lower than that in Xinzhuang (95.5%). In both communities, among the respondents aged 15 years or below, more than one third didn't know the name, endemic areas, and animal reservoirs of schistosomiasis. The majority of respondents in Eryuan acquired their schistosomiasis knowledge from doctors, followed by handouts and hearing from others. The infection rate was once the highest in Yongle, but is now the highest in Xinzhuang, where there are more risk factors for schistosomiasis, such as frequently grazing cattle, digging vegetables or cutting grass in the field, as well as raising cattle by free grazing. CONCLUSION: In short, Eryuan County's overall knowledge rate of schistosomiasis was found to be high. Due to various dominating risk factors, different control strategies should be designed keeping in mind the two different subtypes of endemic areas for schistosomiasis in mountainous regions, namely plateau basins and plateau canyons. PMID- 24955239 TI - Incorporation of Sulfated Hyaluronic Acid Macromers into Degradable Hydrogel Scaffolds for Sustained Molecule Delivery. AB - Synthetically sulfated hyaluronic acid (HA) has been shown to bind proteins with high affinity through electrostatic interactions. While HA-based hydrogels have been used widely in recent years for drug delivery and tissue engineering applications, incorporation of sulfated HA into these networks to attenuate the release of proteins has yet to be explored. Here, we developed sulfated and methacrylate-modified HA macromers and incorporated them into HA hydrogels through free radical-initiated crosslinking. The sulfated HA macromers bound a heparin-binding protein (i.e., stromal cell-derived factor 1-alpha, SDF-1alpha) with an affinity comparable to heparin and did not alter the gelation behavior or network mechanics when copolymerized into hydrogels at low concentrations. Further, these macromers were incorporated into electrospun nanofibrous hydrogels to introduce sulfate groups into macroporous scaffolds. Once incorporated into either uniform or fibrous HA hydrogels, the sulfated HA macromers significantly slowed encapsulated SDF-1alpha release over 12 days. Thus, these macromers provide a useful way to introduce heparin-binding features into radically crosslinked hydrogels to alter protein interactions for a range of applications. PMID- 24955241 TI - Engineering safer-by-design, transparent, silica-coated ZnO nanorods with reduced DNA damage potential. AB - Zinc oxide (ZnO) nanoparticles absorb UV light efficiently while remaining transparent in the visible light spectrum rendering them attractive in cosmetics and polymer films. Their broad use, however, raises concerns regarding potential environmental health risks and it has been shown that ZnO nanoparticles can induce significant DNA damage and cytotoxicity. Even though research on ZnO nanoparticle synthesis has made great progress, efforts on developing safer ZnO nanoparticles that maintain their inherent optoelectronic properties while exhibiting minimal toxicity are limited. Here, a safer-by-design concept was pursued by hermetically encapsulating ZnO nanorods in a biologically inert, nanothin amorphous SiO2 coating during their gas-phase synthesis. It is demonstrated that the SiO2 nanothin layer hermetically encapsulates the core ZnO nanorods without altering their optoelectronic properties. Furthermore, the effect of SiO2 on the toxicological profile of the core ZnO nanorods was assessed using the Nano-Cometchip assay by monitoring DNA damage at a cellular level using human lymphoblastoid cells (TK6). Results indicate significantly lower DNA damage (>3 times) for the SiO2-coated ZnO nanorods compared to uncoated ones. Such an industry-relevant, scalable, safer-by-design formulation of nanostructured materials can liberate their employment in nano-enabled products and minimize risks to the environment and human health. PMID- 24955242 TI - Optimizing photo-Fenton like process for the removal of diesel fuel from the aqueous phase. AB - BACKGROUND: In recent years, pollution of soil and groundwater caused by fuel leakage from old underground storage tanks, oil extraction process, refineries, fuel distribution terminals, improper disposal and also spills during transferring has been reported. Diesel fuel has created many problems for water resources. The main objectives of this research were focused on assessing the feasibility of using photo-Fenton like method using nano zero-valent iron (nZVI/UV/H2O2) in removing total petroleum hydrocarbons (TPH) and determining the optimal conditions using Taguchi method. RESULTS: The influence of different parameters including the initial concentration of TPH (0.1-1 mg/L), H2O2 concentration (5-20 mmole/L), nZVI concentration (10-100 mg/L), pH (3-9), and reaction time (15-120 min) on TPH reduction rate in diesel fuel were investigated. The variance analysis suggests that the optimal conditions for TPH reduction rate from diesel fuel in the aqueous phase are as follows: the initial TPH concentration equals to 0.7 mg/L, nZVI concentration 20 mg/L, H2O2 concentration equals to 5 mmol/L, pH 3, and the reaction time of 60 min and degree of significance for the study parameters are 7.643, 9.33, 13.318, 15.185 and 6.588%, respectively. The predicted removal rate in the optimal conditions was 95.8% and confirmed by data obtained in this study which was between 95-100%. CONCLUSION: In conclusion, photo-Fenton like process using nZVI process may enhance the rate of diesel degradation in polluted water and could be used as a pretreatment step for the biological removal of TPH from diesel fuel in the aqueous phase. PMID- 24955243 TI - Ambient x-ray pollution assessment at inspection gates of airports- a case study of Mehrabad and Imam Khomeini Airports in Iran. AB - BACKGROUND: As a well-known, physical carcinogen, ambient X-ray pollution assessment would be of great importance in today's modern world. Accordingly, the present study was done to measure the exposure level of ambient X-ray at inspection gates of two airports in Iran. According to which, the X-ray was measured at different points of the inspection gates including closed and opened Curtain, as well as seating place of operators beside the X-ray inspection systems. The recorded data were then analyzed by "sign" and t-tests. RESULTS: The total average exposure level of the measured x-ray was 2.68 +/- 0.73 MUsv.h(-1). The measured x-ray exposure level was 2.07 +/- 0.61 (MUsv.h(-1)) released from RAPISCAN X-ray inspection system and 3.3 +/- 1.34 (MUsv.h(-1)) emitted from HEIMANN X-ray inspection system. Comparison of average x-ray doses of the systems in both airports showed that the minimum and maximum exposure levels were recorded at 1(m) far from the devices and at the entrance of the devices, respectively. CONCLUSIONS: The exposure levels at all measurement points were lower than the occupational exposure limit. This reveals the fact that the exposed operators are not probably at risk of adverse health effects. PMID- 24955244 TI - Application of an adsorptive-thermocatalytic process for BTX removal from polluted air flow. AB - BACKGROUND: Zero valent iron and copper oxide nanoparticles (30-60 nm) were coated on a bed of natural zeolite (Clinoptilolite) with 1-2 mm grains and arranged as a dual filter in a stainless steel cylindrical reactor (I.D 4.5 cm and L = 30 cm) to investigating the coated bed removal efficiency for BTX. The experiments were conducted in three steps. First, with an air flow of 1.5 L/min and temperature range of 38 (ambient temperature) to 600 degrees C the BTX removal and mineralization was surveyed. Then, in an optimized temperature the effect of flow rate and pollution loading rate were surveyed on BTX removal. RESULTS: The BTX removal at 300 and 400 degrees C were respectively up to 87.47% and 94.03%. Also in these temperatures respectively 37.21% and 90.42% of BTX mineralization were achieved. In the retention times of 14.1 s and 7.05 s, respectively 96.18% and 78.42% of BTX was removed. CONCLUSIONS: According to the results, this adsorptive-thermocatalytic process with using Clinoptilolite as an adsorbent bed and combined Fe(0) and Cu2O nanoparticles as catalysts can be an efficient and competitive process in the condition of high flow rate and high pollution loading rate with an adequate process temperature of 350 degrees C. PMID- 24955245 TI - The Redox-A3 Reaction. AB - This Highlight details the recent emergence of a new type of A3 reaction (three component condensation of an amine, an aldehyde and an alkyne). In contrast to the classic A3 coupling process, the redox-A3 reaction incorporates an iminium isomerization step and leads to amine alpha-alkynylation. The overall transformation is redox-neutral by virtue of a combined reductive N alkylation/oxidative C-H bond functionalization. PMID- 24955246 TI - The Relationship between the Occupational Exposure of Trichloroethylene and Kidney Cancer. AB - Trichloroethylene (TCE) has been widely used as a degreasing agent in many manufacturing industries. Recently, the International Agency for Research on Cancer presented "sufficient evidence" for the causal relationship between TCE and kidney cancer. The aim of this study was to review the epidemiologic evidences regarding the relationship between TCE exposure and kidney cancer in Korean work environments. The results from the cohort studies were inconsistent, but according to the meta-analysis and case-control studies, an increased risk for kidney cancer was present in the exposure group and the dose-response relationship could be identified using various measures of exposure. In Korea, TCE is a commonly used chemical for cleaning or degreasing processes by various manufacturers; average exposure levels of TCE vary widely. When occupational physicians evaluate work-relatedness kidney cancers, they must consider past exposure levels, which could be very high (>100 ppm in some cases) and associated with jobs, such as plating, cleaning, or degreasing. The exposure levels at a manual job could be higher than an automated job. The peak level of TCE could also be considered an important exposure-related variable due to the possibility of carcinogenesis associated with high TCE doses. This review could be a comprehensive reference for assessing work-related TCE exposure and kidney cancer in Korea. PMID- 24955247 TI - NKT Cell Responses to B Cell Lymphoma. AB - Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally impaired. In a mouse model of blastoid variant mantle cell lymphoma, treatment of tumor-bearing mice with a potent NKT cell agonist, alpha-galactosylceramide (alpha-GalCer), resulted in a significant decrease in disease pathology. Ex vivo studies demonstrated that NKT cells from alpha-GalCer treated mice produced IFN-gamma following alpha-GalCer restimulation, unlike NKT cells from vehicle-control treated mice. These data demonstrate an important role for NKT cells in the immune response to an aggressive hematologic malignancy like mantle cell lymphoma. PMID- 24955248 TI - In Vitro and In Vivo Antimalarial Activity of Ficus thonningii Blume (Moraceae) and Lophira alata Banks (Ochnaceae), Identified from the Ethnomedicine of the Nigerian Middle Belt. AB - Drug resistance in Plasmodium falciparum requires that new drugs must be developed. Plants are a potential source for drug discovery and development. Two plants that used to treat febrile illnesses in Nigeria were tested for in vitro and in vivo antimalarial activity and cytotoxicity in cancer cell lines. Methanol, hexane, and ethyl acetate leaf extracts of Ficus thonningii and Lophira alata were active in in vitro assays against P. falciparum NF54 (sensitive) and K1 (multiresistant) strains. Hexane extracts of F. thonningii and L. alata were the most effective extracts in in vitro assays with IC50 of 2.7 +/- 1.6 MUg/mL and 2.5 +/- 0.3 MUg/mL for NF54 and 10.4 +/- 1.6 MUg/mL and 2.5 +/- 2.1 MUg/mL for K1 strain. All extracts were nontoxic in cytotoxicity assays against KB human cell line with IC50 of over 20 MUg/mL, demonstrating selectivity against P. falciparum. In vivo analysis shows that hexane extracts of both plants reduced parasitaemia. At the maximum dose tested, L. alata had a 74.4% reduction of parasitaemia while F. thonningii had a reduction of 84.5%, both extracts prolonged animal survival in mice infected with P. berghei NK65 when compared with vehicle treated controls. The antiplasmodial activity observed justifies the use of both plants in treating febrile conditions. PMID- 24955249 TI - Alterations of eye movement control in neurodegenerative movement disorders. AB - The evolution of the fovea centralis, the most central part of the retina and the area of the highest visual accuracy, requires humans to shift their gaze rapidly (saccades) to bring some object of interest within the visual field onto the fovea. In addition, humans are equipped with the ability to rotate the eye ball continuously in a highly predicting manner (smooth pursuit) to hold a moving target steadily upon the retina. The functional deficits in neurodegenerative movement disorders (e.g., Parkinsonian syndromes) involve the basal ganglia that are critical in all aspects of movement control. Moreover, neocortical structures, the cerebellum, and the midbrain may become affected by the pathological process. A broad spectrum of eye movement alterations may result, comprising smooth pursuit disturbance (e.g., interrupting saccades), saccadic dysfunction (e.g., hypometric saccades), and abnormal attempted fixation (e.g., pathological nystagmus and square wave jerks). On clinical grounds, videooculography is a sensitive noninvasive in vivo technique to classify oculomotion function alterations. Eye movements are a valuable window into the integrity of central nervous system structures and their changes in defined neurodegenerative conditions, that is, the oculomotor nuclei in the brainstem together with their directly activating supranuclear centers and the basal ganglia as well as cortical areas of higher cognitive control of attention. PMID- 24955251 TI - Comparison of carotid intima-media thickness in pediatric patients with metabolic syndrome, heterozygous familial hyperlipidemia and normals. AB - Background. Our goal was to compare the carotid intimal-medial thickness (CIMT) of untreated pediatric patients with metabolic syndrome (MS), heterozygous familial hyperlipidemia (heFH), and MS+heFH against one another and against a control group consisting of healthy, normal body habitus children. Methods. Our population consisted of untreated pediatric patients (ages 5-20 yrs) who had CIMT measured in a standardized manner. Results. Our population included 57 with MS, 23 with heFH, and 10 with MS+heFH. The control group consisted of 84 children of the same age range. Mean CIMT for the MS group was 469.8 MU m (SD = 67), 443.8 MU m (SD = 61) for the heFH group, 478.3 MU m (SD = 70) for the MS+heFH group, and 423.2 MU m (SD = 45) for the normal control group. Significance differences between groups occurred for heFH versus MS (P = 0.022), heFH versus control (P = 0.038), MS versus control (P = 9.0E - 10), and MS+heFH versus control (P = 0.003). Analysis showed significant negative correlation between HDL and CIMT (r = -0.32, P = 0.03) but not for LDL, triglycerides, BP, waist circumference, or BMI. Conclusion. For pediatric patients, the thickest CIMT occurred for patients with MS alone or for those with MS+heFH. This indicates that MS, rather than just elevated LDL, accounts for more rapid thickening of CIMT in this population. PMID- 24955250 TI - Assessing the current market of sunscreen: a cross-sectional study of sunscreen availability in three metropolitan counties in the United States. AB - Sunscreen use is recommended for the prevention of sunburn and skin cancer. Little is known regarding sunscreen availability in high versus low income communities. We analyzed sunscreen availability in three large metropolitan counties to determine the relationship between availability and community demographics. We included sun care products in all pharmacies and supermarkets open as of July 2013 in representative high and low income zip codes in Cook County, Illinois, Miami-Dade County, Florida, and San Diego County, California. We recorded the percentage of tanning oil, sunscreens with a sun protection factor (SPF) < 15, SPF > 15, physical sunscreens, spray sunscreens, mean price per ounce (PPO), and mean SPF. Of the total products assessed, 11.0% were tanning oils, with physical sunscreens accounting for only 3.4% of the available sunscreens and 46.2% of sunscreens being spray-on. A comparison between higher and lower income zip codes demonstrated a significantly increased percentage of sunscreens with SPF < 15 in high income zip codes. Lower income zip codes had higher percentages of sunscreens with SPF > 15 and higher PPO, even when taking into account SPF. Further studies of sunscreen usage patterns in different populations must take into account sunscreen availability and price, as these significantly differ based on the community demographic. PMID- 24955252 TI - Prostate cancer in South Africa: pathology based national cancer registry data (1986-2006) and mortality rates (1997-2009). AB - Prostate cancer is one of the most common male cancers globally; however little is known about prostate cancer in Africa. Incidence data for prostate cancer in South Africa (SA) from the pathology based National Cancer Registry (1986-2006) and data on mortality (1997-2009) from Statistics SA were analysed. World standard population denominators were used to calculate age specific incidence and mortality rates (ASIR and ASMR) using the direct method. Prostate cancer was the most common male cancer in all SA population groups (excluding basal cell carcinoma). There are large disparities in the ASIR between black, white, coloured, and Asian/Indian populations: 19, 65, 46, and 19 per 100 000, respectively, and ASMR was 11, 7, 52, and 6 per 100 000, respectively. Prostate cancer was the second leading cause of cancer death, accounting for around 13% of male deaths from a cancer. The average age at diagnosis was 68 years and 74 years at death. For SA the ASIR increased from 16.8 in 1986 to 30.8 in 2006, while the ASMR increased from 12.3 in 1997 to 16.7 in 2009. There has been a steady increase of incidence and mortality from prostate cancer in SA. PMID- 24955253 TI - Urodynamic evaluation after high-intensity focused ultrasound for patients with prostate cancer. AB - This prospective study assesses the impact of high-intensity focused ultrasound (HIFU) on lower urinary tract by comparing pre- and postoperative symptoms and urodynamic changes. Thirty consecutive patients with clinically organ-confined prostate cancer underwent urodynamic study before HIFU and then at 3-6 months after surgery. Continence status and symptoms were analyzed by means of International Prostate Symptoms Score IPSS and International Index Erectile Function IIEF5. As a result, there were a significant improvement in bladder outlet, maximum flow at uroflowmetry, and reduction in postvoid residual PVR at 6 month follow-up and a concomitant significant reduction of detrusor pressure at opening and at maximum flow. De novo overactive bladder and impaired bladder compliance were detected in 10% of patients at 3 months, with progressive improvement at longer follow-up. Baseline prostate volume and length of the procedure were predictors of 6-month IPSS score and continence status. In conclusion, following HIFU detrusor overactivity, decreased bladder compliance and urge incontinence represent de novo dysfunction due to prostate and bladder neck injury during surgery. However, urodynamic study shows a progressive improvement in all storage and voiding patterns at 6-month follow-up. Patients with high prostate volume and long procedure length suffered from irritative symptoms even at long term. PMID- 24955254 TI - Insomnia in sweden: a population-based survey. AB - Aims. Estimate the prevalence of insomnia and examine effects of sex, age, health problems, sleep duration, need for treatment, and usage of sleep medication. Methods. A sample of 1,550 subjects aged 18-84 years was selected for a telephone interview. The interview was completed by 1,128 subjects (72.8%). Results. 24.6% reported insomnia symptoms. Insomnia disorder, that is, insomnia symptoms and daytime consequences, was reported by 10.5%. The prevalence was similar among all age groups, with the exception of women aged 40-49 years who demonstrated a significantly higher prevalence, 21.6%. Having at least one physical or psychiatric disorder was reported by 82.8% of subjects with insomnia disorder. Mean sleep duration for subjects with insomnia disorder was 5.77 hours on weeknights and 7.03 hours on days off/weekends. The corresponding figures for subjects without insomnia disorder were 7.04 hours and 7.86 hours, respectively. Among those with insomnia disorder 62.5% expressed a need for treatment, and 20.0% used prescribed sleep medication regularly. Conclusions. Insomnia disorder is highly prevalent in the population. There are significant associations between insomnia disorder and physical and psychiatric disorders. A majority of subjects with insomnia disorder expressed a need for treatment, indicating a public health problem. PMID- 24955255 TI - Efficient electrochemical N-alkylation of N-boc-protected 4-aminopyridines: towards new biologically active compounds. AB - The use of electrogenerated acetonitrile anion allows the alkylation of N-Boc-4 aminopyridine in very high yields, under mild conditions and without by-products. The high reactivity of this base is due to its large tetraethylammonium counterion, which leaves the acetonitrile anion "naked." The deprotection of the obtained compounds led to high yields in N-alkylated 4-aminopyridines. Nonsymmetrically dialkylated 4-aminopyridines were obtained by subsequent reaction of monoalkylated ones with t-BuOK and alkyl halides, while symmetrically dialkylated 4-aminopyridines were obtained by direct reaction of 4-aminopyridine with an excess of t-BuOK and alkyl halides. Some mono- and dialkyl-4 aminopyridines were selected to evaluate antifungal and antiprotozoal activity; the dialkylated 4-aminopyridines 3ac, 3ae and 3ff showed antifungal towards Cryptococcus neoformans; whereas 3cc, 3ee and 3ff showed antiprotozoal activity towards Leishmania infantum and Plasmodium falciparum. PMID- 24955257 TI - Substrate Directed Regioselective Monobromination of Aralkyl Ketones Using N Bromosuccinimide Catalysed by Active Aluminium Oxide: alpha -Bromination versus Ring Bromination. AB - Bromination of aralkyl ketones using N-bromosuccinimide in presence of active Al2O3 provided either alpha -monobrominated products in methanol at reflux or mononuclear brominated products in acetonitrile at reflux temperature with excellent isolated yields depending on the nature of substrate employed. The alpha -bromination was an exclusive process when aralkyl ketones containing moderate activating/deactivating groups were subjected to bromination under acidic Al2O3 conditions in methanol at reflux while nuclear functionalization was predominant when aralkyl ketones containing high activating groups were utilized for bromination in presence of neutral Al2O3 conditions in acetonitrile at reflux temperature. In addition, easy isolation of products, use of inexpensive catalyst, short reaction time (10-20 min), and safe operational practice are the major benefits in the present protocol. PMID- 24955256 TI - Synthesis and biological activities of 4-aminoantipyrine derivatives derived from betti-type reaction. AB - The present work deals with the synthesis and evaluation of biological activities of 4-aminoantipyrine derivatives derived from a three-component Betti reaction. The synthesis was initiated by the condensation of aromatic aldehyde, 4 aminoantipyrine, and 8-hydroxyquinoline in presence of fluorite as catalyst in a simple one-step protocol. The reactions were stirred at room temperature for 10 15 min achieving 92-95% yield. The structures of synthesized derivatives were established on the basis of spectroscopic and elemental analysis. All derivatives 4(a-h) were screened in vivo and in vitro for anti-inflammatory and anthelmintic activity against a reference drug, Diclofenac and Albendazole, respectively. The screening results show that compounds 4c, 4d, 4f, and 4h were found to possess potential anti-inflammatory activity while compounds 4a, 4b, 4e, and 4g are potent anthelmintic agents when compared with reference drugs, respectively. The bioactivity of these derivatives has also been evaluated with respect to Lipinski's rule of five using molinspiration cheminformatics software. PMID- 24955258 TI - Antimicrobial and Dyeing Properties of Reactive Dyes with Thiazolidinon-4-one Nucleus. AB - Four imines, the condensation products of 2,4-dioxo-4-phenylbutanal with four primary amines, were condensed with mercapto acetic acid to obtain thiazolidinon 4-ones which on subsequent condensation with vanillin and isatin separately yielded eight thiazolidin-4-one derivatives. The chemical structures of the synthesized compounds were elucidated by elemental analysis, molecular weight determination, IR and (1)H and (13)C NMR spectral measurements. Antibacterial and antifungal properties were studied in vitro against two bacteria and two fungi. The dyeing potential of synthesized reactive dyes was investigated with regard to silk, wool, cotton, and polyester fabrics under hot and cold dyeing conditions. PMID- 24955259 TI - Correction of Malpositioned Implants through Periodontal Surgery and Prosthetic Rehabilitation Using Angled Abutment. AB - When dental implants are malpositioned in relation to the adjacent teeth and alveolar bone or in an excessive buccal or lingual position, the final prosthesis rehabilitation impairs the peri-implant health of the gingival tissues and the aesthetics of the patient. Thus, the purpose of this case was to report and discuss a multidisciplinary protocol for the treatment of a compromised maxillary tooth in a patient with an abscess in his right central incisor due to an excessive buccal implant position. The patient presented with an implant supported provisional restoration on his right maxillary central incisor and a traumatic injury in his left central incisor. The treatment protocol consisted in (i) abutment substitution to compensate the incorrect angulation of the implant, (ii) clinical crown lengthening, (iii) atraumatic extraction of the left central incisor, and (iv) immediate implant placement. Finally, (v) a custom abutment was fabricated to obtain a harmonious gingival contour around the prosthetic crown. In conclusion, when implants are incorrectly positioned in relation to the adjacent teeth, associated with soft-tissue defects, the challenge to create a harmonious mucogingival contours may be achieved with an interdisciplinary approach and with the placement of an appropriate custom abutment. PMID- 24955260 TI - Endodontic and esthetic management of a dilacerated maxillary central incisor having two root canals using cone beam computed tomography as a diagnostic aid. AB - Traumatic injuries to the primary dentition are quite common. When primary teeth are subjected to trauma, force transmission and/or invasion of the underlying tooth germs lying in close proximity can result in a variety of disturbances in the permanent successors. Few of these disturbances include hypoplasia, dilaceration, or alteration in the eruption sequence and pattern. Dilaceration is defined as an angulation or sharp bend or curve in the linear relationship of the crown of a tooth to its root. A rare case of maxillary left central incisor having crown dilaceration and Vertucci's type II canal configuration with symptomatic periapical periodontitis is reported. Cone beam computed tomography was used for better understanding of the anomaly and complicated root canal morphology. The tooth was successfully managed by nonsurgical root canal therapy and restoration with resin composite to restore esthetics. PMID- 24955261 TI - Pneumomediastinum associated with pneumopericardium and epidural pneumatosis. AB - Spontaneous pneumomediastinum is a relatively rare benign condition. It may rarely be associated with one or combination of pneumothorax, epidural pneumatosis, pneumopericardium, or subcutaneous emphysema. We present a unique case with four of the radiological findings in a 9-year-old male child who presented to our emergency department with his parents with complaints of unproductive cough, dyspnea, and swelling on chest wall. Bilateral subcutaneous emphysema was palpated on anterior chest wall from sternum to midaxillary regions. His anteroposterior and lateral chest radiogram revealed subcutaneous emphysema and pneumomediastinum. His thorax computed tomography to rule out life threatening conditions revealed bilateral subcutaneous, mediastinal, pericardial, and epidural emphysema without pneumothorax. He was transferred to pediatric intensive care unit for close monitorization and conservative treatment. He was followed-up by chest radiographs. He was relieved from symptoms and signs around the fifth day and he was discharged at the seventh day. Diagnosis of pneumomediastinum is often made based on physical findings and plain radiographs. It may not be as catastrophic as it is seen. Close cardiopulmonary monitorization is mandatory for complications and accompanying conditions. Most patients with uncomplicated spontaneous pneumomediastinum respond well to oxygen and conservative management without any specific treatment. PMID- 24955262 TI - Peganum harmala L. Intoxication in a Pregnant Woman. AB - Peganum harmala L. is a plant widely distributed in the Mediterranean region. It is commonly used in traditional medicine in Morocco as sedative and abortifacient but exposes users to the risk of overdose and poisoning. The pharmacologically active compounds of this plant include a number of beta -carboline and quinazoline alkaloids responsible of its pharmacological and toxicological effects. We report the case of a 24-year-old woman, 22 weeks pregnant, intoxicated with the seeds of Peganum harmala L. On admission, she had disturbance of consciousness, uterine contraction, and oliguria. Laboratory tests revealed renal failure and liver injury, and she benefited then from hemodialysis. During hospitalization, she was intubated after deterioration of consciousness and presented a spontaneous expulsion of the fetus. After extubation, she kept unusual sequelae: cerebellar ataxia and peripheral polyneuropathy. Physicians in regions using Peganum harmala L. as traditional medicine must be able to detect symptoms of its toxicity, in order to establish early gastrointestinal decontamination. The prognosis of this intoxication is variable; most cases can be managed successfully; but in high doses of intoxication, evolution can be fatal. PMID- 24955263 TI - Intrauterine growth retardation fetus with trisomy 16 mosaicism. AB - Fetal trisomy 16 is considered uniformly lethal early in gestation. It has been reported to be associated with the variability of clinical features and outcomes. Mosaic trisomy 16 leads to a high risk of abnormality in prenatal cases. Intrauterine growth retardation (IUGR) is a common outcome of mosaic trisomy 16. Herein, we report on the case of Thai male IUGR fetus with trisomy 16 mosaicism. The fetal body was too small. Postmortem investigation of placenta revealed the abnormality including small placenta with furcated cord insertion and single umbilical cord artery. Cytogenetic study demonstrated trisomy 16 that was found 100% in placenta and only 16% in the fetal heart while other organs had normal karyotype. In addition, cardiac and other internal organs examination revealed normal morphology. PMID- 24955264 TI - Idiopathic Acquired Hemophilia A with Undetectable Factor VIII Inhibitor. AB - Objective. We present the case of a 73-year-old female, with no family or personal history of a bleeding disorder, who had a classic presentation for acquired hemophilia A. Factor VIII activity was low but detectable and a factor VIII inhibitor was undetectable. Methods. The patient's plasma was comprehensively studied to determine the cause of the acquired coagulopathy. Using the Nijmegen modification of the Bethesda assay, no factor VIII autoantibody was measureable despite varying the incubation time from 1 to 3 hours. Results. The aPTT was prolonged at 46.8 seconds, which did not correct in the 4 : 1 mix but did with 1 : 1 mix. Using a one stage factor VIII activity assay, the FVIII activity was 16% and chromogenic FVIII activity was also 16%. The patient was treated with recombinant FVII and transfusion, significantly reducing bleeding. Long-term therapy was initiated with cyclophosphamide and prednisone with normalization of FVIII activity. Conclusions. Physicians can be presented with the challenging clinical picture of an acquired factor VIII inhibitor without a detectable inhibitor by the Bethesda assay. Standard therapy for an acquired hemophilia A should be considered. PMID- 24955265 TI - Refractory Classical Hodgkin Lymphoma Presenting with Atypical Cutaneous Involvement and Diagnosis of ZZ Phenotype Alpha-1 Antitrypsin Deficiency. AB - Cutaneous Hodgkin lymphoma is a rare condition. Specific neoplastic involvement can be primary (confined to the skin) or secondary to systemic involvement (metastatic). Cutaneous involvement by HL usually occurs late in the course and is associated with poor prognosis; however in some cases it can exhibit indolent behavior. Skin involvement with nonspecific cutaneous findings may represent a paraneoplastic syndrome. We describe a case of 46-year-old white male patient presented with rash and lymphadenopathy which led to the diagnosis of stage IVE mixed cellularity classical Hodgkin lymphoma with skin involvement. His disease was refractory to multiple lines of chemotherapy including (1) AVD (doxorubicin/bleomycin/dacarbazine), (2) brentuximab, and (3) bendamustine, he later achieved complete remission with (4) GCD (gemcitabine/carboplatin/dexamethasone) salvage regimen. Bleomycin was not given secondary to poor pulmonary function tests. His treatment was complicated after AVD with multiple pneumothoraces which unmasked the diagnosis of ZZ phenotype alpha-1 antitrypsin (ATT) deficiency. Simultaneous existence of Hodgkin lymphoma and ATT is rarely reported. PMID- 24955266 TI - Blinding Orbital Apex Syndrome due to Onodi Cell Mucocele. AB - The onodi cell is a posterior ethmoidal cell that is pneumatized laterally or superiorly to the sphenoid sinus with close proximity to the optic nerve. A mucocele, a benign, expansile, cyst-like lesion of the paranasal sinuses, may uncommonly involve the onodi cell causing compression of the optic nerve and nearby structures. In this paper, we report a rare case of onodi cell mucocele causing orbital apex syndrome, with prompt recovery after endoscopic removal. However, optic neuropathy did not improve and the patient remained blind. PMID- 24955267 TI - Bilateral pseudarthrosis of the femoral neck in a 25-year-old male with hereditary hypophosphatemic rickets. AB - Hereditary hypophosphatemic rickets (HHR) is a rare disorder of renal phosphate wasting and the most common form of heritable rickets. Here, we report a case of an active 25-year-old male with HHR showing atraumatic bilateral femoral neck pseudarthrosis after 4 years of consecutive knee pain. A conservative therapy was administered, taking into account both the risks of surgical treatment and the little impairment even in the sport activities which the patient experienced. PMID- 24955268 TI - Kimura's Disease in a Caucasian Female: A Very Rare Cause of Lymphadenopathy. AB - Introduction. Kimura's disease is a rare chronic inflammatory disorder characterized by the head and neck lymphadenopathy often accompanied by eosinophilia and elevated serum IgE. It is benign condition with unknown etiology usually affecting young men of Asian race. Affected Caucasians are very rare. Case Presentation. We report a clinically and histopathologically typical case of this disease in a 40-year-old Caucasian female. In differential diagnosis particular attention has been paid to angiolymphoid hyperplasia with eosinophilia and neoplasms. Conclusion. The diagnosis of Kimura's disease can be very difficult and misleading; it is important not to ignore histopathological features. The presented patient has been under follow-up with no more symptoms of the disease for the last 1.5 years. PMID- 24955269 TI - Laryngeal giant cell tumor: a case report and review of the literature. AB - Giant cell tumor (GCT) is a benign neoplasm arising most commonly in the long bones. GCTs of the larynx (GCTL) are relatively rare, and only individual case reports are documented in the literature. Patients with such tumors may present with hoarseness and anterior neck swelling. We present a 59-year-old man with hoarseness and enlarging anterior neck mass for 3 months. A fiberscopy revealed a submucosal swelling of the left subglottic trachea. Computed tomography and magnetic resonance imaging of the larynx demonstrated a large, well-defined, inhomogeneous enhancing mass at the left thyroid cartilage, which was obstructed entirely. The anterior neck mass was biopsied for histopathological analysis, which showed multinodularity with intervening vascularized connective tissues. The mass was made up of mononuclear cells and distributed multinucleated giant cells. The mitotic activity of the mononuclear cells was as high as 6 per 10 high power fields. Pathologic consultation resulted in a diagnosis of giant cell tumor. The patient underwent total laryngectomy and, postoperatively, he did well without recurrence or metastasis for two and a half years. PMID- 24955270 TI - Cytopathologic, histopathologic, and immunohistochemical features of intrahepatic clear cell bile duct adenoma: a case report and review of the literature. AB - Intrahepatic clear cell bile duct adenoma is extremely rare, with only 3 previous cases reported in the literature. The cause of cytoplasmic clearing in clear cell bile duct adenoma has not been previously investigated. Distinguishing clear cell bile duct adenoma from other clear cell tumors, particularly clear cell cholangiocarcinoma, can be challenging. Previous studies have shown loss of CD10 expression and focal CD56 expression in cholangiocarcinoma. Expressions of CD10 and CD56 have not been previously studied in clear cell bile duct adenoma. A 37 year-old morbidly obese woman was diagnosed with a 2.8 cm intrahepatic clear cell bile duct adenoma following segmental hepatic resection. Histochemical analysis of the tumor suggested the cause of cytoplasmic clearing in the neoplastic cells to be mucin and not glycogen or lipid. On immunohistochemical staining, the neoplastic cells demonstrated staining for CK7, CA 19-9, polyclonal CEA, CD10 (apical), CD56 (focal), and vimentin. Ki-67 highlighted less than 2% of tumor cell nuclei. This is the first report to study the etiology of cell clearing in clear cell bile duct adenoma. Expression of CD10 in clear cell bile duct adenoma may help distinguish clear cell bile duct adenoma from clear cell cholangiocarcinoma. PMID- 24955271 TI - Intravascular large B-cell lymphoma presenting as interstitial lung disease. AB - Intravascular large B-cell lymphoma (IVLBL) is a rare subtype of diffuse large B cell lymphoma that resides in the lumen of blood vessels. Patients typically present with nonspecific findings, particularly bizarre neurologic symptoms, fever, and skin lesions. A woman presented with shortness of breath and a chest CT scan showed diffuse interstitial thickening and ground glass opacities suggestive of an interstitial lung disease. On physical exam she was noted to have splenomegaly. The patient died and at autopsy was found to have an IVLBL in her lungs as well as nearly all her organs that were sampled. Although rare, IVLBL should be included in the differential diagnosis of interstitial lung disease and this case underscores the importance of the continuation of autopsies. PMID- 24955272 TI - Septic bursitis in an 8-year-old boy. AB - Background. The prepatellar bursa can become inflamed owing to repeated trauma. Prepatellar bursitis is extremely rare in children. Methods. We report the case of an 8-year-old boy who was treated for an erythematous, swollen, and severely painful right knee, fever, inability to bear weight on the leg, and purulent material draining from a puncture wound. We describe the differential diagnosis for tender swollen knee, including infection, gout, rheumatoid arthritis, and osteoarthritis. If untreated, prepatellar bursitis can progress to patellar osteomyelitis. Results. Wound cultures grew Streptococcus pyogenes, with the infection resolving with amoxicillin. Conclusions. A high index of suspicion is necessary in children presenting with prepatellar bursitis to prevent potentially devastating sequelae of infection of the septic joint. PMID- 24955273 TI - Aspiration pneumonitis caused by polyethylene glycol-electrolyte solution treated with conservative management. AB - Polyethylene glycol (PEG) electrolyte solution, Golytely, is an osmotic laxative commonly used in preoperative bowel cleansing. In this case report, a 9-year-old boy developed aspiration pneumonitis following accidental infusion of PEG solution into his right lung following migration of his nasogastric tube (NGT). Hypoxemia and tachypnea without respiratory failure were observed after infusion. Because PEG is a nonabsorbable toxic material, previous case reports have advocated for the performance of bronchoalveolar lavage (BAL) in the treatment of PEG pneumonitis. With close monitoring, our patient was able to be successfully treated without the need for invasive interventions including BAL or intubation. Generalizations about PEG absorption in the lung based on its permeability in the gastrointestinal tract should not deter the use of more conservative treatment in the appropriate patient. PMID- 24955275 TI - A Rare and Unusual Case of Burkitt's Lymphoma Presenting with a Prostate Mass in a 12-Year-Old Boy. AB - Burkitt's lymphoma is the most frequent subtype of non-Hodgkin's lymphoma in childhood. Radiographic findings are protean and can often overlap with other neoplastic and nonneoplastic processes. We present an unusual case of Burkitt's lymphoma in a 12-year-old boy presenting with a one-week history of urinary retention, dysuria, and "tailbone pain," as well as a 4-week history of jaw pain, initially treated as a dental abscess. On dental radiography, the patient was found to have resorption of alveolar bone adjacent to the lower first molars bilaterally, in keeping with "floating teeth," classically associated with Langerhans cell histiocytosis. Additionally, a large, eccentric, prostatic mass was noted, prompting the inclusion of rhabdomyosarcoma on the differential diagnosis, with subsequent definitive diagnosis of Burkitt's lymphoma on tissue and bone marrow biopsy. This case highlights the imaging overlap of these childhood neoplasms with an unusual lymphomatous prostate mass. It is important that the radiologists and pediatricians be aware of this potential overlap and the unusual presentation of Burkitt's lymphoma. PMID- 24955274 TI - The melatonin receptor agonist ramelteon effectively treats insomnia and behavioral symptoms in autistic disorder. AB - Children with autism spectrum disorders (ASD), including autistic disorder, frequently suffer from comorbid sleep problems. An altered melatonin rhythm is considered to underlie the impairment in sleep onset and maintenance in ASD. We report three cases with autistic disorder in whom nocturnal symptoms improved with ramelteon, a selective melatonin receptor agonist. Insomnia and behavior, assessed using the Clinical Global Impression-Improvement Scale, improved in two cases with 2 mg ramelteon and in the third case with 8 mg ramelteon. Our findings demonstrate that ramelteon is effective not only for insomnia, but for behavioral problems as well, in patients with autistic disorder. PMID- 24955276 TI - Bihemispheric posterior inferior cerebellar artery occurring with an azygos anterior cerebral artery: case study. AB - Variations in intracranial vasculature are well known. We report a rare anatomic variation in a patient who underwent cerebral angiography for suspected intracranial aneurysm. Digital subtraction angiography revealed a bihemispheric posterior inferior cerebellar artery (PICA) and an azygous anterior cerebral artery (ACA). There was no evidence of any aneurysm or vascular abnormality. To our knowledge, this is the first reported case of a patient with a common PICA supplying both the cerebellar hemispheres and a common ACA supplying ACA territory bilaterally. It is important for the physician to be aware of these anatomical variations in order to differentiate a normal variant from a pathological condition. PMID- 24955277 TI - An Unusual Case of Ascending Pancreatitis with Mediastinal Involvement: A Case Report with CT and MRI Findings. AB - Fluid collections are common findings of pancreatitis and spread, more often, along preferential drainage pathways in the abdomen. In some rare cases, fluid collections may spread towards extra-abdominal sites like the mediastinum leading to the formation of mediastinal collections. We present the case of a 52-years old man with pain in the right upper quadrant of the abdomen and mid-epigastrium lasting for some hours. Laboratory tests suggested a diagnosis of pancreatitis. CT and subsequent MRI revealed changes consistent with acute exacerbation on chronic pancreatitis spreading to the mediastinum and to the greater omentum. The patient received medical treatment and reported gradual improvement in his laboratory results and CT findings. PMID- 24955278 TI - Large pyoderma gangrenosum-like ulcers: a rare presentation of granulomatosis with polyangiitis. AB - Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis (WG), is a rare systemic vasculitis that classically manifests as necrotizing granulomas of the upper and lower respiratory tract, kidneys, and blood vessels; however, it may affect any organ system, including the skin. Cutaneous manifestations occur in up to 45% of patients during the disease course, and are the presenting feature in 9% to 14% of patients. The most common skin lesion specific to GPA is palpable purpura, with the histopathologic correlate of leukocytoclastic vasculitis. However, a wide range of clinical and histologic features may be seen. We herein report a case of a previously healthy 52-year-old Caucasian man who presented with multiple progressively enlarging painful ulcers on his face, upper extremities, back, and abdomen over a two-month period. Skin biopsies revealed pyoderma gangrenosum-like features. Serological tests were positive for PR3/c-ANCA. Six months later, the patient developed recurrent episodes of sinusitis associated with nasal bleeds and eventually nasal septum perforation. Despite aggressive treatment with Cyclophosphamide and steroids over one year, the patient had persistent nonhealing large ulcers and developed multiple lung nodules with cavitary lesions. PMID- 24955279 TI - Cognitive dysfunction after on-pump operations: neuropsychological characteristics and optimal core battery of tests. AB - Postoperative cognitive dysfunction (POCD) is a mild form of perioperative ischemic brain injury, which emerges as memory decline, decreased attention, and decreased concentration during several months, or even years, after surgery. Here we present results of our three neuropsychological studies, which overall included 145 patients after on-pump operations. We found that the auditory memory span test (digit span) was more effective as a tool for registration of POCD, in comparison with the word-list learning and story-learning tests. Nonverbal memory or visuoconstruction tests were sensitive to POCD in patients after intraoperative opening of cardiac chambers with increased cerebral air embolism. Psychomotor speed tests (digit symbol, or TMT A) registered POCD, which was characteristic for elderly atherosclerotic patients. Finally, we observed that there were significant effects of the order of position of a test on the performance on this test. For example, the postoperative performance on the core tests (digit span and digit symbol) showed minimal impairment when either of these tests was administered at the beginning of testing. Overall, our data shows that the selection of tests, and the order of which these tests are administered, may considerably influence the results of studies of POCD. PMID- 24955281 TI - Morphologic and osteometric analysis of the skull of markhoz goat (Iranian angora). AB - This study provides some comprehensive osteometric and morphologic descriptions of the skull region of the Markhoz goat. Totally, 17 osteometric parameters of eight skulls of Markhoz goat were measured and expressed as mean +/- SD. A skull length of 18.67 +/- 0.66, a cranial length of 11.1 +/- 0.38, a facial length of 10.23 +/- 0.76, a skull index of 47.77 +/- 1.96, a cranial index of 54.04 +/- 2.29, a facial index of 100.77 +/- 6.85 and a foramen magnum index of 89.32 +/- 14.1 were recorded. Morphologically frontal bone did not constitute the caudal extent of frontal surface; rather it was formed by the parietal bone. There were two supraorbital foramina in both sides. The prominent facial tuberosity lies dorsally to the 3rd cheek tooth. The infraorbital foramen was single on either side which was located directly dorsally to the junction of the first and second upper premolar. The orbits were round and complete and located on a frontolateral oblique plane. The basilar part of the occipital bone was surrounded by two pairs of muscular tubercles with similar size. The temporal line was continuous of the temporal crest and ran over the parietal bone. In conclusion, the morphologic and osteometric data of Markhoz goat are comparable to other ruminants. PMID- 24955280 TI - Survey of Dermatophytes in Stray Cats with and without Skin Lesions in Northern Italy. AB - The aim of this study was to determine the prevalence of dermatophytes in stray cats with and without clinical lesions from different colonies in rural and urban areas of Milan and surroundings in northern Italy. Stray cats (273) were caught during a trap-neuter-release (TNR) program conducted in different colonies of northern Italy in both rural and urban areas. Each cat was examined in dark environment with a Wood's lamp prior to sample collection. Hair or scales exhibiting typical fluorescence were removed with a pair of sterile hemostats and cultured. The hair of all cats was then sampled by Mackenzie modified brush technique regardless of the presence or absence of skin lesions attributable to dermatophytosis. All the hair samples were subjected to fungal culture. 15 cats were positive (5.5%). Microsporum canis was the most common dermatophyte isolated (13/15). The only other isolated dermatophyte was Trichophyton mentagrophytes (2/15). Our estimated prevalence of dermatophytes in stray cats was much lower than other Italian studies on the same population. PMID- 24955282 TI - The effect of adjuvant zinc therapy on recovery from pneumonia in hospitalized children: a double-blind randomized controlled trial. AB - Objectives. Pneumonia is one of the common mortality causes in young children. Some studies have shown beneficial effect of zinc supplements on treatment of pneumonia. The present study aimed to investigate the effects of short courses of zinc administration on recovery from this disease in hospitalized children. Methods. In a parallel Double-Blind Randomized Controlled Trial at Ayatollah Golpaygani Hospital in Qom, 120 children aged 3-60 months with pneumonia were randomly assigned 1 : 1 to receive zinc or placebo (5 mL every 12 hours) along with the common antibiotic treatments until discharge. Primary outcome was recovery from pneumonia which included the incidence and resolving clinical symptoms and duration of hospitalization. Results. The difference between two groups in all clinical symptoms at admittance and the variables affecting the disease such as age and sex were not statistically significant (P < 0.05) at baseline. Compared to the placebo group, the treatment group showed a statistically significant decrease in duration of clinical symptoms (P = 0.044) and hospitalization (P = 0.004). Conclusions. Supplemental administration of zinc can expedite the healing process and results in faster resolution of clinical symptoms in children with pneumonia. In general, zinc administration, along with common antibiotic treatments, is recommended in this group of children. It can also reduce the drug resistance caused by multiple antibiotic therapies. This trial is approved by Medical Ethic Committee of Islamic Azad University in Iran (ID Number: 8579622-Q). This study is also registered in AEARCTR (The American Economic Association's Registry for Randomized Controlled Trials). This trial is registered with RCT ID: AEARCTR-0000187. PMID- 24955283 TI - Role of BRCA1 and BRCA2 gene mutations in epithelial ovarian cancer in Indian population: a pilot study. AB - Ovarian cancer is a silent killer as most patients have non-specific symptoms and usually present in advanced stage of the disease. It occurs due to certain genetic alterations and mutations namely founder mutations, 187delAG and 5385insC in BRCA1 and 6174delT in BRCA2 which are associated with specific family histories. These highly penetrant susceptibility genes responsible for approximately half of families containing 2 or more ovarian cancer cases account for less than 40% of the familial excess malignancy risk. The remaining risk may be due to single nucleotide polymorphisms (SNPs) which are single base change in a DNA sequence with usual alternatives of two possible nucleotides at a given position. Preliminary study involving 30 women with histologically proven epithelial ovarian cancer was conducted and their detailed genetic analysis was carried out. Regions of founder mutations on BRCA1 and BRCA2 were amplified and sequenced using primers designed based on 200 bp upstream and downstream regions of the mutation sites. Five sequence variants in BRCA1 were identified of which three novel sequence variants were found in 23 patients while in BRCA2, one novel sequence variant was found. The three founder mutations 187delAG, 5385insC in BRCA1 and 6174delT in BRCA2 were not seen in any of the subjects. PMID- 24955284 TI - Transgene-mediated co-suppression of DNA topoisomerase-1 gene in Caenorhabditis elegans. AB - Ectopic expression of multi-transgenic copies can result in reduced expression of the transgene and can induce silence of endogenous gene; this process is called as co-suppression. Using a transgene-mediated co-suppression technique, we demonstrated the biological function of DNA topoisomerase-1 (top-1) in C. elegans development. Introduction of full-length top-1 transgene sufficiently induced the co-suppression of endogenous top-1 gene, causing embryonic lethality and abnormal germline development. We also found that the co-suppression of top-1 gene affected morphogenesis, lifespan and larval growth that were not observed in top 1 (RNAi) animals. Strikingly, co-suppression effects were significantly reduced by the elimination of top-1 introns, suggesting that efficient co-suppression may require intron(s) in C. elegans. Sequence analysis revealed that the introns 1 and 2 of top-1 gene possess consensus binding sites for several transcription factors, including MAB-3, LIN-14, TTX-3/CEH-10, CEH-1, and CEH-22. Among them, we examined a genetic link between ceh-22 and top-1. The ceh-22 is partially required for the specification of distal tip cells (DTC), which functions as a stem cell niche in the C. elegans gonad. Intriguingly, top-1 (RNAi) significantly enhanced DTC loss in ceh-22 mutant gonads, indicating that top-1 may play an important role in CEH-22-mediated DTC fate specification. Therefore, our findings suggest that transgene-mediated co-suppression facilitates the silencing of the specific genes and the study of gene function in vivo. PMID- 24955285 TI - The interaction of the ErbB4 intracellular domain p80 with alpha-enolase in the nuclei is associated with the inhibition of the neuregulin1-dependent cell proliferation. AB - We have shown that the receptor tyrosine kinase ErbB4 signals neuregulin1 stimulated proliferation of human cells. Some isoforms of ErbB4 are cleaved to release the soluble intracellular domain p80; however, the function of p80 in cell proliferation remained unclear. Here we propose the possibility for p80 as a negative feedback modulator of ErbB4-mediated cell proliferation. Cells exposed to lower doses of neuregulin1 displayed a stimulated proliferation and contained ErbB4 but barely p80. By contrast, cells exposed to its higher doses displayed a suppressed proliferation and contained p80 but barely ErbB4. Analyses with cells overexpressing the p80 wild type and mutants indicated that nuclear p80 inhibits cell proliferation independently of the tyrosine kinase activity. A screen for a novel protein that interacts with p80 identified alpha-enolase, which is reported as a transcriptional inhibitor for the proliferation-associated c-myc gene. The c myc mRNA expression was induced by lower doses of neuregulin1 but was suppressed by its higher doses. Subcellular fractionation demonstrated the localization of not only p80 and alpha-enolase but also the decrease of the functional c-myc amount in the nuclei of cells exposed to higher doses of neuregulin1. These results suggested that p80, which is generated from ErbB4 and translocates to the nuclei, interacts with alpha-enolase and inhibits neuregulin1-dependent ErbB4 mediated cell proliferation by impairing the c-myc gene transcription. PMID- 24955286 TI - Mobility Lab to Assess Balance and Gait with Synchronized Body-worn Sensors. AB - This paper is a commentary to introduce how rehabilitation professionals can use a new, body-worn sensor system to obtain objective measures of balance and gait. Current assessments of balance and gait in clinical rehabilitation are largely limited to subjective scales, simple stop-watch measures, or complex, expensive machines not practical or largely available. Although accelerometers and gyroscopes have been shown to accurately quantify many aspects of gait and balance kinematics, only recently a comprehensive, portable system has become available for clinicians. By measuring body motion during tests that clinicians are already performing, such as the Timed Up and Go test (TUG) and the Clinical Test of Sensory Integration for Balance (CITSIB), the additional time for assessment is minimal. By providing instant analysis of balance and gait and comparing a patient's performance to age-matched control values, therapists receive an objective, sensitive screening profile of balance and gait strategies. This motion screening profile can be used to identify mild abnormalities not obvious with traditional clinical testing, measure small changes due to rehabilitation, and design customized rehabilitation programs for each individual's specific balance and gait deficits. PMID- 24955289 TI - Identifying Adverse Drug Events by Relational Learning. AB - The pharmaceutical industry, consumer protection groups, users of medications and government oversight agencies are all strongly interested in identifying adverse reactions to drugs. While a clinical trial of a drug may use only a thousand patients, once a drug is released on the market it may be taken by millions of patients. As a result, in many cases adverse drug events (ADEs) are observed in the broader population that were not identified during clinical trials. Therefore, there is a need for continued, post-marketing surveillance of drugs to identify previously-unanticipated ADEs. This paper casts this problem as a reverse machine learning task, related to relational subgroup discovery and provides an initial evaluation of this approach based on experiments with an actual EMR/EHR and known adverse drug events. PMID- 24955288 TI - Exploring the Therapeutic Efficacy of Glioma Vaccines Based on Allo- and Syngeneic Antigens and Distinct Immunological Costimulation Activators. AB - The efficacy of a various immunotherapeutic immunisation strategies for malignant glioma brain cancer was evaluated in the syngeneic CNS-1 Lewis rat glioma model. A prototype glioma cancer vaccine, which was composed of multivalent antigens derived from allogeneic and syngeneic cells and lysates, formed the prototype preparation of antigens. These antigens reflect the autologous antigens derived from the patient's surgically removed tumor tissue, as well as allogeneic antigens form glioma tumor tissue surgically removed from donor patients. This antigen mixture provides a broad spectrum of tumor associated antigens (TAA) and helps to prevent escape of tumor immune surveillance when given as a vaccine. This antigen preparation was administered in a therapeutic setting with distinct single or multiple co-stimulation-favouring immunostimulants and evaluated for inhibition of tumor growth. Our prototype vaccine was able to arrest progression of tumor growth when co-delivered in a specific regimen together with the costimulating multi-TLR agonist, Bacille Calmette Guerin (BCG) and interleukin-2, or with the Toll-Like receptor (TLR) 7/8 activator resiquimod. PMID- 24955287 TI - Autoantibodies against C1q as a Diagnostic Measure of Lupus Nephritis: Systematic Review and Meta-analysis. AB - OBJECTIVES: To evaluate the diagnostic accuracy of C1q autoantibodies in identifying lupus nephritis (LN) in patients with systemic lupus erythematosus (SLE). DATA SOURCES AND METHODS: Citation indexes were searched and 370 articles published from 1977 to 2013 were evaluated. The 31 selected studies included in the meta-analysis were cross-sectional in design. Among the 31 studies, 28 compared anti-C1q antibodies in 2769 SLE patients with (n=1442) and without a history of LN (n=1327). Nine studies examined anti-C1q in 517 SLE patients with active (n=249) and inactive LN (n=268). Hierarchical summary receiver operating characteristic (HSROC) random effects models were fitted to pool estimates of accuracy across the studies. RESULTS: Anti-C1q antibodies discriminated between patients with and without a history of LN, with a median specificity of 73.5%. The HSROC model estimated the corresponding sensitivity to be 70.4%. A hypothetical patient with a 55% prior probability of having a history of LN as opposed to no history (the median prevalence across 28 eligible studies) would have a post-test probability of 76.4% following a positive test result (positive predictive value) or 33.0% following a negative test result (negative predictive value). For discriminating active from inactive LN the median specificity of anti C1q antibodies was 80%, with a corresponding estimated sensitivity value 75.7% based on the HSROC model. A hypothetical patient with a 56% prior probability of active as opposed to inactive LN (the median prevalence across the 9 eligible studies) would have a post-test probability of 82.8% following a positive test result or 27.9% following a negative test result. CONCLUSIONS: Although C1q antibodies are associated with lupus nephritis the post-test probabilities are not sufficiently convincing to provide reasonable certainty of the presence or absence of history of disease/active disease. PMID- 24955290 TI - A comprehensive cardiovascular disease lifestyle treatment controlled trial among high-risk African Americans. AB - BACKGROUND: The purpose of this study was to assess the effects of a comprehensive lifestyle intervention on modifiable cardiovascular risk factors among high-risk African Americans. METHODS: The study included a randomized treatment/controlled intervention trial among 136 African Americans residing in Atlanta, GA who were overweight and had elevated blood pressure. The treatment group was exposed to 3-months of a multi-component intervention and the control to an abbreviated 6-week intervention after the completion of the treatment group's intervention. The main outcomes included mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP), mean waist circumference, mean body mass index (BMI), mean number of times exercise per week, mean number of servings of fruits and vegetables per day, and mean level of daily stress. Data were collected at baseline and at 6-month follow-up. Separate linear regressions were used with an established significance level of p < 0.05. RESULTS: Results revealed significant net improvement in treatment group when compared to controls in waist circumference, BMI, times weekly exercise, servings of fruit and vegetables per day (p < 0.001, 0.04, 0.02, 0.002, respectively). Diastolic blood pressure also significantly improved within the treatment group for overall hypertensives from baseline to 6-month follow-up (90.9 mmHg to 83.1 mmHg, p = 0.002). CONCLUSION: These results show that a comprehensive lifestyle intervention can improve cardiovascular risk factor profile among high risk African Americans. Caregivers should encourage patients to participate in such programs and public health policymakers should allocate resources to community based health oriented organizations to implement comprehensive lifestyle program. PMID- 24955291 TI - Yoga and eating disorders: is there a place for yoga in the prevention and treatment of eating disorders and disordered eating behaviours? AB - THIS PAPER ADDRESSES THE QUESTION: what can the practice of yoga offer the field of eating disorders in terms of prevention and treatment? Regarding prevention, preliminary research suggests that yoga may be effective in decreasing risk factors, and increasing protective factors, for eating disorders. Yoga was also found to be helpful in a small number of treatment studies. However, findings are not consistent across studies, which are limited in number, and due to the preliminary nature of this body of research, most studies have weaknesses in their designs (e.g. observational design, no control groups, or small sample sizes). The basic tenets of yoga, anecdotal reports of its effectiveness, its high accessibility and low cost, and initial research findings suggest that yoga may offer promise for the field of eating disorders. Two options are suggested for prevention: (1) eating disorder prevention can be integrated into ongoing yoga classes and (2) yoga can be integrated into eating disorder prevention programmes. Regarding treatment, it is important to examine the effectiveness of different teaching styles and practices for different eating disorders. Potential harms of yoga should also be explored. Further research, using stronger study designs, such as randomised, controlled trials, is needed. PMID- 24955292 TI - General Practitioners are poor at identifying the eating disorders. PMID- 24955293 TI - Sampling Strategies to Evaluate the Performance of Unknown Predictors. AB - The focus of this paper is on how to select a small sample of examples for labeling that can help us to evaluate many different classification models unknown at the time of sampling. We are particularly interested in studying the sampling strategies for problems in which the prevalence of the two classes is highly biased toward one of the classes. The evaluation measures of interest we want to estimate as accurately as possible are those obtained from the contingency table. We provide a careful theoretical analysis on sensitivity, specificity, and precision and show how sampling strategies should be adapted to the rate of skewness in data in order to effectively compute the three aforementioned evaluation measures. PMID- 24955294 TI - Two Natural ent-kauranoids as Novel Wnt Signaling Inhibitors. AB - Constitutively active Wnt signaling frequently occurs in most colon cancers. Therefore, inhibitors of Wnt signaling pathway could provide rational therapeutic effects for colorectal malignancy. Within this paper, we identified two inhibitors of Wnt signaling pathway, rabdoternin B and maoecrystal I from a natural ent-kauranoid library by a dual-luciferase reporter gene assay. The two compounds inhibited Wnt signaling pathway in a concentration-dependent manner and exhibited selective cytotoxicity toward a number of colon carcinoma cell lines SW480, HCT116, and HT29, with only weak cytotoxicity towards the normal colonic epithelial cell line CCD-841-CoN. Rabdoternin B and maoecrystal I treatment induced G2/M phase arrest efficiently in SW480 cells as revealed by flow cytometry analysis. A further study found that maoecrystal I decreased the expression of Wnt signaling target genes, including c-myc, cyclin D1, survivin and Axin2 in colon cancer cells. Collectively our data suggests that rabdoternin B and maoecrystal I are novel inhibitors of canonical Wnt signaling pathway and may possess potentials for colon cancer therapy. PMID- 24955296 TI - Five New Guanacastane-Type Diterpenes from Cultures of the Fungus Psathyrella candolleana. AB - Five new guanacastane-type diterpenes, named guanacastepenes P-T (1-5), were isolated from cultures of the fungus Psathyrella candolleana. Their structures were elucidated on the basis of extensive spectroscopic methods. All of the compounds were tested for their 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) inhibitory activity. Compound 3 exhibited inhibitory activity against both human and mouse isozymes of 11beta-HSD1 with IC50 values of 6.2 and 13.9 MUM, respectively. PMID- 24955295 TI - Evaluation of Various Factors Affecting Bioconversion of l-Tyrosine to l-DOPA by Yeast Yarrowia lipolytica-NCIM 3450 Using Response Surface Methodology. AB - ABSTRACT: 3,4-Dihydroxy l-phenylalanine (l-DOPA) is considered a potent drug for the treatment of Parkinson disease. Physical and nutritional parameters where optimized by using Yarrowia lipolytica-NCIM 3450 to accomplished the highest production of l-DOPA. Screenings of critical components were completed by using a Plackett-Burman design, while further optimization was carried out using the Box Behnken design. The optimized factor levels predicted by the model were pH 6.1, 1.659 g L(-1) yeast extract, 1.491 g L(-1)l-tyrosine and 0.0290 g L(-1) CuSO4. The predicted yield of l-DOPA with these levels was 1.319 g L(-1), while actual yield obtained was 1.273 g L(-1). The statistical analysis revealed that model is significant with F value 19.55 and R(2) value 0.9514. This process resulted in a 3.594-fold increase in the yield of l-DOPA. l-DOPA was confirmed by HPTLC and HPLC analysis. Thus, Yarrowia lipolytica-NCIM 3450 has potential to be a new source for the production of l-DOPA. PMID- 24955297 TI - Triterpenoids and Sterols from the Leaves and Twigs of Melia azedarach. AB - Two new triterpenoids (1 and 2) and a new sterol (3), together with six known constituents (4-9), were isolated from the leaves and twigs of Melia azedarach. Their chemical structures were elucidated on the basis of spectroscopic analysis. PMID- 24955298 TI - Panaxadiol and panaxatriol derivatives as anti-hepatitis B virus inhibitors. AB - ABSTRACT: 28 Derivatives of panaxadiol (PD) and panaxatriol were synthesized and evaluated for their anti-HBV activity on HepG 2.2.15 cells, of which 17 derivatives inhibited HBV DNA replication. Compounds 4, 9, 10, 14, and 15 showed moderate activity against HBV DNA replication with IC50 values ranged from 7.27 to 28.21 MUM compared with PD. In particular, 3-O-2'-thenoyl panaxadiol (4) inhibited not only HBV DNA replication (IC50 = 16.5 MUM, SI > 115.7) but also HBsAg (IC50 = 30.8 MUM, SI > 62.0) and HBeAg (IC50 = 18.2 MUM, SI > 105.14) secretions. Their structure-activity relationships were discussed for guiding future research toward the discovery of new anti-HBV agents. PMID- 24955299 TI - Sterols and Terpenoids from Viburnum odoratissimum. AB - ABSTRACT: A new stigmasterol type natural product, viburodorol A (1), along with eleven known sterols and terpenoids (2-12), were isolated from the aerial parts of Viburnum odoratissimum. The structure of 1 was elucidated on the basis of comprehensive spectroscopic analysis. It's noteworthy that compound 2, the major constituent of this plant, can significantly stimulate glucose absorption in insulin resistant HepG2 cells without affecting cell viability. Furthermore, this compound can also restore the glucose absorption in DXMS-induced insulin resistant 3T3-L1 cells. PMID- 24955300 TI - Synthesis of l-Ascorbic Acid Lactone Derivatives. AB - A small focused library which comprised of l-AA lactone derivatives was built with a facile method. This reported method was optimized by modifying the acidity of the solvent. As a result, 12 l-AA lactones were synthesized. Among these lactones, lactones 8-12 were new compounds. The cytotoxicity of these synthetic compounds were investigated. PMID- 24955301 TI - Differential effect of artemisinin against cancer cell lines. AB - The present study aims at defining the differential cytotoxicity effect of artemisinin toward P815 (murin mastocytoma) and BSR (kidney adenocarcinoma of hamster) cell lines. Cytotoxicity was measured by the growth inhibition using MTT assay. These in vitro cytotoxicity studies were complemented by the determination of apoptotic DNA fragmentation and Annexin V- streptavidin-FITC assay. Furthermore, we examined the in vitro synergism between artemisinin and the chemotherapeutic drug, vincristin. The in vivo study was investigated using the DBA2/P815 (H2d) mouse model. While artemisinin acted on both tumor cell lines, P815 was much more sensitive to this drug than BSR cells, as revealed by the respective IC50 values (12 uM for P815 and 52 uM for BSR cells). On another hand, and interestingly, apoptosis was induced in P815 but not induced in BSR. These data, reveal an interesting differential cytotoxic effect, suggesting the existence of different molecular interactions between artemisinin and the studied cell lines. In vivo, our results clearly showed that the oral administration of artemisinin inhibited solid tumor development. Our study demonstrates that artemisinin caused differential cytotoxic effects depending not only on the concentration and time of exposure but also on the target cells. PMID- 24955302 TI - Microbiota from Litopenaeus vannamei: digestive tract microbial community of Pacific white shrimp (Litopenaeus vannamei). AB - Bacteria capable of producing different extracellular enzymes of potential relevance in digestive processes were isolated from the stomach, hepatopancreas and intestine of Pacific white shrimp Litopenaeus vannamei. A total of 64 strains with proteolytic activity were isolated and grouped into 16 clusters based on morphological characteristics: 4 groups were isolated from the intestine; 5 from the hepatopancreas; and 7 from the stomach. Molecular methods (16S rRNA gene amplification and sequencing) and phenotypic criteria (Gram stain, catalase and oxidase tests, cell and colony morphology) were used to identify strains, which corresponded to Pseudoalteromonas and Vibrio genera. These genera are reported to form part of the digestive tract microbial community in shrimp. Both genera were isolated from all three tested tissues. One member of each morphologic group was selected for analysis of the presence of amylases, lipases/esterases and chitinases. Most of the strains had all the tested enzymes, indicating that the L. vannamei digestive tract microbiotic flora includes groups which have the potential to contribute to the degradation of dietary components. PMID- 24955303 TI - Current Management Strategies for Acute Esophageal Variceal Hemorrhage. AB - Acute esophageal variceal hemorrhage is one of the clinical events that define decompensated cirrhosis and is associated with high rates of morbidity and mortality. Although recent treatment strategies have led to improved outcomes, variceal hemorrhage still carries a 6-week mortality rate of 15-20%. Current standards in its treatment include antibiotic prophylaxis, infusion of a vasoactive drug and endoscopic variceal ligation. The placement of a transjugular intrahepatic portosystemic shunt (TIPS) is considered for patients that have treatment failure or recurrent bleeding. Recurrent hemorrhage is prevented with the combination of a non-selective beta-blocker and endoscopic variceal ligation. These recommendations however assume that all patients with cirrhosis are equal. Based on a review of recent evidence, a strategy in which patients are stratified by Child class, the main predictor of outcomes, is proposed. PMID- 24955305 TI - Journal publishing: never ending saga. PMID- 24955304 TI - Novel Pharmacologic Approaches to Treating Cannabis Use Disorder. AB - With large and increasing numbers of people using cannabis, the development of cannabis use disorder (CUD) is a growing public health concern. Despite the success of evidence-based psychosocial therapies, low rates of initial abstinence and high rates of relapse during and following treatment for CUD suggest a need for adjunct pharmacotherapies. Here we review the literature on medication development for the treatment of CUD, with a particular focus on studies published within the last three years (2010-2013). Studies in both the human laboratory and in the clinic have tested medications with a wide variety of mechanisms. In the laboratory, the following medication strategies have been shown to decrease cannabis withdrawal and self-administration following a period of abstinence (a model of relapse): the cannabinoid receptor agonist, nabilone, and the adrenergic agonist, lofexidine, alone and in combination with dronabinol (synthetic THC), supporting clinical testing of these medication strategies. Antidepressant, anxiolytic and antipsychotic drugs targeting monoamines (norepinephrine, dopamine, and serotonin) have generally failed to decrease withdrawal symptoms or laboratory measures of relapse. In terms of clinical trials, dronabinol and multiple antidepressants (fluoxetine, venlafaxine and buspirone) have failed to decrease cannabis use. Preliminary results from controlled clinical trials with gabapentin and N-acetylcysteine (NAC) support further research on these medication strategies. Data from open label and laboratory studies suggest lithium and oxytocin also warrant further testing. Overall, it is likely that different medications will be needed to target distinct aspects of problematic cannabis use: craving, ongoing use, withdrawal and relapse. Continued research is needed in preclinical, laboratory and clinical settings. PMID- 24955306 TI - Role of active and inactive cytotoxic immune response in human immunodeficiency virus dynamics. AB - OBJECTIVES: Mathematical models can be helpful to understand the complex dynamics of human immunodeficiency virus infection within a host. Most of work has studied the interactions of host responses and virus in the presence of active cytotoxic immune cells, which decay to zero when there is no virus. However, recent research highlights that cytotoxic immune cells can be inactive but never be depleted. METHODS: We propose a mathematical model to investigate the human immunodeficiency virus dynamics in the presence of both active and inactive cytotoxic immune cells within a host. We explore the impact of the immune responses on the dynamics of human immunodeficiency virus infection under different disease stages. RESULTS: Standard mathematical and numerical analyses are presented for this new model. Specifically, the basic reproduction number is computed and local and global stability analyses are discussed. CONCLUSION: Our results can give helpful insights when designing more effective drug schedules in the presence of active and inactive immune responses. PMID- 24955307 TI - Community-Based Risk Communication Survey: Risk Prevention Behaviors in Communities during the H1N1 crisis, 2010. AB - OBJECTIVES: The present study aimed to investigate the prevalence of and factors associated with H1N1 preventive behaviors in a community-based population. METHODS: A cross-sectional study was conducted in three urban and two rural communities in Korea. Interviews were conducted with 3462 individuals (1608 men and 1854 women) aged >= 19 years during February-March 2010. Influenza-related information including anxiety, preventive behaviors and their perceived effectiveness, vaccination status, past influenza-like illness symptoms, and sources of and trust in information was obtained. RESULTS: Among 3462 participants, 173 reported experiencing influenza-like illness symptoms within the past 12 months. The mean H1N1 preventive behavior score was 25.5 +/- 5.5 (out of a possible 40). The percent of participants reporting high perceived effectiveness and high anxiety was 46.2% and 21.4%, respectively. After controlling for potential confounders, H1N1 preventive behavior scores were predicted by a high (beta = 3.577, p < 0.001) or moderate (beta = 2.529, p < 0.001) perception of their effectiveness. Similarly, moderate (beta = 1.516, p < 0.001) and high (beta = 4.103, p < 0.001) anxiety scores predicted high preventive behavior scores. CONCLUSION: Effective methods of promoting population behavior change may be nationwide campaigns through mass media, as well as education and promotion by health care providers and broadcasters. PMID- 24955308 TI - The determinants of participation in physical activity in malaysia. AB - OBJECTIVES: In light of the importance of physical activity, the aim of the present study is to examine the factors affecting participation in physical activity among adults in Malaysia. METHODS: A logistic regression model and the Third National Health and Morbidity Survey consisting of 30,992 respondents were used. RESULTS: Age, income, gender, education, marital status, region, house locality, job characteristics, and medical conditions are significantly associated with participation in physical activity. In particular, old individuals, high income earners, females, the well-educated, widowed or divorced individuals, East Malaysians, urban dwellers, the unemployed, and individuals who are not diagnosed with hypercholesterolemia are less likely to be physically active than others. CONCLUSION: Because sociodemographic and health factors play an important role in determining physical activity, the government should take them into account when formulating policy. PMID- 24955309 TI - The Relationship between Health Behavior and General Health Status: Based on 2011 Korea National Health and Nutrition Examination Survey. AB - OBJECTIVES: The aim of the present study is to investigate the relationship between health behavior and general health status. METHODS: We used data from the 2011 Korea National Health and Nutrition Examination Survey. Mental health was measured by stress recognition and depression. Dietary habit was measured by mixed grain diet. Life pattern was measured by sleeping time and working pattern. Physical activity was measured by walking and exercise. We defined general health status as Euro Quality of Life-5 Dimension (EQ-5Dindex), Euro Quality of Life Visual Analogue Scale (EQ-5Dvas), number of people experienced lying in a sickbed for the last one month, number of days lying in a sickbed for the last one month, and activity limitations. RESULTS: Mental health, dietary habit, life pattern, and physical activity have seven factors. Most of the factors have a significant correlation with EQ-5Dindex, EQ-5Dvas, number of people experienced lying in a sickbed for the last one month, number of days lying in a sickbed for the last one month, and activity limitations. CONCLUSION: Health behavior and general health status have a positive correlation. PMID- 24955310 TI - Emerging Pathogens and Vehicles of Food- and Water-borne Disease Outbreaks in Korea, 2007-2012. AB - OBJECTIVES: Food- and water-borne disease outbreaks (FBDOs) are an important public health problem worldwide. This study investigated the trends in FBDOs in Korea and established emerging causal pathogens and causal vehicles. METHODS: We analyzed FBDOs in Korea by year, location, causal pathogens, and causal vehicles from 2007 to 2012. Information was collected from the FBDOs database in the Korean Centers for Disease Control and Prevention. RESULTS: During 2007-2012, a total of 1794 FBDOs and 48,897 patients were reported. After 2007, FBDOs and patient numbers steadily decreased over the next 2 years and then plateaued until 2011. However, in 2012, FBDOs increased slightly accompanied by a large increase in the number of affected patients. Our results highlight the emergence of norovirus and pathogenic Escherichia coli other than enterohemorrhagic E. coli (EHEC) in schools in 2012. We found that pickled vegetables is an emerging causal vehicle responsible for this problem. CONCLUSION: On the basis of this study we recommend intensified inspections of pickled vegetable manufacturers and the strengthening of laboratory surveillance of relevant pathogens. PMID- 24955311 TI - What does a mathematical model tell about the impact of reinfection in korean tuberculosis infection? AB - OBJECTIVES: According to the Korea Centers for Disease Control and Prevention, new active tuberculosis (TB) cases have increased since 2001. Some key factors explain and characterize the transmission dynamics of Korean TB infection, such as a higher ratio of latent individuals and a new reporting system implemented in 2001, among others. METHODS: We propose a mathematical TB model that includes exogenous reinfection to gain a better understanding of the recent trend for TB incidence. We divide the simulation time window into two periods, 1970-2000 and 2001-2012, according to the implementation date of a new TB detection system. RESULTS: Two sets of parameters, including the transmission rate, the latent period, the recovery rate, and the proportion of exogenous reinfection, are estimated using the least-squares method and calibrated to data on the incidence of active TB. CONCLUSION: Among some key parameters in the model, the case finding effort turned out to be the most significant impacting component on the reduction in the active TB cases. PMID- 24955312 TI - A study of high-risk drinking patterns among generations based on the 2009 Korea national health and nutrition examination survey. AB - OBJECTIVES: The aim of this study was to identify how the drinking patterns of a generation on the paternal side affect those of the next generations by estimating the number of high-risk drinkers by generation according to the Alcohol Use Disorder Identification Test. METHODS: Data were selected from the 2009 Korea National Health and Nutrition Examination Survey conducted by the Korea Centers for Disease Control and Prevention and were analyzed using SPSS 18.0. RESULTS: Later generations started drinking earlier (62.4%, 71.8% and 91.1%, respectively). The majority of the second generation consumed more than 2 4 drinks a month (83.7%), but only a small proportion experienced difficulty in everyday life (9.6%), felt repentance (9.6%), or experienced memory loss (17.9%) after drinking. Unmarried third-generation adults with high-risk-drinking fathers reported more frequent alcohol consumption [odds ratio (OR) 1.441), greater amounts on one occasion (>7 cups for men, OR 1.661; > 5 cups for women, OR 2.078), temperance failure (OR 2.377), and repentance after drinking (OR 1.577). Unmarried third-generation adults with high-risk-drinking grandfathers consumed greater amounts of alcohol on one occasion (OR 3.642), and unmarried third generation women more frequently consumed large amounts of alcohol (>5 cups, OR 4.091). Unmarried third-generation adults with high-risk-drinking fathers were more likely to exhibit high-risk drinking patterns (OR 1.608). Second-generation individuals from a high-risk-drinking first generation were more likely to engage in high-risk drinking (OR 3.705). CONCLUSION: High-risk drinking by a generation significantly affects the high-risk drinking patterns of subsequent generations. PMID- 24955313 TI - Study on the Prevalence of Leptospirosis among Fever Cases Reported from Private Clinics in the Urban areas of Villupuram District, Tamil Nadu, India. AB - OBJECTIVES: To know the prevalence of leptospirosis cases reported in private clinics among fever cases in Villupuram District, Tamil Nadu, India to know its real magnitude of the problem and to diagnose Leptospirosis among fever cases from differential diagnosis. METHODS: 1502 Blood serum samples collected from three urban towns namely Kallakurichi (Latitude: 11 degrees 73' N; Longitude: 78 degrees 97' E), Villupuram (Latitude: 11 degrees 75' N; Longitude: 79 degrees 92' E) and Thindivanam (Latitude: 12 degrees 25' N; Longitude: 79 degrees 65' E) in fifteen clinics based on case definition of leptospirosis delineated by the National Vector Borne Disease Control Programme (NVBDCP), Government of India. Samples were tested in the laboratory of the Zonal Entomological Team (ZET), Cuddalore with Macroscopic Slide Agglutination Test (MSAT) and Ig-M ELISA. RESULT: There were 65 positive cases detected from 1502 blood serum samples in both MSAT and Ig-M ELISA. It could be known that there was 4% cases contributed from private clinics among fever cases. From this study, further it was known that all age groups of people affected irrespective of sexes based on their living condition associated with the environment prevailed of the disease. CONCLUSION: From this study, it was quantified that 4% of cases reported in private clinics among fever cases and its findings ascertained both the importance of differential diagnosis as well as reports that should be included to the Government for knowing its real magnitude for planning. PMID- 24955314 TI - Experiences of Health Related Lifestyles in High Body Fat but Non-obese Female College Students in Korea. AB - OBJECTIVES: The purpose of this study was to describe and understand the lifestyles of non-obese female college students with high body fat (HBF). METHODS: The interview data were collected from 18 female students [body mass index (BMI) <23 kg/m(2) and body fat ratio >=30%] and analyzed by using descriptive phenomenology of Colaizzi. The procedural steps described the phenomenon of interest, collected participants' descriptions of the phenomenon, extracted the meaning of significant statements, organized the meanings into clusters, wrote exhaustive descriptions and then incorporated data into an exhaustive description. RESULTS: The results in 153 restatements, 36 constructed meanings, 22 themes, seven theme clusters, and three categories were deduced. The three categories were: diminished daily concerns of health, changes in living habits by stressors, and perceived unbalance in health. CONCLUSION: This study describes non-obese female university students' experiences with HBF and their lifestyles. The findings have important implications for health promotion for non obese female university students with HBF and must be considered when developing education courses for preparing adults. PMID- 24955315 TI - Sound in the air. PMID- 24955317 TI - Under-reporting of Energy Intake from 24-hour Dietary Recalls in the Korean National Health and Nutrition Examination Survey. AB - OBJECTIVES: Chronic degenerative diseases are closely related to daily eating habits, nutritional status, and, in particular, energy intake. In clarifying these relationships it is very important for dietary surveys to report accurate information about energy intake. This study attempted to identify the prevalence of the under-reporting of energy intake and its related characteristics based on the Korean National Health and Nutrition Examination Survey conducted in the years 2007-2009. METHODS: The present study analyzed dietary intake data from 15,133 adults aged >=19 years using 24-hour dietary recalls. Basal metabolic rates were calculated from the age- and gender-specific equations of Schofield and under-reporting was defined as an energy intake <0.9, represented by the ratio of energy intake to estimated basal metabolic rate. RESULTS: Under reporters (URs) accounted for 14.4% of men and 23.0% of women and the under reporting rate was higher in the age group 30-49 years for both men and women. The results from an analysis of the age-specific socioeconomic characteristics of participants classified as URs showed that under-reporting was high in women living alone and in women with only elementary school education or no education. The results from an analysis of the health-specific characteristics of URs showed that a large proportion of URs had poor self-rated health or were obese, or both, compared with non-URs. The proportion of participants who consumed less than the estimated average requirements for nutrients was significantly higher in URs compared with non-URs. CONCLUSION: The under-reporting of energy intake was associated with age, gender, education level, income level, household status (single-person or multi-person), self-rated health, physical activity, and obesity. PMID- 24955316 TI - Exposure to Dichlorodiphenyltrichloroethane and the Risk of Breast Cancer: A Systematic Review and Meta-analysis. AB - OBJECTIVES: This study extended and updated a meta-analysis of the association between exposure to dichlorodiphenyltrichloroethane (DDT) and the risk of breast cancer. METHODS: We reviewed the published literature on exposure to DDE and breast cancer risk to update a meta-analysis from 2004. The total of 35 studies included 16 hospital-based case-control studies, 11 population-based case-control studies, and 10 nested case-control studies identified through keyword searches in the PubMed and EMBASE databases. RESULTS: The summary odds ratio (OR) for the identified studies was 1.03 (95% confidence interval 0.95-1.12) and the overall heterogeneity in the OR was observed (I (2) = 40.9; p = 0.006). Subgroup meta analyses indicated no significant association between exposure to DDE and breast cancer risk by the type of design, study years, biological specimen, and geographical region of the study, except from population-based case-control studies with estimated DDE levels in serum published in 1990s. CONCLUSION: Existing studies do not support the view that DDE increases the risk of breast cancer in humans. However, further studies incorporating more detailed information on DDT exposure and other potential risk factors for breast cancer are needed. PMID- 24955318 TI - Evaluation of drug abuse relapse event rate over time in frailty model. AB - OBJECTIVES: Drug dependence as a chronic disorder is reversible over time and has a cost burden for individuals, families, and society. An individual who has stopped taking drugs for a long time may start taking drugs again. The variables affecting the reuse of drugs are not well known. Therefore a study of the factors that increase the length of time away from drugs is essential. METHODS: This study used data collected by the Bushehr addiction treatment centers (Tolloe and Pasargadae) from 100 men with drug addiction from March 2006 to September 2010. The shared frailty model was used to study the influence of variables on the duration of time away from drug use. The most common method for entering intra class (personal) correlation is the survival frailty model, which uses parametric survival data for the evaluation of recurrent events. A Weibull distribution for time to event with gamma shared frailty was used. RESULTS: The mean (standard deviation) age and age at onset of opium use of the sample were 33.85 (8.11) and 20.65 (6.87), respectively. About 30% of the men studied had chronic disease and 36% had a mental illness. The mean (frequency mean) of the amount of opium used were 4.73 (3.8) g and 2.54 (1.14) times per day. The desire to end drug use was 97% and 3% for the men with drug addiction and their families, respectively, at the time when the men stopped using opium. The age at onset of opium use [p = 0.046, hazards ratio (HR) = 1.30], history of chronic disease (p = 0.005, HR = 249.635), and marital status (p = 0.06, HR = 0.027) are important in the reuse of opium. CONCLUSION: We found that opium addiction is related to other chronic diseases and to the age at onset of opium use. A prospective study following up individuals with drug addiction who try to stop drug use in addiction treatment centers could help to determine the risk factors of resuming drug use. PMID- 24955319 TI - Virulence Factors of Staphylococcus aureus Isolates in an Iranian Referral Children's Hospital. AB - OBJECTIVES: The clinical importance of Staphylococcus aureus (S. aureus) is attributed to notable virulence factors, surface proteins, toxins, and enzymes as well as the rapid development of drug resistance. The aim of this study was to compare the occurrence of virulence factors produced by S. aureus strains isolated from children in an Iranian referral children's hospital. METHODS: The presence of genes encoding for the enterotoxins A (sea), B (seb), C (sec), D (sed), TSST-1 (tsst), exfoliative toxin A (eta), and exfoliative toxin B (etb) were detected by Multiplex polymerase chain reaction (PCR) using specific primers. In addition, the standardized Kirby-Bauer disc-diffusion method was performed on Mueller-Hinton agar. RESULTS: In total, 133 S. aureus isolates were obtained from different patients. Of these S. aureus isolates, 64 (48%) were methicillin-resistant S. aureus (MRSA), and all of these tested positive for the mecA gene. Regarding the classical enterotoxin genes, sea gene (40.6%) was the most prevalent followed by seb (19.6%), tsst (12.8%), eta (11.3%), etb (9%), sed (4.5%), and sec (3%). Among methicillin-susceptible S. aureus (MSSA) isolates, seb and tsst were the more prevalent toxins in comparison with MRSA isolates (p < 0.05), while the frequency of sea, sed, eta, and etb genes were higher among MRSA isolates (p > 0.05). CONCLUSION: In our study enterotoxin A was produced by 40.6% of the isolates (48% from MRSA and 33% from MSSA isolates) which was higher than in previous reports. According to our results, strict hygiene and preventative measures during food processing are highly recommended. PMID- 24955320 TI - Assessment of the intensive countermeasures in the 2009 pandemic influenza in Korea. AB - OBJECTIVES: It is critical to implement effective multiple countermeasures to mitigate or retain the spread of pandemic influenza. We propose a mathematical pandemic influenza model to assess the effectiveness of multiple countermeasures implemented in 2009. METHODS: Age-specific parameters, including the transmission rate, the proportion of asymptomatic individuals, the vaccination rate, the social distancing rate, and the antiviral treatment rate are estimated using the least-square method calibrated to the incidence data. RESULTS: The multiple interventions (intensive vaccination, social distancing, antivrial treatment) were successfully implemented resulting in the dramatic reduction in the total number of incidence. CONCLUSION: The model output is sensitive to age-specific parameters and this leads to the fact that a more elaborate age group model should be developed and extensive further studies must be followed. PMID- 24955322 TI - Detecting Influenza A (H1N1) pdm09 Virus Infection Using Immunochromatographic Assay. PMID- 24955321 TI - Exposure-Response Relationship Between Aircraft Noise and Sleep Quality: A Community-based Cross-sectional Study. AB - OBJECTIVES: Exposure to aircraft noise has been shown to have adverse health effects, causing annoyance and affecting the health-related quality of life, sleep, and mental states of those exposed to it. This study aimed to determine sleep quality in participants residing near an airfield and to evaluate the relationship between the levels of aircraft noise and sleep quality. METHODS: NEIGHBORING REGIONS OF A MILITARY AIRFIELD WERE DIVIDED INTO THREE GROUPS: a high exposure group, a low exposure group, and a control group. A total of 1082 participants (aged 30-79 years) completed a comprehensive self-administered questionnaire requesting information about demographics, medical history, lifestyle, and the Pittsburgh Sleep Quality Index. RESULTS: Of the 1082 participants, 1005 qualified for this study. The prevalence of sleep disturbance was 45.5% in the control group, 71.8% in the low exposure group, and 77.1% in the high exposure group (p for trend < 0.001). After adjusting for potential confounding factors, we determined the exposure-response relationship between the degree of aircraft noise and sleep quality. Of the participants with a normal mental status, the prevalence of sleep disturbance was 2.61-fold higher in the low exposure group and 3.52-fold higher in the high exposure group than in the control group. CONCLUSION: The relationship between aircraft noise and health should be further evaluated through a large-scale follow-up study. PMID- 24955325 TI - Improved Classification of Mammograms Following Idealized Training. AB - People often make decisions by stochastically retrieving a small set of relevant memories. This limited retrieval implies that human performance can be improved by training on idealized category distributions (Giguere & Love, 2013). Here, we evaluate whether the benefits of idealized training extend to categorization of real-world stimuli, namely classifying mammograms as normal or tumorous. Participants in the idealized condition were trained exclusively on items that, according to a norming study, were relatively unambiguous. Participants in the actual condition were trained on a representative range of items. Despite being exclusively trained on easy items, idealized-condition participants were more accurate than those in the actual condition when tested on a range of item types. However, idealized participants experienced difficulties when test items were very dissimilar from training cases. The benefits of idealization, attributable to reducing noise arising from cognitive limitations in memory retrieval, suggest ways to improve real-world decision making. PMID- 24955324 TI - Cerebrospinal fluid apolipoprotein E and phospholipid transfer protein activity are reduced in multiple sclerosis; relationships with the brain MRI and CSF lipid variables. AB - Apolipoprotein E (apoE), phospholipid transfer protein (PLTP) activity, lipids, total tau and beta amyloid 1-42 (Abeta42) were measured in cerebrospinal fluid (CSF) from controls (n=38) and multiple sclerosis (MS) patients (n=91). ApoE and PLTP activity were significantly reduced in MS compared to non-inflammatory disease controls (NINDC; p<0.05). In NINDC and MS, apoE correlated with PLTP activity (rs=0.399 and 0.591, respectively), Abeta42 (rs= 0.609 and 0.483, respectively), and total tau (rs=0.748 and 0.380, respectively; all p<0.05). CSF apoE and PLTP significantly contributed to the variance of the normalized brain volume (NBV) and T2 lesion volume in MS (p<0.001 and p<0.05, respectively). ApoE correlated with CSF cholesterol and 24-hydroxycholesterol in all groups; PLTP activity correlated with CSF cholesterol in controls (p<0.05). PMID- 24955326 TI - Experiential Avoidance and Male Dating Violence Perpetration: An Initial Investigation. AB - Dating violence among college students represents a prevalent and serious problem. An abundance of research has examined risk and protective factors for dating violence, although only recently has research begun to focus on risk and protective factors that could be amenable to change in intervention programs. One potential risk factor for dating violence may be experiential avoidance. Using the Acceptance and Action Questionnaire - II (AAQ-II; Bond et al., 2011), we examined whether experiential avoidance was associated with male perpetrated dating violence after controlling for age, relationship satisfaction, and alcohol use. Within a sample of male college students in a current dating relationship (N = 109) results demonstrated that experiential avoidance was positively associated with psychological, physical, and sexual aggression perpetration, and that it remained associated with psychological and sexual aggression after controlling for age, relationship satisfaction, and alcohol use. The implications of these findings for future research and prevention programs are discussed. PMID- 24955327 TI - Hemophagocytic lymphohistiocytosis secondary to T-cell/histiocyte-rich large B cell lymphoma. AB - Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome characterized by dysregulation of the immune system. Impaired function of cytotoxic T cells and natural killer cells is often seen, and T-cell malignancies represent most cases of lymphoma-associated HLH. HLH associated with B-cell lymphoma is rare. We describe a case of a 30-year-old man who presented with fever, splenomegaly, and hyperferritinemia. Bone marrow biopsy revealed T cell/histiocyte-rich large B-cell lymphoma, a rare, aggressive B-cell malignancy. This case highlights the interplay between a pro-inflammatory cytokine microenvironment and tumor-mediated immune suppression, and addresses the importance of accurately diagnosing these entities for appropriate clinical management. PMID- 24955329 TI - Seizure Reduction with Fluoxetine in Dravet Syndrome. AB - An adult woman with Dravet syndrome (documented SCN1A mutation) experienced a marked reduction in seizures when treated with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. The seizure reduction may be partly to reductions associated with aging in Dravet patients, but it appears to be due at least in part to the fluoxetine. A prior preliminary study reported that fenfluramine reduces seizures in patients with Dravet syndrome. Fenfluramine may produce this effect by increasing serotonin brain levels, and SSRIs have been found to possess antiepileptic properties in animal models of epilepsy. Given the known cardiac risks of fenfluramine, consideration of randomized clinical trials with SSRIs should be considered in Dravet syndrome and other epilepsies. PMID- 24955330 TI - Growth charts for patients with Hunter syndrome. AB - Children with mucopolysaccharidosis II (MPS II), also known as Hunter syndrome, an X-linked disorder, suffer from a multisystem dysfunction caused by the accumulation of glycosaminoglycans. However, there has been no systemic report on the growth of patients with MPS II. The purpose of this study is to describe the growth patterns of patients with MPS II and to compare with the patterns of age matched controls. Data (height, weight, age, etc.) was collected in a longitudinal study of Japanese male patients with MPS II (n = 111). The mean birth length was 50.31 +/- 1.42 cm, while the mean birth weight was 3.35 +/- 0.39 kg. The mean final height and weight at 18 years and older were 125.63 +/- 9.09 cm and 37.18 +/- 8.72 kg; corresponding to a difference of -46.40 cm and -25.89 kg lower, when compared with healthy Japanese male controls. The mean birth BMI was 10.84 +/- 3.29 kg/m2, while the mean BMI at 18 years was 29.41 +/- 6.15 kg/m2. The growth pattern in patients with MPS II was characterized by overgrowth for the first several years, although growth velocity fell below that of the normal healthy controls after one year of age. No statistical difference in height was observed between patients with the attenuated and severe phenotypes in each age class. In conclusion, this report describes the natural history of growth in patients with MPS II, which can help in monitoring the progression of the disease as well as assessing therapeutic efficacy. PMID- 24955328 TI - Oxidative post-translational modifications and their involvement in the pathogenesis of autoimmune diseases. AB - Tissue inflammation results in the production of numerous reactive oxygen, nitrogen and chlorine species, in addition to the products of lipid and sugar oxidation. Some of these products are capable of chemically modifying amino acids. This in turn results in changes to the structure and function of proteins. Increasing evidence demonstrates that such oxidative post-translational modifications result in the generation of neo-epitopes capable of eliciting both innate and adaptive immune responses. In this paper, we focus on how free radicals and related chemical species generated in inflammatory environments modulate the antigenicity of self-proteins, resulting in immune responses which involve the generation of autoantibodies against key autoantigens in autoimmune diseases. As examples, we will focus on Ro-60 and C1q in systemic lupus erythematosus, along with type-II collagen in rheumatoid arthritis. This review also covers some of the emerging literature which demonstrates that neo-epitopes generated by oxidation are conserved, as exemplified by the evolutionarily conserved pathogen-associated molecular patterns (PAMPs). We discuss how these observations relate to the pathogenesis of both human autoimmune diseases and inflammatory disease, such as atherosclerosis. The potential for these neo epitopes and the immune responses against them to act as biomarkers or therapeutic targets is also discussed. PMID- 24955331 TI - Development of a Multilevel Framework to Increase Use of Targeted Evidence-Based Practices in Addiction Treatment Clinics. AB - Implementing specific evidence-based practices (EBPs) across a set of addiction treatment providers have been a persistent challenge. In the Advancing Recovery(AR) demonstration project, single state agencies, the entities that distribute federal funds for substance use disorder prevention and treatment services, worked in partnership with providers to increase the use of EBPs in the treatment of addiction. The project supported two cohorts of six 2-year awards. Field observations from the first year of implementation guided development of a multilevel framework (the Advancing Recovery Framework). Government entities and other payers can use the framework as a guide for implementing evidence-based clinical practices within treatment networks. The Advancing Recover Framework calls for a combination of policy and organizational changes at both the payer (government agency) and provider levels. Using the Advancing Recovery Framework, 11 of the 12 AR payer/provider partnerships increased use of clinical EPBs. This article identifies key payer policy changes applied during different phases of EBP program implementation. The public health benefit of the demonstration project was broader use of medication-assisted therapy and continuing care in addiction treatment services. PMID- 24955332 TI - Characterize and Gene Expression of Heat Shock Protein 90 in Marine Crab Charybdis japonica following Bisphenol A and 4-Nonylphenol Exposures. AB - OBJECTIVES: Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone important in the maturation of a broad spectrum of protein. In this study, an HSP90 gene was isolated from Asian paddle crab, Charybdis japonica, as a bio-indicator to monitor the marine ecosystem. METHODS: This work reports the responses of C. japonica HSP90 mRNA expression to cellular stress by endocrine disrupting chemicals (EDCs), such as bisphenol A (BPA) and 4-nonylphenol (NP) using real-time. reverse transcription polymerase chain reaction. RESULTS: The deduced amino acid sequence of HSP90 from C. japonica shared a high degree of homology with their homologues in other species. In a phylogenetic analysis, C. japonica HSP90 is evolutionally related with an ortholog of the other crustacean species. The expression of HSP90 gene was almost distributed in all the examined tissues of the C. japonica crab but expression levels varied among the different body parts of the crabs. We examined HSP90 mRNA expression pattern in C. japonica crabs exposed to EDCs for various exposure times. The expression of HSP90 transcripts was significantly increased in C. japonica crabs exposed to BPA and NP at different concentrations for 12, 24, 48 and 96 hours. The mRNA expression of HSP90 gene was significantly induced in a concentration- and time-dependent manner after BPA or NP exposures for 96 hours. CONCLUSIONS: Taken together, expression analysis of Asian paddle crab HSP90 gene provided useful molecular information about crab responses in stress conditions and potential ways to monitor the EDCs stressors in marine environments. PMID- 24955334 TI - The effect of insurance status and parental education on glycemic control and cardiovascular disease risk profile in youth with Type 1 Diabetes. AB - BACKGROUND: Adult studies have shown a correlation between low socioeconomic status and Type 1 Diabetes complications, but studies have not been done in children to examine the effect of socioeconomic status on risk for future complications. This study investigates the relationship between insurance status and parental education and both glycemic control and cardiovascular disease (CVD) risk factors in youth with type 1 diabetes. METHODS: A cross-sectional study of 295 youth with established type 1 diabetes who underwent examination with fasting blood draw and reported insurance status and parental education. RESULTS: Youth with type 1 diabetes and public insurance had higher hemoglobin A1c (HbA1c), body mass index, hs-CRP, and blood pressure (p < 0.05) than those with private insurance. Insulin regimen varied between insurance groups, and differences in HbA1c and CVD risk factors, except for diastolic blood pressure (DBP), were no longer evident after controlling for insulin regimen. Parental education was not associated with HbA1c or CVD risk factors. CONCLUSIONS: Youth with type 1 diabetes and public insurance have worse glycemic control and elevated CVD risk factors compared to those with private insurance, but this was no longer seen when insulin regimen was controlled for. Further research is needed to look at differences between those with public insurance and private insurance that contribute to differences in type 1 diabetes outcomes, and to identify modifiable risk factors in pediatric patients in order to focus earlier interventions to decrease and prevent future diabetes complications. PMID- 24955335 TI - Endoscopic ultrasound-guided fine-needle aspiration studies: Fanning the flames. PMID- 24955333 TI - Impact of omega-6 fatty acids on cardiovascular outcomes: A review. AB - Poly unsaturated fatty acids (PUFAs) have usually been associated with beneficial health effects on early life and later life disease such as cardiovascular diseases (CVD). Emerging evidence, however, suggests that PUFA species (n-3, n-6) have differential health effects. N-6 PUFAs, in particular, have sparked a scientific debate regarding their role in human physiological processes. Current dietary recommendations for n-6 fatty acids have been based on animal studies, insufficient epidemiological evidence and mixed PUFA interventions, therefore, require reconsideration. This review has analyzed human epidemiological and interventional studies, published in the last five years, focusing on n-6 fatty acids' impact on CVD outcomes (CVD events, blood lipids, blood pressure, inflammation, oxidative stress/atherosclerosis). The evidence is mixed, with differential effects within the n-6 fatty acid series. These outcomes are also dependent on ethnicity and background health status. Further, data from developing countries are sparse, thus, well designed intervention trials and population based studies in developing country settings on specific n-6 fatty acid intake and health effects are desired. PMID- 24955336 TI - Endoscopic ultrasound-guided fine needle aspiration: How to obtain a core biopsy? AB - Endoscopic ultrasound (EUS)-guided fine needle aspiration has emerged as the procedure of choice to obtain samples to reach a definitive diagnosis of lesions of the gastrointestinal tract and of adjacent organs. The obtainment of a tissue core biopsy presents several advantages that can substantially contribute to the widespread diffusion of EUS utilization in the community and in countries where cytology expertise may be difficult to be achieved. This article will review the EUS-guided fine needle biopsy techniques developed so far, the clinical results, their limitations as well as their future perspective. PMID- 24955337 TI - To fine needle aspiration or not? An endosonographer's approach to pancreatic cystic lesions. AB - Endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) is an established diagnostic tool in the management of pancreatic cystic lesions (PCLs). Due to the proximity to the target lesion, the fine diagnostic needle travels through only minimal normal tissues. The risks of bleeding, pancreatitis and infection are small. Valuable diagnostic morphological information can be obtained by EUS before the use of FNA. The additional cytopathologic and cyst fluid analysis for the conventional markers such as amylase, carcinoembryonic antigen (CEA) and CA19.9 improves the diagnostic capability. Pancreatic cyst fluid CEA concentration of 192 ng/mL is generally the most agreed cutoff to differentiate mucinous from non-mucinous lesion. A fluid amylase level of <250 IU/L excludes the diagnosis of pseudocyst. Technical tips of EUS-FNA and the limitations of the procedure are discussed. Promising technique and FNA needle modifications have been described to improve the diagnostic yield at the cytopathologic analysis. The use of novel cyst fluid proteomics and deoxyribonucleic acid-based biomarkers of the PCLs are reviewed. Although it is considered a safe procedure, EUS-FNA is not a routine in every patient. Recommendations of the role of EUS-FNA at various common clinical scenarios are discussed. PMID- 24955338 TI - When to puncture, when not to puncture: Pancreatic masses. AB - Endoscopic ultrasound (EUS) has evolved to become a crucial tool for the evaluation of pancreatic diseases, among them solid pancreatic lesions. However, its ability to determine whether a lesion is malignant or not is difficult to establish based only in the endosonographic image. EUS-guided fine needle aspiration (EUS-FNA) allows obtaining a cytological and/or histological sample from pancreatic lesions, with a high overall accuracy and low complication rates. Although the clinical usefulness of EUS-FNA for pancreatic diseases is widely accepted, the indications for tissue diagnosis of pancreatic lesions suspected to be malignant is still controversial. This review highlights the diagnostic accuracy and complications of EUS-FNA, focusing on its current indications. PMID- 24955339 TI - When to puncture, when not to puncture: Submucosal tumors. AB - Subepithelial masses of the gastrointestinal (GI) tract are a frequent source of referral for endosonographic evaluation. Subepithelial tumors most often appear as protuberances in the GI tract with normal overlying mucosa. When there is a need to obtain a sample of the mass for diagnosis, endoscopic ultrasound (EUS) - guided fine-needle aspiration (FNA) is superior to other studies and should be the first choice to investigate any subepithelial lesion. When the decision is made to perform EUS-guided FNA several technical factors must be considered. The type and size of the needle chosen can affect diagnostic accuracy, adequacy of sample size and number of passes needed. The use of a stylet or suction and a fanning or standard technique during EUS-guided FNA are other factors that must be considered. Another method proposed to improve the efficacy of EUS-guided FNA is having an on-site cytopathologist or cytotechnician. Large or well differentiated tumors may be more difficult to diagnose by standard EUS-FNA and the use of a biopsy needle can be used to acquire a histopathology sample. This can allow preservation of tissue architecture and cellularity of the lesion and may lead to a more definitive diagnosis. Alternatives to FNA such as taking bite on-bite samples and endoscopic submucosal resection (ESMR) have been studied. Comparison of these two techniques found that ESMR has a significantly higher diagnostic yield. Most complications associated with EUS-FNA such as perforation, infection and pancreatitis are rare and the severity and incidence of these adverse events is not known. Controversy exists as to the optimal method in which to perform EUS-FNA and larger prospective trials are needed. PMID- 24955341 TI - Do the morphological features of walled off pancreatic necrosis on endoscopic ultrasound determine the outcome of endoscopic transmural drainage? AB - BACKGROUND AND OBJECTIVE: Endoscopic transmural drainage is an effective, but technically demanding treatment modality for walled off pancreatic necrosis (WOPN). The factors that determine the outcome of endoscopic treatment for WOPN have been infrequently studied. We aim to retrospectively correlate the morphological features of WOPN on endoscopic ultrasound (EUS) with the outcome of endoscopic transmural drainage. PATIENTS AND METHODS: Over the last 3 years, 43 patients (36 males; mean age 36.04 +/- 10.06 years) with symptomatic WOPN were treated by an attempted endoscopic drainage. The correlation between the morphological features of WOPN and the type of treatment offered as well as the number of endoscopic procedures undergone by the patient was assessed. RESULTS: The mean size of WOPN was 9.95 +/- 2.75 cm with <10%, 10-40% and >40% solid debris being present in 6, 33, and 4 patients, respectively. Patients with <10% necrotic debris needed only single session of endoscopic drainage, whereas patients with 10-40% solid debris needed two or more sessions. Patients with >40% solid debris either needed direct endoscopic debridement or surgical necrosectomy. The extent of necrosis correlated significantly (r = 0.703, P < 0.001) with the type of treatment received by the patient. With increasing size of the collection (r = 0.320, P = 0.047) and the amount of the solid debris (r = 0.800, P < 0.001), there was a significant increase in the number of endoscopic procedures required for successful outcome by the patient. CONCLUSIONS: The morphological features of WOPN on EUS have important therapeutic implications with collections having large size and more solid debris needing more aggressive therapeutic method for the successful outcome. PMID- 24955340 TI - Can elastography replace fine needle aspiration? AB - Endoscopic ultrasound (EUS) is one of the best diagnostic methods for diseases of the digestive tract and surrounding organs. Whereas EUS-guided fine needle aspiration (FNA) has been very useful for providing histological confirmation for previously hard to reach lesions, elastography is aiming to obtain a "virtual biopsy" by assessing differences in elasticity between the normal and pathological - usually malignant - tissue. A question that arises is whether EUS elastography has reached a stage where it might successfully supplant the use of EUS-FNA in some of its clinical indications. The main indications of EUS-guided FNA are listed in this article and published data on the usage of elastography in these settings is reviewed for each one. In some of the indications, a plethora of studies have been published, notably for the evaluation of solid pancreatic masses and lymph nodes, while in others there is little relevant data (submucosal masses, left liver lesions, left adrenal masses), or elastography simply is not suitable as a diagnostic means (cystic lesions). Our conclusion is that elastography is not yet ready to replace EUS-FNA in its indications, but should complement it in various settings, especially for the assessment of lymph nodes. It can only be considered an alternative on a case-by-case basis, in situations where FNA is regarded as a contraindication. Furthermore, it could be used in conjunction with other imaging techniques, such as contrast-enhanced EUS, in order to further improve the accuracy of non-invasive EUS assessment, possibly making the case for a more limited or targeted use of EUS-FNA in selected cases. PMID- 24955342 TI - Pancreatic cystic lesions: The value of contrast-enhanced endoscopic ultrasound to influence the clinical pathway. AB - BACKGROUND AND OBJECTIVES: Cystic pancreatic lesions are a growing diagnostic challenge. The aim of this study was to proof a new diagnostic concept based on contrast-enhanced endoscopic ultrasound (CE-EUS) for differential diagnosis. PATIENTS AND METHODS: A total of 125 patients with unclear cystic pancreatic lesions were included. The initial diagnostic was made by CE-EUS dividing the lesions in a group without contrast enhancing effect in the cystic wall, septae or nodule indicating pseudocysts or dysontogenetic cysts and a group with contrast enhancing effect in the described structures indicating cystic neoplasias. The investigations were performed using a Pentax echoendoscope and Hitachi Preirus ultrasound machine. The contrast enhancer used was 4.8 mL SonoVue((r)) (Bracco, Italy). The group with suspected cystic neoplasia was referred for endoscopic fine-needle puncture for further diagnostic or treatment decisions. RESULTS: The dividing of the groups by contrast-enhanced ultrasound was feasible because all (n = 56) suspected cystic neoplasias showed a contrast enhancing effect, whereas in only 4 from 69 pseudocystic or dysontogenetic cystic lesions a contrast enhancing effect in the wall could be observed. Endoscopic fine-needle puncture could diagnose all malignant neoplasias and relevant premalignant conditions. The long-term follow-up did not show any development of malignant cystic lesions. CONCLUSION: Using CE-EUS and endoscopic fine-needle puncture as diagnostic criteria seemed to be a feasible method to deal with different cystic lesions in daily practice. PMID- 24955344 TI - A child with unexplained etiology of acute pancreatitis diagnosed by endoscopic ultrasound. PMID- 24955343 TI - Gastritis cystica profunda: Endoscopic ultrasound findings and review of the literature. AB - Gastritis cystica profunda (GCP) is a rare pseudotumor of the stomach characterized by benign growths of deep gastric glands through the muscularis mucosae into the submucosa. We review a case of GCP in a 61-year-old patient with GCP, with emphasis on endoscopic ultrasound findings and present review of the current literature. PMID- 24955345 TI - Endoscopic ultrasound-guided choledechoduodenostomy for palliative biliary drainage of obstructing pancreatic head mass. PMID- 24955346 TI - Safety characterization and antimicrobial properties of kefir-isolated Lactobacillus kefiri. AB - Lactobacilli are generally regarded as safe; however, certain strains have been associated with cases of infection. Our workgroup has already assessed many functional properties of Lactobacillus kefiri, but parameters regarding safety must be studied before calling them probiotics. In this work, safety aspects and antimicrobial activity of L. kefiri strains were studied. None of the L. kefiri strains tested caused alpha- or beta-hemolysis. All the strains were susceptible to tetracycline, clindamycin, streptomycin, ampicillin, erythromycin, kanamycin, and gentamicin; meanwhile, two strains were resistant to chloramphenicol. On the other hand, all L. kefiri strains were able to inhibit both Gram(+) and Gram(-) pathogens. Regarding the in vitro results, L. kefiri CIDCA 8348 was selected to perform in vivo studies. Mice treated daily with an oral dose of 10(8) CFU during 21 days showed no signs of pain, lethargy, dehydration, or diarrhea, and the histological studies were consistent with those findings. Moreover, no differences in proinflammatory cytokines secretion were observed between treated and control mice. No translocation of microorganisms to blood, spleen, or liver was observed. Regarding these findings, L. kefiri CIDCA 8348 is a microorganism isolated from a dairy product with a great potential as probiotic for human or animal use. PMID- 24955347 TI - Impaired intestinal mucosal barrier upon ischemia-reperfusion: "patching holes in the shield with a simple surgical method". AB - Mesenteric ischemia-reperfusion (IR) is associated with impairment of the gut barrier function and the initiation of a proinflammatory cascade with life threatening results. Therefore methods directed to ameliorate IR injury are of great importance. We aimed at describing the effects of postconditioning (PC) on the alterations of the intestinal mucosal function and the inflammatory response upon mesenteric IR. METHODS: Male Wistar rats were gavaged with green fluorescent protein-expressing E. coli suspensions. Animals were randomized into three groups (n = 15), sham-operated, IR-, and PC-groups, and underwent 60 minutes of superior mesenteric artery occlusion, followed by 6 hours of reperfusion. Postconditioning was performed at the onset of reperfusion. Blood and tissue samples were taken at the end of reperfusion, for histological, bacteriological, and plasma examinations. RESULTS: The PC-group presented a more favorable claudin-2, claudin 3, claudin-4, and zonula occludens-1 membrane expression profile, and significantly lower rates of bacterial translocation to distant organs and plasma D-lactate levels compared to the IR-group. Histopathological lesions, plasma I FABP, IL-6, and TNF- alpha levels were significantly lower in the PC-group compared to the IR-group. CONCLUSION: The use of postconditioning improved the integrity of the intestinal mucosal barrier upon mesenteric IR, and thus reduced the incidence of bacterial translocation and development of a systemic inflammatory response. PMID- 24955348 TI - Polymorphism of XRCC1, XRCC3, and XPD genes and risk of chronic myeloid leukemia. AB - The genetic polymorphisms of X-ray repair cross complementing group 1 (XRCC1), X ray repair cross complementing group 3 (XRCC3), and xeroderma pigmentosum complementation group D (XPD) repair genes may lead to genetic instability and leukemogenesis. The purpose of the study was to evaluate the association between XRCC1 Arg399Gln, Arg280His and Arg194Trp, XRCC3 Thr241Met, and XPD Lys751Gln polymorphisms and the risk of developing CML in Romanian patients. A total of 156 patients diagnosed with CML and 180 healthy controls were included in this study. We found no association between CML and XRCC1 or XRCC3 variant genotypes in any of the investigated cases. A significant difference was observed in the variant genotype frequencies of the XPD Lys751Gln polymorphism between the patients with CML and control group (for variant homozygous genotypes, OR = 2.37; 95% CI = 1.20 4.67; P value = 0.016 and for combined heterozygous and variant homozygous genotypes, OR = 1.72; 95% CI = 1.10-2.69; P value = 0.019). This was also observed when analyzing the variant 751Gln allele (OR = 1.54; 95% CI = 1.13-2.11; P value = 0.008). Our results suggest that the XPD Lys751Gln variant genotype increases the risk of CML. PMID- 24955349 TI - Identification of Influenza A/H7N9 virus infection-related human genes based on shortest paths in a virus-human protein interaction network. AB - The recently emerging Influenza A/H7N9 virus is reported to be able to infect humans and cause mortality. However, viral and host factors associated with the infection are poorly understood. It is suggested by the "guilt by association" rule that interacting proteins share the same or similar functions and hence may be involved in the same pathway. In this study, we developed a computational method to identify Influenza A/H7N9 virus infection-related human genes based on this rule from the shortest paths in a virus-human protein interaction network. Finally, we screened out the most significant 20 human genes, which could be the potential infection related genes, providing guidelines for further experimental validation. Analysis of the 20 genes showed that they were enriched in protein binding, saccharide or polysaccharide metabolism related pathways and oxidative phosphorylation pathways. We also compared the results with those from human rhinovirus (HRV) and respiratory syncytial virus (RSV) by the same method. It was indicated that saccharide or polysaccharide metabolism related pathways might be especially associated with the H7N9 infection. These results could shed some light on the understanding of the virus infection mechanism, providing basis for future experimental biology studies and for the development of effective strategies for H7N9 clinical therapies. PMID- 24955350 TI - Hepatoprotective and antioxidant effect of Bauhinia hookeri extract against carbon tetrachloride-induced hepatotoxicity in mice and characterization of its bioactive compounds by HPLC-PDA-ESI-MS/MS. AB - The hepatoprotective and antioxidant activity of Bauhinia hookeri ethanol extract (BHE) against CCl4-induced liver injury was investigated in mice. BHE was administered (500 and 1000 mg/kg/day) along with CCl4 for 6 weeks. The hepatic marker enzymes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were determined in the serum. The antioxidant parameters: glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione transferase (GST), and malondialdehyde (MDA) were estimated in the liver homogenate. BHE treatment significantly inhibited the CCl4-induced increase in ALT (44 and 64%), AST (36 and 46%), ALP (28 and 42%), and MDA (39 and 51%) levels at the tested doses, respectively. Moreover, BHE treatment markedly increased the activity of antioxidant parameters GSH, GPx, GR, GST, and SOD. Histological observations confirmed the strong hepatoprotective activity. These results suggest that a dietary supplement of BHE could exert a beneficial effect against oxidative stress and various liver diseases by enhancing the antioxidant defense status, reducing lipid peroxidation, and protecting against the pathological changes of the liver. The hepatoprotective activity of BHE is mediated, at least in part, by the antioxidant effect of its constituents. The active constituents of BHE were identified by HPLC-PDA-ESI/MS/MS. PMID- 24955351 TI - Diagnostic accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography in the evaluation of the primary tumor in patients with cholangiocarcinoma: a meta-analysis. AB - OBJECTIVE: To meta-analyze published data about the diagnostic accuracy of fluorine-18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) or PET/computed tomography (PET/CT) for primary tumor evaluation in patients with cholangiocarcinoma (CCa). METHODS: A comprehensive literature search of studies published through December 31, 2013, was performed. Pooled sensitivity and specificity were calculated on a per patient based analysis. Subgroup analyses considering the device used (PET versus PET/CT) and the localization of the primary tumor (intrahepatic cholangiocarcinoma (IH-CCa), extrahepatic cholangiocarcinoma (EH-CCa), and hilar cholangiocarcinoma (H-CCa)) were carried out. RESULTS: Twenty-three studies including 1232 patients were included in the meta-analysis. Pooled sensitivity and specificity of (18)F-FDG-PET or PET/CT were 81% and 82%, respectively. Pooled sensitivity and specificity, respectively, were 80% and 89% for PET, 82% and 75% for PET/CT, 95% and 83% for IH-CCa, 84% and 95% for H-CCa, and 76% and 74% for EH-CCa. CONCLUSIONS: (18)F-FDG-PET and PET/CT were demonstrated to be accurate diagnostic imaging methods for primary tumor evaluation in patients with CCa. These tools have a better diagnostic accuracy in patients with IH-CCa than in patients with EH-CCa. Further studies are needed to evaluate the accuracy of (18)F-FDG-PET or PET/CT in patients with H-CCa. PMID- 24955353 TI - Smoking ban policies in Italy and the potential impact of the so-called Sirchia Law: state of the art after eight years. AB - OBJECTIVE: The aim of the present work is to describe the state of the art of tobacco habits in Italy, eight years after the law was introduced. METHODS: Time series analyses, based on estimates of smoking prevalence/consumption derived from the openly available data of national surveys performed during the 2001-2013 period, were performed. Data have been expressed in percentage of smokers and daily cigarettes consumption. Time changes are expressed as expected annual percentage change (EAPC). RESULTS: Over time, the percentage of Italian smokers shows a constant and statistically significant decrease (from 28.9% in 2001 to 20.6% in 2013, EAPC = -2.6%, and P < 0.001). Regarding data stratified by gender, we found a stronger reduction among men (EAPC = -2.9%, P < 0.001) than in women (EAPC = -2.5%, P < 0.001). Similarly, the consumption of tobacco smoking, measured as the number of daily cigarettes smoked, registered a downward trend (P < 0.001). No join point (time point when a significant trend change is detected) resulted from the trend analysis. CONCLUSIONS: Data show a constant decrease of tobacco consumption in Italy, with no join point related to the introduction of the banning law. These findings require to reflect on the priorities of the smoking banning policies that may be focused on other intervention activities such as to increase the price of cigarettes. PMID- 24955352 TI - Clinical genetics of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common progressive neurodegenerative disease and the most common form of dementia in the elderly. It is a complex disorder with environmental and genetic components. There are two major types of AD, early onset and the more common late onset. The genetics of early-onset AD are largely understood with mutations in three different genes leading to the disease. In contrast, while susceptibility loci and alleles associated with late-onset AD have been identified using genetic association studies, the genetics of late onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset AD, the clinical features of EOAD according to genotypes, and the clinical implications of the genetics of AD. PMID- 24955355 TI - Recombinant human factor IX produced from transgenic porcine milk. AB - Production of biopharmaceuticals from transgenic animal milk is a cost-effective method for highly complex proteins that cannot be efficiently produced using conventional systems such as microorganisms or animal cells. Yields of recombinant human factor IX (rhFIX) produced from transgenic porcine milk under the control of the bovine alpha-lactalbumin promoter reached 0.25 mg/mL. The rhFIX protein was purified from transgenic porcine milk using a three-column purification scheme after a precipitation step to remove casein. The purified protein had high specific activity and a low ratio of the active form (FIXa). The purified rhFIX had 11.9 gamma-carboxyglutamic acid (Gla) residues/mol protein, which approached full occupancy of the 12 potential sites in the Gla domain. The rhFIX was shown to have a higher isoelectric point and lower sialic acid content than plasma-derived FIX (pdFIX). The rhFIX had the same N-glycosylation sites and phosphorylation sites as pdFIX, but had a higher specific activity. These results suggest that rhFIX produced from porcine milk is physiologically active and they support the use of transgenic animals as bioreactors for industrial scale production in milk. PMID- 24955356 TI - Bone marrow stem cells added to a hydroxyapatite scaffold result in better outcomes after surgical treatment of intertrochanteric hip fractures. AB - INTRODUCTION: Intertrochanteric hip fractures occur in the proximal femur. They are very common in the elderly and are responsible for high rates of morbidity and mortality. The authors hypothesized that adding an autologous bone marrow stem cells concentrate (ABMC) to a hydroxyapatite scaffold and placing it in the fracture site would improve the outcome after surgical fixation of intertrochanteric hip fractures. MATERIAL AND METHODS: 30 patients were randomly selected and divided into 2 groups of 15 patients, to receive either the scaffold enriched with the ABMC (Group A) during the surgical procedure, or fracture fixation alone (Group B). RESULTS: There was a statistically significant difference in favor of group A at days 30, 60, and 90 for Harris Hip Scores (HHS), at days 30 and 60 for VAS pain scales, for bedridden period and time taken to start partial and total weight bearing (P < 0.05). DISCUSSION: These results show a significant benefit of adding a bone marrow enriched scaffold to surgical fixation in intertrochanteric hip fractures, which can significantly reduce the associated morbidity and mortality rates. CONCLUSION: Bone marrow stem cells added to a hydroxyapatite scaffold result in better outcomes after surgical treatment of intertrochanteric hip fractures. PMID- 24955354 TI - Epidemiology of carbapenemase-producing Enterobacteriaceae and Acinetobacter baumannii in Mediterranean countries. AB - The emergence and global spread of carbapenemase-producing Enterobacteriaceae and Acinetobacter baumannii are of great concern to health services worldwide. These beta-lactamases hydrolyse almost all beta-lactams, are plasmid-encoded, and are easily transferable among bacterial species. They are mostly of the KPC, VIM, IMP, NDM, and OXA-48 types. Their current extensive spread worldwide in Enterobacteriaceae is an important source of concern. Infections caused by these bacteria have limited treatment options and have been associated with high mortality rates. Carbapenemase producers are mainly identified among Klebsiella pneumoniae, Escherichia coli, and A. baumannii and still mostly in hospital settings and rarely in the community. The Mediterranean region is of interest due to a great diversity and population mixing. The prevalence of carbapenemases is particularly high, with this area constituting one of the most important reservoirs. The types of carbapenemase vary among countries, partially depending on the population exchange relationship between the regions and the possible reservoirs of each carbapenemase. This review described the epidemiology of carbapenemases produced by enterobacteria and A. baumannii in this part of the world highlighting the worrisome situation and the need to screen and detect these enzymes to prevent and control their dissemination. PMID- 24955359 TI - Pharmacological treatments in gambling disorder: a qualitative review. AB - Gambling disorder (GD) is a psychiatric condition associated with both social and family costs; DSM-5 currently includes GD among addictive disorders. Despite the high burden of this condition, to date there are no treatment guidelines approved by Food and Drug Administration (FDA). Purpose of this paper is to offer a qualitative overview about the different pharmacologic agents used for the treatment of GD. Our analysis, conducted on a final selection of 75 scientific papers, demonstrates that a variety of pharmaceutical classes have been utilised, with different results. Published data, although limited by brief duration of the studies and small number of enrolled subjects, shows mixed evidence for serotonergic antidepressants, opioid antagonists, and mood stabilizers. Other compounds, such as glutamatergic agents and psychostimulants, deserve further studies. PMID- 24955358 TI - Systemic control of cell division and endoreduplication by NAA and BAP by modulating CDKs in root tip cells of Allium cepa. AB - Molecular mechanism regulated by auxin and cytokinin during endoreduplication, cell division, and elongation process is studied by using Allium cepa roots as a model system. The activity of CDK genes modulated by auxin and cytokinin during cell division, elongation, and endoreduplication process is explained in this research work. To study the significance of auxin and cytokinin in the management of cell division and endoreduplication process in plant meristematic cells at molecular level endoreduplication was developed in root tips of Allium cepa by giving colchicine treatment. There were inhibition of vegetative growth, formation of c-tumor at root tip, and development of endoreduplicated cells after colchicine treatment. This c-tumor was further treated with NAA and BAP to reinitiate vegetative growth in roots. BAP gave positive response in reinitiation of vegetative growth of roots from center of c-tumor. However, NAA gave negative response in reinitiation of vegetative growth of roots from c-tumor. Further, CDKs gene expression analysis from normal, endoreduplicated, and phytohormone (NAA or BAP) treated root tip was done and remarkable changes in transcription level of CDK genes in normal, endoreduplicated, and phytohormones treated cells were observed. PMID- 24955360 TI - Factors associated with falls in community-dwelling older people with focus on participation in sport organizations: the Japan Gerontological Evaluation Study Project. AB - OBJECTIVE: Promoting participation in sport organizations may be a population strategy for preventing falls in older people. In this study, we examined whether participation in sport organizations is associated with fewer falls in older people even after adjusting for multiple individual and environmental factors. METHODS: We used the Japan Gerontological Evaluation Study data of 90,610 people (31 municipalities) who were not eligible for public long-term care. Logistic regression analysis was performed, with multiple falls over the past year as the dependent variable and participation in a sport organization as the independent variable, controlling for 13 factors. These included individual factors related to falls, such as age and sex, and environmental factors such as population density of the habitable area. RESULTS: A total of 6,391 subjects (7.1%) had a history of multiple falls. Despite controlling for 13 variables, those who participated in a sport organization at least once a week were approximately >= 20% less likely to fall than those who did not participate at all (once a week; odds ratio = 0.82 and 95% confidence interval = 0.72-0.95). CONCLUSION: Participation in a sport organization at least once per week might help prevent falls in the community-dwelling older people. PMID- 24955357 TI - The multiple roles of EG-VEGF/PROK1 in normal and pathological placental angiogenesis. AB - Placentation is associated with several steps of vascular adaptations throughout pregnancy. These vascular changes occur both on the maternal and fetal sides, consisting of maternal uterine spiral arteries remodeling and placental vasculogenesis and angiogenesis, respectively. Placental angiogenesis is a pivotal process for efficient fetomaternal exchanges and placental development. This process is finely controlled throughout pregnancy, and it involves ubiquitous and pregnancy-specific angiogenic factors. In the last decade, endocrine gland derived vascular endothelial growth factor (EG-VEGF), also called prokineticin 1 (PROK1), has emerged as specific placental angiogenic factor that controls many aspects of normal and pathological placental angiogenesis such as recurrent pregnancy loss (RPL), gestational trophoblastic diseases (GTD), fetal growth restriction (FGR), and preeclampsia (PE). This review recapitulates EG VEGF mediated-angiogenesis within the placenta and at the fetomaternal interface and proposes that its deregulation might contribute to the pathogenesis of several placental diseases including FGR and PE. More importantly this paper argues for EG-VEGF clinical relevance as a potential biomarker of the onset of pregnancy pathologies and discusses its potential usefulness for future therapeutic directions. PMID- 24955362 TI - Local alignment tool based on Hadoop framework and GPU architecture. AB - With the rapid growth of next generation sequencing technologies, such as Slex, more and more data have been discovered and published. To analyze such huge data the computational performance is an important issue. Recently, many tools, such as SOAP, have been implemented on Hadoop and GPU parallel computing architectures. BLASTP is an important tool, implemented on GPU architectures, for biologists to compare protein sequences. To deal with the big biology data, it is hard to rely on single GPU. Therefore, we implement a distributed BLASTP by combining Hadoop and multi-GPUs. The experimental results present that the proposed method can improve the performance of BLASTP on single GPU, and also it can achieve high availability and fault tolerance. PMID- 24955361 TI - Apoptosis Induction by Polygonum minus is related to antioxidant capacity, alterations in expression of apoptotic-related genes, and S-phase cell cycle arrest in HepG2 cell line. AB - Polygonum minus (Polygonaceae) is a medicinal herb distributed throughout eastern Asia. The present study investigated antiproliferative effect of P. minus and its possible mechanisms. Four extracts (petroleum ether, methanol, ethyl acetate, and water) were prepared by cold maceration. Extracts were subjected to phytochemical screening, antioxidant, and antiproliferative assays; the most bioactive was fractionated using vacuum liquid chromatography into seven fractions (F1-F7). Antioxidant activity was measured via total phenolic content (TPC), 2,2-diphenyl 1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power (FRAP) assays. Antiproliferative activity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Most active fraction was tested for apoptosis induction and cell cycle arrest in HepG2 cells using flow cytometry and confocal microscopy. Apoptotic-related gene expression was studied by RT-PCR. Ethyl acetate extract was bioactive in initial assays. Its fraction, F7, exhibited highest antioxidant capacity (TPC; 113.16 +/- 6.2 mg GAE/g extract, DPPH; EC50: 30.5 +/- 3.2 MUg/mL, FRAP; 1169 +/- 20.3 MUmol Fe (II)/mg extract) and selective antiproliferative effect (IC50: 25.75 +/- 1.5 MUg/mL). F7 induced apoptosis in concentration- and time-dependent manner and caused cell cycle arrest at S-phase. Upregulation of proapoptotic genes (Bax, p53, and caspase-3) and downregulation of antiapoptotic gene, Bcl-2, were observed. In conclusion, F7 was antiproliferative to HepG2 cells by inducing apoptosis, cell cycle arrest, and via antioxidative effects. PMID- 24955363 TI - A new strategy for the surgical management of RLN infiltrated by well differentiated thyroid carcinoma. AB - Well-differentiated thyroid carcinoma (WDTC) represents the most common endocrine malignancy. Despite excellent prognoses exceeding 90% in 10-year follow-up, there are clinically controversial issues. One of these is extrathyroidal tumour extension invading recurrent laryngeal nerve (RLN). The spread outside of the thyroid parenchyma and invasion to the surrounding structures, classified as always T4a, are the most important negative prognostic factor for the WDTC. Conversely, resection of the RLN leads to vocal cord paralysis with hoarseness, possible swallowing problems, and finally decreased quality of life. We propose a new algorithm for intraoperative management based on the MACIS classification, which would allow swift status evaluation pre/intraoperatively and consider a possibility to preserve the infiltrated RLN without compromising an oncological radicality. In the case of a preoperative vocal cord paralysis (VCP) and confirmation of the invasive carcinoma, a resection of the RLN and the nerve graft reconstruction are indicated. Preoperatively, unaffected vocal cord movement and intraoperatively detected RLN infiltration by the invasive WDTC require an individual assessment of the oncological risk by the proposed algorithm. Preservation of the infiltrated RLN is oncologically acceptable only in specific groups of patients of a younger age with a minor size of primary tumour. PMID- 24955365 TI - Women's choice of positions during labour: return to the past or a modern way to give birth? A cohort study in Italy. AB - BACKGROUND: Childbirth medicalization has reduced the parturient's opportunity to labour and deliver in a spontaneous position, constricting her to assume the recumbent one. The aim of the study was to compare recumbent and alternative positions in terms of labour process, type of delivery, neonatal wellbeing, and intrapartum fetal head rotation. METHODS: We conducted an observational cohort study on women at pregnancy term. Primiparous women with physiological pregnancies and single cephalic fetuses were eligible for the study. We considered data about maternal-general characteristics, labour process, type of delivery, and neonatal wellbeing at birth. Patients were divided into two groups: Group-A if they spent more than 50% of labour in a recumbent position and Group-B when in alternative ones. RESULTS: 225 women were recruited (69 in Group-A and 156 in Group-B). We found significant differences between the groups in terms of labour length, Numeric Rating Scale score and analgesia request rate, type of delivery, need of episiotomy, and fetal occiput rotation. No differences were found in terms of neonatal outcomes. CONCLUSION: Alternative maternal positioning may positively influence labour process reducing maternal pain, operative vaginal delivery, caesarean section, and episiotomy rate. Women should be encouraged to move and deliver in the most comfortable position. PMID- 24955364 TI - Antiviral perspectives for chikungunya virus. AB - Chikungunya virus (CHIKV) is a mosquito-borne pathogen that has a major health impact in humans and causes acute febrile illness in humans accompanied by joint pains and, in many cases, persistent arthralgia lasting for weeks to years. CHIKV reemerged in 2005-2006 in several parts of the Indian Ocean islands and India after a gap of 32 years, causing millions of cases. The re-emergence of CHIKV has also resulted in numerous outbreaks in several countries in the eastern hemisphere, with a threat to further expand in the near future. However, there is no vaccine against CHIKV infection licensed for human use, and therapy for CHIKV infection is still mainly limited to supportive care as antiviral agents are yet in different stages of testing or development. In this review we explore the different perspectives for chikungunya treatment and the effectiveness of these treatment regimens and discuss the scope for future directions. PMID- 24955367 TI - Effect of Er,Cr:YSGG laser irradiation with radial firing tips on Candida albicans in experimentally infected root canals. AB - AIM: To compare the disinfection effect of Er,Cr:YSGG laser using radial firing tips with NaOCI in root canals infected with C. albicans and to evaluate the irradiation effect on the dentinal surfaces. MATERIAL AND METHODS: In total seventy-six mandibular premolar teeth were used. In order to standardize the incubation and sterilization procedure, eight teeth were used. Sixty-eight of the root canals were incubated with C. albicans suspension for 72 hours. The specimens were divided into 5 experimental groups. Two groups were constituted as Group 1 was irradiated with 1.5 W laser (n = 8) and group 2, which was irradiated with 2 W laser (n = 8). Two more groups were formed as Group 3 (2 W laser (n = 25) and Group 4 NaOCI (5%) (n = 25). Group 5 (n = 2) did not receive any treatment. Mann-Whitney U and Kruskal-Wallis H tests were used to compare the different laser output powers. Wilcoxon Signed Ranks Test was used in order to compare the Candida cfu/ml levels according to treatment protocols (P < 0.05). RESULTS: Both 1.5 W and 2 W laser resulted in a major reduction of C. albicans without a significant difference. The comparison of the dentin surfaces irradiated with Er,Cr:YSGG laser at two power settings resulted in similar morphological changes. However, NaOCI was found to be more effective in reduction of C. albicans than 2 W laser application. CONCLUSION: According to the results of the present study, the Er,Cr:YSGG laser with radial firing tips presented less antifungal effects on C. albicans in root canals of infected teeth than NaOCl solution. PMID- 24955366 TI - Chondroitin sulfate proteoglycans: structure-function relationship with implication in neural development and brain disorders. AB - Chondroitin sulfate proteoglycans (CSPGS) are extracellular matrix components that contain two structural parts with distinct functions: a protein core and glycosaminoglycan (GAG) side chains. CSPGs are known to be involved in important cell processes like cell adhesion and growth, receptor binding, or cell migration. It is recognized that the presence of CSPGs is critical in neuronal growth mechanisms including axon guidance following injury of nervous system components such as spinal cord and brain. CSPGs are upregulated in the central nervous system after injury and participate in the inhibition of axon regeneration mainly through their GAG side chains. Recently, it was shown that some CSPGs members like aggrecan, versican, and neurocan were strongly involved in brain disorders like bipolar disorder (BD), schizophrenia, and ADHD. In this paper, we present the chemical structure-biological functions relationship of CSPGs, both in health state and in genetic disorders, addressing methods represented by genome-wide and crystallographic data as well as molecular modeling and quantitative structure-activity relationship. PMID- 24955370 TI - Enhanced blood compatibility of metallocene polyethylene subjected to hydrochloric acid treatment for cardiovascular implants. AB - Blood compatibility of metallocene polyethylene (mPE) was investigated after modifying the surface using hydrochloric acid. Contact angle of the mPE exposed to HCl poses a decrease in its value which indicates increasing wettability and better blood compatibility. Surface of mPE analyzed by using FTIR revealed no significant changes in its functional groups after treatment. Furthermore, scanning electron microscope images supported the increasing wettability through the modifications like pit formations and etching on the acid rendered surface. To evaluate the effect of acid treatment on the coagulation cascade, prothrombin time (PT) and activated partial thromboplastin time (APTT) were measured. Both PT and APTT were delayed significantly (P < 0.05) after 60 min exposure implying improved blood compatibility of the surfaces. Hemolysis assay of the treated surface showed a remarkable decrease in the percentage of lysis of red blood cells when compared with untreated surface. Moreover, platelet adhesion assay demonstrated that HCl exposed surfaces deter the attachment of platelets and thereby reduce the chances of activation of blood coagulation cascade. These results confirmed the enhanced blood compatibility of mPE after HCl exposure which can be utilized for cardiovascular implants like artificial vascular prostheses, implants, and various blood contacting devices. PMID- 24955369 TI - Biodegradable and elastomeric poly(glycerol sebacate) as a coating material for nitinol bare stent. AB - We synthesized and evaluated biodegradable and elastomeric polyesters (poly(glycerol sebacate) (PGS)) using polycondensation between glycerol and sebacic acid to form a cross-linked network structure without using exogenous catalysts. Synthesized materials possess good mechanical properties, elasticity, and surface erosion biodegradation behavior. The tensile strength of the PGS was as high as 0.28 +/- 0.004 MPa, and Young's modulus was 0.122 +/- 0.0003 MPa. Elongation was as high as 237.8 +/- 0.64%, and repeated elongation behavior was also observed to at least three times the original length without rupture. The water-in-air contact angles of the PGS surfaces were about 60 degrees . We also analyzed the properties of an electrospray coating of biodegradable PGS on a nitinol stent for the purpose of enhancing long-term patency for the therapeutic treatment of varicose veins disease. The surface morphology and thickness of coating layer could be controlled by adjusting the electrospraying conditions and solution parameters. PMID- 24955368 TI - Genotoxicity of microcystin-LR in in vitro and in vivo experimental models. AB - Microcystin-LR (MCLR) is a cyanobacterial toxin known for its acute hepatotoxicity. Despite being recognized as tumour promoter, its genotoxicity is far from being completely clarified, particularly in organs other than liver. In this work, we used the comet and/or the micronucleus (MN) assays to study the genotoxicity of MCLR in kidney- (Vero-E6) and liver-derived (HepG2) cell lines and in blood cells from MCLR-exposed mice. MCLR treatment (5 and 20 MUM) caused a significant induction in the MN frequency in both cell lines and, interestingly, a similar positive effect was observed in mouse reticulocytes (37.5 MUg MCLR/kg, i.p. route). Moreover, the FISH-based analysis of the MN content (HepG2 cells) suggested that MCLR induces both chromosome breaks and loss. On the other hand, the comet assay results were negative in Vero-E6 cells and in mouse leukocytes, with the exception of a transient increase in the level of DNA damage 30 minutes after mice exposure. Overall, the present findings contributed to increase the weight of evidence in favour of MCLR genotoxicity, based on its capacity to induce permanent genetic damage either in vitro or in vivo. Moreover, they suggest a clastogenic and aneugenic mode of action that might underlie a carcinogenic effect. PMID- 24955371 TI - Prospective evaluation of whole genome microRNA expression profiling in childhood acute lymphoblastic leukemia. AB - Dysregulation of microRNA (miRNA) expression contributes to the pathogenesis of several clinical conditions. The aim of this study is to evaluate the associations between miRNAs and childhood acute lymphoblastic leukemia (ALL) to discover their role in the course of the disease. Forty-three children with ALL and 14 age-matched healthy controls were included in the study. MicroRNA microarray expression profiling was used for peripheral blood and bone marrow samples. Aberrant miRNA expressions associated with the diagnosis and outcome were prospectively evaluated. Confirmation analysis was performed by real time RT PCR. miR-128, miR-146a, miR-155, miR-181a, and miR-195 were significantly dysregulated in ALL patients at day 0. Following a six-month treatment period, the change in miRNA levels was determined by real time RT-PCR and expression of miR-146a, miR-155, miR-181a, and miR-195 significantly decreased. To conclude, these miRNAs not only may be used as biomarkers in diagnosis of ALL and monitoring the disease but also provide new insights into the potential roles of them in leukemogenesis. PMID- 24955372 TI - Stratification of gene coexpression patterns and GO function mining for a RNA-Seq data series. AB - RNA-Seq is emerging as an increasingly important tool in biological research, and it provides the most direct evidence of the relationship between the physiological state and molecular changes in cells. A large amount of RNA-Seq data across diverse experimental conditions have been generated and deposited in public databases. However, most developed approaches for coexpression analyses focus on the coexpression pattern mining of the transcriptome, thereby ignoring the magnitude of gene differences in one pattern. Furthermore, the functional relationships of genes in one pattern, and notably among patterns, were not always recognized. In this study, we developed an integrated strategy to identify differential coexpression patterns of genes and probed the functional mechanisms of the modules. Two real datasets were used to validate the method and allow comparisons with other methods. One of the datasets was selected to illustrate the flow of a typical analysis. In summary, we present an approach to robustly detect coexpression patterns in transcriptomes and to stratify patterns according to their relative differences. Furthermore, a global relationship between patterns and biological functions was constructed. In addition, a freely accessible web toolkit "coexpression pattern mining and GO functional analysis" (COGO) was developed. PMID- 24955373 TI - The use of a modular titanium baseplate with a press-fit keel implanted with a surface cementing technique for primary total knee arthroplasty. AB - Little data exists regarding outcomes following TKA performed with surface cementation for the fixation of modular tibial baseplates with press-fit keels. Thus, we retrospectively reviewed the clinical and radiographic outcomes of 439 consecutive primary TKAs performed with surface cemented tibial components. There were 290 female patients and 149 male patients with average age of 62 years (range 30-84). Two tibial components were revised for aseptic loosening (0.5%) and four tibial components (0.9%) were removed to improve instability (n = 2) or malalignment (n = 2). Complications included 13 deep infections treated with 2 stage revision (12) and fusion (1). These results support the surface cement technique with a modular grit-blasted titanium surface and cruciform stem during primary TKA. PMID- 24955375 TI - S-calprotectin (S100A8/S100A9): a potential marker of inflammation in patients with psoriatic arthritis. AB - OBJECTIVE: To analyse levels of S100A8/S100A9 (calprotectin) and selected cytokines, in blood, in patients with psoriatic arthritis (PsA). METHODS: Sixty five patients with PsA were examined for clinical manifestations and laboratory measurements of S-calprotectin, ESR, hs-CRP, and selected cytokines. Thirty-two patients had mono-/oligoarthritis and 33 had polyarthritis. S-calprotectin, hs CRP, and cytokines were measured using ELISA, immunoturbidimetry, and multiplex technology (Bio-Plex). Patients with PsA were compared with 31 healthy controls. RESULTS: S-calprotectin and hs-CRP levels were significantly higher in patients with PsA compared with controls (P<0.001 and P<0.001, resp.). Patients suffering a polyarthritic disease pattern presented with significantly higher levels of S calprotectin compared with controls and patients with mono-/oligoarthritis (P<0.001 and P=0.017, resp.). The levels of S-calprotectin correlated with hs-CRP (P<0.001; rs=0.441), swollen joint count (P=0.002, rs=0.397), and CXCL10 (P=0.046, rs=0.678) but not with any of the other cytokines evaluated. In multiple logistic regression analysis, S-calprotectin was the only variable significantly associated with psoriatic arthritis (P=0.002, OR=1.006, 95% CI=1.002-1.010). CONCLUSION: S-calprotectin and hs-CRP levels were significantly higher in patients with PsA. A polyarthritic disease pattern showed higher levels of S-calprotectin than mono-/oligoarthritis. S-calprotectin is considered a potential marker of disease activity in patients with PsA. PMID- 24955374 TI - Chromium (VI) uptake and tolerance potential in cotton cultivars: effect on their root physiology, ultramorphology, and oxidative metabolism. AB - Chromium (Cr) is present in our environment as a toxic pollutant, which needs to be removed using phytoremediation technology. In present study, two transgenic cotton cultivars (J208, Z905) and their hybrid line (ZD14) were used to explore their Cr uptake and tolerance potential using multiple biomarkers approach. Four different levels of Cr (CK, 10, 50, and 100 MUM) were applied. Cr caused a significant reduction in root/shoot length, number of secondary roots, and root fresh and dry biomasses at 100 MUM. Cr accumulated more in roots and was found higher in hybrid line (ZD14) as compared with its parent lines (J208, Z905) at all Cr stress levels (10, 50, and 100 MUM). Cr translocation was less than 1 in all cultivars. Ultrastructural studies at 100 MUM Cr showed an increase in number of nuclei and vacuoles and presence of Cr dense granules in dead parts of the cell (vacuoles/cell wall). Malondialdehyde (MDA), hydrogen peroxide (H2O2), total soluble proteins, superoxide dismutase (SOD), peroxidase (POD), ascorbate peroxidase (APX), catalase (CAT), and glutathione reductase (GR) as a whole were upregulated with elevated levels of Cr. Higher Cr uptake by roots, accelerated metabolism, and Cr sequestration in dead parts of the cell indicate that these cotton cultivars can be useful for Cr accumulation and tolerance. PMID- 24955379 TI - Preventable Infections in Children with Leukodystrophy. AB - Children with inherited leukodystrophies have high hospitalization rates, often associated with infection. We studied whether potentially modifiable risk factors (pre-existing in-dwelling central intravenous access, urinary catheter, hardware, or mechanical ventilation; and influenza vaccine) were associated with infection related hospitalization in children with leukodystrophy. Central intravenous access was associated with sepsis (odds ratio (OR) 9.8); urinary catheter was associated with urinary tract infections (OR 9.0); lack of seasonal vaccination was associated with influenza (OR 6.4); and mechanical ventilation was associated with pneumonia (OR 2.7). We conclude that potentially modifiable risk factors are significantly associated with infection and hospitalization in children with leukodystrophies. PMID- 24955378 TI - Next Generation Statistical Genetics: Modeling, Penalization, and Optimization in High-Dimensional Data. AB - Statistical genetics is undergoing the same transition to big data that all branches of applied statistics are experiencing. With the advent of inexpensive DNA sequencing, the transition is only accelerating. This brief review highlights some modern techniques with recent successes in statistical genetics. These include: (a) lasso penalized regression and association mapping, (b) ethnic admixture estimation, (c) matrix completion for genotype and sequence data, (d) the fused lasso and copy number variation, (e) haplotyping, (f) estimation of relatedness, (g) variance components models, and (h) rare variant testing. For more than a century, genetics has been both a driver and beneficiary of statistical theory and practice. This symbiotic relationship will persist for the foreseeable future. PMID- 24955380 TI - Utilizing Focus Groups with Potential Participants and Their Parents: An Approach to Inform Study Design in a Large Clinical Trial. AB - BACKGROUND: In the recent literature, there has been some evidence that exposure of children to anesthetic procedures during the first two years of life may impair cognitive function and learning in later life. We planned a clinical study to quantify this risk, a study involving testing 1,000 children for neurodevelopmental deficits. As a part of this planning, we conducted focus groups involving potential participants and their parents to elicit information regarding three issues: communications with the community and potential participants, recruitment and consent processes, and the return of neurodevelopmental testing results. METHODS: Three focus groups were conducted with the parents of potential participants and one focus group was conducted with an 18-19 year old group; each group consisted of 6-10 participants. The moderated discussions had questions about recruitment, consenting issues, and expectations from the study about return of both overall trial findings and individual research test results. RESULTS: The focus group data gave us an insight on potential participants' views on recruitment, consenting, communications about the study, and expectations about return of both overall trial findings and individual research test results. The concerns expressed were largely addressable. In addition, the concern we had about some parents enrolling their children in the study solely for the sake of getting their child's cognitive function results was dispelled. CONCLUSIONS: We found that the individuals participating in our focus groups were generally enthusiastic about the large clinical study and could see the value in answering the study question. The data from the focus groups were used to inform changes to the recruitment and consent process. Focus group input was also instrumental in affirming the study design regarding return of results. Our experience suggests that the approach we used may serve as a model for other investigators to help inform the various elements of clinical study design, in particular the recruitment and consenting processes and expectations of potential participants regarding the return of individual research findings. PMID- 24955376 TI - The "Trojan Horse" approach to tumor immunotherapy: targeting the tumor microenvironment. AB - Most anticancer therapies including immunotherapies are given systemically; yet therapies given directly into tumors may be more effective, particularly those that overcome natural suppressive factors in the tumor microenvironment. The "Trojan Horse" approach of intratumoural delivery aims to promote immune-mediated destruction by inducing microenvironmental changes within the tumour at the same time as avoiding the systemic toxicity that is often associated with more "full frontal" treatments such as transfer of large numbers of laboratory-expanded tumor-specific cytotoxic T lymphocytes or large intravenous doses of cytokine. Numerous studies have demonstrated that intratumoural therapy has the capacity to minimizing local suppression, inducing sufficient "dangerous" tumor cell death to cross-prime strong immune responses, and rending tumor blood vessels amenable to immune cell traffic to induce effector cell changes in secondary lymphoid organs. However, the key to its success is the design of a sound rational approach based on evidence. There is compelling preclinical data for local immunotherapy approaches in tumor immunology. This review summarises how immune events within a tumour can be modified by local approaches, how this can affect systemic antitumor immunity such that distal sites are attacked, and what approaches have been proven most successful so far in animals and patients. PMID- 24955377 TI - Autoantibody response to murine double minute 2 protein in immunodiagnosis of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Although new therapeutic strategies have been continuously developed and applied to clinical treatment for HCC, the prognosis is still very poor. Thus, early detection of HCC may enhance effective and curative management. In this study, autoantibody responses to MDM2 protein in HCC patient's serum were evaluated by enzyme-linked immunosorbent assay (ELISA) and part sera were evaluated by Western blotting and indirect immunofluorescence assay. Immunohistochemistry (IHC) over tissue array slides was also performed to analyze protein expression of MDM2 in HCC and control tissues. The prevalence of autoantibodies against MDM2 was significantly higher than that in liver cirrhosis (LC), chronic hepatitis (CH), and normal human sera (NHS). The average titer of autoantibodies against MDM2 in HCC serum was higher compared to that in LC, CH, and NHS. A high titer of autoantibodies against MDM2 in ELISA could be observed in the serum in 6 to 9 months before the clinical diagnosis of HCC in the serum of several HCC patients with serial bleeding samples. Our preliminary data indicate that MDM2 and anti MDM2 system may be a potential biomarker for early stage HCC screening and immunodiagnosis. PMID- 24955382 TI - A high performance load balance strategy for real-time multicore systems. AB - Finding ways to distribute workloads to each processor core and efficiently reduce power consumption is of vital importance, especially for real-time systems. In this paper, a novel scheduling algorithm is proposed for real-time multicore systems to balance the computation loads and save power. The developed algorithm simultaneously considers multiple criteria, a novel factor, and task deadline, and is called power and deadline-aware multicore scheduling (PDAMS). Experiment results show that the proposed algorithm can greatly reduce energy consumption by up to 54.2% and the deadline times missed, as compared to the other scheduling algorithms outlined in this paper. PMID- 24955384 TI - Numerical simulation on hydromechanical coupling in porous media adopting three dimensional pore-scale model. AB - A novel approach of simulating hydromechanical coupling in pore-scale models of porous media is presented in this paper. Parameters of the sandstone samples, such as the stress-strain curve, Poisson's ratio, and permeability under different pore pressure and confining pressure, are tested in laboratory scale. The micro-CT scanner is employed to scan the samples for three-dimensional images, as input to construct the model. Accordingly, four physical models possessing the same pore and rock matrix characteristics as the natural sandstones are developed. Based on the micro-CT images, the three-dimensional finite element models of both rock matrix and pore space are established by MIMICS and ICEM software platform. Navier-Stokes equation and elastic constitutive equation are used as the mathematical model for simulation. A hydromechanical coupling analysis in pore-scale finite element model of porous media is simulated by ANSYS and CFX software. Hereby, permeability of sandstone samples under different pore pressure and confining pressure has been predicted. The simulation results agree well with the benchmark data. Through reproducing its stress state underground, the prediction accuracy of the porous rock permeability in pore-scale simulation is promoted. Consequently, the effects of pore pressure and confining pressure on permeability are revealed from the microscopic view. PMID- 24955381 TI - Sleep Disorders in Atypical Parkinsonism. AB - Sleep disorders are commonly seen in atypical parkinsonism, with particular disorders occurring more frequently in specific parkinsonian disorders. Multiple systems atrophy (MSA) is a synucleinopathy often associated with nocturnal stridor which is a serious, but treatable condition highly specific to MSA. In addition, this disorder is strongly associated with rapid eye movement (REM) sleep behavior disorder (RBD), which is also seen in dementia with Lewy bodies (DLB). RBD is far less prevalent in progressive supranuclear palsy (PSP), which is a tauopathy. Insomnia and impaired sleep architecture are the most common sleep abnormalities seen in PSP. Corticobasilar degeneration (CBD) is also a tauopathy, but has far fewer sleep complaints associated with it than PSP. In this manuscript we review the spectrum of sleep dysfunction across the atypical parkinsonian disorders, emphasize the importance of evaluating for sleep disorders in patients with parkinsonian symptoms, and point to sleep characteristics that can provide diagnostic clues to the underlying parkinsonian disorder. PMID- 24955385 TI - Spatial variations in concentration, compositions of glomalin related soil protein in poplar plantations in northeastern China, and possible relations with soil physicochemical properties. AB - Concentration of Glomalin Related Soil Protein is reportedly close related to soil functions, but few data is available for GRSP compositional variations and function related to soil properties. In this paper, soils from 0-20 cm, 20-40 cm, 40-60 cm, 60-80 cm, and 80-100 cm layers were collected in 72 poplar shelterbelts in Songnen Plain (6 regions) for implementing this data shortage. GRSP mainly consists of stretching of O-H, N-H, C-H, C=O, COO-, C-O, and Si-O-Si and bending of C-H and O-H. It has seven fluorescent substances of tyrosine-like protein, tryptophan-like protein, fulvic acid-like, humic acid-like, soluble microbial byproduct-like, nitrobenzoxadiazole-like, and calcofluor white-like, with characteristic X-ray diffraction peak at 2 theta = 19.8 degrees and 129.3 nm grain size as well as 1.08% low crystallinity. Large spatial variations (intersite and intrasite down profile) were found in either GRSP concentration or these compositional traits. Regression analysis clearly manifested that soil pH should be responsible for these variations. However, negative relations between soil bulk density and GRSP quantity were observed, but not its compositional traits. These basic data in poplar shelterbelt forests are good for understanding the underlying mechanism of GRSP in soil functional maintenance. PMID- 24955387 TI - Design of simplified maximum-likelihood receivers for multiuser CPM systems. AB - A class of simplified maximum-likelihood receivers designed for continuous phase modulation based multiuser systems is proposed. The presented receiver is built upon a front end employing mismatched filters and a maximum-likelihood detector defined in a low-dimensional signal space. The performance of the proposed receivers is analyzed and compared to some existing receivers. Some schemes are designed to implement the proposed receivers and to reveal the roles of different system parameters. Analysis and numerical results show that the proposed receivers can approach the optimum multiuser receivers with significantly (even exponentially in some cases) reduced complexity and marginal performance degradation. PMID- 24955386 TI - On topological structures of fuzzy parametrized soft sets. AB - We introduce the topological structure of fuzzy parametrized soft sets and fuzzy parametrized soft mappings. We define the notion of quasi-coincidence for fuzzy parametrized soft sets and investigated its basic properties. We study the closure, interior, base, continuity, and compactness and properties of these concepts in fuzzy parametrized soft topological spaces. PMID- 24955383 TI - The pursuit of happiness measurement: a psychometric model based on psychophysiological correlates. AB - Everyone is interested in the pursuit of happiness, but the real problem for the researchers is how to measure it. Our aim was to deeply investigate happiness measurement through biomedical signals, using psychophysiological methods to objectify the happiness experiences measurements. The classic valence-arousal model of affective states to study happiness has been extensively used in psychophysiology. However, really few studies considered a real combination of these two dimensions and no study further investigated multidimensional models. More, most studies focused mainly on self-report to measure happiness and a deeper psychophysiological investigation on the dimensions of such an experience is still missing. A multidimensional model of happiness is presented and both the dimensions and the measures extracted within each dimension are comprehensively explained. This multidimensional model aims at being a milestone for future systematic study on psychophysiology of happiness and affective states. PMID- 24955388 TI - Privacy-preserving discovery of topic-based events from social sensor signals: an experimental study on Twitter. AB - Social network services (e.g., Twitter and Facebook) can be regarded as social sensors which can capture a number of events in the society. Particularly, in terms of time and space, various smart devices have improved the accessibility to the social network services. In this paper, we present a social software platform to detect a number of meaningful events from information diffusion patterns on such social network services. The most important feature is to process the social sensor signal for understanding social events and to support users to share relevant information along the social links. The platform has been applied to fetch and cluster tweets from Twitter into relevant categories to reveal hot topics. PMID- 24955389 TI - Digital image forgery detection using JPEG features and local noise discrepancies. AB - Wide availability of image processing software makes counterfeiting become an easy and low-cost way to distort or conceal facts. Driven by great needs for valid forensic technique, many methods have been proposed to expose such forgeries. In this paper, we proposed an integrated algorithm which was able to detect two commonly used fraud practices: copy-move and splicing forgery in digital picture. To achieve this target, a special descriptor for each block was created combining the feature from JPEG block artificial grid with that from noise estimation. And forehand image quality assessment procedure reconciled these different features by setting proper weights. Experimental results showed that, compared to existing algorithms, our proposed method is effective on detecting both copy-move and splicing forgery regardless of JPEG compression ratio of the input image. PMID- 24955390 TI - AP-IO: asynchronous pipeline I/O for hiding periodic output cost in CFD simulation. AB - Computational fluid dynamics (CFD) simulation often needs to periodically output intermediate results to files in the form of snapshots for visualization or restart, which seriously impacts the performance. In this paper, we present asynchronous pipeline I/O (AP-IO) optimization scheme for the periodically snapshot output on the basis of asynchronous I/O and CFD application characteristics. In AP-IO, dedicated background I/O processes or threads are in charge of handling the file write in pipeline mode, therefore the write overhead can be hidden with more calculation than classic asynchronous I/O. We design the framework of AP-IO and implement it in OpenFOAM, providing CFD users with a user friendly interface. Experimental results on the Tianhe-2 supercomputer demonstrate that AP-IO can achieve a good optimization effect for the periodical snapshot output in CFD application, and the effect is especially better for massively parallel CFD simulations, which can reduce the total execution time up to about 40%. PMID- 24955392 TI - Parallelized dilate algorithm for remote sensing image. AB - As an important algorithm, dilate algorithm can give us more connective view of a remote sensing image which has broken lines or objects. However, with the technological progress of satellite sensor, the resolution of remote sensing image has been increasing and its data quantities become very large. This would lead to the decrease of algorithm running speed or cannot obtain a result in limited memory or time. To solve this problem, our research proposed a parallelized dilate algorithm for remote sensing Image based on MPI and MP. Experiments show that our method runs faster than traditional single-process algorithm. PMID- 24955391 TI - Assessment of self-perception of transsexual persons: pilot study of 15 patients. AB - BACKGROUND AND AIMS: There have been few studies in the area of Self-Perception in transsexual persons, except for the population of transsexual adolescents. Bearing in mind its importance not only in the assessment of personality but also in predicting adaptive capacity, the goal of our research is based on the examination of Self-Perception of adult transsexual persons. METHOD: The study was conducted using a Rorschach test, which provides an insight into various aspects of Self-Perception. The sample consisted of 15 transsexual persons, who passed the standard diagnostic procedure. RESULTS: The results suggest that transsexual persons manage to maintain Adequate Self-Esteem. Hypervigilance Index and Obsessive Style Index are negative, while the values showing a negative quality of Self-Regard and the capacity for introspection tend to increase. In the process of Self-Introspection, negative and painful emotional states are often perceived. CONCLUSION: The estimation of Self-Perception in adult transsexual persons indicates a trend of subjective perception of a personal imperfection or inadequacy. This is probably the result of experiencing discomfort for a number of years due to gender incongruence and dysphoria, in particular in persons who enter the sex reassignment procedure later in their adulthood. PMID- 24955393 TI - A collaborative recommend algorithm based on bipartite community. AB - The recommendation algorithm based on bipartite network is superior to traditional methods on accuracy and diversity, which proves that considering the network topology of recommendation systems could help us to improve recommendation results. However, existing algorithms mainly focus on the overall topology structure and those local characteristics could also play an important role in collaborative recommend processing. Therefore, on account of data characteristics and application requirements of collaborative recommend systems, we proposed a link community partitioning algorithm based on the label propagation and a collaborative recommendation algorithm based on the bipartite community. Then we designed numerical experiments to verify the algorithm validity under benchmark and real database. PMID- 24955395 TI - In the search of fundamental inner bond strength of solid elements. AB - In order to understand the physics behind the surface properties and nano-scale phenomena, we are motivated first to investigate the inner bond strengths as well as the effect of number of neighboring atoms and their relative distance in addition to space positions (crystallography). Therefore, in order to study the effect of the nature of metallic bond on their physico-chemical properties, we first tried to investigate and introduce a mathematical model for transforming the bulk molar cohesion energy into microscopic bond strengths between atoms. Then an algorithm for estimating the nature of bond type including the materials properties and lattice scale "cutoff" has been proposed. This leads to a new fundamental energy scale free from the crystallography and number of atoms. The results of our model in case of fundamental energy scale of metals not only perfectly describe the inter relation between binding and melting phenomena but also adequately reproduce the bond strength for different bond types with respect to other estimations reported in literatures. The generalized algorithm and calculation methodology introduced here by us are suggested to be used for developing energy scale of bulk crystal materials to explain or predict any particular materials properties related to bond strengths of metallic elements. PMID- 24955394 TI - Rule-based knowledge acquisition method for promoter prediction in human and Drosophila species. AB - The rapid and reliable identification of promoter regions is important when the number of genomes to be sequenced is increasing very speedily. Various methods have been developed but few methods investigate the effectiveness of sequence based features in promoter prediction. This study proposes a knowledge acquisition method (named PromHD) based on if-then rules for promoter prediction in human and Drosophila species. PromHD utilizes an effective feature-mining algorithm and a reference feature set of 167 DNA sequence descriptors (DNASDs), comprising three descriptors of physicochemical properties (absorption maxima, molecular weight, and molar absorption coefficient), 128 top-ranked descriptors of 4-mer motifs, and 36 global sequence descriptors. PromHD identifies two feature subsets with 99 and 74 DNASDs and yields test accuracies of 96.4% and 97.5% in human and Drosophila species, respectively. Based on the 99- and 74 dimensional feature vectors, PromHD generates several if-then rules by using the decision tree mechanism for promoter prediction. The top-ranked informative rules with high certainty grades reveal that the global sequence descriptor, the length of nucleotide A at the first position of the sequence, and two physicochemical properties, absorption maxima and molecular weight, are effective in distinguishing promoters from non-promoters in human and Drosophila species, respectively. PMID- 24955396 TI - Integrating a hive triangle pattern with subpixel analysis for noncontact measurement of structural dynamic response by using a novel image processing scheme. AB - This work presents a digital image processing approach with a unique hive triangle pattern by integrating subpixel analysis for noncontact measurement of structural dynamic response data. Feasibility of proposed approach is demonstrated based on numerical simulation of a photography experiment. According to those results, the measured time-history displacement of simulated image correlates well with the numerical solution. A small three-story frame is then mounted on a small shaker table, and a linear variation differential transformation (LVDT) is set on the second floor. Experimental results indicate that the relative error between data from LVDT and analyzed data from digital image correlation is below 0.007%, 0.0205 in terms of frequency and displacement, respectively. Additionally, the appropriate image block affects the estimation accuracy of the measurement system. Importantly, the proposed approach for evaluating pattern center and size is highly promising for use in assigning the adaptive block for a digital image correlation method. PMID- 24955397 TI - Hemodialysis-associated problems to solve: current and future. PMID- 24955398 TI - Influence of seismic loading on segment opening of a shield tunnel. AB - The influence of seismic loading on segment opening of a shield tunnel was explored using the dynamic finite element method to analyze the distribution of segment opening under multidirectional seismic loading, combined with a typical engineering installation. The calculation of segment opening was deduced from equivalent continuous theory and segment opening was obtained through calculations. The results show that the scope of influence of the foundation excavation on segment opening is mainly resigned to within 5 segment rings next to the diaphragm wall and 4 joints nearest the working well when the tunnel is first excavated followed by the working well in the excavation order. The effect of seismic loading on segment opening is significant, and the minimum increase of the maximal segment opening owing to seismic loading is 16%, while that of the average opening is 27%. Segment opening under bidirectional coupled seismic loading is significantly greater than that under one-dimensional seismic loading. On the basis of the numerical calculations, the seismic acceleration and segment opening caused by seismic action were normalized, and a new calculation method was proposed for predicting the maximal segment opening of a shield tunnel at different depths under conditions of seismic loading. PMID- 24955399 TI - Modeling and simulation of complex network attributes on coordinating large multiagent system. AB - With the expansion of distributed multiagent systems, traditional coordination strategy becomes a severe bottleneck when the system scales up to hundreds of agents. The key challenge is that in typical large multiagent systems, sparsely distributed agents can only communicate directly with very few others and the network is typically modeled as an adaptive complex network. In this paper, we present simulation testbed CoordSim built to model the coordination of network centric multiagent systems. Based on the token-based strategy, the coordination can be built as a communication decision problem that agents make decisions to target communications and pass them over to the capable agents who will potentially benefit the team most. We have theoretically analyzed that the characters of complex network make a significant difference with both random and intelligent coordination strategies, which may contribute to future multiagent algorithm design. PMID- 24955400 TI - Hybrid composite laminates reinforced with Kevlar/carbon/glass woven fabrics for ballistic impact testing. AB - Current study reported a facile method to investigate the effects of stacking sequence layers of hybrid composite materials on ballistic energy absorption by running the ballistic test at the high velocity ballistic impact conditions. The velocity and absorbed energy were accordingly calculated as well. The specimens were fabricated from Kevlar, carbon, and glass woven fabrics and resin and were experimentally investigated under impact conditions. All the specimens possessed equal mass, shape, and density; nevertheless, the layers were ordered in different stacking sequence. After running the ballistic test at the same conditions, the final velocities of the cylindrical AISI 4340 Steel pellet showed how much energy was absorbed by the samples. The energy absorption of each sample through the ballistic impact was calculated; accordingly, the proper ballistic impact resistance materials could be found by conducting the test. This paper can be further studied in order to characterise the material properties for the different layers. PMID- 24955401 TI - How does calcification influence plaque vulnerability? Insights from fatigue analysis. AB - BACKGROUND: Calcification is commonly believed to be associated with cardiovascular disease burden. But whether or not the calcifications have a negative effect on plaque vulnerability is still under debate. METHODS AND RESULTS: Fatigue rupture analysis and the fatigue life were used to evaluate the rupture risk. An idealized baseline model containing no calcification was first built. Based on the baseline model, we investigated the influence of calcification on rupture path and fatigue life by adding a circular calcification and changing its location within the fibrous cap area. Results show that 84.0% of calcified cases increase the fatigue life up to 11.4%. For rupture paths 10D far from the calcification, the life change is negligible. Calcifications close to lumen increase more fatigue life than those close to the lipid pool. Also, calcifications in the middle area of fibrous cap increase more fatigue life than those in the shoulder area. CONCLUSION: Calcifications may play a positive role in the plaque stability. The influence of the calcification only exists in a local area. Calcifications close to lumen may be influenced more than those close to lipid pool. And calcifications in the middle area of fibrous cap are seemly influenced more than those in the shoulder area. PMID- 24955402 TI - Ant colony optimization algorithm for continuous domains based on position distribution model of ant colony foraging. AB - Ant colony optimization algorithm for continuous domains is a major research direction for ant colony optimization algorithm. In this paper, we propose a distribution model of ant colony foraging, through analysis of the relationship between the position distribution and food source in the process of ant colony foraging. We design a continuous domain optimization algorithm based on the model and give the form of solution for the algorithm, the distribution model of pheromone, the update rules of ant colony position, and the processing method of constraint condition. Algorithm performance against a set of test trials was unconstrained optimization test functions and a set of optimization test functions, and test results of other algorithms are compared and analyzed to verify the correctness and effectiveness of the proposed algorithm. PMID- 24955403 TI - Secure and privacy enhanced gait authentication on smart phone. AB - Smart environments established by the development of mobile technology have brought vast benefits to human being. However, authentication mechanisms on portable smart devices, particularly conventional biometric based approaches, still remain security and privacy concerns. These traditional systems are mostly based on pattern recognition and machine learning algorithms, wherein original biometric templates or extracted features are stored under unconcealed form for performing matching with a new biometric sample in the authentication phase. In this paper, we propose a novel gait based authentication using biometric cryptosystem to enhance the system security and user privacy on the smart phone. Extracted gait features are merely used to biometrically encrypt a cryptographic key which is acted as the authentication factor. Gait signals are acquired by using an inertial sensor named accelerometer in the mobile device and error correcting codes are adopted to deal with the natural variation of gait measurements. We evaluate our proposed system on a dataset consisting of gait samples of 34 volunteers. We achieved the lowest false acceptance rate (FAR) and false rejection rate (FRR) of 3.92% and 11.76%, respectively, in terms of key length of 50 bits. PMID- 24955404 TI - Effects of age and stand density of mother trees on early Pinus thunbergii seedling establishment in the coastal zone, China. AB - Effects of age and stand density of mother tree on seed germination, seedling biomass allocation, and seedling growth of Pinus thunbergii were studied. The results showed that age of mother tree did not have significant influences on seed germination, but it was significant on seedling biomass allocation and growth. Seedlings from the minimum and maximum age of mother tree had higher leaf mass ratio and lower root mass ratio than from the middle age of mother tree. Moreover, they also had higher relative height growth rate and slenderness, which were related to their biomass allocation. Stand density of mother tree mainly demonstrated significant effects on seed germination and seedling growth. Seed from higher stand density of mother tree did not decrease germination rate, but had higher mean germination time, indicating that it delayed germination process. Seedlings of higher stand density of mother tree showed higher relative height growth rate and slenderness. These traits of offspring from higher stand density of mother tree were similar to its mother, indicating significant environmental maternal effects. So, mother tree identity of maternal age and environments had important effects on natural regeneration of the coastal P. thunbergii forest. PMID- 24955405 TI - PEM-PCA: a parallel expectation-maximization PCA face recognition architecture. AB - Principal component analysis or PCA has been traditionally used as one of the feature extraction techniques in face recognition systems yielding high accuracy when requiring a small number of features. However, the covariance matrix and eigenvalue decomposition stages cause high computational complexity, especially for a large database. Thus, this research presents an alternative approach utilizing an Expectation-Maximization algorithm to reduce the determinant matrix manipulation resulting in the reduction of the stages' complexity. To improve the computational time, a novel parallel architecture was employed to utilize the benefits of parallelization of matrix computation during feature extraction and classification stages including parallel preprocessing, and their combinations, so-called a Parallel Expectation-Maximization PCA architecture. Comparing to a traditional PCA and its derivatives, the results indicate lower complexity with an insignificant difference in recognition precision leading to high speed face recognition systems, that is, the speed-up over nine and three times over PCA and Parallel PCA. PMID- 24955406 TI - An analysis of patients that underwent computed tomography pulmonary angiography with the prediagnosis of pulmonary embolism in the emergency department. AB - INTRODUCTION: The purpose of this study is to analyze the frequency of other diagnoses and findings in patients that were diagnosed with or not diagnosed with PE following the CTPA in the ED and to analyze the relationship between diagnosis and D-dimer. INSTRUMENT AND METHOD: This study involves all patients that presented to the ED that underwent CTPA with the prediagnosis of PE. The items considered in this study were their reason for presenting to the ED and pretest clinical risks for PE, D-dimer, and CTPA results. FINDINGS: Of the 696 cases, the most common cause was shortness of breath (59.3%). The CTPA showed that 145 (20.83%) patients were suffering from PE. Among the remaining cases, 464 (66.66%) patients had pathological findings other than PE and 87 (12.5%) patients were reported as normal. The most common pathological results other than PE found in CTPA were atelectasis in 244 (39.9%) and ground glass in 165 (23.7%), as well as nonpulmonary results in 70 (10.05%) patients. The differences in D-dimer results of patients diagnosed with PE, patients diagnosed with another pathology, and patients with normal CTPA results were statistically significant (P < 0.001). CONCLUSION: CTPA scanning, performed on the basis of assessment scoring, helps in discovering other fatal pathologies in addition to PE. PMID- 24955407 TI - Comprehensive fractal description of porosity of coal of different ranks. AB - We selected, as the objects of our research, lignite from the Beizao Mine, gas coal from the Caiyuan Mine, coking coal from the Xiqu Mine, and anthracite from the Guhanshan Mine. We used the mercury intrusion method and the low-temperature liquid nitrogen adsorption method to analyze the structure and shape of the coal pores and calculated the fractal dimensions of different aperture segments in the coal. The experimental results show that the fractal dimension of the aperture segment of lignite, gas coal, and coking coal with an aperture of greater than or equal to 10 nm, as well as the fractal dimension of the aperture segment of anthracite with an aperture of greater than or equal to 100 nm, can be calculated using the mercury intrusion method; the fractal dimension of the coal pore, with an aperture range between 2.03 nm and 361.14 nm, can be calculated using the liquid nitrogen adsorption method, of which the fractal dimensions bounded by apertures of 10 nm and 100 nm are different. Based on these findings, we defined and calculated the comprehensive fractal dimensions of the coal pores and achieved the unity of fractal dimensions for full apertures of coal pores, thereby facilitating, overall characterization for the heterogeneity of the coal pore structure. PMID- 24955408 TI - Utilization of geotextile tube for sandy and muddy coastal management: a review. AB - Threats to beaches have accelerated the coastal destruction. In recent decades, geotextile tubes were used around the world to prevent coastal erosion, to encourage beach nourishment, and to assist mangrove rehabilitation. However, the applications of geotextile tube in sandy and muddy coasts have different concerns as the geological settings are different. Applications of geotextile tubes in sandy beaches were mainly to prevent coastline from further erosion and to nourish the beach. However, for the muddy coasts, mangrove rehabilitation and conservation were additional concerns in coastal management schemes. The mangrove forests are natural barriers which can be found on the muddy coasts of many tropical countries. In this paper, the viability of geotextile tubes in sandy and muddy beaches was analysed. The advantages and disadvantages of the utilization of geotextile tubes in coastal management were discussed based on the experiences from the tropical countries such as Mexico, Malaysia, and Thailand. From the case studies, impressive improvements in coastal restoration after installation of geotextile tubes were shown. Based on the discussion, several recommendations to improve the application of geotextile tubes were suggested in this paper. PMID- 24955409 TI - A study on ultraviolet protection of 100% cotton knitted fabric: effect of fabric parameters. AB - The effect of fabric parameters such as weight, thickness, and stitch density on the ultraviolet (UV) protection of knitted fabrics was studied. Different knitting structures such as plain, pineapple, lacoste, and other combinations of different knitting stitches of knit, tuck, and miss as well as half milano, full milano, half cardigan, full cardigan, 1 * 1 rib, and interlock were prepared. Experimental results revealed that weight was the most important factor that affected UV protection while thickness and stitch density were not the leading factor in determining UV protection. PMID- 24955410 TI - Optimal energy consumption analysis of natural gas pipeline. AB - There are many compressor stations along long-distance natural gas pipelines. Natural gas can be transported using different boot programs and import pressures, combined with temperature control parameters. Moreover, different transport methods have correspondingly different energy consumptions. At present, the operating parameters of many pipelines are determined empirically by dispatchers, resulting in high energy consumption. This practice does not abide by energy reduction policies. Therefore, based on a full understanding of the actual needs of pipeline companies, we introduce production unit consumption indicators to establish an objective function for achieving the goal of lowering energy consumption. By using a dynamic programming method for solving the model and preparing calculation software, we can ensure that the solution process is quick and efficient. Using established optimization methods, we analyzed the energy savings for the XQ gas pipeline. By optimizing the boot program, the import station pressure, and the temperature parameters, we achieved the optimal energy consumption. By comparison with the measured energy consumption, the pipeline now has the potential to reduce energy consumption by 11 to 16 percent. PMID- 24955411 TI - Parallel simulation of HGMS of weakly magnetic nanoparticles in irrotational flow of inviscid fluid. AB - The process of high gradient magnetic separation (HGMS) using a microferromagnetic wire for capturing weakly magnetic nanoparticles in the irrotational flow of inviscid fluid is simulated by using parallel algorithm developed based on openMP. The two-dimensional problem of particle transport under the influences of magnetic force and fluid flow is considered in an annular domain surrounding the wire with inner radius equal to that of the wire and outer radius equal to various multiples of wire radius. The differential equations governing particle transport are solved numerically as an initial and boundary values problem by using the finite-difference method. Concentration distribution of the particles around the wire is investigated and compared with some previously reported results and shows the good agreement between them. The results show the feasibility of accumulating weakly magnetic nanoparticles in specific regions on the wire surface which is useful for applications in biomedical and environmental works. The speedup of parallel simulation ranges from 1.8 to 21 depending on the number of threads and the domain problem size as well as the number of iterations. With the nature of computing in the application and current multicore technology, it is observed that 4-8 threads are sufficient to obtain the optimized speedup. PMID- 24955412 TI - Gaseous oxidized mercury dry deposition measurements in the southwestern USA: a comparison between Texas, eastern Oklahoma, and the Four Corners area. AB - Gaseous oxidized mercury (GOM) dry deposition measurements using aerodynamic surrogate surface passive samplers were collected in central and eastern Texas and eastern Oklahoma, from September 2011 to September 2012. The purpose of this study was to provide an initial characterization of the magnitude and spatial extent of ambient GOM dry deposition in central and eastern Texas for a 12-month period which contained statistically average annual results for precipitation totals, temperature, and wind speed. The research objective was to investigate GOM dry deposition in areas of Texas impacted by emissions from coal-fired utility boilers and compare it with GOM dry deposition measurements previously observed in eastern Oklahoma and the Four Corners area. Annual GOM dry deposition rate estimates were relatively low in Texas, ranging from 0.1 to 0.3 ng/m(2)h at the four Texas monitoring sites, similar to the 0.2 ng/m(2)h annual GOM dry deposition rate estimate recorded at the eastern Oklahoma monitoring site. The Texas and eastern Oklahoma annual GOM dry deposition rate estimates were at least four times lower than the highest annual GOM dry deposition rate estimate previously measured in the more arid bordering western states of New Mexico and Colorado in the Four Corners area. PMID- 24955413 TI - Monotone data visualization using rational trigonometric spline interpolation. AB - Rational cubic and bicubic trigonometric schemes are developed to conserve monotonicity of curve and surface data, respectively. The rational cubic function has four parameters in each subinterval, while the rational bicubic partially blended function has eight parameters in each rectangular patch. The monotonicity of curve and surface data is retained by developing constraints on some of these parameters in description of rational cubic and bicubic trigonometric functions. The remaining parameters are kept free to modify the shape of curve and surface if required. The developed algorithm is verified mathematically and demonstrated graphically. PMID- 24955414 TI - The strategic measures for the industrial security of small and medium business. AB - The competitiveness of companies increasingly depends upon whether they possess the cutting-edge or core technology. The technology should be protected from industrial espionage or leakage. A special attention needs to be given to SMB (small and medium business), furthermore, because SMB occupies most of the companies but has serious problems in terms of industrial security. The technology leakages of SMB would account for more than 2/3 of total leakages during last five years. The purpose of this study is, therefore, to analyze the problems of SMB in terms of industrial security and suggest the strategic solutions for SMB in South Korea. The low security awareness and financial difficulties, however, make it difficult for SMB to build the effective security management system which would protect the company from industrial espionage and leakage of its technology. The growing dependence of SMB on network such as internet, in addition, puts the SMB at risk of leaking its technology through hacking or similar ways. It requires new measures to confront and control such a risk. Online security control services and technology deposit system are suggested for such measures. PMID- 24955415 TI - Determinants of default from pulmonary tuberculosis treatment in Kuwait. AB - OBJECTIVES: To determine the prevalence and risk factors of default from pulmonary tuberculosis treatment in Kuwait. DESIGN: Retrospective study. PATIENTS AND METHODS: We studied all patients who were registered for pulmonary tuberculosis treatment between January 1, 2010, and December 31, 2012, and admitted into TB wards in El Rashid Center or treated in the outpatient clinic in TB Control Unit. RESULTS: There were 110 (11.5%) patients who defaulted from treatment. Fifty-six percent of those who defaulted did so in the first 2 months of treatment and 86.4% of them were still bacteriologically positive at the time of default. Key risk factors associated with noncompliance were male sex, low educational level, non-Kuwaiti nations, history of default, and history of concomitant diabetes mellitus, liver disease, or lung cancer. Multiple drug resistance was also associated with default from treatment. CONCLUSION: Default from treatment may be partially responsible for the persistent relatively high rates of tuberculosis in Kuwait. Health professionals and policy makers should ensure that all barriers to treatment are removed and that incentives are used to encourage treatment compliance. PMID- 24955416 TI - Structural safety analysis based on seismic service conditions for butterfly valves in a nuclear power plant. AB - The structural integrity of valves that are used to control cooling waters in the primary coolant loop that prevents boiling within the reactor in a nuclear power plant must be capable of withstanding earthquakes or other dangerous situations. In this study, numerical analyses using a finite element method, that is, static and dynamic analyses according to the rigid or flexible characteristics of the dynamic properties of a 200A butterfly valve, were performed according to the KEPIC MFA. An experimental vibration test was also carried out in order to verify the results from the modal analysis, in which a validated finite element model was obtained via a model-updating method that considers changes in the in situ experimental data. By using a validated finite element model, the equivalent static load under SSE conditions stipulated by the KEPIC MFA gave a stress of 135 MPa that occurred at the connections of the stem and body. A larger stress of 183 MPa was induced when we used a CQC method with a design response spectrum that uses 2% damping ratio. These values were lower than the allowable strength of the materials used for manufacturing the butterfly valve, and, therefore, its structural safety met the KEPIC MFA requirements. PMID- 24955417 TI - Structure-activity relationship for Fe(III)-salen-like complexes as potent anticancer agents. AB - Quantitative structure activity relationship (QSAR) for the anticancer activity of Fe(III)-salen and salen-like complexes was studied. The methods of density function theory (B3LYP/LANL2DZ) were used to optimize the structures. A pool of descriptors was calculated: 1497 theoretical descriptors and quantum-chemical parameters, shielding NMR, and electronic descriptors. The study of structure and activity relationship was performed with multiple linear regression (MLR) and artificial neural network (ANN). In nonlinear method, the adaptive neuro-fuzzy inference system (ANFIS) was applied in order to choose the most effective descriptors. The ANN-ANFIS model with high statistical significance (R (2) train = 0.99, RMSE = 0.138, and Q (2) LOO = 0.82) has better capability to predict the anticancer activity of the new compounds series of this family. Based on this study, anticancer activity of this compound is mainly dependent on the geometrical parameters, position, and the nature of the substituent of salen ligand. PMID- 24955418 TI - Mitigating nitrous oxide emissions from tea field soil using bioaugmentation with a Trichoderma viride biofertilizer. AB - Land-use conversion from woodlands to tea fields in subtropical areas of central China leads to increased nitrous oxide (N2O) emissions, partly due to increased nitrogen fertilizer use. A field investigation of N2O using a static closed chamber-gas chromatography revealed that the average N2O fluxes in tea fields with 225 kg N ha(-1) yr(-1) fertilizer application were 9.4 +/- 6.2 times higher than those of woodlands. Accordingly, it is urgent to develop practices for mitigating N2O emissions from tea fields. By liquid-state fermentation of sweet potato starch wastewater and solid-state fermentation of paddy straw with application of Trichoderma viride, we provided the tea plantation with biofertilizer containing 2.4 t C ha(-1) and 58.7 kg N ha(-1). Compared to use of synthetic N fertilizer, use of biofertilizer at 225 kg N ha(-1) yr(-1) significantly reduced N2O emissions by 33.3%-71.8% and increased the tea yield by 16.2%-62.2%. Therefore, the process of bioconversion/bioaugmentation tested in this study was found to be a cost-effective and feasible approach to reducing N2O emissions and can be considered the best management practice for tea fields. PMID- 24955420 TI - The expanded invasive weed optimization metaheuristic for solving continuous and discrete optimization problems. AB - This paper introduces an expanded version of the Invasive Weed Optimization algorithm (exIWO) distinguished by the hybrid strategy of the search space exploration proposed by the authors. The algorithm is evaluated by solving three well-known optimization problems: minimization of numerical functions, feature selection, and the Mona Lisa TSP Challenge as one of the instances of the traveling salesman problem. The achieved results are compared with analogous outcomes produced by other optimization methods reported in the literature. PMID- 24955419 TI - Intelligent screening systems for cervical cancer. AB - Advent of medical image digitalization leads to image processing and computer aided diagnosis systems in numerous clinical applications. These technologies could be used to automatically diagnose patient or serve as second opinion to pathologists. This paper briefly reviews cervical screening techniques, advantages, and disadvantages. The digital data of the screening techniques are used as data for the computer screening system as replaced in the expert analysis. Four stages of the computer system are enhancement, features extraction, feature selection, and classification reviewed in detail. The computer system based on cytology data and electromagnetic spectra data achieved better accuracy than other data. PMID- 24955421 TI - MicroRNA-222 expression and its prognostic potential in non-small cell lung cancer. AB - Overexpression of miR-222 has been found in several types of cancers; however, the expression of miR-222 in non-small cell lung cancer (NSCLC) and its prognostic values are unclear. This study aimed to investigate whether the miR 222 expression level is related to clinicopathological factors and prognosis of NSCLC. Through a prospective study, 100 pairs of NSCLC tissues and adjacent normal tissues were examined by quantitative reverse-transcription polymerase chain reaction. The correlation between miR-222 expression and clinicopathological features was analyzed, and the significance of miR-222 as a prognostic factor and its relationship with survival were determined. Results showed that the expression levels of miR-222 were significantly elevated in the NSCLC tissue compared with that in adjacent normal tissue. In addition, Cox's proportional hazards model analysis confirmed that miR-222 high expression level was an independent predictor of poor prognosis. In conclusion, miR-222 overexpression is involved in the poor prognosis of NSCLC and can be used as a biomarker for selection of cases requiring especial attention. PMID- 24955422 TI - Interference assembly and fretting wear analysis of hollow shaft. AB - Fretting damage phenomenon often appears in the interference fit assembly. The finite element model of hollow shaft and shaft sleeve was established, and the equivalent stress and contact stress were computed after interference assembly. The assembly body of hollow shaft and shaft sleeve was in whirling bending load, and the contact status (sticking, sliding, and opening) and the distribution of stress along one typical contact line were computed under different loads, interferences, hollow degrees, friction coefficient, and wear quantity. Judgment formula of contact state was fixed by introducing the corrected coefficient k. The computation results showed that the "edge effect" appears in the contact surface after interference fit. The size of slip zone is unchanged along with the increase of bending load. The greater the interference value, the bigger the wear range. The hollow degree does not influence the size of stick zone but controls the position of the junction point of slip-open. Tangential contact stress increases with the friction coefficient, which has a little effect on normal contact stress. The relationship between open size and wear capacity is approximately linear. PMID- 24955423 TI - Adaptive bacteria colony picking in unstructured environments using intensity histogram and unascertained LS-SVM classifier. AB - Features analysis is an important task which can significantly affect the performance of automatic bacteria colony picking. Unstructured environments also affect the automatic colony screening. This paper presents a novel approach for adaptive colony segmentation in unstructured environments by treating the detected peaks of intensity histograms as a morphological feature of images. In order to avoid disturbing peaks, an entropy based mean shift filter is introduced to smooth images as a preprocessing step. The relevance and importance of these features can be determined in an improved support vector machine classifier using unascertained least square estimation. Experimental results show that the proposed unascertained least square support vector machine (ULSSVM) has better recognition accuracy than the other state-of-the-art techniques, and its training process takes less time than most of the traditional approaches presented in this paper. PMID- 24955424 TI - Variation of runoff and precipitation in the Hekou-Longmen region of the Yellow River based on elasticity analysis. AB - Precipitation is very important to the formation of runoff, and studying of runoff variation and its response to precipitation has practical significance to sustainable utilization of water resources. The study used Mann-Kendall test, anomaly accumulation method, and precipitation elasticity of runoff method to analyze the changes in the relation of precipitation and runoff and the contribution of precipitation to runoff change in the Hekou-Longmen region (from 1957 to 2010), Huangfuchuan watershed (from 1954 to 2010), and Yanhe watershed (from 1952 to 2010) in the middle reaches of the Yellow River. The results showed that runoff appeared a significant decreasing trend (P = 0.01) while it was not significant in precipitation in all study areas. In particular, the reductions of average annual runoff in the Hekou-Longmen region, Huangfuchuan watershed, and Yanhe watershed were 72.7%, 87.5%, and 32.2%, respectively, during 2000-2010 compared to the 1950s. There existed two abrupt change points of the runoff in the Hekou-Longmen region and Huangfuchuan watershed, which were detected in 1979 and 1998. But in the Yanhe watershed only one abrupt change point was found in 1996. The precipitation elasticities of runoff were 1.11, 1.09, and 1.26, respectively, and the contributions of precipitation on runoff reduction were 26.4%, 17.9%, and 31.6%, respectively, in the Hekou-Longmen region, Huangfuchuan watershed, and Yanhe watershed. PMID- 24955425 TI - The generalized sidelobe canceller based on quaternion widely linear processing. AB - We investigate the problem of quaternion beamforming based on widely linear processing. First, a quaternion model of linear symmetric array with two component electromagnetic (EM) vector sensors is presented. Based on array's quaternion model, we propose the general expression of a quaternion semiwidely linear (QSWL) beamformer. Unlike the complex widely linear beamformer, the QSWL beamformer is based on the simultaneous operation on the quaternion vector, which is composed of two jointly proper complex vectors, and its involution counterpart. Second, we propose a useful implementation of QSWL beamformer, that is, QSWL generalized sidelobe canceller (GSC), and derive the simple expressions of the weight vectors. The QSWL GSC consists of two-stage beamformers. By designing the weight vectors of two-stage beamformers, the interference is completely canceled in the output of QSWL GSC and the desired signal is not distorted. We derive the array's gain expression and analyze the performance of the QSWL GSC in the presence of one type of interference. The advantage of QSWL GSC is that the main beam can always point to the desired signal's direction and the robustness to DOA mismatch is improved. Finally, simulations are used to verify the performance of the proposed QSWL GSC. PMID- 24955426 TI - Effects of surfactants on the properties of mortar containing styrene/methacrylate superplasticizer. AB - The physical and mechanical properties of mortar containing synthetic cosurfactants as air entraining agent are investigated. The cosurfactants consist of a combination of 2% dodecyl benzene sodium sulfonate (DBSS) and either 1.5% polyvinyl alcohol (PVA) or 1.5% polyoxyethylene glycol monomethyl ether (POE). Also these cosurfactants were used to prepare copolymers latex: styrene/butyl methacrylate (St/BuMA), styrene/methyl methacrylate (St/MMA), and styrene/glycidyl methacrylate (St/GMA), in order to study their effects on the properties of mortar. The properties of mortar examined included flow table, W/C ratio, setting time, water absorption, compressive strength, and combined water. The results indicate that the latex causes improvement in mortar properties compared with cosurfactants. Also polymer latex containing DBSS/POE is more effective than that containing DBSS/PVA. PMID- 24955427 TI - Wheat landraces are better qualified as potential gene pools at ultraspaced rather than densely grown conditions. AB - The negative relationship between the yield potential of a genotype and its competitive ability may constitute an obstacle to recognize outstanding genotypes within heterogeneous populations. This issue was investigated by growing six heterogeneous wheat landraces along with a pure-line commercial cultivar under both dense and widely spaced conditions. The performance of two landraces showed a perfect match to the above relationship. Although they lagged behind the cultivar by 64 and 38% at the dense stand, the reverse was true with spaced plants where they succeeded in out-yielding the cultivar by 58 and 73%, respectively. It was concluded that dense stand might undervalue a landrace as potential gene pool in order to apply single-plant selection targeting pure-line cultivars, attributable to inability of plants representing high yielding genotypes to exhibit their capacity due to competitive disadvantage. On the other side, the yield expression of individuals is optimized when density is low enough to preclude interplant competition. Therefore, the latter condition appears ideal to identify the most promising landrace for breeding and subsequently recognize the individuals representing the most outstanding genotypes. PMID- 24955428 TI - Association of vitamin E with rapid thawing on goat semen. AB - The aim of this study was to evaluate the effects of vitamin E associated with rapid thawing on cryopreserved goat semen. Two bucks were used and eight ejaculates per animal were collected using artificial vagina. Semen was diluted with the following treatments: BIOXCELL (control), BIOXCELL + Equex (sodium lauryl sulphate) and BIOXCELL + vitamin E 100 MUM. Semen was packaged into 0.25 mL straws and cooled at 5 degrees C for 1 hour. Freezing was performed in liquid nitrogen vapor (-155 degrees C) during 15 minutes. Then, the straws were immersed in liquid nitrogen (-196 degrees C). Straws were thawed at 38 degrees C/60 seconds or at 60 degrees C/7 seconds with immediate sperm analysis. Hypoosmotic swelling test was performed adding a 20 MUL aliquot of thawed semen to 1 mL of hypoosmotic solution (100 mOsm . Kg(-1)) followed by incubation during 60 minutes in water bath (38 degrees C). Vitamin E did not affect any studied parameters (P > 0.05). Nevertheless, defrosting rate of 60 degrees C/7 seconds improved sperm membrane functional integrity (P < 0.05). Current knowledge about goat semen cryopreservation is not sufficient to ensure high post-thawing recovery rates; thus, this study brings important data about using antioxidants and different thawing rates on cryopreservation process. PMID- 24955429 TI - Negative and positive association rules mining from text using frequent and infrequent itemsets. AB - Association rule mining research typically focuses on positive association rules (PARs), generated from frequently occurring itemsets. However, in recent years, there has been a significant research focused on finding interesting infrequent itemsets leading to the discovery of negative association rules (NARs). The discovery of infrequent itemsets is far more difficult than their counterparts, that is, frequent itemsets. These problems include infrequent itemsets discovery and generation of accurate NARs, and their huge number as compared with positive association rules. In medical science, for example, one is interested in factors which can either adjudicate the presence of a disease or write-off of its possibility. The vivid positive symptoms are often obvious; however, negative symptoms are subtler and more difficult to recognize and diagnose. In this paper, we propose an algorithm for discovering positive and negative association rules among frequent and infrequent itemsets. We identify associations among medications, symptoms, and laboratory results using state-of-the-art data mining technology. PMID- 24955430 TI - Dual key speech encryption algorithm based underdetermined BSS. AB - When the number of the mixed signals is less than that of the source signals, the underdetermined blind source separation (BSS) is a significant difficult problem. Due to the fact that the great amount data of speech communications and real-time communication has been required, we utilize the intractability of the underdetermined BSS problem to present a dual key speech encryption method. The original speech is mixed with dual key signals which consist of random key signals (one-time pad) generated by secret seed and chaotic signals generated from chaotic system. In the decryption process, approximate calculation is used to recover the original speech signals. The proposed algorithm for speech signals encryption can resist traditional attacks against the encryption system, and owing to approximate calculation, decryption becomes faster and more accurate. It is demonstrated that the proposed method has high level of security and can recover the original signals quickly and efficiently yet maintaining excellent audio quality. PMID- 24955431 TI - Leapfrog/finite element method for fractional diffusion equation. AB - We analyze a fully discrete leapfrog/Galerkin finite element method for the numerical solution of the space fractional order (fractional for simplicity) diffusion equation. The generalized fractional derivative spaces are defined in a bounded interval. And some related properties are further discussed for the following finite element analysis. Then the fractional diffusion equation is discretized in space by the finite element method and in time by the explicit leapfrog scheme. For the resulting fully discrete, conditionally stable scheme, we prove an L (2)-error bound of finite element accuracy and of second order in time. Numerical examples are included to confirm our theoretical analysis. PMID- 24955433 TI - Backbone-modified amphiphilic cyclic di- and tetrasaccharides. AB - Synthesis of amphiphilic, cyclic di- and tetrasaccharides, which incorporate a methylene moiety at the inter-glycosidic bond, is reported. The amphiphilic properties of the new cyclic tetrasaccharide host were identified through assessing the solubilities of guests in aqueous and in organic solvents. The glycosidic bond stability of the cyclic tetrasaccharide under aqueous acidic condition was also verified. PMID- 24955432 TI - Amygdala Atrophy in MCI/Alzheimer's Disease in the BIOCARD cohort based on Diffeomorphic Morphometry. AB - Surface-based deformation markers obtained from diffeomorphic mapping of the amygdala are used to study specific atrophy patterns in a combined mild cognitively impaired and demented cohort compared with cognitively normal aging subjects. Statistical analysis demonstrates with high significance in a small sample of legacy data that deformation-based morphometry provides sensitive markers for locating atrophy in the amygdala. With respect to a high-field amygdala atlas, significant atrophy was found in the basomedial and lateral nucleus subregions. PMID- 24955434 TI - Fast recovery of free energy landscapes via diffusion-map-directed molecular dynamics. AB - The reaction pathways characterizing macromolecular systems of biological interest are associated with high free energy barriers. Resorting to the standard all-atom molecular dynamics (MD) to explore such critical regions may be inappropriate as the time needed to observe the relevant transitions can be remarkably long. In this paper, we present a new method called Extended Diffusion Map-directed Molecular Dynamics (extended DM-d-MD) used to enhance the sampling of MD trajectories in such a way as to rapidly cover all important regions of the free energy landscape including deep metastable states and critical transition paths. Moreover, extended DM-d-MD was combined with a reweighting scheme enabling to save on-the-fly information about the Boltzmann distribution. Our algorithm was successfully applied to two systems, alanine dipeptide and alanine-12. Due to the enhanced sampling, the Boltzmann distribution is recovered much faster than in plain MD simulations. For alanine dipeptide, we report a speedup of one order of magnitude with respect to plain MD simulations. For alanine-12, our algorithm allows us to highlight all important unfolded basins in several days of computation when one single misfolded event is barely observable within the same amount of computational time by plain MD simulations. Our method is reaction coordinate free, shows little dependence on the a priori knowledge of the system, and can be implemented in such a way that the biased steps are not computationally expensive with respect to MD simulations thus making our approach well adapted for larger complex systems from which little information is known. PMID- 24955435 TI - Magnetic moments in graphene with vacancies. AB - Vacancies can induce local magnetic moments in graphene, paving the way to make magnetic functional graphene. Due to the interaction between magnetic moments and conduction carriers, the magnetotransport properties of graphene can be modulated. Here, the effects of vacancy induced magnetic moments on the electrical properties of graphene are studied via magnetotransport measurements and spin-polarized density functional theory calculations. We show by quantum Hall measurements that a sharp resonant Vpi state is introduced in the midgap region of graphene with vacancies, resulting in the local magnetic moment. The coupling between the localized Vpi state and the itinerant carrier is tuned by varying the carrier concentration, temperature, magnetic field, and vacancy density, which results in a transition between hopping transport and the Kondo effect and a transition between giant negative magnetoresistance (MR) and positive MR. This modulated magnetotransport is valuable for graphene based spintronic devices. PMID- 24955436 TI - Sensitive and selective determination of hydroxychloroquine in the presence of uric acid using a new nanostructure self-assembled monolayer modified electrode: optimization by multivariate data analysis. AB - A highly sensitive electrochemical nanosensor was developed using covalent modification of a glassy carbon electrode (GCE) by self-assembly of a novel Schiff base. Scanning electron microscopy (SEM) and electrochemical techniques were used to investigate the immobilization of the self-assembled monolayer (SAM) on the GCE. The electrochemical behavior of hydroxychloroquine (HCQ) in the presence of uric acid (UA) at the surface of the modified electrode was studied using the differential pulse voltammetry (DPV) technique. Response surface methodology (RSM) is used to optimize the effects of various operating variables such as pH, immersion time, scan rate, step potential and modulation amplitude on the voltammetric response of HCQ. RSM formulates a mathematical model which correlates the independent parameters with the peak current of HCQ. The central composite rotatable design (CCRD) has been applied to conduct the experiments. Then, under the optimized conditions, HCQ was determined in the presence of UA. The electrochemical measurements demonstrated that this biosensor responded well to HCQ, confirming that the self-assembly immobilization method was effective. Also, the interference, the storage stability, and the reproducibility of the biosensor were studied and assessed. The developed nanosensor was economical and efficient, making it potentially attractive for application to real sample analysis. PMID- 24955437 TI - Sensitive and selective trypsin detection using redox cycling in the presence of L-ascorbic acid. AB - We report a simple, sensitive, and selective electrochemical method for trypsin detection that can cover a wide range of concentrations. The method is based on the proteolytic generation of an electroactive species (P) by trypsin followed by a signal-amplified electrochemical measurement of P using electrochemical chemical (EC) or electrochemical-chemical-chemical (ECC) redox cycling. The detection is performed using bare indium-tin oxide (ITO) electrodes without washing steps. P is generated by the cleavage of an amide bond between P and oligopeptide (Gly-Pro-Arg) at the C-terminal of Gly-Pro-Arg-P. Four trypsin products including 4-amino-1-naphthol (AN) and their trypsin substrates are investigated to obtain a high signal-to-background ratio in ECC redox cycling. AN and its trypsin substrate produce the highest signal-to-background ratio. The detection limits obtained with ECC redox cycling involving AN (approximately 1 ng mL(-1) and 100 ng mL(-1) with an incubation period of 2 h and 30 min, respectively) in Tris buffer (pH 8.0) are lower than those obtained with EC redox cycling involving AN (approximately 5 ng mL(-1) and 200 ng mL(-1) with an incubation period of 2 h and 30 min, respectively). In trypsin detection using ECC redox cycling, the interference effects of electroactive species such as l ascorbic acid and uric acid are not significant. PMID- 24955438 TI - Constructing a fluorescent probe for specific detection of cysteine over homocysteine and glutathione based on a novel cysteine-binding group but-3-yn-2 one. AB - A but-3-yn-2-one-based 7-diethylaminocoumarin dye was exploited as a fluorescent probe to specifically detect Cys over Hcy/GSH in pure PBS buffer. The probe itself is nonfluorescent due to the donor-excited photoinduced electron transfer (d-PET) process. The Cys-induced Michael addition-rearrangement cascade reaction leads to an amino-substituted product with strong fluorescence due to inhibiting C[double bond, length as m-dash]C isomerization induced fluorescence quenching by a produced intramolecular N-HO hydrogen bond. The Hcy (or GSH)-induced Michael addition reaction leads to a thiol-substituted product (or ), which lacks any intramolecular hydrogen-bonding interaction, and thus displays very poor fluorescence due to the efficient C[double bond, length as m-dash]C isomerization induced fluorescence quenching. Even in the presence of Hcy (or GSH), the probe could also detect Cys with the obvious fluorescence enhancement. Assisted by using a laser scanning confocal microscope, we demonstrated that the probe could selectively image Cys in the human renal cell carcinoma 786-0 cells. PMID- 24955439 TI - Transmission line model analysis of transcription factors binding to oligoduplexes - differentiation of the effect of single nucleotide modifications. AB - Advanced impedance spectroscopy analysis based on the transmission line model (TLM) is explored as a novel QCM acoustic biosensing platform for the detection of the single point mutation effect on the binding of the transcription factors (TFs) to immobilized DNA oligoduplexes and the characterization of the protein DNA mechanical properties. PMID- 24955440 TI - High-sensitivity fluorescence imaging of iron in plant tissues. AB - Here, we report a method for high-sensitivity fluorescence imaging of iron, which demonstrates the abundance and distribution of iron in plant tissues more precisely than conventional histochemical staining procedures. The fluorescence turn-on method is rapid (<20 min), inexpensive to set up, and expected to be readily applicable to any plant tissues. PMID- 24955441 TI - Coordination polymers for catalysis: enhancement of catalytic activity through hierarchical structuring. AB - We utilized a novel strategy, hierarchical structuring, to enhance the catalytic activity of coordination polymers. Hierarchical Prussian white crystals with hollow structures and kinked surfaces were synthesized by using a self aggregation and etching strategy. The hierarchical structure significantly enhanced the catalytic activity of Prussian white in the degradation of methylene blue in comparison to the non-hierarchical Prussian white crystals. PMID- 24955442 TI - A bilayer triangular lattice with crown-like Co(7) spin cluster SBUs exhibiting high spin frustration. AB - A novel bilayer metal-organic framework is assembled with a perfect intralayer triangular subnet and ideal interlayer Td arrangement between unprecedented crown like Co7 cluster units, exhibiting high spin frustration. PMID- 24955444 TI - Preventing otitis media with pneumococcal conjugate vaccine: more data than certainty? PMID- 24955443 TI - Inorganic nanomaterials for bioimaging, targeted drug delivery and therapeutics. AB - Inorganic nanomaterials including gold nanoparticles, mesoporous silica nanoparticles, graphene, magnetic nanoparticles, quantum dots and layered double hydroxides have become one of the most active research fields in biochemistry, biotechnology and biomedicine. Benefiting from the facile synthesis/modification, intrinsically physicochemical properties and good biocompatibility, inorganic nanomaterials have shown great potential in bioimaging, targeted drug delivery and cancer therapies. This Feature Article summarizes recent progress on various inorganic nanocarriers, including the background, synthesis, modification, cytotoxicity, physicochemical properties as well as their applications in biomedicine. PMID- 24955445 TI - From observation to evidence of effectiveness: the haphazard route to finding out if a new intervention works. PMID- 24955446 TI - Base-free oxidation of glycerol using titania-supported trimetallic Au-Pd-Pt nanoparticles. AB - Base-free selective oxidation of glycerol has been investigated using trimetallic Au-Pd-Pt nanoparticles supported on titania and their corresponding bimetallic catalysts. Catalysts were prepared by the sol-immobilization method and characterized by means of TEM, UV/Vis spectroscopy, diffuse reflectance infrared fourier transform spectroscopy, X-ray photoelectron spectroscopy, and microwave plasma-atomic emission spectroscopy. It was found that of the bimetallic catalysts, Pd-Pt/TiO2 was the most active with high selectivity to C3 products. The addition of Au to this catalyst to form the trimetallic Au-Pd-Pt/TiO2, resulted in an increase in activity relative to Pd-Pt/TiO2. The turnover frequency increased from 210 h(-1) with the Pd-Pt/TiO2 catalyst to378 h(-1) for the trimetallic Au-Pd-Pt/TiO2 catalyst with retention of selectivity towards C3 products. PMID- 24955447 TI - Systematic review of the effectiveness of biological therapy for active moderate to severe ulcerative colitis. AB - BACKGROUND AND AIM: The aim of this systematic review was to evaluate the efficacy and safety of biological agents (vedolizumab, abatacept, visilizumab, golimumab) in patients with active moderate to severe ulcerative colitis. METHODS: This paper was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The systematic literature search was performed in PubMed, Embase, Cochrane Library, and other databases until December 27, 2013 to identify randomized controlled trials fulfilling the established inclusion criteria for this review. RESULTS: Eight randomized controlled trials were included in the systematic review. Vedolizumab was significantly more effective compared with placebo (P < 0.05) increasing the percentage of patients with a clinical response, clinical remission and mucosal healing in the induction phase, and patients with a clinical remission and mucosal healing in the maintenance phase. Similarly, golimumab was significantly more effective than placebo (P < 0.05) regarding the percentage of patients with a clinical response and mucosal healing in the induction phase, and patients with a clinical response, clinical remission, and mucosal healing in the maintenance phase. The safety of these two biological agents was comparable with placebo during the treatment (P > 0.05). However, the efficacy of visilizumab or abatacept was related to the higher risk of treatment failure and a worse safety profile than placebo. CONCLUSIONS: The results of the systematic review demonstrated that the efficacy and safety of particular biological agents are differentiated. Vedolizumab and golimumab occurred more effective, and comparably as safe as placebo in patients with active moderate to severe ulcerative colitis increasing the number of available therapeutic options. PMID- 24955448 TI - Efficacy of hybrid therapy as first-line regimen for Helicobacter pylori infection compared with sequential therapy. AB - BACKGROUND AND AIM: Recent prospective studies have shown that the sequential therapy has not achieved the target Helicobacter pylori eradication rate of > 80% in Korea. The aim of this study was to therefore assess the efficacy of the hybrid therapy as a first-line treatment for H. pylori eradication in a prospective trial. METHODS: From December 2012 to August 2013, 184 patients with confirmed H. pylori infections received either the 14-day hybrid therapy or the 14-day sequential therapy. Eradication outcomes were evaluated using a 13C-urea breath test at least 4 weeks after treatment cessation. RESULTS: A total of 184 patients (90 receiving hybrid treatment and 94 receiving sequential treatment) completed the study. The eradication rates of the hybrid and sequential therapy groups were 81.1% (73/90; 95% confidence interval [CI] = 73.0-89.2%) and 79.8% (75/94; 95%CI = 71.7-87.9%), respectively, by intention-to-treat analysis (P = 0.821). By per protocol analysis, eradication rates were 85.9% (73/85; 95%CI = 78.5-93.3%) and 82.0% (73/89; 95%CI = 74.0-89.9%; P = 0.489), respectively. There were no significant intergroup differences in treatment compliance or discontinuation induced by severe side effects. CONCLUSIONS: The hybrid therapy achieved acceptable eradication rate (85.9%), but not statistically significantly higher rates than the sequential therapy (82.0%). Further studies are therefore needed to identify first-line treatments with even better eradication rates in the Korean population. PMID- 24955449 TI - Comparison of efficacy, pharmacokinetics, and immunogenicity between infliximab mono- versus combination therapy in ulcerative colitis. AB - BACKGROUND: The association of concomitant immunosuppressant use with infliximab (IFX) and therapeutic outcomes in correlation with pharmacokinetic properties in ulcerative colitis (UC) remains unclear. AIMS: To assess the effect of concomitant immunosuppressant use on the duration of IFX therapy, and the pharmacokinetic properties of IFX in patients with UC. METHODS: A retrospective analysis of UC patients treated with IFX. Duration of efficacious IFX therapy, and serum IFX and antibody-to-IFX (ATI) levels were compared between those receiving IFX as monotherapy and in combination with an immunosuppressant. RESULTS: Among the 85 UC patients who received IFX, 46 (54.1%) received concomitant immunosuppressants, and 38 (45.9%) received IFX monotherapy. Concomitant immunosuppressant use was associated with increased duration of IFX therapy as 90% of patients receiving immunosuppressants remained on therapy at 1 year versus 61% of patients on monotherapy (Log-rank, P = 0.016). Concomitant immunosuppressant use, as compared with monotherapy, was associated with greater IFX levels (20.4 mg/L vs 10.5 mg/L, P = 0.025) and less frequent ATI formation (4.5% vs 33.3%, P = 0.031). Patients receiving greater than 2.0 mg/kg of azathioprine had greater IFX lev l than those receiving less than 2.0 mg/kg (26.0 vs 10.6 mcg/mL, P = 0.03) and those receiving IFX monotherapy (26.0 vs 11.2 mcg/mL, P = 0.03). The duration of IFX therapy among patients receiving less than 2.0 mg/kg azathioprine was indistinguishable from patients on IFX monotherapy (Log-rank, P = 0.95). CONCLUSION: Concomitant immunosuppressant therapy with IFX improves outcomes in UC as shown by increased duration of therapy, decreased immunogenicity against IFX, and increased blood levels of IFX. Our data suggest that this benefit may be dependent on the dose of concomitant immunosuppression. PMID- 24955451 TI - Randomized trial of 2-L polyethylene glycol + ascorbic acid versus 4-L polyethylene glycol as bowel cleansing for colonoscopy in an optimal setting. AB - BACKGROUND AND AIM: Prior studies have reported 2-L polyethylene glycol (PEG) plus ascorbic acid (PEG + Asc) is an effective alternative to standard 4-L PEG for bowel preparation before colonoscopy, but they are limited because of some confounders. Therefore, we compared the efficacy, patient compliance, satisfaction, and safety of 2-L PEG + Asc versus 4-L PEG for bowel cleansing in optimal preparation strategies. METHODS: In this prospective, randomized, single blind trial, consenting outpatients were randomly assigned to one of two arms. All colonoscopies were scheduled in the morning and cleansing solutions were administered as a split-dose regimen. Bowel-cleansing efficacy in three different segments was measured on a five-point scale with four-point overall grading. Patients' opinions of the preparation regimens were obtained by questionnaire. RESULTS: There was no significant difference between the 2-L PEG + Asc (159/163; 97.5%) and 4-L PEG (162/164; 98.8%) with respect to the overall success of bowel cleansing (mean difference = -1.3 [-4.1-infinity]). Patient compliance, acceptability, and satisfaction were better in the 2-L PEG + Asc arm than the 4-L PEG arm (P < 0.05). Additionally, the incidence of side effects was lower in the 2-L PEG + Asc than the 4-L PEG (overall, 57.7% vs 73.2%, P < 0.05). However, no significant difference was seen in patients' rating of taste. CONCLUSIONS: In an optimal preparation setting, 2-L PEG + Asc has equal efficacy as a bowel cleanser prior to colonoscopy as 4-L PEG, with the advantages of better patient compliance, satisfaction, and safety. PMID- 24955450 TI - Efficacy and safety of esomeprazole with flupentixol/melitracen in treating gastroesophageal reflux disease patients with emotional disorders. AB - BACKGROUND AND AIM: This study was designed to demonstrate the safety and efficacy of esomeprazole combined with flupentixol/melitracen for the treatment of gastroesophageal reflux disease (GERD) patients with emotional disorders. METHODS Two hundred eighty-nine GERD patients with emotional disorders were divided randomly into two groups: group 1 received esomeprazole only (monotherapy) and group 2 received esomeprazole and flupentixol/melitracen (combination therapy). The patients' GERD questionnaire (GerdQ) and hospital anxiety and depression (HAD) scores were obtained before and after treatment. Changes in the scores, rates of symptom remission, and adverse effects were compared between the two groups. RESULTS: After 2 weeks of treatment, the average decrease in GerdQ score in the combination group (4.04 +/- 2.34) was significantly greater than that in the monotherapy group (3.34 +/- 2.74; P < 0.05). Significant differences between the two groups were also found for changes in HAD anxiety scores (5.45 +/- 2.41 vs 3.34 +/- 2.43, P < 0.05), depression scores (5.47 +/- 2.47 vs 3.00 +/- 3.28, P < 0.05), and anxiety-depression scores (5.20 +/- 2.71 vs 3.60 +/- 2.56, P < 0.05). The remission of symptoms (eructation, abdominal pain, anorexia, and other accompanying symptoms) in the combination group was significantly better than that in the monotherapy group, and no significant difference in the incidence of adverse events was observed between the two groups. CONCLUSIONS: The combination therapy has better efficacy than the monotherapy in improving the symptoms of gastroesophageal reflux in patients with emotional disorders. In addition, this combination treatment is safe, with a low incidence of adverse events. PMID- 24955452 TI - Randomized controlled trial of monthly versus biweekly endoscopic variceal ligation for the prevention of esophageal variceal rebleeding. AB - BACKGROUND: Endoscopic variceal ligation (EVL) is effective in preventing esophageal variceal rebleeding. However, the optimal EVL interval remains unclear. AIM: To investigate the effectiveness and safety of EVL using two intersession intervals. methods: From January 2009 to October 2012, 214 patients with acute esophageal variceal bleeding were screened. Emergency ligation was performed for patients with acute variceal bleeding. After achieving hemodynamic stability, eligible patients (n = 70) were randomized to either the monthly group or the biweekly group. RESULTS: Median time from randomization to variceal obliteration was 2.7 months in the monthly group and 1.7 months in the biweekly group, at a mean of 2.3 +/- 2.0 and 3.0 +/- 1.8 sessions, respectively. After a median follow up of 23 months, six patients (17%) in the monthly group and nine patients (26%) in the biweekly group developed upper gastrointestinal rebleeding (P = 0.382). Esophageal variceal rebleeding occurred in six patients (17%) in the monthly group and in seven patients (20%) in the biweekly group (P = 0.759). No rebleeding from EVL ulcers occurred in the monthly group and was 5.7% (n = 2) for the biweekly group. Both treatment groups had similar rates of esophageal variceal recurrence and mortality. Notably, the incidence of post-EVL ulcers in the monthly group was lower than that in the biweekly group (11% vs 57%, P < 0.001). CONCLUSIONS: Patients receiving EVL monthly had similar rebleeding rate, variceal recurrence, and mortality to those receiving EVL biweekly for secondary prophylaxis of variceal bleeding; however, the monthly interval was associated with fewer post-EVL ulcers found at follow-up endoscopies. PMID- 24955453 TI - Experience of the endoscopist increases detection rates of smaller size and higher histological grade polyps. AB - BACKGROUND: Adenoma and polyp detection rates (ADR and PDR, respectively) are important indicators of endoscopy quality, particularly in colorectal carcinoma screening. OBJECTIVE: To assess the influence of the endoscopist's experience on the ADR and PDR. PATIENTS AND METHODS: In this study, 9635 colonoscopies were screened during a 5-year period. Only 5738 were finally analyzed due to exclusion criteria. The endoscopists were separated in three groups of experience according to the number of colonoscopies performed in the past (yearly and total). The number of polyps and adenomas, as well as the size and histology of these polyps were recorded. RESULTS: The ADR and PDR were similar regardless of the experience of the endoscopist, but those with more experience clearly found more polyps of less than 10 mm (P = 0.01) and of less than 3 mm (P < 0.0001). Most of the differences were due to a higher number of flat polyps detected by the experienced group. This study also shows that more experienced endoscopists detect adenomas with more advanced histology (P < 0.0001). CONCLUSION: Even though the ADR and PDR are similar in all groups of endoscopists, the less experienced endoscopists could be missing some of the smaller polyps, sometimes with more advanced histology. PMID- 24955454 TI - Influence of psychiatric diagnosis on treatment uptake and interferon side effects in patients with hepatitis C. AB - BACKGROUND AND AIM: Pegylated-interferon-alpha/ribavirin (PEG-IFN/RBV) treatment can cure hepatitis C virus (HCV) infection but has frequent neuropsychiatric side effects. Patients with pre-existing psychiatric illness may not be offered therapy. We established prevalence of self-reported psychiatric comorbidity among HCV-infected patients in a hospital-liver clinic, and determined the impact of such diagnoses on uptake and tolerance to PEG-IFN/RBV. METHODS: All HCV cases referred for assessment in Australian Capital Territory/surrounding regions April 2004-March 2012 were entered into a clinical database. We conducted univariate and multivariate analyses of variables correlating with uptake of antiviral therapy and frequency of treatment-related side-effects. RESULTS: Of 773 referred patients, 235 (30%) described pre-existing psychiatric illness. Among these, 26% received antiviral therapy, compared with 30% of 538 without psychiatric comorbidity. History of depression (usually validated by liaison psychiatry) was associated with higher incidence of treatment-related neuropsychiatric side effects (odds ratio 2.79 [1.35-5.70], P < 0.05) but did not affect treatment outcome. Twenty-seven patients reported schizophrenia: three (11%) received antiviral therapy, compared with 30% admitting depression and 20% with bipolar affective disorder (all assessed by psychiatrist). In most schizophrenia cases, the reason for not offering antiviral treatment was psychological illness, yet none of five treated (these three plus two others in a psychiatric rehabilitation facility) experienced worsening psychiatric symptoms. CONCLUSIONS: A history of depression is common with hepatitis C but does not affect initiation of antiviral treatment, despite substantially increased risk of psychiatric side-effects. In contrast, pre-existing schizophrenia appears to influence treatment decisions, despite little evidence that PEG-IFN/RBV exacerbates the psychiatric condition, and well-supervised antiviral therapy can have good outcomes. PMID- 24955455 TI - Associations between intakes of individual nutrients or whole food groups and non alcoholic fatty liver disease among Korean adults. AB - BACKGROUND AND AIM: Dietary factors are closely associated with the risk of non alcoholic fatty liver disease (NAFLD). Asian and Western diets differ in energy nutrient composition, fatty-acid composition, and main nutritional sources; therefore, the implications would be limited if the Western-oriented study results were applied to Asian patients. We aimed to identify the nutrient and food group intakes of a typical Asian diet and assess their effects on NAFLD risk. METHODS: In total, 348 subjects were recruited from 5 participating hospitals. Information on sociodemographic characteristics and health-related behaviors were obtained through face-to-face interviews. NAFLD was diagnosed by ultrasound. Dietary intakes were assessed with a 24-h recall applying a multiple pass approach and 4-day food records that included 1 or 2 weekend days. RESULTS: There were no significant differences in health-related behaviors between the cases and controls except for smoking behavior. The cases had elevated triacylglycerol, fasting glucose, and low-density lipoprotein cholesterol levels compared with the controls. In men, after adjusting for variables, low intakes of vitamin C (odds ratio [OR], 4.23), vitamin K (OR, 3.93), folate (OR, 3.37), omega 3 fatty acids (OR, 2.16), and nuts and seeds (OR, 3.66) were associated with a significantly higher risk for developing NAFLD. In women, vitamin K (OR, 2.54) and vegetable (OR, 4.11) intakes showed a significant beneficial effect for lowering NAFLD risk. CONCLUSIONS: Adequate intakes of vitamin C, vitamin K, folate, omega-3 fatty acids, nuts and seeds, and vegetables may help in preventing NAFLD in Korean adults. PMID- 24955456 TI - Role of lamivudine with transarterial chemoembolization in the survival of patients with hepatocellular carcinoma. AB - BACKGROUND AND AIM: The purpose of the present study was to determine whether lamivudine in combination with transarterial chemoembolization (TACE) could reduce hepatitis B virus (HBV) activation and improve the survival of patients with hepatocellular carcinoma (HCC). METHODS: From July 2008 to October 2011, a total of 181 consecutive HBV-related HCC patients undergoing TACE were randomized to two groups (92: lamivudine, 89: control). Follow up was every 3 months. Primary and secondary end-points were time to progression (TTP) and overall survival (OS), respectively, both of which were evaluated by the Kaplan Meier technique and summarized by the hazard ratio. RESULTS: The level of HBV-DNA became undetectable in 42 (45.6%) patients in the lamivudine group, compared with 10 (11.2%) in the control group (P < 0.001). The median TTP was 8.2 months in lamivudine group and 4.3 months in control group (P = 0.005), and lamivudine therapy was an independent protective factor related to TTP (P = 0.006). Moreover, 1-, 2-, and 3-year survival rates were 83%, 69%, and 58% in lamivudine group and 60%, 48%, and 48% in control group, respectively (P = 0.002). With multivariate Cox regression model, lamivudine therapy (P = 0.002) and alpha fetoprotein (AFP) level (P = 0.003) were two independent predictors for OS. CONCLUSION: Lamivudine therapy could reduce HBV activation and improve survival of HCC patients treated with TACE. Lamivudine therapy and AFP level are two independent factors affecting OS. PMID- 24955457 TI - Replicant II--tears in the rain. By Caveman. PMID- 24955458 TI - Progress towards polio eradication worldwide, 2013-2014. PMID- 24955459 TI - Anticipating epidemics. PMID- 24955460 TI - Review of the 2013-2014 winter influenza season, northern hemisphere. PMID- 24955461 TI - Progress towards measles elimination - Eastern Mediterranean Region, 2008-2012. PMID- 24955462 TI - Laboratory careers: catalysts for efficient science. PMID- 24955463 TI - Present danger. PMID- 24955464 TI - Quanundrum. PMID- 24955465 TI - Summer skills. PMID- 24955466 TI - Stem cells: taking a stand against pseudoscience. PMID- 24955467 TI - Regulation: Sell help not hope. PMID- 24955468 TI - Effects of surface material, ventilation, and human behavior on indirect contact transmission risk of respiratory infection. AB - Infectious particles can be deposited on surfaces. Susceptible persons who contacted these contaminated surfaces may transfer the pathogens to their mucous membranes via hands, leading to a risk of respiratory infection. The exposure and infection risk contributed by this transmission route depend on indoor surface material, ventilation, and human behavior. In this study, quantitative infection risk assessments were used to compare the significances of these factors. The risks of three pathogens, influenza A virus, respiratory syncytial virus (RSV), and rhinovirus, in an aircraft cabin and in a hospital ward were assessed. Results showed that reducing the contact rate is relatively more effective than increasing the ventilation rate to lower the infection risk. Nonfabric surface materials were found to be much more favorable in the indirect contact transmission for RSV and rhinovirus than fabric surface materials. In the cases considered in this study, halving the ventilation rate and doubling the hand contact rate to surfaces and the hand contact rate to mucous membranes would increase the risk by 3.7-16.2%, 34.4-94.2%, and 24.1-117.7%, respectively. Contacting contaminated nonfabric surfaces may pose an indirect contact risk up to three orders of magnitude higher than that of contacting contaminated fabric surfaces. These findings provide more consideration for infection control and building environmental design. PMID- 24955469 TI - Aldrin and dieldrin: a reevaluation of the cancer and noncancer dose-response assessments. AB - The dose-response analyses of cancer and noncancer health effects of aldrin and dieldrin were evaluated using current methodology, including benchmark dose analysis and the current U.S. Environmental Protection Agency (U.S. EPA) guidance on body weight scaling and uncertainty factors. A literature review was performed to determine the most appropriate adverse effect endpoints. Using current methodology and information, the estimated reference dose values were 0.0001 and 0.00008 mg/kg-day for aldrin and dieldrin, respectively. The estimated cancer slope factors for aldrin and dieldrin were 3.4 and 7.0 (mg/kg-day)(-1), respectively (i.e., about 5- and 2.3-fold lower risk than the 1987 U.S. EPA assessments). Because aldrin and dieldrin are no longer used as pesticides in the United States, they are presumed to be a low priority for additional review by the U.S. EPA. However, because they are persistent and still detected in environmental samples, quantitative risk assessments based on the best available methods are required. Recent epidemiologic studies do not demonstrate a causal association between aldrin and dieldrin and human cancer risk. The proposed reevaluations suggest that these two compounds pose a lower human health risk than currently reported by the U.S. EPA. PMID- 24955471 TI - Her work is all the buzz. PMID- 24955470 TI - Visualization applications and design studies. PMID- 24955472 TI - Looking at the hard stuff. PMID- 24955473 TI - The authors' reply. PMID- 24955474 TI - Retraction notice to "Carboxylated calixarenes bind strongly to CD69 and protect CD69(+) killer cells from suicidal cell death induced by tumor cell surface ligands" [Bioorg. Med. Chem. 18 (4) (2010) 1434-1440]. PMID- 24955475 TI - Civility and workplace bullying: resonance of Nightingale's persona and current best practices. AB - Conflict or aggression occurring between and among healthcare workers is undermining attempts to create a culture of safety in the workplace. Healthcare occupations have higher rates of workplace bullying (WPB), and intimidating behavior across healthcare settings has been shown to foster medical errors, increase the cost of care, and contribute to poor patient satisfaction and preventable adverse outcomes. WBP is also partially responsible for the high attrition among nurses, a particular concern in the current nursing shortage. Through a narrative that explores Florence Nightingale's professional persona and experience, this article outlines various factors that contribute to incivility and WPB, and provides suggestions for curriculum design that may help preempt incivility in tomorrow's nurses. PMID- 24955477 TI - Andy Witkin: from computer vision to computer graphics. PMID- 24955476 TI - Camera culture. PMID- 24955478 TI - Building an antifouling zwitterionic coating on urinary catheters using an enzymatically triggered bottom-up approach. AB - Catheter associated urinary tract infections are common during hospitalization due to the formation of bacterial biofilms on the indwelling device. In this study, we report an innovative biotechnology-based approach for the covalent functionalization of silicone catheters with antifouling zwitterionic moieties to prevent biofilm formation. Our approach combines the potential bioactivity of a natural phenolics layer biocatalytically conjugated to sulfobetaine-acrylic residues in an enzymatically initiated surface radical polymerization with laccase. To ensure sufficient coating stability in urine, the silicone catheter is plasma-activated. In contrast to industrial chemical methods, the methacrylate containing zwitterionic monomers are polymerized at pH 5 and 50 degrees C using as an initiator the phenoxy radicals solely generated by laccase on the phenolics coated catheter surface. The coated catheters are characterized by X-ray photoelectron spectroscopy (XPS), Fourier transformed infrared (FTIR) analysis, atomic force microscopy (AFM), and colorimetrically. Contact angle and protein adsorption measurements, coupled with in vitro tests with the Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus in static and dynamic conditions, mimicking the operational conditions to be faced by the catheters, demonstrate reduced biofilm formation by about 80% when compared to that of unmodified urinary catheters. The zwitterionic coating did not affect the viability of the human fibroblasts (BJ-5ta) over seven days, corresponding to the extended useful life of urinary catheters. PMID- 24955479 TI - Ionization-induced tautomerization in cytosine and effect of solvation. AB - The recent observation of excitation-induced tautomerization in gas-phase cytosine motivated us to investigate the possibility of facile tautomerization in ionized cytosine and the effect of solvation on the tautomerization barriers. The tautomerization mechanisms were characterized at the density functional theory (DFT)/omegaB97X-D and coupled-cluster singles and doubles (CCSD) levels of theory. Vertical and adiabatic ionization energies (VIEs and AIEs, respectively) of the tautomers of cytosine and the microsolvated species were calculated with the equation-of-motion ionization-potential coupled-cluster (EOM-IP-CCSD) method. We observed that, in microsolvated cytosine, the solvatochromic shifts of the VIEs can be both blue- and red-shifted depending on the tautomers. This is explained by the analysis of the charge-dipole interactions between the cytosine and water molecules. We noticed that, upon ionization, gas-phase tautomerization barriers are reduced by 0-4 kcal/mol, whereas microsolvated (with one water) tautomerization barriers are reduced by 4-5 kcal/mol. We also investigated the tautomerization process in solvation using a continuum model with one active water molecule in the quantum mechanical region. We noticed that, even though bulk solvation has a significant effect on ionization energies, its effect on the ionization-induced tautomerization barrier is minimal. PMID- 24955480 TI - Impact of root-induced mobilization of zinc on stable Zn isotope variation in the soil-plant system. AB - Stable Zn isotopes are increasingly used to trace the source of metal pollution in the environment and to gain a better understanding of the biogeochemical cycle of Zn. In this work, we investigated the effect of plants on Zn isotope fractionation in the soil-plant system of the surface horizon of two Zn-rich Technosols (pH 6.73-7.51, total Zn concentration = 9470-56600 mg kg(-1)). In a column experiment, the presence of Agrostis capillaris L. significantly increased the mobilization of Zn from soil to leachate, predominantly as a result of root induced soil acidification. The zinc isotope compositions of plants and leachates indicated that the Zn uptake by A. capillaris did not fractionate Zn isotopes as compared to the leachates. Within the plant, heavier Zn isotopes were preferentially retained in roots (Delta66Znroot - shoot=+0.24 to +0.40 0/00). More importantly, the Zn released in leachates due to root-induced mobilization was isotopically heavier than the Zn released in the absence of plants (Delta66Zn=+0.16 to +0.18 0/00). This indicates that the rhizosphere activity of A. capillaris mobilized Zn from another pool than the one that spontaneously releases Zn upon contact with the percolating solution. Mobilization of Zn by the roots might thus exert a stronger influence on the Zn isotope composition in the soil solution than the Zn uptake by the plant. This study highlights the key role of the rhizosphere activity in Zn release in soil and demonstrates that stable Zn isotopes provide a useful proxy for the detection of Zn mobilization in soil plant systems. PMID- 24955481 TI - Control hydrogel-hyaluronic acid aggregation toward the design of biomimetic superlubricants. AB - Healthy synovial fluids (SFs) are complex fluids consisting of biopolymers, globule proteins, and lipids and regarded as superlubricants to provide nearly life-long low friction and wear protection of synovial joints in mammals. In this paper, we report that the intricate lubricious mixture can be simulated by the aggregation of hyaluronic acid (HA) and hydrogel particles in aqueous suspensions. In the HA aqueous suspensions added with synthetic polymer microgels, we have effectively captured the bulk rheological properties of healthy SFs. It is also confirmed by light scattering and fluorescence microscopic characterization that added hydrogel particles can enhance the HA network by hydrogel-mediated hydrogen bonding, leading to the fractal HA-hydrogel aggregating networks in aqueous suspensions. The potential application of HA hydrogel particle aggregates as biomimetic superlubricants is supported by the comparable low friction at high load to that of healthy SFs. PMID- 24955482 TI - Tailoring the surface chemistry of activated carbon cloth by electrochemical methods. AB - This paper presents a systematic study of the effect of the electrochemical treatment (galvanostatic electrolysis in a filter-press electrochemical cell) on the surface chemistry and porous texture of commercial activated carbon cloth. The same treatments have been conducted over a granular activated carbon in order to clarify the effect of morphology. The influence of different electrochemical variables, such as the electrode polarity (anodic or cathodic), the applied current (between 0.2 and 1.0 A) and the type of electrolyte (HNO3 and NaCl) have also been analyzed. The anodic treatment of both activated carbons causes an increase in the amount of surface oxygen groups, whereas the cathodic treatment does not produce any relevant modification of the surface chemistry. The HNO3 electrolyte produced a lower generation of oxygen groups than the NaCl one, but differences in the achieved distribution of surface groups can be benefitial to selectively tune the surface chemistry. The porous texture seems to be unaltered after the electro-oxidation treatment. The validity of this method to introduce surface oxygen groups with a pseudocapacitive behavior has been corroborated by cyclic voltammetry. As a conclusion, the electrochemical treatment can be easily implemented to selectively and quantitatively modify the surface chemistry of activated carbons with different shapes and morphologies. PMID- 24955484 TI - Probing electronic excitations in mono- to pentalayer graphene by micro magneto Raman spectroscopy. AB - We probe electronic excitations between Landau levels in freestanding N-layer graphene over a broad energy range, with unprecedented spectral and spatial resolution, using micro magneto-Raman scattering spectroscopy. A characteristic evolution of electronic bands in up to five Bernal-stacked graphene layers is evidenced and shown to remarkably follow a simple theoretical approach, based on an effective bilayer model. (N > 3)-layer graphenes appear as appealing candidates in the quest for novel phenomena, particularly in the quantum Hall effect regime. Our work paves the way toward minimally invasive investigations of magneto-excitons in other emerging low-dimensional systems, with a spatial resolution down to 1 MUm. PMID- 24955485 TI - Reinforcement of interfacial adhesion of a coated polymer layer on a cobalt chromium surface for drug-eluting stents. AB - During the balloon expansion of several commercially available drug-eluting stents, various types of defects in the polymer layer have been observed. The aim of this study is to prevent these defects by increasing the interfacial adhesion between the metal substrate and the drug-in-polymer matrix using poly(caprolactone) (PCL) brushes onto a cobalt-chromium (Co-Cr or CC) alloy surface. The chemical modification of the Co-Cr surface was accomplished by grafting ricinoleic acid (RA) onto the metal substrate followed by surface initiated ring opening polymerization of epsilon-caprolactone. The unmodified, RA grafted (CC-RA), and PCL-grafted Co-Cr substrates (CC-RA-PCL3D and CC-RA-PCL6D) were characterized by various surface analyses. Poly(d,l-lactide) containing sirolimus was spray coated onto the unmodified and modified substrates. The adhesion property of the polymer coating on the PCL-grafted surfaces was improved compared to those of other samples. Among all of the drug-in-polymer coated samples, both CC-RA-PCL3D and CC-RA-PCL6D exhibited a stabilized drug release profile over 49 days. It was also revealed that CC-RA-PCL6D showed the slowest drug release of all the samples. On the basis of these results, the proposed nanocoupling method has shown not only improved adhesion of the drug-in-polymer matrix to the Co-Cr substrate but also controlled drug release. PMID- 24955483 TI - Plasminogen activator inhibitor-1 and susceptibility to lung cancer: a population genetics perspective. AB - AIM: The aim of this study was to investigate the polymorphism frequency of plasminogen activator inhibitor-1 (PAI-1) (rs1799889) 4G/5G in patients with lung cancer. METHODS: In this study, 286 genomic DNAs (154 lung cancer patients+132 subjects without lung cancer) were analyzed. Polymorphisms were determined by using the polymerase chain reaction (PCR) method, with 4G and 5G allele-specific primers. PCR products were assessed by a charge-coupled device camera and exposed to 2% agarose gel electrophoresis. RESULTS: The frequencies of the PAI-1 gene 4G/5G genotypes were found to be 21% 4G/4G, 16% 4G/5G, and 62% 5G/5G in the control group and 31.4% 4G/4G, 30.8% 4G/5G, and 37.8% 5G/5G in the patient group. It was determined that the 5G/5G genotype frequency was high in patients in comparison with other genotypes. CONCLUSIONS: This study found a statistically significant difference between the groups with respect to genotype distribution. Consequently, we can say that the PAI-1 gene 4G/5G polymorphism is associated with lung cancer in Turkey. PMID- 24955486 TI - Comments and replies regarding "Putative indigenous carbon-bearing alteration features in martian meteorite Yamato 000593," by L.M. White, E.K. Gibson, K.L. Thomas-Keprta, S.J. Clemett, and D.S. McKay. Astrobiology, February 2014, 14(2):170-181. PMID- 24955487 TI - Into the deep end: incorporating a global health governance and diplomacy experience in graduate public health training. AB - Global health governance benefits from participants well-versed in the realities of international policy-making. Consequently, educational programmes must establish more opportunities for students to engage in global health policy development. This paper examines a unique global health governance and diplomacy practicum programme at the University of Southern California, designed for Master of Public Health candidates. Through the programme, students act as official non governmental delegates to the World Health Assembly in Geneva, Switzerland through organisational partnerships. Students and collaborating organisations were asked to complete an online post-participation survey examining the perceived quality of the experience. Through the survey, students indicated reinforcement of classroom learning, continued or heightened interest in global health policy and enthusiasm in recommending the programme to other students. Organisations perceived students to be adequately prepared and indicated their continued desire to work with students in the programme. The data collected suggest that the programme was successful in providing students with a worthwhile experience that developed skills in global health diplomacy and promoted interest and critical thinking concerning international policy-making processes. A discussion of strengths and challenges serves as a blueprint for the creation of future practicum programmes. PMID- 24955488 TI - Tumour-stroma crosstalk in the development of squamous cell carcinoma. AB - Squamous cell carcinoma (SCC) represents one of the most frequently diagnosed tumours and contributes significant mortality worldwide. Recent deep sequencing of cancer genomes has identified common mutations in SCC arising across different tissues highlighting perturbation of squamous differentiation as a key event. At the same time significant data have been accumulating to show that common tumour stroma interactions capable of driving disease progression are also evident when comparing SCC arising in different tissues. We and others have shown altered matrix composition surrounding SCC can promote tumour development. This review focuses on some of the emerging data with particular emphasis on SCC of head and neck and skin with discussion on the potential tumour suppressive properties of a normal microenvironment. Such data indicate that regardless of the extent and type of somatic mutation it is in fact the tumour context that defines metastatic progression. PMID- 24955489 TI - Constrained geometric simulation of the nicotinic acetylcholine receptor. AB - Constrained geometric simulations have been performed for the recently published closed-channel state of the nicotinic acetylcholine receptor. These simulations support the theory that correlated motion in the flexible beta-sheet structure of the extracellular domain helps to communicate a "conformational wave", spreading from the acetylcholine binding pocket. Furthermore, we have identified key residues that act at the interface between subunits and between domains that could potentially facilitate rapid communication between the binding site and the transmembrane gate. PMID- 24955490 TI - Homology modelling, docking, pharmacophore and site directed mutagenesis analysis to identify the critical amino acid residue of PknI from Mycobacterium tuberculosis. AB - Tuberculosis is caused by Mycobacterium tuberculosis, an intracellular pathogen. PknI is one of the 11 functional Serine/Threonine Protein Kinases which is predicted to regulate the cell division of M. tuberculosis. In order to find newer drugs and vaccine we need to understand the pathogenesis of the disease. We have used the bioinformatics approach to identify the functionally active residues of PknI and to confirm the same with wet lab experiments. In the current study, we have created homology model for PknI and have done comparative structural analysis of PknI with other kinases. Molecular docking studies were done with a library of kinase inhibitors and T95 was found as the potent inhibitor for PknI. Based on structure based pharmacophore analysis of kinase substrate complexes, Lys 41 along with Asp90, Val92 and Asp96 were identified as functionally important residues. Further, we used site directed mutagenesis technique to mutate Lys 41 to Met resulting in defective cell division of Mycobacterium smegmatis mc(2). Overall, the proposed model together with its binding features gained from pharmacophore docking studies helped in identifying ligand inhibitor specific to PknI which was confirmed by laboratory experiments. PMID- 24955491 TI - Solid state molecular dynamic investigation of an inclusion ferroelectric: [(2,6 diisopropylanilinium)([18]crown-6)]BF4. AB - Many order-disorder-type phase transitions in molecule-based ferroelectrics are related to changes of molecular dynamics. If the molecular motions do not involve reorientations of dipole moments, their ordering fails to contribute directly to spontaneous electric polarization. For understanding ferroelectric mechanisms in these systems, it is important to clarify how such molecular dynamics changes induce structurally symmetry-breaking phase transitions and thus the appearance of spontaneous electric polarization. Systematic characterization of an [18]crown 6 based host-guest inclusion compound, [(DIPA)([18]crown-6)]BF4 (DIPA = 2,6 diisopropylanilinium), shows it is an excellent ferroelectric with a large dielectric anomaly, significant pyroelectricity, and SHG response, and rectangular polarizaiton-electric field hysterisis loops. By the combination of variable-temperature single-crystal structural determination and solid-state NMR observation, it is found that the slowing down of the rotation of the [18]crown-6 molecule and the tumbling of the BF4 anion causes the symmetry breaking, while the spontaneous polarization is induced by the relative displacement between the cationic and anionic sublattices. This investigation will contribute to a deeper understanding of the structure-property relationship in the emerging molecular ferroelectrics. PMID- 24955492 TI - The role of socio-economic position as a moderator of children's healthy food intake. AB - Children of low socio-economic position (SEP) consume poorer diets than those of high SEP; however, there is limited understanding of why socio-economic gradients in diet occur. Some evidence suggests that determinants of dietary intake may differ between SEP groups. The aim of the present study was to determine whether the associations between personal and environmental variables and children's fruit and vegetable intake, and healthy dietary behaviours are moderated by SEP. A total of 395 children aged 9 to 13 years and their parents were recruited in Adelaide, South Australia. Personal and environmental dietary predictors were measured using child-completed online questionnaires and telephone interviews with parents. Dietary intake was measured using an online FFQ. First, dietary predictors were identified using correlated component regression, and subsequently tested for moderation by four SEP indicators using partial least squares structural equation modelling. Fruit and vegetable intake and healthy behaviours were predicted by self-efficacy, attitudes and a supportive home environment. For girls, only the associations of self-efficacy with healthy behaviours were moderated by occupation. For boys, income moderated the associations of fruit and vegetable intake with attitudes, and healthy behaviours with supportive home environments. Occupation and employment moderated the associations of boys' family environments and fruit intake, and attitudes with healthy behaviours. Reducing socio-economic disparities in children's healthy dietary intake may be more successfully achieved by tailoring health promotion policies and interventions according to variables that moderate the relationships between dietary intake and SEP. PMID- 24955493 TI - Cognitive rehabilitation for mild cognitive impairment: developing and piloting an intervention. AB - This was an exploratory study, with the purpose of developing and piloting an intervention for people with mild cognitive impairment (MCI) and their family members using cognitive rehabilitation. A case series design was used with pre- and post-intervention and 3-month follow-up outcome measures. Five participants (two males, three females; mean age 75 years) with a diagnosis of MCI attended the memory clinic with a family member. Intervention consisted of six to eight individual sessions of cognitive rehabilitation consisting of personalized interventions to address individually relevant goals delivered weekly. The main rehabilitation strategies utilized were external aids, personal diary, face-name association, relaxation, and encouraging participants to develop habits and routines. The primary outcome measure was goal attainment as assessed by Goal Attainment Scaling. Secondary outcome measures included measures of memory, anxiety, depression, and activities of daily living. Qualitative data were collected post-intervention by interview. Post-intervention 84% of the goals were attained, with 68% maintained at a 3-month follow-up. Mean anxiety and depression scores decreased during the intervention. No significant changes were recorded on a test of memory. The findings suggest that the strongest effect was in relation to compensatory strategies for prospective and episodic memory deficits. Feedback from participants during qualitative interviews indicated that they found strategies useful and implemented them in their daily routines. The findings support the use of a dyadic cognitive rehabilitation intervention for people with MCI and memory difficulties. PMID- 24955494 TI - Reduced neophobia: a potential mechanism explaining the emergence of self medicative behavior in sheep. AB - Gastrointestinal helminths challenge ruminants in ways that reduce their fitness. In turn, ruminants have evolved physiological and behavioral adaptations that counteract this challenge. For instance, emerging behavioral evidence suggests that ruminants self-select medicinal compounds and foods that reduce parasitic burdens. However, the mechanism/s leading to self-medicative behaviors in sick animals is still unknown. We hypothesized that when homeostasis is disturbed by a parasitic infection, consumers should respond by increasing the acceptability of novel foods relative to healthy individuals. Three groups of lambs (N=10) were dosed with 0 (Control-C), 5000 (Medium-M) and 15000 (High-H) L3 stage larvae of Haemonchus contortus. When parasites had reached the adult stage, all animals were offered novel foods and flavors in pens and then novel forages at pasture. Ingestive responses by parasitized lambs were different from non-parasitized Control animals and they varied with the type of food and flavor on offer. Parasitized lambs consumed initially more novel beet pulp and less novel beet pulp mixed with tannins than Control lambs, but the pattern reversed after 9d of exposure to these foods. Parasitized lambs ingested more novel umami-flavored food and less novel bitter-flavored food than Control lambs. When offered choices of novel unflavored and bitter-flavored foods or different forage species to graze, parasitized lambs selected a more diverse array of foods than Control lambs. Reductions in food neophobia or selection of a more diverse diet may enhance the likelihood of sick herbivores encountering novel medicinal plants and nutritious forages that contribute to restore health. PMID- 24955495 TI - Effects of learning and food form on energy intake and appetitive responses. AB - Energy-yielding beverages reportedly contribute to positive energy balance uniquely. They are highly consumed and evoke weaker satiety signaling and dietary energy compensation than solid foods of the same energy content. This study measured the contribution of learning to appetitive sensations and adjustments of energy intake for preloads varying in energy content and food form in lean and obese adults. One-hundred seven participants received four preload trials before and after a dietary intervention in this randomized cross-over trial with the stipulation that lean and obese individuals were evenly assigned to each intervention. The study entailed monitoring appetitive sensations and daily energy intake after consumption of low and high energy beverage and solid food loads on weekly visit days. Preload testing was conducted at baseline, followed by daily ingestion of one load for 14 days and then retesting responses to the four treatments. Lean individuals compensated precisely for the high energy beverage and solid loads from the onset of the study, whereas the obese did not alter eating patterns after consuming the higher energy beverage load. The learning intervention did not have an effect on the responses to the preloads, as responses in both lean and obese participants did not differ from baseline values. Responses to personality and eating behavior questionnaires revealed differences between the lean and obese groups and weakly, but significantly, predicted challenge meal and total daily energy intake. These data suggest that lean and obese individuals respond to energy in beverage form differently, and this is not altered by purposeful daily exposure to loads varying in physical form and energy content for two weeks. PMID- 24955496 TI - Ability of GLP-1 to decrease food intake is dependent on nutritional status. AB - Gut-derived glucagon like peptide-1 (GLP-1) acts in the postprandial period to stimulate insulin secretion and inhibit gastrointestinal motor and secretory function; whether endogenous peripheral GLP-1 inhibits food intake is less clear. We hypothesized that GLP-1 inhibits food intake in the fed, but not fasted, state. There is evidence that GLP-1 acts via stimulation of vagal afferent neurons (VAN); we further hypothesized that the satiating effects of endogenous GLP-1 in the postprandial period is determined either by a change in GLP-1 receptor (GLP-1R) expression or localization to different cellular compartments in VAN. METHODS: Food intake was recorded following administration of GLP-1 (50MUg/kg or 100MUg/kg) or saline (IP) in Wistar rats fasted for 18h or fasted then re-fed with 3g chow. GLP-1R protein expression and localization on VAN were determined by immunocytochemistry and immunoblots in animals fasted for 18h or fasted then re-fed for 40min. GLP-1R mRNA level was detected in animals fasted for 18h or fasted and re-fed ad libitum for 2h. RESULTS: GLP-1 (100MUg/kg) significantly reduced 40min food intake by 38% in re-fed but not fasted rats (p<0.05). GLP-1R mRNA or protein levels in VAN were unchanged in re-fed compared to fasted rats. However, GLP-1R localization to the plasma membrane was significantly increased in VAN by feeding. CONCLUSION: Feeding changes the ability of peripheral GLP-1 to inhibit food intake. GLP-1Rs are trafficked to the plasma membrane in response to a meal. GLP-1 may play a role in regulating food intake in the postprandial period. PMID- 24955497 TI - Lamotrigine reverses masseter overactivity caused by stress maybe via Glu suppression. AB - Experimental and non-experimental stress significantly increase masseter muscle tone, which has been linked to the symptoms and pathogenesis of several stomatognathic system diseases. Until now, the mechanism underlying this phenomenon has remained unclear. The current study was performed to determine the mechanism of the stress-induced increase in masseter muscle tone and to investigate the effect of lamotrigine on this change. Animals challenged by repeated restraint stress received either saline as a vehicle or lamotrigine in doses of 20, 30 or 40 mg/kg body weight, whereas control animals received saline without stress treatment. Masseter muscle tone was assessed using electromyography. The activity of glutamate-related metabolic enzymes (glutaminase and glutamine synthetase) in the trigeminal motor nucleus was also investigated. Our results showed an interesting phenomenon: masseter muscle activity increased concurrently with the upregulation of the glutamate concentration after stress treatment. The activities of glutaminase and glutamine synthetase in the trigeminal motor nucleus were also upregulated and downregulated, respectively, when the rats were challenged by prolonged stress. The animals treated with lamotrigine at moderate and high doses had significantly decreased masseter muscle tone compared with stressed animals treated with vehicle. These results suggested that increased glutaminase activity and decreased glutamine synthetase activity increased glutamate production and decreased glutamate decomposition, causing an increase in glutamate levels in the trigeminal motor nucleus and eventually increasing masseter muscle tone. The administration of lamotrigine at doses of 30 or 40 mg/kg body weight effectively mitigated the adverse effects of stress on masseter muscle tone via inhibition of glutamate release. PMID- 24955498 TI - The effects of the C-terminal amidation of mastoparans on their biological actions and interactions with membrane-mimetic systems. AB - Polycationic peptides may present their C-termini in either amidated or acidic form; however, the effects of these conformations on the mechanisms of interaction with the membranes in general were not properly investigated up to now. Protonectarina-MP mastoparan with an either amidated or acidic C-terminus was utilized to study their interactions with anionic and zwitterionic vesicles, using measurements of dye leakage and a combination of H/D exchange and mass spectrometry to monitor peptide-membrane interactions. Mast cell degranulation, hemolysis and antibiosis assays were also performed using these peptides, and the results were correlated with the structural properties of the peptides. The C terminal amidation promotes the stabilization of the secondary structure of the peptide, with a relatively high content of helical conformations, permitting a deeper interaction with the phospholipid constituents of animal and bacterial cell membranes. The results suggested that at low concentrations Protonectarina MP interacts with the membranes in a way that both terminal regions remain positioned outside the external surface of the membrane, while the alpha-carbon backbone becomes partially embedded in the membrane core and changing constantly the conformation, and causing membrane destabilization. The amidation of the C terminal residue appears to be responsible for the stabilization of the peptide conformation in a secondary structure that is richer in alpha-helix content than its acidic congener. The helical, amphipathic conformation, in turn, allows a deeper peptide-membrane interaction, favoring both biological activities that depend on peptide structure recognition by the GPCRs (such as exocytosis) and those activities dependent on membrane perturbation (such as hemolysis and antibiosis). PMID- 24955499 TI - Role of N-terminal residues in Abeta interactions with integrin receptor and cell surface. AB - beta-Amyloid (Abeta) is the primary protein component of senile plaques in Alzheimer's disease (AD) and is believed to play a role in its pathology. To date, the mechanism of action of Abeta in AD is unclear. We and others have observed that Abeta interacts either with or in the vicinity of the alpha6 sub unit of integrin, and believe this may be important in its interaction with neuronal cells. In this study, we used confocal microscopy and flow cytometry to explore the residue specific interactions of Abeta40 with the cell surface and the alpha6 integrin receptor sub-unit. We probed the importance of the RHD sequence in Abeta40 and found that removal of the residues or their mutation using the Abeta8-40 or the D7N early onset AD sequence, respectively, led to a greater interaction between Abeta40 and an antibody bound to the alpha6-integrin sub-unit, as measured by fluorescence resonance energy transfer (FRET). These results suggest that the RHD sequence of Abeta40 does not mediate Abeta-alpha6 integrin interactions. However, the cyclic RGD mimicking peptide, Cilengitide, reduced the measured interaction between Abeta40 fibrils without the RHD sequence and an antibody bound to the alpha6-integrin sub-unit. We further probed the role of electrostatic forces on Abeta40-cell interactions and observed that the Abeta sequence that included the N-terminal segment of the peptide had reduced cellular binding at low salt concentrations, suggesting that its first 7 residues contribute to an electrostatic repulsion for the cell surface. These findings contribute to our understanding of Abeta-cell surface interactions and may provide insight into development of novel strategies to block Abeta-cell interactions that contribute to pathology in Alzheimer's disease. PMID- 24955500 TI - Perceived stress during pregnancy and the catechol-O-methyltransferase (COMT) rs165599 polymorphism impacts on childhood IQ. AB - Maternal stress during pregnancy has been associated with a range of adverse outcomes in offspring and the catechol-O-methyltransferase (COMT) gene has been linked to differential susceptibility to the consequences of antenatal stress. This study examined two functional polymorphisms of the COMT gene (rs4680 and rs165599) in relation to maternal perceived stress and childhood cognitive performance. Data from the longitudinal Auckland Birthweight Collaborative (ABC) study was used. Maternal perceived stress over the prior month was measured at birth, 3.5 and 7years. Full-Scale IQ (FSIQ) was measured at ages 7 and 11. At age 11, a total of 546 DNA samples were collected from the child participants. Data were subjected to a series of split-plot ANCOVAs with birthweight for gestational age and maternal school leaving age as covariates. There were direct effects of maternal stress during the last month of pregnancy on offspring FSIQ at ages 7 and 11years. A significant interaction revealed that children exposed to high maternal antenatal stress had significantly lower FSIQ scores at both 7 and 11years of age than those exposed to low stress, only when they were carriers of the rs165599 G allele. At each age, this difference was of approximately 5 IQ points. The G allele of the rs165599 polymorphism may confer genetic susceptibility to negative cognitive outcomes arising from exposure to antenatal stress. This finding highlights the need to consider gene-environment interactions when investigating the outcomes of antenatal stress exposure. PMID- 24955501 TI - Ownership reasoning in children across cultures. AB - To what extent do early intuitions about ownership depend on cultural and socio economic circumstances? We investigated the question by testing reasoning about third party ownership conflicts in various groups of three- and five-year-old children (N=176), growing up in seven highly contrasted social, economic, and cultural circumstances (urban rich, poor, very poor, rural poor, and traditional) spanning three continents. Each child was presented with a series of scripts involving two identical dolls fighting over an object of possession. The child had to decide who of the two dolls should own the object. Each script enacted various potential reasons for attributing ownership: creation, familiarity, first contact, equity, plus a control/neutral condition with no suggested reasons. Results show that across cultures, children are significantly more consistent and decisive in attributing ownership when one of the protagonists created the object. Development between three and five years is more or less pronounced depending on culture. The propensity to split the object in equal halves whenever possible was generally higher at certain locations (i.e., China) and quasi inexistent in others (i.e., Vanuatu and street children of Recife). Overall, creation reasons appear to be more primordial and stable across cultures than familiarity, relative wealth or first contact. This trend does not correlate with the passing of false belief theory of mind. PMID- 24955502 TI - Indicators of causal agency in physical interactions: the role of the prior context. AB - The question how agent and patient roles are assigned to causal participants has largely been neglected in the psychological literature on force dynamics. Inspired by the linguistic theory of Dowty (1991), we propose that agency attributions are based on a prototype concept of human intervention. We predicted that the number of criteria a participant in a causal interaction shares with this prototype determines the strength of agency intuitions. We showed in two experiments using versions of Michotte's (1963) launching scenarios that agency intuitions were moderated by manipulations of the context prior to the launching event. Altering features, such as relative movement, sequence of visibility, and self-propelled motion, tended to increase agency attributions to the participant that is normally viewed as patient in the standard scenario. PMID- 24955503 TI - Effect of strength training in addition to general exercise in the rehabilitation of patients with non-specific neck pain. A randomized clinical trial. AB - BACKGROUND: The optimal type of exercise protocol in the physical rehabilitation of non-specific neck pain has not yet been established. Furthermore, the role of fear-avoidance belief in the maintenance of pain and disability has been highlighted. Research indicates that exercise may be a means to reduce fear avoidance belief, but evidence is scarce. AIM: To compare the effect of two different exercise programs on pain, strength and fear-avoidance belief. DESIGN: Randomized clinical trial. SETTING: A specialized outpatient hospital clinic in Denmark. POPULATION: Twenty-three men and 60 women on sick leave due to non specific neck pain. METHODS: Participants were randomized to either general physical activity (GPA group) or GPA and additional strength training of the neck and shoulder (SST group). The primary outcome was pain intensity. Secondary outcomes were muscle strength of the neck and shoulder and fear-avoidance belief. RESULTS: Pain was significantly reduced within groups with a median of -1 (IQR: 3 to 0, P<0.001) in the SST group and -1 (IQR: -4 to 1, P=0.046) in the GPA group. The difference between groups was not significant. Changes in strength did not differ between groups. Both groups experienced significant increases in neck flexion strength of 14.7 N (IQR: -1 to 28.4, P=0. 001) in the SST group and 6.9 N (IQR: -4.9 to18.6, P=0.014) in the GPA group. Furthermore, the SST group achieved an increase of 18.6 N (IQR: -2.6 to 69.7, P=0.005) in neck extension. Fear avoidance beliefs improved with 6 (IQR: 3 to 12, P<0.001) in the SST group, while the GPA group improved with 3 (IQR: 0 to 8, P=0.004). This between-group difference was significant (P=0.046). CONCLUSION AND REHABILITATION IMPACT: This study indicates that in rehabilitation of subjects severely disabled by non specific neck pain, there is no additional improvement on pain or muscle strength when neck exercises are given as a home-based program with a minimum of supervision. However, strength training of the painful muscles seems to be effective in decreasing fear-avoidance beliefs. PMID- 24955504 TI - Influence of zwitterionic SAMs on protein adsorption and the attachment of algal cells. AB - Zwitterionic polymers are non-fouling materials with immense potential for a range of biological applications. Here, we describe the resistance of zwitterionic self-assembled monolayers prepared from different solution ratios of positively and negatively charged thiols towards the adhesion of proteins, zoospores of the green alga Ulva linza, and cells of the unicellular alga Navicula perminuta. While mixed zwitterionic surfaces with a high hydrophilic nature significantly reduced the adhesion strength of the two algae, the positively and negatively charged components were far less effective. PMID- 24955505 TI - Corneal sensitivity and tear function in neurodegenerative diseases. AB - PURPOSE: To measure corneal sensitivity and tear function in neurodegenerative diseases (NDs) and to compare them with age and sex-matched controls. METHODS: Twenty patients with Alzheimer's disease (AD), 20 patients with multiple sclerosis (MS), 30 patients with Parkinson's disease (PD), 10 patients with Friedreich's ataxia (FA) and 21 patients with epilepsy (EP) who were recruited from the Kirikkale University Neurology Department during 2012 were included in this prospective study. Five groups of age and sex-matched subjects were selected as controls. Corneal sensitivity was measured using a Cochet-Bonnet esthesiometer. Tear function tests included tear break-up time (TBUT) and Schirmer's 1 tests. RESULTS: Compared to their controls, mean corneal sensitivity was significantly reduced in AD, MS, PD and EP patients (all p < 0.05), mean TBUT level was significantly shorter in patients with AD and MS (all p < 0.05) and mean Schirmer's 1 test score was significantly lower in EP patients (p < 0.05). When all groups were compared with each other, reduction of mean corneal sensitivity in AD and PD groups were significantly more than in FA and MS groups (overall p = 0.034). Mean TBUT levels in AD, MS and PD groups were significantly shorter than in FA and EP groups (overall p = 0.001). Mean Schirmer's 1 test scores in AD and PD groups were significantly lower than in MS, FA and EP groups (overall p = 0.040). CONCLUSIONS: Neurodegenerative diseases may be associated with reduced corneal sensitivity and abnormal tear function. PMID- 24955506 TI - The Editor's Letter. PMID- 24955507 TI - Prioritizing the lives of children. PMID- 24955508 TI - Children's rights: a framework for health promotion. PMID- 24955509 TI - From rose-coloured glasses to reality: addressing the family policy deficit in Canada. PMID- 24955510 TI - Serving all children to catch the most vulnerable. PMID- 24955511 TI - Levels of influence in the built environment on the promotion of healthy child development. PMID- 24955512 TI - Social media and the medical industry: a whole new sort of healthcare network. PMID- 24955513 TI - Best practice interventions in childhood injury prevention: a review of what works in developing successful strategies. PMID- 24955514 TI - Childhood obesity prevention: opportunities in healthcare. AB - Childhood obesity is a leading health problem in Canada and is associated with cardiometabolic disease, reduced quality of life and economic impacts. There is an emerging evidence base on obesity-prevention strategies in children that consider the determinants of obesity and that should be considered within the context of a child's family, school, neighbourhood, culture and society. This article reviews approaches to obesity prevention in children, with a focus on the healthcare setting, incorporating both primary and secondary preventions. PMID- 24955515 TI - Ontario's Provincial Council for Maternal and Child Health: building a productive, system-level, change-oriented organization. PMID- 24955516 TI - Advancing family-centred care in child and adolescent mental health: a critical review of the literature. AB - Family-centred care (FCC) is a key factor in increasing health and related system responsiveness to the needs of children and families; unfortunately, it is an unfamiliar service model in children's mental health. This critical review of the literature addresses three key questions: What are the concepts, characteristics and principles of FCC in the context of delivering mental health services to children? What are the enablers, barriers and demonstrated benefits to using a family-centred approach to care in children's mental health? And how can we facilitate moving an FCC model forward in children's mental health? A range of databases was searched for the years 2000-2011, for children ages zero to 18 years. Articles were selected for inclusion if a family-centred approach to care was articulated and the context was the intervention and treatment side of the mental healthcare system. This literature review uncovered a multiplicity of terms and concepts, all closely related to FCC. Two of the most frequently used terms in children's mental health are family centred and family focused, which have important differences, particularly in regard to how the family is viewed. Initial benefits to FCC include improved child and family management skills and function, an increased stability of living situation, improved cost effectiveness, increased consumer and family satisfaction and improved child and family health and well-being. Significant challenges exist in evaluating FCC because of varying interpretations of its core concepts and applications. Nonetheless, a shared understanding of FCC in a children's mental health context seems possible, and examples can be found of best practices, enablers and strategies, including opportunities for innovative policy change to overcome barriers. PMID- 24955517 TI - PKCtheta is dispensable for megakaryopoiesis. PMID- 24955519 TI - Word reading skill predicts anticipation of upcoming spoken language input: a study of children developing proficiency in reading. AB - Despite the efficiency with which language users typically process spoken language, a growing body of research finds substantial individual differences in both the speed and accuracy of spoken language processing potentially attributable to participants' literacy skills. Against this background, the current study took a look at the role of word reading skill in listeners' anticipation of upcoming spoken language input in children at the cusp of learning to read; if reading skills affect predictive language processing, then children at this stage of literacy acquisition should be most susceptible to the effects of reading skills on spoken language processing. We tested 8-year-olds on their prediction of upcoming spoken language input in an eye-tracking task. Although children, like in previous studies to date, were successfully able to anticipate upcoming spoken language input, there was a strong positive correlation between children's word reading skills (but not their pseudo-word reading and meta-phonological awareness or their spoken word recognition skills) and their prediction skills. We suggest that these findings are most compatible with the notion that the process of learning orthographic representations during reading acquisition sharpens pre-existing lexical representations, which in turn also supports anticipation of upcoming spoken words. PMID- 24955518 TI - BRAF V600E in papillary thyroid carcinoma is associated with increased programmed death ligand 1 expression and suppressive immune cell infiltration. AB - BACKGROUND: There remain a small number of patients with papillary thyroid cancer (PTC) who suffer recurrence, metastases, or death. While mutation of the BRAF gene, corresponding to the constitutively active BRAF(V600E) protein, has been associated with worse clinical outcomes in thyroid cancer, the reasons underlying this observation are presently unknown. Disruption of endogenous host immune surveillance and promotion of tumor immune escape is one mechanism by which BRAF(V600E) tumors may achieve more aggressive behavior. This study evaluated the relationship between BRAF(V600E) status and known strategies of tumor-mediated immune suppression. METHODS: Tissue sections of PTC tumors from 33 patients were evaluated by immunohistochemistry for tumor-expressed suppressive ligands and enzymes and effector and suppressor populations of tumor-infiltrating immune cells. Presence of BRAF(V600E) was evaluated by direct DNA sequencing of PTC specimens and the results correlated with tumor-expressed molecules and tumor infiltrating immune cell populations, as well as patient characteristics and pathologic findings. RESULTS: BRAF(V600E) tumors more often express high levels of immunosuppressive ligands programmed death ligand 1 (53% vs. 12.5%) and human leukocyte antigen G (41% vs. 12.5%) compared to BRAF wild-type tumors. There was no association between indoleamine 2,3-dioxygenase 1 expression and BRAF(V600E) status. Furthermore, BRAF(V600E) tumors demonstrate both lower CD8(+) effector to FoxP3(+) regulatory T cell, and CD68(+) pan-macrophage to CD163(+) M2 macrophage ratios, indicating relative increases in suppressive T cell and macrophage components, respectively. CONCLUSIONS: Overall, BRAF(V600E) PTC tumors display a broadly immunosuppressive profile and evidence of disturbed host tumor immune surveillance that may contribute to the poorer outcomes observed in this subset of patients with thyroid cancer. PMID- 24955520 TI - Changes in the lipid profile of Bradybaena similaris (Ferussac, 1821) (Gastropoda, Xanthonychidae) during the development of Eurytrema coelomaticum (Giard and Billet, 1892) (Digenea, Dicrocoeliidae). AB - The effect of experimental exposure of Bradybaena similaris by Eurytrema coelomaticum on the cholesterol and triglycerides total levels circulating in the hemolymph and the neutral lipids in the digestive gland-gonad (DGG) complex of the host snail were studied. In this study, snails were dissected after one, two, and three months of infection to collect the hemolymph and DGG to measure the cholesterol and triacylglycerol levels in the hemolymph and neutral lipid fractions in the tissues. The results for the hemolymph showed that the infection by this trematode resulted in a significant decrease in the concentrations of triacylglycerol during all periods analyzed, as well as, increase in the levels of cholesterol observed after the second and third months of study. This decrease suggests the possible use of triacylglycerol by both parasite and host as alternative substrate in maintaining their energy metabolisms. In parallel, the increase in the contents of cholesterol results from a severe cellular disorganization in snail, especially DGG, as a consequence of the intense plastic processes showed by parasite. Additionally, changes in the neutral lipid profile in the DGG of the infected snails were observed, indicating the importance of these molecules for successful infection. PMID- 24955521 TI - First insight into CD59-like molecules of adult Fasciola hepatica. AB - The present study focussed on investigating CD59-like molecules of Fasciola hepatica. A cDNA encoding a CD59-like protein (termed FhCD59-1) identified previously in the membrane fraction of the F. hepatica tegument was isolated. This homologue was shown to encode a predicted open reading frame (ORF) of 122 amino acids (aa) orthologous to human CD59 with a 25 aa signal peptide, a mature protein containing 10 cysteines and a conserved CD59/Ly-6 family motif "CCXXXXCN". An analysis of cDNAs from two different adult specimens of F. hepatica revealed seven variable types of FhCD59-1 sequences, designated FhCD59 1.1 to FhCD59-1.7, which had 94.3-99.7% amino acid sequence identity upon pairwise comparison. Molecular modeling of FhCD59-1.1 with human CD59 confirmed the presence of the three-finger protein domain found in the CD59 family and predicted three disulphide bonds in the F. hepatica sequence. The interrogation of F. hepatica databases identified two additional sequences, designated FhCD59-2 and FhCD59-3, which had only 23.4-29.5% amino acid identity to FhCD59-1.1. Orthologues of the inferred CD59 protein sequences of F. hepatica were also identified in other flatworms, including Fasciola gigantica, Fascioloides magna, Schistosoma haematobium, Schistosoma japonicum, Schistosoma mansoni, Clonorchis sinensis, Opisthorchis viverrini, Taenia solium, Echinococcus granulosus and the free living Schmidtea mediterannea. The results revealed a considerable degree of sequence complexity in the CD59-like sequence families in F. hepatica and flatworms. Phylogenetic analysis of CD59-like aa sequences from F. hepatica and flatworms showed that FhCD59-2 clustered with the known surface-associated protein SmCD59-2 of S. mansoni. Relatively well-supported clades specific to schistosomes, fasciolids and opisthorchiids were identified. The qPCR analysis of gene transcription showed that the relative expression of these 3 FhCD59-like sequences varied by 11-47-fold during fluke maturation, from the newly excysted juvenile (NEJ) to the adult stage. These findings suggest that different FhCD59 like sequences play distinct roles during the development of F. hepatica. PMID- 24955522 TI - Growth ability of Gram negative bacteria in free-living amoebae. AB - When bacteria and free-living amoebae (FLAs) live both in natural waters and man made aquatic systems, they constantly interact with each other. Some bacteria can survive and grow within FLAs. Therefore, it has recently been thought that FLAs play an important role in spreading pathogenic bacteria in aquatic systems. In this study we investigated the intracellular growing ability of 7 different Gram negative bacteria (Pseudomonas fluorescens, Pseudomonas putida, Pasteurella pneumotropica, Aeromonas salmonicida, Legionella pneumophila serogroup 1, L. pneumophila serogroup 3, L. pneumophila serogroup 6) in four different FLA isolates (A1-A4). Among these, four bacterial isolates (P. fluorescens, P.putida, P.pneumotropica, A.salmonicida) and two free-living amoebae isolates (A3, A4) were isolated from the tap water in our city (Istanbul). It was found that 4 different Gram-negative bacteria could grow in A1, 2 different Gram-negative bacteria could grow in A2, 4 different Gram-negative bacteria could grow in A3, 1 Gram-negative bacterium could grow in A4. In conclusion, we think that this ability of growth could vary according to the characteristics of both bacteria and FLA isolates. Also, other factors such as environmental temperature, bacterial concentration, and extended incubation period may play a role in these interactions. This situation can be clarified with future studies. PMID- 24955523 TI - Schistosomiasis control: praziquantel forever? AB - Since no vaccine exists against schistosomiasis and the molluscs acting as intermediate hosts are not easy to attack, chemotherapy is the main approach for schistosomiasis control. Praziquantel is currently the only available antischistosomal drug and it is distributed mainly through mass administration programs to millions of people every year. A number of positive features make praziquantel an excellent drug, especially with regard to safety, efficacy, cost and ease of distribution. A major flaw is its lack of efficacy against the immature stages of the parasite. In view of its massive and repeated use on large numbers of individuals, the development of drug resistance is a much feared possibility. The mechanism of action of praziquantel is still unclear, a fact that does not favor the development of derivatives or alternatives. A large number of compounds have been tested as potential antischistosomal agents. Some of them are promising, but none so far represents a suitable substitute or adjunct to praziquantel. The research of new antischistosomal compounds is an imperative and urgent matter. PMID- 24955526 TI - One-pot synthesis of fluorescent BSA-Ce/Au nanoclusters as ratiometric pH probes. AB - A facile, one-pot synthetic approach has been developed for the preparation of BSA-Ce/Au NCs. The fluorescence intensities of BSA-Ce/Au NCs at 410 and 650 nm are pH dependent and independent, respectively. The fluorescence intensity ratio (I410/I650) is linear against pH values from 6.0 to 9.0. These stable and biocompatible BSA-Ce/Au NCs have been used as ratiometric probes for monitoring local pH values inside HeLa cells. PMID- 24955524 TI - Akt1 mediates the posterior Hoxc gene expression through epigenetic modifications in mouse embryonic fibroblasts. AB - The evolutionarily conserved Hox genes are organized in clusters and expressed colinearly to specify body patterning during embryonic development. Previously, Akt1 has been identified as a putative Hox gene regulator through in silico analysis. Substantial upregulation of consecutive 5' Hoxc genes has been observed when Akt1 is absent in mouse embryonic fibroblast (MEF) cells. In this study, we provide evidence that Akt1 regulates the 5' Hoxc gene expression by epigenetic modifications. Enrichment of histone H3K9 acetylation and a low level of the H3K27me3 mark were detected at the posterior 5' Hoxc loci when Akt1 is absent. A histone deacetylase (HDAC) inhibitor de-repressed 5' Hoxc gene expression when Akt1 is present, and a DNA demethylating reagent synergistically upregulated HDAC induced 5' Hoxc gene expression. A knockdown study revealed that Hdac6 is mediated in the Hoxc12 repression through direct binding to the transcription start site (TSS) in the presence of Akt1. Co-immunoprecipitation analysis revealed that endogenous Akt1 directly interacted with Hdac6. Furthermore, exogenous Akt1 was enriched at the promoter region of the posterior Hoxc genes such as Hoxc11 and Hoxc12, not the Akt1-independent Hoxc5 and Hoxd10 loci. The regulation of the H3K27me3 mark by Ezh2 and Kdm6b at the 5' Hoxc gene promoter turned out to be Akt1 dependent. Taken together, these results suggest that Akt1 mediates the posterior 5' Hoxc gene expression through epigenetic modification such as histone methylation and acetylation, and partly through a direct binding to the promoter region of the 5' Hoxc genes and/or Hdac6 in mouse embryonic fibroblast cells. PMID- 24955525 TI - Low SOX17 expression: prognostic significance in de novo acute myeloid leukemia with normal cytogenetics. AB - BACKGROUND: Aberrant expression of SRY-box containing gene 17 (SOX17) has been observed in several solid tumors. However, little is known about SOX17 expression in acute myeloid leukemia (AML). The purpose of this study was to investigate the alteration of SOX17 expression and to explore its clinical significance in AML. METHODS: Real-time quantitative PCR (RQ-PCR) was performed to analyze the status of SO1X17 expression in 103 patients with de novo AML and 26 normal controls. The clinical relevance of SOX17 expression was analyzed in AML. RESULTS: SOX17 level in AML was significantly down-regulated compared to controls (p<0.001). Receiver operating characteristic curve (ROC) curve analysis revealed that an area under the ROC curve (AUC) of 0.834 (95% CI 0.765-0.903; p<0.0001) or 0.789 (95% CI 0.690-0.888, p<0.001) in discriminating all patients or cytogenetically normal patients from controls, respectively. The cohort of AML patients was divided into two groups according to the cut-off value of 0.017 (60% sensitivity and 100% specificity, respectively). Cytogenetically normal patients with low SOX17 expression had significantly shorter OS than those with high SOX17 expression (median 4 vs. 25 months, respectively, p=0.035). Multivariate analysis confirmed low SOX17 expression as an independent risk factor. CONCLUSIONS: Our findings indicated that low SOX17 level may define an important risk factor in AML with normal cyotgenetics. PMID- 24955527 TI - Structural and biological trait responses of diatom assemblages to organic chemicals in outdoor flow-through mesocosms. AB - The sensitivity of diatom taxonomy and trait-based endpoints to chemicals has been poorly used so far in Environmental Risk Assessment. In this study, diatom assemblages in outdoor flow-through mesocosms were exposed to thiram (35 and 170 MUg/L), and a hydrocarbon emulsion (HE; 0.01, 0.4, 2 and 20 mg/L). The effects of exposure were assessed for 12 weeks, including 9 weeks post-treatment, using taxonomic structure and diversity, bioindication indices, biological traits, functional diversity indices, indicator classes and ecological guilds. For both chemicals, diversity increased after the treatment period, and responses of ecological traits were roughly identical with an abundance increase of motile taxa tolerant to organic pollution and decrease of low profile taxa. Bioindication indices were not affected. Traits provided a complementary approach to biomass measurements and taxonomic descriptors, leading to a more comprehensive overview of ecological changes due to organic chemicals, including short- and long-term effects on biofilm structure and functioning. PMID- 24955528 TI - Properties of newly-synthesized cationic semi-interpenetrating hydrogels containing either hyaluronan or chondroitin sulfate in a methacrylic matrix. AB - Extracellular matrix components such as hyaluronan (HA) and chondroitin sulfate (CS) were combined with a synthetic matrix of p(HEMA-co-METAC) (poly(2 hydroxyethylmethacrylate-co-2-methacryloxyethyltrimethylammonium)) at 1% and 2% w/w concentration following a previously developed procedure. The resulting semi interpenetrating hydrogels were able to extensively swell in water incrementing their dry weight up to 13 fold depending on the glycosamminoglycan content and nature. When swollen in physiological solution, materials water uptake significantly decreased, and the differences in swelling capability became negligible. In physiological conditions, HA was released from the materials up to 38%w/w while CS was found almost fully retained. Materials were not cytotoxic and a biological evaluation, performed using 3T3 fibroblasts and an original time lapse videomicroscopy station, revealed their appropriateness for cell adhesion and proliferation. Slight differences observed in the morphology of adherent cells suggested a better performance of CS containing hydrogels. PMID- 24955529 TI - Stimuli-Responsive Polymer Brushes for Flow Control through Nanopores. AB - Responsive polymers attached to the inside of nano/micro-pores have attracted great interest owing to the prospect of designing flow-control devices and signal responsive delivery systems. An intriguing possibility involves functionalizing nanoporous materials with smart polymers to modulate biomolecular transport in response to pH, temperature, ionic concentration, light or electric field. These efforts open up avenues to develop smart medical devices that respond to specific physiological conditions. In this work, an overview of nanoporous materials functionalized with responsive polymers is given. Various examples of pH, temperature and solvent responsive polymers are discussed. A theoretical treatment that accounts for polymer conformational change in response to a stimulus and the associated flow-control effect is presented. PMID- 24955530 TI - Soft Polymers for Building up Small and Smallest Blood Supplying Systems by Stereolithography. AB - Synthesis of a homologous series of photo-polymerizable alpha,w polytetrahydrofuranether-diacrylate (PTHF-DA) resins is described with characterization by NMR, GPC, DSC, soaking and rheometrical measurements. The curing speeds of the resins are determined under UV light exposure. Young's modulus and tensile strength of fully cured resins show flexible to soft material attributes dependent on the molar mass of the used linear PTHF-diacrylates. Structuring the materials by stereo lithography (SL) and multiphoton polymerization (MPP) leads to tubes and bifurcated tube systems with a diameter smaller than 2 mm aimed at small to smallest supplying systems with capillary dimensions. WST-1 biocompatibility tests ofm polymer extracts show nontoxic characteristics of the adapted polymers after a washing process. Some polymers show shape memory effect (SME). PMID- 24955531 TI - Quercetin-imprinted nanospheres as novel drug delivery devices. AB - In this work, molecularly imprinted nanospheres for controlled/sustained release of quercetin were synthesized employing methacrylic acid and ethylene glycoldymethacrylate as functional monomer and crosslinking agent, respectively. One pot precipitation polymerization was chosen as polymerization technique to obtain nanosized materials with spherical shape. Morphological and hydrophilic properties by scanning electron microscopy and water content measurements were determined, and recognition and selectivity properties of the imprinted materials were tested using the template quercetin and its structural analogue, the flavonoid catechin. Finally, the applicability of the obtained materials as drug delivery devices was evaluated by performing in vitro release studies in plasma simulating fluids and cytotoxicity testson HeLa cells. PMID- 24955532 TI - Hemocompatibility of Inorganic Physical Vapor Deposition (PVD) Coatings on Thermoplastic Polyurethane Polymers. AB - Biocompatibility improvements for blood contacting materials are of increasing interest for implanted devices and interventional tools. The current study focuses on inorganic (titanium, titanium nitride, titanium oxide) as well as diamond-like carbon (DLC) coating materials on polymer surfaces (thermoplastic polyurethane), deposited by magnetron sputtering und pulsed laser deposition at room temperature. DLC was used pure (a-C:H) as well as doped with silicon, titanium, and nitrogen + titanium (a-C:H:Si, a-C:H:Ti, a-C:H:N:Ti). In-vitro testing of the hemocompatibility requires mandatory dynamic test conditions to simulate in-vivo conditions, e.g., realized by a cone-and-plate analyzer. In such tests, titanium- and nitrogen-doped DLC and titanium nitride were found to be optimally anti-thrombotic and better than state-of-the-art polyurethane polymers. This is mainly due to the low tendency to platelet microparticle formation, a high content of remaining platelets in the whole blood after testing and low concentration of platelet activation and aggregation markers. Comparing this result to shear-flow induced cell motility tests with e.g., Dictostelium discoideum cell model organism reveals similar tendencies for the investigated materials. PMID- 24955533 TI - Increasing the Detection Limit of the Parkinson Disorder through a Specific Surface Chemistry Applied onto Inner Surface of the Titration Well. AB - The main objective of this paper was to illustrate the enhancement of the sensitivity of ELISA titration for neurodegenerative proteins by reducing nonspecific adsorptions that could lead to false positives. This goal was obtained thanks to the association of plasma and wet chemistries applied to the inner surface of the titration well. The polypropylene surface was plasma activated and then, dip-coated with different amphiphilic molecules. These molecules have more or less long hydrocarbon chains and may be charged. The modified surfaces were characterized in terms of hydrophilic-phobic character, surface chemical groups and topography. Finally, the coated wells were tested during the ELISA titration of the specific antibody capture of the alpha synuclein protein. The highest sensitivity is obtained with polar (Theta = 35 degrees ), negatively charged and smooth inner surface. PMID- 24955534 TI - Bone Substitute Effect on Vascularization and Bone Remodeling after Application of phVEGF165 Transfected BMSC. AB - VEGF (vascular endothelial growth factor) promotes vascularization and remodeling of bone substitutes. The aim of this study was to examine the effect of distinct resorbable ceramic carriers on bone forming capacities of VEGF transfected bone marrow stromal cells (BMSC). A critical size defect of the radius in rabbits was filled either by a low surface scaffold called beta-TCP (tricalciumphsphate) or the high surface scaffold CDHA (calcium deficient hydroxy-apatite) loaded with autologous BMSC, which were either transfected with a control plasmid or a plasmid coding for phVEGF165. They were compared to unloaded scaffolds. Thus, six treatment groups (n = 6 in each group) were followed by X-ray over 16 weeks. After probe retrieval, the volume of new bone was measured by micro-CT scans and vascularization was assessed in histology. While only minor bone formation was found in both carriers when implanted alone, BMSC led to increased osteogenesis in both carriers. VEGF promoted vascularization of the scaffolds significantly in contrast to BMSC alone. Bone formation was increased in the beta-TCP group, whereas it was inhibited in the CDHA group that showed faster scaffold degradation. The results indicate that the interaction of VEGF transfected BMSC with resorbable ceramic carrier influences the ability to promote bone healing. PMID- 24955535 TI - Calcium phosphate growth at electropolished titanium surfaces. AB - This work investigated the ability of electropolished Ti surface to induce Hydroxyapatite (HA) nucleation and growth in vitro via a biomimetic method in Simulated Body Fluid (SBF). The HA induction ability of Ti surface upon electropolishing was compared to that of Ti substrates modified with common chemical methods including alkali, acidic and hydrogen peroxide treatments. Our results revealed the excellent ability of electropolished Ti surfaces in inducing the formation of bone-like HA at the Ti/SBF interface. The chemical composition, crystallinity and thickness of the HA coating obtained on the electropolished Ti surface was found to be comparable to that achieved on the surface of alkali treated Ti substrate, one of the most effective and popular chemical treatments. The surface characteristics of electropolished Ti contributing to HA growth were discussed thoroughly. PMID- 24955536 TI - Characterization of Porous TiO2 Surfaces Formed on 316L Stainless Steel by Plasma Electrolytic Oxidation for Stent Applications. AB - In this study, a porous oxide layer was formed on the surface of 316L stainless steel (SS) by combining Ti magnetron sputtering and plasma electrolytic oxidation (PEO) with the aim to produce a polymer-free drug carrier for drug eluting stent (DES) applications. The oxidation was performed galvanostatically in Na3PO4 electrolyte. The surface porosity, average pore size and roughness varied with PEO treatment duration, and under optimum conditions, the surface showed a porosity of 7.43%, an average pore size of 0.44 um and a roughness (Ra) of 0.34 um. The EDS analyses revealed that the porous layer consisted of Ti, O and P. The cross-sectional morphology evidenced a double-layer structure, with a porous titania surface and an un-oxidized dense Ti film towards the interface with 316L SS. After the PEO treatment, wettability and surface free energy increased significantly. The results of the present study confirm the feasibility of forming a porous TiO2 layer on stainless steel by combining sputtering technology and PEO. Further, the resultant porous oxide layer has the potential to be used as a drug carrier for DES, thus avoiding the complications associated with the polymer based carriers. PMID- 24955537 TI - Ciprofloxacin-collagen conjugate in the wound healing treatment. AB - The synthesis of a novel functional biomaterial for wound healing treatment was carried out by adopting a free-radical grafting procedure in aqueous media. With this aim, ciprofloxacin (CFX) was covalently incorporated into collagen (T1C) chains employing an ascorbic acid/hydrogen peroxide redox pair as biocompatible initiator system. The covalent insertion of CFX in the polymeric chains was confirmed by FT-IR and UV analyses, while an antibacterial assay demonstrated the activity of the synthesized conjugate against Staphylococcus aureus and Escherichia coli, microorganisms that commonly infect wounds. A catechin blended conjugate was also tested in order to evaluate the ability to influence fibroblast cell growth. The observed antibacterial activity and stimulation of fibroblast growth support the applicability of CFX-T1C conjugate in wound treatment encouraging the healing process. PMID- 24955538 TI - Time-Dependent Effects of Pre-Aging 3D Polymer Scaffolds in Cell Culture Medium on Cell Proliferation. AB - Protein adsorption is known to direct biological response to biomaterials and is important in determining cellular response in tissue scaffolds. In this study we investigated the effect of the duration of protein adsorption to 3D polymer scaffolds on cell attachment and proliferation. 3D macro-porous polymer scaffolds were pre-aged in serum-containing culture medium for 5 min, 1 d or 7 d prior to seeding osteoblasts. The total amount of protein adsorbed was found to increase with pre-ageing time. Cell attachment and proliferation were measured 1 d and 14 d, respectively, after cell seeding. Osteoblast proliferation, but not attachment, increased with scaffold pre-ageing time and amount of adsorbed serum protein. These results demonstrate that the amount of time that scaffolds are exposed to serum-containing medium can affect cell proliferation and suggest that these effects are mediated by differences in the amount of protein adsorption. PMID- 24955539 TI - Ceramic identity contributes to mechanical properties and osteoblast behavior on macroporous composite scaffolds. AB - Implants formed of metals, bioceramics, or polymers may provide an alternative to autografts for treating large bone defects. However, limitations to each material motivate the examination of composites to capitalize on the beneficial aspects of individual components and to address the need for conferring bioactive behavior to the polymer matrix. We hypothesized that the inclusion of different bioceramics in a ceramic-polymer composite would alter the physical properties of the implant and the cellular osteogenic response. To test this, composite scaffolds formed from poly(lactide-co-glycolide) (PLG) and either hydroxyapatite (HA), beta-tricalcium phosphate (TCP), or bioactive glass (Bioglass 45S(r), BG) were fabricated, and the physical properties of each scaffold were examined. We quantified cell proliferation by DNA content, osteogenic response of human osteoblasts (NHOsts) to composite scaffolds by alkaline phosphatase (ALP) activity, and changes in gene expression by qPCR. Compared to BG-PLG scaffolds, HA-PLG and TCP-PLG composite scaffolds possessed greater compressive moduli. NHOsts on BG-PLG substrates exhibited higher ALP activity than those on control, HA-, or TCP-PLG scaffolds after 21 days, and cells on composites exhibited a 3 fold increase in ALP activity between 7 and 21 days versus a minimal increase on control scaffolds. Compared to cells on PLG controls, RUNX2 expression in NHOsts on composite scaffolds was lower at both 7 and 21 days, while expression of genes encoding for bone matrix proteins (COL1A1 and SPARC) was higher on BG-PLG scaffolds at both time points. These data demonstrate the importance of selecting a ceramic when fabricating composites applied for bone healing. PMID- 24955540 TI - Altered cell mechanics from the inside: dispersed single wall carbon nanotubes integrate with and restructure actin. AB - With a range of desirable mechanical and optical properties, single wall carbon nanotubes (SWCNTs) are a promising material for nanobiotechnologies. SWCNTs also have potential as biomaterials for modulation of cellular structures. Previously, we showed that highly purified, dispersed SWCNTs grossly alter F-actin inside cells. F-actin plays critical roles in the maintenance of cell structure, force transduction, transport and cytokinesis. Thus, quantification of SWCNT-actin interactions ranging from molecular, sub-cellular and cellular levels with both structure and function is critical for developing SWCNT-based biotechnologies. Further, this interaction can be exploited, using SWCNTs as a unique actin altering material. Here, we utilized molecular dynamics simulations to explore the interactions of SWCNTs with actin filaments. Fluorescence lifetime imaging microscopy confirmed that SWCNTs were located within ~5 nm of F-actin in cells but did not interact with G-actin. SWCNTs did not alter myosin II sub-cellular localization, and SWCNT treatment in cells led to significantly shorter actin filaments. Functionally, cells with internalized SWCNTs had greatly reduced cell traction force. Combined, these results demonstrate direct, specific SWCNT alteration of F-actin structures which can be exploited for SWCNT-based biotechnologies and utilized as a new method to probe fundamental actin-related cellular processes and biophysics. PMID- 24955541 TI - A method for quantitative determination of biofilm viability. AB - In this study we present a scheme for quantitative determination of biofilm viability offering significant improvement over existing methods with metabolic assays. Existing metabolic assays for quantifying viable bacteria in biofilms usually utilize calibration curves derived from planktonic bacteria, which can introduce large errors due to significant differences in the metabolic and/or growth rates of biofilm bacteria in the assay media compared to their planktonic counterparts. In the presented method we derive the specific growth rate of Streptococcus mutans bacteria biofilm from a series of metabolic assays using the pH indicator phenol red, and show that this information could be used to more accurately quantify the relative number of viable bacteria in a biofilm. We found that the specific growth rate of S. mutans in biofilm mode of growth was 0.70 h 1, compared to 1.09 h-1 in planktonic growth. This method should be applicable to other bacteria types, as well as other metabolic assays, and, for example, to quantify the effect of antibacterial treatments or the performance of bactericidal implant surfaces. PMID- 24955543 TI - Hesperidin, nobiletin, and tangeretin are collectively responsible for the anti neuroinflammatory capacity of tangerine peel (Citri reticulatae pericarpium). AB - Inhibiting microglial activation-mediated neuroinflammation has become a convincing target for the development of functional foods to treat neurodegenerative diseases. Tangerine peel (Citri reticulatae pericarpium) has potent anti-inflammatory capacity; however, its anti-neuroinflammatory capacity and the corresponding active compounds remain unclear. To this end, the composition of a tangerine peel ethanolic extract was analysed by LC-MS, and the anti-neuroinflammatory ability was evaluated using a lipopolysaccharide (LPS) activated BV2 microglia culture system. Hesperidin is the most predominant flavonoid in tangerine peel, followed by tangeretin and nobiletin. Among the eight tested flavanone glycosides and polymethoxy flavones, only nobiletin displayed a capacity of>50% to inhibit LPS-induced proinflammatory NO, TNF-alpha, IL-1beta and IL-6 secretion at a concentration of 100 MUM. At 2 mg/ml, tangerine peel extract attenuated LPS-induced NO, TNF-alpha, IL-1beta and IL-6 secretion by 90.6%, 80.2%, 66.7%, and 86.8%, respectively. Hesperidin, nobiletin, and tangeretin individually (at concentrations of 135, 40, and 60 MUM, respectively) in 2 mg/ml tangerine peel extract were only mildly inhibitory, whereas in combination, they significantly inhibited LPS-induced proinflammatory cytokine expression at levels equal to that of 2 mg/ml tangerine peel extract. Overall, tangerine peel possesses potent anti-neuroinflammatory capacity, which is attributed to the collective effect of hesperidin, nobiletin, and tangeretin. PMID- 24955542 TI - Bioactive and biodegradable nanocomposites and hybrid biomaterials for bone regeneration. AB - Strategies for bone tissue engineering and regeneration rely on bioactive scaffolds to mimic the natural extracellular matrix and act as templates onto which cells attach, multiply, migrate and function. Of particular interest are nanocomposites and organic-inorganic (O/I) hybrid biomaterials based on selective combinations of biodegradable polymers and bioactive inorganic materials. In this paper, we review the current state of bioactive and biodegradable nanocomposite and O/I hybrid biomaterials and their applications in bone regeneration. We focus specifically on nanocomposites based on nano-sized hydroxyapatite (HA) and bioactive glass (BG) fillers in combination with biodegradable polyesters and their hybrid counterparts. Topics include 3D scaffold design, materials that are widely used in bone regeneration, and recent trends in next generation biomaterials. We conclude with a perspective on the future application of nanocomposites and O/I hybrid biomaterials for regeneration of bone. PMID- 24955544 TI - The ever-changing electrical synapse. AB - A wealth of research has revealed that electrical synapses in the central nervous system exhibit a high degree of plasticity. Several recent studies, particularly in the retina and inferior olive, highlight this plasticity. Three classes of mechanisms can alter electrical coupling over time courses ranging from milliseconds to days. Changes of membrane conductance through synaptic input or spiking activity shunt current and decouple neurons on the millisecond time scale. Such activity can also alter coupling symmetry, rectifying electrical synapses. More stable rectification can be accomplished through molecular asymmetry of the synapse itself. On the minutes time scale, changes in connexin phosphorylation can change coupling quasi-stably with an order of magnitude dynamic range. On the hours to days time scale, changes in expression level of connexins alter coupling through the course of circadian time, over developmental time, or in response to tissue injury. Combined, all of these mechanisms allow electrical coupling to be highly dynamic, changing in response to demands at the whole network level, in small portions of a network, or at the level of an individual synapse. PMID- 24955548 TI - Chasing protons: how isothermal titration calorimetry, mutagenesis, and pKa calculations trace the locus of charge in ligand binding to a tRNA-binding enzyme. AB - Drug molecules should remain uncharged while traveling through the body and crossing membranes and should only adopt charged state upon protein binding, particularly if charge-assisted interactions can be established in deeply buried binding pockets. Such strategy requires careful pKa design and methods to elucidate whether and where protonation-state changes occur. We investigated the protonation inventory in a series of lin-benzoguanines binding to tRNA-guanine transglycosylase, showing pronounced buffer dependency during ITC measurements. Chemical modifications of the parent scaffold along with ITC measurements, pKa calculations, and site-directed mutagenesis allow elucidating the protonation site. The parent scaffold exhibits two guanidine-type portions, both likely candidates for proton uptake. Even mutually compensating effects resulting from proton release of the protein and simultaneous uptake by the ligand can be excluded. Two adjacent aspartates induce a strong pKa shift at the ligand site, resulting in protonation-state transition. Furthermore, an array of two parallel H-bonds avoiding secondary repulsive effects contributes to the high-affinity binding of the lin-benzoguanines. PMID- 24955549 TI - High-level expression, purification and study of bioactivity of fusion protein M IL-2((88)Arg, (125)Ala) in Pichia pastoris. AB - M-IL-2((88)Arg, (125)Ala) is a fusion protein comprising melittin genetically linked to a mutant human interleukin 2((88)Arg, (125)Ala). In this study, we constructed an expression system of M-IL-2((88)Arg, (125)Ala) in Pichia pastoris: GS115/pPICZalpha A/M-IL-2((88)Arg, (125)Ala), and achieved the high-level expression of the fusion protein. The maximum yield of the fusion protein M-IL 2((88)Arg, (125)Ala) reached up to 814.5mg/L, higher than the system in Escherichiacoli. The fusion protein was purified by means of ammonium sulfate fractionation, dialysis and nickel ion affinity chromatography. The molecular weight of the fusion protein is about 26kDa, conforming the theoretical value. And M-IL-2((88)Arg, (125)Ala) possesses strong antigen-specificity by Western blot detection. Bioassay results indicated that the fusion protein could directly inhibit the growth of human ovarian cancer SKOV3 cells and Hela cells in vitro. This study provides an alternative strategy for large-scale production of bioactive M-IL-2((88)Arg, (125)Ala) using P. pastoris as an expression host and paves the way to clinical practice. PMID- 24955550 TI - Saffron aqueous extract prevents metabolic syndrome in patients with schizophrenia on olanzapine treatment: a randomized triple blind placebo controlled study. AB - OBJECTIVE: The aim of this study was to assess whether saffron aqueous extract (SAE) or its active constituent, crocin, prevents olanzapine-induced metabolic syndrome (MetS) and insulin resistance in patients with schizophrenia. METHODS: 66 patients diagnosed with schizophrenia who were on olanzapine treatment (5-20 mg daily) were randomly allocated to receive a capsule of SAE (n=22; 30 mg daily), crocin (n=22; 30 mg daily) or placebo (n=22) in a 12-week triple-blind trial. Patients were screened not to have MetS at baseline and further assessment was done at weeks 6 and 12. Measurement of fasting blood glucose (FBS) and serum lipids were repeated at weeks 2, 6 and 12. Fasting blood levels of insulin and HbA1c were also measured at baseline and week 12. HOMA-IR and HOMA-beta were determined to evaluate insulin resistance. RESULTS: 61 patients completed the trial and no serious adverse effects were reported. Time-treatment interaction showed a significant difference in FBS in both SAE and crocin groups compared to placebo (p=0.004). In addition, SAE could effectively prevent reaching the criteria of metabolic syndrome (0 patients) compared to crocin (9.1%) and placebo (27.3%) as early as week 6. CONCLUSION: SAE could prevent metabolic syndrome compared to crocin and placebo. Furthermore, both SAE and crocin prevented increases in blood glucose during the study. PMID- 24955547 TI - The sentinel role of peptidoglycan recycling in the beta-lactam resistance of the Gram-negative Enterobacteriaceae and Pseudomonas aeruginosa. AB - The peptidoglycan is the structural polymer of the bacterial cell envelope. In contrast to an expectation of a structural stasis for this polymer, during the growth of the Gram-negative bacterium this polymer is in a constant state of remodeling and extension. Our current understanding of this peptidoglycan "turnover" intertwines with the deeply related phenomena of the liberation of small peptidoglycan segments (muropeptides) during turnover, the presence of dedicated recycling pathways for reuse of these muropeptides, beta-lactam inactivation of specific penicillin-binding proteins as a mechanism for the perturbation of the muropeptide pool, and this perturbation as a controlling mechanism for signal transduction leading to the expression of beta-lactamase(s) as a key resistance mechanism against the beta-lactam antibiotics. The nexus for many of these events is the control of the AmpR transcription factor by the composition of the muropeptide pool generated during peptidoglycan recycling. In this review we connect the seminal observations of the past decades to new observations that resolve some, but certainly not all, of the key structures and mechanisms that connect to AmpR. PMID- 24955552 TI - Comparison of sertraline, venlafaxine and desipramine effects on depression, cognition and the daily living activities in Alzheimer patients. AB - RATIONALE: The effects of antidepressants on mood, cognition and the daily activities of Alzheimer patients are ambiguous. The effects of antidepressants SSRIs (serotonin specific reuptake inhibitors), TCAs (tricyclic antidepressants) and SNRIs (serotonin-norepinephrine reuptake inhibitors), in particular, are unknown. OBJECTIVES: This study aimed to compare the effects of sertraline, venlafaxine and desipramine on depression, cognition and the daily activities of Alzheimer patients. METHODS: This randomized double-blind trial was approved by the Research and Ethics Committees of Mashhad University of Medical Sciences. 59 moderate Alzheimer patients with major depressive disorder were randomly divided into 3 groups (sertraline, venlafaxine and desipramine), treated for 12 weeks (150 mg maximum dose) and assessed by the Hamilton Depression Test (HRSD), the Mini Mental State Examination (MMSE) and the Barthel index at the week 0 and the 2(nd), 4(th), 8(th), 12(th) weeks thereafter. Data were analyzed by SPSS software, using ANOVA and paired t-tests. RESULTS: In the sertraline group, the results of all 3 tests, HRSD, MMSE and Barthel, in the 12(th) week showed significant improvements in comparison to the baseline (P<0.05 in all 3 tests). In the venlafaxine group, the results of MMSE and Barthel revealed significant improvements (P<0.05 in both tests). In the desipramine group, there was a significant improvement only in the Barthel test at the 12(th) week (P<0.05). CONCLUSION: In this trial, sertraline treatment was associated with superior effectiveness in relation to depressive, cognitive, and behavioral symptoms. PMID- 24955553 TI - An acyl-SAM analog as an affinity ligand for identifying quorum sensing signal synthases. AB - N-Acylhomoserine lactones (AHLs) are quorum sensing signals produced by Gram negative bacteria. We here report the affinity purification of AHL synthases using beads conjugated with an enzyme inhibitor, which was designed based on the catalytic intermediate acyl-SAM. PMID- 24955554 TI - Electrophilic sulfhydration of 8-nitro-cGMP involves sulfane sulfur. AB - The formation of 8-SH-cGMP from the reaction between hydrogen sulfide and 8-nitro guanosine-3',5'-cyclic monophosphate in the presence of thiols does not take place by nucleophilic attack of the hydrosulfide anion, as previously proposed, but first involves the formation of reactive species containing sulfane sulfur, like persulfides. PMID- 24955551 TI - Baseline vitamin B12 and folate levels do not predict improvement in depression after a single infusion of ketamine. AB - INTRODUCTION: Deficiencies in both vitamin B12 and folate have been associated with depression. Recently, higher baseline vitamin B12 levels were observed in individuals with bipolar depression who responded to the antidepressant ketamine at 7 days post-infusion. This study sought to -replicate this result by correlating peripheral vitamin levels with ketamine's antidepressant efficacy in bipolar depression and major depressive disorder (MDD). METHODS: Baseline vitamin B12 and folate levels were obtained in 49 inpatients with treatment-resistant MDD and 34 inpatients with treatment-resistant bipolar depression currently experiencing a major depressive episode. All subjects received a single intravenous ketamine infusion. Post-hoc Pearson correlations were performed between baseline vitamin B12 and folate levels, as well as antidepressant response assessed by percent change in Hamilton Depression Rating Scale (HDRS) scores from baseline to 230 min, 1 day, and 7 days post-infusion. RESULTS: No significant correlation was observed between baseline vitamin B12 or folate and percent change in HDRS for any of the 3 time points in either MDD or bipolar depression. DISCUSSION: Ketamine's antidepressant efficacy may occur independently of baseline peripheral vitamin levels. PMID- 24955555 TI - Eurothiocin A and B, sulfur-containing benzofurans from a soft coral-derived fungus Eurotium rubrum SH-823. AB - Two new sulfur-containing benzofuran derivatives, eurothiocin A and B (1 and 2), along with five known compounds, zinniol (3), butyrolactone I (4), aspernolide D (5), vermistatin (6), and methoxyvermistatin (7), were isolated from the cultures of Eurotium rubrum SH-823, a fungus obtained from a Sarcophyton sp. soft coral collected from the South China Sea. The new compounds (1 and 2) share a methyl thiolester moiety, which is quite rare among natural secondary metabolites. The structures of these metabolites were assigned on the basis of detailed spectroscopic analysis. The absolute configurations of 1 and 2 were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) data. Compounds 1 and 2 exhibited more potent inhibitory effects against alpha glucosidase activity than the clinical alpha-glucosidase inhibitor acarbose. Further mechanistic analysis showed that both of them exhibited competitive inhibition characteristics. PMID- 24955557 TI - Evidence of superior ferroelectricity in structurally welded ZnSnO3 nanowire arrays. AB - Highly packed LN-type ZnSnO3 NW arrays are grown on ZnO:Al/Si substrates using a hybrid pulsed laser deposition and solvothermal process. Unique "welding" mechanism structurally joins adjacent ZnSnO3 NWs to form a nearly impervious 20 MUm thick nanostructured film that shows high P r of 30 MUC/cm(2) at a low E c of 25 kV/cm for the first time. PMID- 24955556 TI - Accurate dereplication of bioactive secondary metabolites from marine-derived fungi by UHPLC-DAD-QTOFMS and a MS/HRMS library. AB - In drug discovery, reliable and fast dereplication of known compounds is essential for identification of novel bioactive compounds. Here, we show an integrated approach using ultra-high performance liquid chromatography-diode array detection-quadrupole time of flight mass spectrometry (UHPLC-DAD-QTOFMS) providing both accurate mass full-scan mass spectrometry (MS) and tandem high resolution MS (MS/HRMS) data. The methodology was demonstrated on compounds from bioactive marine-derived strains of Aspergillus, Penicillium, and Emericellopsis, including small polyketides, non-ribosomal peptides, terpenes, and meroterpenoids. The MS/HRMS data were then searched against an in-house MS/HRMS library of ~1300 compounds for unambiguous identification. The full scan MS data was used for dereplication of compounds not in the MS/HRMS library, combined with ultraviolet/visual (UV/Vis) and MS/HRMS data for faster exclusion of database search results. This led to the identification of four novel isomers of the known anticancer compound, asperphenamate. Except for very low intensity peaks, no false negatives were found using the MS/HRMS approach, which proved to be robust against poor data quality caused by system overload or loss of lock-mass. Only for small polyketides, like patulin, were both retention time and UV/Vis spectra necessary for unambiguous identification. For the ophiobolin family with many structurally similar analogues partly co-eluting, the peaks could be assigned correctly by combining MS/HRMS data and m/z of the [M + Na]+ ions. PMID- 24955559 TI - Hoodia gordonii: to eat, or not to eat. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hoodia gordonii (family Apocynaceae) has become known globally for its claimed effect of appetite suppression. Despite a relatively large body of evidence of the plant's chemical make-up, peer-reviewed studies to provide scientific information on physiological effects of Hoodia gordonii are relatively sparse. The role of the pregnane glycoside P57-commonly accepted to be responsible for appetite suppression-has been questioned recently. Furthermore, a variety of physiological side-effects associated with consumption of the plant in extracted form questions its suitability for consumption. Although adverse effects have been described before, the relative abundance of non-peer-reviewed data originating from patent documents and lay publication for advertising, which specifically only focus on beneficial outcomes, skews the view of the risk-benefit-balance. Here we provide a review of peer-reviewed studies on the plant's physiological effects. Novel data from an in vivo rodent study further elucidate the benefit-to-risk ratio associated with consumption. CONCLUSIONS: we conclude that although Hoodia gordonii seems to have a desired effect on appetite and weight loss, this effect may at least in part be a secondary symptom of the serious adverse effects that are associated with consumption of the high doses required to achieve therapeutic clinical effect. PMID- 24955560 TI - Antitubercular activity of Arctium lappa and Tussilago farfara extracts and constituents. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Arctium lappa and Tussilago farfara (Asteraceae) are two plant species used traditionally as antitubercular remedies. The aim of this study was (i) to screen Arctium lappa and Tussilago farfara extracts for activity against Mycobacterium tuberculosis and (ii) to isolate and identify the compound(s) responsible for this reputed anti-TB effect. MATERIALS AND METHODS: The activity of extracts and isolated compounds was determined against Mycobacterium tuberculosis H37Rv using a high throughput spot culture growth inhibition (HT-SPOTi) assay. RESULTS: The n-hexane extracts of both plants, the ethyl acetate extract of Tussilago farfara and the dichloromethane phase derived from the methanol extract of Arctium lappa displayed antitubercular activity (MIC 62.5 MUg/mL). Further chemical investigation of Arctium lappa led to the isolation of n-nonacosane (1), taraxasterol acetate (2), taraxasterol (3), a (1:1) mixture of beta sitosterol/stigmasterol (4), isololiolide (5), melitensin (6), trans-caffeic acid (7), kaempferol (8), quercetin (9), kaempferol-3-O glucoside (10). Compounds isolated from Tussilago farfara were identified as a (1:1) mixture of beta sitosterol/stigmasterol (4), trans-caffeic acid (7), kaempferol (8), quercetin (9), kaempferol-3-O-glucoside (10), loliolide (11), a (4:1) mixture of p-coumaric acid/4-hydroxybenzoic acid (12), p-coumaric acid (13). All compounds were identified following analyses of their physicochemical and spectroscopic data (MS, (1)H and (13)C-NMR) and by comparison with published data. This is the first report of the isolation of n-nonacosane (1), isololiolide (5), melitensin (6) and kaempferol-3-O-glucoside (10) from Arctium lappa, and of loliolide (11) from Tussilago farfara. Amongst the isolated compounds, the best activity was observed for p-coumaric acid (13) (MIC 31.3 MUg/mL or 190.9 MUM) alone and in mixture with 4-hydroxybenzoic acid (12) (MIC 62.5 MUg/mL). CONCLUSIONS: The above results provide for the first time some scientific evidence to support, to some extent, the ethno-medicinal use of Arctium lappa and Tussilago farfara as traditional antitubercular remedies. PMID- 24955561 TI - Clinical course of recurrent respiratory papillomatosis: comparison between aggressiveness of human papillomavirus-6 and human papillomavirus-11. AB - BACKGROUND: Recurrent respiratory papillomatosis (RRP) is mainly associated with human papillomavirus (HPV)6 or HPV11. The purpose of this study was to compare clinical outcome, aggressiveness, and treatment response between HPV6- and HPV11 associated RRP. METHODS: A retrospective cohort of 55 patients with RRP (1974 2012) was used. Surgical interventions (n = 814) were analyzed, and complications scored. HPV6/11-specific polymerase chain reaction (PCR) was performed on RRP biopsies. RESULTS: Seventy-six percent of patients (42 of 55) were infected with HPV6 and 24% (13 of 55) with HPV11. The HPV11 group had anatomically more widespread disease. The expected number of surgical interventions was higher in the younger age (<22.4 years) HPV11 group, and the older age (<22.4 years) HPV6 group. Regardless of HPV type, earlier age of onset of RRP resulted in a higher number of surgical interventions. CONCLUSION: Anatomically, HPV11-associated RRP behaves more aggressively. Younger patients with HPV11 and older patients with HPV6 experience a worse clinical course of RRP. PMID- 24955562 TI - The effect of core clinician interpersonal behaviours on depression. AB - BACKGROUND: It is well-established that core clinician interpersonal behaviours are important when treating depression, but few studies have evaluated whether outcome is determined by clinicians' general behaviour rather than by the perception of the individual being treated. METHODS: In the NIMH TDCRP, 157 patients rated their clinician's genuineness, positive regard, empathy and unconditional regard during cognitive behavioural therapy, interpersonal therapy or clinical management with placebo. The association between averaged ratings for each of 27 clinicians and their patients' self- and observer-rated depression outcomes was evaluated, adjusting for the deviation of individual patient ratings from the average for their clinician and other potential confounders. RESULTS: Clinicians in the clinical management condition were rated on average as less genuine and less empathic than those in the psychotherapy conditions. Clinicians' average genuineness, positive regard and empathy were significantly associated with lower depression severity during treatment, but not with recovery from depression, after adjusting for the deviation of the individual patient's rating of their clinician from the average for that clinician, treatment condition and baseline depression severity. Clinician unconditional regard was not significantly associated with outcome. LIMITATIONS: Using averaged ratings of clinician behaviour likely reduced statistical power. CONCLUSIONS: Clinicians' ability to demonstrate genuineness, positive regard and empathy may represent a stable personal characteristic that influences the treatment of depression beyond the individual clinician-patient relationship or an individual patient's perception of their clinician. However, clinicians' ability to demonstrate these behaviours may be poorer when delivering an intervention without a specific rationale or treatment techniques. PMID- 24955563 TI - Toward the identification of neurocognitive subtypes in euthymic patients with bipolar disorder. AB - BACKGROUND: Cross-sectional and meta-analytic studies showed that patients with bipolar disorder (BD) had neurocognitive impairments even during periods of euthymia. The aim of this study was to estimate the prevalence of BD patients with and without clinically significant cognitive impairments, as well as to analyze clinical and functional variables in these subgroups. METHODS: Hundred patients with BD and 40 healthy controls were assessed with an extensive neurocognitive assessment. Soft (some cognitive domain with a performance below 1.5 SD of the mean) and hard (at least two domains with values below 2 SD of the mean) criteria were utilized to define clinically significant cognitive impairments. RESULTS: Using both soft and hard criteria, the prevalence of clinically significant cognitive impairments was higher in people with BD than in healthy controls. 70% of patients only showed failures of small effect (d=0.21 0.35) in 2 measures of executive functions. Moreover, 30% of patients were indistinguishable from healthy subjects in terms of both neurocognitive and psychosocial functioning. On the contrary, 30% of the sample showed more severe cognitive deficits than those usually reported in literature and had the worst psychosocial functioning. CONCLUSIONS: The fact that cognitive impairments are very heterogeneous among euthymic patients with BD could contribute to understanding differences in functional outcome. Theoretical and practical implications of these findings are discussed. PMID- 24955564 TI - Attempted suicide in people with co-occurring bipolar and substance use disorders: systematic review and meta-analysis. AB - BACKGROUND: Both individuals with bipolar (BD) and those with alcohol (AUD) and other substance (SUD) use disorders are likely to attempt suicide. Comorbidity of BD and AUD/SUD may increase the likelihood of suicide attempts. We conducted a meta-analysis to estimate the association of comorbid AUD/SUD and suicide attempts in subjects with BD in the literature to date. METHODS: Electronic databases through January 2013 were searched. Studies reporting rates of suicide attempts in people with co-occurring BD and AUD/SUD were retrieved. Comorbid AUD and SUD and suicide attempts rates as well as demographic, clinical, and methodological variables were extracted from each publication or obtained directly from its authors. RESULTS: Twenty-nine of 222 studies assessed for eligibility met the inclusion criteria, comprising a total of 31,294 individuals with BD, of whom 6308 (20.1%) had documented suicide attempts. There were consistent findings across the studies included. As compared to controls, subjects with BD and comorbid AUD/SUD were more likely to attempt suicide. The cross-sectional association estimates showed random-effects pooled crude ORs of 1.96 (95% CI=1.56-2.47; p<0.01), 1.72 (95% CI=1.52-1.95; p<0.01), and 1.77 (95% CI=1.49-2.10; p<0.01), for combined AUD/SUD, AUD, and SUD. There was no publication bias and sensitivity analyses based on the highest quality studies confirmed core results. LIMITATIONS: The effects of the number and the type of suicide attempts could not be investigated due to insufficient information. CONCLUSIONS: Comorbid AUD and SUD in individuals with BD are significantly associated with suicide attempts. Individuals with this comorbidity should be targeted for intensive suicide prevention efforts. PMID- 24955565 TI - International prescribing patterns for mood illness: the International Mood Network (IMN). AB - OBJECTIVE: To show the feasibility of creating an international network that will build a common database for mood disorders research, and to present initial data on prescribing patterns worldwide. METHODS: An international research database was organized with clinicians and researchers actively treating mood disorders. Participating sites were asked to provide data on 10-50 subjects initially. This work was conducted under the auspices of a committee with representatives from North and South America, Europe, and Asia. Data was pooled from multiple sites using a centralized online system and then analyzed. Each site received IRB approval for its participation in the IMN and the Tufts Medical Center IRB provided approval for the entire project. LIMITATIONS: More than half of the population came from one country (United States) and there is the possibility of cultural bias. RESULTS: Among the 186 subjects enrolled in the IMN, a majority of subjects were prescribed mood stabilizers including lithium (64%), lamotrigine (37%), valproate (31%), and carbamazepine (3%). 79% had a diagnosis of bipolar disorder type I, II or NOS and 21% had a diagnosis of MDD. 81% of subjects used antidepressants at some point. 25% experienced antidepressant-induced mania and 26% had antidepressant-related rapid cycling. Mood stabilizers were prescribed more in Europe (86%), neuroleptics in South America (70%), and antidepressants in Asia (58%). CONCLUSIONS: The results confirm the diversity and feasibility of an international mood disorders database. Important regional differences in psychotropic drug treatment of mood illnesses were observed, with more mood stabilizer use in Europe and South America, and more antidepressant use in non European populations. PMID- 24955567 TI - Standardization of human IL-29 (IFN-lambda1): establishment of a World Health Organization international reference reagent for IL-29 (IFN-lambda1). AB - Human interleukin-29 (IL-29), a helical cytokine with interferon-like activities, is currently being developed as a clinical biotherapeutic to treat chronic hepatitis C infection and some cancers. As such, the World Health Organization (WHO) has recognized a need for biological standardization of IL-29 and the establishment of an internationally available reference reagent of IL-29. In order to accomplish this, an international collaborative study that evaluates WHO candidate reference reagents of IL-29 was instigated by the National Institute for Biological Standards and Control (NIBSC) in 2010 and was carried out in the succeeding year. Two preparations of human sequence recombinant IL-29, one expressed in murine NS0 cells and the other in Escherichia coli, were formulated and lyophilized at NIBSC before evaluation in the collaborative study for their suitability to serve as a reference reagent. The preparations were tested by 6 laboratories from 4 countries using in vitro bioassays and also evaluated for thermal stability within the NIBSC laboratory. On the basis of the results of the collaborative study, both preparations, 07/212 (NS0-derived) and 10/176 (E. coli derived) were judged sufficiently active and stable to serve as a reference reagent. However, since IL-29 produced in E. coli is in development for clinical applications, it was recommended that the preparation coded 10/176 be established as the WHO international reference reagent for human IL-29. This recommendation was accepted, and the IL-29 preparation coded 10/176 was formally established by the WHO ECBS at its meeting in October 2012 as the WHO international reference reagent for IL-29 with an assigned unitage of 5,000 reference units per ampoule. PMID- 24955570 TI - Rapid spontaneous closure and remodelling of a medium-sized symptomatic congenital coronary artery fistula in an infant before the age of 3 months. AB - It is controversial to observe or close symptomatic congenital coronary artery fistula in infants. We herein describe a medium-sized symptomatic congenital coronary artery fistula that underwent rapid spontaneous closure in an infant aged <3 months. PMID- 24955569 TI - Individualized, spectral domain-optical coherence tomography-guided facedown posturing after macular hole surgery: minimizing treatment burden and maximizing outcome. AB - PURPOSE: To evaluate the individualized, optical coherence tomography-guided facedown posturing after macular hole (MH) surgery in minimizing the burden and maximizing outcome. METHODS: A retrospective comparative study. One hundred and seven consecutive eyes with an MH (<500 MUm) received vitrectomy and gas tamponade. After surgery, optical coherence tomography examination was performed from 6 hours to postoperative Day 2. In Group A, with a pro re nata posturing protocol, the duration of facedown posturing was determined from the optical coherence tomography findings. Group A was subdivided as follows: Group A1, facedown posturing required postoperatively and Group A2, no posturing required. When MH closure was confirmed, facedown posturing (if any) was discontinued. If the MH did not close, additional posturing was advised. Group B was the control group, consisted of 42 consecutive eyes with traditional 7 days of posturing. RESULTS: After a single surgery, Group A had the MH closure rate of 96.2%, 95.8% in Group A1 and 97.1% in Group A2, whereas Group B had the MH closure rate of 95.2%. The average posturing period was 42 hours for Group A, 57 hours for Group A1 and 10 hours for Group A2 (P < 0.001). The MH size was correlated significantly with the closure time (R = 0.47, P = 0.005, Spearman correlation coefficient). CONCLUSION: A pro re nata posturing protocol achieves a high MH closure rate with a significant reduction of posturing time especially for pseudophakic eyes. PMID- 24955568 TI - Primary care providers' bereavement care practices: recommendations for research directions. AB - OBJECTIVE: Bereaved patients are often seen in primary care settings. Although most do not require formal support, physicians may be called upon to provide support to some bereaved, particularly those with bereavement-related mental health disorders like complicated grief and bereavement-related depression. Research evidence on physician bereavement care is scant. We make recommendations for future research in this area. DESIGN: Literature review focuses on studies conducted between 1996 and 2013 in the United States. Searches of Medline and PsychInfo, along with hand searches of reference sections, were conducted. RESULTS: The limited existing research indicates substantial gaps in the research literature, especially in the areas of primary care physician skill and capacity, patient-level outcomes, and the quality of research methodology. No US studies have focused specifically on care for bereavement-related mental health disorders. We provide recommendations about how to improve research about primary care bereavement care. CONCLUSIONS: The primary care sector offers ample opportunities for research on bereavement care. With greater research efforts, there may be improvements to quality of bereavement care in primary care, in general, and also to the accurate detection and appropriate referral for bereavement-related mental health conditions. PMID- 24955572 TI - Metacognition, metamemory, and mindreading in high-functioning adults with autism spectrum disorder. AB - Metacognition refers to cognition about cognition and encompasses both knowledge of cognitive processes and the ability to monitor and control one's own cognitions. The current study aimed to establish whether metacognition is impaired in autism spectrum disorder (ASD). According to some theories, the ability to represent one's own mental states (an aspect of metacognition) relies on the same mechanism as the ability to represent others' mental states ("mindreading"). Given numerous studies have shown mindreading is impaired in ASD, there is good reason to predict concurrent impairments in metacognition. Metacognition is most commonly explored in the context of memory, often by assessing people's ability to monitor their memory processes. The current study addressed the question of whether people with ASD have difficulty monitoring the contents of their memory (alongside impaired mindreading). Eighteen intellectually high-functioning adults with ASD and 18 IQ- and age-matched neurotypical adults participated. Metamemory monitoring ability and mindreading ability were assessed by using a feeling-of-knowing task and the "animations" task, respectively. Participants also completed a self-report measure of metacognitive ability. In addition to showing impaired mindreading, participants with ASD made significantly less accurate feeling-of-knowing judgments than neurotypical adults, suggesting that metamemory monitoring (an aspect of metacognition) was impaired. Conversely, participants with ASD self-reported superior metacognitive abilities compared with those reported by neurotypical participants. This study provides evidence that individuals with ASD have metamemory monitoring impairments. The theoretical and practical implications of these findings for our current understanding of metacognition in ASD and typical development are discussed. PMID- 24955571 TI - The effect of disgust and fear modeling on children's disgust and fear for animals. AB - Disgust is a protective emotion associated with certain types of animal fears. Given that a primary function of disgust is to protect against harm, increasing children's disgust-related beliefs for animals may affect how threatening they think animals are and their avoidance of them. One way that children's disgust beliefs for animals might change is via vicarious learning: by observing others responding to the animal with disgust. In Experiment 1, children (ages 7-10 years) were presented with images of novel animals together with adult faces expressing disgust. Children's fear beliefs and avoidance preferences increased for these disgust-paired animals compared with unpaired control animals. Experiment 2 used the same procedure and compared disgust vicarious learning with vicarious learning with fear faces. Children's fear beliefs and avoidance preferences for animals again increased as a result of disgust vicarious learning, and animals seen with disgust or fear faces were also rated more disgusting than control animals. The relationship between increased fear beliefs and avoidance preferences for animals was mediated by disgust for the animals. The experiments demonstrate that children can learn to believe that animals are disgusting and threatening after observing an adult responding with disgust toward them. The findings also suggest a bidirectional relationship between fear and disgust with fear-related vicarious learning leading to increased disgust for animals and disgust-related vicarious learning leading to increased fear and avoidance. PMID- 24955573 TI - Edoxaban in the evolving scenario of non vitamin K antagonist oral anticoagulants imputed placebo analysis and multiple treatment comparisons. AB - BACKGROUND: Edoxaban recently proved non-inferior to warfarin for prevention of thromboembolism in patients with non-valvular atrial fibrillation (AF). We conducted an imputed-placebo analysis with estimates of the proportion of warfarin effect preserved by each non vitamin K antagonist oral anticoagulant (NOAC) and indirect comparisons between edoxaban and different NOACs. METHODS AND FINDINGS: We performed a literature search (up to January 2014), clinical trials registers, conference proceedings, and websites of regulatory agencies. We selected non-inferiority randomised controlled phase III trials of dabigatran, rivaroxaban, apixaban and edoxaban compared with adjusted-dose warfarin in non valvular AF. Compared to imputed placebo, all NOACs reduced the risk of stroke (ORs between 0.24 and 0.42, all p<0.001) and all-cause mortality (ORs between 0.55 and 0.59, all p<0.05). Edoxaban 30 mg and 60 mg preserved 87% and 112%, respectively, of the protective effect of warfarin on stroke, and 133% and 121%, respectively, of the protective effect of warfarin on all-cause mortality. The risk of primary outcome (stroke/systemic embolism), all strokes and ischemic strokes was significantly higher with edoxaban 30 mg than dabigatran 150 mg and apixaban. There were no significant differences between edoxaban 60 mg and other NOACs for all efficacy outcomes except stroke, which was higher with edoxaban 60 mg than dabigatran 150 mg. The risk of major bleedings was lower with edoxaban 30 mg than any other NOAC, odds ratios (ORs) ranging between 0.45 and 0.67 (all p<0.001). CONCLUSIONS: This study suggests that all NOACs preserve a substantial or even larger proportion of the protective warfarin effect on stroke and all cause mortality. Edoxaban 30 mg is associated with a definitely lower risk of major bleedings than other NOACs. This is counterbalanced by a lower efficacy in the prevention of thromboembolism, although with a final benefit on all-cause mortality. PMID- 24955576 TI - Combining neuroprotectants in a model of retinal degeneration: no additive benefit. AB - The central nervous system undergoing degeneration can be stabilized, and in some models can be restored to function, by neuroprotective treatments. Photobiomodulation (PBM) and dietary saffron are distinctive as neuroprotectants in that they upregulate protective mechanisms, without causing measurable tissue damage. This study reports a first attempt to combine the actions of PBM and saffron. Our working hypothesis was that the actions of PBM and saffron in protecting retinal photoreceptors, in a rat light damage model, would be additive. Results confirmed the neuroprotective potential of each used separately, but gave no evidence that their effects are additive. Detailed analysis suggests that there is actually a negative interaction between PBM and saffron when given simultaneously, with a consequent reduction of the neuroprotection. Specific testing will be required to understand the mechanisms involved and to establish whether there is clinical potential in combining neuroprotectants, to improve the quality of life of people affected by retinal pathology, such as age-related macular degeneration, the major cause of blindness and visual impairment in older adults. PMID- 24955577 TI - The value of a BP determination method using a novel non-invasive BP device against the invasive catheter measurement. AB - OBJECTIVE: The aim of this study was to evaluate the accuracy of a new blood pressure (BP) measurement method (Pulse method). METHODS: This study enrolled 45 patients for selective percutaneous coronary intervention (PCI) via right radial artery. A BP device using either oscillometric (Microlife 3AC1-1) or Pulse method(RG-BP11)was used. At the beginning of each PCI, intra-radial BP was measured before Microlife BP or Pulse BP measurement as its own reference, respectively. At the end of PCI, BP was measured again with the measurement order of Microlife BP and Pulse BP reversed. The differences between intra-radial and Microlife (BPi-M) or Pulse BP (BPi-P) on SBP, DBP and mean artery pressure (MAP) were calculated. Meanwhile, in 48 patients the intra-brachial BP and intra-radial artery BP were measured to calculate the brachial -radial BP difference (BPr-b). RESULTS: The intra-radial SBP references used prior to both the Microlife and Pulse SBP that were similar (145.1+/-27.7 vs 145.8+/-24.2 mmHg), but the Microlife SBP was significantly lower than the Pulse SBP (127.7+/-20.5 vs 130.3+/ 22.7 mmHg, P<0.05), thus the SBPi-M was higher than SBPi-P (18.1+/-11.8 vs 14.8+/ 12.8 mmHg, P<0.05). As the mean SBPr-b was 12.4 mmHg, the Pulse SBP was closer to expected intra-brachial SBP by about 3.3 mmHg than was Microlife SBP to expected intra-brachial SBP. Meanwhile, Bland-Altman plots showed that the 95% limits of agreement for intra-radial SBP by Pulse SBP were narrower than those by Microlife SBP (12.0~17.5 vs 15.5~20.6 mmHg). However, the 95% limits of agreement for Pulse DBP and MAP were similar to those for Microlife DBP and MAP. CONCLUSION: Against the invasive BP measurement, the pulse method may provide more accurate SBP and comparable DBP and MAP as compared with the oscillometric method. PMID- 24955575 TI - Development of a novel inhalational model of invasive pulmonary aspergillosis in rats and comparative evaluation of three biomarkers for its diagnosis. AB - Aspergillus fumigatus, a thermotolerant fungus, is the main causative agent of invasive pulmonary aspergillosis (IPA) in immunocompromised patients that is associated with high mortality rates. Early diagnosis of IPA is crucial for mortality reduction and improved prognosis. An experimental inhalational model of IPA was developed in rats and the efficacy of three biomarkers, namely beta-D glucan (BDG), a panfungal marker, galactomannan (GM), a genus-specific marker, and A. fumigatus DNA, a species-specific marker was evaluated in serum and bronchoalveolar lavage (BAL) specimens at different time points postinfection for early diagnosis of IPA. BDG and GM were detected by using commercial Fungitell and Platelia Aspergillus EIA kits, respectively. A. fumigatus DNA was detected by developing a sensitive, single-step PCR assay. IPA was successfully developed in immunosuppressed rats and all animals until 5 days post-infection were positive for A. fumigatus by culture and KOH-calcofluor microscopy also showed A. fumigatus in 19 of 24 (79%) lung tissue samples. Fourteen of 30 (47%) and 27 of 30 (90%) serum and BAL specimens, respectively, were positive for all three biomarkers with 100% specificity (none of sera or BAL specimens of 12 control rats was positive for biomarkers). Our data show that BAL is a superior specimen than serum and combined detection of BDG, GM and A. fumigatus DNA provide a sensitive diagnosis of IPA in an experimental animal model. Moreover, combined detection of GM and DNA in BAL and detection of either GM or DNA in serum was also positive in 27 of 30 (90%) animals. For economic reasons and considering that the positive predictive value of BDG is low, the detection of GM and/or DNA in serum and BAL samples has the potential to serve as an integral component of the diagnostic-driven strategy in high-risk patients suspected for IPA. PMID- 24955574 TI - (-)-Phenserine attenuates soman-induced neuropathology. AB - Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-) Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1 expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy. PMID- 24955578 TI - Liver dysfunction assessed by model for end-stage liver disease excluding INR (MELD-XI) scoring system predicts adverse prognosis in heart failure. AB - AIMS: Liver dysfunction due to heart failure (HF) is often referred to as cardiac or congestive hepatopathy. The composite Model for End-Stage Liver Disease excluding INR (MELD-XI) is a robust scoring system of liver function, and a high score is associated with poor prognosis in advanced HF patients with a heart transplantation and/or ventricular assist device. However, the impact of MELD-XI on the prognosis of HF patients in general remains unclear. METHODS AND RESULTS: We retrospectively analyzed 562 patients who were admitted to our hospital for the treatment of decompensated HF. A MELD-XI score was graded, and patients were divided into two groups based on the median value of MELD-XI score: Group L (MELD XI <10, n = 289) and Group H (MELD-XI >=10, n = 273). We compared all-cause mortality and echocardiographic findings between the two groups. In the follow-up period (mean 471 days), 104 deaths (62 cardiac deaths and 42 non-cardiac deaths) were observed. The event (cardiac death, non-cardiac death, all-cause death)-free rate was significantly higher in group L than in group H (logrank P<0.05, respectively). In the Cox proportional hazard analysis, a high MELD-XI score was found to be an independent predictor of cardiac deaths and all-cause mortality in HF patients. Regarding echocardiographic parameters, right atrial and ventricular areas, inferior vena cava diameter, and systolic pulmonary artery pressure were higher in group H than in group L (P<0.05, respectively). CONCLUSIONS: The MELD XI scoring system, a marker of liver function, can identify high-risk patients with right heart volume overload, higher pulmonary arterial pressure and multiple organ failure associated with HF. PMID- 24955581 TI - Identification of CD24 as a cancer stem cell marker in human nasopharyngeal carcinoma. AB - Cancer stem cells (CSCs) represent a unique sub-population of tumor cells with the ability to initiate tumor growth and sustain self-renewal. Although CSC biomarkers have been described for various tumors, only a few markers have been identified for nasopharyngeal carcinoma (NPC). In this study, we show that CD24+ cells isolated from human NPC cell lines express stem cell genes (Sox2, Oct4, Nanog, Bmi-1, and Rex-1), and show activation of the Wnt/beta-catenin signaling pathway. CD24+ cells possess typical CSC characteristics that include enhanced cell proliferation, increased colony and sphere formation, maintenance of cell differentiation potential in prolonged culture, and enhanced resistance to chemotherapeutic drugs. Notably, CD24+ cells produce tumors following inoculation of as few as 500 cells in immunodeficient NOD/SCID mice. CD24+ cells further show increased invasion ability in vitro, which correlates with enhanced expression of matrix metalloproteinase 2 and 9. In summary, our results suggest that CD24 represents a novel CSC biomarker in NPC. PMID- 24955582 TI - The study of the intercellular trafficking of the fusion proteins of herpes simplex virus protein VP22. AB - BACKGROUND: Genetic modifications can improve the therapeutic efficacy of mesenchymal stem cell (MSC) transplantation in myocardial infarction. However, so far, the efficiency of MSC modification is very low. Seeking for a more efficient way of MSC modification, we investigated the possibility of employing the intercellular trafficking capacity of the herpes simplex virus type-1 tegument protein VP22 on the enhancement of MSC modification. METHODS: Plasmids pVP22-myc, pVP22-EGFP, pEGFP-VP22, pVP22-hBcl-xL and phBcl-xL-VP22 were constructed for the expressions of the myc-tagged VP22 and the fusion proteins VP22-EGFP, EGFP-VP22, VP22-hBcl-xL and hBcl-xL-VP22. MSCs were isolated from rat bone marrow and the surface markers were identified by Flowcytometry. COS-1 cells were transfected with the above plasmids and co-cultured with untransfected MSCs, the intercellular transportations of the constructed proteins were studied by immunofluorescence. The solubility of VP22-hBcl-xL and hBcl-xL-VP22 was analyzed by Western blot. RESULTS: VP22-myc could be expressed in and spread between COS-1 cells, which indicates the validity of our VP22 expression construct. Flowcytometry analysis revealed that the isolated MSCs were CD29, CD44, and CD90 positive and were negative for the hematopoietic markers, CD34 and CD45. The co culturing and immunofluorescence assay showed that VP22-myc, VP22-EGFP and EGFP VP22 could traffic between COS-1 cells and MSCs, while the evidence of intercellular transportation of VP22-hBcl-xL and hBcl-xL-VP22 was not detected. Western blot analysis showed that VP22-hBcl-xL and hBcl-xL-VP22 were both insoluble in the cell lysate suggesting interactions of the fusion proteins with other cellular components. CONCLUSIONS: The intercellular trafficking of VP22 myc, VP22-EGFP and EGFP-VP22 between COS-1 cells and MSCs presents an intriguing prospect in the therapeutic application of VP22 as a delivery vehicle which enhances genetic modifications of MSCs. However, VP22-hBcl-xL and hBcl-xL-VP22 failed to spread between cells, which are due to the insolubility of the fusion protein incurred by interactions with other cellular components. PMID- 24955583 TI - Trends in prevalence of dyslipidaemias and the risk of mortality in Lithuanian urban population aged 45-64 in relation to the presence of the dyslipidaemias and the other cardiovascular risk factors. AB - The aim of this study was to provide reliable information on dyslipidaemias, to estimate the trend of the prevalence of dyslipidaemias and other selected cardiovascular disease (CVD) risk factors at population level, and to evaluate the risk of all-cause and CVD mortality in relation to presence of mixed dyslipidaemias and other CVD risk factors. METHODS: Data from the five surveys (1983-2008) are presented. A random sample of 9,209 subjects aged 45-64 was selected for statistical analysis. During follow-up there were 1653 death cases from any cause, 864 deaths from CVD. Estimates of hazard ratios (HR) and 95% confidence intervals (CI) were based on the multivariate Cox proportional hazards regression for all-cause mortality and CVD mortality. RESULTS: During 25 year period the prevalence of normal total cholesterol level (<5.2 mmol/L) significantly increased only in women; triglycerides and high density lipoprotein (HDL) cholesterol did not change in men and women. Findings in our longitudinal study showed that in men and women mixed dyslipidaemias (HDL cholesterol <1.03 mmol/L plus triglycerides >=1.70 mmol/L) significantly increased the risk for all cause and CVD mortality (respectively in men HR = 1.30; HR = 1.15, in women HR = 1.83; HR = 2.13). These mixed dyslipidaemia combinations combination with the other risk factors such as arterial hypertension, high fasting glucose level increased all-cause and CVD mortality risk in men and women; while, these mixed dyslipidaemias plus smoking increased all-cause and CVD mortality risk only in men compared to never smokers without these dyslipidaemias (respectively HR = 1.89; HR = 1.92); and these dyslipidaemias plus obesity increased all-cause and CVD mortality risk in women (respectively HR = 2.25; HR = 2.39) and CVD mortality risk in men (HR = 1.72), as compared to responders without obesity and these dyslipidaemias. CONCLUSION: Mixed dyslipidaemias (reduced HDL cholesterol plus elevated triglycerides) significantly increased the risk for all-cause and CVD mortality in this Lithuanian population aged 45-64 years. PMID- 24955584 TI - No sustained attention differences in a longitudinal randomized trial comparing mindfulness based stress reduction versus active control. AB - BACKGROUND: Mindfulness Based Stress Reduction (MBSR) is a secular form of meditation training. The vast majority of the extant literature investigating the health effects of mindfulness interventions relies on wait-list control comparisons. Previous studies have found that meditation training over several months is associated with improvements in cognitive control and attention. METHODOLOGY/PRINCIPAL FINDINGS: We used a visual continuous performance task (CPT) to test the effects of eight weeks of mindfulness training on sustained attention by comparing MBSR to the Health Enhancement Program (HEP), a structurally equivalent, active control condition in a randomized, longitudinal design (ClinicalTrials.gov, NCT01301105) focusing on a non-clinical population typical of MBSR participants. Researchers were blind to group assignment. 63 community participants were randomized to either MBSR (n = 31) or HEP (n = 32). CPT analyses were conducted on 29 MBSR participants and 25 HEP participants. We predicted that MBSR would improve visual discrimination ability and sustained attention over time on the CPT compared to HEP, with more home practice associated with greater improvements. Our hypotheses were not confirmed but we did find some evidence for improved visual discrimination similar to effects in partial replication of other research. Our study had sufficient power to demonstrate that intervention groups do not differ in their improvement over time in sustained attention performance. One of our primary predictions concerning the effects of intervention on attentional fatigue was significant but not interpretable. CONCLUSIONS: Attentional sensitivity is not affected by mindfulness practice as taught in MBSR, but it is unclear whether mindfulness might positively affect another aspect of attention, vigilance. These results also highlight the relevant procedural modifications required by future research to correctly investigate the role of sustained attention in similar samples. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01301105. PMID- 24955585 TI - A large cohort study concerning age-dependent impacts of anthropometric variables on spirometric parameters in nonsmoking healthy adults. AB - BACKGROUNDS: Although height (H) has been considered the principal anthropometric variable governing lung function, the age-dependent differences in its influences on determining spirometric parameters (SPs) have not been conclusively investigated. Moreover, there has been no study centered on age-dependent effects of other anthropometric variables, including body weight (BW) and body fat mass (BFM) on SPs. In addition, the age-dependent influences of these anthropometric variables are anticipated to differ quantitatively between male and female participants. METHODS: A total of 16,919 nonsmoking healthy Japanese adults (men: 6,116, women: 10,803) were partitioned into six groups stratified by gender and age at intervals of 20-years: young-, middle-, and advanced-age groups of either gender. Using a model in which a SP was described by a logarithmic additive function of age, H, BW, and BFM, we determined the partial regression coefficients of the respective anthropometric variables to predict the reference means of SPs, including FVC, FEV1, FEV1/FVC, PEF, FEF50, and FEF75, in the six groups. RESULTS/DISCUSSION: Although the impact of H on FVC and FEV1 was relatively homogeneous irrespective of gender and age, its homogeneity faded for flow parameters, particularly in the female middle- and advanced-age groups, indicating that the age-dependent contribution of H to SPs was enhanced more in women. The impact of BW on SPs differed depending on age, and this effect was also more conspicuous for female participants. H and BW generally exerted positive effects on SPs, whereas BFM had negative effects. Opposite effects of BW and BFM were observed in the female middle-age group in particular. CONCLUSIONS: The effects of anthropometric variables on spirometric parameters are highly age dependent, particularly in women, leading to the conclusion that the assumption of age-independent, constant partial regression coefficients of anthropometric variables while predicting the reference mean of a certain spirometric parameter may result in substantial errors. PMID- 24955586 TI - Higher maternal protectiveness is associated with higher odds of child overweight and obesity: a longitudinal Australian study. AB - In recent years there has been an increasing interest in overprotective parenting and the potential role it plays in child development. While some have argued that a trend towards increased parental fear and reduced opportunity for independent mobility may be linked to increasing rates of child overweight and obesity, there is limited empirical information available to support this claim. Using data from the Longitudinal Study of Australian Children, this study aimed to examine the longitudinal relationships between maternal protectiveness and child overweight and obesity. A cohort of 4-5 year old children was followed up at 6-7, 8-9 and 10 11 years of age (n = 2596). Measures included a protective parenting scale administered when children were 6-7 and 8-9 years of age, child body mass index (BMI), family characteristics including household income, neighbourhood disadvantage, child's position amongst siblings, and maternal BMI, education, employment, mental health and age at first birth. International Obesity Taskforce age- and sex-specific BMI cut points were used to determine if children were in the normal, overweight or obese BMI range. There was no association between maternal protectiveness and the odds of children being overweight or obese at age 4-5, 6-7 or 8-9 years. However at age 10-11 years, a 1 standard deviation increase in maternal protectiveness was associated with a 13% increase in the odds of children being overweight or obese. The results provide evidence of a relationship between maternal protectiveness and child overweight and obesity, however further research is required to understand the mechanism(s) that links the two concepts. PMID- 24955588 TI - Continuous milking of dairy cows disrupts timing of peak IgG concentration appearance in mammary secretions. AB - The length of the dry period in commercial dairy production is under close scrutiny. While the main concern is the composition and volume of milk produced, the evaluation of colostrum quality under these new paradigms has suggested a decline in IgG concentrations, while some reports indicate no change. Colostrum quality has been defined as an adequate concentration (>50 mg/ml) of immunoglobulin in the secretions to provide the newborn with maximal disease resistance. We investigated the appearance of IgG in mammary pre- and post partum secretions in cows without a dry period (continuously milked, Dry0) and compared the secretions with cows that experienced a dry period of 60 d (Dry60). Blood was collected during the experimental period and plasma analysed for progesterone (P4) and prolactin (Prl). Approximately -6 d relative to parturition, the Dry0 animals exhibited increased concentration of IgG in their secretions to an average of ~35 mg/ml that remained rather constant through subsequent pregnancy and following parturition. Dry0 cows were producing an average IgG concentration in parturition colostrum of 44.2+/-17.6 mg/ml that was not different than that of controls (66.86+/-16.8 mg/ml). However, Dry0 cows exhibited high variation, different peak times (day) of IgG concentration including times that occurred both pre and post parturition. IgG mass of the Dry0 cows remained rather constant pre- and post partum and did not show the same declining mass following parturition that was shown for the Dry60 cows. The change in plasma P4 and Prl were shown to have no timing effect on colostrum IgG concentration. PMID- 24955589 TI - Maternal dispositional empathy and electrodermal reactivity: Interactive contributions to maternal sensitivity with toddler-aged children. AB - The present study investigated maternal dispositional empathy and skin conductance level (SCL) reactivity to infant emotional cues as joint predictors of maternal sensitivity. Sixty-four mother-toddler dyads (31 boys) were observed across a series of interaction tasks during a laboratory visit, and maternal sensitivity was coded from approximately 55 minutes of observation per family. In a second, mother-only laboratory visit, maternal SCL reactivity to infant cues was assessed using a cry-laugh audio paradigm. Mothers reported on their dispositional empathy via a questionnaire. As hypothesized, mothers with greater dispositional empathy exhibited more sensitive behavior at low, but not high, levels of SCL reactivity to infant cues. Analyses examining self-reported emotional reactivity to the cry-laugh audio paradigm yielded a similar finding: Dispositional empathy was related to greater sensitivity when mothers reported low, but not high, negative emotional reactivity. Results provide support for Dix's (1991) affective model of parenting that underscores the combined contribution of the parent's empathic tendencies and his or her own emotional experience in response to child emotions. Specificity of the Empathy * Reactivity interaction is discussed with respect to the context in which reactivity was assessed (infant cry vs. laugh) and the type of sensitivity examined (sensitivity to the child's distress vs. nondistress). PMID- 24955590 TI - Adolescents' relationship with God and internalizing adjustment over time: the moderating role of maternal religious coping. AB - A growing literature supports the importance of understanding the link between religiosity and youths' adjustment and development, but in the absence of rigorous, longitudinal designs, questions remain about the direction of effect and the role of family factors. This paper investigates the bidirectional association between adolescents' relationship with God and their internalizing adjustment. Results from 2-wave, SEM cross-lag analyses of data from 667 mother/adolescent dyads in Belfast, Northern Ireland (50% male, M age = 15.75 years old) supports a risk model suggesting that greater internalizing problems predict a weaker relationship with God 1 year later. Significant moderation analyses suggest that a stronger relationship with God predicted fewer depression and anxiety symptoms for youth whose mothers used more religious coping. PMID- 24955592 TI - Sharing a driver's context with a caller via continuous audio cues to increase awareness about driver state. AB - In an experiment using a driving simulator we investigated whether sharing information of a driver's context with a remote caller via continuous audio cues can make callers more aware of the driving situation. Increased awareness could potentially help in making the conversation less distracting. Prior research has shown that although sharing context using video can create such beneficial effects, it also has some practical disadvantages. It is an open question whether other modalities might also provide sufficient context for a caller. In particular, the effects of sharing audio, a cheaper, more salient, and perhaps more practical alternative than video, are not well understood. We investigated sharing context using direct cues in the form of realistic driving sounds (e.g., car honks, sirens) and indirect cues in the form of elevated heartbeats. Sound sharing affected the caller's perception of the driver's busyness. However, this had at most a modest effect on conversation and driving performance. An implication of these results is that although sharing sounds can increase a caller's awareness of changes in the driver's busyness, they need more training or information on how to leverage such context information to reduce disruption to driving. Limitations and implications are discussed. PMID- 24955591 TI - Sanctification of marriage and spiritual intimacy predicting observed marital interactions across the transition to parenthood. AB - We examined whether 164 heterosexual, married couples' reports of the sanctification of their marriage and their spiritual intimacy predicted their observed behavior across the transition to parenthood, using highly conservative statistical strategies to control for time-invariant factors and time-varying factors (marital love, collaborative communication skills) that could explain away these links. Spouses provided self-reports of marital sanctification and love, and joint reports of spiritual intimacy and collaboration by each partner. Criterion variables were positive and negative behaviors that spouses exhibited during dyadic discussions of marital conflicts, videotaped during pregnancy and when the couple's first infant was 3, 6, and 12 months old. Using bivariate fixed effects regression models to control unmeasured time-invariant predictors (e.g., stable traits), his and her sanctification of marriage predicted more observed positivity by 1 or both spouses, and his and her spiritual intimacy predicted more positivity and less negativity by both spouses. Using multivariate regression analyses that controlled for demographic factors, the interdependency of spouses' responses, and salient time-varying marital (spouses' love and collaborative skills), her spiritual intimacy predicted more positivity by both spouses and less negativity by him, and his sanctification marginally predicted more positivity and less negativity by him. Findings offer rigorous causal modeling that spousal reports about marital spirituality influence observed spousal behavior by using longitudinal data to rule out unmeasured and measured third-variable confounds, multiple reporters (husbands, wives), multiple methods (self and joint reports, direct observation), and cross-informant data (spousal reports about him predicting her behavior, and vice versa). PMID- 24955593 TI - The value of cough peak flow in the assessment of cough efficacy in neuromuscular patients. A cross sectional study. AB - BACKGROUND: Cough efficacy assessment is of clinical relevance in neuromuscular patients. Tests of varying complexity and invasiveness, such as cough peak flow (CPF), maximal expiratory pressure (PEmax) and gastric pressure during cough (Cough Pgas) are routinely available. AIM: To assess the value of CPF, PEmax and Cough Pgas in the detection of ineffective cough in patients suffering from neuromuscular diseases. DESIGN: Prospective observational study. SETTING: Outpatient laboratory for respiratory muscle function assessment. POPULATION: Forty-nine patients with neuromuscular diseases (25 F, age 50 +/- 15 years). METHODS: Each patient performed spirometry, CPF, PEmax, Cough Pgas and maximal inspiratory pressure (PImax). Normal values for each test were determined from published and in-house lab data. RESULTS: In all patients, vital capacity ranged from 46 to 119% of pred. Twenty seven percent of patients resulted under the lower normal limit of CPF and this percentage was significantly lower as compared to that of PEmax and Cough Pgas (51% and 53% respectively, P=0.013). Combining all three tests, the percentage of patients resulting below normal was 22% (P=0.638, as compared to CPF results alone). Additionally, CPF correlated significantly with PImax, PEmax, and Cough Pgas (P<0.01 for each correlation) and by multiple regression analysis PImax and PEmax contributed 65% of CPF variance. CONCLUSION: Our study shows that in neuromuscular patients, PEmax and Cough Pgas values may overdiagnose an ineffective cough. CPF, a non invasive and easy to perform test, is a global measure of voluntary cough. CLINICAL REHABILITATION SETTING:CPF may be relevant in the routine evaluation of patients with neuromuscular diseases, both in research and in rehabilitation settings. PMID- 24955594 TI - Race, discrimination, and cardiovascular disease. PMID- 24955595 TI - Mention of a patient's "race" in clinical presentations. PMID- 24955596 TI - Incorporating genetic testing ancestry results into medical decisions. PMID- 24955597 TI - The prejudiced patient. PMID- 24955598 TI - Exploring matters of race through dialogue in the University of Michigan Medical School's longitudinal case studies program. PMID- 24955599 TI - Complex systems for a complex issue: race in health research. PMID- 24955600 TI - The racially unequal impact of the US organ procurement system. PMID- 24955602 TI - Race: a starting place. PMID- 24955601 TI - Minority-group recruitment goals in federally funded clinical research: what's in a number? PMID- 24955603 TI - The American Medical Association and race. PMID- 24955605 TI - Questioning the rationale for affirmative action. PMID- 24955604 TI - In defense of affirmative action--by any means necessary. PMID- 24955607 TI - The clinical nanomedicine handbook. PMID- 24955606 TI - Carmustine induces platelet apoptosis. AB - Carmustine is one of the alkylating chemotherapeutic agents, which are used to treat various types of cancers, such as brain tumors, Hodgkins and non-Hodgkins lymphoma and multiple myeloma. However, carmustine has the side effect of thrombocytopenia, and the mechanism is not completely understood. In this study, we show that carmustine dose-dependently induced depolarization of mitochondrial inner transmembrane potential (DeltaPsim), up-regulation of Bax, down-regulation of Bcl-2 and caspase-3 activation. Carmustine did not induce surface expression of P-selectin or PAC-1 binding, whereas, obviously reduced collagen and thrombin induced platelet aggregation. Dicumarol, c-Jun NH2-terminal kinase-specific inhibitor, reduced carmustine-induced DeltaPsim depolarization in platelets. The numbers of circulating platelets were reduced, and the tail bleeding time was significantly increased in mice that were injected with carmustine. Taken together, these data indicate that carmustine induced platelet apoptosis, suggesting the possible pathogenesis of thrombocytopenia in patients treated with carmustine. PMID- 24955609 TI - Maternal prepregnancy BMI, offspring's early postnatal growth, and metabolic profile at age 5-6 years: the ABCD Study. AB - CONTEXT: Maternal prepregnancy body mass index (pBMI) and offspring's accelerated postnatal growth have adverse consequences for later cardiometabolic health, but it is unknown how these two factors interact. OBJECTIVE: To assess the association between maternal pBMI and offspring's metabolic profile at age 5-6 years and determine the role (independent/mediating/moderating) of offspring's postnatal growth in this association. DESIGN/PARTICIPANTS: In total, 1459 mother child pairs from the prospective ABCD study with known maternal pBMI, offspring postnatal growth (weight and weight-for-length gain) between age 1-3 months (Delta SD score). MAIN OUTCOME MEASURES: We analyzed metabolic components of offspring at age 5-6 years, including waist-to-height-ratio (WHtR), systolic/diastolic blood pressure (SBP/DBP), fasting glucose, triglycerides, and high-density lipoprotein-cholesterol values, both individually (Z-scores) and combined (sum Z-scores; metabolic score). RESULTS: Maternal pBMI was positively associated with offspring's WHtR (beta = 0.025; 95% confidence interval [CI], 0.010-0.039), SBP (beta = 0.020; 95% CI, 0.005-0.0035), DBP (beta = 0.016; 95% CI, 0.000-0.031), and metabolic score (beta = 0.078; 95% CI, 0.039-0.118) after adjusting. Adding postnatal growth had no relevant impact on these effect sizes. Postnatal weight gain was independently associated with WHtR (beta = 0.199; 95% CI, 0.097-0.300), fasting glucose values (beta = 0.117; 95% CI, 0.008-0.227), metabolic score (beta = 0.405; 95% CI, 0.128-0.682). Postnatal weight-for-length gain was independently associated with WHtR (beta = 0.145; 95% CI, 0.080-0.211), and metabolic score (beta = 0.301; 95% CI, 0.125-0.477). An interaction between maternal pBMI and postnatal weight gain was present in the association with SBP (P = .021) and metabolic score (P = .047), and between maternal pBMI and postnatal weight-for-length gain in the association with triglycerides (P = .022) and metabolic score (P = .042). CONCLUSIONS: Both high maternal pBMI and postnatal accelerated growth are associated with adverse metabolic components in early childhood. No evidence was found for a mediating role of postnatal growth. The combination of high maternal pBMI and postnatal accelerated growth amplified individual effects. PMID- 24955610 TI - Effect of fat loss on arterial elasticity in obese adolescents with clinical insulin resistance: RESIST study. AB - CONTEXT: Reduced arterial elasticity contributes to an obesity-related increase in cardiovascular risk in adults. OBJECTIVE: To evaluate the effect of fat loss on arterial elasticity in obese adolescents at risk of type 2 diabetes. DESIGN: A secondary data analysis of the RESIST study was performed in two hospitals in Sydney, Australia. PARTICIPANTS: The study included 56 subjects (ages, 10 to 17 y; 25 males) with prediabetes and/or clinical features of insulin resistance. INTERVENTION: A 12-month lifestyle plus metformin intervention. OUTCOMES: Arterial elasticity and systemic vascular resistance were measured using radial tonometry pulse contour analysis, percentage body fat (%BF) was measured by dual energy x-ray absorptiometry, and insulin sensitivity index was derived from an oral glucose tolerance test and lipids. RESULTS: Adolescents (n = 31) with decreased %BF (mean change [range], -4.4% [-18.3 to -0.01%]) after the intervention had significant increases in the mean large arterial elasticity index (mean change [95%CI], 5.1 [1.9 to 8.2] mL/mm Hg * 10; P = .003) and insulin sensitivity index (0.5 [0.1 to 0.9]; P = .010) and a decrease in systemic vascular resistance (-82 [-129 to -35] dyne * s * cm(-5); P = .001). There were no significant changes in these parameters in adolescents who increased their %BF. Nor was there any significant change in the mean small arterial elasticity index in either group. CONCLUSION: Long-term follow-up of these adolescents is warranted to assess whether the observed changes in vascular elasticity will lead to a clinical benefit including reduced cardiovascular morbidity and mortality. PMID- 24955608 TI - Adipose tissue 12/15 lipoxygenase pathway in human obesity and diabetes. AB - CONTEXT: Visceral adipose tissue (VAT) is a key contributor to chronic inflammation in obesity. The 12/15-lipoxygenase pathway (ALOX) is present in adipose tissue (AT) and leads to inflammatory cascades that are causal for the onset of insulin resistance in rodent models of obesity. OBJECTIVE: The pathophysiology of the ALOX 12/15 pathway in human AT is unknown. We characterized the ALOX pathway in different AT depots in obese humans with or without type 2 diabetes (T2D). DESIGN: This study includes a cross-sectional cohort of 46 morbidly obese (body mass index >39 kg/m(2)) nondiabetic (n = 25) and T2D (n = 21) subjects. SETTING: This study was conducted at Eastern Virginia Medical School (Norfolk, Virginia) in collaboration with Sentara Metabolic and Weight Loss Surgery Center (Sentara Medical Group, Norfolk, Virginia). PATIENTS: Twenty-five obese (body mass index 44.8 +/- 4.4 kg/m(2)) nondiabetic (hemoglobin A1c 5.83% +/- 0.27%) and 21 obese (43.4 +/- 4.1 kg/m(2)) and T2D (hemoglobin A1c 7.66% +/- 1.22%) subjects were included in the study. The subjects were age matched and both groups had a bias toward female gender. MAIN OUTCOMES AND MEASURES: Expression of ALOX isoforms along with fatty acid substrates and downstream lipid metabolites were measured. Correlations with depot-specific inflammatory markers were also established. RESULTS: ALOX 12 expression and its metabolite 12(S)-hydroxyeicosatetraenoic acid were significantly increased in the VAT of T2D subjects. ALOX 15A was exclusively expressed in VAT in both groups. ALOX 12 expression positively correlated with expression of inflammatory genes IL 6, IL-12a, CXCL10, and lipocalin-2. CONCLUSIONS: ALOX 12 may have a critical role in regulation of inflammation in VAT in obesity and T2D. Selective ALOX 12 inhibitors may constitute a new approach to limit AT inflammation in human obesity. PMID- 24955611 TI - Dual-energy X-ray absorptiometry is a valid method to estimate visceral adipose tissue in adult patients with Prader-Willi syndrome during treatment with growth hormone. AB - CONTEXT: Visceral adipose tissue (VAT) is established as a risk factor for type 2 diabetes and cardiovascular disease, but the radiation exposure and cost of computed tomography (CT) measurements limits its daily clinical use. OBJECTIVE: The main objective of this study was to compare the degree of agreement between VAT measurements by a new dual-energy X-ray absorptiometry (DXA) application and one of the standard methods, CT, in a population of patients with Prader-Willi syndrome (PWS) before and after GH treatment. Furthermore, we tested whether VAT estimations by these two methods are equivalent in assessing the metabolic risk in this population. DESIGN AND PATIENTS: Data from the Norwegian population of a multicenter study in adults with genetically proven PWS were used. Subjects with complete anthropometry, biochemical, and imagistic measurements at all study visits (baseline and after 12 and 24 months of GH treatment) (n = 14, six men) were included. VAT was quantified both using CT scans (GE Lightspeed 16 Pro) of the abdomen at L2-L3 level and a total body DXA scan (GE Healthcare Lunar Prodigy). RESULTS: VAT DXA was strongly associated with VAT CT at baseline (r = 0.97) and after 12 (r = 0.90) and 24 months (r = 0.89) of GH treatment (all P < .001). We found moderate to strong positive correlations between VAT by both methods, and blood pressure, weight, body mass index, waist circumference, glucose metabolism, and other fat depots (arms, legs, android, trunk, total body) but no association with age, gender, blood lipids, and IGF-I. Adiponectin was negatively associated with the amount of VAT. At baseline, the highest correlation with homeostasis model assessment of insulin resistance (HOMA-IR) was found for VAT DXA (r = 0.76, P = .001) and VAT CT (r = 0.75, P = .002), respectively. CONCLUSION: VAT can be accurately estimated by DXA, in patients with PWS, and might contribute to the assessment of the metabolic risk. PMID- 24955612 TI - Supplements: To take or not to take? That is the question. PMID- 24955614 TI - Brief report: Neurocognitive functioning in adolescents following childhood maltreatment and evidence for underlying planning & organizational deficits. AB - Children and adolescents with a history of childhood maltreatment are at risk for a host of psychiatric conditions, although the underlying neurocognitive functioning of these individuals remains largely understudied. This study examined the neurocognitive functioning of childhood maltreatment victims in an adolescent psychiatric inpatient setting. The sample consisted of adolescent inpatients (ages 13-19) that completed intellectual testing as part of a neuropsychological/psychological assessment during hospitalization (n = 39). The sample was grouped based on childhood maltreatment history with one group categorized by maltreatment history (n = 15) and the other group characterized by no maltreatment history (n = 24). Analyses revealed statistically significant differences (p < .01) between maltreatment groups on the majority of assessed domains. When controlling for intelligence, only performance differences on the RCFT remained. RCFT differences remained after controlling for the influence of visual-motor and visual-perceptual/visual-spatial functioning, highlighting the influence of organizational and planning difficulties in those individuals with maltreatment history. Group differences in the frequency of impaired performance for neuropsychological tasks were largest (p < .001) for FSIQ and RCFT. Compromised neurocognitive functioning may negatively contribute to the clinical presentation of this population, highlighting the importance of the child neuropsychologist in the effective treatment of children and adolescents with a history of childhood maltreatment. PMID- 24955615 TI - A medusa-like beta-cyclodextrin with 1-methyl-2-(2'-carboxyethyl) maleic anhydrides, a potential carrier for pH-sensitive drug delivery. AB - We developed a new pH-sensitive drug delivery carrier based on beta-cyclodextrin (beta-CD) and 1-methyl-2-(2'-carboxyethyl) maleic anhydrides (MCM). The primary hydroxyl groups of beta-CD were successfully attached to MCM residues to produce a medusa-like beta-CD-MCM. The MCM residue was conjugated with cephradine (CP) with high efficiency ( > 90%). More importantly, beta-CD-MCM-CP responded to the small pH drop from 7.4 to 5.5 and released greater than 80% of the drugs within 0.5 h at pH 5.5. In addition, the inclusion complex between beta-CD-MCM-CP and the adamantane derivative was formed by simple mixing to show the possibility of introducing multi-functionality. Based on these results, beta-CD-MCM can target weakly acidic tissues or organelles, such as tumours, inflammatory tissues, abscesses or endosomes, and be easily modified with various functional moieties, such as ligands for cell binding or penetration, enabling more efficient and specific drug delivery. PMID- 24955613 TI - Pigmented rice bran and plant sterol combination reduces serum lipids in overweight and obese adults. AB - OBJECTIVE: This study investigated the dietary effect of including pigmented rice bran with or without plant sterols on lipid profiles during energy restriction induced weight loss in overweight and obese adults not taking cholesterol lowering medication. In addition, the study examined the effect of intervention on biomarkers of oxidative stress and inflammation. METHODS: A group of 24 overweight and obese adults (age: 43 +/- 6 years, body mass index 32 +/- 1 kg/m(2), 18 females) were randomized to a 25% calorie-restricted diet containing either pigmented rice bran (RB) or the RB with addition of plant sterols (RB+PS) snack bars for 8 weeks. The individualized nutrient-balanced diet contained ~70% of daily energy needs assessed from indirect calorimetry measured resting energy expenditure (EE) and physical activity-related EE assessed using accelerometry. Anthropometrics, blood pressure, blood lipids, glucose, urinary F2-isoprostanes, C-reactive protein, insulin, and leptin were measured at baseline and after 8 weeks of intervention. RESULTS: Participants lost approximately 4.7 +/- 2.2 kg (p < 0.001). Weight loss was not significant between the RB+PS and RB group (p = 0.056). Changes in body fat corresponded to changes in body weight. Average decrease in total cholesterol was significantly higher in the RB+PS group than in the RB group (difference 36 +/- 25 g/dL vs 7 +/- 16 g/dL; p = 0.044). A similar pattern was observed for the decrease in low-density lipoprotein (LDL) cholesterol (difference 22.3 +/- 25.2 g/dL vs 4.4 +/- 18.9 g/dL; p = 0.062). Changes in systolic blood pressure, serum levels of leptin, and F2-isoprostanes were significant between baseline values and after 8 weeks on the diet in both groups (p < 0.05) but did not differ between the 2 groups. CONCLUSIONS: A nutrient-balanced and energy-restricted diet supplemented with rice bran and plant sterols resulted in a significant decrease in total and LDL cholesterol in overweight and obese adults. PMID- 24955616 TI - Silica-installed redox nanoparticles for novel oral nanotherapeutics - improvement in intestinal delivery with anti-inflammatory effects. AB - Silica nanoparticles were synthesized via a sol-gel method in which tetraethyl orthosilicate was hydrolyzed by the alkaline core of the nitroxide radical containing nanoparticle (RNP). The silica nanoparticles were successively captured in the RNP core to obtain silica/RNP nanocomposite (siRNP). Alternatively, siRNP was prepared using commercially available silica nanoparticles. The amount of elemental Si present in the siRNPs was controlled from 3 wt% to 12 wt%. Notably, the obtained siRNPs were stable in acidic media, whereas the starting RNP disintegrated immediately. Crosslinking of the RNP by the entrapped silica might improve stability of the siRNPs under such acidic conditions. Rebamipide was found to be stably encapsulated in the cores of the prepared siRNPs even under acidic conditions, probably due to the both basic environment of the cores and absorption tendencies of the entrapped silica. Under neutral to alkaline conditions, release of the rebamipide is accelerated, which is probably due to the repulsion between the anionic silica surface and the anionic rebamipide. Rebamipide-loaded siRNPs (rebamipide@siRNP) were orally administered to mice, and the plasma level of rebamipide was checked at predetermined time intervals, showing a significantly higher uptake of rebamipide in the plasma when compared to orally-administered free rebamipide. Because siRNP possesses nitroxide radicals in the core, it is confirmed that dextran sodium sulfate-induced colon inflammation was effectively suppressed by the oral administration of rebamipide@siRNP in mice. PMID- 24955617 TI - The effects of dendrimer size and central metal ions on photosensitizing properties of dendrimer porphyrins. AB - A series of dendrimer porphyrins (G(n)DP(M); n = generation of dendrimer, n = 1 3; M = coordination metal, M = freebase, Zn, Pt) were prepared and their photosensitizing properties were compared. All G(n)DP(M) exhibited sharp absorption in organic solvents. However, the Soret absorptions of G(n)DP(M)(CO(2)H) in 10 mM phosphate buffer solution (pH = 7.4) are broader than those of G(n)DP(M) in organic solvents, indicating inhomogeneous microenvironments of the focal porphyrin derivatives. All G(3)DP(M)(CO(2)H) successfully formed globular polyion complex micelles that were uniform in size. Under dark conditions, all G(n)DP(M)(CO(2)H) showed negligible cytotoxicity. However, all samples exhibited concentration-dependent photocytotoxicity under light irradiation. In vitro photocytotoxicity as well as singlet oxygen generation revealed that G(3)DP(Zn)(CO(2)H) is the best dendritic PS of the three different dendrimer porphyrin species. PMID- 24955618 TI - Aceclofenac-loaded chondroitin sulfate conjugated SLNs for effective management of osteoarthritis. AB - Abstract Background: In intra-articular drug delivery, there are number of shortcomings such as lymphatic drainage from the synovial cavity, frequent dosing, adverse side effects and patient discomfort in the management of osteoarthritis (OA). PURPOSE: This research work reports the development and characterization of aceclofenac-loaded chondroitin sulfate (CS) conjugated (CS SLN) and unconjugated solid lipid nanoparticles (SLN) for the effective management of OA. METHODS: The SLNs were prepared using modified solvent injection method and coupled with CS. They were further characterized for size and size distribution, zeta potential, surface morphology, % entrapment efficiency and in vitro drug release profile. Anti-inflammatory activity and in vivo performance was also predicted. RESULTS: The particle size of the SLN and CS SLN was found to be 143.4 +/- 0.9 nm and 154.2 +/- 1.1 nm, respectively. SLNs exhibited sustained drug release (SLN, 64.25 +/- 0.75%; CS-SLN, 57.82 +/- 0.62%) in vitro for more than 24 h. In vivo performance studies revealed the highest uptake of SLNs by the knee joint. DISCUSSION: SLNs enhanced accumulation at the knee joint due to specific interactions with CD44, annexin and leptin receptors attributed to CS coupling. CONCLUSION: CS-SLN could be potentially effective vector for the treatment or management of OA. PMID- 24955620 TI - Plantar loading during cutting while wearing a rigid carbon fiber insert. AB - CONTEXT: Stress fractures are one of the most common injuries in sports, accounting for approximately 10% of all overuse injuries. Treatment of fifth metatarsal stress fractures involves both surgical and nonsurgical interventions. Fifth metatarsal stress fractures are difficult to treat because of the risks of delayed union, nonunion, and recurrent injuries. Most of these injuries occur during agility tasks, such as those performed in soccer, basketball, and lacrosse. OBJECTIVE: To examine the effect of a rigid carbon graphite footplate on plantar loading during 2 agility tasks. DESIGN: Crossover study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 19 recreational male athletes with no history of lower extremity injury in the past 6 months and no previous metatarsal stress fractures were tested. MAIN OUTCOME MEASURE(S): Seven 45 degrees side-cut and crossover-cut tasks were completed in a shoe with or without a full-length rigid carbon plate. Testing order between the shoe conditions and the 2 cutting tasks was randomized. Plantar-loading data were recorded using instrumented insoles. Peak pressure, maximum force, force-time integral, and contact area beneath the total foot, the medial and lateral midfoot, and the medial, middle, and lateral forefoot were analyzed. A series of paired t tests was used to examine differences between the footwear conditions (carbon graphite footplate, shod) for both cutting tasks independently (alpha = .05). RESULTS: During the side-cut task, the footplate increased total foot and lateral midfoot peak pressures while decreasing contact area and lateral midfoot force-time integral. During the crossover-cut task, the footplate increased total foot and lateral midfoot peak pressure and lateral forefoot force-time integral while decreasing total and lateral forefoot contact area. CONCLUSIONS: Although a rigid carbon graphite footplate altered some aspects of the plantar-pressure profile during cutting in uninjured participants, it was ineffective in reducing plantar loading beneath the fifth metatarsal. PMID- 24955621 TI - Classification of lower extremity movement patterns based on visual assessment: reliability and correlation with 2-dimensional video analysis. AB - CONTEXT: Abnormal movement patterns have been implicated in lower extremity injury. Reliable, valid, and easily implemented assessment methods are needed to examine existing musculoskeletal disorders and investigate predictive factors for lower extremity injury. OBJECTIVE: To determine the reliability of experienced and novice testers in making visual assessments of lower extremity movement patterns and to characterize the construct validity of the visual assessments. DESIGN: Cross-sectional study. SETTING: University athletic department and research laboratory. PATIENTS OR OTHER PARTICIPANTS: Convenience sample of 30 undergraduate and graduate students who regularly participate in athletics (age = 19.3 +/- 4.5 years). Testers were 2 experienced physical therapists and 1 novice postdoctoral fellow (nonclinician). MAIN OUTCOME MEASURE(S): We took videos of 30 athletes performing the single-legged squat. Three testers observed the videos on 2 occasions and classified the lower extremity movement as dynamic valgus, no change, or dynamic varus. The classification was based on the estimated change in frontal-plane projection angle (FPPA) of the knee from single-legged stance to maximum single-legged squat depth. The actual FPPA change was measured quantitatively. We used percentage agreement and weighted kappa to examine tester reliability and to determine construct validity of the visual assessment. RESULTS: The kappa values for intratester and intertester reliability ranged from 0.75 to 0.90, indicating substantial to excellent reliability. Percentage agreement between the visual assessment and the quantitative FPPA change category was 90%, with a kappa value of 0.85. CONCLUSIONS: Visual assessments were made reliably by experienced and novice testers. Additionally, movement-pattern categories based on visual assessments were in excellent agreement with objective methods to measure FPPA change. Therefore, visual assessments can be used in the clinic to assess movement patterns associated with musculoskeletal disorders and in large epidemiologic studies to assess the association between lower extremity movement patterns and musculoskeletal injury. PMID- 24955623 TI - A generalizability theory study of athletic taping using the Technical Skill Assessment Instrument. AB - CONTEXT: Athletic taping skills are highly valued clinical competencies in the athletic therapy and training profession. The Technical Skill Assessment Instrument (TSAI) has been content validated and tested for intrarater reliability. OBJECTIVE: To test the reliability of the TSAI using a more robust measure of reliability, generalizability theory, and to hypothetically and mathematically project the optimal number of raters and scenarios to reliably measure athletic taping skills in the future. SETTING: Mount Royal University. DESIGN: Observational study. PATIENTS OR OTHER PARTICIPANTS: A total of 29 university students (8 men, 21 women; age = 20.79 +/- 1.59 years) from the Athletic Therapy Program at Mount Royal University. INTERVENTION(S): Participants were allowed 10 minutes per scenario to complete prophylactic taping for a standardized patient presenting with (1) a 4-week-old second-degree ankle sprain and (2) a thumb that had been hyperextended. Two raters judged student performance using the TSAI. MAIN OUTCOME MEASURE(S): Generalizability coefficients were calculated using variance scores for raters, participants, and scenarios. A decision study was calculated to project the optimal number of raters and scenarios to achieve acceptable levels of reliability. Generalizability coefficients were interpreted the same as other reliability coefficients, with 0 indicating no reliability and 1.0 indicating perfect reliability. RESULTS: The result of our study design (2 raters, 1 standardized patient, 2 scenarios) was a generalizability coefficient of 0.67. Decision study projects indicated that 4 scenarios were necessary to reliably measure athletic taping skills. CONCLUSIONS: We found moderate reliability coefficients. Researchers should include more scenarios to reliably measure athletic taping skills. They should also focus on the development of evidence-based practice guidelines and standards of athletic taping and should test those standards using a psychometrically sound instrument, such as the TSAI. PMID- 24955622 TI - Electrolyte and plasma responses after pickle juice, mustard, and deionized water ingestion in dehydrated humans. AB - CONTEXT: Some athletes ingest pickle juice (PJ) or mustard to treat exercise associated muscle cramps (EAMCs). Clinicians warn against this because they are concerned it will exacerbate exercise-induced hypertonicity or cause hyperkalemia. Few researchers have examined plasma responses after PJ or mustard ingestion in dehydrated, exercised individuals. OBJECTIVE: To determine if ingesting PJ, mustard, or deionized water (DIW) while hypohydrated affects plasma sodium (Na(+)) concentration ([Na(+)]p), plasma potassium (K(+)) concentration ([K(+)]p), plasma osmolality (OSMp), or percentage changes in plasma volume or Na(+) content. DESIGN: Crossover study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 9 physically active, nonacclimated individuals (age = 25 +/- 2 years, height = 175.5 +/- 9.0 cm, mass = 78.6 +/- 13.8 kg). INTERVENTION(S): Participants exercised vigorously for 2 hours (temperature = 37 degrees C +/- 1 degrees C, relative humidity = 24% +/- 4%). After a 30-minute rest, a baseline blood sample was collected, and they ingested 1 mL/kg body mass of PJ or DIW. For the mustard trial, participants ingested a mass of mustard containing a similar amount of Na(+) as for the PJ trial. Postingestion blood samples were collected at 5, 15, 30, and 60 minutes. MAIN OUTCOME MEASURE(S): The dependent variables were [Na(+)]p, [K(+)]p, OSMp, and percentage change in plasma Na(+) content and plasma volume. RESULTS: Participants became 2.9% +/- 0.6% hypohydrated and lost 96.8 +/- 27.1 mmol (conventional unit = 96.8 +/- 27.1 mEq) of Na(+), 8.4 +/- 2 mmol (conventional unit = 8.4 +/- 2 mEq) of K(+), and 2.03 +/ 0.44 L of fluid due to exercise-induced sweating. They ingested approximately 79 mL of PJ or DIW or 135.24 +/- 22.8 g of mustard. Despite ingesting approximately 1.5 g of Na(+) in the PJ and mustard trials, no changes occurred within 60 minutes postingestion for [Na(+)]p, [K(+)]p, OSMp, or percentage changes in plasma volume or Na(+) content (P > .05). CONCLUSIONS: Ingesting a small bolus of PJ or large mass of mustard after dehydration did not exacerbate exercise-induced hypertonicity or cause hyperkalemia. Consuming small volumes of PJ or mustard did not fully replenish electrolytes and fluid losses. Additional research on plasma responses pre-ingestion and postingestion to these treatments in individuals experiencing acute EAMCs is needed. PMID- 24955625 TI - Role of total hip replacement arthroplasty between transplantation and acute kidney injury. AB - Osteonecrosis of the femoral head is a severely disabling complication of steroid immunosuppression in renal transplant patients. The increased number of patients undergoing transplantation has increased the number of transplant recipients undergoing total hip replacement arthroplasty (THRA). In this study, we retrospectively assessed patients who underwent THRA from May 2004 to February 2014, and evaluated their demographic and clinical characteristics, the results of peri-operative laboratory tests, the amounts of fluids transfused during surgery, and anesthesia time. Our results found that post-operative acute kidney injury (AKI) was significantly associated with transplantation, and transplantation was an independent factor predictive of post-operative AKI, so transplant recipients are at risk for AKI following THRA. Total hip replacement is a safe and effective treatment for transplant recipients and, in view of their limited life expectancy, should be considered at an early stage in their treatment. PMID- 24955624 TI - Medial tibiofemoral-joint stiffness in males and females across the lifespan. AB - CONTEXT: Analyzing ligament stiffness between males and females at 3 maturational stages across the lifespan may provide insight into whether changes in ligament behavior with aging may contribute to joint laxity. OBJECTIVE: To compare the stiffness of the medial structures of the tibiofemoral joint and the medial collateral ligament to determine if there are differences at 3 distinct ages and between the sexes. DESIGN: Cross-sectional study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 108 healthy and physically active volunteers with no previous knee surgery, no acute knee injury, and no use of exogenous hormones in the past 6 months participated. They were divided into 6 groups based on sex and age (8-10, 18-40, 50-75 years). MAIN OUTCOME MEASURE(S): Ligament stiffness of the tibiofemoral joint was measured with an arthrometer in 0 degrees and 20 degrees of tibiofemoral-joint flexion. The slope values of the force strain line that represents stiffness of the medial tibiofemoral joint at 0 degrees and the medial collateral ligament at 20 degrees of flexion were obtained. RESULTS: When height and mass were controlled, we found a main effect (P < .001) for age group: the 8- to 10-year olds were less stiff than both the 18 to 40- and the 50- to 75-year-old groups. No effects of sex or tibiofemoral joint position on stiffness measures were noted when height and mass were included as covariates. CONCLUSIONS: Prepubescent medial tibiofemoral-joint stiffness was less than postpubescent knee stiffness. Medial tibiofemoral-joint stiffness was related to height and mass after puberty in men and women. PMID- 24955626 TI - Reproducibility of angle metrics using the time-domain anterior segment optical coherence tomography: intra-observer and inter-observer variability. AB - PURPOSE: To evaluate the reproducibility of anterior chamber angle measurements obtained by the Zeiss Visante anterior segment optical coherence tomography (AS OCT). METHODS: Twenty eyes from 20 normal subjects with open anterior chamber angles were studied. The anterior chamber angle was imaged using the Visante AS OCT. The angle-opening distance (AOD 500, AOD 750), trabercular iris space area (TISA 500, TISA 750) and scleral spur angle (SS angle) at the inferior angle location were measured. All the subjects underwent imaging in a darkened room (1 foot candles measured at the eye). Images were graded in a masked fashion by certified Doheny Image Reading Center graders. For intra-grader reproducibility assessments, images were re-graded by the same grader 1 week later after random sorting of images. For inter-grader assessments, a second masked grader independently reviewed the images. Intraclass correlation coefficients (ICC) were used to assess reproducibility. RESULTS: Inferior angle measurements of AOD (500, 750), TISA (500, 750) and SS angle for 20 normal eyes were calculated. The intra observer ICC calculations showed excellent reproducibility for all measurements (AOD 500 = 0.95, AOD 750 = 0.97, TISA 500 = 0.93, TISA 750 = 0.94, SS = 0.96; p < 0.001 for all). The inter-observer ICC calculations showed lower reproducibility for all measurements (AOD 500 = 0.71, p < 0.001; AOD 750 = 0.82, p < 0.001; TISA 500 = 0.49, p = 0.08; TISA 750 = 0.61, p = 0.02; SS = 0.75). CONCLUSION: Determination of anterior chamber angle measurements was possible with the time domain AS-OCT, but only modest inter-observer reproducibility was found even among experienced graders. PMID- 24955627 TI - pH-Sensitive Hydrogel for Micro-Fluidic Valve. AB - The deformation behavior of a pH-sensitive hydrogel micro-fluidic valve system is investigated using inhomogeneous gel deformation theory, in which the fluid structure interaction (FSI) of the gel solid and fluid flow in the pipe is considered. We use a finite element method with a well adopted hydrogel constitutive equation, which is coded in commercial software, ABAQUS, to simulate the hydrogel valve swelling deformation, while FLUENT is adopted to model the fluid flow in the pipe of the hydrogel valve system. The study demonstrates that FSI significantly affects the gel swelling deformed shapes, fluid flow pressure and velocity patterns. FSI has to be considered in the study on fluid flow regulated by hydrogel microfluidic valve. The study provides a more accurate and adoptable model for future design of new pH-sensitive hydrogel valves, and also gives a useful guideline for further studies on hydrogel fluidic applications. PMID- 24955629 TI - Cell attachment to hydrogel-electrospun fiber mat composite materials. AB - Hydrogels, electrospun fiber mats (EFMs), and their composites have been extensively studied for tissue engineering because of their physical and chemical similarity to native biological systems. However, while chemically similar, hydrogels and electrospun fiber mats display very different topographical features. Here, we examine the influence of surface topography and composition of hydrogels, EFMs, and hydrogel-EFM composites on cell behavior. Materials studied were composed of synthetic poly(ethylene glycol) (PEG) and poly(ethylene glycol) poly(epsilon-caprolactone) (PEGPCL) hydrogels and electrospun poly(caprolactone) (PCL) and core/shell PCL/PEGPCL constituent materials. The number of adherent cells and cell circularity were most strongly influenced by the fibrous nature of materials (e.g., topography), whereas cell spreading was more strongly influenced by material composition (e.g., chemistry). These results suggest that cell attachment and proliferation to hydrogel-EFM composites can be tuned by varying these properties to provide important insights for the future design of such composite materials. PMID- 24955628 TI - A Pulsatile Bioreactor for Conditioning of Tissue-Engineered Cardiovascular Constructs under Endoscopic Visualization. AB - Heart valve disease (HVD) is a globally increasing problem and accounts for thousands of deaths yearly. Currently end-stage HVD can only be treated by total valve replacement, however with major drawbacks. To overcome the limitations of conventional substitutes, a new clinical approach based on cell colonization of artificially manufactured heart valves has been developed. Even though this attempt seems promising, a confluent and stable cell layer has not yet been achieved due to the high stresses present in this area of the human heart. This study describes a bioreactor with a new approach to cell conditioning of tissue engineered heart valves. The bioreactor provides a low pulsatile flow that grants the correct opening and closing of the valve without high shear stresses. The flow rate can be regulated allowing a steady and sensitive conditioning process. Furthermore, the correct functioning of the valve can be monitored by endoscope surveillance in real-time. The tubeless and modular design allows an accurate, simple and faultless assembly of the reactor in a laminar flow chamber. It can be concluded that the bioreactor provides a strong tool for dynamic pre-conditioning and monitoring of colonized heart valve prostheses physiologically exposed to shear stress. PMID- 24955630 TI - Silica as a matrix for encapsulating proteins: surface effects on protein structure assessed by circular dichroism spectroscopy. AB - The encapsulation of biomolecules in solid materials that retain the native properties of the molecule is a desired feature for the development of biosensors and biocatalysts. In the current study, protein entrapment in silica-based materials is explored using the sol-gel technique. This work surveys the effects of silica confinement on the structure of several model polypeptides, including apomyoglobin, copper-zinc superoxide dismutase, polyglutamine, polylysine, and type I antifreeze protein. Changes in the secondary structure of each protein following encapsulation are monitored by circular dichroism spectroscopy. In many cases, silica confinement reduces the fraction of properly-folded protein relative to solution, but addition of a secondary solute or modification of the silica surface leads to an increase in structure. Refinement of the glass surface by addition of a monosubstituted alkoxysilane during sol-gel processing is shown to be a valuable tool for testing the effects of surface chemistry on protein structure. Because silica entrapment prevents protein aggregation by isolating individual protein molecules in the pores of the glass material, one may monitor aggregation-prone polypeptides under solvent conditions that are prohibited in solution, as demonstrated with polyglutamine and a disease-related variant of superoxide dismutase. PMID- 24955631 TI - Surface treatment of polymeric materials controlling the adhesion of biomolecules. AB - This review describes different strategies of surface elaboration for a better control of biomolecule adsorption. After a brief description of the fundamental interactions between surfaces and biomolecules, various routes of surface elaboration are presented dealing with the attachment of functional groups mostly thanks to plasma techniques, with the grafting to and from methods, and with the adsorption of surfactants. The grafting of stimuli-responsive polymers is also pointed out. Then, the discussion is focused on the protein adsorption phenomena showing how their interactions with solid surfaces are complex. The adsorption mechanism is proved to be dependent on the solid surface physicochemical properties as well as on the surface and conformation properties of the proteins. Different behaviors are also reported for complex multiple protein solutions. PMID- 24955632 TI - Platelet-rich plasma favors proliferation of canine adipose-derived mesenchymal stem cells in methacrylate-endcapped caprolactone porous scaffold niches. AB - Osteoarticular pathologies very often require an implementation therapy to favor regeneration processes of bone, cartilage and/or tendons. Clinical approaches performed on osteoarticular complications in dogs constitute an ideal model for human clinical translational applications. The adipose-derived mesenchymal stem cells (ASCs) have already been used to accelerate and facilitate the regenerative process. ASCs can be maintained in vitro and they can be differentiated to osteocytes or chondrocytes offering a good tool for cell replacement therapies in human and veterinary medicine. Although ACSs can be easily obtained from adipose tissue, the amplification process is usually performed by a time consuming process of successive passages. In this work, we use canine ASCs obtained by using a Bioreactor device under GMP cell culture conditions that produces a minimum of 30 million cells within 2 weeks. This method provides a rapid and aseptic method for production of sufficient stem cells with potential further use in clinical applications. We show that plasma rich in growth factors (PRGF) treatment positively contributes to viability and proliferation of canine ASCs into caprolactone 2-(methacryloyloxy) ethyl ester (CLMA) scaffolds. This biomaterial does not need additional modifications for cASCs attachment and proliferation. Here we propose a framework based on a combination of approaches that may contribute to increase the therapeutical capability of stem cells by the use of PRGF and compatible biomaterials for bone and connective tissue regeneration. PMID- 24955634 TI - Cell growth on different types of ultrananocrystalline diamond thin films. AB - Unique functional materials provide a platform as scaffolds for cell/tissue regeneration. Investigation of cell-materials' chemical and biological interactions will enable the application of more functional materials in the area of bioengineering, which provides a pathway to the novel treatment for patients who suffer from tissue/organ damage and face the limitation of donation sources. Many studies have been made into tissue/organ regeneration. Development of new substrate materials as platforms for cell/tissue regeneration is a key research area. Studies discussed in this paper focus on the investigation of novel ultrananocrystalline diamond (UNCD) films as substrate/scaffold materials for developmental biology. Specially designed quartz dishes have been coated with different types of UNCD films and cells were subsequently seeded on those films. Results showed the cells' growth on UNCD-coated culture dishes are similar to cell culture dishes with little retardation, indicating that UNCD films have no or little inhibition on cell proliferation and are potentially appealing as substrate/scaffold materials. The mechanisms of cell adhesion on UNCD surfaces are proposed based on the experimental results. The comparisons of cell cultures on diamond-powder-seeded culture dishes and on UNCD-coated dishes with matrix assisted laser desorption/ionization-time-of-flight mass spectroscopy (MALDI-TOF MS) and X-ray photoelectron spectroscopy (XPS) analyses provided valuable data to support the mechanisms proposed to explain the adhesion and proliferation of cells on the surface of the UNCD platform. PMID- 24955635 TI - Development of an Interaction Assay between Single-Stranded Nucleic Acids Trapped with Silica Particles and Fluorescent Compounds. AB - Biopolymers are easily denatured by heating, a change in pH or chemical substances when they are immobilized on a substrate. To prevent denaturation of biopolymers, we developed a method to trap a polynucleotide on a substrate by hydrogen bonding using silica particles with surfaces modified by aminoalkyl chains ([A-AM silane]/SiO2). [A-AM silane]/SiO2 was synthesized by silane coupling reaction of N-2-(aminoethyl)-3-aminopropyltrimethoxysilane (A-AM silane) with SiO2 particles with a diameter of 5 MUm at 100 degrees C for 20 min. The surface chemical structure of [A-AM silane]/SiO2 was characterized by Fourier transform infrared spectroscopy and molecular orbital calculations. The surface of the silica particles was modified with A-AM silane and primary amine groups were formed. [A-AM silane]/SiO2 was trapped with single-stranded nucleic acids [(Poly-X; X = A (adenine), G (guanine) and C (cytosine)] in PBS solution at 37 degrees C for 1 h. The single-stranded nucleic acids were trapped on the surface of the [A-AM silane]/SiO2 by hydrogen bonding to form conjugated materials. The resulting complexes were further conjugated by derivatives of acridine orange (AO) as fluorescent labels under the same conditions to form [AO:Poly-X:A-AM silane]/SiO2 complexes. Changes in the fluorescence intensity of these complexes originating from interactions between the single-stranded nucleic acid and aromatic compounds were also evaluated. The change in intensity displayed the order [AO: Poly-G: A-AM silane]/SiO2 > [AO:Poly-A:A-AM silane]/SiO2 >> [AO:Poly C:A-AM silane]/SiO2. This suggests that the single-stranded nucleic acids conjugated with aminoalkyl chains on the surfaces of SiO2 particles and the change in fluorescence intensity reflected the molecular interaction between AO and the nucleic-acid base in a polynucleotide. PMID- 24955633 TI - Extracellular matrix molecules facilitating vascular biointegration. AB - All vascular implants, including stents, heart valves and graft materials exhibit suboptimal biocompatibility that significantly reduces their clinical efficacy. A range of biomolecules in the subendothelial space have been shown to play critical roles in local regulation of thrombosis, endothelial growth and smooth muscle cell proliferation, making these attractive candidates for modulation of vascular device biointegration. However, classically used biomaterial coatings, such as fibronectin and laminin, modulate only one of these components; enhancing endothelial cell attachment, but also activating platelets and triggering thrombosis. This review examines a subset of extracellular matrix molecules that have demonstrated multi-faceted vascular compatibility and accordingly are promising candidates to improve the biointegration of vascular biomaterials. PMID- 24955636 TI - Biocompatibility of chitosan carriers with application in drug delivery. AB - Chitosan is one of the most used polysaccharides in the design of drug delivery strategies for administration of either biomacromolecules or low molecular weight drugs. For these purposes, it is frequently used as matrix forming material in both nano and micron-sized particles. In addition to its interesting physicochemical and biopharmaceutical properties, which include high mucoadhesion and a great capacity to produce drug delivery systems, ensuring the biocompatibility of the drug delivery vehicles is a highly relevant issue. Nevertheless, this subject is not addressed as frequently as desired and even though the application of chitosan carriers has been widely explored, the demonstration of systems biocompatibility is still in its infancy. In this review, addressing the biocompatibility of chitosan carriers with application in drug delivery is discussed and the methods used in vitro and in vivo, exploring the effect of different variables, are described. We further provide a discussion on the pros and cons of used methodologies, as well as on the difficulties arising from the absence of standardization of procedures. PMID- 24955639 TI - High-throughput assay of levansucrase variants in search of feasible catalysts for the synthesis of fructooligosaccharides and levan. AB - Bacterial levansucrases polymerize fructose residues of sucrose to beta-2,6 linked fructans-fructooligosaccharides (FOS) and levan. While beta-2,1-linked FOS are widely recognized as prebiotics, the health-related effects of beta-2,6 linked FOS are scarcely studied as they are not commercially available. Levansucrase Lsc3 (Lsc-3) of Pseudomonas syringae pv. tomato has very high catalytic activity and stability making it a promising biotechnological catalyst for FOS and levan synthesis. In this study we evaluate feasibility of several high-throughput methods for screening and preliminary characterization of levansucrases using 36 Lsc3 mutants as a test panel. Heterologously expressed and purified His-tagged levansucrase variants were studied for: (1) sucrose-splitting activity; (2) FOS production; (3) ability and kinetics of levan synthesis; (4) thermostability in a Thermofluor assay. Importantly, we show that sucrose splitting activity as well as the ability to produce FOS can both be evaluated using permeabilized levansucrase-expressing E. coli transformants as catalysts. For the first time we demonstrate the key importance of Trp109, His113, Glu146 and Glu236 for the catalysis of Lsc3. Cost-effective and high-throughput methods presented here are applicable not only in the levansucrase assay, but have a potential to be adapted for high-throughput (automated) study of other enzymes. PMID- 24955637 TI - Control of scar tissue formation in the cornea: strategies in clinical and corneal tissue engineering. AB - Corneal structure is highly organized and unified in architecture with structural and functional integration which mediates transparency and vision. Disease and injury are the second most common cause of blindness affecting over 10 million people worldwide. Ninety percent of blindness is permanent due to scarring and vascularization. Scarring caused via fibrotic cellular responses, heals the tissue, but fails to restore transparency. Controlling keratocyte activation and differentiation are key for the inhibition and prevention of fibrosis. Ophthalmic surgery techniques are continually developing to preserve and restore vision but corneal regression and scarring are often detrimental side effects and long term continuous follow up studies are lacking or discouraging. Appropriate corneal models may lead to a reduced need for corneal transplantation as presently there are insufficient numbers or suitable tissue to meet demand. Synthetic optical materials are under development for keratoprothesis although clinical use is limited due to implantation complications and high rejection rates. Tissue engineered corneas offer an alternative which more closely mimic the morphological, physiological and biomechanical properties of native corneas. However, replication of the native collagen fiber organization and retaining the phenotype of stromal cells which prevent scar-like tissue formation remains a challenge. Careful manipulation of culture environments are under investigation to determine a suitable environment that simulates native ECM organization and stimulates keratocyte migration and generation. PMID- 24955640 TI - 3-Aminothiophene-2-acylhydrazones: non-toxic, analgesic and anti-inflammatory lead-candidates. AB - Different chemotypes are described as anti-inflammatory. Among them the N acylhydrazones (NAH) are highlighted by their privileged structure nature, being present in several anti-inflammatory drug-candidates. In this paper a series of functionalized 3-aminothiophene-2-acylhydrazone derivatives 5a-i were designed, synthesized and bioassayed. These new derivatives showed great anti-inflammatory and analgesic potency and efficacy. Compounds 5a and 5d stand out in this respect, and were also active in CFA-induced arthritis in rats. After daily treatment for seven days with 5a and 5d (50 umol/Kg), by oral administration, these compounds were not renal or hepatotoxic nor immunosuppressive. Compounds 5a and 5d also displayed good drug-scores and low risk toxicity calculated in silico using the program OSIRIS Property Explorer. PMID- 24955638 TI - Biomimetic strategies for bone repair and regeneration. AB - The osseointegration rate of implants is related to their composition and surface roughness. Implant roughness favors both bone anchoring and biomechanical stability. Osteoconductive calcium phosphate (Ca-P) coatings promote bone healing and apposition, leading to the rapid biological fixation of implants. It has been clearly shown in many publications that Ca-P coating accelerates bone formation around the implant. This review discusses two main routes for the manufacturing of polymer-based osteoconductive scaffolds for tissue engineering, namely the incorporation of bioceramic particles in the scaffold and the coating of a scaffold with a thin layer of apatite through a biomimetic process. PMID- 24955641 TI - Translating biotechnology to knowledge-based innovation, peace, and development? Deploy a Science Peace Corps--an open letter to world leaders. AB - Scholarship knows no geographical boundaries. This science diplomacy and biotechnology journalism article introduces an original concept and policy petition to innovate the global translational science, a Science Peace Corps. Service at the new Corps could entail volunteer work for a minimum of 6 weeks, and up to a maximum of 2 years, for translational research in any region of the world to build capacity manifestly for development and peace, instead of the narrow bench-to-bedside model of life science translation. Topics for translational research are envisioned to include all fields of life sciences and medicine, as long as they are linked to potential or concrete endpoints in development, foreign policy, conflict management, post-crisis capacity building, and/or peace scholarship domains. As a new instrument in the global science and technology governance toolbox, a Science Peace Corps could work effectively, for example, towards elucidating the emerging concept of "one health"--encompassing human, environmental, plant, microbial, ecosystem, and planet health--thus serving as an innovative crosscutting pillar of 21(st) century integrative biology. An interdisciplinary program of this caliber for development would link 21(st) century life sciences to foreign policy and peace, in ways that can benefit many nations despite their ideological differences. We note that a Science Peace Corps is timely. The Intergovernmental Panel on Climate Change (IPCC) of the United Nations released the Fifth Assessment Report on March 31, 2014. Worrisomely, the report underscores that no person or nation will remain untouched by the climate change, highlighting the shared pressing life sciences challenges for global society. To this end, we recall that President John F. Kennedy advocated for volunteer work that has enduring, transgenerational, and global impacts. This culminated in establishment of the Peace Corps in 1961. Earlier, President Abraham Lincoln aptly observed, "nearly all men can stand adversity, but if you want to test a man's character, give him power." We therefore petition President Barack Obama, other world leaders, and international development agencies in positions of power around the globe, to consider deploying a Science Peace Corps to cultivate the essential (and presently missing) ties among life sciences, foreign policy, development, and peace agendas. A Science Peace Corps requires support by a credible and independent intergovernmental organization or development agency for funding, and arbitration in the course of volunteer work when the global versus local (glocal) value-based priorities and human rights intersect in synergy or conflict. In all, Science Peace Corps is an invitation to a new pathway for competence in 21(st) century science that is locally productive and globally competitive. It can open up scientific institutions to broader considerations and broader inputs, and thus cultivate vital translational science in a world sorely in need of solidarity and sustainable responses to the challenges of 21(st) century science and society. PMID- 24955643 TI - Creating a new kind of healthcare delivery channel-the online mental health marketplace. PMID- 24955642 TI - Supplementating with dietary astaxanthin combined with collagen hydrolysate improves facial elasticity and decreases matrix metalloproteinase-1 and -12 expression: a comparative study with placebo. AB - Photoaging accounts for most age-related changes in skin appearance. It has been suggested that both astaxanthin, a potent antioxidant, and collagen hydrolysate can be used as antiaging modalities in photoaged skin. However, there is no clinical study using astaxanthin combined with collagen hydrolysate. We investigated the effects of using a combination of dietary astaxanthin and collagen hydrolysate supplementation on moderately photoaged skin in humans. A total of 44 healthy subjects were recruited and treated with astaxanthin (2 mg/day) combined with collagen hydrolysate (3 g/day) or placebos, which were identical in appearance and taste to the active supplementation for 12 weeks. The elasticity and hydration properties of facial skin were evaluated using noninvasive objective devices. In addition, we also evaluated the expression of procollagen type I, fibrillin-1, matrix metalloproteinase-1 (MMP-1) and -12, and ultraviolet (UV)-induced DNA damage in artificially UV-irradiated buttock skin before and after treatment. The supplement group showed significant improvements in skin elasticity and transepidermal water loss in photoaged facial skin after 12 weeks compared with the placebo group. In the supplement group, expression of procollagen type I mRNA increased and expression of MMP-1 and -12 mRNA decreased compared with those in the placebo group. In contrast, there was no significant difference in UV-induced DNA damage between groups. These results demonstrate that dietary astaxanthin combined with collagen hydrolysate can improve elasticity and barrier integrity in photoaged human facial skin, and such treatment is well tolerated. PMID- 24955644 TI - Biosensors based on porous cellulose nanocrystal-poly(vinyl alcohol) scaffolds. AB - Cellulose nanocrystals (CNCs), which offer a high aspect ratio, large specific surface area, and large number of reactive surface groups, are well suited for the facile immobilization of high density biological probes. We here report functional high surface area scaffolds based on cellulose nanocrystals (CNCs) and poly(vinyl alcohol) (PVA) and demonstrate that this platform is useful for fluorescence-based sensing schemes. Porous CNC/PVA nanocomposite films with a thickness of 25-70 nm were deposited on glass substrates by dip-coating with an aqueous mixture of the CNCs and PVA, and the porous nanostructure was fixated by heat treatment. In a subsequent step, a portion of the scaffold's hydroxyl surface groups was reacted with 2-(acryloxy)ethyl (3-isocyanato-4 methylphenyl)carbamate to permit the immobilization of thiolated fluorescein substituted lysine, which was used as a first sensing motif, via nucleophile based thiol-ene Michael addition. The resulting sensor films exhibit a nearly instantaneous and pronounced change of their fluorescence emission intensity in response to changes in pH. The approach was further extended to the detection of protease activity by immobilizing a Forster-type resonance energy transfer chromophore pair via a labile peptide sequence to the scaffold. This sensing scheme is based on the degradation of the protein linker in the presence of appropriate enzymes, which separate the chromophores and causes a turn-on of the originally quenched fluorescence. Using a standard benchtop spectrometer to monitor the increase in fluorescence intensity, trypsin was detected at a concentration of 250 MUg/mL, i.e., in a concentration that is typical for abnormal proteolytic activity in wound fluids. PMID- 24955645 TI - Chest CT findings in EBUS-TBNA-proven anthracosis in enlarged mediastinal lymph nodes. AB - PURPOSE: We demonstrate the multislice computed tomography (MSCT) findings of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) proven hilar and mediastinal lymph node enlargement with signs of anthracosis. MATERIALS AND METHODS: 53 enlarged lymph nodes in 39 patients (28 male, 11 female) with EBUS-TBNA-confirmed anthracosis were analyzed retrospectively. RESULTS: The mean short axis diameter of the enlarged lymph nodes with signs of anthracosis was 13.7 mm. Lymph nodes most often showed an oval shape (84 %) and were well defined in 66 % of cases. Lymph node confluence was observed in 32 % of cases. Calcifications were documented in 24.5 % of cases. Contrast enhancement and fatty involution were seen seldom (3.8 %). Lymph node necrosis was not seen. CONCLUSION: Lymph node anthracosis may be found most often in enlarged, well defined lymph nodes with an oval shape, frequently associated with confluence and calcifications. PMID- 24955646 TI - CT-guided screw fixation of vertical sacral fractures in local anaesthesia using a standard CT. AB - PURPOSE: To evaluate time efficiency, radiation dose, precision and complications of percutaneous iliosacral screw placement under CT-guidance in local anaesthesia. MATERIAL AND METHODS: Retrospective analysis of 143 interventions in 135 patients during a period of 42 months. Implant failures could be evaluated in 85/182 screws and bony healing or refracturing in 46/182 screws. RESULTS: A total of 182 iliosacral screw placements in 179 vertical sacral fractures (105 unilateral, 37 bilateral) took place in 135 patients. 166/179 of the sacral fractures were detected in Denis zone 1,10 in Denis zone 2 and 3 in Denis zone 3. No screw misplacements including the simultaneous bilateral procedures were noted. The average time for a unilateral screw placement was 23 minutes (range: 14 -52 minutes) and 35 minutes (range: 21 - 60 minutes) for simultaneous bilateral screwing. The dose length product was 365 mGy * cm (range: 162 - 1014 mGy * cm) for the unilateral and 470 mGy * cm (range: 270 - 1271 mGy * cm) for the bilateral procedure. 1 gluteal bleeding occurred as the only acute minor complication (0.7 %). Fracture healing was verified with follow-up CTs in 42/46 sacral fractures after screw placement. Backing out occurred in 12/85 screws between 6 and 69 days after intervention. In 8 patients contralateral stress fractures were detected after unilateral screw placement between day 10 and 127 (average: 48 days). CONCLUSION: CT-guided iliosacral screw placement in sacral fractures is a safe tool providing a very high precision. The radiation dose is in the order of a diagnostic CT of the pelvis for both unilateral and bilateral screws. Contralateral stress fractures in unilateral screw placements have to be considered during the first weeks after intervention. PMID- 24955648 TI - Determination of the resonance energy and width of the (2)B(2g) shape resonance of ethylene with the method of analytical continuation in the coupling constant. AB - The method of analytical continuation in the coupling constant, which allows us to determine the energy and width of a shape resonance, has been applied to the study of the (2)B2g shape resonance of ethylene. The procedure was done in two steps. In the first step, we used commercially available quantum-chemistry programs to calculate the electronic energy of a neutral molecule and of a negative ion. In both calculations, the Hamiltonian was altered by the inclusion of an additional attractive potential that helps to keep the negative ion bound. In the second step, the energy difference between the neutral molecule and its negative ion was analytically continued by the use of the statistical Pade approximation. PMID- 24955647 TI - High temporal and high spatial resolution MR angiography (4D-MRA). AB - In the first decade of the twenty-first century, whole-body magnetic resonance scanners with high field strengths (and thus potentially better signal-to-noise ratios) were developed. At the same time, parallel imaging and "echo-sharing" techniques were refined to allow for increasingly high spatial and temporal resolution in dynamic magnetic resonance angiography ("time-resolved" = TR-MRA). This technological progress facilitated tracking the passage of intra-venously administered contrast agent boluses as well as the acquisition of volume data sets at high image refresh rates ("4D-MRA"). This opened doors for many new applications in non-invasive vascular imaging, including simultaneous anatomic and functional analysis of many vascular pathologies including arterio-venous malformations. Different methods were established to acquire 4D-MRA using various strategies to acquire k-space trajectories over time in order to optimize imaging according to clinical needs. These include "keyhole"-based techniques (e. g. 4D TRAK), TRICKS - both with and without projection - and HYPR-reconstruction, TREAT, and TWIST. Some of these techniques were first introduced in the 1980 s and 1990 s, were later enhanced and modified, and finally implemented in the products of major vendors. In the last decade, a large number of studies on the clinical applications of TR-MRA was published. This manuscript provides an overview of the development of TR-MRA methods and the 4D-MRA techniques as they are currently used in the diagnosis, treatment and follow-up of vascular diseases in various parts of the body. PMID- 24955649 TI - Climate and atmosphere simulator for experiments on ecological systems in changing environments. AB - Grand challenges in global change research and environmental science raise the need for replicated experiments on ecosystems subjected to controlled changes in multiple environmental factors. We designed and developed the Ecolab as a variable climate and atmosphere simulator for multifactor experimentation on natural or artificial ecosystems. The Ecolab integrates atmosphere conditioning technology optimized for accuracy and reliability. The centerpiece is a highly contained, 13-m(3) chamber to host communities of aquatic and terrestrial species and control climate (temperature, humidity, rainfall, irradiance) and atmosphere conditions (O2 and CO2 concentrations). Temperature in the atmosphere and in the water or soil column can be controlled independently of each other. All climatic and atmospheric variables can be programmed to follow dynamical trajectories and simulate gradual as well as step changes. We demonstrate the Ecolab's capacity to simulate a broad range of atmospheric and climatic conditions, their diurnal and seasonal variations, and to support the growth of a model terrestrial plant in two contrasting climate scenarios. The adaptability of the Ecolab design makes it possible to study interactions between variable climate-atmosphere factors and biotic disturbances. Developed as an open-access, multichamber platform, this equipment is available to the international scientific community for exploring interactions and feedbacks between ecological and climate systems. PMID- 24955650 TI - Neurofibrillar tangle surrogates: histone H1 binding to patterned phosphotyrosine peptide nanotubes. AB - Living cells contain a range of densely phosphorylated surfaces, including phospholipid membranes, ribonucleoproteins, and nucleic acid polymers. Hyperphosphorylated surfaces also accumulate in neurodegenerative diseases as neurofibrillar tangles. We have synthesized and structurally characterized a precisely patterned phosphotyrosine surface and establish this assembly as a surrogate of the neuronal tangles by demonstrating its high-affinity binding to histone H1. This association with nucleic acid binding proteins underscores the role such hyperphosphorylated surfaces may play in disease and opens functional exploration into protein-phosphorylated surface interactions in a wide range of other complex assemblies. PMID- 24955651 TI - Mapping bright and dark modes in gold nanoparticle chains using electron energy loss spectroscopy. AB - We present a scanning transmission electron microscopy-electron energy loss spectroscopy (STEM-EELS) investigation of gold nanosphere chains with lengths varying from 1 to 5 particles. We show localized EELS signals from the chains and identify energy-loss peaks arising due to l = 1, 2, 3, 4, and 5 plasmon modes through the use of EELS mapping. We also show the evolution of the energy of these modes as the length of a given chain increases, and we find that a chain containing N particles can accommodate at least N experimentally observable modes, in addition to the transverse mode. As the chain length is increased by the addition of one more gold particle to the chain, the new N + 1 mode becomes the highest energy mode, while the existing modes lower their energy and eventually asymptote as they delocalize along the chain. We also show that modes become increasingly difficult to detect with the EELS technique as l approaches N. The data are compared to numerical simulations. PMID- 24955653 TI - Enhancement of the stability of electron field emission behavior and the related microplasma devices of carbon nanotubes by coating diamond films. AB - The enhanced lifetime stability for the carbon nanotubes (CNTs) by coating hybrid granular structured diamond (HiD) films on Au-decorated CNTs/Si using a two-step microwave plasma enhanced chemical vapor deposition process was reported. Electron field emission (EFE) properties of HiD/Au/CNTs emitters show a low turn on field (E0) of 3.50 V/MUm and a high emission current density (Je) of 0.64 mA/cm(2) at an applied field of 5.0 V/MUm. There is no notable current degradation or fluctuation over a period of tau(HiD/Au/CNTs) = 360 min for HiD/CNTs EFE emitters tested under a constant current of 4.5 MUA. The robustness of the HiD/CNTs EFE emitter is overwhelmingly superior to that of bare CNTs EFE emitters (tau(CNTs) = 30 min), even though the HiD/Au/CNTs do not show the same good EFE properties as CNTs, which are E0 = 0.73 V/MUm and Je = 1.10 mA/cm(2) at 1.05 V/MUm. Furthermore, the plasma illumination (PI) property of a parallel plate microplasma device fabricated using the HiD/Au/CNTs as a cathode shows a high Ar plasma current density of 1.76 mA/cm(2) at an applied field of 5600 V/cm with a lifetime of plasma stability of about 209 min, which is markedly better than the devices utilizing bare CNTs as a cathode. The CNT emitters coated with diamond films possessing marvelous EFE and PI properties with improved lifetime stability have great potential for the applications as cathodes in flat-panel displays and microplasma display devices. PMID- 24955652 TI - Targeting prostate carcinoma by G3-C12 peptide conjugated N-(2 hydroxypropyl)methacrylamide copolymers. AB - Prostate carcinoma is the second leading cause of cancer-related deaths. Increased expression of membrane-bound galectin-3 by prostate carcinoma cell has been found to correlate with more poorly differentiated and increased metastatic potential. In the present study, different amount of galectin-3-binding peptide, G3-C12 (the sequence ANTPCGPYTHDCPVKR), was attached to N-(2 hydroxypropyl)methacrylamide (HPMA) copolymers as targeting moiety. The results of qPCR and competitive binding test indicated that the expression level of galectin-3 in two metastatic prostate carcinoma cell lines (PC-3 and DU145 cells) could be significantly suppressed by the addition of G3-C12-modified HPMA copolymers (PG1 and PG2), demonstrating the high affinity of PG1 and PG2 to galectin-3. Due to the multivalent effects of moieties, the uptake of copolymers was remarkably enhanced with the increasing amount of conjugated G3-C12 peptide. A higher internalization of PG1 and PG2 occurred in PC-3 cells via caveolin- and clathrin-mediated endocytosis, whereas a clathrin-mediated uptake process was involved in DU145 cells. The in vivo biodistribution and pharmacokinetics of nonmodified ((131)I-pHPMA) and G3-C12-modified ((131)I-PG1 and (131)I-PG2) copolymers were estimated on a well-established mice model bearing PC-3 xenografts by (131)I-SPECT-imaging. Higher tumor accumulation of (131)I-PG1 (1.60 +/- 0.08% ID/g, p < 0.05) and (131)I-PG2 (1.54 +/- 0.06% ID/g, p < 0.05) was observed compared with (131)I-pHPMA (1.19 +/- 0.04% ID/g) at 2 h post-intravenous injection. Although the amount of conjugated G3-C12 peptide performed a remarkable in vitro effect on the affinity and internalization of HPMA copolymers to the galectin-3 overexpressed prostate carcinoma cells, the molecular weight and ligand modification all play important roles on their in vivo tumor accumulation. PMID- 24955654 TI - Molecular dynamics study of the controlled destabilization of an RNA hairpin structure by a covalently attached azobenzene switch. AB - As shown in recent experimental studies, photoswitches like azobenzene can act as efficient regulators of the folding and unfolding of DNA and RNA duplexes. Here we explore the details of the conformational changes induced by azobenzene attachment, focusing upon a small 14-mer RNA hairpin structure. The azobenzene chromophore is covalently bound to the stem region adjacent to a UUCG tetraloop which is known to represent a particularly stable structure. Since the characteristic time scale of conformational changes exceeds the nanosecond scale (and by far exceeds the ultrafast time scale of trans-to-cis photoswitching), equilibrium simulations using enhanced sampling by replica exchange molecular dynamics (REMD) are employed to investigate the influence of trans versus cis azobenzene attachment on the stability of the hairpin. We report on the analysis of fluctuations and conformational landscapes, along with calculations of relative melting temperatures. The simulations are found to reproduce certain experimentally predicted trends for azobenzene-modified RNA; in particular, both trans and cis conformers have a destabilizing effect. This effect is significantly enhanced for the cis conformer, even though the latter tends to flip out of the double-stranded stem region. PMID- 24955655 TI - Assessment of antioxidative, chelating, and DNA-protective effects of selected essential oil components (eugenol, carvacrol, thymol, borneol, eucalyptol) of plants and intact Rosmarinus officinalis oil. AB - Selected components of plant essential oils and intact Rosmarinus officinalis oil (RO) were investigated for their antioxidant, iron-chelating, and DNA-protective effects. Antioxidant activities were assessed using four different techniques. DNA-protective effects on human hepatoma HepG2 cells and plasmid DNA were evaluated with the help of the comet assay and the DNA topology test, respectively. It was observed that whereas eugenol, carvacrol, and thymol showed high antioxidative effectiveness in all assays used, RO manifested only antiradical effect and borneol and eucalyptol did not express antioxidant activity at all. DNA-protective ability against hydrogen peroxide (H2O2)-induced DNA lesions was manifested by two antioxidants (carvacrol and thymol) and two compounds that do not show antioxidant effects (RO and borneol). Borneol was able to preserve not only DNA of HepG2 cells but also plasmid DNA against Fe(2+) induced damage. This paper evaluates the results in the light of experiences of other scientists. PMID- 24955656 TI - Surface-assisted dehydrogenative homocoupling of porphine molecules. AB - The templated synthesis of porphyrin dimers, oligomers, and tapes has recently attracted considerable interest. Here, we introduce a clean, temperature-induced covalent dehydrogenative coupling mechanism between unsubstituted free-base porphine units yielding dimers, trimers, and larger oligomers directly on a Ag(111) support under ultrahigh-vacuum conditions. Our multitechnique approach, including scanning tunneling microscopy, near-edge X-ray absorption fine structure and photoelectron spectroscopy complemented by theoretical modeling, allows a comprehensive characterization of the resulting nanostructures and sheds light on the coupling mechanism. We identify distinct coupling motifs and report a decrease of the electronic gap and a modification of the frontier orbitals directly associated with the formation of triply fused dimeric species. This new on-surface homocoupling protocol yields covalent porphyrin nanostructures addressable with submolecular resolution and provides prospective model systems towards the exploration of extended oligomers with tailored chemical and physical properties. PMID- 24955657 TI - Molybdopterin biosynthesis: trapping of intermediates for the MoaA-catalyzed reaction using 2'-deoxyGTP and 2'-chloroGTP as substrate analogues. AB - MoaA is a radical S-adenosylmethionine (AdoMet) enzyme that catalyzes a complex rearrangement of guanosine-5'-triphosphate (GTP) in the first step of molybdopterin biosynthesis. In this paper, we provide additional characterization of the MoaA reaction product, describe the use of 2'-chloroGTP to trap the GTP C3' radical, generated by hydrogen atom transfer to the 5'-deoxyadenosyl radical, and the use of 2'-deoxyGTP to block a late step in the reaction sequence. These probes, coupled with the previously reported trapping of an intermediate in which C3' of the ribose is linked to C8 of the purine, allow us to propose a plausible mechanism for the MoaA-catalyzed reaction. PMID- 24955659 TI - Highly transparent and durable superhydrophobic hybrid nanoporous coatings fabricated from polysiloxane. AB - Highly transparent and durable superhydrophobic hybrid nanoporous coatings with different surface roughnesses were fabricated via a simple solidification-induced phase-separation method using a liquid polysiloxane (PSO) containing SiH and SiCH?CH2 groups as precursors and methyl-terminated poly(dimethylsiloxane)s (PDMS) as porogens. Owing to the existence of SiCHn units, the hybrid material is intrinsically hydrophobic without modification with expensive fluorinated reagents. The roughness of the coating can be easily controlled at the nanometer scale by changing the viscosity of PDMS to achieve both superhydrophobicity and high transparency. The influence of surface roughness on the transparency and hydrophobicity of the coatings was investigated. The enhancement from hydrophobic to superhydrophobic with increasing surface roughness can be explained by the transition from the Wenzel state to the Cassie state. The optimum performance coating has an average transmittance higher than 85% in the visible-light range (400-780 nm), a water contact angle of 155 degrees , and a slide angle lower than 1 degrees . The coatings also exhibit good thermal and mechanical stability and durable superhydrophobicity, which paves the way for real applications of highly transparent superhydrophobic coatings. PMID- 24955658 TI - Surface-modified P(HEMA-co-MAA) nanogel carriers for oral vaccine delivery: design, characterization, and in vitro targeting evaluation. AB - Oral drug delivery is a route of choice for vaccine administration because of its noninvasive nature and thus efforts have focused on efficient delivery of vaccine antigens to mucosal sites. An effective oral vaccine delivery system must protect the antigen from degradation upon mucosal delivery, penetrate mucosal barriers, and control the release of the antigen and costimulatory and immunomodulatory agents to specific immune cells (i.e., APCs). In this paper, mannan-modified pH responsive P(HEMA-co-MAA) nanogels were synthesized and assessed as carriers for oral vaccination. The nanogels showed pH-sensitive properties, entrapping and protecting the loaded cargo at low pH values, and triggered protein release after switching to intestinal pH values. Surface decoration with mannan as carbohydrate moieties resulted in enhanced internalization by macrophages as well as increasing the expression of relevant costimulatory molecules. These findings indicate that mannan-modified P(HEMA-co-MAA) nanogels are a promising approach to a more efficacious oral vaccination regimen. PMID- 24955660 TI - Bidirectional relationships between client and counselor speech: the importance of reframing. AB - In the study of motivational interviewing (MI), counselor skill has been posited to influence client language about change or "change talk." This study investigates the relationship between a specific counselor behavior, valenced reflective listening, and client change talk in a MI intervention with substance using adolescents. A combination of recorded in-person and telephone (n = 223) sessions were sequentially coded using the Motivational Interviewing Skill Code 2.5. Reflections were categorized by valence, meaning they included content that was either moving toward (i.e., positive reflection) or away from change (i.e., negative reflection). Client language was coded as either moving toward change, away from change, or neutral about change. Probability analyses showed positive reflections were 11 times more likely to be followed by change talk and 71% less likely to be followed by counter change talk. Negative reflections were 19 times more likely to be followed by counter change talk and 65% less likely to be followed by change talk. Client language was also predictive of counselor reflections, such that positive reflections were 10 times more likely to occur after client change talk and negative reflections were 19 times more likely to follow counter change talk. Because the percentage of change talk expressed in a session has been shown to be positively related to improved behavioral outcomes, counselors should avoid unintentional reflections of counter change talk and use reframing techniques to change the valence of client change language. Implications for MI practice and training are discussed. PMID- 24955661 TI - Alcohol consumption and partner violence among women entering substance use disorder treatment. AB - To test the hypothesized role of alcohol consumption as a proximal risk factor for partner violence, a within-subjects analysis compared levels of alcohol consumption in violent versus nonviolent conflict events among substance-abusing women and their male partners. Participants were married or cohabiting women (N = 145) who had recently begun a substance abuse treatment program and reported both a violent and a nonviolent relationship conflict event with their male partner in the prior 6 months. The average age was 38, and 83% were White. Male partners did not participate in the study. The female participant provided information about the male partner. Women were interviewed regarding a violent conflict event in which physical violence occurred and a nonviolent conflict event in which psychological aggression occurred without physical violence. The interview assessed quantity of alcohol consumed and use of other drugs prior to each conflict. Alcohol consumption was significantly greater prior to violent versus nonviolent conflict events for all measures of women's alcohol consumption examined: any drinking, heavy drinking, number of drinks in the 12 hr preceding the conflict event, and estimated blood alcohol concentration at time of the event. Male partners' alcohol consumption showed similar results. Use of other drugs in women, but not men, was significantly more likely prior to physical conflicts. These within-subject comparisons help to rule out individual difference explanations for the alcohol-violence association and indicate that the quantity of alcohol consumption is an important proximal risk factor for partner violence in substance-abusing women and their male partners. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 24955662 TI - Alcohol use disorder in women: Risks and consequences of an adolescent onset and persistent course. AB - Women are more vulnerable to the deleterious effects of both acute and protracted alcohol use than men, but women's lower levels of alcohol consumption and alcohol use disorder (AUD) have resulted in a paucity of investigations on the development of alcohol problems in women. In particular, it is not clear to what extent the cascading effects of key etiological factors that contribute to an especially severe course of AUD in men also underlie the development of AUD in women. To fill this gap, we examined the adolescent risk factors and adult consequences associated with an adolescent onset and persistent course of AUD in a community sample of women (n = 636) from ages 17 to 29. Women with AUD exhibited greater psychopathology and psychosocial impairment than those without, with an adolescent onset and persistent course indicative of the greatest severity. Notably, high levels of impairment across all women with AUD reduced the utility of onset and course to differentiate profiles of risk and impairment. In contrast to previous work in men, even women whose AUD symptoms desisted continued to exhibit impairment, suggesting that an adolescent onset of AUD is associated with enduring consequences for women's health and functioning, even after ostensible "recovery." PMID- 24955663 TI - Young adult social development as a mediator of alcohol use disorder symptoms from age 21 to 30. AB - Little research has examined social development in the young adult years relative to childhood and adolescence. This study tested the hypothesized pathways of the social development model (SDM) in young adulthood for predicting symptoms of alcohol use disorder (AUD) and positive functioning at age 30. A longitudinal panel study originally drawn from Seattle, Washington, elementary schools was examined. The sample included 808 participants with high retention and was gender balanced and ethnically diverse. Analyses focused on ages 21, 27, and 30. SDM constructs were assessed with self-reports of past-year behavior and combined multiple life domains. AUD symptoms corresponding to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (American Psychiatric Association, 1994) criteria were assessed using the Diagnostic Interview Schedule. Positive functioning combined measures of constructive engagement in work and school, civic engagement, physical exercise, and lack of depressive symptoms. The study found that AUD symptoms were moderately stable from age 21 to 30; however, developmental pathways hypothesized by the SDM at age 27 played a significant role in partially mediating this association. Alcohol-specific factors were key mediating mechanisms, whereas prosocial factors played little role. Conversely, prosocial factors had an important role in predicting positive functioning at age 30, whereas there were no significant pathways involving alcohol-specific factors. Findings suggest that age 27 is not too late for interventions targeting adult social development to help diminish alcohol use disorder symptoms by age 30. Alcohol-specific factors such as reducing perceived opportunities or rewards for heavy alcohol use or challenging beliefs accepting of drunkenness are likely to be key ingredients of effective adult interventions. PMID- 24955664 TI - Anxiety, sedation, and simulated driving in binge drinkers. AB - The current study evaluated the relationships among trait anxiety, subjective response to alcohol, and simulated driving following a simulated alcohol binge. Sixty drinkers with a binge history completed the State Trait Anxiety Inventory (STAI), the Alcohol Use Questionnaire, and subsequently completed a driving simulation. Participants were then administered 0.2 g/kg ethanol at 30-min intervals (cumulative dose 0.8 g/kg). Following alcohol consumption, the Biphasic Alcohol Effects Scale (BAES) and visual analog scales of subjective impairment and driving confidence were administered, after which simulated driving was reassessed. Due to the emphasis on simulated driving after drinking in the current study, subjective response to alcohol (i.e., self-reported sedation, stimulation, impairment, and confidence in driving ability) was assessed once following alcohol consumption, as this is the time when drinkers tend to make decisions regarding legal driving ability. Alcohol increased driving speed, speeding tickets, and collisions. Sedation following alcohol predicted increased subjective impairment and decreased driving confidence. Subjective impairment was not predicted by sensitivity to stimulation or trait anxiety. High trait anxiety predicted low driving confidence after drinking and this relationship was mediated by sedation. Increased speed after alcohol was predicted by sedation, but not by trait anxiety or stimulation. Anxiety, combined with the sedating effects of alcohol, may indicate when consumption should cease. However, once driving is initiated, sensitivity to sedation following alcohol consumption is positively related to simulated driving speed. PMID- 24955665 TI - Relations among affect, abstinence motivation and confidence, and daily smoking lapse risk. AB - This study tested the hypothesis that changes in momentary affect, abstinence motivation, and confidence would predict lapse risk over the next 12-24 hr using Ecological Momentary Assessment (EMA) data from smokers attempting to quit smoking. One hundred and three adult, daily, treatment-seeking smokers recorded their momentary affect, motivation to quit, abstinence confidence, and smoking behaviors in near real time with multiple EMA reports per day using electronic diaries postquit. Multilevel models indicated that initial levels of negative affect were associated with smoking, even after controlling for earlier smoking status, and that short-term increases in negative affect predicted lapses up to 12, but not 24, hr later. Positive affect had significant effects on subsequent abstinence confidence, but not motivation to quit. High levels of motivation appeared to reduce increases in lapse risk that occur over hours although momentary changes in confidence did not predict lapse risk over 12 hr. Negative affect had short-lived effects on lapse risk, whereas higher levels of motivation protected against the risk of lapsing that accumulates over hours. An increase in positive affect was associated with greater confidence to quit, but such changes in confidence did not reduce short-term lapse risk, contrary to expectations. Relations observed among affect, cognitions, and lapse seem to depend critically on the timing of assessments. PMID- 24955667 TI - Do peer perceptions mediate the effects of ADHD symptoms and conduct problems on substance use for college students? AB - Although extensive research suggests that attention-deficit/hyperactivity disorder (ADHD) and conduct problems (CP; symptoms of oppositional defiant disorder, conduct disorder, and antisocial personality disorder) contribute to risk for substance use, why these symptoms increase risk for substance use remains unclear. Given that research indicates that perceived peer tolerance and perceived peer substance use affect substance use, we evaluated the degree to which these peer-perception constructs mediated the association that ADHD symptoms, CP symptoms, and their interaction share with substance use (i.e., alcohol use, marijuana use, and illicit drug use). Participants were college students (N = 627; 60% female; 47% European American) with a mean age of 20.23 years. Results indicated that perceived peer use significantly mediated the association of ADHD symptoms with alcohol, marijuana, and illicit drug use, whereas perceived peer use only mediated the association between CP symptoms and alcohol use. Perceived peer tolerance significantly mediated the association that both CP and ADHD symptoms had with marijuana use, but not alcohol or illicit drug use. Finally, CP symptoms moderated the indirect effect that ADHD symptoms had on alcohol use through perceived peer tolerance. At low levels of CP symptoms, increases in ADHD symptoms corresponded to increases in perceived peer tolerance, which was related to increased alcohol use. However, at high levels of CP symptoms, increases in ADHD symptoms corresponded to decreases in perceived peer tolerance, which was associated with decreased alcohol use. Implications of findings are discussed. PMID- 24955666 TI - Stages of change, clinical presentation, retention, and treatment outcomes in treatment-seeking outpatient problem gambling clients. AB - Specific stages of change have been associated with clinical variables before and during the course of addiction treatment. However, few studies have specifically focused on these relationships for problem and pathological gamblers. The present study examined the relationships between pretreatment stages of change and clinical treatment variables in a sample of 71 treatment-seeking problem and pathological gamblers. The participants were administered the following instruments: the University of Rhode Island Change Assessment (URICA), the NORC DSM-IV Screen for Gambling Problems (NODS), and the Outcome Questionnaire 45 (OQ 45). The researchers hypothesized that there would be a relationship among pretreatment stages of change and (a) severity of gambling problems at onset of treatment, (b) severity of psychosocial problems at onset of treatment, (c) retention in treatment, and (d) level of psychosocial improvement through therapy. The results indicate that (a) precontemplation was negatively related to reported gambling problems at outset of treatment, and contemplation and maintenance were positively related to reported gambling problems at the outset of treatment; (b) action was positively associated with level of psychosocial functioning at outset of treatment; (c) action was negatively associated with retention in treatment; and (d) maintenance was negatively associated with level of improvement in psychosocial functioning through therapy. Implications for treatment of this population include the ability to adjust treatment plans and interventions with increased awareness of potential barriers and obstacles unique to pretreatment stages of change. PMID- 24955668 TI - Adolescent substance use in Israel: The roles of exposure to political traumas and posttraumatic stress symptoms. AB - Previous studies have not examined the potential mediating role of posttraumatic stress symptoms (PTS) and moderating roles of gender and ethnicity among adolescents in the aftermath of political traumas, especially in the Middle East. This study of Israeli adolescents aimed to begin bridging these gaps in knowledge. We addressed the following hypotheses: (a) greater exposure to multiple political traumas would be associated with adolescent substance use; (b) greater PTS would be associated with adolescent substance use; (c) PTS would mediate the association of exposure to multiple political traumas on substance use; and (d) gender and ethnicity would moderate the pathways from exposure and PTS to substance use. A nationally representative sample included 4,733 Grade 10 and 11 students (half were females; 36.8% were Arabs). Results of bootstrapping estimations found a significant direct link between exposure to multiple political traumas and substance use, as well as an indirect link through PTS. Gender moderated the relationship between PTS and substance use, while ethnicity moderated the association between exposure and substance use. Specifically, female adolescent substance use decreased when their PTS increased. Arab adolescents who had greater exposure to multiple political traumas used more substances. PTS may be an important mechanism by which trauma exposure is associated with increased substance use. Screening adolescents for PTS and substance use, shortly after political trauma, is essential to address the potential risk factors in vulnerable adolescents. PMID- 24955670 TI - Bidirectional effects of parenting and youth substance use during the transition to middle and high school. AB - The current study assessed bidirectional relationships between supportive parenting behaviors (i.e., involvement, positive parenting), parental control strategies (i.e., parental monitoring, effective discipline), and youth substance use in a sample of aggressive youth during the transitions to middle and high school. Participants were drawn from the control group of a larger longitudinal study and were followed from 4th through 9th grade. Cross-lagged developmental models were evaluated using structural equation modeling. Youth substance use at 6th, 7th, and 8th grade influenced positive parenting at 7th, 8th, and 9th grade, but did not influence parental involvement or monitoring at any grade. Parental involvement, monitoring, and positive parenting at earlier grades did not influence youth substance use at later grades. Reciprocal relationships were observed between effective discipline and youth substance use at all grades. Results are consistent with models of bidirectionality that suggest that parents and children adjust their behavior based on the response of the other. Findings may impact our understanding of the development of youth substance use across time and improve interventions designed to reduce this behavior during periods of transition. PMID- 24955669 TI - One-year outcomes and mediators of a brief intervention for drug abusing adolescents. AB - Two manually guided brief interventions were evaluated with a randomized, controlled trial. Adolescents (aged 13-17 years) suspected of abusing alcohol and other drugs and their parent were randomly assigned to receive either a 2-session adolescent only (BI-A), 2-session adolescent and additional parent session (BI AP), or assessment only control condition (CON). Adolescents were identified in a school setting, and the intervention was delivered by trained counselors. Outcome analyses (N = 284; 90% of those enrolled) of relative change (from intake to 12 months) and absolute status (at 12 months) revealed a general pattern of reductions in drug use behaviors, particularly with the cannabis outcome measures, in both active conditions (BI-A and BI-AP). Students in the control condition showed worse outcome compared with the BI-A and BI-AP groups. Among the 4 mediating variables measured at 6 months, use of additional services, motivation to change, and parenting practices had significant influences on 12 month outcome; problem-solving skills approached significance as a mediator. The potential value of a brief intervention for drug abusing adolescents is discussed. PMID- 24955671 TI - Childhood sexual abuse, distress, and alcohol-related problems: Moderation by drinking to cope. AB - Previous studies have found relationships between childhood sexual abuse (CSA) and problem alcohol use. However, few studies have explored mechanisms that may explain this relationship. The present study examined whether (a) distress mediated the relationship between CSA and both heavy drinking and alcohol consequences, (b) coping motives for drinking moderated the paths between distress and both heavy drinking and alcohol consequences, and (c) these relationships remained significant after controlling for other forms of abuse/trauma. Three hundred ninety-five undergraduate women completed survey measures of childhood abuse/trauma, alcohol use/consequences, distress, and drinking motives. Data were analyzed using path analyses. Results supported a moderated-mediation model in which distress mediated the relationship between CSA and alcohol consequences, but only among those who endorsed coping motives for drinking. After controlling for other forms of abuse/maltreatment, the moderated mediated pathway was no longer significant, but there remained a direct path between CSA and alcohol consequences. The present study provides support for tension-reduction models of alcohol use among CSA-exposed women and demonstrates the moderating role of coping motives. The present study also highlights the need for future studies to control for other forms of abuse/trauma and suggests that other mechanisms and contextual variables need to be explored to explain the CSA/alcohol-use pathway. PMID- 24955672 TI - Effects of normative feedback for drinkers who consume less than the norm: Dodging the boomerang. AB - Several alcohol interventions designed for college students attempt to correct exaggerated perceptions of alcohol use on college campuses through the use of personalized normative feedback. Personalized normative feedback has been shown to be effective in reducing drinking as a stand-alone intervention and as a part of a multicomponent intervention. This feedback is typically targeted to heavier drinkers to create a discrepancy between their personal beliefs and behavior and the actual lower levels of use on campus. However, little is known about how this form of normative feedback might affect lighter drinkers who learn that they are drinking less than the typical student at their school. The risk is a potential boomerang effect, or an increase in drinking among lighter drinkers receiving personalized feedback. The current study examined four samples from three geographic locations: two using computer-delivered personalized normative feedback alone and two delivering personalized feedback in the context of a brief motivational intervention. We found no evidence for a boomerang effect among lighter drinkers receiving personalized normative feedback in any of the four samples. These findings help to assuage fears of increasing drinking among lighter drinkers through widespread implementation of normative interventions for college students in the absence of screening for current drinking status. PMID- 24955673 TI - College drinking problems and social anxiety: The importance of drinking context. AB - Social anxiety more than quadruples the risk of developing an alcohol use disorder, yet it is inconsistently linked to heavy alcohol use. Elucidation of the relation between social anxiety and alcohol use is an important next step in treating and preventing risky drinking. College students routinely face potentially anxiety-provoking social situations (e.g., meeting new people) and socially anxious undergraduates are especially vulnerable to alcohol-related impairment. Drinking to cope with social anxiety is thought to reinforce alcohol use, yet research on coping-motivated drinking among socially anxious students has yielded inconsistent findings. Further, undergraduate drinking varies by drinking context, yet the role of context in drinking behaviors among socially anxious individuals remains unclear. The current study sought to examine the relationship of social anxiety and drinking quantity in specific drinking contexts among undergraduates (N = 611). We also evaluated whether relevant drinking contexts mediated the relationship between social anxiety and alcohol related problems. Clinically elevated social anxiety was related to heavier consumption in negative emotion (e.g., feeling sad or angry) and personal/intimate (e.g., before sexual intercourse) contexts, but not social/convivial contexts (e.g., parties, bars). Quantity of alcohol consumed in negative emotion and personal/intimate contexts mediated the relationship between social anxiety and drinking problem severity. Drinking in personal/intimate contexts demonstrated a unique mediational role. Findings suggest that heavy drinking in particular contexts (especially personal/intimate and negative emotion) may play an important role in drinking problems among socially anxious individuals. PMID- 24955675 TI - Development and evaluation of the Marijuana Reduction Strategies Self-Efficacy Scale. AB - To evaluate several psychometric properties of a questionnaire designed to assess college students' self-efficacy to employ 21 cognitive-behavioral strategies intended to reduce the amount and/or frequency with which they consume marijuana, we recruited 273 marijuana-using students to rate their confidence that they could employ each of the strategies. Examination of frequency counts for each item, principal components analysis, internal consistency reliability, and mean interitem correlation supported retaining all 21 items in a single scale. In support of criterion validity, marijuana use-reduction self-efficacy scores were significantly positively correlated with cross-situational confidence to abstain from marijuana, and significantly negatively correlated with quantity and frequency of marijuana use and marijuana-related problems. In addition, compared with respondents whose use of marijuana either increased or remained stable, self efficacy was significantly higher among those who had decreased their use of marijuana over the past year. This relatively short and easily administered questionnaire could be used to identify college students who have low self efficacy to employ specific marijuana reduction strategies and as an outcome measure to evaluate educational and skill-training interventions. PMID- 24955674 TI - Computer-delivered, home-based, attentional retraining reduces drinking behavior in heavy drinkers. AB - To examine the impact of a computer-delivered, home-based, alcohol-specific attention modification program (AMP), 41 heavy drinking college students were randomly assigned to AMP or an attention control condition (ACC). Participants selected 10 alcohol-related words most relevant to their own drinking experience as well as 10 neutral words not related to alcohol. These personalized stimuli were used in an attention retaining program based upon the probe detection paradigm twice weekly for 4 weeks. Participants in the AMP condition reported decreased drinking, whereas those in the ACC condition reported no change in their drinking. These preliminary data suggest that a computer-delivered, home delivered, attention-retraining for alcohol treatment may be an inexpensive and efficacious adjunct to standard alcohol treatments. PMID- 24955677 TI - Descriptive and injunctive social norms' interactive role in gambling behavior. AB - Social norms have a fundamental impact on behavior, yet little research has examined social norms regarding gambling and no research has examined possible interaction effects. The current study examined the interaction between perceived approval of gambling by others (i.e., injunctive norms) and perceived prevalence of gambling by others (i.e., descriptive norms) on the respondent's gambling frequency and problems, in a sample of relatively frequent gamblers. The current study examined 2 distinct reference groups: 1 close in proximity (i.e., family and friends) and 1 distally located (i.e., other students). The sample consisted of 252 undergraduates who gambled at least twice a month. Two interactions were observed on gambling frequency based on the proximity of the reference groups; however, only descriptive norms significantly predicted gambling problems. When the reference group was closer in proximity, the positive relationship between perceptions of family and friends' gambling frequency and the individual's own gambling was stronger for individuals who believed that their friends and family members highly approved of gambling. When the reference group was distally located, differences in respondents' gambling frequency emerged only in contexts in which they perceived other students to gamble infrequently. Specifically, when respondents perceived that other students gambled infrequently and disapproved of gambling, respondents gambled the most frequently. The results suggest that individuals are influenced by their perceptions of others' attitudes and behaviors, regardless of proximity, and that these perceptions of others' behavior are strongly associated with gambling problems. PMID- 24955676 TI - Mindfulness predicts lower affective volatility among African Americans during smoking cessation. AB - Recent research suggests that mindfulness benefits emotion regulation and smoking cessation. However, the mechanisms by which mindfulness affects emotional and behavioral functioning are unclear. One potential mechanism, lower affective volatility, has not been empirically tested during smoking cessation. This study examined longitudinal associations among mindfulness and emotional responding over the course of smoking cessation treatment among predominantly low socioeconomic status (SES) African American smokers, who are at high risk for relapse to smoking and tobacco-related health disparities. Participants (N = 399, 51% female, mean age = 42, 48% with annual income <$10,000) completed a baseline measure of trait mindfulness. Negative affect, positive affect, and depressive symptoms were assessed at five time points during smoking cessation treatment (up to 31 days postquit). Volatility indices were calculated to quantify within person instability of emotional symptoms over time. Over and above demographic characteristics, nicotine dependence, and abstinence status, greater baseline trait mindfulness predicted lower volatility of negative affect and depressive symptoms surrounding the quit attempt and up to 1 month postquit, ps < 0.05. Although volatility did not mediate the association between greater mindfulness and smoking cessation, these results are the first to show that mindfulness is linked to lower affective volatility (or greater stability) of negative emotions during the course of smoking cessation. The present study suggests that mindfulness is linked to greater emotional stability and augments the study of mindfulness in diverse populations. Future studies should examine the effects of mindfulness-based interventions on volatility and whether lower volatility explains effects of mindfulness-based treatments on smoking cessation. PMID- 24955679 TI - Student perceptions of specific components within a personalized feedback intervention. AB - Previous research suggests that personalized feedback interventions (PFI) can be an effective tool in reducing risky alcohol use among college students; however, little is known about how students perceive the individual components that are typically used during PFIs. In the current study, participants (N = 219, 63.5% female, 84% Caucasian, undergraduates enrolled in introductory psychology courses) reported their drinking behavior in the past month, and then immediately received a computerized PFI based on their self-reported alcohol use. The PFI was modeled from the Brief Alcohol Screening and Intervention for College Students (BASICS) approach and included 10 separate feedback components presented in random order. Participants provided acceptability ratings on each of the 10 components. Overall, participants found the PFI generally acceptable, with females rating the PFI as more acceptable than males, and binge drinkers (defined as 5 or more drinks on an occasion for males and 4 or more drinks for females) rating the PFI more acceptable than nonbinge drinkers. Differences in acceptability emerged across the 10 components, as participants rated the practical cost components (e.g., money spent on alcohol, calories consumed) as more acceptable than didactic information (e.g., impact of blood alcohol levels) and personal negative consequences. The results are similar to a previous study that examines student reactions to PFIs (Miller & Leffingwell, 2013). Overall, the findings suggest that college students prefer certain feedback components to others. Moreover, the findings indicate that future research is needed to examine the relationship between preferred components and treatment outcomes to determine which components are most effective for reducing risky drinking. PMID- 24955678 TI - White problem gamblers discount delayed rewards less steeply than their African American and Hispanic counterparts. AB - Impulsivity is a core process underlying addictive behaviors, including nonpharmacological addictive behaviors such as problem gambling. Although considerable attention has been given to the investigation of delay discounting within the context of addiction-related behaviors, relatively little research has examined the relationship between discounting and individual variables, such as race/ethnicity. The purpose of this study was to compare discounting rates in the three most prevalent racial/ethnic groups in the United States: Whites, African Americans, and Hispanics. The study was conducted with 315 problem gamblers. Participants completed a delay-discounting questionnaire involving choices between a smaller amount of money delivered immediately and a larger amount delivered later. A hyperbolic discounting function estimated delay-discounting rates based on participants' indifference points obtained via the questionnaires. Results showed significant effects of race/ethnicity on delay discounting. White gamblers discounted delayed money at lower rates than African Americans and Hispanics, even after controlling for confounding variables. These data suggest that among individuals who develop problem gambling, Whites are less impulsive than African Americans and Hispanics, at least in terms of choosing between delayed and immediate reinforcers. These results have implications for evaluating the onset and treatment of addictive disorders from a health-disparities perspective. PMID- 24955680 TI - Prevalence and correlates of transactional sex among an urban emergency department sample: Exploring substance use and HIV risk. AB - Men and women involved in transactional sex (TS) report increased rates of HIV risk behaviors and substance use problems as compared with the general population. When people engaged in TS seek health care, they may be more likely to utilize the emergency department (ED) rather than primary care services. Our goal was to examine the prevalence and correlates of TS involvement among an ED sample of men and women. Adults ages 18-60 were recruited from an urban ED, as part of a larger randomized control trial. Participants (n = 4,575; 3,045 women, 1,530 men) self-administered a screening survey that assessed past 3-month substance use (including alcohol, marijuana, illicit drugs, and prescription drugs) and HIV risk behaviors, including TS (i.e., being paid in exchange of a sexual behavior), inconsistent condom use, multiple partners, and anal sex. Of the sample, 13.3% (n = 610) reported TS within the past 3 months (64.4% were female). Bivariate analysis showed TS was significantly positively associated with alcohol use severity, marijuana use, and both illicit and prescription drug use, and multiple HIV risk behaviors. These variables (except marijuana) remained significantly positively associated with TS in a binary logistic regression analysis. The prevalence of recent TS involvement among both male and female ED patients is substantial. These individuals were more likely to report higher levels of alcohol/drug use and HIV risk behaviors. The ED may be a prime location to engage both men and women who are involved in TS in behavioral interventions for substance use and sexual risk reduction. PMID- 24955681 TI - How do we know when to celebrate? AB - This editorial presents a brief historical overview of emerging knowledge since the 1970s that led to the birth of a new discipline, Family Practice (now Family Medicine). Family Medicine residencies were required to include training on mental health, family dynamics, communication skills, and other behavioral science topics. The next two decades witnessed an explosion of clinical research. High users of general medical services were found to have a two- to threefold higher prevalence of mental illness. These patients consumed disproportionate amounts of health care dollars, suggesting that cost containment may require mental health treatment. Over the last 30 years researchers have demonstrated that combining biomedical and psychosocial expertise in collaborative treatment models produces better outcomes for patients with mental illness, with physical illness, and for the majority who have a complicated mixture of biopsychosocial ailments. The advent of collaboration between disciplines and the integration of service designs is something to celebrate. In this issue of Families, Systems and Health, representatives of eight organizations, spanning behavioral health, nursing, medicine, and interdisciplinary practice, all endorse behavioral health integration in the health home. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 24955682 TI - A response to "joint principles: integrating behavioral health care into the patient-centered medical home". AB - Comments on the article "Joint principles: Integrating behavioral health care into the patient-centered medical home" (see record 2014-24217-011). The American Association for Marriage and Family Therapy (AAMFT) represents a mental health profession with a long track record in integrated primary care, particularly with family medicine. The authors begin by affirming several core themes in the joint principles-behavioral health (JP-BH) statement. They then offer a systemic/relational perspective on the patient-centered medical home that goes beyond the focus of the JP-HP. PMID- 24955683 TI - Principles on integrating behavioral health into medical homes must not designate leaders as "physicians only". AB - Nurse practitioners have long included high-quality behavioral health in the care they provide to individuals and families nationwide. Just as the principles of the medical home have been an integral part of nurse practitioners' practice, so has the concept of whole person orientation incorporating both physical and mental or behavioral health care. It is therefore encouraging that organized medicine has embraced integrated physical and behavioral health care in patient centered medical homes, a position that could help improve the wellbeing of patients all throughout the United States. Although the American Association of Nurse Practitioners (AANP) has long supported such integration, we do not support the physician-centric joint principles included in the current issue of Annals of Family Medicine (The Working Party Group on Integrated Behavioral Healthcare et al., 2014), as they create provider and leadership roles that are too narrow and restrictive for the provision of health care in the 21st century. As written, they limit access to high-quality care and restrict patient choice of health care providers. PMID- 24955684 TI - Statement of the American Psychological Association in response to the "joint principles: integrating behavioral health care into the patient-centered medical home". AB - Comments on the article "Joint principles: Integrating behavioral health care into the patient-centered medical home" (see record 2014-24217-011), presented by the Working Party Group on Integrated Behavioral Healthcare. The American Psychological Association (APA) shares concerns about the lack of reference to behavioral health care in the original 2007 Joint Principles of the Patient Centered Medical Home for which this new document is intended to supplement but not replace. The decision to support the supplemental Joint Principles was not an easy one for APA, as there is one area of significant concern. That concern is related to the use of the term "physician-directed medical practice" PMID- 24955685 TI - The National Association of Social Workers' commentary on "joint principles: integrating behavioral health care into the patient-centered medical home". AB - The "Joint Principles: Integrating Behavioral Health Care Into the Patient Centered Medical Home" provide a unique opportunity for increased collaboration in delivering health and behavioral health services. The National Association of Social Workers (NASW) provides commentary on these important principles. PMID- 24955686 TI - Collaborative Family Healthcare Association commentary on the "joint principles: Integrating behavioral health care into the patient-centered medical home". AB - The Collaborative Family Healthcare Association (CFHA) welcomes the opportunity to comment on the complementary set of Joint Principles underscoring the Integration of Behavioral Health Care Into the Patient-Centered Medical Home (The Working Party Group on Integrated Behavioral Healthcare et al., 2014). CFHA is an organization that promotes comprehensive and cost-effective models of health care delivery that integrate mind and body, individual and family, patients, providers, and communities. CFHA appreciates that the Joint Principles do not explicitly endorse any single model of collaboration between behavioral health and medical practice. Rather, they broadly emphasize integration, affirming the only way to have a whole person orientation is to adopt a biopsychosocial spiritual perspective. This commentary will highlight areas of notable strength within the Joint Principles, as well as challenge the language, if not perspective, on a few critical elements. PMID- 24955687 TI - The American Psychiatric Association response to the "joint principles: integrating behavioral health care into the patient-centered medical home". AB - Comments on the article "Joint principles: Integrating behavioral health care into the patient-centered medical home" (see record 2014-24217-011). The American Psychiatric Association Workgroup on Integrated Care supports the recommendations made in these Joint Principles and recognizes the significant benefit of treating behavioral and general medical conditions concurrently. The workgroup offers comments on this effort as it pertains to health care in general and psychiatric practice. PMID- 24955688 TI - Behavioral health integration: a critical component of primary care and the patient-centered medical home. AB - Comments on the article "Joint principles: Integrating behavioral health care into the patient-centered medical home" (see record 2014-24217-011). The Patient Centered Primary Care Collaborative, an organization representing a diverse group of stakeholders promoting primary care and the patient-centered medical home, strongly agrees that patients need a primary care system that better integrates behavioral and mental health. As the medical home model of care evolves in light of the scientific evidence, we must not lose sight of measuring what impacts patients and their families most-and patient-centered medical home (PCMH) recognition/certification programs should include the integration of mental and behavioral health if we are sincere in achieving the objectives. PMID- 24955689 TI - Commentary by the American College of Physicians on the "joint principles: integrating behavioral health care into the patient-centered medical home". AB - Comments on the article "Joint principles: Integrating behavioral health care into the patient-centered medical home" (see record 2014-24217-011). The American College of Physicians (ACP) supports the intent of these "Joint Principles" for behavioral health care and agrees that the incorporation of behavioral health care within the patient-centered medical home model is incomplete. ACP believes that these principles should be labeled as guidelines, rather than Joint Principles. ACP is also concerned with the use of overgeneralizations within the document that do not include a cited evidence base. PMID- 24955690 TI - The development of joint principles: integrating behavioral health care into the patient-centered medical home. AB - This article describes the development of the Joint Principles of The Patient Centered Medical Home (PCMH) by the Working Party Group on Integrated Behavioral Healthcare. The Joint Principles establish the primacy of integrated behavioral health care as a core principle of the PCMH. PMID- 24955691 TI - Joint principles: Integrating behavioral health care into the patient-centered medical home. AB - The Patient-centered Medical Home (PCMH) is an innovative, improved, and evolving approach to providing primary care that has gained broad acceptance in the United States. The Joint Principles of the PCMH, formulated and endorsed in February 2007, are sound and describe the ideal toward which we aspire. However, there is an element running implicitly through these joint principles that is difficult to achieve yet indispensable to the success of the entire PCMH concept. The incorporation of behavioral health care has not always been included as practices transform to accommodate to the PCMH ideals. This is an alarming development because the PCMH will be incomplete and ineffective without the full incorporation of this element, and retrofitting will be much more difficult than prospectively integrating into the original design of the PCMH. Therefore we offer a complementary set of joint principles that recognizes the centrality of behavioral health care as part of the PCMH. This document follows the order and language of the original joint principles while emphasizing what needs to be addressed to insure incorporation of the essential behavioral elements. It is intended to supplement and not replace the original Joint Principles document, which still stands. PMID- 24955692 TI - The biobehavioral family model as a framework for examining the connections between family relationships, mental, and physical health for adult primary care patients. AB - Family and romantic relationships have been linked to adults' mental and physical health. Previous research has not explored possible mediators of these associations. The Biobehavioral Family Model (BBFM) is a biopsychosocial approach to health that integrates family emotional climate, biobehavioral reactivity (emotion dysregulation), and physical health outcomes into a comprehensive model. The present study examined the ability of the BBFM to explain connections between family processes and health for primarily uninsured, low-income adult primary care patients. Patient participants (18-65 years) reported their family functioning, romantic relationship satisfaction, anxiety, depression, illness symptoms, and physical well-being (n = 125). We used path analyses to test separate models using family functioning and romantic relationship satisfaction as measures of family emotional climate. For Model 1, pathways between family functioning and depression, and depression and disease activity were significant, whereas the pathway between family functioning and disease activity was nonsignificant, indicating a mediation relationship. Anxiety also fits as an additional mediator (chi2 = 4.135, p = .247, CFI = .992, RMSEA = .055). For Model 2, a significant mediation relationship was found; depression and anxiety mediate the association between romantic relationship satisfaction and disease activity (chi2 = 11.309, p = .503, CFI = 1.000, RMSEA = .000). Findings support the ability of the BBFM to explain the health quality of low-income, urban primary care patients. We offer clinical implications and recommendations for future research. PMID- 24955698 TI - Health care reform, 2014: no matter what the question, mission is the answer. AB - In this column, the president of the Collaborative Family Healthcare Association (CFHA) addresses the lack of understanding and agreement to the question What is health care reform? It is a daunting task to understand, let alone redesign, the most expensive (but not most effective or most efficient) health care system in the world. In this critical window of opportunity, influencing positive movement through leadership, communication, and teamwork is a strategic priority of the CFHA and its journal, Family Systems & Health. The emphases on comprehensive, coordinated, and cost-effective care, although novel concepts for many, have been core features of CFHA's philosophy for almost two decades (see CFHA's mission statement). As we mark the halfway point in this pivotal year in health care reform, we continue to struggle. CFHA can help illuminate the path of what health care reform can be and what it can do for each citizen in our communities. PMID- 24955699 TI - Top-down attentional processes modulate the coding of atypical biological motion kinematics in the absence of motor signals. AB - The acquisition of sensorimotor parameters that control goal-directed motor behaviors occurs by observing another person in the absence of efferent and afferent motor signals. This is observational practice. During such observation, biological motion properties associated with the observed person are coded into a representation that controls motor learning. Understanding the underlying processes, specifically associated with coding biological motion, has theoretical and practical significance. Here, we examined the following questions. Experiment 1: Are the underlying velocity characteristics associated with observed biological motion kinematics imitated? Experiment 2: Is attention involved in imitating biological motion kinematics? Experiment 3: Can selective attention modulate how biological motion kinematics are imitated/represented? To this end, participants practiced by observing a model performing a movement sequence that contained typical or atypical biological motion kinematics. The differences in kinematics were designed to dissociate the movement constraints of the task and the anatomical constraints of the observer. This way, we examined whether novel motor behaviors are acquired by adopting prototypical movements or coding biological motion. The kinematic analyses indicated the timing and spatial position of peak velocity were represented. Using a dual-task protocol, we attenuated the coding of biological motion kinematics (Experiment 2) and augmented coding using a selective attention protocol (Experiment 3). Findings indicated that velocity characteristics of biological motion kinematics are coded during observational practice, most likely through bottom-up sensorimotor processes. By modulating motion coding using 2 attentional protocols, we showed that bottom-up processes are influenced by input modulation, which is consistent with top-down control during observational practice. PMID- 24955701 TI - Clinical trials and drug development. PMID- 24955700 TI - The role of reward prediction in the control of attention. AB - Previously rewarded stimuli involuntarily capture attention. The learning mechanisms underlying this value-driven attentional capture remain less understood. We tested whether theories of prediction-based associative reward learning explain the conditions under which reward feedback leads to value-based modulations of attentional priority. Across 4 experiments, we manipulated whether stimulus features served as unique predictors of reward outcomes. Participants received monetary rewards for correctly identifying a color-defined target in an initial search task (training phase) and then immediately completed a second, unrewarded visual search task in which color was irrelevant (test phase). In Experiments 1-3, monetary reward followed correct target selection during training, but critically, no target-defining features carried uniquely predictive information about reward outcomes. Under these conditions, we found no evidence of attentional capture by the previous target colors in the subsequent test phase. Conversely, when target colors in the training phase of Experiment 4 carried uniquely predictive information about reward magnitude, we observed significant attentional capture by the previously rewarded color. Our findings show that value-based attentional priority only develops for stimulus features that carry uniquely predictive information about reward, ruling out a purely motivational account and suggesting that mechanisms of reward prediction play an important role in shaping attentional priorities. PMID- 24955702 TI - Risks and benefits of phase 1 clinical trial participation. AB - BACKGROUND: The results from phase 1 clinical trials can allow new treatments to progress further in drug development or halt that process altogether. At the forefront of phase 1 clinical trials is the safety of every patient participant, which is particularly true when testing new oncologic treatments in which patients may risk potentially toxic treatments in the hope of slowing the progression of or even curing their disease. METHODS: We explore the benefits and risks that patients experience when participating in phase 1 clinical trials. RESULTS: Rules and regulations have been put into place to protect the safety and interests of patients while undergoing clinical trials. Selecting patients with cancer who will survive long enough to accrue data for these trials continues to be challenging. New prognostic models have been validated to help health care professionals select those patients who will likely benefit from participation in phase 1 trials. There also are long-lasting positive and negative impacts on those patients who choose to participate in phase 1 clinical trials. CONCLUSIONS: Modern phase 1 clinical trials represent a therapeutic option for many patients who progress through frontline therapy for their malignancies. Recent phase 1 clinical trials testing targeted therapies have increased responses in many diseases in which other lines of therapy have failed. Patients still face many risks and benefits while enrolled in a phase 1 trial, but the likelihood of treatment response in the era of rational, targeted therapy is increased when compared with the era of cytotoxic therapy. PMID- 24955703 TI - Phase 1 trial design: is 3 + 3 the best? AB - BACKGROUND: Concerns have been recognized about the operating characteristics of the standard 3 + 3 dose-escalation design. Various innovative phase 1 trial designs have been proposed to address the issues and new challenges posed by molecularly targeted agents. However, in spite of these proposals, the conventional design is still the most widely utilized. METHODS: A review of the literature of phase 1 trials and relevant statistical studies was performed. RESULTS: Beyond statistical simulations, sparse clinical data exist to support or refute many of the shortcomings ascribed to the 3 + 3 rule method. Data from phase 1 trials demonstrate that traditional designs identified the correct dose and relevant toxicities with an acceptable level of precision in some instances; however, no single escalation method was proven superior in all circumstances. CONCLUSIONS: Design selection should be guided by the principle of slow escalation in the face of toxicity and rapid dose increases in the setting of minimal or no adverse events. When the toxicity of a drug is uncertain or a narrow therapeutic window is suggested from preclinical testing, then a conservative 3 + 3 method is generally appropriate. However, if the therapeutic window is wide and the expected toxicity is low, then rapid escalation with a novel rule- or model-based design should be employed. PMID- 24955704 TI - Participation of the elderly population in clinical trials: barriers and solutions. AB - BACKGROUND: Despite the fact that cancer disproportionately affects the elderly, most participants of clinical cancer trials are relatively young. This misrepresentation greatly affects the oncology treatment of the elderly population (> 65 years of age). Few studies have attempted to identify the problems related to discrepancy based on age for clinical trial participation. METHODS: A literature review was performed to identify barriers and solutions to enrollment of elderly persons for clinical cancer trials. RESULTS: Physician related barriers include perception about treatment tolerance, drug metabolism, a lack of evidence for efficacy, and age bias. Lack of autonomy, concerns about quality of life and toxicities, accessibility to clinical trials, and logistical and financial difficulties are common patient-related barriers. Trial-related barriers include eligibility criteria based on performance status, organ dysfunction, and the presence of comorbidities. Solutions, such as improved communication, and coordinating logistical challenges may help overcome some of these challenges. Studies designed for the geriatric population could modify the perception and behavior of health care professionals and improve patient participation in clinical trials. CONCLUSIONS: Implementing some of these solutions and increased research may help overcome shortfalls in elderly enrollment, thus allowing for more effective treatment of older patients. PMID- 24955705 TI - Studying cancer treatment in the elderly patient population. AB - BACKGROUND: Data relating to cancer treatment in the older patient population are limited because older individuals have been under-represented in clinical trials. The goal of this review was to establish which factors hinder the participation of older individuals to clinical trials and to examine possible solutions. METHODS: The literature relating to cancer treatment in the older patient population was reviewed. RESULTS: The benefit of systemic cancer treatment may decrease with age, and risks may be increased due to reduced life expectancy and reduced tolerance of stress in the older population. Therefore, a multipronged approach is recommended for clinical studies in these patients, including phase 2 studies limited to persons 70 years of age and older, stratification by life expectancy and predicted treatment tolerance in phase 3 studies, and registration studies to establish predictive variables for treatment-related toxicity in older individuals. CONCLUSIONS: A combination of prospective and registration studies may supply adequate information to study cancer treatments in the older patient population. PMID- 24955706 TI - BRAF mutations: signaling, epidemiology, and clinical experience in multiple malignancies. AB - BACKGROUND: Mutations in BRAF were first reported in 2002. Since that time, the molecular basis for oncogenic signaling has been elucidated in multiple malignancies. The development of v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors has helped improve clinical outcomes in malignant melanoma and is suggested by case reports in other malignancies. METHODS: A review of pertinent articles examining the mechanisms of BRAF signaling in various cancer types and an update on clinical trials of BRAF inhibitions are presented. RESULTS: Clinical response to BRAF inhibition varies by malignancy. In melanoma, single-agent vemurafenib or dabrafenib prolongs overall survival compared with chemotherapy, but both are limited by the development of acquired resistance in many patients. Results of early-phase clinical trials and case reports demonstrate responses in V600E-mutant non-small-cell lung cancer, thyroid cancer, and hairy cell leukemia. However, no significant difference in progression-free survival was seen in colorectal cancer with single-agent vemurafenib. Overcoming resistance to BRAF inhibition with combination therapy is an active area of research. CONCLUSIONS: The detection of BRAF mutations represents an advance in delivering molecularly targeted therapies to patients with a variety of cancers. Acquired resistance limits the ability of BRAF inhibitors to produce long-term remissions; however, combining BRAF inhibitors with the mitogen-activated protein kinase pathway and/or other pathway inhibitors represents a promising method to improve long-term outcomes. PMID- 24955707 TI - PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. AB - BACKGROUND: Immunotherapeutic approaches to treating cancer have been evaluated during the last few decades with limited success. An understanding of the checkpoint signaling pathway involving the programmed death 1 (PD-1) receptor and its ligands (PD-L1/2) has clarified the role of these approaches in tumor-induced immune suppression and has been a critical advancement in immunotherapeutic drug development. METHODS: A comprehensive literature review was performed to identify the available data on checkpoint inhibitors, with a focus on anti-PD-1 and anti PD-L1 agents being tested in oncology. The search included Medline, PubMed, the ClinicalTrials.gov registry, and abstracts from the American Society of Clinical Oncology meetings through April 2014. The effectiveness and safety of the available anti-PD-1 and anti-PD-L1 drugs are reviewed. RESULTS: Tumors that express PD-L1 can often be aggressive and carry a poor prognosis. The anti-PD-1 and anti-PD-L1 agents have a good safety profile and have resulted in durable responses in a variety of cancers, including melanoma, kidney cancer, and lung cancer, even after stopping treatment. The scope of these agents is being evaluated in various other solid tumors and hematological malignancies, alone or in combination with other therapies, including other checkpoint inhibitors and targeted therapies, as well as cytotoxic chemotherapy. CONCLUSIONS: The PD-1/PD L1 pathway in cancer is implicated in tumors escaping immune destruction and is a promising therapeutic target. The development of anti-PD-1 and anti-PD-L1 agents marks a new era in the treatment of cancer with immunotherapies. Early clinical experience has shown encouraging activity of these agents in a variety of tumors, and further results are eagerly awaited from completed and ongoing studies. PMID- 24955708 TI - AKT goes cycling. PMID- 24955709 TI - Novel pancreatic cancer vaccines could unleash the army within. AB - BACKGROUND: Despite recent progress with novel chemotherapy regimens, pancreatic ductal adenocarcinoma remains the fourth leading cause of cancer death in the United States. Innovative approaches to treatment of this disease are needed to accelerate progress. METHODS: A review was conducted of the results of 2 pancreatic cancer vaccine programs with results that have shown promise in early phase clinical trials. RESULTS: In a phase 2 trial, a cell-based allogeneic pancreatic cancer vaccine exploiting the hyperacute rejection response targeted against alpha-1,3 galactosyl epitopes (algenpantucel-L) has shown improvement in disease-free and overall survival rates in the adjuvant setting compared with a historical control. This vaccine has advanced to ongoing phase 3 trials. Compared with GVAX alone, a second whole-cell vaccine employing GM-CSF-expressing pancreatic cancer cells (GVAX) to enhance the antigen presentation in a priming phase followed by a Listeria-based vaccine targeting mesothelin in a boost phase improved survival rates. This vaccine platform is undergoing additional phase 2 testing. CONCLUSIONS: Allogenic whole-cell pancreatic adenocarcinoma vaccines show promise in early-phase trials and have the potential to improve survival rates by unleashing antitumor immunity. PMID- 24955710 TI - Histopathological and immunophenotypical features of intestinal-type adenocarcinoma of the gallbladder and its precursors. AB - BACKGROUND: Intestinal-type adenocarcinoma of the gallbladder is an unusual malignancy associated with low- and high-grade intraepithelial neoplasms. The literature on the clinicopathologic characteristics of the precursor lesions of gallbladder cancer is limited, due in part to the variability in its definition and terminology. METHODS: Here we report one case of intestinal-type adenocarcinoma of the gallbladder with distinctive morphology and associated precursor lesions. All of the hematoxylin and eosin stained slides were reviewed. Immunostains were performed using the avidin-biotin complex method for CK20, CK7, CDX2, MUC1, MUC2, and MUC-5AC. We also reviewed the literature discussing the current terminology from the World Health Organization for these lesions. RESULTS: A 70-year-old man presented with epigastric abdominal pain and bloating. Computed tomography demonstrated a large heterogeneous gallbladder mass. Macroscopically, the gallbladder was 7.5 x 5.5 x 4.5 cm with smooth serosa. The lumen was occupied by a 5.0 x 4.5 x 3.0 cm irregular friable exophytic mass. The remaining mucosa had a tan brown to pink color with granular/papillary excrescences of up to 0.7 cm in thickness. Histologically, the tubulopapillary adenoma was lined by pseudostratified columnar epithelium with low and extensive high-grade dysplasia. Goblet cell and cystic dilatation were present in some glands. Immunohistochemistry showed that the intestinal type was positive for CK20, CK7, and CDX2, focally positive for MUC1/2, and negative for MUC-5AC. CONCLUSION: This case showed the complete spectrum of the progression of intestinal-type intracholecystic papillary-tubular neoplasms of the gallbladder. PMID- 24955711 TI - Follicular lymphoma with progression to diffuse large B-cell lymphoma and concurrent CD5-negative mantle cell lymphoma-3 entities in a lymph node. AB - A 68-year-old woman with a history of follicular lymphoma had pathological findings of grade 3B follicular lymphoma, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) identified in 1 lymph node. The DLBCL appeared to be a transformation of the follicular lymphoma. The nodules were diffusely and strongly positive for CD20, BCL6, and BCL2. CD43 highlighted smaller lymphocytes in a fraction of the nodules. BCL1 staining was variable with a mixture of nodular and mantle zone patterns. The diffuse areas showed weaker positivity for CD10, BCL2, and BCL6. CD3 and CD5 highlighted intermixed T cells. The Ki-67 proliferative index was overall estimated to be 60%. Fluorescent in situ hybridization performed on the lymph node was positive for CCND1/IGH. The patterns of BCL1 and BCL6 staining demonstrated 2 separate populations of neoplastic B lymphocytes. PMID- 24955720 TI - Effect of hemodialysis on platelet function in end-stage renal disease Egyptian patients using in vitro closure time test (PFA-100 analyzer). AB - In patients with end-stage renal disease (ESRD), hemorrhagic complications are commonly encountered due to abnormalities in primary hemostasis, in particular, platelet (PLT) dysfunction and impaired PLT-vessel wall interaction. The pathogenesis of altered PLT function is considered multifactorial. Dialysis procedures had a favorable impact on bleeding complications in uremic patients. We aimed to evaluate the effect of hemodialysis on PLT function in patients with ESRD on a regular hemodialysis program. This study was carried on 40 ESRD Egyptian patients undergoing regular hemodialysis. Twenty healthy subjects were studied as a control group. Samples were assayed for PLT function by PLT function analyzer-100 (PFA-100) before and after the hemodialysis session. Prolonged closure time (CT) was found in 90% of patients before hemodialysis session and returned to normal ranges after hemodialysis session in 22% of those patients. The CT was longer among patients before and after hemodialysis session compared to controls (p < 0.01 and p = 0.02, respectively), while it was shorter among patients after hemodialysis session compared to before hemodialysis session (p = 0.004). Hemoglobin (Hb) level and hematocrit (Hct) values were higher in control group compared to patient group before hemodialysis session (p < 0.01 and p = 0.001, respectively), patients after hemodialysis session (p < 0.01 and p = 0.02, respectively) and also in patients after hemodialysis compared to before hemodialysis session (p = 0.001 and p < 0.01, respectively). The percentage change in PLT count was positively correlated with that of Hb (p = 0.01). We concluded that PLT dysfunction is encountered in ESRD Egyptian patients, and hemodialysis has the ability to correct some part of these hemostatic disturbances. PMID- 24955712 TI - Retroperitoneoscopic resection of primary paraganglioma: single-center clinical experience and literature review. AB - BACKGROUND AND PURPOSE: Paraganglioma (PG) is a rare neuroendocrine entity. Surgical resection is recommended as the mainstay of treatment due to the uncontrolled hypertension, close proximity to major vessels, variable location, and higher potential malignancy. With rapid development of minimally invasive techniques during the past decade, laparoscopic resection of retroperitoneal PG has been reported with successful results. There are only a few publications describing retroperitoneal access, however. In the present study, we proposed to summarize our experience on retroperitoneal laparoscopic resection in 10 patients and systematically review relevant publications to evaluate its safety and efficacy. PATIENTS AND METHODS: From June 2009 to October 2013, 10 patients with PG who were treated with retroperitoneoscopy were included in the study. Minimal effective dosage alpha-blockade with phenoxybenzamine was routinely used. Preoperative, intraoperative, and postoperative baseline data were collected and analyzed. Meanwhile, two reviewers independently searched and identified 8 retrospective studies and 23 case reports in the Medline, Embase, and Science Citation Index between 1998 and 2013. RESULTS: Operations in 9 of 10 patients were successfully completed without conversion; one case was converted to open surgery because of left accessory renal artery injury. Mean operative time, blood loss, and postoperative hospital stay were 97.8+/-20.6 minutes, 44.4+/-8.2 mL, and 4.8+/-3.5 days, respectively. There were three complications in this series, including accessory renal artery injury, renal vein injury, and chylorrhea. CONCLUSIONS: Retroperitoneoscopic resection is feasible, effective, and safe in the treatment of patients with PG according to our preliminary clinical experience and has distinct advantages including direct access to the tumor, less intraperitoneal interference, precise dissection, and minimal invasiveness. PMID- 24955722 TI - After the clinic? Researching sexual health technology in context. AB - There is great interest in what testing, pharmaceutical, information and social media technology can do for sexual health. Much programmatic and research activity is focused on assessing how these technologies can be used to best effect. Less obvious are analyses that place technology into historical, political and real-world settings. Developing an 'in-context' analysis of sexual health technology, this paper draws on interviews with leading community advocates, researchers and clinicians in Australia, Canada and the UK and looks across examples, including social media, rapid HIV testing, pre-Exposure Prophylaxis for HIV and polymerase chain reaction Chlamydia testing. The analysis is framed by studies of techno-society and the dialectics of sex-affirmative advocacy with biomedical authority and attends to: the rationalistic and affective dimensions of the imaginary associated with technology; the role of technology in the re-spatialisation and re-temporalisation of the sexual health clinic; and the re-invention of technology in its real-world contexts. This in context approach is important for: the effective implementation of new technology; strengthening the social science contribution to the field; and enriching social theory in general on life in techno-societies. PMID- 24955721 TI - Association study of CREB1 polymorphisms and suicidality in MDD: results from a European multicenter study on treatment resistant depression. AB - PURPOSE: Mood disorders are present in more than 90% of suicides, and a genetic vulnerability to suicidality is well established. Numerous lines of evidence relate the transcription factor Cyclic adenosine monophosphate Response Element Binding protein (CREB1) to suicide, and to the aetiology of major depressive disorder (MDD). Our aim was to test for association between CREB1 single nucleotide polymorphisms (SNPs) and both suicide risk (SR) and a personal history of suicide attempt (SA) in MDD patients. MATERIALS AND METHODS: A sample of 250 MDD patients collected in the context of a European multicenter resistant depression study and treated with antidepressants over a period of at least 4 weeks were genotyped for five CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690). To assess suicidality, the Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D) were applied. RESULTS: Neither single-marker nor haplotypic association were found between SR and/or a personal history of SA with any of the investigated SNPs after multiple testing correction. For females, an association between rs2709376 and a personal history of SA was found (p = 0.016), however not resisting multiple testing correction. CONCLUSIONS: Although we found significant CREB1 single marker association with a personal history of SA in female MDD patients, this finding could not be confirmed in haplotypic analyses after multiple testing correction. Larger well-defined cohorts are required to confirm or refute a possible association of CREB1 and SA in female MDD patients. PMID- 24955723 TI - The effectiveness of combined gating and re-scanning for treating mobile targets with proton spot scanning. An experimental and simulation-based investigation. AB - Organ motion is one of the major obstacles in radiotherapy and charged particle therapy. Even more so, the theoretical advantages of dose distributions in scanned ion beam therapy may be lost due to the interplay between organ motion and beam scanning. Several techniques for dealing with this problem have been devised. In re-scanning, the target volume is scanned several times to average out the motion effects. In gating and breath-hold, dose is only delivered if the tumour is in a narrow window of position. Experiments have been performed to verify if gating and re-scanning are effective means of motion mitigation. Dose distributions were acquired in a lateral plane of a homogeneous phantom. For a spherical target volume and regular motion gating was sufficient. However, for realistic, irregular motion or a patient target volume, gating did not reduce the interplay effect to an acceptable level. Combining gating with re-scanning recovered the dose distributions. The simplest re-scanning approach, where a treatment plan is duplicated several times and applied in sequence, was not efficient. Simulations of different combinations of gating window sizes and re scanning schemes revealed that reducing the gating window is the most efficient approach. However, very small gating windows are not robust for irregular motion. PMID- 24955725 TI - Adsorption and reaction of sub-monolayer films of an ionic liquid on Cu(111). AB - The reactive interaction of the ionic liquid 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide [BMP][TFSA] with Cu(111) was investigated by scanning tunnelling microscopy (STM) and X-ray photoelectron spectroscopy (XPS) under ultrahigh vacuum (UHV) conditions. Decomposition between 300 K and 350 K is manifested by changes in the surface structure monitored with STM. XPS reveals that mainly the [TFSA] anion is decomposed. PMID- 24955724 TI - What does the aromatic ring number mean for drug design? AB - INTRODUCTION: During the last decade, there has been an increased focus on understanding the factors that influence the chance of success of a drug molecule in development. Recent publications have highlighted that the aromatic ring count of a drug molecule also has an influence on its developability profile. AREAS COVERED: This article reviews both the positive and negative consequences of including aromatic rings in drug molecules based on the recent literature and presents a thorough review of recent publications describing the influence of aromatic ring count on compound developability. These conclusions are analysed alongside their implications for the medicinal chemist. The authors also highlight the limitations of recent analyses; this includes a particular emphasis on the restricted diversity of the compound collections used. EXPERT OPINION: Modern medicinal chemists work in a very restricted area of the available drug like chemical space, although there is evidence that safe compounds can be identified outside of conventional drug-like chemical space. It is true that current evidence implies that drug molecules with > 3 aromatic rings in are undesirable and that heteroaromatics perform better than carboaromatic overall. However, the analyses performed so far have only used compounds designed for oral administration, which were provided from pharmaceutical companies' collections, and were therefore limited in diversity. PMID- 24955728 TI - Dipole-induced conductivity enhancement by n-type inclusion in a p-type system: alpha-Fe2O3-PEDOT:PSS nanocomposites. AB - Hematite (alpha-Fe2O3) nanoparticles of two different shapes but of same size (ca. 40 nm) were dispersed in PEDOT:PSS matrices in various concentration ranges (0-7 wt%) to study the consequent changes in conductivity in the dark and under solar illumination conditions. Within a distinct range of concentration, a distinct increase in the conductivity was observed for both spherical and cubical particle population. We ascribed this effect to the generalized Poole-Frenkel theory of conduction in conjunction with the basic depletion width properties of heterojunctions and electrostatic dipole moments, and verified our assumptions through data fitting. A difference in conductivity between sphere- and cube-based alpha-Fe2O3-PEDOT:PSS nanocomposites was also observed and ascribed to the electrostatic edge effect on the nanoparticles. The dispersion of alpha-Fe2O3 nanocrystals was confirmed by high-resolution electron microscopy, whereas the electrical properties and modulations thereof were followed by recording current voltage characteristics. PMID- 24955729 TI - Electrolytes based on alkoxysilyl-functionalized ionic liquids: viscoelastic properties and conductivity. AB - Ionic liquids can be successfully used as electrolytes in electrochemical devices when they are in their quasi-solid state. Among several methods of solidification, a sol-gel process was chosen and a set of alkoxysilyl functionalized iodide imidazolium-based ionic liquids were synthesized. The electrolytes were prepared by mixing these ionic liquids with a non-polymerisable ionic liquid (1-methyl-3-propylimidazolium iodide (MPIm(+)I(-))). Iodine was dissolved in an electrolyte matrix in order to form an I3(-)/I(-) redox couple. The change of the structure from sol to gel was followed by rheological tests in order to show the effect of different rheological parameters on the gelation process. The solvolysis with glacial acetic acid and condensation were followed by rheological experiments on the samples taken from a batch, and in situ on the rheometer. The formed three-dimensional sol-gel networks of various alkoxysilyl functionalized ionic liquids differed in their microstructures and viscoelastic properties that were correlated with conductivity. The results show that the conductivity of approximately 10(-3) S cm(-1) at room temperature was achieved for the gels with relatively high values of elastic modulus and noticeable viscous contribution. It is shown that not only the viscosity but also the viscoelastic behavior and especially the relationship between viscous and elastic moduli (phase shift) together with the time of gelation are essential for the high conductivity of electrolytes. PMID- 24955726 TI - Silencing of EEF2K (eukaryotic elongation factor-2 kinase) reveals AMPK-ULK1 dependent autophagy in colon cancer cells. AB - EEF2K (eukaryotic elongation factor-2 kinase), also known as Ca (2+)/calmodulin dependent protein kinase III, functions in downregulating peptide chain elongation through inactivation of EEF2 (eukaryotic translation elongation factor 2). Currently, there is a limited amount of information on the promotion of autophagic survival by EEF2K in breast and glioblastoma cell lines. However, the precise role of EEF2K in carcinogenesis as well as the underlying mechanism involved is still poorly understood. In this study, contrary to the reported autophagy-promoting activity of EEF2K in certain cancer cells, EEF2K is shown to negatively regulate autophagy in human colon cancer cells as indicated by the increase of LC3-II levels, the accumulation of LC3 dots per cell, and the promotion of autophagic flux in EEF2K knockdown cells. EEF2K negatively regulates cell viability, clonogenicity, cell proliferation, and cell size in colon cancer cells. Autophagy induced by EEF2K silencing promotes cell survival and does not potentiate the anticancer efficacy of the AKT inhibitor MK-2206. In addition, autophagy induced by silencing of EEF2K is attributed to induction of protein synthesis and activation of the AMPK-ULK1 pathway, independent of the suppression of MTOR activity and ROS generation. Knockdown of AMPK or ULK1 significantly abrogates EEF2K silencing-induced increase of LC3-II levels, accumulation of LC3 dots per cell as well as cell proliferation in colon cancer cells. In conclusion, silencing of EEF2K promotes autophagic survival via activation of the AMPK-ULK1 pathway in colon cancer cells. This finding suggests that upregulation of EEF2K activity may constitute a novel approach for the treatment of human colon cancer. PMID- 24955732 TI - Biobank classification: communicating biorepository diversity. PMID- 24955731 TI - Effect of DHA on plasma fatty acid availability and oxidative stress during training season and football exercise. AB - The aim was to determine the effects of a diet supplemented with 1.14 g per day of docosahexaenoic acid (DHA) for eight weeks on the plasma oxidative balance and anti-inflammatory markers after training and acute exercise. Fifteen volunteer male football players were randomly assigned to placebo or experimental and supplemented groups. Blood samples were taken under resting conditions at the beginning and after eight weeks of training under resting and post-exercise conditions. The experimental beverage increased the plasma DHA availability in non-esterified fatty acids (NEFAs) and triglyceride fatty acids (TGFAs) and increased the polyunsaturated fatty acid (PUFA) fraction of NEFAs but had no effects on the biomarkers for oxidative balance in plasma. During training, plasma protein markers of oxidative damage, the haemolysis degree and the antioxidant enzyme activities increased, but did not affect lipid oxidative damage. Training season and DHA influenced the circulating levels of prostaglandin E2 (PGE2). Acute exercise did not alter the basal levels of plasma markers for oxidative and nitrosative damage of proteins and lipids, and the antioxidant enzyme activities, although DHA-diet supplementation significantly increased the PGE2 in plasma after acute exercise. In conclusion, the training season and acute exercise, but not the DHA diet supplementation, altered the pattern of plasma oxidative damage, as the antioxidant system proved sufficient to prevent the oxidative damage induced by the acute exercise in well-trained footballers. The DHA-diet supplementation increased the prostaglandin PGE2 plasma evidencing anti-inflammatory effects of DHA to control inflammation after acute exercise. PMID- 24955730 TI - Systemic cytokine and interferon responsiveness Patterns in HIV and HCV mono and co-infections. AB - The role of host response-related factors in the fast progression of liver disease in individuals co-infected with HIV and HCV viruses remains poorly understood. This study compared patterns of cytokines, caspase-1 activation, endotoxin exposure in plasma as well as interferon signaling in peripheral blood mononuclear cells from HIV/HCV co-infected (HIV(+)/HCV(+)), HCV mono-infected (HIV(-)/HCV(+)), HIV mono-infected (HIV(+)/HCV(-)) female patients and HIV- and HCV-uninfected women (HIV(-)/HCV(-)) who had enrolled in the Women's Interagency HIV Study (WIHS). HIV(+)/HCV(+) women had higher plasma levels of pro inflammatory cytokines as well as caspase-1 compared with other groups. Both HIV(+)/HCV(+) and HIV(+)/HCV(-) women had significantly higher sCD14 levels compared with other groups. Peripheral blood mononuclear cells from HCV mono infected patients had reduced levels of phosphorylation of STAT1 compared with other groups as well as lower basal levels of expression of the IFN-stimulated genes, OAS1, ISG15, and USP18 (UBP43). Basal expression of USP18, a functional antagonist of ISG15, as well as USP18/ISG15 ratios were increased in the HIV(+)/HCV(+) group compared with HIV(-)/HCV(+) and HIV(+)/HCV(-) groups. A more pronounced systemic inflammatory profile as well as increased expression ratios of USP18 to ISG15 may contribute to the more rapid progression of liver disease in HIV(+)/HCV(+) individuals. PMID- 24955733 TI - Assessment of DNA encapsulation, a new room-temperature DNA storage method. AB - A new procedure for room-temperature storage of DNA was evaluated whereby DNA samples from human tissue, bacteria, and plants were stored under an anoxic and anhydrous atmosphere in small glass vials fitted in stainless-steel, laser-sealed capsules (DNAshells((r))). Samples were stored in DNAshells((r)) at room temperature for various periods of time to assess any degradation and compare it to frozen control samples and those stored in GenTegraTM tubes. The study included analysis of the effect of accelerated aging by using a high temperature (76 degrees C) at 50% relative humidity. No detectable DNA degradation was seen in samples stored in DNAshells((r)) at room temperature for 18 months. Polymerase chain reaction experiments, pulsed field gel electrophoresis, and amplified fragment length polymorphism analyses also demonstrated that the protective properties of DNAshells((r)) are not affected by storage under extreme conditions (76 degrees C, 50% humidity) for 30 hours, guaranteeing 100 years without DNA sample degradation. However, after 30 hours of storage at 76 degrees C, it was necessary to include adjustments to the process in order to avoid DNA loss. Successful protection of DNA was obtained for 1 week and even 1 month of storage at high temperature by adding trehalose, which provides a protective matrix. This study demonstrates the many advantages of using DNAshells((r)) for room temperature storage, particularly in terms of long-term stability, safety, transport, and applications for molecular biology research. PMID- 24955734 TI - How to design biospecimen identifiers and integrate relevant functionalities into your biospecimen management system. AB - Effective tracking of biospecimens within a biobank requires that each biospecimen has a unique identifier (ID). This ID can be found on the sample container as well as in the biospecimen management system. In the latter, the biospecimen ID is the key to annotation data such as location, quality, and sample processing. Guidelines such as the Best Practices from the International Society of Biological and Environmental Repositories only state that a unique identifier should be issued for each sample. However, to our knowledge, all guidelines lack a specific description of how to actually generate such an ID and how this can be supported by an IT system. Here, we provide a guide for biobankers on how to generate a biospecimen ID for your biobank. We also provide an example of how to apply this guide using a longitudinal multi-center research project (and its biobank). Starting with a description of the biobank's purpose and workflows through to collecting requirements from stakeholders and relevant documents (i.e., guidelines or data protection concepts), and existing IT systems, we describe in detail how a concept to develop an ID system can be developed from this information. The concept contains two parts: one is the generation of the biospecimen ID according to the requirements of stakeholders, existing documentation such as guidelines or data protection concepts, and existing IT-infrastructures, and the second is the implementation of the biospecimen IDs and related functionalities covering the handling of individual biospecimens within an existing biospecimen management system. From describing the concept, the article moves on to how the new concept supports both existing or planned biobank workflows. Finally, the implementation and validation step is outlined to the reader and practical hints are provided for each step. PMID- 24955736 TI - Donor verification using Short Tandem Repeat (STR) analysis directly from blood collected in PAXgene RNA tubes. AB - Biorepository processing includes nucleic acid extractions in batch mode from a large number of blood samples from many different donors. Handling such a large number of biospecimens presents the challenge of ensuring that samples are not switched or mislabeled during processing. One approach for confirming donor identity from DNA samples is the use of multiplexed fluorescent PCR for detecting Short Tandem Repeat (STR) allelic-size polymorphisms for a set of common autosomal loci. While donor identity of DNA extracted directly from blood collected in standard tubes containing anticoagulants can be easily verified by generating STR profiles, RNA from blood collected in PAXgene Blood RNA tubes (PAXgene RNA tubes) is depleted of DNA and is not amenable to STR fingerprinting for donor identity verification. We investigated the feasibility of isolating DNA directly from blood collected in PAXgene RNA tubes for use as template for STR DNA fingerprinting for blood donor identity verification. We determined that DNA extraction can be performed manually with the QIAamp DNA Blood Minikit or on the QIAxtractor instrument with minimal pre-processing protocol additions, and that DNA isolated from blood collected in PAXgene RNA tubes is of sufficient quantity and quality for successful STR fingerprint analysis. Adaptation of quality assurance methods such as the PAXgene RNA tube DNA extraction/STR fingerprinting assay described here is a good practice that ensures that biobanking collections provide scientists with high quality, donor-verified biomaterial. PMID- 24955735 TI - Viable mononuclear cell stability study for implementation in a proficiency testing program: impact of shipment conditions. AB - The impact of shipping temperatures and preservation media used during transport of either peripheral blood mononuclear cells (PBMCs) or Jurkat cells was assessed, in view of implementing of a proficiency testing scheme on mononuclear cell viability. Samples were analyzed before and after shipment at different temperatures (ambient temperature, dry ice, and liquid nitrogen) and in different preservation media (serum with cryoprotectant, commercial cryopreservation solution, and room temperature transport medium). Sample quality was assessed by viability assays (Trypan Blue dye exclusion, flow cytometry, Cell Analysis System cell counting (CASY)), and by ELISpot functional assay. The liquid nitrogen storage and shipment were found to be the most stable conditions to preserve cell viability and functionality. However, we show that alternative high quality shipment conditions for viable cells are dry ice shipment and commercial cryopreservation solution. These were also cost-efficient shipment conditions, satisfying the requirements of a proficiency testing scheme for viable mononuclear cells. Room temperature transport medium dramatically and adversely affected the integrity of mononuclear cells. PMID- 24955737 TI - Swietokrzyski biobank. PMID- 24955739 TI - Efficacy of oral valproic acid in patients with retinitis pigmentosa. AB - PURPOSE: To evaluate the efficacy of valproic acid (VPA) on visual function in patients with retinitis pigmentosa (RP). METHODS: Thirty patients (60 eyes) with typical RP were recruited for the study. Of these, 15 patients received oral VPA (500 mg once daily) for a period of 1 year (group 1) and the remaining 15 received no treatment (group 2) and served as controls. The effect of VPA on visual function was determined in terms of visual acuity, amplitude and implicit time in multifocal electroretinography (mfERG), and visual evoked response (VER) performed at presentation and at the third month, sixth month, and 1 year in both groups. Side effects of oral VPA were also monitored. RESULTS: At 1-year follow up, 14 of 15 patients in group 1 had improvement in median best corrected visual acuity (BCVA) from 1.8 [Range (R) 1-3] at baseline to 1.3 (R, 0.6-1.3) (P<0.001). In contrast, there was a slight decrease in median BCVA from 1.8 (0.8- 3) logarithm of the minimum angle of resolution (logMAR) at baseline to 1.83 (P=0.3) in the control arm. There was also a statistically significant increase in improvement in amplitude and latency/implicit time in mfERG and VER in this group (P<0.001). However, no such improvement was observed in the control arm. CONCLUSIONS: Thus, VPA seems to have a positive effect on the visual functions in RP patients. Long-term studies evaluating the dose modifications, genetic analysis, and change in visual fields will add to our current knowledge. PMID- 24955740 TI - Estimation of 24-hour urinary sodium excretion using spot urine samples. AB - The present study evaluated the reliability of equations using spot urine (SU) samples in the estimation of 24-hour urine sodium excretion (24-HUNa). Equations estimating 24-HUNa from SU samples were derived from first-morning SU of 101 participants (52.4 +/- 11.1 years, range 24-70 years). Equations developed by us and other investigators were validated with SU samples from a separate group of participants (n = 224, 51.0 +/- 10.9 years, range 24-70 years). Linear, quadratic, and cubic equations were derived from first-morning SU samples because these samples had a sodium/creatinine ratio having the highest correlation coefficient for 24-HUNa/creatinine ratio (r = 0.728, p < 0.001). In the validation group, the estimated 24-HUNa showed significant correlations with measured 24-HUNa values. The estimated 24-HUNa by the linear, quadratic, and cubic equations developed from our study were not significantly different from measured 24-HUNa, while estimated 24-HUNa by previously developed equations were significantly different from measured 24-HUNa values. The limits of agreement between measured and estimated 24-HUNa by six equations exceeded 100 mmol/24-hour in the Bland-Altman analysis. All equations showed a tendency of under- or over estimation of 24-HUNa, depending on the level of measured 24-HUNa. Estimation of 24-HUNa from single SU by equations as tested in the present study was found to be inadequate for the estimation of an individual's 24-HUNa. PMID- 24955741 TI - Generation of multipotent early lymphoid progenitors from human embryonic stem cells. AB - During human embryonic stem cell (ESC) hematopoietic differentiation, the description of the initial steps of lymphopoiesis remains elusive. Using a two step culture procedure, we identified two original populations of ESC-derived hematopoietic progenitor cells (HPCs) with CD34(+)CD45RA(+)CD7(-) and CD34(+)CD45RA(+)CD7(+) phenotypes. Bulk cultures and limiting dilution assays, culture with MS5 cells in the presence of Notch ligand Delta-like-1 (DL-1), and ex vivo colonization tests using fetal thymic organ cultures showed that although CD34(+)CD45RA(+)CD7(-) HPCs could generate cells of the three lymphoid lineages, their potential was skewed toward the B cell lineages. In contrast, CD34(+)CD45RA(+)CD7(+) HPCs predominantly exhibited a T/natural killer (NK) cell differentiation potential. Furthermore these cells could differentiate equivalently into cells of the granulo-macrophagic lineage and dendritic cells and lacked erythroid potential. Expression profiling of 18 markers by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) revealed that CD34(+)CD45RA(+)CD7(-) and CD34(+)CD45RA(+)CD7(+) HPCs express genes of the lymphoid specification and that CD34(+)CD45RA(+)CD7(-) cells express B-cell associated genes, while CD34(+)CD45RA(+)CD7(+) HPCs display a T-cell molecular profile. Altogether, these findings indicate that CD34(+)CD45RA(+)CD7(-) and CD34(+)CD45RA(+)CD7(+) HPCs correspond to candidate multipotent early lymphoid progenitors polarized toward either the B or T/NK lineage, respectively. This work should improve our understanding of the early steps of lymphopoiesis from pluripotent stem cells and pave the way for the production of lymphocytes for cell-based immunotherapy and lymphoid development studies. PMID- 24955742 TI - The decrease in aqueous tear production associated with pepper spray. AB - PURPOSE: Pepper spray is used both by civilians and by law enforcement. Burning sensation occurs when exposed to skin, pain and temporary blindness occurs when exposed to the eyes. This study focused on the effect of pepper spray on lacrimal tear production and subsequently on corneal sensitivity in a large group after an intense exposure. METHODS: Ninety-six people who were exposed to pepper spray during the Gezi park protests volunteered. Subjects were asked if they wore any protective goggles and if they irrigated their eyes after exposure. They were asked to record their symptoms regarding dry eye in a standardized questionnaire. Schirmer I and II tests were performed. RESULTS: Eighty-two people wore protective goggles during exposure, whereas 14 people did not have any protection. Both Schirmer results in unprotected subjects were significantly lower than that in protected subjects. Schirmer I and II results of unprotected subjects were not statistically different, whereas they were statistically different in protected subjects. Thirty-five percent of unprotected subjects and 24% of protected subjects expressed symptoms of dry eye. DISCUSSION: The active ingredient of pepper spray is oleoresin capsicum. It is randomly diffused to polymodal nerve terminals, leading to opening of non-selective cationic channels and block neuronal transmission. The lower results of both Schirmer in unprotected group emphasize the importance of a protective Google glass around the eyes during exposal, serving as a barrier minimalizing the contact of the spray with the eyes. The combination of the low results and lack of symptoms could suggest that corneal reflex lacrimation in our subjects was not abundant enough. The findings of this study could not fully represent long term findings but it could be assumed that our findings could be indicative of the sensory denervation and alterations demonstrated in studies investigating the long term effects of oleoresin capsicum. PMID- 24955744 TI - Cytocompatibility and Mechanical Properties of Short Phosphate Glass Fibre Reinforced Polylactic Acid (PLA) Composites: Effect of Coupling Agent Mediated Interface. AB - In this study three chemical agents Amino-propyl-triethoxy-silane (APS), sorbitol ended PLA oligomer (SPLA) and Hexamethylene diisocyanate (HDI) were identified to be used as coupling agents to react with the phosphate glass fibre (PGF) reinforcement and the polylactic acid (PLA) polymer matrix of the composite. Composites were prepared with short chopped strand fibres (l = 20 mm, phi = 20 um) in a random arrangement within PLA matrix. Improved, initial composite flexural strength (~20 MPa) was observed for APS treated fibres, which was suggested to be due to enhanced bonding between the fibres and polymer matrix. Both APS and HDI treated fibres were suggested to be covalently linked with the PLA matrix. The hydrophobicity induced by these coupling agents (HDI, APS) helped to resist hydrolysis of the interface and thus retained their mechanical properties for an extended period of time as compared to non-treated control. Approximately 70% of initial strength and 65% of initial modulus was retained by HDI treated fibre composites in contrast to the control, where only ~50% of strength and modulus was retained after 28 days of immersion in PBS at 37 degrees C. All coupling agent treated and control composites demonstrated good cytocompatibility which was comparable to the tissue culture polystyrene (TCP) control, supporting the use of these materials as coupling agent's within medical implant devices. PMID- 24955743 TI - Mangiferin attenuates TH1/TH2 cytokine imbalance in an ovalbumin-induced asthmatic mouse model. AB - Mangiferin is a major bioactive ingredient in Mangifera indica Linn. (Anacardiaceae) leaves. Aqueous extract of such leaves have been used as an indigenous remedy for respiratory diseases like asthma and coughing in traditional Chinese medicine. However, underlying molecular mechanisms of mangiferin on anti-asthma remain unclear. In our present study, we investigated the anti-asthmatic effect of mangiferin on Th1/Th2 cytokine profiles and explored its underlying immunoregulatory mechanism in mouse model of allergic asthma. Mangiferin significantly reduced the total inflammatory cell counts and eosinophil infiltration, decreased the production of ovalbumin-specific IgE in serum and PGD2 in BALF. The antibody array analysis showed that mangiferin down regulated the levels of one group of cytokines/chemokines including Th2-related IL-4, IL-5, IL-13, and others IL-3, IL-9, IL-17, RANTES, TNF-alpha, but simultaneously up-regulated Th1-related IFN-gamma, IL-2 and IL-10 and IL-12 expression in serum. Thus it attenuates the imbalance of Th1/Th2 cells ratio by diminishing the abnormal mRNA levels of Th1 cytokines (IFN-gamma and IL-12) and Th2 cytokines (IL-4, IL-5 and IL-13). Finally, mangiferin substantially inhibited the activation and expression of STAT-6 and GATA-3 in excised lung tissues. Our results suggest that mangiferin can exert anti-asthmatic effect. The underlying mechanism may attribute to the modulation of Th1/Th2 cytokine imbalance via inhibiting the STAT6 signaling pathway. PMID- 24955738 TI - Telemedicine approaches to evaluating acute-phase retinopathy of prematurity: study design. AB - PURPOSE: Detecting sight-threatening retinopathy of prematurity (ROP) relies on a diagnostic examination (DE) performed by an experienced ophthalmologist. An alternative may be a telemedicine system where retinal images of at-risk infants are graded by readers to determine features of ROP indicating the need for a DE. METHODS: The multicenter Telemedicine Approaches to Evaluating Acute-phase ROP (e ROP) Study is a cohort study of 2000 infants with birth weights <1251 g. At each visit, ophthalmologists perform DEs and non-physician imagers obtain iris and five retinal images with the disc positioned in the center, right, left, up and down. Images are uploaded to a secure server for grading by non-physician readers for the detection of plus disease, stage 3 ROP and/or zone I disease, any of which indicates "referral-warranted ROP" (RW-ROP). Images from all infants with RW-ROP and a random sample of infants without RW-ROP (based on DEs) are selected for grading. Gradings are compared to DEs to determine the validity and evaluate reliability, feasibility, safety, and cost-effectiveness of the telemedicine system. RESULTS: e-ROP is conducted in 12 Clinical Centers in the US and Canada with Study Headquarters, the Data Coordinating Center and the Image Reading Center in Philadelphia and the ROP Data Center in Oklahoma City. A total of 27 study center coordinators, 34 ophthalmologists, 26 imagers, and 4 readers have been certified. All study data are submitted using a secure web-based system. CONCLUSION: The design and findings of this study will be useful to conduct other ROP studies or evaluate telemedicine for other diseases. PMID- 24955746 TI - Hydration-induced phase separation in amphiphilic polymer matrices and its influence on voclosporin release. AB - Voclosporin is a highly potent, new cyclosporine-A derivative that is currently in Phase 3 clinical trials in the USA as a potential treatment for inflammatory diseases of the eye. Voclosporin represents a number of very sparingly soluble drugs that are difficult to administer. We therefore selected it as a model drug that is dispersed within amphiphilic polymer matrices, and investigated the changing morphology of the matrices using neutron and x-ray scattering during voclosporin release and polymer resorption. The hydrophobic segments of the amphiphilic polymer chain are comprised of desaminotyrosyl-tyrosine ethyl ester (DTE) and desaminotyrosyl-tyrosine (DT), and the hydrophilic component is poly(ethylene glycol) (PEG). Water uptake in these matrices resulted in the phase separation of hydrophobic and hydrophilic domains that are a few hundred Angstroms apart. These water-driven morphological changes influenced the release profile of voclosporin and facilitated a burst-free release from the polymer. No such morphological reorganization was observed in poly(lactide-co-glycolide) (PLGA), which exhibits an extended lag period, followed by a burst-like release of voclosporin when the polymer was degraded. An understanding of the effect of polymer composition on the hydration behavior is central to understanding and controlling the phase behavior and resorption characteristics of the matrix for achieving long-term controlled release of hydrophobic drugs such as voclosporin. PMID- 24955745 TI - Tissue engineering of corneal endothelium. AB - Human corneal endothelial cells (HCECs) do not replicate after wounding. Therefore, corneal endothelial deficiency can result in irreversible corneal edema. Descemet stripping automated endothelial keratoplasty (DSAEK) allows selective replacement of the diseased corneal endothelium. However, DSAEK requires a donor cornea and the worldwide shortage of corneas limits its application. This review presents current knowledge on the tissue engineering of corneal endothelium using cultured HCECs. We also provide our recent work on tissue engineering for DSAEK grafts using cultured HCECs. We reconstructed DSAEK grafts by seeding cultured DiI-labelled HCECs on collagen sheets. Then HCEC sheets were transplanted onto the posterior stroma after descemetorhexis in the DSAEK group. Severe stromal edema was detected in the control group, but not in the DSAEK group throughout the observation period. Fluorescein microscopy one month after surgery showed numerous DiI-labelled cells on the posterior corneal surface in the DSAEK group. Frozen sections showed a monolayer of DiI-labelled cells on Descemet's membrane. These findings indicate that cultured adult HCECs, transplanted with DSAEK surgery, maintain corneal transparency after transplantation and suggest the feasibility of performing DSAEK with HCECs to treat endothelial dysfunction. PMID- 24955747 TI - Mineralization content alters osteogenic responses of bone marrow stromal cells on hydroxyapatite/polycaprolactone composite nanofiber scaffolds. AB - Synthetic tissue scaffolds have a high potential impact for patients experiencing osteogenesis imperfecta. Using electrospinning, tissue scaffolds composed of hydroxyapatite/polycaprolactone (HAp/PCL) composite nanofibers were fabricated with two different HAp concentrations-1% and 10% of the solid scaffold weight. After physico-chemical scaffold characterization, rat bone marrow stromal cells were cultured on the composite scaffolds in maintenance medium and then in osteogenic medium. Quantitative PCR, colorimetric assays, immunofluorescent labeling, and electron microscopy measured osteogenic cell responses to the HAp/PCL scaffolds. In maintenance conditions, both Hap/PCL scaffolds and control scaffolds supported cell colonization through seven days with minor differences. In osteogenic conditions, the 10% HAp scaffolds exhibited significantly increased ALP assay levels at week 3, consistent with previous reports. However, qPCR analysis demonstrated an overall decrease in bone matrix-associated genes on Hap/PCL scaffolds. Osteopontin and osteocalcin immunofluorescent microscopy revealed a trend that both mineralized scaffolds had greater amounts of both proteins, though qPCR results indicated the opposite trend for osteopontin. Additionally, type I collagen expression decreased on HAp scaffolds. These results indicate that cells are sensitive to minor changes in mineral content within nanofibers, even at just 1% w/w, and elucidating the sensing mechanism may lead to optimized osteogenic scaffold designs. PMID- 24955750 TI - Biocompatibility of bacterial cellulose based biomaterials. AB - Some bacteria can synthesize cellulose when they are cultivated under adequate conditions. These bacteria produce a mat of cellulose on the top of the culture medium, which is formed by a three-dimensional coherent network of pure cellulose nanofibers. Bacterial cellulose (BC) has been widely used in different fields, such as the paper industry, electronics and tissue engineering due to its remarkable mechanical properties, conformability and porosity. Nanocomposites based on BC have received much attention, because of the possibility of combining the good properties of BC with other materials for specific applications. BC nanocomposites can be processed either in a static or an agitated medium. The fabrication of BC nanocomposites in static media can be carried out while keeping the original mat structure obtained after the synthesis to form the final nanocomposite or by altering the culture media with other components. The present article reviews the issue of biocompatibility of BC and BC nanocomposites. Biomedical aspects, such as surface modification for improving cell adhesion, in vitro and in vivo studies are given along with details concerning the physics of network formation and the changes that occur in the cellulose networks due to the presence of a second phase. The relevance of biocompatibility studies for the development of BC-based materials in bone, skin and cardiovascular tissue engineering is also discussed. PMID- 24955751 TI - Extracellular Matrix is an Important Component of Limbal Stem Cell Niche. AB - Extracellular matrix plays an important role in stem cell niche which maintains the undifferentiated stem cell phenotype. Human corneal epithelial stem cells are presumed to reside mainly at the limbal basal epithelium. Efforts have been made to characterize different components of the extracellular matrix that are preferentially expressed at the limbus. Mounting evidence from experimental data suggest that these components are part of the stem cell niche and play a role in the homeostasis of limbal stem cells. The extracellular matrix provides a mechanical and structural support as well as regulates cellular functions such as adhesion, migration, proliferation, self-renewal and differentiation. Optimization of the extracellular matrix components might be able to recreate an ex vivo stem cell niche to expand limbal stem cells. PMID- 24955748 TI - Strategic design and fabrication of engineered scaffolds for articular cartilage repair. AB - Damage to articular cartilage can eventually lead to osteoarthritis (OA), a debilitating, degenerative joint disease that affects millions of people around the world. The limited natural healing ability of cartilage and the limitations of currently available therapies make treatment of cartilage defects a challenging clinical issue. Hopes have been raised for the repair of articular cartilage with the help of supportive structures, called scaffolds, created through tissue engineering (TE). Over the past two decades, different designs and fabrication techniques have been investigated for developing TE scaffolds suitable for the construction of transplantable artificial cartilage tissue substitutes. Advances in fabrication technologies now enable the strategic design of scaffolds with complex, biomimetic structures and properties. In particular, scaffolds with hybrid and/or biomimetic zonal designs have recently been developed for cartilage tissue engineering applications. This paper reviews critical aspects of the design of engineered scaffolds for articular cartilage repair as well as the available advanced fabrication techniques. In addition, recent studies on the design of hybrid and zonal scaffolds for use in cartilage tissue repair are highlighted. PMID- 24955752 TI - Lurasidone for the treatment of depressive symptoms in schizophrenia: analysis of 4 pooled, 6-week, placebo-controlled studies. AB - OBJECTIVE: Depressive symptoms are common in schizophrenia and can worsen outcomes and increase suicide risk. Lurasidone is an atypical antipsychotic agent indicated for the treatment of schizophrenia and for the treatment of major depressive episodes associated with bipolar I disorder. This post hoc analysis evaluated the effect of lurasidone on depressive symptoms in patients with schizophrenia. METHODS: Patient-level data were pooled from 4 similarly designed, double-blind, placebo-controlled, 6-week registration studies of lurasidone (40 160 mg/d) in adult patients with an acute exacerbation of schizophrenia. Changes in depressive symptoms, measured by the Montgomery-Asberg Depression Rating Scale (MADRS), were analyzed for the overall sample and for subgroups of patients stratified by baseline MADRS scores. RESULTS: MADRS assessments at baseline and endpoint (day 42 or last observation carried forward [LOCF]) were available for 1330 patients. Patients receiving lurasidone experienced significantly greater decreases in MADRS score (-2.8, least-squares [LS] mean change, LOCF) compared with patients receiving placebo (-1.4, P < .001, effect size 0.24). Analysis of change in MADRS score (LOCF) by baseline symptom severity (MADRS score of >=12, >=14, >=16, >=18) showed significantly greater improvement for lurasidone-treated patients across all severity groups; effect sizes ranged from 0.25 to 0.34. Among patients with a baseline MADRS score of >=12, depressive symptom remission (defined as MADRS score <10 at LOCF endpoint) was attained by 45.0% of lurasidone treated patients and 36.3% of patients receiving placebo (P < .05). CONCLUSIONS: In a pooled analysis of short-term, placebo-controlled studies, lurasidone significantly improved depressive symptoms in patients with schizophrenia. PMID- 24955754 TI - DNA hydrogel by multicomponent assembly for encapsulation and killing of cells. AB - In this work, a new multifunctional assembled hydrogel was prepared by incorporating gadolinium ions (Gd(3+)) with salmon-sperm DNA and polythiophene derivative (PT-COOH) through chelation interactions. Efficient energy transfer from PT-COOH to Gd(3+) ions takes place followed by sensitization of oxygen molecule to generate reactive oxygen species (ROS) under light irradiation. Cancer cells can be encapsulated into the hydrogel in situ as the formation of hydrogel followed by killing by the ROS. Integration of imaging modality with therapeutic function within a single assembled hydrogel is therefore anticipated to be a new and challenging design element for new hydrogel materials. PMID- 24955749 TI - Building biocompatible hydrogels for tissue engineering of the brain and spinal cord. AB - Tissue engineering strategies employing biomaterials have made great progress in the last few decades. However, the tissues of the brain and spinal cord pose unique challenges due to a separate immune system and their nature as soft tissue. Because of this, neural tissue engineering for the brain and spinal cord may require re-establishing biocompatibility and functionality of biomaterials that have previously been successful for tissue engineering in the body. The goal of this review is to briefly describe the distinctive properties of the central nervous system, specifically the neuroimmune response, and to describe the factors which contribute to building polymer hydrogels compatible with this tissue. These factors include polymer chemistry, polymerization and degradation, and the physical and mechanical properties of the hydrogel. By understanding the necessities in making hydrogels biocompatible with tissue of the brain and spinal cord, tissue engineers can then functionalize these materials for repairing and replacing tissue in the central nervous system. PMID- 24955753 TI - Individual with subclinical atherosclerosis have impaired proliferation of blood outgrowth endothelial cells, which can be restored by statin therapy. AB - BACKGROUND: To study the regenerative capacity of the endothelium in patients with coronary artery disease (CAD), we cultured blood outgrowth endothelial cells (BOECs) of patients with premature CAD and their first degree relatives (FDR). Additionally we evaluated the influence of statin treatment on circulating BOEC precursors in subjects with subclinical atherosclerosis. METHODS AND RESULTS: Patients with premature CAD (men <51 yr, women <56 yr) and their FDRs were included. Based on coronary calcification (CAC) scores FDRs were divided in a group of healthy subjects (CAC = 0) and subjects with subclinical atherosclerosis (CAC>0). We did not observe differences in the number of BOEC colonies and proliferation between premature CAD patients and FDRs. FDRs with subclinical atherosclerosis had lower colony numbers compared with healthy FDRs, however this was not statistically significant, and BOEC proliferation was significantly impaired (OR = 0.45, 95% CI 0.21-0.96). Unexpectedly, the number of BOEC colonies and BOEC proliferation were similar for premature CAD patients and healthy FDRs. Since a considerable number of premature CAD patients used statins, we studied the number of BOEC precursors as well as their proliferative capacity in ten individuals with subclinical atherosclerosis, before and after statin therapy. Interestingly, FDRs with subclinical atherosclerosis showed a significant increase in the number of BOEC colonies after statin therapy. CONCLUSION: BOEC proliferation of subjects with subclinical atherosclerosis is impaired compared with healthy controls. In these subjects, statin therapy significantly increased the number of circulating BOEC precursors as well as their proliferative capacity, revealing a beneficial effect of statins on endothelial regeneration. PMID- 24955756 TI - Redox-driven molecular switches consisting of bis(benzodithiolyl)bithienyl scaffold and mesogenic moieties: synthesis and complexes with liquid crystalline polymer. AB - Molecular switches composed of a benzodithiolylbithienyl scaffold and biphenyl or terphenyl mesogenic substituents were designed and synthesized. The molecular switches could undergo redox-triggered interconversion between the cationic form and cyclized neutral form, and this was confirmed using cyclic voltammetry and UV vis spectroscopy. Binary complexes consisting of the molecular switches and a liquid crystalline polymer (LCP) were prepared to investigate the function of these redox-active molecular switches as actuating dopants. X-ray diffraction measurements were performed to determine the differences between the layer spacings of the complexes in the liquid crystalline phase with the oxidized and reduced states of the molecular switches. The LCP that was doped with the oxidized cationic form of the molecular switch had layer spacings that were up to 4% larger than the layer spacings in the polymer that was doped with the reduced cyclized molecular switch. Our approach will allow stimulus-responsive deformable materials to be constructed and give an impetus for fabricating redox-driven soft actuators. PMID- 24955755 TI - Cardiac surgery capacity in sub-saharan Africa: quo vadis? AB - BACKGROUND: Current data on cardiac surgery capacity on which to base effective concepts for developing sustainable cardiac surgical programs in Africa are lacking or of low quality. METHODS: A questionnaire concerning cardiac surgery in Africa was sent to 29 colleagues-26 cardiac surgeons and 3 cardiologists in 16 countries. Further, data on numbers of surgeons practicing in Africa were retrieved from the Cardiothoracic Surgery Network (CTSNet). RESULTS: There were 25 respondents, yielding a response rate of 86.2%. Three models emerged: the Ghanaian/German model with a senior local consultant surgeon (Model 1); surgeons visiting for a short period to perform humanitarian surgery (Model 2); and expatriate surgeons on contract to develop cardiac programs (Model 3). The 933 cardiothoracic surgeons listed by CTSNet translated into one surgeon per 1.3 million people. In North Africa, the figure was three surgeons per 1 million and in sub-Saharan Africa (SSA), one surgeon per 3.3 million people. The identified 156 cardiac surgeons represented a surgeon to population ratio of 1:5.9 million people. In SSA, the ratio was one surgeon per 14.3 million. In North Africa, it was one surgeon per 1.1 million people. Open heart operations were approximately 12 per million in Africa, 2 per million in SSA, and 92 per million people in North Africa. CONCLUSION: Cardiothoracic health care delivery would worsen in SSA without the support of humanitarian surgery. Although all three models have potential for success, the Ghanaian/German model has proved to be successful in the long term and could inspire health care policy makers and senior colleagues planning to establish cardiac programs in Africa. PMID- 24955757 TI - Phosphorus and water budgets in an agricultural basin. AB - Water and phosphorus (P) budgets of a large agricultural basin located in South Florida (Everglades Agricultural Area, EAA) were computed from 2005 to 2012. The annual surface outflow P loading from the EAA averaged 157.2 mtons originating from Lake Okeechobee (16.4 mtons, 10.4%), farms (131.0 mtons, 83.4%), and surrounding basins (9.8 mtons, 6.2%) after attenuation. Farms, urban areas, and the adjacent C-139 basin contributed 186.1, 15.6, and 3.8 mtons/yr P to the canals, respectively. The average annual soil P retention was estimated at 412.5 mtons. Water and P budgets showed seasonal variations with high correlation between rainfall and P load in drainage and surface outflows. Moreover, results indicated that the canals acted as a P sink storing 64.8 mtons/yr. To assess the P loading impact of farm drainage on the canals and on the outflow, dimensionless impact factors were developed. Sixty-two farms were identified with a high and a medium impact factor I1 level contributing 44.5% of the total drainage P load to the canals, while their collective area represented less than 23% of the EAA area (172 farms). Optimizing the best management practice (BMP) strategies on these farms could minimize the environmental impacts on the downstream sensitive wetlands areas. PMID- 24955760 TI - Photochemical properties of trans-1-chloro-3,3,3-trifluoropropene (trans CHCl?CHCF3): OH reaction rate constant, UV and IR absorption spectra, global warming potential, and ozone depletion potential. AB - Measurements of the rate constant for the gas-phase reactions of OH radicals with trans-1-chloro-3,3,3-trifluoropropene (trans-CHCl?CHCF3) were performed using a flash photolysis resonance-fluorescence technique over the temperature range 220 370 K. The reaction rate constant exhibits a noticeable curvature of the temperature dependence in the Arrhenius plot, which can be represented by the following expression: kt-CFP (220-370 K) = 1.025 * 10(-13) * (T/298)(2.29) exp(+384/T) cm(3 )molecule(-1) s(-1). The room-temperature rate constant was determined to be kt-CFP (298 K) = (3.29 +/- 0.10) * 10(-13) cm(3) molecule(-1) s( 1), where the uncertainty includes both two standard errors (statistical) and the estimated systematic error. For atmospheric modeling purposes, the rate constant below room temperature can be represented by the following expression: kt-CFP (220-298 K) = (7.20 +/- 0.46) * 10(-13) exp[-(237 +/- 16)/T] cm(3) molecule(-1) s(-1). There was no difference observed between the rate constants determined at 4 kPa (30 Torr) and 40 kPa (300 Torr) at both 298 and 370 K. The UV and IR absorption cross sections of this compound were measured at room temperature. The atmospheric lifetime, global warming potential, and ozone depletion potential of trans-CHCl?CHCF3 were estimated. PMID- 24955759 TI - Further optimization of the reliability of the 28-joint disease activity score in patients with early rheumatoid arthritis. AB - BACKGROUND: The 28-joint Disease Activity Score (DAS28) combines scores on a 28 tender and swollen joint count (TJC28 and SJC28), a patient-reported measure for general health (GH), and an inflammatory marker (either the erythrocyte sedimentation rate [ESR] or the C-reactive protein [CRP]) into a composite measure of disease activity in rheumatoid arthritis (RA). This study examined the reliability of the DAS28 in patients with early RA using principles from generalizability theory and evaluated whether it could be increased by adjusting individual DAS28 component weights. METHODS: Patients were drawn from the DREAM registry and classified into a "fast response" group (N = 466) and "slow response" group (N = 80), depending on their pace of reaching remission. Composite reliabilities of the DAS28-ESR and DAS28-CRP were determined with the individual components' reliability, weights, variances, error variances, correlations and covariances. Weight optimization was performed by minimizing the error variance of the index. RESULTS: Composite reliabilities of 0.85 and 0.86 were found for the DAS28-ESR and DAS28-CRP, respectively, and were approximately equal across patients groups. Component reliabilities, however, varied widely both within and between sub-groups, ranging from 0.614 for GH ("slow response" group) to 0.912 for ESR ("fast response" group). Weight optimization increased composite reliability even further. In the total and "fast response" groups, this was achieved mostly by decreasing the weight of the TJC28 and GH. In the "slow response" group, though, the weights of the TJC28 and SJC28 were increased, while those of the inflammatory markers and GH were substantially decreased. CONCLUSIONS: The DAS28-ESR and the DAS28-CRP are reliable instruments for assessing disease activity in early RA and reliability can be increased even further by adjusting component weights. Given the low reliability and weightings of the general health component across subgroups it is recommended to explore alternative patient-reported outcome measures for inclusion in the DAS28. PMID- 24955761 TI - Intramolecular cyclization of alkynyl alpha-ketoanilide utilizing [1,2]-phospha Brook rearrangement catalyzed by phosphazene base. AB - A novel catalytic cyclization reaction of alkynyl alpha-ketoanilide was developed by utilizing the [1,2]-phospha-Brook rearrangement. This reaction involves the generation of an amide enolate via the umpolung process, that is the addition of dialkyl phosphite to a keto moiety followed by the [1,2]-phospha-Brook rearrangement, and the subsequent intramolecular addition of the enolate to an alkyne to afford 3,4-dihydro-2-quinolone derivatives. Under high-temperature reaction conditions, further rearrangement of the allylic phosphate moiety occurs to provide 2-quinolone derivatives. PMID- 24955762 TI - Functional annotation and structural characterization of a novel lactonase hydrolyzing D-xylono-1,4-lactone-5-phosphate and L-arabino-1,4-lactone-5 phosphate. AB - A novel lactonase from Mycoplasma synoviae 53 (MS53_0025) and Mycoplasma agalactiae PG2 (MAG_6390) was characterized by protein structure determination, molecular docking, gene context analysis, and library screening. The crystal structure of MS53_0025 was determined to a resolution of 2.06 A. This protein adopts a typical amidohydrolase (beta/alpha)8-fold and contains a binuclear zinc center located at the C-terminal end of the beta-barrel. A phosphate molecule was bound in the active site and hydrogen bonds to Lys217, Lys244, Tyr245, Arg275, and Tyr278. Both docking and gene context analysis were used to narrow the theoretical substrate profile of the enzyme, thus directing empirical screening to identify that MS53_0025 and MAG_6390 catalyze the hydrolysis of d-xylono-1,4 lactone-5-phosphate (2) with kcat/Km values of 4.7 * 10(4) and 5.7 * 10(4) M(-1) s(-1) and l-arabino-1,4-lactone-5-phosphate (7) with kcat/Km values of 1.3 * 10(4) and 2.2 * 10(4) M(-1) s(-1), respectively. The identification of the substrate profile of these two phospho-furanose lactonases emerged only when all methods were integrated and therefore provides a blueprint for future substrate identification of highly related amidohydrolase superfamily members. PMID- 24955765 TI - uPAR targeted radionuclide therapy with (177)Lu-DOTA-AE105 inhibits dissemination of metastatic prostate cancer. AB - The urokinase-type plasminogen activator receptor (uPAR) is implicated in cancer invasion and metastatic development in prostate cancer and provides therefore an attractive molecular target for both imaging and therapy. In this study, we provide the first in vivo data on an antimetastatic effect of uPAR radionuclide targeted therapy in such lesions and show the potential of uPAR positron emission tomography (PET) imaging for identifying small foci of metastatic cells in a mouse model of disseminating human prostate cancer. Two radiolabeled ligands were generated in high purity and specific activity: a uPAR-targeting probe ((177)Lu DOTA-AE105) and a nonbinding control ((177)Lu-DOTA-AE105mut). Both uPAR flow cytometry and ELISA confirmed high expression levels of the target uPAR in PC-3M LUC2.luc cells, and cell binding studies using (177)Lu-DOTA-AE105 resulted in a specific binding with an IC50 value of 100 nM in a competitive binding experiment. In vivo, uPAR targeted radionuclide therapy significantly reduced the number of metastatic lesions in the disseminated metastatic prostate cancer model, when compared to vehicle and nontargeted (177)Lu groups (p < 0.05) using bioluminescence imaging. Moreover, we found a significantly longer metastatic free survival, with 65% of all mice without any disseminated metastatic lesions present at 65 days after first treatment dose (p = 0.047). In contrast, only 30% of all mice in the combined control groups treated with (177)Lu-DOTA-AE105mut or vehicle were without metastatic lesions. No treatment-induced toxicity was observed during the study as evaluated by observing animal weight and H&E staining of kidney tissue (dose-limiting organ). Finally, uPAR PET imaging using (64)Cu-DOTA-AE105 detected all small, disseminated metastatic foci when compared with bioluminescence imaging in a cohort of animals during the treatment study. In conclusion, uPAR targeted radiotherapy resulted in a significant reduction in the number of metastatic lesions in a human metastatic prostate cancer model. Furthermore, we have provided the first evidence of the potential for identification of small metastatic lesions using uPAR PET imaging in disseminated prostate cancer, illustrating the promising strategy of uPAR theranostics in prostate cancer. PMID- 24955764 TI - Early responses of natural killer cells in pigs experimentally infected with 2009 pandemic H1N1 influenza A virus. AB - Natural killer (NK) cells are important players in the innate immune response against influenza A virus and the activating receptor NKp46, which binds hemagglutinin on the surface of infected cells, has been assigned a role in this context. As pigs are natural hosts for influenza A viruses and pigs possess both NKp46- and NKp46+ NK cells, they represent a good animal model for studying the role of the NKp46 receptor during influenza. We explored the role of NK cells in piglets experimentally infected with 2009 pandemic H1N1 influenza virus by flow cytometric analyses of cells isolated from blood and lung tissue and by immunostaining of lung tissue sections. The number of NKp46+ NK cells was reduced while NKp46- NK cells remained unaltered in the blood 1-3 days after infection. In the lungs, the intensity of NKp46 expression on NK cells was increased during the first 3 days, and areas where influenza virus nucleoprotein was detected were associated with increased numbers of NKp46+ NK cells when compared to uninfected areas. NKp46+ NK cells in the lung were neither found to be infected with influenza virus nor to be undergoing apoptosis. The binding of porcine NKp46 to influenza virus infected cells was verified in an in vitro assay. These data support the involvement of porcine NKp46+ NK cells in the local immune response against influenza virus. PMID- 24955763 TI - CRISPLD2 is a target of progesterone receptor and its expression is decreased in women with endometriosis. AB - Endometriosis, defined as the presence of endometrial cells outside of the uterine cavity, is a major cause of infertility and pelvic pain, afflicting more than 10% of reproductive age women. Endometriosis is a chronic inflammatory disease and lipopolysaccharide promotes the proliferation and invasion of endometriotic stromal cells. Cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2) has high affinity for lipopolysaccharide and plays a critical role in defense against endotoxin shock. However, the function of CRISPLD2 has not been studied in endometriosis and uterine biology. Herein, we examined the expression of CRISPLD2 in endometrium from patients with and without endometriosis using immunohistochemistry. The expression of CRISPLD2 was higher in the secretory phase in human menstrual cycle compared to proliferative phase. The expression of CRISPLD2 was significantly decreased in the endometrium of women with endometriosis in the early secretory phase compared to women without endometriosis. The increase of CRISPLD2 expression at the early secretory and dysregulation of its expression in endometriosis suggest progesterone (P4) regulation of CRISPLD2. To investigate whether CRISPLD2 is regulated by P4, we examined the expression of the CRISPLD2 in the uteri of wild-type and progesterone receptor knock out (PRKO) mice. The expression of CRISPLD2 was significantly increased after P4 treatment in the wild-type mice. However, CRISPLD2 expression was significantly decreased in the (PRKO) mice treated with P4. During early pregnancy, the expression of CRISPLD2 was increased in decidua of implantation and post-implantation stages. CRISPLD2 levels were also increased in cultured human endometrial stromal cells during in vitro decidualization. These results suggest that the CRISPLD2 is a target of the progesterone receptor and may play an important role in pathogenesis of endometriosis. PMID- 24955766 TI - Quantifying 'causality' in complex systems: understanding transfer entropy. AB - 'Causal' direction is of great importance when dealing with complex systems. Often big volumes of data in the form of time series are available and it is important to develop methods that can inform about possible causal connections between the different observables. Here we investigate the ability of the Transfer Entropy measure to identify causal relations embedded in emergent coherent correlations. We do this by firstly applying Transfer Entropy to an amended Ising model. In addition we use a simple Random Transition model to test the reliability of Transfer Entropy as a measure of 'causal' direction in the presence of stochastic fluctuations. In particular we systematically study the effect of the finite size of data sets. PMID- 24955767 TI - Human intestinal cells modulate conjugational transfer of multidrug resistance plasmids between clinical Escherichia coli isolates. AB - Bacterial conjugation in the human gut microbiota is believed to play a major role in the dissemination of antibiotic resistance genes and virulence plasmids. However, the modulation of bacterial conjugation by the human host remains poorly understood and there is a need for controlled systems to study this process. We established an in vitro co-culture system to study the interaction between human intestinal cells and bacteria. We show that the conjugation efficiency of a plasmid encoding an extended spectrum beta-lactamase is reduced when clinical isolates of Escherichia coli are co-cultured with human intestinal cells. We show that filtered media from co-cultures contain a factor that reduces conjugation efficiency. Protease treatment of the filtered media eliminates this inhibition of conjugation. This data suggests that a peptide or protein based factor is secreted on the apical side of the intestinal cells exposed to bacteria leading to a two-fold reduction in conjugation efficiency. These results show that human gut epithelial cells can modulate bacterial conjugation and may have relevance to gene exchange in the gut. PMID- 24955769 TI - Unentangled star-shape poly(epsilon-caprolactone)s as phthalate-free PVC plasticizers designed for non-toxicity and improved migration resistance. AB - We develop a nontoxic unentangled star-shape poly(epsilon-caprolactone) (UESPCL) plasticizer with excellent migration resistance for the production of phthalate free flexible poly(vinyl chloride) (PVC) by means of the ring-opening polymerization of epsilon-caprolactone, initiated from the multifunctional core, combined with end-capping, and vacuum purification processes. UESPCL is a transparent liquid at room temperature and exhibits unentangled Newtonian behavior because of its extremely short branched segments. UESPCL is biologically safe without producing an acute toxicity response. Torque analysis measurements reveals that UESPCL offers a faster fusion rate and a higher miscibility with PVC compared to a typical plasticizer, di(2-ethylhexyl) phthalate (DEHP). The solid state (1)H nuclear magnetic resonance (NMR) spectrum reveals that PVC and UESPCL are miscible with an average domain size of less than 8 nm. The flexibility and transparency of the PVC/UESPCL mixture, that is, phthalate-free flexible PVC, are comparable to the corresponding properties of the PVC/DEHP mixture, and the stretchability and fracture toughness of PVC/UESPCL are superior to the corresponding properties of the PVC/DEHP system. Most of all, PVC/UESPCL shows excellent migration resistance with a weight loss of less than 0.6% in a liquid phase, whereas DEHP migrated out of PVC/DEHP into a liquid phase with a weight loss of about 10%. PMID- 24955768 TI - Anthropogenic litter in urban freshwater ecosystems: distribution and microbial interactions. AB - Accumulation of anthropogenic litter (i.e. garbage; AL) and its ecosystem effects in marine environments are well documented. Rivers receive AL from terrestrial habitats and represent a major source of AL to marine environments, but AL is rarely studied within freshwater ecosystems. Our objectives were to 1) quantify AL density in urban freshwaters, 2) compare AL abundance among freshwater, terrestrial, and marine ecosystems, and 3) characterize the activity and composition of AL biofilms in freshwater habitats. We quantified AL from the Chicago River and Chicago's Lake Michigan shoreline, and found that AL abundance in Chicago freshwater ecosystems was comparable to previously reported data for marine and terrestrial ecosystems, although AL density and composition differed among habitats. To assess microbial interactions with AL, we incubated AL and natural substrates in 3 freshwater ecosystems, quantified biofilm metabolism as gross primary production (GPP) and community respiration (CR), and characterized biofilm bacterial community composition via high-throughput sequencing of 16S rRNA genes. The main driver of biofilm community composition was incubation location (e.g., river vs pond), but there were some significant differences in biofilm composition and metabolism among substrates. For example, biofilms on organic substrates (cardboard and leaves) had lower GPP than hard substrates (glass, plastic, aluminum and tiles). In addition, bacterial communities on organic substrates were distinct in composition from those on hard substrates, with higher relative abundances of bacteria associated with cellulose decomposition. Finally, we used our results to develop a conceptual diagram designed to unite the study of AL in terrestrial and freshwater environments with the well-established field of marine debris research. We suggest this broad perspective will be useful for future studies which synthesize AL sources, ecosystem effects, and fate across multiple ecosystem types, and will benefit management and reduction of global AL accumulations. PMID- 24955770 TI - Interaction of Astramol poly(propyleneimine) dendrimers with DNA and poly(methacrylate) anion in water and water-salt solutions. AB - Interaction of poly(propyleneimine) dendrimers DAB-dendr-(NH2)x of five generations (x = 4, 8, 16, 32, and 64) with either calf thymus DNA or tagged by pyrenyl groups poly(methacrylate) anion (PMA*) as well as destruction of formed polyelectrolyte complexes by the added sodium chloride were studied by fluorescence quenching techniques. DNA-containing complexes (dendriplexes) were investigated by ethidium bromide assay, whereas formation of PMA* complexes was estimated by fluorescence of the pyrenyl groups that remained free of contact with the dendrimers-quenchers. The ion pairing with DNA phosphate groups was pH sensitive and accompanied by inaccessibility of a part of the dendrimer amino groups even in slightly acidic media. The growth of the generation number resulted in successive stabilization of the dendriplexes against the added salt. The dendriplexes of all dendrimers except DAB-dendr-(NH2)4 were stable at physiological ionic strength. In contrast to the highly charged cationic polymer poly(N-ethyl-4-vinylpyridinium) bromide of different degrees of polymerization, the dendrimers formed more stable complexes with flexible PMA* rather than with DNA, proving the inaccessibility of a part of the amino groups for the rigid double helix. The revealed regularities appear to be a platform for design of dendriplexes with controllable stability, in particular fulfilling the requirements imposed for gene delivery vehicles. PMID- 24955771 TI - Autoregressive higher-order hidden Markov models: exploiting local chromosomal dependencies in the analysis of tumor expression profiles. AB - Changes in gene expression programs play a central role in cancer. Chromosomal aberrations such as deletions, duplications and translocations of DNA segments can lead to highly significant positive correlations of gene expression levels of neighboring genes. This should be utilized to improve the analysis of tumor expression profiles. Here, we develop a novel model class of autoregressive higher-order Hidden Markov Models (HMMs) that carefully exploit local data dependent chromosomal dependencies to improve the identification of differentially expressed genes in tumor. Autoregressive higher-order HMMs overcome generally existing limitations of standard first-order HMMs in the modeling of dependencies between genes in close chromosomal proximity by the simultaneous usage of higher-order state-transitions and autoregressive emissions as novel model features. We apply autoregressive higher-order HMMs to the analysis of breast cancer and glioma gene expression data and perform in-depth model evaluation studies. We find that autoregressive higher-order HMMs clearly improve the identification of overexpressed genes with underlying gene copy number duplications in breast cancer in comparison to mixture models, standard first- and higher-order HMMs, and other related methods. The performance benefit is attributed to the simultaneous usage of higher-order state-transitions in combination with autoregressive emissions. This benefit could not be reached by using each of these two features independently. We also find that autoregressive higher-order HMMs are better able to identify differentially expressed genes in tumors independent of the underlying gene copy number status in comparison to the majority of related methods. This is further supported by the identification of well-known and of previously unreported hotspots of differential expression in glioblastomas demonstrating the efficacy of autoregressive higher-order HMMs for the analysis of individual tumor expression profiles. Moreover, we reveal interesting novel details of systematic alterations of gene expression levels in known cancer signaling pathways distinguishing oligodendrogliomas, astrocytomas and glioblastomas. An implementation is available under www.jstacs.de/index.php/ARHMM. PMID- 24955772 TI - A novel viable allele of Arabidopsis CULLIN1 identified in a screen for superroot2 suppressors by next generation sequencing-assisted mapping. AB - Map-based cloning (MBC) is the conventional approach for linking phenotypes to genotypes, and has been successfully used to identify causal mutations in diverse organisms. Next-generation sequencing (NGS) technologies offer unprecedented possibilities to sequence the entire genomes of organisms, thereby in principle enabling direct identification of causal mutations without mapping. However, although mapping-by-sequencing has proven to be a cost effective alternative to classical MBC in particular situations, methods based solely on NGS still have limitations and need to be refined. Aiming to identify the causal mutations in suppressors of Arabidopsis thaliana superroot2 phenotype, generated by ethyl methane sulfonate (EMS) treatment, we combined NGS and classical mapping, to rapidly identify the point mutations and restrict the number of testable candidates by defining the chromosomal intervals containing the causal mutations, respectively. The NGS-assisted mapping approach we describe here facilitates unbiased identification of virtually any causal EMS-generated mutation by overlapping the identification (deep sequencing) and validation (mapping) steps. To exemplify the useful marriage of the two approaches we discuss the strategy used to identify a new viable recessive allele of the Arabidopsis CULLIN1 gene in the non-reference Wassilewskija (Ws-4) accession. PMID- 24955775 TI - Synergistic foaming and surface properties of a weakly interacting mixture of soy glycinin and biosurfactant stevioside. AB - The adsorption of the mixtures of soy glycinin (11S) with a biosurfactant stevioside (STE) at the air-water interface was studied to understand its relation with foaming properties. A combination of several techniques such as dynamic surface tension, dilatational rheology, fluorescence spectroscopy, and isothermal titration calorimetry (ITC) was used. In the presence of intermediate STE concentrations (0.25-0.5%), the weak binding of STE with 11S in bulk occurred by hydrophobic interactions, which could induce conformational changes of 11S, as evidenced by fluorescence and ITC. Accordingly, the strong synergy in reducing surface tension and the plateau in surface elasticity for mixed 11S-STE layers formed from the weakly interacting mixtures were clearly observed. This effect could be explained by the complexation with STE, which might facilitate the partial dissociation and further unfolding of 11S upon adsorption, thus enhancing the protein-protein and protein-STE interfacial interactions. These surface properties were positively reflected in foams produced by the weakly interacting system, which exhibited good foaming capacity and considerable stability probably due to better response to external stresses. However, at high STE concentrations (1-2%), as a consequence of the interface dominated by STE due to the preferential adsorption of STE molecules, the surface elasticity of layers dramatically decreased, and the resultant foams became less stable. PMID- 24955773 TI - Fine physical and genetic mapping of powdery mildew resistance gene MlIW172 originating from wild emmer (Triticum dicoccoides). AB - Powdery mildew, caused by Blumeria graminis f. sp. tritici, is one of the most important wheat diseases in the world. In this study, a single dominant powdery mildew resistance gene MlIW172 was identified in the IW172 wild emmer accession and mapped to the distal region of chromosome arm 7AL (bin7AL-16-0.86-0.90) via molecular marker analysis. MlIW172 was closely linked with the RFLP probe Xpsr680 derived STS marker Xmag2185 and the EST markers BE405531 and BE637476. This suggested that MlIW172 might be allelic to the Pm1 locus or a new locus closely linked to Pm1. By screening genomic BAC library of durum wheat cv. Langdon and 7AL-specific BAC library of hexaploid wheat cv. Chinese Spring, and after analyzing genome scaffolds of Triticum urartu containing the marker sequences, additional markers were developed to construct a fine genetic linkage map on the MlIW172 locus region and to delineate the resistance gene within a 0.48 cM interval. Comparative genetics analyses using ESTs and RFLP probe sequences flanking the MlIW172 region against other grass species revealed a general co linearity in this region with the orthologous genomic regions of rice chromosome 6, Brachypodium chromosome 1, and sorghum chromosome 10. However, orthologous resistance gene-like RGA sequences were only present in wheat and Brachypodium. The BAC contigs and sequence scaffolds that we have developed provide a framework for the physical mapping and map-based cloning of MlIW172. PMID- 24955776 TI - Indazole- and indole-5-carboxamides: selective and reversible monoamine oxidase B inhibitors with subnanomolar potency. AB - Indazole- and indole-carboxamides were discovered as highly potent, selective, competitive, and reversible inhibitors of monoamine oxidase B (MAO-B). The compounds are easily accessible by standard synthetic procedures with high overall yields. The most potent derivatives were N-(3,4-dichlorophenyl)-1-methyl 1H-indazole-5-carboxamide (38a, PSB-1491, IC50 human MAO-B 0.386 nM, >25000-fold selective versus MAO-A) and N-(3,4-dichlorophenyl)-1H-indole-5-carboxamide (53, PSB-1410, IC50 human MAO-B 0.227 nM, >5700-fold selective versus MAO-A). Replacement of the carboxamide linker with a methanimine spacer leading to (E)-N (3,4-dichlorophenyl)-1-(1H-indazol-5-yl)methanimine (58) represents a further novel class of highly potent and selective MAO-B inhibitors (IC50 human MAO-B 0.612 nM, >16000-fold selective versus MAO-A). In N-(3,4-difluorophenyl-1H indazole-5-carboxamide (30, PSB-1434, IC50 human MAO-B 1.59 nM, selectivity versus MAO-A>6000-fold), high potency and selectivity are optimally combined with superior physicochemical properties. Computational docking studies provided insights into the inhibitors' interaction with the enzyme binding site and a rationale for their high potency despite their small molecular size. PMID- 24955774 TI - The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model. AB - Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia) as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra epidermal nerve fibers (IENFs) in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved. PMID- 24955777 TI - Diurnal cortisol rhythms in youth from risky families: effects of cumulative risk exposure and variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) [corrected]. AB - Building on research on cumulative risk and psychopathology, this study examines how cumulative risk exposure is associated with altered diurnal cortisol rhythms in an ethnically diverse, low-income sample of youth. In addition, consistent with a diathesis-stress perspective, this study explores whether the effect of environmental risk is moderated by allelic variation in the promoter region of the serotonin transporter gene-linked polymorphic region (5-HTTLPR). Results show that youth with greater cumulative risk exposure had flatter diurnal cortisol slopes, regardless of 5-HTTLPR genotype. However, the association of cumulative risk with average cortisol output (area under the curve [AUC]) was moderated by the 5-HTTLPR genotype. Among youth homozygous for the long allele, greater cumulative risk exposure was associated with lower cortisol AUC, driven by significant reductions in cortisol levels at waking. In contrast, there was a trend-level association between greater cumulative risk and higher cortisol AUC among youth carrying the short allele, driven by a trend-level increase in bedtime cortisol levels. Findings are discussed with regard to the relevance of dysregulated diurnal cortisol rhythms for the development of psychopathology and the implications of genetically mediated differences in psychophysiological adaptations to stress. PMID- 24955779 TI - Poly(styrene-alt-maleic anhydride)-based diblock copolymer micelles exhibit versatile hydrophobic drug loading, drug-dependent release, and internalization by multidrug resistant ovarian cancer cells. AB - Amphiphilic diblock copolymers of poly(styrene-alt-maleic anhydride)-b poly(styrene) (PSMA-b-PS) and poly(styrene-alt-maleic anhydride)-b-poly(butyl acrylate) (PSMA-b-PBA) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerizations. Polymers were well-controlled with respect to molecular weight evolution and polydispersity indices (PDI < 1.2). Additionally, RAFT allowed for control of diblock compositions (i.e., ratio of hydrophilic PSMA blocks to hydrophobic PS/PBA blocks) and overall molecular weight, which resulted in reproducible self-assembly of diblocks into micelle nanoparticles with diameters of 20-100 nm. Parthenolide (PTL), a hydrophobic anticancer drug, was loaded and released from the micelles. The highest loading and prolonged release of PTL was observed from predominantly hydrophobic PSMA-b PS micelles (e.g., PSMA100-b-PS258), which exhibited the most ordered hydrophobic environment for more favorable core-drug interactions. PSMA100-b-PS258 micelles were further loaded with doxorubicin (DOX), as well as two hydrophobic fluorescent probes, nile red and IR-780. While PTL released quantitatively within 24 h, DOX, IR-780, and nile red showed release over 1 week, suggesting stronger drug-core interactions and/or hindrance due to less favorable drug-solvent interactions. Finally, uptake and intracellular localization of PSMA100-b-PS258 micelles by multidrug resistant (MDR) ovarian cancer cells was observed by transmission electron microscopy (TEM). Additionally, in vitro analyses showed DOX-loaded PSMA-b-PS micelles exhibited greater cytotoxicity to NCI/ADR RES cells than equivalent free DOX doses (75% reduction in cell viability by DOX-loaded micelles compared to 40% reduction in viability by free DOX at 10 MUM DOX), likely due to avoidance of MDR mechanisms that limit free hydrophobic drug accumulation. The ability of micelles to achieve intracellular delivery via avoidance of MDR mechanisms, along with the versatility of chemical constituents and drug loading and release rates, offer many advantages for a variety of drug delivery applications. PMID- 24955778 TI - Disruption of allosteric response as an unprecedented mechanism of resistance to antibiotics. AB - Ceftaroline, a recently approved beta-lactam antibiotic for treatment of infections by methicillin-resistant Staphylococcus aureus (MRSA), is able to inhibit penicillin-binding protein 2a (PBP2a) by triggering an allosteric conformational change that leads to the opening of the active site. The opened active site is now vulnerable to inhibition by a second molecule of ceftaroline, an event that impairs cell-wall biosynthesis and leads to bacterial death. The triggering of the allosteric effect takes place by binding of the first antibiotic molecule 60 A away from the active site of PBP2a within the core of the allosteric site. We document, by kinetic studies and by determination of three X-ray structures of the mutant variants of PBP2a that result in resistance to ceftaroline, that the effect of these clinical mutants is the disruption of the allosteric trigger in this important protein in MRSA. This is an unprecedented mechanism for antibiotic resistance. PMID- 24955780 TI - Extractables and leachables considerations for prefilled syringes. AB - INTRODUCTION: Use of pre-filled syringes as both a packaging and delivery system for pharmaceutical drug products is accelerating. Pre-filled syringes must meet the quality and suitability for use requirements for both systems, including compatibility with the drug product. Relevant incompatibilities between pre filled syringes and drug products include the safety of syringe-based leachables that accumulate in drug products and the ability of leachables to interact with the drug product's ingredients as such interactions can affect safety, efficacy, stability and physical viability. AREAS COVERED: Relevant suitability considerations for pre-filled syringes are discussed herein and specific examples of suitability for use issues for pre-filled syringes are cited, focusing on extractables associated with pre-filled syringes and leachables derived from such syringes. Aspects considered include the toxicological impact of leachables, their ability to alter the efficacy of drug products and to produce other undesirable outcomes such as aggregation and immunogenic responses. EXPERT OPINION: Materials used in pre-filled syringes and the conditions of use minimize the traditional safety risk associated with leachables. However, drug products that use pre-filled syringes are prone to non-traditional interactions such as disruption of protein conformation, leading to potential efficacy, safety and quality issues. In order to qualify pre-filled syringes for use, the traditional approach of measuring extractables and leachables and inferring their effect must be augmented by rigorous compatibility testing. Research into the fundamental relationship between leachables and drug substances will be necessary so the more time- and cost-efficient 'measure and infer' approach can be widely implemented. PMID- 24955781 TI - Prognostic impact of pretransplantation hyperferritinemia in adults undergoing allogeneic hematopoietic SCT: a meta-analysis. PMID- 24955782 TI - Successful HLA haploidentical hematopoietic SCT in chronic granulomatous disease. PMID- 24955783 TI - Post-allograft pomalidomide and reversible hepatotoxicity. PMID- 24955784 TI - Hospital admissions following outpatient administration of high-dose melphalan and autologous SCT for AL amyloidosis. PMID- 24955786 TI - Resolution of chronic active EBV infection and coexisting pulmonary arterial hypertension after cord blood transplantation. PMID- 24955785 TI - Risk associations between HLA-DPB1 T-cell epitope matching and outcome of unrelated hematopoietic cell transplantation are independent of HLA-DPA1. AB - HLA-DP antigens are beta-alpha heterodimers encoded by polymorphic HLA-DPB1 and DPA1 alleles, respectively, in strong linkage disequilibrium (LD) with each other. Non-permissive unrelated donor (UD)-recipient HLA-DPB1 mismatches across three different T-cell epitope (TCE) groups are associated with increased mortality after hematopoietic SCT (HCT), but the role of HLA-DPA1 is unclear. We studied 1281 onco-hematologic patients after 10/10 HLA-matched UD-HCT facilitated by the National Marrow Donor Program. Non-permissive mismatches defined solely by HLA-DPB1 TCE groups were associated with significantly higher risks of TRM compared to permissive mismatches (hazard ratio (HR) 1.30, confidence interval (CI) 1.06-1.53; P=0.009) or allele matches. Moreover, non-permissive HLA-DPB1 TCE group mismatches in the graft versus host (GvH) direction significantly decreased the risk of relapse compared to permissive mismatches (HR 0.55, CI 0.37-0.80; P=0.002) or allele matches. Splitting each group into HLA-DPA1*02:01 positive or negative, in frequent LD with HLA-DPB1 alleles from two of the three TCE groups, or into HLA-DPA1 matched or mismatched, did not significantly alter the observed risk associations. Our findings suggest that the effects of clinically non permissive HLA-DPB1 TCE group mismatches are independent of HLA-DPA1, and that selection of donors with non-permissive DPB1 TCE mismatches in GvH direction might provide some protection from disease recurrence. PMID- 24955787 TI - The reliability of the Leeds Movement Performance Index (LMPI): a new tool for neurological physiotherapy. AB - BACKGROUND: Measuring movement performance in people with neurological damage requires a tool that reflects physiotherapy assessment and clinical reasoning. The Leeds Movement Performance Index (LMPI) was previously developed by a group of neurological physiotherapists to fulfill these requirements. OBJECTIVE: To assess the reliability of the LMPI for use in neurological physiotherapy practice. METHODS: Twelve senior neurological physiotherapists were trained to use the LMPI and then asked to measure the movement performance of five patients whose movement had been previously video-recorded for this purpose. A retest session was completed after two weeks. Data were analysed to establish internal and external reliability. RESULTS: Internal reliability was assessed using Cronbach's alpha coefficient, applied to the entire scale (0.862) and to each item (range 0.795-0.892). External (inter-rater) reliability was assessed by a calculation of the intraclass correlation coefficient for scores awarded by multiple raters (0.959), with individual item reliability ranging from 0.874 to 0.968. External (test-retest) reliability was assessed by calculating the Spearman's rank correlation coefficient between scores obtained on two testing occasions (0.792) with values of individual items ranging from 0.397 to 0.674. A variance components analysis partitioned variance into components arising from between-patient variability (55.2%) between-therapist variability (7.8%) and between-testing variability (2.8%). CONCLUSIONS: RESULTS indicate that the LMPI is a reliable measurement tool when used by senior neurological physiotherapists. PMID- 24955789 TI - New dihydro-beta-agarofuran sesquiterpenes from Parnassia wightiana wall: isolation, identification and cytotoxicity against cancer cells. AB - Five new (4-8) and three known (1-3) dihydro-beta-agarofuran sesquiterpene polyesters were isolated from the whole plants of Parnassia wightiana. The structures of all compounds were elucidated through spectroscopic analysis including 2D-NMR and HR-MS. The absolute configuration of these compounds was established by X-ray diffraction analysis, comparison of NOESY spectra and biogenetic means. The cytotoxities of compounds 2-8 were evaluated in vitro against HL-60, SMMC-7721, A549, MCF-7 and SW480 cell lines. Compounds 5-7 exhibited the highest activities with IC50 values of 11.8-30.1 MUM in most cases. The SAR revealed that the introduction of hydroxyl group was able to significantly improve the activities of the compounds for most of the cell lines. PMID- 24955788 TI - Chronology and chronicity of altered resting-state functional connectivity after traumatic brain injury. AB - Whereas traumatic brain injury (TBI) results in widespread disruption of neural networks, changes in regional resting-state functional connectivity patterns after insult remain unclear. Specifically, little is known about the chronology of emergent connectivity alterations and whether they persist after a critical recovery window. We used resting-state functional magnetic resonance imaging and seed-voxel correlational analyses in both cross-sectional and longitudinal designs to probe intrinsic connectivity patterns involving the posterior cingulate cortex (PCC) and hippocampi, regions shown to be important in the default mode network (DMN) and vulnerable to neuropathology. A total of 22 participants in the chronic stage of moderate-to-severe TBI and 18 healthy controls were included for cross-sectional study. Longitudinal analyses included 13 individuals in the TBI group for whom data approximately 3 months after injury (subacute) were available. Overall, results indicated dissociable connectivity trajectories of the PCC and hippocampi during recovery from TBI, with PCC alterations characterized by early hypersynchrony with the anterior DMN that is gradually reduced, and hippocampal changes marked by increasing synchrony with proximal cortex and subcortex. The PCC also showed increasing antiphase synchrony with posterior attentional regions, and the hippocampi showed decreasing antiphase synchrony with frontal attentional regions. Antiphase synchrony of the hippocampus and dorsolateral prefrontal cortex at the subacute stage of TBI was positively associated with attentional performance on neuropsychological tests at both the subacute and chronic stages. Our findings highlight the heterogeneity of regional whole-brain connectivity changes after TBI, and suggest that residual connectivity alterations exist in the clinically stable phase of TBI. Parallels between the chronicity of the observed effects and findings in neurodegenerative disease are discussed in the context of potential long-term outcomes of TBI. PMID- 24955790 TI - TRAF6 inhibition rescues dexamethasone-induced muscle atrophy. AB - Tumor necrosis factor receptor-associated factor 6 (TRAF6), a unique E3 ubiquitin ligase and adaptor protein, is involved in activation of various signaling cascades. Recent studies identify TRAF6 as one of the novel regulators of skeletal muscle atrophy. The role of TRAF6 in glucocorticoid-induced muscle atrophy, however, remains to be elucidated. In this study, we show that TRAF6 and its downstream signaling molecules, muscle atrophy F-box (MAFBx) and muscle ring finger 1 (MuRF1), were all upregulated in dexamethasone-induced atrophy of mouse C2C12 myotubes or mouse tibialis anterior (TA) muscle. To further investigate the role of TRAF6 in dexamethasone-induced muscle atrophy, TRAF6-siRNA was used to transfect cultured C2C12 myotubes or was injected into the TA muscle of mice respectively, and we note that TRAF6 knockdown attenuated dexamethasone-induced muscle atrophy in vitro and in vivo, and concomitantly decreased the expression of MuRF1 and MAFBx. Our findings suggest that a decreased expression of TRAF6 could rescue dexamethasone-induced skeletal muscle atrophy through, at least in part, regulation of the expression of MAFBx and MuRF1. PMID- 24955792 TI - Genetic variations of TAP1 gene exon 3 affects gene expression and Escherichia coli F18 resistance in piglets. AB - Firstly, our research group identified Sutai pigs' phenotypes that exhibited extreme resistance and susceptibility to the Escherichia coli F18 respectively, and then eight ETEC (Enterotoxigenic Escherichia coli) F18-resistant piglets and eight ETEC F18-sensitive piglets were selected. Then, the TAP1 (Transporter associated with antigen processing) mRNA relative expression levels were analyzed in 11 tissues of the resistant and susceptible phenotypes. Simultaneously, we detected the genetic variations in exon 3 of the TAP1 gene and evaluated the TAP1 mRNA expression levels among the different genotype pigs to study the effects of the genetic variation on gene expression, and the E. coli F18 resistance. The results revealed higher expression levels in the resistant genotypes than that in the susceptible genotypes in 11 tissues, with significant differences in the spleen, lymph node, lung, thymus, duodenum and jejunum. Furthermore, a G729A mutation was identified in the TAP1 gene exon 3, and this mutation deviates from Hardy-Weinberg equilibrium (p < 0.01). The TAP1 mRNA levels in GG genotype were significantly higher than that in the other two genotypes, with significant differences in the liver, lung, kidney, thymus, lymph node, duodenum and jejunum tissues. We speculated that high expression of the TAP1 gene might confer resistance against the E. coli F18, the G729A mutation had a significant effect on the mRNA expression, and individuals with the GG genotype possessed a stronger ability to resist the E. coli F18 infection. PMID- 24955793 TI - Trust - that's a big one: intimate partnership values among urban Latino youth. AB - Romantic relationships play a central role in young people's social development and sexual health. This paper examines romantic relationship ideals valued by urban Latino youth in San Francisco and their experiences in achieving their ideals in their current relationship. We draw on in-depth interviews with 33 young men and women aged 16-22 years in San Francisco, California. In spite of, or perhaps related to, the prevailing perception that their peers were unfaithful in their relationships, young people in this study identified trust as one of the most important characteristics of a romantic relationship. Trust was related not only to fidelity, but also vulnerability and emotional intimacy. Understanding valued relationship ideals and factors that facilitate and impede their attainment is critical in promoting healthy relationships. PMID- 24955794 TI - Interactions of adsorbed CO2 on water ice at low temperatures. AB - We present a computational study into the adsorption properties of CO2 on amorphous and crystalline water surfaces under astrophysically relevant conditions. Water and carbon dioxide are two of the most dominant species in the icy mantles of interstellar dust grains and a thorough understanding of their solid phase interactions at low temperatures is crucial for understanding the structural evolution of the ices due to thermal segregation. In this paper, a new H2O-CO2 interaction potential is proposed and used to model the ballistic deposition of CO2 layers on water ice surfaces, and to study the individual binding sites at low coverages. Contrary to recent experimental results, we do not observe CO2 island formation on any type of water substrate. Additionally, density functional theory calculations are performed to assess the importance of induced electrostatic interactions. PMID- 24955795 TI - Carbapenemase reports from the Balkans: a systematic review. AB - The spread of carbapenemase-producing bacteria constitutes a worldwide problem of major importance to public health. The detection of these enzymes is often reported by most European countries and infection control measures are implemented in order to limit their dissemination. Despite the strong evidence indicating the Balkans as a reservoir for carbapenemase-encoding genes, especially for NDM-1, data published in the English literature seem to be scarce for many of the Balkan countries. We systematically reviewed studies on carbapenemase-producing bacteria from each country of the Balkan Peninsula and correlated them with foreign reports on carbapenemase detection due to patient transfer from the Balkans to the rest of Europe. PMID- 24955796 TI - Anidulafungin versus fluconazole: clinical focus on IDSA and ESCMID guidelines. AB - Invasive infections by Candida spp. play a major role in the management of the critically ill patient. Rates of positive blood cultures for Candida species have risen fivefold in the past ten years, placing this pathogen between the fourth and the sixth-leading cause of nosocomial bloodstream infections in the United States and Europe. Candida albicans is still the cause of approximately 50% of invasive candidiasis, with heterogeneous epidemiology. The echinocandin class, along with voriconazole and liposomal amphotericin B, was recommended by 2009 IDSA guidelines with AI evidence for the treatment of candidaemia, reserving the use of fluconazole in selected situations. Conversely fluconazole was downgraded to CI recommendation (marginal use), with BI evidence for voriconazole and liposomal amphotericin B, maintaining AI (strong support) for echinocandins by 2012 ESCMID guidelines for the diagnosis and management of Candida disease in non neutropenic adult patients. Our brief analysis of randomized trials, whereby recommendations are supported, aims to discuss the possible reasons for the different consideration of fluconazole by the two above mentioned guidelines. PMID- 24955797 TI - Effect of oral cephalexin in the treatment of BCG lymphadenitis. AB - Lymphadenitis and abscess formation are the most common side effects of vaccination with Bacille Calmette Guerin (BCG). The lower the child's age at the time of vaccination, the higher the incidence of BCG lymphadenitis tends to be. Although various therapeutic approaches are in use for the treatment of BCG lymphadenitis, there is no consensus on which of them is optimal. This study aimed to determine whether oral cephalexin treatment hastens recovery from BCG lymphadenitis. The study involved 40 children (24 boys and 16 girls) with BCG lymphadenitis who were referred to Qazvin Children's Hospital, Qazvin University of Medical Sciences between December 2008 and the end of September 2009. The patients were randomly assigned to two groups of 20 patients each (12 boys and 8 girls in each group): group A patients did not receive any treatment and served as controls, and group B patients were treated with 50 mg/kg/day cephalexin syrup, administered in four doses, for 10 days. In all patients, clinical examination was normal, except for lymphadenitis. In all patients, BCG vaccination had been performed at birth, and polymerase chain reaction tests were positive for tuberculous bacilli. The recovery period and requirement of fine needle aspiration did not significantly differ between the two groups (P 0.05). This study showed that treatment with cephalexin does not hasten recovery from BCG lymphadenitis. PMID- 24955798 TI - [Budget impact analysis of efavirenz daily dose reduction at the Verona University Hospital]. AB - Efavirenz is a non-nucleoside-reverse-transcriptase-inhibitor used as part of highly-active-antiretroviral-therapy for the treatment of the human immunodeficiency virus (HIV) type 1 infection. The present paper aims to describing the impact of efavirenz dose reduction on the pharmaceutical budget at the Verona University Hospital. A budget impact analysis comparing two prescribing scenarios was conducted: all patients treated with the efavirenz full dose (600 mg per day) vs. a proportion of patients treated with a reduced dose (200-400 mg per day). All outpatients referring to the Infectious Disease Clinic in the period November 2009-October 2011 were selected. Out of 132 patients treated with efavirenz, 25 were not considered, mainly due to a too short treatment period. Of the remaining 107 patients, 68 received the full dose, while 39 received a reduced dosage. The analysis included the cost of the drug and of diagnostic tests, from the National Health Service perspective. The daily dose reduction of efavirenz saved 54,664 euros (a 30% expenditure reduction). In sum, new strategies for pharmaceutical system sustainability are necessary; despite forthcoming expiring patents of several drugs, spending on antiretroviral drugs is expected to rise. This paper suggests a way of linking clinical benefits and cost reduction. PMID- 24955791 TI - Identification of drivers from cancer genome diversity in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers with a dismal outcome. The complicated molecular pathogenesis of HCC caused by tumor heterogeneity makes it difficult to identify druggable targets useful for treating HCC patients. One approach that has a potential for the improvement of patient prognosis is the identification of cancer driver genes that play a critical role in the development of HCC. Recent technological advances of high throughput methods, such as gene expression profiles, DNA copy number alterations and somatic mutations, have expanded our understanding of the comprehensive genetic profiles of HCC. Integrative analysis of these omics profiles enables us to classify the molecular subgroups of HCC patients. As each subgroup classified according to genetic profiles has different clinical features, such as recurrence rate and prognosis, the tumor subclassification tools are useful in clinical practice. Furthermore, a global genetic analysis, including genome-wide RNAi functional screening, makes it possible to identify cancer vulnerable genes. Identification of common cancer driver genes in HCC leads to the development of an effective molecular target therapy. PMID- 24955799 TI - [Trends in infective endocarditis in a medium-sized University Hospital in Italy: analysis of 232 cases]. AB - The aim of this study was to evaluate the epidemiological and clinical characteristics of 232 cases of infective endocarditis (IE), admitted to the Clinica delle Malattie Infettive of Perugia Italy from 1973 to 2012. The analysis was retrospective until 2004. After this year, all the consecutive IE cases were included by utilizing the same prospective observational protocol of the Italian Study on Endocarditis (SEI). Out of 232 EI cases, 200 (86.2 %) were definite. Over the 40-year period, a statistically significant increase was observed in the patients' age, the rate of IE admissions and prosthetic device IEs. The rate of healthcare-associated IEs also increased in the last 10 years (p=NS). Diabetes mellitus was the most frequent comorbidity. There were no variations in the rate of S. aureus and streptococcal IEs. Central nervous system complications and surgery were reported in 19.4 percent and 29.3 percent of the cases, respectively. The in-hospital mortality was 18.9 percent. In conclusion, the epidemiological and clinical trends of this study are in agreement with the literature. The difference in S. aureus endocarditis, neurological complications and surgery rates may be due to the fact that this was a single centre and, for its first part, a retrospective study. A shared, multidisciplinary protocol may be useful to improve the outcome of patients with IE and its epidemiology. PMID- 24955800 TI - Listeria monocytogenes-associated meningitis and arthritis in an immunocompetent 65-year-old woman: a case report. AB - We report an unusual case of concurrent meningitis and infectious monoarthritis due to Listeria monocytogenes in a 65-year-old woman presenting to our department with a transient gastrointestinal tract illness. During hospitalization the patient's neurological status deteriorated, presenting signs of meningeal irritation along with signs of inflammation and oedema of the right knee. Blood cultures and cultures of the cerebrospinal fluid and of the sinovial fluid aspirate showed growth of L. monocytogenes gram positive rods. The patient received a three-week course of intravenous meropenem with significant improvement. To the best of our knowledge this is the first case of concurrent listerial meningitis and arthritis in an immunocompetent patient. Despite the rarity of the disease in healthy individuals a high index of suspicion is required for unusual manifestations of listerial infections especially among high risk groups such as the elderly. PMID- 24955801 TI - An atypical deep neck infection in a two-year-old child. AB - Non-tuberculous mycobacteria are one of the major causes of lymphadenitis in children and seldom of deep neck infections. We reported the case of an immunocompetent two-year-old girl with adenitis and retropharyngeal abscess caused by an atypical mycobacterium. She had a positive tuberculin skin test, whereas the Quantiferon TB Gold test was negative. The child underwent a complete nodal excision. The search for acid fast bacilli was positive and Mycobacterium scrofulaceum was isolated from the surgically removed material. The retropharyngeal abscess was treated only with antimicrobial therapy, which resulted in an appreciable size reduction of the abscess. After two months antimicrobial treatment was interrupted, and complete resolution was achieved after twelve months. No relapse of disease or possible long-term complications were observed. The surgical wound healed completely, with normal overlying skin and a good aesthetic result. The clinical management of atypical mycobacteria lymphadenitis and retropharyngeal abscess in children is discussed. PMID- 24955802 TI - Chlamydia trachomatis conjunctivitis in a male teenager: a case report. AB - An 18 year old man was seen at a Sexually Transmitted Infections (STIs) clinic for counselling and treatment of Chlamydia trachomatis genital infection which had been diagnosed during a screening survey of high school students. For two months he had reported conjunctival hyperaemia, increased tearing, itching, and mucopurulent secretions, predominantly on the left eye. His ophthalmologist had made a diagnosis of follicular conjunctivitis and lower superficial punctate keratitis (left eye more than right eye), irresponsive to topical treatment. Chlamydial conjunctivitis was suspected and confirmed by a positive nucleic acid amplification test (NAAT) performed on conjunctival scraping. The patient was treated with azithromycin 1 g single dose orally and tetracycline/betamethasone eye ointment for one month. A complete resolution of symptoms was observed three months after aetiological treatment. This case highlights the need to include C. trachomatis infection in the differential diagnosis of acute or chronic follicular conjunctivitis among sexually active young individuals. PMID- 24955803 TI - Tuberculosis of the tongue in a patient with rheumatoid arthritis treated with methotrexate and adalimumab. AB - In recent years Tumor Necrosis Factor alpha (TNF alfa) inhibitors have been highly effective in treating rheumatoid arthritis (RA). However, patients receiving these inhibitors have an increased risk of developing tuberculosis (TB). We describe a rare case of tuberculosis of the tongue in an RA patient treated with methotrexate (MTX) and the TNF alfa inhibitor adalimumab (ADA) for the previous six years. Pretreatment tuberculin skin test (TST) was negative. The patient was admitted to our division complaining of a sore throat for months. Clinical examination revealed a swollen non-healing ulcer at the base of the tongue, which was suspected to be a squamous cell carcinoma. Histopathological assessment unexpectedly revealed a chronic granulomatous inflammation compatible with tuberculosis. TST was strongly positive and the T Spot TB test was also reactive. MTX and ADA were discontinued and the patient received antituberculous treatment with complete healing of the lesion. After three months our patient had a worsening RA that was treated with MTX and rituximab with no TB related adverse events. This case highlights the importance of considering tuberculosis in the differential diagnosis of ulcerative lesions of the oral cavity, especially in immunocompromised patients treated with TNF alfa inhibitors. Rituximab can be a valid alternative therapy in such patients. PMID- 24955804 TI - Leclercia adecarboxylata bacteraemia in an immunocompromised patient with metabolic syndrome. AB - Leclercia adecarboxylata is being increasingly diagnosed as a causative agent of infection due to the availability of rapid molecular diagnostic techniques Few cases of bacteraemia in subjects with underlying medical conditions have been reported. We report a case of L. adecarboxylata bacteraemia in an immunocompromised patient with metabolic syndrome. PMID- 24955805 TI - [Seven cases of port-a-cath contamination caused by Pantoea agglomerans in the Oncological Service of Iseo Hospital, Brescia (Italy)]. AB - Pantoea agglomerans, a gram negative bacillus in the Enterobacteriaceae family, has been isolated from feculent material, plants and soil. Soft tissue and bone joint infections due to P. agglomerans following penetrating trauma by vegetation and bacteraemia in association with intravenous fluid, total parenteral nutrition, blood products and anaesthetic agent contamination have been reported. Between October 2009 and January 2010 seven cases of port a cath contamination caused by P. agglomerans were observed in the Oncological Service of our hospital. All patients presented with septic fever after heparinization of the central venous catheter. 5/7 patients were female; mean age was 67 years (range 58-75). 6/7 patients were affected by colorectal adenocarcinoma, 1/7 by mammarian cancer. Mean time from CVC insertion was 23.8 months (range 13-42) at the time of fever. In three cases, port a cath was removed following the oncologist prescription. P. agglomerans was isolated from the catheter tip in one case and from CVC blood culture in 6-7 cases. In all cases peripheral blood cultures were negative. Patients were treated with ciprofloxacin lock therapy and systemic therapy (per os), obtaining negative cultures from port a cath. Notwithstanding the absence of isolation of Pantoea strains from environmental cultures, after educational intervention, which underlined some faulty procedures in CVC management, no further cases were observed. PMID- 24955807 TI - Dynamic self-assembly of coordination polymers in aqueous solution. AB - The construction of supramolecular polymers has been intensively pursued because the nanostructures formed through weak non-covalent interactions can be triggered by external stimuli leading to smart materials and sensors. Self-assemblies of coordination polymers consisting of metal ions and organic ligands in aqueous solution also provide particular contributions in this area. The main motivation for developing those coordination polymers originates from the value-added combination between metal ions and ligands. This review highlights the recent progress of the dynamic self-assembly of coordination polymers that result from the sophisticated molecular design, towards fabricating stimuli-responsive systems and bio-related materials. Dynamic structural changes and switchable physical properties triggered by various stimuli are summarized. Finally, the outlook for aqueous nanostructures originated from the dynamic self-assembly of coordination polymers is also presented. PMID- 24955808 TI - Direct evidence by in situ IR CO monitoring of the formation and the surface segregation of a Pt-Sn alloy. AB - The heat of CO adsorption on the Pt atoms of a Pt-Sn alloy phase could be specifically determined from in situ DRIFTS data and was found to be about half that measured on a plain Pt reference. Surprisingly, a reversible surface segregation of the Pt-Sn alloy was observed at temperatures below 175 degrees C. PMID- 24955806 TI - [Malaria in endemic areas of Northern Italy and in the Italian context: remedies and substitutes in the nineteenth century medical practice]. AB - Some areas of Northern Italy, especially Ferrara during the nineteenth century, represent privileged observatories regard to malaria, a disease that affected the poor, but did not spare the rich and powerful people. The so called Delta of the River Po, as well as the Maremma and other lowland areas in Italy, was particularly noted for its marshland environment (mosquito breeding grounds). Spared from Malaria because of the better hygienic conditions of the city that restricted the proliferation of anopheles, Ferrara represented an important study centre due to the presence of renowned physicians and scientists who exchanged knowledge and findings in the medical academies. Among these, Antonio Campana was very attentive to the latest scientific findings, and wrote about antimalarial remedies in his famous Ferrarese Pharmacopoeia. This paper analyses the main remedies listed in the various editions of Campana Pharmacopoeia since 1798 and particularly that of 1841, in the reports from the Accademia Medico Chirurgica di Ferrara and of Argenta physicians of the mid nineteenth century and in the Reports (1871 and 1876) from Alessandro Bennati, director of Arcispedale Santa Anna and concerned with hospital practice. Other printed documents referring to the town of Argenta are discussed. PMID- 24955809 TI - The effect of CXCL12 on endothelial progenitor cells: potential target for angiogenesis in intracerebral hemorrhage. AB - Endothelial progenitor cells (EPCs) may contribute to vascular repair and angiogenesis. Chemokine (C-X-C motif) ligand 12 (CXCL12/SDF-1) is known to play an important role in the mobilization and recruitment of progenitor cells. Therefore, we assessed the function of CXCL12 as a stimulating molecule of angiogenesis in EPCs and the underlying mechanism after intracerebral hemorrhage (ICH). Isolated EPCs from male Sprague-Dawley rats, stimulate with various doses of CXCL12. Then, 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess the proliferation of EPCs, and cell migration and adhesion were analyzed by transwell chamber assay. Furthermore, mRNA levels of endothelial markers von Willebrand Factor (vWF), Tie-2, and vascular endothelial cadherin (VE-cadherin) were explored by real-time polymerase chain reaction. Capillary tube and vessel formation in vitro and in vivo were detected after pretreatment with the C-X-C chemokine receptor type 4 (CXCR4) inhibitor AMD3100. Following stimulation with various doses of CXCL12, an obvious dose-dependent increase in the proliferation, migration, and adhesion of EPCs was confirmed. Furthermore, the mRNA levels of endothelial markers vWF, Tie-2, and VE-cadherin were also demonstrated in CXCL12-treated EPCs, indicating that CXCL12 could regulate EPC differentiation to endothelial cells. Importantly, these increases depended on the activation of CXCR4 signaling, as pretreatment with CXCR4 inhibitor AMD3100 dramatically dampened the CXCL12-induced effects. Additionally, blocking CXCR4 signaling dampened CXCL12-induced angiogenic activity both in vitro and in vivo. Following construction of a rodent ICH model, scaffolds delivering CXCL12 together with EPCs resulted in an evident increase in blood vessel formation; however, this increase in blood vessels was attenuated with delivery of AMD3100. CXCL12 stimulates EPCs to induce angiogenesis though the CXCR4 pathway after ICH. Consequently, our findings provide a potential target for angiogenesis in ICH. PMID- 24955810 TI - Single-step preparation and image-based counting of minute volumes of human blood. AB - Current flow-based blood counting devices require significant medical infrastructure and are not appropriate for field use. In this article we report on the development of a sample preparation, measurement, and analysis method that permits automated and accurate counting of red blood cells (RBCs), white blood cells (WBCs), and platelets, as well as allowing a 3-part differential of the WBCs to be performed on extremely small volumes of whole blood. This method is compatible with portable instrumentation that can be deployed in the field. The method consists of serially diluting blood samples first with sodium dodecyl sulfate dissolved in phosphate buffered saline, then in acridine orange dissolved in phosphate buffered saline, followed by fluorescence and dark field imaging with low magnification objectives. Image analysis is performed to extract cell counts and differentials. We performed a paired analysis of 20 volunteers with complete blood count values both within and beyond the normal reference range using a commercial automated hematology analyzer and the image-based method, with the new method achieving accuracies comparable to that of the commercial system. Because the sample preparation and imaging are simple and inexpensive to implement, this method has applications for pediatrics, clinician offices, and global health in regions that do not have access to central hematology laboratories. PMID- 24955811 TI - On the probability of cure for heavy-ion radiotherapy. AB - The probability of a cure in radiation therapy (RT)-viewed as the probability of eventual extinction of all cancer cells-is unobservable, and the only way to compute it is through modeling the dynamics of cancer cell population during and post-treatment. The conundrum at the heart of biophysical models aimed at such prospective calculations is the absence of information on the initial size of the subpopulation of clonogenic cancer cells (also called stem-like cancer cells), that largely determines the outcome of RT, both in an individual and population settings. Other relevant parameters (e.g. potential doubling time, cell loss factor and survival probability as a function of dose) are, at least in principle, amenable to empirical determination. In this article we demonstrate that, for heavy-ion RT, microdosimetric considerations (justifiably ignored in conventional RT) combined with an expression for the clone extinction probability obtained from a mechanistic model of radiation cell survival lead to useful upper bounds on the size of the pre-treatment population of clonogenic cancer cells as well as upper and lower bounds on the cure probability. The main practical impact of these limiting values is the ability to make predictions about the probability of a cure for a given population of patients treated to newer, still unexplored treatment modalities from the empirically determined probability of a cure for the same or similar population resulting from conventional low linear energy transfer (typically photon/electron) RT. We also propose that the current trend to deliver a lower total dose in a smaller number of fractions with larger-than conventional doses per fraction has physical limits that must be understood before embarking on a particular treatment schedule. PMID- 24955813 TI - Clinical decision making for the evaluation and management of coccydynia: 2 case reports. AB - STUDY DESIGN: Case report. BACKGROUND: Coccydynia is a painful condition of the sacrococcygeal region, with symptoms associated with sitting and rising from a seated position. There is no gold standard for diagnosis of this condition; however, coccyx mobility assessment, pain provocation testing, and imaging have been proposed as reasonable diagnostic approaches. Once correctly diagnosed, treatment options for coccydynia include conservative management and surgical excision. The purpose of this report is to describe the different but successful clinical management strategies of 2 patients with coccydynia. CASE DESCRIPTION: Two women, 26 and 31 years of age, presented to physical therapy with persistent coccygeal pain that increased with prolonged sitting and intensified when transitioning from sit to stand. One patient had a traumatic onset of symptoms, in contrast to the other patient, for whom prolonged sitting was the precipitating factor. Both individuals were considered to have hypomobility of the sacrococcygeal joint, as assessed through intrarectal mobility testing, which also reproduced their symptoms. In both patients, examination of the lumbar spine was negative for alleviation or reproduction of symptoms. The patient with a traumatic onset of symptoms was referred to physical therapy at the onset of her symptoms, whereas the patient with a nontraumatic onset of symptoms was initially treated with a cortisone injection and, when symptoms returned 1 year later, was referred to physical therapy. Both individuals underwent manual therapy to the sacrococcygeal joint over 3 treatment sessions. OUTCOMES: The patient with traumatic onset of symptoms had almost complete resolution of symptoms, whereas the patient with a nontraumatic onset only had temporary relief. This patient required further diagnostic examination and surgical excision. DISCUSSION: Although the mechanisms of injury were different, both patients presented with similar clinical symptoms, and both were considered to have coccydynia through coccyx mobility assessment and pain provocation testing. Successful clinical outcomes were achieved in both cases; however, the interventions were significantly different. Level of Evidence Therapy, level 4. PMID- 24955812 TI - A double-blind, placebo-controlled study of selegiline transdermal system in depressed adolescents. AB - OBJECTIVE: A randomized, double-blind, placebo-controlled flexible-dose, parallel group trial was conducted at 26 clinical investigational sites in the United States to examine the safety and efficacy of the selegiline transdermal system (STS) (EMSAM(r)) in adolescents (ages 12-17 years) meeting American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM IV) criteria for moderate to severe major depressive disorder (MDD) without psychotic features. METHODS: Adolescents (n=308) with moderate to severe MDD were randomized to either STS (n=152) or placebo (n=156). Two hundred and fifteen (69.8%) subjects completed the study and 17 (5.5%) reported discontinuation because of adverse events (AEs). The primary efficacy outcome measure was the mean change from baseline to end of study (week 12 last observation carried forward [LOCF]) in the Children's Depression Rating Scale-Revised (CDRS-R) total score. Secondary outcome measures included end-point Clinical Global Impressions Severity (CGI-S) and Clinical Global Impressions - Improvement (CGI-I). RESULTS: Patients on STS or placebo had a significant decline from baseline (p<0.001) on their CDRS-R total score with mean reductions+/-SD as follows: STS 21.4+/-16.6; placebo 21.5+/-16.5. Both groups had similar response rates (58.6% vs. 59.3%) defined as CGI-I of 1 or 2 at study end. However, these between-group efficacy findings were without statistical significance. The overall incidence of reported AEs was 62.5% for STS-treated patients and 57.7% for placebo-treated patients. Most commonly reported AEs in STS or placebo groups were application site reactions (STS=24.3%; placebo=21.8%), headache (STS=17.1%; placebo=16.7%), and nausea (STS=7.2%; placebo=7.7%). Treatment groups did not differ on any laboratory parameters, vital signs, or electrocardiogram (ECG) findings. No suspected hypertensive crises were reported in the trial. CONCLUSIONS: These data demonstrated that the STS was safe and well tolerated in this adolescent sample. However, both STS-treated and placebo-treated subjects demonstrated a decline from baseline in depressive symptoms (CDRS-R total score) over the length of the study, without statistical superiority by either group. PMID- 24955814 TI - Diagnostic and procedural imaging curricula in physical therapist professional degree programs. AB - STUDY DESIGN: Descriptive survey. OBJECTIVE: To describe the status of diagnostic and procedural imaging curricula within United States physical therapist professional degree programs. BACKGROUND: As patient direct access to physical therapy services increases, the ability to refer patients directly for diagnostic imaging could promote more efficient delivery of care. Appropriate patient referral is contingent on physical therapists having the requisite knowledge base and skills. While evidence describing imaging competence of physical therapists with advanced training in military institutions exists, evidence is lacking for other physical therapists, including new graduates of physical therapist professional degree programs. METHODS: Faculty members teaching imaging at 206 United States physical therapist professional degree programs recognized by the Commission on Accreditation in Physical Therapy Education were recruited via e mail correspondence. An e-mail attachment included the survey on which faculty reported imaging curricula and faculty qualifications, attitudes, and experiences. RESULTS: Faculty from 155 (75.2%) programs responded to the survey, with imaging being included in the curriculum of 152 programs. Content was integrated by required standalone courses or clinical science track courses, and/or through elective courses. The average reported estimate of imaging contact hours was 24.4 hours (range, 2-75 hours). Emphasis was on the musculoskeletal system, including 76.3% of the required standalone course content. Student competence was assessed in 147 (96.7%) programs, primarily by written (66.7%) and practical (19.7%) examinations. Faculty rated student competence on a scale of 1 (not competent) to 5 (competent), with ratings ranging from a high of 4.0 (identifying normal anatomy on plain-film radiography) to a low of 1.9 (identifying common tissue pathological processes/injuries on ultrasound). CONCLUSION: While a majority of programs reported including imaging curricula, variability was noted in all curricular aspects. These results may serve as a benchmark for faculty to assess existing curricula, allow for further development of imaging curricula, and provide a benchmark for the profession regarding current level of training for recent graduates of entry-level physical therapist professional degree programs. PMID- 24955815 TI - Functional outcomes after surgical management of articular cartilage lesions in the knee: a systematic literature review to guide postoperative rehabilitation. AB - STUDY DESIGN: Systematic literature review. OBJECTIVE: To systematically review the literature relative to muscle performance, knee joint biomechanics, and performance-based functional outcomes following articular cartilage repair and restoration surgical procedures in the knee. BACKGROUND: Articular cartilage injuries are associated with functional limitations, poor quality of life, and the potential for long-term disability. This review systematically evaluates evidence related to muscle performance, joint biomechanics, and performance-based functional outcomes following articular cartilage procedures, and discusses their implications for rehabilitation. METHODS: The online databases of PubMed (MEDLINE), CINAHL, SPORTDiscus, and Scopus were searched (inception to September 2013). Studies pertaining to muscle performance, knee joint biomechanics, and performance-based measures of function following articular cartilage procedure in the knee were included. RESULTS: Sixteen articles met the specified inclusion criteria. Seven studies evaluated muscle performance, all showing persistent deficits in quadriceps femoris muscle strength for up to 7 years postprocedure. Quadriceps femoris strength deficits of greater than 20% were noted in 33% and 26% of individuals at 1 and 2 years following microfracture and autologous chondrocyte implantation (ACI), respectively. Two studies evaluated knee mechanics post-ACI, showing persistent deficits in knee kinematics and kinetics for up to 12 months postprocedure compared to uninjured individuals. Seven studies showed improved functional capacity (6-minute walk test) over time, and 3 studies showed persistent performance deficits during higher-level activities (single-leg hop test) for up to 6 years postprocedure. Five studies comparing weight-bearing protocols (accelerated versus traditional/current practice) following ACI found few differences between the groups in function and gait mechanics; however, persistent gait alterations were observed in both groups compared to uninjured individuals. CONCLUSION: Significant quadriceps femoris strength deficits, gait deviations, and functional deficits persist for 5 to 7 years following ACI and microfracture surgical procedures. Future research regarding rehabilitation interventions to help mitigate these deficits is warranted. Level of Evidence Prognosis, level 2a-. PMID- 24955817 TI - Core-shell-corona-structured polyelectrolyte brushes-grafting magnetic nanoparticles for water harvesting. AB - A novel superhydrophilic material, charged polymer brushes-grafted magnetic core shell-corona composite nanoparticles (Fe3O4@SiO2@PSPMA), was developed to harvest water through the hydration effect. Because of both the strong hydration capability and the good swelling performance, the negatively charged polymer brushes, PSPMA brushes, endow the composite nanoparticles with superhydrophilicity and a good water-absorbing performance like a sponge, while the magnetic Fe3O4 cores allow easy separation of Fe3O4@SiO2@PSPMA nanoparticles with absorbed water from oil/water mixture under an external magnetic field. The functional particles have the capability of harvesting water droplets whether floating on an oil surface or in the oil. This water-absorbing material uses selective wettability to harvest water and achieve oil-water separation and may be useful in finding novel approaches for recycling water from sewage and removing water in the petroleum industry. PMID- 24955816 TI - Validation of a BMI cut-off point to predict an adverse cardiometabolic profile with adiposity measurements by dual-energy X-ray absorptiometry in Guatemalan children. AB - OBJECTIVE: To identify a body fat percentage (%BF) threshold related to an adverse cardiometabolic profile and its surrogate BMI cut-off point. DESIGN: Cross-sectional study. SETTING: Two public schools in poor urban areas on the outskirts of Guatemala City. SUBJECTS: A convenience sample of ninety-three healthy, prepubertal, Ladino children (aged 7-12 years). RESULTS: Spearman correlations of cardiometabolic parameters were higher with %BF than with BMI-for age Z-score. BMI-for-age Z-score and %BF were highly correlated (r=0.84). The %BF threshold that maximized sensitivity and specificity for predicting an adverse cardiometabolic profile (elevated homeostasis model assessment-insulin resistance index and/or total cholesterol:HDL-cholesterol ratio) according to receiver operating characteristic curve analysis was 36 %. The BMI-for-age Z-score cut-off point that maximized the prediction of BF >= 36 % by the same procedure was 1.5. The area under the curve (AUC) for %BF and for BMI data showed excellent accuracy to predict an adverse cardiometabolic profile (AUC 0.93 (sd 0.04)) and excess adiposity (AUC 0.95 (sd 0.02)). CONCLUSIONS: Since BMI standards have limitations in screening for adiposity, specific cut-off points based on ethnic-/sex- and age specific %BF thresholds are needed to better predict an adverse cardiometabolic profile. PMID- 24955818 TI - An examination of sociodemographic correlates of ecstasy use among high school seniors in the United States. AB - BACKGROUND: Although ecstasy (MDMA) use is not as prevalent in the United States (US) as it was in the early 2000s, use remains popular among adolescents and young adults. Few recent studies have examined ecstasy use in national samples among those at particularly high risk for use-adolescents approaching adulthood. Research is needed to delineate sociodemographic correlates of use in this group. METHODS: Data were examined from a nationally representative sample of high school seniors in the US (modal age = 18) from the Monitoring the Future study (years 2007-2012; weighted N = 26,504). Data from all cohorts were aggregated and correlates of recent (last 12-month) use of ecstasy were examined. RESULTS: Roughly 4.4% of high school seniors reported use of ecstasy within the last year. Females and religious students were consistently at lower odds for use. Black and Hispanic students, and students residing with two parents, were at lower odds for ecstasy use, until controlling for other drug use. Odds of use were consistently increased for those residing in a city, students with weekly income of >$50 from a job, and students earning >$10 weekly from other sources. Lifetime use of alcohol, cigarettes, marijuana, and other illicit drugs each robustly increased odds of ecstasy use. CONCLUSION: Subgroups of high school seniors, defined by specific sociodemographic factors, and those who have used other drugs, are currently at high risk for ecstasy initiation and use. Since ecstasy is regaining popularity in the US, prevention efforts should consider these factors. PMID- 24955820 TI - Inhalable PEGylated Phospholipid Nanocarriers and PEGylated Therapeutics for Respiratory Delivery as Aerosolized Colloidal Dispersions and Dry Powder Inhalers. AB - Nanomedicine is making groundbreaking achievements in drug delivery. The versatility of nanoparticles has given rise to its use in respiratory delivery that includes inhalation aerosol delivery by the nasal route and the pulmonary route. Due to the unique features of the respiratory route, research in exploring the respiratory route for delivery of poorly absorbed and systemically unstable drugs has been increasing. The respiratory route has been successfully used for the delivery of macromolecules like proteins, peptides, and vaccines, and continues to be examined for use with small molecules, DNA, siRNA, and gene therapy. Phospholipid nanocarriers are an attractive drug delivery system for inhalation aerosol delivery in particular. Protecting these phospholipid nanocarriers from pulmonary immune system attack by surface modification by polyethylene glycol (PEG)ylation, enhancing mucopenetration by PEGylation, and sustaining drug release for controlled drug delivery are some of the advantages of PEGylated liposomal and proliposomal inhalation aerosol delivery. This review discusses the advantages of using PEGylated phospholipid nanocarriers and PEGylated therapeutics for respiratory delivery through the nasal and pulmonary routes as inhalation aerosols. PMID- 24955822 TI - Corneal biomechanical comparison of pseudoexfoliation syndrome, pseudoexfoliative glaucoma and healthy subjects. AB - PURPOSE: To evaluate the differences in corneal biomechanical properties between healthy subjects and patients with pseudoexfoliation syndrome (PEX) and pseudoexfoliative glaucoma (PEXG) using the ocular response analyzer (ORA). MATERIALS AND METHODS: One hundred eighteen eyes of 45 healthy, 43 PEX and 30 PEXG eyes were included in to the study. Corneal biomechanical parameters measurements were obtained using ORA. The main parameters assessed were corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated pressure measurement (IOPg) and corneal compensated intraocular pressure (IOPcc). Ultrasound pachymetry was used for measurement of central corneal thickness (CCT). RESULTS: In healthy subjects, PEX and PEXG eyes' mean CH values were 10.3 +/- 1.4, 8.2 +/- 1.4 and 6.8 +/- 1.7 mmHg, respectively. The difference in mean CH between the PEXG and other two groups were statistically significant (p < 0.001). Mean CRF values were 10.3 +/- 0.7, 7.9 +/- 1.6 and 7.9 +/- 1.9 mmHg, in healthy subjects PEX and PEXG, respectively. The difference in mean CRF between the PEX and PEXG was not statistically significant (p = 0.630), however the mean CRF was significantly higher in healthy subjects, compared to other two groups. Mean CCT were 546.3 +/- 28, 525.5 +/- 35 and 509 +/- 36 MU, in healthy subjects, PEX and PEXG, respectively. The differences on CCT were also significant among the three groups (p < 0.001). CONCLUSION: In this study, the corneal biomechanical features of subjects with PEX were found to be changed as compared to healthy controls. In these patients; CH, CRF and CCT were decreased which was more obvious in patients with PEXG in comparison to PEX patients. PMID- 24955821 TI - Health-related quality of life among people aged >=65 years with self-reported visual impairment: findings from the 2006-2010 behavioral risk factor surveillance system. AB - PURPOSE: To examine the association between health-related quality of life (HRQoL) and visual impairment among people aged >=65 years. METHODS: We used cross-sectional data from the 2006-2010 Behavioral Risk Factor Surveillance System to examine six HRQoL measures: self-reported health, physically unhealthy days, mentally unhealthy days, activity limitation days, life satisfaction, and disability. Visual impairment was categorized as no, a little, and moderate/severe. We examined the association between self-reported visual impairment and HRQoL using logistic regression accounting for the survey's complex design. RESULTS: People with self-reported moderate/severe visual impairment had more frequent (>=14) physically unhealthy days, mentally unhealthy days, and activity limitation days in the last 30 days compared to those reporting a little or no visual impairment. After controlling for all covariates (age, sex, marital status, race/ethnicity, education, income, diabetes, heart disease, stroke, heart attack, body mass index, leisure time activity, smoking, and medical care cost concerns) and comparing to those with no self-reported visual impairment, people reporting a little visual impairment were more likely to have fair/poor health (odds ratio, OR, 1.2, 95% confidence interval, CI, 1.1 1.3), life dissatisfaction (OR 1.6, 95% CI 1.3-2.0), and disability (OR 1.5, 95% CI 1.3-1.6), and those with self-reported moderate/severe visual impairment had more fair/poor health (OR 1.8, 95% CI 1.6-2.0), life dissatisfaction (OR 2.3, 95% CI 1.8-2.9), and disability (OR 2.0, 95% CI 1.8-2.2). They also had more frequent physically unhealthy days (OR 1.9, 95% CI 1.7-2.1), mentally unhealthy days (OR 1.8, 95% CI 1.5-2.1), and activity limitations days (OR 1.9, 95% CI 1.6-2.2). CONCLUSION: Poor HRQoL is strongly associated with the severity of self-reported visual impairment among people aged >=65 years. PMID- 24955823 TI - Neurophysiological and behavioral responses of gypsy moth larvae to insect repellents: DEET, IR3535, and picaridin. AB - The interactions between insect repellents and the olfactory system have been widely studied, however relatively little is known about the effects of repellents on the gustatory system of insects. In this study, we show that the gustatory receptor neuron (GRN) located in the medial styloconic sensilla on the maxillary palps of gypsy moth larvae, and known to be sensitive to feeding deterrents, also responds to the insect repellents DEET, IR3535, and picaridin. These repellents did not elicit responses in the lateral styloconic sensilla. Moreover, behavioral studies demonstrated that each repellent deterred feeding. This is the first study to show perception of insect repellents by the gustatory system of a lepidopteran larva and suggests that detection of a range of bitter or aversive compounds may be a broadly conserved feature among insects. PMID- 24955824 TI - Invading and expanding: range dynamics and ecological consequences of the greater white-toothed shrew (Crocidura russula) invasion in Ireland. AB - Establishing how invasive species impact upon pre-existing species is a fundamental question in ecology and conservation biology. The greater white toothed shrew (Crocidura russula) is an invasive species in Ireland that was first recorded in 2007 and which, according to initial data, may be limiting the abundance/distribution of the pygmy shrew (Sorex minutus), previously Ireland's only shrew species. Because of these concerns, we undertook an intensive live trapping survey (and used other data from live-trapping, sightings and bird of prey pellets/nest inspections collected between 2006 and 2013) to model the distribution and expansion of C. russula in Ireland and its impacts on Ireland's small mammal community. The main distribution range of C. russula was found to be approximately 7,600 km2 in 2013, with established outlier populations suggesting that the species is dispersing with human assistance within the island. The species is expanding rapidly for a small mammal, with a radial expansion rate of 5.5 km/yr overall (2008-2013), and independent estimates from live-trapping in 2012-2013 showing rates of 2.4-14.1 km/yr, 0.5-7.1 km/yr and 0-5.6 km/yr depending on the landscape features present. S. minutus is negatively associated with C. russula. S. minutus is completely absent at sites where C. russula is established and is only present at sites at the edge of and beyond the invasion range of C. russula. The speed of this invasion and the homogenous nature of the Irish landscape may mean that S. minutus has not had sufficient time to adapt to the sudden appearance of C. russula. This may mean the continued decline/disappearance of S. minutus as C. russula spreads throughout the island. PMID- 24955825 TI - Electrophysiological characterization of dopamine neuronal activity in the ventral tegmental area across the light-dark cycle. AB - Direct evidence that dopamine (DA) neurotransmission varies during the 24 h of the day is lacking. Here, we have characterized the firing activity of DA neurons located in the ventral tegmental area (VTA) using single-unit extracellular recordings in anesthetized rats kept on a standard light-dark cycle. DA neuronal firing activity was measured under basal conditions and in response to intravenous administration of increasing doses of amphetamine (AMPH: 0.5, 1, 2, 5 mg/kg), apomorphine (APO: 25, 50, 100, 200 ug/kg) and melatonin (MLT: 0.1, 1, 10 mg/kg) at different time intervals of the light-dark cycle. DA firing activity peaked between 07:00 and 11:00 h (3.5 +/- 0.3 Hz) and between 19:00 and 23:00 h (4.1 +/- 0.7 Hz), with lowest activity occurring between 11:00 and 15:00 h (2.4 +/- 0.2 Hz) and between 23:00 and 03:00 h (2.6 +/- 0.2 Hz). The highest number of spontaneously active neurons was observed between 03:00 and 06:00 h (2.5 +/- 0.3 neurons/track), whereas the lowest was between 19:00 and 23:00 h (1.5 +/- 0.2 neurons/track). The inhibitory effect of AMPH on DA firing rate was similar in both phases. The inhibitory effect of low dose of APO (25 MUg/kg, dose selective for D2 autoreceptor) was more potent in the dark phase, whereas APO effects at higher doses were similar in both phases. Finally, MLT administration (1 mg/kg) produced a moderate inhibition of DA cell firing in both phases. These experiments demonstrate the existence of an intradiurnal rhythmic pattern of VTA DA neuronal firing activity and a higher pharmacological response of D2 autoreceptors in the dark phase. PMID- 24955826 TI - Biodegradation of methyl parathion by whole cells of marine-derived fungi Aspergillus sydowii and Penicillium decaturense. AB - Seven marine fungi strains (Aspergillus sydowii CBMAI 934, A. sydowii CBMAI 935, A. sydowii CBMAI 1241, Penicillium decaturense CBMAI 1234, Penicillium raistrickii CBMAI 931, P. raistrickii CBMAI 1235, and Trichoderma sp. CBMAI 932) were screened by their growth in the presence of methyl parathion (MP) in a solid culture medium. The strains with best growth were A. sydowii CBMAI 935 and P. decaturense CBMAI 1234. Biodegradation reactions were performed in 10, 20 and 30d in a malt extract liquid medium containing commercial MP and whole cells of A. sydowii CBMAI 935 and P. decaturense CBMAI 1234. In 20d, A. sydowii CBMAI 935 was able to degrade all pesticide, whereas P. decaturense CBMAI 1234 promoted a complete degradation in 30d. A. sydowii CBMAI 935 and P. decaturense CBMAI 1234 could degrade the product of the MP enzymatic hydrolysis, p-nitrophenol, on average of 51 and 40% respectively. Both strains used MP as a sole source of carbon and provided satisfactory results. Metabolites detected in the medium showed that the presumable reaction pathway occurred through the activation of MP to its more toxic form, methyl paraoxon, which was further degraded to p nitrophenol. PMID- 24955827 TI - Use of an ophthalmic viscosurgical device for experimental retinal detachment in rabbit eyes. AB - To investigate the temporary tamponade effects of an ophthalmic viscosurgical device (OVD) for experimental retinal tears, we performed vitrectomy in four rabbit eyes and created a posterior vitreous detachment and artificial retinal tear to produce retinal detachment. The retina was flattened with liquid perfluorocarbon (PFC), the area peripheral to the tear was photocoagulated, an OVD was applied to the retinal tear surface below the PFC and the PFC was removed by aspiration. In the control group, PFC was removed without application of OVD. At one, three and seven days postoperatively, funduscopy and optical coherence tomography (OCT) were performed to examine the sealing process of the retinal tear. In OVD-treated eyes, the OVD remained on the retinal surface, and the retinal tear was patched for >= 3 days postoperatively. By seven days postoperatively, the OVD on the retinal surface had disappeared, and the retina was reattached. In control eyes, the edge of the retinal tear was rolled, and retinal detachment persisted. In OVD-treated eyes, the border of the retinal tear was indistinct, and the defect area was significantly decreased. These results show that application of an OVD effectively seals retinal tears and eliminates retinal detachments. PMID- 24955828 TI - Design and in vitro biocompatibility of a novel ocular drug delivery device. AB - The capsule drug ring (CDR) is a reservoir and delivery agent, which is designed to be placed within the capsular bag during cataract surgery. Prototypes were manufactured by hot melt extrusion of Bionate II(r), a polycarbonate urethane. The devices have been optimized using Avastin(r) as the drug of interest. In vitro biocompatibility was assessed with human lens epithelial cell (B-3), mouse macrophage (J774A.1) and mouse fibroblast (L-929) cell lines. Cell migration and proliferation were assessed after in vitro culture. Pro-inflammatory cytokines (i.e., MIP-1beta, MIP-1alpha, MCP-1, IL-1beta, TNF and TGF-beta1) were quantified using cytometric bead array (CBA). Preliminary in vivo biocompatibility and pharmacokinetics testing has been performed in rabbits. PMID- 24955829 TI - Heat generation and transfer behaviors of ti-coated carbon steel rod adaptable for ablation therapy of oral cancer. AB - For the purpose of developing a novel ablation therapy for oral cancer, the heat generation and transfer properties of a Ti-coated carbon steel rod with 20-mm length and 1.8-mm outer diameter were investigated by means of a high-frequency induction technique at 300 kHz. The heat generation measurement performed using water (15 mL) revealed that the difference of the inclination angles (theta = 0 degrees , 45 degrees and 90 degrees ) relative to the magnetic flux direction only slightly affects the heating behavior, exhibiting the overlapped temperature curves during an induction time of 1200 s. These results suggest that the effect of the shape magnetic anisotropy is almost eliminated, being convenient for the precise control of the ablation temperature in clinical use. In the experiments utilizing a tissue-mimicking phantom, the heat transfer concentrically occurred in the lateral direction for both the planar surface and a 10-mm deep cross section. However, the former exhibited a considerably lower increase in temperature (DeltaT), probably due to the effect of heat dissipation to the ambient air. No significant heat transfer was found to occur to the lower side of the inserted Ti-coated carbon steel rod, which is situated in the longitudinal direction. PMID- 24955830 TI - Cultivation of human microvascular endothelial cells on topographical substrates to mimic the human corneal endothelium. AB - Human corneal endothelial cells have a limited ability to replicate in vivo and in vitro. Allograft transplantation becomes necessary when an accident or trauma results in excessive cell loss. The reconstruction of the cornea endothelium using autologous cell sources is a promising alternative option for therapeutic or in vitro drug testing applications. The native corneal endothelium rests on the Descemet's membrane, which has nanotopographies of fibers and pores. The use of synthetic topographies mimics the native environment, and it is hypothesized that this can direct the behavior and growth of human microvascular endothelial cells (HMVECs) to resemble the corneal endothelium. In this study, HMVECs are cultivated on substrates with micron and nano-scaled pillar and well topographies. Closely packed HMVEC monolayers with polygonal cells and well developed tight junctions were formed on the topographical substrates. Sodium/potassium (Na+/K+) adenine triphosphatase (ATPase) expression was enhanced on the microwells substrate, which also promotes microvilli formation, while more hexagonal-like cells are found on the micropillars samples. The data obtained suggests that the use of optimized surface patterning, in particular, the microtopographies, can induce HMVECs to adopt a more corneal endothelium-like morphology with similar barrier and pump functions. The mechanism involved in cell contact guidance by the specific topographical features will be of interest for future studies. PMID- 24955832 TI - Multinucleation during C. trachomatis infections is caused by the contribution of two effector pathways. AB - Chlamydia trachomatis is an obligate intracellular bacterial pathogen and the second leading cause of sexually transmitted infections in the US. Infections cause significant morbidity and can lead to serious reproductive sequelae, including an epidemiological link to increased rates of reproductive cancers. One of the overt changes that infected cells exhibit is the development of genomic instability leading to multinucleation. Here we demonstrate that the induction of multinucleation is not conserved equally across chlamydial species; C. trachomatis L2 caused high levels of multinucleation, C. muridarum intermediate levels, and C. caviae had very modest effects on multinucleation. Our data show that at least two effector pathways together cause genomic instability during infection leading to multinucleation. We find that the highly conserved chlamydial protease CPAF is a key effector for one of these pathways. CPAF secretion is required for the loss of centrosome duplication regulation as well as inducing early mitotic exit. The second effector pathway involves the induction of centrosome position errors. This function is not conserved in three chlamydial species tested. Together these two pathways contribute to the induction of high levels of genomic instability and multinucleation seen in C. trachomatis infections. PMID- 24955833 TI - Genetic deletion of transglutaminase 2 does not rescue the phenotypic deficits observed in R6/2 and zQ175 mouse models of Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin gene. Tissue transglutaminase 2 (TG2), a multi-functional enzyme, was found to be increased both in HD patients and in mouse models of the disease. Furthermore, beneficial effects have been reported from the genetic ablation of TG2 in R6/2 and R6/1 mouse lines. To further evaluate the validity of this target for the treatment of HD, we examined the effects of TG2 deletion in two genetic mouse models of HD: R6/2 CAG 240 and zQ175 knock in (KI). Contrary to previous reports, under rigorous experimental conditions we found that TG2 ablation had no effect on either motor or cognitive deficits, or on the weight loss. In addition, under optimal husbandry conditions, TG2 ablation did not extend R6/2 lifespan. Moreover, TG2 deletion did not change the huntingtin aggregate load in cortex or striatum and did not decrease the brain atrophy observed in either mouse line. Finally, no amelioration of the dysregulation of striatal and cortical gene markers was detected. We conclude that TG2 is not a valid therapeutic target for the treatment of HD. PMID- 24955834 TI - Honey bee Apis mellifera parasites in the absence of Nosema ceranae fungi and Varroa destructor mites. AB - Few areas of the world have western honey bee (Apis mellifera) colonies that are free of invasive parasites Nosema ceranae (fungi) and Varroa destructor (mites). Particularly detrimental is V. destructor; in addition to feeding on host haemolymph, these mites are important vectors of several viruses that are further implicated as contributors to honey bee mortality around the world. Thus, the biogeography and attendant consequences of viral communities in the absence of V. destructor are of significant interest. The island of Newfoundland, Province of Newfoundland and Labrador, Canada, is free of V. destructor; the absence of N. ceranae has not been confirmed. Of 55 Newfoundland colonies inspected visually for their strength and six signs of disease, only K-wing had prevalence above 5% (40/55 colonies = 72.7%). Similar to an earlier study, screenings again confirmed the absence of V. destructor, small hive beetles Aethina tumida (Murray), tracheal mites Acarapis woodi (Rennie), and Tropilaelaps spp. ectoparasitic mites. Of a subset of 23 colonies screened molecularly for viruses, none had Israeli acute paralysis virus, Kashmir bee virus, or sacbrood virus. Sixteen of 23 colonies (70.0%) were positive for black queen cell virus, and 21 (91.3%) had some evidence for deformed wing virus. No N. ceranae was detected in molecular screens of 55 colonies, although it is possible extremely low intensity infections exist; the more familiar N. apis was found in 53 colonies (96.4%). Under these conditions, K-wing was associated (positively) with colony strength; however, viruses and N. apis were not. Furthermore, black queen cell virus was positively and negatively associated with K-wing and deformed wing virus, respectively. Newfoundland honey bee colonies are thus free of several invasive parasites that plague operations in other parts of the world, and they provide a unique research arena to study independent pathology of the parasites that are present. PMID- 24955835 TI - LIM and SH3 domain protein 1 (LASP-1) overexpression was associated with aggressive phenotype and poor prognosis in clear cell renal cell cancer. AB - BACKGROUND: LIM and SH3 protein 1 (LASP-1) is a specific focal adhesion protein that is known to be involved in numerous biological and pathological processes. LASP-1 overexpression has been described in several types of cancers, but its expression and role in clear cell renal cell cancer (ccRCC) remains unknown. METHODS: Using immunohistochemistry, we analyzed LASP-1 protein expression in 216 clinicopathologically characterized ccRCC cases. We also examined LASP-1 expression in 20 paired ccRCC tissues and in 2 cell lines by real-time PCR and Western blot. Using RNA interference, we investigated the effects of LASP-1 depletion on tumor cell behavior in vitro. Statistical analyses were used to determine the associations between LASP-1 levels, tumor features and patient outcomes. RESULTS: LASP-1 overexpression was observed in ccRCC tissues (P<0.0001) compared to adjuvant nontumorous tissues, and its expression levels were closely correlated with overall survival and recurrence-free survival (P = 0.044 and 0.006, respectively) in patients with ccRCC. RNA interference-mediated silencing of the LASP-1 gene in 786-0 ccRCC cells significantly inhibited cell migration. CONCLUSIONS: The results of the present study indicate that LASP-1 may serve as a prognostic biomarker for ccRCC patients and may be a promising target for the treatment of ccRCC. PMID- 24955836 TI - Nutraceuticals in joint health: animal models as instrumental tools. AB - Osteoarthritis (OA) is a degenerative joint disease with no curative treatments. Many studies have begun to demonstrate the efficacy of nutraceuticals for slowing down OA. Animal models are utilized as a compulsory step in demonstrating the protective potential of these compounds on joint health. Nevertheless, there exist a wide variety of available OA models and selecting a suitable system for evaluating the effects of a specific compound remains difficult. Here, we discuss animal studies that have investigated nutraceutical effects on OA. In particular, we highlight the large spectrum of animal models that are currently accepted for examining the OA-related effects of nutraceuticals, giving recommendations for their use. PMID- 24955838 TI - Development of anticancer agents: wizardry with osmium. AB - Platinum compounds are one of the pillars of modern cancer chemotherapy. The apparent disadvantages of existing chemotherapeutics have led to the development of novel anticancer agents with alternative modes of action. Many complexes of the heavy metal osmium (Os) are potent growth inhibitors of human cancer cells and are active in vivo, often superior or comparable to cisplatin, as the benchmark metal-based anticancer agent, or clinically tested ruthenium (Ru) drug candidates. Depending on the choice of ligand system, osmium compounds exhibit diverse modes of action, including redox activation, DNA targeting or inhibition of protein kinases. In this review, we highlight recent advances in the development of osmium anticancer drug candidates and discuss their cellular mechanisms of action. PMID- 24955837 TI - Targeting the Wnt signaling pathways in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a life-threatening disorder that is associated with elevated pulmonary pressures and right heart failure resulting from progressive loss and thickening of small pulmonary arteries. Despite their ability to improve symptoms, current therapies fail to prevent disease progression, leaving lung transplantation as the only therapy in end-stage PAH. To overcome the limitations of current therapies, there is an active search for disease-modifying agents capable of altering the natural history of, and improving clinical outcomes in, PAH. The Wnt signaling pathways have emerged as attractive treatment targets in PAH given their role in the preservation of pulmonary vascular homeostasis and the recent development of Wnt-specific compounds and biological therapies capable of modulating pathway activity. In this review, we summarize the literature describing the role of Wnt signaling in the pulmonary circulation and discuss promising advances in the field of Wnt therapeutics that could lead to novel clinical therapies capable of preventing and/or reversing pulmonary vascular pathology in patients with this devastating disease. PMID- 24955839 TI - Quantifying the probability of clinical trial success from scientific articles. AB - We sought to analyze how the number and quality of publications predict clinical trial success for a set of gene-disease associations. Limiting the scope of our analysis to genes in the protein kinase family and to oncology indications, we extracted gene-disease relationships from more than 12 million article titles and abstracts published between 1992 and 2012. We integrated these data with clinical trial information for FDA-approved kinase inhibitors and kinase inhibitors that failed owing to lack of efficacy. We found that, up until the year when a compound enters clinical trials, the cumulative number of publications about a gene-disease relationship corresponding to the compound's mechanism of action is, at the median, 30 for approved compounds but only four for failed compounds. PMID- 24955840 TI - Detection of expressional changes induced by intrauterine growth restriction in the developing rat mammary gland via exploratory pathways analysis. AB - BACKGROUND: Intrauterine growth restriction (IUGR) is thought to lead to fetal programming that in turn contributes to developmental changes of many organs postnatally. There is evidence that IUGR is a risk factor for the development of metabolic and cardiovascular disease later in life. A higher incidence of breast cancer was also observed after IUGR. This could be due to changes in mammary gland developmental pathways. We sought to characterise IUGR-induced alterations of the complex pathways of mammary development at the level of the transcriptome in a rat model of IUGR, using pathways analysis bioinformatics. METHODOLOGY/PRINCIPAL FINDINGS: We analysed the mammary glands of Wistar rats with IUGR induced by maternal low protein (LP) diet at the beginning (d21) and the end (d28) of pubertal ductal morphogenesis. Mammary glands of the LP group were smaller in size at d28, however did not show morphologic changes. We identified multiple differentially expressed genes in the mammary gland using Agilent SurePrint arrays at d21 and d28. In silico analysis was carried out using Ingenuity Pathways Analysis. In mammary gland tissue of LP rats at d21 of life a prominent upregulation of WT1 and CDKN1A (p21) expression was observed. Differentially regulated genes were associated with the extracellular regulated kinase (ERK)-1/-2 pathway. Western Blot analysis showed reduced levels of phosphorylated ERK-1/-2 in the mammary glands of the LP group at d21. To identify possible changes in circulating steroid levels, serum LC-Tandem mass-spectrometry was performed. LP rats showed higher serum progesterone levels and an increased corticosterone/dehydrocorticosterone-ratio at d28. CONCLUSIONS/SIGNIFICANCE: Our data obtained from gene array analysis support the hypothesis that IUGR influences pubertal development of the rat mammary gland. We identified prominent differential regulation of genes and pathways for factors regulating cell cycle and growth. Moreover, we detected new pathways which appear to be programmed by IUGR. PMID- 24955841 TI - Molecular evolution of a novel family of putative calcium transporters. AB - The UPF0016 family is a group of uncharacterized membrane proteins, well conserved through evolution and defined by the presence of one or two copies of an E-Phi-G-D-(KR)-(ST) consensus motif. Our previous results have shown that two members of this family, the human TMEM165 and the budding yeast Gdt1p, are functionally related and might form a new group of cation/Ca2+ exchangers. Most members of the family are made of two homologous clusters of three transmembrane spans, separated by a central loop and assembled with an opposite orientation in the membrane. However, some bacterial members of the family have only one cluster of transmembrane domains. Among these 'single-domain membrane proteins' some cyanobacterial members were found as pairs of adjacent genes within the genome, but each gene was slightly different. We performed a bioinformatic analysis to propose the molecular evolution of the UPF0016 family and the emergence of the antiparallel topology. Our hypotheses were confirmed experimentally using functional complementation in yeast. This suggests an important and conserved function for UPF0016 proteins in a fundamental cellular process. We also show that members of the UPF0016 family share striking similarities, but no primary sequence homology, with members of the cation/Ca2+ exchangers (CaCA) superfamily. Such similarities could be an example of convergent evolution, supporting the previous hypothesis that members of the UPF0016 family are cation/Ca2+ exchangers. PMID- 24955842 TI - Diagnostic accuracy and interobserver agreement of Quasistatic Ultrasound Elastography in the diagnosis of thyroid nodules. AB - PURPOSE: To assess the best technique and the diagnostic accuracy of Quasistatic Ultrasound Elastography (QUE) in thyroid nodules. Interobserver agreement was also evaluated. MATERIALS AND METHODS: A preliminary study of 50 patients with 54 thyroid nodules was performed with quantitative software in order to define the best cut-off value of different imaging methods. All patients underwent total thyroidectomy and histopathology findings served as the standard of reference. Thereafter, 154 nodules in 137 consecutive patients were prospectively evaluated by three operators. Findings at fine-needle aspiration cytology and histopathology (N = 60) served as the standard of reference. RESULTS: The most accurate technique was the axial peri-intranodular measurement method which achieved an area under the ROC curve of 0.961 (95 %CI 0.848 - 1.00) and had an optimal cut-off value of 3.00. QUE in the differentiation of thyroid nodules showed for operator 1: sensitivity 90 % (95 %CI 73.5 - 97.9 %), specificity 92.7 % (95 %CI 86.7 - 96.6 %), LR+ 12.40 (6.54 - 23.50), LR- 0.11 (0.04 - 0.32) and accuracy 91.4 % (95 %CI 85.4 - 97.3 %); for operator 2: sensitivity 86.7 % (95 %CI 69.3 - 96.2 %), specificity 87.1 % (95 %CI 79.9 - 92.4 %), LR+ 6.72 (4.16 - 10.80), LR- 0.15 (0.06 - 0.38) and accuracy 86.9 % (95 %CI 80.0 - 93.7 %); for operator 3: sensitivity 80 % (95 %CI 61.4 - 92.3 %), specificity 83.9 % (95 %CI 76.2 - 89.9 %), LR+ 4.96 (3.20 - 7.70), LR- 0.24 (0.12 - 0.49) and accuracy 81.9 % (95 %CI 74.0 - 89.9 %). Interobserver agreement values between operator 1 and operator 2 (k = 0.79) (p < 0.05, 95 %CI 0.684 - 0.904), between operator 1 and operator 3 (k = 0.73, 95 %CI: 0.607 - 0.854) and between operator 2 and operator 3 (k = 0.71, 95 %CI: 0.584 - 0.835) were significant. CONCLUSION: QUE provides accurate quantitative evaluation of thyroid nodules with low interobserver variability. PMID- 24955843 TI - Changes in the bacterial community of soybean rhizospheres during growth in the field. AB - Highly diverse communities of bacteria inhabiting soybean rhizospheres play pivotal roles in plant growth and crop production; however, little is known about the changes that occur in these communities during growth. We used both culture dependent physiological profiling and culture independent DNA-based approaches to characterize the bacterial communities of the soybean rhizosphere during growth in the field. The physiological properties of the bacterial communities were analyzed by a community-level substrate utilization assay with BioLog Eco plates, and the composition of the communities was assessed by gene pyrosequencing. Higher metabolic capabilities were found in rhizosphere soil than in bulk soil during all stages of the BioLog assay. Pyrosequencing analysis revealed that differences between the bacterial communities of rhizosphere and bulk soils at the phylum level; i.e., Proteobacteria were increased, while Acidobacteria and Firmicutes were decreased in rhizosphere soil during growth. Analysis of operational taxonomic units showed that the bacterial communities of the rhizosphere changed significantly during growth, with a higher abundance of potential plant growth promoting rhizobacteria, including Bacillus, Bradyrhizobium, and Rhizobium, in a stage-specific manner. These findings demonstrated that rhizosphere bacterial communities were changed during soybean growth in the field. PMID- 24955844 TI - Associations between trajectories of perceived racial discrimination and psychological symptoms among African American adolescents. AB - Many African American adolescents experience racial discrimination, with adverse consequences; however, stability and change in these experiences over time have not been examined. We examined longitudinal patterns of perceived racial discrimination assessed in Grades 7-10 and how these discrimination trajectories related to patterns of change in depressive and anxious symptoms and aggressive behaviors assessed over the same 4-year period. Growth mixture modeling performed on a community epidemiologically defined sample of urban African American adolescents (n = 504) revealed three trajectories of discrimination: increasing, decreasing, and stable low. As predicted, African American boys were more frequent targets for racial discrimination as they aged, and they were more likely to be in the increasing group. The results of parallel process growth mixture modeling revealed that youth in the increasing racial discrimination group were four times more likely to be in an increasing depression trajectory than were youth in the low stable discrimination trajectory. Though youth in the increasing racial discrimination group were nearly twice as likely to be in the high aggression trajectory, results were not statistically significant. These results indicate an association between variation in the growth of perceived racial discrimination and youth behavior and psychological well-being over the adolescent years. PMID- 24955846 TI - Role of an active site loop in the promiscuous activities of Amycolatopsis sp. T 1-60 NSAR/OSBS. AB - The o-succinylbenzoate synthase (OSBS) family is part of the functionally diverse enolase superfamily. Many proteins in one branch of the OSBS family catalyze both OSBS and N-succinylamino acid racemization in the same active site. In some promiscuous NSAR/OSBS enzymes, NSAR activity is biologically significant in addition to or instead of OSBS activity. Identifying important residues for each reaction could provide insight into how proteins evolve new functions. We have made a series of mutations in Amycolatopsis sp. T-1-60 NSAR/OSBS in an active site loop, referred to as the 20s loop. This loop affects substrate specificity in many members of the enolase superfamily but is poorly conserved within the OSBS family. Deletion of this loop decreased OSBS and NSAR catalytic efficiency by 4500-fold and 25,000-fold, respectively, showing that it is essential. Most point mutations had small effects, changing the efficiency of both NSAR and OSBS activities <10-fold compared to that of the wild type. An exception was F19A, which reduced kcat/KM(OSBS) 200-fold and kcat/KM(NSAR) 120-fold. Mutating the surface residue R20E, which can form a salt bridge to help close the 20s loop over the active site, had a more modest effect, decreasing kcat/KM of OSBS and NSAR reactions 32- and 8-fold, respectively. Several mutations increased KM of the NSAR reaction more than that of the OSBS reaction. Thus, both activities require the 20s loop, but differences in how mutations affect OSBS and NSAR activities suggest that some substitutions in this loop made a small contribution to the evolution of NSAR activity, although additional mutations were probably required. PMID- 24955845 TI - Isoaspartyl formation in creatine kinase B is associated with loss of enzymatic activity; implications for the linkage of isoaspartate accumulation and neurological dysfunction in the PIMT knockout mouse. AB - Isoaspartate (isoAsp) formation is a common type of spontaneous protein damage that is normally kept in check by the repair enzyme protein-L-isoaspartyl methyltransferase (PIMT). PIMT-KO (knockout) mice exhibit a pronounced neuropathology highlighted by death from an epileptic seizure at 30 to 60 days after birth. The mechanisms by which isoaspartyl damage disrupts normal brain function are incompletely understood. Proteomic analysis of the PIMT-KO mouse brain has shown that a number of key neuronal proteins accumulate high levels of isoAsp, but the extent to which their cellular functions is altered has yet to be determined. One of the major neuronal targets of PIMT is creatine kinase B (CKB), a well-characterized enzyme whose activity is relatively easy to assay. We show here that (1) the specific activity of CKB is significantly reduced in the brains of PIMT-deficient mice, (2) that in vitro aging of recombinant CKB results in significant accumulation of isoAsp sites with concomitant loss of enzymatic activity, and (3) that incubation of in vitro aged CKB with PIMT and its methyl donor S-adenosyl-L-methionine substantially repairs the aged CKB with regard to both its isoAsp content and its enzymatic activity. These results, combined with similarity in phenotypes of PIMT-KO and CKB-KO mice, suggests that loss of normal CKB structure and function contributes to the mechanisms by which isoAsp accumulation leads to CNS dysfunction in the PIMT-KO mouse. PMID- 24955847 TI - The roles of standing genetic variation and evolutionary history in determining the evolvability of anti-predator strategies. AB - Standing genetic variation and the historical environment in which that variation arises (evolutionary history) are both potentially significant determinants of a population's capacity for evolutionary response to a changing environment. Using the open-ended digital evolution software Avida, we evaluated the relative importance of these two factors in influencing evolutionary trajectories in the face of sudden environmental change. We examined how historical exposure to predation pressures, different levels of genetic variation, and combinations of the two, affected the evolvability of anti-predator strategies and competitive abilities in the presence or absence of threats from new, invasive predator populations. We show that while standing genetic variation plays some role in determining evolutionary responses, evolutionary history has the greater influence on a population's capacity to evolve anti-predator traits, i.e. traits effective against novel predators. This adaptability likely reflects the relative ease of repurposing existing, relevant genes and traits, and the broader potential value of the generation and maintenance of adaptively flexible traits in evolving populations. PMID- 24955848 TI - Hypothesis testing in attorney-conducted voir dire. AB - Attorneys may hold expectations about jurors based on stereotypes about the relationships between demographic characteristics and attitudes. Attorneys test their hypotheses about prospective jurors during voir dire, but it is unclear whether their questioning strategies are likely to produce accurate information from jurors. In 2 studies, attorneys and law students formulated voir dire questions to test a particular hypothesis about the attitudes held by a prospective juror (venireperson) and provided their subsequent inferences about that individual given certain hypothetical responses to the questions. Bayes's theorem was used to compare attorneys' actual conclusions about the venireperson with the conclusions they would reach if correctly using the available information. Attorneys' conclusions were biased by the questions they asked, and in some cases, by the hypothesis that they were asked to test. Compared with normative models derived using Bayes' theorem, attorneys overrelied on venirepersons' responses when drawing conclusions about their attitudes. These findings suggest that even if traditional attorney-conducted voir dire elicited accurate information about prospective jurors' attitudes, attorneys may not use that information to draw normatively accurate conclusions about the attitudes that they hold. PMID- 24955849 TI - The land of the free: undocumented families in the juvenile justice system. AB - Approximately 8 million Latinos in the United States are undocumented immigrants, nearly half of whom are parents to a minor. Concerns over deportation may affect the way families with undocumented members perceive legal authorities relative to documented immigrant families. Yet, there have been few studies on how Latinos (documented or undocumented) interact with, and form attitudes about, police and no studies on adjudicated youth from families with an undocumented member. To address this gap, 155 pairs (N = 310) of Latina immigrant mothers and their first time offending sons were interviewed. More than half of the mothers, and 12.3% of youth, were undocumented residents. Controlling for key contextual factors, youth whose mothers were undocumented held more negative attitudes toward the police than youth whose mothers were documented. Youth, however, did not perceive judges differently based on mother's documentation status, suggesting that documentation status relates to police specifically rather than justice system attitudes broadly. The same pattern was noted when considering youth's own documentation status. Because negative attitudes toward police have been associated with decreased reports of victimization and other crimes, policy related to undocumented immigration should consider the unintended effects of such laws. (PsycINFO Database Record PMID- 24955851 TI - Suspect filler similarity in eyewitness lineups: a literature review and a novel methodology. AB - Eyewitness lineups typically contain a suspect (guilty or innocent) and fillers (known innocents). The degree to which fillers should resemble the suspect is a complex issue that has yet to be resolved. Previously, researchers have voiced concern that eyewitnesses would be unable to identify their target from a lineup containing highly similar fillers; however, our literature review suggests highly similar fillers have only rarely been shown to have this effect. To further examine the effect of highly similar fillers on lineup responses, we used morphing software to create fillers of moderately high and very high similarity to the suspect. When the culprit was in the lineup, a higher correct identification rate was observed in moderately high similarity lineups than in very high similarity lineups. When the culprit was absent, similarity did not yield a significant effect on innocent suspect misidentification rates. However, the correct rejection rate in the moderately high similarity lineup was 20% higher than in the very high similarity lineup. When choosing rates were controlled by calculating identification probabilities for only those who made a selection from the lineup, culprit identification rates as well as innocent suspect misidentification rates were significantly higher in the moderately high similarity lineup than in the very high similarity lineup. Thus, very high similarity fillers yielded costs and benefits. Although our research suggests that selecting the most similar fillers available may adversely affect correct identification rates, we recommend additional research using fillers obtained from police databases to corroborate our findings. PMID- 24955850 TI - Performance of Hispanic inmates on the Spanish Miller Forensic Assessment of Symptoms Test (M-FAST). AB - The few psychological assessment measures commercially available for the assessment of Spanish-speaking populations lack strong empirical foundation. This is concerning given the rising numbers of Spanish speakers entering the forensic and correctional systems for whom valid assessment is difficult without linguistically and culturally appropriate measures. In this study, we translated and adapted the Miller Forensic Assessment of Symptoms Test (M-FAST) into Spanish. The general purpose of this study was to investigate the psychometric, linguistic, and conceptual equivalence of the English- and Spanish-language versions of the M-FAST in a sample of 102 bilingual Hispanic incarcerated males. Participants were randomly assigned to one of three feigning conditions (honest, uncoached, or coached) and completed the M-FAST in both English and Spanish on two separate occasions. Both language versions were psychometrically, linguistically, and conceptually equivalent. PMID- 24955852 TI - The relationship between officer orientation and supervision strategies in community corrections. AB - Community corrections (i.e., probation and parole) officers play a crucial role within criminal justice agencies: They have the onerous task to balance the competing demands of rehabilitating offenders while protecting the community. Field studies have suggested that officers' effectiveness depends, in part, on the relative emphasis they place on these demands (i.e., their orientation toward their roles). However, the extent to which officers' orientations toward rehabilitation versus community safety affect their decisions for individual offenders is not clear. We examined the relationship between officer attitudes and supervisory decisions using a quasi-experimental design. In the first stage of the study, we revised a promising measure of officers' role orientation. In the second stage, we examined the revised scale's psychometric properties, and tested how officers' self-reported orientations related to the strategies they used in hypothetical supervision scenarios. The majority of officers reported a balanced approach of control and support, whereas 29.7% reported a preference for one over the other. Regardless of self-reported orientation, officers approached supervision with similar strategies for an offender's first incident of noncompliance, but when an offender showed continued noncompliance, both officers who emphasized control and those who emphasized a balanced approach toward supervision were more likely to use punitive methods to gain compliance than officers who reported emphasizing rehabilitation. This research furthers our understanding of the relationship between self-reported orientation and supervision strategy. Findings will inform agencies' selection and training of community corrections officers. (PsycINFO Database Record PMID- 24955853 TI - Dipeptidyl peptidase I controls survival from Klebsiella pneumoniae lung infection by processing surfactant protein D. AB - Prior work established that a deficiency in the cysteine protease dipeptidyl peptidase I (DPPI) improves survival following polymicrobial septic peritonitis. To test whether DPPI regulates survival from severe lung infections, DPPI(-/-) mice were studied in a Klebsiella pneumoniae lung infection model, finding that survival in DPPI(-/-) mice is significantly better than in DPPI(+/+) mice 8d after infection. DPPI(-/-) mice have significantly fewer bacteria in the lung than infected DPPI(+/+) mice, but no difference in lung histopathology, lung injury, or cytokine levels. To explore mechanisms of enhanced bacterial clearance in DPPI(-/-) mice, we examined the status of pulmonary collectins, finding that levels of surfactant protein D, but not of surfactant protein A, are higher in DPPI(-/-) than in DPPI(+/+) BAL fluid, and that DPPI(-/-) BAL fluid aggregate bacteria more effectively than control BAL fluid. Sequencing of the amino terminus of surfactant protein D revealed two or eight additional amino acids in surfactant protein D isolated from DPPI(-/-) mice, suggesting processing by DPPI. These results establish that DPPI is a major determinant of survival following Klebsiella pneumoniae lung infection and suggest that the survival disadvantage in DPPI(+/+) mice is in part due to processing of surfactant protein D by DPPI. PMID- 24955854 TI - Palmitate attenuates osteoblast differentiation of fetal rat calvarial cells. AB - Aging is associated with the accumulation of ectopic lipid resulting in the inhibition of normal organ function, a phenomenon known as lipotoxicity. Within the bone marrow microenvironment, elevation in fatty acid levels may produce an increase in osteoclast activity and a decrease in osteoblast number and function, thus contributing to age-related osteoporosis. However, little is known about lipotoxic mechanisms in intramembraneous bone. Previously we reported that the long chain saturated fatty acid palmitate inhibited the expression of the osteogenic markers RUNX2 and osteocalcin in fetal rat calvarial cell (FRC) cultures. Moreover, the acetyl CoA carboxylase inhibitor TOFA blocked the inhibitory effect of palmitate on expression of these two markers. In the current study we have extended these observations to show that palmitate inhibits spontaneous mineralized bone formation in FRC cultures in association with reduced mRNA expression of RUNX2, alkaline phosphatase, osteocalcin, and bone sialoprotein and reduced alkaline phosphatase activity. The effects of palmitate on osteogenic marker expression were inhibited by TOFA. Palmitate also inhibited the mRNA expression of fatty acid synthase and PPARgamma in FRC cultures, and as with osteogenic markers, this effect was inhibited by TOFA. Palmitate had no effect on FRC cell proliferation or apoptosis, but inhibited BMP-7-induced alkaline phosphatase activity. We conclude that palmitate accumulation may lead to lipotoxic effects on osteoblast differentiation and mineralization and that increases in fatty acid oxidation may help to prevent these lipotoxic effects. PMID- 24955855 TI - Identification and mutagenesis of the TACE and gamma-secretase cleavage sites in the colony-stimulating factor 1 receptor. AB - Stimulation of macrophages with phorbolesters, bacterial DNA, or lipopolysaccharides causes regulated intramembrane proteolysis or RIPping of the CSF-1 receptor. This process involves TACE-mediated cleavage in the extracellular domain, followed by gamma-secretase-mediated cleavage within the transmembrane region. In the current study, we have identified the TACE cleavage site, which is present twelve residues from the carboxy-terminal end of the extracellular domain. Replacement of fourteen residues at the end of the extracellular domain blocked TACE cleavage. In addition, we identified the gamma-secretase cleavage site, which is present four residues from the carboxy-terminal end of the transmembrane region. Replacement of six residues surrounding this site strongly reduced intramembrane cleavage. Our results provide new insights into the molecular physiology of the CSF-1 receptor and contribute to our understanding of substrate selection by TACE and gamma-secretase. PMID- 24955856 TI - Syntheses of imidazo-, oxa-, and thiazepine ring systems via ring-opening of aziridines/Cu-catalyzed C-N/C-C bond formation. AB - A simple and unpredicted synthetic pathway toward racemic and scalemic tetrahydrodibenzoimidazoazepines has been invented serendipitously proceeding through an S(N)2-type ring-opening of N-activated aziridines with 2 bromobenzylamine followed by a hitherto unprecedented cascade cyclization reaction sequence comprising a Cu-catalyzed cross dehydrogenation C-N coupling and an Ullmann C-C bond formation reaction. The tetrahydrobenzoxazepine and the tetrahydrobenzothiazepine derivatives have also been synthesized via the ring opening of aziridines with 2-bromobenzyl alcohols and -mercaptan, respectively, followed by Cu-catalyzed N-arylation reaction. PMID- 24955857 TI - Detecting the norovirus season in Sweden using search engine data--meeting the needs of hospital infection control teams. AB - Norovirus outbreaks severely disrupt healthcare systems. We evaluated whether Websok, an internet-based surveillance system using search engine data, improved norovirus surveillance and response in Sweden. We compared Websok users' characteristics with the general population, cross-correlated weekly Websok searches with laboratory notifications between 2006 and 2013, compared the time Websok and laboratory data crossed the epidemic threshold and surveyed infection control teams about their perception and use of Websok. Users of Websok were not representative of the general population. Websok correlated with laboratory data (b = 0.88-0.89) and gave an earlier signal to the onset of the norovirus season compared with laboratory-based surveillance. 17/21 (81%) infection control teams answered the survey, of which 11 (65%) believed Websok could help with infection control plans. Websok is a low-resource, easily replicable system that detects the norovirus season as reliably as laboratory data, but earlier. Using Websok in routine surveillance can help infection control teams prepare for the yearly norovirus season. PMID- 24955859 TI - Structural DNA nanotechnology for intelligent drug delivery. AB - Drug delivery carriers have been popularly employed to improve solubility, stability, and efficacy of chemical and biomolecular drugs. Despite the rapid progress in this field, it remains a great challenge to develop an ideal carrier with minimal cytotoxicity, high biocompatibility and intelligence for targeted controlled release. The emergence of DNA nanotechnology offers unprecedented opportunities in this regard. Due to the unparalleled self-recognition properties of DNA molecules, it is possible to create numerous artificial DNA nanostructures with well-defined structures and DNA nanodevices with precisely controlled motions. More importantly, recent studies have proven that DNA nanostructures possess greater permeability to the membrane barrier of cells, which pave the way to developing new drug delivery carriers with nucleic acids, are summarized. In this Concept, recent advances on the design and fabrication of both static and dynamic DNA nanostructures, and the use of these nanostructures for the delivery of various types of drugs, are highlighted. It is also demonstrated that dynamic DNA nanostructures provide the required intelligence to realize logically controlled drug release. PMID- 24955858 TI - Effects of 24 h working on-call on psychoneuroendocrine and oculomotor function: a randomized cross-over trial. AB - OBJECTIVES: On-call duty (OCD) is frequently associated with health and safety risks for both physicians and patients. The lack of studies conducted in clinical care environments and the ongoing public dialogue concerning OCD led to a detailed investigation of a working schedule including sleep fragmentation and extended work hours. DESIGN: Within-person randomized cross-over trial. SETTING: Comparison of a 24h on-call shift (OCD) compared to a routine working-day (non on call, NOC) in hospital. PARTICIPANTS: 30 residents and senior physicians of the Department of Internal Medicine, Neurology and Otorhinolaryngology at the University Hospital Innsbruck. MAIN OUTCOME MEASURES: Sleep variables, cognitive performance (Concentration-Endurance d2 test), emotional status (Eigenschaftswoerterliste 60S), serum-cortisol, urinary cortisol and noradrenaline, heart-rate variability, and saccadic eye movements were determined before and after OCD and NOC respectively. RESULTS: Concentration-endurance performance was significantly reduced after OCD as compared to NOC by 16.4% (p<0.001). Changes in emotional status consisted in a reduction of subjective concentration and performance related activation after OCD by 17.4% (p<0.001) and 16.0% (p<0.001) respectively together with a 21.8% increase of general deactivation (p<0.001) and a 29.2% rise of fatigue (p<0.001). On the contrary, subjective activation and raised mood showed an 18.3% and 21.7% increase after OCD (p<0.01). Urinary noradrenaline excretion (46 MUg/24 h, 19-97) was greater during OCD when compared to NOC (36 MUg/24 h, 10-54, p<0.01). Sympathetic activity measured by heart rate variability was significantly higher during OCD in contrast to NOC (p<0.05). Serum-cortisol was lower in the morning after (132 ng/l, 60-273) than the morning before OCD (p<0.01). Finally, the number of short saccadic latencies was reduced after OCD (p<0.05) compared to NOC. CONCLUSIONS: 24 h OCD alters both, the sympathetic-adrenomedullary system as well as the hypothalamic pituitary-adrenocortical axis. Moreover, physicians' emotional state, cognitive and oculomotor performance seems to be influenced independently from sleep interruptions. The discrepancy between subjective feeling and objective cognitive impairments pose a risk for performing complex manual and cognitive tasks. Hence, our findings argue against an oversimplified interpretation of alterations in the physicians' psychoneuroendocrine structure in terms of impaired mood and neurocognitive deterioration combined with up /dysregulated stress axes associated with OCD as a consequence of sleep deprivation. PMID- 24955860 TI - Bacteriophages as vehicles for gene delivery into mammalian cells: prospects and problems. AB - INTRODUCTION: The identification of more efficient gene delivery vehicles (GDVs) is essential to fulfill the expectations of clinical gene therapy. Bacteriophages, due to their excellent safety profile, extreme stability under a variety of harsh environmental conditions and the capability for being genetically manipulated, have drawn a flurry of interest to be applied as a newly arisen category of gene delivery platforms. AREAS COVERED: The incessant evolutionary interaction of bacteriophages with human cells has turned them into a part of our body's natural ecosystem. However, these carriers represent several barriers to gene transduction of mammalian cells. The lack of evolvement of specialized machinery for targeted cellular internalization, endosomal, lysosomal and proteasomal escape, cytoplasmic entry, nuclear localization and intranuclear transcription poses major challenges to the expression of the phage-carried gene. In this review, we describe pros and cons of bacteriophages as GDVs, provide an insight into numerous barriers that bacteriophages face for entry into and subsequent trafficking inside mammalian cells and elaborate on the strategies used to bypass these barriers. EXPERT OPINION: Tremendous genetic flexibility of bacteriophages to undergo numerous surface modifications through phage display technology has proven to be a turning point in the uncompromising efforts to surmount the limitations of phage-mediated gene expression. The revelatory outcomes of the studies undertaken within the recent years have been promising for phage-mediated gene delivery to move from concept to reality. PMID- 24955861 TI - Effects of brexpiprazole, a novel serotonin-dopamine activity modulator, on phencyclidine-induced cognitive deficits in mice: a role for serotonin 5-HT1A receptors. AB - Brexpiprazole, a serotonin-dopamine activity modulator, is currently being tested in clinical trials as a new therapy for a number of neuropsychiatric diseases, including schizophrenia and major depressive disorder. Accumulating evidence suggests that 5-hydroxytryptamine (5-HT)1A receptors play a role in cognition. This study was undertaken to examine whether brexpiprazole, a novel drug with 5 HT1A receptor partial agonism, could improve cognitive deficits in mice, induced by repeated administration of the N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP). Subsequent subchronic (14 days) oral administration of brexpiprazole (0.3, 1, or 3mg/kg/day) significantly attenuated PCP (10mg/kg/day for 10 days)-induced cognitive deficits in mice, in a dose dependent manner. The effects of brexpiprazole (3mg/kg) were significantly antagonized by co-administration of the selective 5-HT1A receptor antagonist, WAY 100,635 (1.0mg/kg), although WAY-100,635 alone was not effective in this model. These findings suggest that brexpiprazole can ameliorate PCP-induced cognitive deficits in mice via 5-HT1A receptors. Therefore, brexpiprazole could ameliorate cognitive deficits as seen in schizophrenia and other neuropsychiatric diseases. PMID- 24955862 TI - Role of GABAA receptor in modulation of acute thermal pain using a rat model of cholestasis. AB - Increased activity of the endogenous opioid system in cholestasis results in analgesia. GABAA receptors have been ascribed both pronociceptive and antinociceptive roles in pain modulation. Considering the elevated endogenous opioid tone in cholestasis and the existence of close interaction between the GABAergic and opioidergic systems in pain control, the involvement of GABAA receptors in modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated using muscimol and bicuculline as selective GABAA receptor agonist and antagonist respectively. Cholestasis was induced by ligation of the main bile duct using two ligatures and transsection of the duct between them. Cholestatic rats had increased tail-flick latencies (TFLs) compared to non-cholestatic rats. Administration of muscimol (0.2 and 0.4 mg/kg, s.c.) and bicuculline (0.5 and 1mg/kg, s.c.) to the cholestatic groups significantly increased and decreased respectively TFLs compared to the saline treated cholestatic group. Muscimol antinociception in cholestatic animals was attenuated by co-administration of naloxone or bicuculline. Furthermore, the combination of bicuculline and naloxone completely reversed the increased TFLs of cholestatic rats back to the level of unoperated animals. Muscimol and bicuculline injections into non-cholestatic animals did not alter TFLs. At the doses used here, none of the drugs impaired motor coordination, as revealed by the rotarod test. This study shows the involvement of GABAA receptors in pain modulation during cholestasis in rats. PMID- 24955863 TI - N2 ameliorates neural injury during experimental ischemic stroke via the regulation of thromboxane A2 production. AB - Thromboxane A2 (TXA2) promotes ischemic stroke injury and has strong effects in vascular contraction and vascular endothelial cell dysfunction. Agents that reduce TXA2 production have potential for ameliorating neural injury in ischemic stroke. Thromboxane synthetase (TXS) is essential for TXA2 production, and TXS inhibitors have been developed as drugs for the prevention and treatment of stroke. However, ozagrel, a typical TXS inhibitor currently in clinical use, must be delivered via intravenous injection (I.V.). N2, 4-(2-(1H-imidazol-1-yl) ethoxy)-3-methoxybenzoate, is a potential thromboxane synthetase (TXS) inhibitor, which is being developed as an orally available formulation. The aim of this study was to investigate the effects of N2 on focal cerebral ischemia-reperfusion injury and related mechanisms. Neurological deficits, a Y-maze test and infarct volume were measured to evaluate the effects of N2 post-treatment on middle cerebral artery occlusion (MCAO)-induced ischemia/reperfusion (I/R) injury in rats. Furthermore, the influence of N2 on U46619-induced rat aorta contraction was investigated ex vivo. Moreover, we investigated the protective effects of N2 on rat brain microvessel endothelial cells (RBMECs) in hypoxia/deoxygenating (H/R) induced by Na2S2O4 in vitro. Cell viability and TXA2 biosynthesis were measured by 3-(4, 5-dimethylthiazol-2-yl)- 195 2, 5-diphenyltetrazolium bromide (MTT) and enzyme-linked immunosorbent assay (ELISA) assays, respectively. The results showed that N2 treatment effectively improves performance in neurological deficit and the Y-maze test and reduces the infarct volume in I/R rats. U46619 induced rat aorta contraction was inhibited by N2 ex vivo. Furthermore, N2 incubation improved the morphology of RBMECs, increased cell viability, and suppressed TXA2 production by inhibiting TXS during H/R damage. In summary, this study demonstrated that N2 was neural protective in focal cerebral I/R injury, which might be associated with the effects of N2 on endothelium protection and vascular contraction inhibition. In depth, the mechanisms underlying this phenomenon might be the influence of N2 on TXA2 production targeting TXS. PMID- 24955864 TI - Dopamine is involved in the different patterns of copulatory behaviour of Roman high and low avoidance rats: studies with apomorphine and haloperidol. AB - Outbred Roman high- (RHA) and low-avoidance (RLA) rats, originally selected for rapid vs. poor acquisition of active avoidance in a shuttle box, show differential copulatory patterns when exposed to a receptive female. Indeed, in the first copulation test male RHA rats show more mounts, intromissions and ejaculations than RLA rats. Such differences do not disappear in subsequent copulation tests, with sexually experienced RHA rats always showing higher levels of sexual motivation and performance than their RLA counterparts. This study shows that the different copulatory patterns of sexually experienced RHA and RLA rats are differentially facilitated by apomorphine, a mixed D1/D2-like dopamine receptor agonist, and impaired by haloperidol, a D2-like dopamine receptor antagonist, given at doses which facilitate and impair, respectively, copulatory behaviour in Sprague Dawley rats used as an external reference strain. Accordingly, apomorphine-induced facilitation and haloperidol-induced impairment of copulatory behaviour were more robust in RLA than RHA rats, as indicated by their effects on several copulatory parameters including mount, intromission and ejaculation latencies, mount, intromission and ejaculation frequencies, post ejaculatory interval, inter-intromission interval and copulatory efficacy. Pretreatment with haloperidol also reduced the facilitatory effect of apomorphine more effectively in RLA than RHA rats. These results suggest that the different copulatory patterns of RHA and RLA rats are mainly due to a lower dopaminergic tone at level of the mesolimbic and incerto-hypothalamic dopaminergic systems of RLA vs. RHA rats, which play a key role in sexual behaviour. PMID- 24955865 TI - Blockade of median raphe nucleus alpha1-adrenoceptor subtypes increases food intake in rats. AB - Previous studies have shown that the blockade of alpha1-adrenoceptors in the median raphe nucleus (MnR) of free-feeding animals increases food intake. Since there is evidence for the presence of alpha1A-, alpha1B- and alpha1D adrenoceptors in the MnR of rats, this study investigated the involvement of MnR alpha1-adrenoceptor subtypes in the control of feeding behavior, looking for possible differences on the role of each alpha1-adrenoceptor in feeding. Male adult rats weighing 280-300 g with guide cannulae chronically implanted above the MnR were injected with antagonists of alpha1A- (RS100329, 0, 2, 4 or 20 nmol), alpha1B- (Rec 15/2615, 0, 2, 4 or 20 nmol) or alpha1D-adrenoceptor (BMY 7378, 0, 2, 4 or 20 nmol). Subsequently, behavioral evaluation of ingestive and non ingestive parameters was monitored for 1h and the amount of food and water ingested was assessed for 4h. The highest dose (20 nmol) of RS100329 and BMY 7378 increased food intake, feeding duration and frequency, and decreased the latency to start feeding. During the second hour 2 nmol dose of Rec 15/2615 increased food intake and all doses of BMY 7378 decreased water intake. No behavioral alterations were observed during the fourth hour. The results corroborate previous work from our lab in which we describe the involvement of alpha1 adrenoceptors of MnR on food intake control. Moreover, we show evidence that alpha1A- and alpha1D-adrenoceptors mediate feeding responses to adrenaline injections and that the behavioral modifications are of considerable duration, persisting up to 2h after injection of the antagonists. PMID- 24955866 TI - (6aR)-11-amino-N-propyl-noraporphine, a new dopamine D2 and serotonin 5-HT1A dual agonist, elicits potent antiparkinsonian action and attenuates levodopa-induced dyskinesia in a 6-OHDA-lesioned rat model of Parkinson's disease. AB - Parkinson's disease (PD) drug therapy remains a challenge. Dual modulation of dopamine and 5-HT receptors has emerged as a promising approach in anti-PD drug development. Taking advantage of the newly discovered aporphine analogue(s), (6aR)-11-amino-N-propyl-noraporphine (SOMCL-171), which exhibited dual D2/5-HT1A receptor agonistic activity, we studied the effects of the compound on levodopa induced dyskinesia (LID) in a PD animal model. The results demonstrated that SOMCL-171 elicited a potent anti-PD effect in a 6-OHDA-lesioned rat model. Chronic use of SOMCL-171 reduced LID without compromising the antiparkinsonian efficacy. Furthermore, we found that the antidyskinesia effect of SOMCL-171 is associated with its 5-HT1A agonistic activity and the up-regulation of the striatal 5-HT1A receptor. The present data indicated that chronic SOMCL-171 alone produced potent antiparkinsonian effects with weak dyskinesia, compared with that of levodopa. In addition, chronic SOMCL-171 application attenuated the development of levodopa-induced LID at no expense to the antiparkinsonian efficacy. Taken together, our data suggested that dual modulation of D2/5-HT1A receptors may provide a novel approach for drug development in PD and LID. PMID- 24955867 TI - Interaction between the dopaminergic and opioidergic systems in dorsal hippocampus in modulation of formalin-induced orofacial pain in rats. AB - The hippocampus is a region of the brain that serves several functions. The dopaminergic system acts through D1- and D2-like receptors to interfere in pain modulation and the opioid receptors play major roles in analgesic processes and there are obvious overlaps between these two systems. The present study investigated the interaction between the opioidergic and dopaminergic systems in the dorsal hippocampus (CA1) region for formalin-induced orofacial pain. Two guide cannulae were stereotaxically implanted in the CA1 region and morphine (0.5, 1, 2 and 4 MUg/0.5 MUl saline) and naloxone (0.3, 1 and 3 MUg/0.5 MUl saline) were used as the opioid receptor agonist and antagonist, respectively. SKF-38393 (1 MUg/0.5 MUl saline) was used as a D1-like receptor agonist, quinpirole (2 MUg/0.5 MUl saline) as a D2-like receptor agonist, SCH-23390 (0.5 MUg/0.5 MUl saline) as a D1-like receptor antagonist and sulpiride (3 MUg/0.5 MUl DMSO) as a D2-like receptor antagonist. To induce orofacial pain, 50 MUl of 1% formalin was subcutaneously injected into the left side of the upper lip. Our results showed that different doses of morphine significantly reduced orofacial pain in both phases induced by formalin. Naloxone (1 and 3 MUg) reversed morphine induced analgesia in CA1. SKF-38393 and quinpirole with naloxone (1 MUg) significantly decreased formalin-induced orofacial pain in both phases. SCH-23390 had no effect on the antinociceptive response of morphine in both phases of orofacial pain. Sulpiride reversed the antinociceptive effects of morphine only in the first phase, but this result was not significant. Our findings suggest that there is cross-talk between the opioidergic and dopaminergic systems. Opioidergic neurons also exerted antinociceptive effects by modulation of the dopaminergic system in the CA1 region of the brain. PMID- 24955868 TI - When the customer is unethical: the explanatory role of employee emotional exhaustion onto work-family conflict, relationship conflict with coworkers, and job neglect. AB - We integrate deontological ethics (Folger, 1998, 2001; Kant, 1785/1948, 1797/1991) with conservation of resources theory (Hobfoll, 1989) to propose that an employee's repeated exposure to violations of moral principle can diminish the availability of resources to appropriately attend to other personal and work domains. In particular, we identify customer unethical behavior as a morally charged work demand that leads to a depletion of resources as captured by employee emotional exhaustion. In turn, emotionally exhausted employees experience higher levels of work-family conflict, relationship conflict with coworkers, and job neglect. Employee emotional exhaustion serves as the mediator between customer unethical behavior and such outcomes. To provide further evidence of a deontological effect, we demonstrate the unique effect of customer unethical behavior onto emotional exhaustion beyond perceptions of personal mistreatment and trait negative affectivity. In Study 1, we found support for our theoretical model using multisource field data from customer-service professionals across a variety of industries. In Study 2, we also found support for our theoretical model using multisource, longitudinal field data from service employees in a large government organization. Theoretical and practical implications are discussed. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 24955869 TI - Endogenous XIAP, but not other members of the inhibitory apoptosis protein family modulates cerebellar granule neurons survival. AB - Programmed cell death plays a critical role during cerebellar development. In particular, it has been shown in vivo and in vitro that developing cerebellar granule neurons (CGN) die apoptotically. Apoptosis involves a series of morphological changes and the activation of caspases. Inhibitor of apoptosis proteins (IAPs) is implicated in negative regulation of caspase activation and apoptotic cell death. Although apoptotic death of CGN has been extensively studied, there is no information about the role of IAPs in the developing cerebellum. Here, we studied the participation of some members of IAPs in the survival of the developing rat CGN in culture and under physiological conditions. Under these conditions, we found a differential expression pattern of cIAP-1, cIAP-2, XIAP and survivin during cerebellar development in an age-dependent manner, highlighting the significant increase of XIAP levels. We also detected an interaction between XIAP and caspase 3 at postnatal day (P) 12 and 16. On the other hand, we found a significant decrease of XIAP levels in cultured CGN maintained in chronic potassium deprivation, an apoptotic condition, suggesting a possible relationship between XIAP levels and neuronal viability. Under these conditions, we also detected the interaction of XIAP with active caspase-3. The down-regulation of XIAP in CGN cultured under survival conditions (chronic potassium depolarization) induced a reduction of cell viability and an increment of apoptotic cells. These findings support the idea that IAPs could be involved in the survival of CGN and that XIAP might be critical for neuronal survival in cerebellar development and during chronic depolarization in cultured CGN through a mechanism involving caspase inhibition. PMID- 24955870 TI - Levels of brain derived neurotrophic factors across gestation in women with preeclampsia. AB - Preeclampsia (PE) is a major pregnancy complication of placental origin which leads to adverse pregnancy outcome. Brain derived neurotrophic factor (BDNF) is suggested to promote trophoblast growth and regulate placental and fetal development. This study for the first time examines the levels of maternal plasma BDNF at various time points during gestation, cord plasma and placental BDNF levels and their association with birth outcome in women with PE. Normotensive control (NC) women (n=89) and women with PE (n=61) were followed at three different time points [16-20 weeks (T1), 26-30 weeks (T2) and at delivery (T3)]. Maternal blood at all time points and cord blood was collected. Results indicate that maternal BDNF levels at T1 (p=0.050) and T3 (p=0.025) were lower in women with PE than in NC women. Cord BDNF levels at delivery in women with PE were lower (p=0.032) than those in NC women. Placental BDNF gene expression was also lower (p=0.0082) in women with PE than in NC women. Our data suggests that BDNF plays an important role in the development of the materno-fetal-placental unit during pregnancy. Alteration in the levels of BDNF during pregnancy may be associated with an abnormal development of the placenta resulting in PE. PMID- 24955871 TI - An azido-BODIPY probe for glycosylation: initiation of strong fluorescence upon triazole formation. AB - We have designed a low fluorescent azido-BODIPY-based probe AzBOCEt (Az10) that undergoes copper(I)-catalyzed 1,3-dipolar cycloadditions with alkynes to yield strongly fluorescent triazole derivatives. The fluorescent quantum yield of a triazole product T10 is enhanced by 52-fold as compared to AzBOCEt upon excitation at a wavelength above 500 nm. Quantum mechanical calculations indicate that the increase in fluorescence upon triazole formation is due to the lowering of the HOMO energy level of the aryl moiety to reduce the process of acceptor photoinduced electron transfer. AzBOCEt is shown to label alkyne-functionalized proteins in vitro and glycoproteins in cells with excellent selectivity, and enables cell imaging and visualization of glycoconjugates in alkynyl-saccharide treated cells at extremely low concentration (0.1 MUM). Furthermore, the alkyne tagged glycoproteins from cell lysates can be directly detected with AzBOCEt in gel electrophoresis. PMID- 24955872 TI - Copper-catalyzed enantioselective hetero-Diels-Alder reaction of Danishefsky's diene with beta,gamma-unsaturated alpha-ketoesters. AB - A highly enantioselective hetero-Diels-Alder reaction of Danishefsky's diene with beta,gamma-unsaturated alpha-ketoesters was developed for the first time by virtue of chiral copper complexes. This protocol provided a facile access to optically active dihydropyranones bearing a quaternary center with high enantioselectivities and good yields. Furthermore, on the basis of the isolated intermediate analysis, the reaction pathway was substrate-dependent. PMID- 24955873 TI - Contextualizing racial disparities in preterm delivery: a rhetorical analysis of U.S. epidemiological research at the turn of the 21st century. AB - Preterm delivery (PTD), defined as delivery prior to 37 weeks gestation, is a key contributor to persistent racial disparities in infant mortality in the United States. Five major funding initiatives were devoted to advancing PTD epidemiology during the 1990s and 2000s. By examining content and rhetorical features of 94 studies conducted under these initiatives, and published between 1993 and 2011, this paper considers how calls for more "contextual" approaches (focusing on social and environmental contexts) interacted with more "conventional" approaches (focusing on individual-level risk factors) to PTD epidemiology during this period. Contextual advocates initially emphasized complex biosocial reasoning to better connect social adversity with embodied outcomes. Yet responses by researchers invested in conventional approaches, as well as in studies published under new initiatives that explicitly claimed to incorporate contextual insights, often reframed this complex reasoning in biologically reductionist terms. Subsequent contextual advocates then focused on developing statistical methods to support research about social and environmental causes of PTD, and this strategy appears to have gained some traction with conventional researchers. These findings call for closer attention to language and power in both social scientific studies of epidemiological knowledge production, as well as among epidemiologists themselves. PMID- 24955874 TI - Pleasure: a forgotten dimension of physical activity in older age. AB - Pleasure is an under-researched and under theorized concept within health and health-related areas, particularly in relation to physical activity in older age. This gap is addressed here. The paper forms part of a larger qualitative project conducted between March 2011 and July 2013 within which fifty-one physically active older adults (age sixty to ninety-two years) were interviewed about their experiences of physical activity. Twenty-seven of these participants were also involved in a photo elicitation exercise whereby they responded to photographic images of themselves doing their activity. The paper reports in-depth on one of the themes - pleasure - that was initially identified through a rigorous categorical-content analysis of this data. An original typology of pleasure for physical activity in older age is developed, which details four significant ideal types of pleasure: sensual pleasure; documented pleasure; the pleasure of habitual action; and the pleasure of immersion. The implications of this typology for debates around embodiment, affect, and narratives of ageing are discussed in relation to health promotion and future research in this underserved area. PMID- 24955876 TI - The association between involvement in family caregiving and mental health among middle-aged adults in Japan. AB - It is widely known that the mental health of middle-aged adults is closely associated with involvement in family caregiving, as well as socioeconomic and sociodemographic factors. However, most studies focusing on mental health in adulthood have not fully controlled for time-invariant factors. Moreover, the relative importance of factors associated with mental health has remained largely understudied. In the current study, we employed fixed-effects regression models to examine the manner in which middle-aged adults' mental health is associated with involvement in family caregiving and socioeconomic and sociodemographic factors, after controlling for time-invariant factors. Using data from a population-based, six-year panel survey in Japan, we focused on the evolution of the Kessler 6 (K6) scores (range: 0-24) for 26,522 individuals (12,646 men and 13,876 women) aged 50-59 years in 2005 over the subsequent five years. We found that men and women experienced 0.54 (95% CI 0.44-0.64) and 0.57 (95% CI 0.49 0.66) unit increases in their K6 scores, respectively, when they became involved in care provision for any family member. This magnitude of distress exceeded that associated with any socioeconomic or sociodemographic factor examined in this study. Furthermore, we found that care provision to a mother-in-law had an additional, negative association with mental health for female caregivers, as opposed to men. These findings suggest that more panel studies are needed to examine the correlates of mental health among middle-aged adults. PMID- 24955875 TI - Women's empowerment and fertility: a review of the literature. AB - Women's empowerment has become a focal point for development efforts worldwide and there is a need for an updated, critical assessment of the existing evidence on women's empowerment and fertility. We conducted a literature review on studies examining the relationships between women's empowerment and several fertility related topics. Among the 60 studies identified for this review, the majority were conducted in South Asia (n = 35) and used household decision-making as a measure of empowerment (n = 37). Overall, the vast majority of studies found some positive associations between women's empowerment and lower fertility, longer birth intervals, and lower rates of unintended pregnancy, but there was some variation in results. In many studies, results differed based on the measure of empowerment used, sociopolitical or gender environment, or sub-population studied. This article is one of the first evaluations of the literature assessing the relationships between women's empowerment and fertility. We identify several key issues that merit further investigation. PMID- 24955877 TI - Two esterases from the genus Spodoptera degrade sex pheromones and plant volatiles. AB - In moths, high temporal sensitivity in perception of sex pheromones and host plant volatiles suggests the existence of mechanisms acting to maintain antennal sensitivity. The antennal enzymes have been long hypothesized to play a central role in the mechanisms, by rapid metabolism of the odorants soon after the fulfillment of the sensillum receptor activation. In the present study, two putative homologous esterases, SexiCXE13 and SlituCXE13, were cloned by RT-PCR and RACE procedures from Spodoptera exigua and Spodoptera litura, respectively. The phylogenetic tree assigned the two genes into the same group with two previously identified male antennal-specific pheromone-degrading enzymes. SexiCXE13 and SlituCXE13 were expressed in High Five cells, and the enzymatic characteristics and substrate specificity were investigated using the purified recombinant enzymes. Both esterases showed high activity to a variety of acetate substrates, including the sex pheromones, their analogs, and some common plant odorants. Our study, for the first time, provides direct biochemical and molecular evidence that the ubiquitously expressed enzyme has the ability to degrade sex pheromones and plant volatiles, and thus this adds new knowledge to the mechanism underlying the sensitivity of moth olfaction. PMID- 24955879 TI - Hydrogen-rich water reestablishes ROS homeostasis but exerts differential effects on anthocyanin synthesis in two varieties of radish sprouts under UV-A irradiation. AB - The aims of the study were to investigate whether hydrogen gas (H2) was involved in regulation of anthocyanin biosynthesis in two contrasting radish (Raphanus sativus L.) varieties (low [LA] and high [HA] level of anthocyanin) under UV irradiation. The results showed that hydrogen-rich water (HRW) significantly blocked the UV-A-induced increase of H2O2 and O2(*-) accumulation, and enhanced the UV-A-induced increase of superoxide dismutase (SOD) and ascorbate peroxidase (APX) activities in LA and HA. Furthermore, UV-A-induced increase of anthocyanin and total phenols was further enhanced only in HA sprouts cotreated with HRW. LC MS/MS analysis showed that five anthocyanidins existed in HA sprouts, but only two in LA sprouts. Meanwhile, the cyanidin was the most abundant anthocyanidin in HA, and the cyanidin was 2-fold higher cotreated with HRW than UV-A. Molecular analyses showed that the anthocyanin biosynthesis-related genes were upregulated significantly in both HA (in particular) and LA sprouts treated with HRW plus UV A. These data imply that HRW reestablishes reactive oxygen species homeostasis in both LA and HA, but exerts different effects on anthocyanin accumulation between them under UV-A. PMID- 24955878 TI - Gas-phase advanced oxidation for effective, efficient in situ control of pollution. AB - In this article, gas-phase advanced oxidation, a new method for pollution control building on the photo-oxidation and particle formation chemistry occurring in the atmosphere, is introduced and characterized. The process uses ozone and UV-C light to produce in situ radicals to oxidize pollution, generating particles that are removed by a filter; ozone is removed using a MnO2 honeycomb catalyst. This combination of in situ processes removes a wide range of pollutants with a comparatively low specific energy input. Two proof-of-concept devices were built to test and optimize the process. The laboratory prototype was built of standard ventilation duct and could treat up to 850 m(3)/h. A portable continuous-flow prototype built in an aluminum flight case was able to treat 46 m(3)/h. Removal efficiencies of >95% were observed for propane, cyclohexane, benzene, isoprene, aerosol particle mass, and ozone for concentrations in the range of 0.4-6 ppm and exposure times up to 0.5 min. The laboratory prototype generated a OH(*) concentration derived from propane reaction of (2.5 +/- 0.3) * 10(10) cm(-3) at a specific energy input of 3 kJ/m(3), and the portable device generated (4.6 +/- 0.4) * 10(9) cm(-3) at 10 kJ/m(3). Based on these results, in situ gas-phase advanced oxidation is a viable control strategy for most volatile organic compounds, specifically those with a OH(*) reaction rate higher than ca. 5 * 10( 13) cm(3)/s. Gas-phase advanced oxidation is able to remove compounds that react with OH and to control ozone and total particulate mass. Secondary pollution including formaldehyde and ultrafine particles might be generated, depending on the composition of the primary pollution. PMID- 24955880 TI - Growth hormone (GH)-releasing activity of chicken GH-releasing hormone (GHRH) in chickens. AB - Two peptides with sequence similarities to growth hormone releasing hormone (GHRH) have been identified by analysis of the chicken genome. One of these peptides, chicken (c) GHRH-LP (like peptide) was previously found to poorly bind to chicken pituitary membranes or to cloned and expressed chicken GHRH receptors and had little, if any, growth hormone (GH)-releasing activity in vivo or in vitro. In contrast, a second more recently discovered peptide, cGHRH, does bind to cloned and expressed cGHRH receptors and increases cAMP activity in transfected cells. The possibility that this peptide may have in vivo GH releasing activity was therefore assessed. The intravenous (i.v.) administration of cGHRH to immature chickens, at doses of 3-100 MUg/kg, significantly increased circulating GH concentrations within 10 min of injection and the plasma GH levels remained elevated for at least 30 min after the injection of maximally effective doses. The plasma GH responses to cGHRH were comparable with those induced by human (h) or porcine (p) GHRH preparations and to that induced by thyrotropin releasing hormone (TRH). In marked contrast, the i.v. injection of cGHRH-LP had no significant effect on circulating GH concentrations in immature chicks. GH release was also increased from slaughterhouse chicken pituitary glands perifused for 5 min with cGHRH at doses of 0.1 MUg/ml or 1.0 MUg/ml, comparable with GH responses to hGHRH1-44. In contrast, the perifusion of chicken pituitary glands with cGHRH-LP had no significant effect on GH release. In summary, these results demonstrate that cGHRH has GH-releasing activity in chickens and support the possibility that it is the endogenous ligand of the cGHRH receptor. PMID- 24955881 TI - GnIH and GnRH expressions in the central nervous system and pituitary of Indian major carp, Labeo rohita during ontogeny: An immunocytochemical study. AB - Gonadotropin-releasing hormone (GnRH) is the major hypothalamic neuropeptide stimulating gonadotropin secretion in vertebrates. In 2000, gonadotropin inhibitory hormone (GnIH) was discovered as a hypothalamic neuropeptide that inhibits gonadotropin secretion in birds. Subsequent studies have shown that GnIH is present in the brain of other vertebrates. We show for the first time GnIH immunoreactivity in the central nervous system and pituitary during development of Indian major carp, Labeo rohita and compare it with the localization of GnRH. GnIH and GnRH immunoreactivities were observed from the olfactory system to spinal cord throughout development. In the brain, both neuropeptides were localized in the telencephalon, diencephalon including the preoptic area and rhombencephalon. The localization of GnIH and GnRH in the pituitary suggests that these neuropeptides are involved in the regulation of pituitary hormones by an autocrine manner during development. In addition, the presence of GnIH and GnRH in several other brain regions including the olfactory system suggests their involvement in the regulation of other physiological functions. PMID- 24955883 TI - Enhanced fluid flow through nanopores by polymer brushes. AB - In the past few decades, much research has been devoted to nanoscale transport, despite its complexity. Here we present results, which are counterintuitive, showing that adsorption of the polystyrene-b-polyisoprene (PS-b-PI) diblock copolymer to the aluminum oxide nanopore membrane wall considerably reduces the friction of the organic solvents passing through the nanopore channels. The estimated apparent slip length for tetrahydrofuran (THF) liquid flow through 20 nm nanopore membranes increases from 0.13-0.16 MUm for the bare nanopore to 3-13 MUm after PS-b-PI polymer physisorbed to the pore surface to saturation. For the bare nanopore membranes, the slip length remains constant at different flow rates while after polymer adsorption it increases with the liquid flow shear rate. The shear rate dependence of the slip length is understandable from the point of view of polymer chains stretching dynamics under shear flow. The findings of this study may aid in understanding the physics of nannofluidics and have implications for biolubrication effects in biological systems. PMID- 24955882 TI - Characterisation of kisspeptin system genes in an ovoviviparous teleost: Sebastes schlegeli. AB - Kisspeptins are neuropeptides that play important roles in the reproduction and the onset of puberty in vertebrate by activating their receptor, Kissr. In the present study, we first isolated kiss1 and kissr4 genes from an ovoviviparous fish, the black rockfish (Sebastes schlegeli) by homologue cloning. Phylogenetic analysis indicated that the kiss and kissr of S. schlegeli belonged to kiss1 and kissr4 respectively. Quantitative real-time PCR analysis showed that the kissr4 was expressed mainly in the brain and testis, while the kiss1 was expressed predominantly in the heart of both sexes. As for the different gonadal maturation stages the kiss1 showed different expression patterns in different tissues. During the early development stage, expression levels of the ligand and receptor genes showed similar increasing trends. The promoter region of kissr4 contained several putative transcription factor (TF) binding sites which may have the function of regulating kisspeptin system gene expression, providing potential targets for future in-depth investigation. These results together confirmed that the kisspeptin system in S. schlegeli may be involved in reproduction and other activities. Furthermore, our study laid the groundwork for further learning about the evolution and function of kisspeptin system in fish even vertebrate. PMID- 24955885 TI - Knowing what, where, and when: event comprehension in language processing. AB - We investigated the retrieval of location information, and the deployment of attention to these locations, following (described) event-related location changes. In two visual world experiments, listeners viewed arrays with containers like a bowl, jar, pan, and jug, while hearing sentences like "The boy will pour the sweetcorn from the bowl into the jar, and he will pour the gravy from the pan into the jug. And then, he will taste the sweetcorn". At the discourse-final "sweetcorn", listeners fixated context-relevant "Target" containers most (jar). Crucially, we also observed two forms of competition: listeners fixated containers that were not directly referred to but associated with "sweetcorn" (bowl), and containers that played the same role as Targets (goals of moving events; jug), more than distractors (pan). These results suggest that event related location changes are encoded across representations that compete for comprehenders' attention, such that listeners retrieve, and fixate, locations that are not referred to in the unfolding language, but related to them via object or role information. PMID- 24955884 TI - How children perceive fractals: hierarchical self-similarity and cognitive development. AB - The ability to understand and generate hierarchical structures is a crucial component of human cognition, available in language, music, mathematics and problem solving. Recursion is a particularly useful mechanism for generating complex hierarchies by means of self-embedding rules. In the visual domain, fractals are recursive structures in which simple transformation rules generate hierarchies of infinite depth. Research on how children acquire these rules can provide valuable insight into the cognitive requirements and learning constraints of recursion. Here, we used fractals to investigate the acquisition of recursion in the visual domain, and probed for correlations with grammar comprehension and general intelligence. We compared second (n=26) and fourth graders (n=26) in their ability to represent two types of rules for generating hierarchical structures: Recursive rules, on the one hand, which generate new hierarchical levels; and iterative rules, on the other hand, which merely insert items within hierarchies without generating new levels. We found that the majority of fourth graders, but not second graders, were able to represent both recursive and iterative rules. This difference was partially accounted by second graders' impairment in detecting hierarchical mistakes, and correlated with between-grade differences in grammar comprehension tasks. Empirically, recursion and iteration also differed in at least one crucial aspect: While the ability to learn recursive rules seemed to depend on the previous acquisition of simple iterative representations, the opposite was not true, i.e., children were able to acquire iterative rules before they acquired recursive representations. These results suggest that the acquisition of recursion in vision follows learning constraints similar to the acquisition of recursion in language, and that both domains share cognitive resources involved in hierarchical processing. PMID- 24955886 TI - Working memory predicts semantic comprehension in dichotic listening in older adults. AB - Older adults have difficulty understanding spoken language in the presence of competing voices. Everyday social situations involving multiple simultaneous talkers may become increasingly challenging in later life due to changes in the ability to focus attention. This study examined whether individual differences in cognitive function predict older adults' ability to access sentence-level meanings in competing speech using a dichotic priming paradigm. Older listeners showed faster responses to words that matched the meaning of spoken sentences presented to the left or right ear, relative to a neutral baseline. However, older adults were more vulnerable than younger adults to interference from competing speech when the competing signal was presented to the right ear. This pattern of performance was strongly correlated with a non-auditory working memory measure, suggesting that cognitive factors play a key role in semantic comprehension in competing speech in healthy aging. PMID- 24955887 TI - Task instructions and implicit theory of mind. AB - It has been hypothesized that humans are able to track other's mental states efficiently and without being conscious of doing so using their implicit theory of mind (iToM) system. However, while iToM appears to operate unconsciously recent work suggests it does draw on executive attentional resources (Schneider, Lam, Bayliss, & Dux, 2012) bringing into question whether iToM is engaged efficiently. Here, we examined other aspects relating to automatic processing: The extent to which the operation of iToM is controllable and how it is influenced by behavioral intentions. This was implemented by assessing how task instructions affect eye-movement patterns in a Sally-Anne false-belief task. One group of subjects was given no task instructions (No Instructions), another overtly judged the location of a ball a protagonist interacted with (Ball Tracking) and a third indicated the location consistent with the actor's belief about the ball's location (Belief Tracking). Despite different task goals, all groups' eye-movement patterns were consistent with belief analysis, and the No Instructions and Ball Tracking groups reported no explicit mentalizing when debriefed. These findings represent definitive evidence that humans implicitly track the belief states of others in an uncontrollable and unintentional manner. PMID- 24955888 TI - Sometimes it does hurt to ask: the constructive role of articulating impressions. AB - Decisions can sometimes have a constructive role, so that the act of, for example, choosing one option over another creates a preference for that option (e.g., Ariely & Norton, 2008; Payne, Bettman, & Johnson, 1993; Sharot, Velasquez, & Dolan, 2010; Sherman, 1980). In this work we explore the constructive role of just articulating an impression, for a presented visual stimulus, as opposed to making a choice (specifically, the judgments we employ are affective evaluations). Using quantum probability theory, we outline a cognitive model formalizing such a constructive process. We predict a simple interaction, in relation to how a second image is evaluated, following the presentation of a first image, depending on whether there is a rating for the first image or not. The interaction predicted by the quantum model was confirmed across three experiments and a variety of control manipulations. The advantages of using quantum probability theory to model the present results, compared with existing models of sequence order effects in judgment (e.g., Hogarth & Einhorn, 1992) or other theories of constructive processes when a choice is made (e.g., Festinger, 1957; Sharot et al., 2010) are discussed. PMID- 24955889 TI - Bioactive diterpenoids and flavonoids from the aerial parts of Scoparia dulcis. AB - Six new diterpenoids, 4-epi-7alpha-O-acetylscoparic acid A (1), 7alpha hydroxyscopadiol (2), 7alpha-O-acetyl-8,17beta-epoxyscoparic acid A (3), neo dulcinol (4), dulcinodal-13-one (5), and 4-epi-7alpha-hydroxydulcinodal-13-one (6), and a new flavonoid, dillenetin 3-O-(6"-O-p-coumaroyl)-beta-D glucopyranoside (10), along with 12 known compounds, were isolated from the aerial parts of Scoparia dulcis. The 7S absolute configuration of the new diterpenoids 1-4 and 6 was deduced by comparing their NOESY spectra with that of a known compound, (7S)-4-epi-7-hydroxyscoparic acid A (7), which was determined by the modified Mosher's method. The flavonoids scutellarein (11), hispidulin (12), apigenin (15), and luteolin (16) and the terpenoids 4-epi-scopadulcic acid B (9) and betulinic acid (19) showed more potent alpha-glucosidase inhibitory effects (with IC50 values in the range 13.7-132.5 MUM) than the positive control, acarbose. In addition, compounds 1, 11, 12, 15, 16, and acerosin (17) exhibited peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonistic activity, with EC50 values ranging from 0.9 to 24.9 MUM. PMID- 24955890 TI - A procedure for separate recovery of extra- and intracellular DNA from a single marine sediment sample. AB - Extracellular DNA (eDNA) is a ubiquitous biological compound in aquatic sediment and soil. Previous studies suggested that eDNA plays an important role in biogeochemical element cycling, horizontal gene transfer and stabilization of biofilm structures. Previous methods for eDNA extraction were either not suitable for oligotrophic sediments or only allowed quantification but no genetic analyses. Our procedure is based on cell detachment and eDNA liberation from sediment particles by sequential washing with an alkaline sodium phosphate buffer followed by a separation of cells and eDNA. The separated eDNA is then bound onto silica particles and purified, whereas the intracellular DNA from the separated cells is extracted using a commercial kit. The method provides extra- and intracellular DNA of high purity that is suitable for downstream applications like PCR. Extracellular DNA was extracted from organic-rich shallow sediment of the Baltic Sea, glacially influenced sediment of the Barents Sea and from the oligotrophic South Pacific Gyre. The eDNA concentration in these samples varied from 23 to 626ngg(-1) wet weight sediment. A number of experiments were performed to verify each processing step. Although extraction efficiency is higher than other published methods, it is not fully quantitative. PMID- 24955891 TI - Atomistic modeling of vibrational action spectra in polyatomic molecules: nuclear quantum effects. AB - The response of a polyatomic molecule to an infrared (IR) laser pulse of varying frequency has been simulated by classical molecular dynamics simulations and by quantum methods based on the path-integral framework (PIMD), as well as quantum thermal baths (QTBs). The outcome of the trajectories was subsequently processed to predict a dissociation spectrum, from the precalculated rate constant. Naphthalene described by a tight-binding potential energy surface was chosen as a testing ground for the present problem, possibly emitting an hydrogen atom after a 12 ps long pulse. At low field intensities, the heating efficiency of the pulse is found to vary similarly as the IR absorption spectrum for all methods considered, reflecting the validity of linear response in this regime. At fields that are sufficiently high to induce statistical dissociation over mass spectrometry timescales, marked differences appear with the spectral features exhibiting additional broadenings and redshift, especially for quantum mechanical descriptions of nuclear motion. Those excessive broadenings are mostly caused by anharmonicities but also convey the inherent approximations of the semiclassical QTB method and point at limitations of the PIMD simulations when used in such strong out-of-equilibrium conditions. PMID- 24955892 TI - Iron-catalyzed borylation of alkyl electrophiles. AB - The use of low-cost iron(III) acetoacetate (Fe(acac)3) and tetramethylethylenediamine (TMEDA) enables the direct cross-coupling of alkyl halides with bis(pinacolato)diboron. This approach allows for the borylation of activated or unactivated primary, secondary, and tertiary bromides. Moreover, even the borylation of benzylic or allylic chlorides, tosylates, and mesylates are possible. The reactions proceed under mild conditions at room temperature and show broad functional-group compatibility and "robustness" as measured by a modified Glorius robustness screen. PMID- 24955893 TI - The myeloid-binding peptide adenoviral vector enables multi-organ vascular endothelial gene targeting. AB - Vascular endothelial cells (ECs) are ideal gene therapy targets as they provide widespread tissue access and are the first contact surfaces following intravenous vector administration. Human recombinant adenovirus serotype 5 (Ad5) is the most frequently used gene transfer system because of its appreciable transgene payload capacity and lack of somatic mutation risk. However, standard Ad5 vectors predominantly transduce liver but not the vasculature following intravenous administration. We recently developed an Ad5 vector with a myeloid cell-binding peptide (MBP) incorporated into the knob-deleted, T4 fibritin chimeric fiber (Ad.MBP). This vector was shown to transduce pulmonary ECs presumably via a vector handoff mechanism. Here we tested the body-wide tropism of the Ad.MBP vector, its myeloid cell necessity, and vector-EC expression dose response. Using comprehensive multi-organ co-immunofluorescence analysis, we discovered that Ad.MBP produced widespread EC transduction in the lung, heart, kidney, skeletal muscle, pancreas, small bowel, and brain. Surprisingly, Ad.MBP retained hepatocyte tropism albeit at a reduced frequency compared with the standard Ad5. While binding specifically to myeloid cells ex vivo, multi-organ Ad.MBP expression was not dependent on circulating monocytes or macrophages. Ad.MBP dose de-escalation maintained full lung-targeting capacity but drastically reduced transgene expression in other organs. Swapping the EC-specific ROBO4 for the CMV promoter/enhancer abrogated hepatocyte expression but also reduced gene expression in other organs. Collectively, our multilevel targeting strategy could enable therapeutic biological production in previously inaccessible organs that pertain to the most debilitating or lethal human diseases. PMID- 24955897 TI - Medical technology as the object of ethics. PMID- 24955895 TI - LL-37 secreted by epithelium promotes fibroblast collagen production: a potential mechanism of small airway remodeling in chronic obstructive pulmonary disease. AB - Emerging evidence suggests that the process of small airway remodeling is mediated by profibrotic growth factors produced by epithelium, which are capable of activating the underlying mesenchymal cells with excessive collagen production. It has been demonstrated that human cathelicidin antimicrobial protein LL-37 is highly expressed in small airway epithelium from COPD patients. However, it is unknown whether the increased levels of LL-37 in epithelium are involved in the pathogenesis of small airway remodeling in COPD. In this study, we examined the expression of LL-37 in small airways from smokers with COPD and controls (non-smokers and smokers without COPD) by immunohistochemistry, and then the association between LL-37 expression in epithelium and the structural changes of small airway remodeling was analyzed. In vitro, the effect of CSE-induced epithelial secretion of LL-37 on collagen production in human lung fibroblasts (HFL-1 cell line) was studied in a co-culture system. Finally, the signaling pathways involved in the effect of LL-37 on fibroblast collagen production were evaluated. The results showed that LL-37 immunoreactivity in airway epithelium was significantly elevated in smokers with COPD compared with controls. In addition, the magnitude of LL-37 expression in epithelium was positively correlated with airway wall thickness and collagen deposition. In vitro, CSE induced epithelial secretion of LL-37 promoted fibroblast collagen production. Finally, we showed that formyl peptide receptor-like 1 (FPRL1)-dependent extracellular signal-regulated kinase (ERK) signaling pathway was essential for LL-37-induced collagen production in HFL-1 cells. These results suggest that after cigarette smoke exposure, the increased levels of LL-37 in airway epithelium could stimulate collagen production in the underlying lung fibroblasts and may contribute to small airway remodeling in COPD. PMID- 24955896 TI - Mechanical ventilation augments bleomycin-induced epithelial-mesenchymal transition through the Src pathway. AB - Mechanical ventilation used in patients with acute respiratory distress syndrome (ARDS) can damage pulmonary epithelial cells by producing inflammatory cytokines and depositing excess collagen. Src participates in plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor-beta1(TGF-beta1) production during the fibroproliferative phase of ARDS, which involves a process of epithelial-mesenchymal transition (EMT). The mechanisms regulating interactions between mechanical ventilation and EMT are unclear. We hypothesized that EMT induced by high-tidal volume (VT) mechanical stretch-augmented lung inflammation occurs through upregulation of the Src pathway. Five days after administering bleomycin to simulate acute lung injury (ALI), male C57BL/6 mice, either wild type or Src-deficient, aged 3 months, weighing between 25 and 30 g, were exposed to low-VT (6 ml/kg) or high-VT (30 ml/kg) mechanical ventilation with room air for 1-5 h. Nonventilated mice were used as control subjects. We observed that high-VT mechanical ventilation increased microvascular permeability, PAI-1 and TGF-beta1 protein levels, Masson's trichrome staining, extracellular collagen levels, collagen gene expression, fibroblast accumulation, positive staining of alpha-smooth muscle actin and type I collagen, activation of Src signaling and epithelial apoptotic cell death in wild-type mice (P<0.05). Decreased staining of the epithelial marker, Zonula occludents-1, was also observed. Mechanical stretch augmented EMT and epithelial apoptosis were attenuated in Src-deficient mice and pharmacological inhibition of Src activity by PP2 (P<0.05). Our data suggest that high-VT mechanical ventilation-augmented EMT after bleomycin-induced ALI partially depends on the Src pathway. PMID- 24955898 TI - Fifty years of the Sociedad Latinoamericana de Investigacion Pediatrica. PMID- 24955894 TI - Effects of CP-900691, a novel peroxisome proliferator-activated receptor alpha, agonist on diabetic nephropathy in the BTBR ob/ob mouse. AB - Piperidine-based peroxisome proliferator-activated receptor-alpha agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP 900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2alpha), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2alpha) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2alpha), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy. PMID- 24955899 TI - Nutritional status and blood pressure in adolescent students. AB - INTRODUCTION: Obesity is the main risk factor for arterial hypertension andis associatedwitha higher morbidity, both in the short and long term. OBJECTIVES: To compare anthropometric and blood pressure indicators in terms of the nutritional status, to verify the relationship between nutritional status and blood pressure, and to establish the prevalence of hypertension in terms of the nutritional status in both male and female adolescents. METHODS: Cross-sectional, descriptive study on 499 adolescent students aged 11-15 years old. Weight, height, body mass index (BMI), fat percentage, and blood pressure were measured and assessed. The BMI was used to classify participants (normal weight, overweight, obese), and the prevalence of hypertension was determined using values above the 95th percentile. RESULTS: As per the BMI classification, 81% of girls and 76.5% ofboys had normal weight, 15.7% of girls and 15.5% of boys were overweight, and 3.3% of girls and 8% of boys were obese. As per the blood pressure classification, hypertension was observed in 6.4% of boys and in 9% of girls. A relationship was found between nutritional status and blood pressure (boys: c2= 53.48; girls: c2= 85.21). CONCLUSION: Overweight and obese adolescents had more body fat and a higher blood pressure than normal weight adolescents. Also, a relationship was determined betweennutritional status and blood pressure in both male and female students. The higher the BMI, the higher the prevalence of hypertension. PMID- 24955901 TI - Pertussis seroprevalence in adults, post-partum women and umbilical cord blood. AB - Pertussis is a vaccine-preventable disease that affects people of all ages. Young adults who have lost their immunity to pertussis are the major source of infection in infants. Given the steady increase of pertussis cases, new prevention strategies are required. Objective. To assess pertussis seroprevalence in adult blood donors, post-partum women, and umbilical cords. Metod. Measurement of total titers of anti-Bordetella spp. (Bordetella) antibodies using an enzyme linked immunosorbent assay. Serum samples from 103 donors, 101 post-partum women and 100 umbilical cords were analyzed. Titers <80 were considered of low impact against the disease. The assessment included transplacental transfer of antibodies and the umbilical cord/maternal ratio of antibody titers. Results. Donors mean age was: 28 +/- 6 years old. Mediananti-Bordetella titers: 320; interquartile range (IQR):160-320; 10% had titers <80. Post-partum women mean age was: 26 +/- 6 years old. Median anti-Bordetella titers:160 (IQR:80-320), with titers significantly lower than in female donors (p= 0.00002). Titers <80 were found in 30% of post-partum women. Median anti-Bordetella titers in umbilical cords: 160 (IQR: 80-160). Titers <80 were more frequently found in umbilical cords than in mothers (44% versus 30%, p= 0.04). Transplacental transfer was 0.83. Umbilical cord titers were equal to maternal titers in 54% of cases, lower in 37%, and higher only in 8%. Conclusion. Titers of anti-Bordetella antibodies in post-partum women were significantly lower than in female blood donors. Titers <80 were found in 30% of post-partum women and 44% of umbilical cords. These data may account for the high rates of pertussis in young infants who have not yet completed their vaccination schedule. PMID- 24955900 TI - Clinical outcome of neonates with nosocomial suspected sepsis treated with cefazolin or vancomycin: a non-inferiority, randomized, controlled trial. AB - BACKGROUND: Nosocomial infections are a major problem in Neonatal Intensive Care Units. Coagulase negative Staphylococcus (CONS) is the most common causative agent. We evaluated the efficacy of cefazolin versus vancomycin as initial therapy for neonates with presumptive clinical signs of nosocomial sepsis probably caused by CONS. METHODS: Hospitalized newborns infants with clinical signs of very probable bacterial sepsis were included. Two groups were randomly assigned according the initial antibiotic therapy: cefazolin group (CG) or vancomycin group (VG). The primary analysis was performed on an intention-to treat basis. The main outcome measure was the clinical outcome of infants in both groups at the end of antibiotic treatment. RESULTS: We analyzed 109 newborns, 52 in CG and 57 in VG. Baseline characteristics were similar among groups. The percentage of neonates with adequate outcome was 92% in the CG and 86% in the VG: difference: 6% (95% CI: -7% to 19%, p-value non-inferiority, p = 0.007). Seven infants died in the CG (13.5%) and and 11 (19.2%) in the VG; no significant difference (p=0.45). CONCLUSION: Cefazolin was not inferior to vancomycin in achieving an adequate clinical outcome in newborn infants with confirmed or highly probable nosocomial sepsis. PMID- 24955902 TI - Prevention of respiratory infections at day care centers: recommendations and systematic review of the evidence. AB - INTRODUCTION: Attending a day care center is a risk factor for respiratory infections. The objective of this study is to review which nonspecific prevention measures are recommended for day care centers and the evidence of their usefulness in this setting. METHODS: Recommendations regarding nonspecific prevention at national level were searched using Google and the web sites of the Argentine Society of Pediatrics, the ministries of education and the ministries of health from different countries, both in English and Spanish. Recommendations regarding hand hygiene, clearance of secretions, cleaning the environment and elements, breastfeeding, and exclusion of symptomatic subjects were reviewed. A systematic search of the literature was conducted to find intervention studies at day care centers that evaluated the effectiveness of recommendations, published in Spanish and English. Results and the methodological quality of studies were analyzed. RESULTS: Seven guidelines were found. Hand hygiene and environment cleaning were the only recommendations described in all guidelines. The exclusion of symptomatic subjects is mentioned in all, but criteria are heterogeneous. Clearance of nasal secretions and promotion of breastfeeding are outlined only in a few of the guidelines. Eight intervention studies on hand hygiene, cleaning of the environment, and clearance of secretions were found, whose results were heterogeneous and had major methodological limitations. CONCLUSION: A timely and adequate hand hygiene and an appropriate cleaning of the environment have been uniformly recommended by different guidelines as non-specific prevention measures against respiratory infections. The evidence on the usefulness of these measures in this setting is limited. PMID- 24955903 TI - Pneumococcal meningitis: a 12 year experience in a children's hospital prior to the universal immunization with a conjugate vaccine. AB - INTRODUCTION: Pneumococcal meningitis is causedby Streptococcuspneumoniae and hashigh morbidity and mortality rates. The objective of this study was to identify the epidemiological and clinical characteristics, antibiotic sensitivity and evolution of pneumococcal meningitis in children prior to the introduction of the vaccine in Argentina. METHODS: Patients younger than 18 years old hospitalizedat Hospital J. P. Garrahanbetween1999 and 2010 were included. Children's microbiology lab records and case records were reviewed. RESULTS: One hundred and eleven children with S. pneumoniae meningitis were identified. Forty cases were found in the 1999-2002 period, 35 in the 2003-2006 period, and 36 in the 20072010 period. The mean age was 7 months old (range: 1-191). One hundred and four patients were immunocompetent (94%). Only 20 patients (18%) had an underlying disease. The most commonly observed clinical presentation was neurological involvement in 80 patients (75%), and sepsis in59 (53%). Forty-nine patients (44%) had to be admitted to the ICU. A second clinical source of infection was identified in 24 patients (22%); half of these cases corresponded to pneumonia. Positive findings were observed in the cerebrospinal fluid culture of 103 patients (93%) and in the blood culture of 88 (79%). Resistance to penicillin was identified in 15% of cases, while 5% showed resistance to cefotaxime. Antibiotic resistance was reduced over the years. Complications occurred in 56 patients (50%), and 11 (10%) died because of the infection. CONCLUSION: Antimicrobial resistance by S. pneumoniae was reduced over time. It is important to maintain epidemiological surveillance to assess the impact of immunization in Argentina. PMID- 24955904 TI - Nutritional status and blood pressure assessment in vulnerable children from two schools in Cutral Co and Plaza Huincul: a quantitative and qualitative study. AB - INTRODUCTION: Knowing the nutritional status of children is critical to plan primary health care interventions in the setting of the present obesity epidemic and the great increase in the prevalence of childhood metabolic syndrome. For this reason, nutritional status and blood pressure were assessed among children from two schools of high social vulnerability, results were qualitatively analyzed, and community members feedback was obtained in order to be fully aware of the situation and accordingly plan local health interventions. POPULATION AND METHODS: Cross-sectional study conducted at purposively selected schools, with results analyzed using focus groups. The following standards were used: the World Health Organization (WHO) growth standards for weight and height; the National Center for Health Statistics (NCHS) for body mass index (BMI); the National Institutes of Health (NIH) for blood pressure; and Fernandez J., et al. standards for waist circumference. RESULTS: Three hundred and sixty one children were evaluated; of them, 20.8% were overweight, 22.2% were obese and 6.5% were hypertensive. Obesity was more prevalent in boys (p: 0.039), and no relationship was observed between hypertension and central obesity with age and sex. The social factors that influence this situation were described by community representatives. CONCLUSIONS: It was established that this population was malnourished and had a high prevalence of obesity. Results were analyzed by community members who focused on the items to be considered for the intervention. PMID- 24955905 TI - Is there a relationship between rotavirus positive gastroenteritis and ABO blood groups?: a retrospective cohort study. AB - INTRODUCTION: Rotavirus is the most common cause of severe diarrhea in children. There is only a few clinical studies about the relationship between rotavirus gastroenteritis and ABO blood groups. OBJECTIVE: The aim of this study was to investigate the role of blood groups, if any present, in the incidence of rotavirus gastroenteritis, and the severity of the gastroenteritis. METHODS: The file records of babies born in our hospital and diagnosed with acute gastroenteritis in their follow up were investigated retrospectively. RESULTS: The study was conducted with 219 (36.3%) rotavirus positive and 383 (63.6%) rotavirus negative patients. The A blood group was detected more commonly in the rotavirus positive group compared to the rotavirus negative group (50.6 vs. 42.2%, p= 0.047). Hospitalization rates of the cases with rotavirus gastroenteritis among children with the A blood group (30.6 vs. 8%, p= 0.001) were significantly higher. CONCLUSIONS: Rotavirus gastroenteritis was determined to be more common in children with A blood group. The hospitalization rates of such patients were detected to be higher. Therefore, rotavirus gastroenteritis among children with blood group A should be monitored closely. PMID- 24955907 TI - Nineteen-years of pneumococcal invasive disease surveillance in a children's hospital in Mendoza, Argentina. AB - Five hundred and thirty-seven children admitted to Hospital Dr. Notti and diagnosed with invasive pneumococcal disease between 1993 and 2011 were studied. Their median age was 19 months (range= 0-192 months); 34.82% were <1 year old and 23.46%, >60 months old. Pneumonia with or without effusion (48.04%) and meningitis (29.05%) were the most predominant conditions, with a case fatality rate of 6.14%. Identified serotypes corresponded to 14, 5 and 1 in56.86% of cases. Sensitivity to penicillin was observed in99.74% of non-meningeal strains, while sensitivity to ceftriaxone was found in 98.08% ofmeningeal strains. Risk factors inpneumonia with effusionwere associated to age >60 months old, RR: 1.47 (1.06-2.04), p= 0.02, to serotype 5, RR: 2.57 (1.71-3.87), p= 0.0001, and to serotype 1, RR: 1.86 (1.17-2.96), p= 0.014; in the case of meningitis, risk factors were mainly associated to age <1 year old, RR: 2.35 (1.87-3.06), p= 0.0000, and to serotype 18C, RR: 2.19 (1.3-3.7), p= 0.024. Conclusion. Streptococcus pneumonia was a major problem in infants younger than one year old, who predominantly developed meningitis which caused half of deaths, and in children older than 60 months old, who had a prevalence of pneumonia with effusion. Most cases were sensitive to penicillin and ceftriaxone. PMID- 24955906 TI - Treatment of refractory epilepsy with the modified Atkins diet. AB - The modified Atkins diet (MAD) is an alternative therapeutic diet for the treatment of drug-resistant epilepsy. It consists of a diet with 60% energy from fat, 30% from protein, and 10% from carbohydrates. The objective of this article is to present a series of nine patients diagnosed with refractory epilepsy of different etiologies treated with the MAD at our hospital. In our group of nine patients, results obtained were similar to those published by other authors, with adequate adherence, tolerance and response. Of all patients, two achieved a reduction of more than 90% in the number of seizures; four experienced a reduction of 50-90%; two had a reduction of less than 50% in seizure control; and only one patient did not respond to the MAD. No patient had an increase in the number of seizures, and the diet was well-tolerated in all cases. PMID- 24955908 TI - [Septic shock in ICU: advanced therapeutics, immunoparalysis and genomics. State of the art]. AB - New and important concepts have emerged for the advanced management of the child with septic shock in the recent decades. Attending physicians in the Pediatric intensive care unit must be fully aware of them to improve patient care in the critical care unit. It should be considered the use of immune therapy only in selected groups of patients. Continuous renal replacement therapies are well tolerated and their early use prevents deleterious fluid overload. Removal of inflammatory mediators by using high volume hemofiltration may play a role in hyperdynamic septic patients. The use of plasmapheresis is recommended in patients with thrombocytopenia-associated multiple organ failure. Extracorporeal support use should be considered in those with refractory septic shock despite goals directed therapy. The immunoparalysis has been associated with nosocomial infections and late mortality. The information from genetic markers may allow early intervention and preventive genomics-based medicine. PMID- 24955909 TI - [The child with hypertransaminasemia: what's next?]. AB - The raising of serum transaminases is seen with increasing frequency in different scenarios from daily practice. This poses a complex challenge to the pediatrician owing to the scarcity of bibliographic information available on this topic. From the completely asymptomatic patient to the child with signs of chronic liver disease, the full spectrum is highly varied, compelling to guide the investigation efficiently, in order to avoid unnecessary costs and suffering to the patient and their family. Coordinated work with the hepatologist is advisable in most instances. PMID- 24955910 TI - [Guidelines of categorization, organization and functioning of the Pediatric Intensive Care Units and Pediatric Intermediate Care Units in health care facilities: part II: Pediatric Intensive Care Unit Level 2 - Resuscitation Unit Pediatric Intermediate Care Unit]. PMID- 24955911 TI - [Guidelines on children preparticipation physical evaluation. Update]. PMID- 24955912 TI - [Becker's nevus]. PMID- 24955913 TI - [A twelve-years-old girl with multiloculated gynandroblastoma CD99 negative: case report]. AB - The ginandroblastoma is an extremely rare ovarian tumor which shows components of granulosa cells and Sertoli/Leydig cells. We describe a case of a twelve-years old girl who presented abnormal uterine bleeding and progressively growing intraabdominal mass associated with menorrhagia, CA-125 60.4 UI/mL and extension studies reporting cystic mass in the left ovary. She underwent oophorectomy. Pathological study shows a multilocular tumor filled with serous material. Many Call-Exner bodies were observed in the histopathological analysis, 45% of Sertoli/Leydig cells. Immunohistochemistry was reactive for inhibin, calretinin and pCK while AE1/AE3 and CD99 markers were negative. This is the first case report about a multiloculated gynandroblastoma, negative for CD99 in a 12-years old girl. Thus, the study of this clinical case represents a systematic approach for tumors of the sex cord cells. PMID- 24955914 TI - [Combined immunodeficiency with cutaneous manifestations associated with DOCK8 mutation]. AB - Different primary immunodeficiencies present increased levels of IgE and cutaneous infections of viral etiology. We report a case of a 2 y, 8 m old boy with combined immunodeficiency, dermatitis and disseminated molluscum contagiosum. The patient presented high titers of IgE, eosinophilia and pronounced TCD8 lymphopenia. Impaired proliferation assays and abnormal antibody response to vaccination were found. Normal results of ZAP-70 protein, NK function, and HLA I levels, to test quantitatives and functional defects of cytotoxic cells, lead us to suspect a mutation in DOCK8 gene. Positive result in molecular study together with clinical and immunology features in the patient confirmed the diagnosis of this new immunodeficiency, being to the authors' knowledge the first case recorded in a paediatric hospital in our country. PMID- 24955915 TI - [Severe Staphylococcus aureus infections: clinical characteristics, antibiotic susceptibility and use of antimicrobials. Case series]. AB - Infectious due to methicillin-resistant community acquired Staphylococcus aureus is a public health problem of varying magnitude in different geographical areas of the world, representing a major burden on health systems. The debate on the initial empiric antibiotic therapy remains open. We present a case series of hospitalized patients with severe Staphylococcus aureus infections admitted to the pediatric intermediate care unit of Hospital El Cruce. Between May 2008 and December 2010, 43 patients were admitted. Sixty nine percent of isolated Staphylococcus aureus were methicillin-resistant. Although the difference was not statistically significant, methicillin-resistant Staphylococcus aureus infections required more days of hospitalization in critical care unit and developed more secondary sites of infection. Vancomycin, rifampicin and clindamycin were the most commonly prescribed antibiotics. There was a high resistance of Staphylococcus aureus to p-lactams in the series. PMID- 24955917 TI - [Vulvar lichen sclerosus in a girl with Turner syndrome]. AB - Dermatological complications in Turner syndrome are infrequent but occasionally cause significant morbidity. Lichen sclerosus (LS) is a chronic inflammatory mucocutaneous affection characterized by pruritus in the anogenital area. It is yet not clear its pathophysiology but it's linked with genetic factors and autoimmunity. This is a case report of a girl with Turner syndrome with growth hormone treatment that started with vulvar pruritus and was diagnosed as lichen sclerosus. PMID- 24955916 TI - [Nephrobronchial fistula in pediatric patient: case report]. AB - Nephrobronchial fistula is a rare complication of kidney infections, usually occurring in adult patients with xanthogranulomatous pyelonephritis and very occasionally in children. We reported a 12-year-old girl, with a history of myelomeningocele and recurrent urinary tract infection, who presented with a four week fever, cough and dyspnea, developing septic shock and presenting flood of airway by pus which caused cardiac arrest. A diagnosis of left perirenal extensive collection was established by abdominal computed tomography (CT). The patient first had antibiotic therapy and percutaneous drainage was performed draining pus and air. Thoracic and abdominal CT scan was performed corroborating transdiaphragmatic fistula. Total nephrectomy was performed. The patient showed gradual improvement after surgery and total regression of symptoms. Pathologic examination concluded chronic pyelonephritis. This case report illustrates a rare complication in children, the importance of early diagnosis of urinary tract infection in patients with comorbidities and of exhibiting a high index of suspicion to a potentially lethal complication. PMID- 24955918 TI - [Pylephlebitis in pediatric patients]. AB - Pylephlebitis is defined as thrombophlebitis of the portal vein or its tributaries. It is a rare disease commonly associated with acute appendicitis and it has a high rate of morbidity and mortality. Doppler ultrasound and computed tomography scan are the methods of choice to confirm diagnosis. The most frequent long-term complication in these patients is portal vein cavernoma, with subsequent portal hypertension. An early diagnosis, timely antibiotic therapy and removal of infection are essential therapeutic measures to diminish mortality. The need for anticoagulation therapy in children remains controversial. We report on a child with acute abdomen and sepsis with a diagnosis of pylephlebitis secondary to appendiceal inflammation. The patient received long-term antibiotic therapy and subcutaneous anticoagulation. Deferred appendectomy was performed with favorably outcome. PMID- 24955920 TI - Noninvasive brain stimulation for persistent postconcussion symptoms in mild traumatic brain injury. AB - Mild traumatic brain injury (mTBI) is typically followed by various postconcussive symptoms (PCS), including headache, depression, and cognitive deficits. In 15-25% of cases, PCS persists beyond the usual 3-month recovery period, interfering with activities of daily living and responding poorly to pharmacotherapy. We tested the safety, tolerability, and efficacy of repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) for alleviating PCS. Fifteen eligible patients with mTBI and PCS > 3 months postinjury consented to 20 sessions of rTMS (20 * 5-sec trains; 10 Hz at 110% threshold), with clinical and functional magnetic resonance imaging (fMRI) assessments before and after intervention and clinical assessment at 3-month follow-up. Primary outcomes were tolerability, safety, and efficacy, as measured with the PCS Scale. Secondary outcomes included the Cognitive Symptoms Questionnaire, neuropsychological test performance, and working memory task associated activity as assessed with fMRI. Twelve patients completed all sessions. Three withdrew because of worsening symptoms or for an unrelated event. Stimulation intensity was increased gradually across sessions, and all subjects tolerated the protocol by the sixth session. Commonly reported side effects among completers were increased headache (n = 3) and greater sleep disturbance (n = 3). Participants also reported positive outcomes such as less sleep disturbance (n = 3), and better mental focus (n = 3). On average, PCS scores declined by 14.6 points (p = 0.009) and fMRI task-related activation peaks in the DLPFC increased after rTMS. rTMS is safe, tolerated by most patients with mTBI, and associated with both a reduction in severity of PCS and an increase in task-related activations in DLPFC. Assessment of this intervention in a randomized, control trial is warranted. PMID- 24955921 TI - Performance evaluation of the Ingenuity TF PET/CT scanner with a focus on high count-rate conditions. AB - This study evaluated the positron emission tomography (PET) imaging performance of the Ingenuity TF 128 PET/computed tomography (CT) scanner which has a PET component that was designed to support a wider radioactivity range than is possible with those of Gemini TF PET/CT and Ingenuity TF PET/MR. Spatial resolution, sensitivity, count rate characteristics and image quality were evaluated according to the NEMA NU 2-2007 standard and ACR phantom accreditation procedures; these were supplemented by additional measurements intended to characterize the system under conditions that would be encountered during quantitative cardiac imaging with (82)Rb. Image quality was evaluated using a hot spheres phantom, and various contrast recovery and noise measurements were made from replicated images. Timing and energy resolution, dead time, and the linearity of the image activity concentration, were all measured over a wide range of count rates. Spatial resolution (4.8-5.1 mm FWHM), sensitivity (7.3 cps kBq(-1)), peak noise-equivalent count rate (124 kcps), and peak trues rate (365 kcps) were similar to those of the Gemini TF PET/CT. Contrast recovery was higher with a 2 mm, body-detail reconstruction than with a 4 mm, body reconstruction, although the precision was reduced. The noise equivalent count rate peak was broad (within 10% of peak from 241-609 MBq). The activity measured in phantom images was within 10% of the true activity for count rates up to those observed in (82)Rb cardiac PET studies. PMID- 24955922 TI - Structural and functional characterization of a novel molluskan ortholog of TRAF and TNF receptor-associated protein from disk abalone (Haliotis discus discus). AB - Immune signaling cascades have an indispensable role in the host defense of almost all the organisms. Tumor necrosis factor (TNF) signaling is considered as a prominent signaling pathway in vertebrate as well as invertebrate species. Within the signaling cascade, TNF receptor-associated factor (TRAF) and TNF receptor-associated protein (TTRAP) has been shown to have a crucial role in the modulation of immune signaling in animals. Here, we attempted to characterize a novel molluskan ortholog of TTRAP (AbTTRAP) from disk abalone (Haliotis discus discus) and analyzed its expression levels under pathogenic stress. The complete coding sequence of AbTTRAP consisted of 1071 nucleotides, coding for a 357 amino acid peptide, with a predicted molecular mass of 40 kDa. According to our in silico analysis, AbTTRAP resembled the typical TTRAP domain architecture, including a 5'-tyrosyl DNA phosphodiesterase domain. Moreover, phylogenetic analysis revealed its common ancestral invertebrate origin, where AbTTRAP was clustered with molluskan counterparts. Quantitative real time PCR showed universally distributed expression of AbTTRAP in selected tissues of abalone, from which more prominent expression was detected in hemocytes. Upon stimulation with two pathogen-derived mitogens, lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly I:C), transcript levels of AbTTRAP in hemocytes and gill tissues were differentially modulated with time. In addition, the recombinant protein of AbTTRAP exhibited prominent endonuclease activity against abalone genomic DNA, which was enhanced by the presence of Mg(2+) in the medium. Collectively, these results reinforce the existence of the TNF signaling cascade in mollusks like disk abalone, further implicating the putative regulatory behavior of TTRAP in invertebrate host pathology. PMID- 24955923 TI - Functional outcomes, feasibility, and safety of resection of transoral robotic surgery: single-institution series of 35 consecutive cases of transoral robotic surgery for oropharyngeal squamous cell carcinoma. AB - BACKGROUND: This is a single-institution prospective study in a tertiary care center to evaluate feasibility, completeness of resection, and functional outcomes for oropharyngeal squamous cell carcinoma (SCC) treated primarily with transoral robotic-assisted resection. METHODS: Thirty-five patients with T1 and T2 squamous cell carcinoma of the oropharynx were included. They underwent transoral robotic surgery (TORS) between September 2011 and April 2013, with a median follow-up time of 13 months. RESULTS: Main outcome measures were completeness of resection, disease-free survival, and cancer recurrence for the preliminary oncologic outcome; postoperative bleeding, number of days intubated, rate of elective tracheotomy, duration of intensive care and/or intermediate care, speech and swallowing function, and length of nasogastric and/or gastrostomy tube dependency for the functional results. CONCLUSION: Our 1-year (median) functional and early oncologic results of 35 patients with oropharyngeal cancer treated primarily with TORS are encouraging to continue gaining further experiences with this surgical modality on a select subgroup of patients. PMID- 24955925 TI - Pro-oxidant treatment of human prostate carcinoma (DU145) induces autoschizis cell death: autophagosomes build up out of injured endomembranes and mitochondria. AB - One hour after pro-oxidative treatment by either ascorbate (VC), menadione (VK3), or VC: VK3 combination followed by 24-h incubation in culture medium, DU145 human prostate carcinoma cells developed ultrastructural-dependent organelle damage with the sequence Sham > VC > VK3 > VC: VK3. Along the nuclear alterations and the cytoplasm self-excisions reducing cell size, other induced injuries concerned mitochondria and endomembranes that associated with lysosomes. Damaged organelles surrounded by specialized endoplasmic membranes formed autophagosomes out of phagophores that also captured pieces of glycogen-rich cytoplasm. Most autophagosomes amassed in the diminished-size perikarya and corroborated the enhanced cytotoxicity of the VC: VK3 treatment. These accumulations did not initiate cell death, instead were merely signs of excessive "recycling" of damaged organelles. These features may reflect that high lysosomal activities provided foodstuffs in an ultimate strategy of survival of the tumor cells already devastated by reactive oxidative species (ROS) energetic sites. As such they became transient markers preceding cell death induced to occur by autoschizis and not by apoptosis or other cell deaths. This report could provide more support for the usage of this vitamin combination named APATONE as inexpensive potent adjuvant or treatment in prostate cancers. PMID- 24955924 TI - Collagen nanofibers facilitated presynaptic maturation in differentiated neurons from spinal-cord-derived neural stem cells through MAPK/ERK1/2-Synapsin I signaling pathway. AB - Neural stem cells (NSCs) are deemed to be a potential cell therapy for brain and spinal cord reconstruction and regeneration following injury. In this study, we investigated the role of nanofibrous scaffolds on NSCs-derived neurons in the formation of neural networks. Miniature excitatory postsynaptic currents (mEPSCs) were recorded using the whole-cell patch clamp recording method after the spinal cord-derived NSCs were differentiated into neurons and cultured in vitro for 10 14 days. It was observed that the frequency of mEPSCs in the differentiated neurons cultured on both randomly oriented and aligned collagen nanofibrous scaffolds was higher than that on the collagen-coated control and can be inhibited by an ERK inhibitor (PD98059), indicating that the collagen nanofibers affected the maturation of the synapses from presynaptic sites via the MAPK/ERK1/2 pathway. In addition, both of the collagen nanofibers increased the phosphorylation of Synapsin I and facilitated the interaction of p-ERK1/2 and p Synapsin I. All these results suggested that the collagen nanofibrous scaffolds contributed to the presynaptic maturation via the ERK1/2-Synapsin I signaling pathway. PMID- 24955926 TI - Arterial endofibrosis in endurance athletes: angiographic features and classification. AB - PURPOSE: To describe the spectrum of angiographic features of arterial endofibrosis and to assess the patterns of associated lesions. MATERIALS AND METHODS: This retrospective study was compliant with the declaration of Helsinki principles. Files of patients who underwent surgery between January 1998 and December 2009 were retrospectively searched for histologic analysis-proven arterial endofibrosis. Preoperative angiograms were read in consensus by two radiologists. Abnormalities of the common iliac (CIA), external iliac (EIA), and femoral arteries were classified into five types, known as the CEF classification. RESULTS: This study assessed 180 patients (161 men, 19 women) with 195 symptomatic limbs (136 left-side limbs; P < .001). Angiography depicted 28 abnormalities in the CIA (27 stenoses, one dissection), 185 in the EIA (17 thromboses, 167 stenoses, one dissection), one in the common femoral artery (dissection), and 14 in the deep femoral artery (one thrombosis, 13 stenoses). CIA and EIA stenoses predominantly involved the distal and proximal third of the artery respectively. They were mild (CIA and EIA mean severity, 19% +/- 7 and 26% +/- 11, respectively) and long (45% +/- 26 and 51% +/- 26 of the artery, respectively). EIA stenoses were significantly longer in women (P < .003). Upon hip flexion, 23 CIA and 116 EIA stenoses showed kinking (mean amplitude, 76 degrees +/- 23 and 76 degrees +/- 30, respectively). All deep femoral artery stenoses were diaphragm-like and involved the lateral circumflex femoral artery. CIA, EIA, and femoral lesions were not randomly associated (P < .001). ConCLUSION: Arterial endofibrosis mainly affects the central part of the iliac artery and the lateral circumflex femoral artery. The CIA, EIA, and femoral lesion classification may help to distinguish patterns of associated lesions. PMID- 24955927 TI - Added value of shear-wave elastography for evaluation of breast masses detected with screening US imaging. AB - PURPOSE: To evaluate the additional value of shear-wave elastography (SWE) to B mode ultrasonography (US) and to determine an appropriate guideline for the combined assessment of screening US-detected breast masses. MATERIALS AND METHODS: This study was conducted with institutional review board approval, and written informed consent was obtained. From March 2010 to February 2012, B-mode US and SWE were performed in 159 US-detected breast masses before biopsy. For each lesion, Breast Imaging Reporting and Data System (BI-RADS) category on B mode US images and the maximum stiffness color and elasticity values on SWE images were assessed. A guideline for adding SWE data to B-mode US was developed with the retrospective cohort to improve diagnostic performance in sensitivity and specificity and was validated in a distinct prospective cohort of 207 women prior to biopsy. RESULTS: Twenty-one of 159 masses in the development cohort and 12 of 207 breast masses in the validation cohort were malignant. In the development cohort, when BI-RADS category 4a masses showing a dark blue color or a maximum elasticity value of 30 kPa or less on SWE images were downgraded to category 3, specificity increased from 9.4% (13 of 138) to 59.4% (82 of 138) and 57.2% (79 of 138) (P < .001), respectively, without loss in sensitivity (100% [21 of 21]). In the validation cohort, specificity increased from 17.4% (34 of 195) to 62.1% (121 of 195) and 53.3% (104 of 195) (P < .001) respectively, without loss in sensitivity (91.7% [11 of 12]). CONCLUSION: The addition of SWE to B-mode US improved diagnostic performance with increased specificity for screening US detected breast masses. BI-RADS category 4a masses detected at US screening that showed a dark blue color or a maximum elasticity value of 30 kPa or less on SWE images can be safely followed up instead of performing biopsy. PMID- 24955929 TI - CT screening for lung cancer: alternative definitions of positive test result based on the national lung screening trial and international early lung cancer action program databases. AB - PURPOSE: To determine the usefulness of alternative nodule size thresholds in a population undergoing computed tomographic (CT) screening for lung cancer and to compare the reported International Early Lung Cancer Action Program ( I-ELCAP International Early Lung Cancer Action Program ) results with the National Lung Screening Trial ( NLST National Lung Screening Trial ) results. MATERIALS AND METHODS: The institutional review board approved this retrospective analysis. Informed consent was obtained according to HIPAA compliance. Findings in the CT cohort in the NLST National Lung Screening Trial of 25 813 participants who underwent baseline CT in 2002-2004 were reviewed. The frequency of solid and part solid pulmonary nodules and the lung cancer diagnoses using an alternative nodule threshold of 5.0, 6.0, 7.0, 8.0, and 9.0 mm were determined. Proportional reduction in the frequency of positive results and their 95% confidence intervals using each of the alternative thresholds were calculated. RESULTS: The frequency of positive results in the baseline round in the CT arm of the NLST National Lung Screening Trial using the definition of a positive result of any parenchymal, solid or part-solid, noncalcified nodule of 5.0 mm or larger was 15.8% (4080 of 25 813). Using alternative thresholds of 6.0, 7.0, 8.0, and 9.0 mm, the frequencies of positive results were 10.5% (2700 of 25 813, 7.2% (1847 of 25 813), 5.3% (1362 of 25 813), and 4.1% (1007 of 25 813), respectively, and the corresponding proportional reduction in additional CT scans would have been 33.8% (1380 of 1480), 54.7% (2233 of 4080), 66.6% (2718 of 4080), and 73.8% (3013 of 4080), respectively. Concomitantly, the proportion of lung cancer diagnoses determined within the first 12 months would be delayed up to 9 months for 0.9% (two of 232), 2.6% (six of 232), 6.0% (14 of 232), and 9.9% (23 of 232) of the patients, respectively. CONCLUSION: The NLST National Lung Screening Trial results are similar to those previously reported for the I-ELCAP International Early Lung Cancer Action Program and suggest that, even for high-risk participants in the NLST National Lung Screening Trial , higher thresholds of nodule size should be considered and prospectively evaluated. PMID- 24955928 TI - Pattern analysis of dynamic susceptibility contrast-enhanced MR imaging demonstrates peritumoral tissue heterogeneity. AB - PURPOSE: To augment the analysis of dynamic susceptibility contrast material enhanced magnetic resonance (MR) images to uncover unique tissue characteristics that could potentially facilitate treatment planning through a better understanding of the peritumoral region in patients with glioblastoma. MATERIALS AND METHODS: Institutional review board approval was obtained for this study, with waiver of informed consent for retrospective review of medical records. Dynamic susceptibility contrast-enhanced MR imaging data were obtained for 79 patients, and principal component analysis was applied to the perfusion signal intensity. The first six principal components were sufficient to characterize more than 99% of variance in the temporal dynamics of blood perfusion in all regions of interest. The principal components were subsequently used in conjunction with a support vector machine classifier to create a map of heterogeneity within the peritumoral region, and the variance of this map served as the heterogeneity score. RESULTS: The calculated principal components allowed near-perfect separability of tissue that was likely highly infiltrated with tumor and tissue that was unlikely infiltrated with tumor. The heterogeneity map created by using the principal components showed a clear relationship between voxels judged by the support vector machine to be highly infiltrated and subsequent recurrence. The results demonstrated a significant correlation (r = 0.46, P < .0001) between the heterogeneity score and patient survival. The hazard ratio was 2.23 (95% confidence interval: 1.4, 3.6; P < .01) between patients with high and low heterogeneity scores on the basis of the median heterogeneity score. CONCLUSION: Analysis of dynamic susceptibility contrast-enhanced MR imaging data by using principal component analysis can help identify imaging variables that can be subsequently used to evaluate the peritumoral region in glioblastoma. These variables are potentially indicative of tumor infiltration and may become useful tools in guiding therapy, as well as individualized prognostication. PMID- 24955930 TI - Biocompatibility and Alkaline Phosphatase Activity of Phosphorylated Chitooligosaccharides on the Osteosarcoma MG63 Cell Line. AB - Phosphorylated chitooligosaccharides (P-COS) were prepared using a H3PO4, P2O5, Et3PO4 and hexanol solvent system. The P-COS were characterized by Fourier Transform Infrared Spectroscopy (FT-IR), Thermo gravimetric-Differential Thermal Analyzer (TG-DTA), 13C NMR, 31P NMR, X-ray diffraction analysis, solubility studies, biocompatibility and Alkaline Phosphatase Activity (ALP). The results reveal that phosphorylation occurred at the C3 and C6 position of OH groups and the C2 position of NH2 group. FT-IR confirmed no decomposition in pyranose ring in P-COS even with heating and treatment in acidic conditions. The amorphous nature of P-COS was confirmed by X-ray diffraction analysis. Further, the biocompatibility and alkaline phosphatase activity of P-COS were checked against the osteosarcoma MG63 cell line at different concentrations and no cytotoxicity was observed. After 12 h and 24 h of incubation, the ALP activity of P-COS was higher compared with the control group. These results suggest that P-COS is a biocompatible material and in future P-COS could open up a number of promising pharmaceutical and clinical applications to mankind. PMID- 24955931 TI - Autologous Cell Delivery to the Skin-Implant Interface via the Lumen of Percutaneous Devices in vitro. AB - Induced tissue regeneration around percutaneous medical implants could be a useful method to prevent the failure of the medical device, especially when the epidermal seal around the implant is disrupted and the implant must be maintained over a long period of time. In this manuscript, a novel concept and technique is introduced in which autologous keratinocytes were delivered to the interfacial area of a skin-implant using the hollow interior of a fixator pin as a conduit. Full thickness human skin explants discarded from surgeries were cultured at the air-liquid interface and were punctured to fit at the bottom of hollow cylindrical stainless steel fixator pins. Autologous keratinocytes, previously extracted from the same piece of skin and cultured separately, were delivered to the specimens thorough the interior of the hollow pins. The delivered cells survived the process and resembled undifferentiated epithelium, with variations in size and shape. Viability was demonstrated by the lack of morphologic evidence of necrosis or apoptosis. Although the cells did not form organized epithelial structures, differentiation toward a keratinocyte phenotype was evident immunohistochemically. These results suggest that an adaptation of this technique could be useful for the treatment of complications arising from the contact between skin and percutaneous devices in vivo. PMID- 24955933 TI - Antifungal activity and pore-forming mechanism of astacidin 1 against Candida albicans. AB - In a previous report, a novel antibacterial peptide astacidin 1 (FKVQNQHGQVVKIFHH) was isolated from hemocyanin of the freshwater crayfish Pacifastacus leniusculus. In this study, the antifungal activity and mechanism of astacidin 1 were evaluated. Astacidin 1 exhibited antifungal activity against Candida albicans, Trichosporon beigelii, Malassezia furfur, and Trichophyton rubrum. Also, astacidin 1 had fungal cell selectivity in human erythrocytes without causing hemolysis. To understand the antifungal mechanism, membrane studies were done against C. albicans and T. beigelii. Flow cytometric analysis and K(+) measurement showed membrane damage, resulting in membrane permeabilization and K(+) release-induced membrane depolarization. Furthermore, the calcein leakage from liposomes mimicking C. albicans membrane demonstrated that the membrane-active action was driven by pore-forming mechanism. Live cell imaging using fluorescein isothiocyanate-labeled dextrans of various sizes suggested that the radii of pores formed in the C. albicans membrane were 1.4-2.3 nm. Therefore, the present study suggests that astacidin 1 exerts its antifungal effect by damaging the fungal membrane via pore formation. PMID- 24955934 TI - Excited states of multiply-charged anions probed by photoelectron imaging: riding the repulsive Coulomb barrier. AB - Many properties of isolated multiply-charged anions (MCAs) are dictated by the strong intra-molecular Coulomb interactions that are present. The most striking property of MCAs is a long-range repulsive Coulomb barrier (RCB) that arises from the repulsive interaction between an electron and an anion which must be overcome to form a MCA. Excited states provide a route to probing this RCB and the focus of this Perspective is on recent photoelectron experiments, including angularly and temporally resolved, that have provided detailed physical insight into the RCB surfaces, their anisotropy, and their use to monitor molecular dynamics in real-time. An outlook provides some future prospects that studies on MCAs provide in terms of monitoring structural, charge-migration, and solvation dynamics. PMID- 24955935 TI - Interaction between interleukin-1 beta and angiotensin II receptor 1 in hypothalamic paraventricular nucleus contributes to progression of heart failure. AB - The central mechanisms by which interleukin-1 beta (IL-1beta) and angiotension II receptor 1 (AT1-R) contribute to sympathoexcitation in heart failure (HF) are unclear. In this study, we determined whether an interaction between IL-1beta and AT1-R in the paraventricular nucleus (PVN) contributes to progression of HF. Rats were implanted with bilateral PVN cannulae and subjected to coronary artery ligation or sham surgery (Sham). Subsequently, animals were treated for 4 weeks through PVN infusion with either vehicle, losartan (LOS, 200 MUg/day), IL-1beta (IL, 1 MUg/day), or IL-1beta along with LOS (LOS+IL). HF rats had higher levels of corticotropin-releasing hormone (CRH), norepinephrine (NE), and glutamate (Glu); lower levels of gamma-aminobutyric acid (GABA); and more positive fra-like activity in PVN when compared with Sham rats. HF rats also had higher levels of NE, epinephrine (EPI), and IL-1beta in plasma. PVN infusion of LOS attenuated the decreases in GABA and the increases in CRH, NE, and Glu in the PVN of HF rats. IL 1beta could further increase the expression of CRH, NE, Glu, EPI, and IL-1beta and decrease GABA expression. Treatment with IL-1beta along with LOS could eliminate the effects of IL-1beta. These findings suggest that an interaction between AT1-R and IL-1beta in the PVN contributes to progression in HF. PMID- 24955936 TI - A 36 month naturalistic retrospective study of clinic-treated youth with attention-deficit/hyperactivity disorder. AB - OBJECTIVE: The purpose of this study was to investigate factors for pharmacotherapy adherence in patients with attention-deficit/hyperactivity disorder (ADHD), with an emphasis on medication possession ratio (MPR). METHODS: The medical records of 300 clinic-treated youth diagnosed with ADHD were retrospectively reviewed. Patients from March 2005 through January 2009 were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, 4(th) ed., Text Revision (DSM-IV-TR) and psychological tests. Patients were classified based on the time period from the initial visit to the last visit. We selectively compared the early dropout group within 6 months and the long-term medication group over 36 months (LMed) to identify long-term follow-up characteristics. The short-term follow-up group was divided into an early dropout group without pharmacotherapy commencement (EDO) and a short-term medication group (SMed). Sociodemographic data, psychological test scores, and average MPR of the EDO, SMed, and LMed groups were compared. RESULTS: The number of EDO patients was 69 (23.0%) out of the 300 total patients who were studied, and there were 59 SMed patients (19.3%), and 60 LMed patients (20.0%). Compared with other groups, the EDO group included significantly more younger patients, younger parents, higher maternal education level, lower Short Form Korean-Conners' Parent Rating Scale (K CPRS) score, and higher full scale and performance intelligence quotient (IQ). There was no significant correlation between the average MPR and the treatment duration. CONCLUSIONS: Within the first 6 months of visiting the hospital, >40% of the patients dropped out of treatment regardless of methylphenidate (MPH) use. Twenty percent of the subjects showed adherence to MPH medication after 36 months. PMID- 24955937 TI - Sepsis-induced myocardial depression and takotsubo syndrome. AB - Abstract Background and objectives: Myocardial depression in the setting of sepsis and septic shock is common and has been recognized for a long time. The aim of this study is to find out an association and causal link between sepsis and takotsubo syndrome (TS). METHODS: Fifteen cases of TS were studied. Critical review of the literature dealing with sepsis and myocardial depression was done Results: Fifteen cases of sepsis-induced TS are described. Fifty-three per cent of the patients were men. The ages ranged from 39 to 76 years (mean age 60 years). Two-thirds of the patients had ST-elevation myocardial infarction ECG changes. Complications occurred in 80% of the patients. No specific types of sepsis or micro-organisms were associated with the development of TS. Critical review of the sepsis-induced myocardial depression shows that the left ventricular dysfunction, which is reversible within one-to-two weeks, is characterized by segmental ventricular dysfunction, and involvement of the right ventricle in one fourth of cases. These features are also consistent with TS. CONCLUSIONS: Sepsis triggers TS, which may be the cause of the majority of cases of sepsis-induced myocardial depression. Acute cardiac sympathetic disruption with noradrenaline spill-over may be the cause of sepsis-induced TS. PMID- 24955938 TI - Stochastic simulation of prokaryotic two-component signalling indicates stochasticity-induced active-state locking and growth-rate dependent bistability. AB - Signal transduction by prokaryotes almost exclusively relies on two-component systems for sensing and responding to (extracellular) signals. Here, we use stochastic models of two-component systems to better understand the impact of stochasticity on the fidelity and robustness of signal transmission, the outcome of autoregulatory gene expression and the influence of cell growth and division. We report that two-component systems are remarkably robust against copy number fluctuations of the signalling proteins they are composed of, which enhances signal transmission fidelity. Furthermore, we find that due to stochasticity these systems can get locked in an active state for extended time periods when (initially high) signal levels drop to zero. This behaviour can contribute to a bet-hedging adaptation strategy, aiding survival in fluctuating environments. Additionally, autoregulatory gene expression can cause two-component systems to become bistable at realistic parameter values. As a result, two sub-populations of cells can co-exist-active and inactive cells, which contributes to fitness in unpredictable environments. Bistability proved robust with respect to cell growth and division, and is tunable by the growth rate. In conclusion, our results indicate how single cells can cope with the inevitable stochasticity occurring in the activity of their two-component systems. They are robust to disadvantageous fluctuations that scramble signal transduction and they exploit beneficial stochasticity that generates fitness-enhancing heterogeneity across an isogenic population of cells. PMID- 24955939 TI - Ultrathin open-ended porous TiO2 membranes for surface nanopatterning in fabricating nanodot arrays. AB - This communication reports an approach to fabricate large-scale ultrathin open ended porous TiO2 membranes (UOP-TMs) with ordered straight-through pores. Bi nanodot arrays on Si substrates are obtained by using the UOP-TMs as surface patterning masks. PMID- 24955941 TI - Influence of polymer compatibility on the open-circuit voltage in ternary blend bulk heterojunction solar cells. AB - The evolution of the open-circuit voltage (Voc) with composition in ternary blend bulk heterojunction (BHJ) solar cells is correlated with the miscibility of the polymers. Ternary blends based on poly[N-9'-heptadecanyl-2,7-carbazole-alt-5,5 (4',7'-di-2-thienyl-2',1',3'-benzothiadiazole)] (PCDTBT) and poly(3 hexylthiophene-thiophene-diketopyrrolopyrrole) (P3HTT-DPP-10%) with phenyl-C61 butyric acid methyl ester (PC61BM) acceptor were investigated. The Voc is pinned to the lower value of the P3HTT-DPP-10%:PC61BM binary blend even up to 95% PCDTBT in the polymer fraction. This is in stark contrast to the previously investigated system based on P3HTT-DPP-10%, poly(3-hexylthiophene-co-3-(2 ethylhexyl)thiophene) (P3HT75-co-EHT25), and PC61BM, where the Voc varied regularly across the full composition range, as explained by an organic alloy model, implying strong physical and electronic interaction between the polymers. Photocurrent spectral response (PSR) and external quantum efficiency (EQE) measurements indicate that the present system does not exhibit the hallmarks of alloy formation. Measured values of the surface energies of the polymers support miscibility of P3HTT-DPP-10% with P3HT75-co-EHT25 but not with PCDTBT. Surface energy is proposed as a figure of merit for predicting alloy formation and compositional dependence of the Voc in ternary blend solar cells and miscibility between polymers is proposed as a necessary attribute for polymer pairs that will display alloy behavior. PMID- 24955940 TI - Advance care planning: challenges and approaches for pediatricians. AB - BACKGROUND: There is increasing recognition of the value of advance care planning for children with life-limiting conditions. It is important that we acknowledge and reflect on the challenges that this work presents in order to optimize practice. OBJECTIVE: Our aim was to review advance care planning for children with life-threatening or life-limiting conditions (LTLLCs) in our local area. METHODS: We conducted a retrospective case note review. Study subjects were from two National Health Service (NHS) Trusts in Bristol in the United Kingdom. Cases were identified from Child Death Overview Panel data. Forty-two sets of case notes were reviewed in relation to 20 children. Measurements included quantitative and qualitative review of advance care planning in relation to standards set by The Association for Children's Palliative Care (ACT). RESULTS: In 25% of cases there was no documented discussion with families about the approach to end of life (EOL). In 25% of cases there was no evidence of an advance care plan, and the content and accessibility of those that did exist was variable. Forty-five percent of families were not offered a choice with regard to location of care (LOC) in the last months of life and 50% were not offered a choice about location of death (LOD). CONCLUSIONS: We hope that acknowledgement of some of the challenges, alongside recognition of the clear benefits, of planning will help pediatricians to deliver this important area of care. PMID- 24955942 TI - Associations between parental feeding practices, problem food behaviours and dietary intake in New Zealand overweight children aged 4-8 years. AB - OBJECTIVE: Parents report that children's eating behaviours are a major barrier to providing them with a healthy diet. Links between problem eating behaviours and parental feeding practices are not well established and have not previously been examined in overweight children. The aim of the present study was to assess associations between problem food behaviours, dietary intake and parental feeding practices of overweight children aged 4-8 years. DESIGN: Participants were recruited for a lifestyle intervention (n 203). At baseline, children's BMI was measured and parents completed comprehensive questionnaires about the feeding practices they used, the problem food behaviours their children exhibited and the foods their child consumed. A fussy eating scale was developed and associations were determined using correlations and regression analysis, including interactions. SETTING: Dunedin, New Zealand. SUBJECTS: Overweight children aged 4 8 years. RESULTS: Healthy eating guidance and monitoring by parents were related to the consumption of fewer unhealthy foods (B=-0.4, P=0.001 and B=-0.4, P<0.001). Conversely, a lack of parental control (child control) was related to a higher intake of unhealthy foods (B = 0.5, P<0.001). Parents of children who were fussy eaters monitored their child's food intake less (P<0.001) and allowed the child more freedom over what he/she ate (P<0.001). These children consumed fewer fruit and vegetables than those who were not fussy eaters (P<0.001). However, fussy eaters with food-restrictive parents ate more fruit and vegetables (B=2.9, P<0.001). CONCLUSIONS: These results suggest that a more structured food environment might be beneficial for the diet and food behaviours of young overweight children. PMID- 24955943 TI - Frequency-shifted interferometry--a versatile fiber-optic sensing technique. AB - Fiber-optic sensing is a field that is developing at a fast pace. Novel fiber optic sensor designs and sensing principles constantly open doors for new opportunities. In this paper, we review a fiber-optic sensing technique developed in our research group called frequency-shifted interferometry (FSI). This technique uses a continuous-wave light source, an optical frequency shifter, and a slow detector. We discuss the operation principles of several FSI implementations and show their applications in fiber length and dispersion measurement, locating weak reflections along a fiber link, fiber-optic sensor multiplexing, and high-sensitivity cavity ring-down measurement. Detailed analysis of FSI system parameters is also presented. PMID- 24955944 TI - Magnetic field feature extraction and selection for indoor location estimation. AB - User indoor positioning has been under constant improvement especially with the availability of new sensors integrated into the modern mobile devices, which allows us to exploit not only infrastructures made for everyday use, such as WiFi, but also natural infrastructure, as is the case of natural magnetic field. In this paper we present an extension and improvement of our current indoor localization model based on the feature extraction of 46 magnetic field signal features. The extension adds a feature selection phase to our methodology, which is performed through Genetic Algorithm (GA) with the aim of optimizing the fitness of our current model. In addition, we present an evaluation of the final model in two different scenarios: home and office building. The results indicate that performing a feature selection process allows us to reduce the number of signal features of the model from 46 to 5 regardless the scenario and room location distribution. Further, we verified that reducing the number of features increases the probability of our estimator correctly detecting the user's location (sensitivity) and its capacity to detect false positives (specificity) in both scenarios. PMID- 24955932 TI - Calcium orthophosphates as bioceramics: state of the art. AB - In the late 1960s, much interest was raised in regard to biomedical applications of various ceramic materials. A little bit later, such materials were named bioceramics. This review is limited to bioceramics prepared from calcium orthophosphates only, which belong to the categories of bioactive and bioresorbable compounds. There have been a number of important advances in this field during the past 30-40 years. Namely, by structural and compositional control, it became possible to choose whether calcium orthophosphate bioceramics were biologically stable once incorporated within the skeletal structure or whether they were resorbed over time. At the turn of the millennium, a new concept of calcium orthophosphate bioceramics-which is able to promote regeneration of bones-was developed. Presently, calcium orthophosphate bioceramics are available in the form of particulates, blocks, cements, coatings, customized designs for specific applications and as injectable composites in a polymer carrier. Current biomedical applications include artificial replacements for hips, knees, teeth, tendons and ligaments, as well as repair for periodontal disease, maxillofacial reconstruction, augmentation and stabilization of the jawbone, spinal fusion and bone fillers after tumor surgery. Exploratory studies demonstrate potential applications of calcium orthophosphate bioceramics as scaffolds, drug delivery systems, as well as carriers of growth factors, bioactive peptides and/or various types of cells for tissue engineering purposes. PMID- 24955946 TI - A mobile device system for early warning of ECG anomalies. AB - With the rapid increase in computational power of mobile devices the amount of ambient intelligence-based smart environment systems has increased greatly in recent years. A proposition of such a solution is described in this paper, namely real time monitoring of an electrocardiogram (ECG) signal during everyday activities for identification of life threatening situations. The paper, being both research and review, describes previous work of the authors, current state of the art in the context of the authors' work and the proposed aforementioned system. Although parts of the solution were described in earlier publications of the authors, the whole concept is presented completely for the first time along with the prototype implementation on mobile device-a Windows 8 tablet with Modern UI. The system has three main purposes. The first goal is the detection of sudden rapid cardiac malfunctions and informing the people in the patient's surroundings, family and friends and the nearest emergency station about the deteriorating health of the monitored person. The second goal is a monitoring of ECG signals under non-clinical conditions to detect anomalies that are typically not found during diagnostic tests. The third goal is to register and analyze repeatable, long-term disturbances in the regular signal and finding their patterns. PMID- 24955945 TI - Array formatting of the heat-transfer method (HTM) for the detection of small organic molecules by molecularly imprinted polymers. AB - In this work we present the first steps towards a molecularly imprinted polymer (MIP)-based biomimetic sensor array for the detection of small organic molecules via the heat-transfer method (HTM). HTM relies on the change in thermal resistance upon binding of the target molecule to the MIP-type receptor. A flow through sensor cell was developed, which is segmented into four quadrants with a volume of 2.5 MUL each, allowing four measurements to be done simultaneously on a single substrate. Verification measurements were conducted, in which all quadrants received a uniform treatment and all four channels exhibited a similar response. Subsequently, measurements were performed in quadrants, which were functionalized with different MIP particles. Each of these quadrants was exposed to the same buffer solution, spiked with different molecules, according to the MIP under analysis. With the flow cell design we could discriminate between similar small organic molecules and observed no significant cross-selectivity. Therefore, the MIP array sensor platform with HTM as a readout technique, has the potential to become a low-cost analysis tool for bioanalytical applications. PMID- 24955947 TI - The affective response to health-related information and its relationship to health anxiety: an ambulatory approach. AB - Affective reactions to health-related information play a central role in health anxiety. Therefore, using ambulatory assessment, we analysed the time course of negative affect in a control group (CG, n = 60) which only rated their negative affect and an experimental group (EG, n = 97) which also rated the presence of somatic symptoms (e.g., back pain). By means of mixed regression models, we observed a decline of negative affect following the symptom self-ratings in the EG and a stable affect in the CG. The decline of negative affect was not moderated by the degree of health anxiety. Our findings might indicate that evaluating one's health status leads to a general reduction of negative affect in healthy individuals. The results of the study are in line with a bidirectional symptom perception model and underline the crucial role of affect regulation in the processing of health-related information. PMID- 24955948 TI - Prevalence of adverse effects among students taking technique classes: A retrospective study. AB - Objective : The main objective of this study was to determine characteristics of injuries experienced by students while learning chiropractic procedures in the classroom. Methods : Injury was defined as any physical adverse effect such as pain, stiffness, headache, and muscle spasm. Survey questions included age, sex, role, anatomical areas of injury, adjustive technique utilized, types of injury, treatment (if any), and recovery time. The survey was administered among the students in the 5th, 6th, and 8th trimesters of our doctor of chiropractic program. Only students who had completed one or more chiropractic procedures courses at the institution were asked to participate in the study. Results : Female recipients had a higher prevalence of adverse effects as the recipient of the adjustment than did male recipients. The most common site for injury overall was the lower back. The relationship between recipient role and sacroiliac joint injury and the relationship between adjustor role and wrist/hand injury were statistically significant. Students were more likely to be injured in the beginning of their technique education. Conclusion : This study suggests that students in technique courses learning adjustive procedures experience minor adverse physical effects related to the physical skills being learned. Strategies for prevention need to be considered. PMID- 24955949 TI - Research mentoring: Suggestions and encouragement from a reflection exercise. AB - Supervisors direct people, but mentors are valued and trusted advisors. Recently, the author took a course in supervising postgraduate research, which included surveying the literature as well as discussions with colleagues who have various levels of experience in research supervision. Through this exercise, some basic ideas for best practices in research mentoring became clear, particularly for those in professions without a strong history of research and therefore lacking in trained research supervisors. The concept of mentoring, rather than just supervision, gained focus. Three main categories can be identified within the realm of research mentorship: choose your candidate wisely, be diligent, and be nurturing. The purpose of this commentary is to identify methods of supervision of graduate research degree (masters/doctorate level) candidates that may enhance the process, as well as improve the chances of completion, and to encourage academics to learn the techniques of high-quality supervision with a goal of becoming mentors. Additionally, it is hoped that this commentary may encourage students and colleagues without advanced degrees to consider pursuing them; this, in turn would likely lead to more opportunities for supervision, as well as help to create links with other academic and clinical institutions. PMID- 24955950 TI - Coherent X-ray diffraction imaging and characterization of strain in silicon-on insulator nanostructures. AB - Coherent X-ray diffraction imaging (CDI) has emerged in the last decade as a promising high resolution lens-less imaging approach for the characterization of various samples. It has made significant technical progress through developments in source, algorithm and imaging methodologies thus enabling important scientific breakthroughs in a broad range of disciplines. In this report, we will introduce the principles of forward scattering CDI and Bragg geometry CDI (BCDI), with an emphasis on the latter. BCDI exploits the ultra-high sensitivity of the diffraction pattern to the distortions of crystalline lattice. Its ability of imaging strain on the nanometer scale in three dimensions is highly novel. We will present the latest progress on the application of BCDI in investigating the strain relaxation behavior in nanoscale patterned strained silicon-on-insulator (sSOI) materials, aiming to understand and engineer strain for the design and implementation of new generation semiconductor devices. PMID- 24955952 TI - Citrate-linked keto- and aldo-hexose monosaccharide cellulose conjugates demonstrate selective human neutrophil elastase-lowering activity in cotton dressings. AB - Sequestration of harmful proteases as human neutrophil elastase (HNE) from the chronic wound environment is an important goal of wound dressing design and function. Monosaccharides attached to cellulose conjugates as ester-appended aldohexoses and ketohexoses were prepared on cotton gauze as monosccharide citrate-cellulose-esters for HNE sequestration. The monosaccharide-cellulose analogs demonstrated selective binding when the derivatized cotton dressings were measured for sequestration of HNE. Each monosaccharide-cellulose conjugate was prepared as a cellulose citrate-linked monosaccharide ester on the cotton wound dressing, and assayed under wound exudate-mimicked conditions for elastase sequestration activity. A series of three aldohexose and four ketohexose ester cellulose conjugates were prepared on cotton gauze through citric acid-cellulose cross linking esterification. The monosaccharide portion of the conjugate was characterized by hydrolysis of the citrate-monosaccharide ester bond, and subsequent analysis of the free monosaccharide with high performance anion exchange chromatography. The ketohexose and aldohexose conjugate levels on cotton were quantified on cotton using chromatography and found to be present in milligram/gram amounts. The citrate-cellulose ester bonds were characterized with FTIR. Ketohexose-citrate-cellulose conjugates sequestered more elastase activity than aldohexose-citrate-cellulose conjugates. The monosaccharide cellulose conjugate families each gave distinctive profiles in elastase-lowering effects. Possible mechanisms of elastase binding to the monosaccharide-cellulose conjugates are discussed. PMID- 24955951 TI - Atmospheric particulate matter (PM) effect on the growth of Solanum lycopersicum cv. Roma plants. AB - This study shows the direct effect of atmospheric particulate matter on plant growth. Tomato (Solanum lycopersicum L.) plants were grown for 18d directly on PM10 collected on quartz fiber filters. Organic and elemental carbon and polycyclic aromatic hydrocarbons (PAHs) contents were analyzed on all the tested filters. The toxicity indicators (i.e., seed germination, root elongation, shoot and/or fresh root weight, chlorophyll and carotenoids content) were quantified to study the negative and/or positive effects in the plants via root uptake. Substantial differences were found in the growth of the root apparatus with respect to that of the control plants. A 17-58% decrease of primary root elongation, a large amount of secondary roots and a decrease in shoot (32%) and root (53-70%) weights were found. Quantitative analysis of the reactive oxygen species (ROS) indicated that an oxidative burst in response to abiotic stress occurred in roots directly grown on PM10, and this detrimental effect was also confirmed by the findings on the chlorophyll content and chlorophyll-to carotenoid ratio. PMID- 24955953 TI - Incorporation of Exogenous RGD Peptide and Inter-Species Blending as Strategies for Enhancing Human Corneal Limbal Epithelial Cell Growth on Bombyx mori Silk Fibroin Membranes. AB - While fibroin isolated from the cocoons of domesticated silkworm Bombyx mori supports growth of human corneal limbal epithelial (HLE) cells, the mechanism of cell attachment remains unclear. In the present study we sought to enhance the attachment of HLE cells to membranes of Bombyx mori silk fibroin (BMSF) through surface functionalization with an arginine-glycine-aspartic acid (RGD)-containing peptide. Moreover, we have examined the response of HLE cells to BMSF when blended with the fibroin produced by a wild silkworm, Antheraea pernyi, which is known to contain RGD sequences within its primary structure. A procedure to isolate A. pernyi silk fibroin (APSF) from the cocoons was established, and blends of the two fibroins were prepared at five different BMSF/APSF ratios. In another experiment, BMSF surface was modified by binding chemically the GRGDSPC peptide using a water-soluble carbodiimide. Primary HLE were grown in the absence of serum on membranes made of BMSF, APSF, and their blends, as well as on RGD modified BMSF. There was no statistically significant enhancing effect on the cell attachment due to the RGD presence. This suggests that the adhesion through RGD ligands may have a complex mechanism, and the investigated strategies are of limited value unless the factors contributing to this mechanism become better known. PMID- 24955954 TI - Effects of the surfactant polyoxyethylene amine (POEA) on genotoxic, biochemical and physiological parameters of the freshwater teleost Prochilodus lineatus. AB - The surfactant polyoxyethylene amine (POEA) is added to several formulations of glyphosate herbicides that are widely used in agriculture and can contaminate aquatic ecosystems. In the present study, an integrated approach examining genotoxic, biochemical and physiological parameters was employed to evaluate acute effects of POEA on the Neotropical fish Prochilodus lineatus. Juvenile fish were exposed to 0.15 mg.L(-1) (POEA 1), 0.75 mg.L(-1) (POEA 2) and 1.5 mg.L(-1) (POEA 3) of POEA or only water (CTR), and after 24h exposure samples of blood and liver were taken. Compared with CTR, liver of fish exposed to POEA 2 and POEA 3 showed increased activity of 7 ethoxyresorufin-O-deethylase and increased content of glutathione, whereas the activity of glutathione-S-transferase was diminished. On the other hand, fish of the group POEA 1 showed an increase in the activity of superoxide dismutase and in the occurrence of lipid peroxidation. Fish exposed to POEA 3 presented increased hepatic activity of glutathione peroxidase and reduced plasma cortisol. The exposure to POEA at all concentrations tested caused an increase in plasma lactate and a decrease in the hepatic activity of catalase, in the number of red blood cells and in hemoglobin content. The comet assay used for analyzing DNA damage in blood cells indicated the genotoxicity of the surfactant at all concentrations tested. Taken together these results show that POEA can cause effects at various levels, such as hemolysis, DNA damage and lipid peroxidation, which are directly related to an imbalance in the redox state of the fish. PMID- 24955957 TI - Threatened bird valuation in Australia. AB - Threatened species programs need a social license to justify public funding. A contingent valuation survey of a broadly representative sample of the Australian public found that almost two thirds (63%) supported funding of threatened bird conservation. These included 45% of a sample of 645 respondents willing to pay into a fund for threatened bird conservation, 3% who already supported bird conservation in another form, and 15% who could not afford to pay into a conservation fund but who nevertheless thought that humans have a moral obligation to protect threatened birds. Only 6% explicitly opposed such payments. Respondents were willing to pay about AUD 11 annually into a conservation fund (median value), including those who would pay nothing. Highest values were offered by young or middle aged men, and those with knowledge of birds and those with an emotional response to encountering an endangered bird. However, the prospect of a bird going extinct alarmed almost everybody, even most of those inclined to put the interests of people ahead of birds and those who resent the way threatened species sometimes hold up development. The results suggest that funding for threatened birds has widespread popular support among the Australian population. Conservatively they would be willing to pay about AUD 14 million per year, and realistically about AUD 70 million, which is substantially more than the AUD 10 million currently thought to be required to prevent Australian bird extinctions. PMID- 24955959 TI - Development of visual systems for faces and objects: further evidence for prolonged development of the face system. AB - BACKGROUND: The development of face and object processing has attracted much attention; however, studies that directly compare processing of both visual categories across age are rare. In the present study, we compared the developmental trajectories of face and object processing in younger children (8 10 years), older children (11-13 years), adolescents (14-16 years), and adults (20-37). METHODOLOGY/PRINCIPAL FINDINGS: We used a congruency paradigm in which subjects compared the internal features of two stimuli, while the (unattended) external features either agreed or disagreed independent of the identity of the internal features. We found a continuous increase in matching accuracy for faces and watches across childhood and adolescence, with different magnitudes for both visual categories. In watch perception, adult levels were reached at the age of 14-16, but not in face perception. The effect of context and inversion, as measures of holistic and configural processing, were clearly restricted to faces in all age groups. This finding suggests that different mechanisms are involved in face and object perception at any age tested. Moreover, the modulation of context and inversion effects by exposure duration was strongly age-dependent, with the strongest age-related differences found for brief timings below 140 ms. CONCLUSIONS/SIGNIFICANCE: The results of the present study suggest prolonged development of face-specific processing up to young adulthood. The improvement in face processing is qualitatively different from the improvement of general perceptual and cognitive ability. PMID- 24955955 TI - Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints. AB - Inhibitors of the DNA damage checkpoint kinase, Chk1, are highly effective as chemo- and radio-sensitizers in preclinical studies but are not well-tolerated by patients. We exploited the promiscuous nature of kinase inhibitors to screen 9 clinically relevant kinase inhibitors for their ability to sensitize pancreatic cancer cells to a sub-lethal concentration of gemcitabine. Bosutinib, dovitinib, and BEZ-235 were identified as sensitizers that abrogated the DNA damage checkpoint. We further characterized bosutinib, an FDA-approved Src/Abl inhibitor approved for chronic myelogenous leukemia. Unbeknownst to us, we used an isomer (Bos-I) that was unknowingly synthesized and sold to the research community as "authentic" bosutinib. In vitro and cell-based assays showed that both the authentic bosutinib and Bos-I inhibited DNA damage checkpoint kinases Chk1 and Wee1, with Bos-I showing greater potency. Imaging data showed that Bos-I forced cells to override gemcitabine-induced DNA damage checkpoint arrest and destabilized stalled replication forks. These inhibitors enhanced sensitivity to the DNA damaging agents' gemcitabine, cisplatin, and doxorubicin in pancreatic cancer cell lines. The in vivo efficacy of Bos-I was validated using cells derived directly from a pancreatic cancer patient's tumor. Notably, the xenograft studies showed that the combination of gemcitabine and Bos-I was significantly more effective in suppressing tumor growth than either agent alone. Finally, we show that the gatekeeper residue in Wee1 dictates its sensitivity to the 2 compounds. Our strategy to screen clinically relevant kinase inhibitors for off target effects on cell cycle checkpoints is a promising approach to re-purpose drugs as chemosensitizers. PMID- 24955961 TI - Preparation of laponite bioceramics for potential bone tissue engineering applications. AB - We report a facile approach to preparing laponite (LAP) bioceramics via sintering LAP powder compacts for bone tissue engineering applications. The sintering behavior and mechanical properties of LAP compacts under different temperatures, heating rates, and soaking times were investigated. We show that LAP bioceramic with a smooth and porous surface can be formed at 800 degrees C with a heating rate of 5 degrees C/h for 6 h under air. The formed LAP bioceramic was systematically characterized via different methods. Our results reveal that the LAP bioceramic possesses an excellent surface hydrophilicity and serum absorption capacity, and good cytocompatibility and hemocompatibility as demonstrated by resazurin reduction assay of rat mesenchymal stem cells (rMSCs) and hemolytic assay of pig red blood cells, respectively. The potential bone tissue engineering applicability of LAP bioceramic was explored by studying the surface mineralization behavior via soaking in simulated body fluid (SBF), as well as the surface cellular response of rMSCs. Our results suggest that LAP bioceramic is able to induce hydroxyapatite deposition on its surface when soaked in SBF and rMSCs can proliferate well on the LAP bioceramic surface. Most strikingly, alkaline phosphatase activity together with alizarin red staining results reveal that the produced LAP bioceramic is able to induce osteoblast differentiation of rMSCs in growth medium without any inducing factors. Finally, in vivo animal implantation, acute systemic toxicity test and hematoxylin and eosin (H&E) staining data demonstrate that the prepared LAP bioceramic displays an excellent biosafety and is able to heal the bone defect. Findings from this study suggest that the developed LAP bioceramic holds a great promise for treating bone defects in bone tissue engineering. PMID- 24955962 TI - Results from the first six years of national sentinel surveillance for influenza in Kenya, July 2007-June 2013. AB - BACKGROUND: Recent studies have shown that influenza is associated with significant disease burden in many countries in the tropics, but until recently national surveillance for influenza was not conducted in most countries in Africa. METHODS: In 2007, the Kenyan Ministry of Health with technical support from the CDC-Kenya established a national sentinel surveillance system for influenza. At 11 hospitals, for every hospitalized patient with severe acute respiratory illness (SARI), and for the first three outpatients with influenza like illness (ILI) per day, we collected both nasopharyngeal and oropharyngeal swabs. Beginning in 2008, we conducted in-hospital follow-up for SARI patients to determine outcome. Specimens were tested by real time RT-PCR for influenza A and B. Influenza A-positive specimens were subtyped for H1, H3, H5, and (beginning in May 2009) A(H1N1)pdm09. RESULTS: From July 1, 2007 through June 30, 2013, we collected specimens from 24,762 SARI and 14,013 ILI patients. For SARI and ILI case-patients, the median ages were 12 months and 16 months, respectively, and 44% and 47% were female. In all, 2,378 (9.6%) SARI cases and 2,041 (14.6%) ILI cases were positive for influenza viruses. Most influenza-associated SARI cases (58.6%) were in children <2 years old. Of all influenza-positive specimens, 78% were influenza A, 21% were influenza B, and 1% were influenza A/B coinfections. Influenza circulated in every month. In four of the six years influenza activity peaked during July-November. Of 9,419 SARI patients, 2.7% died; the median length of hospitalization was 4 days. CONCLUSIONS: During six years of surveillance in Kenya, influenza was associated with nearly 10 percent of hospitalized SARI cases and one-sixth of outpatient ILI cases. Most influenza-associated SARI and ILI cases were in children <2 years old; interventions to reduce the burden of influenza, such as vaccine, could consider young children as a priority group. PMID- 24955963 TI - Correlates of male circumcision in Eastern and Southern African countries: establishing a baseline prior to VMMC Scale-up. AB - BACKGROUND: Despite the importance of male circumcision (MC) prevalence to HIV prevention efforts in Eastern and Southern Africa, there has been no systematic analysis on the correlates of male circumcision. This analysis identifies correlates of MC in 12 countries in the region with available data. METHODS: Data from the male questionnaire of DHS surveys collected between 2006-2011 in Ethiopia, Kenya, Lesotho, Malawi, Mozambique, Namibia, Rwanda, Swaziland, Tanzania, Uganda, Zambia, and Zimbabwe were analyzed. The dependent variable was self-reported male circumcision status. Independent variables included age, education, wealth quintile, place of residence, ethnicity, religion and region. Bivariate and multivariate analyses were conducted separately for each country. RESULTS: MC prevalence ranged from 8.2 percent in Swaziland to 92.2 percent in Ethiopia. Bivariate analyses showed a consistent positive association between age (being older) and male circumcision. Education, wealth quintile, and place of residence were either not significantly related or differed in the direction of the relationship by country. Multivariate logistic regression showed three variables consistently associated with MC status: age (being older), religion (being Muslim) and ethnicity. DISCUSSION: These data were collected prior to the scale-up of voluntary medical male circumcision (VMMC) programs in 11 of the 12 countries. As the VMMC scale-up intensifies in countries across Eastern and Southern Africa, the correlates of VMMC are likely to change, with (younger) age and education emerging as key correlates of VMMC performed in medical settings. The centuries-long tradition among Muslims to circumcise should continue to favor MC among this group. Non-circumcising ethnicities may become more open to MC if promoted as a health practice for decreasing HIV risk. PMID- 24955964 TI - Seed diversity in the tribe Miconieae (Melastomataceae): taxonomic, systematic, and evolutionary implications. AB - Miconieae is the largest tribe in the Melastomataceae with over 1,850 species. The members of Miconieae display a wide range of morphological diversity, and seed morphology is no exception. Previous studies have found that seed morphological diversity is not congruent with traditional classifications, and suggest that it may reflect evolutionary relationships within Miconieae. Here we characterize seed morphology of 364 species of Miconieae. The morphological data set and a DNA sequence data matrix were analyzed under a parsimony and Bayesian framework. Seed characters were used to test taxonomic and clade hypotheses, to estimate morphological ancestral character states, and to assess phylogenetic signal. The phylogenetic analyses of morphological data retrieved a poorly resolved, low-supported phylogeny; in contrast, a relatively strongly supported phylogeny was estimated using the molecular data. Hypothesis testing procedures could only reject the monophyly of Clidemia, Leandra, and Miconia. The results indicated that the seed morphological characters were homoplasious, but contained phylogenetic signal. The morphological seed types that were described in previous studies did not support any of the clades retrieved by the molecular phylogeny. In contrast with previous investigations, our study shows that although seed morphology is very variable, it does not provide information for supporting some genera or clades within Miconieae. However, it is suggested that seed characters in combination with other vegetative and reproductive traits may aid in the characterization of smaller clades. The presence of phylogenetic signal retrieved by homoplasious characters may indicate that diversification of seed characters could have an adaptive component. Further studies that increase taxon sampling, refine seed trait characterization, and evaluate the alleged relationships between environmental variables and seed diversification will contribute to a better understanding of seed morphology and evolution in this species-rich tribe. PMID- 24955965 TI - [Surgical management of entero-vesical fistulas in Crohn's disease]. AB - BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disease of the intestine that can cause an attack by contiguity of the urinary tract. Although the shape is common and fistulizing 35% of all patients with CD, entero-urinary fistulas are rare and only seen in 2-8% of patients. aim: To report the frequency of occurrence of this complication among the group of surgical forms of CD. Describe the different pathophysiological mechanisms of occurrence of entero vesical fistula (EVF) during the CD. methods: We report, retrospectively, seven observations of EVF complicating MC made during the period from 01/01/1998 until 31/12/2010. results: The mean age of patients was 30 years. There were 3 men and 4 women. All patients had clinical signs and radiological EVF. In six patients, CD was ileo-caecal and the ileo-vesical fistula was between the last loop and the bladder. In one patient, the CD was located only in colon, and the fistula was between sigmoid colon and bladder. Level of the bladder, it was a false EVF in five patients and a true EVF in two patients. In these last two, the fistula of 2 mm, was on the top of the bladder. Treatment consisted in all cases by a disconnect between the digestive tract and bladder, resection with restoration of digestive continuity, and if the case of true EVF, a freshening the edges of the fistula with suture of the bladder's wall and drainage. The postoperative course was uneventful in six patients and marked by an outbreak intraperitoneal abcess in one patient who had evolved under medical treatment. After a mean of eleven months, no recurrence surgery was noted. CONCLUSION: Despite advanced treatment in the context of CD, the indication in EVF is a surgical treatment. Surgery helps fight against the consequences of septic urinary tract, but also to launder bowel disease and reduce the risk of recurrence in the short term. PMID- 24955966 TI - [Serodiagnosis of acute hepatitis in adults patients: results of a prospective study in a central region of Tunisia]. AB - PREREQUIS: Viral hepatitis is a public health problem in many parts of the globe. In Tunisia, the respective responsibility of five viruses (HAV, HDV, HBV, HCV and HEV) in the genesis of acute hepatitis in adults is only roughly indicated in the absence of suitable serological studies, given as important to plan appropriate preventive strategies. OBJECTIVES: To approach the role of viral hepatitis in all adult with acute hepatitis, identify the current share of each virus A, B, C and E in the genesis of hepatitis and to study the epidemiological and evolution of these diseases. METHODS: We conducted a prospective study over two years including patients aged from 15 to 65 years old, with clinical and / or biological acute hepatitis. Data were collected through a standard questionnaire wich covered sociodemographic charactereristics and risk factors. Blood samples were collected and were tested for IgM anti-HAV, IgM anti-HEV, HBsAg, IgM anti HBc, anti-HCV antibodies .When serological tests were negatives, further explorations including immunological test, search for HCV RNA and a pharmacovigilance survey was conducted. Statistical analysis was performed by SPSS version 10.0 RESULTS: 105 patients were included. Acute viral hepatitis was diagnosis in 70 patients (67%). The proportion of patients with acute viral hepatitis A, B, C and E was 51.5% , 38.5%, 4.3% and 5.7% respectively. The risk factors of viral hepatitis A was drinking of untreated water and poor socioeconomic status. In the HBV group, the notion of sexual contact risk was found in 30% of cases. The small numbers of acute hepatitis E and C does not permit us to draw conclusions. CONCLUSION: Our study confirms the shift in age of onset of hepatitis A to the age of adolescence and young adulthood. The respective responsibilities of the different viruses studied in the genesis of acute hepatitis in adults in our area brings us closer of western populations where HAV infection predominates followed by HBV. PMID- 24955967 TI - [Prognostic value of markers of aggressiveness of urinary bladder tumours evaluated by immunohistochemistry]. AB - BACKGROUND: The study of some immunohistochemical markers provides an objective and reproducible prognostic evaluation of urinary bladder tumour. aims: study the expression of the following immunohistochemical markers in Tumours of the bladder: Proliferating Cell Nuclear Antigen (PCNA), Ki67 antigen (MIB1), the C erbB2 proto- antigene, the tumor suppressor gene p53, the receptor for epidermal growth factor (EGF-R), the apoptosis suppressor gene bcl2, the carcinoembryonic antigen (CEA) and epithelial membrane antigen (EMA). methods: Study of retrospective series of 30 patients having tumours of the urinary bladder. results: The expression of PCNA with a cut-off value of 14% is correlated with recurrence (P = 0.010). The expression of PCNA with a cut-off value of 1% is correlated with tumour stage (P = 0.003). The expression of MIB1 with a cut-off value of 47% is correlated with recurrence (P = 0.010). The expression of MIB1 with a cut-off value of 47% is correlated with the tumour progression in stage and?or in grade (P = 0.007). The expression of C-erbB2 with a cutoff value of 28% is correlated in the tumour grade (P = 0.007). The other antibodies didn't demonstrate a prognostic value. CONCLUSION: MIb1 and PCNA being correlated with recurrence, they can be useful with the decision of the rhythm of the endoscopy. The correlation of C-erbB2 with the tumour grade could serve to better graduating bladder tumours. PMID- 24955968 TI - [The name in schizophrenia: a study of 60 patients]. AB - BACKGROUND: Clinical aspects in schizophrenia suggest a unique relationship with the proper name. aim: Discuss the validity of the hypothesis that the non transmission of the surname may be a vulnerability factor in schizophrenia. METHODS: Descriptive cross-sectional study conducted among 60 patients with schizophrenia and their families. Data were collected using a semi-structured interview. results: Seven patients carried a different surname from their father (11.6% of participants). The disparity has only concerned the child with schizophrenia. Family characteristics (birth rank, desired character of pregnancy, family history of schizophrenia) and evolutif profile of the disease were comparable between patients with a family name according to the father and those with a different surname. CONCLUSIONS: It appears that patients with schizophrenia maintain a special relationship with the proper name, which could be involved in the genesis of schizophrenia. Our early hypothesis, supported by the psychoanalytic, transgenerational and behavioral theories, would be a plausible starting point for studies with a broader spectrum including witnesses of the general and psychiatric populations. PMID- 24955969 TI - [Primary immune thrombocytopenia in childhood: a regional study in the south of Tunisia]. AB - BACKGROUND: the primary immune thrombocytopenia (ITP) in children has a favorable evolution in most of cases. aim: describe the epidemiological and therapeutic data and the outcome of primary immune thrombocytopenia in our patients and propose a treatment plan to standardize the management of this disease in our region. methods: We conducted a retrospective study of 140 cases of primary immune thrombocytopenia collected in department of pediatrics and hematology of Hedi Chaker hospital during a period of 15 years. Patients who had a platelet count <= 20 000 and / or mucosal or troublesome lifestyle hemorrhage were treated. results: The mean age was 6 years 7 months with extremes varying from 3 months to 15 years. The bleeding manifestations were dominated by cutaneous bleeding in the form of petechiae or bruise (100%). Epistaxis and gingivorragia were noted in 32,9% and 25,7% of the cases respectively. The most of patient were treated with corticosteroids (79%). Intravenous immunoglobulin was associated with corticosteroids in 7%. An acute ITP occurred in 94 cases (67%) and a chronic ITP in 30 cases (21%). CONCLUSION: In the recently diagnosed ITP, the response delay under association Intravenous immunoglobulin and corticoids is shorter than that of corticoids alone, but the high cost of Intravenous immunoglobulin associated with their immediate side effects compels us to recommend corticoids as a first line of treatment. PMID- 24955970 TI - [Role of intravascular ultrasound (IVUS) in determining the therapeutic strategy for the patients with intermediate coronary lesions]. AB - BACKGROUND: Coronarography presents some limits in assessing intermediate stenosis. Intravascular ultrasound provides tridimensional measurements of the artery, with more reliable data guiding revascularization decision. AIMS: to evaluate the impact of intravascular ultrasound measurements on revascularization decision of intermediate and ambiguous coronary lesions. METHODS: We prospectively analysed 40 patients' coronary arteries from March 2009 to November 2011 by both quantitative coronary angiography (QCA) then intravascular ultrasound, and compared our decision before and after intravascular ultrasound. RESULTS: in the final revascularization decision after intravascular ultrasound, medical treatment rate raised from 22% to 25%, percutaneous coronary intervention dropped from 55% to 50%, and coronary artery bypass graft slightly raised from 23% to 25%. Therapeutic decision changed after intravascular ultrasound in 47% of patients (p=0,01), which reflects an important impact of this technique in management of intermediate coronary lesions. CONCLUSION: Intravascular ultrasound provided more accurate measurements which permitted a better detection of ischemia and influenced notably our therapeutic strategies. PMID- 24955971 TI - A giant omental lipoblastoma in a four-year-old boy. PMID- 24955972 TI - A giant liposarcoma of the neck and the mediastinum. PMID- 24955973 TI - Preoperative clinical diagnosis of an amyand's hernia. PMID- 24955974 TI - [Right congenital diaphragmatic hernia following neonatal streptococcus B pyopneumothorax]. PMID- 24955975 TI - Multiple gastrointestinal hemangiomas treated with argon plasma coagulation. PMID- 24955976 TI - Association of renal cell carcinoma and staghorn calculi complicated with emphysematous pyelonephritis. PMID- 24955978 TI - Admission cell free DNA levels predict 28-day mortality in patients with severe sepsis in intensive care. AB - AIM: The aim of the current study is to assess the mortality prediction accuracy of circulating cell-free DNA (CFD) level at admission measured by a new simplified method. MATERIALS AND METHODS: CFD levels were measured by a direct fluorescence assay in severe sepsis patients on intensive care unit (ICU) admission. In-hospital and/or twenty eight day all-cause mortality was the primary outcome. RESULTS: Out of 108 patients with median APACHE II of 20, 32.4% have died in hospital/or at 28-day. CFD levels were higher in decedents: median 3469.0 vs. 1659 ng/ml, p<0.001. In multivariable model APACHE II score and CFD (quartiles) were significantly associated with the mortality: odds ratio of 1.05, p = 0.049 and 2.57, p<0.001 per quartile respectively. C-statistics for the models was 0.79 for CFD and 0.68 for APACHE II. Integrated discrimination improvement (IDI) analyses showed that CFD and CFD+APACHE II score models had better discriminatory ability than APACHE II score alone. CONCLUSIONS: CFD level assessed by a new, simple fluorometric-assay is an accurate predictor of acute mortality among ICU patients with severe sepsis. Comparison of CFD to APACHE II score and Procalcitonin (PCT), suggests that CFD has the potential to improve clinical decision making. PMID- 24955977 TI - Protozoan parasites of bivalve molluscs: literature follows culture. AB - Bivalve molluscs are key components of the estuarine environments as contributors to the trophic chain, and as filter -feeders, for maintaining ecosystem integrity. Further, clams, oysters, and scallops are commercially exploited around the world both as traditional local shellfisheries, and as intensive or semi-intensive farming systems. During the past decades, populations of those species deemed of environmental or commercial interest have been subject to close monitoring given the realization that these can suffer significant decline, sometimes irreversible, due to overharvesting, environmental pollution, or disease. Protozoans of the genera Perkinsus, Haplosporidium, Marteilia, and Bonamia are currently recognized as major threats for natural and farmed bivalve populations. Since their identification, however, the variable publication rates of research studies addressing these parasitic diseases do not always appear to reflect their highly significant environmental and economic impact. Here we analyzed the peer- reviewed literature since the initial description of these parasites with the goal of identifying potential milestone discoveries or achievements that may have driven the intensity of the research in subsequent years, and significantly increased publication rates. Our analysis revealed that after initial description of the parasite as the etiological agent of a given disease, there is a time lag before a maximal number of yearly publications are reached. This has already taken place for most of them and has been followed by a decrease in publication rates over the last decade (20- to 30- year lifetime in the literature). Autocorrelation analyses, however, suggested that advances in parasite purification and culture methodologies positively drive publication rates, most likely because they usually lead to novel molecular tools and resources, promoting mechanistic studies. Understanding these trends should help researchers in prioritizing research efforts for these and other protozoan parasites, together with their development as model systems for further basic and translational research in parasitic diseases. PMID- 24955979 TI - Delineation of concentration ranges and longitudinal changes of human plasma protein variants. AB - Human protein diversity arises as a result of alternative splicing, single nucleotide polymorphisms (SNPs) and posttranslational modifications. Because of these processes, each protein can exists as multiple variants in vivo. Tailored strategies are needed to study these protein variants and understand their role in health and disease. In this work we utilized quantitative mass spectrometric immunoassays to determine the protein variants concentration of beta-2 microglobulin, cystatin C, retinol binding protein, and transthyretin, in a population of 500 healthy individuals. Additionally, we determined the longitudinal concentration changes for the protein variants from four individuals over a 6 month period. Along with the native forms of the four proteins, 13 posttranslationally modified variants and 7 SNP-derived variants were detected and their concentration determined. Correlations of the variants concentration with geographical origin, gender, and age of the individuals were also examined. This work represents an important step toward building a catalog of protein variants concentrations and examining their longitudinal changes. PMID- 24955980 TI - Acceleration of bone regeneration by local application of lithium: Wnt signal mediated osteoblastogenesis and Wnt signal-independent suppression of osteoclastogenesis. AB - Inhibition of glycogen synthase kinase (GSK)-3 and the consequent activation of the Wnt/beta-catenin signaling pathway have been reported to increase bone volume. To develop a novel pharmacotherapy for injured bone, we investigated whether GSK-3 inhibitor was effective in promoting bone formation. In in vitro experiments, we examined the effects of GSK-3 inhibitors LiCl and SB216763 on osteoblastogenesis of mesenchymal progenitor C3H10T1/2 cells and osteoclastogenesis of osteoclast precursor RAW-D cells. Both inhibitors promoted osteoblast differentiation, assessed by alkaline phosphatase activity and calcium deposition, stimulating the Wnt/beta-catenin signaling pathway and thereby inducing Runx2. On the other hand, the GSK-3 inhibitors suppressed osteoclast differentiation, assessed by tartrate-resistant acid phosphatase staining and number of nuclei in the cells, reducing NFATc1 expression independently of the Wnt/beta-catenin signaling pathway. In subsequently performed in vivo studies, we examined the effect of locally administered Li2CO3 on the recovery from a partial defect made on the rat tibia. Computerized tomography and bone histomorphometry showed that Li2CO3 accelerated bone regeneration in defect lesion with increased lamellar bone ratio compared with the controls. These results suggested that local application of lithium (or other GSK-3 inhibitors) might effectively facilitate recovery from bone injury by promoting osteoblastogenesis and inhibiting osteoclastogenesis. PMID- 24955981 TI - LXR-alpha antagonist meso-dihydroguaiaretic acid attenuates high-fat diet-induced nonalcoholic fatty liver. AB - Collaborative regulation of liver X receptor (LXR) and sterol regulatory element binding protein (SREBP)-1 are main determinants in hepatic steatosis, as shown in both animal models and human patients. Recent studies indicate that selective intervention of overly functional LXRalpha in the liver shows promise in treatment of fatty liver disease. In the present study, we evaluated the effects of meso-dihydroguaiaretic acid (MDGA) on LXRalpha activation and its ability to attenuate fatty liver in mice. MDGA inhibited activation of the LXRalpha ligand binding domain by competitively binding to the pocket for agonist T0901317 and decreased the luciferase activity in LXRE-tk-Luc-transfected cells. MDGA significantly attenuated hepatic neutral lipid accumulation in T0901317- and high fat diet (HFD)-induced fatty liver. The effect of MDGA was so potent that treatment with 1mg/kg for 2 weeks completely reversed the lipid accumulation induced by HFD feeding. MDGA reduced the expression of LXRalpha co-activator protein RIP140 and LXRalpha target gene products associated with lipogenesis in HFD-fed mice. These results demonstrate that MDGA has the potential to attenuate nonalcoholic steatosis mediated by selective inhibition of LXRalpha in the liver in mice. PMID- 24955982 TI - ADP-ribosylation factor 6 regulates endothelin-1-induced lipolysis in adipocytes. AB - Endothelin-1 (ET-1) induces lipolysis in adipocytes, where ET-1 chronic exposure results in insulin resistance (IR) through suppression of glucose transporter (GLUT)4 translocation to the plasma membrane and consequently glucose uptake. ARF6 small GTPase, which plays a vital role in cell surface receptors trafficking, has previously been shown to regulate GLUT4 recycling and thereby insulin signalling. ARF6 also plays a role in ET-1 promoted endothelial cell migration. However, ARF6 involvement in ET-1-induced lipolysis in adipocytes is unknown. Therefore, we investigated the role of ARF6 in ET-1-induced lipolysis in 3T3-L1 adipocytes. This was achieved by studying the effect of inhibitors for the activation of ARF6 and other signalling proteins on ET-1 induced lipolysis and ARF6 activation in the adipocytes. Our results indicate that ET-1 induces, through endothelin type A receptor (ETAR), lipolysis, the ARF6 activation and extracellular-signal regulated kinase (ERK) phosphorylation in adipocytes, further ET-1 stimulated lipolysis is inhibited by the inhibitors of ARF6 activation, ERK phosphorylation and dynamin, which is essential for endocytosis. Our studies also revealed that ARF6 acts upstream of ERK in ET-1-indcued lipolysis. In summary, we determined that ET-1 activation of ETAR signalled through ARF6, which is crucial for lipolysis. PMID- 24955984 TI - Use of high frequency ultrasound to monitor cervical lymph node alterations in mice. AB - Cervical lymph node evaluation by clinical ultrasound is a non-invasive procedure used in diagnosing nodal status, and when combined with fine-needle aspiration cytology (FNAC), provides an effective method to assess nodal pathologies. Development of high-frequency ultrasound (HF US) allows real-time monitoring of lymph node alterations in animal models. While HF US is frequently used in animal models of tumor biology, use of HF US for studying cervical lymph nodes alterations associated with murine models of head and neck cancer, or any other model of lymphadenopathy, is lacking. Here we utilize HF US to monitor cervical lymph nodes changes in mice following exposure to the oral cancer-inducing carcinogen 4-nitroquinoline-1-oxide (4-NQO) and in mice with systemic autoimmunity. 4-NQO induces tumors within the mouse oral cavity as early as 19 wks that recapitulate HNSCC. Monitoring of cervical (mandibular) lymph nodes by gray scale and power Doppler sonography revealed changes in lymph node size eight weeks after 4-NQO treatment, prior to tumor formation. 4-NQO causes changes in cervical node blood flow resulting from oral tumor progression. Histological evaluation indicated that the early 4-NQO induced changes in lymph node volume were due to specific hyperproliferation of T-cell enriched zones in the paracortex. We also show that HF US can be used to perform image-guided fine needle aspirate (FNA) biopsies on mice with enlarged mandibular lymph nodes due to genetic mutation of Fas ligand (Fasl). Collectively these studies indicate that HF US is an effective technique for the non-invasive study of cervical lymph node alterations in live mouse models of oral cancer and other mouse models containing cervical lymphadenopathy. PMID- 24955983 TI - Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma. AB - BACKGROUND: Molecular microbiological analysis of airway samples in asthma has demonstrated an altered microbiome in comparison to healthy controls. Such changes may have relevance to treatment-resistant severe asthma, particularly those with neutrophilic airway inflammation, as bacteria might be anticipated to activate the innate immune response, a process that is poorly steroid responsive. An understanding of the relationship between airway bacterial presence and dominance in severe asthma may help direct alternative treatment approaches. OBJECTIVE: We aimed to use a culture independent analysis strategy to describe the presence, dominance and abundance of bacterial taxa in induced sputum from treatment resistant severe asthmatics and correlate findings with clinical characteristics and airway inflammatory markers. METHODS: Induced sputum was obtained from 28 stable treatment-resistant severe asthmatics. The samples were divided for supernatant IL-8 measurement, cytospin preparation for differential cell count and Terminal Restriction Fragment Length Polymorphism (T-RFLP) profiling for bacterial community analysis. RESULTS: In 17/28 patients, the dominant species within the airway bacterial community was Moraxella catarrhalis or a member of the Haemophilus or Streptococcus genera. Colonisation with these species was associated with longer asthma disease duration (mean (SD) 31.8 years (16.7) vs 15.6 years (8.0), p = 0.008), worse post-bronchodilator percent predicted FEV1 (68.0% (24.0) vs 85.5% (19.7), p = 0.025) and higher sputum neutrophil differential cell counts (median (IQR) 80% (67-83) vs 43% (29-67), p = 0.001). Total abundance of these organisms significantly and positively correlated with sputum IL-8 concentration and neutrophil count. CONCLUSIONS: Airway colonisation with potentially pathogenic micro-organisms in asthma is associated with more severe airways obstruction and neutrophilic airway inflammation. This altered colonisation may have a role in the development of an asthma phenotype that responds less well to current asthma therapies. PMID- 24955986 TI - Association between tuberculosis recurrence and interferon-gamma response during treatment. AB - OBJECTIVES: We investigated the relationship between tuberculosis recurrence and Mycobacterium tuberculosis antigen-stimulated interferon-gamma (IFN-gamma) responses during treatment. METHODS: Plasma IFN-gamma levels in active pulmonary tuberculosis patients (n = 407) were analyzed using QuantiFERON-TB Gold In-TubeTM (QFT-IT) at 0, 2, and 7 months of the 8-month treatment received from 2007 to 2009 and the patients were followed up for another 16 months after treatment. Risk factors for recurrence were assessed using the log-rank test and Cox proportional hazard models. Random coefficient models were used to compare longitudinal patterns of IFN-gamma levels between groups. RESULTS: QFT-IT showed positive results in 95.6%, 86.2%, and 83.5% at 0, 2, and 7 months, respectively. The antigen-stimulated IFN-gamma responses varied significantly during the treatment course (P < 0.0001). Unexpectedly, positive-to-negative conversion of QFT-IT results between 0 and 2 months was significantly associated with earlier recurrence (adjusted hazard ratio, 5.57; 95% confidence interval, 2.28-13.57). Time-dependent changes in IFN-gamma levels were significantly different between the recurrence and nonrecurrence groups (P < 0.0001). CONCLUSIONS: Although the IGRA response varies individually, early response during the treatment course may provide an insight into host immune responses underlying tuberculosis recurrence. PMID- 24955985 TI - Ligand-binding pocket bridges DNA-binding and dimerization domains of the urate responsive MarR homologue MftR from Burkholderia thailandensis. AB - Members of the multiple antibiotic resistance regulator (MarR) family often regulate gene activity by responding to a specific ligand. In the absence of ligand, most MarR proteins function as repressors, while ligand binding causes attenuated DNA binding and therefore increased gene expression. Previously, we have shown that urate is a ligand for MftR (major facilitator transport regulator), which is encoded by the soil bacterium Burkholderia thailandensis. We show here that both mftR and the divergently oriented gene mftP encoding a major facilitator transport protein are upregulated in the presence of urate. MftR binds two cognate sites in the mftR-mftP intergenic region with equivalent affinity and sensitivity to urate. Mutagenesis of four conserved residues previously reported to be involved in urate binding to Deinococcus radiodurans HucR and Rhizobium radiobacter PecS significantly reduced protein stability and DNA binding affinity but not ligand binding. These data suggest that residues equivalent to those implicated in ligand binding to HucR and PecS serve structural roles and that MftR relies on distinct residues for ligand binding. MftR exhibits a two-step melting transition suggesting independent unfolding of the dimerization and DNA-binding regions; urate binding or mutations in the predicted ligand-binding sites result in one-step unfolding transitions. We suggest that MftR binds the ligand in a cleft between the DNA-binding lobes and the dimer interface but that the mechanism of ligand-mediated attenuation of DNA binding differs from that proposed for other urate-responsive MarR homologues. Since DNA binding by MftR is attenuated at 37 degrees C, our data also suggest that MftR responds to both ligand and a thermal upshift by attenuated DNA binding and upregulation of the genes under its control. PMID- 24955988 TI - The effects of age on associative and rule-based causal learning and generalization. AB - We assessed how age influences associative and rule-based processes in causal learning using the Shanks and Darby (1998) concurrent patterning discrimination task. In Experiment 1, participants were divided into groups based on their learning performance after 6 blocks of training trials. High discrimination mastery young adults learned the patterning discrimination more rapidly and accurately than moderate mastery young adults. They were also more likely to induce the patterning rule and use this rule to generate predictions for novel cues, whereas moderate mastery young adults were more likely to use cue similarity as the basis for their predictions. Like moderate mastery young adults, older adults used similarity-based generalization for novel cues, but they did not achieve the same level of patterning discrimination. In Experiment 2, young and older adults were trained to the same learning criterion. Older adults again showed deficits in patterning discrimination and, in contrast to young adults, even when they reported awareness of the patterning rule, they used only similarity-based generalization in their predictions for novel cues. These findings suggest that it is important to consider how the ability to code or use cue representations interacts with the requirements of the causal learning task. In particular, age differences in causal learning seem to be greatest for tasks that require rapid coding of configural representations to control associative interference between similar cues. Configural coding may also be related to the success of rule-based processes in these types of learning tasks. PMID- 24955989 TI - Cognitive declines in healthy aging: evidence from multiple aspects of interference resolution. AB - The present study tested the hypothesis that older adults show age-related deficits in interference resolution, also referred to as inhibitory control. Although oftentimes considered as a unitary aspect of executive function, various lines of work support the notion that interference resolution may be better understood as multiple constructs, including resistance to proactive interference (PI) and response-distractor inhibition (e.g., Friedman & Miyake, 2004). Using this dichotomy, the present study assessed whether older adults (relative to younger adults) show impaired performance across both, 1, or neither of these interference resolution constructs. To do so, we used multiple tasks to tap each construct and examined age effects at both the single task and latent variable levels. Older adults consistently demonstrated exaggerated interference effects across resistance to PI tasks. Although the results for the response-distractor inhibition tasks were less consistent at the individual task level analyses, age effects were evident on multiple tasks, as well as at the latent variable level. However, results of the latent variable modeling suggested declines in interference resolution are best explained by variance that is common to the 2 interference resolution constructs measured herein. Furthermore, the effect of age on interference resolution was found to be both distinct from declines in working memory, and independent of processing speed. These findings suggest multiple cognitive domains are independently sensitive to age, but that declines in the interference resolution constructs measured herein may originate from a common cause. PMID- 24955987 TI - Effects of the floods on dysentery in north central region of Henan Province, China from 2004 to 2009. AB - OBJECTIVES: Zhengzhou, Kaifeng and Xinxiang, the cities in the north central region of Henan Province, suffered from many times floods from 2004 to 2009. We focused on dysentery disease consequences of floods and examined the association between floods and the morbidity of dysentery, based on a longitudinal data. METHODS: A generalized additive mixed model was conducted to examine the relationship between the monthly morbidity of dysentery and floods from 2004 to 2009 in the study areas. The relative risks (RRs) of the floods risk on the morbidity of dysentery were estimated in each city and the whole region. RESULTS: The RRs on dysentery were 11.47 (95% CI: 8.67-15.33), 1.35 (95% CI: 1.23-3.90) and 2.75 (95% CI: 1.36-4.85) in Kaifeng, Xinxiang and Zhengzhou, respectively. The RR on dysentery in the whole region was 1.66 (95% CI: 1.52-1.82). CONCLUSIONS: Our study confirms that flooding has significantly increased the risk of dysentery in the study areas. Additionally, we observed that a sudden and severe flooding can contribute more risk to the morbidity of dysentery than a persistent and moderate flooding. Our findings have significant implications for developing strategies to prevent and reduce health impact of floods. PMID- 24955990 TI - Adult age differences in wrap-up during sentence comprehension: evidence from ex Gaussian distributional analyses of reading time. AB - We report a secondary data analysis investigating age differences in the effects of clause and sentence wrap-up on reading time distributions during sentence comprehension. Residual word-by-word self-paced reading times were fit to the ex Gaussian distribution to examine age differences in the effects of clause and sentence wrap-up on both the location and shape of participants' reaction time (RT) distributions. The ex-Gaussian distribution showed good fit to the data in both younger and older adults. Sentence wrap-up increased the central tendency, the variability, and the tail of the distribution, and these effects were exaggerated among the old. In contrast, clause wrap-up influenced the tail of the distribution only, and did so differentially for older adults. Effects were confirmed via nonparametric vincentile plots. Individual differences in visual acuity, working memory, speed of processing, and verbal ability were differentially related to ex-Gaussian parameters reflecting wrap-up effects on underlying reading time distributions. These findings argue against simple pause mechanisms to explain end-of-clause and end-of-sentence reading time patterns; rather, the findings are consistent with a cognitively effortful view of wrap-up and suggest that age and individual differences in attentional allocation to semantic integration during reading, as revealed by RT distribution analyses, play an important role in sentence understanding. PMID- 24955991 TI - Reading with filtered fixations: adult age differences in the effectiveness of low-level properties of text within central vision. AB - When reading, low-level visual properties of text are acquired from central vision during brief fixational pauses, but the effectiveness of these properties may differ in older age. To investigate, a filtering technique displayed the low, medium, or high spatial frequencies of text falling within central vision as young (18-28 years) and older (65+ years) adults read. Reading times for normal text did not differ across age groups, but striking differences in the effectiveness of spatial frequencies were observed. Consequently, even when young and older adults read equally well, the effectiveness of spatial frequencies in central vision differs markedly in older age. PMID- 24955993 TI - Examining the relationship between subjective and objective memory performance in older adults: a meta-analysis. AB - Are the beliefs that older adults hold about their memory abilities associated with their scores on lab-based memory tasks? A review of the aging literature suggests that the correlation between subjective and objective memory is inconsistent, with some studies reporting significant effects and others reporting null results. A meta-analysis was conducted to quantitatively summarize the relationship between subjective memory, defined as general predictions about memory, and objective memory performance in older adults, and to examine the conditions under which this relationship may be strongest. This meta-analysis included 53 studies, each of which included a normatively aging older adult sample. Overall, the association between subjective and objective memory was small (r = .062, SE = 0.014) but reliably greater than zero. Moderator analyses were conducted to better understand the parameters of this effect. Age, years of education, gender, depression symptoms, length and format of subjective memory measures, and type of objective memory were significantly correlated with effect size. These results caution against relying on general subjective memory belief measures as a substitute for objective assessments of memory. PMID- 24955992 TI - Structure and correlates of cognitive aging in a narrow age cohort. AB - Aging-related changes occur for multiple domains of cognitive functioning. An accumulating body of research indicates that, rather than representing statistically independent phenomena, aging-related cognitive changes are moderately to strongly correlated across domains. However, previous studies have typically been conducted in age-heterogeneous samples over longitudinal time lags of 6 or more years, and have failed to consider whether results are robust to a comprehensive set of controls. Capitalizing on 3-year longitudinal data from the Lothian Birth Cohort of 1936, we took a longitudinal narrow age cohort approach to examine cross-domain cognitive change interrelations from ages 70 to 73 years. We fit multivariate latent difference score models to factors representing visuospatial ability, processing speed, memory, and crystallized ability. Changes were moderately interrelated, with a general factor of change accounting for 47% of the variance in changes across domains. Change interrelations persisted at close to full strength after controlling for a comprehensive set of demographic, physical, and medical factors including educational attainment, childhood intelligence, physical function, APOE genotype, smoking status, diagnosis of hypertension, diagnosis of cardiovascular disease, and diagnosis of diabetes. Thus, the positive manifold of aging-related cognitive changes is highly robust in that it can be detected in a narrow age cohort followed over a relatively brief longitudinal period, and persists even after controlling for many potential confounders. PMID- 24955994 TI - Mood impairs time-based prospective memory in young but not older adults: the mediating role of attentional control. AB - The present study examined age-by-mood interactions in prospective memory and the potential role of attentional control. Positive, negative, or neutral mood was induced in young and older adults. Subsequent time-based prospective memory performance was tested, incorporating a measure of online attentional control shifts between the ongoing and the prospective memory task via time monitoring behavior. Mood impaired prospective memory in the young, but not older, adults. Moderated mediation analyses showed that mood effects in the young were mediated by changes in time monitoring. Results are discussed in relation to findings from the broader cognitive emotional aging literature. PMID- 24955997 TI - Age-related and death-related differences in emotional complexity. AB - The present study aimed to examine an aspect of emotional complexity as seen in covariation between retrospective judgments of positive and negative affects. We assume that individuals can experience positive affect independently of negative affect. Theories argue that emotional complexity increases in old age, but research shows mixed evidence. Additionally, emotional complexity has been shown to decrease in situations prevalent in old age, such as physical illness and disability. Integrating distinct effects of age and distance to death, we propose that emotional complexity may remain intact or even increase in old age, and yet it decreases in light of functional deterioration shortly before death. The current research examined whether emotional complexity decreases as a function of subjective perception of closeness to death (subjective survival probability) or actual closeness to death. We used 3 large-scale databases: 2 cross-sectional (SHARE, N = 17,437, mean age = 64; HRS, N = 6,032, mean age = 67) and 1 longitudinal (CALAS, N = 1,310, mean age at baseline = 83). Hierarchical multiple regressions and multilevel models showed that respondents who perceived themselves as closer to death or were actually closer to death showed lower emotional complexity (a stronger negative correlation between positive and negative affects). Age and emotional complexity were unrelated or positively related, depending on the sample. Findings remained the same after controlling for demographic characteristics, as well as physical and cognitive functioning. The results indicate that both subjective and objective closeness to death are associated with lower emotional complexity. This death-related decrease in emotional complexity is discussed within current theories of aging. PMID- 24955995 TI - Diurnal cortisol rhythm is associated with increased risky decision-making in older adults. AB - Although past research has suggested a link between chronic stress and both physical and mental well-being in older adults, less is known about the degree to which neuroendocrine markers of stress are associated with higher-order cognitive processes such as decision-making. In a sample of healthy older adults (55-85 years), we tested the degree to which variation in the diurnal cortisol rhythm, an index of hypothalamic-adrenal-pituitary axis dynamics, was related to differences in risky decision-making. We found that diurnal cortisol fall predicted performance on the Cups Task, a risky decision-making task that independently tests risk-taking to achieve gains and risk-taking to avoid losses. For potential gains, we found that greater risk-taking was associated with lower diurnal cortisol fall, independent of age or sex of the participant. For risks to avoid potential losses, we found that lower diurnal fall was associated with suboptimal decision-making for men only. Compared with males with more typical diurnal fall, those who displayed lower diurnal fall made more risky choices and demonstrated lower sensitivity to the expected value of the risky choice. We integrate these results with the extant literature on the effects of stress on decision-making and cognitive aging. PMID- 24955998 TI - Loneliness in a day: activity engagement, time alone, and experienced emotions. AB - The experience of chronic loneliness has been associated with poorer physical health and well-being, including declines in cardiovascular health and higher levels of distressed affect. Given the long-term effects of loneliness on health and well-being, much research has focused on loneliness in older age. The purpose of the current study was to obtain a more detailed picture of the experience of loneliness in midlife and older adulthood by incorporating the context of a day's activities. We use a modified day reconstruction task to examine the activities in which middle-age and older adults engaged, the amount of time they spent alone, and the emotions experienced while engaging in a day's activities. Lonely individuals did not participate in different daily activities or spend more time alone during the day; however, loneliness was associated with engaging in more activities alone than with others. In regards to emotional experiences, daily activities yield a different profile of positive emotional experiences for lonelier individuals. The social context of daily activities was an important factor in understanding the effects of loneliness on experienced negative emotions. The results of this study provide insight into the influence of loneliness on the structure of a day and context for understanding the emotional experiences of lonely older adults. PMID- 24956000 TI - Future time perspective and promotion focus as determinants of intraindividual change in work motivation. AB - In the near future, workforces will increasingly consist of older workers. At the same time, research has demonstrated that work-related growth motives decrease with age. Although this finding is consistent with life span theories, such as the selection optimization and compensation (SOC) model, we know relatively little about the process variables that bring about this change in work motivation. Therefore, we use a 4-wave study design to examine the mediating role of future time perspective and promotion focus in the negative association between age and work-related growth motives. Consistent with the SOC model, we found that future time perspective was negatively associated with age, which, in turn, was associated with lower promotion focus, lower work-related growth motive strength, and lower motivation to continue working. These findings have important theoretical implications for the literature on aging and work motivation, and practical implications for how to motivate older workers. PMID- 24955999 TI - The dynamic relationship between cognitive function and positive well-being in older people: a prospective study using the English Longitudinal Study of Aging. AB - There is evidence that having a stronger sense of positive well-being may be a potential resource for healthier aging as represented by slower physical decline, reduced risk of frailty and longer survival. However, it is unclear whether positive well-being is protective of another crucial component of healthy aging, cognitive function, or whether it has a bidirectional relationship with cognitive function. We use multilevel models with within-person centering to estimate the within- and between-person association between cognitive function and positive well-being in 4 waves of data from the English Longitudinal Study of Ageing (ELSA), (N = 10985, aged 50-90 years at wave 1). Our findings show that, although most variation in cognitive function was explained by age, and most variation in well-being was explained by depression, small but significant associations between cognition and well-being remained after variation in age and depression were controlled. In models where cognition was the outcome, the association was mainly because of variation in mean levels of well-being between persons. In models where well-being was the outcome, the association was mainly because of within-person fluctuation in cognitive test performance. Exercise and depression were the most important moderating influences on the association between cognition and positive well-being. Depression had greater effect upon this association for those with higher well-being, but exercise protected cognitive performance against the adverse effects of lower well-being. PMID- 24956002 TI - Middle-aged adults facing skin cancer information: fixation, mood, and behavior. AB - Older adults fixate less on negative parts of skin cancer videos than younger adults, leading them to feel better (Isaacowitz & Choi, 2012). We extended this paradigm to middle-aged adults (ages 35-59, n = 63), whose fixation patterns were measured as they viewed skin cancer videos; mood and behavior were also assessed. Middle-aged adults looked even less at the videos than the other age groups, especially at the negative clips. They also reported the best moods but relatively low levels of learning and positive skin cancer behavior. In some cases, middle-aged adults may show larger "age-related positivity effects" than older adults. PMID- 24956003 TI - Primary care supply moderates the impact of diseases on self-perceptions of aging. AB - Self-perceptions of aging, important indicators of successful aging, are closely linked to health. Previous research has mainly examined the role of individual factors on self-perceptions of aging, but health is partly dependent on contextual factors such as primary care supply. This study therefore examined whether the impact of diseases on self-perceptions of aging is buffered by primary care supply in the district, as it ensures sustained health care continuity. Nationally representative German survey data on health and self perceptions of aging (N = 4,442, 40-85 years) were linked to primary care supply (general practitioner density in regional districts). Multilevel modeling shows that the impact of disease burden (multiple illnesses) was buffered by primary care supply: Disease burden was less strongly associated with negative self perceptions of aging in districts with good primary health care supply. This underlines the importance of health care resources for successful aging. PMID- 24956001 TI - Positive messaging promotes walking in older adults. AB - Walking is among the most cost-effective and accessible means of exercise. Mounting evidence suggests that walking may help to maintain physical and cognitive independence in old age by preventing a variety of health problems. However, older Americans fall far short of meeting the daily recommendations for walking. In 2 studies, we examined whether considering older adults' preferential attention to positive information may effectively enhance interventions aimed at promoting walking. In Study 1, we compared the effectiveness of positive, negative, and neutral messages to encourage walking (as measured with pedometers). Older adults who were informed about the benefits of walking walked more than those who were informed about the negative consequences of failing to walk, whereas younger adults were unaffected by framing valence. In Study 2, we examined within-person change in walking in older adults in response to positively- or negatively-framed messages over a 28-day period. Once again, positively-framed messages more effectively promoted walking than negatively framed messages, and the effect was sustained across the intervention period. Together, these studies suggest that consideration of age-related changes in preferences for positive and negative information may inform the design of effective interventions to promote healthy lifestyles. Future research is needed to examine the mechanisms underlying the greater effectiveness of positively- as opposed to negatively-framed messages and the generalizability of findings to other intervention targets and other subpopulations of older adults. PMID- 24956004 TI - Genetic variants and cognitive aging: destiny or a nudge? AB - One would be hard-pressed to find a human trait that is not heritable at least to some extent, and genetics have played an important role in behavioral science for more than half a century. With the advent of high-throughput molecular methods and the increasing availability of genomic analyses, genetics have acquired a firm foothold in public discourse. However, although the proliferation of genetic association studies and ever-expanding library of single-nucleotide polymorphisms have generated some fascinating results, they have thus far fallen short of delivering the anticipated dramatic breakthroughs. In this collection of eight articles, we present a spectrum of efforts aimed at finding more nuanced and meaningful ways of integrating genomic findings into the study of cognitive aging. The articles present examples of Mendelian randomization in the service of investigating difficult-to-manipulate biochemical properties of human participants. Furthermore, in an important step forward, they acknowledge the interactive effects of genes and physiological risk factors on age-related difference and change in cognitive performance, as well as the possibility of modifying the negative effect of genetic variants by lifestyle changes. PMID- 24956005 TI - Healthy aging increases the cognitive effects of two genes that influence extracellular dopamine. AB - We hypothesized that normal variation in genes influencing the bioavailability of dopamine in prefrontal cortex contribute to inter-individual differences in working memory (WM), particularly in healthy old age. To test this, 858 healthy young, middle-aged, and older people were tested on a spatial WM task and genotyped for catechol-O-methyltransferase (COMT VAL158MET) and dopamine betahydroxylase (DBH; C-1021T) single nucleotide polymorphisms (SNPs). Since these genes encode enzymes influencing levels of extracellular dopamine, important for WM, we reasoned that individuals with low activity alleles of each SNP (less efficient degradation of dopamine by COMT and less efficient conversion of dopamine to norepinephrine by DBH) would have higher levels of extracellular dopamine and therefore better WM performance. We predicted the poorest WM performance in people who are both COMT VAL/VAL and DBH C/C homozygotes, encoding enzymes with high activity. That prediction was borne out, but only in the older group under difficult discrimination. This suggests the high activity alleles of these 2 genes combine in reducing ability to manipulate information in WM among the old. Further, we predicted the best performance in people who inherited both low activity alleles. That prediction was not borne out. That we found genetic effects only among older people and not in midlife indicates that brain changes late in life heighten negative effects of chronically lower levels of extracellular dopamine due to normal genetic variation. We found that age increased the combined effect on WM of the COMT and DBH genes encoding enzymes controlling levels of extracellular dopamine. PMID- 24956006 TI - Cognitive ability, intraindividual variability, and common genetic variants of catechol-O-methyltransferase and brain-derived neurotrophic factor: a longitudinal study in a population-based sample of older adults. AB - Genetic differences play a significant role in generating individual differences in cognitive abilities. Studies have linked common polymorphisms (valine to methionine substitution; VAL/MET) in the catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) to cognitive differences between individuals. However, not all studies support these associations and hence, the impact of these polymorphisms on cognition is unclear. Here, we investigated the effect of COMT VAL158MET and BDNF VAL66MET polymorphisms and their interaction on cognitive performance measured longitudinally over 8 years in a population-based sample of older adults (60-64 years at baseline; n = 400). We used multilevel models to examine differences between individuals with different genotypes in performance on psychometric tests while controlling for age, sex, and education. We observed significant main and interaction effects of COMT and BDNF genotypes on reaction time (RT) and intraindividual variability in RT (IIV-RT). Subjects with at least one copy of the COMT*MET allele (which is associated with higher prefrontal dopamine) had significantly faster RT (both simple and choice RT) and less IIV-RT in both tasks than those without the COMT*MET allele when they also carried one or more BDNF*MET alleles (which is associated with lower activity dependent BDNF secretion). However, RT and IIV-RT did not differ significantly between the COMT genotypes in the absence of the BDNF*MET allele. These polymorphisms had no significant effect on within person change in RT or IIV-RT. Our findings indicate that the interaction between common variants of COMT and BDNF explain individual differences in RT and IIV-RT but do not explain age related decline in these abilities. PMID- 24956009 TI - Formation of condensed 1H-pyrrol-2-ylphosphonates and 1,2-dihydropyridin-2 ylphosphonates via Kabachnik-Fields reaction of acetylenic aldehydes and subsequent 5-exo-dig or 6-endo-dig cyclizations. AB - Kabachnik-Fields reactions of various carbocyclic or heterocyclic acetylenic aldehydes together with subsequent Lewis acid catalyzed cyclizations have been studied. It was found that 5-exo-dig versus 6-endo-dig cyclization mode strongly depends on the structure of starting materials. Thus, nonaromatic acetylenic alpha-anilinomethylphosphonates underwent gold(III)-catalyzed or iodine-mediated 5-exo-dig cyclization to 1H-pyrrol-2-ylphosphonates. In contrast, electron withdrawing heteroaromatic substrates formed 1,2-dihydropyridin-2-ylphosphonate ring containing materials via an exclusive 6-endo-dig ring-closure process. The dual mode of cyclization is possible only for alpha-amino (2 alkynylphenyl)methylphosphonates containing a benzene ring. PMID- 24956007 TI - Genetic complexity of episodic memory: a twin approach to studies of aging. AB - Episodic memory change is a central issue in cognitive aging, and understanding that process will require elucidation of its genetic underpinnings. A key limiting factor in genetically informed research on memory has been lack of attention to genetic and phenotypic complexity, as if "memory is memory" and all well-validated assessments are essentially equivalent. Here we applied multivariate twin models to data from late-middle-aged participants in the Vietnam Era Twin Study of Aging to examine the genetic architecture of 6 measures from 3 standard neuropsychological tests: the California Verbal Learning Test-2, and Wechsler Memory Scale-III Logical Memory (LM) and Visual Reproductions (VR). An advantage of the twin method is that it can estimate the extent to which latent genetic influences are shared or independent across different measures before knowing which specific genes are involved. The best-fitting model was a higher order common pathways model with a heritable higher order general episodic memory factor and three test-specific subfactors. More importantly, substantial genetic variance was accounted for by genetic influences that were specific to the latent LM and VR subfactors (28% and 30%, respectively) and independent of the general factor. Such unique genetic influences could partially account for replication failures. Moreover, if different genes influence different memory phenotypes, they could well have different age-related trajectories. This approach represents an important step toward providing critical information for all types of genetically informative studies of aging and memory. PMID- 24956008 TI - Hypertension moderates the effect of APOE on 21-year cognitive trajectories. AB - We examined whether hypertension moderated the effects of apolipoprotein epsilon4 (APOE epsilon4) on individual differences in level and change in cognitive functions over a 21-year period using data from the Seattle Longitudinal Study (SLS). A total of 563 nondemented adults ages 32 to 74 years in 1984 (M = 51.06, SD = 12.03) were included in the study. Cognitive performance was assessed spanning 7 domains-verbal comprehension, numeric facility, episodic memory, spatial orientation, inductive reasoning, perceptual speed, and cognitive flexibility-over 4 occasions of measurement at 7-year intervals. Multilevel modeling was used to test the cross-sectional and longitudinal effects of hypertension, APOE, and their interaction, after adjusting for age, gender, and education. APOE and hypertension had additive and interactive effects on select cognitive functions. APOE epsilon4 carriers had a performance advantage at baseline on reasoning ability, relative to non-epsilon4 carriers. The additive effect of hypertension on level of cognitive flexibility (i.e., lower performance for hypertensives) was qualified by a significant APOE * Hypertension interaction on the slope. Hypertension moderated the effects of APOE epsilon4 on the rate of change for cognitive flexibility, such that the presence of the APOE epsilon4 allele and hypertension was associated with steeper cognitive decline over a 21 year period. A double dose of genetic vascular risk factors accounted for variation in the slope in normal cognitive aging, suggesting that clinical interventions aimed at lowering vascular risk may benefit cognitive health. PMID- 24956011 TI - Foreword. The SUNDIPS meeting and papers. PMID- 24956010 TI - Determination of four sulfonylurea herbicides in tea by matrix solid-phase dispersion cleanup followed by dispersive liquid-liquid microextraction. AB - Matrix solid-phase dispersion combined with dispersive liquid-liquid microextraction has been developed as a new sample pretreatment method for the determination of four sulfonylurea herbicides (chlorsulfuron, bensulfuron-methyl, chlorimuron-ethyl, and pyrazosulfuron) in tea by high-performance liquid chromatography with diode array detection. The extraction and cleanup by matrix solid-phase dispersion was carried out by using CN-silica as dispersant and carbon nanotubes as cleanup sorbent eluted with acidified dichloromethane. The eluent of matrix solid-phase dispersion was evaporated and redissolved in 0.5 mL methanol, and used as the dispersive solvent of the following dispersive liquid liquid microextraction procedure for further purification and enrichment of the target analytes before high-performance liquid chromatography analysis. Under the optimum conditions, the method yielded a linear calibration curve in the concentration range from 5.0 to 10 000 ng/g for target analytes with a correlation coefficients (r(2)) ranging from 0.9959 to 0.9998. The limits of detection for the analytes were in the range of 1.31-2.81 ng/g. Recoveries of the four sulfonylurea herbicides at two fortification levels were between 72.8 and 110.6% with relative standard deviations lower than 6.95%. The method was successfully applied to the analysis of four sulfonylurea herbicides in several tea samples. PMID- 24956012 TI - Polyglyoxylates: a versatile class of triggerable self-immolative polymers from readily accessible monomers. AB - Self-immolative polymers, which degrade by an end-to-end depolymerization mechanism in response to the cleavage of a stabilizing end-cap from the polymer terminus, are of increasing interest for a wide variety of applications ranging from sensors to controlled release. However, the preparation of these materials often requires expensive, multistep monomer syntheses, and the degradation products such as quinone methides or phthalaldehydes are potentially toxic to humans and the environment. We demonstrate here that polyglyxoylates can serve as a new and versatile class of self-immolative polymers. Polymerization of the commercially available monomer ethyl glyoxylate, followed by end-capping with a 6 nitroveratryl carbonate, provides a poly(ethyl glyoxylate) that depolymerizes selectively upon irradiation with UV light, ultimately generating ethanol and the metabolic intermediate glyoxylic acid hydrate. To access polyglyoxylates with different properties, the polymerization and end-capping approach can also be extended to other glyoxylate monomers including methyl glyoxylate, n-butyl glyoxylate, and benzyl glyoxylate, which can be easily prepared from their corresponding fumaric or maleic acid derivatives. Random copolymers of these monomers with ethyl glyoxylate can also be prepared. Furthermore, using a multifunctional end-cap that is UV-responsive and also enables the conjugation of another polymer block via an azide-alkyne "click" cycloaddition, amphiphilic self immolative block copolymers are also prepared. These block copolymers self assemble into micelles in aqueous solution, and their poly(ethyl glyoxylate) blocks rapidly depolymerize upon UV irradiation. Overall, these strategies are expected to greatly expand the utility of self-immolative polymers by providing access for the first time to self-immolative polymers with tunable properties that can be readily obtained from simple monomers and can be designed to depolymerize into nontoxic products. PMID- 24956014 TI - Stress selectively affects the reactivated components of a declarative memory. AB - When long-term memories are reactivated, they can reenter a transient plastic state in which they are vulnerable to interference or physiological manipulations. The present study attempted to directly affect reactivated memories through a stress manipulation, and compared the effects of stress on reactivated and nonreactivated components of a declarative memory in a within subject design. We presented image pairs that consisted of an image of an animal and an image of an unrelated object. Participants were instructed to memorize the object images. Forty-eight hours later, we presented half of the animal images again in an unrelated task to indirectly reactivate the associated object images. Immediately after reactivation, participants were exposed to cold pressor stress or a warm water control condition. Forty-eight hours later, we assessed memory for the object images with a free recall test. Reactivation boosted memory performance in the control condition, such that reactivated items were better recalled than nonreactivated items. This memory-enhancing effect of reactivation was completely abolished by cold pressor stress. Importantly, stress selectively impacted only the reactivated items while leaving memory for the nonreactivated items unaffected. The present study shows that it is possible to selectively reactivate and modulate specific parts of a declarative memory. PMID- 24956013 TI - Mammilliothalamic tract lesions disrupt tests of visuo-spatial memory. AB - The mammillary bodies and their projections via the mammilliothalamic tract to the anterior thalamic nuclei are known to be important for spatial memory in rodents, but their precise role remains unclear. To determine whether transection of the mammilliothalamic tract can produce deficits on tests of spatial memory even when the navigational demands placed on the animal are limited, rats with discrete mammilliothalamic tract lesions were tested on the ability to use distal visual cues to discriminate between 2 locations within a room, irrespective of the direction traveled (Experiment 1). Animals with mammilliothalamic tract lesions acquired this task more slowly and less accurately than control animals. Consistent with this impairment in discriminating different spatial locations, the same lesions also severely disrupted object-in-place memory but spared performance on standard tests of object recognition memory (Experiment 2). Finally, to compare performance on a task that is known to be sensitive to mammilliothalamic transection and requires animals to actively navigate within their environment, the effect of the lesions on spatial working memory in the radial-arm maze was examined. Taken together, the results suggest that even when there are little or no navigational demands, mammilliothalamic tract damage still results in impoverished encoding of spatial location. PMID- 24956015 TI - Hispidanins A-D: four new asymmetric dimeric diterpenoids from the rhizomes of Isodon hispida. AB - Hispidanins A-D (1-4), four unprecedented asymmetric dimeric diterpenoids, were obtained from the rhizomes of Isodon hispida. Their structures were elucidated by extensive spectroscopic analysis (1D and 2D NMR, MS, UV, IR), as well as single crystal X-ray diffraction analysis. Hispidanin B showed significant cytotoxicities against tumor cell lines SGC7901, SMMC7721, and K562, with IC50 values of 10.7, 9.8, and 13.7 MUM, respectively. PMID- 24956017 TI - Cephalosporins currently in early clinical trials for the treatment of bacterial infections. AB - INTRODUCTION: Healthcare-associated infections caused by multi-drug resistant bacteria remain a major cause of worldwide mortality. With the recent approval of agents such as hetero-resistant cocci (i.e., ceftaroline, ceftobiprole, telavancin) for the treatment of Gram-positive infections by and drugs like fidaxomicin for treating Clostridium difficile, present-day research on antibacterials has largely shifted to developing interventions for diseases caused by Gram-negative bacilli. Cephalosporins have gained significant interest as antipseudomonals to be used in hospitals for treating device- and procedure associated infections. With extended-spectrum activity against many enterobacterial pathogens, the introduction of new antipseudomonal cephalosporin based treatments will mark a significant advancement in the management of hospital-borne diseases. AREAS COVERED: The following review examines the present day status of investigational cephalosporins currently in preclinical, Phase I and Phase II stage development. The article focuses specifically on treatments used for healthcare-associated infections due to Gram-negative bacteria. EXPERT OPINION: There is an urgent need for new antimicrobials to treat nosocomial infections due to multi-drug resistant Gram-negative bacteria. The impending approvals of antipseudomonal cephalosporins co-formulated with a beta-lactamase inhibitor will allow clinicians to treat more hetero-resistant infections with cephalosporins, while avoiding the use of more toxic agents such as colistin. The growing interest in developing new beta-lactamase inhibitor combinatorial treatments with approved beta-lactam antibiotics is anticipated to decrease the number of novel cephalosporins entering clinical trials this decade. PMID- 24956018 TI - Synthesis of (S)-ricinoleic acid and its methyl ester with the participation of ionic liquid. AB - (R)-ricinoleic acid methyl ester obtained from commercial castor oil was transformed in a three-step procedure into its S-enantiomer in overall 36% yield using ionic liquid (1-butyl-3-methylimidazolium acetate) in the key step process. The developed procedure provides easy access to (S)-ricinoleic acid and its methyl ester of over 95% enantiomeric excess. Optical rotations of the newly obtained compounds as well as their chromatographic and spectral characteristics are provided and discussed in the context of enantiopurity both of the substrate material and the final products. PMID- 24956016 TI - Key role of the endothelial TGF-beta/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension. AB - Mutations affecting transforming growth factor-beta (TGF-beta) superfamily receptors, activin receptor-like kinase (ALK)-1, and endoglin (ENG) occur in patients with pulmonary arterial hypertension (PAH). To determine whether the TGF beta/ALK1/ENG pathway was involved in PAH, we investigated pulmonary TGF-beta, ALK1, ALK5, and ENG expressions in human lung tissue and cultured pulmonary artery smooth-muscle-cells (PA-SMCs) and pulmonary endothelial cells (PECs) from 14 patients with idiopathic PAH (iPAH) and 15 controls. Seeing that ENG was highly expressed in PEC, we assessed the effects of TGF-beta on Smad1/5/8 and Smad2/3 activation and on growth factor production by the cells. Finally, we studied the consequence of ENG deficiency on the chronic hypoxic-PH development by measuring right ventricular (RV) systolic pressure (RVSP), RV hypertrophy, and pulmonary arteriolar remodeling in ENG-deficient (Eng+/-) and wild-type (Eng+/+) mice. We also evaluated the pulmonary blood vessel density, macrophage infiltration, and cytokine expression in the lungs of the animals. Compared to controls, iPAH patients had higher serum and pulmonary TGF-beta levels and increased ALK1 and ENG expressions in lung tissue, predominantly in PECs. Incubation of the cells with TGF-beta led to Smad1/5/8 phosphorylation and to a production of FGF2, PDGFb and endothelin-inducing PA-SMC growth. Endoglin deficiency protected mice from hypoxic PH. As compared to wild-type, Eng+/- mice had a lower pulmonary vessel density, and no change in macrophage infiltration after exposure to chronic hypoxia despite the higher pulmonary expressions of interleukin-6 and monocyte chemoattractant protein-1. The TGF-beta/ALK1/ENG signaling pathway plays a key role in iPAH and experimental hypoxic PH via a direct effect on PECs leading to production of growth factors and inflammatory cytokines involved in the pathogenesis of PAH. PMID- 24956019 TI - Isolation and characterisation of methanol-soluble fraction of Alternanthera philoxeroides (Mart.) - evaluation of their antioxidant, alpha-glucosidase inhibitory and antimicrobial activity in in vitro systems. AB - Alternanthera philoxeroides (Mart.) is a tropical weed commonly known as alligator weed. It grows rapidly within a small span of time and easily available all over the world. The objective of this work was to isolate and characterise the major phenolic components present in the methanol-soluble fraction (fraction X) of A. philoxeroides leaves and to explore the biological activity (antioxidant, alpha-glucosidase inhibition and antimicrobial) of the fraction in in vitro system. Chromatographic (HPLC) and spectroscopic (MALDI-TOF, 1H NMR) techniques were used to purify and characterise the phenolics present in fraction X. Five major phenolics (kaempferol, ferulic acid, salicylic acid, syringic acid and chlorogenic acid) were found in fraction X. The fraction showed anti-oxidant property, dose-dependent inhibition of alpha-glucosidase activity and anti microbial activity. Hence fraction X from the weed has therapeutic potential in pathophysiological condition. PMID- 24956023 TI - Crystal structure and magnetic properties of the S = 1/2 quantum spin system Cu7(TeO3)6F2 with mixed dimensionality. AB - The new oxofluoride Cu7(TeO3)6F2 has been synthesized by hydrothermal synthesis. It crystallizes in the triclinic system, space group P1. The crystal structure constitutes a Cu-O framework with channels extending along [001] where the F(-) ions and the stereochemically active lone-pairs on Te(4+) are located. From magnetic susceptibility, specific heat, and Raman scattering measurements we find evidence that the magnetic degrees of freedom of the Cu-O-Cu segments in Cu7(TeO3)6F2 lead to a mixed dimensionality with single Cu S = (1)/2 moments weakly coupled to spin-chain fragments. Due to the weaker coupling of the single moments, strong fluctuations exist at elevated temperatures, and long-range magnetic ordering evolves at comparably low temperatures (TN = 15 K). PMID- 24956021 TI - Icariin stimulates the osteogenic differentiation of rat bone marrow stromal cells via activating the PI3K-AKT-eNOS-NO-cGMP-PKG. AB - Icariin, a prenylated flavonol glycoside isolated from Epimedii herba, has been found to be a potent stimulator of osteogenic differentiation and has potential application in preventing bone loss. However, the signaling pathway underlying its osteogenic effect remains unclear. We hypothesized that the osteogenic activity of icariin is related to the nitric oxide (NO) signal pathway and PI3K/AKT pathway in its upstream. Rat bone marrow stromal cells (rBMSCs) were cultured in osteogenic medium and treated with icariin or together with L-NAME, ODQ, PDE5, and/or LY294002 (the inhibitor of NOS, sGC, cGMP, and PI3K respectively), and effects were examined on the expression of signal messengers (NOS, NO, sGC, cGMP, PKG and PI3K) and the levels of osteogenic markers (alkaline phosphatase or ALP, osteocalcin and calcified nodules). It was found that icariin dose-dependently increased ALP activity, and treatment at the optimal concentration (10(-5)M) increased NOS activity, iNOS and eNOS expression, NO production, sGC and cGMP contents and PKG expression besides the phosphorylation of AKT. The addition of L-NAME, ODQ and PDE5 significantly inhibited the icariin effects on above markers respectively. The addition of LY294002 decreased the p AKT level, NOS activity, eNOS expression and NO production significantly, but had no significant effect on iNOS expression. The addition of any of the four inhibitors also abolished the osteogenic effect of icariin on rBMSCs as indicated by ALP activity, osteocalcin synthesis, calcium deposition and the number and areas of calcified nodules. These results suggest that the osteogenic effect of icariin involves the PI3K-AKT-eNOS-NO-cGMP-PKG signal pathway. Furthermore, dosage response studies showed that icariin at 10(-6)M (a physiologically achievable concentration in vivo) also activated this signal pathway. PMID- 24956020 TI - CSF-1 blockade impairs breast cancer osteoclastogenic potential in co-culture systems. AB - Metastatic bone disease has a major impact on the morbidity and mortality of breast cancer patients, and studies on bone metastasis biology have led to the development of the most widely used drugs for bone metastases treatment: zoledronate (Zol) and denosumab (Den). The aim of the present study was to assess the effect of soluble mediators produced by breast cancer cells on human osteoclast maturation in a co-culture model. We also tested the ability of zoledronate, denosumab and 5H4, an antibody directed against CSF-1, to interfere with the osteoclastogenic potential of breast cancer. The study was performed on the triple negative cell line MDA-MB-231 and on human osteoclasts obtained from the differentiation of peripheral blood monocytes of a healthy volunteer. Osteoclastogenesis was evaluated by TRAP assay after 14days of differentiation with 10% MDA-MB-231-conditioned media or with CSF-1 and RANKL. Den, Zol and 5H4 were administered after 7days of differentiation. MDA-MB-231-conditioned media doubled the differentiation of monocytes into osteoclasts. MDA-MB-231 secreted CSF-1, especially when cells were cultured to confluence. Induced osteoclasts were sensitive to bone-targeted drugs: Den and 5H4 blocked osteoclast differentiation and survival, while Zol induced osteoclast apoptosis. Osteoclasts differentiated by breast cancer cells were less sensitive to Zol than those induced by differentiation factors, whereas sensitivity to Den was similar. Conversely, breast cancer-induced osteoclast activation resulted in a higher sensitivity to 5H4. A significant increase in CSF-1 secretion was observed in osteoclast precursors after treatment with the highest concentration of Den. Further research is ongoing to evaluate the efficacy of 5H4 combination with Den. PMID- 24956022 TI - Interaction of a biguanide compound with membrane model interface systems: probing the properties of antimalaria and antidiabetic compounds. AB - Since membrane penetration is important for drug efficacy, how antimalarial precursor material 1-phenylbiguanide (PBG) interacts with an interface was characterized using a reverse micelle (RM) model system. (1)H NMR studies show that PBG partitions across the membrane interface. Specifically, the (1)H NMR studies showed that the 1-phenylbiguanide compound in an aqueous environment changed when placed near an interface. PBG is known to affect hydrogen bonding in water, and as the size of the RMs changes, the water organization in the water pool is changed. The NOESY spectrum of PBG in AOT RM contains cross-peak signals between the PBG protons and AOT protons, which is consistent with the penetration of the PBG into the interface. At the same time, there is a cross peak between the biguanide moiety and the HOD signal. This shows that these NH protons are near the HOD protons, placing the biguanide functional group in the water pool. Preliminary differential FTIR spectroscopic studies confirmed this location. In summary, we found that PBG interacts with different regions of the interface, with the phenyl group penetrating the hydrophobic interface while the biguanide remains in the water pool. PMID- 24956024 TI - Do as I say, not as I do: a lexical distributional account of English locative verb class acquisition. AB - Children overgeneralise verbs to ungrammatical structures early in acquisition, but retreat from these overgeneralisations as they learn semantic verb classes. In a large corpus of English locative utterances (e.g., the woman sprayed water onto the wall/wall with water), we found structural biases which changed over development and which could explain overgeneralisation behaviour. Children and adults had similar verb classes and a correspondence analysis suggested that lexical distributional regularities in the adult input could help to explain the acquisition of these classes. A connectionist model provided an explicit account of how structural biases could be learned over development and how these biases could be reduced by learning verb classes from distributional regularities. PMID- 24956025 TI - Corticosterone predicts nocturnal restlessness in a long-distance migrant. AB - The decision made by migrating birds to stop refueling and to depart from stopover depends on cues from innate rhythms, intrinsic factors such as fuel reserves, and extrinsic factors such as weather conditions. The physiological mechanism behind this decision, however, is largely unexplored. The transition from refueling to flight involves an increase in both locomotion and energetic demands. Because, at baseline levels, corticosterone stimulates locomotion and is involved in the mobilization of energy, this hormone could encourage departure of migrants. We collected field data on baseline corticosterone, migratory restlessness, and actual departure in northern wheatears at stopover. Additionally, in refueling long-term captive conspecifics, we measured migratory restlessness while simultaneously collecting droppings to determine glucocorticoid metabolite (GCM) levels. We found that migratory restlessness at stopover was positively correlated with corticosterone level. Similarly, in refueling long-term captive birds, migratory restlessness was positively correlated with concurrently measured GCM levels in droppings. To our best knowledge, our study is the first to simultaneously measure a hormonal signal and migratory restlessness. In conclusion, our results are consistent with the hypothesis that, by increasing locomotor activity, baseline corticosterone is involved in the regulation of departure of migrants at stopover. Future studies could reveal how corticosterone is up-regulated in migrants that are ready to depart. PMID- 24956026 TI - Psychosocial stress moderates the relationships between oxytocin, perinatal depression, and maternal behavior. AB - The hormone oxytocin (OT) is of particular interest in the study of childbearing women, as it has a role in the onset and course of labor and breastfeeding. Recent research has linked OT to maternal caregiving behavior towards her infant, and to postpartum depressive symptomatology. There is also evidence that psychosocial adversity affects the oxytocin system. The present study investigated the relationship of endogenous OT in women during pregnancy and at 8weeks postpartum to psychosocial stress, maternal symptoms of depression, and maternal sensitive behavior. It was hypothesized that OT would mediate the effects of maternal depressive symptoms on maternal interactive behavior. We also tested the hypothesis that psychosocial stress would moderate the relationship between OT and maternal depressive symptoms and sensitive behavior. A community sample of 287 women was assessed at 12-14weeks of gestation, 32-34weeks of gestation, and 7-9weeks postpartum. We measured plasma OT, maternal symptoms of depression and psychosocial stress. At the postpartum home visit, maternal behavior in interaction with the infant was videotaped, and then coded to assess sensitivity. In the sample as a whole, OT was not related to maternal depressive symptoms or to sensitive maternal behavior. However, among women who reported high levels of psychosocial stress, higher levels of plasma OT were associated with fewer depressive symptoms and more sensitive maternal behavior. These results suggest that endogenous OT may act as a buffer against the deleterious effects of stress, thereby protecting high risk women from developing depressive symptoms and promoting more sensitive maternal interactive behavior. PMID- 24956027 TI - A non-contact technique for measuring eccrine sweat gland activity using passive thermal imaging. AB - An approach for monitoring eccrine sweat gland activity using high resolution Mid Wave Infrared (MWIR) imaging (3-5 MUm wave band) is described. This technique is non-contact, passive, and provides high temporal and spatial resolution. Pore activity was monitored on the face and on the volar surfaces of the distal and medial phalanges of the index and middle fingers while participants performed a series of six deep inhalation and exhalation exercises. Two metrics called the Pore Activation Index (PAI) and Pore Count (PC) were defined as size-weighted and unweighted measures of active sweat gland counts respectively. PAI transient responses on the finger tips were found to be positively correlated to Skin Conductance Responses (SCRs). PAI responses were also observed on the face, although the finger sites appeared to be more responsive. Results indicate that thermal imaging of the pore response may provide a useful, non-contact, correlate measure for electrodermal responses recorded from related sites. PMID- 24956029 TI - Bio-cathode materials evaluation and configuration optimization for power output of vertical subsurface flow constructed wetland - microbial fuel cell systems. AB - To optimize the performance of a vertical subsurface flow constructed wetland microbial fuel cell (CW-MFC), studies of bio-cathode materials and reactor configurations were carried out. Three commonly used bio-cathode materials including stainless steel mesh (SSM), carbon cloth (CC) and granular activated carbon (GAC) were compared and evaluated. GAC-SSM bio-cathode achieved the highest maximum power density of 55.05 mWm(-2), and it was most suitable for CW MFCs application because of its large surface area and helpful capillary water absorption. Two types of CW-MFCs with roots were constructed, one was placed in the anode and the other was placed in the cathode. Both planted CW-MFCs obtained higher power output than non-planted CW-MFC. Periodic voltage fluctuations of planted CW-MFCs were caused by light/dark cycles, and the influent substrate concentration significantly affected the amplitude of oscillation. The coulombic efficiencies of CW-MFCs decreased greatly with the increase of the influent substrate concentration. PMID- 24956030 TI - Robust enzymatic hydrolysis of Formiline-pretreated oil palm empty fruit bunches (EFB) for efficient conversion of polysaccharide to sugars and ethanol. AB - Oil palm empty fruit bunch (EFB) was pretreated by Formiline process to overcome biomass recalcitrance and obtain hemicellulosic syrup and lignin. Higher formic acid concentration led to more lignin removal but also higher degree of cellulose formylation. Cellulose digestibility could be well recovered after deformylation with a small amount of lime. After digested by enzyme loading of 15 FPU+10 CBU/g solid for 48 h, the polysaccharide conversion could be over 90%. Simultaneous saccharification and fermentation (SSF) results demonstrated that ethanol concentration reached 83.6 g/L with approximate 85% of theoretic yield when performed at an initial dry solid consistency of 20%. A mass balance showed that via Formiline pretreatment 0.166 kg of ethanol could be produced from 1 kg of dry EFB with co-production of 0.14 kg of high-purity lignin and 5.26 kg hemicellulosic syrup containing 2.8% xylose. Formiline pretreatment thus can be employed as an entry for biorefining of EFB. PMID- 24956031 TI - Molecular dynamics simulation of self-diffusion processes in titanium in bulk material, on grain junctions and on surface. AB - The process of self-diffusion of titanium atoms in a bulk material, on grain junctions and on surface is explored numerically in a broad temperature range by means of classical molecular dynamics simulation. The analysis is carried out for a nanoscale cylindrical sample consisting of three adjacent sectors and various junctions between nanocrystals. The calculated diffusion coefficient varies by several orders of magnitude for different regions of the sample. The calculated values of the bulk diffusion coefficient correspond reasonably well to the experimental data obtained for solid and molten states of titanium. Investigation of diffusion in the nanocrystalline titanium is of a significant importance because of its numerous technological applications. This paper aims to reduce the lack of data on diffusion in titanium and describe the processes occurring in bulk, at different interfaces and on surface of the crystalline titanium. PMID- 24956032 TI - Spatialising the contentious politics of ADHD: networks and scalar strategies in health social movement activism. AB - This paper explores the spatial dynamics of health social movement activism in the context of a specific condition, Attention Deficit Hyperactivity Disorder (ADHD). Deploying qualitative research conducted with Irish ADHD organisations, it examines how place and space affect activist networks and the dilemmas that emerge when local 'mobilisations' converge at national and transnational levels. ADHD activism in Ireland has been predominantly localist in orientation, but certain organisations have shifted their activism to the European scale as a means of gaining further political and epistemic recognition for the condition. The paper suggests that health social movement studies would benefit from an engagement with the geographies of inter-scalar relations in analysing organisations' action repertoires. PMID- 24956033 TI - Polarization dressed multi-order fluorescence of Pr3+:Y2SiO5. AB - We report polarization dressed second-, fourth- and sixth-order fluorescence processes in a Pr(3+):Y2SiO5 crystal. By changing the polarization states of dressing fields and generating fields, the fluorescence baselines, suppression and Autler-Townes splitting of emission peaks can be controlled. The polarization dependencies of fluorescence generated from two inequivalent crystallographic sites are compared. The experimental results agree with the dressing theoretical calculations well. PMID- 24956028 TI - The role of temporal structure in the investigation of sensory memory, auditory scene analysis, and speech perception: a healthy-aging perspective. AB - Listening situations with multiple talkers or background noise are common in everyday communication and are particularly demanding for older adults. Here we review current research on auditory perception in aging individuals in order to gain insights into the challenges of listening under noisy conditions. Informationally rich temporal structure in auditory signals--over a range of time scales from milliseconds to seconds--renders temporal processing central to perception in the auditory domain. We discuss the role of temporal structure in auditory processing, in particular from a perspective relevant for hearing in background noise, and focusing on sensory memory, auditory scene analysis, and speech perception. Interestingly, these auditory processes, usually studied in an independent manner, show considerable overlap of processing time scales, even though each has its own 'privileged' temporal regimes. By integrating perspectives on temporal structure processing in these three areas of investigation, we aim to highlight similarities typically not recognized. PMID- 24956035 TI - Corrugated epitaxial graphene/SiC interfaces: photon excitation and probing. AB - Localized energy exchange and mechanical coupling across a few nm gap at a corrugated graphene-substrate interface remain great challenges to study. In this work, an infrared laser is used to excite an unconstrained epitaxial graphene/SiC interface to induce a local thermal non-equilibrium. The interface behavior is uncovered using a second laser beam for Raman excitation. Using Raman peaks for dual thermal probing, the temperature difference across a gap of just a few nm is determined precisely. The interfacial thermal conductance is found to be extremely low: 410 +/- 7 W m(-2) K(-1), indicating poor phonon transport across the interface. By decoupling of the graphene's mechanical and thermal behavior from the Raman wavenumber, the stress in graphene is found to be extremely low, uncovering its flexible mechanical behavior. Based on interface-enhanced Raman, it is found that the increment of interface separation between graphene and SiC can be as large as 2.9 nm when the local thermal equilibrium is destroyed. PMID- 24956034 TI - Isthmin 1 is a secreted protein expressed in skin, mucosal tissues, and NK, NKT, and th17 cells. AB - Using a comprehensive microarray database of human gene expression, we identified that in mammals, a secreted protein known as isthmin 1 (ISM1) is expressed in skin, mucosal tissues, and selected lymphocyte populations. ISM1 was originally identified in Xenopus brain during development, and it encodes a predicted ~50 kDa protein containing a signal peptide, a thrombospondin domain, and an adhesion associated domain. We confirmed the pattern of expression of ISM1 in both human and mouse tissues. ISM1 is expressed by DX5(+) lung lymphocytes that include NK and NKT-like cells, and is also expressed by some CD4(+) T cells upon activation but its expression increases significantly when CD4(+) T cells were polarized to the Th17 lineage in vitro. The presence of IFN-gamma during CD4(+) T cell polarization inhibits ISM1 expression. Given that ISM1 has been reported to have anti-angiogenic properties, these observations suggest that ISM1 is a mediator of lymphocyte effector functions and may participate in both innate and acquired immune responses. PMID- 24956038 TI - Mother-to-child transmission of HBV: review of current clinical management and prevention strategies. AB - Mother-to-child transmission (MTCT) of HBV is responsible for approximately half of the HBV transmission routes and continues to be a challenging problem worldwide. Even after the development of effective vaccines and clear World Health Organization guidelines toward HBV several decades ago, 1-9% newborns of HBV-carrying mothers still acquire HBV in early life as a result of in utero infection. The prevention of MTCT is of high importance, because chronically infected individuals function as a reserve for sustained HBV transmission, and 25% of them can develop asymptomatic liver cirrhosis and hepatocellular carcinoma. In this article, we review the canonical and novel HBV infection routes/mechanisms, influencing factors, diagnostic criteria, and interruption strategies for HBV MTCT. The preventative strategy of HBV MTCT has evolved from routine postpartum HB immune globulin (HBIG) plus HB vaccine schedules to administration of HBIG or nucleoside analogs during pregnancy and minimizing the exposure of maternal body fluids to the newborn during delivery. PMID- 24956036 TI - Characterization of glyphosate resistance in Amaranthus tuberculatus populations. AB - The evolution of glyphosate-resistant weeds has recently increased dramatically. Six suspected glyphosate-resistant Amaranthus tuberculatus populations were studied to confirm resistance and determine the resistance mechanism. Resistance was confirmed in greenhouse for all six populations with glyphosate resistance factors (R/S) between 5.2 and 7.5. No difference in glyphosate absorption or translocation was observed between resistant and susceptible individuals. No mutation at amino acid positions G101, T102, or P106 was detected in the EPSPS gene coding sequence, the target enzyme of glyphosate. Analysis of EPSPS gene copy number revealed that all glyphosate-resistant populations possessed increased EPSPS gene copy number, and this correlated with increased expression at both RNA and protein levels. EPSPS Vmax and Kcat values were more than doubled in resistant plants, indicating higher levels of catalytically active expressed EPSPS protein. EPSPS gene amplification is the main mechanism contributing to glyphosate resistance in the A. tuberculatus populations analyzed. PMID- 24956037 TI - Dissection of a novel autocrine signaling pathway via quantitative secretome and interactome mapping. AB - Epidermal homeostasis is a balancing act governed by a multitude of underlying regulatory events, and several growth factors and signaling pathways have been implicated in regulation of the balance between proliferation and differentiation in keratinocytes. We show here that the signal transducer/transcription factor FIZ1 (Flt3 interacting zinc finger protein-1) is a previously unknown player in this regulatory axis, promoting an increase in proliferation of HaCaT human immortalized keratinocytes that is driven by more rapid G1/S progression and mediated by activation of the MAP/ERK kinase pathway. Utilizing quantitative SILAC-based secretome analysis, we identified the insulin growth factor binding protein IGFBP3 as the key mediating factor, demonstrating that elevated FIZ1 levels promote increased IGFBP3 expression and secretion and a concurrent increased sensitivity to IGF1 signaling, while antibody-based neutralization of IGFBP3 abrogates the FIZ1-induced growth advantage. To identify underlying protein-protein interactions likely to govern these events, we mapped the interactome of FIZ1 and found eight novel binding partners that form complexes with the protein in the cytoplasm and nucleus. These include signal transduction and transcription factors and the cell cycle regulatory NDR (Nuclear Dbf2 related) kinases. Our results provide further insight into the complex balance of epidermal homeostasis and identify FIZ1 as a novel therapeutic target. PMID- 24956041 TI - Changes in functional brain networks following sports-related concussion in adolescents. AB - Sports-related concussion is a major public health issue; however, little is known about the underlying changes in functional brain networks in adolescents following injury. Our aim was to use the tools from graph theory to evaluate the changes in brain network properties following concussion in adolescent athletes. We recorded resting state electroencephalography (EEG) in 33 healthy adolescent athletes and 9 adolescent athletes with a clinical diagnosis of subacute concussion. Graph theory analysis was applied to these data to evaluate changes in brain networks. Global and local metrics of the structural properties of the graph were calculated for each group and correlated with Immediate Post Concussion Assessment and Cognitive Testing (ImPACT) scores. Brain networks of both groups showed small-world topology with no statistically significant differences in the global metrics; however, significant differences were found in the local metrics. Specifically, in the concussed group, we noted: 1) increased values of betweenness and degree in frontal electrode sites corresponding to the (R) dorsolateral prefrontal cortex and the (R) inferior frontal gyrus and 2) decreased values of degree in the region corresponding to the (R) frontopolar prefrontal cortex. In addition, there was significant negative correlation between degree and hub value, with total symptom score at the electrode site corresponding to the (R) prefrontal cortex. This preliminary report in adolescent athletes shows for the first time that resting-state EEG combined with graph theoretical analysis may provide an objective method of evaluating changes in brain networks following concussion. This approach may be useful in identifying individuals at risk for future injury. PMID- 24956040 TI - Interaction of human plasma proteins with thin gelatin-based hydrogel films: a QCM-D and ToF-SIMS study. AB - In the fields of surgery and regenerative medicine, it is crucial to understand the interactions of proteins with the biomaterials used as implants. Protein adsorption directly influences cell-material interactions in vivo and, as a result, regulates, for example, cell adhesion on the surface of the implant. Therefore, the development of suitable analytical techniques together with well defined model systems allowing for the detection, characterization, and quantification of protein adsorbates is essential. In this study, a protocol for the deposition of highly stable, thin gelatin-based films on various substrates has been developed. The hydrogel films were characterized morphologically and chemically. Due to the obtained low thickness of the hydrogel layer, this setup allowed for a quantitative study on the interaction of human proteins (albumin and fibrinogen) with the hydrogel by Quartz Crystal Microbalance with Dissipation Monitoring (QCM-D). This technique enables the determination of adsorbant mass and changes in the shear modulus of the hydrogel layer upon adsorption of human proteins. Furthermore, Secondary Ion Mass Spectrometry and principal component analysis was applied to monitor the changed composition of the topmost adsorbate layer. This approach opens interesting perspectives for a sensitive screening of viscoelastic biomaterials that could be used for regenerative medicine. PMID- 24956043 TI - Science to practice: Cellular therapy of Parkinson disease--a new radiotracer to target transplanted dopaminergic cells with PET. AB - The article by Bu and colleagues (1) introduces N-[2-(diethylamino)ethyl]-(18)F-5 fluoropicolinamide ((18)F-P3BZA) as a promising positron emission tomography (PET) radiotracer to target transplanted porcine retinal pigment epithelial (pRPE) cells in the striatum. This strategy to monitor cellular therapy of Parkinson disease has a high translational potential and in the future may help us to better understand some of the controversial results reported in clinical trials. PMID- 24956044 TI - The radiologist as interpreter and translator. PMID- 24956045 TI - Engaging our patients: shared decision making and interventional radiology. PMID- 24956042 TI - Efficacy and safety of extended-release quetiapine fumarate in youth with bipolar depression: an 8 week, double-blind, placebo-controlled trial. AB - OBJECTIVE: Quetiapine is an atypical antipsychotic with demonstrated efficacy in the treatment of adolescent schizophrenia and pediatric bipolar mania. Large, placebo-controlled studies of interventions in pediatric bipolar depression are lacking. The current study investigated the efficacy and safety of quetiapine extended-release (XR) in patients 10-17 years of age, with acute bipolar depression. METHODS: This multicenter, double-blind, randomized, placebo controlled study investigated quetiapine XR (dose range, 150-300 mg/day) in pediatric outpatients with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnosis of bipolar I or bipolar II disorder (current or most recent episode depressed) treated for up to 8 weeks (ClinicalTrials.gov identifier: NCT00811473). The primary study outcome was mean change in Children's Depression Rating Scale-Revised (CDRS-R) total score. Secondary efficacy outcomes included CDRS-R-based response and remission rates. RESULTS: Of 193 patients randomized to treatment, 144 patients completed the study (75.3% of quetiapine XR group [n=70]; 74.0% of placebo group [n=74]). Least squares mean changes in CDRS-R total score at week 8 were: -29.6 (SE, 1.65) with quetiapine XR and -27.3 (SE, 1.60) with placebo, a between-treatment group difference of -2.29 (SE, 1.99; 95% CI, -6.22, 1.65; p=0.25; mixed-model for repeated measures analysis). Rates of response and remission did not differ significantly between treatment groups. The safety profile of quetiapine XR was broadly consistent with the profile reported previously in adult studies of quetiapine XR and pediatric studies of quetiapine immediate-release (IR). Potentially clinically significant elevations in clinical chemistry values included triglycerides (9.3%, quetiapine XR; 1.4%, placebo group) and thyroid stimulating hormone (4.7%, quetiapine XR; 0%, placebo group). An adverse event potentially related to diabetes mellitus occurred in 3.3% of the quetiapine XR versus no adverse events in the placebo group. CONCLUSIONS: Quetiapine XR did not demonstrate efficacy relative to placebo in this 8 week study of pediatric bipolar depression. Quetiapine XR was generally safe and well tolerated. PMID- 24956046 TI - Technologist-performed handheld screening breast US imaging: how is it performed and what are the outcomes to date? AB - Breast density-inform legislation is increasing the need for data on outcomes of tailored screening. Dense parenchyma can mask cancers, and denser tissue is also more likely to develop breast cancer than fatty tissue. Digital mammography is standard for women with dense breasts. Supplemental screening magnetic resonance imaging should be offered to women who meet high-risk criteria. Supplemental screening ultrasonographic (US) imaging may be appropriate in the much larger group of women with dense breasts. Both physician- and technologist-performed screening US imaging increases detection of node-negative invasive breast cancer. To meet anticipated demand in the United States, screening US images will most likely be acquired by trained technologists rather than physicians. While automated US offers standard documentation, there are few data on outcomes. US has been used diagnostically for decades to characterize masses seen by using mammography, but training specific to screening has been lacking. Standard approaches to training and documentation of technologist-performed handheld screening US imaging are needed. This article reviews the current status of technologist-performed handheld screening breast US imaging. PMID- 24956047 TI - Resting-state functional MR imaging: a new window to the brain. AB - Resting-state (RS) functional magnetic resonance (MR) imaging constitutes a novel paradigm that examines spontaneous brain function by using blood oxygen level dependent contrast in the absence of a task. Spatially distributed networks of temporal synchronization can be detected that can characterize RS networks (RSNs). With a short acquisition time of less than 10 minutes, RS functional MR imaging can be applied in special populations such as children and patients with dementia. Some RSNs are already present in utero, while others mature in childhood. Around 10 major RSNs are consistently found in adults, but their exact spatial extent and strength of coherence are affected by physiologic parameters and drugs. Though the acquisition and analysis methods are still evolving, new disease insights are emerging in a variety of neurologic and psychiatric disorders. The default mode network is affected in Alzheimer disease and various other diseases of cognitive impairment. Alterations in RSNs have been identified in many diseases, in the absence of evident structural modifications, indicating a high sensitivity of the method. Moreover, there is evidence of correlation between RSN alterations and disease progression and severity. However, different diseases often affect the same RSN, illustrating the limited specificity of the findings. This suggests that neurologic and psychiatric diseases are characterized by altered interactions between RSNs and therefore the whole brain should be examined as an integral network (with subnetworks), for example, using graph analysis. A challenge for clinical applications of RS functional MR imaging is the potentially confounding effect of aging, concomitant vascular diseases, or medication on the neurovascular coupling and consequently the functional MR imaging response. Current investigation combines RS functional MR imaging and other methods such as electroencephalography or magnetoencephalography to better understand the vascular and neuronal contributions to alterations in functional connectivity. PMID- 24956051 TI - Case 207: Hodgkin lymphoma with paraneoplastic hypercalcemic pancreatitis. AB - A 15-year-old girl presented with a 2-month history of 30-lb (13.6 kg) weight loss, chest and abdominal pain, nausea, bilious emesis, cough, and shortness of breath. Initial blood count (performed at an outside hospital) showed elevated white blood cell and platelet counts but low hemoglobin and hematocrit levels. On examination, she had adenopathy in the left axillary and supraclavicular regions, fullness in the left chest, and abdominal guarding. Ultrasonography (US)-guided fine-needle aspiration biopsy of the left anterior chest wall mass was nondiagnostic, and lumbar puncture and bone marrow biopsies were negative. At that time, the patient underwent several imaging studies-including chest radiography; bone scanning; contrast material-enhanced computed tomography (CT) of the chest, abdomen, and pelvis; and fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT-all performed within 1 week of each other. Pertinent serum laboratory values at the time of these tests were as follows: calcium level, 17 mg/dL (4.25 mmol/L) (normal range, 8.5-10.5 mg/dL [2.1 2.6 mmol/L]); ionized calcium level, 2.3 mmol/L (normal range, 1.1-1.3 mmol/L); lipase level, 2423 U/L (normal level, <300 U/L); amylase level, 1435 U/L (normal level, <140 U/L); lactate dehydrogenase level, 253 U/L (normal level, <240 U/L), albumin level, 2.6 g/dL (26 g/L) (normal level, 3.5-5.0 g/dL [35-50 g/L]), and creatinine level, 1.7 mg/dL (150.3 MUmol/L) (normal level, <1.2 mg/dL [<106.1 MUmol/L]). A follow-up PET/CT scan was performed approximately 2 months later after initial therapy. PMID- 24956052 TI - Diversity in diagnostic radiology. PMID- 24956053 TI - Many methods of mediastinal division. PMID- 24956054 TI - Association of study quality with completeness of reporting. PMID- 24956056 TI - Eric Nightingale Campbell Milne, MB, ChB, FFR, DMRD, FRCR. PMID- 24956057 TI - Kanji Torizuka, MD, PhD. PMID- 24956060 TI - Effect of Electrical Conductivity Through the Bulk Doping of the Product of Titanocene Dichloride and 2-Nitro-1,4-phenylenediamine. AB - The condensation polymer derived from reaction between titanocene dichloride and 2-nitro-1,4-phenylenediamine was doped by mixing the polymer with different amounts of iodine. This bulk doping of the titanocene polyamine resulted in an increase in bulk conductivity from 10 to over 1,000 fold. Conductivity increased to a doping level of about 10 to 15% iodine. Conductivity decreased as the sample discs were heated returning to pre-doped levels after the samples were heated for eight minutes. It is believed that this decrease in conductivity is due to the surface evaporation of iodine as the samples were heated. MALDI MS and IR results are consistent with the formation of C-I compounds for doped materials. PMID- 24956059 TI - Poly(2-hydroxyethyl methacrylate)-quercetin Conjugate as Biomaterial in Ophthalmology: An "ab initio" Study. AB - A novel polymeric material with antioxidant properties and suitable for ophthalmic application was synthesized by free radical grafting reaction between 2-hydroxyethyl methacrylate and quercetin. The presence of quercetin in the polymeric chain was confirmed by FT-IR and UV-Vis analyses, while an estimation of the amount of quercetin bound per gram of polymer was obtained by the Folin Ciocalteu assay. The conjugate shows high biocompatibility (HET-CAM assay) and antioxidant and anti-inflammatory properties which were extensively investigated by specific in vitro tests. PMID- 24956061 TI - DNA adsorption by magnetic iron oxide nanoparticles and its application for arsenate detection. AB - Iron oxide nanoparticles adsorb fluorescently labeled DNA oligonucleotides via the backbone phosphate and quench fluorescence. Arsenate displaces adsorbed DNA to increase fluorescence, allowing detection of arsenate down to 300 nM. This is a new way of using DNA: analyte recognition relies on its phosphate instead of the bases. PMID- 24956062 TI - Cell communication using intrinsically disordered proteins: what can syndecans say? AB - Because intrinsically disordered proteins are incapable of forming unique tertiary structures in isolation, their interaction with partner structures enables them to play important roles in many different biological functions. Therefore, such proteins are usually multifunctional, and their ability to perform their major function, as well as accessory functions, depends on the characteristics of a given interaction. The present paper demonstrates, using predictions from two programs, that the transmembrane proteoglycans syndecans are natively disordered because of their diverse functions and large number of interaction partners. Syndecans perform multiple functions during development, damage repair, tumor growth, angiogenesis, and neurogenesis. By mediating the binding of a large number of extracellular ligands to their receptors, these proteoglycans trigger a cascade of reactions that subsequently regulate various cell processes: cytoskeleton formation, proliferation, differentiation, adhesion, and migration. The occurrences of 20 amino acids in syndecans 1-4 from 25 animals were compared with those in 17 animal proteomes. Gly + Ala, Thr, Glu, and Pro were observed to predominate in the syndecans, contributing to the lack of an ordered structure. In contrast, there were many fewer amino acids in syndecans that promote an ordered structure, such as Cys, Trp, Asn, and His. In addition, a region rich in Asp has been identified between two heparan sulfate-binding sites in the ectodomains, and a region rich in Lys has been identified in the conserved C1 site of the cytoplasmic domain. These particular regions play an essential role in the various functions of syndecans due to their lack of structure. PMID- 24956063 TI - Fluorescent nanohybrids based on quantum dot-chitosan-antibody as potential cancer biomarkers. AB - Despite undeniable advances in medicine in recent decades, cancer is still one of the main challenges faced by scientists and professionals in the health sciences as it remains one of the world's most devastating diseases with millions of fatalities and new cases every year. Thus, in this work, we endeavored to synthesize and characterize novel multifunctional immunoconjugates composed of quantum dots (QDs) as the fluorescent inorganic core and antibody-modified polysaccharide as the organic shell, focusing on their potential applications for in vitro diagnosis of non-Hodgkin lymphoma (NHL) cancer tumors. Chitosan was covalently conjugated with anti-CD20 polyclonal antibody (pAbCD20) via formation of amide bonds between amines and carboxyl groups. In the sequence, these biopolymer-antibody immunoconjugates were utilized as direct capping ligands for biofunctionalization of CdS QDs (CdS/chitosan-pAbCD20) using a single-step process in aqueous medium at room temperature. The nanostructures were characterized by UV-vis spectroscopy, photoluminescence spectroscopy (PL), FTIR, and transmission electron microscopy (TEM) with selected area electron diffraction. The TEM images associated with the UV-vis optical absorption results indicated formation of ultrasmall nanocrystals with average diameters in the range of 2.5-3.0 nm. Also, the PL results demonstrated that the immunoconjugates exhibited "green" fluorescent activity under ultraviolet excitation. Moreover, using in vitro laser light scattering immunoassay (LIA), the QDs/immunoconjugates have shown binding affinity against antigen CD20 (aCD20) expressed by lymphocyte B cancer cells. In summary, innovative fluorescent nanoimmunoconjugate templates were developed with promising perspectives to be used in the future for detection and imaging of cancer tumors. PMID- 24956064 TI - A qualitative study of shopper experiences at an urban farmers' market using the Stanford Healthy Neighborhood Discovery Tool. AB - OBJECTIVE: To understand factors which enhance or detract from farmers' market shopper experiences to inform targeted interventions to increase farmers' market utilization, community-building and social marketing strategies. DESIGN: A consumer-intercept study using the Stanford Healthy Neighborhood Discovery Tool to capture real-time perceptions via photographs and audio narratives. SETTING: An urban farmers' market in a large metropolitan US city. PARTICIPANTS: Thirty eight farmers' market shoppers, who recorded 748 unique coded elements through community-based participatory research methods. RESULTS: Shoppers were primarily women (65 %), 18-35 years of age (54 %), non-Hispanic (81 %) and white (73 %). Shoppers captured 291 photographs (7.9 (sd 6.3) per shopper), 171 audio narratives (5.3 (sd 4.7) per shopper), and ninety-one linked photograph + audio narrative pairs (3.8 (sd 2.8) per shopper). A systematic content analysis of the photographs and audio narratives was conducted by eight independent coders. In total, nine common elements emerged from the data that enhanced the farmers' market experience (61.8 %), detracted from the experience (5.7 %) or were neutral (32.4 %). The most frequently noted elements were freshness/abundance of produce (23.3 %), product presentation (12.8 %), social interactions (12.4 %) and farmers' market attractions (e.g. live entertainment, dining offerings; 10.3 %). CONCLUSIONS: While produce quality (i.e. freshness/abundance) was of primary importance, other contextual factors also appeared important to the shoppers' experiences. These results may inform social marketing strategies to increase farmers' market utilization and community-building efforts that target market venues. PMID- 24956067 TI - ERP evidence of adaptive changes in error processing and attentional control during rhythm synchronization learning. AB - The ability to detect and use information from errors is essential during the acquisition of new skills. There is now a wealth of evidence about the brain mechanisms involved in error processing. However, the extent to which those mechanisms are engaged during the acquisition of new motor skills remains elusive. Here we examined rhythm synchronization learning across 12 blocks of practice in musically naive individuals and tracked changes in ERP signals associated with error-monitoring and error-awareness across distinct learning stages. Synchronization performance improved with practice, and performance improvements were accompanied by dynamic changes in ERP components related to error-monitoring and error-awareness. Early in learning, when performance was poor and the internal representations of the rhythms were weaker we observed a larger error-related negativity (ERN) following errors compared to later learning. The larger ERN during early learning likely results from greater conflict between competing motor responses, leading to greater engagement of medial-frontal conflict monitoring processes and attentional control. Later in learning, when performance had improved, we observed a smaller ERN accompanied by an enhancement of a centroparietal positive component resembling the P3. This centroparietal positive component was predictive of participant's performance accuracy, suggesting a relation between error saliency, error awareness and the consolidation of internal templates of the practiced rhythms. Moreover, we showed that during rhythm learning errors led to larger auditory evoked responses related to attention orientation which were triggered automatically and which were independent of the learning stage. The present study provides crucial new information about how the electrophysiological signatures related to error monitoring and error-awareness change during the acquisition of new skills, extending previous work on error processing and cognitive control mechanisms to a more ecologically valid context. PMID- 24956066 TI - Mindfulness training modulates value signals in ventromedial prefrontal cortex through input from insular cortex. AB - Neuroimaging research has demonstrated that ventromedial prefrontal cortex (vmPFC) encodes value signals that can be modulated by top-down cognitive input such as semantic knowledge, price incentives, and monetary favors suggesting that such biases may have an identified biological basis. It has been hypothesized that mindfulness training (MT) provides one path for gaining control over such top-down influences; yet, there have been no direct tests of this hypothesis. Here, we probe the behavioral and neural effects of MT on value signals in vmPFC in a randomized longitudinal design of 8 weeks of MT on an initially naive subject cohort. The impact of this within-subject training was assessed using two paradigms: one that employed primary rewards (fruit juice) in a simple conditioning task and another that used a well-validated art-viewing paradigm to test bias of monetary favors on preference. We show that MT behaviorally censors the top-down bias of monetary favors through a measurable influence on value signals in vmPFC. MT also modulates value signals in vmPFC to primary reward delivery. Using a separate cohort of subjects we show that 8 weeks of active control training (ACT) generates the same behavioral impact also through an effect on signals in the vmPFC. Importantly, functional connectivity analyses show that value signals in vmPFC are coupled with bilateral posterior insula in the MT groups in both paradigms, but not in the ACT groups. These results suggest that MT integrates interoceptive input from insular cortex in the context of value computations of both primary and secondary rewards. PMID- 24956069 TI - Epithelial cell foot process effacement in podocytes in focal and segmental glomerulosclerosis: a quantitative analysis. AB - BACKGROUND/AIM: Effacement of the epithelial cell foot processes of glomerular podocytes are thought to be diffuse in the primary form of focal and segmental glomerulosclerosis (FSGS). In contrast, effacements that occur in the secondary form of FSGS are thought to be focal. To evaluate this theory, the extent of epithelial cell foot process effacement was analyzed and compared in podocytes from cases of primary and secondary FSGS. METHODS: Consecutive cases of adult primary and secondary FSGS that were diagnosed between January 1997 and December 2010 were retrospectively retrieved and analyzed. The electron microscopy materials of all specimens were reviewed. Glomerular podocytes from each sample were counted, recorded and analyzed for the percentage of diffuse versus focal epithelial foot process effacement. RESULTS: Seventeen primary and 16 secondary FSGS specimens were reviewed. In the 17 primary FSGS cases, 35.1% of the podocytes were focally fused, and 64.9% were diffusely fused. In the 16 secondary FSGS cases, 72.1% of the podocytes were focally fused. There were significantly more focally fused podocytes in secondary FSGS than in primary FSGS. In contrast, significantly more diffusely fused podocytes were observed in primary FSGS than in secondary FSGS. CONCLUSION: This is the first study to perform a quantitative analysis of the extent of epithelial cell foot process effacement in podocytes in primary and secondary FSGS. This study also confirms that the electron microscopic characteristics of the podocyte effacement process can be used to facilitate the diagnosis of primary versus secondary FSGS. PMID- 24956065 TI - Mapping track density changes in nigrostriatal and extranigral pathways in Parkinson's disease. AB - In Parkinson's disease (PD) the demonstration of neuropathological disturbances in nigrostriatal and extranigral brain pathways using magnetic resonance imaging remains a challenge. Here, we applied a novel diffusion-weighted imaging approach track density imaging (TDI). Twenty-seven non-demented Parkinson's patients (mean disease duration: 5 years, mean score on the Hoehn & Yahr scale=1.5) were compared with 26 elderly controls matched for age, sex, and education level. Track density images were created by sampling each subject's spatially normalized fiber tracks in 1mm isotropic intervals and counting the fibers that passed through each voxel. Whole-brain voxel-based analysis was performed and significance was assessed with permutation testing. Statistically significant increases in track density were found in the Parkinson's patients, relative to controls. Clusters were distributed in disease-relevant areas including motor, cognitive, and limbic networks. From the lower medulla to the diencephalon and striatum, clusters encompassed the known location of the locus coeruleus and pedunculopontine nucleus in the pons, and from the substantia nigra up to medial aspects of the posterior putamen, bilaterally. The results identified in brainstem and nigrostriatal pathways show a large overlap with the known distribution of neuropathological changes in non-demented PD patients. Our results also support an early involvement of limbic and cognitive networks in Parkinson's disease. PMID- 24956068 TI - Exploring sex and gender differences in sleep health: a Society for Women's Health Research Report. AB - Previous attempts have been made to address sleep disorders in women; however, significant knowledge gaps in research and a lack of awareness among the research community continue to exist. There is a great need for scientists and clinicians to consider sex and gender differences in their sleep research to account for the unique biology of women. To understand the role of sex differences in sleep and the state of women's sleep health research, the Society for Women's Health Research convened an interdisciplinary expert panel of well-established sleep researchers and clinicians for a roundtable meeting. Focused discussions on basic and clinical research along with a focus on specific challenges facing women with sleep-related problems and effective therapies led to the identification of knowledge gaps and the development of research-related recommendations. Additionally, sex differences in sleep disorders were noted and discussed in the context of underlying hormonal differences. Differences in sleep behavior and sleep disorders may not only be driven by biological factors but also by gender differences in the way women and men report symptoms. Progress has been made in identifying sex and gender differences in many areas of sleep, but major research gaps in the areas of epidemiology, sleep regulation, sleep quality, diagnosis, and treatment need to be addressed. Identifying the underlying nature of sex and gender differences in sleep research has potential to accelerate improved care for both men and women facilitating better diagnosis, treatment, and ultimately prevention of sleep disorders and related comorbid conditions. PMID- 24956070 TI - Glucose variability indices in type 1 diabetes: parsimonious set of indices revealed by sparse principal component analysis. AB - BACKGROUND: Continuous glucose monitoring (CGM) time-series are often analyzed, retrospectively, to investigate glucose variability (GV), a risk factor for the development of complications in type 1 diabetes (T1D). In the literature, several tens of different indices for GV quantification have been proposed, but many of them carry very similar information. The aim of this article is to select a relatively small subset of GV indices from a wider pool of metrics, to obtain a parsimonious but still comprehensive description of GV in T1D datasets. MATERIALS AND METHODS: A pool of 25 GV indices was evaluated on two CGM time-series datasets of 17 and 16 T1D subjects, respectively, collected during the European Union Seventh Framework Programme project "Diadvisor" (2008-2012) in two different clinical research centers using the Dexcom((r)) (San Diego, CA) SEVEN((r)) Plus. After the indices were centered and scaled, the Sparse Principal Component Analysis (SPCA) technique was used to determine a reduced set of metrics that allows preserving a high percentage of the variance of the whole original set. In order to assess whether or not the selected subset of GV indices is dataset-dependent, the analysis was applied to both datasets, as well as to the one obtained by merging them. RESULTS: SPCA revealed that a subset of up to 10 different GV indices can be sufficient to preserve more than the 60% of the variance originally explained by all the 25 variables. It is remarkable that four of these GV indices (i.e., Index of Glycemic Control, percentage of Glycemic Risk Assessment Diabetes Equation score due to euglycemia, percentage Coefficient of Variation, and Low Blood Glucose Index) were selected for all the considered T1D datasets. CONCLUSIONS: The SPCA methodology appears a suitable candidate to identify, among the large number of literature GV indices, subsets that allow obtaining a parsimonious, but still comprehensive, description of GV. PMID- 24956071 TI - From meiogynin A to the synthesis of dual inhibitors of Bcl-xL and Mcl-1 anti apoptotic proteins. AB - The synthesis of one of the most potent dual inhibitors of the anti-apoptotic proteins Bcl-xL and Mcl-1 is reported. This analogue of a natural sesquiterpenoid dimer meiogynin A was elaborated by a convergent asymmetric synthesis with 36% yield in ten steps. PMID- 24956072 TI - Smart morphable surfaces for aerodynamic drag control. AB - Smart Morphable Surfaces enable switchable and tunable aerodynamic drag reduction of bluff bodies. Their topography, resembling the morphology of golf balls, can be custom-generated through a wrinkling instability on a curved surface. Pneumatic actuation of these patterns results in the control of the drag coefficient of spherical samples by up to a factor of two, over a range of flow conditions. PMID- 24956073 TI - Use of St. John's Wort in potentially dangerous combinations. AB - OBJECTIVES: The objective of this study was to assess how often St. John's wort (SJW) is prescribed with medications that may interact dangerously with it. DESIGN: The study design was a retrospective analysis of nationally representative data from the National Ambulatory Medical Care Survey. SETTINGS: The study setting was U.S. nonfederal outpatient physician offices. SUBJECTS: Those prescribed SJW between 1993 and 2010 were the subjects. OUTCOME MEASURES: The outcome measures were medications co-prescribed with SJW. RESULTS: Twenty eight percent (28%) of SJW visits involved a drug that has potentially dangerous interaction with SJW. These included selective serotonin reuptake inhibitors, benzodiazepines, warfarin, statins, verapamil, digoxin, and oral contraceptives. CONCLUSIONS: SJW is frequently used in potentially dangerous combinations. Physicians should be aware of these common interactions and warn patients appropriately. PMID- 24956075 TI - Eco-directed sustainable prescribing: feasibility for reducing water contamination by drugs. AB - Active pharmaceutical ingredients (APIs) from the purchase and use of medications are recognized as ubiquitous contaminants of the environment. Ecological impacts can range from subtle to overt--resulting from multi-generational chronic exposure to trace levels of multiple APIs (such as in the aquatic environment) or acute exposure to higher levels (such as with wildlife ingestion of improperly discarded waste). Reducing API entry to the environment has relied solely on conventional end-of-pipe pollution control measures such as wastewater treatment and take-back collections of leftover, unwanted drugs (to prevent disposal by flushing to sewers). An exclusive focus on these conventional approaches has ignored the root sources of the problem and may have served to retard progress in minimizing the environmental footprint of the healthcare industry. Potentially more effective and less-costly upstream pollution prevention approaches have long been considered imprudent, as they usually involve the modification of long established norms in the practice of clinical prescribing. The first pollution prevention measure to be proposed as feasible (reducing the dose or usage of certain select medications) is followed here by an examination of another possible approach--one that would rely on the excretion profiles of APIs. These two approaches combined could be termed eco-directed sustainable prescribing (EDSP) and may hold the potential for achieving the largest reductions in API entry to the environment--largely by guiding prescribers' decisions regarding drug selection. EDSP could reduce API entry to the environment by minimizing the need for disposal (as a consequence of avoiding leftover, unwanted medications) and reducing the excretion of unmetabolized APIs (by preferentially prescribing APIs that are more extensively metabolized). The potential utility of the Biopharmaceutics Drug Disposition Classification System (BDDCS) is examined for the first time as a guide for API prescribing decisions by revealing relative API quantities entering sewage via excretion. PMID- 24956074 TI - Impact of nitrogen sources on gene expression and toxin production in the diazotroph Cylindrospermopsis raciborskii CS-505 and non-diazotroph Raphidiopsis brookii D9. AB - Different environmental nitrogen sources play selective roles in the development of cyanobacterial blooms and noxious effects are often exacerbated when toxic cyanobacteria are dominant. Cylindrospermopsis raciborskii CS-505 (heterocystous, nitrogen fixing) and Raphidiopsis brookii D9 (non-N2 fixing) produce the nitrogenous toxins cylindrospermopsin (CYN) and paralytic shellfish toxins (PSTs), respectively. These toxin groups are biosynthesized constitutively by two independent putative gene clusters, whose flanking genes are target for nitrogen (N) regulation. It is not yet known how or if toxin biosynthetic genes are regulated, particularly by N-source dependency. Here we show that binding boxes for NtcA, the master regulator of N metabolism, are located within both gene clusters as potential regulators of toxin biosynthesis. Quantification of intra- and extracellular toxin content in cultures at early stages of growth under nitrate, ammonium, urea and N-free media showed that N-sources influence neither CYN nor PST production. However, CYN and PST profiles were altered under N-free medium resulting in a decrease in the predicted precursor toxins (doCYN and STX, respectively). Reduced STX amounts were also observed under growth in ammonium. Quantification of toxin biosynthesis and transport gene transcripts revealed a constitutive transcription under all tested N-sources. Our data support the hypothesis that PSTs and CYN are constitutive metabolites whose biosynthesis is correlated to cyanobacterial growth rather than directly to specific environmental conditions. Overall, the constant biosynthesis of toxins and expression of the putative toxin-biosynthesis genes supports the usage of qPCR probes in water quality monitoring of toxic cyanobacteria. PMID- 24956076 TI - Assessment of spatial variation in drinking water iodine and its implications for dietary intake: a new conceptual model for Denmark. AB - Iodine is essential for human health. Many countries have therefore introduced universal salt iodising (USI) programmes to ensure adequate intake for the populations. However, little attention has been paid to subnational differences in iodine intake from drinking water caused by naturally occurring spatial variations. To address this issue, we here present the results of a Danish nationwide study of spatial trends of iodine in drinking water and the relevance of these trends for human dietary iodine intake. The data consist of treated drinking water samples from 144 waterworks, representing approx. 45% of the groundwater abstraction for drinking water supply in Denmark. The samples were analysed for iodide, iodate, total iodine (TI) and other major and trace elements. The spatial patterns were investigated with Local Moran's I. TI ranges from <0.2 to 126 MUg L(-1) (mean 14.4 MUg L(-1), median 11.9 MUg L(-1)). Six speciation combinations were found. Half of the samples (n = 71) contain organic iodine; all species were detected in approx. 27% of all samples. The complex spatial variation is attributed both to the geology and the groundwater treatment. TI >40 MUg L(-1) originates from postglacial marine and glacial meltwater sand and from Campanian-Maastrichtian chalk aquifers. The estimated drinking water contribution to human intake varies from 0% to >100% of the WHO recommended daily iodine intake for adults and from 0% to approx. 50% for adolescents. The paper presents a new conceptual model based on the observed clustering of high or low drinking-water iodine concentrations, delimiting zones with potentially deficient, excessive or optimal iodine status. Our findings suggest that the present coarse-scale nationwide programme for monitoring the population's iodine status may not offer a sufficiently accurate picture. Local variations in drinking-water iodine should be mapped and incorporated into future adjustment of the monitoring and/or the USI programmes. PMID- 24956077 TI - Growth of soil bacteria, on penicillin and neomycin, not previously exposed to these antibiotics. AB - There is growing evidence that bacteria, in the natural environment (e.g. the soil), can exhibit naturally occurring resistance/degradation against synthetic antibiotics. Our aim was to assess whether soils, not previously exposed to synthetic antibiotics, contained bacterial strains that were not only antibiotic resistant, but could actually utilize the antibiotics for energy and nutrients. We isolated 19 bacteria from four diverse soils that had the capability of growing on penicillin and neomycin as sole carbon sources up to concentrations of 1000 mg L(-1). The 19 bacterial isolates represent a diverse set of species in the phyla Proteobacteria (84%) and Bacteroidetes (16%). Nine antibiotic resistant genes were detected in the four soils but some of these genes (i.e. tetM, ermB, and sulI) were not detected in the soil isolates indicating the presence of unculturable antibiotic resistant bacteria. Most isolates that could subsist on penicillin or neomycin as sole carbon sources were also resistant to the presence of these two antibiotics and six other antibiotics at concentrations of either 20 or 1000 mg L(-1). The potentially large and diverse pool of antibiotic resistant and degradation genes implies ecological and health impacts yet to be explored and fully understood. PMID- 24956079 TI - Quantification of phylloquinone and menaquinones in feces, serum, and food by high-performance liquid chromatography-mass spectrometry. AB - Vitamin K, comprising phylloquinone (PK) and menaquinones (MKn), is a family of vitamers found in multiple biological and environmental matrices. Advancing emerging evidence for novel and distinct physiologic roles of these vitamers in human health and disease necessitates sensitive and selective methods for quantifying PK and MKn in these matrices. We developed a novel method employing high-performance liquid chromatography-mass spectrometry with atmospheric pressure chemical ionization (LC-APCI-MS) for simultaneous quantification of 11 vitamin K vitamers that can be applied in feces, serum and food. Minimal detectable concentrations of vitamin K vitamers ranged from 1 pmol/g to 30 pmol/g. Limits of quantification ranged from 5 pmol/g to 90 pmol/g. Inter-assay and intra-assay variations were <17% and <8%, respectively, in food, and <12% and <8%, respectively, in feces. Recovery exceeded 80% for all vitamers in both food and feces. The method successfully quantified PK and MKn concentrations in rat chow, feces and serum. In summary, this LC-APCI-MS method provides a sensitive and selective tool for quantifying vitamin K vitamers in feces, serum and food. This method can be applied in human and animal studies examining the role of vitamin K vitamers derived from the diet and gut bacteria synthesis in health and disease. PMID- 24956078 TI - Spatial distributions of and diurnal variations in low molecular weight carbonyl compounds in coastal seawater, and the controlling factors. AB - We studied the spatial distributions of and the diurnal variations in four low molecular weight (LMW) carbonyl compounds, formaldehyde, acetaldehyde, propionaldehyde, and glyoxal, in coastal seawater. The samples were taken from the coastal areas of Hiroshima Bay, the Iyo Nada, and the Bungo Channel, western Japan. The formaldehyde, acetaldehyde, and glyoxal concentrations were higher in the northern part of Hiroshima Bay than at offshore sampling points in the Iyo Nada and the Bungo Channel. These three compounds were found at much higher concentrations in the surface water than in deeper water layers in Hiroshima Bay. It is noteworthy that propionaldehyde was not detected in any of the seawater samples, the concentrations present being lower than the detection limit (1 nanomole per liter (nM)) of the high performance liquid chromatography (HPLC) system we used. Photochemical and biological experiments were performed in the laboratory to help understand the characteristic distributions and fates of the LMW carbonyl compounds. The primary process controlling their fate in the coastal environment appears to be their biological consumption. The direct photo degradation of propionaldehyde, initiated by ultraviolet (UV) absorption, was observed, although formaldehyde and acetaldehyde were not degraded by UV irradiation. Our results suggest that the degradation of the LMW carbonyl compounds by photochemically formed hydroxyl radicals is relatively insignificant in the study area. Atmospheric deposition is a possible source of soluble carbonyl compounds in coastal surface seawater, but it may not influence the carbonyl concentrations in offshore waters. PMID- 24956080 TI - Fast on-site diagnosis of influenza A virus by Palm PCR and portable capillary electrophoresis. AB - A method combining Palm polymerase chain reaction (PCR) and portable capillary electrophoresis (CE) was developed for rapid on-site analysis of influenza A (H1N1) virus. The portable CE system was suitable for rapid diagnosis which was able to detect a sample in ~4 min after sample loading, while the 'Palm PCR' system allowed for high-speed nucleic acid amplification in ~16 min. The analysis time from DNA sample to analysis of amplified target DNA molecule was only ~20 min, which was significantly less than slab gel electrophoresis with other commercially available PCR machine. When the 100-bp DNA ladder was separated, the relative standard deviation values (n=5) for the migration times and peak areas of the 100 and 200-bp DNA molecules were 0.26 and 8.9%. The detection limits were 6.3 and 7.2 pg/MUL, respectively. The combined method was also able to identify two influenza A-associated genes (the HA and NP genes of the novel H1N1 influenza). CE separation was achieved with a sieving matrix of 1% poly(vinylpyrrolidone) (Mr=1,300,000) in 1* TBE buffer (pH 8.45). The combined Palm PCR-portable CE system should provide an improved, fast on-site molecular genetic diagnostic method. PMID- 24956081 TI - Reply: To PMID 24440221. PMID- 24956082 TI - High cAMP attenuation of insulin-stimulated meiotic G2-M1 transition in zebrafish oocytes: interaction between the cAMP-dependent protein kinase (PKA) and the MAPK3/1 pathways. AB - High intra-cellular cyclic nucleotide (cAMP) ensures prophase-I arrest and prevent steroid-induced meiotic G2-M1 transition in full-grown oocytes; however, relatively less information is available for cAMP regulation of growth factor stimulated signalling events in the oocyte model. Here using zebrafish oocytes, we show that priming with dibutyryl cAMP (dbcAMP) or cAMP modulators, e.g. adenylate cyclase activator, forskolin or phosphodiesterase inhibitors (IBMX/cilostamide) block insulin action on germinal vesicle breakdown (GVBD) and histone H1 kinase activation. Though high cAMP priming attenuates insulin-induced MAPK3/1 (ERK1/2) phosphorylation (activation), following 2h of insulin stimulation it fails to block MAPK activation and GVBD. Further, insulin stimulation promotes down regulation of phospho-PKAc (inactivation) and PKA inhibition by H89/PKI-(6-22)-amide overcomes negative regulation by cAMP and induces GVBD and MAPK activation. Moreover, MEK1/2 inhibitor U0126 has no influence on H89-induced GVBD; however, it delays GVBD response in insulin stimulated oocytes. MAPK activation by okadaic acid (OA) promotes GVBD; however, high dbcAMP abrogates OA action suggesting cross-talk between cAMP/PKA and MAPK mediated signalling pathways may contribute significantly in maturing zebrafish oocyte. PMID- 24956083 TI - Preliminary investigation of the dissolution behavior, cytocompatibility, effects of fibrinogen conformation and platelet adhesion for radiopaque embolic particles. AB - Experimental embolic particles based on a novel zinc-silicate glass system have been biologically evaluated for potential consideration in transcatheter arterial embolization procedures. In addition to controlling the cytotoxicity and haemocompatibility for such embolic particles, its glass structure may mediate specific responses via dissolution in the physiological environment. In a 120 h in-vitro dissolution study, ion release levels for silicon (Si4+), sodium (Na+), calcium (Ca2+), zinc (Zn2+), titanium (Ti4+), lanthanum (La3+), strontium (Sr2+), and magnesium (Mg2+), were found to range from 0.04 to 5.41 ppm, 0.27-2.28 ppm, 2.32-8.47 ppm, 0.16-0.20 ppm, 0.12-2.15 ppm, 0.16-0.49 ppm and 0.01-0.12 ppm, respectively for the series of glass compositions evaluated. Initial release of Zn2+ (1.93-10.40 ppm) was only evident after 120 h. All compositions showed levels of cell viabilities ranging from 61.31 +/- 4.33% to 153.7 +/- 1.25% at 25% 100% serial extract dilutions. The conformational state of fibrinogen, known to induce thrombi, indicated that no changes were induced with respect of the materials dissolution by-products. Furthermore, the best-in-class experimental composition showed equivalency to contour PVA in terms of inducing platelet adhesion. The data generated here provides requisite evidence to continue to in vivo pre-clinical evaluation using the best-in-class experimental composition evaluated. PMID- 24956085 TI - Epoxy cross-linked collagen and collagen-laminin Peptide hydrogels as corneal substitutes. AB - A bi-functional epoxy-based cross-linker, 1,4-Butanediol diglycidyl ether (BDDGE), was investigated in the fabrication of collagen based corneal substitutes. Two synthetic strategies were explored in the preparation of the cross-linked collagen scaffolds. The lysine residues of Type 1 porcine collagen were directly cross-linked using l,4-Butanediol diglycidyl ether (BDDGE) under basic conditions at pH 11. Alternatively, under conventional methodology, using both BDDGE and 1-Ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC)/N hydroxysuccinimide (NHS) as cross-linkers, hydrogels were fabricated under acidic conditions. In this latter strategy, Cu(BF4)2.XH2O was used to catalyze the formation of secondary amine bonds. To date, we have demonstrated that both methods of chemical cross-linking improved the elasticity and tensile strength of the collagen implants. Differential scanning calorimetry and biocompatibility studies indicate comparable, and in some cases, enhanced properties compared to that of the EDC/NHS controls. In vitro studies showed that human corneal epithelial cells and neuronal progenitor cell lines proliferated on these hydrogels. In addition, improvement of cell proliferation on the surfaces of the materials was observed when neurite promoting laminin epitope, IKVAV, and adhesion peptide, YIGSR, were incorporated. However, the elasticity decreased with peptide incorporation and will require further optimization. Nevertheless, we have shown that epoxy cross-linkers should be further explored in the fabrication of collagen-based hydrogels, as alternatives to or in conjunction with carbodiimide cross-linkers. PMID- 24956087 TI - A simplified impression protocol for fabrication of anatomical, cement-retained CAD/CAM abutments. AB - The complexity and labor-intensive nature of making implant-level impressions may inhibit some clinicians from recommending dental implant treatment. This paper describes a simplified impression technique for fabricating anatomical, cement retained abutments without removing or inserting implant components. Using digitally coded healing abutments, this protocol bridges the gap between traditional impressions and computer-aided abutment manufacturing. Basic logistic considerations are reviewed, as well as other biomechanic and esthetic advantages, that should optimize overall treatment outcomes. PMID- 24956088 TI - Autologous dental pulp stem cells in periodontal regeneration: a case report. AB - Histologic findings in animal models suggest that the application of dental pulp stem cells (DPSCs) may promote periodontal regeneration in infrabony defects. This case report describes the clinical and radiographic regenerative potential of autologous DPSCs in the treatment of human noncontained intraosseous defects. A chronic periodontitis patient with one vital third molar requiring extraction was surgically treated. The third molar was extracted and used as an autologous DPSCs source to regenerate the infrabony defect on the mandibular right second premolar. At the 1-year examination, the defect was completely filled with bonelike tissue as confirmed through the reentry procedure. PMID- 24956089 TI - Effects of platform switching on crestal bone around implants: a histomorphometric study in monkeys. AB - A number of human comparison studies and case series have demonstrated the effectiveness of using a platform-switched implant-to-abutment connection to prevent peri-implant bone loss and subsequent soft tissue loss. To compare the bone around platform-switched and nonplatform-switched connections, adjacent pairs of both connection types were placed in a one-stage surgical procedure on each side of the mandibles of three monkeys (Macaca fascicularis). Eight weeks after abutment connection, histomorphometric analysis showed that both vertical and horizontal alveolar bone resorption had occurred around the nonplatform switched implants, whereas bone was maintained vertically and new bone formed horizontally around the platform-switched implants. PMID- 24956090 TI - A prospective evaluation of a novel implant designed for immediate loading. AB - This prospective study evaluated the survival rate of immediately loaded anatomically tapered implants with a dual acid-etched, microtextured surface. Patients in a private practice were recruited for placement of 3i T3 tapered implants in single, multiple, and full-arch applications in the mandible and maxilla, in both fresh extraction and healed placement sites. Ninety patients were treated, and 240 implants were placed and immediately loaded: 124 in the maxilla and 116 in the mandible. One hundred twelve definitive prostheses were delivered between 4 and 6 months after implant placement. Over the course of 2 to 12 months of follow-up (mean: 4.8 months), five implants failed in the maxilla and no implants failed in the mandible, a survival rate of 96% for the maxilla and 100% for the mandible. The cumulative survival rate was 98%. PMID- 24956091 TI - Socket preservation procedure with equine bone mineral: a case series. AB - Conventional dentoalveolar osseous augmentation procedures for creating bone volume for dental implant placement often involve the use of grafting materials with or without barrier membranes to foster selective cell and tissue repopulation. A study was conducted to determine the efficacy of equine particulate bone (Equimatrix, Osteohealth) to augment the creation of new bone and preserve the volume of bone at extraction sites for the purpose of placing an implant in an optimal position for restoration. Clinical and histologic evidence supported the suitability of equine particulate bone for extraction site augmentation that allowed dental implant placement after a 6-month healing period. PMID- 24956092 TI - Evaluation of accuracy and precision of a new guided surgery system: a multicenter clinical study. AB - Computer-aided design/computer-assisted manufacture (CAD/CAM) guides for surgery are becoming a widespread tool in implant dentistry. This study sought to evaluate the accuracy and precision of a new guided surgery system. Twenty-five patients were treated in eight centers, and a total of 117 implants were placed using CAD/CAM surgical guides supported by bone, mucosa, and/or teeth. A postoperative computed tomographic (CT) scan of each patient was taken and superimposed on a preoperative CT scan to evaluate any discrepancies between the planned and actual implant positions (apex and platform positions), as well as the implant tilt. Implant placement using bone- and mucosa-supported guides was found to be more precise compared to using guides supported by teeth or a combination of teeth and mucosa. However, the differences were not statistically significant. The accuracy of the guided surgery system is in line with the data found in the literature. Considering the mean positioning discrepancies between the planned and actual implant outcomes, clinicians are advised to maintain a safe distance between implants and anatomical structures of at least 2 mm. In immediate loading cases, relining a provisional prosthesis to compensate for any discrepancies between the virtual and clinical implant positions is recommended. PMID- 24956093 TI - Implant dentistry: a continuing evolution. PMID- 24956094 TI - Human histologic assessment of a platform-switched osseointegrated dental implant. AB - This case report examined crestal bone level maintenance surrounding a platform switched implant that was retrieved due to prosthetic difficulty. The retrieved platform-switched implant threads demonstrated tight contact with the surrounding bone and demonstrated both radiographic and histologic features that were indicative of successful osseointegration. Very high bone-to-implant contact (BIC) without epithelial downgrowth to the implant thread was noted. The BIC consisted of a combination of newly formed bone and native bone. The buccal and lingual bone levels coincided with the original platform position noted at the time of the surgery, and did not appear to resorb at all. The result of the present investigation confirms the maintenance of the crestal bone level for platform-switched implants. PMID- 24956084 TI - Keeping an eye on decellularized corneas: a review of methods, characterization and applications. AB - The worldwide limited availability of suitable corneal donor tissue has led to the development of alternatives, including keratoprostheses (Kpros) and tissue engineered (TE) constructs. Despite advances in bioscaffold design, there is yet to be a corneal equivalent that effectively mimics both the native tissue ultrastructure and biomechanical properties. Human decellularized corneas (DCs) could offer a safe, sustainable source of corneal tissue, increasing the donor pool and potentially reducing the risk of immune rejection after corneal graft surgery. Appropriate, human-specific, decellularization techniques and high resolution, non-destructive analysis systems are required to ensure reproducible outputs can be achieved. If robust treatment and characterization processes can be developed, DCs could offer a supplement to the donor corneal pool, alongside superior cell culture systems for pharmacology, toxicology and drug discovery studies. PMID- 24956095 TI - Platform switching versus conventional technique: a randomized controlled clinical trial. AB - In this controlled prospective study, 53 patients treated at four study centers were randomly assigned to receive either (test) implants with platform switching built into their design or similar nonplatform-switched controls (same manufacturer, surface treatment, etc) for treatment of single and multiple edentulous sites in all four quadrants. Radiographs taken at the time of implant placement, definitive restoration delivery, and 1-year follow-up found significantly less crestal bone loss around the test implants (0.25 mm) compared to the controls (0.65 mm). Notably, bone loss around the control implants had declined by the 1-year follow-up point. PMID- 24956096 TI - Prevalence of maxillary midline papillae recession and association with interdental smile line: a cross-sectional study. AB - The objectives of this study were to record the prevalence and degree of absence of the maxillary midline interdental papilla and the proportion of patients displaying the maxillary midline papilla during maximum smile among a Caucasian population. Papillary recession was found in 46.4% of study participants (n = 211), while the prevalence of visible recession among maxillary midline papilla during maximum smile was 38.4%, which was statistically significantly less than that of patients diagnosed intraorally with loss of papillary height (P < .001). Correlations between age and level of lip line as well as age and visible papillary recession were identified for individuals over 65 years of age. The high prevalence of midline papillary recession in the maxilla found in this population suggests that loss of papillary height constitutes a substantial clinical challenge. PMID- 24956097 TI - Flapped or flapless surgery for narrow-diameter implant placement for overdentures: advantages, disadvantages, indications, and clinical rationale. AB - Narrow-diameter implants for overdenture applications have gained in popularity due to their ability to be placed with simplified and less traumatic surgical protocols in limited-width alveolar ridges. The decision of whether to use a flapped or flapless procedure must be guided by a thorough evaluation and evidence-based diagnosis. This article reviews current principles relating to the use of narrow-diameter implants, along with the advantages and disadvantages of current surgical protocols. The indications for the use of each surgical procedure are demonstrated by case reports that highlight diagnosis, surgical planning, and final treatment outcomes. PMID- 24956098 TI - A novel prosthetic device and method for guided tissue preservation of immediate postextraction socket implants. AB - Preservation of the surrounding hard and soft tissues associated with an immediate postextraction socket implant to replace a nonrestorable tooth in the esthetic zone is one of the greatest challenges facing the dental team. Several studies have documented the biologic and esthetic benefits of bone graft containment with either a custom healing abutment or provisional restoration. Use of a prefabricated shell that replicates the extracted tooth at the cervical region can help achieve guided tissue preservation and sustainable esthetic outcomes in an easy, simple, consistent, and less time consuming way. The following case report of a hopeless maxillary right central incisor in a female patient possessing adjacent teeth with a thin periodontal phenotype illustrates this new treatment device, method, and concept. PMID- 24956099 TI - Coronally advanced flap with and without a xenogenic collagen matrix in the treatment of multiple recessions: a randomized controlled clinical study. AB - Multiple adjacent recession defects were treated in 32 patients using a coronally advanced flap (CAF) with or without a collagen matrix (CM). The percentage of root coverage was 81.49% +/- 23.45% (58% complete root coverage) for CAF sites (control) and 93.25% +/- 10.01% root coverage (72% complete root coverage) for CM plus CAF sites (test). The results achieved in the test group were significantly greater than in the control group, indicating that CM plus CAF is a suitable option for the treatment of multiple adjacent gingival recessions. PMID- 24956101 TI - Matrix metalloproteinase-9 is involved in chronic lymphocytic leukemia cell response to fludarabine and arsenic trioxide. AB - BACKGROUND: Matrix metalloproteinase-9 (MMP-9) contributes to chronic lymphocytic leukemia (CLL) pathology by regulating cell migration and preventing spontaneous apoptosis. It is not known if MMP-9 is involved in CLL cell response to chemotherapy and we address this in the present study, using arsenic trioxide (ATO) and fludarabine as examples of cytotoxic drugs. METHODS: We used primary cells from the peripheral blood of CLL patients and MEC-1 cells stably transfected with an empty vector or a vector containing MMP-9. The effect of ATO and fludarabine was determined by flow cytometry and by the MTT assay. Expression of mRNA was measured by RT-PCR and qPCR. Secreted and cell-bound MMP-9 was analyzed by gelatin zymography and flow cytometry, respectively. Protein expression was analyzed by Western blotting and immunoprecipitation. Statistical analyses were performed using the two-tailed Student's t-test. RESULTS: In response to ATO or fludarabine, CLL cells transcriptionally upregulated MMP-9, preceding the onset of apoptosis. Upregulated MMP-9 primarily localized to the membrane of early apoptotic cells and blocking apoptosis with Z-VAD prevented MMP 9 upregulation, thus linking MMP-9 to the apoptotic process. Culturing CLL cells on MMP-9 or stromal cells induced drug resistance, which was overcome by anti-MMP 9 antibodies. Accordingly, MMP-9-MEC-1 transfectants showed higher viability upon drug treatment than Mock-MEC-1 cells, and this effect was blocked by silencing MMP-9 with specific siRNAs. Following drug exposure, expression of anti-apoptotic proteins (Mcl-1, Bcl-xL, Bcl-2) and the Mcl-1/Bim, Mcl-1/Noxa, Bcl-2/Bax ratios were higher in MMP-9-cells than in Mock-cells. Similar results were obtained upon culturing primary CLL cells on MMP-9. CONCLUSIONS: Our study describes for the first time that MMP-9 induces drug resistance by modulating proteins of the Bcl-2 family and upregulating the corresponding anti-apoptotic/pro-apoptotic ratios. This is a novel role for MMP-9 contributing to CLL progression. Targeting MMP-9 in combined therapies may thus improve CLL response to treatment. PMID- 24956103 TI - Modified neocortical and cerebellar protein expression and morphology in adult rats following prenatal inhibition of the kynurenine pathway. AB - Inhibition of the kynurenine pathway of tryptophan metabolism during gestation can lead to changes in synaptic transmission, neuronal morphology and plasticity in the rat hippocampus. This suggests a role for the kynurenine pathway in early brain development, probably caused by kynurenine modulation of N-methyl-d aspartate (NMDA) glutamate receptors which are activated by the tryptophan metabolite quinolinic acid and blocked by kynurenic acid. We have now examined samples of neocortex and cerebellum of adult animals to assess the effects of a prenatally administered kynurenine-3-monoxygenase inhibitor (Ro61-8048) on protein and mRNA expression, dendritic structure and immuno-histochemistry. No changes were seen in mRNA expression using quantitative real-time polymerase chain reaction. Changes were detected in the expression of several proteins including the GluN2A subunit, unco-ordinated-5H3 (unc5H3), doublecortin, cyclo oxygenase, sonic hedgehog and Disrupted in schizophrenia-1 (DISC1), although no differences in immunoreactive cell numbers were observed. In the midbrain, dependence receptor expression was also changed. The numbers and lengths of individual dendritic regions were not changed but there were significant increases in the overall complexity values of apical and basal dendritic trees. The data support the hypothesis that constitutive kynurenine metabolism plays a critical role in early, embryonic brain development, although fewer effects are produced in the neocortex and cerebellum than in the hippocampus and the nature of the changes seen are qualitatively different. The significant changes in DISC1 and unc5H3 may be relevant to cerebellar dysfunction and schizophrenia respectively, in which these proteins have been previously implicated. PMID- 24956102 TI - Recombinant human bone morphogenetic protein-2 in debridement and impacted bone graft for the treatment of femoral head osteonecrosis. AB - The purpose of this study was to compare the clinical outcomes of impacted bone graft with or without recombinant human bone morphogenetic protein-2 (rhBMP-2) for osteonecrosis of the femoral head (ONFH). We examined the effect of bone grafting through a window at the femoral head-neck junction, known as the "light bulb" approach, for the treatment of ONFH with a combination of artificial bone (Novobone) mixed with or without rhBMP-2. A total of 42 patients (72 hips) were followed-up from 5 to 7.67 years (average of 6.1 years). The patients with and without BMP were the first group (IBG+rhBMP-2) and the second group (IBG), respectively. The clinical effectiveness was evaluated by Harris hip score (HHS). The radiographic follow-up was evaluated by pre-and postoperative X-ray and CT scan. Excellent, good, and fair functions were obtained in 36, 12, and 7 hips, respectively. The survival rate was 81.8% and 71.8% in the first and second group, respectively. However, the survival rate was 90.3% in ARCO stage IIb, c, and only 34.6% in ARCO stage IIIa (P<0.05). It was concluded that good and excellent mid-term follow-up could be achieved in selected patients with ONFH treated with impacted bone graft operation. The rhBMP-2 might improve the clinical efficacy and quality of bone repair. PMID- 24956104 TI - Splitting or lumping? A conservation dilemma exemplified by the critically endangered dama gazelle (Nanger dama). AB - Managers of threatened species often face the dilemma of whether to keep populations separate to conserve local adaptations and minimize the risk of outbreeding, or whether to manage populations jointly to reduce loss of genetic diversity and minimise inbreeding. In this study we examine genetic relatedness and diversity in three of the five last remaining wild populations of dama gazelle and a number of captive populations, using mtDNA control region and cytochrome b data. Despite the sampled populations belonging to the three putative subspecies, which are delineated according to phenotypes and geographical location, we find limited evidence for phylogeographical structure within the data and no genetic support for the putative subspecies. In the light of these data we discuss the relevance of inbreeding depression, outbreeding depression, adaptive variation, genetic drift, and phenotypic variation to the conservation of the dama gazelle and make some recommendations for its future conservation management. The genetic data suggest that the best conservation approach is to view the dama gazelle as a single species without subspecific divisions. PMID- 24956105 TI - Human leukocyte antigen class II haplotypes affect clinical characteristics and progression of type 1 autoimmune hepatitis in Japan. AB - Although we earlier demonstrated that the human leukocyte antigen (HLA) DRB1*04:05 allele was associated with susceptibility to autoimmune hepatitis (AIH) in Japan, the precise relationship of HLA haplotype and the role of amino acid alignment with disease susceptibility and progression has not been fully clarified. We reinvestigated HLA class I A, B, and C and HLA class II DRB1, DQB1, and DPB1 alleles and haplotypes in a larger new cohort of 156 Japanese patients with type 1 AIH and compared them with the published data of 210 healthy subjects. The DRB1*04:05-DQB1*04:01 haplotype was significantly associated with AIH susceptibility (30% vs. 11%, P = 1.2*10(-10); odds ratio [OR] = 3.51) and correlated with elevated serum IgG (3042 vs. 2606 mg/dL, P = 0.041) and anti smooth muscle antigen positivity (77% vs. 34%, P = 0.000006). No associations with HLA-DPB1 alleles were found. The HLA A*24:02 and C*01:02 alleles were associated with disease susceptibility (corrected P = 0.0053 and 0.036, respectively), but this likely constituents of a long ranged haplotype including DRB1*04:05-DQB1*04:01 haplotype. Conversely, the DRB1*15:01-DQB1*06:02 haplotype was associated with protection from both disease onset (5% vs. 13%, P = 0.00057; OR = 0.38) and the development of hepatocellular carcinoma (25% vs. 5%, P = 0.017; OR = 6.81). The frequency of the DRB1*08:03-DQB1*06:01 haplotype was significantly higher in patients who developed hepatic failure (22% vs. 6%, P = 0.034; OR = 4.38). In conclusion, this study established the role of HLA haplotypes in determining AIH susceptibility and progression in the Japanese population. Additional sequencing of the entire HLA region is required to more precisely identify the genetic components of AIH. PMID- 24956107 TI - Comparative population assessments of Nautilus sp. in the Philippines, Australia, Fiji, and American Samoa using baited remote underwater video systems. AB - The extant species of Nautilus and Allonautilus (Cephalopoda) inhabit fore-reef slope environments across a large geographic area of the tropical western Pacific and eastern Indian Oceans. While many aspects of their biology and behavior are now well-documented, uncertainties concerning their current populations and ecological role in the deeper, fore-reef slope environments remain. Given the historical to current day presence of nautilus fisheries at various locales across the Pacific and Indian Oceans, a comparative assessment of the current state of nautilus populations is critical to determine whether conservation measures are warranted. We used baited remote underwater video systems (BRUVS) to make quantitative photographic records as a means of estimating population abundance of Nautilus sp. at sites in the Philippine Islands, American Samoa, Fiji, and along an approximately 125 km transect on the fore reef slope of the Great Barrier Reef from east of Cairns to east of Lizard Island, Australia. Each site was selected based on its geography, historical abundance, and the presence (Philippines) or absence (other sites) of Nautilus fisheries The results from these observations indicate that there are significantly fewer nautiluses observable with this method in the Philippine Islands site. While there may be multiple possibilities for this difference, the most parsimonious is that the Philippine Islands population has been reduced due to fishing. When compared to historical trap records from the same site the data suggest there have been far more nautiluses at this site in the past. The BRUVS proved to be a valuable tool to measure Nautilus abundance in the deep sea (300-400 m) while reducing our overall footprint on the environment. PMID- 24956108 TI - Regulation of Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase by phosphate-modulated quaternary structure dynamics and a potential role for polyphosphate in enzyme regulation. AB - D-3-phosphoglycerate dehydrogenase (PGDH) catalyzes the first reaction in the "phosphorylated" pathway of l-serine biosynthesis. In Mycobacterium tuberculosis, it is a type 1 enzyme (mtPGDH) in that it contains both an ACT domain and an ASB domain in addition to a catalytic domain. The published crystal structures (Protein Data Bank entries 1YGY and 3DC2) show a tartrate molecule interacting with cationic residues at the ASB-ACT domain interfaces and a serine molecule bound at the ACT domain interface. These sites have previously been shown to be involved in the mechanism of serine and substrate inhibition of catalytic activity. This investigation has revealed a mechanism of allosteric quaternary structure dynamics in mtPGDH that is modulated by physiologically relevant molecules, phosphate and polyphosphate. In the absence of phosphate and polyphosphate, the enzyme exists in equilibrium between an inactive dimer and an active tetramer that is insensitive to inhibition of catalytic activity by L serine. Phosphate induces a conversion to an active tetramer and octamer that are sensitive to inhibition of catalytic activity by L-serine. Small polyphosphates (pyrophosphate and triphosphate) induce a conversion to an active dimer that is insensitive to L-serine inhibition. The difference in the tendency of each respective dimer to form a tetramer as well as slightly altered elution positions on size exclusion chromatography indicates that there is likely a conformational difference between the serine sensitive and insensitive states. This appears to constitute a unique mechanism in type 1 PGDHs that may be unique in pathogenic Mycobacterium species and may provide the organisms with a unique metabolic advantage. PMID- 24956106 TI - Hybrid lentivirus-phiC31-int-NLS vector allows site-specific recombination in murine and human cells but induces DNA damage. AB - Gene transfer allows transient or permanent genetic modifications of cells for experimental or therapeutic purposes. Gene delivery by HIV-derived lentiviral vector (LV) is highly effective but the risk of insertional mutagenesis is important and the random/uncontrollable integration of the DNA vector can deregulate the cell transcriptional activity. Non Integrative Lentiviral Vectors (NILVs) solve this issue in non-dividing cells, but they do not allow long term expression in dividing cells. In this context, obtaining stable expression while avoiding the problems inherent to unpredictable DNA vector integration requires the ability to control the integration site. One possibility is to use the integrase of phage phiC31 (phiC31-int) which catalyzes efficient site-specific recombination between the attP site in the phage genome and the chromosomal attB site of its Streptomyces host. Previous studies showed that phiC31-int is active in many eukaryotic cells, such as murine or human cells, and directs the integration of a DNA substrate into pseudo attP sites (pattP) which are homologous to the native attP site. In this study, we combined the efficiency of NILV for gene delivery and the specificity of phiC31-int for DNA substrate integration to engineer a hybrid tool for gene transfer with the aim of allowing long term expression in dividing and non-dividing cells preventing genotoxicity. We demonstrated the feasibility to target NILV integration in human and murine pattP sites with a dual NILV vectors system: one which delivers phiC31-int, the other which constitute the substrate containing an attB site in its DNA sequence. These promising results are however alleviated by the occurrence of significant DNA damages. Further improvements are thus required to prevent chromosomal rearrangements for a therapeutic use of the system. However, its use as a tool for experimental applications such as transgenesis is already applicable. PMID- 24956109 TI - Mitoepigenetics and drug addiction. AB - Being the center of energy production in eukaryotic cells, mitochondria are also crucial for various cellular processes including intracellular Ca(2+) signaling and generation of reactive oxygen species (ROS). Mitochondria contain their own circular DNA which encodes not only proteins, transfer RNA and ribosomal RNAs but also non-coding RNAs. The most recent line of evidence indicates the presence of 5-methylcytosine and 5-hydroxymethylcytosine in mitochondrial DNA (mtDNA); thus, the level of gene expression - in a way similar to nuclear DNA - can be regulated by direct epigenetic modifications. Up to now, very little data shows the possibility of epigenetic regulation of mtDNA. Mitochondria and mtDNA are particularly important in the nervous system and may participate in the initiation of drug addiction. In fact, some addictive drugs enhance ROS production and generate oxidative stress that in turn alters mitochondrial and nuclear gene expression. This review summarizes recent findings on mitochondrial function, mtDNA copy number and epigenetics in drug addiction. PMID- 24956110 TI - Inducing dose sparing with inactivated polio virus formulated in adjuvant CAF01. AB - The development of new low cost inactivated polio virus based vaccines (IPV) is a high priority, and will be required to eradicate polio. In addition, such a vaccine constitutes the only realistic polio vaccine in the post-eradication era. One way to reduce the cost of a vaccine is to increase immunogenicity by use of adjuvants. The CAF01 adjuvant has previously been shown to be a safe and potent adjuvant with several antigens, and here we show that in mice IPV formulated with CAF01 induced increased systemic protective immunity measured by binding and neutralization antibody titers in serum. CAF01 also influenced the kinetics of both the cellular and humoral response against IPV to produce a faster, as well as a stronger, response, dominated by IgG2a, IgG2b, and IgG2c isotypes as well as IPV specific T cells secreting IFN-gamma/IL-2. Finally, as intestinal immunity is also a priority of polio vaccines, we present a vaccine strategy based on simultaneous priming at an intradermal and an intramuscular site that generate intestinal immune responses against polio virus. Taken together, the IPV-CAF01 formulation constitutes a new promising vaccine against polio with the ability to generate strong humoral and cellular immunity against the polio virus. PMID- 24956112 TI - Expression of matrix Gla protein and osteocalcin in the developing tibial epiphysis of mice. AB - This study aimed to investigate the expression of matrix Gla protein (MGP) and osteocalcin (OCN) in the tibial epiphysis of developing mice. At 1, 2, 3, and 4 weeks after birth, tibiae were removed and processed for histochemical observations and western blot analyses under anesthesia. To evaluate bone volume, the specimens were scanned with Micro CT Scanner from the articular cartilage through the growth plate, along the long axis of tibia. At 1 week after birth, OCN reactivity was faint in the region of vascular invasion, while hardly any MGP reactivity was discernible. Subsequently, MGP reactivity was seen on the cartilaginous lacunar walls of hypertrophic chondrocytes, while OCN reactivity was evenly found not only in the bone matrix, but also in the cartilaginous lacunar walls and on the bone surfaces. Furthermore, double-immunostaining clearly showed that MGP reactivity appeared closer to the cartilage matrix than OCN reactivity until postnatal week 3. Interestingly, the immunoreactivities for MGP and OCN both showed tidemarks in the articular cartilage at postnatal week 4, and MGP reactivity was more intense than OCN reactivity. Statistical analyses showed an overall upward trend in MGP and OCN expression levels during tibial epiphysis development, even though OCN was more abundant than MGP at every time point. Taken together, our findings suggest that the expression of MGP and OCN increased gradually in the murine developing tibial epiphysis, and the two mineral-associated proteins may occur at the same location during a particular period, but at different levels. PMID- 24956111 TI - Point-of-care testing for chlamydia and gonorrhoea: implications for clinical practice. AB - OBJECTIVES: Point-of-care (POC) testing for chlamydia (CT) and gonorrhoea (NG) offers a new approach to the diagnosis and management of these sexually transmitted infections (STIs) in remote Australian communities and other similar settings. Diagnosis of STIs in remote communities is typically symptom driven, and for those who are asymptomatic, treatment is generally delayed until specimens can be transported to the reference laboratory, results returned and the patient recalled. The objective of this study was to explore the clinical implications of using CT/NG POC tests in routine clinical care in remote settings. METHODS: In-depth qualitative interviews were conducted with a purposively selected group of 18 key informants with a range of sexual health and laboratory expertise. RESULTS: Participants highlighted the potential impact POC testing would have on different stages of the current STI management pathway in remote Aboriginal communities and how the pathway would change. They identified implications for offering a POC test, specimen collection, conducting the POC test, syndromic management of STIs, pelvic inflammatory disease diagnosis and management, interpretation and delivery of POC results, provision of treatment, contact tracing, management of client flow and wait time, and re-testing at 3 months after infection. CONCLUSIONS: The introduction of POC testing to improve STI service delivery requires careful consideration of both its advantages and limitations. The findings of this study will inform protocols for the implementation of CT/NG POC testing, and also STI testing and management guidelines. PMID- 24956114 TI - Up, down, and all around: scale-dependent spatial variation in rocky-shore communities of Fildes Peninsula, King George Island, Antarctica. AB - Understanding the variation of biodiversity along environmental gradients and multiple spatial scales is relevant for theoretical and management purposes. Hereby, we analysed the spatial variability in diversity and structure of intertidal and subtidal macrobenthic Antarctic communities along vertical environmental stress gradients and across multiple horizontal spatial scales. Since biotic interactions and local topographic features are likely major factors for coastal assemblages, we tested the hypothesis that fine-scale processes influence the effects of the vertical environmental stress gradients on the macrobenthic diversity and structure. We used nested sampling designs in the intertidal and subtidal habitats, including horizontal spatial scales ranging from few centimetres to 1000s of metres along the rocky shore of Fildes Peninsula, King George Island. In both intertidal and subtidal habitats, univariate and multivariate analyses showed a marked vertical zonation in taxon richness and community structure. These patterns depended on the horizontal spatial scale of observation, as all analyses showed a significant interaction between height (or depth) and the finer spatial scale analysed. Variance and pseudo-variance components supported our prediction for taxon richness, community structure, and the abundance of dominant species such as the filamentous green alga Urospora penicilliformis (intertidal), the herbivore Nacella concinna (intertidal), the large kelp-like Himantothallus grandifolius (subtidal), and the red crustose red alga Lithothamnion spp. (subtidal). We suggest that in coastal ecosystems strongly governed by physical factors, fine-scale processes (e.g. biotic interactions and refugia availability) are still relevant for the structuring and maintenance of the local communities. The spatial patterns found in this study serve as a necessary benchmark to understand the dynamics and adaptation of natural assemblages in response to observed and predicted environmental changes in Antarctica. PMID- 24956113 TI - MicroRNA-146b promotes myogenic differentiation and modulates multiple gene targets in muscle cells. AB - MicroRNAs are established as crucial modulators of skeletal myogenesis, but our knowledge about their identity and targets remains limited. In this study, we have identified microRNA-146b (miR-146b) as a novel regulator of skeletal myoblast differentiation. Following up on a previous microRNA profiling study, we establish that the expression of miR-146b is up-regulated during myoblast differentiation in vitro and muscle regeneration in vivo. Inhibition of miR-146b led to reduced myoblast differentiation, whereas overexpression of miR-146b enhanced differentiation. Computational prediction combined with gene expression information has revealed candidates for miR-146b targets in muscles. Among them, the expression of Smad4, Notch1, and Hmga2 are significantly suppressed by miR 146b overexpression in myocytes. In addition, expression levels of Smad4, Notch1 and Hmga2 are decreased during myoblast differentiation and muscle regeneration, inversely correlating to the levels of miR-146b. Importantly, inhibition of endogenous miR-146b prevents the down-regulation of Smad4, Notch1 and Hmga2 during differentiation. Furthermore, miR-146b directly targets the microRNA response elements (MREs) in the 3'UTR of those genes as assessed by reporter assays. Reporters with the seed regions of MREs mutated are insensitive to miR 146b, further confirming the specificity of targeting. In conclusion, miR-146b is a positive regulator of myogenic differentiation, possibly acting through multiple targets. PMID- 24956115 TI - A one-pot parallel reductive amination of aldehydes with heteroaromatic amines. AB - A parallel reductive amination of heteroaromatic amines has been performed using a combination of ZnCl2-TMSOAc (activating agents) and NaBH(OAc)3 (reducing agent). A library of diverse secondary amines was easily prepared on a 50-300 mg scale. PMID- 24956117 TI - Thermoresponsive double network micropillared hydrogels for controlled cell release. AB - Thermoresponsive poly(N-isopropylacrylamide) hydrogels (PNIPAAm) have been widely used for controlled cell detachment. In this study, cell release is enhanced via deswelling with a two-pronged approach combining a double network (DN) design and micropatterning. PNIPAAm hydrogels are prepared as DNs comprised of a tightly crosslinked 1st network and a loosely crosslinked 2nd network. Moreover, the PNIPAAm DN hydrogels are prepared as both planar 1.5 mm-thick slabs as well as micropillar arrays (~200 MUm pillar diameter). Compared to the corresponding conventional single network (SN) hydrogels, DN hydrogels exhibit enhanced thermosensitivity and cell release efficiency, particularly for the micropillar arrays. PMID- 24956116 TI - Bayesian weighting of statistical potentials in NMR structure calculation. AB - The use of statistical potentials in NMR structure calculation improves the accuracy of the final structure but also raises issues of double counting and possible bias. Because statistical potentials are averaged over a large set of structures, they may not reflect the preferences of a particular structure or data set. We propose a Bayesian method to incorporate a knowledge-based backbone dihedral angle potential into an NMR structure calculation. To avoid bias exerted through the backbone potential, we adjust its weight by inferring it from the experimental data. We demonstrate that an optimally weighted potential leads to an improvement in the accuracy and quality of the final structure, especially with sparse and noisy data. Our findings suggest that no universally optimal weight exists, and that the weight should be determined based on the experimental data. Other knowledge-based potentials can be incorporated using the same approach. PMID- 24956118 TI - Differential gene expression analysis in CCLE lesions provides new insights regarding the genetics basis of skin vs. systemic disease. AB - Lupus erythematosus is a heterogeneous autoimmune condition affecting multiple organs including skin, which remains poorly understood. To investigate pathogenetic processes relevant to cutaneous lupus as compared to systemic disease, we generated genome-wide expression data from lesional and non-lesional skin of chronic cutaneous LE (CCLE) patients. We reveal LE skin-associated transcriptional profiles and identify prominent functional pathways. A subset of CCLE differentially expressed genes (DEGs) was found to overlap with systemic lupus, including those linked to interferon and apoptosis. We identified 13 skin associated transcriptional "hot spots" that represent activated chromosomal regions. Seventeen CCLE DEGs (eight within "hot spots") were found to overlap with previously reported SLE-associated susceptibility loci. Additionally, we identify chromosomal regions not previously associated with lupus, potentially harboring distinct susceptibility loci for CCLE. This study suggests that overlapping as well as distinct genetic factors underlie disease pathogenesis in systemic and cutaneous lupus. PMID- 24956120 TI - Flavonostilbenes from Sophora alopecuroides L. as multidrug resistance associated protein 1 (MRP1) inhibitors. AB - Flavonoids have always attracted much attention due to their reversal activity on multidrug resistance (MDR). Eight flavonoids isolated from traditional Chinese medicine Sophora alopecuroides L. were applied to test their effect on MDR associated protein 1 (MRP1) through the established predicting assay. Three flavonostilbenes (alopecurone A, B and D) were first found exhibiting potent inhibitory activity on MRP1. All of them dramatically increased 6 carboxyfluorescein diacetate and doxorubicin accumulation in MRP1-transfected U-2 OS cells. The compounds significantly increased the cytotoxicity and decreased the IC50 value of doxorubicin on the MDR cells (12-, 5- and 8-fold, respectively) at a non-toxic concentration (20 MUM). Besides, Q-PCR analysis reveals that the MRP1 mRNA level in U-2 OS/MRP1 was also markedly decreased by the three compounds. These findings indicate a new therapeutic role of the herb. The three flavonostilbenes may have the possibility for further development as novel therapeutic reversal agents against MDR. PMID- 24956119 TI - High-throughput sequencing analysis of post-liver transplantation HCV E2 glycoprotein evolution in the presence and absence of neutralizing monoclonal antibody. AB - Chronic hepatitis C virus (HCV) infection is the most common cause of end-stage liver disease, often leading to liver transplantation, in which case circulating virions typically infect the transplanted liver within hours and viral concentrations can quickly exceed pre-transplant levels. MBL-HCV1 is a fully human monoclonal antibody recognizing a linear epitope of the HCV E2 envelope glycoprotein (amino acids 412-423). The ability of MBL-HCV1 to prevent HCV recurrence after liver transplantation was investigated in a phase 2 randomized clinical trial evaluating six MBL-HCV1-treated subjects and five placebo-treated subjects. MBL-HCV1 treatment significantly delayed time to viral rebound compared with placebo treatment. Here we report results from high-throughput sequencing on the serum of each of the eleven enrolled subjects prior to liver transplantation and after viral rebound. We further sequenced the sera of the MBL-HCV1-treated subjects at various interim time points to study the evolution of antibody resistant viral variants. We detected mutations at one of two positions within the antibody epitope--mutations of N at position 415 to D, K or S, or mutation of N at position 417 to S. It has been previously reported that N415 is not glycosylated in the wild-type E2 protein, but N417S can lead to glycosylation at position 415. Thus N415 is a key position for antibody recognition and the only routes we identified for viral escape, within the constraints of HCV fitness in vivo, involve mutating or glycosylating this position. Evaluation of mutations along the entire E1 and E2 proteins revealed additional positions that changed moderately before and after MBL-HCV1 treatment for subsets of the six subjects, yet underscored the relative importance of position 415 in MBL-HCV1 resistance. PMID- 24956121 TI - A case of intussusception of the appendix secondary to endometriosis: US and CT findings. AB - Intussusception of the appendix is an uncommon condition that is difficult to diagnose with radiology. Endometriosis causing appendiceal intussusception is a rare condition that has only been reported a few times in the literature. Here, we report a case of appendiceal intussusception caused by endometriosis in a 33 year-old woman who presented with intermittent right lower abdominal pain. Sonography revealed a hypoechoic mass invaginating into the cecum, which was covered by echogenic cecal wall with central dimpling indicating the appendiceal orifice. On CT, the mass was identified as an enhancing mass invaginating into the cecum at the level the appendiceal orifice. PMID- 24956125 TI - Hetero-oligomer nanoparticle arrays for plasmon-enhanced hydrogen sensing. AB - This paper describes how the ability to tune each nanoparticle in a plasmonic hetero-oligomer can optimize architectures for plasmon-enhanced applications. We demonstrate how a large-area nanofabrication approach, reconstructable mask lithography (RML), can achieve independent control over the size, position, and material of up to four nanoparticles within a subwavelength unit. We show how arrays of plasmonic hetero-oligomers consisting of strong plasmonic materials (Au) and reactant-specific elements (Pd) provide a unique platform for enhanced hydrogen gas sensing. Using finite-difference time-domain simulations, we modeled different configurations of Au-Pd hetero-oligomers and compared their hydrogen gas sensing capabilities. In agreement with calculations, we found that Au-Pd nanoparticle dimers showed a red-shift and that Au-Pd trimers with touching Au and Pd nanoparticles showed a blue-shift upon exposure to both high and low concentrations of hydrogen gas. Both Au-Pd hetero-oligomer sensors displayed high sensitivity, fast response times, and excellent recovery. PMID- 24956122 TI - Genetic and environmental continuity in personality development: a meta-analysis. AB - The longitudinal stability of personality is low in childhood but increases substantially into adulthood. Theoretical explanations for this trend differ in the emphasis placed on intrinsic maturation and socializing influences. To what extent does the increasing stability of personality result from the continuity and crystallization of genetically influenced individual differences, and to what extent does the increasing stability of life experiences explain increases in personality trait stability? Behavioral genetic studies, which decompose longitudinal stability into sources associated with genetic and environmental variation, can help to address this question. We aggregated effect sizes from 24 longitudinal behavioral genetic studies containing information on a total of 21,057 sibling pairs from 6 types that varied in terms of genetic relatedness and ranged in age from infancy to old age. A combination of linear and nonlinear meta analytic regression models were used to evaluate age trends in levels of heritability and environmentality, stabilities of genetic and environmental effects, and the contributions of genetic and environmental effects to overall phenotypic stability. Both the genetic and environmental influences on personality increase in stability with age. The contribution of genetic effects to phenotypic stability is moderate in magnitude and relatively constant with age, in part because of small-to-moderate decreases in the heritability of personality over child development that offset increases in genetic stability. In contrast, the contribution of environmental effects to phenotypic stability increases from near zero in early childhood to moderate in adulthood. The life span trend of increasing phenotypic stability, therefore, predominantly results from environmental mechanisms. PMID- 24956126 TI - Microwave assisted tandem Heck-Sonogashira reactions of N,N-di-Boc-protected 6 amino-5-iodo-2-methyl pyrimidin-4-ol in an efficient approach to functionalized pyrido[2,3-d]pyrimidines. AB - A microwave assisted tandem Heck-Sonogashira cross-coupling reaction between 6 N,N-di-Boc-amino-5-iodo-2-methyl pyrimidin-4-ol and various aryl alkynyl substrates has been developed. This process generates novel 5-enynyl substituted pyrimidines, which can be transformed to novel functionalized pyrido[2,3 d]pyrimidines by way of a silver catalyzed cyclization reaction. PMID- 24956128 TI - Prevalence of entomophthoralean fungi (Entomophthoromycota) of aphids (Hemiptera: Aphididae) on solanaceous crops in Argentina. AB - Solanum melongena L. and Capsicum annuum L. were sampled in Argentina to determine the prevalence of fungal diseased aphids. The pathogens identified were Pandora neoaphidis (Remaudiere & Hennebert) Humber and Zoophthora radicans (Brefeld) Batko (Entomophthorales: Entomophthoraceae) on aphids from eggplants; and P. neoaphidis and Entomophthora planchoniana Cornu (Entomophthorales: Entomophthoraceae) on aphids from peppers. The highest fungal prevalence was 45.5% (n=2296) and 98.1% (n=3212) from aphids on eggplants and peppers, respectively. In both crops, significant differences were found on number of infected aphids among developmental stages. P.neoaphidis and E. planchoniana caused epizootics in M. persicae. PMID- 24956123 TI - A meta-analysis and review of holistic face processing. AB - The concept of holistic processing is a cornerstone of face recognition research, yet central questions related to holistic processing remain unanswered, and debates have thus far failed to reach a resolution despite accumulating empirical evidence. We argue that a considerable source of confusion in this literature stems from a methodological problem. Specifically, 2 measures of holistic processing based on the composite paradigm (complete design and partial design) are used in the literature, but they often lead to qualitatively different results. First, we present a comprehensive review of the work that directly compares the 2 designs, and which clearly favors the complete design over the partial design. Second, we report a meta-analysis of holistic face processing according to both designs and use this as further evidence for one design over the other. The meta-analysis effect size of holistic processing in the complete design is nearly 3 times that of the partial design. Effect sizes were not correlated between measures, consistent with the suggestion that they do not measure the same thing. Our meta-analysis also examines the correlation between conditions in the complete design of the composite task, and suggests that in an individual differences context, little is gained by including a misaligned baseline. Finally, we offer a comprehensive review of the state of knowledge about holistic processing based on evidence gathered from the measure we favor based on the 1st sections of our review-the complete design-and outline outstanding research questions in that new context. PMID- 24956129 TI - Analysis of light scattered by turbid media in cylindrical geometry. AB - The angle dependence of the transmitted light through a cylindrical turbid sample (latex suspension, developing milk gel, draining/coarsening milk, and protein foams) in a standard light scattering setup was analyzed in terms of the transport mean free path length or scattering length l* (a measure for the turbidity) and the absorption length labs. By variation of the concentration of an absorbing dye, the independence of l* and labs was demonstrated. The resulting value of the specific extinction coefficient of the dye was found to be in fair agreement with direct spectroscopic determination and practically identical in milk and latex suspensions. The validity of this technique for obtaining l* was demonstrated by monitoring the acid-induced gelation of milk. The possibility to simultaneously determine l* and labs was used to follow the time development of a draining and coarsening protein foam which contained an absorbing dye. It was shown that labs can be used as a measure for the volume fraction of air in the foam. This method of monitoring the transmission of multiple light scattering provides an easy way to determine l* and, specifically for foams, quantitative data dominated by the bulk of the foam. PMID- 24956130 TI - Pedestrian crossing situations: quantification of comfort boundaries to guide intervention timing. AB - INTRODUCTION: Technical systems that warn or brake for vehicle-pedestrian encounters reduce injuries more effectively the earlier an intervention is initiated. However, premature intervention can irritate drivers, leading to system deactivation and, consequently, no injury reduction whatsoever. It has been proposed that no intervention should be initiated as long as attentive drivers are within their comfort zones. This study aims at quantifying driver comfort boundaries for pedestrian crossing situations to offer guidance for the appropriate timing of interventions. METHODS: Sixty two volunteers drove through an intersection on a test track at 30 and 50km/h. A pedestrian dummy was launched from behind an obstruction towards the driving path of the approaching car. Brake onset indicated discomfort. Time to collision (TTC), longitudinal and lateral distance were measured at brake onset. RESULTS: TTC was independent of driving speed ranging from 2.1 to 4.3s with a median of 3.2s. Longitudinal distance ranged from 19 to 48 meters with an apparent difference between driving speeds. Lateral distances differed slightly, but significantly between driving speeds. The median was 3.1m (3.2m for 30km/h and 2.9m for 50km/h) and values ranged from 1.9 to 4.1m. Lateral distance in seconds ranged from 1.9 to 4.3s with a median value of 3.1s (3.2s for 30km/h and 3.0s for 50km/h). DISCUSSION: TTC was independent of driving speed, trial order and volunteer age. It might be considered suitable to intervene in situations where, for example, 90% of drivers have exceeded their comfort boundary, i.e. when drivers have already initiated braking. This percentile value translates to intervention at a TTC of 2.5s (95% confidence 2.4-2.7s). The study was limited to Swedish nationals, fully aware drivers, and two driving speeds, but did not investigate behavioural changes due to system interaction. CONCLUSION: This study showed that TTC at brake onset was a suitable measure for the quantification of driver comfort boundaries in pedestrian crossing situations. All drivers applied their brakes prior to 2.1s TTC. PMID- 24956131 TI - Health status recovery at one year in children injured in a road accident: a cohort study. AB - Despite the frequency of traumatic injuries due to road accidents and potential importance of identifying children at risk of impaired recovery one year after a road accident, there is a lack of data on long-term recovery of health status, except in children with severe traumatic brain injury. The aim of the present study was to evaluate predictive factors of recovery in children one year after road traffic injuries. The prospective cohort study was composed of children aged <16 years, admitted to public or private sector hospitals in the Rhone administrative area of France following a road accident. Recovery of health status one year after the accident and information concerning quality of life and the consequences of the accident for the child or family 1 year after the accident were collected by questionnaire, usually completed by the parents. Victims were in majority male (64.6%) and had mild or moderate injuries (81.9% with Maximum Abbreviated Injury Scale (M-AIS) <3). One year after the accident, 75.0% of the mild-to-moderate and 34.8% of the severe cases estimated health status as fully recovered. After adjustment, severity score (M-AIS>=3) and lower limb injury (AIS>1) were associated with incomplete recovery of health status: weighted odds ratio (ORw), 4.3 [95% confidence interval (95% CI), 1.3-14.6] and ORw, 6.5 [95% CI, 1.9-21.7], respectively. Recovery status correlated significantly with quality of life physical scores (r=0.46), especially body pain (r=0.48) and role/social-physical (r=0.50) and, to a lesser extent, quality of life psychosocial scores (r=0.21). In a cohort of children injured in a road accident, those with high injury severity score and those with lower limb injuries are less likely to recover full health status by 1 year. Impaired health status was associated with a lower physical quality of life score at 1 year. PMID- 24956127 TI - Disruption of protein-tyrosine phosphatase 1B expression in the pancreas affects beta-cell function. AB - Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and energy balance. However, the role of PTP1B in pancreatic endocrine function remains largely unknown. To investigate the metabolic role of pancreatic PTP1B, we generated mice with pancreas PTP1B deletion (panc-PTP1B KO). Mice were fed regular chow or a high-fat diet, and metabolic parameters, insulin secretion and glucose tolerance were determined. On regular chow, panc-PTP1B KO and control mice exhibited comparable glucose tolerance whereas aged panc-PTP1B KO exhibited mild glucose intolerance. Furthermore, high-fat feeding promoted earlier impairment of glucose tolerance and attenuated glucose-stimulated insulin secretion in panc-PTP1B KO mice. The secretory defect in glucose-stimulated insulin secretion was recapitulated in primary islets ex vivo, suggesting that the effects were likely cell-autonomous. At the molecular level, PTP1B deficiency in vivo enhanced basal and glucose-stimulated tyrosyl phosphorylation of EphA5 in islets. Consistently, PTP1B overexpression in the glucose-responsive MIN6 beta cell line attenuated EphA5 tyrosyl phosphorylation, and substrate trapping identified EphA5 as a PTP1B substrate. In summary, these studies identify a novel role for PTP1B in pancreatic endocrine function. PMID- 24956132 TI - The relationship between social capital and traffic law violations: Israeli Arabs as a case study. AB - Social aspects of a community may be correlated with driver's involvement in road traffic accidents. This study focused on examining this association in the context of the social capital theory. A survey of 600 Arab drivers living in 19 towns and villages was conducted using a face-to-face interview. Structural equation modeling was applied to explore paths of associations between the model components. Most of the proposed relationships in the path model were found to be significant, where the model explained 37% of the variation. The results indicate that only volunteering and reciprocity have direct correlations with traffic law violations. While the other correlations (except political involvement), were mediated by attitudes toward traffic laws violation. Hence, it can be concluded that it is not always possible to generalize the positive mechanisms of the social capital theory, and in certain populations such as the Arab minority it can give undesirable results. PMID- 24956133 TI - Structural features of the Nogo receptor signaling complexes at the neuron/myelin interface. AB - Upon spinal cord injury, the central nervous system axons are unable to regenerate, partially due to the repulsive action of myelin inhibitors, such as the myelin-associated glycoprotein (MAG), Nogo-A and the oligodendrocyte myelin glycoprotein (OMgp). These inhibitors bind and signal through a single receptor/co-receptor complex that comprises of NgR1/LINGO-1 and either p75 or TROY, triggering intracellular downstream signaling that impedes the re-growth of axons. Structure-function analysis of myelin inhibitors and their neuronal receptors, particularly the NgRs, have provided novel information regarding the molecular details of the inhibitor/receptor/co-receptor interactions. Structural and biochemical studies have revealed the architecture of many of these proteins and identified the molecular regions important for assembly of the inhibitory signaling complexes. It was also recently shown that gangliosides, such as GT1b, mediate receptor/co-receptor binding. In this review, we highlight these studies and summarize our current understanding of the multi-protein cell-surface complexes mediating inhibitory signaling events at the neuron/myelin interface. PMID- 24956134 TI - A plasmonic optical fiber patterned by template transfer as a high-performance flexible nanoprobe for real-time biosensing. AB - Surface plasmon resonance (SPR) on metal nanostructures offers a promising route for manipulation and interrogation of light in the subwavelength regime. However, the utility of SPR structures is largely limited by currently used complex nanofabrication methods and relatively sophisticated optical components. Here to relieve these restrictions, plasmonic optical fibers are constructed by transferring periodic metal nanostructures from patterned templates onto endfaces of optical fibers using an epoxy adhesive. Patterned metal structures are generally extended from two-dimensional (2D) nanohole arrays to one-dimensional (1D) nanoslit arrays. By controlling the viscosity of the adhesive layer, diverse surface topographies of metal structures are realized with the same template. We design a special plasmonic fiber that simultaneously implements multimode refractive index sensing (transmission and reflection) with remarkably narrow linewidth (6.6 nm) and high figure of merit (60.7), which are both among the best reported values for SPR sensors. We further demonstrate a real-time immunoassay relying on our plasmonic fiber integrated with a special flow cell. Plasmonic optical fibers also take advantages of excellent stability during fiber bending and capability of spectrum filtering. These features enable our plasmonic fibers to open up an alternative avenue for the general community in biosensing and nanoplasmonics. PMID- 24956135 TI - Exploration of the mechanism of pattern-specific treatments in coronary heart disease with network pharmacology approach. AB - Traditional Chinese medicine (TCM) pattern is a valuable classification method in the treatment of complex disease such as coronary heart disease (CHD). In accordance to TCM patterns, our ancestors created many pertinent TCM formulae, which have been used in China for thousands of years and are still playing an important role in China today. However, the biological mechanism of TCM pattern specific formulae remains elusive. In this paper, we chose CHD patterns (Qi stagnation induced blood-stasis syndrome, abbreviated as QSB; Qi-deficiency induced blood-stasis syndrome, abbreviated as QDB) as examples to illustrate the mechanism of their pattern-specific formulae. Using entity grammar systems (EGS) formalism, we built two pharmacologic networks of the formulae and obtained the intersection and difference networks by network comparison. Then we analyzed their common and different mechanisms for treating CHD by GO enrichment analysis. The results indicate that QDB-specific formula takes more special molecular paths to treat CHD, which contribute to more severe pathological changes in comparison with QSB. In this paper, we achieved a better understanding of the pharmacological characteristics of CHD patterns-specific formulae, which is beneficial to explore different therapies for a disease to enhance the effectiveness and pertinence of treatment. PMID- 24956137 TI - Solvent dependent assembly of lanthanide metallacrowns using building blocks with incompatible symmetry preferences. AB - Solvent dependence in the assembly of coordination driven macrocycles is a poorly understood phenomenon. This work presents the solvent dependent assembly of 8 lanthanide metallacrowns (LnMCs) in solution using picoline hydroxamic acid (picHA), Zn(II), and Ln(III) ions. ESI-MS and single-crystal X-ray crystallography reveal the selective assembly of LnZn4(picHA)4(3+), LnZn5(picHA)5(3+), LnZn8(picHA)8(3+), LnZn12(picHA)12(3+), LnZn16(picHA)16(3+), Ln2Zn3(picHA)4(4+), Ln2Zn7-9(picHA)8-10, and Ln4Zn4-5(picHA)8-9 complexes in five different solvents. The coordination preferences of the hard Ln(III) ion and relatively soft Zn(II) ion dictate the solvent selectivity in this system. The LnMCs assemble with open or closed Zn(II) and/or Ln(III) coordination sites based on the behavior of the solvent as an ancillary ligand. This structural promiscuity is attributed to the symmetry incompatible building blocks, which generate assemblies with substantial geometric strain such that no clear thermodynamic minimum exists between the different LnMCs. These LnMCs assemble from a Zn5(picHA)4(2+) intermediate, which is monitored using (1)H NMR and ESI-MS to assess the stability of the complexes and possible assembly pathways based on kinetic considerations. LnMC assemblies that can be generated through central metal substitution reactions such as the LnZn4(picHA)4(3+), LnZn5(picHA)5(3+), and LnZn8(picHA)8(3+) effectively reach equilibrium after 24 h at room temperature. In contrast, LnMCs that must disrupt the Zn5L4(2+) structure to assemble, such as the LnZn16L16(3+), reach equilibrium after heating for 24 h at 65 degrees C. A pathway for LnMC assembly is presented where the Zn5L4(2+) is the key intermediate based on these reaction data and shared structural motifs in the complexes. These results correlate solvent dependent assembly to the building block geometry, highlighting synthetic approaches for generating novel complexes. PMID- 24956136 TI - Broad-spectrum beta-lactams in obese non-critically ill patients. AB - OBJECTIVES: Obesity may alter the pharmacokinetics of beta-lactams. The goal of this study was to evaluate if and why serum concentrations are inadequate when standard beta-lactam regimens are administered to obese, non-critically ill patients. SUBJECTS AND METHODS: During first year, we consecutively included infected, obese patients (body mass index (BMI) ?30 kg m(-2)) who received meropenem (MEM), piperacillin-tazobactam (TZP) or cefepime/ceftazidime (CEF). Patients with severe sepsis or septic shock, or those hospitalized in the intensive care unit were excluded. Serum drug concentrations were measured twice during the elimination phase by high-performance liquid chromatography. We evaluated whether free or total drug concentrations were >1 time (fT>minimal inhibition concentration (MIC)) or >4 times (T>4MIC) the clinical breakpoints for Pseudomonas aeruginosa during optimal periods of time: ?40% for MEM, ?50% for TZP and ?70% for CEF. RESULTS: We included 56 patients (median BMI: 36 kg m(-2)): 14 received MEM, 31 TZP and 11 CEF. The percentage of patients who attained target fT>MIC and T>4MIC were 93% and 21% for MEM, 68% and 19% for TZP, and 73% and 18% for CEF, respectively. High creatinine clearance (107 (range: 6-398) ml min(-1)) was the only risk factor in univariate and multivariate analyses to predict insufficient serum concentrations. CONCLUSIONS: In obese, non-critically ill patients, standard drug regimens of TZP and CEF resulted in insufficient drug concentrations to treat infections due to less susceptible bacteria. Augmented renal clearance was responsible for these low serum concentrations. New dosage regimens need to be explored in this patient population (EUDRA-CT: 2011-004239 29). PMID- 24956139 TI - Exploring the Hamiltonian inversion landscape. AB - The identification of quantum system Hamiltonians through the use of experimental data remains an important research goal. Seeking a Hamiltonian that is consistent with experimental measurements constitutes an excursion over a Hamiltonian inversion landscape, which is the quality of reproducing the data as a function of the Hamiltonian parameters. Recent theoretical work showed that with sufficient experimental data there should be local convexity about the true Hamiltonian on the landscape. The present paper builds on this result and performs simulations to test whether such convexity is observed. A gradient-based Hamiltonian search algorithm is incorporated into an inversion routine as a means to explore the local inversion landscape. The simulations consider idealized noise-free as well as noise-ridden experimental data. The results suggest that a sizable convex domain exists about the true Hamiltonian, even with a modest amount of experimental data and in the presence of a reasonable level of noise. PMID- 24956140 TI - Relationship between interchain interaction, exciton delocalization, and charge separation in low-bandgap copolymer blends. AB - We present a systematic study of the roles of crystallinity, interchain interaction, and exciton delocalization on ultrafast charge separation pathways in donor-acceptor copoloymer blends. We characterize the energy levels, excited state structures, and dynamics of the interchain species by combined ultrafast spectroscopy and computational quantum chemistry approaches. The alkyl side chain of a highly efficient donor-acceptor copolymer for solar cell applications, PBDTTT (poly(4,8-bis-alkyloxybenzo[1,2-b:4,5-b']dithiophene-2,6-diyl-alt (alkylthieno[3,4-b]thiophene-2-carboxylate)-2,6-diyl), is varied to tune the molecular packing and interchain interaction of the polymers in order to elucidate the charge separation pathways originating from intrachain and interchain species. Polymers with linear side chains result in more crystalline polymer domain that lead to preferential formation of interchain excitons delocalizing over more than one polymer backbone in the solid state. Our results demonstrate that the higher polymer crystallinity leads to slower charge separation due to coarser phase segregation and formation of the interchain excited states that are energetically unfavorable for charge separation. Such energetics of the interchain excitons in low-bandgap copolymers calls for optimized solar cell morphologies that are fundamentally different from those based on homopolymers such as P3HT (poly-3-hexylthiophene). A long-range crystalline polymer domain is detrimental rather than beneficial to solar cell performance for a low-bandgap copolymer which is in direct contrast to the observed behavior in P3HT based devices. PMID- 24956138 TI - Hydroxylated derivatives of NPC1161: theoretical insights into their potential toxicity and the feasibility and regioselectivity of their formation. AB - For antimalarial 8-aminoquinoline (8-AQ) drugs, the ionization potential (energy required to remove an electron) of their putative metabolites has been proposed to be correlated in part to their hemotoxicity potential. NPC1161 is a developmental candidate as an 8-AQ antimalarial drug. In this work, the ionization potentials (IPs) of the S-NPC1161 (NPC1161a) hydroxylated derivatives, which are possible metabolites derived from action of endogenous cytochrome P450 (CYP450) enzymes, were calculated at the B3LYP-SCRF(PCM)/6-311++G**//B3LYP/6 31G** level in water. The derivative hydroxylated at N1' (8-amino) was found to have the smallest IP of ~ 430 kJ/mol, predicting that it would be the most hemotoxic. The calculated IPs of the derivatives hydroxylated at the C2 and C7 positions were ~ 475 and ~ 478 kJ/mol, respectively, whereas the calculated IPs of those hydroxylated at all other possible positions were between 480 and 490 kJ/mol. The homolytic bond dissociation energies (HBDEs) of all C-H/N-H bonds in NPC1161a were also calculated. The smaller HBDEs of the C-H/N-H bonds on the 8 amino side chain suggest that these positions are more easily hydroxylated compared to other sites. Molecular orbital analysis implies that the N1' position should be the most reactive center when NPC1161 approaches the heme in CYP450. PMID- 24956141 TI - Spontaneous recovery of severe nilotinib-induced bone marrow aplasia and successful retreatment with dasatinib in a patient with Chronic Phase Chronic Myeloid Leukemia. PMID- 24956142 TI - Response to imatinib therapy in adult patients with chronic myeloid leukemia in Saudi population: a single-center study. AB - No study has been published yet in the Arab world regarding response and outcome of imatinib in patients with chronic myeloid leukemia (CML). This study evaluated a total of 122 patients with CML treated with imatinib between 2001 and 2012. Survival, hematologic, cytogenetic and molecular responses and adverse events were assessed. The 5-year overall survival (OS), event free survival (EFS) and progression-free survival (PFS) rates were: 95.4 +/- 2.3%, 81.4 +/- 4.6% and 90.8 +/- 3.2%, respectively. Significant differences in OS (p = 0.001), EFS (p = 0.001) and PFS (p = 0.001) were noted when patients were stratified by cytogenetic response. Survival by Sokal risk groups was not significant (p = 0.293). Complete hematologic response was achieved in 94 patients (93.1%), cytogenetic response in 84 (83.2%), major molecular response in 62 (61.4%) and complete molecular response in 34 (33.7%). This article presents the first evidence on the effectiveness of imatinib in patients with CML from Saudi Arabia and highlights similarities and differences in response patterns in published studies. PMID- 24956144 TI - Disparate survival outcomes after front-line chemoimmunotherapy in older patients with follicular, nodal marginal zone and small lymphocytic lymphoma. AB - Using Surveillance, Epidemiology and End Results (SEER)-Medicare data (1996 2010), we compared survival and toxicity outcomes in 6993 patients older than 65 years with follicular (FL), nodal marginal zone (NMZL) and small lymphocytic lymphoma (SLL) receiving front-line therapy with rituximab (R), RCHOP (R, cyclophosphamide, doxorubicin, vincristine, prednisone), RCVP (R, cyclophosphamide, vincristine, prednisone) or R-fludarabine-containing regimens within 3 years from diagnosis. We demonstrated significant heterogeneity by histology after various regimens in multivariable survival models. Compared with RCHOP, overall survival was inferior with fludarabine-based regimens in FL (hazard ratio [HR] 1.53, p = 0.0001) and NMZL (HR 1.88, p = 0.0018). Conversely, in SLL outcomes were similar with any regimen. In NMZL and SLL, survival was not significantly different after single-agent R compared with multi-agent combinations. Choice of front-line chemotherapy may thus impact survival in older patients with indolent lymphomas, and heterogeneity by histology should be accounted for in clinical trials. PMID- 24956143 TI - Prognostic significance of geriatric assessment in combination with laboratory parameters in elderly patients with aggressive non-Hodgkin lymphoma. AB - The age-adjusted International Prognostic Index (IPI) is an important prognostic factor for patients with non-Hodgkin lymphoma (NHL). We investigated whether a geriatric assessment (GA) is of additional prognostic value in NHL. In this prospective cohort study of 44 patients aged 70 years or older with NHL receiving rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), a GA was administered before the start of chemotherapy. GA was composed of the Mini Nutritional Assessment (MNA), Groningen Frailty Indicator (GFI), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Mini Mental State Examination (MMSE) and levels of albumin, creatinine, lactate dehydrogenase (LDH) and hemoglobin. Multivariate analyses were performed using logistic regression and the Cox regression model. After adjustment for sex, age, comorbidity and univariate laboratory values with p <= 0.1, abnormal MNA and GFI scores and low hemoglobin level were associated with not being able to complete the intended chemotherapy: odds ratio (OR) 8.29 (95% confidence interval [CI]: 1.24-55.6; p = 0.03), 9.17 (95% CI: 1.51-55.8; p = 0.02) and 5.41 (95% CI: 0.99-29.8; p = 0.05), respectively. Adjusted for sex, age, comorbidity, age-adjusted IPI and univariate laboratory values with p <= 0.1, frailty by GFI and low hemoglobin were associated with worse survival, with a hazard ratio (HR) of mortality of 2.55 (95% CI: 1.07-6.10; p = 0.04) and 4.90 (95% CI: 1.76-13.7; p = 0.002), respectively. We conclude that (risk of) malnutrition, measured with the MNA, frailty, measured with the GFI, and low hemoglobin level had additional predictive value for early treatment withdrawal, and GFI and hemoglobin were, independent of the age-adjusted IPI, predictive for an increased mortality risk. PMID- 24956145 TI - Patients with myelodysplastic syndromes treated with azacitidine in clinical practice: the AVIDA registry. AB - The AVIDA registry evaluated azacitidine usage and effectiveness in unselected patients with myelodysplastic syndromes (MDS) in community practice. Treating physicians made all treatment decisions. Hematologic improvement (HI) and transfusion independence (TI) assessments used International Working Group (IWG) 2000 criteria. Enrolled were 421 patients with MDS (n = 228 International Prognostic Scoring System [IPSS] lower-risk, n = 106 higher-risk, 86 patients unclassified) from 105 US sites. Median follow-up was 7.6 months (range: 0.1 27.6). HI and red blood cell TI rates were similar regardless of administration route or dosing schedule. Safety and tolerability were consistent with previous reports. The AVIDA registry data support azacitidine effectiveness and safety in patients with lower- or higher-risk MDS treated in community practice. PMID- 24956146 TI - No association between MTR rs1805087 A > G polymorphism and non-Hodgkin lymphoma susceptibility: evidence from 11 486 subjects. AB - Numerous investigations have examined the association between MTR rs1805087 A> G polymorphism and non-Hodgkin lymphoma (NHL) susceptibility, yet have generated conflicting results. Therefore, the current meta-analysis was performed to comprehensively reevaluate this association. A systematic literature search of PubMed and Embase databases was conducted to seek eligible publications. The final analysis included 13 publications with a total of 4555 cases of NHL and 6931 controls. Overall, pooled analysis did not yield any statistically significant association between MTR rs1805087 A> G and NHL risk. Stratification analysis by source of controls showed a decreased risk of NHL with the polymorphism of interest in hospital-based studies, while no significant association was observed when data were stratified by ethnicity, sample size and NHL subtype. This meta-analysis does not indicate a major role of the MTR rs1805087 A> G polymorphism in modulating NHL risk. However, well-designed prospective studies with large sample sizes are encouraged to validate our findings. PMID- 24956147 TI - Identification of naphthol derivatives as novel antifeedants and insecticides. 1. AB - A series of beta-naphthol-derived 2-aminobenzothiazolomethylnaphthol derivatives (4a-4q) were synthesized and purified in excellent yields (86-94%) using green protocols and screened for their antifeedant and toxic activities against tobacco caterpillar (Spodoptera litura) and castor semilooper (Achaea janata) using no choice leaf disk and topical bioassay methods. Four of them, 4d, 4f, 4i, and 4j, were identified to be potent antifeedants with ED50 values of 16.4, 19.3, 7.0, and 5.2 MUg/cm(2) against S. litura and 13.9, 17.2, 10.2, and 7.7 MUg/cm(2) against A. janata, respectively, and the mortality rate is >95% for 4i and 4j in the case of S. litura and 4j in case of A. janata at a dosage of 0.2 MUg/insect. Compounds 4d, 4i, and 4m are moderately toxic to A. janata only. Overall, this study identified a novel class of synthetic compounds that do not belong to organochlorides, organophosphates, carbamates, or neonicotinoids as strong antifeedants as well as insecticides. PMID- 24956148 TI - SOCS1/3 expression levels in HSV-1-infected, cytokine-polarized and -unpolarized macrophages. AB - Macrophage subtypes are characterized as proinflammatory (M1) or immunomodulatory and tissue remodeling (M2). Since macrophages play a pivotal role in controlling Herpes simplex virus type-1 (HSV-1) replication, effects of HSV-1 by 24 h of infection were determined in murine J774A.1 macrophages unpolarized (M0) or polarized to either an M1 or M2 phenotype. Morphology, cell viability, and expression of CD14 (co-receptor for lipopolysaccharide), CD86 (B7.2-immune co stimulatory molecule), and suppressors of cytokine signaling (SOCS1 and SOCS3) were determined. M1 macrophages were flattened and vacuolated, while M2 cells appeared elongated with a few vacuoles. Compared with unpolarized M0 cells, M1 cells showed a 31% decrease in viability, a 2-fold increase in the number of CD14(+)-CD86(+) cells, no change in SOCS1 expression, and an 11-fold decrease in SOCS3 expression. M2 cells exhibited a 9% decrease in viability, a 26.0% decrease in the number of CD14(+)-CD86(+) cells, and no change in SOCS1/SOCS3 expression levels compared with M0 cells. After HSV-1 infection, all phenotypes appeared rounded, cell viabilities decreased as did numbers of M1 cells expressing CD14 and CD86. At 24 h after infection, M0 control and M2 cells showed greater virus yield than did the M1 cells, presumably reflecting the loss of viable M1 cells. SOCS1 expression was predominant in uninfected M1-polarized cells and in virus infected control (M0) cells. SOCS1/SOCS3 expression ratio was 7:1 in uninfected M1 macrophages and approached 1:1 in M1 cells at 24 h after infection with HSV-1. In contrast, little differences were seen in SOCS1/SOCS3 expression ratios in uninfected M2-polarized cells or virus-infected M2 cells. These observations suggest that SOCS1/SOCS3 expression ratios can be used to characterize HSV-1 infected and uninfected macrophages. PMID- 24956149 TI - Variable flip angle three-dimensional fast spin-echo sequence combined with outer volume suppression for imaging trabecular bone structure of the proximal femur. AB - BACKGROUND: To demonstrate the feasibility of using a variable flip angle three dimensional fast spin-echo (3D VFA-FSE) sequence combined with outer volume suppression for imaging trabecular bone structure at the proximal femur in vivo at 3 Tesla. METHODS: The 3D VFA-FSE acquisition was optimized to minimize blurring and to provide high signal-to-noise ratio (SNR) from bone marrow. Outer volume suppression was achieved by applying three quadratic-phase radio-frequency pulses. The SNR and trabecular bone structures from 3D VFA-FSE were compared with those from previously demonstrated multiple-acquisition 3D balanced steady-state free precision (bSSFP) using theoretical simulations, ex vivo experiments, and in vivo experiments. RESULTS: Our simulation demonstrated that 3D VFA-FSE can provide at least 35% higher SNR than 3D bSSFP, which was confirmed by the ex vivo and in vivo experiments. The ex vivo experiments demonstrated a good correlation and agreement between bone structural paramters obtained with the two sequences. The proposed sequence depicted trabecular bone structure at the proxiaml femur in vivo well without visible suppression artifacts and provided a mean SNR of 11.0. CONCLUSION: The 3D VFA-FSE sequence combined with outer volume suppression can depict the trabecular bone structure of the proximal femur in vivo with minimal blurring and high SNR efficiency. PMID- 24956151 TI - Non-genetic heterogeneity caused by differential single-cell adhesion. PMID- 24956150 TI - Formation of microparticles in the injured brain of patients with severe isolated traumatic brain injury. AB - The potential pathophysiological role of circulating microparticles (MPs) has been recognized in various conditions, such as cardiovascular and thrombotic diseases. Traumatic brain injury (TBI) has a complex pathophysiology that involves coagulopathy and inflammation. We investigated endothelial-, platelet-, and leukocyte-derived microparticles (EMPs, PMPs, and LMPs, respectively) in 16 patients with severe isolated TBI. Arterial and cerebrovenous samples were taken repeatedly, during 1-72 h after injury. Subpopulations of MPs, exposing tissue factor (TF) and P-selection, were also studied. MP counts in cerebrovenous samples, irrespective of cellular origin, were higher in TBI cases, compared to healthy controls (peak levels of EMPs were approximately 7 times higher, PMPs 1.4 times higher, and LMPs 2 times higher, respectively; p<0.001 for all). MP counts declined sharply from high levels shortly after the trauma toward slightly elevated levels 72 h later. EMPs and PMPs exposing TF, as well as PMPs exposing P selection, showed a transcranial gradient with higher concentration in cerebrovenous, compared to arterial, samples. In contrast, LMPs exposing TF were higher in arterial samples, suggesting accumulation of LMPs in the brain. We conclude that the pattern of circulating MPs is altered after TBI. PMPs exposing P-selection and EMPs exposing TF seem to be generated in the injured brain, whereas LMPs exposing TF are accumulated. The pathophysiological significance of these changes in MP pattern in TBI should be further investigated. Including MPs exposing brain-specific antigens in the assessment of brain injury would give further information of origin and likely give additional information of the size of the injury, given that the MP phenotypes investigated in the present study are not brain-specific markers. PMID- 24956152 TI - Effects of winter cover crops residue returning on soil enzyme activities and soil microbial community in double-cropping rice fields. AB - Residue management in cropping systems is useful to improve soil quality. However, the studies on the effects of residue management on the enzyme activities and microbial community of soils in South China are few. Therefore, the effects of incorporating winter cover crop residue with a double-cropping rice (Oryza sativa L.) system on soil enzyme activities and microbial community in Southern China fields were studied. The experiment has conducted at the experimental station of the Institute of Soil and Fertilizer Research, Hunan Academy of Agricultural Science, China since winter 2004. Four winter cropping systems were used: rice-rice-ryegrass (Lolium multiflorum L.) (R-R-Ry), rice-rice Chinese milk vetch (Astragalus sinicus L.) (R-R-Mv), rice-rice-rape (Brassica napus L.) (R-R-Ra) and rice-rice with winter fallow (R-R-Fa). The result indicated that the enzyme activities in the R-R-Ry, R-R-Mv and R-R-Ra systems were significantly higher (P<0.05) than in the R-R-Fa system during the early and late rice season. The beta-glucosidase activities reached peak values at the tillering stage after residue application, and alkaline phosphatase activities reached peak values at the booting stage after residue application, respectively, the activities of beta-glucosidase and alkaline phosphatase gradually decreased after this. Arylsulfatase activities reached peak values at the maturity stage. Arylamidase activities reached peak values at the maturity stage. The numbers of aerobic bacteria, actinomycete and fungus of residue treatments were significantly higher (P<0.05) than that the R-R-Ra system. However, the number of anaerobic bacteria under the R-R-Ry and R-R-Mv systems was significantly lower (P<0.05) than that under the R-R-Fa system during early rice and late rice growth stage. Thus, incorporation of winter cover crops into rotations may increase enzyme activities and microbial community in soil and therefore improve soil quality. PMID- 24956153 TI - Self-relevant disgust and self-harm urges in patients with borderline personality disorder and depression: a pilot study with a newly designed psychological challenge. AB - BACKGROUND: Borderline personality disorder (BPD) is a common psychiatric condition associated with self-harm. Self-harm is poorly understood and there is currently no treatment for acute presentations with self-harm urges. OBJECTIVES: By using a new task (Self-relevant Task; SRT), to explore emotions related to one's own person (PERSON task) and body (BODY task), to study the correlations of these emotions, specifically disgust, with self-harm urge level changes, and to test the task's potential to be developed into an experimental model of self harming for treatment trials. METHODS: 17 BPD patients, 27 major depressive disorder (MDD) patients, and 25 healthy volunteers performed the SRT. Emotion labels were extracted from task narratives and disgust and self-harm urge level changes measured by visual analogue scales. We used validated rating scales to measure symptom severity. RESULTS: The SRT was effective at inducing negative emotions and self-harm urge changes. Self-harm urge changes correlated with borderline symptom severity. Post-task disgust levels on the visual analogue scales were higher in BPD patients than in healthy controls in the PERSON task, and higher than in both control groups in the BODY task. Changes in disgust levels during the task were significantly greater in the patient groups. Post task disgust levels or changes in disgust were not associated with self-harm urge changes (except the latter in MDD in the PERSON task), but self-harm urge changes and disgust (but no other emotion) narrative labels were on a whole sample level. CONCLUSION: Although associations with the analogue scale measures were not significant, self-disgust reported in the narrative of patients may be associated with a higher probability of self-harm urges. Further research with larger sample sizes is needed to confirm this relationship and to examine whether reducing self disgust could reduce self-harm urges. The SRT was effective and safe, and could be standardized for experimental studies. PMID- 24956154 TI - A vapourized Delta(9)-tetrahydrocannabinol (Delta(9)-THC) delivery system part II: comparison of behavioural effects of pulmonary versus parenteral cannabinoid exposure in rodents. AB - INTRODUCTION: Studies of the rewarding and addictive properties of cannabinoids using rodents as animal models of human behaviour often fail to replicate findings from human studies. Animal studies typically employ parenteral routes of administration, whereas humans typically smoke cannabis, thus discrepancies may be related to different pharmacokinetics of parenteral and pulmonary routes of administration. Accordingly, a novel delivery system of vapourized Delta(9) tetrahydrocannabinol (Delta(9)-THC) was developed and assessed for its pharmacokinetic, pharmacodynamic, and behavioural effects in rodents. A commercially available vapourizer was used to assess the effects of pulmonary (vapourized) administration of Delta(9)-THC and directly compared to parenteral (intraperitoneal, IP) administration of Delta(9)-THC. METHODS: Sprague-Dawley rats were exposed to pure Delta(9)-THC vapour (1, 2, 5, 10, and 20mg/pad), using a Volcano(r) vapourizing device (Storz and Bickel, Germany) or IP-administered Delta(9)-THC (0.1, 0.3, 0.5, 1.0mg/kg), and drug effects on locomotor activity, food and water consumption, and cross-sensitization to morphine (5mg/kg) were measured. RESULTS: Vapourized Delta(9)-THC significantly increased feeding during the first hour following exposure, whereas IP-administered Delta(9)-THC failed to produce a reliable increase in feeding at all doses tested. Acute administration of 10mg of vapourized Delta(9)-THC induced a short-lasting stimulation in locomotor activity compared to control in the first of four hours of testing over 7days of repeated exposure; this chronic exposure to 10mg of vapourized Delta(9) THC did not induce behavioural sensitization to morphine. DISCUSSION: These results suggest vapourized Delta(9)-THC administration produces behavioural effects qualitatively different from those induced by IP administration in rodents. Furthermore, vapourized Delta(9)-THC delivery in rodents may produce behavioural effects more comparable to those observed in humans. We conclude that some of the conflicting findings in animal and human cannabinoid studies may be related to pharmacokinetic differences associated with route of administration. PMID- 24956157 TI - Dendrimeric tetravalent ligands for the serotonin-gated ion channel. AB - Multivalency is widely used in nature in specific recognition processes. This paper describes an approach to multivalency in the pentameric 5-HT3 receptor, a ligand-gated ion channel, which constitutes an example of intrinsically multivalent biological receptors. Owing to the picomolar Ki value, TETRA-L represents an outstanding multivalent ligand for the neurotransmitter receptor. PMID- 24956155 TI - Post-mortem stability of RNA in skeletal muscle and adipose tissue and the tissue specific expression of myostatin, perilipin and associated factors in the horse. AB - Obesity, a major concern for equine welfare, is highly prevalent in the leisure horse population. Skeletal-muscle and adipose tissues are important determinants of maintenance energy requirements. The myostatin and perilipin pathways play key roles in the regulation of muscle mass and lipolysis respectively and have both been associated with obesity predisposition in other mammalian species. High quality samples, suitable for molecular biology, are an essential prerequisite for detailed investigations of gene and protein expression. Hence, this study has evaluated a) the post-mortem stability of RNA extracted from skeletal-muscle and adipose-tissues collected under commercial conditions and b) the tissue-specific presence of myostatin, the moystatin receptor (activin receptor IIB, ActRIIB), follistatin and perilipin, genes and proteins across a range of equine tissues. Objectives were addressed using tissues from 7 Thoroughbred horses presented for slaughter at a commercial abattoir; a) samples were collected at 7 time-points from Masseter muscle and perirenal adipose from 5 minutes to 6 hours post-mortem. Extracted RN was appraised by Optical Density analysis and agarose-gel electrophoresis. b) Quantitative real time PCR and Western Blotting were used to evaluate gene and protein expression in anatomically-defined samples collected from 17 tissues (6 organs, 4 skeletal muscles and 7 discrete adipose depots). The results indicate that, under the present collection conditions, intact, good quality RNA could be extracted from skeletal-muscle for up to 2 hours post mortem. However, RNA from adipose tissue may be more susceptible to degradation/contamination and samples should be collected no later than 30 minutes post-mortem. The data also show that myostatin and ActRIIB genes and proteins were almost exclusively expressed in skeletal muscle. The follistatin gene showed a more diverse gene expression profile, with expression evident in several organs, adipose tissue depots and skeletal muscles. Perilipin gene and protein were almost exclusively expressed by adipose tissue. PMID- 24956158 TI - Statistical model for the mechanical behavior of the tissue engineering non-woven fibrous matrices under large deformation. AB - The fibrous matrices are widely used as scaffolds for the regeneration of load bearing tissues due to their structural and mechanical similarities with the fibrous components of the extracellular matrix. These scaffolds not only provide the appropriate microenvironment for the residing cells but also act as medium for the transmission of the mechanical stimuli, essential for the tissue regeneration, from macroscopic scale of the scaffolds to the microscopic scale of cells. The requirement of the mechanical loading for the tissue regeneration requires the fibrous scaffolds to be able to sustain the complex three dimensional mechanical loading conditions. In order to gain insight into the mechanical behavior of the fibrous matrices under large amount of elongation as well as shear, a statistical model has been formulated to study the macroscopic mechanical behavior of the electrospun fibrous matrix and the transmission of the mechanical stimuli from scaffolds to the cells via the constituting fibers. The study establishes the load-deformation relationships for the fibrous matrices for different structural parameters. It also quantifies the changes in the fiber arrangement and tension generated in the fibers with the deformation of the matrix. The model reveals that the tension generated in the fibers on matrix deformation is not homogeneous and hence the cells located in different regions of the fibrous scaffold might experience different mechanical stimuli. The mechanical response of fibrous matrices was also found to be dependent on the aspect ratio of the matrix. Therefore, the model establishes a structure mechanics interdependence of the fibrous matrices under large deformation, which can be utilized in identifying the appropriate structure and external mechanical loading conditions for the regeneration of load-bearing tissues. PMID- 24956159 TI - Rheological behaviour of reconstructed skin. AB - Reconstructed skins have been developed to replace skin when the integrity of tissue has been compromised following severe injury, and to provide alternative methods validating the innocuousness and effectiveness of dermatological and cosmetic products. However the functional properties of tissue substitutes have not been well characterised, mainly since mechanical measurement devices have not been designed to test cell culture materials in vitro. From the mechanical standpoint, reconstructed skin is a heterogeneous multi-layer viscoelastic material. To characterise the time-dependent behaviour of reconstructed skin, spherical indentation load-relaxation tests were performed with a specific original device adapted to measure small soft tissue samples. Load-relaxation indentation tests were performed on a standard reconstructed skin model and on sub-components of the reconstructed skin (3D-scaffold alone and dermal equivalent). Generalised Maxwell and Kelvin-Voigt rheological models are proposed for analysing the mechanical behaviour of each biological tissue. The results indicated a modification of the rheological behaviour of the samples tested as a function of their biological structure. The 3D-scaffold was modelled using the one-branch Maxwell model, while the dermis equivalent and the reconstructed skin were modeled using a one-branch and a two-branch Kelvin-Voigt model, respectively. Finally, we demonstrated that skin cells contribute to global mechanical behaviour through an increase of the instantaneous relaxation function, while the 3D-scaffold alone influences the mechanical response of long relaxation times. PMID- 24956156 TI - Sex-dependent influence of endogenous estrogen in pulmonary hypertension. AB - RATIONALE: The incidence of pulmonary arterial hypertension is greater in women, suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males, exogenously administered estrogen can protect against pulmonary hypertension (PH). However, in models that display female susceptibility, estrogens may play a causative role. OBJECTIVES: To clarify the influence of endogenous estrogen and sex in PH and assess the therapeutic potential of a clinically available aromatase inhibitor. METHODS: We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH: the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of sex on pulmonary expression of aromatase in these models and in lungs from patients with pulmonary arterial hypertension. MEASUREMENTS AND MAIN RESULTS: Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was caused by reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor alpha also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased bone morphogenetic protein receptor 2 and Id1 expression compared with male. Anastrozole treatment reversed the impaired bone morphogenetic protein receptor 2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared with male. CONCLUSIONS: The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential. PMID- 24956160 TI - Effect of solid distribution on elastic properties of open-cell cellular solids using numerical and experimental methods. AB - Effect of solid distribution between edges and vertices of three-dimensional cellular solid with an open-cell structure was investigated both numerically and experimentally. Finite element analysis (FEA) with continuum elements and appropriate periodic boundary condition was employed to calculate the elastic properties of cellular solids using tetrakaidecahedral (Kelvin) unit cell. Relative densities between 0.01 and 0.1 and various values of solid fractions were considered. In order to validate the numerical model, three scaffolds with the relative density of 0.08, but different amounts of solid in vertices, were fabricated via 3-D printing technique. Good agreement was observed between numerical simulation and experimental results. Results of numerical simulation showed that, at low relative densities (<0.03), Young's modulus increased by shifting materials away from edges to vertices at first and then decreased after reaching a critical point. However, for the high values of relative density, Young's modulus increased monotonically. Mechanisms of such a behavior were discussed in detail. Results also indicated that Poisson's ratio decreased by increasing relative density and solid fraction in vertices. By fitting a curve to the data obtained from the numerical simulation and considering the relative density and solid fraction in vertices, empirical relations were derived for Young's modulus and Poisson's ratio. PMID- 24956161 TI - An insight into the autonomic and haemodynamic mechanisms underlying reflex syncope in children and adolescents: a multiparametric analysis. AB - Around 15% of children and adolescents experience at least one episode of syncope until adulthood. Excluding cardiac disease, the majority of syncopes are of reflex origin and benign in nature. In this situation, a tilt test is conducted to reproduce symptoms and to evaluate cardiovascular adaptations to orthostatism, but its mechanisms are not yet well defined. Here, we investigated haemodynamics and autonomic activity during tilt in young patients. Patients (n=113) with unexplained syncope were enrolled. Tilt followed a standard protocol without provocative agents. A positive response (fainters) was defined as a sudden development of syncope or presyncope associated with hypotension, bradycardia, or both. Haemodynamic parameters, autonomic activity, and baroreflex sensibility were evaluated. Data were analysed on baseline; immediately after tilting; on tilt adaptation; before fainting or before tilt-down for non-fainters; and on tilt-down. A total of 45 patients experienced syncope after a mean time of 18 minutes. During tilting up, fainters showed lower blood pressure and peripheral resistance values, which decreased progressively with time together with baroreflex sensibility. Sympathetic tone increased massively along time till syncope. No changes in cardiac output and heart rate were observed. Results show a strong effort of the autonomic nervous system to adapt to orthostatic stress through different magnitudes of sympathetic output, which was maximal before syncope without apparent modifications of parasympathetic tone. These changes suggest an imbalance between both branches of the autonomic nervous system, not enabling a time-progressive adaptation and leading the subject to faint. PMID- 24956162 TI - Strontium ions substitution in brushite crystals: the role of strontium chloride. AB - The incorporation of strontium chloride to brushite cement was successful to introduce strontium ions within the lattice of brushite crystals. The effect of strontium ions on brushite cement properties was concentration dependent; such that, the addition of 5% and 10% (w/w) SrCl2 significantly increased the cement FST and the addition of 10% SrCl2 decreased the cement tensile strength. Further, cement weight loss was shown to be increased by cement modification with SrCl2. The combination of ionic substitution and the degradability of brushite cements would constitute a system for the local delivery of strontium ions in the treatment of osteoporosis. PMID- 24956163 TI - Multi-composite bioactive osteogenic sponges featuring mesenchymal stem cells, platelet-rich plasma, nanoporous silicon enclosures, and Peptide amphiphiles for rapid bone regeneration. AB - A novel bioactive sponge was created with a composite of type I collagen sponges or porous poly(e-caprolactone) (PCL) scaffolds, platelet-rich plasma (PRP), BMP2 loaded nanoporous silicon enclosure (NSE) microparticles, mineralizing peptide amphiphiles (PA), and mesenchymal stem cells (MSC). Primary MSC from cortical bone (CB) tissue proved to form more and larger colony units, as well as produce more mineral matrix under osteogenic differentiation, than MSC from bone marrow (BM). Coating pre-treatments were optimized for maximum cell adhesion and mineralization, while a PRP-based gel carrier was created to efficiently deliver and retain MSC and microparticles within a porous scaffold while simultaneously promoting cell recruitment, proliferation, and angiogenesis. Components and composite sponges were evaluated for osteogenic differentiation in vitro. Osteogenic sponges were loaded with MSC, PRP, PA, and NSE and implanted subcutaneously in rats to evaluate the formation of bone tissue and angiogenesis in vivo. It was found that the combination of a collagen sponge with CB MSC, PRP, PA, and the BMP2-releasing NSE formed the most bone and was most vascularized by four weeks compared to analogous composites featuring BM MSC or PCL or lacking PRP, PA, and NSE. This study indicates that CB MSC should be considered as an alternative to marrow as a source of stem cells, while the PRP-PA cell and microparticle delivery system may be utilized for diverse tissue engineering applications. PMID- 24956166 TI - Meta-analysis of the association between lumican gene polymorphisms and susceptibility to high Myopia. AB - BACKGROUNDS: Many studies have evaluated the association between lumican (LUM) gene polymorphisms and high myopia. However, the results remain controversial. This meta-analysis aims to comprehensively evaluate the relationship between two common LUM polymorphisms (rs3759223 and rs3759222) and the risk of high myopia. METHODS: A comprehensive literature search for studies published up until September of 2013 was performed. Data were extracted independently by two investigators, and the weighted Odds Ratios (ORs) and 95% Confidence Intervals (CIs) for the associations were obtained by using a random-effects model. RESULTS: Eight studies (1425cases and 1271 controls) were identified for the analysis of the association between rs3759223 polymorphism and high myopia. The results indicated that rs3759223 polymorphism was associated with high myopia under a recessive model (OR = 1.71, 95%CI 1.04-2.81). Further subgroup analysis indicated that this polymorphism was associated with high myopia among Chinese people in the additive model (OR = 1.17, 95%CI 1.06-1.29) and a recessive model (OR = 1.75, 95%CI 1.00-3.06) with control group coming from hospital based population. Four studies (1024 cases and 1163 controls) were identified for the analysis of the association between rs3759222 polymorphism and high myopia. The results indicated that rs3759222 polymorphism was not associated with high myopia in all genetic models, even the subgroup analysis couldn't provide relative proof to assure the outcome. CONCLUSION: This meta-analysis suggests that LUM polymorphisms are associated with the risk of high myopia. However, well-designed studies with larger sample sizes and more ethnic groups are required to further validate this association. PMID- 24956165 TI - Perturbation of the monomer-monomer interfaces of the benzoylformate decarboxylase tetramer. AB - The X-ray structure of benzoylformate decarboxylase (BFDC) from Pseudomonas putida ATCC 12633 shows it to be a tetramer. This was believed to be typical of all thiamin diphosphate-dependent decarboxylases until recently when the structure of KdcA, a branched-chain 2-keto acid decarboxylase from Lactococcus lactis, showed it to be a homodimer. This lent credence to earlier unfolding experiments on pyruvate decarboxylase from Saccharomyces cerevisiae that indicated that it might be active as a dimer. To investigate this possibility in BFDC, we sought to shift the equilibrium toward dimer formation. Point mutations were made in the noncatalytic monomer-monomer interfaces, but these had a minimal effect on both tetramer formation and catalytic activity. Subsequently, the R141E/Y288A/A306F variant was shown by analytical ultracentrifugation to be partially dimeric. It was also found to be catalytically inactive. Further experiments revealed that just two mutations, R141E and A306F, were sufficient to markedly alter the dimer-tetramer equilibrium and to provide an ~450-fold decrease in kcat. Equilibrium denaturation studies suggested that the residual activity was possibly due to the presence of residual tetramer. The structures of the R141E and A306F variants, determined to <1.5 A resolution, hinted that disruption of the monomer interfaces will be accompanied by movement of a loop containing Leu109 and Leu110. As these residues contribute to the hydrophobicity of the active site and the correct positioning of the substrate, it seems that tetramer formation may well be critical to the catalytic activity of BFDC. PMID- 24956167 TI - Transcriptome profiling reveals higher vertebrate orthologous of intra cytoplasmic pattern recognition receptors in grey bamboo shark. AB - From an immunologist perspective, sharks are an important group of jawed cartilaginous fishes and survey of the public database revealed a great gap in availability of large-scale sequence data for the group of Chondrichthyans the elasmobranchs. In an attempt to bridge this deficit we generated the transcriptome from the spleen and kidney tissues (a total of 1,606,172 transcripts) of the shark, Chiloscyllium griseum using the Illumina HiSeq2000 platform. With a cut off of > = 300 bp and an expression value of >1RPKM we used 43,385 transcripts for BLASTX analysis which revealed 17,548 transcripts matching to the NCBI nr database with an E-value of < = 10(-5) and similarity score of 40%. The longest transcript was 16,974 bases with matched to HECT domain containing E3 ubiqutin protein ligase. MEGAN4 annotation pipeline revealed immune and signalling pathways including cell adhesion molecules, cytokine-cytokine receptor interaction, T-cell receptor signalling pathway and chemokine signaling pathway to be highly expressed in spleen, while different metabolism pathways such as amino acid metabolism, carbohydrate metabolism, lipid metabolism and xenobiotic biodegradation were highly expressed in kidney. Few of the candidate genes were selected to analyze their expression levels in various tissues by real time PCR and also localization of a receptor by in-situ PCR to validate the prediction. We also predicted the domains structures of some of the identified pattern recognition receptors, their phylogenetic relationship with lower and higher vertebrates and the complete downstream signaling mediators of classical dsRNA signaling pathway. The generated transcriptome will be a valuable resource to further genetic and genomic research in elasmobranchs. PMID- 24956164 TI - Mechanotransduction: tuning stem cells fate. AB - It is a general concern that the success of regenerative medicine-based applications is based on the ability to recapitulate the molecular events that allow stem cells to repair the damaged tissue/organ. To this end biomaterials are designed to display properties that, in a precise and physiological-like fashion, could drive stem cell fate both in vitro and in vivo. The rationale is that stem cells are highly sensitive to forces and that they may convert mechanical stimuli into a chemical response. In this review, we describe novelties on stem cells and biomaterials interactions with more focus on the implication of the mechanical stimulation named mechanotransduction. PMID- 24956169 TI - Ultrastructural study of symmetrical acral keratoderma. AB - BACKGROUND: Symmetrical acral keratoderma is characterized by symmetrical brown hyperkeratotic patches on the acral extremities. However, no studies about its electron microscopic examination have been documented. OBJECTIVE: Our study was performed to further characterize the histopathology of symmetrical acral keratoderma. METHODS: A biopsy was taken from brown hyperkeratotic patches on the wrists. Investigative studies included light and electron microscopy. RESULTS: Light microscopy showed epidermal basket-weave hyperkeratosis and acanthosis. Ultrastructurally, the epidermis was thickened by acanthosis and compact stratum corneum. The horny cell layers were remarkably thicker in clinical affected skin than in adjacent clinically unaffected and healthy skin. The keratin filaments were remarkably clumped or aggregated and irregularly distributed in the horny, spinous, granular and basal cell layers. The tonofilaments formed tight clumps or aggregated at the perinuclear cytoplasm. CONCLUSION: The main ultrastructural features of symmetrical acral keratoderma were epidermal hyperkeratosis and abnormalities of the keratin filaments and tonofilaments. PMID- 24956168 TI - Panel based MALDI-TOF tumour profiling is a sensitive method for detecting mutations in clinical non small cell lung cancer tumour. AB - BACKGROUND: Analysis of tumour samples for mutations is becoming increasingly important in driving personalised therapy in cancer. As more targeted therapies are developed, options to survey mutations in multiple genes in a single tumour sample will become ever more attractive and are expected to become the mainstay of molecular diagnosis in non-small cell lung cancer (NSCLC) in the future. MATERIALS AND METHODS: 238 non-small cell lung cancer (NSCLC) tumour samples were analysed using a custom panel of 82 mutation assays across 14 oncogenes including KRAS and EGFR using Sequenom iPlex Matrix Assisted Laser Desorption/Ionisation Time of Flight Mass Spectrometry (MALDI-TOF). We compared the data generated for KRAS mutations to those detected by Amplification Refractory Mutation System (ARMS) based DxS TheraScreen K-RAS Mutation Kit. RESULTS: The ARMS detected mutations in 46/238 tumour samples. For samples with mutations detected by both approaches, 99.1% overall agreement was observed. The MALDI-TOF method detected an additional 6 samples as KRAS mutation positive and also provided data on concomitant mutations including PIK3CA and TP53. CONCLUSIONS: The Sequenom MALDI TOF method provides a sensitive panel-based approach which makes efficient use of patient diagnostic samples. This technology could provide an opportunity to deliver comprehensive screening of relevant biomarkers to the clinic earlier in disease management, without the need for repeat biopsy and allow for additional downstream analysis in NSCLC where available tissue may have been exhausted. PMID- 24956170 TI - S100A8/A9 mRNA induction in an ex vivo model of endotoxin tolerance: roles of IL 10 and IFNgamma. AB - OBJECTIVES: Septic syndromes are the leading cause of death in intensive care units. They are characterized by the development of immune dysfunctions such as endotoxin tolerance (ET), whose intensity and duration are associated with increased risk of nosocomial infections and mortality. Alarmins S100A8 and S100A9 have been shown to be increased after septic shock. Importantly, a delayed S100A9 mRNA increase predicts hospital-acquired infection in patients. The aim of this study was to investigate the regulation of S100A8 and S100A9 mRNA expression in an ex vivo model of ET. SUBJECTS AND MEASUREMENTS: ET was reproduced ex vivo by priming healthy peripheral blood mononuclear cells (number of donors = 9 to 10) with low-dose endotoxin (2 ng/ml) before stimulation with high dose endotoxin (100 ng/ml). S100A8 and S100A9 mRNA levels were measured by quantitative real time polymerase chain reactions. MAIN RESULTS: ET was established by observing decreased TNFalpha and increased IL-10 transcriptomic responses to two subsequent endotoxin challenges. Interestingly, ET was associated with increased S100A8 and S100A9 mRNA expression ex vivo. We showed that IL-10 played a role in this process, since S100A8 and S100A9 mRNA increases were significantly abrogated by IL-10 blockade in the model. Conversely, treatment with rIFN-gamma, a pro inflammatory and immunostimulating molecule known to block ET induction, was able to restore normal S100A8 and S100A9 mRNA in this model. CONCLUSIONS: In this ex vivo model, we observed that S100A8 and S100A9 mRNA expression was significantly increased during ET. This reproduced ex vivo the observations we had previously made in septic shock patients. Interestingly, IL-10 blockade and rIFN-gamma treatment partially abrogated S100A8/A9 mRNA increases in this model. Pending confirmation in larger, independent clinical studies, these preliminary results suggest that S100A8 and S100A9 mRNA levels might be used as surrogate markers of ET and as stratification tools for personalized immunotherapy in septic shock patients. PMID- 24956172 TI - Environmental enrichment attenuates nicotine behavioral sensitization in male and female rats. AB - Environmental enrichment decreases nicotine reactivity in male rats, but these effects have not been examined in females. This research was conducted to examine the effects of enrichment on nicotine behavioral sensitization (i.e., nicotine reactivity) in male and female rats. One hundred forty-four Sprague-Dawley rats (72 male, 72 female) were raised in isolation, social enrichment (groups of three rats [SE]), or combined physical enrichment and social enrichment (groups of three rats with novel toys [PESE]) housing conditions. As adults, they received daily subcutaneous injections of saline or nicotine (0.1, 0.5, or 1.0 mg/kg) for 12 days; locomotor activity was measured on drug days 1, 5, 9, and 12. Before drug administration, PESE and SE decreased activity in males; only PESE decreased activity in females, F(2, 120) = 6.51, p < .01. In the drug phase, nicotine behavioral sensitization occurred, F(8.46, 341.04) = 20.71, p < .001, and was greater in females than males, F(8.340, 319.715) = 2.072, p < .05. Enrichment decreased nicotine behavioral sensitization in both sexes, F(16.91, 341.04) = 2.48, p < .01. In conclusion, nicotine behavioral sensitization occurred in male and female rats and was attenuated by environmental enrichment. This research has implications for treatment and prevention strategies in humans. Programs that incorporate aspects of social and environmental stimulation may have enhanced effectiveness in preventing and reducing cigarette smoking and may have implications for relapse prevention. PMID- 24956171 TI - Cardiovascular safety of stimulants in children with attention deficit/hyperactivity disorder: a nationwide prospective cohort study. AB - OBJECTIVE: The purpose of this study was to determine whether stimulant users are at higher risk of a later cardiovascular event than are non-users, examining this association in both a national cohort and a population-based sample of children and adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD). We also aim to examine a possible dose-response relationship in such an association. METHODS: We conducted a longitudinal, prospective cohort study of all children born in Denmark between 1990 and 1999. Within this cohort, children with ADHD were identified. Data from national health registers on psychiatric and somatic diagnoses, stimulant prescriptions, cardiovascular risk factors, pre- and perinatal and sociodemographic covariates in all children and their parents were merged, using the unique personal identification number. Hazard ratios (HR) for cardiovascular events were estimated using Cox regression, adjusted for other known risk factors. RESULTS: In the total population (n=714,258 contributing a total of 6,767,982 person-years) use of stimulants increased the risk of a cardiovascular event; adjusted HR=1.83 (1.10-3.04). In children with ADHD (n=8300) stimulant treatment also increased the risk of a cardiovascular event (adjusted HR=2.20 [2.15-2.24]), with a complex time-dependent dose-response relationship. CONCLUSIONS: This is the first nationwide cohort study of the cardiovascular safety of stimulants in children and adolescents, and it represents, to our knowledge, the longest prospective follow-up study. Cardiovascular events were rare but twice as likely in stimulant users as in non users, both in the total national population and in children with ADHD. We found a complex, time- and dose-dependent interrelationship between cardiovascular adverse events and stimulant treatment in children and adolescents. Our results suggest a safety signal with an increased risk of cardiovascular disease associated with stimulant treatment in children and adolescents, even after adjusting for a number of potential confounders. PMID- 24956173 TI - Human cerebrospinal fluid fatty acid levels differ between supernatant fluid and brain-derived nanoparticle fractions, and are altered in Alzheimer's disease. AB - BACKGROUND: Although saturated (SAFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acids are important structural components of neuronal membranes and precursors of signaling molecules, knowledge of their metabolism in Alzheimer's disease (AD) is limited. Based on recent discovery that lipids in cerebrospinal fluid (CSF) are distributed in both brain-derived nanoparticles (NP) and supernatant fluid (SF), we hypothesized that fatty acid (FA) abundance and distribution into these compartments is altered in early AD pathology. METHODOLOGY AND FINDINGS: We assayed the FA composition and abundance in CSF fractions from cognitively healthy (CH), mild cognitive impairment (MCI), and AD study participants using gas chromatography-mass spectrometry. In the SF fraction, concentration of docosahexaenoic acid [DHA, (C22:6n-3)] was less in AD compared with CH, while alpha linolenic acid [alpha-LNA, (C18:3n-3)] was lower in MCI compared with CH. In the NP fraction, levels of SAFAs (C15:0, C16:0) and a MUFA (C15:1) differentiated CH from MCI, while two MUFAs (C15:1, C19:1) and four PUFAs (C20:2n-6, C20:3n-3, C22:4n-6, C22:5n-3) were higher in AD compared with CH. Levels of even-chain free SAFA and total free FA levels were higher in AD, levels of odd-chain free SAFAs, MUFAs, n-3 PUFAs, and total PUFA, were lower in AD compared with CH. Free n-6 PUFA levels were similar in all three groups. CONCLUSIONS AND SIGNIFICANCE: FA metabolism is compartmentalized differently in NP versus SF fractions of CSF, and altered FA levels reflect the importance of abnormal metabolism and oxidative pathways in AD. Depleted DHA in CSF fractions in AD is consistent with the importance of n-3 PUFAs in cognitive function, and suggests that disturbed PUFA metabolism contributes to AD pathology. This study of FA levels in CSF fractions from different cognitive stages shows potential AD biomarkers, and provides further insight into cell membrane dysfunctions, including mechanisms leading to amyloid production. PMID- 24956174 TI - Cancer metabolism: targeting metabolic pathways in cancer therapy. PMID- 24956176 TI - The (late?) modern family: the family's significance for adolescents in Germany and Israel. AB - This study presents German and Israeli youth's heroes and role models. Two hundred twenty-six students from 22 high schools took part in small group interviews. Despite differences in the normative place of the family in the two cultures, the comparison reveals significant similarities between their views and what attributes the subjects assign to their families. Three main models of family members as hero arise from the data: The Self-made Person; sacrifice and pro-social action; and contending with everyday reality. The results point to a) the fading of traditional heroes from the imagination of youth in post-industrial societies; b) the substantive place the family holds in young people's lives. I suggest that the rise of uncertainty and risk in the current socio-historical constellation, contributes to adolescents' choice of figures from their immediate environments that embody safety and a moral framework. PMID- 24956178 TI - In vitro and in silico studies to explore structural features of flavonoids for aldehyde oxidase inhibition. AB - Aldehyde oxidase (AO), an important enzyme in the biotransformation of drugs and xenobiotics, is inhibited by flavonoids. This enzyme can metabolize both aldehydes and N-heterocycles. In this work, a set of 15 flavonoids was assessed for inhibitory activity on the AO oxidation of vanillin as an aldehyde substrate. Spectrophotometrically determined IC50 values showed that myricetin, quercetin, and epicatechin were the most potent inhibitors. The results also revealed that the inhibition of vanillin oxidation by flavonoids was stronger than that of phenanthridine oxidation (an N-heterocyclic substrate) as reported previously. In order to investigate the important structural features responsible for the inhibitory effects of the studied flavonoids, a quantitative structure-activity relationship (QSAR) analysis was performed. This study showed that the size of the flavonoids was the most important factor inversely affecting their potencies. The QSAR model can be used more broadly to predict the AO inhibitory activity of flavonoid-like structures for application in food-drug and drug-drug interaction studies. PMID- 24956177 TI - Genetic polymorphisms and plasma levels of interleukin-22 contribute to the development of nonsmall cell lung cancer. AB - Interleukin (IL)-22, a relatively new member of the IL-10 family, has been implicated in inflammation and tumorigenesis. The aim of this study was to identify genetic polymorphisms in IL-22 and to measure plasma levels of IL-22 in patients with nonsmall cell lung cancer (NSCLC). Patients with NSCLC had a significantly higher frequency of IL-22 rs2227484 CT genotype (odds ratio [OR]=1.917, 95% confidence interval [CI] 1.001-3.670, p=0.038) and T allele (OR=1.878, 95% CI 1.010-3.491, p=0.049) as compared with controls. The rs2227484 genotype was associated with a 2.263-fold increased risk for advanced NSCLC (p=0.041). Among different subtypes of NSCLC, these associations were more obvious in the adenocarcinoma. Moreover, patients with high frequencies of genotypic polymorphisms had high plasma levels of IL-22. IL-22 polymorphisms and corresponding high levels of IL-22 in plasma may contribute to the development of NSCLC, especially adenocarcinoma. PMID- 24956175 TI - Mobile elements and viral integrations prompt considerations for bacterial DNA integration as a novel carcinogen. AB - Insertional mutagenesis has been repeatedly demonstrated in cancer genomes and has a role in oncogenesis. Mobile genetic elements can induce cancer development by random insertion into cancer related genes or by inducing translocations. L1s are typically implicated in cancers of an epithelial cell origin, while Alu elements have been implicated in leukemia as well as epithelial cell cancers. Likewise, viral infections have a significant role in cancer development predominantly through integration into the human genome and mutating or deregulating cancer related genes. Human papilloma virus is the best-known example of viral integrations contributing to carcinogenesis. However, hepatitis B virus, Epstein-Barr virus, and Merkel cell polyomavirus also integrate into the human genome and disrupt cancer related genes. Thus far, the role of microbes in cancer has primarily been attributed to mutations induced through chronic inflammation or toxins, as is the case with Helicobacter pylori and enterotoxigenic Bacteroides fragilis. We hypothesize that like mobile elements and viral DNA, bacterial and parasitic DNA may also integrate into the human somatic genome and be oncogenic. Until recently it was believed that bacterial DNA could not integrate into the human genome, but new evidence demonstrates that bacterial insertional mutagenesis may occur in cancer cells. Although this work does not show causation between bacterial insertions and cancer, it prompts more research in this area. Promising new sequencing technologies may reduce the risk of artifactual chimeric sequences, thus diminishing some of the challenges of identifying novel insertions in the somatic human genome. PMID- 24956183 TI - Superwetting double-layer polyester materials for effective removal of both insoluble oils and soluble dyes in water. AB - Inspired by the mussel adhesive protein and the lotus leaf, Ag-based double-layer polyester (DL-PET) textiles were fabricated for effective removal of organic pollutants in water. The DL-PET textiles are composed of a top superamphiphilic layer and a bottom superhydrophobic/superoleophilic layer. First, the PET textiles were modified with a layer of polydopamine (PDA) and deposited with Ag nanoparticles to form the PET@PDA@Ag textiles. The top superamphiphilic layer, formed by immobilizing Ag3PO4 nanoparticles on the PET@PDA@Ag textile, shows excellent visible-light photocatalytic activity. The bottom superhydrophobic/superoleophilic layer, formed by modifying the PET@PDA@Ag textile using dodecyl mercaptan, is mechanically, environmentally, and chemically very stable. The water-insoluble oils with low surface tension can penetrate both layers of the DL-PET textiles, while the water with soluble organic dyes can only selectively wet the top layer owing to their unique wettability. Consequently, the water-soluble organic contaminants in the collected water can be decomposed by the Ag3PO4 nanoparticles of the top layer under visible-light irradiation or even sunlight in room conditions. Thus, the DL-PET textiles can remove various kinds of organic pollutants in water including both insoluble oils and soluble dyes. The DL-PET textiles feature unique wettability, high oil/water separation efficiency, and visible-light photocatalytic activity. PMID- 24956179 TI - Vaccination against delta-retroviruses: the bovine leukemia virus paradigm. AB - Bovine leukemia virus (BLV) and human T-lymphotropic virus type 1 (HTLV-1) are closely related d-retroviruses that induce hematological diseases. HTLV-1 infects about 15 million people worldwide, mainly in subtropical areas. HTLV-1 induces a wide spectrum of diseases (e.g., HTLV-associated myelopathy/tropical spastic paraparesis) and leukemia/lymphoma (adult T-cell leukemia). Bovine leukemia virus is a major pathogen of cattle, causing important economic losses due to a reduction in production, export limitations and lymphoma-associated death. In the absence of satisfactory treatment for these diseases and besides the prevention of transmission, the best option to reduce the prevalence of d-retroviruses is vaccination. Here, we provide an overview of the different vaccination strategies in the BLV model and outline key parameters required for vaccine efficacy. PMID- 24956181 TI - Molecular characterization of watermelon chlorotic stunt virus (WmCSV) from Palestine. AB - The incidence of watermelon chlorotic stunt disease and molecular characterization of the Palestinian isolate of Watermelon chlorotic stunt virus (WmCSV-[PAL]) are described in this study. Symptomatic leaf samples obtained from watermelon Citrullus lanatus (Thunb.), and cucumber (Cucumis sativus L.) plants were tested for WmCSV-[PAL] infection by polymerase chain reaction (PCR) and Rolling Circle Amplification (RCA). Disease incidence ranged between 25%-98% in watermelon fields in the studied area, 77% of leaf samples collected from Jenin were found to be mixed infected with WmCSV-[PAL] and SLCV. The full-length DNA-A and DNA-B genomes of WmCSV-[PAL] were amplified and sequenced, and the sequences were deposited in the GenBank. Sequence analysis of virus genomes showed that DNA A and DNA-B had 97.6%-99.42% and 93.16%-98.26% nucleotide identity with other virus isolates in the region, respectively. Sequence analysis also revealed that the Palestinian isolate of WmCSV shared the highest nucleotide identity with an isolate from Israel suggesting that the virus was introduced to Palestine from Israel. PMID- 24956185 TI - A novel self-assembling nanoparticle of Ag-Bi with high reactive efficiency. AB - A novel Ag-Bi nanoparticle has been prepared via a facile precipitation approach. The nanoparticle could achieve purification of contaminated water without supplements and exhibited much higher activity compared to other popular nanoparticles (e.g. nZVI). The excellent performance of Ag-Bi was due in part to a large production of OH radicals. PMID- 24956180 TI - Efficient strategy to generate a vectored duck enteritis virus delivering envelope of duck Tembusu virus. AB - Duck Tembusu virus (DTMUV) is a recently emerging pathogenic flavivirus that has resulted in a huge economic loss in the duck industry. However, no vaccine is currently available to control this pathogen. Consequently, a practical strategy to construct a vaccine against this pathogen should be determined. In this study, duck enteritis virus (DEV) was examined as a candidate vaccine vector to deliver the envelope (E) of DTMUV. A modified mini-F vector was inserted into the SORF3 and US2 gene junctions of the attenuated DEV vaccine strain C-KCE genome to generate an infectious bacterial artificial chromosome (BAC) of C-KCE (vBAC-C KCE). The envelope (E) gene of DTMUV was inserted into the C-KCE genome through the mating-assisted genetically integrated cloning (MAGIC) strategy, resulting in the recombinant vector, pBAC-C-KCE-E. A bivalent vaccine C-KCE-E was generated by eliminating the BAC backbone. Immunofluorescence and western blot analysis results indicated that the E proteins were vigorously expressed in C-KCE-E infected chicken embryo fibroblasts (CEFs). Duck experiments demonstrated that the insertion of the E gene did not alter the protective efficacy of C-KCE. Moreover, C-KCE-E-immunized ducks induced neutralization antibodies against DTMUV. These results demonstrated, for the first time, that recombinant C-KCE-E can serve as a potential bivalent vaccine against DEV and DTMUV. PMID- 24956189 TI - Impact of left ventricular hypertrophy on QT prolongation and associated mortality. AB - BACKGROUND: QT prolongation on electrocardiogram (ECG) is a risk marker of ventricular arrhythmias and all-cause mortality. Left ventricular hypertrophy (LVH) on ECG is also associated with poor outcome. Patients satisfying ECG voltage criteria for LVH frequently show concomitant QT prolongation. OBJECTIVE: This study aimed to explore the impact of marked QT prolongation on all-cause mortality in patients copresenting with LVH voltage criteria and prolonged QT on ECG. METHODS: We evaluated 3364 ECGs with corrected QT (QTc) interval >=460 ms detected by Mayo Clinic's QT alert system from November 2010 through June 2011. Every ECG with QTc interval >=460 ms was evaluated for the presence of LVH voltage criteria by using Sokolow-Lyon voltage, Cornell voltage, and Cornell product. RESULTS: Concomitant LVH voltage criteria were present in 181 of 3364 ECGs (5.3%) with QTc interval >=460 ms. Mortality during a follow-up period of 217 +/- 184 days was 13% (23 of 181). Independent of age and hypertension, the QTc interval predicted mortality in patients with LVH voltage criteria (hazard ratio 1.31 per 10-ms increase; 95% confidence interval 1.09-1.58; P < .01). Patients with LVH voltage criteria and QTc interval >=500 ms had highest mortality (log rank, P < .001). CONCLUSION: The QTc interval was an independent predictor of mortality in patients with concomitant LVH voltage and prolonged QTc interval on ECG. Mortality was highest in those with QTc interval >=500 ms. QT prolongation on ECGs with concomitant LVH voltage criteria should not be regarded as a harmless byproduct of LVH, but should be used as a significant marker of increased mortality risk similar to that in patients without LVH voltage criteria. PMID- 24956184 TI - The role of temperature and humidity on seasonal influenza in tropical areas: Guatemala, El Salvador and Panama, 2008-2013. AB - BACKGROUND: The role of meteorological factors on influenza transmission in the tropics is less defined than in the temperate regions. We assessed the association between influenza activity and temperature, specific humidity and rainfall in 6 study areas that included 11 departments or provinces within 3 tropical Central American countries: Guatemala, El Salvador and Panama. METHOD/FINDINGS: Logistic regression was used to model the weekly proportion of laboratory-confirmed influenza positive samples during 2008 to 2013 (excluding pandemic year 2009). Meteorological data was obtained from the Tropical Rainfall Measuring Mission satellite and the Global Land Data Assimilation System. We found that specific humidity was positively associated with influenza activity in El Salvador (Odds Ratio (OR) and 95% Confidence Interval of 1.18 (1.07-1.31) and 1.32 (1.08-1.63)) and Panama (OR = 1.44 (1.08-1.93) and 1.97 (1.34-2.93)), but negatively associated with influenza activity in Guatemala (OR = 0.72 (0.6-0.86) and 0.79 (0.69-0.91)). Temperature was negatively associated with influenza in El Salvador's west-central departments (OR = 0.80 (0.7-0.91)) whilst rainfall was positively associated with influenza in Guatemala's central departments (OR = 1.05 (1.01-1.09)) and Panama province (OR = 1.10 (1.05-1.14)). In 4 out of the 6 locations, specific humidity had the highest contribution to the model as compared to temperature and rainfall. The model performed best in estimating 2013 influenza activity in Panama and west-central El Salvador departments (correlation coefficients: 0.5-0.9). CONCLUSIONS/SIGNIFICANCE: The findings highlighted the association between influenza activity and specific humidity in these 3 tropical countries. Positive association with humidity was found in El Salvador and Panama. Negative association was found in the more subtropical Guatemala, similar to temperate regions. Of all the study locations, Guatemala had annual mean temperature and specific humidity that were lower than the others. PMID- 24956190 TI - Tissue engineering of the corneal endothelium: a review of carrier materials. AB - Functional impairment of the human corneal endothelium can lead to corneal blindness. In order to meet the high demand for transplants with an appropriate human corneal endothelial cell density as a prerequisite for corneal function, several tissue engineering techniques have been developed to generate transplantable endothelial cell sheets. These approaches range from the use of natural membranes, biological polymers and biosynthetic material compositions, to completely synthetic materials as matrices for corneal endothelial cell sheet generation. This review gives an overview about currently used materials for the generation of transplantable corneal endothelial cell sheets with a special focus on thermo-responsive polymer coatings. PMID- 24956192 TI - Microencapsulation of bioactive principles with an airless spray-gun suitable for processing high viscous solutions. AB - PURPOSE: to design, assemble and test a prototype of a novel production plant, suitable for producing microparticles (MPs) by processing highly viscous feed solutions (FSs). METHODS: the prototype has been built using a commercial air compressor, a piston pump, an airless spray-gun, a customized air-treatment section, a timer, a rotating base, and a filtration section. Preliminary prototype parameter setting was carried out to individuate the best performing nozzle's dimension, the nebulization timing, and the CaCl2 concentration in the gelation fluid. In addition, prototype throughput (1 L to 5 L) and the range of practicable feed solution (FS) viscosities were assayed. A set of four batches was prepared in order to characterize the MPs, in terms of mean particle size and distribution, flow properties, swelling, encapsulation efficiency and release. RESULTS: according to a qualitative scoring, the large nozzle was suitable to nebulize FSs at a higher alginate concentration. Conversely, the small nozzle performed better in the processing of FSs with an alginate concentration up to 2% w/v. Only at the highest degree of viscosity, corresponding to 5% w/v of alginate, the FS processing was not technically possible. Among the CaCl2 concentrations considered, 15% w/v was recognized as the most versatile. The prototype appears to be convenient and suitable to grant a high yield starting from 2 L of FS. The flow behavior of the FSs assayed can be satisfactorily described with the Carreau-Yasuda equation and the throughput begins to slightly decrease for FSs at alginate concentrations exceeding 3% w/v. MP morphology was irregular with crumpled shape. The angle of repose indicates a good flowability and the release studies showed gastro-resistance and potential prolonged release applications. CONCLUSIONS: the novel prototype of production plant is suitable to process large amounts (2 L or more) of FSs, characterized by a high viscosity, to produce MPs suitable for bioactive principle delivery. PMID- 24956193 TI - A Novel Glass Polyalkenoate Cement for Fixation and Stabilisation of the Ribcage, Post Sternotomy Surgery: An ex-Vivo Study. AB - This study investigates the use of gallium (Ga) based glass polyalkenoate cements (GPCs) as a possible alternative adhesive in sternal fixation, post sternotomy surgery. The glass series consists of a Control (CaO-ZnO-SiO2), and LGa-1 and LGa 2 which contain Ga at the expense of zinc (Zn) in 0.08 mol% increments. The additions of Ga resulted in increased working time (75 s to 137 s) and setting time (113 to 254 s). Fourier Transform Infrared (FTIR) analysis indicated that this was a direct result of increased unreacted poly(acrylic acid) (PAA) and the reduction of crosslink formation during cement maturation. LGa samples (0.16 wt % Ga) resulted in an altered ion release profile, particularly for 30 days analysis, with maximum Ca2+, Zn2+, Si4+ and Ga3+ ions released into the distilled water. The additions of Ga resulted in increased roughness and decreased contact angles during cement maturation. The presence of Ga has a positive effect on the compressive strength of the samples with strengths increasing over 10 MPa at 7 days analysis compared to the 1 day results. The additions of Ga had relatively no effect on the flexural strength. Tensile testing of bovine sterna proved that the LGa samples (0.16 wt % Ga) are comparable to the Control samples. PMID- 24956194 TI - Antimicrobial, mechanical and thermal studies of silver particle-loaded polyurethane. AB - Silver-particle-incorporated polyurethane films were evaluated for antimicrobial activity towards two different bacteria: Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Distributed silver particles sourced from silver nitrate, silver lactate and preformed silver nanoparticles were mixed with polyurethane (PU) and variously characterized by field emission scanning electron microscopy (FESEM), fourier transform infra-red (FTIR) spectroscopy, X-ray diffraction (XRD) and contact angle measurement. Antibacterial activity against E.coli was confirmed for films loaded with 10% (w/w) AgNO3, 1% and 10% (w/w) Ag lactate and preformed Ag nanoparticles. All were active against S. aureus, but Ag nanoparticles loaded with PU had a minor effect. The apparent antibacterial performance of Ag lactate-loaded PU is better than other Ag ion-loaded films, revealed from the zone of inhibition study. The better performance of silver lactate-loaded PU was the likely result of a porous PU structure. FESEM and FTIR indicated direct interaction of silver with the PU backbone, and XRD patterns confirmed that face-centred cubic-type silver, representative of Ag metal, was present. Young's modulus, tensile strength and the hardness of silver containing PU films were not adversely affected and possibly marginally increased with silver incorporation. Dynamic mechanical analysis (DMA) indicated greater thermal stability. PMID- 24956196 TI - Immunohistochemical mapping of pro-opiomelanocortin- and pro-dynorphin-derived peptides in the alpaca (Lama pacos) diencephalon. AB - Using an indirect immunoperoxidase technique, we studied the distribution of cell bodies and fibres containing non-opioid peptides (adrenocorticotropin hormone (ACTH), alpha-melanocyte-stimulating hormone) and opioid peptides (beta-endorphin (1-27), alpha-neo-endorphin, leucine-enkephalin) in the alpaca diencephalon. No immunoreactive cell bodies containing ACTH were found. Perikarya containing the other four peptides were observed exclusively in the hypothalamus and their distribution was restricted. Perikarya containing alpha-melanocyte-stimulating hormone or alpha-neo-endorphin showed a more widespread distribution than those containing leucine-enkephalin or beta-endorphin (1-27). Cell bodies containing pro-opiomelanocortin-derived peptides were observed in the arcuate nucleus, anterior and lateral hypothalamic areas and in the ventromedial and supraoptic hypothalamic nuclei, whereas perikarya containing alpha-neo-endorphin (a pro dynorphin-derived peptide) were found in the arcuate nucleus, dorsal and lateral hypothalamic areas, and in the paraventricular, ventromedial and supraoptic hypothalamic nuclei. Immunoreactive cell bodies containing leucine-enkephalin were found in the lateral hypothalamic area and in the paraventricular hypothalamic nucleus. Immunoreactive fibres expressing pro-opiomelanocortin derived peptides were more numerous than those expressing pro-dynorphin-derived peptides. A close anatomical relationship was observed: in all the diencephalic nuclei in which beta-endorphin (1-27)-immunoreactive fibres were found, fibres containing alpha-melanocyte-stimulating hormone or alpha-neo-endorphin were also observed. Fibres containing beta-endorphin (1-27), alpha-melanocyte-stimulating hormone or alpha-neo-endorphin were widely distributed throughout the diencephalon, but fibres containing ACTH or leucine-enkephalin showed a moderate distribution. The distribution of the five peptides studied here is also compared with that reported previously in other mammalian species. The widespread distribution observed indicates that both the pro-dynorphin and the pro opiomelanocortin systems are involved in multiple physiological actions (e.g., food intake, thermoregulation, neuroendocrine and reproductive mechanisms) in the alpaca diencephalon. PMID- 24956199 TI - Closely interconnected network of molybdenum phosphide nanoparticles: a highly efficient electrocatalyst for generating hydrogen from water. AB - A closely interconnected network of MoP nanoparticles (MoP-CA2) with rich nano pores, large specific surface area, and high conductivity can function as a highly active non-noble metal catalyst for electrochemically generating hydrogen from acidic water. The network exhibits nearly 100% Faradaic efficiency and needs overpotentials of 125 and 200 mV to attain current densities of 10 and 100 mA cm( 2) , respectively. The catalytic activity is maintained for at least 24 h. PMID- 24956200 TI - Synthesis and fluorescence properties of N-substituted 1-cyanobenz[f]isoindole chitosan polymers and nanoparticles for live cell imaging. AB - Highly fluorescent N-substituted 1-cyanobenz[f]isoindole chitosans (CBI-CSs) with various degrees of N-substitution (DS) were synthesized by reacting chitosan (CS) with naphthalene-2,3-dicarboxaldehyde (NDA) in the presence of cyanide under mild acidic conditions. Introduction of 1-cyanobenz[f]isoindole moieties into the CS backbone resulted in lowering of polymer thermal stability and crystallinity. The fluorescence quantum yield (Phif) of CBI-CS was found to be DS- and molecular weight-dependent, with Phif decreasing as DS and molecular weight were increased. At similar DS values, CBI-CS exhibited 26 times higher Phif in comparison with fluorescein isothiocyanate-substituted chitosan (FITC-CS). CBI-CS/TPP nanoparticles were fabricated using an ionotropic gelation method in which pentasodium triphosphate (TPP) acted as a cross-linking agent. CS and CBI-CS exhibited low cytotoxicity to normal skin fibroblast cells over a concentration range of 0.1-1000 MUg/mL, while an increased cytotoxicity level was evident in CBI-CS/TPP nanoparticles at concentrations greater than 100 MUg/mL. In contrast with CBI-CS polymers, the CBI-CS/TPP nanoparticles exhibited lower fluorescence; however, confocal microscopy results showed that living normal skin fibroblast cells became fluorescent on nanoparticle uptake. These results suggest that CBI CS and fabricated nanoparticles thereof may be promising fluorescence probes for live cell imaging. PMID- 24956198 TI - Dynamic oxygen-enhanced MRI of cerebrospinal fluid. AB - Oxygen causes an increase in the longitudinal relaxation rate of tissues through its T1-shortening effect owing to its paramagnetic properties. Due to such effects, MRI has been used to study oxygen-related signal intensity changes in various body parts including cerebrospinal fluid (CSF) space. Oxygen enhancement of CSF has been mainly studied using MRI sequences with relatively longer time resolution such as FLAIR, and T1 value calculation. In this study, fifteen healthy volunteers were scanned using fast advanced spin echo MRI sequence with and without inversion recovery pulse in order to dynamically track oxygen enhancement of CSF. We also focused on the differences of oxygen enhancement at sulcal and ventricular CSF. Our results revealed that CSF signal after administration of oxygen shows rapid signal increase in both sulcal CSF and ventricular CSF on both sequences, with statistically significant predominant increase in sulcal CSF compared with ventricular CSF. CSF is traditionally thought to mainly form from the choroid plexus in the ventricles and is absorbed at the arachnoid villi, however, it is also believed that cerebral arterioles contribute to the production and absorption of CSF, and controversy remains in terms of the precise mechanism. Our results demonstrated rapid oxygen enhancement in sulcal CSF, which may suggest inhaled oxygen may diffuse into sulcal CSF space rapidly probably due to the abundance of pial arterioles on the brain sulci. PMID- 24956197 TI - From pan-reactive KV7 channel opener to subtype selective opener/inhibitor by addition of a methyl group. AB - The voltage-gated potassium channels of the KV7 family (KV7.1-5) play important roles in controlling neuronal excitability and are therefore attractive targets for treatment of CNS disorders linked to hyperexcitability. One of the main challenges in developing KV7 channel active drugs has been to identify compounds capable of discriminating between the neuronally expressed subtypes (KV7.2-5), aiding the identification of the subunit composition of KV7 currents in various tissues, and possessing better therapeutic potential for particular indications. By taking advantage of the structure-activity relationship of acrylamide KV7 channel openers and the effects of these compounds on mutant KV7 channels, we have designed and synthesized a novel KV7 channel modulator with a unique profile. The compound, named SMB-1, is an inhibitor of KV7.2 and an activator of KV7.4. SMB-1 inhibits KV7.2 by reducing the current amplitude and increasing the time constant for the slow component of the activation kinetics. The activation of KV7.4 is seen as an increase in the current amplitude and a slowing of the deactivation kinetics. Experiments studying mutant channels with a compromised binding site for the KV7.2-5 opener retigabine indicate that SMB-1 binds within the same pocket as retigabine for both inhibition of KV7.2 and activation of KV7.4. SMB-1 may serve as a valuable tool for KV7 channel research and may be used as a template for further design of better subtype selective KV7 channel modulators. A compound with this profile could hold novel therapeutic potential such as the treatment of both positive and cognitive symptoms in schizophrenia. PMID- 24956195 TI - Enhanced awareness followed reversible inhibition of human visual cortex: a combined TMS, MRS and MEG study. AB - This series of experiments investigated the neural basis of conscious vision in humans using a form of transcranial magnetic stimulation (TMS) known as continuous theta burst stimulation (cTBS). Previous studies have shown that occipital TMS, when time-locked to the onset of visual stimuli, can induce a phenomenon analogous to blindsight in which conscious detection is impaired while the ability to discriminate 'unseen' stimuli is preserved above chance. Here we sought to reproduce this phenomenon using offline occipital cTBS, which has been shown to induce an inhibitory cortical aftereffect lasting 45-60 minutes. Contrary to expectations, our first experiment revealed the opposite effect: cTBS enhanced conscious vision relative to a sham control. We then sought to replicate this cTBS-induced potentiation of consciousness in conjunction with magnetoencephalography (MEG) and undertook additional experiments to assess its relationship to visual cortical excitability and levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA; via magnetic resonance spectroscopy, MRS). Occipital cTBS decreased cortical excitability and increased regional GABA concentration. No significant effects of cTBS on MEG measures were observed, although the results provided weak evidence for potentiation of event related desynchronisation in the beta band. Collectively these experiments suggest that, through the suppression of noise, cTBS can increase the signal-to noise ratio of neural activity underlying conscious vision. We speculate that gating-by-inhibition in the visual cortex may provide a key foundation of consciousness. PMID- 24956201 TI - Adsorption and oxidation of elemental mercury over Ce-MnOx/Ti-PILCs. AB - A series of innovative Ce-Mn/Ti-pillared-clay (Ce-Mn/Ti-PILC) catalysts combining the advantages of PILCs and Ce-Mn were investigated for elemental mercury (Hg0) capture at 100-350 degrees C in the absence of HCl in the flue gas. The fresh and used catalysts were characterized by scanning electron microscopy (SEM), nitrogen adsorption-desorption, X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The catalyst characterization indicated that the 6%Ce 6%MnOx/Ti-PILC catalyst possessed a large specific surface area and high dispersion of Ce and Mn on the surface. The experimental results indicated that the 6%Ce-6%MnOx/Ti-PILC catalyst exhibited high Hg0 capture (>90%) at 100-350 degrees C. During the first stage of the reaction, the main Hg0 capture mechanism for the catalyst was adsorption. As the reaction proceeded, the Hg0 oxidation ability was substantially enhanced. Both the hydroxyl oxygen and the lattice oxygen on the surface of the catalysts participated in Hg0 oxidation. At a low temperature (150 degrees C), the hydroxyl oxygen and lattice oxygen from Ce4+ >Ce3+ and Mn3+->Mn2+ on the surface contributed to Hg0 oxidation. However, at a high temperature (250 degrees C), the hydroxyl oxygen and lattice oxygen from Mn4+->Mn3+ contributed to Hg0 oxidation. Hg0 oxidation was preferred at a high temperature. The 6%Ce-6%MnOx/Ti-PILC catalyst was demonstrated to a good Hg0 adsorbent and catalytic oxidant in the absence of HCl in the flue gas. PMID- 24956202 TI - Triterpenes as uncompetitive inhibitors of alpha-glucosidase from flowers of Punica granatum L. AB - The alpha-glucosidase and maltase inhibitory effects of Punica granatum L. flowers (PGF) were investigated. The methanol extract (PGFMe), n-hexane extract (PGFH), chloroform extract (PGFC) and the remaining water fraction (PGFW) were assayed for their alpha-glucosidase and maltase inhibitory effects. PGFW showed potent alpha-glucosidase inhibition with IC50 of 0.8 MUg/mL followed by PGFMe (IC50 of 4.0 MUg/mL) then PGFC (IC50 of 5.21 MUg/mL) in comparison to acarbose (0.9 MUM). Due to its selectivity towards alpha-glucosidase, PGFC was subjected to bioactivity-guided isolation of its main active constituents. Five known compounds (1-5) were identified as beta-sitosterol (1), oleanolic acid (2), ursolic acid (3), p-coumaric acid (4) and apigenin (5). Ursolic and oleanolic acids showed potent alpha-glucosidase inhibition (IC50 of 39.0 and 35.0 MUM, respectively), while they did not show significant maltase inhibition. Kinetic study using the double Lineweaver-Burk plot revealed that ursolic acid uncompetitively inhibited alpha-glucosidase in comparison with acarbose as a competitive inhibitor. PMID- 24956203 TI - Phospholipase D activity underlies very-low-density lipoprotein (VLDL)-induced aldosterone production in adrenal glomerulosa cells. AB - Aldosterone is the mineralocorticoid responsible for sodium retention, thus increased blood volume and pressure. Excessive production of aldosterone results in high blood pressure as well as renal disease, stroke, and visual loss via both direct effects and effects on blood pressure. Weight gain is often associated with increased blood pressure, but it remains unclear how obesity increases blood pressure. Obese patients typically have higher lipoprotein levels; moreover, some studies have suggested that aldosterone levels are also elevated and represent a link between obesity and hypertension. Very-low-density lipoprotein (VLDL) functions to transport triglycerides from the liver to peripheral tissues. Although previous studies have demonstrated that VLDL can stimulate aldosterone production, the mechanisms underlying this effect are largely unclear. Here we show for the first time that phospholipase D (PLD) is involved in VLDL-induced aldosterone production in both a human adrenocortical cell line (HAC15) and primary cultures of bovine zona glomerulosa cells. Our data also reveal that PLD mediates steroidogenic acute regulatory (StAR) protein and aldosterone synthase (CYP11B2) expression via increasing the phosphorylation (activation) of their regulatory transcription factors. Finally, by using selective PLD inhibitors, our studies suggest that both PLD1 and PLD2 isoforms play an important role in VLDL induced aldosterone production. PMID- 24956204 TI - Routine or selective carotid artery shunting for carotid endarterectomy (and different methods of monitoring in selective shunting). AB - BACKGROUND: Temporary interruption of cerebral blood flow during carotid endarterectomy can be avoided by using a shunt across the clamped section of the carotid artery. This may improve outcome. This is an update of a Cochrane review originally published in 1996 and previously updated in 2009. OBJECTIVES: To assess the effect of routine versus selective or no shunting during carotid endarterectomy, and to assess the best method for selecting people for shunting. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched August 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013, Issue 8), MEDLINE (1966 to August 2013), EMBASE (1980 to August 2013) and Index to Scientific and Technical Proceedings (1980 to August 2013). We handsearched journals and conference proceedings, checked reference lists, and contacted experts in the field. SELECTION CRITERIA: Randomised and quasi-randomised trials of routine shunting compared with no shunting or selective shunting, and trials that compared different shunting policies in people undergoing carotid endarterectomy. DATA COLLECTION AND ANALYSIS: Three review authors independently performed the searches and applied the inclusion criteria. For this update, we identified two new relevant randomised controlled trials. MAIN RESULTS: We included six trials involving 1270 participants in the review: three trials involving 686 participants compared routine shunting with no shunting, one trial involving 200 participants compared routine shunting with selective shunting, one trial involving 253 participants compared selective shunting with and without near-infrared refractory spectroscopy monitoring, and the other trial involving 131 participants compared shunting with a combination of electroencephalographic and carotid pressure measurement with shunting by carotid pressure measurement alone. In general, reporting of methodology in the included studies was poor. For most studies, the blinding of outcome assessors and the report of prespecified outcomes were unclear. For routine versus no shunting, there was no significant difference in the rate of all stroke, ipsilateral stroke or death up to 30 days after surgery, although data were limited. No significant difference was found between the groups in terms of postoperative neurological deficit between selective shunting with and without near-infrared refractory spectroscopy monitoring, However, this analysis was inadequately powered to reliably detect the effect. There was no significant difference between the risk of ipsilateral stroke in participants selected for shunting with the combination of electroencephalographic and carotid pressure assessment compared with pressure assessment alone, although again the data were limited. AUTHORS' CONCLUSIONS: This review concluded that the data available were too limited to either support or refute the use of routine or selective shunting in carotid endarterectomy. Large scale randomised trials of routine shunting versus selective shunting are required. No method of monitoring in selective shunting has been shown to produce better outcomes. PMID- 24956205 TI - Oxycodone for neuropathic pain and fibromyalgia in adults. AB - BACKGROUND: This review is one of a series on drugs used to treat neuropathic pain and fibromyalgia. These conditions are estimated to affect 3 to 10% of adults, and are difficult to treat. Although they probably have different aetiologies, neuropathic pain and fibromyalgia can respond to the same therapies. There have been substantial changes in the standards of evidence considered necessary for assessment of interventions to treat chronic pain, to provide data that are more robust and clinically relevant. Oxycodone is a strong opioid agonist widely used to manage severe pain; this review assesses evidence for oxycodone using current standards of evidence designed to reduce bias. OBJECTIVES: To assess the analgesic efficacy and adverse events of oxycodone for chronic neuropathic pain and fibromyalgia. SEARCH METHODS: On 6 November 2013, we searched CENTRAL, MEDLINE and EMBASE databases. We reviewed the bibliographies of all included studies and of reviews, and also searched two clinical trial databases, ClinicalTrials.gov and the World Health Organisation (WHO) International Clinical Trials Registry Platform, to identify additional published or unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with double-blind assessment of participant outcomes following two weeks of treatment or longer (although the emphasis of the review was on studies of eight weeks or longer) that used a placebo or active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted efficacy and adverse event data, examined issues of study quality, and assessed risk of bias. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, eight to 12 weeks duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that was considered very likely to be biased or used outcomes of limited clinical utility, or both. MAIN RESULTS: We included three studies with 254 participants; 204 had painful diabetic neuropathy and 50 postherpetic neuralgia. Study size ranged from 45 to 159 participants. Two studies used a cross-over design and one a parallel group design; study duration was four or six weeks. Controlled release oxycodone (oxycodone CR) was used in all three studies, with doses titrated up to a maximum of between 60 and 120 mg daily; mean doses achieved ranged between 37 and 45 mg daily. All studies used a placebo comparator, although in one study, an active placebo (benztropine) was used. All studies had one or more sources of potential major bias.No study reported the proportion of participants experiencing at least 50% pain relief or who were very much improved, while one reported the proportion with at least 30% pain relief, two reported at least moderate pain relief, and one reported the number of participants who considered treatment to be moderately effective. No study provided first or second tier evidence for an efficacy outcome. Third tier evidence indicated greater pain intensity reduction and better patient satisfaction with oxycodone than with placebo in all three studies, but such evidence was derived mainly from group mean data, with last observation carried forward (LOCF) imputation or completer analysis, in small studies lasting less than eight weeks (very low quality evidence).Adverse events were more common with oxycodone CR than with placebo. At least one adverse event was experienced by 86% of participants taking oxycodone CR and 63% taking placebo, and the number needed to treat for an additional harmful effect (NNH) was 4.3. The effect of oxycodone on serious adverse events reported was uncertain in comparison with placebo (oxycodone 3.4% versus placebo: 7.0%; RR 0.48 (95% confidence interval (CI) 0.18 to 1.23; very low quality evidence); one death was reported with oxycodone CR, but was not attributed to treatment. Adverse event withdrawals did not differ significantly between groups, occurring in 11% of participants with oxycodone CR and 6.4% with placebo (RR 1.69 (0.83 to 3.43); very low quality evidence). Withdrawals due to lack of efficacy were less frequent with oxycodone CR (1.1%) than placebo (11%), with an NNT to prevent one withdrawal of 10 (RR 0.12 (0.03 to 0.45); very low quality evidence).We found no relevant studies in chronic neuropathic pain conditions other than painful diabetic neuropathy or postherpetic neuralgia, or in fibromyalgia. AUTHORS' CONCLUSIONS: No convincing, unbiased evidence suggests that oxycodone (as oxycodone CR) is of value in treating people with painful diabetic neuropathy or postherpetic neuralgia. There is no evidence at all for other neuropathic pain conditions, or for fibromyalgia. Adverse events typical of opioids appear to be common. PMID- 24956206 TI - Development of antihuman IgG antibodies and hematologic deficits but not clinical abnormalities in C57BL/6 mice after repeated administration of human intravenous immunoglobulin. PMID- 24956207 TI - Editors' note. PMID- 24956208 TI - Isolation of Helicobacter spp. from mice with rectal prolapses. AB - Enterohepatic Helicobacter species (EHS) often are associated with typhlocolitis and rectal prolapse in mice. We sought to describe rectal prolapses histologically, relate lesions to mouse genotype and EHS infection status, and characterize EHS pathogens on our campus. Our mouse population was housed among 6 facilities on our main campus and a seventh, nearby facility. We investigated cases of rectal prolapse over 1 y and included 76 mice, which were broadly categorized according to genotype. Microscopically, lesions ranged from mild to severe typhlocolitis, often with hyperplastic and dysplastic foci. Neoplastic foci tended to occur at the ileocecal-colic junction. Lesions were most severe in strains that had lower-bowel inflammatory disease, notably IL10, Rag1, and Rag2 knockout strains; prolapses occurred in these strains when housed both in areas with endemic EHS and in our Helicobacter-free barrier facility. Most mice with rectal prolapses were immunocompromised genetically modified mice; however, the most frequently sampled strain, the lamellipodin knockout, was noteworthy for its high incidence of rectal prolapse, localized distal colonic and rectal lesions, and lack of known immunodeficiency. This strain is being explored as a model of rectal carcinoma. Most of the colons examined tested PCR-positive for EHS, often with coinfections. Although H. bilis is prevalent on our campus, we did not find this organism in any mice exhibiting clinical signs of rectal prolapse. Identification of H. apodemus in 22% of cases has fueled increased surveillance on our campus to characterize this organism and differentiate it from the closely related H. rodentium. PMID- 24956209 TI - Irradiated compared with nonirradiated NSG mice for the development of a human B cell lymphoma model. AB - NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice are a superior strain for the engraftment of human tumors, as they provide an ideal model to explore the potency, toxicity, and dosage of therapeutic drugs. Although whole-body nonlethal irradiation is often performed to enhance engraftment, the need for irradiation to establish a human B-cell lymphoma model using the NSG strain has not been addressed. In the current study, a mouse model of B-cell lymphoma was established by intravenous injection of human B-cell lymphoma Z138 cells into mice with and without irradiation. Tumor development, signs of engraftment, survivability of engrafted mice, histopathology, and immunohistochemistry were evaluated. Potential sex-associated variations in the model were assessed also. Irradiation of NSG mice did not enhance tumor cell engraftment, and nonirradiated animals had increased survivability. Mice with irradiation survived for a median of 27 d before being euthanized due to signs of morbidity, whereas those without irradiation had a median survival of 35 d. Both irradiated and nonirradiated mice were normal in activity until 3 wk after the injection of cells. At that time, the mice started to show signs of lymphoma including ruffled fur, decreased activity, and hindlimb paralysis. There were no significant differences in evaluated parameters between male and female mice. Therefore, we conclude that a model of B-cell lymphoma can successfully be established by using Z138 cells in nonirradiated male and female NSG mice. PMID- 24956210 TI - Femoral strength after induced lesions in rats (Rattus norvegicus). AB - Rats are a common model for the study of bone healing, with the cranium, femur, and tibia being the bones studied most frequently. This study examines noncritical-sized lesions that would allow rats to continue to bear weight without the need for fixation but that are sufficiently large to enable characterization of the healing process. We compared the femoral bone strength associated with 3 lesion sizes selected for use in future studies. Sprague-Dawley rats (age, 10 to 16 wk) were used to assess the ultimate breaking strength, stress, and break force of normal, unmanipulated femurs. We then created lesions of 3 different sizes in the mid- to distal diaphysis of the left and right femurs and characterized the associated decreases in bone strength. Femurs (n = 85) for this study were collected through tissue sharing from rats used in other acute surgical procedures and were tested by using a 3-point bending flexural materials testing machine. Our hypothesis was that, as a model for bone healing, 3 induced lesions of different sizes would show incremental and proportional decreases in femoral strength, with the intermediate-sized (1.5-mm) lesion demonstrating a decrease of 20% to 40%. A lesion of 1.5 mm yielded a decrease in strength of 17% for both the left and right femurs. The strength of left femurs carrying intermediate lesions was significantly less than that of control, uninjured femur bones. In addition to providing validation for our own future bone-healing project, these data are a useful baseline for other investigators studying bone healing in a rat femur model. PMID- 24956191 TI - Self-setting calcium orthophosphate formulations. AB - In early 1980s, researchers discovered self-setting calcium orthophosphate cements, which are bioactive and biodegradable grafting bioceramics in the form of a powder and a liquid. After mixing, both phases form pastes, which set and harden forming either a non-stoichiometric calcium deficient hydroxyapatite or brushite. Since both of them are remarkably biocompartible, bioresorbable and osteoconductive, self-setting calcium orthophosphate formulations appear to be promising bioceramics for bone grafting. Furthermore, such formulations possess excellent molding capabilities, easy manipulation and nearly perfect adaptation to the complex shapes of bone defects, followed by gradual bioresorption and new bone formation. In addition, reinforced formulations have been introduced, which might be described as calcium orthophosphate concretes. The discovery of self setting properties opened up a new era in the medical application of calcium orthophosphates and many commercial trademarks have been introduced as a result. Currently such formulations are widely used as synthetic bone grafts, with several advantages, such as pourability and injectability. Moreover, their low temperature setting reactions and intrinsic porosity allow loading by drugs, biomolecules and even cells for tissue engineering purposes. In this review, an insight into the self-setting calcium orthophosphate formulations, as excellent bioceramics suitable for both dental and bone grafting applications, has been provided. PMID- 24956211 TI - Videotaped behavior as a predictor of clinical outcome in rhesus macaques (Macaca mulatta). AB - Understanding the behavior of laboratory NHP facilitates health assessment and clinical care. We sought to characterize the behavior of critically ill rhesus macaques (Macaca mulatta) and determine whether specific behaviors or behavioral changes might facilitate the determination of prognosis and clinical endpoints. Twenty-two critically-ill subjects were videorecorded after they were removed from the outdoor breeding colony for diagnostic work-up and treatment. Subjects were categorized as survivors (n = 15) and those that were euthanized according to existing clinical endpoints (n = 7). Behavior before, during, and after cageside examination was compared between these groups with regard to the presence or absence of direct observation. This approach allowed us to determine whether these settings revealed differences between groups or masking of behaviors during direct observation. Before cageside examination, several behaviors (for example, self-grooming and anxiety behaviors) were significantly more common in surviving subjects than in euthanized subjects. Few significant differences in behavior were detectable during or after the examination. Subjects that were eventually euthanized showed more illness-related behaviors; however, not all animals requiring euthanasia showed these signs when an observer was present. Furthermore, euthanized animals spent more time in an alert posture during direct observation than at other times. Therefore, direct observation of critically ill rhesus macaques may not yield the most accurate assessment of illness severity, and using video to assess behavior may be helpful for prognosis. PMID- 24956212 TI - Clinicopathologic characteristics, prevalence, and risk factors of spontaneous diabetes in sooty mangabeys (Cercocebus atys). AB - In 2008, clinical observations in our colony of sooty mangabeys (Cercocebus atys) suggested a high frequency of type 2 diabetes. Postmortem studies of diabetic animals revealed dense amyloid deposits in pancreatic islets. To investigate these findings, we screened our colony (97 male mangabeys; 99 female mangabeys) for the disease from 2008 to 2012. The overall prevalence of diabetes was 11% and of prediabetes was 7%, which is nearly double that reported for other primate species (less than 6%). Fructosamine and triglyceride levels were the best indicators of diabetes; total cholesterol and glycated hemoglobin were not associated with disease. Increasing age was a significant risk factor: prevalence increased from 0% in infants, juveniles, and young adults to 11% in adults and 19% in geriatric mangabeys. Sex, medroxyprogesterone acetate exposure, and SIV status were unrelated to disease. Weight was marginally higher in prediabetics, but body condition did not indicate obesity. Of the 49 mangabeys that were necropsied after clinical euthanasia or death from natural causes, 22 were diabetic; all 22 animals demonstrated pancreatic amyloid, and most had more than 75% of islets replaced with amyloid. We conclude that type 2 diabetes is more common in mangabeys than in other primate species. Diabetes in mangabeys has some unusual pathologic characteristics, including the absence of altered cholesterol levels and glycated hemoglobin but a robust association of pancreatic insular amyloidosis with clinical diabetes. Future research will examine the genetic basis of mangabey diabetes and evaluate additional diagnostic tools using imaging and serum markers. PMID- 24956214 TI - Selective serotonin reuptake inhibitor and bleeding in a cynomolgus macaque (Macaca fascicularis). AB - Selective serotonin reuptake inhibitors (SSRI) are associated with an increased bleeding risk in humans. This report describes a bleeding event in a cynomolgus macaque (Macaca fascicularis) treated with the SSRI sertraline HCl (Zoloft). During the treatment course, the subject presented with a maculopapular rash, cutaneous bleeding, epistaxis, bleeding from the eye, melena, and a severe thrombocytopenia. To our knowledge, this report is the first description of an SSRI-related adverse event in a nonhuman primate. This report demonstrates that the clinical presentation of SSRI-associated bleeding in cynomolgus macaques is consistent with that reported in humans and that complications from SSRI treatment should be considered as a differential diagnosis for maculopapular dermatitis or spontaneous bleeding in this species. PMID- 24956213 TI - Use of (18)F-fluorodeoxyglucose positron emission tomography-computed tomography to aid in diagnosing intestinal adenocarcinoma in 2 rhesus macaques (Macaca mulatta). AB - Two aged female rhesus macaques (Macaca mulatta) presented with weight loss and intermittent inappetence. The signalment and constellation of clinical signs led clinicians to suspect the presence of intestinal adenocarcinoma. Because of each animal's advanced age and inconclusive radiographic findings, a noninvasive diagnostic tool was preferred over exploratory laparotomy to assist in determining a diagnosis. Consequently, 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG) positron emission tomography-CT (FDG-PET-CT) was chosen to aid in confirming a suspicion of gastrointestinal adenocarcinoma in both animals. FDG is a glucose analogue labeled with fluorine-18 and is taken up by highly metabolically active cells, as observed in many cancers. Tomography revealed an annular constriction of the small intestine with focal FDG uptake in one animal, and an FDG avid transmural mass in the ascending colon of the second animal. Necropsy later confirmed both sites to be adenocarcinomas. This report supports the use of FDG PET-CT as an adjunct to conventional radiography in the diagnosis of intestinal adenocarcinoma in nonhuman primates. PMID- 24956215 TI - Extensive vascular mineralization in the brain of a chimpanzee (Pan troglodytes). AB - Spontaneous vascular mineralization (deposition of iron or calcium salts) has been observed in marble brain syndrome, mineralizing microangiopathy, hypothyroidism, Fahr syndrome, Sturge-Weber syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and calciphylaxis in humans and as an aging or idiopathic lesion in the brains of horses, cats, nonhuman primates, mice, rats, cattle, white-tailed deer, and dogs. Here we present a 27-y-old, adult male chimpanzee (Pan troglodytes) with spontaneous, extensive vascular mineralization localized solely to the brain. The chimpanzee exhibited tremors and weakness of the limbs, which progressed to paralysis before euthanasia. Magnetic resonance brain imaging in 2002 and 2010 (immediately before euthanasia) revealed multiple hypointense foci, suggestive of iron- and calcium rich deposits. At necropsy, the brain parenchyma had occasional petechial hemorrhage, and microscopically, the cerebral, cerebellar and brain stem, gray and white matter had moderate to severe mural aggregates of a granular, basophilic material (mineral) in the blood vessels. In addition, these regions often had moderate to severe medial to transmural deposition of mature collagen in the blood vessels. We ruled out common causes of brain mineralization in humans and animals, but an etiology for the mineralization could not be determined. To our knowledge, mineralization in brain has been reported only once to occur in a chimpanzee, but its chronicity in our case makes it particularly interesting. PMID- 24956217 TI - Oral squamous cell carcinoma in a pigtailed macaque (Macaca nemestrina). AB - An adult, gravid, female pigtailed macaque (Macaca nemestrina) presented for facial swelling centered on the left mandible that was approximately 5 cm wide. Differential diagnoses included infectious, inflammatory, and neoplastic origins. Definitive antemortem diagnosis was not possible, and the macaque's condition worsened despite supportive care. Necropsy findings included a mandibular mass that was locally invasive and expansile, encompassing approximately 80% of the left mandibular bone. The mass replaced portions of the soft palate, hard palate, sinuses, ear canal, and the caudal-rostral calvarium and masseter muscle. Histologically, the mass was a neoplasm that was poorly circumscribed, unencapsulated, and infiltrative invading regional bone and soft tissue. The mass consisted of polygonal squamous epithelial cells with intercellular bridging that breached the epithelial basement membrane and formed invasive nests, cords, and trabeculae. The mitotic rate averaged 3 per 400* field of view, with occasional bizarre mitotic figures. Epithelial cells often exhibited dyskeratosis, and the nests often contained compact lamellated keratin (keratin pearls). The neoplasm was positive via immunohistochemistry for pancytokeratin, variably positive for S100, and negative for vimentin, smooth muscle actin, and desmin. The gross, histologic, and immunohistochemical findings were consistent with an aggressive oral squamous cell carcinoma. The neoplasm was negative via PCR for papilloma virus. In general, neoplasia in macaques is rare. Although squamous cell carcinomas are one of the most common oral neoplasia in many species, to our knowledge this case represents the first reported oral squamous cell carcinoma in a pigtailed macaque. PMID- 24956216 TI - Spontaneous leiomyomas of the gastroesophageal junction in a chimpanzee (Pan troglodytes). AB - A 49-y-old, female chimpanzee presented with a history of cardiac failure. Postmortem examination revealed lesions consistent with congestive heart failure and 2 incidental, round, firm, pale-tan intramural nodules (diameter, 2 cm) in the stomach at the gastroesophageal junction (GEJ). Histologically, the GEJ nodules were diagnosed as benign spindle-cell tumors. Immunohistochemical evaluation revealed neoplastic cells diffusely labeled with alpha-smooth muscle actin and vimentin, multifocally labeled for desmin, and were negative for c-kit (CD117). Electron microscopy revealed intracytoplasmic bundles of myofilaments with dense bodies, basal lamina, and few pinocytic vesicles in the neoplastic cells. According to these findings, leiomyomas of the GEJ were diagnosed. Gastrointestinal stromal tumors have been documented to occur in chimpanzees, but there are no reports of GEJ leiomyomas. To our knowledge, this report is the first description of spontaneous leiomyomas of the GEJ in a chimpanzee. PMID- 24956218 TI - Efficient generation and increased reactivity in cationic gold via Bronsted acid or Lewis acid assisted activation of an imidogold precatalyst. AB - Bronsted or Lewis acid assisted activation of an imidogold precatalyst (L-Au-Pht, Pht = phthalimide) offers a superior way to generate cationic gold compared with the commonly used silver-based system. It is also broadly applicable for most common gold-catalyzed reactions. For reactions that require milder conditions, milder acids can be used for optimized efficiency. PMID- 24956220 TI - Pivotal roles of regulating the proline-rich tyrosine kinase 2 (PYK2) signaling in cardiac function and remodeling. PMID- 24956221 TI - Microfluidic generation of multicolor quantum-dot-encoded core-shell microparticles with precise coding and enhanced stability. AB - A novel microfluidic approach is developed to prepare multicolor QDs-encoded core shell microparticles with precise and various barcode and enhanced stability performance. With the protection of the hydrogel shell, the leakage of QDs is avoided and the fluorescent stability is enhanced greatly. By embedding different QDs into different cores, no interaction between different QDs existed and the fluorescence spectrum of each kind of QDs can be recorded, respectively. Compared with QDs mixtures in a single particle, it is unnecessary to separate the emissions of QDs in different colors, and deconvolution algorithms are not needed. Therefore, it still maintains precise coding even if QDs with approximate emission wavelengths are used. PMID- 24956219 TI - Deletion of FoxO1 leads to shortening of QRS by increasing Na(+) channel activity through enhanced expression of both cardiac NaV1.5 and beta3 subunit. AB - Our in vitro studies revealed that a transcription factor, Forkhead box protein O1 (FoxO1), negatively regulates the expression of NaV1.5, a main alpha subunit of the cardiac Na(+) channel, by altering the promoter activity of SCN5a in HL-1 cardiomyocytes. The in vivo role of FoxO1 in the regulation of cardiac NaV1.5 expression remains unknown. The present study aimed to define the role of FoxO1 in the regulation of NaV1.5 expression and cardiac Na(+) channel activity in mouse ventricular cardiomyocytes and assess the cardiac electrophysiological phenotype of mice with cardiac FoxO1 deletion. Tamoxifen-induced and cardiac specific FoxO1 deletion was confirmed by polymerase chain reaction (PCR). Cardiac FoxO1 deletion failed to result in either cardiac functional changes or hypertrophy as assessed by echocardiography and individual ventricular cell capacitances, respectively. Western blotting showed that FoxO1 was significantly decreased while NaV1.5 protein level was significantly increased in mouse hearts with FoxO1 deletion. Reverse transcription-PCR (RT-PCR) revealed that FoxO1 deletion led to an increase in NaV1.5 and Na(+) channel subunit beta3 mRNA, but not beta1, 2, and 4, or connexin 43. Whole patch-clamp recordings demonstrated that cardiac Na(+) currents were significantly augmented by FoxO1 deletion without affecting the steady-state activation and inactivation, leading to accelerated depolarization of action potentials in mouse ventricular cardiomyocytes. Electrocardiogram recordings showed that the QRS complex was significantly shortened and the P wave amplitude was significantly increased in conscious and unrestrained mice with cardiac FoxO1 deletion. NaV1.5 expression was decreased in the peri-infarct (border-zone) of mice with myocardial infarction and FoxO1 accumulated in the cardiomyocyte nuclei of chronic ischemic human hearts. Our findings indicate that FoxO1 plays an important role in the regulation of NaV1.5 and beta3 subunit expressions as well as Na(+) channel activity in the heart and that FoxO1 is involved in the modulation of NaV1.5 expression in ischemic heart disease. PMID- 24956222 TI - Gene expression profile change and growth inhibition in Drosophila larvae treated with azadirachtin. AB - Azadirachtin is a botanical insecticide that affects various biological processes. The effects of azadirachtin on the digital gene expression profile and growth inhibition in Drosophila larvae have not been investigated. In this study, we applied high-throughput sequencing technology to detect the differentially expressed genes of Drosophila larvae regulated by azadirachtin. A total of 15,322 genes were detected, and 28 genes were found to be significantly regulated by azadirachtin. Biological process and pathway analysis showed that azadirachtin affected starch and sucrose metabolism, defense response, signal transduction, instar larval or pupal development, and chemosensory behavior processes. The genes regulated by azadirachtin were mainly enriched in starch and sucrose metabolism. This study provided a general digital gene expression profile of dysregulated genes in response to azadirachtin and showed that azadirachtin provoked potent growth inhibitory effects in Drosophila larvae by regulating the genes of cuticular protein, amylase, and odorant-binding protein. Finally, we propose a potential mechanism underlying the dysregulation of the insulin/insulin like growth factor signaling pathway by azadirachtin. PMID- 24956223 TI - Genetic risk variants of schizophrenia associated with left superior temporal gyrus volume. PMID- 24956224 TI - Word classes in the brain: implications of linguistic typology for cognitive neuroscience. AB - Although recent research on the neural substrates of word classes has generated some valuable findings, significant progress has been hindered by insufficient attention to theoretical issues involving the nature of the lexical phenomena under investigation. This paper shows how insights from linguistic typology can provide cognitive neuroscientists with well-motivated guidelines for interpreting the extant data and charting a future course. At the outset, a fundamental distinction is made between universal and language-particular aspects of word classes. Regarding universals, prototypical nouns involve reference to objects, and their meanings rely primarily on the ventral temporal lobes, which represent the shape features of entities; in contrast, prototypical verbs involve predication of actions, and their meanings rely primarily on posterior middle temporal regions and frontoparietal regions, which represent the visual motion features and somatomotor features of events. Some researchers maintain that focusing on object nouns and action verbs is inappropriate because it conflates the semantic and grammatical properties of each word class. However, this criticism not only ignores the importance of the universal prototypes, but also mistakenly assumes that there are straightforward morphological and/or syntactic criteria for identifying nouns and verbs in particular languages. In fact, at the level of individual languages, the classic method of distributional analysis leads to a proliferation of constructionally based entity-denoting and event denoting word classes with mismatching memberships, and all of this variation must be taken seriously, not only by linguists, but also by cognitive neuroscientists. Many of these word classes involve remarkably close correspondences between grammar and meaning and hence are highly relevant to the neurobiology of conceptual knowledge, but so far hardly any of them have been investigated from a neurolinguistic perspective. PMID- 24956225 TI - Large work function difference driven electron transfer from electrides to single walled carbon nanotubes. AB - A difference in work function plays a key role in charge transfer between two materials. Inorganic electrides provide a unique opportunity for electron transfer since interstitial anionic electrons result in a very low work function of 2.4-2.6 eV. Here we investigated charge transfer between two different types of electrides, [Ca(2)N](+).e(-) and [Ca(24)Al(28)O(64)](4+).4e(-), and single walled carbon nanotubes (SWNTs) with a work function of 4.73-5.05 eV. [Ca(2)N](+) . e(-) with open 2-dimensional electron layers was more effective in donating electrons to SWNTs than closed cage structured [Ca(24)Al(28)O(64)](4+) . 4e(-) due to the higher electron concentration (1.3 * 10(22) cm(-3)) and mobility (~ 200 cm(2) V(-1) s(-1) at RT). A non-covalent conjugation enhanced near-infrared fluorescence of SWNTs as high as 52%. The field emission current density of electride-SWNT-silver paste dramatically increased by a factor of 46,000 (14.8 mA cm(-2)) at 2 V MUm(-1) (3.5 wt% [Ca(2)N](+) . e(-)) with a turn-on voltage of 0.85 V MUm(-1). PMID- 24956226 TI - Association study of childhood obesity with eight genetic variants recently identified by genome-wide association studies. AB - BACKGROUND: Being overweight or obese is becoming increasingly common in low- and middle-income countries. The present study aimed to examine association of eight genetic variants with obesity and to estimate the cumulative effects of these variants in Chinese children. METHODS: We conducted the case-control study in a total of 2,030 subjects. Genotyping of seven novel variants was performed with matrix-assisted laser desorption ionization time of flight mass spectrometry, while rs9939609 was genotyped with tetra-primer amplification refractory mutation system analysis. RESULTS: The association of two fat mass and obesity-associated gene (FTO) single-nucleotide polymorphisms (SNPs; rs9939609 and rs62048402) with body mass index (BMI) or obesity reached nominal significance at P < 0.05. We found a cumulative effect of five SNPs on the risk of overweight and obesity (odds ratio (OR) = 1.197, 95% confidence interval (CI) = 1.068-1.342, P = 0.002). Subjects carrying 9 or more effect alleles had a 127% increased risk of overweight and obesity (OR = 2.270, 95% CI = 1.403-3.671, P = 0.001) compared with subjects who carry 6 or fewer effect alleles. CONCLUSION: We confirmed two FTO SNPs (rs62048402 and rs9939609) had nominal significant effects on BMI or obesity. We identified the cumulative effect of five SNPs on risk of overweight and obesity. The results provided evidence for identifying genetic factors related to childhood obesity. PMID- 24956227 TI - Intestinal fatty acid-binding protein: a possible marker for gut maturation. AB - BACKGROUND: Gut immaturity is linked with postnatal intestinal disorders. However, biomarkers to assess the intestinal developmental stage around birth are lacking. The aim of this study was to gain more insight on intestinal fatty acid binding protein (I-FABP) as an indicator of gut maturity. METHODS: Antenatal I FABP distribution and release was investigated in extremely premature, moderately premature, and term lambs, and these findings were verified in human urinary samples. Ileal I-FABP distribution was confirmed in autopsy material within 24 h postnatally. RESULTS: Median (range) serum I-FABP levels were lower in extremely premature lambs compared with moderately premature lambs (156 (50.0-427) vs. 385 (100-1,387) pg/ml; P = 0.02). Contrarily, median early postnatal urine I-FABP levels in human infants were higher in extremely premature compared with moderately premature and term neonates (1,219 (203-15,044) vs. 256 (50-1,453) and 328 (96-1,749) pg/ml; P = 0.008 and P = 0.04, respectively). I-FABP expression was most prominent in nonvacuolated enterocytes and increased with rising gestational age (GA) in ovine and human tissue samples. The epithelial distribution pattern changed from a phenotype displaying I-FABP-positive enterocytes merely in the crypts early in gestation into a phenotype with I-FABP expressing cells exclusively present in the villus tips at term in ovine and human tissue. CONCLUSION: In this ovine and human study, increasing GA is accompanied by an increase in I-FABP tissue content. Cord I-FABP levels correlate with gestation in ovine fetuses, identifying I-FABP as a marker for gut maturation. Raised postnatal urine I-FABP levels in preterm human infants may indicate intestinal injury and/or inflammation in utero. PMID- 24956229 TI - A highly sensitive and selective fluorescent sensor for detection of Al(3+) using a europium(III) quinolinecarboxylate. AB - Eu2PQC6 has been developed to detect Al(3+) by monitoring the quenching of the europium-based emission, with the lowest detection limit of ~32 pM and the quantitative detection range to 150 MUM. Eu2PQC6 is the first ever example that the europium(III) complex serves as an Al(3+) fluorescent sensor based on "competition-displacement" mode. PMID- 24956230 TI - Pd-catalyzed synthesis of 9,9'-bifluorenylidene derivatives via dual C-H activation of bis-biaryl alkynes. AB - We report a novel Pd-catalyzed alkyne-directed dual C-H activation of bis-biaryl alkynes, which produced important and useful products, 9,9'-bifluorenylidene (9,9'BF) derivatives, in high yields with a broad range of functional group compatibility. The combination of the PdCl2 catalyst with the MnO2 oxidant and PivOH additive is vital for realization of the present catalytic transformation. Mechanistic evidence suggests that this intramolecular arene/alkyne annulation may take place through unusual dual C-H activation followed by annulation with alkynes. PMID- 24956228 TI - Human beta-defensin-3 promotes intestinal epithelial cell migration and reduces the development of necrotizing enterocolitis in a neonatal rat model. AB - BACKGROUND: The aim of this study was to investigate the effects of human beta defensin-3 (hBD3) on intestinal wound healing and in a neonatal rat model of necrotizing enterocolitis (NEC). METHODS: Enterocyte migration and proliferation were detected in vitro and in vivo. The role of chemokine receptor CCR6 and its downstream signaling pathway was assessed. Newborn Sprague-Dawley rats were randomly divided into four groups: Control+NS, Control+hBD3, NEC+NS, and NEC+hBD3. Body weight, histological score, survival time, cytokines expression, and mucosal integrity were evaluated. RESULTS: hBD3 could stimulate enterocyte migration, but not proliferation, both in cultured enterocytes and in the NEC model. Neutralizing antibody and small interfering RNA confirmed this stimulatory effect was mediated by CCR6. Furthermore, hBD3 induced Rho activation, myosin light chain 2 phosphorylation, and F-actin accumulation. The bactericidal activity of hBD3 was maintained throughout a broad pH range. Strikingly, hBD3 administration decreased the incidence of NEC, increased the survival rate, and reduced the severity of NEC. Moreover, hBD3 reduced the proinflammatory cytokines expression in ileum and serum and preserved the intestinal barrier integrity. CONCLUSION: This study provided evidence that the antimicrobial peptide hBD3 might participate in intestinal wound healing by promoting enterocyte migration and show beneficial effects on newborn rats with NEC. PMID- 24956231 TI - Solar-to-hydrogen efficiency exceeding 2.5% achieved for overall water splitting with an all earth-abundant dual-photoelectrode. AB - The solar-to-hydrogen (STH) efficiency of a traditional mono-photoelectrode photoelectrochemical water splitting system has long been limited as large external bias is required. Herein, overall water splitting with STH efficiency exceeding 2.5% was achieved using a self-biased photoelectrochemical-photovoltaic coupled system consisting of an all earth-abundant photoanode and a Si-solar-cell based photocathode connected in series under parallel illumination. We found that parallel irradiation mode shows higher efficiency than tandem illumination especially for photoanodes with a wide light absorption range, probably as the driving force for water splitting reaction is larger and the photovoltage loss is smaller in the former. This work essentially takes advantage of a tandem solar cell which can enhance the solar-to-electricity efficiency from another point of view. PMID- 24956232 TI - Preliminary experiments to quantify liquid movement under mimetic vocal fold vibrational forces. AB - Hydration of vocal fold tissues is essential for self-sustained oscillation. Normal regulatory processes of liquid transport to and from the vocal folds would be expected through the autonomic systems, but the possibility exists that liquid movement may occur locally due to vibrational pressures. Such movement may cause regions of lower or higher concentrations of liquid viscosity and therewith changes in phonation threshold pressure. Hyaluronic acid, a glycosaminoglycan that attracts large quantities of free water, may be a key molecule for transporting or localizing liquids. Some preliminary experiments are reported in which attempts were made to move low-concentration HA liquids with vibration. None of the experiments was conclusive, but collectively they lay some groundwork for future explorations. PMID- 24956233 TI - Metabolomics Reveals Inflammatory-Linked Pulmonary Metabolic Alterations in a Murine Model of House Dust Mite-Induced Allergic Asthma. AB - Although the house dust mite (HDM) is a major environmental aeroallergen that promotes the pathogenesis and severity of allergic asthma, it remains elusive if HDM exposures can induce global metabolism aberrations during allergic airway inflammation. Using an integrated gas and liquid chromatography mass spectrometry based metabolomics and multiplex cytokine profile analysis, metabolic alterations and cytokine changes were investigated in the bronchoalveolar lavage fluid (BALF), serum, and lung tissues in experimental HDM-induced allergic asthma. Allergic pulmonary HDM exposures lead to pronounced eosinophilia, neutrophilia, and increases in inflammatory cytokines. Metabolomics analysis of the BALF, serum, and lung tissues revealed distinctive compartmental metabolic signatures, which included depleted carbohydrates, increased energy metabolites, and consistent losses of sterols and phosphatidylcholines. Pearson correlation analysis uncovered strong associations between specific metabolic alterations and inflammatory cells and cytokines, linking altered pulmonary metabolism to allergic airway inflammation. The clinically prescribed glucocorticoid prednisolone could modulate airway inflammation but was ineffective against the reversal of many HDM-induced metabolic alterations. Collectively, metabolomics reveal comprehensive pulmonary metabolic signatures in HDM-induced allergic asthma, with specific alterations in carbohydrates, lipids, sterols, and energy metabolic pathways. Altered pulmonary metabolism may be a major underlying molecular feature involved during HDM-induced allergic airway inflammation, linked to inflammatory cells and cytokines changes. PMID- 24956234 TI - Protective effect of Ginkgo biloba leaves extract, EGb761, on endotoxin-induced acute lung injury via a JNK- and Akt-dependent NFkappaB pathway. AB - Acute lung injury (ALI) is a clinical syndrome mainly caused by Gram-negative bacteria which is still in need of an effective therapeutic medicine. EGb761, an extract of Ginkgo biloba leaves, has several bioeffects including anti inflammation, cardioprotection, neuroprotection, and free radical scavenging. Preadministration of EGb761 inhibited lipopolysaccharide (LPS)-induced histopathological changes and exchange of arterial blood gas. In addition, LPS induced expression of proinflammatory mediators, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, macrophage inflammatory protein (MIP)-2, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were suppressed by EGb761. The activation of nuclear factor (NF)kappaB, a transcription factor of proinflammatory mediators, and phosphorylation of IkappaB, an inhibitor of NFkappaB, were also reduced by EGb761. Furthermore, we found the inhibitory concentration of EGb761 on phosphorylation of JNK and Akt was less than those of ERK and p38 MAPK. In conclusion, EGb761 is a potential protective agent for ALI, possibly via downregulating the JNK- and Akt-dependent NFkappaB activation pathway. PMID- 24956236 TI - The effects of dodecyl maltoside and sodium dodecyl sulfate surfactants on the stability and aggregation of recombinant interferon Beta-1b. AB - Aggregation often occurs during manufacturing and storage of protein drugs. Detergents such as sodium dodecyl sulfate are commonly used to prevent aggregation but need to be eliminated before final formulation for safety reasons. We studied the ability of dodecylmaltoside (DDM), a nontoxic alkyl saccharide surfactant, to reduce aggregation and increase the stability of interferon beta-1b (IFN)-beta-1b. An increase of 8 degrees C in the Tm of IFN beta-1b was observed when 0.1% of DDM was present in the protein solution. The absorption of DDM on hydrophobic surfaces of IFN-beta-1b enables the surface to become hydrophilic and non-ionic, and increases the stability of the protein. 0.1% DDM also results in a 62% increase in helical and a 25% decrease in beta sheet structures. 0.1% DDM not only suppresses aggregate formation but also improves IFN-beta-1b solubilization. Furthermore, we have showed the protective effect of DDM on the anti-viral activity of IFN-beta-1b in solution. PMID- 24956235 TI - The bright future of single-molecule fluorescence imaging. AB - Single-molecule Forster resonance energy transfer (smFRET) is an essential and maturing tool to probe biomolecular interactions and conformational dynamics in vitro and, increasingly, in living cells. Multi-color smFRET enables the correlation of multiple such events and the precise dissection of their order and timing. However, the requirements for good spectral separation, high time resolution, and extended observation times place extraordinary demands on the fluorescent labels used in such experiments. Together with advanced experimental designs and data analysis, the development of long-lasting, non-fluctuating fluorophores is therefore proving key to progress in the field. Recently developed strategies for obtaining ultra-stable organic fluorophores spanning the visible spectrum are underway that will enable multi-color smFRET studies to deliver on their promise of previously unachievable biological insights. PMID- 24956237 TI - Fast susceptibility-weighted imaging with three-dimensional short-axis propeller (SAP)-echo-planar imaging. AB - BACKGROUND: Susceptibility-weighted imaging (SWI) in neuroimaging can be challenging due to long scan times of three-dimensional (3D) gradient recalled echo (GRE), while faster techniques such as 3D interleaved echo-planar imaging (iEPI) are prone to motion artifacts. Here we outline and implement a 3D short axis propeller echo-planar imaging (SAP-EPI) trajectory as a faster, motion correctable approach for SWI. METHODS: Experiments were conducted on a 3T MRI system. The 3D SAP-EPI, 3D iEPI, and 3D GRE SWI scans were acquired on two volunteers. Controlled motion experiments were conducted to test the motion correction capability of 3D SAP-EPI. The 3D SAP-EPI SWI data were acquired on two pediatric patients as a potential alternative to 2D GRE used clinically. RESULTS: The 3D GRE images had a better target resolution (0.47 * 0.94 * 2 mm, scan time = 5 min), iEPI and SAP-EPI images (resolution = 0.94 * 0.94 * 2 mm) were acquired in a faster scan time (1:52 min) with twice the brain coverage. SAP-EPI showed motion-correction capability and some immunity to undersampling from rejected data. CONCLUSION: While 3D SAP-EPI suffers from some geometric distortion, its short scan time and motion-correction capability suggest that SAP-EPI may be a useful alternative to GRE and iEPI for use in SWI, particularly in uncooperative patients. PMID- 24956239 TI - Souring control in fluid samples of oil industry using a multiple ligand simultaneous docking (MLSD) strategy. AB - We have used docking techniques in order to propose potential inhibitors to the enzymes adenosine phosphosulfate reductase and adenosine triphosphate sulfurylase that are responsible, among other deleterious effects, for causing souring of oil and gas reservoirs. Three candidates selected through molecular docking revealed new and improved polar and hydrophobic interactions with the above-mentioned enzymes. Microbiological laboratory assays performed subsequently corroborated the results of computer modelling that the three compounds can efficiently control the biogenic sulfide production. PMID- 24956238 TI - Phantoms in artists: the lost limbs of Blaise Cendrars,Arthur Rimbaud, and Paul Wittgenstein. AB - There have been an increasing number of reports of postamputation pain and problems linked to phantom limbs over recent years, particularly in relation to war-related amputations. These problems, which are often poorly understood and considered rather mysterious, are still relevant because they are difficult to treat medically. Functional neuroimaging techniques now enable us to better understand their pathophysiology and to consider new rehabilitation techniques. Phantom limbs have often been a source of inspiration to writers, particularly in the period following the First World War, which was responsible for thousands of amputees. Some artists have suffered from postamputation complications themselves and have expressed them through their artistic works. Blaise Cendrars (1887 1961), one of the greatest authors of the twentieth century, suffered from stump pain and phantom limb phenomena for almost half a century following the amputation of his right arm during the First World War. He suffered from these phenomena until the end of his life and his literary work and personal correspondence are peppered with references to them. Arthur Rimbaud (1854-1891), one of the most famous poets in world literature, developed severe stump pain after his right leg was amputated due to a tumor. He survived for only six months after the procedure but left behind an account of the pain he experienced in correspondence to his family. The famous pianist Paul Wittgenstein (1887-1961), whose right arm was amputated during the First World War, became a famous left handed concert pianist. The phantom movements of his right hand helped him to develop the dexterity of his left hand. The impact on the artistic life of these three men provides an original illustration of the various postamputation complications, specifically phantom limbs, stump pain, and moving phantom. PMID- 24956241 TI - Pharmacogenetics in the treatment of chronic lymphocytic leukemia: what does the future hold? PMID- 24956242 TI - New strategies could lead to more personalized therapies for cancer. PMID- 24956240 TI - Increased long-term potentiation at medial-perforant path-dentate granule cell synapses induced by selective inhibition of histone deacetylase 3 requires Fragile X mental retardation protein. AB - Non-selective inhibition of histone deacetylases (HDACs), enzymes that remove acetyl groups from histone core proteins, enhances cognition and NMDAR-dependent long-term potentiation at hippocampal CA3-CA1 synapses. It is not known whether this is a general mechanism by which HDACs modulate plasticity at other hippocampal synapses. Furthermore, it has yet to be tested whether HDAC inhibition can reverse deficits in synaptic plasticity in disease models. Here, we investigated whether inhibition of HDACs, and specifically HDAC3, a class I HDAC isoform known to negatively regulate hippocampus-dependent learning and memory, enhances LTP at medial perforant path-dentate granule cell (MPP-DGC) synapses in wild-type and Fragile X (Fmr1-/y) mice, a model with known LTP deficits at this synapse. The non-selective HDAC inhibitor trichostatin A (TSA) significantly increased the magnitude of LTP at MPP-DGC synapses in wild-type mice, similar to reports at CA3-CA1 synapses. The enhancement of LTP was mimicked by selective HDAC3 inhibition, implicating a role for this isoform in the negative regulation of synaptic plasticity. However, HDAC3 inhibition was completely ineffective in reversing the deficit in LTP at MPP-DGC synapses in slices from Fmr1-/y mice, and in fact, HDAC3 inhibition was unable to induce any improvement whatsoever. These findings indicate that the enhancing effect of HDAC3 inhibition on LTP in wild-type mice requires FMRP, revealing a novel role for FMRP in hippocampal plasticity. PMID- 24956243 TI - Highlights from the latest articles in pharmacogenomics of solid organ transplantation. PMID- 24956245 TI - Clopidogrel dose adjustment after outpatient screening for CYP2C19 variant alleles: a pilot study. AB - This pilot study examined the feasibility of outpatient screening and clopidogrel dose adjustment for patients with previous percutaneous coronary intervention and at least one CYP2C19 loss-of-function allele. After screening a total of 211 outpatients, 50 patients were enrolled in a crossover study comparing 30 days of standard dose (75 mg) to 30 days of high-dose clopidogrel (150 mg). Platelet function was assessed with the VerifyNow P2Y12 assay. In patients with CYP2C19*2, 150 mg daily of clopidogrel was associated with improved ADP-specific platelet inhibition (217 vs 258 P2Y12 reaction units, p = 0.01). Outpatient screening for CYP2C19 loss-of-function polymorphisms is feasible, and a strategy of clopidogrel dose escalation may improve platelet inhibition in appropriately selected patients. PMID- 24956244 TI - Warfarin dose requirements in a patient with the CYP2C9*14 allele. AB - We describe a 64-year-old male of Indian descent with a history of atrial fibrillation who was started on warfarin after hospital admission for acute stroke. He received genotype-guided warfarin dosing as per the standard-of-care at our hospital, with daily dose recommendations provided by the pharmacogenetics service. Genotyping revealed the rare CYP2C9*1/*14 genotype and warfarin insensitive VKORC1 -1639GG and CYP4F2 433Met/Met genotypes. The patient received an initial warfarin loading dose of 4 mg for 2 days, followed by 2-3 mg/day for the following 11 days. He reached a therapeutic international normalized ratio on day 5, which was maintained over the following week. This report adds to the limited data of the effects of the CYP2C9*14 allele on warfarin dose requirements. PMID- 24956246 TI - Exploring effects of EAAT polymorphisms on cognitive functions in schizophrenia. AB - AIM: To evaluate the effect of functional polymorphisms (rs4354668 and rs2731880) of the excitatory amino acid transporters (EAAT1 and 2) on the cognitive dysfunction that characterizes schizophrenia. MATERIALS & METHODS: One hundred and ninety two subjects diagnosed with schizophrenia were assessed with Brief Assessment of Cognition in Schizophrenia, Wisconsin Card Sorting Test, Continuous Performance Test and N-back test and genotyped for rs4354668 and rs2731880. RESULTS: ANOVA showed a significant difference among both EAAT1 and EAAT2 genotype groups on different cognitive measures. Worse performances were observed among carriers of the genotypes associated with lower EAAT expression. CONCLUSION: RESULTS suggest that impaired activity and EAAT expression could influence cognitive performances in schizophrenia, thus representing a target of interest for development of pharmacological strategies aimed to improve cognition. PMID- 24956248 TI - Polymorphisms in translesion polymerase genes influence treatment outcome in malignant mesothelioma. AB - AIM: We evaluated the influence of genetic variability in translesion polymerases REV1 and REV3L on the outcome of cisplatin treatment in malignant mesothelioma patients. MATERIALS & METHODS: In total, 139 malignant mesothelioma patients were genotyped for seven tag SNPs in REV1 and REV3L. Logistic regression and Cox regression were used to assess the influence of SNPs on treatment outcome. RESULTS: Polymorphic REV1 rs3087403 allele and REV1 TGT haplotype were associated with increased risk for leukopenia (p = 0.013 and p = 0.047, respectively) and neutropenia (p = 0.048 and p = 0.024, respectively). REV3L rs465646, rs462779 and REV3L CCGG haplotype were significantly associated with longer overall survival (p = 0.007, p = 0.022 and p = 0.013, respectively). CONCLUSION: Our results suggest for the first time that REV1 and REV3L SNPs might serve as potential predictive markers of outcome of cisplatin-based chemotherapy. Original submitted 7 October 2013; Revision submitted 15 January 2014. PMID- 24956249 TI - No association between genetic or epigenetic variation in insulin growth factors and antipsychotic-induced metabolic disturbances in a cross-sectional sample. AB - AIM: Second-generation antipsychotics (SGA) are known to induce metabolic disturbances. Genetic pathways, such as the IGF pathway could be associated with increased metabolic syndrome (MetS). Additionally, IGF2 methylation varies as a function of environmental influences and is associated with schizophrenia and MetS. The current study aims to evaluate whether genetic and epigenetic variation in genes of the IGF pathway are associated with metabolic disturbances in patients under treatment with SGAs. METHODS: Cross-sectional metabolic data from 438 patients with schizophrenia spectrum disorder was analyzed. Using the Sequenom MassARRAY iPLEX(TM) platform, 27 SNPs of the IGF1 and IGF2 genes and the IGF receptors IGF1R and IGF2R were genotyped. Methylation status of seven IGF2 CpG dinucleotides was evaluated using a Sequenom MALDI-TOF spectrometer. RESULTS & CONCLUSION: There was a significant association between IGF2 methylation and genotype, but no significant association between genetic or epigenetic variability and metabolic parameters in the present study. PMID- 24956247 TI - Replication of SULT4A1-1 as a pharmacogenetic marker of olanzapine response and evidence of lower weight gain in the high response group. AB - AIM: Antipsychotic efficacy biomarkers have the potential to improve outcomes in psychotic patients. This study examined the effect of SULT4A1-1 haplotype status (rs2285162 [A]-rs2285167 [G]) on olanzapine response. PATIENTS & METHODS: We evaluated 87 olanzapine treated subjects from Phases 1, 1B and 2 of the CATIE trial for the impact of SULT4A1-1 status on change in Positive and Negative Syndrome Scale (PANSS) total score using two models of response. We also examined weight change. RESULTS: SULT4A1-1-positive status correlated with superior olanzapine response in Phase 1 (p = 0.004 for model 1 and p = 0.001 for model 2) and Phases 1B/2 (p = 0.05 for model 1 and p = 0.007 for model 2). SULT4A1-1 positive subjects gained significantly less weight per month on olanzapine, 0.15 lbs, than did SULT4A1-1-negative subjects, 2.27 lbs (p = 0.04). CONCLUSION: This study provides a second replication of superior olanzapine response in SULT4A1-1 positive subjects compared with SULT4A1-1-negative subjects. SULT4A1-1-positive subjects treated with olanzapine also gained less weight than SULT4A1-1-negative subjects. PMID- 24956250 TI - Diagnostic accuracy of HLA-B*57:01 screening for the prediction of abacavir hypersensitivity and clinical utility of the test: a meta-analytic review. AB - AIM: To determine diagnostic accuracy of HLA-B*57:01 testing for prediction of abacavir-induced hypersensitivity and to quantify the clinical benefit of pretreatment screening through a meta-analytic review of published studies. METHODS: A comprehensive search was performed up to June 2013. The methodological quality of relevant studies was assessed by the QUADAS-2 tool. The pooled diagnostic estimates were calculated using a random effect model. RESULTS: Despite the presence of heterogeneity in sensitivity or specificity estimates, the pooled diagnostic odds ratio to detect abacavir-induced hypersensitivity on the basis of clinical criteria was 33.07 (95% CI: 22.33-48.97, I(2): 13.9%), while diagnostic odds ratio for detection of immunologically confirmed abacavir hypersensitivity was 1141 (95% CI: 409-3181, I(2): 0%). Pooled analysis of risk ratio showed that prospective HLA-B*57:01 testing significantly reduced the incidence of abacavir-induced hypersensitivity. CONCLUSION: This meta-analysis demonstrates an excellent diagnostic accuracy of HLA-B*57:01 testing to detect immunologically confirmed abacavir hypersensitivity and corroborates existing recommendations. PMID- 24956251 TI - Assessment of CYP450 genetic variability effect on methadone dose and tolerance. AB - AIM: Methadone dose is related to treatment success in individuals under methadone maintenance treatment (MMT). We constructed a gene matrix using previously identified genetic polymorphisms in CYP450 and determined their genetic influence on methadone dose or tolerance. MATERIALS & METHODS: The allelic combinations of CYP450 genetic variants (two from CYP2C19, four from CYP2B6 and five from CYP3A4) were analyzed in 366 MMT heroin dependent patients as possible determinants of methadone dose and tolerance using analysis of covariance. RESULTS: Methadone dose (p = 0.007) and tolerance (p = 0.06) were mainly influenced by CYP2C19 gene dose. Moreover, dominant influence of the CYP2C19 gene dose on methadone dose and tolerance was only found among MMT patients with negative urine morphine test results, but not among those with positive results. CONCLUSION: The findings suggest that CYP2C19 gene dose may serve as a potential indicator for assessing methadone dose and tolerance in MMT patients. PMID- 24956252 TI - Effect of VKORC1, CYP2C9 and CYP4F2 genetic variants in early outcomes during acenocoumarol treatment. AB - AIM: To analyze VKORC1, CYP2C9 and CYP4F2 polymorphisms in relation to the main outcomes in the first stages of acenocoumarol therapy. PATIENTS & METHODS: Nine hundred and forty one patients who had started therapy and in whom time to stable dosage, time to over-anticoagulation and adverse events occurred during 3 first months were retrospectively analyzed. RESULTS: VKORC1 AA patients needed fewer days to reach stable dosage (p = 0.017). International normalized ratio [INR] at 72 h, and VKORC1 and CYP2C9 genotypes conditioned INR values >2.5 (p < 0.001, p = 0.002 and p < 0.001, respectively), whereas CYP4F2 T carriers had a low risk of the same outcome (p = 0.009). In regards to combined genotypes, CYP4F2 had a significant effect on over-anticoagulation at the beginning of therapy except for the VKORC1 AA and CYP2C9*3 combination. CONCLUSION: In addition to VKORC1 and CYP2C9, CYP4F2 gene has a slight but significant role in reaching INR >2.5 during the first weeks of acenocoumarol therapy. PMID- 24956254 TI - Pharmacogenomics of methadone maintenance treatment. AB - Methadone is the major opioid substitution therapy for opioid dependence. Dosage is highly variable and is often controlled by the patient and prescriber according to local and national policy and guidelines. Nevertheless many genetic factors have been investigated including those affecting its metabolism (CYP2B6 consistent results), efflux transport (P-gp-inconsistent results), target MU opioid receptor (MU-opioid receptor-inconsistent results) and a host of other receptors (DRD2) and signaling elements (GIRK2 and ARRB2; not replicated). None by themselves have been able to substantially explain dosage variation (the major but not sole end point). When multiple genes have been combined such as ABCB1, CYP2B6, OPRM1 and DRD2 a greater contribution to dosage variation was found but not as yet replicated. As stabilization of dosage needs to be made rapidly, it is imperative that larger internationally based studies be instigated so that genetic contribution to dosage can be properly assessed, which may or may not tailor to different ethnic groups and each country's policy towards an outcome that benefits all. PMID- 24956255 TI - Pharmacogenetics of drug-induced birth defects: the role of polymorphisms of placental transporter proteins. AB - One of the ongoing issues in perinatal medicine is the risk of birth defects associated with maternal drug use. The teratogenic effect of a drug depends, apart from other factors, on the exposition of the fetus to the drug. Transporter proteins are known to be involved in the pharmacokinetics of drugs and have an effect on drug level and fetal drug exposure. This condition may subsequently alter the risk of teratogenicity, which occurs in a dose-dependent manner. This review focuses on the clinically important polymorphisms of transporter proteins and their effects on the mRNA and protein expression in placental tissue. We also propose a novel approach on how the different genotypes of the polymorphism can be translated into phenotypes to facilitate genetic association studies. The last section looks into the recent studies exploring the association between P glycoprotein polymorphisms and the risk of fetal birth defects associated with medication use during pregnancy. PMID- 24956253 TI - Dose reduction of efavirenz: an observational study describing cost effectiveness, pharmacokinetics and pharmacogenetics. AB - AIM: Antiretroviral treatment implies a high cost to the healthcare system. The aim of this study was to evaluate the clinical and economic impact of efavirenz (EFV) dose adjustment by monitoring plasma concentrations and pharmacogenetic analysis of the 516G>T CYP2B6 polymorphism. MATERIALS & METHODS: One hundred and ninety HIV patients treated with EFV were studied. Plasma EFV concentrations were measured by HPLC with ultraviolet detection, and pharmacogenetic analysis was performed by Real Time (RT)-PCR. RESULTS: One hundred and ninety patients initially treated with a standard dose of EFV (600 mg/day) were studied. In 31 (16.3%) patients, EFV dose was reduced. A total of 87.1% of patients were heterozygous/homozygous carriers (GT/TT). CD4(+) count increased while the minimum steady-state plasma concentration and adverse effects decreased significantly after dose adjustment. Considering only the dose reduction, the adjustments accounted for a saving of 43,539 ?/year. CONCLUSION: The individualization of EFV dosage guided by genotyping 516G>T CYP2B6 and therapeutic drug monitoring could increase the efficiency of EFV use in antiretroviral treatment. PMID- 24956256 TI - Beyond KRAS status and response to anti-EGFR therapy in metastatic colorectal cancer. AB - In patients with metastatic colorectal cancer, overall survival has improved over the last decade mainly due to the use of effective targeted therapies such as anti-EGFR. However, survival improvement is linked to proper selection of patients expected to benefit from these treatments. KRAS codons 12 and 13 mutation status was the first validated molecular biomarker for anti-EGFR antibodies. Today, rare KRAS alterations and NRAS mutations were implemented, defining the 'RAS' status as the new validated marker of response to anti-EGFR antibodies. Moreover, other biomarkers are under investigation to screen for other targets and help with patients selection. Here, we reviewed these promising biomarkers: mutations in the RAS-MAPK and PI3K-AKT pathways genes, MET activation, HER/ErbB receptors activation (EGFR, HER2 and HER3), EGFR ligands, antibody-dependent cell-mediated cytotoxicity) and miRNAs. Further data are needed to define their impact for the treatment of patients with metastatic colorectal cancer. PMID- 24956259 TI - Synergistic inhibitory effect of hyperbaric oxygen combined with sorafenib on hepatoma cells. AB - OBJECTIVES: Hypoxia is a common phenomenon in solid tumors, associated with chemotherapy and radiotherapy resistance, recurrence and metastasis. Hyperbaric oxygen (HBO) therapy can increase tissue oxygen pressure and content to prevent the resistance, recurrence and metastasis of cancer. Presently, Sorafenib is a first-line drug, targeted for hepatocellular carcinoma (HCC) but effective in only a small portion of patients and can induce hypoxia. The purpose of this study is to investigate the effect of HBO in combination with sorafenib on hepatoma cells. METHODS: Hepatoma cell lines (BEL-7402 and SK-Hep1) were treated with HBO at 2 atmosphere absolute pressure for 80 min per day or combined with sorafenib or cisplatin. At different time points, cells were tested for cell growth, colony formation, apoptosis, cell cycle and migration. Finally, miRNA from the hepatoma cells was detected by microRNA array and validated by qRT-PCR. RESULTS: Although HBO, sorafenib or cisplatin alone could inhibit growth of hepatoma cells, HBO combined with sorafenib or cisplatin resulted in much greater synergistic growth inhibition (cell proliferation and colony formation) in hepatoma cells. Similarly, the synergistic effect of HBO and sorafenib on induction of apoptosis was also observed in hepatoma cells. HBO induced G1 arrest in SK-Hep1 not in BEL-7402 cells, but enhanced cell cycle arrest induced by sorafenib in BEL-7402 treated cells. However, HBO had no obvious effect on the migration of hepatoma cells, and microRNA array analysis showed that hepatoma cells with HBO treatment had significantly different microRNA expression profiles from those with blank control. CONCLUSIONS: We show for the first time that HBO combined with sorafenib results in synergistic growth inhibition and apoptosis in hepatoma cells, suggesting a potential application of HBO combined with sorafenib in HCC patients. Additionally, we also show that HBO significantly altered microRNA expression in hepatoma cells. PMID- 24956261 TI - A silver nanowire-based tip suitable for STM tip-enhanced Raman scattering. AB - A chemically synthesized silver nanowire was used for atomic-resolution STM imaging and tip-enhanced Raman scattering (TERS) spectroscopy, yielding excellent reproducibility. This TERS tip will open a new venue to surface analysis, such as molecular finger printing at nanoscales. PMID- 24956260 TI - A novel mouse Fgfr2 mutant, hobbyhorse (hob), exhibits complete XY gonadal sex reversal. AB - The secreted molecule fibroblast growth factor 9 (FGF9) plays a critical role in testis determination in the mouse. In embryonic gonadal somatic cells it is required for maintenance of SOX9 expression, a key determinant of Sertoli cell fate. Conditional gene targeting studies have identified FGFR2 as the main gonadal receptor for FGF9 during sex determination. However, such studies can be complicated by inefficient and variable deletion of floxed alleles, depending on the choice of Cre deleter strain. Here, we report a novel, constitutive allele of Fgfr2, hobbyhorse (hob), which was identified in an ENU-based forward genetic screen for novel testis-determining loci. Fgr2hob is caused by a C to T mutation in the invariant exon 7, resulting in a polypeptide with a mis-sense mutation at position 263 (Pro263Ser) in the third extracellular immunoglobulin-like domain of FGFR2. Mutant homozygous embryos show severe limb and lung defects and, when on the sensitised C57BL/6J (B6) genetic background, undergo complete XY gonadal sex reversal associated with failure to maintain expression of Sox9. Genetic crosses employing a null mutant of Fgfr2 suggest that Fgr2hob is a hypomorphic allele, affecting both the FGFR2b and FGFR2c splice isoforms of the receptor. We exploited the consistent phenotype of this constitutive mutant by analysing MAPK signalling at the sex-determining stage of gonad development, but no significant abnormalities in mutant embryos were detected. PMID- 24956257 TI - Is chronic asthma associated with shorter leukocyte telomere length at midlife? AB - RATIONALE: Asthma is prospectively associated with age-related chronic diseases and mortality, suggesting the hypothesis that asthma may relate to a general, multisystem phenotype of accelerated aging. OBJECTIVES: To test whether chronic asthma is associated with a proposed biomarker of accelerated aging, leukocyte telomere length. METHODS: Asthma was ascertained prospectively in the Dunedin Multidisciplinary Health and Development Study cohort (n = 1,037) at nine in person assessments spanning ages 9-38 years. Leukocyte telomere length was measured at ages 26 and 38 years. Asthma was classified as life-course persistent, childhood-onset not meeting criteria for persistence, and adolescent/adult-onset. We tested associations between asthma and leukocyte telomere length using regression models. We tested for confounding of asthma leukocyte telomere length associations using covariate adjustment. We tested serum C-reactive protein and white blood cell counts as potential mediators of asthma-leukocyte telomere length associations. MEASUREMENTS AND MAIN RESULTS: Study members with life-course-persistent asthma had shorter leukocyte telomere length as compared with sex- and age-matched peers with no reported asthma. In contrast, leukocyte telomere length in study members with childhood-onset and adolescent/adult-onset asthma was not different from leukocyte telomere length in peers with no reported asthma. Adjustment for life histories of obesity and smoking did not change results. Study members with life-course-persistent asthma had elevated blood eosinophil counts. Blood eosinophil count mediated 29% of the life-course-persistent asthma-leukocyte telomere length association. CONCLUSIONS: Life-course-persistent asthma is related to a proposed biomarker of accelerated aging, possibly via systemic eosinophilic inflammation. Life histories of asthma can inform studies of aging. PMID- 24956262 TI - Association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and manual aiming control in healthy subjects. AB - BACKGROUND: Prefrontal dopamine is catabolized by the catechol-O methyltransferase (COMT) enzyme. Current evidence suggests that the val/met single nucleotide polymorphism in the COMT gene can predict the efficiency of executive cognition in humans. Individuals carrying the val allele perform more poorly because less synaptic dopamine is available. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the influence of the COMT polymorphism on motor performance in a task that requires different executive functions. We administered a manual aiming motor task that was performed under four different conditions of execution by 111 healthy participants. Participants were grouped according to genotype (met/met, met/val, val/val), and the motor performance among groups was compared. Overall, the results indicate that met/met carriers presented lower levels of peak velocity during the movement trajectory than the val carriers, but met/met carriers displayed higher accuracy than the val carriers. CONCLUSIONS/SIGNIFICANCE: This study found a significant association between the COMT polymorphism and manual aiming control. Few studies have investigated the genetics of motor control, and these findings indicate that individual differences in motor control require further investigation using genetic studies. PMID- 24956263 TI - Does serum cystatin C level reflect insulin resistance in patients with type 1 diabetes? AB - OBJECTIVES: The aim of study was to evaluate the relationship between serum cystatin C and insulin resistance (IR) in type 1 diabetic patients being the participants of Poznan Prospective Study. DESIGN AND METHODS: The study was performed on 71 Caucasian patients (46 men); with type 1 diabetes, who were recruited into the Poznan Prospective Study, at the age of 39+/-6.1 meanly, and treated with intensive insulin therapy since the onset of the disease. The follow up period and diabetes duration were 15+/-1.6 years. Insulin resistance (IR) was assessed by estimated glucose disposal rate (eGDR) calculation with cut-off point 7.5 mg/kg/min. Patients were divided into two groups, according to the presence or absence of IR. RESULTS: From among 71 patients, 31 patients (43.7%) presented decreased sensitive to insulin with eGDR below 7.5 mg/kg/min. Patients who had eGDR <7.5 mg/kg/min (insulin resistant), compared with subjects with eGDR >7.5 mg/kg/min (insulin sensitive), had higher level of serum cystatin C [0.59 (IQR:0.44-0.84) vs 0.46 (IQR:0.37-0.55) mg/L, p=0.009]. A significant negative correlation between cystatin C and eGDR was revealed (Rs=-0.39, p=0.001). In regression model cystatin C was related to insulin resistance, adjusted for sex, BMI, eGFR and duration of diabetes [OR 0.03 (0.001-0.56), p=0.01]. CONCLUSIONS: Higher level of serum cystatin C is related to decreased insulin sensitivity in patients with type 1 diabetes. This relationship seems to have an important clinical implication. PMID- 24956264 TI - Reproducibility and efficiency of serum-derived exosome extraction methods. AB - OBJECTIVES: Exosomes are emerging as a source of biomarkers with putative prognostic and diagnostic value. However, little is known about the efficiency, reproducibility and reliability of the protocols routinely used to quantify exosomes in the human serum. DESIGN AND METHODS: We used increasing amounts of the same serum sample to isolate exosomes using two different methods: ultracentrifugation onto a sucrose cushion and ExoQuickTM. Quantitative analysis of serum-derived exosomes was performed by determining protein concentration (BCA assay) and the number of nanoparticles (NanosightTM technology). Exosome quality was assessed by Coomassie staining and Western blotting for CD9, LAMP2 exosomal markers and a negative marker Grp94. RESULTS: Correlation between serum volume and the number of isolated exosomes is significant for both methods when exosomes are quantified using protein concentration. However, when the number of nanoparticles is used to quantify exosomes, ExoQuickTM is the only reproducible and efficient method. CD9, LAMP2 and Grp94 exosomal markers are equivalently expressed in both methods. However, exosomes isolated using ultracentrifuge method are strongly contaminated with albumin and IgG. CONCLUSION: ExoQuickTM is an efficient and reproducible method to isolate exosomes for quantitative studies, whereas ultracentrifugation is not. Moreover, high albumin contamination of ultracentrifuged-derived exosomes impairs the use of protein concentration as a mean to quantify serum-derived exosomes. PMID- 24956266 TI - Application of Plackett-Burman and Doehlert designs for optimization of selenium analysis in plasma with electrothermal atomic absorption spectrometry. AB - OBJECTIVES: The aim of this study was the optimization of selenium determination in plasma samples with electrothermal atomic absorption spectrometry using experimental design methodology. DESIGN AND METHODS: 11 variables being able to influence selenium analysis in human blood plasma by electrothermal atomic absorption spectrometry (ETAAS) were evaluated with Plackett-Burman experimental design. These factors were selected from sample preparation, furnace program and chemical modification steps. Both absorbance and background signals were chosen as responses in the screening approach. Doehlert design was used for method optimization. RESULTS: Results showed that only ashing temperature has a statistically significant effect on the selected responses. Optimization with Doehlert design allowed the development of a reliable method for selenium analysis with ETAAS. Samples were diluted 1/10 with 0.05% (v/v) TritonX-100+2.5% (v/v) HNO3 solution. Optimized ashing and atomization temperatures for nickel modifier were 1070 degrees C and 2270 degrees C, respectively. A detection limit of 2.1MUgL(-1) Se was obtained. Accuracy of the method was checked by the analysis of selenium in SeronormTM Trace element quality control serum level 1. The developed procedure was applied for the analysis of total selenium in fifteen plasma samples with standard addition method. Concentrations ranged between 24.4 and 64.6MUgL(-1), with a mean of 42.6+/-4.9MUgL(-1). CONCLUSIONS: The use of experimental designs allowed the development of a cheap and accurate method for selenium analysis in plasma that could be applied routinely in clinical laboratories. PMID- 24956265 TI - Correlations and time course of FGF23 and markers of bone metabolism in maintenance hemodialysis patients. AB - OBJECTIVE: Parathyroid hormone (iPTH) and fibroblast growth factor 23 (FGF23) are elevated in secondary hyperparathyroidism. In hemodialysis, higher dialysate calcium (1.5 mmol/L) induces intradialytic suppression of iPTH, whereas its impact on FGF23 and markers of bone metabolism is unknown. We assessed the time course of FGF23 and markers of bone metabolism in relationship to dialysate calcium. DESIGN AND METHODS: In this prospective cohort study of 19 patients on maintenance hemodialysis, we measured serum calcium (sCa), inorganic phosphate (iP), blood urea nitrogen (BUN), beta2-microglobulin (betaMG), iPTH, FGF23, aminoterminal propeptide type 1 procollagen (P1NP), C-telopeptide of type I collagen for bone degradation (CTX-I), osteocalcin (OC), bone specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase (TRAP5b) during a single hemodialysis session at baseline, 1, 2, and 3h of dialysis. The time course of measured parameters was compared according to groups of prescribed dialysate calcium of 1.25 mmol/L and 1.5 mmol/L. RESULTS: iPTH declined in the 1.5 mmol/L dialysis group as serum calcium increased whereas it tended to increase in the 1.25 mmol/L group without significant changes in serum calcium. Patients on long-term dialysate calcium of 1.5 mmol/L had significantly lower CTX I levels and tended to lower levels of iPTH, FGF23, OC, P1NP and TRAP5b at the start of dialysis compared to those on 1.25 mmol/L. CTX-I, FGF23 and OC but not BALP, P1NP and TRAP5b decreased during dialysis independent of dialysate calcium. CONCLUSIONS: In spite of immediate effects on iPTH, dialysate calcium does not acutely affect other parameters of bone and mineral metabolism. SHORT SUMMARY: Dialysate calcium concentration is known to have both immediate and longer-term impact on parathyroid hormone levels in hemodialysis patients. Little is known about the acute impact of dialysate calcium on bone metabolism. In this cross sectional study of prevalent hemodialysis patients, we found no evidence of immediate short-term dialysate calcium-induced changes of fibroblast growth factor 23 or anabolic and catabolic markers of bone turnover during hemodialysis. However, differences in CTX-I and to a lesser extent other parameters between groups of higher and lower dialysate calcium suggest a longer-term effect that remains to be validated. PMID- 24956267 TI - Discordant diagnoses obtained by different approaches in antithrombin mutation analysis. AB - OBJECTIVES: In hereditary antithrombin (AT) deficiency it is important to determine the underlying mutation since the future risk of thromboembolism varies considerably between mutations. DNA investigations are in general thought of as flawless and irrevocable, but the diagnostic approach can be critical. We therefore investigated mutation results in the AT gene, SERPINC1, with two different approaches. DESIGN AND METHODS: Sixteen patients referred to the Centre for Thrombosis and Haemostasis, Odense University Hospital, with biochemical indications of AT deficiency, but with a negative denaturing high-performance liquid chromatography (DHPLC) mutation screening (routine approach until recently) were included. As an alternative mutation analysis, direct sequencing of all exons and exon-intron boundaries without pre-selection by DHPLC was performed. RESULTS: Out of sixteen patients with a negative DHPLC mutation screening, discordant results were found in ten patients (62.5%) when using direct sequencing: Eight had the Basel mutation (c.218C>T), while two had the Cambridge II mutation (c.1246G>T). For seven of the ten patients this meant an altered clinical risk-assessment for future thromboses. CONCLUSIONS: Awareness must be drawn to the possibility of differences in DNA diagnostics in general and advances when using newer techniques in particular. One should consider re analysis of results obtained by earlier sequencing strategies, as clinically important information can be overlooked. PMID- 24956268 TI - Low vacuum versus low volume tubes and the reduction of hemolyzed specimens from the emergency department. PMID- 24956269 TI - Urinary glycosaminoglycan (uGAG) excretion in healthy pediatric and adolescent population. AB - OBJECTIVES: The influence of age and gender factor on the urinary excretion of total glycosaminoglycans (uGAGs) and their particular types: chondroitin/dermatan sulfates (CS/DSs), heparan sulfates (HSs) and hyaluronan (HA) was analyzed in healthy pediatric and adolescent population. DESIGN AND METHODS: Urine samples were collected from 95 healthy children. Sulfated GAGs excreted in the urine were quantitated using standardized dye-binding method, while the concentrations of HA were determined by immunoassay. RESULTS: Age-dependent decline in total uGAG excretion (r=-0.686; p<0.001), resulting from a decrease in particular GAG fractions i.e. CS/DS (r=-0.757; p<0.001), HS (r=-0.401; p<0.05) and HA (r=-0.638; p<0.001), was found in healthy subjects. The observed differences were not gender specific with the exception of HS, in which excretion declines with age in males (r=-0.501; p<0.05) and does not change in females. Changes in the distribution pattern of uGAG were also found. CS/DS were the predominant uGAG's fraction, representing from 55% to 76% of the total GAGs. Children up to 3 years excreted more GAGs than older subjects and with a higher proportion of CS/DS and less content of HS. Moreover, the relative contribution of HA was increased twofold in adolescents, aged 15-18, as compared to younger subjects. A negative correlation existed between uGAG excretion and body height, except for HS, for which this relationship was found only in males. CONCLUSIONS: Changes in urinary distribution pattern of particular GAG types during physiological human growth and development were found. Evaluation of urinary GAG screening procedures during pathological conditions should be based on the GAG/creatinine ratios with age and gender taken into account. PMID- 24956271 TI - Salivary neurosteroid levels and behavioural profiles of children with attention deficit/hyperactivity disorder during six months of methylphenidate treatment. AB - OBJECTIVE: This prospective study aimed to investigate the relationships between salivary levels of neurosteroids, including dehydroepiandrosterone (DHEA), cortisol, and DHEA/cortisol ratios, and behavioral symptoms in patients with attention-deficit/hyperactivity disorder (ADHD) during treatment with methylphenidate (MPH). METHODS: Fifty-eight ADHD patients (48 boys and 10 girls) were included in the study initially. Forty patients (mean age: 7.77+/-1.64 years; 32 boys and 8 girls) who completed the study received treatment with oral MPH with a dose range of 5-15 mg/day (mean dose: 12.47+/-7.74 mg/day.) for 6 months at the discretion of the psychiatrist. DHEA and cortisol levels were determined from saliva samples collected at 0800 h at baseline and 6 months from baseline. ADHD symptoms were evaluated with the Child Behavior Checklist (CBCL). RESULTS: Salivary DHEA levels (mean difference=9.05 pg/mL, p=0.027) and DHEA/cortisol ratios (mean difference=32.42, p=0.007) in ADHD patients were significantly increased, but the cortisol levels did not change significantly. During a 6 month follow-up, all behavioral problems assessed using the CBCL improved significantly. Changes in salivary DHEA levels were positively correlated with changes in salivary cortisol levels (r=0.44, p=0.004); however, changes in salivary levels of DHEA, cortisol, and the DHEA/cortisol ratio were not significantly correlated with change in any subscales of the CBCL. Mean doses of MPH were not significantly correlated with changes in neurosteroid levels and behavioral symptoms. CONCLUSIONS: These findings provide evidence that MPH administration might affect DHEA levels and DHEA/cortisol ratios. Whether levels of neurosteroids are directly associated with brain function or behavioral problems in ADHD patients warrants further investigation. PMID- 24956270 TI - Large-scale East-Asian eQTL mapping reveals novel candidate genes for LD mapping and the genomic landscape of transcriptional effects of sequence variants. AB - Profiles of sequence variants that influence gene transcription are very important for understanding mechanisms that affect phenotypic variation and disease susceptibility. Using genotypes at 1.4 million SNPs and a comprehensive transcriptional profile of 15,454 coding genes and 6,113 lincRNA genes obtained from peripheral blood cells of 298 Japanese individuals, we mapped expression quantitative trait loci (eQTLs). We identified 3,804 cis-eQTLs (within 500 kb from target genes) and 165 trans-eQTLs (>500 kb away or on different chromosomes). Cis-eQTLs were often located in transcribed or adjacent regions of genes; among these regions, 5' untranslated regions and 5' flanking regions had the largest effects. Epigenetic evidence for regulatory potential accumulated in public databases explained the magnitude of the effects of our eQTLs. Cis-eQTLs were often located near the respective target genes, if not within genes. Large effect sizes were observed with eQTLs near target genes, and effect sizes were obviously attenuated as the eQTL distance from the gene increased. Using a very stringent significance threshold, we identified 165 large-effect trans-eQTLs. We used our eQTL map to assess 8,069 disease-associated SNPs identified in 1,436 genome-wide association studies (GWAS). We identified genes that might be truly causative, but GWAS might have failed to identify for 148 out of the GWAS identified SNPs; for example, TUFM (P = 3.3E-48) was identified for inflammatory bowel disease (early onset); ZFP90 (P = 4.4E-34) for ulcerative colitis; and IDUA (P = 2.2E-11) for Parkinson's disease. We identified four genes (P<2.0E-14) that might be related to three diseases and two hematological traits; each expression is regulated by trans-eQTLs on a different chromosome than the gene. PMID- 24956272 TI - SkipCor: skip-mention coreference resolution using linear-chain conditional random fields. AB - Coreference resolution tries to identify all expressions (called mentions) in observed text that refer to the same entity. Beside entity extraction and relation extraction, it represents one of the three complementary tasks in Information Extraction. In this paper we describe a novel coreference resolution system SkipCor that reformulates the problem as a sequence labeling task. None of the existing supervised, unsupervised, pairwise or sequence-based models are similar to our approach, which only uses linear-chain conditional random fields and supports high scalability with fast model training and inference, and a straightforward parallelization. We evaluate the proposed system against the ACE 2004, CoNLL 2012 and SemEval 2010 benchmark datasets. SkipCor clearly outperforms two baseline systems that detect coreferentiality using the same features as SkipCor. The obtained results are at least comparable to the current state-of-the art in coreference resolution. PMID- 24956273 TI - Growth and phenology of three dwarf shrub species in a six-year soil warming experiment at the alpine treeline. AB - Global warming can have substantial impacts on the phenological and growth patterns of alpine and Arctic species, resulting in shifts in plant community composition and ecosystem dynamics. We evaluated the effects of a six-year experimental soil warming treatment (+4 degrees C, 2007-2012) on the phenology and growth of three co-dominant dwarf shrub species growing in the understory of Larix decidua and Pinus uncinata at treeline in the Swiss Alps. We monitored vegetative and reproductive phenology of Vaccinium myrtillus, Vaccinium gaultherioides and Empetrum hermaphroditum throughout the early growing season of 2012 and, following a major harvest at peak season, we measured the biomass of above-ground ramet fractions. For all six years of soil warming we measured annual shoot growth of the three species and analyzed ramet age and xylem ring width of V. myrtillus. Our results show that phenology of the three species was more influenced by snowmelt timing, and also by plot tree species (Larix or Pinus) in the case of V. myrtillus, than by soil warming. However, the warming treatment led to increased V. myrtillus total above-ground ramet biomass (+36% in 2012), especially new shoot biomass (+63% in 2012), as well as increased new shoot increment length and xylem ring width (+22% and +41%, respectively; average for 2007-2012). These results indicate enhanced overall growth of V. myrtillus under soil warming that was sustained over six years and was not caused by an extended growing period in early summer. In contrast, E. hermaphroditum only showed a positive shoot growth response to warming in 2011 (+21%), and V. gaultherioides showed no significant growth response. Our results indicate that V. myrtillus might have a competitive advantage over the less responsive co occurring dwarf shrub species under future global warming. PMID- 24956274 TI - Phosphomimetic mutation of cysteine string protein-alpha increases the rate of regulated exocytosis by modulating fusion pore dynamics in PC12 cells. AB - BACKGROUND: Cysteine string protein-alpha (CSPalpha) is a chaperone to ensure protein folding. Loss of CSPalpha function associates with many neurological diseases. However, its function in modulating regulated exocytosis remains elusive. Although cspalpha-knockouts exhibit impaired synaptic transmission, overexpression of CSPalpha in neuroendocrine cells inhibits secretion. These seemingly conflicting results lead to a hypothesis that CSPalpha may undergo a modification that switches its function in regulating neurotransmitter and hormone secretion. Previous studies implied that CSPalpha undergoes phosphorylation at Ser10 that may influence exocytosis by altering fusion pore dynamics. However, direct evidence is missing up to date. METHODOLOGY/PRINCIPAL FINDINGS: Using amperometry, we investigated how phosphorylation at Ser10 of CSPalpha (CSPalpha-Ser10) modulates regulated exocytosis and if this modulation involves regulating a specific kinetic step of fusion pore dynamics. The real time exocytosis of single vesicles was detected in PC12 cells overexpressing control vector, wild-type CSPalpha (WT), the CSPalpha phosphodeficient mutant (S10A), or the CSPalpha phosphomimetic mutants (S10D and S10E). The shapes of amperometric signals were used to distinguish the full-fusion events (i.e., prespike feet followed by spikes) and the kiss-and-run events (i.e., square shaped flickers). We found that the secretion rate was significantly increased in cells overexpressing S10D or S10E compared to WT or S10A. Further analysis showed that overexpression of S10D or S10E prolonged fusion pore lifetime compared to WT or S10A. The fraction of kiss-and-run events was significantly lower but the frequency of full-fusion events was higher in cells overexpressing S10D or S10E compared to WT or S10A. Advanced kinetic analysis suggests that overexpression of S10D or S10E may stabilize open fusion pores mainly by inhibiting them from closing. CONCLUSIONS/SIGNIFICANCE: CSPalpha may modulate fusion pore dynamics in a phosphorylation-dependent manner. Therefore, through changing its phosphorylated state influenced by diverse cellular signalings, CSPalpha may have a great capacity to modulate the rate of regulated exocytosis. PMID- 24956275 TI - Two tandem RNase III cleavage sites determine betT mRNA stability in response to osmotic stress in Escherichia coli. AB - While identifying genes regulated by ribonuclease III (RNase III) in Escherichia coli, we observed that steady-state levels of betT mRNA, which encodes a transporter mediating the influx of choline, are dependent on cellular concentrations of RNase III. In the present study, we also observed that steady state levels of betT mRNA are dependent on RNase III activity upon exposure to osmotic stress, indicating the presence of cis-acting elements controlled by RNase III in betT mRNA. Primer extension analyses of betT mRNA revealed two tandem RNase III cleavage sites in its stem-loop region, which were biochemically confirmed via in vitro cleavage assays. Analyses of cleavage sites suggested the stochastic selection of cleavage sites by RNase III, and mutational analyses indicated that RNase III cleavage at either site individually is insufficient for efficient betT mRNA degradation. In addition, both the half-life and abundance of betT mRNA were significantly increased in association with decreased RNase III activity under hyper-osmotic stress conditions. Our findings demonstrate that betT mRNA stability is controlled by RNase III at the post-transcriptional level under conditions of osmotic stress. PMID- 24956276 TI - Crossed pulmonary arteries with hypoplasia of the transverse aortic arch. AB - BACKGROUND: The entity of crossed pulmonary arteries was first described by Jue, Lockman, and Edwards in 1966, in a patient with trisomy 18. Since then, several series have been described, both in terms of the isolated anatomic variant, or its association with other intracardiac or extracardiac anomalies. We describe a rare association that has previously not been reported. Methods and results Institutional Review Board approval for a retrospective chart review was obtained. Over the period 2011 through 2013, we have encountered six patients in whom the crossed origins of the pulmonary arteries from the pulmonary trunk were associated with hypoplasia of the transverse aortic arch, an association that, to the best of our knowledge, has previously not been reported. In all of the patients, the isthmic component of the aortic arch was inserted in an end-to-side manner into the ductal arch, with additional discrete coarctation in half of the patients. CONCLUSION: To the best of our knowledge, no cases of crossed pulmonary arteries have been described in association with hypoplasia of the transverse aortic arch. We draw comparisons between the cases with exclusively tubular hypoplasia, and those with the added problem of the more typical isthmic variant of aortic coarctation. In all cases, the ability to reconstruct cross-sectional images added significantly to the diagnosis and understanding of these complex lesions. These findings have specific surgical implications, which are discussed. PMID- 24956277 TI - Analysis of the transcriptome of Erigeron breviscapus uncovers putative scutellarin and chlorogenic acids biosynthetic genes and genetic markers. AB - BACKGROUND: Erigeron breviscapus (Vant.) Hand-Mazz. is a famous medicinal plant. Scutellarin and chlorogenic acids are the primary active components in this herb. However, the mechanisms of biosynthesis and regulation for scutellarin and chlorogenic acids in E. breviscapus are considerably unknown. In addition, genomic information of this herb is also unavailable. PRINCIPAL FINDINGS: Using Illumina sequencing on GAIIx platform, a total of 64,605,972 raw sequencing reads were generated and assembled into 73,092 non-redundant unigenes. Among them, 44,855 unigenes (61.37%) were annotated in the public databases Nr, Swiss-Prot, KEGG, and COG. The transcripts encoding the known enzymes involved in flavonoids and in chlorogenic acids biosynthesis were discovered in the Illumina dataset. Three candidate cytochrome P450 genes were discovered which might encode flavone 6-hydroase converting apigenin to scutellarein. Furthermore, 4 unigenes encoding the homologues of maize P1 (R2R3-MYB transcription factors) were defined, which might regulate the biosynthesis of scutellarin. Additionally, a total of 11,077 simple sequence repeat (SSR) were identified from 9,255 unigenes. Of SSRs, tri nucleotide motifs were the most abundant motif. Thirty-six primer pairs for SSRs were randomly selected for validation of the amplification and polymorphism. The result revealed that 34 (94.40%) primer pairs were successfully amplified and 19 (52.78%) primer pairs exhibited polymorphisms. CONCLUSION: Using next generation sequencing (NGS) technology, this study firstly provides abundant genomic data for E. breviscapus. The candidate genes involved in the biosynthesis and transcriptional regulation of scutellarin and chlorogenic acids were obtained in this study. Additionally, a plenty of genetic makers were generated by identification of SSRs, which is a powerful tool for molecular breeding and genetics applications in this herb. PMID- 24956281 TI - An integrated framework for joint HRF and drift estimation and HbO/HbR signal improvement in fNIRS data. AB - Nonparametric hemodynamic response function (HRF) estimation in functional near infrared spectroscopy (fNIRS) data plays an important role when investigating the temporal dynamics of a brain region response during activations. Assuming the drift arising from both physical and physiological effects in fNIRS data is Lipschitz continuous; a novel algorithm for joint HRF and drift estimation is derived in this paper. The proposed algorithm estimates the HRF by applying a first-order differencing to the fNIRS time series samples in order to remove the drift effect. An estimate of the drift is then obtained using a wavelet thresholding technique applied to the residuals generated by removing the estimated induced activation response from the fNIRS time-series. It is shown that the proposed HRF estimator is ?N consistent whereas the estimator of the drift is asymptotically optimal. The de-drifted fNIRS oxygenated (HbO) and deoxygenated (HbR) hemoglobin responses are then obtained by removing the corresponding estimated drifts from the fNIRS time-series. Its performance is assessed using both simulated and real fNIRS data sets. The application results reveal that the proposed joint HRF and drift estimation method is efficient both computationally and in terms of accuracy. In comparison to traditional model based methods used for HRF estimation, the proposed novel method avoids the selection of a model to remove the drift component. As a result, the proposed method finds an optimal estimate of the fNIRS drift and offers a model-free approach to de-drift the HbO/HbR responses. PMID- 24956280 TI - In vitro characterization of human adenovirus type 55 in comparison with its parental adenoviruses, types 11 and 14. AB - Human adenovirus type 55 (HAdV-B55) represents a re-emerging human pathogen, and this adenovirus has been reported to cause outbreaks of acute respiratory diseases among military trainees and in school populations around the world. HAdV B55 has been revealed to have evolved from homologous recombination between human adenovirus type 14 (HAdV-B14) and type 11 (HAdV-B11), but it presents different clinical manifestations from parental virus HAdV-B11. In the present paper, we report the distinct biological features of HAdV-B55 in comparison with the parental viruses HAdV-B11 and HAdV-B14 in cell cultures. The results showed that HAdV-B55 replicated well in various cells, similar to HAdV-B11 and HAdV-B14, but that its processing had a slower and milder cytopathic effect in the early stages of infection. Viral fitness analysis showed that HAdV-B55 exhibited higher levels of replication in respiratory cells than did either of its parents. Cytotoxicity and apoptosis analyses in A549 cells indicated that HAdV-B55 was less cytotoxic than HAdV-B11 and HAdV-B14 were and induced milder apoptosis. Finally, thermal sensitivity analysis revealed that HAdV-B55 exhibited lower thermostability than did either HAdV-B11 or HAdV-B14, which may limit the transmission of HAdV-B55 in humans. Together, the findings described here expand current knowledge about this re-emerging recombinant HAdV, shedding light on the pathogenesis of HAdV-B55. PMID- 24956282 TI - Improved myocardial motion estimation combining tissue Doppler and B-mode echocardiographic images. AB - We propose a technique for myocardial motion estimation based on image registration using both B-mode echocardiographic images and tissue Doppler sequences acquired interleaved. The velocity field is modeled continuously using B-splines and the spatiotemporal transform is constrained to be diffeomorphic. Images before scan conversion are used to improve the accuracy of the estimation. The similarity measure includes a model of the speckle pattern distribution of B mode images. It also penalizes the disagreement between tissue Doppler velocities and the estimated velocity field. Registration accuracy is evaluated and compared to other alternatives using a realistic synthetic dataset, obtaining mean displacement errors of about 1 mm. Finally, the method is demonstrated on data acquired from six volunteers, both at rest and during exercise. Robustness is tested against low image quality and fast heart rates during exercise. Results show that our method provides a robust motion estimate in these situations. PMID- 24956283 TI - Silencing of murine transthyretin and retinol binding protein genes has distinct and shared behavioral and neuropathologic effects. AB - The murine genes encoding transthyretin (TTR) and retinol binding protein (RBP) were independently silenced by targeted disruption more than 10 years ago. Studies of both strains showed surprisingly little impact on either thyroid function or retinoid metabolism. Silencing TTR led to a relatively mild behavioral phenotype. In order to gain insight into the behavioral effect and determine if it was related to TTR's function as the carrier of RBP we carried out simultaneous studies with homozygous Rbp4(-/-) and Ttr(-/-) animals 4-7 months of age. Both strains showed behavioral differences relative to Ttr and Rbp4 wild-type animals and each other. The patterns were discrete for each knockout although there was some overlap. Neuropathologic examination of the cortex and hippocampus revealed cortical and hippocampal (CA3) neuronal loss in both and some degree of gliosis, more pronounced in the Rbp4(-/-) mice. There also appeared to be a major reduction in proliferating neuroblasts in the subventricular zone in both strains, which was also more severe in the Rbp4(-/-) mice. This is the first description of behavioral abnormalities in Rbp4(-/-)mice. The data also indicate that it is unlikely that the behaviors seen in Ttr(-/-) mice are related to its function as an RBP carrier. PMID- 24956279 TI - Immunization against multidrug-resistant Acinetobacter baumannii effectively protects mice in both pneumonia and sepsis models. AB - OBJECTIVE: Acinetobacter baumannii is considered the prototypical example of a multi- or pan- drug-resistant bacterium. It has been increasingly implicated as a major cause of nosocomial and community-associated infections. This study proposed to evaluate the efficacy of immunological approaches to prevent and treat A. baumannii infections. METHODS: Mice were immunized with outer membrane vesicles (OMVs) prepared from a clinically isolated multidrug-resistant strain of A. baumannii. Pneumonia and sepsis models were used to evaluate the efficacy of active and passive immunization with OMVs. The probable effective mechanisms and the protective potential of clonally distinct clinical isolates were investigated in vitro using an opsonophagocytic assay. RESULTS: Intramuscular immunization with OMVs rapidly produced high levels of OMV-specific IgG antibodies, and subsequent intranasal challenge with A. baumannii elicited mucosal IgA and IgG responses. Both active and passive immunization protected the mice from challenges with homologue bacteria in a sepsis model. Bacterial burden in bronchoalveolar lavage fluids (BALF), lung, and spleen, inflammatory cell infiltration in BALF and lung, and inflammatory cytokine accumulation in BALF was significantly suppressed in the pneumonia model by both active and passive immunization strategies. The antisera from immunized mice presented with significant opsonophagocytic activities in a dose-dependent manner against not only homologous strains but also five of the other six clonally distinct clinical isolates. CONCLUSIONS: Utilizing immunological characteristics of outer membrane proteins to elevate protective immunity and circumvent complex multidrug resistance mechanisms might be a viable approach to effectively control A. baumannii infections. PMID- 24956278 TI - Modulation of radiation injury response in retinal endothelial cells by quinic acid derivative KZ-41 involves p38 MAPK. AB - Radiation-induced damage to the retina triggers leukostasis, retinal endothelial cell (REC) death, and subsequent hypoxia. Resultant ischemia leads to visual loss and compensatory retinal neovascularization (RNV). Using human RECs, we demonstrated that radiation induced leukocyte adhesion through mechanisms involving p38MAPK, p53, and ICAM-1 activation. Additional phenotypic changes included p38MAPK-dependent tyrosine phosphorylation of the focal adhesion scaffolding protein, paxillin (Tyr118). The quinic acid derivative KZ-41 lessened leukocyte adhesion and paxillin-dependent proliferation via inhibition of p38MAPK p53-ICAM-1 signaling. Using the murine oxygen-induced retinopathy (OIR) model, we examined the effect of KZ-41 on pathologic RNV. Daily ocular application of a KZ 41-loaded nanoemulsion significantly reduced both the avascular and neovascular areas in harvested retinal flat mounts when compared to the contralateral eye receiving vehicle alone. Our data highlight the potential benefit of KZ-41 in reducing both the retinal ischemia and neovascularization provoked by genotoxic insults. Further research into how quinic acid derivatives target and mitigate inflammation is needed to fully appreciate their therapeutic potential for the treatment of inflammatory retinal vasculopathies. PMID- 24956284 TI - Melatonin enhances adult rat hippocampal progenitor cell proliferation via ERK signaling pathway through melatonin receptor. AB - Melatonin, a neurohormone secreted mainly by the pineal gland, has a variety of physiological functions and neuroprotective effects. Previous studies have shown that melatonin could stimulate the proliferation of neural stem/progenitor cells (NS/PCs). Recent studies reported that the activities of mitogen-activated protein kinase (MAPK) of neural stem cells (NSCs) changed in response to the proliferative effect of melatonin. Therefore, the aim of the present study was to explore the proliferative mechanism mediated by melatonin on the adult rat hippocampal NS/PCs. Treatment with melatonin significantly increased the number of neurospheres in a concentration-dependent manner and up-regulated nestin protein. Pretreatment with luzindole, a melatonin receptor antagonist, and PD98059, a mitogen-activated protein kinase kinase (MEK) inhibitor, prevented the increase in the number of neurospheres formed by the activation of melatonin. The levels of phospho-c-Raf and phospho-extracellular signal-regulated kinase 1/2 (ERK1/2) increased when treated with melatonin. Pretreatment with luzindole or PD98059 prevented the melatonin-induced increase in these signaling molecules. The present results showed that melatonin could induce NS/PCs to proliferate by increasing phosphorylation of ERK1/2 and c-Raf through melatonin receptor. These results provide further evidence for a role of melatonin in promoting neurogenesis, adding to the remarkably pleiotropic nature of this neurohormone. This intrinsic modulator deserves further investigation to better understand its physiological and therapeutic implication. PMID- 24956285 TI - Pt-decorated 3D architectures built from graphene and graphitic carbon nitride nanosheets as efficient methanol oxidation catalysts. AB - Homogeneous dispersion of ultrafine Pt nanoparticles on 3D architectures constructed of graphene and exfoliated graphitic carbon nitride results in hybrids with 3D porous structures, large surface area, high nitrogen content, and good electrical conductivity. This leads to excellent electrocatalytic activity, unusually high poison tolerance, and reliable stability for methanol oxidation, making them of interest as catalysts in direct methanol fuel cells. PMID- 24956286 TI - Haplotype analysis of the XRCC1 gene and laryngeal cancer. AB - OBJECTIVE: Several polymorphisms in DNA repair genes have been extensively studied in association with various human cancers, including laryngeal cancer. The present study aimed to investigate the association between polymorphisms of the XRCC1 gene and laryngeal cancer in a Chinese population. METHODS: Five polymorphisms of the XRCC1 gene (rs3213403, rs1799778, rs1001581, rs3213282, and rs3810378) were genotyped by TaqMan in 234 patients with larynx cancer and 230 age- and sex-matched controls without cancer. RESULTS: The rs3213403, rs1799778, and rs3213282 polymorphisms of XRCC1 were associated with larynx cancer. Haplotype analysis indicated that CCA (odds ratio [OR], 5.707; 95% confidence interval [CI], 3.277-9.938; p<0.001), TGG (OR, 4.344; 95% CI, 2.804-6.732; p<0.001), ACA (OR, 1.615; 95% CI, 1.159-2.250; p=0.004), and GCG (OR, 1.702; 95% CI, 1.164-2.489; p=0.005) were associated with an increased risk for larynx cancer, respectively. However, TGA (OR, 0.518; 95% CI, 0.398-0.673; p<0.001) and ACC (OR, 0.314; 95% CI, 0.215-0.457; p<0.001) were associated with a decreased risk for larynx cancer. CONCLUSIONS: The results indicated that XRCC1 genetic polymorphisms were associated with larynx cancer in a Chinese population. PMID- 24956287 TI - Communicating the changes to cervical cancer screening in England: the choice to have an HPV test. PMID- 24956288 TI - Could the uterine junctional zone be used to identify early-stage endometriosis in women? PMID- 24956289 TI - Can new information and communication technologies help in the management of osteoporosis? PMID- 24956290 TI - New targeted cancer therapy for resistant gynecologic cancers. PMID- 24956291 TI - Asptects of mental health care in the gynecological setting. AB - Psychological disorders are commonly associated with gynecological conditions, but are frequently undetected and untreated, and may influence the presentation and treatment outcomes of the physical condition. A literature search was conducted in order to provide a narrative review of psychological aspects of menopause, premenstrual syndrome, premenstrual dysphoric disorder, chronic pelvic pain, incontinence and polycystic ovarian syndrome. All the conditions that have been addressed in this review can be associated with an increased risk of psychological symptoms and disorders. Anxiety and depression are common and are associated with significant morbidity. Gynecological conditions, by their nature, are likely to be accompanied by impairments in social, occupational and personal functioning. Greater emphasis should be placed on the mental health aspects of gynecological conditions. PMID- 24956292 TI - An update on the management of hematologic malignancies in pregnancy. AB - Hematological malignancies during pregnancy are rare, which results in the absence of large prospective studies. The diagnosis is often delayed due to the symptom similarity to those of pregnancy and the recommendation to avoid imaging studies during gestation. Management of hematological malignancies during pregnancy poses challenges both to the patient and the medical team, given the therapy-attributable risks for mother and fetus and the need to consider patient's preferences regarding pregnancy continuation. Chemotherapy during the first trimester is associated with an increased risk for fetal demise and congenital malformations, while these risks diminish as pregnancy progresses. We hereby present a review of updated literature on the management of hematologic malignancies (Hodgkin and non-Hodgkin lymphomas, acute leukemia, multiple myeloma, chronic myeloid leukemia and myeloproliferative neoplasms) during pregnancy. PMID- 24956293 TI - GnRH agonist triggers and their use in assisted reproductive technology: the past, the present and the future. AB - Gonadotropin releasing hormone agonist triggers are very effective in eliminating early-onset ovarian hyperstimulation syndrome (OHSS). However, in most studies they result in inferior pregnancy rates compared to hCG triggers in fresh autologous transfers. This is not due to an effect on embryo quality but rather due to inadequate corpus luteum formation and a defective luteal phase causing poor implantation. Intensive and adjusted steroid support or low-dose hCG may correct this. Late-onset OHSS is eliminated by using a freeze-all strategy. Pregnancy rates after transfer of thawed vitrified embryos are consistently high. A strategy combining a gonadotropin releasing hormone agonist trigger with vitrification of all embryos has been proposed as a means of achieving a truly OHSS-free clinic. PMID- 24956294 TI - Update on prognostic markers for endometrial cancer. AB - Endometrial cancer is the most common gynecologic cancer in the USA and the second most common worldwide after cervical cancer. While common symptomatology of endometrial cancer leads to early diagnosis and favorable 5-year survival in most cases, there is a subset of cancers that have a poorer prognosis. The clinical and pathologic prognostic factors for endometrial cancer are well known and instrumental in determining the need for adjuvant therapy. Recently, research has been focused on the identification of molecular changes leading to different histologic subtypes to improve classification of endometrial cancer. The identification of novel mutations and molecular profiles should enhance our ability to personalize adjuvant treatment with genome-guided targeted therapy. PMID- 24956296 TI - Role of imaging in the pretreatment evaluation of common gynecological cancers. AB - Different treatment options are available for patients with gynecological cancers. Imaging plays an important role in assessment of patients with common cancers involving uterine body, cervix and ovaries, from detection to evaluation of the extent of disease. The purpose of this review is to highlight the role of cross-sectional imaging techniques in treatment stratification and overall management of patients with endometrial, cervical and ovarian cancers. Several imaging techniques used are described, including ultrasound, computed tomography (CT), MRI and PET/CT. Specific imaging appearances of the most common uterine, cervical and ovarian cancers are discussed. Imaging findings corresponding to the 2009 revised International Federation of Gynecology and Obstetrics (FIGO) staging of gynecologic malignancies are also described. In the multidisciplinary evaluation of patients with gynecologic malignancies, the role of the radiologist has become central for accurate diagnosis and evaluation of extent of disease to achieve better treatment selection and planning. PMID- 24956295 TI - Contrast-enhanced dual-energy mammography: a promising new imaging tool in breast cancer detection. AB - Contrast-enhanced dual-energy mammography (CEDM) is a promising new breast imaging tool for breast cancer detection. In CEDM, an iodine-based contrast agent is intravenously administered and subsequently, dual-energy mammography is performed. This results in a set of images containing both a regular mammogram and an image that contains contrast enhancement information. Preliminary studies have indicated that CEDM is superior to conventional mammography and might even match the diagnostic performance of breast MRI. In this review, the imaging technique, protocol and patient handling of CEDM is presented. Furthermore, an overview of current results on CEDM and potential future indications are outlined. PMID- 24956297 TI - Factors to consider in gynecological surgery. AB - Progress is evident in the whole concept of breast cancer treatment and in the assessment of the sentinel node in different cancers of the female in urogynecology, as well as in minimally invasive surgery. In this review we concentrate on the impact of endoscopic surgery. Minimally invasive surgery has evolved in a relatively short period of time to overtake the centuries old visionary and pioneering groundwork of outstanding colleagues in all surgical disciplines. This overview on the development of gynecological surgery highlights past achievements and describes present challenges of endoscopic surgery. It emphasizes future opportunities and possibilities to foster interdisciplinary collaboration and integrate emerging endoscopic, imaging and stereotactic surgical technologies to improve patient safety, enhance quality of care and advance surgical education. PMID- 24956298 TI - Identity processes and personality traits and types in adolescence: directionality of effects and developmental trajectories. AB - Personality traits are hypothesized to be among the most important factors contributing to individual differences in identity development. However, longitudinal studies linking Big Five personality traits to contemporary identity models (in which multiple exploration and commitment processes are distinguished) are largely lacking. To gain more insight in the directionality of effect and the developmental interdependence of the Big Five and identity processes as forwarded in multilayered personality models, the present study assessed personality and identity in 1,037 adolescents 4 times over a period of 3 years. First, using cross-lagged path analysis, Big Five traits emerged as consistent predictors of identity exploration processes, whereas only one significant path from identity exploration to the Big Five was found. Second, using latent class growth analysis, 3 Big Five trajectory classes were identified, resembling the distinctions typically made between resilients, overcontrollers, and undercontrollers. These classes were characterized by different initial levels and (to a lesser extent) rates of change in commitment and exploration processes. In sum, important developmental associations linking personality traits to identity processes were uncovered, emphasizing the potential role of personality traits in identity development. Developmental implications and suggestions for future research are discussed. PMID- 24956300 TI - A novel pulsatile bioreactor for mechanical stimulation of tissue engineered cardiac constructs. AB - After myocardial infarction, the implantation of stem cell seeded scaffolds on the ischemic zone represents a promising strategy for restoration of heart function. However, mechanical integrity and functionality of tissue engineered constructs need to be determined prior to implantation. Therefore, in this study a novel pulsatile bioreactor mimicking the myocardial contraction was developed to analyze the behavior of mesenchymal stem cells derived from umbilical cord tissue (UCMSC) colonized on titanium-coated polytetrafluorethylene scaffolds to friction stress. The design of the bioreactor enables a simple handling and defined mechanical forces on three seeded scaffolds at physiological conditions. The compact system made of acrylic glass, Teflon(r), silicone, and stainless steel allows the comparison of different media, cells and scaffolds. The bioreactor can be gas sterilized and actuated in a standard incubator. Macroscopic observations and pressure-measurements showed a uniformly sinusoidal pulsation, indicating that the bioreactor performed well. Preliminary experiments to determine the adherence rate and morphology of UCMSC after mechanical loadings showed an almost confluent cellular coating without damage on the cell surface. In summary, the bioreactor is an adequate tool for the mechanical stress of seeded scaffolds and offers dynamic stimuli for pre-conditioning of cardiac tissue engineered constructs in vitro. PMID- 24956299 TI - Micro- and nanoengineering approaches to control stem cell-biomaterial interactions. AB - As our population ages, there is a greater need for a suitable supply of engineered tissues to address a range of debilitating ailments. Stem cell based therapies are envisioned to meet this emerging need. Despite significant progress in controlling stem cell differentiation, it is still difficult to engineer human tissue constructs for transplantation. Recent advances in micro- and nanofabrication techniques have enabled the design of more biomimetic biomaterials that may be used to direct the fate of stem cells. These biomaterials could have a significant impact on the next generation of stem cell based therapies. Here, we highlight the recent progress made by micro- and nanoengineering techniques in the biomaterials field in the context of directing stem cell differentiation. Particular attention is given to the effect of surface topography, chemistry, mechanics and micro- and nanopatterns on the differentiation of embryonic, mesenchymal and neural stem cells. PMID- 24956302 TI - Influence of porcine intervertebral disc matrix on stem cell differentiation. AB - For back disorders, cell therapy is one approach for a real regeneration of a degenerated nucleus pulposus. Human mesenchymal stem cells (hMSC) could be differentiated into nucleus pulposus (NP)-like cells and used for cell therapy. Therefore it is necessary to find a suitable biocompatible matrix, which supports differentiation. It could be shown that a differentiation of hMSC in a microbial transglutaminase cross-linked gelatin matrix is possible, but resulted in a more chondrocyte-like cell type. The addition of porcine NP extract to the gelatin matrix caused a differentiation closer to the desired NP cell phenotype. This concludes that a hydrogel containing NP extract without any other supplements could be suitable for differentiation of hMSCs into NP cells. The NP extract itself can be cross-linked by transglutaminase to build a hydrogel free of NP atypical substrates. As shown by side-specific biotinylation, the NP extract contains molecules with free glutamine and lysine residues available for the transglutaminase. PMID- 24956303 TI - Computational Study of pH-sensitive Hydrogel-based Microfluidic Flow Controllers. AB - This computational study investigates the sensing and actuating behavior of a pH sensitive hydrogel-based microfluidic flow controller. This hydrogel-based flow controller has inherent advantage in its unique stimuli-sensitive properties, removing the need for an external power supply. The predicted swelling behavior the hydrogel is validated with steady-state and transient experiments. We then demonstrate how the model is implemented to study the sensing and actuating behavior of hydrogels for different microfluidic flow channel/hydrogel configurations: e.g., for flow in a T-junction with single and multiple hydrogels. In short, the results suggest that the response of the hydrogel-based flow controller is slow. Therefore, two strategies to improve the response rate of the hydrogels are proposed and demonstrated. Finally, we highlight that the model can be extended to include other stimuli-responsive hydrogels such as thermo-, electric-, and glucose-sensitive hydrogels. PMID- 24956301 TI - Controlled Positioning of Cells in Biomaterials-Approaches Towards 3D Tissue Printing. AB - Current tissue engineering techniques have various drawbacks: they often incorporate uncontrolled and imprecise scaffold geometries, whereas the current conventional cell seeding techniques result mostly in random cell placement rather than uniform cell distribution. For the successful reconstruction of deficient tissue, new material engineering approaches have to be considered to overcome current limitations. An emerging method to produce complex biological products including cells or extracellular matrices in a controlled manner is a process called bioprinting or biofabrication, which effectively uses principles of rapid prototyping combined with cell-loaded biomaterials, typically hydrogels. 3D tissue printing is an approach to manufacture functional tissue layer-by-layer that could be transplanted in vivo after production. This method is especially advantageous for stem cells since a controlled environment can be created to influence cell growth and differentiation. Using printed tissue for biotechnological and pharmacological needs like in vitro drug-testing may lead to a revolution in the pharmaceutical industry since animal models could be partially replaced by biofabricated tissues mimicking human physiology and pathology. This would not only be a major advancement concerning rising ethical issues but would also have a measureable impact on economical aspects in this industry of today, where animal studies are very labor-intensive and therefore costly. In this review, current controlled material and cell positioning techniques are introduced highlighting approaches towards 3D tissue printing. PMID- 24956305 TI - The use of thermal techniques for the characterization and selection of natural biomaterials. AB - In this paper we explore the ability of thermal analysis to check elastin and collagen integrity in different biomaterial applications. Differential Scanning Calorimetry (DSC) has been used to analyze the first and second order transitions of the biological macromolecules in the hydrated and dehydrated state. First, we report the characterization of control cardiovascular tissues such as pericardium, aortic wall and valvular leaflet. Their thermal properties are compared to pure elastin and pure collagen. Second, we present results obtained on two collagen rich tissues: pericardia with different chemical treatments and collagen with physical treatments. Finally, more complex cardiovascular tissues composed of elastin and collagen are analyzed and the effect of detergent treatment on the physical structure of collagen and elastin is brought to the fore. PMID- 24956307 TI - Low-dose aspirin for prevention of preeclampsia. PMID- 24956304 TI - Self-assembled matrix by umbilical cord stem cells. AB - Corneal integrity is critical for vision. Corneal wounds frequently heal with scarring that impairs vision. Recently, human umbilical cord mesenchymal stem cells (cord stem cells) have been investigated for tissue engineering and therapy due to their availability and differentiation potential. In this study, we used cord stem cells in a 3-dimensional (3D) stroma-like model to observe extracellular matrix organization, with human corneal fibroblasts acting as a control. For 4 weeks, the cells were stimulated with a stable Vitamin C (VitC) derivative +/-TGF-b1. After 4 weeks, the mean thickness of the constructs was ~30 mm; however, cord stem cell constructs had 50% less cells per unit volume, indicating the formation of a dense matrix. We found minimal change in decorin and lumican mRNA, and a significant increase in perlecan mRNA in the presence of TGF-b1. Keratocan on the other hand decreased with TGF-b1 in both cell lineages. With both cell types, the constructs possessed aligned collagen fibrils and associated glycosaminoglycans. Fibril diameters did not change with TGF-b1 stimulation or cell lineage; however, highly sulfated glycosaminoglycans associated with the collagen fibrils significantly increased with TGF-b1. Overall, we have shown that cord stem cells can secrete their own extracellular matrix and promote the deposition and sulfation of various proteoglycans. Furthermore, these cells are at least comparable to commonly used corneal fibroblasts and present an alternative for the 3D in vitro tissue engineered model. PMID- 24956308 TI - Luliconazole cream (Luzu) for tinea infections. PMID- 24956309 TI - Tobramycin inhalation solution (Bethkis) for cystic fibrosis. PMID- 24956306 TI - A review of gene delivery and stem cell based therapies for regenerating inner ear hair cells. AB - Sensory neural hearing loss and vestibular dysfunction have become the most common forms of sensory defects, affecting millions of people worldwide. Developing effective therapies to restore hearing loss is challenging, owing to the limited regenerative capacity of the inner ear hair cells. With recent advances in understanding the developmental biology of mammalian and non mammalian hair cells a variety of strategies have emerged to restore lost hair cells are being developed. Two predominant strategies have developed to restore hair cells: transfer of genes responsible for hair cell genesis and replacement of missing cells via transfer of stem cells. In this review article, we evaluate the use of several genes involved in hair cell regeneration, the advantages and disadvantages of the different viral vectors employed in inner ear gene delivery and the insights gained from the use of embryonic, adult and induced pluripotent stem cells in generating inner ear hair cells. Understanding the role of genes, vectors and stem cells in therapeutic strategies led us to explore potential solutions to overcome the limitations associated with their use in hair cell regeneration. PMID- 24956310 TI - Lack of CD24 expression in mice reduces the number of leukocytes in the colon. AB - CD24 is an extensively glycosylated membrane protein that is linked to the membrane via a glycosyl-phosphatidylinositol (GPI)-anchor. In mice, CD24 is expressed by hematopoietic and non-hematopoietic cells. CD24-/- mice do not have gross immunological defects, but detailed analysis revealed strongly reduced responses in an experimental autoimmune encephalomyelitis (EAE) model and a massive proliferation of T cells under lymphopenic conditions. It was also demonstrated that preB cells from CD24-/- mice are impaired in alpha4-integrin mediated cell binding. Here we report that CD24-/- mice have strongly reduced numbers of leukocytes in the colon compared to wildtype mice. The reduction comprized all subpopulations. Leukocyte counts in spleen, mesenteric lymph nodes or small intestine were not significantly different. We find that beside leukocytes, CD24 is widely expressed in EpCAM+ epithelial and CD31+ endothelial cells of colon and small intestine. However, in CD24-/- mice the number of CD31+ endothelial cells in colons was strongly reduced and the number of epithelial cells was augmented. Leukocyte transfer experiments provided evidence that the CD24 status of recipient mice, rather than of the transferred cells, is crucial for leukocyte recruitment to the colon. We hypothesize that CD24 on colonic epithelial and endothelial cells is required for the retention and positioning of leukocytes most likely by affecting integrin function. PMID- 24956311 TI - An eye for the I: Preferential attention to the eyes of ingroup members. AB - Human faces, and more specifically the eyes, play a crucial role in social and nonverbal communication because they signal valuable information about others. It is therefore surprising that few studies have investigated the impact of intergroup contexts and motivations on attention to the eyes of ingroup and outgroup members. Four experiments investigated differences in eye gaze to racial and novel ingroups using eye tracker technology. Whereas Studies 1 and 3 demonstrated that White participants attended more to the eyes of White compared to Black targets, Study 2 showed a similar pattern of attention to the eyes of novel ingroup and outgroup faces. Studies 3 and 4 also provided new evidence that eye gaze is flexible and can be meaningfully influenced by current motivations. Specifically, instructions to individuate specific social categories increased attention to the eyes of target group members. Furthermore, the latter experiments demonstrated that preferential attention to the eyes of ingroup members predicted important intergroup biases such as recognition of ingroup over outgroup faces (i.e., the own-race bias; Study 3) and willingness to interact with outgroup members (Study 4). The implication of these findings for general theorizing on face perception, individuation processes, and intergroup relations are discussed. PMID- 24956312 TI - How malleable is categorization by race? Evidence for competitive category use in social categorization. AB - We contrast 3 theoretical viewpoints concerning the factors affecting social categorization by race: (a) the classical theory of social categorization highlighting the role of a priori accessibility and situational factors, (b) the classical theory augmented by a principle of competitive category use, and (c) competition between race (but not gender) and coalition with race (but not gender) encoded only as a proxy to coalition. Study 1 documents a confound that renders important portions of previous research difficult to interpret. In Studies 2 and 3, race categorization was stronger than categorization by more weakly accessible categories when situational support in terms of topic relevance was comparable across categories. A situational focus on race further increased race categorization. Race categorization was reduced in the presence of strongly cued cross-cutting coalitions. Race categorization also was depressed when situational factors promoted comparative processing of cross-cutting categories while cues to potential coalitional divisions were held constant (Study 4). Accessibility, topic relevance, and cuing cross-cutting coalitions had the same effects on gender categorization as found for race categorization (Study 5). Taken together, the results suggest that classical theories of social categorization have to be augmented by a principle of competitive category use that is not limited to a competition between race and coalition. PMID- 24956313 TI - Using abstract language signals power. AB - Power can be gained through appearances: People who exhibit behavioral signals of power are often treated in a way that allows them to actually achieve such power (Ridgeway, Berger, & Smith, 1985; Smith & Galinsky, 2010). In the current article, we examine power signals within interpersonal communication, exploring whether use of concrete versus abstract language is seen as a signal of power. Because power activates abstraction (e.g., Smith & Trope, 2006), perceivers may expect higher power individuals to speak more abstractly and therefore will infer that speakers who use more abstract language have a higher degree of power. Across a variety of contexts and conversational subjects in 7 experiments, participants perceived respondents as more powerful when they used more abstract language (vs. more concrete language). Abstract language use appears to affect perceived power because it seems to reflect both a willingness to judge and a general style of abstract thinking. PMID- 24956314 TI - You can't always give what you want: the challenge of providing social support to low self-esteem individuals. AB - It can be challenging for support providers to facilitate effective social support interactions even when they have the best intentions. In the current article, we examine some reasons for this difficulty, with a focus on support recipients' self-esteem as a crucial variable. We predicted that recipients' receptiveness to support would be influenced by both support strategy and recipient self-esteem and that receptiveness in turn would impact providers' perceived caregiving efficacy and relationship quality. Study 1 (hypothetical scenarios), Study 2 (confederate interaction), and Study 3 (reports of recently received support) showed that individuals with low self-esteem (LSEs) are less receptive than are individuals with high self-esteem (HSEs) to support that positively reframes their experience but are equally receptive to support that validates their negative feelings. In Study 4, providers demonstrated some knowledge that positive reframing would be less helpful to LSEs than to HSEs but indicated equal intention to give such support. Study 5 showed that, in a real interaction, friends were indeed equally likely to offer positive reframing to both LSEs and HSEs but were less likely to offer validation to LSEs. LSEs were less accepting of such support, and in turn providers felt worse about the interaction, about themselves, and about their friendship more broadly. Study 6 confirmed that recipients' receptivity to support directly influenced providers' experience of a support interaction as well as their self- and relationship evaluations. The findings illustrate how well-meaning support attempts that do not match recipients' particular preferences may be detrimental to both members of the dyad. PMID- 24956316 TI - Social class and academic achievement in college: the interplay of rejection sensitivity and entity beliefs. AB - Undergraduates, especially those from lower income backgrounds, may perceive their social class background as different or disadvantaged relative to that of peers and worry about negative social treatment. We hypothesized that concerns about discrimination based on one's social class (i.e., class-based rejection sensitivity or RS-class) would be damaging to undergraduates' achievement outcomes particularly among entity theorists, who perceive their personal characteristics as fixed. We reasoned that a perceived capacity for personal growth and change, characteristic of incremental theorists, would make the pursuit of a college degree and upward mobility seem more worthwhile and attainable. We found evidence across 3 studies that dispositionally held and experimentally primed entity (vs. incremental) beliefs predicted college academic performance as a function of RS-class. Studies 1a and 1b documented that high levels of both entity beliefs and RS-class predicted lower self-reported and official grades, respectively, among undergraduates from socioeconomically diverse backgrounds. In Study 2, high entity beliefs and RS-class at matriculation predicted decreased year-end official grades among lower class Latino students. Study 3 established the causal relationship of entity (vs. incremental) beliefs on academic test performance as a function of RS-class. We observed worse test performance with higher RS-class levels following an entity (vs. incremental) prime, an effect driven by lower income students. Findings from a 4th study suggest that entity theorists with RS-class concerns tend to believe less in upward mobility and, following academic setbacks, are prone to personal attributions of failure, as well as hopelessness. Implications for education and intervention are discussed. PMID- 24956315 TI - A little similarity goes a long way: the effects of peripheral but self-revealing similarities on improving and sustaining interracial relationships. AB - Integrating theory on close relationships and intergroup relations, we construct a manipulation of similarity that we demonstrate can improve interracial interactions across different settings. We find that manipulating perceptions of similarity on self-revealing attributes that are peripheral to the interaction improves interactions in cross-race dyads and racially diverse task groups. In a getting-acquainted context, we demonstrate that the belief that one's different race partner is similar to oneself on self-revealing, peripheral attributes leads to less anticipatory anxiety than the belief that one's partner is similar on peripheral, nonself-revealing attributes. In another dyadic context, we explore the range of benefits that perceptions of peripheral, self-revealing similarity can bring to different-race interaction partners and find (a) less anxiety during interaction, (b) greater interest in sustained contact with one's partner, and (c) stronger accuracy in perceptions of one's partners' relationship intentions. By contrast, participants in same-race interactions were largely unaffected by these manipulations of perceived similarity. Our final experiment shows that among small task groups composed of racially diverse individuals, those whose members perceive peripheral, self-revealing similarity perform superior to those who perceive dissimilarity. Implications for using this approach to improve interracial interactions across different goal-driven contexts are discussed. PMID- 24956318 TI - Honey, I got fired! A longitudinal dyadic analysis of the effect of unemployment on life satisfaction in couples. AB - Previous research on unemployment and life satisfaction has focused on the effects of unemployment on individuals but neglected the effects on their partners. In the present study, we used dyadic multilevel models to analyze longitudinal data from 2,973 couples selected from a German representative panel study to examine the effects of unemployment on life satisfaction in couples over several years. We found that unemployment decreases life satisfaction in both members of the couple, but the effect is more pronounced for those who become unemployed (actors) than for the other couple members (partners). In both couple members, the reaction is attenuated if they share the same labor status after the job loss: Actors experienced a greater drop in life satisfaction if their partners were employed than if they were unemployed at the time of the job loss, and partners reacted negatively to the job loss only if they were employed or inactive in the workforce, but not if they were unemployed themselves. With respect to couple-level moderator variables, we found that both actors and partners reacted more negatively to unemployment if they had children. The reaction was also more negative in male actors than in female actors, but there was no difference between male and female partners. In sum, these findings indicate that changes in life satisfaction can be caused by major life events experienced by significant others. PMID- 24956319 TI - Trio of terror (pregnancy, menstruation, and breastfeeding): an existential function of literal self-objectification among women. AB - Research and theorizing suggest that objectification entails perceiving a person not as a human being but, quite literally, as an object. However, the motive to regard the self as an object is not well understood. The current research tested the hypothesis that literal self-objectification can serve a terror management function. From this perspective, the female body poses a unique existential threat on account of its role in reproduction, and regarding the self as an object is posited to shield women from this threat because objects, in contrast to humans, are not mortal. Across 5 studies, 3 operationalizations of literal self-objectification were employed (a denial of essentially human traits to the self, overlap in the explicit assignment of traits to the self and objects, and implicit associations between self and objects using an implicit association test) in response to 3 aspects of women's bodies involved in reproduction (pregnancy, menstruation, and breastfeeding). In each study, priming mortality led women (but not men, included in Studies 1, 3, 4, and 5) to literally self objectify in conditions where women's reproductive features were salient. In addition, literal self-objectification was found to mediate subsequent responsiveness to death-related stimuli (Study 4). Together, these findings are the first to demonstrate a direct link between mortality salience, women's role in reproduction, and their self-objectification, supporting an existential function of self-objectification in women. PMID- 24956320 TI - Human attribute concepts: relative ubiquity across twelve mutually isolated languages. AB - It has been unclear which human-attribute concepts are most universal across languages. To identify common-denominator concepts, we used dictionaries for 12 mutually isolated languages-Maasai, Supyire Senoufo, Khoekhoe, Afar, Mara Chin, Hmong, Wik-Mungkan, Enga, Fijian, Inuktitut, Hopi, and Kuna-representing diverse cultural characteristics and language families, from multiple continents. A composite list of every person-descriptive term in each lexicon was closely examined to determine the content (in terms of English translation) most ubiquitous across languages. Study 1 identified 28 single-word concepts used to describe persons in all 12 languages, as well as 41 additional terms found in 11 of 12. Results indicated that attribute concepts related to morality and competence appear to be as cross-culturally ubiquitous as basic-emotion concepts. Formulations of universal-attribute concepts from Osgood and Wierzbicka were well supported. Study 2 compared lexically based personality models on the relative ubiquity of key associated terms, finding that 1- and 2-dimensional models draw on markedly more ubiquitous terms than do 5- or 6-factor models. We suggest that ubiquitous attributes reflect common cultural as well as common biological processes. PMID- 24956317 TI - Making sense of misfortune: deservingness, self-esteem, and patterns of self defeat. AB - Drawing on theorizing and research suggesting that people are motivated to view their world as an orderly and predictable place in which people get what they deserve, the authors proposed that (a) random and uncontrollable bad outcomes will lower self-esteem and (b) this, in turn, will lead to the adoption of self defeating beliefs and behaviors. Four experiments demonstrated that participants who experienced or recalled bad (vs. good) breaks devalued their self-esteem (Studies 1a and 1b), and that decrements in self-esteem (whether arrived at through misfortune or failure experience) increase beliefs about deserving bad outcomes (Studies 1a, 1b, 2a, 2b). Five studies (Studies 3-7) extended these findings by showing that this, in turn, can engender a wide array of self defeating beliefs and behaviors, including claimed self-handicapping ahead of an ability test (Study 3), the preference for others to view the self less favorably (Studies 4-5), chronic self-handicapping and thoughts of physical self-harm (Study 6), and choosing to receive negative feedback during an ability test (Study 7). The current findings highlight the important role that concerns about deservingness play in the link between lower self-esteem and patterns of self defeating beliefs and behaviors. The theoretical and practical implications of these findings are discussed. PMID- 24956321 TI - Tuning the electronic effects of aromatic phosphorus heterocycles: an unprecedented phosphinine with significant P(pi)-donor properties. AB - A hitherto unprecedented electronic situation has been observed for a substituted, pyridyl-functionalized phosphinine. In contrast to previous studies, this compound shows considerable pi-donor properties as the result of the rather strong +M effect of the CH3S-substituent, changing the electronic properties of this low-coordinate and aromatic phosphorus heterocycle substantially. PMID- 24956322 TI - Bright and stable CdSe/CdS@SiO2 nanoparticles suitable for long-term cell labeling. AB - We report on the synthesis of luminescent CdSe/CdS@SiO2 nanoparticles and their application to cell labeling. The main novelty of these nanoparticles is the use of newly developed "flash" CdSe/CdS quantum dots (QDs), which are obtained through a new fast and efficient synthesis method recently reported. These core shell QDs are encapsulated in silica nanoparticles through a water-in-oil microemulsion process, resulting in CdSe/CdS@SiO2 nanoparticles with good morphology and controlled architecture. The main asset of these luminescent nanoparticles is their high photoluminescent quantum yield, which is equal to that of the original CdSe/CdS QDs and remains unchanged even after several months of storage in water. Thanks to the remarkable stability of their optical property in aqueous environment and to their low levels of toxicity, the high potential of these nanoparticles for long-term cell labeling is demonstrated. PMID- 24956324 TI - Peer Support for Achieving Independence in Diabetes (Peer-AID): design, methods and baseline characteristics of a randomized controlled trial of community health worker assisted diabetes self-management support. AB - BACKGROUND & OBJECTIVES: Community health workers (CHWs) may be an important mechanism to provide diabetes self-management to disadvantaged populations. We describe the design and baseline results of a trial evaluating a home-based CHW intervention. METHODS & RESEARCH DESIGN: Peer Support for Achieving Independence in Diabetes (Peer-AID) is a randomized, controlled trial evaluating a home-based CHW-delivered diabetes self-management intervention versus usual care. The study recruited participants from 3 health systems. Change in A1c measured at 12 months is the primary outcome. Changes in blood pressure, lipids, health care utilization, health-related quality of life, self-efficacy and diabetes self management behaviors at 12 months are secondary outcomes. RESULTS: A total of 1438 patients were identified by a medical record review as potentially eligible, 445 patients were screened by telephone for eligibility and 287 were randomized. Groups were comparable at baseline on socio-demographic and clinical characteristics. All participants were low-income and were from diverse racial and ethnic backgrounds. The mean A1c was 8.9%, mean BMI was above the obese range, and non-adherence to diabetes medications was high. The cohort had high rates of co-morbid disease and low self-reported health status. Although one third reported no health insurance, the mean number of visits to a physician in the past year was 5.7. Trial results are pending. CONCLUSIONS: Peer-AID recruited and enrolled a diverse group of low income participants with poorly controlled type 2 diabetes and delivered a home-based diabetes self-management program. If effective, replication of the Peer-AID intervention in community based settings could contribute to improved control of diabetes in vulnerable populations. PMID- 24956326 TI - Ultrasensitive nanosensors based on upconversion nanoparticles for selective hypoxia imaging in vivo upon near-infrared excitation. AB - Hypoxia is a distinct feature of malignant solid tumors, which is a possible causative factor for the serious resistance to chemo- and radiotherapy or the development of invasion and metastasis. The exploration of nanosensors with the capabilities like the accurate diagnosis of hypoxic level will be helpful to estimate the malignant degree of tumor and subsequently implement more effective personalized treatment. Here, we report the design and synthesis of nanosensors that can selectively and reversibly detect the level of hypoxia both in vitro and in vivo. The designed nanosensor is composed of two main moieties: oxygen indicator [Ru(dpp)3](2+)Cl2 for detection of hypoxia and upconversion nanoparticles for offering the excitation light of [Ru(dpp)3](2+)Cl2 by upconversion process under 980 nm exposure. The results show that the nanosensors can reversibly become quenched or luminescent under hyperoxic or hypoxic conditions, respectively. Compared with free [Ru(dpp)3](2+)Cl2, the designed nanosensors exhibit enhanced sensitivity for the detection of oxygen in hypoxic regions. More attractively, the nanosensors can image hypoxic regions with high penetration depth because the absorption and emission wavelength are within the NIR and far-red region, respectively. Most importantly, nanosensors display a high selectivity for detection of relevant oxygen changes in cells and zebrafish. PMID- 24956327 TI - Competitive aggregation dynamics using phase wave signals. AB - Coupled equations of the phase equation and the equation of cell concentration n are proposed for competitive aggregation dynamics of slime mold in two dimensions. Phase waves are used as tactic signals of aggregation in this model. Several aggregation clusters are formed initially, and target patterns appear around the localized aggregation clusters. Owing to the competition among target patterns, the number of the localized aggregation clusters decreases, and finally one dominant localized pattern survives. If the phase equation is replaced with the complex Ginzburg-Landau equation, several spiral patterns appear, and n is localized near the center of the spiral patterns. After the competition among spiral patterns, one dominant spiral survives. PMID- 24956328 TI - A one-dimensional moving-boundary model for tubulin-driven axonal growth. AB - A one-dimensional continuum-mechanical model of axonal elongation due to assembly of tubulin dimers in the growth cone is presented. The conservation of mass leads to a coupled system of three differential equations. A partial differential equation models the dynamic and the spatial behaviour of the concentration of tubulin that is transported along the axon from the soma to the growth cone. Two ordinary differential equations describe the time-variation of the concentration of free tubulin in the growth cone and the speed of elongation. All steady-state solutions of the model are categorized. Given a set of the biological parameter values, it is shown how one easily can infer whether there exist zero, one or two steady-state solutions and directly determine the possible steady-state lengths of the axon. Explicit expressions are given for each stationary concentration distribution. It is thereby easy to examine the influence of each biological parameter on a steady state. Numerical simulations indicate that when there exist two steady states, the one with shorter axon length is unstable and the longer is stable. Another result is that, for nominal parameter values extracted from the literature, in a large portion of a fully grown axon the concentration of free tubulin is lower than both concentrations in the soma and in the growth cone. PMID- 24956323 TI - Improving urban African Americans' blood pressure control through multi-level interventions in the Achieving Blood Pressure Control Together (ACT) study: a randomized clinical trial. AB - BACKGROUND: Given their high rates of uncontrolled blood pressure, urban African Americans comprise a particularly vulnerable subgroup of persons with hypertension. Substantial evidence has demonstrated the important role of family and community support in improving patients' management of a variety of chronic illnesses. However, studies of multi-level interventions designed specifically to improve urban African American patients' blood pressure self-management by simultaneously leveraging patient, family, and community strengths are lacking. METHODS/DESIGN: We report the protocol of the Achieving Blood Pressure Control Together (ACT) study, a randomized controlled trial designed to study the effectiveness of interventions that engage patient, family, and community-level resources to facilitate urban African American hypertensive patients' improved hypertension self-management and subsequent hypertension control. African American patients with uncontrolled hypertension receiving health care in an urban primary care clinic will be randomly assigned to receive 1) an educational intervention led by a community health worker alone, 2) the community health worker intervention plus a patient and family communication activation intervention, or 3) the community health worker intervention plus a problem solving intervention. All participants enrolled in the study will receive and be trained to use a digital home blood pressure machine. The primary outcome of the randomized controlled trial will be patients' blood pressure control at 12months. DISCUSSION: Results from the ACT study will provide needed evidence on the effectiveness of comprehensive multi-level interventions to improve urban African American patients' hypertension control. PMID- 24956325 TI - Design and methods of "diaBEAT-it!": a hybrid preference/randomized control trial design using the RE-AIM framework. AB - BACKGROUND: Diabetes prevention is a public health priority that is dependent upon the reach, effectiveness, and cost of intervention strategies. However, understanding each of these outcomes within the context of randomized controlled trials is problematic. PURPOSE: To describe the methods and design of a hybrid preference/randomized control trial using the RE-AIM framework. METHODS: The trial, which was developed using the RE-AIM framework, will contrast the effects of 3 interventions: (1) a standard care, small group, diabetes prevention education class (SG), (2) the small group intervention plus 12 months of interactive voice response telephone follow-up (SG-IVR), and (3) a DVD version of the small group intervention with the same IVR follow-up (DVD-IVR). Each intervention includes personal action planning with a focus on key elements of the lifestyle intervention from the Diabetes Prevention Program (DPP). Adult patients at risk for diabetes will be randomly assigned to either choice or RCT. Those assigned to choice (n=240) will have the opportunity to choose between SG IVR and DVD-IVR. Those assigned to RCT group (n=360) will be randomly assigned to SG, SG-IVR, or DVD-IRV. Assessment of primary (weight loss, reach, & cost) and secondary (physical activity, & dietary intake) outcomes will occur at baseline, 6, 12, and 18 months. CONCLUSION: This will be the first diabetes prevention trial that will allow the research team to determine the relationships between reach, effectiveness, and cost of different interventions. PMID- 24956329 TI - Older partner selection promotes the prevalence of cooperation in evolutionary games. AB - Evolutionary games typically come with the interplays between evolution of individual strategy and adaptation to network structure. How these dynamics in the co-evolution promote (or obstruct) the cooperation is regarded as an important topic in social, economic, and biological fields. Combining spatial selection with partner choice, the focus of this paper is to identify which neighbour should be selected as a role to imitate during the process of co evolution. Age, an internal attribute and kind of local piece of information regarding the survivability of the agent, is a significant consideration for the selection strategy. The analysis and simulations presented, demonstrate that older partner selection for strategy imitation could foster the evolution of cooperation. The younger partner selection, however, may decrease the level of cooperation. Our model highlights the importance of agent's age on the promotion of cooperation in evolutionary games, both efficiently and effectively. PMID- 24956330 TI - Two faces of entropy and information in biological systems. AB - The article attempts to overcome the well-known paradox of contradictions between the emerging biological organization and entropy production in biological systems. It is assumed that quality, speculative correlation between entropy and antientropy processes taking place both in the past and today in the metabolic and genetic cellular systems may be perfectly authorized for adequate description of the evolution of biological organization. So far as thermodynamic entropy itself cannot compensate for the high degree of organization which exists in the cell, we discuss the mode of conjunction of positive entropy events (mutations) in the genetic systems of the past generations and the formation of organized structures of current cells. We argue that only the information which is generated in the conditions of the information entropy production (mutations and other genome reorganization) in genetic systems of the past generations provides the physical conjunction of entropy and antientropy processes separated from each other in time generations. It is readily apparent from the requirements of the Second law of thermodynamics. PMID- 24956331 TI - Pathophysiology of adhesions. AB - Formation of intraperitoneal adhesions after abdominal or pelvic surgery is a very common phenomenon. Although there is no universally accepted definition, they are bridges of scar tissue between the various organs of the peritoneal cavity as a result of a local repair process excessively. Adhesions can be congenital or acquired as a local inflammatory process. Some adhesions can be asymptomatic, but many of them can cause severe complications such as abdominal or pelvic pain, female infertility, and intestinal obstruction. Physicians and patients should be informed of the possibility of postoperative intraperitoneal adhesions and this possibility should be mentioned in the informed consent signed by the patient. The formation of adhesions has multiple proinflammatory mechanisms involved, many with a pathophysiology still incomplete understood. Laparoscopic procedures do not diminish much the possibility of developing postoperative adhesions.Diagnostic imaging is quite uncertain, and the possibilities of preventing with a poor final result. The use of correct surgical technique and avoidance of traumatic intraperitoneal organs maneuvers may help reduce postoperative adhesions incidence. PMID- 24956333 TI - Pancreas transplantation: experience of single center. AB - BACKGROUND: Diabetes is the most common cause of renal failure. In patients with type I diabetes and renal failure,dialysis and insulin therapy can prevent a clinical context that causes rapid death, but they are insufficient to prevent longterm complications. Pancreas and islet cell transplantation inpatients with type I diabetes are the only curative treatment and have recently become more common. METHODS: Between December 2006 and August 2010 a total of 10 patients underwent pancreas transplantation. The patient's data were analysed retrospectively. RESULTS: 10 patients and their data were included in this study. Six patients were male and 4 patients were female. All patients are still alive, with functional grafts. CONCLUSIONS: Pancreas transplantation is the most effective treatment for patients with type I DM. This paper discusses the feasibility of this process and presents the experience of Ankara University in pancreas transplantation. PMID- 24956332 TI - Lower limb perforator propeller flaps - clinical applications. AB - BACKGROUND: A great variety of flaps have been used in lower limb reconstructive surgery: random pattern flaps, axial flaps and free microsurgical transfers with many variants. After further research on the cutaneous blood supply and improvement of microsurgical techniques, perforator propeller flaps began to be studied and used. MATERIAL AND METHOD: A propeller flap is defined as an insular flap mobilized through an axial rotation on a perforator pedicle in order to cover a defect that has to be reconstructed.According to the specialized literature data and to the studies we made on cadavers, this paper establishes a classification based on several criteria: 1) the position of the supplying perforator; 2) the reconstructive necessities and the skin island;3) the flap blood supply; 4) the aesthetic and functional demands of the reconstructed areas. Based on this study we established the specific reconstructive indications for these propeller flaps. CONCLUSIONS: The reconstructive lower limb strategy allows the use of the perforator propeller flaps as first therapeutic option for small and medium defects in certain areas considered as "critical". Knowledge of the pedicle length and the surface of the flaps facilitates the optimum flap choice in the reconstruction of a certain area. PMID- 24956334 TI - Thoracoscopic left splanchnicectomy - role in pain control in unresectable pancreatic cancer. Initial experience. AB - BACKGROUND: The management of opiate-dependent intractable abdominal pain caused by unresectable pancreatic cancer remains challenging. The aim of this study was to evaluate the safety and efficacy of thoracoscopic unilateral left splanchnicectomy for pain control in a first series of 15 patients with unresectable pancreatic cancer. PATIENTS AND METHODS: Fifteen patients suffering from intractable pain due to unresectable pancreatic cancer (stage III and IV)underwent thoracoscopic unilateral left splanchnicectomy. To assess pain severity and the impact of this palliative procedure for pain relief, all patients completed Wong-Baker Faces Pain Rating Scale with a preoperative pain degree between 7 and 9. RESULTS: Surgical intervention duration varied from 30 minutes to 1 hour. Pleural drainage tube was removed 24 hours postoperatively.There were no complications nor deaths.Immediate pain relief (pain degree 0-2) was achieved in all patients after thoracoscopic unilateral splanchnicectomy, same level being registered at first check-up after one month. CONCLUSIONS: Thoracoscopic unilateral left splanchnicectomy decreases the pain substantially and significantly improves the quality of life in patients with unresectable pancreatic cancer. PMID- 24956335 TI - Risk factors for complications after duodenopancreatectomy. Initial results after implementing a standardized perioperative protocol. AB - INTRODUCTION: During 1993-2008 period, in the Surgical Clinic III were conducted several retrospective studies, in order to identify risk factors for complications after cephalic duodenopancreatectomy(DP). As a result of these studies, a preoperative protocol was developed for preparation of patients proposed for DPC, as well as a number of intraoperative technical changes in order to improve postoperative morbidity and mortality. Implementation of the protocol was gradually and inomogenic done in our service. METHODS: The study is prospective, conducted in 2009-2012, ina group of 180 patients and aims to evaluate immediate results after DPC for periampular malignancy, looking to analyze the effects of implementation of the protocol mentioned above.We analyzed the rates of complications (pancreatic fistula,blunt pancreatitis, bleeding from the pancreatic blunt, delayed gastric emptiness), and the factors that might influence their occurrence. RESULTS AND CONCLUSIONS: of the 180 patients, 10 (5.5%) developed pancreatic fistula and 24 (13.3%) had delayed gastric emptiness. Among the factors that have been significant associated with these complications we mention: the pancreatico-jejunalanastomosis and gastro-jejunal transmesocolic assembly. With the implementation of the protocol, the risk factors previously identified in retrospective studies performed in our service(elevated transaminases, experienced surgical team, etc.) have lost significance, but they have not disappeared entirely, due to fact that the conduit proposed was not entirely followed. We believe that the homogeneous application of a perioperative guide, together with a standardized surgical technique, will lead to improve immediate results after DP. PMID- 24956337 TI - Role of laparoscopic peritoneal biopsy in the diagnosis of peritoneal tuberculosis. A seven-year experience. AB - The diagnosis of asymptomatic abdominal tuberculosis,without characteristic laboratory and radiologic findings, is difficult. We therefore investigated the role of diagnostic laparoscopy in patients with suspected peritoneal tuberculosis(PTB). Patients admitted to Hamad General Hospital, Qatar,who underwent laparoscopic peritoneal biopsy for suspected PTB from January 2004 to December 2010 were retrospectively analysed. Factors assessed included patient age, sex, symptoms,clinical signs, CT scan findings, laparoscopic findings andhistopathological diagnosis. A total of 41 patients, 33 males(80.5%) and 8 females (19.5%), of mean age 31 years, underwent laparoscopic peritoneal biopsy for suspected PTB duringthe study period. Abdominal pain was the most common presenting symptom, observed in 33 (80.5%) patients.Computerized tomography (CT) of the abdomen showed as citesin 37 patients (90%), bowel nodules in 22 (54%), peritoneal thickening and nodules in 37 (90%) and enlarged mesenteric lymph nodes in 11 (27%). The classical gross laparoscopic appearance of peritoneal tuberculosis was observed in 38 patients (93%), whereas laparoscopic findings were normal in 3 patients (7%). Histopathological results confirmed granulomatous inflammation in 38 patients (93%). The sensitivity and specificity of gross laparoscopic appearance in diagnosing peritoneal TB were both 100%. Two patients experienced complications from laparoscopy (5%), but there were nolaparoscopy related deaths. Laparoscopic peritoneal biopsy isa rapid and safe method of accurately diagnosing PTB. PMID- 24956336 TI - Laparoscopic treatment of Spiegel hernia by total extraperitoneal (TEP) approach. AB - BACKGROUND: Spiegelian hernia is a rare type of ventral abdominal hernia. Surgical treatment is recommended due to the high risk of complications. Laparoscopic treatment is preferred to open repair, by means of intraperitoneal or extraperitoneal mesh placement, either by transperitoneal(TAPP) or by total extraperitoneal (TEP) approach. Total extraperitoneal approach is rarely reported in the literature. AIM: To evaluate the results of laparoscopic repair of Spiegelhernia by total extraperitoneal approach. MATERIAL AND METHOD: We prospectively studied the patients operated on for Spiegel hernia between October 2009 and March 2013 by laparoscopic TEP approach at Ponderas Hospital. Data regarding symptoms, sex, preoperative work-up,surgical technique, hospital stay and outcome of the procedure were analysed. Follow-up of the patients was achieved at 1week, 1 month, 6 months and yearly postoperatively and patients were evaluated for recurrence, chronic pain, mesh infection, time to reinsertion to normal activities and overall patient satisfaction score. RESULTS: We have treated 4 patients with Spiegel hernia by laparoscopic TEP repair, with mean age 55.25 years (range 50-64), sex ratio 1 (2 2); all patients were symptomatic, all cases had left sided hernias, the surgical intervention was elective in all cases. Mean hospital stay was 1.5 days (range1- 2 days). There was only one postoperative complication ina patient with asymptomatic seroma, with remission in 1 month. There were no recurrences, no mesh infection, no chronic pain or other morbidity at a mean follow-up of 25 months (range 12-53 months). The overall satisfaction score was maximal (5) in all cases. CONCLUSIONS: Spiegelian hernias are rare but surgery is mandatory because of the risk of complications like incarceration and strangulation. In the presented experience, laparoscopic total extraperitoneal approach proved to be an efficient technique,reproducible, with excellent results for Spiegel hernia treated electively. PMID- 24956338 TI - Emergency surgery in colorectal cancer: experience of a county hospital at a 10 year interval. Comparison of immediate postoperative results. AB - A great majority of procedures for colorectal cancer are performed as emergencies, implying a high morbidity and mortality. The aim of this study is to compare the immediate postoperative results of emergency procedures for colorectal cancer between a 10 year interval in a single centre. We performed a retrospective research of the patients files, totalizing 24 emergency operations in 2001 and 22 emergency operations in 2011. We followed demographic data, the complication which lead to emergency surgery, the time interval between the onset of the complication and the time of surgery, the type of procedure performed, postoperative morbidity and mortality. In 2001 we noticed morbidity in 66.66% of the cases (16 patients)and a mortality of 41.66% (10 patients), while in 2011 the postoperative morbidity was 54.54% (12 patients) and a mortality of 36.36% (8 patients). CONCLUSION: although both morbidity and mortality rates decreased in a 10 year interval, they still present high values, and the difference is not statistically significant(p = 0.21 and 0.40). PMID- 24956339 TI - Multiple polyps and colorectal cancer. AB - INTRODUCTION: Malignant degeneration as a possible course of evolution of colorectal polyps renders their diagnosis and therapeutic management a prophylactic act in the prevention of colorectal cancer (CRC). MATERIAL AND METHOD: The study was conducted over a period of 3 years (2008-2011), during which 1,368 colonoscopies were performed in our service. The aim of the study was to identify patients presenting multiple colorectal polyps and to determine their risk factors for developing CRC, as well as to establish the appropriate therapeutic conduct. RESULTS: Presence of multiple polyps was recorded in over 40% of the patients identified with colorectal polyps of any kind. Dysplastic modifications observed during the histopathology exam presented a high incidence in the case of patients with multiple polyps, ranging from low-grade dysplasia to incipient CRC. CONCLUSIONS: Dysplastic modifications and carcinomatous foci were identified mostly among patients with multiple polyps.Only benign lesions or in situ carcinomas benefited from endoscopic treatment, poorly differentiated carcinomas or those invading the submucosa being treated by conventional surgery. Patients diagnosed with colorectal polyps require a rigorous post-therapy follow up protocol, able to identify any eventual polyposis recurrence. PMID- 24956340 TI - Biological prognostic parameters in gastric carcinomas. AB - Gastric cancer is the second leading cause of cancer mortality worldwide. (1) Gastric carcinogenesis involves a variety of factors including diet, habitual factors as well as environmental factors. (2,3) This study aimed to correlate clinicopathological parameters of the cases studied and PCNA and p53 expression using immunohistochemistry. The study group included a total of 32 patients that underwent gastrectomy for gastric cancer.The study parameters were represented by epidemiological aspects (age, sex), clinical characteristics (signs and symptoms),histopathological findings (pTNM staging and degree of differentiation, histological classification, lymph nodes status and presence of vascular invasion) and survival, and immunohistochemical analysis (p53 and PCNA expression) of the study group. Histopathological study showed that most of the cases(26 cases) were of the intestinal type and 6 cases of the diffuse type. Immunohistochemical analysis of p53 protein expression showed an average of 20.75% positive cells, while PCNA expression showed an average of 47.3%. In terms of survival there were 6 cases of death at intervals ranged from 2-189 days,5 cases had subsequent presentations over 12 months, while 8 patients were lost to follow-up. At the time of surgery, 6 patients had distant metastases, while 6 more developed them in a period of 2-12 months after surgery. Identification of biomolecules that highlight potentially aggressive tumors may help modulate the therapeutic approach after surgical resection. PMID- 24956341 TI - Clinical study on cervical phlegmons. AB - The purpose of this paper is to develop an algorithm for the diagnosis and treatment of cervical phlegmons in order to increase the diagnostic accuracy, to reduce the intra and postoperative risks and complication rates and to increase the number of cases with restitutio ad integrum. This is a retrospective clinical study on 21 patients diagnosed with cervical phlegmon. The study group consists of patients with lateral and retropharyngeal phlegmon (18 cases, of which two pharyngeal or cervical oesophagus effractions by foreign body- chicken or fish bone - with pneumomediastinum), retropharyngeal abscess and posttraumatic mediastinal (one case),peritonsillar phlegmon fused in the parapharyngeal space complicated by parapharyngeal haemorrhage after spontaneous drainage of purulent collections (2 cases). Surgical treatment was applied in all cases, associated with intravenous antibiotic medication; the treatment was individualized according to the particularities of each case: the location and extent of the phlegmon, complications, duration of evolution, mechanisms of production, etiology, associated general conditions, age and, not least, the patient's choice. PMID- 24956342 TI - Predicting the outcome of mid-urethral tape surgery for stress urinary incontinence using preoperative urodynamics - a systematic review. AB - Urodynamics are currently widely used in most of urogynecology services, mainly as a diagnostic tool routinely preoperatively or for complicated cases. The urodynamic parameters, mainly Valsalva leak point pressure (VLPP) and maximum urethral closure pressure (MUCP), are increasingly researched for the promising value in predicting the outcome of urinary incontinence surgery. Despite the increasing evidence, their predictive role for mid-urethral sling surgery outcome is still unclear. We systematically searched theliterature for articles published between January 1990 to January 2014, analysing the value of urodynamic variables in predicting the outcome of mid-urethral sling surgery. We calculated relative risks of failure of surgery for patients with low MUCP and VLPP compared with those with high values.Low preoperative MUCP was associated with higher risk of failure for both transobturator and retropubic techniques (RR1.83; 95% confidence interval (CI) 1.44-2.33 and RR 1.41;95% CI 1.17-1.69 respectively). Low preoperative VLPP was predictive as well for higher risk of failure for both transobturator and retropubic routes (RR 1.76; 95% CI 1.37-2.28 and RR 2.01; 95% CI 1.56-2.60 respectively). Concluding, preoperative MUCP and VLPP could be used as predictors for postoperative outcome after mid-urethral sling surgery for SUI. PMID- 24956343 TI - Intraoperative complications after 8150 semirigid ureteroscopies for ureteral lithiasis: risk analysis and management. AB - OBJECTIVES: To evaluate semirigid retrograde ureteroscopy complications on a significant series of patients and to establish the factors associated with the occurrence of intraoperative complications. PATIENTS AND METHODS: Between June 1994 and June 2013, 8150 semirigid ureteroscopic procedures for ureteral lithiasis were performed in 7456 patients. We used semirigid ureteroscopes(8 9.8F Wolf, 8 and 10F Storz, Olympus Endoeye digital 8.5 9.9F). Lithotripsy was done with pneumatic, electrohydraulic or Ho:YAG laser lithotripters. The preoperative parameters including gender, calculi location and size, impaction, degree of hydronephrosis, stone number and associated malformation as well as intraoperative aspects (stone extractors, fragmentation devices, operative time and surgeon experience) were evaluated in relation with complication rate. RESULTS: The stone-free rate after a single ureteroscopic procedure was 90.9%. Intraoperative incidents occurred in 348 cases (4.3%). The overall rate of intraoperative complications was 2.8% (228 cases). These were represented by lesions of the ureteral mucosa (139 cases), perforation (58 cases), bleeding (16 cases), ureteral avulsion (3 cases) and extra-ureteral stone migration (12 cases). Statistical analysis shows a significant association between the complication rate on the one hand and stone size, location and impaction,operative time and surgeon experience on the other hand. CONCLUSIONS: Due to technological advances and increased experience, the semirigid retrograde ureteroscopic treatment of ureteral lithiasis increased efficacy, while the incidence of intraoperative complications decreased. Most of these complications are minor and can be managed by conservative approach. PMID- 24956344 TI - Localisation and preservation of the autonomic nerves in rectal cancer surgery - technical details. AB - Iatrogenic surgical injury to pelvic autonomic nerves followed by genitourinary dysfunctions are well known problems after total partial mesorectal excision for rectal cancer. The purpose of our paper is to present the useful anatomical landmarks for a safe nerve-sparing surgery in rectal oncology. Over the course of a total mesorectal excision we describe and illustrate the key risk zones of autonomic nerve injury based on our experience in rectal surgery and on the revised literature. PMID- 24956345 TI - Efficacy of cetuximab in metastatic colon cancer - case report. AB - In recent years, targeted therapies have proved effective in the treatment of colon cancer, but even in these conditions,metastatic disease is generally considered incurable.Cetuximab is approved for the treatment of advanced colorectal cancer patients with KRAS wild-type, in order to increase survival and hinder progression of the disease. We report a case of a 55 year-old woman, diagnosed with stenosing sigmoid cancer and liver metastases, which underwent multimodal treatment: palliative surgery -Hartmann segmental colectomy, and adjuvant chemotherapy -second line monotherapy with cetuximab, according to standard protocols. After 6 months of XELOX chemotherapy,during which she showed progression of metastatic disease, she was switched to monotherapy with cetuximab, with favorable outcome. Comparing relevant literature, in which complete response to treatment with cetuximab is obtained in low percentages ( 3%) after 3 months of treatment with cetuximab the patient shows clinical and paraclinical complete response and increased quality of life. Proper selection of patients with metastatic colon cancer for treatment with anti-EGFR therapy may lead to prolonged survival and time to progression. PMID- 24956346 TI - A rare case of ileal metastasis from cervical cancer. AB - We present the case of a 70-year-old woman, with a history of radiation-treated and surgically- resected cervical cancer, who was admitted to our clinic for intermittent sub occlusive symptoms. CT scan revealed a liver nodule and intestinal obstruction. The patient underwent surgery for excision of suspected liver metastasis and resolution of intestinal obstruction.Intraoperatively an ileal tumour was found to be the cause of the obstruction. Anatomo-pathological findings were consistent with an ileal metastasis from the cervical cancer.The liver nodule was only an area of focal steatosis. PMID- 24956348 TI - Oesophageal stenosis dilatation through retrograde trans-gastrostomal approach in a patient with systemic scleroderma. AB - AIM: The paper presents the surgical solving of an oesophageal stenosis, using a device of pneumatic dilatation with trans-gastrostomal approach, in a patient with multiple disabling handicaps, secondary severe malnutrition and previously diagnosed with scleroderma. MATERIALS AND METHOD: The patient was admitted with severe cachexia (37 kg, 170 cm), characteristic byzantine face with microstomy, distal phalanges resorption in both superior limbs and complete dysphagia, with limitation of mouth opening.The Barium swallow test revealed distal oesophageal stenosis,with an important dilation of the oesophagus above. RESULTS: A gastrostoma was placed to allow nutrition (Gavriliu procedure), under general anaesthesia with trans-tracheostomal intubation. After 3 years, with her metabolic status improved(59 kg), the patient returned to our clinic asking for a solution for natural feeding. The technical difficulties in solving this case were determined by the limited mouth opening, which made anterograde oro oesophageal balloon dilatation or bougienage impossible, as well as oro-tracheal intubation.Making use of the presence of the gastrostomal orifice,knowing von Hacker's mechanical dilation procedure and using the metallic Key Med kit with balls offered the possibility of the tactics and strategy of guiding a metallic guidewire introduced via the gastrostoma, then trans-stenotic and pulled out through the oral orifice. A modified Foley catheter (personal procedure) was attached to the initial catheter. The trans-stenotic retrograde traction of the Foley balloon was the pneumatic dilator factor that later allowed easy dilatation with the metallic dilator of the Key Med, to the maximum size. The follow-up showed good results, the patient returned to natural nutrition. CONCLUSIONS: The device of oesophageal pneumatic dilatation allows, using the presented surgical technique, a gentle plasty done under radiological supervision and lowers the frequency of accidents. The dilation permits the following use of Key Med kit. The novelty consists in adapting a well-known technique to a new patented device of pneumatic dilation with bidirectional approach under radiological control, for solving this atypical case. PMID- 24956347 TI - Spontaneous rupture of a splenic hydatid cyst with anaphylaxis in a patient with multi-organ hydatid disease. AB - Hidatid cysts of the spleen are a rare occurrence, the spleen being the third most common organ for the development of Echinococcus Granulosus. Splenic hydatid cysts are commonly part of multi-organ hydatid disease. Diagnosis is often established when investigating a splenomegaly or by chance during an unrelated consult. It can also be diagnosed after rupture, be it following trauma (the most common occurrence)or spontaneous. Splenic hydatid cyst rupture requires immediate action and is a life-threatening condition. It results, most often, in splenectomy. We present the case of a patient with multi-organ hydatid disease that presented with a ruptured splenic cyst and developed anaphylaxis. The case was resolved by splenectomy and recovered well. PMID- 24956349 TI - Acute mesenteric ischemia after heart surgery. AB - INTRODUCTION: Acute mesenteric ischemia (AMI) is a rare but very severe complication of heart surgery, due especially to the delay in setting the correct diagnosis and choosing the appropriate treatment. There are 4 types, but the most frequent is nonocclusive mesenteric ischemia (NOMI). The main mechanism is represented by great decrease or maldistribution of the splenic blood flow, with negative impact on the integrity of the intestinal mucosa, bacterial translocation and multiorganic failure. MATERIAL AND METHOD: We present a retrospective study conducted on patients who underwent open heart surgery with cardiopulmonary bypass with non-pulsatile flow. 4 cases of angiographically confirmed NOMI (non-occlusive mesenteric ischemia) were identified. When, based on clinical examination and laboratory findings, acute mesenteric ischemia was suspicioned, superior mesenteric artery angiography was performed via the femoral artery. RESULTS: The main risk factors were represented by: age over 70 years old, left ventricle ejection fraction (LVEF) 35%,aortic clamping time 100 min., chronic kidney failure,counter-pulsation balloon implant, inotropic medication use,like levosimendan, use of blood components 1 unit of erythrocyte mass. Clinical signs were nonspecific. All patients presented hypoventilation, arterial hypotension, oliguria and,from a biological standpoint, metabolic acidosis and leucocytosis. Superior mesenteric artery angiography was the investigation method of choice. Treatment approach was initially medical, followed by resection of the intestine.Mortality was 100%. CONCLUSIONS: Acute mesenteric ischemia is a rare but very severe complication in cardiac surgery. It is primordial that the main risk factors be known, and in case of diagnosis suspicion, that it be set as early as possible, along with immediate initiation of an appropriate course of treatment. PMID- 24956350 TI - Laparoscopic Transabdominal Pre-Peritoneal (TAPP) procedure - step-by-step tips and tricks. AB - Minimally invasive approach for groin hernia treatment is still controversial, but in the last decade, it tends to become the standard procedure for one day surgery. We present herein the technique of laparoscopic Trans Abdominal Pre Peritoneal approach (TAPP). The surgical technique is presented step-by step;the different procedures key points (e.g. anatomic landmarks recognition, diagnosis of "occult" hernias, preperitoneal and hernia sac dissection, mesh placement and peritoneal closure) are described and discussed in detail, several tips and tricks being noted and highlighted. CONCLUSIONS: TAPP is a feasible method for treating groin hernia associated with low rate of postoperative morbidity and recurrence. The anatomic landmarks are easily recognizable. The laparoscopic exploration allows for the treatment of incarcerated strangulated hernias and the intraoperative diagnosis of occult hernias. PMID- 24956351 TI - Preoperatively diagnosed mucocele of the appendix. AB - Mucocele of the appendix is an infrequent entity, characterized by distension of the lumen due to accumulation of mucoid substance and is rarely diagnosed preoperatively. If untreated, mucocele may rupture producing a potentially fatal entity known as pseudomyxoma peritonei. The type of surgical treatment is related to the dimensions and the histology of the mucocele. Appendectomy is used for simple mucocele or for cystadenoma. Right hemi-colectomy is recommended for cystadeno carcinoma. In this paper, we report a case of an asymptomatic 37-year old woman in whom mucocele was found on a routine ultrasound examination and preoperative computed tomography scan. Surgery revealed a big appendix measuring 84 mm in length and 40 mm in diameter. The final pathologic diagnosis was simple mucocele. PMID- 24956352 TI - Palladium-catalyzed formylation of aryl halides with tert-butyl isocyanide. AB - A novel palladium-catalyzed formylation of aryl halides with isocyanide in the presence of Et3SiH has been demonstrated, which provides a strategy toward important aldehydes with moderate to excellent yield. The advantage of this reaction includes milder conditions, convenient operation, lower toxicity, and wide functional group tolerance. PMID- 24956353 TI - The effects of uniquely-processed titanium on biological systems: implications for human health and performance. AB - Titanium is biocompatible and widely utilized in a variety of applications. Recently, titanium in pico-nanometer scale and soluble form (Aqua Titan) has expanded its use to applied human health and performance. The purpose of this article is to review the current evidence associated with specific physiological responses to Aqua Titan-treated materials. In vitro studies have shown that application of Aqua Titan can modify membrane potential and long-term potentiation in isolated hippocampal neurons, suggesting reduced pain memory as a possible mechanism for reported analgesia. Proximal contact with Aqua Titan treated titanium increased gene expression, protein synthesis, cell growth and adhesion in normal cultured muscle and bone cells, suggesting application for Aqua Titan in clinical implant procedures and wound healing. Evidence for beneficial effects on neuromuscular control of muscle-tendon function and improvements in running economy in human athletes was seen when Aqua Titan treated tape was applied to the human triceps surae following fatigue induced by prior strenuous exercise. Finally, behavioral responses and effects on the autonomic nervous system to environmental exposure suggest Aqua Titan may promote a mild relaxant, or stress-suppressive response. Together, data suggest exposure to Aqua Titan-treated materials modulates aspects of growth and function in neuronal and other musculoskeletal cells with possible benefits to musculotendinous recovery from exercise and to the systemic response to stress. PMID- 24956354 TI - Application of sub-micrometer vibrations to mitigate bacterial adhesion. AB - As a prominent concern regarding implantable devices, eliminating the threat of opportunistic bacterial infection represents a significant benefit to both patient health and device function. Current treatment options focus on chemical approaches to negate bacterial adhesion, however, these methods are in some ways limited. The scope of this study was to assess the efficacy of a novel means of modulating bacterial adhesion through the application of vibrations using magnetoelastic materials. Magnetoelastic materials possess unique magnetostrictive property that can convert a magnetic field stimulus into a mechanical deformation. In vitro experiments demonstrated that vibrational loads generated by the magnetoelastic materials significantly reduced the number of adherent bacteria on samples exposed to Escherichia coli, Staphylococcus epidermidis and Staphylococcus aureus suspensions. These experiments demonstrate that vibrational loads from magnetoelastic materials can be used as a post deployment activated means to deter bacterial adhesion and device infection. PMID- 24956355 TI - Density functional theory study of selective deacylation of aromatic acetate in the presence of aliphatic acetate under ammonium acetate mediated conditions. AB - Aromatic acetates can be selectively deprotected in the presence of aliphatic acetates under ammonium acetate mediated condition. B3LYP/6-31++G** level of theory was demonstrated to be successfully used to model the relative reaction rates for deacylation reactions for aliphatic and aromatic ester systems. On the basis of the mechanistic studies, acetate anion is most likely to be the active catalyst for the ester deacylation reactions under ammonium acetate mediated condition. PMID- 24956356 TI - Capturing CO2 into the precipitate of a phase-changing solvent after absorption. AB - The major drawback of aqueous alkanolamine-based CO2 capture processes is the high energy penalty for regeneration. To overcome this weakness, we studied the absorption of CO2 with amines dissolved in nonaqueous solvents. It was observed that triethylenetetramine (TETA) dissolved in ethanol produces a solid precipitate after absorption, which can then be easily separated and regenerated. As a comparison, a TETA/water solution does not form any precipitate after absorbing CO2. The TETA/ethanol solution offers several advantages for CO2 capture in absorption rate, absorption capacity, and absorbent regenerability. Both the rate and capacity of CO2 absorption with the TETA/ethanol solution were significantly higher than with a TETA/water solution, because ethanol not only promotes the solubility of CO2 in the liquid phase but also facilitates the chemical reaction between TETA and CO2. This approach was able to capture 81.8% of the absorbed CO2 in the solid phase as TETA-carbamate. In addition, results show that the decomposition of TETA-carbamate can be completed at 90 degrees C. Moreover, the cycling absorption/regeneration runs of the TETA/ethanol solution display a relatively stable absorption performance. PMID- 24956357 TI - The Cyberchondria Severity Scale (CSS): an examination of structure and relations with health anxiety in a community sample. AB - McElroy and Shevlin (2014) developed the 33-item Cyberchondria Severity Scale (CSS) to allow for a multidimensional assessment of cyberchondria (compulsion, distress, excessiveness, reassurance, and mistrust of medical professional). The present study evaluated psychometric properties of the CSS, including its factor structure, internal consistency, convergent validity, and incremental validity, using a large sample of community adults located in the United States (N=539). Results from a confirmatory factor analysis (CFA) supported the adequacy of the five-factor structure of the CSS. However, results from a higher-order CFA indicated that the mistrust of medical professional factor does not assess the same construct as the other factors of the CSS. The CSS scales evidenced adequate internal consistency and significantly correlated with health anxiety. The distress, excessiveness, and mistrust of medical professional scales correlated significantly more strongly with health anxiety than obsessive-compulsive symptoms and these three scales were the only CSS scales to share unique variance with health anxiety. Implications of these results for future research are discussed. PMID- 24956358 TI - Influence of excited carriers on the optical and electronic properties of MoS2. AB - We study the ground-state and finite-density optical response of molybdenum disulfide by solving the semiconductor Bloch equations, using ab initio band structures and Coulomb interaction matrix elements. Spectra for excited carrier densities up to 10(13) cm(-2) reveal a redshift of the excitonic ground-state absorption, whereas higher excitonic lines are found to disappear successively due to Coulomb-induced band gap shrinkage of more than 500 meV and binding-energy reduction. Strain-induced band variations lead to a redshift of the lowest exciton line by ~110 meV/% and change the direct transition to indirect while maintaining the magnitude of the optical response. PMID- 24956359 TI - Titanium dioxide nanomaterials: self-structural modifications. PMID- 24956360 TI - Alternative nitrogenase and pseudogenes: unique features of the Paenibacillus riograndensis nitrogen fixation system. AB - Biological nitrogen fixation (BNF) is a tightly regulated process that is carried out by diazotrophic microorganisms. The regulatory mechanisms of BNF-related genes are well characterized in Gram-negative models, but they are poorly understood in Gram-positive bacteria. Paenibacillus riograndensis SBR5(T) is a Gram-positive, endospore-forming facultative aerobic diazotroph. Three clusters of BNF-related genes with dissimilar phylogenetic histories were identified in the P. riograndensis genome, and no regulatory genes were recognized. P. riograndensis nifH2 was considered inactive based on transcript and promoter analyses, whereas transcripts of nifH1 and anfH were induced upon nitrogen limited conditions. The functionality of the alternative nitrogenase system was also validated by enzymatic activity analysis. Fragments upstream of the two active clusters seem to harbor primary functional promoter sequences, producing a constitutive expression pattern in Escherichia coli. Sequences upstream of the anf genes were not recognized by this heterologous host, indicating a very distinct promoter pattern. These results shed light upon the evolutionary history of nitrogen fixation genes in this Gram-positive bacterium and highlight the presence of novel regulatory elements that are yet to be described. PMID- 24956361 TI - Type I and III interferon production in response to RNA viruses. AB - The biology of RNA viruses is closely linked to the type I and type III interferon (IFN) response of the host. These viruses display a range of molecular patterns that may be detected by host cells resulting in the induction of IFNs. Consequently, there are many examples of mechanisms employed by RNA viruses to block or delay IFN induction and reduce the expression of IFN-stimulated genes (ISGs), a necessary step in the virus lifecycle because of the capacity of IFNs to block virus replication. Efficient transmission of viruses depends, in part, on maintaining a balance between virus replication and host survival; specialized host cells, such as plasmacytoid dendritic cells, can sense viral molecular patterns and produce IFNs to help maintain this balance. There are now many examples of RNA viruses inducing type I and type III IFNs, and although these IFNs act through different receptors, in many systems studied, they induce a similar spectrum of genes. However, there may be a difference in the temporal expression pattern, with more prolonged expression of ISGs in response to type III IFN compared with type I IFN. There are also examples of synergy between type I and type III IFNs to induce antiviral responses. Clearly, it is important to understand the different roles of these IFNs in the antiviral response in vivo. One of the most striking differences between these 2 IFN systems is the distribution of the receptors: type I IFN receptors are expressed on most cells, yet type III receptor expression is restricted primarily to epithelial cells but has also been demonstrated on other cells, including dendritic cells. There is increasing evidence that type III IFNs are a key control mechanism against RNA viruses that infect respiratory and enteric epithelia. PMID- 24956363 TI - Interframe coding of feature descriptors for mobile augmented reality. AB - Streaming mobile augmented reality applications require both real-time recognition and tracking of objects of interest in a video sequence. Typically, local features are calculated from the gradients of a canonical patch around a keypoint in individual video frames. In this paper, we propose a temporally coherent keypoint detector and design efficient interframe predictive coding techniques for canonical patches, feature descriptors, and keypoint locations. In the proposed system, we strive to transmit each patch or its equivalent feature descriptor with as few bits as possible by modifying a previously transmitted patch or descriptor. Our solution enables server-based mobile augmented reality where a continuous stream of salient information, sufficient for image-based retrieval, and object localization, is sent at a bit-rate that is practical for today's wireless links and less than one-tenth of the bit-rate needed to stream the compressed video to the server. PMID- 24956362 TI - Cut-off value of initial serum beta-hCG level predicting a successful MTX therapy in tubal ectopic pregnancy: a retrospective cohort study. AB - OBJECTIVE: To determine the optimal serum beta-hCG cut-off level to predict MTX treatment success in tubal ectopic pregnancy (EP). STUDY DESIGN: Data of 240 women, who presented between 2003 and 2011 at the Department of Gynecology and Obstetrics, Medical University of Vienna, with tubal EP and who received MTX as primary treatment, were retrieved from the hospital information system (KIS). 198 patients could be included for final evaluation. Statistical analysis included area under the ROC curve, maximal Euclidean and Youden index, chi-squared and a five-fold cross validation. RESULTS: The serum beta-hCG level cut-off value was calculated at 2121mlU/ml with a specificity of 76.54% and sensitivity of 80.56% (AUC 0.789; p<0.001). Patients with an initial serum beta-hCG level below 2121mlU/ml (n=131) experienced MTX treatment failure in 5.3% (n=7), compared to 43.3% (n=29) of patients with an initial serum beta-hCG level equal to or above 2121mlU/ml (n=67). There was no statistically significant correlation between clinical symptoms and the MTX therapy outcome (p=0.580; likelihood quotient p=0.716). CONCLUSION: The correct decision of therapy in patients with tubal ectopic pregnancy still represents a challenge. In this study we can conclude that, according to our results there is no endpoint of initial serum beta-hCG levels, which can be clearly used as cut-off value for the optimal management of tubal EP. However, an initial serum beta-hCG level of less than 2121mlU/ml seems to be a good value to expect a successful MTX treatment. Limitations are the retrospective study design and the inability of classifying clinical symptoms like pain as an objective parameter. Wider implications of the findings may include more detailed patient information and more accurate selection of suitable patients for MTX therapy. PMID- 24956364 TI - Lip segmentation under MAP-MRF framework with automatic selection of local observation scale and number of segments. AB - This paper addresses the problem of segmenting lip region from frontal human face image. Supposing each pixel of the target image has an optimal local scale from the segmentation viewpoint, we treat the lip segmentation problem as a combination of observation scale selection and observed data classification. Accordingly, we propose a hierarchical multiscale Markov random field (MRF) model to represent the membership map of each input pixel to a specific segment and local-scale map simultaneously. Subsequently, lip segmentation can be formulated as an optimal problem in the maximum a posteriori (MAP)-MRF framework. Then, we present a rival-penalized iterative algorithm to implement the segmentation, which is independent of the number of predefined segments. The proposed method mainly features two aspects: 1) its performance is independent of the predefined number of segments, and 2) it takes into account the local optimal observation scale for each pixel. Finally, we conduct the experiments on four benchmark databases, i.e. AR, CVL, GTAV, and VidTIMIT. Experimental results show that the proposed method is robust to the segment number that changes with a speaker's appearance, and can enhance the segmentation accuracy by taking advantage of the local optimal observation scale information. PMID- 24956365 TI - Dynamically removing false features in pyramidal lucas-kanade registration. AB - Pyramidal Lucas-Kanade (LK) optical flow is a real-time registration technique widely employed by a variety of cutting edge consumer applications. Traditionally, the LK algorithm is applied selectively to image feature points that have strong spatial variation, which include outliers in textured areas. To detect and discard the falsely selected features, previous methods generally assess the goodness of each feature after the flow computation is completed. Such a screening process incurs additional cost. This paper provides a handy (but not obvious) tool for the users of the LK algorithm to remove false features without degrading the algorithm's efficiency. We propose a confidence predictor, which evaluates the ill-posedness of an LK system directly from the underlying data, at a cost lower than solving the system. We then incorporate our confidence predictor into the course-to-fine LK registration to dynamically detect false features and terminate their flow computation at an early stage. This improves the registration accuracy by preventing the error propagation and maintains (or increases) the computation speed by saving the runtime on false features. Experimental results on state-of-the-art benchmarks validate that our method is more accurate and efficient than related works. PMID- 24956366 TI - Structure-preserving sparse decomposition for facial expression analysis. AB - Although facial expressions can be decomposed in terms of action units (AUs) as suggested by the facial action coding system, there have been only a few attempts that recognize expression using AUs and their composition rules. In this paper, we propose a dictionary-based approach for facial expression analysis by decomposing expressions in terms of AUs. First, we construct an AU-dictionary using domain experts' knowledge of AUs. To incorporate the high-level knowledge regarding expression decomposition and AUs, we then perform structure-preserving sparse coding by imposing two layers of grouping over AU-dictionary atoms as well as over the test image matrix columns. We use the computed sparse code matrix for each expressive face to perform expression decomposition and recognition. Since domain experts' knowledge may not always be available for constructing an AU dictionary, we also propose a structure-preserving dictionary learning algorithm, which we use to learn a structured dictionary as well as divide expressive faces into several semantic regions. Experimental results on publicly available expression data sets demonstrate the effectiveness of the proposed approach for facial expression analysis. PMID- 24956367 TI - Line Matching in Wide-Baseline Stereo: A Top-Down Approach. AB - This paper introduces a new algorithm for matching lines across images that exploit the epipolar geometry and the coplanarity constraints between pairs of lines. In contrast to common treatment in matching of interest points, we use the epipolar geometry to constrain coplanarity conditions between line-pairs. This treatment eliminates the potential matching problems due to the incomplete line observations with nonmatching endpoints. This observation is used to detect a set of candidate line-pair correspondences. These matching pairs are then verified via local homography transforms derived from the neighboring interest point correspondences. This step results in a line affinity matrix which is processed to obtain matching lines. During this process, we do not use appearance models and show that the proposed treatment performs better than the state-ofthe- art appearance and geometry based methods especially for images with wide-baseline. PMID- 24956369 TI - Semantic pyramids for gender and action recognition. AB - Person description is a challenging problem in computer vision. We investigated two major aspects of person description: 1) gender and 2) action recognition in still images. Most state-of-the-art approaches for gender and action recognition rely on the description of a single body part, such as face or full-body. However, relying on a single body part is suboptimal due to significant variations in scale, viewpoint, and pose in real-world images. This paper proposes a semantic pyramid approach for pose normalization. Our approach is fully automatic and based on combining information from full-body, upper-body, and face regions for gender and action recognition in still images. The proposed approach does not require any annotations for upper-body and face of a person. Instead, we rely on pretrained state-of-the-art upper-body and face detectors to automatically extract semantic information of a person. Given multiple bounding boxes from each body part detector, we then propose a simple method to select the best candidate bounding box, which is used for feature extraction. Finally, the extracted features from the full-body, upper-body, and face regions are combined into a single representation for classification. To validate the proposed approach for gender recognition, experiments are performed on three large data sets namely: 1) human attribute; 2) head-shoulder; and 3) proxemics. For action recognition, we perform experiments on four data sets most used for benchmarking action recognition in still images: 1) Sports; 2) Willow; 3) PASCAL VOC 2010; and 4) Stanford-40. Our experiments clearly demonstrate that the proposed approach, despite its simplicity, outperforms state-of-the-art methods for gender and action recognition. PMID- 24956368 TI - Person re-identification over camera networks using multi-task distance metric learning. AB - Person reidentification in a camera network is a valuable yet challenging problem to solve. Existing methods learn a common Mahalanobis distance metric by using the data collected from different cameras and then exploit the learned metric for identifying people in the images. However, the cameras in a camera network have different settings and the recorded images are seriously affected by variability in illumination conditions, camera viewing angles, and background clutter. Using a common metric to conduct person reidentification tasks on different camera pairs overlooks the differences in camera settings; however, it is very time consuming to label people manually in images from surveillance videos. For example, in most existing person reidentification data sets, only one image of a person is collected from each of only two cameras; therefore, directly learning a unique Mahalanobis distance metric for each camera pair is susceptible to over fitting by using insufficiently labeled data. In this paper, we reformulate person reidentification in a camera network as a multitask distance metric learning problem. The proposed method designs multiple Mahalanobis distance metrics to cope with the complicated conditions that exist in typical camera networks. We address the fact that these Mahalanobis distance metrics are different but related, and learned by adding joint regularization to alleviate over-fitting. Furthermore, by extending, we present a novel multitask maximally collapsing metric learning (MtMCML) model for person reidentification in a camera network. Experimental results demonstrate that formulating person reidentification over camera networks as multitask distance metric learning problem can improve performance, and our proposed MtMCML works substantially better than other current state-of-the-art person reidentification methods. PMID- 24956370 TI - Learning discriminative dictionary for group sparse representation. AB - In recent years, sparse representation has been widely used in object recognition applications. How to learn the dictionary is a key issue to sparse representation. A popular method is to use l1 norm as the sparsity measurement of representation coefficients for dictionary learning. However, the l1 norm treats each atom in the dictionary independently, so the learned dictionary cannot well capture the multisubspaces structural information of the data. In addition, the learned subdictionary for each class usually shares some common atoms, which weakens the discriminative ability of the reconstruction error of each subdictionary. This paper presents a new dictionary learning model to improve sparse representation for image classification, which targets at learning a class specific subdictionary for each class and a common subdictionary shared by all classes. The model is composed of a discriminative fidelity, a weighted group sparse constraint, and a subdictionary incoherence term. The discriminative fidelity encourages each class-specific subdictionary to sparsely represent the samples in the corresponding class. The weighted group sparse constraint term aims at capturing the structural information of the data. The subdictionary incoherence term is to make all subdictionaries independent as much as possible. Because the common subdictionary represents features shared by all classes, we only use the reconstruction error of each class-specific subdictionary for classification. Extensive experiments are conducted on several public image databases, and the experimental results demonstrate the power of the proposed method, compared with the state-of-the-arts. PMID- 24956371 TI - An estimation-theoretic framework for spatially scalable video coding. AB - This paper focuses on prediction optimality in spatially scalable video coding. It draws inspiration from an estimation-theoretic prediction framework for quality (SNR) scalability earlier developed by our group, which achieved optimality by fully accounting for relevant information from the current base layer (e.g., quantization intervals) and the enhancement layer, to efficiently calculate the conditional expectation that forms the optimal predictor. It was central to that approach that all layers reconstruct approximations to the same original transform coefficient. In spatial scalability, however, the layers encode different resolution versions of the signal. To approach optimality in enhancement layer prediction, this paper departs from existing spatially scalable codecs that employ pixel domain resampling to perform interlayer prediction. Instead, it incorporates a transform domain resampling technique that ensures that the base layer quantization intervals are accessible and usable at the enhancement layer despite their differing signal resolutions, which in conjunction with prior enhancement layer information, enable optimal prediction. A delayed prediction approach that complements this framework for spatial scalable video coding is then provided to further exploit future base layer frames for additional enhancement layer coding performance gains. Finally, a low complexity variant of the proposed estimation-theoretic prediction approach is also devised, which approximates the conditional expectation by switching between three predictors depending on a simple condition involving information from both layers, and which retains significant performance gains. Simulations provide experimental evidence that the proposed approaches substantially outperform the standard scalable video codec and other leading competitors. PMID- 24956374 TI - Grunting in tennis increases ball velocity but not oxygen cost. AB - Grunting is widely used by professional tennis players, but no research has been done to verify enhanced performance with grunting. Therefore, the purpose of this study was to determine if grunting enhanced ball velocity in groundstrokes and secondly, to determine if grunting increased the physiological cost of hitting (VO2, HR, VE/VO2, and RPE). Participants were 10 members of the men's (n = 5) and women's (n = 5) tennis teams at a Division I university who had just completed their indoor competitive season. Two hitting sessions were used as players repetitively hit forehand and backhand shots while either grunting or not grunting. Each hitting session consisted of five 2-minute periods with a 1-minute break in between each period. Ball velocity was measured with a radar gun. During each hitting session, players wore a portable metabolic measuring unit. HR was monitored using a Polar monitor, and RPE was assessed using Borg's 6-20 scale. Grunting increased ball velocity (kph) 3.8% compared with non-grunting condition (p < 0.034) with the mean +/- SD being 83.4 +/- 0.6.1 and 80.3 +/- 0.8.7, respectively. The physiological responses (VO2, HR, VE/VO2, and RPE) for the 2 hitting conditions were not significantly different for any variable. When averaged across both hitting conditions, HR over the 5-time periods was higher in periods 3-5 than period (p < 0.018) 1, whereas VE/VO2 and RPE were greater in periods 2-5 than period 1 (p = 0.001). RPE significantly increased over time with periods 2-5 being greater than period 1 (p = 0.001). It was concluded that grunting increased ball velocity without increasing VO2 or VE/VO2 or RPE in comparison with not grunting. It may be worthwhile for players and coaches in tennis and other sports to experiment with grunting to determine possible improvement in performance. PMID- 24956375 TI - Structural basis for ligand exchange on Au(25)(SR)(18). AB - The single-crystal X-ray structure of Au25(SC2H4Ph)16(pBBT)2 is presented. The crystallized compound resulted from ligand exchange of Au25(SC2H4Ph)18 with pBBT as the incoming ligand, and for the first time, ligand exchange is structurally resolved on the widely studied Au25(SR)18 compound. A single ligand in the asymmetric unit is observed to exchange, corresponding to two ligands in the molecule because of the crystallographic symmetry. The ligand-exchanged Au25 is bonded to the most solvent-exposed Au atom in the structure, making the exchange event consistent with an associative mechanism. The apparent nonexchange of other ligands is rationalized through possible selective crystallization of the observed product and differential bond lengths. PMID- 24956373 TI - Beclin 1 and UVRAG confer protection from radiation-induced DNA damage and maintain centrosome stability in colorectal cancer cells. AB - Beclin 1 interacts with UV-irradiation-resistance-associated gene (UVRAG) to form core complexes that induce autophagy. While cells with defective autophagy are prone to genomic instability that contributes to tumorigenesis, it is unknown whether Beclin1 or UVRAG can regulate the DNA damage/repair response to cancer treatment in established tumor cells. We found that siRNA knockdown of Beclin 1 or UVRAG can increase radiation-induced DNA double strand breaks (DSBs), shown by pATM and gammaH2Ax, and promote colorectal cancer cell death. Furthermore, knockdown of Beclin 1, UVRAG or ATG5 increased the percentage of irradiated cells with nuclear foci expressing 53BP1, a marker of nonhomologous end joining but not RAD51 (homologous recombination), compared to control siRNA. Beclin 1 siRNA was shown to attenuate UVRAG expression. Cells with a UVRAG deletion mutant defective in Beclin 1 binding showed increased radiation-induced DSBs and cell death compared to cells with ectopic wild-type UVRAG. Knockdown of Beclin 1 or UVRAG, but not ATG5, resulted in a significant increase in centrosome number (gamma tubulin staining) in irradiated cells compared to control siRNA. Taken together, these data indicate that Beclin 1 and UVRAG confer protection against radiation induced DNA DSBs and may maintain centrosome stability in established tumor cells. PMID- 24956376 TI - Comparison of non-canonical PAMs for CRISPR/Cas9-mediated DNA cleavage in human cells. AB - CRISPR/Cas9-mediated DNA cleavage (CCMDC) is becoming increasingly used for efficient genome engineering. Proto-spacer adjacent motif (PAM) adjacent to target sequence is one of the key components in the design of CCMDC strategies. It has been reported that NAG sequences are the predominant non-canonical PAM for CCMDC at the human EMX locus, but it is not clear whether it is universal at other loci. In the present study, we attempted to use a GFP-reporter system to comprehensively and quantitatively test the efficiency of CCMDC with non canonical PAMs in human cells. The initial results indicated that the effectiveness of NGA PAM for CCMDC is much higher than that of other 14 PAMs including NAG. Then we further designed another three pairs of NGG, NGA and NAG PAMs at different locations in the GFP gene and investigated the corresponding DNA cleavage efficiency. We observed that one group of NGA PAMs have a relatively higher DNA cleavage efficiency, while the other groups have lower efficiency, compared with the corresponding NAG PAMs. Our study clearly demonstrates that NAG may not be the universally predominant non-canonical PAM for CCMDC in human cells. These findings raise more concerns over off-target effects in CRISPR/Cas9 mediated genome engineering. PMID- 24956379 TI - Expiratory air trapping on thoracic computed tomography. A diagnostic subclassification. AB - RATIONALE: Multiple causes for air trapping as identified by expiratory computed tomography (CT) have been reported, but a unified evaluation schema has never been proposed. OBJECTIVES: It was our purpose to identify imaging features that would help distinguish etiologies of mosaic air trapping. METHODS: Cases with the term "air trapping" in the radiology report in 2010 were identified by searching the Radiology Information System of an academic tertiary care center and associated community hospital. Medical records and CT examinations were reviewed for the causes of air trapping. MEASUREMENTS AND MAIN RESULTS: Causes for moderate to severe air trapping could be identified in 201 of 230 (87.4%) cases and could be subdivided into those associated with bronchiectasis (76 of 201, 38%), those associated with interstitial lung disease (62 of 201, 31%), those associated with tree-in-bud opacities (5 of 201, 2%), and those with air trapping alone (58 of 201, 29%). When found with bronchiectasis, nontuberculous mycobacteria, cystic fibrosis, idiopathic bronchiectasis, and transplant-related bronchiolitis obliterans were the most common causes of air trapping. When found with interstitial lung disease, sarcoidosis, hypersensitivity pneumonitis, or unspecified interstitial lung disease were the most common cause of air trapping. When found in isolation, chronic bronchitis, asthma, bronchiolitis obliterans, and unspecified small airways disease were the most common causes of air trapping. Unusual conditions causing isolated air trapping included vasculitis and diffuse idiopathic neuroendocrine cell hyperplasia. CONCLUSION: A variety of conditions can cause air trapping. Associated imaging findings can narrow the differential diagnosis. PMID- 24956381 TI - Prenylated flavonoids from the stems and leaves of Desmodium caudatum and evaluation of their inhibitory activity against the film-forming growth of Zygosaccharomyces rouxii F51. AB - In order to provide scientific evidence for the relationship between the traditional usage, stems and leaves of Desmodium caudatum being used for protecting miso from spoilage, and its Japanese name (miso-naoshi), phytochemical study on the stems and leaves of this plant was carried out. Seven new prenylated flavonoids (1-3, 15-18), together with 19 known compounds (4-14, 19-26), were isolated, and the structures of new compounds were elucidated by extensive spectroscopic analyses. The minimum inhibitory concentrations (MICs) of 28 flavonoids, including 17 compounds (1, 2, 4, 5, 7-14, 20-22, 24, 25) isolated in this study and 11 flavonoids (27-37) previously isolated from the roots of this plant, against the film-forming yeast of Zygosaccharomyces rouxii F51 were determined. Fifteen compounds (2, 4, 5, 11, 12, 14, 21, 22, 25, 27, 28, 32-35) inhibited the film-forming growth of Z. rouxii F51 (MIC values, 7.8-62.5 MUg/mL), among which 2",2"-dimethylpyran-(5",6":7,8)-5,2'-dihydroxy-4'-methoxy-(2R,3R) dihydroflavonol (11) demonstrated potent inhibitory activity with an MIC value of 7.8 MUg/mL. PMID- 24956377 TI - LIM-homeodomain transcription factor Isl-1 mediates kisspeptin's effect on insulin secretion in mice. AB - Kisspeptin and the G protein-coupled receptor 54 (GPR54) are highly abundant in the pancreas. In addition, circulating kisspeptin directly influences insulin secretion through GPR54. However, the mechanisms by which kisspeptin affects insulin release are unclear. The LIM-homeodomain transcription factor, Isl-1, is expressed in all pancreatic islet cells and is involved in regulating both islet development and insulin secretion. We therefore investigated potential interactions between kisspeptin and Isl-1. Our results demonstrate that Isl-1 and GPR54 are coexpressed in mouse pancreatic islet beta-cells and NIT cells. Both in vitro and in vivo results demonstrate that kisspeptin-54 (KISS-54) inhibits Isl-1 expression and insulin secretion and both the in vivo and in vitro effects of KISS-54 on insulin gene expression and secretion are abolished when an Isl-1 inducible knockout model is used. Moreover, our results demonstrate that the direct action of KISS-54 on insulin secretion is mediated by Isl-1. Our results further show that KISS-54 influences Isl-1 expression and insulin secretion through the protein kinase C-ERK1/2 pathway. Conversely, insulin has a feedback loop via the Janus kinase-phosphatidylinositol 3-kinase pathway regulating kisspeptin expression and secretion. These findings are important in understanding mechanisms of insulin secretion and metabolism in diabetes. PMID- 24956378 TI - Androgen receptor enhances kidney stone-CaOx crystal formation via modulation of oxalate biosynthesis & oxidative stress. AB - Males develop kidney stones far more frequently than females with a ratio of 2 3:1, suggesting that androgen receptor (AR) signaling might play a key role in the development of nephrolithiasis. Using the cre-loxP system to selectively knock out AR in glyoxylate-induced calcium oxalate (CaOx) crystal mouse models, we found that the mice lacking hepatic AR had less oxalate biosynthesis, which might lead to lower CaOx crystal formation, and that the mice lacking kidney proximal or distal epithelial AR also had lower CaOx crystal formation. We found that AR could directly up-regulate hepatic glycolate oxidase and kidney epithelial NADPH oxidase subunit p22-PHOX at the transcriptional level. This up regulation might then increase oxalate biosynthesis and oxidative stress that resulted in induction of kidney tubular injury. Targeting AR with the AR degradation enhancer ASC-J9 led to suppression of CaOx crystal formation via modulation of oxalate biosynthesis and oxidative stress in both in vitro and in vivo studies. Taken together, these results established the roles of AR in CaOx crystal formation. PMID- 24956383 TI - Thrombocytopenia in congenital heart disease patients. AB - Thrombocytopenia has been identified as a mechanism of the increased incidence of thromboembolism and death in hypoxemic congenital heart disease (CHD) patients. About 387 CHD patients (344 non-hypoxemic and 43 hypoxemic) were followed-up during a median of 34.3 (24.5; 49.9) months. Demographic, clinical, analytical parameters, and survival curves between CHD with platelet levels above and below 150,000/MUl were determined. On one hand, in the subgroup of non-hypoxemic CHD patients, 8 out of 344 (2.3%) patients showed some type of bleeding and 8 (2.3%) patients showed some type of thrombosis. On the other hand, in the hypoxemic subgroup, 6 out of 43 (13.9%) patients had some type of bleeding and 5 (11.6%) patients showed some type of thrombosis. The binary logistic regression multivariate analysis being under oral anticoagulation/antiplatelet therapy (OR, 4.192 (1.207-14.550), p = 0.024) and having hypoxemia (OR, 4.041 (1.087-15.029); p = 0.037) favored the occurrence of bleeding. Meanwhile, the only factor which favored thrombosis was being hypoxemic (OR, 5.703 (1.334-24.387); p = 0.019). Also, being hypoxemic (OR, 0.217 (0.070-0.670), p = 0.008) and having a high MPV (OR, 0.534 (0.383-0.744); p = 0.001) favored a low platelet count (< 150 * 10(3)/ul). Kaplan-Meier survival analysis showed significant differences between CHD patients with a platelet count lower and higher than 150 * 10(3)/MUl (p = 0.009). Bleeding and thrombotic complications are more frequent in hypoxemic CHD patients irrespective of platelet counts. Larger platelets, as reflected by an increased mean platelet volume, and the higher CRP concentration seen in hypoxemic CHD patients may explain to some extent the higher incidence of thrombotic events in hypoxemic patients. PMID- 24956382 TI - Ob/ob mouse livers show decreased oxidative phosphorylation efficiencies and anaerobic capacities after cold ischemia. AB - BACKGROUND: Hepatic steatosis is a major risk factor for graft failure in liver transplantation. Hepatic steatosis shows a greater negative influence on graft function following prolonged cold ischaemia. As the impact of steatosis on hepatocyte metabolism during extended cold ischaemia is not well-described, we compared markers of metabolic capacity and mitochondrial function in steatotic and lean livers following clinically relevant durations of cold preservation. METHODS: Livers from 10-week old leptin-deficient obese (ob/ob, n = 9) and lean C57 mice (n = 9) were preserved in ice-cold University of Wisconsin solution. Liver mitochondrial function was then assessed using high resolution respirometry after 1.5, 3, 5, 8, 12, 16 and 24 hours of storage. Metabolic marker enzymes for anaerobiosis and mitochondrial mass were also measured in conjunction with non bicarbonate tissue pH buffering capacity. RESULTS: Ob/ob and lean mice livers showed severe (>60%) macrovesicular and mild (<30%) microvesicular steatosis on Oil Red O staining, respectively. Ob/ob livers had lower baseline enzymatic complex I activity but similar adenosine triphosphate (ATP) levels compared to lean livers. During cold storage, the respiratory control ratio and complex I fueled phosphorylation deteriorated approximately twice as fast in ob/ob livers compared to lean livers. Ob/ob livers also demonstrated decreased ATP production capacities at all time-points analyzed compared to lean livers. Ob/ob liver baseline lactate dehydrogenase activities and intrinsic non-bicarbonate buffering capacities were depressed by 60% and 40%, respectively compared to lean livers. CONCLUSIONS: Steatotic livers have impaired baseline aerobic and anaerobic capacities compared to lean livers, and mitochondrial function indices decrease particularly from after 5 hours of cold preservation. These data provide a mechanistic basis for the clinical recommendation of shorter cold storage durations in steatotic donor livers. PMID- 24956384 TI - Adaptation and prosthesis effects on stride-to-stride fluctuations in amputee gait. AB - Twenty-four individuals with transtibial amputation were recruited to a randomized, crossover design study to examine stride-to-stride fluctuations of lower limb joint flexion/extension time series using the largest Lyapunov exponent (lambda). Each individual wore a "more appropriate" and a "less appropriate" prosthesis design based on the subject's previous functional classification for a three week adaptation period. Results showed decreased lambda for the sound ankle compared to the prosthetic ankle (F1,23 = 13.897, p = 0.001) and a decreased lambda for the "more appropriate" prosthesis (F1,23 = 4.849, p = 0.038). There was also a significant effect for the time point in the adaptation period (F2,46 = 3.164, p = 0.050). Through the adaptation period, a freezing and subsequent freeing of dynamic degrees of freedom was seen as the lambda at the ankle decreased at the midpoint of the adaptation period compared to the initial prosthesis fitting (p = 0.032), but then increased at the end compared to the midpoint (p = 0.042). No differences were seen between the initial fitting and the end of the adaptation for lambda (p = 0.577). It is concluded that the lambda may be a feasible clinical tool for measuring prosthesis functionality and adaptation to a new prosthesis is a process through which the motor control develops mastery of redundant degrees of freedom present in the system. PMID- 24956385 TI - Novel population specific autosomal copy number variation and its functional analysis amongst Negritos from Peninsular Malaysia. AB - Copy number variation (CNV) has been recognized as a major contributor to human genome diversity. It plays an important role in determining phenotypes and has been associated with a number of common and complex diseases. However CNV data from diverse populations is still limited. Here we report the first investigation of CNV in the indigenous populations from Peninsular Malaysia. We genotyped 34 Negrito genomes from Peninsular Malaysia using the Affymetrix SNP 6.0 microarray and identified 48 putative novel CNVs, consisting of 24 gains and 24 losses, of which 5 were identified in at least 2 unrelated samples. These CNVs appear unique to the Negrito population and were absent in the DGV, HapMap3 and Singapore Genome Variation Project (SGVP) datasets. Analysis of gene ontology revealed that genes within these CNVs were enriched in the immune system (GO:0002376), response to stimulus mechanisms (GO:0050896), the metabolic pathways (GO:0001852), as well as regulation of transcription (GO:0006355). Copy number gains in CNV regions (CNVRs) enriched with genes were significantly higher than the losses (P value <0.001). In view of the small population size, relative isolation and semi nomadic lifestyles of this community, we speculate that these CNVs may be attributed to recent local adaptation of Negritos from Peninsular Malaysia. PMID- 24956386 TI - sgRNAcas9: a software package for designing CRISPR sgRNA and evaluating potential off-target cleavage sites. AB - Although the CRISPR/Cas9/sgRNA system efficiently cleaves intracellular DNA at desired target sites, major concerns remain on potential "off-target" cleavage that may occur throughout the whole genome. In order to improve CRISPR-Cas9 specificity for targeted genome editing and transcriptional control, we describe a bioinformatics tool "sgRNAcas9", which is a software package developed for fast design of CRISPR sgRNA with minimized off-target effects. This package consists of programs to perform a search for CRISPR target sites (protospacers) with user defined parameters, predict genome-wide Cas9 potential off-target cleavage sites (POT), classify the POT into three categories, batch-design oligonucleotides for constructing 20-nt (nucleotides) or truncated sgRNA expression vectors, extract desired length nucleotide sequences flanking the on- or off-target cleavage sites for designing PCR primer pairs to validate the mutations by T7E1 cleavage assay. Importantly, by identifying potential off-target sites in silico, the sgRNAcas9 allows the selection of more specific target sites and aids the identification of bona fide off-target sites, significantly facilitating the design of sgRNA for genome editing applications. sgRNAcas9 software package is publicly available at BiooTools website (www.biootools.com) under the terms of the GNU General Public License. PMID- 24956387 TI - Gustatory sensitivity and food acceptance in two phylogenetically closely related papilionid species: Papilio hospiton and Papilio machaon. AB - In herbivorous insects, food selection depends on sensitivity to specific chemical stimuli from host-plants as well as to secondary metabolites (bitter) and to sugars (phagostimulatory). Bitter compounds are noxious, unpalatable or both and evoke an aversive feeding response. Instead, sugars and sugar alcohols play a critical role in determining and enhancing the palatability of foods. We assumed that peripheral taste sensitivity may be related to the width of the host selection. Our model consists of two closely phylogenetically related Papilionid species exhibiting a difference in host plant choice: Papilio hospiton and Papilio machaon. The spike activity of the lateral and medial maxillary styloconic taste sensilla was recorded following stimulation with several carbohydrates, nicotine and NaCl, with the aim of characterizing their gustatory receptor neurons and of comparing their response patterns in the light of their different acceptability in feeding behaviour. The results show that: a) each sensillum houses phagostimulant and phagodeterrent cells; b) the spike activity of the gustatory neurons in response to different taste stimuli is higher in P. hospiton than in P. machaon; c) sugar solutions inhibit the spike activity of the deterrent and salt cells, and the suppression is higher in P. machaon than in P. hospiton. In conclusion, we propose that the different balance between the phagostimulant and phagodeterrent inputs from GRNs of maxillary sensilla may contribute in determining the difference in food choice and host range. PMID- 24956388 TI - Transcriptome profiling of the theca interna from bovine ovarian follicles during atresia. AB - The theca interna is a specialized stromal layer that envelops each growing ovarian follicle. It contains capillaries, fibroblasts, immune cells and the steroidogenic cells that synthesize androgens for conversion to estradiol by the neighboring granulosa cells. During reproductive life only a small number of follicles will grow to a sufficient size to ovulate, whereas the majority of follicles will undergo regression/atresia and phagocytosis by macrophages. To identify genes which are differentially regulated in the theca interna during follicular atresia, we undertook transcriptome profiling of the theca interna from healthy (n = 10) and antral atretic (n = 5) bovine follicles at early antral stages (<5 mm). Principal Component Analyses and hierarchical classification of the signal intensity plots for the arrays showed primary clustering into two groups, healthy and atretic. A total of 543 probe sets were differentially expressed between the atretic and healthy theca interna. Further analyses of these genes by Ingenuity Pathway Analysis and Gene Ontology Enrichment Analysis Toolkit software found most of the genes being expressed were related to cytokines, hormones and receptors as well as the cell cycle and DNA replication. Cell cycle genes which encode components of the replicating chromosome complex and mitotic spindle were down-regulated in atretic theca interna, whereas stress response and inflammation-related genes such as TP53, IKBKB and TGFB1 were up regulated. In addition to cell cycle regulators, upstream regulators that were predicted to be inhibited included Retinoblastoma 1, E2 transcription factor 1, and hepatocyte growth factor. Our study suggests that during antral atresia of small follicles in the theca interna, arrest of cell cycle and DNA replication occurs rather than up- regulation of apoptosis-associated genes as occurs in granulosa cells. PMID- 24956390 TI - DNA aptamer evolved by cell-SELEX for recognition of prostate cancer. AB - Morbidity and mortality of prostate cancer (PCa) have increased in recent years worldwide. Currently existing methods for diagnosis and treatment do not make the situation improve, especially for hormone refractory prostate cancer (HRPC). The lack of molecular probes for PCa hindered the early diagnosis of metastasis and accurate staging for PCa. In this work, we have developed a new aptamer probe Wy 5a against PCa cell line PC-3 by cell-SELEX technique. Wy-5a shows high specificity to the target cells with dissociation constants in the nanomolar range, and does not recognize other tested PCa cell lines and other tested tumor cell lines. The staining of clinical tissue sections with fluorescent dye labeled Wy-5a shows that sections from high risk group with metastasis exhibited stronger fluorescence and sections from Benign Prostatic Hyperplasia (BPH) did not exhibit notable fluorescence, which suggests that aptamer Wy-5a may bind to protein related to the progression of PCa. The high affinity and specificity of Wy-5a makes this aptamer hold potential for application in diagnosis and target therapy of PCa. PMID- 24956389 TI - Population structure, historical biogeography and demographic history of the alpine toad Scutiger ningshanensis in the Tsinling Mountains of Central China. AB - Population genetic structure, historical biogeography and historical demography of the alpine toad Scutiger ningshanensis were studied using the combined data mtDNA cytochrome b (cyt b) and the mtDNA cytochrome c oxidase subunit I (COI) as the molecular markers. This species has high genetic variation. There was a significant genetic differentiation among most populations. Three lineages were detected. The phylogenetic relationship analyses and the SAMOVA (spatial analysis of molecular variance) results showed significant phylogeographic structure. 82.15% genetic variation occurred among populations whereas differentiation within populations only contributed 17.85% to the total. Mantel test results showed a significant correlation between the pairwise calculated genetic distance and pairwise calculated geographical distance of the populations (regression coefficient = 0.001286, correlation coefficient = 0.77051, p (rrand>=robs) = 0.0185<0.05), indicating the existence of isolation-by-distance pattern of genetic divergence for cyt b + COI sequence, which suggests that the distribution of genetic variation is due to geographical separation rather than natural selection. The population expansion or contraction and genetic differentiation between populations or lineages could be explained by topography and the repetitive uplifts of the Tsinling Mountains and the climatic cycles during the late Pliocene and Pleistocene. S. ningshanensis experienced a rapid population expansion about 40,000 years before present. The current decline in population size was probably caused by anthropogenic disturbance. Current populations of S. ningshanensis are from different refugia though the location of these refugia could not be determined in our study. Topography, climatic changes and repetitive population expansion/contraction together led to the high level of genetic variation in S. ningshanensis. A total of three management units (MUs) was determined, which must be considered when conservation policy is made in the future. PMID- 24956391 TI - Near infrared spectroscopy (NIRS) as a new non-invasive tool to detect oxidative skeletal muscle impairment in children survived to acute lymphoblastic leukaemia. AB - BACKGROUND: Separating out the effects of cancer and treatment between central and peripheral components of the O2 delivery chain should be of interest to clinicians for longitudinal evaluation of potential functional impairment in order to set appropriate individually tailored training/rehabilitation programmes. We propose a non-invasive method (NIRS, near infrared spectroscopy) to be used in routine clinical practice to evaluate a potential impairment of skeletal muscle oxidative capacity during exercise in children previously diagnosed with acute lymphoblastic leukaemia (ALL). The purpose of this study was to evaluate the capacity of skeletal muscle to extract O2 in 10 children diagnosed with ALL, 1 year after the end of malignancy treatment, compared to a control group matched for gender and age (mean+/-SD = 7.8+/-1.5 and 7.3+/-1.4 years, respectively). METHODS AND FINDINGS: Participants underwent an incremental exercise test on a treadmill until exhaustion. Oxygen uptake ([Formula: see text]), heart rate (HR), and tissue oxygenation status (Delta[HHb]) of the vastus lateralis muscle evaluated by NIRS, were measured. The results showed that, in children with ALL, a significant linear regression was found by plotting [Formula: see text] vs Delta[HHb] both measured at peak of exercise. In children with ALL, the slope of the HR vs [Formula: see text] linear response (during sub maximal and peak work rates) was negatively correlated with the peak value of Delta[HHb]. CONCLUSIONS: The present study proves that the NIRS technique allows us to identify large inter-individual differences in levels of impairment in muscle O2 extraction in children with ALL. The outcome of these findings is variable and may reflect either muscle atrophy due to lack of use or, in the most severe cases, an undiagnosed myopathy. PMID- 24956392 TI - Oxidized LDL induces apoptosis of human retinal pigment epithelium through activation of ERK-Bax/Bcl-2 signaling pathways. AB - PURPOSE: Retinal pigment epithelium (RPE) cell dysfunction and death play a vital role in the pathogenesis of age-related macular degeneration (AMD). We previously reported that oxidized low-density lipoprotein (OX-LDL) induces retinal degeneration in vivo. In this study, we investigated the role of the ERK-Bax/Bcl 2 signaling pathways in OX-LDL-induced apoptosis in human RPE. METHODS: ARPE-19 cells were incubated with 10-100 mg/mL n-LDL or OX-LDL for 24 h. Cell viability was assessed using the Cell Titer 96 Aqueous One Solution cell proliferation assay. RPE apoptosis was measured with a flow cytometer. Reverse transcription polymerase chain reaction was used to detect Bcl-2 and Bax mRNA levels in RPE cells. Bcl-2 and Bax protein expression was measured by western blotting. Activation of extracellular signal-regulated kinase (ERK) protein was evaluated by western blot analysis. One-way analysis of variance was used to compare differences. RESULTS: OX-LDL treatment decreased ARPE-19 cell viability in a dose dependent manner, whereas n-LDL had no effect. Compared with the control group, OX-LDL significantly increased the apoptosis of RPE, 10 mg/mL, 50 mg/mL, 100 mg/mL apoptosis rate was 6.43 +/- 0.19%, 5.12 +/- 0.27%, 5.53 +/- 0.35%, respectively. OX-LDL also increased Bcl-2 expression and decreased Bax expression significantly. The Bcl-2 to Bax ratio was elevated after OX-LDL treatment. Inhibition of ERK downregulated Bax and was associated with RPE apoptosis. CONCLUSIONS: Our data suggest that apoptosis induced by OX-LDL in RPE partly depends on Erk-Bax/Bcl-2 signaling pathway activation. These results may provide further information regarding the effects of OX-LDL in human RPE and their potential role in AMD pathogenesis. PMID- 24956394 TI - An integrated control and readout circuit for implantable multi-target electrochemical biosensing. AB - We describe an integrated biosensor capable of sensing multiple molecular targets using both cyclic voltammetry (CV) and chronoamperometry (CA). In particular, we present our custom IC to realize voltage control and current readout of the biosensors. A mixed-signal circuit block generates sub-Hertz triangular waveform for the biosensors by means of a direct-digital-synthesizer to control CV. A current to pulse-width converter is realized to output the data for CA measurement. The IC is fabricated in 0.18 MUm technology. It consumes 220 MUW from 1.8 V supply voltage, making it suitable for remotely-powered applications. Electrical measurements show excellent linearity in sub- MUA current range. Electrochemical measurements including CA measurements of glucose and lactate and CV measurements of the anti-cancer drug Etoposide have been acquired with the fabricated IC and compared with a commercial equipment. The results obtained with the fabricated IC are in good agreement with those of the commercial equipment for both CV and CA measurements. PMID- 24956393 TI - Comparison of 18F-AIF-NOTA-PRGD2 and 18F-FDG uptake in lymph node metastasis of differentiated thyroid cancer. AB - A widespread application of integrin alphavbeta3 imaging has been emerging in both pre-clinical and clinical studies. But few studies reported its value as compared with 18F-FDG PET, especially for differentiated thyroid cancer (DTC). In this study, we compared the tracer uptake of 18F-AIF-NOTA-PRGD2 and 18F-FDG in lymph node metastasis of DTC to evaluate 18F-AIF-NOTA-PRGD2 as compared with 18F FDG. METHODS: 20 DTC patients with presumptive lymph node metastasis were examined with 18F-AIF-NOTA-PRGD2 and 18F-FDG PET/CT. 16 patients undergoing fine needle aspiration biopsy (FNAB) were evaluated by cytology results. For lesions without FNAB, the findings of clinical staging procedures served as the standard of reference (including neck ultrasound and serum thyroglobulin). RESULTS: A total of 39 presumptive lymph node metastases were visualized on PET/CT images. 35 lesions were confirmed as malignant by FNAB and other clinical findings. The mean 18F-AIF-NOTA-PRGD2 in radioactive iodine-refractory (RAIR) lesions and benign lesions were 2.5+/-0.9 and 2.8+/-0.9 respectively. The mean SUV for 18F FDG in all malignant lesions was 4.5+/-1.6 while in benign lesions it was 3.3+/ 1.2. For all malignant lesions, the mean SUV for 18F-FDG was significantly higher than that for 18F-AIF-NOTA-PRGD2 (P<0.05). No significant correlation was found between the SUVs of 18F-AIF-NOTA-PRGD2 and 18F-FDG for 35 lesions (r = 0.114, P = 0.515). Moreover, 15 lesions of which the diameter larger than 1.5 cm had higher 18F-AIF-NOTA-PRGD2 uptake as compared with the lesions smaller than 1.5 cm. CONCLUSION: Although most lymph node metastases of DTC showed abnormal uptake of 18F-AIF-NOTA-PRGD2, its diagnostic value was inferior to 18F-FDG. No correlation was found between the uptake of 18F-AIF-NOTA-PRGD2 and 18F-FDG, which may suggest the two tracers provide complementary information in DTC lesions. PMID- 24956395 TI - Respiration detection chip with integrated temperature-insensitive MEMS sensors and CMOS signal processing circuits. AB - An airflow sensing chip, which integrates MEMS sensors with their CMOS signal processing circuits into a single chip, is proposed for respiration detection. Three micro-cantilever-based airflow sensors were designed and fabricated using a 0.35 MUm CMOS/MEMS 2P4M mixed-signal polycide process. Two main differences were present among these three designs: they were either metal-covered or metal-free structures, and had either bridge-type or fixed-type reference resistors. The performances of these sensors were measured and compared, including temperature sensitivity and airflow sensitivity. Based on the measured results, the metal free structure with fixed-type reference resistors is recommended for use, because it has the highest airflow sensitivity and also can effectively reduce the output voltage drift caused by temperature change. PMID- 24956396 TI - Step-by-step on-surface synthesis: from manganese phthalocyanines to their polymeric form. AB - On-surface synthesis of tetracyanobenzene molecules with Mn atoms is presented. From metal-organic coordination networks at room temperature, Mn-phthalocyanines and finally small domains of polymeric Mn-phthalocyanines are formed upon annealing on the Ag(111) surface. Step-by-step on-surface reaction is studied in situ by scanning tunnelling microscopy under ultra-high vacuum. PMID- 24956398 TI - Neuroprotective effects of Arctium lappa L. roots against glutamate-induced oxidative stress by inhibiting phosphorylation of p38, JNK and ERK 1/2 MAPKs in PC12 cells. AB - Many studies have shown that glutamate-induced oxidative stress can lead to neuronal cell death involved in the development of neurodegenerative diseases. In this work, protective effects of ethyl acetate extract (EAE) of Arctium lappa L. roots against glutamate-induced oxidative stress in PC12 cells were evaluated. Also, the effects of EAE on antioxidant system, mitochondrial pathway, and signal transduction pathway were explored. Pretreatment with EAE significantly increased cell viability, activities of GSH-Px and SOD, mitochondrial membrane potential and reduced LDH leakage, ROS formation, and nuclear condensation in a dose dependent manner. Furthermore, western blot results revealed that EAE increased the Bcl-2/Bax ratio, and inhibited the up-regulation of caspase-3, release of cytochrome c, phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK 1/2). Therefore, our results indicate that EAE may be a promising neuroprotective agent for the prevention and treatment of neurodegenerative diseases implicated with oxidative stress. PMID- 24956399 TI - The influence of hydroxyl-functionalized multi-walled carbon nanotubes and pH levels on the toxicity of lead to Daphnia magna. AB - The acute toxicity of lead was examined for Daphnia magna in waters with different pH values (5.0, 6.0, 7.0, 8.0 and 9.0) and different concentrations (0.01, 0.10, 0.50 and 1.00 mg/L) of hydroxyl-functionalized multi-walled carbon nanotubes (OH-MWCNTs). The results indicated that pH values could affect the toxicity of lead. With pH values increasing from 5.0 to 9.0, the 24h-LC50 of Pb(II) increased from 0.784 to 9.473 mg/L, suggesting that the toxicity of Pb(II) was dramatically decreased. Although OH-MWCNTs almost caused no lethal effect to D. magna at the studied four concentrations, the combination of OH-MWCNTs and Pb(II) could cause more serious toxic effects to D. magna than Pb(II) alone. This study indicated that the synergistic effect caused by CNTs and lead could not be neglected. PMID- 24956400 TI - Anti-leishmanial effect of itraconazole niosome on in vitro susceptibility of Leishmania tropica. AB - The novel niosomal system aimed to deliver the active drug entity to the target site. The objective of this study was to prepare and evaluate the effect of itraconazole niosome on the in vitro susceptibility of Leishmania tropica as compared to itraconazole alone or tartar emetic. The overall growth rate of promastigotes treated with various concentrations of itraconazole niosome was significantly lower than that of itraconazole alone (IC50=0.24 MUg/ml vs. IC50=0.43 MUg/ml, P<0.01). In contrast, the mean multiplication rate of amastigotes inside the macrophages and also the mean number of amastigotes in each macrophage treated with itraconazole niosome (34.9 and 3.0) were significantly lower (P<0.01) than those treated with itraconazole alone (62.0 and 3.8) or tartar emetic (63.9 and 4.2), respectively. These findings indicated that niosomes could be developed as a novel drug delivery for itraconazole in the in vitro model. Further studies are required to evaluate the effect of itraconazole niosome on volunteer human subjects. PMID- 24956404 TI - New advances in stem cell research: practical implications for regenerative medicine. AB - Regenerative medicine is searching for stem cells that can be safely and efficiently employed for regeneration of damaged solid organs (e.g., the heart, brain, or liver). Ideal for this purpose would be pluripotent stem cells, which, according to their definition, have broad potential to differentiate into all types of adult cells. For almost 20 years, there have been unsuccessful attempts to harness controversial embryonic stem cells (ESCs) isolated from embryos. Induced pluripotent stem cells (iPSCs), generated by genetic modification of adult somatic cells, are a more promising source. However, both iPSC and ESCs are associated with a risk of teratoma formation. At the same time, various types of more-differentiated adult stem and progenitor cells derived from the bone marrow, umbilical cord blood, mobilized peripheral blood, or fat tissue are being employed in clinical trials to regenerate damaged solid organs. However, for most of these cells, there is a lack of convincing documentation for successful regeneration of the treated organs. Beneficial effects of those cells might be explained by paracrine effects of growth factors, cytokines, chemokines, bioactive lipids, and extracellular microvesicles, which are released from the cells and have trophic, antiapoptotic, and angiopoietic effects. Nevertheless, there is evidence that adult tissues harbor a promising population of very rare dormant stem cells with broad differentiation potential. In this review, we will discuss various potential sources of stem cells for regenerative medicine and the mechanisms that explain some of their beneficial effects as well as highlight the results of the first clinical trials. PMID- 24956405 TI - Paramagnetic decoration of DNA origami nanostructures by Eu3+ coordination. AB - The folding of DNA into arbitrary two- and three-dimensional shapes, called DNA origami, represents a powerful tool for the synthesis of functional nanostructures. Here, we present the first approach toward the paramagnetic functionalization of DNA origami nanostructures by utilizing postassembly coordination with Eu(3+) ions. In contrast to the usual formation of toroidal dsDNA condensates in the presence of trivalent cations, planar as well as rod like DNA origami maintain their shape and monomeric state even under high loading with the trivalent lanthanide. Europium coordination was demonstrated by the change in Eu(3+) luminescence upon binding to the two DNA origami. Their natural circular dichroism in the Mg(2+)- and Eu(3+)-bound state was found to be very similar to that of genomic DNA, evidencing little influence of the DNA origami superstructure on the local chirality of the stacked base pairs. In contrast, the magnetic circular dichroism of the Mg(2+)-bound DNA origami deviates from that of genomic DNA. Furthermore, the lanthanide affects the magnetic properties of DNA in a superstructure-dependent fashion, indicative of the existence of superstructure-specific geometry of Eu(3+) binding sites in the DNA origami that are not formed in genomic DNA. This simple approach lays the foundation for the generation of magneto-responsive DNA origami nanostructures. Such systems do not require covalent modifications and can be used for the magnetic manipulation of DNA nanostructures or for the paramagnetic alignment of molecules in NMR spectroscopy. PMID- 24956406 TI - Selective removal of metallic single-walled carbon nanotubes in full length by organic film-assisted electrical breakdown. AB - An organic film-assisted electrical breakdown technique is proposed to selectively remove metallic (m-) single-walled carbon nanotubes (SWNTs) in full length towards creation of pure semiconducting SWNT arrays which are available for the large-scale fabrication of field effect transistors (FETs). The electrical breakdown of horizontally aligned SWNT arrays embedded in organic films resulted in a maximum removal length of 16.4 MUm. The removal of SWNTs was confirmed using scanning electron microscopy and Raman mapping measurements. The on/off ratios of FETs were improved up to ca. 10,000, similar to that achieved for in-air breakdown. The experimental results suggest that exothermic oxidation of organic films induces propagation of oxidation reaction, hence the long-length removal of m-SWNTs. PMID- 24956408 TI - Resveratrol as anti-aging therapy for age-related bone loss. AB - INTRODUCTION: Previous studies have indicated that resveratrol, a natural phytoestrogen, can act as an anti-aging therapy to resist age-related changes of several body tissues. However, the anti-aging effects of resveratrol on bone have been poorly investigated in this natural aging population. Accordingly, this study was design to evaluate the effects of resveratrol on bone mass and biomechanical properties in old rat femora. METHODS: Twenty 22-month-old male Wistar rats were divided into two randomly assigned groups (n=10). The first group was treated for 10 weeks with resveratrol (10 mg/kg per day) and the second group was left untreated (control). Rat femora were collected. Bone mass and bone microestructure were investigated by microcomputed tomography and histomorphometry. Biomechanical properties were determined by a three-point bending test. Plasma levels of CTX (carboxy-terminal telopeptide of type I collagen) and osteocalcin were also determined. Statistical analyses were performed by a Student two-tailed unpaired t-test. In all experiments, a value of p<0.05 was considered significant. RESULTS: Microcomputed tomography analyses demonstrated that resveratrol-treated rats had significant higher bone volume, bone trabecular number, and cortical thickness and lower spacing between trabeculae in comparison to the control group. Histomorphometric analyses confirmed the increase of bone volume in resveratrol-treated rats compared to controls. Resveratrol-treated rats had significant higher bone flexural modulus, stiffness, and ultimate load compared to control group. Treatment was not associated with changes in plasma CTX or osteocalcin. CONCLUSION: These findings demonstrate that resveratrol increases bone microstructure and bone mechanical properties in old male rats, suggesting that resveratrol might be used as anti aging therapy to resist age-induced bone loss. PMID- 24956409 TI - Ruthenium-catalyzed cyclization of anilides with substituted propiolates or acrylates: an efficient route to 2-quinolinones. AB - A Ru-catalyzed cyclization of anilides with propiolates or acrylates affording 2 quinolinones having diverse functional groups in good to excellent yields is described. Later, 2-quinolinones were converted into 3-halo-2-quinolinones and 2 chloroquinolines. The proposed mechanism was strongly supported by experimental evidence and deuterium labeling studies. PMID- 24956413 TI - Unprecedented colorimetric responses of polydiacetylenes driven by plasma induced polymerization and their patterning applications. AB - We report for the first time that polydiacetylenes (PDAs) can be alternatively prepared via a plasma induced polymerization process. The degree of polymerization and colorimetric transitions could be manipulated by controlling the power of plasma radiofrequency, exposure time and by using an acrylic mask, resulting in their great potential for patterning applications. PMID- 24956412 TI - Prebiopsy multiparametric 3T prostate MRI in patients with elevated PSA, normal digital rectal examination, and no previous biopsy. AB - PURPOSE: To find the diagnostic accuracy of 3T multiparametric magnetic resonance imaging (mpMRI) and mpMRI targeted transrectal ultrasound (TRUS)-guided biopsy using visual coregistration (TB) in patients with elevated prostate-specific antigen (PSA), normal digital rectal examination, and no previous biopsy. MATERIALS AND METHODS: Fifty-five patients at two institutions underwent mpMRI, consisting of anatomical T2 -weighted imaging (T2 W), diffusion-weighted imaging (DWI), proton magnetic resonance spectroscopy ((1) H-MRS), and dynamic contrast enhanced MRI (DCE-MRI), followed by TB in addition to 12 core systematic TRUS guided biopsy (SB). Histopathological scorings of biopsy (n = 38) and prostatectomy (n = 17) specimens were used as the reference standard for calculation of diagnostic accuracy values. Clinically significant prostate cancer (SPCa) was defined as 3 mm core length of Gleason score 3+3 or any Gleason grade 4. RESULTS: The sensitivity, specificity, accuracy, and area under the curve (AUC) values for the detection of SPCa on the sextant level for T2 W+DWI+(1) H MRS+DCE-MRI were 72%, 89%, 85%, and 0.81, respectively. The corresponding values for T2 wi+DWI were 61%, 96%, 87%, and 0.79, respectively. The overall PCa detection rate per core in 53 patients was 21% (138 of 648 cores) for SB and 43% (33 of 77 cores) for TB (P < 0.001). CONCLUSION: Prebiopsy mpMRI is an accurate tool for PCa detection and biopsy targeting in patients with elevated PSA. PMID- 24956414 TI - Patterning and biofunctionalization of antifouling hyperbranched polyglycerol coatings. AB - We demonstrate the patterned biofunctionalization of antifouling hyperbranched polyglycerol (HPG) coatings on silicon and glass substrates. The ultralow fouling HPG coatings afforded straightforward chemical handles for rapid bioconjugation of amine containing biomolecular species. This was achieved by sodium periodate oxidation of terminal HPG diols to yield reactive aldehyde groups. Patterned microprinting of sodium periodate and cell adhesion mediating cyclic peptides containing the RGD sequence resulted in an array of covalently immobilized bioactive signals. When incubated with mouse fibroblasts, the HPG background resisted cell attachment whereas high density cell attachment was observed on the peptide spots, resulting in high-contrast cell microarrays. We also demonstrated single-step, in situ functionalization of the HPG coatings by printing periodate and peptide concurrently. Our results demonstrate the effectiveness of antifouling and functionalized HPG graft polymer coatings and establish their use in microarray applications for the first time. PMID- 24956411 TI - Crystal structure of deglycosylated human IgG4-Fc. AB - The Fc region of IgG antibodies, important for effector functions such as antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement activation, contains an oligosaccharide moiety covalently attached to each C(H)2 domain. The oligosaccharide not only orients the C(H)2 domains but plays an important role in influencing IgG effector function, and engineering the IgG-Fc oligosaccharide moiety is an important aspect in the design of therapeutic monoclonal IgG antibodies. Recently we reported the crystal structure of glycosylated IgG4-Fc, revealing structural features that could explain the anti-inflammatory biological properties of IgG4 compared with IgG1. We now report the crystal structure of enzymatically deglycosylated IgG4-Fc, derived from human serum, at 2.7A resolution. Intermolecular C(H)2-C(H)2 domain interactions partially bury the C(H)2 domain surface that would otherwise be exposed by the absence of oligosaccharide, and two Fc molecules are interlocked in a symmetric, open conformation. The conformation of the C(H)2 domain DE loop, to which oligosaccharide is attached, is altered in the absence of carbohydrate. Furthermore, the C(H)2 domain FG loop, important for Fcgamma receptor and C1q binding, adopts two different conformations. One loop conformation is unique to IgG4 and would disrupt binding, consistent with IgG4's anti-inflammatory properties. The second is similar to the conserved conformation found in IgG1, suggesting that in contrast to IgG1, the IgG4 C(H)2 FG loop is dynamic. Finally, crystal packing reveals a hexameric arrangement of IgG4-Fc molecules, providing further clues about the interaction between C1q and IgG. PMID- 24956415 TI - DASH diet, insulin resistance, and serum hs-CRP in polycystic ovary syndrome: a randomized controlled clinical trial. AB - This study was designed to assess the effects of Dietary Approaches to Stop Hypertension (DASH) eating plan on insulin resistance and serum hs-CRP in overweight and obese women with PCOS. This randomized controlled clinical trial was done on 48 women diagnosed with PCOS. Subjects were randomly assigned to consume either the control (n=24) or the DASH eating pattern (n=24) for 8 weeks. The DASH diet consisted of 52% carbohydrates, 18% proteins, and 30% total fats. It was designed to be rich in fruits, vegetables, whole grains, and low-fat dairy products and low in saturated fats, cholesterol, refined grains, and sweets. Sodium content of the DASH diet was designed to be less than 2 400 mg/day. The control diet was also designed to contain 52% carbohydrates, 18% protein, and 30% total fat. Fasting blood samples were taken at baseline and after 8 weeks intervention to measure -insulin resistance and serum hs-CRP levels. -Adherence to the DASH eating pattern, compared to the -control diet, resulted in a significant reduction of serum insulin levels (-1.88 vs. 2.89 MUIU/ml, p=0.03), HOMA-IR score (-0.45 vs. 0.80; p=0.01), and serum hs-CRP levels (-763.29 vs. 665.95 ng/ml, p=0.009). Additionally, a significant reduction in waist (-5.2 vs. 2.1 cm; p=0.003) and hip circumference (-5.9 vs. -1 cm; p<0.0001) was also seen in the DASH group compared with the control group. In conclusion, consumption of the DASH eating pattern for 8 weeks in overweight and obese women with PCOS resulted in the improvement of insulin resistance, serum hs-CRP levels, and abdominal fat accumulation. CLINICAL TRIAL REGISTRATION NUMBER: www.irct.ir: IRCT201304235623N6. PMID- 24956417 TI - Tailoring and understanding the mechanical properties of nanoparticle-shelled bubbles. AB - One common approach to generate lightweight materials with high specific strength and stiffness is the incorporation of stiff hollow microparticles (also known as bubbles or microballoons) into a polymeric matrix. The mechanical properties of these composites, also known as syntactic foams, greatly depend on those of the hollow microparticles. It is critical to precisely control the properties of these bubbles to fabricate lightweight materials that are suitable for specific applications. In this paper, we present a method to tailor the mechanical properties and response of highly monodisperse nanoparticle-shelled bubbles using thermal treatment. We characterize the mechanical properties of individual as assembled bubbles as well as those of thermally treated ones using nanoindentation and quantitative in situ compression tests. As-assembled bubbles display inelastic response, whereas thermally treated bubbles behave elastically. We also show that the stiffness and strength of bubbles are enhanced significantly, as much as 12 and 14 times that of the as-assembled bubbles, respectively, via thermal treatment. We complement the experimental results with finite element analysis (FEA) to understand the effect of shell thickness nonuniformity as well as the inelasticity on the mechanical response and fracture behavior of these bubbles. We demonstrate that the failure mechanism of bubbles incorporated into a polymer composite depends on the structure of the bubbles. PMID- 24956416 TI - Resveratrol prevents hyperleptinemia and central leptin resistance in adult rats programmed by early weaning. AB - We have previously shown that early weaning in rats increases the risk of obesity and insulin resistance at adulthood, and leptin resistance can be a prime factor leading to these changes. Resveratrol is reported to decrease oxidative stress, insulin resistance, and cardiovascular risk. However, there is no report about its effect on leptin resistance. Thus, in this study we have evaluated resveratrol-preventing effect on the development of visceral obesity, insulin, and leptin resistance in rats programmed by early weaning. To induce early weaning, lactating dams were separated into 2 groups: early weaning (EW)--dams were wrapped with a bandage to interrupt lactation in the last 3 days of lactation and control (C)--dams whose pups had free access to milk during throughout lactation period (21 days). At 150 days-old, EW offspring were subdivided into 2 groups: EW+res--treated with resveratrol solution (30 mg/kg BW/day) or EW--receiving equal volume of vehicle solution, both given by gavage during 30 days. Control group received vehicle solution. Resveratrol prevented the higher body weight, hyperphagia, visceral obesity, hyperleptinemia, hyperglycemia, insulin resistance, and hypoadiponectinemia at adulthood in animals that were early weaned. Leptin resistance, associated with lower JAK2 and pSTAT3 and higher NPY in hypothalamus of EW rats were also normalized by resveratrol. The present results suggest that resveratrol is useful as therapeutic tool in treating obesity, mainly because it prevents the development of central leptin resistance. PMID- 24956418 TI - Production of monoclonal antibodies for detection of Citrus leprosis virus C in enzyme-linked immuno-assays and immunocapture reverse transcription-polymerase chain reaction. AB - Citrus leprosis virus C (CiLV-C) causes damage in citrus production in the South and Central America. Since closely related types of citrus viruses have recently been described monoclonal antibodies (MAbs) are needed for accurate and sensitive diagnosis of CiLV-C. In this study, MAbs to the expressed coat protein of CiLV-C were produced for serological detection of CiLV-C in crude extracts of infected tissues in double antibody sandwich enzyme-linked immunosorbent assays (DAS ELISA), dot blot immunosorbent assays (DBIA) and immuonocapture-reverse transcription-polymerase chain reaction (IC-RT-PCR) procedures. Monoclonal antibodies were developed in mice to the purified expressed coat protein of CiLV C. The published standard protocols of DAS-ELISA, DBIA and IC-RT-PCR were followed for the detection of coat protein p29 of CiLV-C in the crude extracts of CiLV-C infected tissues. Two monoclonal antibodies, designated G10 and C11, were identified from four potential candidates for the specific and sensitive detection of coat protein p29 of CiLV-C in the crude citrus extracts of CiLV-C infected tissues in DAS-ELISA, whereas G10 was also selected based on performance for use in the DBIA and IC-RT-PCR diagnostic assays. Sensitivity analysis comparing the three methods for detection of coat protein p29 of CiLV-C determined that IC-RT-PCR was more sensitive than DAS-ELISA and DBIA. The creation of MAbs to CiLV-C allows for the sensitive and accurate detection of the virus from CiLV-C infected citrus leaf tissues. Successful detection of the virus in three diagnostic assays formats provides flexibility to diagnosticians who can use either ELISA or DBIA for screening large numbers of samples, and IC-RT-PCR for rapid, sensitive confirmation testing. PMID- 24956407 TI - Progress and outlook in structural biology of large viral RNAs. AB - The field of viral molecular biology has reached a precipice for which pioneering studies on the structure of viral RNAs are beginning to bridge the gap. It has become clear that viral genomic RNAs are not simply carriers of hereditary information, but rather are active players in many critical stages during replication. Indeed, functions such as cap-independent translation initiation mechanisms are, in some cases, primarily driven by RNA structural determinants. Other stages including reverse transcription initiation in retroviruses, nuclear export and viral packaging are specifically dependent on the proper 3-dimensional folding of multiple RNA domains to recruit necessary viral and host factors required for activity. Furthermore, a large-scale conformational change within the 5'-untranslated region of HIV-1 has been proposed to regulate the temporal switch between viral protein synthesis and packaging. These RNA-dependent functions are necessary for replication of many human disease-causing viruses such as severe acute respiratory syndrome (SARS)-associated coronavirus, West Nile virus, and HIV-1. The potential for antiviral development is currently hindered by a poor understanding of RNA-driven molecular mechanisms, resulting from a lack of structural information on large RNAs and ribonucleoprotein complexes. Herein, we describe the recent progress that has been made on characterizing these large RNAs and provide brief descriptions of the techniques that will be at the forefront of future advances. Ongoing and future work will contribute to a more complete understanding of the lifecycles of retroviruses and RNA viruses and potentially lead to novel antiviral strategies. PMID- 24956420 TI - The Editor's Letter. AB - This second instalment in our Child Health in Canada series explores a multi faceted topic that weighs especially heavy on the minds of parents, teachers, care providers, policy makers, social workers and many others: mental health. After all, as Stan Kutcher asserts in his contribution to this issue, "there can be no health without mental health." PMID- 24956421 TI - The state of child and youth mental health in Canada: past problems and future fantasies. AB - Berezin (1978), a geriatric psychiatrist from Harvard, says that as we get older, our personality does not change, it just gets more so! How can it be then, that in 2010, despite the best efforts of many, the state of child and youth mental health in Canada is unknown to countless people? How can it be that despite the fact that nothing has changed for years, except to get more so, few know about the plight of Canadian child and youth mental health services? How can it be that in Ontario, politicians, regardless of political party (all parties have been in power at some time during the past 20 years), have known the facts about child and youth mental health and have effectively turned a blind eye? PMID- 24956422 TI - Facing the challenge of care for child and youth mental health in Canada: a critical commentary, five suggestions for change and a call to action. AB - Neuropsychiatric disorders contribute most to the global burden of disease in young people (World Health Organization [WHO] 2003), approaching about 30% of the total global disease burden in those aged 10-19 years. Comparative data are not available for Canada, but the proportional burden of mental disorders in Canadian youth would be expected to be higher as our rates of human immunodeficiency virus/acquired immunodeficiency syndrome, tuberculosis, malaria and iron deficiency disorders are substantially less than those in low-income countries. National estimates identify that about 15% of Canadian young people suffer from a mental disorder, but only about one in five of those who require professional mental health care actually receive it (Government of Canada 2006; Health Canada 2002; Kirby and Keon 2006; McEwan et al. 2007; Waddell and Shepherd 2002). And recent reports suggest that the human fallout from this reality may go beyond the well-known negative impacts of early-onset mental disorders on social, interpersonal, vocational and economic outcomes. For example, rates of mental disorder are very high in incarcerated youth, suggesting that, for some, jails are becoming the home for mentally ill young people (Kutcher and McDougall 2009). PMID- 24956419 TI - Distinct regulation of the anterior and posterior myeloperoxidase expression by Etv2 and Gata1 during primitive Granulopoiesis in zebrafish. AB - Neutrophilic granulocytes are the most abundant type of myeloid cells and form an essential part of the innate immune system. In vertebrates the first neutrophils are thought to originate during primitive hematopoiesis, which precedes hematopoietic stem cell formation. In zebrafish embryos, it has been suggested that primitive neutrophils may originate in two distinct sites, the anterior (ALPM) and posterior lateral plate mesoderm (PLPM). An ETS-family transcription factor Etsrp/Etv2/ER71 has been implicated in vasculogenesis and hematopoiesis in multiple vertebrates. However, its role during neutrophil development is not well understood. Here we demonstrate using zebrafish embryos that Etv2 has a specific cell-autonomous function during primitive neutropoiesis in the anterior lateral plate mesoderm (ALPM) but has little effect on erythropoiesis or the posterior lateral plate mesoderm (PLPM) expression of neutrophil marker myeloperoxidase mpo/mpx. Our results argue that ALPM-derived neutrophils originate from etv2 expressing cells which downregulate etv2 during neutropoiesis. We further show that Scl functions downstream of Etv2 in anterior neutropoiesis. Additionally, we demonstrate that mpx expression within the PLPM overlaps with gata1 expression, potentially marking the cells with a dual myelo-erythroid potential. Intriguingly, initiation of mpx expression in the PLPM is dependent on gata1 but not etv2 function. Our results demonstrate that mpx expression is controlled differently in the ALPM and PLPM regions and describe novel roles for etv2 and gata1 during primitive neutropoiesis. PMID- 24956424 TI - "We suffer from being lost": formulating policies to reclaim youth in mental health transitions. AB - The greatest financial and institutional weaknesses in mental health services affect individuals between the ages of 16 and 25. The current project sought to identify bodies of evidence supporting effective transitional pathways and to engage policy leaders in a discussion of youth mental health transitions to highlight stakeholder perspectives. Three efficacious pathways from youth health service environments to adult health service structures were identified in the literature: the Protocol/Reciprocal Agreement Structure, the Transition Program Model and the Shared Management Framework. Evidence was presented to a panel of policy officials occupying various roles, up to the position of assistant deputy minister, from the provincial ministries of health, education, child and youth services and training, colleges and universities in Ontario. The panel was then engaged in a discussion regarding youth mental health transitions, and thematic analysis was used to identify policy- and practice-level considerations. The Shared Management Framework was recommended as the preferred transitional model from a policy perspective; however, continued research is required to determine the appropriateness of this approach for all stakeholders involved in youth mental health transitions. PMID- 24956423 TI - Improving mental health outcomes for children and youth exposed to abuse and neglect. AB - Children exposed to abuse and neglect are at significantly higher risk of developing mental health conditions than are children who grow up in stable families. Multiple complexities arise in supporting the needs of these vulnerable children: complex family circumstances; the need to balance the goals of protecting the children and strengthening family connections; and the involvement of multiple players from biological families to foster parents to case workers to children's mental health professionals. This article draws on case studies, the literature and proven initiatives that have been implemented in a number of children's aid societies in Ontario to demonstrate four strategies that can improve mental health outcomes for children exposed to abuse and neglect. These strategies are increasing admission prevention and early intervention to support at-risk youth at home; supporting transitions from intensive residential treatment back to the community; ensuring youth transitioning to the adult system have the supports they need; and increasing integration in service delivery between children's mental health and child welfare. PMID- 24956425 TI - Reducing mental health stigma: a case study. AB - The purpose of this study was to evaluate a contact-based educational symposium designed to reduce mental health-related stigma in journalism students. Repeated surveys conducted before (n = 89) and again after the intervention (n = 53) were used to assess change. The estimated average response rate for each survey was 90%. The instrument, adapted from prior research, contained items pertaining to stereotypical content, attitudes toward social distance and feelings of social responsibility (Cronbach's alpha =.74). There was a statistically significant reduction in stigma (reflecting a 5% reduction in the aggregated scale score). A large, item-specific change was noted pertaining to attributions of dangerousness and unpredictability (reflecting a 26% improvement). The majority of students reported that the symposium had changed their views of people with a mental illness. Half of these students considered that they would change the way they would report stories involving someone with a mental illness. A potential unexpected negative side effect was that 14% fewer students reported post-test a willingness to go to a doctor if they experienced a mental illness. Though it is difficult to draw firm conclusions from an uncontrolled study, it would appear that this relatively brief, contact-based intervention changed journalism students' views of people with a mental illness. More controlled investigation is needed to rule out alternative explanations that could account for this change. PMID- 24956426 TI - The "Mental" Health of Canada's Indigenous Children and Youth: Finding New Ways Forward. AB - Focusing, as it is meant to do, on child mental health, this special issue of Healthcare Quarterly singles out for attention a distinctive category of concerns that, when viewed through lenses common to many Indigenous peoples, is arguably better left unmarked. That is, attempts to carve up the world in such a way that health concerns centre on matters of the "mind," on the one hand, and on "physical" ill health, on the other, are expressive of a form of self understanding that is more consonant with the classic dualisms of traditional, "Western," Cartesian thought (e.g., the mental in counter-distinction to the physical; selves set off against societies), and quite out of place in those more holistic frameworks of understanding favoured by many of the world's Indigenous peoples (Chandler 2010). Why such putative cultural differences might make a difference - or at least a difference in what is written here - is that any account of health matters in which Indigenous people might actually recognize themselves requires, as a constitutive condition of its coherence, a kind of radical reframing - a shift in axes that replaces the arguably "false" dichotomy between mental and physical health with something better approximated by the much overheard and more broadly inclusive notion of personal and community "well being." PMID- 24956427 TI - Youth justice and mental health in perspective. AB - Research indentifies that a significant proportion of youth within the justice system possess some form of mental health disorder, and that the presence of an emotional disorder can provide important explanatory value regarding the causes of crime. Evidence is now overwhelming that services within the youth justice system need to account for the causes of crime in order to effectively reduce the likelihood of reoffending. Such an ethic within youth justice service delivery not only reduces symptoms and risk within the youth and their families but also is linked to increasing community safety through reductions in reoffending. This review characterizes the relevance of mental health disorder in considering the needs of anti-social youth, and how this appreciation is linked to the delivery of effective services as well as what constitutes supportive youth justice legislation. PMID- 24956428 TI - Experience of emotional stress and resilience in street-involved youth: the need for early mental health intervention. AB - Mental illness left untreated in adolescence and young adulthood can readily become a chronic illness in adulthood, seriously hampering the capacity of individuals to become healthy contributing members of society. Mental health challenges are of paramount importance to the health and well-being of Canadian adolescents and young adults, with 18% of Canadian youth, ages 15-24, reporting a mental illness (Leitch 2007). However, it is unlikely that this statistic accounts for those invisible youth (Rachlis et al. 2009) who are disconnected from families and caregivers, bereft of stable housing and familial support - in other words, youth who are street-involved. Mental health risk is amplified in street-involved youth and, as such, must be recognized as a priority for policy development that commits to accessible mental health programming, in order to realize the potential of these vulnerable youth. PMID- 24956429 TI - Why Worry about Bullying? AB - In this article, the authors review research to identify bullying as a critical public health issue for Canada. Drawing from recent World Health Organization surveys, they examine the prevalence of Canadian children and youth involved in bullying others or being victimized. There is a strong association between involvement in bullying and health problems for children who bully, those who are victimized and those involved in both bullying and being victimized. Health problems can manifest as physical complaints (e.g., headaches), mental health concerns (e.g., depression, anxiety) and psychosocial problems (e.g., substance use, crime). In Canada, there has recently been a disturbing incidence of Canadian children who have committed suicide as a result of prolonged victimization by peers. Healthcare professionals play a major role in protecting and promoting the health and well-being of Canadian children and youth. Given the significant mental and physical health problems associated with involvement in bullying, it is important that clinicians, especially primary care healthcare professionals, be able to identify signs and symptoms of such involvement. Healthcare professionals can play an essential role supporting children and their parents and advocating for the safety and protection for those at risk. By understanding bullying as a destructive relationship problem that significantly impacts physical and mental health, healthcare professionals can play a major role in promoting healthy relationships and healthy development for all Canadian children and youth. This review provides an overview of the nature of bullying and the physical and psychological health problems associated with involvement in bullying. The review is followed by a discussion of the implications for health professionals and a protocol for assessing the potential link between bullying and a child's physical and psychological symptoms. PMID- 24956430 TI - Effectiveness of school-based violence prevention for children and youth: a research report. AB - Aggression, bullying and violence in children and youth are prevalent in Canada (18%) and internationally. The authors evaluated the effectiveness of Roots of Empathy (ROE), a school-based mental health promotion and violence prevention program for children that has been widely implemented but rarely evaluated. Eight school divisions were randomly assigned to either a treatment group that received ROE in 2002-2003 (445 students) or a wait-list control group (315 students). These were compared on three child mental health outcomes (physical aggression, indirect aggression and pro-social behaviour), rated by teachers and students (self-rated). The three wait-list school divisions received ROE in 2003-2004 (new cohort of 265 students) and were compared with the control group from 2002-2003 on the three outcomes, for replication purposes. For both comparisons, the authors report multi-level modelling analyses regarding (1) immediate effects after ROE completion at the end of the school year (pretest to post-test) and (2) long-term ROE effects up to three years after post-test. ROE had replicated, beneficial effects on all teacher-rated outcomes, which were generally maintained or further improved across follow-up. However, ROE had almost no statistically significant or replicated effects on student-rated outcomes. This is the first evaluation to suggest that ROE appears effective when implemented on a large scale under real-world delivery conditions. PMID- 24956431 TI - Transforming Child and Youth Mental Health Care via Innovative Technological Solutions. AB - Live interactive videoconferencing and other technologies offer innovative opportunities for effective delivery of specialized child and adolescent mental health services. In this article, an example of a comprehensive telepsychiatry program is presented to highlight a variety of capacity-building initiatives that are responsive to community needs and cultures; these initiatives are allowing children, youth and caregivers to access otherwise-distant specialist services within their home communities. Committed, enthusiastic champions, adequate funding and infrastructure, creativity and a positive attitude represent key elements in the adaptation of this demonstrated user-friendly modality. PMID- 24956432 TI - Faith in the goodness of people. PMID- 24956433 TI - Clostridium difficile ribotype 126 in southern Taiwan: a cluster of three symptomatic cases. AB - INTRODUCTION: Several virulent Clostridium difficile clones, designated as polymerase chain reaction (PCR) ribotypes 017, 027, or 078, are well recognized in western countries. However, the ribotype distribution of clinical C. difficile isolates in Taiwan remains unclear. METHOD: Between 2010 and 2012, we identified three patients with C. difficile-associated diarrhea (CDAD) at a hospital in southern Taiwan. The C. difficile strains isolated from these patients were further characterized by PCR detection of tcdA, tcdB, tcdC, cdtA, and cdtB, toxinotyping, multilocus sequence typing, ribotyping and repetitive-based PCR. RESULTS: Three C. difficile strains harbored tcdCDelta39 and belonged to multilocus sequence typing 11 (ST11), toxinotype V, and ribotype 126 (a ribotype 078-like clone). Notably, one patient developed pseudomembranous colitis and recurrent CDAD. These three isolates were noted between January 2012 and June 2012 and were identical, as evidenced by repetitive sequence-based PCR, suggestive of case clustering. CONCLUSION: A hypervirulent C. difficile clone, ribotype 126, causing pseudomembranous colitis and recurrent CDAD, is present in southern Taiwan. PMID- 24956434 TI - Strain dynamics of ultrathin VO2 film grown on TiO2 (001) and the associated phase transition modulation. AB - Tuning the metal insulator transition (MIT) behavior of VO2 film through the interfacial strain is effective for practical applications. However, the mechanism for strain-modulated MIT is still under debate. Here we directly record the strain dynamics of ultrathin VO2 film on TiO2 substrate and reveal the intrinsic modulation process by means of synchrotron radiation and first principles calculations. It is observed that the MIT process of the obtained VO2 films can be modulated continuously via the interfacial strain. The relationship between the phase transition temperature and the strain evolution is established from the initial film growth. From the interfacial strain dynamics and theoretical calculations, we claim that the electronic orbital occupancy is strongly affected by the interfacial strain, which changes also the electron electron correlation and controls the phase transition temperature. These findings open the possibility of an active tuning of phase transition for the thin VO2 film through the interfacial lattice engineering. PMID- 24956435 TI - Stranger in a strange land: Ibero-American strain of Mycobacterium tuberculosis in Tibet, China. AB - The Latin-American-Mediterranean (LAM) family is among the largest, diverse and intriguing within Mycobacterium tuberculosis. Widespread in some world regions, as justly reflected by its name, LAM remains in the shadow of the Beijing and East-African Indian families in East Asia. Here, we applied evolutionarily robust markers to the spoligotyped collection of 699 M. tuberculosis clinical isolates recovered from tuberculosis (TB) patients in different provinces across China between 2005 and 2013. As a result, only two isolates were assigned to LAM, hence we conclude that this family has a negligible impact on TB transmission in China. Interestingly, these two isolates represented two grand sublineages within LAM: RD115 and RD-Rio/RD174. Our results highlight the great caution to be taken when interpreting spoligotyping profiles with large deleted blocks. Here, three geographically distant Chinese isolates of spoligotype SIT803 were excluded from LAM. This is in clear contrast with described SIT803 isolates of the LAM family in Russia and Georgia (Mokrousov et al., 2014; Niemann et al., 2010). Interestingly, a drug resistant isolate of the Ibero-American LAM RD-Rio sublineage was recovered from TB patient of Tibetan ethnicity, a resident in the Lhasa district in Tibet. An additional in-depth analysis by whole genome sequencing might help to understand the evolutionary history of this isolate and its possible route to the rural setting of the Tibetan highlands. PMID- 24956437 TI - Infectious prion diseases in humans: cannibalism, iatrogenicity and zoonoses. AB - In contrast with other neurodegenerative disorders associated to protein misfolding, human prion diseases include infectious forms (also called transmitted forms) such as kuru, iatrogenic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease. The transmissible agent is thought to be solely composed of the abnormal isoform (PrP(Sc)) of the host-encoded prion protein that accumulated in the central nervous system of affected individuals. Compared to its normal counterpart, PrP(Sc) is beta-sheet enriched and aggregated and its propagation is based on an autocatalytic conversion process. Increasing evidence supports the view that conformational variations of PrP(Sc) encoded the biological properties of the various prion strains that have been isolated by transmission studies in experimental models. Infectious forms of human prion diseases played a pivotal role in the emergence of the prion concept and in the characterization of the very unconventional properties of prions. They provide a unique model to understand how prion strains are selected and propagate in humans. Here, we review and discuss how genetic factors interplay with strain properties and route of transmission to influence disease susceptibility, incubation period and phenotypic expression in the light of the kuru epidemics due to ritual endocannibalism, the various series iatrogenic diseases secondary to extractive growth hormone treatment or dura mater graft and the epidemics of variant Creutzfeldt-Jakob disease linked to dietary exposure to the agent of bovine spongiform encephalopathy. PMID- 24956436 TI - Biomarkers for virus-induced hepatocellular carcinoma (HCC). AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and is advanced by severe viral hepatitis B or C (HBV or HCV) as well as alcoholic liver disease. Many patients with early disease are asymptomatic therefore HCC is frequently diagnosed late requiring costly surgical resection or transplantation. The available non-invasive detections systems are based on the clinical utility of alpha fetoprotein (AFP) measurement, together with ultrasound and other more sensitive imaging techniques. The hallmark of liver disease and its propensity to develop into fully blown HCC is depended on several factors including the host genetic make-up and immune responses. While common symptoms involve diarrhea, bone pain, dyspnea, intraperitoneal bleeding, obstructive jaundice, and paraneoplastic syndrome, the evolution of cell and immune markers is important to understand viral induced liver cancers in humans. The circulating miRNA, cell and immune based HCC biomarkers are imperative candidates to successfully develop strategies to restrain liver injury. The current molecular genetics and proteomic analysis have lead to the identification of number of key biomarkers for HCC for earlier diagnosis and more effective treatment of HCC patients. In this review article, we provide latest updates on the biomarkers of HBV or HCV-associated HCC and their co-evolutionary relationship with liver cancer. PMID- 24956438 TI - Extracts from New Zealand Undaria pinnatifida Containing Fucoxanthin as Potential Functional Biomaterials against Cancer in Vitro. AB - This study tested extracts from New Zealand seaweed Undaria pinnatifida containing fucoxanthin, in parallel with pure fucoxanthin, in nine human cancer cell lines, for anticancer activity. Growth inhibition effects of extracts from Undaria pinnatifida were found in all types of cancer cell lines in dose- and time- dependent manners. Cytotoxicity of fucoxanthin in three human non-cancer cell lines was also tested. Compared with pure fucoxanthin, our extracts containing low level of fucoxanthin were found to be more effective in inhibiting the growth of lung carcinoma, colon adenocarcinoma and neuroblastoma. Our results suggest that fucoxanthin is a functional biomaterial that may be used as a chemopreventive phytochemical or in combination chemotherapy. Furthermore, we show for the first time that some unknown compounds with potential selective anti cancer effects may exist in extracts of New Zealand Undaria pinnatifida, and New Zealand Undaria pinnatifida could be used as a source for either functional biomaterial extraction or production of functional food. PMID- 24956439 TI - HaCaT Keratinocytes Response on Antimicrobial Atelocollagen Substrates: Extent of Cytotoxicity, Cell Viability and Proliferation. AB - The effective and widely tested biocides: Benzalkonium chloride, bronopol, chitosan, chlorhexidine and irgasan were added in different concentrations to atelocollagen matrices. In order to assess how these antibacterial agents influence keratinocytes cell growth, cell viability and proliferation were determined by using MTT assay. Acquired data indicated a low toxicity by employing any of these chemical substances. Furthermore, cell viability and proliferation were comparatively similar to the samples where there were no biocides. It means that regardless of the agent, collagen-cell-attachment properties are not drastically affected by the incorporation of those biocides into the substrate. Therefore, these findings suggest that these atelocollagen substrates enhanced by the addition of one or more of these agents may render effectiveness against bacterial stains and biofilm formation, being the samples referred to herein as "antimicrobial substrates" a promising view in the design of novel antimicrobial biomaterials potentially suitable for tissue engineering applications. PMID- 24956440 TI - Smooth muscle cell functionality on collagen immobilized polycaprolactone nanowire surfaces. AB - Inhibition of smooth muscle cell (SMC) proliferation and preservation of a differentiated state are important aspects in the management, avoidance and progression of vascular diseases. An understanding of the interaction between SMCs and the biomaterial involved is essential for a successful implant. In this study, we have developed collagen immobilized nanostructured surfaces with controlled arrays of high aspect ratio nanowires for the growth and maintenance of human aortic SMCs. The nanowire surfaces were fabricated from polycaprolactone and were immobilized with collagen. The objective of this study is to reveal how SMCs interact with collagen immobilized nanostructures. The results indicate significantly higher cellular adhesion on nanostructured and collagen immobilized surfaces; however, SMCs on nanostructured surfaces exhibit a more elongated phenotype. The reduction of MTT was significantly lower on nanowire (NW) and collagen immobilized NW (colNW) surfaces, suggesting that SMCs on nanostructured surfaces may be differentiated and slowly dividing. Scanning electron microscopy results reveal that SMCs on nanostructured surfaces are more elongated and that cells are interacting with the nano-features on the surface. After providing differentiation cues, heavy chain myosin and calponin, specific to a contractile SMC phenotype, are upregulated on collagen immobilized surfaces. These results suggest that nanotopography affects cell adhesion, proliferation, as well as cell elongation, while collagen immobilized surfaces greatly affect cell differentiation. PMID- 24956441 TI - Hydrodynamically lubricated and grooved biomimetic self-adapting surfaces. AB - In many machines and mechanical components, there is a need for new bearing technologies to reduce friction and wear, and provide precision control of motion when the load is varied. This can be provided by electronically controlled actuators and sensors on the surfaces, but then the system reliability can be an issue. In contrast, biomimetic surfaces can be created that adapt mechanically to variations in load. This work uses numerical methods to research the use of self adapting surfaces for bearings that are based on the deformable nature of biological materials such as articular cartilage. These surfaces are designed to change their profiles to achieve a desired behavior, without any external control. The surfaces change their profile to control the film height and tilt of the bearing to a near constant value for different loads. If the surfaces are tilted, the grooved self-adapting surfaces will also react with a larger restoring moment than a conventional grooved surface. These surfaces could be beneficial to applications where electrical systems and controls are not feasible. PMID- 24956444 TI - Understanding bistability in yeast glycolysis using general properties of metabolic pathways. AB - Glycolysis is the central pathway in energy metabolism in the majority of organisms. In a recent paper, van Heerden et al. showed experimentally and computationally that glycolysis can exist in two states, a global steady state and a so-called imbalanced state. In the imbalanced state, intermediary metabolites accumulate at low levels of ATP and inorganic phosphate. It was shown that Baker's yeast uses a peculiar regulatory mechanism--via trehalose metabolism -to ensure that most yeast cells reach the steady state and not the imbalanced state. RESULTS: Here we explore the apparent bistable behaviour in a core model of glycolysis that is based on a well-established detailed model, and study in great detail the bifurcation behaviour of solutions, without using any numerical information on parameter values. CONCLUSION: We uncover a rich suite of solutions, including so-called imbalanced states, bistability, and oscillatory behaviour. The techniques employed are generic, directly suitable for a wide class of biochemical pathways, and could lead to better analytical treatments of more detailed models. PMID- 24956442 TI - Microscale assembly directed by liquid-based template. AB - A liquid surface established by standing waves is used as a dynamically reconfigurable template to assemble microscale materials into ordered, symmetric structures in a scalable and parallel manner. The broad applicability of this technology is illustrated by assembling diverse materials from soft matter, rigid bodies, individual cells, cell spheroids and cell-seeded microcarrier beads. PMID- 24956443 TI - The involvement of sigma1 receptors in donepezil-induced rescue of hippocampal LTP impaired by beta-amyloid peptide. AB - Donepezil is a potent acetylcholinesterase inhibitor used for the treatment of Alzheimer's disease (AD). Additional therapeutically relevant target for donepezil is sigma1 receptor (Sig1-R). Beta-amyloid peptide (Abeta) is believed to contribute to the pathogenesis of AD. In our previous work (Kapai et al., 2012), we have shown that donepezil antagonizes the suppressive action of Abeta(1 42) on long-term potentiation (LTP) in rat hippocampal slices. The purpose of the present study was to determine whether Sig1-R is involved into the mechanisms of donepezil action. For this purpose, we have tested whether agonist of Sig1-R PRE 084 mimics, and antagonist of Sig1-R haloperidol abolishes the effect of donepezil. Population spikes (PSs) were recorded from the pyramidal layer of the CA1 region of rat hippocampal slices. Drugs were applied by addition to the perfusate starting 15 min before and ending 5 min after the tetanus. In the control group, the amplitude of PS 30 min post-tetanus reached 153+/-10%. Abeta (200 nM) markedly suppressed the LTP magnitude or even caused the suppression of baseline PS (82+/-8%, P<0.001). This suppression of LTP could be markedly prevented when 1 MUM donepezil was co-administered with Abeta (136+/-11%, P<0.05). Further, we co-administered three substances: Abeta, donepezil and 0.5 MUM haloperidol and have found that haloperidol antagonized the stimulating effect of donepezil on LTP (92+/-6%, P<0.05). Agonist of Sig1-R PRE-084 (0.1-10 MUM) enhanced control LTP and abolished the inhibitory effect of Abeta on LTP in a concentration-dependent manner. The amplitude of PS 30 min post-tetanus reached 183+/-7% (P<0.01) for 10 MUM PRE-084. The results suggest that activation of Sig1 R is involved into the mechanisms of donepezil-induced rescue of hippocampal LTP impaired by Abeta. PMID- 24956445 TI - Prostate cancer cells preferentially home to osteoblast-rich areas in the early stages of bone metastasis: evidence from in vivo models. AB - It has been suggested that metastasis-initiating cells gain a foothold in bone by homing to a metastastatic microenvironment (or "niche"). Whereas the precise nature of this niche remains to be established, it is likely to contain bone cell populations including osteoblasts and osteoclasts. In the mouse tibia, the distribution of osteoblasts on endocortical bone surfaces is non-uniform, and we hypothesize that studying co-localization of individual tumor cells with resident cell populations will reveal the identity of critical cellular components of the niche. In this study, we have mapped the distribution of three human prostate cancer cell lines (PC3-NW1, LN-CaP, and C4 2B4) colonizing the tibiae of athymic mice following intracardiac injection and evaluated their interaction with potential metastatic niches. Prostate cancer cells labeled with the fluorescent cell membrane dye (Vybrant DiD) were found by two-photon microscopy to be engrafted in the tibiae in close proximity (~40 um) to bone surfaces and 70% more cancer cells were detected in the lateral compared to the medial endocortical bone regions. This was associated with a 5-fold higher number of osteoblasts and 7-fold higher bone formation rate on the lateral endocortical bone surface compared to the medial side. By disrupting cellular interactions mediated by the chemokine (C-X-C motif) receptor 4 (CXCR4)/chemokine ligand 12 (CXCL12) axis with the CXCR4 inhibitor AMD3100, the preferential homing pattern of prostate cancer cells to osteoblast-rich bone surfaces was disrupted. In this study, we map the location of prostate cancer cells that home to endocortical regions in bone and our data demonstrate that homing of prostate cancer cells is associated with the presence and activity of osteoblast lineage cells, and suggest that therapies targeting osteoblast niches should be considered to prevent development of incurable prostate cancer bone metastases. PMID- 24956446 TI - Enhancement of optical Faraday effect of nonanuclear Tb(III) complexes. AB - The effective magneto-optical properties of novel nonanuclear Tb(III) complexes with Tb-O lattice (specifically, [Tb9(sal-R)16(MU-OH)10](+)NO3(-), where sal-R = alkyl salicylate (R = -CH3 (Me), -C2H5 (Et), -C3H7 (Pr), or -C4H9 (Bu)) are reported. The geometrical structures of these nonanuclear Tb(III) complexes were characterized using X-ray single-crystal analysis and shape-measure calculation. Optical Faraday rotation was observed in nonanuclear Tb(III) complexes in the visible region. The Verdet constant per Tb(III) ion of the Tb9(sal-Me) complex is 150 times larger than that of general Tb(III) oxide glass. To understand their large Faraday rotation, electron paramagnetic resonance measurements of Gd(III) complexes were carried out. In this Report, the magneto-optical relation to the coordination geometry of Tb ions is discussed. PMID- 24956448 TI - Protein degradation and protection observed in the presence of novel wound dressing components. AB - Chronic wounds typically have excessive levels of matrix metalloproteinases (MMPs) and proinflammatory cytokines that impair healing. Reducing these detrimental proteins may be key to healing chronic wounds. Proprietary protease blends were formulated specifically to degrade excessive amounts of proinflammatory factors that could prevent wound healing. Applications of protease-containing wound dressings to acute and chronic wounds have been observed clinically to resolve inflammation and appear to aid healing. The purpose of this study was to test in vitro a deliberate blend of proteases for the ability to deactivate or activate known proteins associated with inflammation or healing. Purified human target proteins were incubated with test and control solutions and samples removed at various time points. Blinded samples were tested using a novel infrared protein multiplex sandwich-ELISA-type array technique. Many proinflammatory proteins such as MMPs, cytokines and chemokines were susceptible to degradation. Many proteins such as growth factors, cytokines and TIMP1 were resistant to degradation. Not all proinflammatory proteins were deactivated. Family protein structure did not appear to affect susceptibility to degradation or deactivation. These results suggest that specific protease containing wound dressings appear to reduce multiple detrimental components which may disrupt their deleterious effects on the wound bed and microenvironment. By improving the wound microenvironment through the use of definitive proteases, these novel wound dressings may help transition wounds into the subsequent phase of healing. PMID- 24956447 TI - Is macroporosity absolutely required for preliminary in vitro bone biomaterial study? A comparison between porous materials and flat materials. AB - Porous materials are highly preferred for bone tissue engineering due to space for blood vessel ingrowth, but this may introduce extra experimental variations because of the difficulty in precise control of porosity. In order to decide whether it is absolutely necessary to use porous materials in in vitro comparative osteogenesis study of materials with different chemistries, we carried out osteoinductivity study using C3H/10T1/2 cells, pluripotent mesenchymal stem cells (MSCs), on seven material types: hydroxyapatite (HA), alpha-tricalcium phosphate (alpha-TCP) and b-tricalcium phosphate (beta-TCP) in both porous and dense forms and tissue culture plastic. For all materials under test, dense materials give higher alkaline phosphatase gene (Alp) expression compared with porous materials. In addition, the cell density effects on the 10T1/2 cells were assessed through alkaline phosphatase protein (ALP) enzymatic assay. The ALP expression was higher for higher initial cell plating density and this explains the greater osteoinductivity of dense materials compared with porous materials for in vitro study as porous materials would have higher surface area. On the other hand, the same trend of Alp mRNA level (HA > beta-TCP > alpha TCP) was observed for both porous and dense materials, validating the use of dense flat materials for comparative study of materials with different chemistries for more reliable comparison when well-defined porous materials are not available. The avoidance of porosity variation would probably facilitate more reproducible results. This study does not suggest porosity is not required for experiments related to bone regeneration application, but emphasizes that there is often a tradeoff between higher clinical relevance, and less variation in a less complex set up, which facilitates a statistically significant conclusion. Technically, we also show that the base of normalization for ALP activity may influence the conclusion and there may be ALP activity from serum, necessitating the inclusion of "no cell" control in ALP activity assay with materials. These explain the opposite conclusions drawn by different groups on the effect of porosity. PMID- 24956449 TI - Biocompatible polymer/quantum dots hybrid materials: current status and future developments. AB - Quantum dots (QDs) are nanometer-sized semiconductor particles with tunable fluorescent optical property that can be adjusted by their chemical composition, size, or shape. In the past 10 years, they have been demonstrated as a powerful fluorescence tool for biological and biomedical applications, such as diagnostics, biosensing and biolabeling. QDs with high fluorescence quantum yield and optical stability are usually synthesized in organic solvents. In aqueous solution, however, their metallic toxicity, non-dissolubility and photo luminescence instability prevent the direct utility of QDs in biological media. Polymers are widely used to cover and coat QDs for fabricating biocompatible QDs. Such hybrid materials can provide solubility and robust colloidal and optical stability in water. At the same time, polymers can carry ionic or reactive functional groups for incorporation into the end-use application of QDs, such as receptor targeting and cell attachment. This review provides an overview of the recent development of methods for generating biocompatible polymer/QDs hybrid materials with desirable properties. Polymers with different architectures, such as homo- and co-polymer, hyperbranched polymer, and polymeric nanogel, have been used to anchor and protect QDs. The resulted biocompatible polymer/QDs hybrid materials show successful applications in the fields of bioimaging and biosensing. While considerable progress has been made in the design of biocompatible polymer/QDs materials, the research challenges and future developments in this area should affect the technologies of biomaterials and biosensors and result in even better biocompatible polymer/QDs hybrid materials. PMID- 24956450 TI - Ionic and polyampholyte N-isopropylacrylamide-based hydrogels prepared in the presence of imprinting ligands: stimuli-responsiveness and adsorption/release properties. AB - The conformation of the imprinted pockets in stimulus-responsive networks can be notably altered when the stimulus causes a volume phase transition. Such a tunable affinity for the template molecule finds interesting applications in the biomedical and drug delivery fields. Nevertheless, the effect that the binding of the template causes on the stimuli-responsiveness of the network has barely been evaluated. In this work, the effect of two ionic drugs used as templates, namely propranolol hydrochloride and ibuprofen sodium, on the responsiveness of N isopropylacrylamide-based hydrogels copolymerized with acrylic acid (AAc) and N (3-aminopropyl) methacrylamide (APMA) and on their ability to rebind and to control the release of the template was evaluated. The degree of swelling and, in some cases, energetics (HS-DSC) of the transitions were monitored as a function of temperature, pH, and concentration of drug. Marked decrease in the transition temperature of the hydrogels, accompanied by notable changes in the transition width, was observed in physiological NaCl solutions and after the binding of the drug molecules, which reveals relevant changes in the domain structure of the hydrogels as the charged groups are shielded. The ability of the hydrogels to rebind propranolol or ibuprofen was quantified at both 4 and 37 degrees C and at two different drug concentrations, in the range of those that cause major changes in the network structure. Noticeable differences between hydrogels bearing AAc or APMA and between imprinted and non-imprinted networks were also observed during the release tests in NaCl solutions of various concentrations. Overall, the results obtained evidence the remarkable effect of the template molecules on the responsiveness of intelligent imprinted hydrogels. PMID- 24956451 TI - Thrombin production and human neutrophil elastase sequestration by modified cellulosic dressings and their electrokinetic analysis. AB - Wound healing is a complex series of biochemical and cellular events. Optimally, functional material design addresses the overlapping acute and inflammatory stages of wound healing based on molecular, cellular, and bio-compatibility issues. In this paper the issues addressed are uncontrolled hemostasis and inflammation which can interfere with the orderly flow of wound healing. In this regard, we review the serine proteases thrombin and elastase relative to dressing functionality that improves wound healing and examine the effects of charge in cotton/cellulosic dressing design on thrombin production and elastase sequestration (uptake by the wound dressing). Thrombin is central to the initiation and propagation of coagulation, and elastase is released from neutrophils that can function detrimentally in a stalled inflammatory phase characteristic of chronic wounds. Electrokinetic fiber surface properties of the biomaterials of this study were determined to correlate material charge and polarity with function relative to thrombin production and elastase sequestration. Human neutrophil elastase sequestration was assessed with an assay representative of chronic wound concentration with cotton gauze cross-linked with three types of polycarboxylic acids and one phosphorylation finish; thrombin production, which was assessed in a plasma-based assay via a fluorogenic peptide substrate, was determined for cotton, cotton-grafted chitosan, chitosan, rayon/polyester, and two kaolin-treated materials including a commercial hemorrhage control dressing (QuickClot Combat Gauze). A correlation in thrombin production to zeta potential was found. Two polycarboxylic acid cross linked and a phosphorylated cotton dressing gave high elastase sequestration. PMID- 24956452 TI - Molecular Design Properties of OxyVita Hemoglobin, a New Generation Therapeutic Oxygen Carrier: A Review. AB - OxyVita Hb is a new generation hemoglobin based oxygen carrier (HBOC) produced through modification of a zero-linked polymerization mechanism using activators which incorporate cross-linked bovine tetramer hemoglobin into "super-polymeric" macromolecules (Average molecular weight = 17 MDa) for the purpose of oxygen delivery when whole blood or packed red cells are not available. This molecular design approach was generated in order to address several fundamental biochemical and physiological weaknesses of previous generations of HBOCs. Observation during pre-clinical and clinical studies provided evidence that these early generation acellular HBOCs were directly associated with loss of retention within the circulatory system, extravasation across endothelial tissue membranes due to their small molecular size leading to arterial and venous vasoconstriction with coupled increases in mean arterial pressure (MAP). The inherent increase in molecular size and structural stability of the OxyVita Hb is a direct response to addressing these serious weaknesses that have occurred during the evolution of HBOC development within the past two decades. The nature of the zero-linked synthetic route eliminates any chemical linkers remaining in the product, eliminating side reaction concerns, such as reversibility and decomposition due to weak chemical bonds, dependency on temperature and pressure, and residual toxicity. PMID- 24956453 TI - Thoracic paravertebral block and its effects on chronic pain and health-related quality of life after modified radical mastectomy. AB - BACKGROUND AND OBJECTIVES: Patients undergoing breast cancer surgery frequently experience chronic postoperative pain. The primary objective of this randomized study was to determine if thoracic paravertebral block (TPVB) reduced the incidence of chronic pain after a modified radical mastectomy (MRM) when compared with general anesthesia (GA). METHODS: One hundred eighty women undergoing MRM were randomized to 1 of 3 study groups: group 1: standardized GA, group 2: GA with a single-injection TPVB and placebo paravertebral infusion, and group 3: GA with a continuous TPVB. Outcomes assessed postoperatively included acute postoperative pain and analgesic consumption and, at 3 and 6 months, the incidence and severity of chronic pain and physical and mental health-related quality of life (HRQOL). RESULTS: There was no significant difference in the incidence of chronic pain at 3 months (P = 0.13) and 6 months (P = 0.79) after the MRM between the study groups. The relative risk of developing chronic pain (P = 0.25) was also similar between the groups. There was no difference in acute pain (P = 0.22) or postoperative analgesic consumption (P = 0.67) between the groups. Nevertheless, differences were observed in chronic pain-related secondary outcome variables. The TPVB groups reported lower chronic pain scores (P < 0.05), exhibited fewer symptoms and signs of chronic pain (P <= 0.01), and also experienced better physical and mental HRQOL than did the GA group. Chronic pain scores also decreased with time in all study groups (P < 0.05). CONCLUSIONS: There is no significant difference in the incidence or relative risk of chronic pain at 3 and 6 months after an MRM when TPVB is used in conjunction with GA. Nevertheless, patients who receive a TPVB report less severe chronic pain, exhibit fewer symptoms and signs of chronic pain, and also experience better physical and mental HRQOL. PMID- 24956456 TI - Bio-inspired titanium dioxide materials with special wettability and their applications. PMID- 24956454 TI - Adherence to guidelines for the management of local anesthetic systemic toxicity is improved by an electronic decision support tool and designated "Reader". AB - BACKGROUND AND OBJECTIVES: A hardcopy or paper cognitive aid has been shown to improve performance during the management of simulated local anesthetic systemic toxicity (LAST) when given to the team leader. However, there remains room for improvement to ensure a system that can achieve perfect adherence to the published guidelines for LAST management. Recent research has shown that implementing a checklist via a designated reader may be of benefit. Accordingly, we sought to investigate the effect of an electronic decision support tool (DST) and designated "Reader" role on team performance during an in situ simulation of LAST. METHODS: Participants were randomized to Reader + DST (n = 16, rDST) and Control (n = 15, memory alone). The rDST group received the assistance of a dedicated Reader on the response team who was equipped with an electronic DST. The primary outcome measure was adherence to guidelines. RESULTS: For overall and critical percent correct scores, the rDST group scored higher than Control (99.3% vs 72.2%, P < 0.0001; 99.5% vs 70%, P < 0.0001, respectively). In the LAST scenario, 0 (0%) of 15 in the control group performed 100% of critical management steps, whereas 15 (93.8%) of 16 in the rDST group did so (P < 0.0001). CONCLUSIONS: In a prospective, randomized single-blinded study, a designated Reader with an electronic DST improved adherence to guidelines in the management of an in situ simulation of LAST. Such tools are promising in the future of medicine, but further research is needed to ensure the best methods for implementing them in the clinical arena. PMID- 24956455 TI - Clinical accuracy and safety using the SynchroMed II intrathecal drug infusion pump. AB - BACKGROUND AND OBJECTIVES: We evaluated the infusion accuracy and device-related safety of implantable drug infusion pumps in subjects with chronic pain or severe spasticity. METHODS: Nine centers in the United States enrolled patients receiving intrathecal drug delivery systems to manage chronic pain and/or severe spasticity. Infusion accuracy was assessed at 6 and 12 months by comparing syringe-measured delivered volumes to programmer-predicted volumes. Safety was evaluated through analysis of adverse events. Separate laboratory testing conducted by the manufacturer also evaluated infusion accuracy. RESULTS: Eighty of 82 enrolled subjects were implanted. Sixty-five and 54 subjects, respectively, were analyzable for accuracy at 6 and 12 months. On average at 6 months, the pumps were measured to have delivered 1% more than the programmed delivery volume. Analyzed on a per-refill basis, the pumps delivered, on average, 2.5% more than the programmed delivery volume. Differences between per-refill means versus per-subject cumulative means were due to limitations in clinicians' ability to precisely visualize single small syringe-volume differences, or possibly incomplete withdrawal of fluid from the pump. Laboratory testing demonstrated a per-refill mean accuracy error of minus 2.4%. Because average observed flow-rate error at 6 and 12 months (1% overinfusion) was derived from pump residual volume measurements by syringe and carried out in a clinical setting, clinical volume ratios were larger than direct volume measurements by weight observed in the laboratory. No deaths, permanent injuries, or unanticipated adverse device effects occurred. CONCLUSIONS: The pump accurately delivered intrathecal medication in the clinical setting of this study. Adverse events were similar in nature and severity to those described in the product labeling and literature. PMID- 24956457 TI - Ultrasound and shockwave therapy for acute fractures in adults. AB - BACKGROUND: The morbidity and socioeconomic costs of fractures are considerable. The length of time to healing is an important factor in determining a person's recovery after a fracture. Ultrasound may have a therapeutic role in reducing the time to union after fracture. This is an update of a review previously published in February 2012. OBJECTIVES: To assess the effects of low-intensity ultrasound (LIPUS), high-intensity focused ultrasound (HIFUS) and extracorporeal shockwave therapies (ECSW) as part of the treatment of acute fractures in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (2 June 2014), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 5), MEDLINE (1946 to May Week 3 2014), EMBASE (1980 to 2014 Week 22), trial registers and reference lists of articles. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials evaluating ultrasound treatment in the management of acute fractures in adults. Studies had to include participants over 18 years of age with acute fractures, reporting outcomes such as function; time to union; non-union; secondary procedures such as for fixation or delayed union or non-union; adverse effects; pain; costs; and patient adherence. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from the included studies. Treatment effects were assessed using mean differences, standardised mean differences or risk ratios using a fixed-effect model, except where there was substantial heterogeneity, when data were pooled using a random-effects model. Results from 'worst case' analyses, which gave more conservative estimates of treatment effects for time to fracture union, are reported in preference to those from 'as reported' analyses. MAIN RESULTS: We included 12 studies, involving 622 participants with 648 fractures. Eight studies were randomised placebo-controlled trials, two were randomised controlled trials without placebo controls, one was a quasi-randomised placebo-controlled trial and one was a quasi-randomised controlled trial without placebo control. Eleven trials tested LIPUS and one trial tested ECSW. Four trials included participants with conservatively treated upper limb complete fractures and six trials included participants with lower limb complete fractures; these were surgically fixed in four trials. The remaining two trials reported results for conservatively treated tibial stress fractures.'Risk of bias' assessment of the included studies was hampered by the poor reporting of methods, frequently resulting in the risk of bias of individual domains being judged as 'unclear'. Both quasi-randomised studies were at high risk of bias, including selection and attrition bias. Three studies were at low risk of selection bias relating to allocation concealment the majority of studies were at low risk of performance bias as they employed a form of intervention blinding.Only limited data were available from three of only four studies reporting on functional outcome. One study of complete fractures found little evidence of a difference between the two groups in the time to return to work (mean difference (MD) 1.95 days favouring control, 95% confidence interval (CI) -2.18 to 6.08; 101 participants). Pooled data from two studies found LIPUS did not significantly affect the time to return to training or duty in soldiers or midshipmen with stress fractures (MD -8.55 days, 95% CI -22.71 to 5.61; 93 participants).We adopted a conservative strategy for data analysis that was more likely to underestimate than to overestimate a benefit of the intervention. After pooling results from eight studies (446 fractures), the data showed no statistically significant reduction in time to union of complete fractures treated with LIPUS (standardised mean difference (SMD) -0.47, 95% CI -1.14 to 0.20). This result could include a clinically important benefit or harm, and should be seen in the context of the highly significant statistical heterogeneity (I2 = 90%). This heterogeneity was not explained by the a priori subgroup analyses (upper limb versus lower limb fracture, smoking status). An additional subgroup analysis comparing conservatively and operatively treated fractures raised the possibility that LIPUS may be effective in reducing healing time in conservatively managed fractures, but the test for subgroup differences did not confirm a significant difference between the subgroups.Pooled results from five of the eight trials (333 fractures) reporting proportion of delayed union or non union showed no significant difference between LIPUS and control (10/168 versus 13/165; RR 0.75; 95% CI 0.24 to 2.28). Adverse effects directly associated with LIPUS and associated devices were found to be few and minor, and compliance with treatment was generally good. One study reporting on pain scores found no difference between groups at eight weeks (101 participants).One quasi-randomised study found no significant difference in non-union at 12 months between internal fixation supplemented with ECSW and internal fixation alone (3/27 versus 6/30; RR 0.56, 95% CI 0.15 to 2.01). There was a clinically small but statistically significant difference in the visual analogue scores for pain in favour of ECSW at three month follow-up (MD -0.80, 95% CI -1.23 to -0.37). The only reported complication was infection, with no significant difference between the two groups. AUTHORS' CONCLUSIONS: While a potential benefit of ultrasound for the treatment of acute fractures in adults cannot be ruled out, the currently available evidence from a set of clinically heterogeneous trials is insufficient to support the routine use of this intervention in clinical practice. Future trials should record functional outcomes and follow-up all trial participants. PMID- 24956458 TI - Nitrosamine formation in amine scrubbing at desorber temperatures. AB - Amine scrubbing is a thermodynamically efficient and industrially proven method for carbon capture, but amine solvents can nitrosate in the desorber, forming potentially carcinogenic nitrosamines. The kinetics of reactions involving nitrite and monoethanolamine (MEA), diethanolamine (DEA), methylethanolamine (MMEA), and methyldiethanolamine (MDEA) were determined under desorber conditions. The nitrosations of MEA, DEA, and MMEA are first order in nitrite, carbamate species, and hydronium ion. Nitrosation of MDEA, a tertiary amine, is not catalyzed by the addition of CO2 since it cannot form a stable carbamate. Concentrated and CO2 loaded MEA was blended with low concentrations of N-(2 hydroxyethyl) glycine (HeGly), hydroxyethyl-ethylenediamine (HEEDA), and DEA, secondary amines common in MEA degradation. Nitrosamine yield was proportional to the concentration of secondary amine and was a function of CO2 loading and temperature. Blends of tertiary amines with piperazine (PZ) showed n nitrosopiperazine (MNPZ) yields close to unity, validating the slow nitrosation rates hypothesized for tertiary amines. These results provide a useful tool for estimating nitrosamine accumulation over a range of amine solvents. PMID- 24956459 TI - Resonance Raman spectroscopy on [NiFe] hydrogenase provides structural insights into catalytic intermediates and reactions. AB - [NiFe] hydrogenases catalyze the reversible cleavage of hydrogen and, thus, represent model systems for the investigation and exploitation of emission-free energy conversion processes. Valuable information on the underlying molecular mechanisms can be obtained by spectroscopic techniques that monitor individual catalytic intermediates. Here, we employed resonance Raman spectroscopy and extended it to the entire binuclear active site of an oxygen-tolerant [NiFe] hydrogenase by probing the metal-ligand modes of both the Fe and, for the first time, the Ni ion. Supported by theoretical methods, this approach allowed for monitoring H-transfer from the active site and revealed novel insights into the so far unknown structure and electronic configuration of the hydrogen-binding intermediate of the catalytic cycle, thereby providing key information about catalytic intermediates and reactions of biological hydrogen activation. PMID- 24956461 TI - Exploring the potential of self-assembled mixed micelles in enhancing the stability and oral bioavailability of an acid-labile drug. AB - Oral delivery of many drugs is plagued with limited solubility and/or poor stability. This paper aimed to explore the performance of polymeric mixed micelles on solubilization, stabilization and bioavailability enhancement with stiripentol as model drug. Stiripentol-loaded mixed micelles were prepared by solvent-diffusion method: rapid dispersion of an ethanol solution containing stiripentol, monomethoxy poly(ethylene glycol)-b-poly(epsilon-caprolactone) and sodium oleate into water. Stiripentol micelles were characterized by the particle size, entrapment efficiency, in vitro drug release, TEM, DSC and FTIR. The pharmacokinetic profile of stiripentol was determined in rats after oral administration of stiripentol micelles. The obtained stiripentol micelles were 44.2 nm in size with an entrapment efficiency over 90%. It was shown that micelles substantially improved the solubility and gastric stability of stiripentol. The oral absorption of stiripentol was also enhanced to a great extent with a relative bioavailability of 157% and 444% to the commercial formulation (Diacomit(r)) and in-house suspensions. Mixed micelles assembled by di-block copolymer/sodium oleate exhibited a good potential in the improvement of drug stability and bioavailability. It should be a promising carrier for oral delivery of therapeuticals with solubility and stability issues. PMID- 24956460 TI - Tissue-specific expressed antibody variable gene repertoires. AB - Recent developments in genetic technologies allow deep analysis of the sequence diversity of immune repertoires, but little work has been reported on the architecture of immune repertoires in mucosal tissues. Antibodies are the key to prevention of infections at the mucosal surface, but it is currently unclear whether the B cell repertoire at mucosal surfaces reflects the dominant antibodies found in the systemic compartment or whether mucosal tissues harbor unique repertoires. We examined the expressed antibody variable gene repertoires from 10 different human tissues using RNA samples derived from a large number of individuals. The results revealed that mucosal tissues such as stomach, intestine and lung possess unique antibody gene repertoires that differed substantially from those found in lymphoid tissues or peripheral blood. Mutation frequency analysis of mucosal tissue repertoires revealed that they were highly mutated, with little evidence for the presence of naive B cells, in contrast to blood. Mucosal tissue repertoires possessed longer heavy chain complementarity determining region 3 loops than lymphoid tissue repertoires. We also noted a large increase in frequency of both insertions and deletions in the small intestine antibody repertoire. These data suggest that mucosal immune repertoires are distinct in many ways from the systemic compartment. PMID- 24956462 TI - Design and synthesis of a new series of cyclopropylamino-linking diarylpyrimidines as HIV non-nucleoside reverse transcriptase inhibitors. AB - A new series of 29 diarylpyrimidine analogues featuring a cyclopropylamino group between the pyrimidine scaffold and the aryl wing have been synthesized. All of the new compounds have been characterized by spectra analysis. The target molecules were evaluated for their in vitro anti-HIV activity with FDA-approved drugs as references. Some of the compounds exhibited moderate to potent activities against wild-type HIV-1. The compound 4-((4-((cyclopropylamino)(2,5 difluorophenyl)methyl)pyrimidin-2-yl)amino)benzonitrile (1e) displayed potent anti-HIV-1 activity against WT HIV-1 with an IC50 of 0.099 MUM and a selectivity index of 2302. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated. PMID- 24956463 TI - A novel approach to overcome multidrug resistance: utilization of P-gp mediated efflux of paclitaxel to attack neighboring vascular endothelial cells in tumors. AB - We tried to overcome the paclitaxel (PTX) resistance of cancer cells due to P glycoprotein (P-gp) overexpression in the in vivo anti-tumor chemotherapy by utilizing polyethylene glycol-modified liposomal paclitaxel (PL-PTX). First of all, established were PTX-resistant Colon-26 cancer cells (C26/PTX) overexpressing P-gp, which provided IC50 value of PTX solution about 30 times larger than that obtained for control C26 (C26/control) in the in vitro MTT assay. Western blot analysis confirmed P-gp expression in C26/PTX 10 times higher than that in C26/control, indicating that the resistance acquisition of C26/PTX to PTX would be ascribed to the enhanced efflux of PTX by P-gp overexpressed in C26/PTX. However, the in vivo anti-tumor effect of PL-PTX in C26/PTX-bearing mice was similar to that in C26/control-bearing mice. Double immunohistochemical staining of vascular endothelial cells and apoptotic cells within tumor tissues demonstrated that the apoptotic cell death was preferentially observed in vascular endothelial cells in C26/PTX tumors after intravenous administration of PL-PTX, while that was in tumor cells in C26/control tumors. These results suggest that the in vivo anti-tumor effect of PL-PTX in C26/PTX-bearing mice would be ascribed to the cytotoxic action of PTX pumped out of tumor cells by overexpressed P-gp to vascular endothelial cells in tumor tissues. PMID- 24956464 TI - Microbial degradation of crude oil hydrocarbons on organoclay minerals. AB - The role of organoclays in hydrocarbon removal during biodegradation was investigated in aqueous clay/oil microcosm experiments with a hydrocarbon degrading microorganism community. The clays used for this study were Na montmorillonite and saponite. These two clays were treated with didecyldimethylammonium bromide to produce organoclays which were used in this study. The study indicated that clays with high cation exchange capacity (CEC) such as Na-montmorillonite produced an organomontmorillonite that was inhibitory to biodegradation of the crude oil hydrocarbons. Extensive hydrophobic interaction between the organic phase of the organoclay and the crude oil hydrocarbons is suggested to render the hydrocarbons unavailable for biodegradation. However, untreated Na-montmorillonite was stimulatory to biodegradation of the hydrocarbons and is believed to have done so because of its high surface area for the accumulation of microbes and nutrients making it easy for the microbes to access the nutrients. This study indicates that unlike unmodified montmorillonites, organomontmorillonite may not serve any useful purpose in the bioremediation of crude oil spill sites where hydrocarbon removal by biodegradation is desired within a rapid time period. PMID- 24956465 TI - Weed seeds on clothing: a global review. AB - Weeds are a major threat to biodiversity including in areas of high conservation value. Unfortunately, people may be unintentionally introducing and dispersing weed seeds on their clothing when they visit these areas. To inform the management of these areas, we conducted a systematic quantitative literature review to determine the diversity and characteristics of species with seeds that can attach and be dispersed from clothing. Across 21 studies identified from systematic literature searches on this topic, seeds from 449 species have been recorded on clothing, more than double the diversity found in a previous review. Nearly all of them, 391 species, are listed weeds in one or more countries, with 58 classified as internationally-recognised environmental weeds. When our database was compared with weed lists from different countries and continents we found that clothing can carry the seeds of important regional weeds. A total of 287 of the species are listed as aliens in one or more countries in Europe, 156 are invasive species/noxious weeds in North America, 211 are naturalized alien plants in Australia, 97 are alien species in India, 33 are invasive species in China and 5 are declared weeds/invaders in South Africa. Seeds on the clothing of hikers can be carried to an average distance of 13 km, and where people travel in cars, trains, planes and boats, the seeds on their clothing can be carried much further. Factors that affect this type of seed dispersal include the type of clothing, the type of material the clothing is made from, the number and location of the seeds on plants, and seed traits such as adhesive and attachment structures. With increasing use of protected areas by tourists, including in remote regions, popular protected areas may be at great risk of biological invasions by weeds with seeds carried on clothing. PMID- 24956466 TI - Substitution patterns across alternatives as a source of preference heterogeneity in recreation demand models. AB - Recent stated choice studies have shown that, in a context of inter-alternative correlation, individuals can assess alternatives differently. This asymmetry in perception between alternatives with different levels of substitutability becomes one additional, but usually overlooked, source of observed preference heterogeneity. In the context of beach recreation in Mallorca, Spain, this paper extends the investigation on this source of heterogeneity to a revealed preference setting. While the substitution pattern existent across sites is accounted for by means of a nested logit model, nest-specific coefficients are estimated to evaluate the utilities associated with different groups of sites. The results provide empirical evidence to suggest that substitution patterns across alternatives are a statistically significant source of influence on preference heterogeneity leading to different marginal sensitivities for a number of site attributes. PMID- 24956467 TI - Cellulosic biofuels from crop residue and groundwater extraction in the US Plains: the case of Nebraska. AB - This study develops a model of crop residue (i.e. stover) supply and derived demand for irrigation water accounting for non-linear effects of soil organic matter on soil's water holding capacity. The model is calibrated for typical conditions in central Nebraska, United States, and identifies potential interactions between water and biofuel policies. The price offered for feedstock by a cost-minimizing plant facing that stover supply response is calculated. Results indicate that as biofuel production volumes increase, soil carbon depletion per unit of biofuel produced decreases. Consumption of groundwater per unit of biofuel produced first decreases and then increases (after a threshold of 363 dam(3) of biofuels per year) due to plants' increased reliance on the extensive margin for additional biomass. The analysis reveals a tension between biofuel and water policies. As biofuel production raises the economic benefits of relaxing water conservation policies (measured by the "shadow price" of water) increase. PMID- 24956468 TI - In-situ implant containing PCL-curcumin nanoparticles developed using design of experiments. AB - CONTEXT: Polymeric delivery system is useful in reducing pharmacokinetic limitations viz., poor absorption and rapid elimination associated with clinical use of curcumin. Design of experiment is a precise and cost effective tool useful in analyzing the effect of independent variables and their interaction on the product attributes. OBJECTIVE: To evaluate the effect of process variables involved in preparation of curcumin-loaded polycaprolactone (PCL) nanoparticles (CPN). MATERIALS AND METHODS: In the present experiment, CPNs were prepared by emulsification solvent evaporation technique. The effect of independent variables on the dependent variable was analyzed using design of experiments. Anticancer activity of CPN was studied using Ehrlich ascites carcinoma (EAC) model. In-situ implant was developed using PLGA as polymer. RESULTS AND DISCUSSION: The effect of independent variables was studied in two stages. First, the effect of drug polymer ratio, homogenization speed and surfactant concentration on size was studied using factorial design. The interaction of homogenization speed with homogenization time on mean particle size of CPN was then evaluated using central composite design. In the second stage, the effect of these variables (under the conditions optimized for producing particles <500 nm) on percentage drug encapsulation was evaluated using factorial design. CPN prepared under optimized conditions were able to control the development of EAC in Swiss albino mice and enhanced their survival time. PLGA based in-situ implant containing CPN prepared under optimized conditions showed sustained drug release. CONCLUSION: This implant could be further evaluated for pharmacological activities. PMID- 24956469 TI - Introspective reports of reaction times in dual-tasks reflect experienced difficulty rather than timing of cognitive processes. AB - Reports of introspective reaction times (iRTs) have been used to investigate conscious awareness during dual-task situations. Previous studies showed that dual-task costs in RTs (the psychological refractory period, PRP, effect) are not reflected in participants' introspective reports. This finding has been attributed to conscious awareness of Task 2 being delayed while Task 1 is centrally processed. Here, we test this Temporal model and compare it to an alternative that assumes participants base their iRTs on experienced difficulty. We collected iRTs and difficulty estimates after each trial of a PRP paradigm in which the perceptual difficulty of either Task 2 (Experiment 1) or Task 1 (Experiment 2) was manipulated. Our results largely support the difficulty-based account, suggesting that in a dual-task situation, iRTs do not reflect timing of cognitive processes but are strongly influenced by the experience of difficulty. PMID- 24956470 TI - Advanced Insulin Bolus Advisor Based on Run-To-Run Control and Case-Based Reasoning. AB - This paper presents an advanced insulin bolus advisor for people with diabetes on multiple daily injections or insulin pump therapy. The proposed system, which runs on a smartphone, keeps the simplicity of a standard bolus calculator while enhancing its performance by providing more adaptability and flexibility. This is achieved by means of applying a retrospective optimization of the insulin bolus therapy using a novel combination of run-to-run (R2R) that uses intermittent continuous glucose monitoring data, and case-based reasoning (CBR). The validity of the proposed approach has been proven by in-silico studies using the FDA accepted UVa-Padova type 1 diabetes simulator. Tests under more realistic in silico scenarios are achieved by updating the simulator to emulate intrasubject insulin sensitivity variations and uncertainty in the capillarity measurements and carbohydrate intake. The CBR(R2R) algorithm performed well in simulations by significantly reducing the mean blood glucose, increasing the time in euglycemia and completely eliminating hypoglycaemia. Finally, compared to an R2R stand-alone version of the algorithm, the CBR(R2R) algorithm performed better in both adults and adolescent populations, proving the benefit of the utilization of CBR. In particular, the mean blood glucose improved from 166 +/- 39 to 150 +/- 16 in the adult populations (p = 0.03) and from 167 +/- 25 to 162 +/- 23 in the adolescent population (p = 0.06). In addition, CBR(R2R) was able to completely eliminate hypoglycaemia, while the R2R alone was not able to do it in the adolescent population. PMID- 24956472 TI - Genomic analysis of the appearance of ovarian mast cells in neonatal MRL/MpJ mice. AB - In MRL/MpJ mice, ovarian mast cells (OMCs) are more abundant than in other mouse strains, and tend to distribute beneath the ovarian surface epithelium at birth. This study investigated the factors regulating the appearance of neonatal OMCs in progeny of the cross between MRL/MpJ and C57BL/6N strains. F1 neonates had less than half the number of OMCs than MRL/MpJ. Interestingly, MRLB6F1 had more neonatal OMCs than B6MRLF1, although they were distributed over comparable areas. Furthermore, in MRL/MpJ fetuses for which parturition was delayed until embryonic day 21.5, the number of OMCs was significantly higher than in age-matched controls at postnatal day 2. These results suggest that the number of OMCs was influenced by the environmental factors during pregnancy. Quantitative trait locus analysis using N2 backcross progeny revealed two significant loci on chromosome 8: D8Mit343-D8Mit312 for the number of OMCs and D8Mit86-D8Mit89 for their distribution, designated as mast cell in the ovary of MRL/MpJ 1 (mcom1) and mcom2, respectively. Among MC migration-associated genes, ovarian expression of chemokine (C-C motif) ligand 17 at mcom1 locus was significantly higher in MRL/MpJ than in C57BL/6N, and positively correlated with the expression of OMC marker genes. These results indicate that the appearance of neonatal OMCs in MRL/MpJ is controlled by environmental factors and filial genetic factors, and that the abundance and distribution of OMCs are regulated by independent filial genetic elements. PMID- 24956473 TI - Influence of race on microsatellite instability and CD8+ T cell infiltration in colon cancer. AB - African American patients with colorectal cancer show higher mortality than their Caucasian counterparts. Biology might play a partial role, and prior studies suggest a higher prevalence for microsatellite instability (MSI) among cancers from African Americans, albeit patients with MSI cancers have improved survival over patients with non-MSI cancers, counter to the outcome observed for African American patients. CD8+ T cell infiltration of colon cancer is postively correlated with MSI tumors, and is also related to improved outcome. Here, we utilized a 503-person, population-based colon cancer cohort comprising 45% African Americans to determine, under blinded conditions from all epidemiological data, the prevalence of MSI and associated CD8+ T cell infiltration within the cancers. Among Caucasian cancers, 14% were MSI, whereas African American cancers demonstrated 7% MSI (P = 0.009). Clinically, MSI cancers between races were similar; among microsatellite stable cancers, African American patients were younger, female, and with proximal cancers. CD8+ T cells were higher in MSI cancers (88.0 vs 30.4/hpf, P<0.0001), but was not different between races. Utilizing this population-based cohort, African American cancers show half the MSI prevalence of Caucasians without change in CD8+ T cell infiltration which may contribute towards their higher mortality from colon cancer. PMID- 24956474 TI - Betaine and beet molasses enhance L-lactic acid production by Bacillus coagulans. AB - Lactic acid is an important chemical with various industrial applications, and it can be efficiently produced by fermentation, in which Bacillus coagulans strains present excellent performance. Betaine can promote lactic acid fermentation as an effective osmoprotectant. Here, positive effect of betaine on fermentation by B. coagulans is revealed. Betaine could enhance lactic acid production by protecting l-LDH activity and cell growth from osmotic inhibition, especially under high glucose concentrations and with poor organic nitrogen nutrients. The fermentation with 0.05 g/L betaine could produce 17.9% more lactic acid compared to the fermentation without betaine. Beet molasses, which is rich in sucrose and betaine, was utilized in a co-feeding fermentation and raised the productivity by 22%. The efficient lactic acid fermentation by B. coagulans is thus developed by using betaine and beet molasses. PMID- 24956475 TI - Similar multimorbidity patterns in primary care patients from two European regions: results of a factor analysis. AB - OBJECTIVE: To compare the similarities among the multimorbidity patterns identified in primary care patients from two European regions (Spain and the Netherlands) with similar organisational features of their primary care systems, using validated methodologies. METHODOLOGY: This observational, retrospective, multicentre study analysed information from primary care electronic medical records. Multimorbidity patterns were assessed using exploratory factor analysis of the diagnostic information of patients over 14 years of age. The analysis was stratified by age groups and sex. RESULTS: The analysis of Dutch data revealed a higher prevalence of multimorbidity which corresponds with the clustering of a higher number of diseases in each of the patterns. Relevant clinical similarities were found between both countries for three multimorbidity patterns that were previously identified in the original Spanish study: cardiometabolic, mechanical and psychiatric-substance abuse. In addition, the clinical evolution towards complexity of the cardiometabolic pattern with advancing age--already demonstrated in the original study--was corroborated in the Dutch context. A clear association between mechanical and psychosocial disorders was unique to the Dutch population, as well as the recurrent presentation of the psychiatric substance abuse pattern in all age and sex groups. CONCLUSIONS: The similarities found for the cardiometabolic, mechanical and psychiatric-substance abuse patterns in primary care patients from two different European countries could offer initial clues for the elaboration of clinical practice guidelines, if further evidenced in other contexts. This study also endorses the use of primary care electronic medical records for the epidemiologic characterization of multimorbidity. PMID- 24956476 TI - Determination of villous rigidity in the distal ileum of the possum (Trichosurus vulpecula). AB - We investigated the passive mechanical properties of villi in ex vivo preparations of sections of the wall of the distal ileum from the brushtail possum (Trichosurus vulpecula) by using a flow cell to impose physiological and supra-physiological levels of shear stress on the tips of villi. We directly determined the stress applied from the magnitude of the local velocities in the stress inducing flow and additionally mapped the patterns of flow around isolated villi by tracking the trajectories of introduced 3 um microbeads with bright field micro particle image velocimetry (mPIV). Ileal villi were relatively rigid along their entire length (mean 550 um), and exhibited no noticeable bending even at flow rates that exceeded calculated normal physiological shear stress (>0.5 mPa). However, movement of villus tips indicated that the whole rigid structure of a villus could pivot about the base, likely from laxity at the point of union of the villous shaft with the underlying mucosa. Flow moved upward toward the tip on the upper portions of isolated villi on the surface facing the flow and downward toward the base on the downstream surface. The fluid in sites at distances greater than 150 um below the villous tips was virtually stagnant indicating that significant convective mixing in the lower intervillous spaces was unlikely. Together the findings indicate that mixing and absorption is likely to be confined to the tips of villi under conditions where the villi and intestinal wall are immobile and is unlikely to be greatly augmented by passive bending of the shafts of villi. PMID- 24956477 TI - Zoopharmacognosy in diseased laboratory mice: conflicting evidence. AB - Zoopharmacognosy denotes a constellation of learned ingestive responses that promote healing and survival of infected or poisoned animals. A similar self medication phenomenon was reported in diseased laboratory rodents. In particular, a series of studies revealed that autoimmune MRL/lpr mice readily consume solutions paired or laced with cyclophosphamide (CY), an immunosuppressive drug that prevents inflammatory damage to internal organs. However, due to design limitations, it could not be elucidated whether such a response reflects the learned therapeutic effect of CY, or a deficit in sensory input. We presently assess the behavioural effects of prolonged consumption of CY-laced, 16% sucrose solution in a continuous choice paradigm, with tap water available ad lib. Contrary to overall expectation, MRL/lpr mice did not increase their intake of CY with disease progression. Moreover, they ingested lower doses of CY and preferred less CY-laced sucrose solution than age-matched controls. The results obtained could not confirm zoopharmacognosy in diseased MRL/lpr mice, likely due to impaired responsiveness to palatable stimulation, or attenuated survival mechanisms after prolonged inbreeding in captivity. However, by revealing the effectiveness of unrestricted drinking of drug-laced sucrose solution on behavior and immunity, the current study supports broader use of such an administration route in behavioural studies sensitive to external stressors. PMID- 24956479 TI - Ensemble generation and the influence of protein flexibility on geometric tunnel prediction in cytochrome P450 enzymes. AB - Computational prediction of ligand entry and egress paths in proteins has become an emerging topic in computational biology and has proven useful in fields such as protein engineering and drug design. Geometric tunnel prediction programs, such as Caver3.0 and MolAxis, are computationally efficient methods to identify potential ligand entry and egress routes in proteins. Although many geometric tunnel programs are designed to accommodate a single input structure, the increasingly recognized importance of protein flexibility in tunnel formation and behavior has led to the more widespread use of protein ensembles in tunnel prediction. However, there has not yet been an attempt to directly investigate the influence of ensemble size and composition on geometric tunnel prediction. In this study, we compared tunnels found in a single crystal structure to ensembles of various sizes generated using different methods on both the apo and holo forms of cytochrome P450 enzymes CYP119, CYP2C9, and CYP3A4. Several protein structure clustering methods were tested in an attempt to generate smaller ensembles that were capable of reproducing the data from larger ensembles. Ultimately, we found that by including members from both the apo and holo data sets, we could produce ensembles containing less than 15 members that were comparable to apo or holo ensembles containing over 100 members. Furthermore, we found that, in the absence of either apo or holo crystal structure data, pseudo-apo or -holo ensembles (e.g. adding ligand to apo protein throughout MD simulations) could be used to resemble the structural ensembles of the corresponding apo and holo ensembles, respectively. Our findings not only further highlight the importance of including protein flexibility in geometric tunnel prediction, but also suggest that smaller ensembles can be as capable as larger ensembles at capturing many of the protein motions important for tunnel prediction at a lower computational cost. PMID- 24956480 TI - Cell transfection with a beta-cyclodextrin-PEI-propane-1,2,3-triol nanopolymer. AB - Successful gene therapy necessitates safe and efficient gene transfer. This article describes the use of a cationic polymer, which was synthesized by cross linking low molecular weight branched poly(ethylenimine) (PEI) with both beta cyclodextrin and propane-1,2,3-triol, for efficient and safe non-viral gene delivery. Experimentation demonstrated that the polymer had a pH buffering capacity and DNA condensing ability comparable to those of PEI 25 kDa. In B16-F0 cells, the polymer increased the transfection efficiency of naked DNA by 700-fold and yielded better transfection efficiencies than Fugene HD (threefold higher) and PEI 25 kDa (fivefold higher). The high transfection efficiency of the polymer was not affected by the presence of serum during transfection. In addition to B16 F0 cells, the polymer enabled efficient transfection of HepG2 and U87 cells with low cytotoxicity. Our results indicated that our polymer is a safe and efficient transfection reagent that warrants further development for in vitro, in vivo and clinical applications. PMID- 24956478 TI - Glutamate and lipid metabolic perturbation in the hippocampi of asymptomatic borna disease virus-infected horses. AB - Borna disease virus (BDV) is a neurotropic, enveloped, non-segmented, negative stranded RNA virus that infects a wide variety of vertebrate species from birds to humans across a broad global geographic distribution. Animal symptomatology range from asymptomatic infection to behavioral abnormalities to acute meningoencephalitis. Asymptomatic BDV infection has been shown to be more frequent than conventionally estimated. However, the molecular mechanism(s) underyling asymptomatic BDV infection remain largely unknown. Here, based on real time quantitative PCR and Western blotting, a total of 18 horse hippocampi were divided into BDV-infected (n = 8) and non-infected control (n = 10) groups. A gas chromatography coupled with mass spectrometry (GC-MS) metabolomic approach, in conjunction with multivariate statistical analysis, was used to characterize the hippocampal metabolic changes associated with asymptomatic BDV infection. Multivariate statistical analysis showed a significant discrimination between the BDV-infected and control groups. BDV-infected hippocampi were characterized by lower levels of D-myo-inositol-1-phosphate, glutamate, phosphoethanolamine, heptadecanoic acid, and linoleic acid in combination with a higher level of ammonia. These differential metabolites are primarily involved in glutamate and lipid metabolism. These finding provide an improved understanding of hippocampal changes associated with asymptomatic BDV infection. PMID- 24956482 TI - Transaxillary thoracodorsal artery perforator flap: a versatile new technique for hypopharyngeal reconstruction. AB - INTRODUCTION: Reconstruction of the hypopharynx and cervical esophagus after tumor resection remains a challenging problem. Different techniques of reconstruction have been described for such defects. Although free flap reconstruction, including jejunum and fasciocutaneous flaps, has gained popularity for this complex defect, regional flaps are still in use worldwide. PATIENTS AND METHODS: We present our experience using the pedicled thoracodorsal artery perforator (TDAP) flap whereby only a small cuff of latissimus dorsi muscle around the perforators is harvested. The remaining muscle with its nerve supply is preserved. The flap is delivered to the neck through the cervicoaxillary tunnel. It was used as a complete tube in six patients and with an additional attached skin island for reconstruction of the neck skin in another four patients. RESULTS: A total of 11 TDAP flaps were used for reconstruction in 10 patients. All flaps survived except in one patient who suffered from a complete flap loss. This was salvaged by another TDAP flap from the contralateral side. Partial sloughing of the outer part of the pedicled TDAP occurred in one other patient. Pharyngeal fistulas developed in another two patients and eventually healed spontaneously. All patients resumed an oral diet within 2 weeks except two with fistulas. All patients resumed their shoulder active range of motion within 3 weeks. CONCLUSION: The transaxillary TDAP flap is an ideal technique for hypopharyngeal reconstruction. It offers the advantages of free fasciocutaneous flaps, has a wide arc of rotation, a relatively larger flap dimension, a reliable vascular pedicle, and acceptable donor site morbidity. PMID- 24956485 TI - Electronic and cationic spectroscopy of 9-hydroxy-9-fluorene carboxylic acid. AB - Resonance-enhanced multiphoton ionization spectroscopy of supersonically cooled gas-phase 9-hydroxy-9-fluorene carboxylic acid (9HFCA) is reported for its first electronic excited state, S1. The UV-UV hole-burning experiment identifies a single conformer in the molecular beam, stabilized by an intramolecular hydrogen bond. For this Cs symmetric conformer, two low frequencies in the S1 spectrum are assigned: an in-plane rocking mode of the carboxylic acid side chain lies at 58 cm(-1), and an in-plane fluorene bending mode appears at 183 cm(-1). The corresponding mode frequencies in the cation, 58 and 196 cm(-1), are measured by zero electron kinetic energy (ZEKE) spectroscopy upon pumping the S1 vibronic states. The adiabatic ionization potential is measured to be 64 923 +/- 5 cm(-1). In addition, a feature established by ZEKE spectroscopy upon pumping the hot band is found at 67 cm(-1). This is assigned as a hot band of the HO-C9-COOH rocking mode in the neutral ground state. PMID- 24956484 TI - Nerve transfer to the deltoid muscle using the nerve to the long head of the triceps with the da Vinci robot: six cases. AB - BACKGROUND: Nerve transfer to the deltoid muscle using the nerve to the long head of the triceps is a reliable method for restoration of deltoid function. The aim of this retrospective study was to report the results of nerve transfer to the deltoid muscle using the nerve to the long head of the triceps procedure using a robot. METHODS: Our series included six patients (mean age 36.3 years) with total deltoid muscle paralysis. A da Vinci-S robot was placed in position. After dissection of the quadrilateral and triangular spaces, the anterior branch of the axillary nerve and the branch to the long head of the triceps were transected, and then robotically sutured with two 10-0 nylon stiches. In two cases, an endoscopic procedure was tried under carbon dioxide (CO2) insufflation. RESULTS: In all patients except one, deltoid function against resistance (M4) was obtained at the last follow-up evaluation. The average shoulder abduction was 112 degrees. No weakness of elbow extension was observed. In two cases with the endoscopic technique, vision was blurred and conversion to open technique was performed. CONCLUSION: The advantages of robotic microsurgery are motion scaling and disappearance of physiological tremor. Reasons for failure of the endoscopic technique could be explained by insufficient pressure. We had no difficulty using the robot without the sensory feedback. The robot-assisted nerve transfer to deltoid muscle using the nerve to the long head of the triceps was a feasible application for restoration of shoulder abduction after brachial plexus or axillary nerve injury. Therapeutic Study. Level of Evidence IV. PMID- 24956481 TI - Deficiency of formyl peptide receptor 1 and 2 is associated with increased inflammation and enhanced liver injury after LPS-stimulation. AB - INTRODUCTION: Formyl peptide-receptor 1 and 2 (FPR1 and FPR2) in mice were identified as receptors with contrary affinity for the PAMP fMLF. Formyl methionyl-leucyl-phenylalanine is either part of the bacterial membrane and is secreted by the mitochondria of eukaryotic ceslls during apoptosis. Furthermore FPR1 and 2 are described as highly relevant factors for the chemotaxis of immune cells. Their role during the acute liver injury has not been investigated yet. MATERIALS AND METHODS: Constitutive knockout mice for FPR1 (mFPR1-/-), FPR2 (mFPR2-/-) and wild type (WT) mice were challenged with LPS i.p. for 3 h and 6 h. Liver and serum were sampled for further analysis. RESULTS: Liver transaminases were elevated in all mice 3 h and 6 h post LPS stimulation. Gene expression analysis displayed a reduced expression of the pro-inflammatory cytokines IL-6 and CXCL1 after 3 h in the mFPR1-/- compared to wild type and mFPR2-/- mice. After 6 h, IL-6, TNF-alpha and CXCL1 were significantly higher in mice lacking mFPR1 or 2. Consistent to these findings the numbers of CD11b+ and Ly6G+ immune cells were altered in the livers. The analysis of TLR2 and TLR4 revealed time and genotype specific changes in theirs gene expression. Additionally, the liver in mFPR1- and mFPR2-deficient mice seem to be more susceptible to apoptosis by showing a significant higher number of TUNEL+-cells in the liver than WT-mice and displayed less Ki67-positive nuclei in the liver. CONCLUSION: The results suggest a prominent role of FPRs in the regulation of the hepatic inflammatory response after LPS induced liver injury. Deletion of mFPR1 or mFPR2 leads to deregulation of the inflammatory response compared to WT mice, associated with more severe liver injury represented by higher levels of transaminases, apoptotic cells and a reduced regenerative capacity. PMID- 24956483 TI - Etifoxine promotes glia-derived neurite outgrowth in vitro and in vivo. AB - BACKGROUND: Peripheral nerve injuries usually require a graft to facilitate axonal regeneration into the distal nerve stump. Acellular nerve grafts are good candidates for nerve repair, but clinical outcomes from grafts are not always satisfactory. Etifoxine is a ligand of the 18-kDa translocator protein (TSPO) and has been demonstrated to serve multiple functions in nervous system. METHODS: This study aimed to determine the optimal concentration of etifoxine for neurite outgrowth using PC12 cells and verify whether etifoxine could enhance in vivo peripheral nerve regeneration. PC12 cells were exposed to various concentrations of etifoxine (5, 10, 20, and 40 uM). Neuronal-like outgrowth and glia-derived neurotrophic factor (GDNF) mRNA expression were measured, and a rat sciatic nerve transection model was employed. Histological examination was used to evaluate the efficacy of nerve regeneration, and real-time polymerase chain reaction (PCR) evaluated changes in mRNA levels after etifoxine treatment. RESULTS: Our data show that etifoxine increased neuronal-like outgrowth in PC12 cells in a dose dependent manner; however, GDNF expression peaked at 20 uM etifoxine (1.97-fold increase compared with control, p = 0.0046). In vivo studies demonstrated that etifoxine improved sciatic nerve regeneration, modulated immune responses, and boosted neurotrophin expression. CONCLUSIONS: Because of etifoxine's adverse effects, we suggest an optimal etifoxine concentration of 20 uM. Its beneficial role may lie in increased neurotrophin expression, and etifoxine may be a promising therapeutic for patients with peripheral nerve injuries. PMID- 24956487 TI - Enhanced cutaneous bioavailability of dehydroepiandrosterone mediated by nano encapsulation. AB - Polymeric nanocarriers, especially nanospheres (NSs) and nanocapsules (NCs), can promote the penetration of their cargo through the skin barrier, towards improved cutaneous bioavailability. Dehydroepiandrosterone (DHEA), an endogenous hormone exhibiting poor aqueous solubility, was shown to be effective in modulating skin aging processes following topical application. In this study, we designed adequate DHEA preparations, in an attempt to enable local delivery of the active ingredient to the viable skin layers. In addition, the potential efficiency of DHEA NCs on dermal collagen synthesis was evaluated. Cryo-TEM observations and thermal analysis indicated that DHEA was successfully incorporated within a stable NC-based delivery system. Moreover, higher [(3)H]-DHEA levels were recorded in the viable skin layers following different incubation periods of NCs on excised pig skin specimens as compared to DHEA oil solution (free molecule). Furthermore, significantly higher (4-fold) skin flux values were observed for the DHEA NCs as compared to the values elicited by the oil control solution. Finally, collagen synthesis in human skin organ culture, assessed by the incorporation of [(3)H]-proline, was up to 42% higher for DHEA NCs 48h post-topical application than for the untreated specimens. Overall, these results suggest that poly lactic co-glycolic acid (PLGA)-based NCs have promising potential to be used topically for various skin disorders. PMID- 24956486 TI - Controlled release from recombinant polymers. AB - Recombinant polymers provide a high degree of molecular definition for correlating structure with function in controlled release. The wide array of amino acids available as building blocks for these materials lend many advantages including biorecognition, biodegradability, potential biocompatibility, and control over mechanical properties among other attributes. Genetic engineering and DNA manipulation techniques enable the optimization of structure for precise control over spatial and temporal release. Unlike the majority of chemical synthetic strategies used, recombinant DNA technology has allowed for the production of monodisperse polymers with specifically defined sequences. Several classes of recombinant polymers have been used for controlled drug delivery. These include, but are not limited to, elastin-like, silk-like, and silk elastinlike proteins, as well as emerging cationic polymers for gene delivery. In this article, progress and prospects of recombinant polymers used in controlled release will be reviewed. PMID- 24956488 TI - Polymeric micelles loaded with platinum anticancer drugs target preangiogenic micrometastatic niches associated with inflammation. AB - Nanocarriers have been used for specific delivery of therapeutic agents to solid tumors based on the enhanced permeability and retention in cancerous tissues. Despite metastasis is the main reason of cancer-related death and a priority for nanocarrier-based therapies, the targeting ability of nanocarriers to the metastatic disease is poorly understood, especially for preangiogenic micrometastases as nanocarriers usually use the malignant neovasculature for enhancing their accumulation. Thus, herein, we studied the ability of micellar nanocarriers incorporating (1,2-diaminocyclohexane)platinum(II) (DACHPt) for treating liver metastases of bioluminescent murine colon adenocarcinoma C-26, during overt and preangiogenic metastatic stages. After intravenous injection, DACHPt-loaded micelles (DACHPt/m) effectively inhibited the tumor growth in both metastatic tumor models. While the anticancer activity of the micelles against overt metastases was associated with their selective accumulation in cancerous tissues having neovasculature, the ability of DACHPt/m to target preangiogenic metastases was correlated with the inflammatory microenvironment of the niche. This targeting capability of polymeric micelles to preangiogenic metastasis may provide a novel approach for early diagnosis and treatment of metastases. PMID- 24956490 TI - Catalytically and biologically active silver nanoparticles synthesized using essential oil. AB - There are numerous reports on phytosynthesis of silver nanoparticles and various phytochemicals are involved in the reduction and stabilization. Pure explicit phytosynthetic protocol for catalytically and biologically active silver nanoparticles is of importance as it is an environmentally benign green method. This paper reports the use of essential oil of Myristica fragrans enriched in terpenes and phenyl propenes in the reduction and stabilization. FTIR spectra of the essential oil and the synthesized biogenic silver nanoparticles are in accordance with the GC-MS spectral analysis reports. Nanosilver is initially characterized by an intense SPR band around 420 nm, followed by XRD and TEM analysis revealing the formation of 12-26 nm sized, highly pure, crystalline silver nanoparticles. Excellent catalytic and bioactive potential of the silver nanoparticles is due to the surface modification. The chemocatalytic potential of nanosilver is exhibited by the rapid reduction of the organic pollutant, para nitro phenol and by the degradation of the thiazine dye, methylene blue. Significant antibacterial activity of the silver colloid against Gram positive, Staphylococcus aureus (inhibition zone--12 mm) and Gram negative, Escherichia coli (inhibition zone--14 mm) is demonstrated by Agar-well diffusion method. Strong antioxidant activity of the biogenic silver nanoparticles is depicted through NO scavenging, hydrogen peroxide scavenging, reducing power, DPPH and total antioxidant activity assays. PMID- 24956493 TI - Ordered mesoporous mixed metal oxides: remarkable effect of pore size on catalytic activity. AB - We report the synthesis of ordered mesoporous NiAl mixed metal oxides (MMOs) from NiAl-layered double hydroxides (LDHs) through a soft template method using pluronic-F127 as the structure-directing agent. Ordered mesopores were obtained by the thermal decomposition of as-synthesized LDHs at different temperatures. The effects of the pluronic-F127 amount and the calcination temperature on the pore size distribution of the MMO were investigated. NiAl MMOs exhibited excellent catalytic activity in the Knoevenagel condensation of benzaldehyde with acidic methylene group-containing malononitrile. Finally, the dependence of the catalytic activity on the surface properties of NiAl MMOs was investigated. The pore diameter and the pore volume of NiAl MMOs were well correlated with the performance of the catalysts. MMO obtained from the calcination of NiAl F127(3%)LDH at 750 degrees C for 5 h gave the highest conversion (>99%) in the Knoevenagel condensation in 30 min. The optimum pore diameter for the model reaction described here was 7.7 nm, which gave rise to more than 99% conversion with 100% selectivity. Ethanol gave the best conversion at 60 degrees C. The regenerated catalyst showed 93.0 and 89.0% of the initial catalytic activity after the first and the second regeneration cycles, respectively. PMID- 24956491 TI - Spectral studies on a series of metal ion complexes derived from pyrimidine nucleus, TEM, biological and gamma-irradiation effect. AB - A series of thiouracil complexes was prepared, all the prepared compounds are investigated by all possible tools. The ligand coordinates towards two central atoms as a neutral hexadentate mode. The octahedral structure was proposed with Ni(II), Pt(IV) and UO2(II) complexes. Square-pyramidal and square planar with VO(II) and Pd(II) complexes, respectively. VO(II) complex was irradiated by using Gamma radiation to through a light on the probability of geometry changes with the effect of radiation. The parameters calculated from ESR spectra before and after gamma-irradiation reflect the rigidity of the complex towards the effect. Such may discuss the unaffected biological behavior before and after irradiation. XRD patterns were carried out to emphasis on the nature of the particles and the purity of products. The ligand, Pt(IV) and Pd(II) are found in nanometer range. TEM is a sensitive tool used to justify on the microstructure and surface morphology. All the investigated compounds are in nanorange. TG curves reflect a lower thermal stability of all investigated complexes due to the presence of water of crystallization. Finally, a toxic effect was observed with all investigated complexes towards Gram positive bacterium as well as a resistant behavior was observed with Gram negative bacteria. PMID- 24956492 TI - One-step synthesis of diazaspiro[4.5]decane scaffolds with exocyclic double bonds. AB - Unactivated yne-en-ynes reacted with a range of substituted aryl halides in the presence of Pd(OAc)2-PPh3 to afford diazaspiro[4.5]decane with exocyclic double bonds. Three carbon-carbon bonds are formed in this domino reaction, which involves highly regioselective C-C coupling and spiro scaffold steps. PMID- 24956494 TI - Apotirucallane protolimonoids from the Chinese mangrove Xylocarpus granatum Koenig. AB - A series of previously unreported compounds including seven new apotirucallane protolimonoids, xylogranatumines A-G (1-7), were isolated together with three known analogues (8-10) from the twigs and leaves of the Chinese mangrove, Xylocarpus granatum. The structures of these new compounds were elucidated by extensive spectroscopic analysis including 1D and 2D NMR and high-resolution electrospray ionization mass spectrometry (HRESIMS) and by comparison with those of related known compounds in the literature. Xylogranatumine F (6) exhibited cytotoxic activity against A549 tumor cell in vitro. PMID- 24956495 TI - Generation of a recombinant classical swine fever virus stably expressing the firefly luciferase gene for quantitative antiviral assay. AB - Classical swine fever (CSF), caused by classical swine fever virus (CSFV), is a highly contagious swine disease leading to significant economic losses worldwide. Vaccines are widely used to control the disease, and no CSFV-specific antivirals are currently available. To facilitate anti-CSFV molecule discovery, we developed a reporter virus CSFV-N(pro)Fluc stably expressing the firefly luciferase (Fluc) gene in the N(pro) gene. The reporter virus enabled more sensitive and convenient detection of the N(pro) protein expression and the viral replication by luciferase reporter assay than by traditional methods. The CSFV N(pro) protein was detectable as early as 4.5h post-infection. As a proof-of-concept for its utility in rapid antiviral screening, this reporter virus was used to quantify anti-CSFV neutralizing antibodies of 50 swine sera and to assess 12 small interfering RNAs targeting different regions of the CSFV genome. The results were comparable to those obtained by traditional methods. Taken together, the reporter virus CSFV-N(pro)Fluc represents a useful tool for rapid and quantitative screening and evaluation of antivirals against CSFV. PMID- 24956496 TI - Telaprevir-S isomer enhances ribavirin exposure and the ribavirin-related haemolytic anaemia in a concentration-dependent manner. AB - The standard-of-care for the treatment of genotype-1 chronic hepatitis C is based on the combination of direct acting antivirals, such as boceprevir and telaprevir, with ribavirin and pegylated-interferon alfa. These triple regimens give a higher response rate than dual therapy, but on the other hand show a more than 10% higher rate of anaemia. Not enough focus has been given to the interaction between telaprevir and RBV. In this work, we aimed to study and deepen this relationship by comparing ribavirin plasma and intra-erythrocytic concentrations at one month of triple and dual therapy (17 vs. 119 patients). Moreover, we determined telaprevir isomers concentrations and tested them for correlation with ribavirin concentrations and haemoglobin loss at one month of treatment. Finally, all drugs concentration data were tested for their correlation with the renal function during treatment. The comparisons of ribavirin concentration and toxicity data were repeated on a sub-group of 9 patients who had been treated 1 year before with dual therapy and then re-treated with triple therapy. The observed ribavirin plasma and intra-erythrocytic concentrations in triple therapy were significantly higher compared to dual therapy, both in whole group and sub-group comparison. Ribavirin concentrations were significantly correlated to the haemoglobin loss and telaprevir-S isomer concentrations (r(2)=0.317 P(value)=0.023 and r(2)=0.388 P(value)=0.008, respectively). Renal function had a significant decrease from the baseline value, but was not significantly correlated with drugs concentrations. These results highlight for the first time that, in the context of triple therapy with telaprevir, ribavirin exposure is related to the telaprevir-S isomer plasma concentration. We conclude that the addition of telaprevir to the dual therapy increases ribavirin exposure and haemoglobin loss: this effect could probably be managed through the therapeutic drug monitoring of ribavirin and telaprevir-S concentrations. PMID- 24956497 TI - Palladium-catalyzed thiolation of alkanes and ethers with arylsulfonyl hydrazides. AB - A new method for the preparation of alkyl aryl sulfides through direct oxidative thiolation of alkanes or ethers with arylsulfonyl hydrazides using di-tert-butyl peroxide (DTBP) as an oxidant catalyzed by Pd(OAc)2 has been reported. The C-H bonds in various alkanes or ethers were successfully converted into C-S bonds to yield the corresponding sulfides in moderate to good yields. PMID- 24956498 TI - A covalent polyoxomolybdate-based hybrid with remarkable electron reservoir properties. AB - A new polyoxomolybdate-based hybrid platform TBA4[PMo11O39{Sn(p-C6H4I)}] is reported. The presence of a post-functionalisable iodo-aryl moiety allows the grafting of a ferrocenyl moiety onto the POM. The electrochemical characterisation shows the effect of molybdenum on the electron reservoir properties of POM-based hybrids, which are further enhanced upon the addition of an acid. PMID- 24956499 TI - Allogeneic transplantation in multiple myeloma: a potential renaissance in the era of novel therapies? PMID- 24956501 TI - First symbols in a girl with Down syndrome: a longitudinal study from 12 to 18 months. AB - Symbolic uses of objects originate in communicative and triadic contexts (adult child-object). In this longitudinal study we explore the emergence and development of the first symbolic uses in triadic interaction contexts in a girl with Down syndrome between 12 and 18-months of age. We conducted five sessions of video recording, at 12, 131/2, 15, 161/2, and 18 months chronological age. At each session we videotaped the girl and her mother interacting with different objects. Data were coded in semiotic categories used in previous studies (Rodriguez & Moro, 1999) and a microgenetic analysis was conducted for each session. The first symbolic uses by the girl appeared at 131/2 months. Symbols were of different types and levels of complexity, and the adult had an important role in facilitating the production of these symbols. PMID- 24956500 TI - Parenting stress and depressive symptoms in postpartum mothers: bidirectional or unidirectional effects? AB - Despite the consistent link between parenting stress and postpartum depressive symptoms, few studies have explored the relationships longitudinally. The purpose of this study was to test bidirectional and unidirectional models of depressive symptoms and parenting stress. Uniquely, three specific domains of parenting stress were examined: parental distress, difficult child stress, and parent-child dysfunctional interaction (PCDI). One hundred and five women completed the Beck Depression Inventory and the Parenting Stress Index - Short Form at 3, 7, and 14 months after giving birth. Structural equation modeling revealed that total parenting stress predicted later depressive symptoms, however, there were different patterns between postpartum depressive symptoms and different types of parenting stress. A unidirectional model of parental distress predicting depressive symptoms best fit the data, with significant stability paths but non significant cross-lagged paths. A unidirectional model of depressive symptoms predicted significant later difficult child stress. No model fit well with PCDI. Future research should continue to explore the specific nature of the associations of postpartum depression and different types of parenting stress on infant development and the infant-mother relationship. PMID- 24956502 TI - Improving the accuracy of weight status assessment in infancy research. AB - Both researchers and primary care providers vary in their methods for assessing weight status in infants. The purpose of the present investigation was to compare standing-height-derived to recumbent-length-derived weight-for-length standardized (WLZ) scores, using the WHO growth curves, in a convenience sample of infants who visited the lab at 18 and 21 months of age. Fifty-eight primarily White, middle class infants (25 girls) from a semi-rural region of southern Appalachia visited the lab at 18 months, with 45 infants returning 3 months later. We found that recumbent-length-derived WLZ scores were significantly higher at 18 months than corresponding standing-height-derived WLZ scores. We also found that recumbent-length-derived WLZ scores, but not those derived from standing height measures, decreased significantly from 18 to 21 months. Although these differential results are attributable to the WHO database data entry syntax, which automatically corrects standing height measurements by adding 0.7 cm, they suggest that researchers proceed cautiously when using standing-height derived measures when calculating infant BMI z-scores. Our results suggest that for practical purposes, standing height measurements may be preferred, so long as they are entered into the WHO database as recumbent length measurements. We also encourage basic science infancy researchers to include BMI assessments as part of their routine assessment protocols, to serve as potential outcome measures for other basic science variables of theoretical interest. PMID- 24956489 TI - Agile delivery of protein therapeutics to CNS. AB - A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of protein delivery to the brain and aim developing and studying effective brain delivery systems for protein therapeutics. PMID- 24956503 TI - Comparison of tongue muscle characteristics of preterm and full term infants during nutritive and nonnutritive sucking. AB - BACKGROUND: Independent oral feeding requires coordination of suck, swallow and breathe and the lingual musculature plays a significant role in this coordinative action. However, clinical benchmarks of lingual function fundamental to successful feeding have not been explored. AIMS: The present study tests our model for quantifying infant lingual force and size and compares the muscle measures of interest in two cohorts: healthy full-term infants (FT) (N=5) and healthy preterm infants (PT) (N=6). METHOD: Using an instrumented pacifier and bottle nipple, we determined the resultant compressive forces applied to the nipple by the tongue during nutritive (NS) and nonnutritive sucking (NNS). Muscle size was estimated from measures of posterior tongue thickness using ultrasonography. RESULTS: After controlling for weight and post menstrual age, statistically significant differences were found between FT and PT infants beginning to feed for NNS frequency and NS tongue force. Clinically significant differences were detected for NNS tongue force and posterior tongue thickness. Additionally, PT infants demonstrated a significant difference in mean tongue force between NS and NNS and FT infants did not. FT infants demonstrated a significant difference in mean frequency between NS and NNS and PT infants did not. Linear regression indicated that mean posterior tongue thickness alone predicted 55% of the variance in NS force. CONCLUSIONS: Results demonstrate the feasibility of our approach and suggest that infant tongue muscle characteristics necessary for successful feeding differ between healthy full term infants and preterm infants who are beginning oral feeding. PMID- 24956505 TI - Lamellar versus compact self-assembly of lipoguanosine derivatives in thin surface films. AB - We performed a comparative study on the self-assembling properties of four guanosine derivatives with one and two lipophilic chains of two different lengths at the air-water interface and after Langmuir-Blodgett (LB) deposition onto various solid supports (mica, silicon wafer, graphite). At the air-water interface the derivatives with one lipophilic chain exhibit surface compression behaviour with a profound first order phase transition from the liquid-expanded to the liquid-condensed phase. They assemble into lamellar surface formations, whose structural characteristics remain practically unmodified after their transfer onto the solid substrates. Domain regions with orientationally aligned lamellar formations of sizes up to 150MUm(2) can be obtained. The compression behaviour of double-chain derivatives is more diverse. While the derivative with two decanoyl chains exhibits the liquid-expanded as well as the liquid-condensed phase, the derivative with two hexadecanoyl chains reveals only the condensed analogous phase with a relatively high collapse pressure. LB films of double chain derivatives show formation of very homogeneous and compact surface structures with high surface coverage. PMID- 24956504 TI - Generalized estimating equation model and long-term exposure effect of antipsychotics on SH-SY5Y cells against oxidative stressors. AB - A comparison of the neuroprotective effect of different antipsychotics (APDs) over time on naive SH-SY5Y against oxidative stressor insults using the generalized estimating equation (GEE). The hydrogen peroxide (H2O2), N-methyl-4 phenylpyridinium ion (MPP+), and beta-amyloid peptide were used to treat cells with or without APDs (paliperidone, risperidone, olanzapine and haloperidol); cell survival and oxidative stress markers were measured and analyzed. Only haloperidol had higher baseline cytotoxicity than paliperidone. GEE showed the proper exposure time for evaluating the neuroprotection of APDs was 24 h, rather than 48 or 72 h. Paliperidone was superior to other APDs in protecting naive SH SY5Y, had the best effect against H2O2-, MPP+-induced cell death, and caused a significantly higher GST, lower HNE and protein carbonyl productions of naive SH SY5Y after stressor insults, which may implicate a molecular mechanism underlying its neuroprotective action. Repeated GEE measurements can correct for the correlation among the clusters to obtain a more accurate result for evaluating drug outcome. The interaction between drugs and stressors should be taken into account when determining the neuroprotective effect of APDs against different stressors. Paliperidone might be useful in alleviating oxidative stress induced by Abeta25-35 and MPP+, and provide neuroprotection against hydrogen peroxide in naive SH-SY5Y. PMID- 24956506 TI - Use of nonsteroidal anti-inflammatory drugs in the older adult. AB - PURPOSE: Annually, approximately 90 million prescriptions are filled for nonsteroidal anti-inflammatory drugs (NSAIDs) with the number prescribed for older adults approximately three times higher than for younger adults. This article examines the benefits and risk of NSAID use in older adults. DATA SOURCES: Electronic data collection of research studies, evidence-based reviews, consensus statements, and guidelines related to the purpose of this article were analyzed if published between 2000 and 2013 in English from Ovid, MEDLINE, and PubMed databases. CONCLUSIONS: While NSAIDs are commonly used to treat pain and inflammation in older adults, strong consideration must be given to the potential adverse effects. A lack of consistency in the guidelines regarding NSAID use poses further challenges for clinicians in the selection of the best pharmacological approach. When prescribing NSAIDs, adverse events, polypharmacy, comorbidities, and treatment guidelines must be considered. NSAIDs are an appropriate option for pain management in select older adults, often after a trial of acetaminophen and if benefits outweigh risks. Alternative pharmacological and nonpharmacological therapies may be more appropriate in many older adults. IMPLICATIONS FOR PRACTICE: The challenge for clinicians prescribing NSAIDs in the treatment of pain in older adults is to utilize safe, individualized, and evidenced-based pain management regimens. PMID- 24956507 TI - The osteoporosis treatment gap. PMID- 24956508 TI - Mitochondrial encephalomyopathy with cytochrome c oxidase deficiency caused by a novel mutation in the MTCO1 gene. AB - Cytochrome c oxidase (COX) deficiency is one of the most common respiratory chain deficiencies. A woman was presented at the age of 18y with acute loss of consciousness, non-convulsive status epilepticus, slow neurological deterioration, transient cortical blindness, exercise intolerance, muscle weakness, hearing loss, cataract and cognitive decline. Muscle biopsy revealed ragged-red fibers, COX negative fibers and a significant decreased activity of complex IV in a homogenate. Using next generation massive parallel sequencing of the mtDNA, a novel heteroplasmic mutation was identified in MTCO1, m.7402delC, causing frameshift and a premature termination codon. Single fiber PCR showed co segregation of high mutant load in COX negative fibers. Mutation in mitochondrially encoded complex IV subunits should be considered in mitochondrial encephalomyopathies and COX negative fibers after the common mtDNA mutations have been excluded. PMID- 24956509 TI - Inhibitory effect of the carnosine-gallic acid synthetic peptide on MMP-2 and MMP 9 in human fibrosarcoma HT1080 cells. AB - Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade extracellular matrix components and play important roles in a variety of biological and pathological processes such as malignant tumor metastasis and invasion. In this study, we constructed carnosine-gallic acid peptide (CGP) to identify a better MMP inhibitor than carnosine. The inhibitory effects of CGP on MMP-2 and MMP-9 were investigated in the human fibrosarcoma (HT1080) cell line. As a result, CGP significantly decreased MMP-2 and MMP-9 expression levels without a cytotoxic effect. Moreover, CGP may inhibit migration and invasion in HT1080 cells through the urokinase plasminogen activator (uPA) uPA receptor signaling pathways to inhibit MMP-2 and MMP-9. Based on these results, it appears that CGP may play an important role in preventing and treating several MMP-2 and MMP-9-mediated health problems such as metastasis. PMID- 24956512 TI - A path to soluble molecularly imprinted polymers. AB - Molecular imprinting is a technique for making a selective binding site for a specific chemical. The technique involves building a polymeric scaffold of molecular complements containing the target molecule. Subsequent removal of the target leaves a cavity with a structural "memory" of the target. Molecularly imprinted polymers (MIPs) can be employed as selective adsorbents of specific molecules or molecular functional groups. In addition, sensors for specific molecules can be made using optical transduction through lumiphores residing in the imprinted site. We have found that the use of metal ions as chromophores can improve selectivity due to selective complex formation. The combination of molecular imprinting and spectroscopic selectivity can result in sensors that are highly sensitive and nearly immune to interferences. A weakness of conventional MIPs with regard to processing is the insolubility of crosslinked polymers. Traditional MIPs are prepared either as monoliths and ground into powders or are prepared in situ on a support. This limits the applicability of MIPs by imposing tedious or difficult processes for their inclusion in devices. The size of the particles hinders diffusion and slows response. These weaknesses could be avoided if a means were found to prepare individual macromolecules with crosslinked binding sites with soluble linear polymeric arms. This process has been made possible by controlled free radical polymerization techniques that can form pseudo-living polymers. Modern techniques of controlled free radical polymerization allow the preparation of block copolymers with potentially crosslinkable substituents in specific locations. The inclusion of crosslinkable mers proximate to the binding complex in the core of a star polymer allows the formation of molecularly imprinted macromolecules that are soluble and processable. Due to the much shorter distance for diffusion, the polymers exhibit rapid responses. This paper reviews the methods that have been employed for the trace determination of organophosphates in real world samples using MIPs. PMID- 24956513 TI - Biomechanical Conditioning Enhanced Matrix Synthesis in Nucleus Pulposus Cells Cultured in Agarose Constructs with TGFbeta. AB - Biomechanical signals play an important role in normal disc metabolism and pathology. For instance, nucleus pulposus (NP) cells will regulate metabolic activities and maintain a balance between the anabolic and catabolic cascades. The former involves factors such as transforming growth factor-beta (TGFbeta) and mechanical stimuli, both of which are known to regulate matrix production through autocrine and paracrine mechanisms. The present study examined the combined effect of TGFbeta and mechanical loading on anabolic activities in NP cells cultured in agarose constructs. Stimulation with TGFbeta and dynamic compression reduced nitrite release and increased matrix synthesis and gene expression of aggrecan and collagen type II. The findings from this work has the potential for developing regenerative treatment strategies which could either slow down or stop the degenerative process and/or promote healing mechanisms in the intervertebral disc. PMID- 24956514 TI - Potentials of chitosan-based delivery systems in wound therapy: bioadhesion study. AB - Chitosan is currently proposed to be one of the most promising polymers in wound dressing development. Our research focuses on its potential as a vehicle for nano delivery systems destined for burn therapy. One of the most important features of wound dressing is its bioadhesion to the wounded site. We compared the bioadhesive properties of chitosan with those of Carbopol, a synthetic origin polymer. Chitosan-based hydrogels of different molecular weights were first analyzed by texture analysis for gel cohesiveness, adhesiveness and hardness. In vitro release studies showed no difference in release of model antimicrobial drug from the different hydrogel formulations. Bioadhesion tests were performed on pig ear skin and the detachment force, necessary to remove the die from the skin, and the amount of remaining formulation on the skin were determined. Although no significant difference regarding detachment force could be seen between Carbopol based and chitosan-based formulations, almost double the amount of chitosan formulation remained on the skin as compared to Carbopol formulations. The findings confirmed the great potential of chitosan-based delivery systems in advanced wound therapy. Moreover, results suggest that formulation retention on the ex vivo skin samples could provide deeper insight on formulation bioadhesiveness than the determination of detachment force. PMID- 24956510 TI - Imaging the lymphatic system. AB - Visualization of the lymphatic system is clinically necessary during diagnosis or treatment of many conditions and diseases; it is used for identifying and monitoring lymphedema, for detecting metastatic lesions during cancer staging and for locating lymphatic structures so they can be spared during surgical procedures. Imaging lymphatic anatomy and function also plays an important role in experimental studies of lymphatic development and function, where spatial resolution and accessibility are better. Here, we review technologies for visualizing and imaging the lymphatic system for clinical applications. We then describe the use of lymphatic imaging in experimental systems as well as some of the emerging technologies for improving these methodologies. PMID- 24956516 TI - Monodisperse 130 kDa and 260 kDa Recombinant Human Hemoglobin Polymers as Scaffolds for Protein Engineering of Hemoglobin-Based Oxygen Carriers. AB - A recombinant 130 kDa dihemoglobin which is made up of a single-chain tetra-alpha globin and four beta globins has been expressed as a soluble protein in E. coli. The sequence of the single chain tetra-alpha is: alphaI-Gly-alphaII (SerGlyGly)5Ser-alphaIII-Gly-alphaIV. This dihemoglobin has been purified and characterized in vitro by size exclusion chromatography, electrospray mass spectroscopy, equilibrium oxygen binding, and analytical ultracentrifugation. The observed values of P50 and nmax for the dihemoglobin are slightly lower than those observed for the recombinant hemoglobin rHb1.1 (a "monohemoglobin" comprised of two beta globins and an alphaI-Gly-alphaII dialpha-globin chain). Titration of the deoxy form of dihemoglobin with CO shows that all eight heme centers bind ligand. In vivo, dihemoglobin showed increased circulating halflife and a reduced pressor response in conscious rats when compared to rHb1.1. These observations suggest that dihemoglobin is an oxygen carrying molecule with desirable in vivo properties and provides a platform for an isooncotic hemoglobin solution derived solely from a recombinant source. A 260 kDa tetrahemoglobin has also been produced by chemical crosslinking of a dihemoglobin that contains a Lys16Cys mutation in the C-terminal alpha-globin subunit. Tetrahemoglobin also shows reduced vasoactivity in conscious rats that is comparable to that observed for dihemoglobin. PMID- 24956515 TI - Biophysical Properties of Lumbricus terrestris Erythrocruorin and Its Potential Use as a Red Blood Cell Substitute. AB - Previous generations of hemoglobin (Hb)-based oxygen carriers (HBOCs) have been plagued by key biophysical limitations that result in severe side-effects once transfused in vivo, including protein instability, high heme oxidation rates, and nitric oxide (NO) scavenging. All of these problems emerge after mammalian Hbs are removed from red blood cells (RBCs) and used for HBOC synthesis/formulation. Therefore, extracellular Hbs (erythrocruorins) from organisms which lack RBCs might serve as better HBOCs. This review focuses on the erythrocruorin of Lumbricus terrestris (LtEc), which has been shown to be extremely stable, resistant to oxidation, and may interact with NO differently than mammalian Hbs. All of these beneficial properties show that LtEc is a promising new HBOC which warrants further investigation. PMID- 24956517 TI - Synthesis and biological evaluation of a new polymeric conjugate and nanocarrier with osteotropic properties. AB - Bone-seeking (osteotropic) drug delivery systems (ODDS) represent an interesting solution for targeting different types of drugs to the bones. In particular, anticancer and antibacterial agents could take advantage of such therapeutic strategy. We have recently developed an innovative approach to this aim: a new osteotropic biomaterial was prepared, based on the conjugation of a poly(lactide co-glycolide) (PLGA) with the bisphosphonate drug alendronate (PLGA-ALE); its hemo- and cytocompatibility were verified. Starting with this copolymer, an osteotropic nanoparticle system (NP) was produced for the targeted delivery of antineoplastic drugs to osteolytic bone metastases; in particular, doxorubicin was tested as a model drug. The in vitro and in vivo results of the new ODDS are validated in this article. All the experimental data confirmed that the drug retained its activity after loading in the PLGA-ALE NP; they can be thus considered a new promising strategy for active targeting of drugs to bone tissues in different pathological situations. PMID- 24956518 TI - Prediction of true circulatory decompensation in chronic heart failure for optimal timing of mechanical circulatory support: non-invasive arterial ventricular coupling. AB - BACKGROUND: Prospective comparative studies to predict the risk of hemodynamic deterioration in patients referred for transplantation were performed on the basis of standard invasive and non-invasive data and new wave intensity (WI) parameters. METHODS AND RESULTS: Study Group 1 consisted of 151 consecutive outpatients (age 48.7 +/- 12 years; 110 men) with end-stage dilative cardiomyopathy. Group 2, consisting of 11 consecutive patients (age 50 +/- 11 years; 6 men) with sinus rhythm and "true" decompensation, was used to create "critical values" of WI. There were no demographic or somatic (weight and height) differences between the groups. The follow-up period of ambulatory patients was 31 +/- 8 months. Non-invasive WI was studied in the common carotid artery. Complete invasive and non-invasive data were also recorded on the day of investigation. During follow-up 44 pts were lost; there were 15 cardiac deaths (10%), life-saving ventricular assist device implantation in 10 (6.6%) and transplantation in 19 (12.7%). For statistical purposes this group was named the "events" Group B (n = 44). A predisposing factor for events (death, "true" decompensation and "urgent" transplantation in ambulatory patients) was low first peak ("cut-off value" assessed in Group 2 < 4100 mmHg*s3) (OR 45.6, CI 14.5 143.3, p < 0.001). Less powerful predictors of the risk of deterioration were pulmonary capillary pressure (PCP), diastolic pulmonary artery pressure (PAP) and E/A mitral wave relation (p = 0.05). CONCLUSIONS: The new ventricular-arterial coupling parameter 1st peak of WI can potentially be used to distinguish patients at high risk for true deterioration and death. This parameter can be used to predict the need for assist device implantation. PMID- 24956519 TI - Preparation and functional assessment of composite chitosan-nano-hydroxyapatite scaffolds for bone regeneration. AB - Composite chitosan-nano-hydroxyapatite microspheres and scaffolds prepared using a co-precipitation method have shown potential for use in bone regeneration. The goal of this research was to improve the functional properties of the composite scaffolds by modifying the fabrication parameters. The effects of degree of deacetylation (DDA), drying method, hydroxyapatite content and an acid wash on scaffold properties were investigated. Freeze-dried 61% DDA scaffolds degraded faster (3.5 +/- 0.5% mass loss) than air-dried 61% DDA scaffolds and 80% DDA scaffolds, but had a lower compressive modulus of 0.12 +/- 0.01 MPa. Air-dried 80% DDA scaffolds displayed the highest compressive modulus (3.79 +/- 0.51 MPa) and these scaffolds were chosen as the best candidate for use in bone regeneration. Increasing the amount of hydroxyapatite in the air-dried 80% DDA scaffolds did not further increase the compressive modulus of the scaffolds. An acid wash procedure at pH 6.1 was found to increase the degradation of air-dried 80% DDA scaffolds from 1.3 +/- 0.1% to 4.4 +/- 0.4%. All of the formulations tested supported the proliferation of SAOS-2 cells. PMID- 24956520 TI - Synthesis and evaluation of a molecularly imprinted polymer for selective solid phase extraction of irinotecan from human serum samples. AB - A molecularly imprinted polymer (MIP) was synthesized by non-covalent imprinting polymerization using irinotecan as template. Methacrylic acid and 4-vinylpyridine were selected as functional monomers. An optimized procedure coupled to LC-PDA analysis was developed for the selective solid-phase extraction of irinotecan from various organic media. A specific capacity of 0.65 umol*g-1 for the MIP was determined. The high specificity of this MIP was demonstrated by studying the retention behaviour of two related compounds, camptothecin and SN-38. This support was applied for the extraction of irinotecan from human serum samples. PMID- 24956522 TI - Development of ti-coated ferromagnetic needle, adaptable for ablation cancer therapy by high-frequency induction heating. AB - To develop a novel ablation therapy for human solid cancer, the heating properties of a ferromagnetic carbon steel rod and a prototype Ti-coated needle using this carbon steel rod, were investigated in several high-frequency outputs at 300 kHz. In the former, the heating property was drastically different among the three inclination angles (theta = 0 degrees , 45 degrees and 90 degrees ) relative to the magnetic flux direction as a result of the shape magnetic anisotropy. However, the effect of the inclination angles was completely eliminated in the latter. It is considered that the complete non-oriented heating property relative to the magnetic flux direction allows the precise control of the ablation temperature during minimally invasive thermotherapy without a lead wire connected to a fiber-optic thermometer. This newly designed Ti-coated device will be suitable for clinical use combined with its superior biocompatibility for ablation treatments using high-frequency induction heating. PMID- 24956523 TI - Gas-Foamed Scaffold Gradients for Combinatorial Screening in 3D. AB - Current methods for screening cell-material interactions typically utilize a two dimensional (2D) culture format where cells are cultured on flat surfaces. However, there is a need for combinatorial and high-throughput screening methods to systematically screen cell-biomaterial interactions in three-dimensional (3D) tissue scaffolds for tissue engineering. Previously, we developed a two-syringe pump approach for making 3D scaffold gradients for use in combinatorial screening of salt-leached scaffolds. Herein, we demonstrate that the two-syringe pump approach can also be used to create scaffold gradients using a gas-foaming approach. Macroporous foams prepared by a gas-foaming technique are commonly used for fabrication of tissue engineering scaffolds due to their high interconnectivity and good mechanical properties. Gas-foamed scaffold gradient libraries were fabricated from two biodegradable tyrosine-derived polycarbonates: poly(desaminotyrosyl-tyrosine ethyl ester carbonate) (pDTEc) and poly(desaminotyrosyl-tyrosine octyl ester carbonate) (pDTOc). The composition of the libraries was assessed with Fourier transform infrared spectroscopy (FTIR) and showed that pDTEc/pDTOc gas-foamed scaffold gradients could be repeatably fabricated. Scanning electron microscopy showed that scaffold morphology was similar between the pDTEc-rich ends and the pDTOc-rich ends of the gradient. These results introduce a method for fabricating gas-foamed polymer scaffold gradients that can be used for combinatorial screening of cell-material interactions in 3D. PMID- 24956521 TI - Anabolic Actions of the Regenerative Agent Enamel Matrix Derivative (EMD) in Oral Periosteal Fibroblasts and MG 63 Osteoblasts, Modulation by Nicotine and Glutathione in a Redox Environment. AB - Our study seeks to explore anabolic effects of a periodontal regenerative agent enamel matrix derivative (EMD). Its modulation by nicotine and the anti-oxidant glutathione (GSH) are investigated in human periosteal fibroblasts (HPF) and MG63 osteoblasts. Androgen biomarkers of oxidative stress and healing, resulting from radiolabeled androgen substrates are assayed. This in vitro model simulates a redox environment relevant to the periodontal lesion. It aims to confirm the hypothesis that EMD is an effective regenerative agent in a typically redox environment of the periodontal lesion. Monolayer cultures of MG63 osteoblasts and HPF established in culture medium are incubated with androgen substrates, and optimal concentrations of EMD, nicotine and GSH, alone and in combination. EMD significantly enhances yields of 5alpha-dihydrotestosterone (DHT) an effective bioactive metabolite, alone and in combination with GSH, to overcome oxidative effects of nicotine across cultures. The 'in vitro' findings of this study could be extrapolated to "in vivo" applications of EMD as an adjunctive regenerative therapeutic agent in an environment of chronic inflammation and oxidative stress. Increased yields of DHT implicated in matrix synthesis and direct antioxidant capacity, confirm the potential applications for enamel matrix derivative in periodontal regenerative procedures. PMID- 24956524 TI - Sustained Delivery of Chondroitinase ABC from Hydrogel System. AB - In the injured spinal cord, chondroitin sulfate proteoglycans (CSPGs) are the principal responsible of axon growth inhibition and they contribute to regenerative failure, promoting glial scar formation. Chondroitinase ABC (chABC) is known for being able to digest proteoglycans, thus degrading glial scar and favoring axonal regrowth. However, its classic administration is invasive, infection-prone and clinically problematic. An agarose-carbomer (AC1) hydrogel, already used in SCI repair strategies, was here investigated as a delivery system capable of an effective chABC administration: the material ability to include chABC within its pores and the possibility to be injected into the target tissue were firstly proved. Subsequently, release kinetic and the maintenance of enzymatic activity were positively assessed: AC1 hydrogel was thus confirmed to be a feasible tool for chABC delivery and a promising device for spinal cord injury topic repair strategies. PMID- 24956525 TI - Finite-element modeling of viscoelastic cells during high-frequency cyclic strain. AB - Mechanotransduction refers to the mechanisms by which cells sense and respond to local loads and forces. The process of mechanotransduction plays an important role both in maintaining tissue viability and in remodeling to repair damage; moreover, it may be involved in the initiation and progression of diseases such as osteoarthritis and osteoporosis. An understanding of the mechanisms by which cells respond to surrounding tissue matrices or artificial biomaterials is crucial in regenerative medicine and in influencing cellular differentiation. Recent studies have shown that some cells may be most sensitive to low-amplitude, high-frequency (i.e., 1-100 Hz) mechanical stimulation. Advances in finite element modeling have made it possible to simulate high-frequency mechanical loading of cells. We have developed a viscoelastic finite-element model of an osteoblastic cell (including cytoskeletal actin stress fibers), attached to an elastomeric membrane undergoing cyclic isotropic radial strain with a peak value of 1,000 ustrain. The results indicate that cells experience significant stress and strain amplification when undergoing high-frequency strain, with peak values of cytoplasmic strain five times higher at 45 Hz than at 1 Hz, and peak Von Mises stress in the nucleus increased by a factor of two. Focal stress and strain amplification in cells undergoing high-frequency mechanical stimulation may play an important role in mechanotransduction. PMID- 24956527 TI - Age and sex based reference values for incidental coronary artery and thoracic aorta calcifications on routine clinical chest CT: a powerful tool to appreciate available imaging findings. AB - OBJECTIVE: To establish age and gender specific reference values for incidental coronary artery and thoracic aorta calcification scores on routine diagnostic CT scans. These reference values can aid in structured reporting and interpretation of readily available imaging data by chest CT readers in routine practice. METHODS: A random sample of 1572 (57% male, median age 61 years) was taken from a study population of 12,063 subjects who underwent diagnostic chest CT for non cardiovascular indications between January 2002 and December 2005. Coronary artery and thoracic aorta calcifications were graded using a validated ordinal score. The 25th, 50th and 75th percentile cut points were calculated for the coronary artery and thoracic aorta calcification scores within each age/gender stratum. RESULTS: The 75th percentile cut points for coronary artery calcification scores were higher for men than for women across all age groups, with the exception of the lowest age group. The 75th percentile cut points for thoracic aorta calcifications scores were comparable for both genders across all age groups. Based on the obtained age and gender reference values a calculation tool is provided, that allows one to enter an individual's age, gender and calcification scores to obtain the corresponding estimated percentiles. CONCLUSIONS: The calculation tool as provided in this study can be used in daily practice by CT readers to examine whether a subject has high calcifications scores relative to others with the same age and gender. PMID- 24956528 TI - Niacin decreases leukocyte myeloperoxidase: mechanistic role of redox agents and Src/p38MAP kinase. AB - OBJECTIVES: Leukocyte myeloperoxidase (MPO) is a major player in the pathogenesis of various chronic diseases including atherosclerosis. This study proposes the novel concept that niacin, through reactive oxygen species (ROS)-mediated signaling, decreases neutrophil MPO release and its activity, protects apolipoprotein-AI (apo-AI) modification and improves HDL function. METHODS: Human blood leukocytes and leukocytic cell line HL-60 cells were treated with niacin, and stimulated with phorbol myristate acetate (PMA). Cellular and released MPO activity in the medium was measured by assessing chlorination of MPO-specific substrate. MPO protein release in the medium and apo-AI degradation was measured by Western blot analysis. Monocyte adhesion to human aortic primary endothelial cells was measured to assess biological function of HDL/apo-AI. RESULTS: PMA significantly increased leukocyte MPO activity in both intracellular extract and medium. Niacin (0.25-0.5 mM) decreased PMA-induced MPO activity (cellular and released in the media). Niacin also decreased MPO protein mass in the medium without affecting its mRNA expression. Increased NADPH oxidase and ROS production by PMA were also significantly inhibited by niacin. Studies with specific inhibitors suggest that ROS-dependent Src and p38MAP kinase mediate decreased MPO activity by niacin. Niacin blocked apo-AI degradation, and apo-AI from niacin treated cells decreased monocyte adhesion to aortic endothelial cells. CONCLUSIONS: These findings identify niacin as a potent inhibitor of leukocyte MPO release and MPO-mediated formation of dysfunctional HDL. Niacin and niacin related chemical entities may form important therapeutic agents for MPO-mediated inflammatory diseases. PMID- 24956526 TI - Insulin resistance and systemic inflammation, but not metabolic syndrome phenotype, predict 9 years mortality in older adults. AB - BACKGROUND: Although metabolic syndrome (MS) is a typical condition of middle aged/older person, the association between MS and mortality risk has not been confirmed in people over 65 years. We hypothesized that while in the elderly MS phenotype might lose its value in predicting mortality risk, the two core factors of MS, i.e. insulin resistance (IR) and low grade systemic inflammation (LGSI) would not. METHODS: 1011 community-dwelling older individuals (InCHIANTI study) were included. MS phenotype was defined by NCEP-ATP-III criteria. IR was calculated by HOMA; high-sensitivity C reactive protein was measured by ELISA. Subjects were divided into four groups based on presence/absence of IR (HOMA >= 2.27) and LGSI (hs-CRP >= 3 g/L): Group 1: no IR/LGSI (reference); Group 2: LGSI only; Group 3: IR only; Group 4: IR + LGSI. Hazard Ratios (HR) for 9-years cardiovascular (CVD) and total mortality, according to IR/LGSI groups, were estimated in subjects with (n.311) and without MS by Cox model. RESULTS: 31.8% of subjects with MS phenotype had no IR, 45.3% had no LGSI; moreover, 51% of subjects with both IR and LGSI didn't display the MS phenotype. MS phenotype was not associated with CVD (HR: 1.29; 95%C.I.:0.92-1.81) or total (HR: 1.07; 95%C.I.:0.86-1.34) mortality risk, whereas the presence of IR plus LGSI was associated with increased CVD (no MS: HR 2.07, 95%CI: 1.12-3.72; MS: HR 9.88, 95%CI: 2.18-4), and overall (no MS: HR 1.72, 95%CI: 1.001-3.17; MS: HR 1.51, 95%CI: 1.02-2.28) mortality risk. The presence of IR (HR: 6.90, 95%CI: 1.45-32) or LGSI (HR 7.56, 95%CI: 1.63-35) was associated with CVD mortality, only among individuals with MS phenotype. CONCLUSIONS: Among community-dwelling older individuals, IR and LGSI, but not MS phenotype, was associated with 9-years overall and CVD mortality risk. Since a reduced "overlap" between MS phenotype and its physiopathological core (IR and LGSI) might be present with aging, we suggest that the definition of MS might be more holistic in advanced age, and probably comprise the measurement of IR and LGSI. PMID- 24956529 TI - Prevalence of atherogenic dyslipidemia: association with risk factors and cardiovascular risk in Spanish working population. "ICARIA" study. AB - OBJECTIVE: The aim of this study was to assess the prevalence of atherogenic dyslipidemia (AD) and the lipid triad (LT) in the working population in Spain, their associated variables and how far they are linked to cardiovascular risk (CVR). METHODS: Observational cross-sectional study of 70,609 workers (71.5% male (M), 28.5% female (F), mean age 39.2 +/- 10), who attended medical checkups and agreed to participate. Plasma samples were analysed in a central laboratory. AD definition used was: triglycerides >=150 mg/dl and HDL cholesterol <40 mg/dl (M)/<50 mg/dl (F) and LT when LDL cholesterol > 160 mg/dl is further added. Univariate comparisons in the absence and presence of AD and LT and the probability of AD according to different parameters and their possible association with CVR were assessed. CVR was stratified following the European SCORE model for low risk-population. RESULTS: 5.7% (95% CI 4.7-6.9) of the working population have AD and 1.1% (95% CI 1.0-1.2) LT. In univariate analysis, workers with AD and LT had a higher prevalence of obesity, hypertension, smoking and diabetes than those who had not (p < 0.001). In multivariate analysis, BMI, sex, age 40-49, diabetes, tobacco, uric acid, LDL or blood pressure significantly influenced the risk of AD. AD was significantly associated with CVR after adjusting for alcohol and obesity. However, most of the AD subjects (91.8%) were classified as low risk. CONCLUSIONS: About 6% of the working population in Spain meets AD criteria. Assuming that these subjects have increased CVR, AD allows to identify additional 5% of subjects with increased CVR to that one the SCORE model detects, helping to improve cardiovascular risk stratification. PMID- 24956530 TI - Impact of overweight on myocardial infarct size in patients undergoing primary percutaneous coronary intervention: a magnetic resonance imaging study. AB - OBJECTIVE: Although obesity is a risk factor for cardiovascular disease and mortality, several studies have reported that patients with obesity who have suffered acute myocardial infarction or have undergone percutaneous coronary intervention (PCI) have better clinical outcomes than their normal weight counterparts. We evaluated the impact of overweight on myocardial infarct size in patients undergoing primary PCI for ST-segment elevation myocardial infarction (STEMI). METHODS: We performed contrast-enhanced magnetic resonance imaging on 193 patients undergoing primary PCI for STEMI. Infarct size was measured with delayed-enhancement imaging and the area at risk was quantified on T2-weighted images. RESULTS: Baseline characteristics and angiographic findings were not significantly different between the normal weight group (body mass index [BMI] < 25 kg/m(2), n = 110) and the overweight group (BMI >= 25 kg/m(2), n = 83). The median percent infarct volume and area at risk were significantly smaller in the overweight group than the normal weight group (17.9% [9.0-24.9%] vs. 20.8% [11.4 33.1%], p = 0.04 and 29.4% [20.5-37.6%] vs. 36.0% [25.7-49.6%], p < 0.01, respectively). However, the myocardial salvage index was not different between the 2 groups (overweight group vs. normal weight group, 43.2% vs. 39.2%, p = 0.69). BMI >= 25 kg/m(2) was an independent predictor of smaller infarct size in multivariate analysis (Odds ratio 0.51, 95% Confidence interval 0.27-0.97, p = 0.039). CONCLUSION: Overweight (BMI >= 25 kg/m(2)) is independently associated with smaller infarct size in patients undergoing primary PCI for STEMI. PMID- 24956531 TI - Sex-specific associations of cardiovascular risk factors with carotid stiffness- results from the SAPALDIA cohort study. AB - OBJECTIVE: Manifestation of cardiovascular disease (CVD) occurs with clear sex differences. Carotid stiffness (CS) parameters are increasingly used for CVD risk assessment but the sex-specific association with CVD risk factors as well as association patterns between CS parameters are largely unknown, which we investigated in SAPALDIA population-based cohort participants. METHODS: Risk factors of 2545 participants without clinically manifest disease were evaluated in 2001-2003 and different CS parameters were assessed in carotid ultrasound scans in 2010-2011. Stratified and non-stratified mixed linear models and multivariate regression analyses were used to examine sex-specific associations, differences and association patterns of single risk factors and CS parameters. RESULTS: HDL cholesterol was the only significant protective determinant of reduced CS for both sexes (ranges of CS parameters: -3.7; -0.8% of changes in geometric mean per 1SD of the risk factor on an inverted scale) and significant adverse risk factors were BMI (-0.5; 4.7%), systolic (-1.23; 4.7%) and diastolic blood pressure (1.4; 4.4%), heart rate (2.7; 7.9%), C-reactive protein (0.6; 3.3%) and smoking (-2.82; 1%), all p-values of multivariate analyses were <0.01. Sex differences with stiffer CS parameters in men were observed for increased heart rate (p = 0.001) and LDL cholesterol (p < 0.001) and in women for triglyceride (p < 0.003). Similar association patterns were found for most CS parameters. CONCLUSION: Sex-specific associations of cardiovascular risk factors may reflect a sex-specific burden of atherosclerotic risk factors and similar association patterns across different CS parameters within men and women may allow the use of CS parameters in an exchangeable manner. PMID- 24956532 TI - Cardiovascular risk in patients achieving low-density lipoprotein cholesterol and particle targets. AB - OBJECTIVES: Previous research suggests that LDL particle number (LDL-P) may be a better tool than LDL cholesterol (LDL-C) to guide LDL-lowering therapy. Using real-world data, this study has two objectives: [1] to determine the incidence of CHD across LDL-P thresholds; and [2] to compare CHD/stroke events among patients achieving comparably low LDL-P or LDL-C levels. METHODS: A claims analysis was conducted among high-risk patients identified from the HealthCore Integrated Research Database(SM). The impact of LDL levels on risk was compared across cohorts who achieved LDL-P <1000 nmol/L or LDL-C <100 mg/dL. Cohorts were matched to balance demographic and comorbidity differences. RESULTS: Among 15,569 patients with LDL-P measurements, the risk of a CHD event increased by 4% for each 100 nmol/L increase in LDL-P level (HR 1.04; 95% CI 1.02-1.05, p < .0001). The comparative analysis included 2,094 matched patients with >=12 months of follow-up, 1,242 with >=24 months and 705 with >=36 months. At all time periods, patients undergoing LDL-P measurement were more likely to receive intensive lipid lowering therapy and had a lower risk of CHD/stroke than those in the LDL-C cohort (HR: 0.76; 95% CI: 0.61-0.96; at 12 months). CONCLUSIONS: In this real world sample of commercially insured patients, higher LDL-P levels were associated with increased CHD risk. Moreover, high-risk patients who achieved LDL P <1000 nmol/L received more aggressive lipid-lowering therapy than patients achieving LDL-C <100 mg/dL, and these differences in lipids and therapeutic management were associated with a reduction in CHD/stroke events over 12, 24 and 36 months follow-up. PMID- 24956533 TI - Oxidized but not native cardiolipin has pro-inflammatory effects, which are inhibited by Annexin A5. AB - OBJECTIVE: Cardiolipin (CL) is a phospholipid with an unusual dimeric structure containing four double-bonds and is easily oxidized. CL is present in mitochondria. Here we explored potential pro-inflammatory properties implicated in cardiovascular disease (CVD): activation of endothelial cells, 5-lipoxygenase (5-LOX) and leukotriene B4 (LTB4), by oxidized CL (oxCL) and inhibitory effects of Annexin A5, an antithrombotic and antiinflammatory plasma protein. METHODS: In monocytes/macrophages and neutrophils, calcium mobilization was monitored spectrophotometrically with Fura-2 and synthesis of LTB4 was analyzed by EIA. Expression of adhesion molecules on endothelial cells was studied by FACScan. Binding of Annexin A5 were analyzed by ELISA. The mRNA expression of 5-LOX and cyclooxygenase-2 was assessed by Real-Time PCR. RESULTS: We demonstrate that oxCL but not its non-oxidized counterpart CL induces biosynthesis of LTB4 and increases intracellular concentrations of calcium in monocytes/macrophages and neutrophils. oxCL rather than CL selectively elevates gene expression of 5-LOX but not COX-2 in human macrophages. Furthermore, oxCL but not CL raises levels of adhesion molecules ICAM-1 and VCAM-1 in endothelial cells. Annexin A5 can bind oxCL to abolish all these oxCL-induced effects. CONCLUSIONS: oxCL may promote inflammation and related diseases especially in conditions involving unresolved apoptosis and necrosis, such as atherosclerosis, where free oxCL is likely to be released from liberated mitochondria. Increased intracellular calcium could activate 5-LOX to produce Leukotriene B4 (LTB4). Annexin A5 inhibits the pro inflammatory effects of oxCL and its potential therapeutic use when oxCL is implicated in inflammation could be of interest. PMID- 24956537 TI - Expertise finding in bibliographic network: topic dominance learning approach. AB - Expert finding problem in bibliographic networks has received increased interest in recent years. This problem concerns finding relevant researchers for a given topic. Motivated by the observation that rarely do all coauthors contribute to a paper equally, in this paper, we propose two discriminative methods for realizing leading authors contributing in a scientific publication. Specifically, we cast the problem of expert finding in a bibliographic network to find leading experts in a research group, which is easier to solve. We recognize three feature groups that can discriminate relevant experts from other authors of a document. Experimental results on a real dataset, and a synthetic one that is gathered from a Microsoft academic search engine, show that the proposed model significantly improves the performance of expert finding in terms of all common information retrieval evaluation metrics. PMID- 24956535 TI - The relationship of novel adipokines, RBP4 and omentin-1, with carotid atherosclerosis severity and vulnerability. AB - OBJECTIVE: We investigated the relationship of circulating novel adipokines, retinol-binding protein 4 (RBP4) and omentin-1, with advanced carotid atherosclerosis and ultrasound indexes of severity (total plaque area-TPA) and plaque echogenicity and vulnerability (Gray-Scale median - GSM score). METHODS: We enrolled 225 patients with high-grade carotid stenosis (HGCS) who underwent carotid revascularization (73 Symptomatic patients, 152 asymptomatic patients) and 75 age- and sex-matched, asymptomatic individuals with low-grade (<50%) carotid stenosis (LGCS). Seventy-three individuals without current manifestations of atherosclerotic disease served as control group (COG). All participants underwent carotid ultrasound with TPA and GSM score assessment. Moreover, clinical parameters, metabolic profile, and circulating levels of hsCRP and adipokines were assessed. RESULTS: RBP4 was significantly elevated in HGCS (51.44 +/- 16.23 mg/L) compared to LGCS (38.39 +/- 8.85 mg/L), independent of symptoms existence, whereas RBP4 levels in COG were even lower (25.74 +/- 10.72 mg/L, p < 0.001 compared to either HGCS or LGCS). Inversely, serum omentin-1 levels were significantly lower across HGCS (490.41 +/- 172 ng/ml) and LGCS (603.20 +/- 202.43 ng/ml) than COG (815.3 +/- 185.32, p < 0.001). Moreover, the considerable difference between HGCS and LGCS (p < 0.001) was exclusively attributed to the excessive suppression of omentin-1 concentrations in symptomatic versus asymptomatic (p = 0.004) patients. HGCS and LGCS did not differ in the rest of clinical and biochemical parameters. In multiple regression analysis, RBP4 (beta = 0.232, p = 0.025) and hsCRP (beta = 0.300, p = 0.004) emerged as independent determinants of TPA in patients with carotid atherosclerosis. Low serum levels of omentin-1 correlated with GSM score and symptoms but that association was lost in multivariate analysis.. CONCLUSION: RBP4 serum levels were significantly elevated in patients with established carotid atherosclerosis and were positively associated with atherosclerosis severity. The association of low serum omentin-1 with carotid plaque echolucency requires further investigation.. ClinicalTrials.gov Identifier: NCT00636766. PMID- 24956538 TI - A quasi-dense matching approach and its calibration application with Internet photos. AB - This paper proposes a quasi-dense matching approach to the automatic acquisition of camera parameters, which is required for recovering 3-D information from 2-D images. An affine transformation-based optimization model and a new matching cost function are used to acquire quasi-dense correspondences with high accuracy in each pair of views. These correspondences can be effectively detected and tracked at the sub-pixel level in multiviews with our neighboring view selection strategy. A two-layer iteration algorithm is proposed to optimize 3-D quasi-dense points and camera parameters. In the inner layer, different optimization strategies based on local photometric consistency and a global objective function are employed to optimize the 3-D quasi-dense points and camera parameters, respectively. In the outer layer, quasi-dense correspondences are resampled to guide a new estimation and optimization process of the camera parameters. We demonstrate the effectiveness of our algorithm with several experiments. PMID- 24956539 TI - Distributed soft-data-constrained multi-model particle filter. AB - A distributed nonlinear estimation method based on soft-data-constrained multimodel particle filtering and applicable to a number of distributed state estimation problems is proposed. This method needs only local data exchange among neighboring sensor nodes and thus provides enhanced reliability, scalability, and ease of deployment. To make the multimodel particle filtering work in a distributed manner, a Gaussian approximation of the particle cloud obtained at each sensor node and a consensus propagation-based distributed data aggregation scheme are used to dynamically reweight the particles' weights. The proposed method can recover from failure situations and is robust to noise, since it keeps the same population of particles and uses the aggregated global Gaussian to infer constraints. The constraints are enforced by adjusting particles' weights and assigning a higher mass to those closer to the global estimate represented by the nodes in the entire sensor network after each communication step. Each sensor node experiences gradual change; i.e., if a noise occurs in the system, the node, its neighbors, and consequently the overall network are less affected than with other approaches, and thus recover faster. The efficiency of the proposed method is verified through extensive simulations for a target tracking system which can process both soft and hard data in sensor networks. PMID- 24956534 TI - Associations between nonalcoholic fatty liver disease and subclinical atherosclerosis in middle-aged adults: the Coronary Artery Risk Development in Young Adults Study. AB - OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is an obesity-related condition associated with cardiovascular mortality. Yet, whether or not NAFLD is independently related to atherosclerosis is unclear. In a population-based cross sectional sample of middle-aged adults free from liver or heart disease, we tested the hypothesis that NAFLD is associated with subclinical atherosclerosis (coronary artery (CAC) and abdominal aortic calcification (AAC)) independent of obesity. METHODS: Participants from the Coronary Artery Risk Development in Young Adults study with CT quantification of liver fat, CAC and AAC were included (n = 2424). NAFLD was defined as liver attenuation <=40 Hounsfield Units after exclusion of other causes of liver fat. CAC and AAC presence was defined as Agatston score >0. RESULTS: Mean participant age was 50.1 +/- 3.6 years, (42.7% men, 50.0% black) and BMI was 30.6 +/- 7.2 kg/m(2). The prevalence of NAFLD, CAC, and AAC was 9.6%, 27.1%, and 51.4%. NAFLD participants had increased prevalence of CAC (37.9% vs. 26.0%, p < 0.001) and AAC (65.1% vs. 49.9%, p < 0.001). NAFLD remained associated with CAC (OR, 1.33; 95% CI, 1.001-1.82) and AAC (OR, 1.74; 95% CI, 1.29-2.35) after adjustment for demographics and health behaviors. However, these associations were attenuated after additional adjustment for visceral adipose tissue (CAC OR, 1.05; 95% CI, 0.74-1.48, AAC OR = 1.20; 95% CI, 0.86-1.67). There was no interaction by race or sex. CONCLUSION: In contrast to prior research, these findings suggest that obesity attenuates the relationship between NAFLD and subclinical atherosclerosis. Further studies evaluating the role of NAFLD duration on atherosclerotic progression and cardiovascular events are needed. PMID- 24956540 TI - Controller design for TS models using delayed nonquadratic Lyapunov functions. AB - In the last few years, nonquadratic Lyapunov functions have been more and more frequently used in the analysis and controller design for Takagi-Sugeno fuzzy models. In this paper, we developed relaxed conditions for controller design using nonquadratic Lyapunov functions and delayed controllers and give a general framework for the use of such Lyapunov functions. The two controller design methods developed in this framework outperform and generalize current state-of the-art methods. The proposed methods are extended to robust and Hinfinity control and alpha -sample variation. PMID- 24956536 TI - Requirement of JNK1 for endothelial cell injury in atherogenesis. AB - OBJECTIVE: The c-Jun N-terminal kinase (JNK) family regulates fundamental physiological processes including apoptosis and metabolism. Although JNK2 is known to promote foam cell formation during atherosclerosis, the potential role of JNK1 is uncertain. We examined the potential influence of JNK1 and its negative regulator, MAP kinase phosphatase-1 (MKP-1), on endothelial cell (EC) injury and early lesion formation using hypercholesterolemic LDLR(-/-) mice. METHODS AND RESULTS: To assess the function of JNK1 in early atherogenesis, we measured EC apoptosis and lesion formation in LDLR(-/-) or LDLR(-/-)/JNK1(-/-) mice exposed to a high fat diet for 6 weeks. En face staining using antibodies that recognise active, cleaved caspase-3 (apoptosis) or using Sudan IV (lipid deposition) revealed that genetic deletion of JNK1 reduced EC apoptosis and lesion formation in hypercholesterolemic mice. By contrast, although EC apoptosis was enhanced in LDLR(-/-)/MKP-1(-/-) mice compared to LDLR(-/-) mice, lesion formation was unaltered. CONCLUSION: We conclude that JNK1 is required for EC apoptosis and lipid deposition during early atherogenesis. Thus pharmacological inhibitors of JNK may reduce atherosclerosis by preventing EC injury as well as by influencing foam cell formation. PMID- 24956541 TI - Collaborative multifeature fusion for transductive spectral learning. AB - Much existing work of multifeature learning relies on the agreement among different feature types to improve the clustering or classification performance. However, as different feature types could have different data characteristics, such a forced agreement among different feature types may not bring a satisfactory result. We propose a novel transductive learning approach that considers multiple feature types simultaneously to improve the classification performance. Instead of forcing different feature types to agree with each other, we perform spectral clustering in different feature types separately. Each data sample is then described by a co-occurrence of feature patterns among different feature types, and we apply these feature co-occurrence representations to perform transductive learning, such that data samples of similar feature co occurrence pattern will share the same label. As the spectral clustering results in different feature types and the formed co-occurrence patterns influence each other under the transductive learning formulation, an iterative optimization approach is proposed to decouple these factors. Different from co-training that need to iteratively update individual feature type, our method allows all feature types to collaborate simultaneously. It can naturally handle multiple feature types together and is less sensitive to noisy feature types. The experimental results on synthetic, object, and action recognition datasets all validate the advantages of our method compared to state-of-the-art methods. PMID- 24956542 TI - The BCL-2 family protein Bid is critical for pro-inflammatory signaling in astrocytes. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons in the spinal cord, brainstem and motor cortex. Mutations in the superoxide dismutase 1 (SOD1) gene represent a frequent genetic determinant and recapitulate a disease phenotype similar to ALS when expressed in mice. Previous studies using SOD1(G93A) transgenic mice have suggested a paracrine mechanism of neuronal loss, in which cytokines and other toxic factors released from astroglia or microglia trigger motoneuron degeneration. Several pro-inflammatory cytokines activate death receptors and may downstream from this activate the Bcl-2 family protein, Bid. We here sought to investigate the role of Bid in astrocyte activation and non-cell autonomous motoneuron degeneration. We found that spinal cord Bid protein levels increased significantly during disease progression in SOD1(G93A) mice. Subsequent experiments in vitro indicated that Bid was expressed at relatively low levels in motoneurons, but was enriched in astrocytes and microglia. Bid was strongly induced in astrocytes in response to pro-inflammatory cytokines or exposure to lipopolysaccharide. Experiments in bid-deficient astrocytes or astrocytes treated with a small molecule Bid inhibitor demonstrated that Bid was required for the efficient activation of transcription factor nuclear factor-kappaB in response to these pro-inflammatory stimuli. Finally, we found that conditioned medium from wild-type astrocytes, but not from bid-deficient astrocytes, was toxic when applied to primary motoneuron cultures. Collectively, our data demonstrate a new role for the Bcl-2 family protein Bid as a mediator of astrocyte activation during neuroinflammation, and suggest that Bid activation may contribute to non cell autonomous motoneuron degeneration in ALS. PMID- 24956543 TI - Pure word deafness after resection of a Vein of Galen aneurysm and arteriovenous malformation: report of a case. PMID- 24956544 TI - The incidence of postoperative thromboembolic complications following surgical resection of intracranial meningioma. A retrospective study of a large single center patient cohort. AB - BACKGROUND: Patients with meningiomas carry an increased risk for postoperative venous thromboembolic complications (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE). OBJECTIVE: In the present retrospective study we investigated the incidence of VTE and the risk factors involved, in a large cohort of patients surgically treated for an intracranial meningioma at our institution. METHODS: During the period from January 1997 to January 2009, 581 consecutive patients underwent craniotomy for intracranial meningioma. All patients received low-molecular weight heparins as thromboembolism prophylaxis. Patient demographics and tumor characteristics were gathered via retrospective chart review. Postoperative VTE and hemorrhages were noted. Backward stepwise logistic regression was used to determine the risk factors. RESULTS: 80.6% of meningiomas were WHO grade 1; 15.1% WHO grade 2; 4.3% WHO grade 3. Postoperative VTE were observed in 41 patients (7.2%). Of these, DVT was seen in 20 (3.5%) and PE in 26 patients (4.6%). The thromboembolic complication appeared on average 21.1+/-29.2 days post surgery. The 90-day mortality rate after VTE was 11.2% (23.1% for PE and 5.0% for DVT). Postoperative hemorrhages requiring surgical treatment were found in 2.9% of patients. Risk factors for VTE were body mass index (p=0.015) for DVT; weight (p=0.001) and bedridden postoperatively (p=0.001) for PE; and weight (p=0.004) and bedridden postoperatively (p=0.003) for VTE in general. There was no relation between tumor grade and thromboembolic complications. CONCLUSION: The major risk factors for postoperative VTE found in our single center study are patient weight and a bedridden status postoperatively. Prophylactic intervention for this potentially fatal complication should be evaluated against the relative lower risk of postoperative hemorrhages. PMID- 24956545 TI - Supraspinal stimulation for treatment of refractory pain. AB - Refractory pain syndromes often have far reaching effects and are quite a challenge for primary care providers and specialists alike to treat. With the help of site-specific neuromodulation and appropriate patient selection these difficult to treat pain syndromes may be managed. In this article, we focus on supraspinal stimulation (SSS) for treatment of intractable pain and discuss off label uses of deep brain stimulation (DBS) and motor cortex stimulation (MCS) in context to emerging indications in neuromodulation. Consideration for neuromodulatory treatment begins with rigorous patient selection based on exhaustive conservative management, elimination of secondary gains, and a proper psychology evaluation. Trial stimulation prior to DBS is nearly always performed while trial stimulation prior to MCS surgery is symptom dependent. Overall, a review of the literature demonstrates that DBS should be considered for refractory conditions including nociceptive/neuropathic pain, phantom limb pain, and chronic cluster headache (CCH). MCS should be considered primarily for trigeminal neuropathic pain (TNP) and central pain. DBS outcome studies for post stroke pain as well as MCS studies for complex regional pain syndrome (CRPS) show more modest results and are also discussed in detail. PMID- 24956546 TI - The relation of early hypernatremia with clinical outcome in patients suffering from aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: Sodium dysregulation in the course after aneurysmal subarachnoid hemorrhage (aSAH) has been identified as one contributor to adverse clinical outcome. However, the correlation of acute dysnatremia and early brain injury (EBI) remains unclear. We investigated the early course and prognostic relevance of changes in serum sodium concentrations and its relation to EBI after aSAH. METHODS: Retrospectively, the serum sodium concentration (SSC) of 264 patients with aSAH was analyzed. The first SSC was obtained within 8h after initial ictus and then repeatedly analyzed every 8h over the first five days. Incidence of hypernatremia (defined as SSC>145mmol/l) was correlated with initial neurological condition according to World Federation of Neurological Surgeons grade (WFNS), incidence of delayed cerebral ischemia (DCI) and clinical outcome at 12 month according to modified Rankin Scale (mRS). RESULTS: Within 56h, 82 patients (31.1%) developed hypernatremia which correlated significantly with initial neurological condition (p<0.001). Initial SSC within 8h after SAH did not correlate with patient outcome at 12 month (r=-0.026, p=0.694), however SSC obtained 56h after ictus did significantly (r=0.365, p<0.001; OR 4.14 95% CI (1.84-9.31)). A correlation with the incidence of DCI was not found (r=0.079, p=0.217). CONCLUSION: The occurrence of hypernatremia within 56h after aSAH was shown to be an independent predictor for poor neurological outcome. Early serum sodium levels after aSAH can be considered as surrogate markers to predict outcome after aSAH irrespective to the occurrence of DCI. However, prospective studies are necessary to validate this concept. PMID- 24956547 TI - Assessing preventability of maternal mortality in Illinois: 2002-2012. AB - OBJECTIVE: We sought to describe the potential preventability of pregnancy related deaths in Illinois from 2002 through 2012 as determined by perinatal centers following the Illinois maternal death review process. STUDY DESIGN: We conducted a retrospective review of all known maternal deaths in the state from 2002 through 2012 with complete records in the Illinois Department of Public Health's Maternal Mortality Review Form database. The association between causes of death and potential preventability was analyzed for pregnancy-related deaths. RESULTS: There were 610 maternal deaths in Illinois during the study period (31.8 per 100,000 live births). One-third of maternal deaths (n = 210) were directly or indirectly related to pregnancy, 7.0% (n = 43) were possibly related, and 52.6% (n = 321) were unrelated. Vascular causes were the most common cause of pregnancy related death, followed by cardiac causes and hemorrhage. One-third of deaths directly or indirectly related to pregnancy were deemed potentially preventable. Hemorrhage and deaths due to psychiatric causes were most likely to be considered avoidable, while cancer and vascular-related deaths were generally not considered preventable. CONCLUSION: This analysis of pregnancy-related deaths in Illinois, the first in >60 years, found similar causes of death and potential preventability as pregnancy-related death reviews in other states. Analyzing the causes of pregnancy-related death is a critical and necessary step in improving maternal health outcomes, particularly in decreasing potentially preventable pregnancy-related deaths. Greater attention should be directed toward intervening on the provider, systems, and patient factors contributing to preventable deaths. PMID- 24956548 TI - Geographic variation of reproductive health indicators and outcomes in the United States: place matters. AB - The social determinants of health are the circumstances in which people are born, grow up, live, work, and age and the systems put in place to deal with illness. These circumstances, in turn, are shaped by a wider set of forces: economics, social policies, and politics. Reproductive health indicators and conditions that are germane to obstetricians and gynecologists vary across states and regions in the United States as well as within regions and states. The aim of this article is to illustrate this variation with the use of examples of gynecologic malignancies, sexually transmitted infections, teen birth rates, preterm birth rates, and infant mortality rates. Using the example of infant death, the difficulties in "unpacking" the construct of place will be discussed, and a special emphasis is placed on the interaction of race, place, and disparities in shaping perinatal outcomes. Finally, readily available and easy-to-use online data resources will be provided so that obstetricians and gynecologists will be able to assess geographic variation in health indicators and outcomes in their own localities. PMID- 24956549 TI - Evidence of mononuclear cell preactivation in the fasting state in polycystic ovary syndrome. AB - OBJECTIVE: We evaluated mononuclear cell (MNC) preactivation in women with polycystic ovary syndrome (PCOS) by examining the effect of in vitro lipopolysaccharide (LPS) exposure on cytokine release in the fasting state. STUDY DESIGN: Twenty women with PCOS (10 lean, 10 obese) and 20 weight-matched controls (10 lean, 10 obese) volunteered for study participation. Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) release was measured from mononuclear cells isolated from fasting blood samples and cultured in the presence and absence of LPS. Plasma IL-6 was measured from the same fasting blood samples. Insulin sensitivity was derived from an oral glucose tolerance test using the Matsuda index, and truncal fat was measured by dual-energy x-ray absorptiometry. RESULTS: The percent change from baseline in TNF-alpha and IL-6 release from MNC following LPS exposure was increased (P < .04) in lean and obese women with PCOS and obese controls compared with lean controls. Plasma IL-6 was increased (P < .02) in obese women with PCOS compared with lean women with PCOS, which in turn was increased (P < .02) compared with lean controls. The MNC-derived TNF-alpha and IL-6 responses from MNCs were negatively correlated with insulin sensitivity (P < .03) and positively correlated with testosterone (P < .03) and androstenedione (P < .006) for the combined groups. Plasma IL-6 was positively correlated with percentage truncal fat (P < .008). CONCLUSION: In PCOS, increased cytokine release from MNCs following LPS exposure in the fasting state reveals the presence of MNC preactivation. Importantly, this phenomenon is independent of obesity and may contribute to the development of insulin resistance and hyperandrogenism in PCOS. In contrast, the source of plasma IL-6 elevations in PCOS may be excess adiposity. PMID- 24956550 TI - Mode of delivery in women with class III obesity: planned cesarean compared with induction of labor. AB - OBJECTIVE: To compare maternal and neonatal outcomes between planned cesarean delivery and induction of labor in women with class III obesity (body mass index >=40 kg/m(2)). STUDY DESIGN: In this retrospective cohort study, we identified all women with a body mass index >=40 kg/m(2) who delivered a singleton at our institution from January 2007 to February 2013 via planned cesarean or induction of labor (regardless of eventual delivery route) at 37-41 weeks. Patients in spontaneous labor were excluded. The primary outcome was a composite of maternal morbidity including death as well as operative, infection, and thromboembolic complications. The secondary outcome was a neonatal morbidity composite. Additional outcomes included individual components of the composites. Student t, chi(2), and Fisher exact tests were used for statistical analysis. To calculate adjusted odds ratios, covariates were analyzed via multivariable logistic regression. RESULTS: There are 661 mother-infant pairs that met enrollment criteria-399 inductions and 262 cesareans. Groups were similar in terms of prepregnancy weight, pregnancy weight gain, and delivery body mass index. Of the 399 inductions, 258 had cervical ripening (64.7%) and 163 (40.9%) had a cesarean delivery. After multivariable adjustments, there was no significant difference in the maternal morbidity composite (adjusted odds ratio, 0.98; 95% confidence interval, 0.55-1.77) or in the neonatal morbidity composite (adjusted odds ratio, 0.81; 95% confidence interval, 0.37-1.77) between the induction and cesarean groups. CONCLUSION: In term pregnant women with class III obesity, planned cesarean does not appear to reduce maternal and neonatal morbidity compared with induction of labor. PMID- 24956551 TI - Effects of stress and depression on inflammatory immune parameters in pregnancy. AB - There is a substantial body of literature that links psychological stress to adverse pregnancy outcomes, particularly preterm birth. Comparatively few studies have examined potential biologic mechanisms that explain these associations. Attention to inflammatory processes is warranted. This article describes emerging studies that demonstrate that, as in nonpregnant humans and animals, psychological stress and distress (ie, depressive symptoms) predict dysregulation of inflammatory processes in human pregnancy. This includes elevations in circulating inflammatory cytokines, exaggerated inflammatory responses to in vivo biologic challenges, and more robust inflammatory responses to psychological challenges. Continued research in this area is needed to determine the implications of such stress-induced immune dysregulation for birth outcomes and for maternal health and fetal development. PMID- 24956552 TI - Synthesis and antitumor activity of pyrido [2,3-d]pyrimidine and pyrido[2,3-d] [1,2,4]triazolo[4,3-a]pyrimidine derivatives that induce apoptosis through G1 cell-cycle arrest. AB - New series of 2-(2-arylidenehydrazinyl)pyrido[2,3-d]pyrimidines 5a-e and pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines 6-15 were synthesized and evaluated for their cytotoxic activity against two cancer cell lines, namely PC-3 prostate cancer and A-549 lung cancer. Some of the tested compounds displayed high growth inhibitory activity against PC-3 cells. Whereas, compounds 5b and 15f showed relatively potent antitumor activity against PC-3 and A-549 cell lines. In particular, 4-(3-acetyl-5-oxo-6-phenyl-8-(thiophen-2-yl)pyrido[2,3 d][1,2,4]triazolo[4,3-a]pyrimidin-1(5H)-yl)benzenesulfonamide 15f exhibited superior antitumor activity against both cell lines at submicromolar level (IC50 = 0.36, 0.41 MUM, respectively). Moreover, the potential mechanisms of the cytotoxic activity of the promising compound 15f on the more sensitive cell line PC-3 were studied. The data indicated that 15f was able to cause cell cycle arrest at least partly through enhancing the expression level of the cell cycle inhibitor p21 and induced cancer cell apoptosis via caspase-3 dependent pathway. PMID- 24956554 TI - Discovery and SAR studies of a novel class of cytotoxic 1,4-disubstituted piperidines via Ugi reaction. AB - Herein we report a novel class of 1,4-disubstituted piperidines as potential anticancer agents. One-step and efficient synthesis of a structurally diverse library of piperidine-based analogs with five points of diversity has been developed using the Ugi four-component reaction. A structure-activity relationship (SAR) study showed that the presence of a benzyl or a Boc group at the N-1 position together with two or three aromatic groups at the C-4 position of the piperidine ring are important for optimal cytostatic properties. Compounds 20, 22, 27 and 29 were found to be the most potent with a 50% inhibitory concentration (IC50) ranging between 3 and 9.5 MUM in the cancer cell lines evaluated. The NCI60 screen confirmed this 50% cytostatic concentration range for compound 20, irrespective of the nature of the tumor cell lines evaluated. The NCI COMPARE algorithm did not show any significant correlation between the growth inhibition profile of compound 20 with the NCI database compound profiles suggesting a potential novel mechanism of action. PMID- 24956553 TI - Synthesis and antiparasitic activity of new bis-arylimidamides: DB766 analogs modified in the terminal groups. AB - Fifteen novel bis-arylimidamide derivatives with various 6-membered (7a-c) and 5 membered (7d-o) heterocyclic rings replacing the terminal pyridyl rings of the lead compound DB766{(2,5-bis[2-i-propoxy-4-(2-pyridylimino)aminophenylfuran]}, were prepared and evaluated versus Trypanosoma cruzi, Leishmania amazonensis, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Compound 7a with pyrimidine replacing the pyridine rings showed good activity versus T. cruzi, T. brucei rhodesiense and P. falciparum (IC50 = 200 nM, 32 nM and 8.5 nM, respectively). Three compounds (7g, 7i, 7j) with thiazole replacing the pyridine rings gave low micromolar (0.17-0.3 MUM) IC50 values versus L. amazonensis, however only 7g exhibited an acceptable selectivity index (SI = 27). Compounds 7a, 7j and 7m exhibited potent activity against T. brucei rhodesiense (IC50 = 12 60 nM). Ten of the 15 compounds with pyrimidine, pyrrole, thiazole and imidazole terminal units were highly active against P. falciparum (IC50 = 9-87 nM). Both pyrimidine and pyridine terminal groups are advantageous for anti-T. cruzi activity and several different heterocyclic terminal units are effective versus P. falciparum, both findings merit further investigation. PMID- 24956555 TI - Synthesis of new class of spirocarbocycle derivatives by multicomponent domino reaction and their evaluation for antimicrobial, anticancer activity and molecular docking studies. AB - A series of 25 new spirocarbocycles were synthesized by a three component reaction that involves few cyclic nucleophiles, vinyl malononitriles and aldehydes with variable substitution patterns. All the synthesized compounds were evaluated for their antimicrobial activity and the compounds showed significant activity. Synthesized compounds 4c, 4i and 6i showed good anticancer activity against A549 cancer cell line. Molecular docking studies indicated that compound 4i had the greatest affinity for DNA gyrase receptor than others and compound 6i had the greatest affinity for anaplastic lymphoma kinase (ALK) receptor. These compounds can be better therapeutic agents for microbial and cancer cell lines. PMID- 24956556 TI - Structure-activity relationships of 2'-modified-4'-selenoarabinofuranosyl pyrimidines as anticancer agents. AB - Based on the potent anticancer activity of the D-arabino-configured cytosine nucleoside ara-C, novel 2'-substituted-4'-selenoarabinofuranosyl pyrimidines 3a 3u, comprising azido, fluoro, and hydroxyl substituents at C-2' were designed, synthesized, and evaluated for anticancer activity. The 2'-azido group was stereoselectively introduced by the Mitsunobu reaction using diphenylphosphoryl azide (DPPA), and the 2'-fluoro group was stereoselectively introduced through the double inversions of stereochemistry via the episelenium intermediate, which was formed by the participation of the selenium atom. Among the compounds tested, the 2'-fluoro derivative 3t (X = NH2, Y = H, R = F) was found to be the most potent anticancer agent and showed more potent anticancer activity than the control, ara-C in all tested human cancer cell lines (HCT116, A549, SNU638, T47D, and PC-3) except the leukemia cell lines (K562). The anticancer activity of the 2'-substituted-4'-selenonucleosides is in the following order: 2'-F > 2'-OH > 2' N3. PMID- 24956557 TI - Resection for hepatocellular carcinoma with hepatic vein tumour thrombus: pushing the limits beyond the guidelines frontiers. PMID- 24956558 TI - Analysis of wall plasters and natural sediments from the Neolithic town of Catalhoyuk (Turkey) by a range of analytical techniques. AB - Wall plaster sequences from the Neolithic town of Catalhoyuk have been analysed and compared to three types of natural sediment found in the vicinity of the site, using a range of analytical techniques. Block samples containing the plaster sequences were removed from the walls of several different buildings on the East Mound. Sub-samples were examined by IR spectroscopy, X-ray diffraction and X-ray fluorescence to determine the overall mineralogical and elemental composition, whilst thin sections were studied using optical polarising microscopy, IR Microscopy and Environmental Scanning Electron Microscopy with Energy Dispersive X-ray analysis. The results of this study have shown that there are two types of wall plaster found in the sequences and that the sediments used to produce these were obtained from at least two distinct sources. In particular, the presence of clay, calcite and magnesian calcite in the foundation plasters suggested that these were prepared predominantly from a marl source. On the other hand, the finishing plasters were found to contain dolomite with a small amount of clay and no calcite, revealing that softlime was used in their preparation. Whilst marl is located directly below and around Catalhoyuk, the nearest source of softlime is 6.5km away, an indication that the latter was important to the Neolithic people, possibly due to the whiter colour (5Y 8/1) of this sediment. Furthermore, the same two plaster types were found on each wall of Building 49, the main building studied in this research, and in all five buildings investigated, suggesting that the use of these sources was an established practice for the inhabitants of several different households across the site. PMID- 24956559 TI - MicroRNA expression in the aging mouse thymus. AB - MicroRNAs (miRNAs) have been implicated in the process of aging in many model organisms, such as Caenorhabditis elegans, and in many organs, such as the mouse lung and human epididymis. However, the role of miRNAs in the thymus tissues of the aging mouse remains unclear. To address this question, we investigated the miRNA expression profiles in the thymuses of 1-, 10- and 19-month-old mice using miRNA array and qRT-PCR assays. A total of 223 mouse miRNAs were screened, and the expression levels of those miRNAs exhibited gradual increases and decreases over the course of thymus aging. Fifty miRNAs in the 10-month-old thymus and 81 miRNAs in the 19-month-old thymus were defined as differentially expressed miRNAs (p<0.05) in comparison with their levels in the 1-month-old mouse, and approximately one-third of these miRNAs were grouped within 11 miRNA clusters. Each miRNA cluster contained 2 to 5 miRNA genes, and most of the cluster members displayed similar expression patterns, being either increased or decreased. In addition, Ingenuity Pathway Analysis (IPA) software and the IPA database were used to analyze the 12 miRNAs that exhibited significant expression changes, revealing that as many as 15 pathways may be involved. Thus, our current study determined the expression profiles of miRNAs in the mouse thymus during the process of aging. The results suggested that these miRNAs could become meaningful biomarkers for studying thymus aging and that the aging-related alternations in miRNA expression may be involved in the regulation of cell proliferation, apoptosis, development and carcinogenesis/tumorigenesis. PMID- 24956560 TI - Association of PARP-1, NF-kappaB, NF-kappaBIA and IL-6, IL-1beta and TNF-alpha with Graves Disease and Graves Ophthalmopathy. AB - BACKGROUND: Graves Disease (GD) is an autoimmune disorder affected by an interaction of multiple genes such as Nuclear Factor-kappaB (NF-kappaB), Nuclear Factor-kappaB Inhibitor (NF-kappaBIA), Poly (ADP-ribose) polymerase-1 (PARP-1) and cytokines like Interleukin-1beta (IL-1beta), Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-alpha) and mostly accompanied by an ocular disorder, Graves Ophthalmopathy (GO). We hypothesize that there is a relationship between GD, GO, polymorphisms of inflammatory related genes and their association with cytokines, which may play important roles in autoimmune and inflammatory processes. SUBJECTS AND METHODS: To confirm our hypothesis, we studied the polymorphisms and cytokine levels of 120 patients with GD and GO using PCR-RFLP and ELISA methods, respectively. RESULTS: We found that patients with GG genotype and carriers of G allele of PARP-1 G1672A polymorphism are at risk in the group having GD (p=0.0007) while having GA genotype may be protective against the disease. PARP-1 C410T polymorphism was found to be associated with GO by increasing the risk by 1.7 times (p=0.004). Another risk factor for development of GO was the polymorphism of del/ins of NFkB1 gene (p=0.032) that increases the risk by 39%. Levels of cytokines were also elevated in patients with GD, but no association was found between levels of cytokines and the development of GO as there was no change in levels of cytokines. CONCLUSIONS: We suggest that, PARP-1 and NFkB1 gene polymorphisms may be risk factors for developing Graves Disease and Ophthalmopathy. PMID- 24956561 TI - Pramipexole but not imipramine or fluoxetine reverses the "depressive-like" behaviour in a rat model of preclinical stages of Parkinson's disease. AB - Depression is a frequent comorbid disorder in Parkinson's disease and may antedate its motor symptoms. However, mechanisms underlying Parkinson's disease associated depression are unknown and its current medication is insufficient. The aim of the present study was to compare antidepressant-like effects of imipramine, fluoxetine and pramipexole in a model of preclinical stages of Parkinson's disease in rats. 6-Hydroxydopamine was bilaterally injected into the ventrolateral region of the caudate-putamen in rats. This treatment induced moderate decreases in the levels of dopamine and its metabolites in the caudate putamen, nucleus accumbens and frontal cortex and reduced the density of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta and ventral tegmental area. The lesion increased immobility measured in the forced swimming test without influencing locomotor activity. Chronic (13 days) administration of pramipexole (1mg/kg sc/twice a day) reversed prolongation of the immobility time in lesioned animals but did not stimulate their locomotion. Chronic pramipexole activated dopaminergic transmission in the brain structures which might contribute to its effectiveness in the forced swimming test. In contrast, the 13-day administration of imipramine (10mg/kg ip/day) and fluoxetine (10mg/kg ip/day) did not shorten the immobility time in lesioned rats but reduced their locomotion. The present study indicates that already a moderate lesion of dopaminergic neurons induces "depressive-like" behaviour in animals which is reversed by chronic administration of the antiparkinsonian drug, pramipexole. PMID- 24956562 TI - Evolving phenotypic networks in silico. AB - Evolved gene networks are constrained by natural selection. Their structures and functions are consequently far from being random, as exemplified by the multiple instances of parallel/convergent evolution. One can thus ask if features of actual gene networks can be recovered from evolutionary first principles. I review a method for in silico evolution of small models of gene networks aiming at performing predefined biological functions. I summarize the current implementation of the algorithm, insisting on the construction of a proper "fitness" function. I illustrate the approach on three examples: biochemical adaptation, ligand discrimination and vertebrate segmentation (somitogenesis). While the structure of the evolved networks is variable, dynamics of our evolved networks are usually constrained and present many similar features to actual gene networks, including properties that were not explicitly selected for. In silico evolution can thus be used to predict biological behaviours without a detailed knowledge of the mapping between genotype and phenotype. PMID- 24956564 TI - Metals for bone implants. Part 1. Powder metallurgy and implant rendering. AB - New metal alloys and metal fabrication strategies are likely to benefit future skeletal implant strategies. These metals and fabrication strategies were looked at from the point of view of standard-of-care implants for the mandible. These implants are used as part of the treatment for segmental resection due to oropharyngeal cancer, injury or correction of deformity due to pathology or congenital defect. The focus of this two-part review is the issues associated with the failure of existing mandibular implants that are due to mismatched material properties. Potential directions for future research are also studied. To mitigate these issues, the use of low-stiffness metallic alloys has been highlighted. To this end, the development, processing and biocompatibility of superelastic NiTi as well as resorbable magnesium-based alloys are discussed. Additionally, engineered porosity is reviewed as it can be an effective way of matching the stiffness of an implant with the surrounding tissue. These porosities and the overall geometry of the implant can be optimized for strain transduction and with a tailored stiffness profile. Rendering patient-specific, site-specific, morphology-specific and function-specific implants can now be achieved using these and other metals with bone-like material properties by additive manufacturing. The biocompatibility of implants prepared from superelastic and resorbable alloys is also reviewed. PMID- 24956563 TI - The unique polarity phenotype of hepatocytes. AB - Hepatocytes, the main epithelial cell type of the liver, function like all epithelial cells to mediate the vectorial flow of macromolecules into and out of the organ they encompass. They do so by establishing polarized surface domains and by restricting paracellular flow via their tight junctions and cell-cell adhesion. Yet, the cell and tissue organization of hepatocytes differs profoundly from that of most other epithelia, including those of the digestive and urinary tracts, the lung or the breast. The latter form monolayered tissues in which the apical domains of individual cells align around a central continuous luminal cavity that constitutes the tubules and acini characteristic of these organs. Hepatocytes, by contrast, form capillary-sized lumina with multiple neighbors resulting in a branched, tree-like bile canaliculi network that spreads across the liver parenchyme. I will discuss some of the key molecular features that distinguish the hepatocyte polarity phenotype from that of monopolar, columnar epithelia. PMID- 24956565 TI - Three-dimensionally presented anti-fouling zwitterionic motifs sequester and enable high-efficiency delivery of therapeutic proteins. AB - Zwitterions are well known for their anti-biofouling properties. Past investigations of zwitterionic materials for biomedical uses have been centered on exploiting their ability to inhibit non-specific adsorption of proteins. Here, we report that zwitterionic motifs, when presented in three dimensions (e.g. in crosslinked hydrogels), could effectively sequester osteogenic bone morphogenetic protein-2 (rhBMP-2). The ionic interactions between rhBMP-2 and the 3-D zwitterionic network enabled dynamic sequestering and sustained release of the protein with preserved bioactivity. We further demonstrated that the zwitterionic hydrogel confers high-efficiency in vivo local delivery of rhBMP-2. It can template the functional healing of critical-size femoral segmental defects in rats with rhBMP-2 at a loading dose substantially lower than those required for current natural or synthetic polymeric carriers. These findings reveal a novel function of zwitterionic materials beyond their commonly perceived anti biofouling property, and may establish 3-D zwitterionic matrices as novel high efficiency vehicles for protein/ionic drug therapeutic delivery. PMID- 24956566 TI - Improved current and power density with a micro-scale microbial fuel cell due to a small characteristic length. AB - A microbial fuel cell (MFC) is a bio-electrochemical converter that can extract electricity from biomass by the catabolic reaction of microorganisms. This work demonstrates the impact of a small characteristic length in a Geobacteraceae enriched, micro-scale microbial fuel cell (MFC) that achieved a high power density. The small characteristic length increased the surface-area-to-volume ratio (SAV) and the mass transfer coefficient. Together, these factors made it possible for the 100-uL MFC to achieve among the highest areal and volumetric power densities - 83 MUW/cm(2) and 3300 MUW/cm(3), respectively - among all micro scale MFCs to date. Furthermore, the measured Coulombic efficiency (CE) was at least 79%, which is 2.5-fold greater than the previously reported maximum CE in micro-scale MFCs. The ability to improve these performance metrics may make micro scale MFCs attractive for supplying power in sub-100 uW applications, especially in remote or hazardous conditions, where conventional powering units are hard to establish. PMID- 24956567 TI - Sensitive colorimetric biosensing for methylation analysis of p16/CDKN2 promoter with hyperbranched rolling circle amplification. AB - A simple, fast and sensitive colorimetric biosensing method for DNA methylation analysis was developed by combining methylation-sensitive endonuclease based digestion with hyperbranched rolling circle amplification (HRCA) induced signal enhancement. The assay was carried out on a DNA capture probe modified 96-cell microplate with four sequential steps of target recognition, endonuclease-based digestion, isothermal HRCA, and enzyme-catalyzed colorimetric readout within 3h. The semi-quantitative and precise analysis of methylated DNA could be easily achieved by naked eye and absorbance measurements, respectively. The strategy exhibited excellent detection specificity and accuracy with a log-linear response to methylated DNA from 100 fM to 10nM. As a proof of concept, the assay was applied to investigate the methylation status of p16/CDKN2 promoter of breast cancer patients. The methylated p16 concentration was not significantly associated with the clinical parameters. The proposed method allowed efficient methylation detection with simplicity, rapidness, low cost and high sensitivity, showing great promise for application in early diagnosis of methylation-related diseases. PMID- 24956570 TI - Hemispheric processing of mental representations during text comprehension: evidence for inhibition of inconsistent shape information. AB - To successfully understand a text, readers often mentally represent the shape of an object described in a text (e.g., creating a mental image of a sliced tomato when reading about a tomato on a pizza). However, it is currently unclear how the cerebral hemispheres contribute to these mental images during reading. In the current study, participants were presented with sentences consistent with the shape of an object (i.e., the match condition), sentences inconsistent with the shape of an object (i.e., the mismatch condition), or sentences that did not specify the shape of an object (i.e., the neutral condition). Participants read each sentence and then viewed an image of an object that was quickly presented to either the right visual field-left hemisphere (rvf-LH) or the left visual field right hemisphere (lvf-RH). Results indicate that when the shape of an object was implicitly described in the text (in Experiment 1), response times for images presented to the rvf-LH were longer in the mismatch condition than in the neutral or match conditions. However, no response time differences were evident in the lvf-RH. When the shape of an object was explicitly described in the text (in Experiment 2), response times were longer in the mismatch condition than in the neutral and match conditions in both hemispheres. Thus, hemispheric involvement in mental representation depends on how explicit information is described in a text. Furthermore, these findings suggest that readers inhibit information that does not match an object's shape described in a text. PMID- 24956569 TI - Spatiotemporal dynamics during processing of abstract and concrete verbs: an ERP study. AB - Different accounts have been proposed to explain the nature of concept representations. Embodied accounts claim a key involvement of sensory-motor systems during semantic processing while more traditional accounts posit that concepts are abstract mental entities independent of perceptual and motor brain systems. While the involvement of sensory-motor areas in concrete language processing is supported by a large number of studies, this involvement is far from being established when considering abstract language. The present study addressed abstract and concrete verb processing, by investigating the spatiotemporal dynamics of evoked responses by means of high density EEG while participants performed a semantic decision task. In addition, RTs to the same set of stimuli were collected. In both early and late time intervals, ERP scalp topography significantly differed according to word categories. Concrete verbs showed involvement of parieto-frontal networks for action, according to the implied body effector. In contrast, abstract verbs recruited mostly frontal regions outside the motor system, suggesting a non-motor semantic processing for this category. In addition, differently from what has been reported during action observation, the parietal recruitment related to concrete verbs presentation followed the frontal one. The present findings suggest that action word semantic is grounded in sensory-motor systems, provided a bodily effector is specified, while abstract concepts' representation cannot be easily explained by a motor embodiment. PMID- 24956571 TI - Training-induced neural plasticity in visual-word decoding and the role of syllables. AB - To investigate the neural underpinnings of word decoding, and how it changes as a function of repeated exposure, we trained Dutch participants repeatedly over the course of a month of training to articulate a set of novel disyllabic input strings written in Greek script to avoid the use of familiar orthographic representations. The syllables in the input were phonotactically legal combinations but non-existent in the Dutch language, allowing us to assess their role in novel word decoding. Not only trained disyllabic pseudowords were tested but also pseudowords with recombined patterns of syllables to uncover the emergence of syllabic representations. We showed that with extensive training, articulation became faster and more accurate for the trained pseudowords. On the neural level, the initial stage of decoding was reflected by increased activity in visual attention areas of occipito-temporal and occipito-parietal cortices, and in motor coordination areas of the precentral gyrus and the inferior frontal gyrus. After one month of training, memory representations for holistic information (whole word unit) were established in areas encompassing the angular gyrus, the precuneus and the middle temporal gyrus. Syllabic representations also emerged through repeated training of disyllabic pseudowords, such that reading recombined syllables of the trained pseudowords showed similar brain activation to trained pseudowords and were articulated faster than novel combinations of letter strings used in the trained pseudowords. PMID- 24956572 TI - Oxidation and other property changes of retrieved sequentially annealed UHMWPE acetabular and tibial bearings. AB - This investigation analyzed retrieved sequentially crosslinked and annealed (SXL) ultra-high molecular weight polyethylene bearings to determine whether the material is chemically stable in vivo. A series of retrieved tibial and acetabular components were analyzed for changes in ketone oxidation, crosslink density, and free radical concentration. Oxidation was observed to increase with in vivo duration, and the rate of oxidation in tibial inserts was significantly greater than in acetabular liners. SXL acetabular bearings oxidized at a rate comparable to gamma-sterilized liners, while SXL tibial inserts oxidized at a significantly faster rate than their gamma-sterilized counterparts. A significant decrease in crosslink density with increased mean ketone oxidation index was observed, suggesting that in vivo oxidation may be causing material degradation. Furthermore, a subsurface whitened damage region was also found in a subset of the bearings, indicating the possibility of a clinically relevant decrease in mechanical properties of these components. PMID- 24956573 TI - Compensatory postural sway while seated posture during tasks in children with autism spectrum disorder. AB - Postural stability while seated was investigated in 16 children with autism spectrum disorder (ASD) and 16 typically developed (TD) children, aged 7-8 years. The lateral and antero-posterior (A-P) deviations of the centre of pressure (COP) were serially measured during sequential, upper limb, desk-top tasks, including nine subtests. The average COP deviation was larger, especially in the lateral direction, in the group of children with ASD compared with TD children. However, the larger COP deviation in the children with ASD was not generalized across tasks. Analyses of subtests revealed that deviations were different on three and four (of eight) subtests in the lateral and A-P directions, respectively. The time needed to complete each subtest was not correlated with the lateral COP deviation but with A-P deviation during the subtest in the children with ASD. Preserved task performance with marked body sway in the children with ASD suggested that the body sway was not a functionally abnormal movement that disturbed performance but could be a compensatory movement to actually facilitate performance. A new approach with occupational therapy to support such compensatory movement of ASD children could be considered in their school life. Further studies, including those in the classroom, to clarify the relationship between daily task performance and body instability are necessary. PMID- 24956574 TI - Complex coacervates of lactotransferrin and beta-lactoglobulin. AB - HYPOTHESIS: Oppositely charged proteins should interact and form complex coacervates or precipitates at the correct mixing ratios and under defined pH conditions. EXPERIMENTS: The cationic protein lactotransferrin (LF) was mixed with the anionic protein beta-lactoglobulin (B-Lg) at a range of pH and mixing ratios. Complexation was monitored through turbidity and zeta potential measurements. FINDINGS: Complexation between LF and B-Lg did occur and complex coacervates were formed. This behaviour for globular proteins is rare. The charge ratio's of LF:B-Lg varies with pH due to changing (de) protonation of the proteins. Nevertheless we found that the complexes have a constant stoichiometry LF:B-Lg=1:3 at all pH's, due to charge regularization. At the turbidity maximum the zeta potential of complexes is close to zero, indicating charge neutrality; this is required when the complexes form a new concentrated liquid phase, as this must be electrically neutral. Complexes were formed in pH region 5-7.3. On addition of salt (NaCl) complexation is diminished and disappears at a salt concentration of about 100 mMol. The coacervate phase has a very viscous consistency. If we consider the proteins as colloidal particles then the formed complex coacervate phase may have a structure that resembles a molten salt comparable to, for example, AlCl3. PMID- 24956575 TI - One pot synthesis of water-dispersible dehydroascorbic acid coated Fe3O4 nanoparticles under atmospheric air: blood cell compatibility and enhanced magnetic resonance imaging. AB - Water dispersible and biologically important molecule dehydroascorbic acid (DHA, capable to cross the blood brain barrier) coated Fe3O4 superparamagnetic nanoparticles having an average size of ~6 nm were synthesized through one pot aqueous coprecipitation method under atmospheric air. An antioxidant ascorbic acid (AA) used in the synthesis oxidized itself to dehydroascorbic acid (DHA) to consume dissolved or available oxygen in reaction mixture which died away the oxidative impact of atmospheric air and formed DHA encapsulated the Fe3O4 nanoparticles which stabilized the Fe3O4 nanoparticles and significantly enhanced their colloidal solubility in water. Fe3O4 phase, superparamagnetic property, DHA coating and stable colloidal solubility in water were confirmed by means of XPS, VSM, IR and zeta potential analysis respectively. T1, T2 and T2(*) weighted magnetic resonance imaging (MRI) and corresponding relaxivity (r1=0.416, r2=50.28 and r2(*)=123.65 mM(-1) and r2/r1=120.86, r2(*)r1=297.23) of colloidally dispersed DHA-coated nanoparticle water phantom revealed a strong contrast enhancement in T2 and T2(*) weighted images. The compatibility of DHA-coated Fe3O4 nanoparticles toward human blood cells was examined by means of cell counting and cell morphological analysis with the use of optical microscope and scanning electron microscope imaging. PMID- 24956576 TI - Structural and optical property studies on indium doped ZnO nanostructures for solution based organic-inorganic hybrid p-n junctions. AB - In doped ZnO nanocrystallites have established through a facile, low cost and high yield wet-chemical route. The X-ray diffraction measurements revealed the samples to be well crystallized, with a considerable shift in the prominent peak positions, indicating the successful substitution of In ions into the ZnO matrix. The particulate characteristic of the nanostructures was evaluated through the aid of electron microscopes, which revealed both the pristine and In doped ZnO nanocrystals to possess similar morphologies. The UV-vis absorption spectroscopic measurements revealed the doping of In(3+) ions to lead with a red shift in the absorption edge of ZnO nanostructures. The Raman measurements provided conclusive evidence for the substitution of In ions at the Zn sites and their influence on the hexagonal lattice. The hybrid heterostructures made up of polypyrrole/ZnO and polypyrrole/Zn(1-x)In(x)O were established via drop casting a colloidal dispersion containing the prepared nanocrystallites and subsequently chemically in situ polymerizing the pyrrole monomers on the drop casted electrodes. The hybrid p-n junctions were then evaluated using the current-voltage characteristics. PMID- 24956577 TI - A role for cancer stem cells in therapy resistance: cellular and molecular mechanisms. AB - Similar to normal tissue, many tumors have a hierarchical organization where tumorigenic cancer stem cells (CSCs) differentiate into non-tumorigenic progenies. A host of studies have demonstrated that although CSCs and their non tumorigenic progenies within the same clone can share common genotype, they display different epigenetic profiles that results in changes of multiple signaling pathways. Many of these pathways confer cell adaptation to the microenvironmental stresses including inflammation, hypoxia, low pH, shortage in nutrients and anti-cancer therapies. Treatment strategies based on combination of conventional therapies targeting bulk tumor cells and CSC-specific pathway inhibition bear a promise to improve cancer cure compared to monotherapies. In this review we describe the mechanisms of CSC-related therapy resistance including drug efflux by ABC transporters, activation of aldehyde dehydrogenase and developmental pathways, enhanced DNA damage response, autophagy and microenvironmental conditions, and discuss possible therapeutic strategies for improving cancer treatment. PMID- 24956579 TI - Leachability and heavy metal speciation of 17-year old stabilised/solidified contaminated site soils. AB - The long-term leachability, heavy metal speciation transformation and binding mechanisms in a field stabilised/solidified contaminated soil (made ground) from West Drayton site were recently investigated following in situ auger mixing treatment with a number of cement-based binders back in 1996. Two batch leaching tests (TCLP and BS EN 12457) and a modified five step sequential extraction procedure along with X-ray diffraction (XRD) and scanning electron microscopy (SEM) analyses were employed for the testing of the 17-year-old field soil. The results of batch leaching tests show that the treatment employed remained effective at 17 years of service time, with all BS EN 12457 test samples and most of TCLP test samples satisfied drinking water standards. Sequential extraction results illustrate that the leaching of Cu, Ni, Zn, Pb and Cd in all mixes mainly occurred at the Fe/Mn phase, ranging from 43% to 83%. Amongst the five metals tested, Ni was the most stable with around 40% remained in the residual phase for all the different cement-based binder stabilised/solidified samples. XRD and SEM analyses show that the hydration process has been fully completed and further carbonation took place. In summary, this study confirms that such cement-based stabilisation/solidification (S/S) treatment can achieve satisfactory durability and thus is a reliable technique for long-term remediation of heavy metal contaminated soil. PMID- 24956578 TI - An ion-imprinted functionalized SBA-15 adsorbent synthesized by surface imprinting technique via reversible addition-fragmentation chain transfer polymerization for selective removal of Ce(III) from aqueous solution. AB - A novel Ce(III) ion-imprinted polymer (Ce(III)-IIP) has been prepared by surface imprinting technique with reversible addition-fragmentation chain transfer (RAFT) polymerization based on support matrix of SBA-15. The prepared adsorbent is characterized by FT-IR, XRD, SEM, TEM, nitrogen adsorption-desorption, GPC, and TGA. The results suggest that the surface imprinted polymer synthesized by RAFT is a thin layer. For adsorption experiments, Ce(III)-IIP is investigated to remove Ce(III) by column study at different flow rates, initial metal ion concentrations, and adsorption temperature. The dynamic kinetics analyses reveal that the overall adsorption process is successfully fitted with the pseudo-first order kinetic model and the equilibrium time was 60 min. Meanwhile, the experimental data is in good agreement with Thomas model. Ce(III)-IIP has the excellent selectivity and regenerate property. Meanwhile, the proposed method has been successfully applied in the removal of Ce(III) in natural water samples with satisfactory results. All the results suggest that Ce(III)-IIP could be used as an excellent adsorbent for efficient removal of Ce(III) from aqueous solution. PMID- 24956580 TI - Hydrazine borane-induced destabilization of ammonia borane, and vice versa. AB - In the field of solid-state chemical hydrogen storage, ammonia borane NH3BH3 has been widely studied while hydrazine borane N2H4BH3 can be considered as a "novel" material. In the present work, we investigated the behaviour of these boranes when mixed together in a mole ratio of 1:1. Hydrazine borane and ammonia borane destabilize each other. Though stable at 20-25 degrees C, the mixture melts at ~ 30 degrees C and then undergoes significant decomposition, with desorption of hydrogen H2 and hydrazine N2H4 from 67 degrees C. This is explained by the fact that the presence of hydrazine borane disrupts the H(delta+)? H(delta-) network of ammonia borane, and vice versa; the mixture is then much less stable than the pristine boranes. The mixture can nevertheless be stabilized (by heat- or vacuum treatment and thus extraction of evolving hydrogen and hydrazine), making the as obtained solid a potential chemical hydrogen storage material. Over the range 25 300 degrees C, it is able to release ca. 11.4 wt% of almost pure H2. Furthermore forms boron nitride as the solid residue, at temperatures as low as 300 degrees C. PMID- 24956581 TI - Home care technology through an ability expectation lens. AB - Home care is on the rise, and its delivery is increasingly reliant on an expanding variety of health technologies ranging from computers to telephone "health apps" to social robots. These technologies are most often predicated on expectations that people in their homes (1) can actively interact with these technologies and (2) are willing to submit to the action of the technology in their home. Our purpose is to use an "ability expectations" lens to bring together, and provide some synthesis of, the types of utility and disadvantages that can arise for people with disabilities in relation to home care technology development and use. We searched the academic databases Scopus, Web of Science, EBSCO ALL, IEEE Xplore, and Compendex to collect articles that had the term "home care technology" in the abstract or as a topic (in the case of Web of Science). We also used our background knowledge and related academic literature pertaining to self-diagnosis, health monitoring, companionship, health information gathering, and care. We examined background articles and articles collected through our home care technology search in terms of ability expectations assumed in the presentation of home care technologies, or discussed in relation to home care technologies. While advances in health care support are made possible through emerging technologies, we urge critical examination of such technologies in terms of implications for the rights and dignity of people with diverse abilities. Specifically, we see potential for technologies to result in new forms of exclusion and powerlessness. Ableism influences choices made by funders, policy makers, and the public in the development and use of home health technologies and impacts how people with disabilities are served and how useful health support technologies will be for them. We urge continued critical examination of technology development and use according to ability expectations, and we recommend increasing incorporation of participatory design processes to counteract potential for health support technology to render people with disabilities technologically excluded and powerless. PMID- 24956582 TI - Soil-to-plant transfer factors of radioactive Ca, Sm and Pd isotopes: critical assessment of the use of analogies to derive best-estimates from existing non specific data. AB - (45)Ca, (151)Sm and (107)Pd are three radionuclides present in low to intermediate in activity radioactive wastes for which no soil-to-plant Transfer Factors (TF) values are available to be used in biosphere models for Ecological Risk Assessment. In the absence of specific radioecological studies, this work reviews and analyzes the existing literature for stable isotopes of Pd, Sm and Ca in order to derive best estimates for TF values that could be used as Transfer Factors. Alternative methods of extrapolation are also critically assessed. The values have been classified according to climatic zone, plant class and soil type for each element. The overall geometric mean TF values (for all plants and conditions) was calculated as 8.4E-02 for Pd, for which the value of radioRu in TRS-472 is also available. The mean TF for Sm was 4.2E-04. This value was lower than the TF values for radioactive Ce that are proposed as alternative values for Sm in TRS-472. The former may be relevant for long term assessments and the latter could possibly used to describe the short term (151)Sm post-release behaviour. The mean value for Ca is 2.3E-01 but varies considerably among plants of a given class due to the variety of plant Ca uptake behaviors. Alternatively, to limit this variability, Ca data content for dry plant matter, as analyzed using the phylogenetic method, could be used to derive TF values if the conservation of isotopic ratio of (45)Ca to stable Ca in soils and in plants hypothesis is taken into account. The TF for Ca in sub-tropical zones is 10-fold lower than in temperate zones. There is a lot of data available about exchangeable Ca in soil, which mean that we could calculate an available TF. The analysis shows that Ca bioavailability is also a key factor within transfer. PMID- 24956583 TI - Apparent enrichment of organically bound tritium in rivers explained by the heritage of our past. AB - The global inventory of naturally produced tritium (3H) is estimated at 2.65 kg, whereas more than 600 kg have been released during atmospheric nuclear tests (NCRP, 1979; UNSCEAR, 2000) constituting the main source of artificial tritium throughout the Anthropocene. The behaviour of this radioactive isotope in the environment has been widely studied since the 1950s, both through laboratory experiments and, more recently, through field observations (e.g., Cline, 1953; Kirchmann et al., 1979; Daillant et al., 2004; McCubbin et al., 2001; Kim et al., 2012). In its "free" forms, [i.e. 3H gas or 3H hydride (HT); methyl 3H gas (CH3T); tritiated H2O or 3H-oxide (HTO); and Tissue Free Water 3H (TFWT)], tritium closely follows the water cycle. However, 3H bound with organic compounds, mainly during the basic stages of photosynthesis or through weak hydrogen links, is less exchangeable with water, which explains its persistence in the carbon cycle as re underlined recently by Baglan et al. (2013), Jean Batiste and Fourre (2013), Kim et al. (2013a,b). In this paper, we demonstrate that terrestrial biomass pools, historically contaminated by global atmospheric fallout from nuclear testing, have constituted a significant delayed source of organically bound tritium (OBT) for aquatic systems, resulting in an apparent enrichment of OBT as compared to HTO. This finding helps to explain concentration factors (tritium concentration in biota/concentration in water) greater than 1 observed in areas that are not directly affected by industrial radioactive wastes, and thus sheds light on the controversies regarding tritium 'bioaccumulation'. Such apparent enrichment of OBT is expected to be more pronounced in the Northern Hemisphere where fallout was most significant, depending on the nature and biodegradability of terrestrial biomass at the regional scale. We further believe that OBT transfers from the continent to oceans have been sufficient to affect tritium concentrations in coastal marine biota (i.e., near river inputs). Our findings demonstrate that the persistence of terrestrial organic (3)H explains imbalances between organically bound tritium and free (3)H in most river systems in particular those not impacted by releases from nuclear facilities. PMID- 24956584 TI - Development of GI-safe NSAID; progression from the bark of willow tree to modern pharmacology. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for analgesic, anti inflammatory and antithrombotic actions and recently for cancer prevention, but they carries a risk of major gastroduodenal damages from symptomatic ulcers to serious complications leading to fatal outcomes. Therefore, the novel strategies to rescue long-term NSAID requiring patients from NSAID-associated gastroduodenal damages are essential. Besides of current drugs based on classic damaging mechanisms attributable to the decline of gastric mucosal prostaglandin synthesis, reductions of mucosal blood flow, attenuated bicarbonate secretion and mucus synthesis related with prostaglandin levels, effective therapeutics targeted for update mechanisms of NSAID-induced gastroduodenal damages are introduced in this paper based on recent advances in basic science and biotechnology exploring deeper molecular mechanisms of NSAID-induced gastroduodenal damage beyond COX inhibition. PMID- 24956586 TI - Subchronic toxicity, toxicity to reproduction and prenatal developmental toxicity of vinyl laurate. AB - Vinyl laurate (VL), is used in the manufacture of polyvinyl acetate vinyl laurate copolymer a component of gum base for chewing gum production. The potential toxicity of VL to reproduction was examined in a combined repeated dose and reproduction/developmental toxicity screening study (OECD test guideline 422) and a prenatal developmental toxicity screening study (OECD test guideline 414). VL was administered to Wistar rats by gavage at 0 (controls), 50, 250 and 1000mg/kgbw/d. There were no signs of systemic toxicity in the parental animals of either study. Adverse effects on reproductive performance and fetal development that could be attributed to the VL treatment were not observed. Thus, the highest dose level tested was a NOAEL in these two studies. PMID- 24956585 TI - Functional differentiation of cytotoxic cancer drugs and targeted cancer therapeutics. AB - There is no nationally or internationally binding definition of the term "cytotoxic drug" although this term is used in a variety of regulations for pharmaceutical development and manufacturing of drugs as well as in regulations for protecting medical personnel from occupational exposure in pharmacy, hospital, and other healthcare settings. The term "cytotoxic drug" is frequently used as a synonym for any and all oncology or antineoplastic drugs. Pharmaceutical companies generate and receive requests for assessments of the potential hazards of drugs regularly - including cytotoxicity. This publication is intended to provide functional definitions that help to differentiate between generically-cytotoxic cancer drugs of significant risk to normal human tissues, and targeted cancer therapeutics that pose much lesser risks. Together with specific assessments, it provides comprehensible guidance on how to assess the relevant properties of cancer drugs, and how targeted therapeutics discriminate between cancer and normal cells. The position of several regulatory agencies in the long-term is clearly to regulate all drugs regardless of classification, according to scientific risk based data. Despite ongoing discussions on how to replace the term "cytotoxic drugs" in current regulations, it is expected that its use will continue for the near future. PMID- 24956587 TI - Assessment of the skin sensitising potency of the lower alkyl methacrylate esters. AB - There is continued interest in, and imperatives for, the classification of contact allergens according to their relative skin sensitising potency. However, achieving that end can prove problematic, not least when there is an apparent lack of concordance between experimental assessments of potency and the prevalence allergic contact dermatitis as judged by clinical experience. For the purpose of exploring this issue, and illustrating the important considerations that are required to reach sound judgements about potency categorisation, the lower alkyl methacrylate esters (LAM) have been employed here as a case study. Although the sensitising potential of methyl methacrylate (MMA) has been reviewed previously, there is available new information that is relevant for assessment of skin sensitising potency. Moreover, for the purposes of this article, analyses have been extended to include also other LAM for which relevant data are available: ethyl methacrylate (EMA), n-butyl methacrylate (nBMA), isobutyl methacrylate (iBMA), and 2-ethylhexyl methacrylate (EHMA). In addressing the skin sensitising activity of these chemicals and in drawing conclusions regarding relative potency, a number of sources of information has been considered, including estimates of potency derived from local lymph node assay (LLNA) data, the results of guinea pig assays, and data derived from in silico methods and from recently developed in vitro approaches. Moreover, clinical experience of skin sensitisation of humans by LAM has also been evaluated. The conclusion drawn is that MMA and other LAM are contact allergens, but that none of these chemicals has any more than weak skin sensitising potency. We have also explored here the possible bases for this modest sensitising activity. Finally, the nature of exposure to LAM has been reviewed briefly and on the basis of that information, together with an understanding of skin sensitising potency, a risk assessment has been prepared. PMID- 24956588 TI - A review of the evidence on smoking bans and incidence of heart disease. AB - We update an earlier review of smoking bans and heart disease, restricting attention to admissions for acute myocardial infarction. Forty-five studies are considered. New features of our update include consideration of non-linear trends in the underlying rate, a modified trend adjustment method where there are multiple time periods post-ban, comparison of estimates based on changes in rates and numbers of cases, and comparison of effect estimates according to post-ban changes in smoking restrictiveness. Using a consistent approach to derive ban effect estimates, taking account of linear time trends and control data, the reduction in risk following a ban was estimated as 4.2% (95% confidence interval 1.8-6.5%). Excluding regional estimates where national estimates are available, and studies where trend adjustment was not possible, the estimate reduced to 2.6% (1.1-4.0%). Estimates were little affected by non-linear trend adjustment, where possible, or by basing estimates on changes in rates. Ban effect estimates tended to be greater in smaller studies, and studies with greater post-ban changes in smoking restrictiveness. Though the findings suggest a true effect of smoking bans, uncertainties remain, due to the weakness of much of the evidence, the small estimated effect, and various possibilities of bias. PMID- 24956589 TI - Gasoline toxicology: overview of regulatory and product stewardship programs. AB - Significant efforts have been made to characterize the toxicological properties of gasoline. There have been both mandatory and voluntary toxicology testing programs to generate hazard characterization data for gasoline, the refinery process streams used to blend gasoline, and individual chemical constituents found in gasoline. The Clean Air Act (CAA) (Clean Air Act, 2012: S 7401, et seq.) is the primary tool for the U.S. Environmental Protection Agency (EPA) to regulate gasoline and this supplement presents the results of the Section 211(b) Alternative Tier 2 studies required for CAA Fuel and Fuel Additive registration. Gasoline blending streams have also been evaluated by EPA under the voluntary High Production Volume (HPV) Challenge Program through which the petroleum industry provide data on over 80 refinery streams used in gasoline. Product stewardship efforts by companies and associations such as the American Petroleum Institute (API), Conservation of Clean Air and Water Europe (CONCAWE), and the Petroleum Product Stewardship Council (PPSC) have contributed a significant amount of hazard characterization data on gasoline and related substances. The hazard of gasoline and anticipated exposure to gasoline vapor has been well characterized for risk assessment purposes. PMID- 24956590 TI - Inter- and intra-individual variation in urinary biomarker concentrations over a 6-day sampling period. Part 2: personal care product ingredients. AB - An intensive study was conducted to provide data on intra- and inter-individual variation in urinary excretion of a series of ingredients in personal care products (parabens, triclosan, benzophenones) and bisphenol A (BPA, not expected to be an ingredient) in 8 volunteers over 6 days. Exposure diaries recorded use of personal care products with identified target analytes as ingredients. Participants' usual products were replaced with products without the target analytes for 2 of the 6 days. Urine void volumes and times were recorded. Methyl, ethyl, and n-propylparabens, triclosan, benzophenone-3, and BPA were frequently detected (>=70% of samples). Urinary concentrations of the parabens and triclosan were lower on product replacement days. First morning void concentrations correlated moderately to highly with 24-h composite concentrations for all analytes. Intraclass correlation coefficients (ICCs) for spot samples collected on days with usual product use were low for BPA (0.15), moderate for n propylparaben and methylparaben (0.39 and 0.56, respectively), and high for ethylparaben, benzophenone-3, and triclosan (0.76, 0.81, and 0.934, respectively); ICCs were consistently higher on the basis of cr-adjusted concentrations. Hydration status adjustment methods were assessed by comparing unadjusted and adjusted concentrations to urinary excretion rates (ER, ng/kg-h) for all analytes and samples. Specific gravity-adjusted concentrations correlated slightly better with ER than creatinine-adjusted concentrations. Within individual variation in biomarker concentrations was highest for methyl and ethylparabens (2 orders of magnitude variation in spot sample concentrations) and lower for the other analytes (1-1.5 orders of magnitude). This dataset provides insight into the design and interpretation of urinary biomonitoring studies for non-persistent chemicals. PMID- 24956591 TI - Different action of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and its hydroxylated metabolites on ERalpha and ERbeta gene and protein expression. AB - In our previously published data we showed that PBDEs act as endocrine disruptors in ovarian follicles by altering steroid secretion. In this study we try to answer a question if BDE-47 and its hydroxylated metabolites (5-OH-BDE-47 and 6 OH-BDE-47) can act as endocrine disruptors in the ovary by changing the expression of the steroid nuclear receptors, estrogen receptor alpha (ERalpha) and beta (ERbeta), androgen receptor (AR), and receptors associated with the metabolism of xenobiotics and steroid hormones, constitutive androstane receptor (CAR) and pregnane X-receptor (PXR), in porcine ovarian follicles. Expression of mRNA was evaluated by real-time PCR, whereas protein level by western blotting. CAR and PXR mRNAs were not expressed in porcine ovarian follicular cells. BDE-47 and its hydroxylated metabolites had no effect on the expression of AR mRNA and protein. Decreased expression of ERbeta mRNA and protein under BDE-47 influence and increase both ERalpha and ERbeta gene and protein expression in cells exposed to hydroxylated metabolites was noted. These findings indicate that BDE-47, by altering the ratio of ERalpha to ERbeta toward ERalpha, and the hydroxylated metabolites of BDE-47, by increase estrogen receptors expression, may result in excessive ovarian exposure to estrogens. PMID- 24956592 TI - Oxidation, inactivation and aggregation of protein disulfide isomerase promoted by the bicarbonate-dependent peroxidase activity of human superoxide dismutase. AB - Protein disulfide isomerase (PDI) is a dithiol-disulfide oxidoreductase that has essential roles in redox protein folding. PDI has been associated with protective roles against protein aggregation, a hallmark of neurodegenerative diseases. Intriguingly, PDI has been detected in the protein inclusions found in the central nervous system of patients of neurodegenerative diseases. Oxidized proteins are also consistently detected in such patients, but the agents that promote these oxidations remain undefined. A potential trigger of protein oxidation is the bicarbonate-dependent peroxidase activity of the human enzyme superoxide dismutase 1 (hSOD1). Therefore, we examined the effects of this activity on PDI structure and activity. The results showed that PDI was oxidized to radicals that lead to PDI inactivation and aggregation. The aggregates are huge and apparently produced by covalent cross-links. Spin trapping experiments coupled with MS analysis indicated that at least 3 residues of PDI are oxidized to tyrosyl radicals (Y(63), Y(116) and Y(327)). Parallel experiments showed that PDI is also oxidized to radicals, inactivated and aggregated by the action of photolytically generated carbonate radical and by UV light. PDI is prone to inactivation and aggregation by one-electron oxidants and UV light probably because of its high content of aromatic amino acids. PMID- 24956593 TI - 14-3-3zeta regulates nuclear trafficking of protein phosphatase 1alpha (PP1alpha) in HEK-293 cells. AB - Protein phosphatase 1 (PP1) is one of the major Ser/Thr phosphatases in mammalian cells. There are four isoforms of PP1 namely, PP1alpha, PP1beta/delta, PP1gamma1 and PP1gamma2. PP1gamma and PP1beta translocate to the nucleus by binding to a co transporter that contains a nuclear localization signal. The mechanism by which PP1alpha shuttles between the nucleus and the cytosol is not known. In this study, we found that PP1alpha co-immunoprecipitates with 14-3-3zeta from HEK-293 cell lysates. By co-immunoprecipitation and GST pull-down assay, we determined that 14-3-3zeta binds to both PP1alpha (WT) and PP1alpha (T320A), and that phosphorylation of PP1alpha is not required for binding. Using PP1alpha deletion mutants, we located the 14-3-3zeta binding region within PP1alpha residues 159 279. An in vitro assay showed that 14-3-3zeta does not affect PP1alpha activity. When HEK-293 cells expressing PP1alpha and 14-3-3zeta were subjected to subcellular fractionation, the ratio of cytosolic vs. nuclear PP1alpha was significantly higher in cells expressing PP1alpha and 14-3-3zeta than those expressing PP1alpha alone. In cells expressing a dominant negative 14-3-3zeta (K49E), PP1alpha accumulated in the nucleus. Our results show that 14-3-3zeta binds to PP1alpha and causes its retention in the cytosol which suggests that 14 3-3zeta regulates nuclear trafficking of PP1alpha in mammalian cells. PMID- 24956594 TI - Bone and fat: a relationship of different shades. AB - Environmental and behavioral changes which occurred over the last century led simultaneously to a remarkable increase in human lifespan and to the development of health problems associated with functional impairment of organs either regulating or dependent on balanced energy metabolism. Diseases such as diabetes, obesity and osteoporosis are prevalent in our society and pose major challenges with respect to the overall health and economy. Therefore, better understanding of regulatory axes between bone and fat may provide the basis for development of strategies which will treat these diseases simultaneously and improve health and life quality of elderly. PMID- 24956595 TI - Virological characterization of HIV-2 vpx gene mutants in various cell systems. AB - Requirement of intrinsically disordered protein Vpx for HIV-2 replication is cell type dependent. To define Vpx-dependent conditions, replication ability of HIV-2 vpx mutants was analyzed in various cell lines that differ in cellular type, differentiation state and/or expression level of anti-HIV-1 SAMHD1 degraded by Vpx. Induction of Vpx-sensitive anti-HIV-2 state was not always associated with SAMHD1 expression. Compared with our previous data in lymphocytic cells, growth defectiveness of the vpx mutants in differentiated THP-1 cells, a newly established multi-cycle infection system, was considerably different. Taken together, our results suggest that Vpx plays cell-type dependent role through its undetermined structure and/or function. PMID- 24956597 TI - Interactions of Streptococcus iniae with phagocytic cell line. AB - Streptococcus iniae has become one of the most serious aquatic pathogens in the last decade, causing large losses in wild and farmed fish worldwide. There is clear evidence that this pathogen is capable not only of causing serious disease in fish but also of being transferred to and infecting humans. In this study, we investigate the interaction of S. iniae with two murine macrophage cell lines, J774-A1 and RAW 264.7. Cytotoxicity assay demonstrated significant differences between live and UV-light killed IUSA-1 strains. The burst respiratory activity decreased to baseline after 1 and 4 h of exposure for J774-A1 and RAW 264.7, respectively. Immunofluorescent and ultrastructural study of infected cells confirmed the intracellular localization of bacteria at 1 h and 24 h post infection. Using qRT-PCR arrays, we investigated the changes in the gene expression of immune relevant genes associated with macrophage activation. In this screening, we identified 11 of 84 genes up-regulated, we observed over expression of pro-inflammatory response as IL-1alpha, IL-1beta, and TNF-alpha, without a good anti-inflammatory response. Present findings suggest a capacity of S. iniae to modulate a mammalian macrophages cell lines to their survival and replication intracellular, which makes this cell type as a reservoir for continued infection. PMID- 24956596 TI - Herpes virus entry mediator (HVEM) modulates proliferation and activation of regulatory T cells following HSV-1 infection. AB - In many infections, especially those that are chronic such as Herpes Simplex Virus-1 (HSV-1), the outcome may be influenced by the activity of one or more types of regulatory T cells (Tregs). Some infections can cause Treg expansion, but how viruses might promote preferential Treg expansion is has been unclear. In this report, we demonstrate a possible mechanism by which HSV (Herpes Simplex virus-1) infection could act to signal and expands the Treg population. We show that CD4(+) FoxP3(+) Tregs up- regulate HVEM (herpes virus entry mediator), which is a binding site for major viral glycoprotein HSVgD, following HSV infection, which is a binding site for major viral glycoprotein HSVgD. Recombinant HSVgD enhanced the proliferation of CD4(+) FoxP3(+) Tregs cells in-vitro. Furthermore, compared to wild type (WT), HVEM deficient mice (HVEM-/-) generated a weaker Treg responses represented by significantly diminished ratios of CD4(+)FoxP3(+)/CD4(+)FoxP3(-) cells along with diminished proportions of FoxP3(+) Tregscells co-expressing Treg activation markers and a reduced MFI of FoxP3 expression on CD4(+) T cells. Consistent with defective Treg responses, HVEM-/- animals were more susceptible to HSV-1 induced ocular immunopathology, with more severe lesions in HVEM-/- animals. Our results indicate that HVEM regulates Treg responses, and its modulation could represent a useful approach to control HSV induced corneal immunopathology. PMID- 24956598 TI - Vitamin K and musculoskeletal health in postmenopausal women. AB - Aside from its important role in blood clotting, vitamin K is an important dietary factor in regulating bone and cartilage mineralization. The vitamin K requirements to maintain musculoskeletal health may be more than the current recommendations and subclinical vitamin K deficiency may be involved in the pathogenesis of osteoporosis and osteoarthritis. Observational studies suggest that diets low in vitamin K are associated with increased risk of fractures and osteoarthritis in older adults. However, so far randomized controlled trials of vitamin K supplementation in Caucasian populations have not shown clinically significant improvements in bone mineral density at major skeletal sites. Supplementation with vitamin K may reduce the risk of fractures, but this conclusion comes from clinical trials with methodological limitations. At this time, only one randomized controlled trial has examined the effect of vitamin K supplementation on radiographic hand osteoarthritis and found no overall effect. Large well-designed randomized controlled trials are needed to compare the efficacies of vitamin K1 and K2 on fractures and osteoarthritis among older adults. In summary, currently there is not enough evidence to recommend the use of vitamin K supplements for the prevention of bone loss, fractures, or osteoarthritis in postmenopausal women. PMID- 24956599 TI - Religiousness and headache: is there a relation? Results from a representative sample of adults living in a low-income community. AB - BACKGROUND: The use of religious behaviors to alleviate the consequences of stressful life circumstances is a frequent strategy employed by pain sufferers. Specifically in the field of headache research, to date, few studies have assessed spiritual and religious beliefs. OBJECTIVE: The objective of this article is to investigate the relation between religiousness (organizational, non organizational and intrinsic) and headache disorders in a representative sample of adults living in a low-income community. METHODS: This was a cross-sectional, population-based study. In 2005, we conducted door-to-door interviews with 439 people, aged more than 18 years, randomly selected from a low-income community in Brazil. Four regression models were created to explain the relationships between religious involvement and headache, controlling for demographics, depression/anxiety and alcohol use and smoking. RESULTS: Of the 439 households contacted, at least one member from 383 (87.2%) households participated. We interviewed more women (74.4%) and more subjects aged 18-39 years. The mean age was 41.7 (SD 8.5) years. Bivariate analysis shows that high religious attendance, non-organizational religiousness and intrinsic religiousness were associated with presence of headache and presence of migraine. After the logistic regression models, only high non-organizational religiousness remained associated with presence of headache (odds ratio (OR): 1.22 (1.01-1.49)). All other religious variables were unrelated to the presence of headache and its types. CONCLUSION: There is a modest relationship between high non-organizational religiousness and presence of headache. Headache sufferers may use coping strategies such as private religious behaviors to try to overcome suffering. PMID- 24956600 TI - Assessing potential modifications to the activated sludge process to improve simultaneous removal of a diverse range of micropollutants. AB - It is proposed that wastewater treatment facilities meet legislated discharge limits for a range of micropollutants. However, the heterogeneity of these micropollutants in wastewaters make removal difficult to predict since their chemistry is so diverse. In this study, a range of organic and inorganic micropollutants known to be preferentially removed via different mechanisms were selected to challenge the activated sludge process (ASP) and determine its potential to achieve simultaneous micropollutant removal. At a fixed hydraulic retention time (HRT) of 8 h, the influence of an increase in solids retention time (SRT) on removal was evaluated. Maximum achievable micropollutant removal was recorded for all chemicals (estrogens, nonylphenolics and metals) at the highest SRT studied (27 days). Also, optimisation of HRT by extension to 24 h further augmented organic biodegradation. Most notable was the enhancement in removal of the considerably recalcitrant synthetic estrogen 17alpha ethinylestradiol which increased to 65 +/- 19%. Regression analysis indicates that this enhanced micropollutant behaviour is ostensibly related to the concomitant reduction in food: microorganism ratio. Interestingly, extended HRT also initiated nonylphenol biodegradation which has not been consistently observed previously in real wastewaters. However, extending HRT increased the solubilisation of particulate bound metals, increasing effluent aqueous metals concentrations (i.e., 0.45 MUm filtered) by >100%. This is significant as only the aqueous metal phase is to be considered for environmental compliance. Consequently, identification of an optimum process condition for generic micropollutant removal is expected to favour a more integrated approach where upstream process unit optimisation (i.e., primary sedimentation) is demanded to reduce loading of the particle bound metal phase onto the ASP, thereby enabling longer HRT in the ASP to be considered for optimum removal of organic micropollutants. PMID- 24956601 TI - Simplifying modeling of nanoparticle aggregation-sedimentation behavior in environmental systems: a theoretical analysis. AB - Parameters and simplified model approaches for describing the fate of engineered nanoparticles (ENPs) are crucial to advance the risk assessment of these materials. Sedimentation behavior of ENPs in natural waters has been shown to follow apparent first order behavior, a 'black box' phenomenon that is insufficiently understood and therefore of limited applicability. Here we use a detailed Smoluchowski-Stokes model that accounts for homo- and heteroaggregation and sedimentation of ENPs and natural colloids (NCs), to simulate and interpret experimental ENP aggregation-sedimentation data. The model adequately simulated the observed time and initial concentration dependence of CeO2 settling data, and also predicted the conditions for aggregation rate-limitations of overall removal. Heteroaggregation with natural colloids was identified as the dominating removal process. Finally, the empirical apparent first order model data were calibrated against the mechanistic Smoluchowski-Stokes model simulation data, showing excellent fits for a range of NC initial concentrations. Using first order removal rates thus can be considered a valid and informed approximation when modeling ENP fate in the aquatic environment. PMID- 24956602 TI - Heterotrophic denitrification plays an important role in N2O production from nitritation reactors treating anaerobic sludge digestion liquor. AB - Nitrous oxide (N2O) emissions from nitritation reactors receiving real anaerobic sludge digestion liquor have been reported to be substantially higher than those from reactors receiving synthetic digestion liquor. This study aims to identify the causes for the difference, and to develop strategies to reduce N2O emissions from reactors treating real digestion liquor. Two sequencing batch reactors (SBRs) performing nitritation, fed with real (SBR-R) and synthetic (SBR-S) digestion liquors, respectively, were employed. The N2O emission factors for SBR R and SBR-S were determined to be 3.12% and 0.80% of the NH4(+)-N oxidized, respectively. Heterotrophic denitrification supported by the organic carbon present in the real digestion liquor was found to be the key contributor to the higher N2O emission from SBR-R. Heterotrophic nitrite reduction likely stopped at N2O (rather than N2), with a hypothesised cause being free nitrous acid inhibition. This implies that all nitrite reduced by heterotrophic bacteria was converted to and emitted as N2O. Increasing dissolved oxygen (DO) concentration from 0.5 to 1.0 mg/L, or above, decreased aerobic N2O production from 2.0% to 0.5% in SBR-R, whereas aerobic N2O production in SBR-S remained almost unchanged (at approximately 0.5%). We hypothesised that DO at 1 mg/L or above suppressed heterotrophic nitrite reduction thus reduced aerobic heterotrophic N2O production. We recommend that DO in a nitritation system receiving anaerobic sludge digestion liquor should be maintained at approximately 1 mg/L to minimise N2O emission. PMID- 24956603 TI - Ferrate(VI) oxidation of tetrabromobisphenol A in comparison with bisphenol A. AB - Ferrate(VI) (Fe(VI)) oxidative removal of various organic micropollutants mainly depends on the reactivity of Fe(VI) to target micropollutants and coexisting constituents present in source water. This study evaluated the potential of Fe(VI) oxidation of the brominated flame retardant tetrabromobisphenol A (TBBPA) by using reaction kinetics, products identification and toxicity evaluation, and investigated the influencing effects of humic acid and clay particles on Fe(VI) removal of TBBPA in comparison with bisphenol A (BPA). The obtained apparent second-order rate constants (k(app)) for Fe(VI) reaction with TBBPA ranged from 7.9(+/-0.3) * 10(3) M(-1) s(-1) to 3.3(+/-0.1) * 10(1) M(-1) s(-1) with the half life (t1/2) ranging from 1.7 s to 419.3 s at pH 7.0-10 for an Fe(VI) concentration of 10 mg L(-1). Easier oxidation by Fe(VI) was observed for TBBPA than for BPA. Fe(VI) can destroy and transform the TBBPA molecule through beta scission reaction, yielding the chemical species of low bromine-substituted products. More importantly, the oxidation of TBBPA by Fe(VI) led to the loss of its multiple hormonal activities (androgenic, antiestrogenic and antiandrogenic activities). The organic component humic acid decreased the TBBPA and BPA reactions with Fe(VI), while the inorganic component montmorillonite had no effect on their removal within the tested concentrations. Increasing the Fe(VI) dosage can reduce the effects of soluble organic matter and clay particles present in source waters on the degradation process, leading to the complete removal of target micropollutants. PMID- 24956604 TI - Kinetics and efficiency of the hydrated electron-induced dehalogenation by the sulfite/UV process. AB - Hydrated electron (e(aq)(-)), which is listed among the most reactive reducing species, has great potential for removal and detoxification of recalcitrant contaminants. Here we provided quantitative insight into the availability and conversion of e(aq)(-) in a newly developed sulfite/UV process. Using monochloroacetic acid as a simple e(aq)(-)-probe, the e(aq)(-)-induced dehalogenation kinetics in synthetic and surface water was well predicted by the developed models. The models interpreted the complex roles of pH and S(IV), and also revealed the positive effects of UV intensity and temperature quantitatively. Impacts of humic acid, ferrous ion, carbonate/bicarbonate, and surface water matrix were also examined. Despite the retardation of dehalogenation by electron scavengers, the process was effective even in surface water. Efficiency of the process was discussed, and the optimization approaches were proposed. This study is believed to better understand the e(aq)(-)-induced dehalogenation by the sulfite/UV process in a quantitative manner, which is very important for its potential application in water treatment. PMID- 24956605 TI - Phosphorus speciation in a eutrophic lake by 31P NMR spectroscopy. AB - For eutrophic lakes, patterns of phosphorus (P) measured by standard methods are well documented but provide little information about the components comprising standard operational definitions. Dissolved P (DP) and particulate P (PP) represents important but rarely characterized nutrient pools. Samples from Lake Mendota, Wisconsin, USA were characterized using 31-phosphorus nuclear magnetic resonance spectroscopy ((31)P NMR) during the open water season of 2011 in this unmatched temporal study of aquatic P dynamics. A suite of organic and inorganic P forms was detected in both dissolved and particulate fractions: orthophosphate, orthophosphate monoesters, orthophosphate diesters, pyrophosphate, polyphosphate, and phosphonates. Through time, phytoplankton biomass, temperature, dissolved oxygen, and water clarity were correlated with changes in the relative proportion of P fractions. Particulate P can be used as a proxy for phytoplankton-bound P, and in this study, a high proportion of polyphosphate within particulate samples suggested P should not be a limiting factor for the dominant primary producers, cyanobacteria. Hypolimnetic particulate P samples were more variable in composition than surface samples, potentially due to varying production and transport of sinking particles. Surface dissolved samples contained less P than particulate samples, and were typically dominated by orthophosphate, but also contained monoester, diester, polyphosphate, pyrophosphate, and phosphonate. Hydrologic inflows to the lake contained more orthophosphate and orthophosphate monoesters than in-lake samples, indicating transformation of P from inflowing waters. This time series explores trends of a highly regulated nutrient in the context of other water quality metrics (chlorophyll, mixing regime, and clarity), and gives insight on the variability of the structure and occurrence of P containing compounds in light of the phosphorus-limited paradigm. PMID- 24956606 TI - Determinants of performance in a new test of planned agility for young elite basketball players. AB - PURPOSE: To investigate the reliability and determinants of performance in a new test of planned agility in elite junior basketball players. METHODS: Seventeen female (15.1+/-0.4 y, 176.9+/-11.2 cm, 65.7+/-10.9 kg) and 42 male (14.9+/-0.4 y, 193.7+/-8.1 cm, 79.0+/-12.0 kg) elite junior basketball players performed 5 fitness tests presented in a random order, including a 20-m sprint, a planned agility test, a triple bilateral horizontal countermovement jump, and 2 triple unilateral horizontal countermovement jumps (with each leg separately). The novelty of the planned-agility test is that it included both offensive and defensive movements. The determinants of planned agility were assessed by a stepwise-regression analysis, and the reliability of the new test was evaluated by the intraclass correlation coefficient and the typical error of measurement. RESULTS: The main results show good reliability of the new test of planned agility. In addition, the determinants of planned-agility performance were different between genders, with sprint performance explaining 74.8% of the variance for girls, while unilateral jump performance and body mass were the most important for boys, accounting for 24.0% and 8.9% of the variance, respectively, in planned agility. CONCLUSIONS: These results highlight a gender effect on the determinants of planned-agility performance in young elite basketball players and suggest that straight-line sprint and unilateral horizontal tests must be implemented to test elite junior players. PMID- 24956607 TI - Effects of Attentional Focusing Strategies on Muscular Power in Older Women. AB - The purpose of this study was to evaluate the effects of different foci of attention on parameters related to maximum muscular power in older women. Using a counterbalanced within-participant design, 23 physically active young-old women (age 59-69) completed a maximum effort cycle ergometer test following three types of verbal instructions. The external instruction (EXF) was designed to focus attention on moving the pedals as fast as possible, internal instruction (INF) directed attention toward moving the legs as fast as possible, and a control condition (CON) was created in which participants were instructed to perform the task to the best of their abilities. Results indicated that the EXF and CON conditions resulted in greater muscular power compared with the INF condition. Results also indicated that directing attention internally hindered muscular power performance in older women, which is consistent with the predictions of the constrained action hypothesis. PMID- 24956609 TI - Factors affecting physical activity in Ecuadorian adolescents: a focus group study. AB - BACKGROUND: Physical inactivity levels are increasingly prevalent among Ecuadorian adolescents. School-based interventions can be potentially effective in promoting physical activity but must be informed by cultural-specific factors. METHODS: Twelve focus groups were carried out with adolescents (n = 80) in rural and urban Ecuador to identify factors influencing physical activity. In addition, 4 focus group discussions with parents (n = 32) and 4 with school staff (n = 32) were conducted. Individual and environmental factors were questioned using the 'Attitude, Social influences and Self-efficacy' model and the socioecological model as theoretical frameworks. RESULTS: Factors influencing physical activity varied between groups. In the rural area farming and norms for girls impeded leisure-time physical activity, whereas urban groups emphasized traffic and crime concerns. Groups from a low socioeconomic status more frequently mentioned a fear of injuries and financial constraints. Several factors were common for all groups including preferences for sedentary activities, poor knowledge, time constraints and laziness, as well as a lack of opportunities at home and school, unsupportive parental rules and lack of role models. CONCLUSION: A conceptual framework including the identified factors emerged to inform the design of a cultural sensitive school-based intervention to improve physical activity among Ecuadorian adolescents. Future interventions should be tailored to each setting. PMID- 24956608 TI - Impact of park renovations on park use and park-based physical activity. AB - BACKGROUND: Given the concerns about low rates of physical activity among low income minority youth, many community-based organizations are investing in the creation or renovation of public parks to encourage youth to become more physically active. To what degree park renovations accomplish this goal is not known. METHODS: We used the System for Observing Play and Recreation in Communities (SOPARC) to measure park users and their physical activity levels before and after 2 parks were renovated. We compared findings with 4 parks: 2 that were unrenovated parks and 2 that were undergoing renovation. We also surveyed park users and local residents about their use of the parks. RESULTS: Compared with parks that had not yet been renovated, the improved parks saw more than a doubling in the number of visitors and a substantial increase in energy expended in the parks. Increased park use was pronounced in adults and children, but was not seen in teens and seniors. Park renovations were associated with a significantly increased perception of park safety. CONCLUSIONS: Park improvements can have a significant impact on increasing park use and local physical activity. PMID- 24956610 TI - Network community structure detection for directional neural networks inferred from multichannel multisubject EEG data. AB - In many neuroscience applications, one is interested in identifying the functional brain modules from multichannel, multiple subject neuroimaging data. However, most of the existing network community structure detection algorithms are limited to single undirected networks and cannot reveal the common community structure for a collection of directed networks. In this paper, we propose a community detection algorithm for weighted asymmetric (directed) networks representing the effective connectivity in the brain. Moreover, the issue of finding a common community structure across subjects is addressed by maximizing the total modularity of the group. Finally, the proposed community detection algorithm is applied to multichannel multisubject electroencephalogram data. PMID- 24956611 TI - Streaming updates for heart rate variability algorithms. AB - Heart rate variability (HRV) quantifies the fluctuations of the lengths of consecutive heart beat intervals, and is a reliable descriptor of many physiological factors modulating the normal rhythm of the heart. As the heart rate signal is nonstationary, indicators deduced from it may be present at all times, but may also occur episodically at nonpredetermined time instances. The potential for real-time feedback long-term ambulatory recordings is thus apparent. Numerous methods for measuring HRV have been standardized and are in active use, but are typically not designed to operate at real time. In this paper, we study the most popular HRV quantification methods and propose streaming algorithms that maximally utilize previously computed information without altering the output of the methods. We demonstrate speedups of more than two orders of magnitude for typical use-case scenarios. Using our algorithms on embedded systems that compute HRV leads to dramatic decreases in power consumption and in some cases allows for computation of metrics that were not previously possible at real time. PMID- 24956612 TI - Focused current density imaging using internal electrode in magnetic resonance electrical impedance tomography (MREIT). AB - Magnetic resonance electrical impedance tomography (MREIT) is an imaging modality capable of visualizing cross-sectional current density and/or conductivity distributions inside an electrically conducting object. It uses an MRI scanner to measure one component of the magnetic flux density induced by an externally injected current through a pair of surface electrodes. For the cases of deep brain stimulation (DBS), electroporation, and radio frequency (RF) ablation, internal electrodes can be used to improve the quality of the MREIT images. In this paper, we propose a new MREIT imaging method using internal electrodes to visualize a current density distribution within a local region around them. To evaluate its performance, we conducted and analyzed a series of numerical simulations and phantom imaging experiments. We compared the reconstructed current density images using the internal electrodes with the obtained using only the external electrodes. We found that the proposed method using the internal electrodes stably determines the current density in the focused region with better accuracy. PMID- 24956613 TI - Real-time simulation of three-dimensional shoulder girdle and arm dynamics. AB - Electrical stimulation is a promising technology for the restoration of arm function in paralyzed individuals. Control of the paralyzed arm under electrical stimulation, however, is a challenging problem that requires advanced controllers and command interfaces for the user. A real-time model describing the complex dynamics of the arm would allow user-in-the-loop type experiments where the command interface and controller could be assessed. Real-time models of the arm previously described have not included the ability to model the independently controlled scapula and clavicle, limiting their utility for clinical applications of this nature. The goal of this study therefore was to evaluate the performance and mechanical behavior of a real-time, dynamic model of the arm and shoulder girdle. The model comprises seven segments linked by eleven degrees of freedom and actuated by 138 muscle elements. Polynomials were generated to describe the muscle lines of action to reduce computation time, and an implicit, first-order Rosenbrock formulation of the equations of motion was used to increase simulation step-size. The model simulated flexion of the arm faster than real time, simulation time being 92% of actual movement time on standard desktop hardware. Modeled maximum isometric torque values agreed well with values from the literature, showing that the model simulates the moment-generating behavior of a real human arm. The speed of the model enables experiments where the user controls the virtual arm and receives visual feedback in real time. The ability to optimize potential solutions in simulation greatly reduces the burden on the user during development. PMID- 24956614 TI - Active adjoint modeling method in microwave induced thermoacoustic tomography for breast tumor. AB - To improve the model-based inversion performance of microwave induced thermoacoustic tomography for breast tumor imaging, an active adjoint modeling (AAM) method is proposed. It aims to provide a more realistic breast acoustic model used for tumor inversion as the background by actively measuring and reconstructing the structural heterogeneity of human breast environment. It utilizes the reciprocity of acoustic sensors, and adapts the adjoint tomography method from seismic exploration. With the reconstructed acoustic model of breast environment, the performance of model-based inversion method such as time reversal mirror is improved significantly both in contrast and accuracy. To prove the advantage of AAM, a checkerboard pattern model and anatomical realistic breast models have been used in full wave numerical simulations. PMID- 24956617 TI - Segmentation of renal perfusion signals from laser speckle imaging into clusters with phase synchronized dynamics. AB - Renal perfusion signals contain dynamics arising from the renal autoregulation feedback mechanisms as the contraction and dilation of vessels alter flow patterns. We can capture the time-varying dynamics at points across the renal surface using laser speckle imaging. We segment an imaged area of the renal cortex into clusters with phase synchronized dynamics. Our approach first uses phase coherence with a surrogate data derived threshold to identify synchronized pixel pairs. Non-negative matrix factorization is then applied to segment phase coherence estimates into phase synchronized regions. The method is applied to laser speckle imaging of the renal cortex of anaesthetized rats to identify regions on the renal surface with phase synchronized myogenic activity. In three out of six animals imaged after bolus infusion of N(omega)-nitro-l-arginine methyl ester (NAM), the renal surfaces are segmented into clusters with high phase coherence. No more than two clusters were identified during control period for any animal. In the remaining three animals, a strong myogenic signal could not be detected in surface perfusion during control or NAM. This method can be used to identify synchronization in renal autoregulation dynamics across the renal surface. PMID- 24956616 TI - Assessing dynamic spectral causality by lagged adaptive directed transfer function and instantaneous effect factor. AB - It is of significance to assess the dynamic spectral causality among physiological signals. Several practical estimators adapted from spectral Granger causality have been exploited to track dynamic causality based on the framework of time-varying multivariate autoregressive (tvMVAR) models. The nonzero covariance of the model's residuals has been used to describe the instantaneous effect phenomenon in some causality estimators. However, for the situations with Gaussian residuals in some autoregressive models, it is challenging to distinguish the directed instantaneous causality if the sufficient prior information about the "causal ordering" is missing. Here, we propose a new algorithm to assess the time-varying causal ordering of tvMVAR model under the assumption that the signals follow the same acyclic causal ordering for all time lags and to estimate the instantaneous effect factor (IEF) value in order to track the dynamic directed instantaneous connectivity. The time-lagged adaptive directed transfer function (ADTF) is also estimated to assess the lagged causality after removing the instantaneous effect. In this study, we first investigated the performance of the causal-ordering estimation algorithm and the accuracy of IEF value. Then, we presented the results of IEF and time-lagged ADTF method by comparing with the conventional ADTF method through simulations of various propagation models. Statistical analysis results suggest that the new algorithm could accurately estimate the causal ordering and give a good estimation of the IEF values in the Gaussian residual conditions. Meanwhile, the time-lagged ADTF approach is also more accurate in estimating the time-lagged dynamic interactions in a complex nervous system after extracting the instantaneous effect. In addition to the simulation studies, we applied the proposed method to estimate the dynamic spectral causality on real visual evoked potential (VEP) data in a human subject. Its usefulness in time-variant spectral causality assessment was demonstrated through the mutual causality investigation of brain activity during the VEP experiments. PMID- 24956615 TI - High-definition transcranial direct current stimulation induces both acute and persistent changes in broadband cortical synchronization: a simultaneous tDCS-EEG study. AB - The goal of this study was to develop methods for simultaneously acquiring electrophysiological data during high-definition transcranial direct current stimulation (tDCS) using high-resolution electroencephalography (EEG). Previous studies have pointed to the after-effects of tDCS on both motor and cognitive performance, and there appears to be potential for using tDCS in a variety of clinical applications. However, little is known about the real-time effects of tDCS on rhythmic cortical activity in humans due to the technical challenges of simultaneously obtaining electrophysiological data during ongoing stimulation. Furthermore, the mechanisms of action of tDCS in humans are not well understood. We have conducted a simultaneous tDCS-EEG study in a group of healthy human subjects. Significant acute and persistent changes in spontaneous neural activity and event-related synchronization (ERS) were observed during and after the application of high-definition tDCS over the left sensorimotor cortex. Both anodal and cathodal stimulation resulted in acute global changes in broadband cortical activity which were significantly different than the changes observed in response to sham stimulation. For the group of eight subjects studied, broadband individual changes in spontaneous activity during stimulation were apparent both locally and globally. In addition, we found that high-definition tDCS of the left sensorimotor cortex can induce significant ipsilateral and contralateral changes in event-related desynchronization and ERS during motor imagination following the end of the stimulation period. Overall, our results demonstrate the feasibility of acquiring high-resolution EEG during high-definition tDCS and provide evidence that tDCS in humans directly modulates rhythmic cortical synchronization during and after its administration. PMID- 24956618 TI - Which spring is the best? Comparison of methods for virtual stenting. AB - This paper presents a methodology for modeling the deployment of implantable devices used in minimally invasive vascular interventions. Motivated by the clinical need to perform preinterventional rehearsals of a stent deployment, we have developed methods enabling virtual device placement inside arteries, under the constraint of real-time application. This requirement of rapid execution narrowed down the search for a suitable method to the concept of a dynamic mesh. Inspired by the idea of a mesh of springs, we have found a novel way to apply it to stent modeling. The experiments conducted in this paper investigate properties of the stent models based on three different spring types: lineal, semitorsional, and torsional springs. Furthermore, this paper compares the results of various deployment scenarios for two different classes of devices: a stent graft and a flow diverter. The presented results can be of a high-potential clinical value, enabling the predictive evaluation of the outcome of a stent deployment treatment. PMID- 24956619 TI - Temperature increase in the fetus exposed to UHF RFID readers. AB - Exposure to electromagnetic fields (EMFs) has prominently increased during the last decades due to the rapid development of new technologies. Among the various devices emitting EMFs, those based on Radio-frequency identification (RFID) technologies are used in all aspects of everyday life, and expose people unselectively. This scenario could pose a potential risk for some groups of the general population, such as pregnant women, who are expected to be possibly more sensitive to the thermal effects produced by EMF exposure. This is the first paper that addresses the estimation of temperature rise in two pregnant women models exposed to ultrahigh frequency RFID by computational techniques. Results show that the maximum temperature increase of the fetus and of the pregnancy related tissues is relatively high (even about 0.7 degrees C), not too far from the known threshold of biological effects. However, this increase is confined to a small volume in the tissues. PMID- 24956620 TI - The forward problem of electroarthrography: modeling load-induced electrical potentials at the surface of the knee. AB - Electroarthrography (EAG) is a novel technology recently proposed to detect cartilage degradation. EAG consists of recording electrical potentials on the knee surface while the joint is undergoing compressive loading. Previous results show that these signals originating from streaming potentials in the cartilage reflect joint cartilage health. The aim of this study is to contribute to the understanding of the generation of the EAG signals and to the development of interpretation criteria using computer models of the human knee. The knee is modeled as a volume conductor composed of different regions characterized by specific electrical conductivities. The source of the EAG signal is the load induced interstitial fluid flow that transports ions within the compressed cartilage. It is modeled as an impressed current density in different sections of the articular cartilage. The finite-element method is used to compute the potential distribution in two knee models with a realistic geometry. The simulated potential distributions correlate very well with previously measured potential values, which further supports the hypothesis that the EAG signals originate from compressed cartilage. Also, different localized cartilage defects simulated as a reduced impressed current density produce specific potential distributions that may be used to detect and localize cartilage degradation. In conclusion, given the structural and electrophysiological complexity of the knee, computer modeling constitutes an important tool to improve our understanding of the generation of EAG signals and of the various factors that affect the EAG signals so as to help develop the EAG technology as a useful clinical tool. PMID- 24956621 TI - Computer simulation of cardiac propagation: effects of fiber rotation, intramural conductivity, and optical mapping. AB - Cardiac propagation characteristics such as anisotropy ratio and conduction velocities are often determined experimentally from epicardial measurements. We hypothesize that these measurements have inaccuracies due to intramural fiber rotation and transmural electrotonic interactions. We also hypothesize that optical mapping (OM) recordings compound the error, due to contributions from deeper layers. In this study, we studied propagation in a three-dimensional computer model of a slab of tissue with varying thickness and a 120 degrees fiber rotation. Simulation results were further processed to reconstruct OM signals. As expected, simulation results demonstrated that the direction of wave propagation on the epicardial surface is not aligned with the epicardial fiber orientation. This angle difference was most pronounced for thin tissue, and decreased with decreasing intramural conductivity and increasing tissue thickness. This difference also increased with time elapsed poststimulus, as the contribution from deeper layers increased. Observations were confirmed experimentally with OM measurements from isolated rat hearts. Simulations also predicted that OM causes an additional error in measurements due to activity in deeper layers being less aligned. Several alternative approaches for the estimation of fiber orientation and anisotropy ratio were evaluated. Those based on conduction velocity measurements yielded the most accurate estimates when applied to noise-free simulated data. PMID- 24956622 TI - Fifty-three years of reporting colorectal cancer in Nigerians--a systematic review of the published literature. AB - AIMS AND OBJECTIVES: This study aimed to perform a systematic review of all the available published data on CRC in Nigerians over a period of 53 years as a proximate indication of the burden of the disease. MATERIALS & METHODS: The data were sourced from PubMed, MEDLINE, EMBASE and Google Scholar search engines as well as direct contact with some authors. All published studies on histologically confirmed CRC in Nigerians constitute the materials. Selected papers were independently reviewed by the authors. RESULTS: Of 35 papers found, 19 met the criteria and a total of 2497 cases reported in these 19 publications constituted the materials utilised for the review. There is increasing incidence as evident by increase in annual frequency increased from 18.2/annum in the early years (1954-1969) to 86.8/annum in the latter years (1991-2007). The average age incidence was 46 years (peak=41-50 age group); 674 (32%) of all the cases were aged below 40 years. The male to female ratio was 1.3:1. Of the 2238 cases in which site was reported, rectum 1349 (60%) was the commonest site followed by caecum 260 (17%). All the cases were adenocarcinomas and 1043 (56%) were well differentiated. Mucinous carcinoma and signet ring type accounted for 309 (17%) and 32 (2%) respectively. Of 1061 cases in which Duke's staging was reported, 622 (59%) presented in stage B disease followed by stage C 266 (25%). CONCLUSIONS: The incidence is of CRC is increasing in Nigeria. The mean age is low and incidence appears to be increasing in younger patients. PMID- 24956623 TI - Role of optical coherence tomography in posterior segment eye disorders: a review of two cases. AB - Optical Coherence Tomography produces high resolution tomographic in in vivo imaging of biological tissues. The study reviews OCT images of two patients with varied retinal pathologies to determine its usefulness in aiding evaluation and management of retinal diseases. The patients were imaged using OCT conventional fundus photography and angiography. A case each of premacular haemorrhage and idiopathic polypoidal choroidal vasculopathy, are presented highlighting the merits of OCT. OCT establishes the accurate diagnosis of retinal diseases and in monitoring response to therapy. It is complementary to clinical techniques of direct and indirect ophthalmoscopy, conventional fundus photography, fluorescein and indocyanine green angiography thus should be made readily available for use in the evaluation of retinal disorders to enhance their management. PMID- 24956624 TI - Magnetic resonance imaging of multiple spinal extra dural arachnoid cysts: a case report. AB - Extradural arachnoid cysts develop from protrusions of arachnoid herniating through a dural defect. Solitary lesions are more common than multiple lesions. This report is an uncommon multiple spinal extradural arachnoid cysts, illustrating the value of magnetic resonance imaging in the diagnosis. A 42-year old man presented with low back pain radiating into the left leg with associated paraesthesia. Magnetic resonance images showed two well defined expansile lobulated collections. These lesions expanded the spinal canal, appearing as both hyperintense and hypointense on T1 and T2 sequences respectively. The lesions were resected and the dorsal communicating channel was closed. He had remarkable pain reduction thereafter. PMID- 24956626 TI - [Clinical usage and future prospective of guidelines in treatment of hematological malignancies]. PMID- 24956625 TI - Cerebral atrophy and dementia in type 2 diabetes mellitus: report of two cases and review of literature. AB - A report of two cases of cerebral atrophy and dementia possibly arising as a result of poor control of type 2 Diabetes Mellitus are presented The two elderly patients presented to the old age Psychiatric clinic with history of impairment in memory and changes in personality. They had a history of long standing poorly controlled diabetes mellitus. They were assessed using psychometric instruments, laboratory investigation and neuro-imaging. A diagnosis of dementia was made in each of two the patients. The aim of this case report is to draw the attention of the medical community and policy makers to the relationship between type 2 diabetes mellitus and dementia with a view to evolving policy change on the care for the elderly in Nigeria. PMID- 24956627 TI - [Treatment of acute Leukemia]. PMID- 24956628 TI - [Chronic myeloid Leukemia - clinical practice according to the JSH guideline for hematological malignancies]. PMID- 24956629 TI - [Low -grade B cell Lymphoma]. PMID- 24956630 TI - [T/NK-cell Lymphoma]. PMID- 24956631 TI - [Multiple Myeloma]. PMID- 24956632 TI - Special issue on research in biomedical engineering at the National University of Singapore: at the forefront of research in the 21st century. PMID- 24956633 TI - Measuring the breath of life. PMID- 24956635 TI - [Gone to the dogs: rural physician with hidden talent]. PMID- 24956634 TI - [Differential diagnosis of a skin tumour--a case study]. PMID- 24956636 TI - [Claims over 600,000 euro. Compromise with recourse hydra]. PMID- 24956637 TI - [Standard procedure for introducing EBM services defined]. PMID- 24956638 TI - [Independent practice is becoming increasingly rare in MVZ]. PMID- 24956639 TI - [MFA magazine "info praxisteam". Knowledge of senior staff maintained]. PMID- 24956640 TI - [Professional perspective. We junior familty physicians might also still have a few ideas.....]. PMID- 24956641 TI - [Resistant hypertension. Renal denervation is disappointing in a large study]. PMID- 24956642 TI - [Interview with Prof. Dr. med. Michael Bohm: lessons from SYMPLICITY HTN-3. "Denervation only within the scope of studies or registries" (interview by Dr. med. Dirk Einecke)]. PMID- 24956643 TI - [Chronically overweight type 2 diabetes. Bariatric surgery can control diabetes in the medium term]. PMID- 24956644 TI - [Even without smoking. Children with severe asthma are at risk for later COPD]. PMID- 24956645 TI - [Prevention of COPD exacerbation. Walking as "lung training"]. PMID- 24956646 TI - [Nociceptive and neuropathic pain components. Why is backache irritating?]. PMID- 24956647 TI - [Avoid confrontational communication!]. PMID- 24956648 TI - [Unusual autopsy. Cardiac cause of death cannot be identified by livor mortis]. PMID- 24956649 TI - [Child is overweight and parents don't see this]. PMID- 24956650 TI - [Dark red urine]. PMID- 24956652 TI - [Fulminant infection in diabetic foot syndrome]. PMID- 24956651 TI - [New guideline recommends expansion of statin therapy]. PMID- 24956653 TI - [Inexperienced automobile drivers are more easily distracted]. PMID- 24956654 TI - [Focus on the diseased kidney]. PMID- 24956655 TI - [The deadly sins of pharmacotherapy in chronic kidney disease]. PMID- 24956657 TI - [The chronicle lymphedema--an interdisciplinary challenge]. PMID- 24956656 TI - [Vasculitis and the kidney]. PMID- 24956658 TI - [Stable isotope analyses on body tissues of unidentified corpses--diet as a mirror of a person's whereabouts]. PMID- 24956659 TI - [Pulmonary hypertension--diagnostic and current concepts]. PMID- 24956660 TI - [Dysphagia--what is important for primary diagnosis in private practice?]. PMID- 24956661 TI - [Hyperhidrosis - an underestimated comorbidity. Great discomfort should not be tolerated]. PMID- 24956662 TI - [Hypertension. Guidelines recommend fixed combinations]. PMID- 24956663 TI - [Chronic obstructive lung disease. Symptom improvement with aclidinium bromide]. PMID- 24956664 TI - [Integrative approaches to the diagnosis and treatment in urology]. AB - Modern medical science is characterized by the rapid development of diagnostic equipment, the introduction of more sophisticated and science-based technology in the diagnosis and treatment of diseases. Features of the urologist's work in the modern world and the diversity of manifestations of urologic diseases require close cooperation between physicians of different specialties. Interdisciplinary cooperation is necessary and urgent not only for professionals but also for patients. The authors summarize and present the problems that connect urologists with colleagues in medicine, biology, and other areas of our life. PMID- 24956666 TI - [Evaluation of the adhesive characteristics of uropathogenic escherichia coli strains in patients with spinal cord injuries]. AB - The adhesion characteristics of 9 clinical E.coli strains, isolated from the urine of 9 patients with spinal cord injuries in late period were evaluated. Patient age was 21 to 54 years. Neurogenic urination disordes observed in patients were the result of a spinal injury in the cervical (5 patients), thoracic (2 patients) and thoracolumbar (2 patients) spine. The duration of disease ranged from 2 to 12 years. Despite primarily a low adhesion activity of tested strains, the formation of biofilm occurs on the surfaces having both hydrophobic (polystyrene) and hydrophilic (cover glass) properties. After 24 h, according to the photometric evaluation, 7 of 9 strains had weak, 1 - medium, and 1 - high ability to form biofilms. After 48 hours, only 4 strains had low ability to form biofilms, of whom 2 had an increase ability compared to the previous period of observation. Other strains possess the medium ability to form biofilm. When quantifying the ability of bacteria to form biofilms on the surface of the cover glass, it was revealed that a large fraction of the area of the field of view was accounted for microcolonies with size 10 microm2 at 24 hours, and microcolony with size from 100 to 1000 microm2 at 48 h. There were number of significant correlations between parameters studied. After 24 h, the correlation coefficient between the optical density (OD630) and the number, OD630 and proportion of microcolonies with size 10 to 10000 microm2 varied from 0.79 to 0.9. After 48 hours, there was a direct correlation between the OD630 and the number (r = 0.73, P = 0.025), OD630 and proportion (r = 0.81, P = 0.009) of microcolonies with size 1,000 to 10,000 mkm2. PMID- 24956665 TI - [Replacement plastic reconstruction of extended ureteral stricture using buccal mucosa autograft]. AB - The potentials for the use of free buccal mucosa graft in reconstruction plastic surgery of extended uretral stricture are evaluated. From 2007 to 2013, 9 operations in 8 patients (mean age 54,5+/-7,2 years) were performed. The average length of cicatricial uretral stricture was 5,1+/-0,7 cm. 1 patient has lesion in the upper third of the ureter, 4 patients - in the middle portion, and 4 patients - at the bottom portion. The causes of extended uretral stricture were following: long standing calculi (n=3), ureteral injury after ureterolithotripsy (n=2) and after bringing down the calcuus using loop (n=1), radiotherapy (n=3, one patient had bilateral injury). All patients underwent plastic reconstruction of ureter using buccal mucosa graft by "on-lay" type. During the follow-up (median, 42 months, from 3 to 72 months), in 7 (88,9 %) of 8 patients (8 operations) ureteral strictures relapses were not observed. They all had satisfactory renal excretory function without the pronounced violations of passage of urine along the ureter. The excretory urography showed moderate expansion of the ureter at the site of operation in 6 of them. Due to the progression of secondary renal scarring, one patient underwent nephrectomy 1.5 year after reconstruction plastic surgery. In this patient, pronounced anatomical and functional changes in the kidney occurred before the operation. Application of the buccal mucosa graft in reconstruction plastic surgery in extended uretral stricture is high effective due to the relatively low level of early and late postoperative complications and low recurrence rate. PMID- 24956667 TI - [Application of rowatinex in the perioperative period in the extracorporeal shock wave lithotripsy]. AB - Despite the high efficacy and safety of ESWL used to disintegrate stones in pyelocaliceal system and upper ureter, the issue of further reduction of the risk of complications of this procedure remains unresolved. The inclusion ofphytopreparations with anti-inflammatory and lithokinetic properties in the scheme of perioperative treatment is one of the ways for prevent complications of ESWL. The effect of the drug Rowatinex on the process of discharge of calculi fragments after ESWL is evaluated. The frequency and intensity of qualitative changes of urine after appointment this drug were assessed. It is concluded that Rowatinex has positive impact on the final result of ESWL in the case of its inclusion in the complex medical treatment, which manifests in terms of reducing the time of discharge of fragments, mitigation of subjective symptoms, as well as reducing the frequency of subclinical bacteriuria and severe complications. PMID- 24956668 TI - [Surgical treatment of tuberculosis of the kidney with a total lesion of the ureter]. AB - The study was aimed to improve the efficiency of surgical treatment of renal tuberculosis with total lesion of the ureter. The clinical course and the results of surgical treatment of 104 patients with extended or multiple ureteral strictures of specific (n=92) and non-specific (n=12) etiology. Thirty-five patients with nephrotuberculosis underwent percutaneous needle-guided nephrostomy (PNGNS), 79 underwent surgery with removal of organs: open nephrectomy with lumbar access (48), combined nephroureterectomy (31). According to the evaluation the glomerular filtration rate after PNGNS, value less than 10 ml/min led to performing nephrectomy, more than 10 ml/min - ureteroplasty. It was established that combined nephroureterectomy has significant advantages in the case of specific kidney disease, despite a long duration as compared with a nephrectomy. Removal of the kidney with ureter in patient with nephrotuberculosis is the prevention of persistent dysuria, empyema of ureter stump, its possible malignant transformation, and contributes to significant improvement of quality of life of the patient. Of the 35 patients after CHPNS, 25 underwent intestinoplasty of ureter: ileum was used in 23 patients, appendix- in 2 patients. It is shown that reconstructive surgery using small intestine allows to release 92% of patients from a lifetime external drainage of the kidney. PMID- 24956669 TI - [Differential diagnosis and treatment of complex renal cysts detected by ultrasound screening of the abdominal cavity organs]. AB - Ultrasound screening of the abdominal cavity organs was performed in 98 patients, and renal cysts were revealed in 31 patientsare. 11 (26,6%) of 31 patients had renal cysts with complex structure. In 4 patients, complex cysts were located in parapelvic zone, in 7 patients - in different parts of the renal parenchyma. Pharmaco-Doppler sonography and computed tomography with bolus contrast enhancement in 7 patients with complex parenchymal cysts had revealed indirect signs of a malignant process - septums, thickening of the walls of cysts and septums, foci of calcination, increased blood circulation in the thickened renal cyst walls, venous stasis on the periphery of cysts and renal medulla, increasing the density of the thickened walls. Results of morphological studies have confirmed the presence of a malignant process in 5 of these 7 patients. In 4 patients with parapelvic cysts malignant process in ectomized layers was not revealed. PMID- 24956670 TI - [Actual issues of pathogenesis of tuberculosis of male genital organs]. AB - Based on a survey of 467 men with genital tuberculosis, following conclusions were made. The presence of morphological signs of nonspecific prostatitis of toxic-allergic genesis in patients with newly diagnosed tuberculosis of the urinary and genital organs proves the possibility of primary infection of the epididymis with Mycobacterium tuberculosis. Primarily isolated epididymal tuberculosis was diagnosed in 21 (4,5%) patients. Tuberculous of testicles is in direct relationship to the duration of the existence of tuberculous infection in the epididymis. Bilateral tuberculous of the epididymis is always combined with tuberculosis of the prostate. Opportunity of both primary and secondary infection of the prostate gland with Mycobacterium tuberculosis can be considered as proved. 15 (3,2%) patients had initially isolated prostatic tuberculosis. Based on clinical observations, exogenous way of introduction of infection in tuberculosis of genital organs in men was not confirmed. The lymphogenous and hematogenous pathways are leading and most common pathways of Mycobacterium tuberculosis in the male genitals. In patients with tuberculosis of the prostate, which is combined with a lesion of urinary organs, without involvement of scrotum in the pathological process, infection of prostate occurs by urinogenous way. Tuberculosis of the seminal vesicles is always secondary; none of the patients were initially diagnosed with isolated process. Based on the clinical manifestations of the disease and a detailed examination of the patient, it is virtually impossible to establish a particular way of infection in the male genitals. The main value of the information about the possible ways of tuberculosis infection consists of fully examination of reproductive system with histological and bacteriological verification of the diagnosis of each genital organs in each man with suspected tuberculosis. PMID- 24956671 TI - [Evaluation of compensation abilities of kidneys using radionuclide examination]. AB - The article presents the results of evaluation of compensation abilities of kidney based on the identification of volume of functioning renal tissue according to the single-photon emission scintigraphy (SPECT) and planar scintigraphy. The study included adult patients (65 patients with renal cell carcinoma, 32 patients with renal cysts and 20 patients without renal involvement) and pediatric patients aged 1 to 17 years (57 patients with various non-neoplastic lesions of the kidney). The following parameters were used: volume ratio of functioning tissue and the specific activities of the affected and contralateral kidneys, and the volumetric ratio of volumes estimated to the reference kidney volume depending on anthropomorphic data of patient (age and sex). It was found that the maximum compensatory renal reserve occurs in the case of reducing the volume of functioning tissue of the affected kidney and the simultaneous increase in the volume ofcontralateral kidney. PMID- 24956672 TI - [Morphological changes in bladder tissue after submucosal injection of mitomycin C solution in experiment]. AB - The article presents the results of morphological examination of bladder tissue reactions on the submucosal injection of mitomycin-C solution in different (0.1, 0.05, 0.025, and 0.0125%) concentrations. The experiments were conducted using dogs weighing 13-15 kg. Tissue sampling for histological evaluation were performed at 1, 2 and 3 hours, and on Day 7, 14, and 30. Maximum expression of the inflammatory response in the submucosa (edema, foci of lymphohistiocytic infiltration, increased microvascular lumen, diffuse leukocyte infiltration around the vessels of connective tissue between muscle fibers) was developed early after injection of 0.1% mitomycin-C, and it was minimal 3 hours after injection of 0.0125 % solution. PMID- 24956673 TI - [Varicocele in second adulthood and elderly men]. AB - The prevalence ofvaricocele in second adulthood and elderly men was evaluated. It was found that varicocele in this age group occurs in 15.8 % of cases , whereas in men up to 35 years - in 18.3 % of cases. 88.5 % of men older than 35 years had children. Varicocele is often asymptomatic. The course of varicocele includes compensation and decompensation stages. Proportion of adulthood and elderly patients with decompensated stage ofvaricocele in the structure ofurological disease was 0.34 %. Pain is the main manifestation of varicocele at the stage of decompensation in second adulthood and elderly men. For surgical correction of varicocele in such patients, Sayfan technique seems appropriate, which uses transinguinal mini assess (2.5-3 cm incision) allowing to identify and eliminate most of the possible causes of pain: infantile hernia, benign tumors of adipose tissue, fibrotic changes in the tissues along the ilioinguinal nerve. This minimally invasive technique can be used in outpatient surgery. 18 patients underwent surgery using this technique. There were no early postoperative and long-term complications. At 1 to 3 years after surgery, 13 patients were re examined, and relapses were not revealed. PMID- 24956675 TI - [Comparative analysis of histological and long-term oncological outcomes after radical prostatectomy in patients matching johns hopkins and the royal marsden hospital criteria for active monitoring]. AB - A retrospective comparative analysis of results of treatment of patients with prostate cancer who met the most stringent (Johns Hopkins - JH; 74 patients) and the most mild (Royal Marsden Hospital - RMH; 263 patients) selection criteria for the management according to the strategy of active monitoring was performed. Significant differences in the frequency of detection of adverse histological features and biochemical recurrence-free survival after radical prostatectomy in patients eligible for JH and RMH criteria were not identified. Extracapsular extension occurred in 2.7 and 4.9% (P=0,33), seminal vesicle invasion - in 1.4 and 2,6% (P=0.43), positive surgical margins - in 6, 8 and 7.2 % (P=0.56) Gleason score increase - at 6.8 and 9.1 % (P=0.49), respectively. Five-year disease-free survival rates were 95.7 and 95,8% (P=0.41). Regardless of the protocol selection for active monitoring, precise examination of patients and staging of the disease are absolutely necessary, as well as the future well-designed studies on the comparative analysis of the effectiveness of active monitoring and early curative treatment in the settings of national health care. PMID- 24956676 TI - [Experience of use of prolit super septo in the rehabilitation of patients after endoscopic surgery]. AB - Numerous publications on the successful application of prolit super septo ( Greenwood, RF) in metaphylaxis of urolithiasis after extracorporeal shockwave lithotripsy, and in infectiousand inflammatory diseases of the upper and lower urinary tract gave rise to research aimed at investigating the efficacy and safety of long-term use of prolit super septo in patients undergoing various transurethral and percutaneous interventions. From September 2012, to March 2013, 894 transurethral and percutaneous endoscopic interventions were performed. The main group (n=450) consisted of patients treating with prolit super septo at a dose of 2 capsules 2 times a day for a one month in addition to standard uroantiseptic therapy after endourological interventions. The control group (n=444) consisted of patients receiving standard therapy for the same period after same interventions. The evaluation of patients both main and control group was focused on pyuria, daily diuresis, symptoms and quality of life of patients. It was found that after transurethral surgery of the lower urinary tract, the use of prolit super septo reduces the severity of irritative symptoms, improves the quality of life, reduces the leucocyturia, and increases the diuresis. Application of prolit super septo after operations on the upper urinary tract leads to a decrease of leucocyturia, increase of dieresis, and improves the discharge of residual fragments. In patients with oxalate and urate calculi, persistent increase in the pH of urine was noteda, which may be a part of metaphylaxis of urolithiasis. Adverse effects associated with taking of prolit super septo were not observed. PMID- 24956674 TI - [Efficiency of spematon in male infertility]. AB - The article presents the results of the application of spematon in 39 men from infertile couples with different forms of pathospermia (asthenozoospermia, oligozoospermia, teratozoospermia). It is shown that the effect in the first 3 months of use of spematon is mainly associated with normalization of acrosome reaction of sperm cells. It was established that spematon, due to content of L carnitine content, zinc, vitamin E, contributes restoration of induction of acrosome reaction. PMID- 24956677 TI - [Correction of erectile dysfunction in patients undergoing radical prostatectomy]. AB - Radical prostatectomy (RPE) is a widespread surgery in the world performed in patients with localized prostate cancer. Despite the widespread introduction of nerve-sparing radical prostatectomy techniques, erectile dysfunction after radical prostatectomy occurs very frequently, which seriously affect the quality of life of patients. At the present stage of development of medicine, differentiated approach to each patient is required. "Patient's expectation management" is an important prerequisite for successful sexual rehabilitation. The use of conventional methods for correction of erectile dysfunction after radical prostatectomy has its own characteristics. Currently, phosphodiesterase type 5 inhibitors, however, are still first-line agents for the recovery of erectile function. Their combined use with other methods has encouraging results. PMID- 24956678 TI - [Principles of continence in women: the formula of continence]. AB - Urinary incontinence in women is a widespread disease . In recent years, significant progress in its treatment was achieved. Despite this, the mechanisms of continence are still poorly understood. According to the principles of biomechanics, incontinence occurs when bladder pressure exceeds urethra pressure. We represent the formula for calculating the pressure loss of urine, which takes into account the main factors involved in the formation of urethral pressure. According to our data, the involuntary leakage of urine during physical conditions may occur if the bladder pressure exceeds intraurethral pressure, which can be calculated using a formula based on urethral closing pressure and passive resistance of the bladder neck. PMID- 24956679 TI - [Malignant schwannoma of the ureter]. PMID- 24956680 TI - [Intestinoplasty of ureters]. AB - The review provides a comparative evaluation of reconstructive surgery in patients with extensive restrictions of ureter using intestinal transplants. The questions relating to the main stages of intestinal reconstruction of ureters, forming intestinal transplant, technique of creating of anastomoses are discussed; a comparative analysis of long-term results and complications of intestinoplasty of ureters is performed. PMID- 24956681 TI - [Leib-surgeon of cesarean Romanov family V.N. Derevenko and his role in the formation of the ural and domestic urology (to the 400TH anniversary of the house of Romanov)]. PMID- 24956682 TI - [Dzeranov Nikolay Konstantinovich (1951-2014)]. PMID- 24956683 TI - Clinical autopsy: for the sake of the living. PMID- 24956684 TI - Systematic review and metanalysis on community based interventions in tuberculosis care in developing countries. AB - BACKGROUND: We aimed to evaluate the effectiveness of Lay Health Workers (LHW) in increasing case detection rate and treatment success outcome of Tuberculosis cases METHODS: PUBMED,; Google scholar, African Journal Online (AJOL) and other search engines were systematically searched, for literature from 2000 to 2012 for studies that are either: [randomized/cluster randomized/non randomized or prospective cohort study); assessing lay Health care worker participation in tuberculosis (TB) treatment, using the key words (LHW, TB and treatment). Studies were pooled using a random effect model. Of the thirteen studies that fulfilled the inclusion criteria for systemic review, only five were heterogeneous enough for a meta-analysis. RESULTS: There was a marginal effectiveness of LHW involvement in TB treatment success rate, RR 1.09 Confidence Interval. [0.98 1.21]. There was no publication bias; with {p = 0.135 for Eggar's weighed regression analysis}. Restrictive analysis showed a marginally higher summary relative risk in rural based studies RR 1.12, C.I. [1.01-1.24]; compared to urban studies RR 1.01, C.I. [0.91-1.13]. CONCLUSION: The use of Lay Health care workers is associated with a marginal benefit in improving TB treatment success compared to standard facility based TB care. Larger studies are needed to properly prove its superiority. PMID- 24956685 TI - A systematic review of effectiveness of daily oral penicillin v prophylaxis in the prevention of pneumococcal infection in children with sickle cell anaemia. AB - BACKGROUND: Children with sickle cell anaemia (SCA) are highly susceptible to infection caused by pneumococcal bacteria due to functional asplenia amongst other reasons. Pneumococcal infections are severe with high mortality among these children that the need for prophylactic penicillin therapy becomes necessary. The objective of this review is to look for evidence of the effectiveness of daily oral penicillin prophylaxis in the prevention of pneumococcal infection in children with SCA. METHODS: Electronic databases including genetic disorders group haemoglobinopathies trial register, Cochrane library, Pubmed, Turning Research Into Practice (TRIP) and Google were searched for relevant studies. Hand and grey literature searches were also done. Randomized controlled trials comparing oral penicillin prophylaxis for the prevention of pneumococcal infection in children with SCA with placebo or no treatment were searched for. RESULTS: Two trials were found to have met the inclusion criteria for the review. Results of the two included randomized controlled trials showed a significant reduction in the incidence of pneumococcal infection among children with SCA (and (0)-thallasaemia) receiving penicillin compared to the control group treated with placebo. The odds ratios for the two (Gaston et al and Falletta et al) studies were 0.37 (95% CI 0.16 to 0.86) and 0.5 (95% CI 0.1 to 2.71) respectively. CONCLUSION: There is strong evidence that daily oral penicillin prophylaxis greatly reduces the risk of pneumococcal infection in children with SCA under the age of three years and a moderately strong evidence that its, withdrawal at the age of five years did not result in any serious consequences. PMID- 24956687 TI - Knowledge, attitude and practice of perioperative antibiotic prophylaxis among nurse-anaesthetists in Nigeria. AB - BACKGROUND: In Nigeria, nurse-anaesthetists are responsible for administering perioperative prophylactic antibiotics in a large number of operations but this practice is poorly studied. AIMS: The aim of this study was to evaluate the knowledge, attitude and practice of perioperative antibiotic prophylaxis among nurse-anaesthetists in Nigeria. METHODS: A cross-sectional study was conducted among nurse-anaesthetists at an Annual General Meeting/Scientific Conference of Nigeria Association of Nurse-Anaesthetists, using a pre-tested questionnaire. RESULTS: Of 70 questionnaires. 67 were returned. Antibiotic administration at induction of anaesthesia was considered inappropriate by 79.1% (n = 67) and safe by 42.6% (n = 61). There was poor knowledge of indications for intraoperative administration. There was agreement by 81.9% of respondents that anaesthetists should administer prophylactic antibiotics (n = 66) but 72.2% would want the surgeon to indicate the time of administration (n = 60). About 69.3% and 77.2% of respondents administered prophylactic antibiotics before tourniquet application (n = 62) and skin incision (n = 66) respectively in their practice but the latter finding was not corroborated by internal validity check. Availability of a hospital perioperative antibiotic prophylaxis protocol (p = 0.048) and practice for 10 or more years (p = 0.009) were associated with higher knowledge score. CONCLUSION: Inclusion of lectures on perioperative antibiotic prophylaxis in nurse-anaesthesia training curriculum, having hospital perioperative antibiotic prophylaxis protocol, stating in the protocols that surgeons give instructions on timing of antibiotic administration and ensuring adherence to the protocols may improve knowledge and practice of perioperative antibiotic prophylaxis among nurse-anaesthetists. PMID- 24956686 TI - Factors influencing herpes simplex virus type 2 infection among females in Enugu, Enugu State, Nigeria. AB - BACKGROUND: Herpes Simplex Virus infection is a chronic infection of the sensory ganglia with variable levels of epithelial expression. An important feature of HSV infection is the recurrence of disease as a result of periodic or sporadic activation of viral replication. In addition, asymptomatic shedding of herpes viruses may play a significant role in transmission from person to person. This infection being lifelong manifests only in a small proportion of those infected. It has presented public health concern because of its progressively increasing prevalence which some reports say is of epidemic proportion in developing countries and also for its synergistic effect with HIV infection. OBJECTIVES: Determination of antibody prevalence to HSV-2/co-infection with HIV among females attending skin and ANC clinics in UNTH and ESUTH. MATERIALS AND METHODS: One hundred and eighty suitably qualified subjects were appropriately recruited over a period of six months into this study. Essential information was collected using a questionnaire. Venous blood was also obtained for HSV 2 serology, HIV screening, and confirmation, if positive. RESULTS: The antibody prevalence of HSV 2 was found to be 77.8% (n = 137) and 14.6% (n = 20) had clinical diagnosis. The HIV and HSV-2 co-infection rate was 5.11% (n = 9). The risk factors for groups 1 [HSV2 Infection] and 2 [HSV2 & HIV co-infection] were similar with few differences, thus buttressing the fact that their modes of transmission are similar. CONCLUSION: Factors influencing Herpes simplex virus type 2 infection among females in Enugu included among other things older age and increasing number of lifetime sexual partners. PMID- 24956688 TI - Pattern of placenta histopathology in low birth weight babies seen in a tertiary health centre in South-Western Nigeria. AB - BACKGROUND: Pre-term delivery is usually associated with low birth weight and is a known obstectrics problem in our setting. Few Histopathologists are interested in placental pathology, and this is particularly so because consent is often difficult to get from the relatives making few specimens available for study in our environment. OBJECTIVE: Our objective was to evaluate the placental histopathology in low birth weight infants (LBW, birth weight < 2500 g) and to determine if placental histopathological findings are associated with low birth weight and preterm deliveries. METHODS: The placenta of thirty-eight consecutive cases of LBW deliveries at the Obafemi Awolowo University Teaching Hospital, Wesley Guild Hospital, (lesa were histologically examined. RESULTS: A total of thirty-eight LBW placentas were examined. The Male: Female ratio was 1.8:1. The maternal age range 19 - 38 years (mean age = 28.7 yrs +/- 5.37SD). The parity ranged from 0 to 5. The birth weight ranged 0.75 - 2.4kg (mean 1.84kg +/- 0.39SD). The gestational age at delivery range was 25 - 38 weeks (mean 32.85 weeks +/- 3.7SD). Histological examination of the placentae showed that 17 cases (44.7%) had evidence of placenta malaria (PM), 17 cases (44.7%) had chorioamnionitis (CA), 9 cases (23.7%) had villitis, 2 cases (5.3%) had vasculitis and 4 cases (10.5%) had no abnormality. Four sets of twins (8 cases) were among the 38 cases seen. A case of abruptio placenta was delivered by caesarean section, with histological diagnosis of active- chronic malaria. Out of the cases with CA11 (64.7%) had mild CA, 4 (23.6%) moderate while 2 (11.8) had severe infection. Placenta malaria co-infection was also found in 7 (41%) of the CA. Nine (23:7%) had villitis, only 2 cases had umbilical cord vasculitis. Of the cases with PM, 10 (58.8) had active-chronic infection while 7 (41.2%) had evidence of past infection. CONCLUSION: The main placenta findings histologically in LBW babies include chorioamnionitis and placenta malaria infection. These are known contributory factors to preterm labour. Improved maternity care, health education of pregnant women to reduce ascending infection and use of intermittent preventive treatment for malaria in pregnancy will go a long way in improving outcome of pregnancy. PMID- 24956689 TI - Perinatal autopsies in a tertiary health facility in Southwestern Nigeria: a retrospective evaluation of 14 consecutive cases. AB - BACKGROUND: Perinatal autopsy remains a valuable tool in perinatal medicine. It provides an insight into the genetic implications of subsequent pregnancies and also helps reduce parental events such as maternal illness or maternal use of medications. The practice is not popularly acceptable in our environment for socio-cultural reasons. The scarcity of pathologists who are interested in this aspect of pathology is also an issue. No wonder, the literature is scanty on the cases of perinatal autopsy reported in our environment. MATERIAL AND METHODS: This was a retrospective review of patients' medical and autopsy records to measure the perinatal autopsy rate at a tertiary health institution and identify the trends over the last 12 months (January 1, 2010 and December 31, 2010). This study also aim examining any discordance between antemortem diagnoses and postmortem diagnoses. RESULTS: Of 263 perinatal deaths, autopsies were requested and performed in 14 of the cases representing a perinatal autopsy rate of 5.3%. New information was obtained in 64.3% of the cases. The birth weights of the infants ranged from 500g to 3600g with their gestational ages ranged from 22 weeks to 41 weeks. CONCLUSIONS: This study is a preliminary report that serves principally to provide base line data for the ongoing study. PMID- 24956690 TI - Traditional bone setting in the Niger Delta region of Nigeria. AB - BACKGROUND: Traditional bone setting is an age long practice in African societies. It has flourished in spite of the advent of orthodox fracture management in Nigeria and many other African countries. However, complications emanating from their practice have led to suggestions on the need for intervention and control of their activities. OBJECTIVE: We aim to document the current practice of the traditional bone setting in the Niger-Delta region of Nigeria. METHODOLOGY: A structured interview of two traditional bone setters in the surrounding villages of the Delta State University Teaching Hospital, Oghara, Delta State, Nigeria was carried out. In addition we visited their 'clinics' to make on the spot assessment of their practice. RESULTS/FINDINGS: The two practitioners ('A' and 'B') interviewed were both males who inherited the trade from their parents. Practitioner 'A' has both out-patient and in-patient practices while 'B' only treat outpatients in addition to home visits. Basically, both practitioners have similar method of injury treatment which consists of; massaging/manipulation to reduce fractures/dislocations after which the area may be scarified before application of an herbal mixture (Igbudia) followed with bandaging and splinting. CONCLUSION: From this study, it is obvious that the current practice of traditional bone setters in the Niger-Delta region of Nigeria is still crude and far from ideal. There is thus need for a review of their practice with reorientation of their psyche, training, standardisation, certification/licencing, legislative control and eventual integration atthe primary health care level. PMID- 24956691 TI - The profile of chest injuries in a southeastern Nigeria teaching hospital, a 10 year experience. AB - BACKGROUND: Globally, major chest injuries have both high morbidity and mortality. A detailed study of chest injuries in south-eastern Nigeria is here presented. AIMS: To determine the incidence, the predisposing factors, the pattern of presentation and the outcome of management of chest injuries. MATERIALS AND METHODS: This is a retrospective study spanning a period of 10 years (2002-2011). The medical records of all patients with documented chest injuries that presented to our hospital within the period under review, were retrieved and analysed, by simple arithmetic percentages. RESULT: A total of 402 patients (average of 40/year) with the age ranges in the spectrum of 0-10 and 81 90 years, with a mean of 2.2 were found. Gender-wise, 301 males (74.9%) and 101 females (25.1%) were affected. The aetiological or the predisposing factors were blunt chest injuries (61.2%) and penetrating chest injuries (38.8%). In the pattern of presentation, haemothorax (20.9%), haemopneumothorax (16.2%), pneumothorax (17.4%) including simple, open and tension types as well as multiple ribs fractures (7.7%) constituted the majority. In the management strategies, conservative methods were mainly used. The outcome ranged from very good to fair. CONCLUSION: The management of chest injuries in our sub-region like any other developing countries is very much challenging. Concerted efforts are needed to overcome the burden it imposes. PMID- 24956692 TI - Emergency peripartum hysterectomy in a low resource setting: a 5-year analysis. AB - BACKGROUND: Emergency peripartum hysterectomy (EPH) is an important life saving surgical procedure often necessitated by life threatening obstetric haemorrhage. The indications for peripartum hysterectomy differs between develop and developing countries and may reflect the level of obstetric practice in a region. PATIENTS AND METHODS: This was a 5-year retrospective study. The medical records of patients who had emergency peripartum hysterectomy at the University of Port Harcourt Teaching Hospital were reviewed and relevant data were retrieved and analyzed. RESULTS: Sixty two cases of peripartum hysterectomy were performed giving a prevalence rate of 0.38% out of 16,113 total deliveries. Being unbooked was significantly associated with peripartum hysterectomy (x2 = 85.29, p = 0.0000). Peripartum hysterectomy was performed for 20.3% of nulliparous women. Subtotal hysterectomy accounted for 55.9% while total hysterectomy was performed for 44.1% of cases. The commonest indication for peripartum hysterectomy was uterine rupture (57.6%). There was no case of ureteric injury Unbooked mothers were 28 times more likely to die than booked mothers. Unbooked status was significantly associated with maternal mortality (p = 0.00008) and perinatal mortality (p = 0.00000). CONCLUSION: Emergency peripartum hysterectomy still remains indispensible in obstetric practice in low resource setting. Labour and delivery when well supervised will reduce the need for emergency peripartum hysterectomy. Training of specialist in the skill of internal iliac artery ligation is recommended. PMID- 24956693 TI - An unusual presentation of non-Hodgkins lymphoma: a case report. AB - BACKGROUND: Breast lymphoma is an uncommon disease with poor clinical outcome. The rarity of the disease is related to relatively small amount of lymphoid tissues in the breast. The prognosis usually depends on the stage at presentation. OBJECTIVE: To highlight an uncommon presentation of Non-Hodgkin's Lymphoma. CONCLUSION: Non-Hodgkin's lymphoma can affect the breast. A high index of suspicion and prompt histological diagnosis are needed for effective management. PMID- 24956694 TI - Continuous spinal anaesthesia for caesarean section in a parturient with peripartum cardiomyopathy. AB - Peripartum cardiomyopathy is a potentially fatal form of heart failure associated with pregnancy. A 27-year-old Nigerian woman, gravida 1, para 0, presented at 31 weeks' gestation with no previous history of hypertension heart disease, but morbidly obese (body mass index of 42 kg/m2), with uncontrolled and hypertension, severe pulmonary oedema who required an urgent Caesarean section is presented. The patient was admitted into the hospital's ICU for stabilisation. She was placed on oxygen by non-rebreathing face mask while receiving intravenous labetalol and frusemide. Following a worsening clinical state, an urgent Caesarean section was conducted under continuous spinal anaesthesia using 7.5 mg intrathecal 0.5% isobaric bupivacaine and was delivered of a 1.8 Kg live female baby with good Apgar scores. At the end of the surgery, mother and baby were transferred to the ICU and SCBU respectively. After a 7-day intensive treatment she was discharged. Since then she remained symptom-free and her baby was doing well during the period of admission and discharge. This case report illustrated the recognition of peripartum cardiomyopathy and the use of a more haemodynamic stable anaesthetic technique. It also described the need for collaboration of multiple medical specialists before, during delivery and after delivery to provide the best possible outcome for both mother and infant. PMID- 24956696 TI - Personal health budgets: rise of the NHS's happy shoppers. PMID- 24956695 TI - Competition rules needn't be a barrier to better care. PMID- 24956697 TI - Electronic patient records: waking up to a new dawn in data. PMID- 24956699 TI - Performance: diagnosis and cure beat paralysis by analysis. PMID- 24956698 TI - Ten steps to realise personalised healthcare. PMID- 24956700 TI - Open letter: 'working in the NHS is like slipping down a wormhole'. PMID- 24956701 TI - Survey: research under the microscope. PMID- 24956702 TI - Change management: how to lead sharp end of the NHS. PMID- 24956703 TI - Engagement: dancing to a different tune. PMID- 24956704 TI - New medicine: at one Ohio hospital, patients get herbs as well as drugs. PMID- 24956705 TI - Build an environment to lead in. PMID- 24956706 TI - Don't look back: the NHS of the past is a foreign country. PMID- 24956707 TI - Number one priorities. PMID- 24956709 TI - Mental health: not all liaison services are equal. PMID- 24956708 TI - Resilience: showing courage while under fire. PMID- 24956710 TI - Service improvement: empower your staff to dream big. PMID- 24956711 TI - Integration: can data solve the comorbidity. PMID- 24956713 TI - Care for frail older people: your push improve older people's care. PMID- 24956712 TI - NHS England chief executive: welcome back, Simon. Here's your to-do list. PMID- 24956714 TI - Service design: reinvent the ageing process. PMID- 24956715 TI - Policy: learn from the land of rising demand. PMID- 24956716 TI - Care homes: no place like home? PMID- 24956718 TI - Surgical-robot costs put small hospitals in a bind. PMID- 24956717 TI - 8 million enrollment total tops good-news week for Obamacare. PMID- 24956720 TI - Truven's 15 top systems: consistency boosts quality. PMID- 24956719 TI - Deal volume dips while value soars first quarter. PMID- 24956722 TI - The ACA's midterm report card. PMID- 24956721 TI - Setting the bar: 15 top health systems. PMID- 24956723 TI - Physician-industry teamwork advances care. PMID- 24956724 TI - Antitrust laws exist to protect consumers, not providers. PMID- 24956725 TI - Bristol is failing again: my advice on Bristol: consider another hospital. PMID- 24956726 TI - End blame game between managers and doctors. PMID- 24956727 TI - Estates can be change catalysts. PMID- 24956728 TI - Long term conditions: solve the case problem. PMID- 24956729 TI - Long term conditions: case studies: screen test. PMID- 24956730 TI - End of life care: the importance of home. PMID- 24956732 TI - Patient records: too much information? PMID- 24956731 TI - End of life care: case studies: 'we do more with the same resource'. PMID- 24956733 TI - Patient records: case studies: 'we don't need names'. PMID- 24956734 TI - Service improvement: are you ready? PMID- 24956735 TI - Innovation: how do NHS subsidiary companies measure up? PMID- 24956737 TI - Nutrition: food fears prove tough to digest. PMID- 24956736 TI - Patient experience: take care to be compassionate. PMID- 24956738 TI - Service design: be seen and heard in the care discussion. PMID- 24956739 TI - Education: keep an eye on the entrepreneur's prize. PMID- 24956740 TI - A new vision for cataract surgery. PMID- 24956741 TI - [The efficacy of genioglossus advancement and uvulopalatopharyngoplasty for obstructive sleep apnea syndrome]. AB - OBJECTIVE: To evaluate the objective and subjective improvement after multilevel surgery, genioglossus advancement (GA) plus uvulopalatopharyngoplasty (UPPP) for the treatment of obstructive sleep apnea syndrome (OSAS). METHODS: GA and UPPP were undertaken in 24 patients with moderate and severe OSAS between January 2006 and December 2011. Epworth Sleepiness Scale (ESS) score, snoring, the feeling of having slept well and polysomnography were used for the evaluation of surgical outcomes. In addition, we determined whether baseline polysomnography, cephalometry, and authropometry data could predict GA and UPPP success or failure. RESULTS: The mean ESS score decreased significantly from 12.96 to 7.08. The mean apnea-hypopnea index (AHI) improved from 37.3 to 19.33. Objective success as evaluated by a 50% reduction in AHI or by AHI < 15 was obtained in 16 of 24 patients. The lowest oxygen saturation and stage 1 and stage 2 were also improved significantly. There were no major postoperative complications. There were significant differences in SNA, SNB, FX and PNS-P between the success and failure of GA and UPPP. The indication of GA and UPPP were SNA > 79.11 degrees, SNB > 75.69 degrees, FX > 78.67 degrees, and 36.79 mm < PNS-P < 42.29 mm. CONCLUSION: GA and UPPP surgeries are effective and safe for patients with moderate and severe OSAS. However, further studies are necessary to decide definitively if GA and UPPP are appropriate treatments for OSAS. PMID- 24956742 TI - [A relationship between birch pollen counts and meteorological factors in Sapporo]. AB - Occurrence of airborne pollen in Sapporo has been studied for 19 years during the period between 1995 and 2013. There are wide year-to-year variations in the quantities of birch pollens. A simple linear regression with the least squares method was used for studying correlations between the annual quantities of birch pollens and the meteorological factors. A significant positive correlation was found between the hours of sunlight in June of the preceding year and the annual birch pollen concentrations with the correlation coefficient, R = 0.667. Also, we found the significant positive correlation between the hours of sunlight in March and the annual birch pollen concentrations with the correlation coefficient, R = 0.684. These results suggest that the atmospheric birch pollen counts can be predicted from meteorological factors. PMID- 24956743 TI - [Clinical outcome and clinicopathological prognostic factors in adenoid cystic carcinoma of the head and neck]. AB - We retrospectively reviewed the records of the 30 patients with adenoid cystic carcinoma of the head and neck (ACCHN) who had undergone initial treatment in the Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine between 1988 and 2007. The primary tumor site was the parotid gland in 10 patients and the submandibular gland in 4 patients, which account for about a half of the subjects. Thirty patients underwent surgical resection with curative intent as the primary treatment, of which 10 patients had post-operative radiotherapy. The 5-and 10-year disease-specific survival (DSS) was 73.9% and 62.4%, respectively, whereas the 5-and 10-year disease-free survival (DFS) was 64.3% and 59.7%, respectively. A univariate analysis revealed that DSS was significantly correlated with perineural invasion (p = 0.010) and lymphatic invasion (p = 0.036), while DFS was significantly correlated with higher T-stage (p = 0.044), a positive surgical margin (p = 0.012) and perineural invasion (p = 0.019). A multivariate analysis demonstrated that perineural invasion (p = 0.034, risk ratio = 9.530) was the independent prognostic factor for DSS, whereas for DFS it was a positive surgical margin (p = 0.038, risk ratio = 8.897). The histological grade classification, defined specifically for ACC, showed no correlation with the survival. Extended resection with wider margin and additional resection in cases with positive margin may improve treatment results, however, surgical resection alone can prevent neither the development of local recurrence mainly attributed to undetectable perineural invasion, nor that of delayed distant metastasis. Therefore, the roles of adjuvant radiotherapy and effective systemic therapies are also significant in ACCHN, although a reliable regimen for the latter has not yet been established. Development of a personalized strategy for the adjuvant therapy, which should be based on the accurate prediction of the long-term prognosis in combination with dependable molecular biomarkers, would be indispensable in the future to improve the clinical outcome of the patients with ACCHN. PMID- 24956744 TI - [Treatment outcome and failure pattern of olfactory neuroblastoma: a clinical analysis of 14 cases and meta-analysis of Japanese cases]. AB - The olfactory neuroblastoma, first described in 1924, is a rare tumor arising from the olfactory epithelium. Because of its rarity, it is difficult to accrue a large individual series. To elucidate the characteristics of olfactory neuroblastomas in Japan, we report herein on our institutional experience of 14 cases and reviewed 104 cases reported from Japan. In our cases, one out of nine surgically treated patients died during treatment and the remaining 8 patients are alive without disease. Among the five non-surgically treated patients, four patients experienced local treatment failure and the other one patient died of metastasis. In the 104 Japanese cases, 54 patients were treated with multimodality treatment including surgery and radiation. The 3-year overall survival rates for surgically treated patients and non-surgically treated patients were 85% and 73%, respectively. The prognostic factors for survival were modified Kadish stage, Hyams' grade and surgical treatment. Further investigation is required for the validation of endoscopic resection. PMID- 24956745 TI - [Impact of 131I SPECT/CT on the management of differentiated thyroid carcinoma outpatients with radioablation]. AB - OBJECTIVE: The purpose of this study was to comparatively assess the diagnostic accuracy between 131I SPECT/CT and 131I whole-body scintigraphy (WBS) in differentiated thyroid carcinoma outpatients following radioablation. METHODS: a retrospective cohort study was performed in eleven patients with differentiated thyroid carcinoma (fourteen studies), who underwent both 131I WBS and 131I SPECT/CT, 7-10 days after administration of 1,110 MBq of 131I for radioablation, following a total thyroidectomy. A head and neck surgeon and two nuclear medicine specialists first interpreted the WBS images, followed by SPECT/CT images. RESULTS: SPECT/CT led to accurate revisions of the first diagnoses in 13 of 24 cervical foci of 131I uptake on WBS. Out of the 5 distant lesions, which were diagnosed as metastases by WBS alone, 5 (100%) were found out to be benign lesions by SPECT/CT. Thus, WBS was prone to be false-positive both in detecting cervical node metastases (13/28, 46.4%) and distant metastases (5/17, 29.4%). Eventually, SPECT/CT after 131I radioablation altered postoperative patients' management in 42.8% of patients with thyroid carcinoma by upstaging or down staging their disease. CONCLUSION: SPECT/CT after 131I radioablation for differentiated thyroid cancer patients determines more accurately cervical lymph node metastasis, thyroid remnants and distant metastasis than does WBS alone. Both WBS and SPECT/CT after 131I radioablation are highly recommended for appropriate management of differentiated thyroid cancer patients who have undergone a total thyroidectomy. PMID- 24956746 TI - [Clustering Sugi-pollen dispersal patterns for the past 26 years]. AB - BACKGROUND: Pollinosis caused by the pollen of Sugi (Cryptopmeria japonica) trees is the most significant allergic disease occurring in the spring in Japan. For pollinosis patients and medical staff, it is important to know when the pollen dispersion would reach maximum or when the pollen count would decrease as well as knowing what would the total density of pollen grains be. These sorts of information could be useful for the purpose of disease prevention and deciding on the therapeutic regimen. In this study, we presented the sugi-dispersal patterns and cited several examples of the dispersal pattern. METHODS: Airborne pollen grains were collected using a Durham sampler. Total annual pollen counts/cm2 were examined. The sugi-dispersal patterns were classified into several groups by cluster analysis using variables of ten days pollen counts distribution from February to April for the past 26 years. (1987-2012). RESULT: The annual pollen count revealed an alternate rhythm consisting of an "on" year (high pollen count) and an "off" year (low pollen count). The results of the cluster analysis showed eleven off-years classified as one group (group 1), and fifteen on-years classified into three groups (groups 2A, 2B, and 2C). The dispersal pattern in group 1 was almost symmetrical with the pollen count rapidly decreasing until late-March. On the other hand, the patterns in group 2 were asymmetrical. In group 2A and 2B a high rate of dispersion was indicated after maximum dispersion, whereas in group 2C the high rate of dispersion was indicated before maximum dispersion. In group 2A, a major dispersion of almost 3000 grains was noted in late-March, and immediately proceeded to the cypress (Chamaecyparis) pollen season without any decrease seen in pollen dispersion. The periods of dispersion of over 10 pollen grains/cm2 per day were 38, 47, 47 and 51 days in groups 1, 2A, 2B and 2C, respectively. That in group 2 was significantly longer than that in group 1, but there was no significant differences between groups 2A, 2B and 2C. CONCLUSION: In conclusion, in the dispersal pattern whereby a major dispersion was seen in late-March and proceeded to the cypress pollen season such as in group 2A, patients' symptoms might be prolonged or be more serious. This new concept of dispersal pattern could very well be useful for clinical management of pollinosis. PMID- 24956747 TI - Abatements of reduced sulphur compounds, colour, and organic matter from indigo dyeing effluents by electrocoagulation. AB - In the present study, the treatability of indigo dyeing effluents by the electrocoagulation (EC) process using stainless steel electrodes was experimentally investigated. The samples used were concentrated with main pollutant parameters of chemical oxygen demand (COD) (1000-1100 mg/L), reduced sulphur species (over 2000 mg SO2-(3)/L), and colour (0.12-0.13 1/cm). The study focused on the effect of main operation parameters on the EC process performance in terms of abatement of reduced sulphur compounds as well as decolourization and organic matter reduction. Results indicated that the performance of EC proved to be high providing total oxidation of the reduced sulphur compounds, almost complete decolourization, and COD removal up to 90%. Increasing applied current density from 22.5 to 45 mA/cm2 appreciably improved abatement of the reduced sulphur compounds for Sample I, but a further increase in the applied current density to 67.5 mA/cm2 did not accelerate the conversion rate to sulphate. The process performance was adversely affected by increasing initial concentration of the reduced sulphur compounds. Decolourization and organic matter removal efficiency enhanced with increasing applied current density. The main removal mechanism of the reduced sulphur compounds by EC was explained as conversion to sulphate via oxidation. Conversion rate to sulphate fitted pseudo-first-order kinetics very well. PMID- 24956748 TI - COD removal and toxicity decrease from tannery wastewater by zinc oxide-assisted photocatalysis: a case study. AB - This work reports the optimization of degradation conditions and toxicity decrease in the tannery wastewater, collected in the retanning and dyeing steps. This effluent was filtered, diluted in a 1:200 proportion, and investigated as a case study on a bench scale by heterogeneous photocatalysis. These conditions were attained when the suspension, containing 1 g L-1 of ZnO and effluent, was irradiated for 4h at pH 8.0 and 30 degrees C. Physico-chemical parameters such as chemical oxygen demand (COD) decreased from 15,023 to 350 mg O2 L-1; fifth-day biochemical oxygen demand (BODs) from 4374 to 10 mg O2 L-1; total solids from 28,500 to 188 mg L-1; total organic carbon (TOC) from 4685 to 4.93 mg L-1, and turbidity from 331 to 1.15NTU after 4h of irradiation. The LC50 increase from 14.90% to 56.82% in the lethality assay of Artemia salina L. microcrustacean as well as the dissolved oxygen of 6.45mg L-1 indicated efficiency in this treatment. PMID- 24956749 TI - Field study of moving bed biofilm reactor technology for post-treatment of wastewater lagoon effluent at 1 degree C. AB - The goal of this study was to investigate the potential use ofmoving bed biofilm reactor (MBBR) systems as ammonia removal post-treatment units for wastewater (WW) treatment lagoons that demonstrate large temperature changes throughout their operational year (1 - 20 degrees C). The study was carried out over a six month period using laboratory-scale MBBR reactors fed with incoming effluent from a full-scale lagoon. The study shows that significant average ammonia removal rates of 0.26 and 0.11 kgN/m . d were achieved at 20 degrees C and 1C. The increase in the ammonia removal rates with increasing temperature from 1 degrees C to 20 degrees C showed a strong correlation to an applied temperature correction coefficient model. No significant accumulation of effluent nitrite was observed at 1 degrees C or after being fed with synthetic wastewater (SWW); indicating that cold temperatures and transitions from real WW to SWW did not stress the nitrifiers. Furthermore, the study demonstrates that changes in temperature or changes from real WW to SWW do not affect the mass of biofilm attached per MBBR carrier. Hence, based on the results of this study, it is concluded that MBBR is a promising technology for post-treatment ammonia removal of WW lagoon effluent. PMID- 24956750 TI - A comparison between floc morphology and the effluent clarity at a full-scale activated sludge plant using optical monitoring. AB - A charge-coupled device camera was used for the optical monitoring of activated sludge flocs and filaments, and the image analysis results were compared with the effluent clarity at a full-scale activated sludge plant during a three-month period. The study included a maintenance stoppage at the wastewater treatment plant, which was followed by a settling problem. Thus, the study presents the development of floc morphology from poor flocculation to good flocculation. In this case, the evolution of flocs was a slow process, and the optimum floc morphology was achieved before the purification results improved. To diagnose the cause of the settling problems using optical monitoring, four major factors were found to be relevant: the mean area of the flocs, the amount of small particles, the amount of filament and the shape parameters of the flocs. In this case, the settling problem was caused by dispersed growth based on the image analysis results. In conclusion, the method used has the potential for usefulness in the development of monitoring applications to predict plant performance and also to diagnose the causes of the settling problems. PMID- 24956751 TI - Inductively heated plasma waste treatment for energy recovery. AB - An assessment of a decentralized inductively heated plasma waste treatment system for energy recovery has been done. The modular miniaturized high enthalpy plasma source IPG6 is a reference for the system and has been qualified for inert but also chemically aggressive gas compositions. An identification and review of applications were undertaken. Niches of high environmental and societal importance are considered: hospital waste (threshold countries), shipboard waste and marine litter. The wastes are reviewed deriving relevant parameter for a system analysis aiming for the derivation of energy production and efficiencies. The system analysis shows advantageous constellation due to the wastes' energy leading to self-feeding systems. PMID- 24956752 TI - Estimation of parameter uncertainty for an activated sludge model using Bayesian inference: a comparison with the frequentist method. AB - The procedure commonly used for the assessment of the parameters included in activated sludge models (ASMs) relies on the estimation of their optimal value within a confidence region (i.e. frequentist inference). Once optimal values are estimated, parameter uncertainty is computed through the covariance matrix. However, alternative approaches based on the consideration of the model parameters as probability distributions (i.e. Bayesian inference), may be of interest. The aim of this work is to apply (and compare) both Bayesian and frequentist inference methods when assessing uncertainty for an ASM-type model, which considers intracellular storage and biomass growth, simultaneously. Practical identifiability was addressed exclusively considering respirometric profiles based on the oxygen uptake rate and with the aid of probabilistic global sensitivity analysis. Parameter uncertainty was thus estimated according to both the Bayesian and frequentist inferential procedures. Results were compared in order to evidence the strengths and weaknesses of both approaches. Since it was demonstrated that Bayesian inference could be reduced to a frequentist approach under particular hypotheses, the former can be considered as a more generalist methodology. Hence, the use of Bayesian inference is encouraged for tackling inferential issues in ASM environments. PMID- 24956753 TI - Treatment of steam-assisted gravity drainage water using low coagulant dose and Fenton oxidation. AB - The use of coagulation and Fenton oxidation was studied for total organic carbon (TOC) and silica removal from steam-assisted gravity drainage (SAGD) water at 800C and two different concentrations replicating the stream feeding the warm lime softening unit having 675 mg/L TOC and 350 mg/L silica and the blowdown of the once through steam generator having 3700mg/L TOC and 2585 mg/L silica. Coagulation was carried out by the addition of FeCl3, Al(NO3)3 or Ca(NO3)2. The results showed that Fe(III) salt outperformed Al(III) and Ca(II) salts. A two stage addition of 2.5 g FeCl3 per g TOC intermediated by a filtration unit resulted in approximately 72% TOC removal and more than 80% silica removal while maintaining low solid waste. Comparing results pertaining to coagulant concentration and final pH, it can be easily concluded that silica removal is governed by the resultant pH, whereas TOC removal was accomplished through surface neutralization and localized enmeshment coagulation. Fenton oxidation is proposed to further treat the filtrate obtained from the second stage Fe(III) coagulation. An additional 10% TOC removal could be achieved; at seven times lower H202 dose in the presence of Fe2+ or Fe0 reagent. Moreover, the advanced Fenton process resulted in high silica removal as a result of adsorption onto Fe(OH)3 precipitate, which formed at the equilibrium pH of the system. PMID- 24956754 TI - Enhanced phosphorus removal from sewage in mesocosm-scale constructed wetland using zeolite as medium and artificial aeration. AB - Phosphorus (P) contained in sewage maybe removed by mesocosm-scale constructed wetlands (MCW), although removal efficiency is only between 20% and 60%. P removal can be enhanced by increasing wetland adsorption capacity using special media, like natural zeolite, operating under aerobic conditions (oxidation reduction potential (ORP) above +300 mV). The objective of this study was to evaluate P removal in sewage treated by MCW with artificial aeration and natural zeolite as support medium for the plants. The study compared two parallel lines of MCW: gravel and zeolite. Each line consisted in two MCW in series, where the first MCW of each line has artificial aeration. Additionally, four aeration strategies were evaluated. During the operation, the following parameters were measured in each MCW: pH, temperature, dissolved oxygen and ORP. Phosphate (PO4( 3) - P) and chemical oxygen demand (COD), five-day biological oxygen demand (BOD5), total suspended solids (TSS) and ammonium. (NH4(+) - N) were evaluated in influents and effluents. Plant growth (biomass) and proximate analysis for P content into Schoenoplectus californicus were also performed. The results showed that PO4(-3) - P removal efficiency was 70% in the zeolite medium, presenting significant differences (p < .05) with the results obtained by the gravel medium. Additionally, aeration was found to have a significant effect (p < .05) only in the gravel medium with an increase in up to 30% for PO43 - P removal. Thus, S. californicus contributed to 10-20% of P removal efficiency. PMID- 24956755 TI - Generalized regression neural network-based approach for modelling hourly dissolved oxygen concentration in the Upper Klamath River, Oregon, USA. AB - In this study, a comparison between generalized regression neural network (GRNN) and multiple linear regression (MLR) models is given on the effectiveness of modelling dissolved oxygen (DO) concentration in a river. The two models are developed using hourly experimental data collected from the United States Geological Survey (USGS Station No: 421209121463000 [top]) station at the Klamath River at Railroad Bridge at Lake Ewauna. The input variables used for the two models are water, pH, temperature, electrical conductivity, and sensor depth. The performances of the models are evaluated using root mean square errors (RMSE), the mean absolute error (MAE), Willmott's index of agreement (d), and correlation coefficient (CC) statistics. Of the two approaches employed, the best fit was obtained using the GRNN model with the four input variables used. PMID- 24956756 TI - Novel resource utilization of refloated algal sludge to improve the quality of organic fertilizer. AB - Without further management, large amounts of refloated algal sludge from Taihu Lake to retrieve nitrogen and phosphorus resources may result in serious secondary environmental pollution. The possibility of utilization of algal sludge to improve the quality of organic fertilizer was investigated in this study. Variations of physicochemical properties, germination index (GI) and microcystin (MC) content were analysed during the composting process. The results showed that the addition of algal sludge improved the contents of nutrients, common free amino acids and total common amino acids in the novel organic fertilizer. Rapid degradation rates of MC-LR and MC-RR, a high GI value and more abundance of culturable protease-producing bacteria were observed during the composting process added with algal sludge. Growth experiments showed that the novel organic fertilizer efficiently promoted plant growth. This study provides a novel resource recovery method to reclaim the Taihu Lake algal sludge and highlights a novel method to produce a high-quality organic fertilizer. PMID- 24956757 TI - Optimization for the removal of orthophosphate from aqueous solution by chemical precipitation using ferrous chloride. AB - The precipitation reaction between the orthophosphate and Fe2+ ions was studied to describe the optimum condition for the removal of orthophosphate from the aqueous solution. The effects of pH, Fe:P molar ratio, and alkalinity were evaluated for the initial orthophosphate concentrations in the range from 1.55 to 31.00 mg/L - PO4(3-) -P. The optimum pH was found to be 8.0 in all orthophosphate concentration ranges. When the stoichiometric moles of Fe2+ were added, the removal efficiencies were significantly less than the theoretical values. It is likely that the precipitation of Fe(OH)2(s) is partially formed. For the initial orthophosphate concentration of 3.10 mg/L PO4(3-) -P or greater, the removal efficiencies with the Fe:P molar ratio of 3.0:1.0 approached to the theoretical values, yielding greater than 98.5%. If the molar ratio of Fe:P was great enough, the precipitation reaction was completed within 1 h. As the alkalinity increases, the experimental removal efficiencies were significantly greater than the theoretical values. This is because the formation of vivianite is favoured over FeCO3(s). Finally, it was demonstrated that the orthophosphate (1.40-6.80 mg/L PO4(3-) -P) in the secondary effluents from wastewater treatment plants was effectively removed by dosing sufficient amount of Fe2+ ions. PMID- 24956758 TI - Odour in composting processes at pilot scale: monitoring and biofiltration. AB - Although odour emissions associated with the composting process, especially during the hydrolytic stage, are widely known, their impact on surrounding areas is not easily quantifiable, For this reason, odour emissions during the first stage ofcomposting were evaluated by dynamic olfactometry at pilot scale in order to obtain results which can be extrapolated to industrial facilities. The composting was carried out in a commercial dynamic respirometer equipped with two biofilters at pilot scale filled with prunings (Populus) and mature compost obtained from the organic fraction of municipal solid waste. Given that the highest odour emissions occur in the first stage of the composting process, this stage was carried out in a closed system to better control the odour emissions, whose maximum value was estimated to be 2.78 ouF S-1 during the experiments. Odour concentration, the dynamic respiration index and temperature showed the same evolution during composting, thus indicating that odour could be a key variable in the monitoring process. Other variables such as total organic carbon (CTOC) and pH were also found to be significant in this study due to their influence over odour emissions. The efficiency of the biofilters (empty bed residence time of 86 s) was determined by quantifying the odour emissions at the inlet and outlet of both biofilters. The moisture content in the biofilters was found to be an important variable for improving odour removal efficiency, while the minimum moisture percentage to obtain successful results was found to be 55% (odour removal efficiency of 95%). PMID- 24956759 TI - Key factors influencing the potential of catch crops for methane production. AB - Catch crops are grown in crop rotation primarily for soil stabilization. The excess biomass of catch crops was investigated for its potential as feedstock for biogas production. Ten variables affecting catch crop growth and methane potential were evaluated. Field trials and methane potential were studied for 14 different catch crops species, with 19 samples harvested in 2010 and 36 harvested in 2011. Principal component analysis was applied to the data to identify the variables characterizing the potential for the different catch crops species for methane production. Two principal components explained up to 84.6% and 71.6% of the total variation for 2010 and 2011 samples, respectively. Specific methane yield, climate conditions (rainfall and temperature) and total nitrogen in the biomass were the variables classifying the different catch crops. Catch crops in the Brassicaceae and Graminaceae botanical families showed the highest methane yield. This study demonstrates the importance of the crop species when choosing a suitable catch crop for biogas production. PMID- 24956760 TI - Degradation of sulphamethazine by means of an improved photo-Fenton process involving a hydrogen peroxide systematic dosage. AB - Despite being acknowledged as an emerging contaminant, sulphamethazine (SMT) degradation has received scarce attention in the advanced oxidation processes field. Thus, this work addresses the degradation of SMT in water solutions (12 L of 25mgL-1 samples) by means of a photo-Fenton process and a systematic H202 dosage protocol that enhances its performance. A conventional photo-Fenton process led to 86% mineralization after 120 min treatment when adding the Fenton reactants at once (initial concentrations were 10mgL-1 Fe(II) and 200mgL-1 H2O2). Conversely, the process achieved the total mineralization of the samples in less than 75 min when the same amount of H202 was continuously dosed according to a conveniently tuned dosage protocol. In both cases, total SMT degradation was achieved within 10 min. Hence, this work's aim is to determine the efficient dosage conditions of H2O2. The results show that a significant improvement of the photo-Fenton mineralization of SMT solutions is possible by adjusting the dosage of H2O2. PMID- 24956762 TI - Treatment influence on green coconut shells for removal of metal ions: pilot scale fixed-bed column. AB - This work investigates copper, nickel and zinc ion biosorption in single- and multi-component systems in a fixed-bed column using green coconut shells (CS). Approximately 85% of biosorbents are in a particle size ranging from 0.25 to 2 mm. Operational parameters selected include a flow rate of 200 mL min-1 and a bed height of 100 cm, which were selected for a shorter execution time and good adsorption capacity. Empty-bed contact time and Thomas models were applied, showing a good fit with the experimental data. The column adsorption capacity increased after the green CS powder was treated in a column with NaOH at a concentration of 0.1 mol L-1. The highest values of adsorption capacities founded were 0.69, 0.45 and 0.39 mmol L-1 for Cu(II), Ni(II) and Zn(Il), respectively, using green CS treated inside a column with NaOH of 0.1 M. The pH and chemical oxygen demand were monitored in the treatment solution and indicated that the adjustment of these parameters is necessary before disposal of these solutions. A study of desorption using an acid solution was carried out for recovery of metal ions. PMID- 24956761 TI - Effect of mild-temperature H2O2 oxidation on solubilization and anaerobic digestion of waste activated sludge. AB - Efficient sludge management is among the most challenging issues in wastewater treatment today, and anaerobic digestion is regarded as a viable solution. Mild temperature H202 oxidation was examined for enhanced solubilization and biogas production of waste activated sludge (WAS). The effects of pretreatment factors (i.e. temperature and H202 concentration) on the degree of WAS disintegration (DD) and biogas yield (BY) were assessed by response surface analysis within the design space of 60-90 degrees C and 0-200mM H202. Significant sludge disintegration (up to 23.0% DD) and visibly enhanced BY (up to 26.9%) were shown in the pretreatment trials. Two response surface models to describe how DD and BY respond to changes in the pretreatment conditions were successfully constructed (R2 > 0.95, p < 0.05). The models showed totally different response surface shapes, indicating the DD and BY were influenced by pretreatment conditions in very different ways. DD was dominantly affected by temperature and showed higher model responses at the high-temperature region, while the BY response peaked in the low-temperature and mid-level H2O2 region. This observation implies that the enhanced solubilization of WAS was not directly translated into an increase in biogas production. Our results showed that WAS can be efficiently disintegrated by H202 oxidation under mild-temperature conditions for enhanced anaerobic digestibility. Within the explored region of pretreatment conditions, the maximum BY was estimated to be 82.1 mL/gCODadded (32.8% greater than the untreated control) at (60.0 degrees C, 74.2 mM H2O2). PMID- 24956763 TI - Prediction of sulphide build-up in filled sewer pipes. AB - Millions of dollars are being spent worldwide on the repair and maintenance of sewer networks and wastewater treatment plants. The production and emission of hydrogen sulphide has been identified as a major cause of corrosion and odour problems in sewer networks. Accurate prediction of sulphide build-up in a sewer system helps engineers and asset managers to appropriately formulate strategies for optimal sewer management and reliability analysis. This paper presents a novel methodology to model and predict the sulphide build-up for steady state condition in filled sewer pipes. The proposed model is developed using a novel data-driven technique called evolutionary polynomial regression (EPR) and it involves the most effective parameters in the sulphide build-up problem. EPR is a hybrid technique, combining genetic algorithm and least square. It is shown that the proposed model can provide a better prediction for the sulphide build-up as compared with conventional models. PMID- 24956764 TI - Biological removal of methanethiol from gas and water streams by using Thiobacillus thioparus: investigation of biodegradability and optimization of sulphur production. AB - The present work mainly deals with biological oxidation, which was tested using the bacterium Thiobacillus thioparus in semi-batch bioreactor systems to evaluate the removal efficiencies and optimal conditions for the biodegradation of methanethiol (MT) in order to treat the natural gas and refinery output streams. The efficiency of this method is analysed by evaluating the concentration of MT in a bioreactor. The effect of operational parameters, such as initial concentration of MT, pH, temperature, dissolved oxygen (DO), initial concentration of bacteria and reaction time on the degradation of MT, were studied. In this process, MT is converted into elemental sulphur particles as an intermediate in the oxidation process of MT to sulphate. The obtained results showed that the highest degradation rate occurred during the first 300 minutes of reaction time. The optimal conditions of the different initial MT concentrations with 0.3-0.6 bacteria OD, DO of 0.5 ppm, acidic pH value of 6.2 and temperature of 300C are obtained. Acidic pH and oxygen-limiting conditions were applied to obtain 80-85% selectivity for elemental sulphur formation in products. Under the optimal conditions, and for the highest (8.51 mM) and the lowest (0.53 mM) concentration of MT, the biological removal was about 89% and 94%, respectively. PMID- 24956765 TI - Persistence and risk assessment of emamectin benzoate residues on okra fruits and soil. AB - Emamectin benzoate, a synthetic derivative of abamectin, is found effective against fruit borer and jassid in okra crops. The present studies were carried out to study the dissipation pattern of emamectin benzoate on okra and to suggest a suitable waiting period for the safety of consumers. Following three applications of emamectin benzoate (Proclaim 5 SG) at 68.1 and 136.2 g a.i. ha-1, the average initial deposits of emamectin benzoate were observed to be 0.22 and 0.42mg kg-1, respectively. These residues dissipated below the limit of quantification (LOQ) of 0.05 mg kg-1 after 5 days at both the dosages. Soil samples collected after 15 days did not reveal the presence of emamectin benzoate at LOQ of 0.05 mg kg-1. Acceptable daily intake (ADI) of emamectin benzoate is 0.0005 mg kg-1 body weight day-1, which means an adult of 55 kg weight can safely tolerate an intake of 27.50 microg emamectin benzoate. Assuming an average consumption of 80 g okra fruit and multiplying it by average and maximum residues observed on 0 day at recommended dosage, the intake of emamectin benzoate comes out to be about 20 Itg and these values are quite safe in comparison to its ADI. These studies, therefore, suggest that the use of emamectin benzoate at the minimum effective dosages do not seem to pose any hazards to the consumers if a waiting period of 1 day is observed. PMID- 24956766 TI - Influence of soil pH in vegetative filter strips for reducing soluble nutrient transport. AB - Low efficacy of vegetative filter strips (VFS) in reducing soluble nutrients has been reported in research articles. Solubility of phosphorus and nitrogen compounds is largely affected by pH of soil. Changing soil pH may result in a decrease in soluble nutrient transportation through VFS. This study was conducted to evaluate the effect of pH levels of VFS soil on soluble nutrient transport reduction from manure-borne runoff. Soil (loamy sand texture; bulk density 1.3 g cm-3) was treated with calcium carbonate to change pH at different pH treatment levels (5.5-6.5, 6.5-7.5, and 7.5-8.5), soil was packed into galvanized metal boxes, and tall fescue grasses were established in the boxes to simulate VFS. Boxes were placed in an open environment, tilted to a 3.0% slope, and 44.0 L manure-amended water was applied through the VFS by a pump at a rate of 1.45 L min-1. Water samples were collected at the inlet and outlet as well as from the leachate. Samples were analysed for ortho-phosphorus, ammonium nitrogen, nitrate nitrogen, and potassium. Highest transport reductions in ortho-phosphorus (42.4%) and potassium (20.5%) were observed at pH range 7.5-8.5. Ammonium nitrogen transport reduction was the highest at pH level of 6.5-7.5 and was 26.1%. Surface transport reduction in nitrate nitrogen was 100%, but leachate had the highest concentration of nitrate nitrogen. Mass transport reduction also suggested that higher pH in the VFS soil are effective in reducing some soluble nutrients transport. PMID- 24956767 TI - Effect of ozone on algal organic matters as precursors for disinfection by products production. AB - The effect of ozone dose on algae (Microcystic aeruginosa), algal extracellular organic matters (EOM), humic acids (HA) and four model compounds: bovine serum albumin (BSA), starch, deoxyribonucleic acid (DNA) and fish oil as precursors for disinfection by-products (DBPs) production was investigated. Algae showed the highest DBPs formation (71.8 microg mg-1 total organic carbon (TOC)) than other samples. Only BSA showed lower chloroform yield (5.9 microg mg-1 TOC) than haloacetic acids, HAAs (11.2 microg mg-1 TOC). Algae, EOM, starch, DNA, fish oil and HA all showed higher chloroform yields (46.1, 23.8, 8.9, 37.1, 44.0 and 33.7 microg mg-1 TOC, respectively) than HAAs (25.7, 20.2, 6.3, 10.0, 13.1 and 18.4 microg mg-1 TOC, respectively). Pre-ozonation increased DBPs, especially chloroform, formation from algae and DNA significantly. With the increase in ozone doses, DBPs yields of algae and DNA increased 19.0 and 34.5 microg mg-1 TOC, chloroform yields of algae and DNA increased 15.3 and 30.4 microg mg-1 TOC, respectively. However, pre-ozonation decreased DBPs formation from starch, fish oil and HA, and the corresponding decrease amount was 2.4, 26.9 and 9.5 microg mg 1 TOC, respectively. There are no regular change trends of DBPs formation from EOM and BSA with the increase in ozone doses. PMID- 24956768 TI - Influence of hydraulic retention time on partial nitrification of continuous-flow aerobic granular-sludge reactor. AB - This study investigated the effects of hydraulic retention time (HRT) at 12 h, 7.2 h and 2.4 h on partial nitrification efficiency of continuous-flow aerobic granular reactors (CFAGRs) with mature aerobic granules (500 +/- 20mg l-1). At HRT 12 h and 7.2h, the removal efficiency of both ammonia-nitrogen (NH4+ - N) and nitrite accumulation rate were exceeding 90%. At HRT 2.4 h, NH4+ - N removal efficiency was reduced but most of the conversion efficiency to nitrite was only slightly reduced. At HRT < 2.4 h, washout of aerobic granules occurred. In all tests conducted herein, the chemical oxygen demand removal efficiencies exceeded 90%. The clone library results noted the presence of ammonia-oxidizing bacteria belonged to beta-Proteobacteria subclass, including 94% of Nitrosomonas europaea and 6% of Nitrosomonas sp. The polymerase chain reaction and denaturing gradient gel electrophoresis results suggested that Alpha proteobacterium, Pseudoxanthomonas mexicana strain, Sphaerotilus natans and Uncultured gamma proteobacterium were responsible for the aerobic granular stability and processing performance. The present CFAGR successfully implemented continuous partial nitrification using aerobic granules at low HRT. PMID- 24956770 TI - High removal of chemical and biochemical oxygen demand from tequila vinasses by using physicochemical and biological methods. AB - The goal of this research is to find a more effective treatment for tequila vinasses (TVs) with potential industrial application in order to comply with the Mexican environmental regulations. TVs are characterized by their high content of solids, high values of biochemical oxygen demand (BODs), chemical oxygen demand (COD), low pH and intense colour; thus, disposal of untreated TVs severely impacts the environment. Physicochemical and biological treatments, and a combination of both, were probed on the remediation of TVs. The use of alginate for the physicochemical treatment of TVs reduced BOD5 and COD values by 70.6% and 14.2%, respectively. Twenty white-rot fungi (WRF) strains were tested in TV-based solid media. Pleurotus ostreatus 7992 and Trametes trogii 8154 were selected due to their ability to grow on TV-based solid media. Ligninolytic enzymes' production was observed in liquid cultures of both fungi. Using the selected WRF for TVs' bioremediation, both COD and BOD5 were reduced by 88.7% and 89.7%, respectively. Applying sequential physicochemical and biological treatments, BOD5 and COD were reduced by 91.6% and 93.1%, respectively. Results showed that alginate and selected WRF have potential for the industrial treatment of TVs. PMID- 24956771 TI - Use of aerobic granules for treating synthetic high-strength ammonium wastewaters. AB - In this work, two identical sequencing batch reactors (SBRs) with mature aerobic granules were utilized to treat synthetic high-strength ammonium wastewaters with chemical oxygen demand (COD)/total nitrogen (TN) ratios of 3.9-6.9. The contributions of various mechanisms to the removal of ammonium were determined. Ammonium levels of 600-2000 mg-N l-1 had little adverse effect on the COD removal rate (91.6%-95.3%) with an influent COD of 4490-9860 mg l-1. The TN removal rate was slightly reduced from 71.3% to 59.6% as the influent ammonium concentration was increased from 600 to 2000 mg-N l-1. Experimental results indicated that aerobic granules removed 94.5% of COD and 59.6% of TN in the treatment of synthetic high-strength wastewater (9860 mg-COD l-1 and 2000 mg NH+4-Nl-1) during a 12 h cycle. Granular adsorption, air stripping and conversion by nitrification/denitrification were responsible for removing 9%, 15% and 76%, respectively, of the total removed NHf -N. Dissolved oxygen (DO) was a useful process indicator of the biological reactions in the treatment of high-level ammonium wastewaters. PMID- 24956769 TI - Low-temperature selective catalytic reduction of NO on CeO2-CuO/Al2O3 catalysts prepared by different methods. AB - CeO2-CuO/Al2O3 catalysts were prepared by three different methods and their activities for selective catalytic reduction (SCR) of NO with NH3 were investigated. As can be seen from the experimental results, the catalyst prepared by the single-step sol-gel (SG) method showed the best SCR activity and resistance to SO2 and H2O. In order to investigate the relationship between the preparation method and the performance of SCR catalysts, the catalysts were characterized by using Brunauer-Emmett-Teller, X-ray diffraction, temperature programmed reduction with hydrogen, temperature programmed desorption with ammonia, X-ray photoelectron spectroscopy, Fourier transform infrared and thermo gravimetric analysis techniques. It was found that the excellent performance of CeO2-CuO/Al2O3 catalyst prepared by the single-step SG method should be resulted from its large surface area, low crystallinity, high oxygen storage capacity, high NH3 adsorption capacity, high concentration of surface chemisorbed oxygen, weak sulphation process and weak water absorption. PMID- 24956772 TI - Optimal poly (3-hydroxybutyrate/3-hydroxyvalerate) biosynthesis by fermentation liquid from primary and waste activated sludge. AB - In this paper the production of poly (3-hydroxybutyrate/3-hydroxyvalerate) (PHBV) with activated sludge was investigated by using the fermentation liquid from primary sludge (PS) and waste activated sludge (WAS) as carbon source. First, the suitable concentration and ratio of acetic to propionic (acetic/propionic) for PHBV synthesis with desired hydroxyvalerate (HV) fraction was determined. Then, the conditions for producing fermentation liquid with the required acetic/propionic from the PS/WAS mixture were optimized. Finally, this optimized fermentation liquid was used as the carbon source for PHBV synthesis by the aerobic feeding and discharge process. The PHBV content in the sludge reached 65.5%, with 47.8% (mol-C based) of HV unit content, and the corresponding polyhydroxyalkanoates yield per litre of acclimated sludge was 1.44 g/L. This was the first optimal PHBV biosynthesis reported by using activated sludge as the microbe and sludge fermentation liquid as the carbon source. Polymerase chain reaction-based 454 pyrosequencing analysis revealed that Thauera strains were the predominant species in the PHBV biosynthesis system. PMID- 24956773 TI - Application of two bacterial strains for wastewater bioremediation and assessment of phenolics biodegradation. AB - The use of native bacteria is a useful strategy to decontaminate industrial effluents. In this work, two bacterial strains isolated from polluted environments constitutes a promising alternative since they were able to remove several phenolic compounds not only from synthetic solutions but also from effluents derived from a chemical industry and a tannery which are complex matrices. Acinetobacter sp. RTE 1.4 showed ability to completely remove 2 methoxyphenol (1000 mg/L) while Rhodococcus sp. CS 1 not only degrade the same concentration of this compound but also removed 4- chlorophenol, 2,4 dichlorophenol and pentachlorophenol with high efficiency. Moreover, both bacteria degraded phenols naturally present or even exogenously added at high concentrations in effluents from the chemical industry and a tannery in short time (up to 5 d). In addition, a significant reduction of biological oxygen demand and chemical oxygen demand values was achieved after 7 d of treatment for both effluents using Acinetobacter sp. RTE 1.4 and Rhodococcus sp. CS1, respectively. These results showed that Acinetobacter sp. RTE1.4 and Rhodococcus sp. CS 1 might be considered as useful biotechnological tools for an efficient treatment of different effluents, since they showed wide versatility to detoxify these complex matrices, even supplemented with high phenol concentrations. PMID- 24956774 TI - Impact of inocula and operating conditions on the microbial community structure of two anammox reactors. AB - The microbial community structure of the biomass selected in two distinctly inoculated anaerobic oxidation of ammonium (anammox) reactors was investigated and compared with the help of data obtained from 454-pyrosequencing analyses. The anammox reactors were operated for 550 days and seeded with different sludges: sediment from a constructed wetland (reactor I) and biomass from an aerated lagoon part of the oil-refinery wastewater treatment plant (reactor II). The anammox diversity in the inocula was evaluated by 16S rRNA gene-cloning analysis. The diversity of anammox bacteria was greater in the sludge from the oil-refinery (three of the five known genera of anammox were detected) than in the wetland sludge, in which only Candidatus Brocadia was observed. Pyrosequencing analysis demonstrated that the community enriched in both reactors had differing compositions despite the nearly similar operational conditions applied. The dominant phyla detected in both reactors were Proteobacteria, Chloroflexi, Planctomycetes, and Acidobacteria. The phylum Bacteroidetes, which is frequently observed in anammox reactors, was not detected. However, Acidobacteria and GN04 phyla were observed for the first time, suggesting their importance for this process. Our results suggest that, under similar operational conditions, anammox populations (Ca. Brocadia sinica and Ca. Brocadia sp. 40) were selected in both reactors despite the differences between the two initial inocula. Taken together, these results indicated that the type of inoculum and the culture conditions are key determinants of the general microbial composition of the biomass produced in the reactors. Operational conditions alone might play an important role in anammox selection. PMID- 24956775 TI - Supercritical water oxidation of dioxins and furans in waste incinerator fly ash, sewage sludge and industrial soil. AB - Three environmental samples containing dioxins and furans have been oxidized in the presence of hydrogen peroxide under supercritical water oxidation conditions. The samples consisted of a waste incinerator fly ash, sewage sludge and contaminated industrial soil. The reactor system was a batch, autoclave reactor operated at temperatures between 350 degrees C and 450degrees C, corresponding to pressures of approximately 20-33.5 MPa and with hydrogen peroxide concentrations from 0.0 to 11.25 vol%. Hydrogen peroxide concentration and temperature/pressure had a strong positive effect on the oxidation of dioxins and furans. At the highest temperatures and pressure of supercritical water oxidation of 4500C and 33.5 MPa and with 11.25 vol% of hydrogen peroxide, the destruction efficiencies of the individual polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans (PCDD/PCDF) isomers were between 90% and 99%. There did not appear to be any significant differences in the PCDD/PCDF destruction efficiencies in relation to the different sample matrices of the waste incinerator fly ash, sewage sludge and contaminated industrial soil. PMID- 24956776 TI - Speciation of phosphorus in the sediments of Lake Bini (Ngaoundere-Cameroon). AB - In this study, spatial and seasonal variations of phosphorus fractions in Lake Bini sediments were evaluated using a sequential extraction method. The sampling of water and sediments (surface and coring) was carried out at seven sites around the lake during the dry season and the rainy season. The results showed that phosphorus is mainly in the inorganic form (L-P+Ca-P+Fe-P) in the sediments whatever the season may be. The rank order of phosphorus extracts obtained was Fe P>Ca-P>OM-P>L-P>Res-P. The maximum values of phosphorus (sum of each fraction) were obtained in the rainy season at the sites D6 (298.12 +/- 12.37 microg P/g) and D4 (244.93 +/- 11.06 microg P/g) located beside water source 2 and farmland 2, respectively. The average values of the phosphorus content vary from 05.29 +/- 1.05 microg P/g to 102.58 +/- 4.62 microg P/g for the upper layer (0-5 cm depth); 04.67 +/- 0.66 microg P/g to 70.06 +/- 2.82 microg P/g for the medium layer (5-10 cm depth) and finally 04.63 +/- 0.98 microg P/g to 55.24 +/- 5.17 microg P/g for the deep layer (10-15 cm depth). The results of principal component analysis showed that processes which enhance Ca-P and Fe-P accumulation are probably related to the same factor and the origin of P depends on the source of pollution. The nature of the season plays a significant role in the geochemical composition of the sediments in phosphorus and on the eutrophication level of Lake Bini. PMID- 24956777 TI - Application of various methods for removal of polycyclic aromatic hydrocarbons from synthetic solid matrices. AB - In the present study, removal of polycyclic aromatic hydrocarbons (PAHs) from synthetic solid matrices with various methods was investigated. PAH removal experiments were conducted in a specifically designed UV apparatus for this study. Polyurethane foams (PUF) cartridges were used to remove PAHs from the incoming air and to capture PAHs from the evaporated gases. Sodium sulphate (Na2SO4) was used as a synthetic solid matrices. The effects of temperature, UV radiation, titanium dioxide (TiO2) and diethylamine (DEA) dose on the PAH removal were determined. TiO2and DEA were added to the Na2SO4 sample at the rate of 5% and 20% of dry weight of samples. PAHs' removal from the Na2SO4 enhanced with increasing temperature. Sigma12 PAH content in the Na2SO4 reduced up to 95% during UV light application. Moreover, the Sigma12 PAH removal ratio was calculated as 95% with using 5% of TiO2, and increasing of TiO2 dose negatively affected PAH removal. PAH concentration in the samples decreased by 93% and 99% with addition of 5% and 20% DEA, respectively. Especially, 3- and 4-ring PAH compounds evaporated during the PAH removal applications. As expected, evaporation mechanism became more effective at high temperature for light PAH compounds. It was concluded that PAHs can successfully be removed from synthetic solid matrices such as Na2 SO4 with the applications of UV light and UV photocatalysts. PMID- 24956778 TI - Synergistic effects of TiO2 and Cu2O in UV/TiO2/zeolite-based systems on photodegradation of bisphenol A. AB - In this study, TiO2/zeolite (TZ)-based composite was utilized to degrade bisphenol A (BPA) under ultraviolet (UV) irradiation. The effects of the TiO2 and Cu2O doses in TZ and Cu2O/TiO2/zeolite (CTZ) on the rate of BPA removal were identified, respectively. The surface area of TZ declined as the TiO2 loading increased. The photodegradation rate (k) of BPA in the TZ and CTZ systems fitted pseudo-first-order kinetics. Under UV (365 nm) irradiation, the k values of TiO2 (20%)/zeolite (80%), TiO2 (40%)/zeolite (60%), TiO2 (60%)/zeolite (40%), and TiO2 (80%)/zeolite (20%) were 0.51, 0.55, 0.97, and 0.91 h-1, respectively. In the UV (365nm)/TiO2 (60%)/zeolite (40%) system, the k values of CTZ with 1%, 5%, 10%, 20%, and 30% Cu2O added were 1.50, 1.04, 1.15, 1.88, and 0.47h-1, respectively. The photocatalytic activity of TZ was enhanced by adding Cu2O. The optimal dosage of TiO2 in the TZ system was 60% and that of Cu20 in the CTZ system was 20%. p Hydroxybenzaldehyde (p-HBA), p-hydroxyacetophenone (p-HAP), p-hydroxybenzoic acid (p-HBA acid) and hydroquinone (HQ) were intermediates ofBPA photodegradation in the UV/TZ system and the rates of degradation followed the order HQ > p - HBA acid > BPA > p - HAP > p - HBA. PMID- 24956780 TI - Application of a diffusion-reaction kinetic model for the removal of 4 chlorophenol in continuous tank reactors. AB - A continuous tank reactor was used to remove 4-chlorophenol from aqueous solutions, using immobilized soybean peroxidase and hydrogen peroxide. The influence of operational variables (enzyme and substrate concentrations and spatial time) on the removal efficiency was studied. By using the kinetic law and the intrinsic kinetic parameters obtained in a previous work with a discontinuous tank reactor, the mass-balance differential equations of the transient state reactor model were solved and the theoretical conversion values were calculated. Several experimental series were used to obtain the values of the remaining model parameters by numerical calculation and using an error minimization algorithm. The model was checked by comparing the results obtained in some experiments (not used for the determination of the parameters) and the theoretical ones. The good concordance between the experimental and calculated conversion values confirmed that the design model can be used to predict the transient behaviour of the reactor. PMID- 24956779 TI - Separation of sodium chloride from the evaporated residue of the reverse osmosis reject generated in the leather industry--optimization by response surface methodology. AB - Reverse osmosis (RO) concentrate is being evaporated by solar/thermal evaporators to meet zero liquid discharge standards. The resulted evaporated residue (ER) is contaminated with both organic and inorganic mixture of salts. The generation of ER is exceedingly huge in the leather industry, which is being collected and stored under the shelter to avoid groundwater contamination by the leachate. In the present investigation, a novel process for the separation of sodium chloride from ER was developed, to reduce the environmental impact on RO concentrate discharge. The sodium chloride was selectively separated by the reactive precipitation method using hydrogen chloride gas. The selected process variables were optimized for maximum yield ofNaCl from the ER (optimum conditions were pH, 8.0; temperature, 35 degrees C; concentration of ER, 600 g/L and HCl purging time, 3 min). The recovered NaCl purity was verified using a cyclic voltagramm. PMID- 24956781 TI - Long-term operation of a novel pilot-scale six tanks alternately operating activated sludge process in treating domestic wastewater. AB - The performance of a new pilot-scale six tanks activated sludge process has been evaluated for 303 d, receiving real domestic wastewater with a flow rate of 15 24.4 L/h. Partial nitrification via nitrite and microbial community structure were investigated in this system. The result shows that the nitrite accumulation rate was achieved successfully over 94% in the last aerobic compartment through a combination of short hydraulic retention time and low dissolved oxygen (DO) level. Fluorescence in situ hybridization analysis was used to correlate ammonia oxidizing bacteria (AOB) numbers with nutrient removal via nitrite. It was shown that in response to complete and partial nitrification modes, the numbers of AOB population were 7.7 x 10(7) cells/g mixed liquor suspended solids (MLSS) and 5.31 x 10(8) cells/g MLSS, respectively. The morphology of the sludge indicated that there is a small rod-shaped and spherical cluster which was mainly dominantly bacterial according to scanning electron microscope. Higher pollutant removal efficiencies of 86.2%, 98%, and 96.1%, for total nitrogen, NH4+ - N, and total phosphorus, respectively, were achieved by a long-term operation of the six tanks activated sludge process at a low DO concentration and low chemical oxygen demand to nitrogen ratio which were approximately equal to the complete nitrification ldenitrification with the addition of an external carbon source at a concentration of 1.5-2.5 mg/L. PMID- 24956782 TI - Hydraulic conductivity of compacted soils controlled by microbial activity. AB - The hydraulic conductivity defines the displacement of liquids inside porous media and affects the fate and transport of contaminants in the environment. In this research the influence of microbial growth and decay inside soil pores on hydraulic conductivity is analysed. Long-term tests performed in silt-bentonite mixtures permeated with distilled water and a nutrients solution demonstrated that hydraulic conductivity of compacted silt-bentonite samples decreases with time of permeation as a bioclogging mechanism develops. The injection of antibiotics and antifungals in the specimens produces a rebound in the hydraulic conductivity associated with the decay of microbial activity. These results show that biomediated reactions can be used to control the flow rate through compacted soil liners. PMID- 24956783 TI - Water defluoridation by aluminium oxide-manganese oxide composite material. AB - In this study, aluminium oxide-manganese oxide (AOMO) composite material was synthesized, characterized, and tested for fluoride removal in batch experiments. AOMO was prepared from manganese(II) chloride and aluminium hydroxide. The surface area of AOMO was found to be 30.7m2/g and its specific density was determined as 2.78 g/cm3. Detailed investigation of the adsorbent by inductively coupled plasma-optical emission spectrometry, inductively coupled plasma-mass spectrometry, and ion chromatography (for sulphate only) showed that it is composed of Al, Mn, SO4, and Na as major components and Fe, Si, Ca, and Mg as minor components. Thermogravimetric analysis was used to study the thermal behaviour of AOMO. X-ray diffraction analysis showed that the adsorbent is poorly crystalline. The point of zero charge was determined as 9.54. Batch experiments (by varying the proportion of MnO, adsorbent dose, contact time, initial F concentration, and raw water pH) showed that fluoride removal efficiency ofAOMO varied significantly with percentage of MnO with an optimum value of about I11% of manganese oxide in the adsorbent. The optimum dose of the adsorbent was 4 g/L which corresponds to the equilibrium adsorption capacity of 4.8 mg F-/g. Both the removal efficiency and adsorption capacity showed an increasing trend with an increase in initial fluoride concentration of the water. The pH for optimum fluoride removal was found to be in the range between 5 and 7. The adsorption data were analysed using the Freundlich, Langmuir, and Dubinirn-Radushkevich models. The minimum adsorption capacity obtained from the non-linear Freundlich isotherm model was 4.94 mg F-/g and the maximum capacity from the Langmuir isotherm method was 19.2mg F-/g. The experimental data of fluoride adsorption on AOMO fitted well to the Freundlich isotherm model. Kinetic studies showed that the adsorption is well described by a non-linear pseudo-second-order reaction model with an average rate constant of 3.1 x 10(-2) g/min mg. It is concluded that AOMO is a highly promising adsorbent for the removal of excess fluoride from drinking water. PMID- 24956784 TI - Changes in the physicochemical properties and enzymatic activity of waste during bioreduction of pig carcasses. AB - Bioreduction is a novel method for the on-farm storage of fallen stock in a vessel containing water that is heated and aerated, prior to disposal. The combination of a mesophilic temperature and high bacterial population leads to rapid degradation of carcasses due to microbial and enzymatic breakdown of protein material; and ultimately the reduction in volume of waste to be disposed. The system could, however, be improved if more was known about the changes that occur during a bioreduction cycle. Pig carcasses were placed within two commercial-scale bioreduction vessels (BVs) (6.5 m3 capacity) and the changes in physicochemical parameters, enzymatic activity, gas emissions and microbial communities were analysed over 56 days. Analyses showed that each vessel displayed different physicochemical parameters. The microbial communities within both vessels were also distinct, though they converged between days 28 and 42 before again diverging. Of the enzymes assayed, acetylesterases showed the highest activity during initial stages, with a subsequent increase in lipase towards the end. All other enzymes showed little activity in comparison. Despite active aeration of the vessels, conditions were redox-constrained, leading to the emission of gases associated with anaerobic conditions, namely NH3 and H2S. It was concluded that no single parameter governed the biochemical processes and that each BV will have its own unique microbial population and hence rate of decomposition. Further work is needed to increase the rate of bioreduction through bioaugmentation or developing enzyme additives. PMID- 24956785 TI - Evaluating oxidation-reduction properties of dissolved organic matter from Chinese milk vetch (Astragalus sinicus L.): a comprehensive multi-parametric study. AB - Green manuring is a common practice in replenishment of soil organic matter and nutrients in rice paddy field. Owing to the complex interplay of multiple factors, the oxidation--reduction (redox) properties of dissolved organic matter (DOM) from green manure crops are presently not fully understood. In this study, a variety of surrogate parameters were used to evaluate the redox capacity and redox state of DOM derived from Chinese milk vetch (CMV, Astragalus sinicus L.) via microbial decomposition under continuously flooded (CF) and non-flooded (NF) conditions. Additionally, the correlation between the surrogate parameters of CMV DOM and the kinetic parameters of relevant redox reactions was evaluated in a soil-water system containing CMV-DOM. Results showed that the redox properties of CMV-DOM were substantially different between the fresh and decomposed CMV-DOM treatments. Determination of the surrogate parameters via ultraviolet visible/Fourier transform infrared absorption spectroscopy and gel permeation chromatography generally provided high-quality data for predicting the redox capacity of CMV-DOM, while the surrogate parameters determined by elemental analysis were suitable for predicting the redox state of CMV-DOM. Depending on the redox capacity and redox state of various moieties/components, NF-decomposed CMV-DOM could easily accelerate soil reduction by shuttling electrons to iron oxides, because it contained more reversible redox-active functional groups (e.g. quinone and hydroquinone pairs) than CF-decomposed CMV-DOM. This work demonstrates that a single index cannot interpret complex changes in multiple factors that jointly determine the redox reactivity of CMV-DOM. Thus, a multi parametric study is needed for providing comprehensive information on the redox properties of green manure DOM. PMID- 24956786 TI - Water reduction in waste-activated sludge by resettling and filtration in batch. Phase (1): pilot-scale experiments to optimize performance. AB - This article describes an effective procedure for reducing the water content of excess sludge production from a wastewater treatment plant by increasing its concentration and, as a consequence, minimizing the volume of sludge to be managed. It consists of a pre-dewatering sludge process, which is used as a preliminary step or alternative to the thickening. It is made up of two discontinuous sequential stages: the first is resettling and the second, filtration through a porous medium. The process is strictly physical, without any chemical additives or electromechanical equipment intervening. The experiment was carried out in a pilot-scale system, consisting of a column of sedimentation that incorporates a filter medium. Different sludge heights were tested over the filter to verify the influence ofhydrostatic pressure on the various final concentrations of each stage. The results show that the initial sludge concentration may increase by more than 570% by the end of the process with the final volume of sludge being reduced in similar proportions and hydrostatic pressure having a limited effect on this final concentration. Moreover, the value of the hydrostatic pressure at which critical specific cake resistance is reached is established. PMID- 24956787 TI - Adsorption of mercury from water by modified multi-walled carbon nanotubes: adsorption behaviour and interference resistance by coexisting anions. AB - This investigation reports the use of modified multi-walled carbon nanotubes (MWCNTs) with various functional groups for adsorbing inorganic divalent mercury (Hg(II)) from water samples. To elucidate the behaviours and mechanisms of Hg(II) adsorption by modified MWCNTs, their adsorption capacity was studied by considering adsorption isotherms and kinetics. Particular attention was paid to interference of coexisting inorganic ions with Hg(II) adsorption. The results reveal that functionalization with oxygen-containing groups improved the Hg(II) adsorption capacity of the MWCNTs. Kinetic analysis demonstrated that the adsorption of Hg(II) by MWCNTs was closely described by the pseudo-second-order and Elovich models, suggesting that the adsorption of Hg(II) by MWCNTs was significantly affected by chemical adsorption. The kinetic results were also analysed using the intraparticle diffusion model, which revealed that intraparticle diffusion was not the only rate-controlling mechanism. The adsorption of Hg(II) on MWCNTs fell drastically as the ionic strength increased from 0 to 1.0mol/L chloride ions, and declined significantly as the pH increased from 2.2 to 10.5. The elemental maps obtained by energy-dispersive spectrometer (EDS) revealed the formation of surface complexes of chloride ions with functional groups on MWCNTs, which reduced the number of available sites for the adsorption of Hg(II) and strengthened the repulsive forces between Hg(II) and MWCNTs. The EDS results suggest that chloride ions are important in controlling Hg(II) speciation and adsorption on the surfaces of MWCNTs. PMID- 24956788 TI - Stability and removal of dexamethasone sodium phosphate from wastewater using modified clays. AB - Stability and removal of dexamethasone sodium phosphate (DSP) from wastewater produced at Al-Quds University Campus were investigated. Kinetic studies in both pure water and wastewater coming from secondary treatment (activated sludge) demonstrated that the anti-inflammatory DSP underwent degradation to its hydrolytic derivative, dexamethasone, in both media. The first-order hydrolysis rate of DSP in activated sludge at 25 degrees C (3.80 x 10(-6) s-1) was about 12 fold larger than in pure water (3.25 x 10(-7) s-1). The overall performance of the wastewater treatment plant (WWTP) installed in the University Campus was also assessed showing that 90% of spiked DSP was removed together with its newly identified metabolites by the ultra-filtration (UF) system, which consists of a UF hollow fibre (HF) with a 100-kDa cutoff membrane as the pre-polishing stage for the UF spiral wound with a 20-kDa cutoffmembrane. In testing other technologies, the effectiveness of adsorption and filtration by micelle-clay (MC) preparation for removing DSP was ascertained in comparison with activated charcoal. Batch adsorption in aqueous suspensions of the MC composite and activated carbon was well described by Langmuir isotherms showing the best results for MC material. Filtration of DSP water solutions demonstrated a significant advantage of columns filled in with a mixture of sand and MC complex in comparison with activated carbon/sand filters. PMID- 24956789 TI - Mechanisms of Cu2+ migration, recovery and detoxification in Cu2+-, SO4(2-) containing wastewater treatment process with anaerobic granular sludge. AB - In this study, anaerobic granular sludge with sulphate-reducing bacteria (SRB) was applied to treat Cu2+-, SO4(2-) -containing wastewater in an expanded granular sludge bed reactor. The migration and enrichment of copper in anaerobic granular sludge were envaluated. By analysing the sludge with X-ray diffraction, copper was determined to be present as covellite (CuS) in the sludge. Observations at the microscopic level showed that CuS precipitates were absorbed onto granules and gradually migrated from the outer to the interior layer of the granule over time and finally accumulated in the core of the granular sludge. Because of the migration of the CuS precipitates and the protection of the extracellular polymeric substances matrix, SRB were able to tolerate copper concentrations up to 10 mg/L. A copper removal efficiency of about 96% was observed at a steady state for 3 months, and copper was enriched in the granular sludge. PMID- 24956790 TI - Adsorption equilibrium, kinetics and thermodynamics of dichloroacetic acid from aqueous solution using mesoporous carbon. AB - The presence of disinfection by-products, such as trihalomethanes and haloacetic acids in water, is believed to be harmful to human health. In this work, mesoporous carbon was synthesized with the evaporation-induced self-assembly method and employed to evaluate the effects of initial concentration, contact time, pH and temperature on the removal of dichloroacetic acid in batch experiments. Adsorption equilibrium was established in 480 min and the maximum adsorption (350mg/g) of dichloroacetic acid on the mesoporous carbon was observed to occur at 308 K and pH 3.0. Freundlich and Langmuir isotherms were used to analyse the equilibrium data at different temperatures; kinetic data were fitted to the pseudo-first-order and pseudo-second-order models and found that the adsorption capacity, mass transfer coefficient and diffusivity of dichloroacetic acid were directly affected by the physical and chemical parameters. In addition, the various thermodynamic parameters, such as Gibbs free energy (Delta G), enthalpy (Delta H = 54.35 kJmol-1) and entropy (Delta S = 258.36 Jmol-1 K-1) were calculated to analyse the adsorption process. The experimental results indicated that the mesoporous carbon was an excellent adsorbent for dichloroacetic acid removal from aqueous solutions. PMID- 24956791 TI - Effects of sorbent materials on the cryofocusing analysis of gaseous reduced sulphur compounds. AB - The relative performance of different sorbent materials employed in the cryofocusing (e.g. in cold trap (CT) unit) stage was investigated at sub-ambient temperature by the thermal desorption (TD)-gas chromatography (GC)-pulsed flame photometric detector. To this end, the TD-based calibration of five reduced sulphur compounds (RSC: H2S, CH3SH, CS2, DMS and DMDS) and SO2 was carried out via the Peltier cooling system with five types of sorbent combinations such as two single-bed (Tenax TA and Silica gel) plus three multibed types (a combination of either two from the following three sorbents: Tenax TA, Silica gel and Carbopack B). Relative performance of each of all five CT options, if evaluated in terms of response factors for each compound, demonstrated that each CT composition acts as an important criterion to distinguish detection properties between light and heavy sulphur species. Although the relative response of H2S and CH3 SH was systematically distinguishable between the CT types, that of SO2 was the most complicated to interpret. According to this study, the two CT types consisting of Carbopack B and Silica gel (CS-0.4 and CS-0.6) were the optimum choices for sulphur gas analysis in terms of basic QA parameters (sensitivity, reproducibility and linearity). PMID- 24956792 TI - Optimal cultivation of simultaneous ammonium and phosphorus removal aerobic granular sludge in A/O/A sequencing batch reactor and the assessment of functional organisms. AB - In this study, sequencing batch reactor (SBR) with an anaerobic/aerobic/anoxic operating mode was used to culture granular sludge. Optimal adjustment of cycle duration was achieved by the direction ofpH, oxidation reduction potential and dissolved oxygen parameters. The results showed that the treating efficiency was significantly improved as the cycle was shortened from 450 to 360 min and further to 200 min. Nitrogen and phosphorus removal were nearly quantitative after 50 days operation and maintained stable to the end of the study period. The typical cycle tests revealed that simultaneous denitrification and phosphorus removal occurred when aerobic granules were gradually formed. The nitrite effect tests showed that less than 4.8 mg N/L of the nitrite could enhance superficial specific aerobic phosphate uptake rate (SAPUR) under aerobic condition, indicating that the traditional method to evaluate the capability of total phosphate-accumulating organisms (PAOs) was inaccurate. Additionally, a high level of nitrite was detrimental to PAOs. A novel method was developed to determine the activity of each kind of PAOs and other denitrifying organisms. The results showed that (1) nitrate, besides nitrite, could also enhance SAPUR and (2) aerobic granular sludge could perform denitrification even when phosphate was not supplied under anoxic condition, suggesting that other denitrifying organisms besides denitrifying phosphate-accumulating organisms also contributed to denitrification. PMID- 24956793 TI - Chemical sulphate removal for treatment of construction and demolition debris leachate. AB - Construction and demolition debris (CDD) is a product of construction, renovation or demolition activities. It has a high gypsum content (52.4% of total gypsum), concentrated in the CDD sand (CDDS) fraction. To comply with the posed limit of the maximum amount of sulphate present in building sand, excess sulphate needs to be removed. In order to enable reuse of CDDS, a novel treatment process is developed based on washing of the CDDS to remove most of the gypsum, and subsequent sulphate removal from the sulphate-rich CDDS leachate. This study aims to assess chemical techniques, i.e. precipitation and adsorption, for sulphate removal from the CDDS leachate. Good sulphate removal efficiencies (up to 99.9%) from the CDDS leachate can be achieved by precipitation with barium chloride (BaCl2) and lead(II) nitrate (Pb(NO3)2). Precipitation with calcium chloride (CaCl2), calcium carbonate (CaCO3) and calcium oxide (CaO) gave less efficient sulphate removal. Adsorption of sulphate to aluminium oxide (Al2O3) yielded a 50% sulphate removal efficiency, whereas iron oxide-coated sand as adsorbent gave only poor (10%) sulphate removal efficiencies. PMID- 24956794 TI - Valorization of unauthorized sea disposal dredged sediments as a road foundation material. AB - The main objective of this study is to show the ability of fine dredged material (mainly silty material) to be used in road construction project. This paper is divided into three parts. In the first part, the physical, the mineralogical and the mechanical characteristics of the used fine dredged sediments, as well as their chemical composition and environmental impacts are presented. In the second part, the methodology developed to design the road made from dredged fine sediment is developed. The third part of the paper focuses on the presentation of the road construction and the interpretation of analyses made on cores drilled samples from the road and measurements of the deflection of the road. The environmental assessment, based on leaching tests, is also performed at different issues. PMID- 24956795 TI - Ammonium nitrogen removal from the permeates of anaerobic membrane bioreactors: economic regeneration of exhausted zeolite. AB - This study revealed that ammonium exchange of natural zeolite could be an economical method of nitrogen removal from the permeates of anaerobic membrane bioreactors (AnMBRs). It was found that the mass ratio of Na+ to Zeolite - NH4+ - N significantly affected regeneration efficiency (RE), not simply NaCI concentration. Batch experiments showed that the mass ratio of 750g Na+/g Zeolite - NH4+ - N was required to achieve RE over 90% in 2h at pH 9. However, the alkaline regeneration at pH 12 significantly decreased the mass ratio down to 4.2 in batch tests. It was confirmed that the alkaline regeneration only needed NaCl 10 g/L (the mass of Na+ to Zeolite - NH4+ - N of 4.2) for RE of 85% in 2 h of reaction time in continuous column tests. Economic analysis showed that this alkaline regeneration decreased chemical costs over 10 times as compared with a conventional regeneration method. A significant bottleneck of zeolite processes would be the requirement of substituting exhausted zeolite with virgin one, due to the reductions of ammonium exchange capacity and RE. PMID- 24956796 TI - Membrane-integrated hybrid system for the effective treatment of ammoniacal wastewater of coke-making plant: a volume reduction approach. AB - Nanofiltration (NF) of ammoniacal wastewater containing phenol and cyanide has been investigated for effective separation of these hazardous pollutants and for the subsequent downstream chemical treatment resulting in valuable by-product generation. Four different types of composite polyamide commercial NF membranes (Sepro, USA) were tested under different operating conditions including transmembrane pressure and recovery rate (RR). At a transmembrane pressure of 15 bar, the achieved rejection of cyanide and phenol were 95% and 93%, respectively (concentrated stream) when the permeate contained 85% of ammonium-N. A high flux of 120 L m-2 h-1 was achieved during NF at a concentrated mode, with a volumetric cross-flow rate of 800 L h-1 at a pH of 10.0. The RR was 60% for the NF 1 membrane. Fenton's reagents (7.0 and 3.75 g L-1 H202 and FeSO4 . 7H20, respectively) were used to degrade more than 99% of pollutants present in the concentrated stream. In the permeate side, 97% of NH4+ -N was precipitated out as struvite by using Mg2+ : NH4 : PO+4 in 1:1:1 molar ratio at pH 9.0. PMID- 24956797 TI - Radiation-induced removal of sulphadiazine antibiotics from wastewater. AB - The radiation-induced removal of sulphadiazine (SD) belonging to the heterocyclic sulphonamides pharmaceuticals was investigated by gamma irradiation at different conditions in laboratory scale. The influence of initial SD concentrations, pH values, 02 and N2 on SD degradation was determined. The experimental results showed that gamma-ray irradiation was efficient for removing SD from wastewater. SD could be completely removed at an absorbed dose of 10 kGy. The degradation kinetics of SD conformed to the first-order kinetic equation. When SD concentration was in the range of 10-30 mg/L, the dose constant (d) decreased with an increasing initial SD concentration. The mineralization of SD, in terms of total organic carbon removal, was not obvious at a low absorbed dose, but it increased to more than 75% at 100 kGy. The biodegradability of SD was improved after irradiation, suggesting that irradiation could be used as a pretreatment technology for treating SD-containing wastewater. The possible degradation pathway of SD was tentatively proposed based on the analysis of intermediate products during gamma irradiation. PMID- 24956798 TI - Assessing a mixture of biosurfactant and enzyme pools in the anaerobic biological treatment of wastewater with a high-fat content. AB - The use of rhamnolipid-type biosurfactant produced by Pseudomonas aeruginosa was evaluated for solubilization of fat present in effluent from a poultry processing plant, followed by anaerobic biological treatment. The rhamnolipid was used in combination with enzyme pools produced by solid medium fermentation of the fungi Penicillium simplicissimum and Penicillium brevicompactum. In experiments with raw effluent, the accumulation of fat caused the specific methane production (SMP) to be much less than with pretreated effluent (0.074 vs. 0.167 L CH4/g chemical oxygen demand (COD) removed). In experiments with pretreated effluent, the SMP ranged from 0.105 to 0.207 L CH4/g CODremoved. A statistical analysis of the results of four sequential batches found that all variables had a significant effect on the SMP in the fourth batch. A fifth batch was initiated for three conditions, and it led to the highest SMP when compared with the control, which showed similar behaviour for the SMP over time, ending up with values three times greater than the SMP in the control conditions. The residual oil and grease analysis revealed removals from 51% to 90% with pretreated effluent and only 1% in the control conditions with raw effluent. Thus, the best synergistic effect of fat release/hydrolysis of effluent components from a poultry processing plant was found with a 0.5% P. brevicompactum pool and rhamnolipid at half the critical micelle concentration (24 mg/L). PMID- 24956799 TI - Kinetics of concentration decay of specific organic matter in UASB reactors operating with and without return of aerobic sludge. AB - This study aimed at assessing the influence of the return of excess aerobic sludge from a trickling filter (TF) upon the anaerobic digestion process in an upflow anaerobic sludge blanket (UASB) reactor, by evaluating its effect on the kinetics of the decay of specific organic matter (carbohydrates, proteins and lipids), as well as on the concentrations of volatile fatty acids in the UASB reactor. A pilot-scale UASB/TF system was used to perform the experiments, operating with (phase 2) and without (phase 1) excess sludge return from the TF to the UASB reactor. Sampling was carried out at different heights of the UASB reactor (0, 25, 125 and 225-cm height), and profile concentrations were determined for the following parameters: carbohydrates, proteins, lipids and volatile fatty acids. First-order kinetics showed the best fit to the decay of concentrations of carbohydrates, proteins, lipids and chemical oxygen demand (COD) in the UASB reactor. The parameters showing the best fit to the first-order kinetics were proteins and COD, during the sludge return phase. The occurrence of higher apparent reaction constants was further observed during the sludge return phase. For an influent COD concentration of 600 mg L-1 and hydraulic retention times of 2.1, 2.6 and 3.0 h in phase 1, the effluent COD concentrations were 125.3, 88.4 and 62.4 mg L-1, respectively, whereas in phase 2, the effluent COD concentrations were 75.5, 47.6 and 30.1 mg L-1, respectively. PMID- 24956800 TI - Possible source term of high concentrations of mecoprop-p in leachate and water quality: impact of climate change, public use and disposal. AB - Mecoprop-p herbicide is often found in wells and water abstractions in many areas around Europe, the UK inclusive. There is a growing environmental and public health concern about mecoprop-p herbicide pollution in ground and surface water in England. Reviews suggest that extensive work has been carried out on the contribution of mecoprop-p herbicides from agricultural use whilst more work needs to be carried out on the contribution of mecoprop-p herbicide from non agricultural use. The study covers two landfill sites in Weaver/Gowy Catchment. Mecoprop-p herbicide concentrations in the leachate quality range between 0.06 and 290 microg l1 in cells. High concentration ofmecoprop-p herbicide in the leachate quality suggests that there is a possible source term in the waste stream. This paper addresses the gap by exploring possible source terms of mecoprop-p herbicide contamination on landfill sites and evaluates the impact of public purchase, use and disposal alongside climate change on seasonal variations in mecoprop-p concentrations. Mecoprop-p herbicide was found to exceed the EU drinking water quality standards at the unsaturated zone/aquifer with observed average concentrations ranging between 0.005 and 7.96 microg l1. A route map for mecoprop-p herbicide source term contamination is essential for mitigation and pollution management with emphasis on both consumer and producer responsibility towards use of mecoprop-p product. In addition, improvement in data collection on mecoprop-p concentrations and detailed seasonal herbicide sales for non agricultural purposes are needed to inform the analysis and decision process. PMID- 24956801 TI - Impact of operating conditions on the removal of endocrine disrupting chemicals by membrane photocatalytic reactor. AB - This study focuses on the performance of a submerged membrane photocatalytic reactor for the removal of 17beta-oestradiol (E2) in the presence of humic acid (HA). In addition to the impact of operating parameters, such as membrane pore size, ultraviolet (UV) intensity and hydraulic retention time (HRT), the influence of long-term operation was also assessed by advanced characterization of the fouling layer formed on the membrane. The tighter (0.04 microm) hollow fibre polyvinylydene fluoride (PVDF) membrane was found to exhibit not only higher HA removal than the (0.2 microm) module (85% and 75%, respectively), but also greater transmembrane pressure (TMP) values and higher irreversible fouling. Long-term operation conditions have been simulated by conducting an ageing catalyst process and demonstrated a decrease in performance obtained with time. The artificially aged TiO2 resulted in higher TMP values and lower HA removals (about 10-20% decrease) compared with the non-aged catalyst. For E2 removal in the presence of HA, the passive adsorption of the oestrogen onto the organic matter was found to be significant (40% of the E2 adsorbed after I h), demonstrating the importance of the nature of the water matrix for this type of treatment process. An increase in the UV light intensity was observed to favour the E2 elimination, leading to more than 90% removal when using 64 W combined with PVDF membrane and an HRT of 3 h. PMID- 24956802 TI - Effect of vanadium toxicity at its different oxidation states on selected bacterial and protozoan isolates in wastewater systems. AB - This study assesses and compares vanadium toxicity in its different oxidation states towards bacterial isolates (Pseudomonas putida and Bacillus licheniformis) and protozoan isolates (Peranema sp. and Trachelophyllum sp.). The isolates were exposed to various concentrations of V in mixed liquors and their tolerance to V was assessed at 30 degrees C at a pH of 4. The results revealed that the increase in V oxidation state increased its toxicity to bacterial isolates, whereas its toxicity decreased for protozoan isolates. Among the bacterial isolates, P putida was found to be more tolerant to V3+(24h-median lethal concentration (LC50): 390mg/l), V4+(24h-LC50: 230-250mg/l) and V5+(24h-LC50: 180-200mg/l), whereas for the protozoan isolates, Peranema sp. appeared to be more tolerant to V3+(24 h LC50: 110-120 mg/l), V4+(24 h-LC50: 160-170 mg/l) and V5+(24 h-LC50: 160-200 mg/l). A comparison of both groups of organisms revealed Trachelophyllum sp. as the most sensitive organism to V at its various oxidation states. The visual and spectrophotometric methods used to assess V reduction revealed that P. putida was the only isolate able to reduce V5+, V4+ and V3+ to V2+ in mixed liquor media. Vanadium (+2) in concentrations of approximately 46.46 mg/l, 29.57 m mg/l and 38.01 mg/l found in the media was treated with V3+, V4+ and V5+, respectively, and inoculated with P. putida. This study revealed that the ability of V reduction, adopted with P putida, can be an effective strategy to remove V from polluted environments. This study also showed that the toxicity of V, in terms of its oxidation states, differs from one species to another and in kingdoms. PMID- 24956803 TI - Effect of aeration on pollutants removal, biofilm activity and protozoan abundance in conventional and hybrid horizontal subsurface-flow constructed wetlands. AB - The large area demand of constructed wetlands (CWs) is documented as a weak point that can be potentially reduced by applying active aeration. The aim of this study was, therefore, to understand the effects of aeration on the treatment performance, the biofilm activity, the protozoan population size and potential CW footprint reduction of different horizontal flow (HF) CW configurations. Two experimental periods were considered: a first period with low organic loading rate (OLR) and a second period with high OLR. Three HF CW configurations were compared: a conventional (control), an aerated and a hybrid CW (aerated followed by a non-aerated CW). The results obtained reinforced the competence of aerated CW for organic matter removal (81-89% of chemical oxygen demand) while for nitrogen elimination the control (19-24%) and hybrid (8-41%) systems performed better than the aerated system (-6% to 33%). Biofilm activity and protozoa abundance were distinctly higher at the inlet zones when compared with the outlet zones of all CWs, as well as in the aerated systems when compared with the non aerated CWs. The protozoan abundance increased with an increase in the OLR and ciliates were found to be the dominant group. Overall, the active aeration highlighted the efficiency and stability of the CWs for organic matter removal and thus can be used as a promising tool to enhance microbial activity and grazing by protozoa; eventually reducing solid accumulation in the bed media. These beneficial effects contribute to reduce the CWs' area requirements. PMID- 24956804 TI - Coliform bacteria removal from sewage in constructed wetlands planted with Mentha aquatica. AB - The present study evaluated the performance of the species Mentha aquatica in constructed wetlands of horizontal subsurface flow (CW-HSSF) with regard to the removal of coliforms bacteria in an effluent from the primary treatment of sewage as well as to obtain adjustment parameters of the bacterial decay kinetic model along the length of the CW-HSSF. Therefore, four CW-HSSFs measuring 24.0 m x 1.0 m x 0.35 m were built and filled with number 0 gravel as the support medium to a height of 0.20m. Two of the CW-HSSFs were planted with the species M. aquatica, while the other two remained uncultivated. Cultivation of M. aquatica in CW-HSSF resulted in total coliforms (TC) and Escherichia coli (EC) removals from 0.9 to 1.3 log units greater than those obtained in the uncultivated experimental plots, for the hydraulic retention times (HRTs) of 4.5 and 6.0 days. For HRT ranged from 1.5 to 6.0 days, the highest removal efficiencies in counts of TC and EC were obtained when using longer HRT. The mathematical models evaluated showed good fit to average counts of TC and EC highlighting the modified first-order kinetic model with the inclusion of the power parameter in the HRT variable. PMID- 24956805 TI - Turned windrow composting of cow manure as appropriate technology for zero discharge of mulberry pulp wastewater. AB - Turned windrow composting was investigated as appropriate technology for recycling the wastewater (excluding black liquor) from mulberry pulp and paper handicrafts. Two exterior turned windrows (1.5 m width x 1.5 m height x 2.0 m length) with dry leaves/cow manure/sawdust wet weight ratios of 60:40:0 (Pile A) and 55:40:5 (Pile B) were used for the investigation. Changes in the physical and chemical properties of the compost were examined and a phytotoxicity analysis was performed. A soil incubation test and an informal focus group discussion were also conducted. The results revealed that while both piles met the regulatory processing requirements for further reduced pathogens (>or= 55 degrees C for 15 days or longer), the operation without sawdust (Pile A) not only significantly enhanced the thermophilic temperature regime (P < 0.05) but also yielded the highest amount (1.4 m3 ton-1 pile) of wastewater elimination during the first 2 months of composting. It was found that the constant rates of degradation were 0.006 day- 1 (Pile A) and 0.003 day-1 (Pile B), and no pronounced statistically significant difference in N losses was found (P > 0.05). The germination index of two plant species in both piles varied between 126% and 230% throughout the experiment, and no pronounced differences (P > 0.05) among the samples were found. Addition of the compost significantly improved soil organic matter and pH (7-8), as well as reduced the loss of NO3-N. Local discussion groups were initiated to evaluate the cost-benefits, the potential of wastewater removal, the cooperation of community users and supporters, the compost quality and the potential compost market. PMID- 24956806 TI - A study of subsurface wastewater infiltration systems for distributed rural sewage treatment. AB - Three types of subsurface wastewater infiltration systems (SWIS) were developed to study the efficiency of organic pollutant removal from distributed rural sewage under various conditions. Of the three different layered substrate systems, the one with the greatest amount of decomposed cow dung (5%) and soil (DCDS) showed the highest removal efficiency with respect to total nitrogen (TN), where the others showed no significant difference. The TN removal efficiency was increased with an increasing filling height of DCDS. Compared with the TN removal efficiency of 25% in the system without DCDS, the removal efficiency of the systems in which DCDS filled half and one fourth of the height was increased by 72% and 31%, respectively. Based on seasonal variations in the discharge of the typical rural family, the SWIS were run at three different hydraulic loads of 6.5, 13 and 20 cm/d. These results illustrated that SWIS could perform well at any of the given hydraulic loads. The results of trials using different inlet configurations showed that the effluent concentration of the contaminants in the system operating a multiple-inlet mode was much lower compared with the system operated under single-inlet conditions. The effluent concentration ofa pilot scale plant achieved the level III criteria specified by the Surface Water Quality Standard at the initial stage. PMID- 24956807 TI - [Effects of nitrogen, phosphorus and potassium fertilizers on the yield, quality and nutrient uptake of Pulsatilla cernua]. AB - OBJECTIVE: To study the effects of nitrogen (N), phosphorus (P2O5) and potassium (K2O) fertilizers on the growth, yield total saponins content and nutrient absorption of Pulsatilla cernua and provide a theoretical basis for good agriculture practice. METHODS: Field plot experiments was conducted, based on the D-saturation optimal design with three factors of nitrogen, phosphorus and potassium. Samples collected periodically were used for determination the contents of nutrient and total saponins, and for measurement of yield and agronomic characters. RESULTS: Nutrient contents in Pulsatilla cernua varied with growth stage and part under the same growth stage. Nutrient contents in aerial part were higher than that in root, while the proportion of nutritional absorption from seedling stage to the middle growth stage was larger than that at the late growth stage. Yield and total saponins content of Pulsatilla cernua were significantly influenced by the N1P2O5 and K2O applications, among three factors, N had the greatest effects, the next was K2O and P5O2. CONCLUSION: Pulsatilla cerntua under field cultivation should be fertilized properly, top-dressing with these fertilizers during the early growth stage and increasing the proportion of potassium. According to total saponin production of Pulsatilla cernua, the optimum fertilization model for high yield and good quality is 180 kg/hm2 of N, 79.74 kg/hm2 of P2O5, and 225 kg/hm2 of K20, with a N : P2O : K2O ratio of approximately 2.3 : 1 : 2.8. PMID- 24956808 TI - [Characteristic research on soil nutrient of root of Pseudostellaria heterophylla root zone and non-root zone in different planting patterns]. AB - OBJECTIVE: To research the influence of Pseudostellaria heterophylla planting patterns on soil nutrients. METHODS: The root zone and non-root zone soil nutrient status were analyzed, which included the crop rotation, intercropping, relay cropping, 1-year planting, 3-year planting, 6-year planting and 10-year planting. RESULTS: The results showed that there were differences in the soil nutrient of root zone among different planting patterns. The soil nutrient of root zone in seven different planting patterns were all significantly higher than that of non-root zone soil. And the soil nutrients of root zone showed a significant enrichment. The enrichment ratio of total K and Olsen K in 6-year and 10-year planting were both negative value, which indicated that the soil potassium was deficiency. The average pH value of root zone was 0.32 lower than that of non-root zone. There was a significant positive correlation between the organic matter value and the total nitrogen content in root zone and non-root zone (P < 0.01). The soil nutrients were high in crop rotation and intercropping, it would he helpful to improve soil quality and absorption to nutrient. CONCLUSION: The reasonable application of nitrogen fertilizer ,organic fertilizer and potash fertilizer can significantly increase the organic matter content in soil ,and it will help to retain the fertilizer capacity of soil. PMID- 24956809 TI - [Effects of plant growth regulators on cutting propagation of Rosa laevigata]. AB - OBJECTIVE: To explore the optimal plant growth regulator and its suitable concentration for the cutting propagation of Rosa laevigata. METHODS: The cuttings were dealt with 6 kinds of plant growth regulators (IAA,IBA, NAA, PP333, 2, 4-D and ABT) at different concentrations (100, 200 and 500 mg/L) for 50 seconds. After 30 days growth, by analysis of variance and multiple comparisons,the most suitable cutting propagation method for Rosa laevigata was found. RESULTS: Under the same condition, different concentration of different kinds of plant growth regulators had different effects on cutting propagation of Rosa laevigata. Generally speaking,cuttings soaked with 200 mg/L PP333 for 50 seconds was the best,with the high multiple effectiveness index and average root number (12.42); Cuttings soaked with 200 mg/L IBA for 50 seconds also had significant effects, with the second high multiple effectiveness index and the highest survival rate (96.67%). CONCLUSION: 200 mg/L PP333 can promote cutting propagation of Rosa laevigata best. PMID- 24956810 TI - [Identification of common medicinal snakes in medicated liquor of Guangdong by COI barcode sequence]. AB - OBJECTIVE: To identify the common snakes in medicated liquor of Guangdong using COI barcode sequence,and to test the feasibility. METHODS: The COI barcode sequences of collected medicinal snakes were amplified and sequenced. The sequences combined with the data from GenBank were analyzed for divergence and building a neighbor-joining(NJ) tree with MEGA 5.0. RESULTS: The genetic distance and NJ tree demonstrated that there were 241 variable sites in these species, and the average (A + T) content of 56.2% was higher than the average (G + C) content of 43.7%. The maximum interspecific genetic distance was 0.2568, and the minimum was 0. 1519. In the NJ tree,each species formed a monophyletic clade with bootstrap supports of 100%. CONCLUSION: DNA barcoding identification method based on the COI sequence is accurate and can be applied to identify the common medicinal snakes. PMID- 24956811 TI - [Determination of maleic hydrazide residues and its influence on the quality of Atractylodes macrocephala]. AB - OBJECTIVE: To determine maleic hydrazide (MH) residues and discuss its influence on the quality of Atractylodes macrocephala. METHODS: At the bud stage, A. macrocephala different concentration of MH. Then MH residues,the contents of sugar and lactone were determined by HPLC and UV. The quality of A. macrocephala was comprehensively evaluated by independent sample t test and principal component analysis. RESULTS: The range of MH residues was 0.3-2.2 mg/kg. The results of independent sample t test revealed that the trend of the contents of lactone was low-high-low with the increase of MH, and the effect of MH on the content of sugar was barely obvious. Meanwhile, principal component analysis showed that comprehensive evaluation on the quality of A. macrocephala was the best when MH with 75 or 100 times water was applied. CONCLUSION: Proper concentration MH is applied to ensure low concentration MH residues and improve yield and quality of A. macrocephala. PMID- 24956813 TI - [Determination of main active components in crude and processed Corydalis Rhizoma samples from different habitats]. AB - OBJECTIVE: To compare the content of water, ethanol soluble extracts and tetrahydropalmatine in crude and processed Corydalis Rhizoma samples from different habitats. METHODS: Corydalis Rhizoma was processed according to the optimum processing of the Chinese Pharmacopoeia (2010 edition), and then, the difference of the content of water,ethanol soluble extracts and tetrahydropalmatine in crude and processed Corydalis Rhizoma samples were analyzed and compared. RESULTS: From 14 different batches of Corydalis Rhizoma studies, the content of water, ethanol soluble extracts and tetrahydropalmatine in crude Corydalis Rhizoma was 12.8%-14.8%, 16.5%-19.6% and 0.043%-0.075%, respectively; As for Corydalis Rhizoma after processing with vinegar,the content of water, ethanol soluble extracts and tetrahydropalmatine was 7.58%-11.7%, 17.8% 23.5% and 0.046%-0.079%, respectively. CONCLUSION: The content of water, ethanol soluble extracts and tetrahydropalmatine varies slightly in the same type of samples from different habitats,which might be due to the difference in soil and climate in each habitat. PMID- 24956812 TI - [Determination of artemisinic acid in Artemisia annua at different growth stages based on spot area]. AB - OBJECTIVE: Based on the important medicinal applications of artemisinic acid and the superiority of Thin Layer Chromagraphy (TLC), the spot area method of TLC was presented to determine the content changes of artemisinic acid of Artemisia annua at different growing stages. METHODS: The separation conditions including chromatographic solutions and chromogenic agent were optimized. The detection limit and the linear concentration range were analyzed. And the content changes of artemisinic acid of Artemisia annua at different growing stages were detected. RESULTS: The results showed that artemisinic acid extracted from Artemisia annua could be separated completely by the chromatographic solutions composed by petroleum ether,acetone and ethyl acetate (80: 19: 1). The artemisinic acid was clearly colored using the chromogenic agent consisting by ethanol, bromophenol blue and sulfuric acid. The detection limit of TLC was 0.05 mg/mL. The spot area of TLC had a good linear relationship within the range of 0.05-0.6 mg/mL, accorded with regression equation of y = 11.162 x + 0.0823. The results showed that the content of artemisinic acid at 0.041 mg/g in April which below the detection limit of TLC had no color spot. Contrarily, the spots of artemisinic acid were obvious in materials growing from May to September, and content was about 0.7, 1.2, 2.1, 2.4 and 2.7 mg/g, respectively corresponding to results by HPLC. CONCLUSION: The method can be applied to the quantitative analysis of artemisinic acid in Artemisia annua. PMID- 24956814 TI - [HPLC fingerprint study on Chaenomelis fructus and comparative study on different processed products]. AB - OBJECTIVE: To establish HPLC fingerprint of Chaenomelis Fructus and compare HPLC fingerprints of different processed products. METHODS: The mobile phase consisted of acetonitrile-methanol (7:3) (A) and 0.03% phosphoric acid(B) in a gradient mode. Flow rate was 0.8 mL/min. The wavelength was set at 300 nm and column temperature was 30 degrees C. The HPLC chromatograms were analyzed by the "traditional Chinese medicine fingerprint similarity calculation software". RESULTS: The results of methodological study met technical requirements of HPLC fingerprint. Ten batches of samples were divided into three groups by hierarchical cluster analysis and the similarities exceeded 0.90. The HPLC fingerprints of different processed products had obvious differences in area of common peaks but less differences in number of common peaks. CONCLUSION: The HPLC fingerprint method is stable, accurate and reliable and can be used for scientific quality control of Chaenomelis Fructus. The processing temperature and processing materials have effect on the dissolution of chemical compositions in Chaenomelis Fructus. PMID- 24956815 TI - [Identification of Peucedani Radix and its adulterants by DNA barcoding technique]. AB - OBJECTIVE: To identify Peucedani Radix and its adulterants using DNA barcoding technique. METHODS: Total genomic DNA was isolated from Peucedani Radix and its adulterants. Nuclear DNA ITS2 sequences were amplified and purified PCR products were sequenced. Sequence assembly and consensus sequence generation were performed using the CodonCode Aligner V3.0. The Kimura 2-Parameter(K2P) distances were calculated using software MEGA 4. 0. Identification analyses were performed using BLAST1, Nearest Distance and Neighbor-Joining (NJ) methods, and the secondary structure of the ITS2 sequence differences between species were analyzed. RESULTS: Different samples of Peucedani Radix were gathered together and distinguished from its adulterants by NJ tree. The ITS2 secondary structure showed that Peucedani Radix could be differentiated obviously from its adulterants. CONCLUSION: ITS2 sequence is able to identify Peucedani Radix and its adulterants correctly, which provides a scientific basis for fast and accurate identification of the herb. PMID- 24956816 TI - [Chemical constituents from the roots of Ilex pubescens]. AB - OBJECTIVE: To study the chemical constituents from the roots of Ilex pubescens. METHODS: The 95% ethanol extract of the plant was separated by silica gel, Sephadex LH-20 and preparative HPLC chromatography. The structures were elucidated based on the physiochemical properties and spectroscopic analysis. RESULTS: Fifteen compounds were isolated and identified as oleuropein(1), oleoside dimethyl ester(2),8 (Z)-nuezhenide(3),3,4-dicaffeoylquinic acid methyl ester(4),3,4,5-tricaffeoylquinic acid methyl ester (5), isovanillic acid(6), syringic acid(7), 3beta-acetyloleanolic acid (8), 3beta-acetylursolic acid(9), uvaol(10), asiatic acid(11), 2alpha-hydroxyursolic acid(12), oleanolic acid (13), ursolic acid (14), stigmasterol-3-O-beta-D-glucopyranoside (15). CONCLUSION: Compounds 2,3,8,9 are obtained from this genus for the first time,compounds 5 7,10-12 are isolated from this plant for the first time. PMID- 24956817 TI - [Study on chemical constituents in the roots and rhizome of Trillium tschonoskii (III)]. AB - OBJECTIVE: To investigate the chemical constituents in the roots and rhizome of Trillium tschonoskii. METHODS: The roots and rhizome of Trillium tschonoskii were extracted with 70% ethanol and purified by polyamide, silica gel, RP-C18 and Sephadex LH-20 column chromatography. Chemical structures were identified by MS, 1D and 2D NMR experiments. RESULTS: Twelve compounds were isolated and identified from the ethyl acetate and n-butanol as 7,11-dimethyl-3-methylene-10, 11 dihdroxyl-1,6-dodecadien-diol(1),2, 6,10-trimethyl-2,10-dihdroxyl-6-dodecene diol(2),3,7,11-trimethyl-3,9,11-trihydroxyl-1,6-dodecadiene-glycerol(3),p hydroxymethyl-benzyl alcohol(4),20betaF, 22alphaF, 25alphaF-spirostan-5,13-ene 3beta,21alpha-diol(5), 2-methyl-3,4-dihydroxy-hexanedioic acid(6), alpha Lrhamnopyranosyl(7), epitrillenogenin-24-O-acetate-1-O-[2,3,4,-tri-O-acetyl-alpha L-rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside] (8),epitrillenogenin-24-O acetate-1-O-[2,4, -di-O-acetyl-alpha-L-rhamnopyranosyl-(1-->2)-alpha-L arabinopyranoside](9), epitrillenogenin1-O-[2,3,4,-tri-O-acetyl-alpha-L rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside] (10), epitrillenogenin-1-O [2,4, -di-O-acetyl-alpha-Lrhamnopyranosyl-(1-->2) -alpha-L-arabinopyranoside] (11) and epitrillenogenin-1-O-[4-O-acetyl-alpha-L-rhamnopyranosyl-(1-->2) -alpha L-arabinopyranoside] (12). CONCLUSION: Compounds 4-6 are isolated from this genus for the first time, compounds 1-3, 11, 12 are isolated from this plant for the first time. PMID- 24956818 TI - [Study on the chemical constituents of the PTP 1B inhibitory effective parts of Paeoniae Rubra Radix]. AB - OBJECTIVE: To study the chemical constituents of the PTP 1B inhibitory effective parts of Paeoniae Rubra Radix. METHODS: The effective part of Paeoniae Rubra Radix was enriched by Sephadex LH-20. Compounds were isolated by various column chromatography and their structures were elucidated through spectroscopic analysis. RESULTS: Thirteen compounds were identified as: benzoylpaeoniflorin(1), albiflorin(2), paeoniflorigenone(3), methyl gallate(4), adenosine(5),2-amino adenosine(6), 3,3'-Di-O-methylellagic acid(7), 3,3',4-trimethyl ellagic acid(8), dihydrokaempferol(9), glycerol(10), dibutyl phthalate(11). CONCLUSION: Compounds 5-11 are obtained from this plant for the first time. PMID- 24956819 TI - [Composition and antitumor activities of essential oil from the fruits of Dasymaschalon trichophorum]. AB - OBJECTIVE: To study the chemical components and antitumor activities of essential oil from the fruits of Dasymaschalon trichophorum. METHODS: The essential oil from the fruits of Dasymaschalon trichophorum was extracted by steam-stilling and analyzed by GC-MS. The inhibitory effect of extract of Dasymaschalon trichophorum on SPCA-1,BEL-7402, SGC-7901 and K-562 cell proliferation was assayed using the MTU. RESULTS: GC-MS result showed that there were 55 peaks and 30 compounds were identified which weighed 74.98%. The major components were nerolidol (19.887%), caryophyllene (16.714%) and beta-myrcene (9.29%). The essential oil exhibited strong antitumor activity against SPCA-1 human tumor cell line with IC50 value of 6.61 microg/mL. CONCLUSION: This experiment provides scientific foundation for further utilization of Dasymaschalon trichophorum. PMID- 24956820 TI - [Study on the chemical constituents from the roots of Ligularia dentata in Henan]. AB - OBJECTIVE: To study the chemical constituents from the roots of Ligularia dentata in Henna. METHODS: Chemical constituents from the roots of Ligularia dentata in Henan were isolated and purified by silica gel, Sephadex LH-20 column chromatography and solvent crystallization and their structures were identified by spectral methods. RESULTS: Four eremophilane-type sesquiterpenoids were obtained and determined as 3-oxo-8alpha-hydroxy-10alphaH-eremophilan-1,7-dien-8, 12beta-olide(1), 3-oxo-eremophil-1, 7-dien-8, 12beta-olide (2),3-oxo-8alpha ethoxy-10alphaH-eremophil-1,7-dien-8,12-olide(3) and furanoligularenone(4). CONCLUSION: Compound 1-4 are isolated from this plant for the first time and their contents in the roots are high by HPLC analysis except for compound 3. Compound 3 is hardly detected in the fresh EtOH extract and might be derived from other compounds during the extraction. PMID- 24956821 TI - [Study on chemical constituents of Zanthoxyli cortex's ethyl acetate extract]. AB - OBJECTIVE: To study the chemical constituents of Zanthoxyli Cortex. METHODS: The chemical constituents were isolated and purified by silica gel and HP-20, MCI gel, Sephadex LH -20 column chromatography, RP-18 and PTLC. Their structures were elucidated by the analysis of spectral data and chemical properties. RESULTS: Ten compounds were isolated from EtOAc extract and their structures were identified as: asarinin (I), fargesin (II), eudesmin (III), (1R, 2R, 5R, 6S)-2-(3,4 dimethoxyphenyl)-6-(3,4-dihydroxyphenyl)-3,7-dioxabicyclo[3.3.0]-octane(IV), dimethoxysamin(V), rel-(1R,5R,6S)-6-(3,4-dimethoxyphen-yl)-3,7-dioxabicyclo [3.3.0]-octan-2-one(VI), Magnone A(VII), beta-sitoste-rol( VIII), beta armyrin(IX), beta-amyrone(X). CONCLUSION: These compounds isolated from Zanthoxyli Cortex's Ethyl acetate extract are all known compounds. Fargesin(II) and beta-amyrone(X) are isolated from Zanthoxyli Cortex for the first time. PMID- 24956822 TI - [Chemical constituents from the aerial part of Stauntonia obovatifoliola Hayata subsp. urophylla]. AB - OBJECTIVE: To study the chemical constituents of the aerial part of Stauntonia obovatifoliola. METHODS: The chemical constituents of ethyl acetate fraction were isolated and purified by several chromatography. Their structures were elucidated by their physiochemical properties and spectral methods. RESULTS: Six known compounds were isolated and identified as lupeone(1), lupeol(2), stigmasterol(3),3beta-O-acetyloleanolic acid(4), resinone(5) and daucosterol(6). CONCLUSION: Compounds 1-6 are isolated from this plant for the first time. PMID- 24956823 TI - [Effects of heishunpian total alkaloids on Cassia acutifolia induced mice diarrhea and contraction of isolated intestinal smooth muscle in rats]. AB - OBJECTIVE: To observe the effects of Heishunpian total alkaloids on Cassia acutifolia induced mice diarrhea and contraction of isolated intestinal smooth muscle in rats. METHODS: The experiment was carried out with Cassia acutifolia induced mice diarrhea model, small intestinal propulsive rate in mice was used to valuate the effect of Heishunpian total alkaloids on diarrhea mice; The effects of Heishunpian total alkaloids on contraction of isolated intestinal smooth muscle in rats and its mechanism were investigated by monitoring amplitude and tension of isolated intestinal smooth muscle in rats; The chemical constituents of Heishunpian total alkaloids were analyzed by HPLC. RESULTS: Heishunpian total alkaloids could significantly slow down intestine propulsive motility in diarrhea mice (P < 0. 05), and reduce amplitude and tension of isolated small intestinal smooth muscle contraction in normal rats in dose-dependent manner. Heishunpian total alkaloids had a certain inhibitory effect on acetylcholine chloride and neostigmine methylsulfate strengthening small intestine smooth muscle movement, however, had no significantly effect on Atropine sulfate inhibiting small intestine smooth muscle movement. By HPLC analysis, benzoylaconitine, benzoylmesaconitine, benzoylhypaconitine were the main chemical constituents of Heishunpian total alkaloids. CONCLUSION: Heishunpian total alkaloids have a certain role of antidiarrheal and its mechanism may be related to antagonizing muscarinic receptors. PMID- 24956824 TI - [Effects of astragalosides on PC12 cells injury and APP expression induced by dexamethasone and Abeta(25-35)]. AB - OBJECTIVE: To study the effects of Astragaloside (AST) on PC12 cells injury and APP expression induced by dexamethasone (DEX) and beta-amyloid protein 25-35 (Abeta(25-35). METHODS: Logarithmic growth phase of the PC12 cells were seeded in culture plates. DEX 5 micromol/L and Abeta(25-35) 1 micromol/L were used to induce PC12 cells injury. MTT assay was used to detect the PC12 cells activity. RT-PCR was used to detect the APP, alpha-secretase and beta-secretase mRNA level of PC12 cells. Western bloting was used to detect APP protein expression of PC12 cells. RESULTS: MTT results showed that, DEX and Abeta(35-35) co-application could significantly decrease PC12 cells activity (P5 < 0.01). AST (10.20 mg/L) and Ginsenoside Rg1 (16 micromol/L) could increase PC12 cells activity. RT-PCR analysis showed that DEX and Abeta(25-35) co-application could significantly increase the beta-secretase mRNA levels and APP770, lower alpha-secretase mRNA levels. AST (10.20 mg/L) and Rg1 could decrease the elevated APP770, beta secretase mRNA levels and increase the alpha-secretase mRNA level of PCl2 cells. Western bloting analysis result showed that AST (10.20 mg/L) and Rg1 could decrease the APP expression of PC12 cells induced by DEX and Abeta(25-35). CONCLUSION: AST has protective effects on PC12 cell injury induced by DEX and Abeta(25-35). The mechanism may be associated with decreasing the beta-secretase mRNA levels and APP expression, increasing the alpha-secretase mRNA levels. PMID- 24956825 TI - [Effect and mechanism of polyphyllin I on human cervical cancer cell HeLa in vitro]. AB - OBJECTIVE: To study the effect and mechanism of polyphyllin I on human cervical cancer cell HeLa. METHODS: The cell growth and proliferation effect of Polyphyllin I on HeLa cells were measured by MTT assay; Hoechst 33258 fluorescent staining was used to record changes in cell morphology and morphological changes in mitochondria of Polyphyllin I before and after treatment on He La cells. Annexin V-FITC/PI staining was used to detect the ratio of tumor cell apoptosis by flow cytometry. Release of intracellular re active oxygen species (ROS) generation level in HeLa cells was determined by flow cytometry,Caspase-3 activity was measured by fluorescent assay kits. RESULTS: MTT results showed that Polyphyllin I could significantly suppressed the proliferation of HeLa cells and in time-and concentration-dependence manner. The intracellular ROS levels were increased dramatically and the mitochondrial membrane was decreased consistently. Caspase-3 proteins expression levels were increased after Polyphyllin I treatment. CONCLUSION: Polyphyllin I could inhibit HeLa cells growth and proliferation and its mechanism may be related to inducing cell apoptosis. PMID- 24956826 TI - [Effects of polysaccharides from Bletillae Rhizoma on the protection in rats during deep second-degree burn wound healing]. AB - OBJECTIVE: To study the effects of polysaccharides from Bletillae Rhizoma (RBP) on the protection in rats during deep second-degree burn wound healing. METHODS: Thirty SD rats were randomly divided into blank control group, model control group and RBP group. After the establishment of rat deep second-degree burn wound, the wound was observed everyday and was recorded the healing time to calculate healing rate. Venous blood was collected at, 3, 7, 14, 21 and 28 d from burn rats via vena caudalis. Tachypleus RBP a cyte lysate (TAL) was used to assay the content of LPS in the plasma. Enzyme linked immunosorbent assay (ELISA) was employed to determine the levels of related proinflammatory cytokines such as TNF alpha and IL-6 in the serum. Flow cytometry (FCM) was used to measure the positive percent of TLR4 in the peripheral blood at different time points. RESULTS: Compared with model control group, RBP could significantly shorten the healing time (P < 0.01), decreased LPS, TNF-alpha and IL-6 levels in the serum at 7 d after burn (P < 0.01 or P < 0.05). FCM results suggested that RBP obviously decreased the positive percent of TLR4 in the peripheral blood of burn rats at 7 d after burn (P < 0.01 or P < 0.05). CONCLUSION: BSP can promote burn wound healing,which might be associated with reduction the levels of LPS, TLR4 and related proinflammatory cytokines. PMID- 24956827 TI - [Effects of total flavones of Chrysanthemum indicum on proliferation and apoptosis of human osteosarcoma Saos-2 cells]. AB - OBJECTIVE: To study the effects of total flavones of Chrysanthemum indicum on proliferation and apoptosis of human osteosarcoma Saos-2 cells and its mechanism. METHODS: The effect of the total flavones of Chrysanthemum indicum on the proliferation of human osteosarcoma Saos-2 cells was detected by CCK assay, and the morphological changes of cells treated with total flavones of Chrysanthemum indicum were observed using contrast microscope. Flow cytomerty was performed to analyze the apoptotic rate of the cells, and the gene expression levels of Caspase-3, BCL-2, BAX were detected by RT-PCR. RESULTS: The total flavones of Chrysanthemum indicum suppressed the proliferation of osteosarcoma cells in a dose-and time-dependent manner. Under a microscope observation of cell morphology, the volume became smaller ,the number of internal particles was increased. Cell apoptosis rate was positively related to the drug concentration. After treated for 48 hours, Caspase-3 and BAX expression were up-regulated, BCL-2 and BCL-2/BAX were decreased. CONCLUSION: The total flavones of Chrysanthemum indicum can inhibit the proliferation of osteosarcoma cell line Saos-2 by inducing cell apoptosis,the mechanism of which might be related with reducing BCL 2/BAX and activating Caspase-3. PMID- 24956828 TI - [Optimation the extracting technology of Angelica sinensis by central composite design and response surface methodology]. AB - OBJECTIVE: To optimize the extracting technology from Angelica sinensis by central composite design-response surface methodology. METHODS: On the basis of the single factor,independent variables were ethanol concentrations, solvent ratio and ultrasonic time, while dependent variable was the OD value of extraction rates of ferulic acid and liqustilide. A two-order polynomial equation was fitted to estimate the relationship between independent and dependent variables. Response surface method was used to optimize the extracting process. RESULTS: The optimum extraction conditions for Angelica sinesis were obtained as follows: the extracting solvent was methanol concentrations of 70%, 30 fold solvent, extracting for once and for 40 minutes. The deviation between observed and predicted values was 1.23%. CONCLUSION: The result indicates that the central composite design and response surface methodology is simple, convenient and reliable for optimizing the extraction process of Angelica sinesis with higher precision. PMID- 24956829 TI - [Optimization extraction conditions of triphyllin A in Pronephrium triphyllum]. AB - OBJECTIVE: To optimize the extraction conditions for triphyllin A in Pronephrium triphyllum. METHODS: The content of triphyllin A in the Pronephrium triphyllum was determined by HPLC. Concentration and volume of the alcohol,time and times of the extraction were assayed by orthogonal test to detect their influences on the extraction rate of triphyllin A in the Pronephrium triphyllum. RESULTS: Alcohol volume and extraction times had significant influence on the process (P < 0.05) while alcohol concentration and extraction time had no effect. The optimal extraction conditions were as follows:50 fold 60% alcohol, extraction for 3 times and 50 min for each time. CONCLUSION: The extration rate of triphyllin A is higher,and the process can be used for the development and production of Pronephrium triphyllum. PMID- 24956831 TI - [Progress in regulation effect of aromatic refreshing traditional Chinese medicine on BBB permeability and its mechanism]. AB - The blood-brain barrier (BBB) protects the brain against unwanted substances, while, at the same time, limits the transport of many drugs into the brain. Aromatic refreshing traditional Chinese medicine (TCM) can induce resuscitation and modify the permeability of BBB, promoting other drugs entering into the brain with brain protection effect. This paper mainly reviews the research progress in regulation effects and mechanism of usual aromatic refreshing TCM, such as borneol, moschus, styrax, benzoinum and Tatarinow Sweetflag Rhizome, on BBB permeability. To broaden the application of these drugs in modern pharmaceutics in the future, the relatively research should emphasis on combining aromatic refreshing TCM with new formulations and technologies in pharmaceutics, providing novel promising strategies for brain diseases therapy. PMID- 24956830 TI - [Quantitative analysis of six flavonoids of hongzhu capsule by QAMS]. AB - OBJECTIVE: To establish a method of quality assurance for mass-screening (QAMS) for simultaneously determining six flavonoids in Hongzhu Capsules. METHODS: An HPLC (high performance liquid chromatography) method was developed as QAMS to determine neoeriocitrin, prunin, naringin, rhoifolin, miliditin and naringenin in Hongzhu Capsules. Using naringin as the internal reference substance, relative correction factors (RCF) of the five flavonoids were determined and given as follows (1.05, 0.782, 1.89, 1.27, 0.532). The contents of the flavonoids in Hongzhu Capsules were determined by QAMS and validated by the external standard method. RESULTS: RCF values were determined by HPLC with good reproducibility. No significant difference between the quantitative results of QAMS and external standard method was observed. CONCLUSION: The present-developed method is convenient and accurate to determine multiple components when some standard substances are unavailable, thus considered as a potential method for quality control of Hongzhu Capsules. PMID- 24956832 TI - [Effects of different transplanting conditions on survival rate and growing status of Anoictochilus roxburghii plantlets]. AB - The growing status of Anoectochilus roxburghii seedling was observed and the survival rate of seedlings, height, stem diameter and plant fresh weight under the conditions of different transplanting substrate compositions, planting density, shading rate were measured. The results showed that the effects of different transplanting substrates, planting densities, shading rates and nutrient solutions on the growing status of A. roxburghii plantlets varied greatly. A. roxburghii plantlets demonstrated a high survival rate and better growing status under the Following conditions: the ratio of peat and river sand as 2: 1, the planting density as 3 cm x 3 cm, the shading rate as 70%, and the nutrient solution as 1/4MS. The findings of the study provide a solid technical solution for the artificial cultivation of A. roxburghii plantlets. PMID- 24956833 TI - [AFLP analysis on genetic diversity of Haloxylon ammodendron in China]. AB - To determine the genetic diversity of Haloxylon ammodendron collected from 14 sites in 5 provinces, 103 H. ammodendron samples of 12 wild populations and 2 cultivated which collected from 14 sites in 5 provinces were analyzed by amplified fragment length polymorphism (AFLP) DNA markers. PopGen32 and NTSYSpc2.1 was applied to evaluate genetic diversity of H. ammodendron populations. The average percentage of polymorphic loci (PPL) of total H. ammodendron populations was 94.13%, the average Nei's gene diversity index (H(e)) from 14 populations was 0.308 0, and the Shannon's genetic diversity index (I) was 0.467 6. The results indicated that the genetic diversity of H. ammodendron populations was high. Genetic differentiation index (G(st)) was 0.313 8, and the gene flow (N(m)) was 1.093 5 at the population level. The level of gene flow of H. ammodendron showed it possessed the feature of wind-pollinated outcrossing plants. AMOVA analysis indicated that genetic variation of H. ammodendron was much higher within groups (89.34%) than that among groups (10.66%), moreover genetic variation within groups mainly occurred among populations in different producing areas (84.80%). Cluster analysis (UPGMA) was applied to generate dendrogram based on Nei's genetic distances of 14 populations. Samples from Xinjiang and Qinghai were clustered respectively as a clade for their distant genetic relationship, while Samples from Gansu, Inner Mongolia and Ningxia were clustered together for their close genetic relationship. Genetic diversity of H. ammodendron populations is high in China, and genetic differentiation among regions is small, thus abundance within this specie is high at this stage. Therefore, wild nursery and artificial cultivating in different areas are effective measures for the conservation and sustainable utilization of H. ammodendron resources. PMID- 24956834 TI - [Identification and antibacterial effect research of a Tolypocladium strain isolated from sclerotium of Ophiocordyceps gracilis in Xinjiang]. AB - OBJECTIVE: To promote development and utilization of Ophiocordyceps gracilis in xinjiang and provide basic data for researching and sustainable developing medicine fungus related to O. gracilis. METHOD: A white strain SFYT002 isolated from the sclerotium of O. gracilis in Xinjiang was researched by morphological observation, ITS and 18SrDNA sequencing. The ITS and 18SrDNA sequences of the strain were determined, BLAST was compared with the other sequences of Tolypocladium in GenBank. The phylogenetic trees of ITS and 18SrDNA sequences were analyzed in Tolypocladium. In addition, the filter paper method was used to study the antibacterial effects. RESULT: The main morphological characters of this strain were white cotton-like colonies, phialide with inflated base, drastically sharping with partially bending tips, small and transparent budding spores with being always assemble to spearhead and globular, subglobular or ellipse conidiospores. The phylogenetic trees of ITS and 18SrDNA sequences were constructed and analyzed in Tolypocladium. It was resulted that Tolypocladium was confirmed to be monophyletic, and the strain SFYT002 was the same as the systematic position of others of T. inflatum. Meanwhile, the antibacterial test was performed against the 4 common pathogenic bacteria. It was showed that both fermentation and its extracts of different polar from this strain possessed good anti-bacteria capacities. CONCLUSION: The strain SFYT02 was identified as T. inflatum, and inhibited effectively growth of bacteria. PMID- 24956835 TI - [Cloning and gene expression of acetyl-CoA C-acetyl transferase gene (AsAACT) from Aquilaria sinensis]. AB - OBJECTIVE: This study aimed to clone the acetyl-CoA C-acetyl transferase (AACT) gene from Aquilaria sinensis and analyze the bioinformatics and expression of the gene. METHOD: One unique sequence containing partly AACT gene sequence was discovered in our previous transcriptome dataset of A. sinensis. AACT gene was cloned by RT-PCR and RACE strategy with the template of RNA extracted from A. sinensis stem. The bioinformatic analysis of this gene and its corresponding protein was performed. The AsAACT expression in calli was analyzed with GADPH gene as an internal control gene in wounded condition by qRT-PCR technique. RESULT: One unique sequence of AACT, named as AsAACT, was cloned from A. sinensis. The full length of AsAACT cDNA was containing a 1 236 bp ORF that encoded 411 amino acids. The result of qRT-PCR displayed that the highest expression level was at 4 h. which indicated that it was possibly involved in early-stage response to wound. CONCLUSION: Cloning and analyzing AsAACT gene from A. sinensis provided basic information for study the function and expression regulation of AsAACT in terpenoid biosynthesis. PMID- 24956836 TI - [Impact of storage conditions and time on herb of Lonicera macranthoides]. AB - To study the effect of different storage conditions and storage time on herb quality of Lonicera macranthoides, different packaging materials including vacuum plastic bags, plastic bags, woven bags, sealed with endometrial bags, paper bags, sack bags were selected for the study under different storage conditions including room temperature, 5 degrees C refrigerator, low temperature of - 20 degrees C refrigerator and desiccator. Twenty-four batches of samples were used for the study, and active ingredients were determined. The experimental results showed that the ingredients in each storage group changed with the storage time, storage conditions (storage environment, packaging). Under the same storage time, the storage environment (temperature, humidity) had effect on the stability of herb quality. Low temperature had less effect on herb quality. The effect of packaging on herb quality was as following: plastic vacuum packaging > woven with endometrial sealed packaging > plastic bag > woven bag > sack bags > paper bags. Under the same storage conditions, with the increase of storage time, caffeic acid content increased slowly, and other five ingredients content decreased gradually. Storage time affected significantly on the intrinsic quality (chemical composition) and appearance of herb. It is suggested that low temperature (5 degrees C), dark and sealed storage are suitable for storage of L. macranthoides herb, the storage time should be not more than 24 months. PMID- 24956837 TI - [Studies on hydroxyapatite applicatied in coprecipitate of total salvianolic acids phospholipid complex]. AB - The purpose of this research was to prepare total salvianolic acids-phytosome-HA coprecipitate to improve drug dissolution and its micromeritic properties. Firstly, the coprecipitate was prepared by solvent method and in vitro dissolution of tripterine was performed with the salvianolic acid B and danshensu as criteria. At the same time, the micromeritic properties was characterizated, the structure of samples was characterized by TEM, DSC, XRD and FTIR. Results showed that when the ratio of drug to HA was 1:2, it had a better dissolution, the accumulative drug-release percent in vitro at 60 min was over 90%. At the same time, it has good liquidity and low moisture absorption. Its micromeritic properties have improved. It is proved that the drug still existed amorphously by microstructure analysis. The preparation process is simple and feasible, it has practical value. PMID- 24956838 TI - [Preparation of novel gypenosides long-circulating liposomes consisted by sphingomyelin and beta-sitosterol modified by PEG]. AB - OBJECTIVE: To explore the feasibility of preparing novel gypenosides long circulating liposomes with PEG grafted on beta-sitosterol (PEG-Sito). METHOD: Succinicanhydride was adopted to connect beta-sitosterol and PEG 2000. Sphingomyelin and PEG-Sito was used as material to prepare gypenosides long circulating liposomes by using ethanol injection method. Encapsulation efficiency was determined by using protamine precipitation method. H-NMR was used to verify the synthesis of PEG-Sito, the novel gypenosides long-circulating liposomes were characterized by particle size, zeta potential and atomic force microscope. RESULT: The synthesis of PEG-Sito was verified by 1H-NMR. Encapsulation efficiency of long-circulating liposomes prepared by ethanol injection method was 74.3%, particle size was 288.1 nm, zeta potential was -20.25 mV, the morphology were round observed by AFM. CONCLUSION: The novel gypenosides long-circulating liposomes prepared with PEG-Sito was feasible, it had a high encapsulation efficiency and good morphology. PMID- 24956839 TI - [Study on preparation of ginkgolides component solid dispersions micro pill drug release unit]. AB - Microcrystalline cellulose and chitosan were applied to prepare ginkgolides component solid dispersions micro pill drug release unit and study the dissolution of GKS. Microcrystalline cellulose, chitosan as composite carrier, solvent method was used to prepare ginkgolides component solid dispersions. Differential scanning calorimetry was used to Characterization of ginkgolides component solid dispersions. Ginkgolides component solid dispersions as principle agent were prepared for micro-pellet. Comparison of different types, different doses of the adhesive, drug-polymer interactions, and disintegrating agent for the preparation of ginkgolides components of micro-pellet drug release unit, the optimum preparation ginkgolides components of micro-pellet drug release unit was screened by orthogonal design experiment. Preparation of ginkgolides components solid dispersions with microcrystalline cellulose and chitosan at ratio 1: 3. Drug cumulative dissolution was more than 80% in 60 min. Solid dispersion-micro pellet drug release unit can significantly improve the dissolution of ginkgolides components, it has practical application value. PMID- 24956840 TI - [Study on preparation process and formulation optimization of herpetin liposomes]. AB - Herpetin (HPT) is an active monomer constituent isolated from lignanoid in seeds of Herpetospermum caudigerum. HPT shows inhibitory effects in hepatic injury and HBV-DNA and the replication. In the study, we successfully prepare herpetin liposomes by film dispersion method for the first time. The prescription process was optimized, with the entrapment efficiency as the index. According to the optimized prescription, the mass ratio of HPT: phospholipids: cholesterol was 2.44:78.05: 19.51, the hydration and de-molding process was performed with 0.5% F68 solution at 50 degrees C, and the water-bath ultrasonic time was 20 min. The HPT liposomes prepared by this method showed an average entrapment efficiency of (94.50 +/- 2.15)% and a particle size of (119.2 +/- 10.7) nm, which was consistent with the trial expectations and will lay a solid foundation for the hepatic targeting delivery system in future. PMID- 24956841 TI - [Study on decoction's effect of different processed rhizomes of Cibotium barometz on retinoic acid induced male rats osteoporosis]. AB - This study compared the decoction's HPLC figures of the different processed rhizomes of Cibotium barometz including the raw, the sand-baked, the wined, the steamed and the salted, on the basis of which, with the sand-baked Drynaria fortunei decoction as the positive control group, comparingall groups' decoction, concentration of which was 104.2 g x L(-1), for 4 weeks, by their effects (s-TRAP and total scores of OPG, Ca, P, IL-6, TNF-alpha and IL-1) on retinoic acid induced male rats osteoporosis. The experiment results showed the sand-baked and the wined were better than the steamed, the salted and the raw;in the processing methods' selection, the sand-baked was a better heating method than the steamed and the rice wine was the better excipient than the salt. It provided a reference to explain the processing principle of rhizomes of C. barometz and work mechanism of anti-osteoporosis. PMID- 24956842 TI - [Determination of five components in rongxin pills by HPLC]. AB - To establish a method for determination contents of schizandrin, tanshinone I, cryptotanshinone, tanshinone II (A) and schizandrin B in rongxin pills. The HPLC method was performed on an Agilent C18. The mobile phase was composed of methnol and water wish gradient elution. The flow rate was 1.0 mL x min(-1). The column temperature was 30 degrees C and the detection wavelength wash 240 nm. The linear of schizandrin, tanshinone I, cryptotanshinone, Tanshinone II (A) and schizandrin B were 3.000-48.00 (r = 1.000), 3.985-63.76 (r = 0.999 9), 6.370-101.9 (r = 1.000), 8.690-139.0 (r = 0.999 9), 1.700-27.20 mg x L(-1) (r = 0.999 9), respectively. The average recoveries were 98.44%, 100.3%, 99.29%, 99.07%, 98.42%, and RSDs were 0.61%, 1.1%, 0.52%, 0.72%, 0.97%. The method is convenient, accurate and has good precision. It can be used for determination of the preparation. PMID- 24956843 TI - Hernsubanine E, a new hasubanan alkaloid from Stephania hernandifolia. AB - A new hasubanan alkaloid, hernsubanine E (1), as well as two known compounds p hydroxybenzaldehyde (2) and (-)-syringaresinol (3) have been isolated from the whole plants of Stephania hernandifolia by various column chromatographic methods. Their structures were identified by physicochemical properties and spectral analyses. Compounds 2 and 3 were isolated from the genus of Stephania for the first time. PMID- 24956844 TI - [Chemical constituents of leaves of Psidium guajava]. AB - To study the chemical constituents of the 95% ethanol extract of Psidium guajava. Compounds were separated by using a combination of various chromatographic methods including silica gel, D101 macroporous resin, ODS, Sephadex LH-20 and preparative HPLC. Their structures were elucidated by physicochemical properties and spectral data Eighteen compounds were isolated and identified as (+) globulol (1), clovane-2beta, 9alpha-diol (2), 2beta-acetoxyclovan-9alpha-ol (3), (+) -caryolane-1 ,9beta-diol (4), ent-T-muurolol (5), clov-2-ene-9alpha-ol (6), isophytol (7), tamarixetin (8), gossypetin (9), quercetin (10), kaempferol (11), guajaverin (12), avicularin (13), chrysin 6-C-glucoside (14), 3'-O-methyl-3, 4 methylenedioxyellagic acid 4'-O-beta-D-glucopyranoside (15), p-hydroxy-benzoic acid (16), guavinoside A (17) and guavinoside B (18). Compounds 2-9 and 14-16 were isolated from this plant for the first time. The ethanol extract showed 61.3% inhibition against the proliferation of colon cancer cell line SW480. PMID- 24956845 TI - [Chemical constituents of Poria cocos]. AB - The chemical constituents of Poria cocos were studied by means of silica gel, ODS column chromatography, Sephadex LH-20 and preparative HPLC. Thirteen compounds were isolated from this plant. By analysis of the ESI-MS and NMR data, the structures of these compounds were determined as tumulosic acid (1), dehydrotumulosic acid (2), 3beta, 5alpha-dihydroxy-ergosta-7, 22-dien-6-one (3), 3beta, 5alpha, 9alpha-trihydroxy-ergosta-7, 22-diene -6-one (4), ergosta-7, 22 diene-3-one (5), 6, 9-epoxy-ergosta-7,22-diene-3-ol (6), ergosta-4,22-diene-3-one (7), 3beta, 5alpha, 6beta-trihydroxyl-ergosta-7,22-diene (8), ergosta-5, 6-epoxy 7,22-dien-3-ol (9), beta-sitosterol (10), ribitol (11), mannitol (12), and oleanic acid 3-O-acetate (13), respectively. Compounds 3-13 were isolated from the P. cocos for the first time. PMID- 24956846 TI - [Chemical constituents from Ganoderma philippii]. AB - The chemical investigation on Ganoderma philippii led to the isolation of sixteen compounds by silica gel and Sephadex LH-20 column chromatography. On the basis of spectroscopic data analyses, their structures were elucidated as 2, 5 dihydroxyacetophenone (1), methyl gentisate (2), (S) -dimethyl malate (3), muurola-4, 10 (14) -dien-11beta-ol (4), dihydroepicubenol (5), 5 hydroxymethylfuran carboxaldehyde (6), ergosta-7, 22E-dien-3beta-ol (7), ergosta 7, 22E-dien-3-one (8), ergosta-7, 22E-diene-2beta, 3alpha, 9alpha-triol (9), 6/beta-methoxyergo-sta-7, 22E-dien-3beta, 5alpha-diol (10), ergosta-4, 6, 8(14), 22E-tetraen-3-one (11), ergosta4, 6, 8-(14), 22E-etetraen-3beta-ol (12), 5alpha, 8alpha-epidioxy-ergosta-6, 22E-dien-3beta-ol (13), 7alpha-methoxy-5alpha, 6alpha epoxyergosta-8-(14), 22E-dien-3beta-ol (14), ergosta-8, 22E-diene-3beta, 5alpha, 6beta, 7alpha-tetraol (15), and ergosta-5, 23-dien-3beta-ol, acetate (16). All the compounds were obtained from this fungus for the first time, and compounds 4 and 5 were isolated from the Ganoderma genus for the first time. PMID- 24956847 TI - [Chemical constituents from roots of Chirita longgangensis var. hongyao]. AB - To study the chemical constituents from the roots of Chirita longgangensis var. hongyao. The methanol extract was isolated and purified by silica gel, Sephadex LH-20 and preparative HPLC. Their structures were elucidated by MS and spectral data (1H, 13C-NMR). Seven compounds were isolated and identified as plantainoside A (1), plantainoside B (2), calcedarioside C (3), calcedarioside D (4), platyphylloside (5), hirsutanonol (6), and hirsutanonol-5-O-beta-D glucopyranoside (7). Compounds 5-7 were isolated for the first time from the family Gesneriaceae. PMID- 24956848 TI - [Rapid quantification of total nitrogen and end-point determination of hide melting in manufacturing of donkey-hide gelatin]. AB - Hide melting presents itself as one of the most critical processes in the production of donkey-hide gelatin. Here a NIR-based method was established for the rapid analysis of in-process hide melting solutions as well as for end-point determination of this process. Near infrared (NIR) spectra of hide melting solutions were collected in transflective mode. With the contents of total nitrogen determined by the Kjeldahl method as reference values, partial least squares regression (PLSR) was employed to build calibration models between NIR spectra and total nitrogen. Model parameters including wavelength range and PLS factors were optimized to achieve best model performance. Based on the contents of total nitrogen predicted by calibration model, end point of hide melting was determined. The constructed PLS model gave a high correlation coefficient (R2) of 0.991 3 and a root mean square error of prediction (RMSEP) of 0.807 g x L(-1). With the predicted total nitrogen and predefined limit, decisions concerning the proper times of melting were made. This research demonstrated that NIR transflectance spectroscopy could be used to expeditiously determine the contents of total nitrogen which was subsequently chosen as the indictor for determining the end-point of hide melting. The proposed procedure may help avoid unnecessary raw material or energy consumption. PMID- 24956849 TI - [Study on composition of essential oil in above-ground and root of Bupleurum malconense and root of B. chinense by AMDIS and retention index]. AB - Chemical constituents of the essential oil in above-ground and root of Bupleurum malconense and root of B. chinense were investigated by GC-MS compiled with automated mass spectral deconvolution and identification system (AMDIS) and retention index. The results showd that the components of essential oil in B. malconense have some similarities with the one in B. chinense, and both of them have the higher content of caryophyllene oxide which is an active component of anti-inflammatory and analgesic. These results suggested that as a local substitute, B. malconense has a certain scientific basis of the treatment for cold fever. PMID- 24956850 TI - [Determination of skimmin, scopolin and umbelliferone in Tibetan medicine Saussurea hieracioides by HPLC]. AB - This study is aimed to establish a high-performance liquid chromatography (HPLC) method for simultaneous determination of skimmin, scopolin and umbelliferone in Saussurea hieracioides. Samples were analyzed on a Wondasil C18-WR column (4.6 mm x 250 mm, 5 microm) with methanol (A) and water containing 0.1% phosphate (B) as mobile phases for gradient elution at a flow rate of 1.0 mL x min(-1). The detection wavelength and column temperature were set at 325 nm and 35 degrees C, respectively, and the sample size was 10 microL. The results showed that skimmin, scopolin and umbelliferone were simultaneously achieved within 40 min under the above conditions. A good linearity was observed in the range of 0.18-5.6 microg (r = 1.000 0), 0.060-1.8 microg (r = 0.999 9), 0.032-0.97 microg (r = 0.999 8) for skimmin, scopolin and umbelliferone, respectively, with the average recoveries of 99.16% (RSD = 0.41%), 100.3% (RSD = 0.79%), 102.2% (RSD = 0.87%). The method is simple, accurate and reproducible and can be used for the quality control of S. hieracioides. PMID- 24956851 TI - [Effect of paeonol on adhesive function of rat vascular endothelial cells induced by lipopolysaccharide and co-cultured with smooth muscle cells]. AB - OBJECTIVE: To observe the changes in the adhesive function of vascular endothelial cells (VEC) and rat monocytes induced by lipopolysaccharide (LPS) and co-cultured with smooth muscle cells (SMC) and the intervention effect of paeonol (Pae). METHOD: Primary rat vascular endothelial cells (VECs) and rat vascular smooth muscle cells (VSMCs) were cultured by predigesting and adhering tissue blocks. The VEC-VSMC co-culture model was established by Transwell chamber. LPS was used to induce VEC injury. MTT assay and LDH assay were used to determine the VEC activity. ELISA assay was used to detect IL-1beta and TNF-alpha secreted by the VEC. The immunocytochemistry assay was carried out to detect the expression of ICAM-1. The Rose Bengal Staining was used to test adhesive function between VECs and monocytes. RESULT: The concentration of LPS-induced VEC injury was 100 microg x L(-1), and the time was 7 h. after the intervention on the above cell model for 24 h, Paeonol (15, 30, 60 micromol x L(-1)) could effectively inhibit LPS-induced VEC injury and VEC injury, significantly enhance the survival rate of LPS-injured VECs, decrease IL-1beta and TNF-alpha secreted by the injured VEC, and reduce the expression of ICAM-1, so as to inhibit the adhesion of LPS-induced VECs and monocytes. CONCLUSION: Paeonol could inhibit IL-1beta and TNF-alpha expression to protect VECs from being injured by LPS, and reduce ICAM-1 expression to inhibit the adhesion between VECs and monocytes. PMID- 24956852 TI - [Effect of ginsenoside Rb1 on insulin signal transduction pathway in hippocampal neurons of high-glucose-fed rats]. AB - OBJECTIVE: To study the effect of ginsenoside Rb1 on GSKbeta/IDE signal transduction pathway and Abeta protein secretion in hippocampal neurons of high glucose-treated rats. METHOD: Hippocampal neurons of 24 h-old newly born SD rats were primarily cultured, inoculated in culture medium under different conditions, and then divided into the normal group, the high glucose group, the LiCl group and the Rb1 group. After being cultured for 72 h, the expressions of their phosphorylated GSK3beta, total GSK3beta and IDE protein were detected by Western blotting analysis. The mRNA expressions of GSK3beta and IDE were determined by RT PCR. The ELISA assay was used to detect the secretion of Abeta protein in cell supernatant. RESULT: Compared with the normal group, the high glucose group showed increase in the p/tGSK3beta protein ratio and the secretion of Abeta protein and decrease in IDE protein and mRNA (P < 0.05). Compared with the high glucose group, both Rb1 and LiCl groups showed decrease in the p/tGSK3beta protein ratio and the expression of Abeta protein and increase in IDE protein and mRNA expression (P < 0.05). Compared with the LiCl group, the Rb1 group showed no significant difference in the expressions of p/tGSK3beta protein, IDE protein, mRNA and Abeta protein expression. In addition, the GSK3beta mRNA expression of the four groups had no significant difference. CONCLUSION: Ginsenoside Rb1 may reduce the secretion of Abeta protein in hippocampal neurons by reducing the phosphorylation of GSK3beta, down-regulating the ratio of pGSK3beta/GSK3beta and upregulating the expression of IDE. PMID- 24956853 TI - [Study on detoxication of euphorbia pekinensis radix processed with vinegar on rat small intestinal crypt epithelial cells IEC-6]. AB - OBJECTIVE: To compare the difference of Euphorbia Pekinensis Radix before and after being processed with vinegar in the toxicity on rat small intestinal crypt epithelial cells IEC-6, and make a preliminary study on the mechanism of detoxication of Euphorbia Pekinensis Radix processed with vinegar. METHOD: With rat small intestinal crypt epithelial cells IEC-6 as the study object, the MTT method was adopted to detect the effect of Euphorbia Pekinensis Radix before and after being processed with vinegar on IEC-6 cell activity. The morphology of cells were observed by the inverted microscope. The down-regulated mitochondrial apoptosis pathway of enterocytes caused by the vinegar processing was analyzed by using the high content screening. RESULT: Compared with the negative control group, the proliferation inhibition experiment showed that Euphorbia Pekinensis Radix showed a relatively high intestinal cell toxicity (P < 0.01). The results of HCS analysis showed that Euphorbia Pekinensis Radix could significantly reduce the cell nucleus Hoechst fluorescence intensity and mitochondria membrane (P < 0.05, P < 0.01), and increase Annexin V-FITC and PI fluorescence intensity and membrane permeability (P < 0.01, P < 0.01, P < 0.01). After being processed with vinegar, compared with Euphorbia Pekinensis Radix groups with different doses, Euphorbia Pekinensis Radix processed with vinegar could significantly decrease the cell proliferation inhibition effect on enterocytes, increase the cell nuclear Hoechst fluorescence intensity and mitochondria membrane (P < 0.05, P < 0.05), and decrease Annexin V-FITC and PI fluorescence intensity and membrane permeability (P < 0.01, P < 0.01, P < 0.05), and showed a certain dose-effect relationship. CONCLUSION: The vinegar processing can further reduce the toxicity of Euphorbia Pekinensis Radix on enterocytes. Its possible mechanism can decrease the effect of Euphorbia Pekinensis Radix on the permeability of IEC-6 cell membrane, so as to provide a basis for further explanation of the detoxication mechanism of Euphorbia Pekinensis Radix processed with vinegar. PMID- 24956854 TI - [Molecular action mechanism of desoxyrhaponticin and serum albumin characterized by spectroscopy combined with molecular modelling]. AB - OBJECTIVE: To study the molecular action mechanism of active constituents desoxyrhaponticin (DES) and human serum albumin (HSA). METHOD: Under the simulated physiological condition, computer analog technology, fluorescent spectrometry and ultraviolet spectrum were combined to study the binding mechanism between drug and protein. RESULT: Molecular modeling was adopted to establish the binding model between DES and HSA, suggesting that the interaction force maintaining drug and protein is mainly the hydrophobic interaction with a hydrogen-bond interaction. The results from spectroscopy indicated that the interaction between DES and HSA is a dynamic binding process with a high intensity. The value of the binding distance (r) between DES and HSA was low, which demonstrate the occurrence of energy transfer. DES made an impact on HSA' structural domain microcell conformation, which resulted in hydrophobic changes in binding areas. According to the fluorescent phase diagram technical analysis, the changes in the DES-HSA reaction conformational pattern showed a "two-state" model. According to the obtained thermodynamic parameters for the DES-HSA interaction, the interactional force between DES and HSA was mainly a hydrophobic interaction. The fluorescence polarization proved that a non-covalent compound was generated during the interaction between DES and HSA. CONCLUSION: The spectrum experiment showed consistent results with the computer analog technology, which could provided certain reference for studies on the interaction between DES and HSA. PMID- 24956855 TI - [Study on preventive and therapeutic effects of astragali radix on denervated tibial muscle atrophy in rats]. AB - OBJECTIVE: To study the effect of Astragali Radix on the denervated tibial muscle atrophy in rats, and discuss its mechanism. METHOD: Totally 60 SPF-grade Sprague Dawley rats were selected in the common peroneal nerve crush model, and then randomly divided into 6 groups: Astragali Radix high-dose, medium-dose, low-dose groups, the Mecobalamin group, the model group, and the sham operation group. They were administered with drugs after the operation. At 18 d, the pathological section staining and morphological analysis were performed. The wet-weight ratio and section area of tibial muscles were also measured. The real-time fluorescence quantification was adopted to detect the differential expression between Angptl4 and PI3K genes. RESULT: (1) Wet-weight ratio: The wet-weight ratio in Astragali Radix high-dose, medium-dose groups was much higher than that in the model group (P < 0.05 or P < 0.01). (2) Section area: The sham operation group was higher, with regular morphology; Whereas the model group showed significant decrease, with chaotic structure and obvious connective tissue proliferation; Astragali Radix groups and the mecobalamin group showed relatively small section areas, with chaotic structure and unobvious connective tissue proliferation. Compared with the model group, Astragali Radix groups showed significant increase (P < 0.01). (3) Motor end plate: The sham operation group was in uniform brownish black color and oval or round shape; Astragali Radix medium-dose and high-dose group and the mecobalamin group showed rough line edges; Astragali Radix medium dose and low-dose groups and the model group showed decline in the number, with irregular morphology, rough line edges and a light color. (4) Angptl4 and PI3K: Compared with the model group, the Astragali Radix high-dose group showed significant increase (P < 0.05). CONCLUSION: Astragali Radix has a significant effect in preventing and treating denervated tibial muscle atrophy. It may delay the muscle atrophy by increasing Angptl4 and PI3K gene expressions. PMID- 24956856 TI - [Protective effect of jiedu tongluo injection on cerebral edema in rats with lesion of cerebral ischemia/reperfusion]. AB - OBJECTIVE: To investigate the protective effects of Jiedu Tongluo injection on cerebral edema induced by focal lesion of cerebral ischemia/reperfusion, the hydrous content of brain and the expressions of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin and MMP-9 in rats. METHOD: The model of brain middle cerebral artery ischemia/reperfusion was established by the thread approach. After 24 hours of reperfusion, cerebral edema formation was determined by the hydrous content of brain. The permeability of blood brain barrier was evaluated based on the leakage of Evans blue. Enzyme linked immunoadsordent assay (ELISA)was used to examine the expression of ICAM-1, VCAM-1, E-selectin. The expression of MMP-9 was measured by immunohistochemistry. RESULT: JDTL, in the dose of 2 mL x kg(-1) and 4 mL x kg(-1), relieved cerebral edema (P < 0.05, P < 0.01), reduced the expressions of ICAM-1, VCAM-land E selectin and decreased MMP-9 activity (P < 0. 05, P < 0.01) in model rats. CONCLUSION: Jiedu Tongluo injection has a protective effect on rat brain from cerebral edema induced by the injury of focal cerebral ischemia/reperfusion. The mechanism is related to that Jiedu Tongluo injection can reduce the expressions of ICAM-1, VCAM-1 and E-selectin and inhibit of MMP-9 activation in rat brain. PMID- 24956857 TI - [Effect of sodium tanshinone II (A) sulfonate on Ang II -induced atrial fibroblast collagen synthesis and TGF-beta1 activation]. AB - OBJECTIVE: To observe the effect of sodium tanshinone II (A) sulfonate (STS) on Ang II -induced atrial fibroblast collagen synthesis and TGF-beta1 activation. METHOD: Atrial fibroblasts of neonatal rats were cultured to determine the content of collagen protein. The original synthesis rate determined by the [3H] proline incorporation method was taken as the index for myocardial fibrosis. The content of active TGF-beta1 and total TGF-beta1 in cell culture supernatants were tested and cultured by ELISA. The expression of thrombospondin-1 (TSP-1) was assessed by using Western blot. RESULT: Ang II could significantly increase the content of atrial fibroblast collagen and the collagen synthesis rate, the TSP-1 expression and the concentration of active TGF-beta1, without any obvious change in total TGF-beta1. After the STS treatment, all of the indexes, apart from total TGF-beta1, were obviously down-regulated. CONCLUSION: STS could decrease the secretion of Ang II -induced atrial fibroblast collagen and the synthesis rate. Its mechanism is related to the inhibition of TSP-1/TGF-beta1 pathway. PMID- 24956858 TI - [Research on HBV DNA inhibition of plasmid acute infection mouse with betulinic acid]. AB - Betulinic acid is a naturally occurring pentacyclic triterpenoid, which has antiretroviral, antimalarial, and anti-inflammatory properties. The purpose of this study is to investigate the HBV DNA replication inhibition in the mouse model with betulinic acid. Hydrodynamic injection method via the tail vein with the Paywl. 3 plasmid was used to establish the animal mode (n = 15), and the mice were randomly divided into the PBS control group (n = 5), Betulinic acid treatment group (n = 5) and lamivudine control group (n = 5). The day after successful modeling , the mice would have taken Betulinic acid (100 mg x kg(-1)), lamivudine (50 mg x kg(-1)), PBS drugs orally, once daily for 7 days, blood samples were acquired from the orbital venous blood at 3, 5, 7 days after the administering, HBsAg and HBeAg in serum concentration were measured by ELISA and the mice were sacrificed after 7 days, HBV DNA southern detections were used with part of mice livers. The results showed that betulinic acid significantly inhibited the expression of HbsAg in the mice model at the fifth day compared with the control group, and there was no significant differences between the effects of lamivudine and the PBS control group; both the betulinic acid and lamivudine groups had no significant inhibition for the HBeAg expression; the HBV DNA expressions of the liver tissue from the betulinic acid and lamivudine groups were inhibited compared with the control group. Taken together, these results reveal betulinic acid can inhibit the HBsAg expression and replication of the liver HBV DNA in the mouse model. PMID- 24956859 TI - [Pharmacokinetics and relative bioavailability of THC and THC-solid dispersion orally to mice at single dose]. AB - To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting (calculate on THC:400 mg x kg(-1)), used HPLC-MS/MS method to determine the THC concentration of each period at the following times: baseline ( predose ), 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 24 h after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 microg x L(-1) for THC (R2 = 0.999). The limit of detection (LOD) was 0.7 microg x L(-1), respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%. The intra day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions (RSD < 15%). The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. Pharmacokinetic parameters of THC and THC-solid dispersion orally to mice shows as fllows: T(max), were 60 and 15 min, AUC(0-t) were 44 500.43 and 57 497.81 mg x L(-1) x min, AUC(0-infinity) were 51 226.00 and 68 031.48 mg x L(-1) x min, MRT(0-infinity) were 596.915 6, 661.747 7 min, CL(z)/F were 0.007 809 and 0.005 88 L x min(-1) x kg(-1). Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the t(max) was significantly reduced, AUC(0-24 h), AUC(0-infinity) and C(max) were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative bioavailability of THC-solid dispersion show significant improvement compared to THC. PMID- 24956860 TI - [Comparation of gastrointestinal absorption studies of specnuezhenide with salidroside in rats]. AB - The experiment was designed to study the mechanism of increasing efficiency of Ligustrum lucidum steamed with wine. Rats in vivo with gastrointestinal perfusion model were used. The contents of salidroside and specnuezhenide in the fluid of gastrointestinal perfusion of rats were measured by HPLC at different time points after dosing. Then the K(a) and absorption percentage were calculated. Specnuezhenide could be detected in the fluid of gastrointestinal perfusion of specnuezhenide. The K(a) of the specnuezhenide and salidroside in the fetal intestines are 0.055 3 and 0.144 2 h(-1) respectively and the total absorptivity are 24.46% and 60.14% respectively after 4 hours. The K(a) in the stomach are 5.70 and 8.26 h(-1) respectively and the total absorptivity are 34.21% and 47.23% respectively after 4 hours. The experiment proved that specnuezhenide can be metabolized into salidroside which is more beneficial for gastrointestinal absorption. The experiment proved that specnuezhenide can be metabolized into salidroside both in the rat's stomach and the fetal intestine and compared with the specnuezhenide salidroside is more conducive to gastrointestinal absorption. The results suggested that the increasing efficiency on liver and kidney of L. lucidum steamed with wine has business with the fact that Specnuezhe nide is more conducive to the body after it is changed into salidroside. PMID- 24956861 TI - [Study on pharmacokinetics of geniposide in mice administrated by xingnaojing microemulsion and mPEG2000-PLA modified xingnaojing microemulsion]. AB - An HPLC method for the determination of geniposide concentration in mouse plasma was developed and the pharmacokinetics after intranasal administration of Xingnaojing microemulsion (XNJ-M) and mPEG2000-PLA modified Xingnaojing microemulsion (XNJ-MM) were investigated. Eighty mice were treated by XNJ-M and XNJ-MM nasally. The plasma samples were collected at different times and the drug in samples was detected by HPLC. The pharmacokinetic parameters were calculated by the software of Kinetica. The pharmacokinetic parameters of geniposide of XNJ M were C(max) (4.36 +/- 2.69) mg x L(-1), t(max) 1 min, MRT (29.73 +/- 4.54) min, AUC (53.63 +/- 14.03) mg x L(-1) x min. The pharmacokinetic parameters of geniposide of XNJ-MM were C(max) (9.75 +/- 4.14) mg x L(-1), t(max) 1 min, MRT(22.34 +/- 2.90) min, AUC (131.87 +/- 40.13) mg x L(-1) x min. Geniposide can be absorbed into blood in a higher degree after intranasal administration with XNJ-MM compared to XNJ-M, which maybe caused by its less irritating and more absorption. PMID- 24956862 TI - [Clinical study on treatment of carotid atherosclerosis with extraction of polygoni cuspidati rhizoma et radix and crataegi fructus: a randomized controlled trial]. AB - OBJECTIVE: To observe the effect of detoxifying and blood circulation activating Chinese herb extraction of polygonum cuspidatum and hawthorn on carotid intima media thickness (IMT), plaque integral and plaque stability related serum indexes of patients with carotid atherosclerosis. METHOD: Sixty and four cases of carotid artery atherosclerosis patients were assigned randomly to 2 groups: detoxifying and blood circulation activating treatment group (treatment group, 32 cases) and control group (32 cases). Patients in treatment group were treated with capsules of extraction of polygonum cuspidatum and hawthorn, 1 pill po, bid (dosage of administration: polygonum cuspidatum extraction 5.33 mg x kg(-1) x d(-1), hawthorn extraction 5.0 mg x kg(-1) x d(-1)); patients in control group were treated with lovastatin 20 mg po, qd (dosage of administration: 0.33 mg x kg(-1) x d(-1)). The course of treatment was six months. To observe changes of IMT, plaque integral, and detect the level of plaque stability related serum indexes such as Hs-CRP, MMP-1 and TIMP-1. RESULT: After 6 months of treatment, in control group one patient quit the clinical trial because of liver dysfunction and one patient was rejected because of having not followed the therapeutic regimen. 32 cases in treatment group and 30 cases in control group were analyzed. The results showed that IMT and plaque integral of treatment group decreased significantly after the treatment (P < 0.05, P < 0.01), and there was no significant difference compared with control grope. Serum Hs-CRP, MMP-1 and MMP-1/TIMP-1 decreased after the treatment (P < 0.05, P < 0.01), and the treatment group was superior to control group in decreasing serum Hs-CRP (P < 0.05). CONCLUSION: Detoxifying and blood circulation activating Chinese herb extraction of polygonum cuspidatum and hawthorn has good effect of anti-atherosclerosis and promoting plaque stability. Its mechanism might be related with anti-inflammation and inhibiting degradation of extracellular matrix, and deserves further studies. PMID- 24956863 TI - [Effects of xihuangwan in assistant treatment of patients with advanced breast cancer]. AB - In order to explore the possibility of Xihuangwan (XHW)'s application in assistant therapy in patients with breast cancer, short- and long-term clinical efficacy were assessed in this study. Eighty and four patients with advanced breast cancer were selected in this study. They were divided into control group and treatment group randomly and evenly. All patients received surgical treatment followed by chemotherapy regimen composed of PTX + EPI + CTX (TEC regimen). Treatment group received additional assistant treatment of XHW. Short-term clinical efficacy was assessed by KPS, lesion stabilizing rate and side effects in 3-month follow-up study. Long-term clinical efficacy was assessed by overall survival (OS) and free-progression survival (FPS). KPS increased significantly after treatment in all patients (P < 0.05), more significantly in treatment group than in control group after treatment (P < 0.05); lesion stabilizing rate in treatment group increased significantly in treatment group than in control group (92.86% vs. 85.71%, P < 0.05); there was no significant difference between control group and treatment group in occurrence of side effects. Compared with control group, OS and FPS increased significantly in treatment group. Data in this study showed that XHW was suitable in treatment of advanced breast cancer due to its satisfactory short-term and long-term therapeutic effects. PMID- 24956864 TI - [Analysis on composition principles of prescriptions for stranguria in dictionary of traditional Chinese medicine prescription]. AB - By using traditional Chinese medicine inheritance support system to analyze the dominant experience and recessive principles of the prescriptions for stranguria in the dictionary of traditional Chinese medicine prescription (DCMP), we aim to define the medication pattern and rule and to acquire new prescriptions. In dominant experience analysis, we were able to find 22 drugs used over 50 times, including drugs of clearing heat, diuresis and relieving stranguria which are the most used and drugs of clearing heat, cooling blood, benefiting Qi and nourishing Yin. In addition, drugs of activating Qi and Xue, eliminating phlegm and removing toxic are often used, including 34 herb pairs and 5 combinations of three-taste drugs are used more than 35 times. These results fully reflect the composition principles and compatibility characteristic of prescriptions for treating stranguria in DCMP. Thirteen new prescriptions by way of recessive principle excavating were acquired. These new prescriptions might be suitable to clinical treatments of variable syndromes. This article provides an useful clue to research and produce new drugs. PMID- 24956865 TI - [Infect of pingshen decoction on serum HGF, Cys C and TGF-beta1 diabetic nephropathy in early stage]. AB - Study the serum level of HGF, Cys C and TGF-beta1 in type 2 diabetic nephropathy (DN), the infect of Pingshen decoction on those index. Selected 69 cases of 2 type DN and randomly divided into therapy group (36 cases) and control group (33 cases). The therapy group were treated with Pingshen decoction 1 dose/d, bid po. The control group were treated with NephritisShu tablet, 6 tablet, tid po. 8 weeks was a course. Before and after treatment, we examine the serum level of HGF, Cys C and TGF-beta1 by ELISA and immunonephelometry, and compare with 30 cases of healthy control group. The study demonstrates that before treatment, the serum level of HGF in both groups were significantly lower than healthy control group (P < 0.01), but Cys C, TGF-beta1 were significantly higher (P < 0.01). After treatment, the serum level of HGF of both groups were increased. The serum level of HGF of therapy group were significantly higher than of control group (P < 0.01), but the serum level of Cys C and TGF-beta1 were significantly lower than control group (P < 0.01). The serum level of HGF was correlated negatively with Cys C,TGF-beta1. In control group, the UAER, urine beta2-MG and quantity of 24 hour urine protein were significantly decreased after treatment (P < 0.01). The index of urine of therapy group were significantly lower than control group (P < 0.01). Results indicate that test of serum level of HGF and Cys C,TGF-beta1 of diabetic nephropathy have important clinical significance. Pingshen decoction can effectively intervene in the serum level of HGF and Cys C, TGF-beta1 and index of urine. PMID- 24956867 TI - [Concern points and considerations for pharmacodynamic study design of new traditional Chinese medicines]. AB - Pharmacodynamic (PD) studies play an important role in research and development of new traditonal Chinese medicines (TCMs). Phamacologic and toxicologic studies that aim to research drug ability can provide supporting data for the clinical trials and reduce the risk of clinical trials. In recent years, PD studies in TCMs are developing and progressing, but there are still some problems affecting the value of PD studies in the development of new TCMs. The value of PD studies depends on scientific and rational study design. This article summaries some defects in PD study design of new TCMs that are common in the application data, including defects in study type, testing targets, dosing, duration of administration, control group, testing time. This article also discusses some points of concern and specific requirements for PD study design of new TCMs. PMID- 24956866 TI - [Comparative study of embryonic diapauses prevention in western medicine and traditional Chinese medicine]. AB - Embryonic diapauses mean that early embryos stop developing for some reasons in early pregnant stage. The embryo has dead in uterine cavity, but has not yet discharged. The early clinical manifestation in the areas of traditional Chinese medicine (TCM) can be classified as "pregnant vaginal bleeding", "fetal irritability" and other diseases. Embryonic diapause is a common and difficult gynecologic clinical disease. The prevalence rate which is increasing has become a major reproductive health problem. So the prevention research of embryonic diapauses is very significant. In this paper, through the induction and the summary of Chinese and Western medicine dynamic researches and control methods of embryonic diapauses, detailing a list of pathogenesis and treatment progress in embryonic diapauses. Besides, it can lay the foundation for further study and reducing embryonic diapauses incidence, which can promote reproductive health development. PMID- 24956868 TI - [Research on our hospital inventory management status quo of traditional Chinese medicine drugs and treatment method]. AB - Under the background of the new medical reform, a large variety of traditional Chinese medicine from complicated sources, Chinese traditional medicine of actor of true and false of the quality directly affect the drug safety and clinical efficacy, but also relate to the social and economic benefits of hospital. Along with the development of the modern management of medical institutions and drug circulation circulation system reform in our country, the hospital drug inventory, supply and management work is an important topic for the pharmaceutical trading. However, there is always contradiction, dispensary need to supple pharmacy, in order to satisfy the demands of hospital patients with normal diagnosis and treatment work. However, if the drug inventory is too much, not only increases the drug monitoring problem, at the same time, but also causes storage costs rise. Therefore, completing scientific and reasonable storage and management becomes urgent problems at present. Wherefore, our country administration of traditional Chinese medicine in 2007 promulgated the "Chinese traditional medicine yinpian management norms in hospital", aims to standardize management of Chinese traditional medicine quality and improve the safety of drugs. The author through looking up information and visiting survey, to understand the currently existing problems, and summarizes the literature inland and abroad in recent years Chinese medicine drug inventory management work experience, in view of status quo of Chinese medicine inventory management in China, put forward the solution. To guarantee TCM pharmacy management more standardized, more standard, to adapt to the new reform of Chinese traditional medicine industry, improve the management level of hospital, defend the hospital's reputation and the patient's interests. PMID- 24956869 TI - Beware the next big thing. AB - Innovative management ideas that bubble up in other companies pose a perennial quandary for leaders: Should you attempt to borrow new ideas, and if so, which ones and how? Even the most promising practices can be disastrous if they're transplanted into the wrong company, writes Julian Birkinshaw of London Business School. Broadly speaking, there are two ways to borrow from innovative companies, he argues. The first, observe and apply, is the most commonly used approach for adopting new management ideas. It can and does work well, but only under Limited sets of circumstances: when the observed practice easily stands alone or involves just a small constellation of supporting behaviors (think of GE's well-regarded succession-planning process) and when a company's management model or way of thinking is very similar to the originator's (think of two software firms that both use the Agile development approach). The second method is to extract a management practice's essential principle-its underlying logic-and ask a series of questions to determine if it is right for your firm, including: How is your company different from the originating firm? Are the goals of the practice important to your organization? Many management innovations are launched with great fanfare, only to fade in popularity. With careful analysis, you can avoid falling prey to this hype cycle. And even if it turns out that a borrowed idea isn't right for you, the analysis will help you better understand your own management models and sharpen your practices. PMID- 24956870 TI - Blue ocean leadership. AB - Ten years ago, two INSEAD professors broke ground by introducing "blue ocean strategy," a new model for discovering uncontested markets that are ripe for growth. In this article, they apply their concepts and tools to what is perhaps the greatest challenge of leadership: closing the gulf between the potential and the realized talent and energy of employees. Research indicates that this gulf is vast: According to Gallup, 70% of workers are disengaged from their jobs. If companies could find a way to convert them into engaged employees, the results could be transformative. The trouble is, managers lack a clear understanding of what changes they could make to bring out the best in everyone. Here, Kim and Mauborgne offer a solution to that problem: a systematic approach to uncovering, at each level of the organization, which leadership acts and activities will inspire employees to give their all, and a process for getting managers throughout the company to start doing them. Blue ocean leadership works because the managers' "customers"-that is, the people managers oversee and report to-are involved in identifying what's effective and what isn't. Moreover, the approach doesn't require leaders to alter who they are, just to undertake a different set of tasks. And that kind of change is much easier to implement and track than changes to values and mind-sets. PMID- 24956871 TI - Your scarcest resource. AB - Most companies have elaborate procedures for managing capital. They require a compelling business case for any new capital investment. They set hurdle rates. They delegate authority carefully, prescribing spending limits for each level. An organization's time, by contrast, goes largely unmanaged. Bain & Company, with which all three authors are associated, used innovative people analytics tools to examine the time budgets of 17 large corporations. It discovered that companies are awash in e-communications; meeting time has skyrocketed; real collaboration is limited; dysfunctional meeting behavior is on the rise; formal controls are rare; and the consequences of all this are few. The authors outline eight practices for managing organizational time. Among them are: Make meeting agendas clear and selective; create a zero-based time budget; require business cases for all initiatives; and standardize the decision process. Some forward-thinking companies bring as much discipline to their time budgets as to their capital budgets. As a result, they have Liberated countless hours of previously unproductive time for executives and employees, fueling innovation and accelerating profitable growth. PMID- 24956872 TI - Get your team to do what it says it's going to do. AB - It's one thing to set goals-and entirely another to get the people in your organization to actually accomplish them. To make the leap from vision to execution, you can't just define what needs doing; you also need to spell out the details of getting it done. One motivational tool that enables this is "if-then planning," which helps people express and carry out their intentions. If-then plans work because contingencies are built into our neurological wiring, says social psychologist Halvorson. Humans are very good at encoding information in "If x, then y" terms and using such connections to guide their behavior, often unconsciously. When people decide exactly when, where, and how they'll fulfill a goal, they create a link in their brains between the situation or cue (If or when x happens) and the behavior that should follow (then I will do y). This creates powerful triggers for action. To date, most of the research on if-then plans has focused on individuals, but new studies show that they're very effective with groups, improving performance by sharpening focus and prompting members to execute key activities in a timely manner. If-then planning helps organizations avoid poorly expressed goals, groupthink, the tendency to cling to lost causes, and other problems. It pinpoints conditions for success, increases everyone's sense of responsibility, and helps close the troublesome gap between knowing and doing. PMID- 24956873 TI - Managing the "invisibles". AB - Even in an age of relentless self-promotion, some extremely capable professionals prefer to avoid the spotlight. "Invisibles" work in fields ranging from engineering to interpreting to perfumery, but they have three things in common: They are ambivalent about recognition, seeing any time spent courting fame as time taken away from the work at hand. They are meticulous. And they savor responsibility, viewing even high pressure as an honor and a source of fascination. Something else unites Invisibles: They represent a management challenge. The usual carrots don't motivate them; however, managers can take several steps to ensure their satisfaction. Leaders should recognize who their Invisibles are; decide if they want more Invisibles on the team; reward them fairly, soliciting reports on their accomplishments; make the work more intrinisically interesting; and talk to the Invisibles about what works best for them. These actions are well worth taking, as Invisibles not only bring exceptional levels of achievement to an organization but quietly improve the work of those around them, elevating performance and tone across the board. PMID- 24956874 TI - From purpose to impact: Figure out your passion and put it to work. AB - Over the past five years, there's been an explosion of interest in purpose-driven leadership. Academics, business experts, and even doctors make the case that purpose is a key to exceptional leadership and the pathway to greater well-being. Despite this growing understanding, however, a big challenge remains. Few leaders have a strong sense of their own individual purpose, the authors' research and experience show, and even fewer can distill their purpose into a concrete statement or have a clear plan for translating purpose into action. As a result, they limit their aspirations and often fail to achieve their most ambitious professional and personal goals. In this article, the authors present a step-by step framework that leaders can use to identify their purpose and develop an impact plan to achieve concrete results. Effective purpose-to-impact plans use language that is uniquely meaningful to the individual, rather than business jargon. They focus on future, big-picture aspirations and work backward with increasing specificity. And they emphasize the individual's strengths and encourage a holistic view on work and family. PMID- 24956875 TI - [Passionate and affectionate mentor, Keishi Abe]. PMID- 24956876 TI - [Overview of nephrotic syndrome in Japan]. PMID- 24956877 TI - [Epidemiology of nephrotic syndrome in Japan]. PMID- 24956878 TI - [Rituximab for the treatment of nephrotic syndrome]. PMID- 24956879 TI - [Circulating permeability factors in primary focal segmental glomerulosclerosis]. PMID- 24956880 TI - [Autoantibodies in membranous nephropathy]. PMID- 24956881 TI - [Nephrotic syndrome: renal amyloidosis and monoclonal immunoglobulin deposition disease]. PMID- 24956882 TI - [Nephrotic syndrome in diabetic nephropathy and diabetes]. PMID- 24956883 TI - [Lupus nephritis and nephrotic syndrome: diagnosis and treatment]. PMID- 24956884 TI - [Guidelines for the treatment of nephrotic syndrome]. PMID- 24956885 TI - [Pneumonia in maintenance hemodialysis patients: detection rate of causative organisms in sputum varies with time of sampling and quality]. AB - PURPOSE: Previous studies have demonstrated that almost half the deaths caused by infection in hemodialysis patients are due to pneumonia. Causative organisms in pneumonia are not defined. We assessed the positive rate of blood and sputum cultures in a cohort of dialysis patients admitted with pneumonia. METHODS: We retrospectively enrolled 44 consecutive pneumonia patients on maintenance hemodialysis attending on outpatient clinic at a single department of nephrology between October 2005 and March 2013. Pneumonia was defined by the chest computed tomography findings and clinical status. The severity of pneumonia was scored using the pneumonia severity index (PSI) and the presumed causative organisms were identified. RESULTS: Among the 44 subjects, median age was 74 (interquartile range, 68-78) years, 90.9% were men, 28.4% had chronic obstructive pulmonary disease, and 61.4% had diabetes mellitus. Almost all patients (95.5%) were class IV or V on PSI. Blood cultures were all negative, but 36.4% of sputum cultures were positive for causative organisms. The most common pathogens were Staphylococcus aureus (13.6%), Pseudomonas aeruginosa (6.8%), Escherichia coli (4.5%), and Chlamydophila pneumonia (4.5%). The detection rate of causative organisms was related to the quality of the sputum (Group 4 and 5 of the Geckler classification) and was 61.5% in samples collected before dialysis on a day of dialysis, and 36.8% in samples collected on the day before a day of dialysis. In contrast, the detection rate was low (16.7%) when the samples were collected after dialysis on a day of dialysis. CONCLUSION: In hemodialyis patients, the detection rate of causative organisms is elevated if sputum samples are collected before undergoing dialysis on a day of dialysis. Prospective confirmation in a larger number of patients is warranted. PMID- 24956886 TI - [Clinical usefulness of CD68 staining in children with various glomerular diseases]. AB - PURPOSE: Glomerular macrophage accumulation is a common feature of proliferative forms of human glomerulonephritis and kidney injury. Our present study was designed to investigate the role of macrophages in pediatric kidney diseases by using CD68 staining. MATERIAL AND METHODS: Seventy-four patients (39 boys and 35 girls) with pediatric kidney disease yielding 81 specimens were investigated. A monoclonal anti-human CD68 mouse antibody (KP1) was used as a macrophage marker in this study. Paraffin-embedded renal biopsy specimens were stained for immunohistochemical analysis. The average number of macrophages per glomerulus in each patient was calculated as the total number of CD68 (+) cells within all glomeruli divided by the total number of glomeruli in a single section and the average number of observed interstitial macrophages was calculated in 3-5 high power fields. RESULTS: Glomerular macrophage accumulations were increased with crescentic proliferative glomerulonephritis, mesangial proliferative glomerulonephritis, and focal segmental glomerulosclerosis. Glomerular and interstitial macrophage accumulations were correlated with hematuria, proteinuria and renal function (eGFR). In particular, activity and chronicity index, as well as the severity of glomerular IgA, C3, and fibrinogen deposition were correlated with glomerular macrophage accumulation. CONCLUSIONS: Macrophage accumulation observed by CD68 staining was a useful marker in providing a deeper understanding of the clinicopathologic state of children with chronic kidney diseases, and was effective in the selection of treatment. PMID- 24956887 TI - [A case of nephrotic syndrome during TS-1 therapy after resection of rectal cancer and liver metastasis]. AB - We report a case of a 63-year-old Japanese man who developed nephrotic syndrome during long-term TS-1 therapy, and was successfully treated with prednisolone (PSL). At 59 years of age, he underwent low anterior resection for rectal cancer, and resection of the lateral segment of the liver for metastasis, and cholecystectomy. He received chemotherapy with intravenous infusion of fluorouracil (5-FU) 500 mg, levofolinate calcium 350 mg, and hepatic arterial infusion of 5-FU 250 mg. After 6 cycles of 5-FU therapy, TS-1 therapy was started orally at 100 mg/day for 14 days followed by 7 days of rest. Edema appeared after 2 years. Urinary protein excretion was 6.38 g/day and hematuria was observed. His serum creatinine, total protein and albumin were 0.9 mg/dL, 4.9 g/dL and 2.6 g/dL, respectively. These data pointed to nephrotic syndrome. The renal pathology revealed segmental endocapillary proliferative lesions. Postinfectious glomerulonephritis, lupus nephritis and atypical IgA nephropathy were raised for differential diagnosis based on the pathology results. However, drug-induced nephrotic syndrome was suspected from the clinical course and laboratory findings. Discontinuation of TS-1 therapy decreased urinary protein, but increased the level of serum creatinine to 1.5 mg/dL. Seven months later, steroid therapy was started at PSL 60 mg/day. Proteinuria decreased further, and the dose of PSL was tapered and stopped 22 months later. Hypofunction of the kidney persisted with serum creatinine of 1.5 mg/dL, however, urinary protein disappeared. At the onset of nephrotic syndrome, cholestatic type liver injury was observed. During steroid therapy, liver dysfunction worsened, but almost recovered with tapering of the steroid. Another case reported in the literature with the renal pathological diagnosis of nephrotic syndrome associated with TS-1 was a case of thrombotic microangiopathy (TMA). In our case, the pathologic finding was different. Furthermore steroid therapy succeeded in achieving complete remission of the nephrotic syndrome. PMID- 24956888 TI - Biological activity and redistribution of nucleolar proteins of two different cell lines treated with cis-dichloro-1,2-propylenediamine-N,N,N',N'-tetraacetato ruthenium (III) (RAP). AB - The interaction of a newly synthesized antitumor complex cis-dichloro-1,2 propylenediamine-N,N,N',N'-tetraacetato ruthenium (III) (RAP) with DNA was investigated in vitro through a number of techniques including comet assay, immunoprecipitation, and immunolocalization of certain nucleolar proteins (the upstream binding factor (UBF) and fibrillarin) involved in DNA transcription, rRNA processing, and ribosomal assembly. The results showed that RAP binds to the DNA of two cell lines (H4 and Hs-683) causing a delay in cell proliferation rate leading to a number of cellular modifications. These modifications include DNA damage assessed by the single cell gel electrophoresis method (comet assay) and variation in the expression of nucleolar proteins; UBF was more abundant in RAP treated cells, this was explained by the high affinity of this protein to DNA modified by RAP. On the other hand, fibrillarin was found in less quantities in RAP treated cells which was explained by a de-regulation of the ribosomal machinery caused by RAP. PMID- 24956889 TI - Mast cells generate cysteinyl leukotrienes and interferon-beta as well as evince impaired IgE-dependent degranulation upon TLR7 engagement. AB - Mast cells are numerous at anatomical sites close to external environment, virtually at the portals of infection. A few data indicated that these cells express cytoplasmic Toll-like receptors (TLRs) recognizing virus-derived molecules. Accordingly, mast cells could participate in anti-viral defense or/and in viral-related diseases. However, data concerning the influence of viruses on mast cell activity are limited. Thus, the aim of our study was to determine mast cell response to TLR7 ligand, i.e. resiquimod (R848), a synthetic mimic of viral ssRNA. Since mast cells play a central role in allergic reactions the effect of TLR7 agonist was also investigated on FcepsilonRI-dependent mast cell response. Experiments were carried out in vitro on freshly isolated fully mature rat peritoneal mast cells. Mast cells exhibit constitutive TLR7 molecule expression and its up-regulation after the agonist challenge. TLR7-mediated mast cell stimulation resulted in cysteinyl leukotriene (cysLT) and interferon (IFN)-beta synthesis, whereas no histamine and CXCL8 secretion was stated. Moreover, mast cell priming with TLR7 ligand caused the reduction in anti-IgE-induced histamine release. The results suggest that ssRNA viruses could directly activate mast cells to alter their phenotype and to release of potent proinflammatory mediators or indirectly modulate IgE-dependent allergic processes. PMID- 24956890 TI - Limb remote ischemic post-conditioning reduces brain reperfusion injury by reversing eNOS uncoupling. AB - Limb remote ischemic postconditioning (LRIP) can reduce ischemia-reperfusion injury (IRI), but its mechanisms are still unclear. We hypothesize that LRIP reduces IRI by reversing eNOS uncoupling. Focal ischemia was induced in Sprague Dawley rats by middle cerebral artery occlusion for 2 h followed by a 24 h reperfusion. Before this surgery, folic acid (FA) was administered to the drug treatment group by gavage for 11 days. After a 24 h reperfusion, behavioural testing, vascular function, NO concentration and superoxide dismutase activity in the serum were determined. In addition, the infarct size of the brain was also detected. The mRNA of eNOS, nNOS, GTP cyclohydrolase I (GTPCH), P22(phox) and xanthine oxidase (XO) in the ischemic region were detected by RT-PCR, and nitrotyrosine (Tyr-NO2) was detected using Western blot analysis. The results showed that LRIP, FA and FA+LRIP all could improve behavioural score, and increase NO-mediated endothelium-dependent vasomotor responses, reduce infarction of rats subjected to IRI. Western blot and RT-PCR analyses showed that the Tyr NO2 levels and the mRNA expression of NADPH oxidase catalytic subunit P22(phox) and XO were up-regulated in the ischemic brain, which was significantly inhibited by LRIP, FA and FA+LRIP. The mRNA expression of the rate-limiting enzyme in BH4 synthesis, GTPCH, was down-regulated in the ischemic brain, which could be significantly augmented by LRIP and FA+LRIP. It can be concluded that IRI induces eNOS uncoupling in the cerebral ischemic region and LRIP partially reverses the eNOS uncoupling induced by IRI. PMID- 24956891 TI - In vitro evaluation of anti-Alzheimer effects of dry ginger (Zingiber officinale Roscoe) extract. AB - As the disease modifying therapies against Alzheimer's disease (AD) continue to exist as a major challenge of this century, the search for newer drug leads with lesser side effects is on the rise. A large number of plant extracts and phytocompounds are being actively pursued for their anti-Alzheimer effects. In the present study, the antioxidant activity, cholinesterase inhibition, anti amyloidogenic potential and neuroprotective properties of methanolic extract of dry ginger (GE) have been evaluated. The extract contained 18 +/- 0.6 mg/g gallic acid equivalents of total phenolic content and 4.18 +/- 0.69 mg quercetin equivalents/g of dry material. GE expressed high antioxidant activity with an IC50 value of 70 +/- 0.304 microg/mL in DPPH assay and 845.4 +/- 56.62 microM Fe(II) equivalents/g dry weight in FRAP assay respectively. In Ellman's assay for the cholinesterase inhibitory activity, GE had an IC50 value of 41 +/- 1.2 microg/mL and 52 +/- 2 microg/mL for inhibition of acetyl- and butyrylcholinesterase respectively. Also, GE increased the cell survival against amyloid beta (Abeta) induced toxicity in primary adult rat hippocampal cell culture. Aggregation experiments with the thioflavin T binding studies showed that GE effectively prevented the formation of Abeta oligomers and dissociated the preformed oligomers. These findings suggest that methanolic GE influences multiple therapeutic molecular targets of AD and can be considered as an effective nontoxic neutraceutical supplement for AD. PMID- 24956892 TI - Antidepressant-like effects of Brassica juncea L. leaves in diabetic rodents. AB - The objective of the study was to evaluate for antidepressant like activity of a methanolic extract of B. juncea leaves (BJ 100, 200, and 400 mg/kg/day, po), and Imipramine (15 mg/kg/day, po) in alloxan monohydrate (120 mg/kg, ip) induced diabetic and nondiabetic rodents, using behavioural despair, learned helplessness, and tail suspension tests for antidepressants and locomotor activity test for quantifying the behavioural effects of treatments. In addition, effects of BJ treatments on brain levels of norepinephrine, serotonin and dopamine were also estimated. Enhanced depressive states, and motility were observed in diabetic animals. Antidepressant and motor function depressing effects of BJ were apparent in all behavioural tests in diabetic rats and mice only. Decreased contents of dopamine, norepinephrine and serotonin in brain of diabetic rats were also dose dependently compensated by repeated daily BJ treatments. However, brain dopamine level of BJ treated normal rats was higher than that in control nondiabetic. The results suggest that BJ could be a nutritional alternative for combating exaggerated depression commonly associated with diabetes. PMID- 24956893 TI - Insulin secreting and alpha-glucosidase inhibitory activity of hexane extract of Annona squamosa Linn. in streptozotocin (STZ) induced diabetic rats. AB - The hexane extract of A. squamosa (ASHE) in 100 and 400 mg/kg body weight dose raised the insulin level when compared with Glimepiride (1 mg/kg) and also inhibited alpha-glucosidase activity when compared with Acarbose (10 mg/kg) in streptozotocin induced diabetic rats. The ASHE significantly reduced peak blood glucose (Gp30) and area under curve (AUC) in diabetic rats in oral glucose (OGTT) and oral sucrose (OSTT) tolerance test, but there was more reduction of Gp30 value than AUC in OSTT. Thus, it can be suggested that the ASHE, has hypoglycemic role at 2 levels, i.e. it acts as secretagogue and also inhibits the intestinal enzymes, responsible for glucose metabolism. PMID- 24956894 TI - Sequential functional analysis of left ventricle from 2D-echocardiography images. AB - The sequential changes in shape of left ventricle (LV), which are the result of cellular interactions and their levels of organizational complexity, in its long axis view during one cardiac cycle are obtained. The changes are presented in terms of shape descriptors by processing of images obtained from a normal subject and two patients with dilated left ventricular cardio-myopathy. These images are processed, frame by frame, by a semi-automatic algorithm developed by MATLAB. This is consisting of gray scale conversion, the LV contour extraction by application of median and SRAD filters, and morphological operations. By filling the identified region with pixels and number of pixels along its contour the area and perimeter are calculated, respectively. From these the changes in LV volume and shape index are calculated. Based on these the stroke volume (SV) and ejection fraction (EF) are calculated. The changes in LV area, perimeter, volume and shape index in cardiac patients are less than that of normal subject. The calculated SV and EF of normal subject are within the range as obtained by various imaging procedures. PMID- 24956895 TI - Identification and characterization of the Sudanese Bacillus thuringiensis and related bacterial strains for their efficacy against Helicoverpa armigera and Tribolium castaneum. AB - Forty-four isolates of Bacillus thuringiensis like bacteria from various sources in different locations from Sudan were tested for their insecticidal activity. The toxicity of these isolates ranged from 6.6 to 70% to the neonates of cotton bollworm, Helicoverpa armigera at 10 ppm concentration. The most effective ones are Kb-29, St-6 and Wh-1 comparable with HD-1. Toxicity of isolates to larvae of the red flour beetle, Tribolium castaneum ranged from 20 to 100%. Isolates St-2 and St-23 gave 100% larval mortality within 15 days of exposure and were at par with Ab-8, Ab-12, Kb-26, Kb-30, Om-4, Po-2, Po-5, Po-7, Sa-8 and Wh-5 and were also comparable with E. coli clone expressing Cry3 toxin. The most effective five isolates viz., Kb-29, St-2, St-6, St-23 and Wh-1 belonged to B. thuringiensis. The St-6 isolate, which also showed high toxicity to T. castaneum larvae, had cry1 genes along with coleopteran active cry28 genes, but not cry3 genes. Of the 25 isolates characterized with 16s DNA sequencing, seven belonged to Paenibacillus spp., one Lysinibacillus sphaericus, one Bacillus pumilus, four Bacillus spp., and rest 12 belonged to B. thuringiensis. Biochemical characterization in each species showed variation. The present study shows potential of some isolates like Kb-29, St-2, St-6, St-23 and Wh-1 as promising bioinsecticides. PMID- 24956896 TI - Manganese influx and its utilization efficiency in wheat. AB - Manganese deficiency in wheat has become an important nutritional disorder particularly in alkaline calcareous soils where rice-wheat rotation is followed. This experiment was aimed to study the mechanism of Mn efficiency during various developmental stages in six wheat cultivars grown at two Mn levels viz. 0 and 50 mg Mn kg(-1) soil (Mnapplied as MnSO4 x H20) in pots. The Mn vegetative efficiency calculated on the basis of shoot dry weight at anthesis indicated HD 2967 and PBW 550 (bread wheat) as Mn efficient and durums as Mn inefficient. The efficient cultivars recorded highest values for influx, uptake, shoot dry weight, leaf area/plant, SPAD index, F(v)/F(m)ratio and root length that explained their higher efficiencies whereas inefficiency of durum cultivars was attributed to their smaller roots and lower influx. Under Mn deficiency, PDW 314 and PDW 291 retained 68% and 64%, respectively, of total Mn uptake in vegetative parts (stem and leaves) and lowest in grains 7% and 5%, respectively, whereas PBW 550, BW 9178 and HD 2967 retained 29, 37 and 34% in vegetative parts, and 21, 17 and 15 % in grains, respectively at maturity. Higher utilization efficiency of efficient genotypes also indicated that increased Mn uptake with Mn supply produced more efficiently grains in efficient genotypes but vegetative parts in inefficient genotypes. Hence Mn efficiency of a cultivar could be explained by longer roots, higher uptake, influx and efficiency index during vegetative phase and higher grain yield and utilization efficiency during generative phase. PMID- 24956897 TI - In vitro regeneration of Coelogyne nervosa A.Rich. and Eria pseudoclavicaulis Blatt., threatened orchids of Western Ghats, India. AB - The seeds of C. nervosa and E. pseudoclavicaulis were germinated asymbiotically on Knudson C (KC) and Schenk and Hildebrandt basal medium (SH). Growth regulators such as 2,4-Dichlorophenoxyacetic acid (2,4-D) individually and in combinations with benzyladenine (BA) and kinetin were used for callus induction from the protocorm like bodies. Coelogyne nervosa showed maximum (90%) callus induction in Knudson C medium supplemented with 2,4-D (2.26 microM) and Eria pseudoclavicaulis showed 60% callus induction in Schenk and Hildebrandt medium supplemented with 2,4-D (2.26 microM). Calli developed a route of production of protocorm-like bodies and eventually developed into plantlets on transfer to growth regulator free half strength basal medium. The well rooted plants were hardened successfully in the potting mixture containing coconut husk, charcoal, and brick pieces in the ratio 2:1:1. PMID- 24956898 TI - An analysis of vascular system in the compound tendrilled afila leaf in Pisum sativum. AB - Recent work on the venation patterning and morphogenesis of leaf/leaflet has posed the question how different are these in tendrils, which are another type of vegetative lateral organ. Here, the venation patterns of leaflets, stipules and tendrils were compared in the model species, P. sativum. Unlike reticulated venation in leaflets and stipules, venation in tendrils comprised of one or more primary veins. A few secondaries were attached to a primary vein, mostly distally. Bilaterally symmetrical secondary veins were rare. The primary veins in tendrils were daughter strands from dichotomously divided mother veins in rachis, connected finally to vascular strands in stem. A tendril received primary vein from one or more mother strands. Some mother strands contributed primary veins to proximal, distal and terminal domain tendrils of af leaf. The tendrils shared the multi-primary vein character with stipules. Vein redundancy provided a mechanism for survival of tendril/leaf against injury to some of the veins/mother veins. The presence of aborted primary veins that did not reach apex, rows of cambium cells attached to primary vein(s) at apex, the pattern of attachment of primary veins to mother veins and cessation of vein growth in apical direction in aborted tendrils of af lld genotype indicated that the growth of primary veins and tendril was acropetal. Loss-of-function of AF extended the repression of TL and MFP genes on leaflet development from distal and apical domains to proximal domain of leaves in af mutants. PMID- 24956899 TI - First-place essay: familial ties in treating the difficult patient. PMID- 24956900 TI - Pregnant with hematemesis. PMID- 24956901 TI - Under your nose. PMID- 24956902 TI - Patience with the difficult patient. PMID- 24956904 TI - Treating the difficult patient can be a long journey. PMID- 24956903 TI - Avoid getting kicked. PMID- 24956905 TI - Finding my friend's heart in the difficult patient. PMID- 24956906 TI - Doctor heal thyself ... because we won't. PMID- 24956907 TI - Punched in the face. PMID- 24956908 TI - Treating the difficult patient may require stepping out of your comfort zone. PMID- 24956910 TI - Potent antibacterial activities of latamoxef (moxalactam) against ESBL producing Enterobacteriaceae analyzed by Monte Carlo simulation. AB - Latamoxef (LMOX, Moxalactam) is one of the beta-lactam antibiotics which is stable against beta-lactamase. In this study, the antibacterial activity of LMOX was investigated, and Monte Carlo simulation was conducted to determine the appropriate dosing regimens of LMOX against extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. The probability of target attainment (PTA) was analyzed at 40% and 70% of time above minimum inhibitory concentration (MIC) (time above MIC, T(>MIC)) for bacteriostatic and bactericidal effect respectively. All the tested regimens achieved 85% of PTA at 40% of T(>MIC) against ESBL producing Escherichia coli, and all the tested regimens except 1g q12h with 1 hour infusion achieved 85% of PTA at 40% of T(>MIC) against ESBL producing Klebsiella pneumoniae. The effective regimens to achieve 85% of PTA at 70% of T(>MIC )against E. coli were lg ql2h with 4 hours infusion, lg q8h with 1 4 hours infusion, 2g ql2h with 2-4 hours infusion, and lg q6h with 1-4 hours infusion. The effective regimens to achieve 85% of PTA at 70% of T(>MIC) against K. pneumoniae were 1g q8h with 3-4 hours infusion and 1g q6h with 1-4 hours infusion. These results of pharmacokinetics/pharmacodynamics (PK/PD) modeling showed the potent efficacy of LMOX against bacterial infections caused by ESBL producing Enterobacteriaceae. PMID- 24956911 TI - [Epidemiological analysis for enterococci isolated in Aichi prefecture]. AB - We investigated vancomycin-resistant genes for clinical isolates of 353 vancomycin-resistant enterococci in the Aichi Medical University hospital and 120 vancomycin-resistant enterococci from the 8 facilities in Aichi prefecture between April 2008 and January 2013. We detected 8, 105, 21 and 4 strains of enterococci with vanA, vanB, vanC1 and vanC2/C3, respectively. Among enterococci with vancomycin-resistant genes, we detected 4, 3 and 2 enterococci of vancomycin MIC level 4 microg/mL with vanB, vanC1 and vanC2/C3, respectively. According to molecular analysis using repetitive-sequence-based PCR (rep-PCR) for enterococci with vanA or vanB genes, although there have been no similarity for Enterococcus faecium with vanA and Enterococcus faecalis with vanB, high similarity was shown among E. faecium with vanB, which might be nosocomial spread in each hospital. These results showed that molecular analysis for vancomycin-resistant genes would be useful for the management of healthcare-associated infections. PMID- 24956909 TI - [Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2012]. AB - The nationwide surveillance of antibacterial susceptibility to meropenem (MEPM) and other parenteral antibiotics against clinical isolates during 2012 in Japan was conducted. A total of 2985 strains including 955 strains of Gram-positive bacteria, 1782 strains of Gram-negative bacteria, and 248 strains of anaerobic bacteria obtained from 31 medical institutions were examined. The results were as follows; 1. MEPM was more active than the other carbapenem antibiotics tested against Gram-negative bacteria, especially against enterobacteriaceae and Haemophilus influenzae. MEPM was also active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus (MRSA). 2. Of all species tested, there were no species, which MIC90 of MEPM was more than 4-fold higher than those in our previous studies in 2009 or 2006. Therefore, the tendency to increase in antimicrobial resistance rates was not observed. 3. MEPM resistance against Pseudomonas aeruginosa was 17.8% (56/315 strains). Compared to our previous results, it was the lowest than that in 2006 and 2009. 4. Carbapenem resistant Klebsiella pneumoniae, and multi-drug-resistant Acinetobacter species, which emerged in worldwide, were not observed. 5. The proportion of extended spectrum beta-lactamase (ESBL) strains was 6.2% (59/951 strains) in enterobacteriaceae, which increased compared with that of our previous studies in 2009 or before. Whereas, the proportion of metallo-beta-lactamase strains was 1.6% (5/315 strains) in P. aeruginosa, which was stable. In conclusion, the results from this surveillance suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem for serious infections treatment at present, 17 years passed after available for commercial use in Japan. PMID- 24956912 TI - Investigation of the risk factors of anaerobic bacteremia in a case-control study. AB - BACKGROUND: Many case series studies have reported risk factors of infection with anaerobic bacteria, but few factor analysis studies have been conducted. OBJECTIVE: We conducted a case-control study to identify the risk factors of anaerobic bacteremia. METHODS: We compared a number of characteristics of patients with anaerobic bacteremia with those with aerobic bacteremia. Clinical information for 71 patients of anaerobic bacteremia was collected from January 1999 to December 2012 in Aichi Medical University Hospital. For each case, we identified up to four controls matched by the time of the positive blood culture. RESULTS: Multivariate logistic analyses revealed an association between anaerobic bacteremia and malignancy (OR: 3.35, 95% CI: 1.85-6.09), Douglas' pouch drains (OR: 25.90, 95% CI: 2.90-25.00) and chest drains (OR: 3.35, 95% CI: 1.19-9.43) as the primary causative disease, as well as associations between anaerobic bacteremia and the gastrointestinal tract (OR: 3.29, 95% CI: 1.38-7.81), genitourinary tract (OR: 4.98, 95% CI: 2.06-12.05), Douglas' pouch drains (OR: 16.95, 95% CI: 1.82-166.67) and chest drains (OR: 3.62, 95% CI: 1.29-10.20) as the primary causative organs. On the other hand, our study showed that having a central venous catheter was not associated with anaerobic bacteremia. CONCLUSIONS: We demonstrated an association between anaerobic bacteremia and malignancy, gastrointestinal and genitourinary tracts, patients having a Douglas' pouch drains or chest drains. These findings may be useful for developing early appropriate management for anaerobic bacteremia. PMID- 24956914 TI - Evaluation of urinalyses ordered for diagnosis of urinary tract infections at an inpatient psychiatric hospital. AB - OBJECTIVE: A retrospective study was conducted to assess the diagnosis and treatment of urinary tract infections (UTIs) using urinalyses (UA)s at a psychiatric hospital. METHOD: Patients admitted between July 2010 and June 2011 receiving at least one UA during inpatient psychiatric hospitalization were included. Pregnant patients and those with a UA receiving antibiotic treatment in the emergency department were excluded. The primary objective of the study was to characterize and assess the appropriateness of UAs ordered for the diagnosis of UTIs. Secondary objectives included analyzing frequency of cultures obtained, appropriateness of empiric antibiotics, and de-escalation of therapy if warranted. RESULTS: Thirty-nine percent (n = 891/2292) of patients admitted received a UA at least once during their hospitalization. Of 203 patients further evaluated, 78% were asymptomatic, 11% were older than 65 years of age with altered mental status (AMS) or dementia, and 11% had typical UTI symptoms. Thirty one patients were given antibiotics for a UTI during their stay, with a majority of those being asymptomatic (n = 19/31). CONCLUSIONS: A significant proportion of UAs ordered at a psychiatric hospital were inappropriate. When patients were treated, empiric antibiotic selection and length of treatment were appropriate in most instances. PMID- 24956915 TI - Patterns of cortical activation following motor tasks and psychological-inducing movie cues in heroin users: an fMRI study. AB - OBJECTIVE: Drug abuse and addiction are worldwide health problems. However, few studies have used fMRI to investigate the effect of chronic heroin use on brain activation. This is a study along this line. METHOD: fMRI positive sites in the brain were recorded during different motor and sensory activities. RESULTS: Following motor activities, heroin users had more sites globally activated in the brain than in normal volunteers, with ex-heroin users being least reactive. Conversely, a "heroin puffing" movie produced more activation in ongoing-heroin and ex-heroin users than in the normal individuals, whereas a movie with explicit sexual content was less stimulatory in both groups of heroin users compared to normal individuals. CONCLUSIONS: These significant findings relative to the function of specific brain nuclei are discussed. PMID- 24956913 TI - Emotional reactions to pain predict psychological distress in adult patients with Sickle Cell Disease (SCD). AB - Differentiating somatic from emotional influences on the experience of chronic pain has been of interest to clinicians and researchers for many years. Although prior research has not well specified these pathways at the anatomical level, some evidence, both theoretical and empirical, suggest that emotional reactions influence the experience of disease and non-disease-related pains. Other studies suggest that treatments directed at negative emotional responses reduce suffering associated with pain. The current study was conducted to explore the influence of emotional reactions to pain as a predictor of psychological distress in a sample of adult Blacks with Sickle Cell Disease (SCD). Using cross-sectional survey data, we evaluated whether negative emotional reactions to the experience of pain were predictive of psychological distress after controlling for the somatic dimension of pain and age in n = 67 Black patients with Sickle Cell Disease (SCD). Results showed that greater negative emotion associated with pain predicted Somatization (p < .01), Anxiety (p < .05), Phobic Anxiety (p < .05), and Psychoticism (p < .05). Increased negative emotion associated with pain was also predictive of the General Symptoms Index (p < .05) and the Positive Symptoms Total from the SCL-90-R (p < .01). We believe the current study demonstrates that negative emotional reactions to the experience of pain in adults with SCD are predictive of psychological distress above and beyond the influences of age and the direct nociceptive experience. We also believe these data to be valuable in conceptualizing the allocation of treatment resources toward a proactive approach with early identification of patients who are responding poorly for the purpose of potentially reducing later psychopathology. A deeper understanding of the ways that subpopulations cope with chronic disease-related pain may produce models that can be ultimately generalized to the consumers of the majority of healthcare resources. PMID- 24956916 TI - Self-esteem and psychiatric features of Turkish adolescents with psychogenic non epileptic seizures: a comparative study with epilepsy and healthy control groups. AB - OBJECTIVE: Children and adolescents with psychogenic non-epileptic seizures (PNES) and epilepsy are known to have psychosocial problems. The aim of the present study was to compare the psychosocial difficulties, history of stressful life events/abuse, psychiatric diagnosis, and self-esteem of adolescents with PNES to the ones with epilepsy and healthy controls at a tertiary care center in Turkey. METHOD: Thirty-four adolescents with PNES diagnosed by video-EEG were compared with 23 adolescents that have epilepsy and 35 healthy volunteers. Comorbid psychiatric diagnoses of participants were examined by semi-structured interviews using Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version (KSADS-PL). Self-esteem of adolescents was evaluated by Rosenberg Self Esteem Scale (RSES). RESULTS: No differences in sociodemographic features were observed between the groups. The PNES group showed significantly higher rates of parental conflicts, difficulties in relationship with siblings/peers, school under-achievement, and history of stressful events/abuse. The rates of comorbid psychiatric disorders were 64.7% in PNES and 47.8% in epilepsy group. The most common disorders in both groups were attention deficit hyperactivity disorder (ADHD) and depressive disorder. The rate of posttraumatic stress disorder (PTSD) was significantly increased in the PNES group. Additionally, adolescents with PNES displayed significantly lower levels of self-esteem than the other groups. CONCLUSION: It could be concluded that both disorders involved a high risk for developing psychiatric disorders; additionally, adolescents with PNES have higher rates of stressors and lower levels of self-esteem. Findings from this investigation point to the importance of psychiatric interventions in pediatric PNES and also epilepsy. PMID- 24956917 TI - Relationship between extremity fractures and attention-deficit/hyperactivity disorder symptomatology in adults. AB - OBJECTIVE: Recent studies showed that attention deficit hyperactivity disorder (ADHD) is a lifelong disorder which may be seen in adults as well as children. However, information about the relationship between ADHD and general medical conditions in adulthood is limited. This case-control study aims to determine whether ADHD symptoms are associated with extremity fractures and their clinical characteristics. METHODS: Forty patients (25 male and 15 female; aged 18-50 years) who were seen due to extremity fractures and 40 control subjects were enrolled. Childhood and present ADHD symptoms of the participants were assessed using Wender Utah Rating Scale (WURS) and Adult ADHD Self-Report Scale (ASRS), respectively. Trauma type, reason of the trauma, fracture localization, hospitalization requirement, treatment type, and history of previous fracture(s) of the patients were recorded. RESULTS: Total score and all subscale scores of WURS were higher in the fracture groups compared with controls. Patients also had higher ASRS total score and ASRS hyperactivity-impulsivity subscore than the controls did. WURS irritability, inattentiveness, and behavioral problems/impulsiveness subscore and total score were positively correlated with the history of previous fracture. The patients in whom the reason for the fracture was fighting were also showed higher WURS irritability subscore. CONCLUSIONS: Our results suggest that extremity fractures are associated with ADHD symptoms in adults. These findings may provide an insight into better understanding the lifelong negative impact of ADHD on the physical health of its sufferer. PMID- 24956918 TI - Diagnoses of psychiatric disorders in hypothetical patients by non-psychiatric physicians in Japan. AB - OBJECTIVE: This study was undertaken to investigate non-psychiatric physicians' diagnoses of hypothetical patients in clinical scenarios with comorbid medical and psychiatric disease in Japan. METHODS: The non-psychiatric physicians were asked to diagnose eight clinical scenarios describing several typical behavioral health problems in the medical settings. RESULTS: A total of 155 non-psychiatric physicians participated. Many physicians had problems correctly diagnosing depression and hypoactive delirium with medically ill patients. CONCLUSIONS: It is time to incorporate new efficient and effective approaches, such as collaborative care system and proactive delirium prevention programs, to improve overall behavioral health diagnosis and treatment, rather than relying on the rapid recognition of behavioral health problems in primary care/general medical settings. PMID- 24956919 TI - Coping style as a mediator between attachment and mental and physical health in patients suffering from morbid obesity. AB - OBJECTIVE: The presence of mental health problems and limitations in physical functioning is high in patients suffering from morbid obesity. The purpose of the current study was to examine the mediating role of coping style in the relationship between attachment representations and mental health and physical functioning in a morbidly obese population. METHOD: A total of 299 morbidly obese patients who were referred to the Slotervaart bariatric surgery unit in Amsterdam, the Netherlands, completed self-report questionnaires assessing adult attachment style (Experiences in Close Relationship-Revised Questionnaire), coping style (Utrecht Coping List), and patients physical functioning and mental health (Short Form-36). RESULTS: Attachment anxiety (beta = -.490, p < .001) and attachment avoidance (3 = -.387, p < .001) were both found to be related to mental health. In addition, attachment anxiety was also found to be related to physical functioning (beta = - .188,p < .001). Coping style partly mediated these associations. CONCLUSIONS: Findings suggest that coping mediates the association between attachment anxiety and attachment avoidance on the one hand and mental health and physical functioning in patients with morbid obesity on the other hand. PMID- 24956920 TI - Age differences in expected satisfaction with life in retirement. AB - Research on expected quality of life in retirement has focused on the perceptions of individuals either living in retirement or nearing retirement age. In this article, data are reported that examine expectations of (future) retirement quality of life among younger and middle-aged adults. Toward this end, a new scale--the Satisfaction with Life in Retirement Scale--is introduced. As part of the study, a pair of age-specific, theoretically-driven, hierarchically structured path models were tested in which individuals' perceptions of future retirement satisfaction were regressed on indicators of financial knowledge, future time perspective, financial risk tolerance, and parental financial values. Models from both age groups were successful in accounting for variability in perceptions of future retirement satisfaction; however, age differences in the model were observed. The results of this investigation have implications for retirement counselors and intervention specialists who seek to cultivate positive perceptions of late life among individuals of different ages. PMID- 24956921 TI - Prevalence and risk factors for self-neglect among older adults living alone in South Korea. AB - This study aimed to explore the prevalence of and risk factors for self-neglect among older adults who live alone. Data were obtained through face-to-face interview responses of 1,023 older adults living alone in a metropolitan area in South Korea, selected via stratified random sampling, which considered the population variables gender, age group, and district. Descriptive statistics were used to characterize the prevalence of self-neglect, and hierarchical multiple regression analysis was conducted to identify significant risk factors of self neglect. At least 22.8% of the participants could be considered to have one form of elder self-neglect. Consistent with previous research, self-neglect was more prevalent in the older people living alone who had higher levels of depressive symptoms or a lack of family social support. Unexpectedly, self-neglect was more prevalent among respondents with higher levels of education and cognitive abilities, lower levels of medical comorbidities, and more children. Additionally, social networks of friends and use of social services (formal social support) did not affect the frequency of self-neglect. The findings have implications for gerontological practice and policy, especially for older people living alone in South Korea. PMID- 24956922 TI - The heterogeneous course of depressive symptoms for the dementia caregiver. AB - Caregiving may be burdensome to caregivers, negatively affecting health and impacting decisions to institutionalize patients. It is unclear how caregiver depression changes over longer periods or whether heterogeneous trajectories for caregivers are apparent. The goals of this article are to characterize the course of depressive symptoms among caregivers over time and to examine the impact of baseline patient and caregiver characteristics on these trajectories. Patients with dementia and their caregivers were followed every 6 months for up to 6 years or until death (n = 133). Growth mixture modeling identified trajectories of caregiver depression over time. Most caregivers had stable trajectories of symptoms, with a smaller subset showing evidence of wear-and-tear. Patient clinical characteristics had no impact on symptom course for caregivers. Future work should utilize a longitudinal perspective and consider that there may be heterogeneous trajectories for caregivers. Those caregivers who follow a wear-and tear trajectory may require targeted interventions to improve outcomes. PMID- 24956923 TI - Upstream and downstream correlates of older people's engagement in social networks: what are their effects on health over time? AB - This study tested the effects of social network engagement and social support on the health of older people moving into retirement, using a model which includes social context variables. A prospective survey of a New Zealand population sample aged 54-70 at baseline (N = 2,282) was used to assess the effects on mental and physical health across time. A structural equation model assessed pathways from the social context variables through network engagement to social support and then to mental and physical health 2 years later. The proposed model of effects on mental health was supported when gender, economic living standards, and ethnicity were included along with the direct effects of these variables on social support. These findings confirm the importance of taking social context variables into account when considering social support networks. Social engagement appears to be an important aspect of social network functioning which could be investigated further. PMID- 24956924 TI - Parent status and generativity within the context of race. AB - Generativity, or providing for the next generation (Erikson, 1950), is usually associated with midlife, and related to parenting. However, the extent to which grandparenting or non-parenting are associated with generativity, especially within the context of race, is less well known. The current study uses narrative data from the Foley Longitudinal Study of Adulthood (FLSA; N = 150) to examine the relationship between generativity and parent status--parents, grandparents, as well as non-parents--in midlife African Americans and Whites. Responses to questions concerning future plans in Life Story narratives were coded for four subtypes of generative expression: general generativity, productive generativity, generative caring, and generative need to be needed; these subtypes of generativity were associated with parent status in different ways for middle-aged men and women of each race group. The findings highlight the importance of context, providing a glimpse of expressions of generativity at the intersection of parent status and race. PMID- 24956925 TI - An administrative data validation study of the accuracy of algorithms for identifying rheumatoid arthritis: the influence of the reference standard on algorithm performance. AB - BACKGROUND: We have previously validated administrative data algorithms to identify patients with rheumatoid arthritis (RA) using rheumatology clinic records as the reference standard. Here we reassessed the accuracy of the algorithms using primary care records as the reference standard. METHODS: We performed a retrospective chart abstraction study using a random sample of 7500 adult patients under the care of 83 family physicians contributing to the Electronic Medical Record Administrative data Linked Database (EMRALD) in Ontario, Canada. Using physician-reported diagnoses as the reference standard, we computed and compared the sensitivity, specificity, and predictive values for over 100 administrative data algorithms for RA case ascertainment. RESULTS: We identified 69 patients with RA for a lifetime RA prevalence of 0.9%. All algorithms had excellent specificity (>97%). However, sensitivity varied (75-90%) among physician billing algorithms. Despite the low prevalence of RA, most algorithms had adequate positive predictive value (PPV; 51-83%). The algorithm of "[1 hospitalization RA diagnosis code] or [3 physician RA diagnosis codes with >=1 by a specialist over 2 years]" had a sensitivity of 78% (95% CI 69-88), specificity of 100% (95% CI 100-100), PPV of 78% (95% CI 69-88) and NPV of 100% (95% CI 100-100). CONCLUSIONS: Administrative data algorithms for detecting RA patients achieved a high degree of accuracy amongst the general population. However, results varied slightly from our previous report, which can be attributed to differences in the reference standards with respect to disease prevalence, spectrum of disease, and type of comparator group. PMID- 24956926 TI - Shared signatures of social stress and aging in peripheral blood mononuclear cell gene expression profiles. AB - Chronic social stress is a predictor of both aging-related disease and mortality risk. Hence, chronic stress has been hypothesized to directly exacerbate the process of physiological aging. Here, we evaluated this hypothesis at the level of gene regulation. We compared two data sets of genome-wide gene expression levels in peripheral blood mononuclear cells (PBMCs): one that captured aging effects and another that focused on chronic social stress. Overall, we found that the direction, although not necessarily the magnitude, of significant gene expression changes tends to be shared between the two data sets. This overlap was observable at three levels: (i) individual genes; (ii) general functional categories of genes; and (iii) molecular pathways implicated in aging. However, we also found evidence that heterogeneity in PBMC composition limits the power to detect more extensive similarities, suggesting that our findings reflect an underestimate of the degree to which age and social stress influence gene regulation in parallel. Cell type-specific data on gene regulation will be important to overcome this limitation in the future studies. PMID- 24956928 TI - Full-electron ligand-to-ligand charge transfer in a compact Re(I) complex. AB - Ligand-to-ligand charge transfer (LLCT) states in transition metal complexes are often characterized by fractional electron transfer due to coupling of the LLCT state with many other states via the metal. We designed and characterized a compact Re(I) complex that displays essentially full-electron charge transfer in the LLCT excited state. The complex, [Re(DCEB)(CO)3(L)](+) (DCEB = 4,4' dicarboxyethyl-2,2'-bipyridine), referred to as ReEBA, features two redox active ligands with strong electron accepting (DCEB) and electron donating (L is 3 dimethylaminobenzonitrile (3DMABN)) properties. The lowest energy excited state formed with a ca. 10 ps time constant and was characterized as the full-electron 3DMABN -> DCEB LLCT state using time-resolved infrared spectroscopy (TRIR), transient absorption spectroscopy, and DFT computations. Analysis of a range of vibrational modes helped to assign the charge transfer characteristics of the complex. The LLCT state lifetime in ReEBA shows a strong dependence on the solvent polarity and features solvent dependent frequency shifts for several vibrational reporters. The formation of a full-electron LLCT state (~92%) was enabled by tuning the redox properties of the electron accepting ligand (DCEB) and simultaneously decoupling the redox active group of the electron donating ligand (3DMABN) from the metal center. This strategy is generally applicable for designing compact transition metal complexes that have full-electron LLCT states. PMID- 24956929 TI - Synthesis and characterization of Ag-Co-Ni nanowires. AB - This work provides an electrodeposition-based methodology for synthesizing multicomponent nanowires containing Ag, Co and Ni atoms. Nanowire morphology was obtained by using an anodic alumina membrane with cylindrical pores of ~ 200-nm diameter. Structural, compositional and magnetic characterization revealed that the as-synthesized nanowires adopted a core-shell microstructure. The core (axial region) contained pure Ag phase volumes with a plate-like morphology oriented perpendicular to the nanowire axis. The shell (peripheral region) contained pure Ag nanoparticles along with superparamagnetic Co and Ni rich clusters. PMID- 24956927 TI - Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study. AB - BACKGROUND: Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia. METHODS: We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls. RESULTS: Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls. CONCLUSIONS: We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis. PMID- 24956931 TI - Regional assessment of CO2-solubility trapping potential: a case study of the coastal and offshore Texas Miocene interval. AB - This study presents a regional assessment of CO2-solubility trapping potential (CSTP) in the Texas coastal and offshore Miocene interval, comprising lower, middle, and upper Miocene sandstone. Duan's solubility model [Duan et al. Mar. Chem. 2006, 98, 131-139] was applied to estimate carbon content in brine saturated with CO2 at reservoir conditions. Three approaches (simple, coarse, and fine) were used to calculate the CSTP. The estimate of CSTP in the study area varies from 30 Gt to 167 Gt. Sensitivity analysis indicated that the CSTP in the study area is most sensitive to storage efficiency, porosity, and thickness and is least sensitive to background carbon content in brine. Comparison of CSTP in our study area with CSTP values for seven other saline aquifers reported in the literature showed that the theoretical estimate of CO2-solubility trapping potential (TECSTP) has a linear relationship with brine volume, regardless of brine salinity, temperature, and pressure. Although more validation is needed, this linear relationship may provide a quick estimate of CSTP in a saline aquifer. Results of laboratory experiments of brine-rock-CO2 interactions and the geochemical model suggest that, in the study area, enhancement of CSTP caused by interactions between brine and rocks is minor and the storage capacity of mineral trapping owing to mineral precipitation is relatively trivial. PMID- 24956932 TI - Generalized, painful, ulcerated skin lesions in primary cutaneous CD8-positive aggressive T-cell lymphoma. PMID- 24956930 TI - Interaction of myelin basic protein with cytoskeletal and signaling proteins in cultured primary oligodendrocytes and N19 oligodendroglial cells. AB - BACKGROUND: The classic myelin basic protein (MBP) isoforms are intrinsically disordered proteins of 14-21.5 kDa in size arising from the Golli (Gene in the Oligodendrocyte Lineage) gene complex, and are responsible for formation of the multilayered myelin sheath in the central nervous system. The predominant membrane-associated isoform of MBP is not simply a structural component of compact myelin but is highly post-translationally modified and multi-functional, having interactions with numerous proteins such as Ca2+-calmodulin, and with actin, tubulin, and proteins with SH3-domains, which it can tether to a lipid membrane in vitro. It co-localizes with such proteins in primary oligodendrocytes (OLGs) and in early developmental N19-OLGs transfected with fluorescently-tagged MBP. RESULTS: To provide further evidence for MBP associations with these proteins in vivo, we show here that MBP isoforms are co-immunoprecipitated from detergent extracts of primary OLGs together with actin, tubulin, zonula occludens 1 (ZO-1), cortactin, and Fyn kinase. We also carry out live-cell imaging of N19 OLGs co-transfected with fluorescent MBP and actin, and show that when actin filaments re-assemble after recovery from cytochalasin D treatment, MBP and actin are rapidly enriched and co-localized at certain sites at the plasma membrane and in newly-formed membrane ruffles. The MBP and actin distributions change similarly with time, suggesting a specific and dynamic association. CONCLUSIONS: These results provide more direct evidence for association of the predominant 18.5-kDa MBP isoform with these proteins in primary OLGs and in live cells than previously could be inferred from co-localization observations. This study supports further a role for classic MBP isoforms in protein-protein interactions during membrane and cytoskeletal extension and remodeling in OLGs. PMID- 24956933 TI - Bilateral upper limb digital gangrene in a patient on maintenance hemodialysis. AB - Upper limb gangrene is uncommon compared to lower limb gangrene. But digital gangrene is seen occasionally in patients on maintenance hemodialysis. Of the various causes described, atherosclerosis, diabetic vascular disease, following AV fistula surgery were few of the causes. Herein, we report a case of development of early digital gangrene following AV fistula in a patient on maintenance hemodialysis. PMID- 24956934 TI - Heat shock protein 70 - the next chaperone to target in the treatment of human acute myelogenous leukemia? AB - INTRODUCTION: Heat shock proteins (HSPs) are molecular chaperones that stabilize folding and conformation of mature proteins. HSPs are, therefore, considered as possible therapeutic targets in the treatment of human cancers, including acute myeloid leukemia (AML). This strategy offers the possibility of targeting several oncogenic proteins or several intracellular signaling pathways through the use of a single therapeutic agent. AREAS COVERED: Several specific HSP70 inhibitors have now been developed. We describe: i) the molecular structure of HSP70 and the molecular interactions especially with its co-chaperones; ii) the immunoregulatory functions of HSP70; iii) the expression and function of HSP70 in human AML cells; iv) the molecular and pharmacological characteristics of potential HSP70 inhibitors; and v) the clinical and experimental studies of HSP70 inhibition in human AML. Our review is based on careful selection of relevant publications identified in the PubMed database. EXPERT OPINION: HSP70 inhibitors have antileukemic activity in human AML. However, additional experimental studies using in vitro models as well as animal models are required, including detailed toxicology studies, as a scientific basis for the optimal design of future clinical studies. PMID- 24956935 TI - Protecting effect of caffeine against vinblastine (an anticancer drug) induced genotoxicity in mice. AB - Vinblastine a DNA non-intercalating agent has wide application against several human neoplasms, and found to cause cytogenotoxicity. In this study, clastogenotoxicity of vinblastine (1.5 mg/kg b w) and its prevention by caffeine at different doses (25, 50 and 100 mg/kg b w) administered intraperitoneally was assessed in in vivo mice. It was found that micronucleus level had decreased significantly (up to 28.8%) in 100 mg caffeine treated group at 30 h post treatment. However, it did not exhibit protective effect against chromosomal aberration in spaermatogonial cells at 24 h post treatment. The frequencies of aberrant primary spermatocytes had decreased significantly in 25 and 100 mg caffeine at 4th week of post treatment. Similarly, in 100 mg of caffeine administered, abnormal sperm level had reduced (4.01%) significantly at 8th week post treatment. Thus, caffeine decreased the vinblastine induced chromosomal aberrations and mitotic index in bone marrow cells. In conclusion, this study shows that caffeine exerts protective effect against vinblastin induced cytogenotoxicity. Further studies on molecular mechanism are interesting in order to develop it as an effective drug in cancer chemotherapy. PMID- 24956936 TI - Making the right software choice for clinically used equipment in radiation oncology. AB - The customer of a new system for clinical use in radiation oncology must consider many options in order to find the optimal combination of software tools. Many commercial systems are available and each system has a large number of technical features. However an appraisal of the technical capabilities, especially the options for clinical implementations, is hardly assessable at first view.The intention of this article was to generate an assessment of the necessary functionalities for high precision radiotherapy and their integration in ROKIS (Radiation oncology clinic information system) for future customers, especially with regard to clinical applicability. Therefore we analysed the clinically required software functionalities and divided them into three categories: minimal, enhanced and optimal requirements for high conformal radiation treatment. PMID- 24956937 TI - Integration of existing systematic reviews into new reviews: identification of guidance needs. AB - BACKGROUND: An exponential increase in the number of systematic reviews published, and constrained resources for new reviews, means that there is an urgent need for guidance on explicitly and transparently integrating existing reviews into new systematic reviews. The objectives of this paper are: 1) to identify areas where existing guidance may be adopted or adapted, and 2) to suggest areas for future guidance development. METHODS: We searched documents and websites from healthcare focused systematic review organizations to identify and, where available, to summarize relevant guidance on the use of existing systematic reviews. We conducted informational interviews with members of Evidence-based Practice Centers (EPCs) to gather experiences in integrating existing systematic reviews, including common issues and challenges, as well as potential solutions. RESULTS: There was consensus among systematic review organizations and the EPCs about some aspects of incorporating existing systematic reviews into new reviews. Current guidance may be used in assessing the relevance of prior reviews and in scanning references of prior reviews to identify studies for a new review. However, areas of challenge remain. Areas in need of guidance include how to synthesize, grade the strength of, and present bodies of evidence composed of primary studies and existing systematic reviews. For instance, empiric evidence is needed regarding how to quality check data abstraction and when and how to use study-level risk of bias assessments from prior reviews. CONCLUSIONS: There remain areas of uncertainty for how to integrate existing systematic reviews into new reviews. Methods research and consensus processes among systematic review organizations are needed to develop guidance to address these challenges. PMID- 24956939 TI - Low dose rate radiosensitization of hepatocellular carcinoma in vitro and in patients. AB - Transarterial radioembolization (TARE) with (90)Y microspheres delivers low dose rate radiation (LDR) to intrahepatic tumors. In the current study, we examined clonogenic survival, DNA damage, and cell cycle distribution in hepatocellular carcinoma (HCC) cell lines treated with LDR in combination with varying doses and schedules of 5-fluorouracil (5-FU), gemcitabine, and sorafenib. Radiosensitization was seen with 1 to 3 MUM 5-FU (enhancement ratio 2.2-13.9) and 30 to 100 nM gemcitabine (enhancement ratio 1.9-2.9) administered 24 hours before LDR (0.26 Gy/h to 4.2 Gy). Sorafenib radiosensitized only at high concentrations (3-10 MUM) when administered after LDR. For a given radiation dose, greater enhancement was seen with LDR compared to standard dose rate therapy. Summarizing our clinical experience with low dose rate radiosensitization, 13 patients (5 with HCC, 8 with liver metastases) were treated a total of 16 times with TARE and concurrent gemcitabine. Six partial responses and one complete response were observed with a median time to local failure of 7.1 months for all patients and 9.9 months for patients with HCC. In summary, HCC is sensitized to LDR with clinically achievable concentrations of gemcitabine and 5-FU in vitro. Encouraging responses were seen in a small cohort of patients treated with TARE and concurrent gemcitabine. Future studies are needed to validate the safety and efficacy of this approach. PMID- 24956938 TI - MicroRNA-196a and -196b as Potential Biomarkers for the Early Detection of Familial Pancreatic Cancer. AB - Screening programs are recommended for individuals at risk (IAR) from families with familial pancreatic cancer (FPC). However, reliable imaging methods or biomarkers for early diagnosis of pancreatic ductal adenocarcinoma (PC) or its precursor lesions are still lacking. The ability of circulating microRNAs (miRNAs) to discriminate multifocal high-grade precursor lesions or PC from normal was examined. The presence of miRNA-21, -155, -196a, -196b and -210 was analyzed in the serum of transgenic KPC mice to test their ability to distinguish mice with different grades of pancreatic intraepithelial neoplasia (mPanIN1-3) or PC from control mice. Serum levels of miR-196a and -196b were significantly higher in mice with PanIN2/3 lesions (n = 10) or PC (n = 8) as compared to control mice (n = 10) or mice with PanIN1 lesions (n = 10; P = .01). In humans, miR-196a and -196b were also diagnostic. Patients with PC, sporadic (n = 9) or hereditary (n = 10), and IAR with multifocal PanIN2/3 lesions (n = 5) had significantly higher serum levels than patients with neuroendocrine pancreatic tumors (n = 10) or chronic pancreatitis (n = 10), IAR with PanIN1 or no PanIN lesions (n = 5), and healthy controls (n = 10). The combination of both miR-196a and -196b reached a sensitivity of 1 and specificity of 0.9 (area under the curve = 0.99) to diagnose PC or high-grade PanIN lesions. In addition, preoperative elevated serum levels of miR-196a and -196b in patients with PC or multifocal PanIN2/3 lesions dropped to normal after potential curative resection. The combination of miR-196a and -196b may be a promising biomarker test for the screening of IAR for FPC. PMID- 24956940 TI - Strategic Co-Location in a Hybrid Process Involving Desalination and Pressure Retarded Osmosis (PRO). AB - This paper focuses on a Hybrid Process that uses feed salinity dilution and osmotic power recovery from Pressure Retarded Osmosis (PRO) to achieve higher overall water recovery. This reduces the energy consumption and capital costs of conventional seawater desalination and water reuse processes. The Hybrid Process increases the amount of water recovered from the current 66.7% for conventional seawater desalination and water reuse processes to a potential 80% through the use of reclaimed water brine as an impaired water source. A reduction of up to 23% in energy consumption is projected via the Hybrid Process. The attractiveness is amplified by potential capital cost savings ranging from 8.7%-20% compared to conventional designs of seawater desalination plants. A decision matrix in the form of a customizable scorecard is introduced for evaluating a Hybrid Process based on the importance of land space, capital costs, energy consumption and membrane fouling. This study provides a new perspective, looking at processes not as individual systems but as a whole utilizing strategic co-location to unlock the synergies available in the water-energy nexus for more sustainable desalination. PMID- 24956941 TI - Successful integration of membrane technologies in a conventional purification process of tannery wastewater streams. AB - The aim of this work is to design and integrate an optimized batch membrane process in a conventional purification process used for the treatment of tannery wastewater. The integration was performed by using two spiral wound membrane modules in series, that is, nanofiltration and reverse osmosis, as substitutes to the biological reactor. The membrane process was designed in terms of sensible fouling issues reduction, which may be observed on the nanofiltration membrane if no optimization is performed. The entity of the fouling phenomena was estimated by pressure cycling measurements, determining both the critical and the threshold flux on the nanofiltration membrane. The obtained results were used to estimate the need of the overdesign of the membrane plant, as well as to define optimized operating conditions in order to handle fouling issues correctly for a long period of time. Finally, the developed membrane process was compared, from a technical and economic point of view, with the conventional biological process, widely offered as an external service near tannery production sites, and, here, proposed to be substituted by membrane technologies. PMID- 24956942 TI - Performance and long term stability of mesoporous silica membranes for desalination. AB - This work shows the preparation of silica membranes by a two-step sol-gel method using tetraethyl orthosilicate in ethanolic solution by employing nitric acid and ammonia as co-catalysts. The sols prepared in pH 6 resulted in the lowest concentration of silanol (Si-OH) species to improve hydrostability and the optimized conditions for film coating. The membrane was tested to desalinate 0.3 15 wt % synthetic sodium chloride (NaCl) solutions at a feed temperature of 22 degrees C followed by long term membrane performance of up to 250 h in 3.5 wt % NaCl solution. Results show that the water flux (and salt rejection) decrease with increasing salt concentration delivering an average value of 9.5 kg m-2 h-1 (99.6%) and 1.55 kg m-2 h-1 (89.2%) from the 0.3 and 15 wt % saline feed solutions, respectively. Furthermore, the permeate salt concentration was measured to be less than 600 ppm for testing conditions up to 5 wt % saline feed solutions, achieving below the recommended standard for potable water. Long term stability shows that the membrane performance in water flux was stable for up to 150 h, and slightly reduced from thereon, possibly due to the blockage of large hydrated ions in the micropore constrictions of the silica matrix. However, the integrity of the silica matrix was not affected by the long term testing as excellent salt rejection of >99% was maintained for over 250 h. PMID- 24956943 TI - Temperature and Pressure Effects of Desalination Using a MFI-Type Zeolite Membrane. AB - Zeolites are potentially a robust desalination alternative, as they are chemically stable and possess the essential properties needed to reject ions. Zeolite membranes could desalinate "challenging" waters, such as saline secondary effluent, without any substantial pre-treatment, due to the robust mechanical properties of ceramic membranes. A novel MFI-type zeolite membrane was developed on a tubular alpha-Al2O3 substrate by a combined rubbing and secondary hydrothermal growth method. The prepared membrane was characterised by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and single gas (He or N2) permeation and underwent desalination tests with NaCl solutions under different pressures (0.7 MPa and 7 MPa). The results showed that higher pressure resulted in higher Na+ rejection and permeate flux. The zeolite membrane achieved a good rejection of Na+ (~82%) for a NaCl feed solution with a TDS (total dissolved solids) of 3000 mg.L-1 at an applied pressure of 7 MPa and 21 degrees C. To explore the opportunity for high salinity and high temperature desalination, this membrane was also tested with high concentration NaCl solutions (up to TDS 90,000 mg.L-1) and at 90 degrees C. This is the first known work at such high salinities of NaCl. It was found that increasing the salinity of the feed solution decreased both Na+ rejection and flux. An increase in testing temperature resulted in an increase in permeate flux, but a decrease in ion rejection. PMID- 24956945 TI - The Effects of Sulfonated Poly(ether ether ketone) Ion Exchange Preparation Conditions on Membrane Properties. AB - A low cost cation exchange membrane to be used in a specific bioelectrochemical system has been developed using poly(ether ether ketone) (PEEK). This material is presented as an alternative to current commercial ion exchange membranes that have been primarily designed for fuel cell applications. To increase the hydrophilicity and ion transport of the PEEK material, charged groups are introduced through sulfonation. The effect of sulfonation and casting conditions on membrane performance has been systematically determined by producing a series of membranes synthesized over an array of reaction and casting conditions. Optimal reaction and casting conditions for producing SPEEK ion exchange membranes with appropriate performance characteristics have been established by this uniquely systematic experimental series. Membrane materials were characterized by ion exchange capacity, water uptake, swelling, potential difference and NMR analysis. Testing this extensive membranes series established that the most appropriate sulfonation conditions were 60 degrees C for 6 h. For mechanical stability and ease of handling, SPEEK membranes cast from solvent casting concentrations of 15%-25% with a resulting thickness of 30-50 um were also found to be most suitable from the series of tested casting conditions. Drying conditions did not have any apparent impact on the measured parameters in this study. The conductivity of SPEEK membranes was found to be in the range of 10-3 S cm-1, which is suitable for use as a low cost membrane in the intended bioelectrochemical systems. PMID- 24956944 TI - Affinity separation of lectins using porous membranes immobilized with glycopolymer brushes containing mannose or N-acetyl-d-glucosamine. AB - Porous membranes with glycopolymer brushes were prepared as biomaterials for affinity separation. Glycopolymer brushes contained acrylic acid and D-mannose or N-acetyl-D-glucosamine, and were formed on substrates by surface-initiated atom transfer radical polymerization. The presence of glycopolymer brush was confirmed by X-ray photoelectron spectroscopy, contact angle, and ellipsometry measurements. The interaction between lectin and the glycopolymer immobilized on glass slides was confirmed using fluorescent-labeled proteins. Glycopolymer immobilized surfaces exhibited specific adsorption of the corresponding lectin, compared with bovine serum albumin. Lectins were continuously rejected by the glycopolymer-immobilized membranes. When the protein solution was permeated through the glycopolymer-immobilized membrane, bovine serum albumin was not adsorbed on the membrane surface. In contrast, concanavalin A and wheat germ agglutinin were rejected by membranes incorporating D-mannose or N-acetyl-D glucosamine, respectively. The amounts of adsorbed concanavalin A and wheat germ agglutinin was increased five- and two-fold that of adsorbed bovine serum albumin, respectively. PMID- 24956946 TI - Study of the effect of nanoparticles and surface morphology on reverse osmosis and nanofiltration membrane productivity. AB - To evaluate the significance of reverse osmosis (RO) and nanofiltration (NF) surface morphology on membrane performance, productivity experiments were conducted using flat-sheet membranes and three different nanoparticles, which included SiO2, TiO2 and CeO2. In this study, the productivity rate was markedly influenced by membrane surface morphology. Atomic force microscopy (AFM) analysis of membrane surfaces revealed that the higher productivity decline rates associated with polyamide RO membranes as compared to that of a cellulose acetate NF membrane was due to the inherent ridge-and-valley morphology of the active layer. The unique polyamide active layer morphology was directly related to the surface roughness, and was found to contribute to particle accumulation in the valleys causing a higher flux decline than in smoother membranes. Extended RO productivity experiments using laboratory grade water and diluted pretreated seawater were conducted to compare the effect that different nanoparticles had on membrane active layers. Membrane flux decline was not affected by particle type when the feed water was laboratory grade water. On the other hand, membrane productivity was affected by particle type when pretreated diluted seawater served as feed water. It was found that CeO2 addition resulted in the least observable flux decline, followed by SiO2 and TiO2. A productivity simulation was conducted by fitting the monitored flux data into a cake growth rate model, where the model was modified using a finite difference method to incorporate surface thickness variation into the analysis. The ratio of cake growth term (k1) and particle back diffusion term (k2) was compared in between different RO and NF membranes. Results indicated that k2 was less significant for surfaces that exhibited a higher roughness. It was concluded that the valley areas of thin-film membrane surfaces have the ability to capture particles, limiting particle back diffusion. PMID- 24956947 TI - Pretreatment and membrane hydrophilic modification to reduce membrane fouling. AB - The application of low pressure membranes (microfiltration/ultrafiltration) has undergone accelerated development for drinking water production. However, the major obstacle encountered in its popularization is membrane fouling caused by natural organic matter (NOM). This paper firstly summarizes the two factors causing the organic membrane fouling, including molecular weight (MW) and hydrophilicity/hydrophobicity of NOM, and then presents a brief introduction of the methods which can prevent membrane fouling such as pretreatment of the feed water (e.g., coagulation, adsorption, and pre-oxidation) and membrane hydrophilic modification (e.g., plasma modification, irradiation grafting modification, surface coating modification, blend modification, etc.). Perspectives of further research are also discussed. PMID- 24956948 TI - Can biochemistry usefully guide the search for better polymer electrolytes? AB - I review some considerations that suggest that the biochemical products of evolution may provide hints concerning the way forward for the development of better electrolytes for lithium polymer batteries. PMID- 24956950 TI - Measuring the molecular dimensions of wine tannins: comparison of small-angle X ray scattering, gel-permeation chromatography and mean degree of polymerization. AB - The molecular size of wine tannins can influence astringency, and yet it has been unclear as to whether the standard methods for determining average tannin molecular weight (MW), including gel-permeation chromatography (GPC) and depolymerization reactions, are actually related to the size of the tannin in wine-like conditions. Small-angle X-ray scattering (SAXS) was therefore used to determine the molecular sizes and corresponding MWs of wine tannin samples from 3 and 7 year old Cabernet Sauvignon wine in a variety of wine-like matrixes: 5-15% and 100% ethanol; 0-200 mM NaCl and pH 3.0-4.0, and compared to those measured using the standard methods. The SAXS results indicated that the tannin samples from the older wine were larger than those of the younger wine and that wine composition did not greatly impact on tannin molecular size. The average tannin MWs as determined by GPC correlated strongly with the SAXS results, suggesting that this method does give a good indication of tannin molecular size in wine like conditions. The MW as determined from the depolymerization reactions did not correlate as strongly with the SAXS results. To our knowledge, SAXS measurements have not previously been attempted for wine tannins. PMID- 24956949 TI - Feeding butter with elevated content of trans-10, cis-12 conjugated linoleic acid to lean rats does not impair glucose tolerance or muscle insulin response. AB - BACKGROUND: Numerous studies have investigated the effects of isolated CLA supplementation on glucose homeostasis in humans and rodents. However, both the amount and relative abundance of CLA isomers in supplemental form are not representative of what is consumed from natural sources. No study to date has examined the effects of altered CLA isomer content within a natural food source. Our goal was to increase the content of the insulin desensitizing CLAt10,c12 isomer relative to the CLAc9,t11 isomer in cow's milk by inducing subacute rumenal acidosis (SARA), and subsequently investigate the effects of this milk fat on parameters related to glucose and insulin tolerance in rats. METHODS: We fed female rats (~2.5 to 3 months of age) CLA t10,c12 -enriched (SARA) butter or non-SARA butter based diets for 4 weeks in either low (10% of kcal from fat; 0.18% total CLA by weight) or high (60% of kcal from fat; 0.55% total CLA by weight) amounts. In an effort to extend these findings, we then fed rats high (60% kcal) amounts of SARA or non-SARA butter for a longer duration (8 weeks) and assessed changes in whole body glucose, insulin and pyruvate tolerance in comparison to low fat and 60% lard conditions. RESULTS: There was a main effect for increased fasting blood glucose and insulin in SARA vs. non-SARA butter groups after 4 weeks of feeding (p < 0.05). However, blood glucose and insulin concentration, and maximal insulin-stimulated glucose uptake in skeletal muscle were similar in all groups. Following 8 weeks of feeding, insulin tolerance was impaired by the SARA butter, but not glucose or pyruvate tolerance. The non-SARA butter did not impair tolerance to glucose, insulin or pyruvate. CONCLUSIONS: This study suggests that increasing the consumption of a naturally enriched CLAt10,c12 source, at least in rats, has minimal impact on whole body glucose tolerance or muscle specific insulin response. PMID- 24956951 TI - Body surface temperature distribution in relation to body composition in obese women. AB - Adipose tissue levels and human obesity are known to be associated with increased heat production. At the same time, subcutaneous adipose tissue provides an insulating layer that impedes heat loss. The energy implications of obesity and body thermoregulatory mechanisms remain relatively poorly understood. This study attempted to examine the potential relationship between body composition (subcutaneous and visceral fat) determined by bioimpedance as well as BMI (body mass index), and skin surface temperature distribution recorded at rest. One specific aim of this study was to draw a thermal map of body areas in obese women and compare this with women of normal body mass, and thus to identify body regions within which heat transfer is particularly impeded. As high fat content is a good insulator, it could reduce the body's ability to respond effectively to changes in environmental temperature, which would be problematic for thermal homeostasis. Our results showed that core temperature did not differ between obese and normal body mass participants, while skin temperature of most body surfaces was lower in obese subjects. The results of regression analysis showed that the mean body surface temperature (Tmean) decreased with increasing percentage of body fat (PBF) of the abdominal area. The opposite relationship was observed for the front area of the hand (simultaneous increase in Tmean and PBF). We also found a negative correlation between BMI and Tmean of the thigh areas, both the front and the back. From this it could be concluded that the mean body surface temperature is dependent on body fat. PMID- 24956952 TI - A reduced core to skin temperature gradient, not a critical core temperature, affects aerobic capacity in the heat. AB - The purpose of this study was to determine the impact of the core to skin temperature gradient during incremental running to volitional fatigue across varying environmental conditions. A secondary aim was to determine if a "critical" core temperature would dictate volitional fatigue during running in the heat. 60 participants (n=49 male, n=11 female; 24+/-5 yrs, 177+/-11 cm, 75+/ 13 kg) completed the study. Participants were uniformly stratified into a specific exercise temperature group (18 degrees C, 26 degrees C, 34 degrees C, or 42 degrees C) based on a 3-mile run performance. Participants were equipped with core and chest skin temperature sensors and a heart rate monitor, entered an environmental chamber (18 degrees C, 26 degrees C, 34 degrees C, or 42 degrees C), and rested in the seated position for 10 min before performing a walk/run to volitional exhaustion. Initial treadmill speed was 3.2 km h(-1) with a 0% grade. Every 3 min, starting with speed, speed and grade increased in an alternating pattern (speed increased by 0.805 km h(-1), grade increased by 0.5%). Time to volitional fatigue was longer for the 18 degrees C and 26 degrees C group compared to the 42 degrees C group, (58.1+/-9.3 and 62.6+/-6.5 min vs. 51.3+/-8.3 min, respectively, p<0.05). At the half-way point and finish, the core to skin gradient for the 18 degrees C and 26 degrees C groups was larger compared to 42 degrees C group (halfway: 2.6+/-0.7 and 2.0+/-0.6 vs. 1.3+/-0.5 for the 18 degrees C, 26 degrees C and 42 degrees C groups, respectively; finish: 3.3+/-0.7 and 3.5+/-1.1 vs. 2.1+/-0.9 for the 26 degrees C, 34 degrees C, and 42 degrees C groups, respectively, p<0.05). Sweat rate was lower in the 18 degrees C group compared to the 26 degrees C, 34 degrees C, and 42 degrees C groups, 3.6+/-1.3 vs. 7.2+/-3.0, 7.1+/-2.0, and 7.6+/-1.7 g m(-2) min(-1), respectively, p<0.05. There were no group differences in core temperature and heart rate response during the exercise trials. The current data demonstrate a 13% and 22% longer run time to exhaustion for the 18 degrees C and 26 degrees C group, respectively, compared to the 42 degrees C group despite no differences in beginning and ending core temperatures or baseline 3-mile run time. This capacity difference appears to result from a magnified core to skin gradient via an environmental temperature advantageous to convective heat loss, and in part from an increased sweat rate. PMID- 24956953 TI - The effect of seasonal temperature variation on behaviour and metabolism in the freshwater mussel (Unio tumidus). AB - Temperature plays a critical role in determining the biology of ectotherms. Many animals have evolved mechanisms that allow them to compensate biological rates, i.e. adjust biological rates to overcome thermodynamic effects. For low energy organisms, such as bivalves, the costs of thermal compensation may be greater than the benefits, and thus prohibitive. To examine this, two experiments were designed to explore thermal compensation in Unio tumidus. Experiment 1 examined seasonal changes in behaviour in U. tumidus throughout a year. Temperature had a clear effect on burrowing rate with no evidence of compensation. Valve closure duration and frequency were also strongly affected by seasonal temperature change, but there was slight evidence of partial compensation. Experiment 2 examined oxygen consumption during burrowing, immediately following valve opening and at rest in summer (24 degrees C), autumn (14 degrees C), winter (4 degrees C), and spring (14 degrees C) acclimatized U. tumidus. Again, there was little evidence of burrowing rate compensation, but some evidence of partial compensation of valve closure duration and frequency. None of the oxygen compensation rates showed any evidence of thermal compensation. Thus, in general, there was only very limited evidence of thermal compensation of behaviour and no evidence of thermal compensation of oxygen compensation rates. Based upon this evidence, we argue that there is no evolutionary pressure for these bivalves to compensate these biological rates. Any pressure may be to maintain or even lower oxygen consumption as their only defence against predation is to close their valves and wait. An increase in oxygen consumption will be detrimental in this regard so the cost of thermal compensation may outweigh the benefits. PMID- 24956954 TI - Using thermal stress to model aspects of disease states. AB - Exposure to acute heat or cold stress elicits numerous physiological responses aimed at maintaining body temperatures. Interestingly, many of the physiological responses, mediated by the cardiovascular and autonomic nervous systems, resemble aspects of, or responses to, certain disease states. The purpose of this Perspective is to highlight some of these areas in order to explore how they may help us better understand the pathophysiology underlying aspects of certain disease states. The benefits of using this human thermal stress approach are that (1) no adjustments for inherent comparative differences in animals are needed, (2) non-medicated healthy humans with no underlying co-morbidities can be studied in place of complex patients, and (3) more mechanistic perturbations can be safely employed without endangering potentially vulnerable populations. Cold stress can be used to induce stable elevations in blood pressure. Cold stress may also be used to model conditions where increases in myocardial oxygen demand are not met by anticipated increases in coronary blood flow, as occurs in older adults. Lower-body negative pressure has the capacity to model aspects of shock, and the further addition of heat stress improves and expands this model because passive-heat exposure lowers systemic vascular resistance at a time when central blood volume and left-ventricular filling pressure are reduced. Heat stress can model aspects of heat syncope and orthostatic intolerance as heat stress decreases cerebral blood flow and alters the Frank-Starling mechanism resulting in larger decreases in stroke volume for a given change in left-ventricular filling pressure. Combined, thermal perturbations may provide in vivo paradigms that can be employed to gain insights into pathophysiological aspects of certain disease states. PMID- 24956955 TI - Direct effects of incubation temperature on morphology, thermoregulatory behaviour and locomotor performance in jacky dragons (Amphibolurus muricatus). AB - Incubation temperature is one of the most studied factors driving phenotypic plasticity in oviparous reptiles. We examined how incubation temperature influenced hatchling morphology, thermal preference and temperature-dependent running speed in the small Australian agamid lizard Amphibolurus muricatus. Hatchlings incubated at 32 degrees C grew more slowly than those incubated at 25 and 28 degrees C during their first month after hatching, and tended to be smaller at one month. These differences were no longer significant by three months of age due to selective mortality of the smallest hatchlings. The cooler incubation treatments (25 degrees C and 28 degrees C) produced lizards that had deeper and wider heads. Hatchlings from 28 degrees C had cooler and more stable temperature preferences, and also had lower body temperatures during a 2-h thermoregulatory behaviour trial. Locomotor performance was enhanced at higher body temperatures, but incubation temperature had no measurable effect either independently or in interaction with body temperature. Our study demonstrates that incubation temperature has direct effects on morphology and thermoregulatory behaviour that appears to be independent of any size-dependent effects. We postulate a mechanistic link between these two effects. PMID- 24956956 TI - Influence of in ovo thermal manipulation on lipid metabolism in embryonic duck liver. AB - The growth and development of poultry embryos are easily affected by environmental factors, such as the incubation temperature and humidity. Metabolism, including lipid metabolism, during the embryonic stage is also important for the growth and development of poultry. Our study aimed to investigate the effects of incubation temperature on embryonic lipid metabolism in the liver of ducks. To fully evaluate the effects, thermal treatment was given between embryonic ages 11 and 24 days with a 1 degrees C higher incubation temperature than the control group, and lipid metabolism parameters in the liver and blood serum were analyzed both at embryonic stage day 20 and 2 weeks post hatching. Our results showed no significant changes in the embryonic stage in total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) in the blood serum (P>0.05). Additionally, the mRNA expression levels and enzyme activities of fatty acid synthase (FAS), acetyl CoA carboxylase (ACC), and elongase of very long chain fatty acids (ELOVL) did not show significant changes either in the embryonic stage or at hatching day 20 (P>0.05). However, there were significant changes in the gene expression and enzyme activities of TC, LDL-C and FAS at post hatching stages (P<=0.05). These results may indicate that the thermal treatment has less influence on lipid metabolism in the embryonic stage but has a much stronger effect in the post-hatching stage. PMID- 24956958 TI - Coloration affects heating and cooling in three color morphs of the Australian bluetongue lizard, Tiliqua scincoides. AB - The color-mediated thermoregulation hypothesis predicts that dark body color (low reflectance) allows organisms to gain heat more efficiently than does pale coloration (high reflectance). This prediction is intuitive and widely assumed to be true, but has poor empirical support. We used rare, captive-bred, mutant melanistic, albino and wild-type Australian bluetongue lizards, Tiliqua scincoides to measure the effects of skin reflectance on the heating and cooling rates. We measured heating under an artificial radiant heat source and cooling rates in an ice-cooled box using live lizards in a room with still air. The effect of skin reflectance on heat transfer was clear, despite the substantial influence of body size. Melanistic T. scincoides showed low reflectance and gained heat faster than highly reflective albinos. Melanistic lizards also lost heat faster than albinos. Wild-type lizards were intermediate in reflectance, gained heat at rates indistinguishable from melanistic lizards, and lost heat at rates indistinguishable from albino lizards. This study system allowed us to control for variables that were confounded in other studies and may explain the inconsistent support for the color-mediated thermoregulation hypothesis. Our results provide clear evidence that skin reflectance influences the rate of heating and cooling in ectotherms. PMID- 24956957 TI - Effect of thermal stress on HSP70 expression in dermal fibroblast of zebu (Tharparkar) and crossbred (Karan-Fries) cattle. AB - The present studies were conducted to investigate the difference response of dermal fibroblasts to heat stress in Tharparkar and Karan-Fries cattle. Skin is the most important environmental interface providing a protective envelope to animals. In skin, dermal fibroblasts are the most regular cell constituent of dermis that is crucial for temperature homeostasis. The study aimed to examine the reactive oxygen species (ROS) formation, cytotoxicity (%) and heat shock protein 70 (HSP70) genes expression in dermal fibroblast of Tharparkar and Karan Fries cattle and to assess whether resistance of dermal fibroblast to heat stress is breed specific. Dermal fibroblasts from ear pinna of Tharparkar and Karan Fries cattle were exposed at 25 degrees C, 37 degrees C, 40 degrees C and 44 degrees C for 3 h to measure the ROS, cytotoxicity (%) and HSP 70 (HSPA1A, HSPA2 and HSPA8) genes' expression. The results showed that ROS formation at low temperature (25 degrees C) decreased in both breeds as compared to control (37 degrees C) and the differences were significant (P<0.0001). Heat stress at 40 degrees C did not increase ROS formation significantly in Tharparkar but increased significantly (P<0.001) in Karan-Fries cattle. The overall cytotoxicity (%) was also found to be significantly different (P<0.001) between Tharparkar and Karan-Fries cattle, and on exposure to different temperatures (P<0.001). The cytotoxicity (%) in dermal fibroblast cells of Karan-fries cows was more than Tharparkar. The expression studies indicated that all HSP70 genes (HSPA8, HSPA1A and HSPA2) were up-regulated at different temperatures in both breeds. In Tharparkar, the relative mRNA expression of HSPA8 gene was higher but HSPA1A and HSPA2 genes were low as compared to Karan-Fries cattle. At 40 and 44 degrees C, the relative expressions of inducible HSP 70 genes (HSPA1A and HSPA2) were higher in Karan-Fries than Tharparkar. In summary, dermal fibroblast resistance to heat shock differed between breeds. Dermal fibroblasts of Tharparkar were observed to be more heat tolerant than crossbred Karan-Fries cattle. The study concludes that zebu cattle (Tharparkar) dermal fibroblasts are more adapted to tropical climatic condition than crossbreed cattle (Karan-Fries). Differences exist in dermal fibroblasts of heat adapted and non-adapted cattle. PMID- 24956960 TI - Investigation on nanoparticle distribution for thermal ablation of a tumour subjected to nanoparticle assisted thermal therapy. AB - This study investigates the effect of the distribution of nanoparticles delivered to a skin tumour for the thermal ablation conditions attained during thermal therapy. Ultimate aim is to define a distribution of nanoparticles as well as a combination of other therapeutic parameters to attain thermal ablation temperatures (50-60 degrees C) within whole of the tumour region. Three different cases of nanoparticle distributions are analysed under controlled conditions for all other parameters viz. irradiation intensity and duration, and volume fraction of nanoparticles. Results show that distribution of nanoparticles into only the periphery of tumour resulted in desired thermal ablation temperature in whole of tumour. For the tumour size considered in this study, an irradiation intensity of 1.25 W/cm(2) for duration of 300 s and a nanoparticle volume fraction of 0.001% was optimal to attain a temperature of >=53 degrees C within the whole tumour region. It is concluded that distribution of nanoparticles in peripheral region of tumour, along with a controlled combination of other parameters, seems favourable and provides a promising pathway for thermal ablation of a tumour subjected to nanoparticle assisted thermal therapy. PMID- 24956959 TI - Immunolocalization of aquaporins 1, 3, and 5 in the nasal respiratory mucosa of a panting species, the sheep (Ovis aries). AB - The nasal respiratory mucosa is the primary site for evaporative water loss in panting species, necessitating the movement of water across the nasal epithelium. Aquaporins (AQP) are protein channels that facilitate water movement in various fluid transporting tissues of non-panting species. Whether the requirement for enhanced capacity for transepithelial water movement in the nasal respiratory mucosa of panting species has led to differences in AQP localization is unknown. Using immunohistochemistry, we report the localization of AQP1, 3, and 5 in the nasal respiratory mucosa of sheep being exposed to ambient temperatures of ~21 degrees C or ~38 degrees C for 4.5 h before death (n=3/treatment). Exposure to either treatment resulted in panting. While exposure to ~38 degrees C resulted in a higher respiratory frequency (mean difference: 82 breaths min(-1); P<0.001) than exposure to ~21 degrees C, there was no difference in the localization of AQPs. Connective tissue and vascular endothelial cells expressed AQP1. Glandular acini expressed AQP1 and apically localized AQP5, which was also present in glandular duct cells. Ciliated columnar epithelial cells expressed AQP5 apically and AQP3 basolaterally. Basal cells expressed AQP3. The distribution and co localization of AQPs in the ovine nasal respiratory mucosa is different to that reported in non-panting species and may reflect the physiological demands associated with enhanced respiratory evaporation. We propose that AQP1, 3, and 5 may constitute a transepithelial water pathway via glandular secretions and across the surface epithelium, which provides a possible means for rapid and controllable water movement in the nasal respiratory mucosa of a panting species. PMID- 24956961 TI - Shallow hypothermia depends on the level of fatty acid unsaturation in adipose and liver tissues in a tropical heterothermic primate. AB - Optimal levels of unsaturated fatty acids have positive impacts on the use of prolonged bouts of hypothermia in mammalian hibernators, which generally have to face low winter ambient temperatures. Unsaturated fatty acids can maintain the fluidity of fat and membrane phospholipids at low body temperatures. However, less attention has been paid to their role in the regulation of shallow hypothermia, and in tropical species, which may be challenged more by seasonal energetic and/or water shortages than by low temperatures. The present study assessed the relationship between the fatty acids content of white adipose and liver tissues and the expression of shallow hypothermia in a tropical heterothermic primate, the gray mouse lemur (Microcebus murinus). The adipose tissue is the main tissue for fat storage and the liver is involved in lipid metabolism, so both tissues were expected to influence hypothermia dependence on fatty acids. As mouse lemurs largely avoid deep hypothermia (i.e. torpor) use under standard captive conditions, the expression of hypothermia was triggered by food-restricting experimental animals. Hypothermia depth increased with time, with a stronger increase for individuals that exhibited higher contents of unsaturated fatty acids suggesting that they were more flexible in their use of hypothermia. However these same animals delayed the use of long hypothermia bouts relative to individuals with a higher level of saturated fatty acids. This study evidences for the first time that body fatty acids unsaturation levels influence the regulation of body temperature not only in cold-exposed hibernators but also in tropical, facultative heterotherms. PMID- 24956962 TI - The impact of clonidine on sedation after adenotonsillectomy: a prospective audit. AB - AIMS: Clonidine may be used intraoperatively to decrease emergence delirium in children, but the drug's impact on postoperative sedation is poorly quantified. METHODS: A prospective audit of children (<=15 years) undergoing (adeno) tonsillectomy or adenoidectomy over a period of 4 months was carried out. All children received sevoflurane for induction and maintenance of anesthesia. The use of clonidine as an adjunct was left to the discretion of the anesthesiologist. Postoperative sedation was assessed using the University of Michigan Sedation Scale (UMSS) at 30 min intervals until discharge. Arousal was characterized using a zero asymptote model. The impact of clonidine dose on half time to an awake state after anesthesia was investigated using nonlinear mixed effects models. Survival analysis was used to explore the effect of clonidine dose on discharge time. RESULTS: The mean age of children (n = 177) was 5.4 sd 3.3 years, range 0.8-15.0 years and weight was 23.8 SD 11.4 kg, range 10.0-76.4 kg. There were 73 children given clonidine 0.29-4.80 mcg.kg(-1) after induction. The half-time to emergence was 10.8 (95% CI 8.5, 13.2) min. Emergence half-time was increased to 15 min with clonidine 0.5 mcg.kg(-1), 20 min with clonidine 1.5 mcg.kg(-1), 25 min with clonidine 2 mcg.kg(-1) and 65 min with clonidine 4 mcg.kg(-1). Clonidine doses 0.5-3 mcg.kg(-1) did not affect hospital discharge time. CONCLUSIONS: Clonidine administered intraoperatively for (adeno) tonsillectomy or adenoidectomy prolonged emergence from anesthesia. Doses of 0.5 3 mcg.kg(-1) caused greater sedation in the postanesthesia care unit but did not impact on hospital discharge times. PMID- 24956963 TI - Vas deferens neuro-effector junction: from kymographic tracings to structural biology principles. AB - The vas deferens is a simple bioassay widely used to study the physiology of sympathetic neurotransmission and the pharmacodynamics of adrenergic drugs. The role of ATP as a sympathetic co-transmitter has gained increasing attention and furthered our understanding of its role in sympathetic reflexes. In addition, new information has emerged on the mechanisms underlying the storage and release of ATP. Both noradrenaline and ATP concur to elicit the tissue smooth muscle contractions following sympathetic reflexes or electrical field stimulation of the sympathetic nerve terminals. ATP and adenosine (its metabolic byproduct) are powerful presynaptic regulators of co-transmitter actions. In addition, neuropeptide Y, the third member of the sympathetic triad, is an endogenous modulator. The peptide plus ATP and/or adenosine play a significant role as sympathetic modulators of transmitter's release. This review focuses on the physiological principles that govern sympathetic co-transmitter activity, with special interest in defining the motor role of ATP. In addition, we intended to review the recent structural biology findings related to the topology of the P2X1R based on the crystallized P2X4 receptor from Danio rerio, or the crystallized adenosine A2A receptor as a member of the G protein coupled family of receptors as prototype neuro modulators. This review also covers structural elements of ectonucleotidases, since some members are found in the vas deferens neuro-effector junction. The allosteric principles that apply to purinoceptors are also reviewed highlighting concepts derived from receptor theory at the light of the current available structural elements. Finally, we discuss clinical applications of these concepts. PMID- 24956964 TI - Time to do more: addressing clinical inertia in the management of type 2 diabetes mellitus. AB - AIMS: Clinical inertia, the tendency to maintain current treatment strategies despite results demanding escalation, is thought to substantially contribute to the disconnect between clinical aspirations for patients with diabetes and targets achieved. We wished to explore potential causes of clinical inertia among physicians and people with diabetes. METHODS: A 20-min online survey of 652 adults with diabetes and 337 treating physicians in six countries explored opinions relating to clinical inertia from both perspectives, in order to correlate perceptions and expectations relating to diagnosis, treatment, diabetes complications and therapeutic escalation. RESULTS: Physicians had low expectations for their patients, despite the belief that the importance of good glycaemic control through lifestyle and pharmacological interventions had been adequately conveyed. Conversely, people with diabetes had, at best, a rudimentary understanding of the risks of complications and the importance of good control; indeed, only a small proportion believed lifestyle changes were important and the majority did not intend to comply. CONCLUSIONS: The principal findings of this survey suggest that impairments in communication are at the heart of clinical inertia. This manuscript lays out four key principles that we believe are achievable in all environments and can improve the lives of people with diabetes. PMID- 24956966 TI - Microbiota and neurodevelopmental windows: implications for brain disorders. AB - Gut microbiota is essential to human health, playing a major role in the bidirectional communication between the gastrointestinal tract and the central nervous system. The microbiota undergoes a vigorous process of development throughout the lifespan and establishes its symbiotic rapport with the host early in life. Early life perturbations of the developing gut microbiota can impact neurodevelopment and potentially lead to adverse mental health outcomes later in life. This review compares the parallel early development of the intestinal microbiota and the nervous system. The concept of parallel and interacting microbial-neural critical windows opens new avenues for developing novel microbiota-modulating based therapeutic interventions in early life to combat neurodevelopmental deficits and brain disorders. PMID- 24956965 TI - A flavonoid fraction purified from Rutaceae aurantiae (Daflon(R)) inhibiting AGE formation, reduces urinary albumin clearance and corrects hypoalbuminemia in normotensive and hypertensive diabetic rats. AB - AIM: Advanced glycation endproducts (AGEs) have been shown to contribute to alteration of glomerular permselectivity to proteins in diabetes. Oxidative stress is required for AGE formation. Therefore we studied the effect of an antioxidant micronized purified flavonoid fraction (MPFF, Daflon(R) 500 mg), on urinary albumin clearance in diabetic rats. METHODS: Hyperglycaemia was induced by streptozotocin 55 mg/kg IM at days 0 and 7 in normotensive Wistar rats (NWR, diabetes duration 5 months) or hypertensive Wistar Kyoto rats (SHR, diabetes duration 2 months). MPFF was administered at 300 mg/kg/day, from day -2 until sacrifice. RESULTS: After 5 months of diabetes in NWR, MPFF reduced albumin clearance from 729+/-92 to 392+/-60 nl/min/kg, p<0.01, and restored albuminemia from 20.4+/-0.9 to 24.0+/-1 g/l, p<0.05; albumin fractional clearance was significantly diminished in the flavonoid-treated diabetic rats (0.360+/ 0.0370/00 versus 1.335+/-0.4300/00 in the diabetic controls, p<0.001); MPFF did not significantly modify blood glucose and plasma fructosamine levels. After 2 months of diabetes in SHR, MPFF reduced albumin clearance from 243+/-121 to 101+/ 47 nl/min/kg, p<0.05, and restored albuminemia from 21.1+/-1.6 to 26.7+/-2.2 g/l (p<0.05); MPFF also decreased plasma fluorescence characteristic of AGEs (p<0.02). Besides hesperetin, a main metabolite of MPFF recovered in plasma, inhibited in vitro the formation of the crosslinking AGE pentosidine in collagen incubated with high glucose (p<0.001). CONCLUSION: Our results confirm the role of glycoxidative stress in diabetic nephropathy. MPFF might be useful as complementary treatment for preventing diabetic microangiopathy. PMID- 24956967 TI - Stereoselective bromocyclization of allylated aldoxime ethers. AB - The intramolecular bromoamination of allylated aldoxime ethers leads first to isoxazolidinium salts which then undergo a skeletal rearrangement to form bromo 5,6-dihydro-4H-1,3-oxazines. Aliphatic aldoxime ethers with alpha-protons undergo multiple brominations before rearrangement. PMID- 24956968 TI - Performance based on sEMG activity is related to psychosocial components: differences between back and abdominal endurance tests. AB - The influence of psychosocial components on back and abdominal endurance tests in patients with persistent non-specific low back pain should be investigated to ensure the correct interpretation of these measures. Three-hundred and thirty-two patients (291 men and 41 women) from 19 to 63years performed an abdominal and back muscle endurance test after completing some psychosocial questionnaires. During the endurance tests, surface electromyography signals of the internal obliques, the external obliques, the lumbar multifidus and the iliocostalis were recorded. Patients were dichotomized as underperformers and good performers, by comparing their real endurance time, to the expected time of endurance derived from the normalized median frequency slope. Independent t-tests were performed to examine the differences on the outcome of the questionnaires. In the back muscle endurance test, the underperformers had significantly lower (p<0.05) scores on some of the physical subscales of the SF-36. The underperformers group of the AE test scored significantly higher on the DRAM MZDI (p=0.018) and on the PCS scale (p=0.020) and showed also significantly lower scores on the SF-36 (p<0.05). Back muscle endurance tests are influenced by physical components, while abdominal endurance tests seem influenced by psychosocial components. PMID- 24956969 TI - Erratum to: National Survey on Excellence Centers and Reference Centers for Hypertension Diagnosis and Treatment: Geographical Distribution, Medical Facilities and Diagnostic Opportunities. PMID- 24956970 TI - A randomized controlled trial of the effects of aerobic dance training on blood lipids among individuals with hypertension on a thiazide. AB - PURPOSE: Hypertension is associated with dyslipidemia. Thiazides adversely affect serum lipid levels in hypertensives. There is currently a dearth of information on benefits of aerobic exercise training on serum lipid levels in individuals on thiazides and this study aimed at bridging this gap in knowledge. METHODS: This randomized-controlled trial involved 120 newly-diagnosed adults with essential hypertension (>=65 years). They were treated with 50 mg of hydrochlorothiazide + 5 mg of hydrochloride amiloride and 5 or 10 mg of amlodipine for 4-6 weeks before they were randomly assigned into exercise group (EG) and control croup (CG). Only EG underwent 12-week aerobic dance training at 50-70 % of heart rate reserve three times per week. Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglyceride and total cholesterol were measured and recorded at baseline and post-study. RESULTS: Eighty-eight (45 in EG and 43 in CG) of 120 participants randomly assigned to groups completed the study. Systolic (p = 0.370) and diastolic (p = 0.771) blood pressures (BP) were similar between the two groups at baseline. Systolic (p < 0.001) and diastolic (p < 0.001) BPs reduced significantly in exercise and control groups. LDL-C (from 120.10 +/- 33.41 to 110.50 +/- 31.68 mg/dl; p = 0.037) and triglyceride (from 117.49 +/- 45.12 to 100.63 +/- 35.42 mg/dl; p = 0.002) decreased in EG post-study but no significant between-group differences were observed. CONCLUSIONS: Although, LDL-C and triglyceride are reduced after aerobic dance training, they were not any more than without it. Aerobic dance training has favorable effects on LDL-C, triglyceride, and systolic and diastolic BP in individuals with hypertension on a thiazide. PMID- 24956973 TI - Gas-phase chemistry of molecular containers. AB - The remarkable technical advances in mass spectrometry during the last decades, including soft ionisation techniques, the coupling of electrospray ionisation to flow reactors, and the broad scope of tandem mass spectrometric experiments applicable to mass-selected ions allow investigating the chemistry of molecular capsules in solution as well as in the absence of any environment. With these methods, mass spectrometry is capable of answering many questions starting from providing analytical characterisation data (elemental composition, stoichiometry, etc.) to structural aspects (connectivities, positions of building blocks in supramolecular complexes) and to the examination of solution and gas-phase reactivity including reactions inside molecular containers. The present article reviews this work with a focus rather on the chemical questions that can be answered than on the technical specialities of (tandem) mass spectrometry. PMID- 24956971 TI - Should thiazide diuretics be given as first line antihypertensive therapy or in addition to other medications? AB - INTRODUCTION: The recommendation to start antihypertensive therapy with diuretics (D) might produce delay in blood pressure (BP) control and, possibly, increase cost/benefit ratio. AIM: We evaluate the effects of D in relation to the administration of other anti-hypertensive medications, in clinical practice. METHODS: General practitioners recruited 2,409 hypertensive patients with indication to antihypertensive therapy, who were randomized to start treatment with chlorthalidone (12.5-25 mg daily, group D) or any other single medications (excluding thiazides, group A). The patients have been followed for at least 2 years. RESULT: Among the 2,409 patients recruited (42.5 % women), 1,205 were randomized in group D and 1,204 in group A, of which 1,051 (or 87 %) and 1026 (or 85 %) respectively, completed the study. The number of patients in optimal BP control was similar in the two groups (65.0 vs 64.0 %; p = NS). During follow-up, the group D had prescribed a slightly greater number of medications compared to the group A who added D as second line (2.3 vs 2.1; p < 0.0001). In particular group D took more beta-blockers (27.1 vs 14.9 %; p < 0.0001) with a similar number of patients in optimal BP control (64.35 vs 63.9 %; p = NS). CONCLUSION: The beginning of antihypertensive therapy with diuretics is more often subject to the addition of one or more medications to obtain an effective blood pressure control, since the diuretic administered at the beginning of the antihypertensive regimen is only rarely associated with optimal blood pressure control. PMID- 24956972 TI - An anthocyanin-rich strawberry extract protects against oxidative stress damage and improves mitochondrial functionality in human dermal fibroblasts exposed to an oxidizing agent. AB - This study investigates the protective effect of the Sveva strawberry polyphenol rich extract on human dermal fibroblasts against AAPH-induced oxidative stress. The HPLC-DAD/ESI-MS analysis was used for evaluating the phenolic composition of the fruits. Sveva strawberry presented a high anthocyanin content (639.79 mg per kg fresh fruit), representing ~86.08% of the total phenolic content, with Pg-3 glc as the most abundant representative (611.18 mg per kg fresh fruit). Only one ellagitannin (agrimoniin) was identified, while two quercetins, three kaempherol derivates, and three ellagic acid derivatives were detected and quantified. Strawberry pre-treatment (0.5 mg ml(-1)) markedly increased human dermal fibroblast viability, with a significant reduction of apoptotic and dead cells, and suppressed AAPH-induced ROS generation, after only 30 minutes of incubation with the oxidizing agent, and lipid peroxidation, against a range of AAPH concentrations tested. Notably, the strawberry extract also improved the mitochondrial functionality: the basal respiratory performance after treatment was ~1.59-fold higher compared to control cells, while pre-treatment with strawberry extract before oxidative damage increased ~2.70-fold compared to stressed cells. Our results confirm that the strawberry possesses antioxidant properties, and may be useful for the prevention of free radical-induced skin damage. PMID- 24956974 TI - Direct comparison of a covalently-linked dyad and a 1:1 mixture of tetrabenzoporphyrin and fullerene as organic photovoltaic materials. AB - A p-i-n organic photovoltaic cell with tetrabenzoporphyrin (BP), a BP-C60 dyad and PCBM for the p-, i- and n-layers, respectively, gave a better fill factor and power conversion efficiency than the corresponding p-i-n cell having a 1:1 blend film of BP and PCBM as the i-layer. PMID- 24956977 TI - Potential cardioprotective action of GLP-1: from bench to bedside. PMID- 24956975 TI - Effects of the 2011 flood in Thailand on birth outcomes and perceived social support. AB - OBJECTIVE: To determine the effects of displacement due to flooding during pregnancy on birth outcomes (infant birth weight and gestational age) and the moderating effect of perceived social support on the relationship between displacement and birth outcomes. DESIGN: A descriptive, longitudinal study. SETTING: A university-affiliated hospital in Pathum Thani, Thailand. PARTICIPANTS: Pregnant women (N = 175) in the third trimester that had uncomplicated pregnancies and no history of mental illness. METHODS: During pregnancy, the participants completed standardized measurements of depression symptoms, perceived social support, and questionnaires concerning the effect of the flood. After giving birth, infant birth weight and gestational age at birth were retrieved from delivery records. RESULTS: Seventy percent (n = 123) of the participants experienced displacement during the flood. The displaced women had a mean infant birth weight of 175 grams less than that of the nondisplaced women, t(173) = -2.38, p = .02, whereas infant gestational age was not different. Displacement and other variables explained approximately 8% of the variance in infant birth weight. The interaction term between displacement and perceived social support was statistically significant and additionally explained the variance in infant birth weight, F(6, 168) = 3.24, p = .005. CONCLUSION: Being displaced during pregnancy due to a natural disaster affected fetal growth rather than length of gestation. Health care providers should closely monitor maternal weight gain and fetal growth of pregnant women who experience displacement. Among the displaced women, social support was associated with higher infant birth weight; therefore, high levels of perceived social support may be protective for pregnant women who experience stressful events such as displacement from flooding. PMID- 24956976 TI - Depressive symptoms in first-episode psychosis: a 10-year follow-up study. AB - AIMS: The present study examined if any patient characteristics at baseline predicted depressive symptoms at 10 years and whether patients prone to depressive symptoms in the first year of treatment had a different prognosis in the following years. METHOD: A total of 299 first-episode psychosis (FEP) patients with schizophrenia spectrum disorders were assessed for depressive symptoms with PANSS depression item (g6) at baseline, and 1, 2, 5 and 10 years of follow up. At 10 years, depressive symptoms were also assessed with Calgary Depression Scale for Schizophrenia (CDSS). A PANSS g6 >= 4 and CDSS score >= 6 were used as a cut-off score for depression. RESULTS: A total of 122 (41%) patients were scored as depressed at baseline, 75 (28%) at 1 year, 50 (20%) at 2 years, 33 (16%) at 5 years, and 35 (19%) at 10 years of follow up. Poor childhood social functioning and alcohol use at baseline predicted depression at 10 years of follow up. Thirty-eight patients were depressed at both baseline and 1 year follow up. This group had poorer symptomatic and functional outcome in the follow up period compared to a group of patients with no depression in the first year of treatment. CONCLUSION: Depressive symptoms are frequent among FEP patients at baseline but decrease after treatment because their general symptoms have been initiated. Patients with poor social functioning in childhood and alcohol use at baseline are more prone to have depressive symptoms at 10 years of follow up. Patients struggling with depressive symptoms in the first year of treatment should be identified as having poorer long-term prognosis. PMID- 24956978 TI - Chronic obstructive pulmonary disease: pathophysiological impact on heart failure in real clinical situation. PMID- 24956980 TI - Development of a policy and procedure for accidental chemotherapy overdose. AB - A policy regarding rapid response to chemotherapy overdoses was developed by the authors in an attempt to minimize morbidity and mortality. The parameters of a chemotherapy overdose were defined to promote early recognition of an overdose incident. Resources needed to guide potential therapeutic interventions and required monitoring were developed. The policy defines the immediate actions to be taken in the event of a chemotherapy overdose. The availability of a chemotherapy overdose policy provides an enhanced level of safety for patients by ensuring that appropriate treatment is initiated without delay. The development of the policy was in response to the reporting of a tragic error at another institution. Healthcare providers must recognize and address potential areas of vulnerability to maximize patient safety. PMID- 24956981 TI - Does broccoli protect from osteoarthritis? PMID- 24956979 TI - IP6K structure and the molecular determinants of catalytic specificity in an inositol phosphate kinase family. AB - Inositol trisphosphate kinases (IP3Ks) and inositol hexakisphosphate kinases (IP6Ks) each regulate specialized signalling activities by phosphorylating either InsP3 or InsP6 respectively. The molecular basis for these different kinase activities can be illuminated by a structural description of IP6K. Here we describe the crystal structure of an Entamoeba histolytica hybrid IP6K/IP3K, an enzymatic parallel to a 'living fossil'. Through molecular modelling and mutagenesis, we extrapolated our findings to human IP6K2, which retains vestigial IP3K activity. Two structural elements, an alpha-helical pair and a rare, two turn 310 helix, together forge a substrate-binding pocket with an open clamshell geometry. InsP6 forms substantial contacts with both structural elements. Relative to InsP6, enzyme-bound InsP3 rotates 55 degrees closer to the alpha helices, which provide most of the protein's interactions with InsP3. These data reveal the molecular determinants of IP6K activity, and suggest an unusual evolutionary trajectory for a primordial kinase that could have favored efficient bifunctionality, before propagation of separate IP3Ks and IP6Ks. PMID- 24956982 TI - Crohn's disease in spondyloarthritis. PMID- 24956983 TI - Usefulness of anti-SRP antibody testing in inflammatory myopathies. PMID- 24956984 TI - Arterial vasculopathy in systemic sclerosis: computerized tomography (CT) angiographic features of macrovascular and microvascular upper limbs arteries. AB - OBJECTIVE: To describe the CT angiographic findings of arterial vasculopathy in the major vessels as well as medium and micro vascular affection of the whole upper limbs arterial tree in patients with systemic sclerosis (SSc) with and without digital ulceration. METHODS: Twenty-two cases with systemic sclerosis (12 limited and 10 diffuse) were recruited for the study. All patients fulfilled the American Rheumatism Association (ACR) criteria for the classification of SSc. For all patients routine laboratory investigations were performed including complete lipid profile. Computed tomography angiography (CTA) studies for the whole upper limb arterial tree were performed for both upper limbs in all cases. RESULTS: CTA studies showed involvement of subclavian arteries in 3 cases and axillary artery was involved in five cases. Brachial artery was affected in 5 cases. In the forearm the radial artery was affected in 4 cases with bilateral involvement in two cases (6 vessels), while ulnar artery was affected in five cases. Unilateral non visualization of the superficial palmar arch was observed in two cases with limited disease, while thinning out of the vessel wall with poor distal run off in 18 cases. A higher number of arterial vasculopathy was significantly associated with systolic pulmonary artery pressure (P=0.001). CONCLUSIONS: Macrovascular arterial vasculopathy of upper limbs may occur in SSc irrespective of the disease pattern. Major arteries can be affected in association with other medium sized arteries of the forearms and microvascular arterial branches of the hands. PMID- 24956985 TI - Dumbbell-shaped cervical spine schwannoma causing myelopathy in a patient with rheumatoid arthritis. PMID- 24956987 TI - Three-decade trends in the distribution of organisms causing septic arthritis in native joints: single-center study of 374 cases. AB - OBJECTIVE: A rise in the incidence of septic arthritis due to methicillin resistant Staphylococcus aureus (MRSA) has been reported in several parts of the world. Here, our objective was to look for changes over the last 30years in the distribution and antibiotic susceptibility profiles of organisms responsible for septic arthritis. METHODS: We conducted a single-center retrospective study of all cases of septic arthritis documented by joint specimens and/or blood cultures between 1979 and 2008. Prosthetic joint infections were excluded. RESULTS: We enrolled 374 patients, of whom 127, 136, and 111 were included during each decade, respectively. We detected no significant time trends in the proportions of staphylococci (67%, 65%, and 64%), streptococci (14%, 21%, and 17%), or Gram negative rods (7%, 10%, and 14%). Tuberculosis was more common during the earliest decade (1979-1988, n=10, 4, 2%; P<0.05). No significant changes occurred in the proportions of methicillin-resistant staphylococci or MRSA (13%, 11%, 15%). Age and prevalence of risk factors for infection increased over time. CONCLUSION: The distribution and susceptibility of organisms causing septic arthritis has changed little over time. Our findings do not support the use of broader-spectrum antibiotics when empirical treatment is deemed necessary at our center. PMID- 24956988 TI - Is there specific neurological disorders of primary Sjogren's syndrome? AB - Neurological manifestations of primary Sjogren's syndrome are multiple and appear frequently. Depending on data analysis, patient recruitment, and diagnosis criteria used to defined primary Sjogren's syndrome or neurological manifestations, the estimated prevalence is between 0 and 70%. Peripheral neurological complications seem the most common, particularly sensory-motors axonal neuropathies. Neuronopathy seems to be the most specific neurological complication of primary Sjogren's syndrome. Central manifestations of primary Sjogren's syndrome are not uncommon, but the neurological complication's spectrum is not well defined. Neuromyelitis optica is regularly found among central complications. To conclude, although central and peripheral complications of primary Sjogren's syndrome are difficult to assess, partly because of the wide spectrum of possible manifestations, it is around 20%. Neuronopathy is still the most specific complication. PMID- 24956986 TI - Persistence of ultrasound synovitis in patients with rheumatoid arthritis fulfilling the DAS28 and/or the new ACR/EULAR RA remission definitions: results of an observational cohort study. AB - OBJECTIVE: The primary aim of the study was to evaluate whether rheumatoid arthritis (RA) patients considered to be in remission according to clinical criteria sets still had persisting ultrasound (US) synovitis. We further intended to evaluate the capacity of our US score to discriminate between the patients with a clinically active disease versus those in remission. METHODS: This is an observational study nested within the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) rheumatoid arthritis cohort. A validated US score (SONAR score) based on a semi-quantitative B-mode and Doppler (PwD) score as part of the regular clinical workup by rheumatologists in different clinical settings was used. To define clinically relevant synovitis, the same score was applied to 38 healthy controls and the 90st percentile was used as cut-off for 'relevant' synovitis. RESULTS: Three hundred and seven patients had at least one US examination and concomitant clinical information on disease activity. More than a third of patients in both DAS28 and ACR/EULAR remission showed significant gray scale synovitis (P=0.01 and 0.0002, respectively) and PwD activity (P=0.005 and 0.0005, respectively) when compared to controls. The capacity of US to discriminate between the two clinical remission groups and patients with active disease was only moderate. CONCLUSION: This observational study confirms that many patients considered to be in clinical remission according the DAS and the ACR/EULAR definitions still have residual synovitis on US. The prognostic significance of US synovitis and the exact place of US in patients reaching clinical remission need to be further evaluated. PMID- 24956989 TI - Tomosynthesis for early diagnosis of sacro-iliitis. PMID- 24956990 TI - Biopharmaceuticals for rheumatic diseases in Latin America, Europe, Russia, and India: innovators, biosimilars, and intended copies. AB - A biosimilar is a biopharmaceutical product intended to be comparable to a previously licensed biopharmaceutical agent. The goal of such products is to increase the accessibility of biopharmaceutical therapy for rheumatoid arthritis by reducing costs. They are not like generic drugs, in that they may differ from the reference products in manufacturing, composition, and formulation. Regulatory authorities strive to ensure the absence of clinically meaningful differences between biosimilars and their reference drugs. However, small molecular differences may potentially affect pharmacodynamics (including affinity), pharmacokinetics, and immunogenicity. Intended copies are non-innovator biopharmaceutical products that, unlike biosimilars, do not have enough clinical evidence to demonstrate biosimilarity. For approval of a biosimilar, most countries require preclinical and clinical studies demonstrating comparability with the reference drug. The margin for determining equivalence or non inferiority is determined on a case-by-case basis in each country, as there are no general criteria. The European Medicines Agency and US Food and Drug Administration have stringent regulatory processes to ensure comparability of biosimilars with their reference drugs. There are also post-marketing surveillance requirements to monitor safety. Only one biosimilar, CT-P13, has been approved for rheumatoid arthritis. However, in countries with less stringent regulation, intended copies are being commercialized and safety problems have been documented. Consequently, in such countries, there is an urgent need for appropriate regulatory processes to be established. Attempts to close the affordability gap of biopharmaceuticals should not open another gap between patients treated with an innovator drug and an intended copy. PMID- 24956991 TI - Increased RANKL-mediated osteoclastogenesis by interleukin-1beta and endoplasmic reticulum stress. AB - OBJECTIVE: The mechanism by which IL-1beta and thapsigargin (TG)-induced endoplasmic reticulum (ER) stress modulate the receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis remains elusive. Thus, we investigated the osteoclast-specific and ER signals in osteoclastogenesis of bone marrow-derived cells. METHODS: Bone marrow cells (BMCs) were obtained from 5 week-old male ICR mice and cultured to be differentiated into osteoclasts with M CSF and RANKL in the presence or absence of IL-1beta, TG, or 4-phenylbutyric acid (PBA), an ER stress-reducing drug. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and resorption pit assay with a dentine slice. The molecular mechanism of IL-1beta and ER stress in osteoclastogenesis was investigated in BMCs transfected with siRNA for GRP78, PERK and IRE1 using reverse transcription-polymerase chain reaction and immunoblotting for osteoclast-specific and ER stress signaling molecules. RESULTS: IL-1beta and ER stress induced by TG-augmented the formation of osteoclasts, which was significantly inhibited by PBA and was mediated with osteoclast-specific signals, including c-Fos, NFATc1, and ER stress- associated signaling pathways, such as PERK, IRE1, GRP78, and eIF2alpha. siRNA-mediated knockdown of ER stress signals inhibited the expression of NFATc1 and c-Fos, thus reducing IL-1beta and/or TG-induced formation of osteoclasts. CONCLUSIONS: Osteoclastogenesis by IL-1beta and/or ER stress is mainly associated with upregulation of eIF2alpha, GRP78, PERK and IRE1. These results suggest that the signaling pathway of ER stress-induced osteoclast formation might be a new therapeutic target to prevent inflammatory and destructive arthritic disease such as RA and diverse osteoporosis. PMID- 24956992 TI - Responsibilities, resources, and challenges. PMID- 24956993 TI - Position of the Academy of Nutrition and Dietetics: nutrition and lifestyle for a healthy pregnancy outcome. AB - It is the position of the Academy of Nutrition and Dietetics that women of childbearing age should adopt a lifestyle optimizing health and reducing risk of birth defects, suboptimal fetal development, and chronic health problems in both mother and child. Components leading to a healthy pregnancy outcome include healthy prepregnancy weight, appropriate weight gain and physical activity during pregnancy, consumption of a wide variety of foods, appropriate vitamin and mineral supplementation, avoidance of alcohol and other harmful substances, and safe food handling. Pregnancy is a critical period during which maternal nutrition and lifestyle choices are major influences on mother and child health. Inadequate levels of key nutrients during crucial periods of fetal development may lead to reprogramming within fetal tissues, predisposing the infant to chronic conditions in later life. Improving the well-being of mothers, infants, and children is key to the health of the next generation. This position paper and the accompanying practice paper (www.eatright.org/members/practicepapers) on the same topic provide registered dietitian nutritionists and dietetic technicians, registered; other professional associations; government agencies; industry; and the public with the Academy's stance on factors determined to influence healthy pregnancy, as well as an overview of best practices in nutrition and healthy lifestyles during pregnancy. PMID- 24956994 TI - Academy of Nutrition and Dietetics: revised 2014 standards of professional performance for registered dietitian nutritionists in management of food and nutrition systems. AB - Management in food and nutrition systems is presented with an ever-challenging tension between effective utilization of manpower resources, mechanical equipment, financial management, material production, and time constraints to produce optimal products. Management drives opportunities for personal development for multiple levels of its employee workforce. Given an increasing need to deliver high-quality food and services to satisfied customers, the Management in Food and Nutrition Systems Dietetic Practice Group, with guidance from the Academy of Nutrition and Dietetics Quality Management Committee, has developed the Revised 2014 Standards of Professional Performance, which replace the 2009 Standards, as a tool for registered dietitian nutritionists working in food and nutrition systems management within health care and non-health care organizations. These Standards of Professional Performance consist of six domains of professionalism: Quality in Practice, Competence and Accountability, Provision of Services, Application of Research, Communication and Application of Knowledge, and Utilization and Management of Resources. Within each standard, specific indicators provide measurable action statements that illustrate how strong communication skills, attention to customer satisfaction, use of various resources, and application of personnel management principles can be applied to practice. The indicators describe three skill levels (ie, competent, proficient, and expert) for registered dietitian nutritionists managing food and nutrition systems. PMID- 24956995 TI - Energy balance at a crossroads: translating the science into action. PMID- 24956996 TI - What medical nutrition therapy guideline is recommended post-cholecystectomy? PMID- 24956997 TI - Changes in alpha7beta1 integrin signaling after eccentric exercise in heat shocked rat soleus. AB - INTRODUCTION: alpha7beta1 integrin links the extracellular matrix to the focal adhesion (FA) in skeletal muscle and serves as a stabilizing and signal relayer. Heat shock (HS) induces expression of proteins that interact with the FA. METHODS: Male Wistar rats were assigned to 1 of 3 groups: control (CON); eccentric exercise (EE); or EE+HS (HS). Soleus muscle was analyzed at 2 h and 48 h post-exercise. RESULTS: The 120-kDa alpha7 integrin decreased in the EE and HS groups, and the 70-kDa peptide decreased in the EE group at 2 h post-exercise. Total expression of focal adhesion kinase (FAK) and RhoA were decreased in EE and HS at 2 h post-exercise. Expression of phosphorylated FAK(397) decreased in the EE group but not the HS group at 2 h post-exercise. CONCLUSIONS: Long-duration EE may cause alterations in the FA in rat soleus muscle through the alpha7 integrin subunit and FAK. PMID- 24956998 TI - Brain tumor classification on intraoperative contrast-enhanced ultrasound. AB - PURPOSE: Contrast-enhanced ultrasound (CEUS) imaging of tissue perfusion is based on microbubble echo detection. CEUS can visualize tumors based on local perfusion variations. The acquired video data are qualitatively interpreted by subjective visualization in clinical practice. An automated CEUS classifier was developed for intraoperative identification of tumor tissue and especially tumor borders. METHODS: Support vector machines (SVM) were trained using CEU data sets to differentiate tumor and non-tumor tissue in glioblastoma patients. The classification was based on features derived from model functions approximated to time courses for each pixel in the video data. Classification performance was evaluated with single and cross- patient training data sets. RESULTS: The minimum mean classification error (14.6 %) with single patient data set training was achieved by SVM training using a sigmoid combination of model function parameter sets. A comparison of different model functions showed that the minimum average classification error (17.4 %) in a cross-validation study with 13 patients was achieved with the sigmoid model using an automatic relevance detection kernel. CONCLUSION: CEUS-based classification map images derived from approximated model functions can be generated with moderate accuracy and have significant potential to support intraoperative decisions concerning glioblastoma tumor borders. PMID- 24956999 TI - In vitro establishment of ivermectin-resistant Rhipicephalus microplus cell line and the contribution of ABC transporters on the resistance mechanism. AB - The cattle tick Rhipicephalus microplus is one of the most economically damaging livestock ectoparasites, and its widespread resistance to acaricides is a considerable challenge to its control. In this scenario, the establishment of resistant cell lines is a useful approach to understand the mechanisms involved in the development of acaricide resistance, to identify drug resistance markers, and to develop new acaricides. This study describes the establishment of an ivermectin (IVM)-resistant R. microplus embryonic cell line, BME26-IVM. The resistant cells were obtained after the exposure of IVM-sensitive BME26 cells to increasing doses of IVM in a step-wise manner, starting from an initial non-toxic concentration of 0.5 MUg/mL IVM, and reaching 6 MUg/mL IVM after a 46-week period. BME26-IVM cell line was 4.5 times more resistant to IVM than the parental BME26 cell line (lethal concentration 50 (LC50) 15.1 +/- 1.6 MUg/mL and 3.35 +/- 0.09 MUg/mL, respectively). As an effort to determine the molecular mechanisms governing resistance, the contribution of ATP-binding cassette (ABC) transporter was investigated. Increased expression levels of ABC transporter genes were found in IVM-treated cells, and resistance to IVM was significantly reduced by co incubation with 5 MUM cyclosporine A (CsA), an ABC transporter inhibitor, suggesting the involvement of these proteins in IVM-resistance. These results are similar to those already described in IVM-resistant tick populations, and suggest that similar resistance mechanisms are involved in vitro and in vivo. They reinforce the hypothesis that ABC transporters are involved in IVM resistance and support the use of BME26-IVM as an in vitro approach to study acaricide resistance mechanisms. PMID- 24957002 TI - Triazole-assisted ruthenium-catalyzed C-H arylation of aromatic amides. AB - Site-selective ruthenium(II)-catalyzed direct arylation of amides was achieved through C?H cleavages with modular auxiliaries, derived from easily accessible 1,2,3-triazoles. The triazolyldimethylmethyl (TAM) bidentate directing group was prepared in a highly modular fashion through copper(I)-catalyzed 1,3-dipolar cycloaddition and allowed for ruthenium-catalyzed C?H arylations on arenes and heteroarenes, as well as alkenes, by using easy-to-handle aryl bromides as the arylating reagents. The triazole-assisted C?H activation strategy was found to be widely applicable, to occur under mild reaction conditions, and the catalytic system was tolerant of important electrophilic functionalities. Notably, the flexible triazole-based auxiliary proved to be a more potent directing group for the optimized ruthenium(II)-catalyzed direct arylations, compared with pyridyl substituted amides or substrates derived from 8-aminoquinoline. PMID- 24957000 TI - Neospora caninum prevalence in dogs raised under different living conditions. AB - Neospora caninum is an important cause of abortion in dairy cattle worldwide. Dogs are important in the epidemiology of N. caninum because they act as definitive hosts shedding oocysts in the environment. Vertical transmission of the parasite is well recognized as an important aspect of the epidemiology of the parasite but the importance of horizontal transmission has been less studied. A N. caninum competitive ELISA was used to examine serum samples from 600 dogs that were raised under 4 different living conditions. Samples from 138 dogs living on 24 dairies with a prevalence (0-70%) of anti-N. caninum antibodies in the cattle, 294 pet dogs without neurological signs, 76 from pet dogs exhibiting neurological signs, and 92 stray dogs were examined. The overall seroprevalence of N. caninum was 23.5% (95% CI = +/- 2.99) in the 600 dogs. Significant (P < 0.05) differences were observed between the 4 different populations of dogs. The number of N. caninum positive samples were: 51 (36.9%, 95% CI = +/- 3.09) of 138 dogs from dairies, 31 (10.5%, 95% CI = +/- 6.38) of 294 pet dogs without neurological signs, disorders, 22 (28.9%, 95% CI = +/- 6.70) of 76 pet dogs with neurological signs, and 37 (40.2%, 95% CI = +/- 2.83) of 92 stray dogs. Seropositivity to N. caninum in dogs from dairies was associated with a high prevalence of N. caninum antibodies in the cattle. At the 3 dairies where no dogs were present, the seroprevalence to N. caninum in the cattle was significantly lower (P < 0.05) than in the 21 dairies where dogs were present. Seroprevalence was significantly higher (P < 0.05) in male dogs (97 of 366; 26.5%, 95% CI = +/- 3.40) than in female dogs (44 of 234; 18.8%, 95% CI = +/- 5.65). Seroprevalence in dogs increased with age suggesting postnatal exposure to N. caninum infection however, this increase was not significant (P > 0.05). The prevalence of N. caninum antibodies was not significantly (P>0.05) different in dogs based on breed. These findings suggest a relationship between N. caninum infection of dogs from dairies and cattle on these dairies. However, further research is required to determine what is the most important way dogs acquire infection and how to prevent dogs from shedding oocysts. PMID- 24957001 TI - Culicoides (Diptera: Ceratopogonidae) host preferences and biting rates in the Netherlands: comparing cattle, sheep and the black-light suction trap. AB - Host preference is an important determinant of feeding behaviour in biting insects and a critical component in the transmission of vector-borne diseases. The aim of the study was to quantify Culicoides (Diptera: Ceratopogonidae) host preferences and biting rates using tethered livestock at pasture (a dairy cow and a sheep) and to compare the numbers of biting midges aspirated off them to those captured simultaneously in a black-light suction trap acting as a surrogate host. Culicoides collections were made hourly over seven hours (from five hours before official sunset to two hours after) between 27 May and 19 June, 2013 at a dairy farm (eastern Netherlands). The study involved 13 replicates of a site * host randomised design. Culicoides collected by black-light suction trap and by direct aspiration were identified to species morphologically and age-graded. The C. obsoletus complex, C. dewulfi and C. pulicaris predominated on the back and flanks of the animals, C. punctatus on the belly, and C. chiopterus on the legs. Using comparable collection periods, 9.3 times (95% confidence interval: 8.6 10.0) more Culicoides were caught on the cow than on the sheep and 25.4 times (95% confidence interval: 18.4-35.1) less in the black-light suction trap compared to the sheep. Mean Culicoides biting rates on the cow across the 7-h collection period were 4.6, 3.5, 1.0, 1.0 and 0.5 min(-1) for C. dewulfi, the C. obsoletus complex, C. chiopterus, C. punctatus and C. pulicaris, respectively; for the sheep they were 0.6, 0.4 and 0.1 min(-1) for the C. obsoletus complex, C. dewulfi and C. punctatus, respectively. Though midges were aspirated off livestock during each of the seven hours, they only began to appear in the black light suction trap 5h later, from sunset onwards. After sunset, its efficacy improved markedly, but occurred when midge activity overall had begun to decline. Though it was quite accurate in ranking Culicoides species abundance, the black light suction trap proved to be of limited value for determining hours of peak biting activity, levels of abundance, and host preference, in Culicoides. PMID- 24957003 TI - Palliative care-related self-report problems among cancer patients in East Africa: a two-country study. AB - PURPOSE: Palliative care-related problems have not been measured in Africa in line with the WHO definition. This study aimed to measure the three-day period intensity of multidimensional problems (physical, psychological, social, and spiritual) among advanced cancer patients in Kenya and Uganda. METHODS: Adults with advanced malignant disease gave self-report data to the African Palliative Outcome Scale (POS). RESULTS: Among 210 respondents, more than half had an underlying HIV diagnosis (51.9 %). The worst ranked POS items were pain and information. In three multivariable ordinal logistic regression models with the 3 POS factors as dependent variables, for the first model (factor 1 physical and psychological well-being), as age increased, the well-being also improved (B = 0.022, p = 0.037), and as physical function score worsened, factor score also worsened (B = -0.685, p < 0.001). In the second model (factor 2 interpersonal well-being), a trend toward significance was found for gender, with being male predicting a higher (better) factor score (B = 0.502, p = 0.067). For the third model (factor 3 existential and spiritual), increasing age was predictive of higher (better) factor score (B = 0.023, p = 0.032), and worsening function was predictive of lower (worse) factor score (B = -0.543, p < 0.001). CONCLUSIONS: This novel data revealed pain and information to plan for the future to affect patients most severely, underlining the importance of analgesia and social support. HIV infection did not affect the level of need. Our data suggest increasing need as function declines; therefore, home-based models with adequate family support are essential. PMID- 24957004 TI - 'Knowledge is power': perceived needs and preferred services of male partners of women newly diagnosed with breast cancer. AB - PURPOSE: The aim of this qualitative exploratory study was to assess the perceived needs and preferred services of male partners of women newly diagnosed with breast cancer. METHODS: Twenty-seven male partners participated in semi structured telephone interviews. Interviews were recorded and transcribed verbatim. An inductive analysis was used to identify the patterns, themes and categories from the data. RESULTS: A diagnosis of breast cancer and subsequent treatment significantly affect the male partners of women diagnosed with this illness, creating 'needs' that require coping responses. To help them support their wife and family, they relied on their internal resources and informal sources of support. Many participants suggested that the health care system provides information addressing their needs to facilitate their role of caring for their wife. The findings did not support the clinical assumption that men would be interested in a men's group focused on them and their needs. CONCLUSIONS: The diagnosis of breast cancer significantly affected the male partners, creating the need for support services including information on a variety of topics. An information binder tailored specifically to their needs was the preferred method of facilitating their husbandly role and coping. Findings did not support the clinical assumption that men would be interested in a men's group focused on them and their needs. PMID- 24957005 TI - Robustness of interrelated traffic networks to cascading failures. AB - The vulnerability to real-life networks against small initial attacks has been one of outstanding challenges in the study of interrelated networks. We study cascading failures in two interrelated networks S and B composed from dependency chains and connectivity links respectively. This work proposes a realistic model for cascading failures based on the redistribution of traffic flow. We study the Barabasi-Albert networks (BA) and Erdos-Renyi graphs (ER) with such structure, and found that the efficiency sharply decreases with increasing percentages of the dependency nodes for removing a node randomly. Furthermore, we study the robustness of interrelated traffic networks, especially the subway and bus network in Beijing. By analyzing different attacking strategies, we uncover that the efficiency of the city traffic system has a non-equilibrium phase transition at low capacity of the networks. This explains why the pressure of the traffic overload is relaxed by singly increasing the number of small buses during rush hours. We also found that the increment of some buses may release traffic jam caused by removing a node of the bus network randomly if the damage is limited. However, the efficiencies to transfer people flow will sharper increase when the capacity of the subway network alpha(S) > alpha0. PMID- 24957006 TI - A colorimetric and near-infrared fluorescent probe with high sensitivity and selectivity for acid phosphatase and inhibitor screening. AB - A dual-channel including a colorimetric and fluorescent probe based on the aggregation-caused quenching (ACQ) and enzymolysis approach has been presented to screen acid phosphatase (ACP) and its inhibitor. Moreover, the ACP activity was determined by real time assay. PMID- 24957008 TI - Growth problems in children with IBD. AB - Crohn's disease in childhood causes linear growth retardation, which has a substantial effect on management of this disease. By contrast, growth is rarely a problem in children presenting with ulcerative colitis. Depending on how growth failure is defined, approximately one-third of children with Crohn's disease have growth retardation at diagnosis. Although corticosteroids can suppress growth, decreased height at diagnosis demonstrates that this finding is a consequence of the disease and not merely an adverse effect of treatment. Both inflammation and undernutrition contribute to decreased height velocity. Increased cytokine production acts both on the hepatic expression of insulin-like growth factor 1 (IGF-1) and at chondrocytes of the growth plates of long bones. Growth hormone insensitivity caused by deranged immune function is a major mechanism in growth retardation. Resolution of inflammation is the cornerstone of treatment, but current studies on growth hormone and IGF-1 might yield therapies for those children whose inflammation is refractory to treatment. PMID- 24957009 TI - Gut microbiota. Tackling the effects of diet and exercise on the gut microbiota. PMID- 24957007 TI - Mitogen-Activated Protein Kinase Phosphatase (MKP)-1 in Nervous System Development and Disease. AB - Mitogen-activated protein kinase phosphatase (MKP)-1 provides a negative feedback mechanism for regulating mitogen-activated protein kinase (MAPK) activity and thus a variety of cellular processes such as proliferation, differentiation, growth and apoptosis. MKP-1 is established as a central regulator of a variety of functions in the immune, metabolic and cardiovascular systems, and it is now increasingly acknowledged as having a role to play in the nervous system. It has been implicated in regulating processes of neuronal cell development and death as well as in glial cell function. Reduced MKP-1 levels have been observed in models of neurological conditions including Huntington's disease, multiple sclerosis, ischemia and cerebral hypoxia. It has also been suggested to have a role to play in psychiatric disorders such as major depressive disorder. Here, we discuss the role of MKP-1 in nervous system development and disease and examine current evidence providing insight into MKP-1 as a potential therapeutic target for various diseases of the central nervous system. PMID- 24957010 TI - IBD. TH9 cells might have a role in the pathogenesis of ulcerative colitis. PMID- 24957012 TI - Controllable conversion of plasmonic Cu2-xS nanoparticles to Au2S by cation exchange and electron beam induced transformation of Cu2-xS-Au2S core/shell nanostructures. AB - Self-doped Cu2-xS nanocrystals (NCs) were converted into monodisperse Cu2-xS-Au2S NCs of tunable composition, including pure Au2S, by cation exchange. The near infrared (NIR) localized surface plasmon resonance (LSPR) was dampened and red shifted with increasing Au content. Cation exchange was accompanied by elimination of cation vacancies and a change in crystal structure. Partially exchanged Cu2-xS-Au2S core/shell structures evolved to dumbbell-like structures under electron irradiation in the transmission electron microscope (TEM). PMID- 24957011 TI - The complex interplay among bacterial motility and virulence factors in different Escherichia coli infections. AB - Motility mediated by the flagella of Escherichia coli is important for the bacteria to move toward host cells. Here, we present the relationship among bacterial motility, virulence factors, antimicrobial susceptibility, and types of infection. A total of 231 clinical E. coli isolates from different infections were collected and analyzed. Higher-motility strains (motility diameter >=6.6 mm) were more common in spontaneous bacterial peritonitis (SBP) (SBP 59 %, colonization 32 %, urinary tract infection 16 %, urosepsis 34 %, and biliary tract infection 29 %; p < 0.0001). Compared with the higher-motility group, there was a higher prevalence of afa and ompT genes (p = 0.0160 and p = 0.0497, respectively) in E. coli strains with lower motility. E. coli isolates with higher and lower motility were in different phylogenetic groups (p = 0.018), with a lower prevalence of A and B1 subgroups in higher-motility strains. Also, the patterns of virulence factors and antibiotic susceptibility of E. coli isolates derived from various infections were significantly different. This study demonstrates that the prevalence of higher-motility strains was greater in E. coli isolates from SBP compared to other types of infection. Various types of E. coli infection were associated with differences in bacterial motility, virulence factors, and antibiotic susceptibility. More bacterial virulence factors may be necessary for the development of extraintestinal infections caused by E. coli isolates with lower motility. PMID- 24957013 TI - Resveratrol protects against cigarette smoke-induced oxidative damage and pulmonary inflammation. AB - This study was carried out to investigate the effects of resveratrol on cigarette smoke (CS)-induced lung injury. Experimental mice were administrated with 1 mg/kg or 3 mg/ kg resveratrol orally, 1 h prior to CS exposure (five cigarettes a day for 3 consecutive days). Airway inflammation and gene expression changes were assessed. CS exposure increased the number of pulmonary inflammatory cells, coupled with elevated production of tumor necrosis factor alpha and interleukin-6 in bronchoalveolar lavage fluids. Resveratrol treatment decreased CS-induced lung inflammation. Resveratrol restored the activities of superoxide dismutase, GSH peroxidase, and catalase in CS-treated mice. CS significantly enhanced the nuclear translocation of nuclear factor kappaB (NF-kappaB) and NF-kappaB DNA binding activity, which was impaired by resveratrol pretreatment. In addition, resveratrol promoted CS-induced heme oxygenase-1 (HO-1) expression and activation. Our results collectively indicate that resveratrol attenuates CS induced lung oxidative injury, which involves decreased NF-kappaB activity and the elevated HO-1 expression and activity. PMID- 24957014 TI - Modulation of activity of known cytotoxic ruthenium(III) compound (KP418) with hampered transmembrane transport in electrochemotherapy in vitro and in vivo. AB - To increase electrochemotherapy (ECT) applicability, the effectiveness of new drugs is being tested in combination with electroporation. Among them two ruthenium(III) compounds, (imH)[trans-RuCl4(im)(DMSO-S)] (NAMI-A) and Na[trans RuCl4(ind)2] (KP1339), proved to possess increased antitumor effectiveness when combined with electroporation. The objective of our experimental work was to determine influence of electroporation on the cytotoxic and antitumor effect of a ruthenium(III) compound with hampered transmembrane transport, (imH)[trans RuCl4(im)2] (KP418) in vitro and in vivo and to determine changes in metastatic potential of cells after ECT with KP418 in vitro. In addition, platinum compound cisplatin (CDDP) and ruthenium(III) compound NAMI-A were included in the experiments as reference compounds. Our results show that electroporation leads to increased cellular accumulation and cytotoxicity of KP418 in murine melanoma cell lines with low and high metastatic potential, B16-F1 and B16-F10, but not in murine fibrosarcoma cell line SA-1 in vitro which is probably due to variable effectiveness of ECT in different cell lines and tumors. Electroporation does not potentiate the cytotoxicity of KP418 as prominently as the cytotoxicity of CDDP. We also showed that the metastatic potential of cells which survived ECT with KP418 or NAMI-A does not change in vitro: resistance to detachment, invasiveness, and re-adhesion of cells after ECT is not affected. Experiments in murine tumor models B16-F1 and SA-1 showed that ECT with KP418 does not have any antitumor effect while ECT with CDDP induces significant dose-dependent tumor growth delay in the two tumor models used in vivo. PMID- 24957015 TI - [Asthenia, weight loss and inflammation in a 63-year-old woman]. PMID- 24957016 TI - Electron paramagnetic resonance radiation dose assessment in fingernails of the victim exposed to high dose as result of an accident. AB - In this paper, we report results of radiation dose measurements in fingernails of a worker who sustained a radiation injury to his right thumb while using 130 kVp X-ray for nondestructive testing. Clinically estimated absorbed dose was about 20 25 Gy. Electron paramagnetic resonance (EPR) dose assessment was independently carried out by two laboratories, the Naval Dosimetry Center (NDC) and French Institut de Radioprotection et de Surete Nucleaire (IRSN). The laboratories used different equipments and protocols to estimate doses in the same fingernail samples. NDC used an X-band transportable EPR spectrometer, e-scan produced by Bruker BioSpin, and a universal dose calibration curve. In contrast, IRSN used a more sensitive Q-band stationary spectrometer (EMXplus) with a new approach for the dose assessment (dose saturation method), derived by additional dose irradiation to known doses. The protocol used by NDC is significantly faster than that used by IRSN, nondestructive, and could be done in field conditions, but it is probably less accurate and requires more sample for the measurements. The IRSN protocol, on the other hand, potentially is more accurate and requires very small amount of sample but requires more time and labor. In both EPR laboratories, the intense radiation-induced signal was measured in the accidentally irradiated fingernails and the resulting dose assessments were different. The dose on the fingernails from the right thumb was estimated as 14 +/- 3 Gy at NDC and as 19 +/ 6 Gy at IRSN. Both EPR dose assessments are given in terms of tissue kerma. This paper discusses the experience gained by using EPR for dose assessment in fingernails with a stationary spectrometer versus a portable one, the reasons for the observed discrepancies in dose, and potential advantages and disadvantages of each approach for EPR measurements in fingernails. PMID- 24957017 TI - Use of the DBD-FISH technique for detecting DNA breakage in response to high doses of X-rays. AB - The aim of this study was to generate a dose-response curve using the DNA breakage detection-fluorescent in situ hybridization (DBD-FISH) test as a biomarker of initial genetic effects induced by high doses of X-rays. A dose response curve was obtained by measuring the ex vivo responses to increasing doses (0-50 Gy) of X-rays in the peripheral blood lymphocytes of ten healthy donors. The overall dose-response curve was constructed using integrated density (ID; area * fluorescence intensity) as a measure of genetic damage induced by irradiation. The correlation coefficient was high (r = 0.934, b(0) = 10.408, and b(1) = 0.094). One-way ANOVA with the Student-Newman-Keuls test for multiple comparisons showed significant differences among the average ln ID values according to dose. Our results suggest the usefulness of the DBD-FISH technique for measuring intrinsic individual cellular radio sensitivity ex vivo. PMID- 24957018 TI - Cocoa extracts reduce oligomerization of amyloid-beta: implications for cognitive improvement in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, characterized by pathological aggregates of amyloid peptide-beta (Abeta) and tau protein. Currently available therapies mediate AD symptoms without modifying disease progression. Polyphenol-rich diets are reported to reduce the risk for AD. OBJECTIVE: In the present study, we investigated the AD disease-modifying effects of cocoa, a rich source of flavanols, which are a class of polyphenols. We hypothesized that cocoa extracts interfere with amyloid-beta oligomerization to prevent synaptic deficits. METHODS: We tested the effects of three different cocoa extracts, viz. Natural, Dutched, and Lavado extracts, on Abeta42 and Abeta40 oligomerization, using photo induced cross-linking of unmodified proteins technique. To assess the effects of cocoa extracts on synaptic function, we measured long term potentiation in mouse brain hippocampal slices exposed to oligomeric Abeta. RESULTS: Our results indicate that cocoa extracts are effective in preventing the oligomerization of Abeta, with Lavado extract being most effective. Lavado extract, but not Dutched extract, was effective in restoring the long term potentiation response reduced by oligomeric Abeta. CONCLUSION: Our findings indicate that cocoa extracts have multiple disease-modifying properties in AD and present a promising route of therapeutic and/or preventative initiatives. PMID- 24957021 TI - Stable isotope tracer analysis in isolated mitochondria from mammalian systems. AB - Mitochondria are a focal point in metabolism, given that they play fundamental roles in catabolic, as well as anabolic reactions. Alterations in mitochondrial functions are often studied in whole cells, and metabolomics experiments using 13C-labeled substrates, coupled with mass isotopomer distribution analyses, represent a powerful approach to study global changes in cellular metabolic activities. However, little is known regarding the assessment of metabolic activities in isolated mitochondria using this technology. Studies on isolated mitochondria permit the evaluation of whether changes in cellular metabolic activities are due to modifications in the intrinsic properties of the mitochondria. Here, we present a streamlined approach to accurately determine 13C, as well as 12C enrichments in isolated mitochondria from mammalian tissues or cultured cells by GC/MS. We demonstrate the relevance of this experimental approach by assessing the effects of drugs perturbing mitochondrial functions on the mass isotopomer enrichment of metabolic intermediates. Furthermore, we investigate 13C and 12C enrichments in mitochondria isolated from cancer cells given the emerging role of metabolic alterations in supporting tumor growth. This original method will provide a very sensitive tool to perform metabolomics studies on isolated mitochondria. PMID- 24957020 TI - Application of stable isotope-assisted metabolomics for cell metabolism studies. AB - The applications of stable isotopes in metabolomics have facilitated the study of cell metabolisms. Stable isotope-assisted metabolomics requires: (1) properly designed tracer experiments; (2) stringent sampling and quenching protocols to minimize isotopic alternations; (3) efficient metabolite separations; (4) high resolution mass spectrometry to resolve overlapping peaks and background noises; and (5) data analysis methods and databases to decipher isotopic clusters over a broad m/z range (mass-to-charge ratio). This paper overviews mass spectrometry based techniques for precise determination of metabolites and their isotopologues. It also discusses applications of isotopic approaches to track substrate utilization, identify unknown metabolites and their chemical formulas, measure metabolite concentrations, determine putative metabolic pathways, and investigate microbial community populations and their carbon assimilation patterns. In addition, 13C-metabolite fingerprinting and metabolic models can be integrated to quantify carbon fluxes (enzyme reaction rates). The fluxome, in combination with other "omics" analyses, may give systems-level insights into regulatory mechanisms underlying gene functions. More importantly, 13C-tracer experiments significantly improve the potential of low-resolution gas chromatography-mass spectrometry (GC-MS) for broad-scope metabolism studies. We foresee the isotope-assisted metabolomics to be an indispensable tool in industrial biotechnology, environmental microbiology, and medical research. PMID- 24957023 TI - Xanthan Gum Removal for 1H-NMR Analysis of the Intracellular Metabolome of the Bacteria Xanthomonas axonopodis pv. citri 306. AB - Xanthomonas is a genus of phytopathogenic bacteria, which produces a slimy, polysaccharide matrix known as xanthan gum, which involves, protects and helps the bacteria during host colonization. Although broadly used as a stabilizer and thickener in the cosmetic and food industries, xanthan gum can be a troubling artifact in molecular investigations due to its rheological properties. In particular, a cross-reaction between reference compounds and the xanthan gum could compromise metabolic quantification by NMR spectroscopy. Aiming at an efficient gum extraction protocol, for a 1H-NMR-based metabolic profiling study of Xanthomonas, we tested four different interventions on the broadly used methanol-chloroform extraction protocol for the intracellular metabolic contents observation. Lower limits for bacterial pellet volumes for extraction were also probed, and a strategy is illustrated with an initial analysis of X. citri's metabolism by 1H-NMR spectroscopy. PMID- 24957024 TI - Effects of Inorganic Carbon Limitation on the Metabolome of the Synechocystis sp. PCC 6803 Mutant Defective in glnB Encoding the Central Regulator PII of Cyanobacterial C/N Acclimation. AB - Cyanobacteria are the only prokaryotes performing oxygenic photosynthesis. Non diazotrophic strains such as the model Synechocystis sp. PCC 6803 depend on a balanced uptake and assimilation of inorganic carbon and nitrogen sources. The internal C/N ratio is sensed via the PII protein (GlnB). We analyzed metabolic changes of the DglnB mutant of Synechocystis sp. PCC 6803 under different CO2 availability. The identified metabolites provided a snapshot of the central C/N metabolism. Cells of the DglnB mutant shifted to carbon-limiting conditions, i.e. a decreased C/N ratio, showed changes in intermediates of the sugar storage and particularly of the tricarboxylic acid cycle, arginine, and glutamate metabolism. The changes of the metabolome support the notion that the PII protein is primarily regulating the N-metabolism whereas the changes in C-metabolism are probably secondary effects of the PII deletion. PMID- 24957022 TI - Rationales and approaches for studying metabolism in eukaryotic microalgae. AB - The generation of efficient production strains is essential for the use of eukaryotic microalgae for biofuel production. Systems biology approaches including metabolite profiling on promising microalgal strains, will provide a better understanding of their metabolic networks, which is crucial for metabolic engineering efforts. Chlamydomonas reinhardtii represents a suited model system for this purpose. We give an overview to genetically amenable microalgal strains with the potential for biofuel production and provide a critical review of currently used protocols for metabolite profiling on Chlamydomonas. We provide our own experimental data to underpin the validity of the conclusions drawn. PMID- 24957025 TI - Metabolic profiling of human peripheral blood mononuclear cells: influence of vitamin d status and gender. AB - Metabolic profiling of peripheral blood mononuclear cells (PBMC) could serve as a less invasive and more direct alternative to tissue biopsies or serum in metabolomic research. We conducted two exploratory independent studies in order to characterise PBMC's metabolomic profile following short-term vitamin D3 supplementation and to determine gender effects. In the first study, eight healthy males and females aged 40-65 y were randomly selected for profiling of PBMCs after receiving either 15 ug of vitamin D3 or placebo for four weeks. In the second study, twenty younger healthy males and females were studied. Cell metabolites were extracted and deproteinised using methanol/chloroform/water method and analysed by GC-MS. Higher vitamin D status had no effect on the fatty acid profile of PBMCs, but inflammatory biomarkers and adipokines correlated positively with stearic acid levels. In the second study, no gender-specific metabolites were identified. Valine, leucine and aspartic acid were identified as potential BMI-sensitive amino acids. Larger studies are needed to confirm the influence of BMI on these parameters. This work clearly demonstrates the utility of metabolomics profiling of PBMCs and paves the way for future applications of metabolomics in identifying metabolic profiles of blood cells as a measure for dietary intakes or physiological status. PMID- 24957026 TI - Contrasting strategies of photosynthetic energy utilization drive lifestyle strategies in ecologically important picoeukaryotes. AB - The efficiency with which absorbed light is converted to net growth is a key property for estimating global carbon production. We previously showed that, despite considerable evolutionary distance, Dunaliella tertiolecta (Chlorophyceae) and Thalassiosira weissflogii (Bacillariophyceae) share a common strategy of photosynthetic energy utilization and nearly identical light energy conversion efficiencies. These findings suggested that a single model might be appropriate for describing relationships between measures of phytoplankton production. This conclusion was further evaluated for Ostreococcus tauri RCC1558 and Micromonas pusilla RCC299 (Chlorophyta, Prasinophyceae), two picoeukaryotes with contrasting geographic distributions and swimming abilities. Nutrient dependent photosynthetic efficiencies in O. tauri were similar to the previously studied larger algae. Specifically, absorption-normalized gross oxygen and carbon production and net carbon production were independent of nutrient limited growth rate. In contrast, all measures of photosynthetic efficiency were strongly dependent on nutrient availability in M. pusilla. This marked difference was accompanied by a diminished relationship between Chla:C and nutrient limited growth rate and a remarkably greater efficiency of gross-to-net energy conversion than the other organisms studied. These results suggest that the cost-benefit of decoupling pigment concentration from nutrient availability enables motile organisms to rapidly exploit more frequent encounters with micro-scale nutrient patches in open ocean environments. PMID- 24957027 TI - Quantitative Metabolomics and Instationary 13C-Metabolic Flux Analysis Reveals Impact of Recombinant Protein Production on Trehalose and Energy Metabolism in Pichia pastoris. AB - Pichia pastoris has been recognized as an effective host for recombinant protein production. In this work, we combine metabolomics and instationary 13C metabolic flux analysis (INST 13C-MFA) using GC-MS and LC-MS/MS to evaluate the potential impact of the production of a Rhizopus oryzae lipase (Rol) on P. pastoris central carbon metabolism. Higher oxygen uptake and CO2 production rates and slightly reduced biomass yield suggest an increased energy demand for the producing strain. This observation is further confirmed by 13C-based metabolic flux analysis. In particular, the flux through the methanol oxidation pathway and the TCA cycle was increased in the Rol-producing strain compared to the reference strain. Next to changes in the flux distribution, significant variations in intracellular metabolite concentrations were observed. Most notably, the pools of trehalose, which is related to cellular stress response, and xylose, which is linked to methanol assimilation, were significantly increased in the recombinant strain. PMID- 24957028 TI - Short-Term Intra-Subject Variation in Exhaled Volatile Organic Compounds (VOCs) in COPD Patients and Healthy Controls and Its Effect on Disease Classification. AB - Exhaled volatile organic compounds (VOCs) are of interest for their potential to diagnose disease non-invasively. However, most breath VOC studies have analyzed single breath samples from an individual and assumed them to be wholly consistent representative of the person. This provided the motivation for an investigation of the variability of breath profiles when three breath samples are taken over a short time period (two minute intervals between samples) for 118 stable patients with Chronic Obstructive Pulmonary Disease (COPD) and 63 healthy controls and analyzed by gas chromatography and mass spectroscopy (GC/MS). The extent of the variation in VOC levels differed between COPD and healthy subjects and the patterns of variation differed for isoprene versus the bulk of other VOCs. In addition, machine learning approaches were applied to the breath data to establish whether these samples differed in their ability to discriminate COPD from healthy states and whether aggregation of multiple samples, into single data sets, could offer improved discrimination. The three breath samples gave similar classification accuracy to one another when evaluated separately (66.5% to 68.3% subjects classified correctly depending on the breath repetition used). Combining multiple breath samples into single data sets gave better discrimination (73.4% subjects classified correctly). Although accuracy is not sufficient for COPD diagnosis in a clinical setting, enhanced sampling and analysis may improve accuracy further. Variability in samples, and short-term effects of practice or exertion, need to be considered in any breath testing program to improve reliability and optimize discrimination. PMID- 24957030 TI - Fast "Feast/Famine" Cycles for Studying Microbial Physiology Under Dynamic Conditions: A Case Study with Saccharomyces cerevisiae. AB - Microorganisms are constantly exposed to rapidly changing conditions, under natural as well as industrial production scale environments, especially due to large-scale substrate mixing limitations. In this work, we present an experimental approach based on a dynamic feast/famine regime (400 s) that leads to repetitive cycles with moderate changes in substrate availability in an aerobic glucose cultivation of Saccharomyces cerevisiae. After a few cycles, the feast/famine produced a stable and repetitive pattern with a reproducible metabolic response in time, thus providing a robust platform for studying the microorganism's physiology under dynamic conditions. We found that the biomass yield was slightly reduced (-5%) under the feast/famine regime, while the averaged substrate and oxygen consumption as well as the carbon dioxide production rates were comparable. The dynamic response of the intracellular metabolites showed specific differences in comparison to other dynamic experiments (especially stimulus-response experiments, SRE). Remarkably, the frequently reported ATP paradox observed in single pulse experiments was not present during the repetitive perturbations applied here. We found that intracellular dynamic accumulations led to an uncoupling of the substrate uptake rate (up to 9-fold change at 20 s.) Moreover, the dynamic profiles of the intracellular metabolites obtained with the feast/famine suggest the presence of regulatory mechanisms that resulted in a delayed response. With the feast famine setup many cellular states can be measured at high frequency given the feature of reproducible cycles. The feast/famine regime is thus a versatile platform for systems biology approaches, which can help us to identify and investigate metabolite regulations under realistic conditions (e.g., large-scale bioreactors or natural environments). PMID- 24957031 TI - Biotechnological screening of microalgal and cyanobacterial strains for biogas production and antibacterial and antifungal effects. AB - Microalgae and cyanobacteria represent a valuable natural resource for the generation of a large variety of chemical substances that are of interest for medical research, can be used as additives in cosmetics and food production, or as an energy source in biogas plants. The variety of potential agents and the use of microalgae and cyanobacteria biomass for the production of these substances are little investigated and not exploited for the market. Due to the enormous biodiversity of microalgae and cyanobacteria, they hold great promise for novel products. In this study, we investigated a large number of microalgal and cyanobacterial strains from the Culture Collection of Algae at Gottingen University (SAG) with regard to their biomass and biogas production, as well antibacterial and antifungal effects. Our results demonstrated that microalgae and cyanobacteria are able to generate a large number of economically-interesting substances in different quantities dependent on strain type. The distribution and quantity of some of these components were found to reflect phylogenetic relationships at the level of classes. In addition, between closely related species and even among multiple isolates of the same species, the productivity may be rather variable. PMID- 24957029 TI - MALDI Mass Spectrometry Imaging for Visualizing In Situ Metabolism of Endogenous Metabolites and Dietary Phytochemicals. AB - Understanding the spatial distribution of bioactive small molecules is indispensable for elucidating their biological or pharmaceutical roles. Mass spectrometry imaging (MSI) enables determination of the distribution of ionizable molecules present in tissue sections of whole-body or single heterogeneous organ samples by direct ionization and detection. This emerging technique is now widely used for in situ label-free molecular imaging of endogenous or exogenous small molecules. MSI allows the simultaneous visualization of many types of molecules including a parent molecule and its metabolites. Thus, MSI has received much attention as a potential tool for pathological analysis, understanding pharmaceutical mechanisms, and biomarker discovery. On the other hand, several issues regarding the technical limitations of MSI are as of yet still unresolved. In this review, we describe the capabilities of the latest matrix-assisted laser desorption/ionization (MALDI)-MSI technology for visualizing in situ metabolism of endogenous metabolites or dietary phytochemicals (food factors), and also discuss the technical problems and new challenges, including MALDI matrix selection and metabolite identification, that need to be addressed for effective and widespread application of MSI in the diverse fields of biological, biomedical, and nutraceutical (food functionality) research. PMID- 24957032 TI - Adiponectin isoforms differentially affect gene expression and the lipidome of primary human hepatocytes. AB - Adiponectin (APN) exerts multiple beneficial effects in obesity and protects from liver injury. Different APN isoforms circulate in serum, and here, the effect of low molecular weight (LMW) and higher molecular weight (HMW) APN on primary human hepatocytes (PHH) has been analyzed. APN is not detected in hepatocyte lysates; levels are strongly increased by HMW-APN, but not by LMW-APN, suggesting the distinct uptake/degradation of APN isoforms by PHH. Several genes with a role in fibrosis, glucose and lipid metabolism known to be regulated by HMW-APN are not affected by the LMW-isoform. Follistatin is reduced by HMW-APN and induced by LMW APN in supernatants of PHH. Fibroblast growth factor 21 is repressed by both isoforms. Cellular triglycerides and cholesterol levels are not reduced by APN. Total phospholipids, including plasmalogens and sphingomyelins, are not changed upon APN incubation, while distinct species are either induced or repressed. Unexpectedly, total ceramide is increased by LMW-APN. Current data show that APN isoforms differentially affect hepatocyte gene expression, but do not grossly alter the hepatocyte lipidome. PMID- 24957033 TI - Reliable Metabolic Flux Estimation in Escherichia coli Central Carbon Metabolism Using Intracellular Free Amino Acids. AB - 13C metabolic flux analysis (MFA) is a tool of metabolic engineering for investigation of in vivo flux distribution. A direct 13C enrichment analysis of intracellular free amino acids (FAAs) is expected to reduce time for labeling experiments of the MFA. Measurable FAAs should, however, vary among the MFA experiments since the pool sizes of intracellular free metabolites depend on cellular metabolic conditions. In this study, minimal 13C enrichment data of FAAs was investigated to perform the FAAs-based MFA. An examination of a continuous culture of Escherichia coli using 13C-labeled glucose showed that the time required to reach an isotopically steady state for FAAs is rather faster than that for conventional method using proteinogenic amino acids (PAAs). Considering 95% confidence intervals, it was found that the metabolic flux distribution estimated using FAAs has a similar reliability to that of the PAAs-based method. The comparative analysis identified glutamate, aspartate, alanine and phenylalanine as the common amino acids observed in E. coli under different culture conditions. The results of MFA also demonstrated that the 13C enrichment data of the four amino acids is required for a reliable analysis of the flux distribution. PMID- 24957034 TI - Metabolome consistency: additional parazoanthines from the mediterranean zoanthid parazoanthus axinellae. AB - Ultra-high pressure liquid chromatography coupled to high resolution mass spectrometry (UHPLC-MS/MS) analysis of the organic extract obtained from the Mediterranean zoanthid Parazoanthus axinellae yielded to the identification of five new parazoanthines F-J. The structures were fully determined by comparison of fragmentation patterns with those of previously isolated parazoathines and MS/MS spectra simulation of in silico predicted compounds according to the metabolome consistency. The absolute configuration of the new compounds has been assigned using on-line electronic circular dichroism (UHPLC-ECD). We thus demonstrated the potential of highly sensitive hyphenated techniques to characterize the structures of a whole family of natural products within the metabolome of a marine species. Minor compounds can be characterized using these techniques thus avoiding long isolation processes that may alter the structure of the natural products. These results are also of interest to identify putative bioactive compounds present at low concentration in a complex mixture. PMID- 24957035 TI - Influence of missing values substitutes on multivariate analysis of metabolomics data. AB - Missing values are known to be problematic for the analysis of gas chromatography mass spectrometry (GC-MS) metabolomics data. Typically these values cover about 10%-20% of all data and can originate from various backgrounds, including analytical, computational, as well as biological. Currently, the most well known substitute for missing values is a mean imputation. In fact, some researchers consider this aspect of data analysis in their metabolomics pipeline as so routine that they do not even mention using this replacement approach. However, this may have a significant influence on the data analysis output(s) and might be highly sensitive to the distribution of samples between different classes. Therefore, in this study we have analysed different substitutes of missing values namely: zero, mean, median, k-nearest neighbours (kNN) and random forest (RF) imputation, in terms of their influence on unsupervised and supervised learning and, thus, their impact on the final output(s) in terms of biological interpretation. These comparisons have been demonstrated both visually and computationally (classification rate) to support our findings. The results show that the selection of the replacement methods to impute missing values may have a considerable effect on the classification accuracy, if performed incorrectly this may negatively influence the biomarkers selected for an early disease diagnosis or identification of cancer related metabolites. In the case of GC-MS metabolomics data studied here our findings recommend that RF should be favored as an imputation of missing value over the other tested methods. This approach displayed excellent results in terms of classification rate for both supervised methods namely: principal components-linear discriminant analysis (PC-LDA) (98.02%) and partial least squares-discriminant analysis (PLS-DA) (97.96%) outperforming other imputation methods. PMID- 24957036 TI - Surveillance of C-allocation in microalgal cells. AB - When microalgae are exposed to changing environmental conditions, e.g., light dark cycles or oscillations in nutrient availability (CO2, nitrogen, phosphate or silicate) they respond with metabolic changes in the carbon allocation pattern. Short time regulations in the time range of few seconds to minutes can be mirrored best by mass spectroscopy based metabolomics. However, these snap shots do not reflect the alterations in the carbon flow to the cellular macromolecules like protein, carbohydrate or lipid. In this review it is shown how the combination of FTIR spectroscopy and Chla-in-vivo-fluorescence based electron transport rates can reveal changes in the metabolic flux rates of carbon during a shift of the environmental conditions. The review will demonstrate in which time range FTIR spectroscopy can deliver significant information and how FTIR spectroscopy data can synergistically support metabolome analysis by mass spectroscopy. PMID- 24957038 TI - Molar-based targeted metabolic profiling of cyanobacterial strains with potential for biological production. AB - Recently, cyanobacteria have become one of the most attractive hosts for biochemical production due to its high proliferative ability and ease of genetic manipulation. Several researches aimed at biological production using modified cyanobacteria have been reported previously. However, to improve the yield of bioproducts, a thorough understanding of the intercellular metabolism of cyanobacteria is necessary. Metabolic profiling techniques have proven to be powerful tools for monitoring cellular metabolism of various organisms and can be applied to elucidate the details of cyanobacterial metabolism. In this study, we constructed a metabolic profiling method for cyanobacteria using 13C-labeled cell extracts as internal standards. Using this method, absolute concentrations of 84 metabolites were successfully determined in three cyanobacterial strains which are commonly used as background strains for metabolic engineering. By comparing the differences in basic metabolic potentials of the three cyanobacterial strains, we found a well-correlated relationship between intracellular energy state and growth in cyanobacteria. By integrating our results with the previously reported biological production pathways in cyanobacteria, we found putative limiting step of carbon flux. The information obtained from this study will not only help gain insights in cyanobacterial physiology but also serve as a foundation for future metabolic engineering studies using cyanobacteria. PMID- 24957037 TI - Breath analysis in disease diagnosis: methodological considerations and applications. AB - Breath analysis is a promising field with great potential for non-invasive diagnosis of a number of disease states. Analysis of the concentrations of volatile organic compounds (VOCs) in breath with an acceptable accuracy are assessed by means of using analytical techniques with high sensitivity, accuracy, precision, low response time, and low detection limit, which are desirable characteristics for the detection of VOCs in human breath. "Breath fingerprinting", indicative of a specific clinical status, relies on the use of multivariate statistics methods with powerful in-built algorithms. The need for standardisation of sample collection and analysis is the main issue concerning breath analysis, blocking the introduction of breath tests into clinical practice. This review describes recent scientific developments in basic research and clinical applications, namely issues concerning sampling and biochemistry, highlighting the diagnostic potential of breath analysis for disease diagnosis. Several considerations that need to be taken into account in breath analysis are documented here, including the growing need for metabolomics to deal with breath profiles. PMID- 24957040 TI - Hemorrhagic events in cancer patients treated with aflibercept: a meta-analysis. AB - Aflibercept (Ziv-aflibercept, VEGF Trap, AVE005) is an engineered protein that functions as a decoy receptor to bind vascular endothelial growth factor A (VEGF A). Hemorrhagic events, including epistaxis, gastrointestinal bleeding, and pulmonary bleeding, is one of its major adverse effects, but the incidence rate and overall risk has not been systematically studied. Therefore, we conducted a meta-analysis of published clinical trials to investigate the incidence and relative risk of hemorrhagic events in cancer patients treated with aflibercept. Electronic databases including PubMed, Embase, Cochrane databases, and American Society of Clinical Oncology abstracts were searched. Eligible studies were phase II and III prospective clinical trials of cancer patients treated with aflibercept with toxicity profile on hemorrhagic events. Overall incidence rates, relative risk (RR), and 95 % confidence intervals (CI) were calculated using fixed or random effects models depending on the heterogeneity of the included studies. A total of 4,538 patients with a variety of solid tumors from 13 prospective clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade hemorrhagic events in cancer patients were 22.1 % (95 % CI, 16.5-29.7 %) and 4.2 % (95 % CI, 3.9-4.6 %), respectively. The relative risks of hemorrhagic events of aflibercept compared to control were increased for all-grade (RR = 2.63; 95 % CI, 2.07-3.34) and high-grade (RR = 2.45, 95 % CI, 1.62-3.72) hemorrhagic events. The risk of developing high-grade hemorrhagic events with aflibercept was comparable to that of bevacizumab (RR = 1.26; 95 % CI, 0.89-1.79). Aflibercept is associated with an increased risk of developing hemorrhagic events in patients with solid tumors. Close monitoring and management of hemorrhagic events are recommended. PMID- 24957039 TI - Prevalence of RET/PTC1 and RET/PTC3 gene rearrangements in Chennai population and its correlation with clinical parameters. AB - Thyroid cancer is one of the most common endocrine disorders in the world. In India, about 42 million people suffer from various thyroid disorders. However, based on population-based cancer registry (PBCR) and Chennai cancer registry, thyroid cancer is emerging as a common cancer particularly in Chennai. Papillary thyroid carcinoma is considered as the most prevalent cancer constituting about 80-85 % of thyroid malignancies. Rearranged during transfection (RET)/papillary thyroid carcinoma (PTC) gene rearrangements are one of the major genetic alterations found in papillary thyroid carcinoma. This present study aims at estimating the frequency of RET/PTC1 and RET/PTC3 gene rearrangements in Chennai population and investigating the correlation between RET/PTC gene expressions with clinical parameters. Formalin-fixed paraffin-embedded (FFPE) tumor tissues obtained from 30 patients with papillary thyroid carcinoma were analyzed. Initially, to differentiate classic and follicular variants of papillary thyroid carcinoma samples, immunohistochemistry was performed. Thereafter, total RNA was isolated, and quantitative evaluation of RET/PTC1 and RET/PTC3 gene rearrangements by real-time PCR was performed. Chi-square test was performed to understand the correlation between positive and negative mutations of RET/PTC messenger RNA (mRNA) expression with clinical parameters. RET/PTC3 gene rearrangements were identified in 26/30 (86.67 %) cases, and none of the patient in our series had RET/PTC1 gene rearrangements. There was no statistically significant difference observed between positive and negative mutations of RET/PTC3 mRNA expression with clinic pathological parameters. Our results indicate that RET/PTC3 gene rearrangements are the most prevalent form of rearrangements in PTCs of Chennai population. PMID- 24957041 TI - CRR9p polymorphism as a protective factor for lung cancer. AB - A number of studies have investigated the association between CRR9p polymorphism and risk of lung cancer (LC), yet the role in LC pathogenesis remains unclear owing to inconsistencies across studies. We searched PubMed, Embase, and Web of Science for all medical literature published until January 2014. Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were obtained by means of the fixed effects model. Data from eight studies satisfying the predesigned inclusion criteria were selected for this meta-analysis. We found a statistically significant evidence for a protective effect on the overall LC risk (TT vs. CC: OR = 0.78, 95 % CI = 0.70-0.87, P het = 0.299; TT vs. CT + CC: OR = 0.81, 95 % CI = 0.73-0.90, P het = 0.113; T vs. C: OR = 0.90, 95 % CI = 0.86-0.95, P het = 0.758; TT + CT vs. CC: OR = 0.92, 95 % CI = 0.87-0.98, P het = 0.892). Both Caucasian and Asian populations were suggested to have a reduced risk of developing such cancer. In the analysis of the association between rs401681 and non-small cell lung cancer (NSCLC) risks, all of the contrast models showed similar results except the CT vs. CC genetic model (OR = 0.93, 95 % CI = 0.84 1.02, P het = 0.568). Our meta-analysis provides supportive evidence that CRR9p polymorphism may influence a risk of LC and NSCLC in a protective model. PMID- 24957043 TI - Expression profile of CYP1A1 and CYP1B1 enzymes in endometrial tumors. AB - The cytochrome P450 CYP1A1 and CYP1B1 enzymes are phase I extrahepatic enzymes involved in the activation of pro-carcinogenic compounds to carcinogenic metabolites. Although differential overexpression of CYP1A1 and CYP1B1 has been documented at the messenger RNA (mRNA) and protein level, studies that have examined CYP1 expression by enzyme activity assays are limited. In the current study, the expression of CYP1A1 and CYP1B1 was investigated in a panel of human tumors of endometrial origin by quantitative reverse transcriptase PCR (qRT-PCR), Western blotting, and enzyme activity assays. The data revealed that approximately 36 % (5/14) and 43 % (6/14) of the endometrial tumors overexpressed CYP1A1 and CYP1B1 mRNA, whereas in 57 % of the endometrial tumors, CYP1 mRNA levels were downregulated. The mean mRNA levels of CYP1B1 and CYP1A1 in endometrial tumors did not show a significant difference compared to normal tissues (p > 0.05). Western blotting confirmed the qRT-PCR results and CYP1A1 and CYP1B1 proteins were shown to be downregulated in 7/14 (50 %) of the tumors and overexpressed in 4/14 (29 %) of the tumors. As regards to enzyme activity, 21 % (3/14) of the endometrial samples revealed elevated CYP1 activity levels across the tumor counterparts. Overall, the data suggest a putative downregulation of CYP1A1 and CYP1B1 expression in endometrial tumors, whereas overexpression of active CYP1 enzymes in 21 % of the tumors highlights the potential use of the latter enzymes as chemotherapeutic targets in endometrial cancer. PMID- 24957042 TI - Inhibitory effects of sea buckthorn procyanidins on fatty acid synthase and MDA MB-231 cells. AB - Fatty acid synthase (FAS) is overexpressed in many human cancers including breast cancer and is considered to be a promising target for therapy. Sea buckthorn has long been used to treat a variety of maladies. Here, we investigated the inhibitory effect of sea buckthorn procyanidins (SBPs) isolated from the seeds of sea buckthorn on FAS and FAS overexpressed human breast cancer MDA-MB-231 cells. The FAS activity and FAS inhibition were measured by a spectrophotometer at 340 nm of nicotinamide adenine dinucleotide phosphate (NADPH) absorption. We found that SBP potently inhibited the activity of FAS with a half-inhibitory concentration (IC50) value of 0.087 MUg/ml. 3-4,5-Dimethylthiazol-2-yl-2,3 diphenyl tetrazolium bromide (MTT) assay was used to test the cell viability. SBP reduced MDA-MB-231 cell viability with an IC50 value of 37.5 MUg/ml. Hoechst 33258/propidium iodide dual staining and flow cytometric analysis showed that SBP induced MDA-MB-231 cell apoptosis. SBP inhibited intracellular FAS activity with a dose-dependent manner. In addition, sodium palmitate could rescue the cell apoptosis induced by SBP. These results showed that SBP was a promising FAS inhibitor which could induce the apoptosis of MDA-MB-231 cells via inhibiting FAS. These findings suggested that SBP might be useful for preventing or treating breast cancer. PMID- 24957044 TI - ClonorESTdb: a comprehensive database for Clonorchis sinensis EST sequences. AB - BACKGROUND: Clonorchiasis, which is primarily caused by liver fluke (Platyhelminthes), is a fatal infectious disease that is mainly associated with bile duct malignancy and the subsequent development of cholangiocarcinoma. Thus, a genomic approach now represents an important step to further our knowledge of biology and the pathology of these parasites. The results of expressed sequence tags (ESTs) sequencing need to be well organized into databases to provide an integrated set of tools and functional information. FINDINGS: Here, the ClonorESTdb database represents a collection of Clonorchis sinensis ESTs that is intended as a resource for parasite functional genomics. A total of 55,736 successful EST sequences, which are cleaned and clustered into non-redundant 13,305 C. sinensis assembled EST sequences (6,497 clusters and 6,808 singletons), were obtained from three in-house prepared cDNA libraries of C. sinensis at different developmental stages. The assembled consensus sequences were annotated using the BLAST algorithm or/and hmm against NCBI NR, UniProt, KEGG and InterProScan. The ClonorESTdb database provides functional annotation, their expression profiles, tandem repeats and putative single nucleotide polymorphisms with utility tools such as local BLAST search and text retrieval. CONCLUSIONS: This resource enables the researcher to identify and compare expression signatures under different biological stages and promotes ongoing parasite drug and vaccine development and biological research.Database URL:http://pathod.cdc.go.kr/clonorestdb/. PMID- 24957047 TI - The Food and Drug Administration's role in promoting consistent labels for generic drugs. PMID- 24957046 TI - Safety and tissue yield for percutaneous native kidney biopsy according to practitioner and ultrasound technique. AB - BACKGROUND: Although percutaneous renal biopsy remains an essential tool in the diagnosis and treatment of renal diseases, in recent times the traditional procedure of nephrologists has been performed by non-nephrologists rather than nephrologists at many institutions. The present study assessed the safety and adequacy of tissue yield during percutaneous renal biopsy according to practitioners and techniques based on ultrasound. METHODS: This study included 658 native renal biopsies performed from 2005 to 2010 at a single centre. The biopsies were performed by nephrologists or expert ultrasound radiologists using the ultrasound-marked blind or real-time ultrasound-guided techniques. RESULTS: A total of 271 ultrasound-marked blind biopsies were performed by nephrologists, 170 real-time ultrasound-guided biopsies were performed by nephrologists, and 217 real-time ultrasound-guided biopsies were performed by radiologists during the study period. No differences in post-biopsy complications such as haematoma, need for transfusion and intervention, gross haematuria, pain, or infection were observed among groups. Glomerular numbers of renal specimens from biopsies performed by nephrologists without reference to any technique were higher than those obtained from real-time ultrasound-guided biopsies performed by expert ultrasound radiologists. CONCLUSIONS: Percutaneous renal biopsy performed by nephrologists was not inferior to that performed by expert ultrasound radiologists as related to specimen yield and post-biopsy complications. PMID- 24957048 TI - Effects of boron deficiency on major metabolites, key enzymes and gas exchange in leaves and roots of Citrus sinensis seedlings. AB - Boron (B) deficiency is a widespread problem in many crops, including Citrus. The effects of B-deficiency on gas exchange, carbohydrates, organic acids, amino acids, total soluble proteins and phenolics, and the activities of key enzymes involved in organic acid and amino acid metabolism in 'Xuegan' [Citrus sinensis (L.) Osbeck] leaves and roots were investigated. Boron-deficient leaves displayed excessive accumulation of nonstructural carbohydrates and much lower CO2 assimilation, demonstrating feedback inhibition of photosynthesis. Dark respiration, concentrations of most organic acids [i.e., malate, citrate, oxaloacetate (OAA), pyruvate and phosphoenolpyruvate] and activities of enzymes [i.e., phosphoenolpyruvate carboxylase (PEPC), NAD-malate dehydrogenase, NAD malic enzyme (NAD-ME), NADP-ME, pyruvate kinase (PK), phosphoenolpyruvate phosphatase (PEPP), citrate synthase (CS), aconitase (ACO), NADP-isocitrate dehydrogenase (NADP-IDH) and hexokinase] involved in glycolysis, the tricarboxylic acid (TCA) cycle and the anapleurotic reaction were higher in B deficient leaves than in controls. Also, total free amino acid (TFAA) concentration and related enzyme [i.e., NADH-dependent glutamate 2-oxoglutarate aminotransferase (NADH-GOGAT) and glutamate OAA transaminase (GOT)] activities were enhanced in B-deficient leaves. By contrast, respiration, concentrations of nonstructural carbohydrates and three organic acids (malate, citrate and pyruvate), and activities of most enzymes [i.e., PEPC, NADP-ME, PK, PEPP, CS, ACO, NAD-isocitrate dehydrogenase, NADP-IDH and hexokinase] involved in glycolysis, the TCA cycle and the anapleurotic reaction, as well as concentration of TFAA and activities of related enzymes (i.e., nitrate reductase, NADH-GOGAT, glutamate pyruvate transaminase and glutamine synthetase) were lower in B deficient roots than in controls. Interestingly, leaf and root concentration of total phenolics increased, whereas that of total soluble protein decreased, in response to B-deficiency. In conclusion, respiration, organic acid (i.e., glycolysis and the TCA cycle) metabolism, the anapleurotic pathway and amino acid biosynthesis were upregulated in B-deficient leaves with excessive accumulation of carbohydrates to 'consume' the excessive carbon available, but downregulated in B-deficient roots with less accumulation of carbohydrates to maintain the net carbon balance. PMID- 24957045 TI - Risk factors for knee replacement due to primary osteoarthritis, a population based, prospective cohort study of 315,495 individuals. AB - BACKGROUND: Osteoarthritis (OA) of the knee is a common and disabling condition. We wanted to investigate the modifiable risk factors Body Mass Index (BMI) and physical activity, using knee replacement (KR) as a marker for severely symptomatic disease, focusing on the interaction between these risk factors. METHODS: 315,495 participants (mean age 43.0 years) from national health screenings were followed prospectively with respect to KR identified by linkage to the Norwegian Arthroplasty Register. Data were analysed by Cox proportional hazard regression. RESULTS: During 12 years of follow up 1,323 individuals received KR for primary OA. There was a dose-response relationship between BMI and heavy labour, and later KR. Comparing the highest versus the lowest quarter of BMI, the relative risk was 6.2 (95% CI: 4.2-9.0) in men and 11.1 (95% CI: 7.8 15.6) in women. Men reporting intensive physical activity at work had a relative risk of 2.4 (95% CI: 1.8-3.2) versus men reporting sedentary activity at work, the corresponding figure in women being 2.3 (95% CI: 1.7-3.2). The effect of BMI and physical activity at work was additive. The heaviest men with the most strenuous work had a RR of 11.7 (95% CI: 5.9-23.1) compared to the ones with the lowest BMI and most sedentary work. For women the corresponding RR was 15.8 (95% CI: 8.2-30.3). There was no association between physical activity during leisure and KR. CONCLUSION: We found that a high BMI and intensive physical activity at work both contribute strongly to the risk of having a KR. As the two risk factors seem to act independently, people with strenuous physical work with a high BMI are at particularly high risk for severely disabling OA of the knee, and should be targeted with effective preventive measures. PMID- 24957049 TI - The autonomic balance predicts cardiac responses after the first dose of fingolimod. AB - BACKGROUND: Predictive markers of cardiac side effects would be helpful for the stratification and individualized monitoring of multiple sclerosis (MS) patients prescribed with fingolimod. OBJECTIVE: To test whether the autonomic balance predicts a cardiac response after the first dose of fingolimod. METHODS: A total of 55 consecutive relapsing-remitting MS (RRMS) patients underwent 'head-up tilt', Valsalva maneuver, deep breathing and handgrip tests before their first dose of fingolimod. The normalized unit of the high frequency (HF) component (HF normalized units; HFnu), reflecting mostly vagal activity; and the low frequency (LF) component (LF normalized units; LFnu) reflecting mostly sympathetic activity, were considered for the analysis of heart rate (HR) variability. The patients' HR and electrocardiographic parameters ((the interval between P wave and ventricular depolarization (PR); the interval between Q and T waves (QT)) were recorded during 6-hour post-dose monitoring. RESULTS: We found significant correlations between measures of parasympathetic function and fingolimod-induced bradycardia. Subjects with higher Valsalva ratio and HR variation during deep breathing had, in fact, nadir HR <= 50 beats/minute (bpm) after the first fingolimod dose. Conversely, significant negative correlations were found between measures of sympathetic function and fingolimod-induced PR interval increase. Subjects with lower LFnu at rest and less increase of blood pressure on the handgrip test showed a PR interval increase > 20 ms after fingolimod. CONCLUSIONS: Assessing autonomic control of cardiovascular functions can be useful to predict cardiac effects after the first fingolimod dose. PMID- 24957050 TI - Accreditation of Professional Preparation Programs for School Health Educators: The Changing Landscape. AB - The health education profession is committed to maintaining the highest standards of quality assurance, including accreditation of professional preparation programs in both school and community/public health education. Since 2001, the Society for Public Health Education (SOPHE) has increased attention to strengthening accreditation processes for preservice programs. This article focuses on the preparation of school health educators and the evolving philosophies and approaches concerning quality assurance, with particular attention to recent changes in teacher education and national professional accreditation entities. The unification of the National Council for Accreditation of Teacher Education (NCATE) and the Teacher Education Accreditation Council (TEAC) to form the Council for the Accreditation of Educator Preparation (CAEP) as the single voice for teacher accreditation presents an opportunity to create a model unified accreditation system. Such a system can improve and enhance the stature of the teaching profession, raise expectations and the performance standards for teacher education candidates, and strengthen the standards for the evidence used to support claims of quality. During this transition period from NCATE and TEAC to CAEP, a School Health Education Accreditation Working Group convened by SOPHE recommended to the SOPHE Board of Trustees that SOPHE urge health education professionals to monitor and provide input into the emerging standards and processes for school health educator program accreditation. The Working Group also recommended that both health education professionals and the stakeholder professional organizations advocate for strong quality assurance standards for school health educator professional preparation programs. The Working Group anticipates future changes in quality assurance processes and curricula to keep pace with new accreditation requirements and the results from the latest role delineation research for health education specialists. PMID- 24957051 TI - Interatrial conduction disturbance in postoperative atrial fibrillation: a comparative study of P-wave dispersion and Doppler myocardial imaging in cardiac surgery. AB - OBJECTIVE: Disturbances of interatrial conduction have been proposed as one of the contributing mechanisms of postoperative atrial fibrillation (AF). P-wave dispersion has been recognized as a sensitive tool for detecting interatrial conduction disturbances. Doppler myocardial imaging (DMI) has been validated as a non-invasive tool to indirectly reflect electrical atrial activation and therefore is used in this study to detect possible interatrial electromechanical disturbances after cardiac surgery. METHODS: 30 patients (23 men, age 62 +/- 1 years) admitted for coronary bypass surgery with no prior history of AF were included in this investigation. Echocardiography and electrocardiograms (ECG) were obtained on the day before and after surgery. In addition to standard echocardiography, DMI-loops were acquired from the apical window. The following time intervals were derived off-line from the free right atrial (RA), left atrial (LA) lateral and LA posterior wall: onset P-wave to start (P to A'start), to peak (P to A'peak) and to end of atrial deformation (total electromechanical activity). These intervals were compared to each other and to P-wave dispersion derived from the recorded ECGs. RESULTS: All patients were in sinus rhythm during their postoperative assessment, but 11 patients presented episodes of AF within the first three postoperative days. Atrial electromechanical activation was earliest in the RA and latest in the lateral LA. In patients with AF, P-wave dispersion was significantly prolonged postoperatively (mean: +18.6 ms; 95% confidence interval (CI): 12.1-25.2 ms; p < 0.001) compared to non-AF patients (mean: -2.4 ms; CI: -6.6-1.9 ms). P dispersion was closely correlated to P to A'start intervals (from RA to LA lat.: preop.: rho = 0.74, postop.: rho = 0.87; p < 0.001). Prolonged right to left conduction interval was associated with an elevated risk for AF (from RA to LA lat.: odds ratio 1.13 (CI:1.03-1.24); p: 0.007. CONCLUSION: DMI enabled detection of interatrial conduction disturbances in concordance to findings of prolonged postoperative P-wave dispersion. Equally effective to P-wave dispersion, this simple and reproducible tool might help to early identify the risk for postoperative AF, thus extending the informative value of routine postoperative echocardiography. PMID- 24957052 TI - Self-reported adverse drug reactions and their influence on highly active antiretroviral therapy in HIV infected patients: a cross sectional study. AB - BACKGROUND: Patients on antiretroviral therapy have higher risk of developing adverse drug reactions (ADRs). The impact of ADRs on treatment adherence, treatment outcomes and future treatment options is quiet considerable. Thus, the purpose of this study was to describe the common self-reported ADRs and their impact on antiretroviral treatment. METHODS: Cross-sectional study was conducted at antiretroviral therapy (ART) clinic of Gondar University Hospital. Semi structured interview questionnaire was used to extract self-reported ADRs, socio demographic, and psycho-social variables. Variables related to antiretroviral medication, laboratory values and treatment changes were obtained from medical charts. Chi-square and odds ratio with 95% confidence interval were used to determine the associations of dependent variables. RESULT: A total of 384 participants were enrolled. At least one adverse drug reaction was reported by 345 (89.8%) study participants and the mean number of ADRs reported was 3.7 (+/ 0.2). The most frequently reported ADRs were nausea (56.5%) and headache (54.9%). About 114 (31.0%) participants considered antiretroviral therapy to be unsuccessful if ADRs occurred and only 10 (2.6%) decided to skip doses as ADRs were encountered. Based on chart review, treatment was changed for 78 (20.3%) patients and from which 79% were due to documented ADRs (p = 0.00). Among them, CNS symptoms (27.4%) and anemia (16.1%) were responsible for the majority of changes. Around four percent of patients were non-adherent to ART. Non-adhered participants and those on treatment changes were not statistically associated with self-reported ADRs. Only unemployment status (AOR = 1.76 (1.15 - 2.70), p = 0.01) and ADR duration of less than one month (AOR = 1.95 (1.28-2.98), p = 0.001) were significantly associated with self-reported adverse effects of three or more in the multivariate analysis. CONCLUSION: Self-reported ADRs to antiretroviral therapy are quite common. More of the reactions were of short lasting and their impact on adherence and treatment change were less likely. However, documented ADRs were the most prevalent reasons for ART switch. Moreover, the level of unemployment was a strong predictor of self-reported ADRs. PMID- 24957053 TI - Accuracy of using computer-aided rapid prototyping templates for mandible reconstruction with an iliac crest graft. AB - BACKGROUND: This study aimed to evaluate the accuracy of surgical outcomes in free iliac crest mandibular reconstructions that were carried out with virtual surgical plans and rapid prototyping templates. METHODS: This study evaluated eight patients who underwent mandibular osteotomy and reconstruction with free iliac crest grafts using virtual surgical planning and designed guiding templates. Operations were performed using the prefabricated guiding templates. Postoperative three-dimensional computer models were overlaid and compared with the preoperatively designed models in the same coordinate system. RESULTS: Compared to the virtual osteotomy, the mean error of distance of the actual mandibular osteotomy was 2.06 +/- 0.86 mm. When compared to the virtual harvested grafts, the mean error volume of the actual harvested grafts was 1412.22 +/- 439.24 mm3 (9.12% +/- 2.84%). The mean error between the volume of the actual harvested grafts and the shaped grafts was 2094.35 +/- 929.12 mm3 (12.40% +/- 5.50%). CONCLUSIONS: The use of computer-aided rapid prototyping templates for virtual surgical planning appears to positively influence the accuracy of mandibular reconstruction. PMID- 24957054 TI - Galectin-8 elicits pro-inflammatory activities in the endothelium. AB - Galectins (Gals), a family of mammalian lectins, play diverse roles under physiological and pathological conditions. Here, we analyzed the tandem-repeat Gal-8 synthesis, secretion and effects on the endothelium physiology. Gal-8M and Gal-8L isoforms were secreted under basal conditions by human microvascular endothelial cells (HMEC-1). However, expression and secretion of the Gal-8M isoform, but not Gal-8L, were increased in response to bacterial lipopolysaccharide (LPS) stimulus and returned to control values after LPS removal. Similarly, cell surface Gal-8 exposure was increased after stimulation with LPS. To evaluate Gal-8 effects on the endothelium physiology, HMEC-1 cells were incubated in the presence of recombinant Gal-8M. Pretreated HMEC-1 cells became proadhesive to human normal platelets, indicating that Gal-8 actually activates endothelial cells. This effect was specific for lectin activity as it was prevented by the simultaneous addition of lactose, but not by sucrose. Endothelial cells also increased their exposition of von Willebrand factor after Gal-8 treatment, which constitutes another feature of cell activation that could be, in turn, responsible for the observed platelet adhesion. Several pro inflammatory molecules were abundantly produced by Gal-8 stimulated endothelial cells: CXCL1 (GRO-alpha), GM-CSF, IL-6 and CCL5 (RANTES), and in a lower degree CCL2 (MCP-1), CXCL3 (GRO-gamma) and CXCL8 (IL-8). In agreement, Gal-8M induced nuclear factor kappa B phosphorylation. Altogether, these results not only confirm the pro-inflammatory role we have already proposed for Gal-8 in other cellular systems but also suggest that this lectin is orchestrating the interaction between leukocytes, platelets and endothelial cells. PMID- 24957055 TI - Structure, interactions and evolutionary implications of a domain-swapped lectin dimer from Mycobacterium smegmatis. AB - Crystal structure determination of the lectin domain of MSMEG_3662 from Mycobacterium smegmatis and its complexes with mannose and methyl-alpha-mannose, the first effort of its kind on a mycobacterial lectin, reveals a structure very similar to beta-prism II fold lectins from plant sources, but with extensive unprecedented domain swapping in dimer formation. The two subunits in a dimer often show small differences in structure, but the two domains, not always related by 2-fold symmetry, have the same structure. Each domain carries three sugar-binding sites, similar to those in plant lectins, one on each Greek key motif. The occurrence of beta-prism II fold lectins in bacteria, with characteristics similar to those from plants, indicates that this family of lectins is of ancient origin and had evolved into a mature system before bacteria and plants diverged. In plants, the number of binding sites per domain varies between one and three, whereas the number is two in the recently reported lectin domains from Pseudomonas putida and Pseudomonas aeruginosa. An analysis of the sequences of the lectins and the lectin domains shows that the level of sequence similarity among the three Greek keys in each domain has a correlation with the number of binding sites in it. Furthermore, sequence conservation among the lectins from different species is the highest for that Greek key which carries a binding site in all of them. Thus, it would appear that carbohydrate binding influences the course of the evolution of the lectin. PMID- 24957056 TI - Numerical Simulation of Particle Distribution in Capillary Membrane during Backwash. AB - The membrane filtration with inside-out dead-end driven UF-/MF- capillary membranes is an effective process for particle removal in water treatment. Its industrial application increased in the last decade exponentially. To date, the research activities in this field were aimed first of all at the analysis of filtration phenomena disregarding the influence of backwash on the operation parameters of filtration plants. However, following the main hypothesis of this paper, backwash has great potential to increase the efficiency of filtration. In this paper, a numerical approach for a detailed study of fluid dynamic processes in capillary membranes during backwash is presented. The effect of particle size and inlet flux on the backwash process are investigated. The evaluation of these data concentrates on the analysis of particle behavior in the cross sectional plane and the appearance of eventually formed particle plugs inside the membrane capillary. Simulations are conducted in dead-end filtration mode and with two configurations. The first configuration includes a particle concentration of 10% homogeneously distributed within the capillary and the second configuration demonstrates a cake layer on the membrane surface with a packing density of 0:6. Analyzing the hydrodynamic forces acting on the particles shows that the lift force plays the main role in defining the particle enrichment areas. The operation parameters contribute in enhancing the lift force and the heterogeneity to anticipate the clogging of the membrane. PMID- 24957057 TI - Advancement in electrospun nanofibrous membranes modification and their application in water treatment. AB - Water, among the most valuable natural resources available on earth, is under serious threat as a result of undesirable human activities: for example, marine dumping, atmospheric deposition, domestic, industrial and agricultural practices. Optimizing current methodologies and developing new and effective techniques to remove contaminants from water is the current focus of interest, in order to renew the available water resources. Materials like nanoparticles, polymers, and simple organic compounds, inorganic clay materials in the form of thin film, membrane or powder have been employed for water treatment. Among these materials, membrane technology plays a vital role in removal of contaminants due to its easy handling and high efficiency. Though many materials are under investigation, nanofibers driven membrane are more valuable and reliable. Synthetic methodologies applied over the modification of membrane and its applications in water treatment have been reviewed in this article. PMID- 24957058 TI - Performance modeling and cost analysis of a pilot-scale reverse osmosis process for the final purification of olive mill wastewater. AB - A secondary treatment for olive mill wastewater coming from factories working with the two-phase olive oil production process (OMW-2) has been set-up on an industrial scale in an olive oil mill in the premises of Jaen (Spain). The secondary treatment comprises Fenton-like oxidation followed by flocculation sedimentation and filtration through olive stones. In this work, performance modelization and preliminary cost analysis of a final reverse osmosis (RO) process was examined on pilot scale for ulterior purification of OMW-2 with the goal of closing the loop of the industrial production process. Reduction of concentration polarization on the RO membrane equal to 26.3% was provided upon increment of the turbulence over the membrane to values of Reynolds number equal to 2.6 * 104. Medium operating pressure (25 bar) should be chosen to achieve significant steady state permeate flux (21.1 L h-1 m-2) and minimize membrane fouling, ensuring less than 14.7% flux drop and up to 90% feed recovery. Under these conditions, irreversible fouling below 0.08 L h-2 m-2 bar-1 helped increase the longevity of the membrane and reduce the costs of the treatment. For 10 m3 day-1 OMW-2 on average, 47.4 m2 required membrane area and 0.87 ? m-3 total costs for the RO process were estimated. PMID- 24957059 TI - Interface Properties between Lithium Metal and a Composite Polymer Electrolyte of PEO18Li(CF3SO2)2N-Tetraethylene Glycol Dimethyl Ether. AB - The electrochemical properties of a composite solid polymer electrolyte, consisting of poly(ethylene oxide) (PEO)-lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) and tetraethylene glycol dimethyl ether (TEGDME) was examined as a protective layer between lithium metal and a water-stable lithium ion-conducting glass ceramic of Li1+x+y(Ti,Ge)2-xAlxP3 ySiyO12 (LTAP). The lithium ion conductivity and salt diffusion coefficient of PEO18LiTFSI were dramatically enhanced by the addition of TEGDME. The water stable lithium electrode with PEO18LiTFSI-2TEGDME, as the protective layer, exhibited a low and stable electrode resistance of 85 Omega.cm2 at 60 degrees C, after 28 days, and low overpotentials of 0.3 V for lithium plating and 0.4 V for lithium stripping at 4.0 mA.cm-2 and 60 degrees C. A Li/PEO18LiTFSI 2TEGDME/LTAP/saturated LiCl aqueous solution/Pt, air cell showed excellent cyclability up to 100 cycles at 2.0 mAh.cm-2. PMID- 24957060 TI - Testing the Chemical/Structural Stability of Proton Conducting Perovskite Ceramic Membranes by in Situ/ex Situ Autoclave Raman Microscopy. AB - Ceramics, which exhibit high proton conductivity at moderate temperatures, are studied as electrolyte membranes or electrode components of fuel cells, electrolysers or CO2 converters. In severe operating conditions (high gas pressure/high temperature), the chemical activity towards potentially reactive atmospheres (water, CO2, etc.) is enhanced. This can lead to mechanical, chemical, and structural instability of the membranes and premature efficiency loss. Since the lifetime duration of a device determines its economical interest, stability/aging tests are essential. Consequently, we have developed autoclaves equipped with a sapphire window, allowing in situ Raman study in the 25-620 degrees C temperature region under 1-50 bar of water vapor/gas pressure, both with and without the application of an electric field. Taking examples of four widely investigated perovskites (BaZr0.9Yb0.1O3-delta, SrZr0.9Yb0.1O3-delta, BaZr0.25In0.75O3-delta, BaCe0.5Zr0.3Y0.16Zn0.04O3-delta), we demonstrate the high potential of our unique set-up to discriminate between good/stable and instable electrolytes as well as the ability to detect and monitor in situ: (i) the sample surface reaction with surrounding atmospheres and the formation of crystalline or amorphous secondary phases (carbonates, hydroxides, hydrates, etc.); and (ii) the structural modifications as a function of operating conditions. The results of these studies allow us to compare quantitatively the chemical stability versus water (corrosion rate from ~150 um/day to less than 0.25 um/day under 200-500 degrees C/15-80 bar PH2O) and to go further in comprehension of the aging mechanism of the membrane. PMID- 24957062 TI - Gypsum (CaSO4.2H2O) Scaling on Polybenzimidazole and Cellulose Acetate Hollow Fiber Membranes under Forward Osmosis. AB - We have examined the gypsum (CaSO4.2H2O) scaling phenomena on membranes with different physicochemical properties in forward osmosis (FO) processes. Three hollow fiber membranes made of (1) cellulose acetate (CA), (2) polybenzimidazole (PBI)/polyethersulfone (PES) and (3) PBI-polyhedral oligomeric silsesquioxane (POSS)/polyacrylonitrile (PAN) were studied. For the first time in FO processes, we have found that surface ionic interactions dominate gypsum scaling on the membrane surface. A 70% flux reduction was observed on negatively charged CA and PBI membrane surfaces, due to strong attractive forces. The PBI membrane surface also showed a slightly positive charge at a low pH value of 3 and exhibited a 30% flux reduction. The atomic force microscopy (AFM) force measurements confirmed a strong repulsive force between gypsum and PBI at a pH value of 3. The newly developed PBI-POSS/PAN membrane had ridge morphology and a contact angle of 51.42 degrees +/- 14.85 degrees after the addition of hydrophilic POSS nanoparticles and 3 min thermal treatment at 95 degrees C. Minimal scaling and an only 1.3% flux reduction were observed at a pH value of 3. Such a ridge structure may reduce scaling by not providing a locally flat surface to the crystallite at a pH value of 3; thus, gypsum would be easily washed away from the surface. PMID- 24957061 TI - Correlation of Gas Permeability in a Metal-Organic Framework MIL-101(Cr) Polysulfone Mixed-Matrix Membrane with Free Volume Measurements by Positron Annihilation Lifetime Spectroscopy (PALS). AB - Hydrothermally stable particles of the metal-organic framework MIL-101(Cr) were incorporated into a polysulfone (PSF) matrix to produce mixed-matrix or composite membranes with excellent dispersion of MIL-101 particles and good adhesion within the polymer matrix. Pure gas (O2, N2, CO2 and CH4) permeation tests showed a significant increase of gas permeabilities of the mixed-matrix membranes without any loss in selectivity. Positron annihilation lifetime spectroscopy (PALS) indicated that the increased gas permeability is due to the free volume in the PSF polymer and the added large free volume inside the MIL-101 particles. The trend of the gas transport properties of the composite membranes could be reproduced by a Maxwell model. PMID- 24957063 TI - Study of hydrophilic electrospun nanofiber membranes for filtration of micro and nanosize suspended particles. AB - Polymeric nanofiber membranes of polyvinyl chloride (PVC) blended with polyvinylpyrrolidone (PVP) were fabricated using an electrospinning process at different conditions and used for the filtration of three different liquid suspensions to determine the efficiency of the filter membranes. The three liquid suspensions included lake water, abrasive particles from a water jet cutter, and suspended magnetite nanoparticles. The major goal of this research work was to create highly hydrophilic nanofiber membranes and utilize them to filter the suspended liquids at an optimal level of purification (i.e., drinkable level). In order to overcome the fouling/biofouling/blocking problems of the membrane, a coagulation process, which enhances the membrane's efficiency for removing colloidal particles, was used as a pre-treatment process. Two chemical agents, Tanfloc (organic) and Alum (inorganic), were chosen for the flocculation/coagulation process. The removal efficiency of the suspended particles in the liquids was measured in terms of turbidity, pH, and total dissolved solids (TDS). It was observed that the coagulation/filtration experiments were more efficient at removing turbidity, compared to the direct filtration process performed without any coagulation and filter media. PMID- 24957064 TI - Effect of Preparation Methods on Crystallization Behavior and Tensile Strength of Poly(vinylidene fluoride) Membranes. AB - Poly(vinylidene fluoride) (PVDF) membranes were prepared by non solvent induced phase separation (NIPS), melt spinning and the solution-cast method. The effect of preparation methods with different membrane formation mechanisms on crystallization behavior and tensile strength of PVDF membranes was investigated. Fourier transform infrared spectroscopy-attenuated total reflectance (FTIR-ATR) and X-ray diffraction (XRD) were employed to examine the crystal form of the surface layers and the overall membranes, respectively. Spherulite morphologies and thermal behavior of the membranes were studied by polarized light optical microscopy (PLO) and differential scanning calorimetry (DSC) separately. It was found that the crystallization behavior of PVDF membranes was closely related to the preparation methods. For membranes prepared by the NIPS method, the skin layers had a mixture of alpha and beta phases, the overall membranes were predominantly alpha phase, and the total crystallinity was 60.0% with no spherulite. For melt spinning membranes, the surface layers also showed a mixture of alpha and beta phases, the overall membranes were predominantly alpha phase. The total crystallinity was 48.7% with perfect spherulites. Whereas the crystallization behavior of solution-cast membranes was related to the evaporation temperature and the additive, when the evaporation temperature was 140 degrees C with a soluble additive in the dope solution, obvious spherulites appeared. The crystalline morphology of PVDF exerted a great influence on the tensile strength of the membranes, which was much higher with perfect spherulites. PMID- 24957065 TI - Al2O3 Disk Supported Si3N4 Hydrogen Purification Membrane for Low Temperature Polymer Electrolyte Membrane Fuel Cells. AB - Reformate gas, a commonly employed fuel for polymer electrolyte membrane fuel cells (PEMFCs), contains carbon monoxide, which poisons Pt-containing anodes in such devices. A novel, low-cost mesoporous Si3N4 selective gas separation material was tested as a hydrogen clean-up membrane to remove CO from simulated feed gas to single-cell PEMFC, employing Nafion as the polymer electrolyte membrane. Polarization and power density measurements and gas chromatography showed a clear effect of separating the CO from the gas mixture; the performance and durability of the fuel cell was thereby significantly improved. PMID- 24957066 TI - The Fouling of Zirconium(IV) Hydrous Oxide-Polyacrylate Dynamically Formed Membranes during the Nanofiltration of Lactic Acid Solutions. AB - The results of investigations of flux decline during nanofiltration (NF) of lactic acid solutions using dynamically formed zirconium(IV) hydrous oxide/polyacrylate membranes (Zr(IV)/PAA) under conditions resulting in low and high lactic acid rejection are reported. The experimental permeate flux versus time curves were analyzed in the frame of resistance in a series model with the aim of developing the characteristic of resistances. Analysis of experimental data and results of calculations showed that the reduction of fouling effects in the investigated system could be achieved due to appropriate hydrodynamic process conditions and regular rinsing with deionized water. PMID- 24957067 TI - Insights on the study of nafion nanoscale morphology by transmission electron microscopy. AB - Nafion is one of the most common materials used for polyelectrolyte membranes and is the standard to which novel materials are compared. In spite of great interest in Nafion's nanostructure, it is still a subject of controversy. While multiple research efforts have addressed Nafion's morphology with Transmission Electron Microscopy, the results of these efforts have often been inconsistent and cannot satisfactorily describe the membrane structure. One of the reasons for differences in the reported results is the lack of sufficient control over the damage caused by electron beam irradiation. In this work, we describe some aspects of damage in the material that have a strong influence on the results. We show that irradiation causes mass loss and phase separation in the material and that the morphologies that have been observed are, in many cases, artifacts caused by damage. We study the effect of the sample temperature on damage and show that, while working at low temperature does not prevent damage and mass loss, it slows formation of damage-induced artifacts to the point where informative low-dose images of almost undamaged material may be collected. We find that charging of the sample has a substantial effect on the damage, and the importance of charge neutralization under irradiation is also seen by the large reduction of beam induced movement with the use of an objective aperture or a conductive support film. To help interpret the low-dose images, we can apply slightly higher exposures to etch away the hydrophobic phase with the electron beam and reveal the network formed by the hydrophilic phase. Energy loss spectroscopy shows evidence that fluorine removal governs the beam damage process. PMID- 24957068 TI - Recruiting "Friends of Medical Progress": Evolving Tactics in the Defense of Animal Experimentation, 1910s and 1920s. AB - In 1923, Thomas Barbour of Harvard announced the creation of a national lay organization, the Society of Friends of Medical Progress (FMP), to defend animal research in the United States against a resurgent antivivisection movement. After decades of successful behind-the-scenes lobbying and avoiding the public spotlight, medical scientists significantly altered their tactics and sought public engagement, at least by proxy. Although the authority of scientific medicine was rising, women's suffrage, the advent of the ballot initiative, and a growing alliance of antivivisectionists and other groups in opposition to allopathic medicine so altered the political landscape that medical scientists reconsidered formerly rejected ideas such partnering with laymen. Medical scientists, Walter B. Cannon and Simon Flexner chief among them, hoped that the FMP would relieve the scientists of a time-consuming burden and defend against government regulation of medical institutions without the charge of material self interest. However, financial problems and the frequent conflicts that arose between the lay leadership and Flexner eventually undermined the FMP's value as a defender of animal experimentation and reveal the distrust of reformers like Flexner who did not believe that laymen could speak for scientific medicine. PMID- 24957069 TI - Waiting for the flu: cognitive inertia and the Spanish influenza pandemic of 1918 19. AB - This study looks at public awareness and understanding of the Spanish flu in the United States between June 1918, when the flu became "Spanish," and the end of September when the deadly second wave reached the majority of the country. Based on an extensive reading of local newspapers, it finds a near universal lack of preparation or panic or other signs of personal concern among those in the unaffected areas, despite extensive and potentially worrying coverage of the flu's progress. The normal reaction to news of the inexorable approach of a pandemic of uncertain virulence is anxiety and action. The Spanish flu produced neither in the uninfected areas for a month. The most likely reason appears to be cognitive inertia-the tendency of existing beliefs or habits of thought to blind people to changed realities. This inertia grew out of the widespread understanding of flu as a seasonal visitor that while frequently unpleasant almost never killed the strong and otherwise healthy. This view of the flu was powerful enough that it blinded many in the unaffected regions to the threat for weeks even in the face of daily or near daily coverage of the pandemic's spread. PMID- 24957071 TI - Telomere shortening: a diagnostic tool and therapeutic target for cardiovascular disease? PMID- 24957070 TI - Rate of telomere shortening and cardiovascular damage: a longitudinal study in the 1946 British Birth Cohort. AB - AIM: Cross-sectional studies reported associations between short leucocyte telomere length (LTL) and measures of vascular and cardiac damage. However, the contribution of LTL dynamics to the age-related process of cardiovascular (CV) remodelling remains unknown. In this study, we explored whether the rate of LTL shortening can predict CV phenotypes over 10-year follow-up and the influence of established CV risk factors on this relationship. METHODS AND RESULTS: All the participants from the MRC National Survey of Health and Development (NSHD) with measures of LTL and traditional CV risk factors at 53 and 60-64 years and common carotid intima-media thickness (cIMT), cardiac mass and left ventricular function at 60-64 years were included. LTL was measured by real-time polymerase chain reaction and available at both time points in 1033 individuals. While LTL at 53 years was not linked with any CV phenotype at 60-64 years, a negative association was found between LTL and cIMT at 60-64 years (beta = -0.017, P = 0.015). However, the strongest association was found between rate of telomere shortening between 53 and 60-64 years and values of cIMT at 60-64 years (beta = -0.020, P = 0.006). This association was not affected by adjustment for traditional CV risk factors. Cardiac measurements were not associated with cross-sectional or longitudinal measures of LTL. CONCLUSION: These findings suggest that the rate of progression of cellular ageing in late midlife (reflected by the rate of LTL attrition) relates to vascular damage, independently from contribution of CV risk factor exposure. PMID- 24957072 TI - Fibrosis or hypertrophy: let TIMPs decide. PMID- 24957073 TI - TP53 mutational status and cetuximab benefit in rectal cancer: 5-year results of the EXPERT-C trial. AB - In this updated analysis of the EXPERT-C trial we show that, in magnetic resonance imaging-defined, high-risk, locally advanced rectal cancer, adding cetuximab to a treatment strategy with neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX is not associated with a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) in both KRAS/BRAF wild-type and unselected patients. In a retrospective biomarker analysis, TP53 was not prognostic but emerged as an independent predictive biomarker for cetuximab benefit. After a median follow-up of 65.0 months, TP53 wild-type patients (n = 69) who received cetuximab had a statistically significant better PFS (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and OS (92.7% vs 67.5% at 5 years; HR = 0.16; 95% CI = 0.04 to 0.70; two-sided P = .02 by Cox regression) than TP53 wild-type patients who were treated in the control arm. An interaction between TP53 status and cetuximab effect was found (P < .05) and remained statistically significant after adjusting for statistically significant prognostic factors and KRAS. PMID- 24957075 TI - A new predictive molecular marker for cetuximab benefit in rectal cancer? PMID- 24957078 TI - Stress-induced phase transformation and optical coupling of silver nanoparticle superlattices into mechanically stable nanowires. AB - One-dimensional silver materials display unique optical and electrical properties with promise as functional blocks for a new generation of nanoelectronics. To date, synthetic approaches and property engineering of silver nanowires have primarily focused on chemical methods. Here we report a simple physical method of metal nanowire synthesis, based on stress-induced phase transformation and sintering of spherical Ag nanoparticle superlattices. Two phase transformations of nanoparticles under stress have been observed at distinct length scales. First, the lattice dimensions of silver nanoparticle superlattices may be reversibly manipulated between 0-8 GPa compressive stresses to enable systematic and reversible changes in mesoscale optical coupling between silver nanoparticles. Second, stresses greater than 8 GPa induced an atomic lattice phase transformation, which induced sintering of silver nanoparticles into micron length scale nanowires. The nanowire synthesis mechanism displays a dependence on both nanoparticle crystal surface orientation and presence of particular grain boundaries to enable nanoparticle consolidation into nanowires. PMID- 24957081 TI - Test-retest reliability of the GAITRite walkway system for the spatio-temporal gait parameters while dual-tasking in post-stroke patients. AB - PURPOSE: To examine the test-retest reliability of spatio-temporal gait parameters during performance of single- and dual-tasking in post-stroke patients. METHOD: This study was conducted using a single-group repeated-measures design, involving a baseline measurement session and a follow-up session two days later. Forty-three chronic stroke patients (>6 months) participated in this study. Spatio-temporal gait parameters under the single- and dual-task conditions at a self-selected comfortable gait speed were measured using the GAITRite walkway system. Intraclass correlation coefficients [ICC(2,1)] were calculated for determination of reliability between sessions. The level of agreement between the two sessions was determined using Bland-Altman 95% limits of the agreement plots. RESULTS: In all gait parameters, a significant difference was observed between the single- and dual-task conditions (p < 0.05). For the single condition, ICC (95% CI) was very good for all measures, ranging from 0.98 to 0.99 (0.97-0.99). In addition, for the dual-task condition, ICC (95% CI) was good to very good for all measures, ranging from 0.69 to 0.90 (0.49-0.99). CONCLUSIONS: The results of current study demonstrated that the test-retest reliability of the GAITRite system for measurement of spatio-temporal gait parameters under single- and dual-task conditions was good to very good. Therefore, we suggest that measurement of spatio-temporal gait parameters under a dual-task condition using the GAITRite system would be useful for clinical assessment in post-stroke patients. IMPLICATIONS FOR REHABILITATION: Improvement of walking ability provides opportunities for stroke patients to participate in the community. Our finding, additional cognitive tasks can interfere with the independently basic activities of daily living in stroke patients, may provide basic information for use in development of rehabilitation programs for stroke patients. Spatio temporal gait parameters under the dual-task condition measured using the GAITRite system may be useful for clinical assessment in post-stroke patients. PMID- 24957079 TI - The in vitro biological properties of Mg-Zn-Sr alloy and superiority for preparation of biodegradable intestinal anastomosis rings. AB - BACKGROUND: Magnesium (Mg) alloy is a metal-based biodegradable material that has received increasing attention in the field of clinical surgery, but it is currently seldom used in intestinal anastomosis. This study was conducted to comprehensively assess a ternary magnesium (Mg)-zinc (Zn)-strontium (Sr) alloy's biological superiorities as a preparation material for intestinal anastomosis ring. MATERIAL AND METHODS: Mouse L-929 fibroblasts were cultured with Mg-Zn-Sr alloy extract and compared with both positive (0.64% phenol) and negative (original broth culture) controls. The cell morphology of different groups was examined using microscopy, and a cytotoxicity assessment was performed. Fresh anticoagulated human blood was mixed with Mg-Zn-Sr alloy extract and compared with both positive (distilled water) and negative (normal saline) controls. The absorbance of each sample at 570 nm was used to calculate the Mg-Zn-Sr alloy hemolysis ratio in order to test the Mg alloy's blood compatibility. Bacterial cultures of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus were added to Mg-Zn-Sr alloy block samples and compared with positive (Ceftazidime), negative (316LSS stainless steel), and blank controls. The broth cultures were sampled to compare their bacterial colony counts so as to evaluate the antibacterial properties of the Mg-Zn-Sr alloy. The Mg-Zn-Sr alloy was surface-coated with a layer of poly(lactic-co-glycolic acid) carrying everolimus. The surface morphology and degradability of the coating were examined so as to demonstrate feasibility of coating, which can release the drug evenly. RESULTS: The experiments proved that Mg-Zn-Sr alloy has good biocompatible, antibacterial, and drug-loaded coating performances, which are lacking in existing intestinal anastomosis devices/materials. CONCLUSIONS: The Mg-Zn-Sr alloy increases biocompatibility, and yields a safer and better therapeutic effect; therefore, it is a novel biomaterial that is feasible for use when preparing biodegradable intestinal anastomosis rings. PMID- 24957082 TI - Early infant male circumcision for human immunodeficiency virus prevention: knowledge and attitudes of women attending a rural hospital in Swaziland, Southern Africa. AB - Swaziland has the highest prevalence of human immunodeficiency virus (HIV) in the world at 26% of the adult population. Medical male circumcision (MMC) has been shown to reduce the risk of acquiring HIV from heterosexual sex by up to 60% and the Government of Swaziland has been promoting adult male circumcision. Infant circumcision commenced in 2013 so it is important to understand the knowledge and views of women as potential mothers, around infant circumcision for medical purposes to inform the development of the service. This study interviewed 14 women of reproductive age attending the outpatient department of Good Shepherd Mission Hospital (GSMH), a rural district hospital, on their knowledge of and attitudes to early infant male circumcision (EIMC). Participants were highly knowledgeable about the health benefits of medical circumcision, although knowledge of the comparative risks and benefits of EIMC to adult circumcision was poor. All participants would have a son circumcised; the preferred age varied from early infancy to adolescence. Complications and pain were the main barriers whilst religious and cultural reasons were mentioned both for and against circumcision. A variety of family members are important in the decision to circumcise a young boy. Acceptability of medical circumcision was high in this study, but concerns about safety, pain, autonomy and cultural factors reduce the acceptability of infant circumcision more specifically. It will be important to provide accurate, culturally sensitive information about infant circumcision to mothers, fathers and grandparents using existing hospital and community services provided at GSMH and throughout Swaziland. Where possible services for MMC should be available to males of all ages so that families and young men may choose the most favourable age for circumcision. PMID- 24957076 TI - Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer. AB - BACKGROUND: Obesity increases the risk of cancer death among postmenopausal women with estrogen receptor-positive (ER+) breast cancer, but the direct evidence for the mechanisms is lacking. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating this epidemiologic phenomenon. METHODS: We analyzed transcriptomic profiles of pretreatment biopsies from a prospective cohort of 137 ER+ breast cancer patients. We generated transgenic (MMTV TGFalpha;A (y) /a) and orthotopic/syngeneic (A (y) /a) obese mouse models to investigate the effect of obesity on tumorigenesis and tumor progression and to determine biological mechanisms using whole-genome transcriptome microarrays and protein analyses. We used a coculture system to examine the impact of adipocytes/adipokines on breast cancer cell proliferation. All statistical tests were two-sided. RESULTS: Functional transcriptomic analysis of patients revealed the association of obesity with 59 biological functional changes (P < .05) linked to cancer hallmarks. Gene enrichment analysis revealed enrichment of AKT-target genes (P = .04) and epithelial-mesenchymal transition genes (P = .03) in patients. Our obese mouse models demonstrated activation of the AKT/mTOR pathway in obesity-accelerated mammary tumor growth (3.7- to 7.0-fold; P < .001; n = 6-7 mice per group). Metformin or everolimus can suppress obesity-induced secretion of adipokines and breast tumor formation and growth (0.5-fold, P = .04; 0.3-fold, P < .001, respectively; n = 6-8 mice per group). The coculture model revealed that adipocyte-secreted adipokines (eg, TIMP-1) regulate adipocyte-induced breast cancer cell proliferation and invasion. Metformin suppress adipocyte-induced cell proliferation and adipocyte-secreted adipokines in vitro. CONCLUSIONS: Adipokine secretion and AKT/mTOR activation play important roles in obesity-accelerated breast cancer aggressiveness in addition to hyperinsulinemia, estrogen signaling, and inflammation. Metformin and everolimus have potential for therapeutic interventions of ER+ breast cancer patients with obesity. PMID- 24957083 TI - Microbial co-culture: harnessing intermicrobial signaling for the production of novel antimicrobials. PMID- 24957084 TI - Antimalarial drug delivery to the mosquito: an option worth exploring? PMID- 24957080 TI - Tethering membrane fusion: common and different players in myoblasts and at the synapse. AB - Membrane fusion is essential for the communication of membrane-defined compartments, development of multicellular organisms and tissue homeostasis. Although membrane fusion has been studied extensively, still little is known about the molecular mechanisms. Especially the intercellular fusion of cells during development and tissue homeostasis is poorly understood. Somatic muscle formation in Drosophila depends on the intercellular fusion of myoblasts. In this process, myoblasts recognize each other and adhere, thereby triggering a protein machinery that leads to electron-dense plaques, vesicles and F-actin formation at apposing membranes. Two models of how local membrane stress is achieved to induce the merging of the myoblast membranes have been proposed: the electron-dense vesicles transport and release a fusogen and F-actin bends the plasma membrane. In this review, we highlight cell-adhesion molecules and intracellular proteins known to be involved in myoblast fusion. The cell-adhesion proteins also mediate the recognition and adhesion of other cell types, such as neurons that communicate with each other via special intercellular junctions, termed chemical synapses. At these synapses, neurotransmitters are released through the intracellular fusion of synaptic vesicles with the plasma membrane. As the targeting of electron-dense vesicles in myoblasts shares some similarities with the targeting of synaptic vesicle fusion, we compare molecules required for synaptic vesicle fusion to recently identified molecules involved in myoblast fusion. PMID- 24957087 TI - In vitro antibiofilm activity of bioactive glass S53P4. AB - AIM: This work aimed to investigate the ability of different formulations of bioactive glass (BAG)-S53P4 to interfere with bacterial biofilm produced on prosthetic material by methicillin-resistant Staphylococcus aureus and multi-drug resistant Pseudomonas aeruginosa. MATERIALS & METHODS: Antibiofilm activity of three formulations of bioglass was assessed at different time points through two different analyses: Crystal Violet and confocal laser scanning microscopy assays. RESULTS: Significant differences in the whole biofilm were observed between BAG S53P4-treated and control samples, while no marked changes in antibiofilm activity were observed among the tested formulations. Data from colorimetric assay were confirmed by confocal laser scanning microscopy analysis, which evidenced the significant reduction in biomass and a decrease of total cell volume when both S. aureus and P. aeruginosa biofilms were treated with BAG S53P4. CONCLUSION: BAG-S53P4 can be considered as an excellent adjuvant in the treatment of prosthetic infections related to biofilm. PMID- 24957086 TI - Latest developments on Streptococcus suis: an emerging zoonotic pathogen: part 2. AB - First International Workshop on Streptococcus suis, Beijing, China, 12-13 August 2013. This second and final chapter of the report on the First International Workshop on Streptococcus suis follows on from Part 1, published in the April 2014, volume 9, issue 4 of Future Microbiology. S. suis is a swine pathogen and a zoonotic agent afflicting people in close contact with infected pigs or pork meat. Although sporadic cases of human infections had been reported worldwide, deadly S. suis outbreaks emerged in Asia. The severity of the disease underscores the lack of knowledge on the virulence and zoonotic evolution of this human infecting agent. The pathogenesis of the infection, interactions with host cells and new avenues for treatments were among the topics discussed during the First International Workshop on S. suis (China 2013). PMID- 24957089 TI - Using multilocus sequence typing to study bacterial variation: prospects in the genomic era. AB - Multilocus sequence typing (MLST) indexes the sequence variation present in a small number (usually seven) of housekeeping gene fragments located around the bacterial genome. Unique alleles at these loci are assigned arbitrary integer identifiers, which effectively summarizes the variation present in several thousand base pairs of genome sequence information as a series of numbers. Comparing bacterial isolates using allele-based methods efficiently corrects for the effects of lateral gene transfer present in many bacterial populations and is computationally efficient. This 'gene-by-gene' approach can be applied to larger collections of loci, such as the ribosomal protein genes used in ribosomal MLST (rMLST), up to and including the complete set of coding sequences present in a genome, whole-genome MLST (wgMLST), providing scalable, efficient and readily interpreted genome analysis. PMID- 24957088 TI - Transcriptional response to vancomycin in a highly vancomycin-resistant Streptomyces coelicolor mutant. AB - AIM: The main objective of this study is to understand the mechanism of vancomycin resistance in a Streptomyces coelicolor disrupted mutant highly resistant to vancomycin. MATERIALS & METHODS: Different techniques have been performed in the study including gene disruption, primer extension, antibiotic susceptibility tests, electron microscopy, confocal microscopy, cell wall analysis and microarrays. RESULTS: During the phenotypical characterization of mutant strains affected in phosphate-regulated genes of unknown function, we found that the S. coelicolor SCO2594 disrupted mutant was highly resistant to vancomycin and had other phenotypic alterations such as antibiotic overproduction, impaired growth and reduction of phosphate cell wall content. Transcriptomic studies with this mutant indicated a relationship between vancomycin resistance and cell wall stress. CONCLUSION: We identified a S. coelicolor mutant highly resistant to vancomycin in both high and low phosphate media. In addition to Van proteins, others such as WhiB or SigE appear to be involved in this regulatory mechanism. PMID- 24957090 TI - Amino acid capture and utilization within the Mycobacterium tuberculosis phagosome. AB - Mycobacterium tuberculosis, the agent of TB, is a facultative intracellular bacterial pathogen that replicates inside host macrophages and other phagocytes within a membrane-bound vacuole or phagosome. How M. tuberculosis captures and exploits vital nutrients inside host cells is an intensive research area that might lead to novel therapeutics for tuberculosis. Recent reports provided evidence that M. tuberculosis relies on amino acid uptake and degradation pathways to thrive inside its host. This opens novel research venues for the development of innovative antimicrobials against TB. PMID- 24957091 TI - Shrinkage of the human core microbiome and a proposal for launching microbiome biobanks. AB - The Human Microbiome Project (HMP) revealed the significance of the gut microbiome in promoting health. Disruptions in microbiome composition are associated with the pathogenesis of numerous diseases. The indigenous microflora has co-evolved with humans for millions of years and humans have preserved the inherited microbiomes through consumption of fermented foods and interactions with environmental microbes. Through modernization, traditional foods were abandoned, native food starters were substituted with industrial products, vaccines and antibiotics were used, extreme hygiene measures were taken, the rate of cesarean section increased, and breast feeding changed into formula. These factors have reduced human exposure to microbial symbionts and led to shrinkage of the core microbiome. Reduction in microbiome biodiversity can compromise the human immune system and predispose individuals to several modern diseases. This article suggests launching microbiome biobanks for archiving native microbiomes, supervising antibiotic use, probiotic design and native starter production, as well as advertising a revisit to native lifestyles. PMID- 24957092 TI - Shared characteristics between Mycobacterium tuberculosis and fungi contribute to virulence. AB - Mycobacterium tuberculosis, an etiologic agent of tuberculosis, exacts a heavy toll in terms of human morbidity and mortality. Although an ancient disease, new strains are emerging as human population density increases. The emergent virulent strains appear adept at steering the host immune response from a protective Th1 type response towards a Th2 bias, a feature shared with some pathogenic fungi. Other common characteristics include infection site, metabolic features, the composition and display of cell surface molecules, the range of innate immune receptors engaged during infection, and the ability to form granulomas. Literature from these two distinct fields of research are reviewed to propose that the emergent virulent strains of M. tuberculosis are in the process of convergent evolution with pathogenic fungi, and are increasing the prominence of conserved traits from environmental phylogenetic ancestors that facilitate their evasion of host defenses and dissemination. PMID- 24957093 TI - Quorum sensing-mediated regulation of staphylococcal virulence and antibiotic resistance. AB - Accessory gene regulator (agr)-mediated quorum sensing plays a central role in staphylococcal pathogenesis. It primarily upregulates secreted virulence factors and downregulates cell surface proteins, thereby governing invasiveness of staphylococci and cell dispersal from biofilms. Except for alpha- and beta-PSMs, which are directly controlled by AgrA, the effector functions of agr are primarily mediated by RNAIII, a regulatory RNA encoded by this operon. agr phenotype and expression considerably influence the chronicity of an infection. It has also been linked with altered susceptibility of Staphylococcus aureus against antibiotics. Four classes of S. aureus and Staphylococcus epidermidis AIPs exist based on sequence variation, and lead to inter-strain and species cross-inhibition. Certain agr classes have been associated with specific clonal complexes, disease syndromes and intermediate-susceptibility to glycopeptides. It is also being investigated as a prophylactic and therapeutic target. This article describes the presently available literature regarding the role of agr in S. aureus and S. epidermidis infections. PMID- 24957074 TI - ABCA transporter gene expression and poor outcome in epithelial ovarian cancer. AB - BACKGROUND: ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. METHODS: The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two sided. RESULTS: Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. CONCLUSIONS: Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC. PMID- 24957094 TI - Laboratory diagnosis of mucormycosis: current status and future perspectives. AB - Fungal infections caused by members of the Mucorales order are rapidly progressing and fatal. The importance of mucormycosis has grown in recent years as the number of patients with predisposing factors has increased dramatically. Clinical symptoms are elusive and conventional techniques are often insensitive and unspecific; in particular, cultures are often negative even though direct microscopy is positive. For early diagnosis of the causative agent of disease and subsequently guiding therapy to improving patients' outcome, molecular assays are promising add-ons. This article provides an overview on current laboratory methods for diagnosing mucormycosis with a special focus on new molecular-based tools. We aim to highlight the pros and cons of various techniques at hand. Given the increase in number and the severity of these infections, molecular approaches for improved diagnosis are highly warranted. PMID- 24957095 TI - Exploring azole antifungal drug resistance in Aspergillus fumigatus with special reference to resistance mechanisms. AB - Aspergillus fumigatus, a ubiquitously distributed opportunistic pathogen, is the global leading cause of aspergillosis. Azole antifungals play an important role in the management of aspergillosis. However, over a decade, azole resistance in A. fumigatus isolates has been increasingly reported with variable prevalence worldwide and it is challenging the effective management of aspergillosis. The high mortality rates observed in patients with invasive aspergillosis caused by azole-resistant A. fumigatus (ARAF) isolates pose serious challenges to the clinical microbiologist for timely identification of resistance and appropriate therapeutic interventions. The majority of ARAF isolates contain alterations in the cyp51A gene; however, there have been increasing reports on non-cyp51A mutations contributing to azole resistant phenotypes. This review highlights the emergence and various mechanisms implicated in the development of azole resistance in A. fumigatus. We further present recent developments related to the environmental route in the emergence of ARAF isolates and discuss the therapeutic options available. PMID- 24957096 TI - Effect of intubation and mechanical ventilation on exhaled nitric oxide in preterm infants with and without bronchopulmonary dysplasia measured at a median postmenstrual age of 49 weeks. AB - BACKGROUND: Exhaled nitric oxide (eNO) is a marker of established airway inflammation in adults and children, but conflicting results have been reported in preterm infants when postnatal eNO is measured during tidal breathing. This study investigated the extent to which intubation and mechanical ventilation (MV) affect eNO and NO production (V'NO) in preterm infants with and without bronchopulmonary dysplasia (BPD). PATIENTS AND METHODS: A total of 176 very low birth weight (VLBW) infants (birth weight <1500 g), including 74 (42%) with and 102 (58%) without BPD, were examined at a median postmenstrual age of 49 weeks. Of the 176 infants, 84 (48%) did not require MV, 47 (27%) required MV for <7 days and 45 (26%) required MV for >=7 days. Exhaled NO and tidal breathing parameters were measured in sleeping infants during tidal breathing, respiratory mechanics were assessed by occlusion tests, and arterialized capillary blood gas was analyzed. RESULTS: eNO was significantly correlated with tidal breathing parameters, while V'NO was correlated with growth parameters, including age and body length (p < 0.001 each). Infants who were intubated and received MV for <7 days had significantly lower eNO (p < 0.01) and V'NO (p < 0.01) than non ventilated infants. In contrast, eNO and V'NO did not differ significantly in non ventilated infants and those receiving MV for >=7 days. Multivariate analysis showed that independent on the duration of MV eNO (p = 0.003) and V'NO (p = 0.018) were significantly increased in BPD infants comparable with the effects of intubation and MV on eNO (p = 0.002) and V'NO (p = 0.017). CONCLUSIONS: Preterm infants with BPD show only weak postnatal increases in eNO and V'NO, but these changes may be obscured by the distinct influences of breathing pattern and invasive respiratory support. This limits the diagnostic value of postnatal eNO measurements in the follow-up of BPD infants. PMID- 24957099 TI - Ipsilateral hypoglossal and oculosympathetic paresis in carotid dissection. PMID- 24957101 TI - Introduction. Outcome measures in haemophilia: a systematic review. PMID- 24957097 TI - Non-linear association of serum 25-hydroxyvitamin D with urinary albumin excretion rate in normoalbuminuric subjects. AB - BACKGROUND: Vitamin D deficiencies and increases in urinary albumin excretion (UAE) are both important and potentially related health problems; however, the nature of their relationship has not been established in normoalbuminuric subjects. METHODS: We obtained data from 14,594 normoalbuminuric Korean adults who underwent voluntary health screenings. We used a generalized additive model to examine the threshold level for relationship between serum 25-hydroxyvitamin D [25(OH)D] and urinary-albumin creatinine ratio (UACR) levels. We conducted multivariate logistic regression for high-normal UAE (UACR, 10-29 mg/g), according to various categories of vitamin D status. RESULTS: The generalized additive model confirmed a non-linear relationship between serum 25(OH)D and UACR levels, and the threshold concentration of 25(OH)D was 8.0 ng/mL after multivariate adjustment. Comparing subjects who fell into the lowest category of serum 25(OH)D levels with subjects who were in the reference range (the highest category), we observed that the multivariate adjusted odds ratio (OR) for high normal UAE was significantly increased, regardless of the criteria used to categorize vitamin D levels: OR of the 1st quartile over the 4th quartile, 1.20 (95% CI, 1.04-1.39); OR of the 1.0-4.9th percentile over the 50-100th percentile, 1.56 (95% CI, 1.25-1.93); and OR of vitamin D deficiency group over vitamin D sufficiency group, 1.28 (95% CI, 1.08-1.52). CONCLUSIONS: We demonstrated that there was an inverse relationship between serum 25(OH)D less than 8.0 ng/mL and UACR in normoalbuminuric subjects, suggesting that severe vitamin D deficiency could cause an increase in UAE in subjects with normoalbuminuria. PMID- 24957102 TI - Outcome measures in haemophilia: a systematic review. AB - Haemophilia A and B are hereditary X-linked disorders due to deficiency (or absence) of coagulation factor VIII or IX, respectively. Bleeding risk is related to the severity of factor deficiency. Repeated joint bleeding can lead to a severe haemophilic arthropathy resulting in disabilities. Outcome measurements in persons with haemophilia (PWH) have been limited to laboratory evaluation (factor VIII or IX levels) and clinical outcomes (such as bleeding frequency), morbidity (for example linked with arthropathy) and mortality. Due to the new standard of care of PWH, there is a need to consider other outcome measures, such as the early detection and quantification of joint disease, health-related quality of life (QoL) and economic or cost-utility analyses. To investigate this, we performed a 10-yr systematic overview of outcome measures in haemophilia. Only clinical trials including at least 20 patients with haemophilia A or B were included. To facilitate the search strategy, eight issues of outcome measures were selected: physical scores, imaging technique scores, functional scores, QoL measurement, mortality, bleeding frequency, cost and outcome and bone mineral density. The results of these will be discussed. Clearly defined outcomes in haemophilia care are important for many reasons, to evaluate new treatments, to justify treatment strategies, to allow a good follow-up, to perform studies and to allocate resources. The use of such scoring systems is clearly recommended by experts in haemophilia care. However, most centres do not perform such scores outside clinical trials due to reasons such as lack of time and resources. PMID- 24957098 TI - Knockdown of malic enzyme 2 suppresses lung tumor growth, induces differentiation and impacts PI3K/AKT signaling. AB - Mitochondrial malic enzyme 2 (ME2) catalyzes the oxidative decarboxylation of malate to yield CO2 and pyruvate, with concomitant reduction of dinucleotide cofactor NAD(+) or NADP(+). We find that ME2 is highly expressed in many solid tumors. In the A549 non-small cell lung cancer (NSCLC) cell line, ME2 depletion inhibits cell proliferation and induces cell death and differentiation, accompanied by increased reactive oxygen species (ROS) and NADP(+)/NADPH ratio, a drop in ATP, and increased sensitivity to cisplatin. ME2 knockdown impacts phosphoinositide-dependent protein kinase 1 (PDK1) and phosphatase and tensin homolog (PTEN) expression, leading to AKT inhibition. Depletion of ME2 leads to malate accumulation and pyruvate decrease, and exogenous cell permeable dimethyl malate (DMM) mimics the ME2 knockdown phenotype. Both ME2 knockdown and DMM treatment reduce A549 cell growth in vivo. Collectively, our data suggest that ME2 is a potential target for cancer therapy. PMID- 24957100 TI - microRNA-99a acts as a tumor suppressor and is down-regulated in bladder cancer. AB - BACKGROUND: Increasing evidences have documented that microRNAs (miRNAs) act as oncogenes or tumor suppressors in a variety types of cancer. The discovery of tumor associated miRNAs in serum of patients gives rise to extensive investigation of circulating miRNAs in many human cancers which support the use of plasma/serum miRNAs as noninvasive means of cancer detection. However, the aberrant expression of miRNAs and the circulating miRNAs in bladder cancer are less reported. METHODS: We used Taqman probe stem-loop real-time PCR to accurately measure the levels of miR-99a in bladder cancer cell lines, 100 pairs of bladder cancer tissues, the adjacent non-neoplastic tissues and plasma collected from bladder cancer patients or control patients. miR-99a mimics were re-introduced into bladder cancer cells to investigate its role on regulating cell proliferation which was measured by CCK-8 assay and cell cycle analysis. RESULTS: miR-99a was significantly down-regulated in bladder cancer tissues, and even the lower expression of miR-99a was correlative with the more aggressive phenotypes of bladder cancer. Meanwhile, enforced expression of miR-99a can inhibit the cell proliferation of bladder cancer cells. Furthermore, investigation of the expression of miR-99a in plasma of bladder cancer patients showed that miR-99a was also decreased in plasma of bladder cancer patients. The results strongly supported miR-99a as the potential diagnostic marker of bladder cancer. CONCLUSIONS: Our data indicated that miR-99a might act as a tumor suppressor in bladder cancer and was significantly down-regulated in development of bladder cancer. PMID- 24957103 TI - Methods for individualising factor VIII dosing in prophylaxis. AB - Haemophilia A is a sex-linked disorder characterised chiefly by recurrent, spontaneous joint and muscle bleedings resulting from deficiency of factor VIII (FVIII). Recurrent joint bleeds result in haemophilic arthropathy. Unless treated with factor replacement therapy, many patients with severe haemophilia become disabled. The first clinical evidence favouring prophylaxis originated from the studies in Sweden and the Netherlands in the 1960s. Later on, it was shown that prophylaxis could prevent arthropathy, if started early in life, or slow its progression in adults with established arthropathy. The optimal dosing of FVIII in long-term prophylaxis has still not been determined, and there is growing evidence that the dose and frequency of FVIII should be individualised. We conducted a systematic search of PubMed to identify all relevant articles on FVIII prophylaxis in severe haemophilia A. We focused on articles with detailed information about individualisation of prophylaxis. Long-term prophylaxis in haemophilia was introduced in Sweden in the late 1950s. However, standard prophylactic regimens may not be appropriate for all patients with severe haemophilia. Factors such as age, joint status, co-morbidities and differences in pharmacokinetics lead to interindividual variation in factor requirement. Dose tailoring of FVIII by clinical outcome was first described in 1994. Since then, several dose-finding studies questioned the necessity to maintain preinfusion levels of FVIII above 1%. Individualising prophylaxis by dose tailoring is now recommended. Each country should adopt policies for individualising prophylaxis in patients with severe haemophilia. This would lead to a better distribution of the available source of factor concentrates. PMID- 24957104 TI - Perinatal aspects of haemophilia. AB - Haemophilia is an X-linked recessive genetic disease of haemostasis. Women carriers may present with a bleeding tendency similar to milder forms of the disease. Haemophilic newborns present risk factors and patterns of bleeding that are challenging. Identification of carriers and genetic counselling before conception is considered optimal to help decide on available conception options and during pregnancy to help minimise bleeding risks for both carrier mother and affected baby. Preimplantation genetic diagnosis is attractive to many couples at risk of having a child with haemophilia and relevant technology is becoming more available although it has both practical and ethical limitations. Pregnancy in carriers should be managed by a multidisciplinary team in a comprehensive treatment centre. The optimal mode of delivery for carriers expecting a baby known to have or being at risk of haemophilia is an issue of great debate. The general consensus among authors is avoidance of instrumental delivery, foetal scalp electrodes and blood sampling in pregnancies at risk of carrying an affected foetus, as well as early recourse to Caesarean section as guided by obstetric indications. Intracranial haemorrhage, although infrequent, is one the most devastating types of bleeding in haemophilic newborns and can occur regardless of the mode of delivery or the severity of haemophilia. Early screening is proposed for all infants with severe or moderate haemophilia who have had traumatic delivery and/or have evidence of extracranial haemorrhage. Women with postpartum haemorrhage should have a bleeding work-up. PMID- 24957105 TI - Immunosuppressive agents in the treatment of inhibitors in congenital haemophilia A and B--a systematic literature review. AB - The development of inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX) in patients with haemophilia is a serious complication of treatment with coagulation factor concentrates. Antibodies develop in 10-15% of haemophilia A and in up to 5% of haemophilia B patients. Several strategies have been developed over the years to facilitate the eradication of inhibitors and reduce the cost. These include plasmapheresis and/or extracorporeal protein A absorption to remove the inhibitor from the plasma, and immunosuppression and/or immune modulation to suppress the production of inhibitory antibodies. Different immunosuppressive (IS) agents have been described with varying success. To evaluate the outcome of these agents, we performed a systematic literature review using the PubMed database. The total number of articles identified was 345; 299 papers were excluded leaving 46 papers to be included in the study. No randomised studies were identified, only case reports and case series. The most frequently used agents in the 46 case reports and cohort studies identified were cyclophosphamide and rituximab. All cases exposed to cyclophosphamide, rituximab and other IS agents had a complete success rate of 40-44%, 40-63% and 33-56%, respectively. However, the definition of success was not consistent among the studies. In conclusion, our review of the literature indicates that IS agents in combination with FVIII or FIX could be an option and may be cost-effective in many patients. The risk of adverse events seems to be relatively low. To fully explore the effect of IS agents, randomised studies are warranted. PMID- 24957106 TI - On-demand treatment in persons with severe haemophilia. AB - There are two main modes of replacement therapy for haemophilia patients: either to stop bleeding (on-demand) or regular infusions of clotting factor to prevent bleeds (prophylaxis). Fifty yr of clinical experience have provided evidence of the superiority of prophylaxis by showing a reduction in bleeds and development of arthropathy. Prophylaxis has been described extensively in terms of efficacy and health-economic aspects; however, on-demand treatment has received less attention. The aim of this study was to critically review the published literature on PubMed and discuss potential gaps of knowledge in on-demand treatment in persons with severe haemophilia without inhibitors by focusing on two key aspects: how on-demand treatment is provided and what outcome measures have been reported. We identified 134 papers of which 112 were excluded. Of the remaining 22 papers, 16 were comparative studies between prophylaxis and on demand treatment and six were descriptions of on-demand treatment. The results showed limited reporting on data related to the key aspects of treatment on demand. Early studies looked at degrees of joint bleeds and different treatment regimens in finding the optimal dose. However, from the late 1980s, there was almost no research into on-demand therapy except efficacy and safety studies of new rFVIII products and studies to prove superiority of prophylaxis over treatment on-demand. The success of on-demand therapy may depend on several factors, for example time to initial dose after a bleed and duration of treatment. Data on these key factors are limited and highlight the necessity of research to optimise replacement therapy. PMID- 24957107 TI - Assay discrepancy in mild haemophilia A. AB - There are three main methods used to assay factor VIII (FVIII) activity: the one stage and two-stage clotting assays and the two-stage chromogenic method. The most commonly used assay for the diagnosis of haemophilia A is the automated one stage FVIII assay. The classical two-stage FVIII assays are less frequently used. The chromogenic FVIII:C assay is a variant of the two-stage assay. It is easier to use and therefore used more commonly. Recently significant assay discrepancy has been recognised in the FVIII:C measurements in approximately one-third of mild haemophilia A patients. This so-called discrepant mild haemophilia A is characterised by a high ratio of one-stage/two-stage assay with one-stage FVIII levels that are typically more than double those of the two-stage coagulation assay. There are several mutations that destabilise the FVIIIa structure that can explain this result of a more pronounced decrease of the chromogenic FVIII:C activity compared with the one-stage activity. These mutations are clustered at the interfaces of the A1, A2 and A3 domains of the FVIII protein. The inverse discrepancy, where the one-stage assay gives lower FVIII:C results than the chromogenic assay, seems to be associated with mutations found close to important sites for thrombin cleavage or FIX binding. We are carrying out a study of mild haemophilia A samples from the Malmo Haemophilia Centre of families with a unique F8 genotype. The activity of FVIII will be measured using a chromogenic assay and two different one-stage assays. We hope to estimate the true size of assay discrepancy. AIM: This project will review assay discrepancy in mild/moderate haemophilia A and the risk of misdiagnosis. The overall aim is to estimate the size of the problem and to learn from the literature and experiences from our centre as well as to suggest recommendations on how to avoid misdiagnosis. PMID- 24957108 TI - Deep sequencing of small RNA libraries reveals dynamic expression patterns of microRNAs in multiple developmental stages of Bactrocera dorsalis. AB - In eukaryotes, microRNAs (miRNAs) are small, conserved, noncoding RNAs that have emerged as critical regulators of gene expression. The oriental fruit fly Bactrocera dorsalis is one of the most economically important fruit fly pests in East Asia and the Pacific. Although transcriptome analyses have greatly enriched our knowledge of its structural genes, little is known about post-transcriptional regulation by miRNAs in this dipteran species. In this study, small RNA libraries corresponding to four B. dorsalis developmental stages (eggs, larvae, pupae and adults) were constructed and sequenced. Approximately 30.7 million reads of 18-30 nucleotides were obtained, with 123 known miRNAs and 60 novel miRNAs identified amongst these libraries. More than half of the miRNAs were stage-specific during the four developmental stages. A set of miRNAs was found to be up- or down regulated during development by comparison of their reads at different developmental stages. Moreover, a small part of miRNAs owned both miR-#-3p and miR-#-5p types, with enormously variable miR-#-3p/miR-#-5p ratios in the same library and amongst different developmental stages for each miRNA. Taking these findings together, the current study has uncovered a number of miRNAs and provided insights into their possible involvement in developmental regulation by expression profiling of miRNAs. Further analyses of the expression and function of these miRNAs could increase our understanding of regulatory networks in this insect and lead to novel approaches for its control. PMID- 24957109 TI - Characterization of ibrutinib-sensitive and -resistant mantle lymphoma cells. AB - Ibrutinib inhibits Bruton tyrosine kinase (BTK), a key component of early B-cell receptor (BCR) signalling pathways. A multicentre phase 2 trial of ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) demonstrated a remarkable response rate. However, approximately one-third of patients have primary resistance to the drug while other patients appear to lose response and develop secondary resistance. Understanding the molecular mechanisms underlying ibrutinib sensitivity is of paramount importance. In this study, we investigated cell lines and primary MCL cells that display differential sensitivity to ibrutinib. We found that the primary cells display a higher BTK activity than normal B cells and MCL cells show differential sensitivity to BTK inhibition. Genetic knockdown of BTK inhibits the growth, survival and proliferation of ibrutinib-sensitive but not resistant MCL cell lines, suggesting that ibrutinib acts through BTK to produce its anti-tumour activities. Interestingly, inhibition of ERK1/2 and AKT, but not BTK phosphorylation per se, correlates well with cellular response to BTK inhibition in cell lines as well as in primary tumours. Our study suggests that, to prevent primary resistance or to overcome secondary resistance to BTK inhibition, a combinatory strategy that targets multiple components or multiple pathways may represent the most effective approach. PMID- 24957110 TI - Attitudes towards cannabis use and genetic testing for schizophrenia. AB - AIM: Within schizophrenia, genetic factors contribute greatly to risk, yet genetic testing for the disorder is not available. For some individuals with specific genotypes, cannabis use may increase risk of schizophrenia. It is possible that genetic tests could be offered in the future to inform individuals of the risk of schizophrenia if they use cannabis. Previous research, however, provides little guidance on how young adults might respond to such tests. METHODS: We assessed a group of young adults (n = 83) to determine how the perceived magnitude of increased risk for schizophrenia in the presence of cannabis use influences decisions to undergo genetic testing, as well as subsequent attitudes and intentions towards cannabis use. RESULTS: Participants were significantly more likely to indicate willingness to get tested if the results identified a 10% risk versus a 2% risk of schizophrenia. Participants also indicated that if the results of their test reflected increased risk due to cannabis use, it would be more important to avoid cannabis in the 10% risk scenario as compared to the 2% risk scenario. These findings remained consistent among a subset of participants who indicated cannabis use. CONCLUSIONS: Results suggest that cannabis users and non-users were positively influenced in terms of intentions to change behaviour based on the magnitude of risk conveyed by genetic testing. These findings provide an initial step towards understanding young people's attitudes towards genetic testing and may help prepare interventions specifically tailored around cannabis use reduction for people at risk for schizophrenia. PMID- 24957111 TI - Hereditary angioedema as the cause of death from asphyxia: postmortem computed tomography study. PMID- 24957112 TI - Impact of Bjerkandera adusta colonization on chronic cough. PMID- 24957113 TI - Maculopapular-type drug eruption caused by sitagliptin phosphate hydrate: a case report and mini-review of the published work. PMID- 24957115 TI - Successful treatment of a bullous urticaria with omalizumab. PMID- 24957114 TI - Measurement of Japanese cedar pollen-specific IgE in nasal secretions. AB - BACKGROUND: Japanese cedar pollen (JCP) is the most common allergen for seasonal allergic rhinitis in Japan. Little is known about local production of immunoglobulin (Ig)E in people with or without Japanese cedar pollinosis. The aims of this study were to measure levels of JCP-specific IgE in nasal secretions and determine correlations with levels in serum. METHODS: Forty-six subjects were enrolled in this study, comprising 24 symptomatic subjects, 9 asymptomatic subjects sensitized to JCP, and 13 subjects not sensitized to JCP. Nasal secretions were obtained during a period of Japanese cedar dispersal, and levels of JCP-specific IgE were measured with CAP-fluorescent enzyme immunoassay. Serum JCP-specific IgE and total IgE were also measured using the same method. RESULTS: Among the 46 subjects enrolled, JCP-specific IgE in nasal secretions was measureable in 43 subjects. Irrespective of symptom development, sensitized subjects showed higher levels of JCP-specific IgE in nasal secretions than non sensitized subjects. A significant moderate correlation was observed between JCP specific IgE levels in nasal secretions and serum in all 43 subjects. With stratification by subject group, only symptomatic subjects showed a substantial correlation between JCP-specific IgE levels in nasal secretions and serum. CONCLUSIONS: Our results imply a certain association between JCP-specific IgE in nasal secretions and sensitization of Japanese cedar pollinosis. Therefore, levels of allergen-specific IgE in nasal secretions can be used as an alternative diagnostic marker for allergic rhinitis patients. PMID- 24957116 TI - Comparison of nasal nitric oxide levels between the inferior turbinate surface and the middle meatus in patients with symptomatic allergic rhinitis. AB - BACKGROUND: Because of the anatomical complexity and the high output of the human nose, it has been unclear whether nasal nitric oxide (NO) serves as a reliable marker of allergic rhinitis (AR). We examined whether nasal NO levels in the inferior turbinate (IT) surface and the middle meatus (MM) differ in symptomatic AR patients. METHODS: We measured fractional exhaled NO (FeNO) and nasal NO in normal subjects (n = 50) and AR patients with mild symptoms (n = 16) or moderate or severe symptoms (n = 27). Nasal NO measurements were obtained using an electrochemical analyzer connected to a catheter and an air-suction pump (flow rate 50mL/sec). RESULTS: Compared to the normal subjects, the AR patients showed significantly higher nasal FeNO and nasal NO levels in the IT area. No significant difference in the MM area was observed among the three groups. The MM area showed higher NO levels than the IT area in all three groups. The ratio of nasal NO levels of the MM area to the IT area (MM/IT ratio) was significantly lower in the AR groups. The moderate/severe AR patients showed significantly higher nasal NO in the IT area (104.4 vs. 66.2ppb) and lower MM/IT ratios than those in the mild AR patients. The analysis of nasal brushing cells revealed significantly higher eosinophil cationic protein and nitrotyrosine levels in the AR groups. CONCLUSIONS: Nasal NO assessment in the IT area directly reflects persistent eosinophilic inflammation and may be a valid marker to estimate the severity of AR. PMID- 24957118 TI - Friedel-Crafts Crosslinked Highly Sulfonated Polyether Ether Ketone (SPEEK) Membranes for a Vanadium/Air Redox Flow Battery. AB - Highly conductive and low vanadium permeable crosslinked sulfonated poly(ether ether ketone) (cSPEEK) membranes were prepared by electrophilic aromatic substitution for a Vanadium/Air Redox Flow Battery (Vanadium/Air-RFB) application. Membranes were synthesized from ethanol solution and crosslinked under different temperatures with 1,4-benzenedimethanol and ZnCl2 via the Friedel Crafts crosslinking route. The crosslinking mechanism under different temperatures indicated two crosslinking pathways: (a) crosslinking on the sulfonic acid groups; and (b) crosslinking on the backbone. It was observed that membranes crosslinked at a temperature of 150 degrees C lead to low proton conductive membranes, whereas an increase in crosslinking temperature and time would lead to high proton conductive membranes. High temperature crosslinking also resulted in an increase in anisotropy and water diffusion. Furthermore, the membranes were investigated for a Vanadium/Air Redox Flow Battery application. Membranes crosslinked at 200 degrees C for 30 min with a molar ratio between 2:1 (mol repeat unit:mol benzenedimethanol) showed a proton conductivity of 27.9 mS/cm and a 100 times lower VO2+ crossover compared to Nafion. PMID- 24957117 TI - Development of interactive algorithm for clinical management of acute events related to sickle cell disease in emergency department. AB - Sickle cell disease (SCD ORPHA232; OMIM 603903) is a rare hereditary red cell disorder, which global distribution is changed in the last decade due to immigration-fluxes from endemic areas to Western-countries. One of the main clinical manifestations of SCD are the acute painful vaso-occlusive crisis, which cause frequent accesses of SCD patients to the emergency departments (EDs). This has generated the requirement of feasible tools for emergency givers. In the context of the scientific-Italian-Society for the study of Thalassemias and Hemoglobinopathies (SITE), we developed an algorithm with interactive windows to guide physicians in managing SCD patients in EDs. PMID- 24957119 TI - Carbon nanotube- and carbon fiber-reinforcement of ethylene-octene copolymer membranes for gas and vapor separation. AB - Gas and vapor transport properties were studied in mixed matrix membranes containing elastomeric ethylene-octene copolymer (EOC or poly(ethylene-co octene)) with three types of carbon fillers: virgin or oxidized multi-walled carbon nanotubes (CNTs) and carbon fibers (CFs). Helium, hydrogen, nitrogen, oxygen, methane, and carbon dioxide were used for gas permeation rate measurements. Vapor transport properties were studied for the aliphatic hydrocarbon (hexane), aromatic compound (toluene), alcohol (ethanol), as well as water for the representative samples. The mechanical properties and homogeneity of samples was checked by stress-strain tests. The addition of virgin CNTs and CFs improve mechanical properties. Gas permeability of EOC lies between that of the more permeable PDMS and the less permeable semi-crystalline polyethylene and polypropylene. Organic vapors are more permeable than permanent gases in the composite membranes, with toluene and hexane permeabilities being about two orders of magnitude higher than permanent gas permeability. The results of the carbon-filled membranes offer perspectives for application in gas/vapor separation with improved mechanical resistance. PMID- 24957120 TI - A pervaporation study of ammonia solutions using molecular sieve silica membranes. AB - An innovative concept is proposed to recover ammonia from industrial wastewater using a molecular sieve silica membrane in pervaporation (PV), benchmarked against vacuum membrane distillation (VMD). Cobalt and iron doped molecular sieve silica-based ceramic membranes were evaluated based on the ammonia concentration factor downstream and long-term performance. A modified low-temperature membrane evaluation system was utilized, featuring the ability to capture and measure ammonia in the permeate. It was found that the silica membrane with confirmed molecular sieving features had higher water selectivity over ammonia. This was due to a size selectivity mechanism that favoured water, but blocked ammonia. However, a cobalt doped silica membrane previously treated with high temperature water solutions demonstrated extraordinary preference towards ammonia by achieving up to a 50,000 mg/L ammonia concentration (a reusable concentration level) measured in the permeate when fed with 800 mg/L of ammonia solution. This exceeded the concentration factor expected by the benchmark VMD process by four fold, suspected to be due to the competitive adsorption of ammonia over water into the silica structure with pores now large enough to accommodate ammonia. However, this membrane showed a gradual decline in selectivity, suspected to be due to the degradation of the silica material/pore structure after several hours of operation. PMID- 24957121 TI - Nanocomposites for Improved Physical Durability of Porous PVDF Membranes. AB - Current commercial polymer membranes have shown high performance and durability in water treatment, converting poor quality waters to higher quality suitable for drinking, agriculture and recycling. However, to extend the treatment into more challenging water sources containing abrasive particles, micro and ultrafiltration membranes with enhanced physical durability are highly desirable. This review summarises the current limits of the existing polymeric membranes to treat harsh water sources, followed by the development of nanocomposite poly(vinylidene fluoride) (PVDF) membranes for improved physical durability. Various types of nanofillers including nanoparticles, carbon nanotubes (CNT) and nanoclays were evaluated for their effect on flux, fouling resistance, mechanical strength and abrasion resistance on PVDF membranes. The mechanisms of abrasive wear and how the more durable materials provide resistance was also explored. PMID- 24957122 TI - Preparation of Polyvinylidene Fluoride (PVDF) Hollow Fiber Hemodialysis Membranes. AB - In this study, the polyvinylidene fluoride (PVDF) hollow fiber hemodialysis membranes were prepared by non-solvent induced phase separation (NIPS). The influences of PVDF membrane thickness and polyethylene glycol (PEG) content on membrane morphologies, pore size, mechanical and permeable performance were investigated. It was found that membrane thickness and PEG content affected both the structure and performance of hollow fiber membranes. The tensile strength and rejection of bovine serum albumin (BSA) increased with increasing membrane thickness, while the Ultrafiltration flux (UF) flux of pure water was the opposite. The tensile strength, porosity and rejection of BSA increased with increasing PEG content within a certain range. Compared with commercial F60S membrane, the PVDF hollow fiber membrane showed higher mechanical and permeable performance. It was proven that PVDF material had better hydrophilicity and lower BSA adsorption, which was more suitable for hemodialysis. All the results indicate that PVDF hollow fiber membrane is promising as a hemodialysis membrane. PMID- 24957123 TI - Improvement of membrane performances to enhance the yield of vanillin in a pervaporation reactor. AB - In membrane reactors, the interaction of reaction and membrane separation can be exploited to achieve a "process intensification", a key objective of sustainable development. In the present work, the properties that the membrane must have to obtain this result in a pervaporation reactor are analyzed and discussed. Then, the methods to enhance these properties are investigated for the photocatalytic synthesis of vanillin, which represents a case where the recovery from the reactor of vanillin by means of pervaporation while it is produced allows a substantial improvement of the yield, since its further oxidation is thus prevented. To this end, the phenomena that control the permeation of both vanillin and the reactant (ferulic acid) are analyzed, since they ultimately affect the performances of the membrane reactor. The results show that diffusion of the aromatic compounds takes place in the presence of low concentration gradients, so that the process is controlled by other phenomena, in particular by the equilibrium with the vapor at the membrane-permeate interface. On this basis, it is demonstrated that the performances are enhanced by increasing the membrane thickness and/or the temperature, whereas the pH begins to limit the process only at values higher than 6.5. PMID- 24957124 TI - Solidification Behavior of Polymer Solution during Membrane Preparation by Thermally Induced Phase Separation. AB - The solidification behavior of poly(vinylidene fluoride) (PVDF) solution during membrane preparation by thermally induced phase separation (TIPS) was investigated. Apparatus newly developed in our laboratory was used to quantitatively measure membrane stiffness during phase separation. In this apparatus, a cooling polymer solution, placed on a stage, is moved upwards and the surface of the polymer solution contacts a sphere attached to the tip of a needle. The displacement of a blade spring attached to the needle is then measured by a laser displacement sensor. Different phase separation modes, such as liquid-liquid (L-L) phase separation and solid-liquid (S-L) phase separation (polymer crystallization) were investigated. In the case of S-L phase separation, the stiffness of the solution surface began to increase significantly just before termination of crystallization. In contrast, L-L phase separation delayed solidification of the solution. This was because mutual contact of the spherulites was obstructed by droplets of polymer-lean phase formed during L-L phase separation. Thus, the solidification rate was slower for the L-L phase separation system than for the S-L phase separation system. PMID- 24957125 TI - Preparation and Characterization of Nanocomposite Polymer Membranes Containing Functionalized SnO2 Additives. AB - In the research of new nanocomposite proton-conducting membranes, SnO2 ceramic powders with surface functionalization have been synthesized and adopted as additives in Nafion-based polymer systems. Different synthetic routes have been explored to obtain suitable, nanometer-sized sulphated tin oxide particles. Structural and morphological characteristics, as well as surface and bulk properties of the obtained oxide powders, have been determined by means of X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier Transform Infrared (FTIR) and Raman spectroscopies, N2 adsorption, and thermal gravimetric analysis (TGA). In addition, dynamic mechanical analysis (DMA), atomic force microscopy (AFM), thermal investigations, water uptake (WU) measurements, and ionic exchange capacity (IEC) tests have been used as characterization tools for the nanocomposite membranes. The nature of the tin oxide precursor, as well as the synthesis procedure, were found to play an important role in determining the morphology and the particle size distribution of the ceramic powder, this affecting the effective functionalization of the oxides. The incorporation of such particles, having sulphate groups on their surface, altered some peculiar properties of the resulting composite membrane, such as water content, thermo mechanical, and morphological characteristics. PMID- 24957126 TI - Performance and Long-Term Stability of Pd/PSS and Pd/Al2O3 Membranes for Hydrogen Separation. AB - The present work is focused on the investigation of the performance and long-term stability of two composite palladium membranes under different operating conditions. One membrane (Pd/porous stainless steel (PSS)) is characterized by a ~10 um-thick palladium layer on a porous stainless steel substrate, which is pretreated by means of surface modification and oxidation; the other membrane (Pd/Al2O3) is constituted by a ~7 um-thick palladium layer on an asymmetric microporous Al2O3 substrate. The operating temperature and pressure ranges, used for studying the performance of these two kinds of membranes, are 350-450 degrees C and 200-800 kPa, respectively. The H2 permeances and the H2/N2 selectivities of both membranes were investigated and compared with literature data. At 400 degrees C and 200 kPa as pressure difference, Pd/PSS and Pd/Al2O3 membranes exhibited an H2/N2 ideal selectivity equal to 11700 and 6200, respectively, showing stability for 600 h. Thereafter, H2/N2 selectivity of both membranes progressively decreased and after around 2000 h, dropped dramatically to 55 and 310 for the Pd/PSS and Pd/Al2O3 membranes, respectively. As evidenced by Scanning Electron Microscope (SEM) analyses, the pinholes appear on the whole surface of the Pd/PSS membrane and this is probably due to release of sulphur from the graphite seal rings. PMID- 24957127 TI - Electron microscopy of Ag-(Ni-O) core-shell nanowires. AB - This report provides information about an electrodeposition-based two-step synthesis methodology for producing core-shell Ag-(Ni-O) nanowires and their detailed structural and compositional characterization using electron microscopy technique. Nanowires were produced by employing anodic alumina templates with a pore diameter of 200 nm. In the first step of the synthesis process, nanocrystalline Ni-O was electrodeposited in a controlled manner such that it heterogeneously nucleated and grew only on the template pore walls without filling the pores from bottom upwards. This alumina template with pore walls coated with Ni-O was then utilized as a template during the electrodeposition of Ag in the second step. Electrodeposited Ag filled the template pores to finally produce Ag-(Ni-O) core-shell nanowires with an overall diameter of 200 nm. PMID- 24957128 TI - Multiple ecto-nucleoside triphosphate diphosphohydrolases facilitate intracellular replication of Legionella pneumophila. AB - Legionella pneumophila is an opportunistic pathogen that replicates within alveolar macrophages resulting in the onset of severe atypical pneumonia. Previously we have identified Lpg1905, a eukaryotic-type ecto-NTPDase (nucleoside triphosphate diphosphohydrolase) from L. pneumophila that was required for optimal intracellular replication and virulence in a mouse lung infection model. In the present study, we characterized the activity of a second eukaryotic-type NTPDase, Lpg0971, from L. pneumophila. We observed that recombinant Lpg0971 hydrolysed only ATP and exhibited divalent cation preference for manganese (II) ions. Similar to lpg1905, an lpg0971 mutant carrying the plasmid pMIP was attenuated in a mouse lung infection model and impaired for replication in human macrophages and amoebae. Increased trafficking of the LCV (Legionella-containing vacuole) to a LAMP-1 (lysosome-associated membrane protein-1)-positive compartment was observed for both the lpg1905 and lpg0971 mutants carrying pMIP. Complementation with either lpg1905 or lpg0971 restored intracellular replication, suggesting that a minimum level of ATPase activity was required for this function. A double lpg1905/0971 mutant was not more impaired for intracellular replication than the single mutants and complementation of the double mutant with lpg0971, but not lpg1905, restored intracellular replication. This suggested that although the NTPDases have overlapping activities they have distinct functions. Unlike many eukaryotic-type proteins from L. pneumophila, neither Lpg1905 nor Lpg0971 were translocated into the host cell by the Dot/Icm (defective in organelle trafficking/intracellular multiplication) type IV secretion system. Overall our data suggest that the ability of L. pneumophila to replicate in eukaryotic cells relies in part on the ability of the pathogen to hydrolyse ATP within an intracellular compartment. PMID- 24957130 TI - The value of information for managing contaminated sediments. AB - Effective management of contaminated sediments is important for long-term human and environmental health, but site-management decisions are often made under high uncertainty and without the help of structured decision support tools. Potential trade-offs between remedial costs, environmental effects, human health risks, and societal benefits, as well as fundamental differences in stakeholder priorities, complicate decision making. Formal decision-analytic tools such as multicriteria decision analysis (MCDA) move beyond ad hoc decision support to quantitatively and holistically rank management alternatives and add transparency and replicability to the evaluation process. However, even the best decisions made under uncertainty may be found suboptimal in hindsight, once additional scientific, social, economic, or other details become known. Value of information (VoI) analysis extends MCDA by systematically evaluating the impact of uncertainty on a decision. VoI prioritizes future research in terms of expected decision relevance by helping decision makers estimate the likelihood that additional information will improve decision confidence or change their selection of a management plan. In this study, VoI analysis evaluates uncertainty, estimates decision confidence, and prioritizes research to inform selection of a sediment capping strategy for the dibenzo-p-dioxin and -furan contaminated Grenland fjord system in southern Norway. The VoI model extends stochastic MCDA to model decisions with and without simulated new information and compares decision confidence across scenarios with different degrees of remaining uncertainty. Results highlight opportunities for decision makers to benefit from additional information by anticipating the improved decision confidence (or lack thereof) expected from reducing uncertainties for each criterion or combination of criteria. This case study demonstrates the usefulness of VoI analysis for environmental decisions by predicting when decisions can be made confidently, for prioritizing areas of research to pursue to improve decision confidence, and for differentiating between decision-relevant and decision-irrelevant differences in evaluation perspectives, all of which help guide meaningful deliberation toward effective consensus solutions. PMID- 24957129 TI - Changes in sex ratio from fertilization to birth in assisted-reproductive treatment cycles. AB - BACKGROUND: In Western gender-neutral countries, the sex ratio at birth is estimated to be approximately 1.06. This ratio is lower than the estimated sex ratio at fertilization which ranges from 1.07 to 1.70 depending on the figures of sex ratio at birth and differential embryo/fetal mortality rates taken into account to perform these estimations. Likewise, little is known about the sex ratio at implantation in natural and assisted-reproduction-treatment (ART) cycles. In this bioessay, we aim to estimate the sex ratio at fertilization and implantation using data from embryos generated by standard in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) in preimplantation genetic diagnosis cycles. Thereafter, we compare sex ratios at implantation and birth in cleavage- and blastocyst-stage-transfer cycles to propose molecular mechanisms accounting for differences in post-implantation male and female mortality and thereby variations in sex ratios at birth in ART cycles. METHODS: A literature review based on publications up to December 2013 identified by PubMed database searches. RESULTS: Sex ratio at both fertilization and implantation is estimated to be between 1.29 and 1.50 in IVF cycles and 1.07 in ICSI cycles. Compared with the estimated sex ratio at implantation, sex ratio at birth is lower in IVF cycles (1.03 after cleavage-stage transfer and 1.25 after blastocyst-stage transfer) but similar and close to unity in ICSI cycles (0.95 after cleavage stage transfer and 1.04 after blastocyst-stage transfer). CONCLUSIONS: In-vitro culture-induced precocious X-chromosome inactivation together with ICSI-induced decrease in number of trophectoderm cells in female blastocysts may account for preferential female mortality at early post-implantation stages and thereby variations in sex ratios at birth in ART cycles. PMID- 24957131 TI - Glomerular disease: The search goes on: suPAR is not the elusive FSGS factor. PMID- 24957132 TI - Glomerular disease: To the rescue--migrating renin lineage cells heal the injured glomerular mesangium. PMID- 24957133 TI - Alternative splicing in Drosophila neuronal development. AB - Post-transcriptional pre-mRNA splicing has emerged as a critical step in the gene expression cascade greatly influencing diversification and spatiotemporal control of the proteome in many developmental processes. The percentage of genes targeted by alternative splicing (AS) is shown to be over 95% in humans and 60% in Drosophila. Therefore, it is evident that deregulation of this process underlies many genetic diseases. Among all tissues, the brain shows the highest transcriptome diversity, which is not surprising in view of the complex inter- and intracellular networks underlying the development of this organ. Reports of isoforms known to function at different steps during Drosophila nervous system development are rapidly increasing as well as knowledge on their regulation and function, highlighting the role of AS during neuronal development in Drosophila. PMID- 24957137 TI - Hydrogen adsorption and diffusion around Si(0 0 1)/Si(1 1 0) corners in nanostructures. AB - While the diffusion of hydrogen on silicon surfaces has been relatively well characterized, both experimentally and theoretically, diffusion around corners between surfaces, as will be found on nanowires and nanostructures, has not been studied. Motivated by nanostructure fabrication by Patterned Atomic Layer Epitaxy, we present a density functional theory study of the diffusion of hydrogen around the edge formed by the orthogonal (0 0 1) and (1 1 0) surfaces in silicon. We find that the barrier from (0 0 1) to (1 1 0) is approximately 0.3 eV lower than from (1 1 0) to (0 0 1), and that it is comparable to diffusion between rows on a clean surface, with no significant effect on the hydrogen patterns at the growth temperatures used. PMID- 24957134 TI - A chemically defined 2,3-trans procyanidin fraction from willow bark causes redox sensitive endothelium-dependent relaxation in porcine coronary arteries. AB - Extracts of the bark of willow species (Salix spp.) are popular herbal remedies to relieve fever and inflammation. The effects are attributed to salicin and structurally related phenolic metabolites, while polyphenols including procyanidins are suggested to contribute to the overall effect of willow bark. This study aimed at investigating the relaxant response to a highly purified and chemically defined 2,3-trans procyanidin fraction in porcine coronary arteries. The procyanidin sample produced a concentration-dependent relaxation in U46619 precontracted tissues. Relaxation was predominantly mediated through the redox sensitive activation of the endothelial phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway, leading to the subsequent activation of endothelial nitric oxide synthase (eNOS) by phosphorylation, as evidenced by Western blotting using human umbilical vein endothelial cells (HUVECs). That the relaxant response to Salix procyanidins was reactive oxygen species (ROS)-dependent with O2(-) as the key species followed from densitometric analysis using 2,7 dichlorodihydrofluorescein diacetate (DCFH-DA assay) and employment of various ROS inhibitors, respectively. The data also suggested the modification of intracellular Ca(2+) levels and KCa channel functions. In addition, our organ bath studies showed that Salix procyanidins reversed the abrogation of the relaxant response to bradykinin by oxidized low-density lipoproteins (oxLDL) in coronary arteries, suggesting a vasoprotective effect of willow bark against detrimental oxLDL in pathological conditions. Taken together, our findings suggest for the first time that 2,3-trans procyanidins may contribute not only to the beneficial effects of willow bark but also to health-promoting benefits of diverse natural products of plant origin. PMID- 24957135 TI - Abiotic methanogenesis from organosulphur compounds under ambient conditions. AB - Methane in the environment is produced by both biotic and abiotic processes. Biomethanation involves the formation of methane by microbes that live in oxygen free environments. Abiotic methane formation proceeds under conditions at elevated temperature and/or pressure. Here we present a chemical reaction that readily forms methane from organosulphur compounds under highly oxidative conditions at ambient atmospheric pressure and temperature. When using iron(II/III), hydrogen peroxide and ascorbic acid as reagents, S-methyl groups of organosulphur compounds are efficiently converted into methane. In a first step, methyl sulphides are oxidized to the corresponding sulphoxides. In the next step, demethylation of the sulphoxide via homolytic bond cleavage leads to methyl radical formation and finally to methane in high yields. Because sulphoxidation of methyl sulphides is ubiquitous in the environment, this novel chemical route might mimic methane formation in living aerobic organisms. PMID- 24957136 TI - Understanding of the risk of HIV infection among the elderly in Ga-Rankuwa, South Africa. AB - The literature pertaining to the elderly shows that HIV infection among this population is on the increase, suggesting that the elderly population engages in activities risky for HIV infection. Reports on such behaviour include frequent sexual relations with much younger people and having multiple partners. A study was carried out in Ga-Rankuwa, a black township in Gauteng Province, South Africa to explore and describe the understanding of these elderly people regarding their risks of HIV infection and AIDS. Using a qualitative, exploratory design, three focus-group interviews were conducted with 32 women aged over 50 years. Findings revealed that older persons have knowledge about transmission of HIV infection and AIDS. However, a few had misconceptions as to how HIV infection is transmitted, as they believed that poor nutrition and sharing facilities play a role. Knowledge of mechanisms of protecting themselves against infection, such as use of a condom during coitus and wearing gloves when caring for infected family members, was also evident. The elderly indicated that they would prefer an older person, who they could identify with, to educate them more about HIV infection and AIDS. Although majority of participants had knowledge of how HIV is transmitted, and issues that put them at risk of transmission, a few the older persons had misconceptions about how HIV is transmitted due to lack of knowledge, as they believed that poor nutrition and sharing facilities can transmit infection. The lack of knowledge underscores the importance of addressing sexual risk with older people. It was very clear that more needs to be done in terms of education campaigns to dispel the myths of HIV infection and to empower the elderly. PMID- 24957138 TI - Do glial cells play an anti-oxidative role in Huntington's disease? AB - Oxidative stress is a condition of imbalance between reactive oxygen species (ROS) formation and antioxidant capacity as a result of dysfunction of the antioxidant system. ROS can be served as a second messenger at low or moderate concentration, while excessive amount of ROS under oxidative stress condition would destroy macromolecules like proteins, DNA, and lipids, finally leading to cell apoptosis or necrosis. Changes in these macromolecules are involved in various pathological changes and progression of diseases, especially neurodegenerative diseases. Neurodegenerative diseases are morphologically featured by progressive neuronal cell loss, accompanied with inclusions formed by protein aggregates in neurons or glial cells. Neurons have always received much more attention than glial cells in neurodegenerative diseases. Actually, glial cells might play a key role in the functioning of neurons and cellular survival through an antioxidant way. Additionally, neurons can modulate the activities of glia either. Herein, the main purposes of this review are to mention the connection between Huntington's disease (HD) and oxidative stress, to summarize the characteristics and functions of glial cells in HD, to state the cross talk between neurons and glial cells, and to emphasize the conclusive role of activation of Keap1-Nrf2-ARE pathway in glial cells against oxidative stress in HD. PMID- 24957139 TI - Characterizing the likelihood of dengue emergence and detection in naive populations. AB - BACKGROUND: Vector-borne disease transmission is dependent on the many nuances of the contact event between infectious and susceptible hosts. Virus acquisition from a viremic human to a susceptible mosquito is often assumed to be nearly perfect and almost always uniform across the infectious period. Dengue transmission models that have previously addressed variability in human to vector transmission dynamics do not account for the variation in infectiousness of a single individual, and subsequent infection of naive mosquitoes. Understanding the contribution of this variability in human infectiousness is especially important in the context of introduction events where an infected individual carries the virus into a population of competent vectors. Furthermore, it could affect the ability to detect an epidemic (and the timing of detection) following introduction. METHODS: We constructed a stochastic, compartmental model to describe the heterogeneity of human viremia and calculate the probability of a successful introduction, taking into account the viremia level (and thus acquisition potential) of the index case on, and after, the day of introduction into a susceptible population and varying contact rates between the human and mosquito populations. We then compared the results of this model with those generated by a simpler model that has the same average infectiousness but only a single infectious class. RESULTS: We found that the infectivity of the index case as well as the contact rate affected the probability of emergence, but that contact rate had the most significant effect. We also found that the interaction between contact rate and the infectiousness of the index case affected the time to detection relative to the peak of the epidemic curve. Additionally, when compared to our model that accounts for variable infectiousness, a model with a single infectious class underestimates the probability of emergence and transmission intensity. CONCLUSION: Understanding the interplay between individual human heterogeneity of infectiousness and the rate of contact with the vector population will be important when predicting the likelihood, detection, and magnitude of an outbreak. PMID- 24957140 TI - Impact of heterocirculene molecular symmetry upon two-dimensional crystallization. AB - Despite the development of crystal engineering, it remains a great challenge to predict the crystal structure even for the simplest molecules, and a clear link between molecular and crystal symmetry is missing in general. Here we demonstrate that the two-dimensional (2D) crystallization of heterocirculenes on a Au(111) surface is greatly affected by the molecular symmetry. By means of ultrahigh vacuum scanning tunneling microscopy, we observe a variety of 2D crystalline structures in the coverage range from submonolayer to monolayer for D(8h) symmetric sulflower (C16S8), whereas D(4h)-symmetric selenosulflower (C16S4Se4) forms square and rectangular lattices at submonolayer and monolayer coverages, respectively. No long-range ordered structure is observed for C(1h)-symmetric selenosulflower (C16S5Se3) self-assembling at submonolayer coverage. Such different self-assembly behaviors for the heterocirculenes with reduced molecular symmetries derive from the tendency toward close packing and the molecular symmetry retention in 2D crystallization due to van der Waals interactions. PMID- 24957141 TI - Betaeta-fibrinogen gene promoter A -455 allele associated with poor longterm survival among 55-71 years old Caucasian women in Finnish stroke cohort. AB - BACKGROUND: Women die of stroke more often than men. After menopause, the incidence of ischemic stroke increases rapidly. Elevated fibrinogen levels and smoking have been associated with an increased risk of stroke. In gene-cluster haplotype analyses, the beta-fibrinogen (FGB) promoter -455 G/A polymorphic locus was most strongly associated with elevated plasma fibrinogen levels. We investigated whether the FGB -455 G/A polymorphism and smoking might interact with sex on longterm survival of acute stroke sufferers. METHODS: The Stroke Aging Memory (SAM) cohort comprising 486 consecutive stroke patients (55-85 years, 246 men, 240 women) subjected to clinical and MRI examination was followed over 12.5 years. During this period 347 (71.4%) patients died. The genotypes of the FGB -455 G/A polymorphism were determined by PCR. RESULTS: The FGB -455 G/A polymorphism genotype distributions were 64.7%, 32.1%, and 3.2% for GG, GA, and AA, respectively. During the follow-up, the FGB -455 A + genotype did not associate with survival, nor was there any genotype-by-smoking interaction on poor outcome in the total study population. However, women aged 55-71 years who carried the FGB -455 A-allele showed worse survival regardless of smoking status compared to non-smoking FGB -455 GG homozygotes (non-smokers, crude HR = 5.21, 95% CI: 1.38-19.7; smokers, crude HR = 7.03, 95% CI: 1.81-27.3). This association persisted in adjusted analyses. No such association was observed for women in the oldest age-group, nor among men. CONCLUSION: The A + genotype of the FGB -455 G/A polymorphism associated with poor survival among 55-71 years old Caucasian women in the Finnish stroke cohort. PMID- 24957142 TI - A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia. AB - Recent genomic studies have provided a refined genetic map of acute lymphoblastic leukemia (ALL) and increased the number of potential prognostic markers. Therefore, we integrated copy-number alteration data from the 8 most commonly deleted genes, subordinately, with established chromosomal abnormalities to derive a 2-tier genetic classification. The classification was developed using 809 ALL97/99 patients and validated using 742 United Kingdom (UK)ALL2003 patients. Good-risk (GR) genetic features included ETV6-RUNX1, high hyperdiploidy, normal copy-number status for all 8 genes, isolated deletions affecting ETV6/PAX5/BTG1, and ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B. All other genetic features were classified as poor risk (PR). Three-quarters of UKALL2003 patients had a GR genetic profile and a significantly improved event-free survival (EFS) (94%) compared with patients with a PR genetic profile (79%). This difference was driven by a lower relapse rate (4% vs 17%), was seen across all patient subgroups, and was independent of other risk factors. Even genetic GR patients with minimal residual disease (>0.01%) at day 29 had an EFS in excess of 90%. In conclusion, the integration of genomic and cytogenetic data defines 2 subgroups with distinct responses to treatment and identifies a large subset of children suitable for treatment deintensification. PMID- 24957144 TI - Postthrombotic syndrome following upper extremity deep vein thrombosis in children. AB - Despite its relatively estimated high occurrence, the characterization of pediatric upper extremity deep vein thrombosis (UE-DVT) and of UE postthrombotic syndrome (PTS) is still lacking. We investigated the occurrence, characteristics, and predictors of UE-PTS in a cohort of children with objectively confirmed UE DVT. Patients were analyzed in 3 groups according to DVT pathogenesis and neonatal status: primary (G1), secondary neonates (G2neonates), and non-neonates (G2non-neonates). A total of 158 children (23 G1, 25 G2neonates, and 110 G2non neonates) were included. The most common triggering factors were effort-related (87%) in G1 and central lines in G2neonates (100%) and in G2non-neonates (92%). PTS scores >=1, as per the Modified Villalta Scale, were identified in 87% of primary patients, 16% of G2neonates, and 49% of G2non-neonates. Survival analysis showed that the time to PTS score >=1 significantly differed among group (log rank test P < .0001). A multivariable logistic regression showed that DVT pathogenesis and imaging-determined degree of thrombus resolution at the end of therapy were independent predictors of a PTS score >=2. In conclusion, pediatric UE-PTS frequency and severity depend on UE-DVT pathogenesis (primary/secondary) and, within the secondary group, on patient's age. Line-related UE-PTS has a more benign course, particularly in neonates. PMID- 24957143 TI - Trends in survival of patients with primary plasma cell leukemia: a population based analysis. AB - Primary plasma cell leukemia (pPCL) is a rare malignancy with an aggressive course and poor outcome. There has been significant improvement in the survival of multiple myeloma patients over the past decade as a result of incorporating autologous stem cell transplantation (ASCT) and novel agents into treatment regimens. However, it is unknown whether these therapies have had a similar impact on the survival of patients with pPCL. We conducted an analysis of the Surveillance, Epidemiology, and End Results database to evaluate the trends in survival of 445 patients with pPCL between 1973 and 2009. The widespread availability of ASCT and use of novel agents in the upfront setting of multiple myeloma and pPCL began after 1995 and 2006, respectively. The median overall survival based on periods of diagnosis were 5, 6, 4, and 12 months for those diagnosed during 1973-1995, 1996-2000, 2001-2005, and 2006-2009, respectively (P = .001). Thus, the current study confirms the recent survival improvement in pPCL within a large US population that may be associated with the use of better therapeutic strategies. PMID- 24957146 TI - The endothelial protein C receptor enhances hemostasis of FVIIa administration in hemophilic mice in vivo. AB - Recombinant activated human factor VII (rhFVIIa) is an established hemostatic agent in hemophilia, but its mechanism of action remains unclear. Although tissue factor (TF) is its natural receptor, rhFVIIa also interacts with the endothelial protein C receptor (EPCR) through its gamma-carboxyglutamic acid (Gla) domain, with unknown hemostatic consequences in vivo. Here, we study whether EPCR facilitates rhFVIIa hemostasis in hemophilia using a mouse model system. Mouse activated FVII (mFVIIa) is functionally homologous to rhFVIIa, but binds poorly to mouse EPCR (mEPCR). We modified mFVIIa to gain mEPCR binding using 3 amino acid changes in its Gla domain (L4F/L8M/W9R). The resulting molecule mFVIIa-FMR specifically bound mEPCR in vitro and in vivo and was identical to mFVIIa with respect to TF affinity and procoagulant functions. In macrovascular injury models, hemophilic mice administered mFVIIa-FMR exhibited superior hemostatic activity compared with mFVIIa. This was abolished by blocking mEPCR and was absent in ex vivo whole blood coagulation assays, implicating a specific mFVIIa FMR and endothelial mEPCR interaction. Because mFVIIa-FMR models the TF-dependent and EPCR binding properties of rhFVIIa, our data unmask a novel contribution of EPCR on the action of rhFVIIa administration in hemophilia, prompting the rational design of improved and safer rhFVIIa therapeutics. PMID- 24957145 TI - Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation. AB - Patients with cutaneous T-cell lymphoma (CTCL) are frequently colonized with Staphylococcus aureus (SA). Eradication of SA is, importantly, associated with significant clinical improvement, suggesting that SA promotes the disease activity, but the underlying mechanisms remain poorly characterized. Here, we show that SA isolates from involved skin express staphylococcal enterotoxins (SEs) that induce crosstalk between malignant and benign T cells leading to Stat3 mediated interleukin-10 (IL-10) production by the malignant T cells. The SEs did not stimulate the malignant T cells directly. Instead, SEs triggered a cascade of events involving cell-cell and asymmetric cytokine interactions between malignant and benign T cells, which stimulated the malignant T cells to express high levels of IL-10. Much evidence supports that malignant activation of the Stat3/IL-10 axis plays a key role in driving the immune dysregulation and severe immunodeficiency that characteristically develops in CTCL patients. The present findings thereby establish a novel link between SEs and immune dysregulation in CTCL, strengthening the rationale for antibiotic treatment of colonized patients with severe or progressive disease. PMID- 24957149 TI - Recurrent hemorrhage caused by type 3 von Willebrand disease in a domestic long haired cat. AB - OBJECTIVE: To describe a case of spontaneous epistaxis in a cat with type 3 von Willebrand disease (VWD) and detail the successful management of hemorrhagic episodes on 2 occasions. CASE SUMMARY: A 3.6 kg, 1-year-old, female mixed-breed domestic long-haired cat presented for spontaneous epistaxis. Hemostasis testing at presentation revealed normal prothrombin and activated partial thromboplastin times, a slightly decreased platelet count of 168 * 10(9) /L [168 * 10(3) /MUL] (reference interval 200-500 * 10(9) /L [200-500 * 10(3) /MUL]) and prolonged buccal mucosal bleeding time of 168 seconds (reference interval <150 s). Specific activities of coagulation factors VIII, IX, XI, and XII were all within reference intervals. Plasma von Willebrand factor concentration, however, was markedly reduced at <0.1% of normal. These findings are compatible with a diagnosis of severe type 3 VWD. The initial occurrence of epistaxis resolved spontaneously soon after admission; however, the cat required a packed RBC transfusion for blood loss anemia. Desmopressin acetate was administered, but failed to arrest hemorrhage during a second episode of epistaxis 12 months later. The second episode was successfully controlled by transfusion of 6.7 mL/kg feline fresh frozen plasma. NEW AND UNIQUE INFORMATION: This is the first description of severe type 3 VWD in a domestic cat and only the second report of VWD in this species. Unlike human beings and primates with type 3 VWD, the affected cat did not have a concomitant deficiency of coagulation factor VIII or consistent prolongation of activated partial thromboplastin time. Clinicians should therefore include VWD in the list of differentials for cats with signs of abnormal hemorrhage and confirm the diagnosis with specific measurement of plasma von Willebrand factor concentration. PMID- 24957148 TI - Appraisal of the national response to the caries epidemic in children in Nigeria. AB - BACKGROUND: This article reviews the caries profile for children in Nigeria and proposes an appropriate framework for addressing the silent caries epidemic. DISCUSSION: We reviewed the caries prevalence among children in Nigeria, assessed the existing responses to the caries epidemic including the national oral healthcare delivery situation in the country and discussed the current caries management in children. We then proposed a response framework for Nigeria. We argue that successful interventions will require the adoption of a socio ecological model. This would ensure that the micro-, meso-, exo- and macrosystems required to support the behavioural, structural and biological interventions for promoting caries prevention are addressed. National oral health surveys are required to help understand the epidemiology, social determinants of and factors that undermine the ability of children to access oral health care. A global caries prevention agenda for children would help get the government's support for a national response agenda. Currently, there is no global call for action on the caries epidemic in children. This lack of an agenda needs to be urgently addressed. SUMMARY: A combination of approaches for the prevention of caries in children in Nigeria is needed. A national survey is needed to generate the needed evidence for the planning of community relevant responses to the national caries epidemic in children. The design of a global health agenda for children is an important first step that can facilitate the development of a national oral health programme for children in Nigeria. PMID- 24957155 TI - Eosinophilic gastritis in children: clinicopathological correlation, disease course, and response to therapy. AB - OBJECTIVES: Eosinophilic gastritis (EG), defined by histological criteria as marked eosinophilia in the stomach, is rare, and large studies in children are lacking. We sought to describe the clinical, endoscopic, and histopathological features of EG, assess for any concurrent eosinophilia at other sites of the gastrointestinal (GI) tract, and evaluate response to dietary and pharmacological therapies. METHODS: Pathology files at our medical center were searched for histological eosinophilic gastritis (HEG) with >=70 gastric eosinophils per high power field in children from 2005 to 2011. Pathology slides were evaluated for concurrent eosinophilia in the esophagus, duodenum, and colon. Medical records were reviewed for demographic characteristics, symptoms, endoscopic findings, comorbidities, and response to therapy. RESULTS: Thirty children with severe gastric eosinophilia were identified, median age 7.5 years, 14 of whom had both eosinophilia limited to the stomach and clinical symptoms, fulfilling the clinicopathological definition of EG. Symptoms and endoscopic features were highly variable. History of atopy and food allergies was common. A total of 22% had protein-losing enteropathy (PLE). Gastric eosinophilia was limited to the fundus in two patients. Many patients had associated eosinophilic esophagitis (EoE, 43%) and 21% had eosinophilic enteritis. Response to dietary restriction therapy was high (82% clinical response and 78% histological response). Six out of sixteen patients had persistent EoE despite resolution of their gastric eosinophilia; two children with persistent HEG post therapy developed de novo concurrent EoE. CONCLUSIONS: HEG in children can be present in the antrum and/or fundus. Symptoms and endoscopic findings vary, highlighting the importance of biopsies for diagnosis. HEG is associated with PLE, and with eosinophilia elsewhere in the GI tract including the esophagus. The disease is highly responsive to dietary restriction therapies in children, implicating an allergic etiology. Associated EoE is more resistant to therapy. PMID- 24957156 TI - Development, external validation, and comparative assessment of a new diagnostic score for hepatic steatosis. AB - OBJECTIVES: We used data from population-based studies to determine the accuracy of the Fatty Liver Index (FLI) and the Hepatic Steatosis Index (HSI) in determining individual risk of hepatic steatosis. We also developed a new risk scoring system and validated all three indices using external data. METHODS: We used data from the Study of Health in Pomerania (SHIP; n=4,222), conducted in North-eastern Germany, to validate the existing scoring systems and to develop our own index. Data from the South German Echinococcus Multilocularis and Internal Diseases in Leutkirch (EMIL) study (n=2,177) were used as an external validation data set. Diagnostic performance was evaluated in terms of discrimination (area under the receiver operating characteristic curve (AUC)) and calibration plots. We applied boosting for generalized linear models to select relevant diagnostic separators. RESULTS: The FLI accurately discriminated patients with fatty liver disease from those without (AUC=0.817) but had poor calibration, in that predicted risks differed considerably from observed risks, based on SHIP data. The FLI performed well in discrimination and calibration in the analysis of EMIL data (AUC=0.890). The HSI performed worse than the FLI in analysis of both data sets (SHIP: AUC=0.782 and EMIL: AUC=0.841), showing an extremely skewed calibration. Our newly developed risk score had a good performance in the development data set (SHIP: AUC=0.860) and also good discrimination ability in the validation data (EMIL: AUC=0.876), but it had low calibration based on the validation data set. CONCLUSIONS: We compared the ability of the FLI, HSI, and our own scoring system to determine the risk of hepatic steatosis using two population-based data sets (one for the development of our own system and one for validation). In the development and independent replication data set, all three indices discriminated well between patients with and without hepatic steatosis, but the predicted risks did not match well with the observed risks, when applied to external data. Scoring systems for fatty liver disease could depend on methodological standardization of ultrasound diagnosis and laboratory measurements. PMID- 24957147 TI - JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo. AB - Chronic myeloid leukemia (CML) stem cell survival is not dependent on BCR-ABL protein kinase and treatment with ABL tyrosine kinase inhibitors cures only a minority of CML patients, thus highlighting the need for novel therapeutic targets. The Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)5 pathway has recently been explored for providing putative survival signals to CML stem/progenitor cells (SPCs) with contradictory results. We investigated the role of this pathway using the JAK2 inhibitor, ruxolitinib (RUX). We demonstrated that the combination of RUX, at clinically achievable concentrations, with the specific and potent tyrosine kinase inhibitor nilotinib, reduced the activity of the JAK2/STAT5 pathway in vitro relative to either single agent alone. These effects correlated with increased apoptosis of CML SPCs in vitro and a reduction in primitive quiescent CML stem cells, including NOD.Cg Prkdc(scid) IL2rg(tm1Wjl) /SzJ mice repopulating cells, induced by combination treatment. A degree of toxicity toward normal SPCs was observed with the combination treatment, although this related to mature B-cell engraftment in NOD.Cg-Prkdc(scid) IL2rg(tm1Wjl) /SzJ mice with minimal effects on primitive CD34(+) cells. These results support the JAK2/STAT5 pathway as a relevant therapeutic target in CML SPCs and endorse the current use of nilotinib in combination with RUX in clinical trials to eradicate persistent disease in CML patients. PMID- 24957157 TI - Endoscopic interventions for necrotizing pancreatitis. AB - Interventions for necrotizing pancreatitis have undergone a paradigm shift away from open surgical necrosectomy and toward minimally invasive techniques, with endoscopic transmural drainage (ETD) and necrosectomy emerging as principle forms of treatment. Recent multicenter studies, randomized trials, evidence-based guidelines, and consensus statements have endorsed the safety and efficacy of endoscopic and other minimally invasive techniques for the treatment of walled off necrosis. A comprehensive review of indications, standard and novel approaches, outcomes, complications, and controversies regarding ETD and necrosectomy is presented. Given the inherent challenges and associated risks, endoscopic techniques for the management of necrotizing pancreatitis should be performed at specialized multidisciplinary centers by expert endoscopists well versed in the management of necrotizing pancreatitis. PMID- 24957158 TI - Prevalence, risk factors, and outcomes of interval colorectal cancers: a systematic review and meta-analysis. AB - OBJECTIVES: We performed meta-analysis to estimate pooled prevalence, risk factors, and outcomes of interval colorectal cancers (CRCs). METHODS: Systematic literature search through October 2013, identified population-based studies, reporting prevalence of interval CRCs (CRCs diagnosed within 6-36 months of colonoscopy). We estimated the pooled prevalence, patient, endoscopist, and tumor related risk factors, as well as outcomes of interval CRCs, as compared with detected CRCs (CRCs diagnosed at or within 6 months of colonoscopy). RESULTS: Twelve studies reporting on 7,912 interval CRCs were included. Pooled prevalence of interval CRCs was 3.7% (95% confidence interval (CI)=2.8-4.9%). These cancers were 2.4 times more likely to arise in the proximal colon (6.5%; 95% CI=4.9-8.6%) as compared with distal colon (2.9%; 95% CI=2.0-4.2%). Patients with interval CRCs were older (age >65-70 years vs. <65-70 years: odds ratio (OR)=1.15; 95% CI=1.02-1.30), have more comorbidities (high Charlson comorbidity index: OR=2.00; 95% CI=1.77-2.27), and have diverticular disease (OR=4.25; 95% CI=2.58-7.00). There was a nonsignificant time trend of declining prevalence of interval CRCs from 4.8% in 1990s to 4.2% between 2000 and 2005 and 3.7% beyond 2005. Patients with interval CRCs were less likely to present at an advanced stage (OR=0.79; 95% CI=0.67-0.94), although there was no survival benefit. Considerable heterogeneity was observed in most of the analyses. CONCLUSIONS: Based on meta-analysis, approximately 1 in 27 CRCs are interval CRCs, although the confidence in these estimates is low because of the heterogeneity among the studies. These are more likely to arise in the proximal colon and are diagnosed in older patients, patients with comorbidities or diverticular disease. PMID- 24957159 TI - Prediction of development of liver-related events by transient elastography in hepatitis B patients with complete virological response on antiviral therapy. AB - OBJECTIVES: In the era of antiviral therapy, the prognostic significance of serum hepatitis B virus (HBV) DNA level as a biological gradient substantially diminished, as most patients can achieve complete virological response (CVR). We aimed to investigate the predictive roles of liver stiffness (LS) for liver related events (LREs) among patients with CVR. METHODS: We analyzed 192 patients with chronic HBV infection who achieved CVR (defined as HBV DNA <20 IU/ml) through entecavir therapy. LS values at CVR were measured using transient elastography. LREs were defined as any cirrhotic complication, hepatocellular carcinoma, and liver-related mortality. RESULTS: The median age of the patients was 49 years, and 134 (69.8%) were male. The median LS value at CVR was 8.8 kPa. During follow-up, LREs occurred in 25 (13.0%) patients. When the population was stratified into three groups (<8.0 kPa, 8.0-13.0 kPa, and >13.0 kPa), cumulative LRE incidences increased significantly in association with LS values (log-rank test, P=0.001). Patients with an LS value >13.0 kPa (hazard ratio (HR)=12.336, 95% confidence interval (CI) 1.335-114.010; P=0.027) and 8.0-13.0 kPa (HR=8.832, 95% CI 1.092-71.432; P=0.041) were at significantly greater risk compared with those with an LS value <8.0 kPa. On multivariate analysis, age and LS values were seen to be independent predictors (all P<0.05). When LS values were incorporated into the REACH-B scoring model instead of serum HBV DNA level, a better predictive performance was seen compared with a conventional approach (areas under the receiver operating characteristic curve, 0.814 vs. 0.629, respectively). CONCLUSIONS: LS values at CVR are useful for predicting forthcoming LRE development. Thus, in the era of potent antiviral therapy, tailored surveillance strategies might be established based upon LS values at CVR. PMID- 24957160 TI - Biosimilars: the need, the challenge, the future: the FDA perspective. AB - OBJECTIVES: This article summarizes the brief history of the biosimilars industry, the FDA's regulations and guidance for biosimilars development, and the issues and challenges facing developers and regulators in bringing biosimilars to market. METHODS: Current literature, regulations, and FDA guidance documents were summarized and interpreted to define biosimilars and to present their financial and clinical implications. RESULTS: Some biologic agents that will lose patent protection during the next few years may be replaced with lower cost follow-on biologics. However, unlike generic drugs, biosimilars may be structurally and functionally different from the reference product they are designed to resemble. The FDA has yet to approve any agent via the abbreviated licensure pathway for biosimilars that was passed as part of the Affordable Care Act. The FDA has issued new guidance describing processes by which manufacturers may demonstrate either biosimilarity or interchangeability with an FDA-approved biologic agent, which is required for abbreviated licensure. Biosimilars approved in Europe consist of relatively small molecules; complex large-molecule biosimilars could be subjected to a rigorous and prolonged FDA approval process, which would defeat attempts to develop lower-cost versions of biologic drugs. CONCLUSIONS: Biosimilar development is a consequence of the financial success of biologic therapies and their eventual patent expiration. The pharmaceutical industry must now develop complex biosimilars that resemble FDA-approved biologic agents and invent analytical tools and end points to demonstrate similarity to regulatory authorities. Already in development is a new wave of "biobetter" or "biosuperior" drugs that mimic but also improve upon a biologic drug's chemistry, formulation, or delivery. PMID- 24957161 TI - The rich and the sensitive: diverse fungal communities change functionally with the warming Arctic. AB - Fungi are very abundant and functionally pivotal in Arctic terrestrial ecosystems. Yet, our understanding of their community composition, diversity and particularly their environmental drivers is superficial at the very best. In this issue of Molecular Ecology, Timling et al. (2014) describe perhaps one of the most comprehensive and geographically ambitious molecular studies on Arctic fungal communities to date. The results highlight the potential sensitivity of the fungal communities to plant communities, environmental conditions and therefore to environmental change. Thus, these studies lay a foundation to educated speculation on the fungal community migration northwards as a result of predicted climate change. PMID- 24957162 TI - Why some parasites are widespread and abundant while others are local and rare? AB - Abundances and distributions of species are usually associated. This implies that as a species declines in abundance so does the number of sites it occupies. Conversely, when there is an increase in a species' range size, it is usually followed by an increase in population size (Gaston et al. 2000). This ecological phenomenon, also known as the abundance-occupancy relationship (AOR), is well documented in several species of animals and plants (Gaston et al. 2000) but has been little investigated in parasites. In this issue of Molecular Ecology, Drovetski et al. (2014) investigated the AOR in avian haemosporidians (vector borne blood parasites) using data from four well-sampled bird communities. In support of the AOR, the research group found that the abundance of parasite cytochrome b lineages (a commonly used proxy for species identification within this group of parasites) was positively linked with the abundance of susceptible avian host species and that the most abundant haemospordian lineages were those with larger ranges. Drovetski et al. (2014) also found evidence for both hypotheses proposed to explain the AOR in parasites: the trade-off hypothesis (TOH) and the niche-breadth hypothesis (NBH). Interestingly, the main predictor of the AOR was the number of susceptible hosts (i.e. number of infected birds) and not the number of host species the parasites were able to exploit. PMID- 24957163 TI - Long-term results of a phase II trial with frontline concurrent chemoradiotherapy followed by consolidation chemotherapy for localized nasal natural killer/T-cell lymphoma. AB - PURPOSE: A phase II trial was conducted to evaluate the therapeutic efficacy and safety profiles of frontline concurrent chemoradiotherapy (CCRT) plus consolidation chemotherapy for patients with stage I/II nasal natural killer/T cell lymphoma (NKTCL). PATIENTS AND METHODS: Patients with newly diagnosed, measurable stage I/II nasal NKTCL were eligible. The CCRT included two cycles of the DEP regimen (dexamethasone, etoposide, and cisplatin) every 4 wk with concurrent 5040 cGy radiation in 28 fractions for 5 wk. Patients without disease progression after CCRT were subjected to two cycles of DVIP consisted of dexamethasone, etoposide, ifosphamide, mesna, and cisplatin every 4 wk. The primary endpoint was tumor response rate, and secondary endpoints were survival and toxicities. This phase II study has been registered in the ClinicalTrials.gov (NCT00292695). RESULTS: Thirty-three patients received CCRT, and 29 patients received two cycles of consolidation DVIP after CCRT. Among the 32 evaluable patients, 20 achieved complete response and 6 achieved partial response. The overall and complete response rate was 81% (95% CI, 68-95%) and 63% (95% CI, 46 79%), respectively. The 2-yr and 5-yr progression-free survival rate for intention-to-treat population was 64% (95% CI, 47-80%) and 60% (95% CI, 39-73%), respectively; while the corresponding overall survival rate was 73% (95% CI, 57 88%) and 66% (95% CI, 50-83%), respectively. The most common treatment-related grade 3/4 adverse event was leukopenia (85%). CONCLUSION: Frontline CCRT plus consolidation chemotherapy is feasible and effective for treating localized nasal NKTCL. PMID- 24957164 TI - Review article: why, when and how to de-escalate therapy in inflammatory bowel diseases. AB - BACKGROUND: Therapeutic objectives are currently evolving in inflammatory bowel diseases (IBD) from control of symptoms towards improvement of long-term disease outcomes. In patients achieving remission, safety concerns - infections or neoplasia - and economic issues are prompting de-escalation strategies. AIM: To give a complete overview of studies on de-escalating therapy in IBD. METHODS: A structured search in Pubmed, the Cochrane Library and EMBASE was performed using defined key words (inflammatory bowel diseases, Crohn's disease, ulcerative colitis, immunosuppressants, azathioprine, methotrexate, anti-TNF, infliximab, adalimumab, de-escalation, dose reduction, cessation, stopping, withdrawal), including full text articles and abstracts in English language. RESULTS: Eleven studies were identified, investigating cessation of immunosuppressants (IS) and/or anti-TNF treatments. Patients exposed to a combination of IS and anti-TNF have an increased risk for infections, especially due to opportunistic agent, without any clear signal for associated cancers when compared to those receiving single therapy. In patients receiving IS alone, relapse rate at 12 months following IS cessation is close to 20% and 30% in Crohn's disease (CD) and ulcerative colitis (UC) respectively. There is no study specifically evaluating anti-TNF treatment withdrawal in case of scheduled anti-TNF monotherapy in IBD. In patients receiving combination therapy with IS and infliximab (IFX) for at least 6 months, relapse rate of IFX failure following IS cessation is near to 20% at 24 months and seems to be similar in patients who maintained combination therapy. In case of anti-TNF therapy, cessation in CD patients in combo-therapy proportion of relapse is high, close to 40% and 50% over 1 year and 2 years respectively. Regarding higher risk of adverse events, some special situations - young males, pregnancy and elderly - should be managed specifically and de escalating treatment considered. CONCLUSIONS: De-escalating treatment strategy should be mainly considered in patients with high risk of severe adverse events and low relapse risk (patients in deep remission) after drug withdrawal. For these reasons, cessation of anti-TNF treatment and/or immunosuppressants should be a case by case decision in highly selected patients. PMID- 24957165 TI - Effect of pregnancy on the course of immune thrombocytopenia: a retrospective study of 118 pregnancies in 82 women. AB - In women with pre-existing immune thrombocytopenic purpura (ITP), the effect of pregnancy on the course of the disease is poorly known. We performed a dual centre retrospective cohort study of 118 pregnancies in 82 women with primary ITP. In early pregnancy, the platelet count was <100 * 10(9) /l in 35.6% of pregnancies. During pregnancy the median platelet count nadir was 66 * 10(9) /l (25th-75th percentile: 42-117), with platelet count <30 * 10(9) /l for 26 pregnancies (22%). In 49% of pregnancies, a significant decrease of the platelet count required treatment at least transiently in preparation for delivery. At the time of delivery, the median platelet count was 110 * 10(9) /l (77-155). Compared to before pregnancy, at 3 months post-partum, only 11% of pregnancies [95% confidence interval (95% CI): 6.8-20.2] showed disease worsening. Previous splenectomy was the only factor significantly associated with ITP worsening after pregnancy (53.9% vs. 10.3%, P < 0.001). For 8.3% of the pregnancies (95% CI: 3.8 15.1), neonatal thrombocytopenia required treatment, especially in case of previous maternal splenectomy (adjusted odds ratio 16.7, 95% CI: 2.61-106). The overall risk of exacerbation of ITP and severe thrombocytopenia during pregnancy is acceptable. PMID- 24957166 TI - The short-term impact of vitamin D-based hip fracture prevention in older adults in the United Kingdom. AB - PURPOSE: Vitamin D is a relatively inexpensive drug yet an important hormone in terms of calcium and bone homeostasis. Treatment with vitamin D is associated with reduced fracture risk particularly in an elderly population. Therefore, we assessed the budgetary impact of routine prescription of 800 IU daily colecalciferol on hip fracture among older adults in the United Kingdom. METHODS: Using meta-analysis findings for treatment effect and UK-estimates of incidence, we performed a health economic evaluation of treating the UK population aged 65 and over with 800 IU of vitamin D daily, assessing the impact upon hip fracture costs using incremental attributable costs and excess mortality for a range of age- gender-based treatment strategies. RESULTS: Using only a 1-year horizon, considering only reduction in hip fracture, prescribing colecalciferol 800 IU daily to all adults aged 65 and over, could reduce the number of incident hip fractures from 65,400 to 45,700, saving almost 1,700 associated deaths, whilst saving the UK taxpayer L22 million. CONCLUSIONS: As the UK government seeks to reduce public expenditure in all sectors, investment in prescribed prophylactic colecalciferol 800 IU therapy for adults aged 65 and over is likely to yield cost savings through reduction hip fracture alone in the first year. PMID- 24957167 TI - Oxidatively modified forms of albumin in patients with risk factors of metabolic syndrome. AB - BACKGROUND: Metabolic syndrome (MetS) is a complex metabolic disease connected especially with lipid and carbohydrate disturbances. It is postulated that oxidative stress (OS) is linked to metabolic syndrome, constituting a novel component of its pathogenesis. AIM: We aimed to examine the plasma level of oxidatively modified proteins--advanced oxidation protein products (AOPP) and ischemia modified albumin (IMA)--as well as thiol (SH) groups and evaluate their connection with metabolic agents in relation to MetS prevalence. SUBJECTS AND METHODS: The levels of AOPP, IMA and SH groups were measured spectrophotometrically in 106 patients with MetS risk factors and in 32 control subjects. RESULTS: The levels of examined parameters differed significantly between patients with MetS risk factors and the control group. AOPP significantly correlated with glucose (r = 0.30, p = 0.008), HDL-Ch (r = -0.34, p = 0.005), TG (r = 0.48, p < 0.001) and fibrinogen (r = 0.37, p < 0.001). The levels of AOPP and IMA increased progressively with the number of MetS risk factors, being the most significant for AOPP. The highest values of AOPP were associated with the presence of at least three risk factors. Only AOPP were an independent determinant for MetS occurrence in the studied population (OR = 2.72, p = 0.04). Mutual dependence between metabolic, oxidative stress and inflammatory parameters was revealed. CONCLUSIONS: Oxidative modifications of proteins are increased in MetS and accumulation of MetS risk factors enhances manifestation of OS. AOPP is the most appropriate parameter for determination of OS, with potential diagnostic value in MetS patients. PMID- 24957170 TI - Nanofiltration of Mine Water: Impact of Feed pH and Membrane Charge on Resource Recovery and Water Discharge. AB - Two nanofiltration membranes, a Dow NF 270 polyamide thin film and a TriSep TS 80 polyamide thin film, were investigated for their retention of ionic species when filtering mine influenced water streams at a range of acidic pH values. The functional iso-electric point of the membranes, characterized by changes in retention over a small pH range, were examined by filtering solutions of sodium sulphate. Both membranes showed changes in retention at pH 3, suggesting a zero net charge on the membranes at this pH. Copper mine drainage and synthetic solutions of mine influenced water were filtered using the same membranes. These solutions were characterized by pH values within 2 and 5, thus crossing the iso electric point of both membranes. Retention of cations was maximized when the feed solution pH was less than the iso-electric point of the membrane. In these conditions, the membrane has a net positive charge, reducing the transmission rate of cations. From the recoveries of a range of cations, the suitability of nanofiltration was discussed relative to the compliance with mine water discharge criteria and the recovery of valuable commodity metals. The nanofiltration process was demonstrated to offer advantages in metal recovery from mine waste streams, concomitantly enabling discharge criteria for the filtrate disposal to be met. PMID- 24957168 TI - The effect of leptin promoter and leptin receptor gene polymorphisms on lipid profile among the diabetic population: modulations by atorvastatin treatment and environmental factors. AB - PURPOSE: This study investigated the effect of leptin (LEP) 2548A/G and leptin receptor (LEPR) Q223R polymorphisms on the levels of HDL, LDL, TG, and total cholesterol (t-chol). In addition, the interactions between examined polymorphisms, statin therapy and environmental factors on lipid profile were examined. METHODS: Adult diabetic patients (n-418) were recruited from diabetes/endocrine clinics in north of Jordan. Lipid profile was measured using standard protocols. Genotyping of LEP 2548A/G and LEPR Q223R polymorphisms was carried out using polymerase chain reaction-restriction fragment length polymorphisms. RESULTS: No significant association between LEP 2548A/G and LEPR genotypes and levels of HDL (P = 0.83), LDL (P = 0.40), TG (P = 0.23) and t-chol (P = 0.91). However, in patient on atorvastatin, those with GG or GA genotypes of LEP 2548 experienced significantly higher levels of LDL compared with AA genotype of LEP 2548 (P < 0.002). Patients with dyslipidemia had higher TG in comparison with those without (P < 0.03). Smokers had lower HDL and higher TG levels compared with none smokers or previous smokers (P < 0.002 and P < 0.02, respectively). Female patients tend to have a higher HDL in comparison with male patients (P < 0.05). Patients with HbA1c value greater than or equal to 7 had higher LDL and t-chol compared with patients who had an HbA1c levels of <7 (P < 0.02 and < 0.005, respectively). Patients with disease duration of 5 or more years had a lower HDL compared with those patients with duration of <5 years (P < 0.03). CONCLUSION: In conclusion, and although lipid profile regulation is a multifactorial process, -2548G/A LEP polymorphism seems to affect statins treatment response among diabetic patients. More studies are required to specifically define factors that influence lipid profiles interaction with statin treatment response especially among patients with diabetes. PMID- 24957169 TI - Charcot-Marie-Tooth disease type 2A: from typical to rare phenotypic and genotypic features. AB - IMPORTANCE: Axonal Charcot-Marie-Tooth disease (CMT) is genetically heterogeneous, with 11 genes identified. Axonal CMT has most frequently been associated with mutations in the MFN2 gene (CMT2A). OBJECTIVES: To describe the clinical and molecular features of CMT2A, to delineate prognostic factors, to understand connections between a certain phenotype and more serious clinical consequences, and to identify interactions among the associated genes. EVIDENCE REVIEW: We describe the clinical, molecular, electrophysiological, and additional features of 43 patients with CMT2A. The degree of physical disability was determined by the CMT neuropathy score and adapted to the CMT neuropathy score gradient to evaluate the clinical course. We evaluated all data within the context of the most recent and important publications concerning this issue. FINDINGS: Twenty-five patients had early-onset CMT2A and severe functional disability, with 9 being wheelchair bound, and 18 had late-onset disease and a milder phenotype. Optic atrophy, vocal cord palsy, and auditory impairment were observed in 5, 6, and 2 patients, respectively. Among the 24 patients who underwent magnetic resonance imaging of the spinal cord, 6 had evidence of spinal atrophy with or without hydromyelia. In 1 patient, magnetic resonance imaging revealed hydrocephalus. Twenty different MFN2 mutations were identified, and 14 were considered new variants. Their transmission was predominantly autosomal dominant, with vertical transmission in 8 and de novo occurrence in 3. However, we also identified rare types of transmission, especially a germinal mosaicism and an autosomal recessive inheritance. One patient carried a rare variant in the GDAP1 gene and another in the OPA1 gene in association with MFN2 mutation. CONCLUSIONS AND RELEVANCE: Charcot-Marie-Tooth disease type 2A associated with MFN2 mutations is clinically very heterogeneous. Ranging from a mild to a severe form, CMT2A exhibits various types of transmission. Optic atrophy and vocal cord palsy were observed in patients with severe disability and an early-onset form and also in patients with later onset. Hydromyelia and spinal cord atrophy support central nervous system involvement in CMT2A. PMID- 24957171 TI - Preparation of Sulfobetaine-Grafted PVDF Hollow Fiber Membranes with a Stably Anti-Protein-Fouling Performance. AB - Based on a two-step polymerization method, two sulfobetaine-based zwitterionic monomers, including 3-(methacryloylamino) propyl-dimethyl-(3-sulfopropyl) ammonium hydroxide (MPDSAH) and 2-(methacryloyloxyethyl) ethyl-dimethyl-(3 sulfopropyl) ammonium (MEDSA), were successfully grafted from poly(vinylidene fluoride) (PVDF) hollow fiber membrane surfaces in the presence of N,N'-methylene bisacrylamide (MBAA) as a cross-linking agent. The mechanical properties of the PVDF membrane were improved by the zwitterionic surface layers. The surface hydrophilicity of PVDF membranes was significantly enhanced and the polyMPDSAH-g PVDF membrane showed a higher hydrophilicity due to the higher grafting amount. Compared to the polyMEDSA-g-PVDF membrane, the polyMPDSAH-g-PVDF membrane showed excellent significantly better anti-protein-fouling performance with a flux recovery ratio (RFR) higher than 90% during the cyclic filtration of a bovine serum albumin (BSA) solution. The polyMPDSAH-g-PVDF membrane showed an obvious electrolyte-responsive behavior and its protein-fouling-resistance performance was improved further during the filtration of the protein solution with 100 mmol/L of NaCl. After cleaned with a membrane cleaning solution for 16 days, the grafted MPDSAH layer on the PVDF membrane could be maintain without any chang; however, the polyMEDSA-g-PVDF membrane lost the grafted MEDSA layer after this treatment. Therefore, the amide group of sulfobetaine, which contributed significantly to the higher hydrophilicity and stability, was shown to be imperative in modifying the PVDF membrane for a stable anti-protein-fouling performance via the two-step polymerization method. PMID- 24957172 TI - Effect of Cross-Linking on the Mechanical and Thermal Properties of Poly(amidoamine) Dendrimer/Poly(vinyl alcohol) Hybrid Membranes for CO2 Separation. AB - Poly(amidoamine) (PAMAM) dendrimers were incorporated into cross-linked poly(vinyl alcohol) (PVA) matrix to improve carbon dioxide (CO2) separation performance at elevated pressures. In our previous studies, PAMAM/PVA hybrid membranes showed high CO2 separation properties from CO2/H2 mixed gases. In this study, three types of organic Ti metal compounds were selected as PVA cross linkers that were used to prepare PAMAM/cross-linked PVA hybrid membranes. Characterization of the PAMAM/cross-linked PVA hybrid membranes was conducted using nanoindentation and thermogravimetric analyses. The effects of the cross linker and CO2 partial pressure in the feed gas on CO2 separation performance were discussed. H2O and CO2 sorption of the PAMAM/PVA hybrid membranes were investigated to explain the obtained CO2 separation efficiencies. PMID- 24957173 TI - Polymeric Pseudo-Liquid Membranes from Poly(N-oleylacrylamide). AB - A polymeric pseudo-liquid membrane (PPLM) was constructed from poly(N oleylacrylamide) (PC18AAm), which exhibited a rubbery state under membrane transport conditions and used as the membrane matrix. In the present study, dibenzo-18-crown-6 (DB18C6) and dibenzo-21-crown-7 (DB21C7) were adopted as transporters for alkali metal ions. KCl was adopted as a model substrate for DB18C6 and CsCl the latter. Chiral transporter, O-allyl-N-(9 anthracenylmethyl)cinchonidinium bromide (AAMC) was used as a transporter for chiral separation of a racemic mixture of phenylglycine (Phegly). The l-somer was transported in preference to the antipode. The present study revealed that PPLMs are applicable to membrane transport, such as metal ion transport and chiral separation. PMID- 24957174 TI - Filtration characterization method as tool to assess membrane bioreactor sludge filterability-the delft experience. AB - Prevention and removal of fouling is often the most energy intensive process in Membrane Bioreactors (MBRs), responsible for 40% to 50% of the total specific energy consumed in submerged MBRs. In the past decade, methods were developed to quantify and qualify fouling, aiming to support optimization in MBR operation. Therefore, there is a need for an evaluation of the lessons learned and how to proceed. In this article, five different methods for measuring MBR activated sludge filterability and critical flux are described, commented and evaluated. Both parameters characterize the fouling potential in full-scale MBRs. The article focuses on the Delft Filtration Characterization method (DFCm) as a convenient tool to characterize sludge properties, namely on data processing, accuracy, reproducibility, reliability, and applicability, defining the boundaries of the DFCm. Significant progress was made concerning fouling measurements in particular by using straight forward approaches focusing on the applicability of the obtained results. Nevertheless, a fouling measurement method is still to be defined which is capable of being unequivocal, concerning the fouling parameters definitions; practical and simple, in terms of set-up and operation; broad and useful, in terms of obtained results. A step forward would be the standardization of the aforementioned method to assess the sludge filtration quality. PMID- 24957175 TI - The effect of chain structures on the crystallization behavior and membrane formation of poly(vinylidene fluoride) copolymers. AB - The crystallization behaviors of two copolymers of PVDF were studied, and the effect of copolymerized chains on the crystallization behavior was investigated. The results indicated that both copolymers had a lowered crystallization temperature and crystallinity. The crystallization rate was improved by the copolymer with symmetrical units in PVDF chains, but hindered by asymmetrical units, compared with the neat PVDF. The symmetrical units in PVDF chains favored the beta-crystals with fiber-like structures. According to the solubility parameter rule, methyl salicylate (MS) can be chosen as a diluent for PVDF copolymers. Both diluted systems had liquid-liquid (L-L) regions in the phase diagrams, which was due to the lowered crystallization temperature. PMID- 24957176 TI - Membrane potential generated by ion adsorption. AB - It has been widely acknowledged that the Goldman-Hodgkin-Katz (GHK) equation fully explains membrane potential behavior. The fundamental facet of the GHK equation lies in its consideration of permeability of membrane to ions, when the membrane serves as a separator for separating two electrolytic solutions. The GHK equation describes that: variation of membrane permeability to ion in accordance with ion species results in the variation of the membrane potential. However, nonzero potential was observed even across the impermeable membrane (or separator) separating two electrolytic solutions. It gave rise to a question concerning the validity of the GHK equation for explaining the membrane potential generation. In this work, an alternative theory was proposed. It is the adsorption theory. The adsorption theory attributes the membrane potential generation to the ion adsorption onto the membrane (or separator) surface not to the ion passage through the membrane (or separator). The computationally obtained potential behavior based on the adsorption theory was in good agreement with the experimentally observed potential whether the membrane (or separator) was permeable to ions or not. It was strongly speculated that the membrane potential origin could lie primarily in the ion adsorption on the membrane (or separator) rather than the membrane permeability to ions. It might be necessary to reconsider the origin of membrane potential which has been so far believed explicable by the GHK equation. PMID- 24957177 TI - Experimental investigation into the transmembrane electrical potential of the forward osmosis membrane process in electrolyte solutions. AB - The transmembrane electrical potential (TMEP) in a forward osmosis membrane process with a single electrolyte solution as the draw and feed solutions was investigated by experiments. The effects of membrane orientation, the electrolyte species (KCl, NaCl, MgCl2, and CaCl2), concentration and concentration ratio of solutions at both sides of membrane on water flux and TMEP were investigated. The results showed that the TMEPs at different membrane orientation cannot completely coincide, which confirmed the effect of membrane asymmetry. The ion diffusion coefficients significantly affected the TMEP across the membrane, with different patterns for different electrolytes and concentrations. PMID- 24957178 TI - Synthesis and Characterisation of ETS-10/Acetate-based Ionic Liquid/Chitosan Mixed Matrix Membranes for CO2/N2 Permeation. AB - Mixed matrix membranes (MMMs) were prepared by incorporating organic surfactant free hydrothermally synthesised ETS-10 and 1-ethyl-3-methylimidazolium acetate ionic liquid (IL) to chitosan (CS) polymer matrix. The membrane material characteristics and permselectivity performance of the two-component membranes were compared with the three-component membrane and the pure CS membrane. The addition of IL increased CO2 solubility of the polymer, and, thus, the CO2 affinity was maintained for the MMMs, which can be correlated with the crystallinity, measured by FT-IR, and void fraction calculations from differences between theoretical and experimental densities. The mechanical resistance was enhanced by the ETS-10 nanoparticles, and flexibility decreased in the two component ETS-10/CS MMMs, but the flexibility imparted by the IL remained in three-component ETS-10/IL/CS MMMs. The results of this work provide insight into another way of facing the adhesion challenge in MMMs and obtain CO2 selective MMMs from renewable or green chemistry materials. PMID- 24957179 TI - Heterogeneous catalysis for sustainable biodiesel production via esterification and transesterification. AB - Concern over the economics of accessing fossil fuel reserves, and widespread acceptance of the anthropogenic origin of rising CO2 emissions and associated climate change from combusting such carbon sources, is driving academic and commercial research into new routes to sustainable fuels to meet the demands of a rapidly rising global population. Here we discuss catalytic esterification and transesterification solutions to the clean synthesis of biodiesel, the most readily implemented and low cost, alternative source of transportation fuels to meet future societal demands. PMID- 24957180 TI - Alteration of root growth by lettuce, wheat, and soybean in response to wear debris from automotive brake pads. AB - Brakes from motor vehicles release brake pad wear debris (BPWD) with increased concentrations of heavy metals. Germination and root-elongation assays with lettuce, wheat, and soybean were used to provide an initial evaluation of the phytotoxicity of either a water extract of BPWD or BPWD particulates. In terms of germination, the only effect observed was that lettuce germination decreased significantly in the BPWD particulate treatment. Lettuce and wheat showed decreased root length and root-elongation rate in the presence of the BPWD particulates, whereas lettuce produced a significantly greater number of lateral roots in response to BPWD extract. There was no significant effect of either BPWD treatment on soybean root elongation or lateral roots. Treatment with BPWD extracts or particulates caused significant alterations in the bending pattern of the plant roots. These initial results suggest that BPWD may have effects on the early growth and development of plants. PMID- 24957181 TI - Thiamine transporter-2 deficiency: outcome and treatment monitoring. AB - BACKGROUND: The clinical characteristics distinguishing treatable thiamine transporter-2 deficiency (ThTR2) due to SLC19A3 genetic defects from the other devastating causes of Leigh syndrome are sparse. METHODS: We report the clinical follow-up after thiamine and biotin supplementation in four children with ThTR2 deficiency presenting with Leigh and biotin-thiamine-responsive basal ganglia disease phenotypes. We established whole-blood thiamine reference values in 106 non-neurological affected children and monitored thiamine levels in SLC19A3 patients after the initiation of treatment. We compared our results with those of 69 patients with ThTR2 deficiency after a review of the literature. RESULTS: At diagnosis, the patients were aged 1 month to 17 years, and all of them showed signs of acute encephalopathy, generalized dystonia, and brain lesions affecting the dorsal striatum and medial thalami. One patient died of septicemia, while the remaining patients evidenced clinical and radiological improvements shortly after the initiation of thiamine. Upon follow-up, the patients received a combination of thiamine (10-40 mg/kg/day) and biotin (1-2 mg/kg/day) and remained stable with residual dystonia and speech difficulties. After establishing reference values for the different age groups, whole-blood thiamine quantification was a useful method for treatment monitoring. CONCLUSIONS: ThTR2 deficiency is a reversible cause of acute dystonia and Leigh encephalopathy in the pediatric years. Brain lesions affecting the dorsal striatum and medial thalami may be useful in the differential diagnosis of other causes of Leigh syndrome. Further studies are needed to validate the therapeutic doses of thiamine and how to monitor them in these patients. PMID- 24957182 TI - Functional ingredients from microalgae. AB - A wide variety of natural sources are under investigation to evaluate their possible use for new functional ingredient formulation. Some records attested the traditional and ancient use of wild harvested microalgae as human food but their cultivation for different purposes started about 40 years ago. The most popular species are Arthrospira (traditional name, Spirulina), Chlorella spp., Dunaliella spp. and Haematococcus spp. Microalgae provide a bewildering array of opportunities to develop healthier food products using innovative approaches and a number of different strategies. Compared to other natural sources of bioactive ingredients, microalgae have many advantages such as their huge biodiversity, the possibility to grow in arid land and with limited fresh water consumption and the flexibility of their metabolism, which could be adapted to produce specific molecules. All these factors led to very sustainable production making microalgae eligible as one of the most promising foods for the future, particularly as source of proteins, lipids and phytochemicals. In this work, a revision of the knowledge about the use of microalgae as food and as a source of functional ingredients has been performed. The most interesting results in the field are presented and commented upon, focusing on the different species of microalgae and the activity of the nutritionally relevant compounds. A summary of the health effects obtained together with pros and cons in the adoption of this natural source as functional food ingredients is also proposed. PMID- 24957183 TI - Additional MR contrast dosage for radiologists' diagnostic performance in detecting brain metastases: a systematic observer study at 3 T. AB - PURPOSE: To evaluate the diagnostic performance of a double-dose administration of gadolinium for brain metastases at 3 T in a systematic observer test. MATERIALS AND METHODS: Postcontrast MR images of 39 patients (total 104 metastases) were obtained by 3D T1-weighted sequences with both standard and cumulative double dose contrast administration. An observer test involving 9 radiologists (5 board-certified radiologists and 4 residents) was performed, and their diagnostic performance with the two doses was compared by means of sensitivity, false-positives, reading time, and a figure-of-merit. RESULTS: Compared to the standard dose, the double dose showed higher sensitivity (P < 0.0001), higher false-positive/case (P < 0.05), longer reading time (P < 0.05), and higher figure-of-merit (P < 0.0001). Particularly in small lesions (< 5 mm), sensitivity with the double dose (61.5%, P < 0.0001) was approximately twice as high as that with the standard dose (29.5%). Artifacts and blood vessels were the most common imaging findings resulting in false-positives. CONCLUSIONS: The double dose improved detection for metastases smaller than 5 mm at 3 T and thus resulted in better diagnostic performance of radiologists. However, a higher dose might result in prolonged reading time and increased false-positives, presumably due to increased vessel signals and frequency of flow-related artifacts. PMID- 24957186 TI - Use of permanent marker to deposit a protection layer against FIB damage in TEM specimen preparation. AB - Permanent marker deposition (PMD), which creates permanent writing on an object with a permanent marker, was investigated as a method to deposit a protection layer against focused ion beam damage. PMD is a simple, fast and cheap process. Further, PMD is excellent in filling in narrow and deep trenches, enabling damage free observation of high aspect ratio structures with atomic resolution in transmission electron microscopy (TEM). The microstructure, composition, gap filling ability and planarization of the PMD layer were studied using dual beam focused ion beam, transmission electron microscopy, energy dispersive X-ray spectroscopy and electron energy loss spectroscopy. It was found that a PMD layer is basically an amorphous carbon structure, and that such a layer should be at least 65 nm thick to protect a surface against 30 keV focused ion beam damage. We suggest that such a PMD layer can be an excellent protection layer to maintain a pristine sample structure against focused ion beam damage during transmission electron microscopy specimen preparation. PMID- 24957185 TI - Hyaluronan expression as a significant prognostic factor in patients with malignant peripheral nerve sheath tumors. AB - Hyaluronan (HA) regulates malignant tumor growth, invasion, and metastasis. However, few studies have focused on the roles of HA in tumorigenicity in malignant peripheral nerve sheath tumors (MPNST). In this study, we sought to clarify the prognostic value of HA in patients with MPNST. Specimens obtained from 15 patients with neurofibroma and 30 with MPNST were subjected to HA staining and scored as three grades. Protein expressions of HA synthase 1-3 were examined in the 22 MPNST tissue samples available. Statistically higher HA positivity was observed in MPNST as compared with neurofibroma (P = 0.020). The univariate analysis revealed that increased HA expression, age, neurofibromatosis type 1 (NF1) status, large tumor size, and histological grade were significantly associated with reduced overall survival of patients with MPNST; while increased HA expression, NF1 status, tumor size, and histological grade were correlated with disease-free survival. However, HA synthase 1-3 expression related to neither overall survival nor disease-free survival of these patients. In multivariate analysis, large tumor size (P = 0.022) was an independent prognostic factor for overall survival, and HA expression (P = 0.028) and tumor size (P = 0.002) were independent prognostic factors for disease-free survival. Statistically higher levels of HA in the human MPNST cells were observed compared with neurofibroma cells in vitro. Our results demonstrate that HA expression can be a useful marker in differentiating MPNST from neurofibroma, and in identifying patients with a poor prognosis. Hyaluronan-targeting therapy for patients with MPNST may have potential as a therapeutic tool. PMID- 24957187 TI - Newer antiepileptic drugs: evidence based use. AB - Several new antiepileptic drugs (AED's) have been approved by the FDA in the last 2 decades. The newer AED's score over the older ones, in terms of improved tolerability, safety, improved pharmacokinetics and lower drug-drug interactions. However, efficacy may not be significantly higher. This article reviews the newer antiepileptics approved in the pediatric age group and the evidence for or against their clinical use. PMID- 24957189 TI - Effect of pre-irradiation with different doses, wavelengths, and application intervals of low-level laser therapy on cytochrome c oxidase activity in intact skeletal muscle of rats. AB - Modulation of cytochrome c oxidase activity has been pointed as a possible key mechanism for low-level laser therapy (LLLT) in unhealthy biological tissues. But recent studies by our research group with LLLT in healthy muscles before exercise found delayed skeletal muscle fatigue development and improved biochemical status in muscle tissue. Therefore, the aim of this study was to evaluate effects of different LLLT doses and wavelengths in cytochrome c oxidase activity in intact skeletal muscle. In this animal experiment, we irradiated the tibialis anterior muscle of rats with three different LLLT doses (1, 3, and 10 J) and wavelengths (660, 830, and 905 nm) with 50 mW power output. After irradiation, the analyses of cytochrome c oxidase expression by immunohistochemistry were analyzed at 5, 10, 30 min and at 1, 2, 12, and 24 h. Our results show that LLLT increased (p < 0.05) cytochrome c oxidase expression mainly with the following wavelengths and doses: 660 nm with 1 J, 830 nm with 3 J, and 905 nm with 1 J at all time points. We conclude that LLLT can increase cytochrome c oxidase activity in intact skeletal muscle and that it contributes to our understanding of how LLLT can enhance performance and protect skeletal muscles against fatigue development and tissue damage. Our findings also lead us to think that the combined use of different wavelengths at the same time can enhance LLLT effects in skeletal muscle performance and other conditions, and it can represent a therapeutic advantage in clinical settings. PMID- 24957188 TI - RUNX3 expression is associated with sensitivity to pheophorbide a-based photodynamic therapy in keloids. AB - Runt-related transcription factor 3 (RUNX3) has recently been reported to be a possible predictor of sensitivity of cancer cells for photodynamic therapy (PDT), a promising therapeutic modality for keloids. In this study, we aimed to elucidate the implications of RUNX3 for keloid pathogenesis and sensitivity to pheophorbide a-based PDT (Pa-PDT). RUNX3 and proliferating cell nuclear antigen (PCNA) expression were examined in 6 normal skin samples and 32 keloid tissue samples by immunohistochemistry. We found that RUNX3 expression was detected more often in keloid tissues than in dermis of normal skin. In keloid tissues, RUNX3 expression was significantly increased in patients presenting with symptoms of pain or pruritus, and was also significantly related to PCNA expression. The therapeutic effect of Pa-PDT was comparatively investigated in keloid fibroblasts (KFs) with and without RUNX3 expression. Significant differences were found after Pa-PDT between KFs with and without RUNX3 expression in cell viability, proliferative ability, type I collagen expression, generation of reactive oxygen species (ROS), and apoptotic cell death. In addition, RUNX3 expression was significantly decreased after Pa-PDT in KFs, and KFs with downregulation of RUNX3 showed significantly increased cell viability after Pa-PDT. Pa-PDT may be a potential therapeutic modality for keloids, and RUNX3, as a possible contributor to keloid pathogenesis, may improve sensitivity to Pa-PDT in KFs. PMID- 24957191 TI - [Laparoscopic oncological surgery of the lower gastrointestinal tract: state of evidence]. PMID- 24957190 TI - Association of thoracic epidural analgesia with risk of atrial arrhythmias after pulmonary resection: a retrospective cohort study. AB - PURPOSE: Atrial arrhythmias are common after non-cardiac thoracic surgery. We tested the hypothesis that TEA reduces the risk of new-onset atrial arrhythmias after pulmonary resection. METHODS: We evaluated patients who had pulmonary resection. New-onset atrial arrhythmias detected before hospital discharge was our primary outcome. Secondary outcomes included other cardiovascular complications, pulmonary complications, time-weighted average pain score over 72 h, and duration of hospitalization. Patients with combination of general anesthesia and TEA were matched on propensity scores with patients given general anesthesia only. The matched groups were compared by use of logistic regression, linear regression, or Cox proportional hazards regression, as appropriate. RESULTS: Among 1,236 patients who had pulmonary resections, 937 received a combination of general anesthesia and TEA (TEA) and 299 received general anesthesia only (non-TEA). We successfully matched 311 TEA patients with 132 non TEA patients. We did not find a significant association between TEA and postoperative atrial arrhythmia (odds ratio (95 % CI) of 1.05 (0.50, 2.19), P = 0.9). TEA was not significantly associated with length of hospital stay or postoperative pulmonary complications (odds ratio (95 % CI) of 0.71 (0.22, 2.29), P = 0.47). TEA patients experienced fewer postoperative cardiovascular complications; although the association was not statistically significant (odds ratio (95 % CI) of 0.30 (0.06, 1.45), P = 0.06). Time-weighted average pain scores were similar in the two groups. CONCLUSION: TEA was not associated with reduced occurrence of postoperative atrial arrhythmia. Although postoperative pulmonary complications were similar with and without TEA, TEA patients tended to experience fewer cardiovascular complications. PMID- 24957193 TI - Luminescent gold and silver complexes with the monophosphane 1-(PPh2)-2-Me C2B10H10 and their conversion to gold micro- and superstructured materials. AB - Gold and silver complexes containing the monophosphane 1-PPh2-2-Me-l,2-C2B10H10 with different coordination numbers (2, 3) have been synthesized: [M(7,8-(PPh2)2 C2B9H10)(1-PPh2-2-Me-C2B10H10)] (M = Ag, Au) and [Au2(MU-1,n-C2B10H10)(1-PPh2-2 Me-C2B10H10)2] (n = 2, 12). Solid-state pyrolysis of [AuCl(1-PPh2-2-Me-C2B10H10)] and [Au2(MU-1,12-C2B10H10)(1-PPh2-2-Me-C2B10H10)2] in air and of solutions of [AuCl(1-PPh2-2-Me-C2B10H10)] deposited on silicon and silica at 800 degrees C results in single-crystal Au, confirmed by diffraction and SEM-EDS. The morphology of the pyrolytic products depends on the thermolytic conditions, and different novel 3-D superstructures or microcrystals are possible. We also propose a mechanism for the thermal conversion of these precursors to structural crystalline and phase pure materials. The presence of the carborane monophosphane seems to originate quenching of the luminescence at room temperature in the complexes [Au2(MU-1,n-C2B10H10)(1-PPh2-2-Me-C2B10H10)2], in comparison with other [Au2(MU-1,n-C2B10H10)L2] species (L = monophosphane). PMID- 24957192 TI - Dilution-stable PAMAM G1-grafted polyrotaxane supermolecules deliver gene into cells through a caveolae-dependent pathway. AB - Numerous preclinical studies have demonstrated that polycation mediated gene delivery systems successfully achieved efficient gene transfer into cells and animal models. However, results of their clinical trials to date have been disappointing. That self-assembled gene and polycation systems should be stable undergoing dilution in the body is one of the prerequisites to ensuring efficiency of gene transfer in clinical trials, but it was neglected in most preclinical studies. In this account, we developed the dilution-stable PAMAM G1 grafted polyrotaxane (PPG1) supermolecules in which PAMAM G1-grafted alpha cyclodextrins are threaded onto a PEG chain capped with hydrophobic adamantanamine. The PPG1/pDNA polyplex (approximate 100 nm in diameter) was very stable and kept its initial particle size and a uniform size distribution at ultrahigh dilution, whereas DNA/PEI 25K polyplex was above three times bigger at a 16-fold dilution than the initial size and their particle size distribution indicated multiple peaks mainly due to forming loose and noncompacted aggregates. PPG1 supermolecules showed significantly superior transfection efficiencies compared to either PEI 25K or Lipofectamine 2000 in most cell lines tested including normal cells (HEK293A) and cancer cells (Bel7402, HepG2, and HeLa). Furthermore, we found that the PPG1 supermolecules delivered DNA into HEK293A through a caveolae-dependent pathway but not a clathrin-dependent pathway as PEI 25K did. These findings raised the intriguing possibility that the caveolae dependent pathway of PPG1 supermolecule/pDNA polyplex avoiding lysosomal degradation was attributed to their high transfection efficiency. The dilution stable PPG1 supermolecule polyplex facilitating caveolae-dependent internalization has potential applications to surmount the challenges of high dilutions in the body and lysosomal degradation faced by most gene therapy clinical trials. PMID- 24957194 TI - The consensus-based approach for gene/enzyme replacement therapies and crystallization strategies: the case of human alanine-glyoxylate aminotransferase. AB - Protein stability is a fundamental issue in biomedical and biotechnological applications of proteins. Among these applications, gene- and enzyme-replacement strategies are promising approaches to treat inherited diseases that may benefit from protein engineering techniques, even though these beneficial effects have been largely unexplored. In the present study we apply a sequence-alignment statistics procedure (consensus-based approach) to improve the activity and stability of the human AGT (alanine-glyoxylate aminotransferase) protein, an enzyme which causes PH1 (primary hyperoxaluria type I) upon mutation. By combining only five consensus mutations, we obtain a variant (AGT-RHEAM) with largely enhanced in vitro thermal and kinetic stability, increased activity, and with no side effects on foldability and peroxisomal targeting in mammalian cells. The structure of AGT-RHEAM reveals changes at the dimer interface and improved electrostatic interactions responsible for increased kinetic stability. Consensus based variants maintained the overall protein fold, crystallized more easily and improved the expression as soluble proteins in two different systems [AGT and CIPK24 (CBL-interacting serine/threonine-protein kinase) SOS2 (salt-overly sensitive 2)]. Thus the consensus-based approach also emerges as a simple and generic strategy to increase the crystallization success for hard-to-get protein targets as well as to enhance protein stability and function for biomedical applications. PMID- 24957195 TI - Hydroxyl radical induced oxidation of theophylline in water: a kinetic and mechanistic study. AB - Oxidative destruction and mineralization of emerging organic pollutants by hydroxyl radicals (OH) is a well established area of research. The possibility of generating hazardous by-products in the case of OH reaction demands extensive investigations on the degradation mechanism. A combination of pulse radiolysis and steady state photolysis (H2O2/UV photolysis) followed by high resolution mass spectrometric (HRMS) analysis have been employed to explicate the kinetic and mechanistic features of the destruction of theophylline, a model pharmaceutical compound and an identified pollutant, by OH in the present study. The oxidative destruction of this molecule, for intermediate product studies, was initially achieved by H2O2/UV photolysis. The transient absorption spectrum corresponding to the reaction of OH with theophylline at pH 6, primarily caused by the generation of (T8-OH), was characterised by an absorption band at 330 nm (k2 = (8.22 +/- 0.03) * 10(9) dm(3) mol(-1) s(-1)). A significantly different spectrum (lambdamax: 340 nm) was observed at highly alkaline pH (10.2) due to the deprotonation of this radical (pKa~ 10.0). Specific one electron oxidants such as sulphate radical anions (SO4(-)) and azide radicals (N3) produce the deprotonated form (T(-H)) of the radical cation (T(+)) of theophylline (pKa 3.1) with k2 values of (7.51 +/- 0.04) * 10(9) dm(3) mol(-1) s(-1) and (7.61 +/- 0.02) * 10(9) dm(3) mol(-1) s(-1) respectively. Conversely, oxide radicals (O(-)) react with theophylline via a hydrogen abstraction protocol with a rather slow k2 value of (1.95 +/- 0.02) * 10(9) dm(3) mol(-1) s(-1). The transient spectral studies were complemented by the end product profile acquired by HRMS analysis. Various transformation products of theophylline induced by OH were identified by this technique which include derivatives of uric acids (i, iv & v) and xanthines (ii, iii & vi). Further breakdown of the early formed product due to OH attack leads to ring opened compounds (ix-xiv). The kinetic and mechanistic data furnished in the present study serve as a basic frame work for the construction of OH induced water treatment systems as well as to understand the biological implications of compounds of this kind. PMID- 24957197 TI - Molecular packing determines singlet exciton fission in organic semiconductors. AB - Carrier multiplication by singlet exciton fission enhances photovoltaic conversion efficiencies in organic solids. This decay of one singlet exciton into two triplet states allows the extraction of up to two electrons per harvested photon and, hence, promises to overcome the Shockley-Queisser limit. However, the microscopic mechanism of singlet exciton fission, especially the relation between molecular packing and electronic response, remains unclear, which therefore hampers the systematic improvement of organic photovoltaic devices. For the model system perfluoropentacene, we experimentally show that singlet exciton fission is greatly enhanced for a slip-stacked molecular arrangement by addressing different crystal axes featuring different packing schemes. This reveals that the fission process strongly depends on the intermolecular coupling: slip-stacking favors delocalization of excitations and allows for efficient exciton fission, while face-to-edge molecular orientations commonly found in the prevailing herringbone molecular stacking patterns even suppress it. Furthermore, we clarify the controversially debated role of excimer states as intermediary rather than competitive or precursory. Our detailed findings serve as a guideline for the design of next-generation molecular materials for application in future organic light-harvesting devices exploiting singlet exciton fission. PMID- 24957196 TI - 'Nobody really gets it': a qualitative exploration of youth mental health in deprived urban areas. AB - AIM: To examine the experience of developing and living with mental health and substance use disorders among young people living in urban-deprived areas in Ireland to inform primary care interventions. METHOD: Semi-structured qualitative interviews with 20 young adults attending health and social care agencies in two deprived urban areas, and analysed using thematic analysis. RESULTS: Five themes were identified: experiencing symptoms, symptom progression, delay accessing help, loss of control/crisis point, and consequences of mental health and substance use disorders. As young people delayed help, symptoms disrupted normal life progression and they found themselves unable to engage in everyday activities, and living with reduced potential. Living in deprived areas influenced the development of problems: many had added stressors, less familial support and early exposure to violence, addiction and bereavement. CONCLUSION: Young people in urban-deprived areas are especially vulnerable to mental health and substance use disorders. Early identification in primary care appears necessary in halting symptom and illness progression, improving young people's chances of achieving their potential. PMID- 24957199 TI - Ipsilesional and contralesional regions participate in the improvement of poststroke aphasia: a transcranial direct current stimulation study. AB - In the past few years, noninvasive cerebral stimulations have been used to modulate language task performance in healthy and aphasic patients. In this study, a dual transcranial direct current stimulation (tDCS) on anterior and posterior language areas was applied for 2 weeks to a patient with a possible crossed aphasia following a right hemisphere stroke. Inhibitory cathodal stimulation of the right Brodmann areas (BA) 44/45 and simultaneous anodal stimulation of the left BA 44/45 improved the patient's performance in picture naming. Conversely, the same bilateral montage on BA 39/40 did not produce any significant improvement; finally, electrode polarity inversion over BA 39/40 yielded a further improvement compared with the first anterior stimulation. Our findings suggest that ipsilesional and contralesional areas could be useful in poststroke functional reorganization and provide new evidences for the therapeutic value of tDCS in aphasia. PMID- 24957198 TI - The role of CT analyses of the sternal end of the clavicle and the first costal cartilage in age estimation. AB - The ossification patterns of medial clavicle and the first costal cartilage represent interesting features of the same anatomical region which are accessible for conventional radiographic and computed tomography (CT) examinations in the same field of view. This study encompassed Serbian population and was carried out to examine whether CT analyses of medial clavicle and the first costal cartilage could be successfully applied, either individually or conjointly, in the age assessment. The study was based on CT examinations of thoracic region of 154 patients, aged between 15 and 35 years. Besides radiodensity and stages of epiphyseal cartilage ossification of medial clavicle, the study detected other features that expressed significant correlation with age, such as calculated anterior to posterior cortical thickness ratio, medullar canal diameter, and clavicular shaft diameter. However, although calculated ossified and calcified linear projections' (OCP) stages correlated to age, the distinction between stages was not satisfying. The interaction between the ossification status of medial clavicle and OCP was not significantly influenced by age. The results of our study outlined interesting new age predictors with mutual relationship: acquired radio density of the sternal epiphyseal-metaphyseal region and radio density of the first costal cartilage. Intersex variability was observed in several age-related features: calculated anterior to posterior cortical thickness ratio, diameter of medullar canal, and diameter of the clavicular shaft. Altogether, our study identified several radiological features of the first costal cartilage and medial clavicle that correlated with age and which could be applied as additional guidance for age estimation in each specific case. PMID- 24957200 TI - Deep brain stimulation for the treatment of epilepsy: circuits, targets, and trials. AB - Deep brain stimulation (DBS) has proven remarkably safe and effective in the treatment of movement disorders. As a result, it is being increasingly applied to a range of neurologic and psychiatric disorders, including medically refractory epilepsy. This review will examine the use of DBS in epilepsy, including known targets, mechanisms of neuromodulation and seizure control, published clinical evidence, and novel technologies. Cortical and deep neuromodulation for epilepsy has a long experimental history, but only recently have better understanding of epileptogenic networks, precise stereotactic techniques, and rigorous trial design combined to improve the quality of available evidence and make DBS a viable treatment option. Nonetheless, underlying mechanisms, anatomical targets, and stimulation parameters remain areas of active investigation. PMID- 24957202 TI - Angiotensin receptor type 2 activation induces neuroprotection and neurogenesis after traumatic brain injury. AB - Angiotensin II receptor type 2 (AT(2)) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT(2) was also linked to induced neuronal proliferation and differentiation in vitro. In this study, we examined the therapeutic potential of AT(2) activation following traumatic brain injury (TBI) in mice, a brain pathology that displays ischemia like secondary damages. The AT(2) agonist CGP42112A was continuously infused immediately after closed head injury (CHI) for 3 days. We have followed the functional recovery of the injured mice for 35 days post-CHI, and evaluated cognitive function, lesion volume, molecular signaling, and neurogenesis at different time points after the impact. We found dose-dependent improvement in functional recovery and cognitive performance after CGP42112A treatment that was accompanied by reduced lesion volume and induced neurogenesis in the neurogenic niches of the brain and also in the injury region. At the cellular/molecular level, CGP42112A induced early activation of neuroprotective kinases protein kinase B (Akt) and extracellular-regulated kinases 1/2 (ERK1/2), and the neurotrophins nerve growth factor and brain-derived neurotrophic factor; all were blocked by treatment with the AT(2) antagonist PD123319. Our results suggest that AT(2) activation after TBI promotes neuroprotection and neurogenesis, and may be a novel approach for the development of new drugs to treat victims of TBI. PMID- 24957204 TI - Electrical control of large magnetization reversal in a helimagnet. AB - Reversal of magnetization M by an electrical field E has been a long-sought phenomenon in materials science because of its potential for applications such as memory devices. However, the phenomenon has rarely been achieved and remains a considerable challenge. Here we report the large M reversal by E in a multiferroic Ba0.5Sr1.5Zn2(Fe0.92Al0.08)12O22 crystal without any external magnetic field. Upon sweeping E through the range of +/-2 MV m(-1), M varied quasi-linearly in the range of +/-2 MUB per f.u., resulting in the M reversal. Strong electrical modulation of M at zero magnetic field were observable up to ~?n150 K. Nuclear magnetic resonance measurements provided microscopic evidence that the electric field and the magnetic field play equivalent roles in modulating the volume of magnetic domains. Our results suggest that the soft ferrimagnetism and the associated transverse conical state are key ingredients to achieve the large magnetization reversal at fairly high temperatures. PMID- 24957203 TI - Uralsaponins M-Y, antiviral triterpenoid saponins from the roots of Glycyrrhiza uralensis. AB - Thirteen new oleanane-type triterpenoid saponins, uralsaponins M-Y (1-13), and 15 known analogues (14-28) were isolated from the roots of Glycyrrhiza uralensis Fisch. The structures of 1-13 were identified on the basis of extensive NMR and MS data analyses. The sugar residues were identified by gas chromatography and ion chromatography coupled with pulsed amperometric detection after hydrolysis. Saponins containing a galacturonic acid (1-3) or xylose (5) residue are reported from Glycyrrhiza species for the first time. Compounds 1, 7, 8, and 24 exhibited good inhibitory activities against the influenza virus A/WSN/33 (H1N1) in MDCK cells with IC50 values of 48.0, 42.7, 39.6, and 49.1 MUM, respectively, versus 45.6 MUM of the positive control oseltamivir phosphate. In addition, compounds 24 and 28 showed anti-HIV activities with IC50 values of 29.5 and 41.7 MUM, respectively. PMID- 24957205 TI - Evaluation of magical thinking: validation of the Illusory Beliefs Inventory. AB - Magical thinking has been related to obsessive-compulsive disorder; yet, little research has examined this construct in other anxiety disorders. The Illusory Beliefs Inventory (IBI) is a recently developed measure of magical thinking. The aim of this study was to investigate the psychometric properties of this new measure and to determine if magical thinking accounts for pathological worry beyond the well-researched constructs of intolerance of uncertainty (IU) and perfectionism. A sample of 502 participants completed an online survey. Confirmatory factor analysis identified a three-factor solution for the IBI, and the measure had good internal consistency (alpha = .92), test-retest reliability (r = .94) and discriminant validity. Magical thinking, IU, and perfectionism all predicted pathological worry; however, magical thinking accounted for less than 1% of unique variance in worry, suggesting that it is not strongly related to worry. Further investigation regarding the validity and clinical utility of the IBI is required. PMID- 24957201 TI - Heterogeneity of leucine-rich repeat kinase 2 mutations: genetics, mechanisms and therapeutic implications. AB - Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD. PMID- 24957206 TI - The role of targeted therapy for gastrointestinal tumors. AB - Many targeted drugs have been studied to target the molecular pathways involved in the development of gastrointestinal cancers. Anti-VEGF, anti-EGFR agents, and recently also multi-kinase inhibitor regorafenib, have already been available for the treatment of metastatic colorectal cancer patients. To date, Her-2 positive, gastric cancer patients, are also treated with trastuzumab, while the multi targeted inhibitor, sorafenib, represents the standard treatment for hepatocellular carcinoma patients. Finally, sunitinib and everolimus, have been approved for the treatment of the neuroendocrine gastroenteropancreatic tumors. Actually a great number of further drugs are under preclinical and clinical development. The aim of this review is to provide a comprehensive overview of the state of art, focusing on the new emerging strategies in the personalized treatment of gastrointestinal tumors. PMID- 24957208 TI - The CROWN initiative: journal editors invite researchers to develop core outcomes in women's health. AB - Clinical trials, systematic reviews and guidelines compare beneficial and non beneficial outcomes following interventions. Often, however, various studies on a particular topic do not address the same outcomes, making it difficult to draw clinically useful conclusions when a group of studies is looked at as a whole. This problem was recently thrown into sharp focus by a systematic review of interventions for preterm birth prevention, which found that among 103 randomised trials, no fewer than 72 different outcomes were reported. There is a growing recognition among clinical researchers that this variability undermines consistent synthesis of the evidence, and that what is needed is an agreed standardised collection of outcomes--a "core outcomes set"--for all trials in a specific clinical area. Recognising that the current inconsistency is a serious hindrance to progress in our specialty, the editors of over 50 journals related to women's health have come together to support The CROWN (CoRe Outcomes in WomeN's health) Initiative. PMID- 24957207 TI - Vitamin E supplementation modifies adaptive responses to training in rat skeletal muscle. AB - Aim of the present study was to test, by vitamin E treatment, the hypothesis that muscle adaptive responses to training are mediated by free radicals produced during the single exercise sessions. Therefore, we determined aerobic capacity of tissue homogenates and mitochondrial fractions, tissue content of mitochondrial proteins and expression of factors (PGC-1, NRF-1, and NRF-2) involved in mitochondrial biogenesis. Moreover, we determined the oxidative damage extent, antioxidant enzyme activities, and glutathione content in both tissue preparations, mitochondrial ROS production rate. Finally we tested mitochondrial ROS production rate and muscle susceptibility to oxidative stress. The metabolic adaptations to training, consisting in increased muscle oxidative capacity coupled with the proliferation of a mitochondrial population with decreased oxidative capacity, were generally prevented by antioxidant supplementation. Accordingly, the expression of the factors involved in mitochondrial biogenesis, which were increased by training, was restored to the control level by the antioxidant treatment. Even the training-induced increase in antioxidant enzyme activities, glutathione level and tissue capacity to oppose to an oxidative attach were prevented by vitamin E treatment. Our results support the idea that the stimulus for training-induced adaptive responses derives from the increased production, during the training sessions, of reactive oxygen species that stimulates the expression of PGC-1, which is involved in mitochondrial biogenesis and antioxidant enzymes expression. On the other hand, the observation that changes induced by training in some parameters are only attenuated by vitamin E treatment suggests that other signaling pathways, which are activated during exercise and impinge on PGC-1, can modify the response to the antioxidant integration. PMID- 24957209 TI - Microinjection free delivery of miRNA inhibitor into zygotes. AB - The development of gene delivery systems into embryos is challenging due to technical difficulties, delivery efficiency and toxicity. Here, we developed an organic compound (VisuFect)-mediated gene delivery system for zygotes. The VisuFect, which is hydrophilic and Cy5.5-labeled, was conjugated with poly(A) oligo (VFA). The VFA into CHO cells showed clathrin-mediated internalization and no toxicity. The VFA successfully penetrated through the zona pellucida of fertilized eggs of various species including pigs, zebrafish, drosophilas and mice. The experiment with VisuFect-mediated delivery of the miR34c inhibitor showed similar results with direct microinjection of the miR34c inhibitor by suppressing the development of zygotes up to the blastocyst stage. Noticeable features of the VisuFect will provide great benefits for further studies on gene function in sperms and embryos. PMID- 24957211 TI - Perturbed angular correlation studies of uniaxial compressive stressed zinc, titanium, rutile, Ti2AlN, and Nb2AlC. AB - We use the perturbed angular correlation method with (111)In-(111)Cd probe atoms to in situ study the changes in the electric field gradient at room temperature of polycrystalline Ti(2)AlN and Nb(2)AlC, titanium and zinc, and rutile samples, as a function of cyclic uniaxial compressive loads. The load dependence of the quadrupole coupling constant nuQ was found to be large in titanium and zinc but small in Ti(2)AlN, Nb(2)AlC and rutile. Reversible and irreversible increases in the electric field gradient distribution widths were found under load and after releasing the load, respectively. Annihilation of dislocations, as well as elastic deformation, are considered to contribute to the reversible behavior. The irreversible response must be caused by a permanent increase in dislocation and point defect densities. The deformation induced broadening of the electric field gradient can be recovered by post-annealing of the deformed sample. PMID- 24957210 TI - Efficacy of citric acid denture cleanser on the Candida albicans biofilm formed on poly(methyl methacrylate): effects on residual biofilm and recolonization process. AB - BACKGROUND: It is well known that the use of denture cleansers can reduce Candida albicans biofilm accumulation; however, the efficacy of citric acid denture cleansers is uncertain. In addition, the long-term efficacy of this denture cleanser is not well established, and their effect on residual biofilms is unknown. This in vitro study evaluated the efficacy of citric acid denture cleanser treatment on C. albicans biofilm recolonization on poly(methyl methacrylate) (PMMA) surface. METHODS: C. albicans biofilms were developed for 72 h on PMMA resin specimens (n = 168), which were randomly assigned to 1 of 3 cleansing treatments (CTs) overnight (8 h). CTs included purified water as a control (CTC) and two experimental groups that used either a 1:5 dilution of citric acid denture cleanser (CT5) or a 1:8 dilution of citric acid denture cleanser (CT8). Residual biofilms adhering to the specimens were collected and quantified at two time points: immediately after CTs (ICT) and after cleaning and residual biofilm recolonization (RT). Residual biofilms were analyzed by quantifying the viable cells (CFU/mL), and biofilm architecture was evaluated by confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Denture cleanser treatments and evaluation periods were considered study factors. Data were analyzed using two-way ANOVA and Tukey's Honestly Significant Difference (HSD) test (alpha = 0.05). RESULTS: Immediately after treatments, citric acid denture cleansing solutions (CT5 and CT8) reduced the number of viable cells as compared with the control (p < 0.01). However, after 48 h, both CT groups (CT5 and CT8) showed biofilm recolonization (p < 0.01). Residual biofilm recolonization was also detected by CLSM and SEM analysis, which revealed a higher biomass and average biofilm thickness for the CT8 group (p < 0.01). CONCLUSION: Citric acid denture cleansers can reduce C. albicans biofilm accumulation and cell viability. However, this CT did not prevent biofilm recolonization. PMID- 24957212 TI - Regulation of wound healing and fibrosis by hypoxia and hypoxia-inducible factor 1. AB - Wound healing is a complex multi-step process that requires spatial and temporal orchestration of cellular and non-cellular components. Hypoxia is one of the prominent microenvironmental factors in tissue injury and wound healing. Hypoxic responses, mainly mediated by a master transcription factor of oxygen homeostasis, hypoxia-inducible factor-1 (HIF-1), have been shown to be critically involved in virtually all processes of wound healing and remodeling. Yet, mechanisms underlying hypoxic regulation of wound healing are still poorly understood. Better understanding of how the wound healing process is regulated by the hypoxic microenvironment and HIF-1 signaling pathway will provide insight into the development of a novel therapeutic strategy for impaired wound healing conditions such as diabetic wound and fibrosis. In this review, we will discuss recent studies illuminating the roles of HIF-1 in physiologic and pathologic wound repair and further, the therapeutic potentials of HIF-1 stabilization or inhibition. PMID- 24957214 TI - The influence of water pH on the genesis of cadmium-induced cancer in a rat model. AB - Cadmium is a heavy metal that is widely used in industry and can cause tumours in multiple organs. The purpose of our study was to investigate the effect of water pH in the genesis of cadmium-induced cancer. We divided 98 male Wistar rats into 7 groups: group A - 15 rats that received cadmium chloride (CdCl2- 400 mg/L) in their drinking water at a neutral pH of 7.0; group B - 15 rats that received CdCl2(400 mg/L) in their drinking water at an acidic pH of 5.0; group C - 15 rats that received CdCl2(400 mg/L) in their drinking water at a basic pH of 8.0; group D - 15 rats that received water at an acidic pH of 5.0; group E - 15 rats that received water at a basic pH of 8.0; group F - 15 rats that received water at a neutral pH of 7.0; and group G - 8 rats that were subcutaneously injected with a single dose of cyclophosphamide (50 mg/kg). Groups A through F were euthanised 6 months after the start of the experiment and group G was euthanised 24 hours after cyclophosphamide injection. We collected the liver, kidneys, pancreas, prostate, seminal vesicles and testes for histopathological analysis and the bone marrow for micronuclei testing. In all of the groups, neither neoplastic lesions nor an increase in micronuclei (p>0.05) were observed in the liver, kidney, pancreas, seminal vesicles and testes. We found that animals exposed to cadmium had grade one prostatic intraepithelial neoplasia, but this was found more frequently in animals from group B (p<0.05). The acidic pH increased the formation of pre-neoplastic lesions in the prostate glands of cadmium-exposed animals. PMID- 24957213 TI - Neuronal activity-dependent regulation of MicroRNAs. AB - MicroRNAs are non-coding short (~23 nucleotides) RNAs that mediate post transcriptional regulation through sequence-specific gene silencing. The role of miRNAs in neuronal development, synapse formation and synaptic plasticity has been highlighted. However, the role of neuronal activity on miRNA regulation has been less focused. Neuronal activity-dependent regulation of miRNA may fine-tune gene expression in response to synaptic plasticity and memory formation. Here, we provide an overview of miRNA regulation by neuronal activity including high throughput screening studies. We also discuss the possible molecular mechanisms of activity-dependent induction and turnover of miRNAs. PMID- 24957216 TI - Is evening dosing of antihypertensive therapy ready for prime time? PMID- 24957215 TI - The ability of an oral formulation of afoxolaner to block the transmission of Babesia canis by Dermacentor reticulatus ticks to dogs. AB - BACKGROUND: Canine babesiosis due to Babesia canis is an endemic disease in many European countries. A vaccine is available in some countries, but it does not prevent the infection and just helps in reducing the gravity of clinical signs. Therefore, the major way to help preventing the disease is by controlling tick infestations on dogs.To assess the preventive efficacy of afoxolaner (NexGard(r)), a new oral anti- flea and tick product, against Babesia canis infected adult Dermacentor reticulatus in an experimentally controlled study. METHODS: Sixteen healthy mixed breed adult dogs, negative for Babesia canis antibodies were included in a single centre, randomized, blinded and controlled study to evaluate the impact of treatment with afoxolaner on the transmission of Babesia canis to dogs exposed to Dermacentor reticulatus. The dogs were randomly allocated into two groups of 8 dogs each. One group remained untreated. In the other group, dogs were treated orally with a novel formulation of afoxolaner (NexGard(r)) on day 0. All dogs were infested each by 50 adult Dermacentor reticulatus ticks (equal sex ratio) at days 7, 14, 21 and 28. The Dermacentor reticulatus ticks were confirmed to harbour Babesia canis by Polymerase Chain Reaction (PCR). RESULTS: The treatment was well tolerated by all dogs without any adverse effects. Babesia canis was transmitted by D. reticulatus to all untreated control dogs, confirmed following demonstration of hyperthermia, detection of B. canis parasites in blood smears and PCR assay from blood and serology. These confirmed infected dogs were subsequently treated with imidocarb and diminazene. The treated dogs remained negative based on all criteria until the last study, Day 56, confirming that the oral treatment of dogs with NexGard(r) prevented transmission of Babesia canis and development of clinical babesiosis for up to 28 days. CONCLUSION: This is the first demonstration that an oral acaricidal treatment may prevent the transmission of a pathogen despite the need for the tick to attach and start feeding before being killed by the acaricide. PMID- 24957217 TI - Exogenous and endogenous hyaluronic acid reduces HIV infection of CD4(+) T cells. AB - Preventing mucosal transmission of HIV is critical to halting the HIV epidemic. Novel approaches to preventing mucosal transmission are needed. Hyaluronic acid (HA) is a major extracellular component of mucosa and the primary ligand for the cell surface receptor CD44. CD44 enhances HIV infection of CD4(+) T cells, but the role of HA in this process is not clear. To study this, virions were generated with CD44 (HIVCD44) or without CD44 (HIVmock). Exogenous HA reduced HIV infection of unstimulated CD4(+) T cells in a CD44-dependent manner. Conversely, hyaluronidase-mediated reduction of endogenous HA on the cell surface enhanced HIV binding to and infection of unstimulated CD4(+) T cells. Exogenous HA treatment reduced activation of protein kinase C alpha via CD44 on CD4(+) T cells during infection with HIVCD44. These results reveal new roles for HA during the interaction of HIV with CD4(+) T cells that may be relevant to mucosal HIV transmission and could be exploitable as a future strategy to prevent HIV infection. PMID- 24957219 TI - Parents as Teachers Health Literacy Demonstration project: integrating an empowerment model of health literacy promotion into home-based parent education. AB - The Parents as Teachers (PAT) Health Literacy Demonstration project assessed the impact of integrating data-driven reflective practices into the PAT home visitation model to promote maternal health literacy. PAT is a federally approved Maternal, Infant, Early Childhood Home Visiting program with the goal of promoting school readiness and healthy child development. This 2-year demonstration project used an open-cohort longitudinal design to promote parents' interactive and reflective skills, enhance health education, and provide direct assistance to personalize and act on information by integrating an empowerment paradigm into PAT's parent education model. Eight parent educators used the Life Skills Progression instrument to tailor the intervention to each of 103 parent child dyads. Repeated-measures analysis of variance, paired t tests, and logistic regression combined with qualitative data demonstrated that mothers achieved overall significant improvements in health literacy, and that home visitors are important catalysts for these improvements. These findings support the use of an empowerment model of health education, skill building, and direct information support to enable parents to better manage personal and child health and health care. PMID- 24957218 TI - The deficiency of Galphaq leads to enhanced T-cell survival. AB - We have previously reported that Galphaq, the alpha subunit of the Gq protein, had important roles in dendritic cell migration, B-cell survival and autoimmunity. In this study, we showed that the deficiency of Galphaq led to enhanced T-cell survival. Cultured Gnaq(-/-) T cells exhibited survival advantages both in medium alone and in the presence of anti-CD3 stimulation. Gnaq(-/-) T cells still exhibited a survival advantage when they were cultured in the presence of interleukin (IL)-2 or IL-7. Gnaq(-/-) T cells were more resistant to activation-induced cell death (AICD) in vitro. The survival advantage of Gnaq( /-) T cells was further confirmed by transferring T cells into syngeneic hosts in vivo. Galphaq deficiency might promote T-cell survival by upregulated Bcl-xL expression and downregulated Fas and FasL expressions. Furthermore, upon T-cell receptor (TCR) ligation, Akt activity was increased in Gnaq(-/-) T cells in comparison with wild-type (WT) T cells. The survival advantage of Gnaq(-/-) T cells was significantly attenuated after adding Akt inhibitor. Taken together, our data demonstrated a negative role of Galphaq in regulating T-cell survival. PMID- 24957220 TI - Alcohol tax pass-through across the product and price range: do retailers treat cheap alcohol differently? AB - BACKGROUND AND AIMS: Effective use of alcohol duty to reduce consumption and harm depends partly on retailers passing duty increases on to consumers via price increases, also known as 'pass-through'. The aim of this analysis is to provide evidence of UK excise duty and sales tax (VAT) pass-through rates for alcohol products at different price points. SETTING: March 2008 to August 2011, United Kingdom. DESIGN AND MEASUREMENTS: Panel data quantile regression estimating the effects of three duty changes, two VAT changes and one combined duty and VAT change on UK alcohol prices, using product-level supermarket price data for 254 alcohol products available weekly. Products were analysed in four categories: beers, ciders/ready to drink (RTDs), spirits and wines. FINDINGS: Within all four categories there exists considerable heterogeneity in the level of duty pass through for cheaper versus expensive products. Price increases for the cheapest 15% of products fall below duty rises (undershifting), while products sold above the median price are overshifted (price increases are higher than duty increases). The level of undershifting is greatest for beer [0.85 (0.79, 0.92)] and spirits [0.86 (0.83, 0.89)]. Undershifting affects approximately 67% of total beer sales and 38% of total spirits sales. CONCLUSIONS: Alcohol retailers in the United Kingdom appear to respond to increases in alcohol tax by undershifting their cheaper products (raising prices below the level of the tax increase) and overshifting their more expensive products (raising prices beyond the level of the tax increase). This is likely to impact negatively on tax policy effectiveness, because high-risk groups favour cheaper alcohol and undershifting is likely to produce smaller consumption reductions. PMID- 24957221 TI - Accumulation of STIM1 is associated with the degenerative muscle fibre phenotype in ALS and other neurogenic atrophies. AB - AIM: Upon denervation, skeletal muscle fibres initiate complex changes in gene expression. Many of these genes are involved in muscle fibre remodelling and atrophy. Amyotrophic lateral sclerosis (ALS) leads to progressive neurodegeneration and neurogenic muscular atrophy (NMA). Disturbed calcium homeostasis and misfolded protein aggregation both in motor neurones and muscle fibres are key elements of ALS pathogenesis that are mutually interdependent. Therefore, we hypothesized that the calcium sensor STIM1 might be abnormally modified and involved in muscle fibre degeneration in ALS and other types of NMA. METHODS: We examined ALS and NMA patient biopsy and autopsy tissue and tissue from G93A SOD1 mice by immunohistochemistry and immunoblotting. RESULTS: In normal human and mouse muscle STIM1 was found to be differentially expressed in muscle fibres of different types and to concentrate at neuromuscular junctions, compatible with its known role in calcium sensing. Denervated muscle fibres of sALS and NMA cases and SOD1 mice showed diffusely increased STIM1 immunoreactivity along with ubiquitinated material. In addition, distinct focal accumulations of STIM1 were observed in target structures within denervated fibres of sALS and other NMA as well as SOD1 mouse muscles. Large STIM1 immunoreactive structures were found in ALS-8 patient muscle harbouring the P56S mutation in the ER protein VAPB. CONCLUSION: These findings suggest that STIM1 is involved in several ways in the reaction of muscle fibres to denervation, probably reflecting alterations in calcium homeostasis in denervated muscle fibres. PMID- 24957222 TI - Summaries for patients. Screening for abdominal aortic aneurysm: U.S. Preventive Services Task Force recommendation statement. PMID- 24957225 TI - Enzymatic synthesis and purification of a defined RIG-I ligand. AB - Receptor-based nucleic acid sensing constitutes one of the most fundamental mechanisms of our innate immune system to sense viral infection. RIG-I is a cytosolic RNA helicase that senses the presence of 5' triphosphate RNA species, a common feature of many negative strand RNA viruses. We here describe a protocol to enzymatically synthesize and to purify a defined RIG-I ligand that can be used to study RIG-I activation in vitro and in vivo. PMID- 24957224 TI - Detection of RNA modifications by HPLC analysis and competitive ELISA. AB - Over 100 different RNA modifications exist that are introduced posttranscriptionally by enzymes at specific nucleotide positions. Ribosomal RNA (rRNA) and transfer RNA (tRNA) exhibit the most and diverse modifications that presumably optimize their structure and function. In contrast, oxidative damage can lead to random modifications in rRNA and messenger RNA (mRNA) that strongly impair functionality. RNA modifications have also been implicated in avoiding self-RNA recognition by the immune system or immune evasion by pathogens. Here, we describe the detection of RNA modifications by HPLC analysis and competitive ELISA. PMID- 24957226 TI - Crystallization of mouse RIG-I ATPase domain: in situ proteolysis. AB - RIG-I is a key pattern recognition receptor that recognizes cytoplasmic viral RNA. Upon ligand binding, it undergoes a conformational change that induces an active signaling conformation. However, the details of this conformational change remain elusive until high-resolution crystal structures of different functional conformations are available. X-ray crystallography is a powerful tool to study structure-function relationships, but crystallization is often the limiting step of the method. Here, we describe the in situ in-drop proteolysis of RIG-I that yielded crystals of the ATPase domain of mouse RIG-I suitable for structure determination. PMID- 24957227 TI - Isolation of RIG-I-associated RNAs from virus-infected cells. AB - When a novel innate pattern recognition receptor (PRR) is identified, a question comes up immediately: Which molecular pattern(s) can it recognize? One approach that can be taken to answer this question for nucleic acid-binding receptors is the detailed analysis of synthetic ligands (DNA, RNA, or hybrids) to narrow in on the minimal patterns that activate a given receptor. However, this may not always lead to a satisfying answer. A complementary albeit technically more demanding way to tackle this question is to examine which nucleic acids are actually bound by the receptor in a setting of cellular infection. Here, we describe a basic protocol to isolate RNAs bound to the RNA receptors of the RIG-I-like helicase family from virus-infected cells via immunoprecipitation (IP). The isolated RNA can then be used to analyze its origin, characteristics, and immunostimulatory properties with a variety of methods. PMID- 24957223 TI - Changes in breast cancer risk distribution among Vermont women using screening mammography. AB - BACKGROUND: Screening mammography utilization in Vermont has declined since 2009 during a time of changing screening guidelines and increased interest in personalized screening regimens. This study evaluates whether the breast cancer risk distribution of the state's screened population changed during the observed decline. METHODS: We examined the breast cancer risk distribution among screened women between 2001 and 2012 using data from the Vermont Breast Cancer Surveillance System. We estimated each screened woman's 5-year risk of breast cancer using the Breast Cancer Surveillance Consortium risk calculator. Annual screening counts by risk group were normalized and age-adjusted to the Vermont female population by direct standardization. RESULTS: The normalized rate of low risk (5-year breast cancer risk of <1%) women screened increased 8.3% per year (95% confidence interval [CI] = 4.8 to 11.9) between 2003 and 2008 and then declined by -5.4% per year (95% CI = -8.1 to -2.6) until 2012. When stratified by age group, the rate of low-risk women screened declined -4.4% per year (95% CI = 8.8 to 0.1; not statistically significant) for ages 40 to 49 years and declined a statistically significant -7.1% per year (95% CI = -12.1 to -2.0) for ages 50 to 74 years during 2008 to 2012. These declines represented the bulk of overall decreases in screening after 2008, with rates for women categorized in higher risk levels generally exhibiting small annual changes. CONCLUSIONS: The observed decline in women screened in Vermont in recent years is largely attributable to reductions in screening visits by women who are at low risk of developing breast cancer. PMID- 24957228 TI - Structure modeling of Toll-like receptors. AB - Toll-like receptors (TLRs) recognize invasion of microbial pathogens and initiate innate immune responses that are essential for inhibiting pathogen dissemination and for the development of acquired immunity. To understand how these receptors work, it is crucial to investigate them from a structural perspective. High throughput genome sequencing projects have led to the identification of more than 3,000 TLR sequences. However, only several structures of TLRs have been determined because structure determination by X-ray diffraction or nuclear magnetic resonance spectroscopy experiments remains difficult and time-consuming. Protein structure modeling methods are powerful tools for bridging the gap between sequence determination and structure determination. Due to different repeat numbers and distinct arrangements of leucine-rich repeats (LRRs) contained in TLR ectodomains, an automated homology modeling method often failed to predict a proper model. Here, we describe an LRR template assembly method for homology modeling of TLRs. This method was successfully validated through the comparison of a predicted model with the crystal structures, and showed better performance than other Protein structure modeling tools. The resulting models can be used to perform protein-ligand interaction studies or to design mutagenesis experiments, and hence to investigate TLR ligand-binding mechanisms. PMID- 24957230 TI - Viral nucleic acid recognition in human nonimmune cells: in vitro systems. AB - The innate immune system detects viral infections through a variety of receptors that sense the virus via their nucleic acid genome and evokes initial antiviral responses. Nonimmune cells possess pathogen-recognition mechanisms that enable them to respond to virus by the expression of RNA or DNA recognition receptors, thereby initiating the first steps in the host-pathogen interaction and inducing the production of pro-inflammatory and antiviral mediators. To better understand the activation of innate-immune defense mechanisms by nonimmune cells, we describe an experimental procedure that mimics viral infection, using four human nonimmune cell culture models under stimulation with synthetic analogues of RNA and DNA virus. Furthermore, we exemplify two viral infection models using cultured nonimmune cells and hepatitis C virus (HCV) or polyomavirus BK (BKV). In addition, we report the importance of siRNA technique in gene regulation in order to identify specific markers involved in innate antiviral responses in these cells. PMID- 24957229 TI - Nucleic acid recognition in dendritic cells. AB - The immune system consists of specialized cell types with distinct functions in order to provide an effective innate and adaptive immune defense against harmful invading pathogens like bacteria, viruses, fungi, parasites, or other substances threatening the integrity of the organism. Once the immune system recognizes such pathogens via pattern recognition receptors (PRRs), they are taken up, processed, and presented as antigens on MHC class I and II to T lymphocytes by specialized cells called dendritic cells (DCs). At the same time pathogen components which bind to PRRs in DCs trigger potent cytokine and chemokine responses. Although other cell types like macrophages can also take up, process, and present antigens to naive T lymphocytes, DCs are the cells with the greatest capacity to do so. Thus, DCs are also called professional antigen presenting cells (APCs), which induce a strong adaptive immune response and thereby act as a bridge between the innate and adaptive immune system. This chapter provides detailed instructions on how to generate various types of DCs from human peripheral blood mononuclear cells (PBMCs) and murine bone marrow, as well as stimulation conditions for activation of these cells by PRR ligands in vitro. PMID- 24957231 TI - Analysis of nucleic acid-induced nonimmune cell death in vitro. AB - Foreign nucleic acids are recognized by germ-line-encoded receptors expressed in immune and nonimmune cells. Activation of the nucleic acid-specific pattern recognition receptors by foreign nucleic acid promotes production of inflammatory cytokines (mostly type I IFNs) and at the later stage leads to cell death. Here, we describe reliable and simple methods to quantify cell death caused by nucleic acid recognition. Additionally, we report two different methods to discriminate between two cell death modalities: apoptosis and necrosis. PMID- 24957232 TI - In vitro analysis of nucleic acid recognition in B lymphocytes. AB - In contrast to murine B cells, Toll-like receptor (TLR) expression in human B cells is mainly restricted to endosomally localized TLR7 and -9, receptors for RNA and DNA, respectively. Most importantly, B lymphocytes lack classical phagocytic receptors and instead internalize antigen only via the B cell receptor (BCR), a surface immunoglobulin specific for a defined antigen. BCR ligation triggers internalization of particulate antigens and physically associated molecules among them bacterial DNA or RNA. Thereby, this process provides access to endosomal nucleic acid-sensing TLRs. Co-stimulation of BCR and TLR ultimately leads to T cell-independent B cell activation. Here, we explain how this process can be experimentally mimicked in human peripheral blood B cells, e.g., using a microsphere-based system that promotes uptake of nucleic acid-based TLR ligands via BCR engagement. PMID- 24957233 TI - Mapping of optimal CD8 T cell epitopes. AB - Defining the optimal epitope of a CD8 T cell response towards a certain antigen is a multistep procedure that requires the performance of peptide truncation design, ELISPOT peptide titration assays, and assessing the HLA class I restriction of the defined epitope via intracellular cytokine staining assays with B cell lines and epitope-specific CD8 T cell lines. PMID- 24957234 TI - A modular approach to suppression assays: TLR ligands, conditioned medium, and viral infection. AB - The suppressive function of regulatory T-cells (Treg) requires precise control to allow an efficient adaption of the T-cell response to the requirements of the immune defense. In the setting of infection, an abrogation of the suppressive effect of Treg on the activation and proliferation of T-effector (Teff) cells is a central precondition to allow fast and efficient clearance of the infectious agent. Experimentally, the suppressive function of Treg on Teff can be indirectly measured in coculture proliferation assays. This versatile tool provides a readout of T cell proliferation in the presence of Treg through the measurement of a proliferation marker such as the incorporation of radioactively labeled thymidine ((3)H Thymidine), carboxyfluorescein succinimidyl ester (CFSE) or 5 Bromo-2'-deoxyuridine (BrdU). In a modular approach, the culture conditions can thereby be adapted to evaluate the effect of any cell type, live and inactivated microorganisms, molecularly defined immunostimulatory ligands, and cytokines on the interplay of Teff and Treg function. Here, we demonstrate how the suppression assay can be used as a multifunctional tool to provide insights into the interaction of Treg with Teff under a variety of conditions in vitro. PMID- 24957235 TI - MicroRNA methodology: advances in miRNA technologies. AB - There is an emerging trend in microRNA research and thus substantial progress in microRNA technologies. In this chapter we provide insights into the main microRNA specific methodologies and critical steps of microRNA expression profiling, target gene identification, and functional confirmation of microRNA effects up to in vivo application of antagomirs. PMID- 24957236 TI - Expression profiling by real-time quantitative polymerase chain reaction (RT qPCR). AB - Real-time quantitative PCR is a variation of the standard PCR technique that is commonly used to quantify nucleic acid. However, in this technique the amount of amplified specific sequence can be quantified at each stage of the PCR cycle. If investigated sequence is present in large number of copies in particular sample, amplification product is detected already in earlier cycles; if the sequence is rare, amplification is observed in later cycles. Quantification of amplified product is acquired using fluorescent probes or fluorescent DNA-binding dyes. Accumulation of fluorescent signal can be measured by real-time PCR instruments during each of 35-45 cycwwles of the PCR reaction, which simplify the procedure by eliminating the visualization of the amplified products using gel electrophoresis. Real-time-PCR allows quantifying the amount of product already during the PCR reaction as soon as it is detectable. Correctly performed, this method may be used for precise gene expression analysis in life science, medicine, and diagnostics and has become the standard method of choice for the quantification of mRNA. However in the past few years it became obvious that real time PCR is complex and variability of RNA templates, assay designs, inappropriate data normalization, and data interpretation may cause diverse analytical problems. PMID- 24957237 TI - Evaluating the role of nucleic acid antigens in murine models of systemic lupus erythematosus. AB - Impaired apoptotic cell clearance is thought to contribute to the pathogenesis of systemic autoimmune disease, in particular systemic lupus erythematosus (SLE). Endogenous RNA- and DNA-containing autoantigens released from dying cells can engage Toll-like receptors (TLR) 7/8 and TLR9, respectively in a number of immune cell types, thereby promoting innate and adaptive immune responses. Mouse models of lupus reliably phenocopy many of the characteristic features of SLE in humans and these models have proved invaluable in defining disease mechanisms. TLR7 signaling is essential for the development of autoantibodies to RNA and RNA associated proteins like Sm and RNP, while TLR9 signaling is important for the development of antibodies to DNA and chromatin. TLR7 deficiency ameliorates end organ disease, but, surprisingly, TLR9 deficiency exacerbates disease, possibly as a result of TLR7 overactivity in TLR9-deficient mice. Deficiency of interferon regulatory factor 5 (IRF5) inhibits autoantibody production and ameliorates disease likely due to its role in both TLR7 and TLR9 signaling. In this report we describe methods to analyze two commonly used mouse models of SLE in which TLRs and/or IRF5 have been shown to play a role in disease pathogenesis. PMID- 24957238 TI - Induction and analysis of nephrotoxic serum nephritis in mice. AB - The nephrotoxic serum nephritis (NTN) model is an integral part of experimental glomerulonephritis (GN) research. Here, we discuss how the murine NTN model can be induced and effectively used to mimic an immune complex-mediated GN. Further, we differentiate between heterologous and autologous models by comparing pathophysiology and phenotypic manifestations. PMID- 24957239 TI - Isolation of intratumoral leukocytes of TLR-stimulated tumor-bearing mice. AB - Toll-like receptor (TLR) ligands hold promise for cancer immunotherapy. The isolation of intratumoral leukocytes of tumor-bearing mice is a useful technique for analyzing the immunological effects of TLR ligands on the tumor microenvironment. These isolated immune cells can be directly used for analysis (e.g., by flow cytometry) or cultured for functional in vitro studies. Here, we describe the isolation of intratumoral leukocytes by density gradient centrifugation. This technique can be used to isolate leukocytes from freshly dissected murine tumors. PMID- 24957240 TI - Bifunctional siRNAs for tumor therapy. AB - Double-stranded RNA molecules carrying a triphosphate moiety represent a molecular structure by which the host recognizes viral infections. Such RNA molecules can be generated synthetically by chemical synthesis or by in vitro transcription (see Chapter 2, Hornung et al.). Similar to viruses, they initiate an antiviral immune response, e.g., by stimulation of the immune system. Short, double-stranded RNA in the cytosol can also trigger the RNA interference mechanism, which also has been considered as an antiviral response. Notably, synthetic RNAs that are designed to be specific for a certain host mRNA inhibit expression of the respective gene, leading to specific gene silencing. Both effects-gene silencing and immunostimulation-are interesting from a therapeutic perspective, e.g., for cancer therapy. Notably, both effects can be activated by a single molecule, an siRNA carrying a triphosphate moiety. This chapter provides information how to design such compounds with respect to the associated signaling pathways and the techniques to evaluate bifunctional RNAs in the context of tumor therapy. PMID- 24957242 TI - Alkylation or Silylation for Analysis of Amino and Non-Amino Organic Acids by GC MS? AB - Gas chromatography-mass spectrometry (GC-MS) is a widely used analytical technique in metabolomics. GC provides the highest resolution of any standard chromatographic separation method, and with modern instrumentation, retention times are very consistent between analyses. Electron impact ionization and fragmentation is generally reproducible between instruments and extensive libraries of spectra are available that enhance the identification of analytes. The major limitation is the restriction to volatile analytes, and hence the requirement to convert many metabolites to volatile derivatives through chemical derivatization. Here we compared the analytical performance of two derivatization techniques, silylation (TMS) and alkylation (MCF), used for the analysis of amino and non-amino organic acids as well as nucleotides in microbial-derived samples. The widely used TMS derivatization method showed poorer reproducibility and instability during chromatographic runs while the MCF derivatives presented better analytical performance. Therefore, alkylation (MCF) derivatization seems to be preferable for the analysis of polyfunctional amines, nucleotides and organic acids in microbial metabolomics studies. PMID- 24957244 TI - Role of cereal secondary metabolites involved in mediating the outcome of plant pathogen interactions. AB - Cereal crops such as wheat, rice and barley underpin the staple diet for human consumption globally. A multitude of threats to stable and secure yields of these crops exist including from losses caused by pathogens, particularly fungal. Plants have evolved complex mechanisms to resist pathogens including programmed cell death responses, the release of pathogenicity-related proteins and oxidative bursts. Another such mechanism is the synthesis and release of secondary metabolites toxic to potential pathogens. Several classes of these compounds have been identified and their anti-fungal properties demonstrated. However the lack of suitable analytical techniques has hampered the progress of identifying and exploiting more of these novel metabolites. In this review, we summarise the role of the secondary metabolites in cereal crop diseases and briefly touch on the analytical techniques that hold the key to unlocking their potential in reducing yield losses. PMID- 24957245 TI - Would current international agreements prevent a pandemic? PMID- 24957243 TI - Volatile metabolites. AB - Volatile organic compounds (volatiles) comprise a chemically diverse class of low molecular weight organic compounds having an appreciable vapor pressure under ambient conditions. Volatiles produced by plants attract pollinators and seed dispersers, and provide defense against pests and pathogens. For insects, volatiles may act as pheromones directing social behavior or as cues for finding hosts or prey. For humans, volatiles are important as flavorants and as possible disease biomarkers. The marine environment is also a major source of halogenated and sulfur-containing volatiles which participate in the global cycling of these elements. While volatile analysis commonly measures a rather restricted set of analytes, the diverse and extreme physical properties of volatiles provide unique analytical challenges. Volatiles constitute only a small proportion of the total number of metabolites produced by living organisms, however, because of their roles as signaling molecules (semiochemicals) both within and between organisms, accurately measuring and determining the roles of these compounds is crucial to an integrated understanding of living systems. This review summarizes recent developments in volatile research from a metabolomics perspective with a focus on the role of recent technical innovation in developing new areas of volatile research and expanding the range of ecological interactions which may be mediated by volatile organic metabolites. PMID- 24957246 TI - WHO-histological criteria for myeloproliferative neoplasms: reproducibility, diagnostic accuracy and correlation with gene mutations and clinical outcomes. AB - Bone marrow histology is included in the diagnostic criteria of myeloproliferative neoplasms (MPNs). However, some concerns have emerged about its reproducibility. To evaluate the diagnostic accuracy of histology and to assess its correlation with presence of mutations and clinical outcomes, two pathologists reviewed the bone marrow biopsies corresponding to 211 patients with MPN. Despite the low agreement in the evaluation of individual histopathological characteristics, the concordance among pathologists when establishing the diagnosis was good (Kappa index 0.67). The specificity of histology was 100%, 98.5% and 98% in polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF), respectively, whereas the sensitivity of histological diagnosis was low in PV and ET (32.5% and 54% respectively) and acceptable in PMF (75%). Thirteen out of 146 (9%) patients with clinical ET were diagnosed as prefibrotic PMF. No histological agreement or MPN otherwise unspecified was more frequently observed in JAK2 V617F-positive ET than in CALR mutated cases, whereas megakaryocytic abnormalities and prefibrotic PMF were more frequently observed in CALR-mutated ET. In conclusion, histological criteria of MPN have a limited diagnostic accuracy due to low sensitivity. Patients with JAK2 V617F-positive MPN have a heterogeneous histology while CALR-positive ET is associated with megakaryocyte abnormalities and prefibrotic PMF. PMID- 24957248 TI - Colorimetric and luminescent bifunctional Ru(II) complexes for rapid and highly sensitive recognition of cyanide. AB - Four ruthenium(II) complexes, [Ru(bpy)2L1](PF6)2, [Ru(bpy)2L2](PF6)2, [Ru(dmb)2L1](PF6)2, and [Ru(dmb)2L2](PF6)2, where bpy = 2,2'-bipyridine, dmb = 4,4'-dimethyl-2,2'-bipyridine, L1 = 4-methyl-2,2'-bipyridine-4'-carboxaldehyde, and L2 = 4,4'-diformyl-2,2'-bipyridine, have been characterized for sensing cyanide based on the well-known formation of cyanohydrins. The structure of [Ru(dmb)2L2](PF6)2 is also determined by single crystal X-ray diffraction. Their cyanide anion binding properties in pure and aqueous acetonitrile solution were thoroughly examined by UV-Vis absorption and photoluminescence (PL) spectroscopy. Upon the addition of cyanide to the solution of ruthenium(II) complexes at 298 K, a color change from orange to yellow and a luminescent variation from dark red to red-orange can be observed by the naked eye. The large blue shift of the absorption and emission spectra and significant enhancement of the emission intensity upon the addition of cyanide could be attributed to the formation of a cyanohydrin group by the selective reaction of the aldehyde group of the ruthenium(II) complexes with cyanide. Importantly, these kinds of ruthenium(II) complexes show a unique recognition of cyanide ions over other anions. The results reveal that this kind of ruthenium(II) complex containing an aldehyde group is an eligible sensor for cyanide anions. PMID- 24957247 TI - Ozone dosing alters the biological potential and therapeutic outcomes of plasma rich in growth factors. AB - BACKGROUND AND OBJECTIVE: Until now, ozone has been used in a rather empirical way. This in-vitro study investigates, for the first time, whether different ozone treatments of plasma rich in growth factors (PRGF) alter the biological properties and outcomes of this autologous platelet-rich plasma. MATERIAL AND METHODS: Human plasma rich in growth factors was treated with ozone using one of the following protocols: a continuous-flow method; or a syringe method in which constant volumes of ozone and PRGF were mixed. In both cases, ozone was added before, during and after the addition of calcium chloride. Three ozone concentrations, of the therapeutic range 20, 40 and 80 MUg/mL, were tested. Fibrin clot properties, growth factor content and the proliferative effect on primary osteoblasts and gingival fibroblasts were evaluated. RESULTS: Ozone treatment of PRGF using the continuous flow protocol impaired formation of the fibrin scaffold, drastically reduced the levels of growth factors and significantly decreased the proliferative potential of PRGF on primary osteoblasts and gingival fibroblasts. In contrast, treatment of PRGF with ozone using the syringe method, before, during and after the coagulation process, did not alter the biological outcomes of the autologous therapy. CONCLUSION: These findings suggest that ozone dose and the way that ozone combines with PRGF may alter the biological potential and therapeutic outcomes of PRGF. PMID- 24957249 TI - Asymmetric Stetter reactions catalyzed by thiamine diphosphate-dependent enzymes. AB - The intermolecular asymmetric Stetter reaction is an almost unexplored transformation for biocatalysts. Previously reported thiamine diphosphate (ThDP) dependent PigD from Serratia marcescens is the first enzyme identified to catalyze the Stetter reaction of alpha,beta-unsaturated ketones (Michael acceptor substrates) and alpha-keto acids. PigD is involved in the biosynthesis of the potent cytotoxic agent prodigiosin. Here, we describe the investigation of two new ThDP-dependent enzymes, SeAAS from Saccharopolyspora erythraea and HapD from Hahella chejuensis. Both show a high degree of homology to the amino acid sequence of PigD (39 and 51 %, respectively). The new enzymes were heterologously overproduced in Escherichia coli, and the yield of soluble protein was enhanced by co-expression of the chaperone genes groEL/ES. SeAAS and HapD catalyze intermolecular Stetter reactions in vitro with high enantioselectivity. The enzymes possess a characteristic substrate range with respect to Michael acceptor substrates. This provides support for a new type of ThDP-dependent enzymatic activity, which is abundant in various species and not restricted to prodigiosin biosynthesis in different strains. Moreover, PigD, SeAAS, and HapD are also able to catalyze asymmetric carbon-carbon bond formation reactions of aldehydes and alpha-keto acids, resulting in 2-hydroxy ketones. PMID- 24957250 TI - Insight into hyaluronic acid molecular weight control. AB - Hyaluronic acid (HA) is a ubiquitous polysaccharide found in humans, animals, bacteria, algae and molluscs. Simple yet sophisticated, HA demonstrates unique and valuable rheological properties. In solution, HA behaves as a stiffened random coil and the resultant behaviour, even at low concentrations, is far from Newtonian or 'ideal'. These rheological properties are heavily influenced by molecular weight (MW), so it is not surprising that many of the biological functions of HA are dependent on molecular size. The current billion dollar market for HA continues to grow rapidly, both in gross production and the number of applications for its use. Increasing demand, in conjunction with a reticence to use animal-derived HA, has revitalised the market for HA produced by bacterial fermentation. Although the genes and pathways involved in bacterial production of HA are well characterised, the mechanisms that underlie HA MW control are less well understood. By performing a thorough analysis of the proposed mechanisms of MW control in bacterial fermentation, this mini-review tries to elucidate the challenges and future directions for bacterial HA biosynthesis. PMID- 24957251 TI - Oxidative stress response in Pseudomonas putida. AB - Pseudomonas putida is widely distributed in nature and is capable of degrading various organic compounds due to its high metabolic versatility. The survival capacity of P. putida stems from its frequent exposure to various endogenous and exogenous oxidative stresses. Oxidative stress is an unavoidable consequence of interactions with various reactive oxygen species (ROS)-inducing agents existing in various niches. ROS could facilitate the evolution of bacteria by mutating genomes. Aerobic bacteria maintain defense mechanisms against oxidative stress throughout their evolution. To overcome the detrimental effects of oxidative stress, P. putida has developed defensive cellular systems involving induction of stress-sensing proteins and detoxification enzymes as well as regulation of oxidative stress response networks. Genetic responses to oxidative stress in P. putida differ markedly from those observed in Escherichia coli and Salmonella spp. Two major redox-sensing transcriptional regulators, SoxR and OxyR, are present and functional in the genome of P. putida. However, the novel regulators FinR and HexR control many genes belonging to the E. coli SoxR regulon. Oxidative stress can be generated by exposure to antibiotics, and iron homeostasis in P. putida is crucial for bacterial cell survival during treatment with antibiotics. This review highlights and summarizes current knowledge of oxidative stress in P. putida, as a model soil bacterium, together with recent studies from molecular genetics perspectives. PMID- 24957252 TI - Probing the shielding properties of aptameric protective groups. AB - Site-specific derivatization of chemically equivalent functional groups has recently been facilitated by the introduction of high-affinity aptamers as non covalent protective groups. More specifically, a series of RNA aptamers have proven to be highly efficient in enhancing the regioselectivity of reactions with the aminoglycoside antibiotic neomycin B, which carries several chemically indistinguishable amino and hydroxy groups. Since small-molecule targets tend to exhibit multiple modes of binding with a single aptamer, the impact of secondary binding sites on the regioselectivity should be considered. To address this issue, we investigated a series of well-characterized RNA aptamers that bind neomycin B and propose a mechanism that accounts for the regioselective outcome of these transformations. We further demonstrate that the regioselectivity induced by non-covalent aptamer protective groups is determined by the number of binding sites, their affinity, and the mode of interaction with the guest molecule. PMID- 24957253 TI - Mental disorders and mental health service use across Asian American subethnic groups in the United States. AB - This study analyzed the National Epidemiological Survey on Alcohol and Related Conditions data, 2001-2002, to compare the prevalence and odds of DSM-IV mood, anxiety, and substance use disorders and mental health service use across Asian American subethnic groups (648 East Asians, 485 Southeast Asians, 298 South Asians). Asian American subethnic groups varied in lifetime prevalence of psychiatric disorders (p=0.004), mainly due to differences in the presence of any substance use disorder (p=0.06), and specifically, drug use disorders (p=0.02). While Southeast Asians had the highest prevalence of substance use disorders (16.7%), fewer Southeast Asians with substance use disorders used mental health services (11.1%) compared to South Asians with substance use disorders (24.2%). East Asians compared to South Asians had significantly lower odds of mental health service use for substance use disorders (confidence interval=0.08-0.84). Asian American subethnic groups vary in the prevalence of mental disorders and in mental health service use, especially for substance use disorders. PMID- 24957254 TI - Interaction of one anthraquinone derivative with ctDNA analyzed by spectroscopic and modeling methods. AB - The interaction of one anthraquinone derivative (AOMan) with calf thymus deoxyribonucleic acid (ctDNA) was systematically investigated at physiological pH 7.4 by fluorescence spectroscopy and molecular modeling. Binding constants of ctDNA with AOMan were calculated at different temperatures. Thermodynamic parameters, enthalpy and entropy changes were calculated according to Van't Hoff equation, which indicated that the reaction was spontaneous and predominantly enthalpically driven. The increasing viscosity of ctDNA indicated that AOMan could intercalate into the base pairs of ctDNA. This conclusion was also demonstrated by the results obtained from KI quenching, denatured DNA studies and fluorescence polarization experiment. Furthermore, the molecular modeling results showed that anthraquinone ring tended to slide into the G-C rich region of ctDNA through the hydrogen bond, which are consistent with the results from experimental methods. Studying the binding interaction of target anthraquinones with DNA is one of the key steps in their DNA-changing action and the design of new drugs. PMID- 24957255 TI - The first clinical application of the spiral intestinal lengthening and tailoring (silt) in extreme short bowel syndrome. AB - AIM: Spiral Intestinal Lengthening and Tailoring (SILT) invented by our team is a new technique that offers minimal mesenteric handling and a more physiological result compared to the STEP procedure. Its feasibility has been tested in animal models and now we report the first successful human application in extreme short bowel syndrome. MATERIALS AND METHODS: A 3-year-old girl suffered subtotal loss of her small bowel and ileocaecal junction as a result of midgut volvulus. Only 15 cm of jejunum remained intact. Parenteral nutrition (PN), gastrostomy feeding, controlled bowel expansion and SILT procedure were applied. RESULTS: The length of the jejunum increased from the initial 15 to 22 cm during 12 months of PN and bowel expansion. Eleven centimeter of distended bowel was further lengthened up to 20 cm by SILT giving a total small bowel length of 31 cm. Oral and gastrostomy feedings were commenced 5 days postoperatively. There were no surgical complications 6 months after the procedure. The patient's liver function was preserved, she was weaned off PN, discharged from hospital, but remained on gastrostomy top up feeding. The net weight gain of the patient was 1,800 g 6 months after the procedure. CONCLUSION: SILT procedure is a safe and feasible technique for human intestinal lengthening and tailoring. PMID- 24957256 TI - Health utility of patients with advanced gastrointestinal stromal tumors (GIST) after failure of imatinib and sunitinib: findings from GRID, a randomized, double blind, placebo-controlled phase III study of regorafenib versus placebo. AB - BACKGROUND: In this analysis we report patients with advanced gastrointestinal stromal tumors (GIST) refractory to imatinib and sunitinib therapy as derived from the EuroQol-5D (EQ-5D) for progression-free (PF) and progressive disease health status. METHODS: Data were analyzed from a phase III trial conducted at 57 hospitals in 17 countries (trial registration number, NCT01271712). Patients with advanced GIST were randomized (2:1) to receive blinded treatment using oral regorafenib 160 mg daily or placebo, plus best supportive care (BSC) in both groups, for the first 3 weeks of each 4-week cycle. EQ-5D-3L was administered on day 1 of each cycle before contact with their physician and before any study related procedures. The effect of disease progression on the utility of EQ-5D was tested with paired-samples comparison and general linear mixed modeling (GLMM). RESULTS: One hundred and eighty five patients [93 % of the intention-to-treat (ITT) population] completed 803 EQ-5D questionnaires: 77.7 % in progression-free (PF) state, 6.5 % at progression, 13.9 % following first progression, and 1.9 % after second progression. Mean baseline utility was 0.767 (SD 0.221) with no significant between-group differences for active treatment and BSC. The first post-progression health state was 0.647 (SD 0.343), suggesting significantly impaired health-related quality of life after confirmed disease progression showed a decrease of -0.120 (paired samples t test, p = 0.001). GLMM showed no effect of study treatment or cycle number on utility. CONCLUSIONS: We demonstrate a significant and clinically meaningful difference in health state utility values between PF and progression. Utility values remained stable over successive regorafenib cycles after controlling for disease status and treatment type. PMID- 24957257 TI - The connection between language and the world: a paradox of the linguistic turn? AB - Alex Gillespie and Flora Cornish draw on the dialogic turn as they consider that, in order to interpret the meaning of an utterance, it is necessary to emphasize its contextual nature. Among other aspects, they address what context is and what is being done while speaking. Taking these two issues as point of departure, it is worth pondering on (1) what revolves around language and what the status of nonlinguistic semiotic systems is for the philosophers of language, (2) Umberto Eco's critique of the Philosophy of Language, which has not problematized the pre linguistic relationship with things, and (3) how ontogenesis may shed light on this scheme where linguistic and nonlinguistic aspects are inevitably interrelated. I will reflect on the pragmatic aspects in adult-child communication at its pre-linguistic level. I will underscore the key role played by the object as a complex referent and as a tool for communication. PMID- 24957258 TI - Optimal surgical care for adolescent idiopathic scoliosis: an international consensus. AB - PURPOSE: The surgical management of adolescent idiopathic scoliosis (AIS) has seen many developments in the last two decades. Little high-level evidence is available to support these changes and guide treatment. This study aimed to identify optimal operative care for adolescents with AIS curves between 40 degrees and 90 degrees Cobb angle. METHODS: From July 2012 to April 2013, the AOSpine Knowledge Forum Deformity performed a modified Delphi survey where current expert opinion from 48 experienced deformity surgeons, representing 29 diverse countries, was gathered. Four rounds were performed: three web-based surveys and a final face-to-face meeting. Consensus was achieved with >= 70% agreement. Data were analyzed qualitatively and quantitatively. RESULTS: Consensus of what constitutes optimal care was reached on greater than 60 aspects including: preoperative radiographs; posterior as opposed to anterior (endoscopic) surgical approaches; use of intraoperative spinal cord monitoring; use of local autologous bone (not iliac crest) for grafts; use of thoracic and lumbar pedicle screws; use of titanium anchor points; implant density of <80% for 40 degrees -70 degrees curves; and aspects of postoperative care. Variability in practice patterns was found where there was no consensus. In addition, there was consensus on what does not constitute optimal care, including: routine pre- and intraoperative traction; routine anterior release; use of bone morphogenetic proteins; and routine postoperative CT scanning. CONCLUSIONS: International consensus was found on many aspects of what does and does not constitute optimal operative care for adolescents with AIS. In the absence of current high-level evidence, at present, these expert opinion findings will aid health care providers worldwide define appropriate care in their regions. Areas with no consensus provide excellent insight and priorities for future research. PMID- 24957260 TI - The clinicopathological features associated with skip N2 metastases in patients with clinical stage IA non-small-cell lung cancer. AB - OBJECTIVES: Understanding the clinicopathological features of patients with skip N2 metastases (SN2) in clinical early stage lung cancer is important for surgical planning and other treatment considerations; however, the factors associated with SN2 are unclear. This study aimed to investigate the clinicopathological features associated with SN2 in patients with clinical stage IA (cIA) non-small-cell lung cancer (NSCLC). METHODS: We retrospectively studied patients with cIA NSCLC who underwent pulmonary resection (at least lobectomy) and extensive lymphadenectomy (more than ND2a-1) at our institution between January 2004 and December 2010. We investigated the following factors for their association with SN2: age; sex; tumour marker (carcinoembryonic antigen); tumour size on computed tomography (CT), evaluated with a lung-window (LW) and a mediastinal-window (MW) setting; pathology, with or without adenocarcinoma; differentiation; visceral pleural invasion (VPI) and vascular/lymphatic invasion. RESULTS: In total, 422 patients were enrolled, with the following pathological node (pN) statuses: 331 pN0 (78.4%), 39 pN1 (9.3%) and 52 pN2 (12.3%). There were 21 (23.1%) SN2 cases among the patients with nodal metastases. When the cut-off level was defined as a receiver operating characteristic curve with MW (11.5 mm), the sensitivity and specificity of SN2 was 95.2% and 42.9%, respectively. VPI was a statistically independent relevant factor for SN2 in both the patients with cIA and in those with nodal involvement. The VPI classification comprised 59 PL-0 (64.8%), 12 PL-1 (13.2%) and 20 PL-2 (22.0%) with nodal metastases, and there was a significant difference between the three groups (P = 0.03) according to SN2 frequency. There was no difference between VPI 1 and 2 (P = 0.27). CONCLUSIONS: In conclusion, our study suggests that the incidence of SN2 is significantly associated with VPI in patients with cIA NSCLC. Although MW (>11.5 mm) had a low specificity in the assessment of SN2, it had a high sensitivity, suggesting the possibility of a superior benefit compared with LW. Standard hilar and mediastinal lymph node dissection should be required in patients with suspicious VPI and MW (>11.5 mm) on preoperative CT. PMID- 24957259 TI - Comparison between pain at discography and morphological disc changes at axial loaded MRI in patients with low back pain. AB - PURPOSE: Discogenic pain is induced by axial load, but there are no studies evaluating the influence of dynamic MRI in relation to provoked pain at discography. The aim of this study was to investigate the relationship between discography-induced pain and morphological disc changes, occurring during axial loaded MRI (alMRI). A secondary aim was to compare and register the frequency of provoked concordant pain at alMRI and discography. METHODS: 41 patients with assumed discogenic pain were investigated with MRI, alMRI and pressure-controlled discography (PCD) (119 discs). Provoked pain at both discography and alMRI was classified as concordant or discordant with daily pain as reference. A concordant discogram required pain intensity >=5/10 (numerical rating scale) at <=50 psi and one negative control disc. A concordant provocation at alMRI required pain intensity >=5/10. The relationship between concordant pain at discography and morphological disc measures (degeneration, height, bulge, angle, area, and circumference) at MRI/alMRI was investigated. RESULTS: Changes in the morphological appearance occurred in at least one disc level in all patients when loaded and unloaded MRI were compared. However, no significant differences between concordant and discordant discograms in terms of morphological disc features at conventional MRI or alMRI were found. 78 % of the patients reported concordant provoked pain during the alMRI. CONCLUSIONS: In the majority of patients with low back pain, discography as well as alMRI provoked concordant pain. Loading of the spine, alMRI, revealed however no clinically useful morphological characteristics in the discs with concordant discograms. Alternative or more sensitive diagnostic methods are needed to understand load induced discogenic pain. PMID- 24957261 TI - Refined indications will improve outcomes after frozen elephant trunk surgery. PMID- 24957264 TI - Small intestinal permeability in patients with eosinophilic oesophagitis during active phase and remission. AB - BACKGROUND: Eosinophilic oesophagitis (EoE) is presumed to be an isolated oesophageal disease; yet other allergic diseases associated with eosinophilic infiltration of target tissues, such as asthma and eczema, show perturbed functions of other sites that may be involved in the diathesis of allergy modulation. AIM: To analyse small intestinal permeability in patients with active EoE and in a separate group of patients in remission. METHODS: Small bowel permeability was determined using a dual sugar method by calculating lactulose:mannitol (L:M) ratio in 17 patients who met consensus criteria for active EoE (>15 eos/HPF) and 8 patients in remission (<5 eos/HPF). Data from 28 healthy controls was used for comparison. RESULTS: Patients with active EoE had significantly higher L:M ratios when compared to controls (0.045 vs. 0.033, p<0.001) and to EoE in remission (0.041 vs. 0.027, p<.001). There was no significant difference in L:M between the group with EoEin remission and healthy controls. The current data show that L:M ratio of 0.033 also provides a reasonable cut-off that defined the active EoE group compared to patients in remission. The main component explaining the change in L:M ratio was increased absorption (and excretion) of lactulose ((1601 +/- 106 ug) when compared to the EoE remission (969 +/- 91 ug) and control (1043 +/- 92 ug, p<.001) groups. CONCLUSIONS: Small bowel permeability is overall increased in patients with active EoE, and is normal in patients with EoE in remission when compared to healthy controls. The role of the small bowel in active EoE deserves further investigation. PMID- 24957262 TI - Mitochondrial metabolism, reactive oxygen species, and macrophage function fishing for insights. AB - Metabolism and defense mechanisms that protect against pathogens are two fundamental requirements for the survival of multicellular organisms. Research into metabolic disease has revealed these core mechanisms are highly co dependent. This emerging field of research, termed immunometabolism, focuses on understanding how metabolism influences immunological processes and vice versa. It is now accepted that obesity influences the immune system and that obesity driven inflammation contributes to many diseases including type 2 diabetes, cardiovascular disease and Alzheimer's disease. The immune response requires the reallocation of nutrients within immune cells to different metabolic pathways to satisfy energy demands and the production of necessary macromolecules. One aspect of immunometabolic research is understanding how these metabolic changes help regulate specific immune cell functions. It is hoped that further understanding of the pathways involved in managing this immunological-metabolic interface will reveal new ways to treat metabolic disease. Given their growing status as principle drivers of obesity-associated inflammation, monocytes/macrophages have received much attention when studying the consequences of inflammation within adipose tissue. Less is known regarding how metabolic changes within macrophages (metabolic reprogramming) influence their immune cell function. In this review, we focus on our current understanding of how monocytes/macrophages alter their intracellular metabolism during the immune response and how these changes dictate specific effector functions. In particular, the immunomodulatory functions of mitochondrial metabolism and mitochondrial reactive oxygen species. We also highlight how the attributes of the zebrafish model system can be exploited to reveal new mechanistic insights into immunometabolic processes. PMID- 24957263 TI - Ribavirin uptake into human hepatocyte HHL5 cells is enhanced by interferon-alpha via up-regulation of the human concentrative nucleoside transporter (hCNT2). AB - Ribavirin is a broad spectrum antiviral that increases the response rate in chronic hepatitis C patients when administered in combination with IFNalpha. Ribavirin is a purine nucleoside derivative, transported into hepatocytes by nucleoside transporters. hCNT2 is the best candidate to mediate ribavirin uptake into hepatocytes due to its high-affinity for purines and its capacity to concentrate its substrates intracellularly. The aim of this study was to determine whether hCNT2 function is under IFNalpha modulation. IFNalpha treatment of the nontransformed human hepatocyte-derived cell line HHL5 induced a rapid and transient increase in hCNT2 activity after cytokine addition. hCNT2 activity up regulation was associated with increased ribavirin accumulation into cells. This increase was consistent with the translocation of hCNT2-containing vesicles to the plasma membrane via a mechanism requiring ERK 1/2 and ROCK activation and cytoskeleton integrity. Longer treatments with IFNalpha induced transcriptional activation of the hCNT2-encoding gene (SLC28A2), resulting in a sustained increase in hCNT2-related activity. These observations are proof of concept for at least one of the putative mechanisms underlying the synergistic responses induced by combination therapy with IFNalpha and ribavirin. PMID- 24957266 TI - Predicting potential responses to future climate in an alpine ungulate: interspecific interactions exceed climate effects. AB - The altitudinal shifts of many montane populations are lagging behind climate change. Understanding habitual, daily behavioural rhythms, and their climatic and environmental influences, could shed light on the constraints on long-term upslope range-shifts. In addition, behavioural rhythms can be affected by interspecific interactions, which can ameliorate or exacerbate climate-driven effects on ecology. Here, we investigate the relative influences of ambient temperature and an interaction with domestic sheep (Ovis aries) on the altitude use and activity budgets of a mountain ungulate, the Alpine chamois (Rupicapra rupicapra). Chamois moved upslope when it was hotter but this effect was modest compared to that of the presence of sheep, to which they reacted by moving 89-103 m upslope, into an entirely novel altitudinal range. Across the European Alps, a range-shift of this magnitude corresponds to a 46% decrease in the availability of suitable foraging habitat. This highlights the importance of understanding how factors such as competition and disturbance shape a given species' realised niche when predicting potential future responses to change. Furthermore, it exposes the potential for manipulations of species interactions to ameliorate the impacts of climate change, in this case by the careful management of livestock. Such manipulations could be particularly appropriate for species where competition or disturbance already strongly restricts their available niche. Our results also reveal the potential role of behavioural flexibility in responses to climate change. Chamois reduced their activity when it was warmer, which could explain their modest altitudinal migrations. Considering this behavioural flexibility, our model predicts a small 15-30 m upslope shift by 2100 in response to climate change, less than 4% of the altitudinal shift that would be predicted using a traditional species distribution model-type approach (SDM), which assumes that species' behaviour remains unchanged as climate changes. Behavioural modifications could strongly affect how species respond to a changing climate. PMID- 24957265 TI - IL-9 and its receptor are predominantly involved in the pathogenesis of UC. AB - OBJECTIVE: Several pathogenic roles attributed over the past two decades to either T helper (Th)1 or Th2 cells are increasingly becoming associated with interleukin (IL)-17 and most recently IL-9 signalling. However, the implication of IL-9 in IBD has not been addressed so far. DESIGN: We investigated the expression of IL-9 and IL-9R by using peripheral blood, biopsies and surgical samples. We addressed the functional role of IL-9 signalling by analysis of downstream effector proteins. Using Caco-2 cell monolayers we followed the effect of IL-9 on wound healing. RESULTS: IL-9 mRNA expression was significantly increased in inflamed samples from patients with UC as compared with controls. CD3(+) T cells were major IL-9-expressing cells and some polymorphonuclear leucocytes (PMN) also expressed IL-9. IL-9 was co-localised with the key Th9 transcription factors interferon regulatory factor 4 and PU.1. Systemically, IL-9 was abundantly produced by activated peripheral blood lymphocytes, whereas its receptor was overexpressed on gut resident and circulating PMN. IL-9 stimulation of the latter induced IL-8 production in a dose-dependent manner and rendered PMN resistant to apoptosis suggesting a functional role for IL-9R signalling in the propagation of gut inflammation. Furthermore, IL-9R was overexpressed on gut epithelial cells and IL-9 induced STAT5 activation in these cells. Moreover, IL-9 inhibited the growth of Caco-2 epithelial cell monolayers in wound healing experiments. CONCLUSIONS: Our results provide evidence that IL-9 is predominantly involved in the pathogenesis of UC suggesting that targeting IL-9 might become a therapeutic option for patients with UC. PMID- 24957267 TI - Insights into substrate binding and catalysis in bacterial type I dehydroquinase. AB - Structural, biochemical and computational studies to study substrate binding and the role of the conserved residues of the DHQ1 (type I dehydroquinase) enzyme active site are reported in the present paper. The crystal structure of DHQ1 from Salmonella typhi in complex with (2R)-2-methyl-3-dehydroquinic acid, a substrate analogue, was solved at 1.5 A. The present study reveals a previously unknown key role for conserved Glu46, Phe145 and Met205 and Gln236, Pro234 and Ala233 residues, with the latter three being located in the flexible substrate-covering loop. Gln236 was shown to be responsible for the folding of this loop and for the dramatic reduction of its flexibility, which triggers active site closure. Glu46 was found to be key in bringing the substrate close to the lysine/histidine catalytic pocket to initiate catalysis. The present study could be useful in the rational design of inhibitors of this challenging and recognized target for the development of novel herbicides and antimicrobial agents. PMID- 24957268 TI - Synthesis of 2,3-dihydro-1H-indazoles by Rh(III)-catalyzed C-H cleavage of arylhydrazines. AB - A rhodium-catalyzed efficient method for the synthesis of 2,3-dihydro-1H indazoles is described. The reaction of arylhydrazines with olefins results in the corresponding 2,3-dihydro 1H-indazoles with exclusive regioselectivity via C H bond activation. The utility of the methodology is illustrated by a rapid synthesis of 1H-indazoles under mild reaction conditions in half an hour. PMID- 24957269 TI - Water-soluble luminescent cyclometalated gold(III) complexes with cis-chelating bis(N-heterocyclic carbene) ligands: synthesis and photophysical properties. AB - A new class of cyclometalated Au(III) complexes containing various bidentate C deprotonated C^N and cis-chelating bis(N-heterocyclic carbene) (bis-NHC) ligands has been synthesized and characterized. These are the first examples of Au(III) complexes supported by cis-chelating bis-NHC ligands. [Au(C^N)(bis-NHC)] complexes display emission in solutions under degassed condition at room temperature with emission maxima (lambdamax ) at 498-633 nm and emission quantum yields of up to 10.1 %. The emissions are assigned to triplet intraligand (IL) pi >pi* transitions of C^N ligands. The Au(III) complex containing a C^N (C deprotonated naphthalene-substituted quinoline) ligand with extended pi conjugation exhibits prompt fluorescence and phosphorescence of comparable intensity with lambdamax at 454 and 611 nm respectively. With sulfonate functionalized bis-NHC ligand, four water-soluble luminescent Au(III) complexes, including those displaying both fluorescence and phosphorescence, were prepared. They show similar photophysical properties in water when compared with their counterparts in acetonitrile. The long phosphorescence lifetime of the water soluble AuIII complex with C-deprotonated naphthalene-substituted quinoline ligand renders it to function as ratiometric sensor for oxygen. Inhibitory activity of one of these water-soluble Au(III) complexes towards deubiquitinase (DUB) UCHL3 has been investigated; this complex also displayed a significant inhibitory activity with IC50 value of 0.15 MUM. PMID- 24957270 TI - Variability in CRP, regulatory T cells and effector T cells over time in gynaecological cancer patients: a study of potential oscillatory behaviour and correlations. AB - BACKGROUND: The inflammatory marker, C reactive protein has been proposed to also be a biomarker for adaptive immune responses in cancer patients with a possible application in time based chemotherapy. Fluxes in serum CRP levels were suggested to be indicative of a cyclical process in which, immune activation is followed by auto-regulating immune suppression. The applicability of CRP as a biomarker for regulatory or effector T cells was therefore investigated in a cohort of patients with gynaecological malignancies. METHODS: Peripheral blood samples were obtained from a cohort of patients at 7 time points over a period of 12 days. Serum and mononuclear cells were isolated and CRP levels in serum were detected using ELISA while regulatory and effector T cell frequencies were assessed using flow cytometry. To test periodicity, periodogram analysis of data was employed while Pearson correlation and the Wilcoxon signed rank test were used to determine correlations. RESULTS: The statistical analysis used showed no evidence of periodic oscillation in either serum CRP concentrations or Teff and Treg frequencies. Furthermore, there was no apparent correlation between serum CRP concentrations and the corresponding frequencies of Tregs or Teffs. Relative to healthy individuals, the disease state in the patients neither significantly affected the mean frequency of Tregs nor the mean coefficient of variation within the Treg population over time. However, both Teff mean frequency and mean coefficient of variation were significantly reduced in patients. CONCLUSION: Using our methods we were unable to detect CRP oscillations that could be used as a consistent serial biomarker for time based chemotherapy. PMID- 24957272 TI - Redox and luminescent properties of robust and air-stable N-heterocyclic carbene group 4 metal complexes. AB - Robust and air-stable homoleptic group 4 complexes of the type M(L)2 [1-3; M = Ti, Zr, Hf; L = dianionic bis(aryloxide) N-heterocyclic carbene (NHC) ligand] were readily synthesized from the NHC proligand 1,3-bis(3,5-di-tert-butyl-2 hydroxyphenyl)imidazolinium chloride (H3L,Cl) and appropriate group 4 precursors. As deduced from cyclic voltammetry studies, the homoleptic bis-adduct zirconium and hafnium complexes 2 and 3 can also be oxidized, with up to four one-electron oxidation signals for the zirconium derivative 2 (three reversible signals). Electron paramagnetic resonance data for the one-electron oxidation of complexes 1-3 agree with the formation of ligand-centered species. Compounds 2 and 3 are luminescent upon excitation in the absorption band at 362 nm with emissions at 485 and 534 nm with good quantum yields (phi = 0.08 and 0.12) for 2 and 3, respectively. In contrast, the titanium complex 1 does not exhibit luminescent properties upon excitation in the absorption band at 310 and 395 nm. Complexes 2 and 3 constitute the first examples of emissive nonmetallocene group 4 metal complexes. PMID- 24957271 TI - Jumping-like translocation-a rare chromosomal rearrangement in a patient with Burkitt lymphoma/leukemia. AB - Chromosomal translocations are acquired genetic rearrangements in human cancers. Jumping translocations are rare nonreciprocal rearrangements involving the same donor chromosome segment translocated to two or more recipient chromosomes. In this report, we describe a patient with Burkitt lymphoma/leukemia (BL) and a complex karyotype including a t(2;8)(p12;q24), copy-neutral loss of heterozygosity at 17p13.1-p13.3 and 19q13.1-q13.2, trisomy 20, and two uncommon chromosomal aberrations. The first uncommon aberration was a complex rearrangement of chromosome 15 (probably the consequence of chromothripsis) masked by an apparently balanced reciprocal translocation, t(11;15)(p11.2;q21). The second one was a special type of unbalanced "vice versa" jumping translocation, which involved the same acceptor chromosome arm (13q) and various donor chromosome segments. It is unclear whether both atypical rearrangements are the consequence of the TP53 alteration or whether assumed chromothripsis influenced the development of the jumping-like translocation. However, the presence of the t(11;15)(p11.2;q21) in all pathological cells suggests that it occurred in the early stage of the disease, whereas the jumping-like translocation, as an additional change, subsequently accelerated the progression of the disease. PMID- 24957274 TI - Novel intelligent PID control of traveling wave ultrasonic motor. AB - A simple control strategy with acceptable control performance can be a good choice for the mass production of ultrasonic motor control system. In this paper, through the theoretic and experimental analyses of typical control process, a simpler intelligent PID speed control strategy of TWUM is proposed, involving only two expert rules to adjust the PID control parameters based on the current status. Compared with the traditional PID controller, this design requires less calculation and more cheap chips which can be easily involved in online performance. Experiments with different load torques and voltage amplitudes show that the proposed controller can deal with the nonlinearity and load disturbance to maintain good control performance of TWUM. PMID- 24957273 TI - A discrete time-varying internal model-based approach for high precision tracking of a multi-axis servo gantry. AB - In this paper, we consider the discrete time-varying internal model-based control design for high precision tracking of complicated reference trajectories generated by time-varying systems. Based on a novel parallel time-varying internal model structure, asymptotic tracking conditions for the design of internal model units are developed, and a low order robust time-varying stabilizer is further synthesized. In a discrete time setting, the high precision tracking control architecture is deployed on a Voice Coil Motor (VCM) actuated servo gantry system, where numerical simulations and real time experimental results are provided, achieving the tracking errors around 3.50/00 for frequency varying signals. PMID- 24957275 TI - Enhancing tilt range of electrostatic torsional micromirrors using robust adaptive critic-based neurofuzzy control. AB - Electrostatic torsional micromirrors, as instances of Micro Electro Mechanical Systems (MEMS), have many optical network applications; such as optical wavelength-selective switches, optical cross-connects, etc. For all these applications, the micromirror needs to have minimal overshoot and settling time in order to minimize the time between two successive switching operations. Moreover, the controllability and stability of a torsional micromirror are major challenges due to high nonlinearities in its dynamic characteristics. In this paper, a robust adaptive critic-based neurofuzzy controller is proposed for electrostatic torsional micromirrors, which can improve the performance of the mirror tilting and enhance the robustness of the system to any stochastic perturbations. Furthermore, utilizing this adaptive neurofuzzy controller, which is based on a proportional and derivative (PD) critic, the micromirror "pull-in" phenomenon is crucially eliminated. Thus, the mirror tilting range is significantly expanded. Moreover, the stability of the closed-loop system is guaranteed via the Lyapunov theorem. The robust adaptive critic-based neurofuzzy controller is simulated for a 1-DOF electrostatic torsional micromirror and the results show the effectiveness of this approach for various tilt ranges and conditions. In addition, the robustness of this controller is examined in the presence of input noises and parameter uncertainties. PMID- 24957276 TI - IMC-PID-fractional-order-filter controllers design for integer order systems. AB - One of the reasons of the great success of standard PID controllers is the presence of simple tuning rules, of the automatic tuning feature and of tables that simplify significantly their design. For the fractional order case, some tuning rules have been proposed in the literature. However, they are not general because they are valid only for some model cases. In this paper, a new approach is investigated. The fractional property is not especially imposed by the controller structure but by the closed loop reference model. The resulting controller is fractional but it has a very interesting structure for its implementation. Indeed, the controller can be decomposed into two transfer functions: an integer transfer function which is generally an integer PID controller and a simple fractional filter. PMID- 24957277 TI - Plant-wide process monitoring based on mutual information-multiblock principal component analysis. AB - Multiblock principal component analysis (MBPCA) methods are gaining increasing attentions in monitoring plant-wide processes. Generally, MBPCA assumes that some process knowledge is incorporated for block division; however, process knowledge is not always available. A new totally data-driven MBPCA method, which employs mutual information (MI) to divide the blocks automatically, has been proposed. By constructing sub-blocks using MI, the division not only considers linear correlations between variables, but also takes into account non-linear relations thereby involving more statistical information. The PCA models in sub-blocks reflect more local behaviors of process, and the results in all blocks are combined together by support vector data description. The proposed method is implemented on a numerical process and the Tennessee Eastman process. Monitoring results demonstrate the feasibility and efficiency. PMID- 24957278 TI - Lipase catalyzed inclusion of gastrodigenin for the evolution of blue light emitting peptide nanofibers. AB - We report lipase catalysed regioselective inclusion of gastrodigenin (p hydroxybenzyl alcohol: HBA) to a peptide Nmoc-Leu-Trp-OH at physiological pH 7.4. The resultant Nmoc-Leu-Trp-HBA from a reaction cycle of dissipative self-assembly evolves into blue light emitting peptide nanofibers. PMID- 24957279 TI - What nano can do for energy storage. PMID- 24957289 TI - Brain networks: the next steps. Comment on: "Understanding brain networks and brain organization" by Luiz Pessoa. PMID- 24957290 TI - Implementation is crucial but must be neurobiologically grounded. Comment on "Toward a computational framework for cognitive biology: unifying approaches from cognitive neuroscience and comparative cognition" by W. Tecumseh Fitch. PMID- 24957291 TI - Reporter cell activity within hydrogel constructs quantified from oxygen independent bioluminescence. AB - By providing a three-dimensional (3D) support to cells, hydrogels offer a more relevant in vivo tissue-like environment as compared to two-dimensional cell cultures. Hydrogels can be applied as screening platforms to investigate in 3D the role of biochemical and biophysical cues on cell behaviour using bioluminescent reporter cells. Gradients in oxygen concentration that result from the interplay between molecular transport and cell metabolism can however cause substantial variability in the observed bioluminescent reporter cell activity. To assess the influence of these oxygen gradients on the emitted bioluminescence for various hydrogel geometries, a combined experimental and modelling approach was implemented. We show that the applied model is able to predict oxygen gradient independent bioluminescent intensities which correlate better to the experimentally determined viable cell numbers, as compared to the experimentally measured bioluminescent intensities. By analysis of the bioluminescence reaction dynamics we obtained a quantitative description of cellular oxygen metabolism within the hydrogel, which was validated by direct measurements of oxygen concentration within the hydrogel. Bioluminescence peak intensities can therefore be used as a quantitative measurement of reporter cell activity within a hydrogel, but an unambiguous interpretation of these intensities requires a compensation for the influence of cell-induced oxygen gradients on the luciferase activity. PMID- 24957292 TI - Near-infrared dye bound albumin with separated imaging and therapy wavelength channels for imaging-guided photothermal therapy. AB - Development of theranostic agent for imaging-guided photothermal therapy has been of great interest in the field of nanomedicine. However, if fluorescent imaging and photothermal ablation are conducted with the same wavelength of light, the requirements of the agent's quantum yield (QY) for imaging and therapy are controversial. In this work, our synthesized near-infrared dye, IR825, is bound with human serum albumin (HSA), forming a HSA-IR825 complex with greatly enhanced fluorescence under 600 nm excitation by as much as 100 folds compared to that of free IR825, together with a rather high absorbance but low fluorescence QY at 808 nm. Since high QY that is required for fluorescence imaging would result in reduced photothermal conversion efficiency, the unique optical behavior of HSA IR825 enables imaging and photothermal therapy at separated wavelengths both with optimized performances. We thus use HSA-IR825 for imaging-guided photothermal therapy in an animal tumor model. As revealed by in vivo fluorescence imaging, HSA-IR825 upon intravenous injection shows high tumor uptake likely owing to the enhanced permeability and retention effect, together with low levels of retentions in other organs. While HSA is an abundant protein in human serum, IR825 is able to be excreted by renal excretion as evidenced by high-performance liquid chromatography (HPLC). In vivo tumor treatment experiment is finally carried out with HSA-IR825, achieving 100% of tumor ablation in mice using a rather low dose of IR825. Our work presents a safe, simple, yet imageable photothermal nanoprobe, promising for future clinical translation in cancer treatment. PMID- 24957293 TI - Dextran-based fluorescent nanoprobes for sentinel lymph node mapping. AB - Biopsy of sentinel lymph node (SLN) has become a common practice to predict whether tumor metastasis has occurred, so proper SLN positioning tracers are highly required. Due to many drawbacks of SLN tracers currently used, developing ideal, biosafe SLN imaging agents is always an urgent issue. The current study designed a novel fluorescent nanoprobe for accurate SLN mapping. Dextran-based nanogel (DNG) was prepared through a highly efficient self-assembly assisted approach and serves as a multi-functional platform for conjugating wide spectra emitting fluorescent agents. The newly fabricated fluorescent DNG (FDNG) could be designed with optimum size and stable fluorescent intensity for specific SLN imaging. Furthermore, a long-term dynamic course in vivo (from 1 min to 72 h) revealed the satisfactory specificity, sensitivity, and stability for SLN mapping. Most importantly, both in vitro and in vivo evaluations indicated that FDNG had fine biosafety and biocompatibility with lymphatic endothelial cells. All these results supported that FDNG could be used as highly efficient molecular imaging probes for specific, sensitive, stable, non-invasive, and safe SLN mapping, which provides efficient and accurate location for SLN biopsy and thus predicts tumor metastasis as well as directs therapies. Besides, our recent studies further demonstrated that DNG could also serve as a specific and controllable drug carrier, indicating a potential application for specific therapies of various lymph-associated diseases. PMID- 24957296 TI - Body mass index delineates ALS from FTD: implications for metabolic health. AB - Weight loss and catabolic changes are increasingly recognized as factors that influence outcomes in patients with amyotrophic lateral sclerosis (ALS). An association between disease progression and low BMI has been reported in ALS; however, it remains unknown whether low BMI occurs across all forms of ALS and whether BMI changes with the development of cognitive impairment across the spectrum between ALS and frontotemporal dementia (FTD). One hundred and three ALS patients (56 limb predominant, 18 bulbar predominant, 13 ALS plus, 16 ALSFTD) were recruited and compared to 19 behavioral variant FTD (bvFTD) patients and a group of age-matched healthy controls. BMI was measured at the initial clinical visit. Patients were characterized as underweight, normal, overweight or obese, based on the current World Health Organization (WHO) guidelines. Limb and bulbar ALS patients had significantly lower BMI than ALS plus, ALSFTD, and bvFTD patient groups. When BMI was categorized using WHO guidelines the majority of the limb and bulbar ALS patients were either underweight or normal weight, whilst the majority of the ALS plus, ALSFTD and bvFTD patients were either overweight or obese. On follow-up BMI assessment the limb and bulbar groups tended to decline whilst ALS plus, ALSFTD and bvFTD groups remained stable or increased. BMI is significantly higher in ALS individuals with cognitive deficits. The present findings have prognostic implications for disease progression and may help delineate the metabolic profile across the ALSFTD spectrum. PMID- 24957294 TI - Temporal and spatial patterning of transgene expression by near-infrared irradiation. AB - We investigated whether near-infrared (NIR) light could be employed for patterning transgene expression in plasmonic cell constructs. Hollow gold nanoparticles with a plasmon surface band absorption peaking at ~750 nm, a wavelength within the so called "tissue optical window", were used as fillers in fibrin-based hydrogels. These composites, which efficiently transduce NIR photon energy into heat, were loaded with genetically-modified cells that harbor a heat activated and ligand-dependent gene switch for regulating transgene expression. NIR laser irradiation in the presence of ligand triggered 3-dimensional patterns of transgene expression faithfully matching the illuminated areas of plasmonic cell constructs. This non-invasive technology was proven useful for remotely controlling in vivo the spatiotemporal bioavailability of transgenic vascular endothelial growth factor. The combination of spatial control by means of NIR irradiation along with safe and timed transgene induction presents a high application potential for engineering tissues in regenerative medicine scenarios. PMID- 24957295 TI - Near-infrared fluorescence imaging of cancer mediated by tumor hypoxia and HIF1alpha/OATPs signaling axis. AB - Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the mechanistic properties of a specific group of NIR heptamethine carbocyanines including MHI-148 dye we identified and synthesized, and demonstrated these dyes to achieve cancer specific imaging and targeting via a hypoxia-mediated mechanism. We found that cancer cells and tumor xenografts exhibited hypoxia-dependent MHI-148 dye uptake in vitro and in vivo, which was directly mediated by hypoxia-inducible factor 1alpha (HIF1alpha). Microarray analysis and dye uptake assay further revealed a group of hypoxia-inducible organic anion-transporting polypeptides (OATPs) responsible for dye uptake, and the correlation between OATPs and HIF1alpha was manifested in progressive clinical cancer specimens. Finally, we demonstrated increased uptake of MHI-148 dye in situ in perfused clinical tumor samples with activated HIF1alpha/OATPs signaling. Our results establish these NIRF dyes as potential tumor hypoxia-dependent cancer-targeting agents and provide a mechanistic rationale for continued development of NIRF imaging agents for improved cancer detection, prognosis and therapy. PMID- 24957297 TI - Verapamil-responsive coital cephalalgia as reversible cerebral vasoconstriction prodrome. PMID- 24957298 TI - The effect of telestroke systems among neighboring hospitals: more and better? The Madrid Telestroke Project. AB - A telestroke system was established between a community hospital lacking an on call neurologist and a comprehensive stroke center only 13 km away. Our goal was to analyze the impact of telestroke on the number of intravenous thrombolysis (IVT), door-to-needle times and stroke outcomes. An observational before-and after study of patients with acute ischemic stroke (IS) who were attended in a community hospital during the 2 years before the telestroke system was implemented (pre-telestroke group) and the first 2 years after telestroke was established (telestroke group). The number of IVT, the door-to-needle time (min), the outcomes [modified Rankin Scale (mRS)] and the safety (mortality and hemorrhagic transformations) were compared between groups. During the pre telestroke years, 259 patients with IS were attended (28 phone activations), 12 of whom received IVT (4.7 %). During the telestroke years, 225 patients with IS were attended (42 telestroke activations), of whom 18 (8 %) received IVT. The door-to-needle times were lower in the telestroke group [median interquartile range: 66 (54) vs. 143.5 (48) min, P < 0.0001]. The safety was similar in both groups; however, the 3-month mRS scores were lower in the telestroke group (P = 0.049). The multiple linear regression analysis showed a negative association between telestroke and door-to-needle time [beta-coefficient (SE) = -59.089 (14.461)], adjusted for confounders. In conclusion, telestroke systems are effective, even between nearby hospitals, shortening door-to-needle time and improving stroke outcomes. PMID- 24957299 TI - Short rapid steps to provoke freezing of gait in Parkinson's disease. AB - Freezing of gait (FOG) is both common and debilitating in patients with Parkinson's disease. Due to its episodic nature, it is a challenge to provoke FOG in clinical practice and in the research setting. Turning is most sensitive to provoke FOG, particularly when performed as rapidly as possible. Walking with short steps is an alternative approach to provoke FOG. Here, we assessed a modified version of this test, consisting of the instruction to make short steps as rapidly as possible. We evaluated what the diagnostic value of this new test is compared to rapid turning. 28 patients with Parkinson's disease participated, who all had objective FOG. Patients performed the following tasks two times: (1) normal walking, (2) walking as rapidly as possible, (3) walking with short steps, (4) walking with short steps as rapidly as possible and (5) making full rapid turns in both directions. FOG was provoked in 20 subjects (71 %). The most effective test to provoke FOG was rapid full turns (64 % of subjects). FOG occurred more often when patients walked with rapid short steps (50 %) compared to walking with short steps at normal speed (18 %). The combination of 'full rapid turns' and 'walking with short steps rapidly' yielded the highest sensitivity of provoking FOG (0.71, CI 0.51-0.86). The most sensitive way to provoke FOG is by asking patients to make full rapid turns, but if negative, walking with short steps as rapidly as possible can identify further subjects with FOG. PMID- 24957300 TI - Intramolecular electrophilic aromatic substitution in gas-phase fragmentation of protonated N-benzylbenzaldimines. AB - In this study, the gas-phase fragmentations of protonated N-benzylbenzaldimines were investigated by electrospray ionization tandem mass spectrometry (ESI MS(n)). Upon collisional activation, several characteristic fragment ions are produced and their fragmentation mechanisms are rationalized by electrophilic aromatic substitution accompanied by benzyl cation transfer. (1) For N-(p methoxybenzylidene)-1-phenylmethanimine, concomitant with a loss of HCN, a product ion at m/z 121 was observed. It is proposed to be generated from electrophilic substitution at the ipso-position by transferring benzyl cation rather than cleavage of the C-N double bond. (2) For N-(m-methoxybenzylidene)-1 phenylmethanimine, a product ion at m/z 209 was obtained, corresponding to the elimination of NH(3) carrying two hydrogens from the two aromatic rings respectively. This process can be rationalized by two sequential electrophilic substitutions and cyclodeamination reaction based on the benzyl cation transfer. Deuterium-labeled experiments, density functional theory (DFT) calculation and substituent effect results also corroborate the proposed mechanism. PMID- 24957301 TI - Purple anthocyanin colouration on lower (abaxial) leaf surface of Hemigraphis colorata (Acanthaceae). AB - The functional significance of anthocyanin colouration of lower (abaxial) leaf surfaces is not clear. Two anthocyanins, 5-O-methylcyanidin 3-O-(3"-(beta glucuronopyranosyl)-beta-glucopyranoside) (1) and 5-O-methylcyanidin 3-O-beta glucopyranoside (2), were isolated from Hemigraphis colorata (Blume) (Acanthaceae) leaves with strong purple abaxial colouration (2.2 and 0.6mg/gfr.wt., respectively). The glycosyl moiety of 1, the disaccharide 3"-(beta glucuronopyranosyl)-beta-glucopyranoside), has previously been reported to occur only in a triterpenoid saponin, lindernioside A. The structural assignment of the aglycone of 1 and 2 is the first complete characterisation of a natural 7-hydroxy 5-methoxyanthocyanidin. Compared to nearly all naturally occurring anthocyanidins, the 5-O-methylation of this anthocyanidin limits the type of possible quinoidal forms of 1 and 2 to be those forms with keto-function in only their 7- and 4'-positions. PMID- 24957303 TI - What should we intend for minimally invasive treatment of colorectal cancer? AB - Non-inferiority of laparoscopic treatment of colorectal cancer (CRC) has been demonstrated in randomized controlled trials although operative and perioperative management varies widely among centers. Literature data in English language published up to April 15, 2014 were analyzed in order to give an up to date analysis that would highlights the key aspects of a modern and factual minimally invasive treatment of CRC. Laparoscopic resection is the first choice treatment of colon cancer. Laparoscopic resection of rectal cancer should be considered an investigational procedure to be performed in high volume centers with special interest in laparoscopy and colorectal surgery. Less invasive approaches should be taken into account with the aim of reducing surgical stress. The adoption of ERAS programs has demonstrated to optimize short-term results. Future research should be directed to prove possible long-term advantages, in terms of overall and disease-free survival, of minimally invasive treatment of CRC. PMID- 24957304 TI - Rate of stroke death after depression: a 40-year longitudinal study extension of Chichester/Salisbury Catchment area study. AB - BACKGROUND: This study examined clinically diagnosed depression as a risk factor for incidence of death by stroke in a prospective clinically based design study. Risk for stroke was examined separately by sex in a long-term follow-up study spanning 40 years. METHODS: Patients who were diagnosed with depression in the Chichester (population 100,000)/Salisbury (population 85,000) Catchment Area Study were followed up for 40 years. Death certificates were used to determine the cause of death in the cohort. Death rates in the general population, adjusted for age, gender, and year, were used as a control. RESULTS: Clinical depression was found to be a risk factor for subsequent death from stroke in men but not in women. Death by stroke was a statistically significant cause of death in the men with diagnoses of endogenous depression but not in those men diagnosed with reactive depression. The strength of the relationship of depression with stroke increased over time. CONCLUSIONS: These findings suggest that the identification of depressive symptoms at younger ages may have an impact on the primary prevention of stroke in later life. The notion that depression has stronger effects over a long period is consistent with a view that severe clinical depression and physical illness occur concurrently, one exacerbating the other, and health is degraded through slow-acting, cumulative processes. Data were unavailable for the type of stroke or the health-risk behaviors (smoking, diet, and so forth) in the cohort which constituted a limitation of the study. Neither is it known what proportion of the cohort suffered a nonlethal stroke nor to what extent the treatment of clinical depression militates against suffering a lethal stroke. PMID- 24957302 TI - Randomized trial comparing mindfulness training for smokers to a matched control. AB - Smoking continues to take an enormous toll on society, and although most smokers would like to quit, most are unsuccessful using existing therapies. These findings call on researchers to develop and test therapies that provide higher rates of long-term smoking abstinence. We report results of a randomized controlled trial comparing a novel smoking cessation treatment using mindfulness training to a matched control based on the American Lung Association's Freedom From Smoking program. Data were collected on 175 low socioeconomic status smokers in 2011-2012 in a medium sized midwestern city. A significant difference was not found in the primary outcome; intent-to-treat biochemically confirmed 6-month smoking abstinence rates were mindfulness=25.0%, control=17.9% (p=0.35). Differences favoring the mindfulness condition were found on measures of urges and changes in mindfulness, perceived stress, and experiential avoidance. While no significant differences were found in quit rates, the mindfulness intervention resulted in positive outcomes. PMID- 24957306 TI - Do the antithrombotic therapy at the time of intracerebral hemorrhage influence clinical outcome? analysis between the difference of antiplatelet and anticoagulant agents and clinical course. AB - BACKGROUND: It is controversial whether taking antiplatelet agents (APs) or anticoagulant agents (ACs) could influence clinical outcome after intracerebral hemorrhage (ICH). METHODS: We retrospectively investigated 557 ICH patients between September 2008 and August 2013. We reviewed patients' characteristics, hematoma volume, deterioration (hematoma expansion, surgical hematoma evacuation, or death), and clinical outcome in modified Rankin Scale. RESULTS: A total of 397 were classified as neither AP nor AC ("Nothing"), 81 as single AP (44 as aspirin [ASA], 22 as clopidogrel or ticlopidine [CLP/TIC], 7 as cilostazol, 8 as dual antiplatelet therapy), 43 as single AC (40 as warfarin, 2 as rivaroxaban, 1 as dabigatran), and 36 as both AP and AC (AP + AC). The clinical outcome was worse in APs than in "Nothing" (P = .021). Among APs, CLP/TIC showed poorer clinical outcome than ASA (P = .020). Deterioration was observed more frequently in AC than in "Nothing" (P < .001) and the clinical outcome was also worse in AC than in "Nothing" (P < .001). AP + AC use resulted in deterioration more frequently than "Nothing" (P < .001) and in poorer outcome than in "Nothing" (P < .001). CONCLUSIONS: The use of antithrombotic agents could be associated with the deterioration after admission and the poor clinical outcome. CLP/TIC use may affect the poor outcome compared with ASA use. PMID- 24957305 TI - Gallstone disease and the risk of stroke: a nationwide population-based study. AB - BACKGROUND: Gallstone disease (GD) and stroke share a number of risk factors including diabetes and hyperlipidemia. This nationwide population-based study was designed to estimate the risk of stroke after a diagnosis of GD. METHODS: Data were obtained from the Taiwan National Health Insurance Research Database. A total of 135,512 patients with a diagnosis of GD and 271,024 age- and gender matched non-GD control patients were included to assess the risk of stroke using Cox proportional hazard regression. RESULTS: During the study period (2000-2003), 12,234 (153.67/10,000 person-years) strokes occurred among the GD patients, and 20,680 (114.83/10,000 person-years) among the controls. The diagnosis of GD carried a higher risk of developing ischemic and hemorrhagic stroke, with a hazard ratio (HR) of 1.28 and 1.33 (95% confidence interval [CI], 1.25-1.31 and 1.25-1.41, both P < .0001), respectively. Stroke risk was increased in both genders but at a higher rate in younger age. The GD group had significantly higher prevalence rate of comorbidities that are known stroke risk factors, including hypertension, diabetes, and coronary artery disease. Stroke risk was higher in the GD group with or without any of these comorbidities. CONCLUSIONS: In this population-based longitudinal follow-up study, GD carried a significantly higher stroke risk, particularly for younger age with or without stroke risk factors. Stroke preventive measures maybe needed for patients with GD, especially those of younger age and with stroke risk factor(s). PMID- 24957307 TI - The roles and issues of P2Y12 percent inhibition assessed by VerifyNow assay for patients undergoing Neurointervention: a prospective study. AB - BACKGROUND: Antiplatelet agents have an important role in the prevention of ischemic complications during endovascular treatment. The aim of this study was to identify correlations between the clinical outcomes of neurointervention. This study also aimed to determine the optimal cutoff for P2Y12 percent inhibition to prevent ischemic and bleeding complications and to confirm the accuracy of the cutoff value. METHODS: A prospective study was conducted for all patients (n = 66) who received antiplatelet therapy during neurointervention at Toyama University Hospital during a 25-month period. Platelet reactivity was measured before the procedure using the VerifyNow and filter pressure methods. The primary outcome was the 30-day incidence of adverse clinical events, defined as ischemic or bleeding events, in relation to P2Y12 percent inhibition distribution. RESULTS: Multivariate analysis showed that P2Y12 percent inhibition was an independent predictor for bleeding (P = .021, odds ratio [OR] = 3.45; 95% confidence interval [CI], 2.31-4.88) and ischemic (P = .045, OR = 3.63; 95% CI, 2.11-7.12) events. In receiver operating characteristic curve analysis, P2Y12 percent inhibition could significantly discriminate between patients with and without bleeding and ischemic events. The optimal cutoffs for bleeding (74%) and ischemic events (26%) were used to define 3 groups: those with poor response, sufficient response, and hyper-response. Ischemic and bleeding complications were significantly different among the 3 groups. CONCLUSIONS: Optimal threshold, measured using the VerifyNow P2Y12 assay, can be identified using specific thresholds (26% < percent inhibition < 74%) to define patients at lower risk for ischemic and bleeding events. The threshold for hyper-response can highly predict bleeding events in perioperative period. On the other hands, cutoff value for poor response may be affected by various factors. PMID- 24957308 TI - Cognitive function of patients with adult moyamoya disease. AB - BACKGROUND: Neurocognitive impairment is one of several unsolved social issues faced by patients with moyamoya disease. Although efforts have been made to investigate cognitive function using neuropsychologic tasks, generalizability has been limited. Here, in a preliminary study, we used structured neuropsychologic tasks to establish a standardized neuropsychologic assessment for adult moyamoya patients with and without difficulty in social independence. METHODS: Ten patients with neuroradiologically confirmed adult moyamoya disease (3 male, 7 female) participated. Half of all subjects did not have difficulty with social independence (group 1) and the others had (group 2). Group differences were evaluated after basic cognitive abilities and frontal lobe function were tested. RESULTS: Although the mean age of group 1 was substantially higher than that of group 2, disease duration did not differ significantly between groups. Means scores for intelligence functions including all subtests for basic cognitive abilities were higher in group 1 compared with group 2. Scores from only 2 frontal lobe evaluation tasks (Trail Making Test B and Theory of Mind) were significantly different between groups. CONCLUSIONS: This preliminary study provides a profile of neurocognitive dysfunction in adult patients with moyamoya disease using structured neuropsychologic tasks. A broad range of cognitive functions was disrupted particularly in the patients who had difficulty with social independence. To obtain stronger evidence regarding neurocognitive dysfunction in patients with moyamoya disease, a multicenter prospective study is essential. PMID- 24957310 TI - A traveling "spot sign" in recurrent amaurosis fugax and central retinal artery occlusion. AB - Sudden monocular blindness is frequently caused by central retinal artery occlusion (CRAO) from embolic sources. Treatment options are insufficient, and spontaneous prognosis toward visual recovery is poor. In addition to ophthalmologic evaluation, transorbital sonographic assessment of the central retinal artery may help establish early diagnosis by Doppler sonographic proof of occlusion and, in some cases, by B-mode detection of an intra-arterial "spot sign". We report the case of a patient with recurrent amaurosis fugax and subsequent CRAO. Ultrasound examination after 2 incidences of amaurosis fugax demonstrated a patent but stenotic central retinal artery, with stenosis caused by an embolus visualized as a "spot sign". The following day, persisting amaurosis suddenly developed. Sonographic re-evaluation revealed downstream dislodgment of the "spot sign" and complete arterial occlusion. Thrombolytic treatment did not result in clinical improvement. In conclusion, this case report describes a single case of repeated amaurosis fugax and deterioration to CRAO via embolization into the central retinal artery and consecutive downstream dislodgment. It emphasizes that ultrasound may render valuable diagnostic information in patients with acute central retinal artery embolization toward its embolic etiology and its risk of subsequent deterioration. PMID- 24957309 TI - Impact of aneurysm location on cardiopulmonary dysfunction after subarachnoid hemorrhage. AB - BACKGROUND: Cardiopulmonary dysfunction may occur after aneurysmal subarachnoid hemorrhage (SAH), but its characteristics have not been fully clarified. We investigated the impact of aneurysm location on systemic hemodynamics after SAH. METHODS: This multicenter prospective cohort study measured hemodynamic parameters in relation to aneurysm location in patients with SAH using a single indicator transpulmonary thermodilution system (PiCCO) on days 1-14. RESULTS: Of 204 subjects enrolled, 58 had aneurysms of the anterior communicating artery (ACA), 61 of the middle cerebral artery (MCA), 57 of the internal carotid artery (ICA), and 28 of the vertebrobasilar artery (VA/BA). Patient characteristics were similar except for predominance of coiling in the VA/BA. Patients with ACA aneurysm had a lower systemic vascular resistance index (SVRI) in the acute phase and afterload mismatch (lower cardiac index [CI] and higher SVRI) in the spasm phase. Those with ICA aneurysm had a lower CI in the acute phase, and those with VA/BA aneurysm had a warm shock-like condition (higher CI and lower SVRI) in the spasm phase. Patients with MCA aneurysm showed no specific characteristics in CI and SVRI with a significant improvement in B-type natriuretic peptide. Extravascular lung water index was high independent of left cardiac dysfunction. In multivariate analysis, age and ACA were independently related to poor global ejection fraction after SAH. CONCLUSIONS: Aneurysm location affects cardiac output, vascular resistance, and pulmonary edema in biphasic fashion. Patient age and location of aneurysm in the ACA may be risk factors for cardiac failure after SAH. PMID- 24957311 TI - Relationship between poststroke cognition, baseline factors, and functional outcome: data from "efficacy of nitric oxide in stroke" trial. AB - BACKGROUND: Poststroke cognitive impairment is common and identification of prognostic factors associated with it and its relationship with other functional outcomes may help in developing preventative strategies. METHODS: Previously independent patients with acute stroke, enrolled into the ongoing "Efficacy of Nitric Oxide in Stroke" trial, were assessed by telephone on day 90 for cognitive impairment using modified versions of "Mini Mental State Examination" (MMSE-M) and "Telephone Instrument for Cognitive Status" (TICS-M) scales and category fluency. The relationship of cognitive impairment with baseline prognostic factors and other functional outcomes at day 90 were studied. RESULTS: The analysis included 1572 patients, mean age 69 years (standard deviation, 12), and female 40%. By 90 days, 246 patients had died, and cognitive impairment was present in 38%. Increasing age, stroke severity, heart rate, and presence of cerebral atrophy on baseline neuroimaging were associated with cognitive impairment (all P < .001). Hypertension and atrial fibrillation were also associated with category fluency and MMSE-M, respectively. Cognition was significantly related to other functional outcomes, TICS-M with dependency (modified Rankin Scale, rs = -.562, P < .001); disability (Barthel Index, rs = .577, P < .001); mood (Zung Depression Score, rs = -.542, P < .001); and quality of life (Euro Quality of life-5 Descriptor, rs = .519, P < .001). CONCLUSIONS: In previously independent individuals, cognitive impairment was common 3 months after stroke and related to increasing age, stroke severity, hypertension, atrial fibrillation, and cerebral atrophy on brain scanning. Cognition was related to dependency, disability, low mood, and quality of life. Hence, treatment directed toward reducing dependency might also reduce cognitive impairment. PMID- 24957312 TI - Prevalence of ischemic and hemorrhagic strokes in Qena Governorate, Egypt: community-based study. AB - BACKGROUND: Stroke is a major health problem in developing countries. In a previous survey, the prevalence rate of stroke in the Nile Valley governorate of Assiut was significantly higher than other Arabic countries. In view of this, we carried out a follow-up study in a second Nile Valley governorate (Qena). METHODS: A community-based, three-phase, door-to-door study with random sampling of 10 areas in Qena governorate (first phase), involving 8027 inhabitant with 4172 males (51.97%) and 3855 females (48.03%). There were 4427 urban residents (55.15%) and 3600 residents (44.85%) from the rural community. In the second phase, participants were screened using the questionnaire for stroke, whereas the third phase involved neurologic evaluation of all suspected cases, with diagnosis of stroke confirmed by evaluation of computed tomography (CT) scans. The Mini Mental State Examination and National Institute of Health Stroke Scale were evaluated for each patient. RESULTS: Of the 8027 participants, 74 were identified as positive cases with a crude prevalence rate 922 of 100,000, an age-adjusted local prevalence rate of 777 of 100,000 and an age-adjusted prevalence rate of Egyptian population 566.6 of 100,000. The highest age-specific prevalence rates were recorded among subjects 70 years of age or older (8,392 of 100,000). The crude prevalence rate of ischemic stroke was significantly higher than that of hemorrhagic stroke (797 vs 125 of 100,000). Illiterate participants had a significantly higher crude prevalence rate than those who were literate (3567 vs 704 of 100,000). There was no significant difference in the prevalence rate between rural and urban areas or between males and females. Fifty patients (67.57%) had 1 or more risk factors of stroke, with hypertension being the most common (62.16%), followed by diabetes mellitus (36.49%). CONCLUSIONS: The overall prevalence rate of stroke is nearly the same as in other Egyptian governorates and is higher than other Arabic countries. PMID- 24957313 TI - A literature review of indirect costs associated with stroke. AB - BACKGROUND: Stroke is a leading cause of mortality and long-term disability. However, the indirect costs of stroke, such as productivity loss and costs of informal care, have not been well studied. To better understand this, we conducted a literature review of the indirect costs of stroke. METHODS: A literature search using PubMed, MEDLINE, and EconLit, with the key words stroke, cerebrovascular disease, subarachnoid hemorrhage, intracerebral hemorrhage, cost of-illness, productivity loss, indirect cost, economic burden, and informal caregiving was conducted. We identified original research articles published during 1990-2012 in English-language peer-reviewed journals. We summarized indirect costs by study type, cost categories, and study settings. RESULTS: We found 31 original research articles that investigated the indirect cost of stroke. Six of these investigated indirect costs only; the other 25 studies were cost-of-illness studies that included indirect costs as a component. Of the 31 articles, 6 examined indirect costs in the United States, with 2 of these focused solely on indirect costs. Because of diverse methods, kinds of data, and definitions of cost used in the studies, the literature indicated a very wide range internationally in the proportion of the total cost of stroke that is represented by indirect costs (from 3% to 71%). CONCLUSIONS: Most of the literature indicates that indirect costs account for a significant portion of the economic burden of stroke, and there is a pressing need to develop proper approaches to analyze these costs and to make better use of relevant data sources for such studies or establish new ones. PMID- 24957314 TI - Safety and efficacy of intravenous recombinant tissue plasminogen activator administered in the 3- to 4.5-hour window in Korea. AB - BACKGROUND: The safety and efficacy of intravenous tissue plasminogen activator (IV-TPA) in the 3- to 4.5-hour window were largely driven from Western populations, but have not been systematically explored in Korean population. METHODS: We compared outcomes of acute ischemic stroke patients treated in the 3- to 4.5-hour window versus those in the 0- to 3-hour window, using a prospective multicenter registry database. Safety outcomes included symptomatic intracranial hemorrhage (SICH) and 3-month mortality and efficacy outcomes were the proportions of modified Rankin Scale (mRS) 0-1 and mRS 0-2 and the overall mRS distribution at 3 months. RESULTS: Among 723 patients consecutively treated with IV-TPA alone, 616 were treated within 3 hours and 107 treated between 3 and 4.5 hours. The median onset-to-treatment time was 115 minutes for 0- to 3-hour group and 217 minutes for 3- to 4.5-hour group. The SICH rate was higher in the 3- to 4.5-hour group than in the 0- to 3-hour group (4.7% vs. 3.1%), but the difference was not significant (adjusted odds ratio [OR] [95% confidence interval {CI}], .81 [.20-3.35]). There were no significant differences between the 3- to 4.5-hour and 0- to 3-hour groups in the 3-month mortality (19.6% vs. 12.0%), mRS 0-1 (39.3% vs. 42.9%), mRS 0-2 (48.6% vs. 55.7%), and the overall mRS distribution (adjusted proportional OR [95% CI], .94 [.63-1.41]) after adjusting for covariates. CONCLUSIONS: IV-TPA treatment can be safely and efficaciously administered to eligible Korean patients up to the extended time window of 4.5 hours. However, efforts to expedite the treatment should not be neglected. PMID- 24957315 TI - Safety of standard-dose (.9-mg/kg) alteplase intravenous thrombolysis for acute ischemic stroke in Afro-Caribbeans, French West Indies. AB - BACKGROUND: Pharmacobiologic data suggested that people of African ancestry were more sensitive to the recombinant tissue plasminogen activator, alteplase, than Caucasians. Furthermore, the higher incidences of hypertension and diabetes mellitus in black populations could contribute to a higher cerebral bleeding risk. However, standard-dose (.9-mg/kg) alteplase safety for stroke has never been evaluated in blacks. This study was undertaken to evaluate standard-dose alteplase safety to treat strokes in an Afro-Caribbean population. METHODS: Parenchymal hemorrhage and symptomatic intracerebral hemorrhage rates in Afro Caribbean Martinicans given standard-dose alteplase for acute stroke were evaluated based on prospectively collected data from 2007 to 2010 and compared with those from studies on predominantly Caucasian stroke victims. RESULTS: Parenchymal hemorrhage type 2 and symptomatic intracerebral hemorrhages, as defined by the third European Cooperative Acute Stroke Study, respectively, occurred in 15 (10.1%) and 12 (8.1%) of the 148 thrombolyzed Afro-Caribbeans, respectively. This excess bleeding risk (parenchymal hemorrhage type 2) concerned more patients >70 than those 70 years of age or lesser (respectively, 17.6% [13 of 74] vs. 2.7% [2 of 74]). Older age was the only factor significantly associated with a higher parenchymal hemorrhage type 2 risk (P = .02). CONCLUSIONS: The excess hemorrhagic risk after standard-dose alteplase infusion into older Afro-Caribbean patients warrants further study to determine the possible role of cerebral microangiopathy and should be evaluated in different black populations. PMID- 24957316 TI - Dual task walking reveals cognitive dysfunction in community-dwelling elderly subjects: the Sefuri brain MRI study. AB - The aim of our study was to investigate the effects of subclinical brain lesions and cognitive function on gait performance with or without concurrent cognitive task in community-dwelling elderly subjects. Participants without dementia (92 men and 109 women with a mean age of 67.8 years) underwent brain magnetic resonance imaging, neuropsychologic tests, and gait measurements. Impaired gait velocity of the Timed Up and Go test was associated with deep white matter lesions (odds ratio [OR], 2.338; 95% confidence interval [CI], 1.120-4.880) and diabetes mellitus (OR, 2.725; 95% CI, 1.120-6.630) after adjusted for age, sex, education, and cognitive function tests. Impaired gait velocity of dual task walking was associated with age and the score of Rivermead Behavioral Memory Test (OR, .899/1 point higher; 95% CI, .813-.994), whereas deep white matter lesions were not significantly associated with dual task walking. The present study showed that gait represents not only physical functioning but also subclinical cognitive dysfunction particularly memory impairment in healthy elderly subjects. PMID- 24957317 TI - Naturally occurring tumours in the basal metazoan Hydra. AB - The molecular nature of tumours is well studied in vertebrates, although their evolutionary origin remains unknown. In particular, there is no evidence for naturally occurring tumours in pre-bilaterian animals, such as sponges and cnidarians. This is somewhat surprising given that recent computational studies have predicted that most metazoans might be prone to develop tumours. Here we provide first evidence for naturally occurring tumours in two species of Hydra. Histological, cellular and molecular data reveal that these tumours are transplantable and might originate by differentiation arrest of female gametes. Growth of tumour cells is independent from the cellular environment. Tumour bearing polyps have significantly reduced fitness. In addition, Hydra tumours show a greatly altered transcriptome that mimics expression shifts in vertebrate cancers. Therefore, this study shows that spontaneous tumours have deep evolutionary roots and that early branching animals may be informative in revealing the fundamental mechanisms of tumorigenesis. PMID- 24957318 TI - Understanding pandemic influenza behaviour: An exploratory biopsychosocial study. AB - Pandemic influenza represents an ongoing public health threat. Understanding the associated behavioural domain is vital for future intervention development. Cross sectional qualitative research employing purposive sampling employed a combination of one-to-one semi-structured interviews (n = 57) and focus groups (n = 59). Data were analysed using (1) inductive thematic analysis and (2) theoretical thematic analysis focusing upon resonance with psychosocial and sociocultural constructs. Two broad themes highlighted an important duality regarding the determinants of pandemic behaviour: (1) psychosocial determinants (e.g. agency, cognitions and identity) and (2) sociocultural determinants (e.g. social context and capacity). These findings suggest this duality should shape future intervention development. PMID- 24957320 TI - Screening for abdominal aortic aneurysm: U.S. Preventive Services Task Force recommendation statement. AB - DESCRIPTION: Update of the 2005 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for abdominal aortic aneurysm (AAA). METHODS: The USPSTF commissioned a systematic review that assessed the evidence on the benefits and harms of screening for AAA and strategies for managing small (3.0 to 5.4 cm) screen-detected AAAs. POPULATION: These recommendations apply to asymptomatic adults aged 50 years or older. RECOMMENDATION: The USPSTF recommends 1-time screening for AAA with ultrasonography in men aged 65 to 75 years who have ever smoked. (B recommendation). The USPSTF recommends that clinicians selectively offer screening for AAA in men aged 65 to 75 years who have never smoked. (C recommendation). The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for AAA in women aged 65 to 75 years who have ever smoked. (I statement). The USPSTF recommends against routine screening for AAA in women who have never smoked. (D recommendation). PMID- 24957321 TI - Resection, transplantation and local regional therapies for liver adenomas. AB - Hepatocellular adenoma (HCA) is a rare benign liver-cell neoplasm, occurring predominantly in young obese women using oral contraceptives. HCA is a heterogeneous disease, which includes four subtypes (including unclassified) associated with various risks of haemorrhagic complications and malignant transformation. Magnetic resonance imaging is the modality of choice for both diagnosis and subtype characterization of HCA whereas percutaneous biopsy has only limited impact on the therapeutic strategy. In men HCA should be always resected while in women surgery should only be considered for lesions >=5 cm and after cessation of hormonal therapy. Women with single or multiple HCAs <5 cm may be followed with regular MRI imaging since the vast majority of HCA remains stable or decreases in size. Pregnancy should not be discouraged provided close sonographic surveillance is undertaken. PMID- 24957319 TI - Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy. AB - Weekly gemcitabine therapy is the major treatment offered for patients with pancreatic adenocarcinoma cancer; however, relative resistance of tumor cells to chemotherapy, rapid regrowth, and metastasis are the main causes of death within a year. Recently, the daily continuous administration of chemotherapy in low doses--called metronomic chemotherapy (MC)--has been shown to inhibit primary tumor growth and delay metastases in several tumor types; however, its use as a single therapy is still in question due to its moderate therapeutic benefit. Here, we show that the combination of weekly gemcitabine with MC of the same drug delays tumor regrowth and inhibits metastasis in mice implanted orthotopically with pancreatic tumors. We further demonstrate that weekly gemcitabine, but not continuous MC gemcitabine or the combination of the two drug regimens, promotes rebound myeloid-derived suppressor cell (MDSC) mobilization and increases angiogenesis in this tumor model. Furthermore, Bv8 is highly expressed in MDSCs colonizing pancreatic tumors in mice treated with weekly gemcitabine compared to MC gemcitabine or the combination of the two regimens. Blocking Bv8 with antibodies in weekly gemcitabine-treated mice results in a significant reduction in tumor regrowth, angiogenesis, and metastasis. Overall, our results suggest that pro-tumorigenic effects induced by weekly gemcitabine are mediated in part by MDSCs expressing Bv8. Therefore, both Bv8 inhibition and MC can be used as legitimate 'add-on' treatments for preventing post-chemotherapy pancreatic cancer recurrence, progression, and metastasis following weekly gemcitabine therapy. PMID- 24957322 TI - Minimal supportive treatment in natalizumab-related PML in a MS patient. PMID- 24957324 TI - Bronchopulmonary lophomoniasis: emerging disease or unsubstantiated legend? AB - The relationship between Lophomonas, a genus of multiflagellated protozoa, and respiratory pathology has recently received attention. Here, we summarize the origin, mode of transmission, pathogenic mechanism and relevant clinical data of bronchopulmonary lophomoniasis. PMID- 24957325 TI - UK government rules out a "sugar tax". PMID- 24957323 TI - Quantitatively mapping cellular viscosity with detailed organelle information via a designed PET fluorescent probe. AB - Viscosity is a fundamental physical parameter that influences diffusion in biological processes. The distribution of intracellular viscosity is highly heterogeneous, and it is challenging to obtain a full map of cellular viscosity with detailed organelle information. In this work, we report 1 as the first fluorescent viscosity probe which is able to quantitatively map cellular viscosity with detailed organelle information based on the PET mechanism. This probe exhibited a significant ratiometric fluorescence intensity enhancement as solvent viscosity increases. The emission intensity increase was attributed to combined effects of the inhibition of PET due to restricted conformational access (favorable for FRET, but not for PET), and the decreased PET efficiency caused by viscosity-dependent twisted intramolecular charge transfer (TICT). A full map of subcellular viscosity was successfully constructed via fluorescent ratiometric detection and fluorescence lifetime imaging; it was found that lysosomal regions in a cell possess the highest viscosity, followed by mitochondrial regions. PMID- 24957326 TI - Securinega alkaloids from the fruits of Flueggea suffruticosa. AB - Phytochemical investigation on the fruits of Flueggea suffruticosa resulted in the isolation of three new Securinega alkaloids, secu'amamine H (1), 15beta methoxy-14,15-dihydrosecurinine (3), and securinol E (7), as well as eight known ones (2, 4-6, and 8-11). Their structures were elucidated by means of spectroscopic techniques (1D and 2D NMR, MS, UV, and IR). The absolute configurations of the new compounds were established by single-crystal X-ray diffraction and CD analyses. PMID- 24957327 TI - Facilitated group supervision: harnessing the power of peers. PMID- 24957329 TI - Development of radio dramas for health communication pilot intervention in Canadian Inuit communities. AB - A mixed-methods approach was used to develop a culturally appropriate health intervention over radio within the Inuit community of Pangnirtung, Nunavut (NU), Canada. The radio dramas were developed, recorded and tested pre-intervention through the use of Participatory Process and informed by the extended elaboration likelihood model (EELM) for education-communication. The radio messages were tested in two focus groups (n = 4 and n = 5) to determine fidelity of the radio dramas to the EELM theory. Focus group feedback identified that revisions needed to be made to two characteristics required of educational programmes by the EELM theorem: first, the quality of the production was improved by adding Inuit youth recorded music and second, the homophily (relatability of characters) of radio dramas was improved by re-recording the dramas with voices of local youth who had been trained in media communication studies. These adjustments would not have been implemented had pre-intervention testing of the radio dramas not taken place and could have reduced effectiveness of the overall intervention. Therefore, it is highly recommended that media tools for health communication/education be tested with the intended target audience before commencement of programmes. Participatory Process was identified to be a powerful tool in the development and sustainability of culturally appropriate community health programming. PMID- 24957330 TI - Maternal venous hemodynamics in gestational hypertension and preeclampsia. AB - BACKGROUND: To evaluate characteristics of venous hemodynamics, together with cardiac and arterial function, in uncomplicated pregnancies (UP), non-proteinuric gestational hypertension (GH) and preeclampsia (PE). METHODS: In this observational cross-sectional study, venous hemodynamics was assessed using a standardised protocol for combined electrocardiogram (ECG)-Doppler ultrasonography, together with a non-invasive standardised cardiovascular assessment using impedance cardiography (ICG) in 13 women with UP, 21 with GH, 34 with late onset PE >= 34 w (LPE) and 22 with early onset PE < 34 w (EPE). ECG Doppler parameters were impedance index at the level of hepatic veins (HVI) and renal interlobar veins (RIVI) together with venous pulse transit times (VPTT), as well as resistive and pulsatility index, and arterial pulse transit time (APTT) at the level of uterine arcuate arteries. ICG parameters were aortic flow velocity index (VI), acceleration index (ACI) and thoracic fluid content. Mann Whitney U-test, Kruskall-Wallis test and linear regression analysis with heteroskedastic variance was used for statistical analysis. RESULTS: RIVI in both kidneys was >15% higher (P <= .010) in LPE and EPE, as compared to GH and UP. Next to this, >30% lower values for VI and ACI (P <= .029), and > 15% lower values for APTT (P <= .012) were found in GH, LPE and EPE, as compared to GH. CONCLUSION: In comparison to UP, similar abnormalities of central arterial function and APTT were found in GH, EPE and LPE. Proteinuria of LPE and EPE was associated with increased RIVI, this was not observed in GH. PMID- 24957332 TI - Morphologic characterization of meniscal root ligaments in the human knee with magnetic resonance microscopy at 11.7 and 3 T. AB - OBJECTIVE: To determine the feasibility of using MR microscopy to characterize the root ligaments of the human knee at both ultra-high-field (11.7 T) and high field (3 T) strengths. MATERIALS AND METHODS: Seven fresh cadaveric knees were used for this study. Six specimens were imaged at 11.7 T and one specimen at 3 T using isotropic or near-isotropic voxels. Histologic correlation was performed on the posteromedial root ligament of one specimen. Meniscal root ligament shape, signal intensity, and ultrastructure were characterized. RESULTS: High resolution, high-contrast volumetric images were generated from both MR systems. Meniscal root ligaments were predominantly oval in shape. Increased signal intensity was most evident at the posteromedial and posterolateral root ligaments. On the specimen that underwent histologic preparation, increased signal intensity corresponded to regions of enthesis fibrocartilage. Collagen fascicles were continuous between the menisci and root ligaments. Predominantly horizontal meniscal radial tie fibers continued into the root ligaments as vertical endoligaments. CONCLUSION: MR microscopy can be used to characterize and delineate the distinct ultrastructure of the root ligaments on both ultra-high field- and high-field-strength MR systems. PMID- 24957335 TI - Crossover between magnetism and superconductivity in LaFeAsO with low H-doping level. AB - By making a systematic study of the hydrogen-doped LaFeAsO system by means of dc resistivity, dc magnetometry, and muon-spin spectroscopy, we addressed the question of universality of the phase diagram of rare-earth-1111 pnictides. In many respects, the behaviour of LaFeAsO(1-x)H(x) resembles that of its widely studied F-doped counterpart, with H(-) realizing a similar (or better) electron doping in the LaO planes. In an x = 0.01 sample we found a long-range spin density wave (SDW) order with TN = 119 K, while at x = 0.05 the SDW establishes only at 38 K and, below Tc = 10 K, it coexists at a nanoscopic scale with bulk superconductivity. Unlike the abrupt magnetic-superconducting transition found in the La-1111 compound, the presence of a crossover region makes the H-doped system qualitatively similar to other Sm-1111, Ce-1111, and Nd-1111 families. PMID- 24957334 TI - Pregnancy in acute promyelocytic leukaemia after front-line therapy with arsenic trioxide and all-trans retinoic acid. PMID- 24957331 TI - Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking. AB - BACKGROUND: Dopaminergic neurons in the ventral tegmental area of the brain are an important site of convergence of drugs and stress. We previously identified a form of long-term potentiation of gamma-aminobutyric acid (GABA)ergic synapses on these neurons (LTPGABA). Our studies have shown that exposure to acute stress blocks this LTP and that reversal of the block of LTPGABA is correlated with prevention of stress-induced reinstatement of cocaine-seeking behavior. METHODS: Sprague-Dawley rats were subjected to cold-water swim stress. Midbrain slices were prepared following stress, and whole-cell patch clamp recordings of inhibitory postsynaptic currents were performed from ventral tegmental area dopamine neurons. Antagonists of glucocorticoid receptors and kappa opioid receptors (kappaORs) were administered at varying time points after stress. Additionally, the ability of a kappa antagonist administered following stress to block forced swim stress-induced reinstatement of cocaine self-administration was tested. RESULTS: We found that an acute stressor blocks LTPGABA for 5 days after stress through a transient activation of glucocorticoid receptors and more lasting contribution of kappaORs. Even pharmacological block of kappaORs beginning 4 days after stress has occurred reversed the block of LTPGABA. Administration of a kappaORs antagonist following stress prevents reinstatement of cocaine-seeking behavior. CONCLUSIONS: A brief stressor produces changes in the reward circuitry lasting several days. Our findings reveal roles for glucocorticoid receptors and kappaORs as mediators of the lasting effects of stress on synaptic plasticity. kappaORs antagonists reverse the neuroadaptations underlying stress-induced drug-seeking behavior and may be useful in the treatment of cocaine addiction. PMID- 24957338 TI - [Non-invasive prenatal testing: a new era has already come]. PMID- 24957339 TI - Lung recruitment strategy and surfactant in delivery room. AB - The aim of neonatal resuscitation is to establish an effective ventilation, avoiding lung damage. PEEP and T-piece use, as well as Sustained Lung Inflation, lower O2 target and appropriately timed surfactant administration analyzed. A new "gentle" respiratory approach in delivery room can improve newborn respiratory outcome. PMID- 24957337 TI - Molecular mechanism for Rabex-5 GEF activation by Rabaptin-5. AB - Rabex-5 and Rabaptin-5 function together to activate Rab5 and further promote early endosomal fusion in endocytosis. The Rabex-5 GEF activity is autoinhibited by the Rabex-5 CC domain (Rabex-5CC) and activated by the Rabaptin-5 C2-1 domain (Rabaptin-5C21) with yet unknown mechanism. We report here the crystal structures of Rabex-5 in complex with the dimeric Rabaptin-5C21 (Rabaptin-5C212) and in complex with Rabaptin-5C212 and Rab5, along with biophysical and biochemical analyses. We show that Rabex-5CC assumes an amphipathic alpha-helix which binds weakly to the substrate-binding site of the GEF domain, leading to weak autoinhibition of the GEF activity. Binding of Rabaptin-5C21 to Rabex-5 displaces Rabex-5CC to yield a largely exposed substrate-binding site, leading to release of the GEF activity. In the ternary complex the substrate-binding site of Rabex-5 is completely exposed to bind and activate Rab5. Our results reveal the molecular mechanism for the regulation of the Rabex-5 GEF activity. PMID- 24957336 TI - Host-induced bacterial cell wall decomposition mediates pattern-triggered immunity in Arabidopsis. AB - Peptidoglycans (PGNs) are immunogenic bacterial surface patterns that trigger immune activation in metazoans and plants. It is generally unknown how complex bacterial structures such as PGNs are perceived by plant pattern recognition receptors (PRRs) and whether host hydrolytic activities facilitate decomposition of bacterial matrices and generation of soluble PRR ligands. Here we show that Arabidopsis thaliana, upon bacterial infection or exposure to microbial patterns, produces a metazoan lysozyme-like hydrolase (lysozyme 1, LYS1). LYS1 activity releases soluble PGN fragments from insoluble bacterial cell walls and cleavage products are able to trigger responses typically associated with plant immunity. Importantly, LYS1 mutant genotypes exhibit super-susceptibility to bacterial infections similar to that observed on PGN receptor mutants. We propose that plants employ hydrolytic activities for the decomposition of complex bacterial structures, and that soluble pattern generation might aid PRR-mediated immune activation in cell layers adjacent to infection sites. PMID- 24957340 TI - Lung recruitment strategies and surfactant in neonatal intensive care unit. AB - Several studies in the lamb model have shown that hyperinflation of the lungs early in life may cause a blunted response to surfactant with signs of lung injury and any attempt to recruit lung volume in the surfactant deficient preterm infant by large lung inflations at birth should be potentially dangerous. As regards the situation when surfactant is given later, as rescue treatment for established RDS, the evidence for a clinically beneficial effect of a recruitment maneuver is yet insufficient and, hopefully, future studies will gather more data on this aspect. PMID- 24957341 TI - Weaning of infants from non invasive ventilation. AB - Non invasive ventilation (NIV) is commonly used to treat RDS in preterm infants. Although less risky than invasive ventilation, NIV has some potential side effects and appropriate weaning is therefore desirable. However, criteria for the definition of stability prior to attempting NIV weaning as well as the best weaning strategies need to be more investigated. The aim of this review is to identify criteria and interventions that can facilitate correct weaning from NIV. PMID- 24957342 TI - Weaning from invasive respiratory support in newborn: is there just one strategy? AB - Despite a even more frequent use to non-invasive respiratory support, mechanical ventilation is stilloften necessary for supporting premature infants with lung disease. Protracted mechanical ventilation is associatedwith increased morbidity and mortality and thus the earliest weaning from invasive respiratory supportis desirable. Weaning protocols may be helpful in achieving more rapid reduction in support. However,no consensus has been reached on criteria to identify when patients are ready to wean or how to achieve it. Inthis article, available evidence is reviewed and reasonable evidence-based recommendations for weaning andextubation are provided. PMID- 24957343 TI - Lung ultrasound: diagnostic and therapeutic issues. AB - BACKGROUND: Lung ultrasound (LUS) is becoming more and more utilised in the clinical field inadults, children and neonates in course of respiratory diseases. It can be done at bed side and repeated as muchis needed without risks (namely irradiation). METHODS: The technique of LUS execution and the normal andpathologic patterns of LUS in neonates are described. RESULTS: The LUS findings in the different respiratoryneonatal diseases are peculiar and consistently repeatable. CONCLUSION: The use of LUS in neonates may indicatein real time the diagnosis of the respiratory disease. Should be considered as an extension of the clinicalexam and must be done by the clinician in charge of the patient. PMID- 24957344 TI - Neurodevelopmental outcomes of premature infants with bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD) is a chronic lung disorder common among very preterm infants affecting significantly not only mortality and morbidity but also neurodevelopmental outcomes. This review aims to identify the short and long-term neurodevelopmental outcomes of infants with BPD, considering that the new definition of BPD allows to relate severity of BPD with greater risk of developmental delay. PMID- 24957345 TI - Surfactant administration in spontaneous breathing with N-CPAP for RDS. AB - Surfactant administration in spontaneous breathing with N-CPAP seems to be a promising approach in the management of neonatal RDS. Both recent RCTs and single centre experience have shown feasibility and good respiratory outcomes with this approach even in extremely preterm infants with respiratory failure. The results of these studies seem to demonstrate that avoiding mechanical ventilation and manual inflation (therefore the risk of high positive pressure and inappropriate tidal volume) it is possible to reduce the risk of VILI and the evolution towards BPD. Further large clinical studies are needed to confirm this hypothesis. PMID- 24957346 TI - Clinical management of the neonatal pneumomediastinum. AB - pneumomediastinum (PM) occurs in approximately 0.1% of newborns but its incidence is underestimatedbecause it is often asymptomatic. PM generally has a benign course. Our knowledge of PM is insufficient,and its management is mainly based on the best practice and experience of each hospital rather thanon evidence-based data. PMID- 24957347 TI - Foreword. AB - This supplement of Acta Biomedica collects the Proceedings of the workshop "Meeting sul surfattante... PMID- 24957349 TI - Preparation and fluorescence properties of color tunable phosphors Ca3Y2(Si3O9)2:Dy3+. AB - A novel reddish-orange phosphor, Ca3Y(2-2x)(Si3O9)2:2xDy(3+), was synthesized via conventional solid-state reaction. Its photoluminescence properties were investigated. With increasing Dy(3+) concentration, the luminescence intensity first increases, reaches the greatest, and then decreases. The concentration quenching mechanism is based on the electric dipole-dipole interaction. The decay times were also determined. PMID- 24957348 TI - PET imaging of Oatp-mediated hepatobiliary transport of [(11)C] rosuvastatin in the rat. AB - A novel positron emission tomography (PET) tracer, [(11)C]-rosuvastatin (RSV), was developed to dynamically and noninvasively measure hepatobiliary transport and tissue distribution of [(11)C]-RSV in rats. METHODS: Male Sprague-Dawley rats were administered either an Oatp inhibitor, rifampin (RIF, 40 mg/kg iv bolus plus 1.85 mg/min/kg iv infusion, n = 3), or the corresponding vehicle (saline, n = 3) for at least 90 min. Then, while these infusions were ongoing, the animals received [(11)C]-rosuvastatin (~1 mCi/30 s, iv infusion). After [(11)C]-RSV administration, the lower abdominal region of the rats was imaged for 90 min. Time-activity curves for liver, intestine, and kidney were obtained and corrected for vascular content prior to noncompartmental and compartmental (five compartment model) analysis. RESULTS: The majority of the [(11)C]-RSV dose was distributed into the liver. In the presence of RIF, the area under the [(11)C] RSV radioactivity blood concentration-time profile (AUC0-90 min) was increased by ~3-fold. Relative to the control animals, RIF reduced the distribution of [(11)C] RSV radioactivity into the liver and kidney (tissue AUC0-15 min/blood AUC0-15 min) by 54% and 73% respectively. Compartmental modeling showed that RIF decreased CLBL, CLLI, CLBK, and CLK0 but had no effect on CLLB, where B, L, I, K, and 0 represent blood, liver, intestine, kidney, and irreversible loss. CONCLUSION: [(11)C]-RSV can be used to dynamically and noninvasively quantify hepatobiliary transport and hepatic concentration of the drug, in the absence and presence of drug interactions, in rats and could be used for the same purpose in humans. PMID- 24957350 TI - International collaboration at its finest. PMID- 24957351 TI - Regioselective synthesis of cytarabine monopropionate by using a fungal whole cell biocatalyst in nonaqueous medium. AB - The utilization of a dehydrated fungal biocatalyst of Aspergillus oryzae cells was successfully performed to achieve efficient acylation modification of a polar nucleoside cytarabine (ara-C). Organic solvents showed evident influence on the reaction catalyzed by the A. oryzae whole-cells. Except for hexane-pyridine, the catalytic activity and regioselectivity of the whole-cells clearly increased with increasing the polarity of the hydrophobic organic solvents used. The effects of some crucial factors on the reaction were further examined. The best reaction medium, hydrophobic solvent concentration, vinyl propionate/ara-C ratio, reaction temperature and shaking speed were confirmed as isopropyl ether (IPE)-pyridine, 30% (v/v), 90, 30 degrees C and 140-180 rpm, respectively. The cell biocatalyst also showed good thermal stabilities in both IPE-pyridine and hexane-pyridine systems. In addition, the desired 3'-O-propional derivative of ara-C was synthesized with the yields of 88.3% and regioselectivity (>70%). The resulting biocatalytic system appears to be an effective alternative, and can thus be employed for application in highly regioselective modification of nucleoside analogues. PMID- 24957353 TI - Ambulatory oxygen for people with chronic obstructive pulmonary disease who are not hypoxaemic at rest. AB - BACKGROUND: People with chronic obstructive pulmonary disease (COPD) often become transiently hypoxaemic (low oxygen levels in blood) on exercise, necessitating oxygen therapy to improve breathlessness and exercise capacity and to reduce disability. Ambulatory oxygen therapy refers to provision of oxygen therapy during exercise and activities of daily living. Ambulatory oxygen therapy is often used by patients on long-term oxygen therapy (LTOT) during exercise or by non-LTOT users with or without resting hypoxaemia when they show evidence of exercise de-saturation and demonstrate improvement in exercise capacity with supplemental oxygen. OBJECTIVES: To determine the longer-term efficacy of ambulatory oxygen therapy only in patients with COPD who do not meet the criteria for LTOT, with respect to improvement in exercise capacity, mortality, quality of life and other relevant measures of improvement. SEARCH METHODS: The Cochrane Airways Group Specialised Register, including MEDLINE, EMBASE and CINAHL, was searched. Online clinical trial registers, including Controlled Clinical Trials (www.controlled-trials.com), government registries (clinicaltrials.gov) and World Health Organization (WHO) registries (www.who.int/trialsearch), were screened for ongoing and recently completed studies. Bibliographies of included studies were searched for additional trials that may meet the inclusion criteria and were not retrieved by the above search strategy. Authors of identified trials were contacted to provide other published and unpublished studies. Searches were current as of November 2012. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compare ambulatory oxygen therapy provided through portable oxygen cylinders/battery-powered devices or liquid oxygen canisters versus placebo air cylinders, usual medical care or co-intervention in study participants with COPD who did not meet criteria for LTOT. DATA COLLECTION AND ANALYSIS: We used standard methods as expected by The Cochrane Collaboration. MAIN RESULTS: Four studies met the inclusion criteria (331 participants), with two studies producing a statistically and clinically significant benefit in favour of the intervention for dyspnoea post exercise.The quality of life domain for all four included studies produced a statistically significant benefit for the subcategories of dyspnoea and fatigue, in favour of the oxygen group (dyspnoea mean difference (MD) 0.28, 95% confidence interval (CI) 0.10 to 0.45; P value 0.002; fatigue MD 0.17, 95% CI 0.04 to 0.31; P value 0.009). No evidence of any effect was reported for survival, and limited benefits were observed for exercise capacity (as measured by step test and distance walk test), with one study showing a statistically significant improvement in the number of steps taken in the oxygen group for group N-of-1 studies only. No other statistically significant benefits were observed for exercise capacity among the other trials or individual N-of-1 studies. AUTHORS' CONCLUSIONS: In patients with COPD with moderate hypoxia, current evidence on ambulatory oxygen therapy reveals improvements in dyspnoea post exercise and in the dyspnoea and fatigue domain of quality of life. However, evidence for the clinical utility and effectiveness of ambulatory oxygen in improving mortality and exercise capacity was not evident in this review. Methodologically rigorous RCTs with sufficient power to detect a difference are required to investigate the role of ambulatory oxygen in the management of COPD. PMID- 24957352 TI - One-pot synthesis of cinnamylideneacetophenones and their in vitro cytotoxicity in breast cancer cells. AB - A series of cinnamylideneacetophenones were synthesized via a modified Claisen Schmidt condensation reaction and evaluated for cytotoxicity against breast cancer cells using the Alamar BlueTM assay. Derivatives 17 and 18 bearing a 2 nitro group on the B ring, exhibited sub-micromolar cytotoxicity in MCF-7 cells (IC50=71 and 1.9 nM), respectively. Derivative 17 also displayed sub-micromolar (IC50=780 nM) cytotoxicity in MDA-MB-468 cells. Additionally, 17 and 18 displayed significantly less cytotoxicity than the chemotherapeutic doxorubicin in non tumorigenic MCF-10A cells. This study provides evidence supporting the continued development of nitro-substituted cinnamylideneacetophenones as small molecules to treat breast cancer. PMID- 24957355 TI - Amusia and cognitive deficits in schizophrenia: is there a relationship? AB - The current study explored the music perception ability of individuals diagnosed with schizophrenia and its relationship with other cognitive abilities and psychotic symptom severity. The persons with schizophrenia performed significantly worse than the control group on the Montreal Battery of Evaluation of Amusia (MBEA) (p<0.001). The music perception ability of persons with schizophrenia was related to other cognitive abilities (attention, verbal memory, spatial memory, and executive function) and the severity of psychotic symptoms. PMID- 24957354 TI - Effects of age on white matter integrity and negative symptoms in schizophrenia. AB - The current study examined the relationship between white matter integrity as indexed by diffusion tensor imaging and negative symptom severity in schizophrenia. The current study included statistical controls for age effects on the relationship of interest, a major weakness of the existing literature on the subject. Participants included 59 chronic schizophrenia patients, and 31 first episode schizophrenia patients. Diffusion-weighted neuroimaging was used to calculate fractional anisotropy (FA) in each major brain region (frontal, temporal, parietal, and occipital lobes). Negative symptoms were measured using the Scale for the Assessment of Negative Symptoms (SANS) in all schizophrenia patients. Significant bivariate correlations were observed between global SANS scores and global FA, as well as in most brain regions. These relationships appeared to be driven by SANS items measuring facial expressiveness, poor eye contact, affective flattening, inappropriate affect, poverty of speech, poverty of speech content, alogia, and avolition. However, upon addition of age as a covariate, the observed relationships became non-significant. Further analysis revealed very strong age effects on both FA and SANS scores in the current sample. The findings of this study refute previous reports of significant relationships between DTI variables and negative symptoms in schizophrenia, and they suggest an important confounding variable to be considered in future studies in this population. PMID- 24957357 TI - Influence of ISDN, L-NAME and selenium on microcirculation, leukocyte endothelium interaction and angiogenesis after frostbite. AB - BACKGROUND: The body of knowledge regarding the different facets of frostbite injury continues to expand. However, beside the administration of physiological saline, local rewarming, local disinfection and symptomatic medications, today no causal therapy is known which would accelerate angiogenesis and wound healing. The aim of this study was to investigate the influences of dilative acting drugs on microcirculation, angiogenesis and leukocyte behavior. MATERIALS AND METHODS: Ears of male hairless mice (n=40) were inflicted with full thickness frostbites using a cold air jet. Then the affects of four intraperitoneal injections of isosorbitdinitrate (ISDN, n=10), l-nitroarginine-methyl-ester (l-NAME, n=10), selenium (n=10) or sodium chloride (n=10; each administered to one of four corresponding study groups), on microcirculation, leukocyte-endothelial interaction and angiogenesis were investigated over a 12-day period using intravital fluorescent microscopy. RESULTS: Angiogenesis was most improved by ISDN (36.8 vs. 54.5% non-perfused area on day 3, 3.9 vs. 17.0% on day 7 compared to selenium, p<0.006). Venular diameter was most significantly dilated in the ISDN-group, l-NAME showed significantly decreased diameter over the complete time of 12 days. ISDN had positive influences on edema formation, which was significantly reduced compared to control (27% lower values compared to control; p=0.007 on day 3). The l-NAME-group showed the significant highest leukocyte adhesion compared to control on days 7 and 12 (53% resp. 58% higher, p<0.006). CONCLUSION: Overall, out of all the drugs tested, ISDN improved angiogenesis, dilated venules and decreased edema formation and therefore seems to have the greatest positive impact on these crucial parameters after frostbite injury. PMID- 24957358 TI - The clinical features of burns resulting from two aerial devices set off in a public fireworks display: 149 case reports. AB - We report the clinical features of 149 cases with aerial devices burns in a public fireworks display. The characteristic features included sudden onset, masses of terrified burn victims, small and deep wounds, mild disease conditions, and favorable prognosis. Unlike in home or illegal fireworks displays, the body areas most often involved were the extremity, chest, abdomen, and back, and most of the victims were adults in these public fireworks displays. PMID- 24957359 TI - Surgical treatment of recurrent prolapse after stapled haemorrhoidopexy. AB - BACKGROUND: Recurrent prolapse after stapled haemorrhoidopexy is a late complication of the procedure which can present with accompanying symptoms and may require surgery. We describe a technique for treating symptomatic patients, aimed at obtaining remission of symptoms and avoiding recurrences. METHODS: After excisional haemorrhoidectomy, a transverse incision is performed on the proximal part of the mucocutaneous bridge, above the plane of the internal sphincter. A flap of anal mucosa is gently raised. Haemorrhoidal tissue is not removed. LigaSureTM may be useful in focussing coagulation and reducing heat diffusion. Denudation of the internal sphincter allows the removal of potential retained staples. Then, stitches are placed between the proximal part of the flap and the proximal divided edge of the rectal mucosa. Excessive devascularisation of the flap must be avoided. RESULTS: From January 2007 to January 2011, we treated 11 patients. The procedures lasted a mean of 38.2 +/- 11.1 min. One patient (9 %) suffered from bleeding during the night before being discharged, but this did not require surgery, and another (9 %) had urinary retention. No other perioperative complications were observed. The mean visual analogue scale score 1 day and 1 week after surgery was 4.7 +/- 1.3 and 2.3 +/- 0.5, respectively. At mean follow up of 4 +/- 1.8 years, neither symptomatic nor asymptomatic recurrences have been observed. Two out of three patients presenting with urgency reported regression of symptoms (66.7 %). In all patients suffering from pain after stapled haemorrhoidopexy, the procedure achieved pain relief (2/2, 100 %). No stenoses occurred. CONCLUSIONS: This technique is a promising alternative after failed stapled haemorrhoidopexy. Morbidity is low. The procedure may effectively treat associated symptoms. PMID- 24957360 TI - Robotic transanal total mesorectal excision: a pilot study. AB - BACKGROUND: The introduction of transanal minimally invasive surgery (TAMIS) in 2009 allowed colorectal surgeons to approach transanal access with a different perspective. This has lead to the development of TAMIS for total mesorectal excision (TME). We have previously described robotic transanal TME and here report our initial experience with the first three human cases performed at a single institution. METHODS: Three patients with distal rectal cancer were selective to undergo robotic transanal TME. All resections were carried out with intent to cure; they were performed by a single attending colorectal surgeon over an 11-month period. RESULTS: Three patients underwent robotic transanal TME. The average age was 45 years (range 26-59) with mean BMI of 32 kg/m(2) (range 21 38.5). The average tumor size was 2.5 cm. All lesions were located in the distal 5 cm of the rectum. In each case, the distal and circumferential resection margins were free of tumor. The resection quality of the mesorectal envelope was Grade I and Grade II. There was no major morbidity or mortality on short-term follow-up. CONCLUSIONS: Robotic transanal TME is a new modality for en bloc rectal cancer surgery, and the technique is feasible. Further study is necessary to assess the benefit of this novel approach. PMID- 24957361 TI - Ligation of intersphincteric fistula tract (LIFT) to treat anal fistula: systematic review and meta-analysis. AB - Sphincter-preserving approaches to treat anal fistula do not jeopardize continence; however, healing rates are suboptimal. In this context, ligation of the intersphincteric fistula tract (LIFT) can be considered promising offering high success rates and a relatively simple procedure. This review aimed to investigate the outcomes of LIFT to treat anal fistula. We conducted a systematic review of the Pubmed, Web of Science, and Cochrane databases, to retrieve all relevant scientific original articles and scientific abstracts (Web of Science) related to the LIFT procedure for anal fistula between January 2007 and March 2013. The search yielded 24 original articles including 1,110 patients; these included one randomized controlled study, three case control studies, and 20 case series. Most studies included patients with trans-sphincteric or complex fistula, not amenable to fistulotomy. During a pooled mean 10.3 months of follow-up, the mean success, incontinence, intraoperative, and postoperative complication rates were 76.4, 0, 0, and 5.5%, respectively. A sensitivity analysis showed that the impact on success in terms of follow-up duration, study size, and combining other procedures was limited. There was no association between pre-LIFT drainage seton and success of LIFT. Ligation of the intersphincteric fistula tract appears to be an effective and safe treatment for trans-sphincteric or complex anal fistula. Combining other procedures and a pre-LIFT drainage seton does not seem to confer any added benefit in terms of success. However, given the lack of prospective randomized trials, interpretation of these data must be cautious. Further trials are mandatory to identify predictive factors for success, and true effectiveness of the LIFT compared to other sphincter-preserving procedures to treat anal fistula. PMID- 24957362 TI - The importance of perceived care and connectedness with friends and parents for adolescent social anxiety. AB - Nonclinical social anxiety in adolescence can be highly problematic, as it likely affects current and especially new social interactions. Relationships with significant others, such as close friends, mothers, and fathers, could aid socially anxious adolescents' participation in social situations, thereby helping reduce feelings of social anxiety. We examined whether making friends as well as high friendship quality help reduce social anxiety over time, and whether friends', mothers', and fathers' care interact in reducing social anxiety. Using longitudinal data from 2,194 participants in a social network (48% girls; Mage = 13.58) followed for 3 years, we estimated friendship selection and influence processes via a continuous time-modeling approach using SIENA. We controlled for the effects of depressive symptoms, self-esteem, gender, age, and family structure. Our findings suggest that perceived care by friends mediated the effect of making friends on social anxiety. Perceptions of mother and father, as well as friend care and connectedness, respectively, did not interact in decreasing social anxiety. Nonetheless, care and connectedness with mothers, fathers, and friends jointly predicted decreases in social anxiety. Caring relationships with friends and parents each play a role in mutually protecting early adolescents against increasing in social anxiety over time. PMID- 24957363 TI - Akt1 activity regulates vessel maturation in a tissue engineering model of angiogenesis. AB - Akt kinase is a central signal transduction node that integrates extracellular cues that regulate cell migratory, proliferative, and morphological functions during angiogenesis. However, how Akt activity is modulated and contributes to subsequent vessel maturation is unclear. In this study we investigated the role of Akt1 in vessel maturation using human dermal microvascular endothelial cells (HDMVECs) expressing constitutively active and hemiphosphorylated Akt1 epi alleles with graded kinase activity. HDMVECs expressing Akt1 epi-alleles were analyzed in vivo in a tissue engineering setting using a model of angiogenesis comprising cell-seeded poly-L-lactic acid scaffolds implanted subcutaneously into NOD/SCID murine hosts. The resultant intraimplant microvasculature was quantified for vascular parameters, including vessel diameter, perfusion, vascular density, and pericyte coverage. We found that constitutive Akt1 kinase activity in implanted HDMVECs correlated with loss of neovasculature function. Further, we found that the presence of coimplanted vascular smooth muscle cells (vSMCs) in the implants failed to promote blood vessel growth and maturation in a graded, Akt1 kinase activity-dependent manner. These results indicate that constitutive Akt1 activity disrupts the normal blood vessel growth and maturation. Therefore, we suggest that a downregulation of Akt1 activity is necessary for vSMC-induced maturation of newly formed blood vessels to occur. PMID- 24957364 TI - Hypophosphatemic rickets: etiology, clinical features and treatment. AB - Hypophosphatemic rickets (HR) is a genetic disorder, which prevents sufficient reabsorption of phosphate in the proximal renal tubule, with increased phosphate excretion, resulting in rickets. The more common form of HR is an X-linked inherited trait, with a prevalence of 1/20,000. The defective gene is located on the X chromosome, but females may present with a wide variety of clinical manifestations. The less common form of HR is caused by autosomal-dominant transmission. Activating mutations of the fibroblast growth factor 23 (FGF-23) gene and inactivating mutations in the phosphate regulating gene (PHEX gene with homologies to endopeptidases on the X chromosome), involved in the regulation of FGF-23, have been identified and have been implicated in the pathogenesis of these disturbances. A review of etiopathogenesis and clinical, differential diagnostic and therapeutic aspects of HR, with a particular emphasis on bone impairment, is reported. PMID- 24957365 TI - Perturbations of lipid metabolism indexed by lipidomic biomarkers. AB - The lipidome of the liver and the secreted circulating lipoproteins can now be interrogated conveniently by automated mass spectrometric methods. Multivariate analysis of the liver and serum lipid composition in various animal modes or in human patients has pointed to specific molecular species markers. The perturbations of lipid metabolism can be categorized on the basis of three basic pathological mechanisms: (1) an accelerated rate of de novo lipogenesis; (2) perturbation of the peroxisome pathway of ether-lipid and very-long-chain fatty acid biosynthesis; (3) a change in the rate of interconversion of essential omega 3 and -6 polyunsaturated fatty acids. This review provides examples to illustrate the practicalities of lipidomic studies in biomedicine. PMID- 24957367 TI - Comparative Chemistry of Aspergillus oryzae (RIB40) and A. flavus (NRRL 3357). AB - Aspergillus oryzae and A. flavus are important species in industrial biotechnology and food safety and have been some of the first aspergilli to be fully genome sequenced. Bioinformatic analysis has revealed 99.5% gene homology between the two species pointing towards a large coherence in the secondary metabolite production. In this study we report on the first comparison of secondary metabolite production between the full genome sequenced strains of A. oryzae (RIB40) and A. flavus (NRRL 3357). Surprisingly, the overall chemical profiles of the two strains were mostly very different across 15 growth conditions. Contrary to previous studies we found the aflatrem precursor 13 desoxypaxilline to be a major metabolite from A. oryzae under certain growth conditions. For the first time, we additionally report A. oryzae to produce parasiticolide A and two new analogues hereof, along with four new alkaloids related to the A. flavus metabolites ditryptophenalines and miyakamides. Generally the secondary metabolite capability of A. oryzae presents several novel end products likely to result from the domestication process from A. flavus. PMID- 24957366 TI - Mass spectrometry based lipidomics: an overview of technological platforms. AB - One decade after the genomic and the proteomic life science revolution, new 'omics' fields are emerging. The metabolome encompasses the entity of small molecules-Most often end products of a catalytic process regulated by genes and proteins-with the lipidome being its fat soluble subdivision. Within recent years, lipids are more and more regarded not only as energy storage compounds but also as interactive players in various cellular regulation cycles and thus attain rising interest in the bio-medical community. The field of lipidomics is, on one hand, fuelled by analytical technology advances, particularly mass spectrometry and chromatography, but on the other hand new biological questions also drive analytical technology developments. Compared to fairly standardized genomic or proteomic high-throughput protocols, the high degree of molecular heterogeneity adds a special analytical challenge to lipidomic analysis. In this review, we will take a closer look at various mass spectrometric platforms for lipidomic analysis. We will focus on the advantages and limitations of various experimental setups like 'shotgun lipidomics', liquid chromatography-Mass spectrometry (LC-MS) and matrix assisted laser desorption ionization-time of flight (MALDI-TOF) based approaches. We will also examine available software packages for data analysis, which nowadays is in fact the rate limiting step for most 'omics' workflows. PMID- 24957369 TI - The Effect of LC-MS Data Preprocessing Methods on the Selection of Plasma Biomarkers in Fed vs. Fasted Rats. AB - The metabolic composition of plasma is affected by time passed since the last meal and by individual variation in metabolite clearance rates. Rat plasma in fed and fasted states was analyzed with liquid chromatography quadrupole-time-of flight mass spectrometry (LC-QTOF) for an untargeted investigation of these metabolite patterns. The dataset was used to investigate the effect of data preprocessing on biomarker selection using three different softwares, MarkerLynxTM, MZmine, XCMS along with a customized preprocessing method that performs binning of m/z channels followed by summation through retention time. Direct comparison of selected features representing the fed or fasted state showed large differences between the softwares. Many false positive markers were obtained from custom data preprocessing compared with dedicated softwares while MarkerLynxTM provided better coverage of markers. However, marker selection was more reliable with the gap filling (or peak finding) algorithms present in MZmine and XCMS. Further identification of the putative markers revealed that many of the differences between the markers selected were due to variations in features representing adducts or daughter ions of the same metabolites or of compounds from the same chemical subclasses, e.g., lyso-phosphatidylcholines (LPCs) and lyso-phosphatidylethanolamines (LPEs). We conclude that despite considerable differences in the performance of the preprocessing tools we could extract the same biological information by any of them. Carnitine, branched-chain amino acids, LPCs and LPEs were identified by all methods as markers of the fed state whereas acetylcarnitine was abundant during fasting in rats. PMID- 24957368 TI - Quantification of Signaling Lipids by Nano-Electrospray Ionization Tandem Mass Spectrometry (Nano-ESI MS/MS). AB - Lipids, such as phosphoinositides (PIPs) and diacylglycerol (DAG), are important signaling intermediates involved in cellular processes such as T cell receptor (TCR)-mediated signal transduction. Here we report identification and quantification of PIP, PIP2 and DAG from crude lipid extracts. Capitalizing on the different extraction properties of PIPs and DAGs allowed us to efficiently recover both lipid classes from one sample. Rapid analysis of endogenous signaling molecules was performed by nano-electrospray ionization tandem mass spectrometry (nano-ESI MS/MS), employing lipid class-specific neutral loss and multiple precursor ion scanning for their identification and quantification. Profiling of DAG, PIP and PIP2 molecular species in primary human T cells before and after TCR stimulation resulted in a two-fold increase in DAG levels with a shift towards 1-stearoyl-2-arachidonoyl-DAG in stimulated cells. PIP2 levels were slightly reduced, while PIP levels remained unchanged. PMID- 24957372 TI - Investigation of Phenolic Acids in Suspension Cultures of Vitis vinifera Stimulated with Indanoyl-Isoleucine, N-Linolenoyl-L-Glutamine, Malonyl Coenzyme A and Insect Saliva. AB - Vitis vinifera c.v. Muscat de Frontignan (grape) contains various high valuable bioactive phenolic compounds with pharmaceutical properties and industrial interest which are not fully exploited. The focus of this investigation consists in testing the effects of various biological elicitors on a non-morphogenic callus suspension culture of V. vinifera. The investigated elicitors: Indanoyl isoleucine (IN), N-linolenoyl-L-glutamine (LG), insect saliva (IS) and malonyl coenzyme A (MCoA) were aimed at mimicking the influence of environmental pathogens on plants in their natural habitats and at provoking exogenous induction of the phenylpropanoid pathway. The elicitors' indanoyl-isoleucine (IN), N-linolenoyl-L-glutamine (LG) and insect saliva (IS), as well as malonyl coenzyme A (MCoA), were independently inoculated to stimulate the synthesis of phenylpropanoids. All of the enhancers positively increased the concentration of phenolic compounds in grape cells. The highest concentration of phenolic acids was detected after 2 h for MCoA, after 48 h for IN and after 24 h for LG and IS respectively. At the maximum production time, treated grape cells had a 3.5-fold (MCoA), 1.6-fold (IN) and 1.5-fold (IS) higher phenolic acid content compared to the corresponding control samples. The HPLC results of grape cells showed two major resveratrol derivatives: 3-O-Glucosyl-resveratrol and 4-(3,5 dihydroxyphenyl)-phenol. Their influences of the different elicitors, time of harvest and biomass concentration (p < 0.0001) were statistically significant on the synthesis of phenolic compounds. The induction with MCoA was found to demonstrate the highest statistical effect corresponding to the strongest stress response within the phenylpropanoid pathway in grape cells. PMID- 24957370 TI - Genetics of Polyketide Metabolism in Aspergillus nidulans. AB - Secondary metabolites are small molecules that show large structural diversity and a broad range of bioactivities. Some metabolites are attractive as drugs or pigments while others act as harmful mycotoxins. Filamentous fungi have the capacity to produce a wide array of secondary metabolites including polyketides. The majority of genes required for production of these metabolites are mostly organized in gene clusters, which often are silent or barely expressed under laboratory conditions, making discovery and analysis difficult. Fortunately, the genome sequences of several filamentous fungi are publicly available, greatly facilitating the establishment of links between genes and metabolites. This review covers the attempts being made to trigger the activation of polyketide metabolism in the fungal model organism Aspergillus nidulans. Moreover, it will provide an overview of the pathways where ten polyketide synthase genes have been coupled to polyketide products. Therefore, the proposed biosynthesis of the following metabolites will be presented; naphthopyrone, sterigmatocystin, aspyridones, emericellamides, asperthecin, asperfuranone, monodictyphenone/emodin, orsellinic acid, and the austinols. PMID- 24957373 TI - Intracellular Metabolite Pool Changes in Response to Nutrient Depletion Induced Metabolic Switching in Streptomyces coelicolor. AB - A metabolite profiling study of the antibiotic producing bacterium Streptomyces coelicolor A3(2) has been performed. The aim of this study was to monitor intracellular metabolite pool changes occurring as strains of S. coelicolor react to nutrient depletion with metabolic re-modeling, so-called metabolic switching, and transition from growth to secondary metabolite production phase. Two different culture media were applied, providing depletion of the key nutrients phosphate and L-glutamate, respectively, as the triggers for metabolic switching. Targeted GC-MS and LC-MS methods were employed to quantify important primary metabolite groups like amino acids, organic acids, sugar phosphates and other phosphorylated metabolites, and nucleotides in time-course samples withdrawn from fully-controlled batch fermentations. A general decline, starting already in the early growth phase, was observed for nucleotide pools and phosphorylated metabolite pools for both the phosphate and glutamate limited cultures. The change in amino acid and organic acid pools were more scattered, especially in the phosphate limited situation while a general decrease in amino acid and non amino organic acid pools was observed in the L-glutamate limited situation. A phoP deletion mutant showed basically the same metabolite pool changes as the wild-type strain M145 when cultivated on phosphate limited medium. This implies that the inactivation of the phoP gene has only little effect on the detected metabolite levels in the cell. The energy charge was found to be relatively constant during growth, transition and secondary metabolite production phase. The results of this study and the employed targeted metabolite profiling methodology are directly relevant for the evaluation of precursor metabolite and energy supply for both natural and heterologous production of secondary metabolites in S. coelicolor. PMID- 24957374 TI - Shotgun Lipidomics by Sequential Precursor Ion Fragmentation on a Hybrid Quadrupole Time-of-Flight Mass Spectrometer. AB - Shotgun lipidomics has evolved into a myriad of multi-dimensional strategies for molecular lipid characterization, including bioinformatics tools for mass spectrum interpretation and quantitative measurements to study systems-lipidomics in complex biological extracts. Taking advantage of spectral mass accuracy, scan speed and sensitivity of improved quadrupole linked time-of-flight mass analyzers, we developed a bias-free global lipid profiling acquisition technique of sequential precursor ion fragmentation called MS/MSALL. This generic information-independent tandem mass spectrometry (MS) technique consists of a Q1 stepped mass isolation window through a set mass range in small increments, fragmenting and recording all product ions and neutral losses. Through the accurate MS and MS/MS information, the molecular lipid species are resolved, including distinction of isobaric and isomeric species, and composed into more precise lipidomic outputs. The method demonstrates good reproducibility and at least 3 orders of dynamic quantification range for isomeric ceramides in human plasma. More than 400 molecular lipids in human plasma were uncovered and quantified in less than 12 min, including acquisitions in both positive and negative polarity modes. We anticipate that the performance of sequential precursor ion fragmentation both in quality and throughput will lead to the uncovering of new avenues throughout the biomedical research community, enhance biomarker discovery and provide novel information target discovery programs as it will prospectively shed new insight into affected metabolic and signaling pathways. PMID- 24957371 TI - Lipidomics of glycosphingolipids. AB - Glycosphingolipids (GSLs) contain one or more sugars that are attached to a sphingolipid moiety, usually to a ceramide, but in rare cases also to a sphingoid base. A large structural heterogeneity results from differences in number, identity, linkage, and anomeric configuration of the carbohydrate residues, and also from structural differences within the hydrophobic part. GSLs form complex cell-type specific patterns, which change with the species, the cellular differentiation state, viral transformation, ontogenesis, and oncogenesis. Although GSL structures can be assigned to only a few series with a common carbohydrate core, their structural variety and the complex pattern are challenges for their elucidation and quantification by mass spectrometric techniques. We present a general overview of the application of lipidomics for GSL determination. This includes analytical procedures and instrumentation together with recent correlations of GSL molecular species with human diseases. Difficulties such as the structural complexity and the lack of standard substances for complex GSLs are discussed. PMID- 24957375 TI - Atlantinone A, a Meroterpenoid Produced by Penicillium ribeum and Several Cheese Associated Penicillium Species. AB - Atlantinone A has been isolated from the psychrotolerant fungus Penicillium ribeum. The exact structure of the compound was confirmed by mass spectrometric and 1- and 2D NMR experiments. Atlantinone A was originally only produced upon chemical epigenetic manipulation of P. hirayamae, however in this study the compound was found to be produced at standard growth conditions by the following species; P. solitum, P. discolor, P. commune, P. caseifulvum, P. palitans, P. novae-zeelandiae and P. monticola. A biosynthetic pathway to atlantinone A starting from andrastin A is proposed. PMID- 24957376 TI - Canonical modeling of the multi-scale regulation of the heat stress response in yeast. AB - Heat is one of the most fundamental and ancient environmental stresses, and response mechanisms are found in prokaryotes and shared among most eukaryotes. In the budding yeast Saccharomyces cerevisiae, the heat stress response involves coordinated changes at all biological levels, from gene expression to protein and metabolite abundances, and to temporary adjustments in physiology. Due to its integrative multi-level-multi-scale nature, heat adaptation constitutes a complex dynamic process, which has forced most experimental and modeling analyses in the past to focus on just one or a few of its aspects. Here we review the basic components of the heat stress response in yeast and outline what has been done, and what needs to be done, to merge the available information into computational structures that permit comprehensive diagnostics, interrogation, and interpretation. We illustrate the process in particular with the coordination of two metabolic responses, namely the dramatic accumulation of the protective disaccharide trehalose and the substantial change in the profile of sphingolipids, which in turn affect gene expression. The proposed methods primarily use differential equations in the canonical modeling framework of Biochemical Systems Theory (BST), which permits the relatively easy construction of coarse, initial models even in systems that are incompletely characterized. PMID- 24957377 TI - Human metabolic network: reconstruction, simulation, and applications in systems biology. AB - Metabolism is crucial to cell growth and proliferation. Deficiency or alterations in metabolic functions are known to be involved in many human diseases. Therefore, understanding the human metabolic system is important for the study and treatment of complex diseases. Current reconstructions of the global human metabolic network provide a computational platform to integrate genome-scale information on metabolism. The platform enables a systematic study of the regulation and is applicable to a wide variety of cases, wherein one could rely on in silico perturbations to predict novel targets, interpret systemic effects, and identify alterations in the metabolic states to better understand the genotype-phenotype relationships. In this review, we describe the reconstruction of the human metabolic network, introduce the constraint based modeling approach to analyze metabolic networks, and discuss systems biology applications to study human physiology and pathology. We highlight the challenges and opportunities in network reconstruction and systems modeling of the human metabolic system. PMID- 24957378 TI - Comparative Lipidomic Profiling of S. cerevisiae and Four Other Hemiascomycetous Yeasts. AB - Glycerophospholipids (GP) are the building blocks of cellular membranes and play essential roles in cell compartmentation, membrane fluidity or apoptosis. In addition, GPs are sources for multifunctional second messengers. Whereas the genome and proteome of the most intensively studied eukaryotic model organism, the baker's yeast (Saccharomyces cerevisiae), are well characterized, the analysis of its lipid composition is still at the beginning. Moreover, different yeast species can be distinguished on the DNA, RNA and protein level, but it is currently unknown if they can also be differentiated by determination of their GP pattern. Therefore, the GP compositions of five different yeast strains, grown under identical environmental conditions, were elucidated using high performance liquid chromatography coupled to negative electrospray ionization-hybrid linear ion trap-Fourier transform ion cyclotron resonance mass spectrometry in single and multistage mode. Using this approach, relative quantification of more than 100 molecular species belonging to nine GP classes was achieved. The comparative lipidomic profiling of Saccharomyces cerevisiae, Saccharomyces bayanus, Kluyveromyces thermotolerans, Pichia angusta, and Yarrowia lipolytica revealed characteristic GP profiles for each strain. However, genetically related yeast strains show similarities in their GP compositions, e.g., Saccharomyces cerevisiae and Saccharomyces bayanus. PMID- 24957380 TI - Overexpression of BID in thyroids of transgenic mice increases sensitivity to iodine-induced autoimmune thyroiditis. AB - BACKGROUND: BID functions as a bridge molecule between death-receptor and mitochondrial related apoptotic pathways to amplify apoptotic signaling. Our previous studies have demonstrated a substantial increase in BID expression in primary normal thyroid epithelia cells treated with inflammatory cytokines, including the combination of IFNgamma and IL-1beta or IFNgamma and TNFalpha. The aim of this study was to determine whether an increase in BID expression in thyroid can induce autoimmune thyroiditis. METHODS: A transgenic mouse line that expresses human BID in thyroid cells was established by fusing a mouse thyroglobulin (Tg) promoter upstream of human BID (Tg-BID). We tested whether the increased expression of pro-apoptotic BID in thyroid would induce autoimmune thyroiditis, both in the presence and absence of 0.3% iodine water. RESULTS: Our data show that Tg-BID mice in a CBA/J (H-2 k) background do not spontaneously develop autoimmune thyroiditis for over a year. However, upon ingestion of iodine in the drinking water, autoimmune thyroiditis does develop in Tg-BID transgenic mice, as shown by a significant increase in anti-Tg antibody and mononuclear cell infiltration in the thyroid glands in 30% of mice tested. Serum T4 levels, however, were similar between iodine-treated Tg-BID transgenic mice and the wild type mice. CONCLUSIONS: Our data demonstrate that increased thyroid expression of BID facilitates the development of autoimmune thyroiditis induced by iodine uptake. However, the overexpression of BID itself is not sufficient to initiate thyroiditis in CBA/J (H-2 k) mice. PMID- 24957379 TI - Stoichiometry based steady-state hepatic flux analysis: computational and experimental aspects. AB - The liver has many complex physiological functions, including lipid, protein and carbohydrate metabolism, as well as bile and urea production. It detoxifies toxic substances and medicinal products. It also plays a key role in the onset and maintenance of abnormal metabolic patterns associated with various disease states, such as burns, infections and major traumas. Liver cells have been commonly used in in vitro experiments to elucidate the toxic effects of drugs and metabolic changes caused by aberrant metabolic conditions, and to improve the functions of existing systems, such as bioartificial liver. More recently, isolated liver perfusion systems have been increasingly used to characterize intrinsic metabolic changes in the liver caused by various perturbations, including systemic injury, hepatotoxin exposure and warm ischemia. Metabolic engineering tools have been widely applied to these systems to identify metabolic flux distributions using metabolic flux analysis or flux balance analysis and to characterize the topology of the networks using metabolic pathway analysis. In this context, hepatic metabolic models, together with experimental methodologies where hepatocytes or perfused livers are mainly investigated, are described in detail in this review. The challenges and opportunities are also discussed extensively. PMID- 24957382 TI - Patient complexity, prescriber continuity and acute care. PMID- 24957381 TI - Predictors of statin compliance after switching from branded to generic agents among managed-care beneficiaries. AB - OBJECTIVES: To identify patient demographics and characteristics associated with compliance to statin therapy after switching from branded to generic agents DESIGN: Retrospective cohort study using electronic health records and pharmacy claims data from Sutter Health's ambulatory-care medical network PATIENTS: Managed-care beneficiaries, >= 18 years of age, who were switched from branded to generic statins between 1 January 2003 and 31 December 2012 MAIN MEASURES: Compliance was calculated as days of therapy dispensed divided by days from first to last generic prescription fill over 6 months, and was defined as a medication possession ratio >= 0.80. We used multivariable logistic regression to assess factors associated with compliance. Adjusted ORs and 95% CI were generated. KEY RESULTS: We identified 5,156 patients who were switched from branded to generic statins; 73% of patients were compliant in the 6 months after switching. After statistical adjustment, higher compliance was associated with each 10-year increase in age (OR: 1.13; 95% CI: 1.07, 1.19; p < 0.001), receipt of a generic statin equivalent in potency to the prior branded statin (OR: 1.41; 95% CI: 1.16, 1.70; p < 0.001), and compliance with prior branded statin (OR: 4.68; 95% CI: 4.07, 5.39; p < 0.001). Lower compliance was seen among Hispanic patients compared to non-Hispanic white patients (OR: 0.68; 95% CI: 0.52, 0.91; p = 0.009). Also, a switch to a higher potency generic statin, regardless of prior dose/potency, was negatively associated with compliance after switching (OR: 0.87; 95% CI: 0.80, 0.94; p = 0.001). CONCLUSIONS: The majority of patients switched from branded to generic agents were compliant with therapy in the first 6 months after switching. The potential for non-compliance to generic statin therapy, particularly among younger or Hispanic patients or when dose/potency changes are made, should be considered prior to switching. For these patients, counseling or close monitoring may be required to optimize generic interchange. PMID- 24957383 TI - Incorporating standardized nursing languages into an electronic nursing documentation system in Korea: a pilot study. AB - PURPOSE: The purposes of this study were to (a) develop and implement a standardized nursing languages-based electronic nursing documentation system in Korea, and (b) explore nurses' experience with NANDA-I, Nursing Interventions Classification, and Nursing Outcomes Classification languages in relation to nursing workflow. METHODS: The system was developed by the research team and implemented in a tertiary hospital in Korea. Ten nurses used the system and interviews were conducted to explore nurses' experiences with the standardized nursing languages. FINDINGS: The most frequently used NANDA-I, Nursing Interventions Classification, and Nursing Outcomes Classification were identified. Nurses' experiences with standardized nursing languages and how they impact nursing workflow were analyzed. CONCLUSIONS AND IMPLICATIONS: Obtaining valid and comparable data from this system will be critical in improving patient safety, quality, and evidence-based practice. PMID- 24957384 TI - Climate change drives a shift in peatland ecosystem plant community: implications for ecosystem function and stability. AB - The composition of a peatland plant community has considerable effect on a range of ecosystem functions. Peatland plant community structure is predicted to change under future climate change, making the quantification of the direction and magnitude of this change a research priority. We subjected intact, replicated vegetated poor fen peat monoliths to elevated temperatures, increased atmospheric carbon dioxide (CO2 ), and two water table levels in a factorial design to determine the individual and synergistic effects of climate change factors on the poor fen plant community composition. We identify three indicators of a regime shift occurring in our experimental poor fen system under climate change: nonlinear decline of Sphagnum at temperatures 8 degrees C above ambient conditions, concomitant increases in Carex spp. at temperatures 4 degrees C above ambient conditions suggesting a weakening of Sphagnum feedbacks on peat accumulation, and increased variance of the plant community composition and pore water pH through time. A temperature increase of +4 degrees C appeared to be a threshold for increased vascular plant abundance; however the magnitude of change was species dependent. Elevated temperature combined with elevated CO2 had a synergistic effect on large graminoid species abundance, with a 15 times increase as compared to control conditions. Community analyses suggested that the balance between dominant plant species was tipped from Sphagnum to a graminoid-dominated system by the combination of climate change factors. Our findings indicate that changes in peatland plant community composition are likely under future climate change conditions, with a demonstrated shift toward a dominance of graminoid species in poor fens. PMID- 24957385 TI - Completely extradural intraspinal arteriovenous malformation in the lumbar spine: a case report. AB - INTRODUCTION: Spinal vascular malformations can be classified in arteriovenous malformations, cavernomas, and capillary telangiectasias. Arteriovenous malformations are the most common spinal vascular anomaly and may be located intra- and/or perimedullary. According to their nidus type and hemodynamic flow patterns, they can be differentiated into fistulous, glomerular and juvenile categories. In our case, a hyperintense extradural mass was misinterpreted as a neurinoma. The histological analysis revealed typical signs of an arteriovenous malformation. CASE PRESENTATION: A 57-year-old Caucasian woman presented with back pain and hypesthesia in digiti two to four of her left foot. Magnetic resonance imaging showed a long-segment intraspinal extradural soft-tissue mass in the left L4 - S1 paravertebral region with homogeneous enhancement of contrast medium. Due to another similar lesion in the lower ankle and additional cutaneous manifestations, the suspected diagnosis was a systemic disease with neurinomas (e.g. Recklinghausen's disease). To clear up the origin and type of this lesion exploratory surgery with a hemilaminectomy of L5 was performed. This showed abnormally arterialized, dilated, and tortuous vessels. After complete resection, the intra-operative impression of an arteriovenous malformation was confirmed by a neuropathologist. CONCLUSIONS: Completely extradural intraspinal arteriovenous malformations in the lumbar spine are extremely rare. In magnetic resonance imaging they are often misinterpreted as a tumor. Arteriovenous malformations can cause compression and venous congestion, or mask symptoms like a spinal disk herniation.In cases presenting with these symptoms and magnetic resonance imaging findings, an extradural intraspinal arteriovenous malformation should be considered as a possible diagnosis. Pre-operative angiography or magnetic resonance imaging angiography can be used to verify the diagnosis. PMID- 24957386 TI - Comparison of AI techniques for prediction of liver fibrosis in hepatitis patients. AB - Globally one in twelve people have the Hepatitis B or Hepatitis C virus. Diagnosis and treatment of this disease is guided by liver biopsies where a small amount of tissue is removed by a surgeon and examined by a pathologist to determine the fibrosis stage from F(0) (no damage) to F(4) (cirrhosis). Biopsies are costly and carry some risk for the patient. Non-invasive techniques for determining fibrosis stage have been developed and evaluated since 2003. Non invasive methods have utilized serum markers, imaging test, and genetic studies. The accuracy of these non-invasive techniques has not achieved sufficient acceptance and so the invasive biopsy is still considered the gold standard.Clinical decision support systems (CDSS) use decision support system theory and technology to assist clinicians in the evaluation and treatment process. Using historical clinical data and the relationship processed by Artificial Intelligence (AI) techniques to aid physicians in their decision making process is the goal of CDSS. The CDSS provides a large number of medical support functions to help clinicians make the most reasonable diagnosis and choose the best treatment measures.This paper applies four artificial intelligence predictive techniques to publicly available data on 424 Hepatitis B and Hepatitis C patients. Demographic and standard serum markers are utilized to predict fibrosis stage and compare these predictions to known biopsy results. A final decision tree evaluation is applied to make a final prediction. We have also developed a publically available web application that can be used as a prototype for presenting AI predictive results in a CDSS environment based on these models. This technique along with others could mitigate the need for some liver biopsies in the more than 500 million Hepatitis B and C patients worldwide with additional validation and verification. PMID- 24957387 TI - Cryptographically supported NFC tags in medication for better inpatient safety. AB - Reliable sources report that errors in drug administration are increasing the number of harmed or killed inpatients, during healthcare. This development is in contradiction to patient safety norms. A correctly designed hospital-wide ubiquitous system, using advanced inpatient identification and matching techniques, should provide correct medicine and dosage at the right time. Researchers are still making grouping proof protocol proposals based on the EPC Global Class 1 Generation 2 ver. 1.2 standard tags, for drug administration. Analyses show that such protocols make medication unsecure and hence fail to guarantee inpatient safety. Thus, the original goal of patient safety still remains. In this paper, a very recent proposal (EKATE) upgraded by a cryptographic function is shown to fall short of expectations. Then, an alternative proposal IMS-NFC which uses a more suitable and newer technology; namely Near Field Communication (NFC), is described. The proposed protocol has the additional support of stronger security primitives and it is compliant to ISO communication and security standards. Unlike previous works, the proposal is a complete ubiquitous system that guarantees full patient safety; and it is based on off-the-shelf, new technology products available in every corner of the world. To prove the claims the performance, cost, security and scope of IMS-NFC are compared with previous proposals. Evaluation shows that the proposed system has stronger security, increased patient safety and equal efficiency, at little extra cost. PMID- 24957388 TI - The quantification of the QT-RR interaction in ECG signal using the detrended fluctuationanalysis and ARARX modelling. AB - In this paper, the detrended fluctuation analysis DFA is used to investigate and quantify the QT-RR interaction in different pathologic cases in order to distinguish between them. The study is carried out on the ECG signals of MIT-BIH universal database. Different ECG signals related to cardiac pathological cases are concerned with this study. These are: Premature Ventricular Contraction (PVC) (9 cases), Right Bundle Branch Block (RBBB) (4 cases), Left Bundle Branch Block (LBBB) (2 cases), Atrial Premature Beat (APB) (4 cases), Paced Beat (PB) (4 cases), and other pathologic cases with different severity (10 cases). All this cases are compared to the 15 normal cases. The obtained results show that the DFA can identify the healthy subject from the pathologic cases according to the values of the scaling exponent alpha. The results indicate that alpha varies between 0.5 and 1 in all cases which means that there is a long range correlation in RR and QT series. The QT and RR series are also modelled using the ARARX model. The parameters of the model are then extracted. The power spectral density (PSD) is estimated by using these parameters in order to provide further information about the causal interactions within the signals and also to determine the power scaling exponent beta. This scaling exponent confirms the relationship between RR and QT intervals in all the studied cases except in APB and PB cases where the behaviour is similar to that of the white noise. The QT variability degrees are calculated and the DFA is applied on it. The obtained results show a long range correlation between RR and QT intervals in all cases and an ambiguity in the APB case. The DFA is compared to the Poincare method in order to evaluate the algorithm performance using the Fuzzy Sugeno classifier is used for this purpose. PMID- 24957389 TI - Sensor-based architecture for medical imaging workflow analysis. AB - The growing use of computer systems in medical institutions has been generating a tremendous quantity of data. While these data have a critical role in assisting physicians in the clinical practice, the information that can be extracted goes far beyond this utilization. This article proposes a platform capable of assembling multiple data sources within a medical imaging laboratory, through a network of intelligent sensors. The proposed integration framework follows a SOA hybrid architecture based on an information sensor network, capable of collecting information from several sources in medical imaging laboratories. Currently, the system supports three types of sensors: DICOM repository meta-data, network workflows and examination reports. Each sensor is responsible for converting unstructured information from data sources into a common format that will then be semantically indexed in the framework engine. The platform was deployed in the Cardiology department of a central hospital, allowing identification of processes' characteristics and users' behaviours that were unknown before the utilization of this solution. PMID- 24957390 TI - Design of a dynamic transcranial magnetic stimulation coil system. AB - To study the brain activity at the whole-head range, transcranial magnetic stimulation (TMS) researchers need to investigate brain activity over the whole head at multiple locations. In the past, this has been accomplished with multiple single TMS coils that achieve quasi whole-head array stimulation. However, these designs have low resolution and are difficult to position and control over the skull. In this study, we propose a new dynamic whole-head TMS mesh coil system. This system was constructed using several sagittal and coronal directional wires. Using both simulation and real experimental data, we show that by varying the current direction and strength of each wire, this new coil system can form both circular coils or figure-eight coils that have the same features as traditional TMS coils. Further, our new system is superior to current coil systems because stimulation parameters such as size, type, location, and timing of stimulation can be dynamically controlled within a single experiment. PMID- 24957391 TI - An ontological case base engineering methodology for diabetes management. AB - Ontology engineering covers issues related to ontology development and use. In Case Based Reasoning (CBR) system, ontology plays two main roles; the first as case base and the second as domain ontology. However, the ontology engineering literature does not provide adequate guidance on how to build, evaluate, and maintain ontologies. This paper proposes an ontology engineering methodology to generate case bases in the medical domain. It mainly focuses on the research of case representation in the form of ontology to support the case semantic retrieval and enhance all knowledge intensive CBR processes. A case study on diabetes diagnosis case base will be provided to evaluate the proposed methodology. PMID- 24957392 TI - A hybrid method based on fuzzy clustering and local region-based level set for segmentation of inhomogeneous medical images. AB - medical images are more affected by intensity inhomogeneity rather than noise and outliers. This has a great impact on the efficiency of region-based image segmentation methods, because they rely on homogeneity of intensities in the regions of interest. Meanwhile, initialization and configuration of controlling parameters affect the performance of level set segmentation. To address these problems, this paper proposes a new hybrid method that integrates a local region based level set method with a variation of fuzzy clustering. Specifically it takes an information fusion approach based on a coarse-to-fine framework that seamlessly fuses local spatial information and gray level information with the information of the local region-based level set method. Also, the controlling parameters of level set are directly computed from fuzzy clustering result. This approach has valuable benefits such as automation, no need to prior knowledge about the region of interest (ROI), robustness on intensity inhomogeneity, automatic adjustment of controlling parameters, insensitivity to initialization, and satisfactory accuracy. So, the contribution of this paper is to provide these advantages together which have not been proposed yet for inhomogeneous medical images. Proposed method was tested on several medical images from different modalities for performance evaluation. Experimental results approve its effectiveness in segmenting medical images in comparison with similar methods. PMID- 24957393 TI - The association between computer literacy and training on clinical productivity and user satisfaction in using the electronic medical record in Saudi Arabia. AB - The association of computer literacy, training on clinical productivity and satisfaction of a recently implemented Electronic Medical Record (EMR) system in Prince Sultan Medical Military City ((PSMMC)) was investigated. The scope of this study was to explore the association between age, occupation and computer literacy and clinical productivity and users' satisfaction of the newly implemented EMR at PSMMC as well as the association of user satisfaction with age and position. A self-administrated questionnaire was distributed to all doctors and nurses working in Alwazarat Family and Community Center (a Health center in PSMMC). A convenience sample size of 112 healthcare providers (65 Nurses and 47 physicians) completed the questionnaire. A combination of correlation, One Way ANOVA and t-tests were used to answer the research questions. Participants had high levels of self-reported literacy on computers and satisfaction of the system. Both levels were higher among physicians than among nurses. A moderate but significant (at p < 0.01 level) correlation was found between computer literacy and users' satisfaction towards the system (R = 0.343). Age was weakly, but significantly (at p < 0.05), positively correlated with satisfaction with the system (R = 0.29). Self-reported system productivity and satisfaction was statistically correlated at p < 0.01 (R = 0.509). High level of satisfaction with training on using the system was not positively correlated with overall satisfaction of using the system. This study demonstrated that EMR users with high computer literacy skills were more satisfied with using the EMR than users with low computer literacy skills. PMID- 24957394 TI - An automatic fuzzy-based multi-temporal brain digital subtraction angiography image fusion algorithm using curvelet transform and content selection strategy. AB - Recently image fusion has prominent role in medical image processing and is useful to diagnose and treat many diseases. Digital subtraction angiography is one of the most applicable imaging to diagnose brain vascular diseases and radiosurgery of brain. This paper proposes an automatic fuzzy-based multi temporal fusion algorithm for 2-D digital subtraction angiography images. In this algorithm, for blood vessel map extraction, the valuable frames of brain angiography video are automatically determined to form the digital subtraction angiography images based on a novel definition of vessel dispersion generated by injected contrast material. Our proposed fusion scheme contains different fusion methods for high and low frequency contents based on the coefficient characteristic of wrapping second generation of curvelet transform and a novel content selection strategy. Our proposed content selection strategy is defined based on sample correlation of the curvelet transform coefficients. In our proposed fuzzy-based fusion scheme, the selection of curvelet coefficients are optimized by applying weighted averaging and maximum selection rules for the high frequency coefficients. For low frequency coefficients, the maximum selection rule based on local energy criterion is applied to better visual perception. Our proposed fusion algorithm is evaluated on a perfect brain angiography image dataset consisting of one hundred 2-D internal carotid rotational angiography videos. The obtained results demonstrate the effectiveness and efficiency of our proposed fusion algorithm in comparison with common and basic fusion algorithms. PMID- 24957395 TI - Factors related to health information exchange participation and use. AB - This study examines factors facilitating and delaying participation and use of the Health Information Exchange (HIE) in Louisiana. Semi-structured qualitative interviews were conducted with health care representatives throughout the state. Findings suggest that Meaningful Use requirements are a critical factor influencing the decision to participate in the HIE, specifically the mandate that hospitals be able to electronically transfer summary of care documents. Creating buy-in within a few large hospital networks legitimized the HIE and hastened interest in those markets. Fees charged by electronic health record (EHR) vendors to develop HIE interfaces have been prohibitive. Funding from the federal incentive program is intended to offset the costs associated with EHR implementation and increase the likelihood that HIEs can provide value to the population; however, costs and time delays of EHR interface development may be key barriers to fully integrated HIEs. State HIEs may benefit from targeted involvement of state health care leaders who can champion the potential value of the HIE. PMID- 24957396 TI - Combined Spline and B-spline for an improved automatic skin lesion segmentation in dermoscopic images using optimal color channel. AB - In a computerized image analysis environment, the irregularity of a lesion border has been used to differentiate between malignant melanoma and other pigmented skin lesions. The accuracy of the automated lesion border detection is a significant step towards accurate classification at a later stage. In this paper, we propose the use of a combined Spline and B-spline in order to enhance the quality of dermoscopic images before segmentation. In this paper, morphological operations and median filter were used first to remove noise from the original image during pre-processing. Then we proceeded to adjust image RGB values to the optimal color channel (green channel). The combined Spline and B-spline method was subsequently adopted to enhance the image before segmentation. The lesion segmentation was completed based on threshold value empirically obtained using the optimal color channel. Finally, morphological operations were utilized to merge the smaller regions with the main lesion region. Improvement on the average segmentation accuracy was observed in the experimental results conducted on 70 dermoscopic images. The average accuracy of segmentation achieved in this paper was 97.21 % (where, the average sensitivity and specificity were 94 % and 98.05 % respectively). PMID- 24957397 TI - Mobile PHRs compliance with Android and iOS usability guidelines. AB - Mobile Personal Health Records (PHRs) have achieved a particularly strong market share since the appearance of more powerful mobile devices and popular worldwide mobile application markets such as Apple's App Store and Android's Google Play. However, Android and Apple have a set of recommendations on design and usability targeted towards developers who wish to publish apps in their stores: Android Design Guidelines and iOS Human Interface Guidelines. This paper aims to evaluate compliance with these guidelines by assessing the usability recommendations of a set of 24 selected mobile PHR applications. An analysis process based on a well known Systematic Literature Review (SLR) protocol was used. The results show that the 24 mobile PHR applications studied are not suitably structured. 46 % of these applications do not use any of the recommended patterns, using instead lists or springboards, which are deprecated patterns for top-level menus. 70 % of the PHRs require a registration to be able to test the application when these interactions should be delayed. Our study will help both PHR users to select user-friendly mobile PHRs and PHR providers and developers to identify the good usability practices implemented by the applications with the highest scores. PMID- 24957398 TI - A structural equation modeling approach for the adoption of cloud computing to enhance the Malaysian healthcare sector. AB - The investments and costs of infrastructure, communication, medical-related equipments, and software within the global healthcare ecosystem portray a rather significant increase. The emergence of this proliferation is then expected to grow. As a result, information and cross-system communication became challenging due to the detached independent systems and subsystems which are not connected. The overall model fit expending over a sample size of 320 were tested with structural equation modelling (SEM) using AMOS 20.0 as the modelling tool. SPSS 20.0 is used to analyse the descriptive statistics and dimension reliability. Results of the study show that system utilisation and system impact dimension influences the overall level of services of the healthcare providers. In addition to that, the findings also suggest that systems integration and security plays a pivotal role for IT resources in healthcare organisations. Through this study, a basis for investigation on the need to improvise the Malaysian healthcare ecosystem and the introduction of a cloud computing platform to host the national healthcare information exchange has been successfully established. PMID- 24957399 TI - Retinal blood vessel segmentation with neural network by using gray-level co occurrence matrix-based features. AB - This paper focuses on the issue of extracting retina vessels with supervised approach. Since the green channel in the retina image has the best contrast between vessel and non-vessel, this channel is used to separate vessels. In our approach we are proposing a technique of using gray-level co-occurrence matrix method for composition of the retinal images. It is based on fact that the co occurrence matrix of retina image describes the transition of intensities between neighbour pixels, indicating spatial structural information of retina image. So, we first extract the features vector based on specified characteristics of the gray-level co-occurrence matrix and then we use these features vector to train a neural network approach for the classification method which makes our proposed approach more effective. Obtained results from the experiments in DRIVE and STARE database shows the advantage of the proposed method in contrast to current methods. This advantage is evaluated by the criteria of sensitivity, specificity, area under ROC and accuracy. The result of such a conversion as the input vector of a multilayer perceptron neural network will be trained and tested. Although in recent years different methods have been presented in this respect, but results of simulation shows that the proposed algorithm has a very high efficiency than the other researches. PMID- 24957401 TI - [Modern imaging in neurology and psychiatry]. PMID- 24957400 TI - Cost-effectiveness and diagnostic effectiveness analyses of multiple algorithms for the diagnosis of Lynch syndrome. AB - BACKGROUND AND AIMS: The optimal algorithm to identify Lynch syndrome (LS) among patients with colorectal cancer (CRC) is unclear. The definitive test for LS, germline testing, is too expensive to be applied in all cases. Initial screening with the revised Bethesda Guidelines (RBG) cannot be applied in a considerable number of cases due to missing information. METHODS: We developed a model to evaluate the cost-effectiveness of 10 strategies for diagnosing LS. Three main issues are addressed: modeling estimates (20-40%) of RBG applicability; comparing sequential or parallel use of microsatellite instability (MSI) and immunohistochemistry (IHC); and a threshold analysis of the charge value below which universal germline testing becomes the most cost-effective strategy. RESULTS: LS detection rates in RBG-based strategies decreased to 64.1-70.6% with 20% inapplicable RBG. The strategy that uses MSI alone had lower yield, but also lower cost than strategies that use MSI sequentially or in parallel with IHC. The use of MSI and IHC in parallel was less affected by variations in the sensitivity and specificity of these tests. Universal germline testing had the highest yield and the highest cost of all strategies. The model estimated that if charges for germline testing drop to $633-1,518, universal testing of all newly diagnosed CRC cases becomes the most cost-effective strategy. CONCLUSIONS: The low applicability of RBG makes strategies employing initial laboratory-based testing more cost-effective. Of these strategies, parallel testing with MSI and IHC offers the most robust yield. With a considerable drop in cost, universal germline testing may become the most cost-effective strategy for the diagnosis of LS. PMID- 24957402 TI - Projection MR imaging of peripheral arterial calcifications. AB - PURPOSE: Both CT and MR angiography are accurate for the evaluation of luminal abnormalities in peripheral arterial disease (PAD). However, only CT (requiring exposure to potentially hazardous ionizing radiation) provides a reliable means to detect vascular calcifications. In this study, we demonstrate the feasibility of detecting peripheral arterial calcifications with MRI. METHODS: The institutional investigational review board approved the study. Seven patients with PAD and iliofemoral arterial calcifications shown by prior CT angiography (CTA) were studied. The imaging techniques included: 1) dual-echo three dimensional (3D) gradient recalled echo (GRE) pulse sequence using flow compensation and in-phase echo times (TE); and 2) prototype version of 3D point wise encoding time reduction with radial acquisition (PETRA), which enables imaging with an ultra-short TE. RESULTS: With both techniques after grayscale inversion, vascular calcifications appeared bright, as did cortical bone, and were readily distinguished from the vessel lumen and surrounding soft tissues. The location and conformation of the calcifications corresponded with CT. The second echo GRE provided the highest contrast-to-noise ratios; whereas PETRA was best suited for the creation of thick projection images. CONCLUSION: In this pilot study, MRI was able to detect vascular calcifications. Projection imaging using PETRA provided a similar appearance to, and allowed direct comparison with, CT. PMID- 24957403 TI - Photodynamic decontamination of foodstuff from Staphylococcus aureus based on novel formulations of curcumin. AB - Increasing antibiotic resistance is one of the world's greatest health problems. The food chain is an important factor in the transfer of resistant germs from animals to humans. This study focuses on photodynamic inactivation (PDI), employing curcumin bound to polyvinylpyrrolidone (PVP-C) and NovaSol(r)-curcumin as photosensitizers, as potent tool for the decontamination of cucumber, pepper and chicken meat from Staphylococcus aureus (serving as the model for methicillin resistant S. aureus, MRSA). Both curcumin and PVP have been approved as food additives, consequently exhibiting excellent biocompatibility. Vegetables and meat were contaminated with S. aureus and sprinkled with PVP-C and NovaSol(r) curcumin at concentrations of 50 and 100 MUM, respectively. Illumination was performed immediately using visible light (435 nm, 9.4 mW cm(-2), 33.8 J cm(-2)). The PDI efficiency was determined by quantitative analyses of colony forming units 24 h post illumination. Additionally, the long-term effects of the photodynamic inactivation on cucumbers were investigated by quantitative analyses of the viable bacterial fraction after 24 and 48 h. Photodynamic inactivation of S. aureus revealed a mean reduction of 2.6 log10 (99.8%) for cucumbers, 2.5 log10 (99.7%) for pepper and 1.7 log10 (98%) for chicken meat relative to control samples. The bactericidal effect compared to controls seems to last for at least 48 h. Furthermore, no visible changes of the exterior appearance of foodstuff after photodynamic decontamination were observed. Photodynamic inactivation may therefore constitute a safe, economic and effective decontamination technique, which is harmless to health and not noticeable to consumers. PMID- 24957404 TI - MicroRNA-199a-3p and microRNA-34a regulate apoptosis in human osteosarcoma cells. AB - miRNAs (microRNAs) are small non-coding RNAs [18-25 nt (nucleotides)] that regulate gene expression mainly through affecting post-transcriptional modification. Osteosarcoma is an aggressive sarcoma of the bone characterized by a high level of genetic instability and recurrent DNA deletions and amplifications. miRNAs play an important role in cancer cell growth and migration; however, the potential roles of miRNAs in osteosarcoma remain largely uncharacterized. In this paper, miR-199a and miR-34a were discussed the mechanisms of apoptosis using miRNA mimics in human osteosarcoma cells. The results demonstrated that miR-199a and miR-34a could induce the apoptosis of human osteosarcoma cells via p53 signalling pathway. PMID- 24957405 TI - Cognitive effort avoidance and detection in people with schizophrenia. AB - Many people with schizophrenia exhibit avolition, a difficulty initiating and maintaining goal-directed behavior, considered to be a key negative symptom of the disorder. Recent evidence indicates that patients with higher levels of negative symptoms differ from healthy controls in showing an exaggerated cost of the physical effort needed to obtain a potential reward. We examined whether patients show an exaggerated avoidance of cognitive effort, using the demand selection task developed by Kool, McGuire, Rosen, and Botvinick (Journal of Experimental Psychology. General, 139, 665-682, 2010). A total of 83 people with schizophrenia or schizoaffective disorder and 71 healthy volunteers participated in three experiments where instructions varied. In the standard task (Experiment 1), neither controls nor patients showed expected cognitive demand avoidance. With enhanced instructions (Experiment 2), controls demonstrated greater demand avoidance than patients. In Experiment 3, patients showed nonsignificant reductions in demand avoidance, relative to controls. In a control experiment, patients showed significantly reduced ability to detect the effort demands associated with different response alternatives. In both groups, the ability to detect effort demands was associated with increased effort avoidance. In both groups, increased cognitive effort avoidance was associated with higher IQ and general neuropsychological ability. No significant correlations between demand avoidance and negative symptom severity were observed. Thus, it appears that individual differences in general intellectual ability and effort detection are related to cognitive effort avoidance and likely account for the subtle reduction in effort avoidance observed in schizophrenia. PMID- 24957407 TI - Molecular brass: Cu4Zn4, a ligand protected superatom cluster. AB - The first example of ligand protected Cu-Zn clusters is described. Reaction of [CpCu(CN(t)Bu)] with [Zn2Cp*2] yields [(CuCN(t)Bu)4(ZnCp*)4] (1a) and [(CuCN(t)Bu)4(ZnCp*)3(ZnCp)] (1b). According to DFT calculations, the [Cu4Zn4] unit fulfils the unified superatom model for cluster valence shell closing. PMID- 24957406 TI - Musical chords and emotion: major and minor triads are processed for emotion. AB - Musical chords are arguably the smallest building blocks of music that retain emotional information. Major chords are generally perceived as positive- and minor chords as negative-sounding, but there has been debate concerning how early these emotional connotations may be processed. To investigate this, emotional facial stimuli and musical chord stimuli were simultaneously presented to participants, and facilitation of processing was measured via event-related potential (ERP) amplitudes. Decreased amplitudes of the P1 and N2 ERP components have been found to index the facilitation of early processing. If simultaneously presented musical chords and facial stimuli are perceived at early stages as belonging to the same emotional category, then early processing should be facilitated for these congruent pairs, and ERP amplitudes should therefore be decreased as compared to the incongruent pairs. ERPs were recorded from 30 musically naive participants as they viewed happy, sad, and neutral faces presented simultaneously with a major or minor chord. When faces and chords were presented that contained congruent emotional information (happy-major or sad minor), processing was facilitated, as indexed by decreased N2 ERP amplitudes. This suggests that musical chords do possess emotional connotations that can be processed as early as 200 ms in naive listeners. The early stages of processing that are involved suggest that major and minor chords have deeply connected emotional meanings, rather than superficially attributed ones, indicating that minor triads possess negative emotional connotations and major triads possess positive emotional connotations. PMID- 24957410 TI - Comparative safety of endovascular and open surgical repair of abdominal aortic aneurysms in low-risk male patients. AB - OBJECTIVE: The prevalence of significant comorbidities among patients with abdominal aortic aneurysms (AAAs) has contributed to widespread enthusiasm for endovascular AAA repair (EVAR). However, the advantages of EVAR in patients at low risk for open surgical repair (OSR) remain unclear. The objective of this study was to assess perioperative outcomes of EVAR and OSR in low-risk patients. METHODS: Patients undergoing EVAR and OSR for infrarenal AAAs were identified in the 2007 to 2010 National Surgical Quality Improvement Program data sets. AAA specific risk stratification, by the Medicare aneurysm scoring system, was used to create matched low-risk (score <3) cohorts. Perioperative morbidity and mortality were assessed by crude comparisons of matched groups and regression models. RESULTS: Of 11,753 elective patients undergoing EVAR, 4339 (37%) were deemed low risk (score <3). A matched cohort of 1576 low-risk patients was developed from a total of 3804 (41%) undergoing OSR. The low-risk cohorts included only male patients and those <75 years of age, without significant cardiac, pulmonary, or vascular comorbidities. Mean age in both low-risk groups was 67 +/- 6 years (P = NS). EVAR patients had higher rates of obesity (40% vs 33%; P < .001), diabetes (16% vs 13%; P = .005), history of cardiac intervention (24% vs 19%; P < .001), cardiac surgery (23% vs 20%; P = .02), steroid use (4% vs 2%; P = .002), and bleeding disorders/anticoagulation (9% vs 6%; P = .001) compared with OSR patients. There were no other differences between the matched cohorts. EVAR was associated with reduced 30-day mortality (0.5% vs 1.5%; P < .01) and reduced rates of major complications, including the following: sepsis (0.7% vs 3.2%; P < .01), unplanned intubation (1.0 vs 5.4%; P < .001), pneumonia (0.8% vs 6.1%; P < .001), acute renal failure (0.4% vs 2.7%; P < .001), and early reoperation (3.7% vs 6.0%; P < .001). Furthermore, EVAR was associated with reduced perioperative morbidity across organ systems, including venous thromboembolism (0.1% vs 0.3%; P = .001), transfusion requirement of more than 4 units (2.0% vs 13.0%; P < .001), cardiac arrest (0.2 vs 0.8; P = .001), neurologic deficits (0.2% vs 0.5%; P = .032), and urinary tract infections (1.2% vs 2%; P = .02). CONCLUSIONS: Our results demonstrate that even among those male patients at low risk for OSR on the basis of comorbidities, EVAR is associated with reduced perioperative mortality and major complications. Whereas clinical decisions must account for safety and long-term effectiveness, the short-term benefit of EVAR is evident even among male patients at the lowest risk for OSR. PMID- 24957409 TI - Early and delayed rupture after endovascular abdominal aortic aneurysm repair in a 10-year multicenter registry. AB - OBJECTIVE: Rupture after abdominal endovascular aortic aneurysm repair (EVAR) is a function of graft maintenance of the seal and fixation. We describe our 10-year experience with rupture after EVAR. METHODS: From 2000 to 2010, 1736 patients with abdominal aortic aneurysm (AAA) from 17 medical centers underwent EVAR in a large, regional integrated health care system. Preoperative demographic and clinical data of interest were collected and stored in our registry. We retrospectively identified patients with postoperative rupture, characterized as "early" and "delayed" rupture (<=30 days and >30 days after the initial EVAR, respectively), and identified predictors associated with delayed rupture. RESULTS: The overall follow-up rate was 92%, and the median follow-up was 2.7 years (interquartile range, 1.2-4.4 years) in these 1736 EVAR patients. We identified 20 patients with ruptures; 70% were male, the mean age was 79 years, and mean AAA size at the initial EVAR was 6.3 cm. Six patients underwent initial EVAR for rupture (n = 2) or symptomatic presentation (n = 4). Of the 20 post-EVAR ruptures, 25% (five of 20) were early, all occurring within 2 days after the initial EVAR. Of these five patients, four had intraoperative adverse events leading directly to rupture, with one type I and one type III endoleak. Of the five early ruptures, four patients underwent endovascular repair and one received repair with open surgery, resulting in two perioperative deaths. Among the remaining 15 patients, the median time from initial EVAR to rupture was 31.1 months (interquartile range, 13.8-57.3 months). Most of these delayed ruptures (10 of 15) were preceded by AAA sac increases, including three patients with known endoleaks who underwent reintervention. At the time of delayed rupture, nine of 15 patients had new endoleaks. Among all 20 patients, six patients did not undergo repair (all delayed patients) and died, nine underwent repeated EVAR, and five had open repair. For patients who underwent repair for delayed rupture, mortality at 30 days and 1 year were 44.4% and 66.7%, respectively. Multivariable Cox regression analysis identified age 80 to 89 (hazard ratio, 3.3; 95% confidence interval, 1.1-9.4; P = .03), and symptomatic or ruptured initial indication for EVAR (hazard ratio, 7.4; 95% confidence interval, 2.2-24.8; P < .01) as significant predictors of delayed rupture. CONCLUSIONS: Rupture after EVAR is a rare but devastating event, and mortality after repair exceeds 60% at 1 year. Most delayed cases showed late AAA expansion, thereby implicating late loss of seal and increased endoleaks as the cause of rupture in these patients and mandating vigilant surveillance. PMID- 24957408 TI - Different stressors elicit different responses in the salivary biomarkers cortisol, haptoglobin, and chromogranin A in pigs. AB - Most commonly, salivary cortisol is used in pig stress assessment, alternative salivary biomarkers are scarcely studied. Here, salivary cortisol and two alternative salivary biomarkers, haptoglobin and chromogranin A were measured in a pig stress study. Treatment pigs (n = 24) were exposed to mixing and feed deprivation, in two trials, and compared to untreated controls (n = 24). Haptoglobin differed for feed deprivation vs control. Other differences were only found within treatment. Treatment pigs had higher salivary cortisol concentrations on the mixing day (P < 0.05). Chromogranin A concentrations were increased on the day of refeeding (P < 0.05). Haptoglobin showed a similar pattern to chromogranin A. Overall correlations between the salivary biomarkers were positive. Cortisol and chromogranin A were moderately correlated (r = 0.49, P < 0.0001), correlations between other markers were weaker. The present results indicate that different types of stressors elicited different physiological stress responses in the pigs, and therefore including various salivary biomarkers in stress evaluation seems useful. PMID- 24957411 TI - Interest of cytogenetic and FISH evaluation for prognosis evaluation in 198 patients with acute myeloid leukemia in first complete remission in a single institution. AB - The prognostic interest of cytogenetic remission and fluorescent in situ hybridization (FISH) evaluation in patients with abnormal karyotype acute myeloid leukemia (AML) has been poorly studied. Among 198 patients that reached complete remission (CR), 24 did not reach cytogenetic remission (CyCR). CyCR had no prognosis impact, especially in patients with intermediate or unfavorable cytogenetic. Twenty of 52 evaluated patients in CyCR did not reach FISH CR. FISH CR was associated with better OS (p=0.004) and tended to be associated with better disease-free survival (DFS) (p=0.08). FISH evaluation may be a useful tool for prognosis evaluation and minimal residual disease (MRD) assessment in patients with abnormal cytogenetic AML. PMID- 24957412 TI - Insights in Hodgkin Lymphoma angiogenesis. AB - Angiogenesis is a hallmark of tumor growth and progression in solid and hematological malignancies. Different cellular components of the tumor microenvironment such as macrophages, mast cells, circulating endothelial cells and angiogenic factors, including vascular endothelial growth factor and its receptors are involved in the maintenance of Hodgkin Lymphoma. In this review article, we highlight relevant literature focusing on the relationships between angiogenesis and Hodgkin Lymphoma as well as discussing anti-angiogenic treatments in this malignancy. PMID- 24957413 TI - Impaired NK cells and increased T regulatory cell numbers during cytotoxic maintenance therapy in AML. AB - Cyclic cytotoxic maintenance therapy can be applied to patients with AML in post remission. We studied the immune status of AML patients in complete remission and the effect of maintenance therapy on different immune cell populations. Patients in complete remission had reduced NK, TH and Treg counts and a reduced NK activation capacity. In the course of cytotoxic maintenance therapy, NK counts further declined, while TH and Treg cells increased, with lower proliferative potential of TH cells. We conclude that immunotherapeutic approaches in post remission have to consider reduced NK cell function and further impairment of cellular immune responses during cytotoxic therapy. PMID- 24957414 TI - Electromyogram features during linear torque decrement and their changes with fatigue. AB - PURPOSE: Surface electromyogram (EMG) spike shape analysis (SSA) has recently been proposed as an adjunct tool to EMG time and frequency domain analysis to increase our knowledge of motor unit (MU) control strategies. The study was aimed to understand more in MU deactivation strategy during torque decrement, and its possible changes in fatigued muscle, using a combination of traditional time and frequency domain analysis and SSA techniques. METHODS: EMG was detected from the biceps brachii of 11 untrained male subjects during static down-going ramp contractions (90-0% of the maximal voluntary contraction, MVC) under non-fatigued (DGR) and fatigued (FDGR) conditions. The root mean square (RMS) and mean frequency (MF), as well as SSA parameters, were calculated on 1-s EMG windows centred on each 10 % MVC step for both conditions. RESULTS: In both the DGR and FDGR EMG-RMS, mean spike amplitude and mean spike slope decreased by 50 % in the 90-60 % MVC. The mean spike frequency also decreased by 50 % in the 30-10 % MVC. Except the "mean number of spikes per second" all the other estimated EMG parameters were significantly different during FDGR compared to DGR. CONCLUSION: The dynamics of EMG parameters during torque decrement would support a MU deactivation strategy which relies more on MU de-recruitment in the high % MVC range and more on firing rate reduction in the low % MVC range. The adopted integrated approach to EMG signal processing could indicate that SSA is an important tool to disclose alterations in motor control due to fatigue. PMID- 24957415 TI - Decoupling of laxity and cortical activation in functionally unstable ankles during joint loading. AB - PURPOSE: Recent studies have highlighted central nervous system alterations following ligamentous injury that may contribute to joint instability. However, research has not observed cortical responses to joint loading or sensory changes in the context of joint laxity following injury. METHODS: Forty-two subjects were stratified into healthy (CON), unstable (UNS), and coper (COP) groups using ankle injury and instability history. Event-related desynchronization (%) from electroencephalography quantified somatosensory cortex activity as the ankle was loaded using an arthrometer. RESULTS: Cortical activation increased as the ankle was loaded (F = 63.05, p < 0.001), but did not differ between groups (F = 1.387, p = 0.268), despite greater laxity in UNS (F = 3.58, p = 0.038). CONCLUSIONS: Increased somatosensory cortex activity was observed with joint loading; however, though UNS demonstrated a degree of mechanical instability, no differences in magnitude of cortical activation were observed. Continued research should explore how the relationship between cortical activation and joint stiffness is affected following ligamentous injury. PMID- 24957416 TI - Changes in heart rate variability during the induction and decay of heat acclimation. AB - PURPOSE: We evaluated the changes in core temperature, heart rate, and heart rate variability (HRV) during the induction and decay of heat acclimation. METHODS: Ten males (23 +/- 3 years; 79.5 +/- 3.5 kg; 15.2 +/- 4.5 percent body fat; 51.13 +/- 4.61 mLO(2)?kg(-1)?min(-1) peak oxygen uptake) underwent a 14-day heat acclimation protocol comprising of 90-min cycling at ~50 % peak oxygen uptake at 40 degrees C and ~20 % relative humidity. Core temperature, heart rate, and 102 HRV measures were recorded during a heat tolerance test conducted at baseline (day 0) and at the end of the induction (day 14) and decay (day 28) phases. RESULTS: Heat acclimation resulted in significantly reduced core temperature [rectal (chi (2) = 1298.14, p < 0.001); esophageal (chi (2) = 1069.88, p < 0.001)] and heart rate (chi (2) = 1230.17, p < 0.001). Following the decay phase, 26, 40, and 60 % of the heat acclimation-induced reductions in rectal temperature, esophageal temperature, and heart rate, respectively, were lost. Heat acclimation was accompanied by profound and broad changes in HRV: at the end of the induction phase, 75 of the 102 variability measures computed were significantly different (p < 0.001), compared to only 47 of the 102 at the end of the decay phase. CONCLUSIONS: Heat acclimation is accompanied by reduced core temperature, significant bradycardia, and marked alterations in HRV, which we interpret as being related to vagal dominance. The observed changes in core temperature persist for at least 2 weeks of non-exposure to heat, while the changes in heart rate and HRV decay faster and are only partly evident after 2 weeks of non-exposure to heat. PMID- 24957417 TI - A chitosan-Au-hyperbranched polyester nanoparticles-based antifouling immunosensor for sensitive detection of carcinoembryonic antigen. AB - Analysts are always interested in finding new functional nanomaterials and devices with good properties for electrochemical sensor applications. In this paper, hyperbranched polyester nanoparticles with carboxylic acid functional groups (HBPE-CA NPs) were synthesized and combined with chitosan wrapped around Au nanoparticles (CS-Au NPs) to prepare a novel and sensitive electrochemical immunosensor by adsorption of carcinoembryonic antibody (anti-CEA) on the (HBPE CA)/CS-Au NPs modified glass carbon electrode (GCE). Under the optimized conditions, the proposed immunosensor displayed a good amperometric response to carcinoembryonic antigen (CEA). Moreover, based on the antibiofouling properties, the immunosensor could be used for the direct detection of CEA in whole blood, and exhibited a wide detection range (1-10(7) fg mL(-1)), and a low detection limit of 0.251 fg mL(-1) (signal/noise = 3). Control experiments were also carried out by using ascorbic acid (AA), uric acid (UA), human immunoglobulin G (IgG), BSA and glucose in the absence of CEA. The good stability and repeatability of this immunosensor were also proven. Importantly, the results of the detection of clinical whole blood specimens with the proposed immunosensor showed good consistency with the data determined by enzyme-linked immunosorbent assay (ELISA) in serum samples. Furthermore, the developed immunosensor could provide a promising immunoassay strategy for clinical applications, since the values we measured in whole blood directly are likely closer to the real values. PMID- 24957418 TI - Effect of patient risk on the volume-outcome relationship in obstetric delivery services. AB - Health care organizations that offer more delivery services are assumed to provide better quality of care, and a higher rate of cesarean section (CS) is generally assumed to be an indicator of poor quality of care. This study analyzed whether the volume-outcome relationship in delivery services, measured by the rate of CS, differed depending on the risk status of delivery patients. Delivery claims were identified in the National Patient Sample (NPS) for 2009. The study hospitals were categorized into low and high delivery-volume groups, and patients were categorized into three risk groups (below average, medium, and high) based on their risk status. Risk factors were included in the adjustment model to identify differences among patients and produce risk-adjusted CS rates. Risk adjusted CS rates did not differ significantly between patients in low- and high volume hospitals when the sample was not divided according to risk status. However, when the sample was divided according to patient risk status, significant differences in risk-adjusted CS rates in the below-average- and medium-risk groups were revealed between low- and high-volume hospitals. No such significant difference was observed for the high-risk group. The largest difference in CS rates between low- and high-volume hospitals was observed in the medium-risk group, and the high-risk group showed the smallest difference between the two volume groups. The high-risk group had the highest CS rates, and the below-average-risk group had the lowest CS rates. Although we found the traditional volume-outcome relationship in delivery patients, the data also revealed that patient risk status influenced this relationship. Policies and interventions based on volume-outcome theory should differ according to patient risk status. PMID- 24957419 TI - Managed entry agreements for pharmaceuticals in Australia. AB - In Australia, a number of managed entry agreements have been developed to enable national coverage of new medicines. Non-outcome based agreements are usually pricing arrangements that involve price or volume rebate agreements. In February 2013, there were at least 71 special pricing arrangements in place, including 26 for medicines restricted to use in hospitals. Health outcome based agreements can be made at the individual or population level. At the individual level, there were 28 medicines funded subject to continuation rules involving documentation of adequate benefit within the individual; some of these medicines also had price agreements in place. At the population level, only one outcome-based agreement has been implemented so far, for bosentan, a medicine marketed for pulmonary hypertension. In May 2010, a memorandum of understanding signed between the Australian Government and Medicines Australia, the peak pharmaceutical industry organisation, included the possibility for industry to request consideration of a 'Managed Entry Scheme' as part of the funding submission process for medicines with high clinical needs. It includes the possibility of a randomised controlled trial (RCT)-based entry scheme. Although this form of managed entry has yet not been trialed in Australia, several 2012/2013 funding recommendations included requests by the decision making committee for further evidence development. PMID- 24957423 TI - The primary determinants of radiation use during fixation of proximal femur fractures. AB - OBJECTIVES: To establish the primary determinants of operative radiation use during fixation of proximal femur fractures. DESIGN: Retrospective cohort study. SETTING: Level I trauma centre. COHORT: 205 patients treated surgically for subtrochanteric and intertrochanteric femoral fractures. MAIN OUTCOME MEASURES: Fluoroscopy time, dose-area-product (DAP). RESULTS: Longer fluoroscopy time was correlated with higher body mass index (p=0.04), subtrochanteric fracture (p<0.001), attending surgeon (p=0.001), and implant type (p<0.001). Increased DAP was associated with higher body mass index (p<0.001), subtrochanteric fracture (p=0.002), attending surgeon (p=0.003), lateral body position (p<0.001), and implant type (p=0.05). CONCLUSION: The strongest determinants of radiation use during surgical fixation of intertrochanteric and subtrochanteric femur fractures were location of fracture, patient body position, patient body mass index, and the use of cephalomedullary devices. Surgeon style, presumably as it relates to teaching efforts, seems to strongly influence radiation use. PMID- 24957425 TI - The mechanism of homogeneous CO2 reduction by Ni(cyclam): product selectivity, concerted proton-electron transfer and C-O bond cleavage. AB - Homogeneous CO2 reduction catalyzed by [Ni(I)(cyclam)](+) (cyclam = 1,4,8,11 tetraazacyclotetradecane) exhibits high efficiency and selectivity yielding CO only at a relatively low overpotential. In this work, a density functional theory study of the reaction mechanism is presented. Earlier experiments have revealed that the same reaction occurring on mercury surfaces generates a mixture of CO and formate. According to the proposed mechanism, an eta(1)-CO2 adduct is the precursor for CO evolution, whereas formate is obtained from an eta(1)-OCO adduct. Our calculations show that generation of the eta(1)-CO2 adduct is energetically favored by ~14.0 kcal/mol relative to that of the eta(1)-OCO complex, thus rationalizing the product selectivity observed experimentally. Binding of eta(1)-CO2 to Ni(I) only leads to partial electron transfer from the metal center to CO2. Hence, further CO2 functionalization likely proceeds via an outer-sphere electron-transfer mechanism, for which concerted proton coupled electron transfer (PCET) is calculated to be the most feasible route. Final C-O bond cleavage involves rather low barriers in the presence of H3O(+) and H2CO3 and is therefore essentially concerted with the preceding PCET. As a result, the entire reaction mechanism can be described as concerted proton-electron transfer and C-O bond cleavage. On the basis of the theoretical results, the limitations of the catalytic activity of Ni(cyclam) are discussed, which sheds light on future design of more efficient catalysts. PMID- 24957424 TI - Increased mortality associated with EMS transport of gunshot wound victims when compared to private vehicle transport. AB - BACKGROUND: Recent studies suggest that mode of transport affects survival in penetrating trauma patients. We hypothesised that there is wide variation in transport mode for patients with gunshot wounds (GSW) and there may be a mortality difference for GSW patients transported by emergency medical services (EMS) vs. private vehicle (PV). STUDY DESIGN: We studied adult (>=16 years) GSW patients in the National Trauma Data Bank (2007-2010). Level 1 and 2 trauma centres (TC) receiving >=50 GSW patients per year were included. Proportions of patients arriving by each transport mode for each TC were examined. In-hospital mortality was compared between the two groups, PV and EMS, using multivariable regression analyses. Models were adjusted for patient demographics, injury severity, and were adjusted for clustering by facility. RESULTS: 74,187 GSW patients were treated at 182 TCs. The majority (76%) were transported by EMS while 12.6% were transported by PV. By individual TC, the proportion of patients transported by each category varied widely: EMS (median 78%, interquartile range (IQR) 66-85%), PV (median 11%, IQR 7-17%), or others (median 7%, IQR 2-18%). Unadjusted mortality was significantly different between PV and EMS (2.1% vs. 9.7%, p<0.001). Multivariable analysis demonstrated that EMS transported patients had a greater than twofold odds of dying when compared to PV (OR=2.0, 95% CI 1.73 2.35). CONCLUSIONS: Wide variation exists in transport mode for GSW patients across the United States. Mortality may be higher for GSW patients transported by EMS when compared to private vehicle transport. Further studies should be performed to examine this question. PMID- 24957426 TI - Adjustable intraocular lens technology. PMID- 24957427 TI - Fishtail on a line technique for capsular tension ring insertion. AB - We describe a capsular tension ring (CTR) insertion technique that is a modification of the previously described fishtail technique. A suture line is used to pull the leading eyelet out through the main incision to form the fish configuration. Similar to the fishtail technique, this insertion technique minimizes the risk for zonular damage or a capsule tear because the CTR is not dialed into the capsular bag. The advantage of the suture line is that it prevents over bending of the CTR during insertion through the main incision, which can occur using the traditional fishtail technique. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 24957428 TI - Use of a microscope-mounted wide-angle point of view camera to record optimal hand position in ocular surgery. AB - We describe the use of a microscope-mounted wide-angle point-of-view camera to record optimal hand positions in ocular surgery. The camera is mounted close to the objective lens beneath the surgeon's oculars and faces the same direction as the surgeon, providing a surgeon's view. A wide-angle lens enables viewing of both hands simultaneously and does not require repositioning the camera during the case. Proper hand positioning and instrument placement through microincisions are critical for effective and atraumatic handling of tissue within the eye. Our technique has potential in the assessment and training of optimal hand position for surgeons performing intraocular surgery. It is an innovative way to routinely record instrument and operating hand positions in ophthalmic surgery and has minimal requirements in terms of cost, personnel, and operating-room space. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24957429 TI - Refractive accuracy with light-adjustable intraocular lenses. AB - PURPOSE: To evaluate efficacy, predictability, and stability of refractive treatments using light-adjustable intraocular lenses (IOLs). SETTING: University Hospital Virgen de la Arrixaca, Murcia, Spain. DESIGN: Prospective nonrandomized clinical trial. METHODS: Eyes with a light-adjustable IOL (LAL) were treated with spatial intensity profiles to correct refractive errors. The effective changes in refraction in the light-adjustable IOL after every treatment were estimated by subtracting those in the whole eye and the cornea, which were measured with a Hartmann-Shack sensor and a corneal topographer, respectively. The refractive changes in the whole eye and light-adjustable IOL, manifest refraction, and visual acuity were obtained after every light treatment and at the 3-, 6-, and 12 month follow-ups. RESULTS: The study enrolled 53 eyes (49 patients). Each tested light spatial pattern (5 spherical; 3 astigmatic) produced a different refractive change (P<.01). The combination of 2 light adjustments induced a maximum change in spherical power of the light-adjustable IOL of between -1.98 diopters (D) and +2.30 D and in astigmatism of up to -2.68 D with axis errors below 9 degrees. Intersubject variability (standard deviation) ranged between 0.10 D and 0.40 D. The 2 required lock-in procedures induced a small myopic shift (range +0.01 to +0.57 D) that depended on previous adjustments. CONCLUSIONS: Light-adjustable IOL implantation achieved accurate refractive outcomes (around emmetropia) with good uncorrected distance visual acuity, which remained stable over time. Further refinements in nomograms and in the treatment's protocol would improve the predictability of refractive and visual outcomes with these IOLs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24957430 TI - Safety and efficacy of an intraocular Fresnel prism intraocular lens in patients with advanced macular disease: initial clinical experience. AB - PURPOSE: To perform a pilot study of a new in-the-bag Fresnel prism intraocular lens (IOL) designed to deviate the image from diseased to healthy retina in eyes with bilateral age-related macular degeneration (AMD). SETTING: Anterior segment subspeciality practice, Pretoria, South Africa. DESIGN: Prospective nonmasked trial. METHOD: Cataract surgery and unilateral implantation of the prismatic IOL were performed in patients with bilateral AMD and cataract. Outcomes were surgical complications, subjective and objective visual improvement, and undesirable optical effects. RESULTS: Three eyes of 3 patients were evaluated. All patients reported displacement of the scotoma, and no patient reported diplopia. The only complication was posterior capsule opacification (1 eye). CONCLUSIONS: Patients noted improved vision and no diplopia. This pilot was performed using a prototype IOL with single power and single angle of deviation; however, there is scope for individual patient optimization. This new technology merits further research and development because it may benefit large numbers of patients with stable end-stage AMD. FINANCIAL DISCLOSURE: Dr. Claoue has a financial interest in the patent controlling the Fresnel prism IOL. Dr. Potgieter has no financial or proprietary interest in any material or method mentioned. PMID- 24957431 TI - Expression of p53 and caspase-8 in lens epithelial cells of diabetic cataract. AB - PURPOSE: To determine expression of apoptotic factors p53 and caspase-8 in human lens epithelial cells (LECs) of cataract patients with or without diabetic retinopathy (DR), the duration of diabetes mellitus (DM), and the level of glycated hemoglobin (hemoglobin A1c [HbA1c]). SETTING: St. Mary's Hospital, Catholic University of Korea, Seoul, South Korea. DESIGN: Randomized prospective study. METHODS: The LECs were isolated during cataract surgery. The isolated samples were classified into 4 groups as follows: patients without DM (Group 1), patients with DM but not DR (Group 2), diabetic patients with nonproliferative DR (Group 3), and diabetic patients with proliferative DR (Group 4). To explore the mechanism of apoptosis, the expressions of p53 and caspase-8 were measured by immunohistochemical staining and compared with the data according to the duration of DM, HbA1c levels, and severity of DR. RESULTS: All groups comprised 15 eyes. The expressions of P53 and caspase-8 were higher in Groups 2, 3, and 4 than in Group 1 (P<.001). The expressions were statistically significantly increased with a longer duration of DM, higher HbA1c levels, and advanced DR. CONCLUSIONS: The expressions of P53 and caspase-8 were strong in patients with DM and advanced DR. Knowledge of these relationships may lead to a better understanding of the development of diabetic cataract. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24957432 TI - Air reinjection and endothelial cell density in Descemet membrane endothelial keratoplasty: five-year follow-up. AB - PURPOSE: To evaluate 5-year endothelial cell loss after Descemet membrane endothelial keratoplasty (DMEK), compare it with reported rates for Descemet stripping endothelial keratoplasty (DSEK) and penetrating keratoplasty (PKP), and investigate potential association between cell loss and air reinjection. SETTING: Price Vision Group, Indianapolis, Indiana, USA. DESIGN: Retrospective comparative case series. METHODS: Consecutive DMEK procedures performed between March 2008 and April 2013 were reviewed. The inclusion criterion was at least 6 months of follow-up. Endothelial cell density was recorded preoperatively and 1, 3, and 6 months and annually through 5 years postoperatively. Potential association between air reinjection and endothelial cell loss was evaluated by repeated measures analysis of variance. RESULTS: Of the 926 procedures performed, 673 eyes met the inclusion criterion. Indications for DMEK included Fuchs dystrophy (n = 595), pseudophakic corneal edema (n = 30), failed endothelial keratoplasty (n = 39), and failed PKP (n = 9). The median endothelial cell loss was 26% at 1 month, increasing to 39% at 5 years in cross-sectional and longitudinal analyses. Cell loss was similar in eyes with no (n = 471) or 1 (n = 155) air reinjection and significantly higher in eyes with 2 or more air reinjections (n = 47, P=.017). CONCLUSIONS: The median 5-year cell loss of 39% with DMEK compared favorably with prior reports of DSEK (53%) and PKP (70%) performed for similar indications. Similar to DSEK, most DMEK cell loss was associated with the surgical procedure itself; subsequent cell loss occurred at a slower rate than after PKP. Cell loss was not significantly increased in eyes with a single air reinjection. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24957433 TI - Patient satisfaction and clinical outcomes with laser refractive surgery performed by surgeons in training. AB - PURPOSE: To evaluate the refractive error quality of life (RQL) improvement, patient satisfaction, and clinical results of laser refractive surgery performed by residents or fellows. SETTING: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, USA. DESIGN: Case series. METHODS: This study reviewed the clinical results of consecutive refractive surgery cases performed between March 2010 and February 2012 by ophthalmology residents or fellows. One-year postoperative analysis of the RQL and patient satisfaction in a subgroup of patients was completed using the National Eye Institute Refractive Error Correction Quality of Life-42 instrument (NEI RQL-42), and a comparison with NEI published normative data and post-refractive data was performed. RESULTS: Data were obtained from 138 eyes that had laser in situ keratomileusis and 4 eyes that had photorefractive keratectomy. The 1-year postoperative analysis of the RQL and patient satisfaction was completed in 34 patients. After 6 months postoperatively, the mean uncorrected distance visual acuity was 0.01 logMAR (95% confidence interval [CI], -0.012 to 0.023). The mean postoperative residual refractive error spherical equivalent was -0.20 diopter (D) (95% CI, 0.26 to -0.13). No eye lost corrected distance visual acuity. Equivalent or better satisfaction in the RQL was found in all but 1 of the 13 scale scores of the NEI RQL-42 compared with previously published NEI data. CONCLUSIONS: Laser refractive surgery performed by residents and fellows showed high patient satisfaction and an improved RQL 1-year postoperatively. Clinical outcomes validated the safety and efficacy of refractive surgery performed by surgeons in training. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24957435 TI - Collagen copolymer toric phakic intraocular lens for myopic astigmatism: one-year follow-up. AB - PURPOSE: To assess the predictability, stability, safety, and efficacy of a collagen copolymer toric phakic intraocular lens (pIOL) to correct moderate and high astigmatism. SETTING: Fernandez-Vega Ophthalmological Institute, Oviedo, Spain. DESIGN: Case series. METHODS: After implantation of the TV4b toric Implantable Collamer Lens pIOL, the uncorrected (UDVA) and corrected (CDVA) distance visual acuities, refraction, toric pIOL vault, and adverse effects were evaluated over 12 months. RESULTS: The study enrolled 35 eyes of 20 patients with a mean sphere of -5.46 diopters (D) +/- 4.17 (SD) and mean cylinder of -3.14 +/- 1.19 D. At 12 months, the mean sphere was -0.04 +/- 0.16 D, with 97% of eyes being within +/-0.50 D of the target (r(2) = 0.99), and the mean cylinder was 0.29 +/- 0.42 D. For the astigmatism components, 80% of eyes were within +/-0.25 D of both J0 (r(2) = 0.99) and J45 (r(2) = 0.99). The mean decimal UDVA was 0.89 +/- 0.16 and the mean decimal CDVA, 0.95 +/- 0.12. No eye lost lines of CDVA, and 43% of eyes gained 1 or more lines. The safety index was 1.08 at 12 months. More than 50% of eyes had a Snellen UDVA of 20/20. The efficacy index was 0.97 at 3 months and 1.01 at 12 months. CONCLUSION: The visual and refractive outcomes were good and highly stable throughout the follow-up, indicating that this toric pIOL model is predictable, safe, and effective in correcting low and high levels of astigmatism. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24957434 TI - Variation in the effectiveness of refractive surgery during the year: results from the Hamburg Weather Study. AB - PURPOSE: To examine the impact of seasonality on the refractive and visual outcomes of laser in situ keratomileusis (LASIK) in myopic eyes. SETTING: Department of Ophthalmology and Care Vision Refractive Centers, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. DESIGN: Retrospective cross sectional data analysis. METHODS: Two subgroups were defined. The first comprised patients having surgery during meteorological winter and the second, patients having surgery during meteorological summer. The manifest refraction and uncorrected and corrected visual acuities were assessed preoperatively and postoperatively. Robust regression analysis was applied with the efficacy index, safety index, and postoperative SE as dependent variables. RESULTS: This study comprised 1052 eyes of 1052 consecutive myopic patients (419 men, 633 women; mean age at surgery 35.0 years +/- 9.0 [SD]) with a mean preoperative refractive spherical equivalent (SE) of -3.88 +/- 1.85 diopters (D). At the 1-month follow up (mean 33.0 +/- 5.0 days), the mean postoperative SE was -0.18 +/- 0.44 D. The efficacy index was 0.023 higher in eyes with refractive surgery during summer than in eyes treated during winter (P=.032), indicating less efficacy during winter. The differences in the safety index and postoperative SE between summer and winter were not statistically significant. No eye had a change of more than 1 line on the logMAR scale (corrected distance visual acuity). CONCLUSIONS: Although the difference in the efficacy index was statistically significant, the difference in the outcomes of LASIK was not clinically relevant, which shows the procedure's highly standardized reliability. Prospective longitudinal studies are warranted to address meteorotropic reactions by evaluating defined meteorological parameters. FINANCIAL DISCLOSURE(S): No author has a financial or proprietary interest in any material or method mentioned. PMID- 24957436 TI - Ocular comorbidity and self-assessed visual function after cataract surgery. AB - PURPOSE: To study the association between ocular comorbidities and the change in patient-perceived visual function, postoperative patient-perceived visual function, and visual satisfaction after cataract surgery. SETTING: Forty-one Swedish cataract surgical units. DESIGN: Clinic-based cross-sectional study. METHODS: Patients who had cataract surgery from 2008 to 2011 completed the Catquest-9SF questionnaire preoperatively and 3 months postoperatively. Questionnaire data were converted into interval data using Rasch analysis. Multiple regression and logistic regression models were used to examine possible predictors associated with self-assessed visual function after cataract surgery. RESULTS: The total questionnaire was completed by 10,364 patients. Patients without diabetic retinopathy, corneal guttata, glaucoma, macular degeneration, any other comorbidity, or the presence of more than 1 ocular comorbidity had greater improvement in self-assessed visual function than their counterparts. Patients with other factors such as young age, female sex, short preoperative surgical waiting time, and low preoperative and high postoperative corrected distance visual acuities (CDVAs) also had significantly greater improvement in self-assessed visual function than their counterparts. Young patients and those with no specific ocular comorbidities, a short surgical waiting time, and low preoperative and high postoperative CDVAs had significantly higher self-assessed postoperative visual function than their counterparts. Patients without the mentioned ocular comorbidities and a high postoperative CDVA had a higher odds ratio of general satisfaction rather than dissatisfaction than their counterparts. CONCLUSIONS: Multiple ocular comorbidities, age, preoperative waiting time, and preoperative and postoperative CDVAs affected patients' improvement and self-assessed visual function after cataract surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24957437 TI - Image quality of grating target in model eye when viewed through a small-aperture corneal inlay. AB - PURPOSE: To evaluate the quality of the image of a grating target placed in a model eye and viewed through a small-aperture corneal inlay. SETTING: Kyorin Eye Center, Tokyo, Japan. DESIGN: Experimental study. METHODS: A Kamra corneal inlay was placed on the anterior surface of a fluid-filled model eye, and a United States Air Force target and a calibrated scale were placed on the inner surface of the model eye. With a flat contact lens or a contact or noncontact wide-angle viewing system, the contrast of the grating images and the field of view through the inlay were compared with those without the inlay. RESULTS: A blurred dark ring was observed with the flat contact lens and MiniQuad wide-viewing contact lens in the model eye with the inlay. The contrast of the gratings was significantly decreased at 16 cycles/mm (P=.028), 32 cycles/mm (P=.046), and 64 cycles/mm (P=.015). With the Resight noncontact wide-angle viewing system, the field of view was reduced from 62 degrees to 32 degrees when the front lens was at 7.0 mm and slightly reduced from 75 degrees to 62 degrees at 5.0 mm with the inlay. CONCLUSIONS: The contrast of grating images observed through the inlay was significantly reduced when viewed with the flat contact lens. The field of view through the wide-angle viewing system was also altered. However, the noncontact wide-angle viewing system may be recommended for vitreous surgeries in eyes with the inlay by adjusting the distance of the front lens from the cornea. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24957438 TI - Chromatic aberration and polychromatic image quality with diffractive multifocal intraocular lenses. AB - PURPOSE: To evaluate the impact of target distance on polychromatic image quality in a virtual model eye implanted with hybrid refractive-diffractive intraocular lenses (IOLs). SETTING: School of Optometry, Indiana University, Bloomington, Indiana, USA. DESIGN: Experimental study. METHODS: A pseudophakic model eye was constructed by incorporating a phase-delay map for a diffractive optical element into a reduced eye model incorporating ocular chromatic aberration, pupil apodization, and higher-order monochromatic aberrations. The diffractive element was a monofocal IOL with a +3.2 diopter (D) diffractive power or 2 types of bifocal IOLs (nonapodized or apodized) with a +2.92 D addition (add) power. Polychromatic point-spread functions and image quality for white and monochromatic light were quantified for a series of target vergences, wavelengths, and pupil diameters using modulation transfer functions and image quality metrics. RESULTS: Ocular longitudinal chromatic aberration was largely corrected by the monofocal design and by both bifocal designs for near targets. In the bifocal design, add power and the ratio of distance:near image quality changed significantly with wavelength and pupil size. Also, image quality for distance was better with the apodized design. CONCLUSIONS: Achromatization by the diffractive IOL provided significant improvement in polychromatic retinal image quality. Along with apodization and higher-order aberrations, it can significantly affect the near-distance balance provided by a diffractive multifocal IOL. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24957440 TI - Corneal perforation by an astigmatic keratotomy performed with an optical coherence tomography-guided femtosecond laser. AB - We present a case of corneal perforation secondary to an intrastromal astigmatic keratotomy performed with an optical coherence tomography-guided femtosecond laser. The keratotomy was concomitant with cataract surgery and resulted in a flat anterior chamber prior to the start of lens extraction. Interrupted nylon sutures were placed to seal the keratotomy prior to phacoemulsification. Escape of cavitation bubbles into the anterior chamber or the liquid interface can alert the surgeon to the possibility of unintended perforation of the endothelium or the epithelium, respectively. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 24957439 TI - Adjustable intraocular lens power technology. AB - We present an overview of the adjustable intraocular lens (IOL) technologies that are available or under development. This includes IOL technologies that can be adjusted using secondary surgical procedures, such as the multicomponent IOL, the mechanically adjustable IOL, and the repeatedly adjustable IOL; IOLs that can be adjusted noninvasively in the postoperative setting, such as the magnetically adjustable IOL, the liquid crystal IOLs with wireless control; and IOLs that can be adjusted using the femtosecond laser or 2-photon chemistry. Finally, we discuss the preclinical and clinical studies of the light-adjustable intraocular lens (LAL) that is available commercially in Europe and Mexico and in the final stages of clinical evaluation in the United States. The general principles of each technology, as well as their research status, are described. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24957441 TI - Pars plana vitrectomy for dystrophic calcification of a silicone intraocular lens in association with asteroid hyalosis. AB - We present a case in which a pars plana vitrectomy (PPV) was performed to halt the progressive dystrophic calcification of an intraocular lens (IOL) and the need for an IOL exchange. With limited follow-up, the patient's visual complaints have resolved, the dystrophic calcification of the IOL has stabilized, and good visual acuity has been retained. To our knowledge, this is the first report of a patient with progressive dystrophic calcification of silicone IOLs in association with asteroid hyalosis treated primarily with a PPV. In certain cases, PPV may be considered in patients with dystrophic calcification in association with asteroid hyalosis and may prevent the need for a late IOL exchange. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 24957442 TI - Refractive corneal inlay for near vision improvement after cataract surgery. AB - We present the case of a patient who had refractive corneal inlay implantation for near vision improvement after bilateral cataract surgery. The patient had a history of bilateral cataract, and a 2-step procedure was suggested to improve her near and distance visual acuities. The first step was bilateral cataract extraction with a power target of plano intraocular lens implantation. Six months later, a refractive corneal inlay, Presbia Microlens, was implanted in the nondominant eye in the intracorneal pocket made with the femtosecond laser. No intraoperative or postoperative complications occurred. The bilateral uncorrected near visual acuity improved from less than Jaeger (J)6 to J1 and remained stable during the 2-year follow-up. The refractive corneal inlay is a safe, simple, and efficient method for improving near visual acuity in patients after cataract surgery. FINANCIAL DISCLOSURE: Dr. Pallikaris is the chair of the medical advisory board of Presbia Cooperatief U.A. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 24957443 TI - Persistent concerns regarding intracameral cefuroxime. PMID- 24957444 TI - Epithelial thickness changes following realignment of a malpositioned free cap. PMID- 24957445 TI - Femtosecond laser-assisted cataract surgery in a subluxated traumatic cataract. PMID- 24957446 TI - Glaucoma surgical problem: July consultation #1. PMID- 24957447 TI - July consultation #2. PMID- 24957448 TI - July consultation #4. PMID- 24957449 TI - July consultation #3. PMID- 24957450 TI - July consultation #5. PMID- 24957451 TI - July consultation #6. PMID- 24957452 TI - July consultation #7. PMID- 24957453 TI - July consultation #8. PMID- 24957454 TI - Vector analysis with the femtosecond laser. PMID- 24957455 TI - Reply: To PMID 24480562. PMID- 24957456 TI - Risk for longer suction-on times in femtosecond laser-assisted cataract surgery. PMID- 24957457 TI - Reply: To PMID 24439954. PMID- 24957458 TI - Pain during dominant-side or nondominant-side phacoemulsification. PMID- 24957459 TI - Visual experience of the cataract patient after surgery. PMID- 24957460 TI - Reply: To PMID 24291336. PMID- 24957463 TI - Association between UTI and urinary tract abnormalities: a case-control study in Erbil City/Iraq. AB - OBJECTIVE: To determine the proportion of ultrasound abnormalities of the urinary system between two groups of children: affected with urinary tract infection (UTI) and unaffected (control). Further, to determine the most common microorganisms causing UTI in those children with urinary tract abnormalities. METHODS: A case-control study was carried out in Erbil, Iraq between September and December 2012. Ultrasound examinations were carried out on 64 children affected with UTI and on 64 unaffected with UTI (control) in order to detect differences, in the presence of abnormalities, in the urinary tract between the two groups. RESULTS: A majority (59.4%) of children affected with UTI had ultrasound abnormalities, compared with 26.6% of the control group (P<0.001). Escherichia coli was the most common microorganism in both groups, although the difference was not statistically significant. More than one half (75%) of patients with UTI were female, compared with 25% who were male (P<0.001). CONCLUSION: More than one half of the children in the present study who presented with UTI were found to have ultrasound abnormalities. E. coli was the most common causative pathogen for children with or without ultrasound abnormalities. PMID- 24957461 TI - p38 MAPK-inhibited dendritic cells induce superior antitumour immune responses and overcome regulatory T-cell-mediated immunosuppression. AB - Dendritic cell (DC)-based cancer immunotherapy is a promising method, but so far has demonstrated limited clinical benefits. Regulatory T cells (Tregs) represent a major obstacle to cancer immunotherapy approaches. Here we show that inhibiting p38 MAPK during DC differentiation enables DCs to activate tumour-specific effector T cells (Teff), inhibiting the conversion of Treg and compromising Treg inhibitory effects on Teff. Inhibition of p38 MAPK in DCs lowers expression of PPARgamma, activating p50 and upregulating OX40L expression in DCs. OX40L/OX40 interactions between DCs and Teff and/or Treg are critical for priming effective and therapeutic antitumour responses. Similarly, p38 MAPK inhibition also augments the T-cell stimulatory capacity of human monocyte-derived DCs in the presence of Treg. These findings contribute to ongoing efforts to improve DC based immunotherapy in human cancers. PMID- 24957462 TI - Urogenital function after cloacal reconstruction, two techniques evaluated. AB - OBJECTIVE: Current surgical techniques for cloacal reconstruction are posterior sagittal anorecto vagino urethroplasty (PSARVUP) and posterior sagittal anorectoplasty (PSARP) with total urogenital mobilization (TUM). The aim of this study was to explore the results of reconstructive cloaca surgery in the Netherlands and evaluate urogenital function after PSARVUP and TUM. PATIENTS AND METHODS: Medical records from five pediatric surgical departments in the Netherlands were studied for patients with cloacal malformations treated between 1985 and 2009. Forty-two patients were eligible, and patients with short common channels were categorized into PSARVUP and TUM groups. Groups were compared using Fisher's exact test. RESULTS: Median age at time of surgery was 9 months (range 1 121). In 24 patients (57%) a PSARVUP was done, in 18 patients (43%) TUM. Median follow-up was 142 months (range 15-289). At follow-up spontaneous voiding was seen in 29 patients (69%). Clean intermittent catheterization (CIC) was needed in 14 patients (33%); a urinary diversion was created in 10 patients (24%). In total 32 patients (76%) were dry with no involuntary loss of urine per urethra. Recurrent urinary tract infections were seen in 23 patients (55%). When comparing PSARVUP and TUM groups in our series of patients with short common channels, there were no differences in urological outcome. Normal menstruation was present in 11 of the 20 patients who reached puberty (55%). CONCLUSION: Urogenital functional outcome after reconstructive surgery for cloacal malformations was similar in PSARVUP and TUM groups in patients with short common channels. A thorough urological follow-up is needed to establish the long-term bladder function and urinary incontinence results to prevent long-term risks of recurrent UTI. Albeit without differences between PSARVUP and TUM groups, 45% of the patients present with abnormal or absent menstruations. Gynecological follow-up is mandatory in all patients with cloacal malformations 6 months after the first sign of puberty. PMID- 24957464 TI - Unstented laparoscopic pyeloplasty in young children (1-5 years old): a comparison with a repair using double-J stent or transanastomotic externalized stent. AB - OBJECTIVE: To evaluate feasibility of unstented laparoscopic pyeloplasty in young children to prevent pyelonephritis and second anaesthesia. PATIENTS AND METHODS: During 2006-2013, 70 children (1-5 years old) underwent laparoscopic pyeloplasty for high grade hydronephrosis. Unstented repair was indicated in 34 children (GroupL1), double-J stent was placed in 21 patients (Group L2) and uretero pyelostomy stent (Cook) in 15 patients (Group L3). Stenting was preferred in large thin-walled pelvis, thin ureter, kidney malrotation, and unfavourable course of crossing vessels. The outcome was compared with age-matched group of 52 children who had open surgery during 1996-2006 (Groups O1, O3). RESULTS: Operation times were significantly shorter in Groups L1 and L2 than in Group L3; the times were shorter in open repairs. Three patients with crossing vessels from Group L1 had urine leakage and one had obstruction (11.4%). In Group L2, one patient had obstruction, one incorrect placement of the stent, and one girl had serious pyelonephritis (14.3%). In Group L3, displacement of uretero-pyelostomy occurred in one patient (6.7%). There is no statistical difference between laparoscopic groups and between laparoscopic and open groups. CONCLUSION: Unstented laparoscopic pyeloplasty is a safe procedure in selected young children with favourable anatomical conditions preventing additional anaesthesia and stent related complications. PMID- 24957466 TI - Generic drugs for the treatment of ocular conditions: changing the treatment landscape. AB - As global spending on medicinal products continues to rise, the availability of lower-cost generic substitutes is increasingly driving health care decision making. US FDA does not require strict demonstration of human bioequivalence and/or therapeutic studies for the approval of generic ophthalmic compounds. Bioequivalence between generic and innovator compounds is presumed on the basis of matching active and inactive ingredient profiles. Generic compounds may differ from innovator agents with regards to performance under environmental stress, relative acidity and bottle size/rigidity. Matching ingredient profiles may therefore not result in consistently comparable drug compositions and clinical effects. PMID- 24957465 TI - Reading between the lines; understanding drug response in the post genomic era. AB - Following the fanfare of initial, often dramatic, success with small molecule inhibitors in the treatment of defined genomic subgroups, it can be argued that the extension of targeted therapeutics to the majority of patients with solid cancers has stalled. Despite encouraging FDA approval rates, the attrition rates of these compounds remains high in early stage clinical studies, with single agent studies repeatedly showing poor efficacy In striking contrast, our understanding of the complexity of solid neoplasms has increased in huge increments, following the publication of large-scale genomic and transcriptomic datasets from large collaborations such as the International Cancer Genome Consortium (ICGC http://www.icgc.org/) and The Cancer Genome Atlas (TCGA http://cancergenome.nih.gov/). However, there remains a clear disconnect between these rich datasets describing the genomic complexity of cancer, including both intra- and inter-tumour heterogeneity, and what a treating oncologist can consider to be a clinically "actionable" mutation profile. Our understanding of these data is in its infancy and we still find difficulties ascribing characteristics to tumours that consistently predict therapeutic response for the majority of small molecule inhibitors. This article will seek to explore the recent studies of the patterns and impact of mutations in drug resistance, and demonstrate how we may use this data to reshape our thinking about biological pathways, critical dependencies and their therapeutic interruption. PMID- 24957467 TI - Nature of strong hole pairing in doped Mott antiferromagnets. AB - Cooper pairing instability in a Fermi liquid is well understood by the BCS theory, but pairing mechanism for doped Mott insulators still remains elusive. Previously it has been shown by density matrix renormalization group (DMRG) method that a single doped hole is always self-localized due to the quantum destructive interference of the phase string signs hidden in the t-J ladders. Here we report a DMRG investigation of hole binding in the same model, where a novel pairing-glue scheme beyond the BCS realm is discovered. Specifically, we show that, in addition to spin pairing due to superexchange interaction, the strong frustration of the phase string signs on the kinetic energy gets effectively removed by pairing the charges, which results in strong binding of two holes. By contrast, if the phase string signs are "switched off" artificially, the pairing strength diminishes significantly even if the superexchange coupling remains the same. In the latter, unpaired holes behave like coherent quasiparticles with pairing drastically weakened, whose sole origin may be attributed to the resonating-valence-bond (RVB) pairing of spins. Such non BCS pairing mechanism is therefore beyond the RVB picture and may shed important light on the high-T(c) cuprate superconductors. PMID- 24957469 TI - Health policy basics: physician quality reporting system. AB - The U.S. health care system is in the midst of transforming from a fee-for service system to a value-based system that delivers high-quality and cost effective care. Quality reporting programs and increasing transparency of performance are meant to encourage physicians and hospitals to invest in improving the delivery of care. In 2006, the Centers for Medicare & Medicaid Services implemented the Physician Quality Reporting System (PQRS). The PQRS is an incentive and penalty payment program for eligible professionals who report data on quality measures for covered professional services furnished to Medicare beneficiaries. The program gives eligible professionals the opportunity to assess the quality of care they are providing to their patients and compare their performance on a given measure with that of their peers. This article discusses the history of PQRS, the 2014 PQRS, and how it affects other quality programs. PMID- 24957468 TI - Survey of selected tick-borne diseases in dogs in Finland. AB - BACKGROUND: Due to climate changes during the last decades, ticks have progressively spread into higher latitudes in northern Europe. Although some tick borne diseases are known to be endemic in Finland, to date there is limited information with regard to the prevalence of these infections in companion animals. We determined the antibody and DNA prevalence of the following organisms in randomly selected client-owned and clinically healthy hunting dogs living in Finland: Ehrlichia canis (Ec), Anaplasma phagocytophilum (Ap), Borrelia burgdorferi (Bb) and Bartonella. METHODS: Anti-Ap, -Bb and -Ec antibodies were determined in 340 Finnish pet dogs and 50 healthy hunting dogs using the 4DX Snap(r)Test (IDEXX Laboratories). In addition, PCRs for the detection of Ap and Bartonella DNA were performed. Univariate and multivariate logistic regression analyses were used to identify risk factors associated with seropositivity to a vector borne agent. RESULTS: The overall seroprevalence was highest for Ap (5.3%), followed by Bb (2.9%), and Ec (0.3%). Seropositivities to Ap and Bb were significantly higher in the Aland Islands (p <0.001), with prevalence of Ap and Bb antibodies of 45 and 20%, respectively. In healthy hunting dogs, seropositivity rates of 4% (2/50) and 2% (1/50) were recorded for Ap and Bb, respectively. One client-owned dog and one hunting dog, both healthy, were infected with Ap as determined by PCR, while being seronegative. For Bartonella spp., none of the dogs tested was positive by PCR. CONCLUSIONS: This study represents the first data of seroprevalence to tick borne diseases in the Finnish dog population. Our results indicate that dogs in Finland are exposed to vector borne diseases, with Ap being the most seroprevalent of the diseases tested, followed by Bb. Almost 50% of dogs living in Aland Islands were Ap seropositive. This finding suggests the possibility of a high incidence of Ap infection in humans in this region. Knowing the distribution of seroprevalence in dogs may help predict the pattern of a tick borne disease and may aid in diagnostic and prevention efforts. PMID- 24957470 TI - Unique canal communicating between both maxillary sinuses through the palatine recess with hypertrophy of sinuses. AB - The result of an inappropriate growth of the jaws is in many cases related to abnormalities in the rest of the facial skeleton. We present a 21-year-old patient with a possibly unique anomaly of the maxillary sinus in skeletal class III dentofacial deformity. This anatomical variant has not to our knowledge been previously reported and all clinicians should be aware of it. It presented not only as hypertrophy of the sinuses but also as a communication between the two maxillary sinuses, and might be associated with a severe III class deformity with an extremely narrow maxilla. We describe this as a narrowed maxillary canal with no septum or membrane. PMID- 24957471 TI - C392T polymorphism of the Wnt10a gene in non-syndromic oral cleft in a northeastern Chinese population. AB - Non-syndromic oral cleft is one of the most common congenital malformations, and more than 40 genes may be involved in its aetiology. Recent studies have shown that the Wnt10a gene may also contribute. We recruited 198 patients with non syndromic oral clefts, comprising 96 elementary families (restricted to the patients and their parents) and 187 controls, to investigate their associations with the risk of such clefts and their subgroups in a Chinese Han population. The variant evaluated in this study was a single nucleotide polymorphism - specifically, a missense mutation C392T of Wnt10a. Polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) was used to genotype the marker, and case-control and family-based associations were analysed. Although in the case-control study there were no significant differences in frequency distributions of genotypes or alleles between cases and controls in the groups with cleft palate and cleft lip and palate, the genotypic and allelic frequencies of C392T in the total groups and the group with cleft lip alone differed significantly from those in the controls (p=0.04, and 0.01, respectively). A transmission disequilibrium test showed a transmitted disequilibrium in C392T. In conclusion, we found an association between the C392T variant and non-syndromic oral clefts. PMID- 24957472 TI - Orthognathic Y-splint: a CAD/CAM-engineered maxillary repositioning wafer assembly. PMID- 24957473 TI - Tanshinol protects hippocampus and attenuates vascular dementia development. AB - Tanshinol (3-(3',4'-dihydroxyphenyl)-(2R)-lactic acid, TSL) is widely used in traditional Chinese medicine for the treatment of cardiovascular and cerebrovascular diseases. Here, we assessed whether TSL protected hippocampus and attenuated vascular dementia (VD) development in rats. The behavioral analysis showed that TSL could decrease the distance and latency time, and increase the swim speed in water maze in rats subjected to VD. TSL remarkably increased acetylcholine level and decreased acetylcholinesterase activity in rats subjected to VD. Likewise, TSL remarkably decreased malondialdehyde and increased superoxide dismutase levels in rats subjected to VD. Furthermore, treatment with TSL reduced the level of dead neurons in dentate gyrus. In addition, TSL upregulated growth-associated protein 43 (GAP43) and vascular endothelial growth factor (VEGF) expression and downregulated phosphorylated Akt (p-AKt) and phosphorylated glycogen synthase kinase (p-GSK3beta) expression in hippocampus in rats subjected to VD. These results suggest that TSL may be a potential compound in VD model. PMID- 24957474 TI - Invasive group A streptococcal infection in the Northern Territory, Australia: case report and review of the literature. AB - The increasing incidence of invasive group A streptococcus has been well documented in the temperate climates of North America, Europe and the United Kingdom. Studies also suggest that there are high rates of invasive group A streptococcus infection within the indigenous population of Northern Australia. This review article presents the case of infant Aboriginal twins with invasive group A streptococcal infection complicated by streptococcal toxic shock syndrome, highlighting both the severity and high transmissibility of invasive group A streptococcal disease. We review the epidemiology of group A streptococcal infection and suggest a potential role for chemoprophylaxis of household contacts to reduce the burden of disease within the indigenous population of Northern Australia. PMID- 24957476 TI - A laryngoscopy-based classification system for perioperative abnormal vocal cord movement in thyroid surgery. AB - OBJECTIVE: A retrospective cohort study to develop a classification scheme for abnormal vocal cord movement (AVCM) before and after thyroid surgery. METHODS: Clinical and laryngoscopic data from patients who underwent partial or total thyroidectomy were analysed. AVCM was classified as mild (type I), moderate (type II) or severe (type III), according to laryngoscopic findings. RESULTS: The study included 1619 patients, of whom 39 had preoperative AVCM and 65 had postoperative AVCM. Recovery rates for preoperative, postoperative and total type I AVCM were higher than the corresponding type III AVCM. Recovery rates for total type II AVCM were higher than those for type III AVCM at 1, 3 and 6 months postoperatively. Asymptomatic patients had better recovery rates than symptomatic patients. CONCLUSION: We have developed a useful classification system for patients with AVCM after thyroidectomy. Pre- and postoperative laryngoscopy can identify asymptomatic AVCM and is essential to evaluate the extent of recurrent laryngeal nerve injury in these patients. PMID- 24957478 TI - Outcomes after stereotactic body radiotherapy for lung tumors, with emphasis on comparison of primary lung cancer and metastatic lung tumors. AB - BACKGROUND: The goal of this study was to determine the prognostic factors associated with an improved overall outcome after stereotactic body radiotherapy (SBRT) for primary lung cancer and metastatic lung tumors. METHODS: A total of 229 lung tumors in 201 patients were included in the study. SBRT of 45 Gy in 3 fractions, 48 Gy in 4 fractions, 60 Gy in 8 fractions or 60 Gy in 15 fractions was typically used to treat 172 primary lungs cancer in 164 patients and 57 metastatic lung tumors in 37 patients between January 2001 and December 2011. Prognostic factors for local control (LC) and overall survival (OS) were analyzed using a Cox proportional hazards model. RESULTS: The median biologically effective dose was 105.6 Gy based on alpha/beta = 10 (BED10). The median follow up period was 41.9 months. The 3-year LC and OS rates were 72.5% and 60.9%, and the 5-year LC and OS rates were 67.8% and 38.1%, respectively. Radiation pneumonitis of grades 2, 3 and 5 occurred in 22 patients, 6 patients and 1 patient, respectively. Multivariate analyses revealed that tumor origin (primary lung cancer or metastatic lung tumor, p < 0.001), tumor diameter (p = 0.005), BED10 (p = 0.029) and date of treatment (p = 0.011) were significant independent predictors for LC and that gender (p = 0.012), tumor origin (p = 0.001) and tumor diameter (p < 0.001) were significant independent predictors for OS. CONCLUSIONS: SBRT resulted in good LC and tolerable treatment-related toxicities. Tumor origin and tumor diameter are significant independent predictors for both overall survival and local control. PMID- 24957477 TI - Ethics in occupational health: deliberations of an international workgroup addressing challenges in an African context. AB - BACKGROUND: International codes of ethics play an important role in guiding professional practice in developing countries. In the occupational health setting, codes developed by international agencies have substantial import on protecting working populations from harm. This is particularly so under globalisation which has transformed processes of production in fundamental ways across the globe. As part of the process of revising the Ethical Code of the International Commission on Occupational Health, an Africa Working Group addressed key challenges for the relevance and cogency of an ethical code in occupational health for an African context through an iterative consultative process. DISCUSSION: Firstly, even in the absence of strong legal systems of enforcement, and notwithstanding the value of legal institutionalisation of ethical codes, guidelines alone may offer advantageous routes to enhancing ethical practice in occupational health. Secondly, globalisation has particularly impacted on health and safety at workplaces in Africa, challenging occupational health professionals to be sensitive to, and actively redress imbalance of power. Thirdly, the different ways in which vulnerability is exemplified in the workplace in Africa often places the occupational health professional in invidious positions of Dual Loyalty. Fourth, the particular cultural emphasis in traditional African societies on collective responsibilities within the community impacts directly on how consent should be sought in occupational health practice, and how stigma should be dealt with, balancing individual autonomy with ideas of personhood that are more collective as in the African philosophy of ubuntu. To address stigma, practitioners need to be additionally sensitive to how power imbalances at the workplace intersect with traditional cultural norms related to solidarity. Lastly, particularly in the African context, the inseparability of workplace and community means that efforts to address workplace hazards demand that actions for occupational health extend beyond just the workplace. SUMMARY: A stronger articulation of occupational health practice with advocacy for prevention should be an ethical norm. Ethical codes should ideally harmonize and balance individual and community needs so as to provide stronger moral authority guidelines. There is a need to consider an African Charter on Bioethics as complementary and strengthening of existing codes for the region. PMID- 24957480 TI - BMA annual meeting: BMA chairman attacks government for "bleeding every penny" out of NHS. PMID- 24957479 TI - Commentary: competencies in pediatric psychology: polishing pandora's box. PMID- 24957481 TI - Muscle temperature and sweating during exercise: a new link? PMID- 24957483 TI - Iliac crest bone grafting: raising awareness of a common pitfall. PMID- 24957484 TI - Nonviral gene transfer into human meniscal cells. Part II: effect of three dimensional environment and overexpression of human fibroblast growth factor 2. AB - PURPOSE: Our aim was to study the effect of three-dimensional (3D) environment and overexpression of human fibroblast growth factor 2 (FGF-2) on meniscal fibrochondrocytes in vitro. METHODS: Human meniscal fibrochondrocytes were transfected with expression plasmid vectors carrying the Photinus pyralis luciferase gene, the Escherichia coli beta-galactosidase gene or a human FGF-2 cDNA. Modified fibrochondrocytes were cultivated in 3D alginate hydrogel or cell pellets or in 2D monolayer culture. RESULTS: The levels of luciferase activity showed a peak at day two and returned to baseline levels by day 11, regardless of the type of cultivation. Both 3D environments supported the secretion of human FGF-2 protein upon FGF-2 transfection. Overexpression of human FGF-2 by genetically modified human meniscal fibrochondrocytes stimulated proliferation but not glycosaminoglycan synthesis only in 3D culture. Culture in alginate spheres resulted in a larger difference in cell numbers compared with pellet cultures. CONCLUSIONS: Three-dimensional alginate spheres are well suited for the culture of genetically modified human meniscal fibrochondrocytes. These data are of value for cell-based approaches to meniscal repair using genetically modified human meniscal fibrochondrocytes overexpressing human FGF-2. PMID- 24957485 TI - Ileal brake activation: macronutrient-specific effects on eating behavior? AB - BACKGROUND: Activation of the ileal brake, by infusing lipid directly into the distal part of the small intestine, alters gastrointestinal (GI) motility and inhibits food intake. The ileal brake effect on eating behavior of the other macronutrients is currently unknown. OBJECTIVE: The objective of this study was to investigate the effects of ileal infusion of sucrose and casein on food intake, release of GI peptides, gastric emptying rate and small-bowel transit time with safflower oil as positive control. DESIGN: This randomized, single blind, crossover study was performed in 13 healthy subjects (6 male; mean age 26.4+/-2.9 years; mean body mass index 22.8+/-0.4 kg m(-2)) who were intubated with a naso-ileal catheter. Thirty minutes after the intake of a standardized breakfast, participants received an ileal infusion, containing control ((C) saline), safflower oil ((HL) 51.7 kcal), low-dose casein ((LP) 17.2 kcal) or high dose casein ((HP) 51.7 kcal), low-dose sucrose ((LC) 17.2 kcal) and high-dose sucrose ((HC) 51.7 kcal), over a period of 90 min. Food intake was determined during an ad libitum meal. Visual analogue score questionnaires for hunger and satiety and blood samples were collected at regular intervals. RESULTS: Ileal infusion of lipid, protein and carbohydrate resulted in a significant reduction in food intake compared with control (HL: 464.3+/-90.7 kcal, P<0.001; HP: 458.0+/ 78.6 kcal, P<0.005; HC: 399.0+/-57.0 kcal, P<0.0001 vs control: 586.7+/-70.2 kcal, P<0.001, respectively). A reduction in energy intake was still apparent when the caloric amount of infused nutrients was added to the amount eaten during the ad libitum meal.Secretion of cholecystokinin and peptide YY but not of glucagon-like peptide-1 (7-36) was increased during ileal perfusion of fat, carbohydrates and protein. During ileal perfusion of all macronutrients, a delay in gastric emptying and intestinal transit was observed, but differences were not significant compared with control. CONCLUSION: Apart from lipids, also sucrose and casein reduce food intake on ileal infusion, thereby activating the ileal brake. In addition to food intake, also satiety and GI peptide secretion were affected. PMID- 24957487 TI - Optimal needle design for minimal insertion force and bevel length. AB - This research presents a methodology for optimal design of the needle geometry to minimize the insertion force and bevel length based on mathematical models of cutting edge inclination and rake angles and the insertion force. In brachytherapy, the needle with lower insertion force typically is easier for guidance and has less deflection. In this study, the needle with lancet point (denoted as lancet needle) is applied to demonstrate the model-based optimization for needle design. Mathematical models to calculate the bevel length and inclination and rake angles for lancet needle are presented. A needle insertion force model is developed to predict the insertion force for lancet needle. The genetic algorithm is utilized to optimize the needle geometry for two cases. One is to minimize the needle insertion force. Using the geometry of a commercial lancet needle as the baseline, the optimized needle has 11% lower insertion force with the same bevel length. The other case is to minimize the bevel length under the same needle insertion force. The optimized design can reduce the bevel length by 46%. Both optimized needle designs were validated experimentally in ex vivo porcine liver needle insertion tests and demonstrated the methodology of the model-based optimal needle design. PMID- 24957489 TI - Pressure-induced change of the electronic state in the tetragonal phase of CaFe2As2. AB - We have investigated the electronic states of single-crystal CaFe2As2 under hydrostatic pressure using (57)Fe Mossbauer spectroscopy and magnetization measurements. The center shift and the quadrupole splitting were refined from observed (57)Fe Mossbauer spectra using the single-crystalline sample under pressure at room temperature. A discontinuous decrease in the pressure dependence of the refined center shift was observed at 0.33 GPa without any anomaly in the pressure dependence of the refined quadrupole splitting, indicating a purely electronic state change in CaFe2As2 with a tetragonal structure. Such a change is shown to be reflected in the peak-like anomalies observed in the pressure dependences of the magnetic susceptibility at 0.26 GPa above 150 K. Our results reveal that this pressure-induced electronic state change suppresses the tetragonal-to-orthorhombic structural phase transition accompanied by an antiferromagnetic ordering. We further observed superconductivity in CaFe2As2 below ~ 8 K around 0.33 GPa although our sample was not in a single phase at this pressure. These findings suggest that the electronic state change observed in CaFe2As2 with the tetragonal structure is relevant to the appearance of the pressure-induced superconductivity in AFe2As2. PMID- 24957482 TI - Functional status at 18 months of age as a predictor of childhood disability after neonatal hypoxic-ischemic encephalopathy. AB - AIM: In children with neonatal hypoxic-ischemic encephalopathy (HIE), we examined the association between 18-month functional status by parental report and disability at 6-7 years. METHOD: Prospective observational study involving participants in the NICHD randomized controlled trial of hypothermia for HIE. Parent questionnaires-Functional Status-II (FS-II), Impact on Family (IOF) and Family Resource Scale (FRS) at 18 months were correlated with 6- to 7-year developmental assessments. Disability at 6-7 years was defined as IQ < 70, gross motor functional classification scale level III-V, bilateral blindness, deafness, or epilepsy. RESULTS: Rates of severe HIE (32 vs. 15%), public insurance (73% vs. 47%) and IOF scales were higher and mean (SD) FS-II independence (I) {54 (SD 35) vs. 98 (SD 8)} and general health (GH) {87 (SD 14) vs. 98 (SD 6)} scores were significantly lower in children with disability (n=37) at 6-7 years, compared to those (n=74) without disability. FS-II I scores were significantly associated with disability (OR 0.92; 95% CI 0.87-0.97; p=0.003). On path analysis, severe HIE, greater IOF and public insurance were associated with poorer 18-month FS-II I scores, which, in turn, were associated with disability at 6 to 7 years. INTERPRETATION: Poor independent functioning by parental report at 18 months in children with HIE was associated with childhood disability. PMID- 24957490 TI - Doping cobalt into a [Zn7] cluster-based MOF to tune magnetic behaviour and induce fluorescence signal mutation. AB - An in situ doping strategy was successfully applied to tune the magnetic behaviour and induce fluorescence signal mutation of a spindle heptanuclear zinc cluster-based MOF, by only modifying its structural composition. The Co(II)-doped Zn(II)-MTV-M'MOF exhibits canted antiferromagnetism and weaker fluorescence properties. PMID- 24957486 TI - Is obesity predictive of cardiovascular dysfunction independent of cardiovascular risk factors? AB - INTRODUCTION: Obesity is thought to exert detrimental effects on the cardiovascular (CV) system. However, this relationship is impacted by the co occurrence of CV risk factors, type 2 diabetes (T2DM) and overt disease. We examined the relationships between obesity, assessed by body mass index (BMI) and waist circumference (WC), and CV function in 102 subjects without overt CV disease. We hypothesized that obesity would be independently predictive of CV remodeling and functional differences, especially at peak exercise. METHODS: Brachial (bSBP) and central (cSBP) systolic pressure, carotid-to-femoral pulse wave velocity (PWVcf) augmentation index (AGI; by SphygmoCor), and carotid remodeling (B-mode ultrasound) were examined at rest. Further, peak exercise cardiac imaging (Doppler ultrasound) was performed to measure the coupling between the heart and arterial system. RESULTS: In backward elimination regression models, accounting for CV risk factors, neither BMI nor WC were predictors of carotid thickness or PWVcf; rather age, triglycerides and hypertension were the main determinants. However, BMI and WC predicted carotid cross-sectional area and lumen diameter. When examining the relationship between body size and SBP, BMI (beta=0.32) and WC (beta=0.25) were predictors of bSBP (P<0.05), whereas, BMI was the only predictor of cSBP (beta=0.22, P<0.05) indicating a differential relationship between cSBP, bSBP and body size. Further, BMI (beta=-0.26) and WC (beta=-0.27) were independent predictors of AGI (P<0.05). As for resting cardiac diastolic function, WC seemed to be a better predictor than BMI. However, both BMI and WC were inversely and independently related to arterial-elastance (net arterial load) and end-systolic elastance (cardiac contractility) at rest and peak exercise. CONCLUSION: These findings illustrate that obesity, without T2DM and overt CV disease, and after accounting for CV risk factors, is susceptible to pathophysiological adaptations that may predispose individuals to an increased risk of CV events. PMID- 24957491 TI - The Fabrication of Biomimetic Chitosan Scaffolds by Using SBF Treatment with Different Crosslinking Agents. AB - In this study, a chitosan substrate was modified by simulated body fluid (SBF) treatment, in which the effect of the chosen crosslinking agent was investigated. Two crosslinking agents, glutaraldehyde (GA) and sodium tripolyphosphate (TPP), were used before the SBF process. By using TPP as the crosslinking agent, the Ca/P ratio and the degree of crystallinity were very close to the natural bone matrix. On the contrary, the substrate properties were very different from natural bone when the crosslinking agent GA was used. The results indicate that the produced substrates were biomimetic when the TPP was applied. On the SBF modified chitosan substrates with TPP crosslinking, the cultured osteoblastic cells expressed better proliferation, mitochondria activity and differentiation ability. The chitosan crosslinked using TPP was a good template in the SBF process, which resulted in a highly biomimetic layer. This biomimetic substrate possesses excellent biocompatibility and osteoconduction ability, promising high potential in the promotion of bone tissue engineering. PMID- 24957488 TI - Influence of clearance on the time-dependent performance of the hip following hemiarthroplasty: a finite element study with biphasic acetabular cartilage properties. AB - Hip hemiarthroplasty is a common treatment for femoral neck fracture. However, the acetabular cartilage may degenerate after hemiarthroplasty leading to postoperative failure and the need for revision surgery. The clearance between the acetabular cartilage and head of the prosthesis is one of the potential reasons for this failure. In this study, the influence of joint clearance on the biomechanical function of a generic hip model in hemiarthroplasty was investigated using biphasic numerical simulation. Both a prolonged loading period of 4000 s and dynamic gait load of 10 cycles were considered. It was found that a larger clearance led to a higher stress level, a faster reduction in load supported by the fluid and a faster cartilage consolidation process. Additionally, the mechanical performance of the acetabular cartilage in the natural model was similar to that in the hemiarthroplasty model with no clearance but different from the hemiarthroplasty models with clearances of 0.5mm and larger. The results demonstrated that a larger clearance in hip hemiarthroplasty is more harmful to the acetabular cartilage and prosthesis heads with more available dimensions (i.e. smaller increments in diameter) could be manufactured for surgeons to achieve a lower clearance, and reduced contact stress in hemiarthroplasty surgeries. PMID- 24957492 TI - A model for transport phenomena in a cross-flow ultrafiltration module with microchannels. AB - Cross-flow ultrafiltration of macromolecular solutions in a module with microchannels is expected to have the advantages of fast diffusion from the membrane surface and a high ratio of membrane surface area to feed liquid volume. Cross-flow ultrafiltration modules with microchannels are expected to be used for separation and refining and as membrane reactors in microchemical processes. Though these modules can be applied as a separator connected with a micro-channel reactor or a membrane reactor, there have been few papers on their performance. The purpose of this study was to clarify the relationship between operational conditions and performance of cross-flow ultrafiltration devices with microchannels. In this study, Poly Vinyl Pyrrolidone (PVP) aqueous solution was used as a model solute of macromolecules such as enzymes. Cross-flow ultrafiltration experiments were carried out under constant pressure conditions, varying other operational conditions. The permeate flux decreased in the beginning of each experiment. After enough time passed, the permeate flux reached a constant value. The performance of the module was discussed based on the constant values of the flux. It was observed that the permeate flux increased with increasing transmembrane pressure (TMP) and feed flow rate, and decreased with an increase of feed liquid concentration. A model of the transport phenomena in the feed liquid side channel and the permeation through the membrane was developed based on the concentration and velocity distributions in the feed side channel. The experimental results were compared with those based on the model and the performance of the ultrafiltration module is discussed. PMID- 24957493 TI - Control of porosity and pore size of metal reinforced carbon nanotube membranes. AB - Membranes are crucial in modern industry and both new technologies and materials need to be designed to achieve higher selectivity and performance. Exotic materials such as nanoparticles offer promising perspectives, and combining both their very high specific surface area and the possibility to incorporate them into macrostructures have already shown to substantially increase the membrane performance. In this paper we report on the fabrication and engineering of metal reinforced carbon nanotube (CNT) Bucky-Paper (BP) composites with tuneable porosity and surface pore size. A BP is an entangled mesh non-woven like structure of nanotubes. Pure CNT BPs present both very high porosity (>90%) and specific surface area (>400 m2/g). Furthermore, their pore size is generally between 20-50 nm making them promising candidates for various membrane and separation applications. Both electro-plating and electroless plating techniques were used to plate different series of BPs and offered various degrees of success. Here we will report mainly on electroless plated gold/CNT composites. The benefit of this method resides in the versatility of the plating and the opportunity to tune both average pore size and porosity of the structure with a high degree of reproducibility. The CNT BPs were first oxidized by short UV/O3 treatment, followed by successive immersion in different plating solutions. The morphology and properties of these samples has been investigated and their performance in air permeation and gas adsorption will be reported. PMID- 24957494 TI - Synthesis of Carbon Nanotube (CNT) Composite Membranes. AB - Carbon nanotubes are attractive approach for designing of new membranes for advanced molecular separation because of their unique transport properties and ability to mimic biological protein channels. In this work the synthetic approach for fabrication of carbon nanotubes (CNTs) composite membranes is presented. The method is based on growth of multi walled carbon nanotubes (MWCNT) using chemical vapour deposition (CVD) on the template of nanoporous alumina (PA) membranes. The influence of experimental conditions including carbon precursor, temperature, deposition time, and PA template on CNT growth process and quality of fabricated membranes was investigated. The synthesis of CNT/PA composites with controllable nanotube dimensions such as diameters (30-150 nm), and thickness (5-100 um), was demonstrated. The chemical composition and morphological characteristics of fabricated CNT/PA composite membranes were investigated by various characterisation techniques including scanning electron microscopy (SEM), energy dispersive x-ray spectroscopy (EDXS), high resolution transmission electron microscopy (HRTEM) and x-ray diffraction (XRD). Transport properties of prepared membranes were explored by diffusion of dye (Rose Bengal) used as model of hydrophilic transport molecule. PMID- 24957495 TI - Direct contact membrane distillation of dairy process streams. AB - Membrane distillation (MD) was applied for the concentration of a range of dairy streams, such as whole milk, skim milk and whey. MD of a pure lactose solution was also investigated. Direct contact MD (DCMD) mode experiments were carried out in continuous concentration mode, keeping the warm feed/retentate and cold permeate stream temperatures at 54 degrees C and 5 degrees C respectively. Performance in terms of flux and retention was assessed. The flux was found to decrease with an increase of dry-matter concentration in the feed. Retention of dissolved solids was found to be close to 100% and independent of the dry-matter concentration in the feed. Fourier Transform Infrared Spectroscopy (FTIR) of the fouled membranes confirms organics being present in the fouling layer. PMID- 24957496 TI - Characteristics of filter cake exfoliation in upward ultrafiltration of nanoparticle suspensions. AB - Downward and upward ultrafiltration (UF) was performed using the suspensions of nanosized colloidal silica with different particle diameters and their filtration rates were compared. In downward UF, the filtration rate decreases as the particle diameter decreases because the specific filtration resistance of the filter cake becomes significantly higher. In contrast, the filtration rate in upward UF increases with the decrease in the particle diameter because the filter cake consisting of small particles is exfoliated much more easily under the influence of gravity than that of large ones. In order to evaluate the characteristics of the filter cake exfoliation, the steady filtration rate in the upward mode was measured. The steady filtration rate has a tendency to decrease with particle concentration as well as mean particle diameter. Therefore, when the small particles are added into a given concentration of large particle suspension, the mean particle diameter decreases and the total particle concentration increases due to the dosage of small particles. This results in a maximum of the steady filtration rate at a certain dosage of small particles. Moreover, an estimation equation was proposed for predicting the steady filtration rate in upward UF of colloidal silica suspensions with various mean particle diameters and total particle concentrations. PMID- 24957497 TI - Continuous membrane-based screening system for biocatalysis. AB - The use of membrane reactors for enzymatic and co-factor regenerating reactions offers versatile advantages such as higher conversion rates and space-time-yields and is therefore often applied in industry. However, currently available screening and kinetics characterization systems are based on batch and fed-batch operated reactors and were developed for whole cell biotransformations rather than for enzymatic catalysis. Therefore, the data obtained from such systems has only limited transferability for continuous membrane reactors. The aim of this study is to evaluate and to improve a novel screening and characterization system based on the membrane reactor concept using the enzymatic hydrolysis of cellulose as a model reaction. Important aspects for the applicability of the developed system such as long-term stability and reproducibility of continuous experiments were very high. The concept used for flow control and fouling suppression allowed control of the residence time with a high degree of precision (+/-1% accuracy) in a long-term study (>100 h). PMID- 24957498 TI - Volatile Organic Compound (VOC) Removal by Vapor Permeation at Low VOC Concentrations: Laboratory Scale Results and Modeling for Scale Up. AB - Petroleum transformation industries have applied membrane processes for solvent and hydrocarbon recovery as an economic alternative to reduce their emissions and reuse evaporated components. Separation of the volatile organic compounds (VOCs) (toluene-propylene-butadiene) from air was performed using a poly dimethyl siloxane (PDMS)/alpha-alumina membrane. The experimental set-up followed the constant pressure/variable flow set-up and was operated at ~21 degrees C. The membrane is held in a stainless steel module and has a separation area of 55 * 10 4 m2. Feed stream was set to atmospheric pressure and permeate side to vacuum between 3 and 5 mbar. To determine the performance of the module, the removed fraction of VOC was analyzed by Gas Chromatography/Flame Ionization Detector (GC/FID). The separation of the binary, ternary and quaternary hydrocarbon mixtures from air was performed at different flow rates and more especially at low concentrations. The permeate flux, permeance, enrichment factor, separation efficiency and the recovery extent of the membrane were determined as a function of these operating conditions. The permeability coefficients and the permeate flux through the composite PDMS-alumina membrane follow the order given by the Hildebrand parameter: toluene > 1,3-butadiene > propylene. The simulated data for the binary VOC/air mixtures showed fairly good agreement with the experimental results in the case of 1,3-butadiene and propylene. The discrepancies observed for toluene permeation could be minimized by taking into account the effects of the porous support and an influence of the concentration polarization. Finally, the installation of a 0.02 m2 membrane module would reduce 95% of the VOC content introduced at real concentration conditions used in the oil industry. PMID- 24957499 TI - Limb girdle muscular dystrophy due to LAMA2 mutations: diagnostic difficulties due to associated peripheral neuropathy. AB - We report an eleven year old girl with early motor difficulties initially diagnosed with a peripheral neuropathy in another hospital based on abnormal electrophysiological findings. Our clinical assessment did not highlight obvious clinical features supporting a peripheral neuropathy but evidence of mild proximal weakness. Electrophysiological studies performed at our hospital revealed evidence of a sensorimotor demyelinating polyneuropathy with possible axonal involvement. Brain magnetic resonance imaging (MRI) revealed subtle white matter signal abnormalities, interpreted as nonspecific. Given the patient's proximal weakness and a mildly elevated serum creatine kinase, we performed a muscle biopsy. The muscle had mildly dystrophic features and subtly depleted laminin alpha2 expression. There was diffusely upregulated laminin alpha5 expression, and depletion of laminin alpha2 in intramuscular motor nerves, which made us suspect a partial laminin alpha2 (merosin) deficiency. Muscle MRI showed predominant posterior and medial compartments involvement. The patient was found to have autosomal recessively inherited double heterozygous LAMA2 mutations. This case illustrates the mild end of the partial merosin deficiency phenotypic spectrum, and highlights how careful assessment of laminin alpha2 expression in intramuscular motor nerves can be a helpful diagnostic clue in partial merosin deficiency. PMID- 24957501 TI - Clinical pharmacology of the anti-IL-17 receptor antibody brodalumab (KHK4827) in Japanese normal healthy volunteers and Japanese subjects with moderate to severe psoriasis: a randomized, dose-escalation, placebo-controlled study. PMID- 24957503 TI - Effectiveness of different nursing handover styles for ensuring continuity of information in hospitalised patients. AB - BACKGROUND: An accurate handover of clinical information is of great importance to continuity and safety of care. If clinically relevant information is not shared accurately and in a timely manner it may lead to adverse events, delays in treatment and diagnosis, inappropriate treatment and omission of care. During the last decade the call for interventions to improve handovers has increased. These interventions aim to reduce the risk of miscommunication, misunderstanding and the omission of critical information. OBJECTIVES: To determine the effectiveness of interventions designed to improve hospital nursing handover, specifically:to identify which nursing handover style(s) are associated with improved outcomes for patients in the hospital setting and which nursing handover style(s) are associated with improved nursing process outcomes. SEARCH METHODS: We searched the following electronic databases for primary studies: Cochrane EPOC Group specialised register (to 19 September 2012), Cochrane Central Register of Controlled Trials (CENTRAL) (to 1 March 2013), MEDLINE (1950 to 1 March 2013) OvidSP, EMBASE (1947 to 1 March 2013) OvidSP, CINAHL (Cumulative Index to Nursing and Allied Health Literature) (1980 to 1 March 2013) EbscoHost and ISI Web of Knowledge (Science Citation Index and Social Sciences Citation Index) (to 9 July 2012). The Database of Abstracts of Reviews (DARE) was searched for related reviews. We screened the reference lists of included studies and relevant reviews. We also searched the WHO International Clinical Trials Registry Platform (ICTRP) http://www.who.int/ictrp/en/ and Current Controlled Trials www.controlled trials.com/mrct and we conducted a search of grey literature web sites. SELECTION CRITERIA: Randomised controlled trials (RCTs or cluster-RCTs) evaluating any nursing handover style between nurses in a hospital setting with the aim of preventing adverse events or optimising the transfer of accurate essential information required for continuity of care, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: The search identified 2178 citations, 28 of which were considered potentially relevant. After independent review of the full text of these studies, no eligible studies were identified for inclusion in this review due to the absence of studies with a randomised controlled study design. AUTHORS' CONCLUSIONS: There was no evidence available to support conclusions about the effectiveness of nursing handover styles for ensuring continuity of information in hospitalised patients because we found no studies that fulfilled the methodological criteria for this review. As a consequence, uncertainty about the most effective practice remains. Research efforts should focus on strengthening the evidence abut the effectiveness of nursing handover styles using well designed, rigorous studies. According to current knowledge, the following guiding principles can be applied when redesigning the nursing handover process: face-to face communication, structured documentation, patient involvement and use of IT technology to support the process. PMID- 24957500 TI - Genetic variation at IL12B, IL23R and IL23A is associated with psoriasis severity, psoriatic arthritis and type 2 diabetes mellitus. AB - BACKGROUND: Common DNA variants in IL12B, IL23R and IL23A have been associated with an increased susceptibility to psoriasis (Ps) and psoriatic arthritis (PsA). Metabolic comorbidities and cardiovascular risk factors have also been associated to both Ps and PsA. OBJECTIVE: To analyze the effect of single nucleotide polymorphisms (SNPs) previously linked to Ps (IL12B rs6887695 and rs3212227, IL23R rs2201841 and rs11209026, and IL23Ars2066808) in the main phenotype and metabolic/cardiovascular characteristics among Ps patients from a Northern Spanish population. METHODS: The aforementioned genetic variants were determined in a total of 405 chronic plaque Ps patients and 426 controls. Subsequent statistical analysis included stratification for psoriatic clinical characteristics (age of onset, disease severity, familial psoriasis, HLA-Cw6, nail psoriasis) plus diabetes mellitus type 2, arterial hypertension, dyslipidemia and ischemic cardiac events as comorbidities. RESULTS: An association between IL23R rs11209026-GG genotype with a more severe disease (p=0.02, OR=2.11, 95% CI=1.13-3.95). Carriers of the IL23A rs2066808-A allele were significantly more frequent among PsA patients (p=0.016, OR= 3.04, 95% CI=1.19-7.78). We found significant associations between three SNP genotypes and type 2 diabetes: IL12B rs6887695-CC (p=0.03, OR=2.90, 95% CI=1.09-7.69), IL12B rs3212227-CC (p=0.035, OR=5.90, 95% CI= 1.35-25.73) and IL23R rs2201841-GG (p= 0.027, OR=2.69, 95% CI=1.09-6.66). CONCLUSION: In our population, genetic variation at IL12B, IL23R and IL23A has an influence not only on the risk for Ps but also on disease severity and type 2 diabetes mellitus. PMID- 24957502 TI - Lysine ubiquitination and acetylation of human cardiac 20S proteasomes. AB - PURPOSE: Altered proteasome functions are associated with multiple cardiomyopathies. While the proteasome targets polyubiquitinated proteins for destruction, it itself is modifiable by ubiquitination. We aim to identify the exact ubiquitination sites on cardiac proteasomes and examine whether they are also subject to acetylations. EXPERIMENTAL DESIGN: Assembled cardiac 20S proteasome complexes were purified from five human hearts with ischemic cardiomyopathy, then analyzed by high-resolution MS to identify ubiquitination and acetylation sites. We developed a library search strategy that may be used to complement database search in identifying PTM in different samples. RESULTS: We identified 63 ubiquitinated lysines from intact human cardiac 20S proteasomes. In parallel, 65 acetylated residues were also discovered, 39 of which shared with ubiquitination sites. CONCLUSION AND CLINICAL RELEVANCE: This is the most comprehensive characterization of cardiac proteasome ubiquitination to date. There are significant overlaps between the discovered ubiquitination and acetylation sites, permitting potential crosstalk in regulating proteasome functions. The information presented here will aid future therapeutic strategies aimed at regulating the functions of cardiac proteasomes. PMID- 24957504 TI - Homogeneous Pd-catalyzed transformation of terminal alkenes into primary allylic alcohols and derivatives. AB - Synthesis of primary alcohols from terminal alkenes is an important process in both bulk and fine chemical syntheses. Herein, a homogeneous Pd-complex-catalyzed transformation of terminal alkenes into primary allylic alcohols, by using 5 mol % [Pd(PPh3)4] as a catalyst, and H2O, CO2, and quinone derivatives as reagents, is reported. When alcohols were used instead of H2O, allylic ethers were obtained. A proposed mechanism includes the addition of oxygen nucleophiles at the less-hindered terminal position of pi-allyl Pd intermediates. PMID- 24957505 TI - Childhood attachment and schizophrenia: the "attachment-developmental-cognitive" (ADC) hypothesis. AB - Schizophrenia is a complex psychiatric syndrome whose exact causes remain unclear. However, current scientific consensus has highlighted the importance of neurodevelopmental and neurocognitive processes in the development of schizophrenic symptoms. Research over the past three decades, motivated by the findings of the World Health Organization's large-scale studies, has highlighted the importance of psychosocial adversities - including childhood abuse and neglect - in this disorder. In this paper, I propose a hypothesis based on John Bowlby's framework of attachment theory, which I have termed the attachment developmental-cognitive (ADC) hypothesis. The ADC hypothesis integrates recent developments related to (1) existing models of schizophrenia, (2) studies examining the effect of attachment on brain biology and cognitive development, and (3) various known facts about the course and outcome of this disorder. In doing so, it explains how disturbed childhood attachment leads to core psychological and neurochemical abnormalities which are implicated in the genesis of schizophrenia and also affect its outcome. The ADC hypothesis compasses and expands on earlier formulations, such as the "social defeat" and "traumagenic" models, and has important implications regarding the prevention and treatment of schizophrenia. Ways of testing and refining this hypothesis are outlined as avenues for future research. Though provisional, the ADC hypothesis is entirely consistent with both biological and psychosocial research into the origins of schizophrenia. PMID- 24957506 TI - Pulmonary arterial hypertension and sepsis: prothrombotic profile and inflammation can changes pulmonary mechanics? AB - Pulmonary arterial hypertension (PAH) is associated to cellular and structural alterations of lung vasculature. Endothelial dysfunction promotes vasoconstriction, smooth muscle hypertrophy, intimal proliferation, angioproliferative plexiform lesions, and in situ thrombosis increasing pulmonary vascular resistance and arterial stiffness. Indeed, an inflammatory component has been defined in PAH on the last years. Sepsis is a systemic complex syndrome, of infectious origin. The presence of inflammation is well established in this condition and it is also considered a risk factor for acute lung injury. Thrombotic events play important role in sepsis pathophysiology. The association between PAH and sepsis potentiate the metabolic oxygen consumption/offer imbalance, with very high mortality risk. Furthermore, it is possible that the association of these two conditions should intensify thrombotic events on pulmonary microcirculation, reducing area of pulmonary vascular bed available for blood flow. For the other side, an inflammation synergism observed on these two conditions should increase the respiratory system impedance. PMID- 24957507 TI - Updates in biological therapies for knee injuries: tendons. AB - Tendons are subjected to tendinopathies caused by inflammation, degeneration, and weakening of the tendon, due to overuse and trauma, which may eventually lead to tendon rupture. Recently, there has been increasing interest in biological approaches to augment tissue healing. Tendon healing occurs through a dynamic process with inflammation, cellular proliferation, and tissue remodeling. In this review article, we discuss the more frequently proposed biological therapies for tendon injuries as platelet-rich plasma, mesenchymal stem cells, extracorporeal shockwave, and scaffolds. PMID- 24957509 TI - Reappraising Past and Future Transitional Events: The Effects of Mental Focus on Present Perceptions of Personal Impact and Self-Relevance. AB - This research examined how instructions to focus on the concrete details (experience focus) versus broader life significance (coherence focus) influence present perceptions of transitional impact and self-relevance for past and future transitional events. Participants (Study 1, N = 119; Study 2, N = 251) selected a past or future transition and wrote about it using either an experiential or coherence focus. Participants then rated the event on transitional impact, self relevance, and other phenomenological characteristics. Individuals instructed to use a coherence focus on a past transition reported higher levels of material and psychological impact and rated the event as more self-relevant, compared to those instructed to use an experiential focus. The manipulation did not influence ratings for future events. Controlling for temporal distance and emotional valence did not alter the findings. Future transitions were regarded as more personally important than past transitions. Appraisals of the impact and self relevance of transformative past events (but not future events) are affected by the mental focus adopted at retrieval. The findings are considered in light of essential differences between remembering and forecasting and support the notion that a coherence focus promotes adaptive self-reflection by affording people the cognitive means with which to reconcile transitional experiences. PMID- 24957508 TI - Reverse sural fasciocutaneous flap with a cutaneous pedicle to cover distal lower limb soft tissue defects: experience of 109 clinical cases. AB - BACKGROUND: Soft tissue defects over the mid- and distal third tibia, heel, dorsum and plantar aspect of the foot and over the medial, lateral and posterior aspect of the ankle are a common scenario in clinical orthopaedic practice. In this article, we describe the utility of the reverse sural fasciocutaneous flap with a cutaneous pedicle in 109 clinical cases with distal lower limb soft tissue defects. MATERIALS AND METHODS: A total of 109 patients were operated on for moderate (5-15 cm) and large (more than 15 cm) soft tissue defects at various sites along the lower limb including foot, heel and sole with the reverse sural fasciocutaneous flap. The defects were secondary to trauma (61 cases), diabetic ulcers (12 cases), post-traumatic scar contracture (8 cases), venous ulcer (4 cases), wound dehiscence (10 cases), leprotic non-healing ulcer (1 case), post infective wound (1 case), radiation-induced ulcer following radiotherapy for synovial cell sarcoma (1 case), post-fibromatosis excision (1 case), post dermatofibrosarcoma excision (1 case), post-heel melanoma excision (1 case) and actinomycosis foot (1 case). Patients were assessed for flap uptake and healing of defects. RESULTS: Among the 102 cases analysed, 81 were male and 21 female with an average age of 32.7 years. The average size of the flaps was 148.10 +/- 59.54 cm(2). The flap healed uneventfully in 89.21 % of patients. Edge necrosis occurred in 9 cases. Donor site regrafting was required in 7 patients. CONCLUSION: The reverse sural fasciocutaneous flap with a cutaneous pedicle is a quick, versatile, easy and safe soft tissue defect coverage technique to cover most of the soft tissue defects of the lower limb in common orthopaedic practice and does not require any microvascular repair, though it may be cosmetically unappealing in a few cases. LEVEL OF EVIDENCE: IV (Case series). PMID- 24957511 TI - Malignant rhabdoid tumor of the small intestine in adults: a brief review of the literature and report of a case. AB - A malignant rhabdoid tumor was first described as a subtype of Wilms tumor in 1978. The most frequent location of these tumors is the kidney, and they are common in childhood. The extrarenal localization of these tumors has been described mainly in the central nervous system (called atypical teratoid-rhabdoid tumors), liver, soft tissues and colon. Localization in the small intestine is uncommon and since the 1990s, only a few cases of malignant rhabdoid tumors in the small intestine have been reported. This tumor is very aggressive and the prognosis is poor. We herein present our personal experience with a rhabdoid tumor of the jejunum in a 76-year-old male, and also provide an analysis of the cases of malignant rhabdoid tumor of the small intestine previously described in the literature as for a brief review. We also compared the previous reports and our present case to try to identify prognostic factors. PMID- 24957510 TI - Emerging roles for extracellular vesicles in tissue engineering and regenerative medicine. AB - Extracellular vesicles (EVs)-comprising a heterogeneous population of cell derived lipid vesicles including exosomes, microvesicles, and others-have recently emerged as both mediators of intercellular information transfer in numerous biological systems and vehicles for drug delivery. In both roles, EVs have immense potential to impact tissue engineering and regenerative medicine applications. For example, the therapeutic effects of several progenitor and stem cell-based therapies have been attributed primarily to EVs secreted by these cells, and EVs have been recently reported to play direct roles in injury-induced tissue regeneration processes in multiple physiological systems. In addition, EVs have been utilized for targeted drug delivery in regenerative applications and possess unique potential to be harnessed as patient-derived drug delivery vehicles for personalized medicine. This review discusses EVs in the context of tissue repair and regeneration, including their utilization as drug carriers and their crucial role in cell-based therapies. Furthermore, the article highlights the growing need for bioengineers to understand, consider, and ultimately design and specifically control the activity of EVs to maximize the efficacy of tissue engineering and regenerative therapies. PMID- 24957512 TI - 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-Monophosphate (AICAR), a Highly Conserved Purine Intermediate with Multiple Effects. AB - AICAR (5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-monophosphate) is a natural metabolic intermediate of purine biosynthesis that is present in all organisms. In yeast, AICAR plays important regulatory roles under physiological conditions, notably through its direct interactions with transcription factors. In humans, AICAR accumulates in several metabolic diseases, but its contribution to the symptoms has not yet been elucidated. Further, AICAR has highly promising properties which have been recently revealed. Indeed, it enhances endurance of sedentary mice. In addition, it has antiproliferative effects notably by specifically inducing apoptosis of aneuploid cells. Some of the effects of AICAR are due to its ability to stimulate the AMP-activated protein kinase but some others are not. It is consequently clear that AICAR affects multiple targets although only few of them have been identified so far. This review proposes an overview of the field and suggests future directions. PMID- 24957513 TI - A historical overview of natural products in drug discovery. AB - Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. This brief review aims to highlight historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery. Furthermore a discussion of how natural product chemistry has resulted in the identification of many drug candidates; the application of advanced hyphenated spectroscopic techniques to aid in their discovery, the future of natural product chemistry and finally adopting metabolomic profiling and dereplication approaches for the comprehensive study of natural product extracts will be discussed. PMID- 24957515 TI - Metabolomic and Lipidomic Analysis of the Heart of Peroxisome Proliferator Activated Receptor-gamma Coactivator 1-beta Knock Out Mice on a High Fat Diet. AB - The peroxisome proliferator-activated receptor-gamma coactivators (PGC-1) are transcriptional coactivators with an important role in mitochondrial biogenesis and regulation of genes involved in the electron transport chain and oxidative phosphorylation in oxidative tissues including cardiac tissue. These coactivators are thought to play a key role in the development of obesity, type 2 diabetes and the metabolic syndrome. In this study we have used a combined metabolomic and lipidomic analysis of cardiac tissue from the PGC-1beta null mouse to examine the effects of a high fat diet on this organ. Multivariate statistics readily separated tissue from PGC-1beta null mice from their wild type controls either in gender specific models or in combined datasets. This was associated with an increase in creatine and a decrease in taurine in the null mouse, and an increase in myristic acid and a reduction in long chain polyunsaturated fatty acids for both genders. The most profound changes were detected by liquid chromatography mass spectrometry analysis of intact lipids with the tissue from the null mouse having a profound increase in a number of triglycerides. The metabolomic and lipodomic changes indicate PGC-1beta has a profound influence on cardiac metabolism. PMID- 24957516 TI - Ischemic and functional mitral regurgitation in heart failure: natural history and treatment. AB - Functional mitral regurgitation (FMR) occurs when normal or nearly normal mitral leaflets are prevented from proper coaptation by underlying left ventricular (LV) dysfunction, mitral annular dilation, or both. FMR is associated with an adverse prognosis in nonischemic or ischemic LV dysfunction. Multiple studies have confirmed that even mild FMR portends a worse prognosis, and that the risk of FMR is independent of LV volumes and other clinical risk factors. FMR can be difficult to quantitate echocardiographically because it is load dependent and can vary considerably from exam to exam. There is a systematic tendency to underestimate FMR severity by echocardiography because the regurgitant orifice in FMR is typically elliptical, but the formula for calculating regurgitant orifice area assumes circular geometry. Treatment of FMR begins with guideline-directed medical therapy (GDMT) for LV dysfunction and heart failure, including cardiac resynchronization, if indicated. Revascularization should be considered for ischemic FMR, when indicated. Finally, mitral valve surgery should be considered in patients undergoing CABG in whom moderate or greater FMR is present, and also when severe symptomatic FMR persists despite optimal GDMT and revascularization. Percutaneous options for treatment of FMR are in development but are not currently approved in the US. PMID- 24957518 TI - Student nurses' attitudes toward dying patients in central Anatolia. AB - PURPOSE: This study was descriptively conducted to explore attitudes of nursing students related to caring for dying patients in central Anatolia. METHODS: The study was completed with 222 third-year students of nursing school originating from three universities in Turkey. RESULT: It was explored that Frommelt Attitudes Toward Care of the Dying Scale (FATCOD) scores of the students who had previously cared for terminal patients at the clinics were significantly higher, and the scores of those who regarded themselves as nonbeliever in terms of religion were significantly lower (p < .05). CONCLUSION: It was seen that nursing students' FATCOD scores were at a moderate level. IMPLICATIONS FOR NURSING PRACTICE: We are of the opinion that it will be helpful that nursing students should be trained about the care for dying patients during their formal education. PMID- 24957517 TI - Variable recombination dynamics during the emergence, transmission and 'disarming' of a multidrug-resistant pneumococcal clone. AB - BACKGROUND: Pneumococcal beta-lactam resistance was first detected in Iceland in the late 1980s, and subsequently peaked at almost 25% of clinical isolates in the mid-1990s largely due to the spread of the internationally-disseminated multidrug resistant PMEN2 (or Spain6B-2) clone of Streptococcus pneumoniae. RESULTS: Whole genome sequencing of an international collection of 189 isolates estimated that PMEN2 emerged around the late 1960s, developing resistance through multiple homologous recombinations and the acquisition of a Tn5253-type integrative and conjugative element (ICE). Two distinct clades entered Iceland in the 1980s, one of which had acquired a macrolide resistance cassette and was estimated to have risen sharply in its prevalence by coalescent analysis. Transmission within the island appeared to mainly emanate from Reykjavik and the Southern Peninsular, with evolution of the bacteria effectively clonal, mainly due to a prophage disrupting a gene necessary for genetic transformation in many isolates. A subsequent decline in PMEN2's prevalence in Iceland coincided with a nationwide campaign that reduced dispensing of antibiotics to children in an attempt to limit its spread. Specific mutations causing inactivation or loss of ICE-borne resistance genes were identified from the genome sequences of isolates that reverted to drug susceptible phenotypes around this time. Phylogenetic analysis revealed some of these occurred on multiple occasions in parallel, suggesting they may have been at least temporarily advantageous. However, alteration of 'core' sequences associated with resistance was precluded by the absence of any substantial homologous recombination events. CONCLUSIONS: PMEN2's clonal evolution was successful over the short-term in a limited geographical region, but its inability to alter major antigens or 'core' gene sequences associated with resistance may have prevented persistence over longer timespans. PMID- 24957519 TI - Host restriction in Salmonella: insights from Rab GTPases. AB - Salmonella enterica is a foodborne intracellular pathogen that can invade intestinal epithelial cells and survive in macrophages of susceptible hosts. Although belonging to the same species, individual Salmonella enterica serovars behave as very different pathogens. Indeed, they can cause very different diseases (from mild gastroenteritis to deadly systemic diseases) and have distinctive host selectivity. Salmonella enterica serovars Typhi (S. Typhi) is a unique serovar that has evolved to infect only humans and cause typhoid fever, a life-threatening systemic disease killing more than 200,000 people every year. The mechanisms that make S. Typhi able to infect only humans are mostly unknown. Recently, an antimicrobial traffic pathway dependent on the Rab GTPase Rab32 and its exchange factor BLOC-3 was found to be critical to kill S. Typhi in macrophages from non-susceptible hosts, suggesting that this pathway delivers an antimicrobial factor to the S. Typhi vacuole. Here we discuss this finding in the light of the current knowledge of pathogen killing mechanisms. PMID- 24957520 TI - Gradenigo's syndrome secondary to chronic otitis media on a background of previous radical mastoidectomy: a case report. AB - INTRODUCTION: Gradenigo's syndrome is nowadays a rare condition characterized by a triad of otorrhea, facial pain with trigeminal nerve involvement and abducens nerve palsy. Most cases are caused by medial extension of acute otitis media into a pneumatized petrous apex and surgical drainage is usually the treatment of choice. We present a case highlighting the pathological mechanism of this disease, demonstrate rare radiological findings associated with this patient, and showcase successful medical treatment without surgical intervention. CASE PRESENTATION: A 63-year-old Thai man presented with complete Gradenigo triad as a complication of chronic otomastoiditis in spite of clinical history of previous radical mastoidectomy and a nonpneumatization of the petrous apex. Magnetic resonance imaging showed abnormal prominent enhancement at the roof of his right temporal bone, and the dura overlying the floor of right middle cranial fossa and right cavernous sinus. Magnetic resonance imaging also detected right petrous apicitis. With the use of intravenous antibiotics and topical antibiotic eardrops, recovery was observed within 5 days with complete resolution within 2 months. CONCLUSIONS: Although there is little evidence to support the use of medical therapy in the treatment of Gradenigo's syndrome resulting from chronic ear disease, we here demonstrate successful conservative treatment of Gradenigo's syndrome following chronic otitis media in a patient who underwent previous radical mastoidectomy. PMID- 24957514 TI - Targeted chiral analysis of bioactive arachidonic Acid metabolites using liquid chromatography-mass spectrometry. AB - A complex structurally diverse series of eicosanoids arises from the metabolism of arachidonic acid. The metabolic profile is further complicated by the enantioselectivity of eicosanoid formation and the variety of regioisomers that arise. In order to investigate the metabolism of arachidonic acid in vitro or in vivo, targeted methods are advantageous in order to distinguish between the complex isomeric mixtures that can arise by different metabolic pathways. Over the last several years this targeted approach has become more popular, although there are still relatively few examples where chiral targeted approaches have been employed to directly analyze complex enantiomeric mixtures. To efficiently conduct targeted eicosanoid analyses, LC separations are coupled with collision induced dissociation (CID) and tandem mass spectrometry (MS/MS). Product ion profiles are often diagnostic for particular regioisomers. The highest sensitivity that can be achieved involves the use of selected reaction monitoring/mass spectrometry (SRM/MS); whereas the highest specificity is obtained with an SRM transitions between an intense parent ion, which contains the intact molecule (M) and a structurally significant product ion. This review article provides an overview of arachidonic acid metabolism and targeted chiral methods that have been utilized for the analysis of the structurally diverse eicosanoids that arise. PMID- 24957521 TI - Validation of the 4DSQ somatization subscale in the occupational health care setting as a screener. AB - PURPOSE: Somatoform disorders (physical symptoms without medical explanation that cause dysfunction) are prevalent in the occupational health (OH) care setting and are associated with functional impairment and absenteeism. Availability of psychometric instruments aimed at assessing somatoform disorders is limited. In the OH setting, so far only the Patient-Health-Questionnaire 15 has been validated as screener for somatoform disorder, and has been shown to have moderate validity. The Four-Dimensional Symptom Questionnaire (4DSQ) is frequently used in the OH setting but the Somatization subscale is not validated yet. The aim of this study is to validate the 4DSQ Somatization subscale as screener for DSM-IV somatoform disorder in the OH setting by using the MINI interview as gold standard. METHODS: Employees absent from work due to physical symptoms, for a period longer than 6 weeks and shorter than 2 years, were asked to participate in this study. They filled out the 4DSQ and underwent a MINI interview by telephone for DSM-IV classification. Specificity and sensitivity scores were calculated for all possible cut-off scores and a receiver operator curve was computed for the Somatization subscale. 95 % confidence intervals (95 % CIs) were calculated for sensitivity and specificity. RESULTS: The Somatization subscale of the 4DSQ has an optimal cut point of 9, with specificity and sensitivity equal to 64.3 % [95 % CI (53.6; 73.7 %)] and 60.9 % [95 % CI (40.8; 77.8 %)], respectively. Receiver operator curves showed an area under the curve equal to 0.61 [SE = 0.07; 95 % CI (0.48; 0.75)] for the Somatization subscale of the 4DSQ. CONCLUSION: The 4DSQ Somatization subscale is a questionnaire of moderate sensitivity and specificity. PMID- 24957522 TI - Bayesian methods for the design and interpretation of clinical trials in very rare diseases. AB - This paper considers the design and interpretation of clinical trials comparing treatments for conditions so rare that worldwide recruitment efforts are likely to yield total sample sizes of 50 or fewer, even when patients are recruited over several years. For such studies, the sample size needed to meet a conventional frequentist power requirement is clearly infeasible. Rather, the expectation of any such trial has to be limited to the generation of an improved understanding of treatment options. We propose a Bayesian approach for the conduct of rare disease trials comparing an experimental treatment with a control where patient responses are classified as a success or failure. A systematic elicitation from clinicians of their beliefs concerning treatment efficacy is used to establish Bayesian priors for unknown model parameters. The process of determining the prior is described, including the possibility of formally considering results from related trials. As sample sizes are small, it is possible to compute all possible posterior distributions of the two success rates. A number of allocation ratios between the two treatment groups can be considered with a view to maximising the prior probability that the trial concludes recommending the new treatment when in fact it is non-inferior to control. Consideration of the extent to which opinion can be changed, even by data from the best feasible design, can help to determine whether such a trial is worthwhile. PMID- 24957525 TI - Hierarchical, self-similar structure in native squid pen. AB - The structure of native squid pen (gladius) was investigated in two different species on different length scales. By combining microscopy, atomic force microscopy (AFM), and X-ray diffraction, the experiments probed length scales from millimetres down to nanometres. The gladii showed a hierarchical, self similar structure in the optical experiments with fibres of different size oriented along the long axis of the gladius. The fibre-like structure was reproduced at the nanoscale in AFM measurements and fibres with diameters of 500 MUm, 100 MUm, 10 MUm, 2 MUm and 0.2 MUm were observed. Their molecular structure was determined using X-ray diffraction. In the squid gladius, the chitin molecules are known to form nano-crystallites of monoclinic lattice symmetry wrapped in a protein layer, resulting in beta-chitin nano-fibrils. Signals corresponding to the alpha-coil protein phase and beta-chitin crystallites were observed in the X-ray experiments and their orientation with respect to the fibre axis was determined. The size of a nano-fibril was estimated from the X-ray experiments to be about 150 * 300 A. About 100 of these nano-fibrils are needed to form a 0.2 MUm thick micro-fibre. We found that the molecular structure is highly anisotropic with ~90% of the alpha-coils and beta-chitin crystallites oriented along the fibre-axis, indicating a strong correlation between the macroscale structure and molecular orientation. PMID- 24957523 TI - [Active surveillance of low risk prostate cancer]. AB - In Europe prostate cancer is one of the most common cancers among men. The diagnostics always include a control of the prostate-specific antigen (PSA) level and examination of a representative tissue sample from the prostate. With these findings it is possible to evaluate the degree of progression of the cancer and its prognosis. Several treatment options for localized prostate cancer are given by national and international guidelines including radical prostatectomy, percutaneous radiation therapy, or brachytherapy and surveillance of the cancer with optional treatment at a later stage. For the latter treatment option, known as active surveillance, strict criteria have to be met. The advantage of active surveillance is that only patients with progressive cancer are subjected to radical therapy. Patients with very slow or non-progressing cancer do not have to undergo therapy and thus do not have to suffer from the side effects. The basic idea behind active surveillance is that some cancers will not progress to a stage that requires treatment within the lifetime of the patient and therefore do not require treatment at all. Unfortunately the criteria for active surveillance are not definitive enough at the current time leading only to a delay in effective treatment for many patients. The surveillance strategy has without doubt a high significance among the treatment options for prostate cancer; however, at the current time it lacks reliable indicators for a certain prognosis. Therefore, patients must be informed in detail about the advantages and disadvantages of active surveillance. PMID- 24957524 TI - Association between global biomarkers of oxidative stress and hip fracture in postmenopausal women: a prospective study. AB - Human studies suggest that oxidative stress is a risk factor for osteoporosis, but its relationship with fracture risk is poorly understood. The purpose of the present study was to investigate the association between biomarkers of oxidative stress and hip fracture in postmenopausal women. We conducted a prospective study in the Nurses' Health Study among 996 women aged 60 years or older at baseline blood collection in 1989-1990. Plasma fluorescent oxidation products (FlOPs) were measured at three excitation/emission wavelengths (360/420 nm named as FlOP_360; 320/420 nm named as FlOP_320; and 400/475 nm named as FlOP_400). FlOPs are generated from many different pathways (lipid, protein, and DNA) and reflect a global oxidation burden. FlOP assay is 10-100 times more sensitive than measurement of malondialdehyde. We used Cox proportional hazards regression model to investigate the association between baseline plasma FlOPs and the risk of hip fracture, adjusting for multiple hip fracture risk factors such as age, history of osteoporosis, history of hypertension, prior fracture, and smoking status. Forty-four hip fractures (4.4%) were identified during the follow-up (maximum = 23 years). In the multivariable model, the hazard ratios (HRs) of hip fracture in the second and third tertiles of FlOP_320 were 2.11 (95% confidence interval [CI] = 0.88-5.10) and 2.67 (95% CI = 1.14-6.27), respectively, in comparison with the lowest tertile, and the risk increased linearly with increasing FlOP_320 (p for trend = 0.021). Neither FlOP_360 nor FlOP_400 was significantly associated with risk of hip fracture (tertile 3 versus tertile 1: HR = 0.70, 95% CI = 0.32-1.54, p for trend = 0.386 for FlOP_360; and HR = 0.88, 95% CI = 0.40-1.96, p for trend = 0.900 for FlOP_400). In this prospective study, higher plasma FlOP_320 was an independent risk factor for hip fracture. Our results need further confirmation. PMID- 24957526 TI - HLA-A*02:01:79, a novel allele, which has arisen by silent mutation in codon 230. AB - A*02:01:79 is identical to A*02:01:01:01, except for one nucleotide change at nt 762 in exon 4 from C to T. PMID- 24957528 TI - Deadenylation-a piece of PANcake. PMID- 24957529 TI - Iron deficiency: an emerging therapeutic target in heart failure. AB - In patients with heart failure, iron deficiency is frequent but overlooked, with a prevalence of 30%-50%. Since it contributes to cardiac and peripheral muscle dysfunction, iron deficiency is associated with poorer clinical outcomes and a greater risk of death, independent of haemoglobin level. Therefore, iron deficiency emerges as a new comorbidity and a therapeutic target of chronic heart failure in addition to chronic renal insufficiency, anaemia and diabetes. In a series of placebo-controlled, randomised studies in patients with heart failure and iron deficiency, intravenous iron had a favourable effect on exercise capacity, functional class, LVEF, renal function and quality of life. These clinical studies were performed in the context of a renewed interest in iron metabolism. During the past 10 years, knowledge about the transport, storage and homeostasis of iron has improved dramatically, and new molecules involved in iron metabolism have been described (eg, hepcidin, ferroportin, divalent metal transporter 1). Recent European guidelines recommend the monitoring of iron parameters (ie, serum ferritin, transferrin saturation) for all patients with heart failure. Ongoing clinical trials will explore the benefits of iron deficiency correction on various heart failure parameters. PMID- 24957527 TI - Global characterization of the oocyte-to-embryo transition in Caenorhabditis elegans uncovers a novel mRNA clearance mechanism. AB - The oocyte-to-embryo transition (OET) is thought to be mainly driven by post transcriptional gene regulation. However, expression of both RNAs and proteins during the OET has not been comprehensively assayed. Furthermore, specific molecular mechanisms that regulate gene expression during OET are largely unknown. Here, we quantify and analyze transcriptome-wide, expression of mRNAs and thousands of proteins in Caenorhabditis elegans oocytes, 1-cell, and 2-cell embryos. This represents a first comprehensive gene expression atlas during the OET in animals. We discovered a first wave of degradation in which thousands of mRNAs are cleared shortly after fertilization. Sequence analysis revealed a statistically highly significant presence of a polyC motif in the 3' untranslated regions of most of these degraded mRNAs. Transgenic reporter assays demonstrated that this polyC motif is required and sufficient for mRNA degradation after fertilization. We show that orthologs of human polyC-binding protein specifically bind this motif. Our data suggest a mechanism in which the polyC motif and binding partners direct degradation of maternal mRNAs. Our data also indicate that endogenous siRNAs but not miRNAs promote mRNA clearance during the OET. PMID- 24957532 TI - Oscillatory carbonylation using alkyne-functionalised poly(ethylene glycol). AB - In this study palladium-catalysed oscillatory carbonylation has been achieved using mono alkyne-terminated poly(ethylene glycol) methyl ether substrates. Reproducible, synchronised oscillations in pH and solution turbidity have been recorded over several days. A reaction network accounting for the observed phenomena has been proposed. PMID- 24957531 TI - The opposite associations of long-chain versus very long-chain monounsaturated fatty acids with mortality among patients with coronary artery disease. AB - OBJECTIVE: Epidemiological evidence suggests that different lengths of carbon chains might predict cardiovascular disease (CVD) events differently. However, little data exist concerning the effects of specific types of monounsaturated fatty acids (MUFAs) stratified by chain length. Therefore, the study aimed to explore whether the associations of long-chain MUFAs (LC-MUFAs: 16:1n-7 and 18:1n 9) and very long-chain MUFAs (VLC-MUFAs: 20:1n-9, 22:1n-9 and 24:1n-9) with mortality were different among patients with coronary artery disease (CAD). METHODS: Erythrocyte membrane fatty acids were measured at baseline in 1320 Chinese patients with CAD (56.2% were newly diagnosed) in the Guangdong Coronary Artery Cohort from 2008 to 2011. Cox proportional hazards models were used to estimate the association of each MUFA with risk of all-cause mortality and CVD mortality. RESULTS: During 4229 person-years of follow-up, 104 deaths occurred, 80 of which were due to CVD. There were no statistically significant associations between overall MUFAs and all-cause mortality and CVD mortality. When we stratified MUFAs, comparing with the lowest quartile, multivariable-adjusted HRs in the top quartile of LC-MUFAs were 0.40 (95% CI 0.21 to 0.75) for all-cause mortality and 0.41 (95% CI 0.20 to 0.85) for CVD mortality, whereas multivariable adjusted HRs in the highest quartile of VLC-MUFAs were 2.72 (95% CI 1.47 to 5.01) for all-cause mortality and 2.58 (95% CI 1.30 to 5.10) for CVD mortality. CONCLUSIONS: This study showed an inverse association between LC-MUFAs and mortality and a positive association between VLC-MUFAs and mortality among patients with CAD. These findings may help explain some of the reported controversial effects of MUFAs. PMID- 24957530 TI - Causes of mortality with ticagrelor compared with clopidogrel in acute coronary syndromes. AB - OBJECTIVE: To describe specific causes of death and evaluate whether bleeding events and infection contributed to mortality in all ticagrelor-treated and clopidogrel-treated patients with acute coronary syndromes. METHODS: In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor significantly reduced rates of vascular and total death compared with clopidogrel. In the 905 patients who died postenrolment in the PLATO trial (n=18 624), reviewers, blinded to study treatment, subclassified direct causes of death and evaluated whether infection or bleeding events contributed to fatal events. RESULTS: Among vascular deaths, there were significantly fewer sudden deaths (63 (0.7%) vs 98 (1.1%), p<0.01) but no significant difference in deaths caused by acute myocardial infarction (179 (1.9%) vs 194 (2.1%), p=0.43) or heart failure (31 (0.3%) vs 42 (0.5%), p=0.20) with ticagrelor compared with clopidogrel. For non-vascular deaths, there was no difference between treatments in deaths directly caused by infection. Although, patients treated with ticagrelor were at lower risk for death where infection was either a direct cause or contributed to death (51 (0.5%) vs 76 (0.8%), HR 0.67 (0.47 to 0.95), p<0.05) but not for bleeding (42 (0.5%) vs 42 (0.5%), HR 0.99 (0.65 to 1.53), p=0.98). CONCLUSIONS: In this post hoc analysis, ticagrelor compared with clopidogrel reduced total and cardiovascular mortality, which appeared to be mainly mediated by a reduction in sudden death. Importantly, bleeding causing or contributing to death did not differ between treatments. CLINICAL TRIAL REGISTRATION NUMBER: NCT00391872 (http://www.clinicaltrial.gov). PMID- 24957533 TI - Pregnancy outcomes of expectant management of stable mild to moderate chronic hypertension as compared with planned delivery. AB - OBJECTIVE: To compare outcomes between elective delivery at 37 weeks of pregnancy and expectant management among pregnant women with mild to moderate chronic hypertension. METHODS: In a two-center study, 76 women with mild to moderate chronic hypertension were randomly allocated to planned delivery at 37 completed weeks (group A) or expectant management for spontaneous onset of labor or reaching 41 weeks (group B) between April 2012 and October 2013. Differences were compared by t test, chi(2) test, or Fisher exact test. Odds ratios (ORs) with 95% confidence interval (CIs) were determined. RESULTS: There were no differences in superimposed pre-eclampsia (SPE), severe hypertension, preterm delivery, placental abruption, oligohydramnios, intrauterine growth restriction, or perinatal mortality between the groups. Group B had higher gestational age at delivery (P=0.001) and birth weight (P=0.01), but lower cesarean (OR 3.4; 95% CI, 1.2-10.3; P=0.03) and neonatal care unit admission (OR 5.4; 95% CI, 1.4-21.0; P=0.01) rates. More women with SPE were diagnosed before than after 37 weeks in group B (P=0.01). Overall, patients who developed SPE had more adverse pregnancy outcomes than those who did not. CONCLUSION: Mild to moderate chronic hypertension could be managed expectantly up to 41 weeks if SPE did not develop. PMID- 24957535 TI - The genetics of music accomplishment: evidence for gene-environment correlation and interaction. AB - Theories of skilled performance that emphasize training history, such as K. Anders Ericsson and colleagues' deliberate-practice theory, have received a great deal of recent attention in both the scientific literature and the popular press. Twin studies, however, have demonstrated evidence for moderate-to-strong genetic influences on skilled performance. Focusing on musical accomplishment in a sample of over 800 pairs of twins, we found evidence for gene-environment correlation, in the form of a genetic effect on music practice. However, only about one quarter of the genetic effect on music accomplishment was explained by this genetic effect on music practice, suggesting that genetically influenced factors other than practice contribute to individual differences in music accomplishment. We also found evidence for gene-environment interaction, such that genetic effects on music accomplishment were most pronounced among those engaging in music practice, suggesting that genetic potentials for skilled performance are most fully expressed and fostered by practice. PMID- 24957534 TI - Efficacy and acceptability of a mifepristone-misoprostol combined regimen for early induced abortion among women in Mexico City. AB - OBJECTIVE: To evaluate the experience of women receiving mifepristone-misoprostol for early induced abortion in public sector facilities in the Federal District of Mexico City. METHODS: An open-label prospective study was conducted with 1000 pregnant women who sought induced abortion with a pregnancy of up to 63days of gestation, as measured from the date of their last menstrual period. The study was conducted in three public sector healthcare facilities: two secondary level hospitals and one primary care clinic. Women ingested 200mg mifepristone on day 1, followed by 800MUg buccal misoprostol 24hours later, and they returned for follow-up on day 8. The primary outcome was complete abortion without recourse to surgical intervention. RESULTS: A total of 971 women received mifepristone misoprostol and were included in the analysis for efficacy of treatment. The overall efficacy of the combined medical abortion regimen studied was 97.3% (n=945); the success rate did not vary significantly by gestational age (95.9% 100%; P=0.449). Most women (n=922, 95.0%) had a successful induced abortion with only one dose of misoprostol. CONCLUSION: The combined mifepristone and buccal misoprostol regimen was found to be highly effective and acceptable among Mexican women. www.ClinicalTrials.gov: NCT00386282. PMID- 24957536 TI - The highs and lows of object impossibility: effects of spatial frequency on holistic processing of impossible objects. AB - Holistic processing, the decoding of a stimulus as a unified whole, is a basic characteristic of object perception. Recent research using Garner's speeded classification task has shown that this processing style is utilized even for impossible objects that contain an inherent spatial ambiguity. In particular, similar Garner interference effects were found for possible and impossible objects, indicating similar holistic processing styles for the two object categories. In the present study, we further investigated the perceptual mechanisms that mediate such holistic representation of impossible objects. We relied on the notion that, whereas information embedded in the high-spatial frequency (HSF) content supports fine-detailed processing of object features, the information conveyed by low spatial frequencies (LSF) is more crucial for the emergence of a holistic shape representation. To test the effects of image frequency on the holistic processing of impossible objects, participants performed the Garner speeded classification task on images of possible and impossible cubes filtered for their LSF and HSF information. For images containing only LSF, similar interference effects were observed for possible and impossible objects, indicating that the two object categories were processed in a holistic manner. In contrast, for the HSF images, Garner interference was obtained only for possible, but not for impossible objects. Importantly, we provided evidence to show that this effect could not be attributed to a lack of sensitivity to object possibility in the LSF images. Particularly, even for full spectrum images, Garner interference was still observed for both possible and impossible objects. Additionally, performance in an object classification task revealed high sensitivity to object possibility, even for LSF images. Taken together, these findings suggest that the visual system can tolerate the spatial ambiguity typical to impossible objects by relying on information embedded in LSF, whereas HSF information may underlie the visual system's susceptibility to distortions in objects' spatial layouts. PMID- 24957538 TI - Community health workers and stand-alone or integrated case management of malaria: a systematic literature review. AB - A systematic literature review was conducted to assess the effectiveness of strategies to improve community case management (CCM) of malaria. Forty-three studies were included; most (38) reported indicators of community health worker (CHW) performance, 14 reported on malaria CCM integrated with other child health interventions, 16 reported on health system capacity, and 13 reported on referral. The CHWs are able to provide good quality malaria care, including performing procedures such as rapid diagnostic tests. Appropriate training, clear guidelines, and regular supportive supervision are important facilitating factors. Crucial to sustainable success of CHW programs is strengthening health system capacity to support commodity supply, supervision, and appropriate treatment of referred cases. The little evidence available on referral from community to health facility level suggests that this is an area that needs priority attention. The studies of integrated CCM suggest that additional tasks do not reduce the quality of malaria CCM provided sufficient training and supervision is maintained. PMID- 24957539 TI - Detection of sickle cell hemoglobin in Haiti by genotyping and hemoglobin solubility tests. AB - Sickle cell disease is a growing global health concern because infants born with the disorder in developing countries are now surviving longer with little access to diagnostic and management options. In Haiti, the current state of sickle cell disease/trait in the population is unclear. To inform future screening efforts in Haiti, we assayed sickle hemoglobin mutations using traditional hemoglobin solubility tests (HST) and add-on techniques, which incorporated spectrophotometry and insoluble hemoglobin separation. We also generated genotype data as a metric for HST performance. We found 19 of 202 individuals screened with HST were positive for sickle hemoglobin, five of whom did not carry the HbS allele. We show that spectrophotometry and insoluble hemoglobin separation add-on techniques could resolve false positives associated with the traditional HST approach, with some limitations. We also discuss the incorporation of insoluble hemoglobin separation observation with HST in suboptimal screening settings like Haiti. PMID- 24957537 TI - Rickettsial infections in Southeast Asia: implications for local populace and febrile returned travelers. AB - Rickettsial infections represent a major cause of non-malarial febrile illnesses among the residents of Southeast Asia and returned travelers from that region. There are several challenges in recognition, diagnosis, and management of rickettsioses endemic to Southeast Asia. This review focuses on the prevalent rickettsial infections, namely, murine typhus (Rickettsia typhi), scrub typhus (Orientia tsutsugamushi), and members of spotted fever group rickettsiae. Information on epidemiology and regional variance in the prevalence of rickettsial infections is analyzed. Clinical characteristics of main groups of rickettsioses, unusual presentations, and common pitfalls in diagnosis are further discussed. In particular, relevant epidemiologic and clinical aspects on emerging spotted fever group rickettsiae in the region, such as Rickettsia honei, R. felis, R. japonica, and R. helvetica, are presented. Furthermore, challenges in laboratory diagnosis and management aspects of rickettsial infections unique to Southeast Asia are discussed, and data on emerging resistance to antimicrobial drugs and treatment/prevention options are also reviewed. PMID- 24957540 TI - Comparing the usefulness of the 1997 and 2009 WHO dengue case classification: a systematic literature review. AB - The 1997 and 2009 WHO dengue case classifications were compared in a systematic review with 12 eligible studies (4 prospective). Ten expert opinion articles were used for discussion. For the 2009 WHO classification studies show: when determining severe dengue sensitivity ranges between 59-98% (88%/98%: prospective studies), specificity between 41-99% (99%: prospective study) - comparing the 1997 WHO classification: sensitivity 24.8-89.9% (24.8%/74%: prospective studies), specificity: 25%/100% (100%: prospective study). The application of the 2009 WHO classification is easy, however for (non-severe) dengue there may be a risk of monitoring increased case numbers. Warning signs validation studies are needed. For epidemiological/pathogenesis research use of the 2009 WHO classification, opinion papers show that ease of application, increased sensitivity (severe dengue) and international comparability are advantageous; 3 severe dengue criteria (severe plasma leakage, severe bleeding, severe organ manifestation) are useful research endpoints. The 2009 WHO classification has clear advantages for clinical use, use in epidemiology is promising and research use may at least not be a disadvantage. PMID- 24957542 TI - An evaluation of the performance of direct agglutination test on filter paper blood sample for the diagnosis of visceral leishmaniasis. AB - The attack phase of the visceral leishmaniasis (VL) elimination program in Bangladesh aims to decrease the burden of VL incidence from close to 20 cases to less than one case per 10,000 at sub-district level. The consolidation phase will aim to confirm no increase in VL in endemic areas through active surveillance. During this phase, a reliable diagnostic tool for mass screening is required. Here, we report the diagnostic sensitivity and specificity of a filter paper based agglutination test (FP-DAT) for diagnosis of VL in patients admitted to an upazila health complex in Mymensingh, a VL-endemic region of Bangladesh. The sensitivity of both the conventional direct agglutination test (DAT) and FP-DAT were 100% and 96%, respectively. The specificity of both assays was 100%. However, when the performances of the two assays were compared using McNamar's test, neither the sensitivity nor the specificity of the FP-DAT differed significantly from conventional DAT. PMID- 24957544 TI - Effectiveness trial of community-based I Choose Life-Africa human immunodeficiency virus prevention program in Kenya. AB - We measured the effectiveness of a human immunodeficiency virus (HIV) prevention program developed in Kenya and carried out among university students. A total of 182 student volunteers were randomized into an intervention group who received a 32-hour training course as HIV prevention peer educators and a control group who received no training. Repeated measures assessed HIV-related attitudes, intentions, knowledge, and behaviors four times over six months. Data were analyzed by using linear mixed models to compare the rate of change on 13 dependent variables that examined sexual risk behavior. Based on multi-level models, the slope coefficients for four variables showed reliable change in the hoped for direction: abstinence from oral, vaginal, or anal sex in the last two months, condom attitudes, HIV testing, and refusal skill. The intervention demonstrated evidence of non-zero slope coefficients in the hoped for direction on 12 of 13 dependent variables. The intervention reduced sexual risk behavior. PMID- 24957543 TI - The use of spatial analysis to estimate the prevalence of canine leishmaniasis in Greece and Cyprus to predict its future variation and relate it to human disease. AB - Climatic, environmental, and demographic changes favor the emergence of neglected vector-borne diseases like leishmaniasis, which is spreading through dogs, the principle host of the protozoan Leishmania infantum. Surveillance of the disease in dogs is important, because the number of infected animals in an area determines the local risk of human infection. However, dog epidemiological studies are costly. Our aim was to evaluate the Emerging Diseases in a Changing European Environment (EDEN) veterinary questionnaire as a cost-effective tool in providing reliable, spatially explicit indicators of canine leishmaniasis prevalence. For this purpose, the data from the questionnaire were compared with data from two epidemiological studies on leishmaniasis carried out in Greece and Cyprus at the same time using statistical methods and spatial statistics. Although the questionnaire data cannot provide a quantitative measure of leishmaniasis in an area, it indicates the dynamic of the disease; information is obtained in a short period of time at low cost. PMID- 24957541 TI - Phylogeography of Rickettsia rickettsii genotypes associated with fatal Rocky Mountain spotted fever. AB - Rocky Mountain spotted fever (RMSF), a tick-borne zoonosis caused by Rickettsia rickettsii, is among the deadliest of all infectious diseases. To identify the distribution of various genotypes of R. rickettsii associated with fatal RMSF, we applied molecular typing methods to samples of DNA extracted from formalin-fixed, paraffin-embedded tissue specimens obtained at autopsy from 103 case-patients from seven countries who died of RMSF. Complete sequences of one or more intergenic regions were amplified from tissues of 30 (29%) case-patients and revealed a distribution of genotypes consisting of four distinct clades, including the Hlp clade, regarded previously as a non-pathogenic strain of R. rickettsii. Distinct phylogeographic patterns were identified when composite case patient and reference strain data were mapped to the state and country of origin. The phylogeography of R. rickettsii is likely determined by ecological and environmental factors that exist independently of the distribution of a particular tick vector. PMID- 24957545 TI - Cyclospora cayetanensis in a pediatric hospital in Morelia, Mexico. AB - Cyclospora cayetanensis, a coccidian parasite, can cause gastrointestinal illness in humans and is characterized by watery and persistent diarrhea and abdominal pain. Cyclosporiasis has been associated with traveler's diarrhea. The infection is acquired through food and waterborne transmission, particularly by consumption of contaminated fresh fruits and vegetables. In the present study, stool samples from 8,877 children were examined for ova and parasites at the Pediatric Hospital of Morelia in Michoacan, Mexico, during 2000-2009. Sixty children (0.67%) had Cyclospora in their stools. Diarrhea (45.8%), abdominal pain (39.6%), and vomiting (18.8%) were the most frequent symptoms of cases with cyclosporiasis. Most of the cases (93.3%) were observed during June-August, the rainy season. In 45 children, Cyclospora was the only parasitic pathogen detected (75%); 15 children were co-infected with commensal, pathogenic, or both groups of parasites. Our findings suggest that C. cayetanensis is endemic to Michoacan and shows characteristically temporal patterns. PMID- 24957546 TI - Intra- and interseasonal autoregressive prediction of dengue outbreaks using local weather and regional climate for a tropical environment in Colombia. AB - Dengue fever transmission results from complex interactions between the virus, human hosts, and mosquito vectors-all of which are influenced by environmental factors. Predictive models of dengue incidence rate, based on local weather and regional climate parameters, could benefit disease mitigation efforts. Time series of epidemiological and meteorological data for the urban environment of Cali, Colombia are analyzed from January of 2000 to December of 2011. Significant dengue outbreaks generally occur during warm-dry periods with extreme daily temperatures confined between 18 degrees C and 32 degrees C--the optimal range for mosquito survival and viral transmission. Two environment-based, multivariate, autoregressive forecast models are developed that allow dengue outbreaks to be anticipated from 2 weeks to 6 months in advance. These models have the potential to enhance existing dengue early warning systems, ultimately supporting public health decisions on the timing and scale of vector control efforts. PMID- 24957548 TI - pSnakes: a new radial active contour model and its application in the segmentation of the left ventricle from echocardiographic images. AB - Active contours are image segmentation methods that minimize the total energy of the contour to be segmented. Among the active contour methods, the radial methods have lower computational complexity and can be applied in real time. This work aims to present a new radial active contour technique, called pSnakes, using the 1D Hilbert transform as external energy. The pSnakes method is based on the fact that the beams in ultrasound equipment diverge from a single point of the probe, thus enabling the use of polar coordinates in the segmentation. The control points or nodes of the active contour are obtained in pairs and are called twin nodes. The internal energies as well as the external one, Hilbertian energy, are redefined. The results showed that pSnakes can be used in image segmentation of short-axis echocardiogram images and that they were effective in image segmentation of the left ventricle. The echo-cardiologist's golden standard showed that the pSnakes was the best method when compared with other methods. The main contributions of this work are the use of pSnakes and Hilbertian energy, as the external energy, in image segmentation. The Hilbertian energy is calculated by the 1D Hilbert transform. Compared with traditional methods, the pSnakes method is more suitable for ultrasound images because it is not affected by variations in image contrast, such as noise. The experimental results obtained by the left ventricle segmentation of echocardiographic images demonstrated the advantages of the proposed model. The results presented in this paper are justified due to an improved performance of the Hilbert energy in the presence of speckle noise. PMID- 24957547 TI - Time to disease-related pain and first opioid use in patients with metastatic castration-resistant prostate cancer treated with sipuleucel-T. AB - BACKGROUND: Sipuleucel-T has demonstrated improved overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This analysis examined the effect of sipuleucel-T on time to disease-related pain (TDRP) and time to first use of opioid analgesics (TFOA) in mCRPC using data pooled from three randomized phase III studies in men with asymptomatic or minimally symptomatic mCRPC (D9901 (NCT00005947), D9902A (NCT01133704), D9902B (IMPACT; NCT00065442)). METHODS: Four-hundred and twenty-eight asymptomatic patients were analyzed for TDRP; 737 patients were analyzed for TFOA. Pain status was collected using logs adjudicated by blinded, independent reviewers. Opioid use for cancer related pain was identified from medically reviewed reports of concomitant medication. Disease-related pain was defined as pain post enrollment. TDRP and TFOA were analyzed using the Kaplan-Meier method and Cox regression. RESULTS: Treatment with sipuleucel-T was not associated with a significant difference in TDRP (hazard ratio (HR)=0.819; 95% confidence interval (CI): 0.616-1.089; P=0.170; median TDRP 5.6 months for sipuleucel-T and 5.3 months for control, respectively), although 39.3% of sipuleucel-T-treated patients and 18.9% of control patients were pain-free at 12 months. However, there was a significant delay in TFOA with sipuleucel-T (HR=0.755; 95% CI: 0.579-0.985; P=0.038). Median TFOA for sipuleucel-T was 12.6, and 9.7 months for control, with 50.6% and 43.1% opioid-free at 12 months, respectively. Kaplan-Meier curves for both end points began to diverge at 6 months. CONCLUSIONS: Sipuleucel-T was associated with longer TFOA but not significantly longer TDRP. Both end points demonstrated evidence of a delayed treatment effect, consistent with an active immunotherapy. PMID- 24957549 TI - Synthesis of water-soluble Ag2Se QDs as a novel resonance Rayleigh scattering sensor for highly sensitive and selective ConA detection. AB - Ag2Se quantum dots (QDs) have attracted a lot of interest due to their potential applications in biosensing and bioimaging. A strategy is presented that involves coupling of selenium powder reduction with the binding of silver ions, and thioglycollic acid (TGA) and glycine as stabilizers to obtain ultrasmall Ag2Se QDs at 85 degrees C in aqueous solution. This strategy avoids high temperatures, high pressures and organic solvents so that water-soluble 3 nm Ag2Se QDs can be directly obtained. The conjugation of ConA to TGA stabilized Ag2Se QDs by hydrogen bonds leads to the adsorption of ConA to Ag2Se QDs and forms the aggregation and leads to the generation of resonance Rayleigh scattering (RRS) as a readout signal for the sensing events. The reaction mechanism of Ag2Se QD RRS enhancement is studied in this work. The resulting RRS sensor enables the detection of ConA with limit of detection reaching 0.08 MUg mL(-1) concentration in a wide linear range from 0.27 MUg mL(-1) to 35 MUg mL(-1). The recovery of spiked ConA in human serum samples ranges from 94% to 106%. The relative standard deviation (RSD) for eleven replicate detections is 3.6%. Our results correlate many important experimental observations and will fuel the further growth of this field. PMID- 24957551 TI - Survival and tumour control probability in tumours with heterogeneous oxygenation: a comparison between the linear-quadratic and the universal survival curve models for high doses. AB - BACKGROUND: The validity of the linear-quadratic (LQ) model at high doses has been questioned due to a decreasing agreement between predicted survival and experimental cell survival data. A frequently proposed alternative is the universal survival curve (USC) model, thought to provide a better fit in the high dose region. The comparison between the predictions of the models has mostly been performed for uniform populations of cells with respect to sensitivity to radiation. This study aimed to compare the two models in terms of cell survival and tumour control probability (TCP) for cell populations with mixed sensitivities related to their oxygenation. METHODS: The study was performed in two parts. For the first part, cell survival curves were calculated with both models assuming various homogeneous populations of cells irradiated with uniform doses. For the second part, a realistic three-dimensional (3D) model of complex tumour oxygenation was used to study the impact of the differences in cell survival on the modelled TCP. Cellular response was assessed with the LQ and USC models at voxel level and a Poisson TCP model at tumour level. RESULTS: For hypoxic tumours, the disputed continuous bend of the LQ survival curve was counteracted by the increased radioresistance of the hypoxic cells and the survival curves started to diverge only at much higher doses than for oxic tumours. This was also reflected by the TCP curves for hypoxic tumours for which the difference in D50 values for the LQ and USC models was reduced from 5.4 to 0.2 Gy for 1 and 3 fractions, respectively, in a tumour with only 1.1% hypoxia and from 9.5 to 0.4 Gy in a tumour with 11.1% hypoxia. CONCLUSIONS: For a large range of fractional doses including hypofractionated schemes, the difference in predicted survival and TCP between the LQ and USC models for tumours with heterogeneous oxygenation was found to be negligible. PMID- 24957550 TI - Relationship between the prognostic and predictive value of the intrinsic subtypes and a validated gene profile predictive of loco-regional control and benefit from post-mastectomy radiotherapy in patients with high-risk breast cancer. AB - BACKGROUND: Breast cancer is characterized by great molecular heterogeneity demonstrated, e.g. by the intrinsic subtypes. Administration of post-mastectomy radiotherapy (PMRT) does, however, not reflect this heterogeneity. A gene profile (DBCG-RT profile) has recently been developed and validated, and has shown prognostic impact in terms of loco-regional failure and predictive impact for PMRT. Reports have also shown predictive value in terms of benefit of PMRT from intrinsic subtypes and derived approximations. The aim of this study was to examine: 1) the agreement between various methods for determining the intrinsic subtypes; and 2) the relationship between the prognostic and predictive impact of the DBCG-RT profile and the intrinsic subtypes. MATERIAL AND METHODS: Intrinsic subtypes and the DBCG-RT profile was determined from microarray analysis based on fresh frozen tissue from 191 patients included in the Danish Breast Cancer Cooperative Group (DBCG) 82bc trial. Corresponding formalin-fixed, paraffin embedded tissue was available from 146 of these patients and from another 890 DBCG82bc patients. Estrogen receptor, progesterone receptor, HER2, CK5/6, Ki-67 and EGFR were combined into immunohistochemical approximations of the intrinsic subtypes. Endpoint considered was loco-regional recurrence (LRR). RESULTS: The DBCG-RT profile identified a group of patients with low risk of LRR and no additional benefit from PMRT among all subtypes. Combining six immunohistochemical markers identified a subgroup of triple negative patients with high risk of LRR and significant benefit from PMRT. Agreement in the different assignments of tumors to the subtypes was suboptimal, and the clinical outcome and predicted benefit from PMRT varied according to the method used for assignment. CONCLUSION: The prognostic and predictive information obtained from the DBCG-RT profile cannot be substituted by any approximation of the tumors intrinsic subtype. The predictive value of the intrinsic subtypes in terms of PMRT was influenced by the method used for assignment to the intrinsic subtypes. PMID- 24957552 TI - Temporal patterns of late bowel and bladder radiotherapy toxicity in a randomised controlled trial assessing duration of neo-adjuvant hormones in prostate cancer. AB - BACKGROUND: To assess the temporal patterns of late gastrointestinal (GI) and genitourinary (GU) radiotherapy toxicity and resolution rates in a randomised controlled trial (All-Ireland Cooperative Oncology Research Group 97-01) assessing duration of neo-adjuvant (NA) hormone therapy for localised prostate cancer. MATERIAL AND METHODS: Node negative patients with > 1 of: PSA > 20 ng/mL, Gleason score >= 7, and stage T3 or more, were included. Follow-up, including toxicity assessment, was three-monthly in the early stages and yearly thereafter. RESULTS: Median follow-up from the end of RT was 6.8 years. In the interval between 90 days following the end of RT and the last toxicity assessment, GI and GU toxicity (any grade) was found in 50% and 51% of 240 and 241 patients, respectively. For those who did develop toxicity, the median time from end of RT until the first development of any grade GI or GU toxicity was 1.2 years and 1.6 years, respectively, whilst median time to final resolution was 1.6 years and 2.2 years, respectively. Grade 2 (G2) or greater GI and GU toxicity occurred in 29 (12.1%) and 40 (16.6%) patients, respectively. The proportion with unresolved G2 + GI and GU toxicity was 89% and 79%, respectively, in year 1, 69% and 65% in year 2, 59% and 52% in year 3 and 27% and 32% in year 5. CONCLUSION: Long-term toxicities continue to occur many years after NA hormone therapy and RT. The rate of occurrence does not appear to reduce within the time frame during which our patients were followed. The percentage of patients suffering from G2 + toxicity at any time is however low. Resolution of these toxicities continues for the duration of the follow-up. PMID- 24957554 TI - Evaluation of an application for intensity-based deformable image registration and dose accumulation in radiotherapy. AB - BACKGROUND: Methods to accurately accumulate doses in radiotherapy (RT) are important for tumour and normal tissues being influenced by geometric uncertainties. The purpose of this study was to investigate a pre-release deformable image registration (DIR)-based dose accumulation application, in the setting of prostate RT. MATERIAL AND METHODS: Initially accumulated bladder and prostate doses were assessed (based on 8-9 repeat CT scans/patient) for nine prostate cancer patients using an intensity-based DIR and dose accumulation algorithm as provided by the Dynamic Adaptive Radiation Therapy (DART) software. The accumulated bladder and prostate dose-volume histograms (DVHs) were compared on a range of parameters (paired Wilcoxon signed-rank test, 5% significance level) to DVHs derived using an in-house developed dose accumulation method based on biomechanical, contour-driven DIR (SurfaceRegistration). Finally, both these accumulated dose distributions were compared to the 'static' DVH, assessed from the planning CT. RESULTS: Over the population, doses accumulated with DART were overall lower than those from SurfaceRegistration (p < 0.05: D2%, gEUD and NTCP (bladder); Dmin (prostate)). The magnitude of these differences peaked for the bladder gEUD with a population median of 47 Gy for DART versus 57 Gy for SurfaceRegistration. Across the ten bladder dose/volume parameters investigated, the most pronounced individual differences were observed between the 'accumulated' DVHs and the 'static' DVHs, with deviations in mean dose up to 22 Gy. CONCLUSION: Substantial and significant differences were observed in the dose distributions between the two investigated DIR-based dose accumulation applications. The most pronounced individual differences were seen for the bladder and relative to the planned dose distribution, encouraging the use of repeat imaging data in RT planning and evaluation for this organ. PMID- 24957553 TI - Results of delayed triage by HPV testing and cytology in the Norwegian Cervical Cancer Screening Programme. AB - BACKGROUND: High-risk human papilloma virus (hrHPV) testing was added to the cytology triage of women with equivocal screening smears in the Norwegian programme for cervical cancer screening in 2005. In this population-based observational before and after study we assessed the effect of changing the screening algorithm. MATERIAL AND METHODS: In periods before and after the change 75 852 and 66 616 women, respectively, were eligible for triage, i.e. they had smear results of unsatisfactory, atypical squamous cells of undetermined significance (ASC-US), or low-grade squamous intraepithelial lesion (LSIL) at routine screening. The triage was delayed as supplementary testing started six months after the initial screening. The groups were compared with respect to results of triage and later three-year cumulative incidence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). RESULTS: Before and after the change in the screening algorithm 5.2% (3964/75 852) and 8.1% (5417/66 616) of women, respectively, were referred to colposcopy. Among women referred to colposcopy cumulative incidence of CIN2+ (positive predictive value of referral) increased from 42.0% [95% confidence interval (CI): 40.3 - 43.7%] in the period with cytology only to 48.0% (95% CI 46.6 - 49.4%) after the start of HPV testing. For women recalled to ordinary screening the three-year cumulative incidence decreased from 2.7% (95% CI 2.5 - 2.9%) to 1.0% (95% CI 0.9 - 1.2%) during the same period. Among women with LSIL at routine screening and HPV testing in triage, 52.5% (1976/3766) were HPV positive. CONCLUSION: The new algorithm with HPV testing implemented in 2005 resulted in an increased rate of referral to colposcopy, but in a better risk stratification with respect to precancerous disease. PMID- 24957555 TI - Time-trends on incidence and survival in a nationwide and unselected cohort of patients with skeletal osteosarcoma. AB - BACKGROUND: This study describes time-trends on epidemiology, subtypes and histopathological entities of osteosarcoma (OS) in a nationwide and unselected cohort of OS patients in Norway between 1975 and 2009. Few nationwide studies are published, and we still have particularly limited knowledge regarding patients not included in clinical trials comprising about half of the OS population. METHOD: Histologically verified skeletal OS for all subgroups were included, resulting in 473 eligible cases from a total of 702 evaluated patients. To ensure completeness, the present cohort was based on all cases reported to the Norwegian Cancer Registry, complemented with data from all Norwegian hospitals involved in sarcoma management. Survival analyses were performed with overall and sarcoma specific survival as endpoints. RESULTS: Mean annual age-standard incidence amounted to about 3.8 per million in male and 2.8 per million in female with no clear time-trends. The male to female ratio was 1.4. Peak incidence was observed in the second decade for both genders. Conventional OS comprised 71.2% of all cases, while low grade OS represented 10.4% and telangiectatic OS only 1.3%. The most common primary site of OS was femur and tibia, respectively. The axial to appendicular ratio increased with the age. The overall 10-year survival did increase from about 30% during the late 1970s to around 50% 20 years later, with no subsequent improvement during the last two decades. Axial tumours, age above 40 years and overt metastatic disease at time of diagnosis were all negative prognostic factors. CONCLUSION: No improvement in the overall survival for OS since the 1990s was documented. The survival rates are still poor for elderly people, patients with axial disease and in the primary metastatic setting. The average incidence rate of skeletal OS in Norway was in line with international figures. PMID- 24957556 TI - Clinical use of iterative 4D-cone beam computed tomography reconstructions to investigate respiratory tumor motion in lung cancer patients. AB - BACKGROUND: Cone beam computed tomography (CBCT) provides means for respiratory resolved volumetric imaging of the thorax. However, merely sorting the acquired projections into respiratory phases and performing a series of conventional three dimensional (3D) reconstructions lead to clinically prohibitive reconstruction artifacts. This problem can be mitigated by iterative 4D reconstruction. We present a clinical evaluation of two iterative 4D-CBCT reconstruction algorithms during stereotactic body radiation therapy. MATERIAL AND METHODS: Two types of iterative 4D-CBCT reconstructions were performed utilizing: 1) total variation (TV) minimization; and 2) optical flow (OF) based deformable registration between phases. The reconstructions were initially evaluated on a lung phantom with a moveable target insert. Subsequently, 4D-CBCT reconstructions were performed for 19 patients on 2-3 CBCT projection datasets previously acquired for conventional 3D-CBCT reconstruction (~650 half-fan projections per scan in a full one-minute gantry rotation). The 4D reconstructions were imported into a treatment planning system, where the gross tumor volume (GTV) was delineated and used to extract the tumor motion amplitude. RESULTS: For both phantom and patient scans, the iterative 4D-CBCT reconstructions had sufficient quality for GTV delineation when the breathing period was faster than 3.5 seconds (15 of 19 patients), but not for slower breathing periods (4 patients). The 3D tumor motion amplitude for the patients was significantly lower (p = 10(-6), Wilcoxon signed rank test) in the OF reconstructions (mean 4.0 mm) than in the TV reconstructions (mean 5.3 mm). CONCLUSION: TV and OF iterative 4D-CBCT reconstruction of the thorax in a lung phantom and for 19 patients was demonstrated from standard CBCT scans and used to estimate the daily lung tumor motion. PMID- 24957557 TI - CT-planned internal mammary node radiotherapy in the DBCG-IMN study: benefit versus potentially harmful effects. AB - BACKGROUND: The DBCG-IMN is a nationwide population-based cohort study on the effect of internal mammary node radiotherapy (IMN-RT) in patients with node positive early breast cancer. Due to the risk of RT-induced heart disease, only patients with right-sided breast cancer received IMN-RT, whereas patients with left-sided breast cancer did not. At seven-year median follow-up, a 3% gain in overall survival with IMN-RT has been reported. This study estimates IMN doses and doses to organs at risk (OAR) in patients from the DBCG-IMN. Numbers needed to harm (NNH) if patients with left-sided breast cancer had received IMN-RT are compared to the number needed to treat (NNT). MATERIAL AND METHODS: Ten percent of CT-guided treatment plans from the DBCG-IMN patients were selected randomly. IMNs and OAR were contoured in 68 planning CT scans. Dose distributions were re calculated. IMNs and OAR dose estimates were compared in right-sided versus left sided breast cancer patients. In six left-sided patients, IMN-RT was simulated, and OAR doses were compared to those in the original plan. The NNH resulting from the change in mean heart dose (MHD) was calculated using a published model for risk of RT-related ischemic heart death. RESULTS: In original plans, the absolute difference between right- and left-sided V90% to the IMNs was 38.0% [95% confidence interval (5.5%; 70.5%), p < 0.05]. Heart doses were higher in left sided plans. With IMN-RT simulation without regard to OAR constraints, MHD increased 4.8 Gy (0.9 Gy; 8.7 Gy), p < 0.05. Resulting NNHs from ischemic heart death were consistently larger than the NNT with IMN-RT. CONCLUSION: Refraining from IMN-RT on the left side may have spared some ischemic heart deaths. Assuming left-sided patients benefit as much from IMN-RT as right-sided patients, the benefits from IMN-RT outweigh the costs in terms of ischemic heart death. PMID- 24957559 TI - Normal tissue sparing in a phase II trial on daily adaptive plan selection in radiotherapy for urinary bladder cancer. AB - Background: Patients with urinary bladder cancer often display large changes in the shape and size of their bladder target during a course of radiotherapy (RT), making adaptive RT (ART) appealing for this tumour site. We are conducting a clinical phase II trial of daily plan selection-based ART for bladder cancer and here report dose-volume data from the first 20 patients treated in the trial. MATERIAL AND METHODS: All patients received 60 Gy in 30 fractions to the bladder; in 13 of the patients the pelvic lymph nodes were simultaneously treated to 48 Gy. Daily patient set-up was by use of cone beam computed tomography (CBCT) guidance. The first 5 fractions were delivered with large, population-based (non adaptive) margins. The bladder contours from the CBCTs acquired in the first 4 fractions were used to create a patient-specific library of three plans, corresponding to a small, medium and large size bladder. From fraction 6, daily online plan selection was performed, where the smallest plan covering the bladder was selected prior to each treatment delivery. A total of 600 treatment fractions in the 20 patients were evaluated. RESULTS: Small, medium and large size plans were used almost equally often, with an average of 10, 9 and 11 fractions, respectively. The median volume ratio of the course-averaged PTV (PTV-ART) relative to the non-adaptive PTV was 0.70 (range: 0.46-0.89). A linear regression analysis showed a 183 cm(3) (CI 143-223 cm(3)) reduction in PTV-ART compared to the non-adaptive PTV (R(2) = 0.94). CONCLUSION: Daily adaptive plan selection in RT of bladder cancer results in a considerable normal tissue sparing, of a magnitude that we expect will translate into a clinically significant reduction of the treatment-related morbidity. PMID- 24957558 TI - Feasibility of experimental BT4C glioma models for somatostatin receptor 2 targeted therapies. AB - Somatostatin receptor subtype 2 (sstr2) is regarded as a potential target in malignant gliomas for new therapeutic approaches. Therefore, visualizing and quantifying tumor sstr2 expression in vivo would be highly relevant for the future development of sstr2-targeted therapies. The purpose of this study was to evaluate sstr2 status in experimental BT4C malignant gliomas. METHODS: Rat BT4C malignant glioma cells were injected into BDIX rat brain or subcutaneously into nude mice. Tumor uptake of [(68)Ga]DOTA-(Tyr(3))-Octreotide ([(68)Ga]DOTATOC), a somatostatin analog binding to sstr2, was studied by positron emission tomography/computed tomography (PET/CT). Additionally, subcutaneous tumor-bearing mice underwent PET imaging with 5-deoxy-5-[(18)F]fluororibose-NOC ([(18)F]FDR NOC), a novel glycosylated peptide tracer also targeting sstr2. Ex vivo tissue radioactivity measurements, autoradiography and immunohistochemistry were performed to study sstr2 expression. RESULTS: Increased tumor uptake of [(68)Ga]DOTATOC was detected at autoradiography with mean tumor-to-brain ratio of 68 +/- 30 and tumor-to-muscle ratio of 9.2 +/- 3.8 for rat glioma. High tumor-to muscle ratios were also observed in subcutaneous tumor-bearing mice after injection with [(68)Ga]DOTATOC and [(18)F]FDR-NOC with both autoradiography (6.7 +/- 1.5 and 4.3 +/- 0.8, respectively) and tissue radioactivity measurements (6.5 +/- 0.8 and 4.8 +/- 0.6, respectively). Furthermore, sstr2 immunohistochemistry showed positive staining in both tumor models. However, surprisingly low tumor signal compromised PET imaging. Mean SUVmax for rat gliomas was 0.64 +/- 0.28 from 30 to 60 min after [(68)Ga]DOTATOC injection. The majority of subcutaneous tumors were not visualized by [(68)Ga]DOTATOC or [(18)F]FDR-NOC PET. CONCLUSIONS: Experimental BT4C gliomas show high expression of sstr2. Weak signal in PET imaging, however, suggests only limited benefit of [(68)Ga]DOTATOC or [(18)F]FDR NOC PET/CT in this tumor model for in vivo imaging of sstr2 status. PMID- 24957560 TI - [Novel oral anticoagulants in patients with atrial fibrillation, how to avoid accidents?]. AB - Know the indications of these new drugs, and respect them. Do not confuse easiness of administration and absence of precautions. Renal function: a key parameter before and during treatment. Know when to use a low-dose drug regimen. Cardioversion: lack of safety evidence for some drugs. Drug interactions: beware of P-glycoprotein and cytochrome P450. PMID- 24957561 TI - Vaccinations and malaria prophylaxis for long-term travellers travelling from Greece: a prospective, questionnaire-based analysis. AB - The purpose of this prospective, questionnaire-based study is to assess pre travel vaccinations and malaria prophylaxis for long-term travellers who receive pre-travel advice in Greece. A total of 4721 travellers were studied from January 1, 2009 through December 31, 2012. Travellers sought pre-travel advice at a mean of 19.7 days (range: 0-349 days) before departure. Long-term travellers (>= 1 month) accounted for 2205 (46.7%) of all travellers. Long-term travellers had a mean age of 34.5 years. The majority of them were men (79.8%). In terms of destinations, 84% were visiting malaria-endemic countries and sub-Saharan Africa was the most common destination (17.7%). Most long-term travellers pursued trips for work purposes (70%), visited urban areas (79.6%) and stayed in hotels (29.2%). Yellow fever, typhoid fever, hepatitis A and tetanus/diphtheria vaccines were administered to 1647 (74.7%), 741 (33.6%), 652 (29.5%), and 589 (26.7%) travellers, respectively. Yellow fever vaccine was administered to 339 (87%) and 132 (71%) of long-term travellers to sub-Saharan Africa and South America respectively, whereas typhoid vaccine to 119 (90.8%) and 330 (84.6%) of those travelling to the Indian subcontinent and sub-Saharan Africa respectively. Rabies vaccine was administered to 14 (0.6%) of them. Malaria prophylaxis was recommended to 446 (20%) of long-term travellers. Mefloquine was the most commonly (49%) prescribed agent, and was prescribed to 26.7% of long-term travellers to sub-Sahara Africa. In conclusion, this study revealed that recommendations for vaccine and malaria prophylaxis for long-term travellers to developing countries should be more selective, based on the assessment of all travellers' and travel characteristics, in order to provide adequate pre-travel preparation for this high risk group of travellers. More focused studies are suggested in order to understand the particular needs of long-term travellers. Increasing awareness of travellers and travel health consultants is very important. PMID- 24957562 TI - Effects of approach and services under differential response on long term child safety and welfare. AB - An outcome analysis was conducted based on an extended follow-up of the implementation of differential response program reforms in Child Protective Services offices in 10 counties in a Midwestern U.S. State. Random assignment was conducted of families that were first determined to be appropriate for family assessments. Experimental families (n=2,382) were each assigned to a non-forensic family assessment, and control families (n=2,247) each received a forensic investigation. Families were assigned continuously over a 15-month period and then tracked from 45 to 60 months from the date of assignment. Detailed information on services provided and family responses was obtained via two subsamples of experimental and control families. Measures of family engagement and service reception and utilization were utilized to determine instrumental outcomes introduced through family assessments. Improved family engagement and increased and broadened services were found to have occurred, and it was theorized that these changes mediated extended outcomes. Extended outcomes included reductions of rates of subsequent screened-in reports of child maltreatment, proportions of families that experienced child removals, and instances of new safety threats and problems in parenting. Differences in outcomes were found among the participating counties with 4 counties accounting for most outcome differences. The relationships between instrumental and extended outcomes were discussed with suggestions for further research. PMID- 24957565 TI - [No more excuses... this vaccine, yes!]. PMID- 24957563 TI - Different meal, same flavor: cospeciation and host switching of haemosporidian parasites in some non-passerine birds. AB - BACKGROUND: Previous studies have shown that haemosporidian parasites (Haemoproteus (Parahaemoproteus) and Plasmodium) infecting passerine birds have an evolutionary history of host switching with little cospeciation, in particular at low taxonomic levels (e.g., below the family level), which is suggested as the main speciation mechanism of this group of parasites. Recent studies have characterized diverse clades of haemosporidian parasites (H. (Haemoproteus) and H. (Parahaemoproteus)) infecting non-passerine birds (e.g., Columbiformes, Pelecaniiformes). Here, we explore the cospeciation history of H. (Haemoproteus) and H. (Parahaemoproteus) parasites with their non-passerine hosts. METHODS: We sequenced the mtDNA cyt b gene of both haemosporidian parasites and their avian non-passerine hosts. We built Bayesian phylogenetic hypotheses and created concensus phylograms that were subsequently used to conduct cospeciation analyses. We used both a global cospeciation test, PACo, and an event-cost algorithm implemented in CoRe-PA. RESULTS: The global test suggests that H. (Haemoproteus) and H. (Parahaemoproteus) parasites have a diversification history dominated by cospeciation events particularly at the family level. Host-parasite links from the PACo analysis show that host switching events are common within families (i.e., among genera and among species within genera), and occasionally across different orders (e.g., Columbiformes to Pelecaniiformes). Event-cost analyses show that haemosporidian coevolutionary history is dominated by host switching and some codivergence, but with duplication events also present. Genetic lineages unique to raptor species (e.g., FALC11) commonly switch between Falconiformes and Strigiformes. CONCLUSIONS: Our results corroborate previous findings that have detected a global cospeciation signal at the family taxonomic level, and they also support a history of frequent switching closer to the tips of the host phylogeny, which seems to be the main diversification mechanism of haemosporidians. Such dynamic host-parasite associations are relevant to the epidemiology of emerging diseases because low parasite host specificity is a prerequisite for the emergence of novel diseases. The evidence on host distributions suggests that haemosporidian parasites have the potential to rapidly develop novel host-associations. This pattern has also been recorded in fish-monogenean interactions, suggesting a general diversification mechanism for parasites when host choice is not restricted by ecological barriers. PMID- 24957566 TI - Balancing the benefits and harms of low-dose computed tomography screening for lung cancer: Medicare's options for coverage. PMID- 24957564 TI - [Multicenter program for the integrated care of newborns with perinatal hypoxic ischemic insult (ARAHIP)]. AB - INTRODUCTION: Newborns with perinatal indicators of a potential hypoxic-ischemic event require an integrated care in order to control the aggravating factors of brain damage, and the early identification of candidates for hypothermia treatment. PATIENTS AND METHODS: The application of a prospective, populational program that organizes and systematizes medical care during the first 6 hours of life to all newborns over 35 weeks gestational age born with indicators of a perinatal hypoxic-ischemic insult. The program includes 12 hospitals (91,217 m(2)); two level i centers, five level ii centers, and five level iii hospitals. The program establishes four protocols: a) detection of the newborn with a potential hypoxic-ischemic insult, b) surveillance of the neurological repercussions and other organ involvement, c) control and treatment of complications, d) procedures and monitoring during transport. RESULTS: From June 2011 to June 2013, 213 of 32325 newborns above 35 weeks gestational age met the criteria of a potential hypoxic-ischemic insult (7.4/1000), with 92% of them being cared for following the program specifications. Moderate-severe hypoxic ischemic encephalopathy was diagnosed in 33 cases (1/1,000), and 31 out of the 33 received treatment with hypothermia (94%). CONCLUSIONS: The program for the Integrated Care of Newborns with Perinatal Hypoxic-Ischemic Insult has led to providing a comprehensive care to the newborns with a suspected perinatal hypoxic ischemic insult. Aggravators of brain damage have been controlled, and cases of moderate-severe hypoxic-ischemic encephalopathy have been detected, allowing the start of hypothermia treatment within the first six hours of life. Populational programs are fundamental to reducing the mortality and morbidity of hypoxic ischemic encephalopathy. PMID- 24957567 TI - Hemophilic synovitis of the knee: radiosynovectomy or arthroscopic synovectomy? AB - Radiosynovectomy (RS) is the best choice for patients with persistent synovitis of the knee unresponsive to a 3-month trial of prophylactic factor replacement. If three consecutive RSs with 6-month intervals have been ineffective, an arthroscopic synovectomy should be indicated in patients older than 12 years of age (adolescents). In children younger than 12 years of age, adequate prophylaxis should be maintained, with arthroscopic synovectomy always being the last resort. In the knee, we recommend Yttrium-90 at a dose of 90 mBq in children and 185 mBq in adults. Although the dose of radiation of RS is minimal and neither articular nor systemic neoplastic changes related to RS have been reported so far, all patients must be given the opportunity to consider the risk/benefit ratios. Our current recommendation is to use knee RS in hemophilia patients older than 12 years of age (adolescents). PMID- 24957568 TI - Cuprate-like electronic properties in superlattices with Ag(II)F2 square sheet. AB - Using the generalized gradient approximation augmented with maximally localized Wannier functions analysis, we present the formation of cuprate-like electronic structures in Ag(II)F2-related superlattices resulted from the confinement together with structural chemical modification. The out-of-plane electronic reconstruction leads to electron doping of AgF2 plane and gradually destablizes the antiferromagnetic state. Eventually a stable nonmagnetic metallic state emerges by applying in-plane tensile strain, in which the shape of effective Fermi surface of AgF2 plane exhibits the key feature of high-temperature cuprate superconductor. PMID- 24957569 TI - Intermediate-length colonoscope needs more training duration than long-length colonoscope. AB - OBJECTIVE: Few data are available on the influence of a colonoscope length for trainees, which could affect both the duration of training and colonoscopy quality. We conducted this study to validate which scope needs more duration for training to reach technical competence and to shows better quality indicators during diagnostic colonoscopy. MATERIALS AND METHODS: We conducted a prospective randomly assigned study from April 2010 to February 2011 at Asan Medical Center. Among the 1329 patients enrolled, 1200 colonoscopies were analyzed. We compared cecal intubation rate, adenoma detection rate, cecal intubation time (<20 min), and withdrawal time between the trainees using the intermediate-length colonoscope and those using long-length colonoscope. RESULTS: Trainees who used the long-length colonoscope showed a higher overall cecal intubation rate (88.2% vs. 81.0%, p = 0.001) and adenoma detection rate (49.7% vs. 34.2%, p < 0.001) than those using the intermediate-length colonoscope. The successful cecal intubation rate improved significantly and reached the requisite standard of competence (>90%) after 90 procedures in the long-length colonoscope group. However, the trainees using the intermediate-length colonoscope reached the requisite standard of competence after 150 procedures. Logistic regression analysis revealed that prolonged cecal intubation was associated with the use of the intermediate-length colonoscope, poor colon preparation, a small number of esophagastroduodenoscopy or sigmoidoscopy procedures conducted, and pain during procedures. CONCLUSIONS: During the same training period, use of the long-length colonoscope in trainee was better in terms of reaching competency and quality indicators, and was less painful for the patients during colonoscopic procedures. PMID- 24957572 TI - Atlantic salmon show capability for cardiac acclimation to warm temperatures. AB - Increases in environmental temperature predicted to result from global warming have direct effects on performance of ectotherms. Moreover, cardiac function has been observed to limit the tolerance to high temperatures. Here we show that two wild populations of Atlantic salmon originating from northern and southern extremes of its European distribution have strikingly similar cardiac responses to acute warming when acclimated to common temperatures, despite different local environments. Although cardiac collapse starts at 21-23 degrees C with a maximum heart rate of ~150 beats per min (bpm) for 12 degrees C-acclimated fish, acclimation to 20 degrees C considerably raises this temperature (27.5 degrees C) and maximum heart rate (~200 bpm). Only minor population differences exist and these are consistent with the warmer habitat of the southern population. We demonstrate that the considerable cardiac plasticity discovered for Atlantic salmon is largely independent of natural habitat, and we propose that observed cardiac plasticity may aid salmon to cope with global warming. PMID- 24957571 TI - Effectiveness of nurse home visiting for families in rural South Australia. AB - AIM: To evaluate the effectiveness of a 2-year post-natal home-visiting programme delivered by nurses to socially disadvantaged mothers in rural regions of South Australia. METHODS: The intervention group consisted of 225 mothers who lived in rural regions and enrolled in the programme between 2010 and 2012. The comparison group consisted of 239 mothers who lived in rural areas between 2008 and 2009 when the programme was not yet available. All participants were eligible for enrolment in the home-visiting programme. Participants in both groups were assessed at baseline (mean child age = 15.2 weeks, SD = 2.4), prior to programme enrolment, and again when children were aged 9, 18 and 24 months. Outcomes were evaluated using the Parent Stress Index, Kessler Psychological Distress Scale, Ages and Stages Questionnaire, Child Behaviour Checklist, and MacArthur Communicative Developmental Inventory. RESULTS: During the follow-up period, there was little difference in the pattern of scores across the two groups. Mixed models adjusting for baseline differences between the groups did not identify any significant Group * Time interactions. This suggests that the linear trajectories of scores on outcomes did not differ significantly between the two groups. CONCLUSIONS: Findings suggest that the home-visiting programme did not have a measurable effect on maternal or child outcomes. However, the programme was relatively early in its rollout, and the greater challenges of recruitment, training and support, along with rural nurses' broader responsibilities for delivering other maternal and child health services, may explain why effects seen in the metropolitan area were not evident in rural regions. PMID- 24957574 TI - Parental-adolescent drug use discussions: physiological responses and associated outcomes. AB - PURPOSE: Although talking to youth about drugs is often recommended to parents, we know little about how parents actually discuss drugs with their children in the moment and how parental advice is linked to youth arousal and substance use. This study examined observed parental drug use advice and parenting behaviors during parent-adolescent drug use discussions and associations with adolescent physiological responses and substance use. METHODS: Fifty-eight 12-17 year olds and their primary caregivers participated in a laboratory session in which parents and youth discussed the topic of alcohol and/or drug use for 10 minutes. This discussion was videotaped and coded for drug use advice (rules against drug use, information on drug use consequences, scenarios or learning advice [discussing drug use scenarios and what the child has learned about drugs]) and general parenting behaviors (parental warmth and/or support, negative and/or critical parenting). Before, during, and after the discussions, adolescents' heart rate, blood pressure (BP), and salivary cortisol levels were assessed. RESULTS: Parental discussion of scenarios and/or learning was associated with lower adolescent BP responses to the discussions and lower likelihood of substance use. Parental discussion of rules against drug use was associated with higher heart rate and BP responses and greater likelihood of substance use. Criticism and/or negative parenting was associated with higher cortisol responses and greater likelihood of substance use at a trend level. CONCLUSIONS: Parenting characterized by greater discussion of drug use scenarios and less stating of rules against drug use and criticism may make youth feel more comfortable and be linked to lower substance use. PMID- 24957575 TI - Injection practices in Nepal: health policymakers' perceptions. AB - BACKGROUND: The unnecessary and unsafe use of injections is common in developing countries like Nepal. Policymakers have an important role in promoting rational and safe injection use. Hence, the present study was carried out to explore the perception of health policymakers regarding safe injection practice in Nepal. METHODS: An exploratory qualitative study design was used in this study. Key policymakers from both the central and regional level were selected using purposive sampling. A semi-structured questionnaire advocated by the World Health Organization (WHO) was used after modifying the context. Interviews were conducted to clarify doubts and obtain additional information. The data was analyzed manually using deductive content analysis technique. RESULTS: In total, eleven policymakers participated. All unanimously agreed that injection safety is a problem and seven participants reported that injections are overused. They shared the opinion that injections are administered by various providers, including formal and informal health providers, and also quacks. Almost half the respondents reported that the National Drug Policy discourages injection overuse, while others reported that the policy contains no provisions regarding injection overuse. Most policymakers stated that only single-use disposable injection equipment is used to provide injection, while others thought that sterilizable glass syringe is also used. More than half of the participants believed that the quality of injection equipment available in the Nepalese market is not regulated by any government institution. Almost two-third of the policymakers stated that syringes and needles are not reused, while the rest thought syringes might be reused without sterilization in some parts of the country. Almost half of the respondents stated that illegal commercialization of used syringes exists in Nepal. Almost all respondents thought that health care institutions have a waste management plan, while more than half of them opined that such plans are limited to tertiary care hospitals located in the capital. CONCLUSIONS: The result of this study revealed a divergence of views among policymakers, even among those in the same ministry. Though there has been some effort from the government to increase the safety of injection practices, greater efforts are required, especially with regard to standardization of policies and procedures related to injection practice. PMID- 24957577 TI - NMR characterization of chemically synthesized branched alpha-dextrin model compounds. AB - 1H and 13C NMR chemical shifts were accurately determined by consistent referencing for an extensive set of chemically synthesized branched alpha-glucan model compounds. The model compounds include anomerically fixed and reducing oligosaccharides ranging in size from isomaltose to a doubly branched decasaccharide. Both the 13C1 chemical shift and the 13C6 chemical shifts in alpha-(1->6) glycosidic bonds are strongly dependent on the chemical structure in the vicinity of the branch point, especially on the addition of glucopyranosyl units towards the non-reducing end of the backbone chain. The conformational sampling at the branch point of the branched alpha-glucan model compounds was experimentally probed with homo-nuclear scalar couplings. Substitution at O6 consistently increases the fraction of C6-O6 trans conformations, but to a lesser extent, if the attachment occurs at the reducing end residue. Increasingly complex structures in the vicinity of the branch point increase the population of the gauche-trans conformation of the C5-C6 bond. This population change is found to correlate with the 13C6 chemical shift. PMID- 24957576 TI - Evaluating the effectiveness of opportunistic eye screening model for people with diabetes attending diabetes clinic at Mnazi Mmoja Hospital, Zanzibar. AB - BACKGROUND: Diabetes and its related microvascular complications like Diabetic retinopathy are showing an alarming rise in developing countries like Zanzibar. Objective of the present study is to evaluate the impact of integrating eye screening for all subjects attending the diabetes clinic at Mnazi Mmoja Hospital in Zanzibar and to estimate the prevalence of visual impairment and diabetic retinopathy among the subjects. METHODS: This is a cross sectional study involving 356 randomly selected patients who had attended the diabetes clinic between July and August 2012. All subjects underwent comprehensive eye examination including fundus evaluation after dilatation by a cataract surgeon and an ophthalmologist, independently. Data was collected using the designated questionnaire and analysed using the SPSS software. Blindness and visual impairment was defined as presenting VA <3/60 and <6/18 to 6/60 in the better eye respectively and DR was graded using the International classification of Diabetic Retinopathy severity grading scale. RESULTS: A total of 356/967 subjects were recruited in a duration of 2 months; 176 (49.4%) were male and the mean age was 52.21 (SD 15.3). Targeted eye screening of diabetics showed that 231/356 (65%) of the subjects had eye problems, including potentially blinding conditions that required immediate intervention in contrast to the existing self reported referral where only 10% of an average of 200 diabetics underwent eye checkup in a year. The prevalence of visual impairment was 20.2%; 95% CI: 16.4-24.7 and blindness in 9.3%; 95% CI: 6.7 -12.7. The prevalence of DR was 28.3% and sight threatening DR was reported in 9%. Among the DR cases, 30% had sight threatening DR including 28% macular edema, 2% severe NPDR and PDR. Multivariate analysis showed a higher risk for any DR in older subjects >50 years (OR: 2.19; 95% CI: 1.14 - 4.25) and in females (OR: 1.92; 95% CI: 1.07 - 3.44). CONCLUSION: Opportunistic DR screening model achieved higher yield of identification of visual impairment and DR compared to the yield of 10% of existing self reported Diabetic eye screening model at Zanzibar. Integration of eye screening at diabetes clinics helps in early identification and provision of appropriate treatment for reducing blindness due to diabetes. PMID- 24957578 TI - Complete dysphagia with undiagnosed achalasia: endoscopic removal of barium bolus using a Roth Net. PMID- 24957570 TI - Genetics of auditory mechano-electrical transduction. AB - The hair bundles of cochlear hair cells play a central role in the auditory mechano-electrical transduction (MET) process. The identification of MET components and of associated molecular complexes by biochemical approaches is impeded by the very small number of hair cells within the cochlea. In contrast, human and mouse genetics have proven to be particularly powerful. The study of inherited forms of deafness led to the discovery of several essential proteins of the MET machinery, which are currently used as entry points to decipher the associated molecular networks. Notably, MET relies not only on the MET machinery but also on several elements ensuring the proper sound-induced oscillation of the hair bundle or the ionic environment necessary to drive the MET current. Here, we review the most significant advances in the molecular bases of the MET process that emerged from the genetics of hearing. PMID- 24957579 TI - The changing pace of insular life: 5000 years of microevolution in the Orkney vole (Microtus arvalis orcadensis). AB - Island evolution may be expected to involve fast initial morphological divergence followed by stasis. We tested this model using the dental phenotype of modern and ancient common voles (Microtus arvalis), introduced onto the Orkney archipelago (Scotland) from continental Europe some 5000 years ago. First, we investigated phenotypic divergence of Orkney and continental European populations and assessed climatic influences. Second, phenotypic differentiation among Orkney populations was tested against geography, time, and neutral genetic patterns. Finally, we examined evolutionary change along a time series for the Orkney Mainland. Molar gigantism and anterior-lobe hypertrophy evolved rapidly in Orkney voles following introduction, without any transitional forms detected. Founder events and adaptation appear to explain this initial rapid evolution. Idiosyncrasy in dental features among different island populations of Orkney voles is also likely the result of local founder events following Neolithic translocation around the archipelago. However, against our initial expectations, a second marked phenotypic shift occurred between the 4th and 12th centuries AD, associated with increased pastoral farming and introduction of competitors (mice and rats) and terrestrial predators (foxes and cats). These results indicate that human agency can generate a more complex pattern of morphological evolution than might be expected in island rodents. PMID- 24957580 TI - Potential applicability of persuasive communication to light-glow reduction efforts: a case study of marine turtle conservation. AB - Artificial lighting along coastlines poses a significant threat to marine turtles due to the importance of light for their natural orientation at the nesting beach. Effective lighting management requires widespread support and participation, yet engaging the public with light reduction initiatives is difficult because benefits associated with artificial lighting are deeply entrenched within modern society. We present a case study from Queensland, Australia, where an active light-glow reduction campaign has been in place since 2008 to protect nesting turtles. Semi-structured questionnaires explored community beliefs about reducing light and evaluated the potential for using persuasive communication techniques based on the theory of planned behavior (TPB) to increase engagement with light reduction. Respondents (n = 352) had moderate to strong intentions to reduce light. TPB variables explained a significant proportion of variance in intention (multiple regression: R (2) = 0.54-0.69, P < 0.001), but adding a personal norm variable improved the model (R (2) = 0.73 0.79, P < 0.001). Significant differences in belief strength between campaign compliers and non-compliers suggest that targeting the beliefs reducing light leads to "increased protection of local turtles" (P < 0.01) and/or "benefits to the local economy" (P < 0.05), in combination with an appeal to personal norms, would produce the strongest persuasion potential for future communications. Selective legislation and commitment strategies may be further useful strategies to increase community light reduction. As artificial light continues to gain attention as a pollutant, our methods and findings will be of interest to anyone needing to manage public artificial lighting. PMID- 24957585 TI - Acute three-vessel cervical arterial occlusion due to spontaneous quadruple cervical artery dissection. AB - Cervical artery dissection (CAD) is one of the most frequent causes (14.5%) of stroke in young adults. Cases with involvement of more than two arteries are rare. Arnold et al described 11 cases (1.5%) with triple CAD of a reported 740 patients and just a single (0.1%) quadruple case in the same population. Simultaneous dissection of the four principal vessels is extremely rare. According to Papagiannaki et al, the incidence of simultaneous three or four CADs is 1-3/million in the general population. To the best of our knowledge, there are only three published cases of spontaneous quadruple CAD. PMID- 24957583 TI - Uncommon antenatal presentation of tuberous sclerosis. AB - This is a case of a newborn male who was diagnosed in the first month of life with tuberous sclerosis following an incidental ultrasound finding of unilateral ventriculomegaly at 36+6 weeks gestation. The antenatal ultrasound scan at 36+6 weeks was performed to establish fetal lie. Subsequent fetal brain MRI showed lesions that were initially thought to be haemorrhages, but turned out to be features of tuberous sclerosis. The baby also had five cardiac rhabdomyomas and multiple ash leaf macules. This was an unusual presentation of tuberous sclerosis, which on average is diagnosed later (mean age of diagnosis is 5 years). It also illustrates two important points: that subependymal nodules and haemorrhage can have a similar radiological appearance on antenatal MRI and cranial ultrasound and that routine antenatal ultrasound screening will miss the majority of cardiac rhabdomyomas. PMID- 24957584 TI - Cerebral hypoperfusion secondary to radiation arteritis presenting with recurrent syncope. AB - Radiation arteritis can lead to significant extracranial carotid artery stenosis, affecting the circle of Willis. Cerebral hypoperfusion due to arterial insufficiency is often considered as a differential diagnosis in cases of syncope but rarely proven. We present a case of a 61-year-old man with repeated episodes of syncope-negative cardiac investigations. He had a history of cervical radiation therapy for tonsillar squamous cell carcinoma 15 years previously. Carotid duplex revealed bilateral carotid occlusive disease. MR angiography showed severe multilevel extracranial carotid stenosis bilaterally with occluded left vertebral artery. A diagnosis of cerebral hypoperfusion was performed following single-photon emission CT scan. The patient underwent a left subclavian to carotid bypass, which alleviated his symptoms. PMID- 24957586 TI - Breast augmentation with an unknown substance. AB - Before the widespread use of silicone implants various foreign substances were injected directly into the breasts. The nature of these materials sometimes remains unknown and can cause various complications requiring surgical intervention. Preoperative diagnostic imaging can help characterise the type and distribution of the injected material, thereby assisting in making decisions regarding treatment. We report a case of breast augmentation with an unknown substance, aiming to highlight some imaging characteristics of different breast augmentation substances. PMID- 24957587 TI - An unusual case of bowel perforation. AB - Bowel perforation is a potentially fatal complication of obstruction, ischaemia, trauma, surgery and medications. It is recognised by clinical suspicion based on history, symptoms of severe abdominal pain and signs such as rebound tenderness, as well as imaging showing free air in the abdomen. Bevacizumab (aka avastin) is an antineoplastic recombinant monoclonal antibody that inhibits angiogenesis in a variety of malignancies. Colonic perforation is a recognised but rare complication of this therapy, likely due to aforementioned bowel ischaemia or compromised mucosal microcirculation which increases susceptibility to injury. We are presenting a case of an unrecognised bowel perforation caused in a patient with abdominal carcinomatosis. PMID- 24957588 TI - Thiersch wiring as a temporary procedure in a haemodynamically unstable patient with an incarcerated rectal procidentia. PMID- 24957589 TI - Pulmonary infarction in acute pulmonary embolism: reversed halo sign. PMID- 24957590 TI - Portal venous gas after a caudal block. PMID- 24957592 TI - Coexisiting adenoma and granuloma involving the right inferior parathyroid gland with adjacent ectopic thymic tissue. AB - Inflammatory lesions, particularly granulomas, involving adenoma of the parathyroid gland are rare. Ectopic thymic tissue is commonly associated with the thyroid and/or parathyroid gland due to their close embryonic relationship. We report a rare case of coexisting adenoma and granuloma of the parathyroid gland with adjacent ectopic thymic tissue. PMID- 24957591 TI - Flexor pollicis longus tenosynovitis caused by Mycobacterium marinum infection. PMID- 24957593 TI - Neuropathic arthropathy and syringomyelia complicating a case of ankylosing spondylitis with peripheral arthritis. PMID- 24957594 TI - Simultaneous improvement of tics and parkinsonism after pallidal DBS. PMID- 24957596 TI - First pass cable artefact correction for cardiac C-arm CT imaging. AB - Cardiac C-arm CT imaging delivers a tomographic region-of-interest reconstruction of the patient's heart during image guided catheter interventions. Due to the limited size of the flat detector a volume image is reconstructed, which is truncated in the cone-beam (along the patient axis) and the fan-beam (in the transaxial plane) direction. To practically address this local tomography problem correction methods, like projection extension, are available for first pass image reconstruction. For second pass correction methods, like metal artefact reduction, alternative correction schemes are required when the field of view is limited to a region-of-interest of the patient. In classical CT imaging metal artefacts are corrected by metal identification in a first volume reconstruction and generation of a corrected projection data set followed by a second reconstruction. This approach fails when the metal structures are located outside the reconstruction field of view. When a C-arm CT is performed during a cardiac intervention pacing leads and other cables are frequently positioned on the patients skin, which results in propagating streak artefacts in the reconstruction volume. A first pass approach to reduce this type of artefact is introduced and evaluated here. It makes use of the fact that the projected position of objects outside the reconstruction volume changes with the projection perspective. It is shown that projection based identification, tracking and removal of high contrast structures like cables, only detected in a subset of the projections, delivers a more consistent reconstruction volume with reduced artefact level. The method is quantitatively evaluated based on 50 simulations using cardiac CT data sets with variable cable positioning. These data sets are forward projected using a C-arm CT system geometry and generate artefacts comparable to those observed in clinical cardiac C-arm CT acquisitions. A C-arm CT simulation of every cardiac CT data set without cables served as a ground truth. The 3D root mean square deviation between the simulated data set with and without cables could be reduced for 96% of the simulated cases by an average of 37% (min -9%, max 73%) when using the first pass correction method. In addition, image quality improvement is demonstrated for clinical whole heart C-arm CT data sets when the cable removal algorithm was applied. PMID- 24957597 TI - PubServer: literature searches by homology. AB - PubServer, available at http://pubserver.burnham.org/, is a tool to automatically collect, filter and analyze publications associated with groups of homologous proteins. Protein entries in databases such as Entrez Protein database at NCBI contain information about publications associated with a given protein. The scope of these publications varies a lot: they include studies focused on biochemical functions of individual proteins, but also reports from genome sequencing projects that introduce tens of thousands of proteins. Collecting and analyzing publications related to sets of homologous proteins help in functional annotation of novel protein families and in improving annotations of well-studied protein families or individual genes. However, performing such collection and analysis manually is a tedious and time-consuming process. PubServer automatically collects identifiers of homologous proteins using PSI-Blast, retrieves literature references from corresponding database entries and filters out publications unlikely to contain useful information about individual proteins. It also prepares simple vocabulary statistics from titles, abstracts and MeSH terms to identify the most frequently occurring keywords, which may help to quickly identify common themes in these publications. The filtering criteria applied to collected publications are user-adjustable. The results of the server are presented as an interactive page that allows re-filtering and different presentations of the output. PMID- 24957595 TI - Suggested avenues to reduce the stigma of mental illness in the Middle East. AB - BACKGROUND: Stigma toward mentally ill individuals acts as a barrier to accessing care and receiving treatment. AIM: To review current evidence pertaining to stigma toward mental illness in the Middle East in order to inform effective and sustainable interventions in this region. METHODS: We conducted a systematic literature search using the PubMed database and evaluated all identified studies according to specific inclusion criteria. RESULTS: Stigma toward individuals with mental illness does exist in the Middle East. Stigmatizing attitudes are particularly high toward culturally proscribed mental illnesses like alcohol abuse and lower for other disorders such as depression and psychosis. CONCLUSIONS: We propose the following initiatives to reduce stigma toward mental illness in the Middle East: (a) educate families to enable them to support their affected relatives, (b) increase cooperation between psychiatrists and faith healers and (c) educate young people in schools to increase their awareness and understanding of mental illnesses and to combat negative stereotypes. PMID- 24957598 TI - CstF-64 supports pluripotency and regulates cell cycle progression in embryonic stem cells through histone 3' end processing. AB - Embryonic stem cells (ESCs) exhibit a unique cell cycle with a shortened G1 phase that supports their pluripotency, while apparently buffering them against pro differentiation stimuli. In ESCs, expression of replication-dependent histones is a main component of this abbreviated G1 phase, although the details of this mechanism are not well understood. Similarly, the role of 3' end processing in regulation of ESC pluripotency and cell cycle is poorly understood. To better understand these processes, we examined mouse ESCs that lack the 3' end processing factor CstF-64. These ESCs display slower growth, loss of pluripotency and a lengthened G1 phase, correlating with increased polyadenylation of histone mRNAs. Interestingly, these ESCs also express the tauCstF-64 paralog of CstF-64. However, tauCstF-64 only partially compensates for lost CstF-64 function, despite being recruited to the histone mRNA 3' end-processing complex. Reduction of tauCstF-64 in CstF-64-deficient ESCs results in even greater levels of histone mRNA polyadenylation, suggesting that both CstF-64 and tauCstF-64 function to inhibit polyadenylation of histone mRNAs. These results suggest that CstF-64 plays a key role in modulating the cell cycle in ESCs while simultaneously controlling histone mRNA 3' end processing. PMID- 24957600 TI - Remarkable acceleration of a DNA/RNA inter-strand functionality transfer reaction to modify a cytosine residue: the proximity effect via complexation with a metal cation. AB - Modified nucleosides in natural RNA molecules are essential for their functions. Non-natural nucleoside analogues have been introduced into RNA to manipulate its structure and function. We have recently developed a new strategy for the in situ modification of RNA based on the functionality transfer reaction between an oligodeoxynucleotide probe and an RNA substrate. 2'-Deoxy-6-thioguanosine (6-thio dG) was used as the platform to anchor the transfer group. In this study, a pyridinyl vinyl ketone moiety was newly designed as the transfer group with the expectation that a metal cation would form a chelate complex with the pyridinyl-2 keto group. It was demonstrated that the (E)-pyridinyl vinyl keto group was efficiently and specifically transferred to the 4-amino group of the opposing cytosine in RNA in the presence of NiCl2 with more than 200-fold accelerated rate compared with the previous system with the use of the diketo transfer group. Detailed mechanistic studies suggested that NiCl2 forms a bridging complex between the pyridinyl keto moiety and the N7 of the purine residue neighboring the cytosine residue of the RNA substrate to bring the groups in close proximity. PMID- 24957599 TI - The Cryptosporidium parvum ApiAP2 gene family: insights into the evolution of apicomplexan AP2 regulatory systems. AB - We provide the first comprehensive analysis of any transcription factor family in Cryptosporidium, a basal-branching apicomplexan that is the second leading cause of infant diarrhea globally. AP2 domain-containing proteins have evolved to be the major regulatory family in the phylum to the exclusion of canonical regulators. We show that apicomplexan and perkinsid AP2 domains cluster distinctly from other chromalveolate AP2s. Protein-binding specificity assays of C. parvum AP2 domains combined with motif conservation upstream of co-regulated gene clusters allowed the construction of putative AP2 regulons across the in vitro life cycle. Orthologous Apicomplexan AP2 (ApiAP2) expression has been rearranged relative to the malaria parasite P. falciparum, suggesting ApiAP2 network rewiring during evolution. C. hominis orthologs of putative C. parvum ApiAP2 proteins and target genes show greater than average variation. C. parvum AP2 domains display reduced binding diversity relative to P. falciparum, with multiple domains binding the 5'-TGCAT-3', 5'-CACACA-3' and G-box motifs (5' G[T/C]GGGG-3'). Many overrepresented motifs in C. parvum upstream regions are not AP2 binding motifs. We propose that C. parvum is less reliant on ApiAP2 regulators in part because it utilizes E2F/DP1 transcription factors. C. parvum may provide clues to the ancestral state of apicomplexan transcriptional regulation, pre-AP2 domination. PMID- 24957601 TI - Genomic mapping of cAMP receptor protein (CRP Mt) in Mycobacterium tuberculosis: relation to transcriptional start sites and the role of CRPMt as a transcription factor. AB - Chromatin immunoprecipitation identified 191 binding sites of Mycobacterium tuberculosis cAMP receptor protein (CRP(Mt)) at endogenous expression levels using a specific alpha-CRP(Mt) antibody. Under these native conditions an equal distribution between intragenic and intergenic locations was observed. CRP(Mt) binding overlapped a palindromic consensus sequence. Analysis by RNA sequencing revealed widespread changes in transcriptional profile in a mutant strain lacking CRP(Mt) during exponential growth, and in response to nutrient starvation. Differential expression of genes with a CRP(Mt)-binding site represented only a minor portion of this transcriptional reprogramming with ~ 19% of those representing transcriptional regulators potentially controlled by CRP(Mt). The subset of genes that are differentially expressed in the deletion mutant under both culture conditions conformed to a pattern resembling canonical CRP regulation in Escherichia coli, with binding close to the transcriptional start site associated with repression and upstream binding with activation. CRP(Mt) can function as a classical transcription factor in M. tuberculosis, though this occurs at only a subset of CRP(Mt)-binding sites. PMID- 24957603 TI - Citrullination of DNMT3A by PADI4 regulates its stability and controls DNA methylation. AB - DNA methylation is a central epigenetic modification in mammals, with essential roles in development and disease. De novo DNA methyltransferases establish DNA methylation patterns in specific regions within the genome by mechanisms that remain poorly understood. Here we show that protein citrullination by peptidylarginine deiminase 4 (PADI4) affects the function of the DNA methyltransferase DNMT3A. We found that DNMT3A and PADI4 interact, from overexpressed as well as untransfected cells, and associate with each other's enzymatic activity. Both in vitro and in vivo, PADI4 was shown to citrullinate DNMT3A. We identified a sequence upstream of the PWWP domain of DNMT3A as its primary region citrullinated by PADI4. Increasing the PADI4 level caused the DNMT3A protein level to increase as well, provided that the PADI4 was catalytically active, and RNAi targeting PADI4 caused reduced DNMT3A levels. Accordingly, pulse-chase experiments revealed stabilization of the DNMT3A protein by catalytically active PADI4. Citrullination and increased expression of native DNMT3A by PADI4 were confirmed in PADI4-knockout MEFs. Finally, we showed that PADI4 overexpression increases DNA methyltransferase activity in a catalytic dependent manner and use bisulfite pyrosequencing to demonstrate that PADI4 knockdown causes significant reduction of CpG methylation at the p21 promoter, a known target of DNMT3A and PADI4. Protein citrullination by PADI4 thus emerges as a novel mechanism for controlling a de novo DNA methyltransferase. Our results shed new light on how post-translational modifications might contribute to shaping the genomic CpG methylation landscape. PMID- 24957604 TI - Identification of RNA binding motifs in the R2 retrotransposon-encoded reverse transcriptase. AB - R2 non-LTR retrotransposons insert at a specific site in the 28S rRNA genes of many animal phyla. R2 elements encode a single polypeptide with reverse transcriptase, endonuclease and nucleic acid binding domains. Integration involves separate cleavage of the two DNA strands at the target site and utilization of the released 3' ends to prime DNA synthesis. Critical to this integration is the ability of the protein to specifically bind 3' and 5' regions of the R2 RNA. In this report, alanine mutations in two conserved motifs N terminal to the reverse transcriptase domain were generated and shown to result in proteins that retained the ability to cleave the first strand of the DNA target, to reverse transcribe RNA from an annealed primer and to displace annealed RNA when using DNA as a template. However, the mutant proteins had greatly reduced ability to bind 3' and 5' RNA in mobility shift assays, use the DNA target to prime reverse transcription and conduct second-strand DNA cleavage. These motifs thus appear to participate in all activities of the R2 protein known to require specific RNA binding. The similarity of these R2 RNA binding motifs to those of telomerase and group II introns is discussed. PMID- 24957602 TI - The organization of RNA contacts by PTB for regulation of FAS splicing. AB - Post-transcriptional steps of gene expression are regulated by RNA binding proteins. Major progress has been made in characterizing RNA-protein interactions, from high resolution structures to transcriptome-wide profiling. Due to the inherent technical challenges, less attention has been paid to the way in which proteins with multiple RNA binding domains engage with target RNAs. We have investigated how the four RNA recognition motif (RRM) domains of Polypyrimidine tract binding (PTB) protein, a major splicing regulator, interact with FAS pre-mRNA under conditions in which PTB represses FAS exon 6 splicing. A combination of tethered hydroxyl radical probing, targeted inactivation of individual RRMs and single molecule analyses revealed an unequal division of labour between the four RRMs of PTB. RNA binding by RRM4 is the most important for function despite the low intrinsic binding specificity and the complete lack of effect of disrupting individual RRM4 contact points on the RNA. The ordered RRM3-4 di-domain packing provides an extended binding surface for RNA interacting at RRM4, via basic residues in the preceding linker. Our results illustrate how multiple alternative low-specificity binding configurations of RRM4 are consistent with repressor function as long as the overall ribonucleoprotein architecture provided by appropriate di-domain packing is maintained. PMID- 24957605 TI - DNA polymerase IV mediates efficient and quick recovery of replication forks stalled at N2-dG adducts. AB - Escherichia coli DNA polymerase IV (Pol IV, also known as DinB) is a Y-family DNA polymerase capable of catalyzing translesion DNA synthesis (TLS) on certain DNA lesions, and accumulating data suggest that Pol IV may play an important role in copying various kinds of spontaneous DNA damage including N(2)-dG adducts and alkylated bases. Pol IV has a unique ability to coexist with Pol III on the same beta clamp and to positively dissociate Pol III from beta clamp in a concentration-dependent manner. Reconstituting the entire process of TLS in vitro using E. coli replication machinery and Pol IV, we observed that a replication fork stalled at (-)-trans-anti-benzo[a]pyrene-N(2)-dG lesion on the leading strand was efficiently and quickly recovered via two sequential switches from Pol III to Pol IV and back to Pol III. Our results suggest that TLS by Pol IV smoothes the way for the replication fork with minimal interruption. PMID- 24957608 TI - Indian health ministry orders encephalitis vaccination in select districts after more than 500 deaths. PMID- 24957606 TI - ATM regulates NF-kappaB-dependent immediate-early genes via RelA Ser 276 phosphorylation coupled to CDK9 promoter recruitment. AB - Ataxia-telangiectasia mutated (ATM), a member of the phosphatidylinositol 3 kinase-like kinase family, is a master regulator of the double strand DNA break repair pathway after genotoxic stress. Here, we found ATM serves as an essential regulator of TNF-induced NF-kB pathway. We observed that TNF exposure of cells rapidly induced DNA double strand breaks and activates ATM. TNF-induced ROS promote nuclear IKKgamma association with ubiquitin and its complex formation with ATM for nuclear export. Activated cytoplasmic ATM is involved in the selective recruitment of the E3-ubiquitin ligase beta-TrCP to phospho IkappaBalpha proteosomal degradation. Importantly, ATM binds and activates the catalytic subunit of protein kinase A (PKAc), ribosmal S6 kinase that controls RelA Ser 276 phosphorylation. In ATM knockdown cells, TNF-induced RelA Ser 276 phosphorylation is significantly decreased. We further observed decreased binding and recruitment of the transcriptional elongation complex containing cyclin dependent kinase-9 (CDK9; a kinase necessary for triggering transcriptional elongation) to promoters of NF-kappaB-dependent immediate-early cytokine genes, in ATM knockdown cells. We conclude that ATM is a nuclear damage-response signal modulator of TNF-induced NF-kappaB activation that plays a key scaffolding role in IkappaBalpha degradation and RelA Ser 276 phosphorylation. Our study provides a mechanistic explanation of decreased innate immune response associated with A-T mutation. PMID- 24957607 TI - Structural basis of nucleic acid binding by Nicotiana tabacum glycine-rich RNA binding protein: implications for its RNA chaperone function. AB - Glycine-rich RNA-binding proteins (GR-RBPs) are involved in cold shock response of plants as RNA chaperones facilitating mRNA transport, splicing and translation. GR-RBPs are bipartite proteins containing a RNA recognition motif (RRM) followed by a glycine-rich region. Here, we studied the structural basis of nucleic acid binding of full-length Nicotiana tabacum GR-RBP1. NMR studies of NtGR-RBP1 show that the glycine-rich domain, while intrinsically disordered, is responsible for mediating self-association by transient interactions with its RRM domain (NtRRM). Both NtGR-RBP1 and NtRRM bind specifically and with low micromolar affinity to RNA and single-stranded DNA. The solution structure of NtRRM shows that it is a canonical RRM domain. A HADDOCK model of the NtRRM-RNA complex, based on NMR chemical shift and NOE data, shows that nucleic acid binding results from a combination of stacking and electrostatic interactions with conserved RRM residues. Finally, DNA melting experiments demonstrate that NtGR-RBP1 is more efficient in melting CTG containing nucleic acids than isolated NtRRM. Together, our study supports the model that self-association of GR-RBPs by the glycine-rich region results in cooperative unfolding of non-native substrate structures, thereby enhancing its chaperone function. PMID- 24957610 TI - Effect of polarizable lone pair cations on the second-harmonic generation (SHG) properties of noncentrosymmetric (NCS) Bi(2-x)Y(x)TeO5 (x = 0-0.2). AB - Y(3+)-doped noncentrosymmetric (NCS) bismuth tellurite materials, Bi(2-x)Y(x)TeO5 (x = 0, 0.1, and 0.2), have been synthesized through standard solid-state reactions and structurally characterized by powder neutron diffraction. The reported NCS materials crystallize in the orthorhombic space group Abm2 (no. 39), and exhibit pseudo-three-dimensional frameworks that are composed of BiO3, BiO5, and TeO3 polyhedra. Detailed diffraction studies show that the cell volume of Bi(2-x)Y(x)TeO5 decreases with an increasing amount of Y(3+)on the Bi(3+) sites. However, no ordering between Bi(3+) and Y(3+) was observed in the Bi(2 x)Y(x)TeO5. Powder second-harmonic generation (SHG) measurements, using 1064 nm radiation, reveal that Bi2TeO5, Bi(1.9)Y(0.1)TeO5, and Bi(1.8)Y(0.2)TeO5 exhibit SHG efficiencies of approximately 300, 200, and 60 times that of alpha-SiO2, respectively. The reduction in SHG for Y(3+)-doped materials is consistent with the lack of net moment originating from polyhedra with a polarizable Bi(3+) cation. PMID- 24957611 TI - The absolute configuration for inthomycin C: revision of previously published work with a reinstatement of the (3R)-configuration for (-)-inthomycin C. AB - Stereochemical evidence is presented to demonstrate that (-)-inthomycin C has (3R)- and not (3S)-stereochemistry. Careful reappraisal of the previously published work2-5 now indicates that the Hatakeyama, Hale, Ryu, and Taylor teams all have synthesized (-)-(3R)-inthomycin C. The newly measured [alpha]D of pure ( )-(3R)-inthomycin C (98% ee) is -7.9 (c 0.33, CHCl3) and not -41.5 (c 0.1, CHCl3) as was previously reported in 2012. PMID- 24957609 TI - Gambierol inhibition of voltage-gated potassium channels augments spontaneous Ca2+ oscillations in cerebrocortical neurons. AB - Gambierol is a marine polycyclic ether toxin produced by the marine dinoflagellate Gambierdiscus toxicus and is a member of the ciguatoxin toxin family. Gambierol has been demonstrated to be either a low-efficacy partial agonist/antagonist of voltage-gated sodium channels or a potent blocker of voltage-gated potassium channels (Kvs). Here we examined the influence of gambierol on intact cerebrocortical neurons. We found that gambierol produced both a concentration-dependent augmentation of spontaneous Ca(2+) oscillations, and an inhibition of Kv channel function with similar potencies. In addition, an array of selective as well as universal Kv channel inhibitors mimicked gambierol in augmenting spontaneous Ca(2+) oscillations in cerebrocortical neurons. These data are consistent with a gambierol blockade of Kv channels underlying the observed increase in spontaneous Ca(2+) oscillation frequency. We also found that gambierol produced a robust stimulation of phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2). Gambierol-stimulated ERK1/2 activation was dependent on both inotropic [N-methyl-d-aspartate (NMDA)] and type I metabotropic glutamate receptors (mGluRs) inasmuch as MK-801 [NMDA receptor inhibitor; (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], S-(4)-CGP [S-(4)-carboxyphenylglycine], and MTEP [type I mGluR inhibitors; 3-((2-methyl-4-thiazolyl)ethynyl) pyridine] attenuated the response. In addition, 2-aminoethoxydiphenylborane, an inositol 1,4,5-trisphosphate receptor inhibitor, and U73122 (1-[6-[[(17b)-3-methoxyestra-1,3,5(10)-trien-17 yl]amino]hexyl]-1H-pyrrole-2,5-dione), a phospholipase C inhibitor, both suppressed gambierol-induced ERK1/2 activation, further confirming the role of type I mGluR-mediated signaling in the observed ERK1/2 activation. Finally, we found that gambierol produced a concentration-dependent stimulation of neurite outgrowth that was mimicked by 4-aminopyridine, a universal potassium channel inhibitor. Considered together, these data demonstrate that gambierol alters both Ca(2+) signaling and neurite outgrowth in cerebrocortical neurons as a consequence of blockade of Kv channels. PMID- 24957612 TI - Membrane characterization by microscopic and scattering methods: multiscale structure. AB - Several microscopic and scattering techniques at different observation scales (from atomic to macroscopic) were used to characterize both surface and bulk properties of four new flat-sheet polyethersulfone (PES) membranes (10, 30, 100 and 300 kDa) and new 100 kDa hollow fibers (PVDF). Scanning Electron Microscopy (SEM) with "in lens" detection was used to obtain information on the pore sizes of the skin layers at the atomic scale. White Light Interferometry (WLI) and Atomic Force Microscopy (AFM) using different scales (for WLI: windows: 900 * 900 um2 and 360 * 360 um2; number of points: 1024; for AFM: windows: 50 * 50 um2 and 5 * 5 um2; number of points: 512) showed that the membrane roughness increases markedly with the observation scale and that there is a continuity between the different scan sizes for the determination of the RMS roughness. High angular resolution ellipsometric measurements were used to obtain the signature of each cut-off and the origin of the scattering was identified as coming from the membrane bulk. PMID- 24957613 TI - Effect of Ammonium- and Phosphonium-Based Ionic Liquids on the Separation of Lactic Acid by Supported Ionic Liquid Membranes (SILMs). AB - Biodegradable polymers have attracted much attention from an environmental point of view. Optically pure lactic acid that can be prepared by fermentation is one of the important raw materials for biodegradable polymer. The separation and purification of lactic acid from the fermentation broth are the major portions of the production costs. We proposed the application of supported ionic liquid membranes to recovering lactic acid. In this paper, the effect of ionic liquids, such as Aliquat 336, CYPHOS IL-101, CYPHOS IL-102, CYPHOS IL-104, CYPHOS IL-109 and CYPHOS IL-111 on the lactic acid permeation have been studied. Aliquat 336, CYPHOS IL-101 and CYPHOS IL-102 were found to be the best membrane solvents as far as membrane stability and permeation of lactic acid are concerned. CYPHOS IL 109 and CYPHOS IL-111 were found to be unsuitable, as they leak out from the pores of the supported liquid membrane (SLM), thereby allowing free transport of lactic acid as well as hydrochloric acid. CYPHOS IL-102 was found to be the most adequate (Permeation rate = 60.41%) among these ionic liquids as far as the separation of lactic acid is concerned. The permeation mechanisms, by which ionic liquid-water complexes act as the carrier of lactate and hydrochloric acid, were proposed. The experimental permeation results have been obtained as opposed to the expected values from the solution-diffusion mechanism. PMID- 24957614 TI - Electroformation of Giant Vesicles on Indium Tin Oxide (ITO)-Coated Poly(ethylene terephthalate) (PET) Electrodes. AB - Electroformation of cell-sized lipid membrane vesicles (giant vesicles, GVs) from egg yolk phosphatidylcholine was examined using a poly(ethylene terephthalate) sheet coated with indium tin oxide (ITO-PET) as the electrode material. With sinusoidal ac voltage, GV formation occurred in a similar manner to that on an ITO-glass electrode widely used in electroformation. Difference in the specific electrical resistance of ITO-PET did not significantly affect electroformation. The present results indicate that ITO-PET may be used as more flexible and less expensive electrode material in electroformation. In order to obtain insights into electroformation, other electric voltage forms, static dc and dc pulses, were also tested in place of commonly used sinusoidal ac. Under the present conditions, the best GV formation was observed with dc pulses of negative polarity. The result with static dc demonstrated that the mechanical vibration of swelling lipid seen with sinusoidal ac voltage was not essential for GV formation. On the positive electrode, the electroswelling of lipid mainly yielded non-spherical membranous objects. Pre-application of positive dc voltage on lipid hindered GV formation in electroswelling of the lipid with ac. PMID- 24957615 TI - Experimental study of fouling and cleaning of sintered stainless steel membrane in electro-microfiltration of calcium salt particles. AB - Sintered stainless steel (SSS) microfiltration membranes, which served as electrode directly, were used for the experiment of separating Alamin, a calcium salt and protein containing particles, found in dairy processing. Fouling and cleaning of the SSS membranes under the application of an external electric field were studied. The imposed electric field was found, diverging the pH of permeate and retentate. This in turn altered the solubility of the calcium salt and impacted the performance of electro microfiltration membrane. Using electric field as an enhanced cleaning-in-place (CIP) method in back flushing SSS membrane was also studied. PMID- 24957616 TI - Electrochemical impedance spectroscopy-a simple method for the characterization of polymer inclusion membranes containing aliquat 336. AB - Electrochemical impedance spectroscopy (EIS) has been used to estimate the non frequency dependent (static) dielectric constants of base polymers such as poly(vinyl chloride) (PVC), cellulose triacetate (CTA) and polystyrene (PS). Polymer inclusion membranes (PIMs) containing different amounts of PVC or CTA, along with the room temperature ionic liquid Aliquat 336 and plasticizers such as trisbutoxyethyl phosphate (TBEP), dioctyl sebecate (DOS) and 2-nitrophenyloctyl ether (NPOE) have been investigated. In this study, the complex and abstract method of EIS has been applied in a simple and easy to use way, so as to make the method accessible to membrane scientists and engineers who may not possess the detailed knowledge of electrochemistry and interfacial science needed for a rigorous interpretation of EIS results. The EIS data reported herein are internally consistent with a percolation threshold in the dielectric constant at high concentrations of Aliquat 336, which illustrates the suitability of the EIS technique since membrane percolation with ion exchangers is a well-known phenomenon. PMID- 24957617 TI - Analysis of Salmonella enterica serovar Typhimurium variable-number tandem-repeat data for public health investigation based on measured mutation rates and whole genome sequence comparisons. AB - Variable-number tandem repeats (VNTRs) mutate rapidly and can be useful markers for genotyping. While multilocus VNTR analysis (MLVA) is increasingly used in the detection and investigation of food-borne outbreaks caused by Salmonella enterica serovar Typhimurium (S. Typhimurium) and other bacterial pathogens, MLVA data analysis usually relies on simple clustering approaches that may lead to incorrect interpretations. Here, we estimated the rates of copy number change at each of the five loci commonly used for S. Typhimurium MLVA, during in vitro and in vivo passage. We found that loci STTR5, STTR6, and STTR10 changed during passage but STTR3 and STTR9 did not. Relative rates of change were consistent across in vitro and in vivo growth and could be accurately estimated from diversity measures of natural variation observed during large outbreaks. Using a set of 203 isolates from a series of linked outbreaks and whole-genome sequencing of 12 representative isolates, we assessed the accuracy and utility of several alternative methods for analyzing and interpreting S. Typhimurium MLVA data. We show that eBURST analysis was accurate and informative. For construction of MLVA based trees, a novel distance metric, based on the geometric model of VNTR evolution coupled with locus-specific weights, performed better than the commonly used simple or categorical distance metrics. The data suggest that, for the purpose of identifying potential transmission clusters for further investigation, isolates whose profiles differ at one of the rapidly changing STTR5, STTR6, and STTR10 loci should be collapsed into the same cluster. PMID- 24957618 TI - Characterization of two UDP-Gal:GalNAc-diphosphate-lipid beta1,3 galactosyltransferases WbwC from Escherichia coli serotypes O104 and O5. AB - Escherichia coli displays O antigens on the outer membrane that play an important role in bacterial interactions with the environment. The O antigens of enterohemorrhagic E. coli O104 and O5 contain a Galbeta1-3GalNAc disaccharide at the reducing end of the repeating unit. Several other O antigens contain this disaccharide, which is identical to the mammalian O-glycan core 1 or the cancer associated Thomsen-Friedenreich (TF) antigen. We identified the wbwC genes responsible for the synthesis of the disaccharide in E. coli serotypes O104 and O5. To functionally characterize WbwC, an acceptor substrate analog, GalNAcalpha diphosphate-phenylundecyl, was synthesized. WbwC reaction products were isolated by high-pressure liquid chromatography and analyzed by mass spectrometry, nuclear magnetic resonance, galactosidase and O-glycanase digestion, and anti-TF antibody. The results clearly showed that the Galbeta1-3GalNAcalpha linkage was synthesized, confirming WbwCECO104 and WbwCECO5 as UDP-Gal:GalNAcalpha diphosphate-lipid beta1,3-Gal-transferases. Sequence analysis revealed a conserved DxDD motif, and mutagenesis showed the importance of these Asp residues in catalysis. The purified enzymes require divalent cations (Mn(2+)) for activity and are specific for UDP-Gal and GalNAc-diphosphate lipid substrates. WbwC was inhibited by bis-imidazolium salts having aliphatic chains of 18 to 22 carbons. This work will help to elucidate mechanisms of polysaccharide synthesis in pathogenic bacteria and provide technology for vaccine synthesis. PMID- 24957620 TI - Suppression of conformation-compromised mutants of Salmonella enterica serovar Typhimurium MelB. AB - The crystal structure of the Na(+)-coupled melibiose permease of Salmonella enterica serovar Typhimurium (MelBSt) demonstrates that MelB is a member of the major facilitator superfamily of transporters. Arg residues at positions 295, 141, and 363 are involved in interdomain interactions at the cytoplasmic side by governing three clusters of electrostatic/polar interactions. Insertion of (one at a time) Glu, Leu, Gln, or Cys at positions R295, R141, and R363, or Lys at position R295, inhibits active transport of melibiose to a level of 2 to 20% of the value for wild-type (WT) MelBSt, with little effect on binding affinities for both sugar and Na(+). Interestingly, a spontaneous suppressor, D35E (periplasmic end of helix I), was isolated from the R363Q MelBSt mutant. Introduction of the D35E mutation in each of the mutants at R295, R141 (except R141E), or R363 rescues melibiose transport to up to 91% of the WT value. Single-site mutations for the pair of D35 and R175 (periplasmic end of helix VI) were constructed by replacing Asp with Glu, Gln, or Cys and R175 with Gln, Asn, or Cys. All mutants with mutations at R175 are active, indicating that a positive charge at R175 is not necessary. Mutant D35E shows reduced transport; D35Q and D35C are nearly inactivated. Surprisingly, the D35Q mutation partially rescues both R141C and R295Q mutations. The data support the idea that Arg at position 295 and a positive charge at positions 141 and 363 are required for melibiose transport catalyzed by MelBSt, and their mutation inhibits conformational cycling, which is suppressed by a minor modification at the opposite side of the membrane. PMID- 24957619 TI - DNA ligase C1 mediates the LigD-independent nonhomologous end-joining pathway of Mycobacterium smegmatis. AB - Nonhomologous end joining (NHEJ) is a recently described bacterial DNA double strand break (DSB) repair pathway that has been best characterized for mycobacteria. NHEJ can religate transformed linear plasmids, repair ionizing radiation (IR)-induced DSBs in nonreplicating cells, and seal I-SceI-induced chromosomal DSBs. The core components of the mycobacterial NHEJ machinery are the DNA end binding protein Ku and the polyfunctional DNA ligase LigD. LigD has three autonomous enzymatic modules: ATP-dependent DNA ligase (LIG), DNA/RNA polymerase (POL), and 3' phosphoesterase (PE). Although genetic ablation of ku or ligD abolishes NHEJ and sensitizes nonreplicating cells to ionizing radiation, selective ablation of the ligase activity of LigD in vivo only mildly impairs NHEJ of linearized plasmids, indicating that an additional DNA ligase can support NHEJ. Additionally, the in vivo role of the POL and PE domains in NHEJ is unclear. Here we define a LigD ligase-independent NHEJ pathway in Mycobacterium smegmatis that requires the ATP-dependent DNA ligase LigC1 and the POL domain of LigD. Mycobacterium tuberculosis LigC can also support this backup NHEJ pathway. We also demonstrate that, although dispensable for efficient plasmid NHEJ, the activities of the POL and PE domains are required for repair of IR-induced DSBs in nonreplicating cells. These findings define the genetic requirements for a LigD-independent NHEJ pathway in mycobacteria and demonstrate that all enzymatic functions of the LigD protein participate in NHEJ in vivo. PMID- 24957622 TI - Chemosensory regulation of a HEAT-repeat protein couples aggregation and sporulation in Myxococcus xanthus. AB - Chemosensory systems are complex, highly modified two-component systems (TCS) used by bacteria to control various biological functions ranging from motility to sporulation. Chemosensory systems and TCS both modulate phosphorelays comprised of histidine kinases and response regulators, some of which are single-domain response regulators (SD-RRs) such as CheY. In this study, we have identified and characterized the Che7 chemosensory system of Myxococcus xanthus, a common soil bacterium which displays multicellular development in response to stress. Both genetic and biochemical analyses indicate that the Che7 system regulates development via a direct interaction between the SD-RR CheY7 and a HEAT repeat domain-containing protein, Cpc7. Phosphorylation of the SD-RR affects the interaction with its target, and residues within the alpha4-beta5-alpha5 fold of the REC domain govern this interaction. The identification of the Cpc7 interaction with CheY7 extends the diversity of known targets for SD-RRs in biological systems. PMID- 24957621 TI - Alkali metals in addition to acidic pH activate the EvgS histidine kinase sensor in Escherichia coli. AB - Two-component signal transduction systems (TCSs) in bacteria perceive environmental stress and transmit the information via phosphorelay to adjust multiple cellular functions for adaptation. The EvgS/EvgA system is a TCS that confers acid resistance to Escherichia coli cells. Activation of the EvgS sensor initiates a cascade of transcription factors, EvgA, YdeO, and GadE, which induce the expression of a large group of acid resistance genes. We searched for signals activating EvgS and found that a high concentration of alkali metals (Na(+), K(+)) in addition to low pH was essential for the activation. EvgS is a histidine kinase, with a large periplasmic sensor region consisting of two tandem PBPb (bacterial periplasmic solute-binding protein) domains at its N terminus. The periplasmic sensor region of EvgS was necessary for EvgS activation, and Leu152, located within the first PBPb domain, was involved in the activation. Furthermore, chimeras of EvgS and PhoQ histidine kinases suggested that alkali metals were perceived at the periplasmic sensor region, whereas the cytoplasmic linker domain, connecting the transmembrane region and the histidine kinase domain, was required for low-pH perception. PMID- 24957623 TI - Interplay between two bacterial actin homologs, MamK and MamK-Like, is required for the alignment of magnetosome organelles in Magnetospirillum magneticum AMB-1. AB - Many bacterial species contain multiple actin-like proteins tasked with the execution of crucial cell biological functions. MamK, an actin-like protein found in magnetotactic bacteria, is important in organizing magnetosome organelles into chains that are used for navigation along geomagnetic fields. MamK and numerous other magnetosome formation factors are encoded by a genetic island termed the magnetosome island. Unlike most magnetotactic bacteria, Magnetospirillum magneticum AMB-1 (AMB-1) contains a second island of magnetosome-related genes that was named the magnetosome islet. A homologous copy of mamK, mamK-like, resides within this islet and encodes a protein capable of filament formation in vitro. Previous work had shown that mamK-like is expressed in vivo, but its function, if any, had remained unknown. Though MamK-like is highly similar to MamK, it contains a mutation that in MamK and other actins blocks ATPase activity in vitro and filament dynamics in vivo. Here, using genetic analysis, we demonstrate that mamK-like has an in vivo role in assisting organelle alignment. In addition, MamK-like forms filaments in vivo in a manner that is dependent on the presence of MamK and the two proteins interact in a yeast two-hybrid assay. Surprisingly, despite the ATPase active-site mutation, MamK-like is capable of ATP hydrolysis in vitro and promotes MamK filament turnover in vivo. Taken together, these experiments suggest that direct interactions between MamK and MamK-like contribute to magnetosome alignment in AMB-1. PMID- 24957624 TI - Amino acid residues of RegA important for interactions with the CbbR-DNA complex of Rhodobacter sphaeroides. AB - CbbR and RegA (PrrA) are transcriptional regulators of the Calvin-Benson-Bassham (CBB) CO2 fixation pathway (cbbI and cbbII) operons of Rhodobacter sphaeroides. The CbbR and RegA proteins interact, but CbbR must be bound to the promoter DNA in order for RegA-CbbR protein-protein interactions to occur. RegA greatly enhances the ability of CbbR to bind the cbbI promoter or greatly enhances the stability of the CbbR/promoter complex. The N-terminal receiver domain and the DNA binding domain of RegA were shown to interact with CbbR. Residues in alpha helix 7 and alpha-helix 8 of the DNA binding domain (helix-turn-helix) of RegA directly interacted with CbbR, with alpha-helix 7 positioned immediately above the DNA and alpha-helix 8 located in the major groove of the DNA. A CbbR protein containing only the DNA binding motif and the linker helix was capable of binding to RegA. In contrast, a truncated CbbR containing only the linker helix and recognition domains I and II (required for effector binding) was not able to interact with RegA. The accumulated results strongly suggest that the DNA binding domains of both proteins interact to facilitate optimal transcriptional control over the cbb operons. In vivo analysis, using constitutively active mutant CbbR proteins, further indicated that CbbR must interact with phosphorylated RegA in order to accomplish transcriptional activation. PMID- 24957625 TI - GxySBA ABC transporter of Agrobacterium tumefaciens and its role in sugar utilization and vir gene expression. AB - Monosaccharides available in the extracellular milieu of Agrobacterium tumefaciens can be transported into the cytoplasm, or via the periplasmic sugar binding protein, ChvE, play a critical role in controlling virulence gene expression. The ChvE-MmsAB ABC transporter is involved in the utilization of a wide range of monosaccharide substrates but redundant transporters are likely given the ability of a chvE-mmsAB deletion strain to grow, albeit more slowly, in the presence of particular monosaccharides. In this study, a putative ABC transporter encoded by the gxySBA operon is identified and shown to be involved in the utilization of glucose, xylose, fucose, and arabinose, which are also substrates for the ChvE-MmsAB ABC transporter. Significantly, GxySBA is also shown to be the first characterized glucosamine ABC transporter. The divergently transcribed gene gxyR encodes a repressor of the gxySBA operon, the function of which can be relieved by a subset of the transported sugars, including glucose, xylose, and glucosamine, and this substrate-induced expression can be repressed by glycerol. Furthermore, deletion of the transporter can increase the sensitivity of the virulence gene expression system to certain sugars that regulate it. Collectively, the results reveal a remarkably diverse set of substrates for the GxySBA transporter and its contribution to the repression of sugar sensitivity by the virulence-controlling system, thereby facilitating the capacity of the bacterium to distinguish between the soil and plant environments. PMID- 24957626 TI - Accumulation of phosphatidic acid increases vancomycin resistance in Escherichia coli. AB - In Gram-negative bacteria, lipopolysaccharide (LPS) contributes to the robust permeability barrier of the outer membrane, preventing entry of toxic molecules such as antibiotics. Mutations in lptD, the beta-barrel component of the LPS transport and assembly machinery, compromise LPS assembly and result in increased antibiotic sensitivity. Here, we report rare vancomycin-resistant suppressors that improve barrier function of a subset of lptD mutations. We find that all seven suppressors analyzed mapped to the essential gene cdsA, which is responsible for the conversion of phosphatidic acid to CDP-diacylglycerol in phospholipid biosynthesis. These cdsA mutations cause a partial loss of function and, as expected, accumulate phosphatidic acid. We show that this suppression is not confined to mutations that cause defects in outer membrane biogenesis but rather that these cdsA mutations confer a general increase in vancomycin resistance, even in a wild-type cell. We use genetics and quadrupole time of flight (Q-TOF) liquid chromatography-mass spectrometry (LC-MS) to show that accumulation of phosphatidic acid by means other than cdsA mutations also increases resistance to vancomycin. We suggest that increased levels of phosphatidic acid change the physical properties of the outer membrane to impede entry of vancomycin into the periplasm, hindering access to its target, an intermediate required for the synthesis of the peptidoglycan cell wall. PMID- 24957627 TI - Acetyl coenzyme A synthetase is acetylated on multiple lysine residues by a protein acetyltransferase with a single Gcn5-type N-acetyltransferase (GNAT) domain in Saccharopolyspora erythraea. AB - Reversible lysine acetylation (RLA) is used by cells of all domains of life to modulate protein function. To date, bacterial acetylation/deacetylation systems have been studied in a few bacteria (e.g., Salmonella enterica, Bacillus subtilis, Escherichia coli, Erwinia amylovora, Mycobacterium tuberculosis, and Geobacillus kaustophilus), but little is known about RLA in antibiotic-producing actinomycetes. Here, we identify the Gcn5-like protein acetyltransferase AcuA of Saccharopolyspora erythraea (SacAcuA, SACE_5148) as the enzyme responsible for the acetylation of the AMP-forming acetyl coenzyme A synthetase (SacAcsA, SACE_2375). Acetylated SacAcsA was deacetylated by a sirtuin-type NAD(+) dependent consuming deacetylase (SacSrtN, SACE_3798). In vitro acetylation/deacetylation of SacAcsA enzyme was studied by Western blotting, and acetylation of lysine residues Lys(237), Lys(380), Lys(611), and Lys(628) was confirmed by mass spectrometry. In a strain devoid of SacAcuA, none of the above mentioned Lys residues of SacAcsA was acetylated. To our knowledge, the ability of SacAcuA to acetylate multiple Lys residues is unique among AcuA-type acetyltransferases. Results from site-specific mutagenesis experiments showed that the activity of SacAcsA was controlled by lysine acetylation. Lastly, immunoprecipitation data showed that in vivo acetylation of SacAcsA was influenced by glucose and acetate availability. These results suggested that reversible acetylation may also be a conserved regulatory posttranslational modification strategy in antibiotic-producing actinomycetes. PMID- 24957628 TI - Genetic and environmental influences on the relationship between adult ADHD symptoms and self-reported problem drinking in 6024 Dutch twins. AB - BACKGROUND: Cross-sectional and longitudinal studies have shown a positive association between attention deficit hyperactivity disorder (ADHD) and problematic alcohol use in adults. To what extent this association is explained by genetic and environmental factors is largely unknown. METHOD: Data on ADHD and alcohol consumption were collected by self-report in 6024 adult Dutch twins. ADHD symptoms were assessed by three subscales of the Conners' Adult ADHD Rating Scales - Self-Report: Screening Version (CAARS-S:SV): inattentiveness, hyperactivity and the ADHD index (ADHD-I). Problem drinking was defined as at least two self-reported alcohol-related problems on the CAGE questionnaire. Structural equation modelling was applied to the bivariate twin data to estimate genetic and environmental influences. RESULTS: Heritability of ADHD symptoms ranged between 32% and 40% and heritability of problem drinking was 50%. The positive correlation between ADHD symptoms and problem drinking was confirmed in this general population sample, with phenotypic correlations between 0.20 and 0.28 and genetic correlations between 0.39 and 0.50. Phenotypic correlations are primarily (61-100%) explained by genetic influences with non-shared environmental influences explaining the remaining covariance. No significant quantitative or qualitative gender differences in covariance structure were found. CONCLUSIONS: This study convincingly shows that ADHD symptoms and problem drinking are moderately but significantly correlated in adults and that genetic correlations are primarily underlying this association. This suggests that early interventions are required to prevent adolescents with ADHD from developing problematic levels of alcohol use. Furthermore, clinicians who treat alcohol-dependent patients should be aware that the patient may have a co-morbid condition of ADHD; integrated interventions are required. PMID- 24957630 TI - Impact of fiducial arrangement and registration sequence on target accuracy using a phantom frameless stereotactic navigation model. AB - Modern frameless stereotactic techniques utilize scalp fiducial markers for registration. Anecdotal reports from surgeons indicate a variety of methods for improving accuracy using different fiducial arrangements and registration sequences. The few published studies on registration accuracy do not provide a simple and systematic method for determining target accuracy. Nine different arrangements of ten fiducial markers were attached to a model. Ten separate markers were designated as targets for evaluation of registration accuracy. We systematically registered each of the arrangements over multiple trials, in one of four sequences, and then measured the targets. The target coordinates were compared against the established target values, and a root-mean-square deviation (RMSD) was derived. A systematic multivariate analysis determined the effects of different variables on the RMSD. We found no correlation between the "Registration Accuracy" provided by Medtronic (Medtronic Navigation, Louisville, CO, USA) and our RMSD representing targeting accuracy (R=0.008). RMSD did vary for different fiducial arrangements. We found no significant difference between the various sequences of fiducial arrangement. Thus, regardless of fiducial arrangement, registration sequence has no impact on accuracy. Fiducial arrangements distributed optimally across the skull, however, allowed for significantly improved accuracy. Further studies are required to determine which different arrangements of fiducials are relevant for specific procedures. PMID- 24957629 TI - Effect of posterior subsidence on cervical alignment after anterior cervical corpectomy and reconstruction using titanium mesh cages in degenerative cervical disease. AB - Subsidence after anterior cervical reconstruction using a titanium mesh cage (TMC) has been a matter of debate. The authors investigated and analyzed subsidence and its effect on clinical and radiologic parameters after cervical reconstruction using a TMC for degenerative cervical disease. Thirty consecutive patients with degenerative cervical spine disorders underwent anterior cervical corpectomy followed by reconstruction with TMC. Twenty-four patients underwent a single-level corpectomy, and six patients underwent a two-level corpectomy. Clinical outcomes were assessed using a Visual Analogue Scale (VAS), the Japanese Orthopedic Association (JOA) score and the Neck Disability Index (NDI). Fusion status, anterior and posterior subsidence of the TMC, segmental angle (SA) and cervical sagittal angle (CSA) were assessed by lateral and flexion-extension radiographs of the neck. The mean follow-up period was 27.6 months (range, 24 to 49 months). The VAS, NDI and JOA scores were all significantly improved at the last follow-up. No instances of radiolucency or motion-related pseudoarthrosis were detected on radiographic analysis, yielding a fusion rate of 100%. Subsidence occurred in 28 of 30 patients (93.3%). The average anterior subsidence of the cage was 1.4 +/- 0.9 mm, and the average posterior subsidence was 2.9 +/- 1.2 mm. The SA and CSA at the final follow-up were significantly increased toward a lordotic angle. Anterior cervical reconstruction using TMC and plating in patients with cervical degenerative disease provides good clinical and radiologic outcomes. Cage subsidence occurred frequently, especially at the posterior part of the cage. Despite the prominent posterior subsidence of the TMC, SA and CSA were improved on final follow-up radiographs, suggesting that posterior subsidence may contribute to cervical lordosis. PMID- 24957632 TI - Development of an iron(II)-catalyzed aerobic catechol cleavage and biomimetic synthesis of betanidin. AB - An aerobic iron(II)-catalyzed cleavage of catechols was developed. This reaction allows for the preparation of 2-methoxy-2 H-pyrans that can be employed as versatile building blocks for synthesis. The utility of this biomimetic oxidative cleavage is featured in the synthesis of betanidin, a natural colorant with antioxidant properties. PMID- 24957631 TI - Epigenomes: the missing heritability in human cardiovascular disease? AB - Cardiovascular disease is a tremendous burden on human health and results from malfunction of various networks of biological molecules in the context of environmental stress. Despite strong evidence of heritability, many common forms of heart disease (heart failure in particular) have not yielded to genome-wide association studies to identify causative mutations acting via the disruption of individual molecules. Increasing evidence suggests, however, that genetic variation in noncoding regions is strongly linked to disease susceptibility. We hypothesize that epigenomic variation may engender different chromatin environments in the absence of (or in parallel with) changes in protein or mRNA sequence and abundance. In this manner, distinct-genetically encoded-chromatin environments can exhibit distinct responses to environmental stresses that cause heart failure, explaining a significant portion of the altered susceptibility that is observed in human disease. PMID- 24957633 TI - The meat industry: do we think and behave globally or locally? AB - For generations, those that produce livestock and meat generally felt that their country or geographical region (i.e., provenance) reflected a basis for product differentiation. This occurs to the extent that geography of production often is considered a "brand." For example, there exists "U.S. Grain-Fed Beef" or "Kobe Black Wagyu" or "Uruguayan Grass-Fed Lamb" or "Danish Pork." However, for most meat trade, industry has evolved beyond this. With the exception perhaps of farms onto which livestock are born, meat company's profits are not generally tied to geographical considerations. Most major companies (e.g., JBS, Marfrig, Tyson, Cargill, Danish Crown, Nippon Meat Packers, etc.) operate in multiple countries and represent to consumers the production of a number of locations. However, there also now exist entrepreneurial options for meat production and "local" sales, albeit at lesser volumes. This discussion explores "global" and "local" meat marketing options. PMID- 24957634 TI - Maintenance treatments for opiate -dependent adolescents. AB - BACKGROUND: The scientific literature examining effective treatments for opioid dependent adults clearly indicates that pharmacotherapy is a necessary and acceptable component. Nevertheless, no reviews have been published that systematically assess the effectiveness of pharmacological maintenance treatment in adolescents. OBJECTIVES: To assess the effectiveness of any maintenance treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions for retaining adolescents in treatment, reducing the use of substances and improving health and social status. SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Group's Trials Register (January 2014), the Cochrane Central Register of Controlled Trials (2014, Issue 1), PubMed (January 1966 to January 2014), EMBASE (January 1980 to January 2014), CINAHL (January 1982 to January 2014), Web of Science (1991 to January 2014) and reference lists of articles. SELECTION CRITERIA: Randomised and controlled clinical trials of any maintenance pharmacological interventions either alone or associated with psychosocial intervention compared with no intervention, placebo, other pharmacological intervention, pharmacological detoxification or psychosocial intervention in adolescents (13 to 18 years). DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included two trials involving 189 participants. One study, with 35 participants, compared methadone with levo-alpha-acetylmethadol (LAAM) for maintenance treatment lasting 16 weeks, after which patients were detoxified. The other study, with 154 participants, compared maintenance treatment with buprenorphine-naloxone and detoxification with buprenorphine. We did not perform meta-analysis because the two studies assessed different comparisons.In the study comparing methadone and LAAM, the authors declared that there was no difference in the use of a substance of abuse or social functioning (data not shown). The quality of the evidence was very low. No side effects, such as nausea, vomiting, constipation, weakness or fatigue, were reported by study participants.In the comparison between buprenorphine maintenance and buprenorphine detoxification, maintenance treatment appeared to be more efficacious in retaining patients in treatment (drop-out risk ratio (RR) 0.37; 95% confidence interval (CI) 0.26 to 0.54), but not in reducing the number of patients with a positive urine test at the end of the study (RR 0.97; 95% CI 0.78 to 1.22). Self reported opioid use at one-year follow-up was significantly lower in the maintenance group, even though both groups reported a high level of opioid use (RR 0.73; 95% CI 0.57 to 0.95). More patients in the maintenance group were enrolled in other addiction treatment programmes at 12-month follow-up (RR 1.33; 95% CI 0.94 to 1.88). The quality of the evidence was low. No serious side effects attributable to buprenorphine naloxone were reported by study participants and no patients were removed from the study due to side effects. The most common side effect was headache, which was reported by 16% to 21% of patients in both groups AUTHORS' CONCLUSIONS: It is difficult to draft conclusions on the basis of only two trials. One of the possible reasons for the lack of evidence could be the difficulty of conducting trials with young people for practical and ethical reasons.There is an urgent need for further randomised controlled trials comparing maintenance treatment with detoxification treatment or psychosocial treatment alone before carrying out studies that compare different pharmacological maintenance treatments. These studies should have long follow-up and measure relapse rates after the end of treatment and social functioning (integration at school or at work, family relationships). PMID- 24957635 TI - An MR-conditional high-torque pneumatic stepper motor for MRI-guided and robot assisted intervention. AB - Magnetic resonance imaging allows for visualizing detailed pathological and morphological changes of soft tissue. MR-conditional actuations have been widely investigated for development of image-guided and robot-assisted surgical devices under the Magnetic resonance imaging (MRI). This paper presents a simple design of MR-conditional stepper motor which can provide precise and high-torque actuation without adversely affecting the MR image quality. This stepper motor consists of two MR-conditional pneumatic cylinders and the corresponding supporting structures. Alternating the pressurized air can drive the motor to rotate each step in 3.6 degrees with the motor coupled to a planetary gearbox. Experimental studies were conducted to validate its dynamics performance. Maximum 800 mN m output torque is achieved. The motor accuracy independently varied by two factors: motor operating speed and step size, was also investigated. The motor was tested within a 3T Siemens MRI scanner (MAGNETOM Skyra, Siemens Medical Solutions, Erlangen, Germany) and a 3T GE MRI scanner (GE SignaHDx, GE Healthcare, Milwaukee, WI, USA). The image artifact and the signal-to-noise ratio (SNR) were evaluated for study of its MRI compliancy. The results show that the presented pneumatic stepper motor generated 2.35% SNR reduction in MR images. No observable artifact was presented besides the motor body itself. The proposed motor test also demonstrates a standard to evaluate the pneumatic motor capability for later incorporation with motorized devices used under MRI. PMID- 24957636 TI - Short duration electrical stimulation to enhance neurite outgrowth and maturation of adult neural stem progenitor cells. AB - New therapies are desperately needed for human central nervous system (CNS) regeneration to circumvent the lack of innate regenerative ability following traumatic injuries. Previously attempted therapies have been stymied by barriers to CNS regeneration largely because of protective mechanisms such as the blood brain barrier, inhibitory molecules, and glial scar formation. The application of electric stimulation (ES) has shown promise for enhancing peripheral nervous system regeneration, but is in its infancy in CNS regeneration. The objective of this study is to better understand how short duration ES can be harnessed to direct adult neural stem progenitor cell (NSPC) neurogenesis, neurite extension, and maturation. Herein, NSPCs were exposed to physiological levels of electrical stimulation of 0.53 or 1.83 V/m (applied power supply setting of 1.2 and 2.5 V) of direct current (DC) for 10 min/days for 2 days with a total differentiation time of 3 days. Culturing conditions consisted of either mitogenic growth factors or the neuronal differentiation factor interferon-gamma (IFN-gamma). Stimulated NSPCs showed lengths that were over five times longer than unstimulated controls (112.0 +/- 88.8 MUm at 0.53 V/m vs. 21.3 +/- 8.5 MUm for 0 V/m with IFN-gamma) with the longest neurites reaching up to 600 um. Additionally, ES resulted in mature neuronal morphologies and signs of differentiation through positive betaIII tubulin, neuronal nuclei (NeuN), and better organized filamentous-actin (f-actin) staining with growth cone formation. Additionally, the neurites and soma of stimulated NSPCs showed increases in intracellular Ca(2+) during stimulation, signifying the presence of functional neurons capable of electrical conductance and communication with other cells. Our study demonstrates that short stimulation times (10 min/ day) result in significant neurite extension of stem cells in a quick time frame (3 days). This ES modality is potentially advantageous for promoting axon re-growth at an injury site using delivered adult stem cells; however, significant work still remains to understand both the delivery approach of cells as well as ES application in vivo. PMID- 24957637 TI - Screening and correlates of neurotic disorders among general medical outpatients in Xi'an China. AB - PURPOSE: Little is known about the distribution and correlates of neurotic disorders among general medical outpatients. The aim was to identify the population distribution and associated factors of neurotic disorders among general medical outpatients. DESIGN AND METHODS: A cross-sectional design was used. Computer-assisted interviews of 372 general outpatients aged 16 years or older in Xi'an China were conducted using a Chinese version of the World Health Organization Composite International Diagnostic Interview version 3.0 (CIDI-3.0). FINDINGS: The estimated lifetime prevalence of any ICD-10 neurotic disorder among general medical outpatients was 10.8%. The most prevalent subtype of neurotic disorders was specific phobias (5.7%) followed by obsessive-compulsive disorders (3.8%) and social phobias (1.3%). General outpatients who visited the department of internal medicine (OR = 6.55, 95% CI 1.51-28.38), who were under 40 years old (OR = 4.44, 95% CI 2.05-9.62), had less than high school education (OR = 4.19, 95% CI 1.79-9.79), and were female (OR = 2.25, 95% CI 1.14-4.47) were most likely to report neurotic disorders. PRACTICE IMPLICATIONS: Effective identification of neurotic disorders is crucial for its early detection and targeted intervention among general medical outpatients. Those outpatients who had younger age and lower education level, and were female and had visited internal medicine departments require additional attention. PMID- 24957638 TI - BMP-2, hypoxia, and COL1A1/HtrA1 siRNAs favor neo-cartilage hyaline matrix formation in chondrocytes. AB - Osteoarthritis (OA) is an irreversible pathology that causes a decrease in articular cartilage thickness, leading finally to the complete degradation of the affected joint. The low spontaneous repair capacity of cartilage prevents any restoration of the joint surface, making OA a major public health issue. Here, we developed an innovative combination of treatment conditions to improve the human chondrocyte phenotype before autologous chondrocyte implantation. First, we seeded human dedifferentiated chondrocytes into a collagen sponge as a scaffold, cultured them in hypoxia in the presence of a bone morphogenetic protein (BMP), BMP-2, and transfected them with small interfering RNAs targeting two markers overexpressed in OA dedifferentiated chondrocytes, that is, type I collagen and/or HtrA1 serine protease. This strategy significantly decreased mRNA and protein expression of type I collagen and HtrA1, and led to an improvement in the chondrocyte phenotype index of differentiation. The effectiveness of our in vitro culture process was also demonstrated in the nude mouse model in vivo after subcutaneous implantation. We, thus, provide here a new protocol able to favor human hyaline chondrocyte phenotype in primarily dedifferentiated cells, both in vitro and in vivo. Our study also offers an innovative strategy for chondrocyte redifferentiation and opens new opportunities for developing therapeutic targets. PMID- 24957639 TI - Construction of a genome-scale kinetic model of mycobacterium tuberculosis using generic rate equations. AB - The study of biological systems at the genome scale helps us understand fundamental biological processes that govern the activity of living organisms and regulate their interactions with the environment. Genome-scale metabolic models are usually analysed using constraint-based methods, since detailed rate equations and kinetic parameters are often missing. However, constraint-based analysis is limited in capturing the dynamics of cellular processes. In this paper, we present an approach to build a genome-scale kinetic model of Mycobacterium tuberculosis metabolism using generic rate equations. M. tuberculosis causes tuberculosis which remains one of the largest killer infectious diseases. Using a genetic algorithm, we estimated kinetic parameters for a genome-scale metabolic model of M. tuberculosis based on flux distributions derived from Flux Balance Analysis. Our results show that an excellent agreement with flux values is obtained under several growth conditions, although kinetic parameters may vary in different conditions. Parameter variability analysis indicates that a high degree of redundancy remains present in model parameters, which suggests that the integration of other types of high-throughput datasets will enable the development of better constrained models accounting for a variety of in vivo phenotypes. PMID- 24957640 TI - An UPLC-ESI-MS/MS Assay Using 6-Aminoquinolyl-N-Hydroxysuccinimidyl Carbamate Derivatization for Targeted Amino Acid Analysis: Application to Screening of Arabidopsis thaliana Mutants. AB - In spite of the large arsenal of methodologies developed for amino acid assessment in complex matrices, their implementation in metabolomics studies involving wide-ranging mutant screening is hampered by their lack of high throughput, sensitivity, reproducibility, and/or wide dynamic range. In response to the challenge of developing amino acid analysis methods that satisfy the criteria required for metabolomic studies, improved reverse-phase high performance liquid chromatography-mass spectrometry (RPHPLC-MS) methods have been recently reported for large-scale screening of metabolic phenotypes. However, these methods focus on the direct analysis of underivatized amino acids and, therefore, problems associated with insufficient retention and resolution are observed due to the hydrophilic nature of amino acids. It is well known that derivatization methods render amino acids more amenable for reverse phase chromatographic analysis by introducing highly-hydrophobic tags in their carboxylic acid or amino functional group. Therefore, an analytical platform that combines the 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) pre-column derivatization method with ultra performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) is presented in this article. For numerous reasons typical amino acid derivatization methods would be inadequate for large scale metabolic projects. However, AQC derivatization is a simple, rapid and reproducible way of obtaining stable amino acid adducts amenable for UPLC-ESI-MS/MS and the applicability of the method for high throughput metabolomic analysis in Arabidopsis thaliana is demonstrated in this study. Overall, the major advantages offered by this amino acid analysis method include high-throughput, enhanced sensitivity and selectivity; characteristics that showcase its utility for the rapid screening of the preselected plant metabolites without compromising the quality of the metabolic data. The presented method enabled thirty-eight metabolites (proteinogenic amino acids and related compounds) to be analyzed within 10 min with detection limits down to 1.02 * 10 11 M (i.e., atomole level on column), which represents an improved sensitivity of 1 to 5 orders of magnitude compared to existing methods. Our UPLC-ESI-MS/MS method is one of the seven analytical platforms used by the Arabidopsis Metabolomics Consortium. The amino acid dataset obtained by analysis of Arabidopsis T-DNA mutant stocks with our platform is captured and open to the public in the web portal PlantMetabolomics.org. The analytical platform herein described could find important applications in other studies where the rapid, high-throughput and sensitive assessment of low abundance amino acids in complex biosamples is necessary. PMID- 24957642 TI - Development of Metabolic Indicators of Burn Injury: Very Low Density Lipoprotein (VLDL) and Acetoacetate Are Highly Correlated to Severity of Burn Injury in Rats. AB - Hypermetabolism is a significant sequela to severe trauma such as burns, as well as critical illnesses such as cancer. It persists in parallel to, or beyond, the original pathology for many months as an often-fatal comorbidity. Currently, diagnosis is based solely on clinical observations of increased energy expenditure, severe muscle wasting and progressive organ dysfunction. In order to identify the minimum number of necessary variables, and to develop a rat model of burn injury-induced hypermetabolism, we utilized data mining approaches to identify the metabolic variables that strongly correlate to the severity of injury. A clustering-based algorithm was introduced into a regression model of the extent of burn injury. As a result, a neural network model which employs VLDL and acetoacetate levels was demonstrated to predict the extent of burn injury with 88% accuracy in the rat model. The physiological importance of the identified variables in the context of hypermetabolism, and necessary steps in extension of this preliminary model to a clinically utilizable index of severity of burn injury are outlined. PMID- 24957643 TI - 1H Nuclear Magnetic Resonance (NMR) Metabolomic Study of Chronic Organophosphate Exposure in Rats. AB - 1H NMR spectroscopy and chemometric analysis were used to characterize rat urine obtained after chronic exposure to either tributyl phosphate (TBP) or triphenyl phosphate (TPP). In this study, the daily dose exposure was 1.5 mg/kg body weight for TBP, or 2.0 mg/kg body weight for TPP, administered over a 15-week period. Orthogonal signal correction (OSC) -filtered partial least square discriminant analysis (OSC-PLSDA) was used to predict and classify exposure to these organophosphates. During the development of the model, the classification error was evaluated as a function of the number of latent variables. NMR spectral regions and corresponding metabolites important for determination of exposure type were identified using variable importance in projection (VIP) coefficients obtained from the OSC-PLSDA analysis. As expected, the model for classification of chronic (1.5-2.0 mg/kg body weight daily) TBP or TPP exposure was not as strong as the previously reported model developed for identifying acute (15-20 mg/kg body weight) exposure. The set of majorly impacted metabolites identified for chronic TBP or TPP exposure was slightly different than those metabolites previously identified for acute exposure. These metabolites were then mapped to different metabolite pathways and ranked, allowing the metabolic response to chronic organophosphate exposure to be addressed. PMID- 24957641 TI - Current understanding of the formation and adaptation of metabolic systems based on network theory. AB - Formation and adaptation of metabolic networks has been a long-standing question in biology. With recent developments in biotechnology and bioinformatics, the understanding of metabolism is progressively becoming clearer from a network perspective. This review introduces the comprehensive metabolic world that has been revealed by a wide range of data analyses and theoretical studies; in particular, it illustrates the role of evolutionary events, such as gene duplication and horizontal gene transfer, and environmental factors, such as nutrient availability and growth conditions, in evolution of the metabolic network. Furthermore, the mathematical models for the formation and adaptation of metabolic networks have also been described, according to the current understanding from a perspective of metabolic networks. These recent findings are helpful in not only understanding the formation of metabolic networks and their adaptation, but also metabolic engineering. PMID- 24957645 TI - Polyamines under Abiotic Stress: Metabolic Crossroads and Hormonal Crosstalks in Plants. AB - Polyamines are essential compounds for cell survival and have key roles in plant stress protection. Current evidence points to the occurrence of intricate cross talks between polyamines, stress hormones and other metabolic pathways required for their function. In this review we integrate the polyamine metabolic pathway in the context of its immediate metabolic network which is required to understand the multiple ways by which polyamines can maintain their homeostasis and participate in plant stress responses. PMID- 24957644 TI - Separation technique for the determination of highly polar metabolites in biological samples. AB - Metabolomics is a new approach that is based on the systematic study of the full complement of metabolites in a biological sample. Metabolomics has the potential to fundamentally change clinical chemistry and, by extension, the fields of nutrition, toxicology, and medicine. However, it can be difficult to separate highly polar compounds. Mass spectrometry (MS), in combination with capillary electrophoresis (CE), gas chromatography (GC), or high performance liquid chromatography (HPLC) is the key analytical technique on which emerging "omics" technologies, namely, proteomics, metabolomics, and lipidomics, are based. In this review, we introduce various methods for the separation of highly polar metabolites. PMID- 24957647 TI - Mathematical modeling of plant metabolism-from reconstruction to prediction. AB - Due to their sessile lifestyle, plants are exposed to a large set of environmental cues. In order to cope with changes in environmental conditions a multitude of complex strategies to regulate metabolism has evolved. The complexity is mainly attributed to interlaced regulatory circuits between genes, proteins and metabolites and a high degree of cellular compartmentalization. The genetic model plant Arabidopsis thaliana was intensely studied to characterize adaptive traits to a changing environment. The availability of genetically distinct natural populations has made it an attractive system to study plant environment interactions. The impact on metabolism caused by changing environmental conditions can be estimated by mathematical approaches and deepens the understanding of complex biological systems. In combination with experimental high-throughput technologies this provides a promising platform to develop in silico models which are not only able to reproduce but also to predict metabolic phenotypes and to allow for the interpretation of plant physiological mechanisms leading to successful adaptation to a changing environment. Here, we provide an overview of mathematical approaches to analyze plant metabolism, with experimental procedures being used to validate their output, and we discuss them in the context of establishing a comprehensive understanding of plant-environment interactions. PMID- 24957646 TI - Optimality principles in the regulation of metabolic networks. AB - One of the challenging tasks in systems biology is to understand how molecular networks give rise to emergent functionality and whether universal design principles apply to molecular networks. To achieve this, the biophysical, evolutionary and physiological constraints that act on those networks need to be identified in addition to the characterisation of the molecular components and interactions. Then, the cellular "task" of the network-its function-should be identified. A network contributes to organismal fitness through its function. The premise is that the same functions are often implemented in different organisms by the same type of network; hence, the concept of design principles. In biology, due to the strong forces of selective pressure and natural selection, network functions can often be understood as the outcome of fitness optimisation. The hypothesis of fitness optimisation to understand the design of a network has proven to be a powerful strategy. Here, we outline the use of several optimisation principles applied to biological networks, with an emphasis on metabolic regulatory networks. We discuss the different objective functions and constraints that are considered and the kind of understanding that they provide. PMID- 24957648 TI - Minimal cut sets and the use of failure modes in metabolic networks. AB - A minimal cut set is a minimal set of reactions whose inactivation would guarantee a failure in a certain network function or functions. Minimal cut sets (MCSs) were initially developed from the metabolic pathway analysis method (MPA) of elementary modes (EMs); they provide a way of identifying target genes for eliminating a certain objective function from a holistic perspective that takes into account the structure of the whole metabolic network. The concept of MCSs is fairly new and still being explored and developed; the initial concept has developed into a generalized form and its similarity to other network characterizations are discussed. MCSs can be used in conjunction with other constraints-based methods to get a better understanding of the capability of metabolic networks and the interrelationship between metabolites and enzymes/genes. The concept could play an important role in systems biology by contributing to fields such as metabolic and genetic engineering where it could assist in finding ways of producing industrially relevant compounds from renewable resources, not only for economical, but also for sustainability, reasons. PMID- 24957649 TI - Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans. AB - STX209 is an exploratory drug comprising the single, active R-enantiomer of baclofen which is in later stage clinical trials for the treatment of fragile x syndrome (FXS) and autism spectrum disorders (ASD). New clinical data in this article on the metabolism and pharmacokinetics of the R- and S-enantiomers of baclofen presents scientific evidence for stereoselective metabolism of only S baclofen to an abundant oxidative deamination metabolite that is sterically resolved as the S-enantiomeric configuration. This metabolite undergoes some further metabolism by glucuronide conjugation. Consequences of this metabolic difference are a lower Cmax and lower early plasma exposure of S-baclofen compared to R-baclofen and marginally lower urinary excretion of S-baclofen after racemic baclofen administration. These differences introduce compound-related exposure variances in humans in which subjects dosed with racemic baclofen are exposed to a prominent metabolite of baclofen whilst subjects dosed with STX209 are not. For potential clinical use, our findings suggest that STX209 has the advantage of being a biologically defined and active enantiomer. PMID- 24957651 TI - A topological characterization of medium-dependent essential metabolic reactions. AB - Metabolism has frequently been analyzed from a network perspective. A major question is how network properties correlate with biological features like growth rates, flux patterns and enzyme essentiality. Using methods from graph theory as well as established topological categories of metabolic systems, we analyze the essentiality of metabolic reactions depending on the growth medium and identify the topological footprint of these reactions. We find that the typical topological context of a medium-dependent essential reaction is systematically different from that of a globally essential reaction. In particular, we observe systematic differences in the distribution of medium-dependent essential reactions across three-node subgraphs (the network motif signature of medium dependent essential reactions) compared to globally essential or globally redundant reactions. In this way, we provide evidence that the analysis of metabolic systems on the few-node subgraph scale is meaningful for explaining dynamic patterns. This topological characterization of medium-dependent essentiality provides a better understanding of the interplay between reaction deletions and environmental conditions. PMID- 24957652 TI - Genomic and phylogenetic characterization of Shuni virus. AB - Shuni virus (SHUV), a member of the genus Orthobunyavirus, has in a recent study been associated with neurological disease in horses in South Africa. After its first isolation in 1966 from an asymptomatic bovine, very little attention was given to the genetic characterisation of SHUV. The association of SHUV with severe neurological disease in several horses in South Africa prompted us to determine the full genome sequence of a horse neurovirulent isolate to compare it to other members of the genus Orthobunyavirus, as well as the partially sequenced genome of the prototype SHUV strain. The availability of a full genome sequence will facilitate the development of a reverse genetics system to study SHUV molecular biology and pathogenesis. PMID- 24957650 TI - What mRNA Abundances Can Tell us about Metabolism. AB - Inferring decreased or increased metabolic functions from transcript profiles is at first sight a bold and speculative attempt because of the functional layers in between: proteins, enzymatic activities, and reaction fluxes. However, the growing interest in this field can easily be explained by two facts: the high quality of genome-scale metabolic network reconstructions and the highly developed technology to obtain genome-covering RNA profiles. Here, an overview of important algorithmic approaches is given by means of criteria by which published procedures can be classified. The frontiers of the methods are sketched and critical voices are being heard. Finally, an outlook for the prospects of the field is given. PMID- 24957653 TI - Efficacy of a high-growth reassortant H1N1 influenza virus vaccine against the classical swine H1N1 subtype influenza virus in mice and pigs. AB - Swine influenza (SI) is an acute, highly contagious respiratory disease caused by swine influenza A viruses (SwIVs), and it poses a potential global threat to human health. Classical H1N1 (cH1N1) SwIVs are still circulating and remain the predominant subtype in the swine population in China. In this study, a high growth reassortant virus (GD/PR8) harboring the hemagglutinin (HA) and neuraminidase (NA) genes from a novel cH1N1 isolate in China, A/Swine/Guangdong/1/2011 (GD/11) and six internal genes from the high-growth A/Puerto Rico/8/34(PR8) virus was generated by plasmid-based reverse genetics and tested as a candidate seed virus for the preparation of an inactivated vaccine. The protective efficacy of this vaccine was evaluated in mice and pigs challenged with GD/11 virus. Prime and boost inoculation of GD/PR8 vaccine yielded high titer serum hemagglutination inhibiting (HI) antibodies and IgG antibodies for GD/11 in both mice and pigs. Complete protection of mice and pigs against cH1N1 SIV challenge was observed, with significantly fewer lung lesions and reduced viral shedding in vaccine-inoculated animals compared with unvaccinated control animals. Our data demonstrated that the GD/PR8 may serve as the seed virus for a promising SwIVs vaccine to protect the swine population. PMID- 24957655 TI - beta cells keep bad epigenetic memories of palmitate. AB - Palmitic acid, or hexadecanoic acid, a 16-carbon saturated fatty acid (FA), accounts for approximately 38% of the total circulating FA in lean or obese humans. In an article published in BMC Medicine, Hall et al. report that cultured islets from healthy donors, when exposed to palmitate, undergo changes in CpG methylation that are associated with modifications of expression in 290 genes. Their results provide a first look at the mechanisms used by the endocrine pancreas of humans to keep a durable genomic imprint from their exposure to FA that can influence gene expression and possibly cell phenotype in the long term. It is likely that such studies will help understand the epigenetic response of beta cells to a disturbed metabolic environment, especially one created by obesity. PMID- 24957654 TI - Advances in the treatment of obstructive sleep apnea. AB - OPINION STATEMENT: This article focuses on the treatment of obstructive sleep apnea (OSA), using the most recent available data. The first choice of treatment for patients with moderate or severe obstructive sleep apnea is continuous positive airway pressure (CPAP), which was first described in 1981 (Sullivan et al. Lancet 1(8225):862-5, 1981) and works by splinting the airway open to facilitate proper airflow. For patients with mild OSA, other treatments may be considered including positional therapy, weight loss, or oral appliances. Oral appliances are continuing to become more mainstream, and may be a reasonable first-line treatment even for some patients with moderate OSA, such as those who cannot tolerate or do not want to use CPAP. Some evidence suggests that adherence to mandibular advancement devices (MADs), a type of oral appliance, may be superior to that of CPAP. Recent evidence has suggested that the MAD may be similar to CPAP in preventing cardiovascular mortality in OSA, though objective measurement of MAD adherence was not available in the study. Objective adherence monitors are now available for oral appliances and should prove valuable for clinicians. Pharmacotherapy has not been shown to be significantly effective in the treatment of OSA and should be considered as an adjunctive treatment class, though some emerging evidence may support pharmacotherapy for specific purposes, such as acetazolamide for high-altitude travelers and zonisamide for weight loss. Upper airway surgical intervention remains a second- or third-line treatment class for moderate to severe OSA, though multiple case series of maxillomandibular advancement (MMA) have shown considerable, statistically significant improvements in AHI. Weight loss should always be recommended for patients with OSA who are overweight or obese, as weight loss may result in improvement in OSA. Bariatric operations are effective for obesity and are reasonable considerations for obese patients, although a recent randomized controlled trial found that bariatric intervention failed to achieve superiority over conventional weight loss therapy in terms of apnea-hypopnea index (AHI) reduction. PMID- 24957658 TI - Land use effects on phosphorus sequestration in soil aggregates in western Iran. AB - Cultivating native lands may alter soil phosphorus (P) distribution and availability. The present study aimed to determine the distribution of P in soil aggregates for different long-term land management practices. The partitioned P in labile (L), Fe/Al-bound, Ca-bound, organic pools, and total P in four aggregate size fractions were determined for five land uses (forest, vineyard after 30 years, wetland, alfalfa, and wheat cultivated soil after 20 years). Both native land uses (forest and wetland) were distinguished by high and low amounts of large macro- and micro-aggregates, respectively, compared with disturbed soils (vineyard, alfalfa, and wheat soils). Labile P in large macro-aggregates were higher in native land use when compared with the other land uses, which led to increasing lability of P and accelerated water pollution. Soils under native conditions sequestered more Ca-bound P in large macro-aggregates than the soils in disturbed conditions. Conversion of native lands to agricultural land caused enhanced organic P storage in aggregates smaller than the 2 mm from 31.0 to 54.3%. Soils under forest had 30% total P more than the vineyard for the aggregates >2 mm after 30 years land use change. However, the amount of P in smaller (<2 mm) sized aggregates was increased by 29% for the vineyard when compared with the forest. The P storage as bound Ca particles for the large macro aggregates had negative correlation with the micro-aggregates. PMID- 24957656 TI - Enhanced adherence of methicillin-resistant Staphylococcus pseudintermedius sequence type 71 to canine and human corneocytes. AB - The recent worldwide spread of methicillin-resistant Staphylococcus pseudintermedius (MRSP) in dogs is a reason for concern due to the typical multidrug resistance patterns displayed by some MRSP lineages such as sequence type (ST) 71. The objective of this study was to compare the in vitro adherence properties between MRSP and methicillin-susceptible (MSSP) strains. Four MRSP, including a human and a canine strain belonging to ST71 and two canine non-ST71 strains, and three genetically unrelated MSSP were tested on corneocytes collected from five dogs and six humans. All strains were fully characterized with respect to genetic background and cell wall-anchored protein (CWAP) gene content. Seventy-seven strain-corneocyte combinations were tested using both exponential- and stationary-phase cultures. Negative binomial regression analysis of counts of bacterial cells adhering to corneocytes revealed that adherence was significantly influenced by host and strain genotype regardless of bacterial growth phase. The two MRSP ST71 strains showed greater adherence than MRSP non ST71 (p < 0.0001) and MSSP (p < 0.0001). This phenotypic trait was not associated to any specific CWAP gene. In general, S. pseudintermedius adherence to canine corneocytes was significantly higher compared to human corneocytes (p < 0.0001), but the MRSP ST71 strain of human origin adhered equally well to canine and human corneocytes, suggesting that MRSP ST71 may be able to adapt to human skin. The genetic basis of the enhanced in vitro adherence of ST71 needs to be elucidated as this phenotypic trait may be associated to the epidemiological success and zoonotic potential of this epidemic MRSP clone. PMID- 24957659 TI - Convulsions during cataract surgery under peribulbar anesthesia: a case report. AB - INTRODUCTION: Locoregional anesthesia techniques are increasingly used for cataract surgery. From these techniques, peribulbar anesthesia has been very successful over the retrobulbar anesthesia seen its effectiveness and safety. However, peribulbar anesthesia is not without risk. CASE PRESENTATION: A 70-year old African man was scheduled for cataract surgery and lens implant for his right eye. His medical history included hypertension, diabetes mellitus and gall bladder surgery. There were no personal or family antecedents of allergy, epilepsy or taking food or toxic drug. No abnormalities were detected in his preoperative evaluation. In the operating room, standard monitoring was installed and a peripheral venous catheter 18g was inserted. Peribulbar anesthesia was realized with two injections in primary gaze position. The anesthetic mixture contained lidocaine 2% and bupivacaine 0.5%. The needle used was 25GA, 19mm, 3/4 inch. The first injection was performed in his lower temporal peribulbar space with 5mL of mixture; the second injection was performed with 3mL of mixture in his upper nasal peribulbar space. These injections were performed after a negative aspiration test and followed by manual compression of his globe for 5 minutes. Five minutes after peribulbar anesthesia, his blood pressure increased to 209/115mmHg requiring three bolus of nicardipine (3.0mg) to reduce his blood pressure to 134/56mmHg. One minute after, he had generalized tonic-clonic seizures. Tracheal intubation was performed. His capillary blood glucose was 170mg/dL, axillary temperature was 36.5 degrees C, and his serum electrolytes were normal. He recovered spontaneous ventilation 1.5 hours later. A neurological examination noted no deficit. Extubation was performed 15 minutes later without incident. A brain computed tomography and electroencephalogram were unremarkable. He was discharged on the second day and operated on 1 month later under general anesthesia. CONCLUSIONS: Various serious complications can occur during locoregional anesthesia techniques in ophthalmic surgery. The mastering and perfecting of these techniques by practitioners and compliance with safety standards in anesthesia are the only way to guarantee the prevention of such complications. PMID- 24957660 TI - Hierarchical nested trial design (HNTD) for demonstrating treatment efficacy of new antibacterial drugs in patient populations with emerging bacterial resistance. AB - In the last decade or so, pharmaceutical drug development activities in the area of new antibacterial drugs for treating serious bacterial diseases have declined, and at the same time, there are worries that the increased prevalence of antibiotic-resistant bacterial infections, especially the increase in drug resistant Gram-negative infections, limits available treatment options . A recent CDC report, 'Antibiotic Resistance Threats in the United States', indicates that antimicrobial resistance is one of our most serious health threats. However, recently, new ideas have been proposed to change this situation. An idea proposed in this regard is to conduct randomized clinical trials in which some patients, on the basis of a diagnostic test, may show presence of bacterial pathogens that are resistant to the control treatment, whereas remaining patients would show pathogens that are susceptible to the control. The control treatment in such trials can be the standard of care or the best available therapy approved for the disease. Patients in the control arm with resistant pathogens can have the option for rescue therapies if their clinical signs and symptoms worsen. A statistical proposal for such patient populations is to use a hierarchical noninferiority superiority nested trial design that is informative and allows for treatment-to control comparisons for the two subpopulations without any statistical penalty. This design can achieve in the same trial dual objectives: (i) to show that the new drug is effective for patients with susceptible pathogens on the basis of a noninferiority test and (ii) to show that it is superior to the control in patients with resistant pathogens. This paper addresses statistical considerations and methods for achieving these two objectives for this design. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. PMID- 24957661 TI - Where did platelets go in 2012? A survey of platelet transfusion practice in the North of England. AB - OBJECTIVES: To record the fate of transfused platelet doses in the North of England, and thereby assist with demand-planning and help target teaching on appropriate use. BACKGROUND: Platelet use has risen recently to the extent that donation practice has changed to meet demand. Two national comparative audits have shown inappropriate use and the 2010 audit concluded that current U.K. guidelines for platelet usage should be completely implemented at a local level. It is necessary to know how platelets are used and by whom in order to facilitate guideline concordance. METHODS: All hospital trusts in the North East and Cumbria recorded data on all platelet doses transfused in two separate 4-week periods in 2012. Data were entered onto an electronic survey tool. RESULTS: One thousand and five hundred and seventy-four reports were received, documenting 1937 transfused doses--96% of total issues for the study periods. One thousand and forty-five platelet doses (54%) were given for haematological indications. The second commonest indication was cardiac surgery (201 doses, 10% of the total) followed by non-haematological oncology (127 doses, 6.5%), critical care (106 doses, 5%) and liver disease (50 doses, 2.5%). The commonest haematological indication was acute myeloid leukaemia, 310 doses, (16% of all platelet use), followed by stem cell transplantation, 271 doses (14%). Seventy-two percent of platelet doses were given prophylactically, the majority without any planned procedure. CONCLUSION: The commonest indication for platelet use, where reinforcement of guidelines will be productive, is prophylaxis in haematological disease. Use of platelets in cardiac surgery is also worthy of close scrutiny. PMID- 24957662 TI - Deletion of bone-marrow-derived receptor for AGEs (RAGE) improves renal function in an experimental mouse model of diabetes. AB - AIMS/HYPOTHESIS: The AGEs and the receptor for AGEs (RAGE) are known contributors to diabetic complications. RAGE also has a physiological role in innate and adaptive immunity and is expressed on immune cells. The aim of this study was to determine whether deletion of RAGE from bone-marrow-derived cells influences the pathogenesis of experimental diabetic nephropathy. METHODS: Groups (n = 8/group) of lethally irradiated 8 week old wild-type (WT) mice were reconstituted with bone marrow from WT (WT -> WT) or RAGE-deficient (RG) mice (RG -> WT). Diabetes was induced using multiple low doses of streptozotocin after 8 weeks of bone marrow reconstitution and mice were followed for a further 24 weeks. RESULTS: Compared with diabetic WT mice reconstituted with WT bone marrow, diabetic WT mice reconstituted with RG bone marrow had lower urinary albumin excretion and podocyte loss, more normal creatinine clearance and less tubulo-interstitial injury and fibrosis. However, glomerular collagen IV deposition, glomerulosclerosis and cortical levels of TGF-beta were not different among diabetic mouse groups. The renal tubulo-interstitium of diabetic RG -> WT mice also contained fewer infiltrating CD68(+) macrophages that were activated. Diabetic RG -> WT mice had lower renal cortical concentrations of CC chemokine ligand 2 (CCL2), macrophage inhibitory factor (MIF) and IL-6 than diabetic WT -> WT mice. Renal cortical RAGE ligands S100 calgranulin (S100A)8/9 and AGEs, but not high mobility box protein B-1 (HMGB-1) were also decreased in diabetic RG -> WT compared with diabetic WT -> WT mice. In vitro, bone-marrow-derived macrophages from WT but not RG mice stimulated collagen IV production in cultured proximal tubule cells. CONCLUSIONS/INTERPRETATION: These studies suggest that RAGE expression on haemopoietically derived immune cells contributes to the functional changes seen in diabetic nephropathy by promoting macrophage infiltration and renal tubulo-interstitial damage. PMID- 24957664 TI - Bending elastic properties of a block copolymer-rich lamellar phase doped by a surfactant: a neutron spin-echo study. AB - The influence of the short alkyl-chain ionic surfactant OTAB on the dynamic behavior of an inverse block copolymer-rich lamellar phase was investigated by neutron spin-echo spectroscopy (NSE). The observed intermediate scattering function can be described by a sum of two contributions. For high scattering vectors the model of Zilman-Granek plus a slow diffusional mode can be used to describe the experimental data and the bending elastic modulus kappa for a polymer-rich membrane is calculated. At low scattering vectors the relaxation curves are strongly influenced by de Gennes narrowing arising from the structure factor of the Lalpha phase. Hence, the computed relaxation rates in this q-range are inversely proportional to the static structure factor. The present study demonstrates the necessity to directly investigate the dynamic behavior of lamellar phases and that an analysis of the width of the Bragg peaks can be insufficient to derive information about the single membrane elasticity, especially when both kappa and B[combining macron] depend on the composition of the membrane. PMID- 24957663 TI - Maternal diabetes modulates kidney formation in murine progeny: the role of hedgehog interacting protein (HHIP). AB - AIMS/HYPOTHESIS: We hypothesised that maternal diabetes impairs kidney formation in offspring via augmented expression of hedgehog interacting protein (HHIP). Our gene-array results were performed in neonatal kidneys from our murine model of maternal diabetes and indicated that Hhip expression was significantly modulated by maternal diabetes. METHODS: We systematically examined the functional role of HHIP in kidney formation in our murine maternal diabetes model and elucidated the potential mechanisms related to dysnephrogenesis in vitro. RESULTS: The kidneys of the offspring of diabetic dams, compared with those of the offspring of control non-diabetic dams, showed retardation of development--small kidneys and less ureteric bud (UB) branching morphogenesis. Augmented HHIP expression was observed in the offspring of diabetic dams, initially localised to differentiated metanephric mesenchyme and UB epithelium and subsequently in maturing glomerular endothelial and tubulointerstitial cells. The heightened HHIP targeting TGF-beta1 signalling was associated with dysmorphogenesis. In vitro, HHIP overexpression decreased sonic hedgehog and paired box gene 2 proteins (SHH and PAX2, respectively) and increased transcriptional nuclear factor-kappa B (NFkappaB, p50/p65), phosphorylation of p53, and TGF-beta1 expression. In contrast, overexpression of PAX2 inhibited HHIP and NFkappaB and activated SHH, N-myc and p27(Kip1) expression. Moreover, high glucose stimulated HHIP expression, and then targeted TGF-beta1 signalling. Thus, PAX2, via a negative autocrine feedback mechanism, attenuated the stimulatory effect of high glucose on HHIP expression. CONCLUSIONS/INTERPRETATION: Maternal diabetes modulates kidney formation in young progeny mediated, at least in part, via augmented HHIP expression. PMID- 24957665 TI - HLA-G gene polymorphisms associated with susceptibility to rheumatoid arthritis disease and its severity in Brazilian patients. AB - We analyzed the possible association between human leukocyte antigen-G (HLA-G) genetic variants, supposed to regulate HLA-G expression, and the susceptibility to develop rheumatoid arthritis (RA) as well as its clinical manifestations. The 5'upstream regulatory region (5'URR) and 3'untranslated region (3'UTR) regions of the HLA-G gene were screened in 127 RA patients and 128 controls: 10 5'URR and 3 3'UTR HLA-G polymorphisms as well as two haplotypes were associated with risk for RA development, while a polymorphism in the 5'URR showed an association with the degree of disease activity. These findings, although the number of cases analyzed is limited and the P-values are modest, indicate a possible association between HLA-G gene polymorphisms and susceptibility to develop RA disease and its severity. PMID- 24957666 TI - Lipid nanotechnologies for structural studies of membrane-associated proteins. AB - We present a methodology of lipid nanotubes (LNT) and nanodisks technologies optimized in our laboratory for structural studies of membrane-associated proteins at close to physiological conditions. The application of these lipid nanotechnologies for structure determination by cryo-electron microscopy (cryo EM) is fundamental for understanding and modulating their function. The LNTs in our studies are single bilayer galactosylceramide based nanotubes of ~20 nm inner diameter and a few microns in length, that self-assemble in aqueous solutions. The lipid nanodisks (NDs) are self-assembled discoid lipid bilayers of ~10 nm diameter, which are stabilized in aqueous solutions by a belt of amphipathic helical scaffold proteins. By combining LNT and ND technologies, we can examine structurally how the membrane curvature and lipid composition modulates the function of the membrane-associated proteins. As proof of principle, we have engineered these lipid nanotechnologies to mimic the activated platelet's phosphtaidylserine rich membrane and have successfully assembled functional membrane-bound coagulation factor VIII in vitro for structure determination by cryo-EM. The macromolecular organization of the proteins bound to ND and LNT are further defined by fitting the known atomic structures within the calculated three-dimensional maps. The combination of LNT and ND technologies offers a means to control the design and assembly of a wide range of functional membrane associated proteins and complexes for structural studies by cryo-EM. The presented results confirm the suitability of the developed methodology for studying the functional structure of membrane-associated proteins, such as the coagulation factors, at a close to physiological environment. PMID- 24957667 TI - Oncolytic immunotherapy using recombinant vaccinia virus GLV-1h68 kills sorafenib resistant hepatocellular carcinoma efficiently. AB - BACKGROUND: Sorafenib is the standard systemic therapy for unresectable or recurrent hepatocellular carcinoma (HCC) but adds minimal increase in survival. Therefore, there is a great need to develop novel therapies for advanced or recurrent HCC. One emerging field of cancer treatment involves oncolytic viruses that specifically infect, replicate within, and kill cancer cells. In this study, we examined the ability of GLV-1h68, a recombinant vaccinia virus derived from the vaccine strain that was used to eradicate smallpox, to kill sorafenib resistant (SR) HCC cell lines. METHODS: Four SR HCC cell lines were generated by repeated passage in the presence of sorafenib. Median inhibitory concentration was determined for all cell lines. The infectivity, viral replication, and cytotoxicity of GLV-1h68 were assayed for both parental and SR HCC cells. RESULTS: Infectivity increased in a time and concentration-dependent manner in all cell lines. All cell lines supported efficient replication of virus. No difference between the rates of cell death between the parental and SR cell lines was observed. CONCLUSION: Our results demonstrate that the oncolytic vaccinia virus GLV-1h68 kills both parental and SR HCC cell lines efficiently. This study indicates that patients who have failed treatment with sorafenib remain viable candidates for oncolytic therapy. PMID- 24957668 TI - Histone deacetylase inhibitor treatment attenuates coagulation imbalance in a lethal murine model of sepsis. AB - BACKGROUND: Sepsis has a profound impact on the inflammatory and hemostatic systems. In addition to systemic inflammation, it can produce disseminated intravascular coagulation, microvascular thrombosis, consumptive coagulopathy, and multiple organ failure. We have shown that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), improves survival in a lethal model of cecal ligation and puncture (CLP) in mice, but its effect on coagulation remains unknown. The goal of this study was to quantify the impact of SAHA treatment on coagulopathy in sepsis. METHODS: C57BL/6J mice were subjected to CLP, and 1 hour later given intraperitoneally either SAHA dissolved in dimethyl sulfoxide (DMSO) or DMSO only. Sham-operated animals were handled in similar manner without CLP. Blood samples were collected by cardiac puncture and evaluated using the TEG 5000 Thrombelastograph Hemostasis Analyzer System. RESULTS: Compared with the sham group, all animals in DMSO vehicle group died within 72 hours, and developed coagulopathy that manifested as prolonged initial fibrin formation and fibrin cross-linkage time, and decreased clot formation speed, platelet function, and clot rigidity. SAHA treatment significantly improved survival and was associated with improvement in fibrin cross-linkage and clot formation, as well as platelet function and clot rigidity, without a significant impact on the clot initiation parameters. CONCLUSION: SAHA treatment enhances survival and attenuates sepsis-associated coagulopathy by improving fibrin cross-linkage, rate of clot formation, platelet function, and clot strength. HDACI may represent a novel therapeutic strategy for correcting sepsis associated coagulopathy. PMID- 24957670 TI - Surgery for diverticulitis is associated with high risk of in-hospital mortality and morbidity in older patients with end-stage renal disease. AB - INTRODUCTION: End-stage renal disease (ESRD) is associated with poor medical outcomes. This study aimed to compare early outcomes of elective and emergency operation for diverticulitis among older adults with and without a diagnosis of ESRD. METHODS: Patients 65 years of age and older with a primary diagnosis of diverticulitis who underwent operative intervention were identified in the 100% Medicare Provider Analysis and Review (MEDPAR) inpatient file from 2004 to 2007. Outcomes between the ESRD and non-ESRD patients (elective and emergent) undergoing operation for diverticulitis were compared. A subgroup analysis in patients only undergoing elective or emergent operation was performed. Multivariable analyses were conducted. In addition, a propensity-matched analysis was applied comparing early outcomes between ESRD patients and well-matched controls consisting of non-ESRD patients. RESULTS: A total of 53,560 patients were identified, with 996 (1.86%) ESRD patients. After propensity matching, 962 ESRD and well-matched non-ESRD patients were identified. In the matched cohort, ESRD patients had greater rates of in-hospital mortality (30.9% vs 7.9%, P < .001), shock/sepsis, pulmonary compromise, wound infection, and acute myocardial infarction. An ostomy was placed more frequently in the ESRD patients (71.3% vs 58.7%, P < .001). Duration of stay and hospital charges also were greater in the ESRD group (18 vs 11 days, P < .001; $137,998.3 vs $67,502.2, P < .001). Similar results were seen when outcomes between matched elective ESRD and elective non ESRD patients were compared. There was no difference on in-hospital mortality on subgroup analyses between elective versus emergent surgery in the ESRD population (25.4% vs 31.1%, P = .133). On multivariable analysis, ESRD patients had greater odds of in-hospital mortality, and most individual complications when compared with the non-ESRD patients. In addition, the odds of in-hospital mortality and morbidity were greater in the elective ESRD group when compared with elective non ESRD group and also in the emergent ESRD group when compared with the emergent non-ESRD group. CONCLUSION: Given the high mortality and morbidity in both the emergent and elective setting that is associated with operative resection, we believe that, when possible, nonoperative management should be the preferred approach for acute diverticulitis in the setting of ESRD in patients older than 65 years. PMID- 24957669 TI - Estradiol treatment promotes cardiac stem cell (CSC)-derived growth factors, thus improving CSC-mediated cardioprotection after acute ischemia/reperfusion. AB - INTRODUCTION: Studies from our group and others have indicated that paracrine function is one of major mechanisms underlying stem cell-mediated cardioprotection. To improve therapeutic efficacy of cardiac stem cells (CSCs), modification of CSCs to enhance their paracrine actions is of great interest. We have shown previously that stem cells from female sex produced greater levels of protective growth factors compared with male stem cells. In addition, 17beta estradiol (E2)-treated mesenchymal stem cells provided better protection in the ischemia/reperfusion (I/R)-injured myocardium compared with untreated cells. In this study, therefore, we hypothesized that (1) treatment with E2 would improve CSC-mediated acute protection of cardiac function after global I/R; and (2) this greater protection in E2-treated CSCs would be attributable to the beneficial effect of E2 on paracrine actions of CSCs. METHOD: CSCs were harvested from C57BL mouse hearts. Myocardial I/R was performed in isolated mouse hearts via a Langendorff model. A total of 0.1 * 10(6)/mL of untreated CSCs or E2-treated CSCs was infused into mouse hearts before ischemia or during the initiation of reperfusion. Heart tissue was used for analysis of activation of caspase-3 and STAT3. Secretion of vascular endothelial growth factor and stromal cell-derived factor 1alpha by CSCs and E2-treated CSCs was determined. In addition, the conditioned medium from the cultivation of CSCs and E2-modified CSCs was used to treat cardiomyocytes during hypoxia. RESULTS: E2-treated CSCs produced greater levels of vascular endothelial growth factor and stromal cell-derived factor 1alpha compared with untreated CSCs. Preischemic infusion of CSCs and E2-treated CSCs improved myocardial function, increased activation of myocardial STAT3 (a prosurvival signaling), and reduced active caspase-3 after acute I/R compared with the vehicle group. The greater protection was observed in E2-treated CSC group than in CSC group. Additionally, infusion of E2-treated CSCs, but not untreated CSCs, during the initiation of reperfusion protected cardiac function after I/R, further indicating the beneficial effect of E2 on CSC protective function. CONCLUSION: Treatment with E2 enhanced CSC-derived protective factor production and improved CSC-mediated protection of cardiac function and myocyte survival after acute I/R, suggesting that in vitro modification of CSCs may improve their therapeutic outcome. PMID- 24957672 TI - 2014 Society of University Surgeons presidential address. PMID- 24957673 TI - Diarylrhodates as promising active catalysts for the arylation of vinyl ethers with Grignard reagents. AB - Anionic diarylrhodium complexes, generated by reacting [RhCl(cod)]2 with 2 equiv of aryl Grignard reagents, were found to be effective active catalysts in cross coupling reactions of vinyl ethers with aryl Grignard reagents, giving rise to the production of vinyl arenes. In this catalytic system, vinyl-O bonds were preferably cleaved over Ar-O or Ar-Br bonds. A lithium rhodate complex was isolated, and its crystal structure was determined by X-ray crystallography. PMID- 24957671 TI - Citrullinated histone H3: a novel target for the treatment of sepsis. AB - INTRODUCTION: We have recently demonstrated that in a rodent model of lipopolysaccharide (LPS)-induced shock, an increase in circulating citrullinated histone H3 (Cit H3) is associated with lethality of sepsis, and treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor (HDACI), significantly improves survival. However, the role of Cit H3 in pathogenesis and therapeutics of sepsis are largely unknown. The present study was designed to test whether treatment with HDACI could inhibit cellular Cit H3 production, and inhibition of peptidylarginine deiminase (PAD, an enzyme producing Cit H3) with Cl-amidine (PAD inhibitor) or neutralization of blood Cit H3 with anti-Cit H3 antibody could improve survival in a clinically relevant mouse model of cecal ligation and puncture (CLP)-induced septic shock. METHODS: Three experiments were carried out. In experiment I, HL-60 neutrophilic cells grown on a coverslip were treated with LPS (100 ng/mL) in the presence or absence of SAHA (5 MUmol) for 3 hours, and subjected to immunostaining with anti-Cit H3 antibody to assess effect of SAHA on Cit H3 production under a fluorescence microscope. The ratio of Cit H3 positive cells was calculated as mean values +/- SD (n = 3). In experiment II, male C57BL/6J mice were subjected to CLP, and 1 hour later randomly divided into 2 groups for intraperitoneal injection as follows: (1) Dimethyl sulfoxide (DMSO), (2) SAHA (50 mg/kg) in DMSO, and (3) Cl amidine (80 mg/kg) in DMSO (n = 10/group). In experiment III, male C57BL/6J mice were divided into control and treatment groups, and subjected to CLP. Two hours later, immunoglobulin (Ig)G and Cit H3 antibody (20 mg/kg IV; n = 5/group) were injected into the control and treatment groups, respectively. Survival was monitored for <=10 days. RESULTS: In experiment I, LPS induced Cit H3 production in the HL-60 cells, and SAHA treatment inhibited H3 citrullination significantly (P < .05). In experiment II, all vehicle-injected mice died within 3 days with increased circulating Cit H3 levels, whereas treatment with HDACI or Cl-amidine notably improved long-term survival (P < .01). In experiment III, administration of IgG did not improve survival, but a single treatment with Cit H3 specific antibody significantly improved survival (P < .014). CONCLUSION: Inhibition of HDAC or PAD significantly suppresses Cit H3 production in vitro and improves survival in vivo. Neutralization of Cit H3 significantly improves survival in septic mice. Collectively, our findings indicate for the first time that Cit H3 could not only serve as a potential biomarker, but also a novel therapeutic target in sepsis. PMID- 24957674 TI - Yeast X-chromosome-associated protein 5 (Xap5) functions with H2A.Z to suppress aberrant transcripts. AB - Chromatin regulatory proteins affect diverse developmental and environmental response pathways via their influence on nuclear processes such as the regulation of gene expression. Through a genome-wide genetic screen, we implicate a novel protein called X-chromosome-associated protein 5 (Xap5) in chromatin regulation. We show that Xap5 is a chromatin-associated protein acting in a similar manner as the histone variant H2A.Z to suppress expression of antisense and repeat element transcripts throughout the fission yeast genome. Xap5 is highly conserved across eukaryotes, and a plant homolog rescues xap5 mutant yeast. We propose that Xap5 likely functions as a chromatin regulator in diverse organisms. PMID- 24957676 TI - Too much job control? Two studies on curvilinear relations between job control and eldercare workers' well-being. AB - BACKGROUND: Longer life expectancy and changes in family patterns in Western societies have increased the need for professional caregivers to the elderly. A detailed understanding of job resources, especially of job control, may help preserve eldercare workers' work-related well-being. OBJECTIVES: The aim of the present study was to determine optimal levels of job control for eldercare workers' work-related well-being. DESIGN: Cross-sectional (Study 1) and longitudinal (Study 2) data were used to assess the linear and non-linear relations between job control and eldercare workers' work-related well-being. As indicators of well-being, irritation was examined cross-sectionally, whereas burnout and engagement were used in the longitudinal study. In both studies, demographic variables and time pressure were included as controls. In Study 2, results were additionally controlled for baseline levels of the outcome variables. PARTICIPANTS: Study participants were recruited from the nursing staff of 10 publicly financed nursing homes for the elderly (Study 1) and from 18 privately and 20 publicly financed nursing homes for the elderly (Study 2). In both studies, eldercare workers (i.e., registered nurses, orderlies, and nursing assistants) were invited to answer paper-pencil questionnaires. In Study 1, 606 persons followed this invitation (response rate: 65%). In Study 2, 591 persons provided data on both measurement points (response rate: 35% of Time 1 participants). The samples of both studies were predominantly female and between 20 and 65 years of age. METHODS: Hierarchical multiple regressions with linear and quadratic terms were conducted. RESULTS: Curvilinear effects of job control were found in both studies. In Study 1, low as well as high levels of job control were associated with higher levels of irritation compared to medium levels of job control. The longitudinal data from Study 2 supported these results. Eldercare workers with higher and lower levels of job control reported a higher tendency to depersonalize care recipients and a lower tendency to feel dedicated to, absorbed by and vigorous at work than those with medium levels of job control. CONCLUSIONS: Higher levels of job control are not necessarily advantageous for work-related well-being of eldercare workers. PMID- 24957675 TI - Promotion of waterpipe tobacco use, its variants and accessories in young adult newspapers: a content analysis of message portrayal. AB - The objective of our study was to identify waterpipe tobacco smoking advertisements and those that promoted a range of products and accessories used to smoke waterpipe tobacco. The content of these advertisements was analyzed to understand the messages portrayed about waterpipe tobacco smoking in young adult (aged 18-30) newspapers. The study methods include monitoring of six newspapers targeting young adults from four major cities in the Southeastern United States over a 6-month period. A total of 87 advertisements were found; 73.5% (64) were distinct and content analyzed. The study results showed that of the advertisements analyzed, 25% advertised waterpipe tobacco smoking, 54.7% featured waterpipe tobacco smoking and other tobacco use, 14.1% featured non-tobacco waterpipe variants (i.e. vaporizers), and 6.3% featured waterpipe apparatus accessories (e.g. charcoal, hoses). The sociability (34%) and sensuality (29.7%) of waterpipe smoking were promoted themes. Alternative to cigarette use messages (3.1%), and harm-reduction messages (17.1%) emphasized that smoking waterpipe tobacco using the featured accessory or waterpipe variant was a healthier experience than cigarette smoking. The study concluded that the messages that promoted waterpipe tobacco smoking to young adults are parallel to those used to promote cigarette use. Tobacco control professionals should continue to monitor young adult newspapers as a source of waterpipe-related advertising. PMID- 24957678 TI - Infliximab-associated autoimmune limbic encephalitis: a case report. PMID- 24957677 TI - Early stages of building a rare disease registry, methods and 2010 data from the Belgian Neuromuscular Disease Registry (BNMDR). AB - The Belgian Neuromuscular Disease Registry, commissioned in 2008, aims to collect data to improve knowledge on neuromuscular diseases and enhance quality health services for neuromuscular disease patients. This paper presents a clear outline of the strategy to launch a global national registry. All patients diagnosed with one of the predefined 62 neuromuscular disease groups and living in Belgium may be included in the yearly updated Registry. Basic core data is harvested through a newly designed web application by the six accredited neuromuscular reference centres. In 2010, 3,424 patients with a neuromuscular disorder were registered. The most prevalent disease group in the Registry is Hereditary Motor and Sensory Neuropathy, as similarly stated by other studies, albeit the prevalence in Belgium is five times lower: 6.5 per 100,000 in the north of Belgium, versus 17.0 41.0 per 100,000 in other areas of Europe. Very few patients were captured in the south of the country. With the aim to collect valuable epidemiological data, the registry targets to gather high quality data, that the sample to be representative of the population and that it be complete. The past 5 years of building the registry have improved its quality, albeit the consistent gap in data from the south of the country prevails, influencing the estimated prevalence of these diseases. To this day, the true burden of neuromuscular diseases in Belgium is not known but actions have been undertaken to address these issues. PMID- 24957679 TI - Blue shift of spontaneous emission in hyperbolic metamaterial. AB - Spontaneous emission is one of the most fundamental quantum phenomena in optics. Following the seminal work of Purcell and in agreement with the Fermi's Golden Rule, its rate can be controlled with the photonic density of states (PDOS). In recent years, this effect has been demonstrated in metamaterials with hyperbolic dispersion--highly anisotropic composite materials, which have a broad-band singularity of the density of photonic states. At this time, we show that hyperbolic metamaterials can control spontaneous emission spectra as well. Experimentally, DCM laser dye has been embedded into lamellar metal/dielectric metamaterial. The observed 18 nm blue shift of emission is explained by strong dispersion of the density of photonic states. On the other hand, practically no spectral shift has been observed in the excitation spectra of the same dye. This suggests that the effect of PDOS on spontaneous emission is very different from its effect on excitation and absorption. PMID- 24957680 TI - Post-extinction conditional stimulus valence predicts reinstatement fear: relevance for long-term outcomes of exposure therapy. AB - Exposure therapy for anxiety disorders is translated from fear conditioning and extinction. While exposure therapy is effective in treating anxiety, fear sometimes returns after exposure. One pathway for return of fear is reinstatement: unsignaled unconditional stimuli following completion of extinction. The present study investigated the extent to which valence of the conditional stimulus (CS+) after extinction predicts return of CS+ fear after reinstatement. Participants (N = 84) engaged in a differential fear conditioning paradigm and were randomised to reinstatement or non-reinstatement. We hypothesised that more negative post-extinction CS+ valence would predict higher CS+ fear after reinstatement relative to non-reinstatement and relative to extinction retest. Results supported the hypotheses and suggest that strategies designed to decrease negative valence of the CS+ may reduce the return of fear via reinstatement following exposure therapy. PMID- 24957681 TI - Spectrometric analysis and scanning electronic microscopy of two pleural plaques from mediaeval Portuguese period. AB - During an archaeological excavation at a mediaeval monastery (Flor da Rosa, Crato, Portugal), a skeleton of a adult woman was found with two calcifications in the thoracic cage. The location and the macroscopic analysis of the calcifications allowed them to be assigned as pleural plaques. Spectrometric analysis and scanning electronic microscopy enabled to establish that it originated with an infectious process. These results associated with the lesions found in the ribs and vertebrae strongly suggest tuberculosis as the cause of these pleural plaques. PMID- 24957682 TI - AKT inhibition synergistically enhances growth-inhibitory effects of gefitinib and increases apoptosis in non-small cell lung cancer cell lines. AB - OBJECTIVES: EGFR inhibitors are ineffective against most EGFR wild-type non-small cell lung cancer, for which novel treatment strategies are needed. AKT signalling is essential for mediating EGFR survival signals in NSCLC. We evaluated the combination of gefitinib and two different AKT inhibitors, the allosteric inhibitor AKTi-1/2 and the ATP-competitive pan-AKT inhibitor AZD5363, in EGFR mutant (HCC-827 and PC-9) and -wild-type (NCI-H522, NCI-H1651), non-small cell lung cancer cell lines. MATERIALS AND METHODS: Drug interaction was studied in two EGFR mutant and two EGFR wild-type non-small cell lung cancer cell lines by calculating combination index (CI) using median effect analysis. The effects on p EGFR, p-ERK, p-AKT, p-S6 and apoptosis were studied by Western blot analysis. RESULTS: The combination of gefitinib and AKTi-1/2 or AZD5363 showed synergistic growth inhibition in all cell lines. CI values for the combination of gefitinib and AKTi-1/2 were 0.35 (p=0.0048), 0.56 (p=0.036), 0.75 (p=0.13) and 0.64 (p=0.0003) in NCI-H522, NCI-H1651, HCC-827 and PC-9 cell lines, respectively; CI values of 0.45 (p=0.0087) and 0.22 (p<0.0001) were observed in NCI-H522 and PC-9 cells, respectively, when gefitinib was combined with AZD5363. Additive inhibition of signalling output through AKT and key downstream proteins (S6) and increased apoptosis were demonstrated. CONCLUSION: Dual inhibition of EGFR and AKT may be a useful up-front strategy for patients with EGFR-mutant and -wild type non-small cell lung cancer. PMID- 24957683 TI - A phase II trial of the Src-kinase inhibitor saracatinib after four cycles of chemotherapy for patients with extensive stage small cell lung cancer: NCCTG trial N-0621. AB - INTRODUCTION: To assess the efficacy and the Src-kinase inhibitor saracatinib (AZD-0530) after four cycles of platinum-based chemotherapy for extensive stage small cell lung cancer (SCLC). METHODS: Patients with at least stable disease received saracatinib at a dose of 175 mg/day by mouth until disease progression, unacceptable toxicity, or patient refusal. The primary endpoint was the 12-week progression-free survival (PFS) rate from initiation of saracatinib treatment. Planned interim analysis in first 20 patients, where 13 or more patients alive and progression-free at 12-weeks would allow continued enrollment to 40 total patients. RESULTS: All 23 evaluable patients received platinum based standard chemotherapy. Median age was 58 years (range: 48-82). 96% of patients had a performance status of 0/1. Median of two cycles given (range: 1-34). All 23 (100%) patients have ended treatment, most for disease progression (19/23). The 12-week PFS rate was 26% (6/23; 95% CI: 10-48%). From start of standard chemotherapy, median PFS was 4.7 months (95% CI: 4.5-5.1) and median OS was 11.2 months (95% CI: 9.9-13.8). Eight (35%) and three (13%) patients experienced at least one grade 3/4 or grade 4 AE, respectively. Commonly occurring grade 3/4 adverse events were thrombocytopenia (13%), fatigue (9%), nausea (9%), and vomiting (9%). CONCLUSIONS: Saracatinib at a dose of 175 mg/day by mouth is well tolerated. However, the PFS rate observed at the pre-planned interim analysis did not meet the criteria for additional enrollment. PMID- 24957685 TI - Magnetic resonance features of pyogenic brain abscesses and differential diagnosis using morphological and functional imaging studies: a pictorial essay. AB - The aim of this paper is to illustrate the potential of magnetic resonance imaging (MRI) in diagnosis, differential diagnosis, treatment planning and evaluation of therapy effectiveness of pyogenic brain abscesses, through the use of morphological (or conventional) and functional (or advanced) sequences. Conventional MRI study is useful for the identification of lesions, to determine the location and morphology and allows a correct hypothesis of nature in the most typical cases. However, the differential diagnosis from other brain lesions, such as non-pyogenic abscesses or necrotic tumors (high-grade gliomas and metastases) is often only possible through the use of functional sequences, as the measurement of diffusion with apparent diffusion coefficient (DWI-ADC), proton magnetic resonance spectroscopy ((1)H-MRS) and perfusion weighted imaging (PWI), which complement the morphological sequences and provide essential information on structural, metabolic and hemodynamic characteristics allowing greater neuroradiological confidence. Modern diagnostic MRI of pyogenic brain abscesses cannot be separated from knowledge, integration and proper use of the morphological and functional sequences. PMID- 24957686 TI - Pristimerin, a natural anti-tumor triterpenoid, inhibits LPS-induced TNF-alpha and IL-8 production through down-regulation of ROS-related classical NF-kappaB pathway in THP-1 cells. AB - Pristimerin, a naturally occurring quinonemethide triterpenoid compound, is known to exert a variety of pharmacological activities. In the present study, we investigated the molecular actions of pristimerin against LPS-induced inflammatory responses in human monocytic THP-1 cells. The results showed that pristimerin inhibited the production of TNF-alpha and IL-8 in a dose-dependent manner. To explore the possible mechanisms underlying these inhibitions by pristimerin, we examined the intracellular ROS level and the NF-kappaB protein signaling pathway. Pristimerin clearly scavenged LPS-induced intracellular ROS production. In addition, pristimerin prevented LPS-induced NF-kappaB activation through the inhibition of phosphorylation of IKKalpha/beta, phosphorylation and degradation of IkappaBalpha, as well as phosphorylation and nuclear translocation of NF-kappaB p65. These findings suggest that pristimerin down-regulates the expression of pro-inflammatory mediators through blocking of NF-kappaB activation by inhibiting interconnected ROS/IKK/NF-kappaB signaling pathways. PMID- 24957684 TI - Engineered single nucleotide polymorphisms in the mosquito MEK docking site alter Plasmodium berghei development in Anopheles gambiae. AB - BACKGROUND: Susceptibility to Plasmodium infection in Anopheles gambiae has been proposed to result from naturally occurring polymorphisms that alter the strength of endogenous innate defenses. Despite the fact that some of these mutations are known to introduce non-synonymous substitutions in coding sequences, these mutations have largely been used to rationalize knockdown of associated target proteins to query the effects on parasite development in the mosquito host. Here, we assay the effects of engineered mutations on an immune signaling protein target that is known to control parasite sporogonic development. By this proof-of principle work, we have established that naturally occurring mutations can be queried for their effects on mosquito protein function and on parasite development and that this important signaling pathway can be genetically manipulated to enhance mosquito resistance. METHODS: We introduced SNPs into the A. gambiae MAPK kinase MEK to alter key residues in the N-terminal docking site (D-site), thus interfering with its ability to interact with the downstream kinase target ERK. ERK phosphorylation levels in vitro and in vivo were evaluated to confirm the effects of MEK D-site mutations. In addition, overexpression of various MEK D-site alleles was used to assess P. berghei infection in A. gambiae. RESULTS: The MEK D-site contains conserved lysine residues predicted to mediate protein-protein interaction with ERK. As anticipated, each of the D-site mutations (K3M, K6M) suppressed ERK phosphorylation and this inhibition was significant when both mutations were present. Tissue-targeted overexpression of alleles encoding MEK D-site polymorphisms resulted in reduced ERK phosphorylation in the midgut of A. gambiae. Furthermore, as expected, inhibition of MEK-ERK signaling due to D-site mutations resulted in reduction in P. berghei development relative to infection in the presence of overexpressed catalytically active MEK. CONCLUSION: MEK-ERK signaling in A. gambiae, as in model organisms and humans, depends on the integrity of conserved key residues within the MEK D-site. Disruption of signal transmission via engineered SNPs provides a purposeful proof of-principle model for the study of naturally occurring mutations that may be associated with mosquito resistance to parasite infection as well as an alternative genetic basis for manipulation of this important immune signaling pathway. PMID- 24957687 TI - Allogeneic pluripotent stem cells suppress airway inflammation in murine model of acute asthma. AB - New strategies are needed to suppress airway inflammation and prevent or reverse airway remodeling in asthma. Reprogramming induced pluripotent stem cells (iPSCs) have the potential of embryonic stem cells (ESCs) and provide a resource for stem cell-based utility. The aim of this study was to evaluate the histopathological and immunomodulatory effects of ESCs and iPSCs for potential allogenic application in a murine model of acute asthma. BALB/c mice were sensitized with alum-absorbed ovalbumin (OVA) and then challenged with 1% aerosolized OVA. 5*10(5) ESCs and iPSCs were administrated intranasally on the last day of nebulization. Mice were sacrificed after 24 h, and serum allergen specific antibody level, airway remodeling, cytokine levels in lung supernatants, and eosinophilic infiltration in BAL fluid were examined. As a result, more ESCs and iPSCs integrated into the lungs of mice in OVA groups than those of the controls. Epithelial, smooth muscle and basal membrane thicknesses as well as goblet cell hyperplasia occurring in airway remodeling were significantly suppressed by pluripotent stem cells in both distal and proximal airways. Percentage of eosinophils decreased significantly in BAL fluid as well as serum allergen specific IgE and IL-4 levels in lung supernatants. On the contrary, regulatory cytokine - IL-10 level - was enhanced. Application of especially ESCs significantly increased the percentage of Treg subsets. Our comparative results showed that i.n. delivery of miRNA-based reprogrammed iPSCs is beneficial in attenuating airway inflammation in a murine model of acute asthma, and that cells also have similar immunomodulatory effects in mice. PMID- 24957689 TI - Promising future therapies for asthma. AB - Asthma affects 300 million people worldwide and that number has been increasing especially in developed countries. The current standard of care for asthma treatment is based on 2 key pathological features of asthma, airway inflammation and airway obstruction. Improving bronchodilation can be accomplished with ultra long acting beta2 agonists or long-acting muscarinic agonists used in combination with inhaled corticosteroids. These combinations have already been used effectively for the treatment of COPD. An inhaled phosphodiesterase inhibitor has been shown to improve bronchodilation and decrease airway inflammation. Directly altering the airway smooth muscle with bronchial thermoplasty in select patients has demonstrated long-term benefits but must be measured with immediate post procedure complications. The development of monoclonal antibodies to directly target specific cytokines has had mixed results. In eosinophilic asthma blocking IL-4, IL-5 and IL-13 have improved asthma outcomes. The promise of more directed therapy for asthma appears closer than ever with increased options available for the clinician in the near future. PMID- 24957688 TI - 14-3-3gamma protein attenuates lipopolysaccharide-induced cardiomyocytes injury through the Bcl-2 family/mitochondria pathway. AB - Previous studies have indicated that 14-3-3gamma is upregulated by stress in LPS induced cardiovascular injury. In this study, we investigated the interaction of 14-3-3gamma and Bcl-2 family members in the control of the mitochondrial permeability transition (MPT) to test the hypothesis that abundant levels of 14-3 3gamma can protect against LPS-induced injury via a Bcl-2 family/mitochondria pathway. The cardiomyocytes were treated with LPS (1mg l(-1)) for 6h; the interaction between 14-3-3gamma and phospho-Bad(S112) was detected by co immunoprecipitation (co-IP); the levels of Bcl-2 family members in the cytosolic and mitochondrial fractions were examined by Western blot; the apoptosis and mitochondrial membrane potential (DeltaPsim) were detected by flow cytometry; and the mitochondrial permeability transition pore (mPTP) opening was tested by mitochondrial swelling. Our results revealed that LPS treatment results in cardiomyocyte injury, and these effects were significantly attenuated by pFLAG-14 3-3gamma. Moreover, LPS treatment induced Bax translocation to the mitochondria, DeltaPsim loss, mitochondrial swelling, and cytochrome c release, and pFLAG-14-3 3gamma reversed these effects induced by LPS. Moreover, overexpressed 14-3-3gamma protein could assist Bad(S112) phosphorylation and interact with it to form a complex, which might result in the disassociation of Bcl-2 from the Bad/Bcl-2 complex and its translocation from the cytosol to the mitochondria. Our data firstly confirmed that a high level of 14-3-3gamma protects against LPS-induced cardiomyocyte injury likely through a pathway associated with the regulation of the subcellular localizations of Bcl-2 and Bad that results in the prevention of mPTP opening, the maintenance of DeltaPsim, and ultimately the inhibition of apoptosis. PMID- 24957690 TI - Baccatin III, a precursor for the semisynthesis of paclitaxel, inhibits the accumulation and suppressive activity of myeloid-derived suppressor cells in tumor-bearing mice. AB - Myeloid-derived suppressor cells (MDSCs) mediate tumor-associated immune suppression in both cancer patients and tumor-bearing animals. Reduction or elimination of MDSCs reduces the rate of tumor progression and improves cancer therapies that employ mechanisms of immunity. Here we show that baccatin III, which is the precursor for the semisynthesis of paclitaxel, exerts anti-tumor immunomodulatory activity in very low doses (0.05-0.5mg/kg), although it is regarded as an inactive derivative of paclitaxel. Oral administration of baccatin III significantly reduced the growth of tumors induced by engrafting BALB/c mice with either 4 T1 mammary carcinoma or CT26 colon cancer cells. Baccatin III (0.5mg/kg) did not exert anti-tumor activity in athymic nude mice. Baccatin III decreased the accumulation of MDSCs in the spleens of the tumor-bearing mice. Furthermore, MDSCs isolated from baccatin III-treated mice, compared with those isolated from vehicle-treated mice, had a significantly reduced suppressive effect on T cells treated with the anti-CD3 and anti-CD28 monoclonal antibodies. Moreover, these cells produced significantly reduced amounts of reactive oxygen species and nitric oxide. These results suggest that baccatin III reduced tumor progression by inhibiting the accumulation and suppressive function of MDSCs. PMID- 24957691 TI - Increasing safe teenaged driving: time to integrate the growing evidence base. PMID- 24957693 TI - Family planning: choices and challenges for developing countries. AB - While slow and uneven progress has been made on maternal health, attaining the 1994 Cairo International Conference on Population and Development (ICPD) goal for achieving universal access to reproductive health remains elusive for many developing countries. Assuring access to sexual and reproductive health services, including integrated family planning services, remains a critical strategy for improving the health and well-being of women and alleviating poverty. Family planning not only prevents maternal, infant, and child deaths, but also empowers women to engage fully in socioeconomic development and provides them with reproductive choices. This paper will discuss the current landscape of contraception in developing countries, including options available to women and couples, as well as the challenges to its provision. Finally, we review suggestions to improve access and promising strategies to ensure all people have universal access to reproductive health options. PMID- 24957694 TI - Analysis of entanglement measures and LOCC maximized quantum Fisher information of general two qubit systems. AB - Entanglement has been studied extensively for unveiling the mysteries of non classical correlations between quantum systems. In the bipartite case, there are well known measures for quantifying entanglement such as concurrence, relative entropy of entanglement (REE) and negativity, which cannot be increased via local operations. It was found that for sets of non-maximally entangled states of two qubits, comparing these entanglement measures may lead to different entanglement orderings of the states. On the other hand, although it is not an entanglement measure and not monotonic under local operations, due to its ability of detecting multipartite entanglement, quantum Fisher information (QFI) has recently received an intense attraction generally with entanglement in the focus. In this work, we revisit the state ordering problem of general two qubit states. Generating a thousand random quantum states and performing an optimization based on local general rotations of each qubit, we calculate the maximal QFI for each state. We analyze the maximized QFI in comparison with concurrence, REE and negativity and obtain new state orderings. We show that there are pairs of states having equal maximized QFI but different values for concurrence, REE and negativity and vice versa. PMID- 24957692 TI - The color of health: skin color, ethnoracial classification, and discrimination in the health of Latin Americans. AB - Latin America is one of the most ethnoracially heterogeneous regions of the world. Despite this, health disparities research in Latin America tends to focus on gender, class and regional health differences while downplaying ethnoracial differences. Few scholars have conducted studies of ethnoracial identification and health disparities in Latin America. Research that examines multiple measures of ethnoracial identification is rarer still. Official data on race/ethnicity in Latin America are based on self-identification which can differ from interviewer ascribed or phenotypic classification based on skin color. We use data from Brazil, Colombia, Mexico, and Peru to examine associations of interviewer ascribed skin color, interviewer-ascribed race/ethnicity, and self-reported race/ethnicity with self-rated health among Latin American adults (ages 18-65). We also examine associations of observer-ascribed skin color with three additional correlates of health - skin color discrimination, class discrimination, and socio-economic status. We find a significant gradient in self rated health by skin color. Those with darker skin colors report poorer health. Darker skin color influences self-rated health primarily by increasing exposure to class discrimination and low socio-economic status. PMID- 24957696 TI - pi-pi interaction of aromatic groups in amphiphilic molecules directing for single-crystalline mesostructured zeolite nanosheets. AB - One of the challenges in material science has been to prepare macro- or mesoporous zeolite. Although examples of their synthesis exist, there is a need for a facile yet versatile approach to such hierarchical structures. Here we report a concept for designing a single quaternary ammonium head amphiphilic template with strong ordered self-assembling ability through pi-pi stacking in hydrophobic side, which stabilizes the mesostructure to form single-crystalline mesostructured zeolite nanosheets. The concept is demonstrated for the formation of a new type of MFI (zeolite framework code by International Zeolite Association) nanosheets joined with a 90 degrees rotational boundary, which results in a mesoporous zeolite with highly specific surface area even after calcination. Low binding energies for this self-assembling system are supported by a theoretical analysis. A geometrical matching between the arrangement of aromatic groups and the zeolitic framework is speculated for the formation of single-crystalline MFI nanosheets. PMID- 24957697 TI - Serum AFBP levels are elevated in patients with nonalcoholic fatty liver disease. AB - OBJECTIVE: Adipocyte fatty acid-binding-protein (A-FABP), retinol-binding protein 4 (RBP4), and lipocalin-2 have been identified as adipokines that may link obesity, insulin resistance, and metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is regarded as a manifestation of metabolic syndrome. We evaluated the relationship of A-FABP, RBP4, and lipocalin-2 to variables related to metabolic syndrome and NAFLD. METHODS: A total of 140 subjects (72 males and 68 females) were included in this study. Subjects were divided into two groups (NAFLD, n = 73 and normal, n = 67) based on the detection of a fatty liver by ultrasonography. RESULTS: Serum A-FABP levels were higher in the NAFLD group than in the normal group (18.42 +/- 7.24 ng/mL vs. 15.74 +/- 7.02 ng/mL, p = 0.022). After adjusting for age and sex, we observed that body mass index (BMI), diastolic blood pressure, waist circumference, body fat percentage, triglycerides, and serum RBP4 levels were positively associated with serum A-FABP levels in all subjects. Multiple linear regression analysis revealed that systolic blood pressure, diastolic blood pressure, and serum RBP4 levels were independently associated with serum A-FABP levels. In logistic regression analysis, patients in the higher quartiles of A-FABP levels had higher odds ratios (OR) for the presence of NALFD than patients in the lower quartiles (OR: 3.56; 95% confident interval or CI: 1.25, 10.14). CONCLUSIONS: We observed higher serum A-FABP levels in the NAFLD group than in the normal group. However, serum RBP4 and lipocalin-2 levels appeared to have different relationships with several variables related to metabolic syndrome and NAFLD, which contradict results of previous studies. PMID- 24957698 TI - Cysteine-cystine redox cycling in a gold-gold dual-plate generator-collector microtrench sensor. AB - Thiols and disulfides are ubiquitous and important analytical targets. However, their redox properties, in particular on gold sensor electrodes, are complex and obscured by strong adsorption. Here, a gold-gold dual-plate microtrench dual electrode sensor with feedback signal amplification is demonstrated to give well defined (but kinetically limited) steady-state voltammetric current responses for the cysteine-cystine redox cycle in nondegassed aqueous buffer media at pH 7 down to micromolar concentration levels. PMID- 24957700 TI - The impact of microgravity-based proteomics research. AB - Proteomics is performed in microgravity research in order to determine protein alterations occurring qualitatively and quantitatively, when single cells or whole organisms are exposed to real or simulated microgravity. To this purpose, antibody-dependent (Western blotting, flow cytometry, Luminex((r)) technology) and antibody-independent (mass spectrometry, gene array) techniques are applied. The anticipated findings will help to understand microgravity-specific behavior, which has been observed in bacteria, as well as in plant, animal and human cells. To date, the analyses revealed that cell cultures are more sensitive to microgravity than cells embedded in organisms and that proteins changing under microgravity are highly interactive. Furthermore, one has to distinguish between primary gravity-induced and subsequent interaction-dependent changes of proteins, as well as between direct microgravity-related effects and indirect stress responses. Progress in this field will impact on tissue engineering and medicine and will uncover possibilities of counteracting alterations of protein expression at lowered gravity. PMID- 24957701 TI - The BdGAMYB protein from Brachypodium distachyon interacts with BdDOF24 and regulates transcription of the BdCathB gene upon seed germination. AB - MAIN CONCLUSION: BdDOF24 interacting with BdGAMYB regulates the BdCathB gene upon germination. During barley seed germination, hydrolytic enzymes (alpha-amylases, proteases, etc.) synthesized in the aleurone layer in response to gibberellins (GA), catalyse the mobilization of storage reserves accumulated in the endosperm during seed maturation. In Brachypodium distachyon, the BdCathB gene that encodes a Cathepsin B-like thiol-protease, orthologous to the wheat Al21 and barley HvCathB, is highly induced in germinating seeds and its expression is regulated by transcription factors (TFs) encoded by genes BdGamyb and BdDof24, orthologous to the barley HvGamyb and BPBF-HvDof24, respectively. Transcripts of both TF genes increase during germination and treatments with abscisic acid (ABA) or paclobutrazol (PAC, an inhibitor of GA biosynthesis) decrease mRNA expression of BdGamyb but do not affect that of BdDof24. Besides, proteins BdDOF24 and BdGAMYB interact in yeast-2 hybrid systems and in plant nuclei, and in transient expression assays in aleurone layers BdDOF24 is a transcriptional repressor and BdGAMYB is an activator of the BdCathB promoter, as occurs with the putative orthologous in barley BPBF-HvDOF24 and HvGAMYB. However, when both TFs are co bombarded, BdDOF24 enhances the activation driven by BdGAMYB while BPBF-HvDOF24 strongly decreases the HvGAMYB-mediated activation of the BdCathB promoter. The different results obtained when BdDOF24 and BPBF-HvDOF24 interact with BdGAMYB and HvGAMYB are discussed. PMID- 24957702 TI - Hydraulic adjustments in aspen (Populus tremuloides) seedlings following defoliation involve root and leaf aquaporins. AB - MAIN CONCLUSION: Changes in root and leaf hydraulic properties and stimulation of transpiration rates that were initially triggered by defoliation were accompanied by corresponding changes in leaf and root aquaporin expression. Aspen (Populus tremuloides) seedlings were subjected to defoliation treatments by removing 50, 75 % or all of the leaves. Root hydraulic conductivity (Lpr) was sharply reduced in plants defoliated for 1 day and 1 week. The decrease in L pr could not be prevented by stem girdling and it was accompanied in one-day-defoliated plants by a large decrease in the root expression of PIP1,2 aquaporin and an over twofold decrease in hydraulic conductivity of root cortical cells (L pc). Contrary to L pr and L pc, 50 and 75 % defoliation treatments profoundly increased leaf lamina conductance (K lam) after 1 day and this increase was similar in magnitude for both defoliation treatments. Transpiration rates (E) rapidly declined after the removal of 75 % of leaves. However, E increased by over twofold in defoliated plants after 1 day and the increases in E and K lam were accompanied by five- and tenfold increases in the leaf expression of PIP2;4 in 50 and 75 % defoliation treatments, respectively. Defoliation treatments also stimulated net photosynthesis after 1 day and 3 weeks, although the increase was not as high as E. Leaf water potentials remained relatively stable following defoliation with the exception of a small decrease 1 day after defoliation which suggests that root water transport did not initially keep pace with the increased transpirational water loss. The results demonstrate the importance of root and leaf hydraulic properties in plant responses to defoliation and point to the involvement of PIP aquaporins in the early events following the loss of leaves. PMID- 24957699 TI - Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease? AB - Adiponectin is the most abundant peptide secreted by adipocytes, being a key component in the interrelationship between adiposity, insulin resistance and inflammation. Central obesity accompanied by insulin resistance is a key factor in the development of metabolic syndrome (MS) and future macrovascular complications. Moreover, the remarkable correlation between coronary artery disease (CAD) and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes mellitus (T2DM) may share a common biological background. We summarize here the current knowledge about the influence of adiponectin on insulin sensitivity and endothelial function, discussing its forthcoming prospects and potential role as a therapeutic target for MS, T2DM, and cardiovascular disease. Adiponectin is present in the circulation as a dimer, trimer or protein complex of high molecular weight hexamers, >400 kDa. AdipoR1 and AdipoR2 are its major receptors in vivo mediating the metabolic actions. Adiponectin stimulates phosphorylation and AMP (adenosin mono phosphate) kinase activation, exerting direct effects on vascular endothelium, diminishing the inflammatory response to mechanical injury and enhancing endothelium protection in cases of apolipoprotein E deficiency. Hypoadiponectinemia is consistently associated with obesity, MS, atherosclerosis, CAD, T2DM. Lifestyle correction helps to favorably modify plasma adiponectin levels. Low adiponectinemia in obese patients is raised via continued weight loss programs in both diabetic and nondiabetic individuals and is also accompanied by reductions in pro-inflammatory factors. Diet modifications, like intake of fish, omega-3 supplementation, adherence to a Mediterranean dietary pattern and coffee consumption also increase adiponectin levels. Antidiabetic and cardiovascular pharmacological agents, like glitazones, glimepiride, angiotensin converting enzyme inhibitors and angiotensin receptor blockers are also able to improve adiponectin concentration. Fibric acid derivatives, like bezafibrate and fenofibrate, have been reported to enhance adiponectin levels as well. T cadherin, a membrane-associated adiponectin-binding protein lacking intracellular domain seems to be a main mediator of the antiatherogenic adiponectin actions. The finding of novel pharmacologic agents proficient to improve adiponectin plasma levels should be target of exhaustive research. Interesting future approaches could be the development of adiponectin-targeted drugs chemically designed to induce the activaton of its receptors and/or postreceptor signaling pathways, or the development of specific adiponectin agonists. PMID- 24957703 TI - Mean platelet volume: a predictor of mortality in diabetic and non-diabetic patients with STEMI? PMID- 24957704 TI - Effect of menopause on the modified Rodnan skin score in systemic sclerosis. AB - INTRODUCTION: We aimed to evaluate the effect of menopause on skin thickening, as measured by the modified Rodnan skin score (mRSS), in women with systemic sclerosis (SSc). METHODS: We identified women with either limited or diffuse SSc, aged >= 18 years, enrolled within the Canadian Scleroderma Research Group (CSRG) cohort, between 2004 and 2011. As part of the CSRG cohort, subjects undergo annual assessments with standardized questionnaires and physical examinations. We performed multivariate regression analyses using generalized estimating equation (GEE) to determine the effect of menopause on the mRSS, adjusting for relevant covariates including notably age, follow-up time, and disease duration. RESULTS: We identified 1070 women with SSc, contributing a total of 3546 observations over the study period. Of these women, at baseline, 65% had limited disease and 35% diffuse disease. In multivariate analyses, we observed a substantial effect of postmenopausal status on the mean mRSS in women with diffuse disease subtype [ 2.62 units, 95% confidence interval (CI) -4.44, -0.80] and significant interaction between menopausal status and disease subtype (2.04 units, 95% CI 0.20, 3.88). The effect of postmenopausal status on the mean mRSS was smaller in women with limited SSc (-0.58, 95% CI -1.50, 0.34). CONCLUSIONS: Our results suggest that menopause has a substantial effect on skin thickening in diffuse SSc, with postmenopausal status being associated with a lower mean mRSS compared to premenopausal status. PMID- 24957706 TI - Silencing of JMJD2B induces cell apoptosis via mitochondria-mediated and death receptor-mediated pathway activation in colorectal cancer. AB - OBJECTIVE: To investigate the molecular mechanism of colorectal cancer (CRC) cell apoptosis induced by the Jumonji domain containing 2B (JMJD2B) silencing. METHODS: Both HCT116 and LoVo CRC cell lines were used for analyses. Cell apoptosis after JMJD2B silencing was determined by flow cytometry. JC-1 fluorescence probe was applied to measure the mitochondrial outer membrane permeabilization by flow cytometry and fluorescence microscopy. Immunofluorescence was used to detect cytochrome C translocation from mitochondria to cytosol after JMJD2B silencing. The efficacy of JMJD2B silencing on the protein levels of Bcl-2 family, caspase proteins, CCAAT/enhancer binding protein homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) were detected by Western blot. RESULTS: JMJD2B silencing induced CRC cell apoptosis via a decrease of the anti-apoptotic gene Bcl-2 family expression, leading to the translocation of Bak and Bax proteins and the promotion of mitochondrial membrane disruption, resulting in the release of cytochrome C from mitochondria and subsequent caspase-9 and caspase-3 cleavage. It also increased the amount of cleaved caspase-8 involved in the death receptor-related apoptotic pathway. Bcl-2 homology 3 interacting-domain death agonist (Bid), a specific caspase-8 substrate involved in the Fas signaling pathway, subsequently induced cleavage via caspase 8 activation. However, levels of CHOP and GRP78 remained unchanged after JMJD2B silencing. CONCLUSIONS: JMJD2B silencing induced CRC cell apoptosis via both mitochondria-related and death receptor-related pathways. The cleavage of Bid activated by caspase-8 might serve as a crosstalk mediator between these two pathways in CRC. PMID- 24957705 TI - The CANadian Pediatric Weight management Registry (CANPWR): study protocol. AB - BACKGROUND: Over recent decades, the prevalence of pediatric obesity has increased markedly in developed and developing countries, and the impact of obesity on health throughout the lifespan has led to urgent calls for action. Family-based weight management interventions that emphasize healthy lifestyle changes can lead to modest improvements in weight status of children with obesity. However, these interventions are generally short in duration, reported in the context of randomized controlled trials and there are few reports of outcomes of these treatment approaches in the clinical setting. Answering these questions is critical for improving the care of children with obesity accessing outpatient health services for weight management. In response, the CANadian Pediatric Weight management Registry (CANPWR) was designed with the following three primary aims: 1. Document changes in anthropometric, lifestyle, behavioural, and obesity-related co-morbidities in children enrolled in Canadian pediatric weight management programs over a three-year period; 2. Characterize the individual-, family-, and program-level determinants of change in anthropometric and obesity-related co-morbidities; 3. Examine the individual-, family-, and program-level determinants of program attrition. METHODS/DESIGN: This prospective cohort, multi-centre study will include children (2-17 years old; body mass index >=85(th) percentile) enrolled in one of eight Canadian pediatric weight management centres. We will recruit 1,600 study participants over a three-year period. Data collection will occur at presentation and 6-, 12-, 24-, and 36-months follow-up. The primary study outcomes are BMI z-score and change in BMI z-score over time. Secondary outcomes include anthropometric (e.g., height, waist circumference,), cardiometabolic (e.g., blood pressure, lipid profile, glycemia), lifestyle (e.g., dietary intake, physical activity, sedentary activity), and psychosocial (e.g., health-related quality of life) variables. Potential determinants of change and program attrition will include individual-, family-, and program-level variables. DISCUSSION: This study will enable our interdisciplinary team of clinicians, researchers, and trainees to address foundational issues regarding the management of pediatric obesity in Canada. It will also serve as a harmonized, evidence-based registry and platform for conducting future intervention research, which will ultimately enhance the weight management care provided to children with obesity and their families. PMID- 24957707 TI - Widespread host-dependent hybrid unfitness in the pea aphid species complex. AB - Linking adaptive divergence to hybrid unfitness is necessary to understand the ecological factors contributing to reproductive isolation and speciation. To date, this link has been demonstrated in few model systems, most of which encompass ecotypes that occupy relatively early stages in the speciation process. Here we extend these studies by assessing how host-plant adaptation conditions hybrid fitness in the pea aphid, Acyrthosiphon pisum. We made crosses between and within five pea aphid biotypes adapted to different host plants and representing various stages of divergence within the complex. Performance of F1 hybrids and nonhybrids was assessed on a "universal" host that is favorable to all pea aphid biotypes in laboratory conditions. Although hybrids performed equally well as nonhybrids on the universal host, their performance was much lower than nonhybrids on the natural hosts of their parental populations. Hence, hybrids, rather than being intrinsically deficient, are maladapted to their parents' hosts. Interestingly, the impact of this maladaptation was stronger in certain hybrids from crosses involving the most divergent biotype, suggesting that host dependent postzygotic isolation has continued to evolve late in divergence. Even though host-independent deficiencies are not excluded, hybrid maladaptation to parental hosts supports the hypothesis of ecological speciation in this complex. PMID- 24957709 TI - Anatomic guidance for stereotactic microneurosurgery: a modern necessity and the example of Mavridis' area. PMID- 24957710 TI - Estimating cancer risk from dental cone-beam CT exposures based on skin dosimetry. AB - The aim of this study was to measure entrance skin doses on patients undergoing cone-beam computed tomography (CBCT) examinations, to establish conversion factors between skin and organ doses, and to estimate cancer risk from CBCT exposures. 266 patients (age 8-83) were included, involving three imaging centres. CBCT scans were acquired using the SCANORA 3D (Soredex, Tuusula, Finland) and NewTom 9000 (QR, Verona, Italy). Eight thermoluminescent dosimeters were attached to the patient's skin at standardized locations. Using previously published organ dose estimations on various CBCTs with an anthropomorphic phantom, correlation factors to convert skin dose to organ doses were calculated and applied to estimate patient organ doses. The BEIR VII age- and gender dependent dose-risk model was applied to estimate the lifetime attributable cancer risk. For the SCANORA 3D, average skin doses over the eight locations varied between 484 and 1788 uGy. For the NewTom 9000 the range was between 821 and 1686 uGy for Centre 1 and between 292 and 2325 uGy for Centre 2. Entrance skin dose measurements demonstrated the combined effect of exposure and patient factors on the dose. The lifetime attributable cancer risk, expressed as the probability to develop a radiation-induced cancer, varied between 2.7 per million (age >60) and 9.8 per million (age 8-11) with an average of 6.0 per million. On average, the risk for female patients was 40% higher. The estimated radiation risk was primarily influenced by the age at exposure and the gender, pointing out the continuing need for justification and optimization of CBCT exposures, with a specific focus on children. PMID- 24957708 TI - Constitutive IRF8 expression inhibits AML by activation of repressed immune response signaling. AB - Myeloid differentiation is blocked in acute myeloid leukemia (AML), but the molecular mechanisms are not well characterized. Meningioma 1 (MN1) is overexpressed in AML patients and confers resistance to all-trans retinoic acid induced differentiation. To understand the role of MN1 as a transcriptional regulator in myeloid differentiation, we fused transcriptional activation (VP16) or repression (M33) domains with MN1 and characterized these cells in vivo. Transcriptional activation of MN1 target genes induced myeloproliferative disease with long latency and differentiation potential to mature neutrophils. A large proportion of differentially expressed genes between leukemic MN1 and differentiation-permissive MN1VP16 cells belonged to the immune response pathway like interferon-response factor (Irf) 8 and Ccl9. As MN1 is a cofactor of MEIS1 and retinoic acid receptor alpha (RARA), we compared chromatin occupancy between these genes. Immune response genes that were upregulated in MN1VP16 cells were co targeted by MN1 and MEIS1, but not RARA, suggesting that myeloid differentiation is blocked through transcriptional repression of shared target genes of MN1 and MEIS1. Constitutive expression of Irf8 or its target gene Ccl9 identified these genes as potent inhibitors of murine and human leukemias in vivo. Our data show that MN1 prevents activation of the immune response pathway, and suggest restoration of IRF8 signaling as therapeutic target in AML. PMID- 24957711 TI - Sensorimotor tests, such as movement control and laterality judgment accuracy, in persons with recurrent neck pain and controls. A case-control study. AB - Assessing sensorimotor abilities, such as movement control, becomes increasingly important for the management of patients with neck pain because of the potential contribution to the development of chronic neck pain. Our aim was to evaluate whether sensorimotor tests could discriminate between persons with neck pain and persons without neck pain and to assess correlations among the assessments. A matched case-control study with 30 persons with recurrent neck pain and 30 controls was conducted. We tested two-point discrimination (TPD), joint position error (JPE), muscle activation with the craniocervical flexion test (CCFT), laterality judgment accuracy and movement control (MC). We administered the Fear Avoidance Beliefs Questionnaire (FABQ), the Neck Disability Index (NDI) and the painDetect questionnaire. According to the areas under the curve (AUC), tests for the JPE (0.69), CCFT (0.73), MC (0.83) and laterality judgment accuracy (0.68) were able to discriminate between persons with and without neck pain. Among the five tests, laterality judgment accuracy exhibited moderate to large correlations with the JPE and MC, and moderate correlations were observed between the TPD and CCFT (r between -0.4 and -0.5). We recommend the assessment of various aspects of sensorimotor ability and of central representation of the body schema, even in patients with mild neck pain. For clinical practice, we recommend the craniocervical flexion test, testing of laterality judgment accuracy and three movement control tests (cervico-thoracic extension, protraction-retraction of the head and quadruped cervical rotation). PMID- 24957713 TI - Characteristics and functions of human cytomegalovirus UL128 gene/protein. AB - Human cytomegalovirus (HCMV) ORF UL128 protein is highly conserved among viral field isolates and functions in two different molecular forms, monomeric UL128 protein and in a complex with glycoproteins gH, gL, UL130, and UL131A protein. Monomeric UL128 protein works as soluble chemokine analogue to attract peripheral blood mononuclear cells (PBMCs) and selectively induces expression of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in PBMCs. The gH/gL/UL128/UL130/UL131A complex is indispensable for entry into both endothelial and epithelial cells. In conclusion, UL128 plays an important role in HCMV infection. PMID- 24957712 TI - The clinical significance of immediate symptom responses to manual therapy treatment for neck pain: observational secondary data analysis of a randomized trial. AB - The objective was to explore aspects of symptom responses to manual therapy treatment for neck pain. An observational secondary data analysis of a randomized trial was conducted. 181 participants seeking care from a physiotherapist or chiropractor for a new episode of neck pain were included. Outcome variables included recovery-time and participant-perceived effect of treatment (GPE) at 3 months. There was a significant reduction of >=1.4 points (95%CI 1.2-1.5) in pre- and post-treatment pain scores at each occasion of treatment. There was also small but significant increases in pain of <=0.7 points (95%CI 0.4-1.0) between each treatment session, without regression to the preceding pre-treatment level. The relationships between immediate post-treatment effects and longer-term outcomes were explored using multivariate regression analyses. There was significant univariate association between recovery time and cumulative post treatment changes in pain from the second, third and fourth (Exp(B) = 1.2) treatment sessions, as well as the presence of post-treatment headache (Exp(B) = 0.7) and other minor adverse symptoms (Exp(B) = 0.6). There was significant univariate association between GPE at 3-months and cumulative pain responses from first (B = 0.2), second (B = 0.3), third (B = 0.3) and fourth (B = 0.4) treatment sessions. The change in pain after session 1 was independently associated with GPE (B = 0.2). There was a consistently significant difference of >=0.7 points (95%CI 0.43-0.89) in the different methods of reporting pain. Our results showed that manual therapy for neck pain involves a "two-steps forward, one-step back" recovery pattern. Whilst minor adverse events are undesirable, they do not seem to be significantly associated with long-term recovery. PMID- 24957715 TI - Peripheral blood mononuclear cells from field cattle immune to bovine viral diarrhea virus (BVDV) are permissive in vitro to BVDV. AB - The aim of this study was to determine the in vitro permissivity of peripheral blood mononuclear cells (PBMCs) from bovine viral diarrhea virus (BVDV)-immune field cattle to homologous and heterologous BVDVs. PBMCs from seventeen BVDV naive and sixteen BVDV-immune animals were infected with noncytopathic BVDV-1 or BVDV-2. The immune status of cattle was indicated by the presence of virus neutralizing antibodies, while viral load of PBMCs was determined by real-time RT PCR. The results revealed that the PBMCs from naive or immune animals were permissive to either BVDV-1 or BVDV-2, but the viral load was significantly higher for the naive than for the immune animals. Furthermore, the load of homologous virus in PBMCs from immune animals was lower than that of heterologous virus. Our results provide evidence that the PBMCs from BVDV-immune cattle in field are susceptible to reinfection with homologous or heterologous BVDV, albeit to a lower extent in the former case. PMID- 24957714 TI - Use of IgY antibody to recombinant avian reovirus sigmaC protein in the virus diagnostics. AB - Avian reovirus (ARV) is an important agent of several diseases causing considerable losses in poultry farming. An outer capsid protein (sigmaC) of ARV, is known as a virus-cell attachment protein essential for virus infectivity. In this study, the sigmaC gene of ARV was cloned and expressed in Escherichia coli. The expressed recombinant protein was used as immunogen for raising a specific IgY antibody in laying hens. At 14 weeks post immunization, the antibody titers in serum and egg yolk reached 302,000 and 355,000, respectively. The IgY antibody was capable to neutralize ARV in BHK-21 cells and it strongly reacted in ELISA with ARV but not with heterologous viruses. The IgY antibody detected ARV in field samples of infected animal tissues in dot blot assay. These results suggest that an efficient, economic and rapid diagnostics of ARV can be performed routinely using the IgY antibody against a recombinant ARV sigmaC protein. PMID- 24957716 TI - Alterations in microRNA expression profile in rabies virus-infected mouse neurons. AB - Rabies virus (RABV) is known to cause a fatal infection in many mammalian species, yet its pathogenesis remains poorly understood. This study was performed to analyze the microRNA (miRNA) expression profiles in RABV-infected primary neurons of mice. A total of 53 miRNAs were found to be differentially expressed in RABV-infected samples compared with mock samples in a time-dependent manner. Among them, the expression of ten miRNAs was validated by real-time RT-PCR. Potential target genes of differentially expressed miRNAs were predicted by TargetScan. Further bioinformatics analysis indicated that these predicted targets were overrepresented in neuronal function-related Gene Ontology (GO) terms and biological pathways. The results of this study suggest that RABV may cause neuronal dysfunction by regulating cellular miRNA expression. PMID- 24957717 TI - Genetic diversity, host range, and distribution of tomato yellow leaf curl virus in Iran. AB - Tomato yellow leaf curl virus (TYLCV) is considered one of the most important tomato pathogens in tropical and subtropical regions including Iran. During the years 2007 to 2009, a total number of 510 symptomatic and asymptomatic vegetable, ornamental and weed samples were collected from fields and greenhouses in ten provinces of Iran. Symptoms included stunting, yellowing, leaf curl and flower senescence. PCR with specific primers showed TYLCV infection in 184 samples (36%) such as cucumber, pepper, tomato and several weeds from seven provinces. Based on the geographical origin, host range and symptoms, twenty three representative isolates were selected for phylogenetic analysis. An amplicon with a size about 608 base pair (bp) comprising partial sequence of the coat (CP) and movement protein (MP) coding regions of the viral genome was sequenced and compared with the corresponding selected sequences available in GenBank for Iran and worldwide. Phylogenetic analyses on the basis of the nucleotide sequences indicated two geographically separated clades. Isolates collected from Hormozgan, Khuzestan and Kerman provinces were grouped together with other Iranian isolates including TYLCV-Ir2, TYLCV-Kahnooj, and an isolate from Oman. It was also revealed that isolates collected from Boushehr, Fars, Tehran, and Isfahan placed close to the Iranian isolate TYLCV-Abadeh and isolates from Israel and Egypt. No correlation was found between the genetic variation and the host species, but selected Iranian isolates were grouped on the basis of the geographical origins. Results of this study indicated a high genetic diversity among Iranian TYLCV isolates. PMID- 24957718 TI - Detection and molecular characterization of Egyptian isolates of grapevine viruses. AB - Selected commercial and/or local vineyards and nurseries in three different governorates of Egypt (Alexandria, El-Beheira and El-Menofia) were surveyed for symptoms indicative of infection by grapevine viruses. Leaf samples from red fruited and white-fruited Vitis vinefera were tested for grapevine leafroll associated viruses (GLRaV-1, GLRaV-2, and GLRaV-3), grapevine viruses A and B (GVA, GVB), grapevine rupestris stem pitting virus (GRSPaV), grapevine fanleaf virus (GFLV), and grapevine fleck virus (GFKV) from early April to late October 2010. Incidence of these viruses was assessed by RT-PCR in 60 different samples. Selected amplicons were sequenced. While GVA was the most wide spread (30%), GLRaV-1, GVB, GFLV, and GFKV were not detected during the survey. However, GVA, GLRaV-2, GLRaV-3, and GRSPaV were detected in the form of single infection or in mixed infections of 2 to 4 viruses. Phylogenetic analysis was performed on all Egyptian isolates of GLRaV-2 (4), GLRaV-3 (7), GVA (3), and GRSPaV (6). GRSPaV was detected for the first time in Egypt. Phylogenetic analysis provided insights into the evolutionary relationship between the reported Egyptian isolates and other previously reported isolates. PMID- 24957719 TI - Nucleic acid testing of hepatitis B virus, hepatitis C virus, and human immunodeficiency virus 1, 2 in blood donors in the General University Hospital, Prague. AB - The Roche Cobas TaqScreen MPX Test v1 - multiplex reverse transcription-real time (MPX RT-Real Time) PCR, performed on Cobas s201 for HCV RNA, HBV DNA, HIV-1 RNA /group M and O/, and HIV-2 RNA was introduced as a supplement to the currently used imunoanalysis method for blood donor's testing (Abbott CMIA - chemiluminescent microparticle imunoassay, performed on Architect i2000 for anti HCV, hepatitis B surface antigen (HBsAg)), anti-HIV-1 /group M and O/, anti-HIV-2 and p24 HIV). The results of study could provide valuable arguments to support the discussion about the NAT implementation into the standards of blood donor's testing in the Czech Republic. Two groups of samples were tested. In the first one, 5074 samples from consecutive blood donors, and in the second one, 5 repository preseroconverted samples from repeat blood donors, who were subsequently confirmed positive for Viral Hepatitis and/or HIV/AIDS by the National Reference Laboratory (NRL), were tested. One sample was found reactive by chemiluminescent microparticle immuno assay (CMIA) and nucleic acid test (NAT) (confirmed HBV-positive in NRL), 31 samples were CMIA-only reactive (15 anti-HCV, 4 HBsAg, 12 anti-HIV/p24, all confirmed negative in NRL) and one pool (6 samples) was found reactive (further individual NAT was negative for all samples) in the first group of samples. One sample was NAT-only reactive (confirmed HCV-positive in NRL) in the second group of samples. Our study confirmed that screening of infectious markers using NAT can reduce the risk of transmitting the monitored infections by blood transfusion in the Czech Republic, even as a country with currently good epidemiological situation. PMID- 24957720 TI - Immunodetection and N-terminal sequencing of DNA replication proteins of bacteriophage BFK20 - lytic phage of Brevibacterium flavum. AB - Phages are excellent models for studying the mechanism of DNA replication in prokaryotes. Identification of phage proteins involved in phage DNA replication is the first prerequisite for elucidation of the phage replication module. We focused on replication proteins gp41 (a putative helicase from SF2 superfamily), gp43 (a RepA-like protein), and gp44 (a putative DNA polymerase A) of phage BFK20 grown in Brevibacterium flavum. To identify them in the phage-host system, we prepared antibodies to these proteins which were cloned and expressed in Escherichia coli as his-tagged recombinant proteins. After purification to homogeneity the recombinant proteins served for raising specific polyclonal antibodies in mice. Using these antibodies in Western blot analysis the phage proteins gp41, gp43 and gp44 were detected during the phage growth cycle. The proteins gp41 and gp43, prepared from cell lysate by ammonium sulphate precipitation, were N-terminally sequenced and found to contain the sequences N SVKPRELR-C and N-MLGSTML-C, respectively. This means that gp41 starts with serine but not with common methionine. We consider these findings an initial but important step towards more thorough characterization of replication proteins of phage BFK20. PMID- 24957721 TI - Differential identification of three species of Curtovirus using loop-mediated isothermal amplification. AB - Rapid and sensitive detection methods for three species of Curtovirus were developed using a loop-mediated isothermal amplification (LAMP) technique. A universal primer set for detecting the three main species of Curtovirus at the same time, and three kinds of species-specific primer sets were designed and used for LAMP reactions. Results from the LAMP reactions were visualized both by color changes after adding SYBR Green I staining dye and by DNA laddering on agarose gel electrophoresis. The optimal conditions for the curtovirus LAMP reaction were confirmed at 60 degrees C for the universal primers and at 62 degrees C for the three species-specific primer sets. Amplification of curtoviruses by LAMP reaction was ten-fold more sensitive than that by polymerase chain reaction. Primers designed for curtovirus detection in this study did not anneal to or amplify DNA from other DNA or RNA viruses (tomato yellow leaf curl virus, tomato spotted wilt virus, and potato virus Y). Taken together, the primer sets and reaction conditions developed in this study show that the LAMP technique could be a useful tool to detect the three species of Curtovirus simultaneously and distinguish them in the laboratory and the field. PMID- 24957722 TI - Development of polyclonal antibodies against nucleocapsid protein of watermelon silver mottle virus and their application to diagnostic. AB - Watermelon silver mottle virus (WSMoV) is an emerging disease of cucurbit crops in South China. Production of high-quality antibodies is necessary for the development of serological methods for detection of this virus. The nucleocapsid protein (NP) gene of WSMoV was amplified from WSMoV-infected watermelon leaves by RT-PCR and cloned into vector pET-28a (+) for prokaryotic expression. After identification via enzyme digestion and sequencing, the recombinant clone was transformed into Escherichia coli Rosetta (DE3) for protein expression. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) results showed that the molecular weight of the WSMoV NP fusion protein was 34.1 kDa. The fusion protein was purified and used as antigen for the preparation of polyclonal antisera in rabbits. Results of indirect ELISA and western blot analysis showed that the antisera reacted specifically with WSMoV NP. In addition, sensitivity and specificity of the antisera were examined on a number of infected field samples by indirect ELISA. These findings will facilitate further immunological and serological studies of WSMoV. . PMID- 24957723 TI - A Semliki Forest virus expression system as a model for investigating the nuclear import and export of hepatitis B virus nucleocapsid protein. AB - HBV core protein (HBc), the major component of nucleocapsid is known to have an essential role in the virus life cycle as the transporter of virus genome to the host nucleus; however, molecular details of the intracellular transport of HBc remain unknown. In this study, we investigated the intracellular distribution of the HBc protein resulting from Semliki Forest virus (SFV)-driven HBc gene and HBV RNA pregenome (pgRNA) expression in BHK-21 cells. Fluorescent confocal microscopy revealed extensive HBc protein synthesis in the cytoplasm 12 hr post infection (p.i.) with recombinant pSFV1/HBc or pSFV1/HBVpgRNA viruses. Twenty-four hr p.i., the HBc protein showed asymmetric, predominantly nuclear localization in most cells. However, 42 hr p.i., the number of cells containing intranuclear HBc protein, dramatically decreased to ~ 5%, while cytoplasmic HBc protein was detected in all cells. Remarkably, 24 hr p.i. with pSFV1/HBVpgRNA virus, cytoplasmic HBc protein colocalized with HBs protein. We conclude that a HBs-HBc interaction partially prevents the transport of HBc from the cytoplasm to nucleus. The SFV-driven system can be used for identification of new factors involved in the HBV nuclear import and export. PMID- 24957724 TI - Detection and sequence analysis of grapevine virus B isolates from China. AB - The presence of grapevine virus B (GVB) was detected in 188 grapevine samples from China by double antibody sandwich ELISA (DAS-ELISA) and reverse transcription-PCR (RT-PCR). The accuracy of detection by RT-PCR was confirmed by sequencing amplified PCR fragments. Seventeen samples were GVB-positive by DAS ELISA and five by RT-PCR. The isolate QMW proved to be positive by RT-PCR only, and four isolates (DGWH, DGW, QM, and JFL) could be detected by both methods. Among the five GVB-positive samples detected by RT-PCR, two isolates were originally collected from Henan province and three from Liaoning province. The expected 722 bp DNA fragment, covering partial ORF3 through partial ORF5, was amplified from the five GVB infected samples. Sequence analysis revealed that the molecular variants? composition of GVB in the different isolates was complex. Clones of DGWH, DGW, QM, and JFL isolate shared high nucleotide identities, while the identities among the clones of isolate QMW varied. The variants of GVB isolates obtained in this study showed nucleotide identities from 81.1% to 97.9% among themselves, and 79.1% to 98.5% identity with five previously published GVB isolates in NCBI. The alignment of partial ORF3 and the phylogenetic relationships of ORF4 revealed that the molecular variants of Chinese GVB isolates could be clustered into three groups. Only isolate DGW was in the same group with the reported GVB isolates from other countries; the other four GVB isolates in this study were clustered into two groups. PMID- 24957725 TI - Mutations in Pol gene of hepatitis B virus in patients with chronic hepatitis B before and after therapy with nucleoside/nucleotide analogues. AB - Chronic hepatitis B (CHB) is one of the most common infections worldwide. Currently approved treatments of CHB include nucleoside/nucleotide analogues (NAs). However, long-term NA therapy is associated with accumulation of resistant mutations within the hepatitis B virus (HBV) polymerase gene. The incidence of naturally occurring HBV mutations leading to primary antiviral resistance has not been fully elucidated yet. The objective of present study was to detect the frequency of mutations within the HBV polymerase gene in 263 patients naive to nucleoside/nucleotide analogues. Prevalence of HBV Pol gene mutations secondary to NA treatment in patients without pre-existing antiviral resistance mutations was also examined. Retrospective analysis showed that HBV Pol gene mutations were present in 7 out of 263 patients prior to the treatment. Mutations observed in NA naive CHB patients were associated only with resistance to lamivudine and adefovir. Compensatory mutations were observed as well. In the course of antiviral treatment, HBV Pol gene mutations were identified in 65 out of the remaining 256 CHB patients (25.39%), while no mutations of any type were detected in 160 patients (62.5%). The profiles of detected mutations were comparable to those observed in other studies that focused on the analysis of clinically relevant NA-resistant mutations. In conclusion, we found out that antiviral resistance mutations may pre-exist in the overall viral population present in untreated patients, although the incidence of HBV Pol gene mutations in NA-naive CHB patients was low and reached only up to 2.66%. However, possible circulation and transmission of NAs-resistant HBV mutants in human population should be taken into account. PMID- 24957726 TI - Ovine herpesvirus 1 (OVHV-1) thymidine kinase locus sequence analysis: evidence that OVHV-1 belongs to the Macavirus genus of the Gammaherpesvirinae subfamily. AB - The HindIII-HincII fragment of the 5.5 kbp H11 HindIII clone of ovine herpesvirus 1 (OvHV-1) was cloned and its primary structure was determined by preparation of nested deletion subclones and their sequencing. Sequence analysis of the overlapping clones revealed that 3239 bp OvHV-1 fragment contains complete thymidine kinase (TK) gene, a partial open reading frame of ORF20 and that encoding glycoprotein H (gH). The conserved OvHV-1 TK displayed the highest similarity to homologous TK proteins encoded by members of the Macavirus genus of the Gammaherpesvirinae subfamily. These data including our previous analysis of the partial sequence of VP23 homologue might serve as further evidence that OvHV 1 should be categorized within the genus Macavirus of the Herpesviridae family. PMID- 24957728 TI - Citrate-hydrazine hydrogen-bonding driven single-step synthesis of tunable near IR plasmonic, anisotropic silver nanocrystals: implications for SERS spectroscopy of inorganic oxoanions. AB - A simplified, single-step aqueous synthesis route to tunable anisotropic silver nanocrystals (NCs) has been developed by tailoring the hydrogen-bonding interactions between a mild stabilizer, sodium citrate, and a mild reductant, hydrazine hydrate. The structure directing ability of the H-bonding interaction was harnessed by keeping a stoichiometric excess of hydrazine under ambient conditions (pH 7, 25 degrees C). Decreasing the synthesis temperature to 5 degrees C imparts rigidity to the citrate-hydrazine H-bonding network, and the plasmon peak moves from 500 to 550 nm (using 40 mM hydrazine). On lowering the pH from 7 to 5, the H-bonding is further strengthened due to partial protonation of citrate and the plasmon peak is tuned to 790 nm. Further, we found that, at 5 degrees C and pH 5, there also exists a sub-stoichiometric regime in which maximum tunability of the plasmon peak (790->1010 nm) is achieved with 1 mM hydrazine. HR-TEM reveals that the near-IR plasmonic NCs are nanopyramids having a pentagonal base with edge length varying from 15 nm to 30 nm. Through second derivative FTIR analysis, a correlation between hydrogen-bonded molecular vibrations and the plasmon tunability has been established. The anisotropic NCs exhibit significant Raman enhancement on the citrate molecules. Further, a solution-phase, non-resonant SERS spectroscopic detection method for an inorganic contaminant of ground water, arsenite, has also been developed. PMID- 24957727 TI - Isolation of a goose parvovirus from swan and its molecular characteristics. AB - Goose parvovirus (GPV) causes high mortality and morbidity in goslings and Muscovy ducklings. In this study, a GPV was isolated from a 20-day old swan in Shanghai, China. Complete genome of the swan isolate contained 5,050 nt and showed the highest homology with Taiwanese GPV isolates from 1982. In comparison with the Chinese mainland GPV isolates reported previously, the swan isolate shows two deletions, particularly at positions 67-80 and 334-347 in inverted terminal repeats (ITRs). These findings suggest that the swan could serve as a potential host for GPV and provide insights into molecular characteristics and etiology of GPV. PMID- 24957729 TI - Comparative composition and antioxidant activity of Peptide fractions obtained by ultrafiltration of egg yolk protein enzymatic hydrolysates. AB - The objective of the study was to compare the antioxidant activity of two distinct hydrolysates and their peptide fractions prepared by ultrafiltration (UF) using membranes with molecular weight cut-off of 5 and 1 kDa. The hydrolysates were a delipidated egg yolk protein concentrate (EYP) intensively hydrolyzed with a combination of two bacterial proteases, and a phosphoproteins (PPP) extract partially hydrolyzed with trypsin. Antioxidant activity, as determined by the oxygen radical absorbance capacity (ORAC) assay, was low for EYP and PPP hydrolysates with values of 613.1 and 489.2 uM TE*g-1 protein, respectively. UF-fractionation of EYP hydrolysate increased slightly the antioxidant activity in permeate fractions (720.5-867.8 uM TE*g-1 protein). However, ORAC values were increased by more than 3-fold in UF-fractions prepared from PPP hydrolysate, which were enriched in peptides with molecular weight lower than 5 kDa. These UF-fractions were characterized by their lower N/P atomic ratio and higher phosphorus content compared to the same UF-fractions obtained from EYP TH. They also contained high amounts of His, Met, Leu, and Phe, which are recognized as antioxidant amino acids, but also high content in Lys and Arg which both represent target amino acids of trypsin used for the hydrolysis of PPP. PMID- 24957730 TI - Thinking in Terms of Structure-Activity-Relationships (T-SAR): A Tool to Better Understand Nanofiltration Membranes. AB - A frontier to be conquered in the field of membrane technology is related to the very limited scientific base for the rational and task-specific design of membranes. This is especially true for nanofiltration membranes with properties that are based on several solute-membrane interaction mechanisms. "Thinking in terms of Structure-Activity-Relationships" (T-SAR) is a methodology which applies a systematic analysis of a chemical entity based on its structural formula. However, the analysis become more complex with increasing size of the molecules considered. In this study, T-SAR was combined with classical membrane characterization methods, resulting in a new methodology which allowed us not only to explain membrane characteristics, but also provides evidence for the importance of the chemical structure for separation performance. We demonstrate an application of the combined approach and its potential to discover stereochemistry, molecular interaction potentials, and reactivity of two FilmTec nanofiltration membranes (NF-90 and NF-270). Based on these results, it was possible to predict both properties and performance in the recovery of hydrophobic ionic liquids from aqueous solution. PMID- 24957731 TI - Electroformation of giant vesicles on a polymer mesh. AB - Electroformation of cell-sized lipid membrane vesicles (giant vesicles, GVs) from egg yolk phosphatidylcholine under applied electric voltage was examined on a substrate of a polymer mesh placed between two planar indium tin oxide coated glass electrodes. Under appropriate conditions, GVs were formed in good yield on meshes of various polymer materials, namely, hydrophobic poly(propylene), poly(ethylene terephthalate), a carbon fiber/nylon composite, and relatively hydrophilic nylon. Arranging threads in a mesh structure with appropriate openings improved GV formation compared to simply increasing the number of threads. For optimal electroformation of GVs, the size and shape of a mesh opening were crucial. With a too large opening, GV formation deteriorated. When the sides of an opening were partially missing, GV formation did not occur efficiently. With an adequate opening, a deposited lipid solution could fill the opening, and a relatively uniform lipid deposit formed on the surface of threads after evaporation of the solvent. This could supply a sufficient amount of lipids to the opening and also prevent a lipid deposit from becoming too thick for electroformation. As a result, good GV formation was often observed in openings filled with swelled lipid. PMID- 24957732 TI - Monitoring protein fouling on polymeric membranes using ultrasonic frequency domain reflectometry. AB - Novel signal-processing protocols were used to extend the in situ sensitivity of ultrasonic frequency-domain reflectometry (UFDR) for real-time monitoring of microfiltration (MF) membrane fouling during protein purification. Different commercial membrane materials, with a nominal pore size of 0.2 um, were challenged using bovine serum albumin (BSA) and amylase as model proteins. Fouling induced by these proteins was observed in flat-sheet membrane filtration cells operating in a laminar cross-flow regime. The detection of membrane associated proteins using UFDR was determined by applying rigorous statistical methodology to reflection spectra of ultrasonic signals obtained during membrane fouling. Data suggest that the total power reflected from membrane surfaces changes in response to protein fouling at concentrations as low as 14 MUg/cm2, and results indicate that ultrasonic spectra can be leveraged to detect and monitor protein fouling on commercial MF membranes. PMID- 24957733 TI - Nickel (II) Preconcentration and Speciation Analysis During Transport from Aqueous Solutions Using a Hollow-fiber Permeation Liquid Membrane (HFPLM) Device. AB - Nickel (II) preconcentration and speciation analysis using a hollow fiber supported liquid membrane (HFSLM) device was studied. A counterflow of protons coupled to complexation with formate provided the driving force of the process, while Kelex 100 was employed as carrier. The influence of variables related to module configuration (acceptor pH and carrier concentration) and to the sample properties (donor pH) on the preconcentration factor, E, was simultaneously studied and optimized using a 3 factor Doehlert matrix response surface methodology. The effect of metal concentration was studied as well. Preconcentration factors as high as 4240 were observed depending on the values of the different variables. The effects of the presence of inorganic anions (NO2 , SO42-, Cl-, NO3-, CO32-, CN-) and dissolved organic matter (DOM) in the form of humic acids were additionally considered in order to carry out a speciation analysis study. Nickel preconcentration was observed to be independent of both effects, except when cyanide was present in the donor phase. A characterization of the transport regime was performed through the analysis of the dependence of E on the temperature. E increases with the increase in temperature according to the equation E(K) = -8617.3 + 30.5T with an activation energy of 56.7 kJ mol-1 suggesting a kinetic-controlled regime. Sample depletion ranged from 12 to 1.2% depending on the volume of the donor phase (100 to 1000 mL, respectively). PMID- 24957734 TI - Recent trends in nanofibrous membranes and their suitability for air and water filtrations. AB - In recent decades, engineered membranes have become a viable separation technology for a wide range of applications in environmental, food and biomedical fields. Membranes are now competitive compared to conventional techniques such as adsorption, ion exchangers and sand filters. The main advantage of membrane technology is the fact that it works without the addition of any chemicals, with relatively high efficiency and low energy consumption with well arranged process conductions. Hence they are widely utilized in biotechnology, food and drink manufacturing, air filtration and medical uses such as dialysis for kidney failure patients. Membranes from nanofibrous materials possess high surface area to volume ratio, fine tunable pore sizes and their ease of preparation prompted both industry and academic researchers to study their use in many applications. In this paper, modern concepts and current research progress on various nanofibrous membranes, such as water and air filtration media, are presented. PMID- 24957735 TI - Functionality in Electrospun Nanofibrous Membranes Based on Fiber's Size, Surface Area, and Molecular Orientation. AB - Electrospinning is a versatile method for forming continuous thin fibers based on an electrohydrodynamic process. This method has the following advantages: (i) the ability to produce thin fibers with diameters in the micrometer and nanometer ranges; (ii) one-step forming of the two- or three-dimensional nanofiber network assemblies (nanofibrous membranes); and (iii) applicability for a broad spectrum of molecules, such as synthetic and biological polymers and polymerless sol-gel systems. Electrospun nanofibrous membranes have received significant attention in terms of their practical applications. The major advantages of nanofibers or nanofibrous membranes are the functionalities based on their nanoscaled-size, highly specific surface area, and highly molecular orientation. These functionalities of the nanofibrous membranes can be controlled by their fiber diameter, surface chemistry and topology, and internal structure of the nanofibers. This report focuses on our studies and describes fundamental aspects and applications of electrospun nanofibrous membranes. PMID- 24957736 TI - ESCRT: nipping the wound in the bud? AB - Rapid repair of plasma membrane wounds is critical for cellular survival. Exocytic patches, membrane tension reduction and endocytosis were previously proposed to mediate resealing. A recent study implicating the ESCRT complex adds to the growing evidence that repair involves removal of damaged plasma membrane, and not simply patching the wound. PMID- 24957737 TI - DNA replication: damage tolerance at the assembly line. AB - Damage tolerance mechanisms ensure resumption of DNA synthesis at damage replisome encounters. Replication fork reversal (RFR) is one such widely recognized mechanism that acts on replisomes where lagging strand synthesis continues upon leading strand synthesis block. The possibility to form such a structure is highly counter to our current understanding of the replisome dynamics of single replisomes. Here, I suggest a model that takes coupled bidirectional replisome organization into account to solve this apparent contradiction. PMID- 24957738 TI - Acute-phase proteins in relation to neuropsychiatric symptoms and use of psychotropic medication in Huntington's disease. AB - Activation of the innate immune system has been postulated in the pathogenesis of Huntington's disease (HD). We studied serum concentrations of C-reactive protein (CRP) and low albumin as positive and negative acute-phase proteins in HD. Multivariate linear and logistic regression was used to study the association between acute-phase protein levels in relation to clinical, neuropsychiatric, cognitive, and psychotropic use characteristics in a cohort consisting of 122 HD mutation carriers and 42 controls at first biomarker measurement, and 85 HD mutation carriers and 32 controls at second biomarker measurement. Significant associations were found between acute-phase protein levels and Total Functioning Capacity (TFC) score, severity of apathy, cognitive impairment, and the use of antipsychotics. Interestingly, all significant results with neuropsychiatric symptoms disappeared after additional adjusting for antipsychotic use. High sensitivity CRP levels were highest and albumin levels were lowest in mutation carriers who continuously used antipsychotics during follow-up versus those that had never used antipsychotics (mean difference for CRP 1.4 SE mg/L; P=0.04; mean difference for albumin 3 SE g/L; P<0.001). The associations found between acute phase proteins and TFC score, apathy, and cognitive impairment could mainly be attributed to the use of antipsychotics. This study provides evidence that HD mutation carriers who use antipsychotics are prone to develop an acute-phase response. PMID- 24957739 TI - 2-nitroveratryl as a photocleavable thiol-protecting group for directed disulfide bond formation in the chemical synthesis of insulin. AB - Chemical synthesis of peptides can allow the option of sequential formation of multiple cysteines through exploitation of judiciously chosen regioselective thiol-protecting groups. We report the use of 2-nitroveratryl (oNv) as a new orthogonal group that can be cleaved by photolysis under ambient conditions. In combination with complementary S-pyridinesulfenyl activation, disulfide bonds are formed rapidly in situ. The preparation of Fmoc-Cys(oNv)-OH is described together with its use for the solid-phase synthesis of complex cystine-rich peptides, such as insulin. PMID- 24957740 TI - Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary. AB - Serotonin syndrome and neuroleptic malignant syndrome are two drug toxidromes that have often overlapping and confusing clinical pictures. We report a case of a young man who presented with alteration of mental status, autonomic instability and neuromuscular hyperexcitability following ingestion of multiple psychiatric and antiepileptic medications. The patient satisfied criteria for serotonin syndrome and neuroleptic malignant syndrome, and based on the characteristic clinical features, laboratory findings and clinical course it was concluded that the patient had both toxidromes. The patient was managed with cyproheptadine and supportive measures, and recovered over the course of 3 weeks. A brief review of literature highlighting the diagnostic clues as well as the importance of recognising and distinguishing the often missed and confounding diagnoses follows. PMID- 24957741 TI - White matter integrity in older females is altered by increased body fat. AB - OBJECTIVE: To assess whether the pattern of diffusion changes among a cohort of individuals showing BMI-related increases in white matter volume reflects healthy expansion of myelin or damaged white matter. METHODS: Diffusion MRI measures (axial, radial, and fractional anisotropy) were obtained from 94 females, aged 52 92. Relationships between BMI and diffusion measures were assessed controlling for age, hypertension, and diabetes status using general linear modeling. Associations between diffusion measures and cognitive status (memory, executive functions, and visuomotor speed) were assessed using multiple regressions, controlling for age, education, hypertension, and diabetes status. RESULTS: Higher levels of BMI were associated with lower axial diffusion in frontal, temporal, parietal, internal capsule, and cerebellar white matter. Lower fractional anisotropy was observed in bilateral temporal white matter and the right corticospinal tract, with higher radial diffusion in temporal and temporoparietal white matter. Importantly, diffusion measures predicted reductions in executive functioning, memory, and visuomotor speed. CONCLUSIONS: The pattern of diffusion changes in regions of white matter showing BMI-related volume increases are not due to expansion of normal myelin, but instead suggests damage to white matter that has important consequences for cognitive functioning. PMID- 24957742 TI - Patterns of concurrent substance use among nonmedical ADHD stimulant users: results from the National Survey on Drug Use and Health. AB - AIMS: To examine patterns of concurrent substance use among adults with nonmedical ADHD stimulant use. METHODS: We used latent class analysis (LCA) to examine patterns of past-year problematic substance use (meeting any criteria for abuse or dependence) in a sample of 6103 adult participants from the National Surveys on Drug Use and Health 2006-2011 who reported past-year nonmedical use of ADHD stimulants. Multivariable latent regression was used to assess the association of socio-demographic characteristics, mental health and behavioral problems with the latent classes. RESULTS: A four-class model had the best model fit, including (1) participants with low probabilities for any problematic substance use (Low substance class, 53.3%); (2) problematic users of all types of prescription drugs (Prescription drug class, 13.3%); (3) participants with high probabilities of problematic alcohol and marijuana use (Alcohol-marijuana class, 28.8%); and (4) those with high probabilities of problematic use of multiple drugs and alcohol (Multiple substance class, 4.6%). Participants in the 4 classes had distinct socio-demographic, mental health and service use profiles with those in the Multiple substance class being more likely to report mental health and behavioral problems and service use. CONCLUSION: Nonmedical users of ADHD stimulants are a heterogeneous group with a large subgroup with low prevalence of problematic use of other substances. These subgroups have distinct patterns of mental health comorbidity, behavior problems and service use, with implications for prevention and treatment of nonmedical stimulant use. PMID- 24957743 TI - The zinc matrix metalloproteinase ZMP-2 increases survival of Caenorhabditis elegans through interference with lipoprotein absorption. AB - Matrix metalloproteinases are zinc-dependent endopeptidases conserved throughout the animal kingdom which primarily degrade components of the extracellular matrix. In the nematode Caenorhabditis elegans, the zinc matrix metalloproteinase (ZMP-2) was demonstrated to increase resistance versus heat and bacterial pathogens. Here, we show that the survival reducing activities caused by the knockdown of zmp-2 in C. elegans essentially requires the presence of vitellogenin-6, a protein homologous to mammalian apolipoprotein B, and RME-2, a receptor mediating endocytosis of cholesterol particles. Measurements of reactive oxygen species inside and outside C. elegans revealed that knockdown of zmp-2 causes a prooxidative extracellular mileu which is a prerequisite for the reduction of survival. Interestingly, RNAi for the foxo transcription factor daf 16 completely prevented those survival reducing effects of zmp-2 RNAi, and RNAi in mutants of the steroid signalling pathway revealed that DAF-16 acts by inhibition of DAF-9 and DAF-12. In conclusion, our study demonstrates survival reducing activities caused by the functional loss of ZMP-2 in C. elegans. Those effects are mediated by the transport of oxidized cholesterol adducts which then trigger the inhibition of DAF-9 and DAF-12 through the activation of DAF-16. PMID- 24957744 TI - Seroepidemiology of Middle East respiratory syndrome (MERS) coronavirus in Saudi Arabia (1993) and Australia (2014) and characterisation of assay specificity. AB - The pseudoparticle virus neutralisation test (ppNT) and a conventional microneutralisation (MN) assay are specific for detecting antibodies to Middle East respiratory syndrome coronavirus (MERS-CoV) when used in seroepidemiological studies in animals. Genetically diverse MERS-CoV appear antigenically similar in MN tests. We confirm that MERS-CoV was circulating in dromedaries in Saudi Arabia in 1993. Preliminary data suggest that feral Australian dromedaries may be free of MERS-CoV but larger confirmatory studies are needed. PMID- 24957745 TI - Middle East respiratory syndrome coronavirus (MERS-CoV) RNA and neutralising antibodies in milk collected according to local customs from dromedary camels, Qatar, April 2014. AB - Antibodies to Middle East respiratory syndrome coronavirus (MERS-CoV) were detected in serum and milk collected according to local customs from 33 camels in Qatar, April 2014. At one location, evidence for active virus shedding in nasal secretions and/or faeces was observed for 7/12 camels; viral RNA was detected in milk of five of these seven camels. The presence of MERS-CoV RNA in milk of camels actively shedding the virus warrants measures to prevent putative food borne transmission of MERS-CoV. PMID- 24957746 TI - Assessment of the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic in the Middle East and risk of international spread using a novel maximum likelihood analysis approach. AB - The emergence of the novel Middle East (ME) respiratory syndrome coronavirus (MERS-CoV) has raised global public health concerns regarding the current situation and its future evolution. Here we propose an integrative maximum likelihood analysis of both cluster data in the ME and importations in a set of European countries to assess the transmission scenario and incidence of sporadic infections. Our approach is based on a spatial-transmission model integrating mobility data worldwide and allows for variations in the zoonotic/environmental transmission and under-ascertainment. Maximum likelihood estimates for the ME, considering outbreak data up to 31 August 2013, indicate the occurrence of a subcritical epidemic with a reproductive number R of 0.50 (95% confidence interval (CI): 0.30-0.77) associated with a daily rate of sporadic introductions psp of 0.28 (95% CI: 0.12-0.85). Infections in the ME appear to be mainly dominated by zoonotic/environmental transmissions, with possible under ascertainment (ratio of estimated to observed (0.116) sporadic cases equal to 2.41, 95% CI: 1.03-7.32). No time evolution of the situation emerges. Analyses of flight passenger data from ME countries indicate areas at high risk of importation. While dismissing an immediate threat for global health security, this analysis provides a baseline scenario for future reference and updates, suggests reinforced surveillance to limit under-ascertainment, and calls for alertness in high importation risk areas worldwide. PMID- 24957750 TI - Think about the care in healthcare. PMID- 24957748 TI - The 2014 Hajj and Umrah - current recommendations. PMID- 24957751 TI - Predictors of Nurse Support for the Introduction of the Cardiometabolic Health Nurse in the Australian Mental Health Sector. AB - PURPOSE: A cardiometabolic specialist nursing role could potentially improve physical health of people with serious mental illness. DESIGN AND METHODS: A national survey of Australian nurses working in mental health settings investigated predictors of support for the role. FINDINGS: Predictors included belief in physical healthcare neglect, interest in training; higher perceived value of improving physical health care. PRACTICE IMPLICATIONS: The findings suggest that nurses see the cardiometabolic health nurse role as a promising initiative for closing gaps in cardiometabolic health care and skilling other nurses in mental health. However, as the majority of variance in cardiometabolic health nurse support was unexplained, more research is urgently needed on factors that explain differences in cardiometabolic health nurse endorsement. PMID- 24957747 TI - Epidemiological surveillance of colonising group B Streptococcus epidemiology in the Lisbon and Tagus Valley regions, Portugal (2005 to 2012): emergence of a new epidemic type IV/clonal complex 17 clone. AB - This study presents the serotype distribution and the antibiotic resistance profile of 953 colonising group B Streptococcus (GBS) recovered from women of child bearing age (15 to 49 years) between 2005 and 2012 in the Lisbon and Tagus Valley region, Portugal. Overall, serotypes Ia, II, III, and V were the most common, accounting 752 of the 953 isolates (about 80%). However, there were changes in GBS distribution, in particular in the two last years of the study. Of note, the proportion of serotype IV isolates increased from 1% (2/148) in 2006 to 20% (19/97) in 2012. Also, considerable proportions of serotype IV isolates from 2010 to 2012 were respectively resistant to erythromycin (9/43; 21%) or clindamycin (6/43; 14%). The identification of nine serotype IV isolates presenting a novel association with the clonal complex (CC) 17 lineage, involving a putative capsular switch, may accentuate their virulence potential and ecological success. Molecular analysis of this subgroup of isolates revealed the presence of rib, IS (insertion sequence) 861 and GBSi1 group II intron within the C5a peptidase gene (scpB) - laminin-binding protein gene (lmb) region, reflecting high clonality and a putative common origin. A close surveillance of the emergent type IV/CC17 isolates is crucial considering the potential impact over GBS treatment guidelines and capsular vaccine development. PMID- 24957752 TI - In silico analysis of Acinetobacter baumannii phospholipase D as a subunit vaccine candidate. AB - The rate of human health care-associated infections caused by Acinetobacter baumannii has increased significantly in recent years for its remarkable resistance to desiccation and most antibiotics. Phospholipases, capable of destroying a phospholipid substrate, are heterologous group of enzymes which are believed to be the bacterial virulence determinants. There is a need for in silico studies to identify potential vaccine candidates. A. baumannii phospholipase D (PLD) role has been proved in increasing organism's resistance to human serum, destruction of host epithelial cell and pathogenesis in murine model. In this in silico study high potentials of A. baumannii PLD in elicitation of humoral and cellular immunities were elucidated. Thermal stability, long half life, non-similarity to human and gut flora proteome and non-allergenicity were in a list of A. baumannii PLD positive properties. Potential epitopic sequences were also identified that could be used as peptide vaccines against A. baumannii and various other human bacterial pathogens. PMID- 24957753 TI - In a randomized case-control trial with 10-years olds suffering from attention deficit/hyperactivity disorder (ADHD) sleep and psychological functioning improved during a 12-week sleep-training program. AB - OBJECTIVES: We tested the hypothesis that sleep training would improve emotional, social and behavioural functioning in children with attention deficit/hyperactivity disorder (ADHD) compared to children with ADHD without such intervention and to healthy controls. METHODS: Forty children with ADHD were randomly assigned to intervention and control conditions. Parents of 20 children with ADHD were instructed and thoroughly supervised in improving their children's sleep schedules and sleep behaviour. Parents of the other 20 children with ADHD and parents of 20 healthy children received general information about sleep hygiene. At baseline and 12 weeks later, parents and children completed questionnaires related to children's sleep and psychological functioning. RESULTS: Relative to the control groups, children in the intervention group improved sleep quantitatively and qualitatively (F values < 3.33, P values < 0.05). The intervention group children reported improvements in mood, emotions, and relationships (F values < 2.99, P values < 0.05). Parents reported that their children improved in physical and psychological wellbeing, mood, emotions, relationships, and social acceptance (F values < 3.02, P values < 0.05). CONCLUSIONS: Training and monitoring parents of children with ADHD in regulating and supervising children's sleep schedules leads to positive changes in the emotions, behaviour and social lives of these children. PMID- 24957754 TI - Dosimetry analyses comparing high-dose-rate brachytherapy, administered as monotherapy for localized prostate cancer, with stereotactic body radiation therapy simulated using CyberKnife. AB - The purpose of this study was to perform dosimetry analyses comparing high-dose rate brachytherapy (HDR-BT) with simulated stereotactic body radiotherapy (SBRT). We selected six consecutive patients treated with HDR-BT monotherapy in 2010, and a CyberKnife SBRT plan was simulated for each patient using computed tomography images and the contouring set used in the HDR-BT plan for the actual treatment, but adding appropriate planning target volume (PTV) margins for SBRT. Then, dosimetric profiles for PTVs of the rectum, bladder and urethra were compared between the two modalities. The SBRT plan was more homogenous and provided lower dose concentration but better coverage for the PTV. The maximum doses in the rectum were higher in the HDR-BT plans. However, the HDR-BT plan provided a sharper dose fall-off around the PTV, resulting in a significant and considerable difference in volume sparing of the rectum with the appropriate PTV margins added for SBRT. While the rectum D5cm(3) for HDR-BT and SBRT was 30.7 and 38.3 Gy (P < 0.01) and V40 was 16.3 and 20.8 cm(3) (P < 0.01), respectively, SBRT was significantly superior in almost all dosimetric profiles for the bladder and urethra. These results suggest that SBRT as an alternative to HDR-BT in hypofractionated radiotherapy for prostate cancer might have an advantage for bladder and urethra dose sparing, but for the rectum only when proper PTV margins for SBRT are adopted. PMID- 24957755 TI - Development and reproducibility evaluation of a Monte Carlo-based standard LINAC model for quality assurance of multi-institutional clinical trials. AB - Technical developments in radiotherapy (RT) have created a need for systematic quality assurance (QA) to ensure that clinical institutions deliver prescribed radiation doses consistent with the requirements of clinical protocols. For QA, an ideal dose verification system should be independent of the treatment-planning system (TPS). This paper describes the development and reproducibility evaluation of a Monte Carlo (MC)-based standard LINAC model as a preliminary requirement for independent verification of dose distributions. The BEAMnrc MC code is used for characterization of the 6-, 10- and 15-MV photon beams for a wide range of field sizes. The modeling of the LINAC head components is based on the specifications provided by the manufacturer. MC dose distributions are tuned to match Varian Golden Beam Data (GBD). For reproducibility evaluation, calculated beam data is compared with beam data measured at individual institutions. For all energies and field sizes, the MC and GBD agreed to within 1.0% for percentage depth doses (PDDs), 1.5% for beam profiles and 1.2% for total scatter factors (Scps.). Reproducibility evaluation showed that the maximum average local differences were 1.3% and 2.5% for PDDs and beam profiles, respectively. MC and institutions' mean Scps agreed to within 2.0%. An MC-based standard LINAC model developed to independently verify dose distributions for QA of multi-institutional clinical trials and routine clinical practice has proven to be highly accurate and reproducible and can thus help ensure that prescribed doses delivered are consistent with the requirements of clinical protocols. PMID- 24957756 TI - Structural Identification of O-Linked Oligosaccharides Using Exoglycosidases and MSn Together with UniCarb-DB Fragment Spectra Comparison. AB - The availability of specific exoglycosidases alongside a spectral library of O linked oligosaccharide collision induced dissociation (CID) MS fragments, UniCarb DB, provides a pathway to make the elucidation of O-linked oligosaccharides more efficient. Here, we advise an approach of exoglycosidase-digestion of O-linked oligosaccharide mixtures, for structures that do not provide confirmative spectra. The combination of specific exoglycosidase digestion and MS2 matching of the exoglycosidase products with structures from UniCarb-DB, allowed the assignment of unknown structures. This approach was illustrated by treating sialylated core 2 O-linked oligosaccharides, released from the human synovial glycoprotein (lubricin), with a alpha2-3 specific sialidase. This methodology demonstrated the exclusive 3 linked nature of the sialylation of core 2 oligosaccharides on lubricin. When specific exoglycosidases were not available, MS3 spectral matching using standards was used. This allowed the unusual 4-linked terminal GlcNAc epitope in a porcine stomach to be identified in the GlcNAc1 4Galb1-3(GlcNAcb1-6)GalNAcol structure, indicating the antibacterial epitope GlcNAca1-4. In total, 13 structures were identified using exoglycosidase and MSn, alongside UniCarb-DB fragment spectra comparison. UniCarb-DB could also be used to identify the specificity of unknown exoglycosidases in human saliva. Endogenous salivary exoglycosidase activity on mucin oligosaccharides could be monitored by comparing the generated tandem MS spectra with those present in UniCarb-DB, showing that oral exoglycosidases were dominated by sialidases with a higher activity towards 3-linked sialic acid rather than 6-linked sialic acid. PMID- 24957757 TI - From cycling between coupled reactions to the cross-bridge cycle: mechanical power output as an integral part of energy metabolism. AB - ATP delivery and its usage are achieved by cycling of respective intermediates through interconnected coupled reactions. At steady state, cycling between coupled reactions always occurs at zero resistance of the whole cycle without dissipation of free energy. The cross-bridge cycle can also be described by a system of coupled reactions: one energising reaction, which energises myosin heads by coupled ATP splitting, and one de-energising reaction, which transduces free energy from myosin heads to coupled actin movement. The whole cycle of myosin heads via cross-bridge formation and dissociation proceeds at zero resistance. Dissipation of free energy from coupled reactions occurs whenever the input potential overcomes the counteracting output potential. In addition, dissipation is produced by uncoupling. This is brought about by a load dependent shortening of the cross-bridge stroke to zero, which allows isometric force generation without mechanical power output. The occurrence of maximal efficiency is caused by uncoupling. Under coupled conditions, Hill's equation (velocity as a function of load) is fulfilled. In addition, force and shortening velocity both depend on [Ca2+]. Muscular fatigue is triggered when ATP consumption overcomes ATP delivery. As a result, the substrate of the cycle, [MgATP2-], is reduced. This leads to a switch off of cycling and ATP consumption, so that a recovery of [ATP] is possible. In this way a potentially harmful, persistent low energy state of the cell can be avoided. PMID- 24957758 TI - Differentiating hepatocellular carcinoma from hepatitis C using metabolite profiling. AB - Hepatocellular carcinoma (HCC) accounts for most liver cancer cases worldwide. Contraction of the hepatitis C virus (HCV) is considered a major risk factor for liver cancer. In order to identify the risk of cancer, metabolic profiling of serum samples from patients with HCC (n=40) and HCV (n=22) was performed by 1H nuclear magnetic resonance spectroscopy. Multivariate statistical analysis showed a distinct separation of the two patient cohorts, indicating a distinct metabolic difference between HCC and HCV patient groups based on signals from lipids and other individual metabolites. Univariate analysis showed that three metabolites (choline, valine and creatinine) were significantly altered in HCC. A PLS-DA model based on these three metabolites showed a sensitivity of 80%, specificity of 71% and an area under the receiver operating curve of 0.83, outperforming the clinical marker alpha-fetoprotein (AFP). The robustness of the model was tested using Monte-Carlo cross validation (MCCV). This study showed that metabolite profiling could provide an alternative approach for HCC screening in HCV patients, many of whom have high risk for developing liver cancer. PMID- 24957759 TI - Influence of the RelA Activity on E. coli Metabolism by Metabolite Profiling of Glucose-Limited Chemostat Cultures. AB - Metabolite profiling of E. coli W3110 and the isogenic DrelA mutant cells was used to characterize the RelA-dependent stringent control of metabolism under different growth conditions. Metabolic profiles were obtained by gas chromatography-mass spectrometry (GC-MS) analysis and revealed significant differences between E. coli strains grown at different conditions. Major differences between the two strains were assessed in the levels of amino acids and fatty acids and their precursor metabolites, especially when growing at the lower dilution rates, demonstrating differences in their metabolic behavior. Despite the fatty acid biosynthesis being the most affected due to the lack of the RelA activity, other metabolic pathways involving succinate, lactate and threonine were also affected. Overall, metabolite profiles indicate that under nutrient-limiting conditions the RelA-dependent stringent response may be elicited and promotes key changes in the E. coli metabolism. PMID- 24957760 TI - Computational methods for metabolomic data analysis of ion mobility spectrometry data-reviewing the state of the art. AB - Ion mobility spectrometry combined with multi-capillary columns (MCC/IMS) is a well known technology for detecting volatile organic compounds (VOCs). We may utilize MCC/IMS for scanning human exhaled air, bacterial colonies or cell lines, for example. Thereby we gain information about the human health status or infection threats. We may further study the metabolic response of living cells to external perturbations. The instrument is comparably cheap, robust and easy to use in every day practice. However, the potential of the MCC/IMS methodology depends on the successful application of computational approaches for analyzing the huge amount of emerging data sets. Here, we will review the state of the art and highlight existing challenges. First, we address methods for raw data handling, data storage and visualization. Afterwards we will introduce de noising, peak picking and other pre-processing approaches. We will discuss statistical methods for analyzing correlations between peaks and diseases or medical treatment. Finally, we study up-to-date machine learning techniques for identifying robust biomarker molecules that allow classifying patients into healthy and diseased groups. We conclude that MCC/IMS coupled with sophisticated computational methods has the potential to successfully address a broad range of biomedical questions. While we can solve most of the data pre-processing steps satisfactorily, some computational challenges with statistical learning and model validation remain. PMID- 24957761 TI - Characterization of the Interaction Between the Small Regulatory Peptide SgrT and the EIICBGlc of the Glucose-Phosphotransferase System of E. coli K-12. AB - Escherichia coli is a widely used microorganism in biotechnological processes. An obvious goal for current scientific and technical research in this field is the search for new tools to optimize productivity. Usually glucose is the preferred carbon source in biotechnological applications. In E. coli, glucose is taken up by the phosphoenolpyruvate-dependent glucose phosphotransferase system (PTS). The regulation of the ptsG gene for the glucose transporter is very complex and involves several regulatory proteins. Recently, a novel posttranscriptional regulation system has been identified which consists of a small regulatory RNA SgrS and a small regulatory polypeptide called SgrT. During the accumulation of glucose-6-phosphate or fructose-6-phosphate, SgrS is involved in downregulation of ptsG mRNA stability, whereas SgrT inhibits glucose transport activity by a yet unknown mechanism. The function of SgrS has been studied intensively. In contrast, the knowledge about the function of SgrT is still limited. Therefore, in this paper, we focused our interest on the regulation of glucose transport activity by SgrT. We identified the SgrT target sequence within the glucose transporter and characterized the interaction in great detail. Finally, we suggest a novel experimental approach to regulate artificially carbohydrate uptake in E. coli to minimize metabolic overflow in biotechnological applications. PMID- 24957762 TI - A Guideline to Univariate Statistical Analysis for LC/MS-Based Untargeted Metabolomics-Derived Data. AB - Several metabolomic software programs provide methods for peak picking, retention time alignment and quantification of metabolite features in LC/MS-based metabolomics. Statistical analysis, however, is needed in order to discover those features significantly altered between samples. By comparing the retention time and MS/MS data of a model compound to that from the altered feature of interest in the research sample, metabolites can be then unequivocally identified. This paper reports on a comprehensive overview of a workflow for statistical analysis to rank relevant metabolite features that will be selected for further MS/MS experiments. We focus on univariate data analysis applied in parallel on all detected features. Characteristics and challenges of this analysis are discussed and illustrated using four different real LC/MS untargeted metabolomic datasets. We demonstrate the influence of considering or violating mathematical assumptions on which univariate statistical test rely, using high-dimensional LC/MS datasets. Issues in data analysis such as determination of sample size, analytical variation, assumption of normality and homocedasticity, or correction for multiple testing are discussed and illustrated in the context of our four untargeted LC/MS working examples. PMID- 24957763 TI - Validated and predictive processing of gas chromatography-mass spectrometry based metabolomics data for large scale screening studies, diagnostics and metabolite pattern verification. AB - The suggested approach makes it feasible to screen large metabolomics data, sample sets with retained data quality or to retrieve significant metabolic information from small sample sets that can be verified over multiple studies. Hierarchical multivariate curve resolution (H-MCR), followed by orthogonal partial least squares discriminant analysis (OPLS-DA) was used for processing and classification of gas chromatography/time of flight mass spectrometry (GC/TOFMS) data characterizing human serum samples collected in a study of strenuous physical exercise. The efficiency of predictive H-MCR processing of representative sample subsets, selected by chemometric approaches, for generating high quality data was proven. Extensive model validation by means of cross validation and external predictions verified the robustness of the extracted metabolite patterns in the data. Comparisons of extracted metabolite patterns between models emphasized the reliability of the methodology in a biological information context. Furthermore, the high predictive power in longitudinal data provided proof for the potential use in clinical diagnosis. Finally, the predictive metabolite pattern was interpreted physiologically, highlighting the biological relevance of the diagnostic pattern. PMID- 24957765 TI - Analysis and Design of Stimulus Response Curves of E. coli. AB - Metabolism and signalling are tightly coupled in bacteria. Combining several theoretical approaches, a core model is presented that describes transcriptional and allosteric control of glycolysis in Escherichia coli. Experimental data based on microarrays, signalling components and extracellular metabolites are used to estimate kinetic parameters. A newly designed strain was used that adjusts the incoming glucose flux into the system and allows a kinetic analysis. Based on the results, prediction for intracelluar metabolite concentrations over a broad range of the growth rate could be performed and compared with data from literature. PMID- 24957764 TI - Determining enzyme kinetics for systems biology with nuclear magnetic resonance spectroscopy. AB - Enzyme kinetics for systems biology should ideally yield information about the enzyme's activity under in vivo conditions, including such reaction features as substrate cooperativity, reversibility and allostery, and be applicable to enzymatic reactions with multiple substrates. A large body of enzyme-kinetic data in the literature is based on the uni-substrate Michaelis-Menten equation, which makes unnatural assumptions about enzymatic reactions (e.g., irreversibility), and its application in systems biology models is therefore limited. To overcome this limitation, we have utilised NMR time-course data in a combined theoretical and experimental approach to parameterize the generic reversible Hill equation, which is capable of describing enzymatic reactions in terms of all the properties mentioned above and has fewer parameters than detailed mechanistic kinetic equations; these parameters are moreover defined operationally. Traditionally, enzyme kinetic data have been obtained from initial-rate studies, often using assays coupled to NAD(P)H-producing or NAD(P)H-consuming reactions. However, these assays are very labour-intensive, especially for detailed characterisation of multi-substrate reactions. We here present a cost-effective and relatively rapid method for obtaining enzyme-kinetic parameters from metabolite time-course data generated using NMR spectroscopy. The method requires fewer runs than traditional initial-rate studies and yields more information per experiment, as whole time-courses are analyzed and used for parameter fitting. Additionally, this approach allows real-time simultaneous quantification of all metabolites present in the assay system (including products and allosteric modifiers), which demonstrates the superiority of NMR over traditional spectrophotometric coupled enzyme assays. The methodology presented is applied to the elucidation of kinetic parameters for two coupled glycolytic enzymes from Escherichia coli (phosphoglucose isomerase and phosphofructokinase). 31P-NMR time-course data were collected by incubating cell extracts with substrates, products and modifiers at different initial concentrations. NMR kinetic data were subsequently processed using a custom software module written in the Python programming language, and globally fitted to appropriately modified Hill equations. PMID- 24957766 TI - Flux-p: automating metabolic flux analysis. AB - Quantitative knowledge of intracellular fluxes in metabolic networks is invaluable for inferring metabolic system behavior and the design principles of biological systems. However, intracellular reaction rates can not often be calculated directly but have to be estimated; for instance, via 13C-based metabolic flux analysis, a model-based interpretation of stable carbon isotope patterns in intermediates of metabolism. Existing software such as FiatFlux, OpenFLUX or 13CFLUX supports experts in this complex analysis, but requires several steps that have to be carried out manually, hence restricting the use of this software for data interpretation to a rather small number of experiments. In this paper, we present Flux-P as an approach to automate and standardize 13C based metabolic flux analysis, using the Bio-jETI workflow framework. Exemplarily based on the FiatFlux software, it demonstrates how services can be created that carry out the different analysis steps autonomously and how these can subsequently be assembled into software workflows that perform automated, high throughput intracellular flux analysis of high quality and reproducibility. Besides significant acceleration and standardization of the data analysis, the agile workflow-based realization supports flexible changes of the analysis workflows on the user level, making it easy to perform custom analyses. PMID- 24957767 TI - Ensemble kinetic modeling of metabolic networks from dynamic metabolic profiles. AB - Kinetic modeling of metabolic pathways has important applications in metabolic engineering, but significant challenges still remain. The difficulties faced vary from finding best-fit parameters in a highly multidimensional search space to incomplete parameter identifiability. To meet some of these challenges, an ensemble modeling method is developed for characterizing a subset of kinetic parameters that give statistically equivalent goodness-of-fit to time series concentration data. The method is based on the incremental identification approach, where the parameter estimation is done in a step-wise manner. Numerical efficacy is achieved by reducing the dimensionality of parameter space and using efficient random parameter exploration algorithms. The shift toward using model ensembles, instead of the traditional "best-fit" models, is necessary to directly account for model uncertainty during the application of such models. The performance of the ensemble modeling approach has been demonstrated in the modeling of a generic branched pathway and the trehalose pathway in Saccharomyces cerevisiae using generalized mass action (GMA) kinetics. PMID- 24957769 TI - Metabolic adaptation and protein complexes in prokaryotes. AB - Protein complexes are classified and have been charted in several large-scale screening studies in prokaryotes. These complexes are organized in a factory-like fashion to optimize protein production and metabolism. Central components are conserved between different prokaryotes; major complexes involve carbohydrate, amino acid, fatty acid and nucleotide metabolism. Metabolic adaptation changes protein complexes according to environmental conditions. Protein modification depends on specific modifying enzymes. Proteins such as trigger enzymes display condition-dependent adaptation to different functions by participating in several complexes. Several bacterial pathogens adapt rapidly to intracellular survival with concomitant changes in protein complexes in central metabolism and optimize utilization of their favorite available nutrient source. Regulation optimizes protein costs. Master regulators lead to up- and downregulation in specific subnetworks and all involved complexes. Long protein half-life and low level expression detaches protein levels from gene expression levels. However, under optimal growth conditions, metabolite fluxes through central carbohydrate pathways correlate well with gene expression. In a system-wide view, major metabolic changes lead to rapid adaptation of complexes and feedback or feedforward regulation. Finally, prokaryotic enzyme complexes are involved in crowding and substrate channeling. This depends on detailed structural interactions and is verified for specific effects by experiments and simulations. PMID- 24957770 TI - Comparative Analysis of End Point Enzymatic Digests of Arabino-Xylan Isolated from Switchgrass (Panicum virgatum L) of Varying Maturities using LC-MSn. AB - Switchgrass (Panicum virgatum L., SG) is a perennial grass presently used for forage and being developed as a bioenergy crop for conversion of cell wall carbohydrates to biofuels. Up to 50% of the cell wall associated carbohydrates are xylan. SG was analyzed for xylan structural features at variable harvest maturities. Xylan from each of three maturities was isolated using classical alkaline extraction to yield fractions (Xyl A and B) with varying compositional ratios. The Xyl B fraction was observed to decrease with plant age. Xylan samples were subsequently prepared for structure analysis by digesting with pure endo xylanase, which preserved side-groups, or a commercial carbohydrase preparation favored for biomass conversion work. Enzymatic digestion products were successfully permethylated and analyzed by reverse-phase liquid chromatography with mass spectrometric detection (RP-HPLC-MSn). This method is advantageous compared to prior work on plant biomass because it avoids isolation of individual arabinoxylan oligomers. The use of RP-HPLC- MSn differentiated 14 structural oligosaccharides (d.p. 3-9) from the monocomponent enzyme digestion and nine oligosaccharide structures (d.p. 3-9) from hydrolysis with a cellulase enzyme cocktail. The distribution of arabinoxylan oligomers varied depending upon the enzyme(s) applied but did not vary with harvest maturity. PMID- 24957771 TI - Metabolic Consequences of TGFb Stimulation in CulturedPrimary Mouse Hepatocytes Screened from Transcript Data with ModeScore . AB - TGFb signaling plays a major role in the reorganization of liver tissue upon injury and is an important driver of chronic liver disease. This is achieved by a deep impact on a cohort of cellular functions. To comprehensively assess the full range of affected metabolic functions, transcript changes of cultured mouse hepatocytes were analyzed with a novel method (ModeScore), which predicts the activity of metabolic functions by scoring transcript expression changes with 987 reference flux distributions, which yielded the following hypotheses. TGFb multiplies down-regulation of most metabolic functions occurring in culture stressed controls. This is especially pronounced for tyrosine degradation, urea synthesis, glucuronization capacity, and cholesterol synthesis. Ethanol degradation and creatine synthesis are down-regulated only in TGFb treated hepatocytes, but not in the control. Among the few TGFb dependently up-regulated functions, synthesis of various collagens is most pronounced. Further interesting findings include: down-regulation of glucose export is postponed by TGFb, TGFb up regulates the synthesis capacity of ketone bodies only as an early response, TGFb suppresses the strong up-regulation of Vanin, and TGFb induces re-formation of ceramides and sphingomyelin. PMID- 24957772 TI - Glycomic expression in esophageal disease. AB - Glycosylation is among the most common post translation modifications of proteins in humans. Decades of research have demonstrated that aberrant glycosylation can lead to malignant degeneration. Glycoproteomic studies in the past several years have identified techniques that can successfully characterize a glycan or glycan profile associated with a high-grade dysplastic or malignant state. This review summarizes the current glycomic and glycoproteomic literature with specific reference to esophageal cancer. Esophageal adenocarcinoma represents a highly morbid and mortal cancer with a defined progression from metaplasia (Barrett's esophagus) to dysplasia to neoplasia. This disease is highlighted because (1) differences in glycan profiles between the stages of disease progression have been described in the glycoproteomic literature; (2) a glycan biomarker that identifies a given stage may be used as a predictor of disease progression and thus may have significant influence over clinical management; and (3) the differences in glycan profiles between disease and disease-free states in esophageal cancer are more dramatic than in other cancers. PMID- 24957773 TI - Error propagation analysis for quantitative intracellular metabolomics. AB - Model-based analyses have become an integral part of modern metabolic engineering and systems biology in order to gain knowledge about complex and not directly observable cellular processes. For quantitative analyses, not only experimental data, but also measurement errors, play a crucial role. The total measurement error of any analytical protocol is the result of an accumulation of single errors introduced by several processing steps. Here, we present a framework for the quantification of intracellular metabolites, including error propagation during metabolome sample processing. Focusing on one specific protocol, we comprehensively investigate all currently known and accessible factors that ultimately impact the accuracy of intracellular metabolite concentration data. All intermediate steps are modeled, and their uncertainty with respect to the final concentration data is rigorously quantified. Finally, on the basis of a comprehensive metabolome dataset of Corynebacterium glutamicum, an integrated error propagation analysis for all parts of the model is conducted, and the most critical steps for intracellular metabolite quantification are detected. PMID- 24957768 TI - Tumor-associated glycans and their role in gynecological cancers: accelerating translational research by novel high-throughput approaches. AB - Glycans are important partners in many biological processes, including carcinogenesis. The rapidly developing field of functional glycomics becomes one of the frontiers of biology and biomedicine. Aberrant glycosylation of proteins and lipids occurs commonly during malignant transformation and leads to the expression of specific tumor-associated glycans. The appearance of aberrant glycans on carcinoma cells is typically associated with grade, invasion, metastasis and overall poor prognosis. Cancer-associated carbohydrates are mostly located on the surface of cancer cells and are therefore potential diagnostic biomarkers. Currently, there is increasing interest in cancer-associated aberrant glycosylation, with growing numbers of characteristic cancer targets being detected every day. Breast and ovarian cancer are the most common and lethal malignancies in women, respectively, and potential glycan biomarkers hold promise for early detection and targeted therapies. However, the acceleration of research and comprehensive multi-target investigation of cancer-specific glycans could only be successfully achieved with the help of a combination of novel high throughput glycomic approaches. PMID- 24957774 TI - Medicinal plants: a public resource for metabolomics and hypothesis development. AB - Specialized compounds from photosynthetic organisms serve as rich resources for drug development. From aspirin to atropine, plant-derived natural products have had a profound impact on human health. Technological advances provide new opportunities to access these natural products in a metabolic context. Here, we describe a database and platform for storing, visualizing and statistically analyzing metabolomics data from fourteen medicinal plant species. The metabolomes and associated transcriptomes (RNAseq) for each plant species, gathered from up to twenty tissue/organ samples that have experienced varied growth conditions and developmental histories, were analyzed in parallel. Three case studies illustrate different ways that the data can be integrally used to generate testable hypotheses concerning the biochemistry, phylogeny and natural product diversity of medicinal plants. Deep metabolomics analysis of Camptotheca acuminata exemplifies how such data can be used to inform metabolic understanding of natural product chemical diversity and begin to formulate hypotheses about their biogenesis. Metabolomics data from Prunella vulgaris, a species that contains a wide range of antioxidant, antiviral, tumoricidal and anti inflammatory constituents, provide a case study of obtaining biosystematic and developmental fingerprint information from metabolite accumulation data in a little studied species. Digitalis purpurea, well known as a source of cardiac glycosides, is used to illustrate how integrating metabolomics and transcriptomics data can lead to identification of candidate genes encoding biosynthetic enzymes in the cardiac glycoside pathway. Medicinal Plant Metabolomics Resource (MPM) [1] provides a framework for generating experimentally testable hypotheses about the metabolic networks that lead to the generation of specialized compounds, identifying genes that control their biosynthesis and establishing a basis for modeling metabolism in less studied species. The database is publicly available and can be used by researchers in medicine and plant biology. PMID- 24957775 TI - Glycomics approaches for the bioassay and structural analysis of heparin/heparan sulphates. AB - The glycosaminoglycan heparan sulphate (HS) has a heterogeneous structure; evidence shows that specific structures may be responsible for specific functions in biological processes such as blood coagulation and regulation of growth factor signalling. This review summarises the different experimental tools and methods developed to provide more rapid methods for studying the structure and functions of HS. Rapid and sensitive methods for the facile purification of HS, from tissue and cell sources are reviewed. Data sets for the structural analysis are often complex and include multiple sample sets, therefore different software and tools have been developed for the analysis of different HS data sets. These can be readily applied to chromatographic data sets for the simplification of data (e.g., charge separation using strong anion exchange chromatography and from size separation using gel filtration techniques. Finally, following the sequencing of the human genome, research has rapidly advanced with the introduction of high throughput technologies to carry out simultaneous analyses of many samples. Microarrays to study macromolecular interactions (including glycan arrays) have paved the way for bioassay technologies which utilize cell arrays to study the effects of multiple macromolecules on cells. Glycan bioassay technologies are described in which immobilisation techniques for saccharides are exploited to develop a platform to probe cell responses such as signalling pathway activation. This review aims at reviewing available techniques and tools for the purification, analysis and bioassay of HS saccharides in biological systems using "glycomics" approaches. PMID- 24957777 TI - Changes in primary and secondary metabolite levels in response to gene targeting mediated site-directed mutagenesis of the anthranilate synthase gene in rice. AB - Gene targeting (GT) via homologous recombination allows precise modification of a target gene of interest. In a previous study, we successfully used GT to produce rice plants accumulating high levels of free tryptophan (Trp) in mature seeds and young leaves via targeted modification of a gene encoding anthranilate synthase-a key enzyme of Trp biosynthesis. Here, we performed metabolome analysis in the leaves and mature seeds of GT plants. Of 72 metabolites detected in both organs, a total of 13, including Trp, involved in amino acid metabolism, accumulated to levels >1.5-fold higher than controls in both leaves and mature seeds of GT plants. Surprisingly, the contents of certain metabolites valuable for both humans and livestock, such as gamma-aminobutyric acid and vitamin B, were significantly increased in mature seeds of GT plants. Moreover, untargeted analysis using LC-MS revealed that secondary metabolites, including an indole alkaloid, 2-[2-hydroxy-3-beta-d-glucopyranosyloxy-1-(1H-indol-3-yl)propyl] tryptophan, also accumulate to higher levels in GT plants. Some of these metabolite changes in plants produced via GT are similar to those observed in plants over expressing mutated genes, thus demonstrating that in vivo protein engineering via GT can be an effective approach to metabolic engineering in crops. PMID- 24957779 TI - Perinatal distress and depression in Malawi: an exploratory qualitative study of stressors, supports and symptoms. AB - Quantitative studies have demonstrated that depression and anxiety in the perinatal period are common amongst women in low- and middle-income countries and are associated with a range of psychosocial and health-related stressors. In this exploratory qualitative study conducted in southern Malawi, we investigated the thoughts and emotions experienced by women in pregnancy and the postnatal period, their expectations of support from husband and others, problems and difficulties faced and the impact of these on psychological wellbeing. We conducted 11 focus group discussions with a total of 98 parous women. A thematic analysis approach was used. Three major themes were identified: pregnancy as a time of uncertainty, the husband (and others) as support and stressor, and the impact of stressors on mental health. Pregnancy was seen as bringing uncertainty about the survival and wellbeing of both mother and unborn child. Poverty, lack of support, HIV, witchcraft and child illness were identified as causes of worry in the perinatal period. Husbands were expected to provide emotional, financial and practical support, with wider family and friends having a lesser role. Infidelity, abuse and abandonment were seen as key stressors in the perinatal period. Exposure to stressors was understood to lead to altered mental states, the symptoms of which are consistent with the concept of common perinatal mental disorder. This study confirms and expands on evidence from quantitative studies and provides formative data for the development of a psychosocial intervention for common perinatal mental disorder in Malawi. PMID- 24957782 TI - Effect of socioeconomic position on patient outcome after hysterectomy. AB - OBJECTIVE: To investigate the association between socioeconomic position (assessed by education, employment and income) and complications following hysterectomy and assess the role of lifestyle, co-morbidity and clinical conditions on the relationship. DESIGN: Register-based cohort study. SETTING AND POPULATION: The study included nearly all Danish women (n = 22 150) registered with a benign elective hysterectomy in the Danish Hysterectomy Database in 2004 2008. METHODS: Data were analyzed using logistic regression models estimating the odds ratio with 95% confidence intervals. MAIN OUTCOME MEASURES: Complications following hysterectomy. RESULTS: Seventeen percent of the women experienced complications in relation to the hysterectomy. Women with less than high school education and unemployed women had higher odds of infection, complications and readmission than women with more than high school education and employed women. Furthermore, unemployed women had higher odds of hospitalization >4 days than women in employment. Lifestyle factors (smoking and body mass index) and co morbidity status seemed to explain most of the social differences. However, an association between women with less than high school education and all complications remained unexplained. Furthermore, differences in lifestyle and co morbidity status only partially explained the higher odds of infection, complications and hospitalization >4 days for unemployed than employed women. CONCLUSION: Women with a low socioeconomic position have significantly higher odds of complications following hysterectomy compared with women with a high socioeconomic position. Unhealthy lifestyle and presence of co-morbidity in women with low socioeconomic position partially explains the differences in complications. PMID- 24957781 TI - Interpersonal psychotherapy for postpartum depression: a systematic review. AB - Interpersonal psychotherapy (IPT) is a dynamically informed and present-focused psychotherapy originally conceived for patients with unipolar depression and subsequently modified for other disorders, including postpartum depression (PPD). The aim of this paper is to review the evidence on the efficacy of IPT for PPD. We conducted a systematic review of studies published between 1995 and April 2013 assessing the efficacy of IPT for PPD using PubMed and PsycINFO. We included the following: (i) articles that presented a combination of at least two of the established terms in the abstract, namely, interpersonal [all fields] and ("psychotherapy" [MeSH terms] or psychotherapy [all fields]) and (perinatal [all fields] or postpartum [all fields]) and ("depressive disorder" [MeSH terms] or ("depressive" [all fields] and "disorder" [all fields]) or depressive disorder [all fields] or "depression" [all fields] or depression [MeSH terms]); (ii) manuscripts in English; (iii) original articles; and (iv) prospective or retrospective observational studies (analytical or descriptive), experimental, or quasi-experimental. Exclusion criteria were as follows: (i) other study designs, such as case reports, case series, and reviews; (ii) non-original studies including editorials, book reviews, and letters to the editor; and (iii) studies not specifically designed and focused on IPT. We identified 11 clinical primary trials assessing the efficacy of IPT for PPD, including 3 trials with group interventions (G-IPT) and one that required the presence of the partner (PA-IPT). We also identified six studies interpersonal-psychotherapy-oriented preventive interventions for use in pregnancy. IPT studies showed overall clinical improvement in the most commonly used depression measures in postpartum depressed women (EPDS, HDRS, BDI) and often-full recovery in several cases of treated patients. Evidence from clinical trials indicates that, when administered in monotherapy (or in combination with antidepressants), IPT may shorten the time to recovery from PPD and prolong the time spent in clinical remission. PMID- 24957776 TI - Systematic applications of metabolomics in metabolic engineering. AB - The goals of metabolic engineering are well-served by the biological information provided by metabolomics: information on how the cell is currently using its biochemical resources is perhaps one of the best ways to inform strategies to engineer a cell to produce a target compound. Using the analysis of extracellular or intracellular levels of the target compound (or a few closely related molecules) to drive metabolic engineering is quite common. However, there is surprisingly little systematic use of metabolomics datasets, which simultaneously measure hundreds of metabolites rather than just a few, for that same purpose. Here, we review the most common systematic approaches to integrating metabolite data with metabolic engineering, with emphasis on existing efforts to use whole metabolome datasets. We then review some of the most common approaches for computational modeling of cell-wide metabolism, including constraint-based models, and discuss current computational approaches that explicitly use metabolomics data. We conclude with discussion of the broader potential of computational approaches that systematically use metabolomics data to drive metabolic engineering. PMID- 24957778 TI - Distinct HIV-1 entry phenotypes are associated with transmission, subtype specificity, and resistance to broadly neutralizing antibodies. AB - BACKGROUND: The efficiency of CD4/CCR5 mediated HIV-1 entry has important implications for pathogenesis and transmission. The HIV-1 receptor affinity profiling (Affinofile) system analyzes and quantifies the infectivity of HIV-1 envelopes (Envs) across a spectrum of CD4/CCR5 expression levels and distills these data into a set of Affinofile metrics. The Affinofile system has shed light on how differential CD4/CCR5 usage efficiencies contributes to an array of Env phenotypes associated with cellular tropism, viral pathogenesis, and CCR5 inhibitor resistance. To facilitate more rapid, convenient, and robust analysis of HIV-1 entry phenotypes, we engineered a reporter Affinofile system containing a Tat- and Rev-dependent Gaussia luciferase-eGFP-Reporter (GGR) that is compatible with the use of pseudotyped or replication competent viruses with or without a virally encoded reporter gene. This GGR Affinofile system enabled a higher throughput characterization of CD4/CCR5 usage efficiencies associated with differential Env phenotypes. RESULTS: We first validated our GGR Affinofile system on isogenic JR-CSF Env mutants that differ in their affinity for CD4 and/or CCR5. We established that their GGR Affinofile metrics reflected their differential entry phenotypes on primary PBMCs and CD4+ T-cell subsets. We then applied GGR Affinofile profiling to reveal distinct entry phenotypes associated with transmission, subtype specificity, and resistance to broadly neutralizing antibodies (BNAbs). First, we profiled a panel of reference subtype B transmitted/founder (T/F) and chronic Envs (n = 12) by analyzing the infectivity of each Env across 25 distinct combinations of CD4/CCR5 expression levels. Affinofile metrics revealed that at low CCR5 levels, our panel of subtype B T/F Envs was more dependent on high levels of CD4 for HIV-1 entry compared to chronic Envs. Next, we analyzed a reference panel of 28 acute/early subtype A-D Envs, and noted that subtype C Envs could be distinguished from the other subtypes based on their infectivity profiles and relevant Affinofile metrics. Lastly, mutations known to confer resistance to VRC01 or PG6/PG19 BNAbs, when engineered into subtypes A-D Envs, resulted in significantly decreased CD4/CCR5 usage efficiency. CONCLUSIONS: GGR Affinofile profiling reveals pathophysiological phenotypes associated with varying HIV-1 entry efficiencies, and highlight the fitness costs associated with resistance to some broadly neutralizing antibodies. PMID- 24957784 TI - Treatment planning: A key milestone to prevent treatment dropout in adolescents with borderline personality disorder. AB - OBJECTIVE: The aim of this study was to gain a broader appreciation of processes involved in treatment dropout in adolescents with borderline personality disorder (BPD). DESIGN: A constructivist grounded theory was chosen using a multiple-case research design with three embedded levels of analysis (adolescent, parent, and care setting). METHOD: Theoretical sampling and the different stages of analysis specific to grounded theory were performed according to the iterative process of constant comparative analysis. Twelve cases were examined (nine dropouts among adolescents with BPD and for the purpose of falsification, one dropout of suicidal adolescent without BPD and two completed treatments among adolescents with BPD). To document the cases, three groups of informants were recruited (adolescents, parents, and therapists involved in the treatment) and 34 interviews were conducted. RESULTS: Psychological characteristics, perception of mental illness and mental health care, and help-seeking context were the specific treatment dropout vulnerabilities identified in adolescents with BPD and in their parents. However, their disengagement became an issue only when care-setting response--including mitigation of accessibility problems, adaptation of services to needs of adolescents with BPD, preparation for treatment, and concern for clinicians' disposition to treat--was ill-suited to these treatment dropout vulnerabilities. Treatment planning proves to be a key milestone to properly engage adolescents with BPD and their parent. CONCLUSIONS: Systematic assessment of treatment dropout vulnerabilities before the intervention plan is laid out could foster better-suited responses of the care setting thus decreasing the incidence of treatment discontinuation in adolescents with BPD. PRACTITIONER POINTS: Treatment dropout vulnerabilities specific to adolescents with BPD and their parents can be detected before the beginning of treatment. Premature treatment termination may be prevented if the care setting considers these vulnerabilities at treatment planning. Fears and negative reaction to treatment can be attenuated if the reasons behind the therapeutic orientation are explained and if the adolescent understand how the treatment will affect his condition. Concerns for autonomy of the adolescent, parental help-seeking context as well as ensuring that the clinician has the skills, interest, and motivation to work with the family may have a positive effect on families' commitment to treatment. PMID- 24957780 TI - Depressive symptoms in the transition to menopause: the roles of irritability, personality vulnerability, and self-regulation. AB - Although the transition to menopause represents a period of risk for depressive symptoms, there is little research into personality or trait-like factors that may confer vulnerability to depression during the transition to menopause. This study investigated whether the personality trait of self-criticism moderated the effects of irritability on depressive symptoms in women transitioning to menopause and whether these effects were mediated by lower levels of emotional regulation. Participants were 376 women, of whom 157 had entered the transition phase to menopause. These women in the transition phase completed measures of self-criticism, irritable mood, emotional regulation, and depressive symptoms. All analyses controlled for attitudes toward menopause and somatic symptoms. Moderated mediation regression analyses showed that higher levels of irritability were associated with poorer emotional regulation in highly self-critical women, but not in less self-critical women, and poorer emotional regulation was, in turn, related to higher levels depressive symptoms. Findings suggest that the transition to menopause may represent an especially vulnerable period for women with high levels of self-criticism. Although irritability is transitory for most women, for women who are highly self-critical, irritability may tax their ability to self-regulate and lead to more encompassing symptoms of depression. PMID- 24957783 TI - Derivation of normative data for the COPD assessment test (CAT). AB - BACKGROUND: The tradition classification of the severity of COPD, based on spirometry, fails to encompass the heterogeneity of the disease. The COPD assessment test (CAT), a multi-dimensional, patient-filled questionnaire, assesses the overall health status of patients, and is recommended as part of the assessment of individuals with COPD. However, information regarding the range of values for the test in a non-COPD population (normative values) is limited, and consequently, knowledge regarding the optimal cut-off, and the minimum clinically important difference (MCID) for the test remain largely empirical. METHODS: CanCOLD is a population-based multi-center cohort study conducted across Canada, the methodology of which is based on the international BOLD initiative. The study includes subjects with COPD, at-risk individuals who smoke, and healthy control subjects. CAT questionnaires were administered at baseline to all subjects. Among non-COPD subjects, normative values for the CAT questionnaire, and psychometric properties of the test were characterized. Predictors of high CAT scores were identified using multivariable logistic regression. RESULTS: Of the 525 non-COPD subjects enrolled, 500 were included in the analysis. Mean FEV1/FVC ratio among the 500 included subjects was 0.77 (SD 0.49); the mean predicted FEV1 was 99.38% (SD 16.88%). The overall mean CAT score was 6 (SD 5.09); scores were higher among females (6.43, SD 5.59), and subjects over 80 years of age (mean 7.58, SD 6.82). Cronbach alpha for the CAT was 0.79, suggesting a high internal consistency for the test. A score of 16 was the 95th percentile for the population, and 27 subjects (5.4%) were found to have a CAT score > =16. Current smoking (aOR 3.41, 95% CI 1.05, 11.02), subject-reported physician-diagnosed asthma (aOR 7.59, 95% CI 2.71, 21.25) and musculoskeletal disease (aOR 4.09, 95% CI 1.72, 9.71) were found to be significantly associated with a score >=16. CONCLUSIONS: The characterization of CAT scores in the general population will be useful for norm based comparisons. Longitudinal follow-up of these subjects will help in the optimization of cut-offs for the test. PMID- 24957785 TI - Modulation of insulin dose titration using a hypoglycaemia-sensitive algorithm: insulin glargine versus neutral protamine Hagedorn insulin in insulin-naive people with type 2 diabetes. AB - AIMS: To examine whether insulin glargine can lead to better control of glycated haemoglobin (HbA1c) than that achieved by neutral protamine Hagedorn (NPH) insulin, using a protocol designed to limit nocturnal hypoglycaemia. METHODS: The present study, the Least One Oral Antidiabetic Drug Treatment (LANCELOT) Study, was a 36-week, randomized, open-label, parallel-arm study conducted in Europe, Asia, the Middle East and South America. Participants were randomized (1:1) to begin glargine or NPH, on background of metformin with glimepiride. Weekly insulin titration aimed to achieve median prebreakfast and nocturnal plasma glucose levels <=5.5 mmol/l, while limiting values <=4.4 mmol/l. RESULTS: The efficacy population (n = 701) had a mean age of 57 years, a mean body mass index of 29.8 kg/m2, a mean duration of diabetes of 9.2 years and a mean HbA1c level of 8.2% (66 mmol/mol). At treatment end, HbA1c values and the proportion of participants with HbA1c <7.0 % (<53 mmol/mol) were not significantly different for glargine [7.1 % (54 mmol/mol) and 50.3%] versus NPH [7.2 % (55 mmol/mol) and 44.3%]. The rate of symptomatic nocturnal hypoglycaemia, confirmed by plasma glucose <=3.9 or <=3.1 mmol/l, was 29 and 48% less with glargine than with NPH insulin. Other outcomes were similar between the groups. CONCLUSION: Insulin glargine was not superior to NPH insulin in improving glycaemic control. The insulin dosing algorithm was not sufficient to equalize nocturnal hypoglycaemia between the two insulins. This study confirms, in a globally heterogeneous population, the reduction achieved in nocturnal hypoglycaemia while attaining good glycaemic control with insulin glargine compared with NPH, even when titrating basal insulin to prevent nocturnal hypoglycaemia rather than treating according to normal fasting glucose levels. PMID- 24957786 TI - Crosstalk between protective autophagy and NF-kappaB signal in high glucose induced podocytes. AB - Despite a great deal of recent studies focused on the pivotal role of autophagy in maintaining podocyte energy homeostasis, the mechanisms of autophagy in regulating transcriptional factors under high glucose (HG) condition are not fully understood. Here, we evaluated the effect of HG on nuclear factor-kappa B (NF-kappaB) signaling and autophagic process. The results showed that HG promoted autophagy in podocytes. Bafilomycin A1 (Baf A1) further enhanced this effect, but 3-methyadenine (3-MA) inhibited it. The proautophagic effects of HG manifested in the form of enhanced podocyte expression of light chain 3 (LC3)-II. In these cells, blockade of NF-kappaB signal by ammonium pyrrolidinethiocarbamate constrained in effectively reducing LC3-II up-regulation and increasing podocyte apoptosis. Furthermore, the autophagy inhibitors, such as Baf A1 and 3-MA, significantly enhanced HG-induced NF-kappaB activation and increased apoptosis. Thus, we conclude that the accumulation of autophagosomes results from enhancement of the autophagic flux, but not the blockage of autophagosome lysosome fusion by HG. We also prove that HG-induced apoptosis, autophagy, and NF kappaB signal are in a close crosstalk through a yet undetermined mechanism in podocytes. PMID- 24957787 TI - Unilateral hippocampal infarction associated with an attempted suicide: a case report. AB - INTRODUCTION: In our case report we describe the case of a patient who experienced a stroke in her left hippocampus that was found following an attempted suicide via glyphosate overdose. To the best of our knowledge this is the first case report to describe a hippocampal infarction associated with a drug overdose. CASE PRESENTATION: A 64-year-old Japanese woman was brought to our emergency department after ingestion of an unknown dose of glyphosate surfactant herbicide in order to attempt suicide. On admission, she was assumed to be presenting with depression or psychiatric illness, however, sudden-onset memory deficit became apparent. The patient manifested delirium, confusion, and severe anxiety. In addition, short-term memory loss was prominent, with the patient forgetting her attempted suicide. Following an array of standard tests and a brain computed tomography scan (which only showed an old infraction), we performed a magnetic resonance imaging scan and neuropsychological evaluations. The brain magnetic resonance image revealed a small high-intensity lesion in the dorsal part of the left hippocampal body, and memory tests demonstrated severe short-term recall deficits. We diagnosed her with a left hippocampal infarction and administered a course of 75mg of clopidogrel. She gradually became less confused over the course of a week, and a follow-up memory test revealed partial improvement in some domains. No abnormalities were found on a follow-up brain scan. However, despite rehabilitation, memory impairments remain. CONCLUSIONS: It is important to note that had the symptom of short-term memory been absent or less severe, she might have been misdiagnosed with depression or another psychiatric illness. Although a computed tomography scan failed to detect hippocampal lesions, a diffusion-weighted magnetic resonance imaging scan clearly revealed a lesion within the left hippocampus. Therefore, in addition to assessments focusing on psychiatric illnesses that might be the root cause of an attempted suicide, organic factors should be considered along with radiological examination and precise memory assessments for diagnosing similar cases. PMID- 24957788 TI - Preoperative pain and function profiles reflect consistent TKA patient selection among US surgeons. AB - BACKGROUND: As the number of primary total knee arthroplasties (TKAs) performed in the United States increases, policymakers have questioned whether the indications and timing of TKA have evolved so that surgery is offered earlier. QUESTIONS/PURPOSES: We analyzed data from a US national TKA cohort to evaluate variation in surgeon selection criteria for elective unilateral TKA based on preoperative patient-reported pain and function scores. METHODS: Preoperative SF 36 (Physical Component Summary [PCS]/physical function) scores and Knee Injury and Osteoarthritis Outcome Score (KOOS) (pain, activities of daily living/function) of 4900 patients undergoing elective unilateral TKA enrolled in this national database of prospectively followed patients from 22 states were evaluated. The 25th, 50th, and 75th percentile pain and function scores for patients cared for in 24 orthopaedic offices with 20 or more patients in the database were compared to assess whether consistent preoperative criteria are used in selecting patients undergoing TKA across settings. RESULTS: The preoperative global function (PCS median, 32.6; national norm, 50; SD, 10) and knee-specific function (KOOS median, 51.5; maximum score, 100; SD, 17) percentile scores represented substantial patient disability, because both values approached 2 SDs below ideal. Consistency in patients across 24 surgeon offices, and more than 100 surgeons, was noted because site-specific medians varied from the national median by less than the minimum clinically important change. CONCLUSIONS: These data suggest that despite the rapidly growing use of TKA, surgeons in the participating sites use consistent patient criteria in scheduling TKA. Today's patients report significant pain and disability, supporting the need for TKA. PMID- 24957789 TI - Prognostic significance of heme oxygenase-1, S100 calcium-binding protein A4, and syndecan-1 expression in primary non-muscle-invasive bladder cancer. AB - We investigated the prognostic significance of heme oxygenase-1 (HO-1), S100 calcium-binding protein A4 (S100A4), and syndecan-1 (SYND1) expression in patients with primary non-muscle-invasive bladder cancer (NMIBC). Immunohistochemical studies were performed on tissue specimens from 109 patients diagnosed with primary NMIBC following complete transurethral resection, with the expression dichotomized as negative/mild ("low") versus moderate/strong ("high") according to scores based on staining area and intensity. The effect of each biomarker on recurrence-free survival (RFS) and progression-free survival (PFS) was analyzed. The predictive accuracy for RFS and PFS in multivariate Cox regression models with or without (the baseline model) biomarkers was estimated using the Harrell concordance index. High HO-1, S100A4, and SYND1 expressions were observed in 33.0%, 36.7%, and 63.3% cases, respectively. High HO-1 and S100A4 expressions were significantly associated with various adverse pathological characteristics (high T stage and grade); SYND1 expression was inversely correlated with these characteristics (all, P < .05). In the baseline multivariate model, multifocality, intravesical therapy, and T stage were significant predictors for RFS, whereas intravesical therapy and T stage had marginal statistical significance in predicting PFS. In the multivariate model with the biomarkers, the 3 biomarkers were significant predictors for RFS; and HO 1 expression was a significant predictor for PFS. Addition of the 3 biomarkers to the baseline model significantly increased the predictive accuracy for RFS from 0.754 to 0.828 (P = .043). Our findings suggest that HO-1, S100A4, and SYND1 expressions have prognostic value in primary NMIBC; thus, their evaluation might be useful for determining treatment strategies. PMID- 24957791 TI - Marginalized multilevel hurdle and zero-inflated models for overdispersed and correlated count data with excess zeros. AB - Count data are collected repeatedly over time in many applications, such as biology, epidemiology, and public health. Such data are often characterized by the following three features. First, correlation due to the repeated measures is usually accounted for using subject-specific random effects, which are assumed to be normally distributed. Second, the sample variance may exceed the mean, and hence, the theoretical mean-variance relationship is violated, leading to overdispersion. This is usually allowed for based on a hierarchical approach, combining a Poisson model with gamma distributed random effects. Third, an excess of zeros beyond what standard count distributions can predict is often handled by either the hurdle or the zero-inflated model. A zero-inflated model assumes two processes as sources of zeros and combines a count distribution with a discrete point mass as a mixture, while the hurdle model separately handles zero observations and positive counts, where then a truncated-at-zero count distribution is used for the non-zero state. In practice, however, all these three features can appear simultaneously. Hence, a modeling framework that incorporates all three is necessary, and this presents challenges for the data analysis. Such models, when conditionally specified, will naturally have a subject-specific interpretation. However, adopting their purposefully modified marginalized versions leads to a direct marginal or population-averaged interpretation for parameter estimates of covariate effects, which is the primary interest in many applications. In this paper, we present a marginalized hurdle model and a marginalized zero-inflated model for correlated and overdispersed count data with excess zero observations and then illustrate these further with two case studies. The first dataset focuses on the Anopheles mosquito density around a hydroelectric dam, while adolescents' involvement in work, to earn money and support their families or themselves, is studied in the second example. Sub models, which result from omitting zero-inflation and/or overdispersion features, are also considered for comparison's purpose. Analysis of the two datasets showed that accounting for the correlation, overdispersion, and excess zeros simultaneously resulted in a better fit to the data and, more importantly, that omission of any of them leads to incorrect marginal inference and erroneous conclusions about covariate effects. PMID- 24957792 TI - Hyperhaemolysis in a patient with HbH disease. PMID- 24957790 TI - A data-driven approach to modeling the tripartite structure of multidrug resistance efflux pumps. AB - Many bacterial pathogens are becoming increasingly resistant to antibiotic treatments, and a detailed understanding of the molecular basis of antibiotic resistance is critical for the development of next-generation approaches for combating bacterial infections. Studies focusing on pathogens have revealed the profile of resistance in these organisms to be due primarily to the presence of multidrug resistance efflux pumps: tripartite protein complexes which span the periplasm bridging the inner and outer membranes of Gram-negative bacteria. An atomic-level resolution tripartite structure remains imperative to advancing our understanding of the molecular mechanisms of pump function using both theoretical and experimental approaches. We develop a fast and consistent method for constructing tripartite structures which leverages existing data-driven models and provide molecular modeling approaches for constructing tripartite structures of multidrug resistance efflux pumps. Our modeling studies reveal that conformational changes in the inner membrane component responsible for drug translocation have limited impact on the conformations of the other pump components, and that two distinct models derived from conflicting experimental data are both consistent with all currently available measurements. Additionally, we investigate putative drug translocation pathways via geometric simulations based on the available crystal structures of the inner membrane pump component, AcrB, bound to two drugs which occupy distinct binding sites: doxorubicin and linezolid. These simulations suggest that smaller drugs may enter the pump through a channel from the cytoplasmic leaflet of the inner membrane, while both smaller and larger drug molecules may enter through a vestibule accessible from the periplasm. PMID- 24957793 TI - Does dynamic vulcanization induce phase separation? AB - Immiscible and miscible blends of poly(vinylidene fluoride) (PVDF) and acrylic rubber (ACM) were subjected to dynamic vulcanization to investigate the effect of crosslinking on phase separation. As a result of different processability, mixing torque behavior of miscible and immiscible blends was significantly different from one another. Scanning electron microscopy (SEM) was used to investigate the morphology of the system. After dynamic vulcanization, submicron ACM droplets were observed in the samples near the binodal curve of the system under mixing conditions. Small angle X-ray scattering (SAXS) and differential scanning calorimetry (DSC) analysis were used to investigate the effect of dynamic vulcanization on the lamellar structure of the system. It was shown that for samples near the boundary of phase separation, increasing the crosslink density led to a decrease in the lamellar long period (L) as a sign of increment of crosslink density induced phase decomposition. Effects of shear rate on the final morphology of the system were investigated by changing the mixing temperature and by comparing the results of dynamic vulcanization at one phase and two phase regions. PMID- 24957794 TI - Comparison of the solubilizing efficiencies of some pH lowering (sulphur and (NH4)2SO4) amendments on Cd and Zn mobility in soils. AB - The use of conventional methods to clean up the soil is very expensive and destructive to the ecosystem. The concept of phytoextraction has been introduced to safely manage soils contaminated with heavy metals. However, using plants to remediate polluted soils is a lengthy process. This has necessitated the use of amendments to potentially enhance solubilization of metals in order to increase their bioavailability in the soil solution. A pot experiment was conducted to study the effect of some selected pH lowering amendments [elemental sulphur and (NH4)2SO4] on the solubility and availability of Cd and Zn. The application of these amendments resulted in a decrease in the pH of the soil. The decrease in pH significantly enhanced the solubilization and the mobility of Cd and Zn into the soil solution. The CaCl2 extraction protocol was employed to study the effects of the various amendments on the mobility of Cd and Zn. PMID- 24957795 TI - Trace elements in blood of sea turtles Lepidochelys olivacea in the Gulf of California, Mexico. AB - This study determined the concentrations of heavy metals in blood collected from Pacific Ridley sea turtles (Lepidochelys olivacea) inhabiting the coast of Guasave, Mexico, in the Gulf of California. The highest reported metal concentration in blood was Zn, followed by Se. Of nonessential toxic metals, As was reported in higher percentage compared to Cd. The concentrations of metals detected were present as follows: Zn > Se > Mn > As > Ni > Cd > Cu. Cd concentration in blood is higher in our population in comparison with other populations of L. olivacea, and even higher in other species of sea turtles. Our study reinforces the usefulness of blood for the monitoring of the levels of contaminating elements, and is easily accessible and nonlethal for sea turtles. PMID- 24957796 TI - Career decisions and gender: the illusion of choice? PMID- 24957797 TI - Self-assembly of gold nanoparticles on deep eutectic solvent (DES) surfaces. AB - Self-assembly of gold nanoparticles was obtained by sputter deposition on DES. SAXS and TEM investigations reveal the formation of spherical nanoparticles with a mean diameter of 5 +/- 0.5 nm. For extended sputtering times, the number density of AuNPs increases linearly and a very pronounced 1st and 2nd shell ordering is observed. PMID- 24957802 TI - Re: Shoulder silhouette and axilla reconstruction with free composite elbow tissue transfer following interscapulothoracic amputation. PMID- 24957801 TI - Incidence of heterotopic ossification in direct anterior total hip arthroplasty: a retrospective radiographic review. AB - Heterotopic ossification (HO) is a complication following total hip arthroplasty (THA) with traditional approaches. The direct anterior approach (DAA) has become a popular approach for THA; however, no study has evaluated HO formation following DAA THA. We examined the incidence of HO in a consecutive series of THA using the DAA in two separate hospitals. Standard preoperative radiographs were examined to determine the type of degenerative arthritis, and follow-up radiographs of at least 6 months after surgery were evaluated for the presence and classification of HO. The overall incidence of HO after DAA THA in this study was 98/236, or 41.5%, which falls within the reported range from recent studies involving more traditional approaches to the hip. PMID- 24957803 TI - Vascular anatomy of the medial sural artery perforator flap: a new classification system of intra-muscular branching patterns. AB - BACKGROUND: The medial sural artery perforator (MSAP) flap is a versatile fasciocutaneous flap. The main difficulty encountered when raising the MSAP flap is in obtaining adequate pedicle length during intra-muscular dissection. The objective of this study was to determine the pattern of intra-muscular course of the MSAP flap pedicle. METHODS: 14 cadaveric specimens were dissected and CT angiograms of 84 legs were examined. The intra-muscular branching pattern and depths of the medial sural artery branches were analyzed. The number of perforators, position of the dominant perforator and both intra-muscular and total pedicle length were also recorded and compared to existing anatomical data. RESULTS: Three types of arterial branching pattern were identified within the medial gastrocnemius, demonstrating one (31%), two (59%) or three or more (10%) main branches. A dominant perforator from the medial sural artery was present in 92% of anatomical specimens (13/14). Vertically, the location of the perforator from the popliteal crease was on average 13 cm (+/-2 cm). Transversely, the perforator originated 2.5 cm (+/-1 cm) from the posterior midline. Using CT angiography it was possible in 10 consecutive patients to identify a more superficial intra-muscular branch and determine the leg with the optimal branching pattern type for flap harvest. CONCLUSIONS: This study is the first to describe the variability of the intra-muscular arterial anatomy of the medial head of gastrocnemius muscle. Surgeons utilizing the MSAP flap option should be aware of the possible branching pattern types and consequently the differing perforator distribution and depths of intra-muscular branches. Routine use of pre operative CT angiogram may help determine which leg has the most favorable branching pattern type and intra-muscular course for flap harvest. PMID- 24957804 TI - Evaluation of the effectiveness of hydrogen-peroxide-based disinfectants on biofilms formed by Gram-negative pathogens. AB - BACKGROUND: Hydrogen peroxide (H2O2)-based disinfectants are widely used in a number of different healthcare settings to control bacterial colonization and contamination, and reduce the risk of cross-infection. Efficacy tests of these formulations are performed on planktonic cultures, although it is well known that biofilms are the dominant form of bacterial contamination and more difficult to eradicate. AIM: To determine if the biofilms of three different Gram-negative pathogens associated with multi-drug-resistant phenotypes can be eradicated effectively using different H2O2-based disinfectants. METHODS: Planktonic cultures and single-species 24-h biofilms of seven strains of Acinetobacter spp., seven strains of Klebsiella pneumoniae and seven strains of Pseudomonas aeruginosa, including clinical isolates, were exposed to working concentrations of H2O2 and H2O2-based formulations for 1 min to 24h. Survival was monitored. FINDINGS: The levels of susceptibility of planktonic cultures to unformulated and formulated H2O2 were similar in all organisms and strains tested, with minimum inhibitory concentrations ranging from 0.5 to 20mM H2O2. However, biofilms showed up to 266-fold less sensitivity to H2O2 and its formulations. The level of reduced susceptibility correlated with the strain's propensity to form biofilm, and differed between species. The two formulations with additional acidic active ingredients performed better at short exposure times, whereas ethanol-containing products required longer exposure times to be effective. CONCLUSION: Biofilms of a significant number of clinical isolates of multi-drug-resistant nosocomial pathogens are not susceptible to working concentrations of several H2O2-based disinfectants. This may compromise the ability to control these pathogens with such products. PMID- 24957805 TI - National European guidelines for the prevention of Clostridium difficile infection: a systematic qualitative review. AB - BACKGROUND: Clostridium difficile is the most frequent infectious cause of nosocomial diarrhoea and a major topic in infection prevention. AIM: To overview current national European guidelines for C. difficile infection (CDI) prevention and review the recommendations in respect of their evidence base and conformity to each other and the European Centre for Disease Control and Prevention (ECDC) guidance. METHODS: In 34 European countries, the ECDC healthcare-associated infection (HCAI) surveillance National Contact Points and other HCAI experts (NCPs) were invited to complete an online questionnaire and to supply their guidelines. Guidelines not available in English, French or German were translated into English. For the qualitative analysis, a matrix with key measures based on the 2008 ECDC guidance was established. The review process was conducted independently by two reviewers. RESULTS: All 34 NCPs responded to the questionnaire and supplied 15 guidelines in total. Six of 34 (18%) countries reported having used the ECDC guidance as a basis for the development or revision of their national guideline. There was wide variation in the scope and detailing. Only six of the documents and the ECDC guidance supplied a rating for the strength of recommendations. The rating systems varied in how the categories were defined. Furthermore, the stated strength for similar measures varied across different guidelines. CONCLUSION: The ECDC guidance has not yet had a strong influence on the development or revision of national CDI prevention guidelines. One possible explanation for the variations is the necessity to adapt recommendations to national conditions. The use of internationally recognized instruments for the development of guidelines could help to improve their quality. Recommendations about monitoring or auditing the implementation would make them more useful. PMID- 24957806 TI - Increasing frequency of severe clinical toxicity after use of 2,4-dinitrophenol in the UK: a report from the National Poisons Information Service. AB - OBJECTIVE: 2,4-Dinitrophenol (DNP) increases energy consumption by uncoupling oxidative phosphorylation. Although not licensed as a medicine, it is sometimes used by 'body sculptors' and for weight loss as a 'fat burning' agent. This research was performed to characterise patterns of presentation, clinical features and outcomes of patients reported to the National Poisons Information Service (NPIS) in the UK after exposure to DNP. METHODS: NPIS telephone enquiry records and user sessions for TOXBASE, the NPIS online information database, related to DNP, were reviewed from 1 January 2007 to 31 December 2013. RESULTS: Of the 30 separate systemic exposures to DNP reported by telephone to NPIS during the study period (27 males, 3 females, with a median age of 23.5 years), there were 3 during 2007-2011 (inclusive), 5 during 2012 and 22 during 2013. TOXBASE user sessions also increased sharply from 6 in 2011 to 35 in 2012 and 331 in 2013. The modes of exposure reported in telephone enquiries were chronic (n=2), acute (n=12) and subacute (n=16). Commonly reported clinical features were fever (47%), tachycardia (43%), sweating (37%), nausea or vomiting (27%), skin discolouration or rash (23%), breathing difficulties (23%), abdominal pain (23%), agitation (13%) and headache (13%). There were five (17%, 95% CI 6.9% to 34%) fatalities, four involving acute overdose. CONCLUSIONS: The study indicates a substantial recent increase in clinical presentations with toxicity caused by exposure to DNP in the UK with an associated high mortality. Further steps are needed to warn potential users of the severe and sometimes fatal toxicity that may occur after exposure to this compound. PMID- 24957807 TI - Prehospital administered fascia iliaca compartment block by emergency medical service nurses, a feasibility study. AB - INTRODUCTION: Patients with a proximal femur fracture are often difficult to evacuate from the accident scene. Prehospital pain management for this vulnerable group of patients may be challenging. Multiple co-morbidities, polypharmacy and increased age may limit the choice of suitable analgesics. The fascia iliaca compartment (FIC) block may be an alternative to intravenous analgesics. However this peripheral nerve block is mainly applied by physicians.In the Netherlands, prehospital emergency care is mostly provided by EMS-nurses. Therefore we examined whether well-trained EMS-nurses are able to successfully perform a FIC block in order to ensure timely and appropriate effective analgesia.The study was study was registered in the Netherlands Trial Register (NTR-nr 3824). METHODS: Ten EMS nurses were educated in the performance of a FIC-block. Indications, technique, side-effects and complications were discussed. Hereafter the trained EMS-nurses staffed ambulance teams were dispatched to patients with a suspicion for a proximal femur fracture. After confirmation of the diagnosis, the block was performed and 0.3 ml/kg lidocaine (10 mg/ml) with adrenaline 5 MUg/ml was injected. The quality of pain relief, occurrence of complications and patient satisfaction were evaluated. RESULTS: In 108 patients a block was performed. One hundred patients could be included. Every EMS nurse performed at least 10 FIC blocks. The block was effective in 96 patients. The initial median (NRS)-pain score decreased after block performance to a score of 6 (after 10 minutes), 4 (after 20 minutes) and 3 (after 30 minutes). At arrival at the Emergency Department the median pain score was 3. Dynamic NRS-pain scores when transferring the patient from the accident scene to the ambulance stretcher, during transportation to the hospital and when transferring the patient to a hospital bed were, 4, 3 and 3.5 respectively. Patient satisfaction was very high. No complications were noted. CONCLUSION: Additional educated EMS-nurses are able to successfully perform a FIC-block for providing acute pain relief to patients with a suspected proximal femur fracture. PMID- 24957809 TI - Incidence and outcomes of acute kidney injury following orthotopic lung transplantation: a population-based cohort study. AB - BACKGROUND: Acute kidney injury (AKI) is a serious complication following lung transplantation (LTx). We aimed to describe the incidence and outcomes associated with AKI following LTx. METHODS: A retrospective population-based cohort study of all adult recipients of LTx at the University of Alberta between 1990 and 2011. The primary outcome was AKI, defined and classified according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, in the first 7 post operative days. Secondary outcomes included risk factors, utilization of renal replacement therapy (RRT), occurrence of post-operative complications, mortality and kidney recovery. RESULTS: Of 445 LTx recipients included, AKI occurred in 306 (68.8%), with severity classified as Stage I in 38.9% (n = 173), Stage II in 17.5% (n = 78) and Stage III in 12.4% (n = 55). RRT was received by 36 (8.1%). Factors associated with AKI included longer duration of cardiopulmonary bypass [per minute, odds ratio (OR) 1.003; 95% confidence interval (CI), 1.001-1.006; P = 0.02], and mechanical ventilation [per hour (log-transformed), OR 5.30; 95% CI, 3.04-9.24; P < 0.001], and use of cyclosporine (OR 2.03; 95% CI, 1.13-3.64; P = 0.02). In-hospital and 1-year mortality were significantly higher in those with AKI compared with no AKI (7.2 versus 0%; adjusted P = 0.001; 14.4 versus 5.0%; adjusted P = 0.02, respectively). At 3 months, those with AKI had greater sustained loss of kidney function compared with no AKI [estimated glomerular filtration rate, mean (SD): 68.9 (25.7) versus 75.3 (22.1) mL/min/1.73 m(2), P = 0.01]. CONCLUSIONS: By the KDIGO definition, AKI occurred in two-thirds of patients following LTx. AKI portended greater risk of death and loss of kidney function. PMID- 24957812 TI - Controlling the window size in mesoporous SBA-16. AB - The structure of the mesoporous silica SBA-16 has been interrogated by careful elimination of the organic templating agent using ozone treatment. It is shown that the as-synthesised material consists of large cages connected by very narrow, ca. 7 A, windows. These windows open up to about 20 A following a calcination treatment that suggests that the functionality of SBA-16 could be changed markedly depending upon the post-synthesis treatment. The structure of SBA-16 is compared with surfaces of constant mean curvature. This illustrates that although most of the structure conforms to a surface of constant mean curvature the necks in the structure near the windows deviate strongly. This confirms that attractive forces in this region during synthesis play an important role in shaping the final structure. Following calcination the structure changes as the silica framework relaxes to a constant surface energy. PMID- 24957808 TI - Quality standards for predialysis education: results from a consensus conference. AB - This position statement was compiled following an expert meeting in March 2013, Zurich, Switzerland. Attendees were invited from a spread of European renal units with established and respected renal replacement therapy option education programmes. Discussions centred around optimal ways of creating an education team, setting realistic and meaningful objectives for patient education, and assessing the quality of education delivered. PMID- 24957798 TI - CCL2 enhances pluripotency of human induced pluripotent stem cells by activating hypoxia related genes. AB - Standard culture of human induced pluripotent stem cells (hiPSCs) requires basic Fibroblast Growth Factor (bFGF) to maintain the pluripotent state, whereas hiPSC more closely resemble epiblast stem cells than true naive state ES which requires LIF to maintain pluripotency. Here we show that chemokine (C-C motif) ligand 2 (CCL2) enhances the expression of pluripotent marker genes through the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) protein. Moreover, comparison of transcriptomes between hiPSCs cultured with CCL2 versus with bFGF, we found that CCL2 activates hypoxia related genes, suggesting that CCL2 enhanced pluripotency by inducing a hypoxic-like response.Further, we show that hiPSCs cultured with CCL2 can differentiate at a higher efficiency than culturing withjust bFGF and we show CCL2 can be used in feeder-free conditions [corrected]. Taken together, our finding indicates the novel functions of CCL2 in enhancing its pluripotency in hiPSCs. PMID- 24957810 TI - A nephrology guide to reading and using systematic reviews of randomized trials. AB - Conscientious integration of the best available evidence in the care of an individual patient could be challenging for a busy clinician. A well-conducted systematic review can adequately inform not only the clinicians, but also the policy makers and researchers about the benefits and risks of a particular intervention. In this article, we describe how to critically appraise the methods and interpret the results of a systematic review of interventional trials and apply the findings of a systematic review to the clinical questions. PMID- 24957811 TI - Time course of asymmetric dimethylarginine and symmetric dimethylarginine levels after successful renal transplantation. AB - BACKGROUND: Although renal transplantation (Tx) improves the outcome of patients with renal disease, cardiovascular (CV) risk remains high. Recently, it was demonstrated that asymmetric dimethylarginine (ADMA) levels predict CV events and graft survival in renal transplant recipients (RTRs). Little is known about the impact of renal Tx on the plasma levels of ADMA and symmetric dimethylarginine (SDMA). The present study aimed to define the time course of ADMA and SDMA after Tx. METHODS: We prospectively followed 167 incident RTRs with visits at the time of Tx and 3 and 12 months thereafter. At all visits, demographics and relevant biochemistry were recorded and blood was sampled for analysis of ADMA and SDMA (high-performance liquid chromatography). Eighty-four patients had an additional sampling in the immediate postoperative period. In a case-controlled substudy (n = 31), we compared ADMA and SDMA levels between RTRs and chronic kidney disease (CKD) patients, matched for glomerular filtration rate, gender, age, CV history and diabetes. RESULTS: Overall, plasma ADMA and SDMA levels decreased after Tx. The decline of SDMA was more pronounced and paralleled the recovery of renal function. Interestingly, the decline of ADMA was preceded by an increase in the immediate postoperative period. In the case-controlled substudy, SDMA levels were similar, whereas ADMA levels were significantly higher in RTRs compared with the CKD counterparts (P = 0.003). CONCLUSION: ADMA levels follow a biphasic pattern after successful renal Tx with a transient rise in the immediate postoperative period followed by a decline. Levels remain elevated compared with CKD patients, matched for age, gender, diabetes, CV history and renal function. PMID- 24957815 TI - Assessment of pain during endotracheal suction in the pediatric intensive care unit. AB - This research was planned as a two-level definitive and comparative study to evaluate pain during endotracheal suction (ETS) in pediatric intensive care units (PICUs). This study was comprised of patients admitted to and the nurses working in the PICU. Cases were selected among PICU patients (N = 65) who met the study criteria and nurses (N = 18) who cared for them from January 1 to July 2, 2008. Routine ETS was applied as the first level of the study. For the second level, an inquiry on the knowledge of nurses about suction was given to the nurses, and they were asked to apply suction according to the guidelines they were given. All the obtained data were evaluated by statistical package for the social sciences (SPSS) for Windows 14.0. In summary, 33.8% (n = 22) of the patients were between ages 1 and 12 months, and 64.6% (n = 42) were boys. Although group 2 patients (patient who is in experimental group) had higher scores on the Wong-Baker faces pain rating and Face, Legs, Activity, Cry, Consolability scales, no statistical difference was found between the two groups (p > .05). Patients who received bolus doses of analgesia and sedative drugs had lower Wong-Baker faces pain rating (4.38 +/- 0.96; n = 4) and Face, Legs, Activity, Cry, Consolability scores (4.61 +/- 1.94; n = 4) (p > .05). According to these findings, the patients were distressed because of the pain related with suction. Therefore, it is recommended that suction guidelines be used in PICUs during ETS. PMID- 24957813 TI - In vitro wear behavior of zirconia opposing enamel: a systematic review. AB - PURPOSE: The aim of this systematic review was to assess enamel wear on teeth opposing zirconia restorations and to evaluate factors related to the wear of natural teeth opposing zirconia restorations. MATERIALS AND METHODS: Five electronic databases were searched through May 2013 without limitations. The terms "antagonist*," "enamel," "wear," and "zirconi*" were used. Titles and abstracts were initially screened, and those that fulfilled the inclusion criteria were selected for a full-text assessment. Studies that evaluated only the material wear were not included. RESULTS: The database search strategy retrieved 142 potentially eligible studies. After the duplicate studies were removed, 62 studies were obtained. Titles and abstracts that fulfilled the inclusion criteria were selected for a full-text assessment (25). Seven laboratory studies met the inclusion criteria. In addition, reference lists from the finally selected studies were also screened. CONCLUSIONS: There was a large variation in relation to wear test method quantification, applied force, lateral movement, number and frequency of cycles, number of specimens, and enamel specimen preparation. In all studies, enamel wear rates were lower against polished zirconia. Differences in the test methods did not allow for comparisons of wear rates among the studies. CLINICAL SIGNIFICANCE: Polishing the surface is recommended for a full-contour zirconia restoration because polished zirconia presents favorable wear behavior opposing natural teeth. PMID- 24957814 TI - Medical and surgical management for chronic thromboembolic pulmonary hypertension: a single center experience. AB - INTRODUCTION: Pulmonary endarterectomy (PE) is the treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to analyze our experience in the medical and surgical management of CTEPH. METHODS: We included 80 patients diagnosed with CTEPH between January 2000 and July 2012. Thirty two patients underwent PE and 48 received medical treatment (MT). We analyzed functional class (FC), six-minute walking distance (6MWD) and pulmonary hemodynamics. Mortality in both groups and periods were analyzed. RESULTS: Patients who underwent PE were younger, mostly men, and had longer 6MWD. No differences were observed in pulmonary hemodynamics or FC at diagnosis. One year after treatment, all PE patients versus 41% in MT group were at FCI-II. At follow-up, the PE group showed greater increase in 6MWD, and greater reduction in mean pulmonary arterial pressure and pulmonary vascular resistance than the MT group (P<.05). Overall survival in the MT group at 1 and 5years was 83% and 69%, respectively. Conditional survival in patients alive 100days post-PE at 1 and 5years was 95% and 88%, respectively. Surgical mortality in operated patients in the first period (2000-2006) was 31,3%, and 6,3% in the second (2007-2012). CONCLUSIONS: PE provides good clinical results, and improves pulmonary hemodynamics in patients who successfully overcome the immediate postoperative period. After a learning period, the current operatory mortality in our center is similar to international standards. PMID- 24957816 TI - Nurses' provision of parental guidance regarding school-aged children's postoperative pain management: a descriptive correlational study. AB - Involving parents in children's pain management is essential to achieve optimal outcomes. Parents need to be equipped with sufficient knowledge and information. Only a limited number of studies have explored nurses' provision of parental guidance regarding the use of nonpharmacologic methods in children's pain management. This study aimed to examine nurses' perceptions of providing preparatory information and nonpharmacologic methods to parents, and how their demographics and perceived knowledge adequacy of these methods influence this guidance. A descriptive correlational study using questionnaire surveys was conducted to collect data from a convenience sample of 134 registered nurses working in seven pediatric wards of two public hospitals in Singapore. Descriptive statistics, independent-samples t test, and multiple linear regression were used to analyze the data. Most nurses provided various types of cognitive information to parents related to their children's surgery, whereas information about children's feelings was less often provided. Most nurses provided guidance to parents on positioning, breathing technique, comforting/reassurance, helping with activities of daily living, relaxation, and creating a comfortable environment. Nurses' provision of parental guidance on preparatory information and nonpharmacologic methods was significantly different between subgroups of age, education, parent or not, and perceived knowledge adequacy of nonpharmacologic methods. Nurses' perceived knowledge adequacy was the main factor influencing their provision of parental guidance. More attention should be paid to nurses who are younger, have less working experience, and are not parents. There is a need to educate nurses about nonpharmacologic pain relief methods to optimize their provision of parental guidance. PMID- 24957817 TI - Efficacy of relaxation intervention on pain, self-efficacy, and stress-related variables in patients following total knee replacement surgery. AB - Following total knee replacement (TKR) surgery, patients frequently experience intense levels of pain, stress, and anxiety that may reduce their self-efficacy and thus affect their postoperative recovery. Relaxation intervention is beneficial to help patients manage physical pain and emotional tension. However, evidence for the efficacy of relaxation intervention on patients following TKR is still inconclusive. This study aimed to investigate whether a relaxation intervention helped to reduce pain, stress, and anxiety, and whether it helped to increase perceived relaxation and self-efficacy in patients following TKR. A single-group, pretest-posttest quasi-experimental study was carried out at a tertiary hospital in Singapore. A convenience sampling of 18 participants was recruited. Patients received three-session, individual-based relaxation interventions comprised of breathing exercises, muscle relaxation, and guided imagery. Data were collected by self-reported questionnaires and physiologic measures and were analyzed using descriptive statistics, paired t test, and repeated measure analysis of variance. Intent-to-treat analyses were used to deal with missing data. Following the intervention, participants reported significantly lower pain, stress, and anxiety and greater perceived relaxation and self-efficacy. Findings from this study contribute to both nursing science and clinical practice. The relaxation intervention can be offered as part of standard care for patients following TKR in hospitals. PMID- 24957818 TI - Urinary proteomics and molecular determinants of chronic kidney disease: possible link to proteases. AB - Chronic kidney disease (CKD) is the gradual decrease in renal function. Currently available biomarkers are effective only in detecting late stage CKD. Biomarkers of early stage CKD and prognostic biomarkers are required. We review the major findings in urinary proteomics in CKD during the last five years. Significant progress has been made and today urinary proteomics is applied in large randomized trials, and in patient management. Many of the biomarkers indicate altered protease activity. We therefore also review the literature on proteases associated with renal function loss. We anticipate in silico prediction tools of protease activity and additional system biology studies may contribute to biomarker discovery and elucidate the role of proteases in CKD development and progression. These approaches will enable the deciphering of the molecular pathophysiology of CKD, and hence definition of the most appropriate therapeutic targets in the future. Together with stable biomarker panels available today, this will significantly improve patient management. PMID- 24957819 TI - Amylin receptor signaling in the nucleus accumbens negatively modulates MU-opioid driven feeding. AB - Amylin is a peptide co-secreted with insulin that penetrates into the brain, and produces satiation-like effects via actions in the brainstem, hypothalamus, and mesencephalon. Little is known, however, about the effects of amylin in the nucleus accumbens shell (AcbSh), where a circumscribed zone of intense amylin receptor (AMY-R) binding overlaps reported mappings of a 'hotspot' for MU-opioid receptor (MU-OR) amplification of food reward. Here, the ability of intra-AcbSh AMY-R signaling to modulate MU-OR-driven feeding was explored. Amylin (1-30 ng) was administered with the MU-OR agonist, D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) (0.25 MUg), directly into the AcbSh of ad libitum-maintained rats. Amylin dose-dependently reversed DAMGO-induced hyperphagia; 3 ng of amylin reduced DAMGO mediated feeding by nearly 50%. This dose was, however, completely ineffective at altering DAMGO-induced feeding in the anterior dorsal striatum. Intra-AcbSh amylin alone (3-30 ng) modestly suppressed 10% sucrose intake in ad libitum maintained rats, and chow in food-deprived rats, but only at the 30-ng dose. This result indicates that reversal of AcbSh DAMGO-induced feeding at a 10-fold lower dose was neither due to malaise nor motoric impairment. Finally, intra-AcbSh infusion of the AMY-R antagonist, AC187 (20 MUg), significantly attenuated the ability of prefeeding to suppress DAMGO-induced food intake, with no effects in non-prefed rats. Hence, AMY-R signaling negatively modulates MU-OR-mediated appetitive responses at the level of the AcbSh. The results with AC187 indicate that endogenous AMY-R transmission in the AcbSh curtails opioid function in the postprandial period, suggesting a novel pathway for peripheral-central integration in the control of appetitive motivation and opioid reward. PMID- 24957820 TI - Effectiveness of antimicrobial peptide immobilization for preventing perioperative cornea implant-associated bacterial infection. AB - Titanium (Ti) is a promising candidate biomaterial for an artificial corneal skirt. Antimicrobial peptide (AMP) immobilization may improve the bactericidal effect of the Ti substrate. In this study, we tested the bactericidal efficacy of a functionalized Ti surface in a rabbit keratitis model. A corneal stromal pocket was created by a femtosecond laser. The Ti films were then inserted into the pocket, and Staphylococcus aureus or Pseudomonas aeruginosa was inoculated into the pocket above the implant films. The corneas with Ti-AMP implants were compared with the corneas implanted with unprotected Ti by slit lamp observation and anterior segment optical coherence tomography (AS-OCT). Inflammatory responses were evaluated by bacterium counting, hematoxylin-eosin staining, and immunostaining. There was a lower incidence and a lesser extent of infection on rabbit corneas with Ti-AMP implants than on those with unprotected Ti implants. The bactericidal effect of AMP against S. aureus was comparable to that of postoperative prophylactic antibiotic treatment; hence, SESB2V AMP bound to the Ti implant provided functional activity in vivo, but its efficacy was greater against S. aureus than against P. aeruginosa. This work suggests that SESB2V AMP can be successfully functionalized in a rabbit keratitis model to prevent perioperative corneal infection. PMID- 24957821 TI - Micafungin at physiological serum concentrations shows antifungal activity against Candida albicans and Candida parapsilosis biofilms. AB - We assessed the in vitro activity of micafungin against preformed Candida biofilms by measuring the concentration of drug causing the most fungal damage and inhibition of regrowth. We studied 37 biofilm-producing Candida spp. strains from blood cultures. We showed that micafungin was active against planktonic and sessile forms of Candida albicans strains and moderately active against Candida parapsilosis sessile cells. Concentrations of micafungin above 2 MUg/ml were sufficiently high to inactivate regrowth of Candida sessile cells. PMID- 24957822 TI - Synergy of streptogramin antibiotics occurs independently of their effects on translation. AB - Streptogramin antibiotics are divided into types A and B, which in combination can act synergistically. We compared the molecular interactions of the streptogramin combinations Synercid (type A, dalfopristin; type B, quinupristin) and NXL 103 (type A, flopristin; type B, linopristin) with the Escherichia coli 70S ribosome by X-ray crystallography. We further analyzed the activity of the streptogramin components individually and in combination. The streptogramin A and B components in Synercid and NXL 103 exhibit synergistic antimicrobial activity against certain pathogenic bacteria. However, in transcription-coupled translation assays, only combinations that include dalfopristin, the streptogramin A component of Synercid, show synergy. Notably, the diethylaminoethylsulfonyl group in dalfopristin reduces its activity but is the basis for synergy in transcription-coupled translation assays before its rapid hydrolysis from the depsipeptide core. Replacement of the diethylaminoethylsulfonyl group in dalfopristin by a nonhydrolyzable group may therefore be beneficial for synergy. The absence of general streptogramin synergy in transcription-coupled translation assays suggests that the synergistic antimicrobial activity of streptogramins can occur independently of the effects of streptogramin on translation. PMID- 24957824 TI - Mathematical model to quantify the effects of risk factors on carbapenem resistant Acinetobacter baumannii. AB - Carbapenem-resistant Acinetobacter baumannii (CRAB) infections are increasing, and they are associated with an increased risk of mortality in hospitalized patients. Linear regression is commonly used to identify concurrent trends, but it cannot quantify the relationship between risk factors and resistance. We developed a model to quantify the impact of antibiotic consumption on the prevalence of CRAB over time. Data were collected from January 2007 to June 2013 from our institution. Quarterly antibiotic consumption was expressed as defined daily dose/1,000 inpatient days. Six-month prevalence of CRAB was expressed as a percentage of all nonrepeat A. baumannii isolates tested. Individual trends were identified using linear regression. Antibiotic consumption from 2007 to 2011 was input as a step function in a relationship with CRAB. Model fit was evaluated by visual inspection and the residual sum of squares. The final model was validated using the best-fit (95% confidence interval) parameter estimates and antibiotic consumption to predict CRAB prevalence from January 2012 to June 2013. Cefepime, ertapenem, and piperacillin-tazobactam consumption and CRAB prevalence increased significantly over time. CRAB prevalence was best correlated to ertapenem (use sensitive; r2=0.76), and accounting for additional concurrent antibiotic use did not significantly improve model fit. Prospective validation with ertapenem consumption correlated well with CRAB observations, suggesting good predicting ability of the model. Our model provided the quantitative impact of antibiotic consumption on CRAB. We plan to further refine this model to account for multiple risk factors. Interventions should focus on controlling risk factors with the highest impact on resistance. PMID- 24957823 TI - Phase I safety, pharmacokinetics, and pharmacogenetics study of the antituberculosis drug PA-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin. AB - There is an urgent need for new antituberculosis (anti-TB) drugs, including agents that are safe and effective with concomitant antiretrovirals (ARV) and first-line TB drugs. PA-824 is a novel antituberculosis nitroimidazole in late phase clinical development. Cytochrome P450 (CYP) 3A, which can be induced or inhibited by ARV and antituberculosis drugs, is a minor (~20%) metabolic pathway for PA-824. In a phase I clinical trial, we characterized interactions between PA 824 and efavirenz (arm 1), lopinavir/ritonavir (arm 2), and rifampin (arm 3) in healthy, HIV-uninfected volunteers without TB disease. Participants in arms 1 and 2 were randomized to receive drugs via sequence 1 (PA-824 alone, washout, ARV, and ARV plus PA-824) or sequence 2 (ARV, ARV with PA-824, washout, and PA-824 alone). In arm 3, participants received PA-824 and then rifampin and then both. Pharmacokinetic sampling occurred at the end of each dosing period. Fifty-two individuals participated. Compared to PA-824 alone, plasma PA-824 values (based on geometric mean ratios) for maximum concentration (Cmax), area under the concentration-time curve from 0 to 24 h (AUC0-24), and trough concentration (Cmin) were reduced 28%, 35%, and 46% with efavirenz, 13%, 17%, and 21% with lopinavir-ritonavir (lopinavir/r) and 53%, 66%, and 85% with rifampin, respectively. Medications were well tolerated. In conclusion, lopinavir/r had minimal effect on PA-824 exposures, supporting PA-824 use with lopinavir/r without dose adjustment. PA-824 exposures, though, were reduced more than expected when given with efavirenz or rifampin. The clinical implications of these reductions will depend upon data from current clinical trials defining PA 824 concentration-effect relationships. (This study has been registered at ClinicalTrials.gov under registration no. NCT01571414.). PMID- 24957825 TI - Defining daptomycin resistance prevention exposures in vancomycin-resistant Enterococcus faecium and E. faecalis. AB - Daptomycin is used off-label for enterococcal infections; however, dosing targets for resistance prevention remain undefined. Doses of 4 to 6 mg/kg of body weight/day approved for staphylococci are likely inadequate against enterococci due to reduced susceptibility. We modeled daptomycin regimens in vitro to determine the minimum exposure to prevent daptomycin resistance (Dapr) in enterococci. Daptomycin simulations of 4 to 12 mg/kg/day (maximum concentration of drug in serum [Cmax] of 57.8, 93.9, 123.3, 141.1, and 183.7 mg/liter; half life [t1/2] of 8 h) were tested against one Enterococcus faecium strain (S447) and one Enterococcus faecalis strain (S613) in a simulated endocardial vegetation pharmacokinetic/pharmacodynamic model over 14 days. Samples were plated on media containing 3* the MIC of daptomycin to detect Dapr. Mutations in genes encoding proteins associated with cell envelope homeostasis (yycFG and liaFSR) and phospholipid metabolism (cardiolipin synthase [cls] and cyclopropane fatty acid synthetase [cfa]) were investigated in Dapr derivatives. Dapr derivatives were assessed for changes in susceptibility, surface charge, membrane depolarization, cell wall thickness (CWT), and growth rate. Strains S447 and S613 developed Dapr after simulations of 4 to 8 mg/kg/day but not 10 to 12 mg/kg/day. MICs for Dapr strains ranged from 8 to 256 mg/liter. Some S613 derivatives developed mutations in liaF or cls. S447 derivatives lacked mutations in these genes. Dapr derivatives from both strains exhibited lowered growth rates, up to a 72% reduction in daptomycin-induced depolarization and up to 6-nm increases in CWT (P<0.01). Peak/MIC and AUC0-24/MIC ratios (AUC0-24 is the area under the concentration-time curve from 0 to 24 h) associated with Dapr prevention were 72.1 and 780 for S447 and 144 and 1561 for S613, respectively. Daptomycin doses of 10 mg/kg/day may be required to prevent Dapr in serious enterococcal infections. PMID- 24957826 TI - Pyochelin potentiates the inhibitory activity of gallium on Pseudomonas aeruginosa. AB - Gallium (Ga) is an iron mimetic that has successfully been repurposed for antibacterial chemotherapy. To improve the antibacterial potency of Ga on Pseudomonas aeruginosa, the effect of complexation with a variety of siderophores and synthetic chelators was tested. Ga complexed with the pyochelin siderophore (at a 1:2 ratio) was more efficient than Ga(NO3)3 in inhibiting P. aeruginosa growth, and its activity was dependent on increased Ga entrance into the cell through the pyochelin translocon. PMID- 24957827 TI - Serratia marcescens arn, a PhoP-regulated locus necessary for polymyxin B resistance. AB - Polymyxins, which are increasingly being used to treat infections caused by multidrug-resistant bacteria, perform poorly against Serratia marcescens. To investigate the underlying mechanisms, Tn5 mutagenesis was performed and two mutants exhibiting increased polymyxin B (PB) susceptibility were isolated. The mutants were found to have Tn5 inserted into the arnB and arnC genes. In other bacteria, arnB and arnC belong to the seven-gene arn operon, which is involved in lipopolysaccharide (LPS) modification. LPSs of arn mutants had greater PB-binding abilities than that of wild-type LPS. Further, we identified PhoP, a bacterial two-component response regulator, as a regulator of PB susceptibility in S. marcescens. By the reporter assay, we found PB- and low-Mg2+-induced expression of phoP and arn in the wild-type strain but not in the phoP mutant. Complementation of the phoP mutant with the full-length phoP gene restored the PB MIC and induction by PB and low Mg2+ levels, as in the wild type. An electrophoretic mobility shift assay (EMSA) further demonstrated that PhoP bound directly to the arn promoter. The PB challenge test confirmed that pretreatment with PB and low Mg2+ levels protected S. marcescens from a PB challenge in the wild-type strain but not in the phoP mutant. Real-time reverse transcriptase-PCR also indicated that PB serves as a signal to regulate expression of ugd, a gene required for LPS modification, in S. marcescens through a PhoP-dependent pathway. Finally, we found that PB-resistant clinical isolates displayed greater expression of arnA upon exposure to PB than did susceptible isolates. This is the first report to describe the role of S. marcescens arn in PB resistance and its modulation by PB and Mg2+ through the PhoP protein. PMID- 24957828 TI - Relationship between glycopeptide production and resistance in the actinomycete Nonomuraea sp. ATCC 39727. AB - Glycopeptides and beta-lactams inhibit bacterial peptidoglycan synthesis in Gram positive bacteria; resistance to these antibiotics is studied intensively in enterococci and staphylococci because of their relevance to infectious disease. Much less is known about antibiotic resistance in glycopeptide-producing actinomycetes that are likely to represent the evolutionary source of resistance determinants found in bacterial pathogens. Nonomuraea sp. ATCC 39727, the producer of A40926 (the precursor for the semisynthetic dalbavancin), does not harbor the canonical vanHAX genes. Consequently, we investigated the role of the beta-lactam-sensitive D,D-peptidase/D,D-carboxypeptidase encoded by vanYn, the only van-like gene found in the A40926 biosynthetic gene cluster, in conferring immunity to the antibiotic in Nonomuraea sp. ATCC 39727. Taking advantage of the tools developed recently to genetically manipulate this uncommon actinomycete, we varied vanYn gene dosage and expressed vanHatAatXat from the teicoplanin producer Actinoplanes teichomyceticus in Nonomuraea sp. ATCC 39727. Knocking out vanYn, complementing a vanYn mutant, or duplicating vanYn had no effect on growth but influenced antibiotic resistance and, in the cases of complementation and duplication, antibiotic production. Nonomuraea sp. ATCC 39727 was found to be resistant to penicillins, but its glycopeptide resistance was diminished in the presence of penicillin G, which inhibits VanYn activity. The heterologous expression of vanHatAatXat increased A40926 resistance in Nonomuraea sp. ATCC 39727 but did not increase antibiotic production, indicating that the level of antibiotic production is not directly determined by the level of resistance. The vanYn-based self-resistance in Nonomuraea sp. ATCC 39727 resembles the glycopeptide resistance mechanism described recently in mutants of Enterococcus faecium selected in vitro for high-level resistance to glycopeptides and penicillins. PMID- 24957829 TI - Long-term dissemination of CTX-M-5-producing hypermutable Salmonella enterica serovar typhimurium sequence type 328 strains in Russia, Belarus, and Kazakhstan. AB - In this paper, we present evidence of long-term circulation of cefotaxime resistant clonally related Salmonella enterica serovar Typhimurium strains over a broad geographic area. The genetic relatedness of 88 isolates collected from multiple outbreaks and sporadic cases of nosocomial salmonellosis in various parts of Russia, Belarus, and Kazakhstan from 1996 to 2009 was established by multilocus tandem-repeat analysis (MLVA) and multilocus sequence typing (MLST). The isolates belong to sequence type 328 (ST328) and produce CTX-M-5 beta lactamase, whose gene is carried by highly related non-self-conjugative but mobilizable plasmids. Resistance to nalidixic acid and low-level resistance to ciprofloxacin is present in 37 (42%) of the isolates and in all cases is determined by various single point mutations in the gyrA gene quinolone resistance-determining region (QRDR). Isolates of the described clonal group exhibit a hypermutable phenotype that probably facilitates independent acquisition of quinolone resistance mutations. PMID- 24957830 TI - Fosmidomycin decreases membrane hopanoids and potentiates the effects of colistin on Burkholderia multivorans clinical isolates. AB - Burkholderia cepacia complex (Bcc) pulmonary infections in people living with cystic fibrosis (CF) are difficult to treat because of the extreme intrinsic resistance of most isolates to a broad range of antimicrobials. Fosmidomycin is an antibacterial and antiparasitic agent that disrupts the isoprenoid biosynthesis pathway, a precursor to hopanoid biosynthesis. Hopanoids are involved in membrane stability and contribute to polymyxin resistance in Bcc bacteria. Checkerboard MIC assays determined that although isolates of the Bcc species B. multivorans were highly resistant to treatment with fosmidomycin or colistin (polymyxin E), antimicrobial synergy was observed in certain isolates when the antimicrobials were used in combination. Treatment with fosmidomycin decreased the MIC of colistin for isolates as much as 64-fold to as low as 8 MUg/ml, a concentration achievable with colistin inhalation therapy. A liquid chromatography-tandem mass spectrometry technique was developed for the accurate quantitative determination of underivatized hopanoids in total lipid extracts, and bacteriohopanetetrol cyclitol ether (BHT-CE) was found to be the dominant hopanoid made by B. multivorans. The amount of BHT-CE made was significantly reduced upon fosmidomycin treatment of the bacteria. Uptake assays with 1-N phenylnaphthylamine were used to determine that dual treatment with fosmidomycin and colistin increases membrane permeability, while binding assays with boron dipyrromethene-conjugated polymyxin B illustrated that the addition of fosmidomycin had no impact on polymyxin binding. This work indicates that pharmacological suppression of membrane hopanoids with fosmidomycin treatment can increase the susceptibility of certain clinical B. multivorans isolates to colistin, an agent currently in use to treat pulmonary infections in CF patients. PMID- 24957831 TI - Renal handling of amphotericin B and amphotericin B-deoxycholate and potential renal drug-drug interactions with selected antivirals. AB - Amphotericin B (AmB) is excreted via the renal excretion route. This excretion process may result in nephrotoxicity. However, relevant information on the precise renal excretion mechanisms is not available. The aim of the study was to analyze the possible interaction of AmB or its prodrug AmB deoxycholate (AmB-DOC) with the typical renal organic anion transporters (OATs) and organic cation transporters (OCTs), using cellular and organ models. The relevant transport systems were then investigated in terms of the drug-drug interactions of AmB-DOC with antivirals that might potentially be used concomitantly. To analyze the renal excretion mechanisms of [(3)H]AmB, perfused rat kidney was employed. HeLa and MDCK II cells transiently transfected with human OAT1 (hOAT1) or hOCT2 were used as the cellular models. A significant tubular secretion of AmB was demonstrated in the perfused rat kidney. The cellular studies performed confirmed the active transport of AmB into cells. AmB did not interact with hOAT1 but strongly inhibited hOCT2. In contrast, AmB-DOC inhibited both hOAT1 and hOCT2. However, [(3)H]AmB cellular uptake by hOAT1 and hOCT2 was not found. AmB-DOC interacted significantly with adefovir, tenofovir, and cidofovir in hOAT1 transfected cells at supratherapeutic concentrations. In conclusion, the significant potency of AmB and AmB-DOC for inhibiting the transporters was demonstrated in this study. The secretion of AmB in the renal tubules is likely not related to the transporters here, since the drug was not proven to be a substrate for them. Drug-drug interactions of AmB and the antivirals used in this study on the investigated transporters are not probable. PMID- 24957832 TI - Characterization of drug-resistant influenza virus A(H1N1) and A(H3N2) variants selected in vitro with laninamivir. AB - Neuraminidase inhibitors (NAIs) play a major role for managing influenza virus infections. The widespread oseltamivir resistance among 2007-2008 seasonal A(H1N1) viruses and community outbreaks of oseltamivir-resistant A(H1N1)pdm09 strains highlights the need for additional anti-influenza virus agents. Laninamivir is a novel long-lasting NAI that has demonstrated in vitro activity against influenza A and B viruses, and its prodrug (laninamivir octanoate) is in phase II clinical trials in the United States and other countries. Currently, little information is available on the mechanisms of resistance to laninamivir. In this study, we first performed neuraminidase (NA) inhibition assays to determine the activity of laninamivir against a set of influenza A viruses containing NA mutations conferring resistance to one or many other NAIs. We also generated drug-resistant A(H1N1) and A(H3N2) viruses under in vitro laninamivir pressure. Laninamivir demonstrated a profile of susceptibility that was similar to that of zanamivir. More specifically, it retained activity against oseltamivir resistant H275Y and N295S A(H1N1) variants and the E119V A(H3N2) variant. In vitro, laninamivir pressure selected the E119A NA substitution in the A/Solomon Islands/3/2006 A(H1N1) background, whereas E119K and G147E NA changes along with a K133E hemagglutinin (HA) substitution were selected in the A/Quebec/144147/2009 A(H1N1)pdm09 strain. In the A/Brisbane/10/2007 A(H3N2) background, a large NA deletion accompanied by S138A/P194L HA substitutions was selected. This H3N2 variant had altered receptor-binding properties and was highly resistant to laninamivir in plaque reduction assays. Overall, we confirmed the similarity between zanamivir and laninamivir susceptibility profiles and demonstrated that both NA and HA changes can contribute to laninamivir resistance in vitro. PMID- 24957833 TI - Comparative efficacies of cloxacillin-daptomycin and the standard cloxacillin rifampin therapies against an experimental foreign-body infection by methicillin susceptible Staphylococcus aureus. AB - We compared the efficacies of daptomycin (doses equivalent to 8 to 10 mg/kg of body weight/day in humans) and cloxacillin alone with those of cloxacillin rifampin and cloxacillin-daptomycin combinations, using a tissue cage methicillin susceptible Staphylococcus aureus (MSSA) infection model. Monotherapies were less effective than combinations (P<0.05), and daptomycin resistance emerged. Cloxacillin-daptomycin proved as effective as cloxacillin-rifampin and prevented the appearance of resistance; this combination may be an alternative anti-MSSA therapy, which may offer greater benefits in the early treatment of prosthetic joint infections (PJI). PMID- 24957834 TI - Structural insights into and activity analysis of the antimicrobial peptide myxinidin. AB - The marine environment has been poorly explored in terms of potential new molecules possessing antibacterial activity. Antimicrobial peptides (AMPs) offer a new potential class of pharmaceuticals; however, further optimization is needed if AMPs are to find broad use as antibiotics. We focused our studies on a peptide derived from the epidermal mucus of hagfish (Myxine glutinosa L.), which was previously characterized and showed high antimicrobial activity against human and fish pathogens. In the present work, the activities of myxinidin peptide analogues were analyzed with the aim of widening the original spectrum of action of myxinidin by suitable changes in the peptide primary structure. The analysis of key residues by alanine scanning allowed for the design of novel peptides with increased activity. We identified the amino acids that are of the utmost importance for the observed antimicrobial activities against a set of pathogens comprising both Gram-negative and Gram-positive bacteria. Overall, optimized bactericidal potency was achieved by adding a tryptophan residue at the N terminus and by the simultaneous substitution of residues present in positions 3, 4, and 11 with arginine. These results indicate that the myxinidin analogues emerge as an attractive alternative for treating drug-resistant infectious diseases and provide key insights into a rational design for novel agents against these pathogens. PMID- 24957835 TI - Genetic environment of the lnu(B) gene in a Streptococcus agalactiae clinical isolate. PMID- 24957837 TI - In vitro efficacy of brincidofovir against variola virus. AB - Brincidofovir (CMX001), a lipid conjugate of the acyclic nucleotide phosphonate cidofovir, is under development for smallpox treatment using "the Animal Rule," established by the FDA in 2002. Brincidofovir reduces mortality caused by orthopoxvirus infection in animal models. Compared to cidofovir, brincidofovir has increased potency, is administered orally, and shows no evidence of nephrotoxicity. Here we report that the brincidofovir half-maximal effective concentration (EC50) against five variola virus strains in vitro averaged 0.11 MUM and that brincidofovir was therefore nearly 100-fold more potent than cidofovir. PMID- 24957836 TI - Exposure of Staphylococcus aureus to subinhibitory concentrations of beta-lactam antibiotics induces heterogeneous vancomycin-intermediate Staphylococcus aureus. AB - Glycopeptides are known to select for heterogeneous vancomycin-intermediate Staphylococcus aureus (h-VISA) from susceptible strains. In certain clinical situations, h-VISA strains have been isolated from patients without previous exposure to glycopeptides, such as cystic fibrosis patients, who frequently receive repeated treatments with beta-lactam antibiotics. Our objective was to determine whether prolonged exposure to beta-lactam antibiotics can induce h VISA. We exposed 3 clinical vancomycin-susceptible methicillin-resistant Staphylococcus aureus (MRSA) strains to ceftazidime, ceftriaxone, imipenem, and vancomycin (as a control) at subinhibitory concentrations for 18 days in vitro. Population analyses showed progressive increases in vancomycin resistance; seven of the 12 derived strains obtained after induction were classified as h-VISA according to the following criteria: area under the curve (AUC) on day 18/AUC of Mu3 of >=90% and/or growth on brain heart infusion (BHI) agar with 4 mg/liter vancomycin. The derived isolates had thickened cell walls proportional to the level of glycopeptide resistance. Genes known to be associated with glycopeptide resistance (vraSR, yvqF, SA1703, graRS, walKR, and rpoB) were PCR sequenced; no de novo mutations were observed upon beta-lactam exposure. To determine whether trfA, a gene encoding a glycopeptide resistance factor, was essential in the selection of h-VISA upon beta-lactam pressure, a trfA-knockout strain was generated by allelic replacement. Indeed, beta-lactam exposure of this mutated strain showed no capacity to induce vancomycin resistance. In conclusion, these results showed that beta-lactam antibiotics at subinhibitory concentrations can induce intermediate vancomycin resistance in vitro. This induction required an intact trfA locus. Our results suggest that prior use of beta-lactam antibiotics can compromise vancomycin efficacy in the treatment of MRSA infections. PMID- 24957839 TI - 1,4-azaindole, a potential drug candidate for treatment of tuberculosis. AB - New therapeutic strategies against multidrug-resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl beta-D-ribose 2'-epimerase (DprE1). Further, this series was optimized to improve its physicochemical properties and pharmacokinetics in mice. Here, we describe the short-listing of a potential clinical candidate, compound 2, that has potent cellular activity, drug-like properties, efficacy in mouse and rat chronic TB infection models, and minimal in vitro safety risks. We also demonstrate that the compounds, including compound 2, have no antagonistic activity with other anti-TB drugs. Moreover, compound 2 shows synergy with PA824 and TMC207 in vitro, and the synergy effect is translated in vivo with TMC207. The series is predicted to have a low clearance in humans, and the predicted human dose for compound 2 is <=1 g/day. Altogether, our data suggest that a 1,4-azaindole (compound 2) is a promising candidate for the development of a novel anti-TB drug. PMID- 24957838 TI - Bactericidal activity, absence of serum effect, and time-kill kinetics of ceftazidime-avibactam against beta-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. AB - Avibactam, a non-beta-lactam beta-lactamase inhibitor with activity against extended-spectrum beta-lactamases (ESBLs), KPC, AmpC, and some OXA enzymes, extends the antibacterial activity of ceftazidime against most ceftazidime resistant organisms producing these enzymes. In this study, the bactericidal activity of ceftazidime-avibactam against 18 Pseudomonas aeruginosa isolates and 15 Enterobacteriaceae isolates, including wild-type isolates and ESBL, KPC, and/or AmpC producers, was evaluated. Ceftazidime-avibactam MICs (0.016 to 32 MUg/ml) were lower than those for ceftazidime alone (0.06 to >=256 MUg/ml) against all isolates except for 2 P. aeruginosa isolates (1 blaVIM-positive isolate and 1 blaOXA-23-positive isolate). The minimum bactericidal concentration/MIC ratios of ceftazidime-avibactam were <=4 for all isolates, indicating bactericidal activity. Human serum and human serum albumin had a minimal effect on ceftazidime-avibactam MICs. Ceftazidime-avibactam time-kill kinetics were evaluated at low MIC multiples and showed time-dependent reductions in the number of CFU/ml from 0 to 6 h for all strains tested. A >=3-log10 decrease in the number of CFU/ml was observed at 6 h for all Enterobacteriaceae, and a 2-log10 reduction in the number of CFU/ml was observed at 6 h for 3 of the 6 P. aeruginosa isolates. Regrowth was noted at 24 h for some of the isolates tested in time-kill assays. These data demonstrate the potent bactericidal activity of ceftazidime-avibactam and support the continued clinical development of ceftazidime-avibactam as a new treatment option for infections caused by Enterobacteriaceae and P. aeruginosa, including isolates resistant to ceftazidime by mechanisms dependent on avibactam-sensitive beta-lactamases. PMID- 24957841 TI - Prevention of transmission of multidrug-resistant organisms during catheter exchange using antimicrobial catheters. AB - Exchanging a central venous catheter (CVC) over a guide wire for a fresh uncoated CVC in the presence of bacteremia can result in cross-infection of the newly exchanged CVC. A recent retrospective clinical study showed that exchanging a catheter over a guide wire in the presence of bacteremia using an antimicrobial minocycline-rifampin (M/R) catheter may improve outcomes. To expand on this, we developed an in vitro cross-contamination model of exchange to evaluate the efficacy of different antimicrobial CVCs in preventing cross-contamination of multidrug-resistant organisms during exchange. Uncoated CVCs were allowed to form biofilm by methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans. After 24 h, the biofilm-colonized CVCs were placed in a glass tube containing bovine calf serum plus Mueller-Hinton broth, and each catheter was exchanged over a guide wire for a fresh uncoated or an M/R-, chlorhexidine-silver sulfadiazine (CHX/SS)-, or chlorhexidine-M/R (CHX-M/R)-coated CVC. Cross-contamination of exchanged catheters was enumerated by sonication and quantitative plating methods. The exchange of M/R CVCs completely prevented cross-contamination by MRSA biofilms compared to control exchanged CVCs (P<0.0001). Exchange with CHX/SS CVCs reduced but did not completely prevent cross-contamination by MRSA (P=0.005). Exchange with CHX-M/R CVCs completely prevented cross-contamination by MRSA, P. aeruginosa, and C. albicans biofilms (P<0.0001). Furthermore, CHX-M/R CVCs were superior to M/R CVCs against P. aeruginosa and C. albicans (P=0.003) and were superior to CHX/SS CVCs against MRSA and P. aeruginosa (P=0.01). In conclusion, exchange with the novel CHX-M/R CVC was the only exchange effective in completely and concurrently preventing cross-contamination from bacteria and Candida. PMID- 24957840 TI - Levofloxacin-ceftriaxone combination attenuates lung inflammation in a mouse model of bacteremic pneumonia caused by multidrug-resistant Streptococcus pneumoniae via inhibition of cytolytic activities of pneumolysin and autolysin. AB - In this study, our objective was to determine whether a synergistic antimicrobial combination in vitro would be beneficial in the downregulation of pneumococcal virulence genes and whether the associated inflammation of the lung tissue induced by multidrug-resistant Streptococcus pneumoniae infection in vivo needs to be elucidated in order to consider this mode of therapy in case of severe pneumococcal infection. We investigated in vivo changes in the expression of these virulence determinants using an efficacious combination determined in previous studies. BALB/c mice were infected with 10(6) CFU of bacteria. Intravenous levofloxacin at 150 mg/kg and/or ceftriaxone at 50 mg/kg were initiated 18 h postinfection; the animals were sacrificed 0 to 24 h after the initiation of treatment. The levels of cytokines, chemokines, and C-reactive protein (CRP) in the serum and lungs, along with the levels of myeloperoxidase and nitric oxide the inflammatory cell count in bronchoalveolar lavage fluid (BALF), changes in pneumolysin and autolysin gene expression and COX-2 and inducible nitric oxide synthase (iNOS) protein expression in the lungs were estimated. Combination therapy downregulated inflammation and promoted bacterial clearance. Pneumolysin and autolysin expression was downregulated, with a concomitant decrease in the expression of COX-2 and iNOS in lung tissue. Thus, the combination of levofloxacin and ceftriaxone can be considered for therapeutic use even in cases of pneumonia caused by drug-resistant isolates. PMID- 24957842 TI - Population pharmacokinetics of bedaquiline (TMC207), a novel antituberculosis drug. AB - Bedaquiline is a novel agent for the treatment of pulmonary multidrug-resistant Mycobacterium tuberculosis infections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminal t1/2 was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, and Vc/F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies. PMID- 24957844 TI - Effect of the teen driving plan on the driving performance of teenagers before licensure: a randomized clinical trial. AB - IMPORTANCE: Many studies have failed to show an effect of parent-supervised practice driving on the driving performance of teenagers; nevertheless, most Graduated Driver Licensing programs have provisions that require supervised practice. OBJECTIVE: To determine whether a web-based intervention, the Teen Driving Plan (TDP), can improve the driving performance of teenagers before licensure as measured by the Teen On-road Driving Assessment (tODA). DESIGN, SETTING, AND PARTICIPANTS: Randomized, single-blind, clinical trial among 217 dyads (1 parent: 1 teenaged learner's-permit holder) to test TDP effectiveness on increasing the quantity and diversity of supervised practice and improving the teenagers' prelicensed driving performance. The study was conducted from December 2011 through January 2013 in Southeastern Pennsylvania. INTERVENTIONS: Dyads were randomized (3:2) to receive the TDP or the Pennsylvania driver's manual (control group). The TDP is a psychoeducational intervention designed to increase the quantity and diversity of parent-supervised practice. Materials are grouped by the following driving environments: empty parking lots, suburban residential streets, intermediate (1- or 2-lane) roads, highways, rural roads with curves and elevation changes, and commercial districts. MAIN OUTCOMES AND MEASURES: The main outcomes were self-reported practice driving across 6 environments and 2 conditions and driving performance as measured by the teenagers' completion of the standardized and validated tODA 24 weeks after enrollment. Certified professional driving evaluators blinded to randomization status terminated the tODA if they determined that the teenager could not safely complete it. We examined mean differences in the quantity of supervised practice, differences in the overall proportion of teenagers in each group that had assessments terminated for unsafe driving, and the point of termination during the assessment. RESULTS: The TDP dyads reported more practice in 5 of the 6 environments and at night and in bad weather compared with the control dyads. Overall, 5 of 86 TDP teenagers (6%) had the tODA terminated compared with 10 of 65 control teenagers (15%) (risk difference [TDP - control], -9% [95% CI, -21% to 2%]; P = .06). The hazard ratio for exposure to TDP was 0.35 (95% CI, 0.12-1.03; P = .05, log-rank test). CONCLUSIONS AND RELEVANCE: Preliminary evidence suggests that the TDP improves supervised practice and the driving performance of prelicensed teenaged drivers. Future studies can explore how to revise the TDP to enhance the treatment effect and how best to disseminate the TDP without compromising implementation fidelity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01498575. PMID- 24957845 TI - State of the art: stem cells in equine regenerative medicine. AB - According to Greek mythology, Prometheus' liver grew back nightly after it was removed each day by an eagle as punishment for giving mankind fire. Hence, contrary to popular belief, the concept of tissue and organ regeneration is not new. In the early 20th century, cell culture and ex vivo organ preservation studies by Alexis Carrel, some with famed aviator Charles Lindbergh, established a foundation for much of modern regenerative medicine. While early beliefs and discoveries foreshadowed significant accomplishments in regenerative medicine, advances in knowledge within numerous scientific disciplines, as well as nano- and micromolecular level imaging and detection technologies, have contributed to explosive advances over the last 20 years. Virtually limitless preparations, combinations and applications of the 3 major components of regenerative medicine, namely cells, biomaterials and bioactive molecules, have created a new paradigm of future therapeutic options for most species. It is increasingly clear, however, that despite significant parallels among and within species, there is no 'one-size-fits-all' regenerative therapy. Likewise, a panacea has yet to be discovered that completely reverses the consequences of time, trauma and disease. Nonetheless, there is no question that the promise and potential of regenerative medicine have forever altered medical practices. The horse is a relative newcomer to regenerative medicine applications, yet there is already a large body of work to incorporate novel regenerative therapies into standard care. This review focuses on the current state and potential future of stem cells in equine regenerative medicine. PMID- 24957843 TI - Epidemiology and predictors of multidrug-resistant community-acquired and health care-associated pneumonia. AB - There are limited U.S. data describing the risk factors for multidrug-resistant organism (MDRO) isolation in community-acquired pneumonia (CAP) and health care associated pneumonia (HCAP). However, concern for the presence of these pathogens drives the prescribing of empiric broad-spectrum antibiotics for CAP and HCAP. A retrospective study of all adults hospitalized with community-onset pneumonia (CAP and HCAP) at a large U.S. medical center from January 2010 to December 2011 was conducted. The objective was to ascertain the rate of pneumonia caused by MDROs and to evaluate whether HCAP is a risk factor for MDRO pneumonia. Univariate and propensity score-adjusted multivariate analyses were performed. A total of 521 patients (50.5% CAP and 49.5% HCAP) were included. The most common etiologies of pneumonia were primary viral and Streptococcus pneumoniae. MDROs were isolated in 20 (3.8%) patients overall, and MDROs occurred in 5.9% and 1.9% of HCAP and CAP patients, respectively. The presence of an MDRO was not associated with HCAP classification (odds ratio [OR]=1.95; 95% confidence interval [95% CI], 0.66 to 5.80; P=0.23) or with most of its individual components (hemodialysis, home infusion, home wound care, and >=48-h hospitalization in the last 90 days). Independent predictors of MDRO included the following: Pseudomonas aeruginosa colonization/infection in the previous year (OR=7.43; 95% CI, 2.24 to 24.61; P<0.001), antimicrobial use in the previous 90 days (OR=2.90; 95% CI, 1.13 to 7.45; P=0.027), admission from a nursing home (OR=4.19; 95% CI, 1.55 to 11.31; P=0.005), and duration of hospitalization in the previous 90 or 180 days (P=0.013 and P=0.002, respectively). MDROs were uncommon in HCAP and CAP. HCAP did not predict MDRO isolation. Local etiology of community onset pneumonia and specific MDRO risk factors should be integrated into therapeutic decisions to prevent empirical overprescribing of antibiotics for methicillin-resistant Staphylococcus aureus (MRSA) and P. aeruginosa. PMID- 24957846 TI - Do stingers affect scapular kinematics in rugby players? AB - BACKGROUND: Scapular dyskinesis is observed in subjects with pathologic conditions of the shoulder; however, there is limited information about the factors related to scapular dyskinesis among participants in rugby. The purpose of this study was to investigate the incidence, reliability, and relationships between scapular dyskinesis and variables related to the shoulder in high-school rugby players. METHODS: A total of 164 Japanese high-school rugby players were evaluated with questionnaires, physical examinations, and a video analysis during their preseason. After evaluation of the inter-rater reliability of a classification of scapular dyskinesis, the outcomes were analyzed to assess the relationships between scapular dyskinesis and other variables during the preseason. The data were assessed with a logistic regression analysis calculating the odds ratios (OR). RESULTS: The inter-rater reliability among 3 blinded observers based on the Fleiss kappa value and percentage agreement was .52 and 79.0%, respectively, which indicates that the method is moderately reliable. Scapular dyskinesis was identified in 16 (10.1%) shoulders among 159 players, with type I being prominent. A multivariate logistic regression analysis revealed that a type I dyskinesis was significantly associated with a past history of stingers with projected pain to the affected side of the shoulder (OR, 3.7) and the player's competitive grade at the time of the survey (OR, 3.9). CONCLUSIONS: Scapular dyskinesis is significantly associated with a past history of stingers. This suggests that stingers are a causative factor of scapular dyskinesis in the rugby population. Our method of evaluating scapular dyskinesis in collision athletes exhibits moderate reliability. PMID- 24957847 TI - Patient age is a factor in early outcomes after shoulder arthroplasty. AB - BACKGROUND: Elderly and young patients alike are undergoing shoulder replacement at increased rates. In an era of outcomes reporting, risk adjustment, and cost containment, identifying patients likely to have adverse events is increasingly important. Our objective was to determine whether patient age is independently associated with postoperative in-hospital complications or increased hospital charges after shoulder arthroplasty. METHODS: We used the Nationwide Inpatient Sample to analyze 58,790 patients undergoing total shoulder arthroplasty or hemiarthroplasty between 2000 and 2008. Multivariate analysis with logistic regression modeling was used to compare groups. Our objective was to determine whether age had an independent impact on the likelihood of postoperative in hospital complications, mortality rate, length of stay, or charges after shoulder arthroplasty. RESULTS: Patients aged 80 years or older had an increased in hospital mortality rate (0.5%) compared with patients aged 50 to 79 years (0.1%) and patients aged younger than 50 years (0.1%). Predictors of death included female gender, total shoulder arthroplasty versus hemiarthroplasty, and Deyo score. Increased age was associated with slightly increased hospital charges. Length of stay was longer in patients aged 80 years or older compared with younger patients. After shoulder arthroplasty, postoperative anemia occurred more often in patients aged 80 years or older. Other postoperative complications including pulmonary embolism, infection, and cardiac complications were similar among groups. CONCLUSION: Older patients tend to have longer hospital stays, an increased incidence of postoperative anemia, and slightly higher charges after shoulder arthroplasty. Advanced age is not associated with an increased incidence of pulmonary embolism, infection, and cardiac complications. Further research is warranted to explain the relationship between age and early postoperative outcomes. PMID- 24957848 TI - Effects of epistasis on infectivity range during host-parasite coevolution. AB - Understanding how parasites adapt to changes in host resistance is crucial to evolutionary epidemiology. Experimental studies have demonstrated that parasites are more capable of adapting to gradual, rather than sudden changes in host phenotype, as the latter may require multiple mutations that are unlikely to arise simultaneously. A key, but as yet unexplored factor is precisely how interactions between mutations (epistasis) affect parasite evolution. Here, we investigate this phenomenon in the context of infectivity range, where parasites may experience selection to infect broader sets of genotypes. When epistasis is strongly positive, we find that parasites are unlikely to evolve broader infectivity ranges if hosts exhibit sudden, rather than gradual changes in phenotype, in close agreement with empirical observations. This is due to a low probability of fixing multiple mutations that individually confer no immediate advantage. When epistasis is weaker, parasites are more likely to evolve broader infectivity ranges if hosts make sudden changes in phenotype, which can be explained by a balance between mutation supply and selection. Thus, we demonstrate that both the rate of phenotypic change in hosts and the form of epistasis between mutations in parasites are crucial in shaping the evolution of infectivity range. PMID- 24957849 TI - GenoType HelicoDR test in the determination of antimicrobial resistance of Helicobacter pylori in Korea. AB - OBJECTIVE: Antimicrobial resistance of Helicobacter pylori is most important factor in eradication success. GenoType HelicoDR test has been developed for rapid detection of antimicrobial resistance. The present study evaluated the clinical usefulness of GenoType HelicoDR test in Korea. MATERIALS AND METHODS: To detect 23S rRNA for clarithromycin resistance and gyrA mutations for fluoroquinolone resistance, both DNA sequencing after minimal inhibitory test (MIC) and GenoType HelicoDR test were performed in H. pylori isolates from the gastric mucosa of 101 patients. The eradication results of clarithromycin and moxifloxacin-containing triple therapy were evaluated by the 23S rRNA and gyrA mutations. RESULTS: For 42 isolates with A2143G mutation by GenoType HelicoDR, 83.3% (35/42) of concordance rate was estimated with DNA sequencing method and 85.7% (36/42) for MIC test. For 43 isolates with N87K mutation by GenoType HelicoDR, 71.1% (31/43) of concordance rate was estimated with DNA sequencing and 88.4% (38/43) for MIC test. The sensitivity and specificity of GenoType HelicoDR test in determination of 23S rRNA mutation were 94.9% and 87.1%, and those of gyrA 98.2% and 80.0%. The sensitivity and specificity of GenoType HelicoDR test in determination of clarithromycin resistance based on MIC test were 55.0% and 80.0%, for fluoroquinolone 74.4% and 70.0%. CONCLUSION: GenoType HelicoDR test is useful to determine mutations responsible for clarithromycin or fluoroquinolone containing eradication failure but has a limitation for the clinical applicability in determination of resistance. PMID- 24957851 TI - Malaria control in Nepal 1963-2012: challenges on the path towards elimination. AB - BACKGROUND: Malaria is still a priority public health problem of Nepal where about 84% of the population are at risk. The aim of this paper is to highlight the past and present malaria situation in this country and its challenges for long-term malaria elimination strategies. METHODS: Malariometric indicator data of Nepal recorded through routine surveillance of health facilities for the years between 1963 and 2012 were compiled. Trends and differences in malaria indicator data were analysed. RESULTS: The trend of confirmed malaria cases in Nepal between 1963 and 2012 shows fluctuation, with a peak in 1985 when the number exceeded 42,321, representing the highest malaria case-load ever recorded in Nepal. This was followed by a steep declining trend of malaria with some major outbreaks. Nepal has made significant progress in controlling malaria transmission over the past decade: total confirmed malaria cases declined by 84% (12,750 in 2002 vs 2,092 in 2012), and there was only one reported death in 2012. Based on the evaluation of the National Malaria Control Programme in 2010, Nepal recently adopted a long-term malaria elimination strategy for the years 2011-2026 with the ambitious vision of a malaria-free Nepal by 2026. However, there has been an increasing trend of Plasmodium falciparum and imported malaria proportions in the last decade. Furthermore, the analysis of malariometric indicators of 31 malaria-risk districts between 2004 and 2012 shows a statistically significant reduction in the incidence of confirmed malaria and of Plasmodium vivax, but not in the incidence of P. falciparum and clinically suspected malaria. CONCLUSIONS: Based on the achievements the country has made over the last decade, Nepal is preparing to move towards malaria elimination by 2026. However, considerable challenges lie ahead. These include especially, the need to improve access to diagnostic facilities to confirm clinically suspected cases and their treatment, the development of resistance in parasites and vectors, climate change, and increasing numbers of imported cases from a porous border with India. Therefore, caution is needed before the country embarks towards malaria elimination. PMID- 24957850 TI - An investigation of a PRESAGE(r) in vivo dosimeter for brachytherapy. AB - Determining accurate in vivo dosimetry in brachytherapy treatment with high dose gradients is challenging. Here we introduce, investigate, and characterize a novel in vivo dosimeter and readout technique with the potential to address this problem. A cylindrical (4 mm * 20 mm) tissue equivalent radiochromic dosimeter PRESAGE(r) in vivo (PRESAGE(r)-IV) is investigated. Two readout methods of the radiation induced change in optical density (OD) were investigated: (i) volume averaged readout by spectrophotometer, and (ii) a line profile readout by 2D projection imaging utilizing a high-resolution (50 micron) telecentric optical system. Method (i) is considered the gold standard when applied to PRESAGE(r) in optical cuvettes. The feasibility of both methods was evaluated by comparison to standard measurements on PRESAGE(r) in optical cuvettes via spectrophotometer. An end-to-end feasibility study was performed by a side-by-side comparison with TLDs in an (192)Ir HDR delivery. 7 and 8 Gy was delivered to PRESAGE(r)-IV and TLDs attached to the surface of a vaginal cylinder. Known geometry enabled direct comparison of measured dose with a commissioned treatment planning system. A high resolution readout study under a steep dose gradient region showed 98.9% (5%/1 mm) agreement between PRESAGE(r)-IV and Gafchromic(r) EBT2 Film. Spectrometer measurements exhibited a linear dose response between 0-15 Gy with sensitivity of 0.0133 +/- 0.0007 DeltaOD/(Gy ? cm) at the 95% confidence interval. Method (ii) yielded a linear response with sensitivity of 0.0132 +/- 0.0006 (DeltaOD/Gy), within 2% of method (i). Method (i) has poor spatial resolution due to volume averaging. Method (ii) has higher resolution (~1 mm) without loss of sensitivity or increased noise. Both readout methods are shown to be feasible. The end-to-end comparison revealed a 2.5% agreement between PRESAGE(r)-IV and treatment plan in regions of uniform high dose. PRESAGE(r)-IV shows promise for in vivo dose verification, although improved sensitivity would be desirable. Advantages include high-resolution, convenience and fast, low-cost readout. PMID- 24957852 TI - Two different approaches for pharmacokinetic modeling of exhaled drug concentrations. AB - Online measurement of drug concentrations in patient's breath is a promising approach for individualized dosage. A direct transfer from breath- to blood concentrations is not possible. Measured exhaled concentrations are following the blood-concentration with a delay in non-steady-state situations. Therefore, it is necessary to integrate the breath-concentration into a pharmacological model. Two different approaches for pharmacokinetic modelling are presented. Usually a 3 compartment model is used for pharmacokinetic calculations of blood concentrations. This 3-compartment model is extended with a 2-compartment model based on the first compartment of the 3-compartment model and a new lung compartment. The second approach is to calculate a time delay of changes in the concentration of the first compartment to describe the lung-concentration. Exemplarily both approaches are used for modelling of exhaled propofol. Based on time series of exhaled propofol measurements using an ion-mobility-spectrometer every minute for 346 min a correlation of calculated plasma and the breath concentration was used for modelling to deliver R(2) = 0.99 interdependencies. Including the time delay modelling approach the new compartment coefficient k(e0lung) was calculated to k(e0lung) = 0.27 min(-1) with R(2) = 0.96. The described models are not limited to propofol. They could be used for any kind of drugs, which are measurable in patient's breath. PMID- 24957853 TI - Junior Radiologists' Forum (JRF): National trainee survey. AB - AIM: To gather information in order to highlight areas within training that could be improved and share ideas of good practice and, in addition, to compare national results with those of local training schemes. MATERIALS AND METHODS: A request to participate in the survey was emailed to 1158 radiology trainees across 36 UK training schemes in October 2012. The electronic replies were anonymous. The survey remained active for 6 weeks. The data were collated and analysed by members of the JRF. The survey itself was divided into seven sections, covering a diverse range of topics. RESULTS: Six hundred and four trainees from 36 UK training schemes completed the survey, resulting in a response rate of 52%. PMID- 24957854 TI - Re: UK intussusception audit: a national survey of practice and audit of reduction rates. A reply. PMID- 24957855 TI - Feasibility of gadoxetate disodium-enhanced MR cholangiography in chronic cholestatic biliary disease. AB - AIM: To investigate the feasibility of gadoxetate disodium-enhanced magnetic resonance (MR) cholangiography in chronic obstructive cholestatic biliary disease in the clinical setting. MATERIALS AND METHODS: Twenty-three patients with dilated bile duct trees and ten volunteers underwent gadoxetate disodium-enhanced liver MR cholangiography and were enrolled in the present retrospective study. Gadoxetate disodium was given in a standardized manner as a bolus injection at a dose of 0.25 mmol/kg of body weight (0.1 ml/kg). Region of interest-based measurement of mean enhancement of the dilated bile ducts was performed in series before gadoxetate disodium administration and during hepatobiliary phases. RESULTS: Direct comparison of mean bile duct enhancement during hepatobiliary phases in the clinical imaging window between healthy volunteers [4.7 +/- 2.2 arbitrary units (au)] and patients with dilated bile ducts (0.1 +/- 0.3 au) revealed significantly lower or absent enhancement in dilated bile ducts (p = 0.001). CONCLUSION: Standard clinical gadoxetate disodium-enhanced MR cholangiography is not a reliable technique for the evaluation of the biliary trees, because of altered biliary gadoxetate disodium elimination in patients with chronic obstructive biliary diseases. PMID- 24957856 TI - Re: UK intussusception audit: a national survey of practice and audit of reduction rates. PMID- 24957857 TI - The risk of endoleak following stent covering of the internal iliac artery during endovascular aneurysm repair. AB - AIM: To investigate the risk of endoleak during endovascular aneurysm repair (EVAR) involving the distal common iliac artery (CIA) when the internal iliac artery (IIA) is covered without prior coil embolization. MATERIALS AND METHODS: Retrospective analysis of 145 (125 men, 20 women) consecutive EVAR cases. Clinical notes and radiological images were reviewed, and data collected on patient demographics, aneurysm morphology, covering of the IIA with or without embolization, presence of endoleaks, and patient symptoms relating to IIA ischaemia. RESULTS: A total of 29 IIAs (10%) were covered in a total of 25 patients. Seven IIAs (24%) were embolized before stent covering (Embolization group), and 22 IIAs (76%) were covered only without embolization (Cover group). There was no statistically significant difference in the mean size of the abdominal aortic aneurysm diameter or CIA diameter between each group. No endoleaks from IIA retrograde filling were found in either group. CONCLUSION: The results of the present study do not support the traditional view that coverage of the IIA without prior embolization carries a high risk of endoleak, with no endoleaks seen in all 22 cases. Large-scale trials are required. However, the advent of branched-stenting techniques and the emergence of their success in long term follow-up may preclude the former. PMID- 24957858 TI - Utility of chest CT for differentiating primary and secondary achalasia. AB - AIM: To determine the computed tomography (CT) findings of primary and secondary achalasia and to assess the utility of CT for differentiating these conditions. METHODS: A computerized search revealed 13 patients with primary achalasia and 15 with secondary achalasia who underwent chest CT during a 10-year period. The images were reviewed to determine whether there was distal oesophageal narrowing (including the length/contour of narrowing), oesophageal dilation, oesophageal wall thickening (including degree/symmetry/pattern of thickening), a soft-tissue mass at the gastro-oesophageal junction, mediastinal adenopathy, or other findings of malignant tumour. RESULTS: Eleven (85%) of 13 patients with primary achalasia had distal oesophageal narrowing at CT that was smooth in all patients; four (31%) had oesophageal wall thickening that was smooth and symmetric in all patients; none had a soft-tissue mass at the gastro-oesophageal junction or mediastinal lymphadenopathy; and two (15%) had pulmonary metastases from unrelated lung cancers. In contrast, 12 (80%) of 15 patients with secondary achalasia had distal oesophageal narrowing at CT; 11 (73%) had distal oesophageal wall thickening that was nodular/lobulate and asymmetric in seven (64%) and smooth and symmetric in four (36%); six (40%) had a soft-tissue mass at the gastro-oesophageal junction; seven (47%) had mediastinal lymphadenopathy; and all 15 had other findings of malignant tumour. CONCLUSION: CT is a useful technique for differentiating primary and secondary achalasia. Distal oesophageal wall thickening that is nodular/lobulate and asymmetric, a soft-tissue mass at the gastro-oesophageal junction, mediastinal lymphadenopathy, and pulmonary, hepatic, or osseous metastases are findings that favour secondary achalasia. PMID- 24957859 TI - DUF1220 protein domains drive proliferation in human neural stem cells and are associated with increased cortical volume in anthropoid primates. AB - Genome sequences encoding DUF1220 protein domains show a burst in copy number among anthropoid species and especially humans, where they have undergone the greatest human lineage-specific copy number expansion of any protein coding sequence in the genome. While DUF1220 copy number shows a dosage-related association with brain size in both normal populations and in 1q21.1-associated microcephaly and macrocephaly, a function for these domains has not yet been described. Here we provide multiple lines of evidence supporting the view that DUF1220 domains function as drivers of neural stem cell proliferation among anthropoid species including humans. First, we show that brain MRI data from 131 individuals across 7 anthropoid species shows a strong correlation between DUF1220 copy number and multiple brain size-related measures. Using in situ hybridization analyses of human fetal brain, we also show that DUF1220 domains are expressed in the ventricular zone and primarily during human cortical neurogenesis, and are therefore expressed at the right time and place to be affecting cortical brain development. Finally, we demonstrate that in vitro expression of DUF1220 sequences in neural stem cells strongly promotes proliferation. Taken together, these data provide the strongest evidence so far reported implicating DUF1220 dosage in anthropoid and human brain expansion through mechanisms involving increasing neural stem cell proliferation. PMID- 24957860 TI - Altered neuronal architecture and plasticity in the visual cortex of adult MMP-3 deficient mice. AB - Matrix metalloproteinases (MMPs) are Zn(2+)-dependent endopeptidases considered to be essential for normal brain development and neuroplasticity by modulating extracellular matrix proteins, receptors, adhesion molecules, growth factors and cytoskeletal proteins. Specifically, MMP-3 has recently been implicated in synaptic plasticity, hippocampus-dependent learning and neuronal development and migration in the cerebellum. However, the function(s) of this enzyme in the neocortex is understudied. Therefore, we explored the phenotypical characteristics of the neuronal architecture and the capacity for experience dependent cortical plasticity in the visual cortex of adult MMP-3-deficient (MMP 3(-/-)) mice. Golgi-Cox stainings revealed a significant reduction in apical dendritic length and an increased number of apical obliques for layer V pyramidal neurons in the visual cortex of adult MMP-3(-/-) mice compared to wild-type (WT) animals. In addition, a significant upregulation of both phosphorylated and non phosphorylated neurofilament protein (NF)-high, phosphorylated NF-medium, NF-low and alpha-internexin was detected in the visual cortex of MMP-3(-/-) mice. To assess the effect of MMP-3 deficiency on cortical plasticity, we monocularly enucleated adult MMP-3(-/-) mice and analyzed the reactivation of the contralateral visual cortex 7 weeks post-enucleation. In contrast to previous results in C57Bl/6J adult mice, activity remained confined to the binocular zone and did not expand into the monocular regions indicative for an aberrant open-eye potentiation. Permanent hypoactivity in the monocular cortex lateral and medial to V1 also indicated a lack of cross-modal plasticity. These observations demonstrate that genetic inactivation of MMP-3 has profound effects on the structural integrity and plasticity response of the visual cortex of adult mice. PMID- 24957861 TI - Variability of physicians' thresholds for neuroimaging in children with recurrent headache. AB - BACKGROUND: We sought to determine the extent to which physicians agree about the appropriate decision threshold for recommending magnetic resonance imaging in a clinical practice guideline for children with recurrent headache. METHODS: We surveyed attending physicians in Canada practicing in community pediatrics, child neurology, pediatric radiology, and pediatric neurosurgery. For children in each of six risk categories, physicians were asked to determine whether they would recommend for or against routine magnetic resonance imaging of the brain in a clinical practice guideline for children with recurrent headache. RESULTS: Completed surveys were returned by 114 physicians. The proportion recommending routine neuroimaging for each risk group was 100% (50% risk), 99% (10% risk), 93% (4% risk), 54% (1% risk), 25% (0.4% risk), 4% (0.01% risk). Community pediatricians, physicians in practice >15 years, and physicians who believed they ordered neuroimaging less often than peers were less likely to recommend neuroimaging for the 1% risk group (all p < 0.05). CONCLUSIONS: There is no consensus among pediatric specialists regarding the appropriate decision threshold for neuroimaging in a clinical practice guideline for children with recurrent headache. Because of the impact that individual threshold preferences may have on guidelines, these findings support the need for careful composition of guideline committees and consideration of the role of patient and family preferences. Our findings also support the need for transparency in guidelines regarding how evidence was translated into recommendations and how conflicts were resolved. PMID- 24957863 TI - Randomized controlled trial comparing the efficacy of mosapride plus omeprazole combination therapy to omeprazole monotherapy in gastroesophageal reflux disease. AB - OBJECTIVE: We investigated whether the prokinetic activity of mosapride, a 5 hydroxytryptamine 4 receptor agonist, in combination with proton pump inhibitor (PPI) would ameliorate symptoms of gastroesophageal reflux disease (GERD) in Japanese patients. METHODS: Patients who experienced reflux symptoms more than twice weekly were eligible for this study. In all, 60 patients were randomized to receive mosapride 5 mg thrice daily combined with omeprazole 10 mg once daily (GO group), or omeprazole alone (O group) for 4 weeks. The patients completed the frequency scale for the symptoms of GERD (FSSG) at the beginning and the end of the study. The primary outcome compared changes in the FSSG reflux-related symptom (RS) score between treatment groups during the study period. RESULTS: The FSSG RS scores significantly decreased both in the GO group and the O group, with no differences in improvement between the groups (-5.86 for the GO group vs -4.89 for the O group, P = 0.49). In non-erosive reflux disease (NERD) patients the improvement was significantly lower than that in erosive GERD patients (-4.00 vs 7.67, P = 0.02). However, the addition of mosapride was effective in subgroup analyses of specific symptoms, such as burping. CONCLUSIONS: Combining mosapride with PPI provided no additional amelioration of reflux symptoms compared to PPI alone. Both regimens provided less relief from reflux symptoms in NERD than in erosive GERD patients. The addition of mosapride ameliorated reflux in patients with symptoms like burping. PMID- 24957862 TI - Monitoring the effects of dexamethasone treatment by MRI using in vivo iron oxide nanoparticle-labeled macrophages. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a chronic disease causing recurring inflammatory joint attacks. These attacks are characterized by macrophage infiltration contributing to joint destruction. Studies have shown that RA treatment efficacy is correlated to synovial macrophage number. The aim of this study was to experimentally validate the use of in vivo superparamagnetic iron oxide nanoparticle (SPION) labeled macrophages to evaluate RA treatment by MRI. METHODS: The evolution of macrophages was monitored with and without dexamethasone (Dexa) treatment in rats. Two doses of 3 and 1 mg/kg Dexa were administered two and five days following induction of antigen induced arthritis. SPIONs (7 mg Fe/rat) were injected intravenously and the knees were imaged in vivo on days 6, 10 and 13. The MR images were scored for three parameters: SPION signal intensity, SPION distribution pattern and synovial oedema. Using 3D semi automated software, the MR SPION signal was quantified. The efficacy of SPIONs and gadolinium chelate (Gd), an MR contrast agent, in illustrating treatment effects were compared. Those results were confirmed through histological measurements of number and area of macrophages and nanoparticle clusters using CD68 immunostaining and Prussian blue staining respectively. RESULTS: Results show that the pattern and the intensity of SPION-labeled macrophages on MRI were altered by Dexa treatment. While the Dexa group had a uniform elliptical line surrounding an oedema pocket, the untreated group showed a diffused SPION distribution on day 6 post-induction. Dexa reduced the intensity of SPION signal 50-60% on days 10 and 13 compared to controls (P = 0.00008 and 0.002 respectively). Similar results were found when the signal was measured by the 3D tool. On day 13, the persisting low grade arthritis progression could not be demonstrated by Gd. Analysis of knee samples by Prussian blue and CD68 immunostaining confirmed in vivo SPION uptake by macrophages. Furthermore, CD68 immunostaining revealed that Dexa treatment significantly decreased the area and number of synovial macrophages. Prussian blue quantification corresponded to the macrophage measurements and both were in agreement with the MRI findings. CONCLUSIONS: We have demonstrated the feasibility of MRI tracking of in vivo SPION-labeled macrophages to assess RA treatment effects. PMID- 24957865 TI - Synthesis of hollow mesoporous silica nanoparticles with tunable shell thickness and pore size using amphiphilic block copolymers as core templates. AB - This paper presents a facile method for the fabrication of uniform hollow mesoporous silica nanoparticles (HMSNs) with tunable shell thickness and pore size. In this method, a series of amphiphilic block copolymers of polystyrene-b poly (acrylic acid) (PS-b-PAA) with different hydrophobic block (PS) lengths were first synthesized via atom transfer radical polymerization (ATRP). The as synthesized PS-b-PAA and cetyltrimethylammonium bromide (CTAB) were subsequently used as co-templates to fabricate HMSNs. This approach allows the control of shell thickness and pore size distribution of the synthesized HMSNs simply by changing the amounts of PS-b-PAA and CTAB, respectively. In vitro cytotoxicity and hemolysis assays demonstrated that the synthesized HMSNs had a low and shell thickness-dependent cytotoxicity and hemolytic activity. Therefore, these HMSNs have great potential for biomedical applications due to their good biocompatibility and ease of synthesis. PMID- 24957867 TI - ["Hic gaudet mors succurere vitae", autopsy findings of the Mainz Institute of Pathology 1971-2010. An analysis on the occasion of the 100 year jubilee]. AB - In the past numerous analyses have studied several aspects of autopsies in particular with regard to the decline of frequency; however, long-term studies spanning more than one decade have rarely been published, especially in recent years. On the occasion of the 100 year jubilee the archive data of the Institute of Pathology of the University of Mainz were analyzed for autopsies performed between 1971 and 2010. In this cohort, we focused on patients over 14 years old (n = 14,724) who died in the University hospital. We compared the number of autopsies with the total number of deceased patients and, in addition, studied several epidemiological aspects with special relevance for the cause of death (COD). In 1973 the peak autopsy frequency was reached with a value of 73.4 % followed by a decrease to 49.1 % in 1980. In the following decade a relatively steady state was achieved (frequency 53.3 % in 1985, and 43.2 % in 1990), followed by a remarkable decline after the 1990s (1997: 26.4 %, 1998: 15.9 % and 2010: 5.6 %). The mean overall age increased during the observation period (59.1 years in 1971 and 67.5 years in 2008). Among the COD groups cardiovascular diseases were predominantly recorded (between 35 % in the 1970s and 39 % in 1995 2010), followed by infectious diseases (between 20 and 25 %). Malignancies represented the third most common COD group with an increase in frequency from approximately 10.5 % in the 1970s to 17 % observed in the last decade. Among the single specific CODs, pulmonary embolism was most often encountered in the 1970s (about 11.5 %), while in the following decades myocardial infarction predominated (up to 15.8 % between 1995 and 2010). In the overall period, lung cancer was the single most common malignancy of the CODs (between 2.5 and 3.9 %). These data confirmed previous studies showing that in Germany the autopsy frequency began to decline remarkably in the 1990s. Besides general aspects, the specific local causes for these phenomena are discussed. PMID- 24957868 TI - Formation of oligovesicular vesicles by micromanipulation. AB - Cell-sized lipid bilayer membrane vesicles (giant vesicles, GVs) or semi-vesicles were formed from egg yolk phosphatidylcholine on a platinum electrode under applied electric voltage by electroformation. Micromanipulation of the semi vesicle by first pressing its membrane with a glass microneedle and then withdrawing the needle left a GV in the interior of the vesicle. During the process, an aqueous solution of Ficoll that filled the needle was introduced into the newly formed inner vesicle and remained encapsulated. Approximately 50% of attempted micromanipulation resulted in the formation of an inner daughter vesicle, "microvesiculation". By repeating the microvesiculation process, multiple inner GVs could be formed in a single parent semi-vesicle. A semi vesicle with inner GVs could be detached from the electrode by scraping with a microneedle, yielding an oligovesicular vesicle (OVV) with desired inner aqueous contents. Microvesiculation of a GV held on the tip of a glass micropipette was also possible, and this also produced an OVV. Breaking the membrane of the parent semi-vesicle by micromanipulation with a glass needle after microvesiculation, released the inner GVs. This protocol may be used for controlled formation of GVs with desired contents. PMID- 24957864 TI - Genetic predisposition to schizophrenia associated with increased use of cannabis. AB - Cannabis is the most commonly used illicit drug worldwide. With debate surrounding the legalization and control of use, investigating its health risks has become a pressing area of research. One established association is that between cannabis use and schizophrenia, a debilitating psychiatric disorder affecting ~1% of the population over their lifetime. Although considerable evidence implicates cannabis use as a component cause of schizophrenia, it remains unclear whether this is entirely due to cannabis directly raising risk of psychosis, or whether the same genes that increases psychosis risk may also increase risk of cannabis use. In a sample of 2082 healthy individuals, we show an association between an individual's burden of schizophrenia risk alleles and use of cannabis. This was significant both for comparing those who have ever versus never used cannabis (P=2.6 * 10(-4)), and for quantity of use within users (P=3.0 * 10(-3)). Although directly predicting only a small amount of the variance in cannabis use, these findings suggest that part of the association between schizophrenia and cannabis is due to a shared genetic aetiology. This form of gene-environment correlation is an important consideration when calculating the impact of environmental risk factors, including cannabis use. PMID- 24957866 TI - Basal ganglia and thalamic morphology in schizophrenia and bipolar disorder. AB - In this study, we examined the morphology of the basal ganglia and thalamus in bipolar disorder (BP), schizophrenia-spectrum disorders (SCZ-S), and healthy controls (HC) with particular interest in differences related to the absence or presence of psychosis. Volumetric and shape analyses of the basal ganglia and thalamus were performed in 33 BP individuals [12 without history of psychotic features (NPBP) and 21 with history of psychotic features (PBP)], 32 SCZ-S individuals [28 with SCZ and 4 with schizoaffective disorder], and 27 HC using FreeSurfer-initiated large deformation diffeomorphic metric mapping. Significant volume differences were found in the caudate and globus pallidus, with volumes smallest in the NPBP group. Shape abnormalities showing inward deformation of superior regions of the caudate were observed in BP (and especially in NPBP) compared with HC. Shape differences were also found in the globus pallidus and putamen when comparing BP and SCZ-S groups. No significant differences were seen in the nucleus accumbens and thalamus. In summary, structural abnormalities in the caudate and globus pallidus are present in BP and SCZ-S. Differences were more apparent in the NPBP subgroup. The findings herein highlight the potential importance of separately examining BP subgroups in neuroimaging studies. PMID- 24957869 TI - Fabrication and biocompatibility of electrospun silk biocomposites. AB - Silk fibroin has attracted great interest in tissue engineering because of its outstanding biocompatibility, biodegradability and minimal inflammatory reaction. In this study, two kinds of biocomposites based on regenerated silk fibroin are fabricated by electrospinning and post-treatment processes, respectively. Firstly, regenerated silk fibroin/tetramethoxysilane (TMOS) hybrid nanofibers with high hydrophilicity are prepared, which is superior for fibroblast attachment. The electrospinning process causes adjacent fibers to 'weld' at contact points, which can be proved by scanning electron microscope (SEM). The water contact angle of silk/tetramethoxysilane (TMOS) composites shows a sharper decrease than pure regenerated silk fibroin nanofiber, which has a great effect on the early stage of cell attachment behavior. Secondly, a novel tissue engineering scaffold material based on electrospun silk fibroin/nano hydroxyapatite (nHA) biocomposites is prepared by means of an effective calcium and phosphate (Ca-P) alternate soaking method. nHA is successfully produced on regenerated silk fibroin nanofiber within several min without any pre-treatments. The osteoblastic activities of this novel nanofibrous biocomposites are also investigated by employing osteoblastic-like MC3T3-E1 cell line. The cell functionality such as alkaline phosphatase (ALP) activity is ameliorated on mineralized silk nanofibers. All these results indicate that this silk/nHA biocomposite scaffold material may be a promising biomaterial for bone tissue engineering. PMID- 24957870 TI - Liquid phase micro-extraction of linear alkylbenzene sulfonate anionic surfactants in aqueous samples. AB - Hollow fiber liquid phase micro-extraction (LPME) of linear alkylbenzene sulfonates (LAS) from aqueous samples was studied. Ion pair extraction of C10, C11, C12 and C13 homologues was facilitated with trihexylamine as ion-pairing agent, using di-n-hexylether as solvent for the supported liquid membrane (SLM). Effects of extraction time, acceptor buffer concentration, stirring speed, sample volume, NaCl and humic acids were studied. At 10-50 ug L-1 linear R2-coefficients were 0.99 for C10 and C11 and 0.96 for C12. RSD was typically ~15%. Three observations were especially made. Firstly, LPME for these analytes was unusually slow with maximum enrichment observed after 15-24 h (depending on sample volume). Secondly, the enrichment depended on LAS sample concentration with 35-150 times enrichment below ~150 ug L-1 and 1850-4400 times enrichment at 1 mg L-1. Thirdly, lower homologues were enriched more than higher homologues at low sample concentrations, with reversed conditions at higher concentrations. These observations may be due to the fact that LAS and the amine counter ion themselves influence the mass transfer at the water-SLM interface. The observations on LPME of LAS may aid in LPME application to other compounds with surfactant properties or in surfactant enhanced membrane extraction of other compounds. PMID- 24957872 TI - Membrane bioreactor technology for the development of functional materials from sea-food processing wastes and their potential health benefits. AB - Sea-food processing wastes and underutilized species of fish are a potential source of functional and bioactive compounds. A large number of bioactive substances can be produced through enzyme-mediated hydrolysis. Suitable enzymes and the appropriate bioreactor system are needed to incubate the waste materials. Membrane separation is a useful technique to extract, concentrate, separate or fractionate the compounds. The use of membrane bioreactors to integrate a reaction vessel with a membrane separation unit is emerging as a beneficial method for producing bioactive materials such as peptides, chitooligosaccharides and polyunsaturated fatty acids from diverse seafood-related wastes. These bioactive compounds from membrane bioreactor technology show diverse biological activities such as antihypertensive, antimicrobial, antitumor, anticoagulant, antioxidant and radical scavenging properties. This review discusses the application of membrane bioreactor technology for the production of value-added functional materials from sea-food processing wastes and their biological activities in relation to health benefits. PMID- 24957871 TI - Self-Assembling Peptide Surfactants A6K and A6D Adopt a-Helical Structures Useful for Membrane Protein Stabilization. AB - Elucidation of membrane protein structures have been greatly hampered by difficulties in producing adequately large quantities of the functional protein and stabilizing them. A6D and A6K are promising solutions to the problem and have recently been used for the rapid production of membrane-bound G protein-coupled receptors (GPCRs). We propose that despite their short lengths, these peptides can adopt alpha-helical structures through interactions with micelles formed by the peptides themselves. These alpha-helices are then able to stabilize alpha helical motifs which many membrane proteins contain. We also show that A6D and A6K can form beta-sheets and appear as weak hydrogels at sufficiently high concentrations. Furthermore, A6D and A6K together in sodium dodecyl sulfate (SDS) can form expected beta-sheet structures via a surprising alpha-helical intermediate. PMID- 24957873 TI - Effect of counter electrode in electroformation of giant vesicles. AB - Electroformation of cell-sized lipid membrane vesicles (giant vesicles, GVs), from egg yolk phosphatidylcholine, was examined varying the shape of the counter electrode. Instead of a planar ITO (indium tin oxide) electrode commonly used, platinum wire mesh was employed as a counter electrode facing lipid deposit on a planar formation electrode. The modification did not significantly alter GV formation, and many GVs of 30-50 um, some as large as 100 um, formed as with the standard setup, indicating that a counter electrode does not have to be a complete plane. When the counter electrode was reduced to a set of two parallel platinum wires, GV formation deteriorated. Some GVs formed, but only in close proximity to the counter electrode. Lower electric voltage with this setup no longer yielded GVs. Instead, a large onion-like multilamellar structure was observed. The deteriorated GV formation and the formation of a multilamellar structure seemed to indicate the weakened effect of the electric field on lipid deposit due to insufficient coverage with a small counter electrode. Irregular membranous objects formed by spontaneous swelling of lipid without electric voltage gradually turned into multilamellar structure upon following application of voltage. No particular enhancement of GV formation was observed when lipid deposit on a wire formation electrode was used in combination with a large planar counter electrode. PMID- 24957875 TI - [(18) F]CuCF3 : a [(18) F]trifluoromethylating agent for arylboronic acids and aryl iodides. AB - Positron emission tomography has emerged as the leading method for medical imaging with fluorine-18 as the most widely used radioactive isotope. Here we report a semi-automated method for the preparation of valuable [(18) F]trifluoromethylcopper, as well as its use for the radiosynthesis of [(18) F]trifluoromethylarenes and heteroarenes. Mild conditions of [(18) F]trifluoromethylation make this method particularly useful for the radiosynthesis of pharmacologically relevant [(18) F]trifluoromethylarenes and heteroarenes. PMID- 24957877 TI - Children of cancer patients: prevalence and predictors of emotional and behavioral problems. AB - BACKGROUND: Children of patients with cancer are at increased risk for developing emotional and behavioral problems. This study explored the prevalence and predictors of emotional and behavioral problems in Children of cancer patients in a multisite research project. METHODS: A cross-sectional sample of N = 235 families was recruited simultaneously in 5 university medical centers. The participants, including parents (N = 402) and children (N = 324; ages 11-21 years) completed standardized questionnaires. Emotional and behavioral problems in children were measured by the Strengths and Difficulties Questionnaire (SDQ). On the basis of previous research and using a mixed-model approach, child-, parent-, family- and cancer-related variables were examined in addition to socioeconomic status as potential predictors. Descriptive statistics and a multiple random coefficient model were used in the analyses. RESULTS: Compared to norms, Children of cancer patients show increased mean levels of emotional and behavioral symptoms. The best predictor of emotional and behavioral problems from the perspectives of the child, the healthy parent, and the ill parent was general family dysfunction. Although family dysfunction was identified as the main predictor, the analysis revealed that the main part of variance was related to the individual child's level. CONCLUSIONS: The results indicate that screening for child mental health problems and family dysfunction in oncological and psychosocial treatment units can identify the families most in need of psychosocial support. Psychological services need to be both family-oriented and child-centered and focus on family dysfunction to prevent mental health problems in children. PMID- 24957876 TI - Parasites alter the pathological phenotype of lupus nephritis. AB - Lupus nephritis is one of the most serious complications of systemic lupus erythematosus and manifests with considerable phenotypic and histological heterogeneity. In particular, diffuse proliferative lupus nephritis (DPLN) and membranous lupus nephritis (MLN) represent morphologic forms that are polar opposites. DPLN is associated with autoimmune responses dominated by Th1 immune response associated with high levels of interferon (IFN)-gamma. In contrast, a Th2 cytokine response is associated with the pathogenesis of MLN. MRL/lpr mice develop human LN-like immune complex-associated nephritis and provide a suitable histological model for human DPLN. Infection with Schistosoma mansoni skewed a Th2-type immune response induction and IL-10 in MRL/lpr mice, drastically changing the pathophysiology of glomerulonephritis from DPLN to MLN accompanied by increased IgG1 and IgE in the sera. T cells in 32-week-old MRL/lpr mice infected with S. mansoni expressed significantly more IL-4 and IL-10 than T cells of uninfected mice; T cells with IFN-gamma were comparable between infected and uninfected MR/lpr mice. Thus, the helminthic infection modified the cytokine microenvironment and altered the pathological phenotype of autoimmune nephritis. PMID- 24957878 TI - i-Motif DNA: structure, stability and targeting with ligands. AB - i-Motifs are four-stranded DNA secondary structures which can form in sequences rich in cytosine. Stabilised by acidic conditions, they are comprised of two parallel-stranded DNA duplexes held together in an antiparallel orientation by intercalated, cytosine-cytosine(+) base pairs. By virtue of their pH dependent folding, i-motif forming DNA sequences have been used extensively as pH switches for applications in nanotechnology. Initially, i-motifs were thought to be unstable at physiological pH, which precluded substantial biological investigation. However, recent advances have shown that this is not always the case and that i-motif stability is highly dependent on factors such as sequence and environmental conditions. In this review, we discuss some of the different i motif structures investigated to date and the factors which affect their topology, stability and dynamics. Ligands which can interact with these structures are necessary to aid investigations into the potential biological functions of i-motif DNA and herein we review the existing i-motif ligands and give our perspective on the associated challenges with targeting this structure. PMID- 24957879 TI - Chemical biology on the genome. AB - In this article I discuss studies towards understanding the structure and function of DNA in the context of genomes from the perspective of a chemist. The first area I describe concerns the studies that led to the invention and subsequent development of a method for sequencing DNA on a genome scale at high speed and low cost, now known as Solexa/Illumina sequencing. The second theme will feature the four-stranded DNA structure known as a G-quadruplex with a focus on its fundamental properties, its presence in cellular genomic DNA and the prospects for targeting such a structure in cels with small molecules. The final topic for discussion is naturally occurring chemically modified DNA bases with an emphasis on chemistry for decoding (or sequencing) such modifications in genomic DNA. The genome is a fruitful topic to be further elucidated by the creation and application of chemical approaches. PMID- 24957880 TI - Oligonucleotide-templated reactions based on Peptide Nucleic Acid (PNA) probes: concept and biomedical applications. AB - Sensing technologies based on Peptide Nucleic Acids (PNAs) and oligonucleotide templated chemistry are perfectly suited for biomedical applications (e.g., diagnosis, prognosis and stratification of diseases) and could compete well with more traditional amplification technologies using expensive dual-labelled oligonucleotide probes. PNAs can be easily synthesised and functionalised, are more stable and are more responsive to point-mutations than their DNA counterpart. For these reasons, fluorogenic PNAs represent an interesting alternative to DNA-based molecular beacons for sensing applications in a cell free environment, where cellular uptake is not required. PMID- 24957882 TI - The wheat-Septoria conflict: a new front opening up? AB - In the utopic absence of abiotic and/or biotic stressors, attaining the predicted increase (up to 70%) in wheat demand by 2050 in response to global population trends is a challenge. This objective becomes daunting, however, when one factors in the continuous constraint on global wheat production posed by Septoria tritici blotch (STB) disease. This is because, despite resistant loci being identified, a deficit of commercially relevant STB-resistant wheat germplasm remains. The issue is further compounded for growers by the emergence and prevalence of fungicide resistant/insensitive strains of the causative pathogen Zymoseptoria tritici (formerly known as Mycosphaerella graminicola/Septoria tritici). However, biotechnology-based research is providing new opportunities in this struggle. As the exome response of wheat to STB attack begins to be deciphered, genes intrinsic to resistant and susceptible phenotypes will be identified. Combined with the application of genome-editing techniques and a growing appreciation of the complexity of wheat's and the dynamism of Z. tritici's genome, the generation of resulting STB-resistant wheat varieties will counter the prevalent threat of STB disease in wheat-production systems. PMID- 24957883 TI - A multilevel analysis of fruit growth of two tomato cultivars in response to fruit temperature. AB - Fruit phenotype is a resultant of inherent genetic potential in interaction with impact of environment experienced during crop and fruit growth. The aim of this study was to analyze the genetic and physiological basis for the difference in fruit size between a small ('Brioso') and intermediate ('Cappricia') sized tomato cultivar exposed to different fruit temperatures. It was hypothesized that fruit heating enhances expression of cell cycle and expansion genes, rates of carbon import, cell division and expansion, and shortens growth duration, whereas increase in cell number intensifies competition for assimilates among cells. Unlike previous studies in which whole-plant and fruit responses cannot be separated, we investigated the temperature response by varying fruit temperature using climate-controlled cuvettes, while keeping plant temperature the same. Fruit phenotype was assessed at different levels of aggregation (whole fruit, cell and gene) between anthesis and breaker stage. We showed that: (1) final fruit fresh weight was larger in 'Cappricia' owing to more and larger pericarp cells, (2) heated fruits were smaller because their mesocarp cells were smaller than those of control fruits and (3) no significant differences in pericarp carbohydrate concentration were detected between heated and control fruits nor between cultivars at breaker stage. At the gene level, expression of cell division promoters (CDKB2, CycA1 and E2Fe-like) was higher while that of the inhibitory fw2.2 was lower in 'Cappricia'. Fruit heating increased expression of fw2.2 and three cell division promoters (CDKB1, CDKB2 and CycA1). Expression of cell expansion genes did not corroborate cell size observations. PMID- 24957884 TI - Maternal hypertriglyceridemia: A link between maternal overweight-obesity and macrosomia in gestational diabetes. AB - OBJECTIVE: Infants born from overweight and obese mothers with glucose-controlled gestational diabetes (GDM) tend to be large-for-gestational age (LGA). It is hypothesized that this is due to an excessive rise in maternal triglyceride levels. METHODS: Two-hundred and seventy nine singleton GDM pregnancies were divided into three groups according to prepregnancy BMI: normal weight (BMI = 20 24.9; n = 128), overweight (BMI = 25-29.9; n = 105), and obese (BMI >= 30; n = 46). Individual z-scores (ZS) of maternal triglycerides and of newborn weight (NWZS) were calculated as deviations from published 50th percentiles. Mean z scores (MZS) were the average of triglyceride ZSs. MZS of triglycerides, HbA1c and NWZS were compared. Variables are expressed as mean +/- SD. RESULTS: In the three groups respectively: LGA (%) = 10.1%, 19.0% and 30.4% (P = 0.015). Birth weight (g) = 3274.2 +/- 501.3, 3342.4 +/- 620.2 and 3366.3+/-644.7 (RSPEARMAN = 0.111, P = 0.027). HbA1c (%) = 5.2 +/- 0.39, 5.3 +/- 0.50 and 5.4 +/- 0.47 (P = NS). Triglyceride MZS = 1.20 +/- 1.13, 1.52 +/- 1.37 and 1.62 +/- 1.42 (RSPEARMAN = 0.116, P = 0.024). Correlations between triglyceride MZS and NWZS were, respectively: r = 0.12 (P = NS), r = 0.42 (P <0.001), and r = 0.47 (P < 0.001). CONCLUSIONS: In overweight and obese GDM mothers, maternal triglycerides are partially responsible for LGA infants despite good maternal glucose control during pregnancy. PMID- 24957874 TI - The Role of the Transmembrane RING Finger Proteins in Cellular and Organelle Function. AB - A large number of RING finger (RNF) proteins are present in eukaryotic cells and the majority of them are believed to act as E3 ubiquitin ligases. In humans, 49 RNF proteins are predicted to contain transmembrane domains, several of which are specifically localized to membrane compartments in the secretory and endocytic pathways, as well as to mitochondria and peroxisomes. They are thought to be molecular regulators of the organization and integrity of the functions and dynamic architecture of cellular membrane and membranous organelles. Emerging evidence has suggested that transmembrane RNF proteins control the stability, trafficking and activity of proteins that are involved in many aspects of cellular and physiological processes. This review summarizes the current knowledge of mammalian transmembrane RNF proteins, focusing on their roles and significance. PMID- 24957881 TI - Scar-modulating treatments for central nervous system injury. AB - Traumatic injury to the adult mammalian central nervous system (CNS) leads to complex cellular responses. Among them, the scar tissue formed is generally recognized as a major obstacle to CNS repair, both by the production of inhibitory molecules and by the physical impedance of axon regrowth. Therefore, scar-modulating treatments have become a leading therapeutic intervention for CNS injury. To date, a variety of biological and pharmaceutical treatments, targeting scar modulation, have been tested in animal models of CNS injury, and a few are likely to enter clinical trials. In this review, we summarize current knowledge of the scar-modulating treatments according to their specific aims: (1) inhibition of glial and fibrotic scar formation, and (2) blockade of the production of scar-associated inhibitory molecules. The removal of existing scar tissue is also discussed as a treatment of choice. It is believed that only a combinatorial strategy is likely to help eliminate the detrimental effects of scar tissue on CNS repair. PMID- 24957886 TI - A multiparametric serum marker panel as a complementary test to mammography for the diagnosis of node-negative early-stage breast cancer and DCIS in young women. AB - BACKGROUND: The sensitivity of mammography for the detection of small lesions, including node-negative early-stage (T1N0) primary breast cancer (PBC) and ductal carcinoma in situ (DCIS), is significantly decreased in young patients. From a clinical standpoint, an inconclusive mammogram reflects the inability of clinicians to confidently decide whether patients should be referred for biopsy or for follow-up with repeat imaging. METHODS: Specific ELISAs were developed for a panel of 13 well-recognized breast autoantigens (HSP60, FKBP52, PRDX2, PPIA, MUC1, GAL3, PAK2, P53, CCNB1, PHB2, RACK1, RUVBL1, and HER2). Circulating autoantibody levels were measured in a cohort of 396 serum samples from histologically confirmed DCIS (n = 87) or T1N0 PBC (n = 153) and healthy controls (n = 156). RESULTS: Individually, antibodies against CCNB1, FKBP52, GAL3, PAK2, PRDX2, PPIA, P53, and MUC1 demonstrated discriminatory power between breast cancer and healthy control groups. At 90% sensitivity, the overall combined specificity of the autoantibody serum screening test was 42%. Adjustment for higher sensitivities of 95% and 99% resulted in 30% and 21% specificities, respectively (33% and 18% in T1N0 PBC and 28% and 21% in DCIS). Finally, in patients with node-negative early-stage breast cancer younger than 50 years, the autoantibody assay exhibited 59% specificity with a fixed sensitivity at 90%. CONCLUSIONS: Our autoantibody panel allows accurate detection of early breast cancer and DCIS, notably in younger patients. IMPACT: Clinical assessment of this autoantibody panel displays a potential to facilitate clinical management of early-stage breast cancer detection in cases of inconclusive mammogram. PMID- 24957885 TI - VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2. AB - Arteriovenous malformation (AVM) refers to a vascular anomaly where arteries and veins are directly connected through a complex, tangled web of abnormal AV fistulae without a normal capillary network. Hereditary hemorrhagic telangiectasia (HHT) types 1 and 2 arise from heterozygous mutations in endoglin (ENG) and activin receptor-like kinase 1 (ALK1), respectively. HHT patients possess AVMs in various organs, and telangiectases (small AVMs) along the mucocutaneous surface. Understanding why and how AVMs develop is crucial for developing therapies to inhibit the formation, growth, or maintenance of AVMs in HHT patients. Previously, we have shown that secondary factors such as wounding are required for Alk1-deficient vessels to develop skin AVMs. Here, we present evidences that AVMs establish from nascent arteries and veins rather than from remodeling of a preexistent capillary network in the wound-induced skin AVM model. We also show that VEGF can mimic the wound effect on skin AVM formation, and VEGF-neutralizing antibody can prevent skin AVM formation and ameliorate internal bleeding in Alk1-deficient adult mice. With topical applications at different stages of AVM development, we demonstrate that the VEGF blockade can prevent the formation of AVM and cease the progression of AVM development. Taken together, the presented experimental model is an invaluable system for precise molecular mechanism of action of VEGF blockades as well as for preclinical screening of drug candidates for epistaxis and gastrointestinal bleedings. PMID- 24957888 TI - Absolute Configuration of the New 3-epi-cladocroic Acid from the Mediterranean Sponge Haliclona fulva. AB - The marine sponge Haliclona fulva (previously described as Reniera fulva) is widespread in the Mediterranean Sea. The chemical study of the sponge led to the isolation and identification of a new compound: 3-epi-cladocroic acid (1) alongside the previously reported cladocroic acid (2) and some other known compounds previously isolated. The structure was fully determined on the basis of extensive analysis by 1D and 2D NMR, as well as GC-MS/MS. The absolute configuration was determined by comparison of the experimental electronic circular dichroism (ECD) spectra with theoretically calculated spectra; these results may be extended to other asymetric cyclopropane carboxylic acids. PMID- 24957887 TI - The Metabolic Interplay between Plants and Phytopathogens. AB - Plant diseases caused by pathogenic bacteria or fungi cause major economic damage every year and destroy crop yields that could feed millions of people. Only by a thorough understanding of the interaction between plants and phytopathogens can we hope to develop strategies to avoid or treat the outbreak of large-scale crop pests. Here, we studied the interaction of plant-pathogen pairs at the metabolic level. We selected five plant-pathogen pairs, for which both genomes were fully sequenced, and constructed the corresponding genome-scale metabolic networks. We present theoretical investigations of the metabolic interactions and quantify the positive and negative effects a network has on the other when combined into a single plant-pathogen pair network. Merged networks were examined for both the native plant-pathogen pairs as well as all other combinations. Our calculations indicate that the presence of the parasite metabolic networks reduce the ability of the plants to synthesize key biomass precursors. While the producibility of some precursors is reduced in all investigated pairs, others are only impaired in specific plant-pathogen pairs. Interestingly, we found that the specific effects on the host's metabolism are largely dictated by the pathogen and not by the host plant. We provide graphical network maps for the native plant-pathogen pairs to allow for an interactive interrogation. By exemplifying a systematic reconstruction of metabolic network pairs for five pathogen-host pairs and by outlining various theoretical approaches to study the interaction of plants and phytopathogens on a biochemical level, we demonstrate the potential of investigating pathogen-host interactions from the perspective of interacting metabolic networks that will contribute to furthering our understanding of mechanisms underlying a successful invasion and subsequent establishment of a parasite into a plant host. PMID- 24957889 TI - Metabonomic Response to Milk Proteins after a Single Bout of Heavy Resistance Exercise Elucidated by 1H Nuclear Magnetic Resonance Spectroscopy. AB - In the present study, proton NMR-based metabonomics was applied on femoral arterial plasma samples collected from young male subjects (milk protein n = 12 in a crossover design; non-caloric control n = 8) at different time intervals (70, 220, 370 min) after heavy resistance training and intake of either a whey or calcium caseinate protein drink in order to elucidate the impact of the protein source on post-exercise metabolism, which is important for muscle hypertrophy. Dynamic changes in the post-exercise plasma metabolite profile consisted of fluctuations in alanine, beta-hydroxybutyrate, branched amino acids, creatine, glucose, glutamine, glutamate, histidine, lipids and tyrosine. In comparison with the intake of a non-caloric drink, the same pattern of changes in low-molecular weight plasma metabolites was found for both whey and caseinate intake. However, the study indicated that whey and caseinate protein intake had a different impact on low-density and very-low-density lipoproteins present in the blood, which may be ascribed to different effects of the two protein sources on the mobilization of lipid resources during energy deficiency. In conclusion, no difference in the effects on low-molecular weight metabolites as measured by proton NMR-based metabonomics was found between the two protein sources. PMID- 24957890 TI - Characterisation of the metabolites of 1,8-cineole transferred into human milk: concentrations and ratio of enantiomers. AB - 1,8-Cineole is a widely distributed odorant that also shows physiological effects, but whose human metabolism has hitherto not been extensively investigated. The aim of the present study was, thus, to characterise the metabolites of 1,8-cineole, identified previously in human milk, after the oral intake of 100 mg of this substance. Special emphasis was placed on the enantiomeric composition of the metabolites since these data may provide important insights into potential biotransformation pathways, as well as potential biological activities of these substances, for example on the breastfed child. The volatile fraction of the human milk samples was therefore isolated via Solvent Assisted Flavour Evaporation (SAFE) and subjected to gas chromatography mass spectrometry (GC-MS). The absolute concentrations of each metabolite were determined by matrix calibration with an internal standard, and the ratios of enantiomers were analysed on chiral capillaries. The concentrations varied over a broad range, from traces in the upper ng/kg region up to 40 ug/kg milk, with the exception of the main metabolite alpha2-hydroxy-1,8-cineole that showed concentrations of 100-250 ug/kg. Also, large inter- and intra-individual variations were recorded for the enantiomers, with nearly enantiomerically pure alpha2-hydroxy- and 3-oxo-1,8-cineole, while all other metabolites showed ratios of ~30:70 to 80:20. PMID- 24957892 TI - Metabolic Changes in Synechocystis PCC6803 upon Nitrogen-Starvation: Excess NADPH Sustains Polyhydroxybutyrate Accumulation. AB - Polyhydroxybutyrate (PHB) is a common carbon storage polymer among heterotrophic bacteria. It is also accumulated in some photoautotrophic cyanobacteria; however, the knowledge of how PHB accumulation is regulated in this group is limited. PHB synthesis in Synechocystis sp. PCC 6803 is initiated once macronutrients like phosphorus or nitrogen are limiting. We have previously reported a mutation in the gene sll0783 that impairs PHB accumulation in this cyanobacterium upon nitrogen starvation. In this study we present data which explain the observed phenotype. We investigated differences in intracellular localization of PHB synthase, metabolism, and the NADPH pool between wild type and mutant. Localization of PHB synthase was not impaired in the sll0783 mutant; however, metabolome analysis revealed a difference in sorbitol levels, indicating a more oxidizing intracellular environment than in the wild type. We confirmed this by directly measuring the NADPH/NADP ratio and by altering the intracellular redox state of wild type and sll0783 mutant. We were able to physiologically complement the mutant phenotype of diminished PHB synthase activity by making the intracellular environment more reducing. Our data illustrate that the NADPH pool is an important factor for regulation of PHB biosynthesis and metabolism, which is also of interest for potential biotechnological applications. PMID- 24957891 TI - Recent applications of metabolomics toward cyanobacteria. AB - Our knowledge on cyanobacterial molecular biology increased tremendously by the application of the "omics" techniques. Only recently, metabolomics was applied systematically to model cyanobacteria. Metabolomics, the quantitative estimation of ideally the complete set of cellular metabolites, is particularly well suited to mirror cellular metabolism and its flexibility under diverse conditions. Traditionally, small sets of metabolites are quantified in targeted metabolome approaches. The development of separation technologies coupled to mass spectroscopy- or nuclear-magnetic-resonance-based identification of low molecular mass molecules presently allows the profiling of hundreds of metabolites of diverse chemical nature. Metabolome analysis was applied to characterize changes in the cyanobacterial primary metabolism under diverse environmental conditions or in defined mutants. The resulting lists of metabolites and their steady state concentrations in combination with transcriptomics can be used in system biology approaches. The application of stable isotopes in fluxomics, i.e. the quantitative estimation of carbon and nitrogen fluxes through the biochemical network, has only rarely been applied to cyanobacteria, but particularly this technique will allow the making of kinetic models of cyanobacterial systems. The further application of metabolomics in the concert of other "omics" technologies will not only broaden our knowledge, but will also certainly strengthen the base for the biotechnological application of cyanobacteria. PMID- 24957894 TI - Isolation and Expression of a cDNA Encoding Methylmalonic Aciduria Type A Protein from Euglena gracilis Z. AB - In animals, cobalamin (Cbl) is a cofactor for methionine synthase and methylmalonyl-CoA mutase (MCM), which utilizes methylcobalamin and 5' deoxyadenosylcobalamin (AdoCbl), respectively. The cblA complementation class of inborn errors of Cbl metabolism in humans is one of three known disorders that affect AdoCbl synthesis. The gene responsible for cblA has been identified in humans (MMAA) as well as its homolog (meaB) in Methylobacterium extorquens. Recently, it has been reported that human MMAA plays an important role in the protection and reactivation of MCM in vitro. However, the physiological function of MMAA is largely unknown. In the present study, we isolated the cDNA encoding MMAA from Euglena gracilis Z, a photosynthetic flagellate. The deduced amino acid sequence of the cDNA shows 79%, 79%, 79% and 80% similarity to human, mouse, Danio rerio MMAAs and M. extorquens MeaB, respectively. The level of the MCM transcript was higher in Cbl-deficient cultures of E. gracilis than in those supplemented with Cbl. In contrast, no significant differences were observed in the levels of the MMAA transcript under the same two conditions. No significant difference in MCM activity was observed between Escherichia coli that expressed either MCM together with MMAA or expressed MCM alone. PMID- 24957893 TI - Exometabolomics approaches in studying the application of lignocellulosic biomass as fermentation feedstock. AB - Lignocellulosic biomass is the future feedstock for the production of biofuel and bio-based chemicals. The pretreatment-hydrolysis product of biomass, so-called hydrolysate, contains not only fermentable sugars, but also compounds that inhibit its fermentability by microbes. To reduce the toxicity of hydrolysates as fermentation media, knowledge of the identity of inhibitors and their dynamics in hydrolysates need to be obtained. In the past decade, various studies have applied targeted metabolomics approaches to examine the composition of biomass hydrolysates. In these studies, analytical methods like HPLC, RP-HPLC, CE, GC-MS and LC-MS/MS were used to detect and quantify small carboxylic acids, furans and phenols. Through applying targeted metabolomics approaches, inhibitors were identified in hydrolysates and their dynamics in fermentation processes were monitored. However, to reveal the overall composition of different hydrolysates and to investigate its influence on hydrolysate fermentation performance, a non targeted metabolomics study needs to be conducted. In this review, a non-targeted and generic metabolomics approach is introduced to explore inhibitor identification in biomass hydrolysates, and other similar metabolomics questions. PMID- 24957895 TI - Knowledge discovery in spectral data by means of complex networks. AB - In the last decade, complex networks have widely been applied to the study of many natural and man-made systems, and to the extraction of meaningful information from the interaction structures created by genes and proteins. Nevertheless, less attention has been devoted to metabonomics, due to the lack of a natural network representation of spectral data. Here we define a technique for reconstructing networks from spectral data sets, where nodes represent spectral bins, and pairs of them are connected when their intensities follow a pattern associated with a disease. The structural analysis of the resulting network can then be used to feed standard data-mining algorithms, for instance for the classification of new (unlabeled) subjects. Furthermore, we show how the structure of the network is resilient to the presence of external additive noise, and how it can be used to extract relevant knowledge about the development of the disease. PMID- 24957896 TI - Gas-Chromatography Mass-Spectrometry (GC-MS) Based Metabolite Profiling Reveals Mannitol as a Major Storage Carbohydrate in the Coccolithophorid Alga Emiliania huxleyi. AB - Algae are divergent organisms having a wide variety of evolutional histories. Although most of them share photosynthetic activity, their pathways of primary carbon metabolism are rather diverse among species. Here we developed a method for gas chromatography-mass spectroscopy (GC-MS) based metabolite profiling for the coccolithophorid alga Emiliania huxleyi, which is one of the most abundant microalgae in the ocean, in order to gain an overview of the pathway of primary metabolism within this alga. Following method optimization, twenty-six metabolites could be detected by this method. Whilst most proteogenic amino acids were detected, no peaks corresponding to malate and fumarate were found. The metabolite profile of E. huxleyi was, however, characterized by a prominent accumulation of mannitol reaching in excess of 14 nmol 106 cells-1. Similarly, the accumulation of the 13C label during short term H13CO3- feeding revealed a massive redistribution of label into mannitol as well as rapid but saturating label accumulation into glucose and several amino acids including aspartate, glycine and serine. These results provide support to previous work suggesting that this species adopts C3 photosynthesis and that mannitol functions as a carbon store in E. huxleyi. PMID- 24957897 TI - Characterization of Flavan-3-ols and Expression of MYB and Late Pathway Genes Involved in Proanthocyanidin Biosynthesis in Foliage of Vitis bellula. AB - Proanthocyanidins (PAs) are fundamental nutritional metabolites in different types of grape products consumed by human beings. Although the biosynthesis of PAs in berry of Vitis vinifera has gained intensive investigations, the understanding of PAs in other Vitis species is limited. In this study, we report PA formation and characterization of gene expression involved in PA biosynthesis in leaves of V. bellula, a wild edible grape species native to south and south west China. Leaves are collected at five developmental stages defined by sizes ranging from 0.5 to 5 cm in length. Analyses of thin layer chromatography (TLC) and high performance liquid chromatography-photodiode array detector (HPLC-PAD) show the formation of (+)-catechin, (-)-epicatechin, (+)-gallocatechin and (-) epigallocatechin during the entire development of leaves. Analyses of butanol-HCl boiling cleavage coupled with spectrometry measurement at 550 nm show a temporal trend of extractable PA levels, which is characterized by an increase from 0.5 cm to 1.5 cm long leaves followed by a decrease in late stages. TLC and HPLC-PAD analyses identify cyanidin, delphinidin and pelargonidin produced from the cleavage of PAs in the butanol-HCl boiling, showing that the foliage PAs of V. bellula include three different types of extension units. Four cDNAs, which encode VbANR, VbDFR, VbLAR1 and VbLAR2, respectively, are cloned from young leaves. The expression patterns of VbANR and VbLAR2 but not VbLAR1 and VbDFR follow a similar trend as the accumulation patterns of PAs. Two cDNAs encoding VbMYBPA1 and VbMYB5a, the homologs of which have been demonstrated to regulate the expression of both ANR and LAR in V. vinifera, are also cloned and their expression profiles are similar to those of VbANR and VbLAR2. In contrast, the expression profiles of MYBA1 and 2 homologs involved in anthocyanin biosynthesis are different from those of VbANR and VbLAR2. Our data show that both ANR and LAR branches are involved in PA biosynthesis in leaves of V. bellula. PMID- 24957898 TI - General indicators confounding Kraepelin: predictive indicators of misdiagnosing borderline as bipolar. PMID- 24957899 TI - Beyond rhetoric: we need a strategy for patient involvement in the health service. PMID- 24957900 TI - Sexual behaviour and sexual and reproductive health education: a cross-sectional study in Romania. AB - BACKGROUND: Up-to-date, genuine sexual and reproductive health (SRH) education programmes have been possible in Romania only since communism collapsed in 1990. Since 2006, Romania has had no national strategy in this field. Under current global circumstances (high labour mobility, internationally mixed marriages), issues previously considered solely national have become worldwide concerns. METHODS: In 2011-2012, 1215 respondents homogeneously distributed on background, gender, educational level and age group (18-74) were sampled. This article uses a 96-item questionnaire about family and SRH, presenting results on nine items: first intercourse (FI), virginity, knowing first sexual partner, safe sex, number of sexual partners and sexual education. The data were analysed using Pearson chi square tests and latent class analysis. RESULTS: Some participants (7.2%) engaged in FI at age 15 or earlier. The average age at FI was lower for men (18.08), for individuals with a lower education level (18.07) and for those in rural areas (18.27), compared with that for women, those with more education and those in urban areas, respectively. The average age at FI was over 2.5 years lower for people aged 18-24 (16.99) than for those aged 60-74 (p < 0.001). More than 60% were not married or partnered with their FI partner, and 17.8% engaged in FI less than a month after meeting their partner. Less than one-fourth practiced safe sex at FI, with higher proportions for the urban sample, those with an average level of education and those aged 18-35 (p < 0.001). Higher average numbers of sexual partners were found among men (6.56, compared with 2.37 among women), in urban areas (5.07, compared with 3.75 in rural areas) and among those with higher levels of education (p < 0.005). On average, subjects first received information on SRH at 15.39 years of age, with only 10% listing the school, doctors or medics as a source. CONCLUSIONS: Unsafe sex, early initiation of sexual activity and poor SRH education from schools, experts and parents require a multidisciplinary approach within prevention programmes, especially among the populations at risk: rural residents, those with low levels of education and youth. PMID- 24957901 TI - A quantum-mechanical study of the reaction mechanism of sulfite oxidase. AB - The oxidation of sulfite to sulfate by two different models of the active site of sulfite oxidase has been studied. Both protonated and deprotonated substrates were tested. Geometries were optimized with density functional theory (TPSS/def2 SV(P)) and energies were calculated either with hybrid functionals and large basis sets (B3LYP/def2-TZVPD) including corrections for dispersion, solvation, and entropy, or with coupled-cluster theory (LCCSD(T0)) extrapolated toward a complete basis set. Three suggested reaction mechanisms have been compared and the results show that the lowest barriers are obtained for a mechanism where the substrate attacks a Mo-bound oxo ligand, directly forming a Mo-bound sulfate complex, which then dissociates into the products. Such a mechanism is more favorable than mechanisms involving a Mo-sulfite complex with the substrate coordinating either by the S or O atom. The activation energy is dominated by the Coulomb repulsion between the Mo complex and the substrate, which both have a negative charge of -1 or -2. PMID- 24957902 TI - Laparoendoscopic single-site (LESS) robot-assisted partial nephrectomy (RAPN) reduces postoperative wound pain without a rise in complication rates. AB - OBJECTIVE: To compare long-term functional outcomes and pain scale scores of patients who underwent laparoendoscopic single-site (LESS)- robot-assisted partial nephrectomy (RAPN) to those who underwent conventional RAPN (C-RAPN), as LESS surgery is increasingly being adopted by urologists worldwide to reduce morbidities and scarring associated with surgical interventions. PATIENTS AND METHODS: In all, 167 consecutive patients who had RAPN were identified from our Institutional Review Board-approved computerised database between October 2006 to July 2012. Patients were stratified into two groups: 80 patients who underwent C RAPN and 79 who underwent LESS-RAPN. RESULTS: The LESS-RAPN group had a longer warm ischaemia time [WIT, mean (sd) 26.5 (10.5) vs 19.8 (13.1) min; P = 0.001] and total operation time [TOT, mean (sd) 210.3 (83.4) vs 183.1 (76.1) min; P = 0.033] when compared with the C-RAPN group. While, the LESS-RAPN group and C-RAPN group were not significantly different for the number of patients with negative surgical margins [77 (96.2%) vs 73 (91.4%); P = 0.194), absolute change in postoperative renal function [mean (sd) -6.5 (16.7)% vs -7.6 (16.7)%; P = 0.738) and postoperative complications rate [12 (15.0%) vs 10 (12.6%); P = 0.279). Furthermore, the LESS-RAPN group had lower visual analogue pain scale (VAPS) scores at discharge [mean (sd) 2.1 (1.3) vs 1.7 (1.0); P = 0.048]. CONCLUSIONS: Despite a significantly longer WIT and TOT, the functional outcomes of LESS-RAPN were comparable to those of C-RAPN for tumours of similar mean sizes and complexities, without any detriments in oncological and complications outcomes. On discharge, patients who underwent LESS-RAPN also reported lower pain levels as one of the advantages of minimally invasive surgery. With the development of instrumentation specifically designed for single-site surgery, LESS could be more easily conducted in patients who are interested in improved quality of life outcomes. PMID- 24957903 TI - Response to Almecija and Alba (2014) - On manual proportions in Australopithecus afarensis. PMID- 24957904 TI - Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels. AB - BACKGROUND: The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is a chloride channel that primarily resides in airway epithelial cells. Decreased CFTR expression and/or function lead to impaired airway surface liquid (ASL) volume homeostasis, resulting in accumulation of mucus, reduced clearance of bacteria, and chronic infection and inflammation. METHODS: Expression of CFTR and the cigarette smoke metal content were assessed in lung samples of controls and COPD patients with established GOLD stage 4. CFTR protein and mRNA were quantified by immunohistochemistry and quantitative RT-PCR, respectively. Metals present in lung samples were quantified by ICP-AES. The effect of cigarette smoke on down-regulation of CFTR expression and function was assessed using primary human airway epithelial cells. The role of leading metal(s) found in lung samples of GOLD 4 COPD patients involved in the alteration of CFTR was confirmed by exposing human bronchial epithelial cells 16HBE14o- to metal-depleted cigarette smoke extracts. RESULTS: We found that CFTR expression is reduced in the lungs of GOLD 4 COPD patients, especially in bronchial epithelial cells. Assessment of metals present in lung samples revealed that cadmium and manganese were significantly higher in GOLD 4 COPD patients when compared to control smokers (GOLD 0). Primary human airway epithelial cells exposed to cigarette smoke resulted in decreased expression of CFTR protein and reduced airway surface liquid height. 16HBE14o-cells exposed to cigarette smoke also exhibited reduced levels of CFTR protein and mRNA. Removal and/or addition of metals to cigarette smoke extracts before exposure established their role in decrease of CFTR in airway epithelial cells. CONCLUSIONS: CFTR expression is reduced in the lungs of patients with severe COPD. This effect is associated with the accumulation of cadmium and manganese suggesting a role for these metals in the pathogenesis of COPD. PMID- 24957905 TI - Gemcitabine-induced cardiomyopathy: a case report and review of the literature. AB - INTRODUCTION: Newly developed antineoplastic drugs have resulted in improvements in morbidity and mortality from many forms of cancers. However, some of these new chemotherapeutic agents have potentially lethal side effects, which are now being exposed with their widespread use. Gemcitabine is a nucleoside analog, which is a commonly used agent for various solid organ malignancies. Phase 1 and 2 trials with gemcitabine did not show significant risk for cardiotoxicity; however, with its widespread clinical use over the last decade, a few cases of cardiotoxicity related to gemcitabine use have been reported. Cardiomyopathy after the use of gemcitabine monotherapy is extremely rare; and only one such case has been reported in detail previously. CASE PRESENTATION: We report a case of a 56-year old African American man with pancreatic cancer who presented with signs and symptoms of congestive heart failure after being treated with gemcitabine for two cycles (six doses). A two-dimensional echocardiography showed left ventricular ejection fraction of 15 to 20 percent with global hypokinesia. With the absence of significant risk factors for coronary artery disease and a strong temporal relationship with the initiation of chemotherapy, it was concluded that our patient's cardiomyopathy was related to the use of gemcitabine. Gemcitabine was discontinued and our patient responded well to standard heart failure therapy. Two months later, a repeat echocardiogram showed significant improvements in left ventricular systolic function. CONCLUSIONS: Gemcitabine should be considered as a potential cause of cardiomyopathy in patients receiving chemotherapy with this drug. We need further studies to look into potential mechanisms and treatments of gemcitabine-induced cardiac dysfunction. PMID- 24957907 TI - Vehicle and positive control values from the in vivo rodent comet assay and biomonitoring studies using human lymphocytes: historical database and influence of technical aspects. AB - There is increased interest in the in vivo comet assay in rodents as a follow-up approach for determining the biological relevance of chemicals that are genotoxic in in vitro assays. This is partly because, unlike other assays, DNA damage can be assessed in this assay in virtually any tissue. Since background levels of DNA damage can vary with the species, tissue, and cell processing method, a robust historical control database covering multiple tissues is essential. We describe extensive vehicle and positive control data for multiple tissues from rats and mice. In addition, we report historical data from control and genotoxin-treated human blood. Technical issues impacting comet results are described, including the method of cell preparation and freezing. Cell preparation by scraping (stomach and other GI tract organs) resulted in higher % tail DNA than mincing (liver, spleen, kidney etc) or direct collection (blood or bone marrow). Treatment with the positive control genotoxicant, ethyl methanesulfonate (EMS) in rats and methyl methanesulfonate in mice, resulted in statistically significant increases in % tail DNA. Background DNA damage was not markedly increased when cell suspensions were stored frozen prior to preparing slides, and the outcome of the assay was unchanged (EMS was always positive). In conclusion, historical data from our laboratory for the in vivo comet assay for multiple tissues from rats and mice, as well as human blood show very good reproducibility. These data and recommendations provided are aimed at contributing to the design and proper interpretation of results from comet assays. PMID- 24957906 TI - A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy. AB - Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC association (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 * 10(-74)). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093; OR = 2.3, 95% CI 1.7-3.1, for the T allele, P = 8.6 * 10(-8)) and at 14q32.31 in the TECPR2 gene (rs150571175; OR = 6.1, 95% CI 3.2-11.7, for the A allele, P = 3.2 * 10(-8)). The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 * 10(-9)). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum. PMID- 24957908 TI - Use of BNP and NT-proBNP for the diagnosis of heart failure in the emergency department: a systematic review of the evidence. AB - Our purpose was to determine the test performance characteristics of BNP and NT proBNP in the diagnosis of heart failure for patients presenting to an emergency department or urgent care center. We searched Medline, Embase, AMED, Cochrane, Cochrane Database of Systematic Reviews, and CINAHL for English-language articles published between 1989 and June 2012. Studies were limited to those using FDA approved assays. We examined test performance at three pre-specified cutpoints (manufacturers' suggested, researchers' optimal, and lowest) and considered the effect of age, gender, ethnicity and renal function. We used the QUADAS-2 tool to examine risk of bias and applicability, and the AHRQ Methods Guide to assess the strength of evidence. Seventy-six articles met our inclusion criteria, 37 examined BNP, 25 examined NT-proBNP, and 14 examined both. Pooled sensitivity and specificity for BNP at the three pre-specified cutpoints were 95, 91, and 95 % (sensitivity) and 55, 80, and 67 % (specificity), respectively. For NT-proBNP, sensitivity and specificity at the same cutpoints were 91, 90, and 96 % (sensitivity) and 67, 74, and 55 % (specificity). Both BNP and NT-proBNP perform well to rule out, but less well to rule in, the diagnosis of heart failure among persons presenting to emergency departments or urgent care centers. Both BNP and NT-proBNP levels are positively associated with age and negatively associated with renal function. However, the effect of these factors with respect to selecting optimal cutpoints is unclear. For BNP, 100 pg/mL appears to be a consensus cutpoint. No clear consensus has emerged for NT-proBNP, but the age adjusted cutpoints of 450 pg/mL for <50 years, 900 pg/mL for 50-75 years and 1,800 pg/mL for >75 years appear promising and merit greater scrutiny and validation. PMID- 24957909 TI - Efficacy of isolated left ventricular and biventricular pacing is differentially associated with baseline QRS duration in chronic heart failure: a meta-analysis of randomized controlled trials. AB - Cardiac resynchronization therapy can treat chronic heart failure through either biventricular pacing (BVP) or isolated left ventricular pacing (LVP), and the efficacy is depended on QRS duration. However, the optimal therapeutic choice of pacing or how the QRS influences the efficacy remains uncertain. To investigate this uncertainty, we searched available publications in PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials databases regarding differentials in efficacy parameters between BVP and LVP. A meta-analysis of eight randomized controlled trials found that BVP and LVP were comparable with regard to quality of-life scores, left ventricular ejection fraction, left ventricular end-systolic volume, and mortality or heart transplant rates. However, there was a significant heterogeneity among the trials in 6-min walking distances. Subsequent meta regression indicated that the baseline QRS duration significantly correlated with the standard mean difference between BVP and LVP. As QRS duration increased, the gain in 6-min walking distance with BVP became significantly greater than that of LVP. This suggests that it is necessary to consider the QRS duration when comparing the clinical effects of BVP and LVP. PMID- 24957910 TI - The International Knee Documentation Committee (IKDC) Subjective Short Form: a validity and reliability study. AB - PURPOSE: The purpose of the present research was to translate the original English version of International Knee Documentation Committee (IKDC) Subjective Short Form to Persian and to assess validity and reliability of it in Iranian patients with ACL injury. METHOD: The Persian version of the IKDC Subjective Short Form was administered to 145 patients including 111 men (76 %) and 34 women (24 %) with the clinical diagnosis of knee ACL tear that were referred to our Knee and Shoulder Center at Mashhad University of Medical Sciences, Mashhad, Iran. The Persian IKDC Subjective Short Form and Persian SF-36 questionnaire were completed by patients in the clinic before beginning any treatment intervention. Patients filled out the Persian IKDC 72 h again before receiving a major treatment; we were then able to use the test-retest method to calculate reliability. RESULTS: The average age of the subjects was 30.9 +/- 10.4 years. The calculated ICC with 95 % confidence interval was 0.845. In this study, Cronbach's alpha was 0.845. There were significant correlations between mean total score of the Persian IKDC and all items of the SF36 (P < 0.05) except for MCS (P = 0.055). CONCLUSION: Cronbach's alpha and correlation of IKDC Subjective Short Form and SF-36 demonstrated that the Persian version of IKDC has both strong reliability and validity. The Iranian version of IKDC has favourable validity and reliability and therefore can be used to assess Persian-speaking patients with cruciate ligament injuries. LEVEL OF EVIDENCE: Level II. PMID- 24957912 TI - Ankle arthroscopy to manage sequelae after ankle fractures. AB - PURPOSE: The role of ankle arthroscopy in managing the consequences of ankle fractures is yet to be fully established. This study aims to assess this procedure in terms of the accuracy of preoperative diagnosis, re-operation rate and patient-reported outcomes. METHODS: Sixty-six patients were identified [mean age 40 years (SD 13 years)] who had undergone ankle arthroscopy following a fracture of the distal tibia or fibula. Medical case notes were reviewed to ascertain details of the index injury, intra-operative findings and identify any further procedures. Patients were then contacted using a standardized questionnaire to assess satisfaction and return to normal function. RESULTS: Injury occurred in a mean of 2 years 10 months before arthroscopy (SD 13 months, min 6 months). Forty-nine of 66 fractures (74 %) had been managed operatively. The commonest indication for arthroscopy was anterior impingement (45 %) followed by degenerative change (30 %) and osteochondral lesions (OCL) (18 %). Intra operative findings revealed an unexpected OCL or frank degenerative change in 20 % of patients. Using a Kaplan-Meier estimate 1 year after arthroscopy, 10 % of patients had undergone further surgery. This had increased to 34 % by 4 years after arthroscopy. Four patients underwent ankle fusion. Questionnaires were completed by 55/66 patients (84 %). Only 28 patients (50 %) felt surgery allowed them to return to normal activity. Thirty-nine patients reported a benefit from surgery (75 %) whilst 43 were satisfied (77 %) and 48 (86 %) would recommend the procedure to a friend. CONCLUSIONS: Intra-articular pathology was significantly underestimated preoperatively for one patient in five. Arthroscopy improved symptoms in 75 % of patients who complain of ankle symptoms after fracture of the ankle or distal tibia. However, further procedures were required in 34 % of patients. The findings of this study help guide patient counselling and operative decision-making in this challenging group of patients. LEVEL OF EVIDENCE: IV. PMID- 24957913 TI - Less deep vein thrombosis due to transcutaneous fibular nerve stimulation in total knee arthroplasty: a randomized controlled trial. AB - PURPOSE: It has been known for years that deep vein thrombi (DVT) start to develop during total joint arthroplasty. Previously, we reported effective prevention of venous stasis by transcutaneous electrical nerve stimulation (TENS). It is hypothesized that TENS might be a thromboprophylactic tool for the limb undergoing surgery. The purpose of this study is to clarify the clinical efficacy and safety of TENS in patients during total knee arthroplasty (TKA). METHODS: Ninety patients undergoing primary TKA were involved and randomly allocated to the TENS or control group. In the TENS group, electrical stimulation of the common fibular nerve, which produced a brisk dorsiflexion of the ankle, was performed for the operated leg during surgery. In the control group, no electrical stimulation was applied. Serum D-dimer and soluble fibrin monomer complex (SFMC) levels were measured before surgery, immediately after surgery, and post-operative day (POD) 1. Ultrasonography was performed on POD 1. RESULTS: Immediately after surgery, D-dimer and SFMC levels of each group were significantly lower in the TENS group compared with control (p < 0.05). The incidence of DVT was 11 % (five cases) in the TENS group while 31 % (14 cases) in control (p = 0.02). There were no adverse effects related to TENS. CONCLUSIONS: TENS during TKA showed significant effects on preventing DVT. Sustaining muscle pump activation during surgery prevented not only venous stasis, but also hypercoagulability of blood. Intraoperative TENS is a safe and novel strategy against early post-operative thromboembolism, which is difficult to be completed through existing prophylaxis after total joint arthroplasty. LEVEL OF EVIDENCE: Randomized controlled trial, Level I. PMID- 24957911 TI - Fixed- versus mobile-bearing UKA: a systematic review and meta-analysis. AB - PURPOSE: Two design concepts are currently used for unicondylar knee arthroplasty (UKA) prostheses: fixed bearing (FB) and mobile bearing (MB). While MB prostheses have theoretical advantages over their FB counterparts, it is not clear whether they are associated with better outcomes. A systematic review was conducted to examine survivorship differences and differences in failure modes of between FB and MB designs. METHODS: PubMed, Scirus and Cochrane library databases were searched for medial UKA outcome studies. A total of 44 papers, involving 9,463 knees, were eligible. Outcomes examined included knee function, survivorship and the reasons for, and incidence of, revision for FB and MB prostheses. Random effects meta-analysis was employed to obtain pooled revision rate estimates. Where available, cause-specific time to revision was extracted. RESULTS: Mean follow-up was 8.7 years for FB and 5.9 years for MB prostheses. There were no other relevant baseline differences. The overall crude revision rate for FB and for MB prostheses was 0.90 (95 % confidence interval (CI) 0.65-1.21) and 1.51 (95 % CI 1.11-1.93) per 100 component years, respectively. After stratification on follow-up time and age, the revision rates were not substantially different, aside for younger patients in short term from studies with short-term follow-up. CONCLUSION: No essential differences between the two designs were observed. MB and FB UKA designs have comparable revision rates. As our study is based on predominantly observational data, with large variations in reporting standards, inferences should be drawn with caution. LEVEL OF EVIDENCE: IV. PMID- 24957914 TI - In vitro functional response of human tendon cells to different dosages of low frequency pulsed electromagnetic field. AB - PURPOSE: Chronic tendinopathy is a degenerative process causing pain and disability. Current treatments include biophysical therapies, such as pulsed electromagnetic fields (PEMF). The aim of this study was to compare, for the first time, the functional in vitro response of human tendon cells to different dosages of PEMF, varying in field intensity and duration and number of exposures. METHODS: Tendon cells, isolated from human semitendinosus and gracilis tendons (hTCs; n = 6), were exposed to different PEMF treatments (1.5 or 3 mT for 8 or 12 h, single or repeated treatments). Scleraxis (SCX), COL1A1, COL3A1 and vascular endothelial growth factor-A (VEGF-A) expression and cytokine production were assessed. RESULTS: None of the different dosages provoked apoptotic events. Proliferation of hTCs was enhanced by all treatments, whereas only 3 mT-PEMF treatment increased cell viability. However, the single 1.5 mT-PEMF treatment elicited the highest up-regulation of SCX, VEGF-A and COL1A1 expression, and it significantly reduced COL3A1 expression with respect to untreated cells. The treated hTCs showed a significantly higher release of IL-1beta, IL-6, IL-10 and TGF-beta. Interestingly, the repeated 1.5 mT-PEMF significantly further increased IL-10 production. CONCLUSIONS: 1.5 mT-PEMF treatment was able to give the best results in in vitro healthy human tendon cell culture. Although the clinical relevance is not direct, this investigation should be considered an attempt to clarify the effect of different PEMF protocols on tendon cells, in particular focusing on the potential applicability of this cell source for regenerative medicine purpose, both in surgical and in conservative treatment for tendon disorders. PMID- 24957916 TI - The case for sex- and gender-specific medicine. PMID- 24957915 TI - Estimating cancer incidence using a Bayesian back-calculation approach. AB - We propose a Bayesian hierarchical model for the calculation of incidence counts from mortality data by a convolution equation that expresses mortality through its relationship with incidence and the survival probability density. The basic idea is to use mortality data together with an estimate of the survival distribution from cancer incidence to cancer mortality to reconstruct the numbers of individuals who constitute previously incident cases that give rise to the observed pattern of cancer mortality. This model is novel because it takes into account the uncertainty from the survival distribution; thus, a Bayesian-mixture cure model for survival is introduced. Furthermore, projections are obtained starting from a Bayesian age-period-cohort model. The main advantage of the proposed approach is its consideration of the three components of the model: the convolution equation, the survival mixture cure model and the age-period-cohort projection within a directed acyclic graph model. Furthermore, the estimation are obtained through the Gibbs sampler. We applied the model to cases of women with stomach cancer using six age classes [15-45], [45-55], [55-65], [65-75], [75-85] and [85-95] and validated it by using data from the Tuscany Cancer Registry. The model proposed and the program implemented are convenient because they allow different cancer disease to be analysed because the survival time is modelled by flexible distributions that are able to describe different trends. PMID- 24957917 TI - Thiourea-based fluorescent chemosensors for aqueous metal ion detection and cellular imaging. AB - We describe three significant advances in the use of thioureas as reporting elements for metal-responsive fluorescent chemosensors. First, on the basis of the crystal structure of a chemosensor analogue, we provide a deeper understanding of the details of the thiourea coordination environment. Second, we describe a new generation of chemosensors with higher affinities for Zn(2+) and Cd(2+) than were observed for earlier probes, expanding the scope of this type of probe beyond Hg(2+) detection. Third, we show that a thiourea-based chemosensor can be employed for fluorescence microscopy imaging of Hg(2+) ion concentrations in living mammalian cells. PMID- 24957918 TI - Kagome-like lattice of pi-pi stacked 3-hydroxyphenalenone on Cu(111). AB - We have identified a structurally complex double-layer of 3-hydroxyphenalenone on Cu(111), which exhibits Kagome lattice symmetry. A key feature is the perpendicular attachment of pi-pi stacked molecular dimers on top of molecules that are flat-lying on the substrate, representing a rare example of a three dimensional arrangement of molecules on a two-dimensional surface. PMID- 24957919 TI - Relationship between weight of rescuer and quality of chest compression during cardiopulmonary resuscitation. AB - BACKGROUND: According to the guidelines for cardiopulmonary resuscitation (CPR), the rotation time for chest compression should be about 2 min. The quality of chest compressions is related to the physical fitness of the rescuer, but this was not considered when determining rotation time. The present study aimed to clarify associations between body weight and the quality of chest compression and physical fatigue during CPR performed by 18 registered nurses (10 male and 8 female) assigned to light and heavy groups according to the average weight for each sex in Japan. METHODS: Five-minute chest compressions were then performed on a manikin that was placed on the floor. Measurement parameters were compression depth, heart rate, oxygen uptake, integrated electromyography signals, and rating of perceived exertion. Compression depth was evaluated according to the ratio (%) of adequate compressions (at least 5 cm deep). RESULTS: The ratio of adequate compressions decreased significantly over time in the light group. Values for heart rate, oxygen uptake, muscle activity defined as integrated electromyography signals, and rating of perceived exertion were significantly higher for the light group than for the heavy group. CONCLUSION: Chest compression caused increased fatigue among the light group, which consequently resulted in a gradual fall in the quality of chest compression. These results suggested that individuals with a lower body weight should rotate at 1-min intervals to maintain high quality CPR and thus improve the survival rates and neurological outcomes of victims of cardiac arrest. PMID- 24957920 TI - Highly flexible dye-sensitized solar cells produced by sewing textile electrodes on cloth. AB - Textile forms of solar cells possess special advantages over other types of solar cells, including their light weight, high flexibility, and mechanical robustness. Recent demand for wearable devices has promoted interest in the development of high-efficiency textile-based solar cells for energy suppliers. However, the weaving process occurs under high-friction, high-tension conditions that are not conducive to coated solar-cell active layers or electrodes deposited on the wire or strings. Therefore, a new approach is needed for the development of textile based solar cells suitable for woven fabrics for wide-range application. In this report, we present a highly flexible, efficient DSSC, fabricated by sewing textile-structured electrodes onto casual fabrics such as cotton, silk, and felt, or paper, thereby forming core integrated DSSC structures with high energy conversion efficiency (~5.8%). The fabricated textile-based DSSC devices showed high flexibility and high performance under 4-mm radius of curvature over thousands of deformation cycles. Considering the vast number of textile types, our textile-based DSSC devices offer a huge range of applications, including transparent, stretchable, wearable devices. PMID- 24957921 TI - Sex-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Observational Research Programme Pilot survey on Atrial Fibrillation. AB - AIMS: Sex differences in the epidemiology and clinical management of AF are evident. Of note, females are more symptomatic and if age >65, are at higher risk of thromboembolism if incident AF develops, compared with males. METHODS AND RESULTS: In an analysis from the dataset of the Euro Observational Research Programme on Atrial Fibrillation (EORP-AF) Pilot survey (n = 3119), we examined sex-related differences in presentation, treatment, and outcome of contemporary patients with AF in Europe.Female subjects were older (P < 0.0001), with a greater proportion aged >=75 years, with more heart failure and hypertension. Heart failure with preserved ejection fraction was more common in females (P < 0.0001), as was valvular heart disease (P = 0.0003). Females were more symptomatic compared with males with a higher proportion being EHRA Class III and IV (P = 0.0012). The more common symptoms that were more prevalent in females were palpitations (P < 0.0001) and fear/anxiety (P = 0.0007). Other symptoms (e.g. dyspnoea, chest pain, fatigue, etc.) were not different between males and females. Health status scores were significantly lower for females overall, specifically for the psychological and physical domains (both P < 0.0001) but not for the sexual activity domain (P = 0.9023). Females were less likely to have electrical cardioversion (18.9 vs. 25.5%, P < 0.0001), and more likely to receive rate control (P = 0.002). Among patients recruited in hospital and discharged alive (n = 2009), documented contraindications to vitamin K antagonist (VKA) were evident in 23.8% of females. A CHA2DS2-VASc score >=2 was found in 94.7% of females and 74.6% of males (P < 0.0001), with oral anticoagulants being used in 95.3 and 76.2%, respectively (P < 0.0001). A HAS-BLED score of >=3 was found in 12.2% of females and 14.5% of males. Independent predictors of VKA use in females on multivariate analysis were CHA2DS2-VASc score (P = 0.0007), lower HAS-BLED score (P = 0.0284), and prosthetic mechanical valves (P = 0.0276). CONCLUSION: The EORP-AF Pilot survey provides contemporary data on sex differences in clinical features and management of AF patients participating in the EORP-AF Pilot registry. Female subjects were older and more symptomatic, compared with males, and were more likely to receive rate control. Also, female patients were at higher stroke risk overall, but oral anticoagulation was used in a high proportion of patients. PMID- 24957924 TI - Effects of footwear on three-dimensional tibiotalar and subtalar joint motion during running. AB - Running is a popular form of recreation, but injuries are common and may be associated with abnormal joint motion. The objective of this study was to determine the effect of three footwear conditions - barefoot (BF), an ultraflexible training shoe (FREE), and a motion control shoe (MC) - on 3D foot and ankle motion. Dynamic, biplane radiographic images were acquired from 12 runners during overground running. 3D rotations of the tibiotalar and subtalar joints were quantified in terms of plantarflexion/dorsiflexion (PF/DF), inversion/eversion (IN/EV) and internal/external rotation (IR/ER). Across the early stance phase (defined as footstrike to heel-off), BF running demonstrated greater tibiotalar joint range of motion for PF/DF (28.2 +/- 8.3 degrees ) and IR/ER (7.0 +/- 1.4 degrees ) than the shod conditions (FREE: PF/DF=15.1 +/- 5.9 degrees , IR/ER=4.8 +/- 2.1 degrees ; MC: PF/DF=15.0 +/- 6.2 degrees , IR/ER=4.3 +/- 0.7 degrees ). Also at the tibiotalar joint, BF running resulted in a position significantly more plantarflexed (BF: 2.0 +/- 12.5 degrees , FREE: 15.7 +/- 12.2 degrees , MC: 16.5 +/- 9.3 degrees ) and internally rotated (BF: 12.9 +/ 4.5 degrees , FREE: 10.7 +/- 4.3 degrees , MC: 10.6 +/- 3.9 degrees ) at footstrike compared to both shod conditions. No differences were detected between the shod conditions at any point in the early stance phase at the tibiotalar joint. The MC condition demonstrated significant differences compared to FREE at several points throughout the early stance phase at the subtalar joint, with the greatest differences seen at 30% in PF/DF (MC -1.4 +/- 8.8 degrees : FREE: -0.5 +/- 9.0 degrees ), IN/EV (MC -8.1 +/- 5.7 degrees : FREE -6.3 +/- 5.5 degrees ) and IR/ER (MC -9.5 +/- 5.3 degrees : FREE: -8.7 +/- 5.2 degrees ). These findings indicate that footwear has subtle effects on joint motion mainly between BF and shod conditions at the tibiotalar joint and between shod conditions at the subtalar joint. PMID- 24957922 TI - Nucleotomy reduces the effects of cyclic compressive loading with unloaded recovery on human intervertebral discs. AB - The first objective of this study was to determine the effects of physiological cyclic loading followed by unloaded recovery on the mechanical response of human intervertebral discs. The second objective was to examine how nucleotomy alters the disc's mechanical response to cyclic loading. To complete these objectives, 15 human L5-S1 discs were tested while intact and subsequent to nucleotomy. The testing consisted of 10,000 cycles of physiological compressive loads followed by unloaded hydrated recovery. Cyclic loading increased compression modulus (3%) and strain (33%), decreased neutral zone modulus (52%), and increased neutral zone strain (31%). Degeneration was not correlated with the effect of cyclic loading in intact discs, but was correlated with cyclic loading effects after nucleotomy, with more degenerate samples experiencing greater increases in both compressive and neutral zone strain following cyclic loading. Partial removal of the nucleus pulposus decreased the compression and neutral zone modulus while increasing strain. These changes correspond to hypermobility, which will alter overall spinal mechanics and may impact low back pain via altered motion throughout the spinal column. Nucleotomy also reduced the effects of cyclic loading on mechanical properties, likely due to altered fluid flow, which may impact cellular mechanotransduction and transport of disc nutrients and waste. Degeneration was not correlated with the acute changes of nucleotomy. Results of this study provide an ideal protocol and control data for evaluating the effectiveness of a mechanically-based disc degeneration treatment, such as a nucleus replacement. PMID- 24957923 TI - Modeling the biomechanics of swine mastication--an inverse dynamics approach. AB - A novel reconstructive alternative for patients with severe facial structural deformity is Le Fort-based, face-jaw-teeth transplantation (FJTT). To date, however, only ten surgeries have included underlying skeletal and jaw-teeth components, all yielding sub-optimal results and a need for a subsequent revision surgery, due to size mismatch and lack of precise planning. Numerous studies have proven swine to be appropriate candidates for translational studies including pre operative planning of transplantation. An important aspect of planning FJTT is determining the optimal muscle attachment sites on the recipient's jaw, which requires a clear understanding of mastication and bite mechanics in relation to the new donated upper and/or lower jaw. A segmented CT scan coupled with data taken from literature defined a biomechanical model of mandible and jaw muscles of a swine. The model was driven using tracked motion and external force data of one cycle of chewing published earlier, and predicted the muscle activation patterns as well as temporomandibular joint (TMJ) reaction forces and condylar motions. Two methods, polynomial and min/max optimization, were used for solving the muscle recruitment problem. Similar performances were observed between the two methods. On average, there was a mean absolute error (MAE) of <0.08 between the predicted and measured activation levels of all muscles, and an MAE of <7 N for TMJ reaction forces. Simulated activations qualitatively followed the same patterns as the reference data and there was very good agreement for simulated TMJ forces. The polynomial optimization produced a smoother output, suggesting that it is more suitable for studying such motions. Average MAE for condylar motion was 1.2mm, which reduced to 0.37 mm when the input incisor motion was scaled to reflect the possible size mismatch between the current and original swine models. Results support the hypothesis that the model can be used for planning of facial transplantation. PMID- 24957925 TI - Reflex delays of the trunk muscles in response to postural perturbations: a reliability study. AB - It has been reported that altered neuromuscular control of the trunk is associated with lower back pain. In this context reflex delays of the trunk muscles have often been assessed but the reliability of the tests has not been well established. The aim of this study was to test the reliability of measuring reflex delays of the trunk muscles after two types of postural perturbations. 24 Healthy subjects participated in the intra-session study and 13 of them repeated the test protocol within 1-3 weeks, to determine inter-session reliability. Postural reflex delays to unexpected loading and unloading of the arms were assessed in a standing unrestrained position. Each subject performed 40 trials of each test in order to evaluate muscle responses of 5 trunk muscles using surface electromyography. Overall reliability increased with higher number of the averaged trials. Good intra-session (ICC3,1>0.75) and moderate (ICC3,1>0.60) inter-session reliability were reached in most of the monitored trunk muscles. Within the performed number of trials we did not observe any significant systematic intra- or inter-session bias effect. Averaging a higher number of consecutive trials would be recommended in future research and clinical practice. PMID- 24957926 TI - A meta-ethnographic study of health care staff perceptions of the WHO/UNICEF Baby Friendly Health Initiative. AB - BACKGROUND: Implementation of the Baby Friendly Health Initiative (BFHI) is associated with increases in breastfeeding initiation and duration of exclusive breastfeeding and 'any' breastfeeding. However, implementation of the BFHI is challenging. AIM: To identify and synthesise health care staff perceptions of the WHO/UNICEF BFHI and identify facilitators and barriers for implementation. METHOD: Seven qualitative studies, published between 2003 and 2013 were analysed using meta-ethnographic synthesis. FINDINGS: Three overarching themes were identified. First the BFHI was viewed variously as a 'desirable innovation or an unfriendly imposition'. Participants were passionate about supporting breastfeeding and improving consistency in the information provided. This view was juxtaposed against the belief that BFHI represents an imposition on women's choices, and is a costly exercise for little gain in breastfeeding rates. The second theme highlighted cultural and organisational constraints and obstacles to BFHI implementation including resource issues, entrenched staff practices and staff rationalisation of non-compliance. Theme three captured a level of optimism and enthusiasm amongst participants who could identify a dedicated and credible leader to lead the BFHI change process. Collaborative engagement with all key stakeholders was crucial. CONCLUSIONS: Health care staff hold variant beliefs and attitudes towards BFHI, which can help or hinder the implementation process. The introduction of the BFHI at a local level requires detailed planning, extensive collaboration, and an enthusiastic and committed leader to drive the change process. This synthesis has highlighted the importance of thinking more creatively about the translation of this global policy into effective change at the local level. PMID- 24957927 TI - Aggregating validity indicators embedded in Conners' CPT-II outperforms individual cutoffs at separating valid from invalid performance in adults with traumatic brain injury. AB - Continuous performance tests (CPT) provide a useful paradigm to assess vigilance and sustained attention. However, few established methods exist to assess the validity of a given response set. The present study examined embedded validity indicators (EVIs) previously found effective at dissociating valid from invalid performance in relation to well-established performance validity tests in 104 adults with TBI referred for neuropsychological testing. Findings suggest that aggregating EVIs increases their signal detection performance. While individual EVIs performed well at their optimal cutoffs, two specific combinations of these five indicators generally produced the best classification accuracy. A CVI-5A >=3 had a specificity of .92-.95 and a sensitivity of .45-.54. At >=4 the CVI-5B had a specificity of .94-.97 and sensitivity of .40-.50. The CVI-5s provide a single numerical summary of the cumulative evidence of invalid performance within the CPT-II. Results support the use of a flexible, multivariate approach to performance validity assessment. PMID- 24957929 TI - Sulcus-fixated intraocular lens implantation for the management of negative dysphotopsia. AB - PURPOSE: To determine whether intraocular lens (IOL) exchange with insertion of a sulcus-fixated IOL is an effective treatment for the management of pseudophakic negative dysphotopsia. SETTING: Department of Ophthalmology, Stoke Mandeville Hospital, Buckinghamshire, United Kingdom. DESIGN: Case series. METHODS: Participants in the study were recruited prospectively from the clinic at the time of diagnosis or retrospectively from the operating room logs by identifying all patients who had IOL exchanges over a 4-year period (2009 to 2012). RESULTS: Five eyes of 5 women with negative dysphotopsia were treated with IOL exchange and replacement with a 3-piece IOL (Acrysof MA60AC) inserted in the ciliary sulcus. All patients had a resolution of the negative dysphotopsia symptoms. One patient had primary insertion of a sulcus IOL in the fellow eye and did not develop negative dysphotopsia symptoms. CONCLUSION: Intraocular lens exchange with insertion of a 3-piece IOL in the ciliary sulcus appears to be a safe and effective treatment for the management of pseudophakic negative dysphotopsia. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 24957928 TI - Mortality after cardiac or vascular operations by preexisting serious mental illness status in the Veterans Health Administration. AB - OBJECTIVE: To estimate 1-year mortality risk associated with preoperative serious mental illness (SMI) as defined by the Veterans Health Administration (schizophrenia, bipolar disorder, posttraumatic stress disorder [PTSD], major depression) following nonambulatory cardiac or vascular surgical procedures compared to patients without SMI. Cardiac/vascular operations were selected because patients with SMI are known to be at elevated risk of cardiovascular disease. METHOD: Retrospective analysis of system-wide data from electronic medical records of patients undergoing nonambulatory surgery (inpatient or day-of surgery admission) October 2005-September 2009 with 1-year follow-up (N=55,864; 99% male; <30 days of postoperative hospitalization). Death was hypothesized to be more common among patients with preoperative SMI. RESULTS: One in nine patients had SMI, mostly PTSD (6%). One-year mortality varied by procedure type and SMI status. Patients had vascular operations (64%; 23% died), coronary artery bypass graft (26%; 10% died) or other cardiac operations (11%; 15%-18% died). Fourteen percent of patients with PTSD died, 20% without SMI and 24% with schizophrenia, with other groups intermediate. In multivariable stratified models, SMI was associated with increased mortality only for patients with bipolar disorder following cardiac operations. Bipolar disorder and PTSD were negatively associated with death following vascular operations. CONCLUSIONS: SMI is not consistently associated with postoperative mortality in covariate-adjusted analyses. PMID- 24957930 TI - Stabilization of a computer-aided implant surgical guide using existing dental implants with conversion of an overdenture to a fixed prosthesis. AB - This clinical report describes a technique to stabilize a computer-aided dental implant surgical guide to existing implants. A patient requested conversion of her existing mandibular implant-assisted overdenture into a fixed complete denture. The surgical procedure was planned virtually, and the two existing dental implants were integrated into the surgical plan as a means to fixate the surgical guide. The implants were placed, and the patient's prosthesis was converted into an interim fixed complete denture. PMID- 24957931 TI - Integration of social media in emergency medicine residency curriculum. PMID- 24957933 TI - Association between changes in body composition and risk of developing Type 2 diabetes in Koreans. AB - AIMS: To examine the effects of longitudinal changes in fat mass or lean body mass on risk of Type 2 diabetes in Korean adults. METHODS: Participants included 18 687 Korean adults (aged 20-79 years) who underwent routine medical check-ups in 2007-2008 and again in 2011-2012 with a mean (range) of 4.3 (3.0-5.7) years interval. Total fat, fat-free, and soft fat-free masses were determined using bioelectrical impedance. RESULTS: A total of 692 subjects (3.7%) developed Type 2 diabetes during follow-up. Those who developed diabetes had a greater increase in percent body fat (2.9 +/- 3.0 vs 2.6 +/- 3.2 percentage points, P = 0.043), as well as greater decreases in percent fat-free mass (-3.0 +/- 3.3 vs -2.7 +/- 3.3 percentage points, P = 0.008) and percent soft fat-free mass (-2.8 +/- 3.1 vs 2.4 +/- 3.1 percentage points, P = 0.003) compared with those who did not develop diabetes. In multiple logistic regression analysis, an increase in total fat mass of > 10% was associated with an increased odds ratio for diabetes (1.29, 1.05 1.60), and a decreased total fat mass was associated with lower odds ratio (0.75, 0.58-0.96). A loss of total fat-free mass of > 5% (odds ratio 1.08, 0.90-1.30) or an increase in total fat-free mass (odds ratio 0.96, 0.71-1.28) was not significantly associated with the risk of diabetes after adjustments for baseline waist circumference and glucose levels. CONCLUSIONS: These results show that changes in total body fat mass, but not lean body mass, are associated with development of Type 2 diabetes, independently of baseline measures of general or central obesity. PMID- 24957932 TI - A minimally invasive method for retrieving single adherent cells of different types from cultures. AB - The field of single-cell analysis has gained a significant momentum over the last decade. Separation and isolation of individual cells is an indispensable step in almost all currently available single-cell analysis technologies. However, stress levels introduced by such manipulations remain largely unstudied. We present a method for minimally invasive retrieval of selected individual adherent cells of different types from cell cultures. The method is based on a combination of mechanical (shear flow) force and biochemical (trypsin digestion) treatment. We quantified alterations in the transcription levels of stress response genes in individual cells exposed to varying levels of shear flow and trypsinization. We report optimal temperature, RNA preservation reagents, shear force and trypsinization conditions necessary to minimize changes in the stress-related gene expression levels. The method and experimental findings are broadly applicable and can be used by a broad research community working in the field of single cell analysis. PMID- 24957934 TI - Candida antigens and immune responses: implications for a vaccine. AB - Superficial candidiasis of the oral cavity, vagina and the skin are common mild infections though they may be recalcitrant, as in the case of recurrent vaginitis or denture stomatitis. However, in debilitated people with immune deficiencies, Candida can cause serious invasive infections with high mortality. Both types of patients could benefit from the development of vaccines and monoclonal or polyclonal antibodies of utility for a passive immunization, according to their immune status. Several antigens as mannans, beta-glucans, various adhesins, heat shock protein 90 and acid secreted proteinases can be very useful for the vaccines development. There is a broad and sound experience with many of these antigens in animal models, mainly in rabbits and mice. However, only two vaccines, based on recombinant antigens (rAls3p-N and rSap2t) are currently being tested in clinical trials. PMID- 24957935 TI - Advanced unidirectional photocurrent generation via cytochrome c as reaction partner for directed assembly of photosystem I. AB - Conversion of light into an electrical current based on biohybrid systems mimicking natural photosynthesis is becoming increasingly popular. Photosystem I (PSI) is particularly useful in such photo-bioelectrochemical devices. Herein, we report on a novel biomimetic approach for an effective assembly of photosystem I with the electron transfer carrier cytochrome c (cyt c), deposited on a thiol modified gold-surface. Atomic force microscopy and surface plasmon resonance measurements have been used for characterization of the assembly process. Photoelectrochemical experiments demonstrate a cyt c mediated generation of an enhanced unidirectional cathodic photocurrent. Here, cyt c can act as a template for the assembly of an oriented and dense layer of PSI and as wiring agent to direct the electrons from the electrode towards the photosynthetic reaction center of PSI. Furthermore, three-dimensional protein architectures have been formed via the layer-by-layer deposition technique resulting in a successive increase in photocurrent densities. An intermittent cyt c layer is essential for an efficient connection of PSI layers with the electrode and for an improvement of photocurrent densities. PMID- 24957938 TI - Drug resistance: Overcoming resistance in acute myeloid leukaemia treatment. PMID- 24957945 TI - Measuring myofiber orientations from high-frequency ultrasound images using multiscale decompositions. AB - High-frequency ultrasound (HFU) has the ability to image both skeletal and cardiac muscles. The quantitative assessment of these myofiber orientations has a number of applications in both research and clinical examinations; however, difficulties arise due to the severe speckle noise contained in the HFU images. Thus, for the purpose of automatically measuring myofiber orientations from two dimensional HFU images, we propose a two-step multiscale image decomposition method. It combines a nonlinear anisotropic diffusion filter and a coherence enhancing diffusion filter to extract myofibers. This method has been verified by ultrasound data from simulated phantoms, excised fiber phantoms, specimens of porcine hearts, and human skeletal muscles in vivo. The quantitative evaluations of both phantoms indicated that the myofiber measurements of our proposed method were more accurate than other methods. The myofiber orientations extracted from different layers of the porcine hearts matched the prediction of an established cardiac mode and demonstrated the feasibility of extracting cardiac myofiber orientations from HFU images ex vivo. Moreover, HFU also demonstrated the ability to measure myofiber orientations in vivo. PMID- 24957946 TI - Cytotoxicity of graphene: recent advances and future perspective. AB - Graphene, a unique two-dimensional single-atom-thin nanomaterial with exceptional structural, mechanical, and electronic properties, has spurred an enormous interest in many fields, including biomedical applications, which at the same time ignites a growing concern on its biosafety and potential cytotoxicity to human and animal cells. In this review, we present a summary of some very recent studies on this important subject with both experimental and theoretical approaches. The molecular interactions of graphene with proteins, DNAs, and cell membranes (both bacteria and mammalian cells) are discussed in detail. Severe distortions in structures and functions of these biomacromolecules by graphene are identified and characterized. For example, the graphene is shown to disrupt bacteria cell membranes by insertion/cutting as well as destructive extraction of lipid molecules directly. More interestingly, this cytotoxicity has been shown to have implications in de novo design of nanomedicine, such as graphene-based band aid, a potential 'green' antibiotics due to its strong physical-based (instead of chemical-based) antibacterial capability. These studies have provided a better understanding of graphene nanotoxicity at both cellular and molecular levels, and also suggested therapeutic potential by using graphene's cytotoxicity against bacteria cells. PMID- 24957947 TI - Computational fluid dynamics simulation of airflow in the trachea and main bronchi for the subjects with left pulmonary artery sling. AB - BACKGROUND: Left pulmonary artery sling (LPAS) is a rare but severe congenital anomaly, in which the stenoses are formed in the trachea and/or main bronchi. Multi-detector computed tomography (MDCT) provides useful anatomical images, but does not offer functional information. The objective of the present study is to quantitatively analyze the airflow in the trachea and main bronchi of LPAS subjects through computational fluid dynamics (CFD) simulation. METHODS: Five subjects (four LPAS patients, one normal control) aging 6-19 months are analyzed. The geometric model of the trachea and the two main bronchi is extracted from the MDCT images. The inlet velocity is determined based on the body weight and the inlet area. Both the geometric model and personalized inflow conditions are imported into CFD software, ANSYS. The pressure drop, mass flow ratio through two bronchi, wall pressure, flow velocity and wall shear stress (WSS) are obtained, and compared to the normal control. RESULTS: Due to the tracheal and/or bronchial stenosis, the pressure drop for the LPAS patients ranges 78.9-914.5 Pa, much higher than for the normal control (0.7 Pa). The mass flow ratio through the two bronchi does not correlate with the sectional area ratio if the anomalous left pulmonary artery compresses the trachea or bronchi. It is suggested that the C shaped trachea plays an important role on facilitating the air flow into the left bronchus with the inertia force. For LPAS subjects, the distributions of velocities, wall pressure and WSS are less regular than for the normal control. At the stenotic site, high velocity, low wall pressure and high WSS are observed. CONCLUSIONS: Using geometric models extracted from CT images and the patient specified inlet boundary conditions, CFD simulation can provide vital quantitative flow information for LPAS. Due to the stenosis, high pressure drops, inconsistent distributions of velocities, wall pressure and WSS are observed. The C-shaped trachea may facilitate a larger flow of air into the left bronchus under the inertial force, and decrease the ventilation of the right lung. Quantitative and personalized information may help understand the mechanism of LPAS and the correlations between stenosis and dyspnea, and facilitate the structural and functional assessment of LPAS. PMID- 24957948 TI - Topological ferrimagnetic behaviours of coordination polymers containing manganese(II) chains with mixed azide and carboxylate bridges and alternating F/AF/AF'/AF'/AF interactions. AB - Two Mn(ii) complexes with azide and a new zwitterionic tetracarboxylate ligand 1,2,4,5-tetrakis(4-carboxylatopyridinium-1-methylene)benzene (L(1)), {[Mn5(L(1))2(N3)8(OH)2].12H2O}n () and {[Mn5(L(1))2(N3)8(H2O)2](ClO4)2.6H2O}n (), have been synthesized and characterized crystallographically and magnetically. and contain similar alternating chains constructed by azide and carboxylate bridges. The independent sets of bridges alternate in an ABCCB sequence between adjacent Mn(ii) ions: (EO-N3)2 double bridges (EO = end-on) (denoted as A), [(EO N3)(OCO)2] triple bridges (denoted as B) and [(EO-N3)(OCO)] double bridges (denoted as C). The alternating chains are interlinked into 2D coordination networks by the tetrapyridinium spacers. Magnetic studies demonstrate that the magnetic coupling through the double EO azide bridges is ferromagnetic and that through mixed azide/carboxylate bridges is antiferromagnetic. The unprecedented F/AF/AF'/AF'/AF coupling sequence along the chain dictates an uncompensated ground spin state (S = 5/2 per Mn5 unit) and leads to one-dimensional topological ferrimagnetism, which features a minimum in the chiT versus T plot. PMID- 24957944 TI - Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. AB - The identification of mutationally activated BRAF in many cancers altered our conception of the part played by the RAF family of protein kinases in oncogenesis. In this Review, we describe the development of BRAF inhibitors and the results that have emerged from their analysis in both the laboratory and the clinic. We discuss the spectrum of RAF mutations in human cancer and the complex interplay between the tissue of origin and the response to RAF inhibition. Finally, we enumerate mechanisms of resistance to BRAF inhibition that have been characterized and postulate how strategies of RAF pathway inhibition may be extended in scope to benefit not only the thousands of patients who are diagnosed annually with BRAF-mutated metastatic melanoma but also the larger patient population with malignancies harbouring mutationally activated RAF genes that are ineffectively treated with the current generation of BRAF kinase inhibitors. PMID- 24957949 TI - Microbial exposure in infancy and subsequent appearance of type 1 diabetes mellitus-associated autoantibodies: a cohort study. AB - IMPORTANCE: The role of microbial exposure during early life in the development of type 1 diabetes mellitus is unclear. OBJECTIVE: To investigate whether animal contact and other microbial exposures during infancy are associated with the development of preclinical and clinical type 1 diabetes. DESIGN, SETTING, AND PARTICIPANTS: A birth cohort of children with HLA antigen-DQB1-conferred susceptibility to type 1 diabetes was examined. Participants included 3143 consecutively born children at 2 hospitals in Finland between 1996 and 2004. EXPOSURES: The following exposures during the first year of life were assessed: indoor and outdoor dogs and cats, farm animals, farming, visit to a stable, day care, and exposure to antibiotics during the first week of life. MAIN OUTCOMES AND MEASURES: Clinical and preclinical type 1 diabetes were used as outcomes. The latter was defined as repeated positivity for islet-cell antibodies plus for at least 1 of 3 other diabetes-associated autoantibodies analyzed and/or clinical type 1 diabetes. The autoantibodies were analyzed at 3- to 12-month intervals since the birth of the child. RESULTS: Children exposed to an indoor dog, compared with otherwise similar children without an indoor dog exposure, had a reduced odds of developing preclinical type 1 diabetes (adjusted odds ratio [OR], 0.47; 95% CI, 0.28-0.80; P = .005) and clinical type 1 diabetes (adjusted OR, 0.40; 95% CI, 0.14-1.14; P = .08). All of the other microbial exposures studied were not associated with preclinical or clinical diabetes: the odds ratios ranged from 0.74 to 1.58. CONCLUSIONS AND RELEVANCE: Among the 9 early microbial exposures studied, only the indoor dog exposure during the first year of life was inversely associated with the development of preclinical type 1 diabetes. This finding needs to be confirmed in other populations. PMID- 24957950 TI - Immunogenicity and safety of intradermal trivalent influenza vaccination in nursing home older adults: a randomized controlled trial. AB - OBJECTIVE: To compare the immunogenicity and safety between full-dose (15 MUg) intramuscular (i.m.) and full-dose (15 MUg) intradermal (i.d.) immunization of the trivalent influenza vaccine in nursing home older adults. DESIGN: A single center, randomized, controlled, open-label, parallel group trial from October 2013 to April 2014. SETTING: Nine nursing homes in Hong Kong. PARTICIPANTS: Hundred nursing home older adults (mean age: 82.9 +/- 7.4 years). INTERVENTION: Fifty received i.d. (Intanza) and 50 received i.m. (Vaxigrip) vaccination. MEASUREMENTS: Baseline measurements included demographics, comorbidity, frailty and nutritional status. Day 21 and day 180 immunogenicity (seroconversion rate, seroprotection rate, geometric mean titer [GMT] fold increase in antibody titer) using hemagglutination-inhibition and adverse events were measured. Noninferiority and superiority of i.d. compared with i.m. vaccination in immunogenicity were analyzed. The study was registered on ClinicalTrials.gov; identifier: NCT 01967368. RESULTS: At day 21, noninferiority in immunogenicity of the i.d. vaccination was demonstrated. The seroconversion rate of the H1N1 strain was significantly higher in the i.d. group. At day 180, immunogenicity of both groups fell but the GMT of all strains in i.d. group was higher and the difference was significant for H3N2 strain. The seroconversion rate and GMT fold increase of H3N2 strain was significantly higher in the i.d. group. Local adverse events was significantly more in i.d. group, but they were mild and resolved in 72 hours. CONCLUSIONS: I.d. vaccination is noninferior, and even superior in some parts of immunogenicity assessment, to i.m. vaccination without compromising safety in nursing home older adults. I.d. vaccination is a good alternative to i.m. vaccination in this population. PMID- 24957951 TI - Predicting the invasion depth of esophageal squamous cell carcinoma: comparison of endoscopic ultrasonography and magnifying endoscopy. AB - OBJECTIVE: Predicting the invasion depth of superficial esophageal squamous cell carcinoma (SESCC) is important when selecting among therapeutic strategies. The aim of this study was to compare magnifying endoscopy with narrow-band imaging (ME-NBI) with endoscopic ultrasonography (EUS) for predicting the depth of tumor invasion in patients with SESCC. METHODS: This study enrolled 51 patients with SESCC (52 SESCC lesions) who underwent both ME-NBI and EUS at Pusan National University Hospital during 2010-2013. We reviewed the patients' medical records and compared ME-NBI and EUS findings with histopathological results according to clinicopathological factors. RESULTS: A total of 46 lesions in 45 patients were included in the final analysis. ME-NBI and EUS had overall accuracies of 76.1% and 84.8%, respectively, in distinguishing mucosal from non-mucosal cancers. There were no differences between ME-NBI and EUS in terms of sensitivities and specificities in distinguishing mucosal from non-mucosal cancers (p = 0.500 and p = 0.688, respectively). When both ME-NBI and EUS suggested a mucosal depth of lesion invasion, the frequency of mucosal cancer in the final histopathology was 94%. However, if either ME-NBI or EUS suggested a non-mucosal depth of invasion, the frequency of mucosal cancer was only 21%. CONCLUSION: ME-NBI and EUS are accurate predictors of SESCC invasion depth. If both methods suggest a mucosal depth of lesion invasion, the accuracy of the prediction is increased. Therefore, when possible, it would be better to evaluate the invasion depth of SESCC using both ME-NBI and EUS before deciding to perform endoscopic resection. PMID- 24957952 TI - Cyclic olefin copolymer plasma millireactors. AB - The novelty of this paper lies in the development of a multistep process for the manufacturing of plasma millireactors operating at atmospheric pressure. The fabrication process relies on the integration of metallic electrodes over a cyclic olefin copolymer chip by a combination of photopatterning and sputtering. The developed plasma millireactors were successfully tested by creating air discharges in the gas volume of the millichannel. A sputtered silica layer was deposited on the channel walls to provide a barrier between the plasma and the polymer in order to prevent the alteration of polymer surfaces during the plasma treatment. Interest in this process of employing plasma millireactor as a high reactive environment is demonstrated here by the degradation of a volatile organic compound (acetaldehyde) in ambient air. In this miniaturized device, we obtained a high acetaldehyde conversion (98%) for a specific input energy lower than 200 J L(-1). PMID- 24957953 TI - Risk factors of acute pancreatitis in the elderly Chinese population: a population-based cross-sectional study. AB - OBJECTIVE: Lifestyle changes have led to an increasing incidence of acute pancreatitis (AP) in China. The aims of this study were to evaluate the association between lifestyle as well as medical history and AP in the elderly population and to provide evidence towards the prevention against AP. METHODS: A population-based cross-sectional study was conducted in Daqing, Heilongjiang Province, China. A total of 23 294 residents aged >=55 years were enrolled in the study. A questionnaire survey was conducted to collect data on participants' characteristics, lifestyle and medical history via a face-to-face interview, and compared these data with the medical chart. RESULTS: In total, 45 participants had been diagnosed with AP, that is, a prevalence of 0.19%. No significant differences were observed with respect to their age, gender, marital status or body mass index (BMI) in participants with and without AP. However, those were better educated were more likely to develop AP (P = 0.005). The univariate analysis showed that a high meat intake, smoking, alcohol consumption and a medical history of gallstones were associated with a significant increase in the risk of developing AP (P < 0.05). Furthermore, smoking or alcohol consumption was dose-dependently associated with the risk of AP, particularly in those who smoked at least 15 pack-years or consumed >=56.2 drinks per year. Multivariable logistics analysis suggested that the level of education, smoking and medical history of gallstone are independent risk factors for AP. CONCLUSIONS: Our study indicated that a higher education level, smoking, alcohol consumption and history of gallstones may be potential risk factors for AP in the elderly in northeast China. PMID- 24957954 TI - Neurocysticercosis: the effectiveness of the cysticidal treatment could be influenced by the host immunity. AB - Neurocysticercosis, a clinically and radiologically pleomorphic parasitic disease, is still endemic to most non-developed countries of Latin America, Africa, and Asia. Anti-helminthic drugs (AHD) are generally effective and rapidly destroy parenchymal cysticerci. In contrast, several cycles of AHD are frequently necessary to damage extraparenchymally located parasites. The present study was designed to evaluate whether differences in the immunological profile of the patients is involved in the diversity of the response to AHD. To this end, a global gene expression microarray and a cytokine analysis were made. Responder patients were those showing a radiological reduction greater than 50 % in the parasite burden following AHD treatment. Microarray pre- and post-treatment comparisons showed that a total of eighteen immune-related genes were up regulated in the five responder patients with respect the expression profile seen in the four non-responder subjects. The function of up-regulated genes exerted pro-inflammatory (RORgammaC, Sema4A, SLAMF3, SLAMF6), anti-inflammatory (TGFbeta, TNFRSF25, TNFRS18, SLAMF1, ILF2), or immunomodulatory effects (CXCL2, RUNX3, SLAMF9, TGFBR3). To further explore the causes of the heterogeneity in the response to treatment, a wide ELISA cytokine analysis was performed in serum, PBMC supernatants, and CSF samples from 39 responder and 26 non-responder patients. Responder patients showed higher CSF IL-17A levels (P = 0.04) and higher supernatant IL-6 levels (P = 0.03) 60 days after treatment. These results suggest a possible influence of pro-inflammatory cytokines on the response to AHD as observed by radiological methods, and thus the possible participation of the host immunity in the effectiveness of AHD treatment. PMID- 24957955 TI - Evolutionary mechanism unifies the hallmarks of cancer. AB - The basis for the gene mutation theory of cancer that dominates current molecular cancer research consists of: the belief that gene-level aberrations such as mutations are the main cause of cancers, the concept that stepwise gene mutation accumulation drives cancer progression, and the hallmarks of cancer. The research community swiftly embraced the hallmarks of cancer, as such synthesis has supported the notions that common cancer genes are responsible for the majority of cancers and the complexity of cancer can be dissected into simplified molecular principles. The gene/pathway classification based on individual hallmarks provides explanation for the large number of diverse gene mutations, which is in contrast to the original estimation that only a handful of gene mutations would be discovered. Further, these hallmarks have been highly influential as they also provide the rationale and research direction for continued gene-based cancer research. While the molecular knowledge of these hallmarks is drastically increasing, the clinical implication remains limited, as cancer dynamics cannot be summarized by a few isolated/fixed molecular principles. Furthermore, the highly heterogeneous genetic signature of cancers, including massive stochastic genome alterations, challenges the utility of continuously studying each individual gene mutation under the framework of these hallmarks. It is therefore necessary to re-evaluate the concept of cancer hallmarks through the lens of cancer evolution. In this analysis, the evolutionary basis for the hallmarks of cancer will be discussed and the evolutionary mechanism of cancer suggested by the genome theory will be employed to unify the diverse molecular mechanisms of cancer. PMID- 24957956 TI - Aspects of perceived stigma: the Stigma Inventory for Mental Illness, its development, latent structure and psychometric properties. AB - OBJECTIVE: The aim of this study was to develop a new brief and easy to administer self-stigma scale for mental illness as well as to assess the correlations between self-stigma and psychopathology of chronic schizophrenic patients. METHODS: The Stigma Inventory for Mental Illness (SIMI) was administered to 100 outpatients diagnosed with schizophrenia. Psychopathology and overall functioning were assessed with the Positive and Negative Symptom Scale (PANSS) and Global Assessment Scale (GAS), respectively. RESULTS: The final scale consists of 12 items. Factor analysis concluded to two dimensions: perceptions of social stigma and self-efficacy. Both factors were found to be reliable (high internal consistency and stability coefficients). Significant correlations were present with psychopathology, functioning and selected items from the Community Attitudes toward the Mentally Ill (CAMI) inventory. CONCLUSION: The SIMI scale is a reliable and valid psychometric tool that can be used to assess patient's self stigma and self-efficacy. The findings suggest also that psychopathology has an immediate effect on endorsing self-stigmatizing attitudes. PMID- 24957957 TI - The impacts of elevated autism spectrum disorder traits on clinical and psychosocial features and long-term treatment outcome in adult patients with obsessive-compulsive disorder. AB - BACKGROUND: While a close relation between obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) has been pointed out, there are few studies that have investigated whether highly elevated ASD traits may have significant impacts on clinical and psychosocial features as well as long-term treatment outcome in adult OCD patients. METHODS: We assessed ASD traits using the Autism Spectrum Quotient (AQ) in 81 Japanese patients with OCD. The relation between degree of ASD traits and clinical and psychosocial variables and the 48-week treatment outcomes was analyzed in the subjects. RESULTS: A substantial proportion of the subjects showed higher ASD traits (35%) with more severe depressive or pervasive anxiety status, and social impairments and lower QOL compared to other OCD individuals. However, elevated ASD traits may exert rather smaller impact on the OCD phenomenology along with on the long-term treatment outcome than expected. CONCLUSIONS: Elevated ASD traits may further emphasize the general psychopathological and socio-dysfunctional features rather than clinical aspects associated with OCD. Co-existing depressive or anxious symptom severity may further exacerbate the core-deficits related to ASD pathology. Thus the assessment of ASD traits should be important for understanding the clinical and psychosocial features and treatment responses in OCD patients. PMID- 24957958 TI - Distinctive correlations of sociotropy and autonomy with working models of the self and other. AB - BACKGROUND: Beck's cognitive theory of depression postulates personality vulnerability factors termed sociotropy and autonomy, which are accompanied by characteristic interpersonal styles. Meanwhile, Bartholomew contends that negative working models of the self and other built through insecure attachment relationships are externalized as distinctive interpersonal styles. The present study examined the relationships of sociotropy and autonomy with the self- and other-models, and attempted to promote understanding of the two personality traits from an attachment perspective. METHODS: The subjects were 510 healthy Japanese medical students or hospital staffs. Sociotropy and autonomy were assessed by the Sociotropy-Autonomy Scale, and working models of the self and other were evaluated by the Relationship Scales Questionnaire. RESULTS: The sociotropy score was correlated negatively with the self-model score (beta=-0.52, p<0.001) and positively with the other-model score (beta=0.11, p<0.01). The autonomy score was correlated positively with the self-model score (beta=0.10, p<0.05) and negatively with the other-model score (beta=-0.33, p<0.001). LIMITATIONS: It may be risky to generalize the present results to general populations or other ethnic groups. CONCLUSIONS: The present study suggests that both sociotropy and autonomy are associated with attachment insecurity, but the marked difference in their correlation patterns with the self- and other-models leads to the distinctive interpersonal styles of the two personality orientations. PMID- 24957959 TI - Risk of prostate cancer in patients with schizophrenia. AB - OBJECTIVES: To examine the rate of prostate cancer in a cohort of schizophrenia in-patients in the PSA-era as compared to expected rates. There is conflicting evidence on the relative risk of prostate cancer in men with schizophrenia. METHODS: the study sample was comprised of schizophrenia patients who had been admitted to a tertiary care mental health center between 1990 and 2011. The data for the sample was cross-referenced with the National Cancer Registry. Analyses of Standardized Incidence Rates (SIR) for prostate cancer and for lung cancer (representing an organ system not sensitive to sex hormones) were performed. RESULTS: Of 4,326 schizophrenia patients included in the present study, 181 (4.2%) were diagnosed with cancer at any site. Only 10 of these patients were diagnosed with prostate cancer. This reflects a reduced risk; SIR of 0.56 (95% CI 0.27-1.03). In the same cohort, 33 schizophrenia patients were diagnosed with lung cancer presenting a SIR of 1.43 (95% CI 0.98-2.01) in this sample. CONCLUSIONS: The present study suggests a reduced rate of prostate cancer in patients admitted for schizophrenia. There are several possible explanations for this finding including chronic state of hyperprolactinemia induced by antipsychotic drugs. PMID- 24957960 TI - Physical characterization of mouse deep vein thrombosis derived microparticles by differential filtration with nanopore filters. AB - With the objective of making advancements in the area of pro-thrombotic microparticle characterization in cardiovascular biology, we present a novel method to separate blood circulating microparticles using a membrane-based, nanopore filtration system. In this qualitative study, electron microscopy observations of these pro-thrombotic mouse microparticles, as well as mouse platelets and leukocytes obtained using a mouse inferior vena cava ligation model of deep-vein thrombosis are presented. In particular, we present mouse microparticle morphology and microstructure using SEM and TEM indicating that they appear to be mostly spherical with diameters in the 100 to 350 nm range. The nanopore filtration technique presented is focused on the development of novel methodologies to isolate and characterize blood circulating microparticles that can be used in conjunction with other methodologies. We believe that determination of microparticle size and structure is a critical step for the development of reliable assays with clinical or research application in thrombosis and it will contribute to the field of nanomedicine in thrombosis. PMID- 24957961 TI - Stimuli responsive ionogels for sensing applications-an overview. AB - This overview aims to summarize the existing potential of "Ionogels" as a platform to develop stimuli responsive materials. Ionogels are a class of materials that contain an Ionic Liquid (IL) confined within a polymer matrix. Recently defined as "a solid interconnected network spreading throughout a liquid phase", the ionogel therefore combines the properties of both its solid and liquid components. ILs are low melting salts that exist as liquids composed entirely of cations and anions at or around 100 degrees C. Important physical properties of these liquids such as viscosity, density, melting point and conductivity can be altered to suit a purpose by choice of the cation/anion. Here we provide an overview to highlight the literature thus far, detailing the encapsulation of IL and responsive materials within these polymeric structures. Exciting applications in the areas of optical and electrochemical sensing, solid state electrolytes and actuating materials shall be discussed. PMID- 24957962 TI - Thin hydrogel films for optical biosensor applications. AB - Hydrogel materials consisting of water-swollen polymer networks exhibit a large number of specific properties highly attractive for a variety of optical biosensor applications. This properties profile embraces the aqueous swelling medium as the basis of biocompatibility, non-fouling behavior, and being not cell toxic, while providing high optical quality and transparency. The present review focuses on some of the most interesting aspects of surface-attached hydrogel films as active binding matrices in optical biosensors based on surface plasmon resonance and optical waveguide mode spectroscopy. In particular, the chemical nature, specific properties, and applications of such hydrogel surface architectures for highly sensitive affinity biosensors based on evanescent wave optics are discussed. The specific class of responsive hydrogel systems, which can change their physical state in response to externally applied stimuli, have found large interest as sophisticated materials that provide a complex behavior to hydrogel-based sensing devices. PMID- 24957963 TI - Development of hydrogels and biomimetic regulators as tissue engineering scaffolds. AB - This paper reviews major research and development issues relating to hydrogels as scaffolds for tissue engineering, the article starts with a brief introduction of tissue engineering and hydrogels as extracellular matrix mimics, followed by a description of the various types of hydrogels and preparation methods, before a discussion of the physical and chemical properties that are important to their application. There follows a short comment on the trends of future research and development. Throughout the discussion there is an emphasis on the genetic understanding of bone tissue engineering application. PMID- 24957965 TI - Mechanisms of membrane curvature generation in membrane traffic. AB - During the vesicular trafficking process, cellular membranes undergo dynamic morphological changes, in particular at the vesicle generation and fusion steps. Changes in membrane shape are regulated by small GTPases, coat proteins and other accessory proteins, such as BAR domain-containing proteins. In addition, membrane deformation entails changes in the lipid composition as well as asymmetric distribution of lipids over the two leaflets of the membrane bilayer. Given that P4-ATPases, which catalyze unidirectional flipping of lipid molecules from the exoplasmic to the cytoplasmic leaflets of the bilayer, are crucial for the trafficking of proteins in the secretory and endocytic pathways, changes in the lipid composition are involved in the vesicular trafficking process. Membrane remodeling is under complex regulation that involves the composition and distribution of lipids as well as assembly of proteins. PMID- 24957966 TI - Light responsive polymer membranes: a review. AB - In recent years, stimuli responsive materials have gained significant attention in membrane separation processes due to their ability to change specific properties in response to small external stimuli, such as light, pH, temperature, ionic strength, pressure, magnetic field, antigen, chemical composition, and so on. In this review, we briefly report recent progresses in light-driven materials and membranes. Photo-switching mechanisms, valved-membrane fabrication and light driven properties are examined. Advances and perspectives of light responsive polymer membranes in biotechnology, chemistry and biology areas are discussed. PMID- 24957968 TI - Efficacy of 1,3-butanediol for enhancement of neonatal pig survival. AB - Pre-partum feeding of 1,3-butanediol to sows has been shown to improve the metabolic status and survival rate of neonatal pigs. To evaluate the efficacy of short-term, pre-partum feeding of 1,3-butanediol on pig and sow productivity on a large scale and low concentration was the focus of the research. The secondary objective was to determine if pre-partum feeding of 1,3-butanediol had any effect on survival rate and weight gain of lesser body weight pigs, sow body weight and subsequent sow reproductive performance. In a large commercial unit, 2537 sows were fed one of two pre-partum diets (0% or 4.55% 1,3-butanediol) on Day 108+/-3 of pregnancy. 1,3-butanediol provided 8% of the total metabolizable energy. Pigs born live in those litters were equalized by cross-fostering among sows receiving the same pre-partum diet. Pigs were weaned from the sows at 16+/-3 days post partum and return of sows to estrus and conception rates were determined. Pre partum feeding of 1,3-butanediol reduced (P=0.01) pre-weaning pig mortalities from 1.44 to 1.24 pigs per litter. The reduction in pig mortality was independent of length of 1,3-butanediol feeding (4 to 11 days). In a subset of 750 litters, four lesser birth-weight pigs from each litter were tagged and monitored to determine the effect of 1,3-butanediol on survival rates and pre-weaning weight gain of pigs with the greatest mortality risk. 1,3-butanediol reduced (P=0.01) pre-weaning mortality of these low birth weight pigs by 5.27%. Based on these data, short-term pre-partum feeding of 1,3-butanediol effectively improves pre weaning pig productivity at a lower concentration than previously reported. PMID- 24957967 TI - Novel regulators of rabbit reproductive functions. AB - This is a review of original data concerning new extra- and intracellular regulators of rabbit ovarian functions. Effects of some hormones including leptin, ghrelin, oxytocin, arginine-vasotocin, endothelin (ET-1), gonadotropin releasing hormone (GnRH), adrenocorticotropic hormone (ACTH), growth factors such as insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF), nuclear peroxisome proliferator-activated receptor gamma (PPARgamma), pharmacological regulators of some protein kinases such as protein kinase A (PKA), mitogen activated protein (MAP) kinase, cell division cycle protein 2 homolog (CDC2 kinase, CDK), tyrosine kinases), and plant molecules (resveratrol, rapamycin) on the functions of ovarian cells (proliferation, apoptosis, secretory activity, expression of some protein kinases) and reproductive end points (blood level of reproductive hormones, ovarian morphology, number of ovulations, embryo yield and quality, number and viability of offspring), and their possible interrelationships and practical application in rabbit breeding are reviewed. PMID- 24957969 TI - Plasma steroid hormone concentrations and blood flow of the ovarian structures of the female dromedary (Camelus dromedarius) during growth, dominance, spontaneous ovulation, luteinization and regression of the follicular wave. AB - The objectives of this study were to investigate the ovarian follicular waves and their corresponding hormonal changes in she-camels and to elucidate blood perfusion of the ovarian structures. Three reproductively sound, non-pregnant female camels were examined daily using B-mode and color Doppler to detect changes in their ovarian structures and blood vasculature for 22 follicular waves. Blood area (BA) and percentage (BA%) were determined for the ovarian structures. Three phases of follicular development, those of growth, maturation, and regression, were observed during each follicular wave. Deviation occurred on Day 6.1+/-1.08. Estradiol increased from basal levels of 27.4+/-0.4pg/ml to peak concentrations of 134.4+/-47.5pg/ml as the follicle reached a diameter of 13.2mm. Peripheral progesterone concentrations remained low (<0.4ng/ml) throughout the follicular waves. The blood flow to the dominant follicles increased gradually with follicular growth. The BA and BA% reached the maximum values of 18.4+/ 11.6mm(2) and 6.04+/-2.03%, respectively, when the diameter of the dominant follicle was 17.5+/-3.4mm. The blood flow to the corpus luteum rose markedly after ovulation to reach a maximum BA% and BA at Days 5 and 7, respectively, post ovulation. In conclusion, the follicular wave pattern in dromedaries consists of individually variable periods of growth, maturation and regression. Deviation occurs 6.1+/-1.08d from emergence. Transrectal color-Doppler sonography is a useful technique for noninvasive evaluation of follicular vascularity in camels during various stages of the follicular wave. It provides additional information to assess the developmental stage and activity of the ovarian structures. PMID- 24957964 TI - The BAR Domain Superfamily Proteins from Subcellular Structures to Human Diseases. AB - Eukaryotic cells have complicated membrane systems. The outermost plasma membrane contains various substructures, such as invaginations and protrusions, which are involved in endocytosis and cell migration. Moreover, the intracellular membrane compartments, such as autophagosomes and endosomes, are essential for cellular viability. The Bin-Amphiphysin-Rvs167 (BAR) domain superfamily proteins are important players in membrane remodeling through their structurally determined membrane binding surfaces. A variety of BAR domain superfamily proteins exist, and each family member appears to be involved in the formation of certain subcellular structures or intracellular membrane compartments. Most of the BAR domain superfamily proteins contain SH3 domains, which bind to the membrane scission molecule, dynamin, as well as the actin regulatory WASP/WAVE proteins and several signal transduction molecules, providing possible links between the membrane and the cytoskeleton or other machineries. In this review, we summarize the current information about each BAR superfamily protein with an SH3 domain(s). The involvement of BAR domain superfamily proteins in various diseases is also discussed. PMID- 24957970 TI - Abdominal aortic aneurysm causing lumbar vertebral erosion in Behcet's disease presenting by low back pain. AB - Behcet's disease (BD) is a chronic multi-system disorder commonly seen in Mediterranean, middle east and far eastern populations. In this report, we describe a case of a 55-year-old male with Behcet's disease who presented with a low back pain and sciatica. Imaging studies showed that he had a destruction of the third lumbar vertebra because of abdominal aortic aneurysm-related Behcet's disease. Aortic aneurysms with vertebral body erosion have been rarely reported, but this vascular complication is a life-threatening clinical picture. Therefore, among the causes of chronic lumbar pain in a BD patient, abdominal aortic aneurysm should be remembered. PMID- 24957971 TI - Convergent and correlated evolution of major life-history traits in the angiosperm genus Leucadendron (Proteaceae). AB - Natural selection is expected to cause convergence of life histories among taxa as well as correlated evolution of different life-history traits. Here, we quantify the extent of convergence of five key life-history traits (adult fire survival, seed storage, degree of sexual dimorphism, pollination mode, and seed dispersal mode) and test hypotheses about their correlated evolution in the genus Leucadendron (Proteaceae) from the fire-prone South African fynbos. We reconstructed a new molecular phylogeny of this highly diverse genus that involves more taxa and molecular markers than previously. This reconstruction identifies new clades that were not detected by previous molecular study and morphological classifications. Using this new phylogeny and robust methods that account for phylogenetic uncertainty, we show that the five life-history traits studied were labile during the evolutionary history of the genus. This diversity allowed us to tackle major questions about the correlated evolution of life history strategies. We found that species with longer seed-dispersal distances tended to evolve lower pollen-dispersal distance, that insect-pollinated species evolved decreased sexual dimorphism, and that species with a persistent soil seed bank evolved toward reduced fire-survival ability of adults. PMID- 24957972 TI - First-episode psychosis and migration in Italy (PEP-Ita migration): a study in the Italian mental health services. AB - BACKGROUND: It has been frequently reported a higher incidence of psychotic disorders in immigrants than in native populations. There is, however, a lack of knowledge about risk factors which may explain this phenomenon. A better understanding of the causes of psychosis among first-generation migrants is highly needed, particularly in Italy, a country with a recent massive migration. METHODS/DESIGN: The "Italian study on first-episode psychosis and migration (PEP Ita)" is a prospective observational study over a two-year period (1 January 2012 31 December 2013) which will be carried out in 11 Italian mental health centres. All participating centres will collect data about all new cases of migrants with first-episode psychosis. The general purpose ("core") of the PEP-Ita study is to explore the socio-demographic and clinical characteristics, and the pathways to care of a population of first-episode psychosis migrants in Italy. Secondary aims of the study will be: 1) to understand risk and protective factors for the development of psychotic disorders in migrants; 2) to evaluate the correlations between psychopathology of psychotic disorders in migrants and socio-demographic characteristics, migration history, life experiences; 3) to evaluate the clinical and social outcomes of first-episode psychoses in migrants. DISCUSSION: The results of the PEP-Ita study will allow a better understanding of risk factors for psychosis in first-generation migrants in Italy. Moreover, our results will contribute to the development of prevention programmes for psychosis and to the improvement of early intervention treatments for the migrant population in Italy. PMID- 24957973 TI - Standardized testing with chlorhexidine in perioperative allergy--a large single centre evaluation. AB - BACKGROUND: Perioperative allergic reactions to chlorhexidine are often severe and easily overlooked. Although rare, the prevalence remains unknown. Correct diagnosis is crucial, but no validated provocation model exists, and other diagnostic tests have never been evaluated. The aims were to estimate (i) the prevalence of chlorhexidine allergy in perioperative allergy and (ii) the specificity and sensitivity for diagnostic tests for chlorhexidine allergy. METHODS: We included all patients investigated for suspected perioperative allergic reactions in the Danish Anaesthesia Allergy Centre during 2004-2012. The following tests were performed: specific IgE (Immunocap(r) ; Phadia AB, Sweden), histamine release test (HR) (RefLab ApS, Denmark), skin prick test (SPT) and intradermal test (IDT). Positivity criteria were as follows: specific IgE >0.35 kUA/l; HR class 1-12; SPT mean wheal diameter >=3 mm; IDT mean wheal diameter >= twice the diameter of negative control. Chlorhexidine allergy was post hoc defined as a relevant clinical reaction to chlorhexidine combined with two or more positive tests. Based on this definition, sensitivity and specificity were estimated for each test. RESULTS: In total, 22 of 228 patients (9.6%) met the definition of allergy to chlorhexidine. Estimated sensitivity and specificity were as follows: specific IgE (sensitivity 100% and specificity 97%), HR (sensitivity 55% and specificity 99%), SPT (sensitivity 95% and specificity 97%) and IDT (sensitivity 68% and specificity 100%). CONCLUSIONS: In patients investigated for suspected perioperative allergic reactions, 9.6% were diagnosed with allergy to chlorhexidine. Using our definition of chlorhexidine allergy, the highest combined estimated sensitivity and specificity was found for specific IgE and SPT. PMID- 24957975 TI - Protein capsules with cross-linked, semipermeable, and enzyme-degradable surface barriers for controlled release. AB - This paper describes a method for fabricating protein-based capsules with semipermeable and enzyme-degradable surface barriers. It involves the use of a simple fluidic device to generate water-in-oil emulsion droplets, followed by cross-linking of proteins at the water-oil interface to generate a semipermeable surface barrier. The capsules can be readily fabricated with uniform and controllable sizes and, more importantly, show selective permeability toward molecules with different molecular weights: small molecules like fluorescein sodium salt can freely diffuse through the surface barrier while macromolecules such as proteins can not. The proteins, however, can be released by digesting the surface barrier with an enzyme such as pepsin. Taken together, the capsules hold great potential for applications in controlled release, in particular, for the delivery of protein drugs. PMID- 24957974 TI - Automatic protective ventilation using the ARDSNet protocol with the additional monitoring of electrical impedance tomography. AB - INTRODUCTION: Automatic ventilation for patients with respiratory failure aims at reducing mortality and can minimize the workload of clinical staff, offer standardized continuous care, and ultimately save the overall cost of therapy. We therefore developed a prototype for closed-loop ventilation using acute respiratory distress syndrome network (ARDSNet) protocol, called autoARDSNet. METHODS: A protocol-driven ventilation using goal-oriented structural programming was implemented and used for 4 hours in seven pigs with lavage-induced acute respiratory distress syndrome (ARDS). Oxygenation, plateau pressure and pH goals were controlled during the automatic ventilation therapy using autoARDSNet. Monitoring included standard respiratory, arterial blood gas analysis and electrical impedance tomography (EIT) images. After 2-hour automatic ventilation, a disconnection of the animal from the ventilator was carried out for 10 seconds, simulating a frequent clinical scenario for routine clinical care or intra hospital transport. RESULTS: This pilot study of seven pigs showed stable and robust response for oxygenation, plateau pressure and pH value using the automated system. A 10-second disconnection at the patient-ventilator interface caused impaired oxygenation and severe acidosis. However, the automated protocol driven ventilation was able to solve these problems. Additionally, regional ventilation was monitored by EIT for the evaluation of ventilation in real-time at bedside with one prominent case of pneumothorax. CONCLUSIONS: We implemented an automatic ventilation therapy using ARDSNet protocol with seven pigs. All positive outcomes were obtained by the closed-loop ventilation therapy, which can offer a continuous standard protocol-driven algorithm to ARDS subjects. PMID- 24957976 TI - The aetiology of convulsive status epilepticus: a study of 258 cases in Western China. AB - PURPOSE: To investigate the characteristics of the aetiologies of convulsive status epilepticus (CSE) in Western China and to identify the relationships of these aetiologies with the prognoses. METHODS: Consecutive registration and prospective observation of 258 cases of CSE in the Sichuan Epilepsy Center were performed from 1996 to 2010 to study the aetiology of CSE. The relationships of the aetiologies with the demographics, outcomes and complications of CSE were analysed using a logistic regression model. RESULTS: The mean age was 37.6 +/- 20.21 years. The majority of the CSE (62.4%) cases were acute symptomatic cases, and the primary cause was central nervous system (CNS) infection (33.7%). Histories of epilepsy were present in 51.9% of the patients. Pre-existing epilepsy occurred due to discontinuation or reduction of antiepileptic drugs (AEDs) in 31.3% of the CSE patients. Anoxia/poisoning (p<0.05, OR 8.0, 95% CI 1.34-47.77) was an independent predictor of mortality. CNS infections (p<0.001, OR 8.99, 95% CI 3.52-22.92), cerebrovascular diseases (p =0.001, OR 6.75, 95% CI 2.11-21.61) and anoxia/poisoning (p<0.01, OR 7.64, 95% CI 1.93-30.21) were the major risk factors for complications associated with CSE. CONCLUSIONS: (1) Compared to developed countries, CNS infections seemed to be more likely to be the cause of CSE in developing countries. (2) Noncompliance with AEDs among patients with epilepsy was a prominent and avoidable trigger of CSE. PMID- 24957977 TI - Somatosensory evoked potentials show plastic changes following a novel motor training task with the thumb. AB - OBJECTIVE: Accumulating evidence indicates that plastic changes can be maladaptive in nature, resulting in movement and neurological disorders. The aim of this study was to further the understanding of these neurophysiological changes in sensorimotor integration (SMI) using somatosensory evoked potentials (SEPs) and concurrent performance changes following a repetitive typing task. METHODS: SEPs were recorded following median nerve stimulation at the wrist and performed pre and post intervention. 24 participants were randomly assigned to either an intervention group which performed a 20min repetitive typing task or a control group which participated in a 20min period of mental recitation. RESULTS: The P22-N24 amplitude increased by 59.6%, compared to only 0.96% increase following the control. The P22-N30 SEP peak amplitude increased on average 13.4% following the motor training, compared to only 0.92% following the control. Significant improvement in reaction time when comparing performance of the motor task for the intervention group was observed. CONCLUSIONS: The N24 increase supports the involvement of cerebellar connections and the N30 increase provides further support for changes in SMI following motor learning. SIGNIFICANCE: Combining motor training tasks with electrophysiological techniques gives insight into the mechanisms of disordered SMI and whether the changes are adaptive or maladaptive. PMID- 24957979 TI - HIV self-testing in resource-limited settings: regulatory and policy considerations. AB - HIV self-testing (HIVST) is an emerging HIV testing strategy intended to address challenges of increasing access to preliminary knowledge of serostatus. It offers the potential for tests and testing to reach more people than previously possible, including those who do not seek testing in facilities. With approval of an HIV self-test kit in the USA, increasing evidence from public pilot programs in sub-Saharan Africa showing high acceptability and feasibility, and evidence of the informal sale of rapid HIV test kits in the private sector, options for individuals to access HIV self-testing, as well as consumer-demand, appear to be increasing. More recently WHO and UNAIDS have explored self-testing as an option to achieving greater HIV testing coverage to support global treatment targets. However, for resource-limited settings, technological development, diagnostic device regulation and quality assurance policies are lagging behind. This commentary will examine regulatory and policy issues with HIVST, given its increased prominence as a potential part of the global HIV/AIDS response. PMID- 24957978 TI - Modelling the potential population impact and cost-effectiveness of self-testing for HIV: evaluation of data requirements. AB - HIV testing uptake has increased dramatically in recent years in resource limited settings. Nevertheless, over 50% of the people living with HIV are still unaware of their status. HIV self-testing (HIVST) is a potential new approach to facilitate further uptake of testing which requires consideration, taking into account economic factors. Mathematical models and associated economic analysis can provide useful assistance in decision-making processes, offering insight, in this case, into the potential long-term impact at a population level and the price-point at which free or subsidized HIVST would be cost-effective in a given setting. However, models are based on assumptions, and if the required data are sparse or limited, this uncertainty will be reflected in the results from mathematical models. The aim of this paper is to describe the issues encountered in modeling the cost-effectiveness of introducing HIVST, to indicate the evidence needed to support various modeling assumptions, and thus which data on HIVST would be most beneficial to collect. PMID- 24957980 TI - Antithrombotic and antidiabetic flavonoid glycosides from the grains of Sorghum bicolor (L.) Moench var. hwanggeumchal. AB - A phytochemical study of the grains of S. bicolor, resulting in the isolation of twelve flavonoid glycosides 1-12. Their chemical structures were elucidated on the basis of spectroscopic (1D and 2D NMR) and MS data analyses. All compounds were tested on thrombin time (TT) assay and alpha-glucosidase assay in order to assess their inhibitory effects on blood coagulation and alpha-glucosidase enzyme. At the concentration of 500 MUg/mL, compounds 3, 4, 7 and 10 possessed the potential effects on blood coagulation with inhibitory percentage of 197, 152, 120 and 158 %, respectively, whereas aspirin, which used as a positive control, indicated 181 and 138 % inhibition at 500 and 375 MUg/mL, respectively. Furthermore, compounds 3, 4, 7, 9 and 10 also displayed strong inhibitory effects on alpha-glucosidase enzyme, with 85.2, 55.7, 43.9, 52.7 and 65.2 % inhibition at 100 MUg/mL, respectively, whereas acarbose, as a positive control, possessed only 38.7 % at the same concentration. Taken together, our data suggest that S. bicolor and its flavonoid-enrich extracts could be considered as supplemental and or functional foods having beneficial effects against blood coagulation-induced ischemia, possibly thromboembolism disease, as well as diabetes. PMID- 24957981 TI - [Superficial skin infections and bacterial dermohypodermitis]. AB - Staphylococcus aureus and Streptococcus pyogenes are the two main bacteria involved in skin infections in children. Mild infections like limited impetigo and furonculosis should preferentially be treated by topical antibiotics (mupirocine or fucidic acid). Empiric antimicrobial therapy of dermohypodermitis consists in amoxicillin-clavulanate through oral route (80 mg/kg/d) or parenteral route (150 mg/kg amoxicillin per d. in 3-4 doses) for complicated features: risk factors of extension of the infection, sepsis or fast evolution. Clindamycin (40 mg/kg/d per d. in 3 doses) should be added to the beta-lactam treatment in case of toxinic shock, surgical necrotizing soft tissues or fasciitis infections. PMID- 24957983 TI - Misdiagnosis: predictive value versus sensitivity. PMID- 24957984 TI - In vivo analysis of helper T cell responses in patients with autoimmune polyendocrinopathy - candidiasis - ectodermal dystrophy provides evidence in support of an IL-22 defect. AB - Autoimmune polyendocrinopathy - candidiasis - ectodermal dystrophy (APECED) is caused by mutations in the Autoimmune regulator (AIRE) gene and is associated with neutralizing anti-cytokine autoantibodies. We have used an in vivo challenge model to analyze antigen-specific CD4(+) T cell responses. Bacille Calmette Guerin (BCG)-vaccinated patients and controls were injected tuberculin intradermally, skin blisters were induced by suction on the indurations and on unexposed skin, and the infiltrating cells harvested. The patients had a quantitatively normal CD4(+) T cell response and no significant abnormalities in the expression of T helper type (Th) 1- or Th2-related genes. The expression of interleukin (IL)-22, in contrast, was lower in the patients. Two patients, both with a pre-existing ocular keratopathy, experienced a relapse of keratoconjunctivitis, suggesting a possible immunological basis for this APECED component. Our in vivo data are compatible with a selective IL-22 defect in the activated CD4(+) T cells of APECED patients, affecting also unexposed skin in steady-state conditions. PMID- 24957982 TI - Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus. AB - Optimum clinical protocols require systemic delivery of oncolytic viruses in the presence of an intact immune system. We show that preconditioning with immune modulators, or loading virus onto carrier cells ex vivo, enhances virus-mediated antitumor activity. Our early trials of systemic reovirus delivery showed that after infusion reovirus could be recovered from blood cells--but not from plasma- suggesting that rapid association with blood cells may protect virus from neutralizing antibody. We therefore postulated that stimulation of potential carrier cells directly in vivo before intravenous viral delivery would enhance delivery of cell-associated virus to tumor. We show that mobilization of the CD11b(+) cell compartment by granulocyte macrophage-colony stimulating factor immediately before intravenous reovirus, eliminated detectable tumor in mice with small B16 melanomas, and achieved highly significant therapy in mice bearing well established tumors. Unexpectedly, cytokine conditioning therapy was most effective in the presence of preexisting neutralizing antibody. Consistent with this, reovirus bound by neutralizing antibody effectively accessed monocytes/macrophages and was handed off to tumor cells. Thus, preconditioning with cytokine stimulated recipient cells in vivo for enhanced viral delivery to tumors. Moreover, preexisting neutralizing antibody to an oncolytic virus may, therefore, even be exploited for systemic delivery to tumors in the clinic. PMID- 24957985 TI - The complex degradation and metabolism of quercetin in rat hepatocyte incubations. AB - 1. The current study demonstrated that there is still new information to be obtained on the chemical and biological transformation of the widely studied flavonoid quercetin. 2. In rat hepatocytes, 35 metabolites of quercetin were observed by using high-resolution mass spectrometry. The metabolites included glucuronides, sulfates, mixed sulfate/glucuronide metabolites and methylated versions of these metabolites. 3. Several metabolites were formed from chemical degradation products of quercetin which were found to form in Krebs-Henseleit (KH) buffer, degradants of quercetin were also formed in the buffer under the conditions used for hepatocyte incubations. 4. The degradants and metabolites of quercetin were characterized by using high-resolution MS(2). It was observed that the glutathione (GSH) conjugates of quercetin formed in large amounts in ammonium bicarbonate solution although the pattern of conjugates formed was different from that observed in hepatocytes suggesting some degree on enzymatic control on GSH conjugate formation in the hepatocyte incubations. 5. GSH conjugates were not formed when GSH was included in incubations of quercetin in KH buffer alone and only small amounts of quercetin degradation occurred. Instead, GSH was extensively converted into GSSG, thus presumably reducing the levels of oxygen in the incubation thus preventing quercetin degradation. PMID- 24957986 TI - Macrophages and bisphosphonate-related osteonecrosis of the jaw (BRONJ): evidence of local immunosuppression of macrophages in contrast to other infectious jaw diseases. AB - OBJECTIVES: Bisphosphonates (BIP) are well established in bone diseases. A serious side effect is the bisphosphonate-related osteonecrosis of the jaw (BRONJ). Among different aetiology factors, local suppression of immune functions is gaining interest. The aim of this study was to analyze the function of macrophages in BRONJ in contrast to patients with osteoradionecrosis (ORN) and secondary chronic osteomyelitis (OM) of the jaws. Samples were also taken from patients with bisphosphonate medication (BP) without signs of infection, radiation therapy (RA), and osteoporosis (OP) as controls. MATERIAL AND METHODS: One hundred five patients with surgery to the jaw were included in this study: 33 patients with BRONJ, 17 with ORN, 11 with secondary chronic OM, 8 with RA, 25 with BP medication and 11 with OP. Samples were histologically analysed and monocytes/macrophages stained using CD14 and CD68. The number of positively marked cells was counted per view (pv), and the CD68/CD14 ratio was calculated. Statistically, the Naive-Bayes and decision-tree classifier were used. RESULTS: The number of CD14 positive cells was 10.3 cells/pv in the BRONJ-group in as compared to 5 in the ORN- and 3.8 in the OM-group respectively. The number of CD68 positive cells was 11.4/pv (BRONJ-group) as compared to 14/pv (ORN-group) and 12.7/pv (OM-group). With 0.89, the BRONJ-group showed a statistically different CD68/CD14 ratio than ORN-group with 3.39 and OM-group with 3.03. CONCLUSIONS: Our results indicate a different expression of CD14 and CD68 markers of monocytes/macrophages in BRONJ as compared to other jaw infections. This could be a sign of macrophage immunosuppression by BPs. In contrast, patients receiving BP medication without BRONJ showed no differences to other controls. CLINICAL RELEVANCE: This is the first study that clinically indicates a compromised macrophage function at BRONJ sites in contrast to ORN or secondary OM sites. The BRONJ itself could be forwarded by this effect. PMID- 24957988 TI - NMR-Based Milk Metabolomics. AB - Milk is a key component in infant nutrition worldwide and, in the Western parts of the world, also in adult nutrition. Milk of bovine origin is both consumed fresh and processed into a variety of dairy products including cheese, fermented milk products, and infant formula. The nutritional quality and processing capabilities of bovine milk is closely associated to milk composition. Metabolomics is ideal in the study of the low-molecular-weight compounds in milk, and this review focuses on the recent nuclear magnetic resonance (NMR)-based metabolomics trends in milk research, including applications linking the milk metabolite profiling with nutritional aspects, and applications which aim to link the milk metabolite profile to various technological qualities of milk. The metabolite profiling studies encompass the identification of novel metabolites, which potentially can be used as biomarkers or as bioactive compounds. Furthermore, metabolomics applications elucidating how the differential regulated genes affects milk composition are also reported. This review will highlight the recent advances in NMR-based metabolomics on milk, as well as give a brief summary of when NMR spectroscopy can be useful for gaining a better understanding of how milk composition is linked to nutritional or quality traits. PMID- 24957990 TI - Influence of Freezing and Storage Procedure on Human Urine Samples in NMR-Based Metabolomics. AB - It is consensus in the metabolomics community that standardized protocols should be followed for sample handling, storage and analysis, as it is of utmost importance to maintain constant measurement conditions to identify subtle biological differences. The aim of this work, therefore, was to systematically investigate the influence of freezing procedures and storage temperatures and their effect on NMR spectra as a potentially disturbing aspect for NMR-based metabolomics studies. Urine samples were collected from two healthy volunteers, centrifuged and divided into aliquots. Urine aliquots were frozen either at -20 degrees C, on dry ice, at -80 degrees C or in liquid nitrogen and then stored at -20 degrees C, -80 degrees C or in liquid nitrogen vapor phase for 1-5 weeks before NMR analysis. Results show spectral changes depending on the freezing procedure, with samples frozen on dry ice showing the largest deviations. The effect was found to be based on pH differences, which were caused by variations in CO2 concentrations introduced by the freezing procedure. Thus, we recommend that urine samples should be frozen at -20 degrees C and transferred to lower storage temperatures within one week and that freezing procedures should be part of the publication protocol. PMID- 24957989 TI - Development of a Direct Headspace Collection Method from Arabidopsis Seedlings Using HS-SPME-GC-TOF-MS Analysis. AB - Plants produce various volatile organic compounds (VOCs), which are thought to be a crucial factor in their interactions with harmful insects, plants and animals. Composition of VOCs may differ when plants are grown under different nutrient conditions, i.e., macronutrient-deficient conditions. However, in plants, relationships between macronutrient assimilation and VOC composition remain unclear. In order to identify the kinds of VOCs that can be emitted when plants are grown under various environmental conditions, we established a conventional method for VOC profiling in Arabidopsis thaliana (Arabidopsis) involving headspace-solid-phase microextraction-gas chromatography-time-of-flight-mass spectrometry (HS-SPME-GC-TOF-MS). We grew Arabidopsis seedlings in an HS vial to directly perform HS analysis. To maximize the analytical performance of VOCs, we optimized the extraction method and the analytical conditions of HP-SPME-GC-TOF MS. Using the optimized method, we conducted VOC profiling of Arabidopsis seedlings, which were grown under two different nutrition conditions, nutrition rich and nutrition-deficient conditions. The VOC profiles clearly showed a distinct pattern with respect to each condition. This study suggests that HS-SPME GC-TOF-MS analysis has immense potential to detect changes in the levels of VOCs in not only Arabidopsis, but other plants grown under various environmental conditions. PMID- 24957992 TI - Peak detection method evaluation for ion mobility spectrometry by using machine learning approaches. AB - Ion mobility spectrometry with pre-separation by multi-capillary columns (MCC/IMS) has become an established inexpensive, non-invasive bioanalytics technology for detecting volatile organic compounds (VOCs) with various metabolomics applications in medical research. To pave the way for this technology towards daily usage in medical practice, different steps still have to be taken. With respect to modern biomarker research, one of the most important tasks is the automatic classification of patient-specific data sets into different groups, healthy or not, for instance. Although sophisticated machine learning methods exist, an inevitable preprocessing step is reliable and robust peak detection without manual intervention. In this work we evaluate four state of-the-art approaches for automated IMS-based peak detection: local maxima search, watershed transformation with IPHEx, region-merging with VisualNow, and peak model estimation (PME).We manually generated Metabolites 2013, 3 278 a gold standard with the aid of a domain expert (manual) and compare the performance of the four peak calling methods with respect to two distinct criteria. We first utilize established machine learning methods and systematically study their classification performance based on the four peak detectors' results. Second, we investigate the classification variance and robustness regarding perturbation and overfitting. Our main finding is that the power of the classification accuracy is almost equally good for all methods, the manually created gold standard as well as the four automatic peak finding methods. In addition, we note that all tools, manual and automatic, are similarly robust against perturbations. However, the classification performance is more robust against overfitting when using the PME as peak calling preprocessor. In summary, we conclude that all methods, though small differences exist, are largely reliable and enable a wide spectrum of real world biomedical applications. PMID- 24957987 TI - Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia. AB - BACKGROUND: Tissue acidosis is effective in causing chronic muscle pain. However, how muscle nociceptors contribute to the transition from acute to chronic pain is largely unknown. RESULTS: Here we showed that a single intramuscular acid injection induced a priming effect on muscle nociceptors of mice. The primed muscle nociceptors were plastic and permitted the development of long-lasting chronic hyperalgesia induced by a second acid insult. The plastic changes of muscle nociceptors were modality-specific and required the activation of acid sensing ion channel 3 (ASIC3) or transient receptor potential cation channel V1 (TRPV1). Activation of ASIC3 was associated with increased activity of tetrodotoxin (TTX)-sensitive voltage-gated sodium channels but not protein kinase Cepsilon (PKCepsilon) in isolectin B4 (IB4)-negative muscle nociceptors. In contrast, increased activity of TTX-resistant voltage-gated sodium channels with ASIC3 or TRPV1 activation in NaV1.8-positive muscle nociceptors was required for the development of chronic hyperalgesia. Accordingly, compared to wild type mice, NaV1.8-null mice showed briefer acid-induced hyperalgesia (5 days vs. >27 days). CONCLUSION: ASIC3 activation may manifest a new type of nociceptor priming in IB4 negative muscle nociceptors. The activation of ASIC3 and TRPV1 as well as enhanced NaV1.8 activity are essential for the development of long-lasting hyperalgesia in acid-induced, chronic, widespread muscle pain. PMID- 24957991 TI - Getting your peaks in line: a review of alignment methods for NMR spectral data. AB - One of the most significant challenges in the comparative analysis of Nuclear Magnetic Resonance (NMR) metabolome profiles is the occurrence of shifts between peaks across different spectra, for example caused by fluctuations in pH, temperature, instrument factors and ion content. Proper alignment of spectral peaks is therefore often a crucial preprocessing step prior to downstream quantitative analysis. Various alignment methods have been developed specifically for this purpose. Other methods were originally developed to align other data types (GC, LC, SELDI-MS, etc.), but can also be applied to NMR data. This review discusses the available methods, as well as related problems such as reference determination or the evaluation of alignment quality. We present a generic alignment framework that allows for comparison and classification of different alignment approaches according to their algorithmic principles, and we discuss their performance. PMID- 24957993 TI - Amino Acid biosynthesis pathways in diatoms. AB - Amino acids are not only building blocks for proteins but serve as precursors for the synthesis of many metabolites with multiple functions in growth and other biological processes of a living organism. The biosynthesis of amino acids is tightly connected with central carbon, nitrogen and sulfur metabolism. Recent publication of genome sequences for two diatoms Thalassiosira pseudonana and Phaeodactylum tricornutum created an opportunity for extensive studies on the structure of these metabolic pathways. Based on sequence homology found in the analyzed diatomal genes, the biosynthesis of amino acids in diatoms seems to be similar to higher plants. However, one of the most striking differences between the pathways in plants and in diatomas is that the latter possess and utilize the urea cycle. It serves as an important anaplerotic pathway for carbon fixation into amino acids and other N-containing compounds, which are essential for diatom growth and contribute to their high productivity. PMID- 24957994 TI - Applying Tandem Mass Spectral Libraries for Solving the Critical Assessment of Small Molecule Identification (CASMI) LC/MS Challenge 2012. AB - The "Critical Assessment of Small Molecule Identification" (CASMI) contest was aimed in testing strategies for small molecule identification that are currently available in the experimental and computational mass spectrometry community. We have applied tandem mass spectral library search to solve Category 2 of the CASMI Challenge 2012 (best identification for high resolution LC/MS data). More than 230,000 tandem mass spectra part of four well established libraries (MassBank, the collection of tandem mass spectra of the "NIST/NIH/EPA Mass Spectral Library 2012", METLIN, and the 'Wiley Registry of Tandem Mass Spectral Data, MSforID') were searched. The sample spectra acquired in positive ion mode were processed. Seven out of 12 challenges did not produce putative positive matches, simply because reference spectra were not available for the compounds searched. This suggests that to some extent the limited coverage of chemical space with high quality reference spectra is still a problem encountered in tandem mass spectral library search. Solutions were submitted for five challenges. Three compounds were correctly identified (kanamycin A, benzyldiphenylphosphine oxide, and 1 isopropyl-5-methyl-1H-indole-2,3-dione). In the absence of any reference spectrum, a false positive identification was obtained for 1-aminoanthraquinone by matching the corresponding sample spectrum to the structurally related compounds N-phenylphthalimide and 2-aminoanthraquinone. Another false positive result was submitted for 1H-benz[g]indole; for the 1H-benz[g]indole-specific sample spectra provided, carbazole was listed as the best matching compound. In this case, the quality of the available 1H-benz[g]indole-specific reference spectra was found to hamper unequivocal identification. PMID- 24957995 TI - The central carbon and energy metabolism of marine diatoms. AB - Diatoms are heterokont algae derived from a secondary symbiotic event in which a eukaryotic host cell acquired an eukaryotic red alga as plastid. The multiple endosymbiosis and horizontal gene transfer processes provide diatoms unusual opportunities for gene mixing to establish distinctive biosynthetic pathways and metabolic control structures. Diatoms are also known to have significant impact on global ecosystems as one of the most dominant phytoplankton species in the contemporary ocean. As such their metabolism and growth regulating factors have been of particular interest for many years. The publication of the genomic sequences of two independent species of diatoms and the advent of an enhanced experimental toolbox for molecular biological investigations have afforded far greater opportunities than were previously apparent for these species and re invigorated studies regarding the central carbon metabolism of diatoms. In this review we discuss distinctive features of the central carbon metabolism of diatoms and its response to forthcoming environmental changes and recent advances facilitating the possibility of industrial use of diatoms for oil production. Although the operation and importance of several key pathways of diatom metabolism have already been demonstrated and determined, we will also highlight other potentially important pathways wherein this has yet to be achieved. PMID- 24957996 TI - Metabolic and Transcriptional Reprogramming in Developing Soybean (Glycine max) Embryos. AB - Soybean (Glycine max) seeds are an important source of seed storage compounds, including protein, oil, and sugar used for food, feed, chemical, and biofuel production. We assessed detailed temporal transcriptional and metabolic changes in developing soybean embryos to gain a systems biology view of developmental and metabolic changes and to identify potential targets for metabolic engineering. Two major developmental and metabolic transitions were captured enabling identification of potential metabolic engineering targets specific to seed filling and to desiccation. The first transition involved a switch between different types of metabolism in dividing and elongating cells. The second transition involved the onset of maturation and desiccation tolerance during seed filling and a switch from photoheterotrophic to heterotrophic metabolism. Clustering analyses of metabolite and transcript data revealed clusters of functionally related metabolites and transcripts active in these different developmental and metabolic programs. The gene clusters provide a resource to generate predictions about the associations and interactions of unknown regulators with their targets based on "guilt-by-association" relationships. The inferred regulators also represent potential targets for future metabolic engineering of relevant pathways and steps in central carbon and nitrogen metabolism in soybean embryos and drought and desiccation tolerance in plants. PMID- 24957998 TI - CASMI-The Small Molecule Identification Process from a Birmingham Perspective. AB - The Critical Assessment of Small Molecule Identification (CASMI) contest was developed to provide a systematic comparative evaluation of strategies applied for the annotation and identification of small molecules. The authors participated in eleven challenges in both category 1 (to deduce a molecular formula) and category 2 (to deduce a molecular structure) related to high resolution LC-MS data. For category 1 challenges, the PUTMEDID_LCMS workflows provided the correct molecular formula in nine challenges; the two incorrect submissions were related to a larger mass error in experimental data than expected or the absence of the correct molecular formula in a reference file applied in the PUTMEDID_LCMS workflows. For category 2 challenges, MetFrag was applied to construct in silico fragmentation data and compare with experimentally derived MS/MS data. The submissions for three challenges were correct, and for eight challenges, the submissions were not correct; some submissions showed similarity to the correct structures, while others showed no similarity. The low number of correct submissions for category 2 was a result of applying the assumption that all chemicals were derived from biological samples and highlights the importance of knowing the origin of biological or chemical samples studied and the metabolites expected to be present to define the correct chemical space to search in annotation processes. PMID- 24957997 TI - The future of NMR metabolomics in cancer therapy: towards personalizing treatment and developing targeted drugs? AB - There has been a recent shift in how cancers are defined, where tumors are no longer simply classified by their tissue origin, but also by their molecular characteristics. Furthermore, personalized medicine has become a popular term and it could start to play an important role in future medical care. However, today, a "one size fits all" approach is still the most common form of cancer treatment. In this mini-review paper, we report on the role of nuclear magnetic resonance (NMR) metabolomics in drug development and in personalized medicine. NMR spectroscopy has successfully been used to evaluate current and potential therapies, both single-agents and combination therapies, to analyze toxicology, optimal dose, resistance, sensitivity, and biological mechanisms. It can also provide biological insight on tumor subtypes and their different responses to drugs, and indicate which patients are most likely to experience off-target effects and predict characteristics for treatment efficacy. Identifying pre treatment metabolic profiles that correlate to these events could significantly improve how we view and treat tumors. We also briefly discuss several targeted cancer drugs that have been studied by metabolomics. We conclude that NMR technology provides a key platform in metabolomics that is well-positioned to play a crucial role in realizing the ultimate goal of better tailored cancer medicine. PMID- 24957999 TI - CASMI: And the Winner is . . . AB - The Critical Assessment of Small Molecule Identification (CASMI) Contest was founded in 2012 to provide scientists with a common open dataset to evaluate their identification methods. In this review, we summarize the submissions, evaluate procedures and discuss the results. We received five submissions (three external, two internal) for LC-MS Category 1 (best molecular formula) and six submissions (three external, three internal) for LC-MS Category 2 (best molecular structure). No external submissions were received for the GC-MS Categories 3 and 4. The team of Dunn et al. from Birmingham had the most answers in the 1st place for Category 1, while Category 2 was won by H. Oberacher. Despite the low number of participants, the external and internal submissions cover a broad range of identification strategies, including expert knowledge, database searching, automated methods and structure generation. The results of Category 1 show that complementing automated strategies with (manual) expert knowledge was the most successful approach, while no automated method could compete with the power of spectral searching for Category 2-if the challenge was present in a spectral library. Every participant topped at least one challenge, showing that different approaches are still necessary for interpretation diversity. PMID- 24958000 TI - Small Molecule Identification with MOLGEN and Mass Spectrometry. AB - This paper details the MOLGEN entries for the 2012 CASMI contest for small molecule identification to demonstrate structure elucidation using structure generation approaches. Different MOLGEN programs were used for different categories, including MOLGEN-MS/MS for Category 1, MOLGEN 3.5 and 5.0 for Category 2 and MOLGEN-MS for Categories 3 and 4. A greater focus is given to Categories 1 and 2, as most CASMI participants entered these categories. The settings used and the reasons behind them are described in detail, while various evaluations are used to put these results into perspective. As one author was also an organiser of CASMI, these submissions were not part of the official CASMI competition, but this paper provides an insight into how unknown identification could be performed using structure generation approaches. The approaches are semi automated (category dependent) and benefit greatly from user experience. Thus, the results presented and discussed here may be better than those an inexperienced user could obtain with MOLGEN programs. PMID- 24958002 TI - Metabolite Identification through Machine Learning- Tackling CASMI Challenge Using FingerID. AB - Metabolite identification is a major bottleneck in metabolomics due to the number and diversity of the molecules. To alleviate this bottleneck, computational methods and tools that reliably filter the set of candidates are needed for further analysis by human experts. Recent efforts in assembling large public mass spectral databases such as MassBank have opened the door for developing a new genre of metabolite identification methods that rely on machine learning as the primary vehicle for identification. In this paper we describe the machine learning approach used in FingerID, its application to the CASMI challenges and some results that were not part of our challenge submission. In short, FingerID learns to predict molecular fingerprints from a large collection of MS/MS spectra, and uses the predicted fingerprints to retrieve and rank candidate molecules from a given large molecular database. Furthermore, we introduce a web server for FingerID, which was applied for the first time to the CASMI challenges. The challenge results show that the new machine learning framework produces competitive results on those challenge molecules that were found within the relatively restricted KEGG compound database. Additional experiments on the PubChem database confirm the feasibility of the approach even on a much larger database, although room for improvement still remains. PMID- 24958001 TI - Multiple roles of photosynthetic and sunscreen pigments in cyanobacteria focusing on the oxidative stress. AB - Cyanobacteria have two types of sunscreen pigments, scytonemin and mycosporine like amino acids (MAAs). These secondary metabolites are thought to play multiple roles against several environmental stresses such as UV radiation and desiccation. Not only the large molar absorption coefficients of these sunscreen pigments, but also their antioxidative properties may be necessary for the protection of biological molecules against the oxidative damages induced by UV radiation. The antioxidant activity and vitrification property of these pigments are thought to be requisite for the desiccation and rehydration processes in anhydrobiotes. In this review, the multiple roles of photosynthetic pigments and sunscreen pigments on stress resistance, especially from the viewpoint of their structures, biosynthetic pathway, and in vitro studies of their antioxidant activity, will be discussed. PMID- 24958003 TI - Molecular Formula Identification with SIRIUS. AB - We present results of the SIRIUS2 submission to the 2012 CASMI contest. Only results for Category 1 (molecular formula identification) were submitted. The SIRIUS method and the parameters used are briefly described, followed by detailed analysis of the results and a discussion of cases where SIRIUS2 was unable to come up with the correct molecular formula. SIRIUS2 returns consistently high quality results, with the exception of fragmentation pattern analysis of time-of flight data. We then discuss possibilities for further improving SIRIUS2 in the future. PMID- 24958004 TI - Long-term functional outcomes after artificial urinary sphincter implantation in men with stress urinary incontinence. AB - OBJECTIVE: To evaluate long-term functional outcomes of artificial urinary sphincters (AUSs) and to determine how many men required explantation because of stress urinary incontinence (SUI) caused by sphincter deficiency after prostate surgery. PATIENTS AND METHODS: Men who had undergone placement of an AUS (American Medical Systems AMS 800(r)) between 1984 and 1992 to relieve SUI caused by sphincter deficiency after prostate surgery were included. Continence, defined as no need for pads, was assessed at the end of the follow-up. Kaplan-Meier survival curves estimated the survival rate of the device without needing explantation or revision. RESULTS: In all, 57 consecutive patients were included with a median (interquartile range, IQR) age of 69 (64-72) years. The median (IQR) duration of follow-up was 15 (8.25-19.75) years. At the end of follow-up, 25 patients (43.8%) still had their primary AUS. The AUS was explanted in nine men because of erosion (seven) and infection (two). Survival rates, without AUS explantation, were 87%, 87%, 80%, and 80% at 5, 10, 15, and 20 years, respectively. Survival rates, without AUS revision, were 59%, 28%, 15%, and 5% at 5, 10, 15, and 20 years, respectively. At the end of the follow-up, in intention to-treat analysis, 77.2% of patients were continent. CONCLUSION: In the long term (>10 years) the AMS 800 can offer a high rate of continence to men with SUI caused by sphincter deficiency, with a tolerable rate of explantation and revision. PMID- 24958005 TI - Evidence-based diagnosis, health care, and rehabilitation for children with cerebral palsy. AB - Safer and more effective interventions have been invented for children with cerebral palsy, but the rapid expansion of the evidence base has made keeping up to-date difficult. Unfortunately, outdated care is being provided. The aims were to survey the questions parents asked neurologists and provide evidence-based answers, using knowledge translation techniques. Parents asked the following questions: (1) what's wrong with my baby? An algorithm for early diagnosis was proposed. (2) What is cerebral palsy and what online resources are current? Reputable information websites were sourced and hyperlinks provided. (3) The prognosis? Prognostic data from meta-analyses were summarized in an infographic. (4) What interventions offer the most evidence-supported results? Systematic review data about the most effective interventions was mapped into a bubble chart infographic. Finally, (5) What can we expect? Predictors and facilitators of good outcomes were summarized. This article provides an overview of the most up-to date diagnostic practices and evidence-based intervention options. PMID- 24958006 TI - Evaluation of clinical course and neurocognition in children with self-limited infantile epilepsy in a Turkish cohort study. AB - The outcome of children with self-limited infantile epilepsy was reported to be normal psychosocial and cognitive development as a characteristic criterion. We aimed to investigate the clinical course and neurocognitive outcome in children with self-limited infantile epilepsy in a Turkish cohort. The clinical course, electroencephalographic (EEG) characteristics, neuroimaging, treatment, and outcome of children with self-limited infantile epilepsy were retrospectively analyzed. All infants were reevaluated with the Denver Developmental Screening Test in addition to neurologic examination. Of 44 patients, self-limited familial infantile epilepsy was diagnosed in 8 infants (18.2%) and self-limited nonfamilial infantile epilepsy in 28 (63.6%). Interictal EEGs and neurologic examinations were normal in all cases. Fine motor and gross motor skills, language, adaptive personal/social skills were near-normal in all patients with self-limited familial infantile epilepsy. Delay in language parameters was observed in 2 infants with self-limited nonfamilial infantile epilepsy. Language skills should be thoroughly evaluated with detailed neurocognitive screening tests in patients with self-limited infantile epilepsy. PMID- 24958009 TI - e!DAL--a framework to store, share and publish research data. AB - BACKGROUND: The life-science community faces a major challenge in handling "big data", highlighting the need for high quality infrastructures capable of sharing and publishing research data. Data preservation, analysis, and publication are the three pillars in the "big data life cycle". The infrastructures currently available for managing and publishing data are often designed to meet domain specific or project-specific requirements, resulting in the repeated development of proprietary solutions and lower quality data publication and preservation overall. RESULTS: e!DAL is a lightweight software framework for publishing and sharing research data. Its main features are version tracking, metadata management, information retrieval, registration of persistent identifiers (DOI), an embedded HTTP(S) server for public data access, access as a network file system, and a scalable storage backend. e!DAL is available as an API for local non-shared storage and as a remote API featuring distributed applications. It can be deployed "out-of-the-box" as an on-site repository. CONCLUSIONS: e!DAL was developed based on experiences coming from decades of research data management at the Leibniz Institute of Plant Genetics and Crop Plant Research (IPK). Initially developed as a data publication and documentation infrastructure for the IPK's role as a data center in the DataCite consortium, e!DAL has grown towards being a general data archiving and publication infrastructure. The e!DAL software has been deployed into the Maven Central Repository. Documentation and Software are also available at: http://edal.ipk-gatersleben.de. PMID- 24958008 TI - Does nephrotoxicity exist in pediatric epileptic patients on valproate or carbamazepine therapy? AB - The aim of this study was to investigate the effects of valproate and carbamazepine, on renal glomerular and tubular functions. The patient group comprised 54 children with new-onset epilepsy treated with valproate (n = 30) and carbamazepine (n = 24). Twenty-six healthy children were in the control group. The serum creatinine and cystatin C levels and urinary excretion of N-acetyl-beta d-glucosaminidase (NAG) levels were measured and the glomerular filtration rate (GFR) was estimated. Serum creatinine and cystatin C concentrations were not different between patients and controls. The glomerular filtration rate of the patient groups were higher than those of the control group. Thus, both drugs probably lead to glomerular hyperfiltration and toxicity for glomerular functions. However, urinary N-acetyl-beta-d-glucosaminidase/creatinine levels were significantly higher in patients receiving only valproate (6.1 +/- 5). The difference between carbamazepine and control groups was not significant for urinary N-acetyl-beta-d-glucosaminidase/creatinine levels. Our data suggest that valproate has adverse effects on renal tubular functions. PMID- 24958010 TI - Modeling the effect of soil structure on water flow and isoproturon dynamics in an agricultural field receiving repeated urban waste compost application. AB - Transport processes in soils are strongly affected by heterogeneity of soil hydraulic properties. Tillage practices and compost amendments can modify soil structure and create heterogeneity at the local scale within agricultural fields. The long-term field experiment QualiAgro (INRA-Veolia partnership 1998-2013) explores the impact of heterogeneity in soil structure created by tillage practices and compost application on transport processes. A modeling study was performed to evaluate how the presence of heterogeneity due to soil tillage and compost application affects water flow and pesticide dynamics in soil during a long-term period. The study was done on a plot receiving a co-compost of green wastes and sewage sludge (SGW) applied once every 2 years since 1998. The plot was cultivated with a biannual rotation of winter wheat-maize (except 1 year of barley) and a four-furrow moldboard plow was used for tillage. In each plot, wick lysimeter outflow and TDR probe data were collected at different depths from 2004, while tensiometer measurements were also conducted during 2007/2008. Isoproturon concentration was measured in lysimeter outflow since 2004. Detailed profile description was used to locate different soil structures in the profile, which was then implemented in the HYDRUS-2D model. Four zones were identified in the plowed layer: compacted clods with no visible macropores (Delta), non compacted soil with visible macroporosity (Gamma), interfurrows created by moldboard plowing containing crop residues and applied compost (IF), and the plow pan (PP) created by plowing repeatedly to the same depth. Isoproturon retention and degradation parameters were estimated from laboratory batch sorption and incubation experiments, respectively, for each structure independently. Water retention parameters were estimated from pressure plate laboratory measurements and hydraulic conductivity parameters were obtained from field tension infiltrometer experiments. Soil hydraulic properties were optimized on one calibration year (2007/08) using pressure head, water content and lysimeter outflow data, and then tested on the whole 2004/2010 period. Lysimeter outflow and water content dynamics in the soil profile were correctly described for the whole period (model efficiency coefficient: 0.99) after some correction of LAI estimates for wheat (2005/06) and barley (2006/07). Using laboratory-measured degradation rates and assuming degradation only in the liquid phase caused large overestimation of simulated isoproturon losses in lysimeter outflow. A proper order of magnitude of isoproturon losses was obtained after considering that degradation occurred in solid (sorbed) phase at a rate 75% of that in liquid phase. Isoproturon concentrations were found to be highly sensitive to degradation rates. Neither the laboratory-measured isoproturon fate parameters nor the independently-derived soil hydraulic parameters could describe the actual multiannual field dynamics of water and isoproturon without calibration. However, once calibrated on a limited period of time (9 months), HYDRUS-2D was able to simulate the whole 6-year time series with good accuracy. PMID- 24958011 TI - Assessment of neurotoxic effects of mercury in beluga whales (Delphinapterus leucas), ringed seals (Pusa hispida), and polar bears (Ursus maritimus) from the Canadian Arctic. AB - Marine mammals are indicator species of the Arctic ecosystem and an integral component of the traditional Inuit diet. The potential neurotoxic effects of increased mercury (Hg) in beluga whales (Delphinapterus leucas), ringed seals (Pusa hispida), and polar bears (Ursus maritimus) are not clear. We assessed the risk of Hg-associated neurotoxicity to these species by comparing their brain Hg concentrations with threshold concentrations for toxic endpoints detected in laboratory animals and field observations: clinical symptoms (>6.75 mg/kg wet weight (ww)), neuropathological signs (>4 mg/kg ww), neurochemical changes (>0.4 mg/kg ww), and neurobehavioral changes (>0.1mg/kg ww). The total Hg (THg) concentrations in the cerebellum and frontal lobe of ringed seals and polar bears were <0.5mg/kg ww, whereas the average concentration in beluga whale brain was >3mg/kg ww. Our results suggest that brain THg levels in polar bears are below levels that induce neurobehavioral effects as reported in the literature, while THg concentrations in ringed seals are within the range that elicit neurobehavioral effects and individual ringed seals exceed the threshold for neurochemical changes. The relatively high THg concentration in beluga whales exceeds all of the neurotoxicity thresholds assessed. High brain selenium (Se):Hg molar ratios were observed in all three species, suggesting that Se could protect the animals from Hg-associated neurotoxicity. This assessment was limited by several factors that influence neurotoxic effects in animals, including: animal species; form of Hg in the brain; and interactions with modifiers of Hg associated toxicity, such as Se. Comparing brain Hg concentrations in wildlife with concentrations of appropriate laboratory studies can be used as a tool for risk characterization of the neurotoxic effects of Hg in Arctic marine mammals. PMID- 24958007 TI - Application of advanced neuroimaging modalities in pediatric traumatic brain injury. AB - Neuroimaging is commonly used for the assessment of children with traumatic brain injury and has greatly advanced how children are acutely evaluated. More recently, emphasis has focused on how advanced magnetic resonance imaging methods can detect subtler injuries that could relate to the structural underpinnings of the neuropsychological and behavioral alterations that frequently occur. We examine several methods used for the assessment of pediatric brain injury. Susceptibility-weighted imaging is a sensitive 3-dimensional high-resolution technique in detecting hemorrhagic lesions associated with diffuse axonal injury. Magnetic resonance spectroscopy acquires metabolite information, which serves as a proxy for neuronal (and glial, lipid, etc) structural integrity and provides sensitive assessment of neurochemical alterations. Diffusion-weighted imaging is useful for the early detection of ischemic and shearing injury. Diffusion tensor imaging allows better structural evaluation of white matter tracts. These methods are more sensitive than conventional imaging in demonstrating subtle injury that underlies a child's clinical symptoms. There also is an increasing desire to develop computational methods to fuse imaging data to provide a more integrated analysis of the extent to which components of the neurovascular unit are affected. The future of traumatic brain injury neuroimaging research is promising and will lead to novel approaches to predict and improve outcomes. PMID- 24958012 TI - Inhibition of macrophage migration inhibitory factor reduces diabetic nephropathy in type II diabetes mice. AB - Macrophage migration inhibitory factor (MIF) plays a critical role in inflammation and is elevated in diabetic kidney. However, whether MIF plays a causative role in diabetic nephropathy (DN) remains unclear. In the present study, we have demonstrated that after treatment of 8-week-old diabetic db/db and nondiabetic db/m mice with the MIF inhibitor ISO-1 (20 mg/kg) for 8 weeks, there was a significant decrease in blood glucose, albuminuria, extracellular matrix accumulation, epithelial-mesenchymal transition (EMT), and macrophage activation in the kidney of db/db mice. Incubation of macrophages with MIF induced the production of proinflammatory cytokines, including interleukin (IL) 6, IL-1beta, tumor necrosis factor alpha (TNF-alpha). The conditioned media (CM) of MIF activated macrophages and TNF-alpha induced by MIF caused podocyte damage. Moreover, CM from MIF-activated macrophages induced EMT of renal tubular cells, and this effect was blocked by ISO-1. Thus, MIF inhibition may be a potential therapeutic strategy for DN. This effect may be attributable to its inhibitory effect on macrophage activation in the diabetic kidney. PMID- 24958013 TI - Anti-inflammatory effects of apigenin in lipopolysaccharide-induced inflammatory in acute lung injury by suppressing COX-2 and NF-kB pathway. AB - This study aims to evaluate the possible mechanisms responsible for the anti inflammatory effects of apigenin lipopolysaccharide (LPS)-induced inflammatory in acute lung injury. In this study, the anti-inflammatory effects of apigenin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible mechanisms involved in this protection were investigated. Pretreatment with apigenin prior to the administration of intratracheal LPS significantly induced a decrease in lung wet weight/dry weight ratio in total leukocyte number and neutrophil percent in the bronchoalveolar lavage fluid (BALF) and in IL-6 and IL 1beta, the tumor neurosis factor-alpha (TNF-alpha) in the BALF. These results showed that anti-inflammatory effects of apigenin against the LPS-induced ALI may be due to its ability of primary inhibition of cyclooxygenase-2 (COX-2) gene expression and nuclear factor kB (NF-kB) gene expression of lung. The results presented here suggest that the protective mechanism of apigenin may be attributed partly to decreased production of proinflammatory cytokines through the inhibition of COX-2 and NF-kB activation. The results support that use of apigenin is beneficial in the treatment of ALI. PMID- 24958014 TI - Mesenchymal stem cells alleviate experimental asthma by inducing polarization of alveolar macrophages. AB - The reparative and immunoregulatory properties of mesenchymal stromal cells (MSCs) have made them attractive candidates for cellular therapy. However, the underlying mechanism of the effects of transplanted MSCs on allergic asthma remains elusive. Here, we show that administration of MSCs isolated from human bone marrow provoked a pronounced polarization in alveolar macrophages to M2 subtypes, rather than induced an increase in the total macrophage number, and efficiently inhibited hallmark features of asthma, including airway hyperresponsiveness and eosinophilic accumulation. Moreover, transforming growth factor beta (TGF-beta) signaling pathway appeared to mediate the effects of MSCs on macrophage polarization and subsequently the inhibition of hallmark features of asthma. Inhibition of TGF-beta signaling was sufficient to inhibit the macrophage polarization in response to MSCs and consequently reserved the inhibitory effects of macrophage polarization on hallmark features of asthma. Collectively, our data demonstrate that human MSCs have immunosuppressive activity on asthma, which is mediated by TGF-beta-signaling-dependent alveolar macrophage polarization. PMID- 24958016 TI - An easy route to red emitting homoleptic IrIII complex for highly efficient solution-processed phosphorescent organic light-emitting diodes. AB - A thiophene-phenylquinoline-based homoleptic Ir(III) complex, [Ir(Th-PQ)(3)], has been synthesised by a simple route and utilised as a dopant in solution-processed phosphorescent organic light-emitting diodes (PhOLEDs). It shows the current efficiency of approximately 26 cd A(-1) and the external quantum efficiency of about 21 %, which are the highest values reported to date for PhOLEDs prepared by solution-process. PMID- 24958017 TI - Profiling of mitochondrial proteome in wheat roots. AB - Mitochondria are important organelles for cellular respiration within the eukaryotic cell and have many important functions including vitamin synthesis, amino acid metabolism and photorespiration. To investigate the mitochondrial proteome of the roots of wheat seedlings, a systematic and targeted analysis were carried out on the mitochondrial proteome from 15 day-old wheat seedling root material. Mitochondria were isolated by Percoll gradient centrifugation; and extracted proteins were disassociated and analyzed by Tricine SDS-PAGE couple to LTQ-FTICR mass spectrometry. From the isolated the sample, 184 proteins were identified which is composed of 140 proteins as mitochondria and 44 proteins as other subcellular proteins that are predicted by the freeware sub-cellular predictor. The identified proteins in mitochondria were functionally classified into 12 classes using the ProtFun 2.2 servers based on biological processes. Proteins were shown to be involved in amino acid biosynthesis (17.1%), biosynthesis of cofactors (6.4%), cell envelope (11.4%), central intermediary metabolism (10%), energy metabolism (20%), fatty acid metabolism (0.7%), purines and pyrimidines (5.7%), regulatory functions (0.7%), replication and transcription (1.4%), translation (22.1%), transport and binding (1.4%), and unknown (2.8%). These results indicate that many of the protein components present and functions of identifying proteins are common to other profiles of mitochondrial proteins performed to date. These results are provided the extensive and noble clues, to our knowledge, of mitochondrial proteins from wheat roots. PMID- 24958015 TI - Vitamin D improves cognitive function and modulates Th17/T reg cell balance after hepatectomy in mice. AB - It is known that surgery-induced tissue damage activates the peripheral immune system resulting in the release of inflammatory mediators and cognitive impairment in aged mice. Vitamin D has been shown to have immunomodulatory function, but the molecular basis for it has not been well understood. In this study, we mainly investigated the efficacy and mechanism of vitamin D against postoperative cognitive dysfunction (POCD). The treatment of C57BL mice with vitamin D significantly preserves postoperative cognitive function, markedly inhibits surgery-induced interleukin (IL)-17, IL-6, transforming growth factor beta (TGF-beta), and retinoic acid-related orphan receptor (RORgammat) production, and obviously induces IL-10 and forkhead box p3 (Foxp3) expression. These findings indicate that vitamin D amelioration of POCD is, to a large extent, due to inhibit inflammatory CD4_T cell lineage, T helper 17 (Th17) cells, accompanied with expansion in regulatory T cells (Treg cells), a subset of CD4_T cells that are important in inhibiting inflammation. Our results suggest that Th17 and Treg cell imbalance may play a role in the development of POCD. Vitamin D is useful in the control of inflammatory diseases. PMID- 24958019 TI - Assessment of microwave cooking on the bioaccessibility of cadmium from various food matrices using an in vitro digestion model. AB - Bioaccessibility represents the maximum amount of pollutant ingested with food that is available for intestinal absorption. The measurement of bioaccessibility can achieve a more accurate risk assessment. Thus, in this study, the bioaccessibility of raw/microwave-cooked store-bought food including carrot, potato, white radish, lotus root, sweet corn, long grain rice, soybean, fleshy prawn, eastern oyster, kelp, and common carp were investigated by applying an in vitro digestion method. A validated microwave digestion/ICP-MS method was applied for determining the concentration of Cd. In this study, the concentration of Cd ranged 3.7-215.8 MUg/kg fw in which carrot contained the lowest Cd while the fleshy prawn contained the highest Cd. There are no statistical differences of Cd content in microwave-cooked food and raw food except potato, lotus root, and eastern oyster. Cd in most of the cooked food materials was less bioaccessible than in raw food except sweet corn, potato, and kelp. The bioaccessibility of Cd was around 100 % in either raw or cooked potatoes. Microwave cooking caused the decreasing of bioaccessibility around 0-68 %, depending on different food matrix. Maximal decreasing of Cd bioaccessibility occurred in common carp. Thus, microwave cooking could be a feasible strategy for decreasing Cd bioaccessibility. In addition, the Cd dissolution in oral, gastric, and small intestine phase was different in different food matrix. For most of the investigated food items, Cd was largely migrated either into the oral phase (carrot, potato, white radish, lotus root, raw soybean, kelp, and common carp) or into the gastric phase (sweet corn, cooked soybean, rice, fleshy prawn, and eastern oyster). Our findings will have significant implications for food processing aiming to decrease the absorption of Cd and risk assessment analysis improvements. Further study is needed to use the animal model to validate these results. PMID- 24958018 TI - Association of serum levels of iron, copper, and zinc, and inflammatory markers with bacteriological sputum conversion during tuberculosis treatment. AB - Iron, copper, and zinc are key micronutrients that play an important role in the immune response to Mycobacterium tuberculosis. The present study aimed to evaluate the association between serum levels of those micronutrients, inflammatory markers, and the smear and culture conversion of M. tuberculosis during 60 days of tuberculosis treatment. Seventy-five male patients with pulmonary tuberculosis (mean age, 40.0 +/- 10.7 years) were evaluated at baseline and again at 30 and 60 days of tuberculosis treatment. Serum levels of iron, copper, zinc, albumin, globulin, C-reactive protein, and hemoglobin, and smear and cultures for M. tuberculosis in sputum samples were analyzed. Compared to healthy subjects, at baseline, patients with PTB had lower serum iron levels, higher copper levels and copper/zinc ratio, and similar zinc levels. During the tuberculosis treatment, no significant changes in the serum levels of iron, zinc, and copper/zinc were observed. Lower serum copper levels were associated with bacteriological conversion in tuberculosis treatment (tuberculosis-negative) at 30 days but not at 60 days (tuberculosis-positive). C-reactive protein levels and the C-reactive protein/albumin ratio were lower in tuberculosis-negative patients than in tuberculosis-positive patients at 30 and 60 days after treatment. Albumin and hemoglobin levels and the albumin/globulin ratio in patients with pulmonary tuberculosis increased during the study period, regardless of the bacteriological results. High serum globulin levels did not change among pulmonary tuberculosis patients during the study. Serum copper levels and the C-reactive protein/albumin ratio may be important parameters to evaluate the persistence of non-conversion after 60 days of tuberculosis treatment, and they may serve as predictors for relapse after successful treatment. PMID- 24958020 TI - Prediction of selenoprotein T structure and its response to selenium deficiency in chicken immune organs. AB - Selenoprotein T (SelT) is associated with the regulation of calcium homeostasis and neuroendocrine secretion. SelT can also change cell adhesion and is involved in redox regulation and cell fixation. However, the structure and function of chicken SelT and its response to selenium (Se) remains unclear. In the present study, 150 1-day-old chickens were randomly divided into a low Se group (L group, fed a Se-deficient diet containing 0.020 mg/kg Se) and a control group (C group, fed a diet containing sodium selenite at 0.2 mg/kg Se). The immune organs (spleen, thymus, and bursa of Fabricius) were collected at 15, 25, 35, 45, and 55 days of age. We performed a sequence analysis and predicted the structure and function of SelT. We also investigated the effects of Se deficiency on the expression of SelT, selenophosphate synthetase-1 (SPS1), and selenocysteine synthase (SecS) using RT-PCR and the oxidative stress in the chicken immune organs. The data showed that the coding sequence (CDS) and deduced amino acid sequence of SelT were highly similar to those of 17 other animals. Se deficiency induced lower (P < 0.05) levels of SelT, SPS1, and SecS, reduced the catalase (CAT) activity, and increased the levels of hydrogen peroxide (H2O2) and hydroxyl radical (-OH) in immune organs. In conclusion, the CDS and deduced amino acid sequence of chicken SelT are highly homologous to those of various mammals. The redox function and response to the Se deficiency of chicken SelT may be conserved. A Se-deficient diet led to a decrease in SelT, SecS, and SPS1 and induced oxidative stress in the chicken immune organs. To our knowledge, this is the first report of predictions of chicken SelT structure and function. The present study demonstrated the relationship between the selenoprotein synthases (SPS1, SecS) and SelT expression in the chicken immune organs and further confirmed oxidative stress caused by Se deficiency. Thus, the information presented in this study is helpful to understand chicken SelT structure and function. Meanwhile, the present research also confirmed the negative effects of Se deficiency on chicken immune organs. PMID- 24958021 TI - Effects of different dietary manganese levels on growth performance and N balance of growing mink (Neovision vision). AB - Two experiments were conducted to study the effects of dietary manganese levels on growth performance, nutrients digestibility, and N balance of minks during growing period. In experiment 1, 75 healthy male minks (60 days old) were selected and randomly divided into five groups with different types of diet. The diet was supplemented with 0 (control), 50, 100, 300, and 600 ppm of manganese as MnSO4 of dry matter (DM) in basic diet, respectively. From early July to middle September, the results showed that the final body weights of minks were significantly affected by diets (P < 0.05). Average daily gains (ADG) were significantly higher in the 300-ppm manganese group than those in other groups. The ratio of feed to body weight gain (F/G) was significantly affected by manganese level (P < 0.05). In experiment 2, 45 male minks (75 days old) with the same body weight were selected from each group of experiment 1 to carry out the nutrient digestion and N-balance tests which lasted for 4 days for the collection of the feces and urine, and the diets and treatment codes were same as in experiment 1. The results showed that no significant differences were found in DM, crude protein (CP), and crude carbohydrate (CC) digestibility among all groups (P > 0.05), but ether extract (EE) and gross energy (GE) digestibility were all the highest in the 300-ppm group. N intake and fecal N were similar among all groups (P > 0.05). Urinary N was lower in the 300-ppm group; in contrast, N retention was higher in this group (P < 0.05). In conclusion of experiment 1 and experiment 2, the diet supplemented with 300 ppm of manganese (as manganese sulfate) could improve the growth performance and increase the EE and GE digestibility of mink during the growing period and moreover reduce the nitrogen emissions to the environment, and the optimal total manganese level in mink's diet was 409.16 in DM during the growing period. PMID- 24958022 TI - Type III pleuropulmonary blastoma in a 7-month-old female baby with impending respiratory failure: a case report. AB - INTRODUCTION: Pleuropulmonary blastoma is a very rare, aggressive, embryonal pulmonary neoplasm which mostly affects children under the age of 5. According to the histopathological features, three subtypes of pleuropulmonary blastoma have been recognized: type I (purely cystic), type II (grossly visible cystic and solid elements) and type III (purely solid). Characteristics of type I and type II blastoma allow an earlier diagnosis compared with type III. Here we present a case report of an unusual presentation of type III pleuropulmonary blastoma. CASE PRESENTATION: We describe the case of a 7-month-old female baby of Italian mother and Kurdish father who was diagnosed with type III pleuropulmonary blastoma, which entirely occupied her right hemithorax. CONCLUSIONS: The reported case is an unusual presentation because type III pleuropulmonary blastoma typically occurs in older children. The complete re-expansion of her residual, previously totally compressed, right lung observed immediately after the resection of the lesion suggests an atypical rapid growth of this embryonal tumor in the late phase of gestation or after delivery. This case report suggests that, in addition to other childhood tumors, type III pleuropulmonary blastoma should be included in the differential diagnosis of solid nonhomogeneous thoracic large masses, compressing the mediastinal and chest wall structures in infants. This is an original case report of interest for several specialities such us pediatrics, radiology, surgery and oncology. PMID- 24958023 TI - E-cigarettes in Europe: does regulation swing from overcautious to careless? PMID- 24958027 TI - Hip fracture: a trigger for palliative care in vulnerable older adults. PMID- 24958024 TI - Chemical hazards present in liquids and vapors of electronic cigarettes. AB - Electronic (e-)cigarettes have emerged in recent years as putative alternative to conventional tobacco cigarettes. These products do not contain typical carcinogens that are present in tobacco smoke, due to the lack of combustion. However, besides nicotine, hazards can also arise from other constituents of liquids, such as solvents, flavors, additives and contaminants. In this study, we have analyzed 28 liquids of seven manufacturers purchased in Germany. We confirm the presence of a wide range of flavors to enhance palatability. Although glycerol and propylene glycol were detected in all samples, these solvents had been replaced by ethylene glycol as dominant compound in five products. Ethylene glycol is associated with markedly enhanced toxicological hazards when compared to conventionally used glycerol and propylene glycol. Additional additives, such as coumarin and acetamide, that raise concerns for human health were detected in certain samples. Ten out of 28 products had been declared "free-of-nicotine" by the manufacturer. Among these ten, seven liquids were identified containing nicotine in the range of 0.1-15 ug/ml. This suggests that "carry over" of ingredients may occur during the production of cartridges. We have further analyzed the formation of carbonylic compounds in one widely distributed nicotine free brand. Significant amounts of formaldehyde, acetaldehyde and propionaldehyde were only found at 150 degrees C by headspace GC-MS analysis. In addition, an enhanced formation of aldehydes was found in defined puff fractions, using an adopted machine smoking protocol. However, this effect was delayed and only observed during the last third of the smoking procedure. In the emissions of these fractions, which represent up to 40 % of total vapor volume, similar levels of formaldehyde were detected when compared to conventional tobacco cigarettes. By contrast, carbonylic compounds were hardly detectable in earlier collected fractions. Our data demonstrate the necessity of standardized machine smoking protocols to reliably address putative risks of e-cigarettes for consumers. PMID- 24958025 TI - A testing strategy to predict risk for drug-induced liver injury in humans using high-content screen assays and the 'rule-of-two' model. AB - Drug-induced liver injury (DILI) is a major cause of drug failures in both the preclinical and clinical phase. Consequently, improving prediction of DILI at an early stage of drug discovery will reduce the potential failures in the subsequent drug development program. In this regard, high-content screening (HCS) assays are considered as a promising strategy for the study of DILI; however, the predictive performance of HCS assays is frequently insufficient. In the present study, a new testing strategy was developed to improve DILI prediction by employing in vitro assays that was combined with the RO2 model (i.e., 'rule-of two' defined by daily dose >=100 mg/day & logP >=3). The RO2 model was derived from the observation that high daily doses and lipophilicity of an oral medication were associated with significant DILI risk in humans. In the developed testing strategy, the RO2 model was used for the rational selection of candidates for HCS assays, and only the negatives predicted by the RO2 model were further investigated by HCS. Subsequently, the effects of drug treatment on cell loss, nuclear size, DNA damage/fragmentation, apoptosis, lysosomal mass, mitochondrial membrane potential, and steatosis were studied in cultures of primary rat hepatocytes. Using a set of 70 drugs with clear evidence of clinically relevant DILI, the testing strategy improved the accuracies by 10 % and reduced the number of drugs requiring experimental assessment by approximately 20 %, as compared to the HCS assay alone. Moreover, the testing strategy was further validated by including published data (Cosgrove et al. in Toxicol Appl Pharmacol 237:317-330, 2009) on drug-cytokine-induced hepatotoxicity, which improved the accuracies by 7 %. Taken collectively, the proposed testing strategy can significantly improve the prediction of in vitro assays for detecting DILI liability in an early drug discovery phase. PMID- 24958028 TI - Revascularisation for patients with stable coronary artery disease. PMID- 24958029 TI - Plasmon-driven sequential chemical reactions in an aqueous environment. AB - Plasmon-driven sequential chemical reactions were successfully realized in an aqueous environment. In an electrochemical environment, sequential chemical reactions were driven by an applied potential and laser irradiation. Furthermore, the rate of the chemical reaction was controlled via pH, which provides indirect evidence that the hot electrons generated from plasmon decay play an important role in plasmon-driven chemical reactions. In acidic conditions, the hot electrons were captured by the abundant H(+) in the aqueous environment, which prevented the chemical reaction. The developed plasmon-driven chemical reactions in an aqueous environment will significantly expand the applications of plasmon chemistry and may provide a promising avenue for green chemistry using plasmon catalysis in aqueous environments under irradiation by sunlight. PMID- 24958031 TI - Kinetic performance evaluation and perspectives of contemporary packed column capillary electrochromatography. AB - Capillary electrochromatography (CEC) is in essence a highly efficient and fast separation technique but practical constraints limit the current performance, robustness and routine implementation of the technique. In this work the kinetic performance limit (KPL) curve was used to evaluate commercial packed column CEC; this firstly in order to assess the broader applicability of the kinetic plot approach in electrodriven chromatographic techniques, and secondly to allow a more general unbiased comparison with HPLC performance. Evaluations were performed with a mixture of well retained and electrophoretically neutral phenones, to allow the observation of only chromatographic processes. Initial CEC retention time irreproducibility issues were solved by applying high acetonitrile content (80%) in the mobile phase, and solute retention was increased by increasing the phenone chain length. Comparison was performed with HPLC, with a column packed with an identical stationary phase to allow measurement of the performance under optimal conditions, and not with MU-LC on the CEC column as extra column peak broadening phenomena would thereby negatively affect the MU-LC performance. This comparison demonstrated that current HPLC performance largely outcompetes what is achievable with contemporary packed column CEC. Interestingly, significantly improved CEC performance could be obtained at lower temperatures (10 degrees C) indicating a persistent degree of joule heating phenomena taking place in the contemporary packed column (100MUm) CEC approach. Effective suppression of the latter opens possibilities for increasing the applicable voltage and outperforming HPLC and UHPLC. PMID- 24958030 TI - Another perspective on anosognosia: Self-observation in video replay improves motor awareness. AB - Anosognosia for hemiplegia (AHP), or unawareness of motor deficits contralateral to a brain lesion, has lasting negative implications for the management and rehabilitation of patients. A recent, bedside psychophysical intervention, namely self-observation by video replay, lead to a lasting remission of severe AHP in an acute stroke patient (Fotopoulou, A., Rudd, A., Holmes, P., & Kopelman, M. (2009). Self-observation reinstates motor awareness in anosognosia for hemiplegia. Neuropsychologia, 47, 1256-1260). This procedure has been adjusted and applied here, as the basis of two intervention protocols administered independently to two patients with severe AHP. The first study used multiple, successive sessions of video-based self-observation in an acute patient, targeting first the awareness of upper limb and subsequently lower limb paralysis. The second study used a single session of video-based, self- and other observation in a patient at the chronic stage following onset. Both protocols also involved elements of rapport building and emotional support. The results revealed that video-based self-observation had dramatic, immediate effects on awareness in both acute and chronic stages and it seemed to act as an initial trigger for eventual symptom remission. Nevertheless, these effects did not automatically generalise to all functional domains. This study provides provisional support that video-based self-observation may be included in wider rehabilitation programmes for the management and restoration of anosognosia. PMID- 24958032 TI - Chromatographycally efficient microspherical composites of molecularly imprinted xerogels deposited inside mesoporous silica. AB - A different approach to the preparation of microspheric particles of molecularly imprinted xerogels (MIX) is presented here. The technique consisted of filling up the pores of spherical, mesoporous, bare silica particles with a pregelification mixture by applying pressure. Upon gelification and drying, thin layers of MIX were deposited on the mesopores. Spherical composites of S-naproxen (S-NAP) imprints were produced by following this simple strategy. The performance of the imprints was quite satisfactory in terms of recognition ability (ascertained by selectivity against ibuprofen, alpha=4.9, and an imprinting factor of 13) whereas an outstanding improvement on dynamic features (expressed as column efficiency), as compared to the corresponding bulk format MIX (9 vs. 1.2 theoretical plates/cm), was reached. PMID- 24958033 TI - Multiresidue analysis of 22 sulfonamides and their metabolites in animal tissues using quick, easy, cheap, effective, rugged, and safe extraction and high resolution mass spectrometry (hybrid linear ion trap-Orbitrap). AB - A new high performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) method was developed for a simultaneous multi-residue analysis of 22 sulfonamides (SAs) and their metabolites in edible animal (pig, beef, sheep and chicken) tissues. Sample preparation was optimized on the basis of the "QuEChERS" protocol. The analytes were identified using their LC retention times and accurate mass; the identification was further confirmed by multi-stage high mass accuracy (<5ppm) mass spectrometry. The performance of the method was evaluated according to the EU guidelines for the validation of screening methods for the analysis of veterinary drugs residues. Acceptable values were obtained for: linearity (R(2)<0.99), limit of detection (LOD, 3-26MUg/kg), limit of quantification (LOQ, 11-88MUg/kg), accuracy (recovery 88-112%), intra- and inter day precision 1-14 and 1-17%, respectively, decision limit (CCalpha) and detection capability (CCbeta) around the maximum residue limits (MRL) of SAs (100MUg/kg). The method was validated by analysis of a reference material FAPAS 02188 "Pig kidney" with | Z-score|<0.63. The method was applied to various matrices (kidney, liver, muscle) originated from pig, beef, sheep, and chicken) allowing the simultaneous quantification of target sulfonamides at concentration levels above the MRL/2 and the identification of untargeted compounds such as N(4)-acetyl metabolites using multi-stage high mass accuracy mass spectrometry. PMID- 24958034 TI - Simultaneous determination of polar pharmaceuticals and personal care products in biological organs and tissues. AB - In the present study, a sensitive and accurate isotope dilution method was developed for the simultaneous determination of 17 polar pharmaceutical and personal care product (PPCP) residues (logKow=1.40-5.74), including 14 pharmaceuticals and 3 personal care products, in biological organs and tissues. The proposed method involved enzymatic hydrolysis, followed by sequential clean up using silica gel chromatography and gel permeation chromatography, and analysis via ultra-high-performance liquid chromatography with tandem mass spectrometry. This method yielded acceptable absolute recoveries (48-88%) and internal standard-corrected recoveries (90-130%) for 17 PPCPs. Method detection limits were between 0.0092 and 3.2ngg(-1) wet weight, and the limits of quantification were between 0.020 and 8.7ngg(-1) wet weight. The method can be used to readily detect the target compounds at trace levels while minimizing the required sample volume. The developed method was applied to the determination of 17 PPCPs in the liver and kidney of 17 birds collected from Japan and also in the plasma, liver, and brain of 7 cyprinoid fish from an effluent-dominated stream in Japan. Triclosan was detected in 5 of 11 fish-eating birds but not in non-fish eating birds, suggesting the contamination of prey fish by the chemical. Non steroidal anti-inflammatory drugs, antibacterial agents, and psychotropic agents were frequently detected in the fish tissues. In addition, 7 of the target compounds were found in fish brain. The median brain/plasma ratios of the psychotropic agents ranged from 1.6 (carbamazepine) to 12 (diphenhydramine), indicating high transportability to fish brain. PMID- 24958035 TI - A chemometric approach to determine the phenolic compounds in different barley samples by two different stationary phases: a comparison between C18 and pentafluorophenyl core shell columns. AB - Barley (Hordeum vulgare L.) is a cereal crop that has been cultivated since ancient times. However, its interest as nutritional food and as food ingredient is relatively new. Thus, in this study, the phenolic compounds of eighteen different varieties of barley (4 waxy and 14 non-waxy) grown under the same agronomic conditions in the same experimental field have been determined by HPLC DAD-MS. Two new methodologies were developed using new generation superficially porous HPLC columns with different stationary phases: C18 and pentafluorophenyl (PFP). Twelve free phenolic compounds and eight bound phenolic compounds could be identified in barley samples in less than 22min. The study of different method parameters showed that C18 column was more suitable for the analysis of phenolic compounds of barley. Hierarchical cluster analysis (HCA) was conducted in order to assess the different ability of the two different core shell HPLC columns in the discrimination between "waxy" and "non-waxy" varieties, and only HCA of C18 column could separate waxy and non-waxy genotypes. Significant differences in the content of phenolic compounds between waxy and non-waxy samples were found, being waxy barley samples the ones which presented higher content of free and bound phenolic compounds. Once the best discriminant HPLC column was established, principal component analysis (PCA) was applied and it was able to discriminate between "waxy" and "non-waxy" varieties; however it discriminated the barley samples based only in free phenolic compounds. Because of that, partial least squares discriminant analysis (PLS-DA) and Artificial Neural Networks (ANN) were carried out. PLS-DA and ANN permitted the classification of waxy and non-waxy genotypes from both free and bound phenolic compounds. PMID- 24958036 TI - Assessment of Costs in Congenital Heart Surgery. PMID- 24958037 TI - Fontan Circulation in Adult Patients: Acoustic Radiation Force Impulse Elastography as a Useful Tool for Liver Assessment. AB - OBJECTIVE: The development of liver fibrosis and cirrhosis due to long-standing liver congestion is known to occur in adult patients with Fontan circulation. Hepatic elastography has shown to be a useful tool for the noninvasive assessment and staging of liver fibrosis in chronic liver diseases, although the utility of this technique in Fontan patients remains to be adequately studied. METHODS: Twenty-one patients with Fontan circulation underwent an abdominal ultrasound and an acoustic radiation force impulse (ARFI) elastography. In order to compare the results from this group, a cohort of 14 healthy controls and another group containing 17 patients with cirrhosis were included. The association between the velocity values measured with elastography and clinical and analytical parameters were also studied. RESULTS: Mean shear waves propagation velocity in liver tissue in the Fontan group was 1.86 +/- 0.5 m/s, with 76% of patients over the cirrhosis threshold (1.55 m/s). The control group had a mean velocity of 1.09 +/- 0.06 m/s, while the cirrhotic group obtained 2.71 +/- 0.51 m/s. Seven patients with Fontan circulation had increased liver enzymes. Liver ultrasound showed evidence of chronic liver disease in six patients. Velocity values obtained in the presence or absence of analytical or liver ultrasound abnormalities showed significant differences in the univariate analysis (P = .04 and P = .03 respectively). CONCLUSION: In conclusion, ARFI elastography showed increased wave propagation velocity values in the Fontan population suggesting increased liver stiffness which could be related to advanced fibrosis. A statistically significant association between ARFI values and the presence of analytical and ultrasound abnormalities has been demonstrated. PMID- 24958038 TI - Model-Based Comparison of the Normal and Fontan Circulatory Systems: Part I: Development of a General Purpose, Interactive Cardiovascular Model. AB - BACKGROUND: Every year, approximately 1,000 Fontan operations are performed in the United States. Transplant-free, 30-year survival is only 50%. Although some performance characteristics may be universal among Fontan survivors, others may be patient specific and tunable; in either case, a quantitatively rigorous understanding of the Fontan circulatory arrangement would facilitate improvements in patient surveillance and management. METHODS: To create a computational model of a normal two-year-old and a two-year-old patient with hypoplastic left heart syndrome (HLHS) following staged surgical palliations, we extensively modified the lumped parameter model developed by Clark, a multicompartment model of both pulmonary and systemic circulations. RESULTS: With appropriately scaled parameter values, we achieved a maximum relative error (against target values for clinically realistic hemodynamic variables for the normal two-year-old) of 2.8% and an average relative error of 0.9%. Employing the model of a Fontan operation, we achieved a maximum relative error of 2.0% and the average relative error of 0.8%. CONCLUSIONS: Even with >200 model parameters, once we identified an acceptable set of values for the normal, only 12 required modification in order to attain clinically plausible hemodynamics in the HLHS after Fontan. When placed within the broad context of our extensive model, the impact on cardiac output of the resistance of the total cavopulmonary connection is found to be significantly affected by ventricular elastance and to be much lower in the two-year-old than in patients with markedly lower end-diastolic elastance (higher end-diastolic compliance). PMID- 24958039 TI - A Comparative Histopathological Study of Heparin Coated and Uncoated Polytetrafluoroethylene Shunts in Children With Congenital Heart Defect. AB - OBJECTIVE: Recently, heparin coated polytetrafluoroethylene (PTFE) shunts are available and are believed to improve inherent shunt problems such as thrombosis and excessive and incomplete neointima formation or occlusion. We aimed at comparing the potential histopathological differences in the neointima (in) between uncoated (UCS) PTFE shunts and heparin coated (HCS) PTFE shunts. MATERIALS AND METHODS: Thirteen shunts (six UCS and seven HCS) were analyzed. The specimens were fixed in formalin, embedded in paraffin or in methylmethacrylate, and characterized by standard and immunohistochemical staining. The thickness of pseudointima proliferation was graded as follows: 0 = no cell layers, 1 = few layers <100 um, 2 = partial layers >100 um, 3 = complete layers <300 um, 4 = complete layers >300 um, and 5 = occlusion. RESULTS: Mean shunt size was 3.4 +/- 0.2 mm in UCS and 3.1 +/- 0.2 mm in HCS (P = .053). Mean time of implantation was 163 +/- 75 days in UCS and 97 +/- 52 days in HCS (P = .091). There were no significant differences in the proportion of patients with functionally single ventricle, body surface area, age at implantation, or implantation type, between both groups. Shunt occlusion did not occur. Unplanned shunt explantation due to cyanosis was performed in one patient in each group. Partial thrombus formation was observed in one UCS (P = .462). There was complete endothelialization in 50% of UCS and 86% of HCS (P = .266). The grade of pseudointima proliferation was 1.8 +/- 0.4 in UCS and 1.7 +/- 0.5 in HCS (P = .646). CONCLUSIONS: The histopathological workup of PTFE shunts revealed equally partial endothelialization and discrete pseudointima proliferation in both the groups. The process of endothelialization may be faster in HCS. PMID- 24958040 TI - Heparin Coated and Uncoated Polytetrafluoroethylene Shunts in Children With Congenital Heart Defects. PMID- 24958041 TI - Extracorporeal Membrane Oxygenation in Single Ventricle Lesions Palliated Via the Hybrid Approach. AB - BACKGROUND: Describing outcomes for children with hypoplastic left heart syndrome (HLHS) undergoing hybrid palliation (pulmonary artery band and stent placement in the patent ductus arteriosus) requiring extracorporeal membrane oxygenation (ECMO) support for cardiorespiratory failure. METHODS: We reviewed the Extracorporeal Life Support Organization database for all patients with a diagnosis of an HLHS undergoing hybrid stage 1 palliation supported with ECMO and those patients with hybrid palliation supported with ECMO after comprehensive stage 2 palliation. Patients were identified using a combination of International Classification of Diseases, Ninth Revision and registry diagnosis and procedure codes. We report survival to hospital discharge and ECMO complications. RESULTS: We identified 44 patients with HLHS requiring ECMO following stage 1 hybrid approach. Median age at cannulation was 13.5 days. Only 16% survived to hospital discharge. In all, 20 (50%) patients had a cardiac arrest prior to going onto ECMO and for 3 (19%) patients, ECMO was initiated during cardiopulmonary resuscitation. CONCLUSIONS: Overall survival for ECMO support in patients with HLHS palliated via the hybrid approach is very poor (16%) and is worse than 31% survival reported for ECMO after conventional stage 1 palliation. The reasons for these poor outcomes require further investigation. PMID- 24958043 TI - The Ross Operation in Children and Young Adults: 12-Year Results and Trends From the UK National Database. AB - OBJECTIVES: To determine UK national trends and results of the Ross operation in relation to all aortic valve interventions. METHODS: Examination of the UK Congenital Central Cardiac Audit Database for all aortic valve procedures performed between 2000 and 2011 in children (0-16 years) and young adults (16-30 years). RESULTS: A total of 2,206 aortic valve procedures were performed in children and 1,824 in young adults, the proportions in the two groups being: Ross operation (19% vs 15%, respectively), surgical valvoplasty (9.5% vs 4%), surgical valvotomy (9.5% vs 1%), aortic valve replacement (AVR; 11% vs 55%), aortic root replacement (4% vs 18%), and balloon valvoplasty (47% vs 7%). The 30-day and 1 year survival after Ross is 99.3% and 98.7%, respectively, in the last four years achieving 100%. In children, the proportion of balloon valvoplasty increased from an average of 43% in 2000 to 2006 to 53% in 2007 to 2011, whereas the Ross operation decreased from 22% to 16% (P < .001). In young adults, the figures are an increase from 49% to 58% for AVR compared to a decrease from 23% to 9% for Ross (P < .001). Our own single-center series of 91 patients also shows standard results for early- and long-term survival and freedom from reoperation, but gradually fewer Ross operations performed. The year-on-year changes show a significant decreasing trend locally and nationally. CONCLUSIONS: Despite an excellent track record, the Ross operation is performed less frequently in the United Kingdom. This report is a first step in comparing treatment modalities at national level. PMID- 24958042 TI - The Impact of Differential Case Ascertainment in Clinical Registry Versus Administrative Data on Assessment of Resource Utilization in Pediatric Heart Surgery. AB - BACKGROUND: Resource utilization in congenital heart surgery is typically assessed using administrative data sets. Recent analyses have called into question the accuracy of coding of cases in administrative data; however, it is unclear whether miscoding impacts assessment of associated resource use. METHODS: We merged data coded within both an administrative data set and clinical registry on children undergoing heart surgery (2004-2010) at 33 hospitals. The impact of differences in coding of operations between data sets on reporting of postoperative length of stay (PLOS) and total hospital costs associated with these operations was assessed. RESULTS: For each of the eight operations of varying complexity evaluated (total n = 57,797), there were differences in coding between data sets, which translated into differences in the reporting of associated resource utilization for the cases coded in either data set. There were statistically significant differences in PLOS and cost for seven of the eight operations, although most PLOS differences were relatively small with the exception of the Norwood operation and truncus repair (differences of two days, P < .001). For cost, there was a >5% difference for three of the eight operations and >10% difference for truncus repair (US$10,570; P < .01). Grouping of operations into categories of similar risk appeared to mitigate many of these differences. CONCLUSION: Differences in coding of cases in administrative versus clinical registry data can translate into differences in assessment of associated PLOS and cost for certain operations. This may be minimized through evaluating larger groups of operations when using administrative data or using clinical registry data to accurately identify operations of interest. PMID- 24958044 TI - Peritoneal Drainage Versus Pleural Drainage After Pediatric Cardiac Surgery. AB - BACKGROUND: We aimed to determine whether infants undergoing cardiac surgery would more efficiently attain negative fluid balance postoperatively with passive peritoneal drainage as compared to traditional pleural drainage. METHODS: A prospective, randomized study including children undergoing repair of tetralogy of Fallot (TOF) or atrioventricular septal defect (AVSD) was completed between September 2011 and June 2013. Patients were randomized to intraoperative placement of peritoneal catheter or right pleural tube in addition to the requisite mediastinal tube. The primary outcome measure was fluid balance at 48 hours postoperatively. Variables were compared using t tests or Fisher exact tests as appropriate. RESULTS: A total of 24 patients were enrolled (14 TOF and 10 AVSD), with 12 patients in each study group. Mean fluid balance at 48 hours was not significantly different between study groups, -41 +/- 53 mL/kg in patients with periteonal drainage and -9 +/- 40 mL/kg in patients with pleural drainage (P = .10). At 72 hours however, postoperative fluid balance was significantly more negative with peritoneal drainage, -52.4 +/- 71.6 versus +2.0 +/- 50.6 (P = .04). On subset analysis, fluid balance at 48 hours in patients with AVSD was more negative with peritoneal drainage as compared to pleural, -82 +/- 51 versus -1 +/- 38 mL/kg, respectively (P = .02). Fluid balance at 48 hours in patients with TOF was not significantly different between study groups. CONCLUSION: Passive peritoneal drainage may more effectively facilitate negative fluid balance when compared to pleural drainage after pediatric cardiac surgery, although this benefit is not likely universal but rather dependent on the patient's underlying physiology. PMID- 24958045 TI - Utilizing Three-Dimensional Printing Technology to Assess the Feasibility of High Fidelity Synthetic Ventricular Septal Defect Models for Simulation in Medical Education. AB - BACKGROUND: The current educational approach for teaching congenital heart disease (CHD) anatomy to students involves instructional tools and techniques that have significant limitations. This study sought to assess the feasibility of utilizing present-day three-dimensional (3D) printing technology to create high fidelity synthetic heart models with ventricular septal defect (VSD) lesions and applying these models to a novel, simulation-based educational curriculum for premedical and medical students. METHODS: Archived, de-identified magnetic resonance images of five common VSD subtypes were obtained. These cardiac images were then segmented and built into 3D computer-aided design models using Mimics Innovation Suite software. An Objet500 Connex 3D printer was subsequently utilized to print a high-fidelity heart model for each VSD subtype. Next, a simulation-based educational curriculum using these heart models was developed and implemented in the instruction of 29 premedical and medical students. Assessment of this curriculum was undertaken with Likert-type questionnaires. RESULTS: High-fidelity VSD models were successfully created utilizing magnetic resonance imaging data and 3D printing. Following instruction with these high fidelity models, all students reported significant improvement in knowledge acquisition (P < .0001), knowledge reporting (P < .0001), and structural conceptualization (P < .0001) of VSDs. CONCLUSIONS: It is feasible to use present day 3D printing technology to create high-fidelity heart models with complex intracardiac defects. Furthermore, this tool forms the foundation for an innovative, simulation-based educational approach to teach students about CHD and creates a novel opportunity to stimulate their interest in this field. PMID- 24958046 TI - Completion of the Three-Stage Fontan Pathway Without Cardiopulmonary Bypass. AB - BACKGROUND: The three-stage surgical approach is now accepted as the standard for management of children born with functional single ventricle. However, there is little consensus on the cardiopulmonary bypass strategies employed for these procedures. We have attempted to avoid cardiopulmonary bypass in patients with single ventricle whenever possible to eliminate the adverse effects that are induced by this process. The purpose of this study was to review our experience in patients who underwent all three stages of the Fontan pathway without ever being exposed to bypass. METHODS: A total of 52 patients with single ventricle underwent "off-pump" treatment at all three stages of their surgical management. The time period of the study was from 2002 to 2013. There were 31 males and 21 females. Anatomic diagnoses included double inlet left ventricle (n = 11), pulmonary atresia with intact ventricular septum (n = 11), tricuspid atresia (n = 10), double outlet right ventricle (n = 9), and other (n = 11). RESULTS: There was no operative mortality in the 52 patients undergoing Fontan completion. The patients have been followed for an average of 5.1 +/- 2.5 years, with one late mortality. The median length of hospital stay for the three stages was 17, 5, and 9 days, respectively. Of the 52 patients, 42 were able to undergo all three stages without the need for a blood transfusion. CONCLUSIONS: This series demonstrates the feasibility of achieving a Fontan circulation without patients exposed to cardiopulmonary bypass. There was no operative mortality and low mid term mortality. It is notable that 80% of patients never required a blood transfusion with this approach. The elimination of cardiopulmonary bypass provides several potential clinical benefits in this highly select subset of patients with single ventricle. PMID- 24958047 TI - A Novel Technique for Repair of Complete Atrioventricular Canal Defect: The Central Patch Technique. AB - BACKGROUND: Two-patch, single-patch, and modified single-patch repairs are accepted techniques for repair of complete atrioventricular (AV) canal defects. We propose a novel, alternative technique: the central patch technique. METHODS: For the central patch technique, the superior and inferior bridging leaflets are attached with simple sutures to the right and left of their coaptation point. Both bridging leaflets are incised along a line above the ventricular crest, similar to a traditional single-patch technique. An oval pericardial patch is sewn to the central defect created in the AV valve tissue. Interrupted, horizontal mattress sutures are placed along the ventricular crest, through the midline of the central patch and through the edge of the atrial septal defect (ASD) patch. Tying the sutures simultaneously closes the ventricular septal defect (VSD) and secures the ASD patch to the ventricular crest. Repair of the left AV valve and ASD closure are performed in the routine fashion. RESULTS: Five patients underwent the central patch technique repair of complete AV canal defect. Weight was 4.8 to 6.3 kg; age was four to eight months. Cardiopulmonary bypass and myocardial times averaged 137 minutes and 109 minutes, respectively. No patient had more than mild left AV valve regurgitation or trivial residual VSD at completion of repair. No patient developed left ventricular outflow tract obstruction. CONCLUSION: The central patch technique is applicable to all forms of complete AV canal defect. Subjectively, it offers technical advantages compared to standard techniques and may result in a shorter learning curve for junior congenital heart surgeons. Results are preliminary but are consistent with standard techniques. PMID- 24958048 TI - Impact of Pulsatile Flow Settings on Hemodynamic Energy Levels Using the Novel Diagonal Medos DP3 Pump in a Simulated Pediatric Extracorporeal Life Support System. AB - BACKGROUND: The objective of this study was to evaluate the pump performance of the novel diagonal Medos Deltastream DP3 diagonal pump (MEDOS Medizintechnik AG, , Stolberg, Germany) under nonpulsatile to pulsatile mode with varying differential speed values in a simulated pediatric extracorporeal life support system. METHODS: The experimental circuit consisted of a Medos Deltastream DP3 pump head and console, a Medos Hilite 2400 LT hollow fiber membrane oxygenator (MEDOS Medizintechnik AG), a 14F Medtronic DLP arterial cannula (Medtronic Inc, Minnesota), and a 20F Terumo TenderFlow Pediatric venous return cannula (Terumo Corporation, Michigan). Trials were conducted at flow rates ranging from 500 mL/min to 2,000 mL/min (500 mL/min increments) and pulsatile differential speed values ranging from 500 rpm to 2,500 rpm (500 rpm increments) using human blood (hematocrit 35%). The postcannula pressure was maintained constantly at 60 mm Hg. Real-time pressure and flow data were recorded using a custom-made data acquisition system and Labview software. RESULTS: Under all experimental conditions, pulsatile flow (P) generated significantly greater energy equivalent pressure (EEP), surplus hemodynamic energy (SHE), and total hemodynamic energy (THE) than those of nonpulsatile flow (NP). Under NP, SHE was zero. Higher differential speed values generated greater EEP, SHE, and THE values. There was little variation in the oxygenator pressure drop and the cannula pressure drop in P, compared to NP. CONCLUSIONS: The novel Medos Deltastream DP3 diagonal pump is able to generate physiological quality of P, without backflow. With increased differential rpm, the pump generated greater EEP, SHE, and THE. Physiological quality of pulsatility may be associated with better microcirculation because of greater EEP, SHE, and THE. PMID- 24958049 TI - Staged Left Ventricular Recruitment and Biventricular Conversion in Hypoplastic Left Heart Syndrome. AB - We describe a relatively long left ventricular recruitment pathway consisting of early and serial aortic valvuloplasties and multiple endocardial fibroelastosis resections resulting in successful biventricular conversion of hypoplastic left heart syndrome. PMID- 24958050 TI - A Rare Anomaly of a Single Coronary Artery Arising From the Right Pulmonary Artery in a Neonate. AB - An anomalous origin of the entire coronary circulation from the right pulmonary artery is a very rare congenital malformation. We report on a male newborn presenting with hypoplastic aortic arch and coarctation of the aorta in whom a previously undetected single coronary artery originating from the right pulmonary artery was detected at the time of corrective surgery. The patient underwent a resection of the coarctation with a patch enlargement of the aortic arch and a successful reimplantation of the coronary artery into the aorta. PMID- 24958051 TI - The Right Subclavian Artery Arising as the First Branch of a Left-Sided Aortic Arch. AB - We describe an unusual pattern of branching of a left-sided aortic arch in which the first branch is the right subclavian artery, followed by the common carotid arteries arising from a common trunk. The patient was born with transposition (concordant atrioventricular and discordant ventriculoarterial connections) and had 18q23 deletion. We discuss the implication of these anatomic findings in the light of inferences currently made by echocardiographers when the first branch of the aortic arch fails to bifurcate. We also relate the findings to the concepts of cardiac development and draw comparisons with previous descriptions, and interpretations of the morphogenesis, of the patterns of branching from the aortic arch. PMID- 24958052 TI - Noninvasive Nitric Oxide Therapy in Right Ventricular Systolic Dysfunction Following Arterial Switch Procedure. AB - Right ventricular dysfunction is uncommon following surgical repair of dextrotransposition of great arteries (d-TGA) by the arterial switch procedure. Inhaled nitric oxide (iNO) is a specific pulmonary vasolidator that has proven successful in treating pulmonary hypertension when delivered via endotracheal tube. We present a five-month-old infant with d-TGA and ventricular septal defect (VSD) who developed pulmonary hypertensive crisis, causing severe right ventricular dysfunction with hemodynamic deterioration at day 6 postsurgical repair by VSD closure and arterial switch. He was successfully treated with iNO via nonrebreather face mask avoiding endotracheal reintubation. This modality should be considered in the management of such infants. PMID- 24958053 TI - Multivalvular Replacement and Ventricular Arrhythmias in a Female Child With Congenital Polyvalvular Disease. AB - We report the clinical course of a female child with a normal karyotype and chromosomal microarray who presented as an infant with clinical findings consistent with congenital polyvalvular disease (CPVD). This clinical entity describes patients with multiple congenitally dysplastic valves, often showing nodular or cystic malformation in at least two cardiac valves. This patient then developed medically refractory multifocal ventricular arrhythmia and required radiofrequency ablation at seven months of age. She had good tachycardia control but became symptomatic with right heart failure related to progressive tricuspid, pulmonary, and mitral valve dysfunction necessitating multivalvular replacement at 21 months of age. PMID- 24958054 TI - Combined Rastelli and Bentall Procedures for Pulmonary Atresia With Ventricular Septal Defect and a Large Aortopulmonary Collateral Artery and Ascending Aorta Aneurysm. AB - We report a challenging case of a 32-year-old patient in New York Heart Association (NYHA) class IV with pulmonary atresia, ventricular septal defect, a left aortopulmonary collateral artery, a right modified Blalock-Taussing shunt, and a gigantic aneurysm of the ascending aorta with severe aortic valve insufficiency. A combined Rastelli and Bentall procedure was performed by a joint adult and pediatric cardiovascular surgery team. One year after the operation, the patient is in NYHA class I, working full time. PMID- 24958055 TI - A Rare Case of Pulmonary Artery Sling and Complete Atrioventricular Canal Defect in an Infant With Trisomy 21. AB - Pulmonary artery sling is a very rare congenital vascular anomaly. Patients usually present in infancy with symptoms of airway compression. Patients with trisomy 21 often have upper airway obstruction, most commonly related to pharyngeal causes or subglottic stenosis. Although the incidence of congenital heart defects in patients with trisomy 21 is very high, a review of the literature showed only one previously reported case of pulmonary artery sling in an infant with trisomy 21. We report a case of pulmonary artery sling and complete atrioventricular canal defect in a one-month-old female with trisomy 21. Echocardiography is an important diagnostic method for pulmonary artery sling, but this anomaly may be easily overlooked in the presence of more commonly anticipated defects in this population. PMID- 24958057 TI - Resection of a Giant Left Atrial Appendage Aneurysm via Limited Thoracotomy. AB - A left atrial appendage aneurysm is a rare cause of atrial arrhythmia in a young adult. Resection of the aneurysm is uniformly recommended in order to prevent thromboembolism and stroke. In patients without evidence of clot within the aneurysm, operative resection via a limited thoracotomy provides a safe and effective alternative to median sternotomy with cardiopulmonary bypass. PMID- 24958056 TI - An Unusual Case of Severe Stenosis of the Coronary Sinus Ostium in Association With Double Inlet Left Ventricle. AB - We present a patient with complex single ventricle physiology who was subsequently diagnosed with atresia of the coronary sinus ostium in the setting of myocardial dysfunction following operative palliation. Although a rare cardiac defect, awareness is important as the coronary venous system will often drain to a left superior vena cava (LSVC). If the LSVC is ligated without knowing of this defect, cardiac dysfunction and death can occur. PMID- 24958058 TI - Apical Aortic Conduit Infection 27 Years After Repaired Left Ventricular Outflow Tract Obstruction. AB - Left ventricle to aortic conduits were used for the treatment of complex left ventricular outflow tract obstruction in the pediatric population in the mid 1970s. Although this technique has been largely replaced by the Ross-Konno procedure, many patients still have functioning apicoaortic conduits in place today. Few clinical reports or case series exist in pediatric cohorts documenting the natural history or potential long-term complications of this prosthesis. In this report, we describe our experience managing a patient with Shone's syndrome and an apical aortic porcine-valved conduit remnant that became infected 17 years postconduit valve excision for valvular insufficiency. PMID- 24958059 TI - Coarctoplasty and Stenting in a Case of Ventricular Septal Defect With Eisenmenger's Syndrome: A Clinical Dilemma. AB - Coarctoplasty with stenting is often an effective strategy in cases of recoarctation following surgical repair. The potential benefit of coarctoplasty in a patient with Eisenmenger's syndrome is unknown. We describe the case of a 21 year-old male who presented with claudication of lower limbs. He was known to have congenital heart disease, consisting of ventricular septal defect, patent ductus arteriosus (PDA), and coarctation of the aorta. Coarctation repair and PDA ligation had been done at two months of age. At the time of presentation for evaluation of claudication, echocardiography revealed severe coarctation and evidence of Eisenmenger's syndrome. This patient subsequently underwent balloon angioplasty and stenting of coarctation without any increase in cyanosis. PMID- 24958060 TI - Complete Recovery From Severe Tachycardia-Induced Cardiomyopathy in a Patient With Ebstein's Anomaly. AB - We report the case of a young patient with repaired Ebstein's anomaly who developed severe tachycardia-induced cardiomyopathy and a large apical thrombus as a consequence of sustained atrial flutter with a 2:1 conduction. In spite of a dramatic course in hospital with prolonged mechanical resuscitation and extracorporeal membrane oxygenation, she survived and made a rapid and full recovery. This remarkable case underlines that atrial arrhythmias, the most common complication in adults with congenital heart disease, may have devastating outcomes when timely recognition is missed and treatment delayed-thus, emphasizing the importance of good patient education. PMID- 24958061 TI - "Isolated Atrial Inversion" Without Transposition Physiology: Yet Another "Twisted Heart". AB - Atrial inversion (or mirror-imaged atrial arrangement) occurring in isolation, that is, without corresponding mirror imagery of the viscera, has been previously shown with discordant atrioventricular connections resulting in transposition physiology. We hereby report a case of "isolated atrial inversion" wherein atrioventricular connections were concordant owing to the presence of criss crossing of the ventricular inflows. PMID- 24958062 TI - Apical Hypertrophic Cardiomyopathy in an Infant: First Presentation of Pompe's Disease. AB - Pompe's disease is a type II glycogen storage disorder resulting from deficiency of alpha-1,4 glucosidase. It is usually associated with dilated or hypertrophic cardiomyopathy. Association of apical hypertrophic cardiomyopathy is rarely seen. We present a case of a ten-month-old baby with clinical features of both apical hypertrophic cardiomyopathy and Pompe's disease. PMID- 24958063 TI - Cruciate Fenestration in Ventricular Septal Defect Patch for High-Risk Patients With High Pulmonary Vascular Resistance. AB - Late presentation of patients with large ventricular septal defect (VSD) and elevated pulmonary vascular resistance (PVR) is not uncommon in developing countries. Surgical VSD closure in these patients carries risks of persistent pulmonary hypertension, right ventricular failure, and mortality. Several techniques for creation of valved patches or fenestrated patches have been developed to address these issues. We have successfully used a simple and easily reproducible technique in which a cruciate fenestration is created in the patch used for VSD closure. PMID- 24958064 TI - Combination of oral antibiotics may be effective in severe pediatric ulcerative colitis: a preliminary report. AB - BACKGROUND: The results of previous studies on the effectiveness of antibiotics in ulcerative colitis (UC) seem more effective when used orally. In this retrospective, multicenter study, we aimed to report our experience of using a combination of 3-4 antibiotics in children with moderate-severe refractory UC and IBD-unclassified including metronidazole, amoxicillin, doxycycline, and if during hospital admission, also vancomycin (MADoV). METHODS: All children treated during 2013 with the antibiotic cocktail for 2-3weeks in an attempt to alleviate inflammation in refractory colitis were included. Doxycycline was substituted with oral gentamycin or ciprofloxacin in children younger than 8years or when an allergy was known to one of the drugs. Children were assessed using the PUCAI and CRP weekly for 3weeks. RESULTS: All 15 included children had moderate to severe disease with refractory disease course to multiple immunosuppressants (mean age 13.6+/-5.1years, median disease duration 2 (IQR 0.8-3.2) years, 11 females (73%), and 13 (87%) extensive disease; 14 (93%) were corticosteroid-dependent or resistant, and 12 (80%) refractory to anti-TNF therapy). The cocktail was definitely effective in 7 of the 15 included children (47%) who entered complete clinical remission (PUCAI<10) without additional interventions. Questionable or partial short-term response was noted in another 3 (20%), totaling 67% of patients. CONCLUSION: The use of oral wide-spectrum antibiotic cocktail in pediatric UC seems promising in half of patients, refractory to other salvage therapy. A pediatric randomized controlled trial to assess this intervention is underway. PMID- 24958065 TI - Jumping to the wrong conclusions? An investigation of the mechanisms of reasoning errors in delusions. AB - Understanding how people with delusions arrive at false conclusions is central to the refinement of cognitive behavioural interventions. Making hasty decisions based on limited data ('jumping to conclusions', JTC) is one potential causal mechanism, but reasoning errors may also result from other processes. In this study, we investigated the correlates of reasoning errors under differing task conditions in 204 participants with schizophrenia spectrum psychosis who completed three probabilistic reasoning tasks. Psychotic symptoms, affect, and IQ were also evaluated. We found that hasty decision makers were more likely to draw false conclusions, but only 37% of their reasoning errors were consistent with the limited data they had gathered. The remainder directly contradicted all the presented evidence. Reasoning errors showed task-dependent associations with IQ, affect, and psychotic symptoms. We conclude that limited data-gathering contributes to false conclusions but is not the only mechanism involved. Delusions may also be maintained by a tendency to disregard evidence. Low IQ and emotional biases may contribute to reasoning errors in more complex situations. Cognitive strategies to reduce reasoning errors should therefore extend beyond encouragement to gather more data, and incorporate interventions focused directly on these difficulties. PMID- 24958066 TI - Non-suicidal self-injury disorder in a community sample of adults. AB - Non-suicidal self-injury (NSSI) Disorder has been included in DSM-5 for the first time as a disorder requiring further research. The present study investigated DSM 5 criteria for NSSI Disorder in a community sample of adults and provided an initial investigation of differences between those with and without a diagnosis of NSSI Disorder and NSSI history. Participants over the age of 18 (N=548) completed an online survey using Amazon's MTurk. A lifetime history of NSSI was reported by 23% of the sample. Nearly 3% of the total sample and 11.2% of those with an NSSI history met criteria for NSSI Disorder. Those with NSSI Disorder were similar to participants with an NSSI history who did not meet criteria for the disorder on NSSI frequency and methods, and age of NSSI onset, use of coping strategies, and borderline symptoms, but they differed on automatic reinforcement of the behavior and reported interference with functioning. Endorsement of specific NSSI Disorder criteria, potential implications for the diagnosis, and avenues for future research are discussed. PMID- 24958067 TI - Safety and usefulness of cryopreservation of ovarian tissue to preserve fertility: a 12-year retrospective analysis. AB - STUDY QUESTION: Do the benefits of ovarian tissue cryopreservation outweigh the risks for patients seeking to preserve fertility before gonadotoxic treatment in various indications? SUMMARY ANSWER: In >90% of the patients undergoing cryopreservation of ovarian tissue, oncological treatment was associated with a reduced ovarian reserve and in 30% of patients, premature ovarian failure (POF) occurred within 5 years. WHAT IS KNOWN ALREADY: Ovarian tissue cryopreservation is an effective fertility preservation option, especially for pre-pubertal patients and patients who have a short time between diagnosis of a disease and gonadotoxic treatment. STUDY DESIGN, SETTING, DURATION: This study retrospectively analysed ovarian function and fertility recovery rates, as well as ovarian tissue characteristics, of patients who underwent ovarian tissue cryopreservation at Erasme Hospital between 1999 and 2011. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: A total of 225 patients referred from 15 Belgian oncological units underwent cryopreservation of ovarian tissue before gonadotoxic therapy for malignant or benign diseases. There were 28 patients (12.4%) who died during follow-up due to recurrence of disease. One severe adverse event occurred during anaesthesia for ovarian tissue collection, leading to the death of the patient. Ovarian function and fertility outcomes were available for 114 patients including 13 girls who were pre-pubertal at the time of the procedure. Eight patients had undergone ovarian tissue transplantation in order to restore their fertility after remission of the disease. MAIN RESULTS AND THE ROLE OF CHANCE: Breast cancer and haematological disease were the most frequent indications for ovarian tissue cryopreservation. Overall, 90% of post pubertal patients were diagnosed with poor ovarian reserve (AMH < 0.5 ng/ml) after a mean of 50 months of follow-up (11-125 months), including 30% with POF (FSH > 40 IU/ml). Breast cancer patients had a lower rate of POF than did post pubertal patients with haematological diseases (11 versus 34.5%, respectively), despite the older age (mean 31 versus 23.5 years old, respectively) of the breast cancer patients. Ovarian function returned in 71 post-pubertal patients without the need for grafts of cryopreserved tissue. Spontaneous pregnancies were reported for 33 of them, leading to 34 live births. Among the 13 pre-pubertal patients who reached pubertal age during the follow-up, 10 had POF. Eight patients received cryopreserved ovarian grafts to reverse POF and three of them have already become pregnant. LIMITATIONS, REASONS FOR CAUTION: This study is a retrospective analysis. The cohort was not compared with a control group of patients who did not undergo the procedure. WIDER IMPLICATIONS OF THE FINDINGS: After careful evaluation of the surgical risks, ovarian tissue cryopreservation can be proposed as an efficient option to preserve the fertility of children and young adults facing gonadotoxic therapies. However, alternative procedures such as oocyte or embryo cryopreservation should be considered as first options especially for older patients or if there is high risk of neoplastic cells within the ovaries. STUDY FUNDING/COMPETING INTEREST: This study was supported by the Televie, FNRS-FRSM and Fondation Belge contre le cancer. There are no competing interests to report. PMID- 24958069 TI - Three-finger tracheal palpation to guide endotracheal tube depth in children. AB - BACKGROUND: Accurate endotracheal tube (ETT) depth is critical, especially in children. The current tools used to guide appropriate ETT depth have significant limitations. OBJECTIVES: To evaluate the utility of tracheal palpation in the neck to guide appropriate ETT placement in children. METHODS: A prospective observational study with a convenience sample of 50 children was conducted. During intubation, an investigator palpated the trachea with three fingertips side-by-side extending upward from the suprasternal notch. The anesthesiologist advanced the ETT slowly until palpated at the sternal notch. The investigator stated ETT palpation certainty as 'strongly felt', 'weakly felt', or 'not felt.' Final ETT position was determined by bronchoscopy and categorized as 'ETT too shallow' (tip in proximal 1/4 of trachea), 'ETT too deep' (tip in distal 1/4 of trachea), or 'ETT placement satisfactory' (between those extremes). RESULTS: Thirty boys and 20 girls undergoing dental surgery with nasal intubation were recruited (median age 4.4 years; range 2.0-10.8). The ETT (all >=4 mm ID) was palpable at the sternal notch in all patients: 46 of 50 strongly palpable and 4 of 50 weakly palpable. The experimental methods led to satisfactory ETT placement in 49 of 50 patients, too deep in 1 of 50 patients. Compared with the Pediatrics Advanced Life Support (PALS) predictive formula, satisfactory placement would have been 41 of 50 patients (P < 0.008). Number needed to treat is 6.3 for improvement over the PALS method. CONCLUSIONS: The use of tracheal palpation to guide ETT placement has excellent clinical performance and better guides appropriate ETT depth than the PALS formula in our study population. PMID- 24958068 TI - The effects of lysine analogs during pelvic surgery: a systematic review and meta analysis. AB - Pelvic vasculature is complex and inconsistent while pelvic bones impede access to pelvic organs. These anatomical characteristics render pelvic surgery inherently difficult, and some of these procedures are frequently associated with blood loss that necessitates blood transfusion. The aim of this study was to review the literature on the use of lysine analogs to prevent bleeding and blood transfusion during pelvic surgery. The objective of this study was to assess the safety and efficacy of lysine analogs during pelvic surgery. A systematic literature search was performed using Medline, Cochrane Register of Clinical Trials, Embase, and the reference lists of relevant articles. Randomized controlled trials or observational cohort studies comparing a lysine analog to placebo or standard care were included. Outcomes collected were blood transfusion, blood loss, thromboembolic adverse events (myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism), nonthromboembolic adverse events, and death. There were no language limitations. Fifty-six articles reported on 68 comparisons between a lysine analog and an inactive comparator, involving a total of 7244 patients published between 1961 and 2013. Thirty-nine studies evaluated urologic procedures, and 21 evaluated gynecologic procedures. Thirty-six studies (60%) were published before 1980. Of the 43 randomized comparisons, only 30 (44%) had a score of 3 or higher on Jadad's 5-point scale of methodological quality. Among randomized trials, lysine analogs reduced the risk of blood transfusion (pooled odds ratio [OR], 0.47; 95% confidence interval [CI], 0.35-0.64) and blood loss (pooled OR, 0.22; 95% CI, 0.18-0.27). There was a small statistically insignificant increased risk of thromboembolic events (pooled OR, 1.07; 95% CI, 0.72-1.59) and no-thrombotic serious adverse events (pooled OR, 1.11; 95% CI, 0.67-1.83). In the 17 randomized trials published since the year 2000, only 6 thrombotic events were reported, 4 of which occurred in the placebo arm. Lysine analogs did not increase risk of death (pooled OR, 0.91; 95% CI, 0.34 2.48). These results are significant as they indicate that lysine analogs significantly reduce blood loss and blood transfusion during pelvic surgery. Although there does not appear to be a large increase in the risk of thromboembolic and nonthrombotic adverse events, more data are required to definitively assess these outcomes. Based on this review, lysine analogs during pelvic surgery seem to reduce bleeding and blood transfusion requirements. Although there does not seem to be a significant risk of adverse effects, larger studies would help clarify risks, if any, associated with lysine analog use. PMID- 24958070 TI - A genetic variant in SLC6A20 is associated with Type 2 diabetes in white-European and Chinese populations. AB - AIMS: To investigate whether polymorphisms in SLC6A20 are associated with susceptibility to Type 2 diabetes. METHODS: In the Rotterdam Study, a prospective, population-based cohort (n = 5974), 22 tagging polymorphisms with minor allele frequencies>0.05 across SLC6A20 were studied. Replication studies were performed in an independent Dutch case-control study (DiaGene-Rotterdam Study 2 n = 3133), and in a Chinese Han case-control population (n = 2279). A meta-analysis of the results was performed. RESULTS: In the Rotterdam study, the minor alleles of rs13062383, rs10461016 and rs2286489 increased the risk of Type 2 diabetes (hazard ratio 1.37, 95% CI 1.15-1.63, hazard ratio 1.30 95% CI 1.09 1.54 and hazard ratio 1.20, 95% CI 1.07-1.35, respectively). In the DiaGene/Rotterdam Study 2, the A allele of rs13062383 increased the risk of Type 2 diabetes (odds ratio 1.45, 95% CI 1.19-1.76). In the Chinese Han study, the rs13062383 A allele also increased the risk of Type 2 diabetes (odds ratio 1.21, 95% CI 1.03-1.42). Meta-analysis showed a highly significant association of rs13062383 with Type 2 diabetes (odds ratio 1.35, 95% CI 1.21-1.47; P = 3.3 * 10 8). CONCLUSIONS: In conclusion, rs13062383 in SLC6A20 increased the susceptibility to Type 2 diabetes in populations with different genetic backgrounds. PMID- 24958072 TI - Delayed fatherhood. AB - Birth data from developed countries indicates that the average paternal age is increasing. As the trend to older fatherhood has become established, concerns have been raised that this may be linked to adverse outcomes, such as pregnancy complications, congenital anomalies, and long-term health implications for the child. Since the sperm of older fathers may be impaired due to the general effects of ageing, their offspring may be at risk due to defects in sperm quality at conception. A literature search was performed to identify pregnancy complications, fetal anomalies and health issues for the child when the father is in an older age bracket. Evidence for impairment in the sperm and genetic material of older fathers was reviewed. With an older father, there is evidence of an increase in stillbirths and a slightly increased risk of autism, bipolar disorder and schizophrenia in the offspring later in life. The increased risk of achondroplasia has long been recognised. For the mother, there is an increased rate of Caesarean section. Investigations of other possible adverse outcomes have produced mixed findings. Further robust and longitudinal studies are needed to clarify these issues. PMID- 24958071 TI - Evolutionary optimality in sex differences of longevity and athletic performances. AB - Many sexual differences are known in human and animals. It is well known that females are superior in longevity, while males in athletic performances. Even though some sexual differences are attributed to the evolutionary tradeoff between survival and reproduction, the aforementioned sex differences are difficult to explain by this tradeoff. Here we show that the evolutionary tradeoff occurs among three components: (1) viability, (2) competitive ability and (3) reproductive effort. The sexual differences in longevity and athletic performances are attributed to the tradeoff between viability (survival) and competitive ability that belongs to the physical makeup of an individual, but not related to the tradeoff between survival and reproduction. This provides a new perspective on sex differences in human and animals: females are superior in longevity and disease recovery, while males are superior in athletic performance. PMID- 24958073 TI - Effects of the lapidus arthrodesis and chevron bunionectomy on plantar forefoot pressures. AB - Hallux valgus with or without first ray insufficiency has been strongly implicated as a contributing factor in lesser metatarsal overload. The principle goals of a bunionectomy are to relieve the pain, correct the deformity, and restore first metatarsophalangeal joint congruity. Until now, little evidence has been available to assess the effects of bunionectomy procedures on forefoot pressure. The primary aim of the present prospective study was to evaluate the preoperative and postoperative plantar pressures after 2 specific bunionectomies: the chevron bunionectomy and Lapidus arthrodesis. A total of 68 subjects, 34 in each group, were included for radiographic and pedographic evaluation. Both procedures demonstrated radiographic improvements in the mean intermetatarsal and hallux abductus angles. The mean hallux plantar pressure decreased significantly in both procedure groups (p < .001). However, Lapidus group exhibited an increase in the mean fifth metatarsal head plantar pressure (p = .008) and pressure under the fifth metatarsal as a percentage of the total forefoot pressure (p = .01). Furthermore, the pressure under the second metatarsal as a percentage of the total forefoot pressure decreased significantly (p = .01). This study suggests that the Lapidus arthrodesis and chevron bunionectomy both provide correction for hallux valgus deformity, but when comparing forefoot load sharing pressures, the Lapidus arthrodesis appeared to have greater influence on the load sharing distribution of forefoot pressure than did the bunionectomy employing the chevron osteotomy. PMID- 24958074 TI - Computational electrochemistry: prediction of liquid-phase reduction potentials. AB - This article reviews recent developments and applications in the area of computational electrochemistry. Our focus is on predicting the reduction potentials of electron transfer and other electrochemical reactions and half reactions in both aqueous and nonaqueous solutions. Topics covered include various computational protocols that combine quantum mechanical electronic structure methods (such as density functional theory) with implicit-solvent models, explicit-solvent protocols that employ Monte Carlo or molecular dynamics simulations (for example, Car-Parrinello molecular dynamics using the grand canonical ensemble formalism), and the Marcus theory of electronic charge transfer. We also review computational approaches based on empirical relationships between molecular and electronic structure and electron transfer reactivity. The scope of the implicit-solvent protocols is emphasized, and the present status of the theory and future directions are outlined. PMID- 24958075 TI - Vaccine-preventable diseases in Europe: where do we stand? AB - During the second half of the 20th century, vaccinations led to the control or even eradication of several vaccine-preventable diseases (VPDs) in Europe. However, outbreaks of VPDs continue to occur even in countries with well established vaccination programs. Reasons include the existence of under vaccinated populations, the increasing anti-vaccination movement and the increasing movement of populations across borders. Ensuring adequate levels of herd immunity is the only reliable method for preventing epidemics and a re emergence of VPDs. In order to achieve this, more flexible vaccine delivery platforms are needed targeting the less-privileged people, especially in the context of the current economic crisis. Healthcare personnel and healthcare systems should be prepared to address these challenges in the following years. PMID- 24958076 TI - Acute coronary syndromes: Treatment for low-risk patients with STEMI--challenges remain. PMID- 24958079 TI - Prevention: Smoke-free legislation and acute MI. PMID- 24958077 TI - The pathophysiology of heart failure with preserved ejection fraction. AB - Approximately half of all patients with heart failure have preserved ejection fraction (HFpEF) and, as life expectancies continue to increase in western societies, the prevalence of HFpEF will continue to grow. In contrast to heart failure with reduced ejection fraction (HFrEF), no treatment has been proven in pivotal clinical trials to be effective for HFpEF, largely because of the pathophysiological heterogeneity that exists within the broad spectrum of HFpEF. This syndrome was historically considered to be caused exclusively by left ventricular diastolic dysfunction, but research has identified several other contributory factors, including limitations in left ventricular systolic reserve, systemic and pulmonary vascular function, nitric oxide bioavailability, chronotropic reserve, right heart function, autonomic tone, left atrial function, and peripheral impairments. Multiple individual mechanisms frequently coexist within the same patient to cause symptomatic heart failure, but between patients with HFpEF the extent to which each component is operative can differ widely, confounding treatment approaches. This Review focuses on our current understanding of the pathophysiological mechanisms underlying HFpEF, and how they might be mechanistically related to typical risk factors for HFpEF, including ageing, obesity, and hypertension. PMID- 24958078 TI - Lipid lowering with PCSK9 inhibitors. AB - Statins are the most-effective therapy currently available for lowering the LDL cholesterol (LDL-C) level and preventing cardiovascular events. Additional therapies are necessary for patients who cannot reach the target LDL-C level when taking the maximum-tolerated dose of a statin. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme with an important role in lipoprotein metabolism. Rare gain-of-function mutations in PCSK9 lead to a high LDL-C level and premature coronary heart disease, whereas loss-of-function variants lead to a low LDL-C level and a reduced incidence of coronary heart disease. Furthermore, the PCSK9 level is increased with statin therapy through negative feedback, which promotes LDL-receptor degradation and decreases the efficacy of LDL-C lowering with statins. PCSK9 inhibition is, therefore, a rational therapeutic target, and several approaches are being pursued. In phase I, II, and III trials, inhibition of PCSK9 with monoclonal antibodies has produced an additional 50-60% decrease in the LDL-C level when used in combination with statin therapy, compared with statin monotherapy. In short-term trials, PCSK9 inhibitors were well tolerated and had a low incidence of adverse effects. Ongoing phase III trials will provide information about the long-term safety of these drugs, and their efficacy in preventing cardiovascular events. PMID- 24958081 TI - Prevention: Aspirin in primary prevention needs individual judgements. PMID- 24958083 TI - Dual acquisition of (18)F-FMISO and (18)F-FDOPA. AB - Metabolic imaging using positron emission tomography (PET) has found increasing clinical use for the management of infiltrating tumours such as glioma. However, the heterogeneous biological nature of tumours and intrinsic treatment resistance in some regions means that knowledge of multiple biological factors is needed for effective treatment planning. For example, the use of (18)F-FDOPA to identify infiltrative tumour and (18)F-FMISO for localizing hypoxic regions. Performing multiple PET acquisitions is impractical in many clinical settings, but previous studies suggest multiplexed PET imaging could be viable. The fidelity of the two signals is affected by the injection interval, scan timing and injected dose. The contribution of this work is to propose a framework to explicitly trade-off signal fidelity with logistical constraints when designing the imaging protocol. The particular case of estimating (18)F-FMISO from a single frame prior to injection of (18)F-FDOPA is considered. Theoretical experiments using simulations for typical biological scenarios in humans demonstrate that results comparable to a pair of single-tracer acquisitions can be obtained provided protocol timings are carefully selected. These results were validated using a pre-clinical data set that was synthetically multiplexed. The results indicate that the dual acquisition of (18)F-FMISO and (18)F-FDOPA could be feasible in the clinical setting. The proposed framework could also be used to design protocols for other tracers. PMID- 24958084 TI - Assembly and photocatalysis of two novel 3D Anderson-type polyoxometalate-based metal-organic frameworks constructed from isomeric bis(pyridylformyl)piperazine ligands. AB - Two novel Anderson-type polyoxometalates (POMs)-based metal-organic frameworks (MOFs), namely, H{Cu2(MU2-OH)2L(1)[CrMo6(OH)6O18]}.4H2O (), {Cu2L(2)[CrMo(VI)5Mo(V)(OH)6O18](H2O)4}.4H2O () (L(1) = N,N'-bis(3 pyridinecarboxamide)-piperazine, L(2) = N,N'-bis(4-pyridinecarboxamide) piperazine), are hydrothermally synthesized and structurally characterized by single-crystal X-ray diffraction, IR spectra, powder X-ray diffraction (PXRD) and thermogravimetric analyses (TGA). In complex , the hexadentate [CrMo6(OH)6O18](3 ) polyoxoanion bridges the Cu(II) ions to generate a 2D Cu-POM inorganic layer, which is further extended by the MU2-bridging L(1) ligands (via ligation of pyridyl nitrogen atoms) to form a 3D MOF with a 4,6-connected {4(4).6(10).8}{4(4).6(2)} topology. Complex is also a 3D POM-based MOF exhibiting a {4(2).8(4)} topology, which is constructed from the quadridentate [CrMo(VI)5Mo(V)(OH)6O18](4-) polyoxoanions and MU4-bridging L(2) ligands (via ligation of pyridyl nitrogen and carbonyl oxygen atoms). The different coordination modes of POM polyanions and the isomeric bis(pyridylformyl)piperazine ligands play key roles in the construction of the title complexes. In addition, the photocatalytic activities of the title complexes on the degradation of methylene blue (MB) under UV, visible light and sunlight irradiation have been investigated in detail. PMID- 24958080 TI - Cardiac sodium channel mutations: why so many phenotypes? AB - Mutations of the cardiac sodium channel (Nav1.5) can induce gain or loss of channel function. Gain-of-function mutations can cause long QT syndrome type 3 and possibly atrial fibrillation, whereas loss-of-function mutations are associated with a variety of phenotypes, such as Brugada syndrome, cardiac conduction disease, sick sinus syndrome, and possibly dilated cardiomyopathy. The phenotypes produced by Nav1.5 mutations vary according to the direct effect of the mutation on channel biophysics, but also with age, sex, body temperature, and between regions of the heart. This phenotypic variability makes genotype phenotype correlations difficult. In this Perspectives article, we propose that phenotypic variability not ascribed to mutation-dependent changes in channel function might be the result of additional modifiers of channel behaviour, such as other genetic variation and alterations in transcription, RNA processing, translation, post-translational modifications, and protein degradation. Consideration of these modifiers might help to improve genotype-phenotype correlations and lead to new therapeutic strategies. PMID- 24958085 TI - Directing valvular interstitial cell myofibroblast-like differentiation in a hybrid hydrogel platform. AB - Three dimensional (3D) hydrogel platforms are powerful tools, providing controllable, physiologically relevant microenvironments that could aid in understanding how various environmental factors direct valvular interstitial cell (VIC) phenotype. Continuous activation of VICs and their transformation from quiescent fibroblast to activated myofibroblast phenotype is considered to be an initiating event in the onset of valve disease. However, the relative contribution VIC phenotypes is poorly understood since most 2D culture systems lead to spontaneous VIC myofibroblastic activation. Here, a hydrogel platform composed of photocrosslinkable versions of native valvular extracellular matrix components-methacrylated hyaluronic acid (HAMA) and methacrylated gelatin (GelMA) is proposed as a 3D culture system to study VIC phenotypic changes. These results show that VIC myofibroblast-like differentiation occurs spontaneously in mechanically soft GelMA hydrogels. Conversely, differentiation of VICs encapsulated in HAMA-GelMA hybrid hydrogels, does not occur spontaneously and requires exogenous delivery of TGFbeta1, indicating that hybrid hydrogels can be used to study cytokine-dependent transition of VICs. This study demonstrates that a hybrid hydrogel platform can be used to maintain a quiescent VIC phenotype and study the effect of environmental cues on VIC activation, which will aid in understanding pathobiology of valvular disease. PMID- 24958086 TI - A case control study of environmental and occupational exposures associated with methicillin resistant Staphylococcus aureus nasal carriage in patients admitted to a rural tertiary care hospital in a high density swine region. AB - BACKGROUND: Distinct strains of methicillin resistant Staphylococcus aureus (MRSA) have been identified on livestock and livestock workers. Industrial food animal production may be an important environmental reservoir for human carriage of these pathogenic bacteria. The objective of this study was to investigate environmental and occupational exposures associated with nasal carriage of MRSA in patients hospitalized at Vidant Medical Center, a tertiary hospital serving a region with intensive livestock production in eastern North Carolina. METHODS: MRSA nasal carriage was identified via nasal swabs collected within 24 hours of hospital admission. MRSA carriers (cases) were gender and age matched to non carriers (controls). Participants were interviewed about recent environmental and occupational exposures. Home addresses were geocoded and publicly available data were used to estimate the density of swine in residential census block groups of residence. Conditional logistic regression models were used to derive odds ratio (OR) estimates and 95% confidence intervals (CI). Presence of the scn gene in MRSA isolates was assessed. In addition, multi locus sequence typing (MLST) of the MRSA isolates was performed, and the Diversilab(r) system was used to match the isolates to USA pulsed field gel electrophoresis types. RESULTS: From July - December 2011, 117 cases and 119 controls were enrolled. A higher proportion of controls than cases were current workforce members (41.2% vs. 31.6%) Cases had a higher odds of living in census block groups with medium densities of swine (OR: 4.76, 95% CI: 1.36-16.69) and of reporting the ability to smell odor from a farm with animals when they were home (OR: 1.51, 95% CI: 0.80-2.86). Of 49 culture positive MRSA isolates, all were scn positive. Twenty-two isolates belonged to clonal complex 5. CONCLUSIONS: Absence of livestock workers in this study precluded evaluation of occupational exposures. Higher odds of MRSA in medium swine density areas could reflect environmental exposure to swine or poultry. PMID- 24958087 TI - Rapid neural discrimination of communicative gestures. AB - Humans are biased toward social interaction. Behaviorally, this bias is evident in the rapid effects that self-relevant communicative signals have on attention and perceptual systems. The processing of communicative cues recruits a wide network of brain regions, including mentalizing systems. Relatively less work, however, has examined the timing of the processing of self-relevant communicative cues. In the present study, we used multivariate pattern analysis (decoding) approach to the analysis of magnetoencephalography (MEG) to study the processing dynamics of social-communicative actions. Twenty-four participants viewed images of a woman performing actions that varied on a continuum of communicative factors including self-relevance (to the participant) and emotional valence, while their brain activity was recorded using MEG. Controlling for low-level visual factors, we found early discrimination of emotional valence (70 ms) and self-relevant communicative signals (100 ms). These data offer neural support for the robust and rapid effects of self-relevant communicative cues on behavior. PMID- 24958089 TI - Lung disease in indigenous children. AB - Children in indigenous populations have substantially higher respiratory morbidity than non-indigenous children. Indigenous children have more frequent respiratory infections that are, more severe and, associated with long-term sequelae. Post-infectious sequelae such as chronic suppurative lung disease and bronchiectasis are especially prevalent among indigenous groups and have lifelong impact on lung function. Also, although estimates of asthma prevalence among indigenous children are similar to non-indigenous groups the morbidity of asthma is higher in indigenous children. To reduce the morbidity of respiratory illness, best-practice medicine is essential in addition to improving socio-economic factors, (eg household crowding), tobacco smoke exposure, and access to health care and illness prevention programs that likely contribute to these issues. Although each indigenous group may have unique health beliefs and interfaces with modern health care, a culturally sensitive and community-based comprehensive care system of preventive and long term care can improve outcomes for all these conditions. This article focuses on common respiratory conditions encountered by indigenous children living in affluent countries where data is available. PMID- 24958088 TI - Using siRNA to define functional interactions between melanopsin and multiple G Protein partners. AB - Melanopsin expressing photosensitive retinal ganglion cells (pRGCs) represent a third class of ocular photoreceptors and mediate a range of non-image forming responses to light. Melanopsin is a G protein coupled receptor (GPCR) and existing data suggest that it employs a membrane bound signalling cascade involving Gnaq/11 type G proteins. However, to date the precise identity of the Galpha subunits involved in melanopsin phototransduction remains poorly defined. Here we show that Gnaq, Gna11 and Gna14 are highly co-expressed in pRGCs of the mouse retina. Furthermore, using RNAi based gene silencing we show that melanopsin can signal via Gnaq, Gna11 or Gna14 in vitro, and demonstrate that multiple members of the Gnaq/11 subfamily, including Gna14 and at least Gnaq or Gna11, can participate in melanopsin phototransduction in vivo and contribute to the pupillary light responses of mice lacking rod and cone photoreceptors. This diversity of G protein interactions suggests additional complexity in the melanopsin phototransduction cascade and may provide a basis for generating the diversity of light responses observed from pRGC subtypes. PMID- 24958091 TI - The pan-cancer analysis of gene expression patterns in the context of inflammation. AB - Although several studies have investigated the essential roles of inflammation in tumor progression, not many have systematically analyzed gene expression patterns across diverse cancers in the context of inflammation. In this study, in order to better understand the inflammatory scenario, we initially constructed the inflammatory timeline (IT) based on two gene expression profiles during inflammatory progression (inflammatory bowel disease and Helicobacter pylori infection). Then, we separately identified the differentially expressed genes (DEGs) from 25 cancer-related microarray data. By comparing the distributions of DEGs in the IT, we identified three novel pan-cancer gene expression patterns. In the first pattern, the up-regulated genes in cancers were over-expressed in the early phase of inflammation, while the down-regulated genes were over-expressed in the late phase of inflammation. The second pattern was the opposite of the first one. The third pattern appeared to be transitional between the first and second patterns. We found that some cancers with different tissue origins have similar gene expression patterns. Finally, we identified two sets of tissue independent inflammatory signatures that were over-expressed in early and late phases of inflammation, respectively. The dominant biological processes of early inflammatory signatures were cell proliferation, DNA replication, and DNA repair, whereas the late inflammatory signatures were reflective of innate immune response, neutrophil migration, and antigen processing. These inflammatory signatures may be useful to predict gene expression patterns in human cancers. Therefore, the pan-cancer analysis of gene expression patterns in the context of inflammation provides a novel insight into cancers and an unprecedented opportunity to develop new therapies. PMID- 24958090 TI - Predictive value of "Marsh 1" type histology in subjects with suspected cealic disease. AB - INTRODUCTION: The diagnosis of celiac disease (CD) is based on histology in combination with anti-tissue transglutaminase (a-tTG) and anti-endomysial antibodies (EMAs). The increase of intraepithelial lymphocytes defines the Marsh 1 histology that appears not to be specific for CD. AIM: To explore the positive predictive value (PPV) and clinical relevance of Marsh 1 histology in suspected CD. METHODS: We carried out an observational prospective study including all consecutive subjects with a Marsh 1 histology. All patients were tested for a-tTG and EMAs. Diagnosis of potential CD was defined in the presence of Marsh 1 with positive a-tTG and EMAs. Patients were investigated for symptoms, CD familial aggregation, other diseases, and current medication. RESULTS: Sixty-three patients with Marsh 1 were included. Diagnosis of potential CD was made in 23 subjects (36%), so that Marsh 1 histology showed a PPV of 36%. With regard to familial aggregation, patients with potential CD showed a higher frequency of familiarity for CD (60.8% vs. 15.0%; p < 0.01). No significant difference was detected between CD and non-CD in terms of intestinal and extra-intestinal symptoms. We also documented the presence of conditions other than CD in the remaining population: 7 patients (17.5%) with immuno-mediated diseases while 5 patients (12.5%) showed Helicobacter pylori (HP) infection. About medication, 3 patients (7.5%) were on non-steroidal anti-inflammatory drugs, while another 4 (10%) patients were being treated with other drugs. CONCLUSION: The Marsh 1 type histology is not specific for CD and it can also be associated with immuno mediated disorders, HP infection, and drugs. PMID- 24958092 TI - The outcome of cryoablation in treating advanced pancreatic cancer: a comparison with palliative bypass surgery alone. AB - OBJECTIVE: This study aimed to investigate the efficacy and safety of palliative bypass surgery combined with cryoablation in treating patients with advanced pancreatic cancer and compare this combination therapy with palliative bypass surgery alone. METHODS: Medical records of 118 patients with advanced pancreatic cancer who received palliative bypass surgery combined with cryoablation (the combination treatment group) or bypass surgery alone (the bypass surgery alone group) at the Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital (Tianjin, China) were retrospectively reviewed. Their baseline and peri-operative parameters were collected and compared. RESULTS: In both groups abdominal distension and pain was significantly ameliorated after treatment. Preoperative jaundice was more common in the bypass surgery group while backache was more frequent in the combination treatment group, which were both relieved by treatment. The pre-operative serum bilirubin level was higher in the bypass surgery group and was decreased significantly after treatment. However, a significant reduction in tumor size and serum carbohydrate antigen 19 9 level was found only in the combination treatment group. There was no significant difference in the incidence of postoperative complications and prognosis between the two groups. CONCLUSIONS: Cryoablation can reduce tumor size and relieve the patients' symptoms and signs such as abdominal discomfort and backache, although it could not improve the patients' prognosis significantly. It is a safe and efficient modality when combined with bypass surgery for patients with advanced pancreatic cancer. PMID- 24958093 TI - Timely care for frail older people: the next battleground. PMID- 24958094 TI - Calculating cognitive decline in delirium. PMID- 24958095 TI - Retrospective study of carmustine or lomustine with bevacizumab in recurrent glioblastoma patients who have failed prior bevacizumab. AB - BACKGROUND: Currently, there are no known effective treatments for recurrent glioblastoma once patients have progressed on a bevacizumab-containing regimen. We examined the efficacy of adding nitrosoureas to bevacizumab in patients who progressed while on an initial bevacizumab-containing regimen. METHODS: In this retrospective study, we identified adult patients with histologically confirmed glioblastoma (WHO grade IV) who were treated with lomustine or carmustine in combination with bevacizumab as a second or third regimen after failing an alternative initial bevacizumab-containing regimen. Response rate (RR), 6-month progression free survival (PFS6), and progression-free survival (PFS) were assessed for each treatment. RESULTS: Forty-two patients were identified (28 males) with a median age of 49 years (range, 24-78 y). Of 42 patients, 28 received lomustine (n = 22) or carmustine (n = 6) with bevacizumab as their second bevacizumab-containing regimen, and 14 received lomustine (n = 11) or carmustine (n = 3) as their third bevacizumab-containing regimen. While the median PFS for the initial bevacizumab-containing regimen was 16.3 weeks, the median PFS for the nitrosourea-containing bevacizumab regimen was 6.3 weeks. Patients had an RR of 44% and a PFS6 rate of 26% during the initial bevacizumab regimen and an RR of 0% and a PFS6 rate of 3% during the nitrosourea-containing bevacizumab regimen. There was increased grade 3-4 toxicity (45% vs 19%, P = .010) during the nitrosourea-containing bevacizumab regimen relative to the initial bevacizumab regimen. Median overall survival was 18.7 weeks from initiation of the nitrosourea-containing bevacizumab regimen. CONCLUSION: The addition of lomustine or carmustine to bevacizumab after a patient has already progressed on a bevacizumab-containing regimen does not appear to provide benefit for most patients and is associated with additional toxicity with the doses used in this cohort. PMID- 24958097 TI - The vanishing role of whole brain radiotherapy for primary central nervous system lymphoma. PMID- 24958098 TI - Sex differences in oxidative stress biomarkers. AB - Although an increased oxidative stress has been associated with several pathologies, predictive value of circulating oxidative stress biomarkers remains poorly understood. It has been demonstrated that several pathologies underestimated in women, including cardiovascular diseases, develop differently by gender. In this study, conducted on 195 healthy volunteers, we assessed the putative gender difference in prooxidant and antioxidant status. Our results were successful in demonstrating a significant difference in oxidative stress between sexes, whereas no difference was found in the plasma antioxidant barrier efficiency. To assess whether this difference was due to hormonal status (i.e. estrogen levels), female samples were divided into pre-menopausal and post menopausal groups. No significant difference emerged for both biomarkers. Despite the well-known antioxidant estrogen role, women in this study presented a higher oxidative status than males. This suggests that there is a difference in the production and metabolic deactivation of reactive oxygen metabolite. PMID- 24958096 TI - Malignant clinical features of anaplastic gliomas without IDH mutation. AB - BACKGROUND: Diagnosis of WHO grade III anaplastic gliomas does not always correspond to its clinical outcome because of the isocitrate dehydrogenase (IDH) gene status. Anaplastic gliomas without IDH mutation result in a poor prognosis, similar to grade IV glioblastomas. However, the malignant features of anaplastic gliomas without IDH mutation are not well understood. The aim of this study was to examine anaplastic gliomas, in particular those without IDH mutation, with regard to their malignant features, recurrence patterns, and association with glioma stem cells. METHODS: We retrospectively analyzed 86 cases of WHO grade III anaplastic gliomas. Data regarding patient characteristics, recurrence pattern, and prognosis were obtained from medical records. We examined molecular alterations such as IDH mutation, 1p19q loss, TP53 mutation, MGMT promoter methylation, Ki67 labeling index, and CD133, SOX2, and NESTIN expression. RESULTS: Of the 86 patients with anaplastic gliomas, 58 carried IDH mutation, and 40 experienced recurrence. The first recurrence was local in 25 patients and distant in 15. Patients without IDH mutation exhibited significantly higher CD133 and SOX2 expression (P = .025 and .020, respectively) and more frequent distant recurrence than those with IDH mutation (P = .022). CONCLUSIONS: Patients with anaplastic gliomas without IDH mutation experienced distant recurrence and exhibited glioma stem cell markers, indicating that this subset may share some malignant characteristics with glioblastomas. PMID- 24958099 TI - Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance. AB - Mice lacking the transcription factor NF-E2 p45-related factor 2 (Nrf2) develop more severe nonalcoholic steatohepatitis (NASH), with cirrhosis, than wild-type (Nrf2(+/+)) mice when fed a high-fat (HF) diet for 24 weeks. Although NASH is usually associated with insulin resistance, HF-fed Nrf2(-/-) mice exhibited better insulin sensitivity than HF-fed Nrf2(+/+) mice. In livers of HF-fed mice, loss of Nrf2 resulted in greater induction of lipogenic genes, lower expression of beta-oxidation genes, greater reduction in AMP-activated protein kinase (AMPK) levels, and diminished acetyl coenzyme A (CoA) carboxylase phosphorylation than in the wild-type livers, which is consistent with greater fatty acid (FA) synthesis in Nrf2(-/-) livers. Moreover, primary Nrf2(-/-) hepatocytes displayed lower glucose and FA oxidation than Nrf2(+/+) hepatocytes, with FA oxidation partially rescued by treatment with AMPK activators. The unfolded protein response (UPR) was perturbed in control regular-chow (RC)-fed Nrf2(-/-) mouse livers, and this was associated with constitutive activation of NF-kappaB and JNK, along with upregulation of inflammatory genes. The HF diet elicited an antioxidant response in Nrf2(+/+) livers, and as this was compromised in Nrf2(-/ ) livers, they suffered oxidative stress. Therefore, Nrf2 protects against NASH by suppressing lipogenesis, supporting mitochondrial function, increasing the threshold for the UPR and inflammation, and enabling adaptation to HF-diet induced oxidative stress. PMID- 24958100 TI - Yeast Dun1 kinase regulates ribonucleotide reductase inhibitor Sml1 in response to iron deficiency. AB - Iron is an essential micronutrient for all eukaryotic organisms because it participates as a redox-active cofactor in many biological processes, including DNA replication and repair. Eukaryotic ribonucleotide reductases (RNRs) are Fe dependent enzymes that catalyze deoxyribonucleoside diphosphate (dNDP) synthesis. We show here that the levels of the Sml1 protein, a yeast RNR large-subunit inhibitor, specifically decrease in response to both nutritional and genetic Fe deficiencies in a Dun1-dependent but Mec1/Rad53- and Aft1-independent manner. The decline of Sml1 protein levels upon Fe starvation depends on Dun1 forkhead associated and kinase domains, the 26S proteasome, and the vacuolar proteolytic pathway. Depletion of core components of the mitochondrial iron-sulfur cluster assembly leads to a Dun1-dependent diminution of Sml1 protein levels. The physiological relevance of Sml1 downregulation by Dun1 under low-Fe conditions is highlighted by the synthetic growth defect observed between dun1Delta and fet3Delta fet4Delta mutants, which is rescued by SML1 deletion. Consistent with an increase in RNR function, Rnr1 protein levels are upregulated upon Fe deficiency. Finally, dun1Delta mutants display defects in deoxyribonucleoside triphosphate (dNTP) biosynthesis under low-Fe conditions. Taken together, these results reveal that the Dun1 checkpoint kinase promotes RNR function in response to Fe starvation by stimulating Sml1 protein degradation. PMID- 24958101 TI - Chromosome instability underlies hematopoietic stem cell dysfunction and lymphoid neoplasia associated with impaired Fbw7-mediated cyclin E regulation. AB - The Fbw7 ubiquitin ligase critically regulates hematopoietic stem cell (HSC) function, though the precise contribution of individual substrate ubiquitination pathways to HSC homeostasis is unknown. In the work reported here, we used a mouse model in which we introduced two knock-in mutations (T74A and T393A [changes of T to A at positions 74 and 393]) to disrupt Fbw7-dependent regulation of cyclin E, its prototypic substrate, and to examine the consequences of cyclin E dysregulation for HSC function. Serial transplantation revealed that cyclin E(T74A T393A) HSCs self-renewed normally; however, we identified defects in their multilineage reconstituting capacity. By inducing hematologic stress, we exposed an impaired self-renewal phenotype in cyclin E knock-in HSCs that was associated with defective cell cycle exit and the emergence of chromosome instability (CIN). Importantly, p53 deletion induced both defects in self-renewal and multilineage reconstitution in cyclin E knock-in HSCs with serial transplantation and CIN in hematopoietic stem and progenitor cells. Moreover, CIN was a feature of fatal T cell malignancies that ultimately developed in recipients of cyclin E(T74A T393A); p53-null HSCs. Together, our findings demonstrate the importance of Fbw7 dependent cyclin E control to the hematopoietic system and highlight CIN as a characteristic feature of HSC dysfunction and malignancy induced by deregulated cyclin E. PMID- 24958102 TI - Long noncoding RNA MRUL promotes ABCB1 expression in multidrug-resistant gastric cancer cell sublines. AB - Multidrug resistance (MDR) is the most common cause of chemotherapy failure in gastric cancer (GC) treatment; however, the underlying molecular mechanisms remain elusive. Long noncoding RNAs (lncRNAs) can be involved in carcinogenesis, but the effects of lncRNAs on MDR are poorly understood. We show here that the lncRNA MRUL (MDR-related and upregulated lncRNA), located 400 kb downstream of ABCB1 (ATP-binding cassette, subfamily B, member 1), was significantly upregulated in two multidrug-resistant GC cell sublines, SGC7901/ADR and SGC7901/VCR. Furthermore, the relative expression levels of MRUL in GC tissues were negatively correlated with in vitro growth inhibition rates of GC specimens treated with chemotherapeutic drugs and indicated a poor prognosis for GC patients. MRUL knockdown in SGC7901/ADR and SGC7901/VCR cells led to increased rates of apoptosis, increased accumulation, and reduced doxorubicin (Adriamycin [ADR]) release in the presence of ADR or vincristine. Moreover, MRUL depletion reduced ABCB1 mRNA levels in a dose- and time-dependent manner. Heterologous luciferase reporter assays demonstrated that MRUL might positively affect ABCB1 expression in an orientation- and position-independent manner. Our findings indicate that MRUL promotes ABCB1 expression and is a potential target to reverse the MDR phenotype of GC MDR cell sublines. PMID- 24958103 TI - Novel functional complexity of polycystin-1 by GPS cleavage in vivo: role in polycystic kidney disease. AB - Polycystin-1 (Pc1) cleavage at the G protein-coupled receptor (GPCR) proteolytic site (GPS) is required for normal kidney morphology in humans and mice. We found a complex pattern of endogenous Pc1 forms by GPS cleavage. GPS cleavage generates not only the heterodimeric cleaved full-length Pc1 (Pc1(cFL)) in which the N terminal fragment (NTF) remains noncovalently associated with the C-terminal fragment (CTF) but also a novel (Pc1) form (Pc1(deN)) in which NTF becomes detached from CTF. Uncleaved Pc1 (Pc1(U)) resides primarily in the endoplasmic reticulum (ER), whereas both Pc1(cFL) and Pc1(deN) traffic through the secretory pathway in vivo. GPS cleavage is not a prerequisite, however, for Pc1 trafficking in vivo. Importantly, Pc1(deN) is predominantly found at the plasma membrane of renal epithelial cells. By functional genetic complementation with five Pkd1 mouse models, we discovered that CTF plays a crucial role in Pc1(deN) trafficking. Our studies support GPS cleavage as a critical regulatory mechanism of Pc1 biogenesis and trafficking for proper kidney development and homeostasis. PMID- 24958104 TI - Quantitative in vivo fluorescence cross-correlation analyses highlight the importance of competitive effects in the regulation of protein-protein interactions. AB - Computer-assisted simulation is a promising approach for clarifying complicated signaling networks. However, this approach is currently limited by a deficiency of kinetic parameters determined in living cells. To overcome this problem, we applied fluorescence cross-correlation spectrometry (FCCS) to measure dissociation constant (Kd) values of signaling molecule complexes in living cells (in vivo Kd). Among the pairs of fluorescent molecules tested, that of monomerized enhanced green fluorescent protein (mEGFP) and HaloTag tetramethylrhodamine was most suitable for the measurement of in vivo Kd by FCCS. Using this pair, we determined 22 in vivo Kd values of signaling molecule complexes comprising the epidermal growth factor receptor (EGFR)-Ras extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathway. With these parameters, we developed a kinetic simulation model of the EGFR-Ras-ERK MAP kinase pathway and uncovered a potential role played by stoichiometry in Shc binding to EGFR during the peak activations of Ras, MEK, and ERK. Intriguingly, most of the in vivo Kd values determined in this study were higher than the in vitro Kd values reported previously, suggesting the significance of competitive bindings inside cells. These in vivo Kd values will provide a sound basis for the quantitative understanding of signal transduction. PMID- 24958105 TI - GABP transcription factor (nuclear respiratory factor 2) is required for mitochondrial biogenesis. AB - Mitochondria are membrane-bound cytoplasmic organelles that serve as the major source of ATP production in eukaryotic cells. GABP (also known as nuclear respiratory factor 2) is a nuclear E26 transformation-specific transcription factor (ETS) that binds and activates mitochondrial genes that are required for electron transport and oxidative phosphorylation. We conditionally deleted Gabpa, the DNA-binding component of this transcription factor complex, from mouse embryonic fibroblasts (MEFs) to examine the role of Gabp in mitochondrial biogenesis, function, and gene expression. Gabpalpha loss modestly reduced mitochondrial mass, ATP production, oxygen consumption, and mitochondrial protein synthesis but did not alter mitochondrial morphology, membrane potential, apoptosis, or the expression of several genes that were previously reported to be GABP targets. However, the expression of Tfb1m, a methyltransferase that modifies ribosomal rRNA and is required for mitochondrial protein translation, was markedly reduced in Gabpalpha-null MEFs. We conclude that Gabp regulates Tfb1m expression and plays an essential, nonredundant role in mitochondrial biogenesis. PMID- 24958108 TI - MRC dementia research project will cover two million people. PMID- 24958107 TI - Controversies in family planning: pregnancy termination in women with uterine anatomic abnormalities. PMID- 24958106 TI - Cell activation-induced phosphoinositide 3-kinase alpha/beta dimerization regulates PTEN activity. AB - The phosphoinositide 3-kinase (PI3K)/PTEN (phosphatase and tensin homolog) pathway is one of the central routes that enhances cell survival, division, and migration, and it is frequently deregulated in cancer. PI3K catalyzes formation of phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P3] after cell activation; PTEN subsequently reduces these lipids to basal levels. Activation of the ubiquitous p110alpha isoform precedes that of p110beta at several points during the cell cycle. We studied the potential connections between p110alpha and p110beta activation, and we show that cell stimulation promotes p110alpha and p110beta association, demonstrating oligomerization of PI3K catalytic subunits within cells. Cell stimulation also promoted PTEN incorporation into this complex, which was necessary for PTEN activation. Our results show that PI3Ks dimerize in vivo and that PI3K and PTEN activities modulate each other in a complex that controls cell PI(3,4,5)P3 levels. PMID- 24958109 TI - Preface to the 2014 special focus issue of Bioanalysis on bioanalytical laboratory structure and management. PMID- 24958110 TI - Outsourcing strategy: local versus international contract research organizations. PMID- 24958111 TI - Bioanalysis zone: laboratory management column highlights. PMID- 24958113 TI - A seat at the table: the benefits of integrating bioanalytical sciences into development project teams. PMID- 24958114 TI - A high efficiency, high quality and low cost internal regulated bioanalytical laboratory to support drug development needs. AB - In the recent past, we have seen an increase in the outsourcing of bioanalysis in pharmaceutical companies in support of their drug development pipeline. This trend is largely driven by the effort to reduce internal cost, especially in support of late-stage pipeline assets where established bioanalytical assays are used to analyze a large volume of samples. This article will highlight our perspective of how bioanalytical laboratories within pharmaceutical companies can be developed into the best partner in the advancement of drug development pipelines with high-quality support at competitive cost. PMID- 24958115 TI - Integrating internal and external bioanalytical support to deliver a diversified pharmaceutical portfolio. AB - The portfolios of pharmaceutical companies have diversified substantially over recent years in recognition that monotherapies and/or small molecules are less suitable for modulating many complex disease etiologies. Furthermore, there has been increased pressure on drug-development budgets over this same period. This has placed new challenges in the path of bioanalytical scientists, both within the industry and with contract research organizations (CROs). Large pharmaceutical, biotechnology and small-medium healthcare enterprises have had to make important decisions on what internal capabilities they wish to retain and where CROs offers a significant strategic benefit to their business model. Our journey has involved asking where we believe an internal bioanalytical facility offers the greatest benefit to progressing drug candidates through the drug development cycle and where externalization can help free up internal resources, adding flexibility to our organization in order to deal with the inevitable peaks and troughs in workload. PMID- 24958116 TI - Bioanalytical outsourcing strategy at Janssen Research and Development. AB - The times when all bioanalytical work was supported in-house are long behind us. In the modern bioanalytical laboratory, workload is divided between in-house support and outsourcing to contract research organizations. This paper outlines the outsourcing strategy of the Janssen-regulated bioanalytical group. Keeping the knowledge of the assay and the compound internally is a cornerstone of this strategy and is a driver for balancing the workload between the internal laboratory and contract laboratories. The number of contract laboratories that are being used is limited and criteria for selecting laboratories are discussed. Special attention is paid to the experience with outsourcing clinical studies to China. PMID- 24958117 TI - A community of practice approach to bioanalysis delivery: the role of the Preclinical Bioanalysis and Toxicokinetics department at AstraZeneca. AB - Retaining regulated bioanalysis within AstraZeneca (AZ) is important for the effective delivery of nonclinical and clinical bioanalysis. The focus for the in house team is the delivery of high-throughput bioanalysis and toxicokinetics support for investigational toxicology; however, by retaining GLP compliance, AZ will have an in-house understanding of every candidate drug that is progressed into development by supporting the first rodent GLP study for each project. The majority of nonclinical bioanalysis and all of the clinical bioanalysis are delivered by two external partnership models. This article describes the key benefits of retaining GLP compliance, the partnership interactions, discusses the management of non-GLP support in a GLP environment and how, having practical experience of regulatory facing method development, validation and study execution adds value to the AZ portfolio delivery. PMID- 24958118 TI - How the bioanalytical scientist plays a key role in interdisciplinary project teams in the development of biotherapeutics - a reflection of the European Bioanalysis Forum. AB - The bioanalytical scientist plays a key role in the project team for the drug development of biotherapeutics from the discovery to the marketing phase. Information from the project team members is required for assay development and sample analysis during the discovery, preclinical and clinical phases of the project and input is needed from the bioanalytical scientist to help data interpretation. The European Bioanalysis Forum target team 20 discussed many of the gaps in information and communication between the bioanalytical scientist and project team members as a base for providing a perspective on the bioanalytical scientist's role and interactions within the project team. PMID- 24958119 TI - Global bioanalytical support. AB - With the globalization of drug development, there is an increasing need for global bioanalytical support. Bioanalysis provides pivotal data for toxicokinetic, pharmacokinetic, bioavailability and bioequivalence studies used for regional or global regulatory submission. There are many known complications in building a truly global bioanalytical operation, ranging from lack of global regulatory guidelines and global standard operating procedures to barriers in regional requirements on sample shipping, importation and exportation. The primary objective of this article is to discuss common experiences and challenges facing the biopharmaceutical industry when providing bioanalytical support in a global setting. The key components of global bioanalytical services include the supporting infrastructure, spanning project management, IT support of data management, best practices in bioanalytical method transfer and sample analysis, and comprehensive knowledge of the requirements of bioanalysis guidelines and differences in these guidelines. A case study will highlight best practices for successful management of a global project. PMID- 24958120 TI - The science of laboratory and project management in regulated bioanalysis. AB - Pharmaceutical drug development is a complex and lengthy process, requiring excellent project and laboratory management skills. Bioanalysis anchors drug safety and efficacy with systemic and site of action exposures. Development of scientific talent and a willingness to innovate or adopt new technology is essential. Taking unnecessary risks, however, should be avoided. Scientists must strategically assess all risks and find means to minimize or negate them. Laboratory Managers must keep abreast of ever-changing technology. Investments in instrumentation and laboratory design are critical catalysts to efficiency and safety. Matrix management requires regular communication between Project Managers and Laboratory Managers. When properly executed, it aligns the best resources at the right times for a successful outcome. Attention to detail is a critical aspect that separates excellent laboratories. Each assay is unique and requires attention in its development, validation and execution. Methods, training and facilities are the foundation of a bioanalytical laboratory. PMID- 24958121 TI - Quantification of ghrelin and des-acyl ghrelin in human plasma by using cubic selected reaction-monitoring LCMS. AB - BACKGROUND: Ghrelin is a peptide hormone generally measured in plasma by immunoassays. LCMS/MS was investigated as an alternative method in particular for the quantification of the two forms of the peptide with improved selectivity. MATERIALS & METHODS: A LCMS assay using a cubic-selected reaction-monitoring (LCSRM(3)/MS) mode was developed for the quantification of ghrelin and des-acyl ghrelin in human plasma. RESULTS: The LCSRM(3)/MS method was found to be linear from 50-75 to 2500 pg/ml for the ghrelins using a 0.5-ml plasma sample. The accuracies and precisions at LOQ for des-acyl ghrelin (50 pg/ml) and ghrelin (75 pg/ml) were found to be better than 91 and 2%, respectively. Blood and plasma stabilization was found to be essential for good assay performance. CONCLUSION: Compared to the LCSRM/MS method the addition of an additional MS step did significantly improve the selectivity and therefore the sensitivity. The LCSRM(3)/MS method could be successfully applied for the quantification of ghrelin and des-acyl ghrelin in human plasma samples. PMID- 24958122 TI - Stability studies of binding and functional anti-vaccine antibodies. AB - BACKGROUND: As most vaccines exert their protective capacity by eliciting pathogen-specific antibodies, antibody assays assessing immunogenicity of vaccines in development should be well characterized. Part of the validation of immunogenicity assays for vaccines is the study of stability of antibodies in serum. Materials & methods: Stability of antibodies in human serum was assessed by circumsporozoite-binding IgG ELISA designed for assessing the immunogenicity of a malaria vaccine under development, adenovirus neutralization assay, designed to assess neutralizing antibodies against adenovirus and commercially available test kits for hepatitis A and B. RESULTS: Stability studies indicated stability of serum-binding IgG antibodies and serum-neutralizing antibodies in: long-term storage below -65 degrees C and -20 degrees C; short-term storage; multiple freeze/thaw rounds; during shipment; and during heat inactivation. CONCLUSION: RESULTS have shown the stability of both binding and functional polyclonal antibodies in human serum under stable storage and common usage circumstances. PMID- 24958123 TI - Stability of anti-immunotherapeutic antibodies in frozen human serum samples. AB - BACKGROUND: To generate exhaustive data on the stability of human anti immunotherapeutic antibodies. MATERIALS & METHODS: Samples collected from over 100 different subjects at various timepoints were analyzed shortly after serum collection using specific ELISAs and re-analyzed after long-term storage or multiple cycles of freeze-thaw. The general acceptance criteria for incurred sample reanalysis for ligand-binding assays were applied, as well as alternative stricter acceptance criteria promoted by various white papers. RESULTS: Anti immunotherapeutic antibodies are stable in undiluted serum samples stored at -80 degrees C for at least 3.5 years and 3-12 freeze-thaw cycles. CONCLUSION: Samples were selected to cover the heterogeneity of the polyclonal human immune response, therefore this stability data can be extended to all anti-vaccine and anti-drug antibodies. PMID- 24958124 TI - EBF recommendation for stability testing of anti-drug antibodies; lessons learned from anti-vaccine antibody stability studies. AB - Long- and short-term stability testing of the analyte is one of the key parameters in bioanalytical method validation in support of pharmacokinetics. However, for immunogenicity testing, the scientific rationale for long- and short term stability testing on quality control samples most often spiked with polyclonal antibody raised in a different species should be questioned. Therefore, the European Bioanalysis Forum (EBF) formed a Topic Team to discuss the scientific rationale for stability testing of anti-drug antibodies (ADAs). A review of EBF member companies' experience on ADA stability and on anti-vaccine antibodies from vaccine projects was the basis of this discussion. EBF recommends to perform short-term stability testing of the positive control, but not to perform long-term stability testing of ADAs in nonclinical and clinical studies. PMID- 24958126 TI - Copper-catalyzed direct synthesis of diaryl 1,2-diketones from aryl iodides and propiolic acids. AB - Benzil derivatives such as diaryl 1,2-diketones are synthesized via the direct decarboxylative coupling reaction of aryl propiolic acids and their oxidation. The optimized conditions are that the reaction of aryl propiolic acids and aryl iodides is conducted at 140 degrees C for 6 h in the presence of 10 mol % CuI/Cu(OTf)2 and Cs2CO3, after which HI (aq) is added and further reacted. The method shows good functional group tolerance toward ester, aldehyde, cyano, and nitro groups. In addition, symmetrical diaryl 1,2-diketones are obtained from aryl iodides and propiolic acid in the presence of palladium and copper catalysts. PMID- 24958125 TI - Enzyme architecture: deconstruction of the enzyme-activating phosphodianion interactions of orotidine 5'-monophosphate decarboxylase. AB - The mechanism for activation of orotidine 5'-monophosphate decarboxylase (OMPDC) by interactions of side chains from Gln215 and Try217 at a gripper loop and R235, adjacent to this loop, with the phosphodianion of OMP was probed by determining the kinetic parameters k(cat) and K(m) for all combinations of single, double, and triple Q215A, Y217F, and R235A mutations. The 12 kcal/mol intrinsic binding energy of the phosphodianion is shown to be equal to the sum of the binding energies of the side chains of R235 (6 kcal/mol), Q215 (2 kcal/mol), Y217 (2 kcal/mol), and hydrogen bonds to the G234 and R235 backbone amides (2 kcal/mol). Analysis of a triple mutant cube shows small (ca. 1 kcal/mol) interactions between phosphodianion gripper side chains, which are consistent with steric crowding of the side chains around the phosphodianion at wild-type OMPDC. These mutations result in the same change in the activation barrier to the OMPDC catalyzed reactions of the whole substrate OMP and the substrate pieces (1-beta-D erythrofuranosyl)orotic acid (EO) and phosphite dianion. This shows that the transition states for these reactions are stabilized by similar interactions with the protein catalyst. The 12 kcal/mol intrinsic phosphodianion binding energy of OMP is divided between the 8 kcal/mol of binding energy, which is utilized to drive a thermodynamically unfavorable conformational change of the free enzyme, resulting in an increase in (k(cat))(obs) for OMPDC-catalyzed decarboxylation of OMP, and the 4 kcal/mol of binding energy, which is utilized to stabilize the Michaelis complex, resulting in a decrease in (K(m))(obs). PMID- 24958127 TI - Ghrelin augments the expressions and secretions of proinflammatory adipokines, VEGF120 and MCP-1, in differentiated 3T3-L1 adipocytes. AB - Ghrelin is a physiological-active peptide with growth hormone-releasing activity, orexigenic activity, etc. In addition, the recent study has also suggested that ghrelin possesses the pathophysiological abilities related with type 2 diabetes. However, the ghrelin-direct-effects implicated in type 2 diabetes on peripheral tissues have been still unclear, whereas its actions on the central nervous system (CNS) appear to induce the development of diabetes. Thus, to assess its peripheral effects correlated with diabetes, we investigated the regulatory mechanisms about adipokines, which play a central role in inducing peripheral insulin resistance, secreted from mature 3T3-L1 adipocytes stimulated with ghrelin in vitro . The stimulation with 50 nmol/L ghrelin for 24 h resulted in the significant 1.9-fold increase on vascular endothelial growth factor-120 (VEGF(120)) releases (p < 0.01) and the 1.7-fold on monocyte chemoattractant protein-1 (MCP-1) (p < 0.01) from 3T3-L1 adipocytes, respectively, while ghrelin failed to enhance tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL 1beta), IL-6, IL-10 and adiponectin secretions. In addition, Akt phosphorylation on Ser473 and c-Jun NH2 -terminal protein kinase (JNK) phosphorylation on Thr183/Tyr185 were markedly enhanced 1.4-fold (p < 0.01) and 1.6-fold (p < 0.01) in the ghrelin-stimulated adipocytes, respectively. Furthermore, the treatment with LY294002 (50 MUmol/L) and Wortmannin (10nmol/L), inhibitors of phosphatidylinositol 3-kinase (PI3K), significantly decreased the amplified VEGF(120) secretion by 29% (p < 0.01) and 28% (p < 0.01) relative to the cells stimulated by ghrelin alone, respectively, whereas these inhibitors had no effects on increased MCP-1 release. On the other hand, JNK inhibitor SP600125 (10 MUmol/L) clearly reduced the increased MCP-1, but not VEGF(120), release by 35% relative to the only ghrelin-stimulated cells (p < 0.01). In conclusion, ghrelin can enhance the secretions of proinflammatory adipokines, VEGF(120) and MCP-1, but fails to affect IL-10 and adiponectin which are considered to be anti inflammatory adipokines. Moreover, this augmented VEGF(120) release is invited through the activation of PI3K pathways and the MCP-1 is through JNK pathways. Consequently, our results strongly suggest that ghrelin can induce the development of diabetes via its direct-action in peripheral tissues as well as via in CNS. PMID- 24958128 TI - Development of industrial yeast strain with improved acid- and thermo-tolerance through evolution under continuous fermentation conditions followed by haploidization and mating. AB - Continuous fermentation using the industrial Saccharomyces cerevisiae diploid strain WW was carried out under acidic or high-temperature conditions to achieve acid- or thermo-tolerant mutants. Mutants isolated at pH 2.5 and 41 degrees C showed improved growth and fermentation ability under acidic and elevated temperature conditions. Haploid strains WW17A1 and WW17A4 obtained from the mutated diploid strain WW17A showed better growth and 4.5-6.5% higher ethanol yields at pH 2.7 than the original strains. Haploid strain WW12T4 obtained from mutated diploid strain WW12T showed 1.25-1.50 times and 2.8-4.7 times higher total cell number and cell viability, respectively, than the original strains at 42 degrees C. Strain AT, which had significantly improved acid- and thermo tolerance, was developed by mating strain WW17A1 with WW12T4. Batch fermentation at 41 degrees C and pH 3.5 showed that the ethanol concentration and yield achieved during fermentation by strain AT were 55.4 g/L and 72.5%, respectively, which were 10 g/L and 13.4% higher than that of the original strain WW. The present study demonstrates that continuous cultivation followed by haploidization and mating is a powerful approach for enhancing the tolerance of industrial strains. PMID- 24958129 TI - Creation of an ethanol-tolerant Saccharomyces cerevisiae strain by 266 nm laser radiation and repetitive cultivation. AB - Laser radiation is an efficient approach for rapid improvement of industrial microbial phenotypes. To improve ethanol tolerance in Saccharomyces cerevisiae strains, a 266 nm laser radiation with the use of repetitive cultivation was explored in this work. After irradiated by 266 nm laser radiation and repetitive cultivation, a genetically stable SM4 strain was obtained. The SM4 strain could grow on YPD plate with extra 15% (v/v) ethanol. Moreover, the ethanol production performance of SM4 strain was 29.25% more than that of the wild type strain when they were cultivated in 5% (v/v) ethanol fermentation medium for 72 h. The DNA mutation was the possible characters for the phenotype of SM4 strain. Overall, the 266 nm laser radiation and repetitive cultivation approach might be a novel and useful for breeding fermentation microorganisms. PMID- 24958130 TI - Electricity generating capacity and performance deterioration of a microbial fuel cell fed with beer brewery wastewater. AB - This study focused on using beer brewery wastewater (BBW) to evaluate membrane concentrate disposal and production of electricity in microbial fuel cells. In the membrane treatment of BBW, the membrane permeate concentration was 570 +/- 30 mg/L corresponding to a chemical oxygen demand (COD) removal efficiency of 75 +/- 5%, and the flux values changed between 160 and 40 L/m(2)-h for all membrane runs. For electricity production from membrane concentrate, the highest current density in the microbial fuel cell (MFC) was observed to be 1950 mA/m(2) according to electrode surface area with 36% COD removal efficiency and 2.48% CE with 60% BBW membrane concentrate. The morphologies of the cation exchange membrane and the MFC deterioration were studied using a scanning electron microscope (SEM), attenuated total reflection-Fourier transform infrared (ATR FTIR) spectroscopy, differential scanning calorimetry (DSC), and thermal gravimetric analysis (TGA). A decrease in the thermal stability of the sulfonate (-SO3H) groups was demonstrated and morphological changes were detected in the SEM analysis. PMID- 24958131 TI - Hemicellulase production by Aspergillus niger DSM 26641 in hydrothermal palm oil empty fruit bunch hydrolysate and transcriptome analysis. AB - Palm oil empty fruit bunches (EFB) is an abundant and cheap lignocellulose material in Southeast Asia. Its use as the sole medium for producing lignocellulose-hydrolyzing enzymes would increase its commercial value. A newly isolated Aspergillus niger DSM 26641 was investigated for its capability of producing hemicellulases in EFB hydrolysate obtained by treatment with pressurized hot water (1-20%, w/v) at 120-180 degrees C in a 1 L Parr reactor for 10-60 min. The optimal hydrolysate for the fungal growth and endoxylanase production was obtained when 10% (w/v) of empty fruit bunch was treated at 120 degrees C or 150 degrees C for 10 min, giving an endoxylanase activity of 24.5 mU ml(-1) on RBB-Xylan and a saccharification activity of 5 U ml(-1) on xylan (DNS assay). When the hydrolysates were produced at higher temperatures, longer treatment times or higher biomass contents, only less than 20% of the above maximal endoxylanase activity was detected, possibly due to the higher carbohydrate concentrations in the medium. Transcriptome analysis showed that 3 endoxylanases (expression levels 59-100%, the highest level was set as 100%), 2 beta-xylosidases (4%), 4 side chain-cleaving arabinofuranosidases (1-95%), 1 acetyl xylan esterase (9%) and 2 ferulic acid esterases (0.3-9%) were produced together. PMID- 24958132 TI - Self-pollination rate and floral-display size in Asclepias syriaca (Common Milkweed) with regard to floral-visitor taxa. AB - BACKGROUND: Animals fertilize thousands of angiosperm species whose floral display sizes can significantly influence pollinator behavior and plant reproductive success. Many studies have measured the interactions among pollinator behavior, floral-display size, and plant reproductive success, but few studies have been able to separate the effects of pollinator behavior and post pollination processes on angiosperm sexual reproduction. In this study, we utilized the highly self-incompatible pollinium-pollination system of Asclepias syriaca (Common Milkweed) to quantify how insect visitors influenced male reproductive success measured as pollen removal, female reproductive success measured as pollen deposition, and self-pollination rate. We also determined how floral-display size impacts both visitor behavior and self-pollination rate. RESULTS: Four insect taxonomic orders visited A. syriaca: Coleoptera, Diptera, Hymenoptera, and Lepidoptera. We focused on three groups of visitor taxa within two orders (Hymenoptera and Lepidoptera) with sample sizes large enough for quantitative analysis: Apis mellifera (Western Honey Bee), Bombus spp. (bumble bees) and lepidopterans (butterflies and moths). Qualitatively, lepidopterans had the highest pollinator importance values, but the large variability in the lepidopteran data precluded meaningful interpretation of much of their behavior. The introduced A. mellifera was the most effective and most important diurnal pollinator with regard to both pollen removal and pollen deposition. However, when considering the self-incompatibility of A. syriaca, A. mellifera was not the most important pollinator because of its high self-pollination rate as compared to Bombus spp. Additionally, the rate of self-pollination increased more rapidly with the number of flowers per inflorescence in A. mellifera than in the native Bombus spp. CONCLUSIONS: Apis mellifera's high rate of self-pollination may have significant negative effects on both male and female reproductive successes in A. syriaca, causing different selection on floral-display size than native pollinators. PMID- 24958133 TI - Child sexual abuse, attachment style, and depression: the role of the characteristics of abuse. AB - The aim of the current study was to examine the effects of secure, avoidant, and anxious attachment styles on depressive symptomatology in child sexual abuse (CSA) among young female adult victims. The role of attachment style was studied by considering possible interactive effects with the type of abuse, the relationship with the perpetrator, and the continuity of abuse. Participants were 168 female victims of CSA. Information about the abuse was obtained from a self reported questionnaire. Attachment style was assessed with the Attachment Style Measure (ASM), and the Beck Depression Inventory (BDI) was used to assess depressive symptomatology. Secure and anxious attachment styles were correlated with low and high depression scores respectively. The effects of attachment style were stronger in cases where the abuse consisted of oral sex/penetration, a non family member as perpetrator, and in isolated, compared with continued, abuse. These results confirm that characteristics of CSA (type of abuse, relationship with the perpetrator, and continuity of abuse) can affect the impact of attachment style on depressive symptomatology. PMID- 24958134 TI - Sex offender modus operandi stability and relationship with actuarial risk assessment. AB - Three studies conducted in Vermont yielded data on 82 sexual recidivists' index offenses (Time 1) and sexual reoffenses (Time 2) across 16 modus operandi (MO) characteristics. The current study examines the stability of these 16 characteristics between Time 1 and Time 2 offenses. Probabilities of Time 1-Time 2 characteristic combinations are reported, including when controlling for static risk as measured by the Static-99R and Vermont Assessment of Sex Offender Risk-2 (VASOR-2). Overall, considerable stability of offenders' MO was evident between Time 1 and Time 2 offenses. Victim characteristics and offense behaviors were the most stable MO characteristics, and degree of force used and victim injury were less stable and trended toward less forceful and less injurious reoffenses. Controlling for static risk had little impact on the patterns of MO stability. PMID- 24958135 TI - Intimate partner violence before and during pregnancy: related demographic and psychosocial factors and postpartum depressive symptoms among Mexican American women. AB - Although research examining intimate partner violence (IPV) has expanded in recent years, there has been relatively little examination of the related demographic and psychosocial factors, as well as mental health outcomes, for IPV before and during pregnancy, especially in a Mexican American population. The current study provides a snapshot of the occurrence of IPV in a community sample of low-income, perinatal Mexican American women (n = 320). Results indicated that 13.1% of the women reported IPV before pregnancy and 11.3% reported IPV during pregnancy. For both IPV before and during pregnancy, women born in the United States were more likely to report IPV than foreign-born women. For IPV before pregnancy, women who were not in a serious romantic relationship or reported a history of childhood trauma were also more likely to report IPV. For IPV during pregnancy, women who reported higher general stress and lower social support were also more likely to report IPV. Finally, the current study provided strong evidence that a history of IPV predicted elevated postpartum depressive symptoms, above and beyond the impact of prenatal depressive symptoms. This study brings greater awareness to a complex and harmful situation in an understudied population. Results are discussed in terms of the relation between demographic and psychosocial risk for IPV before and during pregnancy, acculturation, and postpartum depressive symptoms, as well as the implications for the development of future prevention and intervention programs. PMID- 24958136 TI - Impact of appropriate antimicrobial treatment on transition from ventilator associated tracheobronchitis to ventilator-associated pneumonia. AB - INTRODUCTION: Two small randomized controlled trials have suggested beneficial effects of antibiotic treatment in patients with ventilator-associated tracheobronchitis (VAT). The primary aim of this study is to determine the impact of appropriate antibiotic treatment on transition from VAT to ventilator associated pneumonia (VAP) in critically ill patients. The secondary objective was to determine the incidence of VAP in patients with VAT. METHODS: This was a prospective observational multicenter study. All patients with a first episode of VAT were eligible. Patients with tracheostomy at intensive care unit (ICU) admission, and those with VAP prior to VAT were excluded. VAT was defined using all the following criteria: fever > 38 degrees C with no other cause, purulent tracheal secretions, positive tracheal aspirate (>= 10(5) cfu/mL), and absence of new infiltrate on chest X ray. Only VAP episodes diagnosed during the 96 h following VAT, and caused by the same bacteria, were taken into account. Antibiotic treatment was at the discretion of attending physicians. Risk factors for transition from VAT to VAP were determined using univariate and multivariate analysis. All variables from univariate analysis with P values <0.1 were incorporated in the multivariate logistic regression analysis. RESULTS: One thousand seven hundred and ten patients were screened for this study. Eighty-six, and 123 patients were excluded for tracheostomy at ICU admission, and VAP prior to VAT; respectively. One hundred and twenty two (7.1%) patients were included. 17 (13.9%) patients developed a subsequent VAP. The most common microorganisms in VAT patients were Pseudomonas aeruginosa (30%), Staphylococcus aureus (18%), and Acinetobacter baumannii (10%). Seventy-four (60%) patients received antimicrobial treatment, including 58 (47.5%) patients who received appropriate antimicrobial treatment. Appropriate antibiotic treatment was the only factor independently associated with reduced risk for transition from VAT to VAP (OR [95% CI] 0.12[0.02-0.59], P = 0.009). The number of patients with VAT needed to treat to prevent one episode of VAP, or one episode of VAP related to P. aeruginosa was 5, and 34; respectively. CONCLUSIONS: Appropriate antibiotic treatment is independently associated with reduced risk for transition from VAT to VAP. PMID- 24958137 TI - The Critical Assessment of Small Molecule Identification (CASMI): Challenges and Solutions. AB - The Critical Assessment of Small Molecule Identification, or CASMI, contest was founded in 2012 to provide scientists with a common open dataset to evaluate their identification methods. In this article, the challenges and solutions for the inaugural CASMI 2012 are presented. The contest was split into four categories corresponding with tasks to determine molecular formula and molecular structure, each from two measurement types, liquid chromatography-high resolution mass spectrometry (LC-HRMS), where preference was given to high mass accuracy data, and gas chromatography-electron impact-mass spectrometry (GC-MS), i.e., unit accuracy data. These challenges were obtained from plant material, environmental samples and reference standards. It was surprisingly difficult to obtain data suitable for a contest, especially for GC-MS data where existing databases are very large. The level of difficulty of the challenges is thus quite varied. In this article, the challenges and the answers are discussed, and recommendations for challenge selection in subsequent CASMI contests are given. PMID- 24958138 TI - Metabolic profiling of plasma from benign and malignant pulmonary nodules patients using mass spectrometry-based metabolomics. AB - Solitary pulmonary nodule (SPN or coin lesion) is a mass in the lung and can be commonly found in chest X-rays or computerized tomography (CT) scans. However, despite the advancement of imaging technologies, it is still difficult to distinguish malignant cancer from benign SPNs. Here we investigated the metabolic profiling of patients with benign and malignant pulmonary nodules. A combination of gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) was used to profile the plasma metabolites in 17 patients with malignant SPNs, 15 patients with benign SPNs and 20 healthy controls. The metabolic profiles were assayed using OPLS-DA, and further analyzed to identify marker metabolites related to diseases. Both GC/MS- and LC/MS-derived models showed clear discriminations in metabolic profiles among three groups. It was found that 63 metabolites (12 from GC/MS, 51 from LC/MS) contributed to the differences. Of these, 48 metabolites showed same change trend in both malignant and benign SPNs as compared with healthy controls, indicating some common pathways including inflammation and oxidative injury shared by two diseases. In contrast, 14 metabolites constituted distinct profiles that differentiated malignant from benign SPNs, which might be a unique biochemical feature associated with lung cancer. Overall, our data suggested that integration of two highly sensitive and complementary metabolomics platforms could enable a comprehensive metabolic profiling and assist in discrimination malignant from benign SPNs. PMID- 24958140 TI - Evaluation of extraction protocols for simultaneous polar and non-polar yeast metabolite analysis using multivariate projection methods. AB - Metabolomic and lipidomic approaches aim to measure metabolites or lipids in the cell. Metabolite extraction is a key step in obtaining useful and reliable data for successful metabolite studies. Significant efforts have been made to identify the optimal extraction protocol for various platforms and biological systems, for both polar and non-polar metabolites. Here we report an approach utilizing chemoinformatics for systematic comparison of protocols to extract both from a single sample of the model yeast organism Saccharomyces cerevisiae. Three chloroform/methanol/water partitioning based extraction protocols found in literature were evaluated for their effectiveness at reproducibly extracting both polar and non-polar metabolites. Fatty acid methyl esters and methoxyamine/trimethylsilyl derivatized aqueous compounds were analyzed by gas chromatography mass spectrometry to evaluate non-polar or polar metabolite analysis. The comparative breadth and amount of recovered metabolites was evaluated using multivariate projection methods. This approach identified an optimal protocol consisting of 64 identified polar metabolites from 105 ion hits and 12 fatty acids recovered, and will potentially attenuate the error and variation associated with combining metabolite profiles from different samples for untargeted analysis with both polar and non-polar analytes. It also confirmed the value of using multivariate projection methods to compare established extraction protocols. PMID- 24958141 TI - Acylcarnitine profiles in acetaminophen toxicity in the mouse: comparison to toxicity, metabolism and hepatocyte regeneration. AB - High doses of acetaminophen (APAP) result in hepatotoxicity that involves metabolic activation of the parent compound, covalent binding of the reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI) to liver proteins, and depletion of hepatic glutathione. Impaired fatty acid beta-oxidation has been implicated in previous studies of APAP-induced hepatotoxicity. To better understand relationships between toxicity and fatty acid beta-oxidation in the liver in APAP toxicity, metabolomic assays for long chain acylcarnitines were examined in relationship to established markers of liver toxicity, oxidative metabolism, and liver regeneration in a time course study in mice. Male B6C3F1 mice were treated with APAP (200 mg/kg IP) or saline and sacrificed at 1, 2, 4, 8, 24 or 48 h after APAP. At 1 h, hepatic glutathione was depleted and APAP protein adducts were markedly increased. Alanine aminotransferase (ALT) levels were elevated at 4 and 8 h, while proliferating cell nuclear antigen (PCNA) expression, indicative of hepatocyte regeneration, was apparent at 24 h and 48 h. Elevations of palmitoyl, oleoyl and myristoyl carnitine were apparent by 2-4 h, concurrent with the onset of Oil Red O staining in liver sections. By 8 h, acylcarnitine levels were below baseline levels and remained low at 24 and 48 h. A partial least squares (PLS) model suggested a direct association of acylcarnitine accumulation in serum to APAP protein adduct and hepatic glutathione levels in mice. Overall, the kinetics of serum acylcarnitines in APAP toxicity in mice followed a biphasic pattern involving early elevation after the metabolism phases of toxicity and later depletion of acylcarnitines. PMID- 24958142 TI - Tackling CASMI 2012: Solutions from MetFrag and MetFusion. AB - The task in the critical assessment of small molecule identification (CASMI) contest category 2 was to determine the identification of (initially) unknown compounds for which high-resolution tandem mass spectra were published. We focused on computer-assisted methods that tried to correctly identify the compound automatically and entered the contest with MetFrag and MetFusion to score candidate structures retrieved from the PubChem structure database. MetFrag was combined with the metabolite-likeness score, which helped to improve the performance for the natural product challenges. We present the results, discuss the performance, and give details of how to interpret the MetFrag and MetFusion output. PMID- 24958143 TI - Quantitative determination of common urinary odorants and their glucuronide conjugates in human urine. AB - Our previous study on the identification of common odorants and their conjugates in human urine demonstrated that this substance fraction is a little-understood but nonetheless a promising medium for analysis and diagnostics in this easily accessible physiological medium. Smell as an indicator for diseases, or volatile excretion in the course of dietary processes bares high potential for a series of physiological insights. Still, little is known today about the quantitative composition of odorous or volatile targets, as well as their non-volatile conjugates, both with regard to their common occurrence in urine of healthy subjects, as well as in that of individuals suffering from diseases or other physiological misbalancing. Accordingly, the aim of our study was to develop a highly sensitive and selective approach to determine the common quantitative composition of selected odorant markers in healthy human subjects, as well as their corresponding glucuronide conjugates. We used one- and two-dimensional high resolution gas chromatography-mass spectrometry in combination with stable isotope dilution assays to quantify commonly occurring and potent odorants in human urine. The studies were carried out on both native urine and on urine that had been treated by glucuronidase assays, with analysis of the liberated odor active compounds using the same techniques. Analytical data are discussed with regard to their potential translation as future diagnostic tool. PMID- 24958139 TI - A review of applications of metabolomics in cancer. AB - Cancer is a devastating disease that alters the metabolism of a cell and the surrounding milieu. Metabolomics is a growing and powerful technology capable of detecting hundreds to thousands of metabolites in tissues and biofluids. The recent advances in metabolomics technologies have enabled a deeper investigation into the metabolism of cancer and a better understanding of how cancer cells use glycolysis, known as the "Warburg effect," advantageously to produce the amino acids, nucleotides and lipids necessary for tumor proliferation and vascularization. Currently, metabolomics research is being used to discover diagnostic cancer biomarkers in the clinic, to better understand its complex heterogeneous nature, to discover pathways involved in cancer that could be used for new targets and to monitor metabolic biomarkers during therapeutic intervention. These metabolomics approaches may also provide clues to personalized cancer treatments by providing useful information to the clinician about the cancer patient's response to medical interventions. PMID- 24958145 TI - On functional module detection in metabolic networks. AB - Functional modules of metabolic networks are essential for understanding the metabolism of an organism as a whole. With the vast amount of experimental data and the construction of complex and large-scale, often genome-wide, models, the computer-aided identification of functional modules becomes more and more important. Since steady states play a key role in biology, many methods have been developed in that context, for example, elementary flux modes, extreme pathways, transition invariants and place invariants. Metabolic networks can be studied also from the point of view of graph theory, and algorithms for graph decomposition have been applied for the identification of functional modules. A prominent and currently intensively discussed field of methods in graph theory addresses the Q-modularity. In this paper, we recall known concepts of module detection based on the steady-state assumption, focusing on transition-invariants (elementary modes) and their computation as minimal solutions of systems of Diophantine equations. We present the Fourier-Motzkin algorithm in detail. Afterwards, we introduce the Q-modularity as an example for a useful non-steady state method and its application to metabolic networks. To illustrate and discuss the concepts of invariants and Q-modularity, we apply a part of the central carbon metabolism in potato tubers (Solanum tuberosum) as running example. The intention of the paper is to give a compact presentation of known steady-state concepts from a graph-theoretical viewpoint in the context of network decomposition and reduction and to introduce the application of Q-modularity to metabolic Petri net models. PMID- 24958144 TI - Global metabolomics reveals urinary biomarkers of breast cancer in a mcf-7 xenograft mouse model. AB - Global metabolomics analysis has the potential to uncover novel metabolic pathways that are differentially regulated during carcinogenesis, aiding in biomarker discovery for early diagnosis and remission monitoring. Metabolomics studies with human samples can be problematic due to high inter-individual variation; however xenografts of human cancers in mice offer a well-controlled model system. Urine was collected from a xenograft mouse model of MCF-7 breast cancer and analyzed by mass spectrometry-based metabolomics to identify metabolites associated with cancer progression. Over 10 weeks, 24 h urine was collected weekly from control mice, mice dosed with estradiol cypionate (1 mg/mL), mice inoculated with MCF-7 cells (1 * 107) and estradiol cypionate (1 mg/mL), and mice dosed with MCF-7 cells (1 * 107) only (n = 10/group). Mice that received both estradiol cypionate and MCF-7 cells developed tumors from four weeks after inoculation. Five urinary metabolites were identified that were associated with breast cancer; enterolactone glucuronide, coumaric acid sulfate, capric acid glucuronide, an unknown metabolite, and a novel mammalian metabolite, "taurosebacic acid". These metabolites revealed a correlation between tumor growth, fatty acid synthesis, and potential anti-proliferative effects of gut microbiota-metabolized food derivatives. These biomarkers may be of value for early diagnosis of cancer, monitoring of cancer therapeutics, and may also lead to future mechanistic studies. PMID- 24958146 TI - Electrospray Quadrupole Travelling Wave Ion Mobility Time-of-Flight Mass Spectrometry for the Detection of Plasma Metabolome Changes Caused by Xanthohumol in Obese Zucker (fa/fa) Rats. AB - This study reports on the use of traveling wave ion mobility quadrupole time-of flight (ToF) mass spectrometry for plasma metabolomics. Plasma metabolite profiles of obese Zucker fa/fa rats were obtained after the administration of different oral doses of Xanthohumol; a hop-derived dietary supplement. Liquid chromatography coupled data independent tandem mass spectrometry (LC-MSE) and LC ion mobility spectrometry (IMS)-MSE acquisitions were conducted in both positive and negative modes using a Synapt G2 High Definition Mass Spectrometry (HDMS) instrument. This method provides identification of metabolite classes in rat plasma using parallel alternating low energy and high energy collision spectral acquisition modes. Data sets were analyzed using pattern recognition methods. Statistically significant (p < 0.05 and fold change (FC) threshold > 1.5) features were selected to identify the up-/down-regulated metabolite classes. Ion mobility data visualized using drift scope software provided a graphical read-out of differences in metabolite classes. PMID- 24958147 TI - 1H NMR-Based Metabolomic Analysis of Sub-Lethal Perfluorooctane Sulfonate Exposure to the Earthworm, Eisenia fetida, in Soil. AB - 1H NMR-based metabolomics was used to measure the response of Eisenia fetida earthworms after exposure to sub-lethal concentrations of perfluorooctane sulfonate (PFOS) in soil. Earthworms were exposed to a range of PFOS concentrations (five, 10, 25, 50, 100 or 150 mg/kg) for two, seven and fourteen days. Earthworm tissues were extracted and analyzed by 1H NMR. Multivariate statistical analysis of the metabolic response of E. fetida to PFOS exposure identified time-dependent responses that were comprised of two separate modes of action: a non-polar narcosis type mechanism after two days of exposure and increased fatty acid oxidation after seven and fourteen days of exposure. Univariate statistical analysis revealed that 2-hexyl-5-ethyl-3-furansulfonate (HEFS), betaine, leucine, arginine, glutamate, maltose and ATP are potential indicators of PFOS exposure, as the concentrations of these metabolites fluctuated significantly. Overall, NMR-based metabolomic analysis suggests elevated fatty acid oxidation, disruption in energy metabolism and biological membrane structure and a possible interruption of ATP synthesis. These conclusions obtained from analysis of the metabolic profile in response to sub lethal PFOS exposure indicates that NMR-based metabolomics is an excellent discovery tool when the mode of action (MOA) of contaminants is not clearly defined. PMID- 24958148 TI - Integrative analysis of longitudinal metabolomics data from a personal multi omics profile. AB - The integrative personal omics profile (iPOP) is a pioneering study that combines genomics, transcriptomics, proteomics, metabolomics and autoantibody profiles from a single individual over a 14-month period. The observation period includes two episodes of viral infection: a human rhinovirus and a respiratory syncytial virus. The profile studies give an informative snapshot into the biological functioning of an organism. We hypothesize that pathway expression levels are associated with disease status. To test this hypothesis, we use biological pathways to integrate metabolomics and proteomics iPOP data. The approach computes the pathways' differential expression levels at each time point, while taking into account the pathway structure and the longitudinal design. The resulting pathway levels show strong association with the disease status. Further, we identify temporal patterns in metabolite expression levels. The changes in metabolite expression levels also appear to be consistent with the disease status. The results of the integrative analysis suggest that changes in biological pathways may be used to predict and monitor the disease. The iPOP experimental design, data acquisition and analysis issues are discussed within the broader context of personal profiling. PMID- 24958149 TI - Coordinating metabolite changes with our perception of plant abiotic stress responses: emerging views revealed by integrative-omic analyses. AB - Metabolic configuration and adaptation under a range of abiotic stresses, including drought, heat, salinity, cold, and nutrient deprivation, are subjected to an intricate span of molecular pathways that work in parallel in order to enhance plant fitness and increase stress tolerance. In recent years, unprecedented advances have been made in identifying and linking different abiotic stresses, and the current challenge in plant molecular biology is deciphering how the signaling responses are integrated and transduced throughout metabolism. Metabolomics have often played a fundamental role in elucidating the distinct and overlapping biochemical changes that occur in plants. However, a far greater understanding and appreciation of the complexity in plant metabolism under specific stress conditions have become apparent when combining metabolomics with other-omic platforms. This review focuses on recent advances made in understanding the global changes occurring in plant metabolism under abiotic stress conditions using metabolite profiling as an integrated discovery platform. PMID- 24958150 TI - A comprehensive workflow of mass spectrometry-based untargeted metabolomics in cancer metabolic biomarker discovery using human plasma and urine. AB - Current available biomarkers lack sensitivity and/or specificity for early detection of cancer. To address this challenge, a robust and complete workflow for metabolic profiling and data mining is described in details. Three independent and complementary analytical techniques for metabolic profiling are applied: hydrophilic interaction liquid chromatography (HILIC-LC), reversed-phase liquid chromatography (RP-LC), and gas chromatography (GC). All three techniques are coupled to a mass spectrometer (MS) in the full scan acquisition mode, and both unsupervised and supervised methods are used for data mining. The univariate and multivariate feature selection are used to determine subsets of potentially discriminative predictors. These predictors are further identified by obtaining accurate masses and isotopic ratios using selected ion monitoring (SIM) and data dependent MS/MS and/or accurate mass MSn ion tree scans utilizing high resolution MS. A list combining all of the identified potential biomarkers generated from different platforms and algorithms is used for pathway analysis. Such a workflow combining comprehensive metabolic profiling and advanced data mining techniques may provide a powerful approach for metabolic pathway analysis and biomarker discovery in cancer research. Two case studies with previous published data are adapted and included in the context to elucidate the application of the workflow. PMID- 24958151 TI - Physiological and Molecular Timing of the Glucose to Acetate Transition in Escherichia coli. AB - The glucose-acetate transition in Escherichia coli is a classical model of metabolic adaptation. Here, we describe the dynamics of the molecular processes involved in this metabolic transition, with a particular focus on glucose exhaustion. Although changes in the metabolome were observed before glucose exhaustion, our results point to a massive reshuffling at both the transcriptome and metabolome levels in the very first min following glucose exhaustion. A new transcriptional pattern, involving a change in genome expression in one-sixth of the E. coli genome, was established within 10 min and remained stable until the acetate was completely consumed. Changes in the metabolome took longer and stabilized 40 min after glucose exhaustion. Integration of multi-omics data revealed different modifications and timescales between the transcriptome and metabolome, but both point to a rapid adaptation of less than an hour. This work provides detailed information on the order, timing and extent of the molecular and physiological events that occur during the glucose-acetate transition and that are of particular interest for the development of dynamic models of metabolism. PMID- 24958152 TI - A novel methodology to estimate metabolic flux distributions in constraint-based models. AB - Quite generally, constraint-based metabolic flux analysis describes the space of viable flux configurations for a metabolic network as a high-dimensional polytope defined by the linear constraints that enforce the balancing of production and consumption fluxes for each chemical species in the system. In some cases, the complexity of the solution space can be reduced by performing an additional optimization, while in other cases, knowing the range of variability of fluxes over the polytope provides a sufficient characterization of the allowed configurations. There are cases, however, in which the thorough information encoded in the individual distributions of viable fluxes over the polytope is required. Obtaining such distributions is known to be a highly challenging computational task when the dimensionality of the polytope is sufficiently large, and the problem of developing cost-effective ad hoc algorithms has recently seen a major surge of interest. Here, we propose a method that allows us to perform the required computation heuristically in a time scaling linearly with the number of reactions in the network, overcoming some limitations of similar techniques employed in recent years. As a case study, we apply it to the analysis of the human red blood cell metabolic network, whose solution space can be sampled by different exact techniques, like Hit-and-Run Monte Carlo (scaling roughly like the third power of the system size). Remarkably accurate estimates for the true distributions of viable reaction fluxes are obtained, suggesting that, although further improvements are desirable, our method enhances our ability to analyze the space of allowed configurations for large biochemical reaction networks. PMID- 24958154 TI - Expression of sarcomeric tropomyosin in striated muscles in axolotl treated with shz-1, a small cardiogenic molecule. AB - We evaluated the effect of shz-1, a cardiogenic molecule, on the expression of various tropomyosin (TM) isoforms in the Mexican axolotl (Ambystoma mexicanum) hearts. qRT-PCR data show a ~1.5-fold increase in cardiac transcripts of the Nkx2.5 gene, which plays a crucial role in cardiogenesis in vertebrates. Shz-1 augments the expression of transcripts of the total sarcomeric TPM1 (both TPM1alpha & TPM1kappa) and sarcomeric TPM4alpha. In order to understand the mechanism by which shz-1 augments the expression of sarcomeric TPM transcription in axolotl hearts, we transfected C2C12 cells with pGL3.axolotl. We transfected C2C12 cells with pGL3-axolotl TPM4 promoter constructs containing the firefly luciferase reporter gene. The transfected C2C12 cells were grown in the absence or presence of shz-1 (5 MUM). Subsequently, we determined the firefly luciferase activity in the extracts of transfected cells. The results suggest that shz-1 activates the axolotl TPM4 promoter-driven ectopic expression in C2C12 cells. Also, we transfected C2C12 cells with a pGL3.1 vector containing the promoter of the mouse skeletal muscle troponin-I and observed a similar increase in the luciferase activity in shz-1-treated cells. We conclude that shz-1 activates the promoters of a variety of genes including axolotl TPM4. We have quantified the expression of the total sarcomeric TPM1 and observed a 1.5-fold increase in treated cells. Western blot analyses with CH1 monoclonal antibody specific for sarcomeric isoforms show that shz-1 does not increase the expression of TM protein in axolotl hearts, whereas it does in C2C12 cells. These findings support our hypothesis that cardiac TM expression in axolotl undergoes translational control. PMID- 24958155 TI - Spontaneous remission of a squamous cell carcinoma of the floor of the mouth. AB - Spontaneous remission is a rare, but well recognized event in oncology. Certain tumours, such as melanomas, hypernephromas and neuroblastomas, are known for showing spontaneous regression. Similarly, spontaneous regression of oral lymphomas, as well as oropharyngeal and recurrent tongue carcinomas, has been reported. Here, we present a novel case of a patient with a primary squamous cell carcinoma on the floor of the mouth whose tumour regressed spontaneously in three months, without any treatment. We also review of the literature on the spontaneous remission of oral cancer and discuss possible mechanisms for this phenomenon. PMID- 24958153 TI - Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis. AB - OBJECTIVE: To investigate whether revascularisation improves prognosis compared with medical treatment among patients with stable coronary artery disease. DESIGN: Bayesian network meta-analyses to combine direct within trial comparisons between treatments with indirect evidence from other trials while maintaining randomisation. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: A strategy of initial medical treatment compared with revascularisation by coronary artery bypass grafting or Food and Drug Administration approved techniques for percutaneous revascularization: balloon angioplasty, bare metal stent, early generation paclitaxel eluting stent, sirolimus eluting stent, and zotarolimus eluting (Endeavor) stent, and new generation everolimus eluting stent, and zotarolimus eluting (Resolute) stent among patients with stable coronary artery disease. DATA SOURCES: Medline and Embase from 1980 to 2013 for randomised trials comparing medical treatment with revascularisation. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: 100 trials in 93,553 patients with 262,090 patient years of follow-up were included. Coronary artery bypass grafting was associated with a survival benefit (rate ratio 0.80, 95% credibility interval 0.70 to 0.91) compared with medical treatment. New generation drug eluting stents (everolimus: 0.75, 0.59 to 0.96; zotarolimus (Resolute): 0.65, 0.42 to 1.00) but not balloon angioplasty (0.85, 0.68 to 1.04), bare metal stents (0.92, 0.79 to 1.05), or early generation drug eluting stents (paclitaxel: 0.92, 0.75 to 1.12; sirolimus: 0.91, 0.75 to 1.10; zotarolimus (Endeavor): 0.88, 0.69 to 1.10) were associated with improved survival compared with medical treatment. Coronary artery bypass grafting reduced the risk of myocardial infarction compared with medical treatment (0.79, 0.63 to 0.99), and everolimus eluting stents showed a trend towards a reduced risk of myocardial infarction (0.75, 0.55 to 1.01). The risk of subsequent revascularisation was noticeably reduced by coronary artery bypass grafting (0.16, 0.13 to 0.20) followed by new generation drug eluting stents (zotarolimus (Resolute): 0.26, 0.17 to 0.40; everolimus: 0.27, 0.21 to 0.35), early generation drug eluting stents (zotarolimus (Endeavor): 0.37, 0.28 to 0.50; sirolimus: 0.29, 0.24 to 0.36; paclitaxel: 0.44, 0.35 to 0.54), and bare metal stents (0.69, 0.59 to 0.81) compared with medical treatment. CONCLUSION: Among patients with stable coronary artery disease, coronary artery bypass grafting reduces the risk of death, myocardial infarction, and subsequent revascularisation compared with medical treatment. All stent based coronary revascularisation technologies reduce the need for revascularisation to a variable degree. Our results provide evidence for improved survival with new generation drug eluting stents but no other percutaneous revascularisation technology compared with medical treatment. PMID- 24958157 TI - Continuous quality improvement program for hip and knee replacement. AB - Improving quality of care and maximizing efficiency are priorities in hip and knee replacement, where surgical demand and costs increase as the population ages. The authors describe the integrated structure and processes from the Continuous Quality Improvement (CQI) Program for Hip and Knee Replacement Surgical Care and summarize lessons learned from implementation. The Triple Aim framework and 6 dimensions of quality care are overarching constructs of the CQI program. A validated, evidence-based clinical pathway that measures quality across the continuum of care was adopted. Working collaboratively, multidisciplinary experts embedded the CQI program into everyday practices in clinics across Alberta. Currently, 83% of surgeons participate in the CQI program, representing 95% of the total volume of hip and knee surgeries. Biannual reports provide feedback to improve care processes, infrastructure planning, and patient outcomes. CQI programs evaluating health care services inform choices to optimize care and improve efficiencies through continuous knowledge translation. PMID- 24958156 TI - TMD in class III patients referred for orthognathic surgery: psychological and dentition-related aspects. AB - OBJECTIVE: To investigate temporomandibular disorders (TMD), psychosocial, and occlusal variables in class III orthognathic surgery patients with respect to the control subjects, and to compare psychosocial and occlusal features in class III patients with different Research Diagnostic Criteria for TMD (RDC/TMD) diagnoses. MATERIALS AND METHODS: The study enrolled 44 class III patients referred for orthognathic surgery and 44 individuals without a malocclusion. TMD, depression and somatization were assessed by RDC/TMD. Occlusal analysis included Helkimo's Occlusal Index items, overjet and overbite. RESULTS: In the controls, patients with class III deformities had higher prevalence of myogenic TMD, increased grade of chronic pain, and more occlusal deviations. Within the study group, TMD patients reported higher depression score (P < 0.01), myofascial pain was related to higher depression and somatization grades (P < 0.01, P < 0.05 respectively), and disc displacement showed relation with RCP-ICP slide interferences (P < 0.05). CONCLUSION: With respect to subjects without a malocclusion, TMD in class III dentofacial deformities is similar in prevalence, but differs in clinical appearance. Occlusal, but not psychosocial features deviate from those in the controls. While psychosocial variables accompanied TMD and myofascial pain, increased RCP-ICP slide was related to disc displacement in class III patients. PMID- 24958158 TI - Barriers for recess physical activity: a gender specific qualitative focus group exploration. AB - BACKGROUND: Many children, in particular girls, do not reach the recommended amount of daily physical activity. School recess provides an opportunity for both boys and girls to be physically active, but barriers to recess physical activity are not well understood. This study explores gender differences in children's perceptions of barriers to recess physical activity. Based on the socio ecological model four types of environmental barriers were distinguished: natural, social, physical and organizational environment. METHODS: Data were collected through 17 focus groups (at 17 different schools) with in total 111 children (53 boys) from fourth grade, with a mean age of 10.4 years. The focus groups included an open group discussion, go-along group interviews, and a gender segregated post-it note activity. A content analysis of the post-it notes was used to rank the children's perceived barriers. This was verified by a thematic analysis of transcripts from the open discussions and go-along interviews. RESULTS: The most frequently identified barriers for both boys and girls were weather, conflicts, lack of space, lack of play facilities and a newly-found barrier, use of electronic devices. While boys and girls identified the same barriers, there were both inter- and intra-gender differences in the perception of these barriers. Weather was a barrier for all children, apart from the most active boys. Conflicts were perceived as a barrier particularly by those boys who played ballgames. Girls said they would like to have more secluded areas added to the school playground, even in large schoolyards where lack of space was not a barrier. This aligned with girls' requests for more "hanging-out" facilities, whereas boys primarily wanted activity promoting facilities. CONCLUSION: Based on the results from this study, we recommend promoting recess physical activity through a combination of actions, addressing barriers within the natural, social, physical and organizational environment. PMID- 24958160 TI - Implementing a strand of a scalable fault-tolerant quantum computing fabric. AB - With favourable error thresholds and requiring only nearest-neighbour interactions on a lattice, the surface code is an error-correcting code that has garnered considerable attention. At the heart of this code is the ability to perform a low-weight parity measurement of local code qubits. Here we demonstrate high-fidelity parity detection of two code qubits via measurement of a third syndrome qubit. With high-fidelity gates, we generate entanglement distributed across three superconducting qubits in a lattice where each code qubit is coupled to two bus resonators. Via high-fidelity measurement of the syndrome qubit, we deterministically entangle the code qubits in either an even or odd parity Bell state, conditioned on the syndrome qubit state. Finally, to fully characterize this parity readout, we develop a measurement tomography protocol. The lattice presented naturally extends to larger networks of qubits, outlining a path towards fault-tolerant quantum computing. PMID- 24958159 TI - First evidence of a prospective relation between avoidance of internal states and borderline personality disorder features in adolescents. AB - At least two leading developmental models of borderline personality disorder (BPD) emphasize the role of accurate reflection and understanding of internal states as significant to the development of BPD features (Fonagy, Int J Psycho Anal 72:639-656, 1991; Linehan, Cognitive-behavioral treatment of borderline personality disorder, 1993). The current study used the construct of experiential avoidance (EA) to operationalize avoidance of internal states and sought to examine (1) the concurrent relations between EA and borderline features in a large and diverse community sample; and (2) the prospective relation between EA and borderline features over a 1-year follow-up, controlling for baseline levels of borderline features. N = 881 adolescents recruited from public schools in a large metropolitan area participated in baseline assessments and N = 730 completed follow-up assessments. Two main findings were reported. First, EA was associated with borderline features, depressive, and anxiety symptoms at the bivariate level, but when all variables were considered together, depression and anxiety no longer remained significantly associated with borderline features, suggesting that the relations among these symptom clusters may be accounted for by EA as a cross-cutting underlying psychological process. Second, EA predicted levels of borderline symptoms at 1-year follow-up, controlling for baseline levels of borderline symptoms, and symptoms of anxiety and depression. Results are interpreted against the background of developmental theories of borderline personality disorder. PMID- 24958161 TI - Linalool and linalool complexed in beta-cyclodextrin produce anti-hyperalgesic activity and increase Fos protein expression in animal model for fibromyalgia. AB - The analgesic activity of (-)-linalool (LIN), a monoterpene present in essential oils of Lamiaceae species, has been previously demonstrated in rodents. However, its possible use in the treatment of fibromyalgia (FM) was never demonstrated. Additionally, as a short half-life is a limitation for the LIN medicinal application, the employment of drug delivery systems has been used to improve pharmaceutical properties of this compound. We investigated the anti-nociceptive effect of LIN, isolated or in beta-cyclodextrin complex (LIN-CD), in an animal model of chronic non-inflammatory muscle pain (a FM animal model), as well as its effect on the central nervous system (CNS). Male Swiss mice were subjected to two injections of acidic saline (pH 4; 20 MUL/gastrocnemius) and were treated on alternate days, with LIN-CD (25 mg/kg, p.o.), LIN (25 mg/kg, p.o.), tramadol (TRM 4 mg/kg, i.p.), or vehicle (neutral saline). After 60 min, they were screened for mechanical hyperalgesia (von Frey), motor coordination (rotarod), and muscle strength (grip strength meter) for 27 days. The CNS areas involved in the anti hyperalgesic activity were evaluated by immunofluorescence. LIN or LIN-CD produced a significant reduction (p < 0.001) of mechanical hyperalgesia on chronic non-inflammatory muscle pain model, which remained for 24 h only in LIN CD, and these compounds significantly (p < 0.05) activated neurons of the locus coeruleus, nucleus raphe magnus, and periaqueductal gray areas. So, our results suggest that LIN-CD improved analgesic profile of LIN, with a probable involvement of descending pain pathways and the anti-nociceptive effect of linalool in an animal model of chronic non-inflammatory muscle pain. So far, only the investigations in animal models of inflammatory pain and supraspinatus were published. PMID- 24958162 TI - 22q11.2 Deletion syndrome and obstructive sleep apnea. AB - Otolaryngologic problems are common in the 22q11.2 deletion syndrome (DS) population. Structural anomalies and retrognathia may predispose these patients to obstructive sleep apnea (OSA). The current association of OSA in this population is not defined. OBJECTIVE: (1) Define the frequency of OSA in 22q11.2 DS patients referred for polysomnography (PSG). (2) Determine if OSA is present before and/or after surgery to correct velopharyngeal insufficiency (VPI). (3) Determine effect of prior adenotonsillectomy on OSA following VPI surgery. METHODS: Retrospective review of children treated from 2006 to 2013 in a tertiary care setting identified by ICD-9 758.32 (velocardiofacial syndrome) and 279.11 (DiGeorge syndrome). Surgical history and PSG data were abstracted from the identified records. RESULTS: We identified 323 patients with 22q11.2 DS; 57 (18%) were screened at any point in care using PSG and 15 patients had PSG at multiple time points in care. In most cases, indication for PSG was sleep disordered breathing or pre-operative planning. Overall, 33 patients met criteria for OSA on PSG, accounting for 10.2% of our study population; however, the percentage of patients with OSA was significantly higher within the group of 57 patients (58%) who were screened with PSG. Twenty-one of the screened patients (54%) had PSG prior to any pharyngeal surgery and had mild to severe OSA (obstructive apnea/hypopnea index (AHI): median 5.1/h, range 1.9-25.6). Eighteen patients had PSG after adenotonsillectomy; 8 of these patients (44%) had mild to moderate OSA (median AHI 2.95/h, range 1.9-5.4). Seventeen patients had PSG after VPI surgery (palatopharyngeal flap (PPF) n=16, sphincteroplasty n=1). Nine of these patients (53%) had mild to severe OSA (median AHI 3/h, range 1.9-15). Patients who underwent adenotonsillectomy prior to VPI surgery had similar prevalence of OSA (50%, n=12) than those who did not (OSA: 60%, n=5, p=0.70). Most children had mild OSA. CONCLUSION: Prevalence of OSA in this population of 22q11.2 DS patients is higher than expected in the general population. OSA risk is highest after VPI surgery, and may be decreased by adenotonsillectomy. Providers should have awareness of increased prevalence of OSA in patients with 22q11.2 DS. Close monitoring for OSA is warranted given the likelihood of subsequent surgical intervention that can worsen OSA. PMID- 24958163 TI - Differential response of gel-forming mucins to pathogenic middle ear bacteria. AB - OBJECTIVE: To assess the differential response of the secretory gel forming mucins (GFM) to the most common bacterial pathogens causing otitis media, Streptococcus pneumoniae (SP), nontypeable Haemophilus influenza (NTHi), and Moraxella catarrhalis (Mcat), in a culture model of human middle ear epithelium (HMEEC). METHODS: In vitro cultured HMEEC was exposed to 5 MUg/ml of bacterial whole cell lysate (WCL). RNA was extracted to generate cDNA. The expression levels of each of the targeted mucin transcripts, MUC2, MUC5AC, MUC5B and MUC19, were detected by quantitative PCR. RESULTS: The submerged HMEEC exposed to NTHi 86028NP WCL demonstrated a significant increase of MUC2, MUC5AC and MUC5B as compared to the control non-treated cells while MUC19 transcript level remained unchanged. WCL of additional major OM pathogens significantly increase the transcription of these three mucin genes as well. A combination of NTHi and SP further synergistically induced MUC2 and MUC5AC gene expression however, not all NTHi strains synergized with SP in the induction. Addition of Mcat WCL to the synergized combination of NTHi and SP did not participate in the synergistic response of mucins. CONCLUSION: The specific pathogen combinations were important in determining the degree of synergistic effects to GFM expression. The current data are substantive in guiding future work to extend our understanding of OM pathogens and GFMs. PMID- 24958164 TI - Sign reversal of a large circularly polarized luminescence signal by the twisting motion of a bidentate ligand. AB - This work demonstrates sign reversal of large circularly polarized luminescence (CPL) signal based on the hinge-like twisting motion of a bidentate ligand, 3,3 bis(diphenylphosphoryl)-2,2-bipyridine (BIPYPO), in a cis-trans isomerization of chiral europium(III) complexes. X-ray diffraction analysis revealed that twisting motion of BIPYPO provides s-cis and s-trans geometries of a chiral Eu(III) complex containing either tris[3-(trifluoromethylhydroxymethylene)-(+) camphorate] (D-1) or tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate] (D-2). The s-cis Eu(III) complexes show eight-coordinate geometry around the Eu(III) ion, in which the chelate between the phosphoryl oxygen and the Eu(III) ion forces the s-cis geometry of BIPYPO. In contrast, the phosphorus-nitrogen interaction provides a conformational lock for the s-trans geometry of the BIPYPO ligand, inducing a quasi-seven-coordinate Eu(III) complex. The difference in coordination geometry causes the sign change of the CPL signals between the s-cis and s-trans isomers, whereby the s-cis and s-trans isomers of Eu(III) complexes exhibit the positive and negative CPL signals, respectively, for the (5) D0 ->(7) F1 transition. The proportion of the s-trans-D-1 against s-cis-D-1 increases upon changing the solvent from [D3 ]acetonitrile to [D6 ]acetone, inducing a sign change of the CPL signals. The complexes D-1 and D-2 show a biexponential decay with two different lifetimes, suggesting two emitting species, that is, the s-cis and s-trans isomers of Eu(III) complexes. In both cases, the proportions of the longer lifetime components (tau1 ) decrease and instead the shorter lifetime components (tau2 ) increase upon changing the solvent from [D3 ]acetonitrile to [D6 ]acetone. PMID- 24958165 TI - Trajectories of physical functioning and their prognostic indicators: a prospective cohort study in older adults with joint pain and comorbidity. AB - OBJECTIVES: This study aimed to identify and characterize homogeneous subgroups of individuals with distinct trajectories of physical functioning (PF) and to examine prognostic indicators of deterioration in PF in a highly heterogeneous population of older adults with joint pain and comorbidity. STUDY DESIGN: A prospective cohort study among 407 older adults with joint pain and comorbidity provided data over a period of 18 months, with 6 month time-intervals. We used latent class growth modelling (LCGM) to identify underlying subgroups (clusters) with distinct trajectories of PF. Next, we characterized these subgroups and applied multivariable logistic regression analysis to identify prognostic indicators for deterioration in PF. MAIN OUTCOME MEASURES: We measures PF with the RAND-36 PF subscale and several potential sociodemographic, physical and psychosocial prognostic indicators. RESULTS: LCGM identified three clusters. Cluster 1 'good PF' contained 140 participants with good baseline PF and small improvements over time. Cluster 2 'moderate PF' contained 130 participants with moderate baseline PF and deterioration over time. Cluster 3 'poor PF' contained 137 participants with poor baseline PF and deterioration over time. After backward selection, the final model that could best distinguish between improved participants (cluster 1) and deteriorated participants (cluster 2-3) included the following prognostic indicators: higher age, more depressive symptoms, less perceived self-efficacy and more activity avoidance. CONCLUSIONS: Older adults with joint pain and comorbidity either improved or deteriorated in PF over time. The prognostic model facilitates the classification of patients, the provision of more accurate information about prognosis and helps to narrow the focus to the high risk group of poor PF. PMID- 24958166 TI - Use of proton pump inhibitors (PPI) and history of earlier fracture are independent risk factors for fracture in postmenopausal women. The WHILA study. AB - Postmenopausal women in the Western world are highly burdened by osteoporotic fractures. The aim of this study is to investigate risk factors at baseline for fracture in 6416 postmenopausal women during long-term follow-up. At baseline, all women completed a questionnaire regarding background factors, diseases, current use of medications and reproductive and contraceptive history, a physical examination and laboratory analyses. Fracture occurrence after inclusion in the study was recorded with the help of official registries. All significant variables in univariate logistic regression with a decreased or increased risk for fracture were analysed in a multivariate logistic regression. Increased fracture risk was observed in women currently using proton pump inhibitors (PPI), odds ratio (OR) 2.53 (95% confidence interval (CI)) 1.28-4.99, and women having had a fracture after the age of 40, but before inclusion in the study, OR 1.70 (95% CI 1.24-2.32). A protective effect against fractures was observed in women with a positive family history of diabetes OR 0.66 (95% CI 0.44-0.98). A significant interaction was observed between fracture risk, use of PPI and HT status (p=0.014) and women with HT had an increased fracture risk with use of PPI (OR 3.37 (95% CI 1.96-5.80)) compared to women without HT (OR 1.13 (95% CI 0.57 2.24)). In conclusion, usage of PPIs was associated with a doubled risk for fracture in postmenopausal women. Women with previous fractures using PPI should be considered for prophylactic treatment reducing fracture risk. PMID- 24958168 TI - Personal experience and perception of abuse in people with intellectual disabilities. AB - This article presents a qualitative study designed to gain insight into personal experience and perception of abuse in people with intellectual disabilities. Ten members of the organization for people with intellectual disabilities in Zadar, Croatia, who have a diagnosis of light or moderate intellectual disability, were included in the research. Analysis of responses showed that most participants had experienced psychological, physical and financial abuse. The most frequent perpetrators of abuse were identified by participants as friends, acquaintances and volunteer carers. Typical sites for the experience of abuse were school, social clubs/support institutions, the street and the urban environment. Most participants seek assistance and support in cases of abuse through discussion with their loved ones, mostly their parents and friends. In addition to such informal relationships, some participants mentioned the importance of formal forms of support. PMID- 24958167 TI - Neuroprotection of atractylenolide III from Atractylodis macrocephalae against glutamate-induced neuronal apoptosis via inhibiting caspase signaling pathway. AB - Glutamate-induced excitotoxicity appears to play a crucial role in neurological disorders. Neuroprotection against glutamate-induced excitotoxicity has been proposed as a therapeutic strategy for preventing and/or treating these excitotoxicity-mediated diseases. In the present study, atractylenolide III, which exhibited significantly neuroprotective effect against glutamate-induced neuronal apoptosis, was isolated from Atractylodes macrocephala by means of bioactivity-guided fractionation. The inhibitory effect of atractylenolide III on glutamate-induced neuronal apoptosis was in a concentration-dependent manner. The anti-apoptotic property of atractylenolide III might be mediated, in part, via inhibiting caspase signaling pathway. Atractylenolide III may have therapeutic potential in excitotoxicity-mediated neurological diseases. PMID- 24958170 TI - PRIME-XS, a European infrastructure for proteomics. AB - The PRIME-XS consortium is a pan-European infrastructure for proteomics. As a prologue to this special issue of Molecular & Cellular Proteomics on the research activities of the PRIME-XS consortium, we, as the guest editors of this issue, provide an overview of the structure and activities of this consortium, which is funded by the European Union's 7th Framework Programme for Research and Technological Development. PMID- 24958173 TI - Oxygen selective membranes for li-air (o2) batteries. AB - Lithium-air (Li-air) batteries have a much higher theoretical energy density than conventional lithium batteries and other metal air batteries, so they are being developed for applications that require long life. Water vapor from air must be prevented from corroding the lithium (Li) metal negative electrode during discharge under ambient conditions, i.e., in humid air. One method of protecting the Li metal from corrosion is to use an oxygen selective membrane (OSM) that allows oxygen into the cell while stopping or slowing the ingress of water vapor. The desired properties and some potential materials for OSMs for Li-air batteries are discussed and the literature is reviewed. PMID- 24958172 TI - Immobilization of Mucor miehei Lipase onto Macroporous Aminated Polyethersulfone Membrane for Enzymatic Reactions. AB - Immobilization of enzymes is one of the most promising methods in enzyme performance enhancement, including stability, recovery, and reusability. However, investigation of suitable solid support in enzyme immobilization is still a scientific challenge. Polyethersulfone (PES) and aminated PES (PES-NH2) were successfully synthesized as novel materials for immobilization. Membranes with various pore sizes (from 10-600 nm) based on synthesized PES and PES-NH2 polymers were successfully fabricated to be applied as bioreactors to increase the immobilized lipase performances. The influence of pore sizes, concentration of additives, and the functional groups that are attached on the PES backbone on enzyme loading and enzyme activity was studied. The largest enzyme loading was obtained by Mucor miehei lipase immobilized onto a PES-NH2 membrane composed of 10% of PES-NH2, 8% of dibutyl phthalate (DBP), and 5% of polyethylene glycol (PEG) (872.62 ug/cm2). Hydrolytic activity of the immobilized lipases indicated that the activities of biocatalysts are not significantly decreased by immobilization. From the reusability test, the lipase immobilized onto PES-NH2 showed a better constancy than the lipase immobilized onto PES (the percent recovery of the activity of the lipases immobilized onto PES-NH2 and PES are 97.16% and 95.37%, respectively), which indicates that this novel material has the potential to be developed as a bioreactor for enzymatic reactions. PMID- 24958169 TI - Comparative analysis of the secretome from a model filarial nematode (Litomosoides sigmodontis) reveals maximal diversity in gravid female parasites. AB - Filarial nematodes (superfamily Filarioidea) are responsible for an annual global health burden of ~6.3 million disability-adjusted life-years, which represents the greatest single component of morbidity attributable to helminths affecting humans. No vaccine exists for the major filarial diseases, lymphatic filariasis and onchocerciasis; in part because research on protective immunity against filariae has been constrained by the inability of the human-parasitic species to complete their lifecycles in laboratory mice. However, the rodent filaria Litomosoides sigmodontis has become a popular experimental model, as BALB/c mice are fully permissive for its development and reproduction. Here, we provide a comprehensive analysis of excretory-secretory products from L. sigmodontis across five lifecycle stages and identifications of host proteins associated with first stage larvae (microfilariae) in the blood. Applying intensity-based quantification, we determined the abundance of 302 unique excretory-secretory proteins, of which 64.6% were present in quantifiable amounts only from gravid adult female nematodes. This lifecycle stage, together with immature microfilariae, released four proteins that have not previously been evaluated as vaccine candidates: a predicted 28.5 kDa filaria-specific protein, a zonadhesin and SCO-spondin-like protein, a vitellogenin, and a protein containing six metridin-like ShK toxin domains. Female nematodes also released two proteins derived from the obligate Wolbachia symbiont. Notably, excretory-secretory products from all parasite stages contained several uncharacterized members of the transthyretin-like protein family. Furthermore, biotin labeling revealed that redox proteins and enzymes involved in purinergic signaling were enriched on the adult nematode cuticle. Comparison of the L. sigmodontis adult secretome with that of the human-infective filarial nematode Brugia malayi (reported previously in three independent published studies) identified differences that suggest a considerable underlying diversity of potential immunomodulators. The molecules identified in L. sigmodontis excretory-secretory products show promise not only for vaccination against filarial infections, but for the amelioration of allergy and autoimmune diseases. PMID- 24958171 TI - Redox state of pentraxin 3 as a novel biomarker for resolution of inflammation and survival in sepsis. AB - In an endotoxaemic mouse model of sepsis, a tissue-based proteomics approach for biomarker discovery identified long pentraxin 3 (PTX3) as the lead candidate for inflamed myocardium. When the redox-sensitive oligomerization state of PTX3 was further investigated, PTX3 accumulated as an octamer as a result of disulfide bond formation in heart, kidney, and lung-common organ dysfunctions seen in patients with sepsis. Oligomeric moieties of PTX3 were also detectable in circulation. The oligomerization state of PTX3 was quantified over the first 11 days in critically ill adult patients with sepsis. On admission day, there was no difference in the oligomerization state of PTX3 between survivors and non survivors. From day 2 onward, the conversion of octameric to monomeric PTX3 was consistently associated with a greater survival after 28 days of follow-up. For example, by day 2 post-admission, octameric PTX3 was barely detectable in survivors, but it still constituted more than half of the total PTX3 in non survivors (p < 0.001). Monomeric PTX3 was inversely associated with cardiac damage markers NT-proBNP and high-sensitivity troponin I and T. Relative to the conventional measurements of total PTX3 or NT-proBNP, the oligomerization of PTX3 was a superior predictor of disease outcome. PMID- 24958175 TI - Impedance Spectroscopic Investigation of Proton Conductivity in Nafion Using Transient Electrochemical Atomic Force Microscopy (AFM). AB - Spatially resolved impedance spectroscopy of a Nafion polyelectrolyte membrane is performed employing a conductive and Pt-coated tip of an atomic force microscope as a point-like contact and electrode. The experiment is conducted by perturbing the system by a rectangular voltage step and measuring the incurred current, followed by Fourier transformation and plotting the impedance against the frequency in a conventional Bode diagram. To test the potential and limitations of this novel method, we present a feasibility study using an identical hydrogen atmosphere at a well-defined relative humidity on both sides of the membrane. It is demonstrated that good quality impedance spectra are obtained in a frequency range of 0.2-1,000 Hz. The extracted polarization curves exhibit a maximum current which cannot be explained by typical diffusion effects. Simulation based on equivalent circuits requires a Nernst element for restricted diffusion in the membrane which suggests that this effect is based on the potential dependence of the electrolyte resistance in the high overpotential region. PMID- 24958174 TI - Comparison of polytetrafluoroethylene flat-sheet membranes with different pore sizes in application to submerged membrane bioreactor. AB - This study focused on phase separation of activated sludge mixed liquor by flat sheet membranes of polytetrafluoroethylene (PTFE). A 20 liter working volume lab scale MBR incorporating immersed PTFE flat-sheet membrane modules with different pore sizes (0.3, 0.5 and 1.0 MUm) was operated for 19 days treating a synthetic wastewater. The experiment was interrupted twice at days 5 and 13 when the modules were removed and cleaned physically and chemically in sequence. The pure water permeate flux of each membrane module was measured before and after each cleaning step to calculate membrane resistances. Results showed that fouling of membrane modules with 0.3 MUm pore size was more rapid than other membrane modules with different pore sizes (0.5 and 1.0 MUm). On the other hand, it was not clear whether fouling of the 0.5 MUm membrane module was more severe than that of the 1.0 MUm membrane module. This was partly because of the membrane condition after chemical cleaning, which seemed to determine the fouling of those modules over the next period. When irreversible resistance (Ri) i.e., differences in membrane resistance before use and after chemical cleaning was high, the transmembrane pressure increased quickly during the next period irrespective of membrane pore size. PMID- 24958176 TI - Synthesis, Multinuclear NMR Characterization and Dynamic Property of Organic Inorganic Hybrid Electrolyte Membrane Based on Alkoxysilane and Poly(oxyalkylene) Diamine. AB - Organic-inorganic hybrid electrolyte membranes based on poly(propylene glycol) block-poly(ethylene glycol)-block-poly(propylene glycol) bis(2-aminopropyl ether) complexed with LiClO4 via the co-condensation of tetraethoxysilane (TEOS) and 3 (triethoxysilyl)propyl isocyanate have been prepared and characterized. A variety of techniques such as differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, alternating current (AC) impedance and solid-state nuclear magnetic resonance (NMR) spectroscopy are performed to elucidate the relationship between the structural and dynamic properties of the hybrid electrolyte and the ion mobility. A VTF (Vogel-Tamman-Fulcher)-like temperature dependence of ionic conductivity is observed for all the compositions studied, implying that the diffusion of charge carriers is assisted by the segmental motions of the polymer chains. A maximum ionic conductivity value of 5.3 * 10-5 Scm-1 is obtained at 30 degrees C. Solid-state NMR results provide a microscopic view of the effects of salt concentrations on the dynamic behavior of the polymer chains. PMID- 24958177 TI - Membranes for redox flow battery applications. AB - The need for large scale energy storage has become a priority to integrate renewable energy sources into the electricity grid. Redox flow batteries are considered the best option to store electricity from medium to large scale applications. However, the current high cost of redox flow batteries impedes the wide spread adoption of this technology. The membrane is a critical component of redox flow batteries as it determines the performance as well as the economic viability of the batteries. The membrane acts as a separator to prevent cross mixing of the positive and negative electrolytes, while still allowing the transport of ions to complete the circuit during the passage of current. An ideal membrane should have high ionic conductivity, low water intake and excellent chemical and thermal stability as well as good ionic exchange capacity. Developing a low cost, chemically stable membrane for redox flow cell batteries has been a major focus for many groups around the world in recent years. This paper reviews the research work on membranes for redox flow batteries, in particular for the all-vanadium redox flow battery which has received the most attention. PMID- 24958178 TI - UV-Induced Radical Photo-Polymerization: A Smart Tool for Preparing Polymer Electrolyte Membranes for Energy Storage Devices. AB - In the present work, the preparation and characterization of quasi-solid polymer electrolyte membranes based on methacrylic monomers and oligomers, with the addition of organic plasticizers and lithium salt, are described. Noticeable improvements in the mechanical properties by reinforcement with natural cellulose hand-sheets or nanoscale microfibrillated cellulose fibers are also demonstrated. The ionic conductivity of the various prepared membranes is very high, with average values approaching 10-3 S cm-1 at ambient temperature. The electrochemical stability window is wide (anodic breakdown voltages > 4.5 V vs. Li in all the cases) along with good cyclability in lithium cells at ambient temperature. The galvanostatic cycling tests are conducted by constructing laboratory-scale lithium cells using LiFePO4 as cathode and lithium metal as anode with the selected polymer electrolyte membrane as the electrolyte separator. The results obtained demonstrate that UV induced radical photo polymerization is a well suited method for an easy and rapid preparation of easy tunable quasi-solid polymer electrolyte membranes for energy storage devices. PMID- 24958179 TI - NMR and Electrochemical Investigation of the Transport Properties of Methanol and Water in Nafion and Clay-Nanocomposites Membranes for DMFCs. AB - Water and methanol transport behavior, solvents adsorption and electrochemical properties of filler-free Nafion and nanocomposites based on two smectite clays, were investigated using impedance spectroscopy, DMFC tests and NMR methods, including spin-lattice relaxation and pulsed-gradient spin-echo (PGSE) diffusion under variable temperature conditions. Synthetic (Laponite) and natural (Swy-2) smectite clays, with different structural and physical parameters, were incorporated into the Nafion for the creation of exfoliated nanocomposites. Transport mechanism of water and methanol appears to be influenced from the dimensions of the dispersed platelike silicate layers as well as from their cation exchange capacity (CEC). The details of the NMR results and the effect of the methanol solution concentration are discussed. Clays particles, and in particular Swy-2, demonstrate to be a potential physical barrier for methanol cross-over, reducing the methanol diffusion with an evident blocking effect yet nevertheless ensuring a high water mobility up to 130 degrees C and for several hours, proving the exceptional water retention property of these materials and their possible use in the DMFCs applications. Electrochemical behavior is investigated by cell resistance and polarization measurements. From these analyses it is derived that the addition of clay materials to recast Nafion decreases the ohmic losses at high temperatures extending in this way the operating range of a direct methanol fuel cell. PMID- 24958180 TI - Questionable role of adjuvant chemotherapy in rectal cancer patients who had reached pathological complete response after neoadjuvant concurrent chemoradiotherapy: no matter in the East or in the West. PMID- 24958181 TI - How does genome sequencing impact surgery? AB - Cancer is a leading cause of death worldwide. Great efforts are dedicated to the development of prognostic and predictive biomarkers to improve diagnosis and achieve optimal treatment selection, thereby, introducing precision medicine in the multimodality treatment of cancer. Genomic aberrations are the basis of tumour development, representing excellent candidates for the development of promising clinical biomarkers. Over the past decade, single-gene mutations and genomic profiling have been increasingly used in multidisciplinary consultations for risk-assessment and treatment planning for patients with cancer. We discuss the impact of such genetic-based information on surgical decision-making. Single gene mutations have already influenced surgical decision-making in breast, colorectal and thyroid cancer. However, the direct impact of genomic profiling on surgical care has not yet been fully established. We discuss the direct and indirect influences of genomic profiling on surgery, and analyse the limitations and unresolved issues of a genotypic-approach to the surgical management of cancer. PMID- 24958184 TI - Breast cancer: E75-a safe and effective vaccine for the prevention of disease recurrence. PMID- 24958185 TI - Epistaxis and dabigatran, a new non-vitamin K antagonist oral anticoagulant. AB - OBJECTIVE: Dabigatran is a new non-vitamin K antagonist (VKA) anticoagulant with anti-thrombin action, with supposedly fewer haemorrhagic complications. However, there are actually no established agents to reverse its effect, nor specific coagulation time tests for monitoring it. MATERIALS AND METHODS: An observational prospective study was developed, noting epidemiological, clinical and therapeutic features among subjects with epistaxis treated with dabigatran. Results were compared with a group of epistaxis cases of individuals under anticoagulant therapy with VKA (acenocoumarol) and a control group without anticoagulation. RESULTS: Since its inclusion in our health system almost 3 years ago, 19 patients with epistaxis and concomitant use of dabigatran have been attended at the Emergency Unit in our hospital, as against 59 under VKA therapy and 144 without anticoagulation, with a mean admittance rate of 26%, 28% and 14%, respectively. In 3 out of 5 individuals admitted due to dabigatran treatment, previously unobserved renal failure was detected. Blood transfusion was needed in 80% of patients using dabigatran, 58% using VKA and 23% without anticoagulation. Invasive procedures to control nosebleed were required in 80%, 35% and 21%, respectively. Although haemorrhagic risk was lower in dabigatran cases, they showed the longest stay in the hospital when compared to the other groups. CONCLUSIONS: With dabigatran, there are fewer cases of severe epistaxis than with acenocoumarol, but controlling them is more difficult. PMID- 24958182 TI - The oligometastatic state - separating truth from wishful thinking. AB - The oligometastatic paradigm implies that patients who develop a small number of metastatic lesions might achieve long-term survival if all these lesions are ablated with surgery or stereotactic radiotherapy. Clinical data indicate that the number of patients with oligometastatic disease receiving aggressive treatment is increasing rapidly. We examine the key evidence supporting or refuting the existence of an oligometastatic state. Numerous single-arm studies suggest that long-term survival is 'better-than-expected' after ablative treatment. However, the few studies with adequate controls raise the possibility that this long-term survival might not be due to the treatments themselves, but rather to the selection of patients based on favourable inclusion criteria. Furthermore, ablative treatments carry a risk of harming healthy tissue, yet the risk-benefit ratio cannot be quantified if the benefits are unmeasured. If the strategy of treating oligometastases is to gain widespread acceptance as routine clinical practice, there should be stronger evidence supporting its efficacy. PMID- 24958186 TI - [Outcomes following transoral resection of oropharyngeal squamous cell carcinoma]. AB - INTRODUCTION AND OBJECTIVES: The aim of our study was to evaluate outcomes of a minimally invasive approach, using transoral surgery (TOS) as the primary treatment for oropharyngeal carcinoma. METHODS: We reviewed 43 previously untreated patients with oropharyngeal carcinoma, who were treated with TOS. Distribution of the primary tumor site was: tonsil (52%), soft palate (23%), base of the tongue (21%) and posterior wall (4%). Eight patients had a stage I disease, 9 had a stage II disease, 7 had a stage III disease, 16 had a stage IVA, and 3 had stage IVB disease. Eighteen patients underwent postoperative radiotherapy. Records of these patients were reviewed to obtain measures such as local and regional control, overall and disease-specific survival, and speech and swallowing function. RESULTS: The overall recurrence rate was 44%, and the local recurrence rate was 18%. The 5-year overall survival and disease-specific survival rates were 55% and 66%, respectively. Five-year disease-specific survival rates by site were as follows: 100%, 85%, 44%, and 30% for posterior wall, tonsil, soft palate and base of the tongue, respectively. Five-year estimates for local control were 100%, 90%, and 0% for palate, tonsil and for base of the tongue tumors, respectively. All of the patients preserved the larynx and live without tracheotomy and oral alimentation was successfully without feeding tube. CONCLUSIONS: TOS as the primary treatment approach offers a surgical alternative for treatment of the primary oropharyngeal tumor, in the era of chemoradiation therapy. This approach confers a good local control and functional outcomes. PMID- 24958187 TI - 3D culture of tonsil-derived mesenchymal stem cells in poly(ethylene glycol) poly(L-alanine-co-L-phenyl alanine) thermogel. AB - Poly(ethylene glycol)-poly(L-alanine-co-L-phenyl alanine) (PEG-PAF) aqueous solutions undergo sol-to-gel transition as the temperature increases. The transition is driven by the micelle aggregation involving the partial dehydration of the PEG block and the partial increase in beta-sheet content of the PAF block. Tonsil-tissue-derived mesenchymal stem cells (TMSCs), a new stem cell resource, are encapsulated through the sol-to-gel transition of the TMSC-suspended PEG-PAF aqueous solutions. The encapsulated TMSCs are in vitro 3D cultured by using induction media supplemented with adipogenic, osteogenic, or chondrogenic factors, where the TMSCs preferentially undergo chondrogenesis with high expressions of type II collagen and sulfated glycosaminoglycan. As a feasibility study of the PEG-PAF thermogel for injectable tissue engineering, the TMSCs encapsulated in hydrogels are implanted in the subcutaneous layer of mice by injecting the TMSC suspended PEG-PAF aqueous solution. The in vivo studies also prove that TMSCs undergo chondrogenesis with high expression of the chondrogenic biomarkers. This study suggests that the TMSCs can be an excellent resource of MSCs, and the thermogelling PEG-PAF is a promising injectable tissue engineering scaffold, particularly for chondrogenic differentiation of the stem cells. PMID- 24958183 TI - Current and emerging strategies for the prevention of graft-versus-host disease. AB - Graft-versus-host disease (GVHD) represents the most serious and challenging complication of allogeneic haematopoietic stem-cell transplantation (HSCT). New insights on the role of regulatory T-cells, T cells, and antigen-presenting cells have led to an improved understanding of the pathophysiology of GVHD. However, little progress has been made since the introduction of calcineurin-inhibitor based regimens in the mid-1980s. Despite standard prophylaxis with these regimens, GVHD still develops in approximately 40-60% of recipients. Thus, there is a need for developing newer approaches to mitigate GVHD, which may facilitate the use of allogeneic HSCT for the treatment of a wider range of haematological cancers. We discuss the rationale, clinical evidence, and outcomes of current (and widely employed) strategies for GVHD prophylaxis, namely calcineurin inhibitor-based regimens (such as cyclosporine or tacrolimus) combined with methotrexate or mycophenolate mofetil. We assess the clinical evidence for emerging approaches in the prevention of GVHD, including therapies targeting T cells or B cells, the use of mesenchymal stem cells, chemo-cytokine antagonists (such as maraviroc, TNF-alpha inhibitor, IL-2 receptor antagonist, IL-6 inhibitor), and the use of novel molecular regulators that target multiple cell types simultaneously, including atorvastatin, bortezomib, and epigenetic modulators. PMID- 24958188 TI - Comparison of polymerase chain reaction and standard microbiological techniques in presumed bacterial corneal ulcers. AB - To assess utility of PCR in the diagnosis of bacterial corneal ulcer and to compare sensitivity and specificity of this technique with conventional laboratory methods. A prospective nonrandomized investigative study conducted on 122 eyes of presumed bacterial keratitis. Samples were collected for bacterial and fungal culture and Gram stain smear. A separate sample was taken for PCR with 26 gauge needle and was dipped directly into Eppendorff tube with lysis buffer in it. Diagnosis of culture proven bacterial keratitis was established in 53 (43.4 %) and most common bacterial isolate was staphylococcal sp. (83 %). Direct microscopic examination of Gram stained smear revealed presence of bacteria in 24 (23.9 %) specimens and PCR positivity was evident in 56 (45.5 %). In preantibiotic treated eyes culture was positive in 15 (30 %), Gram stain in 9 (18 %), and PCR in 18 (36 %). The same for untreated (fresh) eyes, positivity of culture as well as PCR was noted in 38 (52.7 %) and that of Gram stain was noted in 20 (27.7 %). Sensitivity of Gram stain and PCR was 45.28 and 88.68 % respectively; whereas specificity was 92.75 % for Gram stain and 86.96 % for PCR. The average time taken for PCR reaction was 4-8 h while culture reporting took at least 24-48 h. Our findings suggest that PCR is a good adjunct modality to the "Gold Standard" technique in the diagnosis of bacterial corneal ulcer. PMID- 24958190 TI - Headache and arachnoid cysts. AB - Arachnoid cysts are commonly encountered when neuroimaging is obtained for headaches. Their clinical relevance is not always immediately clear and they may confound medical management. PMID- 24958191 TI - Clusterin variants are not associated with southern Chinese patients with Alzheimer's disease. AB - Recent genome-wide association studies identified clusterin (CLU) to be associated with sporadic Alzheimer's disease. To help clarify the relevance of CLU as genetic determinant of AD, we analyzed its association in southern Chinese Han population. This study comprised 499 sporadic Alzheimer's disease patients and 592 unrelated age- and sex-matched healthy controls. Four single-nucleotide polymorphisms (rs2279590, rs9331888, rs11136000, and rs1532278) within CLU were selected for genotyping. No positive association was found between the CLU variants and AD. Our study suggests that CLU variants may not be an AD susceptibility factor in southern Chinese Han population. PMID- 24958189 TI - Injectable bioadhesive hydrogels with innate antibacterial properties. AB - Surgical site infections cause significant postoperative morbidity and increased healthcare costs. Bioadhesives used to fill surgical voids and support wound healing are typically devoid of antibacterial activity. Here we report novel syringe-injectable bioadhesive hydrogels with inherent antibacterial properties prepared from mixing polydextran aldehyde and branched polyethylenimine. These adhesives kill both Gram-negative and Gram-positive bacteria, while sparing human erythrocytes. An optimal composition of 2.5 wt% oxidized dextran and 6.9 wt% polyethylenimine sets within seconds forming a mechanically rigid (~1,700 Pa) gel offering a maximum adhesive stress of ~2.8 kPa. A murine infection model showed that the adhesive is capable of killing Streptococcus pyogenes introduced subcutaneously at the bioadhesive's surface, with minimal inflammatory response. The adhesive was also effective in a cecal ligation and puncture model, preventing sepsis and significantly improving survival. These bioadhesives represent novel, inherently antibacterial materials for wound-filling applications. PMID- 24958193 TI - Fragile X gene expansions are not associated with dementia. AB - The purpose of this study was to determine the frequency of fragile X mental retardation 1 (FMR1) premutation size expansions in individuals with Alzheimer's disease (AD) and other cognitive disorders compared with control subjects. FMR1 genetic screening was completed in patients being seen in a neurobehavioral or AD clinics. Appropriate controls were also collected. A second cohort was a community based, autopsy confirmed, sample of individuals with normal cognitive function, mild cognitive impairment, or AD. There was not an increased frequency of FMR1 expansions in individuals with cognitive disorders, including AD, compared with control subjects. PMID- 24958192 TI - Genome-wide association interaction analysis for Alzheimer's disease. AB - We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer's disease (AD) (2259 patients and 6017 controls from France). Particularly, in the exhaustive genome-wide epistasis screening we identified AD associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) (p = 0.006, corrected for multiple testing). A replication analysis in the independent AD cohort from Germany (555 patients and 824 controls) confirmed the discovered epistasis signal (p = 0.036). This signal was also supported by a meta-analysis approach in 5 independent AD cohorts that was applied in the context of epistasis for the first time. Transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex (beta = -0.19, p = 0.0006) and cerebellum (beta = -0.23, p < 0.0001) brain regions. This is the first time a replicable epistasis associated with AD was identified using a hypothesis free screening approach. PMID- 24958195 TI - Impact of rhinitis on asthma severity in school-age children. AB - BACKGROUND: In a population-based sample of school-age children, we investigated factors associated with rhinitis, and differences between allergic and nonallergic rhinitis. Amongst children with asthma, we explored the association between rhinitis and asthma severity. METHODS: Children participating in a birth cohort study (n = 906) were reviewed at age 8 years. Asthma was defined as at least two of the following three features: physician-diagnosed asthma, currently using asthma medication and current wheeze. We measured lung function (plethysmography and spirometry) and airway hyper-reactivity (AHR; methacholine challenge). RESULTS: In the analysis adjusted for the presence of asthma, children with rhinitis had significantly higher AHR (P = 0.001). Maternal smoking and absence of breastfeeding were stronger predictors of nonallergic rhinitis, whereas current wheeze and eczema were stronger predictors of allergic rhinitis. Amongst asthmatics (n = 159), when compared to 76 children without rhinitis, those with rhinitis (n = 83) were 2.89-fold (95% CI 1.41-5.91) more likely to experience frequent attacks of wheezing, 3.44-fold (1.19-9.94) more likely to experience severe attacks of wheezing limiting speech, 10.14-fold (1.27-81.21) more likely to have frequent visits to their doctor because of asthma and nine fold (1.11-72.83) more likely to miss school. Reported use of intranasal corticosteroids resulted in a numerically small, but consistent reduction in risk, rendering the associations between rhinitis and asthma severity nonsignificant. CONCLUSION: We observed differences in risk factors and severity between allergic and nonallergic rhinitis. In children with asthma, rhinitis had adverse impact on asthma severity. The use of intranasal corticosteroids resulted in a small, but consistent reduction in the risk. PMID- 24958194 TI - Nonsense mutation in PRNP associated with clinical Alzheimer's disease. AB - Here, we describe a nonsense haplotype in PRNP associated with clinical Alzheimer's disease. The patient presented an early-onset of cognitive decline with memory loss as the primary cognitive problem. Whole-exome sequencing revealed a nonsense mutation in PRNP (NM_000311, c.C478T; p.Q160*; rs80356711) associated with homozygosity for the V allele at position 129 of the protein, further highlighting how very similar genotypes in PRNP result in strikingly different phenotypes. PMID- 24958198 TI - Fabrication of metal nanoelectrodes by interfacial reactions. AB - Despite great improvements in the past decades, the controllable fabrication of metal nanoelectrodes still remains very challenging. In this work, a simple and general way to fabricate metal nanoelectrodes (Ag, Au, and Pt) is developed. On the basis of interfacial reactions at nano-liquid/liquid interfaces supported at nanopipettes, the nanoparticles can be formed in situ and have been used to block the orifices of pipettes to make nanoelectrodes. The effect of the driving force for interfacial reaction at the liquid/liquid interface, the ratio of redox species in organic and aqueous phases, and the surface charge of the inner wall of a pipette have been studied. The fabricated nanoelectrodes have been characterized by scanning electron microscopy (SEM) and electrochemical techniques. A silver electrode with about 10 nm in radius has been employed as the scanning electrochemical microscopy (SECM) probe to explore the thickness of a water/nitrobenzene (W/NB) interface, and this value is equal to 0.8 +/- 0.1 nm (n = 5). This method of fabrication of nanoelectrodes can be extended to other metal or semiconductor electrodes. PMID- 24958197 TI - A skin disease, a blood disease or something in between? An exploratory focus group study of patients' experiences with porphyria cutanea tarda. AB - BACKGROUND: Porphyria cutanea tarda (PCT) is characterized by fragile skin with blistering on sun-exposed areas. Symptoms typically develop in late adulthood and can be triggered by iron overload, alcohol intake, oestrogens and various liver diseases. Treatment consists of phlebotomy to reduce iron, or increasing urinary porphyrin excretion by administering chlorochin. To optimize patient care, health personnel need to understand the subjective experiences of PCT. OBJECTIVES: To explore the experiences of persons with PCT with regard to symptoms, treatment, follow-up and prevention of the disease. METHODS: Interpretive description was used as a qualitative approach. Twenty-one participants attended three focus groups. All participants had experienced PCT symptoms during the last 5 years. RESULTS: Participants' experiences varied from trivializing symptoms and fragile skin to what was described as a desperate situation, with huge blisters, skin falling off and feeling as if one was in a 'horror movie'. For some, itching was very troublesome, preventing sleep and delaying skin healing. In managing PCT a shift in focus from skin to blood was described. PCT was perceived as a chronic and systemic disease causing a range of health problems. Strategies for preventing symptoms ranged from doing nothing to frequent controls and check-ups. CONCLUSIONS: Participants had a systemic perception of PCT, and a tendency to attribute a range of health problems to the condition. This study adds insight into the experiences patients have with PCT. PMID- 24958196 TI - Schwannoma: a rare benign tumor of soft tissues. AB - 'Schwannomas are unusual benign tumors which arise from the surface of neural elements of the body or within the brain. They do not as a rule metastasize but may cause sometimes severe local problems on the nerves, blood vessels and adjacent bone. The tumors arise from the Sheath of Schwann, a structure on the surface of a nerve. The lesions may expand and cause considerable damage to adjacent tissues. They do not arise within bone since there are no Sheaths of Schwann within the osseous tissue but may cause local damage to the bony cortex and sometimes fractures. Rarely the lesions may metastasize and cause patients' death. The treatment is usually local resection, and most often is successful although may cause damage to the adjacent nerve. PMID- 24958199 TI - Vaporization of the prototypical ionic liquid BMImNTf2 under equilibrium conditions: a multitechnique study. AB - The vaporization behaviour and thermodynamics of the ionic liquid 1-butyl-3 methylimidazolium bis(trifluoromethyl)sulfonylimide (BMImNTf2) were studied by combining the Knudsen Effusion Mass Loss (KEML) and Knudsen Effusion Mass Spectrometry (KEMS) techniques. KEML studies were carried out in a large temperature range (398-567) K by using effusion orifices with 0.3, 1, and 3 mm diameters. The vapor pressures so measured revealed no kinetically hindered vaporization effects and provided second-law vaporization enthalpies at the mean experimental temperatures in close agreement with literature. By exploiting the large temperature range covered, the heat capacity change associated with vaporization was estimated, resulting in a value of -66.8 J K(-1) mol(-1), much lower than that predicted from calorimetric measurements on the liquid phase and theoretical calculations on the gas phase. The conversion of the high temperature vaporization enthalpy to 298 K was discussed and the value Delta(l)(g)H(m)(298 K) = (128.6 +/- 1.3) kJ mol(-1) assessed on the basis of data from literature and present work. Vapor pressure data were also processed by the third-law procedure using different estimations for the auxiliary thermal functions, and a Delta(l)(g)H(m)(298 K) consistent with the assessed value was obtained, although the overall agreement is sensitive to the accuracy of heat capacity data. KEMS measurements were carried out in the lower temperature range (393-467) K and showed that the largely prevailing ion species is BMIm(+), supporting the common view of BMImNTf2 vaporizing as individual, neutral ion pairs also under equilibrium conditions. By monitoring the mass spectrometric signal of this ion as a function of temperature, a second-law Delta(l)(g)H(m)(298 K) of 129.4 +/- 7.3 kJ mol(-1) was obtained, well consistent with KEML and literature results. Finally, by combining KEML and KEMS measurements, the electron impact ionization cross section of BMIm(+) was estimated. PMID- 24958201 TI - New potassium-sodium niobate material system: a giant-d33 and high-T(C) lead-free piezoelectric. AB - In this work, we elucidate the influence of Bi(0.5)Li(0.5)ZrO3 (BLZ) content on the phase structure, microstructure, and electrical properties of (1 x)K(0.40)Na(0.60)Nb(0.965)Sb(0.035)O3-xBi(0.5)Li(0.5)ZrO3 lead-free ceramics. We simultaneously achieved a giant d33 and a high T(C) in this material system. The coexistence of rhombohedral and tetragonal phases is responsible for such a large d33 in the ceramics with BLZ contents (x) ranging from 0.025 to 0.035. Doping with BLZ not only induces the formation of the phase boundary, but also maintains a high T(C). The ceramic with x = 0.03 shows an enhanced piezoelectric behaviour (d33 ~ 400 pC N(-1) and k(p) ~ 0.47) together with a high T(C) of 292 degrees C. A good temperature stability for ferroelectricity and piezoelectricity is also observed in these ceramics. This study is the first time that such a good comprehensive performance has been obtained in potassium-sodium niobate materials. We believe that this type of material system possessing giant-d33 and high-T(C) is a promising candidate for use in high-temperature piezoelectric devices. PMID- 24958200 TI - Effects of flavonoid-induced oxidative stress on anti-H5N1 influenza a virus activity exerted by baicalein and biochanin A. AB - BACKGROUND: Different flavonoids are known to interfere with influenza A virus replication. Recently, we showed that the structurally similar flavonoids baicalein and biochanin A inhibit highly pathogenic avian H5N1 influenza A virus replication by different mechanisms in A549 lung cells. Here, we investigated the effects of both compounds on H5N1-induced reactive oxygen species (ROS) formation and the role of ROS formation during H5N1 replication. FINDINGS: Baicalein and biochanin A enhanced H5N1-induced ROS formation in A549 cells and primary human monocyte-derived macrophages. Suppression of ROS formation induced by baicalein and biochanin A using the antioxidant N-acetyl-L-cysteine strongly increased the anti-H5N1 activity of both compounds in A549 cells but not in macrophages. CONCLUSIONS: These findings emphasise that flavonoids induce complex pharmacological actions some of which may interfere with H5N1 replication while others may support H5N1 replication. A more detailed understanding of these actions and the underlying structure-activity relationships is needed to design agents with optimised anti-H5N1 activity. PMID- 24958202 TI - Asymmetric c-fos expression in the ventral orbital cortex is associated with impaired reversal learning in a right-sided neuropathy. AB - BACKGROUND: Recently we showed that unilateral peripheral neuropathic lesions impacted differentially on rat's emotional/cognitive behavior depending on its left/right location; importantly, this observation recapitulates clinical reports. The prefrontal cortex (PFC), a brain region morphofunctionally affected in chronic pain conditions, is involved in the modulation of both emotion and executive function and displays functional lateralization. To test whether the PFC is involved in the lateralization bias associated with left/right pain, c-fos expression in medial and orbital areas was analyzed in rats with an unilateral spared nerve injury neuropathy installed in the left or in the right side after performing an attentional set-shifting, a strongly PFC-dependent task. RESULTS: SNI-R animals required more trials to successfully terminate the reversal steps of the attentional set-shifting task. A generalized increase of c-fos density in medial and orbital PFC (mPFC/OFC), irrespectively of the hemisphere, was observed in both SNI-L and SNI-R. However, individual laterality indexes revealed that contrary to controls and SNI-L, SNI-R animals presented a leftward shift in c-fos density in the ventral OFC (VO). None of these effects were observed in the neighboring primary motor area. CONCLUSIONS: Our results demonstrate that chronic neuropathic pain is associated with a bilateral mPFC and OFC hyperactivation. We hypothesize that the impaired performance of SNI-R animals is associated with a left/right activity inversion in the VO, whose functional integrity is critical for reversal learning. PMID- 24958204 TI - The whole truth about coronary stents: the elephant in the room. PMID- 24958203 TI - Analysis of novel kitasatosporae reveals significant evolutionary changes in conserved developmental genes between Kitasatospora and Streptomyces. AB - Actinomycetes are antibiotic-producing filamentous bacteria that have a mycelial life style. The members of the three genera classified in the family Streptomycetaceae, namely Kitasatospora, Streptacidiphilus and Streptomyces, are difficult to distinguish using phenotypic properties. Here we present biochemical and genetic evidence that helps underpin the case for the continued recognition of the genus Kitasatospora and for the delineation of additional Kitasatospora species. Two novel Kitasatospora strains, isolates MBT63 and MBT66, and their genome sequences are presented. The cell wall of the Kitasatospora strains contain a mixture of meso-and LL-diaminopimelic acid (A2pm), whereby a single DapF surprisingly suffices to incorporate both components into the Kitasatospora cell wall. The availability of two new Kitasatospora genome sequences in addition to that of the previously sequenced Kitasatospora setae KM-6054(T) allows better phylogenetic comparison between kitasatosporae and streptomycetes. This showed that the developmental regulator BldB and the actin-like protein Mbl are absent from kitasatosporae, while the cell division activator SsgA and its transcriptional activator SsgR have been lost from some Kitasatospora species, strongly suggesting that Kitasatospora have evolved different ways to control specific steps in their development. We also show that the tetracycline-producing strain "Streptomyces viridifaciens" DSM 40239 not only has properties consistent with its classification in the genus Kitasatospora but also merits species status within this taxon. PMID- 24958206 TI - Evolution of microstructure, strain and physical properties in oxide nanocomposite films. AB - We, using LSMO:ZnO nanocomposite films as a model system, have studied the effect of film thickness on the physical properties of nanocomposites. It shows that strain, microstructure, as well as magnetoresistance strongly rely on film thickness. The magnetotransport properties have been fitted by a modified parallel connection channel model, which is in agreement with the microstructure evolution as a function of film thickness in nanocomposite films on sapphire substrates. The strain analysis indicates that the variation of physical properties in nanocomposite films on LAO is dominated by strain effect. These results confirm the critical role of film thickness on microstructures, strain states, and functionalities. It further shows that one can use film thickness as a key parameter to design nanocomposites with optimum functionalities. PMID- 24958205 TI - Role of appetite-regulating peptides in the pathophysiology of addiction: implications for pharmacotherapy. AB - Food intake and appetite are regulated by various circulating hormones including ghrelin and glucagon-like-peptide 1 (GLP-1). Ghrelin, mainly released from the stomach, increases food intake, induces appetite, enhances adiposity as well as releases growth hormone. Hypothalamic "ghrelin receptors" (GHS-R1A) have a critical role in food intake regulation, but GHS-R1A are also expressed in reward related areas. GLP-1 is produced in the intestinal mucosa as well as in the hindbrain in response to nutrient ingestion. This gut-brain hormone reduces food intake as well as regulates glucose homeostasis, foremost via GLP-1 receptors in hypothalamus and brain stem. However, GLP-1 receptors are expressed in areas intimately associated with reward regulation. Given that regulation of food and drug intake share common neurobiological substrates, the possibility that ghrelin and GLP-1 play an important role in reward regulation should be considered. Indeed, this leading article describes that the orexigenic peptide ghrelin activates the cholinergic-dopaminergic reward link, an important part of the reward systems in the brain associated with reinforcement and thereby increases the incentive salience for motivated behaviors via this system. We also review the role of ghrelin signaling for reward induced by alcohol and addictive drugs from a preclinical, clinical and human genetic perspective. In addition, the recent findings showing that GLP-1 controls reward induced by alcohol, amphetamine, cocaine and nicotine in rodents are overviewed herein. Finally, the role of several other appetite regulatory hormones for reward and addiction is briefly discussed. Collectively, these data suggest that ghrelin and GLP-1 receptors may be novel targets for development of pharmacological treatments of alcohol and drug dependence. PMID- 24958207 TI - The activation mode of the mechanosensitive ion channel, MscL, by lysophosphatidylcholine differs from tension-induced gating. AB - One of the best-studied mechanosensitive channels is the mechanosensitive channel of large conductance (MscL). MscL senses tension in the membrane evoked by an osmotic down shock and directly couples it to large conformational changes leading to the opening of the channel. Spectroscopic techniques offer unique possibilities to monitor these conformational changes if it were possible to generate tension in the lipid bilayer, the native environment of MscL, during the measurements. To this end, asymmetric insertion of l-alpha lysophosphatidylcholine (LPC) into the lipid bilayer has been effective; however, how LPC activates MscL is not fully understood. Here, the effects of LPC on tension-sensitive mutants of a bacterial MscL and on MscL homologs with different tension sensitivities are reported, leading to the conclusion that the mode of action of LPC is different from that of applied tension. Our results imply that LPC shifts the free energy of gating by interfering with MscL-membrane coupling. Furthermore, we demonstrate that the fine-tuned addition of LPC can be used for controlled activation of MscL in spectroscopic studies. PMID- 24958209 TI - Pharyngocutaneous fistula after total laryngectomy: systematic review of risk factors. AB - BACKGROUND: Pharyngocutaneous fistula (PCF) is the most common surgical complication after total laryngectomy. Controversy still remains regarding the multiple risk factors implicated. The purpose of this study was to evaluate the potential risk factors for PCF. METHODS: The strategy for our literature survey included research in MEDLINE up to December 2013. The risk factors analyzed were age, sex, smoking habit, alcohol use, comorbidity, preoperative hemoglobin level, blood transfusion, preoperative tracheotomy, previous radiotherapy and chemoradiotherapy, primary tumor site, T classification, cartilage invasion, tumor grade, surgical margins, suture material, second layer of suture, reconstruction, tracheoesophageal prosthesis, and neck dissection. RESULTS: The electronic search resulted in 311 studies from which 63 met the inclusion criteria. CONCLUSION: Chronic obstructive pulmonary disease (COPD), previous hemoglobin <12.5g/dL, blood transfusion, previous radiotherapy or chemoradiotherapy, advanced primary tumors, supraglottic subsite, hypopharyngeal tumor site, positive surgical margins, and the performance of neck dissection were risk factors for PCF. PMID- 24958208 TI - Crosstalk between TGF-beta1 and complement activation augments epithelial injury in pulmonary fibrosis. AB - The epithelial complement inhibitory proteins (CIPs) cluster of differentiation 46 and 55 (CD46 and CD55) regulate circulating immune complex-mediated complement activation in idiopathic pulmonary fibrosis (IPF). Our previous studies demonstrated that IL-17A mediates epithelial injury via transforming growth factor beta1 (TGF-beta1) and down-regulates CIPs. In the current study, we examined the mechanistic role of TGF-beta1 in complement activation-mediated airway epithelial injury in IPF pathogenesis. We observed lower epithelial CIP expression in IPF lungs compared to normal lungs, associated with elevated levels of complement component 3a and 5a (C3a and C5a), locally and systemically. In normal primary human small airway epithelial cells (SAECs) treated with TGF-beta1 (10 ng/ml), C3a, or C5a (100 nM), we observed loss of CIPs and increased poly(ADP ribose) polymerase (PARP) activation [also observed with RNA interference (RNAi) of CD46/CD55]. TGF-beta1-mediated loss of CIPs and Snail induction [SNAI1; a transcriptional repressor of E-cadherin (E-CAD)] was blocked by inhibiting mitogen-activated protein kinase (p38MAPK; SB203580) and RNAi silencing of SNAI1. C3a- and C5a-mediated loss of CIPs was also blocked by p38MAPK inhibition. While C3a upregulated TGFb transcripts, both C3a and C5a down-regulated SMAD7 (negative regulator of TGF-beta), and whereas TGF-beta1 induced C3a/C5a receptor (C3aR/C5aR) expression, pharmacologic C3aR/C5aR inhibition protected against C3a /C5a-mediated loss of CIPs. Taken together, our results suggest that epithelial injury in IPF can be collectively amplified as a result of TGF-beta1-induced loss of CIPs leading to complement activation that down-regulates CIPs and induces TGF beta1 expression PMID- 24958210 TI - Birth cohort study on the effects of desert dust exposure on children's health: protocol of an adjunct study of the Japan Environment & Children's Study. AB - INTRODUCTION: Desert dust is estimated to constitute about 35% of aerosol in the troposphere. Desertification, climatic variability and global warming all can contribute to increased dust formation. This study aims to examine possible health effects of desert dust exposure on pregnant women and their children. The purpose of this report was to present the study protocol. METHODS AND ANALYSIS: This 4-year birth cohort study began in 2011 as an adjunct study of the Japan Environment & Children's Study (JECS) involving three regions: Kyoto, Toyama and Tottori. The JECS participants of the three regions above who also agreed to participate in this adjunct study were enrolled prior to delivery. Light Detecting and Ranging (LIDAR) with a polarisation analyser, which can distinguish mineral dust particles from other particles, is used for exposure measurements. Outcomes are allergic symptoms for mothers and development of asthma and other allergic or respiratory diseases for their children. Data are acquired in a timely manner by connecting local LIDAR equipment to an online questionnaire system. Participants answer the online questionnaire using mobile phones or personal computers. ETHICS AND DISSEMINATION: The study protocol was approved by the ethics committees of Kyoto University, University of Toyama and Tottori University. All participants provided written informed consent. The results of this study will be published in peer-reviewed journals and disseminated to the scientific community and general public. TRIAL REGISTRATION NUMBER: UMIN000010826. PMID- 24958211 TI - Understanding how appraisal of doctors produces its effects: a realist review protocol. AB - INTRODUCTION: UK doctors are now required to participate in revalidation to maintain their licence to practise. Appraisal is a fundamental component of revalidation. However, objective evidence of appraisal changing doctors' behaviour and directly resulting in improved patient care is limited. In particular, it is not clear how the process of appraisal is supposed to change doctors' behaviour and improve clinical performance. The aim of this research is to understand how and why appraisal of doctors is supposed to produce its effect. METHODS AND ANALYSIS: Realist review is a theory-driven interpretive approach to evidence synthesis. It applies realist logic of inquiry to produce an explanatory analysis of an intervention that is, what works, for whom, in what circumstances, in what respects. Using a realist review approach, an initial programme theory of appraisal will be developed by consulting with key stakeholders in doctors' appraisal in expert panels (ethical approval is not required), and by searching the literature to identify relevant existing theories. The search strategy will have a number of phases including a combination of: (1) electronic database searching, for example, EMBASE, MEDLINE, the Cochrane Library, ASSIA, (2) 'cited by' articles search, (3) citation searching, (4) contacting authors and (5) grey literature searching. The search for evidence will be iteratively extended and refocused as the review progresses. Studies will be included based on their ability to provide data that enable testing of the programme theory. Data extraction will be conducted, for example, by note taking and annotation at different review stages as is consistent with the realist approach. The evidence will be synthesised using realist logic to interrogate the final programme theory of the impact of appraisal on doctors' performance. The synthesis results will be written up according to RAMESES guidelines and disseminated through peer-reviewed publication and presentations. TRIAL REGISTRATION NUMBER: The protocol is registered with PROSPERO 2014:CRD42014007092. PMID- 24958213 TI - Editorial: dedicated to the memory of Professor Oguz Baskurt. PMID- 24958212 TI - Addressing the evidence to practice gap for complex interventions in primary care: a systematic review of reviews protocol. AB - INTRODUCTION: Getting the results of research implemented into routine healthcare is often a challenge. The disconnect between the development and implementation of evidence into practice is called the 'second translational gap' and is particularly apparent in primary care. To address this gap, we plan to identify, summarise and synthesise currently available evidence by undertaking a systematic review of reviews to: (1) explore barriers and facilitators of implementation of research evidence or complex interventions, and (2) assess the effectiveness of strategies in facilitating implementation of complex interventions in primary care. METHODS AND ANALYSIS: This is a protocol for a systematic review of reviews. We will search MEDLINE, EMBASE, the Cochrane Library, CINAHL and PsycINFO up until December 2013. We will check reference lists of included studies for further studies. Two authors will independently screen the titles and abstracts identified from the search; any discrepancies will be resolved by discussion and consensus. Full-text papers will be obtained and relevant reviews will be selected against inclusion criteria. Eligible reviews have to be based on predominantly primary care in developed countries and examine either factors to implementation or, the effectiveness of strategies to optimise implementation. Data from eligible reviews will be extracted using standardised data abstraction forms. For barriers and facilitators, data will be synthesised using an interpretative meta-synthesis approach. For implementation strategies, findings will be summarised and described narratively and synthesised using a framework approach. All findings will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. ETHICS AND DISSEMINATION: Ethical approval is not required. The review findings will inform the work of the design and implementation of future studies and will be of interest to a wide audience including health professionals, researchers, health service or commissioning managers and policymakers. TRIAL REGISTRATION NUMBER: Protocol registration number (PROSPERO CRD42014009410). PMID- 24958214 TI - Effect of solution and post-mortem time on mechanical and histological properties of liver during cold preservation. AB - BACKGROUND: In liver transplantation, the donor and recipient are in different locations most of the time, and longer preservation periods are inevitable. Hence, the choice of the preservation solution and the duration of the preservation period are critical for the success of the transplant surgery. OBJECTIVE: In this study, we examine the mechanical and histological properties of the bovine liver tissue stored in Lactated Ringer's (control), HTK and UW solutions as a function of preservation period. METHODS: The mechanical experiments are conducted with a shear rheometer on cylindrical tissue samples extracted from 3 bovine livers and the change in viscoelastic material properties of the bovine liver is characterized using the fractional derivative Kelvin-Voigt Model. Also, the histological examinations are performed on the same liver samples under a light microscope. RESULTS: The results show that the preservation solution and period have a significant effect on the mechanical and histological properties of the liver tissue. The storage and loss shear moduli, the number of the apoptotic cells, the collagen accumulation, and the sinusoidal dilatation increase, and the glycogen deposition decreases as the preservation period is longer. CONCLUSIONS: Based on the statistical analyses, we observe that the liver tissue is preserved well in all three solutions for up to 11 h. After then, UW solution provides a better preservation up to 29 h. However, for preservation periods longer than 29 h, HTK is a more effective preservation solution based on the least amount of change in mechanical properties. On the other hand, the highest correlation between the mechanical and histological properties is observed for the liver samples preserved in UW solution. PMID- 24958215 TI - Recent androgen receptor antagonists in prostate cancer. AB - Androgen receptor has been shown to promote prostate cell growth and carcinogenesis of prostate cancer by up-regulating its target genes. Testosterone and dihydrotestosterone are two major hormones which bind to and activate androgen receptor. Targeting both the androgen receptor and the enzymes catalyzing the biosynthesis of testosterone and dihydrotestosterone has been shown to be clinically beneficial in the treatment of prostate cancer. Prostate cancer can become castration-resistant after long term treatment with chemo drugs, so efforts in finding compounds with improved efficiency to castration resistant prostate cancer are urgently needed. In this review we summarized the studies on recent progress in the development of small molecular AR antagonists for the treatment of prostate cancer. PMID- 24958216 TI - Medicinal chemistry discoveries among 1,3,5-triazines: recent advances (2000 2013) as antimicrobial, anti-TB, anti-HIV and antimalarials. AB - The chemistry and an extensive spectrum of biological activities of s-triazines have been examined since several decades and this heterocyclic core has received emerging consensus. This article aims to summarize recent advances (2000-2013) made towards the discovery of antimicrobial, antituberculosis, anti-HIV and antimalarial agents holding 1,3,5-triazine ring as a nucleus with the substitution of several types of nucleophiles. Molecular patterns associated with particular potency have been identified targeting several Gram-positive and Gram negative bacteria and some fungal species, mycobacterium tuberculosis H37Rv, HIV type I and HIV type II, particularly, HIV-1I IIB and HIV- 1ROD strains as well as a variety of P. falciparum malarial strains as chloroquine-resistant K1, chloroquine-susceptible NF54, chloroquine-sensitive 3D7, P. falciparum (D6 clone), P. falciparum (W2 clone), cycloguanil-resistant FCR-3, chloroquine sensitive RKL2. The report will be of considerable interest to gain useful information for the furtherance of drug discovery with extended 1,3,5-triazine designs. PMID- 24958217 TI - Antiaging therapy: a novel target for antilipolytic drugs. AB - Aging has been defined as a gradually decreasing ability to maintain homeostasis and increasing risk to die. Growing evidence supports malfunctioning with age of quality control system. At an older age, accumulation of altered macromolecules and membranes may impair cell functioning; accumulation of altered mitochondria and peroxisomes may boost the yield of ROS per unit of produced energy and accelerate the aging process. Evidence produced that autophagy, an essential part in cell housekeeping during fasting, may help removal of altered membranes, mitochondria and peroxisomes selectively and account for the antiaging effects of caloric restriction. Stimulation of autophagy may improve innate and adaptive immunity; decrease the risk of myopathy, heart disease, liver disease, neurodegeneration and cancer; and retard aging. Functioning of autophagy may decline in well fed adults and is almost negligible at older age. Induction of autophagy may result in "cleaner cells" lower in oxidative status and more resistant to injury and disease. The administration of antilipolytic drugs to fasted animals was shown to intensify autophagy in a physiologically appropriate manner, to enhance submaximal antiaging effects of low level of caloric restriction, to rapidly rescue older cells from the accumulation of altered mtDNA and older peroxisomes, to increase urinary 8-OHdG levels, and counteract the age related hypercholesterolemia in rodents. In conclusion, benefits of long-lasting stimulation of autophagy and protein and organelle turnover shows that antilipolytic drugs might find a novel therapeutic application in antiaging medicine. PMID- 24958218 TI - Novel drug delivery systems for releasing growth factors to the CNS: focus on Alzheimer's and Parkinson's diseases. AB - Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most common neurodegenerative disorders and affect more than 35 million people. Due to the limited effectiveness of available treatments in halting the neurodegenerative process, new therapies, such therapies based on growth factors (GFs), have been investigated. Nevertheless, the efficacies of these new treatments depend not only on the application of neurotrophins but also on the approaches used to deliver these proteins such that they can reach the brain. This review summarises the most widely used drug delivery systems (DDSs) for releasing GFs as possible treatments for AD and PD. PMID- 24958219 TI - Benzocoumarins: isolation, synthesis, and biological activities. AB - Benzocoumarins are coumarins with a phenyl group bonded to 3,4-, 5,6-, 6,7-, or 7,8-positions. Over the past years, significant efforts have been made not only to isolate the novel structural analogs of benzocoumarins with prominent bioactivities but also to design new synthetic methods to synthesize benzocoumarins with better or novel biological properties. The aim of this review is to provide the readers with an overview of the research progress of benzocoumarins from 1953 to May 2014, covering its isolation, synthesis, and biological activities. PMID- 24958220 TI - Dependence of DPPH radical scavenging activity of dietary flavonoid quercetin on reaction environment. AB - Many of nowadays diseases are due to the oxidative stress resulting from imbalance between formation and neutralization of free radicals. Intake of dietary antioxidants is therefore crucial to maintain good health. As the safety of synthetic antioxidants has raised several questions the search for natural efficient antioxidants from chemicals produced by plants has gained increased popularity in recent years. Quercetin is an abundant dietary flavonoid with well known radical scavenging properties being often used as a reference compound in many antioxidant tests. Its reaction with 1,1- diphenyl-2-picrylhydrazyl (artificial DPPH radical) is rapid and stoichiometric; however the published inhibitory constants vary in a very wide range, from 95 nM to 226 uM. The analysis indicates the dependence of antiradical capacity of quercetin on the composition of solvent systems where the reactions are performed and also on the surrounding temperature showing somewhat higher scavenging ability at body temperature compared to room conditions. At the same time, this activity is generally independent on the initial DPPH concentration. These data highlight the importance to consider the reaction environment and conditions when predicting the redox behavior of quercetin in a certain cellular context. Moreover, due to the changes in cellular environment accompanying with different pathogeneses the redox action of polyphenols can essentially vary leading even to the situations where the well-known antioxidant quercetin may reveal prooxidant properties. PMID- 24958221 TI - Selective intra-arterial dual-energy CT angiography (s-CTA) in lower extremity arterial occlusive disease. AB - OBJECTIVE: In patients with peripheral arterial occlusive disease, renal impairment is a common contraindication to iodine and gadolinium contrast media, which limits the utility of conventional computed tomography angiography (CTA) and magnetic resonance angiography (MRA). It is proposed that selective intra arterial dual-energy CT-angiography (s-CTA), that is CTA with intra-arterial injection of an ultra-low dose iodine contrast media, is a feasible, safe and accurate alternative imaging method to conventional non-invasive contrast enhanced vascular imaging in this patient group. The aim of this study was to report a preliminary experience of s-CTA in patients with critical limb ischemia and renal insufficiency with respect to safety, feasibility, and diagnostic accuracy. MATERIALS AND METHODS: Ten non-consecutive patients with ischemic foot ulcers underwent s-CTA of one leg. Procedure related complications were recorded and imaging results were compared with conventional digital subtraction angiography (DSA). RESULTS: A median 17 mL (range 10-19 mL) contrast media (400 mg I/mL) was used. The median baseline plasma creatinine was 163 MUmol/L (range 105-569) pre s-CTA versus 153 MUmol/L (range 105-562) post s-CTA (p = .24). There was no puncture site complication. Among the patients selected for intervention (n = 6 with 30 arterial segments) the s-CTA findings correlated well with the DSA findings; the diagnostic sensitivity was 100%, the specificity 89%, and the accuracy 93%. CONCLUSION: In this pilot study, a novel imaging method (s-CTA) is presented that provides high-quality arterial phase images with ultra-low dose iodine contrast media useful also for patients unsuitable for conventional contrast enhanced imaging methods because of renal insufficiency. PMID- 24958222 TI - Recombinant fusion protein linking factor VIIa with albumin (rVIIa-FP): Tissue distribution in rats. AB - INTRODUCTION: A novel fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP) is currently undergoing clinical investigations. OBJECTIVE: This study was conducted to examine the biodistribution of rVIIa-FP in comparison to recombinant factor VIIa (rFVIIa). MATERIALS AND METHODS: [(3)H]-rVIIa-FP (10mgkg( 1)) or [(3)H]-rFVIIa (1.6mgkg(-1)) were administered intravenously to rats, followed by quantitative whole-body and knee joint autoradiography for 24 ([(3)H] rFVIIa) or 240 ([(3)H]-rVIIa-FP) hours post-dose. Pharmacokinetic and excretion balance analyses were performed. RESULTS: In contrast to [(3)H]-albumin, the tissue distributions of [(3)H]-rVIIa-FP and [(3)H]-rFVIIa were similar. Within the knee, both were rapidly present within synovial and mineralized regions. Importantly, rVIIa-FP- and albumin-derived radioactivity were detectable up to 72 120hours, whereas [(3)H]-rFVIIa signals were already close to detection limits at 24hours. The longest rVIIa-FP retention times were observed in bone marrow and endosteum, in which the retention times were up to 5 times longer for rVIIa-FP compared with rFVIIa. Up to 8hours post-dose, 100% of radioactivity was assigned to unchanged [(3)H]-rVIIa-FP. Elimination of both proteins occurred primarily via the urine. CONCLUSIONS: The data suggest that the FVIIa moiety is directing rVIIa FP's tissue distribution while the albumin moiety is responsible for the prolonged tissue retention. Importantly, rVIIa-FP is highly concentrated and retained over a long period in the growth plate of the knee joint-a vulnerable site in haemophilia patients. Overall, these improved tissue distribution characteristics of rVIIa-FP may enhance compliance and allow a more convenient dosing frequency. PMID- 24958224 TI - Incidence of needle-tract seeding following prostate biopsy for suspected cancer: a review of the literature. AB - With the widespread clinical use of prostate-specific antigen (PSA), biopsy of the prostate has become one of the most commonly performed urological procedures. In general it is well tolerated, although there is some morbidity and risk of infection. In recent years, there have been increasing concerns that prostate biopsy may lead to tumour seeding along the needle tract. The aim of the present paper was to review the evidence on the prevalence of tumour seeding after prostate biopsy and to define the risk of this event in the context of current clinical practice. A PubMed literature search was conducted in January 2014 according to the Preferred Reporting Items for Systematic Reviews and Meta analysis (PRISMA) statement. Literature was examined with emphasis on the incidence of seeding, clinical presentation and on risk factors including type of needle used, transrectal vs transperineal approach, as well as tumour grade and stage. In all, 26 publications were identified reporting needle-tract seeding after prostate biopsy. In all, 42 patients with needle-tract seeding were identified. In most cases, seeding was reported after transperineal biopsy of the prostate, while nine cases occurred after transrectal biopsy. Based on the reviewed series the incidence of seeding appears to be <1%. The increase in the number of biopsies and cores taken at each biopsy over the years has not resulted in an increase in the reported cases of seeding. In conclusion, seeding along the needle track is a rare complication after prostate biopsy. Its actual incidence is presently difficult to quantify. It is reasonable to advise appropriate counselling and take measures to reduce this event where possible; however, we do not advocate avoidance of biopsies as the benefits of appropriate cancer diagnosis and management outweigh any potential risks from seeding. PMID- 24958223 TI - Specific risk scores for specific purposes: use CHA2DS2-VASc for assessing stroke risk, and use HAS-BLED for assessing bleeding risk in atrial fibrillation. PMID- 24958225 TI - Optically-controlled extinction ratio and Q-factor tunable silicon microring resonators based on optical forces. AB - Tunability is a desirable property of microring resonators to facilitate superior performance. Using light to control light, we present an alternative simple approach to tuning the extinction ratio (ER) and Q-factor of silicon microring resonators based on optical forces. We design an opto-mechanical tunable silicon microring resonator consisting of an add-drop microring resonator and a control light-carrying waveguide ("controlling" waveguide). One of the two bus waveguides of the microring resonator is a deformable nanostring put in parallel with the "controlling" waveguide. The tuning mechanism relies on the optical force induced deflection of suspended nanostring, leading to the change of coupling coefficient of microring and resultant tuning of ER and Q-factor. Two possible geometries, i.e. double-clamped nanostring and cantilever nanostring, are studied in detail for comparison. The obtained results imply a favorable structure with the microring positioned at the end of the cantilever nanostring. It features a wide tuning range of ER from 5.6 to 39.9 dB and Q-factor from 309 to 639 as changing the control power from 0 to 1.4 mW. PMID- 24958226 TI - Attenuation of ECG QRS complexes in a patient with takotsubo syndrome due to paraganglioma. PMID- 24958227 TI - Prey pursuit strategy of Japanese horseshoe bats during an in-flight target selection task. AB - The prey pursuit behavior of Japanese horseshoe bats (Rhinolophus ferrumequinum nippon) was investigated by tasking bats during flight with choosing between two tethered fluttering moths. Echolocation pulses were recorded using a telemetry microphone mounted on the bat combined with a 17-channel horizontal microphone array to measure pulse directions. Flight paths of the bat and moths were monitored using two high-speed video cameras. Acoustical measurements of returning echoes from fluttering moths were first collected using an ultrasonic loudspeaker, turning the head direction of the moth relative to the loudspeaker from 0 degrees (front) to 180 degrees (back) in the horizontal plane. The amount of acoustical glints caused by moth fluttering varied with the sound direction, reaching a maximum at 70 degrees -100 degrees in the horizontal plane. In the flight experiment, moths chosen by the bat fluttered within or moved across these angles relative to the bat's pulse direction, which would cause maximum dynamic changes in the frequency and amplitude of acoustical glints during flight. These results suggest that echoes with acoustical glints containing the strongest frequency and amplitude modulations appear to attract bats for prey selection. PMID- 24958228 TI - Stress-induced activation of ventral tegmental mu-opioid receptors reduces accumbens dopamine tone by enhancing dopamine transmission in the medial pre frontal cortex. AB - RATIONALE: Endogenous opioids could play a major role in the mesocorticolimbic dopamine (DA) responses to stress challenge. However, there is still no direct evidence of an influence of endogenous opioids on any of these responses. OBJECTIVE: We assessed whether and how endogenous opioids modulate fluctuations of mesocortical and mesoaccumbens DA tone in rats during a first experience with restraint stress. METHOD: We first evaluated the effects of systemic naltrexone (NTRX) on DA outflow in the medial prefrontal cortex (mpFC) and in the nucleus accumbens (NAc) through dual-probe microdialysis. Second, we assessed the effect of perfusion, through reverse microdialysis, of direct DA receptor agonists in mpFC on NAc DA outflow in NTRX-pretreated stressed rats. Finally, we tested the effects of ventral tegmental area (VTA) perfusion of NTRX, the selective mu1 antagonist naloxonazine and the selective delta antagonist naltrindole on mpFC and NAc DA outflow in stressed rats, with multiple probe experiments. RESULTS: Systemic NTRX, at behaviorally effective doses, selectively prevented the increase of mpFC DA levels and the reduction of NAc DA levels observable during prolonged restraint. Local co-perfusion of D1 and D2 agonists in mpFC recovered inhibition of NAc DA in NTRX-pretreated restrained rats. Finally, intra-VTA perfusion of either NTRX or the mu1 antagonist, but not the delta antagonist, mimicked the effects of systemic NTRX. CONCLUSION: During prolonged experience with a novel unavoidable/uncontrollable stressor, endogenous opioids, through stimulation of mu1 receptors in the VTA, elevate mesocortical DA tone thus reducing DA tone in the NAc DA. PMID- 24958229 TI - Decreased serum TNF-alpha levels in chronic schizophrenia patients on long-term antipsychotics: correlation with psychopathology and cognition. AB - OBJECTIVE: A substantial body of evidence implicates TNF-alpha (TNFalpha) and TNFalpha-related signaling pathways in the pathophysiology of schizophrenia. The current study examined the relationship between TNFalpha serum levels and both psychopathological as well as cognitive symptoms in schizophrenia. MATERIALS AND METHODS: Serum TNFalpha levels were assessed in 89 patients diagnosed with schizophrenia and compared to 43 healthy control subjects matched for age and gender. Schizophrenic symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS), and serum TNFalpha levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: TNFalpha levels were significantly lower in patients with chronic schizophrenia relative to healthy control subjects (p<0.01). Correlation analysis revealed a significant negative correlation between the TNFalpha levels and the PANSS total score (p<0.01). Additionally, TNFalpha levels were significantly negatively correlated with scores on general psychopathology (p<0.01), positive (p<0.05) and cognitive subscales (p<0.05). Stepwise multiple regression analysis identified TNFalpha levels as a significant predictor of scores on the general psychopathology subscale of the PANSS. CONCLUSION: The significant relations observed in the current study between TNFalpha and the PANSS and its subscales suggest that immune disturbance may be involved in the psychopathology and cognitive deficits of schizophrenia. PMID- 24958232 TI - Atypical fibroxanthoma: new insights. AB - Atypical fibroxanthoma (AFX) is an ultraviolet radiation-associated dermal neoplasm. To address the clinicopathologic and molecular features of this particular neoplasm. The author conducted a literature review using PubMed searching for articles relating to AFX. AFX usually appears as a rapidly growing nodular or nodulo-ulcerative lesion. It occurs on sun-exposed skin of elderly peoples. AFX may be composed predominantly of pleomorphic, spindle, epithelioid cells, or admixture of these cells. The differential diagnosis of AFX includes pleomorphic dermal sarcoma, squamous cell carcinoma, malignant melanoma and leiomyosarcoma. Several observations favor a mesenchymal origin for AFX. These reviews address the clinicopathologic features, molecular pathology, prognosis and treatment of this neoplasm. PMID- 24958231 TI - Differential behavioral responses of zebrafish larvae to yohimbine treatment. AB - RATIONALE: Yohimbine demonstrated both anxiogenic and anxiolytic properties under different conditions in rodents. Few studies were conducted on zebrafish, a newly emerged vertebrate model organism. Zebrafish larvae are particularly suitable for high-throughput screening of drug effects. OBJECTIVES: The aim of this study was to elucidate the effect of yohimbine on the anxiety-related behaviors of zebrafish larvae. METHODS: AB strain zebrafish larvae at both 5 and 7 days postfertilization (dpf) were treated with different concentrations of yohimbine. General locomotor activities and thigmotaxis behavior were analyzed under continuous illumination, which represented normal condition, or under alternating light-dark challenges, which represented stressful environment. RESULTS: Under continuous illumination, the 5-dpf larvae demonstrated increased swimming distances at low yohimbine concentrations, whereas the 7-dpf larvae demonstrated progressively decreased swimming distances with increases in yohimbine concentration. Low concentrations of yohimbine reduced thigmotaxis of the larvae, while high concentrations of yohimbine increased it. During the dark period of the light-dark challenge phase, low concentrations of yohimbine increased swimming distances of the larvae at both 5 and 7 dpf, while high concentrations of yohimbine decreased it. Yohimbine induced increased thigmotaxis in both 5- and 7-dpf larvae during the dark period. CONCLUSIONS: Under normal condition (lights on), low doses of yohimbine were anxiolytic in both the 5- and 7-dpf larvae, whereas high doses of yohimbine were anxiogenic only in the 7-dpf larvae. Under mildly stressful condition (lights off), yohimbine treatment demonstrated dose dependent effects to potentiate anxiety-related behaviors in both the 5- and 7 dpf larvae, although the significant dose varied with age. PMID- 24958234 TI - Intramolecular cycloadditions of photogenerated azaxylylenes: an experimental and theoretical study. AB - The mechanism of intramolecular cycloadditions of azaxylylenes photogenerated via excited-state intramolecular proton transfer (ESIPT) in aromatic o-amido ketones and aldehydes bearing unsaturated functionalities was studied experimentally and computationally. In time-correlated single-photon counting experiments, no relation was found between lifetimes of singlet species and the nature of the amide pendant, either unsaturated furanpropanamide, capable of photocyclization, or the acetamide control. Steady-state emission for amido-tetralone derivatives showed comparable dual emission bands, but bromo substitution decreased the intensity of the ESIPT band. The most reactive derivatives of amidobenzaldehydes were virtually lacking the ESIPT band. The quantum yield of cycloaddition is decreased in the presence of triplet quenchers, O2 or trans-piperylene, and improved with heavy atom substitution in the aromatic ring, providing further evidence for the initial mechanistic hypothesis in which the fast singlet-state ESIPT is accompanied by the ISC in the tautomer (azaxylylene), which undergoes stepwise addition to the tethered unsaturated pendants. PMID- 24958233 TI - Acute liver failure caused by severe acute hepatitis B: a case series from a multi-center investigation. AB - BACKGROUND: Few data can be available regarding acute liver failure (ALF) caused by severe acute hepatitis B up to now. This study aims to report such cases from China. FINDINGS: We conducted a multi-center investigation on ALF from 7 tertiary hospitals in different areas of China. A total of 11 patients with ALF caused by severe acute hepatitis B were finally identified. In these patients, there were 10 male and 1 female patients. As a serious complication, apparent hemorrhage occurred in 9 patients. Eventually, in these 11 patients, 4 survived and 7 died. 4 died of heavy bleeding, 2 died of systemic inflammatory response syndrome and 1 died of irreversible coma. No patients received liver transplantation. CONCLUSIONS: ALF caused by severe acute hepatitis B is worthy of formal studies based on its rarity and severity. PMID- 24958230 TI - Cognitive impact of social stress and coping strategy throughout development. AB - RATIONALE: Stress experience during adolescence has been linked to the development of psychiatric disorders in adulthood, many of which are associated with impairments in prefrontal cortex function. OBJECTIVE: The current study was designed to determine the immediate and enduring effects of repeated social stress on a prefrontal cortex-dependent cognitive task. METHODS: Early adolescent (P28), mid-adolescent (P42), and adult (P70) rats were exposed to resident intruder stress for 5 days and tested in an operant strategy-shifting task (OSST) during the following week or several weeks later during adulthood. Engagement of prefrontal cortical neurons during the task was assessed by expression of the immediate early gene, c-fos. RESULTS: Social stress during adolescence had no immediate effects on task performance, but impaired strategy-shifting in adulthood, whereas social stress that occurred during adulthood had no effect. The cognitive impairment produced by adolescent social stress was most pronounced in rats with a passive coping strategy. Notably, strategy-shifting performance was positively correlated with medial prefrontal cortical c-fos in adulthood but not in adolescence, suggesting that the task engages different brain regions in adolescents compared to adults. CONCLUSIONS: Adolescent social stress produces a protracted impairment in prefrontal cortex-mediated cognition that is related to coping strategy. This impairment may be selectively expressed in adulthood because prefrontal cortical activity is integral to task performance at this age but not during adolescence. PMID- 24958235 TI - Behavioural activation therapy for adolescents 'at risk' for psychosis? AB - The following hypothesis explores the possibility of using behavioural activation therapy for adolescents with an at-risk mental state for psychosis. Support is drawn from psychosis-related survey and pilot data as well as a robust evidence base for adult depression. However, we acknowledge that extensive feasibility work is required before exploring this hypothesis further. PMID- 24958236 TI - Identification of pathogenic fungi. PMID- 24958237 TI - Editorial commentary: a Shigella vaccine against prevalent serotypes. PMID- 24958240 TI - Establishment of human cell type-specific iPS cells with enhanced chondrogenic potential. AB - The propensity of induced pluripotent stem (iPS) cells to differentiate into specific lineages may be influenced by a number of factors, including the selection of the somatic cell type used for reprogramming. Herein we report the generation of new iPS cells, which we derived from human articular chondrocytes and from cord blood mononucleocytes via lentiviral-mediated delivery of Oct4, Klf4, Sox2, and cMyc. Molecular, cytochemical, and cytogenic analyses confirmed the acquisition of hallmark features of pluripotency, as well as the retention of normal karyotypes following reprogramming of both the human articular chondrocytes (AC) and the cord blood (CB) cells. In vitro and in vivo functional analyses formally established the pluripotent differentiation capacity of all cell lines. Chondrogenic differentiation assays comparing iPS cells derived from AC, CB, and a well established dermal fibroblast cell line (HDFa-Yk26) identified enhanced proteoglycan-rich matrix formation and cartilage-associated gene expression from AC-derived iPS cells. These findings suggest that the tissue of origin may impact the fate potential of iPS cells for differentiating into specialized cell types, such as chondrocytes. Thus, we generated new cellular tools for the identification of inherent features driving high chondrogenic potential of reprogrammed cells. PMID- 24958241 TI - Functional changes in people with different hearing status and experiences of using Chinese sign language: an fMRI study. AB - The purpose of this study was to assess functional changes in the cerebral cortex in people with different sign language experience and hearing status whilst observing and imitating Chinese Sign Language (CSL) using functional magnetic resonance imaging (fMRI). 50 participants took part in the study, and were divided into four groups according to their hearing status and experience of using sign language: prelingual deafness signer group (PDS), normal hearing non signer group (HnS), native signer group with normal hearing (HNS), and acquired signer group with normal hearing (HLS). fMRI images were scanned from all subjects when they performed block-designed tasks that involved observing and imitating sign language stimuli. Nine activation areas were found in response to undertaking either observation or imitation CSL tasks and three activated areas were found only when undertaking the imitation task. Of those, the PDS group had significantly greater activation areas in terms of the cluster size of the activated voxels in the bilateral superior parietal lobule, cuneate lobe and lingual gyrus in response to undertaking either the observation or the imitation CSL task than the HnS, HNS and HLS groups. The PDS group also showed significantly greater activation in the bilateral inferior frontal gyrus which was also found in the HNS or the HLS groups but not in the HnS group. This indicates that deaf signers have better sign language proficiency, because they engage more actively with the phonetic and semantic elements. In addition, the activations of the bilateral superior temporal gyrus and inferior parietal lobule were only found in the PDS group and HNS group, and not in the other two groups, which indicates that the area for sign language processing appears to be sensitive to the age of language acquisition. LEARNING OUTCOMES: After reading this article, readers will be able to: discuss the relationship between sign language and its neural mechanisms. PMID- 24958239 TI - SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints. AB - BACKGROUND: Genomic disorders are caused by copy number changes that may exhibit recurrent breakpoints processed by nonallelic homologous recombination. However, region-specific disease-associated copy number changes have also been observed which exhibit non-recurrent breakpoints. The mechanisms underlying these non recurrent copy number changes have not yet been fully elucidated. RESULTS: We analyze large NF1 deletions with non-recurrent breakpoints as a model to investigate the full spectrum of causative mechanisms, and observe that they are mediated by various DNA double strand break repair mechanisms, as well as aberrant replication. Further, two of the 17 NF1 deletions with non-recurrent breakpoints, identified in unrelated patients, occur in association with the concomitant insertion of SINE/variable number of tandem repeats/Alu (SVA) retrotransposons at the deletion breakpoints. The respective breakpoints are refractory to analysis by standard breakpoint-spanning PCRs and are only identified by means of optimized PCR protocols designed to amplify across GC-rich sequences. The SVA elements are integrated within SUZ12P intron 8 in both patients, and were mediated by target-primed reverse transcription of SVA mRNA intermediates derived from retrotranspositionally active source elements. Both SVA insertions occurred during early postzygotic development and are uniquely associated with large deletions of 1 Mb and 867 kb, respectively, at the insertion sites. CONCLUSIONS: Since active SVA elements are abundant in the human genome and the retrotranspositional activity of many SVA source elements is high, SVA insertion-associated large genomic deletions encompassing many hundreds of kilobases could constitute a novel and as yet under-appreciated mechanism underlying large-scale copy number changes in the human genome. PMID- 24958243 TI - Indigenous ethnopsychiatry in the north-west of England: the case of 'Barrow Man' AB - This paper describes the appearance and subsequent disappearance of 'Barrow Man' and uses anthropological and social psychological theory to examine the socio cultural, psychological and economic conditions for the existence of the phenomenon. It argues that these conditions were the result of both specific local labour market circumstances and of the effects of global political changes, and argues that to talk about 'Barrow Man' as if it was a psychiatric diagnosis was to identify a moral construct as a mental disorder. It also argues that at the same time the phenomenon was expressive of certain core values that were not readily acknowledged in everyday clinical practice and that it might therefore best be understood as an institutional category. PMID- 24958242 TI - Posture-based processing in visual short-term memory for actions. AB - Visual perception of human action involves both form and motion processing, which may rely on partially dissociable neural networks. If form and motion are dissociable during visual perception, then they may also be dissociable during their retention in visual short-term memory (VSTM). To elicit form-plus-motion and form-only processing of dance-like actions, individual action frames can be presented in the correct or incorrect order. The former appears coherent and should elicit action perception, engaging both form and motion pathways, whereas the latter appears incoherent and should elicit posture perception, engaging form pathways alone. It was hypothesized that, if form and motion are dissociable in VSTM, then recognition of static body posture should be better after viewing incoherent than after viewing coherent actions. However, as VSTM is capacity limited, posture-based encoding of actions may be ineffective with increased number of items or frames. Using a behavioural change detection task, recognition of a single test posture was significantly more likely after studying incoherent than after studying coherent stimuli. However, this effect only occurred for spans of two (but not three) items and for stimuli with five (but not nine) frames. As in perception, posture and motion are dissociable in VSTM. PMID- 24958244 TI - The independent relationships between insomnia, depression, subtypes of anxiety, and chronotype during adolescence. AB - OBJECTIVES: To investigate the independent effects of depression and subtypes of anxiety on insomnia, and vice versa, and the independent effect of chronotype on insomnia, depression, and subtypes of anxiety. METHODS: In all, 318 South Australian high school students from grades 7-11 (age range, 12-18years; mean, 14.97+/-1.34) participated in this cross-sectional study. Validated self-report questionnaires were used to assess insomnia, depression, subtypes of anxiety, and chronotype. RESULTS: After confounder variables were controlled, insomnia predicted depression and panic disorder (PD), whereas insomnia was predicted by depression and generalized anxiety disorder (GAD). Obsessive-compulsive disorder (OCD), separation anxiety (SAD), and social phobia (SP) were not significantly related to insomnia. Eveningness predicted the models in which depression and PD predicted insomnia and vice versa. Eveningness also predicted the models in which insomnia was predicted by OCD, SAD, and SP. CONCLUSIONS: Insomnia independently predicts depression and is predicted by depression and GAD, but not by other forms of anxiety. The independent prediction of insomnia on PD is unlikely to be clinically significant. Chronotype independently predicts and hence is a risk factor for insomnia and depression, but not subtypes of anxiety. Theoretical and clinical implications are discussed. PMID- 24958238 TI - Shigella isolates from the global enteric multicenter study inform vaccine development. AB - BACKGROUND: Shigella, a major diarrheal disease pathogen worldwide, is the target of vaccine development. The Global Enteric Multicenter Study (GEMS) investigated burden and etiology of moderate-to-severe diarrheal disease in children aged <60 months and matched controls without diarrhea during 3 years at 4 sites in Africa and 3 in Asia. Shigella was 1 of the 4 most common pathogens across sites and age strata. GEMS Shigella serotypes are reviewed to guide vaccine development. METHODS: Subjects' stool specimens/rectal swabs were transported to site laboratories in transport media and plated onto xylose lysine desoxycholate and MacConkey agar. Suspect Shigella colonies were identified by biochemical tests and agglutination with antisera. Shigella isolates were shipped to the GEMS Reference Laboratory (Baltimore, MD) for confirmation and serotyping of S. flexneri; one-third of isolates were sent to the Centers for Disease Control and Prevention for quality control. RESULTS: Shigella dysenteriae and S. boydii accounted for 5.0% and 5.4%, respectively, of 1130 Shigella case isolates; S. flexneri comprised 65.9% and S. sonnei 23.7%. Five serotypes/subserotypes comprised 89.4% of S. flexneri, including S. flexneri 2a, S. flexneri 6, S. flexneri 3a, S. flexneri 2b, and S. flexneri 1b. CONCLUSIONS: A broad-spectrum Shigella vaccine must protect against S. sonnei and 15 S. flexneri serotypes/subserotypes. A quadrivalent vaccine with O antigens from S. sonnei, S. flexneri 2a, S. flexneri 3a, and S. flexneri 6 can provide broad direct coverage against these most common serotypes and indirect coverage against all but 1 (rare) remaining subserotype through shared S. flexneri group antigens. PMID- 24958245 TI - Editorial for "Nightmares in narcolepsy--under-investigated symptom?" (SLEEP-D-13 00591) Understanding and treating nightmares in patients with narcolepsy. PMID- 24958247 TI - ZnO nanoparticles inhibit Pseudomonas aeruginosa biofilm formation and virulence factor production. AB - The opportunistic pathogen Pseudomonas aeruginosa produces a variety of virulence factors, and biofilms of this bacterium are much more resistant to antibiotics than planktonic cells. Thirty-six metal ions have been investigated to identify antivirulence and antibiofilm metal ions. Zinc ions and ZnO nanoparticles were found to markedly inhibit biofilm formation and the production of pyocyanin, Pseudomonas quinolone signal (PQS), pyochelin, and hemolytic activity of P. aeruginosa without affecting the growth of planktonic cells. Transcriptome analyses showed that ZnO nanoparticles induce the zinc cation efflux pump czc operon and several important transcriptional regulators (porin gene opdT and type III repressor ptrA), but repress the pyocyanin-related phz operon, which explains observed phenotypic changes. A mutant study showed that the effects of ZnO nanoparticles on the control of pyocyanin production and biofilm formation require the czc regulator CzcR. In addition, ZnO nanoparticles markedly increased the cellular hydrophilicity of P. aeruginosa cells. Our results support that ZnO nanoparticles are potential antivirulence materials against recalcitrant P. aeruginosa infections and possibly other important pathogens. PMID- 24958246 TI - Kinetic model facilitates analysis of fibrin generation and its modulation by clotting factors: implications for hemostasis-enhancing therapies. AB - Current mechanistic knowledge of protein interactions driving blood coagulation has come largely from experiments with simple synthetic systems, which only partially represent the molecular composition of human blood plasma. Here, we investigate the ability of the suggested molecular mechanisms to account for fibrin generation and degradation kinetics in diverse, physiologically relevant in vitro systems. We represented the protein interaction network responsible for thrombin generation, fibrin formation, and fibrinolysis as a computational kinetic model and benchmarked it against published and newly generated data reflecting diverse experimental conditions. We then applied the model to investigate the ability of fibrinogen and a recently proposed prothrombin complex concentrate composition, PCC-AT (a combination of the clotting factors II, IX, X, and antithrombin), to restore normal thrombin and fibrin generation in diluted plasma. The kinetic model captured essential features of empirically detected effects of prothrombin, fibrinogen, and thrombin-activatable fibrinolysis inhibitor titrations on fibrin formation and degradation kinetics. Moreover, the model qualitatively predicted the impact of tissue factor and tPA/tenecteplase level variations on the fibrin output. In the majority of considered cases, PCC AT combined with fibrinogen accurately approximated both normal thrombin and fibrin generation in diluted plasma, which could not be accomplished by fibrinogen or PCC-AT acting alone. We conclude that a common network of protein interactions can account for key kinetic features characterizing fibrin accumulation and degradation in human blood plasma under diverse experimental conditions. Combined PCC-AT/fibrinogen supplementation is a promising strategy to reverse the deleterious effects of dilution-induced coagulopathy associated with traumatic bleeding. PMID- 24958248 TI - Survival of a novel endophytic fungus Phomopsis liquidambari B3 in the indole contaminated soil detected by real-time PCR and its effects on the indigenous microbial community. AB - The recently isolated fungal strain Phomopsis liquidambari B3 can degrade high concentrations of indole, indicating its potential for the bioremediation of indole-contaminated soil. In this study, a specific real-time PCR was developed to detect the survival of P. liquidambari B3 in soil. Subsequently, degradation activity of strain B3 and its effects on indigenous microbial community were analyzed. Results showed the amount of P. liquidambari B3 genomic DNA increased to a maximum 5.67 log (pgg(-1) dry soil) 10 days after inoculation of 5.04 log (pgg(-1) dry soil), and then gradually decreased with time and after 40 days it was below the detection limit. By the end of the experiment (day 40), bioaugmented microsoms showed a 93.7% decrease in indole, while the values for biostimulated and control microcosms were much lower. Higher microbial biomass and enzyme activities were observed in bioaugmented soil. Denaturing gradient gel electrophoresis analysis showed bioaugmentation increased richness of resident microbial community. These results indicate that P. liquidambari B3 is effective for the remediation of indole-contaminated soil and also provides valuable information about the behavior of the inoculant population during bioremediation, which could be directly used in the risk assessment of inoculant population and optimization of bioremediation process. PMID- 24958249 TI - Pediatric video laryngoscope versus direct laryngoscope: a meta-analysis of randomized controlled trials. AB - BACKGROUND: We reviewed the updated literature and performed a meta-analysis based on randomized controlled trials in children to compare the clinical efficacy between video laryngoscopes (VLs) and direct laryngoscopes (DLs). METHODS: We searched articles published in English matching the key words 'video laryngoscope (including Airtraq, GlideScope, Storz, TruView, AWS, Bullard, McGrath)' AND 'direct laryngoscope' AND 'children (including pediatric, infant, neonate)' in PubMed, Ovid, Google Scholar, and the Cochrane Library databases. Only prospective randomized controlled trials (RCTs), which compared the use of VLs and DLs in children, were included. The relative risk (RR), weighted mean difference (WMD), and their corresponding 95% confidence interval (95% CI) were calculated using the quality effects model of the metaxl 1.3 software for outcome data. RESULTS: Fourteen studies were included in this meta-analysis. Although VLs improved the glottis visualization in most children either with normal airways or with potentially difficult intubations, the time to intubation (TTI) was prolonged in comparison to DLs (WMD: 4.9 s; 95% CI: 2.6-7.1). Subgroup analysis showed the GlideScope (WMD: 5.2 s; 95% CI: 2.0-8.5), TruView (WMD: 5.1 s; 95% CI: 0.7-9.5), Storz (WMD: 6.4 s; 95% CI: 4.8-8.1), and Bullard (WMD: 37.5 s; 95% CI: 21.0-54.0) rather than Airtraq (WMD: 0.6 s; 95% CI: -7.7-8.9) prolonged TTI. Although the success rate of the first attempt (RR: 0.96; 95% CI: 0.92-1.00) and associated complications (RR: 1.11; 95% CI: 0.39-3.16) were similar in both groups, VLs were associated with a higher incidence of failure (RR: 6.70; 95% CI: 1.53-29.39). CONCLUSION: This meta-analysis demonstrates that although VLs improved glottis visualization in pediatric patients, this was at the expense of prolonged TTI and increased failures. However, further studies are needed to clarify the efficacy and safety of VLs in hands of nonexperts and in children with airway problems. PMID- 24958250 TI - Acute effects of using an electronic nicotine-delivery device (electronic cigarette) on myocardial function: comparison with the effects of regular cigarettes. AB - BACKGROUND: Electronic cigarettes have been developed and marketed in recent years as smoking substitutes. However, no studies have evaluated their effects on the cardiovascular system. The purpose of this study was to examine the immediate effects of electronic cigarette use on left ventricular (LV) function, compared to the well-documented acute adverse effects of smoking. METHODS: Echocardiographic examinations were performed in 36 healthy heavy smokers (SM, age 36 +/- 5 years) before and after smoking 1 cigarette and in 40 electronic cigarette users (ECIG, age 35 +/- 5 years) before and after using the device with "medium-strength" nicotine concentration (11 mg/ml) for 7 minutes. Mitral flow diastolic velocities (E, A), their ratio (E/A), deceleration time (DT), isovolumetric relaxation time (IVRT) and corrected-to-heart rate IVRT (IVRTc) were measured. Mitral annulus systolic (Sm), and diastolic (Em, Am) velocities were estimated. Myocardial performance index was calculated from Doppler flow (MPI) and tissue Doppler (MPIt). Longitudinal deformation measurements of global strain (GS), systolic (SRs) and diastolic (SRe, SRa) strain rate were also performed. RESULTS: Baseline measurements were similar in both groups. In SM, IVRT and IVRTc were prolonged, Em and SRe were decreased, and both MPI and MPIt were elevated after smoking. In ECIG, no differences were observed after device use. Comparing after-use measurements, ECIG had higher Em (P = 0.032) and SRe (P = 0.022), and lower IVRTc (P = 0.011), MPI (P = 0.001) and MPIt (P = 0.019). The observed differences were significant even after adjusting for changes in heart rate and blood pressure. CONCLUSIONS: Although acute smoking causes a delay in myocardial relaxation, electronic cigarette use has no immediate effects. Electronic cigarettes' role in tobacco harm reduction should be studied intensively in order to determine whether switching to electronic cigarette use may have long-term beneficial effects on smokers' health. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16974547. PMID- 24958251 TI - Longitudinal changes in health behaviours and body weight among Swedish school children--associations with age, gender and parental education--the SCIP school cohort. AB - BACKGROUND: In order to develop health promotion initiatives it is important to identify at what age gender and socioeconomic inequalities in health-related behaviours emerge. The aim of this longitudinal study was to analyse how health related behaviours and weight status differed by age-group, gender, family socio economic status and over time in three cohorts of school children. METHODS: All children in grades 2, 4 and 7 in a Swedish semi-urban municipality were invited to participate (n = 1,359) of which 813 (60%) consented. At baseline and after 2 years a health questionnaire was answered by all children. Height and weight was measured. Fourteen outcomes were analysed. The main and interaction effects of time, gender and parental educational level on the health-related behaviours, weight status and body mass index standard deviation score (BMIsds) were analysed by the Weighted Least Squares method for categorical repeated measures and Analysis of Variance. RESULTS: Nine of 12 health behaviours deteriorated over the two years: consumption of breakfast and lunch, vegetables and fruit, intake of sweetened drinks, TV viewing, club membership, being outdoors, and school recess activity; two behaviours were unchanged: intake of sweets, and active transport. Only sports participation increased with time. Girls consumed more vegetables, less sweetened drinks, performed less sports, were less physically active during recess, and had lower BMIsds, compared to boys. Those with more highly educated parents had more favourable or similar behaviours compared to those with less educated parents in 10 out of 12 health behaviours, the only exception being intake of sweets and being outdoors, and had lower BMIsds. CONCLUSIONS: This study adds to our knowledge regarding the temporal development of health behaviours and weight status in school children. Differences with regard to gender and socioeconomic status were seen already at a young age. These results contribute to our understanding of several important determinants of obesity and chronic diseases and may inform future interventions regarding how to decrease gender and social inequalities in health. PMID- 24958252 TI - Relations between trait impulsivity, behavioral impulsivity, physiological arousal, and risky sexual behavior among young men. AB - The current study examined how impulsivity-related traits (negative urgency, sensation seeking, and positive urgency), behavioral measures of risk taking and reward seeking, and physiological reactivity related to three different risky sexual behaviors in sexually active undergraduate men (N = 135). Regression analyses indicated that sensation seeking and behavioral risk-taking predicted unique variance in number of sexual partners. These findings suggest that, for young men, acquisition of new partners is associated with need for excitement and reward and willingness to take risks to meet those needs. Sensation seeking, behavioral risk-taking, and skin conductance reactivity to arousing stimuli was related to ever having engaged in sex with a stranger, indicating that, for men, willingness to have sex with a stranger is related not only to the need for excitement and risk-taking but also with innate responsiveness to arousing environmental triggers. In contrast, regression analyses indicated that young men who were impulsive in the context of negative emotions were less likely to use condoms, suggesting that emotion-based impulsivity may be an important factor in negligent prophylactic use. This study adds to the current understanding of the divergence between the correlates of risky sexual behaviors and may lend utility to the development of individualized HIV prevention programming. PMID- 24958253 TI - Utility of urgent colonoscopy in acute lower gastro-intestinal bleeding: a single center experience. AB - BACKGROUND: The role of urgent colonoscopy in lower gastro-intestinal bleeding (LGIB) remains controversial. Over the last two decades, a number of studies have indicated that urgent colonoscopy may facilitate the identification and treatment of bleeding lesions; however, studies comparing this approach to elective colonoscopy for LGIB are limited. AIMS: To determine the utility and assess the outcome of urgent colonoscopy as the initial test for patients admitted to the intensive care unit (ICU) with acute LGIB. METHODS: Consecutive patients who underwent colonoscopy at our institution for the initial evaluation of acute LGIB between January 2011 and January 2012 were analysed retrospectively. Patients were grouped into urgent vs. elective colonoscopy, depending on the timing of colonoscopy after admission to the ICU. Urgent colonoscopy was defined as being performed within 24 hours of admission and those performed later than 24 hours were considered elective. Outcomes included length of hospital stay, early re bleeding rates, and the need for additional diagnostic or therapeutic interventions. Multivariable logistic regression analysis was performed to identify factors associated with increased transfusion requirements. RESULTS: Fifty-seven patients underwent colonoscopy for the evaluation of suspected LGIB, 24 of which were urgent. There was no significant difference in patient demographics, co-morbidities, or medications between the two groups. Patients who underwent urgent colonoscopy were more likely to present with hemodynamic instability (P = 0.019) and require blood transfusions (P = 0.003). No significant differences in length of hospital stay, re-bleeding rates, or the need for additional diagnostic or therapeutic interventions were found. Patients requiring blood transfusions (n = 27) were more likely to be female (P = 0.016) and diabetics (P = 0.015). Fourteen patients re-bled at a median of 2 days after index colonoscopy. Those with hemodynamic instability were more likely to re bleed [HR 3.8 (CI 1.06-13.7)], undergo angiography [HR 9.8 (CI 1.8-54.1)], require surgery [HR 13.5 (CI 3.2-56.5)], and had an increased length of hospital stay [HR 1.1 (1.05-1.2)]. CONCLUSION: The use of urgent colonoscopy, as an initial approach to investigate acute LGIB, did not result in significant differences in length of ICU stay, re-bleeding rates, the need for additional diagnostic or therapeutic interventions, or 30-day mortality compared with elective colonoscopy. In a pre-specified subgroup analysis, patients with hemodynamic instability were more likely to re-bleed after index colonoscopy, to require additional interventions (angiography or surgery) and had increased length of hospital stay. PMID- 24958254 TI - Vitamin B12 and its binding proteins in hepatocellular carcinoma and chronic liver diseases. AB - BACKGROUND: The vitamin B12 (B12)-binding protein haptocorrin (HC) has proven to be a potentially useful biomarker in patients with fibrolamellar hepatocellular carcinoma (HCC). Little is known concerning the level of HC and other B12-related proteins in patients with HCC as compared to patients with other chronic liver diseases (CLDs) and healthy controls. We hypothesized that HC could be a biomarker of HCC. AIMS: To investigate levels of HC and B12-related proteins in HCC compared to CLDs and healthy controls. METHODS: We investigated two patient populations: A cross-sectional cohort of HCC patients (n = 130), CLD patients (n = 102) and healthy controls (n = 46) and a cohort of 38 HCC patients studied at baseline and 1, 4, and 12 weeks following ablative treatment. Patients were evaluated by standard biochemistry, Child-Pugh-score and Barcelona Clinic Liver Cancer (BCLC) classification. We analyzed total B12 by routine methods and HC, transcobalamin (TC), B12 saturated TC (holoTC), and the soluble cell surface receptor for holoTC (sCD320) by in-house enzyme-linked immunosorbent assay. RESULTS: HC showed higher median (range) levels for both HCC (590 [290-5860]) and CLD patients (620 [310-4010]) compared to controls (460 [250-2020]) (p < 0.01). Total B12, TC, holoTC, and sCD320 showed elevated levels in both HCC and CLD compared to controls. Only holoTC changed following treatment, without a concurrent change in TC. CONCLUSION: B12 and B12-related proteins (total B12, HC, TC, holoTC, and sCD320) show elevations in both HCC and CLD patients compared to controls, suggesting a relation to CLD in general rather than to primary liver cancer. Thus, HC is not useful as a biomarker for HCC. PMID- 24958255 TI - Comparative pharmacokinetics of naringin in rat after oral administration of chaihu-shu-gan-san aqueous extract and naringin alone. AB - Chaihu-Shu-Gan-San (CSGS), a traditional Chinese medicine (TCM) formula containing seven herbal medicines, has been used in the clinical treatment of gastritis, peptic ulcer, irritable bowel syndrome and depression in China. In order to explore the interaction between naringin and other constituents in CSGS, the pharmacokinetic difference of naringin in rats after oral administration of CSGS aqueous extract and naringin alone was investigated. The pharmacokinetic parameters of naringin in rats were achieved by quantification of its aglycone, naringenin by LC-MS/MS method. The double peaks phenomenon was observed in both serum profiles of rats after orally administered CSGS aqueous extract and naringin alone. However, the T1/2b was significantly decreased in rats given CSGS aqueous extract compared with naringin alone, and the mean residence time (MRT) and the area under the serum concentration-time curve (AUC0-tau) were higher than those of naringin, which indicated that naringin in CSGS had higher bioavailability, longer term efficacy and somewhat faster metabolism and excretion than those of naringin. The results suggested that certain ingredients co-exist in CSGS could influence pharmacokinetic behavior of naringin. This also provides a reference for human studies. PMID- 24958256 TI - Transcriptomics and Metabonomics Identify Essential Metabolic Signatures in Calorie Restriction (CR) Regulation across Multiple Mouse Strains. AB - Calorie restriction (CR) has long been used to study lifespan effects and oppose the development of a broad array of age-related biological and pathological changes (increase healthspan). Yet, a comprehensive comparison of the metabolic phenotype across different genetic backgrounds to identify common metabolic markers affected by CR is still lacking. Using a system biology approach comprising metabonomics and liver transcriptomics we revealed the effect of CR across multiple mouse strains (129S1/SvlmJ, C57BL6/J, C3H/HeJ, CBA/J, DBA/2J, JC3F1/J). Oligonucleotide microarrays identified 76 genes as differentially expressed in all six strains confirmed. These genes were subjected to quantitative RT-PCR analysis in the C57BL/6J mouse strain, and a CR-induced change expression was confirmed for 14 genes. To fully depict the metabolic pathways affected by CR and complement the changes observed through differential gene expression, the metabolome of C57BL6/J was further characterized in liver tissues, urine and plasma levels using a combination or targeted mass spectrometry and proton nuclear magnetic resonance spectroscopy. Overall, our integrated approach commonly confirms that energy metabolism, stress response, lipids regulators and the insulin/IGF-1 are key determinants factors involved in CR regulation. PMID- 24958257 TI - A rapid method for the extraction and analysis of carotenoids and other hydrophobic substances suitable for systems biology studies with photosynthetic bacteria. AB - A simple, rapid, and inexpensive extraction method for carotenoids and other non polar compounds present in phototrophic bacteria has been developed. The method, which has been extensively tested on the phototrophic purple non-sulphur bacterium Rhodospirillum rubrum, is suitable for extracting large numbers of samples, which is common in systems biology studies, and yields material suitable for subsequent analysis using HPLC and mass spectroscopy. The procedure is particularly suitable for carotenoids and other terpenoids, including quinones, bacteriochlorophyll a and bacteriopheophytin a, and is also useful for the analysis of polar phospholipids. The extraction procedure requires only a single step extraction with a hexane/methanol/water mixture, followed by HPLC using a Spherisorb C18 column, with a mobile phase consisting of acetone-water and a non linear gradient of 50%-100% acetone. The method was employed for examining the carotenoid composition observed during microaerophilic growth of R. rubrum strains, and was able to determine 18 carotenoids, 4 isoprenoid-quinones, bacteriochlorophyll a and bacteriopheophytin a as well as four different phosphatidylglycerol species of different acyl chain compositions. The analytical procedure was used to examine the dynamics of carotenoid biosynthesis in the major and minor pathways operating simultaneously in a carotenoid biosynthesis mutant of R. rubrum. PMID- 24958259 TI - Counting and correcting thermodynamically infeasible flux cycles in genome-scale metabolic networks. AB - Thermodynamics constrains the flow of matter in a reaction network to occur through routes along which the Gibbs energy decreases, implying that viable steady-state flux patterns should be void of closed reaction cycles. Identifying and removing cycles in large reaction networks can unfortunately be a highly challenging task from a computational viewpoint. We propose here a method that accomplishes it by combining a relaxation algorithm and a Monte Carlo procedure to detect loops, with ad hoc rules (discussed in detail) to eliminate them. As test cases, we tackle (a) the problem of identifying infeasible cycles in the E. coli metabolic network and (b) the problem of correcting thermodynamic infeasibilities in the Flux-Balance-Analysis solutions for 15 human cell-type specific metabolic networks. Results for (a) are compared with previous analyses of the same issue, while results for (b) are weighed against alternative methods to retrieve thermodynamically viable flux patterns based on minimizing specific global quantities. Our method, on the one hand, outperforms previous techniques and, on the other, corrects loopy solutions to Flux Balance Analysis. As a byproduct, it also turns out to be able to reveal possible inconsistencies in model reconstructions. PMID- 24958258 TI - The complex role of branched chain amino acids in diabetes and cancer. AB - The obesity and diabetes epidemics are continuing to spread across the globe. There is increasing evidence that diabetes leads to a significantly higher risk for certain types of cancer. Both diabetes and cancer are characterized by severe metabolic perturbations and the branched chain amino acids (BCAAs) appear to play a significant role in both of these diseases. These essential amino acids participate in a wide variety of metabolic pathways, but it is now recognized that they are also critical regulators of a number of cell signaling pathways. An elevation in branched chain amino acids has recently been shown to be significantly correlated with insulin resistance and the future development of diabetes. In cancer, the normal demands for BCAAs are complicated by the conflicting needs of the tumor and the host. The severe muscle wasting syndrome experience by many cancer patients, known as cachexia, has motivated the use of BCAA supplementation. The desired improvement in muscle mass must be balanced by the need to avoid providing materials for tumor proliferation. A better understanding of the complex functions of BCAAs could lead to their use as biomarkers of the progression of certain cancers in diabetic patients. PMID- 24958260 TI - Off-the-Vine Ripening of Tomato Fruit Causes Alteration in the Primary Metabolite Composition. AB - The influence of postharvest fruit ripening in the composition of metabolites, transcripts and enzymes in tomato (Solanum lycopersicum L.) is poorly understood. The goal of this work was to study the changes in the metabolite composition of the tomato fruit ripened off-the-vine using the cultivar Micro-Tom as model system. Proton nuclear magnetic resonance (1H NMR) was used for analysis of the metabolic profile of tomato fruits ripened on- and off-the-vine. Significant differences under both ripening conditions were observed principally in the contents of fructose, glucose, aspartate and glutamate. Transcript levels and enzyme activities of ?-amino butyrate transaminase (EC 2.6.1.19) and glutamate decarboxylase (EC 4.1.1.15) showed differences in fruits ripened under these two conditions. These data indicate that the contents of metabolites involved in primary metabolism, and conferring the palatable properties of fruits, are altered when fruits are ripened off-the-vine. PMID- 24958261 TI - Limited influence of oxygen on the evolution of chemical diversity in metabolic networks. AB - Oxygen is thought to promote species and biomolecule diversity. Previous studies have suggested that oxygen expands metabolic networks by acquiring metabolites with different chemical properties (higher hydrophobicity, for example). However, such conclusions are typically based on biased evaluation, and are therefore non conclusive. Thus, we re-investigated the effect of oxygen on metabolic evolution using a phylogenetic comparative method and metadata analysis to reduce the bias as much as possible. Notably, we found no difference in metabolic network expansion between aerobes and anaerobes when evaluating phylogenetic relationships. Furthermore, we showed that previous studies have overestimated or underestimated the degrees of differences in the chemical properties (e.g., hydrophobicity) between oxic and anoxic metabolites in metabolic networks of unicellular organisms; however, such overestimation was not observed when considering the metabolic networks of multicellular organisms. These findings indicate that the contribution of oxygen to increased chemical diversity in metabolic networks is lower than previously thought; rather, phylogenetic signals and cell-cell communication result in increased chemical diversity. However, this conclusion does not contradict the effect of oxygen on metabolic evolution; instead, it provides a deeper understanding of how oxygen contributes to metabolic evolution despite several limitations in data analysis methods. PMID- 24958262 TI - 2-Hydrazinoquinoline as a Derivatization Agent for LC-MS-Based Metabolomic Investigation of Diabetic Ketoacidosis. AB - Short-chain carboxylic acids, aldehydes and ketones are products and regulators of many important metabolic pathways. Their levels in biofluids and tissues reflect the status of specific metabolic reactions, the homeostasis of the whole metabolic system and the wellbeing of a biological entity. In this study, the use of 2-hydrazinoquinoline (HQ) as a novel derivatization agent was explored and optimized for simultaneous liquid chromatography-mass spectrometry (LC-MS) analysis of carboxylic acids, aldehydes and ketones in biological samples. The formation of carboxylic acid derivative is attributed to the esterification reaction between HQ and a carboxyl group, while the production of aldehyde and ketone derivatives is through the formation of Schiff bases between HQ and a carbonyl group. The compatibility of HQ with biological samples was demonstrated by derivatizing urine, serum and liver extract samples. Using this HQ-based approach, the kinetics of type 1 diabetes-induced metabolic changes was characterized by the LC-MS-based metabolomic analysis of urine samples from streptozotocin (STZ)-treated mice. Subsequently, carboxylic acid, aldehyde and ketone metabolites associated with STZ-elicited disruption of nutrient and energy metabolism were conveniently identified and elucidated. Overall, HQ derivatization of carboxylic acids, aldehydes and ketones could serve as a useful tool for the LC-MS-based metabolomic investigation of endogenous metabolism. PMID- 24958264 TI - Computational analyses of spectral trees from electrospray multi-stage mass spectrometry to aid metabolite identification. AB - Mass spectrometry coupled with chromatography has become the major technical platform in metabolomics. Aided by peak detection algorithms, the detected signals are characterized by mass-over-charge ratio (m/z) and retention time. Chemical identities often remain elusive for the majority of the signals. Multi stage mass spectrometry based on electrospray ionization (ESI) allows collision induced dissociation (CID) fragmentation of selected precursor ions. These fragment ions can assist in structural inference for metabolites of low molecular weight. Computational investigations of fragmentation spectra have increasingly received attention in metabolomics and various public databases house such data. We have developed an R package "iontree" that can capture, store and analyze MS2 and MS3 mass spectral data from high throughput metabolomics experiments. The package includes functions for ion tree construction, an algorithm (distMS2) for MS2 spectral comparison, and tools for building platform-independent ion tree (MS2/MS3) libraries. We have demonstrated the utilization of the package for the systematic analysis and annotation of fragmentation spectra collected in various metabolomics platforms, including direct infusion mass spectrometry, and liquid chromatography coupled with either low resolution or high resolution mass spectrometry. Assisted by the developed computational tools, we have demonstrated that spectral trees can provide informative evidence complementary to retention time and accurate mass to aid with annotating unknown peaks. These experimental spectral trees once subjected to a quality control process, can be used for querying public MS2 databases or de novo interpretation. The putatively annotated spectral trees can be readily incorporated into reference libraries for routine identification of metabolites. PMID- 24958263 TI - Studies of Secondary Melanoma on C57BL/6J Mouse Liver Using 1H NMR Metabolomics. AB - NMR metabolomics, consisting of solid state high resolution magic angle spinning (HR-MAS) 1H-NMR, liquid state high resolution 1H-NMR, and principal components analysis (PCA) has been used to study secondary metastatic B16-F10 melanoma in C57BL/6J mouse liver. The melanoma group can be differentiated from its control group by PCA analysis of the estimates of absolute concentrations from liquid state 1H-NMR spectra on liver tissue extracts or by the estimates of absolute peak intensities of metabolites from 1H HR-MAS-NMR data on intact liver tissues. In particular, we found that the estimates of absolute concentrations of glutamate, creatine, fumarate and cholesterol are elevated in the melanoma group as compared to controls, while the estimates of absolute concentrations of succinate, glycine, glucose, and the family of linear lipids including long chain fatty acids, total choline and acyl glycerol are decreased. The ratio of glycerophosphocholine (GPC) to phosphocholine (PCho) is increased by about 1.5 fold in the melanoma group, while the estimate of absolute concentration of total choline is actually lower in melanoma mice. These results suggest the following picture in secondary melanoma metastasis: Linear lipid levels are decreased by beta oxidation in the melanoma group, which contributes to an increase in the synthesis of cholesterol, and also provides an energy source input for TCA cycle. These findings suggest a link between lipid oxidation, the TCA cycle and the hypoxia-inducible factors (HIF) signal pathway in tumor metastases. Thus, this study indicates that the metabolic profile derived from NMR analysis can provide a valuable bio-signature of malignancy and cell hypoxia in metastatic melanoma. PMID- 24958267 TI - Glycerophosphoglycerol, Beta-alanine, and pantothenic Acid as metabolic companions of glycolytic activity and cell migration in breast cancer cell lines. AB - In cancer research, cell lines are used to explore the molecular basis of the disease as a substitute to tissue biopsies. Breast cancer in particular is a very heterogeneous type of cancer, and different subgroups of cell lines have been established according to their genomic profiles and tumor characteristics. We applied GCMS metabolite profiling to five selected breast cancer cell lines and found this heterogeneity reflected on the metabolite level as well. Metabolite profiles of MCF-7 cells belonging to the luminal gene cluster proved to be more different from those of the basal A cell line JIMT-1 and the basal B cell lines MDA-MB-231, MDA-MB-435, and MDA-MB-436 with only slight differences in the intracellular metabolite pattern. Lactate release into the cultivation medium as an indicator of glycolytic activity was correlated to the metabolite profiles and physiological characteristics of each cell line. In conclusion, pantothenic acid, beta-alanine and glycerophosphoglycerol appeared to be related to the glycolytic activity designated through high lactate release. Other physiological parameters coinciding with glycolytic activity were high glyoxalase 1 (Glo1) and lactate dehydrogenase (LDH) enzyme activity as well as cell migration as an additional important characteristic contributing to the aggressiveness of tumor cells. Metabolite profiles of the cell lines are comparatively discussed with respect to known biomarkers of cancer progression. PMID- 24958266 TI - Metabolomics for secondary metabolite research. AB - Metabolomics, the global characterization of metabolite profiles, is becoming an increasingly powerful tool for research on secondary metabolite discovery and production. In this review we discuss examples of recent technological advances and biological applications of metabolomics in the search for chemical novelty and the engineered production of bioactive secondary metabolites. PMID- 24958268 TI - Global LC/MS Metabolomics Profiling of Calcium Stressed and Immunosuppressant Drug Treated Saccharomyces cerevisiae. AB - Previous studies have shown that calcium stressed Saccharomyces cerevisiae, challenged with immunosuppressant drugs FK506 and Cyclosporin A, responds with comprehensive gene expression changes and attenuation of the generalized calcium stress response. Here, we describe a global metabolomics workflow for investigating the utility of tracking corresponding phenotypic changes. This was achieved by efficiently analyzing relative abundance differences between intracellular metabolite pools from wild-type and calcium stressed cultures, with and without prior immunosuppressant drugs exposure. We used pathway database content from WikiPathways and YeastCyc to facilitate the projection of our metabolomics profiling results onto biological pathways. A key challenge was to increase the coverage of the detected metabolites. This was achieved by applying both reverse phase (RP) and aqueous normal phase (ANP) chromatographic separations, as well as electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) sources for detection in both ion polarities. Unsupervised principle component analysis (PCA) and ANOVA results revealed differentiation between wild-type controls, calcium stressed and immunosuppressant/calcium challenged cells. Untargeted data mining resulted in 247 differentially expressed, annotated metabolites, across at least one pair of conditions. A separate, targeted data mining strategy identified 187 differential, annotated metabolites. All annotated metabolites were subsequently mapped onto curated pathways from YeastCyc and WikiPathways for interactive pathway analysis and visualization. Dozens of pathways showed differential responses to stress conditions based on one or more matches to the list of annotated metabolites or to metabolites that had been identified further by MS/MS. The purine salvage, pantothenate and sulfur amino acid pathways were flagged as being enriched, which is consistent with previously published literature for transcriptomics analysis. Thus, broad discovery-based data mining combined with targeted pathway projections can be an important asset for rapidly distilling, testing and evaluating a large amount of information for further investigation. PMID- 24958269 TI - Metabolomic analysis of fission yeast at the onset of nitrogen starvation. AB - Microorganisms naturally respond to changes in nutritional conditions by adjusting their morphology and physiology. The cellular response of the fission yeast S. pombe to nitrogen starvation has been extensively studied. Here, we report time course metabolomic analysis during one hour immediately after nitrogen starvation, prior to any visible changes in cell morphology except for a tiny increase of cell length per division cycle. We semi-quantitatively measured 75 distinct metabolites, 60% of which changed their level over 2-fold. The most significant changes occurred during the first 15 min, when trehalose, 2 oxoglutarate, and succinate increased, while purine biosynthesis intermediates rapidly diminished. At 30-60 min, free amino acids decreased, although several modified amino acids-including hercynylcysteine sulfoxide, a precursor to ergothioneine-accumulated. Most high-energy metabolites such as ATP, S-adenosyl methionine or NAD+ remained stable during the whole time course. Very rapid metabolic changes such as the shut-off of purine biosynthesis and the rise of 2 oxoglutarate and succinate can be explained by the depletion of NH4Cl. The changes in the levels of key metabolites, particularly 2-oxoglutarate, might represent an important mechanistic step to trigger subsequent cellular regulations. PMID- 24958270 TI - Flexible and practical synthesis of 3-oxyindoles through gold-catalyzed intermolecular oxidation of o-ethynylanilines. AB - A novel gold-catalyzed intermolecular oxidation of o-ethynylanilines has been developed. A range of functionalized 3-oxyindoles are readily accessed by utilizing this strategy. Importantly, this gold-catalyzed oxidative process outcompetes the typical indole formation. PMID- 24958265 TI - Metformin: On Ongoing Journey across Diabetes, Cancer Therapy and Prevention. AB - Cancer metabolism is the focus of intense research, which witnesses its key role in human tumors. Diabetic patients treated with metformin exhibit a reduced incidence of cancer and cancer-related mortality. This highlights the possibility that the tackling of metabolic alterations might also hold promising value for treating cancer patients. Here, we review the emerging role of metformin as a paradigmatic example of an old drug used worldwide to treat patients with type II diabetes which to date is gaining strong in vitro and in vivo anticancer activities to be included in clinical trials. Metformin is also becoming the focus of intense basic and clinical research on chemoprevention, thus suggesting that metabolic alteration is an early lesion along cancer transformation. Metabolic reprogramming might be a very efficient prevention strategy with a profound impact on public health worldwide. PMID- 24958271 TI - Active chi-like sequences are present in the ITS1 region of polyembryonic adult Collyriclum faba trematodes encysted in pairs. AB - Collyriclum faba (Plagiochiida: Collyriclidae) adults occur in pairs within subcutaneous cysts. Here, we tested the extensive C. faba infrapopulation for five DNA loci known to display variability among Central European C. faba individuals. The infrapopulation tested shared 100% similarity in four of the five mitochondrial and nuclear DNA loci tested. Contrariwise, the internal transcribed spacer 1 (ITS1) loci in all but one individual differed from each other. We found only 0.0-1.5 base substitutions per 1,000 sites within the cysts, while we found 0.7-9.0 substitutions between the cysts of the single host and 3.0 9.0 substitutions when comparing C. faba individuals isolated from different host individuals. We observed the most of the ITS1 variability within 48 bp repetitive sequences featured by the chi-like sequence 5'-GCTTGTCTGCC-3' at their beginning. Similarly to the extensive C. faba infrapopulation examined, we determined the presence of highly variable number of repetitive sequences within the ITS1 locus of C. faba isolated from multiple host species and from various geographic locations. While similar variability was observed earlier in mutually unrelated specimens of several Schistosomatidae and Microphallidae species, here, we for the first time document it among multiple individuals of a single infracommunity possessing single mitochondrial haplotype. Lower ITS1 evolutionary divergence rates observed between individuals within the cysts when compared to those between the cysts suggest that the recombination occurs at multiple stages of the life cycle. We propose DNA recombination involving chi-like sequences to serve as a general feature shared by multiple families of digenetic trematodes to increase genetic diversity of their polyembryonic populations infecting their definitive hosts. PMID- 24958273 TI - Intermolecular hydroamination of vinylarenes by iminoanilide alkaline-earth catalysts: a computational scrutiny of mechanistic pathways. AB - A thorough computational exploration of the mechanistic intricacies of the intermolecular hydroamination (HA) of vinylarenes by a recently reported class of kinetically stabilised iminoanilide [{N^N}Ae{N(SiMe3)2}?(THF)n] alkaline-earth amido compounds (Ae = Ca, Sr, Ba) is presented. Two distinct mechanistic pathways for catalytic HA mediated by alkaline-earth and rare-earth compounds have emerged over the years that account equally well for the specific features of the process. On one hand, a concerted proton-assisted pathway to deliver the amine product in a single step can be invoked and, on the other, a stepwise sigma insertive pathway that comprises a rapid, reversible migratory olefin insertion step linked to a less facile, irreversible Ae-C alkyl bond aminolysis. The results of the study presented herein, which employed a heavily benchmarked and reliable DFT methodology, supports a stepwise sigma-insertive pathway that involves fast and reversible migratory C=C bond insertion into the polar Ae-N pyrrolido sigma bond. This proceeds with strict 2,1 regioselectivity via a highly polarised four-centre transition state (TS) structure, linked to irreversible intramolecular Ae-C bond aminolysis of the alkaline-earth alkyl intermediate as the energetically favourable mechanism. Turnover-limiting aminolysis is consistent with the significant KIE measured; the DFT-derived effective barrier matches the Eyring parameter empirically determined for the best-performing {N^N}Ba(NR2) catalyst gratifyingly well. It also predicts the observed trend in reactivity (Ca